The comprehensive e-book of named organic reactions and their mechanisms

2nd Edition

Preface The idea for this book was born in 1996 when I was doing my final undergraduate year project at the University of Utrecht. Initially, I thought that I could write this book within a year, but during my PhD I found out that there where more named organic reactions in the literature than I ever thought existed. This project was becoming more and more complicated with time.

So why a comprehensive book of named organic reactions? It is my experience that the existing books in the field only cover the 300 best-known reactions. The literature is full of named reactions. Everyone can name a reaction and of course, I did so. Please note that this book covers reaction named after a person, you will not find in this book reactions like for instance the aldol reaction. Therefore, I hope this book will cover most of the named reactions, but I know that many other named reactions are out there especially in the area of indole syntheses, see Gordon Gribble’s reviews.

The emphasis of this book is to guide people in the right direction to find more information about a certain named organic reaction. The boundary between organic and inorganic is sometimes not clear. The author assumes that the reader of this book has a basic knowledge of organic chemistry at undergraduate level. An example of the reaction is given followed by a step-by-step description of how the reaction occurs and disconnection (I am aware that I use the heading mechanism even if strictly a reaction mechanism is not shown but more a reaction pathway or reaction intermediate.) The reaction is discussed briefly and references are then given. The objective of these th

references is where possible to first reference reactions in March’s the Advanced Organic Chemistry 4

and 5th

editions and then in Smith’s Organic Synthesis 1st and 2nd editions. In addition, references are made to Houben – Weyl, Science of Synthesis (as far as I was able to find copies (volumes 1, 9 and 10) of this masterpiece in London, Thieme please send me a free copy of all the volumes!), Organic Reactions and Organic Syntheses (free online www.orgsyn.org). It must be noted that references to the standard works not always deal with the named organic reaction itself; it sometimes shows an alternative route of making similar compounds. The literature references cover reviews, some classical and some modern articles. In addition, publications in the

free

online

journals

(Arkivoc

www.arkat-usa.org/ark/ARKIVOC/arkivoc_articles.asp

and

Molecules

www.mdpi.org/molecules/index.htm) are covered. I admit that some of the references are difficult to get, but I advice the readers to do a Google search and you will be surprised what you will find online and free of charge. In total there are over 7200 references and covers the literature up until first week January 2005. Finally, some space has been reserved to write down your own comments. I have tried my best to provide as much information as possible, however the reader will discover that there are gaps in the text. This does not mean that there is no information present, it only means that I have not been able to find any information. Please contact me if you have more information about these reactions for me. I have checked over 95% of the references in this book, the reason was that I came across references in the literature that were wrong.

With the build in search or find option in Adobe Acrobat® it is easy to find an author, a particular journal or a cross reference to a named reaction. If the name of the reaction is known it is easier to use the index provided at the end of the document.

Of course, I am indebted to the following group of people who were willing to volunteer to proof read this book. In random order many thanks to Jelle Brinksma, Kiadis, Groningen, The Netherlands, Maria Hopkins, Bodmin,

1

United Kingdom, Derek Crockford, Imperial College London, Adam Ibrahim, University College London, Michel Meijer, Akzo Nobel, Sassenheim, The Netherlands, Howard Carless, Birkbeck College, University of London, Paul Mendonça, Imperial College London and Chris Richards and his students, Queen Mary and Westfield College, University of London. Thank you all for your time and fruitful discussions. I also thank Professor Jacob Zabicky, BenGurion University, Israel for his contribution to the Dische reaction. Acros Organics for their help on the Mann dealkylation reaction and David Kelly, Cardiff University for providing me with additional information on the von Baeyer – Villiger rearrangement. I have to thank my former employer, Birkbeck College, to give me the opportunity to write this book. Finally, I like to thank Sheryl, Samantha and Alexander without them I would have been brain dead years ago. Of course, I did spend too much time writing this book, time that could have been spent with the family. Many thanks to Paul Heelis at Emedia publishers for his advice, patience and hard work to bring this project to a success.

Any mistakes in this book are my responsibility.

Named Organic Reactions, their Genesis will be elucidated.

This book is dedicated to past, present and future chemists.

Enjoy!

Bert Kruiswijk, Aberaman, 11-01-2005.

Contact : [email protected]

2

Forword second edition. I was not planning to do a second edition so soon. However, I had some time on my hands and just did it. Several new named organic reactions books have appeared on the market in the last few months. Some have much more references than this book has, but this book still covers the most named organic reactions. In this edition I have added a few more named organic reactions. I have more in the pipeline, but I am struggling to find references. I have furthermore updated some reaction schemes, added new references and made some changes in the layout and corrected typographical errors and I have added an index at the beginning of every chapter. The literature is covered until the week of15th August 2005.

I need the support of you, the reader, to make this book, THE BOOK on named organic reactions. Any comments or additions, and queries about mechanisms are welcome, please send me an email, and I mean send me an email. References to science of synthesis are very welcome. The best method to search this book is by using the search option in Adobe Acrobat 7.

I like to thank the handful of people who bought the first edition of this book. Thank you for your support. Spread the word, but do not make any illegal copies please. This is an extremely time consuming project, that is running now for 9 years. You would be surprised what it costs to run this project. I will carry on with the work in the hope that one day every chemist has it own copy.

What are the future plans? First of all to expand, and I hope to incorporate a list of chemical transformations cross-referenced to the named reaction and make an index of reagents.

Bert Kruiswijk, Aberaman, 01-09-2005.

3

Common Acronyms

Abbreviations

Chemical name

*

Chiral centre

acac

Acetylacetonate

AIBN

2,2’-Azobisisobutyronitrile

Chemical structure

O

Alkyl

All

Allyl

aq.

Aqueous

Ar

Aryl

Bn

Benzyl

N

N N

N

Alk

O

CH2

Bipy

Bipyridine

N N

Boc

tert-Butoxycarbonyl

BQ

Benzoquinone

O

O

O

Bu

Butyl

Cbz

Benzyloxycarbonyl

O

O

COD

1,5-Cyclooctadiene

Cp

Cyclopentadienyl

CSA

Camphorsulfonic acid

C

O S O

CuTC

Copper(I) thiophene-2-carboxylate

Cu

O

Cyclohexyl

DABCO

1,4-Diazabicyclo[2.2.2]octane

S

N N

4

OH

O O

Cy

O

DAST

Diethylaminosulfur trifluoride

dba

Dibenzylideneacetone

F F S F N

O DCC

Dicyclohexylcarbodiimide

N DDQ

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

C

N

N O N

Cl O

DIBAL

Diisobutylaluminium hydride

DMAP

4-Dimethylaminopyridine

Cl

HAl+ N

DME

N

Dimethoxyethane O O

dpe

1,2-bis(Diphenylphosphino)ethane P

P

DPPF

Diphenylphosphino ferrocene PPh2 Fe PPh2

DTBMP

2,6-di-tert-butyl-4-methylpyridine N

E e

-

EDG

Electrophile Electron Electron donating group

5

EDTA

Ethylenediaminetetraacetic acid

HO

O HO

O

N N

O

O HO

EWG

Electron withdrawing group

FVP

Flash vacuum pyrolysis

L-Glu

L-Glutamic acid

OH

NH2 HO

OH O

Hal

Halogen

Hex

Hexyl

HMPA

Hexamethylphosphoramide

IBX

o-Iodoxybenzoic acid

O

N O P N N

OH O I O O

KAPA

Potassium 3-aminopropylamide

KHMDS

Potassium hexamethyldisilazane

HN K

NH2

Si N

Si

K L

Ligand

LDA

Lithium diisopropylamine N K

LG

Leaving group

LiDBB

Lithium 4,4’-di-tert-butyl-biphenylide

Li LiHMDS

Lithium hexamethyldisilazane

Si N

Si

Li LiTMP

Lithium 2,2,6,6-tetramethylpiperidine N Li

6

mCPBA

meta-Chloroperoxybenzoic acid

HO O O Cl

MOM

Methoxymethyl

MPM

(p-methoxyphenyl)methyl

O

O

MS

Molecular Sieves

Ms

Mesyl

NBS

N-Bromosuccinimide

O N Br O

NCS

N-Chlorosuccinimide

O N Cl O

NMO

N-Methylmorpholine oxide

N+ O-

O

PBNSA

p-Nitrobenzene sulfonic acid

PCC

Pyridinium chlorochromate

O HO S O

O N+ O-

NH+

O Cl

PDC

O Cr O

Pyridinium dichromate

O O Cr N O + - H O Cr O O NH+ O Phen

1,10-Phenanthroline

N

Piv

Pivaloyl

PPFA

N,N-Dimethyl-1-[2-

N C

(diphenylphosphino)ferrocenylethylamine] PPTS

Pyridinium p-toluenesulfonate

O O S NH+ O -

PMHS

Polymethylhydrosiloxane

7

O

Pyr

Pyridine

Rf

Perfluoroalkyl chain

Rl

Large R-group

Rs

Small R-group

RT

Room temperature

S

Solvent

Sia

Siamyl

SMEAH

Sodium bis(2-methoxyethoxy)aluminium

N

Na O

hydride

O O O Al H

H

TADDOL

α,α,α’,α’,-Tetraaryl-1,3-dioxolane-4,5-

H OHAr O Ar

dimethanol

Ar Ar OH

O H TBAF

tert-Butyl ammonium fluoride F-

TBDMS

NH3+

tert-Butyldimethylsilyl Si

TBHP

tert-Butyl hydroperoxide

TBS

tert-Butyldimethylsilyl

O

OH

Si

TEBA

Benzyltriethylammonium chloride

N+ ClTEMPO

2,2,6,6-Tetramethylpiperidinooxy, free radical N O•

TeoC

2-Trimethylsilylethoxycarbonyl

O

Si TES

Triethylsilyl Si

8

C

O

TFE

Trifluoroethanol

F F

OH F

TIPS

Triisopropylsilyl Si

THF

Tetrahydrofuran

TFA

Trifluoroacetic acid

O

HO

O

F

F F

TFP

Tris(2-furyl)phospine

O P O

O

TMBG TMEDA

N’,N’’-Tetramethyl-N-2-tert-butylguanidine N,N,N’,N’-Tetramethylethylenediamine N

N

TMP

2,2,6,6-Tetramethylpiperidine N H

TMS

Trimethylsilyl Si

Tos/Ts

Tosyl

Tr

Trityl

O S O

C

X

Halogen

xs

Excess

9

10

11

ARBUZOV REACTION (MICHAELIS – ARBUZOV) · 56 ARENS – van DORP SYNTHESIS · 58

A

ARNDT – EISTERT SYNTHESIS · 60 ARNDTSEN MÜNCHNONE REACTION · 61

ABRAMOV PHOSPHONYLATION REACTION · 13

ASINGER REACTION · 63

ACHMATOWICZ PYRANONE REACTION · 14

ASSCHER – VOFSI REACTION · 64

ADAMS DECARBOXYLATION · 16

ATHERTON – OPENSHAW – TODD SYNTHESIS · 66

ADKINS – PETERSON FORMALDEHYDE REACTION · 17

AUWERS von – INHOFFEN REARRANGEMENT · 67

ADLER – LONGO PORPHYRIN REACTION · 18

AUWERS von FLAVONOL SYNTHESIS · 68

ADLER PHENOL OXIDATION · 19

AUWERS von INDANE-1-ONE SYNTHESIS · 70

AHMED – STRONG SYNTHESIS · 21

AUWERS von REARRANGEMENT · 72

AKABORI – MOMOTANI AMINO ALCOHOL SYNTHESIS · 22 AKABORI – NEUBERG – FISCHER AMINO ACID REACTION · 23 AKABORI HYDRAZINOLYSIS · 24

D

ALDER – RICKERT REACTION · 25 ALDER ENE REACTION · 26

DIENONE-PHENOL REARRANGEMENT · 67

ALGAR – FLYNN – OYAMADA FLAVANONE REACTION · 28 ALLAN – LOUDON QUINOLINE SYNTHESIS · 30

M

ALLEN – MILLAR – MATHEY REARRANGEMENT · 32 ALLEN REACTION · 33

MAILLARD REACTION · 39

ALPER CARBONYLATION · 35 ALPHEN – HÜTTEL PYRAZOLE REARRANGEMENT · 37 N

AMADORI REARRANGEMENT · 38 ANDERSON – FUCHS REACTION · 40

NEWMAN – BEAL MODIFICATION · 60

ANDO MANDELIC ACID SYNTHESIS · 41 ANDREASCH THIAZOLE SYNTHESIS · 43

S

ANDRUSSOV OXIDATION · 44 ANELLI OXIDATION · 45 ANGELI – RIMINI SYNTHESIS · 46

SCHENCK REACTION · 27

ANGELI FURAZAN OXIDE REARRANGEMENT · 47

SESHADRI MODIFICATION · 29

ANGELO’S D’ ASYMMETRIC MICHAEL ADDITION · 49 ANSCHÜTZ – SCHOLL HYDROXYACETOPHENONE SYNTHESIS

W

· 50 ANSCHÜTZ ANTHRACENE SYNTHESIS · 51

WILDS – MEADER MODIFICATION · 60

ANSCHÜTZ HYDROXYCOUMARIN SYNTHESIS · 52 APPEL – ROBINSON OXIDATION · 54 APPEL REACTION · 55

12

ABRAMOV PHOSPHONYLATION REACTION EXAMPLE :

O H3C

O

O H3C

H H

AcO AcO

P(OCH3)3 AcOH

O

H

O OH

AcO AcO

O P OCH3 OCH3

MECHANISM :

OCH3 H P OCH3 O

OCH3 P OCH3

NaOCH3

O O

O H3C

O

H3C

H

AcO

H AcO

OCH3 P OCH3

H

O

AcO

H AcO

O

O

O H+

O H3C

H

O OH

AcO AcO

O P OCH3 OCH3

DISCONNECTION :

R4

O

R5 R1

R4

R1

H

O

O

R5 O

OH R3 R2

R

R3 R2

O P OCH3 OCH3

H H

R

O

NOTES : The O-benzylated glycal is oxidatively cleaved to the aldehyde sugar bearing a formate ester at C-5. This carbon atom is originally the anomeric carbon atom. The condensation with trimethyl phosphite in glacial acetic acid or with

13

dimethyl phosphonate under basic conditions introduces the dimethylphosphonyl moiety. See also Arbuzov (Michaelis – Arbuzov), Michaelis – Becker – Nylén and Perkow reactions.

REFERENCES : 1) V.S. Abramov, Zh. Obshch. Khim., 1957, 22, 647. 2) J. Thiem; M. Gunther; H. Paulsen; J. Kopf, Chem. Ber., 1977, 110, 3190. 3) H. Molin; J.O. Noren; A. Claesson, Carbohydr. Res., 1989, 194, 209. 4) J.W. Darrow; D.G. Drueckhammer, J. Org. Chem., 1994, 59, 2976. 5) T.C. Harvey; C. Simiand; L. Weiler; S.G. Withers, J. Org. Chem., 1997, 62, 6722. 6) O.I. Kolodiazhnyi, Tetrahedron: Asymmetry, 1998, 9, 1279. 7) S. Hanessian; O. Rogel, J. Org. Chem., 2000, 65, 2667. 8) A.E. Wróblewski; W. Maniukiewicz; W. Karolczak, J. Chem. Soc., Perkin Trans. 1, 2000, 1433. 9) D.S. Stoianova; P.R. Hanson, Org. Lett., 2001, 3, 3285.

COMMENTS :

ACHMATOWICZ PYRANONE REACTION EXAMPLE :

OAc O OH CH3

OAc O OTBS

H3C

VO(acac)2, pyridine TBHP, Ac2O DMAP, DCM

O AcO OTBS

14

MECHANISM :

R1 O H

R2

N

O

H3CO 2 CH3OH NaBr, e0 oC Clauson-Kaas

OCH3 O

R1 R2 O O

R1 H3CO

R1 R2

O

N H

- OCH3

H N

- H+

O

N CH3O

R2 O

DISCONNECTION :

O

R

O N H

R

R1

R1 N

R2 H3CO O

R2

R O O

R1

R1

O

O

OH H3CO

R

NOTES : The synthesis of pyran-3-ones starting with furfuryl alcohols, which are first converted to dialkoxydihydrofurans by e.g. Clauson–Kaas electrochemical oxidation, followed by acid hydrolysis. There is also an aza-analogue known based on furylacetamides. See also Clauson–Kaas reaction.

REFERENCES : 1) O. Achmatowicz, jr.; P. Bukowski; B. Szechner; Z. Zwierzchowska; A. Zamojski, Tetrahedron, 1971, 27, 1973. 2) O. Achmatowicz, jr.; B. Szechner, Carbohydr. Res., 1976, 50, 23. 3) G. Grynkiewicz; O. Achmatowicz, jr.; H. Barton, Rocz. Ann. Soc. Chim. Pol., 1977, 51, 1663. 4) M.A. Ciufolini; C.Y. Wood, Tetrahedron Lett., 1986, 27, 5085. 5) M. van den Heuvel; A.D. Cuiper; H. van der Deen; R.M. Kellogg; B.L. Feringa, Tetrahedron Lett., 1997, 38, 1655. 6) M.A. Ciufolini; T. Shimizu; S. Swaminathan; N. Xi, Tetrahedron Lett., 1997, 38, 4947. 7) M.A. Ciufolini; C.Y.M. Hermann; Q. Dong; T. Shimizu; S. Swaminathan; N. Xi, Synlett, 1998, 105. 8) M.P. Cassidy; A. Padwa, Org. Lett., 2004, 6, 4029.

15

COMMENTS :

ADAMS DECARBOXYLATION EXAMPLE : O

O

O

COOH

O

1) aq. NaHSO3 2) NaOH

MECHANISM :

O

O

O O H

O S

O

OH

O

O

OSO2H

O

O H

acid

O

O H+

DISCONNECTION :

O

O

O

O

R

R

COOH R = H, OH, Alk, OAlk, C6H5

NOTES : Coumarin acids (2-oxo-2H-chromene-3-carboxylic acid) are decarboxylated by heating with aqueous sodium hydrogensulfite followed by treatment with concentrated alkali or acid.

REFERENCES : 1) R. Adams; J. Mathieu, J. Am. Chem. Soc., 1948, 40, 2120. 2) R. Adams; T.E. Bockstahler, J. Am. Chem. Soc., 1952, 74, 5346. 3) F. Cramer; H. Windel, Chem. Ber., 1956, 89, 354.

16

COMMENTS :

ADKINS – PETERSON FORMALDEHYDE REACTION EXAMPLE : H MeOH

Air Metaloxide 250 - 400 oC

H O

NOTES : An air methanol mixture, containing 5 – 8 % methanol vapour is passed over a metal oxide (Iron oxide, molybdenum oxide or iron molybdenum oxide) catalyst to afford 40% aqueous formaldehyde free of methanol.

REFERENCES : 1) H. Adkins; W.R. Peterson, J. Am. Chem. Soc., 1931, 53, 1512. 2) W. Kunz; H. Krauch, Chem.-Ztg., 1958, 82, 802. 3) W.E. Farneth; F. Ohuchi; R.H. Staley; U. Chowdhry; A.W. Sleight, J. Phys. Chem., 1985, 89, 2493. 4) A.M. El–Awad; E.A. Hassan; A.A. Said; K.M. Abd El–Salaam, Monatsh. Chem., 1989, 120, 199.

COMMENTS :

17

ADLER – LONGO PORPHYRIN REACTION EXAMPLE :

H N

N H

OH N

4

N

ethylbenzene 14 days 100 oC

H N

MECHANISM :

N H

Ph

PhCHO, H+ - H2O

N H H

N H

H

Ph

HN H

NH

H

Ph

H

N H

N

H

repeat 4 times

H

Ph

NH

Ph

N

N H

air oxidation

Ph

HN

N

H N

Ph

Ph

Ph

Ph

DISCONNECTION :

R N H

N R

R N H

N

H N

+ 4

4

R

H O

R

NOTES : This is a very low yielding and slow reaction for the formation of porphyrins. Several improved syntheses have been published over the years. See also Lindsey, MacDonald, Rothemund and Taniguchi reactions.

18

REFERENCES : 1) A.D. Adler; F.R. Longo; J. Goldmacher; J. Assour; L. Korsakoff, J. Org. Chem., 1967, 32, 476. 2) J.S. Lindsey; I.C. Schreiman; H.C. Hsu; P.C. Kearney; A.M. Marguretta, J. Org. Chem., 1987, 52, 827. 3) J. Takeda; M. Sato, Chem. Pharm. Bull., 1994, 42, 1005. 4) G. Märkl; M. Reiss; P. Kreitmeier; H. Nöth, Angew. Chem., Int. Ed. Engl., 1995, 34, 2230. 5) M.J. Crossley; P. Thordarson; J.P. Bannerman; P.J. Maynard, J. Porphyrins Phthalocyanines, 1998, 2, 511.

COMMENTS :

ADLER PHENOL OXIDATION EXAMPLE : O O

O

2

1) NaIO4 2) H2O

CH2OH

O

OH

MECHANISM :

OCH3 O O I O HO O

OCH3 H O O

O I

O

OCH3

- HO - IO3

O

O

H OCH3 O

OH2

O

- H+ O

OCH3

19

- HOCH3

O O

DISCONNECTION :

O

OH

R

R R = alkyl

NOTES : Sodium periodate reacts very slowly with unsubstituted phenols, however when alkyl substituents are present on the phenol the periodate is rapidly consumed and the phenolic hydroxyl is oxidised. See also Teuber reaction.

REFERENCES : March : 1171 Smith – March : 1517

1) E. Adler; R. Magnusson, Acta Chem. Scand., 1959, 13, 505. 2) E. Adler; L. Junghahn; U. Lindberg; B. Berggren; G. Westin, Acta Chem. Scand., 1960, 14, 1261. 3) E. Adler; J. Dahlén; G. Westin, Acta Chem. Scand., 1960, 14, 1580. 4) E. Adler; I. Falkehag; B. Smith, Acta Chem. Scand., 1962, 16, 529. 5) E. Adler; S. Brasen; H. Miyake, Acta Chem. Scand., 1971, 25, 2055. 6) E. Adler; K. Holmberg, Acta Chem. Scand., 1974, B28, 465. 7) G. Andersson; P. Bernthsen, Acta Chem. Scand., 1975, B29, 948. 8) J.-P. Gesson; M. Mondon, Bioorg. Med. Chem. Lett., 1993, 3, 735. 9) J.-P. Gesson; L. Hervaud; M. Mondon, Tetrahedron Lett., 1993, 34, 2941. 10) V. Bonnarme; C. Bachmann; A. Cousson; M. Mondon; J.-P. Gesson, Tetrahedron, 1999, 55, 433. 11) S. Quideau; L. Pouységu; D. Deffieux; A. Ozanne; J. Gagnepain; I. Fabre; M. Oxoby, Arkivoc, 2003, 6, 106.

COMMENTS :

20

AHMED – STRONG SYNTHESIS EXAMPLE :

COOH CH3(CH2)3

H

H3C 1) NaNH2 2) Cl(CH2)4I 3) KCN, aq. NaOH 4) Raney Ni, H2

MECHANISM :

R

H

Na+

R

NaNH2

Cl Cl(CH2)xI

CN R

x

R

x

KCN - KCl

COOH

R

x

aq. NaOH

Raney Ni H2

R

x

COOH

DISCONNECTION :

R x

R

COOH

H + Cl(CH2)xI

x = 4,9

NOTES : Alkyl acetylenes react in the presence of sodamide with chloro iodo alkanes to form acetylenic chlorides. These in turn, via the nitrile or Grignard reagent, and with subsequent selective hydrogenation of the triple bond in the presence of Raney nickel are converted into mono-unsaturated fatty acids. (cis-form). See also Raphael synthesis.

REFERENCES : 1) K. Ahmed; F.M. Strong, J. Am. Chem. Soc., 1948, 70, 1699. 2) K. Ahmed; F.M. Bumpus; F.M. Strong, J. Am. Chem. Soc., 1948, 70, 3391. 3) W.J. Gensler, Chem. Rev., 1957, 57, 191.

COMMENTS :

21

AKABORI – MOMOTANI AMINO ALCOHOL SYNTHESIS EXAMPLE :

H H

H H

+

H3C

CH3

COOH 3h 150 - 160 oC

NH2

O

HO NH2

MECHANISM : CH3

CH3 H

H N

Ph + O

O H

H N

CH3

H

H

Ph O

O

H

O H

H CH3 Ph H HO N H CH3

CH3 - CO2

O

DISCONNECTION :

R

H

R1

R

H OH N R2 H

H H O

+

COOH

R1 H

N

R2

NOTES : The formation of an amino alcohol formed by an aldol-addition between an amino acid and an aromatic aldehyde. With tertiary amino groups no reaction takes place. See also Akabori – Neuberg – Fischer and Erlenmeyer – Früstück reactions.

REFERENCES : 1) T. Curtius; G. Lederer, Ber. Dtsch. Chem. Ges., 1886, 19, 2462. 2) S. Akabori; K. Momotani, J. Chem. Soc. Jpn., 1943, 64, 608. 3) K. Dose, Chem. Ber., 1957, 90, 1251. 4) E. Ambach; W. Beck, Chem. Ber., 1985, 118, 2722.

COMMENTS :

22

AKABORI – NEUBERG – FISCHER AMINO ACID REACTION EXAMPLE :

H

H

O Cl

H3C

H3C

Na(Hg) EtOH, HCl

NH3 OEt

CHO NH3 Cl

MECHANISM :

O R

R

H

OEt NH3 Cl

R

Na(Hg) EtOH, HCl

CHO NH3 Cl

H

H N

H N NH

4

S H+ R OH

O

R

H2N

NH4NCS

O

H+

H

R

H

H

H N

N NH 4

H+

SH

N SH

H N

N SH

DISCONNECTION :

H

H R

CHO NH3 Cl

R R1 = H, Alk

CO2R1 NH3 Cl

NOTES : α-Amino acids and their esters are reduced by sodium amalgam and ethanolic hydrogen chloride to the corresponding α-amino aldehydes. It was Fischer, who first discovered the reaction on carbohydrates. Akabori used Neuberg’s approach to reduce the ethyl ester group to the aldehyde, followed by cyclisation to the imidazole. See also Brackeen, Bredereck, Debus – Radziszewski, Maquenne, Wallach and Weidenhagen reactions.

REFERENCES : Houben – Weyl : 11/2, 361

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1890, 23, 937. 2) C. Neuberg, Ber. Dtsch. Chem. Ges., 1908, 41, 956. 3) S. Akabori, J. Chem. Soc. Jpn., 1931, 52, 844. 4) S. Akabori, Ber. Dtsch. Chem. Ges., 1933, 66, 151.

23

5) A. Lawson, J. Chem. Soc., 1956, 307.

COMMENTS :

AKABORI HYDRAZINOLYSIS EXAMPLE :

N

N

O

O

NH2

N H

OH N2H4 DMSO 5 min

O

NH2

N H

NH2

MECHANISM :

H+

H O

H O N H R1

H2N R

H O N OH H Rn

NH2NH2

125 oC

NH2NH2

H

H

O +

H2N R

H

N NH2

O

H2N

+ N NH2

R1 H

+

H

O

Rn

OH

H2N

NOTES : A linear peptide is heated in the presence of anhydrous hydrazine to identify the C-terminus amino acid in the polypeptide.

REFERENCES : 1) S. Akabori; K. Ohno; K. Narita, Bull. Chem. Soc. Jpn., 1952, 25, 214. 2) N. Miyatake; K. Satake; M. Kamo; A. Tsugita, J. Biochem., 1994, 115, 208. 3) N. Koyama; H. Ohmae; S. Tsuji; Y. Tanaka; T. Kurokawa; O. Nishimura, Biotechnol. Appl. Biochem., 2001, 33, 117.

24

4) A.K. Bose; Y.H. Ing; N. Lavlinskaia; C. Sareen; B.N. Pramanik; P.L. Bartner; Y.-H. Liu; L. Heimark, J. Am. Soc. Mass Spectrom., 2002, 13, 839. 5) B.N. Pramanik; Y.H. Ing; A.K. Bose; L.K. Zhang; Y.-H. Liu; S.N. Ganguly; P. Bartner, Tetrahedron Lett., 2003, 44, 2565.

COMMENTS :

ALDER – RICKERT REACTION EXAMPLE :

O CH3

H3C

H3C

CH3 1) H2 2) Heat

CH3

H3C

CH3 O

CH3

MECHANISM :

COOR

COOR COOR

COOR

COOR heat

COOR

H2C CH2

COOR

COOR

+ heat COOR

DISCONNECTION :

R R R R

R = CF3, CO2CH3

25

+

COOR

NOTES : The cycloaddition of electron-deficient alkynes to furan or cyclopentadienes is followed by cycloreversion after selective hydrogenation at the less-hindered double bond. This is a classical method to discriminate between cyclic penta- and hexadienes. Nowadays, the reaction is widely used in the construction of polysubstituted benzenes. See also Carboni – Lindsey and Diels – Alder reactions.

REFERENCES : Houben – Weyl : E6a, 63 Science of Synthesis : 9, 222

1) K. Alder; G. Stein, Ber. Dtsch. Chem. Ges., 1929, 62, 2344. 2) K. Alder; H.F. Rickert, Liebigs Ann. Chem., 1936, 524, 180. 3) D. Schomburg; M. Thielmann; E. Winterfeld, Tetrahedron Lett., 1985, 26, 1705. 4) G.C. Kanakam; N.S. Mani; H. Ramanathan; G.S.R.S. Rao, J. Chem. Soc., Perkin Trans.1, 1989, 1907. 5) A.J. Birch; N.S. Mani; G.S.R.S. Rao, J. Chem. Soc., Perkin Trans.1, 1990, 1423. 6) G.S.R.S Rao, Pure Appl. Chem., 2003, 75, 1443. 7) R.A. Tapia; M.C. Garate; J.A. Valderrama; P.R. Jenkins; J. Fawcett; D.R. Russell, Tetrahedron Lett., 1997, 38, 153. 8) H.K. Hariprakasha; G.S.R.S. Rao, Indian J. Chem., 1998, 37B, 851. 9) S.S. Labadie, Synth. Commun., 1998, 28, 2531.

COMMENTS :

ALDER ENE REACTION EXAMPLE :

O

O +

O

O heat

O

O

26

MECHANISM :

H

H

EWG

EWG

DISCONNECTION :

H

X = Y

X Y

X Y

+ H

R1 R

R1

R1 O

R

R

R1

R3

R

R4

S

NR2

NOTES : This is an orbital-symmetry allowed reaction, using 4-electrons from the π-bonds and 2-electrons from the σ-bond (6electron system). It is a concerted sigmatropic reaction and can take place either intra- or intermolecularly. The thermal intermolecular ene reactions have a higher negative entropy of activation than the Diels-Alder reaction, so they require a higher temperature. Lewis acid catalysis, most through a probably step-wise mechanism, can be used for less-reactive enophiles. Several metallo-ene-type reactions have been published in the literature. The nitroso-ene reaction has been reviewed by Adam et al. If the ene reaction occurs with 1O2 than it is called the Schenck reaction. See also Conia, Diels – Alder, Felkin cyclisation and Riley – Sharpless reactions.

REFERENCES : March : 794 Smith – March : 1021 Smith : 1249 Smith 2nd : 1030 Org. React. : 20, 133 Org. Synth. : 31, 85; 43, 27; 65, 159 Org. Synth. Coll. Vol. : 4, 766; 5, 459; 8, 427 Science of Synthesis : 1, 463

1) K. Alder; F. Pascher; A. Schmitz, Ber. Dtsch. Chem. Ges., 1943, 76, 27. 2) K. Alder; T. Noble, Ber. Dtsch. Chem. Ges., 1943, 76B, 54. 3) W. Oppolzer; V. Snieckus, Angew. Chem., Int. Ed. Engl., 1978, 17, 476. 4) W. Oppolzer; K. Battig, Tetrahedron Lett., 1982, 23, 4669. 5) L.F. Tietze; U. Beifuβ, Angew. Chem., Int. Ed. Engl., 1985, 24, 1042.

27

6) W. Oppolzer; A. Nakao, Tetrahedron Lett., 1986, 27, 5471. 7) B.M. Trost; D.J. Jebaratnam, Tetrahedron Lett., 1987, 28, 1611. 8) W. Oppolzer; T.H. Keller; M. Bedoya–Zurita; C. Stone, Tetrahedron Lett., 1989, 30, 5883. 9) S.C. Ameta; P.B. Punjabi; C.S. Chobisa; N. Mangal; R. Bhardwaj, Asian J. Chem. Rev., 1990, 1, 106. 10) N.C. Ihle; C.H. Heathcock, J. Org. Chem., 1993, 58, 560. 11) M.R. Thompson; C. Tzoganakis; G.L. Rempel, J. Appl. Polym. Sci., 1999, 71, 503. 12) J.S. Johnson; D.A. Evans, Acc. Chem. Res., 2000, 33, 325. 13) R.L. Bindu; C.P.R. Nair; K.N. Ninan, J. Appl. Polym. Sci., 2001, 80, 737. 14) C. Gouri; C.P.R. Nair; R. Ramaswamy, Polym. Int., 2001, 50, 403. 15) W. Adam; O. Krebs, Chem. Rev., 2003, 103, 4131. 16) A.G. Leach; K.N. Houk, Org. Biomol. Chem., 2003, 1, 1389. 17) C.J. Kressierer; T.J.J. Müller, Tetrahedron Lett., 2004, 45, 2029. 18) E.C. Hansen; D. Lee, J. Am. Chem. Soc., 2005, 127, 3252. 19) K.M. Brummund; L. You, Tetrahedron, 2005, 61, 6180.

COMMENTS :

ALGAR – FLYNN – OYAMADA FLAVANONE REACTION EXAMPLE :

OH H

O OH

EtOK, H2O2 O

H

O

28

MECHANISM : R = OCH3, OH :

OH

OH H

H

O

HO, H2O2 R

O

H

R

O

H

O - H2O OCH3 O

R = anything else :

OH

OH H

H

O

HO , H2O2 R

O

H

R

O

H

O

O H H

R

O

O

Ar

base

OH

OH

R

O

DISCONNECTION :

R R1

O

OH H

R = OH, OCH3 R1 = OCH3

Ar R

R1

O

NOTES : Flavanones or ortho-hydroxyphenyl styryl ketones yield flavonols when treated with ethanolic alkali and hydrogen peroxide. In some cases 1-benzofuran-3-ones are formed. Dihydroflavonols and other products have also been isolated. Burke et al. has published some interesting details about the possible mechanism. The Seshadri modification uses methoxychalcones to afford flavonol methyl ethers. See also Auwers flavonol, Baker – Ollis, von Kostanecki (Allan – Robinson), Ranjorwa and Rasoda reactions.

29

REFERENCES : 1) J. Algar; J.P. Flynn, Proc. Roy. Irish Acad., 1934, 42B, 1. 2) T. Oyamada, J. Chem. Soc. Jpn., 1934, 55, 1256. 3) T.A. Geissman; D.K. Fukushima, J. Am. Chem. Soc., 1948, 70, 1686. 4) A.A. Raval; N.M. Shah, J. Org. Chem., 1957, 22, 304. 5) K.J.R. Prasad; C.S.R. Iyer; P.R. Iyer, Indian J. Chem., 1983, 22B, 693. 6) C.J. Adams; L. Main, Tetrahedron, 1991, 47, 4959. 7) M. Bennett; A.J. Burke; W.I. O’Sullivan, Tetrahedron, 1996, 52, 7163. 8) A.D. Roshal; A.V. Grigorovich; A.O. Doroshenko; V.G. Pivovarenko; A.P. Demchenko, J. Photochem. Photobiol. A: Chem., 1999, 127, 89. 9) N. Cotelle, Curr. Top. Med. Chem., 2001, 1, 569.

COMMENTS :

ALLAN – LOUDON QUINOLINE SYNTHESIS EXAMPLE :

NO2

O O S O H

NO2 CH3

N H

1) pyridine 2) aq. KOH O

O

30

MECHANISM :

NO2

HO NO2

O O S O H

N

CH3 +

aq. KOH

N

H

- OTs

O

O NO2

NO2 N

H H

aq. KOH

N

O

H

- H2O

O H+

O

DISCONNECTION :

N

X

R1

R1

R O

X = Cl, OTs R = H, CH3

R O

NOTES : Derivatives of benzaldehyde or benzophenone with a sufficiently mobile chloro- or toluene-p-sulfonyloxy- substituent in the ortho position react with pyridine to form pyridinium salts. The addition of alkali to aqueous solutions of these salts results in the ring-opening of the pyridinium ring, ring-closure affords 3-quinolinyl-2-propenal derivatives. See also von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES : D. Allan; J.D. Loudon, J. Chem. Soc., 1949, 821.

COMMENTS :

31

ALLEN – MILLAR – MATHEY REARRANGEMENT EXAMPLE :

Ph P O Ph OH

1) C6H5COCl Et3N 2) H2O

P Ph

MECHANISM :

P R

CH2I2 benzene

P R

H2O

I I

P R

P

I

H O

OH2

R1

I R

R2 P R

O P R

- HI

R1

R2 P

R3COCl Et2O, Et3N

R O

R1

H O

R O

H2O

R2

P R OH2 O

Cl

R2

R2 P

R3

R1

R1 P

R3

O

H+

32

R3 R OH

R3

DISCONNECTION :

R2

R1

R2

R1 P O

R3

P R

R OH

NOTES : The initial discovery was that certain cyclic phosphonium salts of e.g. 9-phosphafluorene with diiodomethane gave on hydrolysis dihydrophosphaphenanthrenes. Later, it was discovered that phosphole rings could be enlarged through their acylphosphonium salt. See also McCormack – Kukhtin – Ramirez phosphole synthesis.

REFERENCES : 1) D.W. Allen; T. Millar, J. Chem. Soc. (C), 1969, 252. 2) E.M. Richards; J.C. Tebby, J. Chem. Soc. (C), 1971, 1064. 3) F. Mathey, Tetrahedron, 1972, 28, 4171. 4) F. Mathey, Tetrahedron, 1973, 29, 707. 5) J.M. Alcaraz; A. Breque; F. Mathey, Tetrahedron Lett., 1982, 23, 1565. 6) G. Keglevich; A. Szollosy; L. Toke; V. Fulop; A. Kalman, J. Org. Chem., 1990, 55, 6361. 7) G. Keglevich, Synthesis, 1993, 931.

COMMENTS :

ALLEN REACTION EXAMPLE :

Cl

OH P O OH

Cl +

O

O Cl

Cl H

33

O

P

OH O

Cl

MECHANISM :

OR RO P O R1 OR R3 R2

R1

OR RO P OR

O

R2 X R3

X

O RO P O R1 OR R3 R2

OR O R1 P RO OR R 2 R3 X

DISCONNECTION :

O R2O

O

P

N

OR2

O

R1

O

R1

RO OR R3

R2

P

R

R

2 (R2O)3P + R1 R = R1 = H, CH3 R2 = CH3, Et

NO2 Hal

OR RO P + OR

R1 O

R2 X R3

NOTES : This reaction is the synthesis of monovinyl esters of phosphorous acids. The reaction has been extended to the synthesis of oxime esters of dialkylphosphoric acid from trialkyl phosphites and α-halonitro compounds. See also Arbuzov (Michaelis – Arbuzov) reaction.

REFERENCES : 1) J.F. Allen; O.H. Johnson, J. Am. Chem. Soc., 1955, 77, 2871. 2) J.F. Allen, J. Am. Chem. Soc., 1957, 79, 3071.

COMMENTS :

34

ALPER CARBONYLATION EXAMPLE :

Bu

Bu N

N CO, Pd(Ph3)4

O

MECHANISM :

Pd(PPh3)4

Pd(PPh3)3 + PPh3 Pd(PPh3)3CO

Pd(PPh)3 + CO

N

N PPh3 +

Pd(PPh3)3CO

Ph

Pd(PPh3)2CO

Ph

N H Ph N

Ph Pd(PPh3)2CO

Ph

N Ph

Ph N

PPh3

N

Ph CO(Ph3P)2Pd

N

PPh3

N

Pd(PPh3)2CO

Ph

Ph Ph CO

N Ph

O N Pd (PPh3)2CO

N Pd C O (PPh3)2

- PPh3

N

Ph + Pd(PPh3)3CO

N O

35

Ph

Ph N Ph

N Pd

N Pd(II)

Pd(PPh3)3

N

Ph

N

Ph

Ph Ph N Ph

N Pd

N - PPh3

Ph

Ph

PPh3

Ph

Pd(PPh3)2CO

N

Ph

Ph

N

N Pd C O (PPh3)2

N Ph

N

Ph CO

O N Pd (PPh3)2CO

Ph + Pd(PPh3)3CO

N O

DISCONNECTION :

R1

R1

( )n+1 N

O

R

( )n N R

NOTES : This named reaction is a collection of hydroxycarboxylation, carbonylation and hydroformylation of olefins catalysed by metal complexes (Pd, Rh or Co). There are two possible reaction mechanisms.

REFERENCES : 1) H. Alper; C.P. Perera; F.R. Ahmed, J. Am. Chem. Soc., 1981, 103, 1289. 2) H. Alper; C.P. Perera, Organometallics, 1982, 1, 70. 3) H. Alper; J.B. Woell; B. Despeyroux; D.J.H. Smith, J. Chem. Soc., Chem. Commun., 1983, 1270. 4) H. Alper, Tetrahedron Lett., 1987, 28, 3237. 5) H. Alper, Aldrichimica Acta, 1991, 24, 3. 6) P. Giannoccaro; M. Aresta; S. Doronzo; C. Ferragina, Appl. Organomet. Chem., 2000, 14, 581. 7) D.C.D. Butler; G.A. Inman; H. Alper, J. Org. Chem., 2000, 65, 5887. 8) Y.-S. Shou; H. Alper, Angew. Chem., Int. Ed., 2001, 40, 779. 9) S.-M. Lu; H. Alper, J. Org. Chem., 2004, 69, 3558.

36

COMMENTS :

van ALPHEN – HÜTTEL PYRAZOLE REARRANGEMENT EXAMPLE :

H3CO2C

CO2CH3

H3CO2C

Ph Ph

N

N

heat AcOH

Ph

Ph CO CH 2 3 N

N

MECHANISM :

R2

R3

R2 R1

N

R

N

R

R1

N N

N

N

R

Type C

R2 = H Type A

R

R3

R2

R3

R2

R

Type B

R1

R3

R1

N R1

N

DISCONNECTION :

R3

R1 R

N H R2

R

N

R3 N R1

N

N R

R2 R

R1

N

R3

R1

R3

R2

N

37

N

R3 N H

N

NOTES : The formation of the three types (A, B, C) of 3H-pyrazoles has been accommodated in terms of competitive suprafacial [1,5]-shift by a substituent at the quaternary carbon (3-position) to carbon-4 or to the nitrogen atom. A radical pathway is most likely.

REFERENCES : Houben – Weyl : E8b, 549, 810

1) J. van Alphen, Recl. Trav. Chim. Pays-Bas, 1943, 62, 485. 2) J. van Alphen, Recl. Trav. Chim. Pays-Bas, 1943, 62, 491. 3) R. Hüttel; J. Riedl; H. Martin; K. Franke, Chem. Ber., 1960, 93, 1425. 4) R. Huisgen; M.P. Bosch Verderol; H.A. Gieren; V. Lamm, Angew. Chem., Int. Ed. Engl., 1981, 20, 694. 5) M.P. Sammes; A.R. Katritzky, Adv. Heterocycl. Chem., 1983, 34, 1. 6) H. Saschitzky; W. Kramer; R. Neidlein; H. Uhl, J. Chem. Soc., Perkin Trans. 1, 1988, 883. 7) J.A.L. Herbert; B. Iddon; A.G. Robinson; H. Saschitzky, J. Chem. Soc., Perkin Trans. 1, 1988, 991. 8) T. Nagai; M. Hamaguchi, Org. Prep. Proced. Int., 1993, 25, 403. 9) A.S.K. Hashmi; M.A. Grundl; A.R. Nass; F. Naumann; J.W. Bats; M. Bolte, Eur. J. Org. Chem., 2001, 4705.

COMMENTS :

AMADORI REARRANGEMENT EXAMPLE : OH HO HO

O OH

H

N H

C18H37

HO HCl pyridine

38

HO

O OH

OH

N H

C18H37

MECHANISM :

H H HO H H

NRR1 OH H OH O CH2OH

H+

R

- H+

N

H HO H H

H H HO H H

H H HO H H

NRR1 OH H OH OH CH2OH

R

R1 H OH

H HO H H

H OH OH CH2OH

H H HO HO H H

NRR1 OH H OH H O CH2OH N R1 O H OH OH CH2OH

H NRR1

H HO HO H H H2C

H OH O CH2OH

NRR1 H OH OH O

DISCONNECTION :

H H H

NRR1 OH HO H H OH H OH CH2OH

H H HO H H

NRR1 OH H OH O CH2OH

NOTES : N-Substituted glycosylamines derived from primary aromatic amines and certain other bases give 1-deoxy-1-amino-2ketoses slowly at room temperature or rapidly in hot ethanolic solutions in the presence of compounds containing active methylenic hydrogen atoms or in the presence of catalytic amounts of acids. A variety of Lewis acids have been employed as catalysts (CuCl2, MgCl2, SnCl4). There are two mechanisms proposed one by Kuhn et al. and one by Micheel et al. The mechanism of Kuhn is shown here. The first few steps upto the aminoketose (Amadori product) are the early stages of the Maillard reaction. This reaction is not discussed in this book.

REFERENCES : 1) M. Amadori, Atti Accad. Nazl. Lincei, 1925, 2, 337.

39

2) R. Kuhn; F. Weygand, Ber. Dtsch. Chem. Ges., 1937, 70, 769. 3) E. Mitts; R.M. Hixon, J. Am. Chem. Soc., 1944, 66, 483. 4) F. Micheel; I. Dijong, Liebigs Ann. Chem., 1962, 658, 120. 5) A.S. Acharya; R.P. Roy; B. Dorai, J. Protein Chem., 1991, 10, 345. 6) J.J. Turner; N. Wilschut; H.S. Overkleeft; W. Klaffke; G.A. van der Marel; J.H. van Boom, Tetrahedron Lett., 1999, 40, 7039. 7) L. Azema; F. Bringaud; C. Blonski; J. Perie, Bioorg. Med. Chem., 2000, 8, 717. 8) D.R. Cremer; M. Vollenbroeker; K. Eichner, Eur. Food Res. Technol., 2000, 211, 400. 9) J. Venkataraman; K. Aggarwal; P. Balaram, Chem. Biol., 2001, 8, 611. 10) Z. Liu; L.M. Sayre, Chem. Res. Tox., 2003, 16, 232.

COMMENTS :

ANDERSON – FUCHS REACTION EXAMPLE :

Me3Si

PhO2S

PhO2S 1) 4

OTBDMS

Sn

H

Et2O, PhLi, RT 2) KOtBu, - 78 oC 3) TMSCl

OTBDMS

MECHANISM :

4

PhO2S

H3C

Sn

1) PhLi, Et2O, RT 2) KOtBu, - 78 oC

K

CH3

O

O

K

4

PhO2S K

CH3

Me3Si

CH3

H3C

CH3

O

O

CH3

CH3

40

CH3

PhO2S TMSCl - KCl

H3C

O

O

CH3

CH3

DISCONNECTION :

Me3Si

PhO2S

PhO2S

+ R H

R1

R1

R

NOTES : This reaction uses α-silyl or α-stannyl sulfones as latent α-sulfonyl anions. After the conjugate addition of allyl potassium to vinyl sulfones followed by carbon silylation α-silyl sulfones are obtained.

REFERENCES : 1) M. Isobe; M. Kitamura; T. Goto, Tetrahedron Lett., 1979, 20, 3465. 2) M. Isobe; Y. Ichikawa; Y. Funabashi, Tetrahedron, 1986, 42, 2863. 3) D. Scarpetti; P.L. Fuchs, J. Am. Chem. Soc., 1990, 112, 8084. 4) M.B. Anderson; P.L. Fuchs, J. Org. Chem., 1990, 55, 337. 5) M. Lamothe; M.B. Anderson; P.L. Fuchs, Synth. Commun., 1991, 21, 1675.

COMMENTS :

ANDO MANDELIC ACID SYNTHESIS EXAMPLE : O +

EtO

OEt O

O

1) SnCl4 2) aq. KOH, heat 3) HCl, heat

41

COOH OH

MECHANISM :

O EtO

+

OEt O

O

COOEt SnCl4

COOH HCl, heat - CO2

OH

HOOC

aq. KOH, heat

OH COOEt

COOH OH

DISCONNECTION :

R

O COOH

R

+

EtO

OEt O

OH

O

R = H, CH3, CH2Ar, CH(Ph)2

NOTES : Mandelic acids are prepared from ethyl oxomalonate and aromatic hydrocarbons or their derivatives by treatment with suitable condensing agents.

REFERENCES : March : 549 Smith – March : 720 Org. Synth. : 25, 33 Org. Synth. Coll. Vol. : 3, 326

1) T. Ando, J. Chem. Soc. Jpn., 1935, 56, 745. 2) J.L. Riebsomer; J. Irvine; R. Andrews, J. Am. Chem. Soc., 1938, 60, 1015. 3) J.L. Riebsomer; D. Stauffer; F. Glick; F. Lambert, J. Am. Chem. Soc, 1942, 64, 2080. 4) S. Ghosh; S.N. Pardo; R.G. Salomon, J. Org. Chem., 1982, 47, 4692.

COMMENTS :

42

ANDREASCH THIAZOLE SYNTHESIS EXAMPLE :

+

H2N

COOH

NH2

S

S

HOOC

N

HOOC

NH2

HO

MECHANISM :

HOOC HOOC

SH

H N HO OH H2N

HN

OH

NH2

O H+

SH

H+

HOOC

HOOC

H2O

N OH H2N

N SH

- H2O

HO

N

SH

HO

H2N

H S

H2N

NH2

S N

HOOC

- H+

HOOC

HO

DISCONNECTION :

NH2

S

HOOC +

N

HOOC

COOH

H2N

NH2 S

HO

NOTES : The action of thiourea on unsaturated dibasic acids such as maleic or fumaric acids yields derivatives of thiazole. The use of cinnamic acid affords a pyrimidine. See also Asinger, Hantzsch thiazole and Wohl – Marckwald reactions.

REFERENCES : 1) R. Andreasch, Monatsh. Chem., 1895, 16, 789. 2) H. Erlenmeyer; F. Heitz, Helv. Chim. Acta, 1942, 25, 832.

43

COMMENTS :

ANDRUSSOV AMMOXIDATION EXAMPLE :

HCN + 3 H2O

NH3 + CH4 + 1.5 O2 Pt - Rh catalyst

NOTES : This is the hydrogen cyanide production by the ammoxidation of methane over Pt ¯ Rh gauze catalyst. The process has been elaborated wherever natural gas is abundant.

REFERENCES : 1) L. Andrussov, Ber. Dtsch. Chem. Ges., 1927, 60, 2005. 2) L. Andrussov, Angew. Chem., 1935, 48, 593. 3) D.A. Hickman; M. Huff; L.D. Schmidt, Ind. Eng. Chem. Res., 1993, 32, 809. 4) A.S. Bodke; D.A. Olschki; L.D. Schmidt, Appl. Catal. A: General, 2000, 201, 13.

COMMENTS :

44

ANELLI OXIDATION EXAMPLE :

H

OH DCM, H2O, NaHCO3, 0 oC 0.1 KBr OCH3 0.01

O

N O

MECHANISM :

R +

N O

R1

H

- H+

R1

H R1

R + O

N O O

OH

N OH

cat. QX R=H

R

R1

OH O

DISCONNECTION :

R1

R R O

R1

H

OH R1

OH O

NOTES : Primary alcohols are oxidised to aldehydes, secondary alcohols to ketones, in a few minutes at 0 oC in DCM – 0.35 M NaOCl in the presence of a catalytic amount of TEMPO. Co-catalysis by bromide ions and buffer at pH 8.6 with sodium bicarbonate is also required. Further oxidation of the aldehyde to the carboxylic acid is very slow but can be speeded up by the addition of catalytic amounts of phase-transfer catalyst (QX). The TEMPO catalyst can be supported on silica. See also Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl,

45

Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : Org. Synth. : 69, 212 Org. Synth. Coll. Vol. : 8, 367

1) P.L. Anelli; C. Biffi; F. Montanari; S. Quici, J. Org. Chem., 1987, 52, 2559. 2) P.L. Anelli; S. Banfi; F. Montanari; S. Quici, J. Org. Chem., 1989, 54, 2970. 3) A.E.J. de Nooy; A.C. Besemer; H. van Bekkum, Synthesis, 1996, 1153. 4) A. Heeres; H.A. van Doren; K. Gotlieb; I.P. Bleeker, Carbohydr. Res., 1997, 299, 221. 5) T. Fey; H. Fischer; S. Bachmann; K. Albert; C. Bolm, J. Org. Chem., 2001, 66, 8154. 6) A. Dijksman; I.W.C.E. Arends; R.A. Sheldon, Synlett, 2001, 102.

COMMENTS :

ANGELI – RIMINI SYNTHESIS EXAMPLE :

H3C

O

H + O

S O

N H

OH N H

H3C

OH NaOCH3

O

MECHANISM :

O

O S O

N H

S

OH

NaOCH3

O

N

OH

R O R +

H

H O

N H

OH

46

OH O S N O H R O

DISCONNECTION :

OH N H

R O

R

H O

R = Alk, Ar

NOTES : Aldehydes form hydroxamic acids when treated with salts of nitrohydroxamic acid or of benzenesulfohydroxamic acid. With FeCl3 an intensely coloured iron-complex is formed. This can be used as a test for aliphatic and aromatic aldehydes.

REFERENCES : Houben – Weyl : 2, 437

1) A. Angeli, Gazz. Chim. Ital., 1896, 26/2, 17. 2) A. Angeli, Gazz. Chim. Ital., 1897, 27/2, 357. 3) E. Rimini, Gazz. Chim. Ital., 1901, 31/1, 84. 4) H.L. Yale, Chem. Rev., 1943, 33, 228. 5) W. Lwowski, Angew. Chem., Int. Ed. Engl., 1967, 6, 897. 6) A. Hassner; E. Wiederkehr; A.J. Kascheres, J. Org. Chem., 1970, 35, 1952. 7) B.M. Vlasov; O.V. Zaharova, J. Org. Him., 1974, 10, 66. 8) S. Zhou; F. Xie; Z. Xu; S. Ni, Huaxue Shiji, 2001, 23, 154.

COMMENTS :

ANGELI FURAZAN OXIDE REARRANGEMENT EXAMPLE :

H3C H3C

O N O N

OH N EtOH, base

47

O H3C

N

MECHANISM :

H H2C R

O N O N

H+

O N

H2C

ON

CH2

OH N O

+

base, - H

R

N

O

rotation

R

N

O

R

N

DISCONNECTION :

OH N

H3C O

R

N

R

O N O N

NOTES : The ring-opening of furazan-2-oxides (1,2,5-oxadiazol-2-ium-2-olate) and recyclisation with ethanolic base to afford hydroximino-1,2-oxazoles (4-(5H)-isoxazolone oxime).

REFERENCES : Houben – Weyl : E8c, 751

1) P. Tönnies, Ber. Dtsch. Chem. Ges., 1880, 13, 1845. 2) A. Angeli, Ber. Dtsch. Chem. Ges., 1891, 24, 3994. 3) H. Wieland; L. Semper, Liebigs Ann. Chem., 1907, 358, 36. 4) A.J. Boulton; D.E. Coe; P.G. Tsoungas, Gazz. Chim. Ital., 1981, 112, 167. 5) W. Naixing; C. Boren; O. Yuxiang, Propellants, Explosives, Pyrotechnics, 1994, 19, 145.

COMMENTS :

48

d’ANGELO’S ASYMMETRIC MICHAEL ADDITION EXAMPLE :

1) H3C

O

NH2

Ph

H

MS, toluene, reflux 2)

O

CH3CO2

CO2CH3

3) AcOH, H2O, CH3OH, 45 oC

MECHANISM :

R

R

R

EWG N

NH2 H3C H Ph - H2O

O

H3C

EWG

H

N H3C

Ph

H Ph

R EWG +

H3O

O

DISCONNECTION :

R

R

EWG O

O

NOTES : This is an asymmetric version of the Michael reaction (deracemising alkylation) for the enantioselective construction of quaternary stereogenic centres using (S)-1-phenylethylamine. See also Hajos – Parrish – Eder – Sauer – Wiechert and Michael reactions.

REFERENCES : 1) M. Pfau; G. Revial; A. Guignant; J.D. d’Angelo, J. Am. Chem. Soc., 1985, 107, 273. 2) J.D. d’Angelo; G. Revial; T. Volpe; M. Pfau, Tetrahedron Lett., 1988, 29, 4427. 3) J.D. d’Angelo; D. Desmaele; F. Dumas; A. Guigant, Tetrahedron: Asymmetry, 1992, 3, 459.

49

4) J.C.F. Alves; A.B.C. Simas; P.R.R. Costa, Tetrahedron: Asymmetry, 1999, 10, 297. 5) M. Toyota; T. Wada; M. Ihara, J. Org. Chem., 2000, 65, 4565. 6) C. Camara; L. Keller; F. Dumas, Tetrahedron: Asymmetry, 2003, 14, 3263.

COMMENTS :

ANSCHÜTZ – SCHOLL HYDROXYACETOPHENONE SYNTHESIS EXAMPLE :

O

O

OH CH3

KOH 180 oC

OH

O

MECHANISM :

H O

O

O OH

OH

O OH

O

O

OH

OH OH

OH H+

- CO2 O

CH3 O

H

50

O

DISCONNECTION :

O

O

OH

OH CH3

R = H, Alk

O

O

O

OR OH

O

NOTES : 4-Hydroxycoumarin, 4-hydroxycoumarin-3-carboxylic acid or its esters yield on treatment with alkali at 180 oC ohydroxyacetophenones. In some cases the molecule will not decarboxylate and the corresponding salts can be obtained. See also Anschütz hydroxy coumarin, Bargellini, Boyd – Robinson, Knoevenagel coumarin, Pauly – Lockemann, von Pechmann – Duisberg and Perkin coumarin reactions.

REFERENCES : 1) R.A. Anschütz; N.E. Scholl, Liebigs Ann. Chem., 1909, 367, 169. 2) R.A. Anschütz; N.E. Scholl, Liebigs Ann. Chem., 1911, 379, 333. 3) S. Roseman; C.F. Huebner; R. Pankratz; K.P. Link, J. Am. Chem. Soc., 1954, 76, 1650. 4) I.C. Ivanov; S.K. Karagiosov; K. Stoyan; I. Manolov, Arch. Pharm. (Weinheim, Ger.), 1991, 324, 61. 5) O. Bozdağ; G. Ayhan-Kilcigil; M. Tunçbilek; R. Ertan, Turk. J. Chem., 1999, 23, 163.

COMMENTS :

ANSCHÜTZ ANTHRACENE SYNTHESIS EXAMPLE :

H Br 2

+

Br

Br

AlCl3

Br H

51

MECHANISM :

H Br Br

Br Br

AlCl3

H

DISCONNECTION : H X +

X

X X H

X = Cl, Br

NOTES : The synthesis of anthracenes from benzene, 1,1,2,2-tetrachloroethane or 1,1,2,2-tetrabromoethane and aluminium trichloride. See also Friedel – Crafts and Nenitzescu acylation reactions.

REFERENCES : 1) R.A. Anschütz; A. Angelbis, Ber. Dtsch. Chem. Ges., 1884, 17, 165. 2) R.A. Anschütz, Liebigs Ann. Chem., 1886, 235, 150.

COMMENTS :

ANSCHÜTZ HYDROXYCOUMARIN SYNTHESIS EXAMPLE :

H3C

O O

O Cl O

1) NaCH(CO2Et)2 2) aq. KOH

52

OH

O

MECHANISM :

H3C

O

O

O

O Cl

OH O

H

CH(CO2Et)2

O O

CH3

O

OEt CO2Et

CH3 OH O H

O

O H

OEt O CO2Et

O

- CH3COOH - EtOH

CO2Et O

O

O

O

H+

O

aq. KOH

CO2Et OH

OH

DISCONNECTION :

H3C O

O

O O

R

R OH

Cl O

NOTES : Ortho-acetoxybenzoyl chlorides are condensed with sodium diethylmalonate to yield 3-ethoxycarbonyl-4hydroxycoumarins, which are saponified and decarboxylated. See also Anschütz – Scholl, Bargellini, Boyd – Robinson, Knoevenagel coumarin, Pauly – Lockemann, von Pechmann – Duisberg and Perkin coumarin reactions.

REFERENCES : 1) R.A. Anschütz, Ber. Dtsch. Chem. Ges., 1903, 36, 463. 2) R.A. Anschütz, Liebigs Ann. Chem., 1909, 367, 169.

COMMENTS :

53

APPEL – ROBINSON OXIDATION EXAMPLE :

OCH3 OCH3 CH3O

O

OCH3

OH OH

H

H

HO

O

1) Br2, dioxane 2) HI

OH

I OH OH

MECHANISM :

OCH3 OCH3 CH3O

O

OCH3

OCH3 OCH3

H Br2 dioxane

OH

H

CH3O

O

H

O OCH3

OCH3 OCH3 CH3O

OCH3 OCH3

Br CH3O

O

O

Br

OH

OH OCH3

OCH3 OH OH HO

O

HI

I OH OH

DISCONNECTION :

OH

OCH3 OCH3

OH HO

O

CH3O

O

H

I OH OH

OCH3

54

H

OH

Br

NOTES : The oxidation of the tetramethyl ether of D-catechin. Technical dioxane has to be used as solvent. This has most probably to do with the presence peroxide, which is needed for the attack on the pyran ring. Benzoyl peroxide can also be used.

REFERENCES : 1) H. Appel; R. Robinson, J. Chem. Soc., 1935, 426. 2) A.K. Ganguli; T.R. Seshadri; P. Subramanian, Proc. Indian Acad. Sci., 1957, 46, 25.

COMMENTS :

APPEL REACTION EXAMPLE :

O

O

OH PPh3, CCl4, DCM

O

Cl

O

MECHANISM :

PPh3 + CCl4

Ph3PCl + Cl3C

R-OH + Cl3C

R-O + HCCl3

R-O + PPh3Cl

R-O-PPh3 + Cl

R-O-PPh3 + Cl

R-Cl + O=PPh3

DISCONNECTION :

R-OX

R-Hal

Hal = Cl, Br X = H, THP, PMB

55

NOTES : The transformation of mainly primary and secondary alcohols and their THP and PMB ethers into chlorides or bromides with triphenylphosphine and carbon tetrachloride or carbon tetrabromide. The driving force for this reaction is the formation of the triphenylphosphine oxide and the oxidation of the phosphor atom. Vorbrüggen et al. adapted this reaction to prepare oxazolines. See also Blum, Darzens method, Landauer – Rydon, Miller synthesis and Vorbrüggen – Krolikiewicz reactions.

REFERENCES : Smith – March : 519 Smith : 154 Smith 2nd : 123 Org. React. : 29,1 Org. Synth. : 54, 63 Org. Synth. Coll. Vol. : 6, 634

1) R. Appel, Angew. Chem., Int. Ed. Engl., 1975, 14, 801. 2) H. Vorbrüggen; K. Krolikiewicz, Tetrahedron Lett., 1981, 22, 4471. 3) H. Vorbrüggen; K. Krolikiewicz, Tetrahedron, 1993, 49, 9353. 4) A. Scheurer; P. Mosset; W. Bauer; R.W. Saalfrank, Eur. J. Org. Chem., 2001, 3067. 5) J.S. Yadav; R.K. Mishra, Tetrahedron Lett., 2002, 43, 5419. 6) L. Desmaris; N. Percina; L. Cottier; D. Sinou, Tetrahedron Lett., 2003, 44, 7589. 7) T.W. Baughman; J.C. Sworen; K.B. Wagener, Tetrahedron, 2004, 60, 10943.

COMMENTS :

ARBUZOV REACTION (MICHAELIS – ARBUZOV) EXAMPLE :

H3C (CH3CH2O)3P + CH3CH2Br

neat

56

O P OEt OEt

MECHANISM :

(CH3CH2O)P

OEt RCH2 P O CH2CH3 OEt

RCH2-X

X

OEt EtO P CH3CH2X + O R

DISCONNECTION :

R1

O P OR OR

R1

O P OR R

RO

OR P + RX OR

R

OR P + RX OR

O R1 P R R

R

P R

OR

+ RX

NOTES : This reaction in its simplest form consists in the transformation of a trialkyl phosphite into a dialkylalkane phosphonate by warming with concentrated alkyl halide. When the reaction is carried out with an α-bromo ketone it is called the Perkow reaction. Photo-Arbuzov reactions are also known. Furthermore, this reaction can be Lewis acid-catalysed or protic acid catalysed. See also Abramov, Allen, Landauer – Rydon, Michaelis – Becker – Nylén and Perkow reactions.

REFERENCES : March : 959 Smith – March : 1234 Smith : 136 Smith 2nd : 109 Houben – Weyl : 12/1, 150, 171, 251, 433; 12/2, 80, 284, 463; E7a, 628; E7b, 732; E15, 1679 Org. React. : 6, 273; 29, 1

1)

A. Michaelis; R. Kaehne, Ber. Dtsch. Chem. Ges., 1898, 31, 1048.

2)

A.E. Arbuzov, J. Russ. Phys. Chem., 1906, 38, 687.

3)

L.D. Freeman; G.O. Doak, Chem. Rev., 1957, 57, 479.

4)

B.A. Arbuzov, Pure Appl. Chem., 1964, 9, 307.

5)

A. Bhattacharya; G. Thyagarajan, Chem. Rev., 1981, 81, 415.

57

6)

T.B. Brill; S.J. Landon, Chem. Rev., 1984, 84, 577.

7)

G. Baccolini; R. Dalpozzo; V. Mele; E. Mezzina, Phosphorus Sulfur, 1988, 39, 179.

8)

R. Boetzel; G. Hagele, J. Fluorine Chem., 1994, 68, 11.

9)

W. Bhanthumnavin; A. Arif; W.G. Bentrude, J. Org. Chem., 1998, 63, 7753.

10) B. Mugrage; C. Diefenbacher; J. Somers; D.T. Parker; T. Parker, Tetrahedron Lett., 2000, 41, 2047. 11) W. Banthumnavin; W.G. Bentrude, J. Org. Chem., 2001, 66, 980. 12) P.-Y. Renard; P. Vayron; E. Leclerc; A. Valleix; C. Mioskowski, Angew. Chem., Int. Ed., 2003, 42, 3981. 13) A.A. Kadyrov; D.V. Silaev; K.N. Makarov; L.L. Gervits; G.-V. Röschenthaler, J. Fluorine Chem., 2004, 125, 1407. 14) W. Banthumnavin; W.G. Bentrude, J. Org. Chem., 2005, 70, 4643.

COMMENTS :

ARENS – van DORP SYNTHESIS EXAMPLE :

H3C

CH3

H3C +

BrMg

OEt

O

H3C 1) H+ 2) H2, Pd/BaSO4 pyridine 3) H2O

H O H

MECHANISM :

R

R

R1 BrMg

+

HO

OEt

H+

O

R

H

H2O

R1 OEt

OH H H

O

- OEt

OEt

H2 Pd/BaSO4

R1 R

R

R1

O

H

- H2O

R1

H O

H

58

R

R

R1 BrMg

+

OEt

R1

O

R

R H

H

R1 OH

OEt

H+

OH

H2O

OEt

OEt

R1 O

HO H

DISCONNECTION :

R H

OEt

R1 HO H R

O

R

H

R1

R1

+ BrMg

OEt

O O

H

NOTES : A ketone is treated with the organometallic derivative of ethoxyacetylene. If the hydroxy acetylene is hydrogenated α,β-unsaturated aldehydes are obtained. If however the hydroxyl acetylene is treated with acid hydroxyl esters are obtained. This reaction was one of the key steps in the synthesis of vitamin A. For the synthesis of a secondary carbinol, see Isler reaction. See also Favorskii – Babayan, Inhoffen, Isler, Jones – Weedon, Nef synthesis and Reppe acetylene reactions.

REFERENCES : Houben – Weyl : 6/3, 189

1) N.A. Preobrazhenskii; V.V. Shokina, J. Allg. Chem., 1945, 15, 65. 2) D.A. van Dorp; J.F. Arens, Nature, 1947, 160, 189. 3) J.F. Arens; D.A. van Dorp, Recl. Trav. Chim. Pays-Bas, 1948, 67, 973. 4) J.F. Arens, Adv. Org. Chem., 1960, 2, 117. 5) P.P. Monti; E. Harryvan; L. Brandsma, Recl. Trav. Chim. Pays-Bas, 1964, 83, 1211.

COMMENTS :

59

ARNDT – EISTERT SYNTHESIS EXAMPLE :

CH3CH2COOH

1) SOCl2 2) CH2N2 3) Ag+, H2O

CH3CH2CH2COOH

MECHANISM :

N N

O R

Cl

R

R

N N CH2N2

- HCl

O

O

O Ag+ - N2

H O

H

C H

R

H C H

R

O R

DISCONNECTION :

RCH2COOR1

RCOOH + R1OH

RCH2CONH2

RCOOH + NH3

RCH2CONHR1

RCOOH + R1NH2

RCH2COOH

RCOOH + H2O

NOTES : This is the chain elongation of carboxylic acids by one methylene group. A base or 2 equivalents of diazomethane can remove the formed hydrogen chloride. The rearrangement of the ketene with water is called the Wolff rearrangement. When an alkenyl acid chloride or an aromatic acid chloride is used, the reaction is called the Nierenstein reaction. The Newman – Beal modification uses triethylamine (to bind the HCl) and silver benzenecarboxylate, while the Wilds – Meader modification works with higher alcohols and does not use catalysts. Photochemical Arndt – Eistert reactions are also known. See also Büchner – Curtius – Schlotterbeck, Clibbens – Nierenstein, Kowalski and Wolff reactions.

REFERENCES : March : 1083 Smith – March : 573, 1405

60

Smith 2nd : 1199 Houben – Weyl : 8, 556; E5, 283, 287; E6b, 1212; E14b, 1371 Org. React. : 1, 38 Org. Synth. : 26, 13; 50, 77; 53, 35; 69, 180 Org. Synth. Coll. Vol. : 3, 119; 6, 386, 613; 8, 196

1) L. Wolff, Liebigs Ann. Chem., 1912, 394, 23. 2) F. Arndt; B. Eistert; W. Partale, Ber. Dtsch. Chem. Ges., 1927, 60, 1364. 3) F. Arndt, B. Eistert, Ber. Dtsch. Chem. Ges., 1935, 68, 200. 4) A.L. Wilds; A.L. Meader, J. Org. Chem., 1948, 13, 763. 5) M.S. Newman; P. Beal III, J. Am. Chem. Soc., 1949, 71, 1506. 6) A.B. Smith III, J. Chem. Soc., Chem. Commun., 1974, 695. 7) D.M. Piatak; J. Wicha, Chem. Rev., 1978, 78, 199. 8) T. Aoyama; T. Shioiri, Chem. Pharm. Bull., 1981, 29, 3249. 9) K.R. Desai; M.M. Pathak, J. Indian Chem. Soc., 1984, 61, 814. 10) J. Polech; D. Seebach, Liebigs Ann. Chem., 1995, 1217. 11) R.E. Marti; K.H. Bleicher; K.W. Bair, Tetrahedron Lett., 1997, 38, 6145. 12) A.J. Shuker, M.G. Siegel, D.P. Matthews, L.O. Weigel, Tetrahedron Lett., 1997, 38, 6149. 13) A.R. Katritzky; S.M. Zhang; Y.F. Fang, Org. Lett., 2000, 2, 3789. 14) N.T. Patil; J.N. Tilekar; D.D. Dhavale, J. Org. Chem., 2001, 66, 1065. 15) M.R. Linder; J. Podlech, Org. Lett., 2001, 3, 1849. 16) S. Nomoto; A. Shimoyama, Tetrahedron Lett., 2001, 42, 1753. 17) W. Kirmse, Eur. J. Org. Chem., 2002, 2193. 18) A. Gaucher; L. Dutot; O. Barbeau; W. Hamchaoui; M. Wakselman; J-P. Mazaleyrat, Tetrahedron: Asymmetry, 2005, 16, 857.

COMMENTS :

ARNDTSEN MÜNCHNONE REACTION EXAMPLE :

Tol +

N Bn

O

O

H

+ Ph

Cl

CO

Pd2(dba)3, NEt(iPr)2 CH3CN, THF, 55 oC

61

O

Ph N

Tol

Bn

MECHANISM :

O R2

R1 N R

+

Cl

H

R1

R1

R N

H

R2

Cl

N Pd N

bipy Pd0

O

R N R2

O

Cl-

CO

- bipy

O C

Pd R1

O

O

R1

N R

O N R

R1 OC Pd Cl

R2 R2

HCl

R1 O Cl

R N O

R2

CO insertion N

R

Pd O

R2

DISCONNECTION :

O

O

O R2

R1

N R

R2

R1 Cl

+ H

N R

+ CO

NOTES : The palladium-catalysed synthesis of münchnones starting with imines, carbon monoxide and acid chlorides. The mechanism is based on Arndtsen’s palladium-catalysed imidazoline synthesis and resembles the mechanism for amidocarbonylation. See also Wakamatsu synthesis.

62

REFERENCES : 1) M. Beller; M. Eckert; F. Vollmuller; S. Bogdanovic; H. Geissler, Angew. Chem., Int. Ed., 1997, 36, 1494. 2) R.D. Dghaym; R. Dhawan; B.A. Arndtsen, Angew. Chem., Int. Ed., 2001, 40, 3228. 3) R. Dhawan; R.D. Dghaym; B.A. Arndtsen, J. Am. Chem. Soc., 2003, 125, 1474.

COMMENTS :

ASINGER REACTION EXAMPLE :

H3C

O S8 + NH3 +

H3C

N CH3

CH3

S

MECHANISM : First step :

O

O R1

R

NH4

+ NH3

+

+

R1

R H

O

O R1

R

R1

R

+ S8

+

S

H O

S6

NH4 , - NH3

S

R S

S6

+

R1

R

SH

R1

R

S

S6

SH

O +

R1

R

S6

H

R1

R

O

O R1

O

SH

S

Ring formation :

R

O

R

H+

R

H3N

O R2

R1

SH R2

R1

H

R1 - H2O

R

N

R1

R

R2

S R2

63

OH R1

- H2O

R2

N S

R R1

R2

DISCONNECTION :

R R1 R2

N S

O R

S8 + NH3 + 2 R1

R1

R R2

R2

NOTES : The reaction between sulfur, ammonia or amines on ketones to afford thiazolines (imidazolin-5-thiones). The first step is the base-catalysed replacement of an H-atom α to the carbonyl group by a mercapto group. The ring formation can be regarded as an α-aminoalkylation of a thio-acid and subsequent stabilisation by ring-closure with elimination of water. See also Andreasch, Hantzsch thiazole, Mannich and Wohl – Marckwald reactions.

REFERENCES : Houben – Weyl : E5, 1469

1) F. Asinger, Angew. Chem., 1956, 68, 377. 2) F. Asinger, Angew. Chem., 1956, 68, 413. 3) F. Asinger; H. Offermanns, Angew. Chem., Int. Ed. Engl., 1967, 6, 907. 4) J. Martens; H. Offermanns; P. Scherberich, Angew. Chem., Int. Ed. Engl., 1981, 20, 668. 5) A. Domling; I. Ugi, Tetrahedron, 1993, 49, 9495. 6) A. Domling; A. Bayler; I. Ugi, Tetrahedron, 1995, 51, 755. 7) I. Schlemminger; H.-H. Janknecht; W. Maison; W. Saak; J. Martens, Tetrahedron Lett., 2000, 41, 7289.

COMMENTS :

ASSCHER – VOFSI REACTION EXAMPLE :

+ PhSO2Cl

1) Et3N, CuCl CH3CN 2) Et3N

64

O S O Ph

MECHANISM :

O O S Ph + PhSO2Cl

Et3N CuCl CH3CN

Cl

O O S Ph

NEt3

DISCONNECTION :

R

R2

R

R2

R3O2S

R1

H

R1

R3O2S

R1

R

R1

R R2 R3O2S

R R

H R2

R3 = Alkyl, Ar R

SO2R3

H

R

H

CH2 SO2R3

NOTES : The addition of aliphatic and aromatic sulfonyl chlorides to multiple C=C bonds under copper catalysis in acetonitrile.

REFERENCES : Houben – Weyl : E11, 1180

1) M. Asscher; D. Vofsi, J. Chem. Soc., 1964, 4962. 2) J. Sinureich; M. Asscher, J. Chem. Soc., Perkin Trans. 1, 1972, 1543. 3) F. Minisci, Acc. Chem. Res., 1975, 8, 165. 4) J.-P. Pillot; J. Dunoguès; R. Calas, Synthesis, 1977, 469. 5) A.M. Guliev; A.N. Lemeshev; S.P. Kasimova; O.M. Nefedov, Zhur. Org. Khim., 1984, 20, 2333. 6) M.D. Stadnichuk, Russ. J. Gen. Chem., 2003, 73, 1751.

COMMENTS :

65

ATHERTON – OPENSHAW – TODD SYNTHESIS EXAMPLE :

H

Ph

+

N H

O

OEt H P OEt O

OEt N P OEt H O

Ph 1) NaOH, CCl4 PhCH2N+(Ph)Br2) H2O

MECHANISM :

RO

O P

Cl OR

+ CCl4

RO

R2

O P

+ OR

CCl3

R2 H N R1

R1 N RO P O OR

- HCCl3

DISCONNECTION :

R2

R1 N RO P O OR

RO

O P

R2 + H N OR R1

NOTES : The synthesis of phosphoramidates from formamides and dialkyl phosphite. Carbon tetrachloride is the source of positive charged chlorine. Similar results can be obtained with carbon tetrabromide and a large variety of chloro compounds. The procedure has been modified by Lukanov et al. and Zwierzak et al. See also Michaelis – Becker – Nylén reaction.

REFERENCES : 1) F.R. Atherton; H.T. Openshaw; A.R. Todd, J. Chem. Soc., 1945, 382. 2) F.R. Atherton; H.T. Openshaw; A.R. Todd, J. Chem. Soc., 1945, 660. 3) A. Zwierzak, Synthesis, 1975, 507. 4) A. Zwierzak; J. Brylikowska, Synthesis, 1975, 712. 5) L.K. Lukanov; A.P. Venkov; N.M. Mollow, Synthesis, 1985, 971. 6) M. Safta; C. Csunderlik, Rev. Chim. (Bucharest), 1989, 40, 545. 7) M.B. Gazizov; R.A. Khairullin; K.M. Gazizov, Zh. Obshch. Khim., 1989, 59, 1456. 8) K. Troev; E.M.G. Kirilov; D.M. Roundhill, Bull. Chem. Soc. Jpn., 1990, 63, 1284. 9) Y.X. Ding; W.H. Wang; Z.F. Liu, Phosphorus Sulfur, 1996, 118, 113. 10) S.Z. Zhu; J. Zhang; B. Xu; C.Y. Qin, Org. Prep. Proced. Int., 1997, 29, 352.

66

11) X.G. Huang; X.J. Lin; Y.X. Ding, Chin. J. Org. Chem., 2000, 20, 783. 12) Y.X. Ding; X.G. Huang, Synth. Commun., 2001, 31, 449. 13) J.M. Kuiper; R. Hulst; J.B.F.N. Engberts, Synthesis, 2003, 695.

COMMENTS :

von AUWERS – INHOFFEN REARRANGEMENT EXAMPLE :

O

OH

H+ H3C

CH3

CH3 CH3

MECHANISM :

O

OH

H R

H+ R

R

OH

OH

R

R

- H+

R R

R

DISCONNECTION :

O

OH

R1(R)

R1 R

R(R1)

NOTES : The acid or Lewis acid-catalysed rearrangement of dienones to phenols. This reaction is also known under the name of dienone-phenol rearrangement.

67

REFERENCES : March : 1079 Smith – March : 1402

1) K. von Auwers; K. Ziegler, Liebigs Ann. Chem., 1921, 425, 217. 2) H.H. Inhoffen, Angew. Chem., 1940, 53, 471. 3) A. Sandoval; L. Miramontes; G. Rosenkranz; C. Djerassi, J. Am. Chem. Soc., 1951, 73, 990. 4) R. Heck; S. Winstein, J. Am. Chem. Soc., 1957, 79, 3105. 5) V.P. Vitullo; E.A. Logue, J. Org. Chem., 1973, 38, 2265. 6) T. Suehiro; S. Yamazaki, Bull. Chem. Soc. Jpn., 1975, 48, 3655. 7) J.D. Palmer; A.J. Waring, J. Chem. Soc., Perkin Trans. 2, 1979, 1089. 8) K.A. Parker; Y.-h. Koh, J. Am. Chem. Soc., 1994, 116, 11149. 9) M. Kobayashi; K. Uneyama; N. Hamada; S. Kashino, J. Org. Chem., 1995, 60, 6402.

COMMENTS :

von AUWERS FLAVONOL SYNTHESIS EXAMPLE :

O

O H3C

O

1) Br2 2) alkali EtOH

68

H3C

OH O

MECHANISM :

O

O Br2

R

KOH

R O Br

O

O

O

R O

O

Br

Br OH

KOH

OH

R O Br

H

O

OH

R

R O

OH Br

OH

Br

- Br

O

O R

OH O

DISCONNECTION :

R1

R1 O

R

O OH

O

R = H, Alk R1 = Alk, H

R O

NOTES : The formation of flavonol (3-hydroxy-2-phenyl-4H-chromen-4-one) from 2-bromo-2-[bromo(phenyl)methyl]-1benzofuran-3(2H)-one (2-benzylidenecoumaranone dibromide) by warming with aqueous ethanolic alkali hydroxides. Substituents in the ortho or para position to the heterocyclic oxygen atom promote flavonol formation. See also Algar – Flynn – Oyamada, Baker – Ollis, von Kostanecki (Allan – Robinson), Ranjorwa and Rasoda reactions.

REFERENCES : Houben – Weyl : E6b, 73

1) K. von Auwers; K. Müller, Ber. Dtsch. Chem. Ges., 1908, 41, 4233.

69

2) K. von Auwers; P. Pohl, Liebigs Ann. Chem., 1914, 405, 243. 3) T.H. Minton; H. Stephen, J. Chem. Soc., 1922, 121, 1598. 4) S. Wawzonek, Heterocyclic Compounds, 1951, 2, 245. 5) C.W. Bird; R.C. Cookson, J. Org. Chem., 1959, 24, 441. 6) V.I. Rozenberg; V.A. Nikanorov; Z.P. Svitanko; V.I. Bakhmutov; O.A. Reutov, Zhur. Org. Khim., 1981, 17, 2009. (J. Org. Chem. USSR (Engl. Transl.), 1981, 17, 1793.) 7) D.V. Belousov; A.V. Belik, Zh. Org. Khim., 1993, 29, 1303. (J. Org. Chem. USSR (Engl. Transl.), 1993, 29, 1078.)

COMMENTS :

von AUWERS INDANE-1-ONE SYNTHESIS EXAMPLE :

O O

OH

Cl 1) AlCl3, 100 oC 2) 170 oC

Br

70

Br

O

MECHANISM :

O O

Cl

OH

OH

O

O

Cl 170 oC

AlCl3 Br

Br

Br

O CH3

O

OH

OH

O

Br

CH3

O CH2

H AlCl3 Fries rearrangement

Br CH3

CH3

O H3C

OH CH3 O CH3

DISCONNECTION :

O

O

H3C

CH3

O

CH3 O OH

Br

O CH3 O

CH3 OH

O

O

Br

Br

71

Cl

O

NOTES : There are two steps in this synthesis, the first step is a Fries rearrangement of the phenolic ester of an α- or a βhalogenopropionic acid, followed by the cyclisation of the intermediate halogeno-ketone. Coumarones are also produced. See also Fries rearrangement.

REFERENCES : 1) K. von Auwers, Liebigs Ann. Chem., 1924, 439, 132. 2) R.A. Barnes; E.R. Kraft; L. Gordon, J. Am. Chem. Soc., 1949, 71, 3523. 3) B. Muchensturm; F. Diyani, J. Chem. Res., 1995, 11, 2544.

COMMENTS :

von AUWERS REARRANGEMENT EXAMPLE :

H3C

H3C

CHCl2

CH3 1) aq. NaOH 2) CHCl3 3) EtMgBr H3C heat

72

CCl2

MECHANISM :

CH3

H3C 1) 10% aq. NaOH, 95 oC 2) CHCl3

OH H3C

CHCl2 EtMgBr O

CH3

CHCl2

via

heat H

CH3

H3C

CH3

H

CHCl2 CH3

CH3

CH3

H

H

CH3

CH3

favoured

DISCONNECTION :

CH3

H3C

H3C

CCl2

CHCl2

H3C

NOTES :

Certain 3-(dichloromethyl)-6-alkylidine-3-methyl-1,4-cyclohexadienes undergo thermal non-catalytic rearrangement involving aromatisation of the ring and transfer of the dichloromethyl group to the α-carbon of the alkylidene side chain. This reaction is also possible on naphthalene compounds.

REFERENCES :

1) K. von Auwers, Liebigs Ann. Chem., 1907, 352, 217. 2) R.C. Fuson; T.G. Miller, J. Org. Chem., 1952, 17, 316.

COMMENTS :

73

74

BARTON DEAMINATION · 147 BARTON DECARBOXYLATION · 149

B

BARTON PHENYLATION · 150 BÄCKVALL ACETOXYLATION REACTION · 77

BARTON REACTION · 152

BADDELEY REARRANGEMENT · 79

BAUDART ACYLOIN SYNTHESIS · 153

BAEKELAND POLYCONDENSATION · 81

BAUDART SYNTHESIS · 154

BAER – FISCHER SYNTHESIS · 83

BAUDISCH REACTION · 155

BAEYER von – DREWSEN INDIGO SYNTHESIS · 85

BAUM BENZOYLATION · 157

BAEYER von – DREWSEN QUINOLINE SYNTHESIS · 86

BAUMANN – FROMM SYNTHESIS · 158

BAEYER von – EMMERLING INDOLE SYNTHESIS · 88

BAYLIS – HILLMAN – MORITA REACTION · 160

BAEYER von – JACKSON INDOLE SYNTHESIS · 89

BÉCHAMP ARSONYLATION · 162

BAEYER von – PICCARD REACTION · 91

BÉCHAMP REDUCTION · 164

BAEYER von – PICTET CONVERSION OF PYRYLIUM SALTS

BECKMANN REARRANGEMENT · 165 BEDOUKIAN REACTION · 167

(KATRITZKY PYRYLIUM – PYRIDINIUM METHOD) · 91 BAEYER von – VILLIGER REARRANGEMENT · 92

BÉHAL – SOMMELET SYNTHESIS · 168

BAEYER von – VILLIGER TRITYLATION · 94

BEHREND – ROOSEN SYNTHESIS · 169

BAEYER von ALDEHYDE CONDENSATION · 95

BEHREND REARRANGEMENT · 170

BAEYER von CONVERSION OF PYRONE · 97

BELLUŠ – CLAISEN REARRANGEMENT · 171

BAEYER von OXINDOLE SYNTHESIS · 98

BELOUSOV – ZHABOTINSKY REACTION · 173

BAILEY – LIEBESKIND INDOLINES SYNTHESIS · 100

BENARY REACTION · 174

BAILEY CYCLOADDITION · 101

BENET SYNTHESIS · 175

BAILEY PEPTIDE SYNTHESIS · 102

BENKESER REACTION · 176

BAKER – OLLIS SYNTHESIS · 103

BENKESER REDUCTION · 178

BAKER – VENKATARAMAN REARRANGEMENT · 105

BERCHTOLD REACTION · 180

BALABAN – NENITZESCU – PRAILL SYNTHESIS · 106

BERGMAN – MASAMUNE CYCLISATION · 181

BALBIANO OLEFIN OXIDATION · 108

BERGMANN – SCHOTTE REACTION · 183

BALBIANO PYRAZOLE SYNTHESIS · 109

BERGMANN – ZERVARS CARBOBENZOXY METHOD · 184

BALL – GOODWIN – MORTON OXIDATION · 110

BERGMANN ANTHRACENE REACTION · 186

BALLY – SCHOLL SYNTHESIS · 112

BERGMANN AZLACTONE PEPTIDE SYNTHESIS · 187

BALSOHN ADDITION · 113

BERGMANN DEGRADATION OF PEPTIDES · 188

BALZ – SCHIEMANN REACTION · 115

BERNTHSEN ACRIDINE SYNTHESIS · 190

BAMBERGER – GOLDSCHMIDT SYNTHESIS · 116

BERNTHSEN PHENOTHIAZINE SYNTHESIS · 192

BAMBERGER – HEY DIARYL SYNTHESIS · 118

BERSON – WILLCOTT REARRANGEMENT · 193

BAMBERGER ARYLNITRAMINES REARRANGEMENT · 119

BERTRAM – WALBAUM SYNTHESIS · 194

BAMBERGER BENZOTRIAZINE SYNTHESIS · 121

BESTMANN REACTION · 195

BAMBERGER IMIDAZOLE REARRANGEMENT · 122

BETTI REACTION · 196

BAMBERGER REARRANGEMENT · 123

BIELLMANN ALKYLATION · 198

BAMFORD – STEVENS REACTION (CAGLIOTI – SHAPIRO

BIGINELLI PYRIMIDONE SYNTHESIS · 200 BINGEL REACTION · 201

REACTION) · 125 BANERT CASCADE REACTION · 127

BINKLEY TRIFLATE DISPLACEMENT · 202

BARBIER – LOCQUIN – WIELAND DEGRADATION · 129

BIRCH – HAAS REACTION · 205

BARBIER REACTION · 130

BIRCH REDUCTION · 207

BARDHAN – SENGUPTA PHENANTHRENE SYNTHESIS · 132

BIRCKENBACH – GOUBEAU – WATERS REACTION · 209

BARGELLINI REACTION · 133

BIRNBAUM – SIMONINI SYNTHESIS · 210

BARGELLINI RING-CLOSURE · 134

BISCHLER – MÖHLAU INDOLE SYNTHESIS · 211

BARGER DEMETHYLATION · 135

BISCHLER – NAPIERALSKI REACTION · 213

BARRY REACTION · 136

BISCHLER CYCLISATION · 215

BART (BART – SCHMIDT) REACTION · 138

BISCHLER TRIAZINE SYNTHESIS · 216

BARTLETT – CONDON – SCHNEIDER REACTION · 139

BLAISE – GUERIN (BLAISE –LeSUEUR) DEGRADATION · 217

BARTOLI INDOLE SYNTHESIS · 140

BLAISE – MAIRE KETONE SYNTHESIS · 218

BARTON – KELLOGG OLEFINATION · 142

BLAISE KETOESTER REACTION · 219

BARTON – McCOMBIE DEOXYGENATION · 144

BLANC – QUELLET CHLOROMETHYLATION /

BARTON – ZARD PYRROLE SYNTHESIS · 146

CHLOROALKYLATION REACTION · 221 BLANC REACTION · 223

75

BLICKE – PACHTER SYNTHESIS · 224

BROWN HYDROBORATION · 293

BLOMQUIST REACTION · 225

BROWN REACTION · 295

BLUM AZIRIDINE SYNTHESIS · 226

BROWN REARRANGEMENT · 296

BOBBIT REACTION · 228

BRUNNER OXINDOLE RING–CLOSURE · 299

BODROUX – CHICHIBABIN ALDEHYDE SYNTHESIS · 229

BRUYLANTS AMINATION · 300

BODROUX REACTION · 230

BUCHERER – BERGS REACTION · 301

BOEKELHEIDE REACTION · 232

BUCHERER – GROLÉE SYNTHESIS · 303

BÖESEKEN – BALLIO SYNTHESIS · 233

BUCHERER – LE PETIT REACTION · 304

BÖESSNECK – HÉBERT REACTION · 234

BUCHERER CARBAZOLE SYNTHESIS · 306

BOGER – PANEK PYRIDINE SYNTHESIS · 235

BÜCHNER – CURTIUS – SCHLOTTERBECK REACTION · 308

BOGERT – COOK REACTION · 237

BÜCHNER METHOD OF RING ENLARGEMENT · 310

BOGERT – HERRERA SYNTHESIS · 238

BUCHWALD – HARTWIG REACTION · 312

BOHLMANN – RAHTZ REACTION · 239

BUCHWALD ZIRCONOCENE REACTION · 314

BOHN – SCHMIDT REACTION · 240

BUNNETT REACTION · 315

BOHN SYNTHESIS · 242

BURTON – WIEMERS TRIFLUOROMETHYLATION · 317

BONE – SPRANKLING SYNTHESIS · 243

BUTLEROW SUGAR SYNTHESIS · 318

BOON – POLONOVSKI PTERIDINE REACTION · 244 BOORD OLEFIN SYNTHESIS · 245

C

BORCH REDUCTION · 246 BORSCHE – BEECH AROMATIC ALDEHYDE SYNTHESIS · 248

CAGLIOTI – SHAPIRO REACTIONamadori · 126

BORSCHE – BERKHOUT SYNTHESIS · 249 BORSCHE – DRECHSEL CYCLISATION · 250 H

BORSCHE – KENNER SYNTHESIS · 252 BORSCHE – KOELSCH CINNOLINE SYNTHESIS · 253

HARLEY–MASON MODIFICATION · 86

BOSCH – MEISER UREA PROCESS · 255 BOTT – HELLMANN REACTION · 255

K

BÖTTINGER – MICHAELIS REACTION · 257 BOUGAULT SYNTHESIS · 258

KENNER MODIFICATION · 253

BOUIS SYNTHESIS · 259 BOULTON – KATRITZKY REARRANGMENT · 261 BOUVEAULT – BLANC REDUCTION · 262

L

BOUVEAULT – LOCQUIN ACYLOIN SYNTHESIS · 263 BOUVEAULT – LOCQUIN AMINO ACID SYNTHESIS · 265

LUCHE ALLYLATION · 131

BOUVEAULT – WAHL SYNTHESIS · 267 BOUVEAULT ALDEHYDE SYNTHESIS · 268 N

BOUVEAULT HYDROLYSIS OF AMIDES · 269 BOWMAN DEBENZYLATION · 271

NORDLANDER MODIFICATION · 212

BOWMAN REACTION · 274 BOYD – ROBINSON 4-HYDROXYCOUMARINS SYNTHESIS · 276 P

BOYLAND – SIMS ORTHO-HYDROXYANILINE SYNTHESIS · 277 BRACKEEN SYNTHESIS · 278

PRINS REDUCTION · 263

BRADSHER CYCLOADDITION REACTION · 279 BRADSHER REACTION · 281 BRANDI – GUARNA REARRANGEMENT · 282

S

BRANDT ALDEHYDE SYNTHESIS · 283 BRAUN von AMIDE DEGRADATION · 284

SCHELLER MODIFICATION · 138

BRAUN von AMINO ACID SYNTHESIS · 287

SCHMIDT MODIFICATION · 138

BRAUN von CYANOGEN BROMIDE REACTION · 286

STARKEY MODIFICATION · 138

BRECKPOT REACTION · 288 BREDERECK IMIDAZOLE SYNTHESIS · 290 BROOK SILAKETONE REARRANGEMENT · 291

76

BÄCKVALL ACETOXYLATION REACTION EXAMPLE :

AcO

OAc

AcO

OAc

Pd(OAc)2 LiOAc p-Benzoquinone AcOH

Li2PdCl4 LiOAc p-Benzoquinone AcOH

MECHANISM :

OAc

O

O

Pd AcO OAc OH Pd(OAc)2

OAc O Pd

OH

H3C

O

O O

Pd O OAc AcO

AcO

OAc

Pd

O

77

O

O

Chloride effect :

AcO

OAc trans

OAc

OAc Pd(OAc)2 AcOH, RT

O

p-BQ Pd AcO

OAc

O

Pd H3C

O O

LiCl, p-BQ

X AcO

OAc

OAc

Cl

X = AcO cat. Cl-

cis

Cl

O

Pd

X = Cl excess Cl-

cis

O

DISCONNECTION :

R1 AcO

OAc R

AcO

OAc R1

AcO

R1

R

NRR1

78

OAc

R

NOTES :

An efficient method based on the palladium-catalysed 1,4-acetoxy-chlorination of 1,3-dienes and palladium-catalysed amination of allylic substrates. Compared to other methods, this method is more convenient and more general. It allows complete control of the 1,4-relative configuration when the carbons bearing nitrogen and oxygen are stereogenic. The formation of E/Z stereoisomers can be fully controlled (chloride effect). For review on halide effects, see Lautens et al.

REFERENCES : Smith – March : 1051 Org. Synth. : 67, 105 Org. Synth. Coll. Vol. : 8, 9 Science of Synthesis : 1, 70

1) J.-E. Bäckvall; R.E. Nordberg, J. Am. Chem. Soc., 1981, 103, 4959. 2) J.-E. Bäckvall, Pure Appl. Chem., 1983, 55, 1669. 3) J.-E. Bäckvall, Pure Appl. Chem., 1992, 64, 429. 4) J.P. Lyssikatos; M.D. Bednarski, Bioorg. Med. Chem. Lett., 1993, 3, 685. 5) B.M. Trost; R.C. Bunt, J. Am. Chem. Soc., 1998, 120, 70. 6) A. Gogoll; C. Johansson; A. Axén; H. Grennberg, Chem. Eur. J., 2001, 7, 396. 7) K. Fagnou; M. Lautens, Angew. Chem., Int. Ed., 2002, 41, 26.

COMMENTS :

BADDELEY REARRANGEMENT EXAMPLE : CH3 H3C

CH3 CH3

H3C AlCl3, 170 oC

O

CH3 O

79

MECHANISM :

H3C

CH3

H

H3C

CH3

CH3 CH3

H3C

CH3

AlCl3, 170 oC

O

- AlCl3

CH3

O

O AlCl3

DISCONNECTION :

CH3 H3C

H3C

CH3

CH3

CH3

O

O

H3C

CH3 CH3

H3C

CH3

H3C O

O

NOTES :

An excess of aluminium chloride or bromide is used in the isomerisation of alkyl homologues of acetophenone. The aluminium chloride or bromide fixes the carbonyl group and thus prevents condensation, hydrolytic cleavage and it promotes rearrangement. See also Jacobsen rearrangement.

REFERENCES :

1) G. Baddeley, J. Chem. Soc., 1944, 232. 2) D.E. Pearson; J.D. Bruton, J. Org. Chem., 1954, 19, 957.

COMMENTS :

80

BAEKELAND POLYCONDENSATION EXAMPLE :

HO CH2

OH CH2

OH

CH2 OH

CH2

OH H

H

CH2

CH2

+ O

OH

CH2

OH CH2

OH

OH CH2

CH2 OH CH2

OH CH2

CH2

81

CH2 OH

OH

MECHANISM :

OH H

H

+

acid or weak alkaline solution

alkaline solution

O

excess phenol

excess formaldehyde phenolalcohol and phenolpolyalcohol

OH Ph

Ph OH Phenol and acid excess formaldehyde formaldehyde

Resole

Novolake

Resite

OH

OH H2 C

OH C H2

* m

Novolake OH

OH

OH H2 C

R1 R

CH2OCH2 R

R1 R n

m Resole

NOTES :

The production of resins by the interaction of phenols and formaldehyde. See also von Baeyer aldehyde and Lederer – Manasse reactions.

82

REFERENCES : Houben – Weyl : 14/2, 193

1) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1872, 5, 25. 2) L. Lederer, J. Prakt. Chem., 1894, 50, 223. 3) O. Manasse, Ber. Dtsch. Chem. Ges., 1894, 27, 2409. 4) L.H. Baekeland, Chem.- Ztg., 1909, 33, 317. 5) H. Schnell; H. Krimm, Angew. Chem., Int. Ed. Engl., 1963, 2, 373. 6) R. Friedel, Science, 1984, 5, 49.

COMMENTS :

BAER – FISCHER SYNTHESIS EXAMPLE :

H

OH

O

O

HO

O O

OCH3

HO O2N

CH3NO2 NaOEt

OH

H

83

OCH3

MECHANISM :

CH3

H3C O

O H

O H3C

R2 X O

O

CH3

R1

H H O

EtO R2

Ac

X

Ac

R1

X R1

Ac H

O

H

Ac

X = O,S; R1 = R2 = H X = O; R1 = OCH3; R2 = H

O

O OH

H+ H+ O

CH2OH

HO

X

H3C

R1

Ac H

O

H

O

H3C X = O; R1 = OCH3

O

Ac

X HO O OCH3

+

H

DISCONNECTION :

R2

R2

X

O

H R1

H

X R

R1 O

O X = CH2, O, S

OH

NOTES :

The synthesis of 3-nitro and 3-amino sugars by aldol condensation of sugar-derived dialdehydes. This synthesis allows for the introduction of acetyl, alkoxycarbonyl, carbamoyl and cyano groups into the sugar ring.

REFERENCES :

1) H.H. Baer; H.O.L. Fischer, Proc. Nat. Acad. Sci., 1958, 44, 991. 2) H.H. Baer, Adv. Carbohydr. Chem. Biochem., 1969, 24, 67. 3) J.S. Brimacombe; L.W. Doner, J. Chem. Soc., Perkin Trans. 1, 1974, 62. 4) F. Santogo–González; F. Hernández–Mateo, Synlett, 1990, 715. 5) Z. Pakulski, Pol. J. Chem., 1996, 70, 667.

COMMENTS :

84

von BAEYER – DREWSEN INDIGO SYNTHESIS EXAMPLE : H N

CH3

O

2 1) MnO2, H2SO4 2) acetone, aq. NaOH

NO2

N H

O

MECHANISM :

O O

CH3

CH3 NO2

H MnO2, H2SO4

OH acetone, aq. NaOH

NO2

NO2 OH

OH

N O

O

CH3

H OH

H OH OH H O

O H

O - H2O

N CH3 O OH O

OH

O

O - H2O

N O

N OH

CH3

OH O CH3

CH3 OH O

O

O

N OH

N O

H N

N OH H

O

H N OH O

H2O

OH

H N N H+

- H2O O

85

O

N H

CH3

DISCONNECTION :

H N

O

O CH3 N H

NO2

NOTES :

The aldol condensation of o-nitrobenzaldehydes with acetone, pyruvic acid or acetaldehyde to give indigo derivatives. The final coupling of the indoxyl can take place under radical coupling. The Harley–Mason modification gives higher yields. See also von Baeyer – Drewson quinoline and Heumann reactions.

REFERENCES :

1) A. von Baeyer; V. Drewson, Ber. Dtsch. Chem. Ges., 1882, 15, 2856. 2) L.E. Hinkel; E.E. Ayling; W.H. Morgan, J. Chem. Soc., 1932, 985. 3) R.H. Manske, Chem. Rev., 1942, 30, 113. 4) J.A. Harley–Mason, J. Chem. Soc., 1950, 2907. 5) A. Hassner; M.J. Haddadin, Tetrahedron Lett., 1962, 3, 975. 6) S. Torii; T. Yamanaka; H. Tanaka, J. Org. Chem., 1978, 43, 2882. 7) B.T. Golding; C. Pierpoint, Educ. Chem., 1986, 63, 71. 8) L. Fitjer; R. Gerke; W. Lüttke; P. Müller; I. Usón, Tetrahedron, 1999, 55, 14421. 9) C.J. Cooksey, Molecules, 2001, 6, 736.

COMMENTS :

von BAEYER – DREWSEN QUINOLINE SYNTHESIS EXAMPLE :

CH3 NO2

O

1) Sn, HCl 2) H+

86

N

CH3

MECHANISM :

O

O

O

CH3

CH3 Sn, HCl

NO2

N H

NH2

CH3

OH H+

N H

- H2O

CH3

N

CH3

DISCONNECTION : O R R1 N

R1

R

NO2

NOTES : o-Nitrocinnamic aldehydes or o-nitrostyryl ketones derivatives are reduced and cyclised by dehydration to give

quinolines. See also Allan – Loudon, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES :

1) E. Fischer; H. Kunzel, Ber. Dtsch. Chem. Ges., 1883, 16, 163. 2) R.H. Manske, Chem. Rev., 1942, 30, 113. 3) D. Sicker; A. Rabe; A. Zakrewski; G. Mann, J. Prakt. Chem., 1987, 329, 106. 4) M.K. O’Brien; A.W. Sledeski; L.K. Truesdale, Tetrahedron Lett., 1997, 38, 509.

COMMENTS :

87

von BAEYER – EMMERLING INDOLE SYNTHESIS EXAMPLE :

O OH NO2

1) Fe, KOH 2) heat

N H

MECHANISM :

OH

OH

O NO2

O Fe, KOH

heat, - CO2

COOH

- H2O

N OH H

N H

N H

DISCONNECTION :

O RO R1

R1

N H

NO2

NOTES : o-Nitrocinnamic acid undergoes reductive cyclisation when heated with iron fillings and potassium hydroxide to afford

an indole. Several other compounds can induce the cyclisation step. See also von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

88

REFERENCES :

1) A. von Baeyer; A. Emmerling, Ber. Dtsch. Chem. Ges., 1869, 2, 679. 2) F. Beilstein; A. Kuhlberg, Liebigs Ann. Chem., 1872, 163, 121. 3) H.M. Foster; D.W. Hein, J. Org. Chem., 1961, 26, 2539. 4) R.S. Mali; V.J. Yadav, Synthesis, 1984, 862. 5) C. Crotti; S. Cenini; B. Rindone; S. Tollari; F. Demartin, J. Chem. Soc., Chem. Commun., 1986, 784. 6) C.W. Holzapfel; C. Dwyer, Heterocycles, 1998, 48, 1513.

COMMENTS :

von BAEYER – JACKSON INDOLE SYNTHESIS EXAMPLE :

H3C

O CH3 Zn, NH4OH

N H

NO2

MECHANISM :

R

O

H+ O

NO2

- H2O

R NH2

Zn, NH4OH

R N H

89

OH N R H

DISCONNECTION : R1 R

R1 N H

O

R R1 = H, Alk

NO2

NOTES : o-Nitrophenylacetaldehyde and o-nitrobenzyl ketones undergo reductive cyclisation to form indoles. Several reagents

can be used for the cyclisation step. The reaction can easily be mistaken for the Reissert indole synthesis. See also von Baeyer – Emmerling, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) A. von Baeyer; O.R. Jackson, Ber. Dtsch. Chem. Ges., 1880, 13, 187. 2) W. Borsche, Ber. Dtsch. Chem. Ges., 1909, 42, 611. 3) R.A. Weerman, Recl. Trav. Chim. Pays-Bas, 1910, 29, 18. 4) G. Heller, Ber. Dtsch. Chem. Ges., 1917, 50, 1202. 5) S. Raucher; G.A. Koolpe, J. Org. Chem., 1983, 48, 2066. 6) C.J. Moody; K.F. Rahimtoola, J. Chem. Soc., Perkin Trans. 1, 1990, 673. 7) C.J. Moody; A.I. Mprrell, J. Indian Chem. Soc., 1994, 71, 309.

COMMENTS :

90

von BAEYER – PICTET CONVERSION OF PYRYLIUM SALTS (KATRITZKY PYRYLIUM – PYRIDINIUM METHOD) EXAMPLE : ClO4 H3C

O

CH3

H3C

CH3

N

NH3 CH3

CH3

MECHANISM :

CH3

CH3

CH3

aq. NH3

O

O

H

NH2

O

H

H2N

ClO4 CH3 HO H

N H

CH3

- H2O

N

DISCONNECTION :

H3C

ClO4

R ClO4 N CH3

CH3

H3C R = H, Alk, Aryl, OH, NHPh

O

CH3

CH3

NOTES :

The treatment of pyrylium salts with ammonia, primary amines, hydroxylamine or phenylhydrazine gives derivatives of pyridine. The reaction is very common and very frequently used. The oxygen can also be substituted by a sulfur using sodium sulfide. The reaction is also known as von Baeyer – Piccard reaction or Katritzky pyrylium – pyridinium method. See also von Baeyer pyrone and Balaban – Nenitzescu – Praill reactions.

91

REFERENCES : March : 354, 399, 411, 436, 445, 467 Smith – March : 447, 489, 499 Org. Synth. : 60, 34 Org. Synth. Coll. Vol. : 7, 144

1) A. von Baeyer; J. Piccard, Liebigs Ann. Chem., 1911, 384, 208. 2) W. Dilthey, J. Prakt. Chem., 1922, 104, 28. 3) O. King, J. Org. Chem., 1955, 20, 448. 4) A.R. Katritzky; Z. Zuriati; E. Lund, J. Chem. Soc., Perkin Trans. 1, 1980, 1879. 5) A.R. Katritzky, Tetrahedron, 1980, 36, 679. 6) A.R. Katritzky; C.M. Marson, Angew. Chem., Int. Ed. Engl., 1984, 23, 420. 7) A.R. Katritzky; K. Sakizadeh; G. Musumarra, Heterocycles, 1985, 23, 1765. 8) A.R. Katritzky; B. Brycki, J. Am. Chem. Soc., 1986, 108, 7295. 9) T. Bah; D. Rasala; R. Gawinecki, Org. Prep. Proced. Int., 1994, 26, 101. 10) M. Ilies; M.D. Banciu; M.A. Ilies; A. Scozzafava; M.T. Caproiu; C.T. Supuran, J. Med. Chem., 2002, 45, 504. 11) A. Moghimi; M.F. Rastegar; M. Ghandi; M. Taghizadeh; A. Yari; M. Shamsipur; G.P.A. Yap; H. Rahbarnoohi, J. Org. Chem., 2002, 67, 2065.

COMMENTS :

von BAEYER – VILLIGER REARRANGEMENT EXAMPLE : O

O

O CH3CO3H

92

MECHANISM :

H O

O

OH R

R

R1

H+

R

- H+

R1

O

O

O

O

O

Abnormal

R

R1

Criegee intermediate

O H

O O

R1 R2

R2

O

HO

R2

Normal

O R

O

R1

DISCONNECTION :

O R

O O

R1

R

R1

NOTES : The oxidative rearrangement of ketones using peracids, but also e.g. hydrogen peroxides with acids and bis(trimethylsilyl)monoperoxysulfate, to yield esters or lactones. Note that other functional groups can compete for the peroxyacid. The normal von Baeyer – Villiger reaction proceeds via nucleophilic addition to the ketone to afford the Criegee intermediate. This intermediate undergoes an intramolecular migration while at the same time the peroxide bond is cleaved. In the abnormal von Baeyer – Villiger reaction the hydroperoxide bears an extremely good leaving group. The Criegee intermediate gives the dioxirane via an intramolecular nucleophilic displacement. The dioxirane slowly rearranges to the lactone. Enzyme-catalysed and metal-catalysed von Baeyer – Villiger reactions are also known. See also Böeseken – Ballio, Criegee rearrangement and Wagner – Meerwein reactions.

REFERENCES : March : 1098 Smith – March : 1417 Smith : 293 Smith 2nd : 258 Houben – Weyl : 6/2, 707; E3, 639; E5, 651, 712; E6a, 854; E6b, 1162; E7a, 151; E16b, 798; E19c, 408 Org. React. : 9, 73; 43, 251 Org. Synth. : 8, 30 Org. Synth. Coll. Vol. : 1, 131 Science of Synthesis : 10, 582, 617, 624

93

1) A. von Baeyer; V. Villiger, Ber. Dtsch. Chem. Ges., 1899, 32, 3625. 2) A. von Baeyer; V. Villiger, Ber. Dtsch. Chem. Ges., 1900, 33, 858. 3) J.C. Robertson; A.A.M. Swelim, Tetrahedron Lett., 1967, 8, 2871. 4) T. Mitsuhashi; H. Miyadera; O. Simamura, J. Chem. Soc. D, 1970, 1301. 5) W. Adam; A. Rodriguez, J. Org. Chem., 1979, 44, 4969. 6) H. Suginome; S. Yamada, J. Org. Chem., 1985, 50, 2489. 7) M.J. Taschner; L. Peddada, J. Chem. Soc., Chem. Commun., 1992, 1384. 8) C. Bolm; G. Schlingloff; K. Weickhardt, Angew. Chem., Int. Ed. Engl., 1994, 33, 1848. 9) D.R. Kelly, Tetrahedron: Asymmetry, 1996, 7, 1149. 10) G. Strukul, Angew. Chem., Int. Ed., 1998, 37, 1198. 11) M. Renz; B. Meunier, Eur. J. Org. Chem., 1999, 737. 12) C.M. Crudden; A.C. Chen; L.A. Calhoun, Angew. Chem., Int. Ed., 2000, 39, 2852. 13) D.R. Kelly, Chim. Oggi, 2000, 18, 33. 14) D.R. Kelly, Chim. Oggi, 2000, 18, 52. 15) M.D. Mihovilovic; B. Müller; P. Stanetty, Eur. J. Org. Chem., 2002, 3711. 16) M. Snowden; A. Bermudez; D.R. Kelly; J.L. Radkiewicz–Poutsma, J. Org. Chem., 2004, 69, 7148.

COMMENTS :

von BAEYER – VILLIGER TRITYLATION EXAMPLE : OH OH + Ph3COH

H2SO4 HOAc, RT CPh3

MECHANISM :

OH

Ph H

H Ph3COH

H2SO4 - H2O

Ph

Ph3C

Ph

94

O

H

OH Ph3C - H+

DISCONNECTION : R

R

CPh3 R = electron withdrawing

NOTES : The introduction of a triphenylmethyl group into an aromatic ring at the ortho or para position. Electron-withdrawing groups will inhibit this reaction.

REFERENCES : 1) A. von Baeyer; V. Villiger, Chem. Ber., 1902, 35, 3013. 2) D.R. Boyd; G. Chignell, J. Chem. Soc., 1923, 813. 3) C.A. MacKenzie; G. Chuhani, J. Org. Chem., 1955, 20, 336. 4) A.T. Shulgin, J. Org. Chem., 1962, 27, 3868. 5) T. Ohta; K. Shudo; T. Okamoto, Tetrahedron Lett., 1983, 24, 71.

COMMENTS :

von BAEYER ALDEHYDE CONDENSATION EXAMPLE : OH 2

H H

H

+ O

H+

HO

95

OH

MECHANISM :

O

H H

O R

OH

H O

R

H+

H

R H

OH

HO

O

HO

H

R

R

OH

H+

- H2O H2O

H

R

HO

HO

OH

R

DISCONNECTION : R R R1

H

+ 2

R1

R = H, Ar R1 O R1 = N(CH3)2, OH, OCH3

NOTES : Activated aromatic compounds such as N,N-dimethylaniline, phenol or anisole, condense in the presence of acids, with aldehydes, e.g. formaldehyde or benzaldehyde, to form triphenylmethanes. In some cases with formaldehyde and phenol in alkaline solution resins are obtained . See also Baekeland, Lederer – Manasse and Zinke – Ziegler reactions.

REFERENCES : March : 548 Smith – March : 719 Org. Synth. : 2, 17; 42, 57; 55, 45; 68, 234 Org. Synth. Coll. Vol. : 1, 214; 5, 422; 6, 471; 8, 75

96

1) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1872, 5, 25. 2) J. Traubenberg, Angew. Chem., 1923, 36, 515. 3) H.M. Forster; D.W. Hein, J. Org. Chem., 1961, 26, 2539. 4) G. Casiraghi; G. Casnati; G. Puglia; G. Sartori, Synthesis, 1980, 124. 5) G.W. Yeager; D.N. Schissel, Synthesis, 1991, 63. 6) Z.H. Zhang; F. Yang; T.S. Li; C.G. Fu, Synth. Commun., 1997, 27, 3823.

COMMENTS :

von BAEYER CONVERSION OF PYRONE EXAMPLE :

H3C

O

H3C

CH3 1) Me2SO4 2) HClO4 3) (NH4)2CO3

O

N

CH3

OCH3

MECHANISM :

O

OCH3 CH3OSO2O

H3C

O

CH3 OCH3

O H3CO S OCH3 O

H3C

O

OCH3

OCH3

ClO4 H3C

O

CH3

aq. NH3

H3C

O

H3C

CH3 NH2 OCH3

OCH3 - H2O

HO N H

CH3

HClO4

CH3

N

H3C

97

CH3

H3C

CH3 O H2N H+

DISCONNECTION :

OCH3 ClO4 H3C

N R

H3C

O

CH3

CH3 O

NOTES : A pyrone when treated with dimethyl sulfate and perchloric acid and then with ammonium carbonate yields the corresponding 4-methoxypyridine. Many alkyl and aryl pyrylium salts can be converted this way into the corresponding pyridine derivatives. This reaction is a special case of the von Baeyer – Pictet reaction. See also von Baeyer – Pictet (Katritzky pyrylium – pyridinium) reaction.

REFERENCES : 1) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1910, 43, 2337. 2) W. Dilthey, J. Prakt. Chem., 1916, 94, 53. 3) L.F. Cavalieri, Chem. Rev., 1947, 41, 525. 4) K.N. Campbell; J.F. Ackermann; B.K. Campbell, J. Org. Chem., 1950, 15, 221. 5) K. Dimroth, Angew. Chem., 1960, 72, 331. 6) T.S. Balaban; I. Tămăşan; C. Deleanu, Liebigs Ann. Chem., 1992, 173.

COMMENTS :

von BAEYER OXINDOLE SYNTHESIS EXAMPLE :

COOH

O 1) HNO3, H2SO4 2) Sn, HCl

98

N H

MECHANISM :

COOH

COOH HNO3, H2SO4 - H+

Sn, HCl

NO2

O O

OH

- H2O

NH2

N H

DISCONNECTION :

COOH

O N H

NOTES : The formation of an oxindole from o-aminophenylacetic acid. See also Brunner, Gassman oxindole, Hinsberg oxindole, Martinet, Neber – Bosset and Stollé reactions.

REFERENCES : 1) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1878, 11, 582. 2) P. Wispek, Ber. Dtsch. Chem. Ges., 1883, 16, 1577.

COMMENTS :

99

BAILEY – LIEBESKIND INDOLINES SYNTHESIS EXAMPLE :

I 1) tBuLi, Et2O pentane, TMEDA - 78 oC 2) H+

N

N

MECHANISM :

Li Br N R

Li 2.2 tBuLi C5H12, Et2O - 78 oC

N R

n

1) TMEDA 2) heat

N R

E

E+

N R

DISCONNECTION : E Hal N R

Hal = F, Br, I

N R

NOTES : The synthesis of 3-substituted indolines derived from [2-[N-allylamino)phenyl] lithium derivatives. Instead of bromine or iodine, the use of 2-fluoro or 3-fluoro derivatives will afford 3,4-substituted indolines.

REFERENCES : 1) D. Zhang; L.S. Liebeskind, J. Org. Chem., 1996, 61, 2594. 2) W.F. Bailey; X.-L. Jiang, J. Org. Chem., 1996, 61, 2596. 3) W.F. Bailey; M.W. Carson, Tetrahedron Lett., 1997, 38, 1329. 4) T.S. Yokum; P.K. Tungaturthi; M.L. McLaughlin, Tetrahedron Lett., 1997, 38, 5111.

100

COMMENTS :

BAILEY CYCLOADDITION EXAMPLE : O

Ph Ph N N Ph

N N

H N

2 KOCN, AcOH RT, 1 hour

N H Ph

O

MECHANISM :

CF3 N N

F3C

F3C

CF3

CF3

N N F3C

CF3

F3C N N

NC

F3C

CF3

CF3 H

CF3 CN H CN

CN

DISCONNECTION :

R5 R8 R9

N R

R

R4 R R 1 R6 N R1 R3

R7 R2

N N

R1

R1

R4

R5

+

R6

R7

R3

R2

+ R9

R8

R

NOTES : The reaction between hydrazones and cyanic acid, thiocyanic acid, isocyanates and electron-rich olefins and acetylenes afford 1,2,4-triazolo[1,2-a][1,2,4]triazoles.

REFERENCES : 1) J.R. Bailey; N.H. Moore, J. Am. Chem. Soc., 1917, 39, 279. 2) J.R. Bailey; A.T. McPherson, J. Am. Chem. Soc., 1917, 39, 1322. 3) T.P. Forshaw; A.E. Tipping, J. Chem. Soc., Perkin Trans. 1, 1972, 1059. 4) T. Shimizu; Y. Hayashi; M. Miki; K. Teramura, J. Org. Chem., 1987, 52, 2277.

101

5) S. Rádl, Aldrichimica Acta, 1997, 30, 97.

COMMENTS :

BAILEY PEPTIDE SYNTHESIS EXAMPLE :

CH3

H N O

H3C

OEt

H2N

O

+ O

O

O H3C

H3C - 40 --> 25 oC, EtOAc

H2N

H

CO2Et

N H H

MECHANISM : R1

R

H

H2N

O

- H+

O

O

RH

H N

N O

OEt

R H H+

O

H N

N O

O

O

R1

R1

N O

CO2Et

O R

O

H

N

R1

H2N - CO2

CO2Et

H

CO2Et H

DISCONNECTION :

O R H2N

H

R1

R

H

R1

N

CO2Et

N H H

O

O

O

OEt

+ H2N

O

NOTES : Peptides are prepared by the base-catalysed reaction of the corresponding anhydro-N-carboxyamino acids with amino acids or peptide esters in anhydrous solvents at low temperatures. See also Cook – Levy reaction.

102

REFERENCES : 1) J.L. Bailey, J. Chem. Soc., 1950, 3461. 2) R. Katakai; M. Oya; K. Uno; Y. Iwakura, J. Org. Chem., 1972, 37, 327. 3) K. Kircher; H. Berndt; H. Zahn, Liebigs Ann. Chem., 1980, 275. 4) C. Schierlinger; K. Burger, Tetrahedron Lett., 1992, 33, 193.

COMMENTS :

BAKER – OLLIS SYNTHESIS EXAMPLE :

HO

OH

HO 1)

OH

O

OH

O

O Cl

CO2Et

pyridine 2) KOH 3) heat

103

OH

O

OH

MECHANISM : O HO

Cl OH

HO

OH

OEt O

pyridine OH

O

- HCl OH

OH

O

H

OH

+

H

OH O

HO

OH

HO

CO2Et

OH

O

OH CO2Et

O

- H2O

H

O

OH

OH HO

O

HO

CO2Et

O

COOH

HOsaponification OH HO

O

OH

OH

heat - CO2

O

OH

O

OH

O

OH

DISCONNECTION :

O

O

OH

R Ar

Ar

O

OEt

+ EtO

R

O

O

NOTES : Benzyl o-hydroxyphenyl ketones react at room temperature with 2-ethoxy-2-oxoacetyl chloride in pyridine to give 2ethoxycarbonylisoflavones, which are hydrolysed, and decarboxylated. See also Algar – Flynn – Oyamada, von Auwers flavonol, von Kostanecki (Allan – Robinson) acylation, Ranjorwa and Rasoda reactions.

REFERENCES : 1) W. Baker; J. Chadderton; J.B. Harbonne; W.D. Ollis, J. Chem. Soc., 1953, 1852. 2) W.K. Warburton, J. Chem. Soc., Quat. Rev., 1954, 8, 79.

104

COMMENTS :

BAKER – VENKATARAMAN REARRANGEMENT EXAMPLE : O

O CH3

O

O

Benzene K2CO3

O

OH

MECHANISM : OH

O CH3

CH2

O

O

O

O

O -

O

+

HO , - H O O

O

Ph O

O H+

O

OH

DISCONNECTION : O

O

R

R R1

R1 R2

O

O OH

R2

105

O

Ph

NOTES : Originally, the base-catalysed β-diketone transformation of o-aryloxyaryl alkyl ketones into o-hydroxydiaroylmethanes. This reaction is widely used in the synthesis of flavones and other chromone derivatives. See also Algar – Flynn – Oyamada, von Auwers flavonol, Baker – Ollis, von Kostanecki – Robinson (Allan – Robinson), Ranjorwa, Rasoda and Simonis reactions.

REFERENCES : Houben – Weyl : 8, 580; E8a, 318 Org. React. : 8, 59.

1) W. Baker, J. Chem. Soc., 1933, 1381. 2) H.S. Mahal; K. Venkataraman, J. Chem. Soc., 1934, 1767. 3) F.W. Bergstrom; W.C. Fernelius, Chem. Rev., 1937, 20, 444. 4) R. Levine; W.C. Fernelius, Chem. Rev., 1954, 54, 493. 5) A.V.S. Rao; N.V.S. Rao, Curr. Sci., 1966, 35, 149. 6) T. Szell; G. Schobel; L. Balaspiri, Tetrahedron, 1969, 25, 707. 7) G.A. Kraus; B.S. Fultan; S.H. Woo, J. Org. Chem., 1984, 49, 3212. 8) M.S.Y. Khan; M.H. Khan; K. Javed, Indian J. Chem., 1990, 29B, 1101. 9) K. Krohn; E. Roemer, M. Top, Liebigs Ann. Chem., 1996, 271. 10) M.A. Munawar; P.W. Groundwater, J. Chem. Soc. Pakistan, 1999, 21, 146. 11) B.A. Chauder; A.V. Kalinin; N.J. Taylor; V. Snieckus, Angew. Chem., Int. Ed., 1999, 38, 1435. 12) N. Thasana; S. Ruchirawat, Tetrahedron Lett., 2002, 43, 4515.

COMMENTS :

BALABAN – NENITZESCU – PRAILL SYNTHESIS EXAMPLE : Et Et H3C

1) NaClO4 H3C glacial CH3COOH CH3COCl (CH3CO)2O 2) 60 oC, 3 h 3) 20% aq. NH3

106

N

CH3

MECHANISM :

R1 R1

R1

R

R

H

R2 H

R3CO

R2

O

R3

- H2O R3

O

- H+

O

R

R2

H+ O

R3CO

R2 R3

R1

R1 R

R

R3

R2

R3

O

R3

DISCONNECTION : R1 R

R1

R2 R3CO

R3

O

R3

+

R

H R2

NOTES : Pyrylium salts are obtained from olefins by Friedel – Crafts diacetylation. These pyrylium salts can be converted easily to pyridines. See also von Baeyer – Pictet conversion of pyrylium salts (Katritzky pyrylium – pyridinium method).

REFERENCES : March : 354, 399, 411, 436, 445, 467 Smith – March : 447, 489, 499 Org. Synth. : 44, 98, 49, 121 Org. Synth. Coll. Vol. : 5, 1106, 1112, 1114

1) A.T. Balaban; C.D. Nenitzescu, Liebigs Ann. Chem., 1959, 625, 74. 2) A.T. Balaban; C.D. Nenitzescu, J. Chem. Soc., 1961, 3553. 3) A.T. Balaban; C.D. Nenitzescu, J. Chem. Soc., 1961, 3561. 4) A.T. Balaban; C.D. Nenitzescu; M. Gavat; G. Mateescu, J. Chem. Soc., 1961, 3564. 5) P.F.G. Praill; A.L. Whitear, J. Chem. Soc., 1961, 3573.

COMMENTS :

107

BALBIANO OLEFIN OXIDATION EXAMPLE :

H3C

H

H3C

H

+

CH3 (AcO)2Hg H2O

H3C

H3C

CH3

O

O

MECHANISM :

ROH

+ Hg(OAc)2

H3C

H3C

HgOAc OR

H3C

Pd OR Cl

Li2PdCl4 THF, 25 oC

Cl

CH3

H3C O

DISCONNECTION :

R

R1

+

R2

O

R3 O

R2

R

R3

R1

NOTES : Mercuric acetate oxidises olefins in aqueous solution. Mercuric acetate followed by palladium dichloride is also used to oxidise olefins. See also Hofmann – Sand, Kutscheroff – Denigès and Tsuji – Wacker reactions.

REFERENCES : 1) L. Balbiano; V. Paolini, Ber. Dtsch. Chem. Ges., 1902, 35, 2994. 2) L. Balbiano, Gazz. Chim. Ital., 1906, 36/1, 238. 3) L. Balbiano; V. Paolini, Gazz. Chim. Ital., 1906, 36/1, 253. 4) G.T. Rodeheaver; D.F. Hunt, J. Chem. Soc., Chem. Commun., 1971, 818. 5) D.F. Hunt; G.T. Rodeheaver, Tetrahedron Lett., 1972, 13, 3595.

108

COMMENTS :

BALBIANO PYRAZOLE SYNTHESIS EXAMPLE :

O Cl

+

CH3 N N

CH3 N H NH2

MECHANISM :

R H N

H Cl O

Cl

H2N N R

NH2 - H+ HO

H+ R N H NH

Cl

H

R N

N H

N Heat - H2O, - H+

HO

HO

R N

DISCONNECTION : R N N

R

O Cl

+

N NH2 H

NOTES : Epichlorohydrin and hydrazines react to form pyrazolidines, which on heating dehydrate to give pyrazoles. The reaction can also be done in the presence of zinc chloride. See also Knorr pyrazole and von Pechmann reactions.

REFERENCES : 1) L. Balbiano, Gazz. Chim. Ital., 1887, 17, 177. 2) L. Balbiano, Ber. Dtsch. Chem. Ges., 1890, 23, 1452.

109

3) R. Stoermer; O. Martinsen, Liebigs Ann. Chem., 1907, 352, 322. 4) I.L. Finar; K.E. Godfrey, J. Chem. Soc., 1954, 2293.

COMMENTS :

BALL – GOODWIN – MORTON OXIDATION EXAMPLE :

OH

H

MnO2 Petrol

O

MECHANISM :

MnO2

MnO2 O

OH

OH coordination

adsorption

H

OH Mn3+ OH

O

O

desorption H

MnO + H2O + O

DISCONNECTION : R2

R2

R

H R1

O

OH Mn2+ OH

R R3 = H, Alk

110

R3 R1

OH

O Mn4+ OH

NOTES : The oxidation of primary or secondary allylic alcohols in an inert solvent (light petroleum) by manganese dioxide, yields the corresponding aldehyde or ketone. The method has been extended to acetylenic alcohols, heterocyclic alcohols, steroidal allylic alcohols and to aromatic alcohols. The mechanism is most probably radical in nature, but an ionic mechanism has been proposed. See also Anelli, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs,

David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : March : 1167 Smith : 245 Smith 2nd : 213 Houben – Weyl : 7/1, 178

1) S. Ball; T.W. Goodwin; R.A. Morton, Biochem. J., 1948, 42, 516. 2) N.L. Wendler; H.L. Slates; M. Tischler, J. Am. Chem. Soc., 1949, 71, 3267. 3) T.K. Hall; P.R. Story, J. Am. Chem. Soc., 1967, 89, 6759. 4) E.J. Corey; N.W. Gilman; B.E. Ganem, J. Am. Chem. Soc., 1968, 90, 5616. 5) I.M. Goodman, J. Org. Chem., 1969, 34, 3289. 6) G. Struve; S. Seltzer, J. Org. Chem., 1982, 47, 2109. 7) B.M. König; W. Friedrichsen, Tetrahedron Lett., 1987, 28, 4279. 8) X.Y. Xiao; G.D. Prestwich, Synth. Commun., 1990, 20, 3125. 9) J.A. Haugan, Tetrahedron Lett., 1996, 37, 3887. 10) I. Hemeon; N.W. Barnett; N. Gathergood; P.J. Scammells; R.D. Singer, Aust. J. Chem., 2004, 57, 125.

COMMENTS :

111

BALLY – SCHOLL SYNTHESIS EXAMPLE :

O 1) Cu, H2SO4 2) H2SO4 glycerol

O

O

MECHANISM :

O

O Cu, H2SO4 HO CH2OH CHOH CH2OH

CH2

CHO +

H2SO4 - 2 H2O

O

O

- H2O O

O

DISCONNECTION :

R1 R

O

R2

R2 R = H, Alk, Ar R1 = H, Alk, Ar R2 = H, Ar

112

O

H

NOTES : The synthesis of mesobenzanthrones from glycerol or its derivatives and sulfuric acid on anthraquinones or anthranols. The yields are normally low due to the strong acidic conditions used. See also Haworth and Skraup reactions.

REFERENCES : Smith : 1330 Smith 2nd : 1094, 1101 Org. Synth. : 14, 4 Org. Synth. Coll. Vol. : 2, 62

1) O. Bally, Ber. Dtsch. Chem. Ges., 1905, 38, 194. 2) O. Bally; R. Scholl, Ber. Dtsch. Chem. Ges., 1911, 44, 1656. 3) H. Meerwein; J. Klinz, J. Prakt. Chem., 1918, 97, 235. 4) F.G. Baddar; F.L. Warren, J. Chem. Soc., 1938, 401.

COMMENTS :

BALSOHN ADDITION EXAMPLE :

+ 6 H2C CH2

AlCl3

MECHANISM : CH3 H

CH3

H3C H

Cl H+

AlCl3

113

H3C Cl

CH3 Cl

DISCONNECTION :

R

R2

R1

R3

R2

R

R3

R1

R

R2

R1

R3

+

NOTES : The reaction between an olefin or compounds which under the reaction conditions would be expected to react like olefins and benzene (or another isocyclic compound) to give a hexaalkylbenzene. Many groups are tolerated on the aromatic ring. Acids or Lewis acids are normally used as catalysts. The mechanism is similar to the Friedel – Crafts mechanism. See also Friedel – Crafts reaction.

REFERENCES : Org. Synth. : 32, 90 Org. Synth. Coll. Vol. : 4, 702

1) M. Balsohn, Bull. Soc. Chim. Fr., 1879, 31, 539. 2) W.M. Potts; L.L. Carpenter, J. Am. Chem. Soc., 1939, 61, 663. 3) W.S. Calcot; J.M. Tinker; V. Weinmayr, J. Am. Chem. Soc., 1939, 61, 1010. 4) l. Schmerling; V.N. Ipatieff, J. Am. Chem. Soc., 1945, 67, 1862.

COMMENTS :

114

BALZ – SCHIEMANN REACTION EXAMPLE :

NH2

F

1) HNO2 2) HBF4 heat toluene

MECHANISM :

HO N

H O

HBF4

NH2

O N O H

N O - H2O

N O N H

H+

N N

- H2O BF4

N

H+ O N N OH

H

F

F BF3

heat - N2

- BF3

DISCONNECTION :

F

NH2

NOTES : A two-stage preparation of aryl fluorides involving the preparation of a dry diazonium borofluoride by the interaction of an amine, nitrous acid and fluoroboric acid followed by the thermal decomposition of the diazonium borofluoride. See also Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulfinic acid,

Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

115

REFERENCES : March : 671 Smith – March : 875 Houben – Weyl : 5/3, 214; E6b, 1162; E10a, 705; E10/b1, 249; E16a, 1091; E18, 264 Org. React. : 5, 193 Org. Synth. : 43, 12 Org. Synth. Coll. Vol. : 2, 299

1) G. Balz; G. Schiemann, Ber. Dtsch. Chem. Ges., 1927, 60, 1186. 2) R. Stephens; J.C. Tatlow, J. Chem. Soc., Quat. Rev., 1961, 15, 54. 3) K.G. Rutherford; W. Redmond; J. Rigamonti, J. Org. Chem., 1961, 26, 5149. 4) D.E. Horning; D.A. Ross; J.M. Muchowski, Can. J. Chem., 1973, 51, 2347. 5) M. Matsumoto; Y. Ishida; N. Hatanaka, Heterocycles, 1986, 24, 1667. 6) N. Yoneda; T. Fukuhara; T. Kikuchi; A. Suzuki, Synth. Commun., 1989, 19, 865. 7) D.J. Milner, Synth. Commun., 1992, 22, 73. 8) K.K. Laali; V.J. Gettwert, J. Fluorine Chem., 2001, 107, 31. 9) Y. Nishiyama; S. Ishizuka; K. Kurita, Tetrahedron Lett., 2001, 42, 8797. 10) R. Gronheid; G. Lodder; T. Okuyama, J. Org. Chem., 2002, 67, 693.

COMMENTS :

BAMBERGER – GOLDSCHMIDT SYNTHESIS EXAMPLE :

N OH

P2O5

116

N

+

H3C

N N H

CH3

N

O

NH2

H

N

N

H

NH CH3

Et +

HN

HN HN

HN

NH2

NH2

CH3 NH Et

MECHANISM :

H+

N OH

P2O5

N

N

- H2O Beckmann rearrangement H2O

N OH2

H

N

- H2O

OH

DISCONNECTION :

R

N OH

R1

N N

R

N

N

O

NH2 +

R

N N R

R1

NH HN HN

R NH

R NH2

R1

117

R1 +

HN

HN NH2

H

NOTES : Styryl oximes on treatment with phosphorous pentoxide undergo a Beckmann rearrangement followed by internal condensation to yield isoquinolines. Dihydroisoquinolines may be obtained from phenylethyl oximes. Besides the mentioned reaction other sources name the synthesis of 1,2,4-triazines and 1,3,5-triazines the Bamberger –

Goldschmidt reaction (H. Goldschmidt), I have included two examples. See also Beckmann rearrangement, Bischler – Napieralski, Bobbit, Bruckner, Larock indole, Pictet – Gams, Pictet – Sprengler, Pomeranz – Fritsch, Simchen and Schlitter – Müller ring-closure reactions.

REFERENCES : 1) H. Goldschmidt; Y. Rosell, Ber. Dtsch. Chem. Ges., 1890, 23, 487. 2) E. Bamberger; W. Dieckmann, Ber. Dtsch. Chem. Ges., 1892, 25, 534. 3) E. Bamberger; C. Goldschmidt, Ber. Dtsch. Chem. Ges., 1894, 27, 1954. 4) C. Goldschmidt, Ber. Dtsch. Chem. Ges., 1894, 27, 2795. 5) C. Goldschmidt, Ber. Dtsch. Chem. Ges., 1895, 28, 1532. 6) R.H. Manske, Chem. Rev., 1942, 30, 145.

COMMENTS :

BAMBERGER – HEY DIARYL SYNTHESIS EXAMPLE :

NH2

1) CH3COOH 2) NOCl, CH3COONa 3) C6H6

MECHANISM :

Ar NH2

- HNO2

H

CH3COOH - H2O

ON

Ar N

CH3 O

Ar N

H N2O3 (NOCl + CH3COONa)

CH3 O

Ar - N2, - CH3COO

118

Ar1H

Ar N

O O N N O O

Ar

Ar1

CH3

DISCONNECTION : Ar

Ar1

Ar

NH2 + Ar1H

Ar = C6H5, C6H4Cl, C6H4Br, C6H4OAlk, C6H4CN, C6H4Ph Ar1 = Ph, C6H4CH3, C6H4NO2, C6H4COOCH3, C6H4OAlk

NOTES : Acylarylnitrosamines react with liquid aromatic hydrocarbons to yield diaryls. The mechanism is radical in nature. See also Gomberg – Bachman – Hey reaction.

REFERENCES : Org. React. : 2, 224

1) E. Bamberger, Ber. Dtsch. Chem. Ges., 1897, 30, 366. 2) W.S.M. Grieve; D.H. Hey, J. Chem. Soc., 1934, 1797. 3) D.R. Angood; G.H. Williams, Chem. Rev., 1957, 57, 123.

COMMENTS :

BAMBERGER ARYLNITRAMINES REARRANGEMENT EXAMPLE :

H

N

NO2

NH2 NO2 aq. H2SO4

119

MECHANISM :

H

N

NO2

H

H

N

N NO2

H H - NO2 H

N

H NO2

N

H NO2

H H+

DISCONNECTION :

H

N

H

H

N

NO2

NO2 R

R

NOTES : Arylnitramines undergo rearrangement on treatment with aqueous strong acids or with hydrogen chloride in organic solvents or with a mixture of glacial acetic acid and sulfuric acid to give mainly o-nitranilines and a small amount of pnitranilines.

REFERENCES : 1) E. Bamberger; K. Landsteiner, Ber. Dtsch. Chem. Ges., 1893, 26, 482. 2) E. Bamberger, Ber. Dtsch. Chem. Ges., 1899, 32, 1809. 3) P.H. Gore, J. Chem. Soc., 1957, 1437.

COMMENTS :

120

BAMBERGER BENZOTRIAZINE SYNTHESIS EXAMPLE :

Me

N NH2 1) HNO2 2) OMe NH2 N

N

N

OMe

COOH H2SO4

MECHANISM : H+ N NH2

HNO2

N N

N - H2NAr

N

R

H N

HN N

Ar

H

- H+

N

R N

DISCONNECTION :

N R

R1

N R

N

N NH2 R = H, CH3, Br, OCH3 R1 = H, CH3, Ph, COCH3, CH2Ph

+

NOTES : Benzotriazine is synthesised from a hydrazone and aryldiazoamine salts.

REFERENCES : 1) E. Bamberger; E. Wheelwright, Ber. Dtsch. Chem. Ges., 1892, 25, 3201. 2) E. Bamberger; J. Lorenzen, Ber. Dtsch. Chem. Ges, 1892, 25, 3539. 3) E. Bamberger; H. Witter, Ber. Dtsch. Chem. Ges, 1893, 26, 2786. 4) E. Bamberger; R. Padova; E. Ormered, Liebigs Ann. Chem., 1925, 446, 260.

121

R1

H N

Ar

Ar R N

COMMENTS :

BAMBERGER IMIDAZOLE REARRANGEMENT EXAMPLE :

O H N

N

H H N

Ph CO2Et

Cl

O N

Ph

Ph H CO2Et

O NaHCO3

MECHANISM : R

R O

Ph HN

HN Ph

CF3COOH - H2O

O

O

Ph

NH O H+

H+ O

O

CF3

F3C

R N

N

Ph

Ph

R

R Ph

N

O HO

Ph

Ph

N

N

O HO

CF3 O

N

Ph O

R

R Ph

N CF3

CF3

- PhCOOH

- PhCOOH

N

N

O

N Ph

122

O

CF3 O

HN O

Ph

DISCONNECTION :

Ph

H R N

R

Ph H N

N

O

O R1

R2

R1

N R2

NOTES : The cleavage of imidazoles with acid chlorides or similar compounds to enediamides, 2-substituted imidazoles are formed if the enediamides are cyclised again.

REFERENCES : 1) E. Bamberger; B. Berlé, Liebigs Ann. Chem., 1893, 273, 342. 2) H. Kimoto; K.L. Kirk; L.A. Cohen, J. Org. Chem., 1978, 43, 3403. 3) M.E. Grace; M.J. Loosemoore; M.L. Semmel; R.F. Pratt, J. Am. Chem. Soc., 1980, 102, 6784. 4) J. Altman; N. Shoef; M. Wilchek; A. Warshawsky, J. Chem. Soc., Perkin Trans. 1, 1984, 59.

COMMENTS :

BAMBERGER REARRANGEMENT EXAMPLE : H

N

OH

NH2

1) H+ 2) H2O

123

OH

MECHANISM :

H

N

H

OH

N

H O H

H

NH

N H

H H+

- H2O H+ NH

NH

NH2

HX, - H+ H X

X

DISCONNECTION : H

NH2

N

OH

+ HX X

HX = H2O, HF, HCl, HBr, HO3SC6H5, CH3OH

NOTES : Arylnitramines undergo rearrangement on treatment with aqueous strong acids or with hydrogen chloride in organic solvents or with a mixture of glacial acetic acid and sulfuric acid to give mainly o-nitranilines. The reaction seems to resemble the Hoffman – Martius (Reilly – Hickingbottom) reaction. However, while the Hoffman – Martius reaction follows an electrophilic mechanism, the Bamberger reaction seems to follow a nucleophilic mechanism. See also Hoffman – Martius (Reilly – Hickingbottom) and Orton reactions.

REFERENCES : March : 674 Smith – March : 878 Houben – Weyl : 10/1, 1249; E8a, 144; E19c, 382 Org. Synth. : 67, 187 Org. Synth. Coll. Vol. : 8, 16

1) E. Bamberger, Ber. Dtsch. Chem. Ges., 1894, 27, 1347. 2) E.D. Hughes; C.K. Ingold, J. Chem. Soc., Quat. Rev., 1952, 6, 45. 3) J.C. Hardy; M. Venet, Tetrahedron Lett., 1982, 21, 1255. 4) J.C. Fishbein; R.A. McClelland, J. Am. Chem. Soc., 1987, 109, 2824. 5) A. Zoran; O. Khodzhaev; Y. Sasson, Chem. Commun., 1994, 2239. 6) M. Novak; J. Lin, J. Org. Chem., 1999, 64, 6032.

124

7) D. Groskova; M. Stolcova; M. Hronec, Catal. Lett., 2000, 69, 113.

COMMENTS :

BAMFORD – STEVENS REACTION (CAGLIOTI – SHAPIRO REACTION) EXAMPLE :

HO

LiAlH4, THF

CH3 N

N H

HO CH3

Ts

MECHANISM : Dianion mechanism (Shapiro) :

H

N

Ts N

N N Ts H

2 RLi

Li+ N N

- N2 Li

125

H2O

H

Carbene mechanism :

N

H

Ts N

N

H

N

Ts

- Ts-

N N

B aprotic H

C

protic

- N2

H

- N2

H

N N

DISCONNECTION :

O

N2 R

R

R1

R1

R R

O R1

R1

NOTES : The major difference between the Caglioti – Shapiro and the Bamford – Stevens reaction is the use of the base. In the Caglioti – Shapiro reaction two equivalents of base (RLi) are used, and the alkene formed is generally the lesssubstituted one. With other bases, the alkene is often the more-substituted one. When sodium and ethylene glycol are used as base, a carbene mechanism is probable; whereas with other bases, the anion or carbene mechanisms may be involved. See also Cava rearrangement.

REFERENCES : March : 1020 Smith – March : 1335 Smith : 1454 Smith 2nd : 1200 Houben – Weyl : 5/1b, 698; E5, 148; E8b, 492; E8d, 83; E8d, 83; E11, 622; E14b, 606, 626, 1009, 1140, 1330; E19b, 225, 610, 675 Org. React. : 23, 405; 39, 1 Org. Synth. : 51, 66 Org. Synth. Coll. Vol. : 6, 172

126

1) W.R. Bamford; T.S. Stevens, J. Chem. Soc., 1952, 4735. 2) R. Caglioti, Tetrahedron Lett., 1962, 3, 1261. 3) R.H. Shapiro, Tetrahedron Lett., 1968, 9, 345. 4) A. Nikon; P.S. Zurer, J. Org. Chem., 1981, 46, 4685. 5) R.M. Adlington; A.G.M. Barrett, Acc. Chem. Res., 1983, 16, 55. 6) A. Nickon; A.G. Stern; M.C. Ilao, Tetrahedron Lett., 1993, 34, 1391. 7) K. Maruoka; M. Oishi; H. Yamamoto, J. Am. Chem. Soc., 1996, 118, 2289. 8) K.K. Olmstead; A. Nickon, Tetrahedron, 1999, 55, 7389. 9) M.S. Addie; R.J.K. Taylor, Arkivoc, 2000, 1, 660. 10) S. Chandrasekhar; G. Rajaiah; L. Chandraiah; D.N. Swamy, Synlett, 2001, 1779. 11) J.A. May; B.M. Stolz, J. Am. Chem. Soc., 2002, 124, 12426.

COMMENTS :

BANERT CASCADE REACTION EXAMPLE :

HO Cl

NaN3 dioxane-water 3:1 80 oC, 8 h

H N N N

N3

HO

MECHANISM :

N3

X R

+ NaN3

R R1

N

R1 sigmatropic shift R

N N C R1

N

R1

N N

H N N N

Nuc: R

R

127

Nuc R1

DISCONNECTION : H N N N

R2

X + NaN3

R R1

R

R2 = OH, RO, N3, RS

R1

NOTES : The Banert cascade is an organic reaction in which a NH-1,2,3-triazole is prepared from a propargyl halide or sulphate and sodium azide in a dioxane-water mixture at elevated temperatures. This cascade reaction is unusual because it consists of two consecutive rearrangement reactions. The starting material is prepared from propargyl chloride and an aldehyde or ketone such as acetaldehyde. In the first step a azido compound is formed in situ in a nucleophilic displacement of chloride by the azide ion. A 3,3-sigmatropic reaction takes place between the azide and the alkyne to the allenyl azide. This allene rearranges to the triazafulvene in a 1,3-dipolar cycloaddition. The exocyclic alkene in this intermediate is very electrophilic because the triazole group has a dipole moment of 5 Debye. The reaction sequence concludes with nucleophilic attack of a nucleophile or second azide ion on this alkene with more double bond rearrangements and proton abstraction from a proton source. See also Huisgen reaction.

REFERENCES : 1) K. Banert, Chem. Ber., 1989, 122, 911. 2) K. Banert, Chem. Ber., 1989, 122, 1175. 3) K. Banert, Chem. Ber., 1989, 122, 1963. 4) T. Harrison; A.P. Owens; B.J. Williams; C.J. Swain; A. Williams; E.J. Carlson; W. Rycroft; F.D. Tattersall; M.A. Cascieri; G.G. Chicchi; S. Sadowski; N.M.J. Rupniak; R.J. Hargreaves, J. Med. Chem., 2001, 44, 4296. 5) J.C. Loren; K.B. Sharpless, Synthesis, 2005, 1514.

COMMENTS :

128

BARBIER – LOCQUIN – WIELAND DEGRADATION EXAMPLE : COOH

H3C

H3C OH

OH COOH

H3C

H3C

1) H+, EtOH 2) xs PhMgBr 3) H+ 4) CrO3

HO

HO

MECHANISM :

H

O

R H

R1

R

H Ph 1) PhMgX 2) H+

OH

R H R1

- H2O

H

Ph

H

CrO3

R1

O +

R H

OH

Ph

R1 O

DISCONNECTION : O R

H

O

H

R1(H)

R

OH

NOTES : The step-wise degradation of a carboxylic acid in which one carbon atom is removed at the time, by use of alternate

Grignard reactions and oxidation of the resulting carbinols. The presence of a branch in the side chain is demonstrated by the formation of a ketone. The reaction is the oxidative cleavage of a 1,1-diphenyl alkene. See also

Gallagher – Hollander, Hoehn – Mason, Krafft, Miescher, Trost oxidative decarboxylation and Wieland – Dane reactions.

REFERENCES : March : 1182 Smith – March : 1526 Smith : 303 Smith 2nd : 266, 589 Houben – Weyl : E3, 528 Org. Synth. : 24, 38 Org. Synth. Coll. Vol. : 3, 234

129

1) H. Wieland, Ber. Dtsch. Chem. Ges., 1912, 45, 484. 2) P. Barbier; R. Locquin, C.R. Séances Acad. Sci., 1913, 156, 1443. 3) H.K. Black; B.C.L. Weedon, J. Chem. Soc., 1953, 1785. 4) J.R. Dias; R. Ramachandra, Tetrahedron Lett., 1976, 17, 3685. 5) C.S. Subramaniam; P.J. Thomas; V.R. Mamdapur; M.S. Chadha, Synthesis, 1978, 468.

COMMENTS :

BARBIER REACTION EXAMPLE :

I

O CN Mg

MECHANISM :

R X + Pb

R1 R2

single electron transfer

R X + PbI

R1 O

R Pb X

R2

R Pb X

O R Pb X

130

R1

OPbX R2 R

DISCONNECTION : H HO

O

R1 R

H R

NOTES : This reaction is similar to the Grignard reaction but is carried out by adding the halogen compound to a mixture of the second reactant in diethyl ether solution with magnesium or in modern variants zinc, lead, indium or samarium diiodide. Secondary reactions are avoided with this procedure when applied to an unsaturated alkyl halide. The mechanism of the organometallic reagent is identical to the formation of a Grignard reagent. The pathway can be either concerted (as shown) or radical stepwise. Luche introduced a similar reaction between allylic halides and ketones or aldehydes in the presence of zinc in aqueous media sometimes known as the Luche allylation. See also

Grignard – Cologne, Imamoto alkylation and Kagan – Molander reactions.

REFERENCES : Smith – March : 1205 Smith : 685 Smith 2nd : 580

1) P. Barbier, C.R. Séances Acad. Sci., 1899, 128, 110. 2) C. Blomberg; F.A. Hartog, Synthesis, 1977, 18. 3) P. Bauer; G. Molle, Tetrahedron Lett., 1978, 19, 4853. 4) E.C. Ashby, Pure Appl. Chem., 1980, 52, 545. 5) T.M. Williams; R. Crumbie; H.S. Mosher, J. Org. Chem., 1985, 50, 91. 6) C.J. Li, Chem. Rev., 1993, 93, 2023. 7) G.A. Molander; C.R. Harris, J. Am. Chem. Soc., 1996, 118, 4059. 8) C.-J. Li, Tetrahedron, 1996, 52, 5643. 9) J.-Y. Zhou; Y. Jia; G.-F. Sun; S.-H. Wu, Synth. Commun., 1997, 27, 1899. 10) S.H. Kim; E.-H. Han, Tetrahedron Lett., 2000, 41, 6479. 11) J.S. Yadav; B.V.S. Reddy; P.M. Reddy; Ch. Srinivas, Tetrahedron Lett., 2002, 43, 5185. 12) Z. Zha; Z. Xie; C. Zhou; M. Chang; Z. Wang, New. J. Chem., 2003, 27, 1297. 13) H.B. Kagan, Tetrahedron, 2003, 59, 10351. 14) K. Smith; S. Lock; G.A. El–Hiti; M. Wada; N. Miyoshi, Org. Biomol. Chem., 2004, 2, 935.

COMMENTS :

131

BARDHAN – SENGUPTA PHENANTHRENE SYNTHESIS EXAMPLE :

Br

O + COOH

1) KOH 2) Na 3) P2O5 4) Se, heat

MECHANISM : COOR ROOC

Br +

O

Na

OH

O

KOH - KBr

1) saponification 2) decarboxylation

O

Se, heat

P2O5 - H2O

DISCONNECTION :

Br

NOTES : The cyclodehydration of 2-β-phenylethylcyclohexanols gives octahydrophenanthrenes. The method can also be applied to cyclopentanols. See also Bogert – Cook and Darzens synthesis of tetralin reactions.

REFERENCES : Smith : 1330 Smith 2nd : 1095

132

1) J.C. Bardhan; S.C. Sengupta, J. Chem. Soc., 1932, 2520. 2) R.P. Linstead, Ann. Rep. Prog. Chem., 1936, 33, 319. 3) W.B. Renfrow; A. Renfrow; E. Shoun; C.A. Sears, J. Am. Chem. Soc., 1951, 73, 317. 4) J.C. Bardhan; R.N. Adhya; K.C. Bhattacharyya, J. Chem. Soc., 1956, 1346.

COMMENTS :

BARGELLINI REACTION EXAMPLE :

H3C

NH2 OH +

H3C

H3C

O H3C

H N

H3C

CH3

CH3 CH3

NaOH, CHCl3 DCM, BnEt3NCl

O

O

MECHANISM :

O R1 CHCl3

R2 Cl

R2

Cl

O HO- H2O

R1 Cl

CCl3 HO

R3 NH2 OH R1 R4

O R2

Cl

Cl - HCl

Cl

HN

O

R3

R4 R3 R2

R4 - HCl

H N

R4

R1 R2

X

O

X = O, NR

133

R3 NH2 OH R4

O +

R1

R2

R1 R2

O

R1

DISCONNECTION :

R3

H N

O

NOTES : Hindered piperazinones and morpholinones are synthesised from ketones and substituted 2-amino-1-propanols.

REFERENCES : 1) G. Bargellini, Gazz. Chim. Ital., 1906, 36, 329. 2) J.T. Lai, J. Org. Chem., 1980, 45, 754. 3) J.T. Lai, Synthesis, 1981, 40. 4) J.T. Lai, Synthesis, 1984, 122. 5) J.T. Lai, Synthesis, 1984, 124. 6) S.D. Rychnovsky; T. Beauchamp; R. Vaidyanathan; T. Kwan, J. Org. Chem., 1998, 63, 6363.

COMMENTS :

BARGELLINI RING-CLOSURE EXAMPLE : O

Ph Ph

O

Ph + OH

O

Na+

(CH3CO)2O

O

O

MECHANISM :

O

Ph

O Ph

Ph

Ph Tautomerisation

OH HO

Ph O

- H2O

O O H

134

Ph

O

O

DISCONNECTION : R

O Ph

O

R

O

HO

Ph

+ O

OH

NOTES : The production of 3-phenylcoumarins from o-hydroxyacetophenones, an acid anhydride and sodium phenyl acetate. This reaction is a variation of the von Kostanecki (Allan – Robinson) chromone reaction. See also von Kostanecki (Allan – Robinson) and Perkin reactions.

REFERENCES : G. Bargellini, Atti Reale Accad. Naz. Lincei, Rend., 1925, 2, 178.

COMMENTS :

BARGER DEMETHYLATION EXAMPLE :

HO

O H2C

1) SOCl2 2) H2O 3) H+

O

HO

MECHANISM :

O

O H2C O

SOCl2

O

Cl2C

O C H2O - 2 HCl

O

HO HO

135

O

H+

DISCONNECTION : HO

O H2C O

HO

NOTES : Compounds containing the methylenedioxy-group are transformed by treatment with thionyl chloride or phosphorous pentachloride and water into the cyclic carbonate, which is readily hydrolysed to the corresponding diol derivative.

REFERENCES : 1) G. Barger, J. Chem. Soc., 1908, 93, 563. 2) G. Barger; A.J. Ewins, J. Chem. Soc., 1908, 93, 735. 3) G. Barger, J. Chem. Soc., 1908, 93, 2081.

COMMENTS :

BARRY REACTION EXAMPLE :

OH OH HO HO

O

HO O OH H

OH

O

O OH

H

1) HIO4 2) PhNH2NH2 AcOH

136

HO HO

O OH

O

H

MECHANISM : OH OH

OH O

HO

HO HO

OH

H

OH H

HIO4 - HCOOH

H

O

OH

PhNH2NH2 AcOH

O

OH HO

O

O

O

H O

HO HO

H

H

H

N

N

Ph N N Ph

N

+

OH H

H

Ph N

O

O

H O H O

O

N

N Ph

+

OH H

OH

DISCONNECTION :

N R

N

O

Ph R

R1

R1

+ PhNHNH2

NOTES : The main reaction is between a carbonyl compound and phenylhydrazine. With 1,3-linked polysaccharides: This reaction is based on the fact that an acetal of glyoxal can be converted by phenylhydrazine into glyoxalosazone with the liberation of the alcohol. The oxypolysaccharide is warmed with phenylhydrazine in acetic acid solution. This produces a rapid separation of glyoxalosazone and the polysaccharide – the chain length of which is now shorter by one hexose unit – may be readily recovered. The periodic acid-phenylhydrazine treatment may be repeated on the new terminal non-reducing unit, so that the sugar units may be eliminated one by one from the non-reducing end of a polysaccharide chain. With polysaccharide composed of sugar residues some of which contain α-glycol groupings: Periodate oxidation followed by treatment with the phenylhydrazine reagent causes fragmentation of the macromolecule and provides polysaccharide residues, which may be examined by conventional methods. See also

Djerassi – Rylander, Fischer, Hudson – Hirst, Malaprade and Ohle reactions.

REFERENCES : 1) V.C. Barry, Nature, 1943, 152, 537. 2) S.A. Barker; E.J. Bourne; M. Stacey, J. Chem. Soc., 1953, 3084. 3) V.C. Barry; J.E. McCormick; P.W.D. Mitchell, J. Chem. Soc., 1954, 3692. 4) V.C. Barry; P.W.D. Mitchell, J. Chem. Soc., 1954, 4020.

COMMENTS :

137

BART (BART – SCHMIDT) REACTION EXAMPLE :

O As ONa ONa

N N + Na3AsO3 Cl

DISCONNECTION :

O X As ONa ONa

X NH2 X = Aromatic, anthraquinone, heterocyclic

NOTES : The formation of an arylarsonic acid from a diazonium salt and an arsenic compound (alkali arsenite, antimony chloride in the Bart – Schmidt reaction), preferably in the presence of a copper salt or another metal. There is a modification introduced by Scheller (primary aromatic amines are diazotised in the presence of arsenious chloride and a trace of cuprous chloride) and the Starkey modification (The use of the more stable diazonium borofluoride). The Schmidt modification uses a neutral medium and no catalysts. See also Béchamp, Gattermann diazo,

Rosenmund, Sandmeyer diazonium and Scheller reactions.

REFERENCES : Org. React. : 2, 415 Org. Synth. : 15, 59; 26, 60 Org. Synth. Coll. Vol. : 2, 494; 3, 665

1) H. Bart, German Patent., 1910, 250264. 2) H. Schmidt, Liebigs Ann. Chem., 1920, 421, 174. 3) H. Bart, Liebigs Ann. Chem., 1922, 429, 159. 4) E. Scheller, British Patent, 1925, 261026. 5) G.O. Doak, J. Am. Chem. Soc., 1940, 62, 167. 6) A.W. Ruddy; E.B. Starkey; W.H. Hartung, J. Am. Chem. Soc., 1942, 64, 828. 7) F.E. Ray; R. Garascia, J. Org. Chem., 1950, 15, 1233. 8) W.A. Cowdrey; D.S. Davies, J. Chem. Soc., Quat. Rev, 1952, 6, 363.

138

COMMENTS :

BARTLETT – CONDON – SCHNEIDER REACTION EXAMPLE : CH3

CH3 H3C

HCl

Cl CH3

H3C

+

CH3 CH3

H3C

Cl

MECHANISM :

D

O

O

S

CH3

OD

O

D

H3C

D

H3C

OD

O

S

O

OD

H2C CH2D

+

H

O

O

S

OD

O

H3C or

CH3 D

H3C

S

O

O

H

O

O +

H3C CHD

H O

O S

O

+

H

O

O S

O

H3C

OD

The process will repeat itself until a fully deuterated tert-butyl cation is formed CD3 D3C

CD3

The intermolecular hydride transfer takes place between the cation and the proton of the tertiary position of the isobutane.

CD3 D3C

CD3

CH3 H CH3 CH3

CD3 D3C CD3 H

139

OD

CH3

CH3

CH3 H3C

HCl

H3C

H3C

Cl

Cl H - shift

CH3

H3C

H3C

Cl

CH3

Cl

NOTES : The intra- and intermolecular exchange of halogen and hydrogen atoms between organic halides and alkanes.

REFERENCES : 1) P.D. Bartlett; F.E. Condon; A. Schneider, J. Am. Chem. Soc., 1944, 66, 1531. 2) B.E. Burgert, Angew. Makromol. Chem., 1968, 4, 81.

COMMENTS :

BARTOLI INDOLE SYNTHESIS EXAMPLE :

NO2

+3

MgCl

THF, - 70 oC

Br

Br

140

N H

MECHANISM :

O

R

N O

O BrMg

R

N O

MgBr

O

N

O

R

MgBr

MgBr H

BrMg

R

O [3,3]-sigmatropic N rearrangement MgBr

OMgBr

O

N

N MgBr

R

R

H

- C2H4 R

OMgBr N MgBr

H+ R

N H

DISCONNECTION :

R

R

R1

R2 R2

Br

+

N H

R1

MgBr

NO2 Br

NOTES : This indole synthesis is the treatment of an ortho-substituted nitro-aromatic compound with 3 equivalents of vinylmagnesium bromide or chloride. Bartoli and Rosini showed that nitroarenes under similar conditions gave after reductive C-alkylation ortho alkyl anilines. The mechanism of the reaction is not clear in every detail. See also von

Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 384

141

1) G. Bartoli; G. Rosini, Synthesis, 1976, 270. 2) G. Bartoli, Acc. Chem. Res., 1984, 17, 109. 3) G. Bartoli; G. Palmieri; M. Bosco; R. Dalpozzo, Tetrahedron Lett., 1989, 30, 2129. 4) G. Bartoli; M. Bosco; R. Dalpozzo; G. Palmieri; E. Marcantoni, J. Chem. Soc., Perkin Trans. 1, 1991, 2757. 5) G.W. Gribble, Cont. Org. Syn., 1994, 1, 145. 6) G.M. Carrera, jr., G.S. Sheppard, Synlett, 1994, 93. 7) A.P. Dobbs; K. Jones; K.T. Veal, Tetrahedron, 1998, 54, 2149. 8) A.P. Dobbs; M. Voyle; N. Whittal, Synlett, 1999, 1594. 9) D. Harrowven; D. Lai; M.C. Lucas, Synthesis, 1999, 1300. 10) G.W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045. 11) A.P. Dobbs, J. Org. Chem., 2001, 66, 638. 12) K. Knepper; S. Bräse, Org. Lett., 2003, 5, 2829. 13) R. Dalpozzo; G. Bartoli, Curr. Org. Chem., 2005, 9, 163.

COMMENTS :

BARTON – KELLOGG OLEFINATION EXAMPLE :

Ph

NH2

Ph

CH3

Ph

CH3

N Ph

1) H3C

CH3

S 2) Pb(OAc)4 3) Ph3P

142

MECHANISM :

O

H H N N

2

NH2NH2 H2S

Pb(OAc4)

S

N N heat, P(R)3 - N2 R = Bu, Ph, OEt, NEt3

S

n

S

BuLi

DISCONNECTION :

R

O

S

R

or R1

R

R1

R1

R

R1

NOTES : The olefin synthesis by two-fold extrusion of nitrogen and sulfur from a Δ3-1,3,4-thiadiazoline intermediate. Particularly applicable to the synthesis of moderately hindered tetra-substituted ethylenes. See also Corey – Kwiatkowski,

Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Smiles rearrangement, Still – Gennari, Takeda, Tebbe and Wittig olefination reactions.

REFERENCES : 1) D.H.R. Barton; B.J. Willis, J. Chem. Soc., Chem. Commun., 1970, 1225. 2) D.H.R. Barton; E.H. Smith; B.J. Willis, J. Chem. Soc., Chem. Commun., 1970, 1226. 3) R.M. Kellogg; S. Wassenaar, Tetrahedron Lett., 1970, 11, 1987. 4) D.H.R. Barton; B.J. Willis, J. Chem. Soc., Perkin Trans. 1, 1972, 305. 5) J. Buter; S. Wassenaar; R.M. Kellogg, J. Org. Chem., 1972, 37, 4045. 6) M.D. Bachi; O. Goldberg; A. Gross, Tetrahedron Lett., 1978, 19, 4167. 7) J.E. McMurry; G.J. Haley; J.R. Matz; J.C. Clardy; G. van Duyne; R. Gleiter; W. Schäfer; D.H. White, J. Am. Chem. Soc., 1984, 106, 5018.

8) F.J. Hoogesteger; R.W.A. Havenith; J.W. Zwikker; L.W. Jenneskens; H. Kooyman; N. Veldman; A.L. Spek, J. Org. Chem., 1995, 60, 4375.

9) K. Wagner; D. Weiss; R. Beckert, Eur. J. Org. Chem., 2000, 3001.

143

COMMENTS :

BARTON – McCOMBIE DEOXYGENATION EXAMPLE :

H HO H3C

CH3

H

O 1) NaH, CS2, CH3I Benzene, reflux H O 2) nBu3SnH, AIBN reflux

CH3

O H3C

H

O

MECHANISM : ROH 1) NaH 2) CS2 3) XI

R

O

S R

X

SnnBu3 S

O

SnnBu3 S

X

X

O

SnnBu3

R

n

Bu3SnH

RH

144

DISCONNECTION :

RH

ROH

NOTES : The alcohol is converted to a xanthate and then reduced with tributyltin hydride and a catalytic amount of AIBN. The tributyltin hydride can be replaced by silicon hydrides. In this reaction there is no need to convert the alcohol first to a halide. There is a thionocarbonate modification published by Robins.

REFERENCES : Smith – March : 527 Smith 2nd : 140, 407, 1164 Houben – Weyl : E19a, 105, 174, 431 Org. Synth. : 64, 57; 77, 153 Org. Synth. Coll. Vol. : 7, 139; 10, 2378

1) D.H.R. Barton; S.W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 1574. 2) A.G.M. Barrett; P.A. Prokopiou; D.H.R. Barton, J. Chem. Soc., Chem. Commun., 1979, 1175. 3) M.J. Robins; J.S. Wilson, J. Am. Chem. Soc., 1981, 103, 932. 4) D.H.R. Barton; W.B. Motherwell, Pure Appl. Chem., 1981, 53, 15. 5) M.J. Robins; J.S. Wilson; F. Hansske, J. Am. Chem. Soc., 1981, 105, 4059. 6) W. Hartwig, Tetrahedron, 1983, 39, 2609. 7) D.H.R. Barton; S.Z. Zard, Pure Appl. Chem., 1986, 58, 675. 8) D. Crich, Aldrichimica Acta, 1987, 20, 36. 9) J.E. Forbes; S.Z. Zard, Tetrahedron Lett., 1989, 30, 4367. 10) C. Chatgilialoglu; C. Ferrari, Res. Chem. Intermed., 1993, 19, 755. 11) L.N. Mander; M.S. Sherburn, Tetrahedron Lett., 1996, 37, 4255. 12) B. Quiclet–Sire; S.Z. Zard, Tetrahedron Lett., 1998, 39, 9435. 13) Y. Ding; J. Wang; K.A. Abboud; Y. Xu; W.R. Dolbier, jr.; N.G.J. Richards, J. Org. Chem., 2001, 66, 6381. 14) J.U. Rhee; B.I. Bliss; T.V. RajanBabu, J. Am. Chem. Soc., 2003, 125, 1492. 15) H.S. Park; H.Y. Lee; Y.H. Kim, Org. Lett., 2005, 7, 3187.

COMMENTS :

145

BARTON – ZARD PYRROLE SYNTHESIS EXAMPLE : CH3

H3C

H3CO

N C

O

CH3

1) DBU 2) AcO

NO2

H3C

CH3

H

N H

O

MECHANISM : O RO

RO

N C 1) base

O

2) H R1

NO2

R2

R2

B O H

N RO R1

H+

R2 NO2

R1

R2

NO2

R1

H

O

H R1

R2

- HNO2

NO2

R1

R2

B

H

OR H

N +

N

RO

OR H

C

N

O

N H

O

H

DISCONNECTION : R1

R2

OR H

N H

AcO(H)

RO

N C O

O

146

NO2

+ R1

R2

NOTES : The base-catalysed Michael addition of an α-isocyanoacetate to a nitroalkane. The cyclisation of the nitronate anion onto the isocyano group leads to the pyrroline, base-catalysed expulsion of nitrite from the pyrroline and double bond rearrangement would finally give the pyrrole, unsubstituted in the 5-position. See also Clauson–Kaas, Fischer –

Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Org. Synth. : 70, 68 Org. Synth. Coll. Vol. : 9, 242 Science of Synthesis : 9, 489

1) D.H.R. Barton; S.Z. Zard, J. Chem. Soc., Chem. Commun., 1985, 1098. 2) D.H.R. Barton; J. Kervagoret; S.Z. Zard, Tetrahedron, 1990, 46, 7587. 3) T.D. Lash; B.H. Novak; Y. Lin, Tetrahedron Lett., 1994, 35, 2493. 4) E.T. Pelkey; L. Chang; G.W. Gribble, Chem. Commun., 1996, 1909. 5) T.D. Lash; C. Wijesinghe; A.T. Osuma; J.R. Patel, Tetrahedron Lett., 1997, 38, 2031.

COMMENTS :

BARTON DEAMINATION EXAMPLE :

CH3(CH2)16CH2NH2 O

1) H

O O

2) p-TsCl 3) nBu3SnH AIBN

147

CH3(CH2)16CH3 CH3

MECHANISM :

O

R

O R

NH2

H

O

CH3

H N

O

- OAc

p-TsCl H

H N R

O O S O H

R N C

CH3

n

Bu3SnH AIBN

R CH3

DISCONNECTION :

R

R CH3

NH2

NOTES : The free radical deamination of primary amines via isocyanides.

REFERENCES : 1) D.H.R. Barton; G. Bringmann; G. Lamotte; W.B. Motherwell; R.S. Hay Motherwell; A.E.A. Porter, J. Chem. Soc. Perkin Trans. 1, 1980, 2657.

2) D.H.R. Barton; W.B. Motherwell, Heterocycles, 1984, 21, 1. 3) D.H.R. Barton, Aldrichimica Acta, 1990, 23, 3.

COMMENTS :

148

BARTON DECARBOXYLATION EXAMPLE : O Br

Cl 1)

OH N

S

DCC, DMAP 2) nBu3SnH AIBN 3) BrCCl3 AIBN

MECHANISM : O RCOOH OH N

R

O

N S

S

SnnBu3 DCC, DMAP + CO2 + R

N S

RSPh PhSSPh

SnnBu3

DISCONNECTION :

RCOOH

R R1 R1 = SPh, SeH, Br

NOTES : The radical decarboxylation of a mixed anhydride (thiohydroxamic-carboxylic) using nBu3SnH or nBu3SH and interception of radicals as a sulfide (PhSSPh), selenide or bromo (BrCCl3) derivative. Biehl et al. used these esters for the syntheses of thieno[2,3-b]pyridines.

149

REFERENCES : Org. React. : 48, 301 Org. Synth. : 75, 124 Org. Synth. Coll. Vol. : 10, 2318

1) D.H.R. Barton; E.P. Serebryakov, Proc. Chem. Soc., 1962, 309. 2) D.H.R. Barton; D. Crich; W.B. Motherwell, J. Chem. Soc., Chem. Commun., 1983, 939. 3) D.H.R. Barton; D. Crich; W.B. Motherwell, Tetrahedron, 1985, 41, 3901. 4) D.H.R. Barton; S.Z. Zard, Janssen Chim. Acta, 1986, 4, 3. 5) D.H.R. Barton, Aldrichimica Acta, 1990, 23, 3. 6) J. Boivin; E. Fouquet; S.Z. Zard, Tetrahedron Lett., 1991, 32, 4299. 7) F.E. Ziegler; M. Belema, J. Org. Chem., 1997, 62, 1083. 8) A. Stojanovic; P. Renaud, Synlett, 1997, 181. 9) S. Poigny; M. Guyot; M. Samadi, J. Org. Chem., 1998, 63, 1342. 10) M.A. Attardi; M. Taddei, Tetrahedron Lett., 2001, 42, 3519. 11) U.N. Rao; E. Biehl, J. Org. Chem., 2002, 67, 3409.

COMMENTS :

BARTON PHENYLATION EXAMPLE :

OH OH Ph3BiCl2 TMBG

150

MECHANISM : X BiPh2 Ph O R R1

R R1

Ph

OPh R2

R

O

R1

R2

Ph R2

X = Ph, OCO2-, EDG

X BiPh3 O H

R

X = EWG - H+

R1

R2

DISCONNECTION : R

O

R1

R2

Ph OH R

R

OPh

R1

R2

R2 R1

NOTES : The regiospecific arylation of phenols and enols under acidic, basic or neutral conditions by covalent organobismuth(5+) reagents.

REFERENCES : 1) D.H.R. Barton; D.J. Lester; W.B. Motherwell; M.T.B. Papoula, J. Chem. Soc., Chem. Commun., 1980, 246. 2) D.H.R. Barton; J.-C. Blazejewski; B. Charpiot; D.J. Lester; W.B. Motherwell; M.T.B. Papoula, J. Chem. Soc., Chem. Commun., 1980, 827.

3) D.H.R. Barton; B. Charpist; W.B. Motherwell, Tetrahedron Lett., 1982, 23, 3365. 4) D.H.R. Barton; N.Y. Bhatnagar; J.-C. Blazejewski; B. Charpiot; J.-P. Finet; D.J. Lester; W.B. Motherwell; M.T.B. Papoula; S.P. Stanforth, J. Chem. Soc., Perkin Trans. 1, 1985, 2657. 5) D.H.R. Barton; J.-C. Blazejewski; B. Charpiot; J.-P. Finet; W.B. Motherwell; M.T.B. Papoula; S.P. Stanforth, J. Chem. Soc., Perkin Trans. 1, 1985, 2667.

COMMENTS :

151

BARTON REACTION EXAMPLE : H3C

H3C

OCl CH3 H

CH3 Cl

1) NOCl 2) hν 3) H2O

CH3

OH

CH3

MECHANISM :

CH3 H3C H O NO

CH3 H3C H OH

H3C

CH3

NO OH

hν

NOCl ON

H3C H3C

H3C H3C HO

HO

OH

N

CH3 OH

O

CH3 OH

H2O

DISCONNECTION :

O

R

R OH

H3C

H OH

R = H, CH3

NOTES : This method provides a way to oxidise a carbon atom separated from an hydroxyl group by three other carbon atoms via a nitrite ester. The mechanism is similar to the Hoffmann – Löffler – Freytag reaction. See also Hoffmann –

Löffler – Freytag reaction.

REFERENCES : March : 1153 Smith – March : 1463 Smith : 1415 Smith 2nd : 1166

1) D.H.R. Barton; I.M. Beaton; L.E. Geller; M.M. Pechet, J. Am. Chem. Soc., 1960, 82, 2640. 2) D.H.R. Barton; I.M. Beaton, J. Am. Chem. Soc., 1961, 83, 4083. 3) D.H.R. Barton, Pure Appl. Chem., 1968, 16, 1. 4) R.H. Hesse, Adv. Free-Radical Chem., 1969, 3, 83. 5) E.J. Corey; J.F. Arnett; G.N. Widiger, J. Am. Chem. Soc., 1975, 97, 430.

152

6) D.H.R. Barton; R.H. Hesse; M.M. Pechet; L.C. Smith, J. Chem. Soc., Perkin Trans. 1, 1979, 1159. 7) Ž. Čeković; D. Ilijev, Tetrahedron Lett., 1988, 29, 1441. 8) G. Majetich; K. Wheless, Tetrahedron, 1995, 51, 7095. 9) A. Herzog; C.B. Knobler; M.F. Hawthorne, Angew. Chem., Int. Ed. Engl., 1998, 37, 1552. 10) G.H. Hakimelahi; P.-C. Li; A.A. Moosavi–Movahedi; J. Chamani; G.A. Khodarahmi; T.W. Ly; F. Valiyev; K. Leong; S. Hakimelahi; K.-S. Shia; I. Chao, Org. Biomol. Chem., 2003, 2461.

COMMENTS :

BAUDART ACYLOIN SYNTHESIS EXAMPLE :

CH3CO2Et + EtOCH2CO2Et

1) Na, H2O 2) H2 3) HBr 4) Zn 5) KCN, KOH

H3C

COOH

MECHANISM :

H RCO2Et + EtO(CH2)nCO2Et

Na

HO O

H

Br

n

H2

R

HO

n

R

Zn

R

n

Br

1) KCN 2) KOH

R

DISCONNECTION :

R

OEt

HO

n

R

Br

Br HBr

H

OEt

n

RCO2Et + EtO(CH2)nCO2Et

COOH

153

n

COOH

NOTES : The necessary double bond is obtained by reducing an acyloin of suitable structure to a glycol and converting the glycol into the corresponding dibromide. The latter product is treated with zinc.

REFERENCES : P. Baudart, C.R. Séances Acad. Sci., 1945, 220, 404.

COMMENTS :

BAUDART SYNTHESIS EXAMPLE :

Br H CH3O(CH2)7MgBr +

EtO

HOOC(CH2)7

Br H (CH2)7CH3

1) Zn H 2) HBr 3) malonic ester synthesis

(CH2)7CH3 H

MECHANISM : H3CO(CH2)7 H EtO Br H (CH2)7CH3

Br H CH3O(CH2)7MgBr +

EtO

H3CO(CH2)7 Zn

H HOOC(CH2)7

malonic ester synthesis

H

Br H (CH2)7CH3

Br(CH2)7

(CH2)7CH3 HBr

H (CH2)7CH3 H

154

H

(CH2)7CH3 H

DISCONNECTION : O OH

CH3O(CH2)7MgBr + oleic acid O

Br

Br

EtO

OH

H

(CH2)7CH3

elaidic acid

NOTES : The application of this method to the synthesis of a mixture of oleic acid and elaidic acids (C18 chain E/Z at C9). See also Boord, Bowman, Kapp – Knoll, Noller and Robinson – Robinson reactions.

REFERENCES : P. Baudart, C.R. Séances Acad. Sci., 1943, 217, 399.

COMMENTS :

BAUDISCH REACTION EXAMPLE :

N + NH2OH

H2O2 Na3[Fe(CN)5NH3]

155

O

OH

MECHANISM :

NOH + NH2OH

H2O2

O O N

NO 2

O N Cu

Cu2+

OH

O

HO

O

HO

O

H O

N

ON-OH2+

OH H2O

N O---H2O---OH

HO

N O---H2O

- H3O+

- 2 H2O HO

NO

DISCONNECTION : NO R

R OH

OH

NOTES : The formation of o-nitrosophenols by oxidation of aromatic compounds sometimes in the presence of a metal salt to stabilise the nitrosyl radical. The nitrosyl radical is prepared by reduction of nitrous acid or by the oxidation of hydroxylamine.

REFERENCES : Houben – Weyl : 10/1, 1025

1) O. Baudisch; H.S. Smith, Naturwissenschaften, 1939, 27, 769.

156

2) O. Baudisch, Science, 1940, 92, 336. 3) O. Baudisch, J. Am. Chem. Soc., 1941, 63, 622. 4) G. Cronheim, J. Org. Chem., 1947, 12, 1. 5) K. Maruyama; I. Tanimoto; R. Goto, Tetrahedron Lett., 1966, 7, 5889. 6) K. Maruyama; I. Tanimoto, Bull. Chem. Soc. Jpn., 1971, 44, 3120. 7) M.C. Cone; C.R. Melville; J.R. Carney; M.P. Gore; S.J. Gould, Tetrahedron, 1995, 51, 3095.

COMMENTS :

BAUM BENZOYLATION EXAMPLE : O H

H H

NH2 COOH

H 1) PhCOCl 2) aq. NaOH 3) HCl

Ph

N H COOH

MECHANISM : H

H Cl

H2N

COOH 2 NH3 - NH4Cl

H

COOH Ph

H

Cl O

2 NaOH O Ph

ONa

O

H N H

O

Ph

HCl

H

OH H N H

O H

DISCONNECTION : O H R

H

Ph

N H COOH

R

157

NH2 COOH

NOTES : The amino acid reacts with benzoyl chloride in the presence aqueous sodium hydroxide. The reaction is worked up with hydrochloric acid to afford the benzylated amino acid. See also Schotten – Baumann reaction.

REFERENCES : Smith : 662 Smith 2nd : 561 Org. Synth. : 12, 40 Org. Synth. Coll. Vol. : 2, 328

1) J. Baum, Ber. Dtsch. Chem. Ges., 1886, 19, 500. 2) H.E. Carter; C.M. Stevens, J. Biol. Chem., 1941, 138, 627. 3) S. Harada; E. Mizuta; T. Kishi, Tetrahedron, 1981, 37, 1317. 4) Y. Uozumi; A. Tanahashi; T. Hayashi, J. Org. Chem., 1993, 58, 6826. 5) A. Benourgha; J. Verducci; R. Jacquier, Bull. Soc. Chim. Fr., 1995, 132, 824. 6) D.J. Fox; J. Reckless; S.G. Warren; D.J. Grainger, J. Med. Chem., 2002, 45, 360.

COMMENTS :

BAUMANN – FROMM SYNTHESIS EXAMPLE : Ph Ph 2 COOH

3 S, 230 oC

Ph

158

S

Ph

+

Ph

S

MECHANISM : Ph Ph 2

3 S, 230 oC

COOH

HS

COOH

HS

COOH

S, - CO2

Ph

Ph

Ph SH

- H2S

SH

Ph

S

Ph

DISCONNECTION :

Ph

S

+ S

Ph

COOH

NOTES : Sulfur and cinnamic acid or styrene react on heating to form 2,4- and 2,5-diphenylthiophene. The mechanism is assumed to be similar to the Bogert – Herrera reaction. See also Bogert – Herrera, Fiesselmann, Harries pyrrole,

Hinsberg thiophene, Volhard – Erdmann and Willgerodt – Kindler reactions.

REFERENCES : 1) E. Baumann; E. Fromm, Ber. Dtsch. Chem. Ges., 1891, 24, 1446. 2) E. Baumann; E. Fromm, Ber. Dtsch. Chem. Ges., 1895, 28, 890. 3) P. Demerseman; Ng.Ph. Buu-Hoï; R. Royer; A. Cheutin, J. Chem. Soc., 1954, 2720.

COMMENTS :

159

BAYLIS – HILLMAN – MORITA REACTION EXAMPLE : OH

O C9H11

H

+

CH3

O

C9H11

DABCO THF

O CH3

MECHANISM : DABCO :

CO2Me +

N

N

N

N

N

N

O

O H3C

H

OMe

OMe O

O

E2

N

N

OH

N

+

N

CO2Me

O E1cB

OMe OH

160

Phosphines :

(R)3P

R1 + P(R)3

(R)3P

R1

R2CHO - (R)3PO

R2CHO

R2 (R)3P

R1

O

R2

R1

R1

R2

OH R1

DISCONNECTION : R2

OH R1 R1

R2

R1

NOTES : The amine catalyses the conversion of acrylates to α-(hydroxyalkyl) acrylates or of vinyl ketones to α-(hydroxyalkyl) vinyl ketones. The reaction can be catalysed by DABCO, phosphines or transition metal complexes, although DMAP is becoming more popular than DABCO because of its better selectivity and higher yields. Aza and asymmetric Baylis

– Hillman – Morita reactions have also been published. A new interpretation of the reaction mechanism is published by Price et. al. See also Rauhut – Currier reaction.

REFERENCES : Smith – March : 1212 Smith 2nd : 795 Org. React. : 51, 201 Org. Synth. : 68, 64; 75, 106 Org. Synth. Coll. Vol. : 8, 420; 10, 2316 Science of Synthesis : 10, 761

161

1) R. Oda; S. Taninoto, Tetrahedron Lett., 1964, 25, 1653. 2) K. Morita; Z. Suzuki; H. Hirose, Bull. Chem. Soc. Jpn., 1968, 41, 2815. 3) A.B. Baylis; M.E.D. Hillman, U.S. Patent, 1973, 3743669. 4) M.M. Midland; J.I. McLoughlin, Tetrahedron Lett., 1988, 28, 4653. 5) F. Roth; P. Gygax; G. Fráter, Tetrahedron Lett., 1992, 33, 1045. 6) S.E. Drewes; O.L. Njamela; N.D. Emslie; N. Ramesar; J.S. Field, Synth. Commun., 1993, 23, 2807. 7) D. Basavaiah; P.D. Rao; R.S. Hyma, Tetrahedron, 1996, 52, 8001. 8) L.J. Brzezinski; S. Rafel; J.W. Leahy, J. Am. Chem. Soc., 1997, 119, 4317. 9) Y.M.A. Yamada; S. Ikegami, Tetrahedron Lett., 2000, 41, 2165. 10) D. Basavaiah; N. Kumaragurubaran; D.S. Sharada, Tetrahedron Lett., 2001, 42, 85. 11) N.J. Lawrence; J.P. Crump; A.T. McGown; J.A. Hadfield, Tetrahedron Lett., 2001, 42, 3939. 12) M. Shi; C.-J. Wang, Helv. Chim. Acta, 2002, 85, 841. 13) M. Shi; C.-Q. Li; J.-K. Jiang, Molecules, 2002, 7, 721. 14) R. Murugan; E.F.V. Scriven, Aldrichimica Acta, 2003, 36, 21. 15) D. Basavaiah; A.J. Rao; T. Satyanarayana, Chem. Rev., 2003, 103, 811. 16) M. Shi; Y.-M. Xu, J. Org. Chem., 2003, 68, 4784. 17) P.R. Krishna; V. Kannan; P.V.N. Reddy, Adv. Synth. Catal., 2004, 346, 603. 18) K. Jayakanthan; K.P. Madhusudanan; Y.D. Vankar, Tetrahedron, 2004, 60, 397. 19) K.E. Price; S.J. Broadwater; B.J. Walker; D.T. McQuade, J. Org. Chem., 2005, 70, 3980. 20) K.E. Price; S.J. Broadwater; H.M. Jung; D.T. McQuade, Org. Lett., 2005, 7, 147.

COMMENTS :

BÉCHAMP ARSONYLATION EXAMPLE : NH2

NH2 + H3AsO4

AsO(OH)2

162

MECHANISM: NH2

NH2

H

O HO As OH OH

O H As OH HO OH

NH2

- H2O AsO(OH)2

DISCONNECTION : NH2

NH2

AsO(OH)2

NOTES : The direct para-arsonation of aromatic amines, phenols, and certain derivatives with arsenic acid. Ortho-arsonylation does not occur even when the para-position is blocked. This arsonylation is mechanistically similar to sulfonation. See also Bart (Bart – Schmidt) and Rosenmund reactions.

REFERENCES : Org. React. : 2, 415

1) A.J. Béchamp, C.R. Séances Acad. Sci., 1863, 56, 1172. 2) P. Ehrlich; A. Bertheim, Ber. Dtsch. Chem. Ges., 1907, 40, 3292. 3) H.P. Brown; C.S. Hamilton, J. Am. Chem. Soc., 1934, 56, 151.

COMMENTS :

163

BÉCHAMP REDUCTION EXAMPLE : NO2

NH2 Fe, HCl

MECHANISM :

2 Fe + 6 HCl

2 H2O + 2 FeCl3 + H2

NO2

NH2 H2

DISCONNECTION :

Ar

NH2

Ar

NO2

NOTES : The use of ferrous salts or iron in dilute acid in the reduction of aliphatic and aromatic nitro groups to amino groups. See also Zinin reduction.

REFERENCES : March : 1216 Smith – March : 1552 Houben – Weyl : 11/1, 394 Org. Synth. : 11, 32; 15, 55 Org. Synth. Coll. Vol. : 2, 160, 471

1) A.J. Béchamp, Ann. Chim. (Paris), 1854, 42, 186. 2) S.E. Hazlet; C.A. Dornfeld, J. Am. Chem. Soc., 1944, 66, 1781. 3) P.N. Rylander, Aldrichimica Acta, 1979, 12, 53. 4) A. Courtin, Helv. Chim. Acta, 1980, 62, 2280. 5) Z.A. Olovyanishnikova; V.A. Parshin; V.V. Ogorodnikova; M.D. Mashkovskii; V.G. Yashunskii, Pharm. Chem. J., 1987, 21, 756.

164

6) L. Karolyhazy; G. Horvath; P. Mathyus, Acta Pharm. Hung., 2001, 71, 168.

COMMENTS :

BECKMANN REARRANGEMENT EXAMPLE :

OH

N

O N

H

P2O5, CH3SO3H 100 oC, 1 hour

MECHANISM :

R1

R1 R

N

OH

R

H+

N

R1

OH2

C

NR

H

O

H

O

N R R1

R1

OH

N H

R

If a Lewis acid is used as catalyst :

H R1 R

O N

R1

Cl P Cl4

- HCl

R

O R1

N H

R

165

N

O

R1 PCl4

- POCl3

N R

DISCONNECTION : O R1

N H

R1

R R

N

OH

NOTES : The rearrangement of ketoximes to substituted acid amides on treatment with phosphorous pentachoride, polyphosphoric acid, sulfuric acid, acetyl chloride, benzenesulfonyl chloride, boron trifluoride, metallic chlorides or other reagents. Aldoximes normally require the use of polyphosphoric acid. The general observation is that the group in the position anti to the leaving group will migrate preferentially to the nitrogen atom. There are also rearrangements known in the solid state. See also Bamberger – Goldschmidt rearrangement.

REFERENCES : March : 1095 Smith – March : 1415 Houben – Weyl : 10/4, 228; E3, 568; E6b, 141; E7a, 460, 615; E7b, 161, 178, 183; E8a, 254, 736, 759, 1024; E8b, 303; E8c, 682; E8d, 185; E14b, 391; E15, 678; E16c, 909; E16d, 627, 1141; E19c, 408

Org. React. : 11, 1; 35, 1 Org. Synth. : 63, 188; 66, 185 Org. Synth. Coll. Vol. : 7, 254; 8, 568 Science of Synthesis : 10, 75, 258, 582, 740

1) E. Beckmann, Ber. Dtsch. Chem. Ges., 1886, 19, 988. 2) E. Beckmann, Ber. Dtsch. Chem. Ges., 1887, 20, 1507. 3) E.C. Franklin, Chem. Rev., 1934, 14, 219. 4) B. Jones, Chem. Rev., 1944, 35, 335. 5) F.D. Popp; W.E. McEwen, Chem. Rev., 1958, 58, 370. 6) L. Field; P.B. Hughmark; S.H. Shumaker; W.S. Marshall, J. Am. Chem. Soc., 1961, 83, 1983. 7) K. Hattori; K. Maruoka; H. Yamamoto, Tetrahedron Lett., 1982, 23, 3395. 8) H. Nishiyama; K. Sakuta; N. Osaka; H. Arai; M. Matsumoto; K. Itoh, Tetrahedron, 1988, 44, 2413. 9) R.P. Frutos; D.M. Spero, Tetrahedron Lett., 1998, 39, 2475. 10) R. Anilkumar; S. Chandrasekhar, Tetrahedron Lett., 2000, 41, 7235. 11) S. Chandrasekhar; K. Gopalaiah, Tetrahedron Lett., 2001, 42, 8123. 12) M. Boero; T. Ikeshoji; C.C. Liew; K. Terakura; M. Parrinello, J. Am. Chem. Soc., 2004, 126, 6280. 13) M.K. Dongare; V.V. Bhagwat; C.V. Ramana; M.K. Gurhar, Tetrahedron Lett., 2004, 45, 4759. 14) M.A. Iglesias–Arteaga; J. Sandoval–Ramírez; M.Y. Mata–Esma; O. Viñas–Bravo; S. Bernès, Tetrahedron Lett., 2004, 45, 4921. 15) H. Tsuji; T. Setoyama, Chem. Lett., 2005, 34, 1232.

166

COMMENTS :

BEDOUKIAN REACTION EXAMPLE :

CH3

CH3 H3C

O

H3C

O

1) (CH3CO)2O, p-CH3C6H4SO3H, heat 2) Br2, CCl4, 0 oC 3) EtOH, 10 oC 4) HCl, heat

Br

MECHANISM :

OAc

O CH3(CH2)4

H

KOAc Ac2O, heat

CH3(CH2)4

H

OCH3

Br CH3(CH2)4

Br2, CCl4

CH3(CH2)4

OAc

CH3OH

OCH3 Br

Br

HCl H2O, heat

O CH3(CH2)4

H Br

DISCONNECTION : R R1 X

R R1 O R = H, Alk; X = Cl, Br R1 = Alk, Ar

O

NOTES : The synthesis of α-halogen ketones and α-halogen aldehydes from enol acetones. Tosic acid is used for ketones, while potassium acetate is used for aldehydes. See also Fritsch – Kling and Hell – Volhard – Zelinsky reactions.

167

REFERENCES : Org. Synth. : 29, 14 Org. Synth. Coll. Vol. : 3, 127

1) P.Z. Bedoukian, J. Am. Chem. Soc., 1944, 66, 651. 2) P.Z. Bedoukian, J. Am. Chem. Soc., 1944, 66, 1325. 3) P.Z. Bedoukian, J. Am. Chem. Soc., 1957, 79, 889.

COMMENTS :

BÉHAL – SOMMELET SYNTHESIS EXAMPLE : CH3 HO CH2OEt CH3

CH3 H H

HCOOH 100 oC

CH3 O

MECHANISM :

HO

CH3 CH2OH CH3

H2O HCOOH 100 oC

CH3 O

H3C

CH3 H H

H

CH3 O

DISCONNECTION :

R1

H

R1

H

HO R2

O

R = CH3, Et, H R1, R2 = Alk, Ph

CH2OR R2

NOTES : Primary-secondary and primary-tertiary ethylene glycols yield aldehydes when heated with acids (anhydrous formic or oxalic acids). Ethers of the type R2C(OH)CH2OR react particularly easily.

168

REFERENCES : Houben – Weyl : 7/1, 104, 233

1) M.M.A. Béhal; M. Sommelet, Bull. Soc. Chim. Fr., 1904, 31, 92. 2) M.M.A. Béhal; M. Sommelet, Bull. Soc. Chim. Fr., 1904, 31, 300. 3) M. Sommelet, Bull. Soc. Chim. Fr., 1907, 1, 404. 4) R.A. Barnes; W.M. Budde, J. Am. Chem. Soc., 1946, 68, 2339. 5) H. Normant; C. Crisan, Bull. Soc. Chim. Fr., 1959, 463.

COMMENTS :

BEHREND – ROOSEN SYNTHESIS EXAMPLE : O H

N

H N

N N H

O

O H

OH OH

HCl CO(NH2)2

O

OH N

N H

MECHANISM : O

O

H

OH

N

OH

H2N

HCl - 2 H2O

O

H N

N

O N H

O

H

H2N

OH N H

N

DISCONNECTION : O

O R O

N

N

R1

R

OH

N

+

OH N R

N

R, R1 = H, CH3

169

O

N R

OH

H N

H2N O

R1

NOTES : The condensation of isodialuric acids with derivatives of urea. The mechanism can be step-wise. See also Fischer –

Ach, Horbaczewski and Traube reactions.

REFERENCES : 1) R. Behrend; O. Roosen, Ber. Dtsch. Chem. Ges., 1888, 21, 999. 2) R. Behrend; O. Roosen, Liebigs Ann. Chem., 1889, 251, 235. 3) A. Prüsse, Liebigs Ann. Chem., 1925, 441, 203.

COMMENTS :

BEHREND REARRANGEMENT EXAMPLE : CH3

CH3 H3C

CN H

dioxane Et3N

H

CN

H3C

N O

O

N

H

H NO2

NO2

MECHANISM :

R

R2

R1

N O

H

R1

R

R2

R

H N

H R1

H

O

DISCONNECTION : R

R

R2 N O

H

R2

H

H R1

R, R1, R2 = Alk, Ar

170

R2

R1

N O

H

N O

H

NOTES : This is the 1,3-prototropic isomerisation of nitrones. This isomerisation is closely related to the isomerisation of imines.

REFERENCES : 1) R. Behrend; E. Konig, Liebigs Ann. Chem., 1891, 263, 355. 2) R. Behrend, Liebigs Ann. Chem., 1891, 265, 238. 3) C. Neubauer, Liebigs Ann. Chem., 1897, 298, 187. 4) A.C. Cope; A.C. Haven, J. Am. Chem. Soc., 1950, 72, 4896. 5) P.A.S. Smith; S.E. Gloyer, J. Org. Chem., 1975, 40, 2504. 6) K. Suda; E. Sekizuka; Y. Wakamatsu; F. Hino; C. Yijima, Chem. Pharm. Bull., 1985, 33, 1297.

COMMENTS :

BELLUŠ – CLAISEN REARRANGEMENT EXAMPLE :

Cl

Cl O +

Cl

OCH3

171

Et2O

H3C

Cl

O OCH3

MECHANISM :

R H3C

X

R

X

H3C O

R1 O

R1 R

[3,3]-sigmatropic H C X rearrangement 3

R R1 O

base - HY

COY R1 R H3C

X

R1

Y

O

DISCONNECTION :

H3C

R R1

X O

R X = O, S, NR2 R, R1 = H. Alkyl, Cl, CN

H3C

X

+

O R1

NOTES : This is the reaction of an allylic ether, thioether or amine with a ketene. [3,3]-Sigmatropic rearrangement of the zwitterionic intermediate leads to an (E) unsaturated ester, thioester or amide. When applied to cyclic allylic compounds, a ring-enlargement by four carbons in one step takes place to provide medium-ring unsaturated (E)lactones, thiolactones and lactams. See also Carroll (Kimel – Cope), Claisen (Claisen – Ireland) rearrangement,

Cope, Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Johnson – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES : 1) R. Malherbe; D. Belluš, Helv. Chim. Acta, 1978, 61, 3096. 2) R. Malherbe; G. Rist; D. Belluš, J. Org. Chem., 1983, 48, 860. 3) M.R. Kling; G.A. McNaughton–Smith; R.J.K. Taylor, Chem. Commun., 1993, 1593. 4) M. Diederich; U. Nubbemeyer, Angew. Chem., Int. Ed. Engl., 1995, 34, 1026. 5) T.P. Yoon; V.M. Dong; D.W.C. MacMillan, J. Am. Chem. Soc., 1999, 121, 9726. 6) V.M. Dong; D.W.C. MacMillan, J. Am. Chem. Soc., 2001, 123, 2448. 7) J. Gonda, Angew. Chem., Int. Ed., 2004, 43, 3516.

172

COMMENTS :

BELOUSOV – ZHABOTINSKY REACTION EXAMPLE :

1) KBrO3 oscillations

2) CH2(COOH)2 + aq. H2SO4 + KBr 3) [Fe(phen)]2+

MECHANISM :

(A) BrO3- + 5 Br- + 6 H+ (B) BrO3- + 4 Mred + 5 H+ (C) 2 Mox + Ma + BrMA

3 Br2 + 3 H2O 4 Mox + HOBr + 2 H2O Br- + 2 Mred + other products

NOTES : This reaction involves the oxidation of an organic species (malonic acid) from an acidified bromate solution, in the presence of a metal ion catalyst. Different metal ions have been used, with Ce3+/Ce4+ and [Fe(phen)]2+/[Fe(phen)]3+ being more common. The reaction mechanism is still being studied and is extremely complicated but can be divided in 3 main reactions as shown.

REFERENCES : 1) A.M. Zhabotinsky, Proc. Acad. Sci., USSR, 1964, 157, 392. 2) R.J. Fields; E. Körös; R.M. Noyes, J. Am. Chem. Soc., 1972, 94, 8649. 3) R.J. Fields; R.M. Noyes, J. Chem. Phys., 1974, 60, 8649. 4) A.T. Winfree, Proc. Theor. Chem., 1978, 4, 1. 5) B.P. Belousov, Khim. Zhizn., 1982, 7, 65. 6) A.T. Winfree, J. Chem. Educ., 1984, 61, 661. 7) W.-T. Hsu; J.-J. Jwo, Int. J. Chem. Kinet., 2000, 32, 52. 8) J.B. Raoof; R. Ojani; A. Kiani; M. Khosravi; A. Adnani, Bull. Chem. Soc. Jpn., 2005, 78, 258.

173

COMMENTS :

BENARY REACTION EXAMPLE : H Bu

Bu

Br H

O

Li N Ph

O

Me

MECHANISM : O

H+ H3C

Ph RMgX +

N

R1

H3C

R -

Ph

N H

CH3

R

R1 MgX

N Ph

O

N

R1

R1 O

DISCONNECTION :

R

R1

RMgX +

O

O

NOTES : The formation of polyunsaturated aldehydes from vinyl halides and enaminoaldehydes. Lithium metal or a Grignard reagent can be used.

REFERENCES : 1) E. Benary, Chem. Ber., 1930, 63, 1573. 2) E. Benary, Chem. Ber., 1931, 64, 2543.

174

3) A. Pasteur; H. Rivière; B. Tchoubar, Bull. Soc. Chim. Fr., 1965, 2328. 4) F. Näf; R. Decorzant, Helv. Chim. Acta, 1974, 57, 1317. 5) K.K. Mahalanabis; M. Sarkar; S.K.D. Chowdhury; S. Dutta–Bose, Indian J. Chem., 1998, 37B, 1234.

COMMENTS :

BENET SYNTHESIS EXAMPLE : O

O O

Ph Ph

O

Na3PO4, Na2HPO4 HCHO, aq. EtOH

O

O Ph

OH

NOTES : Resorcinol dibenzoate in aqueous ethanol is refluxed with a mixture of sodium hydrogenphosphate and sodium phosphate to hydrolyse one of the benzoate groups. The addition of formaldehyde increases the yield.

REFERENCES : J. Benet, Bull. Soc. Chim. Fr., 1932, 51, 963.

COMMENTS :

175

BENKESER REACTION EXAMPLE :

H

SiCl3

n

Bu3N HSiCl3 CH3CN

H

MECHANISM :

(R)3N + SiHCl3

(R)3N SiHCl3

176

NH3(R)3 + SiCl3

CHCl3 + 3 nBu3N

4.5 eq. HSiCl3

9 eq. HSiCl3

- SiCl4 H H

SiCl3 SiCl3

H

EtOH

EtOH

H H

Si(OEt)3 Si(OEt)3

H

BuLi THF, - 65 oC

BuLi THF, - 65 oC

Si(OEt)3 Si(OEt)3 Si(OEt)3

Si(OEt)3 Si(OEt)3

R H

Si(OEt)3 Si(OEt)3 Si(OEt)3

t

t

H

SiCl3 SiCl3 SiCl3

Si(OEt)3 Si(OEt)3

R

Si(OEt)3 Si(OEt)3 Si(OEt)3

R = Br, Me

R = CH2Ph, C12H25, Br, SiMe3, Me

DISCONNECTION : RCH(SiCl3)2 RCHCl2

RC(SiCl3)3

177

NOTES : In the initial experiments by Benkeser the silicon – carbon bond was formed mainly by the selective reduction of polyhalo compounds with HSiCl3 / nBu3N. However, the method was only highly efficient for synthesising benzylic silanes and analogues. The extension to alkyl halides failed due to the reaction of trichlorosilane with R3NHCl. Later, Corriu et al. optimised the reaction conditions.

REFERENCES : 1) R.A. Benkeser; J.M. Gaul; W.E. Smith, J. Am. Chem. Soc., 1969, 91, 3666. 2) R.A. Benkeser; J.M. Gaul, J. Am. Chem. Soc., 1970, 92, 720. 3) R.A. Benkeser, Acc. Chem. Res., 1971, 4, 94. 4) W.-W. du Mont; L.P. Müller; L. Müller; S. Vollbrecht; A. Zanin, J. Organomet. Chem., 1996, 521, 417. 5) R.J.P. Corriu; M. Granier; G.F. Lanneau, J. Organomet. Chem., 1998, 562, 79. 6) H.H. Karsch; P.A. Schluter; F. Bienlein; M. Herker; E. Witt; A. Sladek; M. Henckel, Zeit. Anorg. Allgem. Chem., 1998, 624, 295.

COMMENTS :

BENKESER REDUCTION EXAMPLE :

OCH3

OCH3

Li, NH3

MECHANISM :

R

R

R +

Li, RNH2

Li, RNH2

178

R

R +

OMe

OMe

OMe

OMe or

eRNH2

OMe

OMe e-

DISCONNECTION :

R

R

NOTES : The hydrogenation of aryls to non-conjugated dienes or mono-olefins with lithium or calcium in low molecular weight amines on a large scale (this is where the Birch reduction usually fails). The same reagents are also effective in the reduction of epoxides. The reaction can also be performed electro-chemical. See also Birch reduction.

REFERENCES : March : 782 Smith – March : 1012 Smith : 466 Smith 2nd : 402 Org. Synth. : 50, 88 Org. Synth. Coll. Vol. : 6, 852

1) R.A. Benkeser; R.E. Robinson; H. Landesman, J. Am. Chem. Soc., 1952, 74, 5669. 2) A.W. Burgstahler; L.R. Warden, J. Am. Chem. Soc., 1961, 83, 2587. 3) R. Eckrich; D. Kuch, Synlett, 1993, 344. 4) P.J.M. van Andel Scheffer; A.H. Wonders; E. Barendrecht, J. Electroanal. Chem., 1994, 366, 135. 5) M.E. Garst; L.J. Dolby; S. Esfandiari; N.A. Fedoruk; N.C. Chamberlain; A.A. Avey, J. Org. Chem., 2000, 65, 7098.

179

COMMENTS :

BERCHTOLD REACTION EXAMPLE :

O N

O

CO2CH3

N

+

1) toluene, 0 oC 2) reflux, 12 h

CO2CH3

CO2CH3 CO2CH3

MECHANISM :

O

O CO2CH3

CO2CH3

N

N

CO2CH3

CO2CH3 O OH

CO2CH3

N CO2CH3 CO2CH3

CO2CH3

HCl reflux

DISCONNECTION :

COOR

COOR

N(R1)2

( )n

( )n COOR

+ COOR

180

NOTES : Dimethyl acetylenedicarboxylate reacts with enamines of cyclic ketones. The formed cyclobutene intermediate rearranges leading to a cyclic ketone with 2 more carbon atoms.

REFERENCES : 1) K.C. Brannock; A. Bell; R.D. Burpitt; C.A. Kelly, J. Org. Chem., 1961, 26, 625. 2) G.A. Berchtold, J. Org. Chem., 1961, 26, 3043. 3) G.A. Berchtold; G.F. Uhlig, J. Org. Chem., 1963, 28, 1459. 4) K.C. Brannock; R.D. Burpitt; J.G. Thweatt, J. Org. Chem., 1963, 28, 1462. 5) K.C. Brannock; R.D. Burpitt; V.W. Goodlett; J.G. Thweatt, J. Org. Chem., 1963, 28, 1464.

COMMENTS :

BERGMAN – MASAMUNE CYCLISATION EXAMPLE : Cl

CCl4 Cl

MECHANISM :

H

R1

solvent

R1

R1

R1

R

R

R

R H

181

DISCONNECTION : R1 R1 R Solvent

R

R1

R

hydrocarbon H H CCl4 Cl Cl CH2OH H CH3OH

NOTES : The Cope rearrangement of hex-3-ene-1,5-diyne, which results in concerted cyclisation to p-benzyne, was first reported by Bergman. Ene-diynes undergo cycloaromatisation, which is a thermally allowed electrocyclic reaction. There are a few examples of aza-Bergman, photo-Bergman and metal-accelerated cyclisations. In the last one the cyclisation can take place at more ambient temperature. See also Cope rearrangement and Myers – Moore – Saito

– Schmittel reactions.

REFERENCES : Smith – March : 1432, 1447 Smith 2nd : 1181

1) N. Darby; C.U. Kim; J.A. Salaun; K.W. Shelton; S. Takada; S. Masamune, J. Chem. Soc. (D), 1971, 23, 1516. 2) R.R. Jones; R.G. Bergman, J. Am. Chem. Soc., 1972, 94, 660. 3) R.G. Bergman, Acc. Chem. Res., 1973, 6, 25. 4) T.P. Lockhart; P.B. Comita; R.G. Bergman, J. Am. Chem. Soc., 1981, 103, 4082. 5) K.C. Nicolaou; W.-M. Dai, Angew. Chem., Int. Ed. Engl., 1991, 30, 1387. 6) K.C. Nicolaou; W.-M. Dai; S.C. Tsay; V.A. Estevez; W. Wrasidlo, Science, 1992, 256, 1172. 7) K.C. Nicolaou, Chem. Br., 1994, 30, 33. 8) J. Wisniewski Grissom; T.L. Calkins; D. Huang; H. McMillen, Tetrahedron, 1994, 50, 4635. 9) M.E. Maier, Synlett, 1995, 13. 10) K.K. Wang, Chem. Rev., 1996, 96, 207. 11) H. Tanaka; H. Yamada; A. Matsuda; T. Takahashi, Synlett, 1997, 381. 12) A. Evenzahav; N.J. Turro, J. Am. Chem. Soc., 1998, 120, 1835. 13) B. Konig, Eur. J. Org. Chem., 2000, 381. 14) G.B. Jones; P.M. Warner, J. Am. Chem. Soc., 2001, 123, 2134. 15) T. Sasaki; M. Inoue; M. Hirama, Tetrahedron Lett., 2001, 42, 5299. 16) J.D. Rule; S.R. Wilson; J.S. Moore, J. Am. Chem. Soc., 2003, 125, 12992. 17) L. Feng; D. Kumar; S.M. Kerwin, J. Org. Chem., 2003, 68, 2234. 18) D.S. Rawat; J.M. Zaleski, Synlett, 2004, 393. 19) K.D. Lewis; A.J. Matzger, J. Am. Chem. Soc., 2005, 127, 9968.

182

COMMENTS :

BERGMANN – SCHOTTE REACTION EXAMPLE :

OH

OH O

HO HO

O 1) C6H5COOOH 2) H2O

HO HO OH

OH

MECHANISM : OH

OH

OH O

O HO HO

C6H5COOOH

HO HO

O HO HO

O H+ H2O

OH

OH

DISCONNECTION :

HO

OH

NOTES : The oxidation of unsaturated sugars with peroxybenzoic acid to produce epimeric carbohydrates. See also Criegee osmium tetroxide, Fenton, Milas, Prévost, Sharpless dihydroxylation and Woodward dihydroxylation reactions.

REFERENCES : 1) M. Bergmann; H. Schotte, Ber. Dtsch. Chem. Ges., 1921, 54, 440. 2) M. Bergmann; H. Schotte, Ber. Dtsch. Chem. Ges., 1921, 54, 1564. 3) P.A. Leuene; R.S. Tipson, J. Biol. Chem., 1931, 93, 631.

183

4) W.T. Haskins; R.M. Hann; C.S. Hadson, J. Am. Chem. Soc., 1942, 64, 1490. 5) W.L. Evans; D.D. Reyndols; E.A. Talley, Adv. Carbohydr. Chem., 1951, 6, 55.

COMMENTS :

BERGMANN – ZERVARS CARBOBENZOXY METHOD EXAMPLE : H

H COOH HOOC

1) C6H5CH2OCOCl 2) Ac2O 3) H2N OEt EtO O O

NH2

O

H COOH N NH2 H COOH

HOOC

4) NaOH 5) H2, Pd/C

MECHANISM : H

H COOH

HOOC O

O

NH2

C6H5CH2OCOCl

H

Cbzo

Ac2O

Cbzo Cbzo

OEt

H2N EtO

N

H O

HO N

H

O

O

OEt H O

H O

Cbzo

N

H

H

H N

H O

OEt

NH2 O

OH

O

HO NaOH

N

O

H

O N H

COOH HOOC

O

H O

H2, Pd/C

OH

184

HOOC

N

H H

COOH

COOH

DISCONNECTION :

O H2N R

R1 N H

R1

R

OCH3

COOH H2N

O

O

+ H2N

OCH3

NOTES : A development of the Fischer peptide synthesis in which an amino acid is transformed by benzyl chloroformate into the N-carbobenzoxy derivative. The protected amino acid is converted into the acid chloride, azide or anhydride, which is condensed with a second amino acid or suitable derivative. The carbobenzoxy group (Cbzo) is removed by catalytic hydrogenation of the resulting peptide. The method permits amino dicarboxylic acids to be used in the preparation of polypeptides. See also Fischer peptide, Leuchs – Bergmann and Sheehan – Frank reactions.

REFERENCES : Org. Synth. : 23, 13 Org. Synth. Coll. Vol. : 3, 167

1) K. Freudenberg; W. Dürr; H. von Hochstetter, Ber. Dtsch. Chem. Ges., 1928, 61, 1735. 2) M. Bergmann; L. Zervars; W. Ross, J. Biol. Chem., 1935, 111, 245. 3) H.D. Springall; H.D. Law, J. Chem. Soc., Quat. Rev., 1956, 10, 234. 4) M. Sokolovsky; M. Wilchek; A. Patchornik, J. Am. Chem. Soc., 1964, 86, 1202. 5) T. Mizuno; J. Takahashi; A. Ogawa, Tetrahedron Lett., 2002, 43, 7765.

COMMENTS :

185

BERGMANN ANTHRACENE REACTION EXAMPLE :

Cl

Ph

Ph

Cl heat Ph

Cl

Ph

MECHANISM :

Ph

Cl

Cl

Cl

Ph

Cl H

Ph Cl

Cl

H+ Ph Ph

Ph Cl

Cl - HCl

H

Ph

Ph

DISCONNECTION : Ph

Ph

Cl

Ph

Cl

Cl

Ph

NOTES : This reaction is exemplified by the fact that 9,10-dichloro-9,10-diphenyl-9,10-dihydroanthracene forms 2-chloro-9,10diphenylanthracene on heating. See also Robert reaction.

REFERENCES : E. Bergmann; O. Blum–Bergmann, J. Am. Chem. Soc., 1937, 59, 1439.

186

COMMENTS :

BERGMANN AZLACTONE PEPTIDE SYNTHESIS EXAMPLE :

O H

+

H N

H3C

H H N

COOH

H2N

1) Ac2O CH3 O 2) H2N H OH 3) H2 4) HCl

O

O H

CH3 COOH

MECHANISM :

O H

+

O

H N

H3C

COOH Ac2O, - 2 H2O

O

Ph O N H3C

H

H H2N

HCl

N H H

CH3

COOH O COOH

O Pd/C, H2

N H3C

H

N COOH H H

COOH

H N O

COOH COOH

COOH

H

Ph

O

NH2

O

H+ N

H

COOH

DISCONNECTION :

R2 H2N

H H N O H

R1

H N

R

COOH O

187

COOH +

R1 H2N

O COOH +

H

R2

H

NOTES : The formation of peptides from amino acids and azlactones of acylated amino acids. The formation of the azlactone is the Erlenmeyer – Früstück reaction. See also Dakin azlactone, Erlenmeyer – Früstück and Erlenmeyer – Plöchl reactions.

REFERENCES : Houben – Weyl : 11/2, 374 Org. React. : 3, 216 Org. Synth. : 19, 1 Org. Synth. Coll. Vol. : 2, 1

1) E. Erlenmeyer; E. Früstück, Liebigs Ann. Chem., 1895, 284, 48. 2) M. Bergmann; F. Stern; C. Witte, Liebigs Ann. Chem., 1926, 449, 277. 3) E. Baltazzi, J. Chem. Soc., Quat. Rev., 1955, 9, 161. 4) H.D. Springall; H.D. Law, J. Chem. Soc., Quat. Rev., 1955, 10, 235. 5) M.R. Harnden, J. Chem. Soc. (C), 1967, 2341. 6) K.K. Babievskii; Yu.A. Davidovich; V.I. Bakhmutov; S.V. Rogozhin, Izv. Akad. Nauk. SSSR Ser. Khim., 1988, 649. (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 37, 549.) 7) I.N. Lisichkina; T.A. Larina; A.S. Peregudov; T.Yu. Vasil’eva; V.M. Belikov, Izv. Akad. Nauk. Ser. Khim., 1999, 904. (Russ. Chem. Bl., 1999, 48, 895.)

COMMENTS :

BERGMANN DEGRADATION OF PEPTIDES EXAMPLE :

H H2N

O H CH3 H

N H

H

O H

N

Bu COOH

H2N 1) PhNCO 2) CH2N2 3) NH2NH2 4) HNO2 5) C6H5CH2OH 6) H2, Pd/C 7) H2O

188

O H CH3 H

N H

O NH2

MECHANISM : O H CH3

H H2N

N H

H

Ph

N

H

N H

O

PhNCO

Bu

H H

N

O

O H N H

H

CH3 O H

N

COOH Ph

N

O

H H

N H

H

Ph O

NH2NH2

N

Bu

O

OCH3

N

O

H H N H

Ph O

N

O H N H

H

H H N H

CH3 O H

H

Bu

O

N3

N

H H N H

H Bu

H2O

H2N

N H

HNO2 NH2

O H CH3 N H

H

O H

N

H Ph

O H

N

C6H5CH2OH

O H CH3 N H

N H

O

N

O H CH3 O N H H N Bu H O

Ph Ph

H H

N

O H

CH2N2

COOH

O H CH3

N H

Bu

Bu N

O

H2, Pd/C - CO2, - toluene

O

O H CH3 N H

H

O

+ BuCHO + NH3

NH2

NH2

DISCONNECTION :

Peptide NH2

H

Peptide N Bu COOH

NOTES : The free amino group of the polypeptide is protected by treatment with phenyl isocyanate and the free carboxyl group is methylated with diazomethane. The ester is converted by hydrazine into the hydrazide, which yields the azide with nitrous acid. Treatment of the azide with benzyl alcohol forms the benzylurethane. This urethane is catalytically hydrogenated (H2, Pd/C) to yield the phenylureide of a polypeptide amide with one less amino acid than the starting material, an identifiable aldehyde and toluene. The peptide amide can be further treated with an equivalent amount of hydrazine and again converted into the hydrazide and through the azide into the benzylurethane and so on. See also

Bergmann – Zervas, Curtius, Edman degradation and Schlack – Kumpf reactions.

189

REFERENCES : 1) M. Bergmann, Science, 1934, 79, 439. 2) M. Bergmann; L. Zervas, J. Biol. Chem., 1936, 113, 341.

COMMENTS :

BERNTHSEN ACRIDINE SYNTHESIS EXAMPLE :

CH3 AcOH, ZnCl2

N H

N

MECHANISM :

H3C

H O

+

H

CH3

CH3

N H

- H2O

190

OH CH3 N

ZnCl2

HO

- H2O

HO

OH H N

HO N H

OH CH3

N

H

DISCONNECTION :

H N RCOOH

R2

R1

+

N R2

R1 R

O

O R

O

H N +

R1

R2

R

NOTES : The synthesis of 5-substituted acridines by heating a diarylamine with an organic acid or anhydride in the presence of a Lewis acid, usually zinc chloride. See also Pfitzinger – Borsche, Ullmann – Fetvadjian and Ullmann – La Torre reactions.

REFERENCES : Smith : 1346 Smith 2nd : 1107 Houben – Weyl : E7b, 133

1) A. Bernthsen, Liebigs Ann. Chem., 1878, 192, 1. 2) F.D. Popp, J. Org. Chem., 1962, 27, 2658. 3) L.H. Klemm; E. Chiang; G.W. Obannon, J. Heterocycl. Chem., 1992, 29, 571. 4) M.D. Mosher; T.D. Morris; S. Westerbuhr; C. Foster, Heterocycl. Commun., 1996, 2, 521. 5) J.A. Seijas; M.P. Vázquez–Tato; M.M. Martínez; J. Rodríguez–Parga, Green Chem., 2002, 4, 390.

COMMENTS :

191

BERNTHSEN PHENOTHIAZINE SYNTHESIS EXAMPLE :

H3C

H3C

N N CH3

N H

S8, I2

S

N

N H

N CH3

DISCONNECTION :

S R

R1

R

R1

N H

N H

NOTES : The synthesis of phenothiazine from diphenyl amine. Iodine or aluminium chloride are used as catalyst. See also

Ferrario – Ackerman reaction.

REFERENCES : 1) A. Bernthsen, Ber. Dtsch. Chem. Ges., 1883, 16, 2896. 2) S.P. Massie, Chem. Rev., 1954, 54, 797. 3) C. Bodea; I. Silberg, Adv. Heterocycl. Chem., 1968, 9, 321. 4) P. López–Alvarado; C. Avendaňo; M.T. Grande; J.C. Menédez, Heterocycles, 1990, 31, 1983. 5) P. López–Alvarado; C. Avendaňo; J.C. Menédez, Heterocycles, 1991, 32, 1003. 6) G. Boyer; F. Chatel; J.-P. Galy, Arkivoc, 2000, 1, 563.

COMMENTS :

192

BERSON – WILLCOTT REARRANGEMENT EXAMPLE :

H CO2CH3

H CO2CH3 H

Ac2O, SnCl4 DCM, 0 oC

MECHANISM :

7 b 6 D a D 1 5 4 2 3

D 6 a 1

rotation about a 7

c

2

D 5 4

rotation about c

2 c

3

6

D 1

7

D 5 4

d 3

D D

D

D D

D

NOTES : Originally, this rearrangement involves the intramolecular skeletal reorganisation of tropilidene. This rearrangement can be expanded to many other systems.

REFERENCES : 1) E. Ciganek, J. Am. Chem. Soc., 1965, 87, 652. 2) J.A. Berson; M.R. Willcottt III, J. Am. Chem. Soc., 1965, 87, 2751. 3).J.A. Berson; M.R. Willcottt III, J. Am. Chem. Soc., 1965, 87, 2752. 4) J.A. Berson; M.R. Willcottt III, J. Am. Chem. Soc., 1966, 88, 2494. 5) J.A. Berson; P.W. Grubb; R.A. Clark; D.R. Hartter; M.R. Willcottt III, J. Am. Chem. Soc., 1967, 89, 4076. 6) N.J. Turro; M. Tobin; L. Friedman; J.B. Hamilton, J. Am. Chem. Soc., 1969, 91, 516. 7) D.G. Barrett; S.H. Gellman, Tetrahedron Lett., 1994, 35, 2299.

193

COMMENTS :

BERTRAM – WALBAUM SYNTHESIS EXAMPLE : CH3

H3C

CH3 CH3 50 % H2SO4 glac. CH3COOH 50 oC

H3C

O

O

CH3

MECHANISM : CH3

CH3 CH3

CH3

H+, CH3COOH, heat

CH3COO

CH3 rearranged carbocation CH3

H3C

CH3 CH3 O H3C

O

H3C

CH3

O

O CH3

DISCONNECTION :

H3C

CH3 CH3 CH3

H3C

O

O CH3

194

NOTES : The formation of isobornyl esters from camphene by the action of organic acids in the presence of sulfuric acid. See also Wagner – Meerwein rearrangement.

REFERENCES : 1) J. Bertram; H. Walbaum, J. Prakt. Chem., 1894, 49, 1. 2) P. Hirsjärvi, Acta. Chem. Scan., 1956, 10, 249.

COMMENTS :

BESTMANN REACTION EXAMPLE : O

CHO O

OH (Ph)3P C C O

MECHANISM : O A Z

X (Ph)3P C C X +

O

Z

A

X H

C Y YH

(Ph)3P C

- OP(Ph)3 Z

H

H3C (Ph)3P C C X

+

N

X

CH3 A

YH

C6H6 reflux

PPh3 X - HN(CH3)2

A C Y

A Y

195

(Ph)3P C

N CH3 H3C

H

Y A

DISCONNECTION :

X H Z

Y A

(Ph)3P C C X

+

O

X = O, NPh Y = heteroatom Z = O, N

Z

A

YH

NOTES : Cumulated ylides react with compounds containing an acidic Y-H bond and a carbonyl group or a nitroso group in the same molecule to give heterocyclic compounds.

REFERENCES : 1) H.-J. Bestmann; G. Schmid, Angew. Chem., Int. Ed. Engl., 1974, 13, 273. 2) H.-J. Bestmann; G. Schmid, Angew. Chem., Int. Ed. Engl., 1974, 13, 473. 3) G. L’Abbe; S. Toppet; G. Verhulst; C. Martens, J. Org. Chem., 1974, 39, 3770. 4) H.-J. Bestmann; G. Schmid; D. Sandmeier, Angew. Chem., Int. Ed. Engl., 1976, 15, 115. 5) H.-J. Bestmann; C. Geismann, Liebigs Ann. Chem., 1977, 282. 6) H.-J. Bestmann; R. Schobert, Angew. Chem. Int. Ed. Engl., 1985, 24, 790.

COMMENTS :

BETTI REACTION EXAMPLE :

O

NH2 +

H

+ N OH

196

1) HCl, H2O 2) KOH

N H

N H

OH

MECHANISM : Ph Ph

OH

H + NH3

2

Ph

O

N

N

Ph

H

Ph

- H2O

O

H O H

H H Ph

H

Ph N

Ph OH

H NH2.HCl OH

Ph

NH2 OH

KOH - KCl - H2O

aq. HCl

DISCONNECTION :

R

H N

R NH2 X R1

OH

X = C, N R = H, Alk, Ar

+

R1CHO + X OH

NOTES : Naphthols, quinolinols condense with aromatic aldehydes and primary aromatic or heterocyclic amines to yield aminomethyl derivatives. In some cases cyclic compounds are obtained. Ammonia and amides have also been employed. The formed amino phenol compounds have been reported as ligands in metal ion-catalysed asymmetric reactions. See also Mannich and Pictet – Spengler reactions.

REFERENCES : Houben – Weyl : 11/1, 759 Org. Synth. : 9, 60 Org. Synth. Coll. Vol. : 1, 381

1) M. Betti, Gazz. Chim. Ital., 1900, 30/2, 301. 2) M. Betti, Gazz. Chim. Ital., 1901, 31/2, 170. 3) F. Pirrone, Gazz. Chim. Ital., 1936, 66, 518. 4) F. Pirrone, Gazz. Chim. Ital., 1937, 67, 529. 5) J.P. Philips, Chem. Rev., 1956, 56, 271.

197

6) H. Möhrle; C. Miller; D. Wendisch, Chem. Ber., 1974, 107, 2675. 7) C. Cardellicchio; G. Ciccarella; F. Naso; E. Schingaro; F. Scordari, Tetrahedron: Asymmetry, 1998, 9, 3667. 8) C. Cimarelli; G. Palmieri; E. Volpini, Tetrahedron: Asymmetry, 2002, 13, 2417. 9) Y. Dong; J. Sun; X. Wang; X. Xu; L. Cao; Y. Hu, Tetrahedron: Asymmetry, 2004, 15, 1667.

COMMENTS :

BIELLMANN ALKYLATION EXAMPLE :

CH3

SPh H3C

1) nBuLi, THF, DABCO O CH3 2) Cl

CH3

H3C

CH3

3) EtNH2, Li

MECHANISM :

R1 R2

R4

R

R1 SPh

R3 R

n

BuLi, DABCO THF

R2

R1

R5

R2

R SPh

R5 R4

EtNH2, Li

R4

R5

SPh

198

R3 R

R3 Br R1 R2

O

DISCONNECTION :

R4

R3 R

R1

R1

R4

R

R3

+ R5

R2

R2

SPh

R5

Hal

NOTES : The coupling of allylic halides and allylic thiocarbanions. The thiophenyl group is removed after activation of the adjacent carbon for nucleophilic attack.

REFERENCES : March : 457 Smith – March : 542 Smith : 744 Smith 2nd : 630 Org. React. : 27,1

1) J.F. Biellmann; J.B. Ducep, Tetrahedron, 1971, 27, 5861. 2) P.A. Grieco; Y. Masaki, J. Org. Chem., 1974, 39, 2135. 3) L.J. Altman; L. Ash; S. Marson, Synthesis, 1974, 129. 4) M. Kodama; K. Shimada; T. Takahashi; C. Kabuto; S. Itô, Tetrahedron Lett., 1981, 22, 4271. 5) J. Butera; J. Rini; P. Helquist, J. Org. Chem., 1985, 50, 3676.

COMMENTS :

199

BIGINELLI PYRIMIDONE SYNTHESIS EXAMPLE :

H2N

NH2

H3C

+

H + O

O

H3C

OEt H+, EtOH, heat

O

O

H N

O H

CH3

N

OEt CH3 O

MECHANISM :

H OH

O O H2N

NH2

O

H+

H+, - H2O

N H

H

NH2

O

O

N H H2N

EtO

EtOOC

N

H3C

O H3C - H+

O

O H2N

H

N

EtO

- H2O

O

H3C

N H

H O

DISCONNECTION : R N

O H

R1

R

NH2 +

N

R2

O

R1

H3C

H

R2

+ O

O

CH3

NOTES : The formation of pyrimidines from aldehydes, β-ketocarboxylic esters and urea. There are four ways to assemble the pyrimidine ring. Over the last 100 years several mechanistic proposals appeared in the literature. The best known modification brought about by the need for better yields is done by Atwal et al. An enone is reacted with a protected urea or thiourea derivative under neutral conditions. Several other improved syntheses have been reported, e.g. bismuth triflate catalysed by Adapa et al. and lithium bromide catalysed by Maiti et al.

REFERENCES : Org. React. : 14, 88; 63, 1

200

1) P. Biginelli, Ber. Dtsch. Chem. Ges., 1891, 24, 1317. 2) L.E. Hinkel; D.H. Hey, Recl. Trav. Chim. Pays-Bas, 1929, 48, 1280. 3) K. Folkers; T.B. Johnson, J. Am. Chem. Soc., 1933, 55, 3784. 4) A. Ehsan; Karimullah, Pak. J. Sci. Ind. Res., 1967, 10, 83. 5) F. Sweet; J.D. Fissekis, J. Am. Chem. Soc., 1973, 95, 8741. 6) K.S. Atwal; G.C. Rovnyak; B.C. O’Reilly; J. Schwartz, J. Org. Chem., 1989, 54, 5898. 7) C.O. Kappe, Tetrahedron, 1993, 49, 6937. 8) C.O. Kappe, J. Org. Chem., 1997, 62, 7201. 9) C.O. Kappe, Molecules, 1998, 3, 1. 10) C.O. Kappe, Acc. Chem. Res., 2000, 33, 879. 11) B.C. Ranu; A. Hajra; U. Jana, J. Org. Chem., 2000, 65, 6270. 12) F.S. Falsone; C.O. Kappe, Arkivoc, 2001, 2, 1111. 13) F. Cohen; L.E. Overman, J. Am. Chem. Soc., 2001, 123, 10782. 14) M. Kidwai; S. Saxena; R. Mohan; R. Venkataramanan, J. Chem. Soc., Perkin Trans. 1, 2002, 1845. 15) F. Cohen; S.K. Collins; L.E. Overman, Org. Lett., 2003, 5, 4485. 16) R. Varala; M.M. Alam; S.R. Adapa, Synlett, 2003, 67. 17) G. Maiti; P. Kundu; C. Guin, Tetrahedron Lett., 2003, 44, 2757. 18) Z.D. Aron; L.E. Overman, Chem. Commun., 2004, 253. 19) A.K. Bose; S. Pednekar; S.N. Ganguly; G. Chakraborty; M.S. Manhas, Tetrahedron Lett., 2004, 45, 8261.

COMMENTS :

BINGEL REACTION EXAMPLE :

2.5 Br

PO3Et2 PO3Et2 H

NaH, Toluene, 60 OC

O

O

OEt P P

OEt OEt OEt 2

201

MECHANISM :

EtOOC

COOEt Br

COOEt

EtOOC

COOEt

- NaBr

Br COOEt Toluene, NaH

NOTES : This is one of the most common fullerene functionalisation methods. It is the nucleophilic cyclopropanation with 2halomalonates. Retro-Bingel reaction have also been investigated.

REFERENCES : 1) C. Bingel, Chem. Ber., 1993, 126, 1957. 2) A. Hirsch; I. Lamparth; H.R. Karfunkel, Angew. Chem., Int. Ed. Engl., 1994, 33, 437. 3) N.N.P. Moonen; C. Thilgen; L. Echegoyen; F. Diederich, Chem. Commun., 2000, 335. 4) K. Fujiwara; K. Komatsu; G.W. Wang; T. Tanaka; K. Hirata; K. Yamamoto; M. Saunders, J. Am. Chem. Soc., 2001,

123, 10715. 5) A.L. Mirakyan; L.J. Wilson, J. Chem. Soc., Perkin Trans. 2, 2002, 1173. 6) Y. Nakamura; M. Suzuki; Y. Imai; J. Nishimura, Org. Lett., 2004, 6, 2797. 7) N. Chronakis; A. Hirsch, Chem. Commun., 2005, 3709.

COMMENTS :

BINKLEY TRIFLATE DISPLACEMENT EXAMPLE :

H3C BzO

H3C

O

HO

OCH3

HO H

1) Tf2O 2) H2O

202

O OCH3

OBz

H

MECHANISM :

H3C HO

O OCH3

OBz

H H2O

H3C BzO

H3C

O

BzO

OCH3

HO

Tf2O

O OCH3

TfO

H

H

Et3N

H3C HO

H3C O OCH3

BzO

TfO Tf2O

O OCH3

BzO H

H

H2O

OBz CH 3

O OCH3

HO H

203

H3C BzO

O OCH3

Br

H Br-

BzO

H3C

H3C

O

BzO

OCH3

HO

O OCH3

TfO

Tf2O Me3C

H

H N CMe3

Me3C

H3C

H3C

O

O

OCH3

TfO Ph

O

O

OCH3

Ph

H

O

O

H

OTf H3C O

H2O O

Ph

X = Br, NO3

OCH3

HO O

H

H3C BzO X

O OCH3 H

H3C HO

O OCH3

OBz

H

NOTES : The interconversion of 2,6-dideoxysugars at room temperature by internal triflate displacement by a neighbouring benzoyl group. The reaction is well-suited for the inversion of configuration. The reaction is similar to the Hanessian –

Hullar reaction except that in the Hanessian – Hullar reaction the intermediate cation can only be captured by the bromide ion and not by other nucleophiles. In this reaction the cation is formed but without an effective nucleophile present. See also Hanessian – Hullar reaction.

204

REFERENCES : 1) R.W. Binkley; M.R. Sivik, J. Carbohydr. Chem., 1986, 5, 647. 2) R.W. Binkley; M.R. Sivik, J. Org. Chem., 1986, 51, 2619. 3) R.W. Binkley, J. Org. Chem., 1991, 56, 3892.

COMMENTS :

BIRCH – HAAS REACTION EXAMPLE : Ph H H3CO H

Ph

H

H H Fe(CO)3

H 1) TFA 2) NH4PF6 0 oC, 3h

H

H

H Fe(CO)3

PF6

MECHANISM :

OCH3 Fe(CO)3 OCH3

H+ or

Fe(CO)3

OCH3 H+ Fe(CO)3

H3CO

H

H3CO

H

H

Fe(CO)3

Fe(CO)3

205

Fe(CO)3

DISCONNECTION :

R6 R1

R5 R4 Fe(CO)3 PF6 R3 R6

R1

R6 R5

R1

R4 Fe(CO)3 PF6

R2

R3

R5endo R5exo R4 Fe(CO)3

R3

R6 R1

R5 R4 Fe(CO)3 PF6 R3

NOTES : The removal of methoxy groups of tricarbonyliron complexes of 1- or 2-methoxycyclohexadienes using concentrated sulfuric acid or trifluoroacetic acid and ammonium hexafluorophosphate to give tricarbonyl-π-cyclohexadienyl iron salts. The reaction proceeds by rearrangement of the diene complex until an allylic leaving group is encountered.

REFERENCES : Science of Synthesis : 1, 765

1) A.J. Birch; M.A. Haas, J. Chem. Soc. (C), 1971, 2465. 2) A.J. Birch; L.F. Kelly; D.J. Thompson, J. Chem. Soc., Perkin Trans. 1, 1981, 1006. 3) A.J. Birch; B. Chauncy; L.F. Kelly; D.J. Thompson, J. Organomet. Chem., 1985, 286, 37. 4) A. McKillop; G.R. Stephenson; H. Finch; S. Swanson, Tetrahedron Lett., 1989, 30, 2607. 5) R.D.A. Hudson; S.A. Osborne; G.R. Stephenson, Tetrahedron, 1997, 53, 4095.

COMMENTS :

206

BIRCH REDUCTION EXAMPLE :

Li, NH3 EtOH

MECHANISM :

OMe

OMe

OMe

OMe or

e-

ROH

OMe

OMe e-

ROH

DISCONNECTION :

OR

OR

CO2R

CO2R

NOTES : The reduction of aromatics using metals and ammonia on a small scale. Other functional groups may react under

Birch conditions. Note the difference in orientation between the donor and acceptor groups. See also Benkeser reduction.

207

REFERENCES : March : 781 Smith – March : 1010 Smith : 463 Smith 2nd : 400 Houben – Weyl : E3, 475; E6a, 496, 857; E6b, 145, 1021, 1224; E7b, 673; E15, 111; E16d, 457, 814 Org. React. : 42, 1 Org. Synth. : 37, 80; 43, 22, 49, 62; 54, 11; 61, 59 Org. Synth. Coll. Vol. : 4, 887; 5, 400, 467; 6, 731; 7, 249 Science of Synthesis : 10, 212

1) F.O. Rice; E. Teller, J. Chem. Phys., 1938, 6, 489. 2) A.J. Birch, J. Chem. Soc, 1944, 430. 3) C.W. Watt, Chem. Rev., 1950, 46, 317. 4) A.J. Birch; H. Smith, J. Chem. Soc., Quat. Rev., 1958, 12, 17. 5) B. Robinson, Chem. Rev., 1969, 69, 785. 6) J.W. Ashmore; G.K. Heimkamp, Org. Prep. Proced. Int., 1976, 8, 223. 7) A.J. Birch; A.L. Hinde; L. Radom, J. Am. Chem. Soc., 1980, 102, 3370. 8) R. Kannan; P. Geetha; S. Swaminathan, Tetrahedron Lett., 1984, 42, 1601. 9) A.G. Schultz; L. Pettus, J. Org. Chem., 1997, 62, 6855. 10) A.G. Schultz, Chem. Commun., 1999, 1263. 11) Z. Guo; A.G. Schultz, J. Org. Chem., 2001, 66, 2154. 12) H. Pellissier; M. Santelli, Org. Prep. Proced. Int., 2002, 34, 611. 13) J. Jiang; Y.-H. Lai, Tetrahedron Lett., 2003, 44, 1271. 14) L.F. Tietze; S. Hölsken; J. Adrio; T. Kinzel; C. Wegner, Synthesis, 2004, 2236. 15) M.C. Elliott; M.J. Gist; F. Binns; R.G. Jones, Tetrahedron Lett., 2004, 45, 2899.

COMMENTS :

208

BIRCKENBACH – GOUBEAU – WATERS REACTION EXAMPLE :

I AgClO4, I2

MECHANISM :

C6H6 + I2

C6H5I + HI

HI + AgClO4

AgI + HClO4

DISCONNECTION :

ArX

ArH Ar = C6H4R, R = H, CH3, Cl, Br, NO2, COOH X = Br, I

NOTES : The halogenation (bromine and iodine) of aromatic compounds (substituted benzene and napthalenes) with halide cations in the presence of silver perchlorate with or without magnesium oxide.

REFERENCES : 1) L. Birckenbach; J. Goubeau, Ber. Dtsch. Chem. Ges., 1932, 65, 395. 2) L. Birckenbach; J. Goubeau, Ber. Dtsch. Chem. Ges., 1933, 66, 1280.

COMMENTS :

209

BIRNBAUM – SIMONINI SYNTHESIS EXAMPLE : O

O H3C

OAg

1) I2 2)

H3C

OEt

O

H3C

OAg

MECHANISM : O

O R R

OAg

I

I2 - CO2 - AgI

R1

O R1

OR

OAg

DISCONNECTION :

O

O R1

R

OR

OAg

NOTES : The decarboxylation of carboxylic acids with iodine to afford esters (2:1 ratio salt ester, a 1:1 ratio will give the alkyl iodide). Lead salts can be used instead of silver salts. See also Hunsdiecker – Borodin, Prévost and Woodward cis-hydroxylation reactions.

REFERENCES : March : 731 Smith – March : 942 Houben – Weyl : 5/4, 659 Org. React. : 9, 332

1) A. Simonini, Monatsh. Chem., 1892, 13, 320. 2) J. Kleinberg, Chem. Rev., 1947, 40, 381. 3) R.G. Johnson; R.K. Ingham, Chem. Rev., 1956, 56, 219. 4) N.J. Bunce; N.G. Murray, Tetrahedron, 1971, 27, 5323.

210

COMMENTS :

BISCHLER – MÖHLAU INDOLE SYNTHESIS EXAMPLE :

Br

+ NH2

C6H5NH2. HBr

N H

O

MECHANISM :

R1

R1

+ X

NH2

N H

- HBr O

O

R1 NH2

R1

R1 N H

N N

H N

R1

R1

R1 N H

211

R1 N H

DISCONNECTION :

R1 N R

R = CH3, Et, (CH3)2

Br

+

R

O

N H

R

NOTES : An α-alkylaminoaryl ketone reacts with an aromatic amine to give an indole. α-Halogeno- and α-hydroxy-ketones can also be employed with intermediate formation of the α-amino compound. It is noteworthy that 2-arylindoles and not the expected 3-aryl compounds are obtained. The Nordlander modification involves a combination of trifluoroacetic acid and trifluoroacetic anhydride to affect the cyclisation. Sundberg later used titanium(IV)chloride in the cyclisation step. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Cadogan –

Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito,

Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 390

1) R. Möhlau, Ber. Dtsch. Chem. Ges., 1881, 14, 171. 2) A. Bischler; H. Brion, Ber. Dtsch. Chem. Ges., 1892, 25, 2860. 3) A. Bischler; P. Firemann, Ber. Dtsch. Chem. Ges., 1893, 26, 1336. 4) K. LeRoi Nelson; R.L. Seefeld, J. Am. Chem. Soc., 1958, 80, 5957. 5) D.St. Black; B.M.K.C. Gatehouse; F. Theobald; L.C.H. Wong, Aust. J. Chem., 1980, 33, 343. 6) J.E. Nordlander; D.B. Catalane; K.D. Kotian; R.M. Stevens; J.E. Haky, J. Org. Chem., 1981, 46, 778. 7) R.J. Sundberg; J.P. Laurino, J. Org. Chem., 1984, 49, 249. 8) J. Graham; A. Ninan; K. Reza; M. Sainsbury; H.G. Shertzer, Tetrahedron, 1992, 48, 167. 9) C.J. Moody; E. Swann, Synlett, 1998, 135. 10) J.R. Henry; J.H. Dodd, Tetrahedron Lett., 1998, 39, 8763.

COMMENTS :

212

BISCHLER – NAPIERALSKI REACTION EXAMPLE : H N

CH3 O

N

1) POCl3 2) KMnO4

CH3

MECHANISM :

N H R

Cl O P Cl Cl

O

R

N H Cl O P Cl O

R

N H

H H

H N

R

Cl O P Cl O

R

N H Cl O P Cl O

N H Cl O P Cl O

- HOP(O)Cl2

H H

N

KMnO4 R

R

DISCONNECTION :

R2

R2

R3

R1 N

R4 R

R

R3 R = Alk, Ar R4 R1, R2 = H, Alk R3, R4 = H, Alk

O N

H

R1

NOTES : The cyclodehydration of β-phenylethylamides to 3,4-dihydroisoquinolines by treatment with phosphorous oxychloride, phosphorous pentoxide, phosphorous pentachloride, polyphosphoric acid, anhydrous zinc chloride or other dehydrating agents. See also Bamberger – Goldschmidt, Bobbit, Bruckner, Larock indole, Pictet – Gams, Pictet

– Sprengler, Pomeranz – Fritsch, Simchen and Schlitter – Müller ring-closure reactions.

213

REFERENCES : March : 549 Smith – March : 721 Smith : 1339 Smith 2nd : 1101 Houben – Weyl : E7a, 612, 622, 648, 672; E7b, 351; E8a, 364 Org. React. : 6, 74 Org. Synth : 56, 3 Org. Synth. Coll. Vol. : 6, 1

1) A. Bischler; B. Napieralski, Ber. Dtsch. Chem. Ges., 1893, 26, 1903. 2) A. Pictet; A. Gams, Ber. Dtsch. Chem. Ges., 1909, 42, 2943. 3) R.H. Manske, Chem. Rev., 1942, 30, 145. 4) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 5) G. Fodor; S. Nagubandi, Tetrahedron, 1980, 36, 1279. 6) C.S. Hilger; B. Fugmann; W. Steglich, Tetrahedron Lett., 1985, 26, 5975. 7) W.D.F. Meutermans; P.F. Alewood, Tetrahedron Lett., 1995, 36, 7709. 8) P.A. Wender; T.E. Smith, J. Org. Chem., 1996, 61, 824. 9) C. Locher, Synth. Commun., 2001, 31, 2895. 10) M. Nicoletti; D.J. O’Hagan; A.M.Z. Slawin, J. Chem. Soc., Perkin Trans. 1, 2002, 116. 11) Z.M.A. Judeh; C.B. Ching; J. Bu; A. McCluskey, Tetrahedron Lett., 2002, 43, 5089. 12) B. Pal; P. Jaisankar; V.S. Giri; S. Mondal; M. Mukherjee, Tetrahedron Lett., 2004, 45, 6489. 13) A. Spaggiari; P. Davoli; L.C. Blaszcak; F. Prati, Synlett, 2005, 661.

COMMENTS :

214

BISCHLER CYCLISATION EXAMPLE : O

CH3 CH3 H

N H3C

N NH3, NaOAc, EtOH 100 - 170 oC

O

N

CH3

MECHANISM : CH3

O

N H3C

CH3

N H

CH3 H

NH3 - H2O

H H3C

O

N

N O

N CH3 OH H H+

CH3 N - H2O

N

CH3

DISCONNECTION : R1

O N

R N

R R2 R = H, Cl, NO2, CN R1 = Alk, Ar R2 = Alk, OH, Cl, Ar

N R2

R1 H O

NOTES : o-Acylamino–aldehydes and –ketones cyclise to yield a quinazoline derivatives by heating with aqueous alcoholic

ammonia or with ammonia in the presence of molten ammonium acetate.

REFERENCES : 1) A. Bischler, Ber. Dtsch. Chem. Ges., 1891, 24, 506. 2) A. Bischler; D. Barad, Ber. Dtsch. Chem. Ges., 1892, 25, 3080. 3) K. Schofield; T. Swain; R.S. Theobald, J. Chem. Soc., 1952, 1924.

215

COMMENTS :

BISCHLER TRIAZINE SYNTHESIS EXAMPLE : H N O2N

N NH2

NO2

1) HCOOH H2N Pd/C, H2 2) K3Fe(CN)6 H2O

N

N

MECHANISM : H+ O

H N R

N H NO2 H N

R

N

R1 Na(Hg) EtOH CH3COOH

N - H2O

R N

O

N H NH2

R

H

R1 N OH H N

H N

R N H

R1

N K3Fe(CN)6 H2O

R1

N R1

DISCONNECTION :

N R N

H N

N

R

NH2

NO2

R1

216

NOTES : The benzotriazine synthesis from o-nitrophenylhydrazines. See also Bamberger triazine reaction.

REFERENCES : 1) A. Bischler, Ber. Dtsch. Chem. Ges., 1899, 22, 2801. 2) A. Bischler; S. Brodsky, Ber. Dtsch. Chem. Ges., 1889, 22, 2809. 3) A. Hempel, J. Prakt. Chem., 1890, 41, 161. 4) R.R. Abramovitch; K. Schofield, J. Chem. Soc., 1955, 2326.

COMMENTS :

BLAISE – GUERIN (BLAISE – LeSUEUR) DEGRADATION EXAMPLE : Cl H3C

O

H 1) Br2 2) aq. EtOH

CH3 O

MECHANISM : Cl R

O

Br Br2

H O

Cl

R

O

H

R

OH

R

H

o

aq. NaOH

O

R

190 - 200 C - CO, - H2O

O

DISCONNECTION : Cl R

O

O

NOTES : The acid chloride is α-brominated followed by hydrolysis with aqueous or alcoholic sodium hydroxide. Thermal degradation at 190 – 200 oC affords the aldehyde.

217

REFERENCES : 1) H.R. LeSueur, J. Chem. Soc., 1904, 85, 827. 2) E.E. Blaise, C.R. Séances Acad. Sci., 1904, 138, 697. 3) E.E. Blaise; E. Guerin, Ber. Schimmel and Co. A.G., Miltitz, Bez. Leipzig, 1929, 11, 17. 4) R.R. Davies; H.H. Hodgson, J. Soc. Chem. Ind., 1943, 62, 128.

COMMENTS :

BLAISE – MAIRE KETONE SYNTHESIS EXAMPLE : CH3

H CH3 Cl AcO

H3C ZnCl +

hydrolysis

O

H H

CH3

H2C O

MECHANISM :

R1

ZnCl +

H R

H R

Cl

H H

O

Cl

AcO H H O

- ZnCl2, hydrolysis

ZnCl

R

R1

HO H H

H R R1

AcO

- H2O

O

R1

H2C O

DISCONNECTION :

R R1

H2C O

H R

R2

H H

O

R1 ZnCl + R3 R2 = H, Alk, Cl R3 = OH, OAc

218

NOTES : The use of organometallic derivatives of zinc in the synthesis of β-hydroxy ketones and α,β-unsaturated ketones from β-acetoxy-acid chlorides. See also Cason and Grignard reactions.

REFERENCES : Org. React. : 8, 29

1) E.E. Blaise; M. Maire, C.R. Séances Acad. Sci., 1907, 145, 73. 2) E.E. Blaise; A. Koehler, Bull. Soc. Chim. Fr., 1910, 7, 215. 3) E. Späth; S.F. Darling, Ber. Dtsch. Chem. Ges., 1930, 63, 737. 4) M.A. Spielman, J. Biol. Chem., 1934, 106, 87. 5) A.K. Schneider; M.A. Spielman, J. Biol. Chem., 1934, 142, 345. 6) J. Cason, Chem. Rev., 1947, 40, 15.

COMMENTS :

BLAISE KETOESTER REACTION EXAMPLE :

CH3 O Br CH3 OCH3

O + N C CH3

Zn, HCl, Benzene

H3C

CH3 O CH3 OCH3

MECHANISM :

R

O

Zn

Br R1

OR2

R

O ZnBr BrZn N

R1 R3

OR2 N ZnBr

R3

219

R

O

R1

OR2

O H2O, H+ R3 - NH4+, HOZnBr

R

O

R1

OR2

DISCONNECTION :

O

R

O R3

R3

R1

N +

R

O

R1

OR2

Br

OR2

NOTES : The synthesis of β-ketoesters from α-bromoesters and nitriles in the presence of zinc. See also Grignard, Horeau –

Ormancey and Reformatsky reactions.

REFERENCES : March : 930 Smith – March : 1213 Houben – Weyl : 7/2a, 518 Org. Synth. : 35, 15; 37, 37; 74, 158 Org. Synth. Coll. Vol. : 4, 120, 444; 9, 275

1) E.E. Blaise, C.R. Séances Acad. Sci., 1901, 132, 38. 2) E.E. Blaise, C.R. Séances Acad. Sci., 1901, 132, 478. 3) J. Cason; K.L. Rinehart, jr.; S.D. Thornton, jr., J. Org. Chem., 1953, 18, 1594. 4) H.B. Kagan; Y. Heng–Suen, Bull. Soc. Chim. Fr., 1960, 1823. 5) S.M. Hammick; Y. Kishi, J. Org. Chem., 1983, 48, 3833. 6) J.J. Duffield; A.C. Regan, Tetrahedron: Asymmetry, 1996, 7, 663. 7) K. Narkunan; B.-L. Uang, Synthesis, 1998, 1713. 8) A.W. Enian, J. Prakt. Chem., 1999, 341, 147. 9) H.M. Deutsch; X.C. Yei; Q. Shi; Z.Z. Liu; M.M. Schweri, Eur. J. Med. Chem., 2001, 36, 303. 10) A.F.L. Creemers; J. Lugtenburg, J. Am. Chem. Soc., 2002, 124, 6324.

COMMENTS :

220

BLANC – QUELLET CHLOROMETHYLATION / CHLOROALKYLATION REACTION EXAMPLE : Cl + CH2O + HCl

ZnCl2

MECHANISM : Blanc variation :

H

H

H+

O

H O H

O H

H

H

H

H+

OH H

- H+

- H2O

OH

CH2

O H H

Cl-

Cl

Quellet variation :

H H3CO

H3CO H

CH3

CH3 H

OH

O H+ H H3CO

CH3 Cl

221

pyridine

H3CO

Cl

DISCONNECTION :

Cl

NOTES : The replacement of a hydrogen atom in an aromatic hydrocarbon by a chloromethyl group, also bromomethyl and some cases iodomethyl groups using formaldehyde or a derivative and hydrogen chloride usually in the presence of a catalyst such as zinc chloride, aluminium chloride, stannic chloride or sulfuric acid. Alkyl and alkoxy substituents increase the reaction rate, while halide, carboxyl and especially nitro groups slow down the reaction. The Quellet variant starts with the phenolether.

REFERENCES : March : 550 Smith – March : 721 Houben – Weyl : 5/3, 1001 Org. React. : 1, 63 Org. Synth. : 20, 59; 24, 30; 25, 69; 29, 35 Org. Synth. Coll. Vol. : 3, 195, 197, 468, 557

1) G. Grassi; C. Maselli, Gazz. Chim. Ital., 1898, 28, 477. 2) M.G. Blanc, Bull. Soc. Chim. Fr., 1923, 33, 313. 3) R. Quelet, C.R. Séances Acad. Sci., 1932, 199, 150. 4) U. Neda; R. Oda, J. Soc. Chem. Ind. Jpn. (Kógyó Kagaku Zassi), 1944, 47, 565. 5) N. Rabjohn, J. Am. Chem. Soc., 1954, 76, 5479. 6) G.A. Olah; D.A. Deal; J.A. Olah, J. Org. Chem., 1976, 41, 1627. 7) A. McKilloq; F.A. Madjdabadi; D.A. Long, Tetrahedron Lett., 1983, 24, 1933. 8) R.H. Mitchell; V.S. Iyer, Synlett, 1989, 55. 9) J. De Mendoza; P.M. Nieto; P. Prados; C. Sanchez, Tetrahedron, 1990, 46, 671. 10) K. Ito; Y. Ohba; E. Shinagawa; S. Nakayama; S. Takahashi; K. Honda; H. Nagafuji; A. Suzuki; T. Sone, J. Heterocycl. Chem., 2000, 37, 1479.

222

COMMENTS :

BLANC REACTION EXAMPLE : O COOH COOH

Ac2O heat

MECHANISM : O

COOH COOH

O

Ac2O - H2O

O

O O

COOH

O

O

Ac2O

COOH

heat - CO2

DISCONNECTION : O R

COOH COOH

R O COOH R

O

R COOH

O

223

NOTES : Adipic and pimelic acids, when heated with acetic anhydride and then distilled give cyclic ketones, whereas succinic and glutaric acids yield cyclic anhydrides. This rule is not always valid. Branching of the carbon chain promotes cyclisation. See Ružička large ring synthesis.

REFERENCES : Houben – Weyl : 7/2, 640

1) H.G. Blanc, C.R. Séances Acad. Sci., 1907, 144, 1356. 2) F. Vocke, Liebigs Ann. Chem., 1934, 508, 1. 3) W.E. Bachman; N.C. Deno, J. Am. Chem. Soc., 1949, 71, 3540.

COMMENTS :

BLICKE – PACHTER SYNTHESIS EXAMPLE :

H2N

N +

N

ON

Ph

H2N

CH3 NaCN

O

N

N N

N

NH2

NH2

MECHANISM :

H2N

- H2O

R

N

N

HCN NH2

NH2 H2N CN R

N H

NH2

N

+ RCHO

N

H2N

H2N

NH2

N

NH2

N N NH2

H2N NaOCH3 CH3OH

R

H N N H

224

N

NH2 N

NH2

H2O2

H2N

N

R

N

NH2

N N NH2

DISCONNECTION :

H2N

N

R

N

N

H2N

R1 N

N

R1 N

H2N

+ RCHO

NH2

NH2

NOTES : Pteridines are synthesised from aminopyrimidines with aldehydes and cyanide. The cyclisation step is done with sodium methoxide. See also Boon – Polonovski, Isay, Taylor and Timmis reactions.

REFERENCES : 1) F.F. Blicke; H.C. Godt, J. Am. Chem. Soc., 1954, 76, 2798. 2) I.J. Pachter; P.E. Nemeth, J. Org. Chem., 1963, 28, 1187. 3) I.J. Pachter, J. Org. Chem., 1963, 28, 1191. 4) I.J. Pachter; P.E. Nemeth; A.J. Villani, J. Org. Chem., 1963, 28, 1197. 5) I.J. Pachter; P.E. Nemeth, J. Org. Chem., 1963, 28, 1203.

COMMENTS :

BLOMQUIST REACTION EXAMPLE :

Cl O

Cl

O 1) Et3N, heat Et3N·HCl, Et2O 2) HCl 3) H2O 4) KOH, heat EtOH

225

O

MECHANISM :

O

O

O

O n

Cl

n

Cl

n

Et3N, heat Et2O

KOH, heat EtOH

O

DISCONNECTION :

O

O

n n

Cl

O

Cl

NOTES : Synthesis of macrocyclic ketones by intramolecular condensation of aliphatic diketenes obtained from acyl chlorides of dicarboxylic acids or acyl chlorides of unsaturated acids.

REFERENCES : 1) A.T. Blomquist; R.D. Spencer, J. Am. Chem. Soc., 1947, 69, 472. 2) A.T. Blomquist; R.D. Spencer, J. Am. Chem. Soc., 1948, 70, 30.

COMMENTS :

BLUM AZIRIDINE SYNTHESIS EXAMPLE :

H Ph

O

H H Ph

1) NaN3 aq. acetone 2) PPh3, Et2O

226

Ph

H N H

Ph

MECHANISM :

H

O

RNH2

H

R PPh3 H N H HO

H R H N H HO PPh3, CCl4

Ph Ph P O N R H H Ph

H+

Ph3PO

H NHR H

H

R N

H

Et3N

DISCONNECTION :

R

R1

H R1 HO

N R2

R2 N

R H

H

NOTES : The synthesis of aziridines from epoxides via amino alcohols or azido alcohols and reaction with phosphines or phosphites. See also Appel, Hassner azide aziridine, Gabriel – Marckwald – Cromwell ethylenimine method, Hoch

– Campbell, Mansuy – Evans, Scheiner and Wenker ring-closure reactions.

REFERENCES : 1) R. Appel; R. Kleinstück, Chem. Ber., 1974, 107, 7. 2) J. Blum; Y. Ittah; I. Shakak, Tetrahedron Lett., 1975, 16, 4607. 3) Y. Ittah; I. Shakak; J. Blum, J. Org. Chem., 1978, 43, 397. 4) Y. Ittah; Y. Sasson; I. Shakak; S. Tsaroom; J. Blum, J. Org. Chem., 1978, 43, 4271. 5) R. Appel; M. Halstenberg, Chem. Ber., 1978, 111, 814. 6) A. Willeit; E.P. Müller; P. Peringer, Helv. Chim. Acta, 1983, 66, 2467. 7) C. Chiappe; P. Crotti; E. Menichetti; M. Pineschi, Tetrahedron: Asymmetry, 1998, 9, 4079.

COMMENTS :

227

BOBBIT REACTION EXAMPLE :

EtO H2N

H +

H 1) H2, Pt 2) H+ 3) H+, EtOH, C6H5CHO

OEt O

N

MECHANISM :

H3C

H

EtO H2N

H

H3C

H3C

OEt

H3C CH3 O

CH3

N CH3

H2, Pt

OEt H OEt

OEt N

H3C

H

CH3

H3C

H3C NH2

H3C

H+

OEt

H3C

H3C H3C

N H OH H

OEt

H - H2O

OEt

H

CH3

H , EtOH PhCHO

Cl

N

H3C

+

CH3

DISCONNECTION : R1 EtO

R2 R R N

R = OH, OCH3 R1, R2 = H, OCH3

R1

OEt N

+ H

O

R2

NOTES : The synthesis of 4-substituted isoquinolines by cyclocondensation of substituted benzylaminoacetals with aromatic aldehydes in the presence of ethanolic hydrogen chloride. This reaction is based on the Fischer modification of the

228

Pomeranz – Fritsch reaction. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bruckner, Larock indole, Pictet – Gams, Pictet – Sprengler, Pomeranz – Fritsch, Schlitter – Müller ring-closure and Simchen reactions.

REFERENCES : Org. React. : 6, 19

1) W.D. Burrows; E.P. Burrows, J. Org. Chem., 1963, 28, 1180. 2) J.M. Bobbit; K.L. Khanna; J.M. Kiely, Chem. Ind. (London), 1964, 1950. 3) R. Grewe; W. Krüger; E. Vangermain, Chem. Ber., 1964, 97, 119. 4) J.M. Bobbit; J.M. Kiely; K.L. Khanna; R. Eberman, J. Org. Chem., 1965, 30, 2247. 5) J.M. Bobbit; D.P. Winter; J.M. Kiely, J. Org. Chem., 1965, 30, 2459. 6) W.J. Genster; K.T. Shamasundar; S. Marbury, J. Org. Chem., 1968, 33, 2861. 7) J.M. Bobbit; T.E. Moore, J. Org. Chem., 1968, 33, 2958.

COMMENTS :

BODROUX – CHICHIBABIN ALDEHYDE SYNTHESIS EXAMPLE :

H3C MgBr

+

OEt H OEt OEt

H

H3C +

H , H2O

O

MECHANISM :

R Br

Mg, Et2O

R MgBr

OEt H OEt + OEt

- MgBrOEt

229

OEt R H OEt

H

R +

H , H2O - 2 EtOH

O

DISCONNECTION :

R

H

R Br

O

NOTES : The products obtained by the action of Grignard reagents on ethyl orthoformate give aldehydes by acid hydrolysis. See also Bouveault aldehyde, Gattermann – Maffezzoli and Zelinsky reactions.

REFERENCES : Houben – Weyl : 6/3, 243; 7/1, 65 Org. Synth. : 16, 41 Org. Synth. Coll. Vol. : 2, 323

1) A.E. Chichibabin, J. Russ. Phys. Chem. Ges., 1903, 35, 1284. 2) F. Bodroux, C.R. Séances Acad. Sci., 1904, 138, 92. 3) L.I. Smith; M. Bayliss, J. Org. Chem., 1941, 6, 437. 4) N.A. LeBel; M.E. Post; J.J. Whang, J. Am. Chem. Soc., 1964, 86, 3759. 5) W.H. Urry; D.J. Trecker; H.D. Hartzler, J. Org. Chem., 1964, 29, 1663. 6) D.K. Hutchinson; P.L. Fuchs, J. Am. Chem. Soc., 1987, 109, 4755.

COMMENTS :

BODROUX REACTION EXAMPLE :

H N + MgI

O

O OCH3

230

N H

MECHANISM :

H N

H N MgI

H3CO

O

MgI

OCH3

O

MgI O + IMgOCH3

N H

DISCONNECTION :

O R

O N H

R2

R

OR1

+

I

R2 N

H

NOTES : An aminomagnesium halide, formed when a primary or secondary amine combines with a Grignard reagent at room temperature, reacts with a simple aliphatic or aromatic ester to yield a substituted amide.

REFERENCES : Houben – Weyl : 13/2a, 278

1) F. Bodroux, C.R. Séances Acad. Sci., 1904, 138, 1427. 2) F. Bodroux, Bull. Soc. Chim. Fr., 1906, 35, 519. 3) H.L. Bassett; C.R. Thomas, J. Chem. Soc., 1954, 1188.

COMMENTS :

231

BOEKELHEIDE REACTION EXAMPLE :

N O

O

CH3 F3C

O O

OH

N CF3

MECHANISM :

O + N O

CH3

F3C

O O

+

CF3

N O

CH3 CF3

O

CF3 - CF3COOH O

O CH2

N O

CF3

N

O

CF3

H+

N

OH

O

O

DISCONNECTION :

N

R N O

OH

R

NOTES : Aromatic pyridine N-oxides react with acylating agents to form 2-substituted pyridines. The negative charge can be delocalised through out the benzene ring giving rise to isomers.

REFERENCES : Smith – March : 1421

1) V. Boekelheide; W.J. Linn, J. Am. Chem. Soc., 1954, 76, 1286. 2) T. Koenig, J. Am. Chem. Soc., 1966, 88, 4045. 3) S. Oae; S. Tamagaki; T. Negero; K. Ogino; S. Kozuka, Tetrahedron Lett., 1968, 9, 917. 4) S. Oae; S. Tamagaki; T. Negero; S. Kozuka, Tetrahedron, 1970, 26, 4051.

232

5) T. Cohen; G.L. Deets, J. Am. Chem. Soc., 1972, 94, 932. 6) J.B.R. de Vains; A.L. Papet; A. Marsura, J. Heterocycl. Chem., 1994, 31, 1069. 7) C. Fontenas; E. Bejan; H.A. Haddon; G.G.A. Balavoine, Synth. Commun., 1995, 25, 629. 8) J.A. Zoltewicz; M.P. Cruskie, jr.; C.D. Dill, Tetrahedron, 1996, 52, 4239. 9) K. Goerlitzer; U. Bartke, Pharmazie, 2002, 57, 804.

COMMENTS :

BÖESEKEN – BALLIO SYNTHESIS EXAMPLE :

CH3 H

O HO

O

O

O

CH3

O

O S OH O

H3C 40 oC

MECHANISM : H+ OH

OH

O

H

O

OH OH H O O

H

H

O H

O

O

OH

-

HO

CH3

O

CH3

CH3 O

O

O

CH3

OH O

H

233

O

DISCONNECTION :

OR

O O

O

R1

R = H, Alk R1 = H, OH

R1 R

NOTES : The oxidation by peracetic acid of aryl aldehydes, ketones, or of compounds containing the group C=CCOR yields esters. Peroxytrifluoroacetic acid is also an effective reagent. See also von Baeyer – Villiger rearrangement and

Dakin phenol aldehyde oxidation.

REFERENCES : Houben – Weyl : 7/1, 489

1) J. Böeseken; A. Kremer, Recl. Trav. Chim. Pays-Bas, 1931, 50, 827. 2) J. Böeseken; A.L. Soesman, Recl. Trav. Chim. Pays-Bas, 1933, 52, 874. 3) J. Böeseken; J. Greup, Recl. Trav. Chim. Pays-Bas, 1939, 56, 528. 4) W.D. Emmons; G.B. Lucas, J. Am. Chem. Soc., 1955, 77, 2287. 5) D.G. Crosby, J. Org. Chem., 1961, 26, 1215.

COMMENTS :

BÖESSNECK – HÉBERT REACTION EXAMPLE :

OH H3C

CCl3 H

H3C K2CO3

234

H O

MECHANISM :

O H3C

H CCl3

H

H3C base

H O

DISCONNECTION : OH R

RCHO

CCl3 H

NOTES : The synthesis of aldehydes by breaking down alcohols that contain α-trichloromethyl groups.

REFERENCES : 1) P. Böessneck, Ber. Dtsch. Chem. Ges., 1885, 18, 1516. 2) P. Hébert, Bull. Soc. Chim. Fr., 1920, 27, 45. 3) K. Bodendorf; J. Mildner; T. Lehmann, Liebigs Ann. Chem., 1949, 563, 1. 4) J. Colonge; A. Perrot, Bull. Soc. Chim. Fr., 1957, 658.

COMMENTS :

BOGER – PANEK PYRIDINE SYNTHESIS EXAMPLE :

N EtO2C

N

CO2Et

N

CO2Et

CO2Et O N

235

EtO2C

N

CO2Et

MECHANISM : O

O N N

N N

H

N

H3C

O

N

N H

N

- N2

N

N

N N

CH3

NH

-

H

DISCONNECTION :

(R4)R3

R4(R3) R

R2

N

N

R1

R2

N

R

R3 +

N

R1

N

R4

NOTES : An electron-deficient heterocyclic aza-diene reacts with an electron-rich dienophile under inverse-electron-demand

Diels – Alder reaction to afford a pyridine. See also Carboni – Lindsey and Diels – Alder reactions.

REFERENCES : Org. Synth. : 66, 142 Org. Synth. Coll. Vol. : 8, 597

1) D.L. Boger; J.S. Panek, J. Org. Chem., 1981, 46, 2179. 2) D.L. Boger; J.S. Panek, M.M. Meier, J. Org. Chem., 1982, 47, 895. 3) D.L. Boger; J.S. Panek, J. Org. Chem., 1982, 47, 3763. 4) D.L. Boger; J.S. Panek, J. Org. Chem., 1983, 48, 621. 5) D.L. Boger, Tetrahedron, 1983, 39, 2869. 6) D.L. Boger; J.S. Panek, J. Am. Chem. Soc., 1985, 107, 5745. 7) A. Rykowski; E. Olender; D. Branowska; H.C. van der Plas, Org. Prep. Proced. Int., 2001, 33, 501. 8) S.P. Stanforth; B. Tarbit; M.D. Wilson, Tetrahedron Lett., 2003, 44, 693.

COMMENTS :

236

BOGERT – COOK REACTION EXAMPLE :

O MgBr +

H2SO4

MECHANISM : OH O MgBr

Br

+

Mg

H2SO4

- H2O

H

H+

Se

DISCONNECTION : O Br R

+

R

NOTES : The synthesis of octohydrophenanthrenes by the cyclodehydration by acid catalysts of a 1-β-arylethylcyclohexanol. Derivatives of 1-β-arylethylcyclohexene are intermediates in the reaction and cyclisation of these intermediate olefins is known as the Bogert reaction. This method can also be applied to cyclopentanol derivatives. See also Bardhan –

Sengupta and Darzens synthesis of tetralin reactions.

REFERENCES : Smith : 1331 Smith 2nd : 1095

1) M.T. Bogert, Science, 1933, 77, 289. 2) J.W. Cook; C.L. Hewitt, J. Chem. Soc., 1933, 1098. 3) E. Bergman, Chem. Rev., 1941, 29, 529.

237

4) F. Bergel; A.l. Morrison, J. Chem. Soc., Quat. Rev., 1948, 2, 376. 5) C. Schmidt; J. Thazhuthavectil, Can. J. Chem., 1973, 51, 3620. 6) D.A. Evans; P.A. Cain; R.Y. Wong, J. Am. Chem. Soc., 1977, 99, 7083.

COMMENTS :

BOGERT – HERRERA SYNTHESIS EXAMPLE : Ph Ph

N

Ph

Ph

S, 200 oC

CH3

S

MECHANISM :

SH

S

Ph N

PhNH2 +

H2S

Ph

H3C

Ph

Ph

CH3

CH2 Ph

SH Ph

CH2

+

H3C

Ph

Ph

Ph CH2 SH

S

S, - H2S

S

Ph

DISCONNECTION :

Aryl

Aryl N

Aryl

S

R

R = H, Alk

RCH2

Aryl

NOTES : The anils of alkyl aryl ketones react with sulfur or selenium to form 2,4-diaryl-thiophenes and –selenophenes. The anil is decomposed by hydrogen disulfide (initially formed as a side reaction from sulfur). See also Baumann – Fromm,

Fiesselmann, Hinsberg thiophene, Volhard – Erdmann and Willgerodt – Kindler reactions.

238

REFERENCES : 1) M.T. Bogert; P.P. Herrera, J. Am. Chem. Soc., 1923, 45, 238. 2) E. Campaigne, J. Am. Chem. Soc., 1944, 66, 684. 3) P. Demerseman; Ng.Ph. Buu-Hoï; R. Royer; A. Cheutin, J. Chem. Soc., 1954, 2720.

COMMENTS :

BOHLMANN – RAHTZ REACTION EXAMPLE :

CO2Et NH2 +

CH3

O CH3

CH3

heat

N

EtO2C

CH3

MECHANISM : R2 RO2C + R1

NH2

O

EtOH 50 oC

R2

RO2C

O RO2C R1

NH2

120 - 160 oC - H2O

R1

DISCONNECTION :

R2

R3

R1 NH2 +

N

R1

R

R

239

O R2 R3

N

R2

NOTES : The formation of pyridines from enamines and ynones in a two-step Michael addition. The reaction can be Lewis acid-catalysed and affords the pyridine ring in a single step. See also Chichibabin pyridine, Gattermann – Skita,

Guareschi – Thorpe, Hantzsch – Beyer, von Meyer – Mohr, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES : 1) F. Bohlmann; D. Rahtz, Chem. Ber., 1957, 90, 2265. 2) M.C. Bagley; K.E. Bashford; C.L. Hesketh; C.J. Moody, J. Am. Chem. Soc., 2000, 122, 3301. 3) M.C. Bagley; J.W. Dale; J. Bower, Synlett, 2001, 1149. 4) M.C. Bagley; J.W. Dale; D.D. Hughes; M. Ohnesorge; N.G. Phillips; J. Bower, Synlett, 2001, 1523. 5) M.C. Bagley; C. Brace; J.W. Dale; M. Ohnesorge; N.G. Phillips; X. Xiong; J. Bower, J. Chem. Soc., Perkin Trans. 1, 2002, 1663.

6) D.D. Hughes; M.C. Bagley, Synlett, 2002, 1332. 7) K.E. Bashford; M.B. Burton; S. Cameron; A.L. Cooper; R.D. Hogg; P.D. Kane; D.A. MacManus; C.A. Matrunola; C.J. Moody; A.A.B. Robertson; M.R. Warne, Tetrahedron Lett., 2003, 44, 1627. 8) M.C. Bagley; J.W. Dale; X. Xiong; J. Bower, Org. Lett., 2003, 5, 4421. 9) M.C. Bagley; J.W. Dale; R.L. Jenkins; J. Bower, Chem. Commun., 2004, 102. 10) M.C. Bagley; X. Xiong, Org. Lett., 2004, 6, 3401. 11) M.C. Bagley; K. Chapaneri; J.W. Dale; X. Xiong; J. Bower, J. Org. Chem., 2005, 70, 1389. 12) M.C. Bagley; C. Glover; D. Chevis, Synlett, 2005, 649.

COMMENTS :

BOHN – SCHMIDT REACTION EXAMPLE :

O

OH

O

OH

OH

O

OH conc. H2SO4 H3BO3 Hg

240

OH

O

OH

MECHANISM :

O

OH

OH

O

OH

O

oleum (SO3 in H2SO4) Hg

O O O S O

OH

O

OH OH

1) HO2) H+ OH

O

OH

O

DISCONNECTION :

OH

O

O

OH OH

OH OH

O

O

OH

NOTES : This reaction involves the hydroxylation of anthraquinones or hydroxyanthraquinones by the action of oleum (10 – 30% SO3 in H2SO4) in the presence of a catalyst such as selenium or mercury. The sulfuric esters are hydrolysed to the hydroxyanthraquinones. If boric acid is added to the reaction mixture concentrated sulfuric acid may be used instead of oleum. See also Dakin phenol aldehyde oxidation.

REFERENCES : 1) R. Bohn, German Patent, 1889, 46654. 2) R.E. Schmidt, German Patent, 1891, 60855. 3) R.E. Schmidt, Angew. Chem., 1928, 41, 41. 4) M. Philips, Chem. Rev., 1929, 6, 157. 5) J. Winkler; W. Jenny, Helv. Chim. Acta, 1965, 48, 119. 6) B.R. Dhruva; V.B. Patil; A.V.R. Rao, Indian J. Chem., 1976, 14B, 622.

COMMENTS :

241

BOHN SYNTHESIS EXAMPLE : O

O

H O N

2 alkali

NH2

N O H

O

O

MECHANISM : O

O

O

H2N

H O N

- 4 H+

NH2

O

O

N O H

O

DISCONNECTION :

O

O

H O N N O H

NH2 O

O

NOTES : The fusion of β-aminoanthraquinone with alkali at 200 – 250 oC yields indanthrone or Indanthrone Blue R. The reaction can be step-wise.

REFERENCES : 1) R. Scholl, Ber. Dtsch. Chem. Ges., 1905, 36, 3410. 2) R. Scholl; S. Edlbacher, Ber. Dtsch. Chem. Ges., 1911, 44, 1727.

COMMENTS :

242

BONE – SPRANKLING SYNTHESIS EXAMPLE : NC Na+

CO2Et + H3C H

CH3 H CH3 CO2Et CH3 HOOC 1) EtOH, 100 oC Br H COOH 2) aq. HCl

MECHANISM :

Na+ H

CN

R

CO2Et

R1

R1

R1 CO2Et Br

R H

CO2Et CN CO2Et

R H

aq. HCl

COOH H COOH

DISCONNECTION : R1 R H

COOH H COOH

R1

NC +

Na

CO2Et

+ R

H

CO2Et Br

NOTES : The condensation of sodium ethyl 2-cyanoacetate with α-bromoaliphatic esters gives alkyl cyanosuccinic diesters; which are hydrolysed and decarboxylated to the corresponding alkylsuccinic acids.

REFERENCES : 1) W.A. Bone; C.H.G. Sprankling, J. Chem. Soc., 1899, 75, 839. 2) W.A. Bone; C.H.G. Sprankling, J. Chem. Soc., 1900, 77, 654.

COMMENTS :

243

BOON – POLONOVSKI PTERIDINE REACTION EXAMPLE : CH3

O

NO2

N

+ N

H2N

Cl

CH3

CH3

N

N

H

CH3 H

CH3

N

N H

CH3

MECHANISM :

R

R NO2

N N

O

R1

H2N

Cl

R2

- HCl

reduction

O

R NH2 R3 R2

N

R1

N H

N

R3

R N

NO2 R3 R2

N

- H2O

O

N H

R1

N

N N

N H

R1

R2 R3

DISCONNECTION : R

R N

N N

N H

R1

+

R2 N

R3

O

NO2

N

Cl

R1

H2N

R2 R3

NOTES : 6-Chloro-5-nitro pyrimidines react with α-aminocarbonyl compounds to afford 7,8-dihydropteridines. See also Blicke –

Pachter, Isay, Taylor and Timmis reactions.

REFERENCES : 1) M. Polonovski; H. Jerome; M. Gabriel Bertrand, C.R. Séances Acad. Sci., 1950, 230, 392. 2) R.W. Boon; W.G.M. Jones; G.R. Ramage, J. Chem. Soc., 1951, 96.

244

COMMENTS :

BOORD OLEFIN SYNTHESIS EXAMPLE : O H

CH3

CH3

1) HCl, EtOH 2) Br2 3) CH3MgBr 4) Zn

MECHANISM :

H

H3C

H

H

OEt OEt

O

HCl, EtOH

Cl

H

Br2

H H

H H Br

- HCl

OEt

RMgX

H Br

Br

OEt H R

Zn

DISCONNECTION :

H3C CH3 H3C CH3 X OR

R1

H3C

CH3

H3C

OR

H3C

CH3

H3C

CH3

H3C CH3 H3C OR X OR H3C CH3 H3C Y X CH3

Y = OCOR, OTs, NR2, SR, OH (X = Br and I)

245

R

NOTES : The synthesis involves four steps. The first three lead to the preparation of a β-ethoxyalkyl bromide and in the fourth step zinc is used for the simultaneous removal of the ethoxy group and bromine. β-Haloacetals yield vinylic ethers. The reaction can be further expanded to esters, tosylates, amines, sulfur and hydroxyl groups. Only in the last case the halogen atom must be bromine or iodine. See also Baudart reaction.

REFERENCES : March : 1034 Smith – March : 1344 Houben – Weyl : 5/1b, 213

1) L.C. Swallen; C.E. Boord, J. Am. Chem. Soc., 1930, 52, 651. 2) L. Crombie, J. Chem. Soc., Quat. Rev., 1952, 6, 131. 3) C.E. Hatch III; J.S. Baum; T. Takashima; K. Kondo, J. Org. Chem., 1980, 45, 3181. 4) J.S. Yadav; R. Ravishankar; S. Lakshman, Tetrahedron Lett., 1994, 35, 3617. 5) J.S. Yadav; R. Ravishankar; S. Lakshman, Tetrahedron Lett., 1994, 35, 3621. 6) P.H. Beusker; R.W.M. Aben; J.-P.G. Seerden; J.M.M. Smits; H.W. Scheeren, Eur. J. Org. Chem., 1998, 2483.

COMMENTS :

BORCH REDUCTION EXAMPLE : H H

O

+ CH3NH2

NaBH3CN

N CH3

O

MECHANISM :

R2

R1 O

+ HNR2

slow

R2 N R1

246

R2

R R

BH3CNfast

H

R N

R1

R

DISCONNECTION :

R H

R

OH R1

O

OH N

R R

N

R1

N

R

R

R1

R R3

R2

OH N

R3

R2

R4 R

R1

R4 R2

R1 H

O

R N

R3

R1

NOTES : The reductive amination of aldehydes or ketones by cyanoborohydride (or triacetoxyborohydride) anion (pH 6-7). Selective reduction of carbonyls to alcohol, oximes to N-alkylhydroxylamines, enamines to amines.

REFERENCES : Smith – March : 526 Smith : 384 Smith 2nd : 336 Org. React. : 4, 174; 59, 1 Org. Synth. : 52, 124 Org. Synth. Coll. Vol. : 6, 499

1) G. Drefahl; E. Keil, J. Prakt. Chem., 1958, 6, 80. 2) R.F. Borch, Tetrahedron Lett., 1968, 9, 61. 3) R.F. Borch; H.D. Durst, J. Am. Chem. Soc., 1969, 91, 3996. 4) R.F. Borch; M.D. Bernstein; H.D. Durst, J. Am. Chem. Soc., 1971, 93, 2897. 5) R.F. Borch; A.I. Hassid, J. Org. Chem., 1972, 37, 1673. 6) A.F. Abdel–Magid; C.A. Maryanoff; K.G. Carson, Tetrahedron Lett., 1990, 31, 5595. 7) T. Henkel; R.M. Brunne; H. Müller; F. Reichel, Angew. Chem., Int. Ed., 1999, 38, 643.

COMMENTS :

247

BORSCHE – BEECH AROMATIC ALDEHYDE SYNTHESIS EXAMPLE : NH2

CHO 1) HNO2, HCl 2) NaOAc CH2=NOH 3) H2O

N

N

MECHANISM : O NH2 N

N2 HCl NaNO2

N

Cl

1) aq. NaOAc 2) H2C=NOH CuSO4 Na2SO3 NaOAc

N

OH

H H2O

N

N

DISCONNECTION : Ar

R Ar O

NH2

R = H, Alk

NOTES : The synthesis of aromatic aldehydes and of alkyl aryl ketones from aldoximes or semicarbazones and aromatic diazonium salts. See also Bouveault – Wahl reaction.

REFERENCES : Houben – Weyl : 10/3,185; E3, 145

1) C. Borsche, Chem. Ber., 1907, 40, 737. 2) K. Johnson; E.F. Degering, J. Org. Chem., 1943, 8, 10. 3) W.F. Beech, J. Chem. Soc., 1954, 1297. 4) R.B. Woodward; F.E. Fader; H. Bickel; A.J. Frey; R.W. Kierstead, Tetrahedron, 1958, 2, 1. 5) R.A. Clendinning; W.H. Rausher, J. Org. Chem., 1961, 26, 2963. 6) S.S. Vernekar; S.D. Jolad; S. Rajagopal, Monatsh. Chem., 1962, 93, 271.

248

COMMENTS :

BORSCHE – BERKHOUT SYNTHESIS EXAMPLE : CH3 O + 2 CH3CHO

HCl

OH

O

CH3

MECHANISM : H+ O

H+ H

O OH H

CH3

H

O

OH H

CH3 O H

O

CH3

O

CH3

CH3

CH3 O

- H2O

CH3 O

O CH3

O

CH3

DISCONNECTION : R1 O

R

R O

R1

+ 2 R1CHO OH

R = H, CH3, COOH, NO2, Cl, NH2, SO3H R1 = H, CCl2, CHCl2, CH3

NOTES : The intermolecular condensation of phenols and aldehydes in the presence of acids to afford 1,3-benzdioxanes.

249

REFERENCES : 1) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1872, 5, 25. 2) A. von Baeyer, Ber. Dtsch. Chem. Ges., 1872, 5, 1094. 3) W. Borsche; H. Berkhout, Liebigs Ann. Chem., 1904, 330, 82. 4) W. Borsche; H. Berkhout, Liebigs Ann. Chem., 1904, 330, 91. 5) F. Bigi; G. Casiraghi; G. Casnati; G. Sartori, Synthesis, 1980, 724.

COMMENTS :

BORSCHE – DRECHSEL CYCLISATION EXAMPLE :

N H

N

1) H+ 2) Pb3O4

250

N H

MECHANISM :

H H N H

N H

N

H+

N H

N

H+ +

H

H

H2 N

[3,3]-sigmatropic rearrangement

NH NH2 H+ H - NH3

H2N

N NH 2 H2

NH2

H+

Pb3O4 - 2 H2

N H

N H

DISCONNECTION :

O + PhNHNH2 N H

NOTES : The phenylhydrazones of cyclohexanone derivatives give tetrahydrocarbazoles in the presence of acids. The main transformation is a [3,3]-sigmatropic rearrangement. The product is oxidised by lead(III,IV) oxide to a carbazole. See also Bucherer carbazole, Fischer indole, Friedel – Crafts and Piloty – Robinson reactions.

REFERENCES : Smith : 1346 Smith 2nd : 1107

1) E. Drechsel, J. Prakt. Chem., 1888, 38, 69. 2) W. Borsche; M. Feise, Ber. Dtsch. Chem. Ges., 1904, 40, 378. 3) N. Campbell; B.M. Barclay, Chem. Rev., 1947, 40, 359. 4) P. Bruck, J. Org. Chem., 1970, 35, 2222.

251

5) B. Miller; E.R. Matjeka, J. Am. Chem. Soc., 1980, 102, 4772. 6) R.A. Abramovitch; A. Bulman, Synlett, 1992, 795. 7) G. Lin; A. Zhang, Tetrahedron, 2000, 56, 7163. 8) G.L. Rebeiro; B.M. Khadilkar, Synthesis, 2001, 370.

COMMENTS :

BORSCHE – KENNER SYNTHESIS EXAMPLE :

H3C

O

H3C + PhNH2

H2SO4

Ac

N CH3

MECHANISM : Kenner variation :

O

O R

R

+ CH2OH

R1 H2N . HCl

H+, - H2O

R1 R

N

252

H N R1

DISCONNECTION :

R1 R

O R

N

R = H, alk R1 = H, Alk, OAlk, Cl, NO2 R2 = CH2OH, Ac

R1

+ R2

H2N

NOTES : The cyclic condensation of a 2-acylcyclohexanone and a primary aromatic amine by hot concentrated sulfuric acid gives a tetrahydrophenanthridine. Alternatively (Kenner modification), the 2-acylcyclohexanone is replaced by a 2-(ωhydroxymethyl)cyclohexanone, which is treated with an arylamine or its hydrochloride with or without the addition of stannic chloride. See also Combes quinoline, Doebner – Miller and Pictet – Hubert reactions.

REFERENCES : 1) W. Borsche, Liebigs Ann. Chem., 1910, 377, 70. 2) J. Kenner; W.H. Ritchie; F.S. Stathem, J. Chem. Soc., 1937, 1169. 3) L. Hollingsworth; V. Petrov, J. Chem. Soc., 1948, 1537.

COMMENTS :

BORSCHE – KOELSCH CINNOLINE SYNTHESIS EXAMPLE :

O

OH CH3

CH2CH3 NH2

1) NaNO2, HCl 2) heat

253

N

N

MECHANISM : H

O

O CH2R NaNO2, HCl

NH2

N

O R

CH2R N

N

N

OH R N

N

DISCONNECTION :

OH

O R

R1 N

R1

N

CH2R NH2

NOTES : A method for the preparation of 4-hydroxycinnolines, which consists of the diazotisation of the appropriate 2aminoaryl ketones. The diazonium salt readily cyclises. See also Pschorr, von Richter and Widman – Stoermer reactions.

REFERENCES : 1) W. Borsche; A. Herbert, Liebigs Ann. Chem., 1941, 546, 293. 2) C.F. Koelsch, J. Org. Chem., 1943, 8, 295. 3) K. Schofield; J.C.E. Simpson, J. Chem. Soc., 1945, 512. 4) M. Fernandez; F. Lopez; R. Tapia; J.A. Valderrama, Synth. Commun., 1989, 19, 3087. 5) L.F. Hennequin; A.P. Thomas; C. Johnstone; E.S.E. Stokes; P.A. Ple; J.-J.M. Lohmann; D.J. Ogilvie; M. Dukes; S.R. Wedge; J.O. Curwen; J. Kendrew; C.L. van der Brempt, J. Med. Chem., 1999, 42, 5369.

COMMENTS :

254

BOSCH – MEISER UREA PROCESS EXAMPLE : O CO2 + 2 NH3

H2N

NH2

MECHANISM : NH3

NH3 NH2

O C O

HO O

H2N - H2O

NH2 O

NOTES : The synthesis of urea from carbon dioxide and ammonia. See also Wöhler urea synthesis.

REFERENCES : C. Bosch; W. Meiser, U.S. Patent, 1922, 1429483.

COMMENTS :

BOTT – HELLMANN REACTION EXAMPLE :

CH3 H3C OH CH3

Cl + Cl

H3C 1) H2SO4, BF3 2) H2O

255

H3C CH O 3

OH

MECHANISM : Cl Cl R1 OH

R

R1

H2SO4 - H2O

R1

R

H2O - H+

O R1

R

R = H, alkyl O R1

OH

R = Cl

DISCONNECTION :

O R1

R R1 OH

O R1

R = H, alkyl, Cl OH

NOTES : The addition of carbenium ions in acidic solution to 1,1-dichloro-1-alkenes or 1-chloro-1-alkenes. Hydrolysis results in a carboxylic acid or ketone, 2 carbon atoms longer. See also Ritter reaction.

REFERENCES : Houben – Weyl : E5, 435; E19c, 324

1) K. Bott, Angew. Chem., 1965, 77, 967. 2) K. Bott; H. Hellmann, Angew. Chem., Int. Ed. Engl., 1966, 5, 870. 3) D.J. Raber; R.C. Fort; E. Wiskott; C.W. Woodworth; P. von Ragué Schleyer; J. Weber; H. Stetter, Tetrahedron, 1971, 27, 3. 4) K. Bott, Angew. Chem., Int. Ed. Engl., 1980, 19, 171.

COMMENTS :

256

BÖTTINGER – MICHAELIS REACTION EXAMPLE :

PhNH2 + SOCl2

Ph N S O

MECHANISM :

O

O S Cl

NH2 Cl

S O

N

- HCl

H

S - HCl

N

Cl

DISCONNECTION :

O S R N

R NH2 R = Alk, Ar

NOTES : Thionylamines are obtained by the action of thionyl chloride on alkyl or aryl primary amines. See also Kaluza reaction.

REFERENCES : Org. Synth. : 49, 70 Org. Synth. Coll. Vol. : 5, 504

1) C. Böttinger, Ber. Dtsch. Chem. Ges., 1878, 11, 1407. 2) A. Michaelis, Liebigs Ann. Chem., 1893, 274, 173. 3) H.M. Kissman; D.S. Tarbell; J. Williams, J. Am. Chem. Soc., 1953, 75, 2959. 4) J.R. Grunwell; A. Kochan, J. Org. Chem., 1973, 38, 1610. 5) S. Sakai; T. Fujinami; K. Komizo, J. Org. Chem., 1975, 40, 3291. 6) H.-J. Niclas; D. Habisch; D. Martin, Tetrahedron, 1979, 35, 2353. 7) J.K. Whitesell; H.K. Yaser, J. Am. Chem. Soc., 1991, 113, 3526. 8) H. Shimizu; N. Okada; M. Yoshimatsu, Tetrahedron Lett., 2001, 42, 4183.

257

COMMENTS :

BOUGAULT SYNTHESIS EXAMPLE : H3CO

OCH3

+

H3CO O

O

O O

OCH3 1) NaOEt 2) H2SO4

O

OCH3

MECHANISM : O O

R1O COOR HO

R1O

NaOEt

COOR

H+ O

COOR1

H2SO4

COOR

COOR O H OHCOOR 1 COOR H

COOR1

OR1 OR

- H2O

O

DISCONNECTION :

R1

O

R1

OR

R2

OR

R3

O

O

R2 OR

R3 O

258

OR1

+ R1O

O

NOTES : This method for the preparation of indene 2,3-dicarboxylic esters involves the cyclisation with sulfuric or polyphosphoric acid of an ester derived from an ethyl β-phenylpropionate and ethyl oxalate. The reaction has been extended to the synthesis of six- and seven-membered rings.

REFERENCES : 1) W. Roser, Liebigs Ann. Chem., 1888, 247, 152. 2) J. Bougeault, C.R. Séances Acad. Sci., 1915, 159, 745. 3) K. Auwers; K. Möller, J. Prakt. Chem., 1925, 109, 124. 4) L.F. Fiesel; E.B. Hershberg, J. Am. Chem. Soc., 1935, 57, 1508. 5) L.F. Fiesel; E.B. Hershberg, J. Am. Chem. Soc., 1935, 57, 1851. 6) E.C. Horning; J. Koo, J. Am. Chem. Soc., 1951, 73, 5826. 7) A. Guy; J.-P. Guette; G. Lang, Synthesis, 1980, 222. 8) C.S. Rao; R. Ramachandra; S. Kshirsagar; D.M. Vashi; V.S.N. Murty, Indian J. Chem., 1983, 22B, 230.

COMMENTS :

BOUIS SYNTHESIS EXAMPLE :

H

H3C CH2

H2C

O

1) CH3MgCl, H2O 2) PBr3 3) Br2 4) aq. KOH 5) Zn

259

MECHANISM :

H

H 1) RMgX 2) H2O

O

H2C

R

H2C

R OH

R

Br Br2

R

Br

Br R

Br

Br

Br

aq. KOH - HBr

R

CH2

H

H

PBr3

CH2 Zn

Br

DISCONNECTION : O

R

H

+ RMgBr

NOTES : Acrolein reacts with a Grignard reagent to give a substituted allyl alcohol after hydrolysis, which with phosphorous tribromide yields by allylic rearrangement a 1-bromo-2-olefin. This olefin adds bromine and hydrogen bromide is then eliminated by treatment with alkali hydroxide. Finally the two bromine atoms are removed by zinc to give the allene derivative.

REFERENCES : M. Bouis, Ann. Chim. (Paris), 1928, 9, 402.

COMMENTS :

260

BOULTON – KATRITZKY REARRANGMENT EXAMPLE :

O N

O

O

Cl

N O N

Cl

N O heat, CH3OH

CH3

CH3

O

MECHANISM :

N O N O

RCH2OSO2CF3 CF3SO3

O N

CH2R N O N O

CF3SO3

N O

N O

OH N

O N H

CF3SO3

R

R N CF3SO3 OH

R

DISCONNECTION :

X Y O

U V N W

Y X

U V W N O

NOTES : Isoxazoles and other five-membered heteroaromatics containing an N-O bond undergo a thermal or base-catalysed rearrangement. The reaction is in some cases reversible.

REFERENCES : Houben – Weyl : E8a, 401, 433; E8b, 527; E8c, 516, 686, 799

1) A.J. Boulton; A.R. Katritzky, Rev. Chim. (Romania), 1962, 7, 691. 2) A.J. Boulton; A.R. Katritzky; A.M. Hamid, J. Chem. Soc. (C), 1967, 2005. 3) S.N. Balasubrahmanyam; A.S. Radhakrishna; A.J. Boulton; T. Kan–Woon, J. Org. Chem., 1977, 42, 897. 4) M. Ruccia; N. Vivona; D. Spinelli, Adv. Heterocycl. Chem., 1981, 29, 141.

261

5) S. Ostrowski; K. Wojciechowski, Can. J. Chem., 1990, 68, 2239. 6) V.G. Andrianov; S.V. Makushenkov; A.V. Eremeev, Mendeleev Commun., 1992, 129. 7) A.R. Katritzky; M.F. Gordeev, Heterocycles, 1993, 35, 483. 8) F. Eckert; G. Rauhut, J. Am. Chem. Soc., 1998, 120, 13478. 9) G. Rauhut, J. Org. Chem., 2001, 66, 5444. 10) A. Peña–Gallego; J. Rodríguez–Otero; E.M. Cabaleiro–Lago, J. Org. Chem., 2004, 69, 7013.

COMMENTS :

BOUVEAULT – BLANC REDUCTION EXAMPLE : O H3C

O

CH3

CH3CH2OH

Na, EtOH

MECHANISM :

O R

HOEt

O OR1

e-

R O

R HOEt

OR1

OH

OH - OEt

H

R

e-

OR1

R

OR1

O

O

OR1

R

H

e-

R

H

eEtOH

RCH2OH

DISCONNECTION : O RCH2OH

R

OR1

NOTES : Although a once popular reduction, it has largely been replaced by modern hydride reducing agents. Sometimes the reduction of an aldehyde, carboxylic acid or ketone under these conditions is called a Bouveault – Blanc reduction. Here, the thermodynamically more stable alcohol will result from the reduction. There is also a Hansley – Prelog –

262

Stoll modification, which uses sodium and a reducing alcohol in an inert solvent such as xylene. (Ind. Eng. Chem., 1947, 39, 55) Another modification is the one by Prins. This reaction, the Prins reduction, relates to the reduction of esters by sodium in diethyl ether – acetic acid mixture in the presence sodium acetate. See also Bouveault –

Locquin acyloin and Hansley – Prelog – Stoll reactions.

REFERENCES : March : 913, 916 Smith – March : 1199, 1551 Houben – Weyl : 8, 643 Org. Synth. : 10, 62; 14, 20; 15, 51; 29, 80; 33, 76 Org. Synth. Coll. Vol. : 2, 154, 372, 468; 3, 671; 4, 798

1) L. Bouveault; G. Blanc, C.R. Séances Acad. Sci., 1903, 136, 1676. 2) H.J. Prins, Chem. Weekblad, 1914, 11, 479. 3) H.J. Prins, Recl. Trav. Chim. Pays-Bas, 1923, 42, 1050. 4) E.M. Kaiser, Synthesis, 1972, 391. 5) E. Albano–Garcia; R.G. Lorica; De leon, Philipine J. of Coconut Studies, 1980, 5, 13. 6) J. Banerji; P. Bose; R. Chakrabarti; B. Das, Indian J. Chem., 1993, 32B, 709. 7) Y. Zhang; C. Ding, Huaxue Tongbao, 1997, 36.

COMMENTS :

BOUVEAULT – LOCQUIN ACYLOIN SYNTHESIS EXAMPLE :

O Et

OEt

+ 4 Na

H+

263

HO

O

Et

Et

MECHANISM : Mechanism 1 :

O

O 2

R

2

Na 2 e-

OR1

- 2 OR1

O

O

R

R

R

O O R R R1O OR1

OR1

2 e-

O

O

R

R

H+

O

OH

R

R

Mechanism 2 :

R

eNa

OR1

OR1 O

OR1 R O

O

R1O R

O

R

H+

e-

R

O

R

O R1O

e-

R

O

OH

R

R

R OR1

OR1 O

O O

O

OR1

R

OR1 O R

R

O

R

e- OR1

R O

O

O

R

R

DISCONNECTION :

O

OH

R

R

O R

O

R1

NOTES : Acyloins are formed by the action of sodium (sometimes potassium or better sodium-potassium alloy) on esters in an inert solvent. Mixed acyloins are similarly obtained. There has been a great deal of controversy over the mechanism of the acyloin reaction. Two possible reaction mechanism are shown here. See also Baudart acyloin synthesis,

Bouveault – Blanc, Claisen and Hansley – Stoll – Prelog reactions.

264

REFERENCES : March : 1228 Smith – March : 1562 Smith : 1442 Smith 2nd : 1189 Org. React. : 4, 256; 23, 259 Org. Synth. : 13, 24; 57, 1 Org. Synth. Coll. Vol. : 2, 114; 6, 167

1) L. Bouveault; R. Locquin, C.R. Séances Acad. Sci., 1903, 136, 1676. 2) J.W. Lynn; J. English, J. Am. Chem. Soc., 1951, 73, 4284. 3) E.V. Heyningen, J. Am. Chem. Soc., 1952, 74, 4861. 4) K.T. Finley, Chem. Rev., 1964, 64, 573. 5) J.J. Bloomfield; D.C. Owsley, J. Org. Chem., 1975, 40, 393. 6) T.S. Daynard; P.S. Eby; J.H. Hutchinson, Can. J. Chem., 1993, 71, 1022.

COMMENTS :

BOUVEAULT – LOCQUIN AMINO ACID SYNTHESIS EXAMPLE :

O EtO

OEt O

O + EtO N O

1) EtONa, NaOEt 2) Raney Ni, H2

265

H2N

OEt

MECHANISM :

EtOOC

COOEt O

EtONa

OEt N O

COOEt

R

EtO

R

base

COOEt

O

R

EtO

N

R

R O

O

OEt N OEt O H+

NOH OEt

R

Raney Ni, H2

R O

NH2 OEt

O OH

NOTES : The synthesis of α-amino acids from malonate esters by nitrosation.

REFERENCES : 1) L. Bouveault; R. Locquin, C.R. Séances Acad. Sci., 1902, 135, 135. 2) L. Bouveault; R. Locquin, Bull. Soc. Chim. Fr., 1904, 31, 1055. 3) N. Hall; J.E. Hynes; A. Lapworth, J. Chem. Soc., 1915, 107, 132. 4) J.C. Shivers; C.R. Hauser, J. Am. Chem. Soc., 1947, 69, 1264. 5) R. Fischer; Th. Wieland, Chem. Ber., 1960, 93, 1387.

COMMENTS :

266

O O

DISCONNECTION :

O

O

OH

EtO

OEt R NH2

BOUVEAULT – WAHL SYNTHESIS EXAMPLE :

H3C

CH3 H

CH3

+ CH3NO2

O

H

1) base 2) H2, Al(Hg)

CH3 O

MECHANISM : H R

R1

+ CH3NO2

base

O R H2 Al(Hg)

O2N R

R

H R1 OH

N OH

H

- H2O

R

H

R1

O

NO2

R1

H H2O

R1

DISCONNECTION : R

H

R1

O

R

H

R1 O

NOTES : Nitro-olefins (obtained by condensing carbonyl compounds with nitro-methane) on reduction with aluminium amalgam yield oximes from which aldehydes may be obtained. See also Borsche – Beech, Henry and Nef reactions.

REFERENCES : Houben – Weyl : 7/1, 272

1) L. Bouveault; A. Wahl, C.R. Séances Acad. Sci., 1902, 134, 1226. 2) L. Bouveault; A. Wahl, Bull. Soc. Chim. Fr., 1903, 29, 643. 3) K. Johnson; E.F. Degering, J. Org. Chem., 1943, 8, 7. 4) K. Johnson; E.F. Degering, J. Org. Chem., 1943, 8, 10.

267

COMMENTS :

BOUVEAULT ALDEHYDE SYNTHESIS EXAMPLE : CH3 N CH3

H O

H

Et 1) EtMgBr 2) HBr, Et2O

O

MECHANISM :

R N

H

H R

+

R1MgBr

R1

O

R

N

Br O MgBr R H+

R1 - (R)2NH - MgBr2

H O

DISCONNECTION :

R1

H

R N

H

O

R

+ R1Br

O

NOTES : Dialkylformamides are treated with a Grignard reagent and the product hydrolysed by acid to yield aldehydes. Lithium compounds can be used instead of Grignard reagents. See also Bodroux – Chichibabin and Claisen –

Mauthner – Bouveault reactions.

REFERENCES : March : 932 Smith – March : 1214 Houben – Weyl : 7/1, 66

1) L. Bouveault, C.R. Séances Acad. Sci., 1903, 137, 987.

268

2) L.I. Smith; J. Nichols, J. Org. Chem., 1941, 6, 489. 3) E.A. Evans, Chem. Ind. (London), 1957, 1596. 4) J. Einhorn; J.L. Luche, Tetrahedron Lett., 1986, 27, 1791. 5) J. Einhorn; J.L. Luche, Tetrahedron Lett., 1986, 27, 1793. 6) H. Meier; H. Aust, J. Prakt. Chem., 1999, 341, 466. 7) S.M. Denton; A. Wood, Synlett, 1999, 55.

COMMENTS :

BOUVEAULT HYDROLYSIS OF AMIDES EXAMPLE :

CH3 O

CH3 O +

H3C H

O N OH

H3C H2SO4

NH2

H

OH

MECHANISM :

O

O R

R NH2

H

O N

H

N O

O

O

H+

R

R N N O H

N N O H H O

- N2, heat

R C O

O R N N O

N H

O

-H+

H2O, - H+

R OH

269

- H2O

R N N

DISCONNECTION :

O

O R

R

NH2

OH

NOTES : The nitrile is converted into the amide by concentrated sulfuric acid and the acid solution is treated with aqueous sodium nitrite to afford the carboxylic acid.

REFERENCES : Houben – Weyl : 8, 432

1) L. Bouveault, Bull. Soc. Chim. Fr., 1893, 9, 368. 2) J.J. Sudborough, J. Chem. Soc., 1895, 67, 602. 3) F.G. Mann; J.W.G. Porter, J. Chem. Soc., 1945, 752. 4) F.J. Kezdy; I. Jaz; A. Bruylants, Bull. Soc. Chim. Belg., 1958, 67, 68.

COMMENTS :

270

BOWMAN DEBENZYLATION MECHANISM : Ketones :

CH2(CO2Et)2

RCH(CO2Et)2

Et3N, RBr

Na, PhCH2OH O R

R O

O

O

R1COCl O

O O

Na+

O

O R H2, Pd/C

O

R1 OH

HO

R1 O

R1 R

heat

O O

Fatty acids :

H CH2(CO2Et)2

Br[CH2]nCO2Et

EtO2C

[CH2]nCO2Et Na, PhCH2OH

CO2Et

O [CH2]nCO2CH2Ph

O O

O O O

O RCOCl

[CH2]nCO2CH2Ph O R O

O

H2, Pd/C

[CH2]nCO2H

[CH2]nCO2H

HO O

OH

O heat R

R O R[CH2]n+2COOH NH2NH2, KOH

271

O EtO2C[CH2]nCOCl +

O

O

O O

1) H2, Pd/C 2) heat

RCH2CO[CH2]nCOOH

CH2(CO2Et)2 CH3[CH2]mBr

O

O O

1) H2, Pd/C 2) Heat

NH2NH2, KOH

[CH2]mCH3 EtO2C CO2Et H

ClCO[CH2]nCO2Et

272

O

[CH2]nCO2Et

Na, PhCH2OH

O [CH ] CO Et 2n 2

O O

CH3[CH2]mCH2CO[CH2]nCOOH

O

O

R[CH2]n+2COOH

[CH2]mCH3

O

R

O

R

NH2NH2, KOH

O

O [CH2]mCH3

CH3[CH2]m+n+2COOH

Olefinic acids :

O

[CH2]nCO2CH2Ph

O

R1OCHRCOCl +

O O

H

O O O

R1O R O

R1OCHRCO[CH2]n+1COOH 1) H2, Pd/C 2) heat

[CH2]nCO2CH2Ph O

R H R1O

R1OCHRCO[CH2]n+1COOR2

R2OH

Meerwein - Ponndorf - Verley reduction or Ni R

R H [CH2]n+1 CO2H

Br HBr HAc/H2SO4

[CH2]n+1 CO2R2 H OH

Zn

H Br

[CH2]n+1 COOH

β-Keto esters and nitriles :

O

O O

RCOCl +

R1

R1

O O

O

R O

O H 1) H2, Pd/C 2) Heat

R1 O

O R O

N

R1 NC

CO2Et H

O

O

R1 O

Na, PhCH2OH

O

273

1) RCOCl 2) H2, Pd/C 3) Heat

R

R1 CN

NOTES : The benzyl esters of acylmalonic acids undergo hydrogenolysis with the formation of the parent keto-acids, which readily lose two molecules of carbon dioxide to give the corresponding ketone. The reaction can be applied in numerous ways. See also Baudart, Bowman, Fonken – Johnson, Kapp – Knoll and Robinson – Robinson reactions.

REFERENCES : 1) D.E. Ames; R.E. Bowman; R.G. Mason, J. Chem. Soc., 1950, 174. 2) R.E. Bowman, J. Chem. Soc., 1950, 177. 3) R.E. Bowman, J. Chem. Soc., 1950, 322. 4) R.E. Bowman, J. Chem. Soc., 1950, 325. 5) D.E. Ames; R.E. Bowman, J. Chem. Soc., 1951, 1079. 6) R.E. Bowman; W.D. Fordham, J. Chem. Soc., 1951, 2758.

COMMENTS :

BOWMAN REACTION EXAMPLE : CH3 HOOC

COOH

Et 1) H+, O 2) Na, EtCOCl 3) AcOH, heat

274

CH3 O

MECHANISM : R O

R HOOC

+ 2 COOH

H+

O

O

O O

O

O

O R1 O

Na, R1COCl

R1

R O

O

AcOH, heat

R + 2 CO2 + 2 O

O

O O O

DISCONNECTION : R

R1

R1

R O

HOOC

COOH

Cl

+ O

NOTES : This synthesis involves the reaction of dihydropyran with a substituted malonic acid in the presence of an acid catalyst to give a malonic diester, which is converted into the sodium-derivative, and treated with an acid chloride to yield a tetrahydropyran diester; all operations are conducted below 40 oC in benzene. To produce the ketone, the reaction mixture is heated under reflux in the presence of a small amount of acetic acid, until no further evolution of carbon dioxide takes place. See also Bowman debenzylation reaction.

REFERENCES : 1) R.E. Bowman, Nature, 1948, 162, 111. 2) R.E. Bowman; W.D. Fordham, J. Chem. Soc., 1951, 2753. 3) R.E. Bowman; W.D. Fordham, J. Chem. Soc., 1952, 3945.

COMMENTS :

275

BOYD – ROBINSON 4-HYDROXYCOUMARINS SYNTHESIS EXAMPLE :

OH

O

O

CH2CH3

+

EtO

OEt

Na

O CH3

O

OH

MECHANISM :

OH

EtO R

R O

OH

O

OH

H OEt

OEt

- EtOH

O

O

O

O R

- EtOH

R

O

OH

DISCONNECTION :

O

O

OH CH2R

R R = H, Alk, Ar OH

O

NOTES : This reaction involves the condensation of o-hydroxyacetophenones and their ω-substituted derivatives with ethyl carbonate using sodium. See also Anschütz hydroxycoumarin, Bargellini, Knoevenagel coumarin, Pauly –

Lockemann, von Pechmann – Duisberg and Perkin coumarin reactions.

REFERENCES : J. Boyd; A. Robertson, J. Chem. Soc., 1948, 174.

COMMENTS :

276

BOYLAND – SIMS ORTHO-HYDROXYANILINE SYNTHESIS EXAMPLE :

Me

N

Me

Me

N

Me OH

1) K2S2O8 2) HCl

MECHANISM :

R

N

(R)2N

R

(R)2N + S2O8

(R)2N

H

+ SO42-

O SO2 O

or

OSO3

2-

SO3 O

N(R)2

N(R)2

OH

OSO3 H+

H

DISCONNECTION :

R

N

R

R1

N

R1

OH

NOTES : The oxidation of anilines with persulfates via arylhydroxylamine-O-sulfonate to ortho-aminophenols and a substantial quantity of para-isomer by attack at the nitrogen atom followed by rearrangement to the product. The ortho product is favoured compared to the Elbs reaction where the para product is preferred. See also Dakin phenol aldehyde oxidation and Elbs reaction.

REFERENCES : March : 554 Smith – March : 724 Org. React. : 35, 421

277

1) E. Boyland; D. Manson; P. Sims, J. Chem. Soc., 1953, 3623. 2) E. Boyland; P. Sims, J. Chem. Soc., 1954, 980. 3) C. Walling; D.M. Camaioni; S.S. Kim, J. Am. Chem. Soc., 1978, 100, 4814. 4) C. Srinivasan; S. Perumal; N. Arumugami, J. Chem. Soc., Perkin Trans. 2, 1985, 1855. 5) J.E. Toth; J. Ray; W.J. Ehlhardt, Bioorg. Med. Chem. Lett., 1992, 2, 1013. 6) E.J. Behrman, J. Org. Chem., 1992, 57, 2266.

COMMENTS :

BRACKEEN SYNTHESIS EXAMPLE : O O

H3CO

O

H3C

OCH3 O

+ NH4OAc

H3C

CH3CHO HOAc

N N H

CH3

MECHANISM :

NH O

O

H3C

NH OCH3

OCH3

+ 2 NH4OAc

OCH3

O

NH

O H+ O

N

OCH3 N

- H2O

H3CO H3C H N

CH3

O N CH3

278

N OH

H

H3C

H3C

O

O

DISCONNECTION : O R1O

O

N

R

N H

O

R

R2

O

R1 + R2CHO

O

NOTES : A versatile one-step imidazole synthesis employing vicinal tricarbonyl compounds. See also Akabori – Neuberg –

Fischer, Bredereck, Debus – Radziszewski, Maquenne, Wallach imidazole and Weidenhagen reactions.

REFERENCES : M.F. Brackeen; J.A. Stafford; P.L. Feldman; D.S. Karanewsky, Tetrahedron Lett., 1994, 35, 1635.

COMMENTS :

BRADSHER CYCLOADDITION REACTION EXAMPLE :

O O

O N

+

O

O

AcOH heat

O

N Br

Br

279

MECHANISM : O O

O O

O N

N

O

DISCONNECTION : R R1

R

N

N

N N

+ R1

NOTES : The [4+2]-addition of a common dienophile with cationic aromatic aza-dienes such as acridizinium or isoquinolinium. See also Diels – Alder reaction.

REFERENCES : 1) C.K. Bradsher; T.W.G. Solomons, J. Am. Chem. Soc., 1958, 80, 933. 2) C.K. Bradsher; J.A. Stone, J. Org. Chem., 1968, 33, 519. 3) C.K. Bradsher; F.H. Day, Tetrahedron Lett., 1971, 12, 409. 4) T.-K. Chen; C.K. Bradsher, J. Org. Chem., 1979, 44, 4680. 5) S. Manna; J.R. Falk; C. Mioskowski, J. Org. Chem., 1982, 47, 5021. 6) R.B. Gupta; R.W. Franck; K.D. Onan; C.E. Soll, J. Org. Chem., 1989, 54, 1097. 7) T.E. Nicolas; R.W. Franck, J. Org. Chem., 1995, 60, 6904. 8) D. Urban; E. Duval; Y. Langlois, Tetrahedron Lett., 2000, 41, 9251.

COMMENTS :

280

BRADSHER REACTION EXAMPLE :

30% HBr AcOH

CH3 O

CH3

MECHANISM :

O H Cl

1) PhMgBr 2) I2, P, AcOH reflux

1) EtMgBr benzene reflux 2) H+

CuCN, 250 oC

Cl

NC

30% HBr AcOH

O Et

DISCONNECTION : O X H X = O, S, Se

Hal

R

NOTES : The cyclo-condensation of diaryl ketones, which contain an arylmethylene group in the ortho-position, in the presence of acidic catalysts, afford condensed aromatic systems. See also Bischler – Napieralski reaction.

REFERENCES : Smith – March : 720 Smith : 1332 Smith 2nd : 1096, 1108 Houben – Weyl : E6a, 888 Science of Synthesis : 10, 239

281

1) C.K. Bradsher, J. Am. Chem. Soc., 1940, 62, 486. 2) C.K. Bradsher, Chem. Rev., 1946, 38, 447. 3) C.D. Saraf; F.A. Vingiello, Synthesis, 1970, 655. 4) J. Ashby; M. Ayad; O. Meth–Cohn, J. Chem. Soc., Perkin Trans. 1, 1973, 1104. 5) C.K. Bradsher, Chem. Rev., 1987, 87, 1277. 6) H. Sard, J. Heterocycl. Chem., 1994, 31, 1085. 7) E. Magnier; Y. Langlois, Tetrahedron Lett., 1998, 39, 837.

COMMENTS :

BRANDI – GUARNA REARRANGEMENT EXAMPLE : H

O

N + N O

OCH3

OCH3

OCH3

OCH3

MECHANISM : R O N C

R N O

R heat N

R H2N

O

O

H O H+

282

heat

R

N H

DISCONNECTION : O R2 RCNO + R1

N H

R1

R

R2

NOTES : Isoxazoline-5-spiro cyclopropanes are prepared by cycloaddition of nitrile oxides with methylenecyclopropane. The rearrangement of these compounds affords 5,6-dihydro-4-pyridones.

REFERENCES : 1) A. Guarna; A. Brandi; A. Goti; F. De Sarlo, J. Chem. Soc., Chem. Commun., 1985, 1518. 2) A. Guarna; A. Brandi; F. De Sarlo; A. Goti; F. Pericciuoli, J. Org. Chem., 1988, 53, 2426. 3) A. Brandi; S. Garro; A. Guarna; A. Goti; F. Cordero; F. De Sarlo, J. Org. Chem., 1988, 53, 2430. 4) A. Goti; B. Arichini; A. Brandi; S. Kozhushkov; C. Gratkowski; A. de Meijere, J. Org. Chem., 1996, 61, 1665. 5) C. Zorn; A. Goti; A. Brandi; K. Johnsen; S.I. Kozhushkov; A. de Meijere, Chem. Commun., 1998, 903. 6) A. Goti; S. Cicchi; F.M. Cordero; V. Fedi; A. Brandi, Molecules, 1999, 4, 1.

COMMENTS :

BRANDT ALDEHYDE SYNTHESIS EXAMPLE :

Bu

Cl O

+ LiH

Bu benzene

283

H O

DISCONNECTION : R

Cl O

R

R

H

O O

O R

R O

S

Et

O CH3COOH

ClCH2COOH

NOTES : Lithium hydride heterogeneously reduces acyl halides to aldehydes. With aliphatic acid chlorides improved yields are obtained by forming the thiol ester which is then treated with lithium hydride. See also Grundmann and Rosenmund

– Saytzeff reactions.

REFERENCES : P. Brandt, Acta Chem. Scand., 1949, 3, 1050.

COMMENTS :

von BRAUN AMIDE DEGRADATION EXAMPLE :

N

O PCl5

+ Cl

284

CH2Cl

C N

MECHANISM :

R N H

R

R1

Cl +

R

N

base - HCl

O

R

O

R

PCl5

R1

Cl N

R

Cl R1

R1 - RCl

RCl +

R N

R1 C N

Cl

DISCONNECTION :

O R1

R

N

N H

R1

NOTES : A reaction in which phosphorous pentahalide converts primary and secondary non aromatic amines to their corresponding chloride or bromide. This method is also valuable for opening nitrogen containing rings. See also

Emde and Hofmann degradation reactions.

REFERENCES : March : 1042 Smith – March : 1350 Houben – Weyl : 5/3, 921; 5/4, 451 Org. Synth. : 9, 70; 10, 66; 25, 65; 29, 75; 37, 12 Org. Synth. Coll. Vol. : 1, 428; 2, 379; 3, 535, 646; 4, 166

1) H. von Pechmann, Ber. Dtsch. Chem. Ges., 1900, 33, 611. 2) J. von Braun, Ber. Dtsch. Chem. Ges., 1904, 37, 2678. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189. 4) B.A. Philips; G. Fodor; J. Gal; F. Letourneau; J.J. Ryan, Tetrahedron, 1973, 29, 3309. 5) R.B. Perni; G.W. Gribble, Org. Prep. Proced. Int., 1983, 15, 297.

COMMENTS :

285

von BRAUN CYANOGEN BROMIDE REACTION EXAMPLE :

BrCN + Et3N

Et2NCN

MECHANISM :

N

Br

N(R)3

N

R N R R

Br

NC_N(R)2 + RBr

DISCONNECTION :

(R)2NCN

BrCN + N(R)3

NOTES : Cyanogen bromide reacts with tertiary nitrogen compounds to break one carbon to nitrogen linkage. The cyano group becomes attached to the nitrogen to form a disubstituted cyanamide and the bromine atom to the carbon. Reactions with secondary amines afford lower yields.

REFERENCES : March : 436 Smith – March : 522 Houben – Weyl : 5/4, 151 Org. React : 7, 198 Org. Synth. : 27, 56 Org. Synth. Coll. Vol. : 3, 608

1) J. von Braun, Ber. Dtsch. Chem. Ges., 1900, 33, 1438. 2) H. Rapoport; C.H. Lovell; H.R. Reist; M.E. Warren, jr., J. Am. Chem. Soc., 1967, 89, 1942. 3) G. Fodor; S. Nagubandi, Tetrahedron, 1980, 36, 1279. 4) J.H. Cooley; E.J. Evain, Synthesis, 1989, 1. 5) S. Laabs; A. Scherrmann; A. Sudau; M. Diederich; C. Kierig; U. Nubbemeyer, Synlett, 1999, 25. 6) S. Chambert; F. Thomasson; J.-L. Décout, J. Org. Chem., 2002, 67, 1898.

286

COMMENTS :

von BRAUN AMINO ACID SYNTHESIS EXAMPLE :

O Ph

NH3 Cl H

N H

Br

COOH

H 1) NH4OH 2) aq. HCl 3) pyridine EtOH, heat

H2N

COOH

MECHANISM :

O

O Ph

H

N H

NH3 Cl

Br

NH4OH

COOH

H

N H

H2N

NH3 Cl

H COOH NH3 Cl

Ph

pyridine EtOH, heat

H2N

H COOH

DISCONNECTION :

R H2N

H

R

COOH

Br

287

H COOH

COOH

aq. HCl

NOTES : In the classic example 6-benzoylaminocaproic acid is converted by phosphorous and bromine through the α-bromo acid (Hell – Vollhard – Zelinsky reaction). This acid is ammonolysed and hydrolysed to dl-serine. The benzoylaminocaproic acid, which can be also be chlorinated with sulfuryl chloride in the presence of iodine, is obtained using a von Braun amide degradation reaction on benzoylpiperidine. The resulting N-(5chloroamyl)benzamide is converted into the acid through the nitrile. See also Erlenmeyer – Früstück and du

Vigneaud reactions.

REFERENCES : Org. Synth. : 19, 18, 61; 21, 60 Org. Synth. Coll. Vol. : 2, 74, 374; 3, 495

1) J. von Braun, Ber. Dtsch. Chem. Ges., 1909, 42, 839. 2) J.C. Eck; C.S. Marvel, J. Biol. Chem., 1934, 106, 387. 3) A. Galat, J. Am. Chem. Soc., 1947, 69, 86. 4) H.E. Carter; C.L. Zirkle, J. Biol. Chem., 1949, 178, 709. 5) H.W. Buston; J. Churchman; J. Bishop, J. Biol. Chem., 1953, 204, 665. 6) R.K. Khare; J.M. Becker; F.R. Naider, J. Med. Chem., 1988, 31, 650. 7) J. Xia; Y. Xia; I.A. Nnanna, J. Agric .Food Chem., 1995, 43, 867.

COMMENTS :

BRECKPOT REACTION EXAMPLE :

H F3C

N

CO2TMS

O

H

TMS

N 1) CH3MgBr, Et2O 2) CH3OH, 50 oC

288

F3C

MECHANISM :

R1 R

N H

O OEt EtMgBr

R2

BrMg

EtO R N

O

R N

R2 O

R1

DISCONNECTION :

R N O

R O

R1

H N R1

R2

OEt R2

R, R1, R2 = H, Alk, Ph, CH2Ph

NOTES : The cyclisation of β-amino alcohols esters to substituted β-lactams with Grignard reagents as base.

REFERENCES : Org. React. : 9, 388

1) R. Breckpot, Bull. Soc. Chim. Belg., 1923, 32, 412. 2) T. Shono; K. Tsubata; N. Okinaga, J. Org. Chem., 1984, 49, 1056. 3) P.T. Bevilacqua; D.D. Keith; J.L. Roberts, J. Org. Chem., 1984, 49, 1430. 4) O. Miyata; M. Namba; M. Ueda; T. Naito, Org. Biomol. Chem., 2004, 2, 1274.

COMMENTS :

289

R1

R2

BREDERECK IMIDAZOLE SYNTHESIS EXAMPLE :

H N

O 1) Br2, NH2CHO 2) NH3, NH2CHO 160 - 170 oC

H3C

N

H3C

MECHANISM :

Ph

Ph

CH3 O

H+

Ph Br2

OH

HCOOH, heat (NH4)2CO3

O

EtCO2K

Br

O

O

Et

O

H

NH Ph

O

Ph

CH2

Ph

Et

N

NH

- NH3

NH2 Et

O N H

H

H

O N H Et

N H N

- H2O

Et

DISCONNECTION : R

R1 R

R1

O

X

N H

N H

X = OH, Br, Cl

290

H

+

N

NH2

Ph

H

Ph

Et

Et

NH3

H can be isolated

+

H Ph

N +

or direct

H+

O

Ph

O

HO

Ph N

H N H Et

NOTES : The synthesis of imidazoles from formamide (acetamide) and α-diketones, α-ketols, α-aminoketones, αoximinoketones. See also Akabori – Neuberg – Fischer, Brackeen, Debus – Radziszewski, Maquenne, Wallach imidazole and Weidenhagen reactions.

REFERENCES : Houben – Weyl : 7/2c, 2239; 11/1, 659; E8c, 15, 48

1) H. Bredereck; G. Theiling, Chem. Ber., 1953, 86, 88. 2) A. Novelli; A. de Santis, Tetrahedron Lett., 1967, 8, 265. 3) R. Paul; J.A. Brockman; W.A. Hallet; M.E. Tarrant; L.W. Torley; F.M. Callahan, J. Med. Chem., 1985, 28, 1704.

COMMENTS :

BROOK SILAKETONE REARRANGEMENT EXAMPLE :

Ph Ph Si Ph Ph O

1) NaOEt 2) H+

Ph Ph Ph Si O OEt

MECHANISM :

Ph

Ph Si Ph

Ph O

EtO

Ph Ph Si EtO

Ph Ph Ph Si O OEt

Ph O

291

H+

Ph Ph Ph Si O OEt

DISCONNECTION :

(R)3SiO R

O M Si(R)3

M n-3

R1

R

n-3

R1

NOTES : The rearrangement of silaketones to silyl ethers with chirality transfer, comprising a family of [1,n]-carbon to oxygen silyl migrations. Aza-Brook, stanna-Brook and radical rearrangements are also known.

REFERENCES : Org. Synth. : 76, 199 Org. Synth. Coll. Vol. : 10, 2352

1) J.L. Speier, J. Am. Chem. Soc., 1952, 74, 1003. 2) A.G. Brook, J. Am. Chem. Soc., 1958, 80, 1886. 3) A.G. Brook; N.V. Schwartz, J. Org. Chem., 1962, 27, 2311. 4) A.G. Brook, Acc. Chem. Res., 1974, 7, 77. 5) T. Matsuda; S. Sato; M. Hattori; Y. Izumi, Tetrahedron Lett., 1985, 26, 3215. 6) P.C.B. Page; S.S. Klair; S. Rosenthal, Chem. Soc. Rev., 1990, 19, 147. 7) P. Janowksi; P. Raubo; J. Wicha, Synlett, 1994, 985. 8) M.E. Jung; C.J. Nichols, J. Org. Chem., 1996, 61, 9065. 9) Y. Wang; M. Dolg, Tetrahedron, 1999, 55, 12751. 10) M.D. Paredes; R. Alonso, J. Org. Chem., 2000, 65, 2292. 11) W.H. Moser, Tetrahedron, 2001, 57, 2065. 12) K. Takeda; Y. Sawada; K. Sumi, Org. Lett., 2002, 4, 1031. 13) G. Liu; S.McN. Sieburth, Org. Lett., 2003, 5, 4677. 14) M.R. Paleo; M.I. Calaza; P. Graña; F.J. Sardina, Org. Lett., 2004, 6, 1061.

COMMENTS :

292

BROWN HYDROBORATION EXAMPLE :

CH3 6 H C 3

CH3

+ B2H6

CH3

H2O2, NaOH

H3C CH3 H OH H3C CH3

MECHANISM : R H

H

H

2

C H

H H B H H

R R

(RCH2CH2)3B R

R H H C C H H BH2

R H

H + BH 3

-

CH2

OOH

B

CH2 O O H

H2C R R

CH2 H C 2 von Baeyer - Villiger like O H2 rearrangement B R C O O C 2 -OOH, H2 CH2 - 3 HOH2C R

293

H H H2O, - H3BO3

R

OH H H

Rhodium-catalysed hydroboration :

PPh3

Cl

O

O

Rh B

H B H

O

R

O PPh3

RhCl(PPh3)3 R PPh3 Cl

PPh3 Cl O H Rh B O PPh3

O

Rh B O PPh3

R

and/or O

PPh3

B R

Cl

O and/or R

O

R

O

PPh3 CH3

B H3C

O

Rh B

O

DISCONNECTION :

R

R R1 H

OH

R1

R2

R2 R3

R3

NOTES : Hydroboration – regioselective and stereoselective (syn) addition of BH3 (RBH2, R2BH) complexes to olefins with one to four substituents. Synthesis of alcohols including optically active alcohols from olefins. See also Bäckvall, Birnbaum – Simonini, Milas, Prévost and Woodward cis-hydroxylation reactions.

REFERENCES : March : 783 Smith – March : 1012 Smith : 506 Smith 2nd : 442 Houben – Weyl : 13/3a; 13/3b; 13/3c Org. React. : 13, 1

294

Org. Synth. : 50, 88; 52, 59; 53, 77; 58, 24; 61, 103; 63, 44, 57; 70, 169; 73, 116; 77, 29, 176 Org. Synth. Coll. Vol. : 6, 137, 719, 852, 919; 7, 339, 402, 427; 9, 95, 522; 10, 2366, 2380

1) H.C. Brown; B.C.S. Rao, J. Am. Chem. Soc., 1956, 78, 2582. 2) H.C. Brown; B.C.S. Rao, J. Am. Chem. Soc., 1959, 81, 6423. 3) H.C. Brown; E-i. Negishi, Pure Appl. Chem., 1972, 29, 527. 4) J.H. Brewster; E-i. Negishi, Science, 1980, 207, 44. 5) H.C. Brown; J.A. Sikorski; S.U. Kulkarni; H.D. Lee, J. Org. Chem., 1982, 47, 863. 6) K.N. Houk; N.G. Rondan; Y.-D. Wu; J.T. Metz; M.N. Paddon–Row, Tetrahedron, 1984, 40, 2257. 7) M. Srebnik; P.V. Ramachandran, Aldrichimica Acta, 1987, 20, 9. 8) H.C. Brown; P.V. Ramachandran, J. Org. Chem., 1989, 54, 4504. 9) K. Burgess; M.J. Ohlmeyer, Chem. Rev., 1991, 91, 1179. 10) G.C. Fu; D.A. Evans; A.R. Muci, Adv. Catal. Processes, 1995, 1, 95. 11) K. Burgess; W.A. van der Donk, Adv. Asymmetric Synth., 1996, 181. 12) M.J. Pender; P.J. Carroll; L.G. Sneddon, J. Am. Chem. Soc., 2001, 123, 12222. 13) E. Hupe; M.I. Calaza; P. Knochel, Tetrahedron Lett., 2001, 42, 8829.

COMMENTS :

BROWN REACTION EXAMPLE :

CH3(CH2)6 OH

1) KAPA 2) H2O

(CH2)12OH

HO [CH2]n

[CH2]m H

DISCONNECTION :

HO [CH2]m+n

H

NOTES : The rapid isomerisation of internal acetylenes by potassium 3-aminopropylamide. The mechanism is not understood.

295

REFERENCES : 1) C.A. Brown; A. Yamashita, J. Am. Chem. Soc., 1975, 97, 891. 2) C.A. Brown; A. Yamashita, J. Chem. Soc., Chem. Commun., 1976, 959. 3) H. Hommes; L. Brandsma, Recl. Trav. Chim. Pays-Bas, 1977, 96, 160. 4) S.R. Macauley, J. Org. Chem., 1980, 45, 734. 5) S.R. Abrams, Can. J. Chem., 1984, 62, 1333. 6) T. Kimmel; D. Becker, J. Org. Chem., 1984, 49, 2494.

COMMENTS :

BROWN REARRANGEMENT EXAMPLE :

CH3

FVP

MECHANISM :

H

H

heat H

H

DISCONNECTION :

R R

H

H

NOTES : This reaction interconverts alkynes and vinylidenes (1,2-shift) and plays an important role in diverse high-temperature chemistry.

REFERENCES : 1) R.F.C. Brown; F.W. Eastwood; K.J. Harrington; G.L. McMullen, Aust. J. Chem., 1974, 27, 2393.

296

2) R.F.C. Brown; F.W. Eastwood; G.P. Jackman, Aust. J. Chem., 1978, 31, 579. 3) R.F.C. Brown; F.W. Eastwood; N.R. Wong, Tetrahedron Lett., 1993, 34, 3607. 4) M. Sarobe; L.W. Jenneskens; J.W. Zwikker; J. Wesseling, J. Chem. Soc., Perkin Trans. 2, 1996, 2125. 5) W. Kirmse, Angew. Chem., Int. Ed. Engl., 1997, 36, 1165. 6) R.F.C. Brown, Eur. J. Org. Chem., 1999, 3211. 7) J. Mabry; R.P. Johnson, J. Am. Chem. Soc., 2002, 124, 6497.

COMMENTS :

BRUCKNER SYNTHESIS EXAMPLE :

Ph H

CH3

CH3 H

1) H2SO4, NaNO3 2) (CH3O)2O, H2SO4, 0 oC 3) HO-, migration 4) EtOH, CH3COOH H2SO4, Hg-electrode 5) deacetylation 6) Et3N, O H3C

Cl

297

N CH3

MECHANISM :

H3C

H CH3 NO2 ON H

H N2O3 (NO + NO2)

H

H CH3 NH2 AcO H

EtOH, CH3COOH H2SO4, Hg-electrode

(CH3CO)2O H2SO4, 0 oC

H CH3 H N Ac HO H

HOmigration OH

OH

CH3

CH3 deacetylation

H CH3 NO2 AcO H

N

O

NH2 R

H+

Cl

O

- H+

H

R

Et3N OH H N HO

CH3 H

CH3 N

- 2 H2O

R

R

DISCONNECTION :

CH3

Ph

O

CH3 +

N

H

H

R

Cl

R

NOTES : A 1-arylpropene is converted by dinitrogen trioxide into a ψ-nitrosite, which by acetylative decomposition yields a 1aryl-2-nitropropyl acetate. This is reduced to the 2-amino compound. The addition of alkali causes an O to N migration of the acetyl group to give a 2-acetamido-1-aryl-propanol which is deacetylated, suitably acylated and cyclised by the Pictet – Gams method. The method has been extended to phenanthridines. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bobbit, Larock indole, Pictet – Gams, Pictet – Sprengler, Pomeranz – Fritsch, Simchen and Schlitter – Müller ring-closure reactions.

REFERENCES : 1) V. Bruckner; A. Kramili, J. Prakt. Chem., 1936, 145, 291. 2) V. Bruckner; G. Fodor; J. Kiss; J. Kovács, J. Chem. Soc., 1948, 885. 3) T.R. Givindachari; K. Nagarajan; B.R. Pai; N. Arumugan, J. Chem. Soc., 1956, 4280.

298

COMMENTS :

BRUNNER OXINDOLE RING–CLOSURE EXAMPLE : CH3

H3C

H3C

CH3

O

O CaO

N N H H

CH3O

N OCH3 H

MECHANISM :

CH3

CH3 O

N H

N

H

CH3 O

CaH2, heat

N

N H

H

O NH NH

[3,3]-sigmatropic rearrangement

CH3

CH3

O O

- NH3

N NH2 H H+

N H

DISCONNECTION :

R1

R1

R2

R2 R3

O

R3 N R

O N N H R

NOTES : Acylphenylhydrazines when heated with alkaline reagents undergo a [3,3]-sigmatropic rearrangement followed by elimination of ammonia to give oxindoles. See also von Baeyer oxindole, Brunner, Gassman oxindole, Hinsberg oxindole, Martinet, Neber – Bosset and Stollé reactions.

299

REFERENCES : Org. Synth. : 37, 60 Org. Synth. Coll. Vol. : 4, 657 Science of Synthesis : 10, 604

1) K. Brunner, Monatsh. Chem., 1896, 17, 267. 2) G. Wahl, Monatsh. Chem., 1918, 38, 525. 3) J. Wolff; M. Taddei, Tetrahedron, 1986, 42, 4267. 4) A.R. Lee; W.-H. Huang; T.-L. Lin; K.-M. Shik; H.-F. Lee; C.-I. Lin, J. Heterocycl. Chem., 1995, 32, 1.

COMMENTS :

BRUYLANTS AMINATION EXAMPLE :

H

CH3

N

H

CH3

N

PrMgBr 0 oC

CH3

CN

MECHANISM :

H3C

CN

N H H

CH3 O

H3C CN

H N

- H2O H+

300

EtMgBr

H N

CH3

DISCONNECTION :

R1

R N

R3 R1

R N

R2

CN

+ R3MgBr

R2

NOTES : The reaction of α-amino nitriles with a Grignard reagent to prepare α-substituted amines.

REFERENCES : Houben – Weyl : E16d, 1112

1) P. Bruylants, Bull. Soc. Chim. Belg., 1924, 33, 467. 2) P. Bruylants, Bull. Soc. Chim. Belg., 1926, 35, 139. 3) H. Ahlbrecht; H. Dollinger, Synthesis, 1985, 743. 4) L.V. Kudzma; H.K. Spencer; S.A. Severnak, Tetrahedron Lett., 1988, 29, 6827. 5) T. Zdrojewski; A. Jonczyk, J. Org. Chem., 1998, 63, 452. 6) C. Agami; F. Couty; G. Evans, Org. Lett., 2000, 2, 2085. 7) D. Enders; C. Thiebes, Synlett, 2000, 1745. 8) L. Bernardi; B.F. Bonini; E. Capitò; G. Dessole; M. Fochi; M. Comes–Franchini; A. Ricci, Synlett, 2003, 1778. 9) M. Prashad; Y. Liu; D. Har; O. Repič; T.J. Blacklock, Tetrahedron Lett., 2005, 46, 5455.

COMMENTS :

BUCHERER – BERGS REACTION EXAMPLE : O H

O H3C

CH3

1) 2 KCN 2) 4 (NH4)2CO3

301

N

H3C H3C

N H O

MECHANISM :

R

R1

R1

R1 R

OH + NH3 - H2O

CN

H

O N

R1

O

R

NH2

H N

CO2

CN

O N O H

O

H+

H

C N

R1

NH2

R

R

N H

R

O

NH H+

R1

O N

O

DISCONNECTION :

O H

N

R R1

N H

R

R1

+ HCN + (NH4)2CO3

O O

NOTES : The synthesis of 5-substituted hydantoins by the interaction of an aldehyde or ketone, hydrogen cyanide and ammonium carbonate, or of the cyanohydrin and ammonium carbonate, or of the α-aminonitrile and ammonium carbonate or carbon dioxide. The ketone, potassium cyanide and ammonium carbonate in alcoholic solution may also be used. See also Corey – Link, Strecker amino acid, Tiemann, Ultee, Urech and Zelinsky – Stadnikoff reactions.

REFERENCES : Houben – Weyl : 11/2, 305, 371 Org. Synth. : 20, 42 Org. Synth. Coll. Vol. : 3, 323

1)

H. Bergs, German Patent, 1929, 566094.

2)

H.T. Bucherer; H.T. Fischbeck, J. Prakt. Chem., 1934, 140, 69.

3)

H.T. Bucherer; W. Steiner, J. Prakt. Chem., 1934, 140, 291.

4)

D.T. Mowry, Chem. Rev., 1948, 42, 189.

5)

E. Ware, Chem. Rev., 1950, 46, 403.

6)

G.L. Grunewald; S.H. Kuttab; M.A. Pleiss; J.B. Mangold; P. Soine, J. Med. Chem., 1980, 23, 754.

7)

C.A. Lopez; G.G. Trigo, Adv. Heterocycl. Chem., 1985, 38, 177.

8)

S.A. Haroutounian; M.P. Georgiadis; M.G. Polissiou, J. Heterocycl. Chem., 1989, 26, 1283.

9)

S. Kubik; R.S. Meisner; J. Rebek, Tetrahedron Lett., 1994, 36, 6635.

10) K. Tanaka, H. Sawaniski, Tetrahedron: Asymmetry, 1995, 6, 1641.

302

11) F.J.C. Martins; A.M. Viljoen; H.G. Kruger; L. Fourie; J. Roscher; A.J. Joubert; P.L. Wessels, Tetrahedron, 2001, 57, 1601.

COMMENTS :

BUCHERER – GROLÉE SYNTHESIS EXAMPLE : H3C H3C N H

CH3

COOH CH3

O

KOH 270 oC

N H

MECHANISM :

H3C N H

COOH

HO

CH3

H3C H3C O

N H

O

NH2 CH3

CH3 O

CH3 N H

CH3

DISCONNECTION :

H3C

CH3 H3C

O N H

N H

COOH CH3

NOTES : This synthesis is typified by the treatment of anilino-isobutyric acid (formed by hydrolysis of the product obtained by the action of aniline on acetone cyanohydrin) with sodium ethoxide or potassium hydroxide at 270 – 320 oC. The

303

product is 3,3-dimethyloxindole, formed by fission of the nitrogen carbon bond. See also von Baeyer oxindole, Brunner, Gassman oxindole, Hinsberg oxindole, Martinet, Neber – Bosset and Stollé reactions.

REFERENCES : 1) H. Bucherer; A. Grolée, Ber. Dtsch. Chem. Ges., 1906, 39, 986. 2) S.G.P. Plant; R. Robinson, Nature, 1950, 165, 36. 3) S.G.P. Plant; M. Tomlinson, Nature, 1950, 165, 928. 4) B. Witkop, J. Am. Chem. Soc., 1950, 72, 614.

COMMENTS :

BUCHERER – LE PETIT REACTION EXAMPLE : 1) (NH4)2SO3, NH3 150 oC, 6 atm OH 2) Na2SO3, NaOH

304

NH2

MECHANISM :

H

O

O

H

O

H

H+

O

H

O

H H+, H2NR

NaSO3 SO3Na H O H

H R H O N H

R

R

N H

R

N

H

R H

H

N

H SO3Na

H

- NaHSO3

- H+

H

H H

- H2O

SO3Na

SO3Na

N

SO3Na

DISCONNECTION :

X

Y

NH2 X = C, N Y = C, N

X

Y

OH

NOTES : The reversible conversion of a naphthylamine (also quinoline and isoquinoline) into a naphthol by an aqueous solution of a sulfite or a hydrogen sulfite. See also Bucherer carbazole synthesis.

REFERENCES : Houben – Weyl : 11/1, 143 Org. React. : 1, 105 Org. Synth. : 22, 19 Org. Synth. Coll. Vol. : 3, 78

305

1) R. LePetit, Bull. Soc. Ind. Mulhouse, 1903, 73, 326. 2) H.T. Bucherer, J. Prakt. Chem., 1904, 69, 49. 3) A. Reiche; H. Seeboth, Liebigs Ann. Chem., 1960, 638, 66. 4) A. Seeboth, Angew. Chem., Int. Ed. Engl., 1967, 6, 307. 5) B.S. Belica; P.S. Manchand, Synthesis, 1990, 539. 6) R.A. Singer; S.L. Buchwald, Tetrahedron Lett., 1999, 40, 1095. 7) A. Canete; M.X. Melendez; C. Saitz; A.L. Zanocco, Synth. Commun., 2001, 31, 2143.

COMMENTS :

BUCHERER CARBAZOLE SYNTHESIS EXAMPLE :

O N H OH

1) aq. NaHSO3 2) C6H5NHNH2

306

MECHANISM :

Ph O

O

H

N C6H5NHNH2

NaHSO3 OH

SO3Na Ph

N

SO3Na

H N

N N

NH2

H+

H

H

H+ [3,3]-sigmatropic rearrangement

SO3Na

SO3Na

NH

NH

NH2

NH2

N H NH2 SO3Na

SO3Na

SO3Na

N H

N H - NaHSO3

- NH3 SO3Na

DISCONNECTION :

O N H OH

NOTES : α-Naphthols yield 1,2-benzocarbazole derivatives when treated with phenylhydrazine and aqueous sodium bisulfite.

With β-naphthols and napthylamines dihydrocarbazole sulfonates will be formed from which 3,4-benzocarbazols are obtained. See also Borsche – Drechsel and Bucherer – Le Petit reactions.

307

REFERENCES : Houben – Weyl : 10/2, 250; E6a, 944 Org. React. : 1, 105

1) H.T. Bucherer; F. Seyde, J. Prakt. Chem., 1908, 77, 403. 2) A. Rieche; H. Seeboth, Liebigs Ann. Chem., 1960, 638, 81. 3) A. Rieche; H. Seeboth, Liebigs Ann. Chem., 1964, 671, 77.

COMMENTS :

BÜCHNER – CURTIUS – SCHLOTTERBECK REACTION EXAMPLE :

O

O H

CH3 CH2N2

308

MECHANISM :

R

H

N N

H N N

O

O R

H

R H

- N2

CH3 O

H

- N2

O H

O

R

R

H

H H

H H

O H H

R

H

R

H

O

DISCONNECTION :

O

R H

H

H R1

R

R R2

R1 = H, Alk, Ar

R1 O

O H

R O

NOTES : The interaction of an aldehyde with diazo-compounds yields products which lose nitrogen to give ketonic derivatives. An epoxide (if R has a strong positive character) or a homologue of the initial aldehyde can also be formed. Ketones react in a similar fashion. See also Arndt – Eistert, Clibbens – Nierenstein, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew, Shi, Weitz – Scheffer and Wolff reactions.

309

REFERENCES : Houben – Weyl : E6b, 1163 Org. React. : 8, 364

1) E. Büchner; T. Curtius, Ber. Dtsch. Chem. Ges., 1885, 18, 2373. 2) F. Schlotterbeck, Ber. Dtsch. Chem. Ges., 1907, 40, 479. 3) J.B. Bastύs, Tetrahedron Lett., 1963, 4, 955. 4) B. Eistert; A. Langbein, Liebigs Ann. Chem., 1964, 678, 78. 5) A.J. Anciaux; A. Demonceau; A.F. Noels; A.J. Hubert; R. Warin; P. Teyssié, J. Org. Chem., 1981, 46, 873. 6) P. Manitto; D. Monti; G. Speranza, J. Org. Chem., 1995, 60, 484.

COMMENTS :

BÜCHNER METHOD OF RING ENLARGEMENT EXAMPLE :

CH3

N2

CH3

CH3 AcO

O AcO

Rh2(mandalate)4 H3C

310

O

MECHANISM : CO2Et CO2Et

EtCO2CH2N2

heat

CO2Et

CO2CH3

CO2CH3 [Rh]

+

[Rh]

[2+2] cycloaddition

reductive elimination

CO2CH3

CO2CH3

DISCONNECTION :

O +

N2

OEt

NOTES : Aromatic hydrocarbons react with ethyl diazoacetate to yield, among other products, derivatives of cycloheptatriene. This method has been applied to the synthesis of the tropolone and azulene ring systems. Other olefinic bonds also react. The use of rhodium carboxylates is to increase the selectivity of the intramolecular C-H insertion. There are two possible ways for the first step. The one involving the metallocyclobutane is shown here. The other way involves a metal-stabilised carbocation where the α-carbon is the electrophilic centre. See also St. Pfau – Plattner reaction.

REFERENCES : Org. React. : 18, 217

1) E. Büchner, Ber. Dtsch. Chem. Ges., 1888, 21, 2637. 2) E. Büchner, Ber. Dtsch. Chem. Ges., 1896, 29, 106. 3) E. Büchner; K. Schottenhammer, Ber. Dtsch. Chem. Ges., 1920, 53, 865. 4) W. von F. Doering; L.H. Knox, J. Am. Chem. Soc., 1957, 79, 352. 5) A.J. Anciaux; A.J. Hubert; A.F. Noels; N. Petiniot; P. Teyssié, J. Org. Chem., 1980, 45, 765. 6) A.J. Anciaux; A. Demonceau; A.F. Noels; A.J. Hubert; R. Warin; P. Teyssié, J. Org. Chem., 1981, 46, 873. 7) G. Maas, Top. Curr. Chem., 1987, 137, 75. 8) C.J. Moody; S. Miah; A.M.Z. Slawin; D.J. Mansfield; I.C. Richards, J. Chem. Soc., Perkin Trans. 1, 1998, 4067. 9) M.P. Doyle; D.G. Ene; D.C. Forbes; T.H. Pillow, Chem. Commun., 1999, 1691. 10) M. Yang; T.R. Webb; P. Livant, J. Org. Chem., 2001, 66, 4945.

311

11) C.J. Lovely; R.G. Browning; V. Badarinarayana; H.V.R. Dias, Tetrahedron Lett., 2005, 46, 2453.

COMMENTS :

BUCHWALD – HARTWIG REACTION EXAMPLE :

Br

+

N H

Pd(OAc)2, dppf, NatOBu, toluene, 120 oC

312

N

MECHANISM :

R Ar

ArH

N R1

ArX LnPd0

0

LnPd

H LnPd

LnPd

Ar

N H

N(R1)CH2R

X LnPd

Ar

Ar

R1 H

R H N R1

DISCONNECTION :

ArNRR1

ArX + HNRR1

ArOR

ArX + HOR

NOTES : This is the direct palladium-catalysed C-N or C-O bond formation of aryl halides with amines in the presence of stoichiometric amount of base. The base should not bear any β-hydrogens. The palladium catalyst is usually complexed with chelating phosphine type ligands.

REFERENCES : Org. Synth. : 78, 23 Org. Synth. Coll. Vol. : 10, 2606

1) M. Kosugi; M. Kameyama; T. Migata, Chem. Lett., 1983, 927. 2) F. Paul; J. Patt; J.F. Hartwig, J. Am. Chem. Soc., 1994, 116, 5969. 3) A.S. Guram; S.L. Buchwald, J. Am. Chem. Soc., 1994, 116, 7901. 4) J.F. Hartwig, Synlett, 1996, 329. 5) G. Mann; J.F. Hartwig; M.S. Driver; C. Fernández–Rivas, J. Am. Chem. Soc., 1998, 120, 827. 6) B.H. Yang; S.L. Buchwald, J. Organomet. Chem., 1999, 576, 125. 7) P. Kočovský; A.V. Malkov; S. Vyskocil; G.C. Lloyd–Jones, Pure Appl. Chem., 1999, 71, 1425.

313

8) R.G. Browning; H. Mahmud; V. Badarinarayana; C.J. Lovely, Tetrahedron Lett., 2001, 42, 7155. 9) D.A. Culkin; J.F. Hartwig, Acc. Chem. Res., 2003, 36, 234. 10) C.L. Cioffi; M.L. Berlin; R.J. Herr, Synlett, 2004, 841. 11) R. Csuk; A. Barthel; C. Raschke, Tetrahedron, 2004, 60, 5737.

COMMENTS :

BUCHWALD ZIRCONOCENE REACTION EXAMPLE :

OCH3

OCH3 Br 1) nBuLi, THF, - 50 oC 2) Cp2Zr(CH3)Cl 3) CH3CN, 80 oC, 24 h 4) aq. HCl

CH3 O

MECHANISM :

CH3 ZrCp2

Br N Bn

2 tBuLi Cp2Zr(CH3)Cl THF, - 78 oC

ZrCp2 - CH4

N Bn I

Cp2Zr

I

I2, DCM

N

N Bn

Bn R I

I R N Bn

R

R

N Bn

o

85 C, toluene

314

N Bn

65 oC, DBU toluene

NOTES : In this reaction zirconocene complexes of mainly substituted benzynes are used for the preparation of a variety of polysubstituted aromatic molecules including indoles. Besides polysubstituted aromatic molecules substituted pyrroles and butenolides are accessible via zirconocene complexes.

REFERENCES : 1) S.L. Buchwald; B.T. Watson; R.T. Lum; W.A. Nugent, J. Am. Chem. Soc., 1987, 109, 7137. 2) S.L. Buchwald; R.B. Nielsen, Chem. Rev., 1988, 88, 1047. 3) S.L. Buchwald; M. Woods Wanamaker; B.T. Watson, J. Am. Chem. Soc., 1989, 111, 776. 4) J.H. Tidwell; D.R. Senn; S.L. Buchwald, J. Am. Chem. Soc., 1991, 113, 4685.

COMMENTS :

BUNNETT REACTION EXAMPLE : O CH3

I

K, NH3 CH3

CH3 O

315

MECHANISM :

K + NH3

KNH2 O

O + KNH2 H3C

CH3

CH3

I

I

e-

O R

R

R

CH3

I

O

O

R CH3

CH3

R

R

DISCONNECTION :

Nu

I

NOTES : The nucleophilic aromatic substitution via a radical chain mechanism of substituted aryl iodides. Potassium or light can be used as a catalyst.

REFERENCES : Org. Synth. : 58, 134 Org. Synth. Coll. Vol. : 6, 451

1) J.K. Kim; J.F. Bunnett, J. Am. Chem. Soc., 1970, 92, 7463. 2) R.A. Rossi; J.F. Bunnett, J. Am. Chem. Soc., 1972, 94, 683. 3) R.A. Rossi; J.F. Bunnett, J. Org. Chem., 1973, 38, 1407. 4) J.F. Bunnett; B.F. Gloor, J. Org. Chem., 1974, 39, 382.

316

5) J.F. Bunnett; X. Creary, J. Org. Chem., 1974, 39, 3173. 6) J.F. Bunnett; X. Creary, J. Org. Chem., 1974, 39, 3612. 7) J.F. Bunnett; J.E. Sundberg, Chem. Pharm. Bull., 1975, 23, 2620. 8) J.F. Bunnett; J.E. Sundberg, J. Org. Chem., 1976, 41, 1702. 9) J.F. Bunnett, Acc. Chem. Res., 1978, 11, 413. 10) J.F. Bunnett; R.P. Traber, J. Org. Chem., 1978, 43, 1867. 11) R.R. Bard; J.F. Bunnett; R.P. Traber, J. Org. Chem., 1979, 44, 4918.

COMMENTS :

BURTON – WIEMERS TRIFLUOROMETHYLATION EXAMPLE :

CF3

I

CF3CdCl CuBr, 60 oC DMF

NO2

NO2

MECHANISM :

CF2CClBr + Cd

DMF

CF3

I

NO2

CF3CdCl + CdBr2

CF3CdCl CuBr, 60 oC

NO2

DISCONNECTION :

Ar

CF3

Ar

317

I

NOTES : The trifluoromethylation of aryl iodides with Cd(Cu) reagents, but mainly with CF3Cu (stabilised by HMPA), which is an excellent CF2 transfer agent. Later work has extended the use of this reagent to a wide range of fluoroalkylated allenes and perfluorovinyl compounds.

REFERENCES : Houben – Weyl : E10, 465 Org. Synth. : 72, 225 Org. Synth. Coll. Vol. : 9, 247

1) D.J. Burton; D.M. Wiemers, J. Am. Chem. Soc., 1985, 107, 5014. 2) D.M. Wiemers; D.J. Burton, J. Am. Chem. Soc., 1986, 108, 832. 3) Z.Y. Yang; D.M. Wiemers; D.J. Burton, J. Am. Chem. Soc., 1992, 114, 4402. 4) K.J. MacNeil; D.J. Burton, J. Org. Chem., 1995, 60, 4085. 5) D.J. Burton; Z.Y. Yang; W. Qiu, Chem. Rev., 1996, 96, 1641. 6) H.K. Nair; D.J. Burton, J. Am. Chem. Soc., 1997, 119, 9137. 7) D.J. Burton, J. Fluorine Chem., 1999, 100, 177.

COMMENTS :

BUTLEROW SUGAR SYNTHESIS EXAMPLE :

2 CH2O

formose

318

MECHANISM :

CH2O (C1)

CHO CH2OH (C2)

CHO CHOH CH2OH (C3)

CHO CHOH CHOH CH2OH

CHO CHOH CHOH CHOH CH2OH

CHO CHOH CHOH CHOH CHOH CH2OH

+ C1

+ C2

CH2OH O CH2OH

CH2OH C O CHOH CH2OH

+ C1

+ C3

CH2OH C O CHOH CHOH CH2OH

CH2OH C O CHOH CHOH CHOH CH2OH

+ C2 + C1

CH2OH C O CHOH HOH2C COH CH2OH

CH2OH CHOH C O CHOH CH2OH

CH2OH CHOH C O CHOH CHOH CH2OH

NOTES : Formaldehyde will give after several sequential aldol condensations a sugar mixture, called formose.

REFERENCES : 1) A. Buterlow, Liebigs Ann. Chem., 1861, 120, 295. 2) R. Breslow, Tetrahedron Lett., 1959, 1, 22. 3) R.D. Partridge; A.H. Weiss; D. Todd, Carbohydr. Res., 1972, 24, 29. 4) Y. Shigemasa; O. Nagae; C. Sakazawa; R. Nakashima; T. Matsuura, J. Am. Chem. Soc., 1978, 100, 1309. 5) A.H. Weiss; R.F. Socha; V.A. Likholobov; M.M. Sakharov, Appl. Catal., 1981, 1, 237. 6) S. Irie, Carbohydr. Res., 1989, 190, 23. 7) W.P. Huskey; I.R. Epstein, J. Am. Chem. Soc., 1989, 111, 3157.

319

COMMENTS :

320

321

CLAY – KINNEAR – PERREN PHOSPHONYL CHLORIDE SYNTHESIS · 378

A

CLEMMENSEN REDUCTION · 379 CLEMO SYNTHESIS · 381

ARNOLD VARIATION · 374

CLIBBENS – NIERENSTEIN SYNTHESIS · 383 CLOKE – WILSON CYCLO PROPYL KETONE REARRANGEMENT B

· 384 COHEN – DANIEWSKI PROCESS · 386

BECKMANN – CHAPMAN REARRANGEMENT · 343

COLEMAN SYNTHESIS · 387 COLLINS OXIDATION · 389

C

COLVIN SYNTHESIS · 391 COMBES ACETYLACETONE SYNTHESIS · 392

CADOGAN – CAMERON–WOOD CYCLISATION · 324

COMBES QUINOLINE SYNTHESIS · 394

CADOGAN – SUNDBERG INDOLE SYNTHESIS · 325

COMINS ADDITION · 395

CADOGAN ARYLATION · 326

CONANT – FINKELSTEIN HALOGEN EXCHANGE · 397

CAMPS QUINOLINE SYNTHESIS · 328

CONIA CYCLISATION · 398

CANNIZZARO REACTION · 329

CONRAD – LIMPACH SYNTHESIS · 399

CARBONI – LINDSEY SYNTHESIS · 331

COOK – HEILBRON THIAZOLE SYNTHESIS · 401

CARGILL REARRANGEMENT · 333

COOK – LEVY PEPTIDE SYNTHESIS · 403

CARROLL METHYLENE ADDITION (KIMEL – COPE

COOPER – FINKBEINER HYDROMAGNESIATION · 404

REARRANGEMENT) · 334

COPE – MAMLOCK – WOLFFENSTEIN OLEFIN SYNTHESIS

CASON (GILMAN – NELSON) SYNTHESIS · 336

(COPE ELIMINATION) · 405

CAVA REARRANGEMENT · 337

COPE REARRANGEMENT · 407

CHAN – LAM COUPLING · 338

COREY – CHAYKOVSKY EPOXIDATION · 408

CHAN REARRANGEMENT · 340

COREY – FUCHS REACTION · 410

CHAN REDUCTION OF ACETYLENES · 341

COREY – HOUSE REACTION · 411

CHAPMAN REARRANGEMENT · 342

COREY – ITSUNO – BAKSHI – SHIBATA ENANTIOSELECTIVE

CHARDONNET de CELLLOSE ESTERIFICATION · 344

BORANE REDUCTION · 413

CHARETTE CYCLOPROPANATION · 344

COREY – KIM OXIDATION · 415

CHATTAWAY ACETYLATION · 346

COREY – KWIATKOWSKI REACTION · 416

CHATTAWAY REARRANGEMENT · 347

COREY – LINK REACTION · 418

CHENEY SYNTHESIS · 349

COREY – NICOLAOU MACROLACTONISATION · 419

CHICHIBABIN PYRIDINE SYNTHESIS · 350

COREY – SCHMIDT OXIDATION · 421

CHICHIBABIN PYRROCOLINE (INDOLIZINE) SYNTHESIS · 351

COREY – SEEBACH PROCEDURE · 423

CHICHIBABIN REACTION · 353

COREY – SEMMELHACK MODIFICATION · 425

CHRÉTIEN – LONGI NITROSATION · 354

COREY – SUGGS OXIDATION · 426

CIAMICIAN – DENNSTEDT REARRANGEMENT · 355

COREY – WINTER ALKENE SYNTHESIS · 428

CIAMICIAN PHOTO COUPLING · 356

CORNFORTH REARRANGEMENT · 430

CIAMICIAN PHOTO DISPROPORTIONATION · 358

COUTURE INDOLE SYNTHESIS · 431

CLAISEN – GEUTHER CONDENSATION · 359

CRABBÉ SYNTHESIS · 433

CLAISEN – HAASE ENOL ESTER TRANSFORMATION · 361

CRAIG EXCHANGE · 434

CLAISEN – MAUTHNER – BOUVEAULT SYNTHESIS · 362

CREIGHTON PROCESS · 436

CLAISEN – SCHMIDT CONDENSATION · 363

CRIEGEE GLYCOL CLEAVAGE · 436

CLAISEN – SHADWELL SYNTHESIS · 365

CRIEGEE OSMIUM TETROXIDE REACTION · 438

CLAISEN – WISLICENUS CONDENSATION · 366

CRIEGEE REARRANGEMENT · 439

CLAISEN CARBONATE ALKYLATION · 368

CROSS – BEVAN – BEADLE REACTION · 441

CLAISEN CINNAMIC ESTER SYNTHESIS · 369

CRUM BROWN – WALKER ELECTROLYSIS · 442

CLAISEN HYDROLYSIS · 371

CURATOLO SYNTHESIS · 443

CLAISEN ORTHO ESTER REARRANGEMENT · 367

CURTIUS REARRANGEMENT · 444

CLAISEN REARRANGEMENT (CLAISEN – IRELAND REARRANGEMENT) · 372 G

CLAR REDUCTION · 375 CLAUSON–KAAS REACTION · 376

GERLACH MODIFICATION · 420

322

H

O

HARGAR REACTION · 446

OXY – COPE REARRANGEMENT · 407

M

W

MARTIN – SHERMAN MODIFICATION · 380

WURTZ AMINE SYNTHESIS · 446

MUMM REARRANGEMENT · 343

323

CADOGAN – CAMERON–WOOD CYCLISATION EXAMPLE : O

O H3C

NO2

H N

H3C

NMe2 O

P(OEt)3

N CH3

O

NMe2

N CH3

MECHANISM :

P(OEt)3

P(OEt)3 N O O P(OEt)3

N O O

N

N O P(OEt)3

N

O

H

P(OEt)3

N H

NOTES : The reduction of aromatic nitro compounds by triethyl phosphite leads to carbazoles, indoles, indazoles, triazoles and related compounds. Microwave-enhanced cyclisations have been reported. See also Cadogan – Sundberg indole reaction.

REFERENCES : Org. Synth. : 48, 113 Org. Synth. Coll. Vol. : 5, 941

1) J.I.G. Cadogan; M. Cameron–Wood, Proc. Chem. Soc., 1962, 361. 2) J.I.G. Cadogan; M. Cameron–Wood; R.K. Mackie; R.J.G. Searle, J. Chem. Soc., 1965, 4831. 3) J.I.G. Cadogan; R.K. Mackie; M.J. Todd, J. Chem. Soc., Chem. Commun., 1966, 491. 4) J.I.G. Cadogan; D.J. Sears; D.M. Smith, J. Chem. Soc., Chem. Commun., 1966, 491.

324

5) V. Amarnath; R. Madhav, Synthesis, 1974, 837. 6) B.R. Hsieh; M.H. Litt, Macromolecules, 1985, 18, 1388. 7) J.-F. Morin; M. Leclerc, Macromolecules, 2001, 34, 4680. 8) G. Zotti; G. Schiavon; S. Zecchin; J.-F. Morin; M. Leclerc, Macromolecules, 2002, 35, 2122. 9) J. Bouchard; S. Wakim; M. Leclerc, J. Org. Chem., 2004, 69, 5705. 10) P. Akkpukkuttan; E. van der Eycken; W. Dehaen, Synlett, 2005, 127.

COMMENTS :

CADOGAN – SUNDBERG INDOLE SYNTHESIS EXAMPLE :

CF3 CF3 CO 5 atm. Se, 100 oC DMF, Et3N

NO2

N H

MECHANISM :

R

R N O

H+

O

P(OEt)3

O OEt N P OEt O OEt

R N OH

325

R N H O

DISCONNECTION :

R R N OH

N O

O

NOTES : The deoxygenation of ortho-nitrostyrenes or ortho-nitrostilbenes with triethyl phosphate. Additional cyclisation of the nitrene or equivalent affords the indole. Instead of triethyl phosphite carbonyl selenide can be used. This reaction is very similar to the von Baeyer – Emmerling. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) J.I.G. Cadogan; M. Cameron–Wood; R.K. Mackie; R.J.G. Searle, J. Chem. Soc., 1965, 4831. 2) R.J. Sundberg, J. Org. Chem., 1965, 30, 3604. 3) K. Jesudoss; P.C. Srinivasan, Synth. Commun., 1994, 24, 1701. 4) C.W. Holzapfel; C. Dwyer, Heterocycles, 1998, 48, 1513. 5) Y. Nishiyama; R. Maema; K. Ohno; M. Hirose; N. Sonoda, Tetrahedron Lett., 1999, 40, 5717.

COMMENTS :

CADOGAN ARYLATION EXAMPLE :

Cl

NH2

pentyl nitrite benzene

326

Cl

MECHANISM :

Cl

NH2

Cl O

N

N N

O

Cl

Cl benzene, - N2

DISCONNECTION :

R R

R1

R

R1

NH2

+

R1

NH2

+

R1

R

N

N

NOTES : Aminopyridines or aminobenzenes are diazotised with pentyl nitrite in refluxing benzene. The resulting diazonium compounds then couple with the solvent to give the desired phenylpyridines or biphenyls. A radical mechanism is also possible. See also Balz – Schiemann, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulphinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : 1) J.I.G. Cadogan, J. Chem. Soc., 1962, 4257. 2) M.P. Seymour; I.W. Duncan; T.M. Jefferies; L.J. Notarianni, J. Chromatogr., 1986, 368, 174. 3) J. Stavenuiter; M. Hamzink; R. van der Hulst; G. Zomer; G. Westra; E. Kriek, Heterocycles, 1987, 26, 2711. 4) E. Mannila; E. Kolehmainen; K. Rissanen, Acta Chem. Scand., 1994, 48, 684. 5) S. Safe; K. Washburn; T. Zacharewski; T. Philips, Chemosphere, 1995, 31, 3017.

COMMENTS :

327

CAMPS QUINOLINE SYNTHESIS EXAMPLE :

CH3

O CH3 H

N

OH CH3 and / or

aq. EtOH, HO-

N

OH

N

CH2CH3

O CH3

MECHANISM :

O

N

O CH3 H

N

O R

N

R

O

CH3 R N

OH

OH

H+

H O

O H

CH2 H O H+

CH3 R N H

OH

CH3 R N

O

CH3 H O H

R H2O

O

N H OH

N

CH2R

328

OH R

N

R

DISCONNECTION :

CH3 O

R N

OH N

OH

CH3 H O

R N

CH2R

NOTES : Hydroxyquinolines are obtained from o-acylaminoacetophenones by treatment with aqueous ethanolic alkali hydroxide. See also Allan – Loudon, von Baeyer – Drewson quinoline, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES : 1) A. Bischler, Ber. Dtsch. Chem. Ges., 1893, 26, 1384. 2) R. Camps, Ber. Dtsch. Chem. Ges., 1899, 32, 3228. 3) R. Camps, Ber. Dtsch. Chem. Ges., 1901, 34, 2703. 4) A. Homer, J. Biol. Chem., 1914, 17, 509. 5) R.H.F. Manske, Chem. Rev., 1942, 30, 113. 6) J. Bornstein; W.J. Reid; D.J. Torres, J. Am. Chem. Soc., 1954, 76, 2760. 7) H. Yanagisawa; H. Nakao; A. Ando, Chem. Pharm. Bull., 1973, 21, 1080.

COMMENTS :

CANNIZZARO REACTION EXAMPLE :

2 PhCHO

PhCH2OH + PhCOOH

NaOH

329

MECHANISM :

O R

O H

OH

R

H O

H

H+

RCH2OH + RCOOH

R

OH

DISCONNECTION :

RCHO

RCH2OH

NOTES : In the classic Cannizzaro reaction there are no α–hydrogens present on the aldehyde. However, 1,4-dialdehydes are converted to γ-lactones using a rhodium phosphine complex, showing that α–hydrogens do not pose a problem. Crossed-Cannizzaro reactions are also possible. A strong base is often necessary and the reaction can be carried out under solvent-free conditions. Photo-Cannizaro reactions have also been reported. See also Cheney, Nord, Tishchenko – Claisen and Tollens reactions.

REFERENCES : March : 1234 Smith – March : 463, 1200, 1508, 1564 Houben – Weyl : E3, 636; E5, 274 Org. React. : 2, 94 Org. Synth. : 18, 79 Org. Synth. Coll. Vol. : 2, 590

1) F. Wöhler; J. von Liebig, Liebigs Ann. Chem., 1832, 3, 249. 2) S. Cannizzaro, Liebigs Ann. Chem., 1853, 88, 129. 3) J. Weiss, Trans. Faraday Soc., 1941, 37, 782. 4) D.R. Lachowitz; R.J. Gritter, J. Org. Chem., 1963, 28, 106. 5) J. Kagan, Tetrahedron Lett., 1966, 7, 6097. 6) R.S. McDonald; C.E. Sibley, Can. J. Chem., 1981, 59, 1061. 7) S.H. Bergens; D.P. Fairlie; B. Bosnich, Organometallics, 1990, 9, 566. 8) Y. Tsujino; C. Wakai; N. Matubayashi; M. Nakahara, Chem. Lett., 1999, 287. 9) A.E. Russell; S.P. Miller; J.P. Morken, J. Org. Chem., 2000, 65, 8381. 10) K. Yoshizawa; S. Toyota; F. Toda, Tetrahedron Lett., 2001, 42, 7983. 11) K. Ishihara; T. Yano, Org. Lett., 2004, 6, 1983. 12) Y. Vida; E. Perez-Inestrosa; R. Suau, Tetrahedron Lett., 2005, 46, 1575.

330

COMMENTS :

CARBONI – LINDSEY SYNTHESIS EXAMPLE :

N N

N N

+

dioxane

S

N N

S

MECHANISM :

N

R1 N N

N + N

N R1

N

- N2

N R2

N N

- HX

R2

R2

N

X

N + N

R1

N N

N

X

X

N - N2

N

N N

331

N N

N N N

N + N

X N N

Y

X

X

N

Y

Y

N

- N2

N

- HX

N N

- HY

N N

Y

X

DISCONNECTION :

R1 N N

N N

N N

R2

NOTES : [4+2]-Cycloadditions are by far the most important reactions of 1,2,4,5-tetrazines. The cycloaddition of 1,2,4,5tetrazines with simple alkenes and alkynes under mild thermal conditions affords 1:1 adducts, with the loss of nitrogen. See also Boger – Panek and Diels – Alder reactions.

REFERENCES : Org. Synth. : 70, 79 Org. Synth. Coll. Vol. : 9, 335

1) R.A. Carboni; R.V. Lindsey, J. Am. Chem. Soc., 1959, 81, 4342. 2) G. Seitz; L. Gorge, Chem. -Ztg., 1984, 108, 331. 3) D.L. Boger, Chem. Rev., 1986, 86, 781. 4) D.L. Boger, Tetrahedron, 1993, 39, 2869. 5) J. Sauer; D.K. Heldmann; J. Hetzenegger; J. Krauthan; H. Sichert; J. Schuster, Eur. J. Org. Chem., 1998, 2885. 6) G.L. Rusinov; R.I. Ishmetova; N.I. Latosh; I.N. Ganebnych; O.N. Chupakhin; V.A. Potemkin, Russ. Chem. Bull., 2000, 49, 355. 7) X.J. Zhou; E.G. Kovalev; J.T. Klug; V. Khordorkovsky, Org. Lett., 2001, 3, 1725.

332

COMMENTS :

CARGILL REARRANGEMENT EXAMPLE :

H

O

O

H

H

O

H

O O

CH3

O OCH3

p-TsOH Benzene

O O HO

CH3

MECHANISM :

CH3

CH3

CH3

H3C

O

H+ O

O

OH

H

DISCONNECTION :

NOTES : A practical method for the conversion of bicyclo[4.2.0]octene systems to bicycle[3.2.1]octene systems in the presence of an acid catalyst.

REFERENCES : 1) R.L. Cargill; J.W. Crawford, Tetrahedron Lett., 1967, 8, 169. 2) R.L. Cargill; J.W. Crawford, J. Org. Chem., 1970, 35, 356. 3) R.L. Cargill; D.M. Pond; S.O. LeGrand, J. Org. Chem., 1970, 35, 359.

333

4) R.L. Cargill; T.E. Jackson; N.P. Peet; D.M. Pond, Acc. Chem. Res., 1974, 7, 106. 5) K. Narasaka; H. Shimadzu; Y. Hayashi, Chem. Lett., 1993, 621. 6) J.D. White; N.-S. Kim; D.E. Hill; J.A. Thomas, Synthesis, 1998, 619.

COMMENTS :

CARROLL METHYLENE ADDITION (KIMEL – COPE REARRANGEMENT) EXAMPLE : CH3 OH

O +

H3C

CH3

O CH3

EtO

1) base 2) CCl4, heat

CH3

CH3 H3C

CH3

O

MECHANISM :

O O

O

H

OH

O CH3

CH3

O base

O

OH

O

O

O

CH3

CH3

CH3

CCl4, heat - CO2

DISCONNECTION : R1 R

O

R O

HO

R1

O

+ R2O

CH3

CH3

NOTES : β,γ-Unsaturated alcohols react with active methylene compounds in the presence of an alkaline catalyst (NaOAc, NaOCH3, KOH) to yield an ethylenic ketone. The reaction involves the thermal rearrangement of allylic esters to β-

334

keto acids followed by decarboxylation to provide γ,δ-unsaturated methylketones. An asymmetric Carroll rearrangement has been developed by Enders using the SAMP hydrazone method. See also Belluš – Claisen rearrangement, Claisen (Claisen – Ireland) rearrangement, Cope, Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Johnson – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES : Smith : 1241 Smith 2nd : 1023 Houben – Weyl : E18, 1061 Org. React. : 22, 1; 41, 1; 43, 2 Org. Synth. : 47, 87; 68, 210 Org. Synth. Coll. Vol. : 5, 767; 8, 235

1) M.F. Carroll, J. Chem. Soc., 1940, 704. 2) M.F. Carroll, J. Chem. Soc., 1940, 1266. 3) W. Kimel; A.C. Cope, J. Am. Chem. Soc., 1943, 65, 1992. 4) M. Tanabe; K. Hayashi, J. Am. Chem. Soc., 1980, 102, 862. 5) S.R. Wilson; M.F. Price, J. Org. Chem., 1984, 49, 722. 6) D. Enders; M. Knopp; J. Runsink; G. Raabe, Angew. Chem., Int. Ed. Engl., 1995, 34, 2278. 7) J.L. Wood; B.M. Stolz; H.-J. Dietrich, J. Am. Chem. Soc., 1995, 117, 10413. 8) G. Raabe; J. Runsink; D. Enders; M. Knopp, Liebigs Ann. / Receuil, 1996, 1095. 9) L.N. Sobenina; A.I. Mikhaleva; O.V. Petrova; R.I. Polovnikova; B.A. Trofimov, Russ. J. Org. Chem., 1997, 33, 1041. 10) J. Nowicki, Molecules, 2000, 5, 1033. 11) A.M.M. Castro, Chem. Rev., 2004, 104, 2939. 12) M.E. Jung; B.A. Duclos, Tetrahedron Lett., 2004, 45, 107. 13) R. Kuwano; N. Ishida; M. Murakami, Chem. Commun., 2005, 3951.

COMMENTS :

335

CASON (GILMAN – NELSON) SYNTHESIS EXAMPLE :

CH3Br + 2

H3C

Cl Mg

O

H3C

2

CH3 O

MECHANISM :

R Br + Mg

R MgBr

2 RMgBr + CdCl2

R2Cd +

2

R1

R2Cd + MgBr2 + MgCl2 Cl

R1

2

R + CdCl2 O

O

DISCONNECTION :

R1

R1

R O

R1 = Ar, Alk

Cl + RHal O

NOTES : The formation of ketones from aliphatic and aromatic acid chlorides and organometallic cadmium compounds. See also Blaise, Blaise – Maire, Grignard and Reformatsky reactions.

REFERENCES : Org. React. : 8, 28 Org. Synth. : 28, 75 Org. Synth. Coll. Vol. : 3, 601

1) H. Gilman; J.F. Nelson, Recl. Trav. Chim. Pays-Bas, 1936, 55, 518. 2) J. Cason, J. Am. Chem. Soc., 1946, 68, 2078. 3) J. Cason, Chem. Rev., 1947, 40, 15. 4) J. Cason; F.F. Schmitz, J. Org. Chem., 1963, 28, 555. 5) R.M. Shisla; W.C. Hammann, J. Org. Chem., 1970, 35, 3224.

336

COMMENTS :

CAVA REARRANGEMENT EXAMPLE :

CH3

CH3

O O N S + H2N O

O

H

O

CH3

N2

NaOH CH3

CH3

MECHANISM :

R

R

O O N S + H2N O

O

H

O

CH3

O N S N O H

CH3

R1

R1 R

NaOH R1

O

R

O N S N O

O

CH3 N2

Na+

R1

DISCONNECTION :

R

R

O N2

O O

R1

R1

337

O + Na S O

CH3

NOTES : The formation of a diazoketone from an α-diketone and p-toluenesulfonylhydrazide. See also Bamford – Stevens and Forster reactions.

REFERENCES : 1) W. Borsche; R. Frank, Liebigs Ann. Chem., 1926, 450, 75. 2) M.P. Cava; R.L. Little, Chem. Ind. (London), 1957, 367. 3) M.P. Cava; R.L. Little; D.R. Napier, J. Am. Chem. Soc., 1958, 80, 2257.

COMMENTS :

CHAN – LAM COUPLING EXAMPLE :

N F3C

B(OH)2 + N H

1.5 Cu(OAc)2 2 Pyridine DCM, RT, air, 2 days

338

F3C

N

N

MECHANISM :

H N

L N Cu(OAc)2 pyridine

O

L II

Cu OAc

+ N OAc

O

ArB(OH)2

L

L

N

O

L

L

CuIII N Ar O2 or disproportionation

II

Cu Ar

+ AcOB(OH)2

O

- Cu0 reductive elimination

- CuI O

N Ar

DISCONNECTION :

R

R Ar

X

ArB(OH)2 +

R1 X = N, S, O R, R1 = Aryl, alkyl, vinyl, H

X H R1

NOTES : An extremely versatile and powerful coupling method involving the formation of a carbon heteroatom bond by the copper mediated oxidative coupling of a boronic acid with an amine, alcohol or thiol. See also Buchwald – Hartwig and Suzuki reactions.

REFERENCES : 1) P.Y.S. Lam; C.G. Clark; S. Saubern; J. Adams; M.P. Winters; D.M.T. Chan; A. Combs, Tetrahedron Lett., 1998, 39, 2941. 2) P.Y.S. Lam; S. Deudon; K.M. Averill; R. Li; M.Y. He; P. DeShong; C.G. Clark, J. Am. Chem. Soc., 2000, 122, 7600. 3) P.Y.S. Lam; G. Vincent; C.G. Clark; S. Deudon; P.K. Jadhav, Tetrahedron Lett., 2001, 42, 3415. 4) P.Y.S. Lam; C.G. Clark; S. Saubern; J. Adams; K.M. Averill; D.M.T. Chan; A. Combs, Synlett, 2002, 674. 5) P.Y.S. Lam; D. Bonne; G. Vincent; C.G. Clark; A.P. Combs, Tetrahedron Lett., 2003, 44, 1691. 6) P.Y.S. Lam; G. Vincent; D. Bonne; C.G. Clark, Tetrahedron Lett., 2003, 44, 4927.

339

COMMENTS :

CHAN REARRANGEMENT EXAMPLE :

CH3

CH3 O

TBSO CH3O

OTBS

CO2CH3 1) 5 LDA, THF, 0 oC 2) 10 Me3SiCl - 78 oC --> 0 oC

O

CH3

CH3 OTMS

TBSO CH3O

CO2CH3 OTMS

OTBS

MECHANISM :

O R

OR1

O

R

base

O O

OR1

O

O OR1

R

OR1

TMSCl

O

O

O

OR1 OTMS

H2O

O

R

OR1 OH

DISCONNECTION :

O

O

R

OR1 O

O

R

base

O TMSO

R

O

O

R

O

O

O

O OR1

R

OH

OR1

O O

340

NOTES : The base-induced rearrangement of α-(acyloxy)acetates to α-hydroxy-β-keto esters. The rearrangement is believed to proceed via an epoxide.

REFERENCES : 1) S.D. Lee; T.H. Chan; K.S. Kwon, Tetrahedron Lett., 1984, 24, 3399. 2) J.D. White; S.C. Jeffrey, J. Org. Chem., 1996, 61, 2600. 3) P. Wipf; J.-L. Methot, Org. Lett., 2001, 3, 1261.

COMMENTS :

CHAN REDUCTION OF ACETYLENES EXAMPLE :

CH3 H3C

HO

CH3

CH3

CH3

H CH3

SMEAH heat

H

CH3

H CH3

HO H

MECHANISM :

OH R H

H3C H

H3C

H

H

Al O O

H3CO

OCH3

Na+

DISCONNECTION :

H3C

OH

R HO

R

HO

H3C

H

H R

341

NOTES : The

stereospecific

reduction

α-acetylenic

of

alcohols

to

E-allyllic

alcohols

using

methoxyethoxy)aluminium hydride (SMEAH, Red-Al). The Lindlar catalyst gives (Z)-allylic alcohols.

REFERENCES : Org. Synth. : 64, 182 Org. Synth. Coll. Vol. : 7, 524

1) K.-K. Chan; N. Cohen; J.P. De Noble; A.C. Specian, jr.; G. Saucy, J. Org. Chem., 1976, 41, 3497. 2) K.-K. Chan; A.C. Specian, jr.; G. Saucy, J. Org. Chem., 1978, 43, 3435. 3) B.M. Trost; M. Lautens, J. Am. Chem. Soc., 1987, 109, 1469.

COMMENTS :

CHAPMAN REARRANGEMENT EXAMPLE :

N CH3 O

heat tetraglyme

N O

CH3

MECHANISM :

C N O R

heat

C N O R

342

C N R O

sodium

bis(2-

DISCONNECTION :

Ar O

Ar N R

Ar

Ar N

R O

Ar = C6H4Alk, C6H4Hal, C6H4OR1, C6H4CN, C6H4COOR1

NOTES : Arylimido esters when heated to 200 oC undergo an intramolecular rearrangement (1,3-oxygen to nitrogen shift) to give acylated diphenylamines. If R is electron-withdrawing then the reaction proceeds more quickly while with electron-donating groups on the aryl ring the reactivity is reduced. This reaction is sometimes called the Beckmann – Chapman rearrangement or the Mumm rearrangement. See also Beckmann rearrangement, Hayashi rearrangement, Newman – Karnes – Kwart, Schönberg and Smiles reactions.

REFERENCES : March : 1155 Smith – March : 1464 Org. React. : 14, 1; 18, 99

1) O. Mumm; H. Hesse; H. Volquartz, Ber. Dtsch. Chem. Ges., 1915, 48, 379. 2) A.W. Chapman, J. Chem. Soc., 1925, 127, 1992. 3) R. Roger; D.G. Nelson, Chem. Rev., 1961, 61, 179. 4) O.H. Wheeler; F. Roman; M.V. Santiago; F. Quiles, Can. J. Chem., 1969, 47, 503. 5) M.S. Newman, Acc. Chem. Res., 1972, 5, 354. 6) L.H. Peterson; A.W. Douglas; R.L. Tolman, J. Heterocycl. Chem., 1981, 18, 659. 7) X. Wang; Y. Cai; Z. Xu, Zhongguo Yaoxue Zazhi, 1997, 32, 774. 8) K.-I. Shohda; T. Wada; M. Sekine, Nucleosides, Nucleotides, 1998, 17, 2199.

COMMENTS :

343

de CHARDONNET CELLULOSE ESTERIFICATION EXAMPLE :

HNO3, H2SO4 [C6H7O2(OH)3]n

hydrolysis

[C6H7O2(ONO2)3]n + 3 n H2O

NOTES : The esterification of cellulose with nitric and sulfuric acid to silk. See also Cross – Bevan – Beadle reaction.

REFERENCES : Houben – Weyl : 14/2, 868

H. de Chardonnet, French patent, 1884, 165349.

COMMENTS :

CHARETTE CYCLOPROPANATION EXAMPLE :

OBn BnO BnO

O OH

OBn O

Pr 10 Et2Zn 10 CH2I2 toluene, - 35 oC

344

BnO BnO

O OH

O

Pr

MECHANISM :

O

O

N(CH3)2

(CH3)2N O

B

O

Ph

N(CH3)2

(CH3)2N

Bu HO

O

O

O

Zn(CH2I)2, 0 oC

B

Bu

O

HO

O Zn

Ph

Ph C H2

I

DISCONNECTION :

R R1

X R

R2 R1

R X = OH, OR4, NHR3 R1

X

X R2

R2

NOTES :

The conversion of allylic alcohols, ethers, and carbamates into the corresponding enantiomerically enriched cyclopropanes using bis(iodomethyl)zinc and dioxaborolane derived ligands. Initial experiments used α-Dglucopyranosides as chiral auxiliary. See also Freund, Gustavson, Hass cyclopropane, Ipatiew cyclopropane, Kishner, Mousseron – Fraisse – McCoy, Nerdel and Simmons – Smith reactions.

REFERENCES : Smith – March : 1084 Smith 2nd : 1212 Org. React. : 58, 1 Org. Synth. : 76, 86

1) A.B. Charette; B. Côté; J.P. Marcoux, J. Am. Chem. Soc., 1991, 113, 8166. 2) Y. Ukaji; M. Nishimura; T. Fujisawa, Chem. Lett., 1992, 61. 3) A.B. Charette; J.P. Marcoux, Tetrahedron Lett., 1993, 34, 7157. 4) A.B. Charette; J.P. Marcoux, Synlett, 1995, 1197. 5) A.B. Charette; H. Juteau; H. Lebel; C. Molinaro, J. Am. Chem. Soc., 1998, 120, 11943.

345

6) K.C. Nicolaou; A. Ritzén; K. Namoto; R.M. Buey; J.F. Díaz; J.M. Andreu; M. Wartmann; K.-H. Altmann; A. O’Brate; P. Giannakakou, Tetrahedron, 2002, 58, 6413.

COMMENTS :

CHATTAWAY ACETYLATION EXAMPLE :

O

OH + (CH3CO)2O

O CH3

aq. Na2CO3, 0 oC

MECHANISM :

O OH

O

O O

base

- CH3COOH

O CH3

O

DISCONNECTION :

Ar

X

CH3 O

Ar XH Ar = C6H4R; R = NO2, NH2, Br, COOH, COOCH3, COOPh X = O, NH

NOTES :

Aromatic hydroxyl- and amino-groups can be acetylated quantitatively by adding acetic anhydride to their dilute solutions in aqueous caustic alkali at 0 oC. See also Einhorn acylation, Galat – Elion, Lumière – Barbier, Schotten – Baumann and Weinreb reactions.

REFERENCES : March : 392

346

Smith – March : 483 Org. Synth. : 21, 22; 28, 68; 34, 1 Org. Synth. Coll. Vol. : 3, 281, 452; 4, 15

1) F.D. Chattaway, J. Chem. Soc., 1931, 2495. 2) E.R. Marshall; J.A. Luck; R.C. Elderfield, J. Org. Chem., 1942, 7, 451. 3) S.S. Israelstam; I.D. Simpson, J. S. African Chem. Inst., 1956, 9, 92. 4) A.B. Maude; A. Williams, J. Chem. Soc., Perkin Trans. 2, 1997, 179.

COMMENTS :

CHATTAWAY REARRANGEMENT EXAMPLE :

O H3C

O

O N

H

CH3

N

CH3

ZnCl2 O

347

CH3

MECHANISM :

O

H H3C

N

O

O

O N

CH3 ZnCl2

H

CH3

N

CH3

O CH3

H

H3C

O

O H

N

O

CH3

CH3

DISCONNECTION : O H

N

O R

R

R1 COR

R = Alk, Ph R1 = H, Cl, Br, CH3

O N

R

R1

NOTES : N,N-Diacylanilines rearrange intermolecularly to acylamino-ketones when heated in the presence of freshly fused zinc

chloride. See also Bamberger rearrangement, Fischer – Hepp, Fries, Hofmann – Martius and Orton reactions.

REFERENCES :

1) F.D. Chattaway, J. Chem. Soc., 1904, 85, 386. 2) J.F.J. Dippy; V. Moss, J. Chem. Soc., 1952, 2205. 3) J. Shorter, Abstr. Pap. Am. Chem. Soc., 1987, 194, 62. 4) B.I. Buzykin; L.P. Sysoeva, Bull. Russ. Acad. Sci-Div. Chem. Sci., 1992, 41, 1115.

COMMENTS :

348

CHENEY SYNTHESIS EXAMPLE :

O

NH.HCl + (CH2O)x + (CH3)2CHCHO

O

1) EtOH 2) CH2O MeOH, KOH

N

CH3

H3C

OH

MECHANISM :

CH3 O

O

H

NH.HCl + (CH2O)x + H3C

EtOH

O O CH2O MeOH, KOH

N H3C

N

CH3

H3C

H O

CH3 OH

DISCONNECTION :

R

N R1

R

CH3 OH CH3

NH.HCl + (CH3)2CHCHO R1

NOTES :

This reaction involves a combination of the Mannich and the crossed Cannizzaro reactions. It affords a variety of 2,2-disubstituted amino-alcohols, analogous in constitution to 2,2-dimethyl-3-(4-morpholinyl)-1-propanol. Certain esters of these compounds exhibit physiological activity. See also Cannizarro and Mannich reactions.

REFERENCES :

1) L.C. Cheney; W.G. Bywater, J. Am. Chem. Soc., 1942, 64, 970. 2) L.C. Cheney, J. Am. Chem. Soc., 1951, 73, 685.

COMMENTS :

349

CHICHIBABIN PYRIDINE SYNTHESIS EXAMPLE :

CH3

3 CH3CHO + NH3

230 oC

H3C

N

MECHANISM :

H3N

H+

H

O

R H

H3N

OH

R

NH2

R

- H2O

H

H

R

O

R

R

+

H

R

O

R

N R

R

H+

O R

H

H

O

OH R

R

R

R

H

H

R

HN

H

- H2O

H+

H

H O

O

HO

O H

H

H

R

H

H

R

O

H

H

H

NH2

N H+

H

R

N

N

R

R

H H3N R

autoxidation

N

- H2O

R

R

R N

R

R

DISCONNECTION :

R R

R H

R

H

R

O + NH3 R

N

350

H

NH

R

NOTES :

The pyridine synthesis from aromatic acetaldehydes and ammonia. The mechanism of this reaction is still not clear, see Sagitullin et al. See also Bohlmann – Rahtz, Gattermann – Skita, Guareschi – Thorpe, Hantzsch – Beyer, von Meyer – Mohr, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES : Houben – Weyl : E7b, 316 Org. Synth. : 30, 41 Org. Synth. Coll. Vol. : 4, 451

1) H. Hübner; A. Geuther, Liebigs Ann. Chem., 1860, 114, 35. 2) E. Dürkopf, Ber. Dtsch. Chem. Ges., 1888, 21, 2713. 3) A.E. Chichibabin, J. Russ. Phys. Chem. Soc., 1906, 37, 1229. 4) M.M. Sprung, Chem. Rev., 1940, 26, 297. 5) R.L. Frank; R.P. Seven, J. Am. Chem. Soc., 1949, 71, 2629. 6) C.P. Farley; E.L. Eliel, J. Am. Chem. Soc., 1956, 78, 3477. 7) J.I. Grayson; R. Dishel, Helv. Chim. Acta, 1984, 67, 2100. 8) G.P. Shkil; R.S. Sagitullin; I.I. Nosonova; A.A. Ferber, Chem. of Heterocycl. Comp., 1996, 32, 127. 9) B.B. Snider; B.J. Neubert, Org. Lett., 2005, 7, 2715.

COMMENTS :

CHICHIBABIN PYRROCOLINE (INDOLIZINE) SYNTHESIS EXAMPLE :

+ N

CH3

H

Cl

CH3

base, heat

H O

351

N

CH3

MECHANISM :

H

Br + N

CH3

Ph

N

H

CH3 aq. NaHCO3 heat

Ph

O

Br O

N Ph

N

CH2 H

N

CH2

CH2 Ph

Ph O H+

O

O

N

- H2O

Ph

DISCONNECTION :

R

N

+ N

CH3

R1

R1

Br

R H O

NOTES :

Pyrrocolines are obtained by the cyclisation of the quaternary compounds formed from α-picolines and α-haloketones. See also Scholtz reaction.

REFERENCES : Houben – Weyl : E6/b1, 323 Science of Synthesis : 10, 765

1) A.E. Chichibabin, Ber. Dtsch. Chem. Ges., 1927, 60, 1607. 2) E.T. Borrows; D.O. Holland, Chem. Rev., 1948, 42, 611. 3) E.M. Roberts; M. Gates; V. Boekelheide, J. Org. Chem., 1955, 20, 1443. 4) A.R. Katritzky; G. Qui; B. Yang; H.-Y. He, J. Org. Chem., 1999, 64, 7618. 5) E.I. Kostik; A. Abiko; A. Oku, J. Org. Chem., 2001, 66, 1638. 6) E.I. Kostik; A. Abiko; A. Oku, J. Org. Chem., 2001, 66, 2618.

352

COMMENTS :

CHICHIBABIN REACTION EXAMPLE :

1) NaNH2 benzene 2) H2O

N

N

NH2

MECHANISM :

N

N

NH2

H NH2

- NaH

N

N H

H

DISCONNECTION :

N

N

NH2

NOTES :

Heterocyclic bases, such as pyridine or quinoline or their derivatives, react with metal amides to yield amino derivatives. Intramolecular reactions are known. For a detailed reaction mechanism see McGill and Rappa.

REFERENCES : March : 668 Smith – March : 873 Houben – Weyl : E7a, 412, 765; E7b, 143, 187 Org. React. : 1, 91

1) A.E. Chichibabin; O.A. Seide, J. Russ. Phys. Chem. Ges., 1914, 40, 1216. 2) A.E. Chichibabin, Ber. Dtsch. Chem. Ges., 1923, 56B, 1879.

353

3) J.F. Bunnett; R.E. Zahler, Chem. Rev., 1951, 49, 273. 4) R. Levine; W.C. Fernelius, Chem. Rev., 1954, 54, 449. 5) D.R. Eckroth, Chem. Ind., 1967, 920. 6) S.V. Kessar; U.K. Nadir; M. Singh, Indian. J. Chem., 1973, 11, 825. 7) H.J.W. van den Haak; H.C. van der Plas; B. van Veldhuizen, J. Org. Chem., 1981, 46, 2134. 8) A. Rykowski; H.C. van der Plas, Synthesis, 1985, 884. 9) H.C. van der Plas; M. Wozniak, Croat. Chem. Acta, 1986, 59, 33. 10) C.K. McGill; A. Rappa, Adv. Heterocycl. Chem., 1988, 44, 3. 11) T.R. Kelly; Y.-J. Lee; R.J. Mears, J. Org. Chem., 1997, 62, 2774. 12) M. Palucki; D.L. Hughes; N. Yasuda; C. Yang; P.J. Reider, Tetrahedron Lett., 2001, 42, 6811.

COMMENTS :

CHRÉTIEN – LONGI NITROSATION EXAMPLE : CH3CH2OH

NaNO2, Al2(SO4)3, H2O

CH3CH2ONO

MECHANISM :

Al2(SO4)3 + 6 NaNO2

3 Na2SO4 + 2 Al(NO2)3

Al2(NO2)3 + 3 H2O

3 HNO2 + Al(OH)3

HNO2 + CnH2n+1OH

CnH2n+1ONO + H2O

DISCONNECTION :

ROH

R-ONO R = Alk

354

NOTES :

The aliphatic alcohol is treated with saturated aqueous sodium nitrite in the presence of aluminium sulfate to afford a nitroso compound.

REFERENCES :

1) A. Crétien; Y. Longi, C.R. Séances Acad. Sci., 1945, 220, 746. 2) P. Bevilard; J. Choucroum, Bull. Soc. Chim. Fr., 1957, 337.

COMMENTS :

CIAMICIAN – DENNSTEDT REARRANGEMENT EXAMPLE : Cl + CHCl3

NaOEt

N H

N

MECHANISM :

CHCl3 + NaOR

CCl2

Cl Cl N H

N H

CCl2

Cl - HCl

OH

DISCONNECTION :

Cl N H

N

355

N

NOTES :

The ring-expansion of pyrroles to pyridines by thermal methods or by the treatment of pyrroles with a variety of reagents, chloroform and sodium ethoxide. See also Reimer – Tiemann reactions.

REFERENCES :

1) G.L. Ciamician; M. Dennstedt, Ber. Dtsch. Chem. Ges., 1881, 14, 1153. 2) M. Dennstedt; J. Zimmermann, Ber. Dtsch. Chem. Ges., 1885, 18, 3316. 3) G.L. Ciamician; P. Silber, Ber. Dtsch. Chem. Ges., 1887, 20, 191. 4) E. Baltazzi; L.I. Krimen, Chem. Rev., 1963, 63, 511. 5) C.W. Reese; C.E. Smithen, J. Chem. Soc., 1964, 928. 6) R. Nicoletti; M.L. Forcellese, Gazz. Chim. Ital., 1965, 95, 83. 7) R.L. Jones; C.W. Reese, J. Chem. Soc. C, 1969, 2249. 8) D. Dhanak; C.W. Reese, J. Chem. Soc., Perkin Trans. 1, 1987, 2829. 9) V. Kral; P.A. Gale; P. Anzenbacher, jr.; K. Jursikova; V. Lynch; J.L. Sessler, Chem. Commun., 1998, 9. 10) R. Castillo; V. Moliner; J. Andrés; M. Oliva; V.S. Safont; S. Bohm, J. Phys. Org. Chem., 1998, 11, 670.

COMMENTS :

CIAMICIAN PHOTO COUPLING EXAMPLE :

O 2

hν i PrOH

356

OH OH

MECHANISM :

H3C

H3C OH

2

2 'H' +

H3C

H3C O R

O

2

O +

R

R

HO OH R

R

2 'H'

R R R

DISCONNECTION :

OH

O OH

R

2

R

CH3

R

NOTES :

The reductive coupling of ketones to diols. The isopropyl alcohol is the proton source. See also Holleman reaction.

REFERENCES :

1) G. Ciamician; P. Silber, Ber. Dtsch. Chem. Ges., 1900, 33, 2911. 2) A. Schönberg; A. Mustafa, Chem. Rev., 1947, 40, 181. 3) H. Göth; P. Cerutti; H. Schmid, Helv. Chim. Acta, 1965, 48, 1395.

COMMENTS :

357

CIAMICIAN PHOTO DISPROPORTIONATION EXAMPLE :

NO2 H O

NO 1) hν 2) EtOH

OH O

MECHANISM :

O N

NO2 H

hν

C

O N

OH O

C

O

NO OH OEt

EtOH O

O

O N O

NO

H

OH C O

O

DISCONNECTION :

NO OR

NO2 H

R = H, Alk

O

O

NOTES :

The rearrangement from o-nitrobenzaldehyde to o-nitrosobenzoic acid in sun light, both in solution and solid state. The reaction is also possible using o-nitrophenylarsenicoxide.

358

REFERENCES :

1) G.L. Ciamician; P. Silber, Ber. Dtsch. Chem. Ges., 1901, 34, 2040. 2) F. Sacks; R. Kempf, Ber. Dtsch. Chem. Ges., 1902, 35, 2715. 3) P. Karrer, Ber. Dtsch. Chem. Ges., 1914, 47, 1784. 4) P. de Mayo; S.T. Reid, J. Chem. Soc., Quat. Rev., 1961, 15, 393.

COMMENTS :

CLAISEN – GEUTHER CONDENSATION EXAMPLE :

O 2 H3C

CH3

O OEt

NaOEt EtOH reflux

CH3 CH3

EtO O

MECHANISM :

H

H

O

2 R H

R

NaOEt EtOH

OEt

RCH2

O - EtOH

OEt

H

O O

R H

OEt

O R

OEt H

DISCONNECTION :

CH2R

O

OR1

R

H

O

H

OR1

2 R H

O

NOTES :

The Claisen – Geuther condensation is the reaction of an ester containing an α-hydrogen that can be removed by base with a second molecule of ester (acetoacetic ester condensation). The Claisen – Schmidt condensation is a

359

variation where the ester enolate anion reacts with an aldehyde. Claisen condensations are easier to carry out with thioesters. Solvent-free reactions are also possible. See also Bouveault – Locquin, Claisen – Schmidt, Claisen – Wislicenus, Dieckmann, Erlenmeyer – Plöchl, Henry, Perkin reaction and Stobbe reactions.

REFERENCES : March : 491 Smith – March : 1223 Smith : 892 Smith 2nd : 746 Houben – Weyl : 8, 560 Org. React. : 1, 266; 15, 1 Org. Synth. : 30, 43; 39, 27 Org. Synth. Coll. Vol. : 4, 461, 536 Science of Synthesis : 10, 148, 601

1) A. Geuther, Liebigs Ann. Chem., 1855, 231, 197. 2) A. Geuther, Arch. Pharm., 1863, 106, 97. 3) L. Claisen; O. Lowman, Ber. Dtsch. Chem. Ges., 1887, 20, 651. 4) F.W. Swamer; C.R. Hauser, J. Am. Chem. Soc., 1950, 72, 1352. 5) R.P. Woodbury; M.W. Rathke, J. Org. Chem., 1977, 42, 1688. 6) J.E. Bartmess; R.L. Hays; G. Caldwell, J. Am. Chem. Soc., 1981, 103, 1338. 7) S. Brandänge, Chem. Scr., 1987, 27, 553. 8) D.H. Hua; Y. Chen; H.-S. Sin; M.J. Meroto; P.D. Robinson; S.W. Newell; E.M. Perchellet; J.B. Ladesich; J.A. Freeman; J.-P. Percheller; P.K. Chiang, J. Org. Chem., 1997, 62, 6888. 9) K. Yoshizawa; S. Toyota; F. Toda, Tetrahedron Lett., 2001, 42, 7983. 10) R.J. Heath; C.O. Rock, Nat. Prod. Rep., 2002, 19, 581. 11) K. Mogilaiah; N.V. Reddy, Synth. Commun., 2003, 33, 73.

COMMENTS :

360

CLAISEN – HAASE ENOL ESTER TRANSFORMATION EXAMPLE :

Ph

CH2 Ph O

Ph

Ph

+

H

O

O

O

MECHANISM :

H+ O O

O

O

O

O

DISCONNECTION :

O

O

R

R1

R

R2

O

H R1

R2

O

NOTES :

The transformation of enol esters into C-acyl derivatives, under the influence of bases. Acid catalysts such as boron trifluoride are also effective. The reaction is intermolecular when base-catalysed and probably intramolecular when acid-catalysed. See also Fries rearrangement.

REFERENCES :

1) L. Claisen; E. Haase, Ber. Dtsch. Chem. Ges., 1900, 33, 3778. 2) A. Michael; G.H. Carlson, J. Am. Chem. Soc., 1935, 57, 165. 3) F.G. Young; F.C. Frostick; J.J. Sanderson; C.R. Hauser, J. Am. Chem. Soc., 1950, 72, 3635. 4) F. Gogan; A.E. O’Briain; E.M. Philbin; N.S. O’Connor; R.F. Timoney; T.S. Wheeler, Tetrahedron, 1958, 3, 140. 5) E.S. Rothman, J. Org. Chem., 1966, 31, 628. 6) T. Széll; Gy. Schöbel; L. Baláspiri, Tetrahedron, 1969, 25, 707. 7) E.S. Rothman; G.C. Moore, J. Org. Chem., 1970, 35, 2351.

361

COMMENTS :

CLAISEN – MAUTHNER – BOUVEAULT SYNTHESIS EXAMPLE :

Cl

H3C O

H

H3C

1) HCN 2) H+, H2O 3) PhNH2 4) H2O

O

MECHANISM :

R

Cl O

R

R H2O

R conc. HCl H2O

O

H N

CN

R HCN, Et2O, pyridine, - HCl

COOH O

PhNH2 - CO2

H O

Ph

DISCONNECTION :

R

H

R

O

Cl O

NOTES :

An acyl chloride is converted into the acyl cyanide by treatment with ethereal hydrogen cyanide in the presence of pyridine. The resulting nitrile when treated with cold concentrated hydrochloric acid yields the keto-acid which when treated with aniline gives the aldimine and then the aldehyde on hydrolysis. See also Brandt, Guyot – Gry – Bouveault and Kolbe aldehyde reactions.

REFERENCES : Houben – Weyl : 7/1, 292

362

1) L. Bouveault, Bull. Soc. Chim. Fr., 1896, 15, 1014. 2) L. Claisen, Ber. Dtsch. Chem. Ges., 1898, 31, 1023. 3) F. Mauthner, Ber. Dtsch. Chem. Ges., 1909, 42, 188. 4) W. Tschelinzeff; W. Schmidt, Ber. Dtsch. Chem. Ges., 1929, 62, 2210. 5) Tadeus; I. Reichstein, Helv. Chim. Acta, 1930, 13, 1275.

COMMENTS :

CLAISEN – SCHMIDT CONDENSATION EXAMPLE :

H CHO

H3C

+

dil. NaOH O

H

O

MECHANISM :

B H

O

H

R1

O

O

- BH+

R

R

HO H H R

O

O OH

+

- BH

R1

R

H

R

R2 R1

H O

363

O R H

O

H

R1

BH+, H2O, - B

R1

DISCONNECTION :

R

H R

R1

B BH+, - B

O

H

R1

H

O H

+

R2

R1 O

NOTES :

The reaction involves the room temperature condensation of an aldehyde or ketone with a compound containing a carbonyl-methylene group. The reaction requires dilute aqueous alkali or acid to occur and affords α,β-unsaturated carbonyl compounds. See also Claisen cinnamic, Claisen – Geuther and Perkin reactions.

REFERENCES : March : 940 Smith – March : 1221 Smith : 886 Smith 2nd : 740 Houben – Weyl : E5, 415 Org. React. : 16, 3 Org. Synth. : 7, 42; 12, 22 Org. Synth. Coll. Vol. : 1, 283; 2, 167 Science of Synthesis : 10, 101

1) A. Wurtz, C.R. Séances Acad. Sci., 1872, 74, 1361. 2) J.G. Schmidt, Ber. Dtsch. Chem. Ges., 1881, 14, 1459. 3) L. Claisen; A. Claparède, Ber. Dtsch. Chem. Ges., 1881, 14, 2460. 4) S.A. Fine; P.D. Pulaski, J. Org. Chem., 1973, 38, 1747. 5) C. Dominquez; J. Plumet; A. Geset; L. Rigal, Can. J. Chem., 1992, 70, 2306. 6) S.V. Popkov; L.V. Kovalenko; M.M. Bobylev; O.Y. Molchanov; M.Z. Krimer; V.P. Taschi; Y.G. Putsykin, Pest. Sci., 1997, 49, 125. 7) R. Tahir; S. Sebti; A. Saber; R. Nazih, Appl. Catal. A, 2001, 206, 217. 8) R. Ballini; G. Bosica; R. Maggi; M. Ricciutelli; P. Righi; G. Sartori; R. Sartorio, Green Chem., 2001, 3, 178. 9) B.M. Choudary; M.L. Kantam; K.V.S. Ranganath; K. Mahendar; B. Sreedhar, J. Am. Chem. Soc., 2004, 126, 3396. 10) P. Formentín; H. García; A. Leyva, J. Mol. Catal. A: Chem., 2004, 214, 137. 11) S. Saravanamurugan; M. Palanichamy; B. Arabindoo; V. Murugesan, J. Mol. Catal. A: Chem., 2004, 218, 101. 12) L.T. Higham; U.P. Kreher; C.L. Raston; J.L. Scott; C.R. Strauss, Org. Lett., 2004, 6, 3257.

COMMENTS :

364

CLAISEN – SHADWELL SYNTHESIS EXAMPLE :

O

O CN

NO2

O

1) Fe2SO4, NaOH 2) H+

N H

MECHANISM :

O

O

O O CN

Cl NO2

KCN, H+

NO2

OH

Fe2SO4 NaOH

NH2

O H+, - H2O

O N H

DISCONNECTION :

O

O

Cl

O N H

NO2

NOTES :

An o-nitrobenzoyl cyanide is hydrolysed to the acid which is reduced by ferrous hydroxide in alkaline solution to the corresponding o-aminophenylglyoxylic acid salt. Acidification yields an isatin derivative. See also Sandmeyer diphenylurea isatin and Sandmeyer isonitrosoacetanilide isatin reactions.

REFERENCES :

1) L. Claisen; J. Shadwell, Ber. Dtsch. Chem. Ges., 1879, 12, 350. 2) J. von Braun; G. Hahn, Ber. Dtsch. Chem. Ges., 1923, 56, 2343. 3) W.C. Sumpter, Chem. Rev., 1944, 34, 393.

365

COMMENTS :

CLAISEN – WISLICENUS CONDENSATION EXAMPLE :

CH(OEt)3 +

NC

CN

Ac2O ZnCl2, heat

H

OEt

NC

CN

MECHANISM :

H EtO

NC

CN

NC

NaOEt

OEt OEt CN

H EtO NC

- HOEt

OEt CN H

H

OH

NC

CN

NaOEt

H3C H EtO O OEt

H EtO

OEt OEt

(CH3CO)2O

H EtO NC

OAc CN

- HOAc

H

366

O

H

OEt

NC

CN

NC

CN

DISCONNECTION :

H

OR CH(OR)3 +

EWG

EWG

EWG

EWG

NOTES :

This reaction involves the condensation of ethyl formate with a compound containing an active hydrogen in the presence of sodium or sodium alkoxide to give a hydroxymethylene compound. A variation of this reaction involves the condensation of ethyl orthoformate in the presence of acetic anhydride with compounds containing active methylene groups to form ethoxymethylene derivatives. For the Claisen ortho ester rearrangement of indol-3ylalkanols see Science of Synthesis. See also Claisen condensation and Knoevenagel condensation.

REFERENCES : Houben – Weyl : 7/1, 44; 8, 580 Org. React. : 1, 266 Org. Synth. : 28, 60 Org. Synth. Coll. Vol. : 3, 395 Science of Synthesis : 10, 593

1) W. Wislicenus, Ber. Dtsch. Chem. Ges., 1887, 20, 2938. 2) L. Claisen, Liebigs Ann. Chem., 1897, 297, 1. 3) R.G. Jones, J. Am. Chem. Soc., 1951, 73, 3684. 4) R.G. Jones, J. Am. Chem. Soc., 1952, 74, 4889. 5) M.J. Dooley; R.J. Quinn; P.J. Scammells, Aust. J. Chem., 1989, 42, 747.

COMMENTS :

367

CLAISEN CARBONATE ALKYLATION EXAMPLE :

O H3C

O

OEt + O

Br

O

O

O CH3

K2CO3 acetone

H3C

CH3

O O

OEt

MECHANISM :

O

O Br

H3C

OEt O

H3C K2CO3 acetone

O

O

O

CH3

OEt O

H3C

O

CH3

O O

OEt

DISCONNECTION :

R OAlk

R OH

R EWG

EWG

EWG

EWG

+

Br R

NOTES :

A widely used method for the alkylation of hydroxyl groups using an alkyl halide and potassium carbonate in acetone. The technique can also be applied to the C-alkylation of β-keto-carboxylic esters and O-alkyl derivatives are also formed. See also Knoevenagel condensation, Perkin alicyclic, Robertson – Robinson reactions.

368

REFERENCES : March : 464 Smith – March : 548 Smith : 875 Smith 2nd : 733 Houben – Weyl : 8, 603 Org. React. : 9, 107 Org. Synth. : 25, 9 Org. Synth. Coll. Vol. : 3, 140

1) L. Claisen, Ber. Dtsch. Chem. Ges., 1890, 23, 976. 2) C. Weygand, Ber. Dtsch. Chem. Ges., 1928, 61, 687. 3) K. von Auwers, Ber. Dtsch. Chem. Ges., 1938, 71, 2082. 4) K.A. Thaker; U.S. Pathak, Indian J. Chem., 1965, 3, 416. 5) A.M. Schoffstall, J. Org. Chem., 1971, 36, 2385. 6) D.P. Curran; M. Shu, Bull. Soc. Chim. Fr., 1993, 130, 314.

COMMENTS :

CLAISEN CINNAMIC ESTER SYNTHESIS EXAMPLE :

H H O

+

O

OCH3

H3C

OCH3 Na

O

369

CH3

MECHANISM :

H+ O H

H+ OH

OR1

O

OR1

Na

O

H3C

O H3C

H

OR1

OR1 O

- H2O

H

DISCONNECTION :

R OR1 H

H +

O

O

OR1

R O

NOTES :

Cinnamic esters are obtained by the condensation of aromatic aldehydes in the presence of sodium metal with esters of the type RCH2CO2R. See also Claisen – Geuther condensation, Claisen – Schmidt, Knoevenagel condensation, and Perkin reactions.

REFERENCES : Houben – Weyl : 4/2, 25; 8, 514; E3, 646 Org. Synth. : 9, 38 Org. Synth. Coll. Vol. : 1, 252

1) L. Claisen, Ber. Dtsch. Chem. Ges., 1890, 23, 976. 2) T.T. Howarth; A.J. Jackson; J. Judge; G.W. Kenner; D.J. Newman, J. Chem. Soc., Perkin Trans. 1, 1974, 490.

COMMENTS :

370

CLAISEN HYDROLYSIS EXAMPLE :

ONa

OEt O

O

1) EtONa, EtOH 2) H2O

MECHANISM :

O R

O

R1

R

O

O

O OR1

R

OH

O

H

R

O

Na+

OH

DISCONNECTION :

RCO2Na

RCO2R1

NOTES :

This method which is suitable for the preparation of unstable acids from their esters involves the addition of the ester to a solution of one mole of sodium ethoxide in absolute ethanol followed by treatment of the solution with one mole of water. An ethereal solution of the ester can also be employed. See also Twitchell process.

REFERENCES : March : 378 Smith – March : 469 Houben – Weyl : 8, 423

L. Claisen, Ber. Dtsch. Chem. Ges., 1905, 38, 693.

COMMENTS :

371

CLAISEN REARRANGEMENT (CLAISEN – IRELAND REARRANGEMENT) EXAMPLE : O

OH heat

MECHANISM :

O

O heat H

372

OH

Lewis acid catalysis :

O

i

OiPr

R1

R1

O LA Lewis acid

R2

i

PrO

R2

O LA

R1

i

PrO

O LA

R1

O

R2

O

R2

i

PrO

R1

O LA O

R2

i

PrO

i

O LA

R1

PrO

O LA

R1

O R2

O

R2

LA Lewis acid

O R1

PrO

i

OiPr

PrO

O

R1

O

O

R2

R2

DISCONNECTION : R1 O

R1 O

R R

R R

373

O O

NOTES :

The classic Claisen rearrangement ([3,3]-sigmatropic rearrangement) involves aromatic allyl ethers. The ester enolate reaction is very similar to the Carroll (Kimel – Cope) reaction and Claisen – Ireland rearrangement, i.e. the rearrangement of allyl esters as enolate anions to γ,δ-unsaturated acids. By using boron enolates the reaction can be made enantioselective. A wide range of Lewis acids has also been used in this rearrangement. The Arnold variation uses strong base (nBuLi) to form the enolate. Thio-Claisen and aza-Claisen rearrangements are also known and have been reviewed. An anion-accelerated Claisen rearrangement has been reported by Denmark et al. Allyl aryl ethers undergo accelerated Claisen rearrangements in the presence of a mixture of water and trialkylalanes. Enzymatic rearrangements have also been reported. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Cope, Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Johnson – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES : March : 1136, 1140 Smith – March : 1449, 1452 Smith : 1238, 1243 Smith 2nd : 642, 848, 950, 1021, 1104 Houben – Weyl : 5/1b, 920; E3, 306, 559, 572, 579; E5, 291, 877, 1097; E6b, 1147; E7b, 683; E8a, 124; E8b, 704; E8d, 761, 770; E10/b2, 198, 218; E15, 294, 3096, 3409; E16d, 411, 1157 Org. React. : 2, 1; 22, 1 Org. Synth. : 53, 116; 66, 29 Org. Synth. Coll. Vol. : 6, 606; 8, 536 Science of Synthesis : 1, 367, 371, 374; 9, 196; 10, 32, 296

1) L. Claisen, Ber. Dtsch. Chem. Ges., 1912, 45, 3157. 2) L. Claisen; O. Eisleb, Liebigs Ann. Chem., 1914, 401, 21. 3) D.S. Tarbell, Chem. Rev., 1940, 27, 495. 4) R.K. Hill; N.W. Gilman, Tetrahedron Lett., 1967, 8, 1421. 5) R.E. Ireland; R.H. Mueller, J. Am. Chem. Soc., 1972, 94, 5897. 6) R.E. Ireland; A.K. Willard, Tetrahedron Lett., 1975, 16, 3975. 7) G.B. Bennett, Synthesis, 1977, 589. 8) M.R. Saidi, Heterocycles, 1982, 19, 1473. 9) S.E. Denmark; M.A. Harmata, J. Am. Chem. Soc., 1982, 104, 4972. 10) Y. Hirano; C. Djerassi, J. Org. Chem., 1982, 47, 2420. 11) J. Cooper; D.W. Knight; P.T. Gallagher, J. Chem. Soc., Chem. Commun., 1987, 1220. 12) F.E. Ziegler, Chem. Rev., 1988, 88, 1423. 13) S. Pereira; M. Srebnik, Aldrichimica Acta, 1993, 26, 17. 14) D. Enders; M. Knopp; R. Schiffers, Tetrahedron: Asymmetry, 1996, 7, 1847. 15) J.J. Gajewski, Acc. Chem. Res., 1997, 30, 219. 16) K. Hiratani; K. Kasuga; M. Goto; H. Uzawa, J. Am. Chem. Soc., 1997, 119, 12677. 17) J. Nowicki, Molecules, 2000, 5, 1033. 18) S.M. Allin; R.D. Baird, Curr. Org. Chem., 2001, 5, 395.

374

19) A.W. Murray, Org. React. Mech., 2001, 473. 20) P. Wipf; S. Rodríguez, Adv. Synth. Catal., 2002, 344, 434. 21) M. Hiersemann; L. Abraham, Eur. J. Org. Chem., 2002, 1451. 22) S.-P. Hong; H.A. Lindsay; T. Yaramasa; X. Zhang; M.C. McIntosh, J. Org. Chem., 2002, 67, 2042. 23) K.C. Majumdar; S. Ghosh; M. Ghosh, Tetrahedron, 2003, 59, 7251. 24) A.M.M. Castro, Chem. Rev., 2004, 104, 2939. 25) J.C. Gilbert; J. Yin; F.H. Fakhreddine; M.L. Karpinski, Tetrahedron, 2004, 60, 51.

COMMENTS :

CLAR REDUCTION EXAMPLE :

O

O

+

Zn, NaCl, ZnCl2 200 - 290 oC, trace water

DISCONNECTION : O R

R1

R

R1

NOTES :

Zinc dust is used as the reducing agent in a molten mixture of sodium chloride and zinc chloride at 200 – 290 oC. The process is assisted by a small quantity of water. The method is of value for the reduction of quinones such as anthraquinone, but can also be applied to other carbonyls of carbocyclic and heterocyclic systems. See also Clemmensen reaction.

375

REFERENCES :

1) E. Clar, U.S. Patent., 1937, 2172020. 2) E. Clar, Ber. Dtsch. Chem. Ges., 1939, 72, 1645. 3) H.W.D. Stubbs; S.H. Tucker, J. Chem. Soc., 1951, 2939.

COMMENTS :

CLAUSON–KAAS REACTION EXAMPLE :

NH3 H3CO

CH3 O

OCH3

Br N

+

O O

376

NaOAc AcOH

O O

MECHANISM :

O

H3CO

electrolysis Br2, MeOH Na2CO3 H2O

OCH3

O

Raney Ni H2

H3CO

O

OCH3

H3CO NH2

HO HN

OCH3

H3CO

OCH3 OH

O O H+ H3CO

OCH3

HO

N

H3CO

OH

N

N

OCH3 CH3COOH

- 2 H2O

- H2O H H3CO HO

N

H3CO

OCH3

N

OCH3

N CH3COOH

- H2O

DISCONNECTION :

N R

O

NOTES :

The transformation of 2,5-dialkoxy substituted tetrahydrofurans into N-substituted pyrroles using primary amines or ammonia via the Paal – Knorr pyrrole reaction. A photo-oxidative analogue has been published by Feringa and Butselaar. See also Achmatowicz, Barton – Zard, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries

pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov, and Zav’yalov reactions.

REFERENCES : Org. Synth. : 40, 29 Org. Synth. Coll. Vol. : 5, 403

377

1) N. Clauson–Kaas; Z. Tyle, Acta Chem. Scand., 1952, 6, 667. 2) N. Elming; N. Clauson–Kaas, Acta Chem. Scand., 1952, 6, 867. 3) H. Gross, Chem. Ber., 1962, 95, 2270. 4) B.L. Feringa; R.J. Butselaar, Tetrahedron Lett., 1982, 23, 1941. 5) Z. Hayoz; A. Aeby; C. Pasquier; R. Neier, Chimia, 1993, 47, 230. 6) R. DiSanto; R. Costi; M. Artico; S. Massa, J. Heterocycl. Chem., 1995, 32, 1779. 7) M. van den Heuvel; A.D. Cuiper; H. van der Deen; R.M. Kellogg; B.L. Feringa, Tetrahedron Lett., 1997, 38, 1655. 8) A.S. Ribeiro; A. Kanazawa; N.M.A.F. Navarro; J.C. Moutet; M. Navarro, Tetrahedron: Asymmetry, 1999, 10, 3735.

COMMENTS :

CLAY – KINNEAR – PERREN PHOSPHONYL CHLORIDE SYNTHESIS EXAMPLE :

CCl4 + PCl3

1) AlCl3 DCM 2) H2O

Cl

Cl O P Cl Cl Cl

MECHANISM :

RCl + PCl3

AlCl3

[RPCl3]+[AlCl4]-

H2O

DISCONNECTION : O R P Cl Cl

RCl

378

O R P Cl + 2 HCl Cl

NOTES :

The synthesis of alkylphosphonyl dichloride by condensation of alkyl chloride with phosphorus trichloride and aluminium chloride, followed by hydrolysis. N-alkyl chlorides with more than 3 carbon atoms afford sec-alkyl phosphonyl dichlorides. A carbonium ion mechanism has been proposed. Hoffmann et al. has introduced a modification of this reaction. See also Arbusov (Michaelis – Arbuzov) and Zinovev – Soborovskii reactions.

REFERENCES : Org. Synth. : 37, 82 Org. Synth. Coll. Vol. : 4, 950

1) J.P. Clay, J. Org. Chem., 1951, 16, 892. 2) A.M. Kinnear; E.A. Perren, J. Chem. Soc., 1952, 3437. 3) K.C. Kennard; C.S. Hamilton, J. Am. Chem. Soc., 1955, 77, 1156. 4) F.W. Hoffmann; T.C. Simmons; L.J. Glunz, J. Am. Chem. Soc., 1957, 79, 3570. 5) V.A. Chauzov; Y.N. Studnev; L.S. Rudnitskaya; A.V. Fokin, Zhur. Obsch. Khim., 1987, 57, 2250. 6) G. Ilia; S. Iliescu; G. Dehelean; A. Popa; L. Pacureanu; L. Macarie, Rev. Chim. (Bucharest), 2001, 52, 101.

COMMENTS :

CLEMMENSEN REDUCTION EXAMPLE :

Et

CH3 O

Zn(Hg) HCl

379

CH3 Et H H

MECHANISM :

Ph

CH3

HCl

Ph

O H+

Zn'

CH3 OH

Cl

Zn''

Zn' Hg

H Zn''

Ph

CH3 OZn'Cl

Cl

CH3 OH

2 e-

Zn''

Hg

Ph

Hg

Hg

-

2e

Zn''

Ph

H

CH3

OZn'Cl

H Hg + ClZn''

Ph

+ HOZn'Cl Ph

HCl

CH3

2 HCl, - Hg - 2 ZnCl2, - H2O

CH3

DISCONNECTION : R1 R

R

H

R1 O

H

NOTES :

The replacement of the carbonyl oxygen of the carbonyl group in an aldehyde or ketone by two hydrogen atoms using amalgamated zinc and hydrochloric acid. The reaction is subject to steric effects. Besides the mechanism shown, there is also, although somewhat contradictory, a heterogenous mechanism involving a zinc carbenoid. The Martin – Sherman modification gives improved yields and simplifies the work-up by adding a layer of toluene to the reaction

mixture. See also Wolff – Kishner – Staudinger reaction.

REFERENCES : March : 1209 Smith – March : 1547 Smith : 469 Smith 2nd : 404, 411, 413, 1094, 1136 Houben – Weyl : 5/1a, 244, 450; E6b, 437; E7b, 258; E8d, 469; E15, 1457 Org. React. : 1, 155; 22, 401 Org. Synth. : 20, 57; 33, 17 Org. Synth. Coll. Vol. : 3, 444; 4, 203

1) E. Clemmensen, Ber. Dtsch. Chem. Ges., 1913, 46, 1837. 2) E.L. Martin, J. Am. Chem. Soc., 1936, 58, 1438.

380

3) K. Suzuki, Bull. Chem. Soc. Jpn., 1962, 35, 735. 4) G.E. Risinger; E.E. Mach; K.W. Barnett, Chem. Ind., 1965, 679. 5) W.T. Borden; T. Ravindranathan, J. Org. Chem., 1971, 36, 4125. 6) M. Zachis; J.A. Rabi, Tetrahedron Lett., 1980, 21, 3735. 7) J. Burdon; R.C. Price, J. Chem. Soc., Chem. Commun., 1986, 893. 8) S.K. Talapatra; S. Chakrabarti; A.K. Mallik; B. Talapatra, Tetrahedron, 1990, 46, 6047. 9) M.T. Bachute; R.B. Mane, Indian J. Chem., 1998, 37B, 281. 10) J.C. Palacios; P. Cintas, J. Chem. Educ., 1998, 75, 938. 11) C. Villiers; M. Ephritikhine, Chem. Eur. J., 2001, 7, 3043. 12) B. Bredenkotter; U. Florke; D. Kuck, Chem. Eur. J., 2001, 7, 3387.

COMMENTS :

CLEMO SYNTHESIS EXAMPLE :

O CO2Et

2 N

+

OEt EtO OEt H

381

N Ac2O heat

N

CO2Et

MECHANISM :

O H

OR RO OR H OR1 N

H

R1O

O

N R1O

H N

RO RO

- HOR

O

H

OR

OR1

H OR1 N

N

O

O

O

R1O

O

N

H

OR COOR1

N OR1

- HOR N

O

HN

O N

N Pd, H2

N

N

OR1

O

O

DISCONNECTION :

O N

COOR

N N COOR

NOTES :

This is a condensation between an orthoformic acid ester and the α-methylene group of two α-pyridyl-acetic acid ethyl esters. This method provides a synthetic route to sparteine alkaloids.

REFERENCES :

1) G.R. Clemo; G.C. Leitch, J. Chem. Soc., 1928, 1811. 2) A. Brossi; O. Schmider, Helv. Chim. Acta, 1962, 45, 1899.

COMMENTS :

382

CLIBBENS – NIERENSTEIN SYNTHESIS EXAMPLE :

H3C

O O

O Cl

CH2N2 Et2O

O

O

MECHANISM :

O

O Cl

CH2N2 Et2O - HCl

O H

N2

HCl + CH2N2

if not all HCl has been destroyed then aq. HCl

Cl

CH3Cl + N2

DISCONNECTION :

H3C O

O O

R

R

Cl

O

O Cl

Ar

Ar

Cl O

O

NOTES :

Aroyl chlorides react with diazomethane in anhydrous diethyl ether to yield ω-chloroacetophenones. Coumaranones may be obtained if an o-hydroxyl group is present. This procedure (one mole diazomethane is added to the acid chloride) varied from Arndt – Eistert’s procedure where the acid chloride is added slowly to a cold solution of an excess diazomethane. See also Arndt – Eistert, Büchner – Curtius – Schlotterbeck and Wolff rearrangement reactions.

383

REFERENCES : Org. React. : 1, 38 Org. Synth. : 26, 13 Org. Synth. Coll. Vol. : 3, 119

1) D.A. Clibbens; M. Nierenstein, J. Chem. Soc., 1915, 107, 1491. 2) M. Nierenstein; D.G. Wang; J.C. Warr, J. Am. Chem. Soc., 1924, 46, 2551. 3) H.H. Lewis; M. Nierenstein; E.M. Rich, J. Am. Chem. Soc., 1925, 47, 1728. 4) T. Malkin; M. Nierenstein, J. Am. Chem. Soc., 1930, 52, 1504. 5) Y. Miyahara, J. Heterocycl. Chem., 1979, 16, 1147.

COMMENTS :

CLOKE – WILSON CYCLO PROPYL KETONE REARRANGEMENT EXAMPLE :

H3C

CH3 CH3 CO2Et

Al2O3, 24 h

MeO

384

MeO

CO2Et O

MECHANISM : Thermal :

D D

D

D D

D

Photochemical :

CO2Et H3C

OEt

R

R

O

hν

CO2Et

R side products :

H3C

R

R

CO2Et

OEt

CO2Et +

+ O

CH3

R CH3

H3C

DISCONNECTION :

R4

R2 R1 R4

R2 R

R1

R3

R3

R

NOTES :

The rearrangement of cyclopropyl ketones or imines to dihydrofurans or dihydropyrroles, either thermally (biradical or concerted), photochemically, or transition metal mediated (Rh(I), Rh(III), Ni(0)). The mechanisms are discussed in full in Organic Reactions.

385

REFERENCES : Org. React. : 33, 247

1) J.B. Cloke, J. Am. Chem. Soc., 1929, 51, 1174. 2) C.L. Wilson, J. Am. Chem. Soc., 1947, 69, 3002. 3) V. Franzen, Chem. Ber., 1962, 95, 571. 4) E.J. Corey; S.W. Walinsky, J. Am. Chem. Soc., 1972, 94, 8932. 5) M.E. Alonso; A. Morales, J. Org. Chem., 1980, 45, 4530. 6) T.S. Bailey; J.B. Bremner; L. Pelosi; B.W. Skeleton; A.H. White, Aust. J. Chem., 1995, 48, 1437.

COMMENTS :

COHEN – DANIEWSKI PROCESS EXAMPLE :

OH PhS

COOH

Ph

1) Al(SPh)3 2) Li+ 3) PhCHO

MECHANISM :

OH PhS

COOH

PhS

SPh

PhS

Li RCHO

Al(SPh)3 Li+

386

R

DISCONNECTION :

PhS

X

PhS

R1

R

R1

SPh R

X = H, SiMe3, CH3, SiMe2,COH(R2)

NOTES :

This is the reductive lithiation of alkyl phenyl sulfides, breaking the Csp3-S bond. The dissolved radical anion is the source of the electrons. The reaction is useful in forming carbanions. See also Rigby – Trost reaction.

REFERENCES : March : 729 Smith – March : 941

1) T. Cohen; W.M. Daniewski, Tetrahedron Lett., 1978, 19, 2991. 2) T. Cohen; W.M. Daniewski; R.B. Weisenfeld, Tetrahedron Lett., 1978, 19, 4665. 3) T. Cohen; J.R. Matz, J. Org. Chem., 1979, 44, 4816. 4) T. Cohen; J.R. Matz, Synth. Commun., 1980, 10, 311. 5) T. Cohen; J.P. Sherbine; J.R. Matz; R.R. Hutchins; B.M. McHenry; P.R. Willey, J. Am. Chem. Soc., 1984, 106, 3245. 6) T. Cohen; M. Bhupathy, Acc. Chem. Res., 1989, 22, 152.

COMMENTS :

COLEMAN SYNTHESIS EXAMPLE :

Et

Et N H + NaOCl Et

N Cl ice water

387

Et

MECHANISM :

NaOCl + H2O

cold

Cl

R1 N H

- H+

R2

HOCl + NaOH

R1 N Cl R2

DISCONNECTION :

R2

R1 N H R2

R1 N Cl

NOTES :

The chlorination of secondary amines at low temperature. The hypochlorous acid is the source of the positive charged chlorine atoms.

REFERENCES : Houben – Weyl : E16a, 878 Org. Synth. : 25, 14 Org. Synth. Coll. Vol. : 3, 159

1) A. Berg, Ann. Chim. (Paris), 1894, 3, 289. 2) G.H. Coleman, J. Am. Chem. Soc., 1933, 55, 3001. 3) V.S. Heasley; P. Kovavic; R.M. Lange, J. Org. Chem., 1966, 31, 3050. 4) J.M. Antelo; F. Arce; J. Casado; R. Castro; M.E. Sanchez; A. Varela, Bull. Soc. Chim. Belg., 1984, 93, 35.

COMMENTS :

388

COLLINS OXIDATION EXAMPLE :

O

OH

O

O

CH3 CH3 CH3

CH3 N O O Cr N O

CH3 CH3

DCM

MECHANISM :

O O Cr O O R1 H R2

H OH R1

H R2

O O Cr O N

O + R1

389

R2

HO

O Cr

OH

Follow-up chemistry of Cr(IV) :

3 CrO(OH)2 or

Cr2O3 + CrO3 + 3 H2O CrO3

CrO(OH)2 OH

R1

O

OH H

R1

R2

R1

R2 .5 Cr2O3 + 1.5 H2O

R2

CrO3H

OH R1

H R2

OH O Cr O O R1 H R2

H

OH Cr HO OH

DISCONNECTION : OH

O R

R1

R = H, Alk, Ar

R

R1

NOTES :

The reagent formed by the reaction of chromium trioxide and pyridine is first removed from the pyridine solvent and then dissolved in dichloromethane, and the alcohol is then added. There is a Ratcliffe modification; Chromium trioxide is added to the solution of pyridine and dichloromethane followed by the alcohol. Chromium-mediated oxidations have a competing pathway involving free-radical intermediates. See also Anelli, Ball – Goodwin – Morton, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn

oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pinnick, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES : Smith – March : 1514 Smith : 229 Smith 2nd : 199, 542

1) J.C. Collins; W.W. Hess; F.J. Frank, Tetrahedron Lett., 1968, 9, 3363. 2) R. Ratcliffe; R. Rodehorst, J. Org. Chem., 1970, 35, 4000.

390

3) M. Li; M.E. Johnson, Synth. Commun., 1995, 25, 533. 4) C. Provent; P. Chautemps; J.L. Pierre, Synth. Commun., 1995, 25, 1907. 5) M. Brackhagen; H. Boye; C. Vogel, J. Carbohydr. Chem., 2001, 20, 31.

COMMENTS :

COLVIN SYNTHESIS EXAMPLE :

O O

O 1) nBuLi, THF, - 78 oC, Me3SiCHN2 2) H2O

MECHANISM :

Me3Si

Ph

O

N2 Ph

Ph

O

Ph

SiMe3 N2

- SiMe3

- N2

O

Ph N2 Ph

Ph

- N2

Ph

391

SiMe3 Ph

- SiMe3

Ph

H

O

+

O N2 EtO P OEt H

OH N2 O2N

Et3N

P

H O

NO2

KOtBu

O2N

N2

O2N

- N2

OEt OEt

H

DISCONNECTION :

O R

R1

R R1 = H, Alk, Ar

R1

NOTES :

A simple one-step procedure of converting ketones and aldehydes into acetylenes using diazomethyltrimethylsilane or dialkyldiazomethylphosphonates. See also Corey – Fuchs and Kowalski reactions.

REFERENCES :

1) E.W. Colvin; B.J. Hamill, J. Chem. Soc., Chem. Commun., 1973, 151. 2) E.W. Colvin; B.J. Hamill, J. Chem. Soc., Perkin Trans. 1, 1977, 869. 3) S. Ohira; K. Okai; T. Moritani, J. Chem. Soc., Chem. Commun., 1992, 721.

COMMENTS :

COMBES ACETYLACETONE SYNTHESIS EXAMPLE :

H3C

CH3 O

O

H3C 1) Na 2) BuBr 3) KOH

392

Bu O

MECHANISM :

H3C

CH3 O

H3C Na

O

CH3 O

R

R X

H3C

O

CH3 O

O

H+ R H3C KOH

O

OH CH3

H3C

R

+ CH3COOK

O

O

DISCONNECTION :

H3C

R

H3C

O

CH3 O

+ RHal

O

NOTES :

Acetylacetone is deprotonated with sodium and reacts with alkyl and aryl halides to yield a C-substituted derivative, which can be decomposed by alkali to a methyl ketone and an acetate.

REFERENCES : Org. Synth. : 20, 6 Org. Synth. Coll. Vol. : 3, 16

A. Combes, C.R. Séances Acad. Sci., 1887, 104, 920.

COMMENTS :

393

COMBES QUINOLINE SYNTHESIS EXAMPLE :

CH3 H3C

+ NH2

CH3 O

H2SO4

O

N

CH3

MECHANISM :

R1

R1 R NH2

R1 O H+

- H2O

O

O

O N

R1 H

N H

R

R

R1 OH

R1 OH

O H N H

H2SO4

R

N H+ R1

R1 OH2

H+

N H

N H

R

R

- H2O

N H

R

R1

R

- H+

N

R

DISCONNECTION :

R1 R2

R2 N

+ NH2

R

R1

R O

O

NOTES :

β-Diketones react with primary arylamines to give β-amino-enone, which can be converted into 2,4-disubstituted quinolines using concentrated sulfuric acid. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

394

REFERENCES : Smith : 1336 Smith 2nd : 1099

1) A. Combes, C.R. Séances Acad. Sci., 1887, 106, 142. 2) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 3) A.T. Coscia; S.C. Dickerman, J. Am. Chem. Soc., 1959, 81, 3098. 4) J.L. Born, J. Org. Chem., 1972, 37, 3952. 5) P.A. Claret, Compr. Org. Chem., 1979, 4, 155. 6) Y. Blache; A. Gueiffier; O. Chavignon; H. Viols; J.C. Teulade; J.P. Chapat, Heterocycles, 1994, 38, 1527. 7) E. Davioud–Charvet; S. Delarue; C. Biot; B. Schwoebel; C.C. Boehme; A. Müssigbrodt; L. Maes; C. Sergheraert; P. Grellier; R.H. Schirmer; K. Becker, J. Med. Chem., 2001, 44, 4268.

COMMENTS :

COMINS ADDITION EXAMPLE :

Ph O + N

H3C

O CH3

Ph

Cl 1)

Cl O O

2) PhMgBr, CuI 3) Li

N

4) SnCl4 5) S8, napthalene

395

N

MECHANISM :

R

Cl

N

Ph

O

RMgX, 5% CuI THF, - 20 oC

N O

PhO

H

N Li PhO

O

THF, RT

Cl R

R

O R

R1

O R1

N

N N

O

O R1

.

SnCl4

N

O

N

N

S8, naphthalene

O

Cl

DCM, - 78oC

DISCONNECTION :

R1

O O

R

+ R1Br +

N

N

R

Cl

NOTES :

The Friedel – Crafts acylation fails in the pyridine series, this is due to the basicity of the nitrogen atom. This reaction can also be used for the regioselective nucleophilic addition to substituted pyridines. See also Emmert – Asendorf, Friedel – Crafts and Wibaut – Arens reactions.

REFERENCES :

1) R.E. Lyle; D.L. Comins, J. Org. Chem., 1976, 41, 3250. 2) D.L. Comins; N.B. Mantlo, Tetrahedron Lett., 1983, 24, 3683. 3) I. Lantos; K. Gombatz; M. McGuire; L. Pridgen; J. Remich; S. Shilcrat, J. Org. Chem., 1988, 53, 4223. 4) D.L. Comins; M.M. Badawi, Heterocycles, 1991, 32, 1869 5) B. Munoz; C. Chen; I.A. McDonald, Biotechnol. Bioeng., 2000, 71, 78.

COMMENTS :

396

CONANT – FINKELSTEIN HALOGEN EXCHANGE EXAMPLE :

Br

+ NaI

I

acetone

MECHANISM : R1

R1 Y I

R

H

Y

Cl

H

R

DISCONNECTION :

RBr

RI

RCl

NOTES :

The preparation of alkyl iodides from their corresponding bromides or chlorides by treatment with sodium iodide in acetone. In the case of 1,2-dihalides an ethylenic derivative is obtained. A mild and general method for the conversion of aryl, heteroaryl and vinyl bromides into their corresponding iodides has been developed by Buchwald.

REFERENCES : March : 430 Smith – March : 517 Smith : 154 Smith 2nd : 125, 1164 Houben – Weyl : 5/4, 595; E15, 1438; E19b, 1632 Org. Synth. : 30, 10 Org. Synth. Coll. Vol. : 4, 84

1) W.H. Perkin; B.F. Duppa, Liebigs Ann. Chem., 1859, 112, 125. 2) H. Finkelstein, Ber. Dtsch. Chem. Ges., 1910, 43, 1528. 3) J.B. Conant; W.R. Kirner, J. Am. Chem. Soc., 1924, 46, 232. 4) W.B. Smith; G.D. Branun, Tetrahedron Lett., 1981, 22, 2055. 5) S.D. Rychnovsky; G. Griesgraber, J. Org. Chem., 1992, 57, 559. 6) T.I. Richardson; S.D. Rychnovsky, J. Am. Chem. Soc., 1997, 119, 12360. 7) A. Klapars; S.L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844.

397

8) J. Liu; Z. Janeba; M.J. Robins, Org. Lett., 2004, 6, 2917.

COMMENTS :

CONIA CYCLISATION EXAMPLE :

H3C

O

O

H3C

CH3 CH3

CH3

base, heat

CH3

MECHANISM :

O

O

Br

O

base

OH

CH3

O

350 oC

DISCONNECTION :

R1 R

R1

n

O

R2 R3

n = 1,2,3,4

398

R

H n

O

R2 R3

NOTES :

The thermal cyclisation (5-exo-trig) of dienones, ynones, diones, and ketoesters to monocyclic spirocyclic derivatives, i.e. an ene reaction of an unsaturated enol in which the carbonyl functionality serves as the ene component. Cobalt-

mediated reactions are also known. See also Alder ene reaction.

REFERENCES :

1) J.-M. Conia; P. Le Perchec, Tetrahedron Lett., 1965, 6, 3305. 2) F. Rouessac; J.-M. Conia, Tetrahedron Lett., 1965, 6, 3313. 3) F. Rouessac; P. Belin; J.-M. Conia, Tetrahedron Lett., 1965, 6, 3319. 4) J.-M. Conia; P. Le Perchec, Synthesis, 1975, 1. 5) G. Rousseau; P. Le Perchec; J.-M. Conia, Tetrahedron Lett., 1977, 18, 45. 6) G. Rousseau; P. Le Perchec; J.-M. Conia, Synthesis, 1978, 67. 7) A.S. Kende; R.C. Newbold, Tetrahedron Lett., 1989, 30, 4329. 8) W.S. Chung; C.C. Ho, Chem. Commun., 1997, 317. 9) J.-L. Renaud; C. Aubert; M. Malacria, Tetrahedron, 1999, 55, 5113. 10) R. Schobert; S. Siegfried; G. Gordon; M. Nieuwenhuyzen; S. Allenmark, Eur. J. Org. Chem., 2001, 1951. 11) G. Rüedi; D.N. Laikov; H.-J. Hansen, Helv. Chim. Acta, 2004, 87, 1990. 12) J.J. Kennedy–Smith; S.T. Staben; F.D. Toste, J. Am. Chem. Soc., 2004, 126, 4526.

COMMENTS :

CONRAD – LIMPACH SYNTHESIS EXAMPLE :

O + NH2

H3C

OEt O

1) 25 oC 2) 250 oC

O

399

N H

CH3

MECHANISM :

H O H

OR

O

OR

OH N

CH3

- HOR

N H

CH3

N H+

CH3

OR O N

CH3

- H2O

H3C

+ NH2

OR O

O

- OR

N H

CH3

CH3

O

O

O

N H

OH

CH3

- H2O

N

OH

DISCONNECTION :

CH3

N

OH

OH

N

NH2

CH3

NOTES :

The formation of 4-hydroxyquinolines by the condensation of β-keto-esters with arylamines under suitable conditions followed by high temperature cyclisation of the resulting β-anilinoacrylate derivative. See also Allan – Loudon, von

400

Baeyer – Drewson quinoline, Camps, Combes quinoline, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm

quinoline and Skraup quinoline reactions.

REFERENCES : Smith : 1335 Smith 2nd : 1098 Houben – Weyl : 8, 627; E7a, 347, 355, 549 Org. Synth. : 24, 68; 28, 38; 29, 70 Org. Synth. Coll. Vol. : 3, 272, 580, 593

1) M. Conrad; L. Limpach, Ber. Dtsch. Chem. Ges., 1887, 20, 944. 2) G.F. Lisk; G.W. Stacy, J. Am. Chem. Soc., 1946, 68, 2686. 3) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 4) R.H. Reitsema, Chem. Rev., 1948, 43, 43. 5) N.D. Heindel; T.A. Brodof; J.E. Kugelschatz, J. Org. Chem., 1966, 3, 222. 6) M. Nasr; A. Zayed; I. Nabih, Pharmazie, 1978, 33, 424. 7) J.A. Moore; T.D. Mitchell, J. Polym. Chem., 1980, 18, 3029. 8) F. Dumont; G. Slegers, Bull. Soc. Chim. Belg., 1995, 104, 505. 9) M. Billah; G.M. Buckley; N. Cooper; H.J. Dyke; R. Egan; A. Ganguly; L. Gowers; A.F. Haughan; H.J. Kendall; C. Lowe; M. Minnicozzi; J.G. Montana; J. Oxford; J.C. Peake; C.L. Picken; J.J. Piwinski; R. Naylor; V. Sabin; N.-Y. Shih; J.B.H. Warneck, Bioorg. Med. Chem. Lett., 2002, 12, 1617.

COMMENTS :

COOK – HEILBRON THIAZOLE SYNTHESIS EXAMPLE :

H3C

CH3 NC

NH2

N CS2

401

H2N

S

SH

MECHANISM :

R NC

R

H

N

NH2 S C S

H R S

N

H+

S

HN H+

H N

N

H2 N

S

SH S

S

R H+

DISCONNECTION :

R

R

N SH

H2N

NC

S

NH2

+ CS2

NOTES :

α-Aminonitriles react with CS2, COS, isothiocyanates and dithiocarboxylic acid salts to afford 2,4-disubstituted-5aminothiazoles.

REFERENCES :

1) A.H. Cook; I. Heilbron; S.F. MacDonald; A.P. Mahadevan, J. Chem. Soc., 1949, 1064. 2) A.C. Davis; A.L. Levy, J. Chem. Soc., 1951, 2419. 3) G. L’Abbe; W. Meutermans; M. Bruynseels, Bull. Soc. Chim. Belg., 1986, 95, 1129. 4) K.A.M. El–Bayouki; W.M. Basyouni, Bull. Soc. Chim. Jpn., 1988, 61, 3794. 5) J.M. Balquist; F.J. Goetz, J. Heterocycl. Chem., 1972, 9, 937.

COMMENTS :

402

COOK – LEVY PEPTIDE SYNTHESIS EXAMPLE :

H3C

O

H N

O

H N

S

1) 2 NH2CH2CO2Et EtOH 2) HCl

S

H3N

CH3 EtO2C

Cl

MECHANISM :

R

EtO2C R

O

H N

2 NH2CH2CO2Et

S +

H

EtOH H

S

H

N

O SH, NH2CH2CO2Et

N S

O

H N

R

HCl

.

CO2Et

+ CS2 + NH3CH2CO2Et

NH2 HCl

DISCONNECTION :

O

R

H

O

N R

H N

CHO2Et NH3 Cl

S S

NOTES :

A 2-thio-5-thiazolidone is employed to achieve in a single operation the addition of a glycyl or similar residue to the ester of an α-amino-acid or peptide. Coupling takes place in the presence of a tertiary base and the product is released by acidification. See also Bailey reaction.

REFERENCES :

1) A.H. Cook; A.L. Levy, J. Chem. Soc., 1950, 637. 2) A.H. Cook; A.L. Levy, J. Chem. Soc., 1950, 646. 3) A.H. Cook; A.L. Levy, J. Chem. Soc., 1950, 651.

403

COMMENTS :

COOPER – FINKBEINER HYDROMAGNESIATION EXAMPLE :

OH 1) PrMgBr 2) TiCl4 3) O2

MECHANISM :

Me3Si Me3Si

CH2OH

1) iBuMgBr 2) Cp2TiCl2

H

BrMg

CH2OH

R

R1 O

Me3Si R R1

H OH

H

Me3Si BF3.Et2O - H2O

CH2OH

R R

O

DISCONNECTION :

OH R

R OH

R

R R2

R1

R2 N H

R3

R1

404

NR3

NOTES :

The titanium-catalysed exchange of HMgX between Grignard reagents and olefins, acetylenes (developed by Sato et al.) or imines (See Crowe et al.). The MgX of the Grignard reagent exchanges and migrates to the terminal position

in the presence of titanium(IV).

REFERENCES : March : 1089 Smith – March : 803 Org. Synth. : 69, 106 Org. Synth. Coll. Vol. : 8, 507

1) G.D. Cooper; H.L. Finkbeiner, J. Org. Chem., 1962, 27, 1493. 2) G.D. Cooper; H.L. Finkbeiner, J. Org. Chem., 1962, 27, 3395. 3) F. Sato; H. Kanbara; Y. Tanaka, Tetrahedron Lett., 1984, 25, 5063. 4) F. Sato; Y. Gao, Chem. Commun., 1995, 659. 5) Sk.R. Amin; W.E. Crowe, Tetrahedron Lett., 1997, 38, 7487.

COMMENTS :

COPE – MAMLOCK – WOLFFENSTEIN OLEFIN SYNTHESIS (COPE ELIMINATION) EXAMPLE :

H H CH3 H3C N CH3 H O

H3C 120 oC

405

H H H H

MECHANISM :

H

R N R O

R +

heat

HO N R

DISCONNECTION :

H

R N R O

NOTES :

The reaction is a thermal syn elimination of an amine oxide. Tertiary amines are readily converted to N-oxides by hydrogen peroxide or peroxyacids. Dehydrosulfenylation is a similar reaction. Selenoxides undergo a similar elimination reaction. See also Hofmann rearrangement and Tschugaeff reaction.

REFERENCES : March : 1018 Smith – March : 1333 Smith : 165 Smith 2nd : 137, 285 Houben – Weyl : 5/1b, 238 Org. React. : 11, 317 Org. Synth. : 39, 40 Org. Synth. Coll. Vol. : 4, 612

1) L. Mamlock; R. Wolffenstein, Ber. Dtsch. Chem. Ges., 1900, 33, 159. 2) A.C. Cope; T.T. Foster; P.H. Towle, J. Am. Chem. Soc., 1949, 71, 3929. 3) C.H. de Puy; R.W. King, Chem. Rev., 1960, 60, 448. 4) B.M. Trost; T.N. Salzmann, J. Org. Chem., 1975, 40, 148. 5) E.J. Corey; M.C. Desai, Tetrahedron Lett., 1985, 26, 5747. 6) E. Ciganek, J. Org. Chem., 1990, 55, 3007. 7) R.D. Bach; M.L. Braden, J. Org. Chem., 1991, 56, 7194. 8) I. Komaromi; J.M.J. Tronchet, J. Phys. Chem. A., 1997, 101, 3554. 9) L. Remen; A. Vasella, Helv. Chim. Acta, 2002, 85, 1118. 10) N.J. Cooper; D.W. Knight, Tetrahedron, 2004, 60, 243.

406

COMMENTS :

COPE REARRANGEMENT EXAMPLE :

H3C

H3C

MECHANISM :

DISCONNECTION : R R

R1

R1

NOTES :

The thermal isomerisation of 1,5-dienes in a [3,3]-sigmatropic rearrangement. The alcohol variant of the Cope rearrangement is called the oxy-Cope rearrangement. For the aza-Cope rearrangement see the Overman pyrrolidine synthesis. Catalytic amounts of palladium(II) enable the rearrangement to take place at about room temperature. See also Claisen (Claisen – Ireland) rearrangement and Overman pyrrolidine synthesis.

REFERENCES : March : 1130 Smith – March : 1444 Smith : 1229, 1236 Smith 2nd : 950, 1006, 1014, 1210 Houben – Weyl : E3, 576; E5, 876; E6b, 234; E8b, 551; E10b2, 197; E15, 3080; E18, 1161

407

Org. React. : 22, 1; 41, 1; 43, 93 Org. Synth. : 74, 169; 76, 199 Org. Synth. Coll. Vol. : 9, 670; 10, 2352 Science of Synthesis : 1, 367; 9, 447; 10, 394

1) A.C. Cope; E.M. Hardy, J. Am. Chem. Soc., 1940, 62, 441. 2) A.C. Cope; J.E. Meili; D.W.H. MacDowell, J. Am. Chem. Soc., 1956, 78, 2551. 3) J.A. Berson; M. Jones, jr., J. Am. Chem. Soc., 1964, 86, 5017. 4) R.K. Hill; N.W. Gilman, Tetrahedron Lett., 1967, 8, 1421. 5) L.E. Overman; A.F. Renaldo, Tetrahedron Lett., 1983, 24, 3757. 6) L.A. Paquette, Angew. Chem., Int. Ed. Engl., 1990, 29, 609. 7) M.J.S. Dewar; C. Jie, Acc. Chem. Res., 1992, 25, 537. 8) D. Enders; M. Knopp; R. Schiffers, Tetrahedron: Asymmetry, 1996, 7, 1847. 9) L.A. Paquette, Tetrahedron, 1997, 53, 13971. 10) L.A. Paquette; Z. Gao; Z. Ni; G.F. Smith, J. Am. Chem. Soc., 1998, 120, 2543. 11) F. Haeffner; K.N. Houk; Y.R. Reddy; L.A. Paquette, J. Am. Chem. Soc., 1999, 121, 11880. 12)J. Nowicki, Molecules, 2000, 5, 1033. 13) C. Schneider, Synlett, 2001, 1079. 14) P. Maurin; S.-H. Kim; S.Y. Cho; J.K. Cha, Angew. Chem., Int. Ed., 2003, 42, 5044. 15) H.M.L. Davies; Q. Jin, J. Am. Chem. Soc., 2004, 126, 10862.

COMMENTS :

COREY – CHAYKOVSKY EPOXIDATION EXAMPLE :

H3C

CH3

CH3 O

Me3SOI, t BuOK DME

408

O

CH3

MECHANISM :

O O

O H2C S CH3 CH3

CH3 H3C S CH3 O I

H3C

S CH2 H3C O

DISCONNECTION :

R

O

R1

O

H R

R2

X R1

+ R2

NOTES :

The reaction of ketones with S-ylides derived from Me3S+I- or Me3SO+I- to give epoxides. However, the dimethylsulfoxonium methylide affords with α,β-unsaturated carbonyl compounds, a conjugate addition takes place and the major product is the cyclopropane. If dimethylsulfonium methylide is used also the α,β-unsaturated carbonyl compounds affords the epoxide. The aziridination of imines has also been published. See also Büchner – Curtius – Schlotterbeck, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew, Shi and Weitz – Scheffer reactions.

REFERENCES : March : 872, 974 Smith – March : 1089, 1247 Smith 2nd : 671 Org. Synth. : 49, 78 Org. Synth. Coll. Vol. : 5, 755

1) E.J. Corey; M. Chaykovsky, J. Am. Chem. Soc., 1962, 84, 867. 2) E.J. Corey; M. Chaykovsky, J. Am. Chem. Soc., 1962, 84, 3782. 3) E.J. Corey; M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353. 4) F. Volatron; O. Eisenstein, J. Am. Chem. Soc., 1987, 109, 2. 5) G.A. Olah; A.-H. Wu, Synthesis, 1990, 887. 6) V.K. Aggarwal, Synlett, 1998, 329. 7) C. Bermand; A. Comel; G. Kirsch, Arkivoc, 2000, 1, 17. 8) S.N. Lakeev; I.O. Maydanova; F.Z. Galin; G.A. Tolstikov, Russ. Chem. Rev., 2001, 70, 655. 9) T. Saito; D. Akiba; M. Sakairi; S. Kanazawa, Tetrahedron Lett., 2001, 42, 57. 10) T. Saito; M. Sakairi; D. Akiba, Tetrahedron Lett., 2001, 42, 5451. 11) J.A. Caccio; A.L. Drahus; R.M. Meis; C.T. Tingle; M. Smrtka; R. Geneste, Synth. Commun., 2003, 33, 2135.

409

COMMENTS :

COREY – FUCHS REACTION EXAMPLE :

O

H H 1) PPh3, CBr4, Zn 2) 2 nBuLi 3) H+

MECHANISM :

Ph3P+-CBr3 Br-

PPh3 + CBr4

Ph3P-CBr2

O Br

H Br

2 nBuLi

Ph3P-CBr2 , Zn - Ph3P=O Br Li Li+ BrH

H+

DISCONNECTION :

O R

R1

R

410

H

NOTES :

This is an alternative aldehyde alkyne elongation. The dibrominated phosphonium ylide is generated in situ by reaction of triphenylphosphine, carbon tetrabromide and zinc. A Wittig reaction between the ylide and an aldehyde gives the 1,1-dibromoalkene. This is treated with n-butyl lithium and forms the α-lithiated bromoalkene, which is in resonance with the vinyl carbenoid, which undergoes H-migration to form an alkyne after acidic work-up. See also Appel, Colvin, Kowalski, Seyferth – Gilbert homologation and Wittig reactions.

REFERENCES : Smith – March : 1233 Smith 2nd : 660

1) E.J. Corey, P.L. Fuchs, Tetrahedron Lett., 1972, 13, 3769. 2) A. Nangia; P.S. Chandrakala, Tetrahedron Lett., 1995, 36, 7771. 3) A.M. Gilbert; R. Miller; W.D. Wulff, Tetrahedron, 1999, 55, 1607. 4) A. Rodríguez; M. Nomen; B.W. Spur; J.J. Godfroid, Tetrahedron Lett., 1999, 40, 5161. 5) A. Wada; G. Babu; S. Shimomoto; M. Ito, Synlett, 2001, 1759. 6) E. Falomir; J. Murga; M. Carda; J.A. Marco, Tetrahedron Lett., 2003, 44, 539. 7) X. Zeng; F. Zeng; E-i. Negishi, Org. Lett., 2004, 6, 3245.

COMMENTS :

COREY – HOUSE REACTION EXAMPLE :

H3C CuLi H3C

+ CH3(CH2)8CH2I

0 oC, Et2O

411

CH3(CH2)8CH2CH3

MECHANISM :

H3C

H Cl

2 H3C

Li, CuI

CH3

CH3

H3C

Cu Li

CH3 + CH3CH2CH2CH2Br

CH3 H3C

CH3

DISCONNECTION :

R1X + R2CuLi

R1R + RCu + LiX

R1 = 1o, 2o, cycloalkyl, allylic, benzylic, aryl, vinylic R = all X = Cl, Br, I

NOTES :

The lithium dialkylcuprate (Gilman reagent) is formed using the alkyl lithium reagent and copper(I) iodide. These reagents are rather unstable but have the ability of to undergo organometallic coupling reactions with alkyl bromides and alkyl iodides. See also Knochel and Ullmann diaryl reactions.

REFERENCES : March : 451 Smith – March : 538 Smith : 761 Smith 2nd : 642 Org. React. : 22, 253 Org. Synth. Coll. Vol. : 6, 248

1) E.J. Corey; G.H. Posner, J. Am. Chem. Soc., 1967, 89, 3911. 2) G.M. Whitesides; W.F. Fischer, jr.; J. San Filippo, jr.; R.W. Bashe; H.O. House, J. Am. Chem. Soc., 1969, 91, 4871. 3) C. Fréjaville; R. Jullien, Tetrahedron Lett., 1971, 12, 2039. 4) C.P. Casey; R.A. Boggs, Tetrahedron Lett., 1971, 12, 2455. 5) L. van Hijfte; R.D. Little, J. Org. Chem., 1985, 50, 3940. 6) B.H. Lipshutz, Synthesis, 1987, 325. 7) T. Schenk; B. Schmidt, J. Labelled Compd. Radiopharm., 1993, 33, 881. 8) B.H. Lipshutz, Acc. Chem. Res., 1997, 30, 277

412

COMMENTS :

COREY – ITSUNO – BAKSHI – SHIBATA ENANTIOSELECTIVE BORANE REDUCTION EXAMPLE :

O

H

OH Cl

Cl BH3 H

Ph

N Ph B O H3C

MECHANISM :

H3C H H2N

CH3 Ph

H3C Ph

H3B

BH3

H H N B O H3B H

Ph

Ph N

O H2B

N

O

B

H2B

H

H O

H

Rs

Rs

Rl

BH3

H

OBH2

Rs

Rl

Ph

H Ph

RsCORl

Ph B H

Ph

CH3 Ph

H Ph

H Ph N

H3C

H H N B O H

BH3

OH

CH3 Ph

H Ph Ph

+ N H3B

B H

413

O

H

OH

Rs

Rl

O B H O Rl

DISCONNECTION :

H

If

O

OH Rl

Ph

N Ph B O H

N Ph B O H3C H Rs

H

If

Ph

Rs

H Rl

Rl

O

OH Rs

Rl

Rs

Rs = smaller group Rl = larger group

NOTES :

The enantioselective reduction of prochiral ketones by borane or catecholborane catalysed by oxazaborolidine. The limitation of Itsuno’s approach was the use of stoichiometric amounts of chiral oxazaborolidine. Corey demonstrated the catalytic enantioselective reduction. The oxazaborolidines can be polymer supported. See also Midland reduction and Noyori hydrogenation.

REFERENCES : March : 915 Smith – March : 1201 Org. React. : 52, 395 Org. Synth. : 74, 50 Org. Synth. Coll. Vol. : 9, 676

1) A. Hirao; S. Itsuno; S. Nakahama; N. Yamazaki, J. Chem. Soc., Chem. Commun., 1981, 315. 2) S. Itsuno; Y. Sakurai; K. Ito; A. Hirao; S. Nakahama, Bull. Chem. Soc. Jpn., 1987, 60, 395. 3) E.J. Corey; R.K. Bakshi, J. Am. Chem. Soc., 1987, 109, 5551. 4) E.J. Corey; R.K. Bakshi; S. Shibata, Tetrahedron Lett., 1990, 31, 611. 5) V.K. Singh, Synthesis, 1992, 605. 6) V. Nevalainen, Tetrahedron: Asymmetry, 1992, 3, 921. 7) L. Deloux; M. Srebnik, Chem. Rev., 1993, 93, 763. 8) E.J. Corey; C.J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1986. 9) A.F. Simpson; C.D. Bodkin; C.P. Butts; M.A. Armitage; T. Gallagher, J. Chem. Soc., Perkin Trans. 1, 2000, 3047. 10) M.D. Price; J.K. Sui; M.J. Kurth; N.E. Schore, J. Org. Chem., 2002, 67, 8086. 11) Z. Dalicsek; F. Pollreisz; Á. Gömöry; T. Soós, Org. Lett., 2005, 7, 3243.

414

COMMENTS :

COREY – KIM OXIDATION EXAMPLE : O

OH CH3

Et 1) CCl4, NCS Cl2, CH3SCH3 2) Et3N

CH3

Et

MECHANISM :

H3C

Cl2 + CH3SCH3

CCl4 NCS

O

S N

CH3

CH3 S H H3C O

OH

O R

R1

R

R1

O N O

H3C S CH3 O R

H

O R

R1

R1

Et3N

DISCONNECTION :

O R

OH R1

R = H, Alk, Ar

R

R1

NOTES :

The oxidation of primary and secondary alcohols to aldehydes and ketones using NCS or NBS and Me2S. Allylic and dibenzylic compounds give halides as products. An odourless method has been introduced. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

415

REFERENCES : March : 433 Smith – March : 519, 1536 Org. Synth. : 58, 122 Org. Synth. Coll. Vol. : 6, 220

1) E.J. Corey; C.U. Kim, J. Am. Chem. Soc., 1972, 94, 7586. 2) E.J. Corey; C.U. Kim; M. Takeda, Tetrahedron Lett., 1972, 13, 4339. 3) R. Baudat; M. Petrzilka, Helv. Chim. Acta, 1979, 62, 1406. 4) N.K.A. Dalgard; K.E. Larsen; K.B.G. Torssel, Acta Chem. Scand., 1984, 38B, 423. 5) K. Hartke; E. Kohrt, Arch. Pharm. (Weinheim, Ger.), 1993, 326, 259. 6) C. Vogel; P. Gries, J. Carbohydr. Chem., 1994, 13, 37. 7) J.T. Pulkkinen; J.J. Vepsalainen, J. Org. Chem., 1996, 61, 8604. 8) M. Kawahara; A. Nishida; M. Nakagawa, Org. Lett., 2000, 2, 675. 9) D. Crich; S. Neelamkavil, Tetrahedron, 2002, 58, 3865. 10) K. Nishide; S-i. Ohsugi; M. Fudesaka; S. Kodama; M. Node, Tetrahedron Lett., 2002, 43, 5177. 11) S-i. Ohsugi; K. Nishide; K. Oono; K. Okuyama; M. Fudesaka; S. Kodama; M. Node, Tetrahedron, 2003, 59, 8393.

COMMENTS :

COREY – KWIATKOWSKI REACTION EXAMPLE :

+

H O P NCH3 H Li NCH3

O

416

1) H2O 2) heat

Ph

H

Ph

H

MECHANISM :

O +

S H3C P OCH3 OCH3

O Ph

n

BuLi - 78 oC THF

S P OCH 3 Ph OCH3

DISCONNECTION :

R

R2

R1

R3

O R

R2 R1

+ R3

S P R4 R5

NOTES :

The synthesis of cis and trans olefins via β-keto and β-hydroxy phosphonamides. See also Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi

(Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 956 Smith – March : 1231

1) E.J. Corey; G.T. Kwiatkowski, J. Am. Chem. Soc., 1966, 88, 5652. 2) E.J. Corey; G.T. Kwiatkowski, J. Am. Chem. Soc., 1966, 88, 5653. 3) E.J. Corey; G.T. Kwiatkowski, J. Am. Chem. Soc., 1966, 88, 5654. 4) J. Mulzer; H.J. Martin; B. List, Tetrahedron Lett., 1996, 37, 9177.

COMMENTS :

417

COREY – LINK REACTION EXAMPLE :

H3C

CCl3

H

H3N

O

O 1)

O

O H Ph 0.1 N

O

R B H

Ph

O B n

Bu

DCM 2) 3) 4) 5)

HO-, N3HOH+ Pd/C, H2

MECHANISM :

R

CCl3

H

O

OH

R

O

-

HO , N3

CCl3

0.1 N

Cl

-

Cl

R

B H O Ph H

O

H

N3 Ph

O B n

Bu

DCM

N3

H

R

COCl

1) HO2) H+

N3

H

R

COOH

H3N Pd/C, H2

H O

R O

DISCONNECTION :

H3N R

H

R

COO

CCl3 O

418

NOTES :

The one-pot conversion of (trichloromethyl)carbinols, generated by oxazaborolidine-catalysed asymmetric reduction of trichloromethyl ketones, into α-azido and α-hydroxy acids. Deprotonation of the carbinol generates the chiral gemdichlorooxirane. The in-situ nucleophile provides the functional group. The azide attacks from the more hindered face, rather than from the less sterically hindered face as in the Bucherer – Bergs and Strecker amino acid reactions. See also Bouveault – Locquin amino acid, von Braun amino acid synthesis, Bucherer – Bergs, Darapsky, Herbst – Engel, Knoop – Oosterlin, O’Donnell, Reeve synthesis, Schöllkopf, Sorensen, Strecker amino acid, Tiemann

amination, Ultee, Urech and Zelinksy – Stadnikoff reactions.

REFERENCES :

1) E.J. Corey; J.O. Link, J. Am. Chem. Soc., 1992, 114, 1906. 2) E.J. Corey; J.O. Link, Tetrahedron Lett., 1992, 33, 3431. 3) E.J. Corey; J.O. Link; Y. Shao, Tetrahedron Lett., 1992, 33, 3435. 4) V.K. Aggarwal; J.K. Barrell; J.M. Worrall; R. Alexander, J. Org. Chem., 1998, 63, 7128. 5) C. Domínguez; J. Ezquerra; S.R. Baker; S. Borrelly; L. Prieto; M. Espada; C. Pedregal, Tetrahedron Lett., 1998, 39, 9305.

6) V.K. Aggarwal; A. Mereu, J. Org. Chem., 2000, 65, 7211. 7) A. Scaffidi; B.W. Skelton; R.V. Stick; A.H. White, Aust. J. Chem., 2004, 57, 723.

COMMENTS :

COREY – NICOLAOU MACROLACTONISATION EXAMPLE :

CH3 O OH

OMOM

O

H3C O

O CH3

CH3

O OH

(2-pyr-S)2, Ph3P, AgClO4, heat

419

HO

OH CH3

MECHANISM :

O

N S

N

N

PPh3

O

S

S

Ph3P HO H

O O

O

N

N

N Ph3P O S HO

S

S HO

- Ph3P=O

O O + N H

O

S

DISCONNECTION :

O

HO

HO

O

O

NOTES :

This reaction allows the lactonisation of hydroxy acids under mild conditions using 2,2’-dipyridyl disulfide and triphenylphosphine (Gerlach – Thalmann modification uses silver perchlorate). Alternative disulfides have also been used by Corey. See also Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael

condensation,

Mitsunobu,

Mukaiyama

macrolactonisation-1,

Mukaiyama

macrolactonisation-2,

Murai

rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkatraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : Smith 2nd : 528

1) H. Gerlach; A. Thalmann, Helv. Chim. Acta, 1974, 57, 2661. 2) E.J. Corey; K.C. Nicolaou, J. Am. Chem. Soc., 1974, 96, 5614. 3) E.J. Corey; K.C. Nicolaou; L.S. Melvin, jr., J. Am. Chem. Soc., 1975, 97, 653. 4) E.J. Corey; K.C. Nicolaou; L.S. Melvin, jr., J. Am. Chem. Soc., 1975, 97, 654. 5) H. Gerlach; A. Thalmann, Helv. Chim. Acta, 1977, 60, 2866.

420

6) K.C. Nicolaou, Tetrahedron, 1977, 33, 683. 7) H. Gerlach; P. Kunzler; K. Oertle, Helv. Chim. Acta, 1978, 61, 1226. 8) H. Gerlach; P. Kunzler, Helv. Chim. Acta, 1980, 63, 2312 9) I. Paterson; M.M. Mansuri, Tetrahedron, 1985, 41, 3569. 10) M.B. Andrus; T.-L. Shih, J. Org. Chem., 1996, 61, 8780. 11) S.-F. Lu; Q. O’yang; Z.-W. Guo; B. Yu; Y.-Z. Hui, J. Org. Chem., 1997, 62, 8400. 12) E. Deretey, J. Mol. Struct.-Theochem., 1999, 459, 273. 13) T. Sasaki; M. Inoue; M. Hirama, Tetrahedron Lett., 2001, 42, 5299.

COMMENTS :

COREY – SCHMIDT OXIDATION EXAMPLE : CH3

CH3

O H3C

OH

PDC DCM

CH3

CH3

H3C

CH3

HO

PDC DMF H3C

O

CH3

MECHANISM :

O O Cr O O R1 H R2

H OH R1

H R2

O O O Cr Cr N H O OO O

H N

421

O + R1

R2

HO

O Cr

OH

Follow-up chemistry of Cr(IV) :

3 CrO(OH)2 or

Cr2O3 + CrO3 + 3 H2O CrO3

CrO(OH)2 OH

R1

O

OH H

R1

R2

R1

R2 .5 Cr2O3 + 1.5 H2O

R2

CrO3H

OH R1

H R2

OH O Cr O O R1 H R2

H

OH Cr HO OH

DISCONNECTION :

OH

O R

R1

R = H, Alk, Ar

R

R1

NOTES :

The oxidation of alcohols, to aldehydes, ketones and carboxylic acids using pyridinium dichromate, a less acidic oxidising agent than PCC. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pinnick, Pfitzner – Moffatt, Sarett, Swern

and Uemura reactions.

REFERENCES : March : 884, 1168 Smith – March : 1514 Smith : 231 Smith 2nd : 201 Org. Synth. : 52, 5; 55, 84; 67, 114; 68, 175; 73, 36; 80, 1 Org. Synth. Coll. Vol. : 6, 373, 644; 8, 13, 43; 9, 132

422

1) W.M. Coates; J.R. Corrigan, Chem. Ind. (London), 1969, 1594. 2) E.J. Corey; G. Schmidt, Tetrahedron Lett., 1979, 20, 399. 3) R.K. Boeckmann, jr.; R.B. Perni, J. Org. Chem., 1986, 51, 5486. 4) A.B. Smith III; Z. Wan, J. Org. Chem., 2000, 65, 3738. 5) F. Yokokawa; T. Asano; T. Shioiri, Org. Lett., 2000, 2, 4169.

COMMENTS :

COREY – SEEBACH PROCEDURE EXAMPLE :

O + H

H

SH

SH

S

1) BF3.Et2O 2) nBuLi 3) CH3Br 4) nBuLi 5) EtBr

S

CH3 Et

MECHANISM :

O + R1

H

SH

SH

S

BF3.Et2O

S

n

BuLi

R1 H O

S

S

R2X

S

S

1) HgCl2 R1 2) CaCO3 aq. acetone

R1 R2

R1 Li

DISCONNECTION :

O R1

O R1

H

+ R2X

O

R2 H

423

H

+ R1X + R2X

R2

NOTES :

The carbonyl group is converted into a cyclic thioacetal that can be easily deprotonated due to the stabilisation effect of the sulfur carbanion. By reversing the polarity (umpolung) of the acyl carbon nucleophilic acylation can take place. These reagents can be used in the synthesis of aldehydes, silyl and germayl ketones, cyclic carbonyl compounds, carbohydrates and α-keto acids.

REFERENCES : Smith – March : 556 Smith : 658 Smith 2nd : 557 Org. Synth. : 50, 72 Org. Synth. Coll. Vol. : 6, 556

1) E.J. Corey; D. Seebach; R. Freedman, J. Am. Chem. Soc., 1966, 89, 434. 2) D. Seebach; R.J. Jones; E.J. Corey, J. Org. Chem., 1967, 33, 300. 3) D. Seebach, Synthesis, 1969, 17. 4) E. Vedejs; P.L. Fuchs, J. Org. Chem., 1971, 36, 366. 5) D. Seebach; E.J. Corey, J. Org. Chem., 1975, 40, 231. 6) E. Juaristi; B. Gordillo; L. Valle, Tetrahedron, 1986, 42, 1963. 7) H.B. Lee; S. Balasubramanian, J. Org. Chem., 1999, 64, 3454. 8) M. Bräuer; J. Weston; E. Anders, J. Org. Chem., 2000, 65, 1193. 9) K. Kazahaya; S. Tsuji; T. Sato, Synlett, 2004, 1640.

COMMENTS :

424

COREY – SEMMELHACK MODIFICATION EXAMPLE :

CH3 H2C

2

CH2Br

1) 2 Ni(CO)4 benzene, heat 2) 2 bromobenzene DMF, heat

MECHANISM :

CH3 2 H2C

CH2Br

H3C

Ni

2 Ni(CO)4 benzene, heat

Br Ni Br

CH3

Br 2 DMF, heat

DISCONNECTION :

R R1

R1Hal +

R

R = H, CH3, CO2Et

NOTES :

Zero-valent nickel complexes such as Ni(COD)2 and Ni(PPh3)4 react readily with aryl and vinyl halides, tosylates and acetates via a π-allyl nickel complex to give symmetrical coupling products. The reaction is a low-temperature analogue of the Ullmann reaction. See also Ullmann reaction.

REFERENCES : Smith – March : 541 Smith 2nd : 1125 Org. React. : 19, 119 Org. Synth. : 52, 115 Org. Synth. Coll. Vol. : 6, 722

425

1) E.J. Corey; M.F. Semmelhack, J. Am. Chem. Soc., 1967, 89, 2755. 2) E.J. Corey; M.F. Semmelhack; L.S. Hegedus, J. Am. Chem. Soc., 1968, 90, 2416. 3) T.T. Tsou; J.K. Kochi, J. Am. Chem. Soc., 1979, 101, 6319. 4) T.T. Tsou; J.K. Kochi, J. Am. Chem. Soc., 1979, 101, 7547. 5) M.F. Semmelhack; P. Helquist; L.D. Jones; L. Keller; L. Mendelson; L. Speltz Ryono; J. Gorzynski Smith; R.D. Stauffer, J. Am. Chem. Soc., 1981, 103, 6460.

COMMENTS :

COREY – SUGGS OXIDATION EXAMPLE :

H3C

O

H3C

O

OH CH3

PCC DCM

H3C

O

H3C

O

O H CH3

MECHANISM :

O O Cr O O R1 H R2

H OH R1

H R2

O N H O Cr O Cl

O + R1

426

R2

HO

O Cr

OH

Follow-up chemistry of Cr(IV) :

3 CrO(OH)2 or

Cr2O3 + CrO3 + 3 H2O CrO3

CrO(OH)2 OH

R1

O

OH H

R1

R2

R1

R2 .5 Cr2O3 + 1.5 H2O

R2

CrO3H

OH R1

H R2

OH O Cr O O R1 H R2

H

OH Cr HO OH

DISCONNECTION :

OH

O R

R1

R = H, Alk, Ar

R

R1

NOTES :

The oxidation of primary and secondary alcohols using pyridinium chlorochromate (slightly more acidic than pyridinium dichromate). See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pinnick, Pfitzner – Moffatt, Sarett, Swern

and Uemura reactions.

REFERENCES : March : 447, 1174, 1188, 1196 Smith – March : 1514, 1531 Smith : 230, 549, 1302 Smith 2nd : 200 Org. Synth. : 52, 5; 55, 84; 72, 189; 75, 69; 76, 110 Org. Synth. Coll. Vol. : 6, 373, 644; 9, 643; 10, 2312; 2343

427

1) E.J. Corey; J.W. Suggs, Tetrahedron Lett., 1975, 16, 2647. 2) Y. Kitagawa; A. Itoh; S. Hashimoto; H. Yamamoto; H. Nozaki, J. Am. Chem. Soc., 1977, 99, 3864. 3) G. Piancatelli; A. Scetteri; M.D. D’Auria, Synthesis, 1982, 245. 4) G. Rosini; R. Ballini, Synthesis, 1983, 543. 5) E.J. Parish; S. Parish; H. Honda, Synth. Commun., 1990, 20, 3265. 6) V. Chakraborty; M. Bordoloi, J. Chem. Res., 1999, 118. 7) S. Servi; A. Acar, Molecules, 2002, 7, 104.

COMMENTS :

COREY – WINTER ALKENE SYNTHESIS EXAMPLE :

OH

H3C

CH3

H3C

OH

1) N

H

H N

CH3

N

N S

2) P(OMe)3

MECHANISM :

N OH

N

OH

O

O S

R3P

O

N

PR3 O O

S PR3

S

H

O

S PR3

PR3 O

428

O

- CO2, PR3

H

Carbene intermediate mechanism :

N OH

N S

OH

S

R3P

O

N

S PR3 O

O

O - R3P=S

O

O

PR3

R3P

O

- CO2

O

H

H

DISCONNECTION :

OH R

R1

R

R1

OH OH R1

R R

R1

OH

NOTES :

The formation of olefins from vicinal diols. Thiocarbonyldiimidazole (TCDI) was originally suggested by Corey, but other reagents can be used (e.g. thiophosgene). The intermediate can be cleaved with an alkyl phosphite or with bis(1,5-cyclooctadiene) nickel. See also Corey – Kwiatkowski, Eastwood, Garegg – Samuelsson, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi

(Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 1028 Smith – March : 1340 Houben – Weyl : E19b, 1696 Org. React. : 30, 457

1) E.J. Corey; R.A.E. Winter, J. Am. Chem. Soc., 1963, 85, 2677. 2) E.J. Corey; F.A. Carey; R.A.E. Winter, J. Am. Chem. Soc., 1965, 87, 934. 3) H. Prinzbach; H. Babsh, Angew. Chem., Int. Ed. Engl., 1975, 14, 753.

429

4) E.J. Corey; P.B. Hopkins, Tetrahedron Lett., 1982, 23, 1979. 5) K. Jaehnisch, Liebigs Ann. Chem. / Receuil, 1997, 757. 6) D. Crich; A.B. Pavlovic; D.J. Wink, Synth. Commun., 1999, 29, 359. 7) C. Palomo; M. Oiarbide; A. Landa; A. Esnal; A. Linden, J. Org. Chem., 2001, 66, 4180.

COMMENTS :

CORNFORTH REARRANGEMENT EXAMPLE :

O

O

OEt

N N

N Ph

O

toluene heat

OEt

Ph

O

N

MECHANISM :

O N Ph O

OEt

N

N Ph

O

O N

N

OEt

OEt

Ph

O

DISCONNECTION :

O

R1

R

O

N Ph

N X

R1

Ph

X

N R1 =

N

N

O

N

X = O, S

430

N

N

R

N

N

O

N

NOTES :

The thermal rearrangement of 4-carbonyl substituted oxazoles via nitrilium ylids.

REFERENCES : Houben – Weyl : E8a, 998; E8b, 60, 182, 325

1) J.W. Cornforth, The chemistry of penicillin, 1949, 698, 705. 2) F. Korte; K. Storiko, Chem. Ber., 1960, 93, 1033. 3) M.J.S. Dewar; I.J. Turchi, J. Org. Chem., 1975, 40, 1521. 4) E.C. Taylor; I.J. Turchi, Chem. Rev., 1979, 79, 181. 5) G. L’Abbe, J. Heterocycl. Chem., 1984, 21, 627. 6) S.L. Corrao; M.J. Macielag; I.J. Turchi, J. Org. Chem., 1990, 55, 4484. 7) G. L’Abbe; A.M. Ilisiu; W. Dehaen; S. Toppet, J. Chem. Soc., Perkin Trans. 1, 1993, 2259. 8) D.R. Williams; E.L. McClymont, Tetrahedron Lett., 1993, 34, 7705

COMMENTS :

COUTURE INDOLE SYNTHESIS EXAMPLE :

O

OH NEt2

N

P O

Ph Ph

1) nBuLi, THF, - 78 oC 2) H2O

431

N

Ph P Ph O

MECHANISM :

O CN H 1) EtMgBr, THF, 0 oC N 2) HCl, H2O CH3

Et H

N CH3

O

(CH2O)n, EtOH, toluene, reflux

O Et CH2OEt

N CH3

Et 1) Ph2PCl, THF, RT 2) K2CO3

Et O K O P Ph N Ph CH3

KHMDS, THF - 10 oC

O N P Ph H3C Ph

Et

HCl, H2O RT

N CH3

DISCONNECTION :

R1 CN N R

N R

H

+ R1Li or R1MgBr

NOTES :

This is a simple indole synthesis based on the intramolecular Horner – Wadsworth – Emmons reaction. The nature of the base dramatically affects the outcome of the reaction. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Horner – Wadsworth – Emmons, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe

indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

432

REFERENCES :

1) A. Couture; E. Deniau; Y. Gimbert; P. Grandclaudon, J. Chem. Soc., Perkin Trans. 1, 1993, 2463. 2) A. Couture; E. Deniau; Y. Gimbert; P. Grandclaudon, Tetrahedron, 1993, 49, 1431.

COMMENTS :

CRABBÉ SYNTHESIS EXAMPLE :

H

OAc H

1) Me2CuLi H3C - 10 oC, Et2O 2) sat. aq. NH4Cl

MECHANISM :

R

OAc R2 R1

R R3 Cu R3

(R3)2Cu

hydrolysis

R2 R1

rearrangement

R

R2

R

R2

H

R1

R3

R1

433

DISCONNECTION :

R

R2

H

R1

OAc R2 R1

R R

R2

R3

R1

NOTES :

The formation of allenes by the reaction of lithium diorganocuprates on propargylic acetates via hydrolysis or rearrangement.

REFERENCES :

1) P. Crabbé; E. Barreiro; J.-M. Dollat; J.-L. Luche, J. Chem. Soc., Chem. Commun., 1976, 183. 2) M.H. Nantz; D.M. Bender; S. Janaki, Synthesis, 1993, 577. 3) W.G. Beyersbergen van Henegouwen; H. Hiemstra, J. Org. Chem., 1997, 62, 8862. 4) S.-K. Kang; T.-G. Baik; A.N. Kulak; Y.-H. Ha; Y. Lim; J. Park, J. Am. Chem. Soc., 2000, 122, 11529.

COMMENTS :

CRAIG EXCHANGE EXAMPLE :

N

NH2

1) HBr 2) HNO2, Br2 3) NaOH

434

N

Br

MECHANISM :

+ 2 HBr N

NH2

N H

N H

NaOH

Br

NH2.HBr

HNO2, Br2

Br

N

N H

N

Br

Br

N

Br

DISCONNECTION :

N

X

N

NH2

NOTES :

α-Halide substituted pyridines are prepared by the diazotisation of an α-aminopyridine in hydrohalogenic acid solution in the presence of excess halogen. This method gives much higher yields than the more common Sandmeyer arylamine halogenation reaction. See also Balz – Schiemann, Cadogan arylation, Demjanov rearrangement, Gattermann diazo, Gattermann sulphinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : Org. Synth. : 26, 16 Org. Synth. Coll. Vol. : 3, 136

1) L.C. Craig, J. Am. Chem. Soc., 1934, 56, 231. 2) T. Kawai; N. Furukawa; S. Oae, Heterocycles, 1985, 23, 177. 3) A.R. Todeschini; A.L.P. de Silva; C.M. da Kelly; S.C. Parrini; E.J. Barreiro, Eur. J. Med. Chem. Chim. Ther., 1998, 33, 189.

COMMENTS :

435

CREIGHTON PROCESS EXAMPLE :

H HO H H

CHO OH H OH OH CH2OH

Hg-cathode Pb-anode [2 H]

H HO H H

CH2OH OH H OH OH CH2OH

NOTES :

The electrolytic sugar reduction (mainly glucose) to the corresponding alcohols (sorbitol) using mercury and lead electrodes.

REFERENCES :

1) H.J. Creighton, U.S. Patent, 1926, 1612361. 2) H.J. Creighton, U.S. Patent, 1929, 1712951. 3) H.J. Creighton, Trans. Electrochem. Soc., 1939, 75, 289. 4) H.J. Creighton, Can. Chem. Process. Ind., 1942, 26, 690. 5) F.D. Popp; H.P. Schultz, Chem. Rev., 1962, 62, 19.

COMMENTS :

CRIEGEE GLYCOL CLEAVAGE EXAMPLE :

O

OH Pb(OAc)4

O

OH

436

MECHANISM :

R

R1

OH

R

Pb(OAc)4 fast

OH

R1

R

O Pb(OAc)3 slow

OH

R1 O

R

O

R1

R + Pb(OAc)2

Pb(OAc)2 R1

R

R1

O

O

R

OH OH

O OAc Pb OAc O

Pb(OAc)4 slow

R1

O Pb(OAc)2

R O

R1

O + Pb(OAc)2

O H B

DISCONNECTION :

R

R1

R OH R3 R2 R1 OH

O +

O

R2

R3

NOTES :

Lead tetraacetate is used for the cleavage of α-glycols. The reaction has a variety of applications including the determination of ring structures in sugars. Also works on β-amino alcohols, glyoxals and α-hydroxy aldehydes or ketones. The cleavage preferentially takes place via a five-membered lead(IV) acid diester. If the OH-groups are fixed in a trans orientation the reaction proceeds slowly via the mono-ester. See also Hudson – Jackson, Lemieux – Johnson, Malprade, Milas, Rigby and Ruff – Fenton reactions.

REFERENCES : March : 1175 Smith – March : 1520 Smith : 304 Smith 2nd : 271 Houben – Weyl : E3, 510 Org. React. : 2, 341

1) R. Criegee, Ber. Dtsch. Chem. Ges., 1931, 64, 260. 2) R. Criegee, Angew. Chem., 1940, 53, 321.

437

3) H.R. Goldschmid; A.S. Perlin, Can. J. Chem., 1960, 38, 2280. 4) C.A. Grob; P.W. Schiess, Helv. Chim. Acta, 1960, 43, 1546. 5) B. Sklarz, J. Chem. Soc., Quat. Rev., 1967, 21, 3. 6) S. Chandrasekhar, C.D. Roy, J. Chem. Soc., Perkin Trans. 2, 1994, 2141. 7) R.M. Goodman, Y. Kishi, J. Am. Chem. Soc., 1998, 120, 9392. 8) L. Candela; I. Jos, Tetrahedron Lett., 2001, 42, 3179.

COMMENTS :

CRIEGEE OSMIUM TETROXIDE REACTION EXAMPLE :

H3C

CH3

H3C

CH3

1) OsO4 2) Na2SO3 Et2O

H3C CH3 H3C CH3 HO OH

MECHANISM :

H3C

CH3

H3C

CH3

H3C CH3 H3C CH3

OsO4

Na2SO3

O O Os O O

DISCONNECTION :

R R1 H

R

R1

H

H

H HO OH

438

H3C CH3 H3C CH3 HO OH

NOTES :

Alkenes react with osmium tetroxide in dry ether to form a cyclic osmic ester, which can be isolated and is subsequently cleaved to the cis-glycol using sodium sulfite. See also Milas, Prévost, Sharpless dihydroxylation and Woodward cis-hydroxylation reactions.

REFERENCES : March : 822 Smith – March : 1048 Smith : 284 Smith 2nd : 248

1) R. Criegee, Liebigs Ann. Chem., 1936, 522, 75. 2) M. Schröder, Chem. Rev., 1980, 80, 187. 3) K.A. Jørgensen; R. Hoffmann, J. Am. Chem. Soc., 1986, 108, 1867.

COMMENTS :

CRIEGEE REARRANGEMENT EXAMPLE :

O O H 1) O2 2) Ph

Cl

O heat, pyridine

439

Ph O

MECHANISM :

O O

Ph O H

O

O

Ph

+ O O O

H

O

H O

Ph O

Ph O

DISCONNECTION : O

R3 R2

OR1 O R

R3

O O

R2

R1

R

O

NOTES :

In the original paper by Criegee, 9-decalyl peresters rearrange rapidly (in solvents of high ionising power) with ionic fission of the oxygen-oxygen link to form the corresponding esters of 1-hydroxy-1,6-epoxycyclodecane. This reaction has been extended to secondary allylic hydroperoxides. See also von Baeyer – Villiger and Wagner – Meerwein reactions.

REFERENCES : Org. React. : 43, 251

1) R. Criegee, Ber. Dtsch. Chem. Ges., 1944, 77, 722. 2) R. Criegee; R. Kaspar, Liebigs Ann. Chem., 1948, 560, 127. 3) E. Hedaya; S. Winstein, J. Am. Chem. Soc., 1967, 89, 1661. 4) F.E. Ziegler; A. Kneisley; J.K. Thottahil; R.T. Wester, J. Am. Chem. Soc., 1988, 110, 5434. 5) R.M. Goodman; Y. Kishi, J. Org. Chem., 1994, 59, 5125. 6) H. Priepke; R. Brückner, Liebigs Ann. / Receuil, 1997, 1645. 7) E. Butkus; S. Stoncius, J. Chem. Soc., Perkin Trans. 1, 2001, 1885. 8) P.A. Krasutsky; I.V. Kolomitsyn; P. Kiprof; R.M. Carlson; N.A. Sydorenko; A.A. Fokin, J. Org. Chem., 2001, 66, 1701. 9) A.P. Marchand; V.S. Kumar; H.K. Hariprakasha, J. Org. Chem., 2001, 66, 2072.

440

COMMENTS :

CROSS – BEVAN – BEADLE REACTION EXAMPLE :

cellulose

HO(cellulose) NaOH, CS2 H+, H2O

MECHANISM :

O(cellulose) cellulose NaOH

H+, H2O

NaO(cellulose) CS2

COS + H2S + HO(cellulose)

NOTES :

The formation of artificial silk from cellulose. See also Chardonnet reaction.

REFERENCES : Houben – Weyl : 14/2, 882

1) C.F. Cross; E.J. Bevan; C. Beadle, British Patent, 1892, 8700. 2) C.F. Cross; E.J. Bevan; C. Beadle, J. Chem. Soc. Ind., 1892, 12, 516.

COMMENTS :

441

S SNa

CRUM BROWN – WALKER ELECTROLYSIS EXAMPLE :

O

O 2

-

H3C

OCH3

O

aq. EtOH

OCH3

O O

O

MECHANISM :

O

O O OR

O OR

- e-

O

CO2 + CH2COOR

O O RO

2 CH2COOR

OR O

DISCONNECTION :

ROOC

OOC

COOR n

R = Alk, n = 0 -15

COOR n

NOTES :

The formation of ω,ω’-dicarboxylic acid esters starting from the mono ester with an ionised carboxylic acid under the Kolbe electrolysis conditions. See also Hofer – Moest and Kolbe electrolytic reactions.

REFERENCES : Houben – Weyl : 8, 500, 599 Org. Synth. : 21, 48; 60, 1 Org. Synth. Coll. Vol. : 3, 401; 7, 181

1) H. Kolbe, Liebigs Ann. Chem., 1849, 69, 259. 2) A. Crum Brown; J. Walker, Liebigs Ann. Chem., 1891, 261, 107. 3) S. Glasstone; A. Hickling, Chem. Rev., 1939, 25, 425. 4) B.C.L. Weedon, J. Chem. Soc., Quat. Rev., 1952, 6, 380. 5) H. Breederveld; E.C. Kooyman, Recl. Trav. Chim. Pays-Bas, 1957, 76, 297. 6) W.A. Bonner; F.D. Mango, J. Org. Chem., 1964, 29, 29.

442

7) W.A. Bonner; F.D. Mango, J. Org. Chem., 1964, 29, 430.

COMMENTS :

CURATOLO SYNTHESIS EXAMPLE :

HO

NH2

H3C

CO2Et

+

N

HN

N

NH2

O

NH2

CH3

MECHANISM :

NH2 HN

H3C

NH2

O

H H3C OH N - H2O

N

HN +

H

O

CH3 N OH O NH2 OEt

CH3

H+

HN H

H

CO2Et

CH3

N

N

HN

H2N N H

N O

OH

DISCONNECTION :

R N

CO2R1

NH2

H2N

+

HN N

NH2 OH

443

R

O

NOTES :

The synthesis of 2-amino-6-hydroxypyrimidines by heating guanidine carbonate with β-ketoesters. See also Traube purine reaction.

REFERENCES :

1) R. Behrend, Ber. Dtsch. Chem. Ges., 1886, 19, 219. 2) J. Jaeger, Liebigs Ann. Chem., 1891, 262, 365.

COMMENTS :

CURTIUS REARRANGEMENT EXAMPLE :

O H

H H

Cl 1) NaN3 2) Heat 3) H2O

444

NH2 H

MECHANISM :

O R

N

N

O

N R

O R

Cl

N N N

O R

N

RNH2

H2O

R N C O

N

N

R

R1NH2

H N

H N

R1

O

R

H N

R1OH

O

R1

O

DISCONNECTION :

RNH2

R

R

H N H N

H N

O R1

R

O O

R1

O

445

Cl

N

N

N

NOTES :

The rearrangement of acid azides to isocyanates with evolution of nitrogen. The isocyanates can be converted into urethanes, ureas, amides and amines. The reaction is carried out in ethanolic solution so that the isocyanate formed first reacts with the alcohol to produce an urethane from which a primary amine can be obtained by hydrolysis. When the azide contains halogen or hydroxyl groups in the α-position, or α,β-unsaturation, the product is an aldehyde or ketone. The alkaline hydrolysis of the isocyanate to sometimes called Wurtz amine synthesis. The photochemical Curtius rearrangement is also known as the Hargar reaction. See also Beckmann, Hofmann degradation, Lossen, Schmidt rearrangement, Tiemann rearrangement and Wolff reactions.

REFERENCES : March : 886, 1091 Smith – March : 1178, 1380, 1384, 1406, 1412 Smith : 1147 Smith 2nd : 862, 955 Houben – Weyl : 11/1, 862; E3, 527; E5, 554; E6b, 140; E8a, 759, 838; E8c, 677; E8d, 79; E16a, 596; E16d, 627; E19c, 408 Org. React. : 3, 337 Org. Synth. : 18, 5; 36, 69; 51, 48 Org. Synth. Coll. Vol. : 2, 24, 4, 819; 6, 910 Science of Synthesis : 10, 75, 177, 258

1) A. Wurtz, Ann. Chim. (Paris), 1854, 42, 43. 2) T. Curtius, Ber. Dtsch. Chem. Ges., 1890, 23, 3023. 3) E. Lieber; R.L. Minnis, jr.; C.N.R. Rao, Chem. Rev., 1965, 65, 381. 4) H.P. Benecke, Tetrahedron Lett., 1977, 18, 997. 5) W. Haefliger; E. Kloppner, Helv. Chim. Acta, 1982, 65, 1837. 6) J.R. Pfister; W.E. Wymann, Synthesis, 1983, 39. 7) A. Kakehi; S. Ito; F. Ishida; Y. Tominaga, J. Org. Chem., 1997, 62, 7888. 8) S. Sunami; T. Sagara; M. Ohkubo; H. Morishima, Tetrahedron Lett., 1999, 40, 1721. 9) C. Bolm; I. Schiffers; I. Atodiresei; C.P.R. Hackenberger, Tetrahedron: Asymmetry, 2003, 14, 3455.

COMMENTS :

446

447

DIELS – ALDER REACTION · 481 DIELS – REESE REACTION · 483

B

DIELS DEHYDRATION · 485 DIMROTH REARRANGEMENT · 486

BEYER’S MODIFICATION · 494

DIONNEAU METHOD · 487 DISCHE REACTION · 488 D

DJERASSI – RYLANDER OXIDATION · 489 DODDS – ROBINSON SYNTHESIS · 491

DAKIN – WEST REACTION · 449

DOEBNER – von MILLER SYNTHESIS · 492

DAKIN AZLACTONE REACTION · 451

DOEBNER MODIFICATION · 496

DAKIN OXIDATION OF BUTYRIC ACID · 452

DOEBNER QUINOLINE SYNTHESIS · 494

DAKIN PHENOL ALDEHYDE OXIDATION · 454

DOERING von – LA FLAMME – MOORE ALLENE SYNTHESIS ·

DANHEISER ANNULATION · 456

497

DANHEISER CYCLOPENTENE ANNULATION · 457

DONDONI HOMOGOLATION · 499

DANISHEFSKY REACTION · 459

DORNOW – WIEHLER ISOXAZOLE REACTION · 500

DARAPSKY AMINO ACID REACTION · 460

DÖTZ HYDROQUINONE SYNTHESIS · 502

DARZENS – ERLENMEYER – CLAISEN CONDENSATION · 462

DOUGLAS – FARAH REACTION · 504

DARZENS METHOD · 463

DOWD – BECKWITH REACTION · 506

DARZENS SYNTHESIS OF TETRALIN · 465

DOYLE – KIRMSE REACTION · 505

DAVID – THIEFFRY OXIDATION · 466

DREIDING – SCHMIDT REACTION · 508

DAVIDSON OXAZOLE SYNTHESIS · 467

DUFF REACTION · 509

DEACON REACTION · 468

DUTHALER – HAFNER ALLYLATION · 511

DEBUS – RADZISZEWSKI IMIDAZOLE SYNTHESIS · 469

DUTT – WORMALL REACTION · 512

DECKER – FORSTER AMINATION · 470 DELÉPINE AMINE SYNTHESIS · 471 H

DELÉPINE OXIDATION · 473 DEMJANOV REARRANGEMENT · 474

HOUSE – BABAD METHOD · 480

DEMOLE SYNTHESIS · 475 DESS – MARTIN PERIODINANE REACTION · 476 DIECKMANN – KOMPPA MODIFICATION · 480

W

DIECKMANN – MEISER SYNTHESIS · 479 DIECKMANN CONDENSATION · 480

WULFF CYCLISATION · 503

448

DAKIN – WEST REACTION EXAMPLE :

O H H3C

H3C

COOH 1) (CH3CO)2O pyridine 2) H2SO4

NH2

H

CH3 N

Ac

MECHANISM :

OH

H R

COOH

(CH3CO)2O - HAc

NH2

O H3C

H

CH3 N H

O H

O

CH3

O

H3C

OAc

pyridine

H

O

N

- OAc

H3C

N

N H

O O

CH3 O CH3

O O

N pyridine

Ac2O

O O

H3C

- OAc

O CH3

CH3 N

O OAc

O

O

CH3

O

N

CH3

R

CH3 H

H3C

O

H3C

H

O

O O

O

H N

O

O

H3C

O O OAc

OAc

O

N O

O

O

O CH3

O

N O

N

O

H

H O

N H - pyridine - CO2

O N H - pyridine

449

N

O CH3 CH3

- Ac2O

DISCONNECTION :

R H O

O

R

O

N

H3C

CH3 CH3

N H

O H

O

NOTES : Amino acids, when heated with aliphatic acid anhydrides under the catalytic influence of a base such as pyridine, undergo decarboxylative C-acylation with formation of the corresponding acylamino-ketones. The corresponding acyl halide may replace the anhydride. See also Dakin azlactone, Erlenmeyer – Plöchl and Kawase rearrangement reactions.

REFERENCES : March : 631 Smith – March : 812 Houben – Weyl : E8a, 927, 1006; E15, 678 Org. Synth. : 33, 1; 45, 1 Org. Synth. Coll. Vol. : 4, 5; 5, 27

1) P.A. Levene; R.E. Steiger, J. Biol. Chem., 1927, 74, 689. 2) H.D. Dakin; R. West, J. Biol. Chem., 1928, 78, 91. 3) H.D. Dakin; R. West, J. Biol. Chem., 1928, 78, 745. 4) H.D. Dakin; R. West, J. Biol. Chem., 1928, 78, 757. 5) J.W. Cornforth; D.F. Elliott, Science, 1950, 112, 534. 6) N.L. Allinger; G.L. Wang; B.B. Dewhurst, J. Org. Chem., 1974, 39, 1730. 7) G.L. Buchanan, Chem. Soc. Rev., 1988, 17, 91. 8) M. Kawase; M. Hirabayashi; H. Koiwai; K. Yamamoto; H. Miyamae, Chem. Commun., 1998, 641. 9) A.G. Godfrey; D.A. Brooks; L.A. Hay; M. Peters; J.R. McCarthy; D. Mitchell, J. Org. Chem., 2003, 68, 2623. 10) M.M. Khodaei; A.R. Khosropour; P. Fattahpour, Tetrahedron Lett., 2005, 46, 1949.

COMMENTS :

450

DAKIN AZLACTONE REACTION EXAMPLE :

O

H H

COOH NH2

1) (CH3CO)2O 2) NaOAc, PhCHO

O CH3

Ph

N

MECHANISM :

H3C COOH NH2 O H H H3C

H3C

O

O

H3C

H

OH CH3

+ O H

H

N NaOAc, PhCHO

N H

CH3

O

O O

Ph

H H

Ph N

H

O HO

Ph

H3C

HO

H

- HOAc

O

N - H2O

O H N

HO

O

N - H2O

O

H3C

O

O O

DISCONNECTION :

R

O

H O

N

R

H O

+

(R1CO)2O +

H

COOH NH2

R1

NOTES : A variant of the Erlenmeyer – Plöchl 5-oxazolone synthesis in which glycine is treated with one mole of acetic anhydride and then with an aldehyde, sodium acetate and more acetic anhydride. See also Dakin – West and Erlenmeyer – Plöchl reactions.

451

REFERENCES : 1) H.D. Dakin, J. Biol. Chem., 1929, 82, 439. 2) E. Baltazzi, J. Chem. Soc., Quat. Rev., 1955, 9, 153.

COMMENTS :

DAKIN OXIDATION OF BUTYRIC ACID EXAMPLE :

CH3CH2CH2CO2H

H3 C NH4OH, H2O2

452

CH3 O

MECHANISM :

COOH H3C

OH

H3C CH3CH2CH2COOH

H2O2

H2O2

HO

H H3C

COOH

H3C O

COOH

O

OH H3C

H3C

O

CH3

+ CO2

O

H H3C

CH3COOH

O

DISCONNECTION :

R

H

HO

OH

+ CO2 + H2O R

O

O

NOTES :

The ammonium salts of butyric, glycolic, lactic, α-oxybutyric, β-oxybutyric, α-oxyisovaleric acids are oxidised by hydrogen peroxide at 37 oC to yield aldehydes with exception of glycolic, β-oxybutyric and butyric acids.

REFERENCES :

1) H.D. Dakin, J. Biol. Chem., 1906, 1, 171. 2) H.D. Dakin, J. Biol. Chem., 1906, 1, 271. 3) H.D. Dakin, J. Biol. Chem., 1908, 4, 77. 4) H.D. Dakin, J. Biol. Chem., 1908, 4, 91.

453

COMMENTS :

DAKIN PHENOL ALDEHYDE OXIDATION EXAMPLE :

O HO

1) H2O2, HO2) hydrolysis

CH3

HO

OH

MECHANISM :

H+

OH OOH H2O2, H2O R

O HO

HO R

O HO O R O

- OOH

HO OOH O

O

R HO

HO

O

R

O

OH

OH

- RCOO

HO

OH

DISCONNECTION : HO O R

OH

R R = NH2, OH

R

NOTES :

The use of peroxide to replace an o- or p-formyl or –acetyl group in phenols or amines with a hydroxyl group. The amine or hydroxyl group must be ortho or para to the carbonyl group. The mechanism is essentially the same as for the von Baeyer – Villiger reaction. Some other unlikely mechanisms including a spirocyclic epoxide intermediate or phenoxide radical mechanism have been proposed. See also Böeseken – Ballio, Bohn – Schmidt, Boyland – Sims and Elbs persulfate oxidation reactions.

454

REFERENCES : March : 1184 Smith – March : 1528 Smith : 297 Smith 2nd : 261 Houben – Weyl : 7/1, 489 Org. Synth. : 3, 28; 26, 90 Org. Synth. Coll. Vol. : 1, 149; 3, 759

1) H.D. Dakin, Amer. Chem. J., 1909, 42, 477. 2) D.H. Rosenblatt; R.W. Rosenthal, J. Chem. Soc., 1918, 218. 3) R. Criegee, Liebigs Ann. Chem., 1948, 560, 127. 4) D.H. Rosenblatt; R.W. Rosenthal, J. Am. Chem. Soc., 1953, 75, 4607. 5) J.B. Lee; B.C. Uff, J. Chem. Soc., 1967, 21, 454. 6) M.B. Hocking; J.H. Ong, Can. J. Chem., 1977, 55, 102. 7) R.-G. Xie; L.-S. Deng; H.-Q. Gu; Y.-M. Fan; H.-M. Zhao, Steroids, 1982, 40, 389. 8) G.W. Kabalka; N.K. Reddy; C. Narayana, Tetrahedron Lett., 1992, 33, 865. 9) N.H. Kirsch; H.-J. Stan, Chemosphere, 1994, 28, 131. 10) R.S. Varma; K.P. Naicker, Org. Lett., 1999, 1, 189. 11) N.J. Lawrence; D. Rennison; M. Woo; A.T. McGown; J.A. Hadfield, Bioorg. Med. Chem. Chem. Lett., 2001, 11, 51. 12) J.L. Zambrano; R. Dorta, Synlett, 2003, 1545.

COMMENTS :

455

DANHEISER ANNULATION EXAMPLE :

SnBu3

OTIPS

SnBu3

1)

TIPSO

OTIPS

O benzene, reflux 2) TIPSOTf, Et3N

MECHANISM :

O

R2

R4

R3

R1 4e electrocyclic cleavage

O

R3 X

R1

R2 [2+2] cycloaddition

4e electrocyclic cleavage

R4

X

R3

R1 6e electrocyclic closure and tautomerisation

R2

R4

X

R3 R2

DISCONNECTION :

OH R1

R1

O

R2

R4 X R = OCH3, SCH3, NCH3 R1 = H, CH3, nHex, farnesyl R2 = H, CH3 R3 = CH3, nPr, Et, OEt, nBu R4 = H, CH3, Cl

R3

R4

+ R

R3 R2

X R2

OH

O R1

R4

R4

H+

456

O

R3

NOTES :

The one-step thermal combination of a heterosubstituted alkyne with a cyclobutenone derivative. The reaction proceeds via a cascade of four pericyclic reactions.

REFERENCES : Smith 2nd : 982

1) R.L. Danheiser; S.K. Gee, J. Org. Chem., 1984, 49, 1672. 2) R.L. Danheiser; S.K. Gee; J.J. Perez, J. Am. Chem. Soc., 1986, 108, 806. 3) R.W. Gleason; B.R. Dixon; R.L. Danheiser, J. Org. Chem., 1992, 57, 6094. 4) R.L. Danheiser; T. Takahashi; B. Bertok; B.R. Dixon, Tetrahedron Lett., 1993, 34, 3845. 5) A.B. Smith III; C.M. Adams; S.A. Kozmin; D.V. Paone, J. Am. Chem. Soc., 2001, 123, 5925.

COMMENTS :

DANHEISER CYCLOPENTENE ANNULATION EXAMPLE : PhMe2Si

SiMe2Ph SiMe2

O +

1.5 TiCl4 DCM, - 78 oC

457

O

SiMe2

MECHANISM :

Cl Cl3Ti

O

O

SiMe3 +

SiMe3

TiCl4, DCM - 78 oC Cl3Ti

Cl3Ti

O

- Cl-

SiMe3

O SiMe3

1,2-shift

Cl Cl3Ti

O

O

SiMe3 SiMe3

NOTES :

In the presence of a Lewis acid an α,β-unsaturated ketone reacts with an alkylsilylallene to afford an alkylsilyl cyclopentene.

REFERENCES : Org. Synth. : 66, 8 Org. Synth. Coll. Vol. : 8, 347

1) R.L. Danheiser; D.J. Carini; A. Basak, J. Am. Chem. Soc., 1981, 103, 1604. 2) R.L. Danheiser; D.J. Carini; D.M. Fink; A. Basak, Tetrahedron, 1983, 39, 935. 3) T.A. Engler; K. Agrios; J.P. Reddy; R. Iyengar, Tetrahedron Lett., 1996, 37, 327. 4) J.C. Friese; S. Krause; H.J. Schafer, Tetrahedron Lett., 2002, 43, 2683.

COMMENTS :

458

DANISHEFSKY REACTION EXAMPLE :

O

O

TMSO

O + OCH3

O

O

H+, THF H3CO

O

H

O

MECHANISM :

OCH3

OCH3

N

TMSO

H3C

H +

O TMS

Ph

H3CO

Ph

Ph

Ph

OTMS

N

O

Ph

H3CO

O

N

O

CH3 O

TFA

OTMS

H3C

DISCONNECTION :

OCH3

OCH3 X RO

X R1 R2

+ TMSO

OCH3 R3 TMSO OCH3 R3 R4

R1

R3

OCH3 +

RO

R2

OCH3 +

RO

R3

R4

TMSO

R = TMS; X = O, NH, NR; R1 = alkyl, aryl; R2 = H, alkyl; R3,R4 = alkyl, aryl, EWG

459

Ph

O

NOTES :

The use of trans-4-methoxybutene-2-one as the diene (Danishefsky diene), giving both high reactivity and high orientational specificity in reactions with unsymmetrical dienophiles, where Y is an electron withdrawing group. There is a step-wise pathway proposed, this is often referred to as Mukaiyama aldol reaction pathway. See also Diels – Alder and Wagner–Jauregg reactions.

REFERENCES : March : 839 Smith – March : 1062 Smith : 1113, 1130 Smith 2nd : 928 Org. Synth. : 61, 147 Org. Synth. Coll. Vol. : 7, 312

1) S.J. Danishefsky; T. Kitahara, J. Am. Chem. Soc., 1974, 96, 7807. 2) S.J. Danishefsky; T. Kitahara; C.F. Yan; J. Morris, J. Am. Chem. Soc., 1979, 101, 6996. 3) S.J. Danishefsky; C.F. Yan; R.K. Singh; R.B. Gammill; P. McMurry; N. Fritsch; J.C. Clardy, J. Am. Chem. Soc., 1979, 101, 7001. 4) S.J. Danishefsky, Acc. Chem. Res., 1981, 14, 400. 5) L. Leveque; M. Le Blanc; R. Pastor, Tetrahedron Lett., 1997, 38, 6001. 6) Y. Yuan; X. Li; K. Ding, Org. Lett., 2002, 4, 3309. 7) M. Shi; S.-C. Cui; Q.-J. Li, Tetrahedron, 2004, 60, 6163. 8) C. Wolf; Z. Fadul; P.A. Hawes; E.C. Volpe, Tetrahedron: Asymmetry, 2004, 15, 1987.

COMMENTS :

DARAPSKY AMINO ACID REACTION EXAMPLE :

COOEt CN

NH2 1) NH2NH2 2) HNO2 3) EtOH 4) aq. HCl

460

COOH

MECHANISM :

O

O

CN

OEt NH2NH3

- EtOH

CN

O N H

NH2

N3 HNO2 H N

N O

CN

heat - N2

CN

EtOH

CN

O OEt

H2O, H+

NH2 COOH

DISCONNECTION :

R

CN

COOH H NH2

R

H NH2

NOTES :

Ethyl alkylcyanoacetate is converted into acylazide via the hydrazide. The azide is treated with alcohol and the resulting cyanourethane hydrolysed to the corresponding α-amino acid. The alkyl cyanoacetate is conveniently prepared by the condensation of ethyl cyanoacetate with an aldehyde to give the corresponding alkylidene compound which is simultaneously hydrogenated. Many amino acids have been prepared this way.

REFERENCES :

1) A. Darapsky; D. Hillers, J. Prakt. Chem., 1915, 92, 297. 2) A. Darapsky, J. Prakt. Chem., 1936, 146, 250. 3) P.E. Gagnon; R. Gaudry; F.E. King, J. Chem. Soc., 1944, 13. 4) P.E. Gagnon; J.L. Boivin, Can. J. Res. B, 1948, 26, 503. 5) P.E. Gagnon; P.A. Boivin; H.M. Craig, Can. J. Chem., 1951, 29, 70.

COMMENTS :

461

DARZENS – ERLENMEYER – CLAISEN CONDENSATION EXAMPLE :

H3C

CH3

Cl

OEt

Cl

O

CH3 H

+

O

H

Et2O, base

CH3 O

MECHANISM :

R1

R1

O

O

O

X

X H

OEt

OEt

R

O R1

O

R X

OEt

R

R

B O

O

R

R OEt

R

R1

O

O

O H

- OEt

R

OH

R1

H+, - CO2

H

O

R

R1

R

DISCONNECTION :

Y

R2 R3

R1 EWG

X

EWG R1

Y +

R2

R3

R1 = alkyl, aryl; X = Br, Cl, I; EWG = CO2R, CN, SO2R, CONR2, C(=O), C(=NR) R2 = alkyl, aryl, H; R3 = alkyl, aryl; Y = O, NR

NOTES :

Ethyl dichloroacetate combines with aldehydes and ketones in the presence of base to yield an α-chloro-βhydroxyester. (The initial step is a Knoevenagel-type reaction.) This can be converted into a glycidic ester or an αchloro acrylic ester. Enantioselective Darzens reactions are also known. The reaction can be carried out on α-halo ketones, α-halo nitriles, α-halo sulfoxides, α-halo sulfones, α-halo N,N-disubstituted amides and α-halo-ketimines. See also Arndt – Eistert, Büchner – Curtius – Schlotterbeck, Clibbens – Nierenstein, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew, Shi, Weitz – Scheffer and Wolff reactions.

REFERENCES : March : 954 Smith – March : 809, 1219 Smith : 902

462

Smith 2nd : 753 Houben – Weyl : 6/3, 406; 7/1, 326; 8, 513; E6a, 49; E14b, 1194 Org. React. : 5, 413; 31, 1 Org. Synth. : 24, 82; 34, 54 Org. Synth. Coll. Vol. : 3, 727; 4, 459

1) E. Erlenmeyer, jr., Liebigs Ann. Chem., 1892, 271, 137. 2) G. Darzens, C.R. Séances Acad. Sci., 1904, 139, 1214. 3) L. Claisen, Ber. Dtsch. Chem. Ges., 1905, 38, 693. 4) M. Ballester, Chem. Rev., 1955, 55, 283. 5) V.F. Martynoff; M.I. Titov, J. Gen. Chem. USSR, 1960, 30, 4072. 6) C.R. Johnson; T.R. Bade, J. Org. Chem., 1982, 47, 1205. 7) R. Annunziata; S. Banfi; S. Colonna, Tetrahedron Lett., 1985, 26, 2471. 8) E.J. Corey; S.Y. Choi, Tetrahedron Lett., 1991, 32, 2857. 9) K. Ohkata; J. Kimura; Y. Shinohara; R. Takagi; Y. Hirago, Chem. Commun., 1996, 2411. 10) S. Arai; T. Shioiri, Tetrahedron Lett., 1998, 39, 2145. 11) K. Tanaka; R. Shiraishi, Green Chem., 2001, 3, 135. 12) S. Arai; T. Shioiri, Tetrahedron, 2002, 58, 1407. 13) M. Mamaghani; K. Tabatabaeian; A. Ghanadzadeh; F. Habibi, Tetrahedron Lett., 2003, 44, 4775. 14) Z. Wang; L. Xu; Z. Mu; C. Xia; H. Wang, J. Mol. Catal. A: Chem., 2004, 218, 157.

COMMENTS :

DARZENS METHOD EXAMPLE :

CH3 H3C

CH3 OH SOCl2 Pyridine

463

H3C

Cl

MECHANISM :

Cl CH3

H3C HO Cl

H S O

CH3 H3C H O

Cl

H3C H3C

H Cl

H O

S Cl O

H

S O

Cl

- SO2, - HCl

CH3

H3C H

Cl

DISCONNECTION :

R Cl

R OH

R Br

NOTES :

An alcohol is treated with thionyl chloride or thionyl bromide in the presence of a tertiary base. See also Appel, Blum and Landauer – Rydon reactions.

REFERENCES : March : 327 Smith – March : 518 Smith : 151 Smith 2nd : 122 Org. Synth. : 12, 20; 14, 18; 25, 84; 31, 37; 36, 3; 53, 13, 70 Org. Synth. Coll. Vol. : 2, 136, 159; 3, 698; 4, 169, 333; 6, 75, 781

1) G.C. Darzens, C.R. Séances Acad. Sci., 1911, 152, 1314. 2) G.C. Darzens, C.R. Séances Acad. Sci., 1911, 152, 1601. 3) W. Gerrard, J. Chem. Soc., 1939, 99. 4) W. Gerrard; H.R. Hudson, J. Chem. Soc., 1963, 1059. 5) F. Mohanazadeh; A.R. Momeni, Org. Prep. Proced. Int., 1996, 28, 492. 6) F.E. Ziegler; R.X. Kover; N.N.K. Lee, Tetrahedron Lett., 2000, 41, 5155.

COMMENTS :

464

DARZENS SYNTHESIS OF TETRALIN EXAMPLE : COOH

COOH 1) H2SO4 2) heat CH3

MECHANISM :

COOH

COOH

COOH

heat

H2SO4

CH3

DISCONNECTION :

NOTES :

A method for the synthesis of tetralin and other tetrahydro-aromatic carboxylic acids. The reaction is typified by the cyclo-isomerisation of allylbenzylacetic acid using sulfuric acid. See also Bardhan – Sengupta and Bogert – Cook reactions.

REFERENCES : Smith : 1332 Smith 2nd : 1096

1) G. Darzens, C.R. Séances Acad. Sci., 1926, 183, 748. 2) J.W. Cook; C.L. Hewett, J. Chem. Soc., 1933, 1098. 3) E. Bergmann, Chem. Rev., 1941, 29, 529. 4) J.N. Chatterjea; S. Lal; U. Jha; J. Carnduff, Indian J. Chem., 1981, 20B, 264.

COMMENTS :

465

DAVID – THIEFFRY OXIDATION EXAMPLE :

H3C

O

HO

Bn O

OCH3 FMOC N Et

O

O

H3C O

1) nBu2SnO, MeOH reflux, Br2 2) nBu3SnOCH3, DCM

OH

O

Bn O

OCH3 FMOC N Et

O

O

OH

MECHANISM :

R2

R2 R1 H

OH OH R

n

R1 H

Bu2SnO MeOH

R2

O SnBu2 O

+ n Br2

R1 R

R

OH

- n SnBu2Br2 O

n

DISCONNECTION :

R2 R1 R

R2 OH

R1 H

O

OH OH R

NOTES :

The oxidation of a sugar diol to a hydroxyl and a carbonyl. nBu3SnOCH3 is used to quench the HBr formed. The bromine oxidises the oxygen-tin bond to give the carbonyl. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones

oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES :

1) J.C. Pommier; M. Ratier; D. Chevolleau, J. Organomet. Chem., 1971, 31, C59. 2) S. David; A. Thieffry, C.R. Séances Acad. Sci., 1974, 279, 1045. 3) S. David; A. Thieffry, J. Chem. Soc., Perkin Trans. 1, 1979, 1568. 4) S. David; A. Thieffry; A. Veyrieres, J. Chem. Soc., Perkin Trans. 1, 1981, 1796. 5) S. David; A. Thieffry, Tetrahedron Lett., 1981, 22, 2885. 6) A.B.C. Simas; K.C. Pais; A.A.T. da Silva, J. Org. Chem., 2003, 68, 5426.

466

COMMENTS :

DAVIDSON OXAZOLE SYNTHESIS EXAMPLE :

CH3

O H

CH3

O

N

O O

1) CH3CO2NH4 2) KOH 3) heat

MECHANISM :

H+

OH

H3C

H3C

O

O

O

EtO

CH3

CH3CO2NH4

OEt

H3C - 2 H2O

EtO

O

O

NH2 CH3 O OH

EtO

N CH3

O

H3C O

aq. KOH

H3C

N

HOOC

O

CH3

O heat - CO2 CH3CO2NH4

H3C

N CH3 O

HO Cl

CH3 O

HCO2NH4

H3C

OEt

467

O

OH H N H

O

CH3

OH

DISCONNECTION :

R N R1

R2

OH

R1

O

O

O R2

R

NOTES :

o-Acyloins when treated with ammonium acetate in acetic acid give oxazole derivatives. See also Fischer oxazole, Japp oxazole and Robinson – Gabriel reactions.

REFERENCES :

1) D. Davidson; M. Weiss; M. Jelling, J. Org. Chem., 1937, 2, 319. 2) R.H. Wiley, Chem. Rev., 1945, 37, 401. 3) G. Theilig, Chem. Ber., 1953, 86, 96. 4) A. Gürsoy; S. Demirayak; G. Çapan; K. Erol; K. Vural, Eur. J. Med. Chem., 2000, 35, 359.

COMMENTS :

DEACON REACTION EXAMPLE :

2 HCl + .5 O2

Cu-salts

H2O + Cl2

MECHANISM :

CuCl2 + .5 O2

CuO + Cl2

CuO + 2 HCl

CuCl2 + H2O

468

NOTES :

Hydrogen chloride is oxidised with oxygen in the presence of copper salts to chlorine. Other catalysts can also be used.

REFERENCES :

1) A. Wehrmeier; D. Lenoir; S.S. Sidhu; P.H. Taylor; W.A. Rubey; B. Dellinger, Environ. Sci. Technol., 1998, 32, 2741. 2) K. Olie; R. Addink; M. Schoonenboom, J. Air & Waste Manage. Assoc., 1998, 48, 101.

COMMENTS :

DEBUS – RADZISZEWSKI IMIDAZOLE SYNTHESIS EXAMPLE :

H3C

CH3

H3C

H N

H3C

N

+ NH3 + PhCHO O

Ph

O

MECHANISM :

H+ O H3N H3C O

H

NH3

Ph H2N H3C HO

CH3 O

OH Ph

NH2 CH3 OH

H

H2N

N H

H3C HO

CH3 OH

- 3 H2O

DISCONNECTION :

R

H N

R

R1

R2 R1

N

O

469

O

+ NH3 + R2CHO

H3C

H N

H3C

N

Ph

NOTES :

This reaction is one of a number of similar imidazole syntheses. The Debus – Radziszewski reaction forms the imidazole ring by condensing α-dicarboxylic compounds with aldehydes and ammonia. There are two modifications by Weidenhagen and Maquenne, each using slightly different conditions. See also Akabori – Neuberg – Fischer, Brackeen, Bredereck, Maquenne, Wallach imidazole and Weidenhagen reactions.

REFERENCES : Houben – Weyl : E8c, 9, 13, 97

1) H. Debus, Liebigs Ann. Chem., 1858, 107, 199. 2) B. Radziszewski; L. Szul, Ber. Dtsch. Chem. Ges., 1884, 17, 1291. 3) S. Balalaie; M.M. Hashemi; M. Akhbari, Tetrahedron Lett., 2003, 44, 1709. 4) N. Kuhn; G. Henkel; J. Kreutzberg, Z. Naturforsch. B, 1991, 46, 1706. 5) J.L. Harper; R.A. Smith; J.J. Bedford; J.P. Leader, Tetrahedron, 1997, 53, 8211.

COMMENTS :

DECKER – FORSTER AMINATION EXAMPLE :

t

But

Bu-NH2 + PhCHO

CH3I

N H

CH3

MECHANISM :

H2N R H

H - H2O

O H+

H

N

R H2O

N H R1

+ PhCHO + HI

470

R R1I

R

N H

R1 I

DISCONNECTION :

R1

R N

R-NH2 + R1-I

H

NOTES :

The conversion of a primary amine to a secondary amine by condensation with an aldehyde, followed by the addition of alkyl halide to a Schiff’s base and followed by subsequent hydrolysis. See also Eschweiler – Clarke, Henze – Humphries, Leuckart and Schiff reactions.

REFERENCES : Houben – Weyl : 11/1, 108, 956; E14b, 994, 1129 Org. Synth. : 44, 72 Org. Synth. Coll. Vol. : 5, 736

1) M.O. Forster, J. Chem. Soc., 1899, 75, 934. 2) H. Decker; P. Becker, Liebigs Ann. Chem., 1913, 395, 362. 3) A.L. Morrison; H. Rinderknecht, J. Chem. Soc., 1950, 1478. 4) Y.B. Wang; Q.G. Du; J.L. Huang, Mac. Mol. Rap. Commun., 1998, 19, 247.

COMMENTS :

DELÉPINE AMINE SYNTHESIS EXAMPLE :

H3C CH2I +

N

N N

N

1) CHCl3 2) HCl, EtOH 3) H2O, NaOH

471

H3C

NH2

MECHANISM :

N R CH2I +

N

N

N

R

3 HCl, EtOH 6 H2O

R

CHCl3

NH3 I

NC6H12N3 I

+

6 CH2O + 3 NH4Cl

NaOH

R

NH2

DISCONNECTION :

R NH2

R CH2X X = Cl, Br, I

NOTES :

Organic halides with hexamethylenetetramine form quaternary compounds, which on treatment with ethanolic hydrogen chloride yield primary amines. See also Gabriel and Sommelet aldehyde reactions.

REFERENCES : Houben – Weyl : E16d, 713 Org. React. : 8, 197 Org. Synth. : 43, 6 Org. Synth. Coll. Vol. : 5, 121

1) M. Delépine, C.R. Séances Acad. Sci., 1895, 120, 501. 2) N.L. Wendler, J. Am. Chem. Soc., 1949, 71, 375. 3) N. Blazevic; D. Kolbah; B. Belin; V. Sunjic; F. Kafjez, Synthesis, 1979, 161. 4) R.A. Henry; R.A. Hollins; C. Lowe–Ma; D.W. Moore; R.A. Nissan, J. Org. Chem., 1990, 55, 1796.

COMMENTS :

472

DELÉPINE OXIDATION EXAMPLE :

O

O

HO H H3CO

HO

Ag2O aq. NaOH

OH H3CO

MECHANISM :

O

O R

H

R

Ag2O aq. NaOH

OH

+ 2 Ag

DISCONNECTION :

R

R COOH

H O

NOTES :

The use of silver oxide in the presence of alkali for the oxidation of aldehydes to acids. Under similar conditions with acetic acid and phosphoric acid aromatic hydrocarbons can be oxidised to the corresponding aldehydes and ketones. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama

oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : Smith : 254 Smith 2nd : 218 Org. Synth. : 30, 101; 33, 94; 36, 36 Org. Synth. Coll. Vol. : 4, 493, 919, 972

473

1) M. Delépine; P. Bonnet, Bull. Soc. Chim. Fr., 1909, 5, 879. 2) F. Asinger, Ber. Dtsch. Chem. Ges., 1942, 75, 656. 3) R.N. Hammer; J. Klemberg, Inorg. Synth., 1953, 4, 12. 4) L. Syper, Tetrahedron Lett., 1967, 8, 4193. 5) S.C. Thomason; D.G. Kubler, J. Chem. Educ., 1968, 45, 546.

COMMENTS :

DEMJANOV REARRANGEMENT EXAMPLE :

OH NH2 1) HNO2 2) H2O

MECHANISM :

N

1) HNO2 2) H+ - HONO, - H2O OH H2O

H

N

NH2

CH2

- N2

OH +

+

OH

DISCONNECTION :

NH2 n

n

NOTES :

This rearrangement by diazotation frequently occurs when a primary amine is treated with nitrous acid and proceeds as shown. Ring expansion or contraction occurs with cyclic amines. See also Balz – Schiemann, Cadogan arylation,

474

Craig exchange, Gattermann diazo, Gattermann sulphinic acid, Godchot – Mousseron, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten, Tiffeneau – Demjanov rearrangement, Wagner – Meerwein and Witt diazotation reactions.

REFERENCES : March : 1074 Smith – March : 1398 Smith : 1293 Smith 2nd : 1067 Houben – Weyl : E19b, 389; E19c, 404 Org. React. : 11, 157

1) E. Linnemann, Liebigs Ann. Chem., 1867, 144, 129. 2) N.J. Demjanov; M. Lushnikov, J. Russ. Physik. Chem. Ges., 1903, 35, 26. 3) P.A.S. Smith; D.R. Baer; S.N. Ege, J. Am. Chem. Soc., 1954, 76, 4564. 4) R. Kotani, J. Org. Chem., 1965, 30, 350. 5) Z. Ou; Z. Chen; O. Jiang, Kexue Tongbao (Foreign Language Edition), 1987, 32, 462. 6) A.G. Stern; A. Nickson, J. Org. Chem., 1992, 57, 5342. 7) D. Fattori; S. Henry; P. Vogel, Tetrahedron, 1993, 49, 1649.

COMMENTS :

DEMOLE SYNTHESIS EXAMPLE :

H

H

Br

Br

O2

475

H

O

Br

Br

DISCONNECTION :

R1

R2

R2

O

R1

R1

R1

R1

R2

R2

R2

O

R1

R2

NOTES :

Di-, tri- and tetrahalogenated ethylenes are autoxidised to halogenated acids with wandering of a proton. The mechanism is not fully understood, initial formation of the epoxide has been proposed.

REFERENCES :

1) E. Demole, Ber. Dtsch. Chem. Ges., 1878, 11, 315. 2) E. Demole; H. Dürr, Ber. Dtsch. Chem. Ges., 1878, 11, 1302. 3) E. Demole, Ber. Dtsch. Chem. Ges., 1878, 11, 1307. 4) F. Swarts, Bull. Acad. Roy. Belg., 1901, 383. 5) E. Erdmann, J. Prakt. Chem., 1912, 85, 78. 6) N. Prileschajew, Ber. Dtsch. Chem. Ges., 1926, 59, 194. 7) R.N. Haszeldine; F. Nyman, J. Chem. Soc., 1959, 1084. 8) H. Cohn; E.D. Bergmann, Isr. J. Chem., 1964, 2, 355.

COMMENTS :

DESS – MARTIN PERIODINANE REACTION EXAMPLE :

H3CO

CH2OH +

AcO OAc I OAc O

O H3CO

H

H3CO

H3CO OCH3

O

OCH3

476

MECHANISM :

O

I COOH

I

O

KBrO3 H2SO4

AcO OAc I OAc O

OH Ac2O

O

O

O

AcO OAc I OAc O

SPh OH +

O AcO I O OAc H PhS

H+

CH3 O

O

O OAc I O + 2 HOAc

SPh O

+

O

DISCONNECTION :

O R

R

H

OH

NOTES :

The oxidation of alcohols to aldehydes or ketones using periodinanes. The aryliodo ester is formed from the Dess – Martin reagent and the alcohol. This ester undergoes a β-elimination and forms the aldehyde. Basic work-up removes

the aryliodo compound. The addition of one equivalent of water has been found to accelerate the reaction. This reagent can furthermore induce cyclisation reactions and has been used for the removal of thioacetals and thioketals. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : Smith – March : 1516 Smith : 241 Smith 2nd : 209 Houben – Weyl : E10b2, 39 Org. React. : 53, 1

477

Org. Synth. : 77, 141 Org. Synth. Coll. Vol. : 10, 2377

1) P.B. Dess; J.C. Martin, J. Am. Chem. Soc., 1978, 100, 300. 2) P.B. Dess; J.C. Martin, J. Org. Chem., 1983, 48, 4155. 3) V. Samano; M.J. Robins, J. Org. Chem., 1990, 55, 5186. 4) P.J. Stang; V.V. Zhdankin, Chem. Rev., 1996, 96, 1123. 5) A. Speicher; V. Bomm; T. Eicher, J. Prakt. Chem., 1996, 338, 588. 6) T. Kitamura; Y. Fujiwara, Org. prep. Proced. Int., 1997, 29, 409. 7) K.-Y. Akiba, Chemistry of Hypervalent Compounds, 1999, 9. 8) D.S. Bose; A.V. Narsaiah, Synth. Commun., 1999, 29, 937. 9) K.C. Nicolaou; Y.L. Zhong; P.S. Baran, Angew. Chem., Int. Ed., 2000, 39, 622. 10) S.S. Chaudhari, Synlett, 2000, 278. 11) V.V. Zhdankin; P.J. Stang, Chem. Rev., 2002, 102, 2523. 12) N.F. Langille; L.A. Dakin; J.S. Panek, Org. Lett., 2003, 5, 575.

COMMENTS :

478

DIECKMANN – MEISER SYNTHESIS EXAMPLE :

O CO2CH3

O

CH2CO2CH3

1) Na, O

H3CO 2) H+ 3) heat

MECHANISM :

CO2CH3

CO2CH3 base

CH2CO2CH3 O

O

OCH3 OH H CO2CH3

CH3OCOH NaOCH3

CHCO2CH3

O O

O heat

- HOCH3 CO2CH3

DISCONNECTION :

O

O R1 R

R1

O

R, R1 = H, OCH3 R R2 = CH3, Et

OCH3 CH2CO2R2

NOTES :

Isocoumarins devoid of substituents in the 3- and 4-position are obtained by the base-catalysed condensation of ethyl formate with an ester of homophthalic acid. The resulting hydroxymethylene derivative is cyclised and the carbomethoxy group in the 4-position is eliminated, e.g. by heat.

REFERENCES :

1) W. Dieckmann; W. Meiser, Ber. Dtsch. Chem. Ges., 1908, 41, 3253. 2) H.W. Johnston; C.E. Kaslow; A. Langsjoen; R.L. Shriner, J. Org. Chem., 1948, 13, 477. 3) A. Kamal; A. Robertson; E.T. Tittensor, J. Chem. Soc., 1950, 3375.

479

COMMENTS :

DIECKMANN CONDENSATION EXAMPLE : O O

O

OCH3

OCH3

H3CO O

Na, THF trace MeOH

MECHANISM :

H

O O O R O

R O

O base

O

O R O

O R1

O R1

- OR1

H

O O O

R

O R1

DISCONNECTION :

O

O

OEt OEt

OEt H

O

O

NOTES :

Esters having hydrogen on the δ- or ε-carbon atom, which is activated by a carbonyl group undergo base-catalysed intramolecular Claisen – Geuther condensation. The Dieckmann – Komppa modification is the condensation between oxalic acid esters and the esters of glutamic acid, followed by the cyclisation to produce α-diketones. The House – Babad method uses phosphonium salts to synthesis cyclic ketones. Solvent-free conditions have also been

reported in the literature. See also Claisen – Geuther reaction.

REFERENCES : March : 492, 1228 Smith – March : 569

480

Smith : 895 Smith 2nd : 749 Houben – Weyl : 8, 574; E6a, 252, 312; E6b, 1212; E7a, 319; 1994, E8b, 518 Org. React. : 1, 1; 6, 410; 15, 1 Org. Synth. : 57, 1; 66, 52 Org. Synth. Coll. Vol. : 6, 167; 8, 112 Science of Synthesis : 9, 314, 318; 10, 58, 166, 281, 673

1) W. Dieckmann, Ber. Dtsch. Chem. Ges., 1894, 27, 102. 2) W. Dieckmann, Ber. Dtsch. Chem. Ges., 1894, 27, 965. 3) B.S. Thyagarajan, Chem. Rev., 1954, 54, 1019. 4) H.O. House; H. Babad, J. Org. Chem., 1963, 28, 90. 5) D.K. Banerjee, Proc. Indian Acad. Sci. Sect. A., 1974, 79, 282. 6) G. Nee; B. Tchoubar, Tetrahedron Lett., 1979, 20, 3717. 7) J.I. Crowley; H. Rapoport, J. Org. Chem., 1980, 45, 3215. 8) M. Patch, Coll. Czech. Chem. Commun., 1990, 55, 1223. 9) S.McN. Sieburth; C.-A. Chen, Synlett, 1995, 928. 10) R. Lin; J. Castells; H. Rapoport, J. Org. Chem., 1998, 63, 4069. 11) F. Toda; T. Suzuki; S. Higa, J. Chem. Soc., Perkin Trans. 1, 1998, 3521. 12) I. Shinohara; M. Okue; Y. Yamada; H. Nagaoka, Tetrahedron Lett., 2003, 44, 4649. 13) A.M. Montaña; F. García; C. Batalla, Tetrahedron Lett., 2004, 45, 8429. 14) S. Sano; H. Shimizu; Y. Nagao, Tetrahedron Lett., 2005, 46, 2883.

COMMENTS :

DIELS – ALDER REACTION EXAMPLE :

+

481

MECHANISM :

DISCONNECTION :

R6 R7

R4

R4 R5R 1

R6

R R2

R5 R8

R7

R8 R9R3

R1

R

R2

R3

+

R9

NOTES :

This reaction, of which there are many variations, involves the addition of a compound containing a double or triple bond (dienophile) across the 1,4-positions of a conjugated system (diene), with the formation of a six membered ring. See also Boger – Panek, Bradsher cycloaddition, Carboni – Lindsey, Corey – Nicolaou, Danishefsky, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wagner–Jauregg, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 839 Smith – March : 1062 Smith : 1113, 1130 Smith 2nd : 928 Houben – Weyl : E3, 639; E5, 428, 772; E8a, 449, 786, 1007, 1010; E16a, 319; E19c, 85 Org. React. : 4, 1; 5, 136; 32, 1; 52, 1; 53, 223 Org. Synth. : 17, 25; 30, 93; 43, 27; 46, 44; 48, 68; 49, 1; 50, 24, 36, 43; 53, 48; 58, 163; 59, 71; 60, 41; 61, 147; 62,

149; 65, 32, 98; 66, 142; 68, 198, 206; 69, 31; 71, 30, 181; 72, 86; 73, 253; 77, 254; 78, 160, 202 Org. Synth. Coll. Vol. : 2, 102; 4, 890; 5, 96, 424, 459, 604; 6, 82, 196, 422, 445, 454, 496; 7, 4, 312, 485; 8, 31,

173, 298, 353, 444, 597; 9, 67; 186, 396, 722; 10, 2390, 2621, 2625 Science of Synthesis : 1, 57, 519, 990; 9, 54, 130, 222, 258, 328; 10, 61, 87, 107, 147, 167, 193, 231, 243, 245,

303, 344, 474, 587, 700, 703, 813, 827

1) O. Diels; K. Alder, Liebigs Ann. Chem., 1928, 460, 98.

482

2) J.A. Norton, Chem. Rev., 1942, 31, 319. 3) J.G. Martin; R.K. Hill, Chem. Rev., 1961, 61, 537. 4) S.B. Needleman; M.C. Chanz Kuo, Chem. Rev., 1962, 62, 405. 5) G. Brieger; J.N. Bennett, Chem. Rev., 1980, 80, 63. 6) R.L. Funk; K.P.C. Vollhardt, Chem. Soc. Rev., 1980, 9, 41. 7) A.J. Fatiadi, Synthesis, 1987, 749. 8) L.F. Tietze; U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131. 9) M.A. Maier; C. Perez, Synlett, 1998, 159. 10) K.A. Ahrendt; C.J. Borths; D.W.C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243. 11) L. Trembleau; L. Patiny; L. Ghosez, Tetrahedron Lett., 2000, 41, 6377. 12) E.J. Corey, Angew. Chem., Int. Ed., 2002, 41, 1651.

COMMENTS :

DIELS – REESE REACTION EXAMPLE :

CO2Me N H N H

N H

+

N CO2Me MeO2C

483

CO2Me

MECHANISM :

O H3CO

+

CO2Me

H +

H

N N

N N H

OCH3

H H

CO2Me

O

Ph N N Ph

AcOH - CH3OH

O

O

H3CO

pyridine xylene - PhNH2

O

O

OMe H

OCH3

N

OCH3 N H

N

O

Ph

OH

DISCONNECTION :

O H3CO Ph N N Ph O

O

OCH3

CO2Me

OCH3 N H O

+

N N

O

H

H

CO2Me

OMe H N N

Ph

OH

NOTES :

Dimethyl acetylenedicarboxylate reacts with hydrazobenzenes to yield an adduct which can be cyclised, under suitable conditions, to heterocyclic compounds.

REFERENCES :

1) O. Diels; J. Reese, Liebigs Ann. Chem., 1934, 511, 168.

484

2) O. Diels; J. Reese, Liebigs Ann. Chem., 1935, 519, 147. 3) E.H. Huntress; J. Bornstein; W.M. Hearon, J. Am. Chem. Soc., 1956, 78, 2225.

COMMENTS :

DIELS DEHYDRATION EXAMPLE :

H H

H

Se powder

HO

NOTES :

The compound to be dehydrated is heated with finely divided selenium. All the dehydrated compounds e.g. cholesterol, hormones, vitamins form γ-methylcyclopentenophenanthrene.

REFERENCES :

1) O. Diels; W. Gädke, Ber. Dtsch. Chem. Ges., 1925, 58, 1231. 2) O. Diels; W. Gädke, Ber. Dtsch. Chem. Ges., 1927, 60, 140. 3) O. Diels; A. Karstens, Ber. Dtsch. Chem. Ges., 1927, 60, 2323. 4) O. Diels; W. Gädke; P. Körding, Liebigs Ann. Chem., 1927, 459, 1. 5) O. Diels; A. Karstens, Liebigs Ann. Chem., 1930, 478, 129. 6) O. Diels, Ber. Dtsch. Chem. Ges., 1936, 69A, 195.

COMMENTS :

485

DIMROTH REARRANGEMENT EXAMPLE :

N N

N

+ EtI NaOH, heat

NH2

N

N H

Et

MECHANISM :

N + CH3I N

N NH2 CH3 I

NH2

O

HN NH2 CH3

Rotation around O C=C bond

warm aq. NaOH

H

H2N

N CH3

O H

NH2 N CH3

N NaOH, heat N

N H

CH3

DISCONNECTION :

N N

N N H

R R = Alk, Ar

N

+ RI NH2

NOTES :

The migration of an alkyl or aryl group from a heterocyclic to an exocyclic nitrogen atom. The reaction has been modified by Katritzky et al. Some authors also include the translocation of heteroatoms within rings of fused systems as a type 1 Dimroth rearrangement.

REFERENCES : Houben – Weyl : E7b, 453; E8a, 337; 784; E8c, 184; E8d, 90, 134, 190, 210, 289, 346

1) O. Dimroth, Liebigs Ann. Chem., 1909, 364, 183. 2) D.J. Brown, Mech. Mol. Migr., 1968, 1, 209. 3) G. L’Abbe, Ind. Chim. Belge, 1971, 36, 3.

486

4) D. Korbonits; P. Kolonits, J. Chem. Soc., Perkin Trans. 1, 1986, 2163. 5) T. Saito; H. Hayashibara; Y. Kumazawa; T. Fujisawa; T. Fuji, Heterocycles, 1990, 31, 1593. 6) A.R. Katritzky; F.-B. Ji; W.-Q. Fan; J.K. Gallos; J.V. Greenhill; R.W. King; P.J. Steel, J. Org. Chem., 1992, 57, 190. 7) A.R. Pagano; H. Zhao; A. Shallon; R.A. Jones, J. Org. Chem., 1998, 63, 3213. 8) E.S.H. El Ashry; Y. El Kilany; N. Rashed; H. Assafir, Adv. Heterocycl. Chem., 2000, 75, 79. 9) R.W. Fischer; M. Misun, Org. Proc. Res. Dev., 2001, 5, 581. 10) J.T. Anders; H. Görls; P. Langer, Eur. J. Org. Chem., 2004, 9, 1897. 11) P.K. Atanassov; A. Linden; H. Heimgartner, Helv. Chim. Acta, 2004, 87, 1873.

COMMENTS :

DIONNEAU METHOD EXAMPLE :

EtO(CH2)6OEt

1) HBr 2) NaI 3) Mg 4) EtOCH2I

EtO(CH2)7OEt

MECHANISM :

EtO(CH2)6OEt

Mg

HBr

EtO(CH2)6MgI

EtO(CH2)6Br

EtOCH2I

NaI

EtO(CH2)7OEt

DISCONNECTION :

EtO(CH2)X+1OEt

EtO(CH2)xOEt

487

EtO(CH2)6I

NOTES :

The diethyl ether of the alcohol when reacted with hydrogen bromide yields an α-bromo-ω-ethoxyalkane, which with sodium iodide gives the corresponding iodo-compound. The Grignard reagent of this compound reacts with ethyl iodomethyl ether yielding the higher homologue of the starting ether.

REFERENCES :

M.R. Dionneau, C.R. Séances Acad. Sci., 1906, 142, 91.

COMMENTS :

DISCHE REACTION EXAMPLE :

O OAc 1) NaOCH3 2) 5% aq. H2SO4 3) (Ph)2NH

AcO

blue coloured complexes

MECHANISM :

O O OH

H

+

Ph

N H

Ph CH3COOH H2SO4

blue coloured complexes

NOTES :

The reaction between the Dische reagent (diphenylamine, acetic acid and sulfuric acid) and 2-deoxypentoses resulting in the development of a blue colour. The reaction depends on the conversion of the pentose to ωhydroxylevulaldehyde which then reacts with diphenylamine to give a mixture of blue coloured complexes.

REFERENCES : Houben – Weyl : E3, 678

488

1) J. Knop, J. Am. Chem. Soc., 1924, 46, 263. 2) I.M. Kolthoff; L.A. Sarver, J. Am. Chem. Soc., 1930, 52, 4179. 3) Z. Dische, Mikrochemie, 1930, 8, 4. 4) Z. Dische; K. Schwarz, Microchim. Acta, 1937, 2, 13. 5) R.E. Deriaz; M. Stacey; E.G. Teece; L.F. Wiggins, J. Chem. Soc., 1949, 1222. 6) W.G. Overend; F. Stafizadeh; M. Stacey, J. Chem. Soc., 1950, 1027. 7) C. Viel, Analysis, 1976, 4, 471.

COMMENTS :

DJERASSI – RYLANDER OXIDATION EXAMPLE :

H3C

H N

CH3 1) RuO4 2) H2O

O

H N

H3C O

CH3 O

MECHANISM :

O

O Ru

RuO4

O

RuO2 +

O

DISCONNECTION :

O H H O H N

R O

R

R1

H N

R1 O

O

489

CHO CHO

NOTES :

The oxidative cleavage of phenols, alkenes, alkynes, oxidation of aromatics to quinones, oxidation of alkyl amides to imides or of ethers to esters using RuO4 or NaIO4. See also Barry, Hudson – Jackson, Lemieux – Johnson, Lemieux – von Rudloff and Malaprade reactions.

REFERENCES : March : 1181, 1200 Smith – March : 1534, 1540 Smith : 301 Smith 2nd : 265 Org. Synth. : 46, 78; 68, 41; 70, 29; 74, 1; 72, 1, 6 Org. Synth. Coll. Vol. : 5, 791; 8, 377; 9, 39, 63, 450, 454

1) C. Djerassi; R.R. Engle, J. Am. Chem. Soc., 1953, 75, 3838. 2) L.M. Berkowitz; P.N. Rylander, J. Am. Chem. Soc., 1958, 80, 6682. 3) J.C. Sheehan; R.W. Tulis, J. Org. Chem., 1974, 39, 2264. 4) K.-I. Tanaka; S. Yoshifuji; Y. Nitta, Chem. Pharm. Bull., 1987, 35, 364. 5) O. Tamura; S. Yoshida; H. Sugita; N. Mita; Y. Uyama; N. Morita; M. Ishiguro; T. Kawasaki; H. Ishibashi; M. Sakamoto, Synlett, 2000, 1553. 6) D.V. Deubel; G. Frenking, Acc. Chem. Res., 2003, 36, 645. 7) J. Frunzke; C. Loschen; G. Frenking, J. Am. Chem. Soc., 2004, 126, 3642.

COMMENTS :

490

DODDS – ROBINSON SYNTHESIS EXAMPLE :

Et

Et

H3CO OCH3 O

1) EtONa, EtI 2) EtMgBr 3) PBr3 4) KOH, EtOH

HO

OH

MECHANISM :

Et H3CO

H3CO OCH3 O H

EtMgBr

1) EtONa 2) EtI

Et

Et

Et

Et OH

H3CO

OCH3 O

OCH3

PBr3 - H2O H3CO

Et

OCH3

Et

KOH EtOH HO

OH

DISCONNECTION : Et

Et H3CO OCH3 O

HO

OH

NOTES :

This is the synthesis of substituted 1,2-diphenyl ethenes. Various modifications of this synthesis have been proposed. These compounds possess anti-oesterogenic properties. See also Kharasch – Kleimann reaction.

REFERENCES :

1) E.C. Dodds; W. Lawson, Nature, 1937, 139, 627.

491

2) E.C. Dodds; L. Goldberg; W. Lawson; R. Robinson, Nature, 1938, 141, 247. 3) D.H. Hey; O.C. Musgrave, J. Chem. Soc., 1949, 3156.

COMMENTS :

DOEBNER – von MILLER SYNTHESIS EXAMPLE :

2

H3C

H + O

H2SO4

NH2

492

N

CH3

MECHANISM :

H

O

NH2

H

H

OH2

N H

N H

[2 + 2]

N H

N

N

N

N H

N H

B H N

N

H+

N H

N H

N

N

N H

H

H

N H

N

N H

N H

oxidation

N

DISCONNECTION :

R H3C R1

N

R1

R

H

+ O

O

+ NH2

NOTES :

The synthesis of quinoline derivatives by condensation, in the presence of sulfuric or hydrochloric acid, of an aromatic amine with (i) an unsaturated aldehyde, or (ii) two molecules of an aldehyde RCH2CHO or (iii) one molecule of RCH2CHO and one molecule of R1CHO. Addition of zinc chloride promotes the reaction. The mechanism is the same as for the Skraup reaction. Although an alternative mechanism has been proposed and is shown here. The Beyer

493

modification consists of the substitution of a methyl ketone for the second molecule of aldehyde. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES : Smith : 1337 Smith 2nd : 1100 Houben – Weyl : E7a, 362, 546 Org. React. : 1, 210

1) W. Koenigs, Ber. Dtsch. Chem. Ges., 1879, 12, 453. 2) O. Doebner; W. von Miller, Ber. Dtsch. Chem. Ges., 1881, 14, 2812. 3) C. Beyer, Ber. Dtsch. Chem. Ges., 1887, 20, 1767. 4) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 5) S. Itoh; Y. Fukui; S. Haranou; M. Ogino; M. Komatsu; Y. Ohshiro, J. Org. Chem., 1992, 57, 4452. 6) Z.P. Zhang; L.M.V. Tillekeratne; R.A. Hudson, Tetrahedron Lett., 1998, 39, 5133. 7) M. Matsugi; F. Tabusa; J.-I. Minamikawa, Tetrahedron Lett., 2000, 41, 8523.

COMMENTS :

DOEBNER QUINOLINE SYNTHESIS EXAMPLE :

COOH + NH2

H

Ph O

C6H5N +

CH3COCOOH EtOH

N

494

Ph

O

N C6H5

Ph

MECHANISM :

R

+

H - H2O

O

NH2

N

O

R

OH

H3C

O

O

C6H5N

R N H

- H2O

O

OH

O

N C6H5

R

C6H5NH2 - H2O

O

N C6H5

R

O - H2O

COOH

N H

COOH

- H2

R

N

R

DISCONNECTION :

COOH

N

R +

C6H5N NH2 O

N C6H5

R

H O

R

NOTES :

An aromatic amine is condensed with pyruvic acid and an aldehyde to give a 2-substituted quinoline-4-carboxylic acid or a 1-aryl-3-(arylimino)pyrrolidinone. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth– Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

495

REFERENCES : Smith : 1338 Smith 2nd : 1100 Houben – Weyl : 2, 444; E7a, 359 Org. React. : 1, 210

1) C. Böttinger, Liebigs Ann. Chem., 1876, 188, 336. 2) O. Doebner, Ber. Dtsch. Chem. Ges, 1883, 16, 2357. 3) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 4) J.M.F. Gagan; D. Lloyd, J. Chem. Soc. (C), 1970, 2480. 5) G.E. Gream; A.K. Serelis, Aust. J. Chem., 1978, 31, 863. 6) D.R. Adams; T. Colman de Saizarboritoria, Synth. Commun., 1987, 17, 1647. 7) A. Gopalsamy; P.V. Pallai, Tetrahedron Lett., 1997, 38, 907.

COMMENTS :

DOEBNER MODIFICATION EXAMPLE :

Ph

H

H +

HOOC

COOH

pyridine

O

COOH

Ph

H

MECHANISM :

R R

H

+

HOOC

COOH

O

HOOC

pyridine

H COOH

- CO2

DISCONNECTION :

R

RCHO +

COOH

HO

OH O

496

O

H

COOH

R

H

NOTES :

The Knoevenagel condensation of malonic acid or ester with aldehydes in the presence of pyridine, usually with the addition of a little piperidine, to give unsaturated acids is known as the Doebner modification. See also Knoevenagel condensation and Perkin reaction.

REFERENCES : March : 948 Smith – March : 1226 Smith : 898 Smith 2nd : 750 Org. React. : 1, 266 Org. Synth. : 24, 92; 25, 51; 31, 35; 33, 62; 59, 1 Org. Synth. Coll. Vol. : 3, 425, 783; 4, 327, 731; 6, 95

1) O. Doebner, Ber. Dtsch. Chem. Ges., 1900, 33, 2140. 2) S.J. Davis; J.A. Elvidge, J. Chem. Soc., 1962, 3350. 3) F.J.C. Herrera; M.S.P. Gonzalez, Carbohydr. Res., 1986, 152, 283. 4) M. Melmer; H. Neudeck, Monatsh. Chem., 1996, 127, 275. 5) A.K. Mitra; A. De; N. Karchaudhuri, Synth. Commun., 1999, 29, 2731.

COMMENTS :

von DOERING – LA FLAMME – MOORE ALLENE SYNTHESIS EXAMPLE :

H3C H3C

H3C

CH3

CH3 1) CHBr3 KOtBu 2) Mg

497

H3C

MECHANISM :

CHBr3 + KOtBu

CBr2

Br

CH3 H3C

CH3

Br

H3C

H3C CBr2

CH3

H3C

CH3

Mg

H3C

RLi

Li

Br H3C

H3C CH3

H3C

H3C

CH3

DISCONNECTION :

R

R CH3

R1

R1

NOTES :

The allene synthesis from olefins via gem-dihalocyclopropanes. von Doering and La Flamme used magnesium while Moore and Skattebøl used an organolithium species. Grignard reagents can also be used. See also Skattebøl

reaction.

REFERENCES :

1) W. von E. Doering; A.K. Hoffmann, J. Am. Chem. Soc., 1954, 76, 6162. 2) W. von E. Doering; P.M. LaFlamme, Tetrahedron, 1958, 2, 75. 3) W.R. Moore; H.R. Ward, J. Org. Chem., 1960, 25, 2073. 4) W.R. Moore; H.R. Ward, J. Org. Chem., 1962, 27, 4179. 5) K.C. Lilje; R.S. Macomber, J. Org. Chem., 1974, 39, 3600. 6) R.R. Kostikov; A.P. Molchanov; H. Hopf, Top. Curr. Chem., 1990, 155, 41. 7) S. Hernandez; M.M. Kirchhoff; S.G. Swartz, jr.; R.P. Johnson, Tetrahedron Lett., 1996, 37, 4907. 8) M.S. Baird; A.V. Nizovtsev; I.G. Bolesov, Tetrahedron, 2002, 58, 1581. 9) C.E. Janßen; N. Krause, Eur. J. Org. Chem., 2005, 2322.

COMMENTS :

498

DONDONI HOMOGOLATION EXAMPLE :

O N Br S

Ph

H

n

1) BuLi 2) TMSCl 3) PhCHO 4) NaH, MeI 5) NaBH4 6) HgCl2

OH

MECHANISM :

H O N

N Br

SiMe3

1) nBuLi 2) TMSCl

S

Ph N SiMe3

PhCHO

S

S

H Me3SiO

Ph N

N

S

S

OSiMe3 H Ph

O Ph 1) NaH, MeI 2) NaBH4 3) HgCl2

H OH

DISCONNECTION :

O R

O R1

R

OR2

R1

NOTES :

The

homologation

of

aldehydes,

ketones,

acyl

chlorides,

ketenes,

two

carbon

(trimethylsilyl)thiazole, acting as a formyl anion synthon. See also Hodges – Vedejs reaction.

REFERENCES : Org. Synth. : 72, 21; 77, 78 Org. Synth. Coll. Vol. : 9, 52

499

homologation

via

2-

1) A. Dondoni; T. Dall’Occo; G. Fautin; M. Fogagnolo; A. Medici; P. Pedrini, J. Chem. Soc., Chem. Commun., 1984, 258. 2) A. Dondoni; G. Fautin; M. Fogagnolo; A. Medici; P. Pedrini, J. Org. Chem., 1988, 53, 1748. 3) A. Dondoni, Pure Appl. Chem., 1990, 62, 643. 4) A. Wagner; M. Mollath, Tetrahedron Lett., 1993, 34, 619. 5) A. Dondoni, Synthesis, 1998, 1681. 6) A.K. Ghosh; A. Bischoff; J. Cappiello, Org. Lett., 2001, 3, 2677.

COMMENTS :

DORNOW – WIEHLER ISOXAZOLE REACTION EXAMPLE :

O

EtO2C H

O2N

+ 2 O2N

CO2Et

H N

EtOH, reflux

500

O2N

O N CO2Et

MECHANISM :

O2N

CO2Et

O2N

H N

+

O

H

CO2Et NO2

HO

OEt

H

O

H

B

O2N H

O2N H+ EtO2C

NO2

NO2

EtO2C

H

B OEt

H O2N

NO2 O

O2N

OEt

O2N O

EtO2C H

EtO2C

OEt - H+

O N

O2N

O

O

O2N

EtO2C

O

EtO2C

O N

OEt

O

O2N EtO2C

O N

OH

- H2O

OEt

CO2Et

O2N

DISCONNECTION :

AlkO2C

O

O N Ar

Ar

CO2Alk

NOTES :

Aryl aldehydes and α-nitroesters condense to afford isoxazoles.

REFERENCES :

1) A. Dornow; G. Wiehler, Liebigs Ann. Chem., 1952, 578, 113. 2) A. Dornow; G. Wiehler, Liebigs Ann. Chem., 1952, 578, 122. 3) S. Umezawa; S. Zen, Bull. Chem. Soc. Jpn., 1963, 36, 1150.

501

O N

O

H

H+ O2N

O N

H

+ 2 O2N

CO2Alk

O

O

OEt

COMMENTS :

DÖTZ HYDROQUINONE SYNTHESIS EXAMPLE :

OH Ph OMe +

(OC)5Cr

Ph

Ph Ph Cr(CO) 3 H3CO

Ph

MECHANISM :

R OCH3

- CO

OCH3 R (CO)5Cr

H3CO

R Cr (CO)4

(CO)4Cr

R

OCH3 R

(CO)3Cr O

OCH3 (CO)4Cr

R

OCH3 O

R R

R

OCH3 Cr(CO)3 R

O

R R

R

502

R Cr(CO)3

DISCONNECTION :

OH R1(R2)

OMe (OC)5Cr

+

R1

R2

R2(R1) Cr(CO) 3 H3CO

NOTES :

The (regiospecific) hydroquinone synthesis from alkynes and Fischer carbonyl carbene chromium complexes. Microwave-assisted reactions are also known. The reactions involving chromium alkynyl carbine complexes is sometimes called Wulff cyclisation.

REFERENCES : Science of Synthesis : 1, 852

1) K.H. Dötz, Angew. Chem., Int. Ed. Engl., 1975, 14, 644. 2) W.D. Wulff; D.C. Yang, J. Am. Chem. Soc., 1984, 106, 7565. 3) N.E. Schore, Chem. Rev., 1988, 88, 1081. 4) K.H. Dötz, New. J. Chem., 1990, 14, 433. 5) S. Chamberlin; W.D. Wulff, J. Org. Chem., 1994, 59, 3047. 6) J. Barluenga, Pure Appl. Chem., 1996, 68, 543. 7) M.L. Waters; M.E. Bos; W.D. Wulff, J. Am. Chem. Soc., 1999, 121, 6403. 8) F. Barluenga; F. Aznar; M.A. Palomero, Angew. Chem., Int. Ed., 2000, 39, 4346. 9) W.H. Moser; L.D. Sun; J.C. Huffman, Org. Lett., 2001, 3, 3389. 10) E.J. Hutchinson; W.J. Kerr; E.J. Magennis, Chem. Commun., 2002, 2262. 11) J.C. Anderson; J.W. Cran; N.P. King, Tetrahedron Lett., 2003, 44, 7771. 12) J.C. Anderson; R.M. Denton; H.G. Hickin; C. Wilson, Tetrahedron, 2004, 60, 2327. 13) S.R. Pulley; B. Czakó, Tetrahedron Lett., 2004, 45, 5511.

COMMENTS :

503

DOUGLAS – FARAH REACTION EXAMPLE : O H3C

S

CH3

S

H3C

1) CH3COOH, 2 Cl2 2) 2 H2O

S

S

CH3

O

MECHANISM :

O H3C

S

S

H3C

CH3

2 H2O - CH3COOH - 2 HCl

CH3COOH, 2 Cl2 - HCl

H3C

S

O

+

Cl

S

OH

+

S

+

H3C

Cl

OH

S

O H3C

H3C

Cl

H3C

S

Cl H3C

S

S

CH3

O

DISCONNECTION :

O R

S

S O

R

R1

S

S

R1

R = Alk, Aryl

NOTES :

Thiosulfonate esters can be prepared by the addition of chlorine to a cold mixture of alkyl disulfides and acetic acid, followed by the addition of water. During the chlorination, alkylsulfenyl, acetyl and alkylsulfinyl chlorides are formed. Hydrolysis of the latter gives alkylsulfinic acid and reacts with alkylsulfenyl chloride to form the thiosulfonate ester. This procedure is very general for the synthesis of thiosulfonates.

REFERENCES : Houben – Weyl : E11, 145

1) I.B. Douglas; B.S. Farah, J. Org. Chem., 1958, 23, 330. 2) I.B. Douglas; B.S. Farah, J. Org. Chem., 1959, 24, 973.

504

3) L. Field; T.F. Parsons, J. Org. Chem., 1965, 30, 657. 4) L. Field; W.S. Hansley; I. McVeigh; Z. Evans, J. Med. Chem., 1971, 14, 202.

COMMENTS :

DOYLE – KIRMSE REACTION EXAMPLE : Ph

Ph O

+

SCH3

O

2.5 mol% [Rh(OAc)2]2 DCM, Reflux

SCH3

MECHANISM :

R1 +

R N2

R1

R1

H

R2

Z

R2 R

R2

- N2

Z

Z H

R

DISCONNECTION :

R1 R1

H

R2 R

Z

R

+ N2

H

R2

Z

NOTES :

The reaction between allylic compounds and diazo compounds, iron, copper or rhodium-catalysed. The reaction involves a [2,3]-sigmatropic rearrangement and is a powerful method for the formation of C-C bonds. Uemura et al. has published a rhodium(II)-catalysed reaction without the use of a diazoalkane.

505

REFERENCES : March : 1142 Smith – March : 1453

1) W. Kirmse; M. Kapps, Chem. Ber., 1968, 101, 994. 2) M.P. Doyle; W.H. Tamblyn; V. Bagheri, J. Org. Chem., 1981, 46, 5094. 3) O. Meyer; P.C. Cagle; K. Weickhardt; D. Vichard; J.A. Gladysz, Pure Appl. Chem., 1996, 68, 79. 4) A.-H. Li; V.K. Aggarwal, Chem. Rev., 1997, 97, 2341. 5) Y. Kato; K. Miki; F. Nishino; K. Ohe; S. Uemura, Org. Lett., 2003, 5, 2619.

COMMENTS :

DOWD – BECKWITH REACTION EXAMPLE :

O

O CH2I CO2CH3

n

Bu3SnH, AIBN, Benzene, reflux

CO2CH3

MECHANISM :

I O

O OPiv

O O H

n

Bu3SnCH2CH=CH2 AIBN, benzene, heat

OPiv O

O

H

H

O

O O

O O

H O

O H OPiv

n

O

Bu3SnCH2CH=CH2 O H

OPiv

506

OPiv

DISCONNECTION :

O

O CH2X CO2R

CO2R

NOTES :

The free radical mediated ring expansion of haloalkyl β-ketoesters. See also Ciamician – Dennstedt rearrangement and Reimer – Tiemann rearrangement.

REFERENCES : Smith – March : 1400 Org. Synth. : 69, 188 Org. Synth. Coll. Vol. : 8, 562

1) P. Dowd; S.C. Choi, J. Am. Chem. Soc., 1987, 109, 3493. 2) A.L.J. Beckwith; D.M. O’Shea; S.W. Westwood, J. Am. Chem. Soc., 1988, 110, 2565. 3) P. Dowd; W. Zhang, Chem. Rev., 1993, 93, 2091. 4) M.T. Crimmins; Z. Wang; L.A. McKerlie, J. Am. Chem. Soc., 1998, 120, 1747. 5) C. Wang; X. Gu; M.S. Yu; D.P. Curran, Tetrahedron, 1998, 54, 8355. 6) D.J. Hart; F. Havas, C.R. Acad. Sci. Paris, Chimie, 2001, 4, 591. 7) M. Sugi; H. Togo, Tetrahedron, 2002, 57, 3171.

COMMENTS :

507

DREIDING – SCHMIDT REACTION EXAMPLE :

O O

O O

HO

O SmI2 O

O

BnO

Br

O

O O

BnO

O

MECHANISM :

O Br

O Br

OCH3

Zn H3C

Zn dust

CH3 O

OCH3 H3C

O

OCH3 O OCH3

CH3 OZnBr

Zn Br H3C

O O O BrZn O

OCH3

DISCONNECTION :

O R

R1 R

O

O

R1

+

Br

OR2

O

NOTES :

The methylene lactone formation starting from ketones or aldehydes and α-(bromoalkyl)acrylic esters. See also Blaise, Gilman – Speeter and Reformatsky reactions.

REFERENCES :

1) A. Löffler; R.D. Pratt; J. Pucknat; G. Gelhard; A.S. Dreiding, Chimia, 1969, 23, 413.

508

2) E. Öhler; K. Reiniger; U. Schmidt, Angew. Chem., Int. Ed. Engl., 1970, 9, 457. 3) A. Löffler; R.D. Pratt; H.P. Rüesch; A.S. Dreiding, Helv. Chim. Acta, 1970, 53, 383. 4) R. Csuk; B. Glänzer; Z. Hu; R. Boese, Tetrahedron, 1994, 50, 1111. 5) R. Csuk; U. Höring; M. Schaade, Tetrahedron, 1996, 52, 9759.

COMMENTS :

DUFF REACTION EXAMPLE :

H3C

N

CH3

H3C

N

CH3

N

1) N

NN O

CH3COOH HCOOH 2) H2SO4 H2O

H

MECHANISM :

OH HO

OH 2

N N

- H2

N H

NN

CH3COOH OH

OH HO N

hydrolysis

2

H O

509

DISCONNECTION :

R

N

R R

O

R

H O

O

N

R O

R

H

NOTES :

A mixture of N,N-dialkylaniline or a phenol, hexamethylenetetramine, acetic and formic acids, is heated and the aminoalkylated product is treated with mineral acid and water. If the o-position is blocked the p-substituted compound is formed. See also Ciamician – Dennstedt, Reimer – Tiemann and Sommelet reactions.

REFERENCES : March : 545 Smith – March : 717 Houben – Weyl : 7/1, 43, 198; E6b, 1074 Org. Synth. : 31, 92; 75, 1 Org. Synth. Coll. Vol. : 4, 866; 10, 96

1) J.C. Duff; E.J. Bills, J. Chem. Soc., 1932, 1987. 2) J.C. Duff, J. Chem. Soc., 1941, 547. 3) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 4) Y. Ogata; A. Kawasaki; F. Sugiura, Tetrahedron, 1968, 24, 5001. 5) T.V. Mathew; V.S. Chauhan, Indian J. Chem., 1987, 26B, 1071. 6) Y. Tanoue; A. Terada; Y. Matsumoto, Bull. Chem. Soc. Jpn., 1989, 62, 2736. 7) S. Wahidulla; L. D’Souza; J. Bhattacharya, Orient. J. Chem., 1997, 13, 127. 8) L.F. Lindoy; G.V. Meehan; S. Svenstrup, Synthesis, 1998, 7, 1029. 9) E. Asato; M. Chinen; A. Yoshino; Y. Sakata; K. Sugiwara, Chem. Lett., 2000, 678.

COMMENTS :

510

DUTHALER – HAFNER ALLYLATION EXAMPLE :

Cl

Ph O O

Ti Ph

OH

Ph Ph

O

Ph O

Ph Ph

1) H3C

H3C

Li Et2O, 0 oC 2) PhCHO, - 74 oC 3) NH4F, H2O

MECHANISM :

Ph

Ph

HO HO Ph

O

Ph

O

Ph

+ CpTiCl3

Cl Et3N, Et2O

Ti

Ph O O

Ph

Ph

Ph

Ph O

O Ph Ph

(R,R)

Ph Ti O Cl O Ph

R

Ph

Ph O

O

R

Ti

M Ph

Ph Ph

Et2O, 0 oC

Ph O O

Ph O

Ph O

Ph Ph

M = Li, MgX

OH R1 R

DISCONNECTION :

OH R R1 R

511

M

+ R1CHO

1) R1CHO 2) NH4F, H2O

NOTES :

The chiral TADDOL titanium complex is used for asymmetric allylation reactions. The chiral diol is available in both enantiomeric forms. The titanium complex may be used in crude form. See also Ibuka – Yamamoto, Matteson, Roush – Hoffmann – Yamamoto and Thomas reactions.

REFERENCES :

1) K. Oertle; H. Beyeler; R.O. Duthaler; W. Lottenbach; M. Riediker; E. Steiner, Helv. Chim. Acta, 1990, 73, 353. 2) R.O. Duthaler; A. Hafner; M. Riediker, Pure Appl. Chem., 1990, 62, 631. 3) A. Hafner; R.O. Duthaler; R. Marti; G. Rihs; P. Rothe–Streit; F. Schwarzenbach, J. Am. Chem. Soc., 1992, 114, 2321. 4) R.O Duthaler; A. Hafner, Chem. Rev., 1992, 92, 807. 5) A. Zellner; M. Schlosser, Synlett, 2001, 1016.

COMMENTS :

DUTT – WORMALL REACTION EXAMPLE :

N3

NH2 1) HNO2, H+ 2) O H2N S O

CH3

3) HO-

MECHANISM :

N2+

NH2 HNO2, H+

H2NSO2R

N

O

R S

N N H

N3 HO-

+ RSO2H

512

O

DISCONNECTION :

N3 R

NH2 R

+ ArSO2H

+ H2NSO2Ar

NOTES :

Aromatic azides and sulfonic acids are obtained by the action of aromatic diazonium salts on aliphatic or aromatic sulfonamides in the presence of alkali.

REFERENCES : Houben – Weyl : 10/3, 808

1) P.K. Dutt; H.R. Whitehead; A. Wormall, J. Chem. Soc., 1921, 119, 2088. 2) P.K. Dutt, J. Chem. Soc., 1924, 125, 1463. 3) H. Bretschneider; H. Rager, Monatsh. Chem., 1950, 81, 970.

COMMENTS :

513

514

ELBS PERSULFATE OXIDATION · 533 ELBS REACTION · 535

E

ELTEKOFF KETONE SYNTHESIS · 536 EABORN – CHVALOVKSÝ REACTION · 516

ELTEKOFF METHYLATION · 537

EABORN REACTION · 517

EMDE DEGRADATION · 538

EASTWOOD REACTION · 518

EMMERT – ASENDORF REACTION · 540

EBELE – SCHIESSLER – ROSS CYCLONITE SYNTHESIS · 519

ENDERS REACTION · 541

ECKEY PROCESS · 520

ENGLER INDOLE SYNTHESIS · 543

EDER REACTION · 520

ERLENMEYER – FRÜSTÜCK SYNTHESIS · 544

EDMAN DEGRADATION · 521

ERLENMEYER – PLÖCHL AZLACTONE SYNTHESIS · 546

EHRLICH – SACHS REACTION · 522

ESCHENMOSER – MEERWEIN – CLAISEN REARRANGEMENT · 547

EHRLICH PYRROLE REACTION · 524 EIJKMAN ADDITION · 525

ESCHENMOSER – TANABE RING CLEAVAGE · 549

EINHORN – BRUNNER REACTION · 527

ESCHENMOSER METHENYLATION · 551

EINHORN – TSCHERNIAC AMIDOMETHYLATION · 528

ESCHENMOSER SULFIDE CONTRACTION · 552

EINHORN ACYLATION · 530

ESCHWEILER – CLARKE REACTION · 554

EINHORN OXIDATION · 531

ÉTARD REACTION · 555

EISLEB AMINOALKYLATION · 532

EVANS REACTION · 558

515

EABORN – CHVALOVKSÝ REACTION EXAMPLE :

O CH3

SiMe3 NO2

NO2

SiMe3

+

O

CH3

CH3

O HNO3, 100 oC

DISCONNECTION :

NO2

SiMe3 R1

R1

R

R

NOTES : The cleavage of aryl-trimethylsilyl bonds using nitrating agents in acetic anhydride. The reaction most likely proceeds via nitrosodesilylation followed by oxidation. It is not known what the exact dominant nitrating entity is, it is assumed that it is a lower nitrogen oxide.

REFERENCES : 1) V. Chalovský; V. Bažant, Coll. Czech. Chem. Commun., 1951, 16, 580. 2) R.A. Benkeser; H. Landesman, J. Am. Chem. Soc., 1954, 76, 904. 3) F.B. Deans; C. Eaborn, J. Chem. Soc., 1957, 498. 4) C. Eaborn; Z.S. Salih; D.R.M. Walton, J. Chem. Soc., Perkin Trans. 2, 1972, 172. 5) P.L. Coe; A.M. Stuart; D.J. Moody, J. Fluorine Chem., 1998, 92, 27.

COMMENTS :

516

EABORN REACTION EXAMPLE :

(C2H5)4Si + I2

(C2H5)3SiI + C2H5I

AlI3

MECHANISM :

AlI3 + Si(R)4

R3Si + [AlRI3]

(R)3Si + I2

(R)3SiI + I

[AlRI3] + I

AlI3 + RI

DISCONNECTION :

(R)4Si

(R)3SiI + RI

NOTES : The formation of alkyl iodide silanes from tetraalkylsilane and iodine in the presence of aluminium iodide. Further reactions are possible, and the product can transhalogenate to give the corresponding fluoro compound. The ease of displacement varies from phenyl >> methyl > ethyl > n/i propyl. See also Ruff reaction.

REFERENCES : 1) C. Eaborn, J. Chem. Soc., 1949, 2755. 2) H.H. Anderson; D.L. Seaton; R.P.T. Rudnicki, J. Am. Chem. Soc., 1951, 73, 2144. 3) R.W. Bott; C. Eaborn; J.A. Waters, J. Chem. Soc., 1963, 681. 4) J.J. Chrusciel, Can. J. Chem., 2000, 78, 1405.

COMMENTS :

517

EASTWOOD REACTION EXAMPLE :

HO H Ph

OH H Ph

Ph CH3COOH (EtO)3CH 110 oC

Ph

H

H

MECHANISM :

H O

H

OEt O

O

O

O

O

- CO2

X - HX

HX - EtOH

- CH3COOH

O

O H

O

H

O

O

O

O

O

- CH3COOH - CO2

DISCONNECTION :

R3

HO OH

R2 R3

R1

R4

R4 R1 R2

NOTES : The treatment of vicinal diols with ethyl orthoformate at elevated temperatures, followed by continued heating at somewhat higher temperatures (160 – 220 oC) in the presence of a carboxylic acid leads to olefin formation (one-pot, one-reagent olefin synthesis). See also Corey – Kwiatkowski, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

518

REFERENCES : March : 1029 Smith – March : 1341 Org. React. : 30, 457

1) G. Crank; F.W. Eastwood, Aust. J. Chem., 1964, 17, 1392. 2) T. Hiyama; H. Nozaki, Bull. Chem. Soc. Jpn., 1973, 46, 2248. 3) S. Hanessian; A. Bargiotti; M. LaRue, Tetrahedron Lett., 1978, 19, 737. 4) J.L. King; B.A. Posner; K.T. Mak; N.C. Yang, Tetrahedron Lett., 1987, 28, 3919.

COMMENTS :

EBELE – SCHIESSLER – ROSS CYCLONITE SYNTHESIS EXAMPLE : NO2 N 3 HCHO + 3 NH4NO3 + 6 Ac2O O2N

N

N

+ 12 AcOH NO2

NOTES : Cyclonite is obtained (60% yield based on formaldehyde) by the addition of paraformaldehyde and ammonium nitrate to acetic anhydride at 70 oC. See also Hale, Knoffler – Bachmann and Wolfram reactions.

REFERENCES : 1) W. de C. Crater, Ind. Eng. Chem., 1948, 40, 1632. 2) R.W. Schiessler; J.H. Ross, U.S. Patent, 1948, 2434230. 3) C.J. McHugh; W.E. Smith; R. Lacey; D. Graham, Chem. Commun., 2002, 2514.

COMMENTS :

519

ECKEY PROCESS NOTES : This process involves the direct esterification of glycidyl fatty acid esters with fatty acids. Eckey’s process of lowtemperature directed interestrification of fats has been modified by Eckey and Formo to include simultaneous alcoholysis as well as ester-ester interchange. In the modified process, in the presence of catalysts (e.g. NaOCH3), melted fats and glycerol interesterify to produce an equilibrium mixture of monoglycerides, diglycerides, triglycerides and free glycerol. Crystallisation of high melting monoglycerides or diglycerides takes place when the temperature of the liquid product is lowered sufficiently. This lowering of the temperature and subsequent crystallisation of a component from the liquid phase disturbs the equilibrium, whose re-establishment is continuously promoted by the rearrangement catalyst. The desired glyceride continues to crystallise out until the supply of its constituent groups is no longer sufficient to maintain the super saturation of the liquid phase with respect to the precipitated solid. The pure single-fatty acid diglycerides were isolated from the crystalline products by tedious solvent crystallisation. A radical pathway is most likely.

REFERENCES : 1) E.W. Eckey, Ind. Eng. Chem., 1948, 40, 1183. 2) E.W. Eckey, U.S. Patent, 1948, 2442531. 3) E.W. Eckey; M.W. Formo, J. Am. Oil. Chem. Soc., 1949, 23, 207. 4) F.J. Baur; W. Lange, J. Am. Chem. Soc., 1951, 73, 3926.

COMMENTS :

EDER REACTION EXAMPLE :

K2C2O4 + 2 HgCl2

2 KCl + Hg2Cl2 + 2 CO2

light

MECHANISM : primary step : HgCl2C2O42- + energy

HgCl + Cl- + C2O4-

520

NOTES : Eder published this reaction as a new chemical way to measure the intensity of UV radiation in daylight. The great energy efficiency indicates that the reaction is most probably a chain reaction.

REFERENCES : 1) J.M. Eder, Chem. Ber., 1880, 13, 166. 2) W.E. Roseveare, J. Am. Chem. Soc., 1930, 52, 2612.

COMMENTS :

EDMAN DEGRADATION EXAMPLE :

H

NH2

PhNCS + H2N CH3 O

1) CH3NO2, sat. HCl 2) Ba(OH)2

H2N

O

H3C

OH

MECHANISM :

R

H N

Ph N

S

H2N

R1

N H

O

H+

R1NH3+Cl- +

S

H H R H+ N S

N Ph

O

N H

R OH

H2N

- PhNCS

O

OH

521

R

H N O

R1 H+

CH3NO2, sat. HCl

DISCONNECTION : H

R

R

OH

H2N

H2N

O

N R1 O

NOTES : This degradation involves the reaction of phenyl isothiocyanate with an amino-group of a peptide at a controlled pH (pH 9) to form the phenyl thiocarbamyl derivative. Cleavage of this derivative in anhydrous nitromethane saturated with hydrogen chloride affords the phenylthiohydantion and the hydrochloride of the amino-acid or peptide lacking the terminal amino-acid. The process can be repeated. See also Schlack – Kumpf reaction.

REFERENCES : 1) P. Edman, Acta Chem. Scand., 1950, 4, 283. 2) P. Edman, Nature, 1956, 177, 667. 3) D. Bethell; G.E. Metcalfe; R.C. Sheppard, J. Chem. Soc., Chem. Commun., 1965, 189. 4) A. Boeijen; R.M.J. Liskamp, Tetrahedron Lett., 1998, 39, 3589. 5) G.E. Reid; S.E. Tichy; J. Perez; R.A.J. O’Hair; R.J. Simpson; H.I. Kenttaman, J. Am. Chem. Soc., 2001, 123, 1184. 6) S.A. Ahmed; M.P. Byrne; M. Jensen; H.B. Hines; E. Brüggemann; L.A. Smith, J. Prot. Chem., 2001, 20, 221. 7) G. Evindar; R.A. Batey, Org. Lett., 2003, 5, 1201.

COMMENTS :

EHRLICH – SACHS REACTION EXAMPLE :

N +

O N

K2CO3, MeOH

N N

522

MECHANISM :

N R O N R

base N

H+

N

- H2O N H2O - H2O O

OH N R

+ RNH2 N

H N oxidation

O N R

N

DISCONNECTION :

O N Ar R N

R

N

O R N

NOTES : Compounds containing a reactive methylene group undergo condensation in aqueous ethanolic base with aromatic nitroso compounds yielding a mixture of azomethines, N-oximino ethers and azoxy compounds. The formation of azomethines is promoted by using absolute methanol as a solvent, anhydrous potassium carbonate as condensing agent and by employing equimolar proportions of the reactants. The azomethines may be hydrolysed to the corresponding ketones or aldehydes and amines.

523

REFERENCES : Houben – Weyl : 7/1, 152

1) P. Ehrlich; F. Sachs, Ber. Dtsch. Chem. Ges., 1899, 32, 2341. 2) D.M.W. Anderson; F. Bell, J. Chem. Soc., 1957, 516. 3) S.P. Belousova; N.V. Vasilev; A.F. Kolomiets; K.M. Nikolaev; G.A. Sokolskii; A.V. Fokin, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1984, 33, 1103. 4) F. Millich; M.T. Eishoubary, Org. Prep. Proced. Int., 1996, 28, 366. 5) D.D. Laskar; D. Prajapati; J.S. Sandhu, Synth. Commun., 2001, 31, 1427.

COMMENTS :

EHRLICH PYRROLE REACTION EXAMPLE :

Me2N

CH3

CH3

H3C

CH3

+ N H

O

CH3

HClO4

HN

Me2N ClO4

CH3

MECHANISM :

OH

OH N H

H

N H

NMe2

H NMe2

NMe2

NMe2

- H2O

N H

N H

H

524

H

DISCONNECTION :

R1 R

R2

R1

R2

H

R3 R

N H

H R3 = aryl, indole, or furan

R3

+ O

N H

NOTES : Pyrroles, unsubstituted in the α-position, condense with aldehydes e.g. p-dimethylaminocinnamic aldehyde in the presence of acid, to give the corresponding derivative. The reaction has been extended to a variety of aldehydes and to indole (β-position) and furan derivatives. The Ehrlich test uses p-dimethylaminocinnamic aldehyde.

REFERENCES : 1) P. Ehrlich, Med. Woche, 1901, 151. 2) S.A. Al-tamrah, Anal. Lett., 1989, 22, 387. 3) P.A. Liddell; T.P. Forsyth; M.O. Senge; K.M. Smith, Tetrahedron, 1993, 49, 1343. 4) J.S. Esteveromero; L.M. Pons; M.C. Garciaalvarezcoque; G. Ramisramos, Anal. Lett., 1994, 27, 1557. 5) C. Kuroda; T. Ueshino; H. Nagano, Bull. Chem. Soc. Jpn., 2004, 77, 1737.

COMMENTS :

EIJKMAN ADDITION EXAMPLE :

H3C H

H3C

H +

AlCl3

COOH

525

H COOH

MECHANISM :

H3C

H3C H H3C Cl H

CH3 HCl

CH3 O - AlCl4

H3C H H3C H

AlCl3

O

H3C H H3C Ph H

CH3 O

H3C H H3C Cl H AlCl3

CH3

CH3 O

CH3 O

DISCONNECTION :

R2

R1 O

R1 R

OR3

R4

+ R2

R4

OR3 O

R

NOTES : The interaction of an aromatic hydrocarbon with an α,β-unsaturated carboxylic acid or ester in the presence of aluminium chloride yields the β-aryl acid. Mesityl oxide reacts similarly with fluorobenzene. See also Friedel – Crafts and Michael reactions.

REFERENCES : 1) J.F. Eijkman, Chem. Weekblad, 1904, 1, 421. 2) J.F. Eijkman, Chem. Weekblad, 1908, 5, 655. 3) E.J. King, J. Am. Chem. Soc., 1927, 49, 562. 4) A. Hoffman, J. Am. Chem. Soc., 1929, 51, 2542. 5) L.I. Smith; C.-P. Lo, J. Am. Chem. Soc., 1948, 70, 2215. 6) J. Colonge; L. Pichat, Bull. Soc. Chim. Fr., 1949, 177. 7) R.V. Christian, jr., J. Am. Chem. Soc., 1952, 74, 1591. 8) A. Mustafa; W. Asker; A.H. Harhash; N.A.L. Kassab, Tetrahedron, 1963, 19, 1577. 9) H.E. Zimmerman; C.J. Samuel, J. Am. Chem. Soc., 1975, 97, 4025. 10) P.S. Hillery; L.A. Cohen, J. Am. Chem. Soc., 1983, 105, 2760. 11) A.R. Maguire; N.R. Buckley; P. O’Leary; G. Ferguson, J. Chem. Soc., Perkin Trans. 1, 1998, 4077.

526

COMMENTS :

EINHORN – BRUNNER REACTION EXAMPLE :

NH2 N H3C H

O

+

H N

CH3 O

N N H3C

CH3COOH

CH3 CH3

N CH3

MECHANISM :

H

O H R

N N

H

R1

H

HO

N R N H N

N

R

R1 HO

O

HO

R2 R1

N N

R1

OH

R2

- H2O

H

R1

O N H

N

N

R2

R

H

N N H

R

R2 R1

H R2

N

H N

- H2O

H O

N N R

N R2

DISCONNECTION :

R1 N N R

N

NH2 N R H

R2

+

H N

O R2

O R1

NOTES : The synthesis of substituted 1,2,4-triazoles by the condensation of a hydrazine with a diacylamine. See also Kaiser triazole and Pellizzari reactions.

527

REFERENCES : 1) A. Einhorn; E. Bischkopff; B. Szelinski, Liebigs Ann. Chem., 1905, 343, 229. 2) K. Brunner, Ber. Dtsch. Chem. Ges., 1914, 47, 2671. 3) M.R. Atkinson; J.B. Polya, J. Chem. Soc., 1952, 3418. 4) M.R. Atkinson; J.B. Polya, J. Chem. Soc., 1954, 141. 5) K.T. Potts, Chem. Rev., 1961, 61, 87.

COMMENTS :

EINHORN – TSCHERNIAC AMIDOMETHYLATION EXAMPLE :

Ph OH

NH2 OH

1) 2 PhCHO NH3, EtOH 2) aq. HCl, heat 3) aq. KOH

MECHANISM :

H+

O H

O

H

H

H

OH H

H

- H+

H H N

R1

H O

O R1

H+

O H

O

O H R1

R1

O H N

N

- H2O

H

H

O

O R1

R1 N CH2 H

R2NH

528

R2 N H

N CH2 H

DISCONNECTION : R1 Ar O

R2

N H

Ar

NH2 O

+ CH2O +

R1

H N

R2

NOTES : The preparation of amidomethyl derivatives of aromatic compounds (Phenols, secondary and tertiary aromatic amines, pyrroles and indoles) or activated methylene groups by treatment of an ethanolic or methanolic mixture of the compound and an amide with hydrogen chloride or chloric acid. See also Mannich reaction.

REFERENCES : March : 550 Smith – March : 722 Houben – Weyl : 11/1, 795 Org. React. : 14, 63 Org. Synth. : 9, 60; 35, 78; 40, 31 Org. Synth. Coll. Vol. : 1, 381; 4, 626; 5, 434

1) A. Einhorn, Liebigs Ann. Chem., 1905, 343, 207. 2) H. Hellmann, Angew. Chem., 1957, 69, 463. 3) F. Lauria; C. Bernardelli; G. Tosolini; W. Logemann, Liebigs Ann. Chem., 1967, 706, 233. 4) I.H. Sanchez; F.J. Lopez; J.J. Soria; M.I. Larraza; H.J. Flores, J. Am. Chem. Soc., 1983, 105, 7640. 5) K.J. Hu; J.S. Bradshaw; V.N. Pastuhok; K.E. Krakowiak; N.K. Dalley; X.X. Zhang; R.M. Izatt, J. Org. Chem., 1998, 63, 4786. 6) K.J.C. van Bommel; F. Westerhof; W. Verboom; D.N. Reinhoudt; R. Hulst, J. Prakt. Chem., 1999, 341, 284.

COMMENTS :

529

EINHORN ACYLATION EXAMPLE :

Cl

+

pyridine

O

O

OH

O

MECHANISM :

Cl

+

+

N N

O

O Cl

OH

+ O

N H Cl

O

DISCONNECTION :

O

O R

R1OH

OR1

+

R

Cl

NOTES : The acylating mixture for alcohols consists of an acyl chloride and pyridine or other tertiary base. See also Chattaway acylation, Galat – Elion, Lumière – Barbier, Schotten – Baumann and Weinreb reactions.

REFERENCES : Houben – Weyl : 2, 332; 8, 545

530

1) M. Dennstedt; J. Zimmermann, Ber. Dtsch. Chem. Ges., 1886, 19, 75. 2) A. Einhorn; F. Hollandt, Liebigs Ann. Chem., 1898, 301, 95. 3) F. Ullmann; G. Nadai, Ber. Dtsch. Chem. Ges., 1908, 41, 1870. 4) J.A. Mills, J. Chem. Soc., 1951, 2332. 5) I. Bauerova; M. Ludwig, Coll. Czech. Chem. Commun., 2000, 65, 1777. 6) A.C. Spivey; A. Maddaford; D.P. Leese; A.J. Redgrave, J. Chem. Soc., Perkin Trans. 1, 2001, 1785.

COMMENTS :

EINHORN OXIDATION EXAMPLE :

OH

CHO O

O H3C H3C

2 TEMPO, 4 NCS, Bu4NCl DCM, H2O

CH3

H3C H3C

CH3

MECHANISM :

R +

N O

H

OH

- H+

N O O

R1

H R1

R + O

N OH

DISCONNECTION :

O R

R OH

H

531

R1

R

NOTES : TEMPO catalyses the oxidation of primary alcohols to aldehydes by N-chlorosuccinimide (NCS), in a biphasic dichloromethane – aqueous buffer system (NaHCO3, K2CO3, pH 8.6) in the presence of tBu4NCl (The phase transfer catalyst). The proton abstraction may occur intra- or intermolecularly. Aliphatic, benzylic and allylic alcohols are readily oxidised without any over-oxidation to the carboxylic acid. Secondary alcohols are oxidised to ketones but in a much lower efficiency. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : Smith – March : 1515

1) J. Einhorn; C. Einhorn; F. Ratajczak; J.-L. Pierre, J. Org. Chem., 1996, 61, 7452. 2) B.B. Snider; B. Shi, Tetrahedron Lett., 2001, 42, 9123.

COMMENTS :

EISLEB AMINOALKYLATION EXAMPLE :

CH3 N H

1) NaNH2 2) ClCH2CH2N(C2H5)2

CH3 N CH2CH2N(C2H5)2

MECHANISM :

CH3 N H

NaNH2 - NH3

CH3 N Cl N

532

CH3 - NaCl

N N

DISCONNECTION :

O R1

O

R nN

R1

R2

R

+

Cl

nN

R2

R3

R3

NOTES : Active hydrogen atoms can be replaced by tert-aminoalkyl groups by treatment of the tert-aminoalkyl chloride with the compound in the presence of sodamide and a suitable solvent. Compounds like β-dichloroethyl ether react similarly. This chemistry is used in the synthesis of pethidine-based analgesics.

REFERENCES : 1) O. Eisleb, Ber. Dtsch. Chem. Ges., 1941, 74, 1433. 2) J.A. Barltrop, J. Chem. Soc., 1946, 958. 3) R.L. Clark; A.A. Pessolano; J. Weijlard; K. Pfister, J. Am. Chem. Soc., 1953, 75, 4963. 4) J. Diamond; W.F. Bruce; F.T. Tyson, J. Org. Chem., 1957, 22, 399.

COMMENTS :

ELBS PERSULFATE OXIDATION EXAMPLE :

OH

OH K2S2O8, H2O

OH

533

MECHANISM :

OH

O

O - H+

S2O82- SO42- H+

OH

H2O OSO3

OH

O

O

+ SO42-

S2O82H

OSO3

DISCONNECTION :

OH

OH R

R

OH

NOTES : This reaction involves the oxidation of monohydric phenols to dihydric phenols or aromatic amines using potassium persulfate in alkaline solution (Boyland – Sims reaction). The second hydroxyl group enters ortho to that already present but if that position is blocked, the para position is favoured. See also Boyland – Sims reaction.

REFERENCES : March : 554 Smith – March : 724 Smith : 261 Smith 2nd : 226 Houben – Weyl : E7b, 572; E11, 1003 Org. React. : 5, 421; 35, 421

1) K. Elbs, J. Prakt. Chem., 1893, 48, 179. 2) S.M. Setha, Chem. Rev., 1951, 49, 91. 3) O.C. Dermer; M.T. Edmison, Chem. Rev., 1957, 57, 77. 4) D.T. Hurst, Aust. J. Chem., 1983, 36, 1285.

534

5) K.G. Watson; A. Serban, Aust. J. Chem., 1995, 48, 1503. 6) E.C. Behrman; S. Chen; E.J. Behrman, Tetrahedron Lett., 2002, 43, 3221.

COMMENTS :

ELBS REACTION EXAMPLE :

O

400 - 450 oC

H3C

MECHANISM :

O

H+ OH

H3C H

H2C OH - H2O

H

H

DISCONNECTION :

O R

R

R1

R1 CH3

535

NOTES : Diaryl ketones with a methyl or methylene substituent adjacent to the carbonyl group undergo cyclodehydration to the corresponding anthracene derivative when pyrolysed. See also Scholl reaction.

REFERENCES : Org. React. : 1, 129 Science of Synthesis : 10, 241

1) A. Behr; W.A. van Dorp, Ber. Dtsch. Chem. Ges., 1873, 6, 753. 2) K. Elbs; E. Larsen, Ber. Dtsch. Chem. Ges., 1884, 17, 2847. 3) E.D. Bergman; J. Blum, J. Org. Chem., 1960, 25, 474. 4) M.S. Newman; V.K. Khanna, J. Org. Chem., 1980, 45, 4507. 5) A. Croisy; J. Mispelter; J.M. Lhoste; F. Zajdela; P. Jaquignon, J. Heterocycl. Chem., 1984, 21, 353.

COMMENTS :

ELTEKOFF KETONE SYNTHESIS EXAMPLE :

CH3 CH3

HO H3C

CH3 1) Br2 CH3 2) H2O, heat

H3C H

O

MECHANISM :

CH3 H3C H3C

H OH

H3C

H3C - H2O

H3C

CH3 CH3

CH3 CH3

CH3 Br2

536

Br

Br

H2O - 2 HBr

H3C H

O

DISCONNECTION :

CH3 CH3

HO

H3C H

H3C

O

CH3 CH3

NOTES : The formation of a ketone from tert-amylalcohol via an olefin and a dibromide.

REFERENCES : Houben – Weyl : 5/4, 162 Org. Synth. : 13, 68 Org. Synth. Coll. Vol. : 2, 408

1) A. Eltekoff, Ber. Dtsch. Chem. Ges., 1878, 11, 989. 2) W.L. Evers; H.S. Rothrock; H.M. Woodburn; E.E. Stahly; F.C. Whitmore, J. Am. Chem. Soc., 1933, 55, 1136. 3) C.M. Suter; H.D. Zook, J. Am. Chem. Soc., 1944, 66, 738. 4) L.J. Andrews; R.M. Kiefer, J. Am. Chem. Soc., 1953, 75, 3547. 5) E.A. Braude; E.A. Evans, J. Chem. Soc., 1955, 3332.

COMMENTS :

ELTEKOFF METHYLATION EXAMPLE :

H3C

CH3

H3C

CH3

CH3 CH2 + CH3Cl

CaO 220 oC

537

H3C CH3 CH3

MECHANISM :

H3C

CH3 + CH3Cl

H3C

CH3 CH3 CH2

CaO

H3C

CH3

H3C

CH3

H3C CH3 H3C Cl H3C CH3

- HCl

+

H3C CH3 CH3

NOTES : Olefins when treated with methyl halide in the presence of catalysts (CaO or PbO) yield a complex mixture of methylated olefins.

REFERENCES : 1) A. Eltekoff, J. Russ. Physik. Chem. Ges., 1878, 10, 86. 2) A. Eltekoff, J. Russ. Physik. Chem. Ges., 1878, 11, 412. 3) V.A. Miller; W.G. Lovell, Ind. Eng. Chem., 1948, 40, 138.

COMMENTS :

EMDE DEGRADATION EXAMPLE :

N Cl H3C CH3

Na(Hg) EtOH

538

CH3 N CH3

MECHANISM :

N CH3 CH3 CH3

CH3 N CH3

Na(Hg) - NaI

CH3

I

DISCONNECTION :

R1

R N R3 X R2

R R2 N R1

NOTES : A modification of the Hofmann degradation which involves treating an alcoholic or aqueous solution of a quaternary ammonium halide with sodium amalgam. The method can be successful where the Hofmann method fails, but cannot be used for the cleavage of ammonium salts with four saturated alkyl substituents. Photochemical Emde reactions are known. See also the von Braun amide and Hofmann degradation reactions.

REFERENCES : March : 446 Smith – March : 530 Houben – Weyl: 11/1, 973; E7b, 202 Org. React. : 7, 143, 278

1) H. Emde, Ber. Dtsch. Chem. Ges., 1909, 42, 2590. 2) H. Emde, Liebigs Ann. Chem., 1912, 391, 88. 3) H. Emde, Helv. Chim. Acta, 1932, 15, 1330. 4) A.J. Birch, J. Chem. Soc., Quat. Rev., 1950, 4, 78. 5) J.G. Cannon; P.R. Khonje; J.P. Long, J. Med. Chem., 1975, 18, 110. 6) V. Partali; S. Jolidon; H.J. Hansen, Helv. Chim. Acta, 1985, 68, 1952. 7) J. Lévy; M. Soufyane; C. Mirand; M.D. de Maindreville; D. Royer, Tetrahedron: Asymmetry, 1997, 8, 4127.

COMMENTS :

539

EMMERT – ASENDORF REACTION EXAMPLE :

+

H3C

CH3 CH3

Al HgCl2

O

N

N H3C

OH

MECHANISM :

O

+

Al HgCl2

N

HO

H2, PtO2

N

H2SO4, 60 oC - H2O

N

N

DISCONNECTION :

R2 N R1

N

OH

O

+

R2

R

R1

R

NOTES : 2-Pyridyldialkylcarbinols are prepared by the condensation of aldehydes or ketones with pyridine or its homologues in the presence of aluminium or magnesium, mercuric chloride and iodine. Small amounts of the 4-pyridyl compound are also formed. Besides open chain aliphatic and aromatic ketones, cyclic ketones can also be used. See also Comins and Friedel – Crafts reactions.

REFERENCES : 1) B. Emmert; E. Asendorf, Ber. Dtsch. Chem. Ges., 1939, 72A, 1188. 2) B. Emmert; E. Pirot, Ber. Dtsch. Chem. Ges., 1941, 74, 714. 3) G.B. Bachmann; M. Hamer; E. Dunning; R.M. Schisla, J. Org. Chem., 1957, 22, 1296. 4) C.E. Crawforth; C.A. Russell; O. Meth–Cohn, J. Chem. Soc., Chem. Commun., 1970, 1406. 5) R. Tschesche; W. Führer, Chem. Ber., 1978, 111, 3502.

540

COMMENTS :

ENDERS REACTION EXAMPLE :

O

O

H3C

CH3

H3C CH3

CH3

1) SAMP 2) LDA, Et2O 3) iC3H7I 4) O3, DCM

CH3

MECHANISM :

O

N

H3C

N

N N

H3C

OCH3

CH3 N NH2

1) LDA, Et2O 2) C3H7I

CH3

H3C

O H3C

CH3

O3, DCM or MeI, HCl

CH3

R R N

N

O O

OCH3

R1

N

R LDA

Li

N

R H3CO

R2

R1

R2

face of attack

541

CH3 CH3

OCH3

OCH3

DISCONNECTION : O R1 *

O R1

R2

R2

E

NOTES : The

asymmetric

electrophilic

substitution

of

aldehydes

and

ketones

via

(S)

or

(R)-1-amino-2-

methoxymethylpyrrolidine (SAMP or RAMP) hydrazones. Even more sterically hindered auxiliary have been prepared (SAMBO, RAMBO, SADP, SAEP, SAPP). See also Evans reaction.

REFERENCES : Smith : 945 Smith 2nd : 787 Org. Synth. : 65, 173, 183 Org. Synth. Coll. Vol. : 8, 26, 403

1) D. Enders; H. Eichenauer, Angew. Chem., Int. Ed. Engl., 1976, 15, 549. 2) D. Enders; H. Eichenauer; U. Baus; H. Schubert; K.A.M. Kremer, Tetrahedron, 1984, 40, 1345. 3) D. Enders; P. Fey; H. Kipphardt, Org. Prep. Proced. Int., 1985, 17, 1. 4) D. Enders; W. Gatzweiler; E. Dedericks, Tetrahedron, 1990, 46, 14757. 5) D. Enders; C. Nubling; H. Schubert, Liebigs Ann. Chem. / Receuil, 1997, 1089. 6) D. Enders; L. Wortmann; R. Peters, Acc. Chem. Res., 2000, 33, 157. 7) D. Enders; K. Funabiki, Org. Lett., 2001, 3, 1575. 8) A. Job; C.F. Janeck; W. Bettray; R. Peters; D. Enders, Tetrahedron, 2002, 58, 2253.

COMMENTS :

542

ENGLER INDOLE SYNTHESIS EXAMPLE :

SO2Ph N

O H3CO

N

+

SO2Ph 1) TiCl4, Ti(OiPr)4 DCM, - 78 oC 2) sat. aq. NH4Cl

H3CO N

HO

SO2Ph

N SO2Ph

H3CO

MECHANISM :

Ti4+

O H3CO

O

H3CO

N

i

TiCl4, Ti(O Pr)4 DCM, - 78 oC N

H3CO N

SO2Ph

Ti3+ H3CO

O

HO H OCH3

H3CO

HO H3CO

SO2Ph

PhO2S N

N SO2Ph SO2Ph N - CH3OH

SO2Ph

N SO2Ph

543

H

SO2Ph N

N OCH3 SO2Ph

NOTES : 2-Alkoxy-4-(N-phenylsulfonyl)imino-1,4-benzoquinones react with allyl-silane or stannanes, enol ethers, styrenes and simple π-systems in the presence of a regioselective Lewis acid. If BF3.Et2O is used benzofurans are obtained. However when TiCl4 is used indoles and dihydro indoles are obtained. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) T.A. Engler; K.O. Lynch, jr.; W. Chai; S.P. Meduna, Tetrahedron Lett., 1995, 36, 2713. 2) T.A. Engler; W. Chai; K.O. Lynch, jr., Tetrahedron Lett., 1995, 36, 7003. 3) T.A. Engler; S.P. Meduna; K.O. LaTessa; W. Chai, J. Org. Chem., 1996, 61, 9297. 4) T.A. Engler; J. Wanner, Tetrahedron Lett., 1997, 38, 6135. 5) H. Tohma; H. Watanabe; S. Takizawa; T. Maegawa; Y. Kita, Heterocycles, 1999, 51, 1785.

COMMENTS :

ERLENMEYER – FRÜSTÜCK SYNTHESIS EXAMPLE :

HO O

HO

N H

HO

H

1) NaHCO3 O 2)

H

3) H+

544

O

NH2

MECHANISM :

HO

O

O

base

N

O

N

H

H

H

O H

+

N

O

O

N

O

H

H H+

OH

+ HO

O

O

HO

O

H NH2

DISCONNECTION :

HO HO O

HO

H

O

NH2

N H

NOTES : The formation of phenyl serine by aldol addition of benzaldehyde and benzylideneglycine in weak alkaline solution followed by acidic hydrolysis. See also Erlenmeyer – Plöchl reaction.

REFERENCES : Houben – Weyl : 11/2, 427; E5, 583

1) E. Erlenmeyer; E. Früstück, Liebigs Ann. Chem., 1895, 284, 36. 2) G. Ehrhart; I. Hennig, Chem. Ber., 1954, 87, 892. 3) H.N.C. Wong; Z.L. Xu; H.M. Chang; C.M. Lee, Synthesis, 1992, 793. 4) V. Dalla; P. Cotelle; J.-P. Catteau, Tetrahedron Lett., 1997, 38, 1577. 5) A.V. Samet; D.J. Coughlin; A.C. Buchanan; A.A. Gakh, Synth. Commun., 2002, 32, 941.

545

COMMENTS :

ERLENMEYER – PLÖCHL AZLACTONE SYNTHESIS EXAMPLE :

O

O O HO

+

N H

O

O H3C H

CH3

H

Ac2O NaOAc

CH3

N CH3

MECHANISM :

H O

O O HO

H O

O

R

O

N H

R

-

OAc, - HOAc

O

H H

R N

N H

O

O

H

H

- H2O

N

R

O

O

R1

R1

O

O H+, - H2O

N R

H H R1

O NH2 O H2, 2 H2O

N

R1

OH

+ RCOOH

O

R

DISCONNECTION :

H R1

O

O O

N

O

O HO H

R

546

+

N R

R1

H

NOTES : Saturated azlactones are obtained by the action of acetic anhydride on α-acylamino acids. Unsaturated azlactones are obtained by the condensation of an aldehyde with an α-acylglycine in the presence of acetic anhydride and usually sodium acetate. Reduction and hydrolysis of these compounds yields amino acids. Ketones like cyclohexanone can also be employed. The reaction is one of the key steps in Monsanto’s L-DOPA synthesis. The reaction of an aldehyde with hippuric acid is often called the Erlenmeyer azlactone synthesis. See also Bergmann azlactone peptide synthesis, Dakin azlactone, Dakin – West and Erlenmeyer – Früstück reactions.

REFERENCES : Houben – Weyl : 11/2, 306, 373; E5, 406, 822 Org. React. : 1, 231; 3, 198 Org. Synth. : 19, 1 Org. Synth. Coll. Vol. : 2, 1

1) J. Plöchl, Ber. Dtsch. Chem. Ges., 1883, 16, 2815. 2) E. Erlenmeyer, jr., Liebigs Ann. Chem., 1893, 275, 1. 3) E. Baltazzi, J. Chem. Soc., Quat. Rev., 1955, 9, 150. 4) R.K. Griffith; H.J. Harwood, J. Org. Chem., 1964, 29, 2658. 5) K. Kaorakova; V.V. Koleva; E.M. Simova; B.I. Kurtev, Dokl. Bolg. Akad. Nauk., 1984, 37, 601. 6) G.G. Ivanova, Tetrahedron, 1992, 48, 177. 7) K.L. Bailey; T.F. Molinski, J. Org. Chem., 1999, 64, 2500. 8) K.A. Monk; D. Sarapa; R.S. Mohan, Synth. Commun., 2000, 30, 3167.

COMMENTS :

ESCHENMOSER – MEERWEIN – CLAISEN REARRANGEMENT EXAMPLE :

OH

+

OCH3 Me2N OCH3 CH3

547

NMe2 heat

O

MECHANISM :

OCH3 Me2N OCH3 CH3

- OCH3

OCH3 HO

Me2N

CH3

proton transfer - CH3OH

CH3 H3C

NMe2 CH3 H2C H

CH3

- HOCH3

O

R2N

CH3

O

CH3

CH3 [3,3]-sigmatropic R2N rearrangement

O

CH3

CH3O

DISCONNECTION :

R3

R

O

R4

HO

R1 R2

R4 R = H, Alk, Ar, OR1, R3 NR2, OSiR3

R1 R2

NOTES : The Claisen rearrangement has been adapted in recent years to provide a viable synthetic sequence for the preparation of functional groups other than aldehydes and ketones. Ester and amide syntheses have been reported which proceed through the Claisen intermediate. The Claisen rearrangement has also been used to generate transtrisubstituted double bonds stereoselectively, angularly-functionalised derivatives, substituted cyclohexenes, acids, and furans. The rearrangement proceeds with very high E-selectivity due to the destabilising 1,3-diaxial interactions in the transition state that would give the Z-isomer. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Claisen (Claisen – Ireland) rearrangement, Cope, Ficini – Claisen, Johnson – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES : Smith : 1243 Smith 2nd : 1025 Houben – Weyl : E10b2, 225 Org. Synth. : 54, 71, 77 Org. Synth. Coll. Vol. : 6, 298, 491

1) A. Eschenmoser; K. Steen; D. Felix; A.E. Wick, Helv. Chim. Acta, 1964, 47, 2425. 2) W. Fleischhacker; B. Richter, Monatsh. Chem., 1992, 123, 837. 3) B. Coates; D.J. Montgomery; P.J. Stevenson, Tetrahedron, 1994, 50, 4025.

548

4) Y. Baba; T. Sakamoto; S. Soejima; K. Kanematsu, Tetrahedron, 1994, 50, 5645. 5) J. Mulzer; J.W. Bats; B. List; T. Opatz; D. Trauner, Synlett, 1997, 441. 6) W. Fleischhacker; B. Richter, Monatsh. Chem., 2000, 131, 997. 7) T.P. Loh; Q.Y. Hu, Org. Lett., 2001, 3, 279. 8) S.N. Gradl; J.J. Kennedy–Smith; J. Kim; D. Trauner, Synlett, 2002, 411.

COMMENTS :

ESCHENMOSER – TANABE RING CLEAVAGE EXAMPLE :

O

CH3

CH3 O

O CH3

1) TsNHNH2 2) base

CH3

MECHANISM :

CH3

O R O R1

TsNHNH2

R

O S O N N H R O R1 R

R O O

R1 R1

549

R

O

O

R1

R1

DISCONNECTION : O

R

R

O

R1

R1

NOTES : The cleavage of α,β-epoxy ketones to an acetylene and a carbonyl compound via a sulfonylhydrazone and a base. The N-aminoaziridine version of the α,β-epoxyketone to alkynone fragmentation is a possible alternative in situations where the simple tosylhydrazone version fails. The tosylhydrazone method often gives good yields at low reaction temperatures, but it tends to be unsuccessful with the epoxides of acyclic enones or those not fully substituted at the β-carbon atom. Basically the reaction is a seven-centre Grob-type fragmentation. See also Grob fragmentation and Wharton reaction.

REFERENCES : March : 1037 Smith – March : 1347 Smith : 600 Smith 2nd : 516 Org. Synth. : 55, 52 Org. Synth. Coll. Vol. : 6, 679

1) M. Tanabe; D. F. Crowe; R. L. Dehn, Tetrahedron Lett., 1967, 8, 3943. 2) R.K. Müller; D. Felix; J. Schreiber; A. Eschenmoser, Helv. Chim. Acta, 1970, 53, 1479. 3) P.J. Kocienski; G.J. Cernigliaro, J. Org. Chem., 1976, 41, 2927. 4) C.B. Reese; H.P. Sanders, Synthesis, 1981, 276. 5) A. Abad; C. Agullo; M. Arno; A.C. Cunat; R.J. Zaragoza, Synlett, 1991, 787. 6) W. Dai; J.A. Katzenellenbogen, J. Org. Chem., 1993, 58, 1900. 7) M. Oda; Y. Masaki; S. Hayashi; R. Miyatake; S. Kuroda, Synthesis, 1999, 859. 8) C. Mück-Lichtenfeld, J. Org. Chem., 2000, 65, 1366.

COMMENTS :

550

ESCHENMOSER METHENYLATION EXAMPLE :

O

O CH2

1) 1.5 LiHMDS THF, - 78 oC 3 [H2C=NMe2]I 2) mCPBA, DCM / aq. NaHCO3

MECHANISM :

O

O

O R1

R H

: Base O

1) oxidation 2) heat

R1

R

Me2N

H2C NMe2 I

R1

R

R1

R

O H O N CH 3 CH3

R1

R

- Me2NOH

CH2

DISCONNECTION :

O R

O R2

R1

R

CH2

R2 R1

O R

O R1

R

R1

CH2

NOTES : The

introduction

of

a

(dimethylamino)methyl

group

dimethyl(methylene)ammonium iodide.

551

into

the

α-position

of

a

carbonyl

group

using

REFERENCES : 1) J. Schreiber; H. Maag; N. Hashimoto; A. Eschenmoser, Angew. Chem., Int. Ed. Engl., 1971, 10, 330. 2) Y. Jasor; M. Gaudry; M.J. Luche; A. Marquet, Tetrahedron, 1977, 33, 295. 3) E. Winterfeldt, J. Prakt. Chem., 1994, 336, 91. 4) F.W. Ng; H. Lin; S.J. Danishefsky, J. Am. Chem. Soc., 2002, 124, 9812.

COMMENTS :

ESCHENMOSER SULFIDE CONTRACTION EXAMPLE :

S H3C

CH3 O O

H3C 1) nBu3P 2) Et3N LiClO4

CH3 O

O

MECHANISM : Alkylative :

H3C

S N

H3C

H

O

Br O

H3C H3C

CH3

S N

H3C base

O

CH3

H3C

S N

B:

H3C H3C H3C

NH

OR1

H3C

CH3 O

CH3 N

H3C

S

R3P - R3P=S

N H3C

H3C R2NH2

CH3 N

H3C

CH3

H

N

552

R2

H

O

(R1)3OBF4

H+

CH3

Oxidative :

H+ H3C

CH3

S

X S

H3C

CH3

+ H3C

N

H

H

N

CH3

Benzoyl peroxide

H3C

N H

O

N O

X S CH3 N N H CH3 H3C O

H3C

H3C

CH3

S CH3

H3C N H

N

R3P

CH3 O

H3C H3C

CH3 N

H

N

O

S PR3

+

CH3

DISCONNECTION :

R

S

R1 O

R

R1 O O

O

NOTES : In both versions, one of the two coupling partners is a thioamide. In the alkylative Eschenmoser sulfide contraction the nucleophilic sulfur atom of the thioamide initiates an SN2 displacement of a suitable leaving group to give the thioiminoester. In the presence of an enolising base, the nucleophilic character of the carbon atom situated between the sulfur atom and the carbonyl group is unveiled and it obligingly attacks the proximal electrophilic thioiminoester carbon. The formation of an episulfide which subsequently collapses in the presence of a phosphine or a phosphite thiophile affords a vinylogous amide. In the oxidative Eschenmoser sulfide contraction the thioamide is oxidised by benzoylperoxide to give either the O-benzoate of the thiolactam-S-oxide or a symmetrical disulfide. The sulfur atom of the thioamide behaves as an electrophile. The nucleophilic enamide attacks the sulfur atom affording a sulfur-bridged intermediate. The vinylogous amidine is obtained after the action of a phosphine on the episulfide.

REFERENCES : March : 1049 Org. Synth. : 55, 127 Org. Synth. Coll. Vol. : 6, 776

553

1) A. Eschenmoser, Pure Appl. Chem., 1969, 20, 1. 2) P. Dubs; E. Götschi; M. Roth; A. Eschenmoser, Chimia, 1970, 24, 34. 3) M. Roth; P. Dubs; E. Götschi; A. Eschenmoser, Helv. Chim. Acta, 1971, 54, 710. 4) A. Corsaro; G. Perrini; M.G. Testa; U. Chiacchio, Phosphorous Sulfur, 1992, 71, 197. 5) D.J. Hart; L.Q. Sun; A.P. Kozikowski, Tetrahedron Lett., 1995, 36, 7787. 6) T.G. Minehan; Y. Kishi, Tetrahedron Lett., 1997, 38, 6811. 7) H.K. Lee; J. Kim; C.S. Pak, Tetrahedron Lett., 1999, 40, 2173. 8) D.W. Ma; H.Y. Sun, Tetrahedron Lett., 2000, 41, 1947. 9) M.C. Elliott; M.S. Long, Tetrahedron Lett., 2002, 43, 9191. 10) D. Russowsky; B.A. da Silveira Neto, Tetrahedron Lett., 2004, 45, 1437.

COMMENTS :

ESCHWEILER – CLARKE REACTION EXAMPLE :

NH2

O

NH2

aq. H H HCO2H

H3C

N

N CH3 H3C

CH3

MECHANISM :

O

H N H

O H

H O

H N CH2

H

O

DISCONNECTION :

R R1 N CH3

R R1 N H

554

O

- CO2

N CH3

NOTES : A method for the methylation of primary and secondary amines in which the amine is heated with formaldehyde and an excess of formic acid (hydride source) at 100 oC (microwave-enhanced methylation reactions are also known.) See also Foster – Decker, Leuckart – Wallach, Pictet – Spengler and Plöchl reactions.

REFERENCES : March : 899 Smith – March : 1188 Houben – Weyl : E16c, 848 Org. React. : 5, 301

1) W. Eschweiler, Ber. Dtsch. Chem. Ges., 1905, 38, 880. 2) H.T. Clarke; H.B. Gillespie; S.Z. Weisshaus, J. Am. Chem. Soc., 1933, 55, 4571. 3) K. Watanabe; T. Wakabayashi, J. Org. Chem., 1980, 45, 357. 4) R.W. Alder; D. Colclough; R.W. Mowlam, Tetrahedron Lett., 1991, 32, 7755. 5) F. Fache; L. Jacquot; M. Lemaire, Tetrahedron Lett., 1994, 35, 3313. 6) P.C.B. Page; H. Heaney; G.A. Rassias; S. Reignier; E.P. Sempler; S. Talib, Synlett, 2000, 104. 7) S. Torchy; D. Barbry, J. Chem. Res., Synop., 2001, 292. 8) J.R. Harding; J.R. Jones; S.-Y. Lu; R. Wood, Tetrahedron Lett., 2002, 43, 9487.

COMMENTS :

ÉTARD REACTION EXAMPLE :

O CH3

H 1) CrO2Cl2, CCl4 2) H2O

555

MECHANISM : Nenitzescu :

Cl

H CH2

CH3

Cl Cr HO O

Cl

O Cr O

Cl

CrO2Cl2

Cl O Cr Cl O Cl Cr Cl HO O

CrO2Cl2

O OH H2O, - CrCl3 - H2CrO4, - HCl

H CrVI --> CrIII, - 2 'H'

Cook :

H H R1

H R2 R

O Cl CrVI Cl O O Cl CrV Cl OH

H

R1

H

R2

R O Cl CrVI Cl O

Cl H Cl R1

O CrV O

O O CrV Cl Cl R

H H R1

R2

O Cl CrVI Cl O

H R1

O Cl CrVI Cl O

R2

O O CrIV Cl Cl R

H2O

H2O H H R1

R1

OH R2 R

H

R2

O H R1

R + Cl2(O)CrVOH

H R2 R

556

R R2

DISCONNECTION : O CH3

H

NOTES : The oxidation of side-chain aryl or cycloalkyl methyl groups to aldehydes using chromyl chloride. There is still a major debate over the mechanism of the oxidation, the proposed mechanisms by Nenitzescu et al. and Cook et al. are presented here.

REFERENCES : March : 1190 Smith – March : 1534 Smith : 316 Smith 2nd : 276 Houben – Weyl : 7/1, 143; E3, 242

1) A. Étard, C.R. Séances Acad. Sci., 1877, 84, 127. 2) J. Thiele; E. Winter, Liebigs Ann. Chem., 1900, 311, 353. 3) L.N. Ferguson, Chem. Rev., 1946, 38, 237. 4) W.H. Hartford; M. Darrin, Chem. Rev., 1958, 58, 25. 5) I. Necsoiu; A.T. Balaban; I. Pascaru; E. Sliam; M. Elian; C.D. Nenitzescu, Tetrahedron, 1963, 19, 1133. 6) F. Freemann; N.J. Yamachika, Tetrahedron Lett., 1969, 10, 3615. 7) C. Caldo, Chim. Ind. (Milan), 1981, 63, 126. 8) I.I. Schiketanz; F. Badea; A. Hanes; I. Necsoiu, Rev. Roum. Chim., 1984, 29, 353. 9) C.K. Cook; J.M. Mayer, J. Am. Chem. Soc., 1994, 116, 1855. 10) C.K. Cook; J.M. Mayer, J. Am. Chem. Soc., 1995, 117, 7139. 11) C. Limberg; R. Köppe; H. Schnöckel, Angew. Chem., Int. Ed., 1998, 37, 496. 12) C. Limberg, Angew. Chem., Int. Ed., 2003, 42, 5932.

COMMENTS :

557

EVANS REACTION EXAMPLE :

O

O

O H3C

N

H3C

O

H3C CH3

o

1) LDA, - 78 C 2) BocN=NBoc 3) LiOH 4) CH2N2 5) TFA 6) H2, Raney Ni

OCH3 NH2

MECHANISM :

Li O

O

O

N

H3C i

LDA, THF, - 78 oC

Pr

R

i

RX i

Pr

O H3C

O

N

H3C

O

N

H3C

O

O

O

O

LiOOH aq. THF

Pr

OH R

Li O

O N

H3C

O

N

H3C

H3C

O H3C

O Ph

LiOOH aq. THF

OH R

558

O RX

LDA, THF, - 78 oC

O

O

R

N

H3C

Ph

H3C

H3C

O

O

Ph

DISCONNECTION :

R

OH E E R

O

E

OH

Product

Reagents

RCOOH RCH2OH RCOOR1 RCOSR RCONR2 Weinreb amide

KOH, LiOH, LiOH/H2O LiBH4, LiAlH4 LiOR, NaOR, BrMgOR, Ti(OR)4 LiSR, BnSAlMe3Li N2H4, n-amylONO, NH4Cl, Cp2Ti(Zr)Cl2 MeONHMe.HCl, AlMe3

NOTES : The use of a temporary template for chiral induction. There are two auxiliaries based on L-valine and norephedrine which are of opposite absolute stereochemistry at the inducting group (iPr and CH3). Almost any acyl chloride can be attached via the nitrogen atom. Chelation between the two carbonyl oxygens fixes the conformation of the auxiliary and alkylation then occurs from the least hindered face. The enolate geometry is always Z-(O). Cleavage can be accomplished by hydrolysis, reduction, esterification or amidation. The so-called non-Evans (still syn) products can be obtained by using a titanium enolate. In this case the oxazolidinone carbonyl is also chelated. See also Enders and Mukaiyama reactions.

REFERENCES : Smith – March : 1221 Smith : 1172 Smith 2nd : 972 Org. Synth. : 68, 77, 83; 80, 57 Org. Synth. Coll. Vol. : 8, 339, 528

1) D.A. Evans; E. Vogel; J.V. Nelson, J. Am. Chem. Soc., 1979, 101, 6120. 2) D.A. Evans, Aldrichimica Acta, 1982, 15, 23. 3) D.A. Evans; M.D. Ennis; D.J. Mathre, J. Am. Chem. Soc., 1982, 104, 1737. 4) D.A. Evans; T.C. Britton; R.L. Dorow; J.F. Dellaria, J. Am. Chem. Soc., 1986, 108, 6395. 5) L.A. Trimble; J.C. Vederas, J. Am. Chem. Soc., 1986, 108, 6397. 6) D.A. Evans; R.L. Dow; T.L. Shih; J.M. Takacs; R. Zahler, J. Am. Chem. Soc., 1990, 112, 5290. 7) A.H. Hoveyda; D.A. Evans, Chem. Rev., 1993, 93, 1307. 8) C.W. Phoon; C. Abell, Tetrahedron Lett., 1998, 39, 2655. 9) D.A. Evans; J.T. Shaw, Actualite Chimique, 2003, 35.

559

10) C.C. Hughes; D. Trauner, Chemtracts: Org. Chem., 2003, 16, 511.

COMMENTS :

560

561

FRANCHIMONT DICARBOXYLIC ACID SYNTHESIS · 630 FRANCHIMONT NITRAMINE REACTION · 631

B

FRANKEL – SHIBASAKI REARRANGEMENT · 632 BEHN REACTION · 641

FRANKLAND – DUPPA REACTION · 633

BERGIUS PROCESS · 600

FRANKLAND SYNTHESIS · 634

BORSCHE – RIED MODIFICATION · 643

FREDENHAGEN PROCESS · 635 FREUDENBERG – SCHÖNBERG XANTHATE REARRANGEMENT · 636

F

FREUND REACTION · 637 FRIEDEL – CRAFTS – KARRER REACTION · 638

FAVORSKII – BABAYAN SYNTHESIS · 563

FRIEDEL – CRAFTS REACTION · 640

FAVORSKII ACETYLENE REARRANGEMENT · 564

FRIEDLÄNDER QUINOLINE SYNTHESIS · 642

FAVORSKII REARRANGEMENT · 565

FRIEDMAN SYNTHESIS · 644

FEIST – BÉNARY FURAN SYNTHESIS · 568

FRIES REARRANGEMENT · 645

FEIST CARBOXYLIC ACID SYNTHESIS · 569

FRITSCH – BUTTENBERG – WIECHELL REARRANGEMENT ·

FELDMAN INDOLE SYNTHESIS · 571

648

FELDMAN SYNTHESIS · 573

FRITSCH – KLING CHLORINATION · 649

FELKIN CYCLISATION · 575

FUJIMOTO – BELLEAU REACTION · 650

FENTON REACTION · 577

FUJIWARA LANTHANIDE REACTION · 652

FERINGA CHIRAL BUTENOLIDE SYNTHESIS · 578

FUKUYAMA INDOLE SYNTHESIS · 653

FERRARIO – ACKERMAN REACTION · 580

FUKUYAMA REDUCTION · 655

FERRIER REARRANGEMENT I · 582

FÜRSTNER INDOLE SYNTHESIS · 657

FERRIER REARRANGEMENT II · 584 FÉTIZON OXIDATION · 585 H

FICINI – CLAISEN REARRANGEMENT · 587 FIESSELMANN THIOPHENE SYNTHESIS · 588

HOMO-FAVORSKII REARRANGEMENT · 566

FINEGAN TETRAZOLE SYNTHESIS · 589 FISCHER – ACH URIC ACID SYNTHESIS · 590 FISCHER – DILTHEY CONDENSATION · 591

N

FISCHER – FINK PYRROLE SYNTHESIS · 593 FISCHER – HEPP REARRANGEMENT · 594

NENCKI MODIFICATION · 641

FISCHER – SPEIER ESTERIFICATION · 595 FISCHER – STECHE SYNTHESIS · 597

P

FISCHER – TROPSCH SYNTHESIS · 598 FISCHER – ZACH REACTION · 600

PERRIER MODIFICATION · 641

FISCHER – ZERWECK PYRROLE ALDEHYDE SYNTHESIS · 602

PETASIS – FERRIER REARRANGEMENT · 585

FISCHER ACETAL SYNTHESIS · 603

PETASIS MODIFICATION · 585

FISCHER ARYLHYDRAZINE SYNTHESIS · 604 FISCHER GLYCOSIDATION · 605 Q

FISCHER INDOLE SYNTHESIS · 607 FISCHER INDOLENINES SYNTHESIS · 609

QUASI-FAVORSKII REARRANGEMENT · 566

FISCHER OXAZOLE SYNTHESIS · 610 FISCHER PEPTIDE SYNTHESIS · 611

R

FISCHER PHENYLHYDRAZINE AND OXAZONE REACTION · 615 FITTIG – EGBERT REARRANGEMENT · 616

RADZIEWANOWSKI MODIFICATION · 641

FITTIG – ERDMANN SYNTHESIS · 617 FITTIG PINACOLONE REARRANGEMENT · 619 FLEMING – MAH ANTHRACENE SYNTHESIS · 620

V

FLOOD REACTION · 622 FONKEN – JOHNSON SYNTHESIS · 623

VILSMEIER – HAACK MODIFICATION · 641

FORSTER – DECKER REACTION · 624 FORSTER REACTION · 625 W

FOULDS – ROBINSON INDOLE / QUINOLINE SYNTHESIS · 627 FOWLER SYNTHESIS · 629

WALLACH DEGRADATION · 566

562

FAVORSKII – BABAYAN SYNTHESIS EXAMPLE :

2

H3C

CH3

OH +

H C C H

H3C

KOH xylene

O

OH CH3

C C CH3

CH3

MECHANISM :

OH H C C H

R

H C

KOH

R1

H C C R1

O H+ C C KOH

OH R R1

OH

OH

R3 R2

R

R3

R R2

R1

O

DISCONNECTION :

OH R

R

C C R2

R1

+

H C C R2

O

R1

NOTES : The synthesis of acetylenic alcohols by addition of ketones with terminal acetylenic hydrocarbons in the presence of anhydrous potassium hydroxide and a solvent like THF, liquid ammonia, DMSO or xylene. Acetylenic γ-glycols may be obtained from acetylene. See also Arens – van Dorp, Carroll (Kimel – Cope) rearrangement, Nef, Reppe acetylene synthesis and Whiting – Nayler reactions.

REFERENCES : March : 948 Smith – March : 1225 Houben – Weyl : E15, 1387

1) A. Favorskii, J. Russ. Physik. Chem. Ges., 1905, 37, 643. 2) A. Babayan, J. All. Chem., 1939, 9, 1631. 3) F. Moulin, Helv. Chim. Acta, 1951, 34, 2416.

563

4) L.A. Kondrat’eva; I.M. Potapova; I.N. Grigina; E.M. Glazunova; V.I. Nikitin, J. Org. Chem. USSR, 1976, 12, 948.

COMMENTS :

FAVORSKII ACETYLENE REARRANGEMENT EXAMPLE :

H3C H

H3C

KOH EtOH, 170 oC

CH3

MECHANISM :

H

EtO

H

+ KOEt H

EtOH - KOEt

EtOH

H

H

H OEt

H3C

CH3

H

H

K

- EtOH

K H3C

H3C

H CH3

K+

H OEt

H3C

OEt

CH2K

CH2K

+ KOEt

DISCONNECTION : H 3C H3C

CH3

H

NOTES : Alkyl substituted acetylenes rearrange by heating with ethanolic potassium hydroxide, e.g. n-propylacetylene gives ethyl methyl acetylene on treatment with ethanolic potassium hydroxide at about 170 oC.

564

REFERENCES : Houben – Weyl : 7/1, 227

A. Favorskii, J. Prakt. Chem., 1888, 37, 382.

COMMENTS :

FAVORSKII REARRANGEMENT EXAMPLE :

O OH

Cl NaOH

O

MECHANISM :

O

O

O H

X

X

X

B O

O X

O

- XOR

OR O

OR ROH

O

565

OR

Homo-Favorskii :

Nuc R R1

O R2 R3

H R4

R5

O

X R5

R4 R3

R

Base

O R3 R2 H

Nuc-H

R1 R2

R

R5 R4

R1

Quasi-Favorskii :

R

O

R2

R1

R3 X

R R2

O

R3

Nuc

R4

Nuc

R1 R4

DISCONNECTION :

O

R

O

X

R2 R3O

+ R3OH

R

R1

R2

R1

Nuc O R3 R2 H R

O

R5 R4

R1

R1 X = Cl, Br, I, OTs

R R2

H R4

R R3

Nuc

O R2 R3

R

O

X R5

R2

R1

R1 R4

R3 X

R4

X = Cl, Br, I R2-4 = H

NOTES : α-Halogenoketones rearrange with loss of halogen by bases into carboxylic acids or their derivatives, with the same number of carbon atoms in the rearranged starting material. Depending on whether the base is hydroxide ion, alkoxide ion or amine, the product is an acid salt, an ester or an amide. The reaction is sometimes called the Wallach degradation, but the classical Wallach degradation is the rearrangement of certain terpene dibromoketones. Many of these products are of uncertain purity and structure. There are two important variants, the homo-Favorskii rearrangement and the quasi-Favorskii rearrangement. The first one takes place when β-halo ketones are treated

566

with base in the presence of a nucleophile, the second one takes place when the α-halo ketone does not have any enolisable hydrogens.

REFERENCES : March : 1080 Smith – March : 1403 Smith 2nd : 802 Houben – Weyl : 4/2, 811; 8, 456; E15, 2862; E16b, 12 Org. React. : 11, 261

1) A. Favorskii; K. Desbout, J. Prakt. Chem., 1895, 51, 533. 2) O. Wallach, Liebigs Ann. Chem., 1918, 414, 271. 3) F.S. Fawcett, Chem. Rev., 1950, 47, 219. 4) R.B. Lotfield, J. Am. Chem. Soc., 1951, 73, 4707. 5) P.E. Eaton; T.W. Cole, jr., J. Am. Chem. Soc., 1964, 86, 962. 6) J.C. Barborak; L. Watts; R. Petit, J. Am. Chem. Soc., 1966, 88, 1328. 7) E. Wenkert; P. Bakuzis; R.J. Baumgarten; C.L. Leicht; H.P. Schenk, J. Am. Chem. Soc., 1971, 93, 3208. 8) J.-M. Conia; J.R. Salaun, Acc. Chem. Res., 1972, 5, 33. 9) F.G. Bordwell; J.G. Strong, J. Org. Chem., 1973, 38, 579. 10) G. Haufe, Synthesis, 1983, 235. 11) H.N.C. Wong; K.L. Lau; K.F. Tam, Top. Curr. Chem., 1986, 133, 83. 11) V. Moliner; R. Castillo; V.S. Safont; M. Oliva; S. Bohn; I. Tuňón; J. Andrés, J. Am. Chem. Soc., 1997, 119, 1941. 12) S. Braverman; M. Cherkinsky; E.V.K.S. Kumar; H.E. Gottlieb, Tetrahedron, 2000, 56, 4521. 13) G. Verniest; F. Bombeke; O.G. Kulinkovich; N. de Kimpe, Tetrahedron Lett., 2002, 43, 599.

COMMENTS :

567

FEIST – BÉNARY FURAN SYNTHESIS EXAMPLE : O Et

O

OEt

O

Cl

+

O

CH3

EtO aq. NaOH

CH3

Et

O

MECHANISM :

O R

H

O B

R

H

Cl CO2Et

R

CO2Et

Cl O

H+ O

EtO2C H3C

CH3 OH CO2Et

CH3

EtO2C OH

R

R O

H

CH3

- H2O

O

DISCONNECTION : O (R3)R2 (R2)R3

O

OR1 O

R2

O OR1

+

R

R3

Cl

O

R

NOTES : This is an initial aldol condensation at the carbonyl carbon of an α-halocarbonyl compound. Intramolecular displacement of the halide by the enolate oxygen atom gives ring-closure. The orientation of R2 and R3 depends if Oor C-alkylation takes place. When ammonia is used as condensing agent pyrrole derivatives are always obtained as secondary products. The chloroketone can be replaced by a 1,2-dichloro-ether, which decomposes in the presence of ammonia to form a monochloroketone or aldehyde. See also Knorr pyrrole reaction.

REFERENCES : Houben – Weyl : E6a, 51, 54, 64 Science of Synthesis : 9, 188; 10, 135

568

1) F. Feist, Ber. Dtsch. Chem. Ges., 1902, 35, 1539. 2) E. Bénary, Ber. Dtsch. Chem. Ges., 1911, 44, 489. 3) E. Bisagni; J.-P. Marquet; J.-D. Bourzat; J.-J. Pepin; J. André–Louisfert, Bull. Soc. Chim. Fr., 1971, 4041. 4) A. Gopalan; P. Magnus, J. Am. Chem. Soc., 1980, 102, 1756. 5) J. Kagan; K.C. Mattes, J. Org. Chem., 1980, 45, 1524. 6) R.C. Cambie; S.C. Moriatti; P.S. Rutledge; P.D. Woodgate, Synth. Commun., 1990, 20, 1923. 7) T. Lavoisier–Gallo; J. Rodriguez, J. Org. Chem., 1997, 62, 3787. 8) M.A. Calter; C. Zhu, Org. Lett., 2002, 4, 205. 9) E. Holtz; P. Langer, Synlett, 2004, 1805.

COMMENTS :

FEIST CARBOXYLIC ACID SYNTHESIS EXAMPLE :

H3C

CH3 CH3 O

HOOC 1) Cl2, hv 120 - 130 oC 2) NaOH EtOH

569

COOH COOH

MECHANISM :

H3C

CH3 CH3 O Cl2, hv 120 - 130 oC

Cl3C

CCl3

HOOC

CCl3

NaOH EtOH

COOH COOH

O

EtOH

Cl3C

CO2Et CCl3 O 21% H2SO4 140 oC

HOOC

COOH CCl3 O

HOOC

COOH

H2 Pd/CaCO3

CH3 O

DISCONNECTION :

HOOC

COOH CH3 H3C CH3

HOOC O

570

O

NOTES : Benzene-polycarboxylic acids are prepared by chlorinating acetylpolymethylbenzenes at high temperatures and hydrolysing the chlorinated product. The acetyl group facilitates the chlorination of the methyl groups.

REFERENCES : F. Feist, Liebigs Ann. Chem., 1932, 496, 99.

COMMENTS :

FELDMAN INDOLE SYNTHESIS EXAMPLE :

N H

Ts

CH3 N Ts

n

1) BuLi, THF 2) THF H3C I

Ph

TfO

MECHANISM :

R

N H

R1

R1

R1 R

R2 n

BuLi THF

H

N Li

R

R2 H

H3C

I

Ph

TfO R2 H3C

N R

R1

- HR2

571

H3C

N R

R1

H3C

R2

N H

Nu R

I

IPh

Ph Nu

R

TfO

- IPh

Nu R

Nu

rearrangement

Nu cycloaddition

R

R1

R

R1

R2

R2

insertion

Nu

Nu R

H

R

H

DISCONNECTION :

R1

Nu R

R2

R

Nu I Ph + Nu

R Nu

TfOH

R

H

Nu

H

R

NOTES : Five-membered nitrogen-containing heterocycles are prepared by inter- or intramolecular [3 atom + 2 atom] combination of sulfonamide anions with alkynyliodonium triflates via vinylidene carbene C-H insertion. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid,

572

Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) K.S. Feldman; M.M. Bruendl; K. Schildknegt, J. Org. Chem., 1995, 60, 7722. 2) K.S. Feldman; M.M. Bruendl; K. Schildknegt; A.C. Bohnstedt, J. Org. Chem., 1996, 61, 5440.

COMMENTS :

FELDMAN SYNTHESIS EXAMPLE :

CO2CH3

H3CO +

H3CO

CO2CH3

H3CO Ph2S2, hν AIBN, benzene 40 oC

H3CO

MECHANISM :

R

PhS

PhS

R

R

PhS

X

X

R X

PhS

PhS

R X

- PhS

R

573

DISCONNECTION :

X OR X OR

OR

X

X +

OR X OR

NOTES : The phenylthio radical-catalysed alkenylation of vinylcyclopropanes to give vinylcyclopentanes with high stereoselectivity.

REFERENCES : 1) K.S. Feldman; R.E. Simpson; M. Parvez, J. Am. Chem. Soc., 1986, 108, 1328. 2) K.S. Feldman; A.L. Romanelli; R.E. Ruckle, jr.; R.F. Miller, J. Am. Chem. Soc., 1988, 110, 3300. 3) K.S. Feldman; T.E. Fisher, Tetrahedron, 1989, 45, 2969. 4) K.S. Feldman; A.L. Romanelli; R.E. Ruckle, jr.; G. Jean, J. Org. Chem., 1992, 57, 100. 5) K.S. Feldman; H. Berven; A. Romanelli, J. Org. Chem., 1993, 58, 6851. 6) C.C. Huval; K.M. Church; D.A. Singleton, Synlett, 1994, 273.

COMMENTS :

574

FELKIN CYCLISATION EXAMPLE :

H 2

(PPh3)2NiCl2 n C3H7MgBr

MgBr H

MECHANISM : Activation of Grignard reagent :

RMgX

R R

R L2NiX2

RMgX

2

L2NiR2

L2Ni

L2Ni

MgX

MgBr

(PPh3)NiCl2 n C3H7MgBr

H

H CH2OD

D2O

H

MgBr

H3C

CH3 O

110 oC D2O

H CH2OD H

575

CH3 H H3C

OH

DISCONNECTION :

Y

Y

M

M

Y R1(R2)

R2(R1)

Y R1

M

R2

M

NOTES : The intramolecular magnesium-ene reaction. The Grignard reagent has to be activated in the presence of a phosphine nickel complex. There are two types of reactions. See also Alder ene, Tsuji – Trost and Tsuji – Wacker reactions.

REFERENCES : March : 794 Smith – March : 1021 Smith : 1249 Smith 2nd : 1030 Org. React. : 20, 133 Org. Synth. : 31, 85; 43, 27; 65, 159 Org. Synth. Coll. Vol. : 4, 766; 5, 459; 8, 427

1) H. Felkin; G. Swierczewski, Tetrahedron Lett., 1972, 13, 1433. 2) H. Felkin; L.D. Swart; G. Swierczewski; J.D. Umpleby, J. Chem. Soc., Chem. Commun., 1975, 242. 3) W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1989, 28, 38.

COMMENTS :

576

FENTON REACTION EXAMPLE :

COOH OH

COOH OH HO

OH

MECHANISM :

H2O2 + Fe2+

Fe3+ + HO- + HO

H2O2 + Fe3+

Fe2+ + H+ + HOO

DISCONNECTION :

OH

O COOH

R

R

COOH H

NOTES : The reaction is named after the method for the oxidation of α-hydroxy acids and 1,2-glycols, using hydrogen peroxide in the presence of a ferrous salt. Fenton discovered in 1894 that several metals have a special oxygen transfer properties which improve the use of hydrogen peroxide. Actually, some metals have a strong catalytic power to generate highly reactive hydroxyl radicals. Nowadays, the Fenton's reaction is used to treat a large variety of water pollution such as phenols, formaldehyde, pesticides, rubber chemicals and so on. See also Haber – Weiss (Haber – Willstätter), Milas and Ruff – Fenton reactions.

REFERENCES : March : 700, 713, 721 Smith – March : 916 Smith : 260, 1433 Smith 2nd : 225, 1182

577

1) H.J.H. Fenton, J. Chem. Soc., 1894, 65, 899. 2) D.J. Mackinnon; W.A. Waters, J. Chem. Soc., 1953, 323. 3) C. Walling, Acc. Chem. Res., 1975, 8, 125. 4) T. Tezuka; N. Narita; W. Ando; S. Oae, J. Am. Chem. Soc., 1981, 103, 3045. 5) M.A. Oturan; J. Pinson; N. Oturan; D. Deprez, New. J. Chem., 1999, 23, 793. 6) A.A. MacKay; J.J. Pignatello, Helv. Chim. Acta, 2001, 84, 2589. 7) A. Bozzi; T. Yuranova; J. Mielczarski; A. Lopez; J. Kiwi, Chem. Commun., 2002, 2202. 8) S. Frelon; T. Douki; A. Favier; J. Cadet, J. Chem. Soc., Perkin Trans. 1, 2002, 2866. 9) I. Melián-Cabrera; F. Kapteijn; J.A. Moulijn, Chem. Commun., 2005, 2178.

COMMENTS :

FERINGA CHIRAL BUTENOLIDE SYNTHESIS EXAMPLE :

O

CH3

H O

1) hν, 1O2, CH3OH Rose bengal 2) CH

O

3

O HO

CSA, C6H6, heat 3) CSA, DCM, heat

578

MECHANISM :

R HO

R1 O

O

CH3

HO

R

R

R1 O O

R1

H O

OH

O

CH3

O

CH3

benzene p-CH3C6H4SO3H

R R1 O O

O

CH3

DISCONNECTION :

CH3 CH3 O

H

O

+ O

HO

O

NOTES : These valuable chiral building blocks (butenolides) are prepared via the reaction of 5-hydroxy-2(5H)-furanones with dor l-menthol followed by recrystallisation or via the single photoxygenation of furfural. These routes are good alternatives for the carbohydrate-derived chiral butenolides. The double bond of these butenolides participates in diastereoselective dihydroxylation, 1,4-conjugate addition, [2+2] photochemical reactions, asymmetric Diels – Alder

579

reactions, 1,3-dipolar cycloadditions and tandem double Michael addition / intramolecular nucleophilic substitution reactions.

REFERENCES : Org. Synth. : 80, 66

1) B.L. Feringa; J.C. de Jong, J. Org. Chem., 1988, 53, 1125. 2) B.L. Feringa; B. de Lange; J.C. de Jong, J. Org. Chem., 1989, 54, 2471. 3) N. Hoffmann; H.-D. Scharf; J. Runsink, Tetrahedron Lett., 1989, 30, 2637. 4) J.F.G.A. Jansen; B.L. Feringa, Tetrahedron: Asymmetry, 1990, 1, 715. 5) J.F.G.A. Jansen; B.L. Feringa, Synth. Commun., 1992, 22, 1367. 6) B. Sundermann; H.-D. Scharf, Tetrahedron: Asymmetry, 1996, 7, 1995. 7) H. Huang; Q. Chen, Tetrahedron: Asymmetry, 1999, 10, 1295.

COMMENTS :

FERRARIO – ACKERMAN REACTION EXAMPLE :

S + 2S O

AlCl3

O

MECHANISM : S + 2S O

AlCl3

580

+ H2S O

DISCONNECTION :

R

S

R

R1

R1 O

O R = R1 = H, CH3, Cl, COCH3

NOTES : Phenoxathiines are obtained by the reaction between diphenyl ethers, sulfur and anhydrous aluminium chloride. The reaction can also be done electrochemically with a carbon-sulfur electrode.

REFERENCES : Org. Synth. : 18, 64 Org. Synth. Coll. Vol. : 2, 485

1) E. Ferrario, Bull. Soc. Chim. Fr., 1911, 9, 536. 2) F. Ackermann, German Patent, 1911, 234743. 3) E.W. Scott; J.R. Johnson, J. Am. Chem. Soc., 1932, 54, 2552. 4) C.M. Suter; F.O. Green, J. Am. Chem. Soc., 1937, 59, 2578. 5) C.L. Deasy, Chem. Rev., 1943, 32, 173. 6) G. Saint–Ruf; J. Servoin–Sidoine; J.P. Coïc, J. Heterocycl. Chem., 1974, 11, 287. 7) W.V. Steele; R.D. Chirico; S.E. Knipmeyer; A. Nguyen, J. Chem. Thermodyn., 1993, 25, 965. 8) D. Elothmani; Q.T. Do; J. Simonet; G. Le Guillanton, Bull. Soc. Chim. Fr., 1994, 131, 779.

COMMENTS :

581

FERRIER REARRANGEMENT I EXAMPLE :

OAc

OAc O

O

AcO

AcO H

H

1) BF3.Et2O 2) EtOH

OAc

OEt

MECHANISM :

OAc

OAc

O

O

AcO

AcO H

H

BF3.Et2O

O

OAc

O BF3

OAc

OAc O

O

AcO H

AcO

ROH

H OR

Et3SiH

OAc O AcO H

582

DISCONNECTION :

OAc O AcO

OAc

H OR

O AcO

OAc

H O

OAc

AcO H

NOTES : The rearrangement of 2,3-unsaturated sugars using boron trifluoride etherate to form the delocalised allyloxocarbenium ion. This ion can be trapped with an alcohol or triethylsiliane.

REFERENCES : 1) R.J. Ferrier, Adv. Carbohydr. Chem., 1965, 20, 67. 2) R.J. Ferrier; N. Prasad, J. Chem. Soc., 1969, 570. 3) J.C. López; A.M. Gomez; S. Valverde; B. Fraser–Reid, J. Org. Chem., 1995, 60, 3851. 4) B. Fraser–Reid, Acc. Chem. Res., 1996, 29, 57. 5) T. Linker; T. Sommermann; T. Gimisis; C. Chatgilialoglu, Tetrahedron Lett., 1998, 39, 9637. 6) S. Konstantinovic; J. Predojevic; S. Gojkovic; V. Pavlovic; J. Csanádi, J. Serbian Chem. Soc., 2001, 66, 499. 7) R.J. Ferrier, Top. Curr. Chem., 2001, 215, 153. 8) B.K. Bettadaiah; P. Srinivas, Tetrahedron Lett., 2003, 44, 7257. 9) S. Anjaiah; S. Chandrasekhar; R. Grée, J. Mol. Catal. A: Chem., 2004, 214, 137. 10) S. Hotha; A. Tripathi, Tetrahedron Lett., 2005, 46, 4555.

COMMENTS :

583

FERRIER REARRANGEMENT II EXAMPLE :

OTs O O

BzO

BzO H OBz

H OTs OCH3

1) NaI, Ac2O, AgF, BzO pyridine 2) HgCl2, aq. acetone

OTs

3) Ac2O, pyridine

MECHANISM :

OTos H2C BzO BzO

O OTos

BzO OMe

NaI Ac2O AgF pyridine

O

BzO

OTos

HgCl2 OMe

aq. acetone

HgCl O

O

BzO

BzO H2O

BzO

TosO

BzO

OMe

O BzO BzO OTs

DISCONNECTION :

O O

584

OTos

OMe

Ac2O pyridine

NOTES : The transformation of unsaturated glycosides into cyclohexanone derivatives by heating in aqueous acetone with mercury(II) salts. The 5-hydroxyl and the 3-substituent of the product are predominately in a trans relationship. The Petasis modification better known as the Petasis – Ferrier rearrangement uses Cp2TiMe2, followed by iBu3Al, and proceeds through a similar oxocarbenium intermediate.

REFERENCES : 1) R.J. Ferrier, J. Chem. Soc., Perkin Trans. 1, 1979, 1455. 2) D.H.R. Barton; S. Augy–Dorey; J. Camara; P. Dalko; J.M. Delaumény; S.D. Géro; B. Quiclet–Sire; P. Stütz, Tetrahedron, 1990, 46, 215. 3) N. Yamauchi; T. Terachi; T. Eguchi; K. Kakinuma, Tetrahedron, 1994, 50, 4125. 4) N.A. Petasis; S.-P. Lu, Tetrahedron Lett., 1996, 37, 141. 5) A.B. Smith III; P.R. Verhoest; K.P. Minbiole; J.J. Lim, Org. Lett., 1999, 1, 909. 6) D.R. Carberry; S. Reignier; J.W. Myatt; N.D. Miller; J.P.A. Harrity, Angew. Chem., Int. Ed., 2002, 41, 2584. 7) A.B. Smith III; C. Sfouggatakis; D.B. Gotchev; S. Shirakami; D. Bauer; W. Zhu; V.A. Doughty, Org. Lett., 2004, 6, 3637. 8) A.B. Smith III; E.F. Mesaros; E.A. Meyer, J. Am. Chem. Soc., 2005, 127, 6948.

COMMENTS :

FÉTIZON OXIDATION EXAMPLE :

H3C

OH

H3C Ag2CO3 on Celite

OH

OH O

MECHANISM :

H

H O Ag

H +

+

Ag O

O O

Ag

O

H Ag+

Ag

O

O

H

H3C

CH3

O O Celite

Ag+

O

585

DISCONNECTION :

R1

R O

R R = H or Alk

R1 OH

NOTES : The oxidation of primary and secondary alcohols using silver carbonate and Celite. The alcohol is reversibly chemisorbed on the Celite surface. In the second irreversible step electron transfer takes place involving a second silver cation. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : March : 1168 Smith : 250 Smith 2nd : 217

1) M. Fétizon; M. Golfier, C.R. Séances Acad. Sci., 1968, 267, 900. 2) M. Fétizon; M. Golfier; M. Morgues, Tetrahedron Lett., 1972, 13, 4445. 3) A. Mckillop; D.W. Young, Synthesis, 1979, 401. 4) B.M. Trost; T.P. Klun, J. Am. Chem. Soc., 1981, 103, 1864. 5) C.H. Heathcock; J.A. Stafford; D.L. Clark, J. Org. Chem., 1992, 57, 2575. 6) A.G.H. Wee; L. Zhang, Org. Prep. Proced. Int., 1996, 28, 339. 7) Y.R. Lee; J.Y. Suk; B.S. Kim, Org. Lett., 2000, 2, 1387. 8) D.A. Evans; G. Borg; K.A. Scheidt, Angew. Chem., Int. Ed., 2002, 41, 3188.

COMMENTS :

586

FICINI – CLAISEN REARRANGEMENT EXAMPLE :

O

O C5H12 O

N

OH

+

O toluene 0.1 PNBSA sealed tube 12 hours

Ph Ph

O

CH3

N C5H12 Ph

Ph

MECHANISM :

R N

R

R

N

R

O

H R

R1

R2

OH

- H+ R2

R1

R N R1

R2

H+

R

R N

O

O

R1 R2

DISCONNECTION :

R R N

H

N

R

O +

R1

R2

OH

R1

R2

NOTES :

The Claisen rearrangement of ynamine and ynamides. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Claisen (Claisen – Ireland) rearrangement, Cope, Eschenmoser – Meerwein – Claisen rearrangement, Johnson – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES :

1) J. Ficini; C. Barbara, Tetrahedron Lett., 1966, 7, 6425. 2) J. Ficini; N. Lumbroso–Bader; J. Pouliquen, Tetrahedron Lett., 1968, 9, 4139. 3) J. Ficini, Tetrahedron, 1976, 32, 1448. 4) T. Nakai; H. Setoi; Y. Kageyama, Tetrahedron Lett., 1981, 22, 4097.

587

5) J.A. Mulder; R.P. Hsung; M.O. Frederick; M.R. Tracey; C.A. Zificsak, Org. Lett., 2002, 3, 1383.

COMMENTS :

FIESSELMANN THIOPHENE SYNTHESIS EXAMPLE :

O H3C

HS

+ H3C

H3C

O

H

OCH3

Cl

OCH3

H3C

CH3OH

S O

MECHANISM :

O R2

O

H

HS

+ R1

Cl

OEt

- HCl

H+ R2

O

R1

S

H OEt O

HO R2 R1

R2

H

OEt

S H O

H

OEt - H2O

R1

S O

DISCONNECTION :

R1 R2

O

R

R1

S O

O

R

OR3

+ R2

R3 = H, Alk

Cl

HS

OR3

NOTES :

1,3-Dicarbonyl compounds or β-chlorovinyl aldehydes react with thioglycolates or other thiols possessing a reactive methylene group (intramolecular aldol condensation) to give thiophene-2-carboxylic esters. Many selenophene are

588

prepared by a modified Fiesselmann synthesis. See also Baumann – Fromm, Bogert – Herrera, Hinsberg thiophene, Volhard – Erdmann and Willgerodt – Kindler reactions.

REFERENCES : Science of Synthesis : 9, 315

1) H. Fiesselmann, German Patent, 1957, 1020641. (Chem. Abs., 1960, 54, 2357b) 2) Z. Arnold; J. Zemlicka, Proc. Chem. Soc., 1958, 227. 3) S. Hauptmann; E.-M. Werner, J. Prakt. Chem., 1972, 314, 499. 4) R. Arnaud; A. Bensadat; A. Ghobsi; A. Laurent; I. Ledrean; S. Lesniak, Bull. Soc. Chim. Fr., 1994, 131, 844. 5) G. Kirsch; D. Prim; F. Leising; G. Mignani, J. Heterocycl. Chem., 1994, 31, 1005. 6) D.F. Andres; E.G. Laurent; B.S. Marquet, Tetrahedron Lett., 1997, 38, 1049.

COMMENTS :

FINEGAN TETRAZOLE SYNTHESIS EXAMPLE :

F3C

F3C C N + N N N C8H17

o

130 C

C8H17 N N N N

MECHANISM :

N H

R R

N

+

H

R

R

N H

N3

N

N N

589

H N

N N N

DISCONNECTION : N N N R1 N

RCN + R1N3

R

NOTES :

The tetrazole synthesis from azides by dipolar cycloaddition with Lewis acid activated nitriles or intramolecularly with nitriles in the presence of acids. See also Huisgen reaction.

REFERENCES :

1) K. von Kereszty; Wolf, German Patent, 1935, 611692. (Chem. Abs., 1935, 29, 5994.) 2) W.G. Finnegan; R.A. Henry; R. Lofquist, J. Am. Chem. Soc., 1958, 80, 3908. 3) W.R. Carpenter, J. Org. Chem., 1962, 27, 2085.

COMMENTS :

FISCHER – ACH URIC ACID SYNTHESIS EXAMPLE :

O H

H N

N N H

O

O

O

H

NH2

(CH3CO)2O ZnCl2 heat

O

H N

N H

N H

N

O

O

MECHANISM : O H O

N N H

H N O

O NH2

H HCl, heat - H2O

590

O

O

H N

N H

N H

N

O

DISCONNECTION :

O R

N

R N

X N R1

N R2

O

O

H N X = O, S R1 = H, Alk, Ar

O

N R2

H N O

O N H R1

NOTES :

Pseudoric acid dehydrates and cyclises with oxalic acid or hydrochloric acid or with zinc chloride in acetic anhydride. The method can be applied to the synthesis of alkylated uric acids and of aminodihydroxypurines. See also Behrend – Roosen, Horbaczewski and Traube reactions.

REFERENCES :

1) E. Fischer; L. Ach, Ber. Dtsch. Chem. Ges., 1895, 28, 2473. 2) E. Fischer, Ber. Dtsch. Chem. Ges., 1895, 28, 2480. 3) H.C. Koppel; R.K. Robins, J. Am. Chem. Soc., 1958, 80, 2751.

COMMENTS :

FISCHER – DILTHEY CONDENSATION EXAMPLE :

H3C H3C

Cl

O O O

+ (NH2)2CO

base

Cl

N

H3C

N

O O

591

H

H3C

H

MECHANISM :

H3C

H3C

CH3

CH3 O

Cl

Cl

H2N

O O

NH2

- HCl

O

H N

Cl O O

N

H3C

N

O

- HCl

NH2

H

H3C

O

O

H

DISCONNECTION :

O

H R

N

R

O R

Cl

N O

R Cl

O O

H

O +

H2N

NH2

NOTES : C,C-Dialkylbarbituric acids are obtained by the reaction of a dialkyl malonyl chloride with urea. A similar condensation

occurs with guanidine.

REFERENCES :

1) E. Fischer; A. Dilthey, Liebigs Ann. Chem., 1904, 335, 334. 2) H.J. Morsman, Helv. Chim. Acta, 1935, 18, 1254.

COMMENTS :

592

FISCHER – FINK PYRROLE SYNTHESIS EXAMPLE :

NOH H3C

H3C

+

CO2Et

OEt O

O

H3C

Zn AcOH

OEt

CO2Et

N H

MECHANISM :

O O

EtO H3C

O O

O tautomerisation

O

EtO H3C

O

OH

OEt

O - H2O

H2N

N H O

CH3

CH3 O

H

OEt

H OEt H3C

N H

O

O

HO proton transfer

H3C

H3C

- H2O

CH3 N H

O

DISCONNECTION :

R2

R2 R

R1

N H

O +

R1

R

H2N O

O

O

NOTES :

The interaction of the diethylacetal of acetylacetaldehyde with ethyl isonitrosoacetoacetate and zinc dust in acetic acid gives ethyl 2-methyl-pyrrole-5-carboxylate. This compound is also obtained when isonitrosobutyrylacetate is employed. The zinc reduces the NOH to NH2. In some systems mixtures of Fischer – Fink and Paal – Knorr products are obtained. See also Barton – Zard, Clauson–Kaas, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Houben – Weyl : E6a, 667

593

1) H. Fischer; E. Fink, Z. Physiol. Chem., 1944, 280, 123. 2) C.A.C. Haley; P. Maitland, J. Chem. Soc., 1951, 3165. 3) K.M. Smith; E.M. Fujinari; R.K. Pandey; H.D. Tabba, J. Org. Chem., 1986, 51, 4667. 4) A.R. Butler; S.D. George, Tetrahedron, 1993, 49, 7017. 5) A.R. Butler; S.D. George, J. Chem. Soc., Perkin Trans. 2, 1994, 315. 6) A. Alberola; L. Caloo; A. Gonzalez–Ortega; A.P. Encabo; M.C. Sanudo, Synthesis, 2001, 1941.

COMMENTS :

FISCHER – HEPP REARRANGEMENT EXAMPLE :

H3C

N

N

H3C

O

N

H

acid, EtOH H

N

O

MECHANISM :

R

N

N

H R N N O

O

R

N

R

H

N

H+ - H+ H

H

H

N O

DISCONNECTION :

R

O

N

R

H

N

H

N

594

N

O

O

N

H

NOTES : N-Nitroso derivatives of secondary N-alkyl or aryl anilines undergo intramolecular rearrangement in acid solution to

form the corresponding (usually p-) nitroso-N-alkyl or aryl anilines. See also Orton rearrangement.

REFERENCES : March : 558 Smith – March : 728 Houben – Weyl : 4/2, 57; 11/1, 834

1) O. Fischer; E. Hepp, Ber. Dtsch. Chem. Ges., 1886, 19, 2991. 2) S.S. Johal; D.L.H. Williams; E. Buncel, J. Chem. Soc., Perkin Trans. 2, 1980, 165. 3) S. Sueyoshi; S. Kamiya, Chem. Pharm. Bull., 1981, 29, 1267. 4) D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1, 1982, 801. 5) J.B. Kyziol, J. Heterocyl. Chem., 1985, 22, 1301. 6) P. Kannan; K. Pitchumani; S. Rajogopal; C. Srinivasan, J. Mol. Catal. A: Chem., 1997, 118, 189. 7) P.I. Morris, Chem. Ind. (London), 1999, 968.

COMMENTS :

FISCHER – SPEIER ESTERIFICATION EXAMPLE :

H3C

O

+ CH3OH

H+

OH

H2O +

H3C

O OCH3

595

MECHANISM :

H Cl O

O R

R

OH

H

H

O R HO

OH

O * H

R1

R1 O*H H O R H2O

O*

R1

O

- H2O R

H

OH2

O

* OR 1

R

* OR 1

DISCONNECTION :

O R

O OR1

R

OH

+ R1OH

NOTES :

The use of mineral acids as catalysts in esterification of carboxylic acids with alcohols.

REFERENCES : March : 393 Smith – March : 484 Org. Synth. : 5, 53; 36, 3 Org. Synth. Coll. Vol. : 1, 237; 4, 169

1) E. Fischer; A. Speier, Ber. Dtsch. Chem. Ges., 1895, 28, 3252. 2) E.D. Hughes, J. Chem. Soc., Quat. Rev., 1948, 2, 110. 3) M.L. Bender, Chem. Rev., 1960, 60, 53. 4) E. Haslam, Tetrahedron, 1980, 36, 2409. 5) D.M. Birney; S.D. Starnes, J. Chem. Educ., 1996, 76, 1560. 6) A.C. Cole; J.L. Jensen; I. Ntai; K.L.T. Tran; K.J. Weaver; D.C. Forbes; J.H. Davis, jr., J. Am. Chem. Soc., 2002, 124, 5962.

7) D.C. Forbes; K.J. Weaver, J. Mol. Catal. A: Chem., 2004, 214, 129.

596

COMMENTS :

FISCHER – STECHE SYNTHESIS EXAMPLE :

H3C CH3

CH3

+

CH3

CH3I

N H

H3C

CH3

CH2 N CH3

N

MECHANISM :

I CH3

H3C

CH3 N H

CH3

Methylation followed by Plancher rearrangement H3C

H3C

CH3

CH3

+

CH3 N H CH 3

N

CH3 CH2

N CH3

DISCONNECTION :

R

R CH3

CH3

N H

+ RI

N H

NOTES :

The formation of indolenines (pseudoindoles) by heating indoles with an alkyl iodide. The migration of an alkyl group of the indole from C-2 to C-3 during methylation with methyl iodide is the Plancher rearrangement. See also Plancher rearrangement.

597

REFERENCES :

1) E. Fischer; A. Steche, Ber. Dtsch. Chem. Ges., 1887, 20, 818. 2) E. Fischer; A. Steche, Liebigs Ann. Chem., 1887, 242, 348.

COMMENTS :

FISCHER – TROPSCH SYNTHESIS EXAMPLE :

x H2 + y CO

catalyst, heat, pressure

598

CH3-(CH2)n-CH3

MECHANISM :

H2C

O C

C

O H2 - H2O

H2 C

CH2

H

H

H

H

H2 C

H2

H2 H C

H2 C

H2 CH3 C

CH3 CH2

H H H2

H

H H H

DISCONNECTION :

CH3-(CH2)n-CH3

H2 + CO

NOTES :

The catalytic hydrogenation of carbon monoxide using enriched synthesis gas from passage of steam over heated coke will afford hydrocarbons, aliphatic alcohols, aldehydes and ketones. The product ratio varies with conditions. The high pressure Synthol process gives mainly oxygenated products and addition of olefins in the presence of cobalt

599

catalyst, while the Oxo synthesis, produces aldehydes. Normal pressure synthesis leads mainly to petroleum-like hydrocarbons. A similar process is the Bergius process.

REFERENCES : Houben – Weyl : 4/2, 164, 183, 184, 186, 254, 332

1) F. Fischer; H. Tropsch, Ber. Dtsch. Chem. Ges., 1923, 56, 2428. 2) F. Fischer; H. Tropsch, Brennstoff-Chem., 1923, 4, 193. 3) P. Biloen; W.M.H. Sachtler, Adv. Catal., 1981, 30, 165. 4) C.K. Rofer–de Poorter, Chem. Rev., 1981, 81, 447. 5) W.A. Herrmann, Angew. Chem., Int. Ed. Engl., 1982, 21, 117. 6) P.M. Maitlis; H.C. Long; R. Quyoum; M.L. Turner; Z.-Q. Wang, Chem. Commun., 1996, 1. 7) G.P. van der Laan; A.A.C.M. Beenackers, Catal. Rev., 1999, 41, 255. 8) N. Tsubaki; Y. Zhang; S. Sun; H. Mori; Y. Yoneyama; X. Li; K. Fujimoto, Catal. Commun., 2001, 2, 311. 9) H. Schulz, Top. Catal., 2003, 26, 73. 10) G.L. Bezemer; U. Falke; A.J. van Dillen; K.P. de Jong, Chem. Commun., 2005, 683.

COMMENTS :

FISCHER – ZACH REACTION EXAMPLE :

OH

OAc O

HO HO OH

O OH

1) excess Ac2O 2) HBr, CH3COOH 3) Zn dust, CH3COOH

600

AcO AcO

MECHANISM :

OAc

OH

O

O HO HO OH

OH

excess Ac2O

AcO AcO OAc

OAc

OAc OAc

O HBr CH3COOH

O

AcO AcO OAc

Br

AcO AcO

Zn dust CH3COOH

DISCONNECTION :

OH

OAc

O

O

HO HO

AcO AcO

OH

OH

NOTES :

The classic synthesis of glucals under acidic conditions. However, this reaction fails in the furanoid glycal synthesis. A modification is based on the reductive elimination work by Scheffold. Vitamin B-12, ammonium chloride and zinc dust in methanol can catalyse the reduction, although it also fails again with the furanoid glycals. For a preparation of these compounds see Ireland et al.

REFERENCES :

1) E. Fischer; K. Zach, Sitzungsber. Kl. Preuss. Akad. Wiss., 1913, 27, 311. 2) E. Fischer; K. Zach, Chem. Zentralblatt, 1913, 1968. 3) R.J. Ferrier, Adv. Carbohydr. Chem. Biochem., 1965, 20, 67. 4) R.J. Ferrier, Adv. Carbohydr. Chem. Biochem., 1969, 24, 199. 5) R. Scheffold; E. Amble, Angew. Chem., Int. Ed. Engl., 1980, 19, 629. 6) R.E. Ireland; S. Thaisrivongs; N. Vanier; C.S. Wilcox, J. Org. Chem., 1980, 45, 48. 7) C. Forbes; R.W. Frank, J. Org. Chem., 1999, 64, 1424. 8) E. Wieczorek, Acros Organics Acta, 2003, 10, 13.

COMMENTS :

601

FISCHER – ZERWECK PYRROLE ALDEHYDE SYNTHESIS EXAMPLE :

CO2Et

H3C

O

CH3

N H

CO2Et

H3C

1) HCl, HCN Et2O 2) H+

CH3

N H

H

MECHANISM :

H3C

CO2Et

H3C

H3C

CO2Et

H+ N C

N C N H

CH3

H

HCl, HCN Et2O H3C

CO2Et

CH3

N H

H+

CO2Et

H

H3C

N H

CH3

CO2Et

.

HCl HN N H

H

CH3

O

H+, H2O

N H

H

CH3

DISCONNECTION :

R

R

R1

R1

O H

N H

R2

N H

R2

NOTES :

An ethereal or chloroform solution of a pyrrole and hydrogen cyanide on treatment with hydrogen chloride yields an αalkimine hydrochloride, which on hydrolysis forms an α-pyrrole aldehyde. If the α-position is already substituted, the βcompound is obtained. See also Gattermann formylation and Hoesch – Houben reactions.

REFERENCES : Houben – Weyl : 7/1, 27

602

1) H. Fischer; W. Zerweck, Ber. Dtsch. Chem. Ges., 1922, 55, 1942. 2) F.F. Blicke; J.A. Faust; J.E. Gearien; R.J. Warzynski, J. Am. Chem. Soc., 1943, 65, 2465. 3) S.F. MacDonald, J. Chem. Soc., 1952, 4184.

COMMENTS :

FISCHER ACETAL SYNTHESIS EXAMPLE :

H

CH3

H H3C

+ EtOH CaCl2

O

OEt OEt

MECHANISM :

EtO H

O

O R

R

OH R OEt H

H

EtO

H

EtOH

H

O

OH2 OEt R H

R

Et H

R

OEt H OEt

EtO

DISCONNECTION :

OR1 R OR1 H

R

H

+ R1OH

O

NOTES :

Acetals are obtained by the action of excess of an alcohol on an aldehyde with e.g. calcium chloride as catalyst.

603

REFERENCES : March : 889 Smith – March : 1180 Smith : 655 Smith 2nd : 554 Houben – Weyl : 7/1, 419 Org. Synth. : 3, 1; 74, 1 Org. Synth. Coll. Vol. : 1, 1; 9, 39

1) E. Fischer; G. Giebe, Ber. Dtsch. Chem. Ges., 1897, 30, 3053. 2) B. Helferich; F.A. Fries, Ber. Dtsch. Chem. Ges., 1925, 58, 1246. 3) R.B. Loftfield, J. Am. Chem. Soc., 1951, 73, 1365. 4) K.C. Brannock, J. Am. Chem. Soc., 1959, 81, 3379. 5) D.K. Black; S.R. Landor, J. Chem. Soc., 1965, 5225. 6) F. Barbot; P. Miginiac, Helv. Chim. Acta, 1979, 62, 1451.

COMMENTS :

FISCHER ARYLHYDRAZINE SYNTHESIS EXAMPLE :

H N

N N 2 Na2SO3

NH2

MECHANISM :

N N

N N SO3Na

NaSO3

H N N SO3Na SO3Na

NaHSO3

H hydrolysis

604

2 NaHSO4 +

N NH2

DISCONNECTION :

Ar

H N

Ar

NH2

N N

NOTES :

Aromatic diazo-compounds on reduction with alkali sulfite yield arylhydrazine sulfonates, which on acid hydrolysis form arylhydrazine salts.

REFERENCES : Org. Synth. : 2, 71 Org. Synth. Coll. Vol. : 1, 432

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1875, 8, 79. 2) E. Fischer, Ber. Dtsch. Chem. Ges., 1875, 8, 589. 3) R. Huisgen; R. Lux, Chem. Ber., 1960, 93, 540.

COMMENTS :

FISCHER GLYCOSIDATION EXAMPLE :

OH

OH O

O

HO OH

H OH

OH H

HO CH3OH HCl, reflux

605

H OH OH

OCH3

MECHANISM :

OH

OH O

O

HO OH

H

HO OH2

H

HCl, reflux

OH OH

H

OH

OH

OH

H

OH O

O

HO H OH

HO

H CH3OH

H OH

OH

OCH3

OH

DISCONNECTION :

R OCH3

R OH R = carbohydrate

NOTES :

The glycosidation of sugars in boiling acidified alcohol. See also Kahne glycosidation, Koenigs – Knorr, Michael glycosidation and Schmidt glycosidation reactions.

REFERENCES :

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1893, 26, 2400. 2) T.S. Patterson; J. Robertson, J. Chem. Soc., 1929, 300. 3) J. Stanek; J. Moravcova; J. Jary, J. Carbohydr. Chem., 1985, 4, 79. 4) J. Wu; A.S. Serianni, Carbohydr. Res., 1991, 210, 51. 5) A. Corma; S. Iborra; S. Miquel; J. Primo, J. Catal., 1996, 161, 713. 6) A. Corma; S. Iborra; S. Miquel; J. Primo, J. Catal., 1998, 180, 218. 7) J.R.J. Ruiz; G. Osswald; M. Petersen; W.D. Fessner, J. Mol. Catal. B: Enzymatic, 2001, 11, 189. 8) A. Nowacki; J. Błażejowski; A. Wiśniewski, J. Mol. Struct. (Theochem), 2003, 664-665, 217.

COMMENTS :

606

FISCHER INDOLE SYNTHESIS EXAMPLE :

CH3 N H

Ph

N

CH3

Ph ZnCl2 170 oC

N H

MECHANISM :

H N

H N

O NH2

+

R1

R

H+

N R

H N

H N

H R

R1

R1

+

NH

NH2 NH2

NH2

+

H [3,3]-sigmatropic rearrangement

H

R

R

R1

R1

H H N

H N R NH2

R

R1

+ NH4+

R1

DISCONNECTION :

R1 R

R1

N H

R +

NH2 N H

O

NOTES :

An aldehyde or ketone hydrazone from an arylhydrazine with a free ortho position, is heated at 180 – 200 oC with e.g. anhydrous zinc chloride, polyphosphoric acid or a Lewis acid catalyst. It is the second step which is technically the named reaction, the formation of an indole from an arylhydrazone of an aldehyde or ketone. The main step in the mechanism is a [3,3]-sigmatropic rearrangement. A palladium-catalysed reaction has been reported by Buchwald et al. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber –

607

Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : March : 1141 Smith – March : 1452 Smith : 1343 Smith 2nd : 847, 1104 Org. React. : 10, 143 Houben – Weyl : 10/2, 546; E6b, 692; E15, 1017; E16a, 815 Org. Synth. : 22, 98 Org. Synth. Coll. Vol. : 3, 725 Science of Synthesis : 10, 288, 316, 339, 366, 370, 698, 723

1) E. Fischer; F. Jourdan, Ber. Dtsch. Chem. Ges., 1883, 16, 2241. 2) R.B. van Order; H.G. Lindwall, Chem. Rev., 1942, 30, 69. 3) B. Robinson, Chem. Rev., 1963, 63, 373. 4) B. Robinson, Chem. Rev., 1969, 69, 227. 5) B. Miller; E.R. Matjeka, Tetrahedron Lett., 1977, 18, 131. 6) A.W. Douglas, J. Am. Chem. Soc., 1978, 100, 6463. 7) H. Ishii, Acc. Chem. Res., 1981, 14, 275. 8) M.J. Martin; L.J. Dorn; J.M. Cook, Heterocycles, 1993, 36, 157. 9) S. Atarashi; J.-K. Choi; D.-C. Ha; D.J. Hart; D. Kuzmich; C.-S. Lee; S. Ramesh; S.C. Wu, J. Am. Chem. Soc., 1997, 119, 6226. 10) Y. Cheng; K.T. Chapman, Tetrahedron Lett., 1997, 38, 1497. 11) S. Wagaw; B.H. Yang; S.L. Buchwald, J. Am. Chem. Soc., 1999, 121, 10251. 12) R.C. Morales; V. Tambyrajah; P.R. Jenkins; D.L. Davies; A.P. Abbott, Chem. Commun., 2004, 158. 13) L. Ackermann; R. Born, Tetrahedron Lett., 2004, 45, 9541. 14) Y-Z. Hu; Y-Q. Chen, Synlett, 2005, 42.

COMMENTS :

608

FISCHER INDOLENINES SYNTHESIS EXAMPLE :

CH3 H3C

CH3 N

N H

H3C

H3C H+

CH3

N

MECHANISM :

H N

H N

O NH2

+

R1

H

R

R1 tautomerisation

N

R H N

N

H+ NH

H

NH2

NH2 +

R R1

H [3,3]-sigmatropic rearrangement H

H

R1

R

R1 R H N

H

N

NH3

NH2 R1

R

R

R1

N - NH4+ R

R1

DISCONNECTION :

H N

N

O NH2

R

R1

+ H R

R1

609

NH2

NOTES :

The Fischer indole synthesis when applied to arylhydrazones of aldehydes and ketones containing a methylene group adjoining the carbonyl group yields 3,3-disubstituted indolenines. See also Fischer indole reaction.

REFERENCES :

1) K. Brunner, Monatsh. Chem., 1895, 16, 849. 2) F.E. King; M. Liguori; R. Robinson, J. Chem. Soc., 1933, 1475. 3) J.Y. Laronze; R. Elboukili; D. Royer; J. Levy; Tetrahedron, 1991, 47, 4915.

COMMENTS :

FISCHER OXAZOLE SYNTHESIS EXAMPLE :

Ph

H

N

HO +

N

O

Ph

Et2O sat. HCl

Ph

O

Ph

MECHANISM :

O H

Ph Ph

N H H

N OH

H

HCl Et2O

OH Cl

H

- H2O

Ph

O

H

Cl

N

Ph

HO - H2O

Ph

Ph - HCl proton transfer

610

N

O N

Cl

O

H

H Ph

DISCONNECTION :

HO

N R

RCHO +

R1

O

N R1

NOTES :

This synthesis involves the condensation in dry hydrogen chloride of an aldehyde with an aldehyde cyanohydrin. The reaction only works in the aromatic series. If however an α-hydroxyamide is used some aliphatic derivatives can be prepared. See also Davidson, Japp, Robinson – Gabriel and Witte – Seeliger reactions.

REFERENCES : Houben – Weyl : E8a, 899

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1896, 29, 205. 2) R.H. Wiley, Chem. Rev., 1945, 37, 401. 3) J.W. Cornforth; R.H. Cornforth, J. Chem. Soc., 1949, 1028. 4) T. Onaka, Tetrahedron Lett., 1971, 12, 4391.

COMMENTS :

FISCHER PEPTIDE SYNTHESIS

MECHANISM : Method 1 :

O H2O N H

H+ H

H N

H3N

N

O

O

611

O O

Method 2 :

H

H

O

H3N

H+, EtOH

O

R

H2N

OEt H CO2Et

EtO

R

Cl

O

N H

O O

H H N

R1

OEt

EtO

N H

H

H2N

R1

R

O

CO2Et R

OEt + EtOH

O

O

H

Method 3 :

H N

EtO

H N H

O

H N

EtO O

H

R

SOCl2

H N

O H R

H N

EtO

COOH

H

O

EtO

R

H N

O R1

Cl R1

H O

H N

EtO

R1 CO2Et

H

O

R

HO-, H2O

O

H2N

H N

R

H

H CO2Et

R1

O H

CO2H

SOCl2

O Cl

Method 4 :

O

NH2 N

2

H

NH2 O

H N

O O

N CO2CH3

heat, - CH3OH

O

N H H

H N

H N H

O O

612

CO2CH3 N

Method 5 :

R

O

H3N H

Cl

H

O

R

H2N

H3N

PCl5, AcCl

O

R

1)

R1 H2N

H

H N

O H

CO2Et

R1 CO2Et

H H R

N

H

O

H3N

HO-, H2O

2) NaOCH3

R1 H

O

O

Method 6 :

R

Cl

Cl

H2N R1

O 1)

H

H2N

H CO2Et

R

H N

O H

R1 PCl5, AcCl

COOH

H 2) hydrolysis

H2N

H N

R

H

O H

H

H R1 Cl

N

H

O O

H2N R2

1)

O

R

H2N

CO2Et

R1

H

N H

R2 COOH

H

H H

N

R H3N

O

NH3

2) hydrolysis

R1 H N

R2 O

O H O

H

NOTES : Method 1 : The amino acid esters on heating yield 2,5-diketopiperazines which on partial hydrolysis give dipeptides.

Method 2 : The amino group of an amino acid is activated by forming the methyl or ethyl ester. It is then protected by

formation of the ethoxy carbonyl derivative. This derivative on treatment with a second amino acid ester forms a dipeptide with the loss of ethanol. The method becomes increasingly difficult as the peptide chain is increased in length.

613

Method 3 : Alternatively, the ethoxycarbonyl-amino acid is converted by thionyl chloride into the acid chloride, which

is condensed with a second amino acid ester. The peptide ester thus formed can in turn be saponified and converted into the acid chloride and condensed with a second amino acid ester and so on. It is impossible to remove the ethoxycarbonyl group.

Method 4 :. Esters of tripeptides lose alcohol on heating and form hexapeptide esters.

Method 5 : An amino acid is converted into the acid chloride with phosphorous pentachloride in acetyl chloride. This

gives a peptide ester on treatment with an amino acid ethyl ester followed by neutralisation with sodium methoxide. The peptide ester can be saponified. Method 6 : An α-chloro- or bromo-acyl chloride is treated with an amino acid ester and the condensation product is

hydrolysed to the acid and converted to the acid chloride with phosphorous pentachloride in acetyl chloride. This is then condensed with a second amino acid ester and so on. The terminal chlorine can be replaced by NH2 with the use of ammonia.

See also Bergmann – Zervars, Leuchs – Bergmann and Sheehan – Frank reactions.

REFERENCES :

1) E. Fischer; E. Fourneau, Ber. Dtsch. Chem. Ges., 1901, 34, 2868. 2) E. Fischer, Ber. Dtsch. Chem. Ges., 1902, 35, 1095. 3) E. Fischer, Ber. Dtsch. Chem. Ges., 1903, 36, 2094. 4) E. Fischer; E. Otto, Ber. Dtsch. Chem. Ges., 1903, 36, 2106. 5) E. Fischer, Ber. Dtsch. Chem. Ges., 1903, 36, 2982. 6) E. Fischer, Ber. Dtsch. Chem. Ges., 1904, 37, 2486. 7) E. Fischer, Ber. Dtsch. Chem. Ges., 1905, 38, 2914. 8) E. Fischer, Ber. Dtsch. Chem. Ges., 1906, 39, 453. 9) E. Fischer, Ber. Dtsch. Chem. Ges., 1906, 39, 2893. 10) M.O. Forster, J. Chem. Soc., 1920, 117, 1157.

COMMENTS :

614

FISCHER PHENYLHYDRAZINE AND OXAZONE REACTION EXAMPLE :

O HO HO

H

Ph N

N

H

N

OH OH

HO

3 C6H5NHNH2

H

HO HO

Ph

N

OH CH2OH

MECHANISM :

O H

OH OH

HO

C6H5NHNH2 - H2O

H O

N

H

OH OH

HO

OH

HOH2C

OH

HO

OH

H - PhNH2 - PhNHNH2 H N

H

H HO HOH2C

N

OH

OHOH

H

H

OH

Ph OH

OH

O CH2OH

N

Ph

H

N H N Ph

N

HOH2C Ph N

H N N

H

HO

OH

H

H H

OH

H2N

H N

CH2OH N H

N N

H PhNHNH2 - NH3

HO HOH2C

OH

OH

N

H

OH OH

DISCONNECTION :

H N

N N

H

N

H

H

R

615

CHO OH R

PhNHNH2

NOTES :

When one molecule of phenyl hydrazine acts upon one molecule of an aldose or ketose a hydrazone results which in most cases is very soluble in water, but if three molecules of the hydrazine react (one of which is reduced to ammonia and aniline) insoluble crystalline substances result, termed osazones, which readily characterises the sugar from which they are obtained. An electron-attracting group in the phenyl hydrazine promotes osazone formation. See also Barry degradation and Ohle cleavage.

REFERENCES :

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1884, 17, 579. 2) F. Weygand, Ber. Dtsch. Chem. Ges., 1940, 73, 1284. 3) H.H. Stroh; A. Arnold; H.G. Scharnow, Chem. Ber., 1965, 98, 1404.

COMMENTS :

FITTIG – EGBERT REARRANGEMENT EXAMPLE :

O

O

O COOH KOH, H2O

Br

MECHANISM :

O

H

O Br

2 KOH - KBr

OH OH

O O

H H

O

616

- H2O

COOH

DISCONNECTION :

O

R R1

R

COOH

O

R1

R2

O Br

R2

NOTES :

3-Bromo-2H-pyran-2-ones on treatment with alkali rearrange to form furan-2-carboxylic acids.

REFERENCES :

1) R. Fittig; G. Egbert, Liebigs Ann. Chem., 1883, 216, 162. 2) W. Will; P. Beck, Ber. Dtsch. Chem. Ges., 1886, 19, 1777. 3) F. Feist, Ber. Dtsch. Chem. Ges., 1901, 32, 1992.

COMMENTS :

FITTIG – ERDMANN SYNTHESIS EXAMPLE :

HOOC

O

O

heat OH

617

MECHANISM :

H O

O

O H+

O

heat, - CO2 HO

O

- H2O O

OH

DISCONNECTION :

HOOC

O

O

OH

NOTES :

Phenylisocrotonic acids when heated yield α-naphtols. Phenylparaconic acids react in a similar way.

REFERENCES :

1) R. Fittig; H. Erdmann, Ber. Dtsch. Chem. Ges., 1883, 16, 43. 2) R. Fittig; H. Erdmann, Liebigs Ann. Chem., 1885, 227, 242. 3) A. Kreutz, Liebigs Ann. Chem., 1902, 321, 130. 4) R. Fittig, Liebigs Ann. Chem., 1904, 330, 292.

COMMENTS :

618

FITTIG PINACOLONE REARRANGEMENT EXAMPLE :

CH3 O

HO OH Ph

CH3 H CH3

Ph

HCOOH heat

CH3 CH3

MECHANISM :

R3 R1 R4

R2 R3

H+

R2

R1

R4 HO OH2

HO OH R4

R1

HO

H2O R4

R3

H2O

R3

R4

R2

R3

O R2 - H+

O R1 H

R2 R1

R3

R4

R2 R1

DISCONNECTION :

R1

R

R2 R R3

O

R1

R2

R3 HO OH

NOTES :

The acid-catalysed carbocation rearrangement of 1,2-diols to ketones. See also Wagner – Meerwein rearrangement.

REFERENCES : March : 1072 Smith – March : 1396 Org. Synth. : 5, 91; 14, 12; 42, 38 Org. Synth. Coll. Vol. : 1, 462; 2, 73; 5, 326

619

1) R. Fittig, Liebigs Ann. Chem., 1860, 114, 54. 2) T. Zincke, Ber. Dtsch. Chem. Ges., 1876, 9, 1761. 3) N.C. Dens; C. Perizzolo, J. Org. Chem., 1957, 22, 836. 4) R.D. Sands; D.G. Botteron, J. Org. Chem., 1963, 28, 2690. 5) K. Suzuki; E. Katayama; G.-I. Tsuchihashi, Tetrahedron Lett., 1983, 24, 4997. 6) M. de Lezaeta; W. Sattar; P. Svoronos; S. Karimi; G. Subramaniam, Tetrahedron Lett., 2002, 43, 9307.

COMMENTS :

FLEMING – MAH ANTHRACENE SYNTHESIS EXAMPLE :

Br 2

1) NaNH2, THF 2) nBuLi, THF LiTMP, reflux

620

MECHANISM :

Br NaNH2 THF

O

+

n

OLi

BuLi

+ OLi

OLi OLi

OLi

DISCONNECTION :

Br

O

NOTES :

In the classic example anthracene is easily prepared in one-step from bromobenzene by using N-lithio-2,2,6,6tetramethylpiperidine in THF. This reaction has been extended to the formation of benzocyclobutenones.

REFERENCES :

1) I. Fleming; T. Mah, J. Chem. Soc., Perkin Trans. 1, 1975, 964. 2) R.V. Stevens; G.S. Bisacchi, J. Org. Chem., 1982, 47, 2393. 3) R.V. Stevens; G.S. Bisacchi, J. Org. Chem., 1982, 47, 2396. 4) L.S. Liebeskind; L.J. Lescosky; C.M. McSwain, jr., J. Org. Chem., 1989, 54, 1435. 5) J.J. Fitzgerald; N.E. Drysdale; R.A. Olofson, J. Org. Chem., 1992, 57, 7122.

621

COMMENTS :

FLOOD REACTION EXAMPLE :

(CH3)3SiOSi(CH3)3

NH4Cl H2SO4

(CH3)3SiCl

MECHANISM :

2 NH4Cl + H2SO4

2 HCl + (NH4)2SO4

((R)3Si)2O + H2SO4 ((R)3Si)2SO4 + 2 HCl

((R)3Si)2SO4 + H2O

(NH4)2SO4

2 (R)3SiCl + H2SO4

DISCONNECTION :

(R)3SiOSi(R)3

(R)3SiCl

NOTES :

Trialkylhalogenosilanes are obtained by treatment of a concentrated sulfuric acid solution of a hexa-alkyldisiloxane with an ammonium halide or by treatment of the intermediate trialkylsilyl sulfate with hydrogen chloride in the presence of ammonium bisulfate (prevents reversal of last step). See also Eaborn reaction.

REFERENCES :

1) E.A. Flood, J. Am. Chem. Soc., 1933, 55, 1735. 2) L.H. Sommer; G.T. Kerr; F.C. Whitmore, J. Am. Chem. Soc., 1948, 70, 445. 3) L. Birkofer; O. Stuhl, Top. Curr. Chem., 1980, 88, 33.

622

COMMENTS :

FONKEN – JOHNSON SYNTHESIS EXAMPLE :

O t

CO2tBu

BuCO2

1) PhCH2Cl, Na 2) Na, Ph Cl O 3) tosic acid, heat

MECHANISM :

t

BuCO2

CO2But

PhCH2Cl Na

t

BuCO2

CO2tBu

Na, Ph

Cl O

O t

BuCO2

t

CO2 Bu

+ 2 CO2 + iC4H8 tosic acid heat

O

DISCONNECTION :

O R

R1

t

BuCO2

623

CO2tBu

+ RCH2Cl + R1COCl

NOTES :

Di-tert-butyl acylalkylmalonates, when heated with p-toluenesulfonic acid or anhydrous acetic acid give isobutylene, carbon dioxide and a ketone. This is a modification of the Bowman debenzylation reaction. See also Baudart, Bowman debenzylation, Kapp – Knoll and Robinson – Robinson reactions.

REFERENCES : Org. Synth. : 34, 26 Org. Synth. Coll. Vol. : 4, 261

G.S. Fonken; W.S. Johnson, J. Am. Chem. Soc., 1952, 74, 831.

COMMENTS :

FORSTER – DECKER REACTION EXAMPLE :

H + EtNH 2

1) CH3I 2) H2O 3) NaOH

O

H3C

H N

Et

MECHANISM :

H2O RNH2 + O OH2 Ph H N R1 R

Ph

H

Ph

- H2O

N

H

Ph

H R1Cl

R

OH Ph H R1 N R H

R1

N

Cl R

R1 + PhCHO + HCl R N H

624

DISCONNECTION :

R2

H N

R2X + RNH2 + R1CHO

R

NOTES :

The conversion of a primary amine into a secondary amine by condensation with an aldehyde, followed by the addition of alkyl halide to the Schiff’s base and subsequent hydrolysis. See also Eschweiler – Clarke, Henze – Humphries and Schiff reactions.

REFERENCES : Houben – Weyl : 11/1, 108, 956 Org. Synth. : 44, 75 Org. Synth. Coll. Vol. : 5, 758

1) M.O.J. Forster, J. Chem. Soc., 1899, 75, 934. 2) H. Decker; P. Becker, Liebigs Ann. Chem., 1913, 395, 362. 3) H.G. Reiber; T.D. Stewart, J. Am. Chem. Soc., 1940, 62, 3026. 4) A.L. Morrison; H. Rinderknecht, J. Chem. Soc., 1950, 1478. 5) Y.B. Wang; Q.G. Du; J.L. Huang, Macromol. Rapid. Commun., 1998, 19, 247.

COMMENTS :

FORSTER REACTION EXAMPLE :

H3C

CH3 CH3

H3C

CH3 CH3

O NOH

O NH2Cl

625

N2

MECHANISM :

O

OH N

R

O H2N Cl

R1 O N

R

R

- ClH N

O R

- H+

R1

N

OH N H N R1 H

- H2O

N

R1

DISCONNECTION :

O N

R

O

N

OH N

R

R1

R1

NOTES :

The formation of diazo derivatives from oximes. See also Bamford – Stevens and Cava reactions.

REFERENCES : Houben – Weyl : 10/4, 582

1) M.O.J. Forster, J. Chem. Soc., 1915, 107, 260. 2) M.P. Cava; R.L. Litle, Chem. Ind. (London), 1957, 367. 3) W. Rundel, Angew. Chem., 1962, 74, 469. 4) M.P. Cava; B.R. Vogt, J. Org. Chem., 1965, 30, 3776. 5) A.M. van Leusen; J. Strating; D. van Leusen, Tetrahedron Lett., 1973, 14, 5207. 6) G. L’Abbe; J.P. Dekerk; M. Deketele, J. Chem. Soc., Chem. Commun., 1983, 588. 7) G. L’Abbe; I. Luyten; S. Toppet, J. Heterocycl. Chem., 1992, 29, 713.

COMMENTS :

626

FOULDS – ROBINSON INDOLE / QUINOLINE SYNTHESIS EXAMPLE :

CH2 N H3C

CH3

H

Br2, KOH EtOH

N H

O

CH3 O O

N H

CH3

O

O OH HO P Cl O

CH3

O

N

CH3

MECHANISM :

Br

Br CH2 N H3C

H

Br2

N H3C

O

H KOH, EtOH - 2 HBr

N

O

H3C

KOH, EtOH - AcOH

O

CH3

CH2

N H

N H

N H

H

CH3 H CH3 CH3

CH3 N H

O

N H

O

627

CH3 - H2O

N

CH3

DISCONNECTION :

N H NO2 N

NOTES :

2-Allyl- or 2-vinyl-anilides on treatment with alcoholic alkali yield indoles, while on treatment with phosphoryl chloride quinoline derivatives are obtained. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Houben – Weyl : E7a, 343

1) R.P. Foulds; R. Robinson, J. Chem. Soc., 1914, 105, 1963. 2) T.W.J. Taylor; P.M. Hobson, J. Chem. Soc., 1936, 181. 3) F. Künzle; J. Schmutz, Helv. Chim. Acta, 1970, 53, 798.

COMMENTS :

628

FOWLER SYNTHESIS EXAMPLE :

CO2CH3

CO2CH3 1) NaBH4 PhO Cl

N

N CO2Ph

O CH3OH, - 78 oC 2) NaBH4-TFA, benzene

MECHANISM :

CO2CH3 N

CO2CH3

CO2CH3 NaBH4 PhO Cl

N CO2Ph

NaBH4-TFA benzene

N CO2Ph

O CH3OH, - 78 oC

DISCONNECTION :

CO2CH3

CO2CH3

N CO2Ph

N

NOTES :

This is the partial reduction of pyridines using a hydride source, sodium borohydride and sodium borohydridetrifluoroacetic acid.

REFERENCES :

1) F.W. Fowler, J. Org. Chem., 1972, 37, 1321. 2) R.J. Sundberg; J.D. Bloom, J. Org. Chem., 1981, 46, 4836. 3) R.J. Sundberg; G. Hamilton; C. Trindle, J. Org. Chem., 1986, 51, 3672. 4) G. Zhao; U.C. Deo; B. Ganem, Org. Lett., 2001, 3, 201.

629

COMMENTS :

FRANCHIMONT DICARBOXYLIC ACID SYNTHESIS EXAMPLE :

HOOC H

Br H COOH

2

H COOH

1) KCN 2) PhCHBrCOOH 3) Hydrolysis 4) Decarboxylation

MECHANISM :

Br

CN

H COOH

HOOC

H COOH

KCN

CN

PhCHBrCOOH

HOOC H

H COOH

H COOH

HOdecarboxylation

DISCONNECTION :

H Ar Ar

Br

COOH COOH

2

Ar

COOH H

H

NOTES :

α-Bromo-acids or –esters react with potassium cyanide to yield cyanodicarboxylic acid derivatives, which can be hydrolysed and partially decarboxylated to give α,β-dicarboxylic acids.

REFERENCES :

1) A.P.N. Franchimont, Ber. Dtsch. Chem. Ges., 1872, 5, 1048.

630

2) R.C. Fuson; O.R. Kreimeier; G.L. Nimmo, J. Am. Chem. Soc., 1930, 52, 4074. 3) H.N. Rydon, J. Chem. Soc., 1936, 593.

COMMENTS :

FRANCHIMONT NITRAMINE REACTION EXAMPLE : H3C

CH3NH2 1) ClCO2Et 2) HNO3 3) NH3 4) acid

H N NO2

MECHANISM :

CH3NH2

2 NH3

H3C ClCO2Et - HCl

N H

CO2Et

H3C

CO2Et N NO2

H3C

H N NO2

HNO3

CH3N(NH4)NO2 + NH2CO2Et

acid

DISCONNECTION :

H R N

R NH2 NO2

NOTES :

The amine is condensed with e.g. ethyl chloroformate and the product nitrated to the secondary nitramide which is decomposed using alkali to yield the salt of the required nitramine.

REFERENCES :

1) E.A. Klobbie, Recl. Trav. Chim. Pays-Bas, 1887, 7, 31.

631

2) A.P.N. Franchimont; E.A. Klobbie, Recl. Trav. Chim. Pays-Bas, 1888, 8, 17. 3) A.P.N. Franchimont, Recl. Trav. Chim. Pays-Bas, 1894, 13, 308. 4) A.H. Lamberton, J. Chem. Soc., Quat. Rev., 1951, 5, 75.

COMMENTS :

FRANKEL – SHIBASAKI REARRANGEMENT EXAMPLE :

H3C

N

CO2tBu

H3C

H

N

CO2tBu

H

Cr(CO)3 acetone, 20 oC

MECHANISM :

"Cr(CO)3" Cr (CO)3 X H

H X

Cr(CO)3 X

H X

DISCONNECTION :

H

H

X

X

632

NOTES :

Arene tricarbonyl chromium complexes have the ability to catalyse the isomerisation (1,5-sigmatropic rearrangement) of conjugated dienes or dienamides.

REFERENCES :

1) E.N. Frankel; E. Selke; C.A. Glass, J. Am. Chem. Soc., 1968, 90, 2446. 2) M. Sodeoka; M. Shibasaki, Chem. Lett., 1984, 579. 3) R. Noyori; H. Takaya, Acc. Chem. Res., 1990, 23, 345. 4) M. Sodeoka; H. Yamada; M. Shibasaki, J. Am. Chem. Soc., 1990, 112, 4906. 5) M. Sodeoka; M. Shibasaki, Synthesis, 1993, 643.

COMMENTS :

FRANKLAND – DUPPA REACTION EXAMPLE :

H3CO

OCH3 O

OH

H3C

+ 2 CH3I

2 Zn 2 HCl

O

OCH3

H3C

O

MECHANISM :

(R1)2Zn

(R1)2Zn

R

R

OEt O

R1

R1

R

O

R1

R1 OZn

H2O

DISCONNECTION :

R1 R1

OH RO

OR

OR O

O

633

O

+ 2 R1I

R

R1 OH

NOTES :

The condensation of dialkyl oxalate with alkyl halides in the presence of zinc to give derivatives of glycolic acid. See also Frankland, Reformatsky and Schorigin – Wanklyn reactions.

REFERENCES : Houben – Weyl : 13/2a, 741

1) E. Frankland, Liebigs Ann. Chem., 1863, 126, 109. 2) E. Frankland; D.F. Duppa, Liebigs Ann. Chem., 1865, 135, 25.

COMMENTS :

FRANKLAND SYNTHESIS EXAMPLE :

EtI + Zn

EtZnI

DISCONNECTION :

R2Zn

2 RI + 2 Zn

NOTES :

Alkyl zinc halides or dialkyl zinc compounds are obtained by treating alkyl halides with zinc. The process can also be applied to aryl radicals. See also Grignard reaction.

REFERENCES : Houben – Weyl : 13/2a, 570 Org. Synth. : 12, 86 Org. Synth. Coll. Vol. : 2, 184

1) E. Frankland, Liebigs Ann. Chem., 1849, 71, 171.

634

2) E. Frankland, Liebigs Ann. Chem., 1853, 85, 329. 3) E. Frankland, Liebigs Ann. Chem., 1853, 85, 3641. 4) W.H. Broch, Nature, 1996, 383, 591. 5) D. Seyferth, Organometallics, 2001, 20, 2940.

COMMENTS :

FREDENHAGEN PROCESS EXAMPLE :

CH3

CH3 NO2

H3C

CH3

KNO3, conc. HF 0 oC

H3C

CH3 NO2

MECHANISM :

(HNO3H)+ + K+ + 2 F-

KNO3 + 2 HF

NO2 + (HNO3H)

+

DISCONNECTION :

NO2 R

R

635

NOTES :

The nitration agent consists of a nitrate, e.g. potassium nitrate in anhydrous or highly concentrated hydrogen fluoride. This is one of the several methods of nitrating aromatic compounds.

REFERENCES :

1) K. Fredenhagen, German Patent, 1930, 529538. (Chem. Abs., 1931, 25, 5175.) 2) G.C. Finger; F.H. Reed; E.W. Maynert; A.M. Weiner, J. Am. Chem. Soc., 1951, 73, 149.

COMMENTS :

FREUDENBERG – SCHÖNBERG XANTHATE REARRANGEMENT EXAMPLE : O H3C

S

heat

S S

S H3C

O

Cl

Cl

MECHANISM :

O

OAr ArO

S

SAr O

R

DISCONNECTION :

RO

RO

SR1

OR1 S

O

636

NOTES :

The rearrangement of S-methyl xanthates to S-methyldithiocarbonates (conversion of alcohols to thiols via xanthates, also phenols to thiophenols via thiocarbamates.) See also Beckmann rearrangement, Hayashi rearrangement, Newman – Karnes – Kwart and Smiles reactions.

REFERENCES : Org. React. : 14, 1

1) K. Freudenberg; A. Wolf, Chem. Ber., 1927, 60, 232. 2) A. Schönberg; L. von Vargha, Chem. Ber., 1930, 63, 178. 3) A. Schönberg; A. Mustafa, Chem. Rev., 1947, 40, 181. 4) D.H. Powers; D.S. Tarbell, J. Am. Chem. Soc., 1956, 78, 70. 5) M.S. Newman, Acc. Chem. Res., 1972, 5, 354. 6) L.W. Jenneskens; C.A.M. Hoefs; U.E. Wiersum, J. Org. Chem., 1989, 54, 5811.

COMMENTS :

FREUND REACTION EXAMPLE :

BrH2C

CH2Br

+ 2 Na

MECHANISM :

Br

Br

Na

Br

Na

637

Br

Br

DISCONNECTION :

Hal

Hal

NOTES :

The production of cyclic hydrocarbons by the internal condensation of dihalogenohydrocarbons with sodium. This method can also be used for 3-, 4-, 5- and 6-membered rings but it best for 3-membered. See also Charette, Gustavson, Hass cyclopropane, Ipatiew cyclopropane, Kishner, Mousseron – Fraisse – McCoy, Nerdel, Perkin, Simmons – Smith and Wurtz – Fittig reactions.

REFERENCES : Houben – Weyl : 13/1, 492

1) A. Freund, Monatsh. Chem., 1882, 3, 625. 2) J.D. Bartleson; R.E. Burk; H.P. Lankelma, J. Am. Chem. Soc., 1946, 68, 2513. 3) R.W. Shortridge; R.A. Craig; K.W. Greenlee; J.M. Derfer; C.E. Boord, J. Am. Chem. Soc., 1948, 70, 946.

COMMENTS :

FRIEDEL – CRAFTS – KARRER REACTION EXAMPLE :

CN + ClCN AlCl3

638

MECHANISM :

Cl

N

AlCl3

Cl

N AlCl3

C N + AlCl4 H CN

C N AlCl4

- HCl - AlCl3

CN

AlCl4

DISCONNECTION :

CN R

R

+ ClCN

NOTES :

The formation of aromatic nitriles by the action of cyanogens halide on aromatic hydrocarbons in the presence of finely divided aluminium chloride. The exact mechanism is not clear. Double aluminium chloride activation has been proposed.

REFERENCES :

1) C. Friedel; J.M. Crafts, Ann. Chim. (Paris), 1884, 1, 449. 2) P. Karrer; E. Zeller, Helv. Chim. Acta, 1919, 2, 482. 3) P. Karrer, E. Rebmann, E. Zeller, Helv.Chim.Acta, 1920, 3, 227. 4) D.T. Mowry, Chem. Rev., 1948, 42, 189. 5) V.P. Wystrach, 1952, US patent 2584409 6) G.W. Gray, B. Jones, J.Chem.Soc., 1954, 679 7) P.H. Gore, F.S. Kamounah, A.Y. Miri, Tetrahedron, 1979, 35, 2927. 8) L. Eberson, F. Radner, Acta Chem.Scand., 1992, 46, 312.

COMMENTS :

639

FRIEDEL – CRAFTS REACTION EXAMPLE :

CH3 + CH3Cl

AlCl3

O O

+ H3C

CH3 AlCl3

Cl

MECHANISM :

AlCl3

R Cl

R Cl AlCl3

R + AlCl4 H R

R Cl AlCl3 AlCl4 - HCl - AlCl3

H Cl

O R

R

AlCl3 R

Cl

O AlCl3

O AlCl3

R

Cl O

- HCl

R

O AlCl3 R

640

DISCONNECTION :

R R1

R1

+ RCl

O O R1

R

R1

+

R

Cl

NOTES :

The condensation of alkyl and acyl halides with aromatic compounds in the presence of aluminium chloride or a related acid catalyst to give hydrocarbons or ketones. The scope of the reaction is wide and comprises of many types of organic condensation reactions promoted by aluminium chloride or similar catalysts. During the recent few decades the term has been freely used to include olefins, alcohols, anhydrides, esters, cyclic and open chain ethers and polymethylenes, e.g. cyclopropane as reactants, and such diverse substances as zinc chloride, ferric chloride, titanium tetrachloride, boron trifluoride, hydrogen fluoride, phosphoric oxide and sulfuric acid as reagents. Some open or cyclic alkanes have been found to react. If the acid chloride and aluminium chloride complex is formed first and then the hydrocarbon is added the reaction is known under the Perrier modification. The use of nitrobenzene as the solvent in the application to phenols is known as the Behn reaction. The Vilsmeier – Haack modification involves the use of an anilide in the presence of phosphorous oxychloride. The use of anhydrous ferric chloride in the Friedel – Crafts reaction is known as the Nencki modification. It is a milder catalyst than aluminium chloride and can be

employed with reactive molecules when the latter is too drastic. The Radziewanowski modification is the alkylation and arylation or aromatics with alkyl and arylhalogens in the presence of aluminium and hydrogen chloride to circumvent the use of the moisture sensitive aluminium chloride. Photo-Friedel – Crafts acylation of 1,4naphthoquines has been reported and also alkylations with silicon compounds. See also Balsohn, Comins, Eijkman, Emmert – Asendorf, Gattermann – Ehrhárdt, Haworth, Prins and Vilsmeier – Haack reactions.

REFERENCES : March : 536 Smith – March : 712 Smith : 1313, 1324 Smith 2nd : 6, 847, 1080, 1090 Houben – Weyl : 4/2, 61, 767; 8, 377; E5, 1447; E6a, 439, 852, 977; E7b, 290; E8a, 750, 986; E19c, 362 Houben – Weyl : 7/2a, 284 Org. Synth. : 14, 40; 21, 103 Org. Synth. Coll. Vol. : 2, 304; 3, 761 Org. React. : 2, 114; 3, 1; 5, 229; 18, 1 Org. Synth. : 4, 73, 81; 8, 26; 10, 32; 12, 16; 23, 100; 29, 38 Org. Synth. Coll. Vol. : 1, 95, 157, 548; 2, 156, 248; 3, 343, 841 Science of Synthesis : 1, 757, 799, 947; 9, 248, 352, 356, 510, 567; 10, 45, 132, 148, 171, 212, 240, 252, 287, 318,

335, 407, 438, 534, 537, 592, 602, 725

641

1) C. Friedel; J.M. Crafts, C.R. Séances Acad. Sci., 1877, 84, 1392. 2) C. Friedel; J.M. Crafts, C.R. Séances Acad. Sci., 1877, 84, 1450. 3) M. Nencki; N. Sieber, J. Prakt. Chem., 1881, 23, 147. 4) C. Radziewanowski, Ber. Dtsch. Chem. Ges., 1895, 28, 1135. 5) W. Gulewitsch, Bert. Dtsch. Chem. Ges., 1904, 37, 1560. 6) J.N. Ray, J. Chem. Soc., 1920, 117, 1335. 7) A.W. Francis, Chem. Rev., 1948, 43, 257. 8) P.H. Gore, Chem. Rev., 1955, 55, 229. 9) B. Snider; A. Jackson, J. Org. Chem., 1982, 47, 5393. 10) L.J. Belen’kii; A.P. Yakabov, Tetrahedron, 1984, 40, 2471. 11) S.C. Eyley, Comp. Org. Syn., 1990, 2, 707. 12) A.S.R. Anjaneyulu; G.S. Rani; U.V. Mallavadhan; Y.L.N. Murthy, Indian J. Chem., 1994, 33B, 847. 13) U. Bierman; J.O. Metzger, Angew. Chem., Int. Ed., 1999, 38, 3675. 14) N.A. Paras; D.W.C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370. 15) M. Oelgemöller; C. Schiel; R. Fröhlich; J. Mattay, Eur. J. Org. Chem., 2002, 2465. 16) D.A. Evans; K.A. Scheidt; K.R. Fandrick; H.W. Lam; J. Wu, J. Am. Chem. Soc., 2003, 125, 10780. 17) M. Bandini; A. Melloni; A. Umani–Ronchi, Angew. Chem., Int. Ed., 2004, 43, 550. 18) M.C. Elliott; S.V. Wordingham, Synlett, 2004, 898. 19) D.A. Evans; K.R. Fandrick; H-J. Song, J. Am. Chem. Soc., 2005, 127, 8942.

COMMENTS :

FRIEDLÄNDER QUINOLINE SYNTHESIS EXAMPLE :

Ph

O Ph NH2

CH3

O +

H3C

CH2CH3

642

ZnCl2 AcOH, heat

N

CH3

MECHANISM :

O

O R1

O + H3C

NH2

CH2R

O

R1 CH3 N CH2R H OH

ZnCl2, AcOH, heat O

- H2O

R1

R1

R1 N H

N H

CH2R

CH2R

- H2O

N

CH2R

DISCONNECTION :

O

R R2/R1 N

R NH2

R1/CH2R2

O + R1

CH2R2

NOTES :

This reaction involves the condensation, acid- or base-catalysed, of an aromatic o-amino carbonyl derivative with a compound containing a methylene group α- to the carbonyl. The orientation of the condensation depends on the orientation of the formed enolate or enol. The use of this reaction has been limited due to the limited availability of the o-aminobenzaldehydes. The Borsche – Ried modification uses Schiff bases instead of o-aminoarylcarbonyls. See

also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES : March : 897 Smith – March : 1186 Houben – Weyl : E8a, 267, 278 Org. React. : 28, 37

1) P. Friedländer, Ber. Dtsch. Chem. Ges., 1882, 15, 2572. 2) R.H. Manske, Chem. Rev., 1942, 30, 113. 3) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 4) H. Eckert, Angew. Chem., Int. Ed. Engl., 1981, 20, 208. 5) M.P. Maquire; K.R. Sheets; K. McVety; A.P. Spada; A. Zilberstein, J. Med. Chem., 1994, 37, 2129. 6) J.I. Ubeda; M. Villacampa; C. Avendano, Synthesis, 1998, 1176. 7) C.S. Cho; B.T. Kim; T.-J. Kim; S.C. Shim, Chem. Commun., 2001, 2576.

643

8) C. Patteux; V. Levacher; G. Dupas, Org. Lett., 2003, 5, 3061. 9) K. Mogilaiah; Ch.S. Reddy, Synth. Commun., 2003, 33, 3131. 10) J.M. Muchowski; M.L. Maddox, Can. J. Chem., 2004, 82, 461. 11) J.S. Yadav; B.V.S. Reddy; K. Premalatha, Synlett, 2004, 963. 12) P. Arumugam; G. Karthikeyan; R. Atchudan; D. Muralidharan; P.T. Perumal, Chem. Lett., 2005, 34, 314. 13) R.J. Anderson; G.B. Raolji; A. Kanazawa; A.E. Greene, Org. Lett., 2005, 7, 2989.

COMMENTS :

FRIEDMAN SYNTHESIS EXAMPLE :

O CN H 0.25 eq. LiAlH4 Et2O, H2O

MECHANISM :

H2O

H+

H N H

N 0.25 LiAlH4 Et2O

O H

NH +

H

H - NH3

O

DISCONNECTION :

O CN H

644

NOTES :

This reaction is exemplified by the treatment of an ethereal solution of cyclopropyl cyanide with lithium aluminium hydride to yield cyclopropane aldehyde.

REFERENCES :

1) L. Friedman, Abstracts 116th ACS meeting, organic division Atlantic City, 1949. 2) L.I. Smith; E.R. Rogier, J. Am. Chem. Soc., 1951, 73, 4047. 3) J.B. Lambert; J.J. Napoli; K.K. Johnson; K.N. Taba; B.S. Packard, J. Org. Chem., 1985, 50, 1291.

COMMENTS :

FRIES REARRANGEMENT EXAMPLE :

O O O

H3C

AlCl3

CH3

OH

MECHANISM : Anionic Fries-rearrangement :

O

Cl

Li

O

O O

NEt2 RLi - 78 oC

O NEt2 Li

O 4-exo-trig

Cl Cl

O HO

NEt2

Cl

645

NEt2

O

O O O

H3C AlCl3

CH3

CH3

+

OH

OH

H2O, - Al(OH)Cl2, - Cl-

AlCl3 O O

O CH3 AlCl3

AlCl3 O CH3

- H+

O

AlCl3

O

AlCl3 H

O

O

or to the para position CH3

CH3

DISCONNECTION :

O R OH

O

O O

R

R OH

NOTES :

Lewis-acid catalysed (AlCl3, BF3, ZnCl2, TiCl4, FeCl3, ZrCl4) rearrangement of phenols to ortho- or para-ketophenols. Meta-directing groups can interfere. The mechanism is still in question. There is also a photo-Fries, an anionic Fries and thia-Fries rearrangement. See also von Auwers indane-1-one, Claisen – Haase, Hoesch – Houben, Limaye and Snieckus rearrangement reactions.

REFERENCES : March : 555 Smith – March : 725

646

Smith : 1348 Smith 2nd : 1108 Houben – Weyl : 4/2, 127; 7/2a, 379; 8, 634; E6a, 484, 983; E6b, 436; E7a, 95; E8a, 303; E10b2, 234; E11, 105; E19c, 382 Org. React. : 1, 342 Org. Synth. : 13, 90 Org. Synth. Coll. Vol. : 2, 543 Science of Synthesis : 10, 45, 93, 95

1) K. Fries; G. Finck, Ber. Dtsch. Chem. Ges., 1908, 41, 4271. 2) A.H. Blatt, Chem. Rev., 1940, 27, 413. 3) Y. Ogata; H. Tabuchi, Tetrahedron, 1964, 20, 1661. 4) A. Jefferson; S. Wangchareontrakul, Aust. J. Chem., 1985, 38, 605. 5) A. Hallberg; A. Svensson; A.R. Martin, Tetrahedron Lett., 1986, 27, 1959. 6) J.A. Miller, J. Org. Chem., 1987, 52, 322. 7) Y. Moriata; T. Agawa; E. Nomura; H. Taniguchi, J. Org. Chem., 1992, 57, 3658. 8) R. Martin, Org. Prep. Proced. Int., 1992, 24, 369. 9) V. Rozenberg; T. Danilova; E. Sergeeva; E. Vorontsov; Z. Starikova; K. Lysenko; Y. Belokon, Eur. J. Org. Chem., 2000, 3295. 10) F.M. Moghaddam; M.G. Dekamin; M. Ghaffarzadeh, Tetrahedron Lett., 2001, 42, 8119. 11) J.P.H. Charmant; A.M. Dyke; G.C. Lloyd–Jones, Chem. Commun., 2003, 380. 12) K.K. Park; J.J. Lee; J. Ryu, Tetrahedron, 2003, 59, 7651. 13) E. Heitling; F. Roessner; E. van Steen, J. Mol. Catal. A: Chem., 2004, 216, 61. 14) S. Paul; M. Gupta, Synthesis, 2004, 1789. 15) K.P. Jayasundera; A.J. Watson; C.M. Taylor, Tetrahedron Lett., 2005, 46, 4311.

COMMENTS :

647

FRITSCH – BUTTENBERG – WIECHELL REARRANGEMENT EXAMPLE :

H NaNH2

Br

MECHANISM :

H Base

X

X

DISCONNECTION :

R1

R

H

R1

X

R R, R1 = aryl

O H

Ph S

R

Cl

H

R

NOTES : α-Elimination from 1,1’-diaryl-2-haloethylenes leading via carbene rearrangement to acetylenes. Typical bases

include sodium amide, alkoxide ion, and organolithium reagents. The reaction is inhibited by electron-withdrawing groups on the aromatic rings. Tykwinski et al. has reported a modification of this reaction. See also Murahashi cross-coupling.

REFERENCES : Smith 2nd : 632

648

Houben – Weyl : E15, 3315; E19b, 86

1) P. Fritsch, Liebigs Ann. Chem., 1894, 279, 319. 2) W.P. Buttenberg, Liebigs Ann. Chem., 1894, 279, 327. 3) H. Wiechell, Liebigs Ann. Chem., 1894, 279, 337. 4) W. Kirmse, Angew. Chem., Int. Ed. Engl., 1965, 4, 1. 5) P.J. Stang, Chem. Rev., 1978, 78, 383. 6) W. Kirmse, Angew. Chem., Int. Ed. Engl., 1997, 36, 1164. 7) S. Eisler; R.R. Tykwinski, J. Am. Chem. Soc., 2000, 122, 10736. 8) H. Rezaei; S. Yamanoi; F. Chemla; J.-F. Normant, Org. Lett., 2000, 2, 419. 9) E.T. Chernick; S. Eisler; R.R. Tykwinski, Tetrahedron Lett., 2001, 42, 8575.

COMMENTS :

FRITSCH – KLING CHLORINATION EXAMPLE :

Et

CH3

Et

+ Cl2

H2O CaCO3

O

CH2Cl O

MECHANISM :

R

CH3 O

4 HCl + 2 CaCO3

Cl

R

Cl

R

Cl

-

O

- Cl H

H

O

2 CaCl2 + 2 H2O + 2 CO2

649

R

Cl O

DISCONNECTION :

R

R

Cl O

CH3 O

NOTES :

The reaction is effected by passing chlorine into the ketone in the presence of water and calcium carbonate. Aqueous calcium chloride may also be added. See also Bedoukian and Hell – Volhard – Zelinsky reactions.

REFERENCES :

1) P. Fritsch, Ber. Dtsch. Chem. Ges., 1893, 26, 597. 2) P. Fritsch, Liebigs Ann. Chem., 1894, 279, 310.

COMMENTS :

FUJIMOTO – BELLEAU REACTION EXAMPLE :

H3C

O

O

CH3

H3C

CH3 1) MeMgBr 2) NaOH

650

O

CH3 CH3

MECHANISM :

H3C

O

CH3

H3C

CH3

CH3

R RCH2MgBr

O

CH3

O

O

MgBr H3C

CH3 CH3

R

CH3

H3C

CH3

O O O MgBr

R

R HO-, H2O

H3C

R

OMgBr

H3C

CH3 - H2O

CH3 CH3

O

H2O

CH3

O

H3C

OH

CH3 CH3

O

O

R

DISCONNECTION :

+ RCH2MgX O

O

O

R

NOTES :

The synthesis of fused cyclohexenones from lactones (an alternative to the Robinson reaction). Lygo et al. introduced a Horner – Wadsworth – Emmons modification of this reaction as an alternative approach to the classical Ferrier cyclisation, which is normally carried out under acidic instead of basic conditions. See also Robinson – Mannich annulation.

REFERENCES :

1) G.I. Fujimoto, J. Am. Chem. Soc., 1951, 73, 1856. 2) B. Belleau, J. Am. Chem. Soc., 1951, 73, 5441. 3) J. Weill–Raynal, Synthesis, 1969, 49. 4) M. Aloui; B. Lygo; H. Trabsa, Synlett, 1994, 115. 5) G. Revial; I. Jabin; M. Redolfi; M. Pfau, Tetrahedron: Asymmetry, 2001, 12, 1683.

COMMENTS :

651

FUJIWARA LANTHANIDE REACTION EXAMPLE : HO OH

O + Yb

2 Ph

Ph

THF

Ph

Ph Ph Ph

MECHANISM :

R1 N R2

2 H

YbII

R2

N

N

R2

+ Yb THF HMPA

R1

R1 R3 H

O R2 R1

R2 R1

YbII R2 N N 2 R3CHO

R1

HH

OCH2R3 Yb R2 N N H

Yb R2 R1

N

N

R2

O

R1 H

HH

R3

NR2 O

R1

+ Yb(OCH2R3)2

NR2

R3

R1 H

R1

DISCONNECTION :

X

X R1

R1 X

X = O, NR2

R1 O

HO R1 R2

H

R2 R1 OH

R1

R2

NOTES :

Lanthanide metals have been utilised for various transformations of organic functional groups or C-C bond formations via coupling reactions. Ytterbium metal causes the coupling reaction of carbonyl and thiocarbonyl compounds, and

652

imines, but also aldimines undergo similar reactions. Other metals than lanthanides are also used. See also Hollemann and Pedersen reactions.

REFERENCES : March : 1225 Smith – March : 1023, 1560

1) T. Fukawa; Y. Fujiwara; K. Yokov; H. Taniguchi, Chem. Lett., 1981, 1771. 2) Z. Hou; K. Takamine; O. Aoki; H. Shiraishi; Y. Fujiwara; H. Taniguchi, J. Org. Chem., 1988, 53, 6077. 3) Y. Fujiwara; K. Takaki; Y. Taniguchi, J. Alloys Compd., 1993, 192, 200. 4) Y. Makioka; M. Tsuno; S. Ueboki; Y. Taniguchi; K. Takaki; Y. Fujiwara, J. Org. Chem., 1996, 61, 372. 5) W.-S. Jin; Y. Makioka; Y. Taniguchi; T. Kitamura; Y. Fujiwara, Chem. Commun., 1998, 1101.

COMMENTS :

FUKUYAMA INDOLE SYNTHESIS EXAMPLE : CH3 CH3 CH3 NC 1) nBu3SnH, AIBN, CH3CN, heat 2) Pd(PPh3)4, Et3N, CH3Cl, reflux

653

N H

MECHANISM :

H

R N S

H R1

R Bu3SnH Et3B toluene

N H

R SSnBu3

R1 SSnBu3

N R1 H

HSnBu3

- HSSnBu3

H

R N H

R SSnBu3

R1

N R1 H

- SSnBu3

R R1 N H

DISCONNECTION :

R N

H

R S

R1

R1 N H

R N

C

R = CH2OAc, CH2OTHP, CH2CH2OTBS, CH2OH R1 = Alk, Benzyl, β-lactam, ester

NOTES :

The synthesis of substituted indoles using an arylisonitrile- or arylthioamide-alkene system via a tin mediated free radical cyclisation. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fürstner, Gassman

654

indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 455

1) T. Fukuyama; X. Chen; G. Peng, J. Am. Chem. Soc., 1994, 116, 3127. 2) Y. Kobayashi; T. Fukuyama, J. Heterocycl. Chem., 1998, 35, 1043. 3) H. Tokuyama; T. Yamashita; M.T. Reding; Y. Kaburagi; T. Fukuyama, J. Am. Chem. Soc., 1999, 121, 3791. 4) M.T. Reding; T. Fukuyama, Org. Lett., 1999, 1, 973. 5) H. Tokuyama; T. Fukuyama, The Chemical Record, 2002, 2, 37.

COMMENTS :

FUKUYAMA REDUCTION EXAMPLE :

O

O SEt

H3CO

H 0.5 mol % Pd/C 2 Et3SiH, THF, RT

655

H3CO

MECHANISM :

O

Pd0 R

O Pd

SR1

R

Et3SiH - Et3SiSR1

Pd

H

Pd0

O R

O SR1

Et3SiPdH

R

H

OSiEt3

OSiEt3 SR1 R Pd H

R Pd

SR1

Et3SiSR1

0

Pd0

Et3SiH

DISCONNECTION :

O R

O H

R

SR1

NOTES :

Thiol esters are reduced with Et3SiH in the presence of palladium on coal to afford aldehydes. The mechanism is not completely understood. Seki has improved the reaction conditions, so that multifunctional ketones can be prepared employing dialkylzincs.

REFERENCES :

1) T. Fukuyama; S.-C. Lin; L. Li, J. Am. Chem. Soc., 1990, 112, 7050. 2) Y. Kanda; T. Fukuyama, J. Am. Chem. Soc., 1993, 115, 8451. 3) A. Fujiwara; T. Kan; T. Fukuyama, Synlett, 2000, 1667. 4) H. Tokuyama; S. Yokoshima; S.-C. Lin; L. Li; T. Fukuyama, Synthesis, 2002, 1121. 5) M. Kimura; M. Seki, Tetrahedron Lett., 2004, 45, 3219. 6) Y. Mori; M. Seki, Tetrahedron Lett., 2004, 45, 7343.

COMMENTS :

656

FÜRSTNER INDOLE SYNTHESIS EXAMPLE :

S

S

N

N O

O H

TiCl3, Zn DME, heat

N

N H

H

MECHANISM :

R

R

N R1

O H

R O TiCl3

TiCl3 N H

O

O

O TiCl3

N H

R1

R

O [Ti]

TiCl3 O

N H

O [Ti] N H R 1

Zn

R1

R

R O

[Ti]

R1 + TiO2

O

N H

R1

DISCONNECTION :

R3

R3 R2 R4

R1

R O

N H

O TiCl3

N R1

N

R4 R2

657

O R1 O

NOTES :

Indoles are prepared by an intramolecular McMurry reaction. The zinc reduces the titanium cation to zerovalent titanium. The reaction can be made catalytic. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, McMurry, Montevecchi, Mori – Ban, Murphy, Naito, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert

indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Org. Synth. : 76, 142 Org. Synth. Coll. Vol. : 10, 382 Science of Synthesis : 10, 456

1) A. Fürstner; D.N. Jumbam, Tetrahedron, 1992, 48, 5991. 2) A. Fürstner; A. Hupperts; A. Ptock; E. Janssen, J. Org. Chem., 1994, 59, 5215. 3) A. Fürstner; B. Bogdanovic, Angew. Chem., Int. Ed. Engl., 1996, 35, 2442.

COMMENTS :

658

659

GLASER – HAY REACTION · 695 GLASER COUPLING (CADIOT – CHODKIEWICZ – EGLINGTON

A

COUPLING) · 695 GODCHOT – MOUSSERON RING CONTRACTION · 696

ADAMS MODIFICATION · 684

GOGTE SYNTHESIS · 697 GOMBERG – BACHMANN – HEY REACTION · 699 C

GOMBERG FREE RADICAL REACTION · 700 GOMBERG SYNTHESIS · 701

CADIOT – CHODKIEWICZ ·REACTION 695

GOULD – JACOBS REACTION · 702 GRAEBE – PICTET SYNTHESIS · 704

E

GRAEBE – ULLMANN CARBAZOLE SYNTHESIS · 705 GRAHAM REACTION · 706

EGLINGTON - GALBRAITH REACTION · 695

GRÄNACHER CONDENSATION · 707 GRANDBERG TRYPTAMINE SYNTHESIS · 709 GRIBBLE INDOLE REDUCTION · 710

G

GRIBBLE REDUCTION · 712 GABRIEL – COLMAN REARRANGEMENT · 661

GRIECO CONDENSATION · 713

GABRIEL – MARCKWALD – CROMWELL AZIRIDINE METHOD ·

GRIECO SELENIDE REACTION · 714 GRIESS DEAMINATION · 715

662 GABRIEL SYNTHESIS · 663

GRIGG COUPLING · 717

GALAT – ELION ACYLATION · 665

GRIGNARD – COLONGE SYNTHESIS · 718

GALLAGHER – HOLLANDER DEGRADATION · 666

GRIGNARD DEHALOGENATION · 719

GAREGG – SAMUELSSON OLEFIN SYNTHESIS · 667

GRIGNARD REACTION · 720

GARIGIPATI SYNTHESIS · 669

GROB – CAMENISCH SYNTHESIS · 722

GASSMAN INDOLE SYNTHESIS · 670

GROB FRAGMENTATION · 723

GASSMAN OXINDOLE SYNTHESIS · 672

GROVENSTEIN – ZIMMERMANN REARRANGEMENT · 725

GASTALDI PYRAZINE SYNTHESIS · 673

GROVES SYNTHESIS · 726

GATTERMANN – CANTZLER SYNTHESIS · 675

GRUBBS REACTION · 727

GATTERMANN – EHRHÁRDT ACYLATION · 676

GRUNDMANN ALDEHYDE SYNTHESIS · 729

GATTERMANN – KOCH REACTION · 677

GRYSZKIEWICZ–TROCHIMOWSKI – McCOMBIE METHOD · 730

GATTERMANN – MAFFEZZOLI SYNTHESIS · 679

GUARESCHI – THORPE CONDENSATION · 731

GATTERMANN – SKITA SYNTHESIS · 680

GUARESCHI HYDROLYSIS · 732

GATTERMANN DIARYL SYNTHESIS · 681

GUERBET REACTION · 733

GATTERMANN DIAZO REACTION · 682

GUSTAVSON CYLISATION · 734

GATTERMANN FORMYLATION · 683

GUSTUS CLEAVAGE · 735

GATTERMANN SULFINIC ACID SYNTHESIS · 685

GUTKNECHT PYRAZINE SYNTHESIS · 737

GAULTIER – GUILLEMARD REARRANGEMENT · 686

GUY – LEMAIRE – GUETTE REACTION · 738

GEWALD HETEROCYCLE SYNTHESIS · 687

GUYOT – GRY – BOUVEAULT SYNTHESIS · 739

GIBBS – WOHL PHTHALIC ANHYDRIDE PROCESS · 689 GIESE REDUCTIVE MERCURY REACTION · 690

H

GILMAN – SPEETER REACTION · 692 GILMAN – van ESS SYNTHESIS · 691

HAY REACTION · 695

GLADSTONE – TRIBE SYNTHESIS · 694

HINKEL MODIFICATION · 684

660

GABRIEL – COLMAN REARRANGEMENT EXAMPLE :

OH

O

N

N K

OCH3

O Cl

O

heat

OH

OCH3

O

MECHANISM :

O

O RO O

N K

N

O Cl

O +

O

OR heat

H O

OH COOR

OR1 O H H

N

NaOEt, EtOH, - HOR1

N O

HOR1 heat

OH

OR

DISCONNECTION :

OH

O

COOR

N H

N

O

OH OH

O OH

N

O N CH2COOR

COOR

NOTES : Phthalimidoacetic esters and phthalimide ketones on treatment with ethanolic sodium ethoxide undergo ringexpansion and yield quinoline derivatives. This method has been applied to the rearrangement of quinolyl glycine and cinchomeryl glycine esters. See also Dieckmann reaction and Gabriel synthesis.

661

REFERENCES : Houben – Weyl : 8, 578; E7a, 590, 682

1) S. Gabriel; J. Colman, Ber. Dtsch. Chem. Ges., 1900, 33, 980. 2) C.F.H. Allen, Chem. Rev., 1950, 47, 275. 3) J.H.M. Hill, J. Org. Chem., 1965, 30, 620. 4) M.T.G. Ivery; J.E. Gready, J. Chem. Res., 1993, 9, 349. 5) S.-K. Kwon, J. Korean Chem. Soc., 1996, 40, 678.

COMMENTS :

GABRIEL – MARCKWALD – CROMWELL AZIRIDINE METHOD EXAMPLE :

Br

NH2

N H

KOH

MECHANISM :

Br

R NH OR1

R NH2 +

R N

Br

base

O

O

O

DISCONNECTION : O

Br OR1

R NH2 +

OR1 N R

O

662

OR1

base

OR1

NOTES : 1,2-Halogenamines are treated with alkali to yield ethylenimines (aziridines). In addition, 5- and 6-membered rings can be formed. See also Blum aziridine, Hassner azide aziridine, Hoch – Campbell, Mansuy – Evans, Scheiner and Wenker ring-closure reactions.

REFERENCES : 1) S. Gabriel, Ber. Dtsch. Chem. Ges., 1888, 21, 1049. 2) W. Marckwald, Ber. Dtsch. Chem. Ges., 1899, 32, 2036. 3) E.L. Jackson, J. Org. Chem., 1951, 16, 1899. 4) V.P. Wystrach; D.W. Kaiser; F.C. Schaefer, J. Am. Chem. Soc., 1955, 77, 5915. 5) A. di Martino; C. Galli; P. Gargano; L. Mandolini, J. Chem. Soc., Perkin Trans. 2, 1985, 1345. 6) H.M.I. Osborn; J. Sweeney, Tetrahedron: Asymmetry, 1997, 8, 1693. 7) S.N. Filigheddu; M. Taddei, Tetrahedron Lett., 1998, 39, 3857. 8) S.N. Filigheddu; S. Masala; M. Taddei, Tetrahedron Lett., 1999, 40, 6503. 9) R.L. Weller; S.R. Rajski, Tetrahedron Lett., 2004, 45, 5807.

COMMENTS :

GABRIEL SYNTHESIS EXAMPLE :

O N H

+

Br

O

663

1) KOH 2) H+, H2O

NH2

MECHANISM :

O

O

O

N H

N

R X

N R -X

KOH O

O

O

O

O

O

OH

OH

OH NHR

OH NHR

N R O

O

OH

O

OH

COOH +

H+, H2O

RNH3 + COOH

DISCONNECTION :

RNH2

RX

NOTES : The synthesis of primary amines by the hydrolysis of N-alkylphthalimides, which are obtained from potassium phthalimide and alkyl halides. See also Delépine amine, Gabriel – Colman, Ing – Manske and Sheehan – Frank reactions.

REFERENCES : March : 426, 657 Smith – March : 500, 513, 864 Smith 2nd : 111 Houben – Weyl : 11/1, 79; E16c, 376 Org. Synth. : 17, 4; 38, 81 Org. Synth. Coll. Vol. : 2, 25; 4, 810

1) C. Graebe; A. Pictet, Ber. Dtsch. Chem. Ges., 1884, 17, 1173. 2) S. Gabriel, Ber. Dtsch. Chem. Ges., 1887, 20, 2224. 3) T. Mukaiyama; T. Taguchi, Tetrahedron Lett., 1970, 11, 3411. 4) M. Sato; S. Elbine, Synthesis, 1981, 472. 5) A. Zwierzak; S.P. Pilichowska, Synthesis, 1982, 922. 6) U. Ragnarsson; L. Grehn, Acc. Chem. Res., 1991, 24, 285.

664

7) M. Lácová; J. Chovanocová; E. Veverková; Š. Toma, Tetrahedron, 1996, 52, 14995. 8) K. Iida; S. Tokiwa; T. Ishii; M. Kajiwara, J. Labelled Compd. Radiopharm., 2002, 45, 569.

COMMENTS :

GALAT – ELION ACYLATION EXAMPLE :

O

O CH3NH2. HCl +

H3C H2N

CH3

melt

N H

CH3

DISCONNECTION :

O R

N H

O RNH2. HCl +

R1

H2N

R1

NOTES : Amines are acylated quickly by heating the amine salt with a slight excess of amide. See also Chattaway acetylation, Einhorn acylation, Lumière – Barbier, Schotten – Baumann and Weinreb reactions.

REFERENCES : 1) A. Galat; G. Elion, J. Am. Chem. Soc., 1943, 65, 1566. 2) E.S. Lane, J. Chem. Soc., 1955, 1079.

COMMENTS :

665

GALLAGHER – HOLLANDER DEGRADATION EXAMPLE :

HO

H3C

OH

H3C COOH

COOH H3C

H3C 1) SOCl2 2) CH2N2 3) HCl 4) Zn, HOAc 5) Br2 6) Collidine 7) CrO3

HO

HO

MECHANISM :

O R

R

COOH

O Cl

SOCl2

N2

CH2N2

O R

R Zn, HOAc

HCl - N2

O

O Cl

H

R

R

CH3

CH3

Br2 Br

O N

R

CH3

RCOOH + CrO3

H

H3C

COOH O

H

- HBr

DISCONNECTION :

H3C

COOH

R

COOH

O

NOTES : A method for the degradation of aliphatic acids, after an initial chain extension by one carbon atom, in which two carbon atoms are eliminated. See also Barbier – Locquin – Wieland, Hoehn – Mason, Krafft, Miescher, Trost oxidative decarboxylation and Wieland – Dane reactions.

666

REFERENCES : Smith : 304 Smith 2nd : 266

1) V.P. Hollander; T.F. Gallagher, J. Biol. Chem., 1946, 162, 549. 2) C.W. Shoppee, Annu. Rep., 1947, 44, 184.

COMMENTS :

GAREGG – SAMUELSSON OLEFIN SYNTHESIS EXAMPLE :

I

OH

O

O

HO HO

I +

N Boc

OBz

N H

N H

Boc

N

H

O

I

OBz Boc

N

Ph3P, I2

MECHANISM : H N

N Ph3PI I

N +

+ 2

N I P (Ph)3

N H

667

N HI

H

OBz

HO H R1

N

R2 H OH

O +

2 N H

N I

2

N P (Ph)3

Ph3P O R1

- (Ph)3PO

I H

R2 H

R1

I

PPh3 H R2

H O Ph3P

R1

R2

H

H

- I2 - (Ph)3PO

I I

DISCONNECTION :

R1

R2

H

H

HO H R1

R2 H OH

NOTES : The conversion of vicinal trans-diol groups into a double bond by an iodine-triphenylphosphine-imidazole reagent. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : 1) P.J. Garegg; B. Samuelsson, Synthesis, 1979, 469. 2) P.J. Garegg; B. Samuelsson, Synthesis, 1979, 813. 3) Z. Pakulski; A. Zamojski, Carbohydr. Res., 1990, 205, 410. 4) F.A. Luzzio; M.E. Menes, J. Org. Chem., 1994, 59, 7267.

COMMENTS :

668

GARIGIPATI SYNTHESIS EXAMPLE :

H

N

CN

NH2 1) CH3Al(Cl)NH2 toluene, 80 oC 2) H2O

MECHANISM :

CH3 Al N Cl R2 R N R1

RCN Cl

R1

Al N H3C R2

H H2O

R

N N R1

R2

toluene, 80 oC

DISCONNECTION :

H R

N N R1

R2

RCN

NOTES : The direct conversion of nitriles to amidines using an aluminium amide reagent. See also Pinner iminoether reaction.

REFERENCES : 1) J.I. Levin; E. Turos; M. Lipton; S.M. Weinreb, Synth. Commun., 1982, 12, 989. 2) R.S. Garigipati, Tetrahedron Lett., 1990, 31, 1969. 3) R.A. Moss; M. Wei; D.C. Merrer; X. Song, Tetrahedron Lett., 1995, 36, 8761.

669

COMMENTS :

GASSMAN INDOLE SYNTHESIS EXAMPLE :

EtO2C

EtO2C

CH3

1) tBuOCl DCM, - 70 oC 2) O

NH2

N H

CH3 SCH3 3) Et3N, - 70 oC -> RT 4) H2, Raney Ni, EtOH, RT

MECHANISM :

O EtO2C

EtO2C

EtO2C

t

BuOCl DCM, - 70 oC

NH2

N Cl

H

CH3

O N H

CH3

S

SCH3 O EtO2C

CH3

Et3N - 70 oC -> RT

N H

S

CH3

H

EtO2C [2,3]-sigmatropic rearrangement

- H2O

EtO2C CH3 N H

Raney Ni H2

670

CH3 S CH3 NH

SCH3 EtO2C

O

CH3 N H

CH3

DISCONNECTION :

R1 R

R2

R2

N H

NH2

NOTES : This procedure is an example of an indole synthesis, which can be utilised to prepare 1-, 2-, 4-, 5-, 6-, or 7-substituted indoles. Indoles substituted on the phenyl ring with nitro, ethoxycarbonyl, chloro, methyl, and acetoxy groups have been prepared. Hydrogen, methyl, and phenyl groups have been placed in the 2-position and the method has been used to prepare 1-methylindoles. The main feature of this reaction is the [2,3]-sigmatropic rearrangement. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Org. Synth. : 56, 72 Org. Synth. Coll. Vol. : 6, 601 Science of Synthesis : 10, 387

1) P.G. Gassman; T.J. van Bergen, J. Am. Chem. Soc., 1973, 95, 590. 2) P.G. Gassman; T.J. van Bergen; G.D. Gruetzmacher, J. Am. Chem. Soc., 1973, 95, 5608. 3) P.G. Gassman; D.P. Gilbert; T.-Y. Luh, J. Org. Chem., 1977, 42, 1340. 4) P.G. Gassman; J.J. Roos; S.J. Lee, J. Org. Chem., 1984, 49, 717. 5) B.M. Savall; W.W. McWhorter, J. Org. Chem., 1996, 61, 8696.

COMMENTS :

671

GASSMAN OXINDOLE SYNTHESIS EXAMPLE :

NH2

1) Me3COCl CH3SCH2COOEt 2) Raney nickel, DCM

O N H

MECHANISM :

O N H

Raney nickel

SCH3

H3CS

H

O NH2

Me3COCl CH3SCH2COOEt

O

OEt

N H

NH2

H3C S 1) Cl 2) Et3N 3) H+

CO2Et HgO, BF3

Cl

O O N H

DISCONNECTION :

O N R

N H

672

R

NOTES : This is the synthesis of oxindoles from anilines. There are two possible reaction pathways. The use of sulfoxide instead of sulfenyl halide has been demonstrated by Wright et al. See also von Baeyer oxindole, Brunner, Gassman indole, Hinsberg oxindole, Martinet, Neber – Bosset and Stollé reactions.

REFERENCES : Science of Synthesis : 10, 603

1) P.G. Gassman; T.J. van Bergen, J. Am. Chem. Soc., 1973, 95, 2718. 2) P.G. Gassman; B.W. Cue, jr.; T.Y. Luh, J. Org. Chem., 1977, 42, 1344. 3) P.D. Johnson; P.A. Aristoff, J. Org. Chem., 1990, 55, 1374. 4) S.W. Wright; L.D. McClure; D.L. Hageman, Tetrahedron Lett., 1996, 37, 4631. 6) J.F.M. da Silva; S.J. Garden; A.C. Pinto, J. Braz. Chem. Soc., 2001, 12, 273.

COMMENTS :

GASTALDI PYRAZINE SYNTHESIS EXAMPLE :

2

H3C

N O

H3C

OH

1) NaHSO3 2) KCN 3) HCl 4) air oxidation 5) NaOH 6) decarboxylation

673

N

OH

N

CH3

MECHANISM :

R

N

2

OH 4 NaHSO3

O

R

O

OH H2N

CN

SO3Na R H N 2 O SO3Na

CN

2 KCN

NH2

O

R

N

CN

NC

N

R

O

H H N CN

R

N

CN

NC

N

R

R OH

NC

NC

R

HO-

N H H

R

R

N

OH

HOOC

N

R

H N SO3Na

R 2

- 2 H2O

R - CO2

N

OH

N

R

HCl

air oxidation

DISCONNECTION :

R

N

CN R

NC

N

R

N

OH

O

NOTES : 2,5-Dicyano-3,6-disubstituted pyrazines are obtained by treatment of an oximino ketone bisulfite with potassium cyanide, followed by heating the reaction product with hydrochloric acid and oxidation. When treated with alkali, the dicyano compound yields a 3,6-disubstituted 2-hydroxypyrazine-5-carboxylic acid, which is decarboxylated to give a 3,6-disubstituted-2-hydroxypyrazine. See also Gutknecht pyrazine and Stadel – Rügheimer reactions.

REFERENCES : 1) G. Gastaldi, Gazz. Chim. Ital., 1921, 51, 233. 2) I.J. Krems; P.E. Spoerri, Chem. Rev., 1947, 40, 279. 3) W.H. Sharp; F.S. Spring, J. Chem. Soc., 1948, 1862. 4) E. Golombok; F.S. Spring, J. Chem. Soc., 1949, 1364. 5) G. Karmas; P.E. Spoerri, J. Am. Chem. Soc., 1957, 79, 680.

COMMENTS :

674

GATTERMANN – CANTZLER SYNTHESIS EXAMPLE :

O N

C + KOCN

N

N

Cu powder

MECHANISM : O C

N N N C O

N

Cu powder - N2

DISCONNECTION :

ArN2+ Cl-

ArNCO

Ar = Ph, C6H4CH3, C6H4OCH3, C6H4Br

NOTES : This reaction involves the formation of aryl isocyanates by the treatment of aromatic diazonium salts with potassium cyanate in the presence of copper. It is a low yielding reaction and hardly used method. See also Sandmeyer diazonium reaction.

REFERENCES : Houben – Weyl : 8, 127

1) L. Gattermann; A. Cantzler, Ber. Dtsch. Chem. Ges., 1890, 23, 1225. 2) L. Gattermann; A. Cantzler, Ber. Dtsch. Chem. Ges., 1892, 25, 1086. 3) W.A. Cowdry; D.S. Davies, J. Chem. Soc., Quat. Rev., 1952, 6, 358.

COMMENTS :

675

GATTERMANN – EHRHÁRDT ACYLATION EXAMPLE :

OCH3

OCH3 Cl

+

AlCl3

O

O

Et

MECHANISM :

O

O R

Cl

R

AlCl3

AlCl3

O

Cl

AlCl3 R

H Cl OR1

OR1

O

O

AlCl3

R - HCl

R OR1 OR1

DISCONNECTION :

O R

O R

OR1

Cl

+ OR1

NOTES : Alkyl ethers of phenols react with acid chlorides in the presence of aluminium chloride to give p-acyl substitution. See also Friedel – Crafts reaction.

REFERENCES : March : 539

676

Smith – March : 718 Smith : 1324 Smith 2nd : 1090 Org. React. : 2, 114; 3, 1; 5, 229

1) L. Gattermann, Ber. Dtsch. Chem. Ges., 1889, 22, 1129. 2) L. Gattermann; R. Ehrhárdt; H. Maisch, Ber. Dtsch. Chem. Ges., 1890, 23, 1199. 3) W.H. Hartung; J.C. Munch; E. Miller; F. Crossley, J. Am. Chem. Soc., 1931, 53, 4149. 4) R. Frenette; M. Kakushima; R. Zamboni; R.N. Young; T.R. Verhoeven, J. Org. Chem., 1987, 52, 304. 5) N. Tanaka; H. Yamazaki; H. Sakuragi; K. Tokumaru, Bull. Chem. Soc. Jpn., 1994, 67, 1434. 6) S.R. Stauffer; C.J. Coletta; R. Tedesco; G. Nishiguchi; K. Carlson; J. Sun; B.S. Katzenellenbogen; J.A. Katzenellenbogen, J. Med. Chem., 2000, 43, 4934.

COMMENTS :

GATTERMANN – KOCH REACTION EXAMPLE :

H CO, HCl AlCl3, Cu2Cl2

O

MECHANISM :

O C O

AlCl3

+ HCl H

Cl H

H

Cl O

O

O

Cl

AlCl3

AlCl3 Cl

AlCl3 H H

H

R

R

- H+ R

R

677

H2O, - AlCl4

O

DISCONNECTION :

R

R

H O

R = alkyl

NOTES : Aromatic aldehydes are obtained by the action of carbon monoxide and hydrogen chloride on aromatic hydrocarbons in the presence of aluminium chloride with or without a cuprous catalyst. A reverse reaction has been reported. See also Gattermann formylation, Karrer, Reimer – Tiemann and Rieche formylation reactions.

REFERENCES : March : 544, 563 Smith – March : 716, 732 Houben – Weyl : 7/1, 16; E3, 32; E6a, 852; E19c, 362, 369 Org. React. : 5, 290 Org. Synth. : 12, 80 Org. Synth. Coll. Vol. : 2, 583

1) L. Gattermann; J.A. Koch, Ber. Dtsch. Chem. Ges., 1897, 30, 1622. 2) P.H. Gore, Chem. Rev., 1955, 55, 235. 3) G.A. Olah; F. Pelizza; S. Kobayashi; J.A. Olah, J. Am. Chem. Soc., 1976, 98, 296. 4) M. Tanaka; M. Fujiwara; Q. Xiu; H. Ando; T.J. Raeker, J. Org. Chem., 1998, 63, 4408. 5) W. Kantlehner; M. Vettel; A. Gissel; E. Hang; G. Ziegler; M. Ciesielski; O. Scherr; R. Haas, J. Prakt. Chem., 2000, 342, 297. 6) I. Doanamona, Rev. Roum. Chim., 2001, 46, 345.

COMMENTS :

678

GATTERMANN – MAFFEZZOLI SYNTHESIS EXAMPLE :

H3C

MgBr

H

+

H

OEt

H3C

- 50 oC

O

O

MECHANISM :

RMgCl +

H

R

OEt

H

O

O

OEt MgCl O

H2O

R

H

DISCONNECTION :

R

H

RBr +

O

H

OEt O

NOTES :

Excess ethyl formate reacts with Grignard reagents at – 50 oC to yield aldehydes after hydrolysis. See also Bodroux – Chichibabin reaction.

REFERENCES : Houben – Weyl : 7/1, 65

1) L. Gattermann; F. Maffezzoli, Ber. Dtsch. Chem. Ges., 1903, 36, 4152. 2) L. Gattermann, Liebigs Ann. Chem., 1912, 393, 215. 3) N. Boccara; P. Maitte, Bull. Soc. Chim. Fr., 1972, 1448.

COMMENTS :

679

GATTERMANN – SKITA SYNTHESIS EXAMPLE :

O OCH3

EtO

Cl

Cl

H3CO

+

2 O

O

O OCH3

NaOEt

NH2

HO

N

OH

MECHANISM :

COOR

ROOC Cl

O

O

O

NH2

OR

- 2 NaCl

RO H

O

ROOC

NH2 O

O

O

RO - ROH

OR COOR OR

Cl

OR O NH2 O

H

O

RO

O OR

- ROH

OR O

N

O

H O

RO

OR

HO

N

OH

DISCONNECTION :

O

O OR

RO HO

N

RO

OH

OR O

O

+

Cl

Cl NH2

NOTES :

Sodium diethyl malonate is condensed with dichloromethylamine to yield pyridine derivatives. See also Bohlmann – Rahtz, Chichibabin pyridine, Guareschi – Thorpe, Hantzsch – Beyer, von Meyer – Mohr, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES :

1) L. Gattermann; A. Skita, Ber. Dtsch. Chem. Ges., 1916, 49, 494. 2) V.P. Litvinov, Russ. Chem. Rev., 2003, 72, 69.

680

COMMENTS :

GATTERMANN DIARYL SYNTHESIS EXAMPLE :

2 PhN2+Cl- + 2 Cu

aq. EtOH

MECHANISM :

2 ArN2+Cl- + 2 Cu

Ar2 + 2 N2 + Cu2Cl2

DISCONNECTION :

2 ArN2+Cl-

Ar2

NOTES :

Aqueous ethanolic solutions of aryl diazonium salts, when treated with precipitated copper powder and other reducing agents (zinc), yields diaryls. See also Gattermann, Gomberg – Bachmann – Hey, Graebe – Ullmann and Pschorr reactions.

REFERENCES :

L. Gattermann, Ber. Dtsch. Chem. Ges., 1890, 23, 1218.

COMMENTS :

681

GATTERMANN DIAZO REACTION EXAMPLE :

N

N

Cl

Cl Cu, aq. HCl

MECHANISM :

ArN2+ + CuCl2-

Ar

CuCl2

N N

ArCl + CuCl + N2

ArN2+

Ar

N N CuCl2

Ar

N N

ArCl + ArN2+ + CuCl + N2

DISCONNECTION :

N

X

N X

X = Cl, Br, CN, NO2

NOTES :

This reaction is very similar to the Gattermann diaryl reaction. The synthesis of aromatic diazonium compounds of halogenated aromatic compounds and aromatic nitriles, using finely divided copper or copper bronze as a catalyst. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann sulfinic

682

acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : Smith – March : 936 Smith 2nd : 168 Org. Synth. : 3, 33; 13, 28 Org. Synth. Coll. Vol.: 1, 170; 2, 130

1) L. Gattermann, Ber. Dtsch. Chem. Ges., 1890, 23, 1218. 2) H.H. Hodgson, Chem. Rev., 1947, 40, 251. 3) E. Pfeil, Angew. Chem., 1953, 65, 155.

COMMENTS :

GATTERMANN FORMYLATION EXAMPLE :

O

CH3 + HCN + HCl

H

1) AlCl3, C6H6 2) H2O CH3

683

MECHANISM :

R

H N H

AlCl3

N AlCl3

H

HCN + HCl

H Cl

Cl H

H

H H N AlCl3 Cl

R

N H

H R

R

H

- AlCl4

H

N H+

H

O H2O, - NH4+

R H

DISCONNECTION :

O

H

R

R

NOTES :

The interaction of an aromatic compound, hydrogen cyanide and hydrogen chloride, usually in the presence of a metallic chloride, to give an aldimine hydrochloride, which is hydrolysed to the corresponding aldehyde. In the Adams modification, zinc cyanide replaces hydrogen cyanide. Sodium cyanide is also employed. In the Hinkel modification aluminium chloride and hydrogen cyanide in chlorobenzene or dichloroethane are used, a larger variety of compounds can be prepared under these conditions. In the Shah – Laiwalla modification rezorcine is synthesised using the Adams modification. See also Duff, Fischer – Zerweck, Hoesch – Houben and Reimer – Tiemann reactions.

REFERENCES : March : 543, 552 Smith – March : 715 Houben – Weyl : 7/1, 20; E3, 19, 94; E6a, 95; E6b, 134; E19c, 366 Org. React. : 5, 290, 387; 9, 37 Org. Synth. : 23, 57 Org. Synth. Coll. Vol. : 3, 549 Science of Synthesis : 9, 240

1) L. Gattermann, Ber. Dtsch. Chem. Ges., 1898, 31, 1149.

684

2) R. Adams; J. Levine, J. Am. Chem. Soc., 1923, 45, 2373. 3) L.E. Hinkel, J. Chem. Soc., 1936, 339. 4) R.C. Shah; M.C. Laiwalla, J. Chem. Soc., 1938, 1828. 5) E. Baltazzi; L.I. Krimen, Chem. Rev., 1963, 63, 526. 6) A. Kreutzberger, Angew. Chem., 1967, 79, 978. 7) Y. Sato; M. Yato; T. Ohwada; S. Saito; K. Shudo, J. Am. Chem. Soc., 1995, 117, 3037.

COMMENTS :

GATTERMANN SULFINIC ACID SYNTHESIS EXAMPLE :

N Cl CF3

N

SO2Cl SO2, CuCl HAc, HCl

CF3

MECHANISM :

ArN2+X- + H2SO3

Cu+

ArSO2H

Oxydation

ArSO3H

DISCONNECTION :

ArN2+X- + H2SO3

ArSO3H

NOTES :

An aryl diazonium salt (sulfate) gives a sulfinic acid, which is readily oxidised to a sulfonic acid, on treatment with sulfurous acid with or without a copper catalyst. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

685

REFERENCES : March : 724 Smith – March : 937 Houben – Weyl : 9, 534 Org. Synth. : 47, 4; 60, 121 Org. Synth. Coll. Vol. : 5, 60; 7, 508

1) L. Gattermann, Ber. Dtsch. Chem. Ges., 1899, 32, 1136. 2) J. Thomas, J. Chem. Soc., 1909, 95, 342. 3) R.D. Haworth; A. Lapworth, J. Chem. Soc., 1923, 123, 2982. 4) W.E. Truce; J.F. Lyons, J. Am. Chem. Soc., 1951, 73, 126.

COMMENTS :

GAULTIER – GUILLEMARD REARRANGEMENT EXAMPLE :

N C

C N

heat

MECHANISM :

H3C

N C

o

180 - 200 C

N C

H3C

DISCONNECTION :

R C N

R N C

686

H3C

C N

NOTES :

This is the thermal isonitrile rearrangement. The development of a new C-C bond is nearly synchronous with breaking of the N-C bond in non-polar solvents. In polar solvents, the mechanism is different, see Rüchardt et al.

REFERENCES : March : 1102 Smith – March : 1421 Smith 2nd : 573

1) A. Gaultier, Ann. Chim. (Paris), 1869, 17, 215. 2) A. Gaultier, Ann. Chim. (Paris), 1869, 17, 233. 3) M.H. Guillemard, C.R. Séances Acad. Sci., 1906, 143, 1158. 4) C. Grundmann, Chem. Ber., 1958, 91, 1380. 5) G. Kohlmaier; B.S. Rabinovitch, J. Phys. Chem., 1959, 63, 1793. 6) J. Casanova, jr.; N.D. Werner; R.E. Schuster, J. Org. Chem., 1966, 31, 3473. 7) G.W. van Dine; R. Hoffmann, J. Am. Chem. Soc., 1968, 90, 3227. 8) M. Meier; C. Rüchardt, Chimia, 1986, 40, 238. 9) J. Pakusch; C. Rüchardt, Chem. Ber., 1991, 124, 971.

COMMENTS :

GEWALD HETEROCYCLE SYNTHESIS EXAMPLE :

COOEt

H N

O O

+ N

O

CH3

+ O

687

S, 50 oC

NH2 S

MECHANISM :

OEt

OEt

N base

O

EtO N

O

OH

O R1 O H

R2

R2 OEt

O

N

S8

R2 O

H+ H+

EtO

R2 NH2

EtO

EtO

S

S H R2

R1

R2

O

NH

S R1

R1

R2 O

N

S S7

S8

R1

R1

N

EtO

O

O base

H

R1

R2 N

N

O

- H2O

R1

+

OEt

OEt

N

H

R1 R2

DISCONNECTION :

R1 R1 R

R2 S

NH2

O

R

SH

R1

O

+

R2

CN

+

R2

CN

+ S

R

NOTES :

The synthesis of 2-aminothiophenes by condensation of malononitriles with ketones. For more about the reaction mechanism see Sabnis et al.

REFERENCES : Houben – Weyl : E6a, 220, 241 Science of Synthesis : 9, 300, 307

1) K. Gewald, Z. Chem., 1962, 2, 205. 2) K. Gewald, Chem. Ber., 1965, 98, 3571. 3) K. Gewald; E. Schinke; H. Boettcher, Chem. Ber., 1966, 99, 94. 4) K. Gewald; E. Schinke, Chem. Ber., 1966, 99, 2712. 5) F.J. Tinney; W.A. Centenko; J.J. Kerbleski; D.T. Connor; R.J. Sorenson; D.J. Herzig, J. Med. Chem., 1981, 24, 878.

688

6) N.P. Peet; S. Sunder; R.J. Barbuch; A.P. Vinogradoff, J. Heterocycl. Chem., 1986, 23, 129. 7) S.M. Sherif, Monatsh. Chem., 1996, 127, 955. 8) R.W. Sabnis; D.W. Rangnekar; N.D. Sonawane, J. Heterocycl. Chem., 1999, 36, 333. 9) G.M. Castanedo; D.P. Sutherlin, Tetrahedron Lett., 2001, 42, 7181. 10) A.P.F. Hoener; B. Henkel; J.-C. Gauvin, Synlett, 2003, 63.

COMMENTS :

GIBBS – WOHL PHTHALIC ANHYDRIDE PROCESS EXAMPLE : O air 450 oC V2O5

O O

NOTES :

Phthalic anhydride is obtained by the oxidation of naphthalene with air at 450 oC in the presence of a catalyst such as vanadium pentoxide.

REFERENCES :

1) J. Walter, J. Prakt. Chem., 1895, 51, 107. 2) H.D. Gibbs; C. Conover, U.S. Patent, 1918, 1285117. 3) A. Wohl, U.S. Patent, 1930, 1787416. 4) A. Wohl, U.S. Patent, 1930, 1787417.

COMMENTS :

689

GIESE REDUCTIVE MERCURY REACTION EXAMPLE :

CH3O

OCH3

OCH3

H3CO

CO2Et

1) Hg(OAc)2 CH3OH 2) NaBH4

MECHANISM :

O

O

O

Hg(OAc)2 AcOH

H

AcO

AcO

HgOAc

O

O

H

-H

H

AcO

Hg

AcO

O

H

H

NaBH(OCH3)3 DCM

H

O

H

H

OAc

H

OAc

DISCONNECTION :

R

H

RHgX +

Y

690

Y

HgH

NOTES :

The sodium trimethoxyborohydride or sodium borohydride or tributyltin hydride reduces the organomercuric acetate to give mercuric hydride. Homolytic cleavage of the mercury-hydrogen bond produces an organomercury-radical, which fragments to give a β-acetoxy radical. This reacts with the reactive enone double bond.

REFERENCES : March : 759 Smith – March : 993 Smith : 179 Smith 2nd : 150 Org. React. : 48, 301

1) B. Giese; K. Heuck, Chem. Ber., 1979, 112, 3759. 2) B. Giese; K. Heuck, Tetrahedron Lett., 1980, 21, 1829. 3) B. Giese; K. Heuck, Chem. Ber., 1981, 114, 1572. 4) S.J. Danishefsky; S. Chackalamannil; B.-J. Uang, J. Org. Chem., 1982, 47, 2231. 5) B. Giese, Angew. Chem., Int. Ed. Engl., 1985, 24, 553. 6) J. Barluenga; M. Yus, Chem. Rev., 1988, 88, 487. 7) D.P. Curran; J.Y. Xu, J. Chem. Soc., Perkin Trans. 1, 1995, 3061. 8) S. Raghavan; K.A. Tony; S.R. Reddy, Tetrahedron Lett., 2001, 42, 8383.

COMMENTS :

GILMAN – van ESS SYNTHESIS EXAMPLE :

O Li

O + OLi

Et2O, Benzene

691

MECHANISM :

O R

R OLi

+ R1Li

R1

LiO

R

OLi

R1 O

DISCONNECTION :

R

O

R1 R

O

OLi

+ R1Li

NOTES :

Phenyl alkyl ketones are prepared by the carbonation of organo lithium compounds.

REFERENCES :

1) H. Gilman; P.R. van Ess, J. Am. Chem. Soc., 1933, 55, 1258. 2) C. Tegnér, Acta. Chem. Scand., 1952, 6, 782. 3) H.F. Bluhm; H.V. Donn; H.D. Zook, J. Am. Chem. Soc., 1955, 77, 4406.

COMMENTS :

GILMAN – SPEETER REACTION EXAMPLE :

O

N +

Br

OEt

Zn

N O

692

MECHANISM :

R

R

R1O

R1O

Br

Zn

O

R

Ph N

R1O O

ZnBr

Ph N

+

O

Ph

O

Ph N

ZnBr

Ph

- ZnBrOR1

R

Ph

DISCONNECTION :

O N R

R

R2 R1O

Br O

R3

R2 +

N R3

NOTES :

The addition of zinc metal to a mixture of an α-bromoester and an imine to afford a β-lactam (Reformatsky reaction). Catalytic and asymmetric versions of the reaction are known. See also Dreiding – Schmidt and Reformatsky reactions.

REFERENCES :

1) H. Gilman; M. Speeter, J. Am. Chem. Soc., 1943, 65, 2255. 2) D.J. Hart; D.-C. Ha, Chem. Rev., 1989, 89, 1447. 3) R. Brieva; J.Z. Crich; C.J. Sih, J. Org. Chem., 1993, 58, 1068. 4) S.E. Denmark; O.J.-C. Nicaise, Chem. Commun., 1996, 999. 5) H. Fujieda; M. Kanai; T. Kambara; A. Iida; K. Tomioka, J. Am. Chem. Soc., 1997, 119, 2060. 6) K. Tomioka; H. Fujieda; S. Hayashi; M.A. Hussein; T. Kambara; Y. Nomura; M. Kanai; K. Koga, Chem. Commun., 1999, 715. 7) M. Benaglia; M. Cinquini; F. Cozzi, Eur. J. Org. Chem., 2000, 563.

COMMENTS :

693

GLADSTONE – TRIBE SYNTHESIS EXAMPLE :

EtI

H2O, Zn-Cu heat

CH3CH3

DISCONNECTION :

Alk

Alk H

I

NOTES :

This reaction comprises the reduction of alkyl halides to the corresponding hydrocarbons using the zinc-copper couple in water or ethanol.

REFERENCES : Org. Synth. : 12, 86 Org. Synth. Coll. Vol. : 2, 184

1) J.H. Gladstone; A. Tribe, J. Chem. Soc., 1873, 26, 445. 2) J.H. Gladstone; A. Tribe, J. Chem. Soc., 1873, 26, 678. 3) J.H. Gladstone; A. Tribe, J. Chem. Soc., 1873, 26, 961. 4) J.H. Gladstone; A. Tribe, J. Chem. Soc., 1884, 45, 154.

COMMENTS :

694

GLASER COUPLING (CADIOT – CHODKIEWICZ – EGLINGTON COUPLING) EXAMPLE :

2 Ph C C H

Ph C C C C Ph

1) KOH 2) Cu, O2

MECHANISM :

2+ N 2

Base, CuI

2

CuI +

H

- 2 CuI

Cu X Cu

N Cu Cu

N

N

R

N

N X

2+

N

N

R

DISCONNECTION :

R C C C C R

R C C H

NOTES :

Copper or silver acetylides containing acetylenic hydrogen on treatment with oxygen gas in the presence of ammonia or amines and ammonium chloride condense by oxidative coupling to form symmetrical di-ynic compounds. When the reaction involves a terminal alkyne it is often called the Cadiot – Chodkiewicz reaction. A reaction of a terminal halogen-substituted alkyne is often called an Eglington – Galbraith reaction. The Hay or Glaser – Hay coupling uses a triethylsilyl protecting group. A strictly pair selective synthesis has been published by Negishi et al. For a DFT study on the Hay modification see Fomine et al. A radical mechanism, although proposed, has been rejected. See also Sonogashira – Hagihara and Ullmann diaryl reactions.

REFERENCES : March : 714 Smith – March : 927 Smith : 680 Smith 2nd : 576, 1186

695

Houben – Weyl : 13/1, 751; E5, 386, 393; E15, 3333 Org. Synth. : 45, 39; 65, 52, 61 Org. Synth. Coll. Vol. : 5, 517; 8, 63, 606

1) C. Glaser, Ber. Dtsch. Chem. Ges., 1869, 2, 422. 2) C. Glaser, Liebigs Ann. Chem., 1870, 154, 159. 3) W. Chodkiewicz; P. Cadiot, C.R. Séances Acad. Sci., 1955, 241, 1055. 4) G. Eglington; A.R. Galbraith, Chem. Ind. (London), 1956, 737. 5) W. Chodkiewicz, Ann. Chim. (Paris), 1957, 2, 819. 6) W.J. Gensler, Chem. Rev., 1957, 57, 215. 7) O.M. Behr; G. Eglington; R.A. Raphael, Chem. Ind. (London), 1959, 699. 8) A.S. Hay, J. Org. Chem., 1962, 27, 3320. 9) N. Ghose; D.R.M. Walton, Synthesis, 1974, 890. 10) F.M. Menger; X.Y. Chen; S. Brocchini; H.P. Hopkins; D. Hamilton, J. Am. Chem. Soc., 1993, 115, 6600. 11) E-i. Negishi; M. Hata; C. Xu, Org. Lett., 2000, 2, 3687. 12) T. Gibtner; F. Hampel; J.-P. Gisselbrecht; A. Hirsch, Chem. Eur. J., 2002, 8, 408. 13) L. Fomina; B. Vazquez; E. Tkatchouk; S. Fomine, Tetrahedron, 2002, 58, 6741.

COMMENTS :

GODCHOT – MOUSSERON RING CONTRACTION EXAMPLE :

NH2 NaNO2, 0 oC

OH

H O

MECHANISM :

NH2 OH

N NaNO2, 0 oC

OH

N

H - N2

696

O H

O

DISCONNECTION :

n

n

n = 1 or 2

NH2 OH

H O

NOTES :

A C6 or C7 2-amino-cycloalkanol yields on treatment with sodium nitrite at 0 oC the cycloalkanoic aldehyde of the lower cycloalkane. See also Demjanov rearrangement, Nametkin rearrangement and Tiffeneau – Demjanov ring enlargement.

REFERENCES :

M. Godchot; M. Mousseron, C.R. Séances Acad. Sci., 1934, 198, 2000.

COMMENTS :

GOGTE SYNTHESIS EXAMPLE :

CH3

CH3

HO

O

O

EtCOCl pyridine

697

Et

O

O

MECHANISM :

R

O

R

HO

O

O

O

R

O

R1 R

heat, - CO2

R1

O

O

R

O

R1COCl pyridine HO

O

O

R1

2 R1COCl pyridine

R1

HO

O

R1 heat, - CO2

O

R1

O

O

DISCONNECTION :

R R R1

O

O

R

O

HO

O

O

R1 R1

O

O

NOTES :

β-Substituted glutaconic anhydrides react in the presence of pyridine with one or two molecules of an acyl chloride to form C-acylation products. These compounds afford α-pyrone derivatives when heated.

REFERENCES :

C.R. Gogte, Proc. Indian Acad. Sci., 1938, 7A, 214.

COMMENTS :

698

GOMBERG – BACHMANN – HEY REACTION EXAMPLE :

+

N N KOH

MECHANISM :

N 2

N

O

N

N

-

N N + HO

- N2 ON=NPh +

ON=NPh

N N OH

DISCONNECTION :

N N

+ R1

R

R/R1

R/R1

NOTES :

Diaryls are produced by the addition of alkali to a mixture of a diazonium salt and a liquid aromatic hydrocarbon or its derivative. Heterocyclic compounds can also be employed and the method is of value for intramolecular cyclisations (Pschorr reaction). See also Bamberger – Hey, Cadogan, Gattermann, Graebe – Ullmann, Pschorr, Ullmann and Vorländer – Meyer reactions.

REFERENCES : March : 715, 1225 Smith – March : 928, 1560 Smith : 1436 Smith 2nd : 1184 Houben – Weyl : E6a, 928; E7b, 595; E8d, 568; E16a, 1129 Org. React. : 2, 224; 9, 409 Org. Synth. : 8, 42; 33, 56 Org. Synth. Coll. Vol. : 1, 113; 4, 718 Science of Synthesis : 9, 357

699

1) E. Bamberger, Ber. Dtsch. Chem. Ges., 1895, 28, 403. 2) M. Gomberg; W.E. Bachmann, J. Am. Chem. Soc., 1924, 46, 2339. 3) D.H. Hey; W.A. Waters, Chem. Rev., 1937, 21, 169. 4) M. Sainsbury, Tetrahedron, 1980, 36, 3329. 5) J.A. Beadle; S.H. Korzeniowski; D.E. Rosenberg; B.J. Garcia–Slanga; G.W. Gokel, J. Org. Chem., 1984, 49, 1594. 6) R. Bolton; G. Williams, Chem. Soc. Rev., 1986, 15, 261. 7) M. Gurczynski; P. Tomasik, Org. Prep. Proced. Int., 1991, 23, 438. 8) Y.H. Lai; J.P. Jiang, J. Org. Chem., 1997, 62, 4412.

COMMENTS :

GOMBERG FREE RADICAL REACTION EXAMPLE :

Ph Ph Ph

Ph

Zn

Ph 2 Ph Ph

Ph Ph

MECHANISM :

2 Ph

Zn

2 Ph

Cl

2 Ph

Cl Ph

Ph

Ph

Ph

Ph

Ph

DISCONNECTION :

Ph

Ph

2 Ph

2 Ph Ph

Cl Ph

NOTES :

Free radicals are obtained by the reaction of triarylmethyl halides with metals.

700

+ ZnCl2

REFERENCES : Houben – Weyl : E6a, 103 Science of Synthesis : 9, 246

1) M. Gomberg, J. Am. Chem. Soc., 1900, 22, 757. 2) E. Müller, Angew. Chem., 1952, 64, 233. 3) J.M. McBride, Tetrahedron, 1974, 30, 2009. 4) B.E. Daikh; R.G. Finke, J. Chem. Soc., Chem. Commun., 1991, 784. 5) L.E. Harrington; J.F. Britten; M.J. McGlinchey, Tetrahedron Lett., 2003, 44, 8057.

COMMENTS :

GOMBERG SYNTHESIS EXAMPLE :

HO

H2C CH2

Cl

Cl2, H2O

MECHANISM :

H3C

CH3 Br

H3C Br

H3C Br2

H3C

HO H

H3C

H

O

+

-H H

DISCONNECTION :

R R2 X

R

R2

R1

R3

OH R1 R3

X = Cl, Br

701

H3C H O

CH3 Br

NOTES :

In the classic example ethylene chloro- or bromohydrin is obtained by treating ethylene with chlorine in the presence of water at temperatures from 0 – 20 oC. The active species can also be HOCl or HOBr. The reaction has been extended to other alkenes.

REFERENCES :

1) M. Gomberg, J. Am. Chem. Soc., 1919, 41, 1414. 2) G. Braun, J. Am. Chem. Soc., 1930, 52, 3176. 3) G. Braun, J. Am. Chem. Soc., 1932, 54, 1135. 4) H.E. Carter; C.L. Zirkle, J. Biol. Chem., 1949, 178, 709. 5) S. Arai; T. Takeuchi; M. Ishikawa; T. Takeuchi; M. Yamazaki; M. Hida, J. Chem. Soc., Perkin Trans. 1, 1987, 481.

COMMENTS :

GOULD – JACOBS REACTION EXAMPLE :

COOH CO2CH3

NH2 1) EtO

N

CO2Et HO

100 oC CO2Et 2) 250 oC 3) dil. NaOH 4) aq. NaOAc

702

COOH

MECHANISM :

OEt OEt O

EtO

H + EtO

O

EtO

OEt OEt

OEt

heat O

O O

EtO NH2 +

H

EtO

OEt O

OEt N

OEt H O

O

OH

OH

heat, - EtOH OH

COOEt

COOH dil. NaOH

N

aq. NaOAc

N

N

DISCONNECTION :

R R OEt

Ar N

+

Ar NH2

HO

COOR1 COOR1

COOH

NOTES :

In this modification of the Knorr quinoline reaction the aromatic amine is heated with ethoxymethylene malonic ester and the resulting acrylate is subjected to high temperature cyclisation. Aminopyridines and aminoquinolines can be employed in this synthesis. See also Conrad – Limpach, Combes, Doebner – Miller and Knorr quinoline reactions.

REFERENCES : Smith : 1335 Smith 2nd : 1099 Org. Synth. : 28, 38 Org. Synth. Coll. Vol. : 3, 272

703

1) R.G. Gould; W.A. Jacobs, J. Am. Chem. Soc., 1939, 61, 2890. 2) R.H. Reitsema, Chem. Rev., 1948, 43, 53. 3) D.G. Markees; L.S. Schwab, Helv. Chim. Acta, 1972, 55, 1379. 4) A. Pipaud; R. Rocher; J. Chenault, Synth. Commun., 1997, 27, 1727. 5) C.G. Dave; R.D. Shah, Heterocycles, 1999, 51, 1819.

COMMENTS :

GRAEBE – PICTET SYNTHESIS EXAMPLE :

N

heat

N

NOTES :

The synthesis of phenanthridine by pyrolytic dehydrogenation of benzylideneaniline.

REFERENCES :

1) C. Graebe, Ber. Dtsch. Chem. Ges., 1884, 17, 1370. 2) A. Pictet; H.J. Ankersmit, Liebigs Ann. Chem., 1891, 266, 138.

COMMENTS :

704

GRAEBE – ULLMANN CARBAZOLE SYNTHESIS EXAMPLE :

NH2 N H

1) HNO2 2) heat

N H

MECHANISM :

N NH2

N

N

N N

N H

heat, - N2 - H+

HNO2

H+

N H

N H

DISCONNECTION :

NH2 N H

N H

NOTES :

2-Aminodiphenylamine on treatment with nitrous acid yields a benzotriazole, which on heating loses nitrogen to give a carbazole. See also Gomberg – Bachmann – Hey, Pschorr and Ullmann fluorenone reactions.

REFERENCES : Houben – Weyl : E6a, 960 Science of Synthesis : 10, 717

1) C. Graebe; F. Ullmann, Liebigs Ann. Chem., 1896, 291, 16. 2) N. Campbell; B. Barclay, Chem. Rev., 1947, 40, 359. 3) P. Nantka–Namirski; J. Zieleniak, Acta Pol. Pharm., 1977, 34, 455. 4) D.J. Hagan; E. Giminez–Arnau; C.H. Schwalbe; M.F.G. Stevens, J. Chem. Soc., Perkin Trans. 1, 1997, 2739.

705

5) D.J. Hagan; D. Chan; C.H. Schwalbe; M.F.G. Stevens, J. Chem. Soc., Perkin Trans. 1, 1998, 915. 6) M.J. Ellis; M.F.G. Stevens, J. Chem. Soc., Perkin Trans. 1, 2001, 3174.

COMMENTS :

GRAHAM REACTION EXAMPLE :

CH3 H

N

NH2

H3C H2O, DMSO NaOCl

Cl

N N

MECHANISM :

N R

H

N NaOX

NH2

N OH - H2O

R

R

X N

X

N - X-

N X

N R

N

X

NaOX

NH2

R -X

R

X

N N

X

R C N

X = Cl, Br R = Alk, cycloalk, haloalk, aryl, vinyl, alkoxy, aryloxy

706

X

X

N N

N X

N

DISCONNECTION :

R

R

R

X

N N

H

NOTES :

In general a nitrile is converted in a two-step process to an amidine. Oxidation of the latter with -OCl or -OBr will afford diazirines. See also Pinner and Schmitz diazirine reactions.

REFERENCES :

1) W.H. Graham, J. Am. Chem. Soc., 1965, 87, 4396. 2) R.A. Moss; J. Włostowska; W. Guo; M. Fedorynski; J.P. Springer; J.M. Hirshfield, J. Org. Chem., 1981, 46, 5048. 3) J. Włostowska; R.A. Moss; W. Guo; M.J. Chang, J. Chem. Soc., Chem. Commun., 1982, 432. 4) R.A. Moss, Acc. Chem. Res., 1989, 22, 15. 5) R.A. Moss; W. Ma; D.C. Merrer; S. Xue, Tetrahedron Lett., 1995, 36, 8761.

COMMENTS :

GRÄNACHER CONDENSATION EXAMPLE :

Ph

O

H

H N

+ O

Ph S

S

1) NaOAc CH3COOH 2) HO-

Ph

COOH

S

SH

MECHANISM :

O

H N

O S

S

H N

O S

NaOAc R

H

S

- H2O R

O H+

R

COOH SH

R

COOH S

707

COOH

OH H N S H+

S

COOH R

SH

Na(Hg) R R

COOH

COOH

Clemmensen reduction

COOH SH

R

O

aq. NH3 heat

NH2OH

R

COOH OH N

COOH reduction

R

NH2

DISCONNECTION :

COOH R R

SH COOH R COOH

R

COOH SH

O COOH

R

NH2

NOTES : An aromatic aldehyde condenses with rhodanine in the presence of sodium acetate and acetic acid to yield an aralrhodanine, which on hydrolysis with alkali gives a thioketo acid. This on treatment with hydroxylamine and sodium ethoxide gives an α-oximino-β-arylpropionic acid, which on heating with acetic anhydride is simultaneously decarboxylated and dehydrated to the nitrile. The oxime can be reduced to the corresponding amino acid. The nitrile can be converted into the amine or acid with one carbon atom more than the starting aldehyde.

REFERENCES : Houben – Weyl : 9, 38 Org. Synth. : 27, 73 Org. Synth. Coll. Vol. : 3, 763

1) C. Gränacher, Helv. Chim. Acta, 1922, 5, 610.

708

2) H.E. Fischer; H. Hibbert, J. Am. Chem. Soc., 1947, 69, 1208. 3) F.J. Allan; G.G. Allan, Recl. Trav. Chim. Pays-Bas, 1959, 78, 67. 4) G. Buchbauer; M. Kern, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 1043.

COMMENTS :

GRANDBERG TRYPTAMINE SYNTHESIS EXAMPLE : NH2 NH2 N H

O

Cl

N H

H

MECHANISM :

NH2 N H

O

Cl - H2O

H

N H

N N H Cl-

Cl

N

N NH2

NH H+

NH2

N H

N

H+

H [3,3]-sigmatropic rearrangement

N H

H+

N H

709

DISCONNECTION :

NH2 NH2 N N H

H

NOTES : The formation of tryptamine from 1-phenyl hydrazine. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 377

I.I. Grandberg, Chem. Heterocycl. Compd. (Engl. Transl.), 1974, 10, 501.

COMMENTS :

GRIBBLE INDOLE REDUCTION EXAMPLE :

N H

NaBH4 HOAc

710

N CH2CH3

MECHANISM :

NaBH4 HOAc

N H

N H

N H

NaBH3CN NaBH4 HOAc

N H

NaBH4 HOAc

N CH2CH3

DISCONNECTION : R1

R1

R2 N CH2R

R2

+ RCOOH

N H

NOTES : Indole nitrogen atom is reduced and alkylated using sodium borohydride and acetic acid. The N-alkylation can be prevented by using sodium cyanoborohydride and acetic acid.

REFERENCES : 1) J.A. Marshall; W.S. Johnson, J. Org. Chem., 1963, 28, 421. 2) G.W. Gribble; P.D. Lord; J. Skotnicki; S.E. Dietz; J.T. Eaton; J.L. Johnson, J. Am. Chem. Soc., 1974, 96, 7812. 3) G.W. Gribble; J.H. Hoffman, Synthesis, 1977, 859. 4) G.W. Gribble; C.F. Nutaitis, Org. Prep. Proced. Int., 1985, 17, 317. 5) G.W. Gribble, Chemtech, 1996, 12, 26. 6) M. Somei; F. Yamada; H. Morikawa, Heterocycles, 1997, 46, 91. 7) G.W. Gribble, Chem. Soc. Rev., 1998, 27, 395. 8) F. He; B.M. Foxman; B.B. Snider, J. Am. Chem. Soc., 1998, 120, 6417. 9) K.C. Nicolaou; B.S. Safina; N. Winssinger, Synlett, 2001, 900.

COMMENTS :

711

GRIBBLE REDUCTION EXAMPLE : O

NaBH4 CF3COOH

MECHANISM :

NaBH4 + CF3COOH H+

O Ar

(CF3CO2)3BH OH Ar

Ar1

OH2

Ar1

CF3COOH

Ar

(CF3CO2)3B H

- H2O

Ar

Ar1

Ar (CF3CO2)3B H

Ar1

DISCONNECTION : O Ar Ar

Ar1

Ar1 OH

Ar

Ar1

NOTES : Diarylketones and diarylmethanols are reduced using sodium borohydride in trifluoroacetic acid.

REFERENCES : 1) G.W. Gribble; R.M. Leese; B.E. Evans, Synthesis, 1977, 172. 2) G.W. Gribble; C.F. Nutaitis, Org. Prep. Proced. Int., 1985, 17, 317. 3) A. Daich; B. Decroix, J. Heterocycl. Chem., 1992, 29, 1789. 4) T. Sattelkau; A.M. Qandil; D.E. Nichols, Synthesis, 2001, 262.

712

Ar1

COMMENTS :

GRIECO CONDENSATION EXAMPLE :

O H

H N H

+ PhNH2 +

TFA, CH3CN H Ar

MECHANISM :

H N

H

COOH

H

O

+

HOOC

CF3COOH CH3CN

NH2 COOH

COOH

H

H N

H

N

H

H

H

H

DISCONNECTION :

R3 R2 R

R N H

R2

O

R1

+ NH2

713

+ R1

H

R3

NOTES : The three component condensation to afford tetrahydroquinolines. The immonium ions derived from the aryl amines and aldehydes function as heterodienes.

REFERENCES : 1) S.D. Larsen; P.A. Grieco, J. Am. Chem. Soc., 1985, 107, 1768. 2) P.A. Grieco; A. Bahsas, Tetrahedron Lett., 1988, 29, 5855.

COMMENTS :

GRIECO SELENIDE REACTION EXAMPLE :

CN CHO

PhSeCN Bu3P, THF

H SePh

MECHANISM :

Bu3P + ArSeCN

RCH2OPBu3 + ArSe

ArSePBu3CN

- Bu3PO

RCH2SeAr

714

RCH2OH

RCH2OPBu3 + ArSe

DISCONNECTION :

O RCOOH R

SePh CN

R

O R

H SeAr

H RCH2OH

RCH2SeAr

NOTES : The formation of selenides from aldehydes, alcohols and carboxylic acids in high yield.

REFERENCES : 1) P.A. Grieco; S. Gilman; M. Nishizawa, J. Org. Chem., 1976, 41, 1485. 2) P.A. Grieco; Y. Yokoyama, J. Am. Chem. Soc., 1977, 99, 5210. 3) P.A. Grieco; Y. Yokoyama; E. Williams, J. Org. Chem., 1978, 43, 1283. 4) A. Krief; A.-M. Laval, Bull. Soc. Chim. Fr., 1997, 134, 869. 5) H. Abe, Yakugaku Zasshi (J. Pharm. Soc. Jpn.), 2003, 123, 423.

COMMENTS :

GRIESS DEAMINATION EXAMPLE : NH2

Cl

HCl, NaNO2

715

MECHANISM :

ArN2+X- + NaX + 2 H2O

ArNH2 + 2 HX + NaNO2 N2O3 + 2 ArNH2 + 2 HNO3

2 ArN2+NO3- + 3 H2O

ArNH2 + NOSO4H

2 ArN2+HSO4- + H2O

ArN2+X- + EtOH

ArH + N2 + CH3CHO + HX

ArN2+X- + H2O

ArOH + N2 + HX

ArN2+X- + HX

ArX + N2 + HX

DISCONNECTION : ArNH2

ArX

NOTES : The formation of aromatic diazo-compounds from primary amines and nitrous acid. The resulting diazo-compound has a high reactivity particularly in the presence of certain catalysts. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulfinic acid, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : Org. React. : 2, 264

1) P. Griess, Liebigs Ann. Chem., 1858, 106, 123. 2) W.A. Cowdrey; D.S. Davies, J. Chem. Soc., Quat Rev., 1952, 6, 358. 3) J.H. Ridd, J. Chem. Soc., Quat. Rev., 1961, 15, 418. 4) H.-L. Pan; T.L. Fletcher, Synthesis, 1973, 610.

COMMENTS :

716

GRIGG COUPLING EXAMPLE :

I N Ac

10 mol% Pd(OAc)2 20 mol% PPh3, CH3CN 3 HCOOH, 60 oC 4

N Ac

NH

MECHANISM : OAc Ph Pd

Ph

I

N

N

Pd(OAc)2

CH2Ph

O

CH2Ph

O PdOAc

Ph

Ph N CH2Ph

CH3 N CH2Ph

H+

O

O

DISCONNECTION :

Hal R

R R1 R1

Hal R2

R R1

717

NOTES : There is some confusion in the literature what exactly the Grigg reaction is. Some references name this reaction for the catalyst system Pd(0) / (R3Sn)2 (R = CH3 or nBu) that effects intra- and intermolecular aryl-aryl, benzyl-aryl, benzyl-benzyl coupling of aryl and benzyl halides in a similar fashion as the Stille – Migita – Kosugi reaction. Other sources use the name in conjunction with the Heck – Fujiwara – Mizoroki reaction of compounds lacking β– hydrogen atoms. This author names this last reaction the Grigg reaction. The tandem cyclisation-anion capture process, which involves interception of the vinyl-palladium intermediate by transfer of a hydride ion from the formic acid. See also Heck – Fujiwara – Mizoroki reaction.

REFERENCES : 1) B. Burns; R. Grigg; V. Sridharan; T. Worakun, Tetrahedron Lett., 1988, 29, 4325. 2) B. Burns; R. Grigg; P. Ratanakul; V. Sridharan; P. Stevenson; T. Worakun, Tetrahedron Lett., 1988, 29, 4329.

COMMENTS :

GRIGNARD – COLONGE SYNTHESIS EXAMPLE :

Et

CH3

+

O

N CH3

CH3

MgBr

2

Et

MgBr 1) THF 2) H2O 3) CH3COCH3

O

CH3 OH CH3

MECHANISM :

R

+

N CH3

O

R RCOCH3

CH3 BrMgO N CH3 R

R

R O CH3 OMgBr

H2O

718

R O H3C OH

DISCONNECTION :

R HO

R

R

H3C

CH3

+

R1

O

O

N R2

MgBr

NOTES : The synthesis of β-hydroxyketones by the action of a Grignard compound of the type R1R2NMgBr in ether or benzene on an excess of alkyl methyl ketone.

REFERENCES : Org. React. : 8, 44

1) V. Grignard; J. Colonge, C.R. Séances Acad. Sci., 1932, 194, 929. 2) M. Stoll; A. Rouvé, Helv. Chim. Acta, 1947, 30, 2019.

COMMENTS :

GRIGNARD DEHALOGENATION EXAMPLE :

Cl

Cl

S

1) Mg 2) H2O

Cl

S

MECHANISM :

HO

X X

S

X

Mg

X

S

Mg

719

H2O

X

+ S

Mg X

DISCONNECTION :

X

X

S

S

X

NOTES : The step-wise removal of halogen atoms from a polyhalo thiophene by formation of a Grignard reagent and subsequent decomposition with water. Halogen atoms in the α-positions are easier to extract than halogen atoms in the β-position.

REFERENCES : Houben – Weyl : 13/2a, 125

1) V. Grignard, C.R. Séances Acad. Sci., 1900, 130, 1322. 2) L. Gattermann, Liebigs Ann. Chem., 1912, 393, 215. 3) W. Steinkopf; H. Jacob; H. Penz, Liebigs Ann. Chem., 1934, 512, 136. 4) W. Steinkopf, Liebigs Ann. Chem., 1940, 543, 128.

COMMENTS :

GRIGNARD REACTION EXAMPLE :

OH

O H3C

CH3

+ PhMgBr

Et2O

720

H3C

CH3 Ph

MECHANISM :

Mg

Mg

Mg

Mg

Mg

R MgX

R X

R X

Mg

R MgX Ionic mechanism : R2

R1 O

R1

R1 R MgX

R

R2 OMgX

R

H+

R2 OH

Radical mechanism : R2

R1 O

R MgX

R

R1

R1

R1 R

R2 OMgX

R2 OMgX

H+

R

R2 OH

DISCONNECTION :

R1 R

O + R-X

OH

R1

R2

R2

NOTES : Any addition of a Grignard reagent (RMgX) to a carbonyl-containing compound is classified as a Grignard reaction. There are many named variations of the Grignard reaction. See also Benary reaction, Blaise ketoester, Blaise – Maire, Bodroux – Chichibabin aldehyde synthesis, Boord olefin synthesis and Bouveault aldehyde reactions.

REFERENCES : March : 799, 920, 924, 932 Smith – March : 1205 Smith : 685 Smith 2nd : 538, 560, 577, 580, 617, 622 Houben – Weyl : 8, 237, 317, 371; 4/2, 83, 643; 13/2a, 54 Org. React. : 19, 1; 41, 135 Org. Synth. : numerous examples Science of Synthesis : 10, 381, 384, 394, 562

1) P. Barbier, C.R. Séances Acad. Sci., 1899, 128, 110. 2) V. Grignard, C.R. Séances Acad. Sci., 1900, 130, 1322. 3) I.T. Millar; H. Heaney, J. Chem. Soc., Quat. Rev., 1957, 11, 109. 4) E.C. Ashby; J.T. Laemmle; H.M. Neumann, Acc. Chem. Res., 1974, 7, 272.

721

5) E.C. Ashby; J.T. Laemmle, Chem. Rev., 1975, 75, 521. 6) S. Munavalli; D.I. Rossman; D.K. Rohrbaugh; C.P. Fergusson; L.J. Szafraniec, J. Fluorine Chem., 1992, 59, 91. 7) A. Terfort; H. Brunner, J. Chem. Soc., Perkin Trans. 1, 1996, 1467. 8) R.W. Hoffmann; O. Knopff; A. Kusche, Angew. Chem., Int. Ed., 2000, 39, 1462. 9) I. Fleming, Chemtracts: Org. Chem., 2001, 14, 505. 10) C. Jones; A.F. Richards; S. Fritsche; E. Hey–Hawkins, Organometallics, 2002, 21, 438.

COMMENTS :

GROB – CAMENISCH SYNTHESIS EXAMPLE :

CH3 H

H3C NO2

H

N

H3C

+

CO2Et

CH3

CO2Et CH3 N CH3

O

MECHANISM :

H

R

H

NO2

N H

H

RNH2 + H3C

CH3

NO2

O H3C

OEt O

RNH2

O

H

EtO - HNO2

H

EtO

O

H3C

N R

O H

H3C

N H

EtO R

H

H

H3C

H3C

NO2 O

CH3

CH3

EtO HNO2

H3C

N R

722

CH3 NO2 N H

R

DISCONNECTION :

H3C

H3C

CO2Et

NO2

H N R

CH3

H

N

H3C

+

R

CO2Et O

NOTES : Pyrroles are synthesised from acetoacetic ester and 1-nitro-2-alkyliminopropanes. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : 1) C.A. Grob; K. Camenisch, Helv. Chim. Acta, 1953, 36, 49. 2) H. Meyer, Liebigs Ann. Chem., 1981, 1534. 3) A. Gómez–Sánchez; B. Marco Stiefel; R. Fernández–Fernández; C. Pascual; J. Bellanato, J. Chem. Soc., Perkin Trans. 1, 1982, 441.

4) F. Boberg; K.-H. Garburg; K.-J. Görlich; E. Pipereit; M. Ruhr, Liebigs Ann. Chem., 1985, 239.

COMMENTS :

GROB FRAGMENTATION EXAMPLE :

O

O O

H

O

1 M HCl MeOH

723

H

CO2CH3

MECHANISM : R2 R5

R1 D

Carbonium 2-step

R1 D

R6 R4

R3

R3

R5

R4

R6

+ R2

-L R1 R2R5 L D

R6 R3

R1 Synchronous

R4

R3

R5

R2

R4

R6

R1

R3

D

+

-L R5 L +

D Carbanion 2-step

R6 R4

R2

DISCONNECTION :

a - b + c = d + X-

a-b-c-d-X O

a - b : HO

c-d:

X- :

, R2N

, HO

,

hal

,

N

OSO2Ar

, HS

, N

,

N N

,

OCOR

,

,

,

N N

N N ,

NR3

,

O

NOTES : The intra- or intermolecular concerted carbon-carbon bond cleavage involving a five atom system. The fragmentation is challenged by nucleophilic substitution, elimination or ring-closure. Carbonium : Good leaving groups (e.g. halogens) favour this pathway. Carbanion : Similar to a E1CB mechanism. Synchronous : The reaction is concerted and needs an anti-periplanar arrangement. See also Eschenmoser – Tanabe ring-cleavage, Marshall – Minnaard and Wharton reactions.

REFERENCES : Smith : 171 Smith 2nd : 143, 510, 850 Houben – Weyl : E6a, 647; E11,300; E19c, 72

1) C.A. Grob; W. Baumann, Helv. Chim. Acta, 1955, 38, 594. 2) C.A. Grob; P.W. Schiess, Angew. Chem., Int. Ed. Engl., 1967, 6, 1.

724

3) M. Shimizu; R. Ando; I. Kuwajama, J. Org. Chem., 1981, 46, 5246. 4) M. Ochiai; T. Ukita; S. Iwaki; Y. Nagao; E. Fujita, J. Org. Chem., 1989, 54, 4832. 5) S. Nagumo; A. Matsukuma; H. Suemune; K. Sakai, Tetrahedron, 1993, 49, 10501. 6) D. Molm; N. Risch, Liebigs Ann. Chem. / Receuil, 1997, 1765. 7) A. Krief; G. Lorvelec; S. Jeanmart, Tetrahedron Lett., 2000, 41, 3871. 8) E.R. Alonso; K.A. Tehrani; M. Boelens; D.W. Knight; V. Yu; N. de Kimpe, Tetrahedron Lett., 2001, 42, 3921. 9) L.A. Paquette; J. Yang; Y.O. Long, J. Am. Chem. Soc., 2002, 124, 6542. 10) K. Vyakaranam; S. Körbe; H. Divišová; J. Michl, J. Am. Chem. Soc., 2004, 126, 15795.

COMMENTS :

GROVENSTEIN – ZIMMERMANN REARRANGEMENT EXAMPLE :

CH3 Ph CH2Cl Ph

Li Ph CH3

Ph

Li, Et2O

MECHANISM : Ph Ph

Ph CH2Cl

Ph

2 Na, Et2O

CH2

Ph

Na+

Ph Ph

Ph

Ph

Na+

Ph

DISCONNECTION :

H

Ph

Ph

Ph Ph

Ph

Ph

725

Cl

NOTES : Phenyl or vinylic rearrangement of alkali metals of 1,1,1-triphenylethane or 2,2-diphenylpropanes. The phenyl ring migrates without an electron pair. See also Fritsch – Buttenberg – Wiechell reaction.

REFERENCES : March : 1072 Smith – March : 1396

1) E. Grovenstein, jr., J. Am. Chem. Soc., 1957, 79, 4985. 2) H.E. Zimmerman; F.J. Smentowski, J. Am. Chem. Soc., 1957, 79, 5455. 3) E. Grovenstein, jr.; L.C. Rogers, J. Am. Chem. Soc., 1964, 86, 854. 4) E. Grovenstein, jr; K.W. Black; S.C. Goel; R.L. Hughes; J.H. Northrop; D.L. Streeter; D. VanDerveer, J. Org. Chem., 1989, 51, 1671.

5) A. Maercker; K. Reider; U. Girreser, Eur. J. Org. Chem., 1998, 1455.

COMMENTS :

GROVES SYNTHESIS EXAMPLE :

EtCl

EtOH + HCl ZnCl2

MECHANISM :

EtOH + HCl

ZnCl2

(EtOH)2ZnCl2

DISCONNECTION :

RCl

ROH + HCl

726

- ZnO - H2O

EtCl

NOTES : Alkyl halides are obtained by treatment of an alcohol with a hydrogen halide in the presence of zinc chloride. It is assumed that the zinc chloride reacts with the alcohol to form (EtOH)2ZnCl2, this will decompose to zinc oxide, water and ethyl chloride.

REFERENCES : March : 431 Smith – March : 518 Smith : 150 Smith 2nd : 121

C.E. Groves, J. Chem. Soc., 1874, 27, 636.

COMMENTS :

GRUBBS REACTION EXAMPLE :

Ph

Ph O PCy3 Cl Ru Cl PCy3

727

Ph Ph

O

MECHANISM :

M

Y

Y

M

M

R R1

R

R

+

R

R1

M

Y R1

R1 R

R1

R1 R

M R

R1

M

R1

R

R1

M

R1 R R

R

R1

R

R1

R

R1

NOTES : Olefin metathesis allows the exchange of substituents between different olefins – a transalkylidenation. The process was first used by Shell for the synthesis of higher olefins (SHOP). A large variety of first and second generation catalysts are commercially available.

REFERENCES : March : 1146 Smith – March : 1457 Smith 2nd : 1215 Org. Synth. : 81, 1

728

1) N. Calderon, Chem. Eng. News, 1967, 45, 51. 2) N. Calderon, Acc. Chem. Res., 1972, 5, 127. 3) R.H. Grubbs, Prog. Inorg. Chem., 1978, 24, 1. 4) S.T. Nguyen; R.H. Grubbs, J. Am. Chem. Soc., 1993, 115, 9858. 5) E.L. Dias; S.T. Nguyen; R.H. Grubbs, J. Am. Chem. Soc., 1997, 119, 3887. 6) M. Ulman; R.H. Grubbs, J. Org. Chem., 1999, 64, 7202. 7) D.F. Taber; K.J. Frankowski, J. Org. Chem., 2003, 68, 6047. 8) R.H. Grubbs, Tetrahedron, 2004, 60, 7117. 9) K.C. Nicolaou; P.G. Bulger; D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4490.

COMMENTS :

GRUNDMANN ALDEHYDE SYNTHESIS EXAMPLE : Cl O

H 1) CH2N2 2) AcOH 3) H2 4) Pb(OAc)4

O

MECHANISM : H R

Cl O

R CH2N2 - HCl

R Pb(OAc)4

O R

N2 O

AcOH - N2

H O

729

O O

CH3

R 1) Al(OiPr)3 2) H2O

HO

OH

DISCONNECTION :

O

O R

R

H

Cl

NOTES : An acid chloride is converted into a diazo-ketone, which by treatment with glacial acetic acid gives an acetoxy-ketone. The reduction (Meerwein – Ponndorf – Verley reduction) of the keto group and simultaneous hydrolysis affords the corresponding glycol. Oxidative cleavage of the glycol (Criegee) yields an aldehyde containing the same number of carbon atoms as the starting material. See also Arndt – Eistert, Brandt, Criegee, Hershberg, McFadyen – Stevens, Meerwein – Ponndorf – Verley, Reissert – Grosheintz – Fischer, Rosenmund – Saytzeff, Sonn – Müller and Stephen reactions.

REFERENCES : March : 475 Smith – March : 532 Houben – Weyl : 7/1, 239; E3, 431 Org. React. : 8, 218

1) C. Grundmann, Liebigs Ann. Chem., 1936, 524, 31. 2) H.K. Mangold, J. Org. Chem., 1959, 24, 405.

COMMENTS :

GRYSZKIEWICZ–TROCHIMOWSKI – McCOMBIE METHOD EXAMPLE :

F

Cl OCH3 O

KF CH2OHCH2OH 190 oC, pressure

730

OCH3 O

DISCONNECTION :

FCH2

OR

ClCH2

O

OR O

FCH2OH

ClCH2OH

NOTES : Fluoro-esters and fluoro-alcohols are obtained by dry heating the corresponding chlorine compounds for some hours in an autoclave with large excess potassium fluoride. See also Swarts reaction.

REFERENCES : Houben – Weyl : 5/3, 151 Org. Synth. : 36, 40 Org. Synth. Coll. Vol. : 4, 525

1) H. McCombie; B.C. Sanders, Nature, 1946, 158, 382. 2) E. Gryszkiewicz–Trochimowski; A. Sporzynski; J. Wnuk, Recl. Trav. Chim. Pays-Bas, 1947, 66, 413. 3) M.F. Sartori, Chem. Rev., 1951, 48, 225.

COMMENTS :

GUARESCHI – THORPE CONDENSATION EXAMPLE :

O

O

EtO

C CH3

CH3

CH3

N H3C

C

N

+ NH3 + H3CO

O

731

HO

N

OH

MECHANISM : O NC

O H3C

+

CH3

OEt

NC

2

NH3

O

O

H+ O H3C NC O H

O

H3C NC H2O

O

O

CH3 CN OH2 N H

H+, hydrolysis

N H

- H2O

H+

+

NC H H2O

N H

O

H3C

CH2COOH

H3C

CH2COOH

O

CH3 CN

H3C NC

OH

O

CH3 CN

NH2 EtO

HO CH3 CH3 NC CN

CH3 CN N H

H3C

O

N H

O

CN

H3C

CH2CN

OH2 O

H3C

CH2CN

DISCONNECTION :

R1

CH2COOH

R

CH2COOH

O

O R

R1

+

R2O

CN

+ NH3

NOTES : Pyridine and piperidine derivatives can be obtained by the condensation of a cyano ester or cyanoacetamide or a primary amine or ammonia and either a ketone, aldehyde, ketonic- or cyanoester. The amides, which are intermediately formed, can also be used. The formed Guareschi imide can be hydrolysed and is sometimes called Guareschi hydrolysis. See also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Hantzsch – Beyer, von Meyer – Mohr, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES : Org. Synth. : 36, 28 Org. Synth. Coll. Vol. : 4, 441

1) I. Guareschi, Mem. Reale Accad. Sci. Torino II, 1896, 46, 7. 2) I. Guareschi, Atti Accad. Sci. Torino, 1900, 36, 443.

732

3) J. Chem. Soc. Abs., 1901, 80i, 630. 4) H. Baron; F.G.P. Renfry; J.F. Thorpe, J. Chem. Soc., 1904, 85, 1726. 5) G.A.R. Kon; J.F. Thorpe, J. Chem. Soc., 1919, 115, 686. 6) I. Guareschi, Gazz. Chim. Ital., 1919, 49, 126. 7) A.I. Vogel, J. Chem. Soc., 1934, 1758. 8) W. Jünemann; H.-J. Opgenorth; H. Scheuermann, Angew. Chem., Int. Ed. Engl., 1980, 19, 388. 9) R.W. Holder; J.P. Daub; W.E. Baker; R.H. Gilbert; N.A. Graf, J. Org. Chem., 1982, 47, 1445. 10) D.J. Collins; A.M. Adams, Aust. J. Chem., 1989, 42, 215. 11) D.Z. Mijin; M.M. Misic–Vukovic, Indian J. Chem., 1998, 37B, 988.

COMMENTS :

GUERBET REACTION EXAMPLE : CH3 HO 2 CH3CH2CH2CH2OH

1) NaOEt 2) H2

H H3C

MECHANISM :

2 CH3CH2CH2CH2OH NaOEt - 2 H2

2 CH3CH2CH2CHO

O

OH H

H

H

NaOEt

NaOEt

H O

O

- H2O

H

H3C HO

CH3 CHO

H

2 H2

H3C

733

CH3

DISCONNECTION :

H

R R

2 RCH2CH2OH

CH2OH

NOTES : This is the condensation of primary and secondary alcohols at high temperatures under the influence of sodium alkoxides. A rhodium promoted reaction has been reported by Burk et al. See also Lebedev and Ostromyslenskii reactions.

REFERENCES : 1) M. Guerbet, C.R. Séances Acad. Sci., 1899, 128, 511. 2) H. Machemer, Angew. Chem., 1952, 64, 213. 3) S. Veibel; J.T. Nielsen, Tetrahedron, 1967, 23, 1723. 4) P.L. Burk; R.L. Pruett; K.S. Campo, J. Mol. Catal., 1985, 33, 1. 5) P.L. Burk; R.L. Pruett; K.S. Campo, J. Mol. Catal., 1985, 33, 15. 6) W. Ueda; T. Kuwabara; T. Oshida; Y. Morikawa, J. Chem. Soc., Chem. Commun., 1990, 1558. 7) G. Knothe, J. Am. Oil. Chem. Soc., 2001, 78, 537. 8) C. Carlini; A. Macinai; A.M. Raspolli Galletti; G. Sbrana, J. Mol. Catal. A: Chem., 2004, 212, 65. 9) C. Carlini; C. Flego; M. Marchionna; M. Noviello; A.M. Raspoli Galletti; G. Sbrana; F. Basile; A. Vaccari, J. Mol. Catal. A: Chem., 2004, 220, 215.

COMMENTS :

GUSTAVSON CYLISATION EXAMPLE :

Cl

Cl

Zn Na2CO3 NaI

734

MECHANISM :

Br

Br

BrZn

Zn

Br

DISCONNECTION :

Hal

Hal

NOTES : A variation of the Freund reaction in which an open chain dihalogen compound is cyclised by the action of zinc dust. See also Charette, Freund, Hass cyclopropane, Ipatiew cyclopropane, Kishner, Mousseron – Fraisse – McCoy, Nerdel, Simmons – Smith and Wurtz reactions.

REFERENCES : Houben – Weyl : 13/1, 492 Org. Synth. : 44, 30 Org. Synth. Coll. Vol. : 5, 328

1) G. Gustavson, J. Prakt. Chem., 1887, 36, 300. 2) H.B. Hass, Ind. Eng. Chem., 1936, 28, 1178. 3) E. Vogel, Angew. Chem., 1960, 72, 4.

COMMENTS :

GUSTUS CLEAVAGE EXAMPLE :

Et

O

Ph Et

I

+ O

Ph ZnCl2, RT, several days

735

OEt O

MECHANISM : O 2

O

R

2

+ ZnCl2

Cl

O

O 2

R

R1

+ (R1)2O

O R1

O

R

R

R1Cl

O O R1

O R1

+ R1

R1 + Cl

R1

+ ZnCl42-

R

O

OR1 R

R1O

R

R1O

X

R

+ R1X

DISCONNECTION :

Ph

O

Alk

Alk

O

O

Alk

NOTES : Alkyl ethers are cleaved by acetyl iodide in the presence of zinc chloride at room temperature during several days. See also Mann dealkylation, Prey and Stoermer reactions.

REFERENCES : 1) H.W. Underwood; R.L. Wakeman, J. Am. Chem. Soc., 1930, 52, 387. 2) E.L. Gustus; P.G. Stevens, J. Am. Chem. Soc., 1933, 55, 374. 3) E.L. Gustus; P.G. Stevens, J. Am. Chem. Soc., 1933, 55, 378. 4) R.L. Burwell, jr., Chem. Rev., 1954, 54, 615.

COMMENTS :

736

GUTKNECHT PYRAZINE SYNTHESIS EXAMPLE :

O

N OH

2 H3C

1) H2 2) air

CH3

H3C

N

CH3

H3C

N

CH3

MECHANISM :

O 2

R

- 2 H2O

O

N OH

R

R1

R1

NH2 O

R

R

O H2N

R1

2

R1

HNO2 R1

N

R

R

N

R1

R

N

oxidation

H2 R1

N

R

R

N

R1

DISCONNECTION :

R1

O 2

R1

N

R

R

R1

NOTES : Dihydropyrazines, which may be oxidised to pyrazines, are obtained by the reduction of oximino-ketones and subsequent treatment with alkali. The oxidation step can take place with mercury(I) oxide, copper(II) sulfate or atmospheric air. See also Gastaldi and Stadel – Rugheimer reactions.

REFERENCES : 1) H. Gutknecht, Ber. Dtsch. Chem. Ges., 1879, 12, 2290. 2) H. Gutknecht, Ber. Dtsch. Chem. Ges., 1880, 13, 1116. 3) I.J. Krems; P.E. Spoerri, Chem. Rev., 1947, 40, 279. 4) Y.T. Pratt, Heterocycl. Comp., 1957, 6, 379.

COMMENTS :

737

GUY – LEMAIRE – GUETTE REACTION EXAMPLE : O

OH

Cl

Cl

Cl

Cl

+

HO

Cl

Cl CCl4, hν, 20 oC

Cl

MECHANISM :

H O

O

Cl

OH Cl

Cl Cl Cl Cl

Cl

DISCONNECTION :

OH Cl OH

R O Cl

R Cl

Cl R

Cl NO2

NOTES : The regioselective ortho or para halogenation or nitration of phenols or naphtols and the corresponding ethers (only para) by hexahalo cyclohexadiene or its nitro derivative. The ortho or para ratio depends on the solvent used.

REFERENCES : 1) A. Guy; M. Lemaire; J.-P. Guette, J. Chem. Soc., Chem. Commun., 1980, 8. 2) A. Guy; M. Lemaire; J.-P. Guette, Tetrahedron, 1982, 38, 2339. 3) A. Guy; M. Lemaire; J.-P. Guette, Jansen Chim. Acta, 1987, 5, 3. 4) A. Guy; M. Lemaire; J. Roussel; J.-P. Guette, Tetrahedron, 1987, 43, 835.

738

COMMENTS :

GUYOT – GRY – BOUVEAULT SYNTHESIS EXAMPLE :

O HO +

OEt H

H3C

HO

O

1) ZnCl2 AcOH 2) H2SO4

O

O

MECHANISM : O R1

COOR2

R +

R1

O O

OH CO2R2

ZnCl2 AcOH

R

H R H2SO4

aq. Cu(OAc)2

COOH R O

Me2N

H R O

739

CH3

O

DISCONNECTION :

COOR2

R

H

+

R O

R = OH, R3R4N

R1

O O

NOTES : The condensation of an α,β-diketo ester with a compound containing replaceable hydrogen (a phenol or a tertaromatic amine) to give an α-hydroxy ester, which is decomposed to an aldehyde. A number of variations are possible. See also Claisen – Mauthner – Bouveault reaction.

REFERENCES : 1) A. Guyot, C.R. Séances Acad. Sci., 1909, 149, 788. 2) A. Guyot; A. Gry, Bull. Soc. Chim. Fr., 1910, 7, 902.

COMMENTS :

740

741

HELFERICH ETHERIFICATION · 794 HELFERICH METHOD · 795

A

HELL – VOLLHARD – ZELINSKY HALOGENATION · 796 HEMETSBERGER – KNITTEL INDOLE SYNTHESIS · 798

ANDO MODIFICATION · 855

HENRY REACTION (KAMLET REACTION) · 799 HENZE – HUMPHREYS AMINE SYNTHESIS · 801 C

HERBST – ENGEL AMINO ACID SYNTHESIS · 802 HERSHBERG SYNTHESIS · 803

CRISTOL – FIRTH MODIFICATION · 871

HERZ REACTION · 805 HERZIG – MEYER N-ALKYL GROUP DETERMINATION · 806

F

HEUMANN INDIGO SYNTHESIS · 807 HEWITT REACTION · 809

FISCHER – NOURI MODIFICATION · 830

HILL REDUCTION · 810 HILLMAN REACTION · 812 HINSBERG OXINDOLE SYNTHESIS · 813

H

HINSBERG REACTION · 815 HINSBERG SULFONE SYNTHESIS · 816

HABER – WEISS REACTION (HABER – WILLSTÄTTER

HINSBERG THIOPHENE SYNTHESIS · 818

REACTION) · 744

HIYAMA AMINOACRYLATE SYNTHESIS · 819

HADDADIN – ISSIDORIDES QUINOXALINE SYNTHESIS (BEIRUT

HIYAMA COUPLING · 820

REACTION) · 745

HO DEHALOGENATION · 822

HAJOS – PARRISH – EDER – SAUER – WIECHERT

HOCH – CAMPBELL AMINO ALCOHOL SYNTHESIS · 823

CYCLISATION · 746 HAKOMORI REACTION · 748

HOCK – LANG OXIDATION · 825

HALE CYCLONITE SYNTHESIS · 749

HODGES – VEDEJS REACTION · 826

HALLER – BAUER REACTION · 750

HOEHN – MASON DEGRADATION · 828

HAMMICK PICOLINIC ACID DECARBOXYLATION · 752

HOESCH – HOUBEN SYNTHESIS · 829

HANESSIAN – HULLAR REACTION · 753

HOFER – MOEST REACTION · 831

HANESSIAN MACROLACTONISATION · 754

HOFMANN – LÖFFLER – FREYTAG REACTION · 832

HANSLEY – PRELOG – STOLL SYNTHESIS · 756

HOFMANN – MARTIUS REARRANGEMENT (REILLY – HICKINBOTTOM) · 833

HANTZSCH – BEYER PYRIDINE SYNTHESIS · 758 HANTZSCH PYRROLE SYNTHESIS · 760

HOFMANN – SAND OXYMERCURATION · 835

HANTZSCH TETRAZOLE SYNTHESIS · 762

HOFMANN DEGRADATION · 836

HANTZSCH THIAZOLE SYNTHESIS · 763

HOFMANN ISONITRILE SYNTHESIS · 838

HARLAY AMINATION · 764

HOFMANN REARRANGEMENT · 839

HARRIES OZONIDE REACTION · 766

HOLLEMANN PINACOL SYNTHESIS · 840

HARRIES PYRROLE SYNTHESIS · 767

HONZL – RUDINGER PEPTIDE SYNTHESIS · 842

HASS – BENDER CARBONYL SYNTHESIS · 768

HOOGEWERFF – VAN DORP SYNTHESIS · 843

HASS CYCLOPROPANE PROCESS · 770

HOOKER REACTION · 844

HASS PROCESS · 771

HOPPE HOMOALDOL REACTION · 846

HASSNER – GHERA – LITTLE RING– CLOSURE · 772

HORBACZEWSKI SYNTHESIS · 847

HASSNER – RUBOTTOM α-HYDROXYLATION · 773

HOREAU – ORMANCEY SYNTHESIS · 849

HASSNER AZIDE AZIRIDINE SYNTHESIS · 774

HORENSTEIN – PÄHLICKE ESTERFICATION · 850

HAUSER – BEAK ORTHO-LITHIATION · 776

HORNER – KNOWLES – KAGAN ASYMMETRIC HYDROGENATION · 851

HAUSER – KRAUS ANNULATION · 778 HAWORTH METHYLATION · 779

HORNER – WADSWORTH – EMMONS REACTION · 854

HAWORTH POLYNUCLEAR AROMATICS SYNTHESIS · 781

HORNING REACTION · 856

HAYASHI – ITO REACTION · 783

HOSOMI – MIYAURA BORYLATION · 857

HAYASHI REARRANGEMENT · 784

HOSOMI – SAKURAI ALLYLATION · 859

HECK – FUJIWARA – MIZOROKI COUPLING · 786

HOUBEN – FISCHER SYNTHESIS · 861

HEGEDUS – MORI – HECK INDOLE SYNTHESIS · 791

HUA REACTION · 863

HEGEDUS INDOLE SYNTHESIS · 790

HUDSON – JACKSON OXIDATION · 864

HEINE REACTION · 791

HUGERSHOFF REACTION · 865

HEINISCH – MATUSZCZAZOV – MERETEIRA REACTION · 792

HUGERSHOFF SYNTHESIS · 866 HUISGEN – WHITE REACTION · 867

742

HUISGEN REACTION · 869

M

HUNSDIECKER – BORODINE REACTION · 870 HUNSDIECKER RING–CLOSURE · 872

MATSUDA VARIANT · 788

HURD – MORI REACTION · 873

MEDZIHRADSKY METHOD · 842

HURTLEY REACTION · 875 R RÜHLMANN VARIATION · 757

743

HABER – WEISS REACTION (HABER – WILLSTÄTTER REACTION) EXAMPLE :

2 H2O2

2 H2O + O2

MECHANISM :

H2O + O2 - + H+

HO + H2O2 O2 - + H+ + H2O2

O2 + HO + H2O

NOTES : This reaction is the reduction of hydrogen peroxide by the superoxide anion to produce the hydroxyl radical, which is a very reactive oxidant. This reaction is often invoked to explain aromatic hydroxylations in living organisms. Many people including Linus Pauling have claimed to be the discoverers of this reaction, but the real discoverers are Haber and Willstätter. See also Fenton reaction.

REFERENCES : 1) F. Haber; R. Willstätter, Ber. Dtsch. Chem. Ges., 1931, 64, 2844. 2) F. Haber; J. Weiss, Naturwissenschaften, 1932, 51, 948. 3) J. Weiss; C.W. Humphreys, Nature, 1949, 163, 691. 4) W.G. Barb; J.H. Baxendale; P. George; K.R. Hargrave, Nature, 1949, 163, 692. 5) C. Beauchamp; I. Fridovich, J. Biol. Chem., 1970, 245, 4641. 6) L. Pauling, Trends Biochem. Sci., 1979, 4, N270. 7) P.E. Starke; J.L. Farber, J. Biol. Chem., 1985, 260, 99. 8) A.U. Khan; M. Kasha, Proc. Natl. Acad. Sci. USA, 1994, 91, 12365. 9) J.P. Kehrer, Toxicology, 2000, 149, 43.

COMMENTS :

744

HADDADIN – ISSIDORIDES QUINOXALINE SYNTHESIS (BEIRUT REACTION) EXAMPLE :

O

N O N O

O N

O

+ Ph

Ph

Et3N, 20 oC

N O

Ph Ph

MECHANISM :

O N O N

O CN N H CN N O

NC CN DMF base - H+

O N H+

N O

NH2

O CH3 N CH3 NMe2 N H O

O CH 3 N CH3 NMe2 N H O

CH3 CH3 N H3C CH3 H

CN

DISCONNECTION :

O N N O

R1(R)

N

R(R1)

O N O

NOTES : Quinoxaline dioxide is prepared from benzofurazan oxide and ketone enolates or enamines. This reaction is also known as the Beirut reaction, named after the American university in Beirut Lebanon.

745

REFERENCES : Houben – Weyl : E8c, 799

1) M.J. Haddadin; C.H. Issidorides, Tetrahedron Lett., 1965, 6, 3253. 2) M.J. Haddadin; G.E. Zahr; T.N. Rawdak; N.C. Chelkot; C.H. Issidorides, Tetrahedron, 1974, 30, 659. 3) K. Ley; F. Seng, Synthesis, 1975, 415. 4) A. Gasco; A.J. Boulton, Adv. Heterocycl. Chem., 1981, 29, 251. 5) S.K. Lin, Yougi Huaxue (Chin. J. Org. Chem.), 1991, 11, 106. 6) M.J. Haddadin; C.H. Issidorides, Heterocycles, 1993, 35, 1503. 7) P.M. Panasyuk; S.F. Mel’nikova; I.V. Tselinskii, Russ. J. Org. Chem., 2001, 37, 892.

COMMENTS :

HAJOS – PARRISH – EDER – SAUER – WIECHERT CYCLISATION EXAMPLE :

H3C O

O CH3

O

H3C 1) (S)-proline, DMF O 2) H2SO4, DMF

746

O

MECHANISM :

CH3

aq. HOAc 70 oC

HO

H3C

H3C

S-(-)-proline DMF, 16 oC

O

O

H3C via

H2SO4, DMF, 95 oC - H2O

H3C

H3C

O

+ O

O

O

H3C

N

O

H CO2-

O

O

OH

O

O H N

CO2-

2-proline mechanism O N

O O

H

O 1-proline mechanism

DISCONNECTION : H3C

O

O O

O

( )n

n = 1,2

H3C

H3C ( )n O

NOTES : The (S)-proline-catalysed intramolecular aldol reaction has high yields and high enantiomeric excess. A review about the possible mechanisms has been written by Agami. Recently, kinetic experiments and quantum mechanical calculations by List and Houk show evidence for a one-proline mechanism. See also d’Angelo’s asymmetric Michael addition, Mannich, Robinson – Mannich annulation and Stork reductive cyclisation reactions.

REFERENCES : Smith – March : 1223 Smith 2nd : 798 Org. Synth. : 63, 26, 37 Org. Synth. Coll. Vol. : 7, 363, 368

747

1) U. Eder; G. Sauer; R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496. 2) Z.G. Hajos; D.R. Parrish, J. Org. Chem., 1974, 39, 1615. 3) C. Agami; F. Meynier; C. Puchot; J. Guithem; C. Pascard, Tetrahedron, 1984, 40, 1031. 4) C. Agami, Bull. Soc. Chim. Fr., 1988, 499. 5) D. Rajagopal; K. Rajagopalan; S. Swaminathan, Tetrahedron: Asymmetry, 1996, 7, 2189. 6) R. Naasz; L.A. Arnold; M. Pineschi; E. Keller; B.L. Feringa, J. Am. Chem. Soc., 1999, 121, 1104. 7) S. Bahmanyar; K.N. Houk, J. Am. Chem. Soc., 2001, 123, 12911. 8) B. List, Synlett, 2001, 1675. 9) Z.G. Hajos, CPS: orgchem/0209001; http://preprint.chemweb.com/orgchem/0209001 10) L. Hoang; S. Bahmanyar; K.N. Houk; B. List, J. Am. Chem. Soc., 2003, 125, 16. 11) S. Bahmanyar; K.N. Houk; H.J. Martin; B. List, J. Am. Chem. Soc., 2003, 125, 2475. 12) B. List, Acc. Chem. Res., 2004, 37, 548. 13) C. Allemann; R. Gordillo; F.R. Clemente; P.H.-Y. Cheong; K.N. Houk, Acc. Chem. Res., 2004, 37, 558.

COMMENTS :

HAKOMORI REACTION EXAMPLE :

HO

H3CO

(CH2)12CH3

(CH2)12CH3

H3CO

HO HO

1) DMSO, NaH H3CO 2) excess CH3I 3) H2O H3CO

N H HO

CH3

O

CH3

O

O

OH

N H

O

OCH3

MECHANISM :

H3C

S O

CH3

H3C NaH DMSO

CH2 S O Na

R O Na ROH - DMSO

748

CH3I

R OCH3

DISCONNECTION :

R OCH3

R OH R = Carbohydrate

NOTES : This reaction is the formation of methyl ethers of sugars using the dimethylsulfinyl anion as base. Instead of methyl iodide, methyl triflate can be used in a protic solvent in the presence of a hindered base. See also Haworth methylation, Irvine – Purdie, Meerwein methylation and Robertson – Robinson reactions.

REFERENCES : 1) S.-I. Hakomori, J. Biochem. (Tokyo), 1964, 55, 205. 2) J. Arnarp; L. Kenne; B. Lindberg; J. Lönngren, Carbohydr. Res., 1975, 44, C5.

COMMENTS :

HALE CYCLONITE SYNTHESIS EXAMPLE :

NO2 N

N N

NN

O2N 1) 2 HNO3, H2O, 0 oC o 2) 100% HNO3, 30 C, 45 min 3) H2O

N

N

NO2

MECHANISM :

N

N N

N N 2 HNO , H O, 0 oC 3 2

NO2 N

N

. N N 2 HNO3

749

1) 100% HNO3, 30 oC O N N 2 2) H2O

N

NO2

DISCONNECTION : NO2 N O2N

N

N

N N

NO2

NN

NOTES : Cyclonite is formed by the treatment of hexamethylenetetramine with concentrated nitric acid at low temperatures. See also Ebele – Schiessler – Ross, Knoffler – Bachmann and Wolfram reactions.

REFERENCES : 1) G.C. Hale, J. Am. Chem. Soc., 1925, 47, 2754. 2) C.J. McHugh; W.E. Smith; R. Lacey; D. Graham, Chem. Commun., 2002, 2514.

COMMENTS :

HALLER – BAUER REACTION EXAMPLE :

O

O

OCH3

NH2 NaNH2 benzene reflux

MECHANISM :

O R

O

O R

R1 NH2

R1 NH2

750

R

+

H2N

R1

DISCONNECTION :

O

O H2N

R

R1

R1

NOTES : The α-position of an alkyl phenyl ketone is step-wise alkylated by an alkyl halide and sodamide, rupture of the alkylated product with sodamide, yields an amide which can be converted into a trisubstituted acetic acid. The reaction is normally applied only to non-enolisable ketones. See also Ziegler alkylation.

REFERENCES : March : 633 Smith – March : 512, 814 Smith 2nd : 730 Houben – Weyl : E5, 1104 Org. React. : 9, 1

1) F.W. Semmler, Ber. Dtsch. Chem. Ges., 1906, 39, 2577. 2) A. Haller; E. Bauer, C.R. Séances Acad. Sci., 1909, 148, 70. 3) A. Haller, Bull. Soc. Chim. Fr., 1922, 31, 1117. 4) A.J. Birch; R. Robinson, J. Chem. Soc., 1942, 490. 5) J.P. Gilday; L.A. Paquette, Org. Prep. Proced. Int., 1990, 22, 167. 6) G. Mehta; D.S. Reddy, Synlett, 1997, 612. 7) R.V. Venkateswaren; G. Mehta, Tetrahedron, 2000, 56, 1399. 8) O. Arjona; R. Medel; J. Plumet, Tetrahedron Lett., 2001, 42, 1287. 9) K. Ishihara; T. Yano, Org. Lett., 2004, 6, 1983.

COMMENTS :

751

HAMMICK PICOLINIC ACID DECARBOXYLATION EXAMPLE : OH N

COOH

C6H5CHO heat

N

H

MECHANISM :

N

COOH

- H+

- CO2

CO2

N

N

Ph

H O

OH

O N

H+

H

N

H

DISCONNECTION :

N

R OH

R = Alk, Ar

N

COOH

+ RCHO

NOTES : The decarboxylation of α-picolinic acid and related acids containing the carboxyl group α- or γ- of the nitrogen atom by an excess of an aldehyde or ketone e.g. benzaldehyde, acetophenone or cyclohexanone yields an α- or γ-pyridyl or related carbinol. See also Zagoumenny diphenyl carbinol reaction.

REFERENCES : 1) P. Dyson; D.L. Hammick, J. Chem. Soc., 1937, 1724. 2) N.H. Cantwell; E.V. Brown, J. Am. Chem. Soc., 1953, 75, 1489. 3) E.V. Brown; M.B. Shambhu, J. Org. Chem., 1971, 36, 2002. 4) V.P. Karandikar; S.B. Chandalia, Indian J. Technol., 1985, 23, 28. 5) R. Grigg; L. Wallace; J.O. Morley, J. Chem. Soc., Perkin Trans. 2, 1990, 51. 6) B. Bohn; N. Heinrich; H. Vorbrüggen, Heterocycles, 1994, 37, 1731. 7) D. Lavorato; J.K. Terlouw; T.K. Dargel; W. Koch; G.A. McGibbon; H. Schwarz, J. Am. Chem. Soc., 1996, 118, 11898.

752

COMMENTS :

HANESSIAN – HULLAR REACTION EXAMPLE :

O

Ph

O HO

O

Ph

O

Br

O

O

O

N Br

+

OH

BaCO3 CCl4 tetrachloroethane

O

OCH3

OH

HO

OCH3

MECHANISM :

Br O

Ph O

Ph

Br O

O

O

O HO

NBS OH OCH3

HO

O

Ph

O

Ph

OH OCH3

HO

O OH OCH3

BrCH2

Br O

O

O

O

Ph HO

O

O HO

OH OCH3

OH OCH3

DISCONNECTION :

O

Ph

O Ph

O

O

Br

NOTES : Benzylidene acetals of the 1,3-dioxane or 1,3-dioxolane type undergo a ring-opening reaction in the presence of NBS (N-bromosuccinimide) to afford in high yield the corresponding O-benzoylated bromohydrins. The reaction is

753

compatible with a variety of functional and protecting groups (ester, ether, amide, halide, epoxide). See also Binkley triflate displacement reaction.

REFERENCES : Org. Synth. : 65, 243 Org. Synth. Coll. Vol. : 8, 363

1) S. Hanessian, Carbohydr. Res., 1966, 2, 86. 2) D. Failla; T.L. Hullar; S.B. Siskin, J. Chem. Soc., Chem. Commun., 1966, 716. 3) S. Hanessian; N.R.J. Plessas, J. Org. Chem., 1969, 34, 1035. 4) S. Hanessian; N.R.J. Plessas, J. Org. Chem., 1969, 34, 1045. 5) S. Hanessian; N.R.J. Plessas, J. Org. Chem., 1969, 34, 1053. 6) T.L. Hullar; S.B. Siskin, J. Org. Chem., 1970, 35, 225. 7) S. Hanessian, Methods Carbohydr. Chem., 1972, 6, 183. 8) S. Aburaki; M. Kinoshita, Bull. Chem. Soc. Jpn., 1979, 52, 198. 9) S.T. Deal; D. Horton, Carbohydr. Res., 1999, 315, 187. 10) M. Baruah; M. Bols, Synlett, 2002, 1111.

COMMENTS :

HANESSIAN MACROLACTONISATION EXAMPLE :

O H2N(CH2)7COOH + nBu2SnO

754

NH heat

MECHANISM :

O O

(CH2)n

O SnR3

(CH2)n

- (R3Sn)2O

O

O

SnR3

(R3Sn)2O

HO(CH2)nCOOH

- R2SnO

R2SnO

O

O

H (CH2)n

O O

(CH2)n

- H2O

OH

O O SnR2

SnR2

DISCONNECTION :

O (CH2)n

X

X = O, NH

HX(CH2)nCOOH

NOTES : The use of organostannyl oxides as catalytic neutral esterification agents in the preparation of macrolides. See also Corey – Nicolaou, Diels – Alder, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ringclosure,

Keck

macrolactonisation,

Kita,

Masamune,

Michael

condensation,

Mitsunobu,

Mukaiyama

macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler,

Venkataraman

–

Wagle,

Vorbrüggen

–

Krolikiewicz,

macrolactonisation reactions.

755

Wittig,

Yamaguchi

and

Yamamoto

REFERENCES : 1) K. Steliou; A. Szczygielska–Nowosielska; A. Favre; M.A. Poupart; S. Hanessian, J. Am. Chem. Soc., 1980, 102, 7578. 2) S. Hanessian; A. Ugolini; D. Dubne; P.J. Hodges; C. Andre, J. Am. Chem. Soc., 1986, 108, 2776.

COMMENTS :

HANSLEY – PRELOG – STOLL SYNTHESIS EXAMPLE :

O CH3CO2(CH2)6CO2CH3

1) 4 Na, xylene heat 2) HOAc

756

(CH2)6 OH

MECHANISM :

O

O

O R

O R (CH2)n O R

2 Na

(CH2)n O R O

O O

C O

O R (CH2)n

(CH2)n O R

-2

C

O

C

O

(CH2)n

C 2 H+

C

C

2 Na

OR O

OH

(CH2)n C

O

OH

O

(CH2)n C

OH

DISCONNECTION :

O

O

(CH2)n

(CH2)n

OR OR

H OH

O

NOTES : This reaction involves intensive heating of a well stirred mixture of an α,ω-dicarboxylic ester in boiling xylene in the absence of air with molten sodium. An intramolecular acyloin condensation takes place to yield a cyclic α-hydroxy ketone (ring sizes 12-36). In the Rühlmann variation trimethylsilyl chloride is added and the released alcoholate is trapped. See also Bouveault – Blanc, Bouveault – Locquin acyloin, Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille –

757

Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : Houben – Weyl : 4/2, 755 Org. React. : 4, 256; 15, 34; 23, 259 Org. Synth. : 36, 79 Org. Synth. Coll. Vol. : 4, 840

1) V.L. Hansley, U.S. Patent, 1941, 2228268. 2) V. Prelog; L. Frenkiel; M. Kobelt; P. Barman, Helv. Chim. Acta, 1947, 30, 1741. 3) M. Stoll; J. Hulstkamp; A. Rouvé, Helv. Chim. Acta, 1947, 30, 1815. 4) C. Ainsworth; F. Chen, J. Org. Chem., 1970, 35, 1272.

COMMENTS :

HANTZSCH – BEYER PYRIDINE SYNTHESIS EXAMPLE :

O

O

H

O

H

CH3

2

O +

H3C

CH3 O

H3C

H3C H

1) NH3, RT 4 days pH 8.5 2) NaNO2 AcOH, RT

758

H3C

CH3 N

CH3

MECHANISM :

NH3

O

H

O

H2N

COOR

H3C

H

O R

H3C

H

O

H

O

H3C

H

O R

+

O +

H3C H

CH3 COOR O

CH3

CH3 H

ROOC

NH H

H3C

ROOC

H

ROOC

COOR O

CH3 H

CH3

COOR ROOC

H3C

N O H

H3C

ROOC H3C

N H

- H2O

CH3 COOR

N H

H COOR CH3 O H

CH3

CH3

H+ COOR

CH3 N O H H

H3C

CH3

CH3

CH3

ROOC HNO3

COOR

H3C

N

CH3

DISCONNECTION :

O

R3

O OR1

R5

N

R2

O

R3

O

+

+ R5

O

O

R4O2C R4 N

R2

R2

+ R5

R3

O

H

+ NH3

+ O

R2

+ NH3

O

CH2CO2R1

R1 R5

O

CH2CO2R1

R4O2C R4O

R3

H

NOTES : The interaction of two moles of a β-keto ester or a 1,5-dicarbonyl compound with aldehyde and ammonia affords dihydropyridine derivatives which are readily oxidised to pyridines. Unsymmetrical 1,4-dihydropyridines can be synthesised by a 2-step synthesis. This reaction has been improved first by Beyer and later by Knoevenagel. See

759

also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Guareschi – Thorpe, von Meyer – Mohr, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES : Houben – Weyl : E7b, 399 Org. Synth. : 14, 30 Org. Synth. Coll. Vol. : 2, 214

1) A. Hantzsch, Liebigs Ann. Chem., 1882, 215, 1. 2) A. Hantzsch, Ber. Dtsch. Chem. Ges., 1884, 17, 1515. 3) C. Beyer, Ber. Dtsch. Chem. Ges., 1891, 24, 1662. 4) E. Knoevenagel; A. Fries, Ber. Dtsch. Chem. Ges., 1898, 31, 761. 5) J.A. Berson; E. Brown, J. Am. Chem. Soc., 1955, 77, 444. 6) U. Eisner; J. Kuthan, Chem. Rev., 1972, 72, 1. 7) R.M. Kellogg; T.J. van Bergen; H. van Dosen; D. Hedstrand; J. Kooi; W.H. Kruizinga; C.B. Troostwijk, J. Org. Chem., 1980, 45, 2854. 8) D.M. Stout; A.I. Meyers, Chem. Rev., 1982, 82, 223. 9) A. Sausins; G. Duburs, Heterocycles, 1988, 27, 269. 10) G.P. Shkil; D. Mutsenietse; L.V. Berdovich; V. Lusis, Chem. Heterocycl. Compd. (Engl. Transl.), 1995, 31, 76. 11) K. Goerlitzer; H.-J. Ewert, Pharmazie, 1996, 51, 17. 12) M. Kidwai; S. Saxena; R. Mohan; R. Venkataramanan, J. Chem. Soc., Perkin Trans. 1, 2002, 1845. 13) N. Nakamichi; Y. Kawashita; M. Hayashi, Synthesis, 2004, 1015.

COMMENTS :

HANTZSCH PYRROLE SYNTHESIS EXAMPLE :

CO2Et H3C

CH2Cl + O

CH3

EtO2C

NH3

O

760

H3C

N H

CH3

MECHANISM :

H3N CH3

EtO2C

EtO2C R

H3C

+ NH3

O

EtO2C

Cl

Cl

R H3C

H3C

N H

N H

EtO2C

EtO2C

- H2O

OH Cl

H3C

H+ EtO2C

R

O

NH2 R

H

N H

H

H3C

- H+

N H

R

DISCONNECTION : CO2Et R1

N R2

R

NH2R2 +

CH2Cl

R1

+

O

R = H, Alk R2 = H, Alk

R

EtO2C O

NOTES : The interaction of α-chloro-aldehydes or ketones with β-ketoesters and ammonia or amines to give pyrroles. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Houben – Weyl : E6a, 631, 648 Science of Synthesis : 9, 444

1) A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474. 2) F. Feist, Ber. Dtsch. Chem. Ges., 1902, 35, 1538. 3) E. Baltazzi; L.I. Krimen, Chem. Rev., 1963, 63, 511. 4) V. Kameswaran, Special publication RSC, 1994, 147, 141. 5) A.W. Trautwein; R.D. Sussmuth; G. Jung, Bioorg. Med. Chem. Lett., 1998, 8, 2381. 6) V.F. Ferreira; M.C.B.V. De Souza; A.C. Cunha; L.O.R. Pereira; M.L.G. Ferreira, Org. Prep. Proced. Int., 2002, 33, 411.

761

COMMENTS :

HANTZSCH TETRAZOLE SYNTHESIS EXAMPLE : NH2 H2N CN + HN3

benzene, 110 oC

H N N N N

MECHANISM :

H R C N + HN3

N

R

N

N

N N

N R

N N H

DISCONNECTION :

R H

N N N N

R CN

R = H, NH2, CN, CO2Et, CON(Et)2, Br

NOTES : The addition of hydrazoic acid to the cyanides leads to the formation of 5-substituted tetrazoles.

REFERENCES : 1) A. Hantzsch; A. Vagt, Liebigs Ann. Chem., 1901, 314, 339. 2) R. Stollé, Ber. Dtsch. Chem. Ges., 1929, 62, 1118. 3) F.R. Benson, Chem. Rev., 1947, 41, 1. 4) J.S. Mihina; R.M. Herbst, J. Org. Chem., 1950, 15, 1082.

762

COMMENTS :

HANTZSCH THIAZOLE SYNTHESIS EXAMPLE : CH3 H3C

CH3

CH2Cl + O

HS

S

NH

N

benzene 95 oC

CH3

MECHANISM :

H+ H3C

H3C

NH2

O S

CH3

Cl

O

NH2

S

CH3 Cl

H3C

OH H N Cl

H3C

CH3

S

H3C

N

- H2O

N

CH3 S

S

CH3

Cl

DISCONNECTION :

R S

R1

N R = Alk, NHR2

CH2Cl O

R +

HS

NH

CH3

NOTES : Thiazoles are formed by the condensation of α-chloro-aldehydes or –ketones with thioamides. See also Andreasch and Wohl – Marckwald reactions.

763

REFERENCES : Org. Synth. : 19, 10; 25, 35 Org. Synth. Coll. Vol. : 2, 31; 3, 332

1) A. Hantzsch, Liebigs Ann. Chem., 1889, 250, 257. 2) R.H. Dodson; L.C. King, J. Am. Chem. Soc., 1945, 67, 2242. 3) M.W. Bredenkamp; C.W. Holzapfel; W.J. van Zyl, Synth. Commun., 1990, 20, 2235. 4) E. Aguilar; A.I. Meyers, Tetrahedron Lett., 1994, 35, 2473. 5) C.J. Moody; M.C. Bagley, J. Chem. Soc., Perkin Trans. 1, 1998, 601. 6) Z.P. Xia; C.D. Smith, J. Org. Chem., 2001, 66, 3459. 7) Q. Qiao; S.-S. So; R.A. Goodnow, jr., Org. Lett., 2001, 3, 3655.

COMMENTS :

HARLAY AMINATION EXAMPLE :

H

O CH3NH2 +

N

CH3

Zn(Ni), EtOH NH3

MECHANISM :

R

R1 O

R R2NH2 - H2O

R1 NR2

764

R Zn(Ni) EtOH, NH3

H

R1 N

R2

DISCONNECTION :

R

R1 O

R

R1 NO2

R H

R1 N

R

R1 N OH

R2

R

R1 N C

NOTES : Ketones are converted directly into amines by treatment with zinc/nickel couple in ethanolic ammonia, ammonia can be replaced by primary amines. The same reaction conditions can be used for the reduction of nitro, nitriles, oximes and isonitriles to amines. See also Eschweiler – Clark, Forster – Decker and Henze – Humphreys reactions.

REFERENCES : 1) V. Harlay; G. Bertrand, C.R. Séances Acad. Sci., 1941, 213, 304. 2) M. Mousseron; P. Froger, Bull. Soc. Chim. Fr., 1947, 843. 3) J. Werner, Ind. Eng. Chem., 1986, 40, 1574.

COMMENTS :

765

HARRIES OZONIDE REACTION EXAMPLE :

H3C

CH3

H3C

CH3

H3C 1) O3, DCM 2) Zn, CH3COOH

H

H3C

H

+ O

O

MECHANISM :

O O

O

O

O

O

O O

O

O Me2S

O O

2

+ Me2SO O

Zn, CH3COOH

2

+ ZnO O

DISCONNECTION :

R1

R

+

R2

O

R3 O

R

R2

R1

R3

NOTES : Alkenes react with ozone to form initially a molozonide and rearranges via the carbonyl oxide to an ozonide which on decomposition gives two carbonyl compounds.

766

REFERENCES : March : 1177 Smith – March : 1522 Smith : 306 Smith 2nd : 267 Org. Synth. : 26, 63; 41, 41 Org. Synth. Coll. Vol. : 3, 673; 5, 489

1) C.F. Schönbein, J. Prakt. Chem., 1855, 66, 282. 2) C. Harries, Liebigs Ann. Chem., 1905, 343, 311. 3) L. Long, jr., Chem. Rev., 1940, 27, 437. 4) P.S. Bailey, Chem. Rev., 1958, 58, 925. 5) R.W. Murray, Acc. Chem. Res., 1968, 1, 313. 6) M. Miura; T. Fujisaka; M. Nojima; S. Kusabayashi; K.J. McCullough, J. Org. Chem., 1985, 50, 1504. 7) J.Z. Gillies; C.W. Gillies; R.D. Suenram; F.J. Lovas, J. Am. Chem. Soc., 1988, 110, 7991. 8) K. Griesbaum; V. Ball, Tetrahedron Lett., 1994, 35, 1163.

COMMENTS :

HARRIES PYRROLE SYNTHESIS EXAMPLE :

H

H

+ NH3

O O

CH3COOH

N H

MECHANISM :

H

H3N H2N O O H+

HO

OH O H+

767

H

N H

OH

- 2 H2O

N H

DISCONNECTION :

R

R1

R

R1 + R2NH2

N R2 R

O O R1

R

R1 + P2S3

S

O O

NOTES : Pyrrole is obtained by the interaction of ammonia and succinic dialdehyde in the presence of acetic acid. If diphosphorous trisulfide is used thiophene derivatives are obtained. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : 1) C. Harries, Ber. Dtsch. Chem. Ges., 1901, 34, 1488. 2) C. Harries, Ber. Dtsch. Chem. Ges., 1902, 35, 1186. 3) J.M. Méndez; B. Flores; F. León; M.E. Martínez; A. Vázques; G.A. García; M. Salmón, Tetrahedron Lett., 1996, 37, 4099.

COMMENTS :

HASS – BENDER CARBONYL SYNTHESIS EXAMPLE :

Br

H

H3C NO2 H3C Na, EtOH

768

O

MECHANISM :

CH3 Br CH3 H NO2 CH3

H3C Na H

H3C

OH N O

O

N O

CH3

+

O H3C N OH

+ H3C

DISCONNECTION :

ArCHO

ArCH2X

X = Cl, Br, I Ar = C6H5, C6H4CH3, C6H4OCH3, C6H4OOCH3, C6H4CF3 C6H4CN, C6H4Br

NOTES : An aromatic aldehyde or ketone are synthesised by reaction of a benzyl halide or polycyclic compounds with the sodium salt of 2-nitroalkanes. See also Kornblum aldehyde and Sommelet aldehyde reactions.

REFERENCES : Houben – Weyl : E3, 251 Org. Synth. : 30, 99 Org. Synth. Coll. Vol. : 4, 932

1) H.B. Hass; M.L. Bender, J. Am. Chem. Soc., 1949, 71, 1767. 2) D.B. Spoelstra; S.H. Weber; R.J.C. Kleipool, Recl. Trav. Chim. Pays-Bas, 1957, 76, 205. 3) A.T. Blomquist; R.E. Stahl; Y.C. Meinwald; B.H. Smith, J. Org. Chem., 1961, 26, 1687. 4) B.H. Klanderman, J. Org. Chem., 1966, 31, 2618. 5) W.W. Epstein; F.W. Sweat, Chem. Rev., 1967, 67, 247. 6) B. Unterhalt; F. Leiblein, Arch. Pharm. (Weinheim, Ger.), 1983, 316, 358. 7) T.A. Klein; J.M. Schkeryantz, Tetrahedron Lett., 2005, 46, 4535.

COMMENTS :

769

HASS CYCLOPROPANE PROCESS EXAMPLE :

H3C

CH3

1) Cl2 2) Zn, aq. EtOH, NaI, Na2CO3

MECHANISM :

H3 C

CH3

ClCH2

CH2Cl

Cl2

Zn, aq. EtOH NaI, Na2CO3

DISCONNECTION :

H3C

CH3

NOTES : Propane in natural gas is chlorinated and 1,3-dichloropropane is separated from the other products and converted to cyclopropane by treatment with zinc dust in aqueous ethanol in the presence of sodium carbonate and sodium iodide. See also Charette, Freund, Gustavson, Ipatiew cyclopropane, Kishner, Mousseron – Fraisse – McCoy, Nerdel and Simmons – Smith reactions.

REFERENCES : Houben – Weyl : 13/1, 492

1) H.B. Hass; G.E. Hinds, Chemisches Zentralblatt, 1938-I, 4237. 2) E. Vogel, Angew. Chem., 1960, 72, 4.

COMMENTS :

770

HASS PROCESS EXAMPLE :

H H H

H H H

+

HNO3

H H

H

420 oC

NO2 H H

MECHANISM :

H

O

O N

H

O

O N

H

H

CH3OH + CH3NO2

H H H

H H

H

O

O H2O + EtNO2

H H H

H

DISCONNECTION :

R NO2

R H

NOTES : Aliphatic hydrocarbons react with nitric acid vapour at 420 oC to afford aliphatic nitro compounds. Straight and branched hydrocarbons can be nitrated. Due to the high temperatures used oxidative cleavage will take place.

REFERENCES : 1) H.B. Hass; E.B. Hodge; B.M. Vanderbilt, U.S. Patent, 1934, 1967667. 2) H.B. Hass; E.B. Hodge; B.M. Vanderbilt, Ind. Eng. Chem., 1936, 28, 339. 3) H.B. Hass; E.F. Riley, Chem. Rev., 1943, 32, 373.

771

COMMENTS :

HASSNER – GHERA – LITTLE RING–CLOSURE EXAMPLE :

O

OCH2OEt H3C

CO2Et

+ PhO2S

Br

PhO2S H3C

1) LDA, THF, - 95 oC 2) 20% aq. CH3COOH EtOCH2O

MECHANISM :

Y

R

R

X

X

Nu Nu Y Y

R

R X

X Nu

Nu

H+ O R

HO R X

X

Nu Nu Y

R R X

X

X = NO2, CO2R1 Nu Nu

772

H

CO2Et

NOTES : Michael initiated ring-closure (MIRC) of especially sulfones affords three, five, six and seven membered rings in the presence of lithium diisopropylamine. After the initial conjugate addition, the ring-closure can be inter- or intramolecular. The [3+2]-cycloadditions are stereoselective. See also Michael reaction.

REFERENCES : 1) R.D. Little; J.R. Dawson, J. Am. Chem. Soc., 1978, 100, 4607. 2) E. Ghera; Y. Ben–David, Tetrahedron Lett., 1979, 20, 4603. 3) R.D. Little; J.R. Dawson, Tetrahedron Lett., 1980, 21, 2609. 4) E. Ghera; T. Yechezkel; A. Hassner, Tetrahedron Lett., 1990, 31, 3653. 5) M.A. Amputch; R. Matamoros; R.D. Little, Tetrahedron, 1994, 50, 5591. 6) E. Ghera; T. Yechezkel; A. Hassner, J. Org. Chem., 1996, 61, 4959. 7) T. Yechezkel; E. Ghera; N.G. Ramesh; A. Hassner, Tetrahedron: Asymmetry, 1996, 7, 2423.

COMMENTS :

HASSNER – RUBOTTOM α-HYDROXYLATION EXAMPLE : O

O

I 1) LDA, TMSCl 2) mCPBA 3) NaI

MECHANISM :

O

OTMS O

OTMS

1) LDA 2) TMSCl

mCPBA

773

O OH H2O

DISCONNECTION : O

O X X = OH, I, NOH

NOTES : This is the α-hydroxylation, iodination, or oximation of carbonyls via silyl enol ethers. See also Vedejs hydroxylation.

REFERENCES : Org. Synth. : 64, 118; 73, 123 Org. Synth. Coll. Vol. : 7, 282; 9, 564

1) J. Rasmussen; A. Hassner, Synthesis, 1973, 682. 2) R.H. Reuss; A. Hassner, J. Org. Chem., 1974, 39, 1785. 3) G.M. Rubottom; R.C. Mott; H.D. Juve, jr., J. Org. Chem., 1981, 46, 2717. 4) G.M. Rubottom; H.D. Juve, jr., J. Org. Chem., 1983, 48, 422. 5) C.-K. Sha; J.-J. Young; T.-S. Jean, J. Org. Chem., 1987, 52, 3919. 6) R. Gleiter; R. Kraemer; H. Irngartinger; C. Bissinger, J. Org. Chem., 1992, 57, 252.

COMMENTS :

HASSNER AZIDE AZIRIDINE SYNTHESIS EXAMPLE :

Ph Br

N3

Ph

Ph BrN3 CH3CN

BrN3 pentane

774

N3

Br

MECHANISM :

Ph

Ph

I CH3

IN3

CH3

Ph

Ph

I

N3

CH3

N H trans

LiAlH4

erythro

N3

Me

KOtBu - HI CH3

Ph

CH3

Ph N3

N

light or heat - N2

LiAlH4

Ph

CH3 N H

DISCONNECTION :

R2 X R1

R3 N3 R4 X = Br, I

R2 N3 R1

R2

R3

R1

R4

R3 Br R4

NOTES : The stereospecific and regioselective addition of IN3 (via iodonium ions) or of BrN3 (ionic or free radical) to olefins and conversion of the adducts to aziridines or azirines. This is a more convenient route than the Wenker synthesis. See also Blum aziridine, Gabriel – Marckwald – Cromwell ethylenimine method, Hoch – Campbell, Mansuy – Evans, Scheiner and Wenker ring–closure reactions.

REFERENCES : Org. Synth. : 51, 53, 112 Org. Synth. Coll. Vol. : 6, 795, 967

775

1) A. Hassner; C. Heathcock, Tetrahedron, 1964, 20, 1037. 2) A. Hassner; C. Heathcock, J. Org. Chem., 1965, 30, 1748. 3) A. Hassner; J.E. Galle, J. Am. Chem. Soc., 1970, 92, 3733. 4) A. Hassner, Acc. Chem. Res., 1971, 4, 9. 5) R. Bushby; S. Mann, J. Chem. Soc., Perkin Trans. 1, 1987, 2497. 6) W. Chamchaang; A.R. Pinhas, J. Org. Chem., 1990, 55, 2943. 7) F.W. Eastwood; P. Perlmutter; Q. Yang, J. Chem. Soc., Perkin Trans.1, 1997, 35.

COMMENTS :

HAUSER – BEAK ORTHO-LITHIATION EXAMPLE :

O

H3C

CH3 N

CH3 H3C

CH3

CH3 N

1) sBuLi, TMEDA 2) CH3I

CH3

O

CH3 H3C

CH3 CH3

MECHANISM :

N Ph Li

O

O

O

O

H BuLi

O N Ph

N Ph

n

Bu BuBr

O

Bu

O N Ph

N Ph

CO2 Li

Li O

Li

O

776

- CO2

O

O t

O N Ph

Li

H

BuLi

DISCONNECTION :

H

E R

R

MDG

MDG O

O MDG =

NEt2

,

O

O NEt2

,

N H

OtBu

NOTES : In general this is the ortho-selective electrophilic functionalisation of aromatic compounds via substituent-controlled lithiation. The Hauser – Beak ortho-lithiation deals with dipole-stabilised carbanions α to nitrogen or a benzylic carbanion.

REFERENCES : Org. React. : 47, 1 Org. Synth. : 74, 23 Org. Synth. Coll. Vol. : 9, 391

1) C.-L. Mao; I.T. Barnish; C.R. Hauser, J. Heterocycl. Chem., 1969, 6, 475. 2) P. Beak; R.A. Brown, J. Org. Chem., 1977, 42, 1823. 3) P. Beak; V. Snieckus, Acc. Chem. Res., 1982, 15, 306. 4) P. Beak; A. Basu; D.J. Gallagher; Y.S. Park; S. Thayumanavan, Acc. Chem. Res., 1996, 29, 552. 5) H.J. Du; J.K. Cha, J. Am. Chem. Soc., 1999, 121, 10012.

COMMENTS :

777

HAUSER – KRAUS ANNULATION EXAMPLE :

OH

O

O CH3

O CN

H

1) LDA, HMPA 2) O H3C

CH3 OH CH3

MECHANISM :

PhO2S

O

O

O LDA, THF - 78 oC

O

SO2Ph R

SO2Ph

H

O R

R1

O

O

O

OH R R1

H+ OH

O

DISCONNECTION :

SO2Ar

R

R1

H +

R OH

R1

CO2Et

O

OCH3 R1

SO2Ar

R H

R

O

+ R1

R2

O

OCH3 O

R2

778

O

O

R1

NOTES : 1-Hydroxy-2,3-disubstituted napthalenes and 1,4-dihydroxy-2,3-disubstituted napthalenes are prepared from ethyl 2carboxybenzyl phenyl sulfoxides and 1H-2-benzofuran-1-one-3-phenyl sulfone with ketones and α,β-unsaturated esters.

REFERENCES : 1) F.M. Hauser; R.P. Rhee, J. Am. Chem. Soc., 1977, 99, 4533. 2) F.M. Hauser; R.P. Rhee, J. Org. Chem., 1978, 43, 178. 3) G.A. Kraus; H. Sugimoto, Tetrahedron Lett., 1978, 19, 2263.

COMMENTS :

HAWORTH METHYLATION EXAMPLE :

OH

OCH3 O

O

HO H

H OH OH

OCH3

H3CO 1) Me2SO4, aq. NaOH 2) HCl, H2O

OH

H OCH3

779

OCH3

MECHANISM :

OCH3

OH

O

O

H3CO

HO H

H OH OH

OCH3

Me2SO4, aq. NaOH

H

H OCH3 OCH3

H+

OCH3

OCH3

O

O H3CO

OCH3

H

H3CO OH2

OCH3 OCH3

OH

H OCH3

OCH3

DISCONNECTION :

R OCH3

R OH R = Carbohydrate

NOTES : This is the O-alkylation of carbohydrates by alkyl sulfate and aqueous alkali. The glycosidic methyl group can be hydrolysed with acid. See also Claisen carbonate alkylation, Fischer glycosidation, Hakomori, Irvine – Purdie, Meerwein methylation, Robertson – Robinson and Williamson reactions.

REFERENCES : Houben – Weyl : 6/3, 35 Org. Synth. : 20, 97 Org. Synth. Coll. Vol. : 3, 800

1) W.S. Denham; H. Woodhouse, J. Chem. Soc., 1913, 103, 1735. 2) W.N. Haworth, J. Chem. Soc., 1915, 107, 13. 3) W.N. Haworth; H. Machemer, J. Chem. Soc., 1932, 2270. 4) R. Kuhn; H. Trischmann, Chem. Ber., 1963, 96, 284.

COMMENTS :

780

HAWORTH POLYNUCLEAR AROMATICS SYNTHESIS EXAMPLE :

O O

+

O

1) AlCl3, 2) Zn, HCl 3) H2SO4 4) Zn, HCl 5) Se

MECHANISM :

O O

O O

AlCl3

O

O AlCl3

O

O

O

O

AlCl3

O

O

O OH

Zn, HCl

O

OH2

H2SO4

- H2O

O +

-H

Se

Zn, HCl

DISCONNECTION :

781

O AlCl3

NOTES : The synthesis of polynuclear aromatic compounds by the Friedel – Crafts condensation of succinic anhydride with an aromatic compound to give a β-aroylpropionic acid. This acid is reduced and treated with moderately concentrated sulfuric acid to yield a cyclic ketone which is in turn reduced. Selenium dehydrogenation gives the polynuclear aromatic compound. See also Friedel – Crafts, Stobbe and Wittig phenanthrene reactions.

REFERENCES : March : 541 Smith – March : 714 Smith : 1329 Smith 2nd : 1094 Org. React. : 5, 229

1) F. Krollpfeiffer; W. Schäfer, Ber. Dtsch. Chem. Ges., 1923, 56, 620. 2) R.D. Haworth, J. Chem. Soc., 1932, 1125. 3) R.D. Haworth, J. Chem. Soc., 1932, 2717. 4) R.D. Haworth; C.R. Marvin; G. Sheldrick, J. Chem. Soc., 1934, 454. 5) D.D. Phillips; M.F. Bruno, J. Org. Chem., 1963, 28, 1627. 6) R. Menicagli; O. Piccolo, J. Org. Chem., 1980, 45, 2581. 7) I. Hashimoto; T. Kawaji; F.D. Badea; T. Sawada; S. Mataka; M. Tashiro; G. Fukata, Res. Chem. Intermed., 1996, 22, 855. 8) P. Wipf; J.-K. Jung, J. Org. Chem., 2000, 65, 6319.

COMMENTS :

782

HAYASHI – ITO REACTION EXAMPLE :

CH3

CH3 Cl Mg

+ 0.8 mol%

i

Bu

i

Bu

PPh2

Fe

NMe2 H

CH3

Pd(PPFA)Cl2

MECHANISM :

Fe

Ph2 P M NMe2

R2

Br

Fe

Br H

R1

Ph

R2 MgCl

CH3

Ph2 P M Br Me2 N MgCl R1 H3C Ph

- MgX2

Fe

PPh2 NMe2

R2

Fe

Ph2 P M NMe2

R1 R2

Ph H3C

H

783

R1

Ph CH3

DISCONNECTION :

R R1

R M

+

R1 X

M = Mg, Zn, Al, Sn, B, Si R1 = aryl, alkenyl X = Cl, Br, I, OSO2CF3, OPO(OR)2

NOTES : The asymmetric carbon-carbon coupling of secondary alkyl magnesium and zinc reagents with aryl and alkenyl halide in the presence of nickel or palladium catalyst co-ordinated with a chiral phosphine ligand give optically active crosscoupling products. See also Kumada – Tamao – Corriu cross coupling.

REFERENCES : 1) C. Consiglio; C. Botteghi, Helv. Chim. Acta, 1973, 56, 460. 2) T. Hayashi; M. Tajika; K. Tamao; M. Kumada, J. Am. Chem. Soc., 1976, 98, 3718. 3) T. Hayashi; M. Konishi; H. Ito; M. Kumada, J. Am. Chem. Soc., 1982, 104, 4962. 4) T. Hayashi; K. Hayashizaki; Y. Ito, Tetrahedron Lett., 1989, 30, 215. 5) M. Uemura; H. Nishimura; T. Hayashi, J. Organomet. Chem., 1994, 473, 129. 6) T. Kamikawa; Y. Uozumi; T. Hayashi, Tetrahedron Lett., 1996, 37, 3161. 7) T. Hayashi, J. Organomet. Chem., 2002, 653, 41.

COMMENTS :

HAYASHI REARRANGEMENT EXAMPLE :

O

Cl OH

O

Cl

H2SO4 CH3 O

OH

CH3 O

784

OH OH

MECHANISM :

O

S

NO2 S

NO2 O

H2SO4, 70 oC

O OH

H2SO4, 135 oC

S

NO2

O

H2O

O

O NO2 O

NO2

O

S

S

O

O

S

O S

O NO2 O

NO2

O

S H2O

O OH NO2 O

DISCONNECTION :

R

O

O Aromatic OH

Aromatic OH R

O

O

NOTES : Certain substituted o-aromatic benzoic acids rearrange via a spirocyclic carbenium intermediate in concentrated sulfuric acid or phosphorous pentoxide to yield isomeric acids. See also Beckmann rearrangement, Freudenberg – Schönberg, Newman – Karnes – Kwart and Smiles reactions.

REFERENCES : Houben – Weyl : E6a, 487

785

1) M. Hayashi, J. Chem. Soc., 1927, 2516. 2) R.B. Sandin; R. Melby; R. Crawford; D. McGreer, J. Am. Chem. Soc., 1956, 78, 3817. 3) M.S. Newman; K.G. Ihrman, J. Am. Chem. Soc., 1958, 80, 3652. 4) M.S. Newman, Acc. Chem. Res., 1972, 5, 354. 5) M. Cushman; T.-C. Choong; J.T. Valko; M.P. Koleck, J. Org. Chem., 1980, 45, 5067. 6) A. Opitz; E. Roemer; W. Haas; H. Gorls; W. Werner; U. Grafe, Tetrahedron, 2000, 56, 5147.

COMMENTS :

HECK – FUJIWARA – MIZOROKI COUPLING EXAMPLE :

N

+

Br

NBu2

N Pd(OAc)2, Et3N

786

NBu2

MECHANISM :

PdII 2 L; 2 e-

KHCO3 + KBr Pd0L2 K2CO3

Ph Br

H PdIIL2 Br

H3CO2C

Ph PdIIL2 Br H3CO2C

Ph

H H3CO2C

PdIIL2Br H Ph H

H H3CO2C

787

PdIIL2Br Ph H H

PdII 2 L; 2 e-

AgHCO3 Pd0L2 AgCO3-

Ph Br

H PdIIL2+

H3CO2C

Ph PdIIL2 Br Ag+

Ph AgBr H H3CO2C

PdIIL2+ H Ph H

Ph PdIIL2+

H H3CO2C

PdIIL2+ Ph H H

H3CO2C

DISCONNECTION :

R

R X

R1

+

R1

R = alkenyl, aryl, allyl, alkynyl, benzyl X = halide, triflate R1 = alkyl, alkenyl, aryl, CO2R, OR, Si(R)3

NOTES : The oxidative cross-coupling reactions of aromatic or vinylic halides or tosylates lacking sp3-β-hydrogens and olefins catalysed by palladium. The catalytic cycle starts with palladium(0), which undergoes oxidative addition, syncarbopalladation, internal rotation, syn-β-H-elimination and finally reductive elimination. Excess silver(I) salts can be used to abstract the halide ion to produce a reactive cationic palladium species. There is a different mechanism for cationic palladium species. The first asymmetric version was reported by Shibasaki in 1989. The Matsuda variant is

788

used by Novartis to synthesis Prosulferontm, a highly active herbicide. See also Grigg, Stille – Kelly, Stille coupling and Suzuki reactions.

REFERENCES : March : 717 Smith – March : 930 Smith : 1363 Smith 2nd : 1119, 1184 Houben – Weyl : E6a, 125; E6b, 138, 574; E7b, 613 Org. React. : 27, 345 Org. Synth. : 61, 82 Org. Synth. Coll. Vol. : 7, 361 Science of Synthesis : 1, 141; 9, 265, 357, 388; 10, 50, 101, 166, 400, 417, 420, 463, 467, 570, 573

1) I. Moritani; Y. Fugiwara, Tetrahedron Lett., 1967, 8, 1119. 2) R.F. Heck, J. Am. Chem. Soc., 1968, 90, 5518. 3) T. Mizoroki; K. Mori; A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581. 4) R.F. Heck; J.P. Nolley, jr., J. Org. Chem., 1972, 37, 2320. 5) P.A. Patel; C.B. Ziegler; N.A. Cortese; J.E. Plevyak; T.C. Zebovitz; M. Terpko; R.F. Heck, J. Org. Chem., 1977, 42, 3903. 6) N.A. Cortese; C.B. Ziegler; B.J. Hrnjez; R.F. Heck, J. Org. Chem., 1978, 43, 2952. 7) Y. Sato; M. Sodeoka; M. Shibasaki, J. Org. Chem., 1989, 54, 4738. 8) A. Lansky; O. Reiser; A. de Meijere, Synlett, 1990, 405. 9) V. Farina; S. Kapadia; B. Krishnan; C. Wang; L.S. Liebeskind, J. Org. Chem., 1994, 59, 5905. 10) G.T. Crisp, Chem. Soc. Rev., 1998, 27, 427. 11) K. Hirabayashi; J. Ando; J. Kawashima; Y. Nishihara; A. Mori; T. Hiyama, Bull. Soc. Chem. Jpn., 2000, 73, 1409. 12) V.P.W. Böhm; W.A. Herrmann, Chem. Eur. J., 2000, 6, 1017. 13) I.P. Beletskaya; A.V. Cherprakov, Chem. Rev., 2000, 100, 3009. 14) J.G. de Vries, Can. J. Chem., 2001, 79, 1086. 15) E.J. Farrington; J.M. Brown; C.F.J. Barnard; E. Rowsell, Angew. Chem., Int. Ed., 2002, 41, 169. 16) R. Imbos; A.J. Minnaard; B.L. Feringa, J. Am. Chem. Soc., 2002, 124, 184. 17) M. Buback; T. Perković; S. Redlich; A. de Meijere, Eur. J. Org. Chem., 2003, 2375. 18) C.E. Willans; J.M.C.A. Mulders; J.G. de Vries; A.H.M. de Vries, J. Organomet. Chem., 2003, 687, 494. 19) J.T. Singleton, Tetrahedron, 2003, 59, 1837. 20) M.T. Reetz; J.G. de Vries, Chem. Commun., 2004, 1559. 21) K. Hirabayashi; Y. Nara; T. Shimizu; N. Kamigata, Chem. Lett., 2004, 33, 1280. 22) J. Xu; D.J. Burton, J. Fluorine Chem., 2004, 125, 725.

789

COMMENTS :

HEGEDUS INDOLE SYNTHESIS EXAMPLE :

CH3 MeO2C

1) PdCl2(CH3CN)2 THF 2) Et3N

NH2

N H

MeO2C

MECHANISM :

MeO2C

PdCl2(CH3CN)2

NH2

Et3N Pd

N H2

MeO2C

Cl

Pd Cl Cl

H

Cl MeO2C

Et3N Pd Cl Cl

N H2

MeO2C

NH2

Pd0 +

- HCl - PdH

CH3 N H

MeO2C

MeO2C

N H

DISCONNECTION :

R

CH3

R

N H

NH2

790

Et3N

NOTES : The indole ring is established via a palladium-catalysed amination (a Tsuji – Wacker type reaction). The reaction is sometimes called Hegedus – Mori – Heck indole synthesis. A ruthenium variant has also been published. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Nenitzescu indole, Piloty – Robinson, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) L.S. Hegedus; G.F. Allen; E.L. Waterman, J. Am. Chem. Soc., 1976, 98, 2674. 2) L.S. Hegedus; G.F. Allen; J.J. Bozell; E.L. Waterman, J. Am. Chem. Soc., 1978, 100, 5800. 3) L.S. Hegedus; J.L. Toro; W.H. Miles; P.J. Harrington, J. Org. Chem., 1987, 52, 3319. 4) L.S. Hegedus; Angew. Chem., Int. Ed. Engl., 1988, 27, 1113. 5) T. Kondo; T. Okada; T. Mitsudo, J. Am. Chem. Soc., 2002, 124, 186.

COMMENTS :

HEINE REACTION EXAMPLE :

O

CH3

CH3 N

H3C

O CH3

NaI acetone

791

H3C

N CH3

MECHANISM :

O

CH3

CH3 O

N

CH3

N

O

H3C

H3C

CH3

CH3

I

N

H3C

CH3

I

DISCONNECTION :

R O

O N

R1

R N

R1

R2

R2

NOTES : The ringexpansion of substituted N-acylaziridines by nucleophilic reagents to afford the corresponding oxazoline.

REFERENCES : 1) H.W. Heine; M.E. Fetter; E.M. Nicholson, J. Am. Chem. Soc., 1959, 81, 2202. 2) H.W. Heine; W.G. Kenyon; E.M. Johnson, J. Am. Chem. Soc., 1961, 83, 2570. 3) H.W. Heine; M.S. Kaplan, J. Org. Chem., 1967, 32, 3069.

COMMENTS :

HEINISCH – MATUSZCZAZOV – MERETEIRA REACTION EXAMPLE :

H N N

NH2

Cl +

NH2

Cl

N

Cl O

Cl

N

N 1) NaH 2) H+

792

N H

O

MECHANISM :

NH2

N

Cl +

NH2 O

Cl

N

Cl

NH2

H N

N H

Cl

N N

Cl

N

H N

N

Cl N

N H N N

Cl

O

N H

N

H N N

Cl

N

O

N H

Cl

N H+

O

O

NaH

O

N N Cl

N H

N H

N

N

Cl - Cl

N

Cl

NaH, - H2

O H N

Cl

N H

O

DISCONNECTION :

H N N Cl

N

NH2

Cl +

N H

O

NH2

Cl

N

N Cl

O

NOTES : This is a very interesting synthesis of 1,2-dihydro-quinoxaline-2-ones derived from ortho-aminoanilide and 3,6dichloropyridazine-4-acid chloride. The authors proposed the reaction mechanism shown but some of the intermediate structures do not appear to be probable.

REFERENCES : 1) G. Heinisch; B. Matuszczazov; K. Mereiter, Heterocycles, 1994, 38, 2081. 2) Y. Kuwatani; M. Iyoda, J. Heterocycl. Chem., 1997, 34, 773.

COMMENTS :

793

HELFERICH ETHERIFICATION EXAMPLE :

OH

OCPh3 O

HO HO

O OH

+ Ph3CCl

HO HO

pyridine heat

OH

OH OH

MECHANISM :

Ph3C Cl OH

OCPh3 O

HO HO

O OH pyridine heat

OH

HO HO

OH OH

DISCONNECTION :

R

R HO

Ph3CO R = carbohydrate

NOTES : Triphenylmethyl ethers of polyhydric alcohols and sugars are obtained by the use of triphenylmethyl chloride in pyridine. In this way the primary alcoholic group is preferentially etherified. It is generally used as a protecting group for alcohols.

REFERENCES : Org. Synth. : 22, 56 Org. Synth. Coll. Vol. : 3, 432

1) B. Helferich; L. Moog; A. Jünger, Ber. Dtsch. Chem. Ges., 1925, 58, 872. 2) B. Helferich; W. Klein, Liebigs Ann. Chem., 1926, 450, 219. 3) F.A. Hochstein; G.F. Wright, J. Am. Chem. Soc., 1949, 71, 2257. 4) G.E. McCasland; S. Proskow, J. Org. Chem., 1957, 22, 122.

794

5) H. Yamamoto; K. Yamamoto; S. Inokawa; M. Yamashita; M.A. Armour; T.T. Nakashima, J. Org. Chem., 1983, 48, 435. 6) S. Hanessian; S.P. Sahoo; M. Botta, Tetrahedron Lett., 1987, 28, 1143. 7) B. Kasnar; D.S. Wise; L.S. Kucera; J.C. Drach; L.B. Townsend, Nucleosides, Nucleotides, 1994, 13, 459. 8) H. Ouyang; S.L. Morris–Natschke; K.S. Ishaq; P. Ward; D. Liu; S. Leonard; D.R. Thakker, J. Med. Chem., 2002, 45, 2857.

COMMENTS :

HELFERICH METHOD EXAMPLE :

OAc

OAc

O

O

AcO

AcO H

H OAc OAc

OAc

H

H

PhOH ZnCl2 125 oC

OAc OAc

OC6H5

MECHANISM :

OAc

OAc O

O

AcO H

H OAc OAc

H+, - HOAc

AcO OAc

OAc

OAc

OAc O AcO H OAc

H

H

H OAc OC6H5

795

PhOH ZnCl2 125 oC

DISCONNECTION :

R OPh

R OAc + PhOH R = Carbohydrate

NOTES : α- and β-Phenyl glycosides are prepared by heating acetates of reducing sugars with a phenol in the presence of acid or Lewis acid catalysts. The acetate group at C-1 is less strongly bound to the carbon atom than the other acetate groups. Normally only the α-phenyl glycosides are formed.

REFERENCES : Org. Synth. : 6, 64 Org. Synth. Coll. Vol. : 1, 364

1) B. Helferich; E. Schmitz–Hillebrecht, Ber. Dtsch. Chem. Ges., 1933, 66, 378. 2) R.T. Williams, J. Chem. Soc., 1940, 1402. 3) M.A. Jermyn, Aust. J. Chem., 1954, 7, 202. 4) B. Helferich; J. Zirner, Chem. Ber., 1963, 96, 385. 5) R. Polt; L. Szabo; J. Treiberg; Y. Li; V.J. Hruby, J. Am. Chem. Soc., 1992, 114, 10249. 6) P. Kosma; M. Strobl; G. Allmaier; E. Schmid; H. Brade, Carbohydr. Res., 1994, 254, 105. 7) D.A. Leigh; J.P. Smart; A.M. Truscello, Carbohydr. Res., 1995, 276, 417. 8) V. Kren; J. Kubisch; P. Sedmera; P. Halada; V. Prikrylová; A. Jegorov; L. Cvak; R. Gebhardt; J. Ulrichová, J. Chem. Soc., Perkin Trans. 1, 1997, 2467.

COMMENTS :

HELL – VOLLHARD – ZELINSKY HALOGENATION EXAMPLE : Br OH

H3C O

PBr3, Br2

796

OH

H3C O

MECHANISM :

Br OH

R

OH

R

+ PBr3

O

O Br

R

R

O

- HOPBr2 PBr2

Br OH Br

Br

R

Br

R

+ Br2 OH

+

OH

R

O

O

Br OH

R

+

Br

R

O

O

DISCONNECTION :

X OH

R O

OH

R X = Cl, Br

O

NOTES : This reaction relates to the preparation of an α-halo substituted acid or ester by the action of the halogen on the acid in the presence of phosphorous or a phosphorous halide, followed by hydrolysis or alcoholysis of the resulting haloacyl halide. Only catalytic amounts of PBr3 are required for this reaction. The reaction does not work with F or I. For α-iodination see Ogata et al. See also Bedoukian reaction.

REFERENCES : March : 590 Smith – March : 777 Smith : 155 Smith 2nd : 125 Houben – Weyl : E5, 220, 465 Org. Synth. : 20, 106; 21, 74; 33, 29; 55, 27 Org. Synth. Coll. Vol. : 3, 523, 848; 4, 348; 6, 190

1) C. Hell, Ber. Dtsch. Chem. Ges., 1881, 14, 891.

797

2) J. Vollhard, Liebigs Ann. Chem., 1887, 242, 141. 3) N. Zelinsky, Ber. Dtsch. Chem. Ges., 1887, 20, 2026. 4) H.B. Watson, Chem. Rev., 1930, 7, 173. 5) H.J. Harwood, Chem. Rev., 1962, 62, 99. 6) Y. Ogata; S. Watanabe, J. Org. Chem., 1980, 45, 2831. 7) H.J. Liu; W.D. Luo, Synth. Commun., 1991, 21, 2097. 8) D.E. Stack; A.L. Hill; C.B. Differdaffer; N.M. Burns, Org. Lett., 2002, 4, 4487.

COMMENTS :

HEMETSBERGER – KNITTEL INDOLE SYNTHESIS EXAMPLE :

CO2Et

CO2Et CO2Et N3

CO2Et

toluene heat

N H

MECHANISM :

CO2Et

CO2Et

CO2Et CO2Et

CO2Et N N N

toluene heat - N2

CO2Et

N

N H

DISCONNECTION :

CO2Et R

CO2Et

R

N H

NOTES :

798

N3

Indoles are obtained by heating araldehydes and α-azidoacetate. The mechanism is not fully known, but the reaction proceeds most probably via the nitrene intermediate. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 439

1) H. Hemetsberger; D. Knittel; H. Weidman, Monatsh. Chem., 1969, 100, 1599. 2) D.M.B. Hickey; A.R. MacKenzie; C.J. Moody; C.W. Rees, J. Chem. Soc., Perkin Trans. 1, 1987, 921. 3) R.E. Bolton; C.J. Moody; M. Pass; C.W. Rees; G. Tojo, J. Chem. Soc., Perkin Trans. 1, 1988, 2491. 4) C.J. Moody; A.L. Beck; W.J. Coates, Tetrahedron Lett., 1989, 30, 4017. 5) S.S Samanta; S.C. Ghosh; A. De, J. Chem. Soc., Perkin Trans. 1, 1997, 3673. 6) P. Magnus; T.E. Mansley, Tetrahedron Lett., 1999, 40, 6909. 7) F.A.F. da Rosa; R.A. Rebelo; M.G. Nascimento, J. Braz. Chem. Soc., 2003, 14, 11.

COMMENTS :

HENRY REACTION (KAMLET REACTION) EXAMPLE :

HO O H3C NO2

+ 3

H

H

1) Na2CO3 2) H+

799

NO2

HO HO

MECHANISM :

HO H3C NO2

H2C NO2

base

O

1) H

NO2 H

2) H+ HO

HO

NO2

NO2

HO 1) base 2) O H

HO

1) base 2) O H 3) H+

H

3) H+

HO H

DISCONNECTION :

OH

O

NO2 R R1

+ R

R2

H

R1

R2 NO2

NOTES : The base-catalysed condensation of primary or secondary nitro alkanes with aldehydes to give nitro-alcohols. There are few examples of catalytic asymmetric Henry reactions with chiral heterobimetallic lanthanoid complexes as catalysts. Kamlet : These alcohols are formed by condensation of the alkali metal salt of an acid-nitro olefin with the bisulfite addition compound of an aromatic aldehyde in the presence of a trace of alkali or weak acid. See also Bouveault – Wahl, Claisen – Geuther and Nef reactions.

REFERENCES : March : 946 Smith : 898 Smith 2nd : 751 Houben – Weyl : E14b, 848, 941; E15, 1132 Org. Synth. : 74, 130 Org. Synth. Coll. Vol. : 9, 636

1) L. Henry, C.R. Séances Acad. Sci., 1895, 120, 1265. 2) J. Kamlet, U.S. Patent, 1939, 2151517. 3) H.B. Hass; E.F. Riley, Chem. Rev., 1943, 32, 406. 4) D. Seebach; E.W. Colvin; F. Leher; T. Weller, Chimia, 1979, 33, 1. 5) R.J. Varma; R. Bahiya; S. Kumar, Tetrahedron Lett., 1997, 38, 5131.

800

6) C. Christensen; K. Juhl; K.A. Jørgensen, Chem. Commun., 2001, 2222. 7) F.A. Luzzio, Tetrahedron, 2001, 57, 915. 8) B. Westermann, Angew. Chem., Int. Ed., 2003, 42, 151. 9) D.A. Evans; D. Seidel; M. Rueping; H.W. Lam; J.T. Shaw; C.W. Downey, J. Am. Chem. Soc., 2003, 125, 12692. 10) T. Risgaard; K.V. Gothelf; K.A. Jørgensen, Org. Biomol. Chem., 2003, 1, 153. 11) Y. Kogami; T. Nakajima; T. Ashizawa; S. Kezuka; T. Ikeno; T. Yamada, Chem. Lett., 2004, 33, 614. 12) Y.-W. Zhong; P. Tian; G.-Q. Lin, Tetrahedron: Asymmetry, 2004, 15, 771. 13) J.C. Borah; S. Gogoi; J. Boruwa; B. Kilita; N.C. Barua, Tetrahedron Lett., 2004, 45, 3689.

COMMENTS :

HENZE – HUMPHREYS AMINE SYNTHESIS EXAMPLE :

BuNH2

H

+ O

H2 Raney Ni 3000 psi, 75 oC

Bu

H N

Et

MECHANISM :

R1 RNH2

R2

R

+

N

- H2O

O

R

R2 R1

H2 Raney Ni

DISCONNECTION :

R R1

N

H RNH2 + R2

R1 = H, Alk R2 = Alk

801

R1

R2 O

R1

N

H R2

NOTES : Secondary amines are obtained by the high pressure hydrogenation of aldimines or ketimines. See also Eschweiler – Clarke, Forster – Decker and Harlay reactions.

REFERENCES : 1) J.Wm. Magee; H.R. Henze, J. Am. Chem. Soc., 1940, 62, 910. 2) H. Henze; D. Humphreys, J. Am. Chem. Soc., 1942, 64, 2878. 3) N.H. Cromwell, Chem. Rev., 1946, 38, 83.

COMMENTS :

HERBST – ENGEL AMINO ACID SYNTHESIS EXAMPLE :

NH2

+

H3C

COOH

H

COOH

H3C

COOH

O

O

MECHANISM :

R1 R

NH2

+

R1

COOH

R1 R

COOH N - CO2

COOH

R H2O

R

- H2O

O

COOH N

COOH

H O

+

H2N

R1 COOH

802

NH2

+

DISCONNECTION :

R

H

+

H2N

O

R

R1

NH2

+

O

COOH

COOH

COOH

R1

NOTES : The formation of amino acids from α-amino acids and α-ketocarboxylic acid by transfer of R-group. See also Knoop – Oosterlin reaction and Strecker amino acid synthesis.

REFERENCES : Houben – Weyl : 11/2, 325

1) R.M. Herbst; L.L. Engel, J. Biol. Chem., 1934, 107, 505. 2) R.M. Herbst, J. Am. Chem. Soc., 1936, 58, 2239. 3) Th. Wieland, Angew. Chem., 1942, 55, 147.

COMMENTS :

HERSHBERG SYNTHESIS EXAMPLE :

Br 1) Mg 2) CH2CHCH2Br 3) (BzO)2AgI 4) KOH 5) Pb(OAc)4

803

H O

MECHANISM :

RBr Mg

R

OBz

R KOH

(BzO)2AgI

CH2Br

H2C

OBz

CH2

R

RMgBr

OH OH

R Pb(OAc)4

H + HCHO O

DISCONNECTION :

R

H O

RBr R = Ph, Bu

NOTES : The olefin obtained by the action of a Grignard reagent on an allyl halide is converted into an α-glycol through the benzoate (Prévost). The glycol is oxidised with lead tetraacetate (Criegee) to the aldehyde. See also Grundmann and Prévost reactions.

REFERENCES : Houben – Weyl : 7/1, 106, 353 Org. React. : 8, 218

E.B. Hershberg, Helv. Chim. Acta, 1934, 17, 351.

COMMENTS :

804

HERZ REACTION EXAMPLE :

S S

NH3 Cl

1) S2Cl2 2) NaOH

S

S N

Cl

MECHANISM :

R

R

R

NH2

NH2

NH2

+ S2Cl2 H R

S

S

- HCl Cl

S

Cl

R

Cl

N

N S

S OH

Cl NaOH

S R

S

H H+ N S O S OH

S NH2

R

S

R

NH2 O

S OH

SNa

- NaHSO3

OH

DISCONNECTION :

R

R NH2

Cl

NH2

SH

NOTES :

Benzo-1,3-thiaza-2-thionium chlorides (Herz compounds) are formed from primary aromatic amines unsubstituted in the ortho-position to the amino group, or their salts and sulfur monochloride (S2Cl2). These thionium salts can be converted into o-aminothiophenols by treatment with alkali. Other aromatic heterocycles can also be used.

REFERENCES : March : 530 Smith – March : 704

805

Houben – Weyl : 9, 40; E8d, 3; E11, 46 Org. Synth. : 22, 16 Org. Synth. Coll. Vol. : 3, 76

1) R. Herz, U.S. Patent, 1928, 1637023. 2) W.K. Warburton, Chem. Rev., 1957, 57, 1011. 3) P. Hope; L.A. Wiles, J. Chem. Soc. (C), 1966, 1642. 4) B.L. Chenard, J. Org. Chem., 1984, 49, 1224. 5) P.S. Belica; P.S. Manchand, Synthesis, 1990, 539. 6) S.N. Sawhney; P. Sharma; K. Bajaj; A. Gupra, Synth. Commun., 1993, 23, 263. 7) G. Grandolini; L. Perioli; V. Ambrogi, Gazz. Chim. Ital., 1997, 127, 411. 8) P.A. Koutentis; C.W. Rees, J. Chem. Soc., Perkin Trans. 1, 2002, 315.

COMMENTS :

HERZIG – MEYER N-ALKYL GROUP DETERMINATION EXAMPLE :

Et

Et N CH3 + HI

heat

Et

N H

CH3I + Et

MECHANISM :

R

R N CH3 + HI R

R

N

CH3 H

806

R I

heat

CH3I +

N H R

DISCONNECTION :

R

R

N CH3

N H R

R

NOTES :

Compounds containing N-alkyl groups, when treated with hydrogen iodide form quaternary alkylammonium iodides, which on pyrolysis yield alkyl iodides. The latter may be determined by Zeisel determination.

REFERENCES : Houben – Weyl : 2, 667

1) J. Herzig; H. Meyer, Ber. Dtsch. Chem. Ges., 1894, 27, 319. 2) J. Herzig; H. Meyer, Monatsh. Chem., 1894, 15, 613. 3) J. Herzig; H. Meyer, Monatsh. Chem., 1897, 18, 379. 4) R. Kuhn; H. Roth, Ber. Dtsch. Chem. Ges., 1934, 67, 1458.

COMMENTS :

HEUMANN INDIGO SYNTHESIS EXAMPLE :

O NH2 2

+ 2 ClCH2COOH

1) HO2) NaOH 3) air

807

N H

H N

O

MECHANISM :

H N

NH2 + ClCH2COOH O

O OH

OH

NaNH2

O

O OH

H

OH

OH N

H2O

N H

N H O

- H2O

N OH H O

COOH N H

COOH NH2 OH

O

H N

N H

O

COOH KOH

O COOH

- CO2

N H O

N H

OH N H

N H O

O

H H N - H2O

N OH H O

N H

DISCONNECTION :

O

N H

N

OH OH

H2O

H+

O

O H

N

O

O

H H N

+ ClCH2COOH

H+ N

COOH NH2

H N

or NH2

O

808

O H N

O

NOTES :

There are two possible pathways for the synthesis of indigo : 1) Phenylglycine on fusion with alkali affords indoxyl which is converted into indigo by atmospheric oxidation. Cyanide moderators may be added. 2) Anthranilic acid is converted into o-carboxyphenylglycine, which on fusion with alkali yields indole. This reaction has been used by BASF to produce indigo since 1897. See also von Baeyer – Drewson indigo reaction.

REFERENCES :

1) K. Heumann, Ber. Dtsch. Chem. Ges., 1890, 23, 3043. 2) K. Heumann, Ber. Dtsch. Chem. Ges., 1890, 23, 3431.

COMMENTS :

HEWITT REACTION EXAMPLE : O Ph P H OH

O Ph P H OEt

O +

EtO

pyridine CHCl3

Cl

MECHANISM :

O Ph P H OH

OH

Ph

Ph P O

OH RO H O Ph P O O R O

Cl

O Ph P H OR

809

O O P OH OR

OH Ph P OR

DISCONNECTION :

O Ph P H OR

R1 = Cl, OR

O Ph P H + OH

O RO

R1

NOTES :

This is the transformation of phenylphosphinic acid to its monoalkyl ester in the presence of pyridine and commercial chloroform. A variety of phenylphosphinate esters can be prepared from the corresponding chloroformates in dichloromethane. Chloroform contains ethanol which gives rise to ethyl phenylphosphinate as impurity.

REFERENCES :

1) D.G. Hewitt, Aust. J. Chem., 1979, 32, 463. 2) H.Y. Lei; M.S. Stoakes; A.W. Schwabacher, Synthesis, 1992, 1255. 3) X. Li; G.K. Scott; A.D. Baxter; R.J. Taylor; J.S. Vyle; R. Cosstick, J. Chem. Soc., Perkin Trans. 1, 1994, 2123. 4) M. Sasaki, J. Pestic. Sci., 1995, 20, 193. 5) K. Afarinkia; H-w. Yu, Tetrahedron Lett., 2003, 44, 781.

COMMENTS :

HILL REDUCTION EXAMPLE : CH3

CH3

OCH3

OCH3 CH2

5% KMnO4, AcOH, H2O, 0 oC

810

COOH

MECHANISM :

R

H

H R

CH2

O

MnO4-

O Mn

H2O O

R HO

O

H MnO4H2O

OH

O R

R H HO OH HO OH

R

OH

H2O R

OMnO2-

O

H H

H

R

OH

HO - 2 H+

- CO2 - H+

OH O

O

OH

DISCONNECTION :

R

R

COOH

CH2

NOTES :

Substituted phenylacetic acids are obtained by the oxidation of the corresponding allylbenzene by potassium permanganate in the presence of acetic acid. The exact reaction mechanism is not known.

REFERENCES :

1) A. Higginbottom; W.F. Short, Recl. Trav. Chim. Pays-Bas, 1934, 53, 1141. 2) P. Hill; W.F. Short, J. Chem. Soc., 1937, 260. 3) A. Higginbottom; P. Hill; W.F. Short, J. Chem. Soc., 1937, 263.

COMMENTS :

811

HILLMAN REACTION EXAMPLE :

H3C

H3C H3C H3C

CH3

B

H3C O B

CO, H2O 150 oC

CH3

H3C

MECHANISM :

R 2 R B R

2 (R)3B + 2 CO

R 2 O

R B

R

O

DISCONNECTION :

R

R 2 (R)3B + 2 CO

B

2 R

O

NOTES :

The carbonylation of organoboranes.

REFERENCES :

1) M.E. Hillman, J. Am. Chem. Soc., 1962, 84, 4715. 2) M.E. Hillman, J. Am. Chem. Soc., 1963, 85, 982 3) L.S. Vasilyev; V.V. Veselovskii; M.I. Struchkova; B.M. Mikhailov, J. Organomet. Chem., 1982, 226, 115. 4) P.J. Persichini III, Curr. Org. Chem., 2003, 7, 1725.

COMMENTS :

812

HINSBERG OXINDOLE SYNTHESIS EXAMPLE :

HO N H

CH3

OSO2Na O

+ HO

N CH3

OSO2Na

MECHANISM : R≠H:

N H H

HO

OSO2Na

HO

OSO2Na

HO

OSO2Na

R - OSO2Na

H

N H R

N R

OH

- OSO2Na

H

OH OH

O N R

813

OH

N R

R=H:

N H

N H

HO

OSO2Na

HO

OSO2Na

H

HO

OSO2Na

H

HO

- OSO2Na

N H

OH

H N

H N N H

N OH H H H N N H

OH

O

DISCONNECTION :

O N H

N R

H N

H

HO

OSO2Na

HO

OSO2Na

HO

OSO2Na

HO

OSO2Na

+

+ N H

O

NH2

NOTES :

Oxindoles are obtained by condensing glyoxal bisulfite with a secondary aryl amine. See also von Baeyer oxindole, Brunner, Gassman oxindole, Martinet, Neber – Bosset and Stollé reactions.

REFERENCES :

1) O. Hinsberg, Ber. Dtsch. Chem. Ges., 1888, 21, 110. 2) H. Burton, J. Chem. Soc., 1932, 546. 3) W.C. Sumpter, Chem. Rev., 1944, 34, 393. 4) M.I. Abasolo; D. Bianchi; F. Atlasovich; C. Gaozza; B.M. Fernandez, J. Heterocycl. Chem., 1990, 27, 157. 5) M.I. Abasolo; B.M. Fernandez; E. Magrini, J. Heterocycl. Chem., 1992, 29, 1279. 6) G.A. Rodrigo; S.G. Renou; D.G. Bekerman; M.I. Abasolo; B.M. Fernandez, J. Heterocycl. Chem., 1997, 34, 505.

814

COMMENTS :

HINSBERG REACTION EXAMPLE :

PrNH2 + PhSO2Cl Et2NH + PhSO2Cl

PhSO2N(Na)Pr aq. NaOH PhSO2NEt2

aq. NaOH

Et3N + PhSO2Cl

no reaction

MECHANISM :

RNH2 + ArSO2Cl

RNHSO2Ar

R2NH + ArSO2Cl

R2NSO2Ar

NaOH

R N SO2Ar Na

DISCONNECTION :

ArSO2N(Na)R

RNH2 + ArSO2Cl

ArSO2NR2

R2NH + ArSO2Cl

NOTES :

A mixture of primary, secondary, and tertiary amines is shaken with benzenesulfonyl chlorides in the presence of dilute alkali under Schotten – Baumann conditions. Primary amines form alkali soluble sulfonamides; while tertiary amines do not react and can usually be separated by distillation. See also Schotten – Baumann reaction.

REFERENCES : Houben – Weyl : 2, 640

1) O. Hinsberg, Ber. Dtsch. Chem. Ges., 1890, 23, 2962.

815

2) R.S. Schreiber; R.L. Shriner, J. Am. Chem. Soc., 1934, 56, 114. 3) W. Seamen; A.R. Norton; J.T. Woods; H.N. Bank, J. Am. Chem. Soc., 1945, 67, 1571. 4) M. Wiechmann, Hoppe-Seylers Zeit. Physiol. Chem., 1977, 358, 967. 5) B. Pfundstein; A.R. Tricker; R. Preussmann, J. Chromatogr. A, 1991, 539, 141.

COMMENTS :

HINSBERG SULFONE SYNTHESIS EXAMPLE : O

OH

H3C O + HO2S

N

aq. EtOH

H O

O S O

CH3 N H

OH

O

MECHANISM :

O

H+ O

H3C O

O S

N

O

H

aq. EtOH OH

O H+ OH

OH

O S O

CH3 N H

816

O

O2 S H

CH3 N H

O

DISCONNECTION :

OH

O

O S R O

O

OH OH R1

O S R O

O R1

OH

O

NOTES :

Sulfinic acids condense with quinones to yield hydroquinone sulfones. See also Thiele reaction.

REFERENCES : Houben – Weyl : 7/3a, 661

1) O. Hinsberg, Ber. Dtsch. Chem. Ges., 1894, 27, 3259. 2) J. Walker, J. Chem. Soc., 1945, 630. 3) R.M. Scribner, J. Org. Chem., 1966, 31, 3671. 4) Y. Ooata; Y. Sawaki; M. Isono, Tetrahedron, 1970, 26, 731. 5) H. Maruyama; T. Hiraoka, J. Org. Chem., 1986, 51, 399. 6) M.P. Lockshin; M.P. Filosa; M.J. Zuraw; P.R. Carlier, J. Org. Chem., 1996, 61, 2556.

COMMENTS :

817

HINSBERG THIOPHENE SYNTHESIS EXAMPLE :

Ph

EtO

+ O

Ph

Ph

Ph O

OEt

S

t

O

OEt

EtO

BuOK t BuOH 60 oC

O

S

O

O

MECHANISM :

O EtO2C

S

CO2Et

EtO2C

t

BuOK t BuOH

S

CO2Et

Ph

Ph O

CO2Et Ph

O

EtO

S

O O

Ph

CO2Et

O

O

O O Ph

S

Ph H Ph

CO2Et

O Ph

Ph

O

Ph H

CO2Et

Ph

Ph

base EtO2C

- OEt

S

S

COOK

- H2O

EtO2C

S

COOK

DISCONNECTION :

R2

R3 OR4

R1O S O

O

R2

R3 +

O

O

R1O

OR4

S O

O

NOTES :

Two aldol condensations between a 1,2-dicarbonyl compound and a thiodiester give thiophenes. The intermediate product is an ester-acid produced by a Stobbe-type condensation. See also Baumann – Fromm, Bogert – Herrera, Fiesselmann, Harries pyrrole, Larock fluorene-2, Larock indole, Stobbe, Volhard – Erdmann and Willgerodt – Kindler reactions.

REFERENCES : Science of Synthesis : 10, 190

818

1) O. Hinsberg, Chem. Ber., 1910, 42, 901. 2) H. Wynberg; H.J. Kooreman, J. Am. Chem. Soc., 1965, 87, 1739. 3) A. Birch; D.A. Crombie, Chem. Ind. (London), 1971, 177. 4) D.J. Chadwick; J. Chambers; G.D. Meakins; R.L. Snowden, J. Chem. Soc., Perkin Trans. 1, 1972, 2079. 5) O. Meth–Cohn; H. Jiang, J. Chem. Soc., Perkin Trans.1, 1998, 3737.

COMMENTS :

HIYAMA AMINOACRYLATE SYNTHESIS EXAMPLE : H

OtBu

OtBu

H3C

H3C CN + H3C

i

2 ( Pr)2NH EtMgBr

O

NH2 O

MECHANISM :

Mg H

R1

O

R1 H

t

O Bu

2 (iPr)2NH EtMgBr

H

R

O

O t

O Bu

t

BuO

R1

R1

H R C N

O +

H

DISCONNECTION : R R1

H2N O

OR2

R CN R = H, CH3 R2 = tBu, Et

819

+

R1CH2

OR2 O

NH2 OtBu

NOTES :

The synthesis of 3-aminoacrylic acids (Z-configuration) or derivatives from nitriles by aldol type condensation using magnesium enolates.

REFERENCES :

1) T. Hiyama; K. Kobayashi, Tetrahedron Lett., 1982, 23, 1597. 2) K. Kobayashi; T. Hiyama, Tetrahedron Lett., 1983, 24, 3509. 3) T. Hiyama; K. Kobayashi; K. Nishide, Bull. Chem. Soc. Jpn., 1987, 60, 2127. 4) T. Hiyama; H. Oishi; Y. Suetsugu; K. Nishide; H. Saimoto, Bull. Chem. Soc. Jpn., 1987, 60, 2139.

COMMENTS :

HIYAMA COUPLING EXAMPLE :

S

F Si F Et

S

I

MeO2C MeO2C

S

allyl-PdCl2 DMF, KF, 100 oC

820

S

MECHANISM :

H [Si] Ar X Pd L2

H

Ph

Ar

Ph

Ar X Pd L2

H

H

Ph H

PdL2

RX

[Si] H

H Ar

R1

R3

R2

R

Ph

R1

R3

[Si]

R2

L Pd R L

H PdLX

R PdL2 X

-L - [SiX]

H

Ph [Si] H Ar Pd X L

R1 R2 R1 = R2 = H R3 = Ph R = Ar

R3

R2

[Si]

L

R3 [Si]

R Pd X L

R1

R3

R2

[Si]

R Pd X L

DISCONNECTION :

R1 R2

R1

R1 SiX3

+

R1 = alkynyl, alkenyl, aryl, alkyl, silyl R2 = alkenyl, aryl, allyl Y = Cl, Br, I, OSO2CF3, OCO2Et X = CH3, (CH3)2F, CH3F2, F3

821

R2 Y

NOTES :

In the presence of a palladium complex, a fluoride ion attacks the silicon atom and does not deactivate the catalyst. The formed anionic species is a penta-coordinated silicate, that transmetallates via a 4-centered transition state in which it becomes hexa-coordinated. The fluorine atom can be replaced by a hydroxyl, alkoxy or other heteroatom. The stereochemical transmetallation in THF at low temperatures proceeds with retention of the configuration while at higher temperatures or in polar solvents inversion dominates. An activator (KF, TBAF, TASF, NaOH) for this reaction is necessary. The Hiyama coupling has better tolerances of functional groups in comparison to other strong nucleophilic organometallic reagents. This reaction has been expanded by the DeShong group to work with hypervalent siloxanes. See also Yamamoto allylation.

REFERENCES :

1) Y. Hatanaka; T. Hiyama, J. Org. Chem., 1988, 53, 918. 2) Y. Hatanaka; S. Kukushima; T. Hiyama, Heterocycles, 1990, 30, 303. 3) T. Hiyama; Y. Hatanaka, Pure Appl. Chem., 1994, 66, 1471. 4) Y. Hatanaka; K. Goda; T. Hiyama, Tetrahedron Lett., 1994, 35, 1279. 5) K. Hirabayashi; J. Kawashima; Y. Nishihara; A. Mori; T. Hiyama, Org. Lett.,1999, 1, 299. 6) S.E. Denmark; Z. Wu, Org. Lett.,1999, 1, 1495. 7) K. Itami; T. Nokami; Y. Ishimura; K. Mitsudo; T. Kamei; J. Yoshida, J. Am. Chem. Soc., 2001, 123, 11577. 8) M.E. Hoke; M.-R. Brescia; S. Bogaczyk; P. DeShong; B.W. King; M.T. Crimmins, J. Org. Chem., 2002, 67, 327.

COMMENTS :

HO DEHALOGENATION EXAMPLE :

O

O Br 1) Ce2(SO4)2, NaI 2) H2O

822

MECHANISM :

O

O Br

R R1

CeI3 O

Br

R Ce2(SO4)2, NaI

I Ce

R

R1

O

I H2O

R1

R R1

DISCONNECTION :

O

O

Br

R

R

R1

R1

NOTES :

This reaction is the dehalogenation of α-halo ketones with an aqueous mixture of cerium(III) sulphate and sodium iodide to produce cerium iodide intermediate to afford ketones.

REFERENCES :

1) T.-L. Ho, J. Chem. Educ., 1978, 55, 355. 2) T.-L. Ho, Synth. Commun., 1979, 9, 241. 3) J.R. Long, Aldrichimica Acta, 1985, 18, 87.

COMMENTS :

HOCH – CAMPBELL AMINO ALCOHOL SYNTHESIS EXAMPLE :

Ph CH3

N OH + 5

MgBr

H3C

823

Ph 1) neat, HCl, 140 oC 2) aq. HCl

OH NH2

MECHANISM :

BrMg O N OH

N MgBr

+

Ph H3C

CH3

PhMgBr

BrMg N

O

N

N Ph Ph

CH3

CH3

Ph 1) PhMgBr 2) H+

Ph

CH3

H N

H2O

H

Ph CH3

Ph

H+

H

OH NH2

N

Ph CH3

Ph

Ph

CH3

DISCONNECTION :

H N

R2 R1

N

OH + R1MgX

R2

R

R

NOTES :

Ethylenimines are obtained by the interaction of ketoximes and Grignard compounds, followed by controlled hydrolysis of the complex formed to give an amino alcohol. See also Blum aziridine, Hassner azide aziridine, Gabriel – Marckwald – Cromwell, Mansuy – Evans, Neber rearrangement, Scheiner and Wenker ring-closure reactions.

REFERENCES :

1) J. Hoch, C.R. Séances Acad. Sci., 1934, 198, 1865. 2) K.N. Campbell; J.F. McKenna, J. Org. Chem., 1939, 4, 198. 3) H.R. Henze; W.D. Compton, J. Org. Chem., 1957, 22, 1036. 4) K. Kotera; K. Kitahonoki, Org. Prep. Proced. Int., 1969, 1, 305. 5) A. Laurent; A. Muller, Tetrahedron Lett., 1969, 10, 759. 6) J.P. Freeman, Chem. Rev., 1973, 73, 283. 7) N. de Kimpe; R. Verhe; L. de Buyck; N. Schamp, J. Org. Chem., 1980, 45, 5319. 8) K. Quinze; A. Laurent; P. Mison, J. Fluorine Chem., 1989, 44, 211.

824

COMMENTS :

HOCK – LANG OXIDATION EXAMPLE :

H3C

CH3

OH O +

O2

H3C

CH3

MECHANISM :

H3C

O

CH3

H3C

O

O

H CH3

H3C

H O

O

H CH3

H3C

H+ - H2O

O2 H O

CH3 H3C

CH3

O

CH3

H3C

O

OH +

H2O, - H+

H3C

CH3 O

DISCONNECTION :

H3C

OH H3C

CH3

CH3

+ O

NOTES :

This reaction involves the autoxidation of certain aromatic hydrocarbons to give hydro-peroxides, e.g. isopropylbenzene yields a peroxide which decomposes with acid to phenol and acetone. Since 1990, a new process

825

utilising the oxidation of toluene (via benzoic acid) has gradually replaced the Hock – Lang process. See also Friedel – Crafts reaction.

REFERENCES : Houben – Weyl : 4/2, 352; 7/2a, 712; E19c, 407, 429

1) H. Hock; S. Lang, Ber. Dtsch. Chem. Ges., 1944, 77, 257. 2) F.H. Seubold, jr.; W.E. Vaughan, J. Am. Chem. Soc., 1953, 75, 3790. 3) H. Hock; H. Kropf, Chem. Ber., 1955, 88, 1544. 4) H. Hock; F. Ernst, Chem. Ber., 1959, 92, 2716.

COMMENTS :

HODGES – VEDEJS REACTION EXAMPLE :

Ph

Ph

O

O

OH

N

Ph

H 1) BH3.THF 2) LiTMP, - 78 oC 3) PhCHO

N

MECHANISM :

Ph

Ph

O H N

1) PhCHO 2) 5% CH3COOH EtOH

H

BH3.THF

Ph

Ph

O N BH3

O

OH

N

Ph

826

LiTMP, - 78 oC

O Li N BH3

O Li+

R

O

O

N

Li N

LDA

OLi

N OLi

R

O

OLi

R

N

N

OH

O

Li

Li

Li

N

H+

O

O

OLi N

Li

B

H

R

R

H

DISCONNECTION :

R1

R1

X

X H

R N

X = O, S

N

NOTES :

The metallation of oxazoles and thiazoles using borane THF complex and lithium 2,2,6,6-tetramethylpiperidine. This borane complex prevents the ring-opening process. The lithium derivative can be trapped with electrophiles. The intermediate borane complex can be isolated. See also Dondoni reaction.

REFERENCES :

1) J.C. Hodges; W.C. Pratt; C.J. Connolly, J. Org. Chem., 1991, 56, 449. 2) S.E. Whitney; B. Rickborn, J. Org. Chem., 1991, 56, 3058. 3) E. Vedejs; S.D. Monahan, J. Org. Chem., 1996, 61, 5192. 4) E. Vedejs; L.M. Luchetta, J. Org. Chem., 1999, 64, 1011.

COMMENTS :

827

HOEHN – MASON DEGRADATION EXAMPLE :

Ph

H3C

COOH Ph

O

HO

O 1) O3 2) PhCHO, NaOEt HO 3) O3 4) HIO4

H

H

MECHANISM :

H3C

Ph

H3C

Ph

O

O

O

O3 HO

HO

H

PhCHO NaOEt

H

Ph H

O H

O

O

O

O

HIO4

O3 HO

H

HO HO

H

O

O

HO

H

DISCONNECTION :

H3C

COOH O

HO

O

HO

H

828

H

Ph Ph

NOTES :

An improvement in the Barbier – Locquin – Wieland degradation in which the elimination of carbons 21 and 22 of the steroid side chain is effected. See also Barbier – Locquin – Wieland degradation, Gallagher – Hollander, Miescher degradation, Trost oxidative decarboxylation and Wieland – Dane degradation reactions.

REFERENCES :

1) W.M. Hoehn; H.L. Mason, J. Am. Chem. Soc., 1938, 60, 1493. 2) R.B. Turner; V.R. Mattox; W.F. McGuckin; E.C. Kendall, J. Am. Chem. Soc., 1952, 74, 5814. 3) V.R. Mattox; R.B. Turner; W.F. McGuckin; E.J.H. Chu; E.C. Kendall, J. Am. Chem. Soc., 1952, 74, 5818.

COMMENTS :

HOESCH – HOUBEN SYNTHESIS EXAMPLE :

CH3 OH

OH O OH

1) CH3CN, HCl, ZnCl2 2) H2O, heat

OH

MECHANISM :

OH RCH2CN +

HCl

N

R

H

+

Cl CH3 OH

HO HCl.HN OH H3C

OH

O H2O, heat

OH

829

DISCONNECTION :

O Ar

ArH + RCN

R

O

+ RCN

N

N

R

NOTES :

This synthesis of phenolic ketones involves the condensation in diethyl ether of phenols or their ethers with nitriles. Pyrroles can be used instead of phenols. The reaction is carried out in the presence of anhydrous zinc chloride or aluminium chloride and hydrogen chloride. The resulting ketimine is hydrolysed. In the abnormal Hoesch reaction an α,β-unsaturated nitrile reacts with a phenol. The phenol adds on to the olefinic double bond. The Fischer – Nouri modification involves the Hoesch – Houben condensation of β-(4-acetoxyphenyl)-propionitrile with phloroglucinol. See also Fischer – Zerweck, Friedel – Crafts, Gattermann – Ehrhárdt, Houben – Fischer, Karrer and Nencki reactions.

REFERENCES : March : 552 Smith – March : 723 Houben – Weyl : E5, 819; E6a, 977; E6b, 73; E19c, 366 Org. React. : 5, 387 Org. Synth. : 15, 70 Org. Synth. Coll. Vol. : 2, 522

1) S. Minovici, Ber. Dtsch. Chem. Ges., 1899, 32, 2206. 2) J. Houben; E. Schmidt, Ber. Dtsch. Chem. Ges., 1913, 46, 2447. 3) K. Hoesch, Ber. Dtsch. Chem. Ges., 1915, 48, 1122. 4) E. Fischer; O. Nouri, Ber. Dtsch. Chem. Ges., 1917, 50, 611. 5) R. Roger; D.G. Nelson, Chem. Rev., 1961, 61, 179. 6) G. Casnati; G. Satori; R. Maggi; F. Bigi, Gazz. Chim. Ital., 1992, 122, 283. 7) Y. Sato; M. Yato; T. Ohwada; S. Saito; K. Shudo, J. Am. Chem. Soc., 1995, 117, 3037. 8) S. Repichet; C. Le Roux; J. Dubac; J.R. Desmurs, Eur. J. Org. Chem., 1998, 2743. 9) D. Basavaiah; T. Satyanarayana, Chem. Commun., 2004, 32.

COMMENTS :

830

HOFER – MOEST REACTION EXAMPLE :

CH3CH2COOH + H2O2

CH3CH2OH

MECHANISM :

2

H2O2 + 2 e-

OH

CH3COOH + H2O2

CH3COOOH + H2O CH3OH + CO2

CH3COOOH

DISCONNECTION :

ROH

RCOOH

NOTES :

This reaction relates to the electrolysis of aqueous solution of a salt of an aliphatic acid to yield an alcohol, e.g., in the electrolysis of an aqueous solution of acetic acid a high efficiency of ethane formation is observed, but if an inorganic acid or potassium salt of an inorganic acid is added, the efficiency is greatly decreased and methyl alcohol is formed instead of ethane. See also Crum Brown – Walker and Kolbe reactions.

REFERENCES : Houben – Weyl : 8, 501

1) H. Kolbe, Liebigs Ann. Chem., 1849, 69, 257. 2) H. Hofer; M. Moest, Liebigs Ann. Chem., 1902, 323, 284. 3) B.C.L. Weedon, J. Chem. Soc., Quat. Rev., 1952, 6, 380. 4) R. Brettle; M.A. Khan, J. Chem. Res., 1989, 15. 5) C. Gerber; D. Seebach, Helv. Chim. Acta, 1991, 74, 1373. 6) M.O.F. Goulart; H.-Y. Schäfer, J. Braz. Chem. Soc., 1999, 10, 153.

831

COMMENTS :

HOFMANN – LÖFFLER – FREYTAG REACTION EXAMPLE :

Cl

CH3 N CH3

H3C N

95% H2SO4 140 oC

H3C

MECHANISM :

X

R1

X R N H

N R

R

R

H+

R1 H R N X

H N R1

+ X

R1

H R N H

H R1

H N

H R N H

R1

R N

H

H

-

HO

R1

R N H

R1 - HX

X

X

DISCONNECTION :

R N

R1

R1

n n

n = 1 or 2

832

X N R

R1

NOTES : N-Haloamines in which one alkyl group has a hydrogen in the 4- or 5-position are heated with sulfuric acid.

Pyrrolidines and piperidines are formed by a free-radical mechanism. N-Haloamides will give γ-lactones. See also Miller – Plöchl reaction.

REFERENCES : March : 1153 Smith – March : 909, 1462 Smith : 1430 Smith 2nd : 1180 Houben – Weyl : E16a, 856; E16d, 649, 655; E19a, 8, 70, 305

1) A.W. Hofmann, Ber. Dtsch. Chem. Ges., 1883, 16, 558. 2) K. Löffler; C. Freytag, Ber. Dtsch. Chem. Ges., 1909, 42, 3427. 3) M.E. Wolff, Chem. Rev., 1963, 63, 55. 4) S.L. Titouani; J.-P. Lavergne; Ph. Viallefont, Tetrahedron, 1980, 36, 2961. 5) P. de Armas; C.G. Francisco, Tetrahedron Lett., 1986, 27, 3195. 6) H. Togo; Y. Hoshina; M. Yokoyama, J. Synth. Org. Chem. Jpn., 1997, 55, 90. 7) H. Togo; Y. Hoshina; M. Yokoyama, Synlett, 2001, 565.

COMMENTS :

HOFMANN – MARTIUS REARRANGEMENT (REILLY – HICKINBOTTOM) EXAMPLE :

NH2

NH2 Et

Et N H

+

HCl, 250 - 300 oC Et

833

MECHANISM :

H Cl H N Et

NH2 + CH3CH2Cl

CH3CH2+ + Cl-

CH3CH2Cl

NH3+

NH2

+ C2H4

+ CH3CH2+

NH2

NH2 + CH3CH2+

+ H+

NH3+

NH2 + H+

DISCONNECTION :

H

NH2

N

R

R

NOTES :

The hydrohalide of N-alkylaniline rearranges intermolecularly on heating to give amino-alkylbenzenes. When Nalkylanilines are heated with certain metal halides, e.g. cobaltous and zinc chlorides, the Reilly – Hickinbottom rearrangement occurs with migration of the alkyl group into the ring. See also Claisen rearrangement, Fischer – Hepp rearrangement, Fries rearrangement, Ladenburg rearrangement and Orton rearrangement.

REFERENCES : March : 560 Smith – March : 729

834

1) A.W. Hofmann; C.A. Martius, Ber. Dtsch. Chem. Ges., 1871, 4, 742. 2) E.D. Hughes; C.K. Ingold, J. Chem. Soc., Quat. Rev., 1952, 6, 45. 3) H. Möhrle; D. Schake, Arch. Pharm. (Weinheim, Ger.), 1992, 325, 695. 4) M.G. Sikos; N.I. Tzerpos; A.K. Zarkadis, Bull. Soc. Chim. Belg., 1996, 105, 759.

COMMENTS :

HOFMANN – SAND OXYMERCURATION EXAMPLE :

H3C

H

H3C

H

H3C HgCl H3C H HO H

1) HgCl2 2) H2O

MECHANISM :

HgX2 H3C

H O R

HgX + X CH3

H3C + HgX

H

H

H

R H3C O CH3 HH HgX H

CH3 HgX H

R - H+

O H

CH3 CH3 HgX H

DISCONNECTION : R Y H

CH3 HgX H

R

+ HgX2 + HY

Y = OH, OR1, OCOR2, NR3R4 X = Halogen, OAc

NOTES :

Olefins react with mercuric salts in aqueous solution to give addition compounds. See also Giese and Kutscheroff – Denigès reaction.

835

REFERENCES : Houben – Weyl : 13/2b, 130

1) G. Denigès, C.R. Séances Acad. Sci., 1898, 126, 1043. 2) K.A. Hofmann; J. Sand, Ber. Dtsch. Chem. Ges., 1900, 33, 1340. 3) J. Chatt, Chem. Rev., 1951, 48, 7. 4) W. Kitching, Organomet. Chem. Rev., 1968, 3, 35.

COMMENTS :

HOFMANN DEGRADATION EXAMPLE :

CH3

H H H3C

NH2 H H

1) xs CH3I 2) Ag2I, H2O 3) heat

H

H H

MECHANISM :

Ag2I + H2O H H3C H

AgOH

H

HO

H NH2

xs CH3I

H

H

H

H N(CH3)3

H3C I

H3C

H

H3C

H

+ N(CH3)3 + H2O

836

DISCONNECTION :

R

R R2

R2

R1

H

NH2 R1 R3

R3

NOTES : Hofmann elimination products are generally the least-substituted alkenes. Where Hofmann degradation does not

work, Emde degradation is often used. See also von Braun amide, Curtius, Emde and Menschutkin reactions.

REFERENCES : March : 1016 Smith – March : 1331 Smith : 163 Smith 2nd : 109, 135, 679 Houben – Weyl : 11/1, 963; E3, 527; E5, 554; E8c, 677 Org. React. : 11, 317; 18, 403 Org. Synth. : 55, 3 Org. Synth. Coll. Vol. : 6, 552

1) A.W. Hofmann, Liebigs Ann. Chem., 1851, 78, 253. 2) A.W. Hofmann, Ber. Dtsch. Chem. Ges., 1881, 14, 494. 3) G. Delodts; G. Dressaire; Y. Langlois, Synthesis, 1979, 510. 4) A.R. Katritzky; A.M.E. El–Mowafy, Chem. Commun., 1981, 96. 5) H. Schonnenschein; E. Schmitz, Synthesis, 1989, 443. 6) Y. Yamamoto; M.V. Sefton, J. Appl. Polym. Sci., 1996, 61, 351. 7) B.M. Novak; J.T. Cafmeyer, J. Am. Chem. Soc., 2001, 123, 11083.

COMMENTS :

837

HOFMANN ISONITRILE SYNTHESIS EXAMPLE :

N

NH2

C

CHCl3 NaOH

MECHANISM :

Cl CHCl3 + HO

CCl2

RNH2

Cl

H N R H

- 2 HCl

R N C

DISCONNECTION :

R NH2

R N C

NOTES :

The formation of isonitriles involves the reaction between chloroform and primary amines under alkaline conditions. Secondary amines hydrolyse with water to N,N-disubstituted formamides.

REFERENCES : March : 417 Smith – March : 506 Houben – Weyl : 2, 643 Org. Synth. : 55, 96 Org. Synth. Coll. Vol. : 6, 232

1) A.W. Hofmann, Liebigs Ann. Chem., 1868, 146, 107. 2) P.A.S. Smith; N.W. Kalenda, J. Org. Chem., 1958, 23, 1599. 3) W.P. Weber; G.W. Gokel, Tetrahedron Lett., 1972, 13, 1637. 4) M.P. Periasamy; H.M. Walborsky, Org. Prep. Proced. Int., 1979, 11, 293.

838

COMMENTS :

HOFMANN REARRANGEMENT EXAMPLE :

CH3 H3C

O

H2N

CH3 H3C

1) KOH, Cl2 2) H2O

NH2

MECHANISM :

R

O

O

O N H

H

OH

R

Br2

N Br

N Br

H R N

O R

OH

H

R N C O H2O

N Br

R

O CO2 + RNH2 O

H

DISCONNECTION :

O RNH2

R

NH2

NOTES :

An amide is converted with intermediate formation of an isocyanate into a primary amine with one less carbon atom by treatment with bromine and alkali or with a hypohalite solution. See also Curtius rearrangement, Lossen rearrangement, Schmidt rearrangement, Tiemann rearrangement and Weerman degradation reactions.

REFERENCES : March : 1090 Smith – March : 1380, 1384

839

Houben – Weyl : 11/1, 854; E8a, 273; E15, 3446; E16a, 888 Org. React. : 3, 267 Org. Synth. : 66, 132; 78, 234 Org. Synth. Coll. Vol. : 8, 132

1) A.W. Hofmann, Ber. Dtsch. Chem. Ges., 1881, 14, 2725. 2) A.O. Sy; J.A. Raksis, Tetrahedron Lett., 1980, 21, 2223. 3) C.J. Kowalski; K.W. Fields, J. Am. Chem. Soc., 1982, 104, 321. 4) M.S. Park; C.-U. Choi, Arch. Pharm. Res., 1993, 16, 152. 5) L.-H. Zhang; G.S. Kauffman; J.A. Pesti; J. Yin, J. Org. Chem., 1997, 62, 6918. 6) Y.H. Jung; J.D. Kim, Arch. Pharm. Res., 2001, 24, 371.

COMMENTS :

HOLLEMANN PINACOL SYNTHESIS EXAMPLE :

O

OH OH

2 Mg(Hg), TiCl4

MECHANISM :

R R

R

+

R1

Ti

II

R1

R

O

R1 TiIII O R1

R R

R O

R hydrolysis

R R

OH OH R

840

R R R

O R1 TiIV O R1

R R 2 R

R1 TiIII O R1

R R R

R R R

Ti O R

O TiIII(R1)2 R

R1

O

O TiIII(R1)2

IV

+

R1

Ti

II

R1

R R

R1

O TiIII + TiIII R1 R 1 O

R R

hydrolysis

OH OH

R R R

DISCONNECTION :

HO OH R R R R

O 2 R

R

NOTES :

The dimerisation of ketones to 1,2-diols using magnesium and other metals. It has been suggested that Ti(II) is the reactive species in these reductive coupling reactions. See also Fujiwara lanthanide, Fürstner indole and McMurry reactions.

REFERENCES : March : 1225 Smith – March : 1023, 1560 Houben – Weyl : E7b, 667

1) M.A.F. Hollemann, Recl. Trav. Chim. Pays-Bas, 1906, 25, 206. 2) E.J. Corey; R.L. Danheiser; S. Chandrasekaran, J. Org. Chem., 1976, 41, 260. 3) J.-M. Pons; J.-P. Zahra; M. Santelli, Tetrahedron Lett., 1981, 22, 3965. 4) A. Clerici; O. Porta, J. Org. Chem., 1985, 50, 76. 5) D.D. Graf; J.P. Campbell; L.L. Miller; K.R. Mann, J. Am. Chem. Soc., 1996, 118, 5480.

COMMENTS :

841

HONZL – RUDINGER PEPTIDE SYNTHESIS EXAMPLE :

H2N H N H H2N Ph O

H2N

H

Ph

1) NaNO2, HCl 2) iPr2NEt H COOH H2N Ph

H N

Ph

O H

COOH

MECHANISM :

H2N H N H

R1

R1

N3

R1

N

N H

H

NaNO2 HCl

O

R

H

R

i

O

H N

H

R

Pr2NEt

H N

O OR3

O R2 H

H H2N

COOR3 R2

DISCONNECTION :

H R1

H

R2 N

N H

H R

O

O

OR3

H

R

H N R1 O

H N

NH2

+

R2 O

NH2 H OR3

NOTES :

In this peptide synthesis acyl azides couple with amino esters. The preparation of the azide has to be done at low temperature, in homogenous solution, at high acidity, and with an organic nitrate or nitrosyl chloride to give the best results. In the Medzihradsky method the hydrazide is converted to the azide in DMF, with aqueous hydrochloric acid and sodium nitrite. See also Bergmann, Fischer peptide synthesis, Leuchs – Bergmann and Sheehan – Frank reactions.

REFERENCES :

1) I. Honzl; I. Rudinger, Coll. Czech. Chem. Commun., 1961, 26, 2333. 2) K. Medzihradsky; V. Bruckner; M. Kajtár; L. Kisfaludy; S. Bajusz; M. Löw, Acta Chim. Acad. Sci. Hung., 1962, 30, 105. 3) M. Zaoral; F. Šorm, Coll. Czech. Chem. Commun., 1965, 30, 1853.

842

4) M.A. Ondetti; V.L. Narayanan; M. von Saltza; J.T. Sheehan; E.F. Sabo; M. Bodanszky, J. Am. Chem. Soc., 1968, 90, 4711.

5) Y.S. Klausner; M. Bodanszky, Synthesis, 1974, 549. 6) I.Y. Hirata; P. Boschcov; M.C.F. Oliveira; M.A. Juliano; A. Miranda; J.R. Chagas; S. Tsuboi; Y. Okada; L. Juliano, Int. J. Pept. and Prot. Res., 1991, 38, 298.

COMMENTS :

HOOGEWERFF – VAN DORP SYNTHESIS EXAMPLE :

O CO2Na N H O

1) aq. NaOH 2) Br2, KOH

NH2

MECHANISM :

O CO2Na

CO2Na N H

NH2

aq. NaOH O

Br2, KOH

NH2

O

DISCONNECTION :

O CO2Na N H NH2 O

NOTES :

Phthalimide is hydrolysed to o-amidobenzoic acid which is submitted to a Hofmann rearrangement. See also Hofmann rearrangement.

843

REFERENCES : Org. Synth. : 16, 1 Org. Synth. Coll. Vol. : 2, 19

S. Hoogewerff; W.A. van Dorp, Recl. Trav. Chim. Pays-Bas, 1891, 10, 5.

COMMENTS :

HOOKER REACTION EXAMPLE : O

O

OH OH O

alkaline KMnO4

844

O

MECHANISM :

O

O CH2R KMnO4

OH

O

O RH2C

CH2R O O Mn O O OH

O

- MnO2 O

RH2C

OH

OH O COOH

OH COOH R O

O

O

1) oxidation 2) base

H O

O O

O COOH HO

O H+

OH

R COOH

O

HO

R COOH

O OH

KMnO4 - CO2

CH2R OH O H OH

OH

R

R

O O Mn O HO OH

O

DISCONNECTION : O

O

R

OH R1

R OH

R1 O

O

NOTES :

Alkaline potassium permanganate oxidation of certain hydroxynapthaquinone derivatives (Lapachol) eliminates –CH2adjoining the quinone ring with the simultaneous interchange of the alkyl and hydroxyl groups. The quinone ring seems to open and to close in a different manner.

REFERENCES :

1) S.C. Hooker, J. Am. Chem. Soc., 1936, 58, 1168. 2) S.C. Hooker, J. Am. Chem. Soc., 1936, 58, 1174. 3) S.C. Hooker; A. Steyermark, J. Am. Chem. Soc., 1936, 58, 1179. 4) L.F. Fieser; M. Fieser, J. Am. Chem. Soc., 1948, 70, 3215.

845

5) M.M. Shemyakin; L.A. Shchukina, J. Chem. Soc., Quat. Rev., 1956, 10, 276. 6) L.F. Fieser; D.H. Sachs, J. Am. Chem. Soc., 1968, 90, 4129. 7) K. Lee; P. Turnbell; H.W. Moore, J. Org. Chem., 1995, 60, 461.

COMMENTS :

HOPPE HOMOALDOL REACTION EXAMPLE :

O

OH

O N

+ 2

O 1.2 nBuLi, 1.2 (-)-sparteine 3 Ti(OiPr)4

CH3 O

N O

MECHANISM :

N H O H3C

O N

Ti(OiPr)4

H3C

H3C

n

N Li

BuLi, (-)-sparteine pentane, cyclohexane Ti(OiPr)3 O O N

O

O N

HO

O O

1) RCHO 2) H+

846

CH3

N

DISCONNECTION :

HO

Rs O

Rl CH3 Rs

O N

O

OH O

Rl CH3

O + RlRsC=O

N

O N

NOTES :

Enantioselective homoaldolisation process Lewis acid catalysed with high e.e.’s and yields induced by (-)-sparteine.

REFERENCES :

1) D. Hoppe; O. Zschage, Angew. Chem., Int. Ed. Engl., 1989, 28, 67. 2) H. Paulsen; D. Hoppe, Tetrahedron, 1992, 48, 5657. 3) H. Paulsen; C. Graeve; D. Hoppe, Synthesis, 1996, 62, 141. 4) D. Hoppe; T. Hense, Angew. Chem., Int. Ed. Engl., 1997, 36, 2282. 5) K.R.K. Prasad; D. Hoppe, Synlett, 2000, 1067. 6) P. Razon; S. Dhulut; S. Bezzenine-Lafollée; J. Courtieu; A. Pancrazi; J. Ardisson, Synthesis, 2005, 102.

COMMENTS :

HORBACZEWSKI SYNTHESIS EXAMPLE :

2

H2N

NH2 O

H +

NH2

H

Cl3C OH O

O

847

O

H N

N H

N H

N

O

MECHANISM :

O

NH2

H2N

OH

H Cl

NH2

O

H2N

O

H2N

O

Cl

- 2 HCl

H2N

Cl

O

OH

H

H2N

N

Cl

H

NH2

N

O

H

H+ H2N H2N O

H N H

O H N

H

O

H N

N H

N H

N

O

O N Cl H

O

DISCONNECTION :

H O H

N

O

H2N

H N N H

H2N

+

NH2

Cl3C OH O

O

O N H

NH2

NH2

+ NH2CH2COOH

O

NOTES :

The condensation of glycine or trichlorolactamide with urea yields uric acid. See also Behrend – Roosen, Fischer – Ach and Traube reactions.

REFERENCES :

1) J. Horbaczewski, Monatsh. Chem., 1882, 3, 796. 2) R. Behrend, Liebigs Ann. Chem., 1925, 441, 215.

COMMENTS :

848

HOREAU – ORMANCEY SYNTHESIS EXAMPLE :

O CN H 1) Zn, Br

CH3 CO2Et CH3

2) Raney Ni, H2 3) heat

MECHANISM :

O CN

CO2Et CH3

Zn, CH3 Br CO2Et CH3

OH

CH3 Raney Ni, H2

CH3

CO2Et CH3

O H heat

DISCONNECTION :

O R

CN

H R

NOTES :

The interaction of an aromatic nitrile with ethyl 2-bromoisobutyrate (Blaise ketoester) in the presence of zinc gives the corresponding β-ketoester. This ester is reduced to the hydroxy-ester, which on heating yields the aldehyde. See also Blaise ketoester and Reformatsky reactions.

REFERENCES :

A. Horeau; A. Ormancey, C.R. Séances Acad. Sci., 1953, 236, 826.

849

COMMENTS :

HORENSTEIN – PÄHLICKE ESTERFICATION EXAMPLE :

COOH HO

OH

O

NEt2.HCl

+ Et2NCH2CH2Cl

H

O

MECHANISM :

O RCOOH + Et2NCH2CH2Cl

R

O

Et N Et

Cl

R

O

NEt2.HCl

O

DISCONNECTION :

R

O

N(R1)2.HCl

RCOOH + (R1)2NCH2CH2Cl

O

NOTES :

This method involves the treatment of acid with a β-dialkylaminoalkyl halide. The resulting salt readily isomerises to the ester.

REFERENCES :

1) H. Horenstein; H. Pählicke, Ber. Dtsch. Chem. Ges., 1938, 71, 1644. 2) F.F. Blicke; C. Otsuki, J. Am. Chem. Soc., 1941, 63, 1945. 3) L. Ružička; P.A. Plattner; B.G. Engel, Helv. Chim. Acta, 1944, 27, 1553. 4) F.F. Blicke; R.H. Cox, J. Am. Chem. Soc., 1955, 77, 5401.

850

5) F.F. Blicke; H. Zinnes, J. Am. Chem. Soc., 1955, 77, 6247. 6) Y.-H. Wu; R.F. Feldkamp; J.R. Corrigan; H.J. Rhodes, J. Org. Chem., 1961, 26, 1524. 7) M.C. Lu; W.E. Wung; L.B. Shih; S. Callejas; J.E. Gearien; E.B. Thompson, J. Med. Chem., 1987, 30, 273.

COMMENTS :

HORNER – KNOWLES – KAGAN ASYMMETRIC HYDROGENATION EXAMPLE :

OCH3

OCH3 Ph

Ph

O H

N

Ac

Rh(COD)2BF4 H2,

O H

O CH3 P N CH3 O

851

N

Ac

MECHANISM :

L

L

L Cl

L

Cl Rh

L

L

- H2

L

H H Rh

Cl

L L

L

L

H2

Rh

Rh Cl

L

L

L

S

L

H2

L

Cl

L

H H

Cl

- H2

S

L

Cl Rh

L

H

H

H

Rh

Rh Cl

H

L Cl

L H

H

S

L

O

PPh2

O

PPh2

852

=

P

P

H H Rh

L

H2

L

L

Rh

Rh

Rh Cl

-L

Cl

L

RO O CH3 Ph

HN

P

P

P Ph

P

O

I

Rh

RhI

O S

S

N H3C

N H

H

* COOR

H2

P

P

III

Ph

Rh O S

COOR H

CH2Ph

Ac

P

H

H H P COOR Rh

H COOR

O

NH

Ph

H3C

NH

CH3

DISCONNECTION :

R H R1

R2 H R3

R

R2

R1

R3

NOTES :

The enantioselective hydrogenation of prochiral olefins with chiral rhodium catalysts and ligands like DIPAMP (Knowles), Chiraphos (Bosnich), Duphos (Burk), DIOP (Kagan), Josiphos (Togni, Spindler), Norphos (Blaser, Spindler), BINAP (Noyori) BICP (Zhang), and Ferrophos (Kang). In the early years chiral Wilkinson type catalysts

were used and monodentate phosphines as ligands (DIOP). In later years bidentate ligands are used affording highly enantioselective hydrogenations.

REFERENCES : Houben – Weyl : 4/1c, 60; E21, 4334

1) L. Horner; H. Siegel; H. Buthe, Angew. Chem., Int. Ed. Engl., 1968, 7, 941. 2) W.S. Knowles; M.J. Sabacky, J. Chem. Soc., Chem. Commun., 1968, 1445. 3) H.B. Kagan; T.-P. Dang, J. Am. Chem. Soc., 1972, 94, 6429.

853

4) H.B. Kagan, Pure Appl. Chem., 1975, 43, 401. 5) J. Halpern; T. Okamoto; A. Zakhariev, J. Mol. Catal., 1976, 2, 65. 6) B.D. Vineyard; W.S. Knowles; M.J. Sabacky; G.L. Bachmann; D.J. Weinkauff, J. Am. Chem. Soc., 1977, 99, 5946. 7) M.J. Burk, J. Am. Chem. Soc., 1991, 113, 8518. 8) J. Kang; J.H. Lee; S.H. Ahn; J.S. Choi, Tetrahedron Lett., 1998, 39, 5523. 9) M. van den Berg; A.J. Minnaard; E.P. Schudde; J. van Esch; A.H.M. de Vries; J.G. de Vries; B.L. Feringa, J. Am. Chem. Soc., 2000, 122, 11539.

10) M. van den Berg; R.M. Haak; A.J. Minnaard; A.H.M. de Vries; J.G. de Vries; B.L. Feringa, Adv. Synth. Catal., 2002, 344, 1003. 11) D. Peña; A.J. Minnaard; J.G. de Vries; B.L. Feringa, J. Am. Chem. Soc., 2002, 124, 14552. 12) W.S. Knowles, Adv. Synth. Catal., 2003, 345, 3. 13) M. Diéguez; O. Pàmies; C. Claver, Chem. Rev., 2004, 104, 3189.

COMMENTS :

HORNER – WADSWORTH – EMMONS REACTION EXAMPLE :

EtO EtO

O P

Ph Ph

NaH, PhCHO 60 oC

Ph

MECHANISM :

R3

O H P R1 R4 R2

R1 R2 P O R3 O R4

CH3 CH3

B R3

R3

H3C O P R1 H3C R4 R2 O P O R4

854

O

R2

CH3

R1

CH3

+

DISCONNECTION :

O R

R

X R

+

R1

R2

R1

R R2

X

X = P(O)R3R4 R

O R

+

R1

R2

NOTES :

This procedure is useful for the transfer of electron-withdrawing groups to the alkene. The asymmetric version has been reported by Shioiri et al. An unusual alternative to this reaction using a diazoacetate and a rhenium catalyst has been reported by Ledford and Carreira. Lithium chloride and an amine can be used for base-sensitive compounds. In the Ando modification ethyl(diarylphosphono)acetates are used. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Hunsdiecker ring-

closure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Raphael, Roush, Ružička large ring synthesis, Schmidt

macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 959 Smith – March : 1233 Smith : 792 Smith 2nd : 665 Houben – Weyl : E3, 647; E7b, 156; E8a, 1001; E15, 644, 2632 Org. Synth. : 45, 44; 78, 177 Org. Synth. Coll. Vol. : 5, 547 Science of Synthesis : 9, 306; 10, 338

1) L. Horner; H. Hoffmann; H.G. Wippel, Chem. Ber., 1958, 91, 61. 2) L. Horner; H. Hoffmann; H.G. Wippel; G. Klahre, Chem. Ber., 1959, 92, 2499. 3) J. Boutagy; R. Thomas, Chem. Rev., 1974, 74, 87. 4) M.A. Blanchette; W. Choy; J.T. Davis; A.P. Essenfeld; S. Masamune; W.R. Roush; T. Sakai, Tetrahedron Lett., 1984, 25, 2183. 5) B.E. Maryanoff; A.B. Reitz, Chem. Rev., 1989, 89, 863. 6) N.A. Meanwell; H.R. Roth; E.C.R. Smith; D.L. Wedding; J.J.K. Wright, J. Org. Chem., 1991, 56, 6897. 7) E. Vedejs; M.J. Peterson, Top. Stereochem., 1994, 21, 1.

855

8) B.E. Ledford; E.M. Carreira, Tetrahedron Lett., 1997, 38, 8125. 9) S. Arai; S. Hamaguchi; T. Shioiri, Tetrahedron Lett., 1998, 39, 2997. 10) K. Ando, J. Org. Chem., 1999, 64, 6815. 11) K. Ando; T. Oishi; M. Hirama; H. Ohno; T. Ibuka, J. Org. Chem., 2000, 65, 4745. 12) A. Lattanzi; L.R. Orelli; P. Barone; A. Massa; P. Iannece; A. Scettri, Tetrahedron Lett., 2003, 44, 1333.

COMMENTS :

HORNING REACTION EXAMPLE :

O

O

O

O

O

O

Pd/C heat

O

OH

O

O

OH

O

DISCONNECTION :

R

R1

R1

R O

OH

NOTES :

The thermolysis of a dibenzylidenephenol to a dibenzylphenol in the presence of a palladium catalyst. The reaction is nowadays used to make crown macrocyles.

REFERENCES :

1) E.C. Horning, Chem. Rev., 1943, 33, 89. 2) E.C. Horning, J. Org. Chem., 1945, 10, 263. 3) J.-M. Conia; P. Amice, Bull. Soc. Chim. Fr., 1968, 8, 3327.

856

4) Z. Aizenshtat; M. Hausmann; Y. Pickholtz; D. Tal; J. Blum, J. Org. Chem., 1977, 42, 2386. 5) L.T. Higham; U.P. Kreher; C.L. Raston; J.L. Scott; C.R. Strauss, Org. Lett., 2004, 6, 3261.

COMMENTS :

HOSOMI – MIYAURA BORYLATION EXAMPLE :

O OAc O Ph

Ph OCH3

H

OCH3 H

O

O B B

O

O

CuCl, LiCl KOAc, DMF

857

B O

O

MECHANISM : Miyaura :

CuCl + KOAc

Cu.KCl O Cl

Cu OAc

K

O B B

O

O

O

OAc

O

B B O

O

O

O B OAc

+

CuOAc + KCl

B Cu.KCl

O

O

CO2R O B O

DISCONNECTION :

RB EWG

EWG

R1

R1

R1

H

BR

RB

EWG

R2 R1

BR

858

AcO

EWG

R2

R1

CO2R

NOTES :

The 1,4-addition of nucleophilic boryl copper species generated in situ from diboronates to simple α,β-unsaturated compounds. This reaction was later expanded to allyl acetates and terminal alkynes. The mechanism under the Hosomi conditions is not fully understood. Miyaura-conditions : CuCl, LiCl, KOAc and DMF. Hosomi-conditions :

CuCl or (CuOTf)2.C6H6, Bu3P and DMF.

REFERENCES :

1) K. Takahashi; T. Ishiyama; N. Miyaura, Chem. Lett., 2000, 982. 2) H. Ito; H. Yamanaka; J-i. Tateiwa; A. Hosomi, Tetrahedron Lett., 2000, 41, 6821. 3) K. Takahashi; T. Ishiyama; N. Miyaura, J. Organomet. Chem., 2001, 625, 47. 4) P.V. Ramachandran; D. Pratihar; D. Biswas; A. Srivastava; M.V.R. Reddy, Org. Lett., 2004, 6, 481.

COMMENTS :

HOSOMI – SAKURAI ALLYLATION EXAMPLE :

H +

Me3Si

1) TiCl4, - 78 oC THF 2) H+, MeOH

O

O

MECHANISM :

R

R Me3Si

R

R1 O

R1 OSiMe3

TiCl4, THF, reflux

859

H+, MeOH

R1 OH

R Me3Si

Bu4N+

Bu4N+F-

R

R1

R1 O Bu4N

O R

R R1

Me3SiF

OSiMe3

R1 OH

H+, MeOH

DISCONNECTION :

R3Si

E

+

E N

E N = R1R2CO, RCOX, R1R2C(OR)2, RX, R1R2CXY (X,Y = OR, Cl, SR, NR2), R1

R3

R2

R4

R1

R3

R1

R2

NO2

R2

R3 XN R4

etc.

O

NOTES :

The Lewis acid mediated inter- or intramolecular addition of allylic silanes to α,β-unsaturated ketones or to ketones, aldehydes and many other compounds, see Hosomi review. Hou et al. reported on a fluoride-triggered reaction, while Baba et al. reported an indium(III) chlorotrimethylsilane catalyst system.

REFERENCES : March : 797 Smith – March : 1024 Smith : 1375 Smith 2nd : 1130 Org. React. : 37, 57 Org. Synth. : 62, 86 Org. Synth. Coll. Vol. : 7, 443

1) A. Hosomi; H. Sakurai, Tetrahedron Lett., 1976, 17, 1295. 2) A. Hosomi; H. Sakurai, J. Am. Chem. Soc., 1977, 99, 1673. 3) H. Sakurai, Pure Appl. Chem., 1982, 54, 1. 4) A. Hosomi, Acc. Chem. Res., 1988, 21, 200. 5) D. Schinzer, Synthesis, 1988, 263. 6) I. Fleming, Comp. Org. Syn., 1991, 2, 563. 7) I.E. Markó; D.J. Bayston, Tetrahedron Lett., 1993, 34, 6595. 8) E. Langkopf; D. Schinzer, Chem. Rev., 1995, 95, 1375.

860

9) T.K.M. Shing; L.-H. Li, J. Org. Chem., 1997, 62, 1230. 10) D.-K. Wang; Y.-G. Zhou; Y. Tang; X.-L. Hou; L.-X. Dai, J. Org. Chem., 1999, 64, 4233. 11) Y. Onishi; T. Ito; M. Yasuda; A. Baba, Eur. J. Org. Chem., 2002, 1578. 12) L. Keller; F. Dumas; M. Pizzonero; J. d’Angelo; G. Morgant; D. Nguyen–Huy, Tetrahedron Lett., 2002, 43, 3225. 13) J. Howarth; P. James; J. Dai, J. Mol. Catal. A: Chem., 2004, 214, 143.

COMMENTS :

HOUBEN – FISCHER SYNTHESIS EXAMPLE :

CN

1) AlCl3 2) base + CCl3CN + HCl 1) AlCl3 2) acid

O

CCl3

MECHANISM :

CN

H HCl.N + CCl3CN + HCl

CCl3

KOH - KCl - H2O - CHCl3

AlCl3 H+, H2O - NH4Cl

861

O

CCl3

DISCONNECTION :

O

CCl3

CN

NOTES :

The ketimine hydrochloride obtained from aromatic hydrocarbons or phenols, when trichloroacetonitrile is used in the Hoesch – Houben synthesis of aryl ketones gives with alkali the corresponding aromatic nitrile in excellent yield. With

acid the trichloromethyl aryl ketones are obtained. See also Friedel – Crafts – Karrer, Houben – Hoesch and Rosenmund – von Braun reactions.

REFERENCES : Houben – Weyl : 4/2, 103; E6a, 976 Org. React. : 5, 390

1) J. Houben; W. Fischer, J. Prakt. Chem., 1929, 123, 313. 2) J. Houben; W. Fischer, Ber. Dtsch. Chem. Ges., 1930, 63, 2464. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189.

COMMENTS :

862

HUA REACTION EXAMPLE :

N H

O

CH3

1) TMSCl, Et3N N toluene 2) CH3Li, - 20 oC, 30 min 25 oC, 1 hour

MECHANISM :

N H

O

TMSCl, Et3N toluene

N TMS

CH3

O

CH3Li

N O Li TMS

N

CH3

DISCONNECTION :

n

n

N

R

N H

O

NOTES :

The nucleophilic addition of alkyl lithium reagents to N-(trimethylsilyl)lactams to give cyclic ketimines in high yields.

REFERENCES :

1) D.H. Hua; S.W. Miao; S.N. Bharathi; T. Katsuhira; A.A. Bravo, J. Org. Chem., 1990, 55, 3682. 2) D.H. Hua; J.G. Park; T. Katsuhira, S.N. Bharathi, J. Org. Chem., 1993, 58, 2144. 3) Y. Ahn; G.I. Cardenas; J. Yang; D. Romo, Org. Lett., 2001, 3, 751.

COMMENTS :

863

HUDSON – JACKSON OXIDATION EXAMPLE :

CH2OH O

H

OH

OH

CH2OH O H H

OCH3

OH

H2O, HIO4

O

H OCH3

O

MECHANISM :

CH2OH O OH

CH2OH O H H

H

OH

OH

OCH3

90% CH3COOH 3 Pb(OAc)4 KOAc, - CO2

O

HOCH2 O

H OCH3

O

aq. Br2, SrCO3

H O

O Sr O

H OCH3 O

DISCONNECTION :

H

H O

HO

O

OH OH

NOTES :

Glycosides are oxidised by periodic acid to yield a dialdehyde by cleavage of the 2,3,4-triol group. The dialdehyde can be further oxidised by bromine water in the presence of strontium carbonate to the strontium salt of the diacid (Barium salts can also be used.). This cleavage type of oxidation, provides a method for the determination of ring structure and for the correlation of the configuration of carbon atom 1 of glycosides. It also affords a direct way of correlating the configuration of sugars with glyceric acid. See also Criegee glycol cleavage, Djerassi – Rylander and Lemieux – Johnson reactions.

REFERENCES :

1) E.L. Jackson; C.S. Hudson, J. Am. Chem. Soc., 1936, 58, 378. 2) E.L. Jackson; C.S. Hudson, J. Am. Chem. Soc., 1937, 59, 994. 3) W.S. McClenahan; R.C. Hockett, J. Am. Chem. Soc., 1938, 60, 2061. 4) A.J. Charlson; A.S. Perlin, Can. J. Chem., 1956, 34, 1804. 5) A.J. Charlson; P.A.J. Gorin; A.S. Perlin, Can. J. Chem., 1956, 34, 1811. 6) R.W. Jeanloz; A. Veyrieres, Biochemistry, 1970, 9, 4153.

864

COMMENTS :

HUGERSHOFF REACTION EXAMPLE :

H3C S N

N CH3

Br2, CHCl3

H

S

MECHANISM :

O R

S N H

O Br2, CHCl3

N R1

R

R

Br

N N Br H R1 O

H O

S

R

S - HBr

N N Br R1 H

S N N R1

DISCONNECTION :

S R

X

R1

S R

X

S

Y

Y

R X = CR2; Y = NH R1 X = NH ; Y = C X = NH ; Y = NR3

X

R1 Y

NOTES :

The oxidative C-S bond formation with iodine, bromine or thionyl chloride. See also Werner reaction.

865

REFERENCES : Houben – Weyl : E8a, 692

1) A. Hugershoff, Ber. Dtsch. Chem. Ges., 1903, 36, 3121. 2) A. Hugershoff, Ber. Dtsch. Chem. Ges., 1903, 36, 3134. 3) T.S. Griffin; T.S. Woods; D.L. Klayman, Adv. Heterocycl. Chem., 1975, 18, 99. 4) J. Garin; C. Guillen; E. Melendez; F.L. Merchan; J. Orduna; T. Tejero, Bull. Soc. Chim. Belg., 1987, 96, 797. 5) H. Schäfer; K. Gewald, J. Prakt. Chem., 1987, 329, 355. 6) M. Dzurilla; P. Kutschy; J. Imrich; S. Brtos, Coll. Czech. Chem. Commun., 1994, 59, 2663.

COMMENTS :

HUGERSHOFF SYNTHESIS EXAMPLE :

2

NH2 + CS2 + S

Ph

EtOH, heat

H N

H N

Ph

S

MECHANISM :

NH2 R

S C S H+

S R

S R

+ N SH H H H2N R

RNH2

- H2S N R

866

N H

S

N H

R

DISCONNECTION :

H

R1 N

R N

R1NH2 + RNH2

H

S

NOTES :

Symmetrical N,N’-diarylthioureas are obtained by heating a primary aryl amine with carbon disulfide and sulfur in ethanol.

REFERENCES :

1) A. Hugershoff, Ber. Dtsch. Chem. Ges., 1899, 32, 2245. 2) Ng.Ph. Buu-Hoï; Ng. D. Xuong; Ng. H. Nam, J. Chem. Soc., 1955, 1573. 3) J.G. Erickson, J. Org. Chem., 1956, 21, 483. 4) U. Berg; I. Petterson, J. Org. Chem., 1987, 52, 5177. 5) G. Bratulescu, Rev. Roum. Chim., 2001, 46, 767. 6) R. Ballini; G. Bosica; D. Fiorini; R. Maggi; P. Righi; G. Sartori; R. Sartorio, Tetrahedron Lett., 2002, 43, 8445.

COMMENTS :

HUISGEN – WHITE REACTION EXAMPLE :

H O

N Cbz

N

O

N2O4, DME

867

Cbz

N

O

MECHANISM :

H N

R1

O N2O4

R

R1 or

N O

R1

N N

O

R1 O

R

N O

R1

N

N O

R O

O

O R

R

DISCONNECTION :

R1

O

O

R1

R

H N

O R

NOTES :

The rearrangement of amides into esters by thermolysis of the corresponding N-nitroso intermediates.

REFERENCES :

1) T. Momose; K. Okumura; H. Tsujimori; K. Inokawa; G. Tanabe; O. Muraoka; Y. Sasaki; C.H. Eugster, Heterocycles, 1993, 36, 921.

2) O. Muraoka; B.-Z. Zheng; K. Okumura; E. Tabata; T. Momose; C.H. Eugster, J. Chem. Soc., Perkin Trans. 1, 1996, 1567. 3) O. Muraoka; B.-Z. Zheng; K. Okumura; E. Tabata; G. Tanabe; M. Kubo, J. Chem. Soc., Perkin Trans. 1, 1997, 113. 4) P. Stanetty; E. Gorner; M.D. Mihovilovic, J. Heterocycl. Chem., 1999, 36, 761.

COMMENTS :

868

HUISGEN REACTION EXAMPLE :

N N N

Ph N N N H

+

SiMe3

RT

SiMe3

MECHANISM :

b a

b c a d e

c

d e

DISCONNECTION :

b

b

c

a d

a

c

+ d

e

e

NOTES :

The cycloaddition of 1,3-dipoles e.g. azides, nitrones, nitrile oxides, diazoalkenes, azomethine ylides with olefins or acetylenes. See also Alder ene, Banert Cascade, Diels – Alder, Finegan and Harries ozonide reactions.

REFERENCES : March : 836 Smith – March : 1059 Smith : 1208 Smith 2nd : 999 Org. React. : 36,1 ; 51, 3 Org. Synth. : 46, 96, 127; 49, 70; 53, 59; 58, 106; 67, 133 Org. Synth. Coll. Vol. : 5, 504, 957, 1124; 6, 670, 592; 8, 231

1) R. Huisgen, Proc. Chem. Soc., 1961, 357. 2) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1968, 7, 321. 3) R. Huisgen, J. Org. Chem., 1968, 33, 2291. 4) P.C. Hiberty; G. Ohanessian; H.B. Schlegel, J. Am. Chem. Soc., 1983, 105, 719.

869

5) S. Denmark; M. Schute; C. Senenayake, J. Org. Chem., 1993, 58, 1859. 6) K. Gothelf, Chem. Commun., 2000, 1449. 7) S. Denmark, C&E News, 2001, 79, 27. 8) Z.P. Demko; K.B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2110. 9) Z.P. Demko; K.B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2113. 10) P. Pérez; L.R. Domingo; M.J. Aurell; R. Contreras, Tetrahedron, 2003, 59, 3117. 11) A. Krasiński; V.V. Fokin; K.B. Sharpless, Org. Lett., 2004, 6, 1237. 12) L.R. Domingo; M.T. Picher, Tetrahedron, 2004, 60, 5053. 13) R.N. Butler; A.G. Coyne; W.J. Cunningham; E.M. Moloney; L.A. Burke, Helv. Chim. Acta, 2005, 88, 1611. 14) S. Hotha; R.I. Anegundi; A.A.Natu, Tetrahedron Lett., 2005, 46, 4585.

COMMENTS :

HUNSDIECKER – BORODINE REACTION EXAMPLE :

COOH

I PbIV, I2, CCl4

MECHANISM :

O +

Ag

R

O

O Br + Br2

Br

R

O

O + RBr

R O Br R O

870

R O

O

R + CO2 + Br

+

O

Cristol – Firth :

HgO + 2 X2

HgX2 + [X2O]

[X2O] + RCOOH

[RCOOX] + HOX

[RCOOX]

- CO2

R X

[R + X ]

DISCONNECTION :

R

R Br

OH O

NOTES :

This reaction can be summarised as a decarboxylative bromination or iodination. The Cristol – Firth modification of this reaction uses a mixture of the acid and mercuric oxide. When iodine is used with a two-fold excess of the acid salt, the reaction is known as the Birnbaum – Simoni reaction, and the product is an ester. There is also a thallium modification. See also Birnbaum – Simoni, Kochi decarboxylation and Prévost reactions.

REFERENCES : March : 730 Smith – March : 899, 942 Smith : 155 Smith 2nd : 125, 254 Houben – Weyl : E5, 367; E7b, 630; E19a, 365 Org. React. : 9, 332; 19, 279 Org. Synth. : 26, 52; 43, 9; 51, 106 Org. Synth. Coll. Vol. : 3, 578; 5, 126; 6, 179

1) A. Borodin, Liebigs Ann. Chem., 1861, 119, 121. 2) H. Hunsdiecker; C. Hunsdiecker, Ber. Dtsch. Chem. Ges., 1942, 75, 291. 3) R.G. Johnson; R.K. Ingham, Chem. Rev., 1956, 56, 219. 4) S.J. Cristol; W.C. Firth, jr., J. Org. Chem., 1961, 26, 280. 5) J.K. Kochi, J. Org. Chem., 1965, 30, 3265. 6) S. Chowdbury; S. Roy, Tetrahedron Lett., 1996, 37, 2623.

871

7) S. Chowdbury; S. Roy, J. Org. Chem., 1997, 62, 199. 8) D. Naskar; S. Roy, Tetrahedron, 2000, 56, 1369. 9) P. Camps; A.E. Lukach; X. Pujol; S. Vasquez, Tetrahedron, 2000, 56, 2703. 10) J.P. Das; S. Roy, J. Org. Chem., 2002, 67, 7861. 11) C. Kuang; Q. Yang; H. Senboku; M. Tokuda, Synthesis, 2005, 1319.

COMMENTS :

HUNSDIECKER RING–CLOSURE EXAMPLE :

O

O

Br OEt

Na2CO3 CH3COEt

O

MECHANISM :

O

O

O

O

Br

Br OEt

n

O

Na2CO3 CH3COEt

OEt OEt

n

n

O

O n

DISCONNECTION :

O

O

Br OEt

n

n

O

872

NOTES :

This preparation involves the intramolecular condensation of an ω-halogenacylacetic ester to yield a cyclic βketoester which on hydrolysis and decarboxylation furnishes the corresponding cyclic ketone. This reaction is carried out in high dilution in methyl ethyl ketone and alkali carbonate is employed as a condensing agent. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons,

Keck

macrolactonisation,

Kita,

Masamune,

Michael

condensation,

Mitsunobu,

Mukaiyama

macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler,

Venkataraman

–

Wagle,

Vorbrüggen

–

Krolikiewicz,

Wittig,

Yamaguchi

macrolactonisation reactions.

REFERENCES : Houben – Weyl : 4/2, 754

1) H. Hundiecker, Ber. Dtsch. Chem. Ges., 1942, 75, 1190. 2) M. Stoll, Helv. Chim. Acta, 1947, 30, 1401.

COMMENTS :

HURD – MORI REACTION EXAMPLE :

O

O

H3CO

H3CO S H

N N CO Et 2

10 equiv. SOCl2 DCM

873

S S

N N

and

Yamamoto

MECHANISM :

CH3 HOOC H3C Cl

N S O

HOOC

H N Cl

OEt O

HOOC

Cl

- HCl

S O

N N

COOH OEt O

H N N S O

- HCl

H N N S O

O OEt

HOOC N N S

O OEt

DISCONNECTION :

N S N

O

R1 R

R1

R

NOTES :

The formation of 1,2,3-thiadiazoles from hydrazones by cyclisation using thionyl chloride.

REFERENCES :

1) C.D. Hurd; R.I. Mori, J. Am. Chem. Soc., 1955, 77, 5359. 2) M. Fujita; T. Kobori; T. Hiyama; K. Kondo, Heterocycles, 1993, 36, 33. 3) P. Stanetty; M. Kremslehner; M. Mullner, J. Heterocycl. Chem., 1996, 33, 1759. 4) P. Stanetty; M. Kremslehner; H. Völlenkle, J. Chem. Soc., Perkin Trans. 1, 1998, 853. 5) Y.Y. Morzherin; T.V. Glukhareva; V.S. Mokrushin; A.V. Tkachev; V.A. Bakulev, Heterocycl. Comm., 2001, 7, 173. 6) O.A. Attanasi; L. de Crescentini; P. Filippone; F. Mantellini, Synlett, 2001, 557. 7) O.A. Attanasi; L. de Crescentini; G. Favi; P. Filippone; G. Giorgi; F. Mantellini; S. Santeusanio, J. Org. Chem., 2003, 68, 1947.

COMMENTS :

874

HURTLEY REACTION EXAMPLE :

OH H3C

Br

HOOC

+

H3CO

S

OCH3 O

O

HOOC CH3

KOtBu Cu, tBuOH

O

S

MECHANISM :

O

O

COO O Br

CuII

Br

Cu

- CuBr

ArBr

+

Nu

Nu

DISCONNECTION :

R1 Ar

H R

R

R1

NOTES :

The arylation of compounds with active methylene groups of the form RCH2R1. Activated aryl halides give good results. The Hurtley reaction uses copper halide catalysts (or palladium complexes) to react unactivated halides.

REFERENCES : March : 663 Smith – March : 869

1) W.R.H. Hurtley, J. Chem. Soc., 1929, 1870. 2) J.A. Lowe; M.E. Newman, Synth. Commun., 1987, 17, 803. 3) H.L. Aalten; G. van Koten; K. Goubitz; C.H. Stam, Organometallics, 1989, 8, 2293. 4) H.L. Aalten; G. van Koten; K. Vrieze; A. van der Kerk–van der Hoof, Recl. Trav. Chim. Pays-Bas, 1990, 109, 46. 5) A. Werner; W. Friedrichsen, Synth. Commun., 1993, 23, 2973. 6) A.E. Shinkwin; W.J.D. Whisk; M.D. Threadgill, Bioorg. Med. Chem., 1999, 7, 297. 7) W. Frosch; S. Black; G. Rheinwald; K. Kohler; L. Zsolnai; G. Huttner; H. Lang, Organometallics, 2000, 19, 5769.

875

COMMENTS :

876

877

IPATIEW – SENDERENS OLEFIN SYNTHESIS · 885 IPATIEW CYCLOPROPANE SYNTHESIS · 886

G

IRVINE – PURDIE SUGAR METHYLATION · 887 ISAY PTERIDINE REACTION · 889

GABRIEL – ISAY REACTION · 889

ISLER SYNTHESIS · 890 IVANOV REACTION · 893 I

IWAO INDOLE SYNTHESIS · 894

IBUKA – YAMAMOTO 1,3-CHIRALITY TRANSFER · 879 K

IMAMOTO ALKYLATION · 880 INANAGA INDOLE SYNTHESIS · 881

KUHN MODIFICATION · 888

ING – MANSKE PROCEDURE · 883 INHOFFEN ALDEHYDE SYNTHESIS · 884

878

IBUKA – YAMAMOTO 1,3-CHIRALITY TRANSFER EXAMPLE :

OTBS

OTBS CO2CH3

H3C

n

OMs

CO2CH3

H3C

.

BuCu(CN)Li BF3

Bu

MECHANISM :

CH3CO2 H

MsO R

OTBS

H H OTBS

CO2CH3

H3C

CO2CH3

H3C

OMs

Nu

OMs

H

CO2CH3

R

H

H

Nu-

MsO H CH3CO2 R

H H

OTBS

OTBS CO2CH3

H3C OMs

H R

H3C

OMs

Nu

H CO2CH3

H

Nu-

DISCONNECTION :

OTBS

OTBS CO2R1

R

CO2R1

R OH

Nu

879

CO2CH3

NOTES : Both (E) and (Z)-α,β-enolates are transformed into (E)-alkenes. This diastereoselectivity is due to unfavourable interactions between the bulky R-group and the hydrogen or between the R-group and the methoxycarbonyl. As a result the nucleophile attacks anti to the mesyloxy group. See also Duthaler – Hafner, Matteson, Roush – Hoffmann – Yamamoto and Thomas reactions.

REFERENCES : 1) T. Ibuka; M. Tanaka; S. Nishii; Y. Yamamoto, J. Am. Chem. Soc., 1989, 111, 4864. 2) T. Ibuka; N. Akimoto; M. Tanaka; S. Nishii; Y. Yamamoto, J. Org. Chem., 1989, 54, 4055. 3) S.H. Chen; R.F. Horvath; J. Joglar; M.J. Fischer; S.J. Danishefsky, J. Org. Chem., 1991, 56, 5834. 4) T. Ibuka; K. Nakai; H. Habashita; K. Bessho; N. Fujii; Y. Chounan; Y. Yamamoto, Tetrahedron, 1993, 49, 9479.

COMMENTS :

IMAMOTO ALKYLATION EXAMPLE :

CH3

H3C I

Br

+ O

Ce, HgCl2

Br OH

MECHANISM :

2 Sm + 2 CH2I2 R

R1

+ 2 SmI2

H2C CH2

+ 2 SmI2

OSmI2 R R1

O CH2I2 + SmI2

ICH2

+ SmI3

OSmI2 R R1 CH2I

OSmI2 R R1 + ICH2

880

R H2O

OH R1 CH2I

DISCONNECTION :

O

R1 R

R2 OH

R1

R2

+ RX

NOTES : The cerium or samarium mediated Barbier-type and Reformatsky-type alkylation of ketones and aldehydes in the presence of esters, nitrile and aryl bromides. See also Barbier, Kagan – Molander and Reformatsky reactions.

REFERENCES : 1) T. Imamoto; T. Kusumoto; Y. Tawarayama; Y. Sugiura; T. Mita; Y. Hatanaka; M. Yokoyama, J. Org. Chem., 1984, 49, 3904. 2) J.R. Long, Aldrichimica Acta, 1985, 18, 87. 3) T. Takeyama; H. Koto; T. Imamoto, Tetrahedron Lett., 1986, 27, 3243. 4) T. Imamoto, Pure Appl. Chem., 1990, 62, 747. 5) T. Imamoto; T. Hatajima; N. Takiyama; T. Takeyama; Y. Kamiya; T. Yoshizawa, J. Chem. Soc., Perkin Trans. 1, 1991, 3127. 6) T. Nishino; Y. Nishiyama; N. Sonoda, Heteroatom Chem., 2000, 11, 65.

COMMENTS :

INANAGA INDOLE SYNTHESIS EXAMPLE :

CH3 Br N Ac

HMPA SmI2.THF

881

N Ac

MECHANISM :

Br HMPA SmI2.THF

N Ac

N Ac

CH3

H

N Ac

N Ac

DISCONNECTION : R

R Br X

X = O, NH, NAc, NR1

X

NOTES : The samarium iodide mediated electron transfer to synthesise 3-substituted indoles or benzofurans. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) J. Inanaga; M. Ishikawa; M. Yamaguchi, Chem. Lett., 1987, 1485. 2) J. Inanaga, Synth. Org. Chem., 1989, 47, 200. 3) J. Inanaga; O. Ujikawa; M. Yamaguchi, Tetrahedron Lett., 1991, 32, 1737. 4) G.A. Molander; C.R. Harris, Chem. Rev., 1996, 96, 307.

COMMENTS :

882

ING – MANSKE PROCEDURE EXAMPLE :

O

O N

N H N H

N2H4, H2O

O

+

NH2

O

MECHANISM :

H O

N

O N N

N R O

R

N2H4 - H2O

H

N H N H

H2O

O

+ RNH2

O

DISCONNECTION :

O RNH2

N R O

NOTES : The N-alkylphthalimide formed in the Gabriel synthesis reacts with ethanolic hydrazine hydrate to form an intermediate product, which is readily decomposed by acids to yield primary amines and phthalyl hydrazine. See also Gabriel synthesis and Sheehan – Frank reactions.

REFERENCES : March : 426 Smith – March : 513 Smith : 473 Smith 2nd : 112, 411 Org. Synth. : 12, 10; 27, 12 Org. Synth. Coll. Vol. : 2, 83; 3, 148

883

1) H.R. Ing; R.H.F. Manske, J. Chem. Soc., 1926, 2348. 2) F.E. King; D.A.A. Kidd, J. Chem. Soc., 1949, 3315. 3) W. Grassmann; E. Schulte–Űbbing, Chem. Ber., 1950, 83, 244. 4) H. Mikda; E. Hanninen, Bioconj. Chem., 1992, 3, 182. 5) M.N. Khan, J. Org. Chem., 1995, 60, 4536. 6) M.N. Khan, J. Org. Chem., 1996, 61, 8063. 7) O.M.S. Curley; J.E. McCormick; R.S. McElhinney; T.B.H. McMurry, Arkivoc, 2003, 4, 180.

COMMENTS :

INHOFFEN ALDEHYDE SYNTHESIS EXAMPLE :

H

H3C

OCH3

+

H

H

CH3

1) Li, NH3 2) Pd/CaCO3, H2 3) TsOH, heat

O

O

MECHANISM :

CH3 OCH3

H3C

OCH3

+

R

R

MgX

OH H

O CH3

R

R Al(PO4)3 - H2O

CH3

aq. H+

OCH3

O

DISCONNECTION :

O R

H3C

H3C

OCH3 O

884

+

R

H

NOTES : This reaction is one of the key steps in the synthesis of β-carotene. 1-Methoxyacetone reacts with an acetylenic Grignard reagent (or with an acetylenic lithium reagent) to yield an acetylenic hydroxy-ether. This ether on partial reduction, either catalytically or by lithium aluminium hydride reduction, furnishes the corresponding ethylenic compound, which on dehydration and subsequent hydrolysis of the enol ether gives the required ethylenic aldehyde. Several modifications appeared shortly after the first publication. See also Arens – van Dorp and Isler reactions.

REFERENCES : Houben – Weyl : 7/1, 113

1) H.H. Inhoffen; F. Bohlmann; K. Bartram; G. Rummert; H. Pommer, Liebigs Ann. Chem., 1950, 570, 54. 2) H.H. Inhoffen; G. Leibner, Liebigs Ann. Chem., 1951, 575, 105. 3) R. Ahmad; B.C.L. Weedon, J. Chem. Soc., 1953, 2125. 4) H.H. Inhoffen; U. Schwieter; C.O. Chischester; G. MacKinney, J. Am. Chem. Soc., 1955, 77, 1053.

COMMENTS :

IPATIEW – SENDERENS OLEFIN SYNTHESIS EXAMPLE :

OH

Al2O3 heat

DISCONNECTION :

R R2

R1

R1 R R2

R R2

R1

885

OH

NOTES : This reaction relates to the preparation of olefins by dehydration of the corresponding alcohol (even 1-dodecanol) by passage of the vapour over heated alumina. See also Senderens diethyl ether synthesis.

REFERENCES : March : 1011 Smith – March : 1326

1) W. Ipatiew, Ber. Dtsch. Chem. Ges., 1903, 36, 1990. 2) J.-B. Senderens, C.R. Séances Acad. Sci., 1909, 148, 227. 3) V.I. Spitzin; I.E. Michailenko; G.N. Pirogowa, J. Prakt. Chem., 1964, 25, 160.

COMMENTS :

IPATIEW CYCLOPROPANE SYNTHESIS EXAMPLE :

H3C

CH3

CH2Br + 2 NaCH(COOEt)2

BrCH2

O

OEt OEt

H2C

H

O

MECHANISM :

(COOEt)2 H3C

Br

H3C CH(COOEt)2

BrCH2

H

- HBr

H

Br Na+

886

CH3 - NaBr

O

OEt OEt

H2C O

DISCONNECTION :

R1

H2C

R1

R2

R

CH2Br +

R3 R2, R3 = CO2R4, CN

BrH2C

R

R3

R2

NOTES : The cyclopropane ring is formed from 1,4-dibromo-olefines and alkali salts of acidic methylene compounds. See also Charette, Freund, Gustavson, Hass cyclopropane, Kishner, Mousseron – Fraisse – McCoy, Nerdel and Simmons – Smith reactions.

REFERENCES : 1) W. Ipatiew, J. Russ. Physik. Chem. Ges., 1901, 33, 540. 2) J. Nickel, Chem. Ber., 1958, 91, 553.

COMMENTS :

IRVINE – PURDIE SUGAR METHYLATION EXAMPLE : OCH3

OH

O

O CH3O

HO H

H OH OH

OCH3

1) CH3I, Ag2O 2) aq. H+

887

OH

H OCH3

OCH3

MECHANISM :

OCH3

OH

O

O

CH3O

HO H

H OH OH

xs CH3I, Ag2O

OCH3 OCH3

OCH3

aq. H+

OCH3

OCH3

OCH3

O

O CH3O

H

H

H OCH3

CH3O H

H2O

OH

H OCH3

OCH3

OCH3

DISCONNECTION :

R OH

R OCH3 R = sugar

NOTES : The exhaustive methylation of a methyl glycoside by repeated treatment with methyl iodide and silver oxide, followed by hydrolysis of the pentamethyl ether with dilute acid to yield the anomeric hydroxyl group. There is a Kuhn modification, which uses barium or strontium oxides or hydroxides in DMF. See also Fischer glycosidation, Hakomori, Haworth methylation, Meerwein methylation, Robertson – Robinson and Williamson reactions.

REFERENCES : 1) T. Purdie; J.C. Irvine, J. Chem. Soc., 1903, 83, 1021. 2) P.A. Finan; C.D. Warren, J. Chem. Soc., 1962, 4214. 3) P. Kováč; J. Hirsch; V. Kováčik, Carbohydr. Res., 1977, 58, 327.

COMMENTS :

888

ISAY PTERIDINE REACTION EXAMPLE :

O H2N

O

N

+ N

H2N

O

O

H

N

NH2

N N

N

H NH2

MECHANISM :

O Ph

O

H2N

O

H2N

HO Ph

NH N

HO

NH2

H N

O

N H

N

O N

N

Ph

H - 2 H2O

NH2

N

N N

H NH2

DISCONNECTION :

O

O (R2)R1 (R1)R2

N N

N N

R1

H

O

H2N

N

+ R2

R

O

H2N

N

H R

NOTES : The synthesis of pteridines from diaminopyrimidines and α-diketones or α-ketoaldehydes. The disadvantage of this synthesis is that the condensation of the heterocyclic 1,2-diamine with an unsymmetrical 1,2-dicarbonyl compound will lead to both 5- and 6-substituted isomers. The Taylor synthesis avoids these problems. This reaction is also known under the name Gabriel – Isay reaction. See also Blicke – Pachter, Boon – Polonovski, Taylor and Timmis reactions.

REFERENCES : 1) S. Gabriel, Ber. Dtsch. Chem. Ges., 1901, 34, 1234. 2) O. Isay, Ber. Dtsch. Chem. Ges., 1906, 39, 250. 3) C.B. Storm; R. Shiman; S. Kaufman, J. Org. Chem., 1971, 36, 3925. 4) J.R. Russell; C.D. Garner; J.A. Joule, Synlett, 1992, 711.

889

COMMENTS :

ISLER SYNTHESIS EXAMPLE :

CH2OH

CH3 O

H CH3

H3C

OEt

1) Cl

H3C H

O NaOEt 2) BrMg OMgBr 3) H2, Pd/C CH3OH

CH3

O

4)

H3C Cl pyridine 5) I2 6) KOH

MECHANISM :

H3C

O

CH3

CH3

+

OEt

Cl O

CH3

NaOEt

OEt H3C

CH3

O

CH3

O CH3

CH3

O H3C

CH3 base - CO2

890

CH3

O H

H

+

H

Na, liq. NH3

Na

+

H

H

H3C

OH

BrMg

OH

OMgBr

2 EtMgBr

H2SO4

CH3

CH3

O H3C

CH3

BrMg CH3

+

OMgBr CH3

CH3 MgBr

H3C

CH3

OMgBr

O hydrolysis

CH3 CH3 H3C

CH3

CH3 OH HO CH3

CH3

CH3

891

CH3

H3C

CH3

H3C

OH

CH3

HO CH3

OH O

H2, Pd/C, CH3OH

CH3

CH3

HO

CH3

CH3

CH3

Cl pyridine

O O

CH3 H3C

HO H3C

allylic rearrangement

CH3

CH3

O

CH3 O OH CH3

CH3 CH3

H3C

O

CH3 O

I2, petrol 80 - 110 oC

saponification

CH3 H3C

CH3 OH CH3

DISCONNECTION : H O

OH CH3

CH3

NOTES : The synthesis of retinol starting with β-Jonon. See also Arens – van Dorp, Darzens – Claisen, Darzens dichloracetate synthesis, Favorskii – Babayan, Inhoffen, Nef synthesis and Reppe acetylene reactions.

REFERENCES : 1) O. Isler; W. Huber; A. Ronco; M. Kofler, Helv. Chim. Acta, 1947, 30, 1911. 2) M. Rosenberger; W. Jackson; G. Saucy, Helv. Chim. Acta, 1980, 63, 1665. 3) S.A. Tanumihardjo, J. Labelled Compd. Radiopharm., 2001, 44, 365.

COMMENTS :

892

IVANOV REACTION EXAMPLE : Ph COOH H H HO Ph

O O

Na+

1) (CH3)2CHMgBr 2) Ph H O

MECHANISM :

H

O

O 2+

Mg H

COOMgBr MgBr

(CH3)2CHMgBr

O Na+

+

O

Ph

H

H

O

Ph COOH H HO Ph

DISCONNECTION :

H Ar R

COOH OH

R

R1

ArCH2COOH + O

R1

NOTES : An arylacetic acid or its sodium salt reacts with isopropyl magnesium halide to form a Grignard complex which with an aldehyde yields a β-substituted α-aryl-β-hydroxypropionic acid or gives with a ketone the corresponding β,βdisubstituted compound. The Ivanov reaction yields a mixture of threo and erythro diastereoisomers. For a mechanistic study see Toullec et al. See also Reformatsky reaction.

REFERENCES : March : 946 Smith – March : 791 Smith : 923 Smith 2nd : 770 Houben – Weyl : E5, 377

893

1) D. Ivanov; A. Spassov, Bull. Soc. Chim. Fr., 1931, 49, 19. 2) F.F. Blicke; P.E. Wright; W.A. Gould, J. Org. Chem., 1961, 26, 2114. 3) F.F. Blicke; S. Raines, J. Org. Chem., 1964, 29, 204. 4) B. Blagoev; D. Ivanov, Synthesis, 1970, 615. 5) D. Ivanov; G. Vassilev; I. Panayotov, Synthesis, 1975, 83. 6) M. Mladenova; B. Blagoev; M. Gaudemar; F. Gaudemarbardone; J.Y. Lallemand, Tetrahedron, 1981, 37, 2157. 7) J. Toullec; M. Mladenova; F. Gaudemarbardone; B. Blagoev, Tetrahedron Lett., 1983, 24, 589. 8) J. Toullec; M. Mladenova; F. Gaudemarbardone; B. Blagoev, J. Org. Chem., 1985, 50, 2563.

COMMENTS :

IWAO INDOLE SYNTHESIS EXAMPLE :

OCH3 SPh N But

H O

1) 2.5 nBuLi, THF, 0 oC O 2) S Ph Si tBu (CH3)2 3) sat. NH4Cl 4) AcOEt, reflux

894

N t

O

Bu

MECHANISM :

R

R

R1

N H

Boc

Li

t

BuLi THF

R1

N Li

Boc

1) Ph 2) H2O

O S

R

R1

S O

R

Ph Si(R2)(R3)2 NH Boc

Sila-Pummerer rearrangement

S

R1

R

Si R2

N H Boc

(R3)2

Ph OSi(R2)(R3)2

R SPh R1

N Boc

mCPBA R1

N Boc

DISCONNECTION :

R1

R1 N R

N H

R

NOTES : N-tert-butoxycarbonylaniline is lithiated with

t

BuLi and subsequently reacted with 1-tert-butyldimethylsilyl-1-

phenylsulfinylethene to give the conjugate addition product. These compounds are without isolation cyclised to the corresponding phenylthioindolines under thermal sila-Pummerer rearrangement. Treatment of these compounds with mCPBA gives the N-protected indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Pummerer, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : M. Iwao, Heterocycles, 1994, 38, 45.

895

COMMENTS :

896

897

JOHNSON POLYENE CYCLISATION · 917 JONES – WEEDON SYNTHESIS · 918

J

JONES HYDROXYPYRAZINE SYNTHESIS · 920 JACOBSEN – KATSUKI EPOXIDATION · 899

JONES OXIDATION · 921

JACOBSEN REARRANGEMENT · 901

JOURDAN – ULLMANN – GOLDBERG SYNTHESIS · 923

JACOBSON INDAZOLE SYNTHESIS · 903

JULIA – BRUYLANTS CYCLOPROPYL CARBINOL REARRANGEMENT · 927

JAPP – KLINGEMANN REACTION · 904 JAPP – MURRAY INDOLE SYNTHESIS · 906

JULIÁ – COLONNA REACTION · 925

JAPP OXAZOLE SYNTHESIS · 907

JULIA – JOHNSON CYCLOPROPYL CARBINOL REARRANGEMENT · 926

JÉGER THF SYNTHESIS · 908 JOHNSON – CLAISEN REARRANGEMENT · 910

JULIA – PARIS – KOCIENSKI – LYTHGOE SYNTHESIS · 927

JOHNSON – McINTOSH – Mc NELIS α-IODINATION · 911

JULIA INDOLE SYNTHESIS · 930

JOHNSON 2-THIOHYDANTOIN SYNTHESIS · 913

JUNG – OLAH – VORONKOV ETHER CLEAVAGE · 931

JOHNSON ALKYNYLATION · 914

JUST SYNTHESIS · 932

JOHNSON ANGULAR METHYLATION · 915

898

JACOBSEN – KATSUKI EPOXIDATION EXAMPLE :

Ph

Ph

CH3

CH3

5 mol% 1 NaOCl (buffered) DCM, 4 oC, 6 hours

O

MECHANISM :

H

But

H

N N Mn O O Cl t But Bu

t

Bu

1

R1

R O Mn

concerted

O R MnV +

R

R1 radical

R

O MnIII

R1

R

R O Mn R1

899

R1 O MnIII

O Mn

oxetane

R1

R

R1 O MnIII

O N Mn OXO N

N Mn OXO N

[O]

R

R1

R R1

R collapse

O

O

N

N Mn OXO

R1

R rotation then collapse

R1 O

DISCONNECTION :

R R1

R2 O

R

R2

R1

R3

R3

NOTES : The asymmetric epoxidation of simple olefins has been performed using chiral derivatives of [Mn(salen)] complexes with oxidants as PhIO (Katsuki) and aqueous NaOCl (Jacobsen). In some cases extra oxidants like Bu4NHSO5 and N-methylmorpholine-N-oxide are used. The mechanism is still controversial. It can either be in a concerted manner, via a radical intermediate or via a manganaoxetane (Åkermark et al.) (although disputed by Jacobsen). See also Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew, Shi and Weitz – Scheffer reactions.

REFERENCES : Smith – March : 1053 Smith 2nd : 244 Org. React. : 48, 1 Org. Synth. : 75, 1; 76, 46 Org. Synth. Coll. Vol. : 10, 29, 96

1) A. Hatayama; N. Hosoya; R. Irie; Y. Ito; T. Katsuki, Synlett, 1992, 407. 2) S. Chang; N.H. Lee; E.N. Jacobsen, J. Org. Chem., 1993, 58, 6939 3) T. Katsuki, Coord. Chem. Rev., 1995, 140, 189. 4) C. Linde; M. Arnold; P.O. Norrby; B. Åkermark, Angew. Chem., Int. Ed. Engl., 1997, 36, 1723. 5) T. Linker, Angew. Chem., Int. Ed. Engl., 1997, 36, 2060.

900

6) C.H. Sugisaki; P.J. Carroll; C.R.D. Correia, Tetrahedron Lett., 1998, 39, 3413. 7) J. El–Bahraoui; O. Weist; D. Feichtinger; D.A. Plattner, Angew. Chem., Int. Ed., 2001, 40, 2073. 8) Y.N. Ito; T. Katsuki, Asymmetric Oxidation Reactions, 2001, 19. 9) H. Sellner; J.K. Karjalainen; D. Seebach, Chem. Eur. J., 2001, 7, 2873. 10) I. Cepanec; H. Mikuldas; V. Vinkovi, Synth. Commun., 2001, 31, 2913. 11) W. Adam; K.J. Roschmann; C.R. Saha–Möller; D. Seebach, J. Am. Chem. Soc., 2002, 124, 5068. 12) T. Katsuki, Synlett, 2003, 281. 13) D.E.J.E. Robinson; S.D. Bull, Tetrahedron: Asymmetry, 2003, 14, 1407. 14) L.P.C. Nielsen; C.P. Stevenson; D.G. Blackmond; E.N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 1360. 15) L. Xinwen; T. Ning; L. Weisheng; T. Minyu, J. Mol. Catal. A: Chem., 2004, 212, 353.

COMMENTS :

JACOBSEN REARRANGEMENT EXAMPLE :

H3C

CH3

H3C

CH3

H3C H2SO4

H3C

CH3 CH3

MECHANISM :

H3C

CH3

H3C

CH3

H2SO4

H3C H3C

H3C

CH3 SO3H

H3C

H3C

CH3

H3C H3C

SO3H

H

CH3 CH3

- H2SO4

H3C

CH3 CH3

901

SO3H CH3 CH3

DISCONNECTION :

R R

R

R = Hal, Alk

R

R

R

R

R

NOTES : This reaction involves the migration of an alkyl group or halogen atom in the presence of sulfuric acid in a sulfonic acid derived polyalkylbenzene, a halogenated polyalkylbenzene or a polyhalogenated benzene with at least four substituents. See also Baddeley rearrangement.

REFERENCES : March : 565 Smith – March : 734 Smith : 1318 Smith 2nd : 1086 Houben – Weyl : 5/4, 246; 9, 530; E19c, 404 Org. React. : 1, 370

1) J. Herzig, Ber. Dtsch. Chem. Ges., 1881, 14, 1205. 2) O. Jacobsen, Ber. Dtsch. Chem. Ges., 1886, 19, 1209. 3) E.N. Marvell; B.M. Graybill, J. Org. Chem., 1965, 30, 4014. 4) H. Hart; J.F. Janssen, J. Org. Chem., 1970, 35, 3637. 5) H. Suzuki; T. Sugiyama, Bull. Chem. Soc. Jpn., 1973, 46, 586. 6) E. Solari; F. Musso; R. Ferguson; C. Floriani; A. Chiesivilla; L. Rizzoli, Angew. Chem., Int. Ed. Engl., 1995, 34, 1510. 7) M. Dotrong; S.M. Lovejoy; J.F. Wolfe; R.C. Evers, J. Heterocycl. Chem., 1997, 34, 817. 8) F. Musso; E. Solari; C. Floriani; K. Schenk, Organometallics, 1997, 16, 4889.

COMMENTS :

902

JACOBSON INDAZOLE SYNTHESIS EXAMPLE :

CH3 O N NO

Ph

N

benzene heat

N

MECHANISM :

CH3 O

CH3 Ph

N N

C6H6 heat

N

N O

O

N - PhCOOH

O

N

Ph

DISCONNECTION :

CH3 O

N N

N NO

Ph

NOTES : Indazoles are obtained by warming a benzene solution of a N-nitrosoacyl-o-toluidide. The producty is formed via an isomerisation of the diazobenzoate.

REFERENCES : 1) P. Jacobson; L. Huber, Ber. Dtsch. Chem. Ges., 1908, 41, 660. 2) K. von Auwers, Ber. Dtsch. Chem. Ges., 1919, 52, 1330. 3) E.C. Franklin, Chem. Rev., 1935, 16, 305. 4) R. Huisgen; L. Krause, Liebigs Ann. Chem., 1951, 574, 157. 5) R. Huisgen; H. Nakaten, Liebigs Ann. Chem., 1954, 586, 84.

903

COMMENTS :

JAPP – KLINGEMANN REACTION EXAMPLE :

N

CH2COOH

1) NaOAc 2) PhN2+

N

N H

N H

Ph

MECHANISM :

O

R1

R

O

HO-, - H2O OH

R

R2

O

R

N

R1

O

R2

R1 O

N

R2 N N

O

R

N

R1 R2

N +

H

O OH

OH

R O H2O - R2COOH

N N R1

H

DISCONNECTION :

O

O

R N H

N

R3

R2 R1

O

R1

R = EWG, EDG R1 = H, alkyl, aryl, acyl, CN, Cl, Br R2 = O-alkyl, O-aryl, OH R3 = alkyl, aryl

904

R R2

+

N

N

NOTES : Diazonium compounds couple with the enolic forms of β-diketones or β-ketonic esters to form O-azo compound, which rearranges to a C-azo compound and hence to a hydrazone. The elimination of e.g. carbon dioxide or acetyl may occur and the name is restricted by some to such elimination reactions. Other systems containing acidic methylene groups behave in a similar fashion.

REFERENCES : March : 592 Smith – March : 779 Houben – Weyl : 10/3, 523; 11/2, 312; E6b, 710, 756; E14b, 451; E16d, 99, 614, 1093 Org. React. : 10, 143 Org. Synth. : 32, 84 Org. Synth. Coll. Vol. : 4, 633 Science of Synthesis : 10, 378

1) F.R. Japp; F. Klingemann, Ber. Dtsch. Chem. Ges., 1887, 20, 2942. 2) F.R. Japp; F. Klingemann, Ber. Dtsch. Chem. Ges., 1887, 20, 3284. 3) F.R. Japp; F. Klingemann, Ber. Dtsch. Chem. Ges., 1887, 20, 3398. 4) R.P. Linstead; A. B.-L. Wang, J. Chem. Soc., 1937, 807. 5) C. Reichardt; E.U. Würthwein, Chem. Ber., 1976, 109, 3735. 6) A.O. Abdelhamid; H.M. Hassaneen; I.M. Abbas; A.S. Shawali, Tetrahedron, 1982, 38, 1527. 7) R. Heckendorn, Bull. Soc. Chim. Belg., 1986, 10, 143. 8) I.M. Bazavova; A.N. Esipenko; V.M. Neplyuev; M.O. Lozinskii, Zh. Org. Khim., 1989, 25, 2225. 9) J.H.M. Lange; J.C. de Jong; H.J. Sanders, Bioorg. Med. Chem. Lett., 1999, 9, 1055. 10) V. Atlan; L. El Kaim; C. Supiot, Chem. Commun., 2000, 1385. 11) A.S. Shawali; M.A. Abdallah; M.A.N. Mosselhi; T.A. Fargaly, Heteroatom Chem., 2002, 13, 136. 12) N.P. Dubash; N.K. Mangu; A. Satyam, Synth. Commun., 2004, 34, 1791.

COMMENTS :

905

JAPP – MURRAY INDOLE SYNTHESIS EXAMPLE :

OH + ZnCl2

NH2

N H

O

MECHANISM :

HO

NH2 OH

Ph OH

N H

- H2O

Ph

O H+ H

H Ph OH N H

Ph

- H+, - H2O

N H

DISCONNECTION :

R1

R

R N H

R2

+ NH2

OH

R2 O

R1

NOTES :

The synthesis of an indole by the condensation of a primary aromatic amine with a benzoin in the presence of zinc chloride. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa

906

indole,

Schmid,

Smith,

Sugasawa

indole,

Sundberg,

Thiele

–

Dimroth,

Thyagarajan,

Watanabe

heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) F.R. Japp; T.S. Murray, J. Chem. Soc., 1894, 65, 889. 2) M.W.G. Coldham; J.W. Lewis; S.G.P. Plant, J. Chem. Soc., 1954, 4528. 3) W.H. Dekker; H.A. Selling; J.C. Overeen, J. Agric. Food Chem., 1975, 23, 785.

COMMENTS :

JAPP OXAZOLE SYNTHESIS EXAMPLE :

Ph + O

CH3CN

H2SO4

OH

O

Ph N CH3

MECHANISM :

Ph

Ph H+ R C N HO

HO

H2SO4

O N

OH H

907

- H2O

N

O R

R

DISCONNECTION :

Ph

Ph

O

N R

+ RCN R = H, CH3, C3H9, Ph O

OH

NOTES :

The addition of a mixture of benzoin and a nitrile (containing hydrogen cyanide) to concentrated sulfuric acid yields a 4,5-diphenyloxazole. See also Davidson, Fischer oxazole, Japp – Murray indole and Robinson – Gabriel reactions.

REFERENCES :

1) F.R. Japp; T.S. Murray, J. Chem. Soc., 1893, 63, 469. 2) R.H. Wiley, Chem. Rev., 1945, 37, 401. 3) W.E. McEwen; J.V. Kindall; R.N. Hazlett; R.H. Glazier, J. Am. Chem. Soc., 1951, 73, 4591.

COMMENTS :

JÉGER THF SYNTHESIS EXAMPLE : H + OH

Pb(OAc)4

O H

908

OAc

MECHANISM :

R1 H OH R2 R n

R1

H

R

R1

H

R

O

O Pb(OAc)3 R2 n

O

H

R1

+ Pb(OAc)3

R2

R2

R

n

n

OH R2

R1 R

Pb(OAc)4

(OAc)3Pb R1 R

+ Pb(OAc)3

n

O

R1

-H R2

n

H

R1

R2

R

OH

+ Pb(OAc)3

R

+

n

O

-H - CH3COOH - Pb(OAc)2

R2 n

DISCONNECTION : R n

n

R

O

R1 HO

R1

NOTES :

The free radical ring-closure of alcohols with Pb(OAc)4 to tetrahydrofurans. 1-Heptanol will afford 2alkyltetrahydrofuran, while secondary aliphatic alcohols will afford a mixture of cis and trans dialkyltetrahydrofurans.

REFERENCES :

1) G. Cainelli; M.Lj. Mihailović; D. Arigoni; O. Jéger, Helv. Chim. Acta, 1959, 42, 1124. 2) V.M. Mićović; R.I. Mamuzić; D. Jeremić; M.Lj. Mihailović, Tetrahedron Lett., 1963, 4, 2091. 3) V.M. Mićović; R.I. Mamuzić; D. Jeremić; M.Lj. Mihailović, Tetrahedron, 1964, 20, 2279. 4) M.Lj. Mihailović; Ź. Čeković, Synthesis, 1970, 209.

COMMENTS :

909

JOHNSON – CLAISEN REARRANGEMENT EXAMPLE :

OH

CO2Et

OEt

EtO +

H3C

10% HCl 125 oC

CH3

Ph

H3C

CH3

CO2Et +

H3C

CH3

CH3 CH3

MECHANISM :

OEt H3C OEt OEt

+

H , - HOEt

H3C

OEt OEt

EtO EtO

R1 HO

EtO

O

R1 O

R2

R2 R1

R1 - EtOH

H

EtO

R2

O

R2

DISCONNECTION :

R2 O

R2 O

R1 R

R1 R

NOTES :

This is another variation of the Claisen rearrangement. It involves ketene acetals which are synthesised from allylic alcohols with orthoesters. The rearrangement of secondary allylic alcohols proceed with high E-selectivity due to the destabilising 1,3-diaxial interactions in the transition state, which would give Z-selectivity. The reaction temperature can be lowered by use clay-catalysed microwave conditions. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Claisen rearrangement (Claisen – Ireland rearrangement), Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Marbet – Saucy and Overman rearrangement reactions.

REFERENCES : March : 1139 Smith – March : 1451 Smith : 1242 Smith 2nd : 1024

910

Houben – Weyl : E10b2, 214

1) W.S. Johnson; L. Werthemann; W.R. Barlett; T.J. Brocksom; T. Li; D.J. Faulkner; M.R. Petersen, J. Am. Chem. Soc., 1970, 92, 741.

2) G.W. Daub; J.P. Edwards; C.R. Okada; J.W. Allen; C.T. Maxey; M.S. Wells; A.S. Goldstein; M.J. Dibley; C.J. Wang; D.P. Ostercamp; S. Chung; P.S. Cunningham; M.A. Berliner, J. Org. Chem., 1997, 62, 1976. 3) J. Nowicki, Molecules, 2000, 5, 1033. 4) A. Giardinà; E. Marcantoni; T. Mecozzi; M. Petrini, Eur. J. Org. Chem., 2001, 713. 5) A. Montero; E. Mann; B. Herradón, Eur. J. Org. Chem., 2004, 3063. 6) J. Pietruszka; N. Schöne, Eur. J. Org. Chem., 2004, 5011.

COMMENTS :

JOHNSON – McINTOSH – Mc NELIS α-IODINATION EXAMPLE : O

O I I2, Et3N DCM, RT

N H

N H

MECHANISM :

O

O I N H

O

H

I2

N H

I

O I

I N H

Et3N

N H

911

H

O

H

I

I2

N H O

O

I

N

I

O

H

O

H

I

I

N

N

I Et3N N H

+

H

DISCONNECTION :

O

O I

NOTES :

α-Iodination of α,β-unsaturated carbonyl compounds (also enaminones) is carried out using iodine in CCl4 and pyridine solvent. In the modifications of this procedure DMAP, triethylamine or trimethylsilyl azide are used. The reaction can be made catalytic. There are two possible reaction mechanisms proposed for the reaction with enaminones.

REFERENCES :

1) J.M. McIntosh, Can. J. Chem., 1971, 49, 3045. 2) C.R. Johnson; J.P. Adams; M.P. Braun; C.B.W. Senanayake; P.M. Wovkulich; M.R. Uskokovic, Tetrahedron Lett., 1992, 33, 917. 3) P. Bovonsombat; G.J. Angara; E. Mc Nelis, Tetrahedron Lett., 1994, 35, 6787. 4) C.-K. Sha; S.-J. Huang, Tetrahedron Lett., 1995, 36, 6927. 5) E-i. Negishi; Z. Tan; S.-Y. Liou; B. Liao, Tetrahedron, 2000, 56, 10197. 6) A.D. Williams; Y. Kobayashi, J. Org. Chem., 2002, 67, 8771. 7) J.M. Kim; J.E. Na; J. N. Lim, Tetrahedron Lett., 2003, 44, 6317.

COMMENTS :

912

JOHNSON 2-THIOHYDANTOIN SYNTHESIS EXAMPLE :

S

H N 2

N H

N

NH2

1) CS2, EtOH 2) ClCO2Et 3) heat

O

O

MECHANISM :

H N 2

H N

NH2 + CS2

EtOH

O

S

O

N H

S H

H+ H N

O N H OEt

Cl O H N Ph

H N

S

O

N H

H+

O S

OEt

H N heat - EtOH - COS

NH2.HCl

S N O

O S N H

N O

DISCONNECTION :

S R N

N H

R

H N

NH2 O

O

NOTES :

An anilide of glycine reacts with carbon disulfide. The formed compound reacts with ethyl chloroformate which on distillation decomposes and rearranges to form the 3-aryl-2-thiohydantion. See also Hugershoff synthesis.

913

REFERENCES :

1) T.B. Johnson; B.H. Nicolet, J. Am. Chem. Soc., 1911, 33, 1973. 2) T.B. Johnson; A.J. Hill; E.B. Kelsey, J. Am. Chem. Soc., 1920, 42, 1711. 3) A.G. Renfrew; T.B. Johnson, J. Am. Chem. Soc., 1929, 51, 254. 4) J.F.R. Kuck; J.J. Herda; W.E. Kovac; J.V. Karabinos, J. Am. Chem. Soc., 1951, 73, 5470.

COMMENTS :

JOHNSON ALKYNYLATION EXAMPLE :

OH

OH

SiMe3

1) F2C=CCl2 KOH Bu4NOH 2) nBuLi 3) TMSCl

MECHANISM :

Li+ Bu O

OH

CF2CHCl2

O H 4 nBuLi

F2C CCl2 KOH, Bu4NOH O

O Li

E

E+

Bu

Bu

914

DISCONNECTION : XH

XH

R R1

R1 X = O, S, NCH3

NOTES :

A base-induced oxygen to carbon rearrangement by conversion of aryl tri- or tetra-haloether into ohydroxyphenylalkynes which under basic conditions can be converted to benzofurans and under acid conditions to 2hydroxyacetophenones.

REFERENCES :

1) R. Subramanian; F. Johnson, J. Org. Chem., 1985, 50, 5430. 2) F. Johnson; R. Subramanian, J. Org. Chem., 1986, 51, 5040. 3) U. Pindur; R. Adam, J. Heterocycl. Chem., 1988, 25, 1.

COMMENTS :

JOHNSON ANGULAR METHYLATION EXAMPLE :

H

O H3C 1)

H

O Ph

2) tBuOK 3) CH3I

915

H

H

O

MECHANISM :

H

O

H

H H

H

O

H H

O

H3C

H

- H2O

O

H

O

O

1) tBuOK, 2) CH3I

O

H3C

O

+

O

O H

H

[O]

H3C

O

CH3 COOH CH2CH2COOH

H

H

DISCONNECTION :

H3C

H

O

O

H

H

NOTES :

The angular methylation of fused ring ketones using base and methyl iodide. This method has been developed for the elaboration of the D-ring of steroids.

REFERENCES :

1) W.S. Johnson, J. Am. Chem. Soc., 1943, 65, 1317. 2) W.S. Johnson; H. Posvic, J. Am. Chem. Soc., 1945, 67, 504. 3) W.S. Johnson; D.S. Allen, jr., J. Am. Chem. Soc., 1957, 79, 1261. 4) W.S. Johnson; D.S. Allen, jr.; R.R. Hindersinn; G.N. Sausen; R. Pappo, J. Am. Chem. Soc., 1962, 84, 2181.

916

COMMENTS :

JOHNSON POLYENE CYCLISATION EXAMPLE :

H3C H3C

CH3

CH3

H

H3C

H3C HOCH2CH2OH ClCH2CH2Cl CF3COOH, 0 oC

H3C OH

O

H

H

H3C

MECHANISM :

H

H3C CH3 O H+

H3C

CH3

CH3

CF3COOH

H3C

CH3 HO H3C

CH3 CH3

CH3

DISCONNECTION :

R3

R R2 n

R R3

R1 R

n

R2

n = 1,2

R1

R2 n

R1 R3

917

H3C

NOTES :

This is a non-enzymic biogenetic-like olefinic cyclisation promoted by a cation-stabilising group. See also Nazarov reaction.

REFERENCES : Smith – March : 1019 Smith : 1058 Smith 2nd : 864, 1072

1) W.S. Johnson; W.H. Lunn; K. Fitzi, J. Am. Chem. Soc., 1964, 86, 1972. 2) W.S. Johnson; N.P. Jensen; J. Hoos, J. Am. Chem. Soc., 1966, 88, 3859. 3) W.S. Johnson, Acc. Chem. Res., 1968, 1, 1. 4) W.S. Johnson; M.B. Gravestock; B.E. McCarry, J. Am. Chem. Soc., 1971, 93, 4332. 5) T. Kametani; K. Fukumoto, Synthesis, 1972, 657. 6) A.S. Gopalan; R. Pieto; B. Mueller; D. Peters, Tetrahedron Lett., 1992, 33, 1679. 7) S.E. Sen; S.L. Roach; S.M. Smith; Y.Z. Zhang, Tetrahedron Lett., 1998, 39, 3969.

COMMENTS :

JONES – WEEDON SYNTHESIS EXAMPLE : H3C H3C

H

Cl O

1) H 2) H+

918

O

Na+ H

MECHANISM :

R

H R

R

Cl

Cl

Cl OH

OH O H

H+ R

H

H O

H+ - HCl

H

DISCONNECTION :

R

H O

R

Cl

+

R1

H

O R1

NOTES :

β-Chlorovinyl methyl ketone reacts with sodium acetylide in liquid ammonia or with acetylenic Grignard complexes to yield acetylenic-chloro-ethylenic carbinols. These carbinols on treatment with dilute acids undergo anionotropic rearrangement followed by elimination of hydrogen chloride to yield conjugated acetylenic-ethylenic aldehydes. See also Arens – van Dorp, Favorskii – Babayan, Inhoffen, Isler, Nef synthesis and Reppe acetylene reactions.

REFERENCES : Houben – Weyl : 7/1, 230

1) E.R.H. Jones; B.C.L. Weedon, J. Chem. Soc., 1946, 937. 2) I.B. Toogood; B.C.L. Weedon, J. Chem. Soc., 1949, 3123.

COMMENTS :

919

JONES HYDROXYPYRAZINE SYNTHESIS EXAMPLE :

H

NH2

H +

O

NH2

H

O

O

1) MeOH, - 30 oC 2) NaOH 3) H+, NaHCO3

H

N

OH

H

N

H

MECHANISM :

H H

O

H2N

O

O

H2N

H

- 2 H2O

H N

HO

HO

O

H H N H

HO

H

N

OH

H

N

H

N

OH

H H H

HO

H N H H

DISCONNECTION :

R1

N

OH

R1

NH2

R2 +

R2

N

O

R

NH2

R

O

O

i

R = H, CH3, Et, Pr, Pr, Ph, CONH2, CH2CH2SCH3 R1 = H, CH3, Ph R2 = H, CH3, Ph

NOTES :

Hydroxypyrazines are obtained by the base-catalysed condensation of an α-amino acid amide with a 1,2-dicarbonyl compound.

REFERENCES :

1) R.G. Jones, J. Am. Chem. Soc., 1949, 71, 78. 2) G. Karmas; P.E. Spoerri, J. Am. Chem. Soc., 1952, 74, 1580. 3) F.L. Muehlmann; A.R. Day, J. Am. Chem. Soc., 1956, 78, 242. 4) M. Mano; T. Seo; K. Toshinori; I. Kaneko; K-i. Imai, Chem. Pharm. Bull., 1980, 28, 2734. 5) N. Sato; K. Matsumoto; M. Takishima; M. Masayuki; K. Mochizuki, J. Chem. Soc., Perkin Trans. 1, 1997, 3167.

920

COMMENTS :

JONES OXIDATION EXAMPLE :

O

OH CrO3, H2SO4 Acetone, 5 oC

MECHANISM :

R

R H

OH R(H)

"H2CrO4"

O H O Cr OH R(H) O

R H+ O

R

H2O

O H O Cr OH R(H) O H

R

921

R(H)

H

O O Cr OH R(H) O H

Follow-up chemistry of Cr(IV) :

3 CrO(OH)2 or

Cr2O3 + CrO3 + 3 H2O CrO3

CrO(OH)2 OH

R1

O

OH H

R1

R2

R1

R2 .5 Cr2O3 + 1.5 H2O

R2

CrO3H

OH R1

H R2

OH O Cr O O R1 H R2

H

OH Cr HO OH

DISCONNECTION :

OH R R(H) H

O R

R(H)

NOTES :

The Jones reagent is generally prepared from CrO3 and H2SO4 and is used in acetone or water. During the reaction Cr6+ is reduced to Cr3+. Double and triple bonds and also chiral centres are not disturbed by this reagent. Silyl ethers however will be cleaved under Jones conditions. Chromium-mediated oxidations have a competing pathway involving free-radical intermediates. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern

and Uemura reactions.

REFERENCES : March : 1167 Smith – March : 1514, 1531 Smith : 228 Smith 2nd : 198, 563, 1260 Houben – Weyl : E16d, 357 Org. React. : 53, 1

922

Org. Synth : 45, 77 Org. Synth. Coll. Vol. : 5, 866

1) K. Bowden; I.M. Heilbron; E.R.H. Jones; B.C.L. Weedon, J. Chem. Soc., 1946, 39. 2) F.H. Westheimer, Chem. Rev., 1949, 45, 419. 3) C. Djerrasi; R.R. Engle; A. Bowers, J. Org. Chem., 1956, 21, 1547. 4) D.J. Collins; N.E. Krause, Aust. J. Chem., 1988, 41, 985. 5) S.L. Scott; A. Bakac; J.H. Espenson, J. Am. Chem. Soc., 1992, 114, 4205. 6) S.F. Lu; Q.O. Yang; Z.-W. Guo; B. Yu; Y.-Z. Hui, J. Org. Chem., 1997, 62, 8400. 7) M.H. Ali; C.J. Wiggin, Synth. Commun., 2001, 31, 1389.

COMMENTS :

JOURDAN – ULLMANN – GOLDBERG SYNTHESIS EXAMPLE :

NH2

Br +

COOH

H N 1) K2CO3, Cu 2) H2SO4 O

923

MECHANISM :

Y

X

L2CuII X

-

L2CuIII X

L2CuIII Y

e

L2CuII Y

-

-e

X Y X2CuIIX2 X

CuIXL2

2L CuIIX2

Cu0 2L

X

Z

CuIX

DISCONNECTION :

H N R

Br

NH2 R1

R

+

R1

COOH O

NOTES :

The condensation of anthranilic acid or derivatives with bromobenzene in the presence of copper and base to give a diphenylamino-o-carboxylic acid, which on treatment with sulfuric acid cyclises to an acridone. In general this reaction is between a halogeno benzene and an N-acylarylamine in the presence of a copper catalyst under drastic reaction conditions. The reaction is reported under ultrasound and microwave irradiation. See also Lehmstedt – Tanasescu, Rosenmund – von Braun and Ullmann diaryl ether synthesis reactions.

REFERENCES : March : 657 Smith – March : 864, 928 Org. React. : 14, 19 Org. Synth. : 19, 6 Org. Synth. Coll. Vol. : 2, 15

1) F. Jourdan, Ber. Dtsch. Chem. Ges., 1885, 18, 1444. 2) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382. 3) I. Goldberg, Ber. Dtsch. Chem. Ges., 1906, 39, 1691.

924

4) N. Tuttle, J. Am. Chem. Soc., 1923, 45, 1906. 5) J.F. Bunnett; R.E. Zahler, Chem. Rev., 1951, 49, 273. 6) G.W. Rewcastle; W.A. Denney, Synthesis, 1985, 217. 7) G.W. Rewcastle; W.A. Denney, Synth. Commun., 1987, 17, 309. 8) T.L. Su; B. Kohler; T.C. Chou; M.W. Chun; K.A. Watanabe, J. Med. Chem., 1992, 35, 2703. 9) A. Monge; F.J. Martinez–Crespo; L. Santamaria; S. Narro; A.L. Decerain; E. Hamilton; A.J. Barker, J. Heterocycl. Chem., 1994, 31, 1455.

10) J.A. Spicer; S.A. Gamage; G.J. Atwell; G.J. Finlay; B.C. Baguley; W.A. Denny, J. Med. Chem., 1997, 40, 1919. 11) S.A. Gamage; J.A. Spicer; G.W. Rewcastle; W.A. Denny, Tetrahedron Lett., 1997, 38, 699. 12) B.H. Lipschutz; H. Ueda, Angew. Chem., Int. Ed., 2000, 39, 4492. 13) A. Klapars; J.C. Antilla; X. Huang; S.L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727. 14) J.H.M. Lange; L.J.F. Hofmeyer; F.A.S. Hout; S.J.M. Osnabrug; P.C. Verveer; C.G. Kruse; R.W. Feenstra, Tetrahedron Lett., 2002, 43, 1101.

15) W. Deng; Y.-F. Wang; Y. Zou; L. Liu; Q.-X. Guo, Tetrahedron Lett., 2004, 45, 2311. 16) E.R. Strieter; D.G. Blackmond; S.L. Buchwald, J. Am. Chem. Soc., 2005, 127, 4120.

COMMENTS :

JULIÁ – COLONNA REACTION EXAMPLE :

O

O

Ph

Ph

O

Ph

aq. H2O2, aq. NaOH, toluene, poly-L-alanine

Ph

DISCONNECTION : O

O O

R1

R2

R2

R1

NOTES :

Initially, the oxidation of (E)-chalcone in a stereoselective manner using a triphasic reaction medium, consisting of aqueous H2O2, a water-immiscible organic solvent and an insoluble polyamino acid. Later it was shown that a range

925

of (E)-disubstituted enones including alkyl, aryl and extended conjugated systems could be converted to the oxiranes. Other electrophilic olefins possessing other substitution patterns have been tried without success. New two phase reaction mediums have been introduced. Not all polyamino acids can be used (poly L-phenylalanine, poly L-valine). It has been established that the chiral matrix adjacent to the amino terminus is responsible for the stereochemistry of the product. An industrially viable process has been patented by Bayer chemicals. See also Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Jacobsen – Katsuki, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew, Shi and Weitz – Scheffer reactions.

REFERENCES : Smith 2nd : 233

1) S. Juliá; J. Masana; J.C. Vega, Angew. Chem., Int. Ed. Engl., 1980, 19, 929. 2) S. Juliá; J. Guixer; J. Masana; J. Rocas; S. Colonna; R. Annuziata; H. Molinari, J. Chem. Soc., Perkin Trans. 1, 1982, 1317. 3) M. Lasterra–Sanchez; S.M. Roberts, Curr. Org. Chem., 1997, 1, 187. 4) S. Ebrahim; M. Wills, Tetrahedron: Asymmetry, 1997, 8, 3163. 5) L. Pu, Tetrahedron: Asymmetry, 1998, 9, 457. 6) R. Takagi; T. Manabe; A. Shiraki; A. Yoneshige; Y. Hiraga; S. Kojima; K. Ohkata, Bull. Chem. Soc. Jpn., 2000, 73, 2115.

7) P.C. Ray; S.M. Roberts, J. Chem. Soc., Perkin Trans. 1, 2001, 149. 8) P.A. Bentley; J.F. Bickley; S.M. Roberts; A. Steiner, Tetrahedron Lett., 2001, 42, 3741. 9) C. Lauret; S.M. Roberts, Aldrichimica Acta, 2002, 35, 47. 10) D.R. Kelly; S.M. Roberts, Chem. Commun., 2004, 2018. 11) D.R. Kelly; T.T.T. Bui; E. Caroff; A.F. Drake; S.M. Roberts, Tetrahedron Lett., 2004, 45, 3885.

COMMENTS :

JULIA – JOHNSON CYCLOPROPYL CARBINOL REARRANGEMENT EXAMPLE :

CH3 Br O

ZnBr2

OH CH3

926

MECHANISM :

CH3

H3C

Br

OH

OH

HBr

CH3

O Br

DISCONNECTION :

X

R

R R1

R1

NOTES :

The synthesis of allyl halides (usually E) by rearrangement of cyclopropyl carbinols (acid-catalysed). This reaction is also known under Julia – Bruylants cyclopropyl carbinol rearrangement.

REFERENCES :

1) M. Julia; S. Julia; R. Guégan, Bull. Soc. Chim. Fr., 1962, 1072. 2) S.F. Brady; M.A. Ilton; W.S. Johnson, J. Am. Chem. Soc., 1968, 90, 2882. 3) H. Nakamura; H. Yamamoto; H. Nozaki, Tetrahedron Lett., 1973, 14, 111. 4) R.L. Carney; W.S. Johnson, J. Am. Chem. Soc., 1974, 96, 2549. 5) M.A. Brimble; H. Prabaharan, Tetrahedron, 1998, 54, 2113. 6) A. Menzek; M. Karakaya, Turk. J. Chem., 2004, 28, 141.

COMMENTS :

JULIA – PARIS – KOCIENSKI – LYTHGOE SYNTHESIS EXAMPLE :

O Hex

Li SO2Ph

+

H

Hex

CH3 CH3

1) Ac2O 2) Na(Hg)

927

CH3 CH3

+

CH3 Hex CH3

MECHANISM :

OLi

O Hex

Li +

H

SO2Ph

CH3

Hex

CH3

SO2Ph

CH3 OAc

Ac2O

OAc CH3

Hex SO2Ph

Na(Hg)

CH3

Na(Hg) - NaSO2Ph

H

CH3 OAc

Hex

CH3

H

H CH3

Hex

CH3

Hex

OAc Hex

CH3

CH3

CH3 CH3

CH3

+

Hex CH3

CH3 9:1

R

O R1

O O S

O

S

H

N

N

R1 R

O

N

R1 R

S

N

S O O

S S O O

R1

S O

R1

R

S O O

anti-elimination, - SO2

R

DISCONNECTION :

R2 R1

R3

R1

R2

+

R3

SO2Ph

O

NOTES :

The formation of a mixture of E/Z isomers substituted olefins by the combination of a sulfone with a carbonyl derivative followed by reductive elimination. Instead of sodium amalgam samarium diiodide can also be used. The use of samarium diiodide can give different results compared to the sodium amalgam method. Several modifications

928

of this reaction have been published by Kocienski, Charette (E, Z-dienes) and Julia. For more on the mechanism see Keck et al. See also Corey – Kwiatkowski, Horner – Wadsworth – Emmons, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Smiles

rearrangement, Still – Gennari, Takeda, Tebbe and Wittig olefination reactions.

REFERENCES :

1) M. Julia; J.M. Paris, Tetrahedron Lett., 1973, 14, 4833. 2) P.J. Kocienski; B. Lythgoe; I. Waterhouse, J. Chem. Soc., Perkin Trans. 1, 1980, 1045. 3) S.H. Chen; R.F. Horvath; J. Joglar; M.J. Fisher; S.J. Danishefsky, J. Org. Chem., 1991, 56, 5834. 4) E. Piers; J.S.M. Wai, Can. J. Chem., 1994, 72, 146. 5) D. Seebach; M.A. Maestro; M. Sefkow; G. Adam; S. Hintermann; A. Neidlein, Liebigs Ann. Chem., 1994, 701. 6) M.Z. Hoemann; K.A. Agrios; J. Aube, Tetrahedron Lett., 1996, 37, 953. 7) B. Breit, Angew. Chem., Int. Ed., 1998, 37, 453. 8) T. Eguchi; K. Ibaragi; K. Kakinuma, J. Org. Chem., 1998, 63, 2689. 9) S. Hofman; G. de Braecke; B. Kenda; P.J. de Clerq, Synthesis, 1998, 479. 11) L.J. Gao; X.Y. Zhao; M. van de Walle; P.J. de Clerq, Eur. J. Org. Chem., 2000, 2755. 12) P.J. Kocienski; A. Bell; P.R. Blakemore, Synlett, 2000, 365. 13) I.E. Markó; F. Murphy; L. Kumps; A. Ates; R. Touillaux; D. Craig; S. Carballares; S. Dolan, Tetrahedron, 2001, 57, 2609. 14) R.G. Carter; D.E. Graves, Tetrahedron Lett., 2001, 42, 6035. 15) P.R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 2563. 16) F. Compostella; L. Franchini; L. Panza; D. Prosperi; F. Ronchetti, Tetrahedron, 2002, 58, 4425. 17) G.E. Keck; K.A. Savin; M.A. Weglarz, J. Org. Chem., 2003, 60, 3194. 18) R. Dumeunier; I.E. Markó, Modern Carbonyl Olefination, 2004, 104. 19) D.A. Alonso; C. Nájera; M. Varea, Tetrahedron Lett., 2004, 45, 445. 20) A. Sorg; R. Brückner, Synlett, 2005, 289.

COMMENTS :

929

JULIA INDOLE SYNTHESIS EXAMPLE :

N H

S

O

Toluene 110 oC

N H

MECHANISM :

R4 R

R3

R1 R2

N H

S

O

H

R [3,3]-sigmatropic rearrangement

R1 R2

R4

N H

R4 S

R3

R

R3

O

R1

S NH2 O R2

R4 R

R4 R

R3

R1 R2

OH N S H

R3 - HSOH

N H

R1 R2

DISCONNECTION : R4 R

R3

R O

R3 R1 R2

N H

R1

N

S

+

R4

MgBr

R2

NOTES :

A clever synthesis of the indole ring system from sulfinamides involving a 1-aza-1’-oxa-[3,3]-sigmatropic rearrangement. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe

heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

930

REFERENCES :

1) J.-B. Baudin; S.A. Julia, Tetrahedron Lett., 1986, 27, 837. 2) J.-B. Baudin; M.-G. Comménil; S.A. Julia; R. Lorne; L. Mauclaire, Bull. Soc. Chim. Fr., 1996, 133, 329.

COMMENTS :

JUNG – OLAH – VORONKOV ETHER CLEAVAGE EXAMPLE :

OCH3 + TMSI

COOH

1) CCl4, 50 oC 2) H2O

O

MECHANISM :

CH3 O

CCl4 50 oC

OCH3

I O Si(CH3)3

+ TMSI O

O + CH3I

COOH H2O

O Si(CH3)3

DISCONNECTION :

O R P OR1 OR1

O R P OH OH

R

R

OR1 O

OH O OH

OR1 R2N

R2N

O

O

931

slow

NOTES :

The cleavage of ethers of esters, carbamates, phosphonates with trimethylsilyl bromides or iodides. See also Appel – Robinson, Gustus cleavage, Herzig – Meyer, Mann dealkylation, Prey, Stoermer dealkylation and Zeisel reactions.

REFERENCES : Smith – March : 520 Smith : 137, 638 Org. Synth. : 59, 35 Org. Synth. Coll. Vol. : 6, 353

1) M.G. Voronkov; Yu.I. Kudobin, Izv. Akad. Nauk. SSSR, Ser. Khim., 1956, 713. 2) T.-L. Ho; G.A. Olah, Angew. Chem., Int. Ed. Engl., 1976, 15, 774. 3) M.E. Jung; M.A. Lyster, J. Am. Chem. Soc., 1977, 99, 968. 4) G.A. Olah; A. Husain; B.P. Singh; A.K. Mehrotra, J. Org. Chem., 1983, 48, 3667. 5) M.E. Jung; L.A. Light, J. Am. Chem. Soc., 1984, 106, 7614. 6) G. Meshitsuka; T. Kondo; J. Nakano, J. Wood Chem. & Tech., 1987, 7, 161.

COMMENTS :

JUST SYNTHESIS EXAMPLE :

OH CO2Et

Cl N

1) [CH(CO2Et)2]-Na+ 2) 240 - 250 oC toluene

932

N

MECHANISM :

Cl N

EtO

CH(CO2Et)2 [CH2(CO2Et)2] Na

H

OEt O

N N

H+ O

OH CO2Et

CO2Et H

240 - 250 oC toluene

O

N

N

DISCONNECTION :

OH CO2Et

Cl

N

N

NOTES :

Quinolines are obtained by the condensation of benzanilide imidochlorides with sodium diethyl malonate followed by the thermal cyclisation of the propionic acid derivatives. Analogous compounds are formed when sodium diethyl malonate is replaced by sodium diethyl acetoacetate. The method is also applicable to napthylbenzyl iminochlorides. See also Conrad – Limpach and Pfitzinger reactions.

REFERENCES :

1) F. Just, Ber. Dtsch. Chem. Ges., 1885, 18, 2623. 2) F. Just, Ber. Dtsch. Chem. Ges., 1885, 18, 2632. 3) R.C. Shah; V.R. Heeramaneck, J. Chem. Soc., 1936, 428. 4) V.R. Heeramaneck; R.C. Shah, J. Chem. Soc., 1937, 867.

COMMENTS :

933

934

KNOEVENAGEL AMINE SYNTHESIS · 994 KNOEVENAGEL CONDENSATION · 995

B

KNOEVENAGEL COUMARIN SYNTHESIS · 997 KNOEVENAGEL CYCLOHEXENONE SYNTHESIS · 998

BREDERECK MODIFICATION · 1012

KNOEVENAGEL DIAZOTATION · 999 KNOFFLER – BACHMANN CYCLONITE SYNTHESIS · 1001 G

KNOOP – OESTERLIN AMINO ACID SYNTHESIS · 1001 KNORR PYRAZOLE SYNTHESIS · 1003

GANEM OXIDATION · 1027

KNORR PYRROLE SYNTHESIS · 1004 KNORR QUINOLINE SYNTHESIS · 1005

K

KNUNYANTS FLUORO ALKYLATION · 1007 KOCH – HAAF REACTION · 1008

KABACHNIK – FIELDS REACTION · 937

KOCHI DECARBOXYLATION · 1009

KABBE CHROMANONE SYNTHESIS · 938

KOCHI REACTION · 1010

KAGAN – MODENA REACTION · 940

KOENIGS – KNORR SYNTHESIS · 1012

KAGAN – MOLANDER REACTION · 941

KOHLER ISOXAZOLE-N-OXIDE SYNTHESIS · 1013

KAHNE – RYU – CURRAN HYDROXYMETHYLATION · 943

KOLBE – SCHMITT REACTION · 1015

KAHNE GLYCOSIDATION · 944

KOLBE ALDEHYDE SYNTHESIS · 1016

KAISER – JOHNSON – MIDDLETON DINITRILE CYCLISATION ·

KOLBE CYANIDE ALKYLATION · 1017

945

KOLBE ELECTROLYTIC SYNTHESIS · 1018

KAISER TRIAZOLE SYNTHESIS · 947

KONDAKOFF OLEFIN REACTION · 1019

KAKIS – KIKUCHI REARRANGEMENT · 948

KONDO – UYEO SYNTHESIS · 1020

KALB – GROSS SYNTHESIS · 949

KÖNIG BENZOXAZINE SYNTHESIS · 1022

KALUZA ISOTHIOCYANATE SYNTHESIS · 950

KOPETSCHNI CONVERSION · 1023

KAMETANI – TSUJI AMINE OXIDATION · 951

KORNBLUM – DELAMARE REARRANGEMENT · 1023

KANEMASA REACTION · 953

KORNBLUM – RUSSELL REACTION · 1024

KAPP – KNOLL SYNTHESIS · 954

KORNBLUM ALDEHYDE SYNTHESIS · 1026

KARRER SYNTHESIS · 956

KÖRNER – CONTARDI REPLACEMENT · 1028

KATO – YAMABE REACTION · 957

KOSER TOSYLATION · 1029

KATOH SYNTHESIS · 958

KOST – SAGITULLIN REARRANGEMENT · 1031

KATSUKI – SHARPLESS EPOXIDATION · 959

KOSTANECKI von (ALLAN – ROBINSON) ACYLATION · 1032

KAUFFMANN DIMERISATION · 962

KOTALI – TSOUNGAS REACTION · 1034

KAWASE REARRANGEMENT · 963

KOWALSKI ESTER HOMOLOGATION · 1036

KECK ALLYLATION · 964

KRAFFT DEGRADATION · 1037

KEKULÉ SYNTHESIS · 965

KRAPCHO DECARBOXYLATION · 1038

KEMP ELIMINATION · 966

KRIEF – REICH – CHOW OLEFINATION · 1040

KENDALL – MATTOX REACTION · 968

KRIEWITZ – PRINS ADDITION · 1041

KENNEDY OXIDATIVE CYCLISATION · 969

KRÖHNKE – ORTOLEVA – KING ALDEHYDE SYNTHESIS · 1043

KENNER SYNTHESIS · 971

KRÖHNKE PYRIDINE SYNTHESIS · 1044

KERK VAN DER – SCHLESINGER REACTION · 972

KUHN – ROTH OXIDATION · 1046

KERP REDUCTION · 973

KUHN – WINTERSTEIN REACTION · 1047

KHARASCH – CURRAN REACTION · 974

KULINKOVICH REACTION · 1048

KHARASCH – KLEIMANN SYNTHESIS · 976

KUMADA – TAMAO – CORRIU CROSS–COUPLING · 1049

KHARASCH – SOSNOVSKY REACTION · 977

KUMADA – TAMAO – FLEMING STEREOSELECTIVE

KHARASCH – URRY REARRANGEMENT · 979

HYDROXYLATION · 1052

KIHARA INDOLE SYNTHESIS · 980

KUMADA REARRANGEMENT · 1054

KILIANI – FISCHER SYNTHESIS · 982

KURSANOV – PARNES IONIC HYDROGENATION · 1056

KILIANI REDUCTION · 983

KUTSCHEROFF – DENIGÈS HYDRATION · 1057

KIMPE de SYNTHESIS · 985 KINDLER SYNTHESIS · 986 M

KINUGASA REACTION · 987 KISHNER CYCLOPROPANE SYNTHESIS · 988

MARASSE MODIFICATION · 1015

KITA ESTERIFICATION · 990 KNOCHEL REACTION · 992

935

P

Z

PRINS REACTION · 975

ZEMPLEN – HELFERICH MODIFICATION · 1012

S SCHROEDER MODIFICATION · 1013

936

KABACHNIK – FIELDS REACTION EXAMPLE :

Bu NH2

H3C

+

CH3

+

O

O H P OEt OEt

H3C O H3C P OEt Bu N OEt H

MECHANISM :

R1 HO

R1

RNH2 +

R2 O

R1

R1

R2 OEt

H

P O

+

R

O

OEt P

OEt

O

OEt

O H P OEt OEt

R1 R2

R2 N

R2

R O H P OEt OEt

OEt

N H

P OEt

O

DISCONNECTION :

R1

R2 O

H

R1

OEt P

O

R2 O

OEt

R1 R2 R

OEt

N H

RNH2

P O

OEt

937

+

+

O H P OEt OEt

O H P OEt OEt

NOTES : The key step in the Kabachnik – Fields reaction is the nucleophilic addition of a nucleophilic amine to a carbonyl compound followed by the addition of a dialkyl or diaryl phosphite. Besides the formation of the aminophosphate, the hydroxyphosphate is observed. The carbonyl compound can be attacked by two nucleophiles, the amine and the phosphite. Both may compete for the electrophile. Gancarz has explained the different ratio of products obtained, in terms of the softer the carbonyl compound, the faster it will react with the softer phosphorus nucleophile and the slower it reacts with the harder amine nucleophile. See also Moedritzer – Irani, Oleksyszyn and Pudovik reactions.

REFERENCES : 1) E.K. Fields, J. Am. Chem. Soc., 1952, 74, 1528. 2) M.I. Kabachnik; T.Ya. Medved, Izv. Akad. Nauk. SSSR, Ser. Chim., 1953, 1126. 3) M.I. Kabachnik; T.Ya. Medved, Izv. Akad. Nauk. SSSR, Ser. Chim., 1954, 1024. 4) M.I. Kabachnik; T.Ya. Medved; N.M. Dyatlova; O.G. Arkhipova; M.V. Rudomino, Russ. Chem. Rev. (Engl. Transl.), 1968, 38, 503. 5) R. Gancarz; I. Gancarz, Tetrahedron Lett., 1993, 34, 145. 6) T. Bailly; R. Burgada, Phosphorus Sulfur, 1995, 101, 131. 7) R. Gancarz, Tetrahedron, 1995, 51, 10627. 8) H.-J. Cristau; A. Coulombeau; A. Genevois–Borella; J.-L. Pirat, Tetrahedron Lett., 2001, 42, 4491.

COMMENTS :

KABBE CHROMANONE SYNTHESIS EXAMPLE :

O

O

O CH3

+

H N

OH

938

O

MECHANISM :

O

H N

+

N - H2O

O

O N N

OH

O

H+ O

OH N

O

O

DISCONNECTION :

O

O R

R1

R O

CH3 OH

R2

O +

R1

R2

NOTES : The synthesis of 4-chromanones by condensation of salicylaldehydes or o-hydroxyaryl ketones with enamines or ketones. This is a Mukaiyama aldol reaction followed by acidic ring-closure of the β-hydroxy ketone.

REFERENCES : 1) H.J. Kabbe; H. Heitzer, Liebigs Ann. Chem., 1976, 511, 511. 2) H.J. Kabbe, Synthesis, 1978, 886. 3) S.E. Kelly; B.C. van der Plas, J. Org. Chem., 1991, 56, 1325. 4) H. Seliger; A. Cascaval; E. Happ, Rev. Roum. Chim., 1992, 37, 485. 5) S-e. Yoo; I.-C. Jeon; K.Y. Yi; K.S. Kim, Bull. Korean Chem. Soc., 2001, 22, 917.

COMMENTS :

939

KAGAN – MODENA REACTION EXAMPLE :

O S

CH3

S

t

BuOOH, Ti(OiPr)4 (+)-DET, DCM, - 78 oC

CH3

MECHANISM :

O

EtO S

Rs

+ ROH

Rl

O

EtO2C

O O

HO Pi r

Ti

ROOH

OiPr i O Pr

2 iPrOH

2 iPrOH EtO

EtO O

EtO2C

O O

Ti i

PrO

O

EtO2C

O R

O O

O Rs

S

Ti

O

R

O OiPr

Rl

Rs

S Rl

DISCONNECTION :

O Rl

S

Rs

Rl

S

Rs

NOTES : The use of diethyltartrate and titanium isopropoxide and hydroperoxides as oxidant in the oxidation of aromatic thioethers. The use of the Sharpless reagent only afforded racemic sulfoxides. By adding one equivalent of water (later 2-propanol) and by adding molecular sieves the reaction was not only made enantioselective but also catalytic. For more details about the active species see Potvin et al. See also Katsuki – Sharpless epoxidation reaction.

940

REFERENCES : March : 1201 Smith – March : 1541 Smith : 320 Smith 2nd : 280 Org. Syn : 68, 49 Org. Syn. Coll. Vol. : 8, 464

1) P. Pitchen; E. Duñach; M.N. Desmukh; H.B. Kagan, J. Am. Chem. Soc., 1984, 106, 8188. 2) F. Di Furia; G. Modena; R. Seraglia, Synthesis, 1984, 325. 3) P. Pitchen; H.B. Kagan, Tetrahedron Lett., 1984, 25, 1049. 4) J.-M. Brunel; P. Diter; M. Duetsch; H.B. Kagan, J. Org. Chem., 1995, 60, 8086. 5) P.G. Potvin; B.G. Fieldhouse, Tetrahedron: Asymmetry, 1999, 10, 1661.

COMMENTS :

KAGAN – MOLANDER REACTION EXAMPLE :

I H O O

4 SmI2 THF

Cl

941

OH H

MECHANISM :

O

O R1

R

R2

O

R SmI2

O

OH

O

R2

R1

R2

R

MeOH

O

R

R2

SmI2

O R R 1 2

OH R1 R 2

R1 R

OH

R1

R

O

OH

NOTES : Samarium and ytterbium reagents are used for the generation of free radicals, useful in Barbier-type reactions, reductions and cyclisations.

REFERENCES : March : 443, 1029, 1225 Smith – March : 528, 568 Org. React. : 46, 211

1) P. Girard; J.L. Namy; H.B. Kagan, J. Am. Chem. Soc., 1980, 102, 2693. 2) G.A. Molander; G. Hahn, J. Org. Chem., 1986, 51, 2596. 3) H.B. Kagan; J.L. Namy, Tetrahedron, 1986, 42, 6573. 4) J.A. Soderquist, Aldrichimica Acta, 1991, 24, 15. 5) G.A. Molander; J.A. McKie, J. Org. Chem., 1991, 56, 4112. 6) G.A. Molander, Chem. Rev., 1992, 92, 29. 7) S. Hanessian; C. Girard; J.L. Chiara, Tetrahedron Lett., 1992, 33, 573. 8) J.L. Namy; P. Girard; H.B. Kagan, New. J. Chem., 1997, 1, 5. 9) A. Krief; A.-M. Laval, Chem. Rev., 1999, 99, 745. 10) T.-Y. Lin; M.-R. Fuh; L.-S. Chan, J. Chin. Chem. Soc., 2001, 48, 843. 11) A. Hölemann; H.-U. Reissig, Org. Lett., 2003, 5, 1463.

COMMENTS :

942

KAHNE – RYU – CURRAN HYDROXYMETHYLATION EXAMPLE :

H3C

H3C

O

HOH2C

I BzO

H

O H

BzO

OH

OH

cat. Ph3GeH, NaBH3CN, AIBN, CO C6H6, THF, 105 oC, 12 hours OCH3

OCH3

MECHANISM :

Sn(C6F13CH2CH2)3H

R

SnX

CO

NaBH3CN

RX Sn

RCH2OH

RC=O

NaBH3CN

RCHO

DISCONNECTION :

RCH2OH

X = Br, I

RX

NOTES : Alkyl or aryl bromides or iodides are converted to the corresponding hydroxymethyl compounds by treatment with a catalytic amount of triphenylgermane or fluorous tin hydrides, NaBH3CN, AIBN in benzene and THF or in the case of the tin compounds benzotrifluoride and tert-butyl alcohol.

REFERENCES : 1) V. Gupta; D. Kahne, Tetrahedron Lett., 1993, 34, 591. 2) I. Ryu; T. Niguma; S. Minakata; M. Komatsu; S. Hadida; D.P. Curran, Tetrahedron Lett., 1997, 38, 7883. 3) T. Nakamura; H. Yorimitsu; H. Shinokubo; K. Oshima, Synlett, 1999, 1415.

943

COMMENTS :

KAHNE GLYCOSIDATION EXAMPLE :

OTIPS OMPM

MPMO OTIPS

O

+

OH

OMPM S Ph

MPMO OTIPS

MPMO

MPMO

O

1.8 Tf2O 5.9 DTBMP 4A MS, DCM - 90 oC

OMPM O OMPM O

TIPSO

OTIPS

OTIPS

MECHANISM :

O R O R R

O S

O R1 F3C S O O R F3C S O O

R

R O

- OTf R

O R

OTf R

R

O NucH Base - TfOH-Base

R R

R

R

R R

944

Nuc

O S

O

S

CF3 R1 - TfOSR OTf

DISCONNECTION :

R

R O

Nuc

R

O

R

R

O S

R1

R

R

R

NOTES : The diastereoselective glycosidation at the anomeric centre of glycosyl sulfoxides with trifluoromethanesulfonic acid. See also Fischer glycosidation, Koenigs – Knorr glycosidation, Michael glycosidation and Schmidt glycosidation reactions.

REFERENCES : Org. React. : 64, 115

REFERENCES : 1) D. Kahne; S. Walker; Y. Cheng; D. van Engen, J. Am. Chem. Soc., 1989, 111, 6881. 2) L. Yan; C.M. Taylor; R. Goodnow, jr.; D. Kahne, J. Am. Chem. Soc., 1994, 116, 6953. 3) D. Crich; H. Li, J. Org. Chem., 2000, 65, 801. 4) H. Pellissier, Tetrahedron, 2004, 60, 5123.

COMMENTS :

KAISER – JOHNSON – MIDDLETON DINITRILE CYCLISATION EXAMPLE :

CN

CN

HBr, HOAc

945

Br

N

NH2

MECHANISM :

N Br

Br

N

N

Br

NH

N

NH2

H+

DISCONNECTION :

Br

N

C N

CN

NC H2N

C N

NH2

S

NC

CN

NH2

CN

NC

CN

CN Br

N H

NC Br

N H

NH2 CN

CN NC

SO3H

CN CN

NOTES : The synthesis of heterocycles by cyclisation of dinitriles with HBr to afford pyridines, imidazoles, thiophenes and pyrroles.

REFERENCES : 1) A.M. Kaiser; J.J. Roemer, U.S. Patent, 1953, 2630433. 2) W.J. Middleton; V.A. Engelhardt; B.S. Fisher, J. Am. Chem. Soc., 1958, 80, 2822. 3) F. Johnson; W.A. Nasutuavicus, J. Org. Chem., 1964, 29, 153.

COMMENTS :

946

KAISER TRIAZOLE SYNTHESIS EXAMPLE : H

O N N CN

+

HCl.NH2NH2.HCl

O H

N N 1) CH3OH, heat 2) H+

N H

NH2

MECHANISM :

H2N H

O N N CN

+ NH2NH2

O H

NH H N O OH HN

- H2O

N

N O HN

N

N H N H2N

HN

+

H

N N H

H N

H N N N H

H

H N N

H+

NH2

H N

O N N H H

O H+

NH2

N

H N

N NH2

O

DISCONNECTION : N N

H

O

R N H

N H

O N

R

NH2

N CN O H

NOTES : The synthesis of 3-amino- and 3-ureido-1,2,4-triazoles by condensation of acyl-3-cyanoureas with hydrazines. See also Einhorn – Brunner and Pellizzari reactions.

REFERENCES : 1) D.W. Kaiser, U.S. Patent, 1945, 2382156. (Chem. Abs., 1946, 40, 368)

947

2) D.W. Kaiser, U.S. Patent, 1946, 2399598. (Chem. Abs., 1946, 40, 4227) 3) A.A. Komzak; J.B. Polya, J. Appl. Chem., 1952, 2, 666.

COMMENTS :

KAKIS – KIKUCHI REARRANGEMENT EXAMPLE :

Ph H

Ph

+ Br2

Ph

Ph

Ph

O

Ph

H

1) Ag+ 2) H2O

MECHANISM :

Ph

Ph H H

Ph

Ph

Br

+ Br2

Br

Ph Ag+ - AgBr

Ph Ph

Ph

Ph

Br Ph H2O

Ph

Ph H OH

H

Ph

Ag+ - AgBr

Ph

Br Ph

Ph H

Ph O H

O

H

Ph

DISCONNECTION :

R

R1

R1 H

O

H

R

R2

R2

NOTES : The formation of ketones by bromination followed by rearrangement of substituted ethylenes using silver(I) salts.

948

REFERENCES : March : 1197 Smith – March : 1538

1) F.J. Kakis; D. Brase; A. Oshima, J. Org. Chem., 1971, 36, 4117. 2) M. Fétizon; F.J. Kakis; V. Ignatiadou–Ragoussis, J. Org. Chem., 1973, 38, 1732. 3) H. Kikuchi; K. Kogure; M. Toyoda, Chem. Lett., 1984, 341. 4) M. Koreeda; L.A. Dixon; J.D. Hsi, Synlett, 1993, 555. 5) K.W. Field; J.S. Moroz, Abstr. Pap. Am. Chem. Soc., 2001, 222, 426.

COMMENTS :

KALB – GROSS SYNTHESIS EXAMPLE :

H N

NH2

O

H

NH4OH K3Fe(CN)6

O

MECHANISM :

H N

R O

NH2

R NH4OH K3Fe(CN)6

N

N

R

H - N2

O

DISCONNECTION :

R

H

H N

R

O

O

949

NH2

H O

NOTES : Aldehydes are obtained by the alkaline oxidation of acylhydrazines (potassium ferricyanide in an excess ammonia solution). Also other oxidation reagents have been used. See also McFadyen – Stevens reaction.

REFERENCES : Houben – Weyl : 7/1, 297 Org. React. : 8, 218

1) L. Kalb; O. Gross, Ber. Dtsch. Chem. Ges., 1926, 59, 727. 2) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 3) H.N. Wingfield; W.R. Harlan; H.R. Hanmer, J. Am. Chem. Soc., 1952, 74, 5796.

COMMENTS :

KALUZA ISOTHIOCYANATE SYNTHESIS EXAMPLE :

Cl

NH2

Cl

N

S

1) CS2, 0 oC Et3N 2) ClCO2Et Et3N, 0 oC

MECHANISM : S S Cl

NH2

CS2, 0 oC Et3N

Cl

N H HNEt3

950

ClCO2Et Et3N, 0 oC

Cl

N

S

DISCONNECTION :

RNH2

RNCS R = Alk, Ar

NOTES : The formation of thioisocyanates from amines. The second step can also be done with lead nitrate. The original Kaluza reaction is not applicable to aryl amines, see Hodgkins et al. See also Böttinger – Michaelis reaction and Hugershoff synthesis.

REFERENCES : Org. Synth. : 6, 72 Org. Synth. Coll. Vol. : 1, 447

1) H. Kaluza, Monatsh. Chem., 1912, 33, 363. 2) E. Schmidt; E. Kammerl; D. Ross, Liebigs Ann. Chem., 1955, 594, 233. 3) J.E. Hodgkins; M.G. Ettlinger, J. Org. Chem., 1956, 21, 404. 4) J.E. Hodgkins; W.P. Reeves; Y.T. Liu, J. Am. Chem. Soc., 1961, 83, 2532. 5) J.E. Hodgkins; W.P. Reeves, J. Org. Chem., 1964, 29, 3098. 6) S. Rádl, Coll. Czech. Chem. Commun., 1992, 57, 656.

COMMENTS :

KAMETANI – TSUJI AMINE OXIDATION EXAMPLE :

MeO NH2

CuCl, O2 pyridine, 60 oC mol. sieves

951

MeO CN

MECHANISM : Oxidation in pyridine :

RCH2NH2

H R

RCH2NH2

"CuII" Pyridine

- e- CuI

H

H N

H

("CuII")

N H H

R

I N + 2 Cu

II

2 "Cu " - 2 H+ - 2 e-

R

Oxidation in acidic organic medium :

RCH2NH2 CuI OAc

1/2 O2

O CuIII OAc

RCH2NH2

RCH2NH2 H CuI OAc

R

H

R

NH2 R

OH N CuIII H H OAc

H2O

H

+ NH3

O

DISCONNECTION :

R

N

R

H

R

NH2

O

NOTES : The oxidation of primary aliphatic or aromatic amines to nitriles by Cu(I) – O2 and pyridine and to aldehydes under acidic media. The addition order of the reagents is very important under the first conditions. First the amine is dissolved in pyridine, an oxygen atmosphere is applied and slowly the copper(I) salt is added. Active species is (pyridine)4Cu4Cl4O2. An improved system involves copper(I) or copper(II) chloride as catalyst, toluene as solvent and molecular sieves as dehydrating agent under atmospheric pressure of oxygen. In both cases the oxidation proceeds through a radical pathway involving ammoniumyl and alkylideneaminyul radicals.

952

REFERENCES : 1) T. Kajimoto; H. Takahashi; J. Tsuji, J. Org. Chem., 1976, 41, 1389. 2) T. Kametani; K. Takahashi; T. Ohsawa; M. Ihara, Synthesis, 1977, 245. 3) P. Capdevielle; A. Lavigne; M. Maumy, Synthesis, 1989, 453. 4) P. Capdevielle; A. Lavigne; M. Maumy, Tetrahedron, 1990, 46, 2835. 5) P. Capdevielle; A. Lavigne; D. Sparfel; J. Baranne–Lafont; N.K. Cuong; M. Maumy, Tetrahedron Lett., 1991, 31, 3305. 6) Y. Maeda; T. Nishimura; S. Uemura, Bull. Chem. Soc. Jpn., 2003, 76, 2399.

COMMENTS :

KANEMASA REACTION EXAMPLE :

N TBSO

OTBS

OH

N O

CH3

+

H

t

1) BuOCl, - 78 C H3C 2) 3.3 iPrOH 3 EtMgBr, DCM

OH

CH3

o

OH

CH3

MECHANISM :

N

Ph

OH OMgBr

+ Ph

H

Cl

OH

N O

N O H O

Ph

MgXn

OH

H H

Et

DISCONNECTION :

N O R

N

R3 R

R1 R2 OH

953

Et

OH H

+

R1

R3 R2

OH

NOTES : This reaction is a magnesium(II) directed nitrile oxide cycloaddition with allylic alcohols.

REFERENCES : 1) S. Kanemassa; M. Nishiuchi; A. Kamimure; K. Hori, J. Am. Chem. Soc., 1994, 116, 2324. 2) S. Kanemassa; K. Okuda; H. Yamamoto; S. Kaga, Tetrahedron Lett., 1997, 38, 4095. 3) K.V. Gothelf; K.A. Jørgensen, Chem. Rev., 1998, 98, 863. 4) J.W. Bode; N. Fraefel; D. Muri; E.M. Carreira, Angew. Chem., Int. Ed., 2001, 40, 2082.

COMMENTS :

KAPP – KNOLL SYNTHESIS EXAMPLE :

OH H3C

CO2Et + BrCH2(CH2)4CO2Et O

15

1) NaOEt 2) Na 3) Cl 8

O 4) dil. KOH 5) H2SO4 6) NaOH HCl 7) NaOEt NH2NH2

954

CH2

O

MECHANISM :

(CH2)5CO2Et H3C

CO2Et

+

H3C

BrCH2(CH2)4CO2Et

NaOEt

O (CH2)5CO2Et H3C O

+

8

Na

H2C

H3C

Cl

Na

O

EtO2C EtO2C(CH2)5

CHO2Et

CO2Et

O CH2 O

dil. KOH

8

O

EtO2C(CH2)5

CO2Et O

6

8

CO2H

CO2Et O H2SO4 8

6

O 1) NaOH CH2 2) HCl

8

CH2

1) NaOEt 2) NH2NH2

CH2 OH 15

O

DISCONNECTION :

H2C CH(CH2)15COOH H3C (CH2)14COOH

OEt O

O

+

Br(CH2)4CH2

OEt O

NOTES : This synthesis of these acids (16, 17- or 17,18-octadecenoic acid) involves the preparation of the unsaturated ketoacids from acetoacetic ester, followed by the reduction of these acids by the Wolff – Kishner – Staudinger method. This method is an example of the Robinson – Robinson synthesis. See also Baudart, Bowman, Noller and Robinson – Robinson reactions.

REFERENCES : R. Kapp; A. Knoll, J. Am. Chem. Soc., 1943, 65, 2062.

COMMENTS :

955

KARRER SYNTHESIS EXAMPLE :

H OH

O

H

OH

+

N Cl 1) ZnCl2 2) H2O

Br OH

OH

MECHANISM :

Br HCl + Br

N Cl

N H H

Cl

N

N

Br O

H

H

N

Cl + O H

H

Cl OH

O OH

ZnCl2

H2O

OH

OH

OH

OH

DISCONNECTION :

OH R

OH BrCN +

H

R

O

NOTES : A phenolic aldehyde is obtained by treating a phenol with cyanogen bromide, hydrogen chloride and zinc chloride. See also Gattermann – Koch, Houben – Fischer and Houben – Hoesch reactions.

REFERENCES : Houben – Weyl : E5, 1444

1) P. Karrer, Helv. Chim. Acta, 1919, 2, 89. 2) J. Renz, Helv. Chim. Acta, 1947, 30, 124.

956

COMMENTS :

KATO – YAMABE REACTION EXAMPLE :

F F F F F

F F F F F F O F P(OEt)2 F F F F F F

I

F

F F F F F F F

1) [(EtO)2P]2O t BuOOtBu CF2ClCCl2F 120 oC, 3h 2) tBuOOH MeOH, CF2ClCCl2F

RfI

[RfP(OEt)2]

MECHANISM :

[(EtO)2P]2O t BuOOtBu CF2ClCCl2F 120 oC, 3h

Rf t

BuOOH MeOH, CF2ClCCl2F

O P OEt OEt

DISCONNECTION :

Rf

O P(OEt)2

RfI

Rf = perfluoroalkyl chain

NOTES : A synthetic route to perfluoroalkyl phosphonates via phosphates. See also Burton – Wiemers reaction.

REFERENCES : 1) M. Kato; M. Yamabe, J. Chem. Soc., Chem. Commun., 1981, 1173. 2) H.K. Nair; D.J. Burton, J. Am. Chem. Soc., 1997, 119, 9137.

957

COMMENTS :

KATOH SYNTHESIS EXAMPLE :

H

Cl

+

COOH 1) Et3N, 170 oC 2) H2O

O

O

MECHANISM :

H Cl

Et3N, 170 oC

O

Cl O

O H H

O

Cl OH

Cl

- H2O

Ph

HOOC

H2O

O

DISCONNECTION :

H

COOH R(R1)

R R or R1 = Alk

Cl R1

O

H + O

NOTES : Acid chlorides of the type RCH2COCl condense with benzaldehydes in the presence of triethylamine to yield substituted cinnamic acids.

958

REFERENCES : 1) Katoh, Sci. Rep. Tokyo Bunrika Daigaku, 1935, 257. (Chem. Zentralbl. 1936, 107, 2324) 2) C.A. VanderWerf, Trans. Kansas Acad. Sci., 1947, 50, 363. (Chem. Abs., 1948, 42, 2571.)

COMMENTS :

KATSUKI – SHARPLESS EPOXIDATION EXAMPLE :

OH

O i

t

Ti( OPr)4, BuOOH DCM, - 20 oC OH EtO2C CO2Et OH

MECHANISM :

(-)-dialkyl tartrate

R2

R1

OH

R3

(+)-dialkyl tartrate

959

OH

OR O

O OH

R

RO

RO

O Ti

O ROH

O RO2C Ti

O

R

OH

OR

O OR

OR

ROH

CO2R OR t

Bu O

RO

RO

O Ti

O RO2C Ti

O

O

CO2R RO

O

CO2R

O RO2C Ti O CO2R

R

O OR

O OR

O

OR

O Ti

O O

O

RO

R

t

Bu O

RO

RO

O Ti

O

O RO2C Ti

CO2R O

t

BuOOH

O

O

ROH

O

OR CO2R

R

DISCONNECTION :

R2 O R R3 R R1 HO

R2

R

R3

R2 O R

HO

R

R1

R3 R1 R HO

NOTES : This is the enantioselective epoxidation of a wide range of allyl alcohols using titanium alkoxide, (+) or (-) diethyltartarate (DET) and t-butyl hydroperoxide (TBHP). It is compatible with a various amount of functional groups. The use of tartrate esters results in enantioselective epoxidation of the alkene. The reaction was later fine-tuned to a catalytic version by the addition of molecular sieves. The reaction is almost insensitive to the identity of R and R1. R2 has to be small for the reaction to be fast and highly enantioselective. R3 has to be hydrogen otherwise the reaction rate will decrease. Titanium has also been replaced by zirconium. See also Buchner – Curtius – Schlotterbeck,

960

Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Mukaiyama – Yamada, Prileschajew, Shi and Weitz – Scheffer reactions.

REFERENCES : Smith – March : 1053 Smith : 275 Smith 2nd : 239 Org. React. : 48, 1 Org. Synth. : 63, 66 Org. Synth. Coll. Vol. : 7, 461

1) T. Nakata; G. Schmid; B. Vranessis; M. Okigawa; T. Smith–Palmer; Y. Kishi, J. Am. Chem. Soc., 1978, 100, 2933. 2) E.J. Corey; A. Marfat; J.R. Falck; J.O. Albright, J. Am. Chem. Soc., 1980, 102, 1433. 3) T. Katsuki; K.B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974. 4) B.E. Rossiter; T. Katsuki; K.B. Sharpless, J. Am. Chem. Soc., 1981, 103, 464. 5) S. Danishefsky; R. Zamboni; M. Kahn; S.J. Etheredge, J. Am. Chem. Soc., 1981, 103, 3460. 6) K.B. Sharpless, Aldrichimica Acta, 1983, 16, 67. 7) S.S. Woodard; M.G. Finn; K.B. Sharpless, J. Am. Chem. Soc., 1991, 113, 106. 8) M.G. Finn; K.B. Sharpless, J. Am. Chem. Soc., 1991, 113, 113. 9) S. Takano; Y. Iwabuchi; K. Ogasawara, Tetrahedron Lett., 1991, 32, 3527. 10) A.H. Hoveyda; D.A. Evans; G.C. Fu, Chem. Rev., 1993, 93, 1307. 11) T. Yoshimitsu; K. Ogasawara, Chem. Commun., 1994, 2197. 12) A.C. Spivey; S.J. Woodhead; M. Weston; B.I. Andrews, Angew. Chem., Int. Ed., 2001, 40, 769. 13) J. Huang; E.J. Corey, Org. Lett., 2003, 5, 3455. 14) N.N. Reed; T.J. Dickerson; G.E. Boldt; K.D. Janda, J. Org. Chem., 2005, 70, 1728.

COMMENTS :

961

KAUFFMANN DIMERISATION EXAMPLE :

Ph

CN

Ph N N

2

1) PhMgBr 2) CuCl, 35 oC 3) O2, 40 oC

Ph

Ph

MECHANISM :

R1

R1 2 R CN R1MgBr

N MgBr

2

CuCl

R

R1

N Cu

2 R

O2

R1 N N

R

R

DISCONNECTION :

R1

R1 2 R CN + R1MgBr

N N R

R

NOTES : Substituted methyleneamidomagnesium halides, which are readily obtainable by the action of Grignard compounds on nitriles, are converted by copper(I) chloride in THF, diethyl ether mixtures into thermally fairly stable copper(I) amides, which react rapidly with oxygen to form ketazines.

REFERENCES : 1) Th. Kauffmann; J. Albrecht; D. Berger; J. Legler, Angew. Chem., Int. Ed. Engl., 1967, 6, 633. 2) Th. Kauffmann; D. Berger, Chem. Ber., 1968, 101, 3022. 3) Th. Kauffmann, Angew. Chem., Int. Ed. Engl., 1974, 13, 291.

COMMENTS :

962

KAWASE REARRANGEMENT EXAMPLE : OH COOH

N t

Bu

O

N 1) TFAA pyridine DMAP 2) 10% HCl dioxane

t

Bu

CF3

O

MECHANISM :

H

O N

N OH R

- H2O

O

CF3

O O

N

CF3

O

TFAA R

R

O

O O O

R N CF3CO2

CF3

N

CF3 O

O

CF3

R

DISCONNECTION :

O O R

N

CF3

COOH

N

O R

CF3

O

NOTES : The base-catalysed reaction of N-acyl prolines with trifluoroacetic anhydride proceeds through mesoionic 1,3oxazolium-5-olates, followed by ring-closure of the pyrrolidine ring. See also Dakin – West reaction.

REFERENCES : 1) M. Kawase, Chem. Commun., 1992, 1076. 2) M. Kawase; H. Miyamae; M. Narita; T. Kurihara, Tetrahedron Lett., 1993, 34, 859. 3) M. Kawase, Tetrahedron Lett., 1994, 35, 149. 4) M. Kawase; S. Saito; H. Kikuchi; H. Miyamae, Heterocycles, 1997, 45, 2185.

963

5) M. Kawase; M. Hirabayashi; H. Koiwai; K. Yamamoto; H. Miyamae, Chem. Commun., 1998, 641.

COMMENTS :

KECK ALLYLATION EXAMPLE :

OCH3

OCH3 H O

OCH3 +

OH

SnBu3 Ti(O Pr)4 (S)-BINOL MS 4 A - 20 oC, DCM

OH

i

MECHANISM :

Ti

Ti

+ R

Cl

Cl

O

Cl

Cl

H

O R Cl Ti Cl O R

H SnBu3

OH H

R

H2O

DISCONNECTION :

HO R

H

O

R1 R

964

R1 H

+ SnBu3

NOTES : This is the efficient catalytic and enantioselective addition of allyl tin reagents to aldehydes. The diastereoselectivity can be controlled by the mode of addition of the Lewis acid and allyl tin reagent. See also Duthaler – Haffner, Hoffmann – Yamamoto, Ibuka – Yamamoto, Matteson and Thomas reactions.

REFERENCES : Org. Synth. : 68, 104; 75, 12 Org. Synth. Coll. Vol. : 8, 23; 10, 2305

1) G.E. Keck; E.P. Boden, Tetrahedron Lett., 1984, 25, 265. 2) G.E. Keck; D. Krishnamurthy; M.C. Grier, J. Am. Chem. Soc., 1993, 115, 6543. 3) G.E. Keck; K.H. Tarbet; L.S. Geraci, J. Am. Chem. Soc., 1993, 115, 8467. 4) B.A. Roe; C.G. Boojamra; J.L. Griggs; C.R. Bertozzi, J. Org. Chem., 1996, 61, 6442. 5) A. Fürstner; K. Langemann, J. Am. Chem. Soc., 1997, 119, 9130. 6) S. Knapp; Y. Dong, Tetrahedron Lett., 1997, 38, 3813. 7) M.J. Mitton–Fry; T. Sammakia; G. Kim, Abstr. Pap. Am. Chem. Soc., 2000, 220, 565. 8) J.D. Ginn; A. Padwa, Org. Lett., 2002, 4, 1515.

COMMENTS :

KEKULÉ SYNTHESIS EXAMPLE : CO2Na

Br moist CO2, Na

965

DISCONNECTION :

O

Ar

ArHal O

NOTES : Aromatic halides react with carbon dioxide in the presence of sodium in an inert solvent to yield salts of acids. Modern variants use transition metals as catalysts.

REFERENCES : A. Kekulé, Liebigs Ann. Chem., 1866, 137, 129.

COMMENTS :

KEMP ELIMINATION EXAMPLE : H

O2N

O2N

CN

N NaOH

O

O

MECHANISM : B + H B

H O2N

O2 N

O2 N N

N

O

O

966

- BH+

CN O

DISCONNECTION :

H O2N

O2N

CN

N O

O

NOTES : The Kemp elimination involves the general base-catalysed removal of a proton from carbon and is known to be highly sensitive to medium effects. Serum albumins and vesicles catalyse the elimination. The important proton transfer from carbon has been a prime target for enzyme mimics.

REFERENCES : 1) D.S. Kemp; M.L. Casey, J. Am. Chem. Soc., 1973, 95, 6670. 2) M.L. Casey; D.S. Kemp; K.G. Paul; D.D. Cox, J. Org. Chem., 1973, 38, 2294. 3) F.M. Menger; M. Ladiku, J. Am. Chem. Soc., 1987, 109, 3145. 4) F. Hollfelder; A.J. Kirby; D.S. Tawfik, Nature, 1996, 383, 60. 5) F.G. McCracken; C.G. Ferguson; D. Vizitiu; Y. Wang; G.R.J. Thatcher, J. Chem. Soc., Perkin Trans. 2, 1999, 911. 6) F. Hollfelder; A.J. Kirby; D.S. Tawfik; K. Kichuchi; D. Hilvert, J. Am. Chem. Soc., 2000, 122, 1022. 7) H. Shulman; E. Keinan, Org. Lett., 2000, 2, 3747. 8) J.E. Klijn; J.B.F.N. Engberts, J. Am. Chem. Soc., 2003, 125, 1825. 9) Y. Hu; K.N. Houk; K. Kikuchi; K. Hotta; D. Hilvert, J. Am. Chem. Soc., 2004, 126, 8197. 10) J.E. Klijn; J.B.F.N. Engberts, Org. Biomol. Chem., 2004, 2, 1789.

COMMENTS :

967

KENDALL – MATTOX REACTION EXAMPLE :

CO2CH3

CO2CH3 Br

Br O

O

NH2

1) HN

NO2 O

O Br

NO2 CH3COOH NaOAc 2) HBr H3C

O OH O

MECHANISM :

CO2CH3

CO2CH3 Br

Br O

O O2N O

NH NH2 NO2 CH3COOH NaOAc - HBr

Br

CO2CH3 Br O

HBr O H3C

O OH

O

968

N NH NO2

NO2

DISCONNECTION :

O

O

Br

NOTES : The method for the introduction of a double bond at the C4 – C5 position in 3-keto-steroids involves the treatment of the 4-bromo-derivative with 2,4-dinitrophenylhydrazine (2,4-DNPH), acetic acid and sodium acetate to yield a hydrazone with elimination of hydrogen bromide. The product reacts with pyruvic acid and hydrogen bromide in chloroform and acetic acid to form the 3-keto-Δ4-steroid. Instead of 2,4-DNPH lithium chloride in dimethylformamide can also be used.

REFERENCES : Houben – Weyl : E14b, 509; E15, 941

1) V.R. Mattox; E.C. Kendall, J. Am. Chem. Soc., 1948, 70, 882. 2) C. Djerassi, J. Am. Chem. Soc., 1949, 71, 1003. 3) Ch.R. Engel, J. Am. Chem. Soc., 1956, 78, 4727. 4) E.W. Warnhoff, J. Org. Chem., 1963, 28, 887.

COMMENTS :

KENNEDY OXIDATIVE CYCLISATION EXAMPLE :

HO OH

1) Re2O7, 2,6-lutidine DCM, RT 2) NaOOH

969

H3C

H H

O

MECHANISM :

R H R OH

R Re2O7

O

OReO3

O Re O O

H

H

H R

O HO Re O O

R NaOOH

O H

OH

DISCONNECTION :

R3 R4

R2 O HO

R3 R4

R3

H R

R1

OH R

R1

R2

R4

R2 O H

R1

R1 R

R3

R

R4 R2

OH

OH

NOTES : The oxidative cyclisation of 5-hydroxyalkenes with rhenium oxide to provide 2-hydroxymethyltetrahydrofurans.

REFERENCES : 1) R.M. Kennedy; S. Tang, Tetrahedron Lett., 1992, 33, 3729. 2) S. Tang; R.M. Kennedy, Tetrahedron Lett., 1992, 33, 5299. 3) S. Tang; R.M. Kennedy, Tetrahedron Lett., 1992, 33, 5303. 4) S.C. Sinha; A. Sinha–Bagchi; E. Keinan, J. Am. Chem. Soc., 1995, 117, 1447. 5) T.B. Towne; F.E. McDonald, J. Am. Chem. Soc., 1997, 119, 6022. 6) S.C. Sinha; E. Keinan; S.C. Sinha, J. Am. Chem. Soc., 1998, 120, 9076.

970

COMMENTS :

KENNER SYNTHESIS EXAMPLE :

CH3

H3C

H3C

Ts

+ H3C

O

N H

CO2Et

N H

1) tBuOK, tBuOH 2) P4O10, benzene 3) EtONa, EtOH

CO2Et

MECHANISM :

CO2Et

CO2Et t

BuOK, tBuOH

N Ts H

N Ts H

H+ O

H3C HO

CH3

CO2Et

H+ H3C

H

H

N Ts

CH3

H3C

CH3 CO2Et

EtONa, EtOH

P4O10, benzene - H2O

CO2Et

N Ts

N Ts

H3C

CH3

CO2Et

N H

DISCONNECTION :

R1

R

N H

CO2Et

R + R1

971

O

Ts

N H

CO2Et

NOTES : An α,β-unsaturated ketone and N-tosyl glycine are reacted to afford a pyrrole. See also Barton – Zard, Clauson– Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : 1) W.G. Terry; A.H. Jackson; G.W. Kenner; G. Kornis, J. Chem. Soc., 1965, 4389. 2) T.D. Lash; M.C. Hoehner, J. Heterocycl. Chem., 1991, 28, 1671.

COMMENTS :

van der KERK – SCHLESINGER REACTION EXAMPLE :

BuMgCl 1) SnCl4, benzene 2) LiAlH4, Et2O

BuSnH

MECHANISM :

BuCl

Mg, Et2O

BuMgCl

SnCl4, benzene

BuSnCl3

LiAlH4, Et2O

BuSnH

DISCONNECTION : BuCl

BuSnH

NOTES : This is the synthesis of butyltin hydride. Instead of tin, silicon or germanium can be used to afford butylsilicon or butylgermanium hydride.

972

REFERENCES : 1) A.E. Finholt; A.C. Bond; K.E. Wilzbach; H.I. Schlesinger, J. Am. Chem. Soc., 1947, 69, 2692. 2) G. Wittig; F.J. Meyer; G. Lange, Liebigs Ann. Chem., 1951, 571, 195. 3) H. Gilman; J. Eisch, J. Org. Chem., 1955, 20, 763. 4) G.J.M. van der Kerk; J.G. Noltes; J.G.A. Luitjen, J. Appl. Chem., 1957, 7, 356. 5) G.J.M. van der Kerk; J.G. Noltes; J.G.A. Luitjen, J. Appl. Chem., 1957, 7, 366.

COMMENTS :

KERP REDUCTION EXAMPLE :

OH

O

CH3

CH3 o

EtOH, 300 C 6 hours

MECHANISM :

R

R Et

O

H

H

O R1

O

Et

H

OH R1

DISCONNECTION :

R

R1

R

OH

R1 O

NOTES : Ketones such as benzophenone and anthraquinone are reduced to the corresponding secondary alcohol when heated with ethanol in a sealed tube at 300 – 320 oC. See also Meerwein – Ponndorf – Verley and Noyori hydrogenation reactions.

973

REFERENCES : W. Kerp, Ber. Dtsch. Chem. Ges., 1895, 28, 1476.

COMMENTS :

KHARASCH – CURRAN REACTION EXAMPLE :

CH2

+ CCl4

CCl3

UV light

Cl

MECHANISM :

CH3 CX3

+ CX4

CH3X + CX3 CHRCH2CX3

+ RCH=CH2

CHRCH2CHRCH2CX3

CHRCH2CX3 + RCH=CH2

H CHRCH2CX3 + CX4

X

DISCONNECTION :

R X

R CX3

974

CX3 + CX3

R

CH2

NOTES : Olefins or acetylenes add in an anti-Markovnikov manner on carbon tetrachloride, carbon tetrabromide, chloroform, bromoform or derivatives of chlorinated acetic acids in the presence of peroxides, or photochemically, to yield addition or polymerisation addition products. The polymers arise from free radicals produced in the reaction. The addition can be transition-metal catalysed. Sometimes this reaction is called the Prins reaction but this causes confusion with the Kriewitz – Prins reaction between formaldehyde and olefins.

REFERENCES : Smith : 689 Smith 2nd : 583, 613 Org. Synth. : 45, 104 Org. Synth. Coll. Vol. : 5, 1076 Science of Synthesis : 1, 969

1) M.S. Kharasch; E.V. Jensen; W.H. Urry, Science, 1945, 102, 128. 2) M.S. Kharasch; E.V. Jensen; W.H. Urry, J. Am. Chem. Soc., 1947, 69, 1100. 3) D.P. Curran, Synthesis, 1988, 417. 4) M.T. Reetz; A. Kindler, J. Organomet. Chem., 1995, 502, C5. 5) R.A. Gossage; L.A. van de Kuil; G. van Koten, Acc. Chem. Res., 1998, 31, 423. 6) F. Simal; L. Wlodarczak; A. Demonceau; A.F. Noels, Tetrahedron Lett., 2000, 41, 6071. 7) M. Albrecht; B.M. Kocks; A.L. Spek; G. van Koten, J. Organomet. Chem., 2001, 624, 271. 8) M. Albrecht; N.J. Hovestad; J. Boersma; G. van Koten, Chem. Eur. J., 2001, 7, 1289. 9) H. Feng; I.K. Kavrakova; D.A. Pratt; J. Tellinghuisen; N.A. Porter, J. Org. Chem., 2002, 67, 6050. 10) J.T. Singleton, Tetrahedron, 2003, 59, 1837. 11) B.T. Lee; T.O. Schrader; B. Martín–Matute; C.R. Kauffman; P. Zhang; M.L. Snapper, Tetrahedron, 2004, 60, 7391.

COMMENTS :

975

KHARASCH – KLEIMANN SYNTHESIS EXAMPLE :

Et

Et

CH3 H3CO

1) HBr 2) NaNH2, liq. NH3 3) KOH, (CH2OH)2 224 oC, 10-5 mm

HO

OH

MECHANISM :

CH3

CH3

H3CO

HBr Et

NaNH2, NH3

H3CO Br

Et

Et

Br

H3CO Et

OCH3

1) NaNH2, liq. NH3 2) KOH, (CH2OH)2 224 oC, 10-5 mm HO - HBr

OH

DISCONNECTION :

Et

Et CH3 H3CO

HO

OH

NOTES : The synthesis of diethylstilbestrol (trans-4,4’-dihydroxy-α,α’-diethylstilbene). See also Dodds – Robinson reaction.

REFERENCES : 1) M.S. Kharasch; M. Kleimann, J. Am. Chem. Soc., 1943, 65, 11. 2) J. Grundy, Chem. Rev., 1957, 57, 281.

976

COMMENTS :

KHARASCH – SOSNOVSKY REACTION EXAMPLE :

Ph H

O OtBu Et

+

Et

Et

Ph CuCl heat

O

CH3

MECHANISM :

O

O O

O

t

OCuII

Bu I

+

t

BuO

Cu

O CuIII O t

+ tBuOH

BuO

O O - CuI

977

O O

PhCO2CuII

DISCONNECTION :

R R1

O

R1 O

R

R2 R

R1

O

O

R2

NOTES : The allylic or propargylic oxidation using tert-butyl peresters as the oxidant in the presence of copper or cobalt salts. The reaction can also be done enantioselective with copper complexes of nitrogen-containing ligands, e.g. C2symmetric bis oxazolines. Oxazolines and thiazolines can be oxidised by this method to the corresponding oxazoles and thiazoles.

REFERENCES : Houben – Weyl : E5, 695

1) M. Kharasch; G. Sosnovsky, J. Am. Chem. Soc., 1958, 80, 756. 2) H. Kropf; R. Schröder; R. Fölsing, Synthesis, 1977, 894. 3) A.L.J. Beckwith; A.A. Zavitsas, J. Am. Chem. Soc., 1986, 108, 8230. 4) A.I. Meyers; F.X. Tavares, Tetrahedron Lett., 1994, 35, 2481. 5) A.I. Meyers; F.X. Tavares, J. Org. Chem., 1996, 61, 8207. 6) Y. Kohmura; T. Katsuki, Synlett, 1999, 1231. 7) P. Brandt; P.G. Andersson, Synlett, 2000, 1092. 8) Y. Kohmura; T. Katsuki, Tetrahedron Lett., 2000, 41, 3941. 9) J. Eames; M. Watkinson, Angew. Chem., Int. Ed., 2001, 40, 3567.

COMMENTS :

978

KHARASCH – URRY REARRANGEMENT EXAMPLE :

H3C + CH3MgI CoCl2

Cl

MECHANISM :

PhMgBr + CoCl2

PhCoCl + MgBrCl + 2 CoCl

2 PhCoCl

+ CoCl Cl

+ CoCl2

+

or

+

NOTES :

Many coupling reactions involving Grignard reagents and organo halides in the presence of cobaltous salts involve the formation of free radicals by the abstraction of a halogen atom from the organo halide. Interchange reactions or rearrangement products are very competing reactions.

979

REFERENCES : Smith : 689 Smith 2nd : 583, 613

1) M.S. Kharasch; D.W. Lewis; W.B. Reynolds, J. Am. Chem. Soc., 1943, 65, 493. 2) W.H. Urry; M.S. Kharasch, J. Am. Chem. Soc., 1944, 66, 1438. 3) M.S. Kharasch; W.H. Urry, J. Org. Chem., 1948, 13, 101. 4) L.H. Slaugh, J. Am. Chem. Soc., 1961, 83, 2734. 5) G.A. Russell; E.G. Jansen; E.T. Strom, J. Am. Chem. Soc., 1964, 86, 1807. 6) K. Maruyama, Bull. Chem. Soc. Jpn., 1964, 37, 897. 7) K. Maruyama, Bull. Chem. Soc. Jpn., 1964, 37, 1013. 8) D. Seyferth; B. Prokai, J. Org. Chem., 1966, 31, 1702. 9) R.G. Gough; J.A. Dixon, J. Org. Chem., 1968, 33, 2148.

COMMENTS :

KIHARA INDOLE SYNTHESIS EXAMPLE :

CH3

I N CH3 O

CH3

n

BuLi THF, - 78 oC

980

N CH3

MECHANISM :

H N

CH3 +

I

R

CH2COR N CH3

Br

I

O

R

R OH n

+

N CH3

N CH3

BuLi

H+, - H2O

DISCONNECTION : R I N R = CH3, C6H11, Ph CH3

N CH3 O

R

NOTES :

The formation of the indole ring via an intramolecular Barbier reaction of phenyl or alkyl N-(2-iodophenyl)-Nmethylaminomethyl ketones. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Barbier, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto

indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

M. Kihara; Y. Iwai; Y. Nagao, Heterocycles, 1995, 41, 2279.

981

COMMENTS :

KILIANI – FISCHER SYNTHESIS EXAMPLE :

HO H H

O

H

O

H OH OH CH2OH

1) HCN 2) NH2OH 3) Na(Hg)

HO HO H H

H H H OH OH CH2OH

MECHANISM :

CHO HO H H OH H OH CH2OH

HCN - H2O

O

H2O

N C HO H HO H H OH H OH CH2OH

HO HO H H

OH

O HO HO H H

H H OH OH CH2OH

NH2OH

H

O

H H OH OH CH2OH

Na(Hg)

OH CH2OH

H O

982

HO HO H H

O

R

R

NH2

H H

DISCONNECTION :

OH H

O

HO HO H H

CHO H H OH OH CH2OH

NOTES :

A method for passing from an aldose to the next higher homologue by the formation of the epimeric cyanohydrins, which are hydrolysed to a mixture of the corresponding acids. These may be separated by fractional crystallisation and subsequent decomposition of the phenylhydrazides. Each acid is converted to the γ-lactone by heating and the latter is reduced by sodium amalgam (pH 3) to the higher aldose. See also Kiliani, Ultee, Urech and Wohl reactions.

REFERENCES : March : 965 Smith – March : 1240 Org. Syn. : 36, 38 Org. Synth. Coll. Vol. : 4, 506

1) F. Winkler, Liebigs Ann. Chem., 1832, 4, 246. 2) H. Kiliani, Ber. Dtsch. Chem. Ges., 1885, 18, 3066. 3) E. Fischer, Ber. Dtsch. Chem. Ges., 1889, 22, 2204. 4) D.T. Mowry, Chem. Rev., 1948, 42, 189. 5) H.B. Wood; H.G. Fletcher, J. Org. Chem., 1961, 26, 1969. 6) D. French; R. Varma, Carbohydr. Res., 1972, 25, 71. 7) A.S. Serianni; H.A. Nunez; R. Barker, J. Org. Chem., 1980, 45, 3329. 8) N. Ahje; F. Vogeleisen; D. Uguen, Tetrahedron Lett., 1996, 37, 5893. 9) J. Roos; F. Effenberger, Tetrahedron: Asymmetry, 1999, 10, 2817.

COMMENTS :

KILIANI REDUCTION EXAMPLE :

H H H H

CHO OH OH OH OH CH2OH

O 1) HCN 2) H2O 3) P, HI 4) Zn, HCl

983

HO

MECHANISM :

H H H H

CHO OH OH OH OH CH2OH

H H H H H

HCN

C N OH OH OH OH OH CH2OH

H2O

H H H H H

COOH OH OH OH OH OH CH2OH

O OH 1) P, HI 2) Zn, HCl

DISCONNECTION :

R

R1

R

COOH

R1 O

R = CH3(CH2)n R1 = H, CH3(CH2)m

R = (CH2OH)n R1 = H, (CH2OH)m

NOTES :

These acids or their corresponding lactone are transformed to the cyanohydrin. Hydrolysis with water affords the polyhydroxylated carboxylic acid when this is reduced by hydrogen iodide in the presence of red phosphorous yields the corresponding aliphatic carboxylic acid. This reaction has been used by Kiliani to proof that D-glucose is an aldohexose. See also Kiliani – Fischer reaction.

REFERENCES :

1) H. Kiliani, Ber. Dtsch. Chem. Ges., 1885, 18, 3066. 2) H. Kiliani, Ber. Dtsch. Chem. Ges., 1888, 21, 915. 3) A.S. Perlin; C.B. Purves, Can. J. Chem., 1953, 31, 227. 4) W.H. Kruizinga; R.M. Kellogg, J. Am. Chem. Soc., 1981, 103, 5183. 5) Z.C. Liu; A. Granata; X.H. Shen; A.S. Perlin, Can. J. Chem., 1992, 70, 2081.

COMMENTS :

984

de KIMPE SYNTHESIS EXAMPLE :

CH3 N tBu H3C H

Cl

H3C

KCN MeOH heat

CH3 H N

t

Bu

CN

MECHANISM :

R1

N

R2

R R1 R2

H Cl

Cl

CN

R1 - H+

N

R H CH3OH - CH3O

CN

H

H N R

R2 Cl

R2

H R R1 N H Cl CN

CN

- Cl

R1

N R

R2

CN

DISCONNECTION :

H R1

N R

R1

N R

Cl

H

R2 R2

CN

NOTES :

α-Cyanoenamines have been prepared from α-chloroaldimines and potassium cyanide in methanol.

REFERENCES :

1) N. de Kimpe; R. Verhé; L. De Buyck; H. Hasma; N. Schamp, Tetrahedron, 1976, 32, 3063. 2) N. de Kimpe; R. Verhé; L. De Buyck; J. Chys; N. Schamp, J. Org. Chem., 1978, 43, 2670. 3) N. de Kimpe; R. Verhé; L. De Buyck; J. Chys; N. Schamp, Synth. Commun., 1979, 9, 901. 4) N. de Kimpe; R. Verhé; L. De Buyck; N. Schamp, Chem. Ber., 1983, 116, 3846. 5) N. de Kimpe; R. Verhé; L. De Buyck; N. Schamp, Can. J. Chem., 1984, 62, 1812.

985

COMMENTS :

KINDLER SYNTHESIS EXAMPLE : O

O

OH

OH OH

CH3COOH, H2SO4 Pd, RT

MECHANISM : In the presence of HClO4 :

O

O

O

OH

OH

OR

OR HX

X

[H]

DISCONNECTION : O

O

OR

OH

OH

NOTES :

Mandelic acids and their esters are hydrogenated to the corresponding derivatives of phenylacetic acid at room temperature in acetic acid containing sulfuric acid. In the presence of perchloric acid the hydrogenation is catalytic. At higher temperatures the phenyl ring can be hydrogenated to a cyclohexyl ring.

REFERENCES :

1) K. Kindler; W. Metzendorf; D-y. Kwok, Ber. Dtsch. Chem. Ges., 1943, 76B, 308. 2) K. Kindler; D-y. Kwok, Liebigs Ann. Chem., 1943, 554, 9.

986

COMMENTS :

KINUGASA REACTION EXAMPLE :

S S

I

+

CH3 H3C

N Ph

N

P

Ph

O

O

H3C

Fe

O

N

Ph

CH3

H3C

CH3 CH3 cat. CuBr base

MECHANISM :

H R

CuLn

O

R

R1

R1

N R2 R

N R2

R

O

O N

R1

OH

CuLn

H O

H

R1

R

O N

base R2

R1

987

R2

CuLn N R2

O

DISCONNECTION :

R

H

O R

N R1

CuLn

+

R1

R2

O N R2

NOTES : cis-β-Lactams are afforded by the reaction between copper acetylides and nitrones. The carbonyl oxygen is derived

from the oxygen of the nitrone. The reaction has been made asymmetric and catalytic in copper. The use of base inverts the stereochemistry of the β-lactams.

REFERENCES :

1) M. Kinugasa; S. Hashimoto, J. Chem. Soc., Chem. Commun., 1972, 466. 2) L.K. Ding; W.J. Irwin, J. Chem. Soc., Perkin Trans. 1, 1976, 2382. 3) M. Miura; M. Enna; K. Okuro; M. Nomura, J. Org. Chem., 1995, 60, 4999. 4) M.M.-C. Lo; G.C. Fu, J. Am. Chem. Soc., 2002, 124, 4572. 5) R. Shintani; G.C. Fu, Angew. Chem., Int. Ed., 2003, 42, 4082. 6) J. Marco–Contelles, Angew. Chem., Int. Ed., 2004, 43, 2198. 7) A. Basak; S.C. Ghosh, Synlett, 2004, 1637.

COMMENTS :

KISHNER CYCLOPROPANE SYNTHESIS EXAMPLE :

H3C

H3C

CH3 CH3 O

+ NH2NH2

988

heat, base

CH3 CH3

MECHANISM :

R1 R1

R + NH2NH2 R2

O

- H2O

R1

R

R2

N NH2

R1 R2

R1

N N

R2

H N N

R

R2

- N2

R

R

DISCONNECTION :

R1

R2 R

R1 R = Alk, H

O

R2

R

NOTES :

Pyrazolines which are obtained by the action of hydrazine on compounds containing the group –CH=CHCO- eliminate nitrogen when treated with alkali to form cyclopropane derivatives. See also Charette, Freund, Hass cyclopropane, Ipatiew cyclopropane, Mousseron – Fraisse – McCoy, Nerdel and Simmons – Smith reactions.

REFERENCES : Org. Synth. : 47, 98 Org. Synth. Coll. Vol. : 5, 929

1) N. Kishner; A. Zavadovskii, J. Russ. Physik. Chem. Ges., 1911, 43, 1132. 2) L.I. Smith; E.R. Rogier, J. Am. Chem. Soc., 1951, 73, 3840. 3) G.S. Hammond; R.W. Todd, J. Am. Chem. Soc., 1954, 76, 4081. 4) R.J. Crawford; M. Ohno, Can. J. Chem., 1974, 54, 3134. 5) R.J. Crawford; H. Tokunaga, Can. J. Chem., 1974, 54, 4033.

COMMENTS :

989

KITA ESTERIFICATION EXAMPLE :

O TESO

O TESO

OH

O O

TESO

1) [RuCl2(p-cymene)]2,

TESO

H OTES

TESO

OEt

TESO OTES

2) CSA, OH O

MECHANISM :

Cl

L

Cl Ru

Ru L

OEt

H

OEt

H

RCOOH

Cl OEt

Cl L Ru

O O R

[RuCl2(p-cymene)]2

H

L= p-cymene

O H

O R

H

OEt

990

OEt

R1X H O R

O

O O

OR2

+ R1XH R

O

OR2

- CH3CO2R2

R

XR1

DISCONNECTION :

O

O R

XR1

X = O, N

R

OH

+ HXR1

NOTES :

1-Ethoxyvinyl esters, prepared from carboxylic acids and ethoxyacetylene in the presence of a catalytic amount of [RuCl2(p-cymene)]2 (in the past mercury(II) compounds were used.), react with alcohols and amines to afford the corresponding O- and N-acylated compounds. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES :

1) H.H. Wasserman; P.S. Wharton, J. Am. Chem. Soc., 1960, 82, 661. 2) B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1963, 82, 593. 3) Y. Kita; S. Akai; N. Ajimura; M. Yoshigi; T. Tsugoshi; H. Yasuda; Y. Tamura, J. Org. Chem., 1986, 51, 4150. 4) Y. Kita; H. Maeda; K. Omori; T. Okuno; Y. Tamura, Synlett, 1993, 273. 5) B.M. Trost; P.E. Harrington, J. Am. Chem. Soc., 2004, 126, 5028.

COMMENTS :

991

KNOCHEL REACTION EXAMPLE :

CO2Et

CO2Et

I

1) Zn 2) CuCN·2LiCl 3)

Cr(CO)3

Cr(CO)3BF4

MECHANISM :

EtO2C

I

EtO2C

Cu(CN)ZnI

Zn CuCN. 2 LiCl OAc HO

BF3.Et2O

EtO2C

O H

OAc

992

Cl

Cl

I

ZnI

Zn

Cl

O Cl

Cu(CN)Li

5 mol% (CH3)2Cu(CN)Li2 THF, - 78 oC

O

ZnCH3

CH3Li - 78 oC Cu(CN)Li

O

TMS

Cl

O

TMSCl

TBAF

Cl

Cl

DISCONNECTION :

R3

R

R1 O

R2

HO

R3Hal + R1 R3

R R2

R

R1

R2 O

NOTES :

Alkyl zinc iodides are poor nucleophiles. However, they are turned into good nucleophiles when they are converted into so-called Knochel cuprates R-Cu(CN)ZnHal with solubilised CuCN. These compounds add to α,β-unsaturated aldehydes in the presence of Lewis acids (1,2-addition), but can also undergo 1,4-additions or give other Michael adducts.

REFERENCES : Org. React. : 58, 417 Org. Synth. : 70, 195; 76, 252 Org. Synth. Coll. Vol. : 9, 502

993

1) M.J. Dunn; R.F.W. Jackson, J. Chem. Soc., Chem. Commun., 1992, 319. 2) P. Knochel; M.J. Rozema; C.E. Tucker; C. Retherford; M. Furlong; S.A. Rao, Pure Appl. Chem., 1992, 64, 361. 3) P. Knochel; R.D. Singer, Chem. Rev., 1993, 93, 2117. 4) I. Gridnev; G. Kanai; N. Miyaura; A. Suzuki, J. Organomet. Chem., 1994, 481, C4. 5) P. Knochel, Chemtracts: Org. Chem., 1995, 8, 205. 6) A.M. Caporusso; S. Filippi; F. Barontini; P. Salvadori, Tetrahedron Lett., 2000, 41, 1227.

COMMENTS :

KNOEVENAGEL AMINE SYNTHESIS EXAMPLE :

H

OH

OH

2 PhNH2 I2

N

N

H

DISCONNECTION :

Ar

N

H

OH + ArNH2

NOTES :

Certain phenols and naphthols react with aromatic amines in the presence of small amounts of iodine to yield secondary amines on dehydration.

REFERENCES :

1) E. Knoevenagel, J. Prakt. Chem., 1914, 89, 1. 2) Ng.Ph. Buu–Hoï, J. Chem. Soc., 1954, 4346.

994

3) M. Kozaki; S. Nakamura; K. Sato; T. Takui; T. Kametani; M. Oda; K. Tokumaru; K. Okada, Tetrahedron Lett., 1998, 39, 5979.

COMMENTS :

KNOEVENAGEL CONDENSATION EXAMPLE :

N O H3C

CH3

+

H3C

H3CO

C O

N

H3C

CO2CH3

N H

MECHANISM :

C

H3CO2C

H3CO2C

N H+ O

N

N H

H

H

N CH3

OH

N

H3CO2C

N

N H

H3C

H

C

CH3 C

N H3C C N N H H H H CO2CH3

N

995

H

CH3

N C H3C

CO2CH3 H

DISCONNECTION : R1(H) R

R

COOH

R1(H)

+ HOOC

COOH

O

NOTES :

The condensation of certain types of compounds containing a highly reactive methylene group with a variety of carbonyl compounds in the presence of a weak base, a primary or secondary amine or an ion-exchange resin. It is possible to condense one or two molecules of the carbonyl compound with the aldehyde. See Claisen cinnamic, Doebner modification and Perkin reactions.

REFERENCES : March : 945 Smith – March : 1219, 1225 Smith : 897 Smith 2nd : 750 Org. React. : 1, 1; 15, 204 Houben – Weyl : 4/2, 25; 6/2, 640; E3, 646; E7a, 195; E7b, 412; E8a, 316 Org. Synth. : 25, 42; 27, 24; 29, 83; 32, 63; 71, 167 Org. Synth. Coll. Vol. : 3, 317, 377, 715; 4, 392; 9, 310 Science of Synthesis : 9, 194, 317

1) F.R. Japp; F.W. Streatfield, J. Chem. Soc., 1883, 43, 27. 2) E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1896, 29, 172. 3) E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1898, 31, 735. 4) G. Charles, Bull. Soc. Chim. Fr., 1963, 1576. 5) J.L. van der Baan; F. Bickelhaupt, Tetrahedron, 1974, 30, 2088. 6) L.F. Tietze; U. Beifuβ, Comp. Org. Syn., 1991, 2, 341. 7) L.F. Tietze; P. Saling, Chirality, 1993, 5, 329. 8) M.L. Kantam; B. Bharathi, Catal. Lett., 1998, 55, 235. 9) G. Alcerreca; R. Sanabria; R. Miranda; G. Arroyo; J. Tamiriz; F. Delgado, Synth. Commun., 2000, 30, 1295. 10) S. Balalaie; N. Nemati, Heterocycl. Commun., 2001, 7, 67. 11) A. Loupy; S.J. Song; S.M. Sohn; Y.M. Lee; T.W. Kwon, J. Chem. Soc., Perkin Trans. 1, 2001, 1220. 12) A. McCluskey; P.J. Robinson; T. Hill; J.L. Scott; J.K. Edwards, Tetrahedron Lett., 2002, 43, 3117. 13) W.-X. Zuo; R. Hua; X. Qiu, Synth. Commun., 2004, 34, 3219. 14) M. Hayashi; N. Nakamura; K. Yamashita, Tetrahedron, 2004, 60, 6777.

996

COMMENTS :

KNOEVENAGEL COUMARIN SYNTHESIS EXAMPLE : CO2Et +

EtO

OH

OEt O

CHO

piperidine toluene reflux

O

O

O

MECHANISM :

HO OH H

EtO

CO2Et

OEt

+ O

Knoevenagel condensation piperidine, toluene, reflux

O

O

EtO

OEt O

- EtOH

O

O

O

DISCONNECTION :

R R2

R1

O

OH

+ R

O R1

R2 CH2 CO2Et

CHO

NOTES :

Coumarin derivatives are obtained by the condensation of o-hydroxyaldehydes with highly reactive methylene compounds, in the presence of piperidine, pyridine and other organic bases. The synthesis can be done also under microwave irradiation. See also Anschütz hydroxyl coumarin, Boyd – Robinson, Dieckmann – Meiser, Knoevenagel condensation, Mentzer, Pauly – Lockemann, von Pechmann – Duisberg, Perkin coumarin and Simonis reactions.

REFERENCES : Org. Synth. : 28, 24

997

Org. Synth. Coll. Vol. : 3, 165

1) E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1898, 31, 2585. 2) S.M. Setha; N.M. Shah, Chem. Rev., 1945, 36, 1. 3) A.K. Bose; M.S. Manhas; M. Ghosh; V.S. Raju; K. Tabei; Z. Urbanczyk–Lipkowska, Heterocycles, 1990, 30, 741. 4) S. Padmanabhan; R. Peri; D.J. Triggle, Synth. Commun., 1996, 26, 827. 5) B.T. Watson; G.E. Christiansen, Tetrahedron Lett., 1998, 39, 6087. 6) T. Sugino; K. Tanaka, Chem. Lett., 2001, 110. 7) A. Kakehi; S. Ito; H. Suga; K. Yasuraoka, Heterocycles, 2001, 54, 185.

COMMENTS :

KNOEVENAGEL CYCLOHEXENONE SYNTHESIS EXAMPLE : CO2Et H3C 2 AcCH2CO2Et + CH2O

1) Pyridine 2) HCl, Et2O

CO2Et O

MECHANISM :

O EtO2C 2 AcCH2CO2Et + CH2O

EtO2C HCl, Et2O

Pyridine

CO2Et

O O CH H CH2 3

O

H CH3

H

CO2Et

H3C

O

EtO2C O

998

CO2Et CH3

DISCONNECTION :

R1(R2) O H (R1)R2

O

R

R2(R1)

R1(R2) O

R

H

+

R1

R2 O

O

O

NOTES :

This reaction involves the condensation of an aldehyde with a 1,3-dicarbonyl compound to yield a 1,5-diketone. This compound undergoes an internal aldol condensation, followed by the loss of water to give an unsaturated ketone of cyclohexane.

REFERENCES :

1) E. Knoevenagel, Liebigs Ann. Chem., 1894, 281, 25. 2) H. Nitta; K. Takimoto; I. Ueda, Chem. Pharm. Bull., 1992, 40, 858. 3) U. Kuhl; U. Holzgrabe, Monath. Chem., 2001, 132, 407.

COMMENTS :

KNOEVENAGEL DIAZOTATION EXAMPLE :

N 2 CH3ONO + PhNH2 + HCl

999

1) EtOH 2) Et2O

Cl

N

MECHANISM :

N2O3

2 RONO

ArNH2 + N2O3

Ar

Ar

N N O H

Ar

H N N O + NO2H N N OH

- H+

H+

Ar

N N + H2O

DISCONNECTION :

ArN2+Cl-

ArNH2

NOTES :

This method relates to the diazotisation of primary aromatic amines by the addition of an alkyl nitrite to an ethanolic solution or suspension of the amine salt followed by precipitation of the diazonium salt with ether. Other media can replace ethanol. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulphinic acid, Griess deamination, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : March : 635 Smith – March : 816 Smith : 197 Smith 2nd : 1057 Org. React. : 2, 262

1) P. Griess, Liebigs Ann. Chem., 1858, 106, 123. 2) E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1890, 23, 2994.

COMMENTS :

1000

KNOFFLER – BACHMANN CYCLONITE SYNTHESIS EXAMPLE : NO2 N

N NN

N

4 HNO3, 2 NH4NO3, 6 (CH3CO)2O

N

O2N

N

NO2

DISCONNECTION :

NO2 N O2N

N

N

N N

NN

NO2

NOTES :

This process is essentially a combination of the Ebele – Schiessler – Ross and the Hale methods. Hexamethylenetetramine dinitrate reacts with ammonium nitrate, nitric acid and acetic anhydride to yield cyclonite. The reaction is also known as the K-method. See also Ebele – Schiessler – Ross, Hale and Wolfram reactions.

REFERENCES :

1) W.E. Bachmann; J.C. Sheehan, J. Am. Chem. Soc., 1949, 71, 1842. 2) C.J. McHugh; W.E. Smith; R. Lacey; D. Graham, Chem. Commun., 2002, 2514.

COMMENTS :

KNOOP – OESTERLIN AMINO ACID SYNTHESIS EXAMPLE :

H3C

H3C

COOH + NH3 O

H2, Pd/C

1001

COOH NH2

MECHANISM :

R

COO

R

+ NH3

R

COO H2, Pd/C

NH

O

COOH NH2

DISCONNECTION :

R

COOH

R

NH2

COO O

NOTES :

Amino acids are obtained by the catalytic reduction of keto-acids in the presence of ammonia. Catalysts such as palladium on coal and Raney nickel may be employed.

REFERENCES : Houben – Weyl : 11/2, 311

1) F. Knoop; H. Oesterlin, Hoppe Seylers Zeit. Physiol. Chem., 1925, 148, 294. 2) H.R.V. Arnstein; R. Bentley, J. Chem. Soc., Quat. Rev., 1950, 4, 186. 3) C.W. Huffman; W.G. Skelly, Chem. Rev., 1963, 63, 625.

COMMENTS :

1002

KNORR PYRAZOLE SYNTHESIS EXAMPLE :

CH3 H3C

CH3 + O

H2N NH2

H3C

O

N

N H

MECHANISM :

H+

H+ O H3C

H HO

H3C OH O H N CH3 NH2

O CH3

H3C

N N H H

OH CH3

H2N NH2 CH3 - 2 H2O

H3C

N H

N

DISCONNECTION :

R1 R2

R

R1 NH2NHR3 +

N R3

R2

R O

O

NOTES :

Pyrazoles are obtained by the condensation of 1,3-dicarbonyl compounds with hydrazines. See also Balbiano and von Pechmann reactions.

REFERENCES :

1) L. Knorr, Ber. Dtsch. Chem. Ges., 1883, 16, 2597. 2) L. Claisen, Liebigs Ann. Chem., 1894, 278, 261. 3) A.R. Katritzky; F.W. Maine, Tetrahedron, 1964, 20, 299. 4) E. Garcia–Egido; V. Spikmans; S.Y.F. Wong; B.H. Warrington, Lab on a Chip, 2003, 3, 73.

1003

COMMENTS :

KNORR PYRROLE SYNTHESIS EXAMPLE :

H3C

+ EtO2C

H3C

CO2Et

O O

NH2

HOAc, heat

CH3

EtO2C

CO2Et CH3

N H

MECHANISM :

R R1

O NH2

+

H

R

R3 O

R2

R

- H+

H

- H2O

R1

H+

HO R3 H R H R2 R1 N H

O R3 H

H+ O R3 H

N H

R1

R2

HO R3 R H R2 R1 N H

- H+

N H

R2

R

- H2O

R1

R3 N H

R2

DISCONNECTION :

R

R3

R

R3

O +

R1

N H

R2

R1

NH2

O

R2

NOTES :

Pyrrole derivatives are prepared by the condensation of 1,3-diketones with α-amino-ketones, which can be obtained from oximino-ketones. This reaction is a modification of the Feist – Bénary reaction. See also Barton – Zard, Clauson–Kaas, Feist – Bénary, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

1004

REFERENCES : Smith : 1021 Smith 2nd : 847, 849 Houben – Weyl : E6a, 624 Org. Synth. : 15, 17; 21, 67 Org. Synth. Coll. Vol. : 2, 202; 3, 513 Science of Synthesis : 9, 469

1) L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635. 2) E. Baltazzi; L.I. Krimen, Chem. Rev., 1963, 63, 516. 3) H. Rapoport; J. Harbuck, J. Org. Chem., 1971, 36, 853. 4) E. Fabiano; B.T. Golding, J. Chem. Soc., Perkin Trans. 1, 1991, 3371. 5) J.M. Hanby; J.C. Hodges, Heterocycles, 1993, 35, 843. 6) Y. Zhang; Y.Z. Jiang; X.T. Liang, Chin. J. Chem., 1997, 15, 371. 7) T.D. Lash, Tetrahedron, 1998, 54, 359. 8) J.A. Bastian; T.D Lash, Tetrahedron, 1998, 54, 6299. 9) A. Alberola; A.G. Ortega; M.L. Sadaba; C. Sanudo, Tetrahedron, 1999, 55, 6555. 10) I. Elghamry, Synth. Commun., 2002, 32, 897. 11) R.K. Bellingham; J.S. Carey; N. Hussain; D.O. Morgan; P. Oxley; L.C. Powling, Org. Proc. Res. Dev., 2004, 8, 279.

COMMENTS :

KNORR QUINOLINE SYNTHESIS EXAMPLE :

CH3 + NH2

H3C

OCH3 O

O

H2SO4

1005

N

OH

MECHANISM :

O H3C NH2

OR O

N H

- ROH

O H+

O

CH3

O CH3

CH3 N H

OH

H+ - H2O

N

OH

DISCONNECTION :

R1 R

R + R1 N

NH2

OH

OEt O

O

NOTES :

The condensation of a β-ketoester with an aryl amine gives the anilide which is cyclised by concentrated sulfuric acid to a 2-hydroxyquinoline. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES : Smith : 1334 Smith 2nd : 1097

1) L. Knorr, Liebigs Ann. Chem., 1886, 236, 69. 2) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 3) A.J. Hodgkinson; B. Staskum, J. Org. Chem., 1969, 34, 1709. 4) P. Lopez–Alvarado; C. Avendano; J.C. Menendez, Synthesis, 1998, 186.

COMMENTS :

1006

KNUNYANTS FLUORO ALKYLATION EXAMPLE :

+

F3 C

CF3 OH CF3

CF3 O

AlCl3

MECHANISM :

O F3C

AlCl3 CF3

F3C

H CF3 O AlCl3 CF3

O AlCl3 CF3

CF3 O AlCl3 CF3

OH CF3 CF3

H+ - AlCl3

DISCONNECTION :

CF3 OH CF3

F3C

CF3

+ O

NOTES :

This is the fluoroalkylation of aromatics using hexafluoroacetone. See also Friedel – Crafts and Swarts reactions.

REFERENCES : Org. Synth. : 63, 154 Org. Synth. Coll. Vol. : 7, 251

1) I.L. Knunyants; C. Ching–Yun; N.P. Gambaryan; E.M. Rokhlis, Zh. Vses. Chim. Obsh., 1960, 5, 114. 2) B.S. Farah; E.E. Gilbert; J.P. Sibilia, J. Org. Chem., 1965, 30, 998. 3) A.V. Fokin, J. Fluorine Chem., 1993, 65, R11.

1007

COMMENTS :

KOCH – HAAF REACTION EXAMPLE :

H3C CH3 H3C OH H3C CH3

aq. H2SO4, HCOOH

H3C CH3 H3C COOH H3C CH3

MECHANISM :

HCOOH

H2O + CO

H O C O

O H

H+

H

O

OH H

DISCONNECTION :

R OH

R

R1

COOH

R

R1

R1

NOTES :

This is the hydrocarboxylation of alcohols and alkenes. If formic acid is used as the source of carbon monoxide and water, the reaction can be done at atmospheric pressure and room temperature. The acid-catalysed hydrocarboxylation of an alkene with carbon monoxide and water under pressure is known as the Koch reaction. See also Koch reaction.

REFERENCES : March : 485, 808 Smith – March : 564, 1035

1008

Smith : 1307 Smith 2nd : 1076 Houben – Weyl : E5, 302, 315; E19c, 367 Org. React. : 17, 213 Org. Synth. : 44, 1; 46, 72 Org. Synth. Coll. Vol. : 5, 20, 739

1) H. Koch, Brennst. Chem., 1955, 36, 321. 2) H. Koch; W. Haaf, Liebigs Ann. Chem., 1958, 618, 251. 3) Y. Takahashi; N. Yoneda; H. Nagai, Chem. Lett., 1982, 1187. 4) R.R. Rao; S. Bhattacharya, Indian J. Chem., 1982, 21B, 405. 5) O. Farooq; M. Marcelli; G.K.S. Prakash; G.A. Olah, J. Chem. Soc., Perkin Trans. 1, 1988, 110, 864. 6) C. Leonte; E. Carp, Rev. Roum. Chim., 1989, 34, 1241. 7) J.L. Emert; D.C. Dankworth; A. Gutierrez; D.J. Martella; S.P. Rucker; J.P. Stokes; W. Thaler; A. Worku; A.B. Padias; H.K. Hall, Macromolecules, 2001, 34, 2766. 8) H. Mori; A. Mori; Q. Xu; Y. Souma, Tetrahedron Lett., 2002, 43, 7871. 9) T. Li; N. Tsumori; Y. Souma; Q. Xu, Chem. Commun., 2003, 2070.

COMMENTS :

KOCHI DECARBOXYLATION EXAMPLE : O H3C

OH Pb(OAc)4, LiCl

Cl

H3C

MECHANISM : O

O R

R OH

Pb(OAc)4 - HOAc

OAc

O Pb AcO

OAc

1009

R LiCl - CO2

Cl

+ Pb(OAc)2 + LiOAc

DISCONNECTION : O R

Cl

R

OH

NOTES :

The oxidative decarboxylation of carboxylic acids with lead(IV) acetate and lithium chloride. See also Hunsdiecker – Borodine and Krapcho reactions.

REFERENCES : Org. React. : 19, 279

1) J.K. Kochi, J. Am. Chem. Soc., 1965, 87, 2500. 2) M. Mannier; J.P. Aycard, Can. J. Chem., 1979, 57, 1257. 3) G.M. Strunz; L. Ya, Can. J. Chem., 1992, 70, 1317.

COMMENTS :

KOCHI REACTION EXAMPLE :

H + BrMg Br

0.5% FeCl3

1010

MECHANISM :

R

CH3

H

H

Br

FeI

CH3

H

III

CH3

FeIII

Fe

Br

H

R

H

CH3 H

H

H

MgBr2

RMgBr

DISCONNECTION :

R2

R

R2

Br + RMgBr

R3

R1

R3

R1

NOTES :

The mechanism can be explained by an oxidative addition of 1-bromoalkene to iron(I) followed by exchange with the organomagnesium bromide and reductive elimination. In order to maintain the stereospecificity the oxidative addition should occur with retention. Copper(I) and silver(I) can also be used for cross-coupling and homo coupling, respectively.

REFERENCES :

1) M. Tamura; J.K. Kochi, J. Am. Chem. Soc., 1971, 93, 1487. 2) M. Tamura; J.K. Kochi, Synthesis, 1971, 303. 3) R.S. Smith; J.K. Kochi, J. Org. Chem., 1976, 41, 502. 4) G.A. Molander; B.J. Rahn; D.C. Shubert; S.E. Bonde, Tetrahedron Lett., 1983, 24, 5449. 5) J.K. Kochi, J. Organomet. Chem., 2002, 653, 11. 6) T. Nagano; T. Hayashi, Org. Lett., 2004, 6, 1297.

1011

COMMENTS :

KOENIGS – KNORR SYNTHESIS EXAMPLE :

CH2OAc CH2OAc O OCH O 3 OAc OAc OAc 1) HBr AcO 2) CH3OH, Ag2CO3 AcO OAc OAc

MECHANISM :

OAc CH2OAc O OAc Br

O AcO AcO

O

Ag2O

AcO

H O

OAc OAc

H3C O

AcO AcO

ROH O

H O

AcO

H3C

CH2OAc O OR OAc H OAc

DISCONNECTION :

CH2OAc O OR OAc

CH2OH O OH OH

AcO

HO

OAc

OH

NOTES :

α and β-Acetylglycosyl bromides on treatment with alcohols and phenols in the presence of excess silver carbonate or oxide yield β-acetylglycosides, which may be deacetylated in alkaline solution. The Zemplen – Helferich modification uses Hg(CN)2 or Hg(OCOCH3)2. The Bredereck modification works with tertiary esters of primary alcohols in

1012

nitromethane in the presence of silver perchlorate, while the Schroeder modification is carried out in the presence of mercury oxide and mercury bromide. See also Fischer glycosidation, Kahne glycosidation, Michael glycosidation and Schmidt glycosidation reactions.

REFERENCES : Org. Synth. : 22, 1 Org. Synth. Coll. Vol. : 3, 11

1) W. Koenigs; E. Knorr, Ber. Dtsch. Chem. Ges., 1901, 34, 957. 2) A.S. Perlin, Can. J. Chem., 1963, 41, 399. 3) F. Imperato, J. Org. Chem., 1976, 41, 3478. 4) A. Miliua; J. Greiner; J.G. Riess, New. J. Chem., 1991, 15, 337. 5) J. Tamura; R. Terayama; T. Shimadate, J. Carbohydr. Chem., 1993, 12, 893. 6) L. Somsak; L. Kovacs; V. Gyollai; E. Osz, Chem. Commun., 1999, 591. 7) M.C.Z. Kasuya; L.X. Wang; Y.C. Lee; M. Mitsuki; H. Nakajima; Y. Miura; T. Sato; K. Hatanaka; S. Yamagata; T. Yamagata, Carbohydr. Res., 2000, 329, 755. 8) G. Desmares; D. Lefebvre; G. Renevret; C. Le Drian, Helv. Chim. Acta, 2001, 84, 880. 9) L. Kroger; J. Thiem, J. Carbohydr. Chem., 2003, 22, 9. 10) F. Stazi; G. Palmisano; M. Turconi; S. Clini; M. Santagostino, J. Org. Chem., 2004, 69, 1097.

COMMENTS :

KOHLER ISOXAZOLE-N-OXIDE SYNTHESIS EXAMPLE :

O N

NO2 O

1013

Ph

O

H

+

1) MeNH2 2) NaOMe

Ph

Ph

MECHANISM :

O N

Ph NO2

O2 N

H

+

MeNH2

O

Ph

Ph

NaOMe Ph

DISCONNECTION :

O

O N

H

R R H

R H

Y = Hal, NO2

O2 N

R H H Y

R R

NOTES :

The base-catalysed cyclisation of 2-isoxazole-2-oxides from 1,3-dinitroalkanes or 1-halo-3-nitro-alkanes.

REFERENCES :

1) E.P. Kohler; G.R. Barrett, J. Am. Chem. Soc., 1924, 46, 2105. 2) E.P. Kohler; N.K. Richtmyer, J. Am. Chem. Soc., 1928, 50, 3092. 3) E.P. Kohler; N.K. Richtmyer, J. Am. Chem. Soc., 1930, 52, 2038. 4) L.I. Smith, Chem. Rev., 1938, 23, 193. 5) A. Dornow; F. Boberg, Liebigs Ann. Chem., 1952, 578, 94. 6) A.T. Nielsen; T.G. Archibald, Tetrahedron Lett., 1968, 9, 3375. 7) A.T. Nielsen; T.G. Archibald, J. Org. Chem., 1969, 34, 984.

COMMENTS :

1014

Ph

O

NO2

Ph

KOLBE – SCHMITT REACTION EXAMPLE :

O Na

ONa 2

+ CO2

OH +

pressure

COO Na

MECHANISM :

Na O

O

OO

O

Na

O

O H

H

NaOPh, - PhOH

O C O

O

ONa

O

OH

COONa O

+

PhOH

DISCONNECTION :

ONa

OH

ONa

+ COONa

NOTES :

The production of phenolic acid (salicylic acid) by the action of carbon dioxide under pressure on phenoxides. The carboxylation occurs mostly in the ortho position. In the Marasse modification the phenol is heated with potassium carbonate and carbon dioxide under pressure. See also Kekulé and Reimer – Tiemann reactions.

REFERENCES : March : 546 Smith – March : 718 Houben – Weyl : 8, 372; E5, 322 Org. Synth. : 10, 94 Org. Synth. Coll. Vol. : 2, 557

1) H. Kolbe, Liebigs Ann. Chem., 1860, 113, 125.

1015

2) H. Kolbe, J. Prakt. Chem., 1875, 120, 151. 3) R. Schmitt, J. Prakt. Chem., 1885, 31, 397. 4) D. Cameron; H. Jeskey; O. Baine, J. Org. Chem., 1950, 15, 233. 5) A.S. Lindsey; H. Jeskey, Chem. Rev., 1957, 57, 583. 6) Y. Kosugi; K. Takahashi, Adv. Chem. Conv., 1998, 114, 487. 7) Y. Kosugi; M.A. Rahim; K. Takahashi; Y. Imaoka; M. Kitayama, Appl. Organometal. Chem., 2000, 14, 841. 8) Y. Kosugi; Y. Imaoka; F. Gotoh; M.A. Rahim; Y. Matsui; K. Sakanishi, Org. Biomol. Chem., 2003, 817.

COMMENTS :

KOLBE ALDEHYDE SYNTHESIS EXAMPLE :

CN

H

1) Zn, AcOH 2) H2O

O

O

MECHANISM :

CN O

CN

Zn AcOH

H2O - HCN

OH

H O

DISCONNECTION :

Ar

H

Ar

O

CN O

NOTES :

Aromatic aldehydes are produced by treatment of aroyl cyanides with zinc dust. The cyanohydrin thus formed is hydrolysed. See also Claisen – Mauthner – Bouveault reaction.

1016

REFERENCES :

1) H. Kolbe, Liebigs Ann. Chem., 1856, 98, 344. 2) Tadeus; I. Reichstein, Helv. Chim. Acta, 1930, 13, 1275.

COMMENTS :

KOLBE CYANIDE ALKYLATION EXAMPLE :

Br

CN

NaCN tri(ethylene glycol)

MECHANISM :

R hal + NaCN

tri(ethylene glycol)

R CN + Nahal

DISCONNECTION :

R CN

R hal

NOTES :

The formation of a nitrile by heating a mixture of water and alcohol with an alkali cyanide and an alkyl halide. See also Pelouze reaction.

REFERENCES : Houben – Weyl : 8, 290; E19a, 6 Org. Synth. 18, 50 Org. Synth. Coll. Vol. : 2, 376

1) F. Wöhler; J. von Liebig, Liebigs Ann. Chem., 1832, 3, 267.

1017

2) L. Friedman; H. Shechter, J. Org. Chem., 1960, 25, 877. 3) B. Saville, Angew. Chem., Int. Ed. Engl., 1967, 6, 928. 4) M.T. Reetz; I. Chatziiosifidis, Angew. Chem., Int. Ed. Engl., 1981, 20, 1017.

COMMENTS :

KOLBE ELECTROLYTIC SYNTHESIS EXAMPLE :

H3C

O 2 H3C P CH2COOH

P

Bu

t

t

Pt-anode CH3ONa, CH3OH

t

O

Bu O

Bu

P CH3

MECHANISM :

H

O

2 R H

O

Pt-anode, - 2e-, alcohol

H

O

H

O

H H

2 R

- 2 CO2

2 R-CH2

R

R H H

DISCONNECTION :

2 RCOOH

R R

NOTES :

This reaction relates to the synthesis of hydrocarbons by the electrolysis of aqueous solutions of alkali salts of aliphatic acids. The decomposition of two alkylcarboxyl anions into carbon dioxide and the dimerisation of two alkyl radicals are involved. There is also a photo-Kolbe reaction. See also Crum Brown – Walker and Hofer – Moest reactions.

REFERENCES : March : 729 Smith – March : 942

1018

Smith : 1417 Smith 2nd : 1167 Houben – Weyl : 8, 500; E19a, 56 Org. Synth. : 41, 24, 33; 60, 1 Org. Synth. Coll. Vol. : 5, 445, 463; 7, 181

1) H. Kolbe, Liebigs Ann. Chem., 1849, 69, 257. 2) S. Glasstone; A. Hickling, Chem. Rev., 1939, 25, 425. 3) E.J. Corey; R.R. Saures, J. Am. Chem. Soc., 1959, 81, 1739. 4) A.K. Vijh; B.E. Conway, Chem. Rev., 1967, 67, 623. 5) J. Knoll; H.J. Schaefer, Angew. Chem., Int. Ed. Engl., 1975, 14, 758. 6) H.-J. Schäfer, Top. Curr. Chem., 1990, 152, 91. 7) M. Sugiya; H. Nohira, Bull. Chem. Soc. Jpn., 2000, 73, 705. 8) M.C. Blount; J.A. Buchholz; J.L. Falconer, J. Catal., 2001, 197, 303.

COMMENTS :

KONDAKOFF OLEFIN REACTION EXAMPLE : O CH3 (CH3CO)2O ZnCl2

MECHANISM :

O X

CH3

X R

Ac2O, ZnI2, ZnCl2, 0 oC

O +

CH3

X

R OAc

R

Al2O3

1019

O +

CH3

X R

DISCONNECTION : O X

X

R R X = CH2, CH2CH2, CH2CH2CH2 R = H, CH3

NOTES :

Cyclic olefins condense in the presence of zinc or stannic chloride, with aliphatic acids or anhydrides.

REFERENCES :

1) J. Kondakoff, J. Russ. Chem. Chem. Soc., 24, 114. 2) J. Kondakoff, J. Russ. Chem. Chem. Soc., 24, 309. 3) J. Kondakoff, J. Prakt. Chem., 1893, 48, 467. 4) E.E. Royals; C.M. Hendry, J. Org. Chem., 1950, 15, 1147. 5) T. Hudlický; T. Srnak, Tetrahedron Lett., 1981, 22, 3351.

COMMENTS :

KONDO – UYEO SYNTHESIS EXAMPLE :

Et

Br + CHO

Cu, 230 - 250 oC

Br

N

NH2

1020

Et

MECHANISM :

Br Br

Br

Br

H H

H2N

HO

O

Cu, 200 oC - H2O

N H

H+ Cu Br

N

N

DISCONNECTION :

R1 R

N

Br

Br R

+ NH2

R1 NH2

NOTES :

Phenanthridines are obtained by heating an o-bromobenzaldehyde and an o-bromoaniline with copper powder at 230 – 250 oC. See also Ullmann diaryl reaction.

REFERENCES :

H. Kondo; S. Uyeo, Ber. Dtsch. Chem. Ges., 1937, 70, 1087.

COMMENTS :

1021

KÖNIG BENZOXAZINE SYNTHESIS EXAMPLE :

O

H N Me . HBr

+

O Br

1) NaOH 2) heat

HO

N Me

O

MECHANISM :

O +

H3C

H N .

HBr

OH O Br

NaOH OH

O

N CH3

Br

heat - HBr

HO

N CH3

DISCONNECTION : O O + HO

N R

R

H N

Br

O

NOTES :

The benzoxazine synthesis from quinines and 2-alkyl or aryl amino ethanol. The open compounds (non-cyclised) show some interesting thermochromic, piezochromic, solvatochromic and fluorescent properties.

REFERENCES :

1) K.-H. König, Chem. Ber., 1959, 92, 257. 2) K.-H. König; G. Letsch, Chem. Ber., 1959, 92, 1789. 3) J.H. Day, Chem. Rev., 1963, 63, 65. 4) J.H. Day; A. Joachim, J. Org. Chem., 1965, 35, 4107. 5) K.D. McMurtrey; G.D. Daves, jr., J. Org. Chem., 1970, 35, 4252.

COMMENTS :

1022

KOPETSCHNI CONVERSION EXAMPLE :

O

O NH2

NO2 (NH4)2S2O8 H2SO4, 100 oC

O

O

NOTES :

Oxidation of aminoanthraquinones to nitroanthraquinones is effected by peracids. In some cases a nitroso derivative is obtained. Acetic acid can facilitate the reaction through the formation of peracetic acid.

REFERENCES :

E. Kopetschni, German Patent, 363930. (Chem. Abs., 1924, 18, 991.)

COMMENTS :

KORNBLUM – DELAMARE REARRANGEMENT EXAMPLE :

CH3 Ph OOtBu H

Ph KOH

CH3 O

MECHANISM :

O

OH

OH

O Et3N O H Et N Et Et

1023

Et3N

O

DISCONNECTION : H R

R1

R

R1 O

O

O R2

NOTES :

The decomposition of dialkyl peroxides by base-catalysed rearrangement. The endoperoxides should have α-protons to undergo the reaction. The reaction depends on the strength of the base used.

REFERENCES :

1) N. Kornblum; H.E. DeLaMare, J. Am. Chem. Soc., 1951, 73, 880. 2) R.G. Salomon, Acc. Chem. Res., 1985, 18, 294. 3) L.J. Roberts; R.G. Salomon; J.D. Morrow; C.J. Brame, FASEB J., 1999, 13, 1157. 4) D.R. Kelly; H. Bansal; J.J.G. Morgan, Tetrahedron Lett., 2002, 43, 9331. 5) E. Mete; R. Altundaş; H. Seçen; M. Balci, Turk. J. Chem., 2003, 27, 145.

COMMENTS :

KORNBLUM – RUSSELL REACTION EXAMPLE :

CH2Cl

O

O OEt O

O

Na+

+

DMF, 0 oC

O O

NO2

1024

OEt

NO2

MECHANISM :

O2N

+ (CH3)2CNO2

O2N

+ (CH3)2CNO2

Cl

Cl

CH2 + Cl-

O2N

O2N Cl

O2N

CH2

+

O2N

(CH3)2CNO2

CH3 H3C

NO2

Luche :

O2N

O2N

O N O

O2N

+ Br

O2N

CHO

OH

O N O

Li+

O2N O2N

+ Br

O N O

+ + Li

NO2 O2N

O2N

Br

Br Br

O2N

O N O

NO2

NO2

1025

Li+

NOTES :

Normally O-alkylation (SN2) takes place between nitronate anions and alkyl halides. However, C-alkylation of nitronate anions via a radical chain reaction takes place when para-nitrobenzyl chlorides are used. Luche et al. discovered that sonification can influence the C/O alkylation ratio.

REFERENCES :

1) N. Kornblum; G.W. Urry; R.C. Kerber, J. Am. Chem. Soc., 1964, 86, 3904. 2) N. Kornblum; R.E. Michel; R.C. Kerber, J. Am. Chem. Soc., 1966, 88, 5660. 3) N. Kornblum; R.E. Michel; R.C. Kerber, J. Am. Chem. Soc., 1966, 88, 5662. 4) G.A. Russell; W.C. Danen, J. Am. Chem. Soc., 1966, 88, 5663. 5) M. Julliard; J.P. Scagliarini; M. Rajzmann; M. Chanon, Chimia, 1986, 40, 16. 6) M.J. Dickens; J.-L. Luche, Tetrahedron Lett., 1991, 32, 4709.

COMMENTS :

KORNBLUM ALDEHYDE SYNTHESIS EXAMPLE : H Br Br O

O DMSO

1026

Br O

MECHANISM :

R H

R1

R

H

O S

H

H

H

O S

- H+

CH3

CH3

H

R

R1

H

H

or R1

X

-X R

H3C

H3C S O

S O

H3C

H

O S

H H

H

- H+

H

R1

R

CH3

H3C

R - S(CH3)2

H

R1

H

O S CH3

R1 O

DISCONNECTION :

R

H

R1 O

R X = Hal, OTs

X R1

NOTES :

The synthesis of aldehydes from primary alkyl halides or tosylates, using dimethyl sulfoxide as oxidant. There are several variations of this reaction. The silver-assisted oxidation and the amine oxide assisted oxidation (sometimes called Ganem oxidation) are the best known variations. See also Kröhnke – Ortoleva – King, Pfitzner – Moffatt and Swern reactions.

REFERENCES : Smith – March : 1535 Houben – Weyl : E3, 248 Org. React. : 39, 297

1) N. Kornblum; J.W. Powers; G.J. Anderson; W.J. Jones; H.O. Larson; O. Levand; W.M. Weaver, J. Am. Chem. Soc., 1957, 79, 6562.

2) W.W. Epstein; F.W. Sweat, Chem. Rev., 1967, 67, 247. 3) D.D. Tanner; E.V. Blackburn; G.E. Diaz, J. Am. Chem. Soc., 1981, 103, 1557. 4) P. Dallemagne; S. Rault; M. Robba, Bull. Soc. Chim. Fr., 1991, 128, 260. 5) W. Hanefeld; S. Wurtz, J. Prakt. Chem., 2000, 342, 445. 6) B. Fischer; E. Kabha; F.P. Gendron; A.R. Beaudoin, Nucleosides, Nucleotides, 2000, 19, 1033.

1027

COMMENTS :

KÖRNER – CONTARDI REPLACEMENT EXAMPLE :

O2N

NO3

O2N

NO2 N

N

NO2

CuSO4 NaNO2

NO2

MECHANISM :

2 ArNH2 + 2 tBuONO + CuCl2

N

N

2 ArCl + 2 tBuOH + CuO + N2 + H2O

NO2 O

N

CH3CN 65 oC

- N2

HO

DISCONNECTION :

N

R

N

R = CN, Hal, NO2

NOTES :

The replacement of diazonium groups in aromatic compounds by halo, cyano or similar groups under the influence of cupric salts. It is limited to negatively substituted diazo-compounds. The reaction has been improved by Suzuki et al. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulphinic acid, Griess deamination, Knoevenagel diazotation, Meerwein arylation, Sandmeyer

diazonium, Schwechten and Witt diazotation reactions.

1028

REFERENCES : Houben – Weyl : 5/3, 846; 5/4, 438 Org. Synth. : 19, 40; 28, 52 Org. Synth. Coll. Vol. : 2, 225; 3, 341

1) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633. 2) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 2650. 3) G. Körner; A. Contardi, Atti. Accad. Nazl. Lincei, 1914, 23II, 464. 4) H.H. Hodgson, Chem. Rev., 1947, 40, 251. 5) M.P. Doyle, J. Org. Chem., 1977, 42, 2426. 6) A.P. Krapcho; S.N. Haydar, Heterocycl. Commun., 1998, 4, 291.

COMMENTS :

KOSER TOSYLATION EXAMPLE :

H3C

OTs

Et +

H

H

I OH

1029

DCM

H3C H TsO

Et H OTs

MECHANISM :

R4 R1

HO

OTs

R3 R2

Ph

+

I

Ph OTs

I OH

R4

R1 R2R3

and / or H

Ph

R4

O I R4

R3

OTs

R1 TsO

R1 R2

R4 R1 TsO

I Ph R3

R3

R1 TsO

+ H2O

OTs

p-TsOH - H2O

R2

R4

I Ph R3

R2

HO

R2 OTs

+ PhI

DISCONNECTION :

O

O R

R1

R

R1

OTs Ph R TsO

I OTs

R

R1

R1 R OTs

R

TsO OTs R3 R2 R R1

I

R3

R2

R

R1

NOTES :

The vic-bis tosylation of alkenes using [hydroxy(tosyloxy)iodo]benzene (HTIB) which is a moderate electrophile on iodine. HTIB can be used for oxytosylation, dioxytosylation, phenyliodination, solvohyperiodination and several other oxidative transformations. See also McNelis rearrangement.

REFERENCES : Org. Synth. : 70, 215 Org. Synth. Coll. Vol. : 9, 477

1030

1) G.F. Koser; R.H. Wettack, J. Org. Chem., 1977, 42, 1476. 2) L. Rebrovic; G.F. Koser, J. Org. Chem., 1984, 49, 2462. 3) R.M. Moriarty; R.K. Vaid; G.F. Koser, Synlett, 1990, 365. 4) S.J. Coates; H.H. Wasserman, Tetrahedron Lett., 1995, 36, 7735. 5) A. Kirschning, Eur. J. Org. Chem., 1998, 2267. 6) V.W. Pike; F. Butt; A. Shah; D.A. Widdowson, J. Chem. Soc., Perkin Trans. 1, 1999, 245. 7) T. Muraki; H. Togo; M. Yokoyama, J. Org. Chem., 1999, 64, 2883. 8) G.F. Koser, Aldrichimica Acta, 2001, 34, 89. 9) V.V. Zhdankin; P.J. Stang, Chem. Rev., 2002, 102, 2523.

COMMENTS :

KOST – SAGITULLIN REARRANGEMENT EXAMPLE :

NO2

NO2

N CH3 CH3

25% aq. EtNH2

N H

Et

MECHANISM :

NO2

N CH3 CH3

H2O

O

H N CH3

NO2

O2 N

O2N 25 % aq. EtNH2

O

N Et H

DISCONNECTION :

O2N O2N N H

R

N R

1031

CH3

- H2O

N H

Et

NOTES :

Nitropyridiniium salts react with primary and secondary amines to afford alkyl or dialkyl anilines as a result of the recyclisation of the pyridine nucleus. The alkyl amine or dialkyl amine group is included in the final product at the open form stage.

REFERENCES :

1) R.S. Sagitullin; S.P. Gromov; A.N. Kost, Tetrahedron, 1978, 34, 2213. 2) A.N. Kost; R.S. Sagitullin; S.P. Gromov, Heterocycles, 1977, 7, 997. 3) G.G. Danagulyan; L.G. Sahakyan, Chem. Heterocycl. Compd. (Engl. Transl.), 2000, 395, 698. 4) G.G. Danagulyan; L.G. Sahakyan; D.A. Tadevosyan, Chem. Heterocycl. Compd. (Engl. Transl.), 2003, 428, 303.

COMMENTS :

von KOSTANECKI (ALLAN – ROBINSON) ACYLATION EXAMPLE :

HO

OH Et OH

O

AcO 1) Ac2O 2) NaOAc heat

1032

O

CH3 CH3

OAc O

MECHANISM : Allan – Robinson :

O HO

OH

AcO

Et OH

CH3 AcO

O

Ac2O

CH3

O

OAc O

Baker Venkataraman rearrangement

O

CH3 O

OAc O

CH3

+

H AcO

O

O

AcO

CH3

base, - H2O OAc O

H

O

CH3

- H2O

CH3

CH3 OAc O

von Kostanecki :

O HO

OH Et OH

AcO

HO

CH3 AcO

O

Ac2O

CH3 OAc O

OAc O

O

AcO

O H CH3

OAc OH

O

CH3

O

AcO

CH2

O

O

- H2O OAc

CH3

DISCONNECTION :

O

R

OH R2

R2 R1 O

R1

+ (RCO)2O

O R = Alk, Ar R1 = H, Alk (up to C16), Ar, OAlk; OAc

NOTES : o-Hydroxyketones when heated with acid anhydrides in the presence of the sodium or potassium salts of the

corresponding acids form chromones, flavones or isoflavones. See also Baker – Venkataraman and Bargellini reactions.

1033

REFERENCES : Org. React. : 8, 59 Org. Synth. : 32, 72; 46, 28 Org. Synth. Coll. Vol. : 4, 478; 5, 251

1) P. Friedländer; H. Rüdt, Ber. Dtsch. Chem. Ges., 1896, 29, 878. 2) L. Kesselhaul; S. von Kostanecki, Ber. Dtsch. Chem. Ges., 1896, 29, 1881. 3) M. Bloch; S. von Kostanecki, Ber. Dtsch. Chem. Ges., 1900, 33, 471. 4) J. Allan; R. Robinson, J. Chem. Soc., 1924, 2192. 5) T. Heap; R. Robinson, J. Chem. Soc., 1926, 2336. 6) G. Wittig, Liebigs Ann. Chem., 1926, 446, 155. 7) L. Farkas; R. Ruegger; H. Wagner; G. Maurer, Chem. Ber., 1977, 110, 737. 8) P.R. Iyer; C.S.R. Iyer; K.J.R. Prasad, Indian J. Chem., 1983, 22B, 1055. 9) M. Hamdi; D. Chergui; Y. Rachedi, Heterocycles, 1984, 21, 633. 10) S.A. Patwardhan; A.S. Gupta, J. Chem. Res., 1984, 395. 11) T. Horie; Y. Kawamura; M. Tsukayam; S. Yoshizaki, Chem. Pharm. Bull., 1989, 37, 1216. 12) R. Dommisse; A.J. Vlietinck; F. Boers; B.-L. Deng; G. Lemiere; J. Lepoivre; A. de Groot, Arch. Pharm., 1997, 330, 313. 13) V.A. Mamedov; A.A. Kalinin; A.T. Gubaidullin; I.A. Litvinov; Ya.A. Levin, Chem. Heterocycl. Compd. (Engl. Transl.), 2003, 39, 96.

COMMENTS :

KOTALI – TSOUNGAS REACTION EXAMPLE :

OH

N

H N Ph CH3

Ph

O

Pb(OAc)4

1034

O

O CH3

MECHANISM :

AcO N

H N

O

N

Ph CH3

Pb(OAc)2 Ph N O CH3

Pb(OAc)4

OH

- Pb(OAc)2

OAc CH3 O N N Ph

OH

OH

H3C

N O OH

H3C

N OAc Ph

N O

- HOAc

O

N - N2 Ph

O CH3 O

CH3 O

Ph O

Ph

DISCONNECTION :

O

O

R

R R1 O

R2

O

+

OH O

H N

R3

NH2

O

R2

NOTES :

The lead tetraacetate forms an α-azoacetate with a hydrazone. Cyclisation to a 1,3,4-oxadiazoline, with migration of the acetoxy group, followed by the displacement of the acetoxy by the phenolic hydroxyl affords a tricyclic intermediate. Nitrogen eliminates and an epoxy-isobenzofuran is formed. Ring-opening after rearrangement gives the product. The exact mechanism is still under investigation. Triacylbenzenes and 2-acylbenzaldehydes can also be made by this method.

REFERENCES :

1) A. Kotali; P.G. Tsoungas, Tetrahedron Lett., 1987, 28, 4321. 2) A. Kotali; U. Glaveri; E. Pavlidou; P.G. Tsoungas, Synthesis, 1990, 1172. 3) A.R. Katritzky; A. Kotali, Tetrahedron Lett., 1990, 31, 6781. 4) A.R. Katritzky; P.A. Harris; A. Kotali, J. Org. Chem., 1991, 56, 5049. 5) A. Kotali; M. Papapetrou; V. Dimos; P.A. Harris, Org. Prep. Proced. Int., 1998, 30, 177.

1035

COMMENTS :

KOWALSKI ESTER HOMOLOGATION EXAMPLE :

OTIPS CO2Et 1) CH2Br2, LiTMP, - 78 oC 2) LiN(TMS)2, - 78 oC 3) nBuLi, 0 oC -> RT 4) TIPSOTf, - 78 oC -> RT

MECHANISM :

O R

OEt

LiCHBr2

OLi R CHBr2 OEt

n

BuLi - 78 oC

LiO

H

R

Br

LiTMP 0 oC -> RT

R = Bulky Base, - 78 oC

O R

LHMDS CHBr2

LiO

Br

R

Br

LiO

Li

R

Br

n

BuLi - 78 oC

R RCH2CO2Et

O EtOH

H

H+ EtOH

R

OLi

TIPSOTf

R

1036

OTIPS

DISCONNECTION :

RCH2CO2Et R

RCO2Et

OTIPS

NOTES :

This reaction is a general method for the direct homologation of esters. The reaction is isoelectronic with the Hofmann rearrangement. See also Arndt – Eistert, Buchner – Curtius – Schlotterbeck, Clibbens – Nierenstein, Colvin, Corey – Fuchs and Hofmann rearrangement reactions.

REFERENCES : Org. Synth. : 71, 146 Org. Synth. Coll. Vol. : 9, 426

1) C.J. Kowalski; M.S. Haque; K.W. Fields, J. Am. Chem. Soc., 1985, 107, 1429. 2) C.J. Kowalski; M.S. Haque, J. Am. Chem. Soc., 1986, 108, 1325. 3) C.J. Kowalski; G.S. Lal; M.S. Haque, J. Am. Chem. Soc., 1986, 108, 7127. 4) C.J. Kowalski; G.S. Lal, Tetrahedron Lett., 1987, 28, 2463. 5) C.J. Kowalski; R.E. Reddy, J. Org. Chem., 1992, 57, 7194. 6) A.B. Smith III; C.M. Adams; S.A. Kozmin; D.V. Paone, J. Am. Chem. Soc., 2001, 123, 5925. 7) D. Gray; C. Concellón; T. Gallagher, J. Org. Chem., 2004, 69, 4844.

COMMENTS :

KRAFFT DEGRADATION EXAMPLE :

O HO

O (CH3CO2)2Ba CrO3

1037

HO

MECHANISM :

(RCH2CO2)2Ba + (CH3CO2)2Ba RCH2COCH3 + 3 O

2 RCH2COCH3 + 2 BaCO3 CrO3

RCOOH + CH3COOH

DISCONNECTION :

RCOOH M = metal

(RCH2COO)2M

NOTES :

This method for the transformation of a higher fatty acid into its next lower homologue involves the formation of the corresponding methyl ketone by dry distillation of the alkaline earth salt with the corresponding acetate. The methyl ketone is oxidised by chromic acid. See also Barbier – Wieland – Locquin, Gallagher – Hollander, Hoehn – Mason and Miescher reactions.

REFERENCES :

1) F. Krafft, Ber. Dtsch. Chem. Ges., 1879, 12, 1664. 2) F. Krafft, Ber. Dtsch. Chem. Ges., 1879, 12, 1668.

COMMENTS :

KRAPCHO DECARBOXYLATION EXAMPLE :

CO2CH3 O H3C

O

1) LiCl DMSO 2) H2O

1038

O H3C

O

MECHANISM :

O

O R

R

CH3

O

R CH2

O

H2O

R CH3

Cl

DISCONNECTION :

O

EWG R H R1

R EWG

OR2 R1

NOTES :

A mild procedure for the decarboxylation of methyl- or ethyl esters of carboxylic acids who normally bear an electron withdrawing group in the α-position. A wide variety of metal salts (e.g. NaCN, LiCl, NaBr, Na2CO3.10H2O) can be used in a dipolar aprotic solvent. See also Kochi decarboxylation.

REFERENCES : March : 629 Smith – March : 808 Smith 2nd : 143 Org. React. : 24, 187 Org. Synth. : 75, 195 Org. Synth. Coll. Vol. : 10, 2328

1) A.P. Krapcho; A.J. Lovey, Tetrahedron Lett., 1973, 14, 957. 2) A.P. Krapcho, Synthesis, 1982, 805. 3) A.P. Krapcho, Synthesis, 1982, 893. 4) J.P. Barnier; A. Loupy; P. Pigeon; M. Ramdani; P. Jacquault, J. Chem. Soc., Perkin Trans. 1, 1993, 397. 5) D.A. Evans; K.A. Scheidt; C.W. Downey, Org. Lett., 2001, 3, 3009. 6) G.A. Molander; D. St. Jean, jr.; J. Haas, J. Am. Chem. Soc., 2004, 126, 1642.

COMMENTS :

1039

KRIEF – REICH – CHOW OLEFINATION EXAMPLE :

O

O 1) LDA, THF 2) PhSeBr 3) AcOH, H2O2

MECHANISM :

O

OH (PhSe)2CH2 n BuLi

CH2SePh MeSO2Cl, Et3N

DISCONNECTION : R2 R

R1

O R

R1

+ (PhSe)2CHR2

NOTES :

The synthesis of olefins by stereospecific reductive elimination of β-hydroxyalkyl selenides using MeSO2Cl, HClO4 or P2I4. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, McMurry, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig olefination reactions.

REFERENCES : Org. React. : 44, 1

1) W. Dumont; P. Bayet; A. Krief, Angew. Chem., Int. Ed. Engl., 1974, 13, 804. 2) J.N. Denis; W. Dumont; A. Krief, Tetrahedron Lett., 1976, 17, 453. 3) H.J. Reich; F. Chow; S.K. Shah, J. Am. Chem. Soc., 1979, 101, 6638. 4) T.K. Sarkar; S.K. Ghosh, Tetrahedron Lett., 1987, 28, 2061. 5) T.K. Sarkar; S.K. Ghosh; T.K. Satapathyi, Tetrahedron, 1990, 46, 1885. 6) P. Gosselin; E. Bonfand; C. Maignan, Synthesis, 1996, 1079. 7) J.T. Kuethe; D.L. Comins, Org. Lett., 1999, 1, 1031.

1040

COMMENTS :

KRIEWITZ – PRINS ADDITION EXAMPLE :

H3C

H3C

+ HCHO + AcOH

H3C

OAc +

H2O

O

AcO

O

MECHANISM :

O H

R

OH H

H

+

H

R

H

H H

H

H R - H+

OH

H

H HO R

H2O

R

OH OH

H

O

O

DISCONNECTION :

R OH R

R

OH OH

NOTES :

Aliphatic aldehydes, especially formaldehyde, condense with olefins in the presence of dilute mineral acids to give 1,3-glycols and m-dioxanes. A little explored variation has been reported by Nussbaumer and Fráter. There are also aza-Prins reactions. See also Ritter reaction.

1041

REFERENCES : March : 820, 967 Smith – March : 1241 Smith : 1310 Smith 2nd : 1079 Houben – Weyl : 4/2, 45; 6/3, 265; E3, 641; E19c, 324, 336 Org. Synth. : 33, 72 Org. Synth. Coll. Vol. : 4, 786

1) O. Kriewitz, Ber. Dtsch. Chem. Ges., 1899, 32, 57. 2) H.J. Prins, Chem. Weekbl., 1919, 16, 64. 3) H.J. Prins, Chem. Weekbl., 1919, 16, 1072. 4) S.H. Tucker; M. Whalley, Chem. Rev., 1952, 50, 483. 5) L.A. Mikeska; E. Arundale, Chem. Rev., 1952, 51, 505. 6) E.E. Smissman; R.A. Mode, J. Am. Chem. Soc., 1957, 59, 3447. 7) D.R. Adams; S.P. Bhatnagar, Synthesis, 1977, 661. 8) B.B. Snider; D.J. Rodini; T.C. Kirk; R. Cordova, J. Am. Chem. Soc., 1982, 104, 555. 9) J. Thivolle–Cazat; I. Tkatchenko, J. Chem. Soc., Chem. Commun., 1982, 1128. 10) N.H. Andersen; S.W. Hadley; J.D. Kelley; E.R. Bacon, J. Org. Chem., 1985, 50, 4144. 11) C. Nussbaumer; G. Fráter, Helv. Chim. Acta, 1987, 70, 793. 12) C. Nussbaumer; G. Fráter, J. Org. Chem., 1987, 52, 2096. 13) R.B. Ruggeri; M.M. Hansen; C.H. Heathcock, J. Am. Chem. Soc., 1988, 110, 8734. 14) B.B. Snider, Comp. Org. Syn., 1991, 2, 527. 15) T.M. Jyothi; M.L. Kaliya; M. Herskowitz; M.V. Landau, Chem. Commun., 2001, 992. 16) S.R. Crosby; J.R. Harding; C.D. King; G.D. Parker; C.L. Willis, Org. Lett., 2002, 4, 3407. 17) B. Patterson; S. Marumoto; S.D. Rychnovsky, Org. Lett., 2003, 5, 3163.

COMMENTS :

1042

KRÖHNKE – ORTOLEVA – KING ALDEHYDE SYNTHESIS EXAMPLE :

O

O

Br

H

1) pyridine 2) base N O

N 3) acid, water

MECHANISM :

H

H R

X

-

R

-X

H

H

HO-

N

N R

H

O N

N

CH3 N CH3

H H O R H R

N CH3 N O

N

- pyridine

CH3

O

CH3

H N O

R

N CH3

H

H+

DISCONNECTION :

R

H

H

R

Hal H

O R = Ar, R1CH=CH-,

R2 O

NOTES :

Halogen compounds of the general formulae ArCH2Hal, RCH=CHCH2Hal and RCOCH2Hal are converted into quaternary pyridinium compounds which react with p-nitrosodimethylaniline to give nitrones. The latter on acid hydrolysis yield aldehydes. In the Ortoleva – King variant pyridine and iodine are used. See also Duff – Bills, Kornblum, Sommelet and Utzinger reactions.

1043

REFERENCES : March : 1194 Smith – March : 1536 Houben – Weyl : 10/4, 375; E3, 231, 402; E6b, 387; E7a, 530; E7b, 321; E8a, 414; E14b, 1484; E15, 938 Org. React. : 8, 203 Org. Synth. : 46, 81 Org. Synth. Coll. Vol. : 5, 825

1) G. Ortoleva, Gazz. Chim. Ital., 1899, 25/1, 503. 2) F. Kröhnke; E. Börner, Ber. Dtsch. Chem. Ges., 1936, 69, 2006. 3) L.C. King, J. Am. Chem. Soc., 1944, 66, 1612. 4) J. Hamer; A. Macalusco, Chem. Rev., 1964, 64, 473. 5) A. Giner–Sorolla, Chem. Ber., 1968, 101, 611. 6) I.N. Chernyuk; M.I. Shevchuk; P.I. Yagodinets; E.M. Volynskaya, Zh. Obshch. Khim., 1981, 51, 1020. 7) J. Alvarez–Builla; J.L. Novella; E. Gálvez; P. Smith; F. Florencio; S. Garciá–Blanco; J. Bellanato; M. Santos, Tetrahedron, 1986, 42, 699.

8) S.N. Kilenyi, Comp. Org. Syn., 1991, 7, 657. 9) T. Bark; A. von Zelewsky, Chimia, 2000, 54, 589. 10) A.V. Malkov; M. Bella; I.G. Stará; P. Kočovský, Tetrahedron Lett., 2001, 42, 3045.

COMMENTS :

KRÖHNKE PYRIDINE SYNTHESIS EXAMPLE :

CH3 O H3C

N

+

H3C

O Et

NH4OAc, HOAc

Br

1044

H3C

N

Et

MECHANISM :

Br O N

H3C

O

O

- HOAc H3C

N

N

H3C

H

Et

CH3

OAc O O

O N

H3C

N

H3C H

CH3 Et

O

CH3

OAc Et

O

N

H3C

- HOAc

CH3

NH2

Et

NH2

+

H NH4OAc

AcOH + NH3

N Et

H+

OAc

CH3

N H

CH3

CH3

CH3

OH

- HOAc - C5H5N

Et

N H

CH3 OH

- H2O

CH3 OAc - HOAc

Et

N

CH3

DISCONNECTION :

R1 R3 R

N

R2

O R

N

+

O

R1 R3

Br

NOTES :

α-Pyridinium methyl ketones salts react with α,β-unsaturated ketones to afford pyridines.

REFERENCES :

1) W. Zecher; F. Kröhnke, Chem. Ber., 1961, 94, 690. 2) W. Zecher; F. Kröhnke, Chem. Ber., 1961, 94, 698. 3) F. Kröhnke, Synthesis, 1976, 1. 4) T.R. Kelly; Y.-J. Lee; R.J. Mears, J. Org. Chem., 1997, 62, 2774.

1045

R2

Et

N H

CH3

COMMENTS :

KUHN – ROTH OXIDATION EXAMPLE :

OAc OAc

EtOOC EtOOC

OAc

CrO3

6 CH3COOH

OAc

NOTES :

The substance is oxidised with sulfuric acid – chromic acid mixture under conditions such that C-methyl groups forms acetic acid which is distilled off and titrated. The method has rather limited use nowadays.

REFERENCES : Smith : 315 Smith 2nd : 276 Houben – Weyl : 2, 274

1) R. Kuhn; F. L’Orsa, Angew. Chem., 1931, 44, 847. 2) R. Kuhn; H. Roth, Ber. Dtsch. Chem. Ges., 1933, 66, 1274. 3) B. Frank; J. Knoke, Chem. Ber., 1962, 95, 579. 4) R. Bentley; C.M. Springer; V.G. Ramsey; G.H. Dialameh; R.E. Olson, J. Biol. Chem., 1968, 243, 174. 5) S.A. Benner; K.G. Devine; L.N. Matveeva: D.H. Powell, Proc. Natl. Acad. Sci. USA, 2000, 97, 2425.

COMMENTS :

1046

KUHN – WINTERSTEIN REACTION EXAMPLE :

H3C

HO

H3C

OH P2I4, CS2, pyridine

CH3

H3C

DISCONNECTION : OH R

R

R

R OH

NOTES :

The trans olefin formation (Grob-type fragmentation) from glycols using P2I4. This is a useful reaction for the preparation of polyenes. See also Corey – Winter reaction.

REFERENCES :

1) R. Kuhn; A. Winterstein, Helv. Chim. Acta, 1928, 11, 87. 2) R. Kuhn; K. Wallenfels, Ber. Dtsch. Chem. Ges., 1938, 71, 1510. 3) H.H. Inhoffen; K. Radscheit; U. Stache; V. Koppe, Liebigs Ann. Chem., 1965, 684, 24. 4) H. Kessler; W. Ott, Tetrahedron Lett., 1974, 15, 1383. 5) T. Hanafusa; S. Imai; K. Ohkata; H. Suzuki; Y. Suzuki, J. Chem. Soc., Chem. Commun., 1975, 885. 6) W.W. Win; K.G. Grohmann; L. Todaro, J. Org. Chem., 1994, 59, 2803. 7) A.R. Valla; D.L. Cartier; R. Labia, Curr. Org. Synth., 2004, 1, 167.

COMMENTS :

1047

KULINKOVICH REACTION EXAMPLE :

O OCH3

OH i

1) EtMgCl, Ti(O Pr)4 THF, 20 oC 2) 5% H2SO4

MECHANISM :

i

Ti

C2H6 2 EtMgBr

(iPrO)2

OH

R

Ti

Et

i

Et

OMgBr i

+ OiPrMgBr

PrO

i

+

H2O, H - iPrOH

RCO2Me

2 OiPrMgBr

Ti(OiPr)2

R

OiPr

PrO

R

Ti PrO

O

OMe

OCH3 Ti O i PrO

PrO

2 EtMgBr

DISCONNECTION :

HO

O

R1 R1

H

OR2

R

NOTES :

An efficient way of preparing hydroxycyclopropanes by treatment of carboxylic esters with a suitable Grignard reagent in the presence of titanium tetraisopropoxide. The proposed key intermediate is the titanacyclopropane. This intermediate is formed by 2 equivalents of Grignard reagent and titanium tetraisopropoxide. The thermally unstable intermediate undergoes β-hydride elimination and reductive elimination to give ethane and the titanacyclopropane. This reaction can be catalytic or non-catalytic. The reaction has been modified by Corey et al.

1048

REFERENCES : Org. Synth. : 80, 111

1) O.G. Kulinkovich; S.V. Sviridov; D.A. Vasilevsky; T.S. Prityckaja, Zh. Org. Khim, 1989, 25, 2245. 2) O.G. Kulinkovich; S.V. Sviridov; D.A. Vasilevsky, Synthesis, 1991, 234. 3) E.J. Corey; S.A. Rao; M.C. Noe, J. Am. Chem. Soc., 1994, 116, 9345. 4) J. Sun; J. Lee; J.K. Cha, Tetrahedron Lett., 1997, 38, 5233. 5) V. Chaplinski; H. Winsel; M. Kordes; A. de Meijere, Synlett, 1997, 111. 6) O.L. Epstein; O.G. Kulinkovich, Tetrahedron Lett., 1998, 39, 1823. 7) O.G. Kulinkovich; A. de Meijere, Chem. Rev., 2000, 100, 2789. 8) A. Esposito; M. Taddei, J. Org. Chem., 2000, 65, 9245. 9) B. Breit, J. Prakt. Chem., 2000, 342, 211. 10) J.R. Al Dulayyami; M.S. Baird; I.G. Bolesov; A.V. Nizovtsev; V.V. Tverezovsky, J. Chem. Soc., Perkin Trans. 2, 2000, 1603. 11) J.J. Eisch; J.N. Gitua; P.O. Otieno; X. Shi, J. Organomet. Chem., 2001, 624, 229. 12) J.C. Lee; M.J. Sung; J.K. Cha, Tetrahedron Lett., 2001, 42, 2059. 13) O.G. Kulinkovich, Chem. Rev., 2003, 103, 2597. 14) J.J. Eisch; A.A. Adeosun; J.N. Gitua, Eur. J. Org. Chem., 2003, 4721. 15) E. Raponi; J.-M. Pons, Tetrahedron Lett., 2003, 44, 9193. 16) O.G. Kulinkovich, Eur. J. Org. Chem., 2004, 4517.

COMMENTS :

KUMADA – TAMAO – CORRIU CROSS–COUPLING EXAMPLE :

Br Bu

Bu

CH3

Me

H + H

H

CO2Me

i

Bu2AlH Pd(Ph3P)Cl2

1049

H H

CO2Me

MECHANISM : Pd-catalysed :

LnPd0 R1 X

R1 R R1 LnPdII X

RLi R1 LnPdII R

1050

LiX

Nickel-catalysed :

L2NiIIX2

2 RMgX

2 MgX2

L2NiIIR2

R R

R1 X R1 L2Ni

R1 R

II

RMgX

X MgX2 R1 X

R1

R1

L2NiII

L2NiII

R

R

R1 X

DISCONNECTION :

R1 R

R1X + RMgX

NOTES :

Nickel and palladium complexes catalyse the reaction of organometallic reagents (Al, Mg, Zn, Zr, Li) with alkenyl or aryl halides to afford cross-coupled products. In the asymmetric version mostly secondary alkyl Grignard reagents are used. Good results are obtained using P,N or N,S-type of ligands (tert-Leuphos, valphos or homomethpos). Much less recognised is the work done by Felkin in this area. Negishi introduced the use of zinc, which increased the scope of this reaction to cross coupling of acyl chlorides, thioesters and Reformatsky reagents. See also Murahashi cross-coupling and Negishi reaction.

REFERENCES : Smith – March : 537 Org. Synth. : 58, 127 Org. Synth. Coll. Vol. : 6, 407

1051

1) C. Chuit; H. Felkin; C. Frajerman; G. Roussi; G. Swierczewski, J. Chem. Soc., Chem. Commun., 1968, 1604. 2) R.J.P. Corriu; J.P. Masse, Chem. Commun., 1972, 144. 3) K. Tamao; K. Sumitani; M. Kumada, J. Am. Chem. Soc., 1972, 94, 4374. 4) S. Baba; E-i. Negishi, J. Am. Chem. Soc., 1976, 98, 6729. 5) M. Kumada, Pure Appl. Chem., 1980, 52, 669. 6) E-i. Negishi; T. Takahashi, Synthesis, 1988, 1. 7) T.Y. Luh, Rev. Heteroatom Chem., 1996, 15, 61. 8) B.H. Lipschutz; T. Tomioka; P.A. Blomgren; J.A. Sclafani, Inorg. Chim. Acta, 1999, 296, 164. 9) E.R. Silcoff; A.S.I. Asadi; T. Sheradsky, J. Polym. Sci. A. Polym. Chem., 2001, 39, 872. 10) F.Y. Kwong; K.S. Chan, Organometallics, 2001, 20, 2570. 11) S. Tasler; B.H. Lipshutz, J. Org. Chem., 2003, 68, 1190. 12) P. Walla; C.O. Kappe, Chem. Commun., 2004, 564. 13) L.-M. Yang; L.-F. Huang; T.-Y. Luh, Org. Lett., 2004, 6, 1461.

COMMENTS :

KUMADA – TAMAO – FLEMING STEREOSELECTIVE HYDROXYLATION EXAMPLE :

O

O O

Si O

H2O2, K2CO3 CH3OH

1052

O

HO OH

MECHANISM : Fleming :

FMe2Si

R1

Ph

R2

R Si O H O O

Ln Hg(OAc)2 HOOAc

Ar LnSi

R OH

R O

LnSi

O

O

O

OH

Ar

ROH

H2O

Ar

Catalytic hydrosilylation :

H M SiX3 H SiX3

H M SiX3

M = Pt, Pd, Rh R

R

H

SiX3 R

* H3C

M SiX3

R SiX3

and/or R

M SiX3 CH3

DISCONNECTION :

R OH

R SiX3

NOTES :

This is the oxidative cleavage of the silicon – carbon bond. The Kumada – Tamao method uses hydrogen peroxide potassium hydrogenfluoride and requires at least one electron-withdrawing group on the silicon atom. While the Fleming method is a two-step method using mercury acetate and peroxyacetic acid. There are 12 main silyl groups

available for oxidation in the literature. See also Stork – Nishiyama radical cyclisation.

1053

REFERENCES : Smith 2nd : 277, 968 Org. Synth. : 69, 96; 73, 94 Org. Synth. Coll. Vol. : 8, 315; 9, 539

1) K. Tamao; T. Kakui; M. Akita; R. Kanatani; J. Yoshida; M. Kumada, Tetrahedron, 1983, 39, 983. 2) K. Tamao; N. Ishida; T. Tanaka; M. Kumada, Organometallics, 1983, 2, 1694. 3) I. Flemming; R. Henning; H. Plaut, J. Chem. Soc., Chem. Commun., 1984, 29. 4) I. Flemming; P.E.J. Sanderson, Tetrahedron Lett., 1987, 28, 4229. 5) K. Tamao, J. Synth. Org. Chem. Jpn., 1988, 46, 861. 6) S.S. Magar; P.L. Fuchs, Tetrahedron Lett., 1991, 31, 7513. 7) G.R. Jones; Y. Landais, Tetrahedron, 1996, 52, 7599. 8) M.R. Elliott; A.-L. Dhimane; M. Malacria, J. Am. Chem. Soc., 1997, 119, 3427. 9) A.G.M. Barrett; J. Head; M.L. Smith; N.S. Stock; A.J.P. White; D.J. Williams, J. Org. Chem., 1999, 64, 6005. 10) K. Itami; K. Mitsudo; J.-I. Yoshida, J. Org. Chem., 1999, 64, 8709. 11) S.E. Denmark; J.J. Cottell, J. Org. Chem., 2001, 66, 4276. 12) H. Usuda; M. Kanai; M. Shibasaki, Org. Lett., 2002, 4, 859.

COMMENTS :

KUMADA REARRANGEMENT EXAMPLE :

Si Si H3C

600 oC

1054

H H Si Si H

MECHANISM :

2 (CH3)3Si

(CH3)2SiSi(CH3)2 (CH3)3Si

+ (CH3)3SiSi(CH3)3

(CH3)3SiH + (CH3)3SiSi(CH3)2CH2 (CH3)3SiCH2Si(CH3)2

(CH3)3SiSi(CH3)2CH2

(CH3)3SiCH2Si(CH3)2H + (CH3)3SiSi(CH3)2CH2

(CH3)3SiCH2Si(CH3)2 + (CH3)3SiSi(CH3)3

DISCONNECTION :

H H Si Si H

Si Si H3C

NOTES :

This is the carbosilane formation under destruction of silicon-silicon bonds. This occurs at temperature above 325 oC.

REFERENCES :

1) K. Shiina; M. Kumada, J. Org. Chem., 1958, 23, 139. 2) H. Sakurai; R. Koh; A. Hosomi; M. Kumada, Bull. Chem. Soc. Jpn, 1966, 39, 2050. 3) M.F. Gozzi; I.V.P. Yoshida, Macromolecules, 1995, 28, 7235. 4) F. Babonneau; J. Maquet; C. Bonhomme; R. Richter; G. Roewer; D. Bahloul, Chem. Mat., 1996, 8, 1415. 5) M. Scarlete; N. McCourt; I.S. Butler; J.F. Harrod, Chem. Mat., 2001, 13, 655.

COMMENTS :

1055

KURSANOV – PARNES IONIC HYDROGENATION EXAMPLE : CH3 H3C H3C

Ph2SiH2 TFA

H

CH3 H3C

MECHANISM :

H+

fast CF3COO

H

O CF3 H

O

HSiR3 slow

C C H H

NOTES :

A non-catalytic hydrogenation of C=C, C=O, C=N bonds and hydrogenolysis of C-OH, C-hal, under the action of a proton donor and a hydride ion donor, normally trifluoroacetic acid and organo silanes. Under these conditions COOH, COOR, CONR2, CN, NO2, SO3R, aromatic rings do not hydrogenate. The hydrogenation of tetra-substituted alkenes often proceeds stereoselectively.

REFERENCES : Org. Synth. : 60, 108 Org. Synth. Coll. Vol. : 7, 393

1) Z.N. Parnes; V.I. Zdanovich; E.E. Kugucheva; G.I. Bassova; D.N. Kursanov, Dokl. Akad. Nauk. USSR, 1966, 166, 122. 2) D.N. Kursanov; Z.N. Parnes; G.I. Bassova; N.M. Loim; V.I. Zdanovich, Tetrahedron, 1967, 23, 2235. 3) D.N. Kursanov; Z.N. Parnes; N.M. Loim, Synthesis, 1974, 633. 4) H. Yamazaki; H. Horikawa; T. Nishitani; T. Iwasaki, Chem. Pharm. Bull., 1990, 38, 2024.

1056

COMMENTS :

KUTSCHEROFF – DENIGÈS HYDRATION EXAMPLE :

H HgO, H2SO4

O

MECHANISM :

OH2 2+

+ Hg

H2O

Hg2+

OH - H+

H

OH H+

Hg+

Hg+

H

H

O

DISCONNECTION :

R

R

R1

R1 R1

O R

NOTES :

The addition of water to a triple bond (Kutscheroff) or to a double bond (Denigès) under mercury salt catalysis. See also Nieuwland and Reppe carbonylation reaction.

REFERENCES : March : 762 Smith – March : 995 Houben – Weyl : E3, 243

1057

1) M. Kutscheroff, Ber. Dtsch. Chem. Ges., 1881, 14, 1540. 2) G. Denigès, Bull. Soc. Chim. Fr., 1898, 19, 494. 3) D.A. Shearer; G.F. Wright, Can. J. Chem., 1955, 33, 1002. 4) H. Arzoumanian; J. Metzger, Synthesis, 1971, 527. 5) G.A. Olah; D. Meidar, Synthesis, 1978, 671.

COMMENTS :

1058

1059

LEUCHS (LEUCHS – BERGMANN) PEPTIDE SYNTHESIS · 1089 LEUCHS ALKYLATION · 1090

L

LEUCKART – PICTET – HUBERT (MORGAN – WALLS) REACTION · 1092

LADENBURG – VYSHNEGRADSKIÎ HYDROGENATION · 1061 LADENBURG CONIINE SYNTHESIS · 1062

LEUCKART – WALLACH REACTION · 1093

LADENBURG REARRANGEMENT · 1063

LEUCKART THIOPHENOL REACTION · 1095

LADENBURG RING-CLOSURE · 1064

LEUSEN van OXAZOLE SYNTHESIS · 1096

LANDAUER – RYDON SYNTHESIS · 1065

LEVINSTEIN PROCESS · 1098

LANDER REARRANGEMENT · 1066

LEY OXIDATION · 1099

LAPWORTH CONDENSATION (BENZOIN CONDENSATION) ·

LIEBEN IODOFORM REACTION · 1100 LIEBESKIND – SROGL REACTION · 1102

1067 LAROCK FLUOREN-9-ONE-2 SYNTHESIS · 1071

LIEBIG BENZYLIC ACID REARRANGEMENT · 1103

LAROCK FLUORENE SYNTHESIS · 1069

LIEPA COUPLING · 1105

LAROCK INDOLE SYNTHESIS · 1073

LIMAYE SYNTHESIS · 1106

LAWESSON THIOCARBONYLATION · 1075

LINDSEY PORPHYRIN SYNTHESIS · 1107

LEBEDEV BUTADIENE PROCESS · 1077

LIPP INDOLE SYNTHESIS · 1109

LEBEDEV METHOXYMETHYLATION · 1077

LOBRY de BRUIN – van EKENSTEIN TRANSFORMATION · 1111

LEDERER – MANASSE REACTION · 1078

LOSSEN REARRANGEMENT · 1112

LEHMSTEDT – TANASESCU REACTION · 1080

LUCHE REDUCTION · 1114

LEHN CRYPTAND SYNTHESIS · 1081

LUMIÈRE – BARBIER ACETYLATION · 1115

LEIMGRUBER – BATCHO ENAMINE / INDOLE SYNTHESIS · 1083

LÜTTRINGHAUS REARRANGEMENT · 1116

LEMIEUX – JOHNSON CLEAVAGE · 1085 LEMIEUX – von RUDLOFF OXIDATION · 1085

S

LESPIEAU – BOURGEL SYNTHESIS · 1086 SCHOELLER MODIFICATION · 1087

LESSER – WEIβ SYNTHESIS · 1087 LETTS NITRILE SYNTHESIS · 1088

1060

LADENBURG – VYSHNEGRADSKIÎ HYDROGENATION EXAMPLE :

N

Na, EtOH

N H

EtOH

N H

MECHANISM :

N

EtOH

Na EtOH

N H

N H

Na

N H

N H

Na EtOH

DISCONNECTION :

N H

N

NOTES : The classic example is the use of sodium in ethanol for the hydrogenation of pyridine to piperidine. Other primary alcohols can be used as solvent. See also Birch and Mendius reactions.

REFERENCES : 1) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1884, 17, 156. 2) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1884, 17, 388. 3) A. Ladenburg; C.F. Roth, Ber. Dtsch. Chem. Ges., 1884, 17, 513. 4) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1887, 20, 1644. 5) R.R. Renshaw; M. Ziff; B. Brodie; N. Kornblum, J. Am. Chem. Soc., 1939, 61, 638. 6) D. Papa; E. Schwenk; E. Klingsberg, J. Am. Chem. Soc., 1951, 73, 253. 7) M. Cerny; A. Trka, Coll. Czech. Chem. Commun., 1983, 48, 3413.

1061

COMMENTS :

LADENBURG CONIINE SYNTHESIS EXAMPLE :

N

CH3

1) CH3CHO 2) Na, EtOH

N H

MECHANISM :

N

CH3

CH3CHO

CH3

N

Na, EtOH

N H

DISCONNECTION :

N

N H

CH3

NOTES : α-Picoline is condensed with acetaldehyde and the resulting 2-propenylpyridine is reduced with sodium in ethanol. See also Ladenburg – Vysnegradskiî reaction.

REFERENCES : 1) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1886, 19, 439 2) A. Ladenburg, Liebigs Ann. Chem., 1888, 247, 80.

1062

COMMENTS :

LADENBURG REARRANGEMENT EXAMPLE :

CH3 +

2 N I CH3

Cu 290 - 300 oC

N CH3 H I

N H

I

MECHANISM :

CH3

N I CH3

Cu 290 - 300 oC

+

+ CH3I CH3 N H I

N

I

N H

DISCONNECTION :

R

N N R N

R

NOTES : N-alkyl or benzyl pyridinium halides rearrange on heating to give a mixture of α- and γ-alkylpyridinium halides. See also Hofmann – Martius – Reilly, Reissert and Sommelet – Hauser reactions.

1063

REFERENCES : Houben – Weyl : E7b, 633 Org. React. : 7, 99

1) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1883, 16, 1410. 2) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1883, 16, 2057. 3) A. Ladenburg, Liebigs Ann. Chem., 1888, 247, 1. 4) G. Koller; H. Ruppersberg, Monatsh. Chem., 1928, 50, 436. 5) H.J.-M. Dou; G. Vernin; M. Fufour; J. Metzger, Bull. Soc. Chim. Fr., 1971, 111.

COMMENTS :

LADENBURG RING-CLOSURE EXAMPLE :

HCl.H2N

NH2.HCl

N.HCl H

Heat

MECHANISM :

NH2.HCl

ClH.H2N

Heat

N.HCl H

+ NH4Cl

DISCONNECTION :

n

N.HCl H

n

n = 1,2

HCl.H2N

1064

NH2.HCl

NOTES : Dry distillation of the hydrochlorides of tetramethylene-1,4-diamine and pentane-1,5-diamine leads to ring-closure affording pyrrolidines and piperidines. See also Hofmann – Löffler – Freytag reaction.

REFERENCES : 1) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1884, 17, 388. 2) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1885, 18, 2957. 3) A. Ladenburg; C.F. Roth, Ber. Dtsch. Chem. Ges., 1886, 19, 2586. 4) J. Tafel; A. Neugebauer, Ber. Dtsch. Chem. Ges., 1890, 23, 1544.

COMMENTS :

LANDAUER – RYDON SYNTHESIS EXAMPLE :

((PhO)3PMe)I

+ C6H11OH

C6H11I

MECHANISM :

PhO (PhO)3PCH3I

+ ROH

PhO

P

O

R

I

CH3

RI +

PhO O P PhO CH3

DISCONNECTION :

R

I

R OH

NOTES : Triphenylphosphite methiodide and derivatives react with alcohols to afford the iodo derivative. See also Appel, Blum, Darzens method and Miller synthesis reactions.

1065

REFERENCES : Org. Synth. : 31, 33; 51, 44 Org. Synth. Coll. Vol. : 4, 325; 6, 830

1) S.R. Landauer; H.N. Rydon, J. Chem. Soc., 1953, 2224. 2) D.G. Coe; S.R. Landauer; H.N. Rydon, J. Chem. Soc., 1954, 2281. 3) P.F. Beal; M.A. Rebenstorf; J.E. Pike, J. Am. Chem. Soc., 1959, 81, 1231. 4) J.P.H. Verheyden; J.G. Moffatt, J. Org. Chem., 1970, 35, 2319. 5) C.Y. Switzer; S.E. Moroney; S.A. Benner, Biochemistry, 1993, 32, 10489.

COMMENTS :

LANDER REARRANGEMENT EXAMPLE :

Ph

Ph

O N N

OH

O O

N N H

heat

MECHANISM :

Ph

Ph

O N N

OR1

O N N R

RX

Ph

R1 O

N N R

X

DISCONNECTION :

R R1

N

O

R

R2

R1

1066

O N

R2

Ph

O O

O

+ N N R1

O

NOTES : The thermal intermolecular rearrangement of aliphatic imino-ethers to afford substituted amides.

REFERENCES : Houben – Weyl : E8c, 631

1) G.D. Lander, J. Chem. Soc., 1903, 83, 406. 2) M. Golfier; R. Micent, Tetrahedron Lett., 1973, 14, 4465. 3) M. Golfier; R. Micent, Tetrahedron Lett., 1974, 15, 3871. 4) M. Golfier; M.-G. Guillerez; R. Micent, Tetrahedron Lett., 1974, 15, 3875.

COMMENTS :

LAPWORTH CONDENSATION (BENZOIN CONDENSATION) EXAMPLE :

H 2

H O

KCN EtOH

OH O

MECHANISM :

O

O Ar

Ar

H

O Ar

H

C N

C N

H O O Ar Ar C H N

H

O

OH Ar

Ar

1067

H

OH

O

C N

H

Ar

Ar

DISCONNECTION :

O

O

OH Ar

Ar

Ar

H

H

NOTES : The reversible condensation of two aromatic aldehyde molecules or one aromatic aldehyde and a glyoxal to afford an α-hydroxy ketone. The reaction is catalysed by the cyanide ion (via cyanohydrins). Deactivating groups on the aromatic ring can inhibit this reaction. There is a thiazolium-ion catalysed reaction known.

REFERENCES : March : 969 Smith – March : 1243 Org. React. : 4, 269

1) A. Lapworth, J. Chem. Soc., 1903, 83, 995. 2) H. Green, J. Chem. Soc., 1926, 328. 3) H.R. Hensel, Angew. Chem., 1953, 65, 491. 4) J.P. Kuebrick; R.L. Schowen; M.-S. Wang; M.E. Lupes, J. Am. Chem. Soc., 1971, 93, 1214. 5) W. Tagaki; Y. Tamura; Y. Yano, Bull. Chem. Soc. Jpn., 1980, 53, 478. 6) J. Castells; E. Dunach, Chem. Lett., 1984, 1859. 7) R. Breslow; R. Kim, Tetrahedron Lett., 1994, 35, 699. 8) D. Enders; K. Breuer; J.H. Teles, Helv. Chim. Acta, 1996, 79, 1217. 9) M.J. White; F.J. Leeper, J. Org. Chem., 2001, 66, 5124. 10) D. Enders; T. Balensiefer, Acc. Chem. Res., 2004, 37, 534.

COMMENTS :

1068

LAROCK FLUORENE SYNTHESIS EXAMPLE :

CH3

I +

CH3

10% PPh3 5% Pd(OAc)2 2 NaOAc n Bu4NCl DMF, 100 oC

1069

MECHANISM :

PdI Ph

Ph

PdI

Pd I H

I

Pd0

Pd(OAc)2

H

Pd H I

H I Pd Pd H

Pd I

H

DISCONNECTION :

R I +

1070

R

H

NOTES : In the presence of a palladium catalyst and NaOAc, aryl iodides react with 1-aryl-1-alkynes to afford 9-alkylidene-9Hfluorenes. This process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) rearrangement of the resulting vinylic palladium intermediate to an arylpalladium species, and (4) aryl-aryl coupling with simultaneous regeneration of the Pd(0) catalyst. See also Graebe – Ullmann, Mascarelli and Ullmann reactions.

REFERENCES : 1) Q. Tian; R.C. Larock, Org. Lett., 2000, 2, 3329. 2) R.C. Larock; Q. Tian, J. Org. Chem., 2001, 66, 7372.

COMMENTS :

LAROCK FLUOREN-9-ONE SYNTHESIS EXAMPLE :

O

Br Pd(PCy)3 cesium pivalate CO (1 atm), DMF

1071

MECHANISM :

PdBr Br

PdBr

Pd0

CO

O

O H Pd Br O

H Pd

Br O

Pd O

DISCONNECTION :

O

Br

NOTES : Another synthesis of fluoren-9-ones based on the palladium-catalysed cyclocarbonylation of ortho-halobiaryls. Fluoren-9-ones containing fused isoquinoline, indole, pyrrole, thiophene, benzothiophene and benzofuran rings can be prepared. The same type of chemistry can also be applied to vinylic halides. See also Larock fluorene and Ullmann fluorenone reactions.

REFERENCES : 1) M.A. Campo; R.C. Larock, Org. Lett., 2000, 2, 3675. 2) M.A. Campo; R.C. Larock, J. Org. Chem., 2002, 67, 5616.

1072

COMMENTS :

LAROCK INDOLE SYNTHESIS EXAMPLE :

H3C I N H

n NH2 1) Pd(OAc)2, Bu4NCl KOAc, DMF, 100 oC

CH3

2)

CH3 OH CH3

CH3

HO CH3

MECHANISM :

NH2 L Cl Pd L I

NH2 L2PdCl

I

CH3

CH3

HO CH3

H3C

NH2 Cl Pd I O H

NH2 Cl I Pd O

H3C

CH3 CH3

H N

H3C

H N

Cl Pd O H CH3 CH3

H3C

CH3

OH CH3 CH3

- PdCl H3C

1073

- HI

DISCONNECTION :

R R X

X = O,N, S

X LG

NOTES : An indole synthesis via a palladium-catalysed heteroannulation of internal alkynes using o-iodoaniline and its derivatives. The use of imines will result in isoquinolines and pyridines, the use of iodothioanisole will result in benzo[b]thiophenes. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) R.C. Larock; E.K. Yum, J. Am. Chem. Soc., 1991, 113, 6689. 2) R.C. Larock; E.K. Yum; M.D. Refvik, J. Org. Chem., 1998, 63, 7652. 3) R.C. Larock, J. Organomet. Chem., 1999, 576, 111. 4) R.C. Larock; K.R. Roesch, Org. Lett., 1999, 1, 1551. 5) R.C. Larock, Pure Appl. Chem., 1999, 71, 1435. 6) R.C. Larock; K.R. Roesch, J. Org. Chem., 2001, 66, 412. 7) K.R. Roesch; H. Zhang; R.C. Larock, J. Org. Chem., 2001, 66, 8042. 8) D. Yue; R.C. Larock, J. Org. Chem., 2002, 67, 1905. 9) T. Kalai; M. Balog; J. Jeko; W.L. Hubbell; K. Hideg, Synthesis, 2002, 2365. 10) H. Zhou; X. Liao; J.M. Cook, Org. Lett., 2004, 6, 249.

COMMENTS :

1074

LAWESSON THIOCARBONYLATION EXAMPLE :

MeO

O

S

+

O

P S S

S P O

S

OMe

MECHANISM :

MeO 2

S

OMe

MeO S P S S

P S S

P4S7

S P

S P OMe

S P

2

OCH3

S OMe R

MeO

R1

S S P P S S

R

O P S S P S

MeO OMe

O

OMe

S

R1 MeO

OMe MeO S

S P O R

S

+ R

P S S

R1 O

R1

S P

P S

S

OMe

1075

DISCONNECTION :

O

S R

R

X

X

X = OR1, NHR1

NOTES : Reagents for the synthesis of thiamides, and thiaesters from the corresponding carbonyl compounds using 2,4-bis(4methoxyphenyl)-1,3-2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent). Sometimes insolubility problems are encountered, instead of Lawesson reagent phenyl phosphoro tetrathionate can be used.

REFERENCES : March : 406, 420, 893 Smith – March : 496, 509, 1184, 1331 Org. Synth. : 62, 158 Org. Synth. Coll. Vol. : 7, 372

1) B.S. Pedersen; S. Scheibye; N.H. Nilsson; S.-O. Lawesson, Bull. Soc. Chim. Belg., 1978, 87, 223. 2) S. Scheibye; J. Kristensen; S.-O. Lawesson, Tetrahedron, 1979, 35, 1339. 3) W. Hoederath; K. Hartke, Arch. Pharm. (Weinheim, Ger.), 1984, 317, 938. 4) M. Yokoyama; Y. Hasegawa; H. Hatanaka; Y. Kawazoe; T. Inamoto, Synthesis, 1984, 827. 5) M.P. Cava; M.I. Levinson, Tetrahedron, 1985, 41, 5061. 6) H. Bartsch; T. Erker, Tetrahedron Lett., 1992, 33, 199. 7) M.C. Aragoni; M. Arca; F. Demartin; F.A. Devillanova; C. Graiff; F. Isaia; V. Lippolis; A. Tiripicchio; G. Verani, Eur. J. Inorg. Chem., 2000, 2239. 8) M.M.M. Raposo; G. Kirsch, Heterocycles, 2001, 55, 1487. 9) M. Jesberger; T.P. Davis; L. Barner, Synthesis, 2003, 1929. 10) S.D. Sharma; S. Kanwar, Org. Proc. Res & Dev., 2004, 8, 658. 11) H. Oshida; A. Ishii; J. Nakayama, Tetrahedron Lett., 2004, 45, 1331. 12) E. Ertas; T. Ozturk, Tetrahedron Lett., 2004, 45, 3405. 13) W. Przychodzeń, Eur. J. Org. Chem., 2005, 2002.

COMMENTS :

1076

LEBEDEV BUTADIENE PROCESS EXAMPLE :

2 CH3CH2OH

H2 + H2O +

450 oC silicates

NOTES : Butadiene (20%) is obtained by the catalytic (Al2O3 + ZnO, silicates) pyrolysis of ethanol. Many side-products are formed at the same time. Acetaldehyde is presumed to be an intermediate in the pyrolysis. See also Guerbet, Ostromyslenskii and Reppe reactions.

REFERENCES : Houben – Weyl : 4/2, 216

1) S.V. Lebedeff, J. Allg. Chem., 1933, 3, 698. 2) G. Egloff; G. Hulla, Chem. Rev., 1945, 36, 63.

COMMENTS :

LEBEDEV METHOXYMETHYLATION EXAMPLE :

CH3OCH2OSO2OCH3 +

CH2

OCH3 CH2CH2OCH3 MeOH

MECHANISM :

(CH3O)2CH2 + SO3

CH3OCH2OSO2OCH3

1077

CH3

CH3O

CH3OCH2OSO2OCH3 + CH3O

CH3

CH3O

CH3

+

Et3N MeOH

OCH3

OCH3

DISCONNECTION :

R

OCH3

R1

CH2OCH3

R CH2 R1

NOTES : Methoxymethyl methyl sulphate (MOM-MSF) is used as an electrophilic reagent for methoxymethylation of alkenes.

REFERENCES : 1) M.Yu. Lebedev; E.S. Balenkova, J. Org. Chem. USSR (Engl. Transl.), 1989, 25, 391. (Zh. Org. Khim., 1989, 25, 434.) 2) M.Yu. Lebedev; E.S. Balenkova, J. Org. Chem. USSR (Engl. Transl.), 1991, 27, 1214. (Zh. Org. Khim., 1991, 27, 1388.)

COMMENTS :

LEDERER – MANASSE REACTION EXAMPLE :

OH

OH aq. HCHO

1078

CH2OH

MECHANISM :

H H

OH +

H

O

H

CH2OH

H

O

O

O

OH

OH

CH2OH O OH

- H2O

H O

DISCONNECTION :

OH

OH

R

NOTES : Phenols condense with aqueous formaldehyde in acid or alkaline solution to yield hydroxybenzyl alcohols. Polymeric structures are very easily formed. See also Baekeland and von Baeyer reactions.

REFERENCES : March : 548 Smith – March : 719 Houben – Weyl : 14/2, 193; E3, 641

1) W. Wolff, Ber. Dtsch. Chem. Ges., 1893, 26, 83. 2) L. Lederer, J. Prakt. Chem., 1894, 50, 223. 3) O. Manasse, Ber. Dtsch. Chem. Ges., 1894, 27, 2409. 4) G. Casiraghi; G. Casnati; A. Pochini; G. Puglia; R. Ungaro; G. Satori, Synthesis, 1981, 143.

COMMENTS :

1079

LEHMSTEDT – TANASESCU REACTION EXAMPLE :

O

O H NO2

Benzene, H2SO4, HNO2

N H

MECHANISM :

O

OH H

NO2

O

Benzene H2SO4 HNO2

N

- H2O

NO2

O

O

N H

N H

H+

DISCONNECTION :

O

O H

R

N

R1

R = R1 = Hal

R

NO2

H

NOTES : o-Nitrobenzaldehydes and benzene (or a halogenated benzene) condense in concentrated sulfuric acid containing a trace of nitrous acid to yield acridones.

REFERENCES : Houben – Weyl : E7b, 120, 139; E8a, 379, 438

1080

1) A. Kliegl, Ber. Dtsch. Chem. Ges., 1908, 41, 1845. 2) I. Tanasescu, Bull. Soc. Chim. Fr., 1927, 41, 528. 3) K. Lehmstedt, Ber. Dtsch. Chem. Ges., 1932, 65, 834. 4) N. Motohashi; J. Emrani; R. Meyer; M. Kawase, Org. Prep. Proced. Int., 1993, 25, 259. 5) L.W. Zhao; B.F. Griggs; C.L. Chen; J.S. Gratzl; C.K. Hse, J. Wood Chem. Tech., 1994, 14, 127. 6) M.V. Alonso; J.J. Rodriquez; M. Oliet; F. Rodriquez; J. Garcia; M.A. Gilarranzi, J. Appl. Polym. Sci., 2001, 82, 2661.

COMMENTS :

LEHN CRYPTAND SYNTHESIS EXAMPLE :

O N 2 H N

O O

Cl N H + 2

O

Cl

N O

O

O

O

O

O N

N O

1081

MECHANISM :

O O O

N

O

O

N

NK

+ 2 Br

O

O

O

O

Br O

O

H2N

N2H4

NH2

O

O

+

HN

NH

+

Cl

LiAlH4

Cl

O

O

O

O

O N

N

N

O

O

O

O

O

O

O O

O

O O

N

Cl O

O

O

O

Cl

O

B2H6, HCl, Dowex O

O

O O

NOTES : The synthesis of diaza-polyoxa-macrobicyclic compounds (cryptands).

REFERENCES : March : 82 Smith – March : 105

1) J. Cheney; J.-M. Lehn; J.P. Sauvage; M.E. Stubbs, J. Chem. Soc., Chem. Commun., 1972, 1100. 2) J.-M. Lehn, Angew. Chem., Int. Ed. Engl., 1990, 29, 1304. 3) T.L. Lauricella; M. López; S.R. Miller; L.E. Echegoyen; G.W. Gokel; L. Echegoyen, J. Org. Chem., 1991, 56, 1524. 4) J.-M. Lehn; J.-P. Vigneron; I. Bkouche–Waksman; J. Guilhem; C. Pascard, Helv. Chim. Acta, 1992, 75, 1069. 5) D.M. Smith; C.-W. Park; J.A. Ibers, Inorg. Chem., 1997, 36, 3798. 6) J.C. Rodríguez–Ubis; M.T. Alonso; O. Juanes; E. Brunet, Luminescence, 2000, 15, 331.

1082

COMMENTS :

LEIMGRUBER – BATCHO ENAMINE / INDOLE SYNTHESIS EXAMPLE :

CH3 Br

NO2

N H

1) (CH3O)2CHNMe2, DMF Br pyrrolidine, 110 oC 2) H2, Raney Ni, toluene

MECHANISM :

H

CH3 N

H3CO CH3 NO2

CH3 NMe2

CH2 CH3O CH3 H N CH3O CH3

OCH3 NO2

NO2

DMF, heat NMe2

NMe2 - CH3OH

NO2

1) Fe, CH3COOH 2) H+

NMe2 N H H

- Me2NH

N H

1083

NH2

DISCONNECTION :

CH3 R1

R1 N H

NO2

NOTES : The first step is the formation of the Leimgruber – Batcho enamine using hot DMF DMA and this enamine can be isolated. The reduction of the nitro group leads directly to the indole with the loss of dimethylamine. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Org. Synth. : 63, 214 Org. Synth. Coll. Vol. : 7, 34 Science of Synthesis : 10, 408, 421

1) A.D. Batcho; W. Leimgruber, U.S. Patent, 1973, 3732245. 2) U. Hengartner; A.D. Batcho; J.F. Blount; W. Leimgruber; M.E. Barscheid; J.W. Scott, J. Org. Chem., 1979, 44, 3748. 3) R.D. Clarke; D.B. Repke, Heterocycles, 1984, 22, 195. 4) W. Haefliger; H. Knecht, Tetrahedron Lett., 1984, 25, 285. 5) D.H. Lloyd; D.E. Nichols, J. Org. Chem., 1986, 51, 4294. 6) M.P. Moyer; J.F. Shiurba; H. Rapoport, J. Org. Chem., 1986, 51, 5106. 7) G.W. Gribble, Cont. Org. Syn., 1994, 1, 145. 8) G.M. Carrera, jr., G.S. Sheppard, Synlett, 1994, 93. 9) D. Harrowven; D. Lai; M.C. Lucas, Synthesis, 1999, 1300. 10) G.W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045. 11) J. Siu; I.R. Baxendale; S.V. Ley, Org. Biomol. Chem., 2004, 2, 160. 12) J.M. Bentley; J.E. Davidson; M.A.J. Ducton; P.R. Giles; R.M. Pratt, Synth. Commun., 2004, 34, 2295.

COMMENTS :

1084

LEMIEUX – JOHNSON CLEAVAGE EXAMPLE :

O O

1) cat. OsO4 2) base 3) NaIO4

MECHANISM :

C C HO OH

1) cat. OsO4 pH 7.7 2) base

2

O

IO4

DISCONNECTION :

R

R1

R2

R3

R

R2

R1

R3

+ O

O

NOTES : The olefin is treated at room temperature with sodium metaperiodate and catalytic amounts of osmium tetroxide to afford aldehydes or ketones. The reaction can also be applied to the determination of isopropylidene groups. The Lemieux – von Rudloff oxidation uses sodium metaperiodate and catalytic amounts of potassium permanganate or ruthenium oxide or trichloride to afford carboxylic acids. See also Barry, Criegee glycol cleavage, Djerassi – Rylander, Fischer and Hudson – Hirst reactions.

REFERENCES : March : 1180 Smith : 301 Smith 2nd : 265 Org. Synth. : 68, 41; 72, 1, 6; 74, 1; 78, 123 Org. Synth. Coll. Vol. : 8, 377; 9, 39, 450, 454; 10, 2617

1) R.U. Lemieux; E. von Rudloff, Can. J. Chem., 1955, 33, 1701. 2) E. von Rudloff, Can. J. Chem., 1955, 33, 1714. 3) R. Pappo; D.S. Allen, jr.; R.U. Lemieux; W.S. Johnson, J. Org. Chem., 1956, 21, 478.

1085

4) T. Kometani; Y. Takeuchi; E. Yoshii, J. Chem. Soc., Perkin Trans. 1, 1981, 1197. 5) F.A. Luzzio; A.V. Mayorov; W.D. Figg, Tetrahedron Lett., 2000, 41, 2275. 6) W. Yu; Y. Mei; Y. Kang; Z. Hua; Z. Jin, Org. Lett., 2004, 6, 3217.

COMMENTS :

LESPIEAU – BOURGEL SYNTHESIS EXAMPLE :

H3C Br

1) NaNH2, 100 - 160 oC lygroine 2) H+

H3C

H

MECHANISM :

R Br

NaNH2, 100 - 160 oC lygroine

Na+

R

H+

R

H

DISCONNECTION :

R R

H Hal

NOTES : The synthesis of monosubstituted ethynes by dehydrobromination of ethenes. The reaction also proceeds with halogen products as RCHXCH2X, RCH2CH2X and RCX2CH3. See also Kendall – Mattox reaction.

REFERENCES : 1) M.R. Lespieau, C.R. Séances Acad. Sci., 1910, 150, 114. 2) M.R. Lespieau, Bull. Soc. Chim. Fr., 1921, 21, 528.

1086

3) M.M. Bourgel, C.R. Séances Acad. Sci., 1923, 176, 689. 4) I.L. Ozanne; C.S. Marvel, J. Am. Chem. Soc., 1930, 52, 5267. 5) R.F. Parcell; C.B. Pollard, J. Am. Chem. Soc., 1950, 72, 2385. 6) L.F. Hatch; H.E. Alexander; J.D. Randolph, J. Org. Chem., 1950, 15, 654. 7) K.N. Campbell; F.C. Fatora, jr.; B.K. Campbell, J. Org. Chem., 1952, 17, 1141. 8) E.V. Dehmlow; M. Lissel, Liebigs Ann. Chem., 1980, 1.

COMMENTS :

LESSER – WEIβ SYNTHESIS EXAMPLE :

Se

N2+ 2

Se, KOH

MECHANISM :

ArN2 X

+ NaSeAr1

NaX + ArN2SeAr1

ArN2SeAr1

ArSeAr1 + N2

DISCONNECTION : Se Ar

ArN2+

Ar1

NOTES : Diazo-compounds on treatment with alkali yield diazonium aryl selenides as intermediate compounds, which at room temperature lose nitrogen to yield diaryl selenides. Higher temperatures are sometimes needed. In the Schoeller modification aryl selenides are obtained by the interaction of solutions of diazonium salts with an alkaline solution of potassium polyselenide.

1087

REFERENCES : Houben – Weyl : 9, 995 Org. Synth. : 18, 27 Org. Synth. Coll. Vol. : 2, 238

1) R. Lesser; R. Weiβ, Ber. Dtsch. Chem. Ges., 1912, 45, 1836. 2) R. Lesser; R. Weiβ, Ber. Dtsch. Chem. Ges., 1914, 47, 2510. 3) A. Schoeller, Ber. Dtsch. Chem. Ges., 1919, 52, 1517.

COMMENTS :

LETTS NITRILE SYNTHESIS EXAMPLE :

COOH

C + KSCN

MECHANISM :

N C S OH R

O

decarboxylation

R C N + CO2 + KHS

DISCONNECTION :

R CN

R COOH

1088

N

NOTES :

Nitriles are obtained by the fusion of an organic acid or the metallic salt of an organic aromatic acid with potassium or lead thiocyanate. Lead, barium or potassium ferrocyanide, lead cyanate, and silver cyanide have been used in the reaction. The reaction fails with amino-, nitro-, or hydroxyl benzoic acids. Aliphatic acids give low yields.

REFERENCES :

1) E.A. Letts, Ber. Dtsch. Chem. Ges., 1872, 5, 669. 2) D.T. Mowry, Chem. Rev., 1948, 42, 189. 3) A. Brack, Biosystems, 1982, 15, 201. 4) C. Schierlinger; K. Burger, Tetrahedron Lett., 1992, 33, 193. 5) C. Palomo; J.M. Aizpurua; R. Urchegui; J.M. Garcia, Chem. Commun., 1995, 2327.

COMMENTS :

LEUCHS (LEUCHS – BERGMANN) PEPTIDE SYNTHESIS EXAMPLE :

O Cl

O O

+

H3C

CH3 H COOH NH2

1) Na2CO3 2) SOCl2 3) heat

H

N

O O

MECHANISM :

Cl

+

O

H

H N O

base - HCl

O H2O R

R heat

O

O

COOH NH2

O

H N

R

O

Cl

PhCH2Cl +

HN H+

COOH

SOCl2

O O O

1089

R

R - CO2

H2N

COOH H

DISCONNECTION :

R

H N

O

O

O

H O

R

R = Alk, R1 = CH3, Ph

COOH

+

Cl

NH2

OR1

NOTES :

Benzyl chloroformate reacts with glycine or a substituted glycine to give the N-carbobenzyloxy-α-amino-acid, the acid chloride of which yields benzyl chloride and an oxazolid-2,5-dione on heating. The latter forms polypeptides on heating or treatment with water or organic bases. See also Bergmann azlactone peptide, Bergmann – Zevars, Fischer peptide and du Vigneaud reactions.

REFERENCES :

1) H. Leuchs, Ber. Dtsch. Chem. Ges., 1906, 39, 857. 2) R.B. Woodward; C.H. Schramm, J. Am. Chem. Soc., 1947, 69, 1551. 3) P.D. Bartlett; R.H. Jones, J. Am. Chem. Soc., 1957, 79, 2153. 4) P.D. Bartlett; D.C. Dittmer, J. Am. Chem. Soc., 1957, 79, 2159. 5) H. Dahn; J.A. Garbarino; C. O’Murchu, Helv. Chim. Acta, 1970, 53, 1370.

COMMENTS :

LEUCHS ALKYLATION EXAMPLE : Ph CH2(CO2Et)2 + .5 PhCH2Cl

EtO

OEt

Na, EtOH O

1090

O

MECHANISM :

Cl EtO

OEt O

EtO NaOEt

O

OEt O

OEt

EtO

O

O

O

DISCONNECTION :

R EtO

EtO

OEt

OEt + RHal

O

O

O

O

NOTES :

To ensure monoalkylation an excess of ethyl acetoacetate or diethyl malonate is treated with an aryl or alkyl halide and ethanolic sodium ethoxide.

REFERENCES : March : 464 Smith – March : 548 Smith : 878 Smith 2nd : 733

H. Leuchs, Ber. Dtsch. Chem. Ges., 1911, 44, 1507.

COMMENTS :

1091

LEUCKART – PICTET – HUBERT (MORGAN – WALLS) REACTION EXAMPLE :

NCO

N AlCl3 PhNO2 Reflux

OH

MECHANISM :

N O H+

H

HN

N

N

H

POCl3

N H H3C OH

O H3C

OH

OH

- H2O, - H+

N H3C

DISCONNECTION :

H2N + RCOOH R N O

N

R = OH

NOTES :

The Lewis acid catalysed amidation of aryls by isocyanates (Leuckart) or by amides (Pictet – Hubert), affording to phenanthridines. See also Bischler – Napieralski and Morgan – Walls reactions.

1092

REFERENCES : Smith : 1347 Smith 2nd : 1108

1) R. Leuckart, Ber. Dtsch. Chem. Ges., 1885, 18, 873. 2) A. Pictet; A. Hubert, Ber. Dtsch. Chem. Ges., 1896, 29, 1182. 3) C.T. Morgan; L.P. Walls, J. Chem. Soc., 1931, 2447. 4) C.T. Morgan; L.P. Walls, J. Chem. Soc., 1932, 2225. 5) R.S. Theobald; K. Schofield, Chem. Rev., 1950, 46, 175. 6) J. Eisch; H. Gilman, Chem. Rev., 1957, 57, 525.

COMMENTS :

LEUCKART – WALLACH REACTION EXAMPLE :

H3C

N H

CH3 +

H3C

CH3 +

HCOOH

H3C

CH3 N CH3

O

CH3

MECHANISM :

R

N H

R2

R1

R3

R2

O H+

R2

R

R3

R1

R2

N R3

- CO2

R1 R N H

R2

R N R1

OH R N R3 R1 HCOOH

HCOO- HCOOH

R3

1093

H+, - H2O

R

R1 N

R2 R3

R

R1 H N

R3

H

R2

O O

+ CO2 + H2O

DISCONNECTION :

R

R1 N

R

R2

N H

R3

R1

+

R2

R3 O

NOTES :

Carbonyl compounds are converted into amines (often as their formyl derivatives), when heated with ammonium formate or formamide. In addition to primary amines, secondary (formyl derivatives) and tertiary amines (formates) are formed in small amounts. Primary and secondary amine formates react similarly to ammonium formate. The reaction has been extended to the preparation of tertiary amines by treatment of ketones with dialkylformamide in the presence of formic acid and magnesium chloride. With the use of Cp*Rh(III) complexes this reaction can be made catalytic. When the reaction is done in the presence of excess formic acid it is referred to as the Leuckart – Wallach reaction, when formaldehyde and formic acid is used it is known as the Eschweiler – Clarke reaction. See also Eschweiler – Clarke reaction.

REFERENCES : March : 899 Smith – March : 1188 Houben – Weyl : 11/1, 648; E16d, 1082 Org. React. : 5, 301 Org. Synth. : 17, 76 Org. Synth. Coll. Vol. : 2, 503

1) R. Leuckart, Ber. Dtsch. Chem. Ges., 1885, 18, 2341. 2) O. Wallach, Liebigs Ann. Chem., 1892, 272, 99. 3) R. Baltly; O. Kauder, J. Org. Chem., 1951, 16, 173. 4) A. Lukasiewicz, Tetrahedron, 1963, 19, 1789. 5) K. Yordanova; V. Shvedov; D. Dantchev, Chem. Ber., 1982, 115, 2635. 6) P.I. Awachie; V.C. Agwada, Tetrahedron, 1990, 46, 1899. 7) A.M. Bellini; E. Mencini; M.P. Quaglio; M. Guarneri; A. Fini, Steroids, 1991, 56, 395. 8) J. Casanova; P. Devi, Synth. Commun., 1993, 23, 245. 9) A.G. Martínez; E.T. Vilar; A.G. Fraile; P.M. Ruiz; R.M. San Antonio; M.P.M. Alcázar, Tetrahedron: Asymmetry, 1999, 10, 1499. 10) M. Kitamura; D. Lee; S. Hayashi; S. Tanaka; M. Yoshimura, J. Org. Chem., 2002, 67, 8685.

COMMENTS :

1094

LEUCKART THIOPHENOL REACTION EXAMPLE :

SH

N2 Cl 1)

S K

OEt S

2) HO 3) H

MECHANISM :

S N2+Cl-

N S S

N

S

OEt OEt

S

SH

S 1) HO2) H+

- N2 OEt

heat heat - COS

S Et

DISCONNECTION :

SH N2+ClR Et

S +

S

KS

OEt

R R

NOTES :

Aromatic diazo-compounds react with potassium alkyl xanthates to yield aromatic xanthates in slightly acidic cuprous solution, which form thiophenols or aryl thioethers on warming.

1095

REFERENCES : Houben – Weyl : 9, 12 Org. Synth. : 27, 81 Org. Synth. Coll. Vol. : 3, 809

1) R. Leuckart, J. Prakt. Chem., 1890, 41, 179. 2) D.S. Tarbell; M.A. McCall, J. Am. Chem. Soc., 1952, 74, 48. 3) T. Schaefer; J.D. Baleja; G.H. Penner, Can. J. Chem., 1985, 63, 2471. 4) G. Petrillo; M. Novi; G. Garbarino; M. Filiberti, Tetrahedron, 1989, 45, 7411. 5) P.A. Baguley; J.C. Walton, Angew. Chem., Int. Ed., 1998, 37, 3072. 6) A. Studer; S. Amrein, Synthesis, 2002, 835. 7) L. Tournier; S.Z. Zard, Tetrahedron Lett., 2005, 46, 971.

COMMENTS :

van LEUSEN OXAZOLE SYNTHESIS EXAMPLE :

O

O

N H N N H

O

N TosMIC, K2CO3 MeOH, reflux, 18 h

1096

N H

O

MECHANISM :

H

Ts

Ts

N C

H H3C

CH3 H

Ts N

H

O

O

C

Ts H

O H

O H

H

N

H H3C

+

N

H H3C

N H3C

K2CO3 CH3OH

O

DISCONNECTION :

C N R

O

R

H

+

H3C

O

O S O

N

NOTES :

Tosylmethylisocyanide (TosMIC), one of the most versatile reagent in organic synthesis, reacts under base catalysis in methanol with aldehydes to afford 4,5-dihydro-1,3-oxazoles which after elimination of sulfinic acid are converted into oxazoles. In general this reagent reacts in non-protic solvents with ketones and aldehydes to afford the nitrile.

REFERENCES : March : 949, 1041 Smith : 674 Smith 2nd : 572 Org. React. : 57, 417 Org. Synth. : 77, 198 Org. Synth. Col. Vol. : 10, 2382

1) A.M. van Leusen; B.E. Hoogenboom; H. Siderius, Tetrahedron Lett., 1972, 13, 2369. 2) A.M. van Leusen; O.H. Oldenziel, Tetrahedron Lett., 1972, 13, 2373. 3) O.H. Oldenziel; D. van Leusen; A.M. van Leusen, J. Org. Chem., 1977, 42, 3114. 4) A.M. van Leusen, Lect. Heterocycl. Chem., 1980, 5, S-111. 5) B.A. Kulkarni; A. Ganesan, Tetrahedron Lett., 1999, 40, 5633. 6) J. Sisko; A.J. Kassick; M. Mellinger; J.J. Filan; A. Allen; M.A. Olsen, J. Org. Chem., 2000, 65, 1516. 7) P. Radha Krishna; V.V. Ramana Reddy; G.V.M. Sharma, Synlett, 2003, 1619.

1097

COMMENTS :

LEVINSTEIN PROCESS EXAMPLE :

H

H

2

Cl

+ SCl2 H

Cl

S

H

MECHANISM :

H H

H H

H H

SCl2

Cl

Cl

SCl H H

H

H

H

H

S

Cl

DISCONNECTION :

Cl

S

Cl

H

H

H

H

NOTES :

The synthesis of vesicant agent H (mustard gas). It contains around 30% sulfur. After distillation it is called agent HD.

REFERENCES :

1) F. Guthrie, J. Chem. Soc., 1860, 12, 109. 2) V. Meyer, Ber. Dtsch. Chem. Ges., 1886, 19, 3259. 3) J.B. Conant; E.B. Hartshorn; G.O. Richardson, J. Am. Chem. Soc., 1920, 42, 585. 4) R.C. Fuson; C.C. Price; R.A. Baumann; O.H. Bullitt; W.R. Hatchard; E.W. Maynert, J. Org. Chem., 1946, 11, 469. 5) R.C. Fuson; C.C. Price; D.M. Burness, J. Org. Chem., 1946, 11, 475. 6) R.C. Fuson; W.E. Parham, J. Org. Chem., 1946, 11, 482. 7) R.C. Fuson; D.M. Burness; R.E. Foster; R.D. Lipscomb, J. Org. Chem., 1946, 11, 499. 8) W.A. Felsing; C.A. Hunting; S.D. Fell, J. Am. Chem. Soc., 1948, 70, 1966.

1098

COMMENTS :

LEY OXIDATION EXAMPLE : CH3

CH3 HO

Br

NMO Pr4NRuO4

O

Br

MECHANISM :

O

O Ru O O

OH H3C

H3C O

5% Pr4NRuO4 4 A MS

O

O H3C

H

O

H

O O

N CH3

Ru(VII) + 2 e2 Ru(V) Ru(VI) + 2 e-

Ru(V) Ru(VI) + Ru(IV) Ru(IV)

DISCONNECTION :

O R

OH R1

R

R1

NOTES :

The oxidation of alcohols with tetra-n-propylammonium perruthenate and N-methylmorpholine. Many other functional groups are tolerated. N-methylmorpholine-N-oxide is used as the stoichiometric oxidant for recycling the catalyst. Primary alcohols are oxidised to aldehydes. Over-oxidation to the carboxylic acid is rare although can be induced by

1099

omitting the molecular sieves used to remove water from the reaction. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn

oxidation, Fétizon, Jones oxidation, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES : Smith 2nd : 211

1) S.V. Ley; W.P. Griffith, J. Chem. Soc., Chem. Commun., 1987, 1625. 2) S.V. Ley; W.P. Griffith, Tetrahedron Lett., 1989, 30, 3204. 3) S.V. Ley, Aldrichimica Acta, 1990, 23, 13. 4) D.G. Lee; L.N. Congson, Can. J. Chem., 1990, 68, 1774. 5) D.G. Lee; Z. Wang; W.D. Chandler, J. Org. Chem., 1992, 57, 3276. 6) S.V. Ley; J. Norman; W.P. Griffith; S.P. Marsden, Synthesis, 1994, 639. 7) B. Hinzen; S.V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997, 1907. 8) R. Lenz; S.V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997, 3291. 9) B. Hinzen; R. Lenz; S.V. Ley, Synthesis, 1998, 977. 10) R.N. MacCoss; E.P. Balskus; S.V. Ley, Tetrahedron Lett., 2003, 44, 7779.

COMMENTS :

LIEBEN IODOFORM REACTION EXAMPLE :

H

CH3 O

I2 Na2CO3

1100

CHI3

MECHANISM :

H

OH

O

H3C

I - H2O H3C

R1

I

I

O -I

R1

O

O

H3C

- H2O

R1

H

H3C

R1

-I

OH O H

- H2O R1

O

O H2C

H2C

R1

R1 I

OH O H

O

- H2O

R1

H IHC

R1

I OH

I

O I2C

-I

I

-I

I3C

O R1

- H2O

I OH

I

O R1

I

I

O R1

O

R1

+ CHI3

I

DISCONNECTION :

R

CHI3

CH3 O

NOTES :

Haloforms are obtained by the action of alkali hypohalites on acetaldehyde or methyl ketones, or their halogenated derivatives or on groups capable of being converted into these under the experimental conditions. The mechanism of the reaction is very complex. It is dependent on the structure of the substrate and the specific reaction conditions.

REFERENCES : Smith : 961 Smith 2nd : 799 Houben – Weyl : 2, 939 Org. Synth. : 69, 238 Org. Synth. Coll. Vol. : 8, 254

1) M. Serullas, Ann. Chim. (Paris), 1822, 20, 165. 2) A. Lieben, Liebigs Ann. Chem., 1870, 7, 218.

1101

3) R.C. Fuson; B.A. Bull, Chem. Rev., 1934, 15, 275. 4) R.N. Seelye; T.A. Turney, J. Chem. Educ., 1959, 36, 572. 5) M.H. Hashmi; H. Mahmood ul; A.B. Lateef, Pak. J. Sci. Res., 1963, 15, 7. 6) J.P. Guthrie; J. Cossar, Can. J. Chem., 1986, 64, 1250. 7) H.C. Hailes; B. Isaac; M.H. Javaid, Tetrahedron, 2001, 57, 10329. 8) A.F.C. Flores; N. Zanatta; A. Rosa; S. Brondani; M.A.P. Martins, Tetrahedron Lett., 2002, 43, 8701. 9) L. Jablonski; T. Billard; B.R. Langlois, Tetrahedron Lett., 2003, 44, 1055.

COMMENTS :

LIEBESKIND – SROGL REACTION EXAMPLE :

O

CH3 N CH3

S

O B(OH)2

+

1% Pd2dba3 3% TFP 1.6 eq.

O

S

O

OCu

MECHANISM :

L Pd

R1

CuTC S

O

L

L R2B(OH)2

R

L Pd

R1

R2

O

+ CuSR + B(OH)2TC

reductive elimination

R1

R2 O

1102

+ Pd0L2

DISCONNECTION :

O

O R1

R1

R1

R2

R2

S

R1

R

+ R2B(OH)2

S R

+ R2B(OH)2

NOTES :

The palladium-catalysed cross-coupling of thioalkyne derivatives and thiol esters with boronic acids in the presence of copper(I) thiophene-2-carboxylate (CuTC) under neutral conditions. Both the copper cation and the carboxylate anion are critical to the reaction. The exact details of the mechanism are not known. See also Sonogashira – Hagihara and Suzuki – Miyaura reactions.

REFERENCES :

1) C. Savarin; J. Srogl; L.S. Liebeskind, Org. Lett., 2000, 2, 3229. 2) L.S. Liebeskind; J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260. 3) C. Savarin; J. Srogl; L.S. Liebeskind, Org. Lett., 2001, 3, 91. 4) L.S. Liebeskind; J. Srogl, Org. Lett., 2002, 4, 979. 5) C. Savarin; J. Srogl; L.S. Liebeskind, Org. Lett., 2002, 4, 4309. 6) Y. Yu; L.S. Liebeskind, J. Org. Chem., 2004, 69, 3554.

COMMENTS :

LIEBIG BENZYLIC ACID REARRANGEMENT EXAMPLE :

O

OH

Ph

Ph CH3 O

10% NaOH Et2O

1103

CH3 COOH

MECHANISM :

H+ O

O Ph

Ph CH3 O

10% NaOH Et2O

OH CH3

HO

Ph

O

CH3 COOH

DISCONNECTION :

R

OH R1 COOH

R1

O

O

R

NOTES :

The base-induced transformation of an α-diketone into the salt of an α-hydroxyacid.

REFERENCES :

1) J. von Liebig, Liebigs Ann. Chem., 1838, 25, 27. 2) S. Selman; J.F. Eastham, J. Chem. Soc., Quat. Rev., 1960, 14, 221. 3) K.S. Warren; O.K. Neville; E.C. Hendley, J. Org. Chem., 1963, 28, 2152. 4) A. Novelli; J.R. Barrio, Tetrahedron Lett., 1969, 10, 3671. 5) F. Toda; K. Tanaka; Y. Kagura; Y. Sahairo, Chem. Lett., 1990, 373. 6) H.H. Wasserman; D.S. Ennis; C.B. Vu; G.K. Schulte, Tetrahedron Lett., 1991, 32, 6039. 7) P.A. Grieco; J.L. Collins; J.C. Huffman, J. Org. Chem., 1998, 63, 9576.

COMMENTS :

1104

LIEPA COUPLING EXAMPLE :

OCH3

OCH3

H3CO

H3CO

N

N

1) VOF3, DCM, 0 oC 2) TFA 3) aq. NaOH

H3CO OCH3

H3CO OCH3

DISCONNECTION :

R

R1

R1

R +

NOTES :

The intramolecular coupling between mainly phenolic aromatic nuclei in the presence vanadium oxytrifluoride.

REFERENCES : Smith 2nd : 1183

1) S.M. Kupchan; A.J. Liepa; V. Kameswaran; R.F. Bryan, J. Am. Chem. Soc., 1973, 95, 6861. 2) D.H.R. Barton; C.J. Porter; D.A. Widdowson, J. Chem. Soc., Perkin Trans. 1, 1974, 346. 3) A.J. Liepa; R.E. Summons, J. Chem. Soc., Chem. Commun., 1977, 826. 4) M.A. Ciufolini; F. Roschangar, J. Am. Chem. Soc., 1996, 118, 12082.

COMMENTS :

1105

LIMAYE SYNTHESIS EXAMPLE :

O HO

CH3

HO

OH

OH

1) AcOCH2CO2Et, H2SO4 2) (CH3CO)2O 3) AlCl3 4) NaOH, heat 5) H2SO4

MECHANISM :

HO

OH

HO

O

H3C

OEt

O

O

O O H3C

H2SO4

O

O HO

O

O

O

O

O

R

RCOCl (RCO)2O

AlCl3 CH3

CH3 O

R

HO

O O

CH3

O

O

HO

R OH

1) NaOH, heat 2) H2SO4

DISCONNECTION : O HO

R HO

OH

OH

NOTES :

The synthesis of 2-acylresorcinols via a Fries rearrangement. See also Fries rearrangement.

1106

REFERENCES : Org. Synth. : 21, 22 Org. Synth. Coll. Vol. : 3, 281

1) D.B. Limaye, Ber. Dtsch. Chem. Ges., 1934, 67, 12. 2) W. Baker, J. Chem. Soc., 1934, 1953.

COMMENTS :

LINDSEY PORPHYRIN SYNTHESIS EXAMPLE :

CH3

4

HN

N N H

1)

O

H3C TFA O 2)

H

S

Pr

N

EtMgBr 4)

O Et

N

NH

Pr H TFA O 3) Ph

Ph

Et

Cl

EtMgBr 5) NaBH4 THF, CH3OH 6) TFA, CH3CN RT 7) DDQ

1107

MECHANISM :

A

H

O +

2

A

N H

H

TFA

NH

HN

D

H

O +

2

D

N H A

H

TFA

NH

HN

H

NH

A

HN

S

O

HN

NH

O B

H

C

O

N

B

EtMgBr

EtMgBr A

NH

A

H

HN

O

O

A

NH

HN

HO

B

C

H

NH

NaBH4 THF, CH3OH

OH B

C

H

D

NH

HN

N

B

1) TFA, CH3CN C 2) DDQ

HN

OH

HO

A

H

+

HN

Cl

N

NH

B

C

D

DISCONNECTION :

A O

O HN

N

N

NH

A

N H

B

C

+

+

D

H

O

O +

D

1108

B

H

S

N

+

C

Cl

NOTES : Lindsey developed two main synthetic routes to porphyrins. The most interesting one is the synthesis of porphyrins

bearing four different substituents. The key components in this synthesis are the dipyrromethanes. See also Adler – Longo, MacDonald, Rothemund and Taniguchi reactions.

REFERENCES :

1) C.-H. Lee; J.S. Lindsey, Tetrahedron, 1994, 50, 11427. 2) C.-H. Lee; F. Li; K. Iwamoto; J. Dadok; A.A. Bothner–By; J.S. Lindsey, Tetrahedron, 1995, 51, 11645. 3) B.J. Littler; M.A. Miller; C.-H. Hung; R.W. Wagner; D.F. O'Shea; P.D. Boyle; J.S. Lindsey, J. Org. Chem., 1999, 64, 1391. 4) B.J. Littler; Y. Ciringh; J.S. Lindsey, J. Org. Chem., 1999, 64, 2864. 5) W.-S. Cho; H.-J. Kim; B.J. Littler; M.A. Miller; C.-H. Lee; J.S. Lindsey, J. Org. Chem., 1999, 64, 7890. 6) P.D. Rao; B.J. Littler; G.R. Geier III; J.S. Lindsey, J. Org. Chem., 2000, 65, 1084. 7) D. Gryko; J.S. Lindsey, J. Org. Chem., 2000, 65, 2249.

COMMENTS :

LIPP INDOLE SYNTHESIS EXAMPLE :

Cl NaOEt 130 - 140 oC

NH2

N H

MECHANISM :

Cl N R H

NaOEt 130 - 140 oC

1109

N R

DISCONNECTION :

Cl R1

R1 N R

N H

R

NOTES : o-Amino-ω-chlorostyrenes on treatment with sodium ethoxide at 130 – 140 oC yield indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe

indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) A. Lipp, Ber. Dtsch. Chem. Ges., 1884, 17, 1067. 2) A. Lipp, Ber. Dtsch. Chem. Ges., 1884, 17, 2507.

COMMENTS :

1110

LOBRY de BRUIN – van EKENSTEIN TRANSFORMATION EXAMPLE :

HO

HO H

O

HO H

O

HO HO

AcO

OH O HO

AcO H

O

AcO AcO

OH O HO

OAc O

AcO H

O OAc O

AcO

O OH 1) NaOD, D2O 2) Ac2O, Pyridine

OH

D O OAc OAc

AcO

MECHANISM :

H

O

H H

OH OH

OH

OH O

H H

R

OH

H R

R

H

O

H HO

O

HO H

H OH R

DISCONNECTION :

OH O

H HO

H R

H

O

H H

OH OH R

NOTES :

The treatment of an aqueous solution of an aldose or ketose sugar with dilute aqueous alkali yields an equilibrium mixture of the epimeric aldose sugars and the related ketose sugar, which gives the same osazone.

1111

REFERENCES :

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1895, 28, 1149. 2) C.A. Lobry de Bruin; W.A. van Ekenstein, Recl. Trav. Chim. Pays-Bas, 1895, 14, 150. 3) Wm.L. Evans, Chem. Rev., 1942, 31, 537. 4) J.F. Mendicino, J. Am. Chem. Soc., 1960, 82, 4975. 5) H. van Bekkum, Carbohydr. Eur., 1995, 13, 46. 6) P. Sedmera; V. Prikrylova; K. Bezouska; E. Rajnochova; J. Thiem; V. Kren, J. Carbohydr. Chem., 1998, 17, 1351. 7) S.J. Angyal, Top. Curr. Chem., 2001, 215, 1.

COMMENTS :

LOSSEN REARRANGEMENT EXAMPLE :

O Ph

N H

OH 1) TsCl, base 2) H2O

PhNH2

MECHANISM :

O R

O N H

O

O

R

N

R1

O

O R N C O R1

B

R

H N

H+ O O

H

- CO2

RNH2

B

1112

H2O

DISCONNECTION :

O RNH2

R

OH

NOTES :

Hydroxamic acids or their acyl derivatives undergo rearrangement to form isocyanates either thermally or when treated with thionyl chloride or alkali. The isocyanates may react further with the components in the system. See also Beckmann, Curtius, Hofmann rearrangement, Schmidt rearrangement, Tiemann rearrangement and Wolff

reactions.

REFERENCES : March : 1054, 1093 Smith – March : 1380, 1413 Houben – Weyl : 10/4, 232; E3, 527; E16d, 1098 Org. React. : 3, 267, 337

1) W. Lossen, Liebigs Ann. Chem., 1872, 161, 347. 2) E.C. Franklin, Chem. Rev., 1934, 14, 219. 3) H.L. Yale, Chem. Rev., 1943, 33, 209. 4) G.B. Bachmann; J.E. Goldmacher, J. Org. Chem., 1964, 29, 2576. 5) H. Ulrich; B. Tucer; R. Richter, J. Org. Chem., 1978, 43, 1544. 6) R.B. Harris; I.B. Wilson, J. Biol. Chem., 1983, 258, 1357. 7) D.A. Casteel; R.S. Gephart; T. Morgan, Heterocycles, 1993, 36, 485. 8) J.L. Romine, Org. Prep. Proced. Int., 1996, 28, 249. 9) R. Anilkumar; S. Chandrasekhar; M. Sridhar, Tetrahedron Lett., 2000, 41, 5291. 10) K. Ohmoto; T. Yamamoto; T. Horiuchi; T. Kojima; K. Hachiya; S. Hashimoto; M. Kawamura; H. Nakai; M. Toda, Synlett, 2001, 299.

COMMENTS :

1113

LUCHE REDUCTION EXAMPLE :

+ CeCl3, NaBH4 MeOH

O

OH trace

OH

MECHANISM :

NaBH4 + CeCl3

HCeCl2

intermediate : H

Cl Ce Cl

O

O OH

DISCONNECTION :

R2

OH R1 H

O R1

R

NOTES :

The addition of cerium salts to NaBH4 gives very chemoselective 1,2-reduction of conjugated aldehydes and ketones. If the complex is formed irreversibly hydride transfer is under kinetic control (1,2-addition). If however the complex forms reversibly the reaction is under thermodynamic control (1,4-reduction). The exact mechanism is complicated. It is believed that an alkoxy borohydride is the active species. The cerium catalyses the formation of this species and increases the electrophilicity of the carbonyl atom.

REFERENCES : Smith – March : 1197 Smith 2nd : 330, 365

1114

1) J.-L. Luche, J. Am. Chem. Soc., 1978, 100, 2226. 2) J.M. Lefour; A. Loupy, Tetrahedron, 1978, 34, 2597. 3) A.L. Gemal; J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454. 4) D.E. Ward; C.K. Rhee; W.M. Zoghaib, Tetrahedron Lett., 1988, 29, 517. 5) M.T. Crimmins; R. O’Mahoney, J. Org. Chem., 1989, 54, 1157. 6) T. Matsuura; S. Yamamura, Tetrahedron Lett., 2000, 41, 4805.

COMMENTS :

LUMIÈRE – BARBIER ACETYLATION EXAMPLE :

OH

OH

O

NH2

CH3COOH H2O

N H

CH3

MECHANISM :

OH

OH

O

HO

N H

H2O

NH2 CH3

CH3

O

DISCONNECTION :

O

R N H

R CH3

NH2

1115

NOTES :

Aromatic amines are acetylated using a solution of acetic anhydride in cold water. See also Chattaway acetylation, Einhorn acylation, Galat – Elion, Schotten – Baumann and Weinreb reactions.

REFERENCES :

A. Lumière; L. Lumière; H. Barbier, Bull. Soc. Chim. Fr., 1905, 33, 783.

COMMENTS :

LÜTTRINGHAUS REARRANGEMENT EXAMPLE :

HO

O + Na

benzene, 60 oC

MECHANISM :

O

C6H5ONa +

Na O Na ONa O

Na

+

1116

DISCONNECTION :

O OH

NOTES :

Diarylethers are rearranged to the o-arylphenol with phenyl sodium under anaerobic conditions.

REFERENCES :

1) A. Lüttringhaus; G. von Sääf, Angew. Chem., 1938, 51, 915. 2) A. Lüttringhaus, Angew. Chem., 1942, 55, 50. 3) A. Lüttringhaus; D. Ambros, Chem. Ber., 1956, 89, 463. 4) R. Huisgen; J. Sauer, Angew. Chem., 1958, 70, 438. 5) H. Prinzbach, Eur. J. Org. Chem., 1998, 4, 735.

COMMENTS :

1117

1118

MENCKE – LASZLO NITRATION OF PHENOLS · 1175 MENDIUS REDUCTION · 1176

F

MENSCHUTKIN REACTION · 1177 MENTZER PYRONE SYNTHESIS · 1178

FUKUYAMA – MITSUNOBU REACTION · 1212

MERLING – von DOERING SYNTHESIS · 1179 METH–COHN QUINOLINE SYNTHESIS · 1180 H

MEYER – HARTMANN SYNTHESIS · 1182 MEYER – SCHUSTER REARRANGEMENT (RUPE REACTION) ·

HOULIHAN MODIFICATION · 1123

1185 MEYER ALKYLATION REACTION · 1187

M

MEYER NITROALKANE REACTION · 1188 MEYER REACTION · 1189

MACDONALD – FISCHER SUGAR DEGRADATION · 1120

MEYER von – MOHR SYNTHESIS · 1183

MACDONALD PORPHYRIN SYNTHESIS · 1121

MEYER von PYRIMIDINE SYNTHESIS · 1190

MADELUNG INDOLE SYNTHESIS · 1122

MEYERS ALDEHYDE SYNTHESIS · 1191

MAGNUS INDOLE SYNTHESIS · 1124

MICHAEL CONDENSATION · 1193

MAITLAND – JAPP REACTION · 1125

MICHAEL GLYCOSIDATION · 1195

MAJETICH ANNULATION · 1127

MICHAELIS – BECKER – NYLÉN PHOSPHONYLATION · 1196

MAKAROV–ZEMLYANSKIĬ – PROKIN SYNTHESIS · 1128

MIDLAND REDUCTION · 1197

MĄKOSZA VICARIOUS NUCLEOPHILIC SUBSTITUTION · 1128

MIESCHER DEGRADATION · 1199

MALAPRADE REACTION · 1130

MIGITA – SANO SYNTHESIS · 1200

MANN ETHER DEALKYLATION · 1131

MILAS HYDROXYLATION OF OLEFINS · 1202

MANNICH REACTION · 1133

MILLER – PLÖCHL SYNTHESIS · 1203

MANSUY – EVANS REACTION · 1135

MILLER – SNYDER ARYL CYANIDE SYNTHESIS · 1204

MAQUENNE SYNTHESIS · 1136

MILLER SYNTHESIS · 1206

MARBET – SAUCY MODIFICATION · 1138

MILLS SYNTHESIS · 1207

MARSCHALK AROMATIC ALKYLATION · 1139

MINISCI AROMATIC AMINATION · 1208

MARSHALL – MINNAARD FRAGMENTATION · 1141

MISLOW – BRAVERMAN – EVANS REARRANGEMENT · 1209

MARTIN INDOLE SYNTHESIS · 1142

MITSUNOBU REACTION · 1211

MARTINET SYNTHESIS · 1143

MOEDRITZER – IRANI REACTION · 1213

MASAMUNE MACROLACTONISATION · 1145

MONTEVECCHI INDOLE SYNTHESIS · 1214

MASCARELLI FLUORENE SYNTHESIS · 1146

MORI – BAN INDOLE SYNTHESIS · 1216

MATHEWS DRY HYDROLYSIS · 1147

MORIN REARRANGEMENT · 1217

MATTESON REACTION · 1149

MOUREAU – MIGNONAC REACTION · 1219

MAURER – DREFAHL SYNTHESIS · 1151

MOUSSERON – FRAISSE – McCOY CYCLOPROPANATION ·

MAYER SYNTHESIS · 1152

1220

MAYO de REACTION · 1153

MOZINGO DESULFURISATION · 1222

McBRIDE REACTION · 1154

MUKAIYAMA – MICHAEL REACTION · 1230

McCLUSKEY FRAGMENTATION · 1156

MUKAIYAMA – YAMADA EPOXIDATION · 1223

McCORMACK – KUKHTIN – RAMIREZ PHOSPHOLE SYNTHESIS

MUKAIYAMA MACROLACTONISATION - 1 · 1224

· 1157

MUKAIYAMA MACROLACTONISATION - 2 · 1226

McFADYEN – STEVENS REACTION · 1158

MUKAIYAMA OXIDATION · 1227

McLAFFERTY REARRANGEMENT · 1159

MUKAIYAMA REACTION · 1229

McMURRY OLEFINATION · 1161

MÜLLER – ROCHOW SYNTHESIS · 1233

McNELIS REARRANGEMENT · 1162

MÜLLER–CUNRADI CONDENSATION · 1231

MEER ter REACTION · 1164

MURAHASHI ALLYLIC ALKYLATION · 1234

MEERWEIN – PONNDORF – VERLEY REDUCTION · 1165

MURAHASHI CROSS-COUPLING REACTION · 1235

MEERWEIN ARYLATION · 1166

MURAI C-C BOND FORMATION · 1237

MEERWEIN METHYLATION · 1168

MURAI COUPLING · 1238

MEINWALD REACTION · 1169

MURAI REARRANGEMENT · 1240

MEINWALD REARRANGEMENT · 1170

MURPHY INDOLE SYNTHESIS · 1242

MEISENHEIMER – JACKSON REACTION · 1172

MYERS – MOORE – SAITO – SCHMITTEL CYCLISATION · 1243

MEISENHEIMER – JANOVSKY SYNTHESIS · 1172

MYERS REDUCTIVE COUPLING · 1246

MEISENHEIMER REARRANGEMENT · 1173

1119

MACDONALD – FISCHER SUGAR DEGRADATION EXAMPLE :

H HO H H

CHO OH H OH OH CH2OH

1) AcOH 2) EtSH, H+ 3) EtSO3H 4) N2H4

CHO HO H H OH H OH CH2OH

MECHANISM :

CHO H OH R

+

EtSH, H - H2O

H

CH(SEt)2 OH R

EtSO3H

H

CH(SO2Et)2 OH NH3 R - CH2(SO2Et)2

CHO R

DISCONNECTION :

CHO H R R = carbohydrate

CHO OH R

NOTES : An aldose is condensed with ethylmercaptan and hydrochloric acid to a mercaptal followed by oxidation with e.g. perpropionic acid to a disulfone. The disulfone is cleaved with ammonia. See also Ruff – Fenton and Wohl reactions.

REFERENCES : Houben – Weyl : E11, 1248

1) E. Fischer, Ber. Dtsch. Chem. Ges., 1894, 27, 673. 2) H.O.L. Fischer; D.L. MacDonald, Annual Rev. Biochem., 1951, 20, 43. 3) D.L. MacDonald; H.O.L. Fischer, J. Am. Chem. Soc., 1952, 74, 2087. 4) D.L. MacDonald; H.O.L. Fischer, J. Am. Chem. Soc., 1955, 77, 4348. 5) C.E. Ballou; H.O.L. Fischer; D.L. MacDonald, J. Am. Chem. Soc., 1955, 77, 5967. 6) E.J. Bourne; R. Stephens, J. Chem. Soc., 1954, 4009. 7) D.L. MacDonald, Methods Carbohydr. Chem., 1962, 1, 73. 8) L.D. Hall; L. Hough; S.H. Shute; T.J. Taylor, J. Chem. Soc., 1965, 1154. 9) A. Senning, Sulfur Lett., 1982, 1, 33.

1120

10) B. Jäger; H. Lay; J. Lehmann; L. Ziser, Carbohydr. Res., 1991, 217, 99.

COMMENTS :

MACDONALD PORPHYRIN SYNTHESIS EXAMPLE :

NH

HN +

1) 0.4 % HI - HOAc 2) NaOAc, air

CHO

OHC NH

HN

H3C

NH

N

N

HN CH3

H3C CH3

CO2CH3

CO2CH3

H3CO2C

CO2CH3

MECHANISM :

O

N H

N H

H N

H N

NH

HO N

O

H

H HN

H

H

N H - 2 H2O

N

N H N further oxidation possible

1121

N OH

DISCONNECTION :

N H N

H

N N H

N H

H N

H

+

N H

O

N H

O

NOTES :

The porphyrin synthesis from dipyrrolemethanes. This reaction is normally used for the synthesis of porphyrins with C2 symmetry. See also Adler – Longo, Lindsey, Rothemund and Taniguchi reactions.

REFERENCES :

1) G.P. Arsenault; E. Bullock; S.F. MacDonald, J. Am. Chem. Soc., 1960, 82, 4384. 2) C.K. Chang, J. Org. Chem., 1981, 46, 4610. 3) K.M. Smith; R.K. Pandey; A.H. Jackson, J. Chem. Soc., Perkin Trans. 1, 1987, 299. 4) C.H. Lee; F.R. Li; K. Iwamoto; J. Dadok; A.A. Bothner–By; J.S. Lindsey, Tetrahedron, 1995, 51, 11645. 5) B.H. Novak; T.D. Lash, J. Org. Chem., 1998, 63, 3998. 6) J.M. Montierth; A.G. Duran; S.H. Leung; K.M. Smith; N.E. Schore, Tetrahedron Lett., 2000, 41, 7423. 7) A. Wickramasinghe; L. Jaquinod; D.J. Nurco; K.M. Smith, Tetrahedron, 2001, 57, 4261. 8) C. Orlewska; W. Maes; S. Toppet; W. Dehaen, Tetrahedron Lett., 2005, 46, 6067.

COMMENTS :

MADELUNG INDOLE SYNTHESIS EXAMPLE :

CH3 O N H

CH3

NaOEt 380 oC

1122

CH3 N H

MECHANISM :

H

H

B

N H

CH3

H

H CH 3

CH3 N H O H+

O

N OH H

CH3 - H2O

N H

DISCONNECTION :

R

R1

R

N

CH3 R1 N H

H

O

NOTES :

Indoles are obtained by heating N-acyl-o-toluidines originally at high temperature with a base, e.g. alkali alkoxide, sodamide, in the absence of air. The Houlihan modification (through lithiation) is preferred above the classic reaction. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe

indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Org. Synth. : 23, 42 Org. Synth. Coll. Vol. : 3, 479 Science of Synthesis : 10, 443

1) J. Mauthner; W. Suida, Monatsh. Chem., 1886, 7, 237. 2) W. Madelung, Ber. Dtsch. Chem. Ges., 1912, 45, 1128. 3) W.J. Houlihan; V.A. Parrino; Y. Uike, J. Org. Chem., 1981, 46, 4511. 4) W.J. Houlihan; Y. Uike; V.A. Parrino, J. Org. Chem., 1981, 46, 4515. 5) W. Verboom; E.O.M. Orlemans; H.J. Berga; M.W. Scheltinga; D.N. Reinhoudt, Tetrahedron, 1986, 42, 5053. 6) A.B. Smith III; J.N. Haseltine; M. Visnick, Tetrahedron, 1989, 45, 2431. 7) I. Hughes, Tetrahedron Lett., 1996, 37, 7595.

1123

8) A.S. Kiselyov, Tetrahedron Lett., 1999, 40, 4119. 9) D.A. Wacker; P. Kasireddy, Tetrahedron Lett., 2002, 43, 5189.

COMMENTS :

MAGNUS INDOLE SYNTHESIS EXAMPLE :

TIPS

H3CO

CH3 MsOH DCM, RT

N Ms

N Ms

H3CO

MECHANISM :

TIPS

TIPS

TIPS H

H

+

H CH3O

N Ms

CH3O TIPS

- H+

CH3O

N Ms

H

N Ms

N Ms

CH3O

CH3 1) protodesilylation 2) rearrangement

CH3O

DISCONNECTION : Si(R1)3 CH3

N R

N R

1124

N Ms

H

NOTES :

3-Methyl indoles are formed after treating triisopropylsilylprop-2-ynylanilines with methanesulfonic acid. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman

indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe

indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) P. Magnus; I.S. Mitchell, Tetrahedron Lett., 1998, 39, 4595. 2) G.W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.

COMMENTS :

MAITLAND – JAPP REACTION EXAMPLE :

O H3C

O H3C

CH3 O

+ 2 Ph

H xs. aq. NaOH > 7days

1125

Ph

CH3 O

Ph

MECHANISM :

O H H3C

O Ph

Ph

OH HH

Ph

HO

CH3 O

Ph

H

OH

Ph

H

O

H

H

O

O

Ph H

Ph - H2O O

DISCONNECTION :

R1

O

R

H

H

R2

R3

O

O

O +

R3

R2

+ R

H

R1

H

O

NOTES :

Single diastereoisomers of THP products can be prepared from a ketone and 2 molecules of aldehydes. Several catalytic variants have been published.

REFERENCES :

1) F.R. Japp; W. Maitland, J. Chem. Soc., 1904, 85, 1473. 2) R. Cornubert; P. Robinet, Bull. Chim. Soc. Fr., 1934, 90. 3) C.A.R. Baxter; D.A. Whiting, J. Chem. Soc. (C), 1968, 1174. 4) R. Sivakumar; N. Satyamurthy; K. Ramalingam; D.J. O’Donnell; K. Ramarajan; K.D. Berlin, J. Org. Chem., 1979, 44, 1559.

5) G. Sabitha; G.S.K. Kumar Reddy; M. Rajkumar; J.S. Yadav; K.V.S. Ramakrishna; A.C. Kunwar, Tetrahedron Lett., 2003, 44, 7455. 6) P.A. Clarke; W.H.C. Martin; J.M. Hargreaves; C. Wilson; A.J. Blake, Chem. Commun., 2005, 1061. 7) P.A. Clarke; W.H.C. Martin, Tetrahedron, 2005, 61, 5433.

COMMENTS :

1126

MAJETICH ANNULATION EXAMPLE : Me3Si H

H

Ph

0.2 Bu4NF, DMF 5 HMPA, 4 A MS

O

Ph O

MECHANISM :

Me3Si F H+

NOTES :

This is an intramolecular Hosomi – Sakurai reaction to set-up different ring sizes (4, 5, 6, 7, 8). See also Hosomi – Sakurai reaction.

REFERENCES :

1) G. Majetich; J. Defauw; K. Hull; T. Shawe, Tetrahedron Lett., 1985, 39, 4711. 2) G. Majetich; A.M. Casares; D. Chapman; M. Behnke, J. Org. Chem., 1986, 51, 1753. 3) G. Majetich; K. Hull; A.M. Casares; V.K. Ketani, J. Org. Chem., 1991, 56, 3958. 4) S.A. May; P.A. Grieco; H.-H. Lee, Synlett, 1997, 493.

COMMENTS :

1127

MAKAROV–ZEMLYANSKIĬ – PROKIN SYNTHESIS EXAMPLE : H

Cl Cl

CH3 H3BO3

NOTES :

1-(Dichloromethyl)benzene is selectively hydrolysed by boric acid. Benzyl chloride or benzotrichloride are unaffected.

REFERENCES :

Ya.Ya. Makarov–Zemlyanskiĭ; S.S. Prokin, J. Appl. Chem. (USSR), 1936, 9, 2207. (Chem. Abs., 1937, 31, 4659.)

COMMENTS :

MĄKOSZA VICARIOUS NUCLEOPHILIC SUBSTITUTION EXAMPLE :

O2N

O2 N + CHCl3 N

NaOMe DMF, liq. NH3

1128

CHCl2 N

MECHANISM :

X R Y

H H

Y

R

X

+

Z

base solvent

Z B , - HX

NO2

NO2

solvent : KOH, tBuOK/DMF, NH3/DMF R

R

Y

Z

Y

Z

H+

NO2

NO2

DISCONNECTION :

O2N

X

O2N

R

+ Z

Y

X = Cl, Br, PhO, PhS Y = SO2Ph, SO2NH2, CN Z = CH, N

Z

Y R

NOTES :

The nucleophilic substitution of hydrogen in the ortho or para position of arenes, heteroarenes or nitro derivatives of these compounds. The mechanism goes via an addition-β-elimination pathway. This synthesis can also be used to make indoles.

REFERENCES : Science of Synthesis : 10, 437, 454, 459, 544

1) J. Goliński; M. Mąkosza, Tetrahedron Lett., 1978, 32, 3495. 2) T. Glinka; M. Mąkosza, J. Org. Chem., 1983, 48, 3860. 3) M. Mąkosza; J. Winiarski, Acc. Chem. Res., 1987, 20, 282. 4) M. Mąkosza, Synthesis, 1991, 103. 5) M. Mąkosza; R. Podraza, Eur. J. Org. Chem., 2000, 193. 6) N.J. Lawrence; J. Liddle; S.M. Bushell; D.A. Jackson, J. Org. Chem., 2002, 67, 457. 7) T. Lemek; M. Mąkosza; D.S. Stephenson; H. Mayr, Angew. Chem., Int. Ed., 2003, 42, 2793.

1129

COMMENTS :

MALAPRADE REACTION EXAMPLE :

CH3 H3C OH H3C OH CH3

2

H3C

HIO4

CH3 O

MECHANISM :

H3C H3C

CH3 OH OH CH3

H3C H3C

CH3 O IO4H3 O CH3

HIO4. 2 H2O

CH3 H3C OIO5H4 H3C OH CH3

2

H3C

CH3

+ HIO3

O

DISCONNECTION :

O R1

R

R R1 R2

O R2

OH OH R3

R3

NOTES :

α-Glycols undergo quantitative fission at room temperature when treated with periodic acid or its salts. Aldehydes are the normal products but the central carbon of a glycerol residue yields formic acid. Cleavage also occurs with compounds with hydroxyl and amino groups attached to adjacent carbon atoms, with α-hydroxyaldehydes or ketones,

1130

and with 1,2-diketones. See also Barry, Criegee glycol cleavage, Djerassi – Rylander, Fischer, Hudson – Hirst, and Lemieux – Johnson reactions.

REFERENCES : March : 1174 Smith – March : 1519 Houben – Weyl : E3, 510 Org. React. : 2, 341

1) L. Malaprade, Bull. Soc. Chim. Fr., 1928, 43, 683. 2) G.H. Schenk, J. Chem. Educ., 1962, 39, 32. 3) A.A. Durani; G.C. Sun; J.H.P. Tyman, Lipids, 1982, 17, 561. 4) J.J.B. Nevado; P.V. Gonzalez, Analyst (London), 1989, 114, 243. 5) N.Q. Jie; D.L. Yang; Q.N. Zhang; J.H. Yang; Z.Q. Song, Anal. Chim. Acta, 1998, 359, 87. 6) A. Afkhami; F. Mosaed, Microchem. J., 2001, 68, 35.

COMMENTS :

MANN ETHER DEALKYLATION EXAMPLE :

SH S Ph2PH, LiAlH4 THF

1131

+

Ph

P Ph

Ph

MECHANISM :

O Ph2PH

LiAlH4, THF

+

Ph2P

CH3

H3 C O

OH + Ph2PCH3

PPh2 Li

DISCONNECTION :

ArSH

Ar

ArOH

Ar

S O

Alk Alk

NOTES :

The dealkylation of certain alkyl aryl sulfides and ethers by arsenide ions or diaryl phosphides. The last reaction is much faster than the first one. See also Gustus cleavage, Prey and Stoermer dealkylation.

REFERENCES :

1) F.G. Mann; B.P. Tong; V.P. Wystrach, J. Chem. Soc., 1963, 1155. 2) F.G. Mann; M.J. Pragnell, Chem. Ind. (London), 1964, 1386. 3) F.G. Mann; M.J. Pragnell, J. Chem. Soc., 1965, 4120. 4) G. Vériot; A. Collet, Acros Organics Acta, 1995, 1, 40.

COMMENTS :

1132

MANNICH REACTION EXAMPLE :

H

CH3

O

+

H

H N

+

O

N

H+

CH3

H

H H

H3C

H3C

CH3

H

O

H3C

H CH3 CH3

MECHANISM :

H

O

H

R1

H+

R

O H

H

R1

R

CH3

O H

H

H N

+

HO CH3

H

R

O H

H

R1

CH3

H H

O

H R

R1

H2C N CH3

CH3

H

H3C

CH3

H+, - H2O

N

N H3C CH3 H2C N CH3

DISCONNECTION :

H R3

R

O

N R1

H R4

R

R2

H N

O R1

+

H

H

R3

O

R4

R2

+ H

NOTES :

The condensation of ammonia or a primary or secondary amine usually as the hydrochloride, with formaldehyde and a compound containing at least one reactive hydrogen atom, e.g. acetophenone, in which the hydrogen is replaced by aminomethyl or substituted aminomethyl. List et al. introduced a proline-catalysed direct asymmetric threecomponent Mannich reaction. Lewis acid catalysed examples are also known. See also Asinger, Betti, Cheney, Einhorn – Tscherniac and Pictet – Sprengler reactions.

REFERENCES : March : 900

1133

Smith – March : 1189 Smith : 958 Smith 2nd : 868 Houben – Weyl : 4/2, 32; 11/1, 731; E3, 642; E6a, 100; E6b, 1091; E8c, 129, 361; E8d, 446; E11, 781; E16d, 1058 Org. React. : 1, 303; 7, 99 Org. Synth. : 23, 30; 35, 78; 37, 18, 52, 73; 57, 95, 102; 59, 153 Org. Synth. Coll. Vol. : 3, 305; 4, 281, 515, 626, 816; 6, 474, 981, 987 Science of Synthesis : 10, 517, 520, 534, 583, 595, 600, 682

1) B. Tollens; C.M. von Marle, Ber. Dtsch. Chem. Ges., 1903, 36, 1347. 2) C. Mannich; W. Krösche, Arch. Pharm. (Weinheim, Ger.), 1912, 250, 647. 3) H. Hellmann, Angew. Chem., 1953, 65, 475. 4) A.P. Kozikowski; H. Ishida, Heterocycles, 1980, 14, 55. 5) P.A. Wender; J.C. Lechleiter, J. Am. Chem. Soc., 1980, 102, 6340. 6) L.A. Overman, Acc. Chem. Res., 1992, 25, 352. 7) L.A. Overman, Aldrichimica Acta, 1995, 28, 107. 8) M. Arend; B. Westermann; N. Risch, Angew. Chem., Int. Ed., 1998, 37, 1044. 9) S.F. Martin, Acc. Chem. Res., 2002, 35, 895. 10) S. Kobayashi; T. Hamada; K. Manabe, J. Am. Chem. Soc., 2002, 124, 5640. 11) A. Córdova, Acc. Chem. Res., 2004, 37, 102. 12) B. List, Acc. Chem. Res., 2004, 37, 548. 13) C. Allemann; R. Gordillo; F.R. Clemente; P. Ha-Yeon Cheong; K.N. Houk, Acc. Chem. Res., 2004, 37, 558. 14) S. Knüppel; C. Wang; G. Kehr; R. Fröhlich; G. Erker, J. Organomet. Chem., 2005, 690, 14.

COMMENTS :

1134

MANSUY – EVANS REACTION EXAMPLE :

CH3

Ph H

H O S O N H Ph

CuOTf Benzene O N S I O

CO2Ph

H3C 5 mol %

CH3

H

CO2Ph

CH3

O

O N N

Ph

Ph

MECHANISM :

Ts N I

NTs I

NTs

Mn(TPP)Cl

DISCONNECTION :

R

Ts N R1

R R2

R2 R1

NOTES : Mansuy et al. investigated the Fe(III) and Mn(III)-derived porphyrin catalysts in the aziridination of olefins employing

(N-(p-tolylsulfonyl)imino)phenyliodinane as the nitrene precursor. Evans et al. extended the scope of this reaction to include both electron-rich and electron-deficient olefins. His study has demonstrated that Cu(I) and Cu(II) chiral bis(oxazoline) complexes are excellent ligands for this reaction. See also Blum aziridine, Gabriel – Marckwald –

1135

Cromwell ethylenimine method, Hassner azide aziridine, Hoch – Campbell, Scheiner and Wenker ring-closure

reactions.

REFERENCES : Smith – March : 1057

1) D. Mansuy; J.P. Mahy; A. Dureault; G. Bedi; P. Battoni, J. Chem. Soc., Chem. Commun., 1984, 1161. 2) J.P. Mahy; G. Bedi; P. Battoni; D. Mansuy, J. Chem. Soc., Perkin Trans. 2, 1988, 1517. 3) D.A. Evans; M.M. Faul; M.T. Bilodeau, J. Org. Chem., 1991, 56, 6744. 4) Z. Li; K.R. Conser; E.N. Jacobsen, J. Am. Chem. Soc., 1993, 115, 5326. 5) D.A. Evans; M.M. Faul; M.T. Bilodeau; B.A. Anderson; D.M. Barnes, J. Am. Chem. Soc., 1993, 115, 5328. 6) D.A. Evans; M.T. Bilodeau; M.M. Faul, J. Am. Chem. Soc., 1994, 116, 2742. 7) D.A. Alonso; P.G. Andersson, J. Org. Chem., 1998, 63, 9455. 8) P. Dauban; R.H. Dodd, Synlett, 2003, 1571. 9) M.L. Kantam; N.V. Lakshmi; B. Kavita; Y. Haritha, Synlett, 2004, 525. 10) H.-L. Kwong; D. Liu; K.-Y. Chan; C.-S. Lee; K.-H. Huang; C.-M. Che, Tetrahedron Lett., 2004, 45, 3965.

COMMENTS :

MAQUENNE SYNTHESIS EXAMPLE :

O2NO HO O

H N

O OH ONO2

1) Cu(OAc)2, NH4OH 2) CH3CHO, NH3

1136

CH3 N

MECHANISM :

OH

O2NO HO

O

HO

OH O

fuming HNO3 H2SO4

OH

NH

R

Cu(OAc)2

NH

OH O

O

O

HO

OH O

NH

O

HO

OH

OH O

O

ONO2

O

HO NH3

O

O

N R

H OH

H O H+

HOOC

H N

HOOC

N

H N R

R decarboxylation - CO2

N

DISCONNECTION :

H N R

RCHO + NH3 +

N

O2NO HO O

O OH ONO2

NOTES :

This reaction is a modification of the Debus – Radziszewski reaction and is very similar to the Weidenhagen reaction. See also Akabori – Neuberg – Fischer, Brackeen, Bredereck, Wallach imidazole and Weidenhagen reactions.

REFERENCES : Houben – Weyl : E8c, 9, 13, 97 Org. Synth. : 22, 65 Org. Synth. Coll. Vol. : 3, 471

Maquenne, Ann. Chim. (Paris), 1891, 24, 522.

1137

COMMENTS :

MARBET – SAUCY MODIFICATION EXAMPLE :

O

O C4H10 O

O

+

N

O

OH C5H12

N

toluene 0.1 PNBSA sealed tube, 100 oC,12 hours

Ph

Ph

C4H10

H C5H12

MECHANISM :

OR +

R1

R1

R1

O

O

OH

+

H

DISCONNECTION :

R1

R1 OR

O

+

OH

NOTES :

The acid-catalysed reaction of allylic alcohols and vinyl ethers, the in situ formed ether undergoes the Claisen rearrangement. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Cope, Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Johnson – Claisen and Overman rearrangement reactions.

REFERENCES : Smith : 1240 Smith 2nd : 1022

1138

1) G. Saucy; L.H. Chopard–dit–Jean; W. Guex; G. Ryser; O. Isler, Helv. Chim. Acta, 1958, 41, 160. 2) R. Marbet; G. Saucy, Chimia, 1960, 14, 361. 3) R. Marbet; G. Saucy, Helv. Chim. Acta, 1967, 50, 2091. 4) D.J. Faulkner; M.R. Petersen, J. Am. Chem. Soc., 1973, 95, 553. 5) C.H. Heathcock; M.A. Henderson, J. Org. Chem., 1988, 53, 4736. 6) S. Pyo; J.F. Skowron; J.K. Cha, Tetrahedron Lett., 1992, 33, 4703. 7) M.O. Frederick; R.P. Hsung; R.H. Lambeth; J.A. Mulder; M.R. Tracey, Org. Lett., 2003, 5, 2663. 8) J.A. Mulder; K.C. Kurtz; R.P. Hsung, Synlett, 2003, 1379.

COMMENTS :

MARSCHALK AROMATIC ALKYLATION EXAMPLE :

O

NH2

O

NH2 CH3

O

1) aq. NaOH 2) Na2S2O4 3) CH2O

1139

O

MECHANISM :

O

OH

OH

OH

Na2S2O4 O

H

OH

OH

OH

O H+

CH3 OH

OH

OH

CH3

OH OH

OH H OH

OH

OH

OH

CH3 OH

CH3

OH

O

OH

O

OH

O2 OH

OH

DISCONNECTION :

O

O

X

O

R

O

X +

X = OH, Y = O X = NH2, Y = NH

H

R

O

NOTES :

The alkylation of quinines or aminoquinones with aldehydes. Sodium dithionite reduction of 1-hydroxy- or aminoanthraquinones to their leuco-forms, followed by condensation with aldehydes to yield the 2-alkylated anthraquinones. 2-Hydroxyanthraquinones yield 1-alkylated products.

REFERENCES :

1) C. Marschalk; F. Koenig; N. Ouroussof, Bull. Soc. Chim. Fr., 1936, 3, 1545. 2) H. Brockmann; W. Müller, Chem. Ber., 1958, 91, 1920. 3) K. Krohn, Angew. Chem., Int. Ed. Engl., 1979, 18, 621. 4) L.M. Harwood; L.C. Hodgekinson; J.K. Sunderland; P. Towers, Can. J. Chem., 1984, 62, 1922. 5) S. Qureshi; G. Shaw, J. Chem. Soc., Perkin Trans. 1, 1985, 875. 6) M.T. Furlong; H.N. Abramson; N.A. Akamike; H.C. Wormser, Synth. Commun., 1990, 20, 2691. 7) B. Deguin; J.-C. Florent; C. Monneret, J. Org. Chem., 1991, 56, 405.

1140

8) M. Helliwell; I.M. Philips; R.G. Pritchard; R.J. Stoodley, Tetrahedron Lett., 1999, 40, 8651.

COMMENTS :

MARSHALL – MINNAARD FRAGMENTATION EXAMPLE :

TsO

OH

1) BH3.THF 2) NaOMe

OH

MECHANISM : OTs

OTs

OTs

2 HO-

BH3 H2B

H

H

HO B

OH OH

DISCONNECTION :

R1O

R

R

R

R

1141

OR1

NOTES :

This is a diene synthesis via a boronate Grob fragmentation. See also Grob fragmentation and Wharton fragmentation.

REFERENCES :

1) J.A. Marshall; G.L. Bundy, J. Am. Chem. Soc., 1966, 88, 4291. 2) J.A. Marshall, Synthesis, 1971, 229. 3) J.A. Marshall; W.F. Huffman; J.A. Ruth, J. Am. Chem. Soc., 1972, 94, 4691. 4) P.S. Wharton; C.E. Sundin; D.W. Johnson; H.C. Kluender, J. Org. Chem., 1972, 37, 34. 5) A.J. Minnaard; J.B.P.A. Wijnberg; A. de Groot, Tetrahedron, 1994, 50, 4755. 6) V.N. Zhabinskii; A.J. Minnaard; J.B.P.A. Wijnberg; A. de Groot, J. Org. Chem., 1996, 61, 4022. 7) A.J. Minnaard; G.A. Stork; J.B.P.A. Wijnberg; A. de Groot, J. Org. Chem., 1997, 62, 2344.

COMMENTS :

MARTIN INDOLE SYNTHESIS EXAMPLE :

N Ac

OH OAc Li2PdCl4

N Ac

MECHANISM :

H N R

OH O

N OAc Li2PdCl4

R

- OAc

- H2O

N R

O

1142

O O

[3,3]-sigmatropic rearrangement

H R

N

O H+ O

DISCONNECTION :

R1

R1 N R

N R

OH

NOTES : N-phenylhydroxamic acids react with vinyl acetate in the presence of Li2PdCl4 to give 2,3-unsubstituted N-acylindoles via hetero-Cope rearrangement of the intermediate N-phenyl-O-vinylhydroxylamine. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) P. Martin, Helv. Chim. Acta, 1984, 67, 1647. 2) P. Martin, Tetrahedron Lett., 1987, 28, 1645.

COMMENTS :

MARTINET SYNTHESIS EXAMPLE :

HO O + NH2

H3CO

OCH3 O

O N H

O

1143

H

MECHANISM :

H+

O

O

RO NH2

N H

O

HO

H OH COOR - H+

N H

O

OR O

O

OR

O

HO

COOR

H O

O H2O, - CO2

N H

N H

DISCONNECTION : HO R

H

O R1O

O N H

OR1 + R O

O

NH2

NOTES :

Alkyl oxomalonate condenses with primary or secondary arylamine to yield a dioxindole-3-carboxylate, which with alkali in the absence of oxygen yields the dioxindole. See also von Baeyer oxindole, Brunner, Gassman oxindole, Hinsberg oxindole, Neber – Bosset and Stollé reactions.

REFERENCES :

1) A. Guyot; J. Martinet, C.R. Séances Acad. Sci., 1913, 156, 1625. 2) W. Langenbeck; R. Jüttemann; F. Hellrung, Liebigs Ann. Chem., 1932, 499, 201. 3) W. Langenbeck; F. Hellrung; R. Jüttemann, Liebigs Ann. Chem., 1934, 512, 276. 4) W.C. Sumpter, Chem. Rev., 1945, 37, 472. 5) K.C. Rice; B.J. Boone; A.B. Rubin; T.J. Rauls, J. Med. Chem., 1976, 19, 887. 6) A. Taylor, J. Chem. Res. (S), 1980, 347. 7) J.F.M. da Silva; S.J. Garden; A.C. Pinto, J. Braz. Chem. Soc., 2001, 12, 273.

COMMENTS :

1144

MASAMUNE MACROLACTONISATION EXAMPLE :

CH3O

O

HO

CH3

CH3O

O

StBu

CH3 O

O H3CO

O

Hg(OCOCF3)2 CH3CN, 25 oC

O O

H3CO

MECHANISM : Proposed intermediate : CH3OH O HgII C S t Bu

CH3OH or

O C

O O

CF3

DISCONNECTION : O

O RO

R OH

R1

+

HO

R1

NOTES :

In this macrolactonisation the activating effect of the thiol ester is used. A rapid lactonisation occurs when S-tert-butyl thioester of hydroxyl acid reacts with an electrophilic Hg(II)-compound. The mechanism has not been fully clarified. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi

and Yamamoto macrolactonisation reactions.

REFERENCES :

1) S. Masamune; H. Yamamoto; S. Kamata; A. Fukuzawa, J. Am. Chem. Soc., 1975, 97, 3513. 2) S. Masamune; S. Kamata; W. Schilling, J. Am. Chem. Soc., 1975, 97, 3515. 3) T. Kaiho; S. Masamune; T. Toyoda, J. Org. Chem., 1982, 47, 1612.

1145

COMMENTS :

MASCARELLI FLUORENE SYNTHESIS EXAMPLE :

NH2 1) HNO2, 0 oC 2) urea, 70 oC

MECHANISM :

N N CH3

- N2

H

CH2

CH2

CH2

1146

B

DISCONNECTION :

R

R

N N CH3 R1

R1

NOTES :

The synthesis of fluorenes from 2-amino-2’-alkylbiphenyls via diazonium salts. See also Gomberg – Bachmann – Hey, Graebe – Ullmann, Larock fluorene, Pschorr and Ullmann fluorenone reactions.

REFERENCES :

1) L. Mascarelli, Gazz. Chim. Ital., 1936, 66, 843. 2) T. Cohen; J. Lipowitz, J. Am. Chem. Soc., 1964, 86, 2514. 3) I. Puskas; E.K. Fields, J. Org. Chem., 1968, 3, 4237.

COMMENTS :

MATHEWS DRY HYDROLYSIS EXAMPLE :

C N

COOH

O OH OH O

1147

MECHANISM :

H+ NH

H+ O

O

R C N OH OH

O OH

O

R

O O

O

O R

O NH2

O

+

N R

- H2O

O

O O

O R

OH

N H

+

O

DISCONNECTION :

R COOH

R C N

NOTES :

This is a one-pot preparation of carboxylic acids ideally under microwave conditions from their corresponding nitriles or amides by a dry hydrolysis process using phthalic acid or anhydride.

REFERENCES :

1) J.A. Mathews, J. Am. Chem. Soc., 1896, 18, 679. 2) J.A. Mathews, J. Am. Chem. Soc., 1898, 20, 648. 3) W.H. Strain; N.Y. Rochester, U.S. Patent, 1950, 2508418. 4) J.T. Eaton; W.D. Rounds; J.H. Urbanowicz; G.W. Gribble, Tetrahedron Lett., 1988, 29, 6553. 5) W.D. Rounds; J.T. Eaton; J.H. Urbanowicz; G.W. Gribble, Tetrahedron Lett., 1988, 29, 6557. 6) F. Chemat; M. Poux; J. Berlan, J. Chem. Soc., Perkin Trans. 2, 1994, 2597. 7) F. Chemat, Tetrahedron Lett., 2000, 41, 3855. 8) F. Chemat, Tetrahedron Lett., 2002, 43, 5555.

COMMENTS :

1148

MATTESON REACTION EXAMPLE :

CH3 CH2Cl2 1) nBuLi 2)

H3C B O O

OH

Cy

Cy 3) ZnCl2 - 100 oC -> RT 4) CH3MgCl - 78 oC -> RT 5) CH2Br2 6) nBuLi - 78 oC -> RT 7) NaOH, H2O2 0 oC -> RT

MECHANISM :

H Cl

O B

Cl

O

Cl

RLi Cl

O

or

B

B

R

Cl

H

R

R R1

H H R2

R o

R1Li, - 78 C

O R3

O

H

O B

R1

O B

H

ZnCl2

Cl2HCLi

O O

B

O

R

O

H2O2, NaOH

R R1

1) CH3Li 2) AcCl 3) H2NOSO3H, H2O

1) LiCH(OCH3)SPh 2) HgCl2 3) H2O2, pH 8

1149

O

H H R2 R R1

R R1

R3 OH H

H H R2 H H R2

R3 NH2 H R3 CHO H

Cl CH2Cl2

B O

1) nBuLi 2) O B O

O

B O

Cy CH3MgCl Cy

O Cy Cy

Cy Cy

3) ZnCl2

B O

1) CH2Br2 2) nBuLi

O

OH

Cy NaOH, H2O2 Cy

DISCONNECTION : H Cl

O

R1

O

R1

B R

O

R1

O

R1

R B

NOTES :

The use of boronate esters of chiral C2-symmetrical 1,2-diols for the enantioselective synthesis of a variety of chiral compounds using an one carbon-chain extension. The rearrangement after the addition of zinc chloride is high diastereoselective. This suggests that the zinc cation might complex with one of the boronic ester oxygens. See also Duthaler – Hafner, Ibuka – Yamamoto, Roush – Hoffmann – Yamamoto and Thomas reactions.

REFERENCES :

1) D.S. Matteson; D. Majumdar, J. Organomet. Chem., 1979, 170, 259. 2) D.S. Matteson; R.J. Moody, Organometallics, 1982, 1, 20. 3) D.S. Matteson; K.M. Sadhu, Organometallics, 1984, 3, 614. 4) D.S. Matteson; K.M. Sadhu; M.L. Peterson, J. Am. Chem. Soc., 1986, 108, 810. 5) D.S. Matteson, Acc. Chem. Res., 1988, 21, 294. 6) D.S. Matteson, Chem. Rev., 1989, 89, 1535. 7) H.C. Brown; P.V. Ramachandran, Pure Appl. Chem., 1994, 66, 201. 8) E.J. Corey; D. Barnes–Seeman; T.W. Lee, Tetrahedron: Asymmetry, 1997, 8, 3711. 9) D.S. Matteson, Tetrahedron, 1998, 54, 10555. 10) C. Laplante; D.G. Hall, Org. Lett., 2001, 3, 1487.

COMMENTS :

1150

MAURER – DREFAHL SYNTHESIS EXAMPLE :

O OH

N2O4

OH

MECHANISM :

RCH2OH + N2O4

RCH2ONO + HNO3 R

RCH2ONO + HNO2

ONO

+ H2O

NOH R

ONO NOH

R HNO2

ONO O

H2O

RCOOH

DISCONNECTION :

RCOOH RCH2OH RCHO

NOTES :

The oxidation of primary or secondary aliphatic or aromatic alcohols by dinitrogen tetroxide to aldehydes or carboxylic acids. The reaction is of value in carbohydrate chemistry. The dinitrogen tetroxide reacts explosively with glycol and glycerol. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Mukaiyama

oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES :

1) J.C. Cohen; H.J. Calvert, J. Chem. Soc., 1897, 71, 1050. 2) K. Maurer; G. Drefahl, Ber. Dtsch. Chem. Ges., 1942, 75, 1489. 3) du Pont de Nemour & Co., U.S. Patent, 1946, 2455405. 4) A.D. Yoffe; P. Gray, J. Chem. Soc., 1951, 1412. 5) E. Battenberg; A. Berg, Chem. Ber., 1953, 86, 640. 6) W. Langenbeck; M. Richter, Chem. Ber., 1956, 89, 202. 7) J.B. Wilkes; R.G. Wall, J. Org. Chem., 1980, 45, 247.

1151

COMMENTS :

MAYER SYNTHESIS EXAMPLE :

CHO + NH2

Na2CO3 Cu, PhNO2

I

N

MECHANISM :

O CHO

N +

Cl

H

Na2CO3 Cu in PhNO2 - HCl

H2N O

H

H - H2O

N H

N

DISCONNECTION :

CHO + NH2

I

CHO

N

+ Cl

H2N

NOTES : o-Aminobenzaldehyde is condensed with a halogenobenzene in the presence of alkali and copper in nitrobenzene or

naphthalene as a solvent. The diphenylamine-aldehyde, thus formed is cyclised by concentrated sulfuric acid to an

1152

acridine. The diphenylamine-aldehydes may also be prepared from o-halogenobenzaldehydes and aromatic amines preferably o-nitroamines. 1-Amino-antraquinones react also with o-chloro benzaldehydes. See also Kondo – Uyeo and Ullmann diaryl reactions.

REFERENCES :

G. Kalischer; F. Mayer, Ber. Dtsch. Chem. Ges., 1916, 49, 1994.

COMMENTS :

de MAYO REACTION EXAMPLE : O

O +

hν

NO2

NO2

MECHANISM :

R O HO

R R1 R2

R4

hν

R1

O HO

R3

R2

R

R3(4) retro-aldol

R4(3)

O

R2

R1 R4(3) O

DISCONNECTION :

O

R3(4) R2

R

R O R1

O

HO

R4(3)

1153

R3(4)

R3

R1 + R2

R4

NOTES :

The photo-addition of enol derivatives of 1,3-diketones and derivatives to olefins. With 1,3-diketones a retro-aldol type reaction occurs to afford 1,5-diketones.

REFERENCES : Houben – Weyl : 4/5b, 924

1) P. de Mayo; H. Takeshita, Can. J. Chem., 1963, 41, 440. 2) P. de Mayo, Acc. Chem. Res., 1971, 4, 41. 3) W. Oppolzer, Pure Appl. Chem., 1981, 53, 1189. 4) W. Oppolzer, Acc. Chem. Res., 1982, 15, 135. 5) T. Godel; W. Oppolzer, Helv. Chim. Acta, 1984, 67, 1154. 6) B.W. Disanayaka; A.C. Weedon, J. Org. Chem., 1987, 52, 2905. 7) T. Hansson; B. Wickberg, J. Org. Chem., 1992, 57, 5370. 8) T.M. Quevillon; A.C. Weedon, Tetrahedron Lett., 1996, 37, 3939. 9) R.H. Blaauw; J.F. Briere; R. De Jong; J.C.J. Benningshof; A.E. van Ginkel; J. Fraanje; K. Goubitz; H. Schenk; F.P.J.T. Rutjes; H. Hiemstra, J. Org. Chem., 2001, 66, 233.

COMMENTS :

McBRIDE REACTION EXAMPLE :

Cl 1) PCl3, AlCl3, DCM 2) H2O

1154

O P

MECHANISM :

Cl

P

Cl

Cl

P

Cl AlCl4

PCl3 AlCl3

Cl

Cl P

AlCl4

O Cl P H2O

DISCONNECTION :

O R3 R P R4 R1 R2

RPX2 +

R1 R 3 R2

R4

NOTES :

An olefin phosphorylation procedure based on the reaction of electron-rich olefinic double bonds with PCl3, in the presence of AlCl3 via a carbocationic intermediate. See also Zinovev – Soborovski (Clayton – Jensen) reaction.

REFERENCES :

1) E. Jungermann; J.J. McBride; R. Clutter; A. Mais, J. Org. Chem., 1962, 27, 606. 2) J.J. McBride; E. Jungermann; J.V. Killheffer; R.J. Clutter, J. Org. Chem., 1962, 27, 1833. 3) S.E. Cremer; B.C. Trivedi, J. Am. Chem. Soc., 1969, 91, 7200. 4) J. Emsley; T.B. Middleton; J.K. Williams, J. Chem. Soc., Dalton Trans., 1976, 979. 5) A. Marinetti; D. Carmichael, Chem. Rev., 2002, 102, 201.

COMMENTS :

1155

McCLUSKEY FRAGMENTATION EXAMPLE :

O CH3

OPh

N

N O

CH3 Ph

O

CH3 Cl

MECHANISM :

R1

R + N R2

O R3

O

R1

Cl

R N R2

O

R

O N

OR3

R1

+ R2Cl OR3

Cl

DISCONNECTION :

R

H N

R R1 N

R1

R2

NOTES :

The N-dealkylation of tertiary amines under mild conditions using chloroformates. Hydrolysis of the carbamate derivative affords the secondary amines. See also von Braun degradation.

REFERENCES :

1) J.D. Hobson; J.G. McCluskey, J. Chem. Soc. (C), 1967, 2015. 2) T.A. Montzka; J.D. Matiskella; R.A. Partyka, Tetrahedron Lett., 1974, 15, 1325. 3) K.C. Rice, J. Org. Chem., 1975, 40, 1850. 4) J.H. Cooley; E.J. Evain, Synthesis, 1989, 1. 5) G. Kim; M.Y. Chumoyer; S.J. Danishefsky; G.K. Schulte, J. Am. Chem. Soc., 1993, 115, 30.

COMMENTS :

1156

McCORMACK – KUKHTIN – RAMIREZ PHOSPHOLE SYNTHESIS EXAMPLE :

Ph

+ O

Ph

OEt EtO P SiMe3 O

Ph O

O P OEt

Ph

MECHANISM :

R P Cl Cl

R P Cl Cl R P O H Cl

H2O - HCl

R P Cl Cl R

- HCl

P O

DISCONNECTION :

R2

R4 R3 O X P R + R2 X

R3

R1 R

P O

R4

R1

NOTES :

The formation of phospholes from butadienes (McCormack) or of dioxaphospholes from 1,2-diketones (Kukhtin – Ramirez). See also Allen – Millar – Mathey rearrangement.

REFERENCES : Org. Synth. : 43, 31, 73 Org. Synth. Coll. Vol. : 5, 501, 787 Science of Synthesis : 9, 564; 10, 827

1) W.B. McCormack, U.S. Patent, 1953, 2663737. 2) W.B. McCormack, U.S. Patent, 1954, 2671079. 3) V.A. Kukhtin, Dokl. Akad. Nauk. SSSR, 1958, 121, 466. 4) F. Ramirez; R.B. Mitra; N.B. Desai, J. Am. Chem. Soc., 1960, 52, 2651.

1157

5) C. Symmes; L.D. Quin, J. Org. Chem., 1976, 41, 238. 6) M. Sekine; M. Nakajima; T. Hata, J. Org. Chem., 1981, 46, 4030. 7) R. Boukerroub; E. Garriques; G. Manuel, Phosphorus, Sulfur and Silicon, 1995, 105, 101. 8) K. Angermund; A. Eckerle; J. Monkiewicz; C. Kruger; G. Wilke, Inorg. Chim. Acta, 1998, 270, 273. 9) G. Hum; K. Wooler; J. Lee; S.D. Taylor, Can. J. Chem., 2000, 78, 642.

COMMENTS :

McFADYEN – STEVENS REACTION EXAMPLE :

O Ph

Ar

O

S

N N H

H

O

O Na2CO3 ethylene glycol

Ph

H

MECHANISM :

O N S Ar H N O R B O H

R N N H

O

O

O R

- N2

H

R

H

DISCONNECTION : O

O R

R

O

Ar S

N N

H

H

O

H

NOTES :

An acid is converted into a hydrazide, which on treatment with benzene- or p-toluenesulfonyl chloride gives an arylsulfonacylhydrazide. This yields on treatment with sodium carbonate in ethylene glycol an aldehyde. This reaction only works on aromatic aldehydes and aliphatic aldehydes with no α-hydrogen atoms. See also Kalb – Gross and Wuyts reactions.

1158

REFERENCES : March : 448 Smith – March : 534 Houben – Weyl : 7/1, 297; E3, 470; E6a, 986; E6b, 437; E11, 622 Org. React. : 8, 218

1) T. Curtius; H. Melsbach, Ber. Dtsch. Chem. Ges., 1900, 33, 2560. 2) J.S. McFadyen; T.S. Stevens, J. Chem. Soc., 1936, 584. 3) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 4) K.A. Jensen; A. Holm, Acta Chem. Scand., 1961, 15, 1787. 5) C.C. Dudman; P. Grice; C.B. Reese, Tetrahedron Lett., 1980, 15, 4645. 6) R.K. Manna; P. Jaisankar; V.S. Giri, Synth. Commun., 1998, 28, 9. 7) A. Gavalda; J.I. Borrell; J. Teixido; S. Nonell; O. Arad; R. Grau; M.C. Canete; A. Juarranz; A. Villanueva; J.C. Stockert, J. Phorp. Phthalo., 2001, 5, 846. 8) P. Jaisankar; B. Pal; V.S. Giri, Synth. Commun., 2002, 32, 2569.

COMMENTS :

McLAFFERTY REARRANGEMENT EXAMPLE :

H3C CH3 O H3C

OH H3C

CH3

CH2

H3C

CH3

H3C

CH3

+

CH3

MECHANISM :

H

O

OH

O +

hν

1159

H3C

CH2

DISCONNECTION :

R1

OH

O

+ R

H

R1

R

NOTES :

Electron-impact-induced cleavage of carbonyl compounds having a hydrogen in the γ-position, to an enolic fragment and an olefin. See also Norrish type II reaction.

REFERENCES : Smith : 1404 Smith 2nd : 1156 Houben – Weyl : E19a, 71

1) F.W. McLafferty, Anal. Chem., 1959, 31, 82. 2) F.W. McLafferty, J. Chem. Soc., Chem. Commun., 1966, 78. 3) D.G.I. Kingston; J.T. Bursey; M.M. Bursey, Chem. Rev., 1974, 74, 215. 4) F. Tureck; V. Hanus, Org. Mass. Spectrom., 1980, 15, 8. 5) H. Budzikiewicz; P. Bold, Org. Mass Spectrom., 1991, 26, 709. 6) R. Oprean; L. Roman; R. Sandulescu, J. Pharmaceut. Biomed., 1996, 14, 1031. 7) Y.P. Tu; J.L. Holmes, J. Am. Chem. Soc., 2000, 122, 5597. 8) M. Rychlik, Org. Mass. Spectrom., 2001, 36, 555. 9) J. Loos; D. Schröder; H. Schwarz, J. Org. Chem., 2005, 70, 1073.

COMMENTS :

1160

McMURRY OLEFINATION EXAMPLE :

2

O

TiCl3, K

MECHANISM :

R O O

O 2 R

Ti0

R

R O

R R R

R R R

R

Ti O R

O O

Ti

R

O

R

R

O

R

R

Ti R

DISCONNECTION :

R

R1

R

R

R1

R

+

O

R1

R1 O

R R

O

R1

O R1

NOTES :

The formation of olefins by coupling or cross coupling of ketones, mediated by low valent titanium in the presence of e.g. K, LiAlH4. The coupling of enol ethers of 1,3-dicarbonyl compounds is also possible. See also Corey – Kwiatkowski, Eastwood, Fürstner, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig olefination reactions.

REFERENCES : March : 1227 Smith – March : 1561 Smith : 1446

1161

Smith 2nd : 1192, 1247 Org. Synth. : 60, 113; 76, 142 Org. Synth. Coll. Vol. : 7, 1 Science of Synthesis : 9, 220, 502; 10, 382, 2346

1) J.E. McMurry, Acc. Chem. Res., 1974, 7, 281. 2) J.E. McMurry; M.P. Fleming, J. Am. Chem. Soc., 1974, 96, 4708. 3) J.E. McMurry; M.P. Fleming, J. Org. Chem., 1976, 41, 896. 4) R. Dams; M. Malinowski; I. Westdorp; H. Geise, J. Org. Chem., 1982, 47, 248. 5) J.E. McMurry, Chem. Rev., 1989, 89, 1513. 6) B.B. Snider; K. Yang, J. Org. Chem., 1992, 57, 3615. 7) C. Villiers; M. Ephritikhine, Angew. Chem., Int. Ed. Engl., 1997, 36, 2380. 8) M. Ephritikhine, Chem. Commun., 1998, 2549. 9) T. Eguchi; K. Ibaragi; K. Kakinuma, J. Org. Chem., 1998, 63, 2689. 10) A. Fürstner, Trans. Met. Org. Synth., 1998, 1, 381. 11) J.M. Harrowfield; R.J. Hart; C.R. Whitaker, Aust. J. Chem., 2001, 54, 423. 12) Md.J. Uddin; P.N.P. Rao; E.E. Knaus, Synlett, 2004, 1513. 13) P. Rajakumar; V. Murali, Tetrahedron, 2004, 60, 2351. 14) N. Stuhr-Hansen, Tetrahedron Lett., 2005, 46, 5491.

COMMENTS :

McNELIS REARRANGEMENT EXAMPLE :

O OH Br

I

H

H Ph

Ph

OTs I OH

I2, RT CH3CN

1162

Br

Ph

MECHANISM :

O OH Br

I CH3

Ph

Ph

OTs I OH

I

O H

Br Ph

Br

CH3

CH3 Ph

I2, RT CH3CN

DISCONNECTION :

O I

OH

R Br

Br

R

R = H, CH3, Ph

Ph

Ph Br

Br

I

R

HO R

O

R1 R, R1 = H, H; H, CH3; CH3, CH3

R1

NOTES :

The rearrangement of haloethynylcarbinols to β,β-dihaloenones using [hydroxyl(tosyloxy)iodo]benzene (HTIB), molecular iodine or N-iodosuccinimide (NIS). HTIB is employed stoichiometrically with iodine or catalytically with NIS and functions as a Lewis acid, activating iodine and NIS as I+. The reaction is very successful in the ring-expansion of cyclic systems. See also Koser tosylation.

REFERENCES :

1) G.J. Angara; P. Bovonsombat; E. McNelis, Tetrahedron Lett., 1992, 33, 2285. 2) P. Bovonsombat; E. McNelis, Tetrahedron Lett., 1992, 33, 7705. 3) E. Djuardi; E. McNelis, Synth. Commun., 1996, 26, 4091. 4) X. Herault; E. McNelis, Tetrahedron, 1996, 52, 10267. 5) E. Djuardi; E. McNelis, Tetrahedron Lett., 1999, 40, 7193. 6) G.F. Koser, Aldrichimica Acta, 2001, 34, 89.

1163

COMMENTS :

ter MEER REACTION EXAMPLE :

Cl H3C

NO2 NO2

1) KNO2 2) NH2OH, HCl 3) NH3, HCl

H3C

NO2

MECHANISM : NO2

Cl H3C

NO2

KNO2 NH2OH, HCl

H3C

N O

NO2 OH NH3 HCl

DISCONNECTION : NO2 R

Cl

NO2

R

NO2

NOTES :

The gem dinitro derivatives are prepared from chloronitro compounds.

REFERENCES : Org. Synth. : 37, 23 Org. Synth. Coll. Vol. : 4, 372

1) E. ter Meer, Liebigs Ann. Chem., 1876, 181, 1. 2) R.B. Kaplan; H. Shechter, J. Am. Chem. Soc., 1961, 83, 3535. 3) I.V. Shugalei; I.V. Tselinskii, Zh. Obshch. Khim., 1994, 64, 309. 4) I.V. Shugalei; I.V. Tselinskii; E.E. Dubinina, Zh. Obshch. Khim., 1995, 65, 693.

1164

H3C

NO2

COMMENTS :

MEERWEIN – PONNDORF – VERLEY REDUCTION EXAMPLE :

OH

O + Et

CH3

H3C

OH CH3

H

Al(OCHMe2)3

Et

O CH3

+

H

H3 C

CH3

MECHANISM :

(CH3)2CHO

Al(OCHMe2)2 O O H3C CH3 R R1 H

Al(OCHMe2)2 O + R R1 H

O R

OCH(CH3)2 Al R1

O

CH3 CH3

H

OH R R1 H

O

DISCONNECTION :

R H

R OH

O R1

R1

NOTES :

Carbonyl compounds are reduced to alcohols by treatment with aluminium or zirconium alkoxides in the corresponding alcohol, which itself is oxidised. The oxidation product is removed as formed to displace the equilibrium in the required direction. Asymmetric reduction are known, see Evans et al. See also Bouveault – Blanc, Kerp, Noyori hydrogenation, Oppenauer and Tishchenko – Claisen reactions.

REFERENCES : March : 913; 917

1165

Smith – March : 1199 Smith : 472 Smith 2nd : 212, 407, 604 Houben – Weyl : 4/2, 85; 7/1, 186 Org. React. : 2, 178; 6, 207

1) H. Meerwein; R. Schmidt, Liebigs Ann. Chem., 1925, 444, 221. 2) W. Ponndorf, Angew. Chem., 1926, 39, 138. 3) A. Verley, Bull. Soc. Chim. Fr., 1925, 37, 537. 4) N.C. Deno; H.J. Peterson; G.S. Saines, Chem. Rev., 1960, 60, 7. 5) C.G. Screttas; C.T. Cazianis, Tetrahedron, 1978, 34, 933. 6) M. Botta; F. DeAngelis; A. Gamacorta; L. Labbiento; R. Nicoletti, J. Org. Chem., 1985, 50, 1916. 7) E.C. Ashby; J.N. Argyropoulos, J. Org. Chem., 1986, 51, 3593. 8) D.A. Evans; S.G. Nelson; M.R. Gagne; A.R. Muci, J. Am. Chem. Soc., 1993, 115, 9800. 9) T. Ooi; T. Miura; K. Maruoka, Angew. Chem., Int. Ed., 1998, 37, 2347. 10) T. Ooi; K. Takaya; T. Miura; H. Ichikawa; K. Maruoka, Synlett, 2000, 1133. 11) K. Nishide; M. Node, Chirality, 2002, 14, 759. 12) M.A. Aramendía; V. Boreau; C. Jiminénez; J.M. Marinas; J.R. Ruiz; F.J. Urbano, J. Chem. Soc., Perkin Trans. 2, 2002, 1122. 13) Y. Zhu; G. Chuah; S. Jaenicke, Chem. Commun., 2003, 2742. 14) L. Sominsky; E. Rozental; H. Gottlieb; A. Gedanken; S. Hoz; S. Hoz, J. Org. Chem., 2004, 69, 1492.

COMMENTS :

MEERWEIN ARYLATION EXAMPLE :

N N

1) CuCl2 2)

CO2Et

3) CuCl2

1166

CO2Et

MECHANISM :

ArN2+X- + CuX2 H

Ar

+ N2 + CuX + X2

Ar

Ar R

Ar

H EWG

EWG R1

R R1

EWG

R

CuCl2

+ CuCl

R1

DISCONNECTION :

EWG R1

Ar R

EWG

H

R1

R

NOTES :

Diazonium compounds, or nitrosoacylanilides react in acetone solution usually in the presence of a cupric or cuprous catalyst, with compounds containing activated or polarised ethylenic bonds (α,β-unsaturated carbonyl compounds) to yield α-halo-β-arylalkanes. A free-radical pathway is most likely. Certain olefins give products corresponding to the dehydrohalogenated adduct. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulfinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Sandmeyer diazonium, Schwechten and Witt diazotation reactions.

REFERENCES : March : 716 Smith – March : 928 Smith : 1435 Smith 2nd : 1184 Houben – Weyl : 4/2, 134; 5/3, 992; E16a, 1098 Org. React. : 11, 189; 24, 225 Org. Synth. : 51, 1 Org. Synth. Coll. Vol. : 6, 21 Science of Synthesis : 9, 246; 10, 412

1) H. Meerwein; E. Büchner; K. van Emster, J. Prakt. Chem., 1939, 152, 237. 2) W.A. Cowdrey; D.S. Davies, J. Chem. Soc., Quat. Rev., 1952, 6, 365. 3) H. Fritz; G. Rihs; P. Sutter; C.D. Weis, J. Heterocycl. Chem., 1981, 18, 1571. 4) P. Sutter; C.D. Weis, J. Heterocycl. Chem., 1987, 24, 69. 5) A.H. Schmidt; G. Schmitt; H. Diedrich, Synthesis, 1990, 579. 6) H. Brunner; C. Blüchel; M.P. Doyle, J. Organomet. Chem., 1997, 541, 89. 7) G. Wurm; H.-J. Gurka, Pharmazie, 1997, 52, 739.

1167

8) T.B. Patrick; T. Juehne; E. Reeb; D. Hennessy, Tetrahedron Lett., 2001, 42, 3553. 9) S. Milanesi; M. Fagnoni; A. Albini, Chem. Commun., 2003, 216.

COMMENTS :

MEERWEIN METHYLATION EXAMPLE :

OH

OCH3 CH2N2

MECHANISM :

N N CH3

N N CH2 + ROH

OR - N2

CH3OR

DISCONNECTION :

CH3OR

ROH

NOTES :

Diazomethane is of value in the methylation of hydroxyl groups, which are activated by neighbouring groups. Polar compounds act as catalysts in the methylation by diazomethane of non-activated hydroxyl groups. Suitable catalysts are HBF4, ZnCl2, FeCl2, MgCl2, Al(OEt)3, B(OEt)3. See also Claisen carbonate alkylation, Fischer glycosidation, Hakomori, Haworth methylation, Irvine – Purdie, Meerwein methylation, Robertson – Robinson and Williamson

reactions.

REFERENCES : March : 388 Smith – March : 479 Smith 2nd : 544 Houben – Weyl : E8d, 763

1168

Org. Synth. : 41, 9 Org. Synth. Coll. Vol. : 5, 245

1) H. Meerwein; W. Burneleit, Ber. Dtsch. Chem. Ges., 1928, 61, 1840. 2) H. Meerwein; G. Hinz, Liebigs Ann. Chem., 1930, 484, 1. 3) M. Neeman; M.C. Caserio; J.D. Roberts; W.S. Johnson, Tetrahedron, 1959, 6, 36. 4) M.M. Kreevoy; S.J. Thomas, J. Org. Chem., 1977, 42, 3979. 5) J.F. McGarrety; T. Smyth, J. Am. Chem. Soc., 1980, 102, 7303.

COMMENTS :

MEINWALD REACTION EXAMPLE :

OTIPS

O H OTBS

O

OTIPS

O

O H OH CO Et 2 OTBS

EtO LDA, THF - 78 oC

MECHANISM :

Li O

H

O +

O

O

O

H O

O OR1

Li R

OR1

R

1169

H2O

O

O OR1 R

DISCONNECTION :

H O

O

O

O

O

O +

OR1

R

OR1

R

NOTES :

Stabilised anions, such as ester enolates and enolates of phosphononitriles, condense with lactones to afford single addition products.

REFERENCES :

1) A.J. Duggan; M.A. Adams; P.J. Brynes; J. Meinwald, Tetrahedron Lett., 1978, 45, 4323. 2) M.-Y. Ríos; F. Veláquez; H.F. Olivo, Tetrahedron, 2003, 59, 6531.

COMMENTS :

MEINWALD REARRANGEMENT EXAMPLE :

O

H

H PhCO3H

1170

H

MECHANISM :

H

O

O

+

H

RCO3H

H

O

O

1,2-shift H

H

O H O

O

H

H +

1,3-shift

-H

H

DISCONNECTION :

O

H

H R1 R

R R1 R

H R1 O

R1 R2

R

R

R3 R1

O

R2 O

R3

NOTES :

The classic reaction is the peracid oxidation of norbornadiene. Nowadays the name is used for the synthetic route to aldehydes and ketones from epoxides. See also von Baeyer – Villiger and Noyori rearrangements.

REFERENCES : Smith – March : 1398

1) J. Meinwald; S.S. Labana; M.S. Chadha, J. Am. Chem. Soc., 1963, 85, 582. 2) J. Meinwald; S.S. Labana; L.L. Labana; G.H. Wahl, jr., Tetrahedron Lett., 1965, 6, 1789.

1171

3) S. Niwayama; S. Kobayashi; M. Ohno, Tetrahedron Lett., 1988, 29, 6313. 4) S. Niwayama; H. Noguchi; M. Ohno; S. Kobayashi, Tetrahedron Lett., 1993, 34, 665. 5) S. Yokoshima; H. Tokuyama; T. Fukuyama, Angew. Chem., Int. Ed., 2000, 22, 4073. 6) H. Rhee; D. Yoon; M.E. Jung, Nucleosides, Nucleotides, 2000, 19, 619. 7) S. Niwayama; J.X. Liu, Tetrahedron: Asymmetry, 2001, 12, 2537. 8) F.W. Ng; H. Lin; Q. Tan; S.J. Danishefsky, Tetrahedron Lett., 2002, 43, 545. 9) I. Karamé; M.L. Tommasino; M. Lemaire, Tetrahedron Lett., 2003, 44, 7687.

COMMENTS :

MEISENHEIMER – JANOVSKY SYNTHESIS EXAMPLE : OCH3

H3CO O2N

O2 N

OCH3 K

MeOK NO2

NO2

MECHANISM :

Cl O2N

Cl NO2

HO-

O2N

NO2 OH

NO2

NO2

Cl O2N

Cl

OH

O2N

NO2

NO2

OH NO2

NO2

NOTES :

The adduct is formed from a polynitroaromatic compound in alkaline solution with alkoxide or hydroxide (Meisenheimer) or with acetone (Janovsky) by SNAr mechanism. The reaction is also known as the Meisenheimer – Jackson reaction. See also Zimmermann reaction.

1172

REFERENCES : March : 642 Smith – March : 851

1) J.V. Janovsky; L. Erb, Ber. Dtsch. Chem. Ges., 1886, 19, 2155. 2) J. Meisenheimer, Liebigs Ann. Chem., 1902, 323, 205. 3) C.L. Jackson; R.B. Earle, J. Am. Chem. Soc., 1903, 29, 89. 4) M.J. Strauss, Chem. Rev., 1970, 70, 667. 5) S.A. Nabi; S. Haque; P.M. Quereshi, Talanta, 1983, 30, 989. 6) V. Machacek; J. Manova; M. Sedlak; V. Sterba, Coll. Czech. Chem. Commun., 1994, 59, 2262. 7) O.V. Leonova; I.V. Shakhkel’dyan; Y.D. Grudtsyn; Y.M. Atroshchenko; S.S. Gitis; P.V. Chudakov; E.G. Nikiforova; N.N. Alekhina; A.Y. Kaminskii, Russ. J. Org. Chem., 2001, 37, 395. 8) Z. Mucsi; A. Szabó; I. Hermecz; Á. Kucsman; I.G. Csizmadia, J. Am. Chem. Soc., 2005, 127, 7615. 9) S.E. Snyder; J.R. Carey; A.B. Shvets; W.H. Pirkle, J. Org. Chem., 2005, 70, 4073.

COMMENTS :

MEISENHEIMER REARRANGEMENT EXAMPLE :

H3CO H3CO

O N

H3CO Et

CH3

H3C

1173

OCH3 O N Et

MECHANISM :

1,2-sigmatropic rearrangement R1 R N O R

R N OR1 R

2,3-sigmatropic rearrangement

O

R N R

R

O N

R

DISCONNECTION :

R1 R N O R

R N OR1 R

R

O N

O

R N

R

R

NOTES :

The formation of O,N,N-trisubstituted hydroxylamines from tertiary amine oxides via [1,2]-R group migration, or [2,3]sigmatropic rearrangement when R1 = allyl. See also Boekelheide, Mislow – Bravermann – Evans, Sommelet – Hauser and Wittig reactions.

REFERENCES : March : 1102 Smith – March : 1420 Houben – Weyl : E16a, 304

1) J. Meisenheimer, Ber. Dtsch. Chem. Ges., 1919, 52, 1667. 2) J. Meisenheimer, Ber. Dtsch. Chem. Ges., 1926, 59, 1848. 3) W.W. Paudler; D.J. Pokorny, J. Org. Chem., 1971, 36, 1720. 4) R.E. Banks; A.K. Brown; R.N. Haszeldine; A. Kenny; A.E. Tipping, J. Fluorine Chem., 1981, 17, 85. 5) D. Enders; H. Kempen, Synlett, 1994, 969. 6) S.G. Davies; G.D. Smyth, Tetrahedron: Asymmetry, 1996, 7, 1001. 7) J.M. Molina; R. El–Bergmi; J.A. Dobado; D. Portal, J. Org. Chem., 2000, 65, 8574. 8) A. Guarna; E.G. Occhiato; M. Pizzetti; D. Scarpi; S. Sisi; M. van Sterkenburg, Tetrahedron: Asymmetry, 2000, 11, 4227.

1174

9) C.S. Penkett; I.D. Simpson, Tetrahedron Lett., 2001, 42, 3029. 10) E.J. Williams; P.W. Kenny; J.G. Kettle; P.G. Mwashimba, Tetrahedron Lett., 2004, 45, 3693.

COMMENTS :

MENCKE – LASZLO NITRATION OF PHENOLS EXAMPLE :

O

O O2N Clayfen toluene

HO

HO

Clayfen: Fe(NO3)3 . 9 H2O K10 clay, acetone

DISCONNECTION :

OH

OH

NO2

NOTES : Ortho nitration of phenols by metal nitrates (mainly Fe(NO3)3) or alkyl nitrates catalysed by bentonite clay (Clayfen). In

the classic Mencke reaction copper(II) nitrate and acetic acid anhydride was used.

1175

REFERENCES :

1) J.B. Mencke, Recl. Trav. Chim. Pays-Bas, 1925, 44, 141. 2) W. Davey; J.R. Gwilt, J. Chem. Soc., 1950, 204. 3) W. Davey; J.R. Gwilt, J. Chem. Soc., 1950, 3348. 4) A. Cornélis; P. Laszlo; P. Pennetreau, J. Org. Chem., 1983, 48, 4771. 5) P. Laszlo, Pure Appl. Chem., 1990, 63, 2027. 6) T.J. Kwok; K. Jayasuriya; R. Damavarapu; B.W. Brodman, J. Org. Chem., 1994, 59, 4942.

COMMENTS :

MENDIUS REDUCTION EXAMPLE :

CN

NH2 Zn H2SO4, EtOH

MECHANISM :

R

N

N

R [H]

H

H

R

NH2

[H]

DISCONNECTION :

R

NH2

R CN

NOTES :

Nitriles are reduced by in situ prepared hydrogen to primary amines by zinc and alcoholic sulfuric acid. There are many reducing agents for nitriles available, e.g. LiAlH4. See also Ladenburg – Vysnegradskiî reaction.

REFERENCES : March : 918

1176

Smith – March : 1204 Smith : 440 Smith 2nd : 316

O. Mendius, Liebigs Ann. Chem., 1862, 121, 129.

COMMENTS :

MENSCHUTKIN REACTION EXAMPLE :

+ CH3Br N

Br CH3CN

N CH3

DISCONNECTION : R2 R3 N R1 R X

RX +

R3

R2 N

R1

NOTES :

This reaction involves the formation of tetra-alkylammonium halides from alkyl halides and tertiary amines, particularly in relation to solvent effects. See also Hofmann degradation.

REFERENCES : March : 411 Smith – March : 499 Smith : 1142 Smith 2nd : 950 Houben – Weyl : 11/2, 593

1177

1) N. Menschutkin, Z. Physik. Chem., 1890, 5, 589. 2) K.E. Weale, J. Chem. Soc., 1954, 2959. 3) K. Matsumoto; S. Hashimoto; Y. Ikemi; S. Otani, Heterocycles, 1984, 22, 1417. 4) G. Wenz; F. Wolf; M. Wagner; S. Kubrik, New J. Chem., 1993, 17, 729. 5) J.-L.M. Abboud; R. Notario; J. Betran; M. Sola, Prog. Phys. Org. Chem., 1993, 19, 1. 6) H.D. Jenkins; E.J. Kelly; C.J. Samuel, Tetrahedron Lett., 1994, 35, 6543. 7) H. Castejon; K.B. Wiberg, J. Am. Chem. Soc., 1999, 121, 2139. 8) J.H. Markgraf; P.K. Sangani; R.J. Manalasan; S.A. Snyder; R.P. Thummel, J. Chem. Res., 2000, 561. 9) E. Owczarek; W. Kwiatkowski; M. Lemieszewski; A. Mazur; M. Rostkowski; P. Paneth, J. Org. Chem., 2003, 68, 8232. 10) B.W. Purse; A. Gissot; J. Rebek, jr., J. Am. Chem. Soc., 2005, 127, 11222.

COMMENTS :

MENTZER PYRONE SYNTHESIS EXAMPLE : OH

OH + HO

Ph

EtO2C

240 - 250 oC 45 h

O

OH

O

HO

O

Ph

MECHANISM :

OH

O

EtO

Ph

O O

HO

OH

HO

HO

OEt

O

O - EtOH

- H2O HO

Ph

1178

HO

O

Ph

DISCONNECTION : O

R1 R2

O

R1

R3O

R2

R O

+

R

O

NOTES :

Benzopyranone is synthesised from phenols and β-ketoesters or unsaturated acids. This reaction is uncatalysed and it is assumed that the first step is the etherification at high temperature to give the phenoxyacrylic ester. The reaction has been enhanced by the use of microwaves. See also Anschütz hydroxycoumarin, Knoevenagel coumarin, Pauly – Lockemann, Pechmann, Perkin, Simonis and Skraup – Priglinger reactions.

REFERENCES :

1) C. Mentzer; W. Molho; P. Vercier, C.R. Séances Acad. Sci., 1952, 232, 1488. 2) C. Mentzer; D. Pillon, C.R. Séances Acad. Sci., 1952, 234, 444. 3) R.N. Lacey, J. Chem. Soc., 1954, 854.

COMMENTS :

MERLING – von DOERING SYNTHESIS EXAMPLE :

Br2 Br

MECHANISM :

H

H H

H Br2

Br

H Br

H2, Pt

H

Br

1179

DISCONNECTION :

NOTES :

Tropilidene is treated with one equivalent of bromine to give dibromotropilidene, which on distillation in vacuo yields the tropylium ion. Hydrogenation of the tropylium ion will afford cycloheptane.

REFERENCES :

1) G. Merling, Ber. Dtsch. Chem. Ges., 1891, 24, 3108. 2) W. von E. Doering; L.H. Knox, J. Am. Chem. Soc., 1954, 76, 3203.

COMMENTS :

METH–COHN QUINOLINE SYNTHESIS EXAMPLE : CH3 H3C

N H

O

CH3 1) DMF, POCl3 75 oC, 2 h 2) Zn, AcOH 75 oC, 1 h

1180

H3C

N

MECHANISM :

Cl

R R1

N

N

R1 N H

O

N H

N

R

R O

R1

POCl3 - HCl

N H

O

- H+

R

R

R1 N H

- H N

POCl3

O

R1 N

Zn, AcOH - HCl

Cl

R R1 N

DISCONNECTION :

R

R R1

R1 N

N H

Cl

O

NOTES :

Acetanilde is converted under Vilsmeier – Haack – Viehe conditions followed by cyclisation and amine expulsion into 2-quinolone which reacts with POCl3 to give 3-substituted-2-chloro-quinolines, which can be dechlorinated with zinc in acetic acid. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, von Niementowski quinoline, Pfitzinger – Borsche, Riehm quinoline, Skraup quinoline and Vilsmeier – Haack – Viehe

reactions.

REFERENCES :

O. Meth–Cohn; S. Rhouati; B. Tarnowski, Tetrahedron Lett., 1979, 20, 4885.

COMMENTS :

1181

MEYER – HARTMANN SYNTHESIS EXAMPLE :

ArIO + ArIO2

Ar2I+IO3-

-

HO

MECHANISM :

O

I

I

I + IO3

C6H5IO2

KI, H2O I

DISCONNECTION :

Ar2I+I-

ArIO + ArIO2

NOTES :

Aryliodoso compounds react with aryliodoxy compounds in the presence of alkali to yield diaryliodonium iodates.

REFERENCES : Houben – Weyl : E16d, 143 Org. Synth. : 22, 52, 70 Org. Synth. Coll. Vol. : 3, 355, 484

1) C. Hartmann; V. Meyer, Ber. Dtsch. Chem. Ges., 1894, 27, 426. 2) I. Mason; E. Race; F.E. Pounder, J. Chem. Soc., 1935, 1669. 3) R.B. Sandin, Chem. Rev., 1943, 32, 249. 4) A.A. Bothner–By; C.W. Vaughan, jr., J. Am. Chem. Soc., 1952, 74, 4400. 5) F.M. Beringer; M. Drexler; E.M. Gindler; C.C. Lumpkin, J. Am. Chem. Soc., 1953, 75, 2705. 6) N.V. Tsarevsky; V. Slaveykova; S. Manev; D. Lazaroz, J. Chem. Educ., 1997, 74, 734.

1182

COMMENTS :

von MEYER – MOHR SYNTHESIS EXAMPLE : Ph NC

H

Ph

+ H3C

NH2

NC

Ph H

NaOEt

O

H3C

N

Ph

MECHANISM :

NC CH3

NC CH2

NaOEt

R C N

CN

NH NC

R

R

NH2

+

H

R

R H2N CN

R NH2

R

NC

NC - NH3

C N

R

N H

R

NH

N

H+

O NC

H CO2Et

H3C

CH3

NH2

NC

H

H3C

N H

O H+

O NC

NC OH

H3C

O

N H

CH3

- H2O

H3C

N

1183

CH3

OEt CH3 OH

- EtOH

NH2

Ar

H+ NC

H

Ar

NC

Ph H

R

Ar

NC NaOEt

O

R

NH2

N O H

Ph

- H2O

R

N

Ph

O R1 NC

H

R2

NH2

R

R H H2N

CN - H2O

R2

R1

R

NC

CN

R2

R2 NH2 NH

R1

NC - NH3

2

R2

CN N H

R2

DISCONNECTION :

R1 NC R

N

R2

O NC R

NC N

R1

R

H NH2

R2 R1 NC R

CN N H

R

NOTES :

Acetonitrile undergoes a base-catalysed condensation with itself or another nitrile to form a dinitrile. These dinitriles react with a variety of compounds (1,3-diketones, arylideneacetophenones, aldehydes and ketones.) in the presence of acids or bases to yield pyridine derivatives. See also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Guareschi – Thorpe, Hantzsch – Beyer, Petrenko–Kritschenko, Riehm pyridine and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES :

1) E. von Meyer, J. Prakt. Chem., 1895, 52, 81. 2) E. Mohr, J. Prakt. Chem., 1897, 56, 124. 3) E. von Meyer, J. Prakt. Chem., 1908, 78, 497. 4) E. von Meyer, J. Prakt. Chem., 1914, 90, 1.

1184

5) E. Mohr, J. Prakt. Chem., 1914, 90, 509. 6) A. Courts; V. Petrow, J. Chem. Soc., 1952, 334.

COMMENTS :

MEYER – SCHUSTER REARRANGEMENT (RUPE REACTION) EXAMPLE :

Ph Ph

Ph

Ph

Ph

+

H

OH

Ph

O

MECHANISM : Meyer – Schuster :

R1 R2

R1

R1 R

OH

H+

C C C R

R

R2

R2

R2

H2O

R1

O H C C C R1 R H+

O

R2

R H

1185

Rupe :

OH

C

C CH

C

H+, - H2O

CH

C

H+

- H+

H CH2

CH2

CH

CH3

OH

O

H2O

DISCONNECTION :

R1

R1

R R2

R2

O

R OH

NOTES :

The acid-catalysed rearrangement of secondary and tertiary α-acetylenic alcohols to α,β-unsaturated carbonyl compounds. Aldehydes result when the acetylenic group is terminal, ketones when it is internal. The conversion of tertiary alkylacetylenic carbinols with a terminal acetylenic group to predominantly α,β-unsaturated ketones and not the expected aldehydes, is referred to as the Rupe rearrangement.

REFERENCES : March : 330 Smith – March : 423 Houben – Weyl : 4/2, 54; 7/1, 109; E15, 3206, 3345; E19c, 199 Org. Synth. : 29, 1 Org. Synth. Coll. Vol. : 3, 22

1) K.H. Meyer; K. Schuster, Ber. Dtsch. Chem. Ges., 1922, 55, 819. 2) H. Rupe; K. Glenz, Liebigs Ann. Chem., 1924, 436, 195. 3) B. Gredy, Ann. Chim (Paris), 1935, 4, 5. 4) M.S. Newman, J. Am. Chem. Soc., 1953, 75, 4740. 5) J.H. Boyer; M. Saunders, jr., J. Org. Chem., 1961, 26, 1644. 6) S. Swaminathan; K.V. Narayanan, Chem. Rev., 1971, 71, 429. 7) D. Crich; J.Z. Crich, Tetrahedron Lett., 1994, 35, 2469. 8) C.Y. Lorber; J.A. Osborn, Tetrahedron Lett., 1996, 37, 853. 9) X. Herault; E. McNelis, New J. Chem., 1997, 21, 377.

1186

10) A. Chihab–Eddine; A. Daich; A. Jilale; B. Decroix, J. Heterocycl. Chem., 2000, 37, 1543.

COMMENTS :

MEYER ALKYLATION REACTION EXAMPLE :

NaSnOONa + CH3I

alkaline EtOH

CH3SnOONa

DISCONNECTION :

RSnOONa RI RPbOONa

R = alkyl

NOTES :

Preparation of alkylstannonic acids by reacting alkali stannite with an alkyl iodide. When applied to alkali arsenites or plumbites the reaction yields alkylarsonic and alkylplumbonic acids, respectively.

REFERENCES :

1) G. Meyer, Ber. Dtsch. Chem. Ges., 1883, 16, 1439. 2) J.G.F. Druce, J. Chem. Soc., 1918, 113, 715. 3) W.R. Cullen, Adv. Organomet. Chem., 1966, 4, 148.

COMMENTS :

1187

MEYER NITROALKANE REACTION EXAMPLE :

CH3(CH2)7Br + AgNO2

CH3(CH2)7NO2

Et2O

MECHANISM :

NO2

I

+

NO2

Ag - AgI

DISCONNECTION :

RNO2

RX X = Br, I R = mainly primary

NOTES :

Aliphatic nitrites and nitro-compounds are obtained by treating alkyl halides with metallic nitrites. The steric outcome of this reaction depends on substrate and solvent. The transition state is both SN1 and SN2 in character.

REFERENCES : Org. React. : 12, 101 Org. Synth. : 34, 37 Org. Synth. Coll. Vol. : 4, 368

1) V. Meyer; O. Stüber, Ber. Dtsch. Chem. Ges., 1872, 5, 203. 2) R.B. Reynolds; H. Adkins, J. Am. Chem. Soc., 1929, 51, 279. 3) H.B. Hass; E.F. Riley, Chem. Rev., 1943, 32, 373. 4) N. Levy; J.D. Rose, J. Chem. Soc., Quat. Rev., 1947, 1, 358. 5) C.W. Plummer; N.L. Drake, J. Am. Chem. Soc., 1954, 76, 2720. 6) J.K. Stille; E.D. Vessel, J. Org. Chem., 1960, 25, 478. 7) R.C. Kerber; G.W. Urry; N. Kornblum, J. Am. Chem. Soc., 1965, 87, 4520. 8) N. Kornblum; W.J. Jones; D.E. Hardies, J. Am. Chem. Soc., 1966, 88, 1704.

1188

COMMENTS :

MEYER REACTION EXAMPLE : CH3 CH3

HO

H3C 1) Br2 2) HI

CH3 O

MECHANISM :

R1

H3C

R

H O Br Br

- HBr

O

R

R 2 HI - I2 - Br

Br

R1 O

DISCONNECTION : R R R1

R1

O

OH

NOTES :

The addition of bromine on an enolic double bond, followed by treatment with hydrogen iodide will give a ketone. This reaction is used to determine the enol ratio in a keto/enol mixture. It is based on the reaction of only the enol with an alcoholic bromine solution. This can be done by direct titration or indirect titration, see Houben – Weyl for more details.

REFERENCES : Houben – Weyl : 2, 388

1189

1) K.H. Meyer, Liebigs Ann. Chem., 1911, 380, 212. 2) F. Arndt; H. Scholz; E. Frobel, Liebigs Ann. Chem., 1935, 521, 99. 3) H. Mauser; B. Nickel, Chem. Ber., 1964, 97, 1745. 4) S.V. Serves; D.N. Sotiropoulos; P.V. Ioannou; H.B.F. Dixon, Phosphorus Sulfur, 1994, 90, 103.

COMMENTS :

von MEYER PYRIMIDINE SYNTHESIS EXAMPLE :

CH3 H3C

H3C

H3C C N

+ 2

C N

1) Na 2) H2O

H

H2N

N N CH3

MECHANISM :

R1 C N R1

R1 C N

N

Na Na N CH3

C

N

C

C N

N

H+ N

N

N

CH3 NH +

H

1190

N

CH3 NH2

DISCONNECTION :

R R1 H2N

R1

N

R C N

+ 2

C N

H

N R

NOTES :

Aliphatic nitriles in diethyl ether solution react in the presence of sodium to yield the imide of the β-ketonitrile, the reaction proceeds probably via the sodium salt. Under vigorous conditions amino pyrimidines are formed (sodium, 150 0C).

REFERENCES :

1) E. von Meyer, J. Prakt. Chem., 1888, 38, 336. 2) E. von Meyer, J. Prakt. Chem., 1889, 39, 188.

COMMENTS :

MEYERS ALDEHYDE SYNTHESIS EXAMPLE :

CH3 O O H3C N H3C

CH3

1) nBuLi 2) CH3I 3) NaBH4 4) H+

1191

H CH3

MECHANISM :

O

O

O n

N

BuLi

CH2R

H

R1X

H

N

N R1

R

O R

NaBH4

N H R1

O

R

H

R1

R

H

H+

H

DISCONNECTION :

O O

R

H

R1

N

+ R1X CH2R

H O CH2R

+ R1X

N

NOTES :

Synthesis of aldehydes from alkyl halides and α-lithio derivatives of dihydro-1,3-oxazines or 2-oxazolines which are used as carbanionic synthons.

REFERENCES : March : 478 Smith – March : 558 Smith : 916 Smith 2nd : 762 Org. Synth. : 51, 24; 54, 42 Org. Synth. Coll. Vol. : 6, 64, 905

1) A.I. Meyers; A. Nabeya; H.W. Adickes; I.R. Politzer, J. Am. Chem. Soc., 1969, 91, 763. 2) A.I. Meyers; A. Nabeya; H.W. Adickes; J.M. Fitzpatrick; G.R. Malone; I.R. Politzer, J. Am. Chem. Soc., 1969, 91, 764. 3) A.I. Meyers; A. Nabeya; H.W. Adickes; I.R. Politzer; G.R. Malone; A.C. Kovelesky; R.L. Nolen; R.C. Portnoy, J. Org. Chem., 1973, 38, 36.

4) A.I. Meyers; N. Nazarenko, J. Org. Chem., 1973, 38, 175.

1192

5) A.I. Meyers; H. Harre; R. Garland, J. Am. Chem. Soc., 1984, 106, 1146. 6) A.I. Meyers, Tetrahedron, 1992, 48, 2589. 7) B. James; A.I. Meyers, Tetrahedron Lett., 1998, 39, 5301.

COMMENTS :

MICHAEL CONDENSATION EXAMPLE :

Ph

Ph EtO2C

OTBDMS

N

+

N

O

H3CO2C

LDA - 70 oC

CH3

O

H3CO2C

CH3

EtO2C H TBDMSO

MECHANISM :

H EWG

EWG

R

R H

H

EWG R1 EWG' H R R2 R3

R1 EWG'

R2

B

R3

DISCONNECTION :

R H R1 R3

R5 R4 R2

R

R, R1 = EWG R2 or R3 or R4 or R5 = EWG

R1

R2

R4

R3

R5

+

NOTES :

The base-catalysed reaction between an acceptor compound containing an activated double or triple bond and a donor compound containing an active α-hydrogen atom, which results in the apparent addition of the component parts of the donor to the multiple bond of the acceptor. It is believed that the carbanion formed from the donor in alkaline

1193

solution attacks the more positive end of the polarised system of the acceptor yielding an anion which after treatment with water yields the ultimate adduct. Less generally is the base-catalysed addition of a pseudo-acidic ketone, ester, nitrile, nitro-compound or sulfone to the α,β-double bond of a conjugated unsaturated ketone, ester or nitrile. The anionic part of the pseudo-acidic addendum attaches to the β-end of the α,β-double bond. Intramolecular Michael condensations have been effected and cyclic products obtained. In the abnormal Michael reaction rearranged products are produced. The reaction involves an equilibrium and reversal, to give the starting materials or different products, is possible. A proline-catalysed enantioselective Michael addition of ketones to nitrostyrene has been reported by Enders and Seki. Cerium(III) chloride catalyses the Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated ketones. See also d’Angelo, Carroll (Kimel – Cope) rearrangement, Corey – Nicolaou, Diels – Alder, Hajos – Parrish – Eder – Sauer – Wiechert, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nagata, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Robinson, Roush, Ružička large

ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 795 Smith – March : 976, 1022 Smith : 956 Smith 2nd : 98, 522, 623, 636, 649, 676, 689, 794, 838, 1066 Houben – Weyl : 7/1, 96; E5, 425, 1088, 1409, 1516; E8d, 765; E16d, 232 Org. React. : 10, 179; 15, 1; 19, 1; 20, 1; 46, 1; 47, 315 Org. Synth. : 4, 29; 15, 14; 26, 24; 30, 80; 32, 86; 38, 52; 39, 52; 41, 38; 49, 121; 53, 1; 55, 99; 56, 36; 58, 158; 60,

117; 63, 26, 37; 64, 27; 65, 98; 66, 37; 69, 226 Org. Synth. Coll. Vol. : 1, 272; 2, 200; 3, 286; 4, 630, 652, 662, 776; 5, 486, 1135; 6, 31, 648, 666, 940; 7, 50, 363,

368, 414; 8, 87, 219, 444 Science of Synthesis : 9, 195, 306, 312, 454, 472, 492; 10, 136, 167, 556

1) L. Claisen, Liebigs Ann. Chem., 1883, 218, 170. 2) A. Michael, J. Prakt. Chem., 1887, 35, 349. 3) H. Wynberg; H.A.P. de Jongh, Recl. Trav. Chim. Pays-Bas, 1963, 82, 202. 4) G.H. Posner; S.-B. Lu; E. Asirvatham, Tetrahedron Lett., 1986, 27, 659. 5) G.H. Posner; E. Asirvatham, Tetrahedron Lett., 1986, 27, 663. 6) D. Enders; J. Wiedemann; W. Bettray, Synlett, 1995, 369. 7) G. Batoli; M. Bosco; M.C. Bellucci; E. Marcantoni; L. Sambri; E. Torregiani, Eur. J. Org. Chem., 1999, 617. 8) D. Enders; A. Seki, Synlett, 2002, 65. 9) R. Antonioletti; P. Bovicelli; S. Malancona, Tetrahedron, 2002, 58, 589. 10) B. List, Acc. Chem. Res., 2004, 37, 548.

1194

COMMENTS :

MICHAEL GLYCOSIDATION EXAMPLE :

OAc

OAc O

AcO AcO

OAc

Br

O

AcO AcO

basic PhOH aq. acetone

OPh

OAc H

MECHANISM :

OAc

CH2OAc O OAc Br

O AcO AcO

O

AcO OAc OAc

H O

H3C O

AcO AcO

CH2OAc O OPh OAc

OPh O

H O

AcO

H3C

OAc

DISCONNECTION :

R OPh

R Br + PhOH R = carbohydrate

NOTES :

An acetohalogeno-sugar reacts with alkali phenoxide to yield the phenylglycoside. This method of glycoside synthesis was modified by Koenigs and Knorr. See also Fischer glycosidation, Kahne glycosidation and Koenigs – Knorr reactions.

1195

REFERENCES :

1) A. Michael, J. Am. Chem. Soc., 1879, 1, 307. 2) W.J. Hickinbottom, J. Chem. Soc., 1930, 1338.

COMMENTS :

MICHAELIS – BECKER – NYLÉN PHOSPHONYLATION EXAMPLE :

O

OTs O H P OEt OEt

O

OEt O P OEt

O O

Et3N

MECHANISM :

O H P OEt OEt

Et3N

O EtO P OEt

OTs

O O

O - -OTs

OEt O P OEt

O

DISCONNECTION :

OR1 R P OR1 O

R OTs R Hal

NOTES :

The reaction is mainly used for the synthesis of phosphonates from alkyl halogens or tosylates. See also Abramov, Allen, Arbuzov (Michaelis – Arbuzov), Atherton – Openshaw – Todd, Landauer – Rydon and Perkow reactions.

1196

REFERENCES : Houben – Weyl : E7b, 913

1) A. Michaelis; Th. Becker, Ber. Dtsch. Chem. Ges., 1897, 30, 1003. 2) P. Nylén, Ber. Dtsch. Chem. Ges., 1924, 57, 1023. 3) A.K. Bhattacharya; G. Thyagarajan, Chem. Rev., 1981, 81, 415. 4) K.M. Kem; N.V. Nguyen; D.J. Cross, J. Org. Chem., 1981, 46, 5188. 5) T. Kato; M. Tejima; H. Ebiike; K. Achiwa, Chem. Pharm. Bull., 1996, 44, 1132. 6) G.M. Ciszewski; J.A. Jackson, Org. Prep. Proced. Int., 1999, 31, 240. 7) B. Iorga; F. Eymery; D. Carmichael; P. Savignac, Eur. J. Org. Chem., 2000, 3103.

COMMENTS :

MIDLAND REDUCTION EXAMPLE :

OH

O

CH3

CH3 H3C

H3C B

1197

MECHANISM :

O R1

H

B O R1

R B R

B OH

O R R1

R1

H2O2, NaOH R

DISCONNECTION :

O

OH R1

R1 * R

R

NOTES :

Alpine-borane (B-isopinocamphenyl-9-borabicyclo[3.3.1]nonane) reduces ketones asymmetrically. See also Corey – Itsuno – Bakshi – Shibata, Horner – Knowles – Kagan and Noyori hydrogenation.

REFERENCES : March : 915 Smith – March 2nd : 1201 Smith 2nd : 347 Org. Synth. : 63, 57 Org. Synth. Coll. Vol. : 7, 402

1) M.M. Midland; A. Tramontano; S.A. Zederic, J. Am. Chem. Soc., 1979, 101, 2352. 2) H.C. Brown; G.G. Pai; P.K. Jadhav, J. Am. Chem. Soc., 1984, 106, 1531. 3) M.M. Midland, Chem. Rev., 1989, 89, 1553. 4) V.K. Singh, Synthesis, 1992, 605. 5) D.R. Williams; M.G. Fromhold; J.D. Earley, Org. Lett., 2001, 3, 2721. 6) L. Xu; N.P.J. Price, Carbohydr. Res., 2004, 339, 1173.

1198

COMMENTS :

MIESCHER DEGRADATION EXAMPLE :

OH

OH

COOH

1) esterification 2) 2 C6H5MgBr 3) NBS 4) C6H5N(CH3)2 5) CrO3

HO

O

HO

MECHANISM :

OR

OH

Ph

OH

Ph OH

O 2 C6H5MgBr - OR

HO

HO Br

OH

Ph

OH

Ph

Ph

- H2O

NBS HO

OH

HO

Ph

OH

Ph CrO3

C6H5N(CH3)2 - HBr

HO

HO

1199

Ph

O

DISCONNECTION :

R

R1

R1

OR2

R

O

O

NOTES :

A modification of the Barbier – Locquin – Wieland reaction for the degradation of aliphatic acids side chains in which three carbons are eliminated at one time. Using N-bromosuccinimide in allyl bromide it is possible simultaneously to affect the α-bromination, elimination of hydrogen bromide, and the bromination of the diene. See also Barbier – Locquin – Wieland, Gallagher – Hollander, Hoehn – Mason, Krafft and Trost oxidative decarboxylation reactions.

REFERENCES : Smith : 304 Smith 2nd : 267

1) C. Meystre; H. Frey; A. Wettenstein; K. Miescher, Helv. Chim. Acta, 1944, 27, 1815. 2) F.S. Spring, J. Chem. Soc., 1950, 3355.

COMMENTS :

MIGITA – SANO SYNTHESIS EXAMPLE :

CH3 OH + SnnBu3

CH3

O O O

2 CF3COOH DCM

O O O

1200

MECHANISM :

R

R

R X

OH SnnBu3

CF3COOH DCM

X

Y

Y

DISCONNECTION :

R

R X

X

OH + SnnBu3

Y

NOTES :

The proton induced [1,4]-elimination of O-(1-hydroxyalkyl)benzyltributylstannanes.

REFERENCES :

1) T. Kauffmann, Angew. Chem., Int. Ed. Engl., 1982, 21, 410. 2) H. Sano; H. Ohtsuka; T. Migata, J. Am. Chem. Soc., 1988, 110, 2014.

COMMENTS :

1201

Y

MILAS HYDROXYLATION OF OLEFINS EXAMPLE :

cat. OsO4 H2O2

O

O

OH OH

MECHANISM :

R R

R R

R O

OsO4

O

Os O O

OsO2 + H2O2

- OsO2

HO

R OH

OsO4

DISCONNECTION :

R R1

R

R1

H

H

H

H HO OH

NOTES :

The syn hydroxylation of a double bond to a 1,2-diol with hydrogen peroxide and catalytic amounts of OsO4 or V2O5 as catalyst to reoxidise the osmium(4+). Ultraviolet light can also be used. See also Criegee osmium tetroxide, Fenton, Prévost, Sharpless dihydroxylation and Woodward dihydroxylation reactions.

REFERENCES : March : 822 Smith – March : 1048 Smith : 280 Smith 2nd : 248 Org. Synth. : 11, 46 Org. Synth. Coll. Vol. : 2, 302

1) N.A. Milas; S. Sussman, J. Am. Chem. Soc., 1936, 58, 1302.

1202

2) J.F. Eastham; G.B. Miles; G.A. Krauth, J. Am. Chem. Soc., 1959, 81, 3114. 3) F.D. Gunstone, Adv. Org. Chem., 1960, 1, 115. 4) C. Venturello; M. Gambaro, Synthesis, 1989, 295. 5) K. Nomiya; H. Yanagibayashi; C. Nozaki; K. Kondoh; E. Hiramatsu; Y. Shimizu, J. Mol. Catal. A: Chem., 1996, 114, 181.

COMMENTS :

MILLER – PLÖCHL SYNTHESIS EXAMPLE :

Ph

Ph Ph

H

+

O

H3C

CN

N H

Ph N CH3

KOH

MECHANISM :

R

R R2

O

H

R1

CN N

H

R2

H

KOH

H

N R1

HO

N CN R1

H

H R

R R2

- H2O

R2

CN

HO

N CN R1

R2

N R1

- HCN

DISCONNECTION :

R

R2 R

R3

N R1

R3

R2 O

1203

+

R1

N H

R

CN

NOTES :

Pyrrole is obtained by treating a mixture of an α,β-unsaturated aldehyde and an aminoacetonitrile with potassium hydroxide. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Houben – Weyl : E6a, 672

1) W. von Miller; I. Plöchl, Ber. Dtsch. Chem. Ges., 1898, 31, 2699. 2) R.W.L. Clark; A. Lapworth, J. Chem. Soc., 1907, 91, 694. 3) S. Borforβ, Ber. Dtsch. Chem. Ges., 1931, 64, 1111. 4) A. Treibs; R. Derra, Liebigs Ann. Chem., 1954, 589, 176. 5) Japan Patent, 7338705. (Chem. Abs., 1974, 80, 133240.)

COMMENTS :

MILLER – SNYDER ARYL CYANIDE SYNTHESIS EXAMPLE : NOH

CN

NC NO2

NO2 DMSO

1204

OH

MECHANISM :

CN NOH

N

O

O2N

- H+

CN

O N

H

DMSO - NO2

NO2

NO2 NO2 CN

CN +

NO2

OH

DISCONNECTION : NOH

CN

OH

NO2

NOTES :

Benzonitriles are synthesised from aldehydes via oxime ethers. p-Cyanophenol can also be prepared from pnitrobenzaldoxime and p-nitrobenzonitrile (sometimes used as a recyclable chain carrier.)

REFERENCES :

1) R.D. Knudsen; H.R. Snyder, J. Org. Chem., 1974, 39, 3343. 2) M.J. Miller; G.M. Loudon, J. Org. Chem., 1975, 40, 126. 3) R.D. Knudsen; A.G. Morrice; H.R. Snyder, J. Org. Chem., 1975, 40, 2878. 4) H.M.S. Kumar; B.V.S. Reddy; P.T. Reddy; J.S. Yadav, Synthesis, 1999, 586. 5) K.V.N. Srinivas; E.B. Reddy; B. Das, Synlett, 2002, 625.

COMMENTS :

1205

MILLER SYNTHESIS EXAMPLE :

H

BOC N H O

OH H CH3 OH

H

BOC N 1) DEAD, Ph3P 2) H2NOCH2Ph 3) H2, Pd/C 4) TiCl3, pH 4 - 10

H

N O

H

MECHANISM :

R

R1 OH R2

O

R

R3 OH

H2NOCH2Ph O

R1 OH R2 R3 N H

Ph3P CCl4 Et3N - H2O

O

R1 R2 R H2, Pd/C

O N O

R2 R3

R1 R2 R3

R

N

SmI2

OH

O

R1

R

R3 N

O

H

DISCONNECTION :

R1 R2 R

R

R3 N

O

O

H

R1 OH R2 R3 OH

NOTES :

An efficient biomimetic β-lactam synthesis has been developed on the basis of cyclisation of substituted βhydroxyhydroxamic acids. DEAD, Ph3P or Ph3P, CCl4, Et3N mediates the cyclisation. See also Appel, Mitsunobu and Vorbrüggen – Krolikiewicz reactions.

REFERENCES :

1) M.J. Miller; P.G. Mattingly; M.A. Morrison; J.F. Kerwin, jr., J. Am. Chem. Soc., 1980, 102, 7026. 2) M.M. Meloni; M. Taddei, Org. Lett., 2001, 3, 337.

1206

COMMENTS :

MILLS SYNTHESIS EXAMPLE :

NH2

N +

O

N glacial CH3COOH

N

MECHANISM :

NH2 N

O

N +

H

O

H

N

N N O

H

- H2O

N

H

DISCONNECTION :

Ar

N

N

Ar

Ar

NH2

+ Ar

N

O

NOTES :

The reaction between a primary arylamine and an aromatic nitroso compound in glacial acetic acid affords symmetrical or unsymmetrical azo compound. It is assumed that the intermediate is an N-anilinohydroxylamine.

REFERENCES : March : 638 Smith – March : 818

1) C. Mills, J. Chem. Soc., 1895, 67, 925. 2) P. Ruggli; C. Pettijean, Helv. Chim. Acta, 1938, 24, 711.

1207

3) Y. Ogata; Y. Takagi, J. Am. Chem. Soc., 1958, 80, 3591. 4) N.R. Ayyanger; S.N. Nail; K.V. Srinivasan, Tetrahedron Lett., 1989, 30, 7253.

COMMENTS :

MINISCI AROMATIC AMINATION EXAMPLE :

NMe2

H3C N Cl

+

H2SO4, FeSO4

H3C

MECHANISM :

Cl

N

2+

Fe

N

+ Fe3+ + Cl

OCH3

OCH3 +

+

N

N

OCH3

OCH3 N

OCH3

OCH3

+ Fe2+ + H+

+ Fe3+ N

N

1208

DISCONNECTION : NMe2

NOTES :

The iron-catalysed free radical amination of aromatics or free radical carbamylation of protonated heterocycles. The majority of the reactions have been carried out in water or aqueous solutions.

REFERENCES : Houben – Weyl : E5, 1050; E7b, 583; E16d, 655

1) F. Minisci; R. Galli, Tetrahedron Lett., 1965, 6, 433. 2) F. Minisci, Synthesis, 1973, 1. 3) F. Minisci, Top. Curr. Chem., 1976, 62, 1. 4) G. Heinisch; G. Lötsch, Angew. Chem., Int. Ed. Engl., 1985, 24, 692. 5) G. Heinisch; G. Lötsch, Synthesis, 1988, 119. 6) M.A.A. Biyouki; R.A.J. Smith; J.J. Bedford; J.P. Leader, Synth. Commun., 1998, 28, 3817. 7) M.K.-H. Doll., J. Org. Chem., 1999, 64, 1372.

COMMENTS :

MISLOW – BRAVERMAN – EVANS REARRANGEMENT EXAMPLE :

OH

CH3 1) nBuLi, PhSCl 2) LDA, MeI 3) MeOH 4) (MeO)3P

1209

OH

MECHANISM :

OH

O

Ph S

O

n

BuLi, PhSCl

Ph

S

Ph

LDA, MeI

heat

CH3

CH3 S O

CH3 MeOH O

S

Ph

(MeO)3P

OH

DISCONNECTION : R1

R1 R X

Y

R2

R

R2 X,Y = C, N, O, S, Se, P

X

Y

NOTES :

The reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides to allyl sulfenates which are cleaved by phosphites to allylic alcohols.

REFERENCES : March : 1143 Smith – March : 1455 Smith : 746 Smith 2nd : 631 Org. React. : 46, 105

1) D.R. Rayner; E.G. Miller; P. Bickart; A.J. Gordon; K. Mislow, J. Am. Chem. Soc., 1966, 88, 3138. 2) E.G. Miller; D.R. Rayner; K. Mislow, J. Am. Chem. Soc., 1966, 88, 3139. 3) S. Braverman; Y. Stabinsky, J. Chem. Soc., Chem. Commun., 1967, 270. 4) D.A. Evans; G.C. Andrews, Acc. Chem. Res., 1974, 7, 147. 5) J. McMurry, Tetrahedron Lett., 1980, 21, 2477. 6) D.K. Jones–Hertzog; W.L. Jorgensen, J. Org. Chem., 1995, 60, 6682. 7) A.K. Mapp; C.H. Heathcock, J. Org. Chem., 1999, 64, 23. 8) T. Shinada; T. Fuji; Y. Ohtani; Y. Yoshida; Y. Ohfune, Synlett, 2002, 1341.

1210

COMMENTS :

MITSUNOBU REACTION EXAMPLE :

Ts

OH

N

Boc

O Boc S N O H

H3C

EtO2C N N CO2Et PPh3

MECHANISM :

CO2Me

HO

OH

CO2Me Ph3P, DEAD

HO

OH

CO2Me

O PPh3

HO

EtO2C N N CO2Et + R3P

EtO2C N N CO2Et PR3

H EtO2C N N CO2Et PR3

R1

O

O H

OCH3

EtO2C

CO2Et N N

+

H

NH R1 EtO2C N R3P O H O

H

R1

O

O PR3

OCH3

+

H O

O Ph

EtO2C

H

O

O H

O

O OCH3

R1

Ph O

1211

O

Ph

OCH3 O

DISCONNECTION :

OH

X R

R

R1

R1

NOTES :

The inter- and intramolecular nucleophilic displacement of alcohols with inversion (The Mitsunobu inversion) using diethylazodicarboxylate (DEAD)-triphenylphosphine or diisopropylazodicarboxylate (DIAD) – triphenylphosphine and a nucleophile. The Mitsunobu reaction can be used for ester, ether, imide, lactam, C-N, C-S, C-halogen, C-C formation and also for dehydration reactions. The use of a fluorous analogue of DEAD has been reported by Dobbs et al. Fukuyama uses Mitsunobu conditions in the preparation of secondary amines from primary amines. This

reaction is also known under the name Fukuyama – Mitsunobu reaction. Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-

closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Miller, Mukaiyama macrolactonisation1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 396 Smith – March : 486, 502, 513 Smith : 138 Smith 2nd : 110, 495, 505, 1264 Houben – Weyl : E6b, 1122; E16a, 1266; E16c, 390, 443; E16d, 581, 726 Org. React. : 42, 335 Org. Synth. : 73, 110; 76, 178 Org. Synth. Coll. Vol. : 9, 607; 10, 2350 Science of Synthesis : 10, 51, 437

1) O. Mitsunobu; M. Yamada, Bull. Chem. Soc. Jpn., 1967, 40, 2380. 2) O. Mitsunobu, Synthesis, 1981, 1. 3) A. Hassner; W. Dehaen, J. Org. Chem., 1990, 55, 2243. 4) G. Neef; A. Seeger; H. Vierhufe, Synth. Commun., 1993, 23, 931. 5) T. Fukuyama; C-k. Jow; M. Chang, Tetrahedron Lett., 1995, 36, 6373. 6) K.C. Nicolaou; C.N.C. Boddy; S. Natarajan; T.-Y. Yue; H. Li; S. Bräse; J.M. Ramanjulu, J. Am. Chem. Soc., 1997, 119, 3421.

7) M. Pasto; A. Moyano; M.A. Pericas; A. Riera, J. Org. Chem., 1997, 62, 8425. 8) T. Bach; K. Kather; O. Kramer, J. Org. Chem., 1998, 63, 1910. 9) Y. Gao; P. Lane–Bell; J.C. Vederas, J. Org. Chem., 1998, 63, 2133.

1212

10) C. Ahn; R. Correia; P. DeShong, J. Org. Chem., 2002, 67, 1751. 11) M.W. Markowicz; R. Dembinski, Org. Lett., 2002, 4, 3785. 12) A.P. Dobbs; C. McGregor–Johnson, Tetrahedron Lett., 2002, 43, 2807. 13) R. Dembinski, Eur. J. Org. Chem., 2004, 2763. 14) C.A. Olsen; M. Witt; S.H. Hansen; J.W. Jaroszewski; H. Franzyk, Tetrahedron, 2005, 61, 6046.

COMMENTS :

MOEDRITZER – IRANI REACTION EXAMPLE : CH2P(O)(OH)2 N CH2P(O)(OH)2

NH2 NH2

1) H3PO3 2) [CH2O]n

N CH2P(O)(OH)2 CH2P(O)(OH)2

MECHANISM :

H2 H N R O H

R NH2 H O

R

H N H

H OH2

OH P HO OH

H

H R N H HO H H O P OH

R H H N H HO P OH O

DISCONNECTION :

R3-nN[CH2P(O)(OH)2]n

R3-nNHn + n CH2O + n HP(O)(OH)2

1213

NOTES :

This is the one-step Mannich-like synthesis of aminoalkylphosphonates. See also Kabachnik – Fields and Richman – Atkins reactions.

REFERENCES :

1) K. Moedritzer; R.R. Irani, J. Inorg. Nucl. Chem., 1961, 22, 297. 2) K. Moedritzer; R.R. Irani, J. Org. Chem., 1966, 31, 1603. 3) P.B. Iveson; M.P. Lowe; J.C. Lockhart, Polyhedron, 1993, 12, 2313. 4) T. Bailly; R. Burgada, Phosphorus Sulfur, 1995, 101, 131. 5) R.W. Alder; C. Ganter; M. Gil; R. Gleiter; C.J. Harris; S.E. Harris; H. Lange; A.G. Orpen; P.N. Taylor, J. Chem. Soc., Perkin Trans.1, 1998, 1643.

6) J.L.W. Griffin; P.V. Coveney; A. Whiting; R. Davey, J. Chem. Soc., Perkin Trans. 2, 1999, 1973. 7) P.V. Coveney; R. Davey; J.L.W. Griffin; Y. He; J.D. Hamelin; S. Stackhouse; A. Whiting, J. Am. Chem. Soc., 2000, 122, 11557.

COMMENTS :

MONTEVECCHI INDOLE SYNTHESIS EXAMPLE :

NH2

PhSSPh AIBN, 150 oC

1214

N H

MECHANISM :

NH2

PhSH

PhS

N H

NH

N H

DISCONNECTION :

Pr Pr N H

NH2

NOTES :

1-(2-Aminophenyl)pent-1-yne can be cyclised to a 2-substituted indole by diphenyldisulfide. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

P.C. Montevecchi; M.L. Navacchia, Tetrahedron Lett., 1998, 39, 9077.

COMMENTS :

1215

MORI – BAN INDOLE SYNTHESIS EXAMPLE :

CO2Me

CO2Me

Br Pd(OAc)2, Ph3P NaHCO3, DMF, 130 oC

N Ac

N Ac

MECHANISM :

O AcO Pd OAc

AcO

OAc Ph3P Pd

O PPh3

PPh3 O O O PPh3

Pd0 + AcO

PPh3O +

CO2CH3

Br Pd

Br Pd0

N Ac

CO2CH3

CO2CH3

PdBr H

O

N Ac

CO2CH3

N Ac

O

NaHCO3

N Ac

DISCONNECTION :

R1

R1 Br N R

N R

R1 = electron withdrawing group

1216

NOTES :

The mechanism for the Mori – Ban indole formation is representative of many palladium-catalysed pyrrole annulation processes. The palladium atom can affect the cyclisation of the o-halo-N-allyl anilines to indoles under Fujiwara – Heck conditions. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe

heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) M. Mori; K. Chiba; Y. Ban, Tetrahedron Lett., 1977, 12, 1037. 2) Y. Ban; T. Wakamatsu; M. Mori, Heterocycles, 1977, 6, 1711. 3) J.J. Li, J. Org. Chem., 1999, 64, 8425. 4) S.M. Sparks; K.J. Shea, Tetrahedron Lett., 2000, 41, 6721.

COMMENTS :

MORIN REARRANGEMENT EXAMPLE :

Ph

Ph

O

O H H

O N H

N O

O S CH3 CH3 CO2CH3

HH

O N p-TsOH xylene heat

1217

H

N O

S CH3 CO2CH3

MECHANISM :

H

OH S

O S

N

N

N N

O

N N

TFA-CHCl3 (1:10) heat

O

O

O N

N

H N O Cbz

H N O Cbz

S N

S N

N N

N N

O - H+

O

O

O

N

N

H N O Cbz

H N O Cbz

DISCONNECTION :

O

S H3C

S N

N

NOTES :

The rearrangement of heterocyclic sulfoxides via an olefinic sulfenic acid, addition of this acid to an olefin affords after loss of a proton a sulfide. The reaction is mainly used for the ring-expansion of penams to cephems.

REFERENCES :

1) R.B. Morin; B.G. Jackson; R.A. Mueller; E.R. Lavagnino; W.B. Scanlon; S.L. Andrews, J. Am. Chem. Soc., 1963, 85, 1896.

2) R.B. Morin; B.G. Jackson; R.A. Mueller; E.R. Lavagnino; W.B. Scanlon; S.L. Andrews, J. Am. Chem. Soc., 1969, 91, 1401.

3) W.J. Gottstein; P.F. Misco; L.C. Cheney, J. Org. Chem., 1972, 37, 2765. 4) P.G. Sammer, Chem. Rev., 1976, 76, 113. 5) C. Enebaeck, Finn. Chem. Lett., 1982, 19.

1218

6) H.D. Mah; W.S. Lee, J. Heterocycl. Chem., 1989, 26, 1447. 7) V. Farina; J. Kant, Synlett, 1994, 565. 8) D.J. Hart; N.A. Magomedov, J. Org. Chem., 1999, 64, 2990. 9) J.D. Freed; D.J. Hart; N.A. Magomedov, J. Org. Chem., 2001, 66, 839.

COMMENTS :

MOUREAU – MIGNONAC REACTION EXAMPLE :

H3C

CH3

H3C + NH3

O

H2, Raney Ni 15 - 20 oC

CH3 NH2

MECHANISM :

H3C

CH3

OH +

H2N R

H3C

O H3C

H3C

CH3 Raney Ni H2

N R

H

R

N CH3 H

- H2O

CH3 N

R

DISCONNECTION :

R R2

R1 N

R3

R R1,R2, R3 = H, Alk

1219

R1 O

+

R2

H N

R3

NOTES :

Aldehydes and ketones are converted into amines by catalytic hydrogenation in ethanol containing one mole of ammonia or an amine (reductive alkylation). Also possible is the catalytic oxidation of aliphatic alcohols into aldehydes or ketones by heating in a stream of oxygen in the presence of nickel or silver. See also Adkins – Peterson, Eschweiler – Clarke, and Leuckart – Wallach reactions.

REFERENCES : March : 898 Smith – March : 1187 Houben – Weyl : 4/2, 51 Org. Synth. : 23, 68; 27, 28 Org. Synth. Coll. Vol. : 3, 328, 717

1) C. Moureau; G. Mignonac, Bull. Soc. Chim. Fr., 1921, 88. 2) C. Moureau; P. Chovin; M. Brunet, Bull. Soc. Chim. Fr., 1948, 96. 3) A. Lebris; G. Lefebvre; F. Coussemant, Bull. Soc. Chim. Fr., 1964, 1366. 4) A. Lebris; G. Lefebvre; F. Coussemant, Bull. Soc. Chim. Fr., 1964, 1584.

COMMENTS :

MOUSSERON – FRAISSE – McCOY CYCLOPROPANATION EXAMPLE : O

H CH3

CH3

+

H3C

Cl

H3C H3CO

OCH3 NaH

O

1220

O

CH3 OCH3 O

MECHANISM :

X

X

OR

H3C

base

O

H

OR

H3C O

O OR1

H X

H3C R1O O

H3C H3CO

O

H CH3 OR

CH3 OCH3

-X O

O

DISCONNECTION :

R R1

X

R2

CH3

+

R2

CH3 R = CH3, Ph, Cl R1, R2 = COOCH3, CN, X = Cl, Br, I

H

R1 R

O Ph

NOTES :

The stereoselective preparation of substituted cyclopropanes by Michael addition. See also Charette, Freund, Gustavson, Hass cyclopropane, Ipatiew, Nerdel and Simmons – Smith reactions.

REFERENCES :

1) R. Fraisse; R. Jacquier, Bull. Soc. Chim. Fr., 1957, 986. 2) L.L. McCoy, J. Am. Chem. Soc., 1958, 80, 6568. 3) M. Mousseron; R. Fraisse; R. Jacquier; G. Bonavent, C.R. Séances Acad. Sci., 1959, 248, 1465. 4) D.T. Warner, J. Org. Chem., 1959, 24, 1536. 5) S. Wawzonek; C.E. Morreal, J. Am. Chem. Soc., 1960, 82, 439. 6) L.L. McCoy, J. Org. Chem., 1960, 25, 2078.

COMMENTS :

1221

MOZINGO DESULFURISATION EXAMPLE :

S H2, Raney Ni EtOH, reflux

CH3

2

DISCONNECTION :

R1 H +

R H

R

S

R1

NOTES :

Hydrogenolysis and desulfurisation is affected by treatment with Raney nickel, which normally contains hydrogen in a suitable solvent.

REFERENCES : March : 728 Smith – March : 940 Org. Synth. : 21, 15; 35, 80; 56, 15, 72 Org. Synth. Coll. Vol. : 3, 181; 4, 638; 6, 581, 601

1) R. Mozingo; D.E. Wolf; S.A. Harris; K. Folkers, J. Am. Chem. Soc., 1943, 65, 1013. 2) H.R. Bollinger; D.A. Prins, Helv. Chim. Acta, 1946, 29, 1061. 3) J. Schut; J.B.F.N. Engberts; H. Wynberg, Synth. Commun., 1972, 2, 415. 4) Y. Kikugawa, J. Chem. Soc., Perkin Trans. 1, 1984, 609.

COMMENTS :

1222

MUKAIYAMA – YAMADA EPOXIDATION EXAMPLE :

O2, Ni(acac)2

O

CHO

MECHANISM :

R

CO2

O

O OH

NiIIIOH

R

O2

ROO

H

R

ROOH

products

O R

O R

OOH

O

NiII

O

O

R

O2

R

O

OO

H2O Propagation

Initiation

Termination

DISCONNECTION :

R

O

R2

R1 R3

R

R2

R1

R3

NOTES :

Although more than stoichiometric amounts of the co-reacting aldehyde are needed, this reaction is very mild, done at room temperature and often display epoxide selectivities up to 100%. The reaction is complete within a few hours. The epoxidising species is the acylperoxy radical. For a detailed study on the mechanism see the work of Wentzel et al. See also Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Prileschajew, Shi and Weitz – Scheffer reactions.

REFERENCES :

1) T. Yamada; T. Takai; O. Rhode; T. Mukaiyama, Bull. Chem. Soc. Jpn., 1991, 64, 2109. 2) T. Takai; E. Hata; T. Yamada; T. Mukaiyama, Bull. Chem. Soc. Jpn., 1991, 64, 2513. 3) T. Nagata; K. Imagawa; T. Yamada; T. Mukaiyama, Bull. Chem. Soc. Jpn., 1995, 68, 3241. 4) T. Mukaiyama, Aldrichimica Acta, 1996, 29, 59. 5) W. Nam; H.J. Kim; S.H. Kim; R.Y.N. Ho; J.S. Valentine, Inorg. Chem., 1996, 35, 1045.

1223

6) N. Mizuno; H. Weiner; R.G. Finke, J. Mol. Catal. A: Chem., 1996, 114, 15. 7) B.B. Wentzel; P.A. Gosling; M.C. Feiters; R.J.M. Nolte, J. Chem. Soc., Dalton Trans., 1998, 2241. 8) B.B. Wentzel; P.L. Alsters; M.C. Feiters; R.J.M. Nolte, J. Org. Chem., 2004, 69, 3453.

COMMENTS :

MUKAIYAMA MACROLACTONISATION -1 EXAMPLE :

O

O Ph

OH

+ BnOH

Ph

OBn

1 mol% TiCl4, 2 AgClO4 0.5 TMSCl F3C

CO O 2

MECHANISM :

O

O

O OH OH

O

O (p-CF3C6H4CO)2O

O

O CF3

DISCONNECTION :

O R

RCOOH + R1OH

OR1

1224

NOTES :

A method for the preparation of carboxylic esters from free carboxylic acids and alcohols by combined use of p(trifluoromethyl)benzoic anhydride and a catalytic amount a titanium(IV) salt together with chlorotrimethylsilane. The method is very suitable for the preparation of cyclic lactone from ω-hydroxy carboxylic acids. In later versions of this reaction medium-sized ring lactones are prepared by treating monomeric cyclic silylcarboxylates prepared in situ from ω-hydroxy carboxylic acids and 1,2-bisdimethylsilylbenzene using RhCl(PPh3)3 and Me2Si(OTf)2 as catalyst. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation

reactions.

REFERENCES :

1) I. Shiina; M. Miyoshi; M. Miyashita; T. Mukaiyama, Chem. Lett., 1994, 515. 2) I. Shiina; T. Mukaiyama, Chem. Lett., 1994, 677. 3) T. Mukaiyama; J. Izumi; I. Shiina, Chem. Lett., 1997, 187.

COMMENTS :

1225

MUKAIYAMA MACROLACTONISATION - 2 EXAMPLE :

CH3

CH3 H3C

H3C

CH3

EtO2C

OTBS

CH3

O

1) NaOH, EtOH, tartaric acid 2) DMAP, Et3N

Ph

OTBS O

N

O

Ac N I CH3

Cl Ph Ac

OH

N O

MECHANISM :

O H O

O O

O

O Br

Br

O

O

NBu3

N Et

N Et

OH

O N Et BF4

BF4

BF4

O O

O

N Et

O O

O O

BF4

DISCONNECTION : O R

RCOOH + R1OH

OR1

1226

+

HO

N Et BF4

NOTES :

The Mukaiyama reagent is used for the macrolactonisation of carboxylic acids and alcohols. Amides can also be formed using this reagent. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi

and Yamamoto macrolactonisation reactions.

REFERENCES :

1) T. Mukaiyama; M. Usui; E. Shimada; K. Saigo, Chem. Lett., 1975, 1045. 2) K. Hojo; S. Kobayashi; K. Soai; T. Mukaiyama, Chem. Lett., 1977, 635. 3) T. Mukaiyama, Angew. Chem., Int. Ed. Engl., 1979, 18, 707. 4) K.C. Nicolaou; M.E. Bunnage; K. Koide, J. Am. Chem. Soc., 1994, 116, 8402. 5) J.J. Folmer; C. Acero; D.L. Thai; H. Rapoport, J. Org. Chem., 1998, 63, 8170.

COMMENTS :

MUKAIYAMA OXIDATION EXAMPLE :

HO

1) PrMgBr THF 2) N

O O N

N

N O

1227

MECHANISM :

R

R H

OH

H

RMgBr

R

OMgBr O

R1

R1

N

R1 O

N

N

N O

DISCONNECTION :

R

R

R1

H

O

OH R1

NOTES :

The oxidation of alcohols using a Grignard reagent and 1,1’-(azodicarbonyl)dipiperidine. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES :

1) K. Narasaka; A. Morikawa; K. Saigo; T. Mukaiyama, Bull. Chem. Soc. Jpn., 1977, 50, 2773. 2) A.I. Meyers; D.L. Comins; D.M. Roland; R. Henning; K. Shimizu, J. Am. Chem. Soc., 1979, 101, 7104.

COMMENTS :

1228

MUKAIYAMA REACTION EXAMPLE :

EtS

OTMS CH3

OH + PhCHO Sn(OTf)2, 20 mol % EtCN, - 78 oC

N

O

Ph

SEt CH3

H

N CH3

MECHANISM :

O Si(CH3)3 R1

OTMS

R2

R3

R4

+

Cl

R5 TiCl4

O

R4

TiCl3 O R5

Cl Cl

Cl

Ti O

- TMSCl

R4 R5

R1

OH

O R3

H2O

R2

1229

R4 R5

R1

O R3 R2

O

OTMS

EtS

R

TMSOTf

Sn(OTf)2

O

OSn(OTf)L

EtS

L Sn(OTf)2L

R TMSOTf

O R

O

H R

H

O R

Sn(OTf)L

SEt

OTf

OTMS

Sn(OTf)2L H

DISCONNECTION :

OH R4 R5

R1

O

R1

OTMS +

R3

R2

R2

R3

R4

R5 O

NOTES :

Silyl enol ethers are not nucleophilic enough to undergo aldol reactions with aldehydes and ketones. However, if a Lewis acid is present which can complex to the aldehyde or ketone carbonyl, then the silyl enol ether can add in an aldol fashion or by addition of fluoride ion the silyl enol ether can add. The stereoselective aldol condensation is based on tin triflate and a chiral alkaloid. The method works best with thioester-derived silyl enol ethers. The addition of Bu3SNF or Bu3Sn(OAc)2 is in most cases crucial for asymmetric induction. This reaction is sometimes called a Mukaiyama – Michael reaction. Solvent-free reactions have been reported.

1230

REFERENCES : March : 937 Smith – March : 1223 Smith : 908 Smith 2nd : 755, 775, 1132 Houben – Weyl : E16c, 390, 443 Org. React. : 28, 203, 46, 1 Org. Synth. : 65, 6 Org. Synth. Coll. Vol. : 8, 323 Science of Synthesis : 1, 992; 9, 477

1) T. Mukaiyama; K. Inomata; M. Muraki, J. Am. Chem. Soc., 1973, 95, 967. 2) T. Mukaiyama; K. Banno; K. Narasaka, J. Am. Chem. Soc., 1974, 96, 7503. 3) T. Mukaiyama; R.W. Stevens; N. Isasawa, Chem. Lett., 1982, 353. 4) T. Yura; N. Iwasawa; T. Mukaiyama, Chem. Lett., 1986, 187. 5) S. Kobayashi; S. Suda; M. Yamada; T. Mukaiyama, Chem. Lett., 1994, 97. 6) T. Mukaiyama, Aldrichimica Acta, 1996, 29, 59. 7) J.T. Kuetke; D.L. Comins, Org. Lett., 1999, 1, 1031. 8) D.A. Evans; K.A. Scheidt; J.N. Johnston; M.C. Willis, J. Am. Chem. Soc., 2001, 123, 4480. 9) I.L. Clézio; J.-M. Escudier; A. Vigroux, Org. Lett., 2003, 5, 161. 10) M.R. Acocella; A. Massa; L. Palombi; R. Villano; A. Scettri, Tetrahedron Lett., 2005, 46, 6141.

COMMENTS :

MÜLLER–CUNRADI CONDENSATION EXAMPLE :

CH3 EtO

+ 3

EtO

OEt EtO

OEt

OEt

1231

MECHANISM :

R

RCH(OCH3)2

OCH3

BF3

OCH3

- H3CO BF3 H

H3CO H

OCH3 +

R

H3CO BF3

OCH3

- BF3

OCH3

R OCH3

H CH3COOH - CH3OH

R

O

DISCONNECTION :

R

OCH3 R H OCH3

H O

NOTES :

The formation of a vinylaldehyde starting with an acetal that will be transformed to an acetal with an extra two carbon atoms.

REFERENCES : Houben – Weyl : 6/3, 289; 7/1, 116

M. Müller–Cunradi; K. Pieroh, U.S. Patent, 1936, 2165962.

COMMENTS :

1232

MÜLLER – ROCHOW SYNTHESIS EXAMPLE :

Si + 2 CH3Cl

(CH3)2SiCl2

Ag, 285 oC

DISCONNECTION :

R2SiX2

2 RX + Si

NOTES :

Alkyl- or aryl halides react in the liquid or vapour phase at about 300 oC with silicon preferably in the presence of a metallic catalyst (silver). The reaction takes place at the surface of the silicon.

REFERENCES :

1) E.G. Rochow, J. Am. Chem. Soc., 1945, 67, 963. 2) E.G. Rochow; W.F. Gilliam, J. Am. Chem. Soc., 1945, 67, 1772. 3) W. Kalchauer; B. Pachaly; G. Geisberger; L. Rosch, Z. Anorg. Allg. Chem., 1992, 618, 148. 4) H. Fichtner; M. Selenina; W. Walkow; R. Zimmermann; H. Lieske, Chemie, Ingenieur; Technik, 1993, 65, 86. 5) C.Y. Lee; J.S. Han; H.S. Oh; B.R. Yoo; I.N. Jung, Bull. Korean Chem. Soc., 2000, 21, 1020.

COMMENTS :

1233

MURAHASHI ALLYLIC ALKYLATION EXAMPLE :

CH3

CH3

OH

CH3Li, CuI

CH3

CH3 I N Bu3P Ph

MECHANISM :

CH3

CH3

CH3

OH

CH3Li, CuI CH3 N Bu3P Ph

OPBu3 CH3 Cu N CH3 Ph

DISCONNECTION :

R OH + R1Li

R R1

NOTES :

The allylic alkylation of allyl alcohols in the presence of copper iodide and phosphinimines.

REFERENCES :

1) Y. Tanigawa; H. Kanamara; A. Sonoda; S. Murahashi, J. Am. Chem. Soc., 1977, 99, 2361. 2) H.L. Goering; S.S. Kantner, J. Org. Chem., 1981, 46, 2144. 3) H.L. Goering; C.C. Tseng, J. Org. Chem., 1985, 50, 1597. 4) C.L. Fan; B. Cazes, Tetrahedron Lett., 1988, 29, 1701.

1234

CH3

COMMENTS :

MURAHASHI CROSS-COUPLING REACTION EXAMPLE :

Br

CH3 + CH3Li

5 mol % Pd(PPh3)4 benzene, reflux

MECHANISM :

Ph

Ph Pd(PPh2CH3)4

Br

CH3

Ph

Ph

Pd(PPh2CH3)2 Br

Pd CH3

Ph

CH3Li Pd(PPh2CH3)2 CH3

1235

LiBr

DISCONNECTION :

R

R

R1

Br + R1Li

NOTES :

The palladium cross-coupling using organolithium compounds. Nickel does not work well with organolithium compounds. Vinyl halides undergo the cross-coupling with organolithium compounds stereoselectively. The rate of the addition of the organolithium compound is crucial. Fast addition will produce α-bromoalkenyl lithium species which will rearrange in a Fritsch – Butenberg – Wiechell fashion. See also Fritsch – Butenberg – Wiechell and Kumada – Tamao – Corriu cross – coupling reactions.

REFERENCES : Org. Synth. : 62, 39 Org. Synth. Coll. Vol. : 7, 172

1) S.-I. Murahashi; Y. Tanba; M. Yamamura; I. Moritani, Tetrahedron Lett., 1974, 15, 3749. 2) M. Yamamura; I. Moritani; S.-I. Murahashi, J. Organomet. Chem., 1975, 91, C39. 3) M. Yamamura; I. Moritani; S.-I. Murahashi, J. Org. Chem., 1978, 43, 4099. 4) S.-I. Murahashi; M. Yamamura; K.-I. Yanagisawa; N. Mita; K. Kondo, J. Org. Chem., 1979, 44, 2408. 5) M.K. Loar; J.K. Stille, J. Am. Chem. Soc., 1981, 103, 4174. 6) E-i. Negishi; T. Takahashi; K. Akiyoshi, J. Chem. Soc., Chem. Commun., 1986, 1338. 7) C. Amatore; M. Azzabi; A. Jutland, J. Am. Chem. Soc., 1991, 113, 8375. 8) C. Amatore; A. Jutland; A. Suarez, J. Am. Chem. Soc., 1993, 115, 9531.

COMMENTS :

1236

MURAI C-C BOND FORMATION EXAMPLE :

CH3 O

CH3 O CH3

+

CH3

Si(OEt)2

RuH2(CO)(PPh3)3 reflux, toluene

Si(OEt)2

MECHANISM :

O CH3

CH3 O

[Ru]

Y

Y

CH3

RuH2(CO)(PPh3)3

O [Ru]

[Ru] O Y CH3

Y

CH3

H

[Ru] O

O

CH3

CH3

O [Ru] H

DISCONNECTION :

R

Si(R1)2

RH R = Ar

1237

[Ru]

NOTES :

A catalytic carbon-carbon bond formation following C-H activation of an aromatic ketone, olefin, aromatic ester or imine. It is proposed that the regioselectivity for the activation α to the ketone on the aromatic ring arises from coordination of the carbonyl to the ruthenium.

REFERENCES : Org. Synth. : 80, 104

1) S. Murai; F. Kakiuchi; S. Sekine; Y. Tanaka; A. Kamatani; M. Sonoda; N. Chatani, Nature, 1993, 366, 529. 2) S. Murai; F. Kakiuchi; S. Sekine; Y. Tanaka; A. Kamatani; M. Sonoda; N. Chatani, Pure Appl. Chem., 1994, 66, 1527. 3) S. Murai; N. Chatani; F. Kakiuchi, Pure Appl. Chem., 1997, 69, 589. 4) T. Matsubara; N. Koga; D.G. Musaev; K. Morokuma, J. Am. Chem. Soc., 1998, 120, 12692. 5) T. Matsubara; N. Koga; D.G. Musaev; K. Morokuma, Organometallics, 2000, 19, 2318. 6) S. Busch; W. Leitner, Adv. Synth. Catal., 2001, 343, 192. 7) R.F.R. Jazzar; M.F. Mahon; M.K. Whittlesey, Organometallics, 2001, 20, 3745. 8) Y. Guari; A. Castellanos; S. Sabo–Etienne; B. Chaudret, J. Mol. Catal. A: Chem., 2004, 212, 77.

COMMENTS :

MURAI COUPLING EXAMPLE :

O

O

1) LiHMDS, THF, HMPA 2) PhN(SO2CF3)2 3) Me2CuLi

1238

O

CH3

MECHANISM :

O

O

1) LiHMDS, THF, HMPA 2) PhN(SO2CF3)2

O

OTf

Me2CuLi

O

CH3

DISCONNECTION :

O

O

R

O

NOTES :

Lactone enolates are treated with N-phenyl triflimide in the presence of THF and HMPA to afford the corresponding enol triflate which on reaction with lithium dialkylcuprates give rise to alkylated cyclic ethers.

REFERENCES :

1) J.E. McMurry; W.J. Scott, Tetrahedron Lett., 1980, 21, 4313. 2) W.J. Scott; J.E. McMurry, Acc. Chem. Res., 1988, 21, 47. 3) K. Tsushima; K. Araki; A. Murai, Chem. Lett., 1989, 1313. 4) K. Tsushima; A. Murai, Chem. Lett., 1990, 761. 5) K. Tsushima; A. Murai, Tetrahedron Lett., 1992, 33, 4345. 6) F. Fei; A. Murai, Synlett, 1995, 863.

COMMENTS :

1239

MURAI REARRANGEMENT EXAMPLE :

Ts N

Ts

N

PtCl2 O

O

MECHANISM :

X

X M M

X

X M

X

X

M

M

M

X

X M

X

1240

DISCONNECTION :

X

X

X

X

SiMe3 X

X + R1OH OR1

R

R

X

X R

R X

X

NOTES :

These are 4 different types of cycloisomerisation reactions of enynes catalysed by PtCl2. All these reaction share a common mechanism comprising a cationic manifold triggered by the π-complexation of the Pt(II) onto the alkyne unit of the substrates. Fürstner et al. added an additional two cycloisomerisations processes. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt

macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES :

1) N. Chatani; N. Furukawa; H. Sakurai; S. Murai, Organometallics, 1996, 15, 901. 2) A. Fürstner; H. Szillat; B. Gabor; R. Mynott, J. Am. Chem. Soc., 1998, 120, 8305. 3) A. Fürstner; H. Szillat; F. Stelzer, J. Am. Chem. Soc., 2000, 122, 6785. 4) A. Fürstner; F. Stelzer; H. Szillat, J. Am. Chem. Soc., 2001, 123, 11863.

1241

COMMENTS :

MURPHY INDOLE SYNTHESIS EXAMPLE :

N

N

BF4

Ph

SO2CH3

N Br

CH3

CH3 N SO2CH3

NaI acetone

Ph

MECHANISM :

N N R

X

N

X N R

N R

X

N R

N R

DISCONNECTION : R NO2 R1 N R2

N R2

1242

H

+

O

R R1

NOTES :

Aryl radical cyclisation (sodium iodide in acetone) onto appropriate vinyl bromides leads to a new route to indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya

reactions.

REFERENCES :

1) C. Lampard; J.A. Murphy; F. Rasheed; N. Lewis; M.B. Hursthouse; D.E. Hibbs, Tetrahedron Lett., 1994, 35, 8675. 2) J.A. Murphy; K.A. Scott; R.S. Sinclair; N. Lewis, Tetrahedron Lett., 1997, 38, 7295. 3) R. Fletcher; M. Kizil; C. Lampard; J.A. Murphy; S.J. Roome, J. Chem. Soc., Perkin Trans. 1, 1998, 2341.

COMMENTS :

MYERS – MOORE – SAITO – SCHMITTEL CYCLISATION EXAMPLE :

OH

O H3CO

H3CO

CH3 heat benzene

H3CO OTMS

CH3

H3CO OTMS

1243

MECHANISM :

H3C

heat, 2.5 h benzene

CH3

H H

H3C

CH3

O

OPh O

O

H

O

O

O

OH

1244

DISCONNECTION :

R R2

R R2 R1

R3

R3

R1

R

R O OH R1

R1

R

R R3

R2

R2

R3 R1

R1

NOTES :

This reaction has been discovered in the natural product neocarzinostatine. The reactive structural element for the Myers cyclisation is an enyne allene, for the Moore cyclisation it is the reaction between enyne and ketenes. The Myers cyclisation reaction of enyne-allenes to α,3-didehydrotoluenes provides a particularly attractive pathway to

carbon biradicals for subsequent synthetic elaborations because the reaction occurs under mild thermal conditions and various synthetic routes to enyne-allenes with diverse chemical structures are becoming available. The Moore cyclisation is similar in producing biradicals containing an aryl and a phenoxy radical centre. The Myers – Saito cyclisation is between an enyne and an allene, the Schmittel cyclisation is a regioalternative of the Myers – Saito cyclisation, to give 5-membered rings. See also Bergman – Masamune cyclisation.

REFERENCES :

1) A.G. Myers; P.J. Proteau; T.M. Handel, J. Am. Chem. Soc., 1988, 110, 7212. 2) R. Nagata; H. Yamanaka; E. Okazaki; I. Saito, Tetrahedron Lett., 1989, 30, 4995. 3) A.G. Myers; P.S. Dragovich; E.Y. Kuo, J. Am. Chem. Soc., 1992, 114, 9369. 4) H.W. Moore; B.R. Yerxa, Chemtracts, 1992, 273. 5) M. Schmittel; M. Strittmatter; S. Kiau, Tetrahedron Lett., 1995, 36, 4975. 6) K.K. Wang, Chem. Rev., 1996, 96, 207. 7) J.W. Grissom; G.U. Gunawardena; D. Klingberg; D. Huang, Tetrahedron, 1996, 52, 6453. 8) M. Schmittel; M. Keller; S. Kiau; M. Stirrmatter, Chem. Eur. J., 1997, 3, 807. 9) P.W. Musch; C. Remenyi; H. Helten; B. Engels, J. Am. Chem. Soc., 2002, 124, 1823. 10) L.K. Sydnes, Chem. Rev., 2003, 103, 1133. 11) L. Feng; D. Kumar; D.M. Birney; S.M. Kerwin, Org. Lett., 2004, 6, 2059.

1245

COMMENTS :

MYERS REDUCTIVE COUPLING EXAMPLE :

SO2Ar N N H Ph

H

1) TBSOTf, Et3N THF, - 78 oC 2) Li OEt EtO

OEt

Ph EtO

H

H

3) AcOH, TFE - 78 oC -> 23 oC

MECHANISM :

SO2Ar N N H R

H

TBS N SO2Ar N TBSOTf, Et3N - 78 oC, THF

R

R1Li - 78 oC THF

H

F3C

N R

R1

R1

H

SiMe2tBu N N H

+ H H

R

R1

H H

H

H

R

R1

R R1

R

TBS N N SO2Ar

OH

TBS N

N N

Li

- N2

1246

H

N R

R1

NH H

DISCONNECTION :

H

H

R

R1

SO2Ar N N H R

+

R1Li

H

R = 1o, 2o, or 3o alkyl, aryl, α-methyl, acetonide protected sugar R1 = 1o or 3o alkyl, phenyl, enolate, β-methyl

NOTES :

The highly efficient reductive coupling of aldehyde tosylhydrazones with alkyl lithium reagents. The elimination of nitrogen proceeds via a radical pathway.

REFERENCES :

1) A.G. Myers; P.J. Kukkola, J. Am. Chem. Soc., 1990, 112, 8208. 2) A.G. Myers; M. Movassaghi, J. Am. Chem. Soc., 1998, 120, 8891.

COMMENTS :

1247

1248

NEWMAN SYNTHESIS · 1275 NICHOLAS SYNTHESIS · 1277

B

NICKL SYNTHESIS · 1279 BOECKMANN PROCEDURE · 1300

NICOLAOU OXIDATION · 1280 NIEMENTOWSKI von QUINAZOLONE REACTION ·

F

1281 NIEMENTOWSKI von QUINOLINE SYNTHESIS ·

FÜRSTNER PROCEDURE · 1300

1283 NIEUWLAND HYDRATION · 1284

N

NISHIMURA – CRISTESCU N-GLYCOSIDATION · NAGARAJAN

–

KUMAR

–

RAO

1285

MACROLACTONISATION · 1250

NOLLER SYNTHESIS · 1286

NAGATA HYDROCYANATION · 1251

NORD SYNTHESIS · 1288

NAITO INDOLE SYNTHESIS · 1253

NORRISH TYPE 1 REARRANGEMENT · 1290

NAMETKIN REARRANGEMENT · 1254

NORRISH TYPE 2 REARRANGEMENT · 1291

NATSUME INDOLE SYNTHESIS · 1256

NOYORI ANNULATION · 1293

NAZAROV CYCLISATION · 1257

NOYORI HYDROGENATION · 1295

NEBER

–

BOSSEL

CINNOLINE

/

OXINDOLE

NOYORI REARRANGEMENT · 1297

SYNTHESIS · 1259

NOZAKI – HIYAMA – KISHI (TAKAI – UTIMOTO)

NEBER REARRANGEMENT · 1261

REACTION · 1298

NEF REACTION · 1262

NUGENT – RAJANBABU EPOXIDE HOMOLYSIS ·

NEF SYNTHESIS · 1264

1301

NEGISHI COUPLING · 1265

NYSTED REACTION · 1302

NENITZESCU ACYLATION · 1267 NENITZESCU INDOLE SYNTHESIS · 1269

T

NERDEL CYCLOPROPANE SYNTHESIS · 1271 TAKAI – UTIMOTO REACTION · 1300

NESMANJANOV FULVENE SYNTHESIS · 1272 NESMANJANOV METALLATION · 1273 NEWMAN – KARNES – KWART REARRANGEMENT · 1274

1249

NAGARAJAN – KUMAR – RAO MACROLACTONISATION EXAMPLE :

O HO

COOH

12

O Boc2O, (iPr)2NEt, DMAP,

13

N

N o

toluene, 90 C

MECHANISM :

O HO

12

COOH

Boc2O, (iPr)2NEt, DMAP,

HO

O O

O

12

dilute with toluene DMAP

O

13

- tBuOH N

N o

toluene, 90 C

DISCONNECTION : O O

HO n+1

n

COOH

8>n>12

NOTES : A useful way of making macrolides using mild reaction conditions (toluene, 90 oC), with low cost reagents (Boc anhydride, Hünigs base and 4-pyrrolidinopyridine). The reaction is also tolerant to olefinic bonds, easy work-up and no tedious purification necessary to remove the by-products. The exact reaction mechanism is not known. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe –

1250

Ziegler,

Venkataraman

–

Wagle,

Vorbrüggen

–

Krolikiewicz,

Wittig,

macrolactonisation reactions.

REFERENCES : 1) V.F. Pozdnow, Tetrahedron Lett., 1995, 36, 7115. 2) M. Nagarajan; V.S. Kumar; B.V. Rao, Tetrahedron Lett., 1997, 38, 5835. 3) N. Nagarajan, Synth. Commun., 1999, 29, 2467. 4) M. Nagarajan; V.S. Kumar; B.V. Rao, Tetrahedron, 1999, 55, 12349. 5) M. Nagarajan, Tetrahedron Lett., 1999, 40, 1207.

COMMENTS :

NAGATA HYDROCYANATION EXAMPLE :

H

H

O

1) (CH3CH2)3Al HCN 2) H+

1251

O

CN

Yamaguchi

and

Yamamoto

MECHANISM :

THF

(Et2AlCN)n

n THF.Et2AlCN

THF.Et2AlCN O

O Et Al CN Et

O AlEt2CN

THF.Et2AlCN

Et2AlO

O Et Al CN CN Et Et Al THF Et

CN

NC Et2AlO

DISCONNECTION :

R R R 1 2 O

R

CN

R1

O

R2

NOTES : Alkylaluminium mediated 1,4-addition of hydrogen cyanide to α,β-unsaturated carbonyl compounds. For more details about the mechanism see J. Am. Chem. Soc., 1972, 94, 4644. See also Michael reaction.

REFERENCES : Org. React. : 25, 255 Org. Synth. : 52, 90, 100 Org. Synth. Coll. Vol. : 6, 14, 436

1) W. Nagata; S. Hirai; H. Itazaki; K. Takeda, J. Org. Chem., 1961, 26, 2413. 2) W. Nagata; M. Yoshioka; S. Hirai, Tetrahedron Lett., 1962, 3, 461. 3) W. Nagata; M. Yoshioka; S. Hirai, J. Am. Chem. Soc., 1972, 94, 4635. 4) W. Nagata; M. Yoshioka; M. Murakami, J. Am. Chem. Soc., 1972, 94, 4644. 5) W. Nagata; M. Yoshioka; M. Murakami, J. Am. Chem. Soc., 1972, 94, 4654. 6) T.F. Gallagher; J.L. Adams, J. Org. Chem., 1992, 57, 3347.

1252

7) M. Ihara; A. Katsumata; M. Egashira; S. Suzuki; Y. Tokunaga; K. Fukumoto, J. Org. Chem., 1995, 60, 5560.

COMMENTS :

NAITO INDOLE SYNTHESIS EXAMPLE :

CH3 Et N

N

CH3 CF3

O

Et THF, 65 oC

N Ph

MECHANISM :

R2 N

N

R2

H+ NR2 HN COCF3

COCF3

NH HN COCF3

H+

R

H

R1

R1

R

R

R1 R2

H R2

N

N

R

R NH R1 COCF3

R1

DISCONNECTION :

R1

R1

R R

N R2

N R2

1253

N

CF3 O

NOTES :

The thermal cyclisation of N-trifluoroacetyl enehydrazines to afford indoles under mild conditions via the Fischer indole reaction. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert

indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

O. Miyata; Y. Kimura; K. Muroya; H. Hiramatsu; T. Naito, Tetrahedron Lett., 1999, 40, 3601.

COMMENTS :

NAMETKIN REARRANGEMENT EXAMPLE :

CH3

CH3

CH3

CH3 OH

CH3

H+ CH3

MECHANISM :

CH3

CH3 CH3

CH3 OH

+

H , - H2O H2O, - H+ CH3

H

CH3 CH3

CH3

CH3 CH3

CH3 CH3

CH3

CH3

1254

CH3

DISCONNECTION :

R

R

X

CH3

CH3

X = OH CH3

CH3 R

R CH 3 CH3 X = Cl CH2

CH3 X CH3 CH3

NOTES :

A retropinacolic rearrangement in the terpene series involving the formation of a carbonium ion, without variation in the ring structure. (As is involved in the racemisation of camphene hydrate by acidic reagents.) See also Wagner – Meerwein rearrangement.

REFERENCES : March : 1070 Smith – March : 1394 Houben – Weyl : 4/2, 16

1) G. Wagner, J. Russ. Physik. Chem. Ges., 1899, 31, 680. 2) H. Meerwein, Liebigs Ann. Chem., 1914, 405, 129. 3) S.S. Nametkin; L. Brüssoff, J. Russ. Physik. Chem. Ges., 1924, 55, 525. 4) J. Kossanyi; B. Furth; J.P. Morizur, Tetrahedron, 1970, 26, 395. 5) P.C. Moews; J.R. Knox; W.R. Vaughan, J. Am. Chem. Soc., 1978, 100, 260. 6) A.G. Martinez; E.T. Vilar; A.G. Fraile; A.H. Fernández; S. de la Moya Cerero; F.M. Jiménzez, Tetrahedron, 1998, 54, 4607.

COMMENTS :

1255

NATSUME INDOLE SYNTHESIS EXAMPLE :

N Ts

1) Ac2O, BF3.Et2O 2) MgBr O

CH3

N Ts

O 3) 6% H2SO4, iPrOH, heat

MECHANISM :

CH3 Ac2O BF3.Et2O

N Ts

N Ts

MgBr

O

O

O CH3 N HO Ts O O

i

6% H2SO4 PrOH, heat

N Ts

CH3

DISCONNECTION :

R

N R1 = OAc, Cl Ts

N Ts

+

R

R1 O

NOTES :

The key step in this indole synthesis is the intramolecular electrophilic cyclisation of C-2 of the pyrrole ring, followed by the functionalisation. The Lewis acid (AlCl3, BF3.Et2O) controls the initial site of the intermolecular electrophilic substitution. The indole ring can be functionalised in several positions around the ring. Several modifications have been reported in the literature. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan,

1256

Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) H. Muratake; M. Natsume, Heterocycles, 1990, 31, 683. 2) K. Okabe; H. Muratake; M. Natsume, Tetrahedron, 1990, 46, 5113. 3) H. Muratake; A. Mikawa; M. Natsume, Tetrahedron Lett., 1992, 33, 4595. 4) H. Muratake; T. Seino; M. Natsume, Tetrahedron Lett., 1993, 34, 4815.

COMMENTS :

NAZAROV CYCLISATION EXAMPLE :

O

O H+ H3C

CH3

H3C

CH3

MECHANISM :

OH

O

HO

H+ H3C

H3C

CH3 OH

H3C

CH3

CH3

H3C

O

CH3

H3C

1257

CH3

H

DISCONNECTION :

O R

O R1

R

X

R

+

X

R

R2

R1 R2

NOTES :

The synthesis of alicyclic five-membered rings by the cyclisation of a divinylacetylene or of a substituted alkyl vinyl ketone by strong acids or UV light. It is a 4π electrocyclisation (via a carbocation intermediate), conrotatary in the presence of a protic acid or Lewis acid, disrotatory under photochemical conditions. Divinyl ketones and allyl compounds can also be employed. There is also a silicon-directed Nazarov cyclisation, and a retro-Nazarov reaction. See also Noyori annulation.

REFERENCES : Smith – March : 1021 Smith : 1308 Smith 2nd : 1077, 1133 Houben – Weyl : E19c, 345 Org. React. : 45, 1

1) D. Vorlander; G. Schroeter, Ber. Dtsch. Chem. Ges., 1903, 36, 1490. 2) J.N. Nazarov, Bull. Acad. Sci. USSR, 1946, 633. 3) H. Nozaki; M. Kurita; R. Noyori, Tetrahedron Lett., 1968, 9, 3635. 4) T.K. Jones; S.E. Denmark, Helv. Chim. Acta, 1983, 66, 2397. 5) C. Santelli–Rouvier; M. Santelli, Synthesis, 1983, 429. 6) S.E. Denmark; K.L. Habermas; G.A. Hite; T.K. Jones, Tetrahedron, 1986, 42, 2821. 7) M.L. Peel, Tetrahedron Lett., 1986, 27, 5947. 8) J.A. Bender; A.E. Blize; C.C. Browder; S. Giese; F.G. West, J. Org. Chem., 1998, 63, 2430. 9) D. Zuev; L.A. Paquette, Chemtracts, 1999, 12, 1019. 10) S. Giese; L. Kastrup; D. Stiens; F.G. West, Angew. Chem., Int. Ed., 2000, 39, 1970. 11) M.A. Tius; C.C. Chu; R. Nieves–Colberg, Tetrahedron Lett., 2001, 42, 2419. 12) M. Haramata; D.R. Lee, J. Am. Chem. Soc., 2002, 124, 14328 13) E. Leclerc; M.A. Tius, Org. Lett., 2003, 5, 1171. 14) C. Bee; E. Leclerc; M.A. Tius, Org. Lett., 2003, 5, 4927. 15) V.K. Aggarwal; A.J. Belfield, Org. Lett., 2003, 5, 5075. 16) M. Janka; W. He; A.J. Frontier; R. Eisenberg, J. Am. Chem. Soc., 2004, 126, 6864. 17) G. Liang; D. Trauner, J. Am. Chem. Soc., 2004, 126, 9544. 18) M. Harmata; P.R. Schreiner; D. Reyoul Lee; P.L. Kirchhoefer, J. Am. Chem. Soc., 2004, 126, 10954. 19) F. Douelle; L. Tal; M.F. Greaney, Chem. Commun., 2005, 660. 20) M.A. Tius, Eur. J. Org. Chem., 2005, 2193.

1258

21) H. Pellissier, Tetrahedron, 2005, 61, 6479. 22) A.J. Frontier; C. Collison, Tetrahedron, 2005, 61, 7577.

COMMENTS :

NEBER – BOSSEL CINNOLINE / OXINDOLE SYNTHESIS EXAMPLE :

OH OH

COOH 1) NaNO2, HCl 2) SnCl2, HCl, 0 oC 3) HCl, heat

NH2

N

N

MECHANISM :

R

R

OH NaNO2, HCl 5 oC HO

HCl, heat NaOH

OH

COOH

COOH NH2

R

OH

N2

SnCl2, HCl 0 oC

+

R

R

R

OH O

O N NH2

N H

COOH NH2

hot aq. base

1259

N

N

Zn H2SO4

N NH2

DISCONNECTION :

OH OH R N

COOH

R

N

R = H, Cl, OCH3

NH2

R OH OH

R1

N

N

COOH R NH2

R1

HO

R

R1

O N NH2

NOTES :

The sodium salt of an o-aminomandelic acid is diazotised and the diazo compound is reduced by stannous chloride to the o-hydrazinomandelic acid. The latter is cyclised in acid solution to yield a 3-hydroxy-cinnoline. α-Substituted derivatives

may

yield

either

4-substituted

3-hydroxy-cinnolines

or

3-substituted

1-aminodioxindoles.

1-

Aminodioxindoles can also be obtained by reduction of the 3-hydroxy cinnoline or by thermal cyclisation of ohydrazinophenylacetic acid. See also von Baeyer oxindole, Brunner, Gassman oxindole, Hinsberg oxindole, Martinet, von Richter, Stollé – Becker and Widman – Stoermer reactions.

REFERENCES :

1) G. Bossel, Diss. Univ. Tübingen, May 1925. 2) P.W. Neber; G. Knöller; K. Herbst; A. Trissler, Liebigs Ann. Chem., 1929, 471, 113. 3) E.J. Alford; K. Schofield, J. Chem. Soc., 1952, 2102. 4) H.E. Baumgarten; P.L. Creger; R.L. Zey, J. Am. Chem. Soc., 1960, 82, 3977. 5) H.E. Baumgarten; P.L. Creger, J. Am. Chem. Soc., 1960, 82, 4634.

COMMENTS :

1260

NEBER REARRANGEMENT EXAMPLE :

H

H

CH3

H3C N OTs

H

KOEt, H2O

CH3

H3C NH2 O

MECHANISM :

EtOH H

R1 Ts

R H

R - OTs

N O

H OEt R R1 N

R1 N H+

H

OEt, - HOEt

H

R1

H

N O

H2O, H+, - EtOH

H

Ts

R

R1

R NH2 O

OEt H2O, H+, - EtOH

H OEt R R1 Ts N O H

H OEt R R1 N H

- OTs

DISCONNECTION :

H

R1

R

H

R1

H

N O

R NH2 O

R1 = H

1261

Ts

NOTES :

This is the base-induced rearrangement of O-acylated ketoximes to the corresponding α-aminoketones. This reaction is important in the synthesis of heterocycles in which aminoketones are used as intermediates. See also Beckmann rearrangement.

REFERENCES : March : 217 Smith – March : 288, 1410 Houben – Weyl : 11/1, 903; E5, 528; E7b, 380; E14b, 431 Org. Synth. : 41, 82; 64, 19 Org. Synth. Coll. Vol. : 5, 909; 7, 149

1) P.W. Neber; A. von Friedolsheim, Liebigs Ann. Chem., 1926, 449, 109. 2) M.J. Hatch; D.J. Cram, J. Am. Chem. Soc., 1953, 75, 38. 3) H.O. House; W.F. Berkowitz, J. Org. Chem., 1963, 28, 2271. 4) C. O’Brien, Chem. Rev., 1964, 64, 81. 5) J.L. LaMattina; R.T. Suleske, Synthesis, 1980, 329. 6) S. Ueda; S. Naruto; T. Yoshida; T. Sawayama; H. Uno, J. Chem. Soc., Chem. Commun., 1985, 218. 7) T.A. Modro; M.J. Mphahlele, Phosphorus Sulfur, 1997, 127, 131. 8) M.F. Oldfield; N.P. Botting, J. Labelled Compd. Radiopharm., 1998, 41, 29. 9) T. Ooi; M. Takahashi; K. Doda; K. Maruoka, J. Am. Chem. Soc., 2002, 124, 7640.

COMMENTS :

NEF REACTION EXAMPLE :

H3C

O

H CH3 NO2

1) NaOH, CH3OH 2) H2SO4

1262

H3C

CH3

MECHANISM :

R H

O N R1 O

R R1

OH N OH OH2

R base - H+

O N O

R1

R H+

R

- H+

OH HO N R1 OH

R1

OH N O

H

R

O R1

O

- H2O

N

H+

R1

R

O

DISCONNECTION : O R

R R1

R1 NO2

NOTES :

Aliphatic primary and secondary nitro-compounds can be converted into aldehydes and ketones respectively by adding the alkali salts of the former to strong mineral acids. This is an important reaction for aldose chain extension. Modern versions of this reaction use LDA as base and MoOPh or Oxone as oxidant.

REFERENCES : March : 948 Smith – March : 1178, 1225 Smith : 899 Smith 2nd : 751 Houben – Weyl : 6a, 641, 647; 7/2a, 843; E3, 396, 587; E14b, 796, 857, 942; E16d, 368 Org. React. : 38, 655 Science of Synthesis : 9, 472

1) M. Konovaloff, J. Russ. Physik. Chem. Ges., 1892, 2, 202. 2) J.U. Nef, Liebigs Ann. Chem., 1894, 280, 263. 3) H.B. Hass; E.F. Riley, Chem. Rev., 1943, 32, 373. 4) W.E. Noland, Chem. Rev., 1955, 55, 137. 5) Y. Nakashita; T. Watanabe; E. Benkert; A. Lorenzi–Riatsch; M. Hesse, Helv. Chim. Acta, 1984, 67, 1207. 6) C.R. Saha–Möller; C.G. Zhao, Synlett, 1998, 1335. 7) P. Ceccherelli; M. Curini; M.C. Marcotullio; F. Epifano; O. Rosati, Synth. Commun., 1998, 28, 3057. 8) S.P. Shahi; Y.D. Vankar, Synth. Commun., 1999, 29, 4321. 9) R. Ballini; M. Petrini, Tetrahedron, 2004, 60, 1017.

1263

COMMENTS :

NEF SYNTHESIS EXAMPLE :

H3C

+ Na

O

Na

O

CH3 H

H3C

Et2O

H CH3

MECHANISM :

H H3C

O

CH3 Et2O

O Na+

OH

H3C

H

H3C

H+

CH3

H CH3

Na+

DISCONNECTION :

OH R

R

R2 R1

R1

+

H

R2

O

NOTES :

Acetylenic carbinols are obtained by treating ketones with the sodium or other metallic derivatives of an acetylenic hydrocarbon in ether or liquid ammonia. See also Arens – van Dorp, Favorskii – Babayan, Inhoffen, Isler and Reppe acetylene reactions.

REFERENCES : Org. React. : 38, 655 Org. Synth. : 20, 40 Org. Synth. Coll. Vol. : 3, 320

1264

1) J.U. Nef, Liebigs Ann. Chem., 1899, 308, 281. 2) C.D. Hurd; W.D. McPhee, J. Am. Chem. Soc., 1947, 69, 239. 3) T. Capecchi; C.B. de Koning; J.P. Michael, J. Chem. Soc., Perkin Trans. 1, 2000, 2681.

COMMENTS :

NEGISHI COUPLING EXAMPLE :

O I

BnO NHTr

Boc N

O 1) activated Zn(Cu) couple 2) Boc N I N

BnO

N NHTr

NHBoc CO2tBu

PdCl2(Ph3P)2, DMA, 40 oC

1265

NHBoc CO2tBu

MECHANISM :

OCH3

2 PdL4 OCH3 R

Br

-2L Br OCH3

2 PdL2 R OCH3

L Br Pd L

Reductive elimination

Oxidative addition

OCH3 L Pd R L

L Br Pd L

OCH3

OCH3 L Pd Br L OCH3

transmetallation

2 RZnX

2 Zn(X)Br

DISCONNECTION :

R1 R2

R1 Hal

+

R2 ZnX

R1 = alkenyl, aryl, allylic, benzylic, propargylic R2 = alkenyl, aryl, alkyny, alkyl, benzylic, allylic

NOTES :

This is the palladium-catalysed cross-coupling between organozinc reagents and organohalides or triflates. It is compatible with many functional groups including ketones, esters, amines and nitriles. See also Hayashi – Ito, Heck – Fujiwara – Mizoroki, Kochi, Kumada – Tamao – Corriu, McMurry, Murahashi, Stille – Kelly, Stille – Migita – Kosugi and Suzuki – Miyaura reactions.

REFERENCES :

1) E-i. Negishi; S. Baba, J. Chem. Soc., Chem. Commun., 1976, 596. 2) E-i. Negishi, Acc. Chem. Res., 1982, 15, 340. 3) E. Erdik, Tetrahedron, 1992, 48, 9577. 4) P. Knochel; R.D. Singer, Chem. Rev., 1993, 93, 2117. 5) E-i. Negishi; C. Copéret; S. Ma; S.-Y. Liou; F. Liu, Chem. Rev., 1996, 96, 365.

1266

6) A. Palmgren; A. Thorarensen; J.-E. Bäckvall, J. Org. Chem., 1998, 63, 3764. 7) B.A. Chauder; A.V. Kalinin; N.J. Taylor; V. Snieckus, Angew. Chem., Int. Ed., 1999, 38, 1435. 8) C.Y. Dai; G.C. Fu, J. Am. Chem. Soc., 2001, 123, 2719. 9) N. Skjaerbaek; P. Vedso; J. Jensen, Synthesis, 2001, 128. 10) S. Ma; H. Ren; Q. Wei, J. Am. Chem. Soc., 2003, 125, 4817. 11) P. Walla; C.O. Kappe, Chem. Commun., 2004, 564. 12) S.L. Wiskur; A. Korte; G.C. Fu, J. Am. Chem. Soc., 2004, 126, 82. 13) G. Zeni; D. Alves; A.L. Braga; H.A. Stefani; C.W. Nogueira, Tetrahedron Lett., 2004, 45, 4823.

COMMENTS :

NENITZESCU ACYLATION EXAMPLE :

O H3C

Cl

+ O

CH3 1) 2 AlCl3 2) cyclohexane heat

MECHANISM :

H +

R

Cl O

O

O

R

R AlCl3

Cl

1267

C6H5NMe2 - HCl

DISCONNECTION :

O R R

Cl

+

O

O R

NOTES :

Acid chlorides condense with cyclo-olefins in the presence of acid catalysts to yield a chloro-ketone which readily loses hydrogen chloride to form an α,β-unsaturated ketone. This method can be applied to ring formation. With C7 rings, ring contraction frequently occurs, cyclopentane and cyclohexane are however unchanged. See also Friedel – Crafts and Scholl reactions.

REFERENCES :

1) J. Kondakov, Bull. Soc. Chim. Fr., 1892, 7, 576. 2) G. Darzens, C.R. Séances Acad. Sci., 1910, 150, 707. 3) C.D. Nenitzescu; J.P. Cantuniari, Liebigs Ann. Chem., 1934, 510, 269. 4) C.D. Nenitzescu; E. Cioranescu, Ber. Dtsch. Chem. Ges., 1936, 69, 1820. 5) S.L. Fries; R. Pinson, J. Am. Chem. Soc., 1951, 73, 3512. 6) E. Klein; W. Rojahn, Tetrahedron Lett., 1971, 12, 3607. 7) S. Nakanishi; J.-I. Nakanishi; T. Takata, Synth. Commun., 1998, 28, 1967.

COMMENTS :

1268

NENITZESCU INDOLE SYNTHESIS EXAMPLE :

H3CO

O H

COOCH3

HO

+ H2N

O CH3

CH3

N H

O

MECHANISM :

O +

H

O

H

CO2R3

N R1

R2

CO2R3 R2

HO

HN OH R1

CO2R3 R2

- H2O

N R1

HO +

OH

CO2R3 R2

HO

HO

O

CO2R3 NHR1

CO2R3 R2

O

N H R1

HN O R1

H+

CO2R3

CO2R3

O

O

R2

R2

N OH

N R1

DISCONNECTION :

O

O

COOR1 HO

H R2 R

R2

R

N

H2N

H

O

1269

OR1

+ R2

R1

NOTES : p-Benzoquinone reacts with ethyl β-aminocrotonate and certain of its N-monosubstituted derivatives to yield

hydroxyindole esters. Also reduction of o,ω-dinitrostyrenes by iron in acetic acid or catalytically, yield indoles. Bernier et al. reported on the internal oxidation – reduction process in nitromethane. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Org. React. : 20, 337 Science of Synthesis : 10, 401, 698

1) C.D. Nenitzescu, Bull. Soc. Chim. România, 1929, 11, 37. 2) R.J.S. Beer; H.F. Davenport; A. Robertson, J. Chem. Soc., 1953, 1262. 3) U. Küklander; W. Hühnermann, Arch. Pharm. (Weinheim, Ger.), 1979, 312, 515. 4) J.L. Bernier; J.P. Henichart, J. Org. Chem., 1981, 46, 4197. 5) M. Kinugawa; H. Arai; H. Nishikawa; T. Ogasa; S. Tomioka; M. Kasai, J. Chem. Soc., Perkin Trans. 1, 1995, 2677. 6) D.M. Ketcha; L.J. Wilson; D.E. Portlock, Tetrahedron Lett., 2000, 41, 6253. 7) S. Brase; C. Gil; K. Knepper, Bioorg. Med. Chem. Lett., 2002, 10, 2415. 8) B. Dotzauer; R. Troschütz, Synlett, 2004, 1039.

COMMENTS :

1270

NERDEL CYCLOPROPANE SYNTHESIS EXAMPLE :

Cl

Cl

Et4NBr CHCl3 O

MECHANISM :

Cl +

Cl

CCl2 O

DISCONNECTION :

X

X

R

R3 R1

HCX3 +

R2

O

R

R3

R1

R2

+

NOTES :

The formation of 1,1-dihalogen-cyclopropanes from olefins, trihalogenmethane and ethyleneoxide (Brönsted base) in the presence of a tetraalkylammonium or phosphonium salt. Dichlorocarbene is the active species. See also Charette, Freund, Gustavson, Hass cyclopropane, Ipatiew cyclopropane, Mousseron – Fraisse – McCoy and Simmons – Smith reactions.

REFERENCES :

1) F. Nerdel; J. Buddrus, Tetrahedron Lett., 1965, 6, 3585. 2) J. Buddrus: F. Nerdel; P. Hentschel; D. Klamann, Tetrahedron Lett., 1966, 7, 5379. 3) F. Nerdel; J. Buddrus; W. Brodowski; P. Weyerstahl, Tetrahedron Lett., 1966, 7, 5385. 4) P. Weyerstahl; D. Klamann; C. Finger; F. Nerdel; J. Buddrus, Chem. Ber., 1967, 100, 1858.

COMMENTS :

1271

NESMANJANOV FULVENE SYNTHESIS EXAMPLE :

Ph OH Ph CONiPr2 Fe

Ph

i

CONiPr2

2M HCl THF

CON Pr2 Ph

Ph

Ph OH

MECHANISM :

Ph OH 2 Ph CONiPr2 Fe

Ph OH Ph CONiPr2 Fe i

CON Pr2 Ph

Ph 2

i

CON Pr2

2M HCl THF

Ph OH

Ph

Ph CONiPr2

Ph OH2

DISCONNECTION :

R1

R1 OH R2 R3

R2 R3

Fe

NOTES :

The directed ortho metalation (Dom) fragmentation sequence to ring-substituted 6-aryl and 6,6-diaryl fulvenes with amide and phosphinyl ring substituents. See also Thiele reaction.

REFERENCES :

1) A.N. Nesmanjanov; V.A. Sazonova; V.N. Drozd, Dokl. Akad. Nauk SSSR, 1964, 154, 1393. 2) A.N. Nesmanjanov; V.A. Sazonova; G.I. Zudkova; L.S. Isaeva, Isz. Akad. Nauk SSSR, Ser. Chim., 1966, 2017. 3) B. Miao; M. Tinkl; V. Snieckus, Tetrahedron Lett., 1999, 40, 2449.

1272

COMMENTS :

NESMANJANOV METALLATION EXAMPLE :

ArN2 Cl HgCl2

Cu, acetone

ArHgCl

MECHANISM :

X

Cl Cl Sb Cl Cl Cl

Ar

X

N N Fe, acetone

X

Cl Sb Cl Cl

Ar

N N

Cl Cl Sb Cl Ar

NOTES :

A benzenediazonium chloride reacts with mercuric chloride to yield a complex which when treated with a reducing agent (copper (iron) powder in acetone), gives an aryl mercuric chloride. If ammonia is present a diaryl mercury is obtained. The more electron donating X is, the faster the reaction proceeds. The halogen atom is abstracted first before the formation of the organometallic bond. Organo compounds of tin, arsenic, bismuth, thallium and lead can be similarly prepared.

REFERENCES :

1) A.N. Nesmanjanov, J. Russ. Physik. Chem. Ges., 1929, 61, 1393. 2) O.A. Reutow; W.W. Kondratjewa, J. Gen. Chem. (USSR), 1954, 24, 1259. 3) O.A. Reutow, Tetrahedron, 1957, 1, 67. 4) R.C. Larock, Tetrahedron, 1982, 38, 1713.

1273

COMMENTS :

NEWMAN – KARNES – KWART REARRANGEMENT EXAMPLE :

H3C

CH3 N O

neat, 258 oC

H3C

CH3 N S

S

O

MECHANISM :

CH3

O

H3C N

H3C

O S

S N CH3

H3C

CH3 N S O

DISCONNECTION :

R

R

R2

R1 N

S

R2

R1 N

O S

O

NOTES :

An aryl group migrates from an oxygen atom to a sulfur atom in an O-aryl N,N-dimethylthiocarbonate. Oxime thiocarbamates thermally rearrange to thio-oxime carbamates and this is thought to proceed through radical intermediates. See also Beckmann rearrangement, Chapman rearrangement, Freudenberg – Schönberg, Hayashi rearrangement and Smiles rearrangement reactions.

1274

REFERENCES : Houben – Weyl : E5, 876

1) H. Kwart; E.R. Evans, J. Org. Chem., 1966, 31, 410. 2) M.S. Newman; H.A. Karnes, J. Org. Chem., 1966, 31, 3980. 3) H.M. Relles; G. Pizzolats, J. Org. Chem., 1968, 33, 2249. 4) B. Cross; R.J.G. Searle; R.E. Woodall, J. Chem. Soc. (C), 1971, 1833. 5) A. Pelter; D. Sumengen, Tetrahedron Lett., 1977, 18, 1945. 6) T.N. Sorrell; E.H. Cheesman, Synth. Commun., 1981, 11, 909. 7) S. Cossu; G. Delogu; O. De Lucchi; D. Fabbri; M.P. Fois, Synth. Commun., 1989, 19, 3431. 8) U.K. Bandarage; J. Simpson; R.A.J. Smith; R.T. Weavers, Tetrahedron, 1994, 50, 3463. 9) S. Cossu; O. De Lucchi; D. Fabbri; G. Valle; G.F. Painter; R.A.J. Smith, Tetrahedron, 1997, 53, 6073.

COMMENTS :

NEWMAN SYNTHESIS EXAMPLE :

O

1) HCN 2) CH3OH, H+ 3) H2O 4) Zn(Hg), HCl 5) BrCH2CO2Et, Zn 6) PCl5 7) AlCl3 8) CH3MgBr

1275

CH3

MECHANISM :

Na(Hg)

1) Zn + BrCH2CO2Et 2) Dehydration 3) Hydrolysis

O

COOH

AlCl3

PCl5 Cl

COOH O

RMgBr - H2O - H2

O

R

- 3 H2

DISCONNECTION :

R O

NOTES :

The syntheses of chrysene and picene and their derivatives starting from 1,3-diphenylpropenone.

1276

REFERENCES :

1) M.S. Newman, J. Am. Chem. Soc., 1938, 60, 2947. 2) M.S. Newman, J. Org. Chem., 1944, 9, 518.

COMMENTS :

NICHOLAS SYNTHESIS EXAMPLE :

OCH3 +

OCH3 Co2(CO)6

O

OTMS CH3

H3C

H3C

CH3

OCH3

O

O

MECHANISM :

Br CHO

1) Br2 2) HC(OCH3)3 MeOH

OCH3

OCH3 OCH3

Br

[Bu4N]OH

OCH3

OCH3 OCH3 Co2(CO)6

Co2(CO)8

Nu OCH3 Co2(CO)6

Lewis Acid - HOCH3

Nu

OCH3 Co2(CO)6

DISCONNECTION :

Nu R1

OH R1

R Co2(CO)6

1277

R Co2(CO)6

NOTES :

The reaction between a propargyl cation stabilised as a dicobalt hexacarbonyl complex and a wide variety of nucleophiles is known as the Nicholas reaction. This reaction is very versatile and enables the introduction of different functional groups, especially by modification of the C-C triple bond, after demetallation. Thus, there have been many applications for this reaction leading recently to the synthesis of complex biologically active compounds. A heterobimetallic cobalt-molybdenum propargylium complex has been reported by Jones et al. See also Pauson – Khand reaction.

REFERENCES : Org. Synth. : 67, 141 Org. Synth. Coll. Vol. : 8, 460 Science of Synthesis : 1, 508

1) K.M. Nicholas; R. Pettit, Tetrahedron Lett., 1971, 12, 3474. 2) R.F. Lockwood; K.M. Nicholas, Tetrahedron Lett., 1977, 18, 4163. 3) K.M. Nicholas, Acc. Chem. Res. 1987, 20, 207. 4) M. Saha; B. Bagby; K.M. Nicholas, Tetrahedron Lett., 1986, 27, 915. 5) A.M. Montaña; K.M. Nicholas; M.A. Khan, J. Org. Chem., 1988, 53, 5193. 6) A.M. Montaña; K.M. Nicholas, J. Org. Chem., 1990, 55, 1569. 7) P. Magnus, Tetrahedron, 1994, 50,1397. 8) G.G.Melikyan; S. Bright; T. Monroe; K.I. Hardcastle; J. Ciurash, Angew. Chem., Int. Ed. Engl., 1998, 37, 161. 9) A.M. Montaña; D. Fernández, Tetrahedron Lett., 1999, 40, 6499. 10) A.M. Montaña; D. Fernández; R. Pagès; A.C. Filippou; G. Kociok–Köhn, Tetrahedron, 2000, 56, 425. 11) J.R. Green, Curr. Org. Chem., 2001, 5, 809 12) A.J. Fletcher; R. Fryatt; D.T. Rutherford; M.R.J. Elsegood; S.D.R. Christie, Synlett, 2001, 1711. 13) A.M. Montaña; M. Cano, Tetrahedron Lett., 2001, 42, 7961. 14) B.J. Theobald, Tetrahedron, 2002, 58, 4133. 15) S.D.R. Christie; R.J. Davoile; R.C.F. Jones, Tetrahedron Lett., 2002, 43, 7167. 16) R. Guo; R. Gibe; J.R. Green, Can. J. Chem., 2004, 82, 366. 17) S.D.R. Christie; R.J. Davoile; M.R.J. Elsegood; R. Fryatt; R.C.F. Jones; G.J. Pritchard, Chem. Commun., 2004, 2474. 18) Y. Ding; J.R. Green, Synlett, 2005, 271.

COMMENTS :

1278

NICKL SYNTHESIS EXAMPLE :

OH

O 1) nBuLi, - 78 oC 2) Br Br toluene, reflux

MECHANISM :

OLi

H

H

OLi +

O Br

Br

Br

DISCONNECTION :

O

R

OH

R

+

Br

Br

NOTES :

The one-step heteroannulation of sodium phenolates with 1,4-dibromo-2-butenes to afford benzofurans. Casiraghi et al. critically examined this reaction.

REFERENCES :

1) J. Nickl, Chem. Ber., 1958, 91, 553. 2) D.M. Cahill; P.V.R. Shannon, J. Chem. Soc. (C), 1969, 938. 3) S. Inoue; H. Kakoi; K. Okada; T. Goto, Chem. Lett., 1979, 253. 4) G. Satori; G. Casiraghi; L. Bolzoni; G. Casnati, J. Org. Chem., 1979, 44, 803. 5) F. Bigi; G. Casiraghi; G. Casnati; G. Sartori, Tetrahedron, 1983, 39, 169.

COMMENTS :

1279

NICOLAOU OXIDATION EXAMPLE :

HO

O

2.2 IBX, 55 oC 2:1 Toluene, DMSO

MECHANISM :

OH

O

O H

R

R

R

IBX R1

R1

H

R1

O

HO

I

O O H

O

HO

I H +

O

O

O

R

- H2O H

O

R1

R R1

O I O O

IBX, - H+

IBX OH

O H

H2O

IBX

1280

DISCONNECTION :

ArCH3

ArCHO O

O

R1

R1 R

R

NOTES :

The use of ortho-iodoxybenzoic acid as oxidising agent for the one-step synthesis of α,β-unsaturated carbonyl compounds from saturated alcohols and carbonyl compounds. Under similar conditions carbons adjacent to aromatic systems can selectively be oxidised. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES :

1) K.C. Nicolaou; Y.-L. Zhong; P.S. Baran, J. Am. Chem. Soc., 2000, 122, 7596. 2) K.C. Nicolaou; P.S. Baran; R. Kranich; Y.-L. Zhong; K. Sugita; N. Zou, Angew. Chem., Int. Ed., 2001, 40, 202. 3) K.C. Nicolaou; P.S. Baran; Y.-L. Zhong, J. Am. Chem. Soc., 2001, 123, 3183. 4) K.C. Nicolaou; C.J.N. Mathison; T. Montagnon, J. Am. Chem. Soc., 2004, 126, 5192. 5) S. Kotha; S. Banerjee; K. Mandal, Synlett, 2004, 2043. 6) J.N. Moorthy; N. Singhal; P. Venkatakrishnan, Tetrahedron Lett., 2004, 45, 5419.

COMMENTS :

von NIEMENTOWSKI QUINAZOLONE REACTION EXAMPLE :

NH2 + COOH

N

O H

NH2

N

KOH O

1281

H

MECHANISM :

NH2

H

OH

NH2

O NH2

- OH

N O H

O H N

O

H+

N

OH N

H

N

- H2O

H

H

O

O

DISCONNECTION :

R2

N R

N

NH2 R

R1

R2

O +

COOH

H

N

R

O

NOTES :

Anthranilic acids or their esters react with amides to yield 4-keto-3,4-dihydroquinazolines. Variants of the essential synthesis, using amidines have been described.

REFERENCES : Houben – Weyl : E8b, 849

1) St. von Niementowski, J. Prakt. Chem., 1895, 51, 564. 2) J.F. Meyer; E.C. Wagner, J. Org. Chem., 1943, 8, 239. 3) R. Pater, J. Heterocycl. Chem., 1971, 8, 699. 4) P. Tomasik; T. Kappe; A. Danel; A.H. Gheath, Polish J. Chem., 1996, 70, 302. 5) M.S. Khajavi; P. Afshani; K.R. Moghadan, Iran J. Chem. & Chem. Eng., 1998, 17, 29. 6) Z.H. Liu; X.L. Sun; S.Y. Zhang, Chin. J. Org. Chem., 2001, 21, 1161.

COMMENTS :

1282

von NIEMENTOWSKI QUINOLINE SYNTHESIS EXAMPLE :

OH NH2 H3C

+

CH3

CH3 1) heat 2) base

O

COOH

N

CH3

MECHANISM :

O

O

NH2

OH

CH3

OH H3C

O

CH3 N OH H CH3

heat +

H

O

O CH3 - H2O

N CH3 OH H

N

H

base - H2O OH

CH3

CH3

CH3

N

CH3

DISCONNECTION :

O

OH R1

R1

OH +

N

NH2

R

R

O

NOTES :

This reaction involves the use of anthranilic acids in place of the o-amino-benzaldehydes used in the Friedländer synthesis of quinolines. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, Pfitzinger – Borsche, Riehm quinoline and Skraup quinoline reactions.

REFERENCES :

1) S. von Niementowski, Ber. Dtsch. Chem. Ges., 1894, 27, 1394. 2) R.H. Manske, Chem. Rev., 1942, 30, 113. 3) T. Hisano, Org. Prep. Proced. Int., 1973, 5, 145. 4) E. Cuny; F.W. Lichtenthaler; A. Moser, Tetrahedron Lett., 1980, 21, 3029.

1283

5) B.P. Suthar, Indian J. Chem., 1982, 21B, 588. 6) R.J. Chong; M.A. Siddiqui; V. Snieckus, Tetrahedron Lett., 1986, 27, 5323. 7) J.K. Son; S.I. Kim; Y. Jahng, Heterocycles, 2001, 55, 1981.

COMMENTS :

NIEUWLAND HYDRATION EXAMPLE :

CH2 O C5H11 C C H

1) HgO, H2O 2) CH3COOH

C5H11

CH3

O

MECHANISM :

R

R

H

HgO R

- H+

HO

R

H H2O

Hg2+

Hg H+

H

R

H

HO

H

H2O

(CH3CO)2O

Hg H H

H

R

O

CH3 O

DISCONNECTION : CH2 O R

O

R C C H

CH3

NOTES :

The hydration and acylation of acetylenes using mercuric oxide and acetic acid or acetic anhydride. This method is very suitable for use on steroid derivatives. See also Kutscheroff – Denigès reaction and Reppe carbonylation.

1284

REFERENCES : March : 762 Smith – March : 995 Houben – Weyl : E3, 243 Org. Synth. : 35, 1; 40, 88 Org. Synth. Coll. Vol. : 4, 13; 5, 1024

1) J.A. Nieuwland, J. Am. Chem. Soc., 1933, 55, 2858. 2) G.F. Hennion; D.B. Killian; T.H. Vaughn; J.A. Nieuwland, J. Am. Chem. Soc., 1934, 56, 1130. 3) G.F. Hennion; J.A. Nieuwland, J. Am. Chem. Soc., 1934, 56, 1802. 4) L. Ružička; H.F. Meldahl, Helv. Chim. Acta, 1938, 21, 1760. 5) C.W. Shoppee; D.A. Prins, Helv. Chim. Acta, 1943, 26, 203. 6) P.F. Hrudlik; A.M. Hrudlik, J. Org. Chem., 1973, 38, 4254. 7) N.W. Boaz, Tetrahedron Lett., 1998, 39, 5505.

COMMENTS :

NISHIMURA – CRISTESCU N-GLYCOSIDATION EXAMPLE :

OH H

N

N (CH3)3SiO

OSi(CH3)3 H

BzO

O

BzO

O

O

Cl

+

N

o

N BzO

OBz

1285

1) heat, 180 C 2) aq. EtOH BzO

OBz

MECHANISM :

N

OSi(CH3)3 H

N

OSi(CH3)3 H N

Cl (CH3)3Si BzO

O

N

O

BzO

O

(CH3)3Si BzO

N O

BzO

N

O

O

Cl

OSi(CH3)3 H

heat, 180 oC

OBz

BzO

BzO

OBz

OBz

OH H

N O

BzO

N

O aq. EtOH BzO

OBz

DISCONNECTION :

X sugar + X

sugar

X = pyrimidine, purine, adenosine, inosine

NOTES :

The synthesis of natural and synthetic nucleosides using trimethylsilyl derivatives of pyrimidines, adenosines, inosines and purines. The aqueous ethanol removes the trimethylsilyl protecting group on the hydroxyl. See also Vorbrüggen nucleoside synthesis.

REFERENCES :

1) R.E. Handschumacher, J. Biol. Chem., 1960, 235, 764. 2) T. Nishimura; I. Iwai, Chem. Pharm. Bull., 1964, 12, 352. 3) T. Nishimura; I. Iwai, Chem. Pharm. Bull., 1964, 12, 357. 4) T. Nishimura; B. Shimizu; I. Iwai, Chem. Pharm. Bull., 1964, 12, 1471. 5) C. Cristescu, Rev. Roum. Chim., 1968, 13, 365.

COMMENTS :

1286

NOLLER SYNTHESIS EXAMPLE :

H Cl

O

1) Br2 2) CH3OH, HBr 3) CH3(CH2)7MgBr 4) Zn 5) NaCN 6) aq. HCl

CH3

HOOC

MECHANISM :

H

H Cl

O

Cl

Br2

O Br

OCH3 Cl

Br

CH3OH HBr

CH3(CH2)7MgBr

Br OCH3 CH3

Cl

Zn Br CH3

Cl

CH3

NC

CH3

HOOC

1287

NaCN

aq. HCl

DISCONNECTION :

O HO O HO

Cl

O

NOTES :

This synthesis in which the position of the double bond is unambiguous is exemplified by the classic preparation of oleic acid and elaidic acid. See also Baudart, Boord, Bowman, Kapp – Knoll and Robinson – Robinson reactions.

REFERENCES :

1) C.R. Noller; R.A. Bannerot, J. Am. Chem. Soc., 1934, 56, 1563. 2) L. Dalton, C & EN, 2004, 82, 24.

COMMENTS :

NORD SYNTHESIS EXAMPLE :

3 CH3CHO

H3C [Al(OEt)4]2Mg

1288

O O

OH CH3

MECHANISM :

R 2

R

H

O

O

H O

Mg R1O

R

R

H

O Mg(OR1)2

O

R

H

R H O

Mg OR1

R1O R

R

O O

O

OR1

R OH

Mg(OR1)2 R

DISCONNECTION :

R O

R O

OH

3 RCH2CHO

R

NOTES :

Magnesium aluminium alkoxides and similar co-ordination catalysts produce a trimeric condensation of α-methylenealdehydes to yield glycol esters. See also Cannizzarro and Tishchenko – Claisen reactions.

REFERENCES :

1) M.S. Kulpinski; F.F. Nord, J. Org. Chem., 1943, 8, 256. 2) M.S. Kulpinski; F.F. Nord, Nature, 1943, 151, 363. 3) F.J. Villani; F.F. Nord, J. Am. Chem. Soc., 1946, 68, 1674. 4) G. Hesse; M. Maurer, Liebigs Ann. Chem., 1962, 658, 21. 5) A. Miyano; D. Tashiro; Y. Kawasaki; S. Sakaguchi; I. Sakaguchi; Y. Ishii, Tetrahedron Lett., 1998, 39, 6901.

COMMENTS :

1289

NORRISH TYPE 1 REARRANGEMENT EXAMPLE :

CH3 CH3 H3C CH3 H3C

O

+

(CH3)3CH +

hν, 313 nm

CH3

H3C CH3 H3C CH3 H3C CH3

MECHANISM :

H3C

CH3 CH3 CH3

H3C

O

hν, 313 nm

O +

(CH3)3C

CH3 CH3

CH3

CH3

- CO H3C CH3 CH3 + H3C H3C CH3

(CH3)3CH +

(CH3)3C

DISCONNECTION :

R1

R1

+ R

R O

O

NOTES :

The homolytic cleavage of the C-C bond which is α to the carbonyl group is observed from (n,π*) excited states for a number of ketones. This rearrangement can also be used for photolactonisations. See also Norrish type II reaction.

REFERENCES : March : 243, 1047 Smith – March : 318, 1354 Smith 2nd : 1155 Houben – Weyl : 4/5b, 1021, 1035

1290

1) R.G.W. Norrish, Trans. Faraday Soc., 1934, 30, 103. 2) R.G.W. Norrish; C.H. Bamford, Nature, 1936, 138, 1016. 3) E.K.C. Lee; R.S. Lewis, Adv. Photochem., 1980, 12, 1. 4) G. Quinkert; N. Heim; J. Glenneberg; U.-M. Billhardt; V. Autze; J.W. Bats; G. Dürner, Angew. Chem., Int. Ed. Engl., 1987, 26, 362. 5) M. Scoponi; F. Pradella; V. Carassati, Coord. Chem. Rev., 1993, 125, 219. 6) A. Ricci; E. Fasani; M. Mella; A. Albini, J. Org. Chem., 2001, 66, 8086. 7) A.G. Griesbeck; H. Heckroth, J. Am. Chem. Soc., 2002, 124, 396.

COMMENTS :

NORRISH TYPE 2 REARRANGEMENT EXAMPLE :

O H3C

H

CH3 CH3

O hν

H3C

1291

CH3

+

H3C

CH3

MECHANISM :

O R

OH

hν

R1

H

HO R1

R1 R

R

R2

R2

R2

β-cleavage

OH +

R

R1

R2

O R

CH3

R1

R2

DISCONNECTION :

O

HO R1 R

R2

+

R

CH3

+

H R O

R1 R2

NOTES :

The principal photochemical reaction from the (n,π*) excited state of ketones containing a hydrogen atom in the γposition is intramolecular hydrogen abstraction. In the absence of steric constraints, a six-center cyclic transition state favours transfer of this hydrogen to the oxygen of the carbonyl group. The primary product of this reaction is a 1,4biradical. See also McLafferty and Norrish type 1 reactions.

REFERENCES : March : 243 Smith – March : 318, 1299 Smith 2nd : 1155 Houben – Weyl : 4/5b, 795, 892, 1017

1) R.G.W. Norrish; C.H. Bamford, Nature, 1936, 138, 1016. 2) R.G.W. Norrish, Trans. Faraday Soc., 1937, 33, 1521. 3) P.J. Wagner, Acc. Chem. Res., 1971, 4, 168.

1292

4) J.C. Scaiano, Acc. Chem. Res., 1982, 15, 252. 5) W. Adam; S. Grabowski; R.M. Wilson, Chem. Ber., 1989, 122, 561. 6) H. Ihmels; J.R. Scheffer, Tetrahedron, 1999, 55, 885. 7) S. de Feyter; E.W.-G. Diau; A.H. Zewail, Angew. Chem., Int. Ed., 2000, 39, 260. 8) A.G. Griesbeck; H. Heckroth, J. Am. Chem. Soc., 2002, 124, 396. 9) M.D. D’Auria; L. Emanuele; G. Poggi; R. Racioppi; G. Romaniello, Tetrahedron, 2002, 58, 5045. 10) S. Chen; B.O. Patrick; J.R. Scheffer, J. Org. Chem., 2004, 69, 2711.

COMMENTS :

NOYORI ANNULATION EXAMPLE : CH3 O H3C CH3 O

CH3

H3C

CH3 Br

Br

H3C

CH3

1) Fe2(CO)9 2) H3C

CH3

MECHANISM :

O

O H3C

H3C

CH3 Br

Fe2(CO)9

Br

O H3C

Fe(CO)4

Fe(CO)4 O

CH3

CH3

H3C R

CH3

R

1293

R

DISCONNECTION :

O R

R

O R

R Br

R1

R1

+

Br

O R

R

O R

R Br

R1

+

Br

R1

R1

R1

NOTES :

A useful carbon-bond forming reaction involving diiron nonacarbonyl with halo-carbonyl compounds. See also Nazarov reaction.

REFERENCES : Smith : 1372 Smith 2nd : 1133 Org. React. : 29, 163

1) R. Noyori; K. Yokoyama; Y. Hayakawa, J. Am. Chem. Soc., 1973, 95, 2722. 2) R. Noyori, Acc. Chem. Res., 1979, 12, 61. 3) M. Takaya; S. Makino; Y. Hayakawa; R. Noyori, J. Am. Chem. Soc., 1978, 100, 1765. 4) J.-L. Paparin; C. Crévisy, Tetrahedron Lett., 2000, 41, 2343.

COMMENTS :

1294

NOYORI HYDROGENATION EXAMPLE :

OH

O CO2CH3

CO2CH3

H2, 30 oC 100 atm Ph2 OAc P Ru P OAc Ph2

MECHANISM :

Br Br

Cl3SiH Et3N, PhCH3

O P Ph2 P Ph2 O

Mg, Ph2POCl THF, PhCH3

P Ph2 P Ph2

Ru(OAc)2

1295

O P Ph2 P Ph2 O

1(S)-(+)CSA

Ph2 OAc P Ru P OAc Ph2

Cl Ar3P B Ru Ar3P HO

2S

O

H+ R

B

R

R Cl B Ar3P Ru Ar3P O H H

Cl Ar3P S Ru Ar3P S H

S

2S Cl Ar3P Ru S Ar3P S

H2

OH

B

R

DISCONNECTION : OH

O

R * R1

R

R1

R1 = CH3, CH2CH3, CO2R2

NOTES :

The homogeneous chiral hydrogenation of unsaturated alcohols, or carboxylic acids, enamides, ketones in the presence of BINAP Ru or Rh complex as catalyst. There are three classes of catalytic systems. For enantioselective hydrogenation a diphosphine ligand or a diphosphine ligand with a diamine ligand can be used. For enantioselective hydrogen transfer a 1,2-diamine ligand is used. The Noyori catalysts are highly-efficient, work under mild-conditions and at 1 – 10 atmosphere of hydrogen pressure. See also Corey – Itsuno – Bakshi – Shibata, Horner – Knowles – Kagan, Kerp and Midland reactions.

REFERENCES : March : 914 Smith – March : 1201 Org. Synth. : 67, 20; 72, 74; 77, 1 Org. Synth. Coll. Vol. : 8, 57; 9, 169

1296

1) A. Miyashita; A. Yasuda; H. Takaya; K. Toriumi; T. Ito; T. Souchi; R. Noyori, J. Am. Chem. Soc., 1980, 102, 7932. 2) H. Takaya; K. Mashima; K. Koyano; M. Yagi; H. Kumobayashi; T. Taketomi; S. Akutagawa; R. Noyori, J. Org. Chem., 1986, 51, 629.

3) R. Noyori, Science, 1990, 248, 1194. 4) R. Noyori; H. Takaya, Acc. Chem. Res., 1990, 23, 345. 5) S.C. Casegreen; S.G. Davis; C.J.R. Hedgecock, Synlett, 1991, 781. 6) R. Noyori, Acta Chem. Scand., 1996, 50, 380. 7) T. Ohkuma; H. Ooka; M. Yamakawa; T. Ikariya; R. Noyori, J. Org. Chem., 1996, 61, 4872. 8) T. Ohkuma; M. Koizumi; H. Doucet; T. Pham; M. Kozawa; K. Murata; E. Katayama; T. Yokozawa; T. Ikariya; R. Noyori, J. Am. Chem. Soc., 1998, 120, 13529. 9) R. Noyori; T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40. 10) P. Waser; M. Rueping; D. Seebach; E. Duchardt; H. Schwalbe, Helv. Chim. Acta, 2001, 84, 1821. 11) R. Noyori; M. Yamakawa; S. Hashiguchi, J. Org. Chem., 2001, 66, 7931. 12) H.P. Dijkstra; G.P.M. van Klink; G. van Koten, Acc. Chem. Res., 2002, 35, 798. 13) C.A. Sandoval; T. Ohkuma; K. Muñiz; R. Noyori, J. Am. Chem. Soc., 2003, 125, 13490. 14) R. Noyori; M. Kitamura; T. Ohkuma, Proc. Natl. Acad. Sci. USA, 2004, 101, 5356.

COMMENTS :

NOYORI REARRANGEMENT EXAMPLE :

O

O

O Pd(PPh3)4 dpe, 140 oC 60 h

HO

MECHANISM :

O R

O

O R1

Pd0

O

R Pd

H

O R1

R

R1 Pd H

1297

O

O - PdH

R

O R1

DISCONNECTION : O R

O

O R1

R

O R1

NOTES :

In the presence of 1,2-bis(diphenylphosphino)ethane catalytic amounts of palladium(0) isomerises cyclic and acyclic α,β-epoxy ketones to β-diketones. Epoxy ketones containing an α-alkyl group react only sluggish. Epoxy esters or nitriles do not react under these conditions. There are two reaction mechanisms proposed the most probable is outlined in the scheme.

REFERENCES :

1) M. Suzuki; A. Watanabe; R. Noyori, J. Am. Chem. Soc., 1980, 102, 2095. 2) M. Fétizon; I. Hanna; R. Zeghdoudi, Synth. Commun., 1986, 16, 1. 3) A.P. Kozikowski; T.R. Nieduzak; T. Konoike; J.P. Springer, J. Am. Chem. Soc., 1987, 109, 5167. 4) M. Suzuki; A. Watanabe; R. Noyori, Recl. Trav. Chim. Pays-Bas, 1988, 107, 230. 5) E. Öhler; H.-S. Kang; E. Zbiral, Synthesis, 1988, 623.

COMMENTS :

NOZAKI – HIYAMA – KISHI (TAKAI – UTIMOTO) REACTION EXAMPLE :

O OCH3 OCH3

+

OH H 0.07 CrCl2 1.7 Mn NaI, TMSCl THF, - 30 oC

1298

CH3

MECHANISM : Fürstner procedure :

OCrX2

RX

RCrX2

R1CHO

R

R1

CrX3

2 CrX2

TMSX Mn

MnX2 OTMS R

R1

Nickel-catalysed :

R CrIII

O

R1 2 CrII

R2

NiII

2 CrIII

O R2

R Ni0

R1 CrIII

R1 X III

R1 NiII X

Cr

oxidative addition

transmetallation

DISCONNECTION :

OH R1 R OH

O R

R1 R

1299

X

+

R1

H

NOTES :

The addition of vinyl, allyl, or aryl halides to aldehydes via an intermediate chromium(III) species is generally achieved by CrCl2 with a catalytic amount of nickel chloride. The reaction can also be catalytic (Fürstner procedure Mno and TMSCl or Boeckmann procedure Mno, TMSCl and NaI) and enantioselective. The Nozaki – Hiyama reaction is the formation of homoallyl alcohols from allylhalogenides, tosylates or phosphates. The Kishi reaction uses vinyl- and arylhalogenides, while in the Takai – Utimoto reaction non-activated alkyl halogenides are used. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Julia – Paris – Kocienski – Lythgoe, Keck

macrolactonisation, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : Smith 2nd : 681, 767 Org. Synth. : 72, 180 Org. Synth. Coll. Vol. : 9, 472 Science of Synthesis : 1, 34

1) Y. Okude; S. Hirano; T. Hiyama; H. Nozaki, J. Am. Chem. Soc., 1977, 99, 3179. 2) T. Hiyama; Y. Okude; K. Kimura; H. Nozaki, Bull. Chem. Soc. Jpn., 1982, 55, 561. 3) K. Takai; M. Tagashira; T. Kuroda; K. Oshima; K. Utimoto; H. Nozaki, J. Am. Chem. Soc., 1986, 108, 6048. 4) K. Takai; K. Nitta; K. Utimoto, J. Am. Chem. Soc., 1986, 108, 7408. 5) Y. Kishii, Pure Appl. Chem., 1992, 64, 354. 6) P. Cintas, Synthesis, 1992, 248. 7) A. Fürstner; N. Shi, J. Am. Chem. Soc., 1996, 118, 12349. 8) R.K. Boeckmann, jr.; R.A. Hudak, J. Org. Chem., 1998, 63, 3524. 9) M. Bandini; P.G. Cozzi; P. Melchiorre; A. Umani–Ronchi, Angew. Chem., Int. Ed., 1999, 38, 3357. 10) A. Fürstner, Chem. Rev., 1999, 99, 991. 11) L.A. Wessjohann; G. Scheid, Synthesis, 1999, 1. 12) D.L. Comins; A.C. Hiebel; S.L. Huang, Org. Lett., 2001, 3, 769. 13) M. Durandetti; J.-Y. Nédélec; J. Périchon, Org. Lett., 2001, 3, 2073. 14) R.E. Taylor; Y. Chen, Org. Lett., 2001, 3, 2221. 15) M.A.N. Zoutani; A. Pancrazi; J. Ardisson, Synlett, 2001, 769. 16) D.P. Arnold; R.D. Hartnell, Tetrahedron, 2001, 57, 1335 17) W.-M. Dai; A. Wu; W. Hamaguchi, Tetrahedron Lett., 2001, 42, 4211. 18) R.A. Pilli; M.M. Victor, Tetrahedron Lett., 2002, 43, 2815.

1300

COMMENTS :

NUGENT – RAJANBABU EPOXIDE HOMOLYSIS EXAMPLE : O O

O

CO2CH3 + Cp2TiCl2

MECHANISM :

TiIV III

O Ti

O

TiIV

Ti(III)

O

Ti(IV)

OTiIV

Cl TiCp2 O

O Cp2TiCl2 THF, RT

TiIV TiIVO Cp2TiCl2 THF, RT

- "TiO"

HO H+, H2O

1301

TiIVO O CO2CH3 +

Cp2TiCl2 THF, RT

Cp2TiCl2 THF, RT OTiIV

O

H3CO TiIVO

O H+, H2O

NOTES :

Bis(cyclopentadienyl)titanium(III) chloride reacts with epoxides by initial C-O homolysis. It has applications in all major classes of free radical chemistry, inter- and intramolecular addition to olefins, H-atom abstraction and electron-transfer reductions.

REFERENCES :

1) W.A. Nugent; T.V. RajanBabu, J. Am. Chem. Soc., 1988, 110, 8561. 2) T.V. RajanBabu; W.A. Nugent, J. Am. Chem. Soc., 1989, 111, 4525. 3) T.V. RajanBabu; W.A. Nugent, J. Am. Chem. Soc., 1994, 116, 986. 4) H.J. Gold, Synlett, 1999, 159.

COMMENTS :

NYSTED REACTION EXAMPLE :

O C11H23

C11H23

H O Br Zn

Zn Br Zn

.

BF3 Et2O, THF

1302

H

DISCONNECTION :

O R

R1

R

R1

NOTES :

[Cyclo-dibromodi-μ-methylene(μ-tetrahydrofuran)trizinc] reacts with aldehydes in the presence of BF3.Et2O, whereas it reacts with ketones in the presence of BF3.Et2O and TiCl2 or TiCl4, TiCl3 to afford methylated products. The reactivity of this reagent itself and the role of the additives still has to be clarified. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : Smith 2nd : 681

1) L.N. Nysted, U.S. Patent, 1975, 3865848. (Chem. Abs., 1975, 83, 10406q.) 2) L.N. Nysted, U.S. Patent, 1976, 3960904. (Chem. Abs., 1976, 85, 94618n.) 3) W. Tocktermann; S. Bruhn; M. Meints; C. Wolff; E.-M. Peters; K. Peters; H.G. von Schnering, Tetrahedron, 1995, 51, 1623.

4) S. Matsubara; M. Sugihara; K. Utimoto, Synlett, 1998, 313. 5) L.A. Paquette; R.E. Hartung; J.E. Hofferberth; I. Vilotijevic; J. Yang, J. Org. Chem., 2004, 69, 2454.

COMMENTS :

1303

1304

OLEKSYSZYN AMINOPHOSPHONIC ACID SYNTHESIS · 1314 OPPENAUER OXIDATION · 1315

O

OPPOLZER ALLYL ALCOHOL SYNTHESIS · 1317 O’DONNELL AMINO ACID SYNTHESIS · 1306

ORTON HALOANILINE REARRANGEMENT · 1318

OHLE CLEAVAGE · 1309

OSTROMYSLENSKI REACTION · 1320

OHSHIRO – HIRAO REDUCTION · 1310

OVERMAN PYRROLIDINE SYNTHESIS · 1321

OLAH CROWDED OLEFIN SYNTHESIS · 1312

OVERMAN REARRANGEMENT · 1322

1305

O’DONNELL AMINO ACID SYNTHESIS EXAMPLE :

O OEt Ph

N

1)

NH3 O2N

Ph

NO2

H COO

CH2Cl

K2CO3, CH3CN Bu4N+Br-, heat 2) H+ 3) pH ~ 6

MECHANISM :

Pd(OAc)2

(+)-BINAP Ph2C

N

P OAc * Pd P OAc

CO2tBu OAc

Epimerisation at α-carbon is fast

Ph P P Pd * * P P

(+)-BINAP

P * Pd P

H

N α COtBu

Ph P

Pd *

P OAc

H3CO2C

CO2CH3

N

CO2tBu

Ph2C

1306

M CH(CO2CH3)2

P

PPh2 PPh2

* = P

DISCONNECTION :

O R1

R5 R1

COO

OR2 R3

N

NH3

+ R5X

R4

NOTES : Schiff bases of glycine can be alkylated in the presence of solid potassium carbonate in refluxing acetonitrile containing a phase transfer catalyst. Subsequent hydrolysis furnishes the corresponding α-alkylated α-amino acid. This method has developed into the enantioselective alkylation of Schiff base acetates with malonate stabilised carbon nucleophiles in the presence of palladium(II) acetate and (+)-BINAP as the chiral ligand. Organoboranes have also been used.

REFERENCES : 1) L. Ghosez; J.P. Antoine; E. Deffense; M. Navarro; V. Libert; M.J. O’Donnell; W.A. Bruder; K. Willey; K. Wojciechowski, Tetrahedron Lett., 1982, 23, 4255. 2) M.J. O’Donnell; B. LeClef; D.B. Rusterholz; L. Ghosez; J.-P. Antoine; M. Navarro, Tetrahedron Lett., 1982, 23, 4259. 3) M.J. O’Donnell; K. Wojciechowski; L. Ghosez; M. Navarro; F. Sainte, Synthesis, 1984, 313. 4) M.J. O’Donnell; J.-B. Falmagne, Chem. Commun., 1985, 1168. 5) M.J. O’Donnell; W.D. Bennett, Tetrahedron, 1988, 44, 5389. 6) M.J. O’Donnell; N. Chen; C. Zhou; A. Murray; C.P. Kubiak; F. Yang; G.G. Stanley, J. Org. Chem., 1997, 62, 3962. 7) M.J. O’Donnell; M.D. Drew; J.T. Cooper; F. Delgado; C. Zhou, J. Am. Chem. Soc., 2002, 124, 9348. 8) M.J. O’Donnell; J.T. Cooper; M.M. Mader, J. Am. Chem. Soc., 2003, 125, 2370. 9) M.J. O’Donnell, Acc. Chem. Res., 2004, 37, 506.

1307

COMMENTS :

ODDO SYNTHESIS EXAMPLE :

CH3 1) CH3MgBr 2) CH3COCl

N H

N H

O

MECHANISM :

R N H

CH3MgHal

N H

MgHal

RCOCl

N H

O

DISCONNECTION :

O N H

N H

R

NOTES : Pyrrole reacts with methylmagnesium halide to yield the 2-pyrrolyl magnesium halide, which with an acid chloride gives the ketone. 3-Indolyl ketones can be similarly obtained. See also Friedel – Crafts and Grignard reactions.

REFERENCES : 1) B. Oddo, Ber. Dtsch. Chem. Ges., 1910, 43, 1012. 2) B. Oddo; Q. Mingoia, Gazz. Chim. Ital., 1925, 55, 235. 3) Ng.Ph. Buu-Hoї; N. Hoán, Recl. Trav. Chim. Pays-Bas, 1949, 68, 3. 4) G.A. Cordell, J. Org. Chem., 1975, 40, 3161.

1308

COMMENTS :

OHLE CLEAVAGE EXAMPLE :

O HO HO H H

Ph

O N N H OH OH CH2OH

NH2

1)

H

H H H

OH OH CH2OH

NH2 2) C6H5NH2 EtOH, reflux

MECHANISM :

O HO HO H H

O

Ph

OH

N

N N H OH OH CH2OH

OH

N HOCH2

NH2

C6H5NHNH2 EtOH, reflux

OH OH

NH2

N

OH

-

N

N H

DISCONNECTION :

Ph

HOH2C

N N H H H

H H H

R

HO H H

OH OH CH2OH

1309

O H OH OH CH2OH

H N

H OH OH CH2OH

Ph

NOTES : A method for the decomposition of a hexose into three-carbon units in which the hexose is first converted into a hydroxytetrahydroxybutylquinoxaline. The latter is refluxed with an ethanolic solution of aniline or a hydrazine. The product varies with the nature of the reactant and the conditions. See also Amadori, Barry and Fischer phenylhydrazine and oxazone reactions.

REFERENCES : March : 905 Smith – March : 1195

1) H. Ohle, Ber. Dtsch. Chem. Ges., 1934, 67, 155. 2) M. Ohle; W. Gross; A. Wolter, Ber. Dtsch. Chem. Ges., 1937, 70, 2148. 3) H. Ohle; M. Hielscher; G. Noetzel, Ber. Dtsch. Chem. Ges., 1943, 76, 1051.

COMMENTS :

OHSHIRO – HIRAO REDUCTION EXAMPLE :

Br O

Br

O H3CO P H OCH3 Et3N, DMF

1310

O

Br

MECHANISM :

R

Br

H+

O H3CO P H OCH3

O H3CO P CH3O

Et3N

Br R

Br

R

Br

- Br

H

R

R H

O H3CO P CH3O

OCH3 H3CO P O

Br

Br

R

Br

R

H+

Br

OCH3 H3CO P O Br R H Br

R

OCH3 H3CO P O

OCH3 H3CO P O Br

R

Br

OCH3 P OCH3 O

- Br

R

Br

Br OCH3 H3CO P O R

Br

R

OCH3 P OCH3 O

1311

H

DISCONNECTION :

R Br

Br R R

H

Br

NOTES : The synthesis of vinyl bromides using reduction of the corresponding 1,1-dibromoalkenes with dimethylphosphite and triethylamine. In some cases large amounts of terminal acetylenic products were found.

REFERENCES : 1) T. Hirao; T. Masunaga; Y. Ohshiro; T. Agawa, J. Org. Chem., 1981, 46, 3745. 2) T. Hirao; T. Masunaga; N. Yamada; Y. Ohshiro; T. Agawa, Bull. Chem. Soc. Jpn., 1982, 55, 909. 3) S. Abbas; C.J. Hayes; S. Worden, Tetrahedron Lett., 2000, 41, 3215.

COMMENTS :

OLAH CROWDED OLEFIN SYNTHESIS EXAMPLE :

O 1) Me3SOI, tBuOK (CH3OCH2)2, heat 2) Me2CuLi, Et2O, 0 oC 3) SOCl2, 0 oC

1312

MECHANISM :

O O S H Cl

OLi

O (R)2CuLi

R

SOCl2 R

H

H - HCl - SO2

R

DISCONNECTION :

R1

R

R2

H

O R1

R2

+ (R)2CuLi

NOTES : The procedure provides an alternative synthesis of crowded (alkylidene)polycycloalkanes from the readily available corresponding ketones using alkyl lithium and thionyl chloride, in cases where Grignard or Wittig methods are not useful. Alternatively, the epoxide can be formed under Corey – Chaykovsky conditions. See also Corey – Chaykovsky, Corey – Kwiatkowski, Eastwood, Fürstner, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig olefination reactions.

REFERENCES : 1) C.W. Shoppee; R.E. Lack; S.C. Sharma; L.R. Smith, J. Chem. Soc. (C), 1967, 1155. 2) G.A. Olah; V.V. Krishnamurthy, J. Am. Chem. Soc., 1982, 104, 3987. 3) G.A. Olah; A-h. Wu; O. Farooq, J. Org. Chem., 1989, 54, 1375. 4) G.A. Olah; A-h. Wu, Synthesis, 1990, 887.

COMMENTS :

1313

OLEKSYSZYN AMINOPHOSPHONIC ACID SYNTHESIS EXAMPLE :

O

O P(OH)2 NH2

H2N O

+ PCl3 +

1) HAc 2) H2O, HCl

O

MECHANISM :

R2

O

O

H

+ 2

O

R1

H NH2

R2

- H2O

H

O

Ph

Ph + H2O

P Cl Ph

R1

NH N R1

P OH - HCl

Ph O

OH P Ph Ph

H

O Ph P H + Ph

R2 H

R1 R2

NH N R1

R1

H O P Ph N Ph H

O

O

DISCONNECTION :

R2 O R1 P R3 H2N OH R2 O R1 R P R3 N OH O H

R1

R2

Cl +

O

R3 P

R NH2

+ R4

O

NOTES : The synthesis of 1-aminoalkanephosphonic and 1-aminoalkanephosphinic acids from ketones or aldehydes, chlorophosphines and carbamates. There are several proposed mechanisms in the literature, the one by Oleksyszyn is shown here. See also Kabachnik – Fields reaction.

REFERENCES : 1) J. Oleksyszyn; R. Tyka; P. Mastalerz, Synthesis, 1978, 479. 2) J. Oleksyszyn, Synthesis, 1981, 444. 3) J. Oleksyszyn; E. Gruszecka, Tetrahedron Lett., 1981, 22, 3537.

1314

4) M. Soroka, Liebigs Ann. Chem., 1990, 331. 5) J. Oleksyszyn; B. Boduszek; C.-M. Kam; J.C. Powers, J. Med. Chem., 1994, 37, 226. 6) J. Oleksyszyn; J.C. Powers, Method. Enzymol., 1994, 244, 423. 7) J. Xu; Y. Ma; L. Duan, Heteroatom. Chem., 2000, 11, 417.

COMMENTS :

OPPENAUER OXIDATION EXAMPLE :

CH3 H OH Et

+

H3C

CH3

Al(OC(CH3)3)3 Benzene

CH3 H OH CH3

O

+

H3C

Et O

MECHANISM :

R2 R H

R

1/3 Al[OC(CH3)3]3 OH

R1

H HOC(CH3)3

O Al/3

R

R1

+

O R3

O

R1

R2 H

O

Al/3

DISCONNECTION :

R

H

R1

R

O

1315

R3

R1 OH

R R1

H R2

O

Al/3 O

R3

NOTES : A reversal of the Meerwein – Ponndorf – Verley reaction involving the oxidation of a primary or secondary hydroxyl compound to the corresponding carbonyl compound, using aluminium alkoxide and an excess of acetone, benzophenone or other ketone which acts as a carbonyl hydrogen acceptor. Anisaldehyde and cinnamaldehyde have also been employed. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES : March : 913 Smith – March : 1516 Smith : 243 Smith 2nd : 211, 407, 604 Houben – Weyl : 4/2, 85, 121; 7/1, 186; E3, 274 Org. React. : 2, 178; 6, 207 Org. Synth. : 21, 8, 18 Org. Synth. Coll. Vol. : 3, 48, 207

1) R.V. Oppenauer, Recl. Trav. Chim. Pays-Bas, 1937, 56, 137. 2) L. Horner; U.B. Kaps, Liebigs Ann. Chem., 1980, 192. 3) B. Byrne; M. Karras, Tetrahedron Lett., 1987, 28, 769. 4) E.C. Ashby, Acc. Chem. Res., 1988, 21, 414. 5) G.A. Molander; J.A. McKie, J. Am. Chem. Soc., 1993, 115, 5821. 6) J.C. van der Waal; K.Q. Tan; H. van Bekkum, Catal. Lett., 1996, 41, 63. 7) K. Ishihara; H. Kurihara; H. Yamamoto, J. Org. Chem., 1997, 62, 5664. 8) K. Krohn, Synthesis, 1997, 1115. 9) A.N. Ajjou, Tetrahedron Lett., 2001, 42, 13. 10) J.-E. Bäckvall, J. Organomet. Chem., 2002, 652, 105. 11) J.E. Jerome; R.H. Sergent, Chem. Ind., 2003, 89, 97.

COMMENTS :

1316

OPPOLZER ALLYL ALCOHOL SYNTHESIS EXAMPLE :

H H3C

CH3

O BrZn

+ H

HO

H

1) Ph

Ph

HO

H

NMe2

n

BuLi, Et2O

2) sat. aq. NH4Cl

MECHANISM :

Proposed transition state for Si-face addition : R3 N

H

L Li

O

H

L L Zn O H

H R1

R

R2

DISCONNECTION :

R1 R2

R1

O R +

HO H

R

H

Br

R2

NOTES : (Z)- and (E)-1-alkenylzinc bromides (starting from alkynes) react with aldehydes (highly Si-face selective addition) in the presence of lithiated (+)-N-methylephedrine or (+)-2-(N,N-dimethylamino)-1,2-diphenylethanol to afford secondary allylalcohols in high optical purity (up to 98%).

REFERENCES : 1) W. Oppolzer; R.N. Radinov, Tetrahedron Lett., 1988, 29, 5645. 2) W. Oppolzer; R.N. Radinov, Tetrahedron Lett., 1991, 32, 5777.

1317

3) W. Oppolzer; R.N. Radinov, Helv. Chim. Acta, 1992, 75, 170.

COMMENTS :

ORTON HALOANILINE REARRANGEMENT EXAMPLE :

Cl

N

O

O

O H

CH3

N

H

CH3

Cl

N

CH3

+

HCl, H2O

Cl

MECHANISM :

O Cl

N

Cl

CH3

H O N

HCl

O H CH3

CH3

N

- Cl2

Cl O H

N

H

H Cl

O H

H

N

CH3

H

N

Cl - H+

CH3

N

O

O

CH3

+ Cl

Cl

1318

CH3

DISCONNECTION :

O H

N

R

Cl

O Cl

N

R

O H

N

R

Cl

NOTES : The conversion of N-chloroacylamides into a mixture of o- and p-halogenoacylamides in the presence of hydrochloric acid (sometimes with iron(III) chloride) and usually in hydroxylic solvents (water, acetic acid), also photochemical rearrangement possible. See also Chattaway rearrangement, Fischer – Hepp rearrangement and Hofmann – Martius (Reilly – Hickinbottom) reaction.

REFERENCES : March : 559 Smith – March : 728

1) G. Bender, Ber. Dtsch. Chem. Ges., 1886, 19, 2272. 2) F.D. Chattaway; K.J.P. Orton, J. Chem. Soc., 1899, 75, 1046. 3) E.D. Hughes; C.K. Ingold, J. Chem. Soc., Quat. Rev., 1952, 6, 34. 4) S. Kinastowski; A. Nowacki, Tetrahedron Lett., 1982, 23, 3723. 5) P. Kanna; C. Venkatachalaphathy; K. Pitchumani, Indian J. Chem., 1999, 38B, 384. 6) J. Yamamoto; M. Tada; H. Kojima; Y. Isoda, J. Jpn. Oil Chem. Soc., 1999, 48, 463. 7) S. Gosh; S. Baul, Synth. Commun., 2001, 31, 2783.

COMMENTS :

1319

OSTROMYSLENSKI REACTION EXAMPLE :

CH3CHO + CH3CH2OH

Al2O3, ZnO 360 - 440 oC

DISCONNECTION :

CH3CHO + CH3CH2OH

NOTES : This reaction comprises the high temperature catalytic condensation of acetaldehyde and ethanol to form butadiene, most likely via 1,3-butanediol. For more about the reaction mechanism see Jones et al. See also Lebedev and Reppe butadiene reactions.

REFERENCES : Houben – Weyl : 4/2, 216

1) I. Ostromyslenski, J. Russ. Physik. Chem. Ges., 1915, 47, 1494. 2) G. Egloff; G. Hulla, Chem. Rev., 1945, 36, 63. 3) W.M. Quattlebaum; W.J. Toussaint; J.T. Dunn, J. Am. Chem. Soc., 1947, 69, 593. 4) H.E. Jones; E.E. Stahly; B.B. Corson, J. Am. Chem. Soc., 1949, 71, 1822.

COMMENTS :

1320

OVERMAN PYRROLIDINE SYNTHESIS EXAMPLE :

O

H

Pr N

CH3

CH3 PhCHO, heat

OCH3

Ph

N Pr

MECHANISM :

H3C

Pr

H N

O

O R

R

PhCHO, heat - H2O

Pr

O

H3C

CH3 O

R

N

Pr Ph

CH3

N

Ph Ph

N Pr

DISCONNECTION :

O R3 R4

R1

RO

R1 N R2

N R2

R3

+ R4CHO

H

NOTES : The carbon – carbon bond formation via tandem Mannich condensation, followed by a cationic aza-Cope rearrangement of the homoallylamines, to afford pyrolidines. See also Cope rearrangement and Mannich reaction.

REFERENCES : 1) L.E. Overman; M.-A. Kakimoto, J. Am. Chem. Soc., 1979, 101, 1310. 2) L.E. Overman; M.-A. Kakimoto; M.E. Okazaki; G.P. Meier, J. Am. Chem. Soc., 1983, 105, 6622. 3) L.E. Overman; L.T. Mendelson; E.J. Jacobsen, J. Am. Chem. Soc., 1983, 105, 6629. 4) M.-P. Heitz; L.E. Overman, J. Org. Chem., 1989, 54, 2591. 5) A. Padwa; B.H. Norman, J. Org. Chem., 1990, 55, 4801. 6) L.E. Overman, Aldrichimica Acta, 1995, 28, 107. 7) S.D. Knight; L.E. Overman; G. Pairaudeau, J. Am. Chem. Soc., 1995, 117, 5776. 8) N.J. Cooper; D.W. Knight, Tetrahedron, 2004, 60, 243.

1321

COMMENTS :

OVERMAN REARRANGEMENT EXAMPLE :

CCl3 H

OH H3C

CH3

1) NaH (cat.) Cl3CCN 2) Pd(II)

N

O

H3C

CH3

MECHANISM :

CCl3 OH R

HN

R1

NaH (cat.) Cl3CCN

CCl3 H

O

R

heat

R1

N

O

R

R1

HgX R H

N

R

R

HgX2 O

HX

CCl3

N

O

H

DISCONNECTION :

CCl3 OH N

O R

R

R1

1322

O CCl3

CCl3

H

N

R1

+ HgX2

NOTES : The formal [3,3]-sigmatropic rearrangement of the trichloroacetimidate of allylic alcohols to allylic trichloroacetamides, thereby transposing the hydroxyl and amino functions with high chirality transfer. An enormous rate acceleration is observed when the reaction is catalysed by mercuric(II) or palladium(II) salts. Contra-thermodynamic cases have also been reported. Excess of mercury salts and triphenyl phosphine are needed to overcome the thermodynamic preference. See also Belluš – Claisen rearrangement, Carroll (Kimel – Cope), Claisen (Claisen – Ireland) rearrangement, Cope, Eschenmoser – Meerwein – Claisen rearrangement, Ficini – Claisen, Johnson – Claisen and Marbet – Saucy reactions.

REFERENCES : 1) L.E. Overman, J. Am. Chem. Soc., 1974, 96, 597. 2) L.E. Overman, J. Am. Chem. Soc., 1976, 98, 2901. 3) L.E. Overman; C.B. Campbell; F.M. Knoll, J. Am. Chem. Soc., 1978, 100, 4822. 4) L.E. Overman, Acc. Chem. Res., 1980, 13, 218. 5) L.E. Overman, Angew. Chem., Int. Ed. Engl., 1984, 23, 579. 6) M. Isobe; Y. Fukuda; T. Nishikawa; P. Chabert; T. Kawai; T. Goto, Tetrahedron Lett., 1990, 31, 3327. 7) M.J. Brown; T. Harrison; P.M. Herrinton; M.H. Hopkins; K.D. Hutchinson; L.E. Overman; P. Mishra, J. Am. Chem. Soc., 1991, 113, 5365. 8) P. Metz; C. Mues; A. Schoop, Tetrahedron, 1992, 48, 1071. 9) A.M. Doherty; B.E. Kornberg; M.D.A. Reily, J. Org. Chem., 1993, 58, 795. 10) T. Nishikawa; M. Asai; N. Ohyabu; M. Isobe, J. Org. Chem., 1998, 63, 188. 11) N.M.A.J. Kriek; E. van der Hout; P. Kelly; K.E. van Meijgaarden; A. Geluk; T.H.M. Ottenhoff; G.A. van der Marel; M. Overhand; J.H. van Boom; A.R.P.M. Valentijn; H.S. Overkleeft, Eur. J. Org. Chem., 2003, 2418. 12) C.E. Anderson; L.E. Overman, J. Am. Chem. Soc., 2003, 125, 12412. 13) A.G. Jamieson; A. Sutherland; C.L. Willis, Org. Biomol. Chem., 2004, 2, 808. 14) C.E. Anderson; Y. Donde; C.J. Douglas; L.E. Overman, J. Org. Chem., 2005, 70, 648.

COMMENTS :

1323

1324

PERKIN BENZOFURAN SYNTHESIS · 1355 PERKIN COUMARIN REARRANGEMENT · 1356

B

PERKIN COUMARIN SYNTHESIS · 1356 PERKIN REACTION · 1358

BOBBIT MODIFICATION · 1391

PERKOW REACTION · 1360 PETASIS REACTION · 1361 H

PETASIS SYNTHESIS · 1363 PETERSON OLEFINATION REACTION · 1364

HALBERKANN VARIANT · 1369

PETRENKO – KRITSCHENKO PIPERIDONE SYNTHESIS · 1366 PEW REDUCTION · 1368

O

PFITZINGER – BORSCHE REACTION · 1369 PFITZNER – MOFFATT OXIDATION · 1370

OGLIALORO MODIFICATION · 1359

PHILLIPS – LADENBURG RING–CLOSURE · 1372 PICTET – GAMS ISOQUINOLINE SYNTHESIS · 1373 PICTET – SPENGLER ISOQUINOLINE SYNTHESIS · 1375

P

PILOTY – ROBINSON SYNTHESIS · 1377 PAAL – KNORR FURAN SYNTHESIS · 1326

PILOTY ALLOXAZINE SYNTHESIS · 1378

PAAL – KNORR PYRROLE SYNTHESIS · 1326

PINNER IMINOETHER SYNTHESIS · 1379

PADBURY – LINDWALL MODIFICATION · 1327

PINNER TRIAZINE SYNTHESIS · 1381

PADWA ANNULATION · 1328

PINNICK OXIDATION · 1382

PAOLINI de REACTION · 1330

PIRIA REACTION · 1383

PAQUETTE OLEFIN SYNTHESIS · 1331

PISHCHIMUKA REARRANGEMENT · 1385

PARHAM CYCLIC ALKYLATION · 1332

PLANCHER REARRANGEMENT · 1386

PARIKH – DOERING von OXIDATION · 1334

PLÖCHL REACTION · 1387

PARNES GEMINAL DIMETHYLATION · 1335

POLONOVSKI REACTION · 1388

PASSERINI REACTION · 1336

POMERANZ – FRITSCH REACTION · 1391

PASTO – MATTESON REARRANGEMENT · 1338

PONZIO REACTION · 1392

PATERNÒ – BÜCHI REACTION · 1339

POSNER TRIOXANE SYNTHESIS · 1393

PAULY – LOCKEMANN SYNTHESIS · 1340

POVAROV REACTION · 1395

PAUSON – KHAND REACTION · 1342

PRÉVOST REACTION · 1396

PAYNE REARRANGEMENT · 1344

PREY REACTION · 1398

PECHMANN von – DUISBERG SYNTHESIS · 1345

PRILESCHAJEW REACTION · 1399

PECHMANN von PYRAZOLE SYNTHESIS · 1347

PSCHORR – HOPPE SYNTHESIS · 1400

PECHMANN von synthesis · 1346

PSCHORR SYNTHESIS · 1402

PEDERSEN COUPLING · 1348

PUDOVIK REACTION · 1403

PEDERSEN CROWN ETHER SYNTHESIS · 1349

PUMMERER REARRANGEMENT · 1404

PELLIZZARI BENZIMIDAZOLE SYNTHESIS · 1351 PELLIZZARI REACTION · 1352

W

PELOUZE SYNTHESIS · 1353 PERKIN ALICYCLIC SYNTHESIS · 1354

WALTHER MODIFICATION · 1369

1325

PAAL – KNORR PYRROLE SYNTHESIS EXAMPLE :

O H3C

CH3

H3C

H N

CH3

NH3

O

MECHANISM :

H+ O O R

R1

R1 HO

O N R - H2O

R1NH2

R

R H

N

R

R

H

R1 R

N

R

R1 N

R2

+

- H2O, H

DISCONNECTION :

R

O O R

R2 + R1NH2

R1 = H, OH, NH2, PhN=

NOTES : The synthesis of pyrroles from 1,4-diketones, ammonia and certain amines, primary amines, hydroxylamine, glycine, hydrazine, and phenylhydrazine. In the presence of acid and without an amine source furans can be synthesised. Sometimes called the Paal – Knorr furan synthesis. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Padwa, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Houben – Weyl : E6a, 34, 64, 202, 205, 593; E6b, 467 Org. Synth. : 16, 25 Org. Synth. Coll. Vol. : 2, 219 Science of Synthesis : 9, 207, 298, 455

1326

1) C. Paal, Ber. Dtsch. Chem. Ges., 1885, 18, 367. 2) L. Knorr, Ber. Dtsch. Chem. Ges., 1885, 18, 299. 3) Ng.Ph. Buu–Hoï; Ng.D. Xuong; J.M. Gazave, J. Org. Chem., 1955, 20, 639. 4) E. Baltazzi; L.I. Krimen, Chem. Rev., 1963, 63, 511. 5) H.H. Wasserman; E. Gosselink; D.D. Kieth; J. Nadelson; R.J. Sykes, Tetrahedron, 1976, 32, 1863. 6) V. Amarnath; K. Amaranth, J. Org. Chem., 1991, 56, 6924. 7) B. Yan; A.P. Decaprio; M. Zhu; S. Bank, Chemical-Biological interactions, 1996, 102, 101. 8) J. Robertson; R.J.D. Hatley; D.J. Watkin, J. Chem. Soc., Perkin Trans. 1, 2000, 3389. 9) M. Curini; F. Montanari; O. Rosati; E. Lioy; R. Margarita, Tetrahedron Lett., 2003, 44, 3923. 10) B. Wang; Y. Gu; C. Luo; T. Yang; L. Yang; J. Suo, Tetrahedron Lett., 2004, 45, 3417. 11) B.K. Banik; I. Banik; M. Renteria; S.K. Dasgupta, Tetrahedron Lett., 2005, 46, 2521.

COMMENTS :

PADBURY – LINDWALL MODIFICATION EXAMPLE :

N

N

1) NaCN, BzCl 2) PhLi, CH3I Et2O 3) KOH, heat EtOH, H2O

CH3

MECHANISM :

N

N

NaCN BzCl

CN

N H3C CN O

Ph

KOH, heat EtOH, H2O

1327

Ph O

N CH3

PhLi, CH3I Et2O

DISCONNECTION :

N

N R

NOTES : This is a modification of the Reissert – Grosheintz – Fischer reaction, which employs isoquinoline. See also Reissert – Henze and Reissert – Grosheintz – Fischer reactions.

REFERENCES : March : 448 Smith – March : 533 Houben – Weyl : 7/1, 291 Org. React. : 7, 99; 8, 218 Org. Synth. : 38, 58; 56, 19 Org. Synth. Coll. Vol. : 4, 641; 6, 115

1) J.J. Padbury; H.G. Lindwall, J. Am. Chem. Soc., 1945, 67, 1268. 2) G.R. Clemo; M. Hoggarth, J. Chem. Soc., 1954, 95.

COMMENTS :

PADWA ANNULATION EXAMPLE :

SO2Ph PhO2S +

PhCH2NH2

SO2Ph

1328

1) NaOMe 2) DDQ

N CH2Ph

MECHANISM :

PhO2S HOCH2

CH2OH

1) PhSCl, Et3N 2) H2O2, HOAc

SO2Ph SO2Ph SO2Ph

PhO2S SO2Ph

H2NCH2Ph

H

SO2Ph SO2Ph

N

SO2Ph

SO2Ph

H N

- SO2Ph

N CH2Ph

DDQ

N CH2Ph

DISCONNECTION :

SO2Ph X

PhO2S X = C, N, O

SO2Ph

NOTES : The pyrrolines and pyrroles by [4+1] annulation of 2,3-bis(phenylsulfonyl)-1,3-butadiene and amines. Also 2,3-dihalo1-phenylsulfonyl-1-propenes are used as versatile reagents for the annulation of furans and cyclopentenones. A versatile range of compounds undergoes the tandem addition – proton exchange addition reaction with 2,3bis(phenylsulfonyl)-1,3-butadiene. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Piloty – Robinson, Schwanert, Trofimov and Zav’yalov reactions.

REFERENCES : Org. Synth. : 74, 147 Org. Synth. Coll. Vol. : 9, 82

1) A. Padwa; B.H. Norman, Tetrahedron Lett., 1988, 39, 2417. 2) A. Padwa; B.H. Norman, J. Org. Chem., 1990, 55, 4801. 3) A. Padwa; M. Ishida; C.L. Muller; S.S. Murphree, J. Org. Chem., 1992, 57, 1170. 4) A. Padwa; S.S. Murphree; Z.J. Ni; S.H. Watterson, J. Org. Chem., 1996, 61, 3829.

1329

COMMENTS :

de PAOLINI REACTION EXAMPLE :

CH3

CH3 N

N

(C6H5CO)2O2

CH3

H

MECHANISM :

CH3 N + CH3

CH3 N CH3

- H+

(C6H5CO)2O2

CH3 N + CH2

Ph

O

Ph

O O

O

CH3

Ph

O

+

N O

O

Ph O

CH3 N H2O

+ CH2O

+

Ph

H

OH O

DISCONNECTION :

R

R N Alk

R1

N H R, R1 = H

R1

NOTES : The dealkylation of tertiary amines with diacylperoxides. It is not exactly understood if the reaction mechanism involves a radical mechanism or nucleophilic substitution or both. The radical mechanism is shown here.

1330

REFERENCES : 1) I. de Paolini; G. Ribet, Gazz. Chim. Ital., 1932, 62, 1041. 2) S. Gambarjan; L. Kasarjan, J. Allg. Chem., 1933, 3, 222. 3) L. Horner; E. Schwenk, Liebigs Ann. Chem., 1950, 566, 69. 4) L. Horner; W. Kirmse, Liebigs Ann. Chem., 1955, 597, 48. 5) L. Horner; H. Brüggemann; K.H. Knapp, Liebigs Ann. Chem., 1959, 626, 1. 6) R. Huisgen; W. Heydkamp; F. Bayerlein, Chem. Ber., 1960, 93, 363.

COMMENTS :

PAQUETTE OLEFIN SYNTHESIS EXAMPLE : CH3

CH3 CH 3 SO2

CH3

1) nBuLi, CH3I 2) nBuLi, LiAlH4 3) heat

CH3 CH3

MECHANISM :

CH3 CH3 SO2

1) nBuLi 2) xs CH3I

SO2

CH3

1) nBuLi 2) LiAlH4 dioxane heat

CH3

DISCONNECTION :

H3C R

H3C

CH3

R

R

1331

O S O

CH3 R

NOTES : The desulfonation of sulfones to alkenes (alternative to Ramberg – Bäcklund). See also Corey – Kwiatkowski, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 1030 Smith – March : 1354 Org. Synth. : 57, 53 Org. Synth. Coll. Vol. : 6, 482

1) J.M. Photis; L.A. Paquette, J. Am. Chem. Soc., 1974, 96, 4715. 2) L.A. Paquette; J.M. Photis, J. Am. Chem. Soc., 1976, 98, 4936. 3) F. Vögtle; L. Rossa, Angew. Chem., Int. Ed. Engl., 1979, 18, 515. 4) W.D. Klobucar; L.A. Paquette; J.F. Blount, J. Org. Chem., 1981, 46, 4021.

COMMENTS :

PARHAM CYCLIC ALKYLATION EXAMPLE :

O Br

O Br

n

BuLi, - 100 oC

MECHANISM : O Br

O Br

n

BuLi, - 100 oC

Li

1332

O Br

- LiBr

DISCONNECTION :

X

X R

n

R1

n

R X = O, CH2 n = 1,2

hal

R1 hal

NOTES : The benzoheterocycle synthesis from di-halides using lithium bromine exchange. The halogen on the side chain can be replaced by a carboxylic acid. This reaction has been extended to a large range of heterocycles.

REFERENCES : 1) W.E. Parham; L.D. Jones; Y.A. Sayed, J. Org. Chem., 1976, 41, 1184. 2) C.K. Bradsher; D.C. Reames, J. Org. Chem., 1978, 43, 3800. 3) C.K. Bradsher; D.A. Hunt, Org. Prep. Proced. Int., 1978, 10, 267. 4) C.K. Bradsher; D.C. Reames, J. Org. Chem., 1981, 46, 1384. 5) W.E. Parham; C.K. Bradsher, Acc. Chem. Res., 1982, 15, 300. 6) M.S. Hendi; K.J. Natalie; S.B. Hendi; J.A. Campbell; T.D. Greenwood; J.F. Wolfe, Tetrahedron Lett., 1989, 30, 275. 7) S. Saeki, J. Syn. Org. Chem. Jpn, 1992, 50, 213. 8) M.I. Collado; I. Manteca; N. Sotomayor; M.J. Villa; E. Lete, J. Org. Chem., 1997, 62, 2080. 9) J. Ruiz; N. Sotomayor; E. Lete, Org. Lett., 2003, 5, 1115. 10) I. González–Temprano; I. Osante; E. Lete; N. Sotomayor, J. Org. Chem., 2004, 67, 3875. 11) I. Osante; E. Lete; N. Sotomayor, Tetrahedron Lett., 2004, 45, 1253.

COMMENTS :

1333

PARIKH – von DOERING OXIDATION EXAMPLE :

H3CO

H N

OCH3

O OCH3

OH

OCH3

O OCH3 Pyridine.SO3, DMSO Et3N, DCM

H3CO OCH3 CH3 H3C TBSO

H N

H3CO

O

H3CO OCH3 CH3 H3C TBSO

OTIPS

OTIPS

MECHANISM :

O S O O O S N H3C CH3

O S O O N

O O

S

O O

CH3 S CH3 OH R1

- SO42-

CH3 S H H3C O R

CH3 S H3C O R R1 H

N

R1

R

O R

R1

DISCONNECTION : OH

O R

R1

R R = H, Alk

R1

NOTES : The oxidation of primary or secondary alcohols, in a similar fashion as the Pfitzner – Moffatt oxidation. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Pfitzner – Moffatt, Pinnick, Sarett, Swern and Uemura reactions.

1334

REFERENCES : Smith – March : 1516

1) J.R. Parikh; W. von E. Doering, J. Am. Chem. Soc., 1967, 89, 5505. 2) K.C. Nicolaou; D.A. Nugiel; E. Couladouros; C.-K. Hwang, Tetrahedron, 1990, 46, 4517. 3) F. Fei; A. Murai, Synlett, 1995, 863. 4) J.S. Panek; C.E. Masse, J. Org. Chem., 1997, 62, 8290. 5) D.A. Evans; J.S. Johnson; E.J. Olhava, J. Am. Chem. Soc., 2000, 122, 1635. 6) A.B. Smith III; P.R. Verhoest; K.P. Minbiole; M. Schelhaas, J. Am. Chem. Soc., 2001, 123, 4834. 7) M.J. Porter; N.J. White; G.E. Howells; D.D.P. Laffan, Tetrahedron Lett., 2004, 45, 6541.

COMMENTS :

PARNES GEMINAL DIMETHYLATION EXAMPLE :

CH3 1.5 Me4Si, 1.5 AlBr3 10 CF3COOH

MECHANISM :

CH3

CH3

O CF3COOH CH3

CH3

TMS AlBr3

AlBr3

H

1335

CH3 CH3

CF3 O

DISCONNECTION :

CH3 n

CH3

CH3

n = 1,2

n

NOTES : The gem-dialkylation of cyclopentane or cyclohexane derivatives (vicinal dihalocyclohexanes or methylcyclohexane) with tetramethylsilane (TMS), Me4Ge, Me4Sn, Me3SnCl, Pr4Ge, Pr4Sn, Bu4Sn, and Bu4Si in the presence of AlBr3.

REFERENCES : 1) Z.N. Parnes; G.I. Bolestova; I.S. Akhrem; M.E. Vol’pin; D.N. Kursanov, J. Chem. Soc., Chem. Commun., 1980, 16, 748. 2) G.I. Bolestova; Z.N. Parnes; F.M. Latypova; D.N. Kursanov, Zhur. Org. Khim., 1981, 17, 1357. 3) G.I. Bolestova; Z.N. Parnes; M.E. Vol’pin, Zhur. Org. Khim., 1989, 25, 1442.

COMMENTS :

PASSERINI REACTION EXAMPLE :

H3C

CH3

Ph CH3 N H +

N C

+

EtCOOH

O

1336

1) heat 2) aq. Na2CO3

H3C OH O

MECHANISM :

R1

O H

O

O

R2 C R3

R1

C N

O HO R2 R3 Acyl rearrangement O N R

R OH

O R2 R1

O

R3

O R2

N R

tautomerism

R1

O

O

R3

N R

H

DISCONNECTION :

O R R 2 3 R1

O O

O H

N

R1COOH +

R N C

+

R2

R3

R

NOTES : Aldehydes and ketones react with aryl isocyanides in the presence of carboxylic acids to yield α-acyloxy-derivatives of N-arylamides. The use of trifluoroacetate esters gives milder hydrolysis conditions than for the normal esters. The reaction has been made catalytic and asymmetric by Denmark et al. Titanium tetrachloride assisted reactions are also known. See also Ugi reaction.

REFERENCES : March : 980 Smith – March : 1252 Smith : 676 Smith 2nd : 574 Houben – Weyl : 8, 355; E5, 1067, 1651

1) M. Passerini, Gazz. Chim. Ital., 1921, 51, 126. 2) I. Ugi, Angew. Chem., Int. Ed. Engl., 1962, 1, 8. 3) H. Eckert, Synthesis, 1977, 332. 4) T. Carofiglio; P.G. Cozzi; C. Floriani; A. Chiesi–Villa; C. Rizzoli, Organometallics, 1993, 12, 2726. 5) J.E. Semple; T.D. Owens; K. Nguyen; O.E. Levy, Org. Lett., 2000, 2, 2769. 6) Q. Xia; B. Ganem, Org. Lett., 2002, 4, 485. 7) G. Jenner, Tetrahedron Lett., 2002, 43, 1235. 8) S.E. Denmark; Y. Fan, J. Am. Chem. Soc., 2003, 125, 7825. 9) V. Nair; C. Rajesh; A.U. Vinod; S. Bindu; A.R. Sreekanth; J.S. Mathen; L. Balagopal, Acc. Chem. Res., 2003, 36, 899.

1337

10) M.A. Mironov; M.N. Ivantsova; M.I. Tokareva; V.S. Mokrushin, Tetrahedron Lett., 2005, 46, 3957.

COMMENTS :

PASTO – MATTESON REARRANGEMENT EXAMPLE :

Br

CH3 B CH3

H3C CH2Br

H3C heat

Br

B

CH2Br

MECHANISM :

Cl H Cl Cl

Ph B Br

Cl Br H OBu

Cl 1) H2O 2) BuOH

Cl

OBu B OBu Ph

Cl H Cl Cl

OBu B OBu Ph

NOTES : The intramolecular rearrangement of α-bromoorganoboranes, consisting in migration of the bromine atom to the boron and the reverse transition of the organic radical to the α-carbon atom. Organoboron compounds formed by the hydroboration of enethiols, enols and vinyl halides also undergo a similar rearrangement.

REFERENCES : 1) D.J. Pasto; J.L. Miesel, J. Am. Chem. Soc., 1962, 84, 4991. 2) D.S. Matteson; R.W.H. Mah, J. Am. Chem. Soc., 1963, 85, 2599. 3) D.J. Pasto; S.R. Snyder, J. Org. Chem., 1966, 31, 2773. 4) L.S. Vasilyev; V.V. Veselovskii; M.I. Struchkova; B.M. Mikhailov, J. Organomet. Chem., 1982, 226, 115.

1338

COMMENTS :

PATERNÒ – BÜCHI REACTION EXAMPLE :

H3C

O H3C

O

O

CH3

O

hν, Benzene

CH3

O

CH3 CH3 O

MECHANISM :

O

O

Ph O

Ph Ph

hν

Ph

+ Ph

Ph O

O

Ph hν

Ph

Ph

Ph

DISCONNECTION :

R2(R4) O R4(R2) R R5(R3) R1 R3(R5)

O R

R4

R5

R2

R3

+ R1

NOTES : The photochemical [2+2] cyclisation of carbonyls and olefins to oxetanes. The irradiation is usually carried out with light of the near UV region, in order to activate only the n --> π* transition of the carbonyl function, thus generating excited carbonyl species. Depending on the substrate this can be in a singlet or triplet excited state. See also Norrish type I and Norrish type II reactions.

1339

REFERENCES : March : 977 Smith – March : 1249 Smith : 1202 Smith 2nd : 994, 1218 Houben – Weyl : E3, 648; E15, 332

1) E. Paternò; C. Chieffi, Gazz. Chim. Ital., 1909, 39, 341. 2) G. Büchi; C.G. Inman; E.S. Lipinsky, J. Am. Chem. Soc., 1954, 76, 4327. 3) S.C. Freilich; K.S. Peters, J. Am. Chem. Soc., 1981, 103, 6255. 4) H.A.J. Carless; J. Beanland; S. Mwesigye–Kibende, Tetrahedron Lett., 1987, 28, 5933. 5) M.D. D’Auria; R. Racioppi; G. Romaniello, Eur. J. Org. Chem., 2000, 3265. 6) T. Bach; J. Schroder, Synthesis, 2001, 1117. 7) W. Adam; V.R. Stegmann, Synthesis, 2001, 1203. 8) M.D. D’Auria; L. Emanuele; G. Poggi; R. Racioppi; G. Romaniello, Tetrahedron, 2002, 58, 5045. 9) M.D. D’Auria; L. Emanuele; R. Racioppi; G. Romaniello, Curr. Org. Chem., 2003, 7, 1443. 10) M.D. D’Auria; L. Emanuele; R. Racioppi, Tetrahedron Lett., 2004, 45, 3877.

COMMENTS :

PAULY – LOCKEMANN SYNTHESIS EXAMPLE :

O

O

CH3 CO2CH3

OH 1) Na, 165 oC 2) KOH

1340

CH3 O

MECHANISM :

O

O

O Na, 165 oC

CH3 CO2CH3

O

O

O

CH2 O CH3

OH

O

OH

OH CH3

- CO2 O

DISCONNECTION :

H3C O

O

O O

R

R OH

OCH3 O

NOTES : Methyl o-acetoxybenzoates on treatment with sodium yield 4-hydroxycoumarins which may be hydrolysed. See also Anschütz hydroxycoumarin, Bargellini, Boyd – Robinson, Knoevenagel coumarin, Mentzer, von Pechmann, von Pechmann – Duisberg, Perkin coumarin and Simonis reactions.

REFERENCES : 1) H. Pauly; K. Lockemann, Ber. Dtsch. Chem. Ges., 1915, 48, 28. 2) E. Ziegler; H. Junek, Monatsh. Chem., 1955, 86, 29.

COMMENTS :

1341

PAUSON – KHAND REACTION EXAMPLE :

O H H CO, Co2(CO)8

MECHANISM :

R

R + Co2(CO)8

R

- 2 CO

R

R Co(CO)3 Co(CO)3

(CO)2Co

R Co(CO)3

- CO R

R R

R

Co(CO)3 Co(CO)3

Co(CO)3 Co(CO)3

CO

CO

O

O

O

R R (CO)6Co2

- Co2(CO)6

R

R

DISCONNECTION :

O R

O R

R2

R R

R2

R O

O

R1 +

R2

R R1

R

R1

NOTES : The cyclopentene synthesis from carbon monoxide, acetylene, and olefins. The reaction is cobalt carbonyl catalysed. The mechanism by Magnus is generally accepted. The reaction is also enantioselective if it is mediated by a chiral amine N-oxide or (S)-BINAP. Entrapped rhodium complexes can also catalyse this reaction. Faster reaction rates and higher yields can be obtained by using ultrasound, solid supports, phosphine oxides or acetonitrile as solvent. Krafft

1342

et al. has published several anomalous Pauson – Khand reactions, while Coogan et al. has studied an overlooked byproduct of the reaction. See also Nicholas reaction.

REFERENCES : Smith – March : 1091 Smith 2nd : 1257 Houben – Weyl : E18, 341 Org. React. : 40,1 Org. Synth. : 80, 93 Science of Synthesis : 1, 512, 596, 962

1) J.U. Khand; G.R. Knox; P.L. Pauson; W.E. Watts, J. Chem. Soc., Perkin Trans.1, 1973, 975. 2) P.L. Pauson, Tetrahedron, 1985, 41, 5855. 3) P. Magnus; L.M. Priciple, Tetrahedron Lett., 1985, 26, 4851. 4) W.J. Kerr; G.G. Kirk; D. Middlemiss, Synlett, 1995, 1085. 5) M.E. Krafft; A.M. Wilson; O.A. Dasse; B. Shao; Y. Cheung; Z. Fu; L.V.R. Boñaga; M.K. Mollman, J. Am. Chem. Soc., 1996, 118, 6080. 6) S.T. Ingate; J. Marco–Contelles, Org. Prep. Proced. Int., 1998, 30, 121. 7) Y. Keun, Coord. Chem. Rev., 1999, 297. 8) W.J. Kerr; D.M. Lindsay; M. McLaughlin; P.L. Pauson, Chem. Commun., 2000, 1467. 9) H. Xiong; R.P. Hsung; L.-L. Wei; C.R. Berry; J.A. Mulder; B. Stockwell, Org. Lett., 2000, 2, 2869. 10) K. Hiroi; T. Watanabe; R. Kawagishi; I. Abe, Tetrahedron: Asymmetry, 2000, 11, 797. 11) T. Sugihara; M. Yamaguchi; M. Nishizawa, Chem. Eur. J., 2001, 7, 1589. 12) M.E. Krafft; L.V.R. Boñaga; J.A. Wright; C. Hirosawa, J. Org. Chem., 2002, 67, 1233. 13) M.A. Pericas; J. Balsells; J. Castro; I. Marchueta; A. Moyano; A. Riera; J. Vazquez; X. Verdaguer, Pure Appl. Chem., 2002, 74, 167. 14) S.E. Gibson (née Thomas); A. Stevenazzi, Angew. Chem., Int. Ed., 2003, 16, 1800. 15) Y. Gimbert; D. Lesage; A. Milet; F. Fournier; A.E. Greene; J.-C. Tabet, Org. Lett., 2003, 5, 4073. 16) K.H. Park; S.U. Son; Y.K. Chung, Tetrahedron Lett., 2003, 44, 2827. 17) P.A. Wender; N.M. Deschamps; T.J. Williams, Angew. Chem., Int. Ed., 2004, 43, 3076. 18) T.J.M. de Bruin; A. Milet; A.E. Greene; Y. Gimbert, J. Org. Chem., 2004, 69, 1075. 19) M.P. Coogan; R.L. Jenkins; E. Nutz, J. Organomet. Chem., 2004, 689, 694. 20) C. Mukai; T. Kozaka; Y. Suzuki; I.J. Kim, Tetrahedron, 2004, 60, 2497. 21) L.V.R. Boñaga; M.E. Krafft, Tetrahedron, 2004, 60, 9795. 22) M. Rodríguez Rivero; J. Adrio; J.C. Carretero, Synlett, 2005, 26. 23) K.H. Park; Y.K. Chung, Synlett, 2005, 545.

1343

COMMENTS :

PAYNE REARRANGEMENT EXAMPLE :

H

O

H3C H trans

CH3 CH3 OH

CH3

CH3

HO 0.5 M NaOH

O erythro

CH3

MECHANISM :

R2 R

O

OH HO

R

-

R1

O R2

O

R

R

O O

R1

R1 R2

H2O

O OH R R1 2

DISCONNECTION :

R1 HX

R2

R4 O

R1

R3 X = NH, O

R4

X R2

H

R3

OH

NOTES : The rearrangement of 2,3-epoxy alcohols to an isomeric one using a base. The configuration at C-2 of the epoxide ring will be inverted via an SN2 mechanism. The product can revert to the starting material under the same conditions. A mixture of compounds is normally obtained. The application of aza-Payne rearrangements has been used for the synthesis of homochiral 1,2-amino alcohols.

REFERENCES : March : 391 Smith – March : 481 Smith 2nd : 229

1344

1) G.B. Payne, J. Org. Chem., 1962, 27, 3819. 2) C.S. Swindwell; B.P. Patel, J. Org. Chem., 1990, 55, 3. 3) T.W. Bell; J.A. Ciaccio, J. Org. Chem., 1993, 58, 5153. 4) T. Ibuka, Chem. Soc. Rev., 1998, 27, 145. 5) S. Inoue; M. Asami; K. Honda; K.S. Shrestha; M. Takahashi; T. Yoshino, Synlett, 1998, 679. 6) S.C. Bergmeier, Tetrahedron, 2000, 56, 2561. 7) A. Bouyacoub; F. Volatron, Eur. J. Org. Chem., 2002, 4143. 8) U. Rinner; P. Siengalewicz; T. Hudlický, Org. Lett., 2002, 4, 115. 9) T. Yamazaki; T. Ichige; T. Kitazume, Org. Lett., 2004, 6, 4073.

COMMENTS :

von PECHMANN – DUISBERG SYNTHESIS EXAMPLE :

O

OH HO

+

OH

OH + HO

O

OH H2SO4

O

EtO

O

CH3 O

O

H2SO4

O

HO CH3

1345

O

MECHANISM :

O

OH H3C

OEt O

O CH3

- EtOH

O

O H+

H+ O

O

O CH3 H OH

O

OH H+, - H2O

HO CH3

CH3

OH

OH H3C

OEt O

O

O OEt

- H+, - H2O

O

O

- EtOH

CH3 O

CH3

+

H

DISCONNECTION :

O

OH

O R1

R1

O

OEt

+ R

R = H, CH3

O

R

NOTES : Coumarins are formed, when a mixture of a phenol and malic acid are heated with e.g. concentrated sulfuric acid. This is formally the von Pechmann synthesis. The von Pechmann – Duisberg synthesis is the coumarin synthesis from phenols and ethyl acetoacetate. There are several proposed mechanisms in the literature. See also Anschütz hydroxycoumarin, Bargellini, Boyd – Robinson, Knoevenagel coumarin, Mentzer, von Pechmann, Pauly – Lockemann, Perkin coumarin and Simonis reactions.

REFERENCES : Smith 2nd : 1109 Houben – Weyl : 6/2, 641 Org. React. : 7, 1 Org. Synth. : 24, 69 Org. Synth. Coll. Vol. : 3, 581

1346

1) H. von Pechmann; C. Duisberg, Ber. Dtsch. Chem. Ges., 1883, 16, 2119. 2) S.M. Sethna; N.M. Shah, Chem. Rev., 1945, 36, 1. 3) M. Miyano; C.R. Dorn, J. Org. Chem., 1972, 37, 259. 4) A.G. Osborne, Tetrahedron, 1981, 37, 2021. 5) J.E.T. Corrie, J. Chem. Soc., Perkin Trans. 1, 1990, 2151. 6) V. Singh; J. Singh; K.P. Kaur; G.L. Kad, J. Chem. Res., 1997, 58. 7) B.M. Reddy; V.R. Reddy; D. Giridhar, Synth. Commun., 2001, 31, 3603. 8) S. Frère; V. Thiéry; T. Besson, Tetrahedron Lett., 2001, 42, 2791. 9) A.C. Khandekar; B.M. Khadikar, Synlett, 2002, 152. 10) P.R. Singh; D.U. Singh; S.D. Samant, Synlett, 2004, 1909.

COMMENTS :

von PECHMANN PYRAZOLE SYNTHESIS EXAMPLE :

H

H + CH2N2

N H

N

MECHANISM :

Ph

Ph

N N Ph

OCH3

Et2O

H O

N

Ph

N

Ph

160 C H

O

R R N H

H

N

N2

R + R1

1347

OCH3

Ph

OCH3

DISCONNECTION :

R2

N

o

O

R1

H N

NOTES : Pyrazole is obtained by treating acetylene with diazomethane derivatives in a 1,3-dipolar cycloaddition. See also Balbiano and Knorr pyrazole reactions.

REFERENCES : 1) E. Buchner, Ber. Dtsch. Chem. Ges., 1889, 22, 842. 2) H. von Pechmann, Ber. Dtsch. Chem. Ges., 1898, 31, 2950. 3) R. Huisgen, Angew. Chem., 1963, 75, 616. 4) T. Aoyama; S. Inoue; T. Shioiri, Tetrahedron Lett., 1984, 25, 433. 5) T. Asaki; T. Aoyama; T. Shioiri, Heterocycles, 1988, 27, 343. 6) D.R. Sauer; S.W. Schneller, J. Org. Chem., 1990, 55, 5535.

COMMENTS :

PEDERSEN COUPLING EXAMPLE :

N NbCl4(THF)2 + 2

NH2

TMS H

1) DME 2) 10% aq. KOH

H2N

MECHANISM :

N NbCl4(THF)2 + 2

TMS H

N NbCl3(DME) DME - 2 TMSCl

NH2 10% aq. KOH

H2N

1348

(DME)Cl3Nb N

DISCONNECTION :

N NH2

R

TMS H

R

R

NH2

R

N

NOTES : The coupling of nitriles or N-(trimethylsilyl)imines promoted by niobium(I) reagent. See also Fujiwara lanthanide reaction.

REFERENCES : 1) L.E. Manzer, Inorg. Chem., 1977, 16, 525. 2) E.J. Roskamp; S.F. Pedersen, J. Am. Chem. Soc., 1987, 109, 3152. 3) J.B. Hartung, jr.; S.F. Pedersen, Organometallics, 1990, 9, 1414.

COMMENTS :

PEDERSEN CROWN ETHER SYNTHESIS EXAMPLE :

O OH + OH

O

O Cl

Cl

1) NaOH, heat n BuOH 2) H2 (70 atm.) Ru, Al2O3 n BuOH, 100 oC

1349

O

O

O O

MECHANISM :

OH 2

+

ClCH2CH2

O

OTHP THPO CH2CH2Cl

OTHP

NaOH 1-Butanol OH

HO +

+

H , CH3OH

O

ClCH2CH2

O

O O

O

CH2CH2Cl

O O O

NaOH 1-Butanol

O

O

O

O O

NOTES : The crown ether formation and its use in substitutions, oxidations etc. The original crown ether discovered by Pedersen has six oxygen atoms exposed along the inside wall of the ring. When atoms of certain metallic elements such as sodium or potassium pass through the center of the ring, they attach themselves to the exposed oxygen atoms and fit like a key in a lock. The second scheme shows an example of the use of crown ethers.

REFERENCES : Org. Synth. : 52, 66; 57, 30 Org. Synth. Coll. Vol. : 6, 301, 395

1) A. Lüttringhaus; K. Ziegler, Liebigs Ann. Chem., 1937, 528, 155. 2) C.J. Pedersen, J. Am. Chem. Soc., 1967, 89, 2495. 3) C.J. Pedersen, J. Am. Chem. Soc., 1971, 93, 4684. 4) A.M. Kolodzijczyk; M. Manning, J. Org. Chem., 1981, 46, 1944. 5) K.E. Krakowiak; J.S. Bradshaw; D.J. Zamecka–Krakowiak, Chem. Rev., 1989, 89, 929. 6) Y. Machida; H. Nishi; K. Nakamura, Chirality, 1999, 11, 173.

COMMENTS :

1350

PELLIZZARI BENZIMIDAZOLE SYNTHESIS EXAMPLE :

CN N NH2

N H

CN N

N

2 BrCN EtOH

H

MECHANISM :

N 2

R N H

CN N H N H

R

NH2

BrCN Et2O - PhNH3+Br-

R O

N H H+

Cl

R1

Et3N N

H+

R heat

N

NH2 O

H

N N

R N H

R1

O R1

DISCONNECTION :

N R N H

H N R1

2 R N H

NH2

NOTES : The thermal rearrangement of 1-aryl-2-cyanohydrazines to afford 2-aminobenzimidazoles.

REFERENCES : 1) G. Pellizari; A. Gaiter, Gazz. Chim. Ital., 1918, 48, 151. 2) C.W. Bird; C.K. Wong, Tetrahedron Lett., 1974, 15, 1251. 3) C.W. Bird; J. Cobb; S.C. Nyburg; A.W. Parkins, Tetrahedron, 1995, 51, 13161. 4) M.T.V.L. Carvalho; A.M. Lobo; P.S. Branco; S. Prabhakar, Tetrahedron Lett., 1997, 38, 3115.

1351

C N

R1 O

COMMENTS :

PELLIZZARI REACTION EXAMPLE :

H2N

H + O

N N

H2N N Ph HO

270 - 290 oC

N H

Ph

MECHANISM :

H+ H2N N O HO H NH2

H+

H Ph

H

HO

N H

H N N

Ph OH

Ph NH O

O

H N N

HO

Ph NH2

H N N

N N HO

H

H

- 2 H2O

Ph

N H

DISCONNECTION :

N N R1

N H

R1 R

NH2 O

+

H2N N R HO

NOTES : The triazole will be formed during distillation of the hydrazide with the amide. See also Einhorn – Brunner reaction.

REFERENCES : 1) G. Pellizzari, Gazz. Chim. Ital., 1911, 41/II, 20. 2) K.T. Potts, Chem. Rev., 1961, 61, 87. 3) E.J. Browne; J.B. Polya, J. Chem. Soc., 1962, 5149.

1352

COMMENTS :

PELOUZE SYNTHESIS EXAMPLE : OEt O S O + KCN OEt

EtCN

MECHANISM :

Et

O

O S

O

O

Et

EtCN

+

O O

O S

O

Et

CN

DISCONNECTION :

AlkCN

(Alk)2SO4 + KCN

NOTES : The cyanide alkylation between potassium cyanide and alkyl sulfates. See also Kolbe cyanide reaction.

REFERENCES : Houben –Weyl : 8, 306

1) J. Pelouze, Liebigs Ann. Chem., 1834, 10, 249. 2) D.T. Mowry, Chem. Rev., 1948, 42, 189.

1353

COMMENTS :

PERKIN ALICYCLIC SYNTHESIS EXAMPLE :

Br

OEt

EtO

+

Br

COOH 1) EtONa 2) HCl

O

O

MECHANISM :

OEt

EtO O

EtONa

O

Br

O

O O

Br

OEt

EtO

O

OEt O

OEt

Br H O

OEt

EtONa

Br

OEt

O OEt OEt

COOH

HCl

O

DISCONNECTION :

EtO n

OEt

COOH

+ O

O

n

Br

Br

NOTES : The synthesis of cycloalkane carboxylic acids from α,ω-dihaloalkanes and sodium diethyl malonate. See also Claisen alkylation, Freund and Knoevenagel condensation reactions.

REFERENCES : Smith : 880

1354

Smith 2nd : 733 Org. Synth. : 23, 16 Org. Synth. Coll. Vol. : 3, 213

1) W.H. Perkin, jr., Chem. Ber., 1883, 16, 1793. 2) L.M. Rice; C.H. Crogan, J. Org. Chem., 1961, 26, 54. 3) M. Julia; M. Maumy, Bull. Soc. Chim. Fr., 1969, 2415. 4) R. Fajgar; J. Pola, J. Org. Chem., 1993, 58, 7709. 5) A. Krause; H. Lackner, Z. Naturforsch. B, 1998, 53, 1043. 6) W. Dmowski; A. Wolniewicz, J. Fluorine Chem., 2000, 102, 141.

COMMENTS :

PERKIN BENZOFURAN SYNTHESIS EXAMPLE : HO

O

O

HO

O COOH

5% KOH

Cl COOH

COOH

MECHANISM :

R

R

Br Br

+ Br2 O

O

O

R

R

O

O heat, KOH

O

Br

- KBr R

R COOH O

- HBr KOH

OH

Br O

O

- CO2

O

1355

DISCONNECTION :

R1

R1 R

X R

COOH O

O

O

NOTES : The base-catalysed rearrangement of 3-halogen-substituted coumarins into the corresponding coumarone-2carboxylic acid.

REFERENCES : Org. React. : 1, 210

1) W.H. Perkin, J. Chem. Soc., 1870, 23, 368. 2) W.H. Perkin, J. Chem. Soc., 1871, 24, 37. 3) B.B. Dey, J. Chem. Soc., 1915, 107, 1606. 4) G.W. Holton; G. Parker; A. Robertson, J. Chem. Soc., 1949, 2049. 5) P. Cagniant; D. Cagniant, Adv. Heterocycl. Chem., 1975, 18, 337. 6) K. Bowden; S. Battah, J. Chem. Soc., Perkin Trans. 2, 1998, 1603.

COMMENTS :

PERKIN COUMARIN SYNTHESIS EXAMPLE :

OH H

O + (CH3CO)2O

CH3CO2Na

O

1356

O

MECHANISM :

OH H

OH + (CH3CO)2O + CH3CO2Na

O

O

O

O

O

O O

- NaOH

DISCONNECTION :

OH

R

R

H O

NOTES : Coumarins unsubstituted in the pyrone ring are obtained by heating an o-hydroxyaryl aldehyde with acetic anhydride and sodium acetate. See also Anschütz hydroxycoumarin, Bargellini, Boyd – Robinson, Dieckmann – Meiser, Knoevenagel, Mentzer, Pauly – Lockemann, von Pechmann – Duisberg and Simonis reactions.

REFERENCES : Org. React. : 1, 210

1) W.H. Perkin, J. Chem. Soc., 1868, 21, 53. 2) W.H. Perkin, J. Chem. Soc., 1868, 21, 181. 3) S.M. Sethna; N.M. Shah, Chem. Rev., 1945, 36, 1. 4) J.A. Mahling; R.R. Schmidt, Liebigs Ann. Chem., 1995, 467. 5) K. Felfoldi; M. Sutyinsky; N. Nagy; I. Palinko, Synth. Commun., 2000, 30, 1543.

COMMENTS :

1357

PERKIN REACTION EXAMPLE :

H O O

H3C

+

O

COOH

CH3

O

base CH3

MECHANISM :

O R

O

O R

R

O H

O

R

R

O

H

B

R

O O

O

O

H

O

O

R

R O

O O

O O

R O

H

R

R

O O

O

R

R

O

H H

O

O

H

R

O

O

O

R O O

R

R R

R O R

O

O

O

O O R

1358

COOH

O

O

O

H

H+

O

R R

DISCONNECTION :

H O

R

O +

R

O O

R

COOH

NOTES : This aldol-type reaction involves the base-catalysed condensation of a carbonyl compound, or in a few cases an imine and an acid anhydride. The alkali salt of the acid can function as the base and amides can be employed instead of anhydrides. Sodium phenylacetate and acetic anhydride react with benzaldehydes to yield α-phenylcinnamic acids. This is the Oglialoro modification of the Perkin reaction (Gazz. Chim. Ital., 1878, 8, 429). See also Claisen cinnamic, Claisen – Schmidt, Doebner, Erlenmeyer – Plöchl, Knoevenagel, Perkin, Pschorr and Stobbe reactions.

REFERENCES : March : 953 Smith – March : 1219, 1229 Smith : 894 Smith 2nd : 748 Org. React. : 1, 210; 3, 198 Org. Synth. : 33, 70 Org. Synth. Coll. Vol. : 4, 777 Houben – Weyl : 4/2, 30; 8, 442 Science of Synthesis : 10, 48, 159, 278

1) W.H. Perkin, J. Chem. Soc., 1868, 21, 53. 2) P.H. Leake, Chem. Rev., 1956, 56, 27. 3) R. Ketcham, J. Chem. Educ., 1964, 41, 565. 4) M. Iwata; S. Emoto, Bull. Chem. Soc. Jpn., 1976, 49, 1369. 5) G. Karminskizamola; L. Fiserjakic; M. Bajic, Heterocycles, 1985, 23, 313. 6) A.Sr. Anjaneyulu; G.S. Rani; U.V. Mallavadhani; L.N. Murthy, Indian J. Chem., 1990, 29B, 219. 7) J.A. Mahling; R.R. Schmidt, Liebigs Ann. Chem., 1995, 467. 8) K. Felfoldi; M. Sutyinszky; N. Naay; I. Palinko, Synth. Commun., 2000, 30, 1543. 9) D.V. Sevenard, Tetrahedron Lett., 2003, 44, 7119.

COMMENTS :

1359

PERKOW REACTION EXAMPLE :

Br

EtO EtO P O O

Br + 2 P(OEt)3 O

O

OEt O P OEt O

MECHANISM :

O

O

C X

(RO)3P

H

O C X

(RO)2P O R

H P(OR)3

O (RO)2P O

H - RX X

DISCONNECTION :

O AlkO

O

P OAlk R

O R1

X + P(OR) 3

R R1

NOTES : The reaction of α-haloketones with trialkyl phosphite to give ketophosphonate or vinylphosphate with a predomantly E-configuration. See also Abramov, Arbusov (Michaelis – Arbuzov) and Michaelis – Becker – Nylén reactions.

REFERENCES : Houben – Weyl : 12/2, 348

1) W. Perkow; K. Ullerich; F. Meyer, Naturwissenschaften, 1952, 39, 353. 2) W. Perkow, Chem. Ber., 1954, 87, 755. 3) F.W. Lichtenthaler, Chem. Rev., 1961, 61, 607. 4) I.J. Borowitz; S. Firstenberg; G.B. Horowitz; D. Schuessler, J. Am. Chem. Soc., 1972, 94, 1623. 5) M. Sekine; M. Nakajima; T. Hata, J. Org. Chem., 1981, 46, 4030. 6) J. Thiem; D. Rasch, Nucleosides, Nucleotides, 1985, 4, 487. 7) P.N. Nagar, Phosphorus Sulfur, 1993, 79, 207. 8) T. Janecki; R. Bodalski, Heteroatom Chem., 2000, 11, 115.

1360

COMMENTS :

PETASIS REACTION EXAMPLE :

O

CH2 O OCH3

CH2 Cp2TiMe2 THF, 60 oC

OCH3

MECHANISM :

Cp2TiCl2

Cp2TiMe2

CH3Li

Petasis mechanism :

O H3C

H3C CH3

+

Cp2 Ti O CH3

Cp Ti

H3C

H

Cp

- CH4

+

O TiCp2

Hughes mechanism :

O H3C

H3C CH3

+

H3C

Cp Ti

H3C

O

Cp

+

TiCp2

H3C

O TiCp2

1361

TiCp2 O

DISCONNECTION :

O R

R

R1

R1

NOTES : The titanium-mediated carbonyl olefination using titanium cyclopentadienide. There are two mechanisms published in the literature the original one by Petasis et al. and one by Hughes et al. The latter one is the accepted one. See also Corey – Kwiatkowski, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 933 Smith – March : 1271 Smith : 813 Smith 2nd : 680 Org. Synth. : 69, 72 Org. Synth. Coll. Vol. : 8, 512

1) N.A. Petasis; E.I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392. 2) N.A. Petasis; E.I. Bzowej, J. Org. Chem., 1992, 57, 1327. 3) N.A. Petasis; S.-P. Lu, J. Am. Chem. Soc., 1995, 117, 6394. 4) N.A. Petasis; S.-P. Lu, Tetrahedron Lett., 1995, 36, 2393. 5) D.L. Hughes; J.F. Payack; D. Cai; T.R. Verhoeven; P.J. Reider, Organometallics, 1996, 15, 663. 6) N.A. Petasis; Y.-H. Hu, J. Org. Chem., 1997, 62, 782. 7) R.C. Hartley; G.J. McKiernan, J. Chem. Soc., Perkin Trans. 1, 2002, 2763. 8) E.C. Meurer; L.S. Santos; R.A. Pilli; M.N. Eberlin, Org. Lett., 2003, 5, 1391. 9) M.J. Cook; D.W. Fleming; T. Gallagher, Tetrahedron Lett., 2005, 46, 297.

COMMENTS :

1362

PETASIS SYNTHESIS EXAMPLE :

Ph O Ph

N H

CH3

+

N

OH

CH3 OH

Ph

H OH B OH

Ph

MECHANISM :

O

OH

OH

R5 N R4

+

R4

H

H

OH

N R5

R6

R6

R3 R2 R1 R3

OR B OR

R2

R4

R4 OH B OH O

R5

OH

R1 H2O - B(OH)3

N R5

N

R2

R3

R6

R6

R1 - H2O

DISCONNECTION :

R3 R4 R2 R1

R5 N

R6 O OH

R3

OR B OR

R2 R1

+

R5 N R6 H

R4

O

O

OH

+

NOTES : This is a three-component variant of the Mannich reaction involving the condensation of an organoboronic acid or boronate with an amine and an α–keto acid. Glyoxal and its derivatives have also been used. See also Mannich reaction.

1363

REFERENCES : 1) N.A. Petasis; I.A. Zavialov, Tetrahedron Lett., 1996, 37, 567. 2) N.A. Petasis; I.A. Zavialov, J. Am. Chem. Soc., 1997, 119, 445. 3) N.A. Petasis; A.K. Yudin; I.A. Zavialov; G.K.S. Prakash; G.A. Olah, Synlett, 1997, 606. 4) G.K.S. Prakash; M. Mandal; S. Schweizer; N.A. Petasis; G.A. Olah, Org. Lett., 2000, 2, 3173. 5) N.A. Petasis; S. Boral, Tetrahedron Lett., 2001, 42, 539. 6) F. Berrée; A. Debache; Y. Marsae; B. Carboni, Tetrahedron Lett., 2001, 42, 3591. 7) T. Koolmeister; M. Södergren; M. Scobic, Tetrahedron Lett., 2002, 43, 5969. 8) D. Naskar; A. Roy; W.L. Seibel, Tetrahedron Lett., 2003, 44, 8861. 9) S. Sugiyama; S. Arai; K. Ishii, Tetrahedron: Asymmetry, 2004, 15, 3149. 10) K.K. Nanda; B.W. Trotter, Tetrahedron Lett., 2005, 46, 2025.

COMMENTS :

PETERSON OLEFINATION REACTION EXAMPLE :

O H3C

CH3

1) Me3Si

MgCl

2) AcOH, NaH

1364

H3C

CH3

MECHANISM :

X R

H R

X

SiMe3 OM

X SiMe3

X

1) base 2) R1CHO

R

R H

SiMe3 OM

X

1) PDC 2) DIBAL

X R

X

R NaOAc, AcOH

H

R SiMe3

KH, THF

OH

X

DISCONNECTION : O R

R

R1

R1

NOTES : The synthesis of alkenes from α-silyl carbanions (lithium or magnesium salt) and carbonyl compounds. In cases where separation of β-silylalcohol diastereoisomers can be achieved, pure Z or E olefins can be isolated. Acidic workup gives anti elimination, while basic conditions gives syn elimination. Advantages of this reaction over the Wittig reaction include, by-products are more easily removed and the reaction suffers less from steric effects. Both concerted and step-wise mechanisms are possible. There is a Corey modification of this reaction. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Ramberg – Bäcklund, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 952 Smith – March : 1228 Smith : 755 Smith 2nd : 638 Houben – Weyl : E11, 292, 779, 1236, 1449; E15, 921 Org. React. : 38,1 Org. Synth. : 73, 50

1365

Org. Synth. Coll. Vol. : 9, 580 Science of Synthesis : 10, 449

1) D.J. Peterson, J. Org. Chem., 1968, 33, 780. 2) E.J. Corey; D. Enders; M.G. Bock, Tetrahedron Lett., 1976, 17, 7. 3) D.J.S. Tsai; D.S. Matteson, Tetrahedron Lett., 1981, 22, 2751. 4) D.J. Ager, Synthesis, 1984, 384. 5) A. Couture; H. Cornet; P. Grandclaudon, J. Organomet. Chem., 1992, 440, 7. 6) D. Bell; E.A. Crowe; N.J. Dixon; G.R. Green; I.S. Mann; M.R. Shipton, Tetrahedron, 1994, 50, 6643. 7) C.-C. Chang; Y.-H. Chen; Y.-T. Hsieh; T.-Y. Luh, J. Org. Chem., 2000, 65, 4694. 8) L.F. van Staden; D. Gravestock; D.J. Ager, Chem. Soc. Rev., 2002, 31, 195. 9) W. Adam; C.M. Ortega–Schulte, Synlett, 2003, 414.

COMMENTS :

PETRENKO–KRITSCHENKO PIPERIDONE SYNTHESIS EXAMPLE :

O O EtO

O

O

O

O OEt

+ 2

Ph

H

+ Ph NH2

EtO Ph

O

1366

OEt N Ph

Ph

MECHANISM :

H

O

O

O

EtO

H

O

Ph

H

O

EtO Ph

OEt

Ph

O

H

OEt Ph OH

- H2O

OH

O

O

O

Ph NH2

H+

H+ O

EtO Ph H N Ph

O

O OEt Ph OH

O

O

EtO

OEt

- H2O Ph

N Ph

Ph

DISCONNECTION :

O

O

O

RO

O

OR R1

N R2

R1

O

O

RO

OR

+ 2

R1

H

+ R2 NH2

O

NOTES : The ring-closure of two molecules of aldehyde with ammonia or primary amines and dialkyl 3-oxopentanedioates. See also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Guareschi – Thorpe, Hantzsch – Beyer, von Meyer – Mohr, Riehm pyridine, Robinson – Schöpf and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES : 1) P. Petrenko–Kritschenko; N. Zoneff, Ber. Dtsch. Chem. Ges., 1906, 39, 1358. 2) P. Petrenko–Kritschenko; S. Schoettle, Ber. Dtsch. Chem. Ges., 1909, 42, 2020. 3) R. Robinson, J. Chem. Soc., 1917, 111, 762. 4) R. Robinson, J. Chem. Soc., 1917, 111, 876. 5) C. Mannich; O. Hieronimus, Ber. Dtsch. Chem. Ges., 1942, 75, 49. 6) H. Leonard, J. Am. Chem. Soc., 1957, 79, 5279. 7) U. Holgrabe; B. Piening; R. Kohlmorgen; E. Stoll, Arch. Pharm. (Weinheim, Ger.), 1988, 321, 917. 8) M. Langlois; D. Yang; J.-L. Soulier; C. Florac, Synth. Commun., 1992, 22, 3115.

COMMENTS :

1367

PEW REDUCTION EXAMPLE :

O

O OH O

Na2S2O4 aq. Na2CO3 100 oC

OH O

MECHANISM :

2 Na2S2O4

4 H2 O

4 NaHSO3 + 4 H+

NOTES : This is the classical reduction of flavonols to dihydroflavonols by sodium hydrosulfite (sodium dithionate) at 100 oC in aqueous sodium carbonate solution. This method is generally used for the reductions of nitroso compounds to amines, azo compounds to amines, ketones to alcohols, and quinines to hydroquinones and aldehydes.

REFERENCES : Org. Synth. : 3, 7; 17, 9; 29, 8; 34, 1; 37, 15 Org. Synth. Coll. Vol. : 1, 49; 2, 39; 3, 69; 4, 15, 247

1) J.C. Pew, J. Am. Chem. Soc., 1948, 70, 3031. 2) O. Louisandre; G. Gelbarg, Bull. Soc. Chim. Fr., 1986, 565.

COMMENTS :

1368

PFITZINGER – BORSCHE REACTION EXAMPLE :

O

COOH OC3H7

O +

O

O

Ph

KOH EtOH

N H

N

Ph

MECHANISM :

O

O

O O

O

OH NH2

KOH, EtOH heat

N H

R1

R

OH

O

O

COOH R1

H+

N

- H2O

N

R

R1

R

DISCONNECTION :

COOH R1

O

O O

N

N H

R

+

R

R1

NOTES : Quinoline-4-carboxylic acids from isatins and α-methylene carbonyl compounds. The Walther modification uses iminonitrile. The Halberkann variant uses N-acetyl isatines for the synthesis of quinolinic acids. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Riehm quinoline and Skraup quinoline reactions.

1369

REFERENCES : Houben – Weyl : E6a, 985; E7a, 388; E7b, 140 Org. Synth. : 40, 54 Org. Synth. Coll. Vol. : 5, 635

1) W. Pfitzinger, J. Prakt. Chem., 1886, 33, 100. 2) J. Halberkann, Ber. Dtsch. Chem. Ges., 1921, 54, 3090. 3) R.H. Manske, Chem. Rev., 1942, 30, 113. 4) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 5) H.R. Henze; J.W. Melton; E.O. Forman, J. Am. Chem. Soc., 1948, 70, 2622. 6) Q.P. Chen; L.W. Deady, Aust. J. Chem., 1993, 46, 987. 7) K. Lackey; D.D. Sternbach, Synthesis, 1993, 993. 8) T.S.T. Wang; R.A. Fawwaz; R.L. van Heertum, J. Labelled Compd. Radiopharm., 1995, 36, 671. 9) C. Rivall; E. Bisagni, J. Heterocycl. Chem., 1997, 34, 441. 10) R.T. Pardasani; P. Pardasani; D. Sherry; V. Chaturvedi, Indian J. Chem., 2001, 40B, 1275. 11) A.V. Ivachtchenko; A.V. Khvat; V.V. Kobak; V.M. Kysil; C.T. Williams, Tetrahedron Lett., 2004, 45, 5473.

COMMENTS :

PFITZNER – MOFFATT OXIDATION EXAMPLE :

OH H3C

O H

CH3

DMSO, DCC, H+ H3C

1370

CH3

MECHANISM :

H3C

S O

CH3 H3C

O

CH3

S O N C N H

N C N H+

H+

O

H3C H3C

H

H

+

S O C H

H3C

CH3

Me2S

N

+

N

H

H

O

B

DISCONNECTION :

O R

OH H3C

R1

H CH3

NOTES : The mild oxidation of alcohols to ketones or aldehydes using DCC-DMSO. Phenyl dichlorophosphate has been shown to be an efficient DMSO-activating agent in this oxidation. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pinnick, Sarett, Swern and Uemura reactions.

REFERENCES : March : 1193 Smith – March : 1516 Smith : 235 Smith 2nd : 206 Houben – Weyl : E11, 852 Org. React. : 39, 297 Org. Synth. : 47, 25 Org. Synth. Coll. Vol. : 5, 242

1) K.E. Pfitzner; J.G. Moffatt, J. Am. Chem. Soc., 1963, 85, 3027. 2) W.W. Epstein; F.W. Sweat, Chem. Rev., 1967, 67, 247.

1371

3) G.H. Jones; J.G. Moffatt, Methods Carbohydr. Chem., 1972, 6, 315. 4) I. Dyong; R. Hermann; G. von Kiedroski, Synthesis, 1979, 526. 5) R. Schobert, Synthesis, 1987, 741. 6) H.-J. Liu; J.M. Nyangulu, Tetrahedron Lett., 1988, 29, 3267. 7) T.T. Tidwell, Synthesis, 1990, 857. 8) B. Sauerbrei; J. Niggemann; S. Gröger; S. Lee; H.G. Floss, Carbohydr. Res., 1996, 280, 223. 9) S. Ichikawa; S. Shuto; A. Matsuda, J. Am. Chem. Soc., 1999, 121, 10270.

COMMENTS :

PHILLIPS – LADENBURG RING–CLOSURE EXAMPLE :

NH2 N

N O

H +

Et N

HO

CH2CH3

HCl

MECHANISM :

NH2 O

NH2 N

O

H HO

H+ N

R

N

R

R - H2O

HCl, - H2O

1372

N

DISCONNECTION :

NH2

N R

N R1

N R1

H

O + HO

R

NOTES :

The formation of benzimidazole starting from mono- or disubstituted N-acyl-o-diamine with substituted aliphatic carboxylic acids (no amino acids).

REFERENCES : Houben – Weyl : E8c, 232, 270

1) A. Ladenburg, Ber. Dtsch. Chem. Ges., 1875, 8, 677. 2) A. Phillips, J. Chem. Soc., 1928, 172. 3) E.W. Malmberg; C.S. Hamilton, J. Am. Chem. Soc., 1948, 70, 2415. 4) J.L. LaMattina; C.J. Mularkski, J. Org. Chem., 1984, 49, 4800. 5) A.M. Tikdari; A.K. Mukerjee, Indian J. Chem., 1987, 26B, 73. 6) T. Fonseca; B. Gigante; T.L. Gilchrist, Tetrahedron, 2001, 57, 1793.

COMMENTS :

PICTET – GAMS ISOQUINOLINE SYNTHESIS EXAMPLE :

H H H3C HO H

Ph

CH3 Ph N

P2O5, reflux

N CH3

O

1373

MECHANISM :

O

H3CO CF3

CF3

OCH3 CF3

CN NaBH4 CoCl2

1) NaCN 2) (CH3O)2SO2

F3C OCH3 CF3

O Ar

HN

Cl

O

POCl3 toluene 90 oC - H2O

H2N

OCH3 N

Ar

Ar

DISCONNECTION :

H N R1

R1

N

R O

R

NOTES :

The isoquinolines synthesis from phenethylamides, phenanthridine from o-acylaminobiaryl with POCl3, SnCl4. Sometimes not the expected product is obtained, as shown in the mechanism scheme. This is a modification of the Bischler – Napieralski reaction. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bobbit, Bruckner, Larock indole, Pictet – Sprengler, Pomeranz – Fritsch, Simchen and Schlitter – Müller ring-closure reactions.

REFERENCES : Houben – Weyl : E7a, 616, 624, 648 Org. React. : 6, 74

1) A. Pinner; A. Hubert, Ber. Dtsch. Chem. Ges., 1896, 29, 1182. 2) A. Pictet; A. Gams, Ber. Dtsch. Chem. Ges., 1909, 42, 2943. 3) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 4) J.H. Boyer; J.R. Patel, Synthesis, 1978, 205. 5) T. Kopczynski; S. Goszczynski, Pol. J. Chem., 1981, 55, 393. 6) T. Kopczynski, Pol. J. Chem., 1985, 59, 375. 7) T. Kopczynski, Pol. J. Chem., 1994, 68, 73. 8) L. Poszavacz; G. Simig, J. Heterocycl. Chem., 2000, 37, 343.

1374

9) L. Poszavacz; G. Simig, Tetrahedron, 2001, 57, 8573.

COMMENTS :

PICTET – SPENGLER ISOQUINOLINE SYNTHESIS EXAMPLE :

+

NH2

CH3CHO

N

HCl, heat

H

R

MECHANISM :

- H2O

NH2 R

N H

H+

H

H H

H

R

O H+

N

H

R

DISCONNECTION :

R1

N

+ RCHO NH2

H

R

1375

H

N H R

NOTES :

The condensation of a β-arylethyl amine with a carbonyl compound (intramolecular aminomethylation) to yield a 1,2, 3,4-tetrahydroisoquinoline. This reaction also works with β-ethyl amine indoles. Asymmetric and superacid-catalysed versions of this reaction have been published, also an oxa-version has been reported. See also Bamberger – Goldschmidt, Betti, Bischler – Napieralski, Bobbit, Bruckner, Eschweiler – Clarke, Larock indole, Mannich, Pictet – Gams, Pomeranz – Fritsch, Simchen and Schlitter – Müller ring-closure reactions.

REFERENCES : Smith : 1340 Smith 2nd : 1073, 1102 Houben – Weyl : 4/2, 33; E7a, 612, 624; E16d, 1073, 1084 Org. React. : 6, 151

1) A. Pictet; T. Spengler; Ber. Dtsch. Chem. Ges., 1911, 44, 2030. 2) B.S. Thyagarajan, Chem. Rev., 1954, 54, 1019. 3) D. Valentine, jr.; J.W. Scott, Synthesis, 1978, 329. 4) D. Soerens; J. Sandrin; F. Ungemach; P. Mokry; G.S. Wu; E. Yamanaka; L. Hutchins; M. DiPierro; J.M. Cook, J. Org. Chem., 1979, 44, 535.

5) E.D. Cox; J.M. Cook, Chem. Rev., 1995, 95, 1797. 6) H. Wang; A. Ganesan, Org. Lett., 1999, 1, 1647. 7) R.R. Cesati III; J.A. Katzenellenbogen, Org. Lett., 2000, 2, 3635. 8) R. Grigg; W.S. MacLachlan; D.T. MacPherson; V. Sridharan; S. Suganthan; M. Thorenton–Pett; J. Zhang, Tetrahedron, 2000, 56, 6585.

9) P. Manini; M. d'Ischia; G. Prota, Bioorg. Med. Chem., 2001, 9, 923. 10) S. Nakamura; M. Tanaka; T. Taniguchi; M. Uchiyama; T. Ohwada, Org. Lett., 2003, 5, 2087. 11) J. Xu; X.Z. Wearing; J.M. Cook, Tetrahedron Lett., 2003, 44, 543. 12) M.S. Taylor; E.N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 10558. 13) T.E. Nielsen; M. Meldal, J. Org. Chem., 2004, 67, 3765. 14) D.A. Bianchi; F. Rúa; T.S. Kaufman, Tetrahedron Lett., 2004, 45, 411. 15) G.D. Cuny, Tetrahedron Lett., 2004, 45, 5167. 16) K. Manabe; D. Nobutou; S. Kobayashi, Bioorg. Med. Chem., 2005, 13, 5154.

COMMENTS :

1376

PILOTY – ROBINSON SYNTHESIS EXAMPLE :

N

Ac2O TsOH

N

N O

CH3

MECHANISM :

N H

N

Ac2O

N H

H

N

O

N H

CH3

N

O

[3,3]-sigmatropic rearrangement

CH3

H N NH H+

O

N NH2

CH3

H+

O

- NH3

N

CH3 H3C

O

DISCONNECTION :

R R1

R

R

N H

R R1

R1

R1

N N

NOTES :

The indole synthesis from azines of enolisable ketones via a [3,3]-sigmatropic rearrangement. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa

indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

1377

REFERENCES :

1) E. Fischer, Liebigs Ann. Chem, 1886, 236, 126. 2) O. Piloty, Ber. Dtsch. Chem. Ges., 1910, 43, 489. 3) G.M. Robinson; R. Robinson, J. Chem. Soc., 1918, 43, 639. 4) B. Robinson, Chem. Rev., 1969, 69, 227. 5) H. Posvic; R. Dombro; H. Ito; T. Telinski, J. Org. Chem., 1974, 39, 2575. 6) F.M. Miao; D. Chantry; T. Harper; D.C. Hodgkin, Acta Crystallogr., Sect. B., 1982, 38, 3152.

COMMENTS :

PILOTY ALLOXAZINE SYNTHESIS EXAMPLE :

O

O H

+ N H

O

H

NOH

N

H2N

O

boiling aq. NaOH

NH2

N

N

O

N H

O

OH N

N

NH2

MECHANISM :

O H O

H

NOH

N

H2N N H

NH2

O

boiling aq. NaOH

O

H+ O H O

N

N N N OH H H

N

N N OH H H

NH2

O

H

H NH2

1378

- H2O

O

N

N N H

N

NH2

DISCONNECTION :

O

O H O

H

N

N N H

N

O

NH2

NOH

N

+ N H

O

H2N

NH2

NOTES :

The ring-closure between 5-(hydroxyimino)pyrimidine-2,4,6-(1H, 3H, 5H)trione and benzene-1,3-diamine to afford a 8aminobenzo[g]pteridine-2,4-(1H, 3H)-dione.

REFERENCES :

1) O. Piloty; K. Finckh, Liebigs Ann. Chem., 1904, 333, 44. 2) F.E. King; R.M. Acheson; A.B. Yorke–Long, J. Chem. Soc., 1948, 1926.

COMMENTS :

PINNER IMINOETHER SYNTHESIS EXAMPLE :

NH2 H3C

N

1) HCl, toluene 2) EtOH, NH3

1379

H3C

NH.HCl

MECHANISM :

OEt H3C

N

H3C NH.HCl

HCl(g) toluene

NH2 EtOH, NH3

H3C

NH.HCl

EtOH

H3C C(OEt)3

DISCONNECTION :

OR2 R OR2 OR1

R

N

NH2 R NH.HCl

NOTES :

The synthesis of imino ethers, amidines and ortho esters from nitriles using hydrogen chloride in toluene. In the alcoholysis mixed ortho esters or amides can be obtained by using a different alcohol. See also Garigipati reaction.

REFERENCES : March : 892 Smith – March : 1183 Houben – Weyl : 6/3, 300; 8, 539, 697 Org. Synth. : 8, 1 Org. Synth. Coll. Vol. : 1, 5

1) A. Gautier, Ann. Chim. (Paris), 1869, 17, 103 2) A. Pinner; F. Klein, Ber. Dtsch. Chem. Ges., 1877, 10, 1889. 3) A. Pinner, Ber. Dtsch. Chem. Ges., 1883, 16, 356. 4) R.L. Shriner; F.W. Neumann, Chem. Rev., 1944, 35, 351. 5) R. Roger; D.G. Neilson, Chem. Rev., 1961, 61, 179. 6) C. Larsen; D.N. Harpp, J. Org. Chem., 1981, 46, 2465. 7) Y.B. Lee; Y.M. Goo; Y.Y. Lee; J.K. Lee, Tetrahedron Lett., 1990, 31, 1169. 8) S. Gaupp; F. Effenberger, Tetrahedron: Asymmetry, 1999, 10, 1777. 9) J. Spychala, Synth. Commun., 2000, 30, 1083.

1380

10) W. Thimann; D. Geffken, Z. Naturforsch., Teil B, 2001, 56, 547.

COMMENTS :

PINNER TRIAZINE SYNTHESIS EXAMPLE :

OH O

NH2 2 Ph

+ NH

N Cl

N

Cl Ph

N

Ph

MECHANISM :

OH

O O

NH2 2 Ar

+ NH

Cl

HN

NH NH

Cl

- 2 HCl

Ar

N

Ar heat, - NH3

HN

Ar

N N

Ar

H+

DISCONNECTION :

OH N

NH2

N 2

R

N

R

R NH

NOTES :

The formation of triazines from two arylamidines or α-chlorinated amidines and phosgene. The intermediate N,N’bisimidylurea cyclises after heating.

REFERENCES :

1) A. Pinner, Ber. Dtsch. Chem. Ges., 1890, 23, 2919. 2) A. Pinner, Ber. Dtsch. Chem. Ges., 1895, 28, 473. 3) T. Rappetort, Ber. Dtsch. Chem. Ges., 1901, 34, 1990.

1381

4) H. Schroeder; C. Grundmann, J. Am. Chem. Soc., 1956, 78, 2447.

COMMENTS :

PINNICK OXIDATION EXAMPLE :

H

O

HO

OCH3 OH

3 NaClO2 BuOH, H2O 7 NaH2PO4, pH 3.5 H2NSO3H

O

OCH3

t

OH

MECHANISM :

ClO2 + H2PO4

H

O

O

Cl

O R

H O

H

O

Cl

R

O

H

R

O H

O

H

O - HOCl

Cl

OH

1382

O

H R

O O Cl

DISCONNECTION :

O R

O OH

R

H

O R1

O OH

R1

H

R = H, alkyl, aryl, alkenyl R1 = alkyl, aryl, allyl, homoallyl

NOTES :

The transformation of aldehydes (aliphatic, aromatic, saturated or unsaturated) to the corresponding carboxylic acid using sodium chlorite and a scavenger, 2-methyl-2-butene, hydrogen peroxide etc. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett, Swern and Uemura reactions.

REFERENCES :

1) B.S. Bal; W.E. Childers, jr.; H.W. Pinnick, Tetrahedron, 1981, 37, 2091. 2) A. Raach; O. Reiser, J. Prakt. Chem., 2000, 342, 605. 3) T. Takemoto; K. Yasuda; S.V. Ley, Synlett, 2001, 1555. 4) L.S.M. Wong; M.S. Sherburn, Org. Lett., 2003, 5, 3603.

COMMENTS :

PIRIA REACTION EXAMPLE :

NH2

NO2

NH2 +

1) NaHSO3 2) aq. HCl SO3Na

1383

MECHANISM :

NO2

NHSO3Na

NH2

SO3Na

SO3Na

NHSO3Na

NaHSO3

HCl H2O

NH2

DISCONNECTION :

Ar

Ar

NH2

NO2

NOTES :

The formation of aromatic amines from aromatic nitro compounds via aminosulfonic acids using hydrogensulphite.

REFERENCES : Houben – Weyl : 9, 521; 11/1, 457

1) R. Piria, Liebigs Ann. Chem., 1851, 78, 31. 2) W.H. Hunter; M.M. Sprung, J. Am. Chem. Soc., 1931, 53, 1432. 3) J.F. Bunnett; R.E. Zahler, Chem. Rev., 1951, 49, 273. 4) R. Budziarek, Chem. Ind. (London), 1978, 583.

COMMENTS :

1384

PISHCHIMUKA REARRANGEMENT EXAMPLE :

S EtO P OEt

S

EtO Cl

P

NaI, heat acetone

O

MECHANISM :

CN EtO EtO

P

S

EtO

I CH3CN

S

S

EtO I

P

- EtI

EtO

P O NC

NC

DISCONNECTION :

R1 R2

P

SR3

R1

O

R2

S P OR

+ R3X

NOTES :

The inter- and intramolecular S-alkylation of thiophosphoric acids, followed by dealkylation.

REFERENCES :

1) P.S. Pishchimuka, Zh. Russ. Fiz-Khim. O-va, 1912, 44, 1521. 2) A.J. Burn; J.I.G. Cadogan, J. Chem. Soc., 1961, 5532. 3) I.M. Aladzheva; O.V. Bykhovskaya; D.I. Lobanov; P.V. Petrovskii; K.A. Lyssenko; T.A. Mastryukova; M.I. Kabachnik, Zh. Obshch. Khim., 1998, 68, 1421. (Russ. J. Gen. Chem., 1998, 68, 1356.) 4) I.L. Odinets; N.M. Vinogradova; O.I. Artyushin; P.V. Petrovskii; K.A. Lyssenko; M.Yu. Antipin; T.A. Mastryukova, Mendeleev Commun., 1999, 129.

5) O.V. Bykhovskaya; I.M. Aladzheva; D.I. Lobanov; P.V. Petrovskii; K.A. Lysenko; T.A. Mastryukova T. A., Russ. J. Gen. Chem., 2001, 77, 359.

COMMENTS :

1385

PLANCHER REARRANGEMENT EXAMPLE : H3C

Ph

Ph

CH2

1) 3 CH3I 2) Alkali

N H

N CH3

MECHANISM : H3C Ph N

CH3

3 CH3I

H

N CH3

I

H3C

Ph

Ph CH2

alkali - HI

N CH3

DISCONNECTION :

H3C

R CH2

N CH3

R R = Alk, Ar

N H

NOTES :

The migration of an alkyl or phenyl group of indoles from C-2 to C-3 or C-3 to C-2 during methylation with methyliodide. The reaction is also known as the Plancher – Brunner rearrangement. See also Fischer – Steche reaction.

REFERENCES :

1) G. Plancher, Ber. Dtsch. Chem. Ges., 1898, 31, 1496. 2) H.S. Boyd–Barrett, J. Chem. Soc., 1932, 321. 3) B. Witkop; J.B. Patrick, J. Am. Chem. Soc., 1951, 73, 1562. 4) A.A. Tolmachev; L.N. Babichenko; I.V. Komarov; S.V. Sereda, Chem. Heterocycl. Compd. (Engl. Transl.), 1992, 28, 430.

5) J. Banerji; M. Saha; S. Kanrar, Indian J. Chem., 1995, 34B, 1095.

1386

COMMENTS :

PLÖCHL REACTION EXAMPLE :

HCHO + NH4Cl

CH3NH2 + NH(CH3)2 + N(CH3)3

MECHANISM :

H NH2

N H

HCHO

N H

H2O HCHO

H

OH H

N

H

CH3 + HCOOH

DISCONNECTION :

R

CH3 N CH3

R

H

R NH2 + HCHO

N CH3

NOTES :

Formaldehyde reacts with amines or ammonium chloride to yield mono-, di-, or trimethylamine and other products. See also Foster – Decker, Leuckart – Wallach, Pictet – Spengler and Sommelet reactions.

1387

REFERENCES :

1) J. Plöchl, Ber. Dtsch. Chem. Ges., 1888, 21, 2117. 2) E.A. Werner, J. Chem. Soc., 1917, 111, 844. 3) S.J. Angyal; R.C. Raissack, Nature, 1948, 161, 723. 4) C. Ringel; H. Kroschwitz; D. Scheller; U. Pohle, Z. Chem., 1982, 22, 72.

COMMENTS :

POLONOVSKI REACTION EXAMPLE :

N O

Ac2O

1388

N

OAc

MECHANISM :

O RCH2N(CH3)R1

(R2CO)2O

H OCOR2 R N R1 CH2 H H OCOR2

- R2COOH

R H

- R2COOH

CH3

RCH2

N R1

R1 N CH2

OCOR2

OCOR2

H

OCOR2 CH3 N H R1

R

R

R1 N CH2OCOR2

H

(R2CO)2O

(R2CO)2O

O

R2 O CH3 R N R1 H COR2

O

R2 H

OCOR2 R

N

R1

H R2

O O

OCOR2

R2 N O

O

CH3

R + RCHO

R2 N R1

R1

1389

+ H2CO

DISCONNECTION :

R

R1 N

R

CH3 O

R1 N O R2

NOTES :

The conversion of heterocyclic N-oxides to α-acetoxyheterocycles. The reaction proceeds via an iminium ion intermediate which becomes the stable reaction product when trifluoroacetic anhydride is employed. This modified procedure is commonly referred to as the Potier – Polonovski reaction. See also Pummerer reaction.

REFERENCES : Houben – Weyl : E3, 333; E6a, 691; E16d, 875 Org. React. : 39, 85

1) M. Polonovski; M. Polonovski, Bull. Soc. Chim. Fr., 1927, 41, 1190. 2) S.C. Bell; P.H.L. Wu, J. Org. Chem., 1965, 30, 3576. 3) R.T. LaLonde; E. Auer; C.F. Wong; V.P. Muralidharan, J. Am. Chem. Soc., 1971, 93, 2501. 4) E. Wenkert; B. Chauncy; K.G. Dave; A.R. Jeffcoat; F.M. Schell; H.P. Schenk, J. Am. Chem. Soc., 1973, 95, 8427. 5) N. Langlois; F. Gueritte; Y. Langlois; P. Potier, J. Am. Chem. Soc., 1976, 98, 7017. 6) M. Lounasmaa; A.M.P. Koskinen, Heterocycles, 1982, 19, 2115. 7) R. Suau; F. Nájera; R. Rico, Tetrahedron, 2000, 56, 9713. 8) O.P. Thomas; A. Zaparucha; H.-P. Husson, Tetrahedron Lett., 2001, 42, 3291. 9) D.-R. Hwang; B.-J. Uang, Org. Lett., 2002, 4, 463. 10) T. Rosenau; P. Schmid; P. Kosma, Tetrahedron, 2005, 61, 3483.

COMMENTS :

1390

POMERANZ – FRITSCH REACTION EXAMPLE :

O H

H2N + H

OEt OEt H

N

MECHANISM :

O

H H

H2N

OEt R OEt

- H2O

N OEt EtO

R

H+ - HOEt

N

N

N H+ - EtOH

OEt R

R

OEt

R

DISCONNECTION :

Ar

Ar

N

CHO

NOTES :

An aryl –aldehyde or –ketone is condensed with an aminoacetal to give an iminoacetal, which undergoes cyclisation on treatment with concentrated sulfuric acid or phosphorus oxychloride. The Bobbit modification involves benzylaminoacetaldehyde. Oxazoles can be formed if there is an electron withdrawing group on the aromatic ring and concentrated sulphuric acid is used. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bobbit, Bruckner, Larock indole, Pictet – Gams, Pictet – Sprengler, Simchen and Schlitter – Müller ring-closure

reactions.

REFERENCES : Smith : 1342 Smith 2nd : 1103 Houben – Weyl : E7a, 616, 624, 635, 638 Org. React. : 6, 191

1391

1) C. Pomeranz, Monatsh. Chem., 1893, 14, 116. 2) P. Fritsch, Ber. Dtsch. Chem. Ges., 1893, 26, 419. 3) C.K. Bradsher, Chem. Rev., 1946, 38, 447. 4) M.J. Bevis; E.J. Forbes; N.N. Naik; B.C. Uff, Tetrahedron, 1971, 27, 1253. 5) D.L. Boger; C.E. Brotherton; M.D. Kelley, Tetrahedron, 1981, 37, 3977. 6) R. Hirsenkorn, Tetrahedron Lett., 1991, 32, 1775. 7) A. Głuszyńska; M.D. Rozwadowska, Tetrahedron: Asymmetry, 2000, 11, 2359. 8) A. Głuszyńska; M.D. Rozwadowska, Tetrahedron: Asymmetry, 2004, 15, 3289.

COMMENTS :

PONZIO REACTION EXAMPLE :

H

N

O2N

OH

NO2

1) N2O4, Et2O 2) H2O

MECHANISM :

COOH

H

COOH

HO N

HO N H

N2O4 Et2O

- CO2

NO2

DISCONNECTION :

R

NO2 R1 NO2

HO R = Alk, Ar

1392

N

R1 R

HO N NO2

NOTES :

Benzaldoximes react with nitrogen tetroxide in diethyl ether to yield mainly dinitrophenylmethanes. Other arylaldoximes and ketoximes react similarly. Suzuki et al. improved the Ponzio reaction.

REFERENCES : Houben – Weyl : 10/1, 113; E14b, 395

1) R. Scholl, Ber. Dtsch. Chem. Ges., 1888, 21, 506. 2) G. Ponzio, Gazz. Chim. Ital., 1897, 27/1, 171. 3) G. Ponzio, J. Prakt. Chem., 1906, 73, 494. 4) J.L. Riebsomer, Chem. Rev., 1945, 36, 157. 5) L.F. Fieser; W. von E. Doering, J. Am. Chem. Soc., 1946, 68, 2252. 6) H. Suzuki; H. Takaoka; H. Yamamoto; T. Ogawa, Bull. Chem. Soc. Jpn., 1988, 61, 2927.

COMMENTS :

POSNER TRIOXANE SYNTHESIS EXAMPLE :

CH3

H

O MeO

Et3SiOOOH

H3C O

O O OMe

1393

MECHANISM :

H3CO

H3CO HO O

O H

OSiEt3

O

- HOSiEt3

H3CO O

O

DISCONNECTION :

RO

R1

RO R1

O O

NOTES :

Triethylsilyl hydrotrioxide reacts with electron-rich olefins to give dioxetanes that react intramolecularly with a keto group in the presence of tert-butyldimethyl silyl triflate to afford 1,2,4-trioxanes.

REFERENCES :

1) E.J. Corey; M.M. Mehrotra; A.U. Khan, J. Am. Chem. Soc., 1986, 108, 2472. 2) G.H. Posner; M. Weitzberg; W.M. Nelson; B.L. Murr; H.H. Seliger, J. Am. Chem. Soc., 1987, 109, 278. 3) G.H. Posner; C.H. Oh; W.K. Milhous, Tetrahedron Lett., 1991, 32, 4235. 4) P.M. O’Neill; N.L. Searle; J.L. Maggs; K.J. Raynes; S.A. Ward; J.L. Maggs; B.K. Park; G.H. Posner, Tetrahedron Lett., 1998, 39, 6065.

5) P.M. O’Neill; A. Miller; J.F. Bickley; F. Scheinmann; C.H. Oh; G.H. Posner, Tetrahedron Lett., 1999, 40, 9133.

COMMENTS :

1394

POVAROV REACTION EXAMPLE :

O N +

H

H

N InCl3, CH3CN RT

N O

NH H

MECHANISM :

H3CO

N

N OEt

10 mol% Yb(OTf)2 CH3CN, RT H3CO

N - EtOH

H

OEt

H

Ph

H3CO

DISCONNECTION :

R2 R3 R N H

R5 R4 R1

R2

R4

R3

R5

+

R N

R1

NOTES :

The imino Diels – Alder reaction of imines derived from aromatic amines with electron-rich alkenes. Initially, boron trifluoride etherate was used as a catalyst but more recent developments are using milder Lewis acid catalysts. See also Diels – Alder reaction.

REFERENCES :

1) L.S. Povarov; B.M. Makhailov, Izv. Akad. Nauk. SSSR, 1963, 955. 2) L.S. Povarov; V.I. Grigos; B.M. Makhailov, Izv. Akad. Nauk. SSSR, 1963, 2039. 3) P. Grieco; A. Bahsas, Tetrahedron Lett., 1988, 29, 5855. 4) P.J. Gregoire; J.M. Mellor; G.D. Merriman, Tetrahedron Lett., 1991, 32, 7099. 5) Y. Makioka; T. Shindo; Y. Taniguchi; K. Takaki; Y. Fujiwara, Synthesis, 1995, 801. 6) Sh. Kobayashi; H. Ishitani; S. Nagayama, Synthesis, 1995, 1195. 7) M. Hadden; P.J. Stevenson, Tetrahedron Lett., 1999, 50, 4793.

1395

8) D.W. Zhang; A.S. Kiselyov, Synlett, 2001, 1173. 9) P.J. Stevenson; M. Nieuwenhuyzen; D. Osborne, Chem. Commun., 2002, 444. 10) D. Osborne; P.J. Stevenson, Tetrahedron Lett., 2002, 43, 5469. 11) P.J. Stevenson; I. Graham, Arkivoc, 2003, 4, 139. 12) H. Twin; R.A. Batey, Org. Lett., 2004, 6, 4913.

COMMENTS :

PRÉVOST REACTION EXAMPLE :

OH H3C

CH3

1) I2, Ph

CH3

H3C

O

OH

Ag O benzene 2) H2O

MECHANISM :

R

I

I I2

R

R

R

R

O Ph

O

O Ph

-I

Ph O

R

O

O

O O R

R

O

Ph Ph

O

HO

R

R

hydrolysis O

Ph O

1396

R

R OH

DISCONNECTION :

HO

R R

R

R

OH

NOTES :

An olefinic compound on treatment with silver iodine dibenzoate or diacetate in a dry solvent (benzene), yields by overall trans-addition the di-ester of the corresponding glycol. See also Birnbaum – Simonini, Borodine – Hunsdiecker, Milas, Sharpless dihydroxylation and Woodward cis-hydroxylation reactions.

REFERENCES : March : 823 Smith – March : 1049 Smith : 289 Smith 2nd : 254 Org. React. : 9, 350 Houben – Weyl : 5/4, 543 Org. Synth. : 59, 169 Org. Synth. Coll. Vol. : 6, 348

1) L. Brunel, Bull. Soc. Chim. Fr., 1905, 33, 382. 2) C. Prévost, C.R. Séances Acad. Sci., 1933, 196, 1129. 3) J. Kleinberg, Chem. Rev., 1947, 40, 381. 4) M. Campbell; M. Saintsbury; R. West, Tetrahedron Lett., 1987, 28, 3865. 5) R.W. Trainor; G.B. Deacon; W.R. Jackson; N. Giunta, Aust. J. Chem., 1992, 45, 1265. 6) E. Ciganek; J.C. Calabrese, J. Org. Chem., 1995, 60, 4439. 7) J.K. Ray; S. Gupta; G.K. Kar; B.C. Roy; J.M. Lin; S. Amin, J. Org. Chem., 2000, 65, 8134. 8) M. Sabat; C.R. Johnson, Tetrahedron Lett., 2001, 42, 1209. 9) J.H. Schauble; E.A. Trauffer; P.P. Deshpande; R.D. Evans, Synthesis, 2005, 1333.

COMMENTS :

1397

PREY REACTION EXAMPLE :

OCH3

OH + N Cl H

heat

MECHANISM :

H O

OCH3 + heat

N Cl H

OH

CH3 - CH3Cl

Cl -

N Cl CH3

DISCONNECTION :

ArOH

Alk

O

Ar

NOTES :

The arylalkylether bond break due to prolonged heating (180 – 200 oC) with water-free pyridine hydrogen chloride. See also Gustus cleavage, Mann dealkylation and Stoermer dealkylation.

REFERENCES : Houben – Weyl : 6/3, 151

1) A. Klemenc, Ber. Dtsch. Chem. Ges., 1916, 49, 1371. 2) A. Klemenc, Ber. Dtsch. Chem. Ges., 1916, 49, 1703. 3) V. Prey, Ber. Dtsch. Chem. Ges., 1941, 74, 1219. 4) R.L. Burwell, jr., Chem. Rev., 1954, 54, 615.

COMMENTS :

1398

PRILESCHAJEW REACTION EXAMPLE :

Ph

OOH

H

H

O

Ph

O

Ph

+

H

H Ph

MECHANISM :

O R O H O

O H

O

R

O

R + O

O

H

O

DISCONNECTION :

R R1

R2 O

R3

R

R2

R1

R3

NOTES :

The epoxydation of olefins with organic peracids. Allenes can give spiro dioxides. See also von Baeyer – Villiger, Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Shi and Weitz – Scheffer reactions.

REFERENCES : March : 826 Smith – March : 1052 Smith : 220 Smith 2nd : 234 Houben – Weyl : 6/3, 385 Org. React. : 7, 378; 9, 332 Org. Synth. : 8, 102; 38, 83; 49, 13 Org. Synth. Coll. Vol. : 1, 494; 4, 860; 5, 191

1) N. Prileschajew, Ber. Dtsch. Chem. Ges., 1909, 42, 4811. 2) D. Swern, Chem. Rev., 1949, 45, 1.

1399

3) G.B. Payne, J. Org. Chem., 1961, 26, 250. 4) I. Kaneti, Tetrahedron, 1986, 42, 4017. 5) W. Adam; R. Curci; J.O. Edwards, Acc. Chem. Res., 1989, 22, 205. 6) K.W. Woods; P. Beak, J. Am. Chem. Soc., 1991, 113, 6281. 7) I. Hilker; D. Bothe; J. Pruss; H.-J. Warnecke, Chem. Eng. Sci., 2001, 56, 427.

COMMENTS :

PSCHORR – HOPPE SYNTHESIS EXAMPLE :

CN NO2

1) SnCl2, HCl 2) NaOEt, H2 3) Na, EtOH

N H

MECHANISM :

CN

CN SnCl2 HCl

NO2

NaOEt H2

NH2

HCO2Amyl Na

CN

NH2 N H

Na, EtOH

CN OH

N H

NH2

1400

N H

DISCONNECTION :

N H

CN

CN NO2 N H

NOTES : o-Nitrophenylacetonitrile is reduced by stannous chloride and hydrochloric acid to the corresponding amine, which

when treated with boiling ethanolic sodium ethoxide in an atmosphere of hydrogen yields 2-aminoindole. The latter on treatment with sodium in ethanol yields an indole. Alternatively, the amine may be treated with sodium in amyl formate to give 3-cyanoindole and hence the indole acid. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer

indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung

indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto

indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) R. Pschorr; G. Hoppe, Ber. Dtsch. Chem. Ges., 1910, 43, 2543. 2) H. Stephen, J. Chem. Soc., 1925, 127, 1874.

COMMENTS :

1401

PSCHORR SYNTHESIS EXAMPLE : O

O

NaNO2, HCl Cu

NH2

MECHANISM :

2 HNO2

H+, - H2O

O

O

N

O

N

O

COOH

COOH H

+ reduction

NO2

NO2

COOH COOH COOH NH2 O

N

O

N

O

H+, - H2O

N N

HN N O COOH

COOH

+ Cu(I)

Cu(I), - H+

Cu

DISCONNECTION :

O

O

NH2

NOTES :

The formation of polycyclics from diazonium salt. Intramolecular copper-catalysed arylation of diazonium salts. See also Borsche – Koelsch, Gomberg – Bachmann – Hey, Graebe – Ullmann fluorene, von Richter cinnoline, Ullmann fluorene and Widman – Stoermer reactions.

1402

REFERENCES : March : 715 Smith – March : 929 Smith : 1436 Smith 2nd : 1185 Houben – Weyl : E7b, 106 Org. React. : 2, 224; 9, 409 Science of Synthesis : 10, 140, 214, 225

1) R. Pschorr, Ber. Dtsch. Chem. Ges., 1896, 29, 496. 2) P.H. Leake, Chem. Rev., 1956, 56, 27. 3) D.E. Rosenberg; J.R. Beadle, Tetrahedron Lett., 1980, 21, 4141. 4) R.I. Duclos, jr.; J.S. Tung; H. Rapoport, J. Org. Chem., 1984, 49, 5243. 5) G. Daidone; S. Plescia; B. Maggio; V. Sprio; F. Benetollo; G. Bombieri, J. Chem. Soc., Perkin Trans. 1, 1993, 285. 6) J. Hassan; M. Sevignon; C. Gozzi; E. Schulz; M. Lemaire, Chem. Rev., 2002, 102, 1359. 7) S. Karady; J.M. Cummins; J.J. Dannenberg; E. del Rio; P.G. Dormer; B.F. Marune; R.A. Reamer; T.L. Sordo, Org. Lett., 2003, 5, 1175.

COMMENTS :

PUDOVIK REACTION EXAMPLE :

O EtO P H OEt

EtO +

CN

NaOCH3 CH3OH

EtO

O P

CN

MECHANISM :

O EtO P H OEt

NaOCH3 CH3OH

O EtO P OEt

EtO CCl3

H O H+

1403

O P

OH

EtO CCl3

NOTES :

The addition of esters of organophosphorous compounds containing a labile P-H bond with alkenes, alkynes, activated carbonyls, imines, isocyanates, isothiocyanates, cyanides and isocyanides. The reaction progresses via a radical or (and) ionic mechanism. See also Kabachnik – Fields reaction.

REFERENCES :

1) A.N. Pudovik, Izv. Akad. Nauk. SSSR, Otd. Khim. Nauk. USSR, 1948, 151. 2) A.N. Pudovik; I.V. Konovalova, Synthesis, 1979, 81. 3) L.V. Nesterov; N.E. Krepysheva; N.A. Aleksandrova, Zh. Obshch. Khim., 1984, 54, 54. 4) V.I. Galkin; A.B. Khabibullina; I.V. Bakhtiyarova; R.A. Cherkasov; A.N. Pudovik, Zh. Obshch. Khim., 1988, 58, 1002. 5) H. Groger; J. Martens, Synth. Commun., 1996, 26, 1903. 6) D. Semenzin; G. Etemad–Moghadam; D. Albouy; O. Diallo; M. Koenig, J. Org. Chem., 1997, 62, 2414. 7) S.J. Chen; J.K. Coward, J. Org. Chem., 1998, 63, 502. 8) O.I. Kolodiazhnyi, Tetrahedron: Asymmetry, 1998, 9, 1279. 9) V.I. Galkin; A.R. Cherkasov; R.A. Cherkasov, Phosphorus Sulfur, 1999, 146, 329. 10) L. Tedeschi; D. Enders, Org. Lett., 2001, 3, 3515. 11) K. Vercruysse–Moreira; C. Déjugnat; G. Etemad–Moghadam, Tetrahedron, 2002, 58, 5651.

COMMENTS :

PUMMERER REARRANGEMENT EXAMPLE :

Ph

O S

O S

Ph Ac2O AcONa

1404

Ph AcO

Ph

MECHANISM :

R1

O S R

H

E+

R1

S R

R2

EO

R1

EO

R2

R1

EO

- H+

S R

R2

R2

R1

R1

- EO-

R

R2

R

R

S

S

S R

H

R2

Nu

S

R1

R2 Nu

DISCONNECTION :

R

S

R1

O

R1

S

R2 Y

R

H R2

NOTES :

There is a similarity to the Nef reaction in that there is an internal oxidation – reduction process. There are several types of Pummerer reactions, an ‘interrupted’ Pummerer, the ‘non-oxidative’ Pummerer (NOPR), which allows for a one-pot replacement of a sulfinyl group with a hydroxyl in a stereospecific SN2-manner and the ’non-oxidative’ chloroPummerer reaction (NOCPR). Seleno- and sila-Pummerer rearrangements are also known. See also Nef, Polonovski, Sommelet – Hauser, Stevens rearrangement and Vilsmeier – Haack – Viehe reactions.

REFERENCES : March : 1236 Smith – March : 1566 Smith : 239 Smith 2nd : 203 Houben – Weyl : E3, 313, 583; E6a, 581; E8c, 159; E7a, 232, 237; E11, 323, 1189; E15, 889; E16b, 879 Org. React. : 40, 157 Science of Synthesis : 10, 102, 523, 612

1) J.A. Smythe, J. Chem. Soc., 1909, 95, 349. 2) R. Pummerer, Ber. Dtsch. Chem. Ges., 1909, 42, 2282. 3) C.R. Johnson; W.G. Philips, J. Am. Chem. Soc., 1969, 91, 682. 4) H.J. Chaves das Neves; M.F. Machete, Tetrahedron Lett., 1977, 18, 187. 5) K. Konno; K. Hashimoto; H. Shirahama; T. Matsumoto, Tetrahedron Lett., 1986, 27, 3865. 6) M. Xia; S. Chen; D.K. Bates, J. Org. Chem., 1996, 61, 9289. 7) A. Padwa; D.E. Gunn, jr.; M.H. Osterhout, Synthesis, 1997, 1353. 8) H. Hagiwara; K. Kafuku; H. Sakai; M. Kirita; T. Hoshi; T. Suzuki; M. Ando, J. Chem. Soc., Perkin Trans. 1, 2000, 2577.

1405

9) J.L. García Ruano; A. Alcudia; M. del Prado; D. Barros; M.C. Maestro, I. Fernández, J. Org. Chem., 2000, 65, 2856. 10) P. Marchand; M. Gulea; M.-T. Averbuch–Pouchot, Synthesis, 2001, 1623. 11) A. Volonterio; P. Bravo; C. Pesenti; M. Zanda, Tetrahedron Lett., 2001, 42, 3985. 12) L.A. McAllister; S. Brand; R. de Gentile; D.J. Procter, Chem. Commun., 2003, 2380. 13) S. Raghavan; A. Rajender; M.A. Rasheed; S.R. Reddy, Tetrahedron Lett., 2003, 44, 8253. 14) J.L. García Ruano; J. Aleman; A. Padwa, Org. Lett., 2004, 6, 1757. 15) K.S. Feldman; D.B. Vidulova, Org. Lett., 2004, 6, 1869. 16) K.S. Feldman; A.G. Karatjas, Org. Lett., 2004, 6, 2849.

COMMENTS :

1406

1407

RIECHE FORMYLATION · 1457 RIEHM PYRIDINE SYNTHESIS · 1458

H

RIEHM QUINOLINE SYNTHESIS · 1459 HENKEL PROCESS · 1413

RIEMSCHNEIDER THIOCARBAMATE SYNTHESIS · 1461

HOCKET – HUDSON OXIDATION · 1489

RIGBY – TROST DEHYDROGENATIVE SULFENYLATION · 1462 RILEY – SHARPLESS OXIDATION · 1463 RITTER REACTION · 1465

R

ROBERT CHLORINATION · 1466 ROBERTSON – ROBINSON METHYLATION · 1468

RADZISZEWSKI AMIDE SYNTHESIS · 1409

ROBINSON – GABRIEL SYNTHESIS · 1469

RAECKE PROCESS · 1410

ROBINSON – MANNICH ANNULATION REACTION · 1470

RAMBERG – BÄCKLUND REACTION · 1413

ROBINSON – ROBINSON KETO-ESTER METHOD · 1472

RANJORWA SYNTHESIS · 1415

ROBINSON – SCHÖPF REACTION · 1473

RAPHAEL SYNTHESIS · 1416

ROBINSON DEHYDROGENATION · 1475

RAPP – STOERMER CONDENSATION · 1418

ROELEN CARBONYLATION · 1476

RAPSON TRIPHENYLENE REACTION · 1420

ROGER SYNTHESIS · 1478

RASCHIG PHENOL PROCESS · 1421

ROSENMUND – SAYTZEFF REDUCTION · 1479

RASODA SYNTHESIS · 1422

ROSENMUND – von BRAUN SYNTHESIS · 1480

RATHKE ESTER SYNTHESIS · 1423

ROSENMUND REACTION · 1481

RAUHUT – CURRIER REACTION · 1424

ROTHEMUND REACTION · 1482

RAUTENSTRAUCH REARRANGEMENT · 1426

ROUSH – HOFFMANN – YAMAMOTO STEREOSELECTIVE

REED REACTION · 1428

ALLYLATIONS · 1484

REETZ TITANIUM ALKYLATION · 1429

ROUSH COUPLING · 1485

REEVE SYNTHESIS · 1431

ROUSH MACROLACTONISATION · 1486

REFORMATSKY REACTION · 1432

ROWE REARRANGEMENT · 1487

REGITZ DIAZO TRANSFER · 1434

RUFF – FENTON DEGRADATION · 1488

REIMER – TIEMANN REACTION · 1435

RUFF REACTION · 1490

REINDERS – RINGER DISPLACEMENT · 1437

RUGGLI SYNTHESIS · 1491

REISSERT – GROSHEINTZ – FISCHER SYNTHESIS · 1438

RUPE REARRANGEMENT · 1492

REISSERT – HENZE REACTION · 1440

RUPPERT FLUOROALKYLATION · 1493

REISSERT INDOLE REACTION · 1442

RUSSIG – LAATSCH REACTION · 1494

REMFRY – HULL SYNTHESIS · 1443

RUŽIČKA LARGE RING SYNTHESIS · 1496

REPPE ACETYLENE SYNTHESIS · 1444

RUŽIČKA OLEFINIC ACID SYNTHESIS · 1497

REPPE BUTADIENE SYNTHESIS · 1445

RUŽIČKA REARRANGEMENT · 1498

REPPE CARBONYLATION · 1447

RYCHNOVSKY POLYOL SYNTHESIS · 1500

REPPE POLYMERISATION · 1449 REPPE VINYLATION · 1450 S

REVERDIN REACTION · 1451 RICHMAN – ATKINS SYNTHESIS · 1452

STORK – JUNG – ROBINSON ANNULATION · 1471

RICHTER von CINNOLINE SYNTHESIS · 1454 RICHTER von REACTION · 1455

1408

RADZISZEWSKI AMIDE SYNTHESIS EXAMPLE :

CH3

CH3 NH2

aq. NaOH H2O2, EtOH 50 oC

CN

O

MECHANISM : H+ R C N HOO

R C N OOH

H2O

R C NH O HO

O H2O2 - O2, - H2O

R

NH2

DISCONNECTION :

O R

R C N NH2

NOTES : Hydrogen peroxide in alkaline solution converts nitriles into amides. There are numerous procedures for this type of conversion. See also Riehmschneider reaction.

REFERENCES : March : 888 Smith – March : 1179 Org. Synth. : 13, 94; 16, 4 Org. Synth. Coll. Vol. : 2, 44, 586

1) Br. Radziszewski, Ber. Dtsch. Chem. Ges., 1885, 18, 355. 2) K.B. Witberg, J. Am. Chem. Soc., 1953, 75, 3961. 3) S. Cacchi; D. Misiti; F. LaTorre, Synthesis, 1980, 243. 4) E.N. Zil’berman, Russ. Chem. Rev., 1984, 33, 900. 5) A.R. Katritzky; B. Pilarski; L. Urogdi, Synthesis, 1989, 949.

1409

COMMENTS :

RAECKE PROCESS EXAMPLE :

COO

K

COO

K

COO Cd2+ 300 - 500 oC CO2, 100 atm

1410

K

OOC

K

MECHANISM :

O O K

Cd2+

K + CO2 O OK

O

O OK

+

CO2

OK

Cd2+, - CO2 K

O

KO

O O

OK

OK

or O

O OK

K

K

OK

+

O OK

K K Cd2+

CO2

KO

O

O Cd2+

OK

CO2

KO O

O

O

KO

OK

KO

1411

O

O

OK

OK O

Cd2+

K + CO2 OK O O

OK

OK O O

O OK

OK

+ OK K

O

CO2

Cd2+, - CO2 O

OK

O

O OK

+

O

KO

OK

OK K

O

KO Cd2+, - CO2

CO2

O OK KO O

1412

O

DISCONNECTION :

COO K

K

OOC

COO

K

COO

K

NOTES : Industrial scale thermal rearrangement or disproportionation of alkaline salts of aromatic acids to symmetrical diacids in the presence of cadmium or other metallic salts. This reaction is also known as the Henkel process.

REFERENCES : March : 565 Smith – March : 733 Houben – Weyl : E5, 294

1) B. Raecke, German Patent, 1952, 936036. 2) B. Raecke, Angew. Chem., 1958, 70, 1. 3) Y. Ogata; M. Hojo; M. Morikawa, J. Org. Chem., 1960, 25, 2082. 4) E. McNelis, J. Org. Chem., 1963, 28, 3188. 5) E. McNelis, J. Org. Chem., 1965, 30, 1209. 6) J. Szammer; L. Otvos, Radiochem. Radioanal. Lett., 1980, 45, 359. 7) K. Fujishiro; S. Mitamuta, Bull. Chem. Soc. Jpn., 1989, 62, 786.

COMMENTS :

RAMBERG – BÄCKLUND REACTION EXAMPLE :

H3C

H O CH3 S H H O Cl

H KOH

1413

H3C

H CH3

MECHANISM : B H O R R S H H O Cl

- BH

O R R S H H O Cl

R H

H R

S O

O

- SO2

H

H

R

R

DISCONNECTION :

O R S R1 O

R R1

NOTES : This is the conversion of dialkyl sulfones to alkenes by rearrangement of α-halosulfones with base. See also Corey – Kwiatkowski, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Petasis reaction, Paquette, Peterson, Still – Gennari, Takeda, Tebbe and Wittig reactions.

REFERENCES : March : 1030 Smith – March : 1342 Smith : 748 Smith 2nd : 632 Houben – Weyl : E5, 447; E11, 1521 Org. React. : 25, 1; 62, 357 Org. Synth. : 49, 18; 65, 90 Org. Synth. Coll. Vol. : 5, 231; 8, 212 Science of Synthesis : 9, 49

1) L. Ramberg; B. Bäcklund, Ark. Kern. Mineral. Geol., 1940, 13A, 50. 2) L.A. Paquette, Acc. Chem. Res., 1968, 1, 209. 3) G.D. Hartman; R.D. Hartman, Synthesis, 1982, 504. 4) L.A. Paquette; P.P. Trova, Tetrahedron Lett., 1986, 27, 1895. 5) K.C. Nicolaou; W.-M. Dai, Angew. Chem., Int. Ed. Engl., 1991, 30, 1387. 6) R.J.K. Taylor, Chem. Commun., 1999, 217. 7) C. Wei; K.-F. Mo; T.-L. Chan, J. Org. Chem., 2003, 68, 2948. 8) E. Block; H.R. jeon; D. Putman; S.-Z. Zhang, Tetrahedron, 2004, 60, 7525.

1414

COMMENTS :

RANJORWA SYNTHESIS EXAMPLE :

O

OH CH3

+ PhCHO

Ph

aq. EtOH KOH O

O

MECHANISM :

H+ O OH

OH CH3

H

OH

Ph

HO-

- H2O O

O

O

Ph PhCHO HO- H2O

O

O H+

H O

Ph

O

Ph

DISCONNECTION :

O

Ar

OH CH3

O

O

1415

+ ArCHO

Ph

NOTES : Flavonols are obtained by treating an o-hydroxyacetophenone with an araldehyde in aqueous ethanolic solution containing alkali. Prolonged agitation and exposure to air are necessary. See also Algar – Flynn – Oyamada, Auwers flavonol, Baker – Ollis, von Kostanecki (Allan – Robinson) acylation and Rasoda reactions.

REFERENCES : 1) S.D. Limaye; D.B. Limaye, Rasáyanam, 1952, 2, 41. (Chem. Abs., 1953, 47, 4879.) 2) F.H. Guidugli; C.E. Ardanaz; J. Kavka; M.E. Garibay; P. Joseph–Nathan, Org. Mass. Spectrom., 1986, 21, 117. 3) H.M. Chawla; S.K. Sharma, Indian J. Chem., 1987, 26B, 1075. 4) S. Pant; B.C. Joshi; U.C. Pant, Indian J. Chem., 1993, 32B, 869.

COMMENTS :

RAPHAEL SYNTHESIS EXAMPLE :

Cl

CH2OSO2CH3 +

H

O 1) EtMgBr 2) NaI 3) NaCH(CO2Et)2 4) decarboxylation 5) Pd/C, H2

OH

1416

MECHANISM :

OH

Cl

Cl

H3C

1) NaI 2) Na+ CH3SO2Cl

H

Cl H

OSO2CH3 H3C

1) EtMgBr 2) NaI

1) EtMgBr 2) NaI

I NaCH(CO2Et)2 hydrolysis and decarboxylation

H3C

(CH2)7COOH H3C(CH2)3

Pd/C, H2

H3C

(CH2)4

1417

(CH2)7COOH

DISCONNECTION :

O

CH2OH

+

OH Cl H

NOTES :

This synthesis utilises the alkylation of an acetylenic Grignard reagent using an alkyl sulfonate. The Grignard complex of 8-chloro-oct-1-yne reacts with oct-2-yn-1-yl methanesulfonate to give a diacetylenic chloride. This compound is converted into the iodide and by the malonation process yields heptadeca-8,11-di-yne-1-carboxylic acid. Catalytic (with palladium on calcium carbonate) partial hydrogenation of this acid yields a product consisting of 63% linoleic acid. See also Ahmed – Strong reaction.

REFERENCES :

1) R.A. Raphael; F. Sondheimer, J. Chem. Soc., 1950, 2100. 2) R.A. Raphael; F. Sondheimer, Nature, 1950, 165, 235.

COMMENTS :

RAPP – STOERMER CONDENSATION EXAMPLE :

OH Cl

CHO

OMe

Br

Cl

+ OH O

1) KOH 2) Pyridine.HCl

1418

O

O

MECHANISM :

Cl

CHO

OMe

Br +

OH

KOH O OH

O Cl

H

OMe pyridine.HCl - H2O

O O

Cl O

O

H

DISCONNECTION :

Cl

Ar

Cl

CHO

OMe

Br +

O

O

OH O

NOTES :

The 2-acylbenzofuran synthesis from salicylaldehydes and α-haloketones.

REFERENCES :

1) E. Rapp, Gazz. Chim. Ital., 1895, 25/2, 285. 2) R. Stoermer, Liebigs Ann. Chem., 1900, 312, 237. 3) V.F. Martynoff, Bull. Soc. Chim. Fr., 1952, 1056. 4) Ng.Ph. Buu-Hoï; G. Saint–Ruf; T.B. Loc; Ng.D. Xuong, J. Chem. Soc., 1957, 2593.

COMMENTS :

1419

RAPSON TRIPHENYLENE REACTION EXAMPLE :

O 1) PhMgBr 2) AlCl3 CS2 3) Se

MECHANISM :

OH O PhMgBr

Se

AlCl3 CS2

DISCONNECTION :

O

NOTES :

The triphenylene synthesis by condensation of cyclohexenyl-cyclohexanones with phenylmagnesium bromide, followed by aluminium chloride or stannic chloride and dehydration with selenium.

REFERENCES :

1) W.S. Rapson, J. Chem. Soc., 1941, 15. 2) P.M.G. Bavin; M.J.S. Dewar, J. Chem. Soc., 1955, 4479. 3) C.C. Barker; R.G. Emmerson; J.D. Periam, J. Chem. Soc., 1958, 1077. 4) C.M. Buess; D.D. Lawson, Chem. Rev., 1960, 60, 313.

1420

COMMENTS :

RASCHIG PHENOL PROCESS EXAMPLE :

OH + 0.5 O2

1) 230 oC, HCl, Cu-Fe 2) 425 oC, SiO2

MECHANISM :

C6H6 + HCl + 0.5 O2

C6H5Cl + H2O

Cu-Fe 230 oC

SiO2 425 oC

C6H5Cl + H2O

C6H5OH + HCl

DISCONNECTION :

OH

NOTES :

The synthesis of phenol from chlorobenzene by catalytic vapour phase hydrolysis with water to yield phenol and hydrogen chloride which is regenerated.

REFERENCES :

1) F. Raschig, French Patent, 1930, 698341. (Chem. Abs.,1931, 25, 3012.) 2) W.H. Prahl, U.S. Patent, 1934, 1963761. 3) W. Mathes, Angew. Chem., 1939, 52, 591.

1421

COMMENTS :

RASODA SYNTHESIS EXAMPLE :

OH

O

Ph

Br Br 1) H2O 2) KOH O

OH O

Ph

MECHANISM :

OH

O

Br

O O

H2O

Br O

O

Br

O

Ph

O

O HO

Ph

O

OH OH

O

Ph

- H2O

O

Ph

OH

OH

Ph

Ph

O

O H+

DISCONNECTION : O

OH

R

Br

R1

R1

Br

OH O

O

R

NOTES :

2’-Acetoxychalkone dibromides on treatment with water and with alkali yield flavones. See also Algar – Flynn – Oyamada, Auwers flavonol, Baker – Ollis, von Kostanecki (Allan – Robinson) acylation and Ranjorwa reactions.

REFERENCES :

1) S.D. Limaye, Rasáyanam, 1950, 2, 1.

1422

2) P.M. Hayden; O’Sullivan; Philbin; T.S. Wheeler, Research, 1952, 5, 396. 3) Science and Culture, 1954, 20, 135. 4) J.E. Gowan; P.M. Hayden; T.S. Wheeler, J. Chem. Soc., 1955, 862.

COMMENTS :

RATHKE ESTER SYNTHESIS EXAMPLE :

O

O

O

H3C

OEt

+

H3C

O Cl

1) MgCl2, Et3N 2) H+

O

H3C

CH3 O

OEt

MECHANISM :

O

ClMgCH(CO2Et)2 + Et3N.HCl

CH2(CO2Et)2 + MgCl2 + Et3N

R

O R

Cl

CO2Et CO2Et

DISCONNECTION :

O R

O

CO2Et

+ R

CO2Et

Cl

EtO

OEt O

O

NOTES :

In the presence of magnesium chloride and triethylamine malonates are C-alkylated by acid chlorides to afford β–keto esters.

REFERENCES :

1) M.W. Rathke; P.J. Cowan, J. Org. Chem., 1985, 50, 2622. 2) R.J. Clay; T.A. Collom; G.L. Karrick; J. Wemple, Synthesis, 1993, 290.

1423

3) D.J. Krysan, Tetrahedron Lett., 1996, 37, 3303.

COMMENTS :

RAUHUT – CURRIER REACTION EXAMPLE :

O

CH3

2

PPh3 CH3CN

O

O

CH3

H3C

MECHANISM :

O

O

R2

O

O Bu3P

R1

O

O

R1

R2

O

R1

R1

Bu3P

Bu3P

1424

O

R2

R2

CN CN

+ Ar3P

CN

ROH Ar3P

Ar3P

CN

CN

NC

CN Ar3P

Ar3P CN

CN

ROH

ROH

NC

CN

CN CN - Ar3P

Ar3P

Ar3P CN

CN

NC

H

DISCONNECTION :

EWG

EWG

EWG

1425

CN

NOTES :

The phosphine-catalysed dimerisation of electron-deficient alkenes in the presence of a small amount of a protolytic source like tert-butyl alcohol. The intramolecular variant, an organocatalytic Michael cycloisomerisation, has been published by Krische et al. Both five- and six-membered ring formations occur readily. See also Bayliss – Hillman – Morita and Michael reactions.

REFERENCES :

1) M.M. Rauhut; H. Currier, U.S. Patent, 1963, 3074999. 2) J.D. McClure, J. Org. Chem., 1970, 35, 3045. 3) D. Basavaiah; V.V.L. Gowriswari; T.K. Bharathi, Tetrahedron Lett., 1987, 28, 4591. 4) S.E. Drewes; N.D. Emslie; N. Karodia, Synth. Commun., 1990, 20, 1915. 5) C.D. Hall; N. Lowther; B.R. Tweedy; A.C. Hall; G. Shaw, J. Chem. Soc., Perkin Trans. 2, 1998, 2047. 6) L.-C. Wang; A.L. Luis; K. Agapiou; H.-Y. Jang; M.J. Krische, J. Am. Chem. Soc., 2002, 124, 2402.

COMMENTS :

RAUTENSTRAUCH REARRANGEMENT EXAMPLE :

OPiv 5% Ph3AuSbF6 CH3CN, - 20 oC

1426

O H

MECHANISM :

O

O

O

O

O O

(Ph3P)AuCl Ph

Ph

Au(PPh3)

Ph

AcO

AcO Ph

Ph

Au(PPh3)

Au(PPh3)

AcO Ph Au(PPh3)

O K2CO3 MeOH

Ph

Also possible :

OAc O

O

O (Ph3P)AuCl

Ph

(Ph3P)Au

O

(Ph3P)Au Ph

Ph

O

O

O

(Ph3P)Au

O (Ph3P)Au Ph

Ph

Ph

O K2CO3 MeOH

Ph

DISCONNECTION :

OR O H R = protecting group

1427

AcO

NOTES :

2-Cyclopentenones are prepared from 1-ethynyl-2-propenyl derivatives catalysed by gold, platinum or palladium complexes.

REFERENCES :

1) V. Rautenstrauch, J. Org. Chem., 1984, 49, 950. 2) V. Mamane; T. Gress; H. Krause; A. Fürstner, J. Am. Chem. Soc., 2004, 126, 8654. 3) X. Shi; D.J. Gorin; F.D. Toste, J. Am. Chem. Soc., 2005, 127, 5802.

COMMENTS :

REED REACTION EXAMPLE :

O H3C

CH3

SO2, Cl2 hν

H3C

S

Cl O

MECHANISM :

Cl2

hν

2 Cl

RH + Cl

R + HCl

R + SO2

RSO2

RSO2

+ Cl2

RSO2Cl + Cl

DISCONNECTION :

RH

RSO2Cl

1428

NOTES :

This reaction is the photochemical sulfochlorination of alkanes and cycloalkanes using sulfur dioxide and chlorine under UV radiation. The reaction is radical induced and the side products are usually alkyl chlorides and disulfo chlorides. See also Hinsberg sulfone synthesis.

REFERENCES : March : 711 Smith – March : 924 Houben – Weyl : 9, 407

1) C.F. Reed, U.S. Patent, 1936, 2046090. 2) H.J. Schumacher; J. Stauff, Angew. Chem., 1942, 55, 341. 3) J.H. Helberger; G. Manecka; H.M. Fischer, Liebigs Ann. Chem., 1949, 562, 23. 4) F. Asinger; B. Fell; H. Scherb, Chem. Ber., 1963, 96, 3068. 5) H.I. Koschek, Chem.- Ztg., 1969, 93, 655.

COMMENTS :

REETZ TITANIUM ALKYLATION EXAMPLE :

H

Ph OH

O

Ph CH3 H

H3C

Me2TiCl2 - 78 oC

H H CH3

Ph OH + H3C

CH3 H H

MECHANISM :

Ph R

O

R

O O

H

R1TiCl3

O Ph

1429

R1 Cl Ti Cl Cl

O R

OH R1

DISCONNECTION :

O

OH R * R1 H

R

H

+

(R1)2TiCl2

NOTES :

Alkyltitanium reagents are used in the chemo and diastereoselective addition from the less hindered side to aldehydes. This chelation control can be used for 1,2-, 1,3-, and 1,4-asymmetric inductions.

REFERENCES : Smith : 1375 Org. Synth. : 67, 180 Org. Synth. Coll. Vol. : 8, 495

1) M.T. Reetz; R. Steinback; J. Westermann; R. Peter, Angew. Chem., Int. Ed. Engl., 1980, 19, 1011. 2) G.H. Posner; L.L. Frye; M. Hulce, Tetrahedron, 1984, 40, 1401. 3) M.T. Reetz, Angew. Chem., Int. Ed. Engl., 1984, 23, 556. 4) M.T. Reetz, Acc. Chem. Res., 1993, 26, 462. 5) T. Poon; C.A. Goudreau; F.G. Favaloro; B.P. Mundy; A. Greenberg; R. Sullivan, Synthesis, 1998, 832. 6) F.G. Favaloro; C.A. Goudreau; B.P. Mundy; T. Poon; S.V. Slobodzian; B.L. Jensen, Synth. Commun., 2001, 31, 1847.

COMMENTS :

1430

REEVE SYNTHESIS EXAMPLE :

O

N

S H

N

1) DBU, CHCl3 2) S H2N

H

H

O

NH2

NaOH, H2O, DME

MECHANISM :

H

H CCl3 OH

KOH

Cl

O

NH2

Cl S

H N H

Cl

S

H

O

O

H

N

S

NH2

N H

N H

DISCONNECTION :

N R1 S

R

N R1

H O

R O

S + R1

N H

N H

R1

NOTES :

2-Imino-4-thiazolidinones are prepared from readily accessible alkyl or aryl trichloromethylcarbinols and thioureas under mild conditions. See also Corey – Link reaction.

REFERENCES :

1) W. Reeve; C.W. Woods, J. Am. Chem. Soc., 1960, 82, 4062. 2) W. Reeve; M. Nees, J. Am. Chem. Soc., 1967, 89, 647. 3) W. Reeve, Synthesis, 1971, 131. 4) J.P. Benner; G.B. Gill; S.J. Parrott; B. Wallace, J. Chem. Soc., Perkin Trans. 1, 1984, 331.

1431

5) J. Blanchet; J. Zhu, Tetrahedron Lett., 2004, 45, 4449.

COMMENTS :

REFORMATSKY REACTION EXAMPLE :

Ph

CH3 + O

Br

CH3 COOEt CH3

CH3 H3C COOEt HO Ph CH3

Zn, hydrolysis

MECHANISM :

O R

O Zn

+

+

Br

O Zn

Br

O

O ZnBr

OR

O R BrZn O

HO

COOR

COOR

hydrolysis

O

DISCONNECTION :

R1

R3

R2 OH CO2R

O + R1

R2

R3

CO2R

NOTES :

This reaction involves the condensation of a carbonyl compound, e.g. an aldehyde, ketone or ester, with a halogenoester in the presence of usually zinc to produce a hydroxy ester. This may be readily dehydrated to the unsaturated acid. The reaction, of which there are many variations, see Blaise reaction, is of value in extending the carbon chain of the aldehyde. Some reactions are germanium, chromium, rhodium or samarium promoted. Diastereoselectivity can

1432

be obtained with the use of ligands containing free-hydroxyl groups. Bartsch et al. reported on high-intensity ultrasound promoted Reformatsky reaction. Aza-type variations have been reported. See also Blaise ketoester, Dreiding – Schmidt, Frankland – Duppa, Gilman – Speeter, Grignard and Ivanov reactions.

REFERENCES : March : 930 Smith – March : 1212 Smith : 962 Smith 2nd : 800 Org. React. : 1, 1; 22, 423; 28, 203 Houben – Weyl : 6/2, 627; 8, 511; 13/2a, 809; E3, 640; E5, 708, 1092; E6b, 854, 1212; E7a, 109, 600; E7b, 44; E16b, 901 Org. Synth. : 21, 51; 37, 37 Org. Synth. Coll. Vol. : 3, 408; 4, 444 Science of Synthesis : 1, 493

1) S. Reformatsky, Ber. Dtsch. Chem. Ges., 1887, 20, 1210. 2) W.J. Gensler, Chem. Rev., 1957, 57, 191. 3) Y.S. Rao, Chem. Rev., 1964, 64, 353. 4) L. Friedrich; N. DeVera; M. Hamilton, Synth. Commun., 1980, 10, 637. 5) H. Mattes; C. Benezra, Tetrahedron Lett., 1985, 26, 5697. 6) A. Fürstner, Synthesis, 1989, 571. 7) A. Fürstner, Angew. Chem., Int. Ed. Engl., 1993, 32, 164. 8) L.W. Bieber; I. Malvestiti; E.C. Storch, J. Org. Chem., 1997, 62, 9061. 9) H. Kagoshima; Y. Hashimoto; D. Oguro; K. Saijo, J. Org. Chem., 1998, 63, 691. 10) K. Kanai; H. Wakabayashi; T. Honda, Org. Lett., 2000, 2, 2549. 11) A. Chattopadhyay; A. Salaskar, Synthesis, 2000, 561. 12) N.A. Ross; R.A. Bartsch, J. Org. Chem., 2003, 68, 360. 13) A. Yanagisawa; H. Takahashi; T. Arai, Chem. Commun., 2004, 580. 14) F. Orsini; G. Sello, Curr. Org. Chem., 2004, 1, 111. 15) M. Shimizu; T. Toyoda, Org. Biomol. Chem., 2004, 2, 2891. 16) J.D. Clark; G.A. Weisenburger; D.K. Anderson; P.-J. Colson; A.D. Edney; D.J. Gallagher; H.P. Kleine; C.M. Knable; M.K. Lantz; C.M.V. Moore; J.B. Murphy; T.E. Rogers; P.G. Ruminski; A.S. Shah; N. Storer; B.E. Wise, Org. Proc. Res. Dev., 2004, 8, 51.

17) R. Ocampo; W.R. Dolbier, jr., Tetrahedron, 2004, 60, 9325.

COMMENTS :

1433

REGITZ DIAZO TRANSFER EXAMPLE :

SO2N3

O +

O

O OtBu

H3C

O OtBu

H3C

DBU

N2

CH3

MECHANISM :

O O

O

O

O

O

N H

DBU

N

N N O

O N S O

O

O

O N S O

O

O

O

N O N S H O N

N N

N2

O

O

O O

N

N

O

O

DISCONNECTION :

EWG EWG

N N

EWG

EWG

EWG

EWG

NOTES :

The simple synthesis of diazo compounds from active methylenes with tosyl azide in the presence of a base. A modification has been introduced by Ledon using a two phase system, organic and water layer containing base and a quaternary ammonium salt.

1434

REFERENCES : March : 593 Smith – March : 780 Houben – Weyl : 10/4, 557 Org. Synth. : 48, 36; 51, 86; 59, 66; 70, 93; 73, 134 Org. Synth. Coll. Vol. : 5, 179; 6, 389, 414; 9, 197, 422

1) M. Regitz, Liebigs Ann. Chem., 1964, 676, 101. 2) M. Regitz; A. Liedhegener, Chem. Ber., 1966, 99, 3128. 3) M. Regitz, Angew. Chem., Int. Ed. Engl., 1967, 6, 733. 4) M. Regitz, Synthesis, 1972, 351. 5) H. Ledon, Synthesis, 1974, 347. 6) D.F. Taber; J.L. Schuhardt, Tetrahedron, 1987, 43, 5677. 7) A.B. Charette; R.P. Wurz; T. Ollevier, J. Org. Chem., 2000, 65, 9252.

COMMENTS :

REIMER – TIEMANN REACTION EXAMPLE :

OH

OH + CHCl3

KOH, EtOH

1435

CHO

MECHANISM :

O

H

O

O base

H

+

O

CCl2

BH

H H CCl3

base

Cl

CCl2

CCl2

+

- Cl

BH

O

O H

CHCl2

CCl2 O

OH

O H+

H

O H

H2O, - 2 HCl

DISCONNECTION :

OH

OH R

R

H O

NOTES :

The preparation of hydroxyaldehydes from phenols, chloroform and a base (alkali, hydroxide, carbonate, pyridine). Hydroxybenzoic acids are obtained if carbon tetrachloride is used. Bromoform and iodoform and trichloroacetic acid have been employed in the reaction. See also Ciamician – Dennstedt, Duff – Bills, Gattermann, Gattermann – Koch and Vilsmeier – Haack – Viehe reactions.

REFERENCES : March : 544 Smith – March : 716 Houben – Weyl : 7/1, 36; E3, 16; E6b, 1053; E7b, 146; E8a, 303 Org. React. : 9, 37; 13, 55; 28, 1 Org. Synth. : 22, 63 Org. Synth. Coll. Vol. : 3, 463

1) K. Reimer, Ber. Dtsch. Chem. Ges., 1876, 9, 423. 2) K. Reimer; F. Tiemann, Ber. Dtsch. Chem. Ges., 1876, 9, 824. 3) K. Reimer; F. Tiemann, Ber. Dtsch. Chem. Ges., 1876, 9, 1285.

1436

4) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 5) H. Wynberg, Chem. Rev., 1960, 60, 169. 6) C.W. Bird; A.L. Brown, Chem. Ind. (London), 1983, 827. 7) R. Neumann; Y. Sasson, Synthesis, 1986, 569. 8) J.C. Cochran; M.G. Melville, Synth. Commun., 1990, 20, 609. 9) B.R. Langlois, Tetrahedron Lett., 1991, 32, 3691. 10) M.E. Jung; T.I. Lazarova, J. Org. Chem., 1997, 62, 1553. 11) R. Ravichandran, J. Mol. Catal. A: Chem., 1998, 130, L205. 12) B.S. Jursic; D.M. Neumann, Tetrahedron Lett., 2001, 42, 8435.

COMMENTS :

REINDERS – RINGER DISPLACEMENT EXAMPLE :

OCH3

NO2

Na, EtOH MeOH CN

CN

MECHANISM :

NO2 OCH3

O2N

OCH3

OCH3 + NO2

EtOH CN

CN

1437

CN

DISCONNECTION :

NO2

OR

+ ROH CN

CN

NOTES :

The nitro group in a nitro-aryl cyanide is displaced by alkoxyl on treatment with sodium dissolved in alcohol.

REFERENCES :

1) W. Reinders; W.E. Ringers, Recl. Trav. Chim. Pays-Bas, 1899, 18, 326. 2) C.K. Bradsher; F.C. Brown; H.K. Porter, J. Am. Chem. Soc., 1954, 76, 2357. 3) J.R. Beck; R.L. Sobczak; R.G. Suhr; J.A. Yahner, J. Org. Chem., 1974, 39, 1839. 4) N. Kornblum; L. Cheng; R.C. Kerber; M.M. Kerstner; B.N. Newton; H.W. Pinnick; R.G. Smith; P.A. Wade, J. Org. Chem., 1976, 41, 1560.

COMMENTS :

REISSERT – GROSHEINTZ – FISCHER SYNTHESIS EXAMPLE :

Cl

Cl Cl

+ N

O

1438

1) KCN 2) H2SO4 benzene

H O

MECHANISM :

Cl N

Cl

+

H2SO4

CN

KCN

N

O

O

Cl

H

N

N O

NH

N

H

O

Cl Cl H2O

H O

H H

O

H

H+

O

NH2

N

NH

N

NH

N

O

H+ Cl

Cl

Cl H O +

N

Cl

O

aq. H+

N

O OH

NH2

DISCONNECTION :

R

H

+

+ O

N

N

COOH

R

Cl O

NOTES :

The synthesis of aldehydes or alkaloids from aliphatic or aromatic acid chlorides via 1-cyano-2-acylisoquinoline or 2cyanoquinoline intermediates. This reaction is very similar to the Reissert – Henze reaction. See also Padbury – Lindwall and Reissert – Henze reactions.

REFERENCES : March : 448 Smith – March : 533

1439

Houben – Weyl : 7/1, 291 Org. React. : 7, 99; 8, 218 Org. Synth. : 38, 58; 56, 19 Org. Synth. Coll. Vol. : 4, 641; 6, 115

1) A. Reissert, Ber. Dtsch. Chem. Ges., 1905, 38, 1603. 2) J.M. Grosheintz; H.O.L. Fischer, J. Am. Chem. Soc., 1941, 63, 2021. 3) W.E. McEwen; R.L. Cobb, Chem. Rev., 1955, 55, 511. 4) F.D. Popp; D.H. Purcell, jr., Synthesis, 1970, 591. 5) H. Suzuki; H. Gyoutoku; H. Yokoo; M. Shinba; Y. Sato; H. Yamada; Y. Murakami, Synlett, 2000, 1196. 6) O. Sieck; S. Schaller; S. Grimme; J. Liebscher, Synlett, 2003, 337.

COMMENTS :

REISSERT – HENZE REACTION EXAMPLE :

CN CH3 N

N

N CO2CH3

O

1) mCPBA 2) BzCl, KCN

CH3 N CO2CH3

O

MECHANISM :

N O

PhCOCl KCN

H N O

CN Ph O

1440

- PhCOOH

N

CN

DISCONNECTION :

N R

CN

N

O

NOTES :

This reaction serves to introduce a cyano group into an α (or occasionally γ) position to the heteronitrogen atom of an azine ring. The pyridine N-oxides can be made by oxidation with hydrogen peroxide or m-chloroperbenzoic acid. The term Reissert compounds comes from the formal addition of an acyl group and a cyano group to a nitrogen atom and carbon atom, respectively of a nitrogen-carbon bond in quinolines, isoquinolines, and related nitrogen heterocycles. See also Reissert – Grosheintz – Fischer reaction.

REFERENCES : Houben – Weyl : E7a, 662

1) A. Reissert, Ber. Dtsch. Chem. Ges., 1905, 38, 1603. 2) M. Henze, Ber. Dtsch. Chem. Ges., 1936, 69, 1566. 3) W.K. Fife; E.F.V. Scriven, Heterocycles, 1984, 22, 2375. 4) N. Nishiwaki; M. Ariga; M. Komatsu; Y. Ohshino, Heterocycles, 1996, 43, 1179. 5) H. Suzuki; C. Iwata; K. Sakurai; K. Tokumoto; H. Takahashi; M. Hanada; Y. Yokoyama; Y. Murakami, Tetrahedron, 1997, 53, 1593. 6) M. Bencková; A. Krutošíková; J. Pullman; N. Prónayová, Chem. Papers, 1999, 53, 118. 7) M. Bencková; A. Krutošíková, Coll. Czech. Chem. Commun., 1999, 64, 539. 8) E. Ichikawa; M. Suzuki; K. Yabu; M. Albert; M. Kanai; M. Shibasaki, J. Am. Chem. Soc., 2004, 126, 11808.

COMMENTS :

1441

REISSERT INDOLE REACTION EXAMPLE :

CH3

H3CO

OCH3

+ NO2

O

CO2Et

1) NaOEt 2) H2O 3) H2, Pt

O

N H

MECHANISM :

CH3

RO +

NO2

O

O

O

O

OR

COOR NO2

NaOEt - HOR

H2O - HOR

COOH NO2

O H2, Pt AcOH

COOH NH2

COOH - H2O

heat

N H

N H

DISCONNECTION :

CH3 N H

NO2

NOTES :

The indole synthesis from o-nitrotoluene and oxalic acid diethyl ester. An important variation of this route was developed by Batcho and Leimgruber at Hofmann–LaRoche, see Org. Synth. 63, 214 or Leimgruber – Batcho reaction for details. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe

heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Houben – Weyl : E7a, 662, 719 Org. Synth. : 43, 40

1442

Org. Synth. Coll. Vol. : 5, 567 Science of Synthesis : 10, 405

1) A. Reissert, Ber. Dtsch. Chem. Ges., 1897, 30, 1030. 2) T. Wieland; O. Unger, Chem. Ber., 1963, 96, 253. 3) H. Suzuki; Y. Yokoyama; C. Miyagi; Y. Murakami, Chem. Pharm. Bull., 1991, 39, 2170. 4) G.A. Kraus; N. Selvakumar, Synlett, 1998, 845. 5) H. Stephensen; F. Zaragoza, Tetrahedron Lett., 1999, 40, 5799. 6) S. Katayama; N. Ae; R. Nagara, J. Org. Chem., 2001, 66, 3474.

COMMENTS :

REMFRY – HULL SYNTHESIS EXAMPLE :

OH

O H2N

O H3C OEt

CH3

N

CH3

+

alkali

H2N

H3C

O

N

MECHANISM :

O

R1 R1

O - HOEt

H2N

OEt

N

R HO

OH

R1 H

N H

O H+

R1

N - H2O

R

HN NH2

O

H

H+ O

R

H+ O

O

H2N

O

N

1443

OH

R

OH

DISCONNECTION :

OH

O

N

OEt

OH

R1

+

R N

R

H2N

O

R1

H2N O

NOTES :

A malondiamide is condensed in alkaline solution with an ester to yield a 2,5- or 4,6-dihydroxypyrimidine. See also Biginelli reaction.

REFERENCES :

1) F.G.P. Remfry, J. Chem. Soc., 1911, 99, 610. 2) R. Hull, J. Chem. Soc., 1951, 2214. 3) D.J. Brown, J. Chem. Soc., 1956, 2312. 4) Z. Budĕšínský; F. Roubínek; E. Svátek, Coll. Czech. Chem. Commun., 1965, 30, 3730.

COMMENTS :

REPPE ACETYLENE SYNTHESIS EXAMPLE :

H3C

HO

CH3 +

2

H

H

H3C

pressure 100 oC

O

CH3

CH3 OH CH3

MECHANISM :

R

+ O

HO

HO

R1 H

H

R R1

R1

R O

1444

R

R

H

OH R1

R1

DISCONNECTION :

HO

OH

R

R R1

R

X

R1 H

X = O, NH

N R1 CH3

R

R

+

H

H

H

NOTES :

The reaction between aldehydes, ketones, amines and alkylolamines with acetylenes, under pressure and high temperature using copper, silver, mercury or gold acetylides as catalysts. See also Arens – van Dorp, Favorskii – Babayan and Nef reactions.

REFERENCES : Houben – Weyl : 4/2, 413

1) W. Reppe, Experientia, 1949, 5, 98. 2) W. Reppe, Liebigs Ann. Chem., 1955, 596, 1.

COMMENTS :

REPPE BUTADIENE SYNTHESIS EXAMPLE :

2

H

H

+

H

H 1) CuC2 2) 2 H2

O

1445

MECHANISM :

2

H

H

+

H

H

HOH2C

CH2OH

CuC2

O H

OH

2 H2 HO

- 2 H2O

H

- H2O

- H2O

O

DISCONNECTION :

2

H

H

+

H

H

O

NOTES :

The reaction between formaldehyde and acetylene in the presence of copper acetylide to afford butadiene. But-2-yne1,4-diol is initially formed and then hydrogenated to butane-1,4-diol which either directly is dehydrated to butadiene or in a two stages via tetrahydrofuran.

REFERENCES :

1) W. Reppe; E. Keyssner, German Patent, 1937, 725326. 2) W. Reppe, Experientia, 1949, 5, 98. 3) W. Reppe, Liebigs Ann. Chem., 1955, 596, 1.

COMMENTS :

1446

REPPE CARBONYLATION EXAMPLE :

H

H

+ H2O +

H2C

C O

Ni(CO)4 THF

COOH H

MECHANISM :

Ni(CO)4

Ni(CO)3 + CO

HCl - 2 CO

HC CH

Cl H Ni CO CO

OC Ni CO CO

H2O, - CO HC CH H

H C

H2C

O H

Ni(CO)2Cl

OC Ni CO

Ni CO OC CO

H2O - CO

CO

H2C

H C

Ni(CO)2Cl

H2C

Ni(CO)2OH

CO, HCl - H2O

H2O - HNi(CO)2Cl

H

COOH H

H O H

O

H2C

O

H2O - HNi(CO)2Cl

Ni(CO)2Cl

H2C O

1447

Ni CO

O

CO, HCl - H2O

DISCONNECTION :

O R

Nu O

R

R

+ CO + NuH

R

+ CO + NuH

CH3 Nu O

R

Nu O R

Nu

O Nu + CO + NuH H3C

Nu O

NOTES :

This reaction is related to a number of reactions of acetylene, alkenes and conjugated dienes at high temperatures and pressures. It tolerates a wide variety of functional groups. The co-reagents are carbon monoxide and a nucleophile, water, alcohol, or acid. Nowadays most of the Reppe carbonylation processes are based on palladium as the catalyst. See also Kutscheroff – Denigès reaction.

REFERENCES : Houben – Weyl : 6/2, 664; E18, 757

1) W. Reppe, Chem. Ing. Tech., 1950, 22, 361. 2) W. Reppe, Liebigs Ann. Chem., 1953, 582, 1. 3) C.W. Bird, Chem. Rev., 1962, 62, 283. 4) R.F. Heck, Adv. Catal., 1977, 26, 323. 5) D. Milstein, Acc. Chem. Res., 1988, 21, 428. 6) F. de Angelis; A. Selloni; A. Sgamellotti; C. Floriani; N. Re; J. Weber, Chem. Phys. Lett., 1998, 291, 57. 7) F. de Angelis; A. Sgamellotti, Organometallics, 2000, 19, 4104. 8) G. Kiss, Chem. Rev., 2001, 101, 3435.

1448

COMMENTS :

REPPE POLYMERISATION EXAMPLE :

4 H

H Ni(CN)2 THF 60 oC, 16 atm

MECHANISM :

Ni + 4 H

H

Ni

DISCONNECTION :

H

H

NOTES :

The [2+2+2+2] cyclomerisation of acetylenes with or without olefins by nickel complexes to afford eight-membered rings. The use of a phosphine ligand increases the yield. The reaction fails using di-substituted alkynes.

REFERENCES : Houben – Weyl : 5/1d, 425

1) W. Reppe; O. Schlichting; K. Klager; T. Toepel, Liebigs Ann. Chem., 1948, 560, 1. 2) W. Reppe; W. Toepel, German Patent., 1950, 68579. 3) W. Reppe, Chem. Ing. Technik, 1950, 22, 369. 4) A.J. Chalk, J. Am. Chem. Soc., 1972, 94, 5928.

1449

5) R.E. Colburn; K.P.C. Vollhardt, J. Am. Chem. Soc., 1986, 108, 5470.

COMMENTS :

REPPE VINYLATION EXAMPLE :

NPh2 O

S Ph OH

Ph

N H

SH

H

H

CH3COOH

O

CH3CONH2 H N

CH3 O

CH3 O

MECHANISM : H H

H

H RO

H OR

H ROH

H OR

NOTES :

The vinylation of organic hydroxyl, sulfhydryl, amino, imino, carbonyl and carboxamide compounds having an active hydrogen atom attached to a heteroatom with mono substituted acetylenes or with acetylene itself under base catalysis. Sodium or potassium alkoxides are used as catalysts at high temperature and under pressure.

1450

REFERENCES : Houben – Weyl : 4/2, 407; 6/3, 90

1) W. Reppe, Experientia, 1949, 5, 93. 2) W. Reppe, Liebigs Ann. Chem., 1956, 601, 81. 3) M. Seefelder, Liebigs Ann. Chem., 1962, 652, 107.

COMMENTS :

REVERDIN REACTION EXAMPLE :

OCH3

OCH3 I HNO3

I

NO2

MECHANISM :

OCH3

H3CO

OCH3

OH

+ HNO3

- HOI O2N

I

3 HOI HOI + HI

I

NO2

2 HI + HIO3 I2 + H2O OCH3

OCH3 I

I2 +

HI + NO2

NO2

1451

DISCONNECTION :

OR

OR I

NO2

I

NOTES :

During nitration of iodophenolether the iodine atom rearranges from para to the ortho position.

REFERENCES :

1) F. Reverdin, Ber. Dtsch. Chem. Ges., 1896, 29, 997. 2) G.M. Robinson, J. Chem. Soc., 1916, 109, 1078. 3) F.B. Daines; A.W. Magers; W.L. Steiner, J. Am. Chem. Soc., 1930, 52, 1570. 4) D.V. Nightingale, Chem. Rev., 1947, 40, 117.

COMMENTS :

RICHMAN – ATKINS SYNTHESIS EXAMPLE :

ArO2S

N

H

H

N

SO2Ar ArO2S +

TsO

OTs

N SO2Ar

N

N

Cs2CO3 DMF N SO2Ar

1452

SO2Ar

MECHANISM :

TsN(CH2CH2NHTs)2

HN(CH2CH2NH2)2 3 CH3C6H4SO2Cl pyridine 50 - 60 oC TsN(CH2CH2NTs)2 Na+

+

TsN(CH2CH2NHTs)2

EtONa EtOH, reflux

O 1) O

o O , 160 - 170 C

2) CH3OH, reflux TsN(CH2CH2NTsCH2CH2OH)2 CH3SO2Cl Et3N, DCM - 15 oC

TsN(CH2CH2NTsCH2CH2OSO2CH3)2

+ TsN(CH2CH2NTs)2 NaH + TsN(CH2CH2NTsCH2CH2OSO2CH3)2

(CH3)2NCHO 100 oC Ts

Ts N

N

Ts N

N Ts

N Ts

N Ts

NOTES :

The Richman – Atkins cyclisation remains one of the most widely used methods for the preparation of macrocyclic polyamines (polyazamacrocycles). This general procedure is best effected by the reaction of a bis-paratoluenesulfonamide salt with a bis-tosylate or mesylate in anhydrous DMF. See also Moedritzer – Irani reaction.

REFERENCES : Org. Synth. : 58, 86 Org. Synth. Coll. Vol. : 6, 652

1) H. Stetter; E.E. Roos, Chem. Ber., 1955, 88, 1390. 2) H. Stetter; K.H. Mayer, Chem. Ber., 1961, 94, 1555. 3) J.E. Richman; T. Atkins, J. Am. Chem. Soc., 1974, 96, 2268. 4) J.-M. Lehn; F. Montavon, Helv. Chim. Acta, 1976, 59, 1566. 5) F.P. Schmidtchen, Chem. Ber., 1980, 113, 864. 6) B.K. Vriesema; J. Buter; R.M. Kellogg, J. Org. Chem., 1984, 49, 110. 7) G. Dijkstra; W.H. Kruizinga; R.M. Kellogg, J. Org. Chem., 1987, 52, 4230.

1453

8) J.A.E. Pratt; I.O. Sutherland; R.F. Newton, J. Chem. Soc., Perkin Trans. 1, 1988, 13. 9) V. Panetta; J.J. Yaouanc; H. Handel, Tetrahedron Lett., 1992, 33, 5505. 10) I. Lazar, Synth. Commun., 1995, 25, 3181. 11) R.C. Hoye; J.E. Richman; G.A. Dantas; M.F. Lightbourne; L.S. Shinneman, J. Org. Chem., 2001, 66, 2722.

COMMENTS :

von RICHTER CINNOLINE SYNTHESIS EXAMPLE :

OH

O NC

NC

CH3 NH2

1) NaNO2 2) H2O 3) heat

N

N

MECHANISM :

COOH

H2O

HONO HCl

NH2

COOH

N

OH

70 oC N OH

COOH N

N

decarboxylation 260 oC, - CO2

N

N

DISCONNECTION :

COOH

OH R N

R

N

NH2

1454

NOTES :

The synthesis of cinnolines from substituted anilines via diazonium salts. See also Borsche – Koelsch, Neber – Bosset and Widman – Stoermer reactions.

REFERENCES :

1) V. von Richter, Ber. Dtsch. Chem. Ges., 1883, 16, 677. 2) M. Busch; M. Klett, Ber. Dtsch. Chem. Ges., 1892, 25, 2847. 3) N.J. Leonard, Chem. Rev., 1945, 37, 269. 4) N.J. Nelson; S.N. Boyd, jr., J. Org. Chem., 1946, 11, 419. 5) C.M. Atkinson; J.C.E. Simpson, J. Chem. Soc., 1947, 808. 6) J.F. Bunnett; J.F. Cormack; F.C. McKay, J. Org. Chem., 1950, 15, 481.

COMMENTS :

von RICHTER REACTION EXAMPLE :

NO2 COOH

Br

1) KCN, 150 oC 2) Hydrolysis

1455

Br

MECHANISM :

O

NO2

N

O

O

CN

N

O C

N

H CN

Br O

Br O

H+

N O

N

N

H

O

O Br

- H2O

COOH

O - N2

Br

OH

Br

OH

OH O

N N

NH2

+

Br N N

Br

H+

Br

Br

DISCONNECTION : NO2

COOH

R

R = Cl, Br, I, OCH3 R

NOTES :

The reaction of m- and p-nitrohalobenzenes with potassium cyanide leading to o- and m-halobenzoic acids with loss of the NO2-group as nitrogen.

REFERENCES : March : 672 Smith – March : 876 Houben – Weyl : E8a, 399 Org. Synth. : 38, 11 Org. Synth. Coll. Vol. : 4, 114

1) V. von Richter, Ber. Dtsch. Chem. Ges., 1871, 4, 21. 2) J.F. Bunnett; J.F. Cormack; F.C. McKay, J. Org. Chem., 1950, 15, 481. 3) J.F. Bunnett; M.M. Rahut, J. Org. Chem., 1956, 21, 944. 4) J.F. Bunnett, J. Chem. Soc., Quat. Rev., 1958, 12, 1. 5) K.M. Ibne–Rasa; E. Koubek, J. Org. Chem., 1963, 28, 3240. 6) A.C. Ellis; I.D. Rae, J. Chem. Soc., Chem. Commun., 1977, 152. 7) E.V. Tretyakov; D.W. Knight; S.F. Vasilevsky, Heterocycl. Commun., 1988, 4, 519.

1456

8) E.V. Tretyakov; D.W. Knight; S.F. Vasilevsky, J. Chem. Soc., Perkin Trans. 1, 1999, 3721.

COMMENTS :

RIECHE FORMYLATION EXAMPLE :

O Cl H

+

OCH3 Cl

H 1) AlCl3 2) H2O

MECHANISM :

+ H

OCH3 H

Cl

Cl OCH3

AlCl3

Cl O

H2O

OCH3 H

O

H

H - HOCH3

DISCONNECTION :

OR ArCHO

Ar R = CH3, Bu, Et X = Cl, OEt

H + H

X X

NOTES :

Dichloromethyl methyl ether formylate reacts with an aromatic under Friedel – Crafts catalysis (TiCl4, SnCl4, AlCl3). Ortho formates can also be used. See also Friedel – Crafts and Gattermann – Koch reactions.

1457

REFERENCES : Org. Synth. : 47, 51 Org. Synth. Coll. Vol. : 5, 49, 365

1) A. Rieche; H. Gross; E. Höft, Chem. Ber., 1960, 93, 88. 2) H. Gross; A. Rieche; G. Matthey, Chem. Ber., 1963, 96, 308. 3) G.J. Bodwell; R. Frim; H. Hopf; M. Rabinovitz, Chem. Ber., 1993, 126, 167. 4) H. Kretzschmann; H. Meier, J. Prakt. Chem., 1994, 336, 247. 5) S. Mayer; G. Guillaumet; J.Y. Merour, Heterocycles, 2001, 55, 1873.

COMMENTS :

RIEHM PYRIDINE SYNTHESIS EXAMPLE :

CH3 H3C

3

CH3 NH3

O

H3C

N

CH3

MECHANISM :

H3C

CH3

+

NH3

NH2

O

HO NH2

+ 2

H3C

H+ O

O

CH3

- H2O

O

NH

NH H

CH3

OH NH

- H2O

N H

1458

- CH4

H3C

N

CH3

DISCONNECTION :

R 3 R

N

H3C

R

+ NH3

O

R

NOTES :

Pyridine is synthesised from 3 equivalents of acetone and one equivalent of ammonia. See also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Guareschi – Thorpe, Hantzsch, Hantzsch – Beyer, von Meyer – Mohr, Petrenko–Kritschenko and Wakatsuki – Yamazaki – Bönnemann reactions.

REFERENCES :

P. Riehm, Liebigs Ann. Chem., 1887, 238, 1.

COMMENTS :

RIEHM QUINOLINE SYNTHESIS EXAMPLE :

CH3 + 2 NH2

H3C

CH3 AlCl3 heat

O

1459

N

CH3

MECHANISM :

H3C

CH3

H3C OH

H3C

+

- H2O

O

CH3 O

CH3 OH

H3C NH2

CH3 AlCl3

CH3 O

N H CH3

CH3

- H2O

N H

CH3

- CH4

N

CH3

CH3

DISCONNECTION :

R O N

R1

R1

R

NOTES :

Quinoline is synthesised from arylaminehydrochlorides and ketones in the presence of phosphorus pentachloride or aluminium chloride. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche and Skraup quinoline reactions.

REFERENCES :

1) C. Engler; P. Riehm, Ber. Dtsch. Chem. Ges., 1885, 18, 2245. 2) J. Levin; P. Riehm, Ber. Dtsch. Chem. Ges., 1886, 19, 1394. 3) P. Riehm, Liebigs Ann. Chem., 1887, 238, 9. 4) D.J. Craig, J. Am. Chem. Soc., 1938, 60, 1458. 5) R.C. Elderfield; J.R. McCarthy, J. Am. Chem. Soc., 1951, 73, 975.

COMMENTS :

1460

RIEMSCHNEIDER THIOCARBAMATE SYNTHESIS EXAMPLE :

OH

O

ArS

ArSCN + H2O

H2SO4

ArS NH

NH2

MECHANISM :

H2O

H O

Ph

Ph S

N

H+

N H

S

Ph - H+

S

O NH

Ph

S

NH2

+

H

DISCONNECTION :

O R

S

R S

NH2

N

NOTES :

Thiocarbamates are formed from thiocyanates and 95% sulfuric acid, followed by hydrolysis with ice-water. See also Radziszewski reaction.

REFERENCES : March : 888 Smith – March : 1179

1) R. Riemschneider; F. Wojahn, Pharmazie, 1949, 4, 460. 2) R. Riemschneider; F. Wojahn; G. Orlick, J. Am. Chem. Soc., 1951, 73, 5905. 3) K. Schmidt; P. Kollek–Bös, J. Am. Chem. Soc., 1953, 75, 6067. 4) R. Riemschneider; G. Orlick, Monatsh. Chem., 1953, 84, 313. 5) E.N. Zil’berman; A.Ya. Lazaris, J. Gen. Chem. USSR, 1963, 33, 1012. 6) A.R. Katritzky; S. Sobiak; C.M. Marson, Magn. Reson. Chem., 1988, 26, 665. 7) J. Fetter; H. Vásárhelyi; M. Kajtár–Peredy; K. Lempert; J. Tamás; G. Czira, Tetrahedron, 1995, 51, 4763. 8) A. Sápi; J. Fetter; K. Lempert; M. Kajtár–Peredy; G. Czira, Tetrahedron, 1997, 53, 12729. 9) A.K. Shiryaev; I.K. Moiseev, Russ. J. Org. Chem., 2001, 37, 746.

1461

COMMENTS :

RIGBY – TROST DEHYDROGENATIVE SULFENYLATION EXAMPLE :

O

OH CH3

PhS

CH3

4 PhSSPh 6 NaOCH3 MeOH

MECHANISM :

O

O

O

PhSSPh NaOCH3

SPh

SPh

SPh

SPh

O

O SPh

- SPh

SPh

O PhS

SPh

OH

O SPh

H

- SPh

H

SPh

DISCONNECTION : OH

O

PhS R

R

1462

SPh

NOTES :

Cyclohexanones undergo a remarkably mild aromatisation accompanying sulfenylation to give o-phenylthio phenols. See also Cohen – Daniewski reaction.

REFERENCES :

1) B.M. Trost; J.H. Rigby, J. Org. Chem., 1976, 41, 3217. 2) B.M. Trost; J.H. Rigby, Tetrahedron Lett., 1978, 19, 1667.

COMMENTS :

RILEY – SHARPLESS OXIDATION EXAMPLE :

O

O SeO2

O

MECHANISM :

O

O Se O

R1

R

O

R

H

R1 H

R O

Se O

O

H

O

O

H

R1

R Se

O

H

R1 O

H+

1463

+ H2O + Se

O HO Se OH

H

O HO Se HO

HOSe

O

H

O HO Se - H2O

HO + Se(OH)2

H2O

DISCONNECTION :

OH R

R O

R

R

O H3C

H

NOTES :

The oxidation active methylene groups carbonyl compounds with SeO2. The Sharpless method involves the hydroxy dehydrogenation with catalytic amount of selenium dioxide. The reaction involves an Alder ene reaction followed by a [2,3]-sigmatropic rearrangement. See also Alder ene reaction.

REFERENCES : March : 698 Smith – March : 915 Smith : 313 Smith 2nd : 273 Houben – Weyl : 7/1, 146 Org. React. : 5, 331; 24, 261

1) H.L. Riley; J.F. Morley; N.A.C. Friend, J. Chem. Soc., 1932, 1875. 2) G.R. Waitkins; C.W. Clark, Chem. Rev., 1945, 36, 235. 3) K.B. Sharpless; R.F. Lauer, J. Am. Chem. Soc., 1972, 94, 7154. 4) K.B. Sharpless; K.M. Gordon, J. Am. Chem. Soc., 1976, 98, 300. 5) M.A. Umbreit; K.B. Sharpless, J. Am. Chem. Soc., 1977, 99, 5526.

1464

6) N.M. Goudgaon; U.R. Nayak, Indian J. Chem., 1985, 24B, 589. 7) V.S. Dalavoy; V.B. Deodhar; U.R. Nayak, Indian J. Chem., 1987, 26B, 1. 8) D.A. Singleton; C. Hang, J. Org. Chem., 2000, 65, 7554. 9) A. Thalén; L.I. Wicksöm, Steroids, 2000, 65, 16.

COMMENTS :

RITTER REACTION EXAMPLE :

O H3C CH 3 CH3CN +

H3C

1) H+ 2) H2O

CH3

H3C

N H

CH3

MECHANISM :

ROH

R

N

+

H R1

OH

R

R+ + R1CN

R

tautomerism

H N

N

C

R1 H2O

R1 O

DISCONNECTION :

R

O N

H

R1 R1 = Alk, Ar, K

R1CN

NOTES :

Nitriles or aldehyde cyanohydrins react with a variety of alkenes, unsaturated carboxylic acids, esters, hydroxy esters or secondary or tertiary alcohols in concentrated sulphuric acid to yield amines. Acetic acid or dibutyl ether may be employed as a solvent. See also Kriewitz – Prins reaction.

1465

REFERENCES : March : 970 Smith – March : 1244 Smith : 1068 Smith 2nd : 892, 1074 Houben – Weyl : 11/2, 561; E5, 1032, 1554; E7a, 652; E7b, 335; E10a, 771; E16d, 650, 733, 1165 Org. React. : 17, 213 Org. Synth. : 42, 16; 44, 44 Org. Synth. Coll. Vol. : 5, 73, 471

1) J.J. Ritter; P.P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045. 2) J.J. Ritter; J. Kalish, J. Am. Chem. Soc., 1948, 70, 4048. 3) T. Gajda; A. Kuziara; S. Zawadski; A. Zwierzak, Synthesis, 1979, 549. 4) G. Fodor; S. Nagubandi, Tetrahedron, 1980, 36, 1279. 5) S. Top; G. Jaoven, J. Org. Chem., 1981, 46, 78. 6) Y.D. Vanka; C.T. Rao, Tetrahedron, 1985, 41, 3405. 7) G.A. Olah; Q. Wang, Synthesis, 1992, 1090. 8) M.V.R. Reddy; B. Mehrotra; Y.D. Vankar, Tetrahedron Lett., 1995, 36, 4861. 9) K. van Emelen; T. de Wit; G.J. Hoornaert; F. Compernolle, Org. Lett., 2000, 2, 3083. 10) F. Schweizer; A. Lohse; A. Otter; O. Hindsgaul, Synlett, 2001, 1434. 11) S. Sakaguchi; T. Hirabayashi; Y. Ishii, Chem. Commun., 2002, 516. 12) V. Justribó; M.I. Colombo, Tetrahedron Lett., 2003, 44, 8023. 13) J.M. Concellón; E. Riego; J.R. Suárez; S. García-Granada; M.R. Díaz, Org. Lett., 2004, 6, 4499.

COMMENTS :

ROBERT CHLORINATION EXAMPLE :

Ph

Ph

OH OCH3

Ph

OH

Cl OCH3

HCl CH3COOH

1466

Ph

MECHANISM :

Ph

OH

Ph

OR

Ph

OH

Ph

OH

Cl OR

OR HCl, - H2O

H+ - H2O

Ph

Ph

DISCONNECTION :

Ph

Cl

Ph

OH

OR

OR

Ph

Ph

OH

NOTES :

This reaction is illustrated by the fact that 9,10-dihydro-9,10-dihydroxy-2-alkoxy-9,10-diphenylanthracene on treatment with hydrochloric acid in acetic acid yields the corresponding 1-chloro compound. See also Bergmann anthracene reaction.

REFERENCES :

1) J. Robert, C.R. Séances Acad. Sci., 1951, 232, 1221. 2) C. Dufraisse; A. Étienne; J. Salmon, Bull. Soc. Chim. Belg., 1953, 62, 21.

COMMENTS :

1467

ROBERTSON – ROBINSON METHYLATION EXAMPLE :

HO

OH

H3CO

OCH3

O

O OH

HO

OH

OH

OCH3 CH3OSO2OCH3 K2CO3, acetone

H3CO

OCH3

OCH3

MECHANISM :

H3C OSO2OCH3 OH

OCH3

O K2CO3 acetone

DISCONNECTION :

ROCH3

ROH

NOTES :

The use of methyl sulfate and potassium carbonate in acetone in the methylation of hydroxy groups. See also Claisen carbonate alkylation, Fischer glycosidation, Hakomori, Haworth methylation, Irvine – Purdie, Meerwein

methylation and Williamson reactions.

REFERENCES : March : 388 Smith – March : 478 Org. Synth. : 6, 96; 9, 12; 13, 56, 102; 20, 97; 29, 63; 31, 90 Org. Synth. Coll. Vol. : 1, 387, 619; 2, 387, 619; 3, 564, 800; 4, 836

1) S.W. George; A. Robertson, J. Chem. Soc., 1937, 1535. 2) F.E. King; W. Bottomly, J. Chem. Soc., 1954, 1399. 3) A. Merz, Angew. Chem., Int. Ed. Engl., 1973, 12, 846. 4) M.E. Jung; S.M. Kaas, Tetrahedron Lett., 1989, 30, 641.

1468

COMMENTS :

ROBINSON – GABRIEL SYNTHESIS EXAMPLE :

H CH3 Ph O

N H

Ph

H3C

N

Ph

O

Ph

O

H2SO4

MECHANISM :

R1

R1 R O

N H

R

O

N

R OH

H2SO4 - H2O

OH

O

R1

N

DISCONNECTION :

R

O

R1 R

R1

N

O

N H

O

NOTES :

The oxazole synthesis from amides derived from α-aminoketones. Also trisubstituted oxazoles can be synthesised by this method. See also Davidson, Fischer oxazole and Japp reactions.

REFERENCES : Houben – Weyl : E8a, 935, 972

1) Laurent, J. Prakt. Chem., 1845, 35, 461. 2) R. Robinson, J. Chem. Soc., 1909, 95, 2167. 3) S. Gabriel, Ber. Dtsch. Chem. Ges., 1910, 43, 1283. 4) R.H. Wiley, Chem. Rev., 1945, 37, 401. 5) H.H. Wasserman; F.-J. Vinick, J. Org. Chem., 1973, 38, 2407.

1469

6) C.T. Brain; J.M. Paul, Synlett, 1999, 1642. 7) K. Akaji; Y. Kiso, Tetrahedron, 1999, 55, 10685.

COMMENTS :

ROBINSON – MANNICH ANNULATION REACTION EXAMPLE :

O

+

base

O

O

MECHANISM :

O H3C

O H3C

+ CH3

Et N

Et

I H3C

O

O

CH3

O O O

O O

O

O

1470

O

- H2O

O

DISCONNECTION : R O

+ O

O

R

NOTES :

The fusion of six-membered rings by reaction of cyclanones with vinyl ketones (base- or acid-catalysed), a tandem Michael addition – aldol condensation. Cyclohexanones and their β-carboxylic esters react also with quaternary salts

of Mannich bases of the type CH3COCH2CH2N+R2CH3 in the presence of bases, e.g. sodamide or sodium alkoxide, to yield bicylic unsaturated ketones. An aza-Robinson reaction has been published by Danishefsky et al. The Stork – Jung – Robinson annulation uses 1-iodo-3-trimethylsilyl-2-butene and derivatives to introduce a 3-oxobutyl group.

See also Hajos – Parrish – Eder – Sauer – Wiechert, Mannich and Wichterle reactions.

REFERENCES : March : 943 Smith – March : 1222 Smith : 956 Smith 2nd : 98, 795, 845 Houben – Weyl : E7b, 675 Org. React. : 7, 113 Org. Synth. : 41, 38; 45, 80; 63, 37 Org. Synth. Coll. Vol. : 5, 486, 869; 7, 368

1) W.S. Rapson; R. Robinson, J. Chem. Soc., 1935, 1285. 2) E.C. DuFeu; F.J. McQuillin; R. Robinson, J. Chem. Soc., 1937, 53. 3) C. Mannich; W. Koch; F. Borowsky, Ber. Dtsch. Chem. Ges., 1937, 70, 355. 4) R. Levine; W.C. Fernelius, Chem. Rev., 1954, 54, 449. 5) G. Stork; M.E. Jung, J. Am. Chem. Soc., 1974, 96, 3682. 6) J. Ellis; J. Dutcher; C. Heathcock, Synth. Commun., 1974, 4, 71. 7) W. Oppolzer; K. Battig; T. Hudlický, Helv. Chim. Acta, 1979, 62, 1493. 8) Y. Houbrechts; P. Laszlo; P. Pennetreau, Tetrahedron Lett., 1986, 27, 705. 9) G. Kim; M. Chu–Moyer; S.J. Danishefsky; G.K. Schulte, J. Am. Chem. Soc., 1993, 115, 30. 10) H. Miyamoto; S. Kanetaka; K. Tanaka; K. Yoshizawa; S. Toyota; F. Toda, Chem. Lett., 2000, 888. 11) B.B. Snider; B. Shi, Tetrahedron Lett., 2001, 42, 9123. 12) M.E. Jung; G. Piizzi, Org. Lett., 2003, 5, 137.

1471

COMMENTS :

ROBINSON – ROBINSON KETO-ESTER METHOD EXAMPLE :

O

O

EtO2C CO2Et

7

Ac

O 7

1) cold dil. alkali 2) heat, dil. H2SO4 3) heat, dil. aq. NaOH

MECHANISM :

O EtO2C CO2Et

Ac

cold dil. alkali

O EtO2C

CO2Et

heat, dil. H2SO4

CO2H

heat, dil. aq. NaOH

O HO2C

O OH O

1472

OH

DISCONNECTION :

O R

COOH

CH3

R

COOH

n

n

O

O CO2Et

NOTES :

This is the graded hydrolysis of an acylalkylacetoacetic ester to a keto-acid. See also Baudart, Bowman, Kapp – Knoll and Noller reactions.

REFERENCES :

1) G.M. Robinson; R. Robinson, J. Chem. Soc., 1925, 127, 175. 2) D.E. Ames; R.E. Bowman; R.G. Mason, J. Chem. Soc., 1950, 174.

COMMENTS :

ROBINSON – SCHÖPF REACTION EXAMPLE :

H3C H + H2NCH3 + HOOC

H O O

N COOH

COOH O

O

MECHANISM :

O O

O

O + NH CH 2 3

H

N

CH3 OH

N

N CH3

CH3

OH

1473

- H2O

H3C N COOH

COOH N CH3 O COOH

OH H3C

H

COOH H3C

N

H3C

N

N

COOH

COOH O

- H2O

O

HO

HOOC

COOH

COOH HCl - CO2

O

O

DISCONNECTION :

H3C

N

COOH COOH

O O

+ CH3NH2 +

OH COOH

O

NOTES :

This is the tropinone synthesis from succinic dialdehyde, methylamine and acetonedicarboxylic acid. See also Mannich and Petrenko–Kritschenko reactions.

REFERENCES : March : 900

1) R. Robinson, J. Chem. Soc., 1917, 111, 762. 2) C. Schöpf; G. Lehmann, Liebigs Ann. Chem., 1935, 518, 1. 3) L.C. Keagle; W.H. Hartung, J. Am. Chem. Soc., 1946, 68, 1608. 4) A.R. Battersby, J. Chem. Soc., Quat. Rev., 1961, 15, 259. 5) R.D. Guthrie; F. McCarthy, J. Chem. Soc. (C), 1967, 62. 6) R.V. Stevens; A.W.M. Lee, J. Am. Chem. Soc., 1979, 101, 7032. 7) J.M. McIntosh, J. Org. Chem., 1988, 53, 447. 8) M. Langlois; D.L. Yang; J.L. Soulier; C. Florac, Synth. Commun., 1992, 22, 3115. 9) T. Jarevang; H. Anke; T. Anke; G. Erkel; O. Sterner, Acta Chem. Scand., 1998, 52, 1350.

1474

COMMENTS :

ROBINSON DEHYDROGENATION EXAMPLE :

OH

OH

OH

OH HO

HO HO

H3C

O

N Cl

Cl

HO

H3C

N X

Cl

Cl O

KOAc, EtOH

DISCONNECTION :

N H

N

NOTES :

This reaction relates to the cyclisation of methyl tetrahydroisoquinolines to aromatic rings by chloranil in ethanolic solution containing potassium acetate.

REFERENCES :

1) R. Robinson: S. Sugasawa, J. Chem. Soc., 1932, 789. 2) S. Sugasawa; Y. Kanaoka, Pharm. Bull., 1955, 3, 266.

COMMENTS :

1475

ROELEN CARBONYLATION EXAMPLE : O + CO + H2

H

Co2(CO)8, 150 oC 230 atm

MECHANISM :

Co2(CO)8 + H2

R

2 HCo(CO)4

- CO

H O

HCo(CO)3

R

CH2 H

H2 R

H

COCo(CO)3

R CH2

Co(CO)4 R

1476

CoH(CO)3

CO

DISCONNECTION :

O

R H R

CH3

H

O

R

NOTES :

The cobalt-catalysed addition of CO, H2 to olefins. See also Koch carbonylation, Reppe and Tsuji – Wacker reactions.

REFERENCES : Houben – Weyl : 7/1, 55; E3, 180, 224; E18, 759

1) O. Roelen, U.S. Patent, 1943, 2327066. 2) O. Roelen, Angew. Chem., 1948, 60, 62. 3) F. Heck; D.S. Breslow, J. Am. Chem. Soc., 1961, 83, 4023. 4) H. Kropf, Angew. Chem., Int. Ed. Engl., 1966, 5, 646. 5) I. Kovacs; F. Ungvary; L. Marko, Organometallics, 1986, 5, 209. 6) S.M. Massiak; J.G. Rabor; S. Elbers; J. Marhenke; S. Bernhard; J.R. Schoonover; P.C. Ford, Inorg. Chem., 2000, 39, 3098.

7) S.K. Goh; D.S. Marynick, Organometallics, 2002, 21, 2262.

COMMENTS :

1477

ROGER SYNTHESIS EXAMPLE : CN N

N

+

CN

NaCN heat

MECHANISM :

CN

CN

CN

R

R

NaCN

R

CN

CN

H+

DISCONNECTION :

CN R

R

CN

CN

+

CN

NOTES :

These compounds are obtained by the addition of acrylonitrile to an excess of a boiling substituted acetonitrile in the presence of sodium cyanide. See also Knoevenagel condensation and Michael reaction.

REFERENCES :

1) C.F. Koelsch, J. Am. Chem. Soc., 1943, 65, 437. 2) A.O. Rogers, U.S. Patent, 1946, 2460536. 3) A.D. Campbell, J. Chem. Soc., 1954, 1377.

COMMENTS :

1478

ROSENMUND – SAYTZEFF REDUCTION EXAMPLE :

H3C

H3C Cl O

H

H2 Pd/BaSO4

O

MECHANISM :

H3C

H3C

H3C Cl

Pd

[Pd]

Cl

H2

O

O

O

H Pd Cl H

H3C H O

DISCONNECTION :

R

H

R

O

Cl O

NOTES :

The hydrogenation of acyl chlorides to aldehydes in the presence of a poisoned palladium catalyst. Carbonyl groups and nitro groups will not be reduced under these conditions. See also Brandt and Grundmann reactions.

REFERENCES : March : 447 Smith – March : 532 Houben – Weyl : 7/1, 285 Org. React. : 4, 362 Org. Synth. : 26, 77; 51, 8 Org. Synth. Coll. Vol. : 3, 685; 6, 1007

1) M. Saytzeff, J. Prakt. Chem., 1873, 6, 130. 2) K.W. Rosenmund, Ber. Dtsch. Chem. Ges., 1918, 51, 585.

1479

3) A.D. Sonntag, Chem. Rev., 1953, 52, 237. 4) D.C. Ayres; B.G. Carpenter; R.C. Denney, J. Chem. Soc., 1965, 3578. 5) A.W. Burgstahler; L.O. Weigel; C.G. Shafer, Synthesis, 1976, 767. 6) J.A. Peters; H. van Bekkum, Recl. Trav. Chim. Pays-Bas, 1981, 100, 21. 7) G. Bold; H. Steiner; L. Moesch; B. Walliser, Helv. Chim. Acta, 1990, 73, 405. 8) V.V. Gruskin; H. Alper, J. Org. Chem., 1991, 56, 5159. 9) V.G. Yadav; S.B. Chandalia, Org. Proc. Res. Dev., 1997, 1, 226. 10) K.H. Chandnani; S.B. Chandalia, Org. Proc. Res. Dev., 1999, 3, 416.

COMMENTS :

ROSENMUND – von BRAUN SYNTHESIS EXAMPLE :

Br

NC OCH3

OCH3

Br CuCN, heat, quinoline

CH3

NC CH3

MECHANISM :

[ArX->Cu]2+

ArX + Cu2+ Cu+ +

[ArX->Cu]2+

Cu2+ + [ArX->Cu]+

[ArX->Cu]+

Ar+ + CuX

Ar+ + -CN

ArCN

DISCONNECTION :

Ar

CN

Ar

1480

X

NOTES :

The copper catalysed nucleophilic substitution of aromatic halogen by copper cyanide. The reactivity order is (I > Br > Cl > F). The presence of amines promotes the reaction. See also Hoesch – Fischer reaction.

REFERENCES : March : 660 Smith – March : 867 Smith : 677 Smith 2nd : 574 Houben – Weyl : 8, 302; E5, 1460; E6a, 465 Org. Synth. : 21, 89; 28, 34 Org. Synth. Coll. Vol. : 3, 212, 631

1) K.W. Rosenmund; E. Struck, Ber. Dtsch. Chem. Ges., 1919, 52, 1749. 2) J. von Braun; G. Manz, Liebigs Ann. Chem., 1931, 488, 111. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189. 4) J.F. Bunnett; R.E. Zahler, Chem. Rev., 1951, 49, 273. 5) L. Friedman; H. Shechter, J. Org. Chem., 1961, 26, 2522. 6) M.S. Newman; H. Boden, J. Org. Chem., 1961, 26, 2525. 7) C. Couture; A.J. Paine, Can. J. Chem., 1985, 63, 111. 8) J.A. Connor; S.W. Leeming; R. Price, J. Chem. Soc., Perkin Trans. 1, 1990, 1127. 9) D.M. Guldi; C. Luo; A. Schwartz; R. Gómez; J.L. Segura; N. Martín; C. Brabec; N.S. Sariciftci, J. Org. Chem., 2002, 67, 1141. 10) J.X. Wu; B. Beck; R.X. Ren, Tetrahedron Lett., 2002, 43, 387.

COMMENTS :

ROSENMUND REACTION EXAMPLE :

HOOC

Br

+ AsO3K3

aq. EtOH

1481

HOOC

AsO(OH)2

MECHANISM :

AsO3 HOOC

Br

aq. EtOH

HO

AsO3

HOOC

- KBr

Br

O

O As OH OH

DISCONNECTION : O As OH OH

R

Br R

NOTES :

The arsonylation by substitution of aromatic halides. The reaction has a very limited scope. See also Bart, Béchamp and Scheller reactions.

REFERENCES : Org. React. : 2, 415

1) G. Meyer, Ber. Dtsch. Chem. Ges., 1883, 16, 1439. 2) K.W. Rosenmund, Ber. Dtsch. Chem. Ges., 1921, 54, 438. 3) C.S. Hamilton; C.G. Ludeman, J. Am. Chem. Soc., 1930, 52, 3284.

COMMENTS :

ROTHEMUND REACTION EXAMPLE :

Ph CHO + 4

4 N H

Ph

N H NH pyridine 220 oC Ph

HN H N Ph

1482

MECHANISM :

+

H

N H

Ar O

H N HO H

H Ar

Ar

N

- H2O

N H

H+

Ar

- 2 H+

Ar N H

NH

HN

O

HO

N H

Ar

Ar H

Ar

N H

- H2O

Ar

N H

Ar N H

HO

N H

Ar

N H

O

Ar

N H

O Ar

Ar Ar HO N

H

NH

Ar

NH H

N

N N

OH HN

HN

Ar Ar

Ar

DISCONNECTION :

Ar Ar

N H NH

Ar

HN

+ 4 Ar

4

H N

N H Ar

1483

CHO

Ar

NOTES :

The porphyrin synthesis from pyrroles and aldehydes. See also Adler – Longo, Lindsey, MacDonald and Taniguchi reactions.

REFERENCES :

1) P. Rothemund, J. Am. Chem. Soc., 1935, 57, 2010. 2) G.M. Badger; R.A. Jones; R.L. Laslett, Aust. J. Chem., 1964, 17, 1028. 3) J.S. Lindsey; H.C. Hsu; I.C. Schraman, Tetrahedron Lett., 1986, 27, 4969. 4) R.G. Little, J. Heterocycl. Chem., 1981, 18, 833. 5) A.M.D.R. Gonsalves; M.M. Pereira, J. Heterocycl. Chem., 1985, 22, 931. 6) J.S. Lindsey; I.C. Schreiman; H.C. Hsu; P.C. Kearney; A.M. Marguretta, J. Org. Chem., 1987, 52, 827. 7) P.J. Chmielewski; L. Latosgrazynski, J. Chem. Soc., Perkin Trans. 2, 1995, 503. 8) M.J. Crossley; P. Thordarson; J.P. Bannerman; P.J. Maynard, J. Porphyrins and Phtalocyanines, 1998, 2, 511. 9) R. Paolesse; L. Jaquinod; D.J. Nurco; S. Mini; F. Sagone; T. Boschi; K.M. Smith, Chem. Commun., 1999, 1307. 10) K.M. Smith, J. Porphyrins and Phtalocyanines, 2000, 4, 319.

COMMENTS :

ROUSH – HOFFMANN – YAMAMOTO STEREOSELECTIVE ALLYLATIONS EXAMPLE :

CH3 OH C9H19CHO + i

B O

PrO2C

- 78 oC

O i

CO2 Pr

1484

C9H19 CH3

MECHANISM :

R1

R2 CO2iPr

H RCHO +

B O i

O

R2 O

B O

R1 R

CO2iPr

O

CO2iPr

PrO2C

CO2iPr

H B O

R1 R

OH

O

R2

CO2iPr

O

R aq. base

R1 R2

DISCONNECTION :

OH R

R1

R B

+ R1CHO

NOTES :

The synthesis of syn or anti homoallylic alcohols from Z or E crotylboronate camphor derived auxiliary and aldehydes (Hoffmann) or of syn homoallylic alcohols from crotylboronate tartrate esters, BF3, and aldehydes (Yamamoto). While Roush used isopropyl tartrate as a chiral auxiliary. The favoured transition state is believed to minimise lonepair lone-pair interactions between aldehyde and carbonyl of the ester group. See also Duthaler – Hafner, Ibuka – Yamamoto, Matteson and Thomas reactions.

REFERENCES : Org. React. : 51, 1

1) T. Gasparis; H. Nöth; W. Storch, Angew. Chem., Int. Ed. Engl., 1979, 18, 326. 2) Y. Yamamoto; H. Yatagai; Y. Naruta; K. Maruyama, J. Am. Chem. Soc., 1980, 102, 7107. 3) W.R. Roush; A.E. Walts; L.K. Hoong, J. Am. Chem. Soc., 1985, 107, 8166. 4) R.W. Hoffmann; B. Landmann, Chem. Ber., 1986, 119, 1039. 5) W.R. Roush; K. Ando; D.B. Powers; A.D. Palkowitz; R.L. Halterman, J. Am. Chem. Soc., 1990, 112, 6339. 6) S. Knapp; Y. Dong, Tetrahedron Lett., 1997, 38, 3813. 7) P.V. Ramachandran, Aldrichimica Acta, 2002, 35, 23. 8) B.W. Gung; X. Xue; W.R. Roush, J. Am. Chem. Soc., 2002, 124, 10692.

1485

COMMENTS :

ROUSH MACROLACTONISATION EXAMPLE :

O

O O

O

O OH OH

O O

O

O

1) (CH3)3COCl, Et3N, THF 2)

O

O

O

O

O

O N

O

O N

MECHANISM :

R

O

O

O OH

CH3 H3C

Cl

H3C

R H3C

O

R1

O

R

H

OR1

O

H3C CH3

O base

DISCONNECTION :

O R1O

O R1 OH +

R

HO

R

NOTES :

Pivaloyl chloride and 4-pyrrolidino pyridine are used as coupling reagents between a carboxylic acid and an alcohol. These reagents were first used by Roush in the synthesis of Verrucarin B. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Hunsdiecker ring-

1486

closure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Petasis reaction, Peterson, Raphael, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation

reactions.

REFERENCES :

1) W.R. Roush; T.A. Blizzard, J. Org. Chem., 1983, 48, 758. 2) W.R. Roush; T.A. Blizzard, J. Org. Chem., 1984, 49, 1772. 3) W.R. Roush; T.A. Blizzard, J. Org. Chem., 1984, 49, 4332.

COMMENTS :

ROWE REARRANGEMENT EXAMPLE :

CH3

CH3 N N

N N

NO2 H+, 180 oC O

O

MECHANISM :

It is assumed that this is the intermediate : R H Ar N N H O

1487

NO2

DISCONNECTION :

R

R N N

N Ar N

Ar

O

O

NOTES :

The ψ-phthalazone – phthalazone rearrangement in the presence of acid at 180 oC.

REFERENCES :

1) F.M. Rowe; E. Levin; A.C. Burns; J.S.H. Davies; W. Tepper, J. Chem. Soc., 1926, 690. 2) F.M. Rowe; D.A.W. Adams; A.T. Peters; A.E. Gillam, J. Chem. Soc., 1937, 90. 3) W.R. Vaughan, Chem. Rev., 1948, 43, 447. 4) W.R. Vaughan; D.I. McCane; G.J. Sloan, J. Am. Chem. Soc., 1951, 73, 2298.

COMMENTS :

RUFF – FENTON DEGRADATION EXAMPLE :

O H HO H H HO

O OH H OH OH

1) Br2 Ca(OH)2 2) Fe2(SO4)3, H2O2 Ba(OAc)2

1488

HO H H HO

H OH OH

MECHANISM :

O H HO H H

OH H OH OH

H HO H H

Br2 Ca(OH)2

HO

CO2Ca OH H OH OH CH2OH

O

Fe2(SO4)3, H2O2 Ba(OAc)2

HO H H

H OH OH

HO

DISCONNECTION :

CHO R

CHO H OH R R = carbohydrate

NOTES :

The oxidative degradation of aldoses via α-hydroxy acids to lower chain aldoses. The use of ferric chloride as a catalyst is called the Hocket – Hudson oxidation. A variant of the Ruff – Fenton reaction is the chain-shortening of aldonyl chlorides with peroxides. In this case there are two different intermediates possible depending the use of base. See also Haber – Weiss, MacDonald – Fischer and Wohl reactions.

REFERENCES : Smith 2nd : 225, 1182 Houben – Weyl : E3, 527, 639

1) H.J.H. Fenton, Proc. Chem. Soc., 1893, 9, 113. 2) O. Ruff, Ber. Dtsch. Chem. Ges., 1898, 31, 1573. 3) R.C. Hockett; C.S. Hudson, J. Am. Chem. Soc., 1934, 56, 1632. 4) H.G. Fletcher; H.W. Diehl; C.S. Hudson, J. Am. Chem. Soc., 1950, 72, 4546. 5) G.N. Richards, Methods Carbohydr. Chem., 1962, 1, 180. 6) H.S. Isbell; H.L. Frush; R. Naves; P. Soontracharoen, Carbohydr. Res., 1981, 90, 111. 7) H.S. Isbell; M.A. Salam, Carbohydr. Res., 1981, 90, 123.

COMMENTS :

1489

RUFF REACTION EXAMPLE :

CH3SiCl3 1) PhNH2 2) HI

CH3SiI3

MECHANISM :

RSiCl3 + 6 C6H5NH2

RSi(HNC6H5)3 + 3 C6H5NH2 . HCl

RSi(NHC6H5)3 + 6 HI

RSiI3 + 3 C6H5NH2 . HI

DISCONNECTION :

RSiI3

RSiCl3

NOTES :

The transhalogenation of alkyl chlorosilanes to alkyl iodosilanes. See also Eaborn reaction.

REFERENCES :

1) O. Ruff, Ber. Dtsch. Chem. Ges., 1908, 41, 3738. 2) H.H. Anderson; D.L. Séaton; R.P.T. Rudnicki, J. Am. Chem. Soc., 1951, 73, 2144. 3) H.H. Anderson, J. Am. Chem. Soc., 1951, 73, 2351.

COMMENTS :

1490

RUGGLI SYNTHESIS EXAMPLE :

H N

NO2

O2N

1) Br2 2) SnCl2, HCl 3) EtOH picric acid 4) KOH, EtOH

N H

MECHANISM :

Br2 NO2

O2N

O O N+

OH -

O N+ O -

NO2 Br

Br

-

O2N

N H

Br

SnCl2 HCl

H2N

NH2 Br

Br

H N

NH2 KOH EtOH - HBr

N H

O N+ O EtOH heat - HBr

DISCONNECTION :

H N

N H

NO2

O2N

NOTES :

1-Nitro-2-[2-(2-nitrophenyl)ethynyl]benzene is brominated to yield o,o’-dinitrostilbene dibromide which is reduced to the diamino-compound. This on boiling with ethanolic picric acid gives 2-(o-aminophenyl)-3-bromoindole which with ethanolic potassium hydroxide yields the di-indole. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger

1491

– Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung

indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) P. Ruggli, Ber. Dtsch. Chem. Ges., 1917, 50, 883. 2) P. Ruggli; O. Schmid, Helv. Chim. Acta, 1935, 18, 1215.

COMMENTS :

RUPE REARRANGEMENT EXAMPLE :

H3C H3C

O

CH3

H3C

H2SO4

COOH

O

CH3 COOH CH3

MECHANISM :

H+

O O

- CO

- H2O

O

OH

OH2

O

O

O

O

O

C O O

H2O

HO

O O

O

1492

O

DISCONNECTION :

H3C O

CH3 COOH CH3

H3C H3C

O

CH3 COOH

NOTES :

The acid-catalysed rearrangement of cinenic acid. The loss and subsequent recapture of carbon monoxide is suggested for the carbonyl transfer in this rearrangement. See also Koch – Haaf reaction.

REFERENCES :

1) H. Rupe; C. Liechtenhan, Ber. Dtsch. Chem. Ges., 1908, 41, 1278. 2) H. Rupe; H. Hirschmann, Helv. Chim. Acta, 1933, 16, 505. 3) H. Dahn; T. Riechstein, Helv. Chim. Acta, 1952, 35, 1. 4) J. Meinwald, J. Am. Chem. Soc., 1955, 77, 1617. 5) J. Meinwald; J.T. Ouderkirk, J. Am. Chem. Soc., 1960, 82, 480. 6) J. Meinwald; H.C. Hwang; D. Christman; A.P. Wolf, J. Am. Chem. Soc., 1960, 82, 483.

COMMENTS :

RUPPERT FLUOROALKYLATION EXAMPLE :

H3C

H3C SiCl

H3C

(Et2N)3P, CF3Br

SiCF3 H3C

MECHANISM :

(Et2N)3P + CF3Br

[(Et2N)3PBr] CF3

1493

RSiCl

RSiCF3

O

HO

CF3

(CH3)3SiCF3

DISCONNECTION :

RnSiCl4-n

Rn+1SiCF3Cl3-n n = 0, 1, 2, 3 R = Ar, Alk

NOTES :

Carbon trifluoride substituted organylchlorosilanes (Ruppert reagent) are synthesised from alkyl or aryl chlorosilanes using (Et2N)3P, and CF3Br.

REFERENCES :

1) I. Ruppert; K. Schlich; W. Volbach, Tetrahedron Lett., 1984, 25, 2195. 2) R.J. Linderman; D.M. Graves, J. Org. Chem., 1989, 54, 661. 3) R. Krishnamurti; D.R. Bellew; G.K.S. Prakash, J. Org. Chem., 1991, 56, 984. 4) K. Iseki; T. Nagai; Y. Kobayashi, Tetrahedron Lett., 1994, 35, 3137. 5) F. Aymard; J.-Y. Nédélec; J. Périchon, Tetrahedron Lett., 1994, 35, 8623.

COMMENTS :

RUSSIG – LAATSCH REACTION EXAMPLE :

O

OCH3 OBu

O

OCH3

1) Na2S2O4 H2O 2) CH3OH, HCl (ClCH2)2, 60 oC

1494

OH

MECHANISM :

O

OCH3

OH

Na2S2O4 H2O O

CH3OH, HCl OH

OH

DISCONNECTION :

OR

O

R1

R1 OH

+ ROH O

NOTES :

Naphthalene-1,4-diols are converted regioselectively to monoalkyl ethers using alcohols containing hydrogen chloride. The starting hydrogenquinone is first reduced by sodium thionite to the 1,4-diol.

REFERENCES :

1) F. Russig, J. Prakt. Chem., 1900, 62, 30. 2) H. Laatsch, Liebigs Ann. Chem., 1980, 140. 3) H. Laatsch, Liebigs Ann. Chem., 1991, 385. 4) Y. Dai; T.J. Katz, J. Org. Chem., 1997, 62, 1274. 5) S.D. Dreher; T.J. Katz; K.-C. Lam; A.L. Rheingold, J. Org. Chem., 2000, 65, 815.

COMMENTS :

1495

RUŽIČKA LARGE RING SYNTHESIS EXAMPLE :

Ce O O

O

O O heat

7

7

MECHANISM :

CH3 CH3

CH3

HO H3C

O LA

O

O

DISCONNECTION :

M

O

O O n

M = metal

O O n

NOTES :

The formation of large ring alicyclic ketones from dicarboxylic acids by thermal decomposition of salts with metals of the second and fourth groups of the periodic table (Ca, Th, Ce). It is good for the preparation of C5, C6, C8, C10 to C30 cyclic ketones. The reaction is of little use nowadays. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Hunsdiecker ring-closure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai

rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Petasis reaction, Peterson, Raphael, Roush, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

1496

REFERENCES : March : 496 Smith – March : 574 Houben – Weyl : 4/2, 754

1) L. Ružička; M. Stoll; H. Schinz, Helv. Chim. Acta, 1926, 9, 249. 2) L. Ružička; W. Brugger; C.F. Seidel; H. Schinz, Helv. Chim. Acta, 1928, 11, 496. 3) L. Ružička, Chem. Ind. (London), 1935, 54, 2. 4) D.K. Fukushima; S. Dobringer; M.S. Heffler; T.H. Kritchevsky; F. Herlag; G. Roberts, J. Am. Chem. Soc., 1955, 77, 6585.

COMMENTS :

RUŽIČKA OLEFINIC ACID SYNTHESIS EXAMPLE :

O 2

HOOC

8

OCH3

8

COOH

H H 1) Na, xylene i i 2) Al(O Pr)3, PrOH, reflux 3) aq. CH3COOH 4) O3, CCl4 5) KMnO4 6) CH2N2, distill, saponification 7) HBr, CH3COOH, Zn, NaI, acetone

MECHANISM :

H2C H2C

(CH2)xCO2Et + R(CH2)yCO2Et

H2C x

HO

y

OH

R

Na xylene HOOC

acetylation, O3 hydrolysis

x

O

x

HO

1497

y

OH

y

R

OH

Al(OiPr)3 i PrOH HOOC

R HBr, AcOH Zn, NaI acetone

x

y

R

DISCONNECTION :

HOOC

x

y

R

H2C

(CH2)xCO2Et + R(CH2)yCO2Et

NOTES :

A mixed acyloin condensation of an unsaturated ester with a saturated ester to yield an unsaturated acyloin, which when submitted to the Meerwein – Ponndorf – Verley reduction, gives an unsaturated glycol. The latter after acetylation of the free hydroxyls is oxidised with ozone to convert the terminal vinyl group into a carboxyl. The dihydroxy acid so obtained is treated with hydrogen bromide in acetic acid to give the dibromo acid, which with zinc yields the mono-olefinic acid.

REFERENCES :

L. Ružička; Pl.A. Plattner; W. Widmer, Helv. Chim. Acta, 1942, 25, 604.

COMMENTS :

RUŽIČKA REARRANGEMENT EXAMPLE :

O H3C

CH3

HO CH 3 H3C O

OH

10% KOH AcO

AcO

1498

MECHANISM :

O H3C

CH3 OH

H3C

AcO 10% KOH Lewis acid H3C H3C

HO CH 3 H3C O

O CH3 OH

H3C

AcO

AcO

via

via

O

O

O

OH OH O

O

O H

DISCONNECTION :

H3C

HO CH 3 O

O H3C

H3C

CH3 OH

H3C AcO H3C H3C

O CH3 OH

AcO

AcO

NOTES :

The base- or acid-catalysed rearrangement of 17α-hydroxy-20-keto steroids to D-homo steroids.

REFERENCES :

1) M. Boussingault, Liebigs Ann. Chem., 1836, 19, 308. 2) L. Ružička; H. Meldahl, Helv. Chim. Acta, 1938, 21, 1760. 3) L. Ružička; H. Meldahl, Helv. Chim. Acta, 1939, 22, 421. 4) N.L. Wender; D. Taub; R.W. Walker, Tetrahedron, 1960, 11, 163. 5) N.G. Steinberg; G.H. Rasmusson; G.F. Reynolds; J.H. Hirshfield; B.H. Arison, J. Org. Chem., 1984, 49, 4731. 6) L. Schor; E.G. Gros; A.M. Seldes, J. Chem. Soc., Perkin Trans. 1, 1992, 453.

1499

COMMENTS :

RYCHNOVSKY POLYOL SYNTHESIS EXAMPLE :

OEt

Cl OH

O

CN

Cl O 1) TMSNMe2 2) DIBAL-H 3) TMSCN, KCN, 18-crown-6 4) CSA, acetone, 2,2-dimethoxy propane

O

MECHANISM :

HO

CO2CH3

SPh

TIPSO 1) TIPSOTf, lutidine, DCM, - 20 oC 2) TMSCl, Et3N, DMAP, DCM, RT 3) DIBAL-H, Et2O, - 78 oC 4) PhSSiMe3, TMSOTf DCM, - 78 oC 5) Acetone, TMSOTf, DCM, - 78 oC

OH

O

LiDBB, THF, - 78 oC ethylene oxide, BF3.Et2O, - 78 oC

O

O

TIPSO O

O

OH 1) PPTS, CuSO4 acetone, RT 2) Bu4NF, THF, RT 3) TsCl, NaOH, THF, RT

SPh

TIPSO O

O

O

O

SnBu3

TIPSO 1) LiDBB, THF, - 78 oC 2) Bu3SnCl, - 78 oC

1500

O

O

SnBu3

TIPSO 1.6

O

O

O

O

O +

O

O

1) 1.4 nBuLi, THF, - 78 oC 2) 2.5 BF3.Et2O, - 78 oC

TIPSO OH

O

O 1) Bu4NF, THF, RT 2) CH3OH, amberlite 15, RT

HO OH

OH

OH

OH

OH

NOTES :

The convergent synthesis of polyol chains in which 2 chains are coupled with control of the newly formed stereogenic centre.

REFERENCES :

1) S.D. Rychnovsky, J. Org. Chem., 1989, 54, 4982. 2) S.D. Rychnovsky; D.J.Skalitzky, Tetrahedron Lett., 1990, 31, 945. 3) S.D. Rychnovsky; G. Griesgraber, J. Org. Chem., 1992, 57, 1559. 4) S.D. Rychnovsky, Chem. Rev., 1995, 95, 2022. 5) C.J. Sinz; S.D. Rychnovsky, Top. Cur. Chem., 2001, 216, 51.

COMMENTS :

1501

1502

SCHMIDLIN – BERGMAN – WILSMORE KETENE SYNTHESIS · 1529

A

SCHMIDT – RUTZ SYNTHESIS · 1530 SCHMIDT GLYCOSIDATION · 1531

ANGELI MODIFICATION · 1511

SCHMIDT MACROLACTONISATION · 1533 SCHMIDT REARRANGEMENT · 1535 B

SCHMITZ DIAZIRIDINE SYNTHESIS · 1537 SCHOLL REACTION · 1538

BRACKMAN – SMITH MODIFICATION · 1511

SCHÖLLKOPF AMINO ACID SYNTHESIS · 1540

BRAUN von – RUDOLPH MODIFICATION · 1609

SCHOLTZ INDOLIZINE SYNTHESIS · 1541 SCHÖNBERG ADDITION · 1543

C

SCHORIGIN – WANKLYN REACTION · 1544 SCHOTTEN – BAUMANN REACTION · 1545

CACCHI COUPLING · 1611

SCHWANERT SYNTHESIS · 1546 SCHWARTZ HYDROZIRCONATION · 1548 SCHWECHTEN REACTION · 1550

F

SCHWEIZER ALLYL AMINE SYNTHESIS · 1551 SCHWEIZER REARRANGEMENT · 1552

FURUGAWA MODIFICATION · 1583

SCRETTAS – YUS METHOD · 1553 SEEBACH – FRÁTER ALKYLATION · 1554 K

SEEBACH SELF-REGENERATION · 1555 SEMMLER – WOLFF – SCHROETER REACTION · 1557

KECK MACROLACTONISATION · 1628

SENDERENS DIETHYL ETHER SYNTHESIS · 1558 SENDERENS KETONE SYNTHESIS · 1559 O

SERINI REACTION · 1560 SEYFERTH – GILBERT HOMOLOGATION · 1561

OHIRA – BESTMANN PROCEDURE · 1562

SEYFERTH – HILBERT REACTION · 1562 SHAPIRO REACTION · 1563

R

SHARPLESS ASYMMETRIC AMINOHYDROXYLATION

RAGUÉ SCHLEYER von ADAMANTISATION · 1525

SHARPLESS DIHYDROXYLATION · 1566

RAPHAEL MACROLACTONISATION · 1619

SHEEHAN – FRANK SYNTHESIS · 1569

(OXYAMINATION) · 1564

SHERADSKY REARRANGEMENT · 1571 SHESTAKOV HYDRAZINE SYNTHESIS · 1572

S

SHEVERDINA – KOCHESHKOV AMINATION · 1574 SABATIER – MAILHE SYNTHESIS · 1505

SHI EPOXIDATION · 1575

SABATIER – SENDERENS REACTION · 1506

SHIBASAKI CYCLISATION · 1577

SAEGUSA INDOLE SYNTHESIS · 1507

SHILOV REACTION · 1579

SAEGUSA REACTION · 1508

SIEGRIST STILBENE SYNTHESIS · 1580

SAKAI REACTION · 1509

SIMCHEN SYNTHESIS · 1582

SANDMEYER DIAZONIUM REACTION · 1510

SIMMONS – SMITH REACTION · 1583

SANDMEYER DIPHENYLUREA ISATIN SYNTHESIS · 1512

SIMONIS CHROMONE CYCLISATION · 1585

SANDMEYER ISONITROSOACETANILIDE ISATIN SYNTHESIS ·

SKATTEBØL DIHALOCYCLOPROPANE REARRANGEMENT · 1586

1514 SARETT OXIDATION · 1515

SKRAUP – PRIGLINGER SYNTHESIS · 1587

SAWDEY REARRANGEMENT · 1517

SKRAUP QUINOLINE SYNTHESIS · 1589

SAYTZEFF SYNTHESIS · 1519

SLYKE van DETERMINATION · 1590

SCHEINER AZIRIDINE SYNTHESIS · 1520

SLYKE van OXIDATIVE DECARBOXYLATION · 1591

SCHENCK REARRANGEMENT · 1521

SMILES REARRANGEMENT · 1593

SCHIFF REACTION · 1522

SMITH – MIDDLETON – ROZEN FLUORINATION · 1594

SCHLACK – KUMPF REACTION · 1523

SMITH – TIETZE COUPLING · 1597

SCHLITTLER – MÜLLER RING-CLOSURE · 1526

SMITH INDOLE SYNTHESIS · 1599

SCHMID INDOLE SYNTHESIS · 1527

SNIECKUS REARRANGEMENT · 1600 SOAI AUTOCATALYSIS · 1602

1503

SOMEI – KAMETANI REACTION · 1604

STOERMER DEALKYLATION · 1651

SOMMELET – HAUSER REACTION · 1605

STOLLÉ – BECKER SYNTHESIS · 1652

SOMMELET ALDEHYDE REACTION · 1607

STOLLÉ SYNTHESIS · 1653

SONN – MÜLLER ALDEHYDE SYNTHESIS · 1608

STONE – WALES REARRANGEMENT · 1655

SONN EXTENSION OF THE HOESCH REACTION · 1610

STORK – NISHIYAMA RADICAL CYCLISATION · 1656

SONOGASHIRA – HAGIHARA COUPLING · 1611

STORK – UENO REACTION · 1657

SORENSON AMINO ACID SYNTHESIS · 1612

STORK CYANOHYDRIN ALKYLATION · 1658

SPASSOW ESTERIFICATION · 1614

STORK ENAMINE ALKYLATION AND ACYLATION · 1660

SPECKAMP RING-CLOSURE · 1615

STORK RADICAL CYCLISATION · 1661

SPENGLER – PFANNENSTIEL OXIDATION · 1616

STORK REDUCTIVE CYCLISATION · 1662

ST. PFAU – PLATTNER SYNTHESIS · 1617

STORY MACROCYCLE SYNTHESIS · 1664

STAAB ACYLATION · 1618

STRECKER AMINO ACID SYNTHESIS · 1665

STACEY ESTERIFICATION · 1619

STRECKER DEGRADATION · 1668

STADEL – RÜGHEIMER PYRAZINE SYNTHESIS · 1622

STRECKER SULFITE ALKYLATION · 1669

STADLER – ZIEGLER REACTION · 1621

STRUKOV SYNTHESIS · 1670

STAUDINGER – PFENNINGER THIIRANE DIOXIDE SYNTHESIS ·

STRYKER REGIOSELECTIVE REDUCTION · 1671 STUFFER – BACKER DISULFONE HYDROLYSIS · 1672

1623 STAUDINGER AZIDE REDUCTION · 1624

SUÁREZ – HEUSLER – KALVODA REACTION · 1674

STAUDINGER KETENE ADDITION · 1625

SUGASAWA INDOLE SYNTHESIS · 1675

STEGLICH – HASSNER ESTERIFICATION · 1627

SUGASAWA INDOXYL SYNTHESIS · 1677

STENHOUSE CLEAVAGE · 1629

SUGASAWA REACTION · 1678

STEPHEN ALDEHYDE SYNTHESIS · 1630

SUNDBERG INDOLE SYNTHESIS · 1679

STEPHENS – CASTRO SYNTHESIS · 1632

SURZUR – TANNER REARRANGEMENT · 1680

STETTER 1,4-DICARBONYL SYNTHESIS · 1633

SÜS REACTION · 1682

STETTER CARBOXYLIC ACID SYNTHESIS · 1636

SUZUKI – MIYAURA VINYL COUPLING · 1683

STEVENS REARRANGEMENT · 1637

SUZUKI (KYODAI) REACTION · 1685

STIEGLITZ REARRANGEMENT · 1638

SUZUKI REDUCTION · 1687

STILES – SISTI FORMYLATION · 1640

SWARTS REACTION · 1688

STILL – GENNARI REACTION · 1641

SWERN OXIDATION · 1689

STILL – WITTIG REARRANGEMENT · 1642

SZARVASY – SCHÖPF CARBOMETHOXYLATION · 1690

STILLE – KELLY COUPLING · 1644 STILLE – MIGITA – KOSUGI COUPLING · 1645

T

STILLE CARBONYL SYNTHESIS · 1648 STOBBE CONDENSATION · 1649

TRUCE – SMILES REARRANGEMENT · 1593

1504

SABATIER – MAILHE SYNTHESIS EXAMPLE :

CH3CH2COOH + HCOOH

TiO2 250 oC

CH3CH2CHO

MECHANISM :

CH3CH2COOH + HCOOH TiO2 250 oC

CH3CH2CHO

+ CO2 + H2O

DISCONNECTION :

RCOOH

RCHO

NOTES : Aliphatic acids when mixed with vapours of formic acid and passed over a titanium dioxide catalyst at 250 – 300 oC yield aldehydes, water and carbon dioxide. See also Akabori – Neuberg – Fischer reaction.

REFERENCES : Houben – Weyl : 7/1, 278

1) P. Sabatier; A. Mailhe, C.R. Séances Acad. Sci., 1912, 154, 561. 2) P. Sabatier; A. Mailhe, C.R. Séances Acad. Sci., 1914, 158, 985.

COMMENTS :

1505

SABATIER – SENDERENS REACTION EXAMPLE :

Ni, H2

DISCONNECTION :

R

R

NOTES : Catalytic hydrogenation of unsaturated compounds with hydrogen and finely divided nickel.

REFERENCES : Houben – Weyl : 2, 288; 4/2, 284

1) P. Sabatier; J.B. Senderens, C.R. Séances Acad. Sci., 1897, 124, 1360. 2) P. Sabatier; J.B. Senderens, C.R. Séances Acad. Sci., 1899, 128, 1173. 3) P. Sabatier, Ber. Dtsch. Chem. Ges., 1911, 44, 1984.

COMMENTS :

1506

SAEGUSA INDOLE SYNTHESIS EXAMPLE :

CH3 N

C

1) 2 LDA diglyme - 78 oC -> RT 2) H2O

N H

MECHANISM :

Li

R R

CH2R H N

C

LDA diglyme

R

N

H Li

N C

R

H H R1X

N

N R1

+

Li

DISCONNECTION :

R CH2R + R1X N R1

N

C

NOTES : The cyclisation of ortho-lithiated o-tolylisocyanides in a 5-endo-dig fashion. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

1507

REFERENCES : 1) Y. Ito; K. Kobayashi; T. Saegusa, J. Am. Chem. Soc., 1977, 99, 3532. 2) Y. Ito; K. Kobayashi; N. Seko; T. Saegusa, Bull. Chem. Soc. Jpn., 1984, 57, 73. 3) M. Mąkosza, Synthesis, 1991, 103. 4) M. Mąkosza; K. Wojciechowski, Liebigs Ann. Chem. / Receuil, 1997, 1805. 5) M. Mąkosza; J. Stalewski; K. Wojciechowski; W. Danikiewicz, Tetrahedron, 1997, 53, 193.

COMMENTS :

SAEGUSA REACTION EXAMPLE : H

CH3

Et

OSiMe3

H Pd(OAc)2 CH3CN

Et

CH3 O

MECHANISM :

TMSO

Pd(OAc)2 - TMSOAc

O

O

HPdOAc

PdOAc

DISCONNECTION :

H

R1

H

R1

R

O

R

OSiMe3

1508

- Pd - HOAc

O

NOTES :

The Saegusa oxidation is a standard method for the conversion of a silyl enol ether into the corresponding α,β-enone. The oxidising agent palladium(II) acetate is added in stoichiometric amounts. The mechanism is analogous to the Tsuji – Wacker oxidation, see Porth et al.

REFERENCES : Science of Synthesis : 1, 113

1) Y. Ito; T. Konoike; T. Saegusa, J. Am. Chem. Soc., 1975, 97, 649. 2) Y. Ito; T. Hirao; T. Saegusa, J. Org. Chem., 1978, 43, 1011. 3) S. Porth; J.W. Bats; D. Trauner; G. Giester; J. Mulzer, Angew. Chem., Int. Ed., 1999, 38, 2015. 4) K.C. Nicolaou; Y.-L. Zhong; P.S. Baran, J. Am. Chem. Soc., 2000, 122, 7596. 5) D.R. Williams; R.A. Turske, Org. Lett., 2000, 2, 3217.

COMMENTS :

SAKAI REACTION EXAMPLE :

CN N N H H3CO

H3CO2C

H

CN N

NaI,

Cl H3C

H CO2CH3

CH3

O reflux, 43 h

1509

H

N H

MECHANISM :

CN N

CN N

H NaI

N Cl H H H3CO H3CO2C

N H

OCH3

H H

CO2CH3

CH3O2C

CH3O2C

CN

CN

N

N H

N H H3CO

H

H

NOTES :

The skeletal rearrangement of a Corynanthe-type derivative.

REFERENCES : Smith 2nd : 1250

T. Koike; H. Takayama; S-i. Sakai, Chem. Pharm. Bull., 1991, 39, 1677.

COMMENTS :

SANDMEYER DIAZONIUM REACTION EXAMPLE :

SO3H

NH2 1) HCl, HNO2 2) Cu2Cl2, HSO3H

1510

H

N

- CH3OH

MECHANISM :

N

N

N

NXCuX

X- N2

CuIX + X-

CuIX2X

+ CuIIX2

- CuIX

DISCONNECTION :

ArN2+

ArNuc

NOTES :

The formation of aromatic halogeno-, nitro- or cyano-compounds from diazonium salts under the catalytic action of cuprous halide or cyanide. The Angeli modification uses copper(I) salts from copper(I) sodium hypophosphite and copper(I) sulfate. The Brackman – Smith modification uses copper(II) chloride hydrate in acetone. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann

sulphinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Schwechten and Witt diazotation reactions.

REFERENCES : March : 532, 723 Smith – March : 874, 936 Smith : 197 Smith 2nd : 168, 1247 Houben – Weyl : 5/4, 438 Org. React. : 2, 262 Org. Synth. : 3, 33, 79; 4, 69; 24, 22; 28, 52; 32, 23 Org. Synth. Coll. Vol. : 1, 162, 170, 514; 3, 185, 341; 4, 160 Science of Synthesis : 10, 257, 736

1) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633. 2) L. Gattermann, Ber. Dtsch. Chem. Ges., 1890, 23, 1218. 3) A. Angeli, Gazz. Chim. Ital., 1891, 21, 258. 4) H.H. Hodgson, Chem. Rev., 1947, 40, 251. 5) W.A. Crowdrey; D.S. Davies, J. Chem. Soc., Quat. Rev., 1952, 6, 358.

1511

6) W. Brackman; P.J. Smith, Recl. Trav. Chim. Pays-Bas, 1966, 85, 857. 7) P.J. Harrington; L.S. Hegedus, J. Org. Chem., 1984, 49, 2657. 8) S.J. Garden; J.C. Torres; A.A. Ferreira; R.D. Silva; A.C. Pinto, Tetrahedron Lett., 1997, 38, 1501. 9) P. Stanetty; T. Dvorak; M.D. Milovilovic, Arkivoc, 2001, 2, 1128. 10) P. Hanson; S.C. Rowell; A.B. Taylor; P.H. Walton; A.W. Timms, J. Chem. Soc., Perkin Trans. 2, 2002, 1126. 11) P. Hanson; J.R. Jones; A.B. Taylor; P.H. Walton; A.W. Timms, J. Chem. Soc., Perkin Trans. 2, 2002, 1135. 12) P. Hanson; S.C. Rowell; P.H. Walton; A.W. Timms, Org. Biomol. Chem., 2004, 2, 1838.

COMMENTS :

SANDMEYER DIPHENYLUREA ISATIN SYNTHESIS EXAMPLE :

O SH N H

N

Ph

1) KCN, PbCO3 2) (NH4)2S 3) H2SO4 4) H+, H2O

1512

O N H

MECHANISM :

CN

SH N H

N

Ph

KCN PbCO3

N H

N

(NH4)2S Ph

AlCl3 O

O H2N N H

S N

N Ph

H2SO4

H+, H2O

N H

Ph

O N H

DISCONNECTION :

O SH

O N H

N H

N

Ph

NOTES :

A symmetrical diarylthiourea is converted into a cyanoformamidine by the action of potassium cyanide and basic lead carbonate. This amidine with ammonium sulfide gives a thioamide, which yields an isatin-2-anil with concentrated sulfuric acid. The anil can be hydrolysed to the isatin. Alternatively, the cyanoformamidine may be treated with aluminium chloride in benzene to give the isatin-2-anil. See also Claisen – Shadwell, Sandmeyer isonitrosoacetanilide isatin and Stollé reactions.

REFERENCES : Houben – Weyl : 7/4, 11

1) T. Sandmeyer, Z. Farb. Textil. Chem., 1903, 2, 129. 2) A. Reissert, Ber. Dtsch. Chem. Ges., 1904, 37, 3708. 3) V.Q. Yen; Ng.Ph. Buu-Hoï; N.D. Xuong, J. Org. Chem., 1958, 23, 1858.

1513

COMMENTS :

SANDMEYER ISONITROSOACETANILIDE ISATIN SYNTHESIS EXAMPLE :

O Cl

Cl O

1) Cl3CHO 2) H2NOH, 100 oC 3) H2SO4, H2O

NH2 Cl

Cl

N H

MECHANISM :

Cl

NOH Cl

Cl

Cl

NOH

N

+ NH2 Cl

1) Cl3CHO 2) H2NOH, 100 oC

N H

Cl

N

O

H

Cl

Cl

1) H2SO4 2) H2O

H2SO4 60 oC

O

O Cl

Cl

O

O Cl

N H

Cl

DISCONNECTION :

O R

R

O N H

NH2

1514

N H

NOTES :

Chloral hydrate, hydroxylamine and an aryl amine condense in acid solution to give an isonitrosoacetanilide, which with concentrated sulfuric acid yields isatin. In neutral solution the chloral oxime reacts with the aromatic amine to yield a diphenylisonitrosoacetamidine. Recently, a modification by Garden et al. uses ethanol a co-solvent. See also Claisen – Shadwell, Sandmeyer diphenylurea isatin and Stollé reactions.

REFERENCES : Houben – Weyl : 7/4, 14 Org. Synth. : 5, 71 Org. Synth. Coll. Vol. : 1, 327

1) T. Sandmeyer, Helv. Chim. Acta, 1919, 2, 234. 2) F.E. Sheibley; J.S. McNulty, J. Org. Chem., 1956, 21, 171. 3) S.J. Garden; J.C. Torres; A.A. Ferreira; R.B. Silva; A.C. Pinto, Tetrahedron Lett., 1997, 38, 1501. 4) G. Loloiu; T. Loloiu; O. Maior, Rev. Chim. (Bucharest), 1998, 49, 861. 5) G.K. Jnaneswara; A.V. Bedekar; V.H. Deshpande, Synth. Commun., 1999, 29, 3627.

COMMENTS :

SARETT OXIDATION EXAMPLE : O

HO O O

CrO3 pyridine

O

O O

O

1515

MECHANISM :

O O Cr O O R1 H R2

H OH R1

H R2

O + R1

R2

HO

O Cr

OH

N O O Cr NO

Follow-up chemistry of Cr(IV) :

3 CrO(OH)2 or

Cr2O3 + CrO3 + 3 H2O CrO3

CrO(OH)2 OH

R1

O

OH H

R1

R2

R1

R2 .5 Cr2O3 + 1.5 H2O

R2

CrO3H

OH R1

H R2

OH O Cr O O R1 H R2

H

OH Cr HO OH

DISCONNECTION :

OH

O R

R1

R = H, Alk, Ar

R

R1

NOTES :

This is a useful general method for the oxidation of primary and secondary alcohols even in the presence of double bonds and thioethers. The main problem is the isolation of the products from the pyridine solution. This oxidation reaction is superseded by the Collins oxidation, which is originally a modification of the Sarett oxidation. Chromium-

1516

mediated oxidations have a competing pathway involving free-radical intermediates. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Swern and Uemura reactions.

REFERENCES : March : 1167 Smith – March : 1514, 1531 Smith : 228 Smith 2nd : 199 Org. React. : 53, 1 Org. Synth. : 52, 5; 55, 84 Org. Synth. Coll. Vol. : 6, 373, 644

1) H.H. Sisler; J.D. Bush; O.E. Accountius, J. Am. Chem. Soc., 1948, 70, 3827. 2) G.I. Poos; G.E. Arth; R.E. Beyler; L.H. Sarett, J. Am. Chem. Soc., 1953, 75, 422. 3) V.I. Stenberg; R.J. Perkins, J. Org. Chem., 1963, 28, 323. 4) P.G. Gassman; P.G. Pape, J. Org. Chem., 1964, 29, 160. 5) J.A. Glinski; B.S. Joshi; Q.P. Jiang; S.W. Pelletier, Heterocycles, 1988, 27, 185. 6) O. Caamaño; F. Fernández; X. García–Mera; J.E. Rodríguez–Borges, Tetrahedron Lett., 2000, 41, 4123.

COMMENTS :

SAWDEY REARRANGEMENT EXAMPLE :

N N O

H

HOOC N

CH3OH NaOH

O

1517

N N N Ph

Ph

MECHANISM :

OCH3 O N

N N H

N O

OH

HN N

- H2O

O

CH3OH

H3CO O

N N Ph N

Ph

HO O

H2O, HO

N N Ph N

Ph

DISCONNECTION :

O OH N N

N

N H

N O

N O

NOTES :

4-Phenylazo-2-phenyloxazolin-5-one is rapidly attacked by methanolic potassium hydroxide or methanolic ammonia with the formation of 1,5-diphenyl-3-carboxy-1H-1,2,4-triazole and 1,5-diphenyl-3-carbamido-1H-1,2,4-triazole, respectively.

REFERENCES :

1) V.K. Kuskov, J. Gen. Chem. USSR (Engl. Transl.), 1951, 21, 165. 2) G.W. Sawdey, J. Am. Chem. Soc., 1957, 79, 1955.

COMMENTS :

1518

SAYTZEFF SYNTHESIS EXAMPLE : H

H

OEt 1) Et2Zn 2) H2O

O

Et

Et OH

MECHANISM :

(R1)2Zn

(R1)2Zn

R

R

OEt O

R1

R1

R

O

R1 OZn

R1 H2O

R

R1 OH

DISCONNECTION :

R2 R

R

R2 OH

R1 O

NOTES :

This method involves the use of zinc, an alkyl halide and a suitable carbonyl compound. See also Frankland – Duppa, Grignard and Schorigin – Wanklyn reactions.

REFERENCES :

G. Wagner; A. Saytzeff, Liebigs Ann. Chem., 1875, 175, 351.

COMMENTS :

1519

SCHEINER AZIRIDINE SYNTHESIS EXAMPLE :

N N N

N

hν

Br

Br

MECHANISM :

Br Br n

Bu

+

Br

N3

N

N

N

hν - N2

n

Bu

N n

Bu

DISCONNECTION :

N N

Ar

N

R2

R1

R3

ArN3 +

R2

R

R

R1 R3

NOTES :

Arylazides react with unactivated olefins to give 1,2,3-∆2-triazoles. Photodecomposition leads to aziridines. See also Blum aziridine, Hassner, Hoch – Campbell, Huisgen, Mansuy – Evans and Wenker ring-closure reactions.

REFERENCES : March : 202 Smith – March : 1057

1) R.C. Elderfield; R.S. McElhinney, J. Org. Chem., 1961, 26, 1923. 2) P. Scheiner, J. Org. Chem., 1965, 30, 7. 3) P. Scheiner, Tetrahedron, 1968, 24, 349. 4) A. Hassner; B.A. Belinka, jr.; M. Haber; P. Hunger, Tetrahedron Lett., 1981, 22, 1863.

1520

COMMENTS :

SCHENCK REARRANGEMENT EXAMPLE :

OOH CH3(CH2)6

OOH

(CH2)7CO2CH3

hexane 40 oC

CH3(CH2)6

(CH2)7CO2CH3

DISCONNECTION :

OOH R

OOH R1

R

R1

NOTES :

The [2,3]-allylic hydroperoxide rearrangement in both acyclic and cyclic systems. Initially discovered in steroidal allylic hydroperoxides. Over the years several reaction mechanisms have been proposed, these are discussed in the review by Beckwith et al.

REFERENCES :

1) G.O. Schenck; O.-A. Neumüller; W. Eisfeld, Liebigs Ann. Chem., 1958, 618, 202. 2) G.O. Schenck; O.-A. Neumüller; W. Eisfeld, Angew. Chem., 1958, 70, 595. 3) G. Ohloff, Pure Appl. Chem., 1975, 43, 481. 4) A.A. Frimer, Chem. Rev., 1979, 79, 359. 5) N.A. Porter, Acc. Chem. Res., 1986, 19, 262. 6) A.L.J. Beckwith; D. Crich; P.J. Duggan; Q. Yao, Chem. Rev., 1997, 97, 3273. 7) J.-J. Helesbeux; O. Duval; C. Dartiguelongue; D. Séraphin; J.-M. Oger; P. Richomme, Tetrahedron, 2004, 60, 2293.

1521

COMMENTS :

SCHIFF REACTION EXAMPLE :

Ph Ph

H

+

HO

N

NH2

O

H

Na2CO3 OH

MECHANISM :

R R

H

H R1NH2

O

H

R

OH N

- H2O

R1

H N R1

DISCONNECTION :

R

H R N R1

H

+ R1NH2

O

NOTES :

The formation of imines from aldehydes and primary amines in the presence of alkali. See also Decker – Forster and Grignard reactions.

1522

REFERENCES : March : 896 Smith – March : 1186 Smith : 904 Smith 2nd : 764 Houben – Weyl : 7/1, 453 Org. Synth. : 21, 108; 50, 66 Org. Synth. Coll. Vol. : 3, 827; 6, 901

1) H. Schiff, Liebigs Ann. Chem., 1864, 3, 343. 2) M.M. Sprung, Chem. Rev., 1940, 26, 297. 3) E.H. Cordes; W.P. Jencks, J. Am. Chem. Soc., 1962, 84, 832. 4) H. Weingarten; J.P. Chupp; W.A. White, J. Org. Chem., 1967, 32, 3246. 5) D.P. Roelofsen; H. van Bekkum, Recl. Trav. Chim. Pays-Bas, 1972, 91, 605. 6) J.J. Eisch; R. Sanchez, J. Org. Chem., 1986, 51, 1848. 7) B.E. Love; J. Ren, J. Org. Chem., 1993, 58, 5556.

COMMENTS :

SCHLACK – KUMPF REACTION EXAMPLE :

H N

O O

O

N H

HO

H

H CH3 O

1) NH4NCS 2) NaOH 3) Ba(OH)2

1523

H3C

COOH NH2

MECHANISM :

H N

O O

H N

O

O

N H

HO

O

H CH3

O

O

NH4NCS

O

H N

N

H

O

H

CH3

N

O

CH3

O

N S

O N H

H+

O NaOH

S

H N O

CH3 H +

O

OH

S

N

H O

N H

H3C Ba(OH)2

COOH NH2

DISCONNECTION :

R1 R

R COOH

H2N

NH2

R1 H N O R2

H COOH

NOTES :

The degradation of peptides using a hydantoine system. See also Bergmann degradation and Edman reactions.

REFERENCES :

1) P. Schlack; W. Kumpf, Hoppe-Seyler’s ZA. Physiol. Chem., 1926, 154, 125. 2) J. Tibbs, Nature, 1951, 168, 910. 3) H.G. Khorana, J. Chem. Soc., Quat. Rev., 1952, 6, 340. 4) B.M. Duggan; R.L. Laslett; J.F.K. Wilshire, Aust. J. Chem., 1996, 49, 541. 5) B.L. Mo; J. Li; S.P. Liang, Prog. Biochem. Biophys., 1999, 26, 219.

COMMENTS :

1524

von RAGUÉ SCHLEYER ADAMANTISATION EXAMPLE :

Br xs AlBr3 HBr 2 days

MECHANISM :

R+ RH

1) RH 2) R+

1) RH 2) R+

RH

DISCONNECTION :

NOTES :

Tricyclic molecules rearrange in a Wagner – Meerwein fashion to adamantane and derivatives if treated with Lewis acids. This is the first synthesis which made adamantine readily available. See also Wagner – Meerwein rearrangement.

REFERENCES : March : 1071

1525

Smith – March : 1396 Org. Synth. : 42, 8 Org. Synth. Coll. Vol. : 5, 16

1) P. von Ragué Schleyer; M.M. Donaldson, J. Am. Chem. Soc., 1960, 82, 4645. 2) V.Z. Williams; P. von Ragué Schleyer; G.J. Gleicher; L.B. Rodewald, J. Am. Chem. Soc., 1966, 88, 3862. 3) Z. Majerski; S.H. Liggers; P. von Ragué Schleyer; A.P. Wolf, J. Chem. Soc., Chem. Commun., 1970, 1596. 4) M.A. McKervey, Tetrahedron, 1980, 36, 971.

COMMENTS :

SCHLITTLER – MÜLLER RING-CLOSURE EXAMPLE :

OEt NH2 +

H

EtO

CH3

N

1) toluene, 125 oC 2) H2SO4, 160 oC

O

CH3

MECHANISM :

H OEt H NH2 R H+

O

N

OEt

- H2O

O H+ H

R

H+ OH

N

N R

OEt OEt

R

H

1526

N

- H2O R

DISCONNECTION :

N

NH2

R

EtO

H

EtO

O

+

R

NOTES :

This reaction is a modification of the Pomeranz – Fritsch reaction using benzylamines and glyoxal semiacetals. The isoquinoline ring-closure of benzylimino acetals using concentrated sulfuric acid at 180 oC. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bobbit, Bruckner, Larock indole, Pictet – Gams, Pictet – Sprengler, Pomeranz – Fritsch and Simchen reactions.

REFERENCES : Smith : 1342 Smith 2nd : 1104 Houben – Weyl : E7a, 625, 640 Org. React. : 6, 192

1) C.K. Bradsher, Chem. Rev., 1946, 38, 447. 2) E. Schlittler; J. Müller, Helv. Chim. Acta, 1948, 31, 914.

COMMENTS :

SCHMID INDOLE SYNTHESIS EXAMPLE :

Ph

Ph N3 O

1) LDA, THF, - 78 oC 2) SOCl2, pyridine

N O

N3 N O

Ph

1527

Ph

MECHANISM :

Ph Cl N R Ph Cl

Ph Cl

O H

O

1) NaH, DMF 2) R1CH2X

OH R1

N H R

1) [(CH3)2CH]2NLi THF, - 78 oC 2) H2O

N CH2R1 R Ph Cl

1) POCl3, Pyridine 2) H2O

R1 N R

DISCONNECTION : R

R R1 N R2

N R2

O CH2R1

NOTES :

In principle this is a ‘reverse-Madelung’ reaction to afford an indole. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman

indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Smith, Sugasawa

indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) H. Greuter; H. Schmid, Helv. Chim. Acta, 1974, 57, 281. 2) P. Molina; M. Alajarin; A. Vidal, Tetrahedron, 1990, 46, 1063.

COMMENTS :

1528

SCHMIDLIN – BERGMAN – WILSMORE KETENE SYNTHESIS EXAMPLE :

H3C

CH3

H2C C O

> 500 oC

O

MECHANISM :

H3C

CH3

2 CH3 + CO

O H3C

CH3 +

CH3

CH4 +

H3C O

O H3C

CH2

CH2

CH3

+

H2C C O

O

DISCONNECTION :

H3 C

H2 C C O

CH3 O

NOTES :

The pyrolysis of acetone to ketene via a radical mechansim.

REFERENCES : Org. React. : 3, 109 Org. Synth. : 4, 39 Org. Synth. Coll. Vol. : 1, 330

1) N.T.M. Wilsmore; A.W. Stewart, Proc. Chem. Soc., 1907, 23, 229. 2) J. Schmidlin; M. Bergman, Ber. Dtsch. Chem. Ges., 1910, 43, 2821. 3) G. Quadbeck, Angew. Chem., 1956, 68, 361.

1529

COMMENTS :

SCHMIDT – RUTZ SYNTHESIS EXAMPLE :

NO2 HO HO H H

CH2NO2 H H OH OH CH2OH

1)

O

O

H

H AcO H H

H OAc OAc CH2OAc

O 2) NaHCO3

MECHANISM :

HO HO H H

CH2NO2 H H OH OH CH2OH

H2, Pd/C

O

AcO AcO H H

O O

H AcO H H

CH2NO2 H H OAc OAc CH2OAc

NO2

CH2NO2 H H OAc OAc CH2OAc

NaHCO3

H H HO H H

1) NaOH 2) H2SO4

O H H OH OH CH2OH

DISCONNECTION :

H

NO2

R

R O R = carbohydrate

1530

H AcO H H

H H OAc OAc CH2OAc

NOTES :

The formation of nitro-olefins from nitro-polyalcohols after acetylation. After this method 2-desoxy-aldoses can be formed.

REFERENCES :

1) E. Schmidt; G. Rutz, Ber. Dtsch. Chem. Ges., 1928, 61, 2142. 2) J.C. Sowden, J. Am. Chem. Soc., 1949, 71, 1897. 3) J.C. Sowden; R. Schaffer, J. Am. Chem. Soc., 1951, 73, 4662. 4) A. Matsuda; K.A. Watanabe, Nucleosides, Nucleotides, 1996, 15, 205.

COMMENTS :

SCHMIDT GLYCOSIDATION EXAMPLE :

H3C

H3C

O

BnO BnO

OTBS

+

OAc

OH

TMSOTf DCM, RT O

CCl3 NH

H3C

O

BnO BnO H3C

O

BnO AllO

OTBS O O

BnO AllO OAc

1531

MECHANISM :

H3C

H3C

O

BnO AllO

NaH, CCl3CN OAc

O

BnO AllO OAc

OH

BF3·Et2O O

CCl3 NH BnO

H3C

H3C

O

BnO AllO O H3C

O

CH3

BnO

BnO AllO O

- CCl3CONH2

CCl3

O O

HO

O

OTBS

O NH

H+

BF3.Et2O H3C

O

BnO BnO

OTBS O

H3C

O

BnO AllO OAc

DISCONNECTION :

carbohydrate

O

carbohydrate

carbohydrate

OH

NOTES :

Electron-deficient nitriles such as trichloroacetonitrile are known to undergo direct and irreversible, base-catalysed addition of alcohols to give O-alkyl trichloroacetimidates. The pioneering work on this reaction was carried out by Nef. But it was Schmidt who demonstrated that this mild, base-catalysed formation of O-alkyl trichloroacetimidates can be extended to the preparation of O-glycosyl trichloroacetimidates. See also Fischer glycosidation, Kahne glycosidation, Koenigs – Knorr glycosidation and Michael glycosidation reactions.

REFERENCES :

1) G. Grundler; R.R. Schmidt, Carbohydr. Res., 1985, 135, 203. 2) R.R. Schmidt, Angew. Chem., Int. Ed. Engl., 1986, 25, 212. 3) K.C. Nicolaou; E.P. Schreiner; W. Stahl, Angew. Chem., Int. Ed. Engl., 1991, 30, 585. 4) K. Toshima; K. Tatsuta, Chem. Rev., 1993, 93, 1503. 5) S.A. Hitchcock; S.H. Boyer; M.Y. Chu–Meyer; S.H. Oslon; S.J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1994, 33, 858.

1532

6) N. Smiljanic; S. Halila; V. Moreau; F. Djedaïni–Pilard, Tetrahedron Lett., 2003, 44, 8999. 7) B. Elchert; J. Li; J. Wang; Y. Hui; R. Rai; R. Ptak; P. Ward; J.Y. Takemoto; M. Bensaci; C.-W.T. Chang, J. Org. Chem., 2004, 69, 1513.

COMMENTS :

SCHMIDT MACROLACTONISATION EXAMPLE :

O OH

HO

Ph

O

O N N N N

S N toluene

MECHANISM :

CH3 CH3

CN

CN

CN 2 H3C

N H

S

I2, NaOH

N H

H3C

S

S H

CH3 RCOOH, PPh3

N CH3

CH3 CN O H3C

N H

S

O R

R1OH

R

1533

OR1

Ph S

Ph

N N N N H

N

N N

S

N C

Ph N

N

N

S

N N N

N

Ph

N H

N

N N N

S

N

O

O

Ph

N

S

R

RCOOH

N

N

N O

H O

R

Ph N

Ph

N N N

S

R S O O

O

N N

R

N N H

R1OH

R

OR1

DISCONNECTION :

O R

R1OH + RCOOH

OR1

NOTES :

The ester, lactone and peptide formation with 1,2-dihydro-4,6-dimethyl-2-thioxo-3-pyridinecarbonitrile or 1-phenyl-2tetrazoline-5-thione. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai

rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES :

1) U. Schmidt; D. Heermann, Angew. Chem., Int. Ed. Engl., 1979, 18, 308. 2) U. Schmidt; M. Dietsche, Angew. Chem., Int. Ed. Engl., 1981, 20, 771. 3) U. Schmidt; J. Werner, J. Chem. Soc., Chem. Commun., 1986, 996.

1534

COMMENTS :

SCHMIDT REARRANGEMENT EXAMPLE :

O

O CN H

NH2

+

HN3

MECHANISM :

O

O R

H+, - H2O

OH

O +

R

HN3

R

N N N H

- N2

H N C O

R

RNH2

H2O - CO2

R

R1

R

R1

+

H

O

H N N N R R1 OH

HN3

OH

R1 N N N R

R1

N R

H2O

+

-H

N

H N

R1

R

OH

O

1535

N OH2

R1 R1

- H2O

R

R

DISCONNECTION :

RNH2

O R

RCN

R

H N

H

OH

RCHO

O H N

R

O R1

R

O

R1

NOTES :

Hydrazoic acid in the presence of a strong mineral acid reacts with carbonyl compounds. It converts acids into amines, aldehydes into nitrile and ketones into amides. With a large excess of hydrazoic acid, aldehydes and ketones yield substituted tetrazoles. See also Curtius rearrangement, Hofmann rearrangement, Lossen rearrangement, and Tiemann rearrangement.

REFERENCES : March : 1093 Smith – March : 1380, 1413 Houben – Weyl : 11/1, 872; E5, 572; E6b, 141, 913; E7b, 161, 178, 183; E8a, 243, 283, 1136 Org. React. : 3, 307

1) R.F. Schmidt, Angew. Chem., 1923, 36, 511. 2) R.F. Schmidt, Ber. Dtsch. Chem. Ges., 1924, 57, 704. 3) F.R. Benson, Chem. Rev., 1947, 41, 1. 4) D.E. Applequist; J.D. Roberts, Chem. Rev., 1954, 54, 1065. 5) G. Fodor; S. Nagubandi, Tetrahedron, 1980, 36, 1279. 6) A. Hassner; R. Fibiger; A.S. Amarsekara, J. Org. Chem., 1988, 53, 22. 7) N. Gálvez; M. Moreno–Maňas; R.M. Sebastián; A. Vallribera, Tetrahedron, 1996, 52, 1609. 8) C.E. Katz; J. Aubé, J. Am. Chem. Soc., 2003, 125, 13948. 9) D.J. Gorin; N.R. Davis; F.D. Toste, J. Am. Chem. Soc., 2005, 127, 11260.

COMMENTS :

1536

SCHMITZ DIAZIRIDINE SYNTHESIS EXAMPLE :

C5H11 C5H11CHO

1) NH2Cl, NH3 2) C5H11CHO, NH3

N N

C5H11

N H C5H11

MECHANISM :

C5H11 C5H11

N N

N H C5H11

2 C5H11CHO, NH3

H C5H11CHO + NH2Cl + NH3

C5H11

N N H

Ag2O

C5H11

N N

DISCONNECTION :

R

R

R1

R1 O

NOTES :

The diaziridine synthesis from chloramines, ammonia and excess aldehyde. In the presence of excess aldehyde formation of bicyclic triazolidines takes place. See also Graham reaction.

1537

REFERENCES : Org. Synth. : 45, 83 Org. Synth. Coll. Vol. : 5, 897

1) E. Schmitz, Angew. Chem., 1959, 71, 127. 2) E. Schmitz, Angew. Chem., Int. Ed. Engl., 1964, 3, 333. 3) A.T. Nielsen; D.W. Moore; R.L. Atkins; D. Mallory; J. DiPol; J.M. LaBerge, J. Org. Chem., 1976, 41, 3221. 4) M.T.H. Liu, Chem. Soc. Rev., 1982, 11, 127. 5) A.N. Mikhailyuk; V.Yu. Petukhova; N.N. Makhova, Mendeleev Commun., 1997, 47. 6) W. Knoll; M.M. Bobek; G. Giester; U.H. Brinker, Tetrahedron Lett., 2001, 42, 9161.

COMMENTS :

SCHOLL REACTION EXAMPLE :

AlCl3, H+ 100 oC

MECHANISM :

- H+

H

H

1538

DISCONNECTION :

Ar-Ar

2 ArH

NOTES :

The preparation of condensed polynuclear aromatics by a Lewis acid catalyst and a protic acid. The reaction requires high temperatures and strong acid catalysts. Both inter- and intramolecular Scholl reactions are possible. See also Eijkman, Elbs reaction and Nenitzescu acylation reactions.

REFERENCES : March : 539 Smith – March : 711 Houben – Weyl : 4/2, 101 Org. Synth. : 33, 37 Org. Synth. Coll Vol. : 4, 482

1) R. Scholl; C. Seer; R. Weitzenböck, Ber. Dtsch. Chem. Ges., 1910, 43, 2202. 2) R. Scholl; C. Seer, Liebigs Ann. Chem., 1912, 394, 111. 3) C.F.H. Allen, Chem. Rev., 1959, 59, 983. 4) F.A. Vingiello; J. Yanez; J.A. Campbell, J. Org. Chem., 1971, 36, 2053. 5) A.C. Buchanan; A.S. Dworkin; G.P. Smith, J. Am. Chem. Soc., 1980, 102, 5262. 6) P. Kovacic; M.B. Jones, Chem. Rev., 1987, 87, 357. 7) M.F. Rozas; O.E. Piro; E.E. Castellano; M.V. Mirifico; E.J. Vasini, Synthesis, 2002, 2399. 8) P. Rempala; J. Kroulík; B.T. King, J. Am. Chem. Soc., 2004, 126, 15002.

COMMENTS :

1539

SCHÖLLKOPF AMINO ACID SYNTHESIS EXAMPLE :

N H3CO

N

NH2

O

OCH3

H3CO 1) nBuLi 2) CH2Br2 3) tBuSK

CH3

OCH3

CH3

H2N

+ O

CH2StBu

MECHANISM :

H2N

i

Pr

H3CO

COOH 1) H2N COOH 2) Me3O+BF4-

i

Pr

N

H3CO

N

OCH3 1) nBuLi, THF - 78 oC 2) RX

OCH3

N N

R

R H+, MeOH

+ H2N

COMe

H2N

COMe

DISCONNECTION :

R E H2N

H3CO

R OCH3

E +

O

N N

H3C

OCH3 CH3

R = H, CH3 E = alkyl halides, aldehydes, ketones, thioketones acid chlorides, epoxides and acrylates

NOTES :

The essence of this method is the alkylation of a chiral glycine anion. The stereoselectivity is due to the complexation of Li+ to the less hindered face of the anion which then guides the approach of the halide electrophile. Major drawback of this approach is the separation of the two amino esters at the end.

REFERENCES :

1) U. Schöllkopf; U. Groth; K.O. Westphalen; C. Deng, Synthesis, 1981, 969. 2) U. Schöllkopf, Pure Appl. Chem., 1983, 55, 1799. 3) R. Gull; U. Schöllkopf, Synthesis, 1985, 1052. 4) W. Hartwig; J. Mittendorf, Synthesis, 1991, 939.

1540

5) T. Gan; J.M. Cook, Tetrahedron Lett., 1997, 38, 1301. 6) P.D. Croce; C. La Rosa; E. Pizzatti, Tetrahedron: Asymmetry, 2000, 11, 2635. 7) H. Zhou; X. Liao; J.M. Cook, Org. Lett., 2004, 6, 249. 8) M. Andrei; C. Römming; K. Undheim, Tetrahedron: Asymmetry, 2004, 15, 1359.

COMMENTS :

SCHOLTZ INDOLIZINE SYNTHESIS EXAMPLE :

H O

N CH3

N

N

1) NH4OAc 2)

Cl

H

2 Cl O Cl

MECHANISM :

O N

CH3

(CH3CO)2O 200 oC

N

O CH3

N

CH3

H O

CH3

HO

O

O N CH3

CH2

O

N

CH3

CH3 H3C O

1541

hydrolysis

N

O

N

Ar Ar

CH3 N

N

2 PhCHO NH4OAc

H+ O

H

H N

Ar H

N HO

H

N - H2O

Ar

N

Ar

Ar

DISCONNECTION :

R

R N

N

R1

CH3

NOTES :

The indolizine synthesis from reaction of pyridinyl ketones with aldehydes in the presence of ammonium acetate or of 2-methyl pyridine and its derivatives with acid anhydrides. See also Chichibabin indolizine reaction.

REFERENCES : Science of Synthesis : 10, 749

1) M. Scholtz, Ber. Dtsch. Chem. Ges., 1912, 45, 734. 2) A.E. Chichibabin; E.N. Stepanow, Ber. Dtsch. Chem. Ges., 1929, 62, 1068. 3) E.T. Borrow; D.O. Holland, Chem. Rev., 1948, 42, 611. 4) V. Boekelheide; R.J. Windgassen, jr., J. Am. Chem. Soc., 1959, 81, 1456. 5) T. Uchida; K. Matsumoto, Synthesis, 1976, 209. 6) R. Sparrapan; M.A. Mendes; M. Carvalho; M.N. Eberlin, Chem. Eur. J., 2000, 6, 321.

COMMENTS :

1542

SCHÖNBERG ADDITION EXAMPLE :

Ar

O

O

+

hν benzene

Ar

O

O

H

H

Ar Ar

MECHANISM :

O O

hν

O

O

O

O

DISCONNECTION :

O

H

O

H

R1

O R1 R

+ R, R1 = H, Alk, Ar

O

R

NOTES :

The quinone addition of olefinic double bonds to dioxanes. Aromatic ethylenes react particularly well, while aliphatic ones lead to side reactions. The mechanism is most probably radical in nature.

REFERENCES :

1) A. Schönberg; A. Mustafa, Nature, 1944, 153, 195. 2) A. Schönberg; W.I. Awad; G.A. Mousa, J. Am. Chem. Soc., 1955, 77, 3850.

COMMENTS :

1543

SCHORIGIN – WANKLYN REACTION EXAMPLE :

2

OEt

Br +

1) Na, C6H6 2) H2O

O

OH

MECHANISM :

Br R1

Br R1

R

R

Cl

R

O

O

R1

R1

R1

R1 ONa

H2O

R1

R OH

DISCONNECTION :

R1 R

R

R1 OH

X

+ 2 R1X

O

NOTES :

This reaction is the organo sodium addition to carbonyl moieties in aldehydes, ketones, carboxylic acid esters and carbon dioxide. See also Grignard and Frankland – Duppa reactions.

REFERENCES :

1) J.A. Wanklyn, Liebigs Ann. Chem., 1858, 107, 125. 2) P. Schorigin, Ber. Dtsch. Chem. Ges., 1907, 40, 3111. 3) E.H. Rood; F.W. Linch, J. Chem. Soc., 1927, 2179. 4) A. Gissot; J.-M. Becht; J.R. Desmours; V. Pévère; A. Wagner; C. Mioskowski, Angew. Chem. Int. Ed., 2002, 41, 340.

1544

COMMENTS :

SCHOTTEN – BAUMANN REACTION EXAMPLE :

Cl H3C OH

+

Ph

Ph NaOH DCM

O

O

Cl H3C NH2

+

OCH3 CH3 N H

Ph

Ph NaOH DCM

O

O

MECHANISM :

O

O R

R

X O

R H

R1NH2 X

O R X H2N R1

- H+

O

- HX

X N R1

R

N H

R1

DISCONNECTION :

Cl R OH

R1 COOR

+

R1 O

R N

R1

Cl H

R NH2

O

+

R1 O

1545

NOTES :

The acylation of alcohols, phenols and amino groups with acid chlorides in the presence of dilute alkali. An excess of alkali and acid chloride is necessary. See also Chattaway acylation, Einhorn acylation, Galat – Elion, Hinsberg reaction, Lumière – Barbier, Schotten – Baumann and Weinreb acetylation reactions.

REFERENCES : March : 392 Smith – March : 482, 506 Houben – Weyl : 8, 545; E6b, 434; E8b, 895

1) C. Schotten, Ber. Dtsch. Chem. Ges., 1884, 17, 2544. 2) E. Baumann, Ber. Dtsch. Chem. Ges., 1886, 19, 3218. 3) N.O.V. Sonntag, Chem. Rev., 1953, 52, 237. 4) J. Altman; D. Ben–Ishai, J. Heterocycl. Chem., 1969, 6, 235. 5) A. Kunugi; K. Tabei, J. Chromatogr., 1987, 398, 320. 6) C.M.R. Low; H.B. Broughton; S.B. Kalindjian; I.M. McDonald, Bioorg. Med. Chem. Lett., 1992, 2, 325. 7) B.S. Jursic; D. Neumann, Synth. Commun., 2001, 31, 555.

COMMENTS :

SCHWANERT SYNTHESIS EXAMPLE : O

OH

OH O

O NH4

heat OH

OH

O

NH4

1546

N H

MECHANISM :

NH4OOC(CHOH)4COONH4

H4NOOC

COONH4 OH

H4NOOC

OH

COONH4

NH3

H4NOOC

NH OH

COONH4 NH O H+

H4NOOC

COONH4 N H

N H

OH

DISCONNECTION :

OH O

HO

OH HO O HO N H

HO

OH

OH O OH

HO O HO

OH

NOTES :

This reaction involves the synthesis of pyrroles by heating ammonium mucate or mucic acid and primary amines. Saccharic acid gives the same product as mucic acid. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Trofimov and Zav’yalov reactions.

REFERENCES : Org. Synth. : 9, 78 Org. Synth. Coll. Vol. : 1, 473

1) H. Schwanert, Liebigs Ann. Chem., 1860, 114, 63. 2) H. Schwanert, Liebigs Ann. Chem., 1860, 116, 257.

1547

COMMENTS :

SCHWARTZ HYDROZIRCONATION EXAMPLE :

H3C

OH OCH3 OTIPS

Et 1) Cp2Zr(H)Cl, benzene 2) O

OCH3 CH3 CH3

OTIPS

N Br O 3) 2 tBuLi 4) MgBr2 5) O Et

H CH3

MECHANISM :

Cp

Cl Zr

Cp

+

THF

H

O O

1548

Cp2

Cl Zr

H (CH2)5CH3

DISCONNECTION :

Ar

X

R1 R1

X X

R

Zr(Cl)Cp2

R1 X

NOTES :

The hydrozirconation with Cp2Zr(Cl)H and Michael addition of the Zr reagent. Other reactions involve transmetallation, complexation, oxidative coupling, carbozirconation and oxidative addition. The highly ionic zirconium-hydrogen bond has an hydridic character. The mechanistic details are poorly understood.

REFERENCES : Org. Synth. : 62, 31; 71, 77, 83; 74, 205 Org. Synth. Coll. Vol. : 7, 245; 9, 143, 162, 640 Science of Synthesis : 2, 681

1) P.C. Wailes; H. Weigold, J. Organomet. Chem., 1970, 24, 405. 2) D.W. Hart; J. Schwartz, J. Am. Chem. Soc., 1974, 96, 8115. 3) D.E. van Horn; E-i. Negishi, J. Am. Chem. Soc., 1978, 100, 2252. 4) J. Schwartz; M.J. Loots; H. Kosugi, J. Am. Chem. Soc., 1980, 102, 1333. 5) E-i. Negishi; T. Takahashi, Aldrichimica Acta, 1985, 18, 31. 6) J.S. Panek; T. Hu, J. Org. Chem., 1997, 62, 4912. 7) J.A. Pool; C.A. Bradley; P.J. Chirik, Organometallics, 2002, 21, 1271.

COMMENTS :

1549

SCHWECHTEN REACTION EXAMPLE :

2

Ph N N

Br

2 Ph Br

MECHANISM :

2-

2

Ar

N N

Br

Ar

+ HgBr2

N N 2

HgBr4

2 Ar

Br

- N2, - HgBr2

DISCONNECTION :

2 Ar

Br

2

Ar

N N

Br

NOTES :

The diazonium exchange against chlorine or bromine by thermic exchange with mercury halogens. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann

sulfinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium and Witt diazotation reactions.

REFERENCES : Houben – Weyl : 5/4, 447

1) H.W. Schwechten, Ber. Dtsch. Chem. Ges., 1932, 65, 1605. 2) S.W. Fenton; A.E. de Wald; R.T. Arnold, J. Am. Chem. Soc., 1955, 77, 979. 3) J.A. LaBudde; C. Heidelberger, J. Am. Chem. Soc., 1958, 80, 1225.

COMMENTS :

1550

SCHWEIZER ALLYL AMINE SYNTHESIS EXAMPLE :

O Ph

N H

PhCHO +

NH2

1) NaH O

2) Br Bu3P 3) NH2NH2

MECHANISM :

OH

Br

Br Bu3P

Bu3P heat

O N H

O

O

N

N

NaH O

O

Ph

Bu Bu P Bu O Ph

H

O

O Bu P Bu Bu

O

Ph

N

NH2

NH2NH2 Ph

O

DISCONNECTION :

R

NH2

RCHO

NOTES :

The synthesis of E-allyl amines from vinylphosphonium salts and aldehydes (via a Wittig reaction). See also Gabriel synthesis and Wittig reactions.

REFERENCES :

1) M.M. Rauhut; G.B. Borswitz; H. Currier Gillham, J. Org. Chem., 1963, 28, 2565. 2) E.E. Schweizer; L.D. Smucker; R.J. Votral, J. Org. Chem., 1966, 31, 467. 3) D.J. Hart; P.A. Cain; D.A. Evans, J. Am. Chem. Soc., 1978, 100, 1548.

1551

4) A.I. Meyers; J.P. Lawson; D.R. Carver, J. Org. Chem., 1981, 46, 3119.

COMMENTS :

SCHWEIZER REARRANGEMENT EXAMPLE :

CH3O Ph Ph

CO2CH3 N

N Ph

N N

1) HC C

NH2

O

KOH MeI NaOMe

PPh3

H3C

CH3

2) N C O Ph

MECHANISM :

Ph

Ph

CO2CH3 N

NH2

HC C PPh3 KOH MeI NaOMe

CO2CH3 O N C N N H3C PPh3 Ar CH3

H3CO Ph N N H3C

DISCONNECTION :

Y N

X Y

X Z

N

N

1552

N

Z

O N Ar CH3

NOTES :

The thermal reaction of allenyl azines, derived from propargylphosphonium salts with ketenes, isocyanates, CS2 or phthalic anhydride to form bi- and tricyclic fused pyrazolo heterocycles.

REFERENCES :

1) E.E. Schweizer; S. Evans, J. Org. Chem., 1978, 43, 4328. 2) E.E. Schweizer; K.-J. Lee, J. Org. Chem., 1984, 49, 1959. 3) E.E. Schweizer; J.E. Hayes; A.L. Rheingold; X. Wei, J. Org. Chem., 1987, 52, 1810. 4) E.E. Schweizer; C. Zhisong; A.L. Rheingold; M. Bruch, J. Org. Chem., 1990, 55, 6363. 5) G.-Y. Lee; Y.-S. Lee; S.M. Koo; K.-J. Lee, Bull. Korean Chem. Soc., 1999, 20, 1359.

COMMENTS :

SCRETTAS – YUS METHOD EXAMPLE :

O Li

OH H3C

Cl 1) nBuLi 2) > 2 Li few mol % t

H3C

Li

t

Bu

Bu

MECHANISM :

R X + C10H8-

R + X + C10H8

R + C10H8-

RC10H8-

R + C10H8-

R + C10H8

1553

DISCONNECTION :

R Li

R X

NOTES :

Organolithium reagents (RLi) are formed in the reaction of lithium dihydronaphthylide (LiC10H8) with alkyl halides. See also Cohen – Daniewski process.

REFERENCES :

1) C.G. Screttas, J. Chem. Soc., Chem. Commun., 1972, 752. 2) J.C. Carnahan; W.D. Closson; J.R. Gauson; D.A. Juckett; K.S. Quaal, J. Am. Chem. Soc., 1976, 98, 2526. 3) C.G. Screttas; M. Micha–Screttas; B.R. Steele, J. Organomet. Chem., 1997, 536-537, 149. 4) D.J. Ramon; M. Yus, Eur. J. Org. Chem., 2000, 225. 5) M. Yus; R.P. Herrera; A. Guijarro, Chem. Eur. J., 2002, 8, 2574.

COMMENTS :

SEEBACH – FRÁTER ALKYLATION EXAMPLE :

OH

HO O

O

H3C

OEt CH3

1) 2 LDA 2)

H3C

OEt CH3

Br

MECHANISM :

Li OH H3C

O

O OEt

2 LDA

O

H3C

Li OEt

R X

1554

OH H3C

O OEt

R

DISCONNECTION :

RS

RL *

O *

RS

OR

RL *

O OR

E

NOTES :

The diastereoselective alkylation of β-hydroxycarbonyl compounds. See also Seebach self-regeneration.

REFERENCES :

1) G. Fráter, Helv. Chim. Acta, 1979, 62, 2825. 2) G. Fráter, Helv. Chim. Acta, 1979, 62, 2829. 3) G. Fráter, Helv. Chim. Acta, 1980, 63, 1383. 4) D. Seebach; D. Wasmuth, Angew. Chem., Int. Ed. Engl., 1981, 20, 971. 5) G. Fráter; U. Müller; W. Günther, Tetrahedron Lett., 1981, 22, 4221. 6) W.R. Roush; T.D. Bannister; M.D. Wendt; J.A. Jablonowski; K.A. Scheidt, J. Org. Chem., 2002, 67, 4275.

COMMENTS :

SEEBACH SELF-REGENERATION EXAMPLE : O

O H

CH3

O H

O 1) LDA, THF, - 78 oC 2) EtI

1555

H

O

O CH3

MECHANISM :

R2

O

HO

O H

R2

O

H

O

+ HO

R1

O

H

O

H+

H

O R1

LDA, THF, - 78 oC

H

OLi R1

R2

RX

R2

O

H

O

O R1 R

OH LiAlH4

HO

R1 R

DISCONNECTION :

LiO

R

O

X X = NR2, O, S

COOH HX H R

R1

NOTES :

Dioxolanes and oxazolinones derived from pivalaldehyde and lactic acid, mandelic acid, and proline give chiral enolates after deprotonation with LDA. These enolates react in highly diastereoselective fashion with alkyl halides, aldehydes and ketones. The R2 and R1 group adopt a 1,3-syn relationship on the 5-membered ring. See also Seebach – Fráter alkylation.

REFERENCES :

1) D. Seebach; R. Naef, Helv. Chim. Acta, 1981, 64, 2704. 2) D. Seebach; R. Naef; G. Calderari, Tetrahedron, 1984, 40, 1313. 3) D. Seebach; A.R. Sting; M. Hoffmann, Angew. Chem., Int. Ed. Engl., 1996, 35, 2708.

COMMENTS :

1556

SEMMLER – WOLFF – SCHROETER REACTION EXAMPLE :

O OH N

CH3

N H

H3C

O

N

H

1) Ac2O, AcOH, 2) HCl, reflux

CH3

N H

O

MECHANISM :

H3C N

OH

N

H

O

H3C

O

H

H

H

N

H

N

- H+

- AcOH H

O

H+

Ac2O, AcOH H

N

O

H+

NH2

N

DISCONNECTION :

O

NH2 R

R

NOTES :

The aromatisation of an α,β-unsaturated cyclohexanone oximes to anilines. See also Beckmann reaction.

1557

REFERENCES : Houben – Weyl : E5, 1041; E7a, 779; E8a, 283; E16d, 1095 Org. React. : 11, 30

1) F.W. Semmler, Ber. Dtsch. Chem. Ges., 1892, 25, 3352. 2) L. Wolff, Liebigs Ann. Chem., 1902, 322, 351. 3) A. Hardy; E.R. Ward; L.A. Day, J. Chem. Soc., 1956, 1979. 4) M.I. El–Sheikh; J.M. Cook, J. Org. Chem., 1980, 45, 2585. 5) Y. Tamura; Y. Yoshimoto; K. Sakai; J. Haruta; Y. Kita, Synthesis, 1980, 483. 6) Y.L. Janin; E. Bisagni, Synthesis, 1993, 57. 7) J.J. Weidner; P.M. Weintraub; R.A. Schnettler; N.P. Peet, Tetrahedron, 1997, 53, 6303.

COMMENTS :

SENDERENS DIETHYL ETHER SYNTHESIS EXAMPLE :

2 EtOH

Al2O3

Et2O

NOTES :

This dehydration is effected by passing ethanol vapour over alumina at about 250 oC. There are over 50 reagents known for this dehydration. See also Ipatiew – Senderens olefin synthesis.

REFERENCES :

1) J.-B. Senderens, Bull. Soc. Chim. Fr., 1909, 5, 480. 2) R.N. Pease; C.C. Yung, J. Am. Chem. Soc., 1924, 46, 390. 3) R.H. Clark; W.E. Graham; A.G. Winter, J. Am. Chem. Soc., 1925, 47, 2748. 4) A.M. Alvarado, J. Am. Chem. Soc., 1928, 50, 790.

COMMENTS :

1558

SENDERENS KETONE SYNTHESIS EXAMPLE :

COOH

O + CH3COOH

ThO2 430 oC

CH3

MECHANISM :

R

RCOOH + R1COOH

R1

+ CO2 + H2O

O

DISCONNECTION :

R

R1

R

OH

R1

OH

+ O

O

O

NOTES :

Ketones are obtained by passing the vapours of fatty acids over catalysts, e.g. heated alumina, thorium oxide. See also Ružička reaction.

REFERENCES : Org. Synth. : 18, 54 Org. Synth. Coll. Vol. : 2, 389

1) J.-B. Senderens, C.R. Séances Acad. Sci., 1912, 154, 1518. 2) J.-B. Senderens, Ann. Chim. Phys., 1913, 28, 243.

COMMENTS :

1559

SERINI REACTION EXAMPLE :

AcO H

H3C

CH3 OH

O H

Zn Heat AcO

AcO

MECHANISM :

Zn R3

O

Zn R3

H+

HO O R R2 R1 H

O H

HO O R R2 R1 H

Zn R3

O

R

O

R1

R2

+

H O O R R2 R1 H

R3COOH

DISCONNECTION :

R3 R

O

HO O R

R1

R2

O R2

R1 H

NOTES :

The glycol desoxyketone configuration changes in a zinc promoted acetic acid elimination. The reaction is also applicable to other cyclic as well as open-chain alcohols. See also Sarett reaction.

1560

REFERENCES : Houben – Weyl : E3, 495

1) K.H. Slotta; K. Neisser, Ber. Dtsch. Chem. Ges., 1938, 71, 2342. 2) A. Serini; W. Logemann; W. Hildebrand, Ber. Dtsch. Chem. Ges., 1939, 72, 391. 3) C.W. Shoppe, Chimia, 1948, 4, 418. 4) T. Goto; K. Kishi, J. Chem. Soc., Jpn., 1962, 83, 1236. 5) E. Ghera, J. Org. Chem., 1970, 35, 660.

COMMENTS :

SEYFERTH – GILBERT HOMOLOGATION EXAMPLE :

O

H

TIPSO

N CH3 O

H O

H OTHP

O H3CO P CH3O t

BuOH

1561

H

TIPSO

N CH3 O

N2

O

OTHP

MECHANISM :

R

R

+

O

O H3CO P CH3O

H

t

O P R2C

O P R2C

BuOK

N2

N2

N2

- O P O P C C R

O P C C R

R

O P R2C C

R

R2C N2 -

O P - N2 R2C C

R

R

DISCONNECTION :

R

R

R1

R1 O

NOTES :

The synthesis of alkynes from aldehydes. The resulting alkynes can be easily turned into diazoethenes. The reaction is also known under the name Seyferth – Hilbert reaction. Milder reaction conditions have been reported in the Ohira – Bestmann procedure. See also Corey – Fuchs and Kowalski reactions.

REFERENCES : Org. Synth. : 65, 119; 74, 108 Org. Synth. Coll. Vol. : 8, 451; 9, 230

1) D. Seyferth; R.S. Marmor; P. Hilbert, J. Org. Chem., 1971, 36, 1379. 2) J.C. Gilbert; U. Weerasooriya, J. Org. Chem., 1982, 47, 1837. 3) J.B. Lambert; R.J. Bosch; E.G. Larson, J. Org. Chem., 1985, 50, 3054. 4) S. Ohira, Synth. Commun., 1989, 19, 561. 5) D.G. Brown; E.J. Velthuisen; J.R. Commerford; R.G. Brisbois; T.R. Hoye, J. Org. Chem., 1996, 61, 2540. 6) J.D. Ha; D. Lee; J.K. Cha, J. Org. Chem., 1997, 62, 4550. 7) P.A. Wender; S.G. Hedge; R.D. Hubbard; L. Zhang, J. Am. Chem. Soc., 2002, 124, 4956.

1562

COMMENTS :

SHAPIRO REACTION EXAMPLE :

H3C

CH3 Ts

H3C

N N H

1) 2 CH3Li 2) H2O

H3C

CH3

H3C

H

MECHANISM :

SO2Ar N N H

N RLi, Et2O

R2 R1

N

SO2Ar N N RLi, Et2O

R2 R1

SO2Ar N

R2 R1

N

E R2

R2

E+

R1

R1

R1

R2

DISCONNECTION : E

O

R

R R1

R1

NOTES :

The formation of unrearranged alkenes, generally the less substituted isomers, by treatment of ketone derived ptoluenesulfonylhydrazones with alkyl lithium reagents. For silicon directing effect see the review by Adlington and Barrett. When sodium in ethylene glycol is used the reaction will give the more substituted alkene and is called the Bamford – Stevens reaction. See also Bamford – Stevens reaction.

1563

REFERENCES : March : 1019 Smith – March : 1334 Smith : 1455 Smith 2nd : 1201 Houben – Weyl : E14b, 606 Org. React. : 23, 3; 39, 1 Org. Synth. : 51, 66; 61, 141; 74, 101, 217 Org. Synth. Coll. Vol. : 6, 172; 7, 77; 9, 147, 281

1) R.H. Shapiro; M.J. Heath, J. Am. Chem. Soc., 1967, 89, 5734. 2) R.H. Shapiro; M.F. Lipton; K.J. Kolonko; R.L. Buswell; L.A. Capuano, Tetrahedron Lett., 1975, 16, 1811. 3) A.R. Chamberlain; J.E. Stemke; F.T. Bond, J. Org. Chem., 1978, 43, 147. 4) R.M. Adlington; A.G.M. Barrett, Acc. Chem. Res., 1983, 16, 55. 5) K. Maruka; H. Yamamoto, Comp. Org. Syn., 1991, 6, 776. 6) T.K. Sarkar; B.K. Ghorai, Chem. Commun., 1992, 1184. 7) U. Siemeling; B. Neumann; H.-G. Stamler, J. Org. Chem., 1997, 62, 3407. 8) O.P. Tormakangas; R.J. Toivola; E.K. Karvinen; A.M.P. Koskinen, Tetrahedron, 2002, 58, 2175. 9) C. Arisandy; A.R. Cowley; S. Barlow, J. Organomet. Chem., 2004, 689, 775.

COMMENTS :

SHARPLESS ASYMMETRIC AMINOHYDROXYLATION (OXYAMINATION) EXAMPLE :

Ts (DHQD)2PHAL

N

O

Ph

OCH3 OH

O Ph

H

OCH3

K2OsO2(OH)4 TsNClNa·3 H2O

Ts (DHQ)2PHAL

N

H

O

Ph

OCH3 OH

1564

MECHANISM :

R

R

HO

N H

H2O

X

X R N O Os N O X R

O O Os O N

OsO4 + ClN-DX

X

L R

O O Os O O

L N X

L R

R

O Os

H2O

N

R

R O

X X N R N R Os O N R X L

R

R

R

HO

O Os L N X

N X H

R

DISCONNECTION :

H

N

X

OH R2

R1

+

OH H R1

N

R2

R1 H

X

N

X R1

OH R2

OH

+

R2

R2

R1 H

N

X

X = Ts, Ms, Cbz, Boc, TeoC, Ac

NOTES :

The catalytic and asymmetric conversion of alkenes into enantiomerically enriched N-protected amino alcohols. This reaction works particularly well on cinnamate substrates. See also Bäckvall and Sharpless dihydroxylation reactions.

1565

REFERENCES : Smith 2nd : 258 Org. Synth. : 61, 85, 93 Org. Synth. Coll. Vol. : 7, 223, 375

1) G. Li; H.-T. Chang; K.B. Sharpless, Angew. Chem., Int. Ed. Engl., 1996, 35, 451. 2) O. Reiser, Angew. Chem., Int. Ed. Engl., 1996, 35, 1308. 3) P. O’Brien, Angew. Chem., Int. Ed., 1999, 38, 326. 4) N.S. Barta; D.R. Sidler; K.B. Somerville; S.A. Weissman; R.D. Larsen; P.J. Reider, Org. Lett., 2000, 2, 2821. 5) M.A. Andersson; R. Epple; V.V. Fokin; K.B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 472. 6) D. Nilov; O. Reiser, Adv. Synth. Catal., 2002, 344, 1169. 7) J.A. Bodkin; M.D. McLeod, J. Chem. Soc., Perkin Trans. 1, 2002, 2733. 8) D.E.J.E. Robinson; S.D. Bull, Tetrahedron: Asymmetry, 2003, 14, 1407.

COMMENTS :

SHARPLESS DIHYDROXYLATION EXAMPLE : CH3 N Bn

Ph O

OH K2OsO4 (DHQD)2PHAL K3Fe(CN)6 CH3SO2NH2 t BuOH, H2O

1566

CH3 N Bn

Ph OH

O

MECHANISM :

AD-mix β

(DHQD)2-PHAL

Rs

Rm

Rl

H

OH Rm H

HO Rs Rl

K2OsO2(OH)4 K2CO3, K3Fe(CN)6 Rs

AD-mix α

O O O Os O L

R1 R

R

O O O Os O L

R1 O Os O O

Rl HO

(DHQ)2-PHAL

R1

Rm H OH

O

R

L L

2 HO2 H2O

R1

Os O

HO

OH

O 2 HO-

organic aqueous O HO OH Os HO OH O

O

O

R

2-

O O HO Os HO O O

2 Fe(CN)642 H2O

2 Fe(CN)632 HO-

1567

2-

DISCONNECTION :

R1 HO

R

R1

OH

R

NOTES :

The enantioselective syn dihydroxylation of olefins using AD-mix-β formed from phthalazinedihydroquinidine or ADmix-α formed from phthalazine-dihydroquinine and OsO4. The key success of this reaction is due to: 1) ligand accelerated catalysis by cinchona alkaloids, 2) potassium ferricyanide as co-oxidant which suppressed nonenantioselective secondary cycle, 3) MeSO2NH2 effect accelerated the hydrolysis of osmium glycolate complex and allowed to perform the reaction at 0 oC boosting enantioselectivity, furthermore it also allows dihydroxylation of tetrasubstituted olefins. The basic conditions favour hydrolysis of the osmium glycolate. The tert–butanol water system provides a biphasic system that prevents oxidation from Os(VI) to Os(VIII). An improved version has been published by Beller et al. The active species is LOsO4. Sharpless and Corey have argued for years about the reaction being a [3+2] or [2+2] mechanism. Although Sharpless is not completely convinced, a [3+2] mechanism is now accepted. See also Criegee osmium tetroxide, Milas, Prévost and Woodward cis-hydroxylation reactions.

REFERENCES : Smith – March : 1050 Smith : 286 Smith 2nd : 250, 345 Org. Synth. : 70, 47; 79, 93 Org. Synth. Coll. Vol. : 9, 383; 10, 603 Science of Synthesis : 1, 1008

1) O. Makowka, Ber. Dtsch. Chem. Ges., 1908, 41, 943. 2) E.N. Jacobsen; I. Markó; W.S. Mungall; G. Schroder; K.B. Sharpless, J. Am. Chem. Soc., 1988, 110, 1968. 3) K.B. Sharpless; W. Amberg; Y.L. Bennani; G.A. Crispino; J. Hartung; K.-S. Jeong; H.-L. Kwong; K. Morikawa; Z.M. Wang; D. Xu; X.-L. Zhang, J. Org. Chem., 1992, 57, 2768. 4) B. Santiago; J.A. Soderquist, J. Org. Chem., 1992, 57, 5844. 5) H.C. Kolb; M.S. van Nieuwenhze, K.B. Sharpless, Chem. Rev., 1994, 94, 2483. 6) E.J. Corey; M.C. Noe, J. Am. Chem. Soc., 1996, 118, 11038. 7) A.J. DelMonte; J. Haller; K.N. Houk; K.B. Sharpless; D.A. Singleton; T. Strassner; A.A. Thomas, J. Am. Chem. Soc., 1997, 119, 9907.

8) E.J. Corey; M.C. Noe; M.J. Grogan, Tetrahedron Lett., 1997, 37, 4899. 9) G.M. Mehltretter; C. Döbler, U. Sundermeier; M. Beller, Tetrahedron Lett., 2000, 41, 8083. 10) S.Y. Jonsson; H. Adolfsson; J.-E. Bäckvall, Org. Lett., 2001, 3, 3463. 11) M.A. Andersson; R. Epple; V.V. Fokin; K.B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 472. 12) D.V. Deubel; G. Frenking, Acc. Chem. Res., 2003, 36, 645. 13) J. Frunzke; C. Loschen; G. Frenking, J. Am. Chem. Soc., 2004, 126, 3642.

1568

14) A. Köckritz; M. Bartoszek; C. Döbler; M. Beller; W. Mägerlein; H.-C. Militzer, J. Mol. Catal. A: Chem., 2004, 218, 55. 15) T. Ishida; R. Akiyama; S. Kobayashi, Adv. Synth. Catal., 2005, 347, 1189.

COMMENTS :

SHEEHAN – FRANK SYNTHESIS EXAMPLE :

O Cl

O

O N O

H 1) (PhCH2O)2PO2Ag H2N 2) H2NCHCH3COOH 3) NH2NH2 4) HCl

N H

COOH CH3

MECHANISM :

O O Cl

O

OCH2Ph P

O

O N

OCH2Ph O

N

(PhCH2O)2PO2Ag

O

O R O HN

COOH H

O H

O H2NCHRCOOH

N

1) NH2NH2 2) HCl

O

1569

H2N

N H

COOH R

O R H2N

R COOH

N O

H

COOH PCl5

H O

O O

O

O R

N O

H2N

R1 COOH MgO

H

R1

R

N

H

O O

H3N

1) NH2NH2 2) HCl

H N

N

H

O

H

H R

Cl

COOH R1

H

O

O

H O

DISCONNECTION :

H2N

R

H O

H N H

COOH

R1

R

R1 H2N

COOH

+

H2N

H

COOH H

NOTES :

1. Phthalylglycyl chloride reacts with silver dibenzylphosphate to yield phthalylglycyldibenzylphosphate. This treated with an amino acid to form a phthalyl peptide which on treatment with hydrazine and subsequently with hydrochloric acid yields a peptide. 2. An amino acid is converted into the phthalimido acid chloride which is condensed with another amino acid molecule in the presence of magnesium oxide. These phthalimido peptides are then converted into the peptide by treatment with hydrazine, followed by hydrochloric acid. See also Bergmann – Zevars carbobenzoxy method, Fischer peptide, Gabriel and Ing – Manske reactions.

REFERENCES :

1) J.C. Sheehan; V.S. Frank, J. Am. Chem. Soc., 1949, 71, 1856. 2) H.N. Rydon, Ann. Reports, 1950, 47, 153. 3) J.C. Sheehan; V.S. Frank, J. Am. Chem. Soc., 1950, 72, 1312. 4) F.E. King; J.W. Clark–Lewis; R. Wade; W.A. Schwindin, J. Chem. Soc., 1957, 873.

1570

COMMENTS :

SHERADSKY REARRANGEMENT EXAMPLE :

+ N

1) tBuOK 2) PPA

HON

F

O

N

MECHANISM :

+ N

F

t

HON

BuOK N

N

O

N H

O

N

O

N

N H

H

PPA - H2O

O

1571

N

O

O

NH

DISCONNECTION :

H R O Y X

RCH2

R N R1

Y X

R N O

NOTES :

The rearrangement of O-arylated oximes via a hetero-Cope rearrangement using 2-fluoropyridine. Hydroxylamines can undergo a similar acid-catalysed rearrangement (e.g. α-acetoxyketones derived from ketoxime derivatives). See also Cope rearrangement.

REFERENCES :

1) T. Sheradsky, Tetrahedron Lett., 1966, 7, 5225. 2) H.O. House; F.A. Richey, jr., J. Org. Chem., 1969, 34, 1430. 3) T. Sheradsky, Tetrahedron Lett., 1970, 11, 25. 4) T. Sheradsky; G. Salemnick, J. Org. Chem., 1971, 36, 1061. 5) Y. Endo; K. Shudo; T. Okamoto, Synthesis, 1983, 471. 6) J.-Y. Laronze; R. El Boukili; D. Cartier; J. Laronze; J. Lévy, Tetrahedron Lett., 1989, 30, 2229. 7) J.-Y. Laronze; R. El Boukili; D. Patigny; S. Dridi; D. Cartier; J. Lévy, Tetrahedron, 1991, 47, 10003. 8) P.H. Boyle; H.D.P. Ali; T.J. McDonald, Arkivoc, 2003, 7, 67.

COMMENTS :

SHESTAKOV HYDRAZINE SYNTHESIS EXAMPLE : CH3

CH3 H3CO

H2N OCH3

COOH 1) KCNO 2) NaClO NH2NH2

1572

HN H3CO

COOH NH2

OCH3

MECHANISM :

CH3

CH3 H3CO

H2N

COOH KCNO

H3CO

H

OCH3

OCH3

N

COOH NH2 O

CH3 NaClO NH2NH2

COOH

HN H3CO

NH2 OCH3

DISCONNECTION :

H R H

H COOH

N

R

COOH NH2

NH2

NOTES :

The synthesis of α-hydrazino acids from α-amino acids via ureas using KCNO and NaOCl or KOCl.

REFERENCES :

1) P. Shestakov, Angew. Chem., 1903, 16, 1061. 2) S. Karady; M.G. Ly; S.H. Pines; M. Sletzinger, J. Org. Chem., 1971, 36, 1949. 3) H. Gustafsson, Acta Chem. Scand., 1975, B29, 93. 4) J. Viret; J. Gabard; A. Collet, Tetrahedron, 1987, 43, 891.

COMMENTS :

1573

SHEVERDINA – KOCHESHKOV AMINATION EXAMPLE :

O Ph Li

N

1) 2 CH3ONH2, CH3Li hexane, Et2O 2) H2O 3) C6H5COCl

H

MECHANISM :

RLi

1) 2 CH3ONH2, CH3Li hexane, Et2O 2) H2O

RNH2

DISCONNECTION :

RNH2

RLi R = alkyl, aryl

NOTES : Beak et al. did modify this reaction to the direct stoichiometric amination of organo lithiums in high yields by

methoxyamine and methyl lithium in a mixture of hexane and diethyl ether.

REFERENCES :

1) N.J. Sherverdina; Z. Kocheshkov, J. Gen. Chem. USSR, 1938, 8, 1825. 2) P. Beak; B.J. Kokko, J. Org. Chem., 1982, 47, 2822. 3) P. Beak; A. Basha; B.J. Kokko; D. Loo, J. Am. Chem. Soc., 1986, 108, 6016. 4) E. Erdik; M. Ay, Chem. Rev., 1989, 89, 1947. 5) J.-C. Dutoit, Synthesis, 1992, 981. 6) A. Casarini; P. Dembech; D. Lazzari; E. Marini; G. Reginato; A. Ricci; G. Seconi, J. Org. Chem., 1993, 58, 5620.

COMMENTS :

1574

SHI EPOXIDATION EXAMPLE :

CH3

CH3

O O

O O O

O O

5 Oxone, 15 NaHCO3 CH3CN, aq. EDTA, 0 oC

MECHANISM :

O Ph

O O

HSO5

Ph O

O

O

O

O

O O Ph O

O

O O

O Ph O

O O O

O O

O

O Ph O

Ph

O

O

O

O O

SO42O O

1575

O

O O SO3

O

OH O SO3

DISCONNECTION :

R R1

R2

O (R,R)

R3

at least one R = H

R

R2

R1

R3

NOTES :

The asymmetric epoxidation of alkenes bearing a wide range of functional groups using a chiral dioxirane readily prepared from Oxone and D-fructose or D-glucose. The glucose derived nitrogen analog is also effective for cis olefins and terminal olefins. See also Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew and Weitz – Scheffer

reactions.

REFERENCES : Org. Synth. : 80, 1, 9

1) Y. Tu; Z.-X. Wang; Y. Shi, J. Am. Chem. Soc., 1996, 118, 9806. 2) Z.-X. Wang; T. Yong; M. Frohn; Y. Shi, J. Org. Chem., 1997, 62, 2328. 3) M. Frohn; Y. Shi, Synthesis, 2000, 1979. 4) D.W. Hoard; E.D. Moher; M.J. Martinelli; B.H. Norman, Org. Lett., 2002, 3, 1813. 5) L. Shu; Y.-M. Shen; C. Burke; D. Goeddel; Y. Shi, J. Org. Chem., 2003, 68, 4963. 6) D.E.J.E. Robinson; S.D. Bull, Tetrahedron: Asymmetry, 2003, 14, 1407. 7) G. Bez; C.-G. Zhao, Tetrahedron Lett., 2003, 44, 7403.

COMMENTS :

1576

SHIBASAKI CYCLISATION EXAMPLE :

O

Pr Pr 1) 5 mol% Pd(Ph3P)4 CO, K2CO3, NMP, reflux 2) 3 THF.Mg2Cl2OTiNCO

Br

N H O

MECHANISM :

TiCl3

Mg, N2 THF

[TiNMg2Cl2.THF]

[3 THF.Mg2Cl2OTiNCO]

CO2

O

R R O

5 mol% Pd(Ph3P)4 CO, K2CO3, NMP, reflux

Br

[3 THF.Mg2Cl2OTiNCO]

O R

R

O

Ln Ti NCO O

N Ti O

O R

O

N H O

1577

Ln

R Ln N Ti O CO O

O

R R O

5 mol% Pd(Ph3P)4 CO, K2CO3, NMP, reflux

Br

O R

R

O

[3 THFMg2Cl2OTiNCO]

O Ti NCO Ln

R Ln Ti N

Ln

N Ti O CO O

O

O

R N H O

DISCONNECTION :

O R

NH2

R

RCN

X O

(RCO)2NH

NOTES :

The incorporation of molecular nitrogen into amides and imides using titanium-nitrogen complexes.

REFERENCES :

1) M. Mori; Y. Uozumi; M. Sibasaki, Tetrahedron Lett., 1987, 28, 6187. 2) Y. Uozumi; N. Kawasaki; E. Mori; M. Mori; M. Shibasaki, J. Am. Chem. Soc., 1989, 111, 3725. 3) Y. Uozomi; M. Mori; M. Shibasaki, Chem. Commun., 1991, 81. 4) Y. Uozomi; M. Mori; M. Shibasaki, J. Synth. Org. Chem. Jpn., 1991, 49, 937.

COMMENTS :

1578

SHILOV REACTION EXAMPLE :

CH4 + H2O

[PtCl4]2K2PtCl6

CH3OH + CH3Cl

MECHANISM :

OH2

Cl

2 Cl

Pt

CH4

II

OH2

Cl

H2O

2 H2O

Cl

H II

Pt

PtII

Cl

H

IV

Pt Cl

H3C

- HCl

CH3OH

H2O

OH2

Cl CH3

II

Pt

Cl

Cl

Cl

CH3

Cl

PtIV Cl

Cl H2O

OH2

Cl

K2PtIVCl6

IV

Pt

CH3

Cl

K2PtIICl4

Cl

DISCONNECTION :

R X

R H X = Cl, OH

1579

OH2

Cl or

Cl

Cl

Cl

OH2

Cl

Cl

Cl

CH3

NOTES :

The platinum-catalysed alkane oxidation consisting of activation of the alkane by platinum(II), two-electron oxidation to create a platinum(IV) species, followed by reductive elimination. Several mechanistic studies on each individual step has been reported in the literature.

REFERENCES :

1) N.F. Gol’dshleger; V.V. Es’kova; A.E. Shilov; A.A. Shteinmann, Zh. Fiz. Khim. (Engl. Transl.), 1972, 46, 785. 2) L.A. Kushch; V.V. Lavrushko; Y.S. Misharin; A.P. Moravsky; A.E. Shilov, New. J. Chem., 1983, 7, 729. 3) G.A. Luinstra; J.A. Labinger; J.E. Bercaw, J. Am. Chem. Soc., 1993, 115, 3004. 4) G.A. Luinstra; L. Wang; S.S. Stahl; J.A. Labinger; J.E. Bercaw, Organometallics, 1994, 13, 755. 5) A.E. Shilov; G.B. Shul’pin, Chem. Rev., 1997, 97, 2879. 6) S.S. Stahl; J.A. Labinger; J.E. Bercaw, Angew. Chem., Int. Ed., 1998, 37, 2180. 7) J.A. Johnson; D. Sames, J. Am. Chem. Soc., 2000, 122, 6321.

COMMENTS :

SIEGRIST STILBENE SYNTHESIS EXAMPLE :

Ph CH3 + O

Ph

Ph

N C KOH DMF

H

1580

O

MECHANISM :

O H NMe2 CH2 H N Ph H

O N

O

HO

N

N

H Ph

NMe2 H Ph

Ph HO

O - H+

N

N H Ph Ph

H

NMe2

H

O

Ph

O

N

+ N

NMe2

Ph

HO-

H

Me2N

H

+ H2N Ph

H

DISCONNECTION :

Ar Ph

Ph

H

ArCH3 + Ph N H

H

NOTES :

The synthesis of stilbenes by base-catalysed condensation of reactive toluenes or naphthalenes with benzalanilines.

REFERENCES :

1) A.E. Siegrist, Helv. Chim. Acta, 1967, 50, 906. 2) A.E. Siegrist; H.R. Meyer, Helv. Chim. Acta, 1969, 52, 1282. 3) M.S. Newman; B. Dhawan; S. Kumar, J. Org. Chem., 1978, 43, 524. 4) F. Kosteyn; G. Zerban; H. Meier, Chem. Ber., 1992, 125, 893. 5) H. Meier; H. Kretzschmann; H. Lang, J. Prakt. Chem., 1994, 336, 121. 6) A. Skibniewski; G. Bluet; N. Druze; O. Riant, Synthesis, 1999, 459.

COMMENTS :

1581

SIMCHEN SYNTHESIS EXAMPLE :

CH2CN COOH

Cl N

2 PCl5 Cl

MECHANISM :

N

COOH

Cl

PCl5 - POCl3, - HCl

Cl

S

S

SCN

N

HCl O

O

DISCONNECTION :

CH2CN R COOH Cl R

N Cl

R

NOH O

Cl

S R

SCN R

N

COOH O

NOTES :

The synthesis of isoquinolines and its derivatives starting from ortho-cyanomethylbenzoic acid compounds using phosphorous pentachloride, hydrogen bromide or iodide. See also Bamberger – Goldschmidt, Bischler – Napieralski, Bobbit, Bruckner, Larock indole, Pictet – Gams, Pictet – Sprengler, Pomeranz – Fritsch and Schlitter – Müller ring-closure reactions.

1582

REFERENCES :

1) G. Simchen, Angew. Chem., Int. Ed. Engl., 1966, 5, 663. 2) G. Simchen; J. Wenzelburger, Chem. Ber., 1970, 103, 413. 3) G. Simchen; G. Entenmann, Angew. Chem., Int. Ed. Engl., 1973, 12, 119.

COMMENTS :

SIMMONS – SMITH REACTION EXAMPLE :

+ CH2I2

Zn(Cu)

MECHANISM :

ICH2ZnI

CH2I2 + ZnCu IZn

I

ICH2ZnI

DISCONNECTION :

R

R R1

R1

NOTES :

Steric effects play an important role. The cyclopropanation generally takes place from the less-hindered side. A neighbouring hydroxyl group speeds up the reaction and places the cyclopropane ring syn to the hydroxyl group. A one-step mechanism has been proposed. The intermediate can be isolated. Also enantioselective Simmons – Smith reaction are known. Sometimes even low-valent samarium can be used. The Furugawa modification uses diethylzinc

1583

instead of Zn(Cu) couple. See also Charette, Freund, Gustavson, Hass cyclopropane, Ipatiew, Kishner, Mousseron – Fraisse – McCoy and Nerdel reactions.

REFERENCES : March : 870 Smith – March : 1088 Smith : 1471 Smith 2nd : 1207, 1212 Houben – Weyl : E19b, 195 Org. React. : 20, 1; 58, 1 Org. Synth. : 41, 72; 59, 113; 67, 176; 76, 86 Org. Synth. Coll. Vol. : 5, 855; 6, 327; 8, 321; 10, 2341 Science of Synthesis : 9, 305

1) H.E. Simmons; R.D. Smith, J. Am. Chem. Soc., 1958, 80, 5323 2) H.E. Simmons; R.D. Smith, J. Am. Chem. Soc., 1959, 81, 4256. 3) R.J. Rawson; I.T. Harrison, J. Org. Chem., 1970, 35, 2057. 4) L.K. Bee; J. Beeby; J.W. Everett; P.J. Garratt, J. Org. Chem., 1975, 40, 2212. 5) G.A. Molander; J.B. Etter, J. Org. Chem., 1987, 52, 3942. 6) H. Takahashi; M. Yoshioka; M. Ohno; S. Kobayashi, Tetrahedron Lett., 1992, 33, 2575. 7) A.H. Hoveyda; D.A. Evans; G.C. Fu, Chem. Rev., 1993, 93, 1307. 8) P. Bertinato; E.J. Sorensen; D. Meng; S.J. Danishefsky, J. Org. Chem., 1996, 61, 8000. 9) D. Cheng; T. Kreethadumrongdat; T. Cohen, Org. Lett., 2001, 3, 2121. 10) M. Nakamura; A. Hirai; E. Nakamura, J. Am. Chem. Soc., 2003, 125, 2341. 11) J. Long; H. Du; K. Li; Y. Shi, Tetrahedron Lett., 2005, 46, 2737.

COMMENTS :

1584

SIMONIS CHROMONE CYCLISATION EXAMPLE :

H3C

OH

O

CH3

EtO2C

CH3

H3C

+

O

CH3

P2O5

CH3 O

MECHANISM :

OH H3C

OEt O

O

H3C

O O P O P O

H3C

OEt O

OEt O

O

OH O

O O

O

P O P

O

O

P

O

P O O OH

EtO O H O O O

CH3 P O

O

CH3

O

O

EtO

O

EtO

H+

O P OH O O

H

O

O

CH3

OEt H

CH3

O

DISCONNECTION :

O R1

CH2R

OH R1

O

1585

O

O

+ RCH2

OEt

H

CH3

NOTES :

The benzopyrone synthesis from phenols and β-ketoesters using phosphorous pentoxide. Coumarins may also be formed. See also Anschütz hydroxycoumarin, Bargellini, Boyd – Robinson, Knoevenagel coumarin, Pauly – Lockemann, von Pechmann – Duisberg and Perkin coumarin reactions.

REFERENCES : Org. React. : 7, 2

1) E. Petschek; H. Simonis, Ber. Dtsch. Chem. Ges., 1913, 46, 2014. 2) S.M. Sethna; N.M. Shah, Chem. Rev., 1945, 36, 1. 3) R.N. Lacey, J. Chem. Soc., 1954, 854. 4) A. Ruwet; D. Janne; M. Renson, Bull. Soc. Chim. Belg., 1970, 79, 81. 5) S.F. Tan, Aust. J. Chem., 1972, 25, 1367. 6) U. Oyman; K. Gunayadin, Bull. Soc. Chim. Belg., 1994, 103, 763.

COMMENTS :

SKATTEBØL DIHALOCYCLOPROPANE REARRANGEMENT EXAMPLE :

1) CHBr3 50% aq. NaOH TEBA DCM 2) CH3Li

MECHANISM :

Br Br

[1,2]-rearrangement

n

BuLi

1586

DISCONNECTION :

Br

Br

NOTES :

This is the rearrangement of gem-dihalocyclopropanes to allenes or of vinyl dihalocyclopropanes to cyclopentadienes and fulvenes by alkyl lithium reagents. See also von Doering – la Flamme – Moore allene synthesis.

REFERENCES : Houben – Weyl : E19b, 403, 449, 500, 607

1) L. Skattebøl, J. Org. Chem., 1966, 31, 2789. 2) L. Skattebøl, Tetrahedron, 1967, 23, 1107. 3) P.M. Warner; R.D. Herold, J. Org. Chem., 1983, 48, 5411. 4) L.A. Paquette; M. Gugelchuk; M.L. McLaughlin, J. Org. Chem., 1987, 52, 4732. 5) B. Dorer; M.H. Prosenc; U. Rief; H.H. Brintzinger, Organometallics, 1994, 13, 3868. 6) N.B. Ivchenko; P.V. Ivchenko; I.E. Nifant’ev, Russ. J. Org. Chem., 2000, 36, 609.

COMMENTS :

SKRAUP – PRIGLINGER SYNTHESIS EXAMPLE :

O

O H3C

O O

O

O

H2SO4 O

O

1587

CH3

MECHANISM :

O

OH

O

OH O

O

O

- 2 H2O H O

O

O

O H H3C

O

O

O

O

O

O

CH3

- CO2 O

DISCONNECTION :

H3C

O

CH3 O

2 O

O

O

NOTES :

Dimethylpyrone is obtained by the action of sulfuric acid on acetic anhydride. The mechanism involves a double dehydration followed by decarboxylation to afford dimethylpyrone.

REFERENCES :

1) Z.H. Skraup; J. Priglinger, Monatsh. Chem., 1910, 31, 363. 2) J. Chem. Soc. Abs., 1910, 98i, 578. 3) E. Philippi; R. Seka, Ber. Dtsch. Chem. Ges., 1921, 54, 1089.

COMMENTS :

1588

SKRAUP QUINOLINE SYNTHESIS EXAMPLE :

OH +

HO OH

NH2

1) H2SO4 150 oC, 20 h 2) PhNO2

N

MECHANISM :

H+ H

O NH2

O

H

H HO H

H

H

N H

N H

PhNO2

N H

N

DISCONNECTION :

OH + N

NH2

R

OH

OH

NOTES :

This synthesis of quinolines involves the interaction of a primary aromatic amine with at least one position ortho to the amino group unsubstituted, glycerol, sulfuric acid or a sulfonic acid, and an oxidising agent, e.g. nitrobenzene, or the nitro compound corresponding to the amine, or arsenic pentoxide. A moderator such as ferrous sulfate, boric acid, or water may be added. See also Allan – Loudon, von Baeyer – Drewson quinoline, Camps, Combes quinoline, Conrad – Limpach, Doebner quinoline, Doebner – von Miller, Foulds – Robinson, Friedländer, Knorr quinoline, Meth–Cohn, von Niementowski quinoline, Pfitzinger – Borsche and Riehm quinoline reactions.

REFERENCES : Smith : 1338 Smith 2nd : 1100 Houben – Weyl : E7a, 362; E7b, 684; E8b, 849 Org. React. : 7, 59; 28, 37 Org. Synth. : 2, 79; 27, 48

1589

Org. Synth. Coll. Vol. : 1, 478; 3, 568

1) W. Koenigs, Ber. Dtsch. Chem. Ges., 1879, 12, 453. 2) Z.H. Skraup, Ber. Dtsch. Chem. Ges., 1880, 13, 2086. 3) R.H. Manske, Chem. Rev., 1942, 30, 113. 4) F.W. Bergstrom, Chem. Rev., 1944, 35, 77. 5) H. Rapoport; A.D. Batcho, J. Org. Chem., 1963, 28, 1753. 6) J.J. Eisch; T. Dluzniewski, J. Org. Chem., 1989, 54, 1269. 7) H. Fujiwara, Heterocycles, 1997, 45, 119. 8) S. Jiranusornkul; B. Sirithunyalug; H. Nemoto; H. Takahata, Heterocycles, 2002, 56, 487. 9) K. Panda; I. Siddiqui; P.K. Mahata; H. Ila; H. Junjappa, Synlett, 2004, 449.

COMMENTS :

van SLYKE DETERMINATION EXAMPLE :

O

H3N O

H2O, HNO2

HOCH2COOH

MECHANISM :

H3NCH2COO

HNO2 - N2

CH2COO

H2O

DISCONNECTION :

H

H HO

H2N

COOH

COOH R

R

1590

HOCH2COOH

NOTES :

Nitrous acid reacts generally quantitatively with α-amino acids to yield nitrogen and α-hydroxy-acids. The general scheme does not accurately describe the whole process. The whole process for glycine is described by Austin. See also Strecker reaction.

REFERENCES :

1) D.D. van Slyke, Ber. Dtsch. Chem. Ges., 1910, 43, 3170. 2) D.D. van Slyke, J. Biol. Chem., 1911, 9, 185. 3) A.T. Austin, J. Chem. Soc., 1950, 149.

COMMENTS :

van SLYKE OXIDATIVE DECARBOXYLATION EXAMPLE :

NH3 O

H3C

CH3CHO

O O

OH OH O

1591

MECHANISM :

O

O OH

O + H2O

OH O

O O

O H O

+

H3N

H

O

R

O

N

COO - H2O

R O

O O

O H N

NH2

H2O

R

- CO2 O

O

O

O NH2

+ RCHO

O O

+

O

O N

O

O

O

blue colour

DISCONNECTION :

H3N

O

R

O

RCHO

NOTES :

α-Amino acids can be estimated by the oxidative decarboxylation which they undergo when boiled at pH 1-5 in aqueous solution with ninhydrin (triketohydrindene hydrate). The blue colour is formed due to the reaction between the ninhydrin and ammonia.

REFERENCES :

1) S. Ruhemann, J. Chem. Soc., 1911, 99, 792. 2) S. Ruhemann, J. Chem. Soc., 1911, 99, 1306. 3) S. Ruhemann, J. Chem. Soc., 1911, 99, 1486. 4) D.D. van Slyke; R.T. Dillon; D.A. MacFadyen; P. Hamilton, J. Biol. Chem., 1941, 141, 627.

1592

COMMENTS :

SMILES REARRANGEMENT EXAMPLE : H N

O O2N

H2N

NaH, 50 oC

O

O2N

O

HO

MECHANISM : H+ O

O O

N O

H2N

O

NaH, 50 oC

H N

O N H

O N

O2N

O

HO

O

DISCONNECTION :

Z X

Z

X

Y

YH X = S, SO, SO2, O, COO YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R

NOTES :

The intramolecular rearrangement by nucleophilic aromatic substitution and aromatic migration (sometimes aliphatic) from one hetero atom to another. The conversion of o-methyldiarylsulfones to o-benzylbenzenesulfinic acids is referred to as the Truce – Smiles rearrangement. See also Chapman rearrangement, Freudenberg – Schönberg rearrangement, Hayashi rearrangement and Newman – Karnes – Kwart reactions.

REFERENCES : March : 675 Smith – March : 879

1593

Houben – Weyl : 9, 330; E6a, 484; E8d, 763; E10b2, 233; E16d, 1154 Org. React. : 18, 403

1) A.A. Levy; H.C. Rains; S. Smiles, J. Chem. Soc., 1931, 3264. 2) W.E. Truce; A.M. Murphy, Chem. Rev., 1951, 48, 69. 3) J.F. Bunnett; R.E. Zahler, Chem. Rev., 1951, 49, 273. 4) G.P. Crowther; C.R. Hauser, J. Org. Chem., 1968, 33, 2228. 5) M.S. Newmann, Acc. Chem. Res., 1972, 5, 354. 6) R. Bayles; M.C. Johnson; R.F. Maisey; R.W. Turner, Synthesis, 1977, 31. 7) Y. Fukazawa; N. Kato; S. Ito, Tetrahedron Lett., 1982, 23, 437. 8) T.N. Gerasimova; E.F. Kolchina, J. Fluorine Chem., 1994, 66, 69. 9) V.J. Huber; R.A. Bartsch, Tetrahedron, 1998, 54, 9281. 10) W.R. Erickson; M.J. McKennon, Tetrahedron Lett., 2000, 41, 4541. 11) D. Boschi; G. Sorba; M. Bertinaria; R. Fruttero; R. Calvino; A. Gasco, J. Chem. Soc., Perkin Trans. 1, 2001, 1751. 12) M.S. Wadia; D.V. Patil, Synth. Commun., 2003, 33, 2725. 13) L.H. Mitchell; N.C. Barvian, Tetrahedron Lett., 2004, 45, 5545. 14) H-P. Buchstaller; U. Anlauf, Synthesis, 2005, 639.

COMMENTS :

SMITH – MIDDLETON – ROZEN FLUORINATION EXAMPLE :

H

H Ph

Ph

COOH Et

1) SF4 2) HF

CF3 Et

MECHANISM :

RCOOH + SF4 RCOF + SF4

RCOF + HF + SOF2 HF

1594

RCF3 + SOF2

R2C N N(R1)2

R

R1 R2C N N R1 I

IF

R1 = H, CH3

R1

R

N N R1

F I

F

R

R1 R N N R1 F I I F

IF

R2CF2

R1 N H R N I F R

R2C N NHR1

R2C N N R1 I H

IF F

R

IF

F

I R1 R N N H F I

OH

CH3 O H3C CH3 H

R2CF2

H3C

HF

H3C

F H

DAST

OSF2NEt2 F H

F

F

H3C

H3C

OSF2NEt2 H

H2C

H CH3

Polar basic solvent

H3C

F

F H Polar non basic solvent

H3C CH3 H3C F

F H3C Non polar solvent

OSF2NEt2 H

H F

1595

DISCONNECTION :

O

F R

F

R

R1

O

F R

R1

F

R

F

OH

NOTES :

Carbonyls are converted to CF2 compounds by SF4 (Smith) or diethylaminosulfur trifluoride (DAST) (Middleton) or by IF on hydrazones (Rozen).

REFERENCES : Org. React. : 21, 1 Org. Synth. : 64, 221 Org. Synth. Coll. Vol. : 7, 528

1) W.C. Smith; C.W. Tullock; E.L. Muettertis; W.R. Hasek; F.S. Fawcett; V.A. Engelhardt; D.D. Coffman, J. Am. Chem. Soc., 1959, 81, 3165.

2) W. Middleton, J. Org. Chem., 1975, 40, 574. 3) S. Rozen; M. Brand; D. Zamir; D. Hebel, J. Am. Chem. Soc., 1987, 109, 896. 4) R.P. Singh; J.M. Shreeve, J. Org. Chem., 2003, 68, 6063. 5) R. Anilkumar; D.J. Burton, Tetrahedron Lett., 2003, 44, 6661.

COMMENTS :

1596

SMITH – TIETZE COUPLING EXAMPLE :

OR

S

S TBS

TBSO 1) tBuLi, THF/HMPA 2) O 2 PMBO

S

OR S TBSO

3) 1.5 TBSCl

MECHANISM :

S

S

R3Si

H

S

S

R3Si

Li

S

O

SiR3 R1 R1

Li R

S

S SiR3 [1,4]-Brook rearrangement O

R1

RO S R1

S

R3SiO S R1

S OH R1

1597

S Li

O R1

O

HMPA

DISCONNECTION :

HO S R1

S OR R1 S +

S RO S R1

O

R

S OH

R1

R1

NOTES :

The one-pot coupling of 2-silylated-1,3-dithianes with epoxides to afford 1,5-polyol fragements. The keystep in the mechanism is the [1,4]-Brook rearrangement. This rearrangement only takes place after the addition of the HMPA. See also Brook rearrangement, and Corey – Seebach reaction.

REFERENCES :

1) P.F. Jones; M.F. Lappert; A.C. Szary, J. Chem. Soc., Perkin Trans. 1, 1973, 2272. 2) L.F. Tietze; H. Geissler; J.A. Gewert; U. Jacobi, Synlett, 1994, 511. 3) A.B. Smith III; A.M. Boldi, J. Am. Chem. Soc., 1997, 119, 6925. 4) K.J. Hale; M.G. Hummersone; G.S. Bhatia, Org. Lett., 2000, 2, 2189. 5) M. Yus; C. Najera; F. Foubelo, Tetrahedron, 2003, 59, 6147.

COMMENTS :

1598

SMITH INDOLE SYNTHESIS EXAMPLE :

H CH3 H N TMS

N 1) 2.2 nBuLi 2) O EtO

N H H N

H H

MECHANISM :

H+ O CH3 H N TMS

Li Li

2.2 nBuLi hexane

N TMS

Li N TMS

RCO2Et

R

R

N

- H2O

R

N H

DISCONNECTION :

R1 CH2R R

RCO2Et +

N H

H N TMS

NOTES :

Dilithium reagents derived from 2-alkyl-N-trimethylsilyl anilines undergo condensation with esters of carboxylic acids to afford substituted indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe,

1599

Reissert indole, Saegusa indole, Schmid, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) A.B. Smith III; M. Visneck; J.N. Haseltine; P.A. Sprengeler, Tetrahedron, 1986, 42, 2957. 2) K.E. Henegar; D.A. Hunt, Heterocycles, 1996, 43, 1471.

COMMENTS :

SNIECKUS REARRANGEMENT EXAMPLE :

O

NEt2 O

OH 1) sBuLi, TMEDA, THF, - 78 oC 2) - 78 oC -> RT

NEt2 O

MECHANISM :

N(R)2 O

O

N(R)2 OCH3

O

O

N(R)2 OCH3

1600

O OH OCH3

DISCONNECTION :

N(R)2 O OH

O

OR

N(R)2 OCH3

OH

O

O

N(R)2

N(R)2 O

O

NOTES :

[1,2]- or [1,4]-carbamoyl migration of benzylic carbamates after direct ortho lithiation with sBuLi or LDA in THF. This is formally an anionic Fries rearrangement. See also Fries rearrangement.

REFERENCES :

1) M.P. Sibi; V. Snieckus, J. Org. Chem., 1983, 48, 1935. 2) M.P. Sibi; S. Chattopadhyay; J.W. Dankwardt; V. Snieckus, J. Am. Chem. Soc., 1985, 107, 6312. 3) V. Snieckus, Chem. Rev., 1990, 90, 879. 4) W. Wang; V. Snieckus, J. Org. Chem., 1992, 57, 424. 5) P. Zhang; R.E. Gawley, J. Org. Chem., 1993, 58, 3223. 6) M. Stratakis, J. Org. Chem., 1997, 62, 3024. 7) C.A. James; V. Snieckus, Tetrahedron Lett., 1997, 38, 8149.

COMMENTS :

1601

SOAI AUTOCATALYSIS EXAMPLE :

CHO

N H3C

N + iPr2Zn

H3C

N

OH N

OH 2 mol%, 0.1% ee

MECHANISM :

CHO

N

+ N

i

N

OZniPr

Pr2Zn N

t

Bu

t

Bu

H+

R

RCHO + (R2)2Zn

R2 OH

very high ee

DISCONNECTION :

N

OH N

R

R N R

CHO

N

OH N

1602

N

NOTES :

This is the asymmetric automultiplication of chiral compounds by asymmetric autocatalysis. Various chiral compounds with very low ee act as chiral initiators in the reaction of pyrimidine-5-carbaldehyde and diisopropylzinc to give 5pyrimidyl alkanol with high ee. Blackmond et al. have shown that the transition state exists of a tetrameric species.

REFERENCES :

1) K. Soai; T. Shibata; H. Morioka; K. Choji, Nature, 1995, 378, 767. 2) T. Shibata; S. Yonekubo; K. Soai, Angew. Chem., Int. Ed., 1999, 38, 659. 3) B.L. Feringa; R.A. van Delden, Angew. Chem., Int. Ed., 1999, 38, 3418. 4) K. Soai, Enantiomer, 1999, 4, 591. 5) K. Soai; T. Shibata; I. Sato, Acc. Chem. Res., 2000, 33, 382. 6) K. Soai; I. Sato; T. Shibata, The Chemical Record, 2001, 1, 321. 7) I. Sato; H. Urabe; S. Ishii; S. Tanji; K. Soai, Org. Lett., 2001, 3, 3851. 8) D.G. Blackmond, Adv. Synth. Catal., 2002, 344, 156. 9) K. Soai; I. Sato, Chirality, 2002, 14, 548. 10) I. Sato; H. Urabe; S. Ishiguro; T. Shibata; K. Soai, Angew. Chem., Int. Ed., 2003, 42, 315. 11) F.G. Buono; D.G. Blackmond, J. Am. Chem. Soc., 2003, 125, 8978. 12) T. Buhse, Tetrahedron: Asymmetry, 2003, 14, 1055. 13) K. Soai; T. Shibata; I. Sato, Bull. Chem. Soc. Jpn., 2004, 77, 1063. 14) I. Sato; M. Shimizu; T. Kawasaki; K. Soai, Bull. Chem. Soc. Jpn., 2004, 77, 1587. 15) I. Sato; K. Kadowaki; Y. Ohgo; K. Soai, J. Mol. Catal. A: Chem., 2004, 216, 209. 16) I. Sato; T. Nakao; R. Sugie; T. Kawasaki; K. Soai, Synthesis, 2004, 1419.

COMMENTS :

1603

SOMEI – KAMETANI REACTION EXAMPLE :

H H

NMe2

H

N

CO2CH3 O

+ O

N H

N

NH NaH, DMF, reflux

H

O

N O H3CO2C

N H

MECHANISM :

P

PMe3

N H

N H

CH3

EWG

CH3

EWG

N CH3 N CH3

CH3 H N CH3

EWG EWG

N H P

PMe3

N CH3 H N CH3 EWG

EWG

EWG

EWG

N H

1604

N

DISCONNECTION :

EWG

EWG CH3 N CH3

N H R

N H

NO2

N H

NOTES :

Gramine derivatives are mono-alkylated with carbon nucleophiles, especially nitro-alkanes in the presence of tri-nbutylphospine as catalyst.

REFERENCES :

1) T. Kametani; N. Kanaya; M. Ihara, J. Am. Chem. Soc., 1980, 102, 3974. 2) M. Somei; Y. Karasawa; C. Kaneko, Heterocycles, 1981, 16, 941. 3) T.D. Cushing; J.F. Sanz–Cervera; R.M. Williams, J. Am. Chem. Soc., 1996, 118, 557.

COMMENTS :

SOMMELET – HAUSER REACTION EXAMPLE :

CH3 CH2N CH3 CH3

CH3 CH2N(CH3)2 NaNH2

1605

MECHANISM :

R N CH3 R

R R N CH2

NR2 CH3

NH2

CH3

CH2

CH2NR2

H CH2NR2

DISCONNECTION :

O R

NMe2 R

O H3C CH 3 N R1

R1

NOTES :

In this rearrangement, a trialkylammonium or dialkylsulfonium residue becomes detached from the side-chain carbon atom of a benzyl or substituted benzyl group and reattaches to the ortho-position of the benzene ring by way of the αcarbon atom of one of the alkyl group. The rearrangement has been effected by sulfuric acid, phosphorous pentoxide, phenyl lithium or photochemically. The reaction may take place with sulfonium salts instead of ammonium salts. See also Stevens reaction.

REFERENCES : March : 673, 1194 Smith – March : 877, 1420, 1455 Smith : 809 Smith 2nd : 670, 677 Houben – Weyl : E6b, 699; E7b, 634; E11, 910, 1362, 1381; E16d, 1140, 1149 Org. React. : 8, 197; 18, 404 Org. Synth. : 34, 61 Org. Synth. Coll. Vol. : 4, 585 Science of Synthesis : 10, 387

1) M. Sommelet, C.R. Séances Acad. Sci., 1937, 205, 56. 2) S.W. Kantor; C.R. Hauser, J. Am. Chem. Soc., 1951, 73, 4122. 3) G.C. Jones; C.R. Hauser, J. Org. Chem., 1962, 27, 3572. 4) J. Biellmann; J. Schmitt, Tetrahedron Lett., 1973, 14, 4615.

1606

5) T.J. Lee; W.J. Holtz, Tetrahedron Lett., 1983, 24, 2071. 6) N. Shirai; Y. Sato, J. Org. Chem., 1988, 53, 194. 7) J.M. Klunder, J. Heterocycl. Chem., 1995, 32, 1687. 8) J. Park, J.H. Shin; C. Lee, Tetrahedron Lett., 1999, 40, 7485. 9) P.B. Alper; K.T. Nguyen, J. Org. Chem., 2003, 68, 2051.

COMMENTS :

SOMMELET ALDEHYDE REACTION EXAMPLE :

CH3 HO H3C

CH3

N CH2Cl

+

N

HO

N N

H2O

N

CHO

H3C

N

MECHANISM :

CH2 X

.

C6H12N4

X

C6H12N4

N

CH2

NH2 - H2

O + NH3

NH H2O

H

1607

DISCONNECTION :

RCHO

RCH2X X = Cl, Br, I

NOTES :

Primary alkyl and aryl halides can be oxidised to aldehydes easily by the use of hexamethylenetetramine. See also Delépine, Duff and Kröhnke reactions.

REFERENCES : March : 1193 Smith – March : 1536 Houben – Weyl : 7/1, 194 Org. React. : 8, 197; 21, 1 Org. Synth. : 33, 93; 47, 76 Org. Synth. Coll. Vol. : 4, 690, 918; 5, 668

1) M. Sommelet, Bull. Soc. Chim. Fr., 1913, 13, 1085. 2) C.W. Shopee, Nature, 1948, 162, 619. 3) V. Franzen, Liebigs Ann. Chem., 1956, 600, 109. 4) M.-C. Zaluski; M. Robba; M. Bonhomme, Bull. Soc. Chim. Fr., 1970, 1445. 5) S. Miyano; H. Fukushima; H. Inagawa; H. Hashimoto, Bull. Chem. Soc. Jpn., 1986, 59, 3285. 6) D. Evans; M.P. Serve; B. Ramalingam; L. Barna; W. Feld, Heterocycles, 1987, 26, 1569. 7) I. Simiti; O. Oniga, Monatsh. Chem., 1996, 127, 733.

COMMENTS :

SONN – MÜLLER ALDEHYDE SYNTHESIS EXAMPLE :

Ph

Ph NOH

Ph 1) PCl5 2) SnCl2, HCl 3) H2O

1608

H O

MECHANISM :

Ph

Ph

Ph NOH

PCl5 - HCl

Ph SnCl2 HCl

Ph

Ph N

- POCl3

Cl Cl O P Cl Cl

H H2O

NPh

H

Ph

NPh·SnCl4

Cl

O

DISCONNECTION :

Ar

H

Ar

O

Cl O

NOTES :

The aromatic aldehyde synthesis from amides or ketoximes, by reduction of imino chlorides. The von Braun – Rudolph modification involves the use of chromous chloride in the reduction of the imido-chlorides. See also Grundmann and Stephen reactions.

REFERENCES : Houben – Weyl : 7/1, 480 Org. React. : 8, 225, 240

1) A. Sonn; E. Müller, Ber. Dtsch. Chem. Ges., 1919, 52, 1929. 2) T.S. Work, J. Chem. Soc., 1942, 429. 3) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 4) G.H. Coleman; R.E. Pyle, J. Am. Chem. Soc., 1946, 68, 2007. 5) F. Effenberger; R. Gleiter, Chem. Ber., 1964, 97, 480.

COMMENTS :

1609

SONN EXTENSION OF THE HOESCH REACTION EXAMPLE :

HO

OH

HO

+ CH2(CN)2

O

1) ZnCl2, HCl 2) H2O 3) H+

OH

OH

O

O

MECHANISM :

HO

HO

OH + CH2(CN)2

OH

ZnCl2 HCl

CN OH

OH HO

OH

HO

O

H2O

NH

O

H+ OH

O

N OH

O

DISCONNECTION :

RO

O

RO

O

OH

R2 OR1

OR1 O

NOTES :

In this extension of the Hoesch reaction, malononitrile or ethyl cyanoacetate is condensed with resorcinol or phloroglucinol. See also Hoesch – Houben reaction.

REFERENCES :

A. Sonn, Ber. Dtsch. Chem. Ges., 1917, 50, 1292.

COMMENTS :

1610

SONOGASHIRA – HAGIHARA COUPLING EXAMPLE :

PhI +

H

H

CuI, (Ph3P)PdCl2 Et2NH

Ph

Ph

MECHANISM :

Ph3P (PPh3)2PdCl2

2 HC CR

PPh3 Pd

R

R

[NEt2H2]Cl

CuI, Et2NH

R C C C C R (PPh3)2Pd

R1X

R1 C C R

(PPh3)2Pd

R1 X

(PPh3)2Pd

HC CR CuI, Et2NH

R1 C C R

[NEt2H2]X

DISCONNECTION :

R1

R1X +

R

R

H

NOTES :

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) and arylated by aryl triflates (bromide, iodides). These reactions are called Cacchi coupling reactions if the reaction is catalysed by Cu(I) and Pd(0) and if triflate reagents are employed, Sonogashira – Hagihara coupling reactions if the reaction is catalysed by Cu(I) and Pd(0) and halides are employed as substrates. Nickel-catalysed reactions have been reported by Beletskaya et al. Stephens – Castro coupling reactions for the non-catalysed coupling of copper acetylides with aryl halides. See also Liebeskind – Srogl and Stephens – Castro reactions.

1611

REFERENCES : March : 718 Smith 2nd : 1124 Org. Synth. : 72, 104; 76, 263 Org. Synth. Coll. Vol. : 9, 117; 10, 2358 Science of Synthesis : 1, 285, 801; 9, 266; 10, 750

1) K. Sonogashira; Y. Tohda; N. Hagihara, Tetrahedron Lett., 1975, 16, 4467. 2) R. Rossi; A. Carpita; F. Bellina, Org. Prep. Proced. Int., 1995, 27, 129. 3) M.W. Miller; C.R. Johnson, J. Org. Chem., 1997, 62, 1582. 4) B.A. Chauder; A.V. Kalinin; N.J. Taylor; V. Snieckus, Angew. Chem., Int. Ed., 1999, 38, 1435. 5) J. Brettar; J.P. Gisselbrecht; M. Gross; N. Solladié, Chem. Commun., 2001, 733. 6) O. Henze; D. Lentz; A. Schäfer; P. Franke; A.D. Schlüter, Chem. Eur. J., 2002, 8, 357. 7) P. Appukkuttan; W. Dehaen; E. van der Eycken, Eur. J. Org. Chem., 2003, 4713. 8) I.P. Beletskaya; G.V. Latyshev; A.V. Tsvetkov; N.V. Lukashev, Tetrahedron Lett., 2003, 44, 5011. 9) N.E. Leadbeater; M. Marco; B.J. Tominack, Org. Lett., 2003, 5, 3919. 10) L. Wang; P. Li; Y. Zhang, Chem. Commun., 2004, 514. 11) N.F. Utesch; F. Diederich; C. Boudon; J.-P. Gisselbrecht; M. Gross, Helv. Chim. Acta, 2004, 87, 698. 12) G. Zeni; D. Alves; J.M. Pena; A.L. Braga; H.A. Stefani; C.W. Nogueira, Org. Biomol. Chem., 2004, 2, 803. 13) M. Amjad; D.W. Knight, Tetrahedron Lett., 2004, 45, 539. 14) A. Köllhofer; H. Plenio, Adv. Synth. Catal., 2005, 347, 1295.

COMMENTS :

SORENSON AMINO ACID SYNTHESIS EXAMPLE :

O H

CO2Et HOOC

N CO2Et O

1) Br(CH2)3Br 2) KOAc 3) NaOH

1612

NH2

CH2OH

MECHANISM :

CH3

CH3 EtO2C

N H

EtO2C R EtO2C

R HOOC

EtO2C

N H

base EtO2C R

CH3 N H

EtO2C

O

O

HOOC hydrolysis

O

CH3 N H

HOOC

RX

O

decarboxylation

CH3 N H

O

DISCONNECTION :

CO2Et

COOH R

H2N R2

N R1

CO2Et

+ R2X

NOTES :

The alkylation at a carbon bearing an active hydrogen atom in this case N-acetylaminomalonic ester. As in the malonic or cyanoacetic ester synthesis, the product can be hydrolysed and decarboxylated to give an α-amino acid. Other acidic CH hydrogens can be hydrolysed too. See also Gabriel synthesis.

REFERENCES : March : 465 Smith – March : 549 Houben – Weyl : 4, 759

1) Z. Sorenson, Bull. Soc. Chim. Fr., 1905, 33, 1042. 2) Z. Sorenson, Bull. Soc. Chim. Fr., 1905, 33, 1052. 3) E.J. Corey; D.E. Cane, J. Org. Chem., 1970, 35, 3405. 4) I.T. Christensen; B. Egbert; B. Nielsen; L. Brehm; P. Krogsgaard–Larsen, J. Med. Chem., 1992, 35, 3512. 5) S. Kanemasa; T. Mori; E. Wada; A. Tatsukawa, Tetrahedron Lett., 1993, 34, 677. 6) R.D.A. Hudson; S.A. Osborne; G.R. Stephenson, Synlett, 1996, 845.

1613

COMMENTS :

SPASSOW ESTERIFICATION EXAMPLE :

t

t

BuOH + AcCl Mg Et2O

BuOAc

MECHANISM :

OH

R OH R1

R R

R1

Cl

- HCl

O O H+

R1

Cl

R

R

O O R

R R

R H2 + MgCl2

2 HCl + Mg

DISCONNECTION :

R R

R R O

(R)3COH + RCOCl

O

NOTES :

A method for the preparation of esters by the reaction of acid chloride with alcohols in benzene or diethyl ether in the presence of magnesium. With ethyl acetoacetate C-acyl derivatives are obtained. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker

ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi, and Yamamoto macrolactonisation

reactions.

1614

REFERENCES : Org. Synth. : 21, 46; 24, 18 Org. Synth. Coll. Vol. : 3, 141, 390

1) A. Spassow, Ber. Dtsch. Chem. Ges., 1937, 70, 1926. 2) A. Spassow, Ber. Dtsch. Chem. Ges., 1937, 70, 2381.

COMMENTS :

SPECKAMP RING-CLOSURE EXAMPLE :

O

O

N

H HCOOH RT

OEt

H

N H

MECHANISM :

H O

N

H

OEt

O

HCOOH RT

O

O

N

O

O

DISCONNECTION :

O

O N

R1

N RO

R1

1615

N O

NOTES :

The cyclisation of olefinic ω-ethoxy lactams which leads to ring-closed products via an α-acyliminium ion. Acetylene derivatives undergo a similar cyclisation.

REFERENCES :

1) H.E. Schoemaker; J. Dijkink; W.N. Speckamp, Tetrahedron, 1978, 34, 163. 2) H.E. Schoemaker; Tj. Boer–Terpstra; J. Dijkink; W.N. Speckamp, Tetrahedron, 1980, 36, 143. 3) W.N. Speckamp; H. Hiemstra, Tetrahedron, 1985, 41, 4367. 4) W.G. Beyersbergen van Henegouwen; H. Hiemstra, J. Org. Chem., 1997, 62, 8862.

COMMENTS :

SPENGLER – PFANNENSTIEL OXIDATION EXAMPLE :

H OH HO

H

O

H

OH OH

O HO

OH

H

HOH2C

O

OH

OH HO 1) Ba(OH)2, O2 2) CO2

O

H O

HO

OH

NOTES :

The oxidation of reductive sugars in alkaline solution with molecular oxygen.

REFERENCES :

1) O. Spengler; A. Pfannenstiel, Z. Wirtschaftsgruppe Zuckind., 1935, 85, Techtl. 547. 2) N.K. Richtmyer; R.M. Hann; C.S. Hudson, J. Am. Chem. Soc., 1939, 61, 340. 3) E. Hardegger; K. Kreis; H. El Khadem, Helv. Chim. Acta, 1951, 34, 2343. 4) E. Hardegger; K. Kreis; H. El Khadem, Helv. Chim. Acta, 1952, 35, 618.

OH

H

HOH2C

1616

COOH

OH

COMMENTS :

ST. PFAU – PLATTNER SYNTHESIS EXAMPLE :

1) N2CH2CO2Et 2) NaOH 3) Pd/C, H2

MECHANISM :

N2CH2CO2Et

CO2Et

NaOH

Pd/C, H2

COOH

DISCONNECTION :

R1

R1 R

+ N2CHR R2

R2

NOTES :

This method of synthesis involves ring enlargement of olefins by addition of ethyl diazoacetate followed by hydrolysis. The resulting acid is dehydrogenated and decarboxylated, generally by distillation in vacuo over palladium on charcoal. See also Buchner and Ciamician – Dennstedt reactions.

REFERENCES :

1) A. St. Pfau; P.A. Plattner, Helv. Chim. Acta, 1939, 22, 202. 2) J.R. Nunn; W.S. Rapson, J. Chem. Soc., 1949, 825. 3) K. Hafner, Angew. Chem., 1958, 70, 419.

1617

4) H.-J. Hansen, Chimia, 1996, 50, 489. 5) H.-J. Hansen, Chimia, 1997, 51, 147.

COMMENTS :

STAAB ACYLATION EXAMPLE : O COOH

t

Bu

+ Br

O

OH O

O N

O

Br N

N

N

MECHANISM :

O R COOH + N

N

N

N

R

N

+ CO2 +

N

N

O

R1OH

R

OR1 O

DISCONNECTION :

O R

RCOOH + R1OH

OR1

1618

N +

N H

N H

NOTES :

The trans acylation of alcohols to esters with N-acyl imidazoles. An easier route using benzotriazole has been published by Katritzky. The macrolactonisation version of this reaction is sometimes called Raphael macrolactonisation. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai

rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi

and Yamamoto macrolactonisation reactions.

REFERENCES : Org. Synth. : 48, 44 Org. Synth. Coll. Vol. : 5, 201

1) H.A. Staab, Chem. Ber., 1956, 89, 1927. 2) H.A. Staab; W. Rohr; A. Mannschreck, Angew. Chem., 1961, 73, 143. 3) H.A. Staab; H. Merdes, Chem. Ber., 1965, 98, 1134. 4) E.W. Colvin; T.A. Purcell; R.A. Raphael, J. Chem. Soc., Perkin Trans. 1, 1976, 1718. 5) T. Kömives, Org. Prep. Proced. Int., 1989, 21, 251. 6) M.J. Ford; S.V. Ley, Synlett, 1990, 255.

COMMENTS :

STACEY ESTERIFICATION EXAMPLE :

EtOH + CH3COOH

EtO (CF3CO)2O

1619

CH3 O

MECHANISM : R1 R1COOH

O

(CF3CO)2O

O O

R1COOR + 2 CF3COOH

CF3

R OH

DISCONNECTION :

H N

R1

R1COOH + RNH2

R

O R1

OR R1COOH + ROH O

R = Alk, Ar

NOTES :

Esters or amides are formed from alcohols and phenols or amines by treatment with carboxylic acids in the presence of trifluoroacetic anhydride. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-

2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES :

1) M. Stacey; E.J. Bourne; J.C. Tatlow; J.M. Tedder, Nature, 1949, 164, 705. 2) J.M. Tedder, Chem. Rev., 1955, 55, 787. 3) S. Oi; Y. Ochiai; S. Miyano, Chem. Lett., 1991, 1575. 4) F. Wüst; C.S. Dence; T.J. McCarthy; M.J. Welch, J. Labelled Compd. Radiopharm., 2000, 43, 1289. 5) N.M. Khvoinova; D.V. Muslin; S.Ya. Khorshev, Russ. J. Gen. Chem. (Engl. Transl.), 2001, 71, 1799.

COMMENTS :

1620

STADLER – ZIEGLER REACTION EXAMPLE :

CH3 S

N N + HS CH3

MECHANISM :

R S N2+ Cl-

+ HS R

N N

R - N2

S

DISCONNECTION :

R

R1

R1

S

N2+ Cl- + HS R

NOTES :

The alkylthiodediazoniation is a very dangerous reaction to carry out due to the formation of diazosulfides. The reaction has been used extensively in industry to produce arylthioglycolic acids. Safer laboratory routes have been prepared by Degani and Fochi.

REFERENCES : Org. Synth. : 12, 76 Org. Synth. Coll. Vol. : 2, 580

1) O. Stadler, Ber. Dtsch. Chem. Ges., 1884, 17, 2075. 2) J.H. Ziegler, Ber. Dtsch. Chem. Ges., 1890, 23, 2469. 3) J.D. Baleja, Synth. Commun., 1984, 14, 215. 4) T. Schaefer; J.D. Baleja, Can. J. Chem., 1986, 64, 1376. 5) M. Barbero; I. Degani; N. Diulgheroff; S. Dughera; R. Fochi; M. Migliaccio, J. Org. Chem., 2000, 65, 5600.

COMMENTS :

1621

STADEL – RÜGHEIMER PYRAZINE SYNTHESIS EXAMPLE :

N

Cl 2 H3C

O

1) 2 NH3 2) O2

H3C

CH3

N

MECHANISM :

Cl

NH2 O

2 R

O

2 NH3

R

- 2 H2O

O H N 2

R

N

R R

N O2

N

R

R

N

DISCONNECTION :

N R

Cl

R R

N

O

NOTES :

The reaction between α-halogenketones and ammonia to afford pyrazine. See also Gastaldi and Gutknecht reactions.

REFERENCES :

1) W. Stadel; L. Rügheimer, Ber. Dtsch. Chem. Ges., 1876, 9, 536. 2) C. Stoehr, J. Prakt. Chem., 1891, 43, 156. 3) F. Tutin, J. Chem. Soc., 1910, 97, 2495. 4) I.J. Krems; P.E. Spoerri, Chem. Rev., 1947, 40, 279.

COMMENTS :

1622

STAUDINGER – PFENNINGER THIIRANE DIOXIDE SYNTHESIS EXAMPLE :

S

2 CH2N2 + SO2

O

O

MECHANISM :

R1 O H S Cl R2 O

O

R2 SO2

Et3N

R1

R3

R1

N2

O S

R2 R4

R3

O O R1 S R3 or R2 R4 N N

R4

DISCONNECTION :

O S

R1 R2

O R1 S R2

O R1 R1

R2 O

N N

H

R1 SO2Cl

R2

R1

N2

+ R2

R2

NOTES :

The thiirane dioxide episulfone synthesis by reaction of diazomethane with sulfenes or SO2.

REFERENCES :

1) H. Staudinger; F. Pfenninger, Ber. Dtsch. Chem. Ges., 1916, 42, 1941. 2) G. Opitz; K. Fischer, Angew. Chem., Int. Ed. Engl., 1965, 4, 70. 3) N.H. Fischer, Synthesis, 1970, 393. 4) H. Quast; F. Kees, Chem. Ber., 1981, 114, 787.

1623

COMMENTS :

STAUDINGER AZIDE REDUCTION EXAMPLE :

NC N3

NC N P(OMe)3

P(OMe)3

MECHANISM :

R1 R

N

N

R1

N R

Ph N N

N

N

N

Ph

Ph P

R1

Ph R

N

N

N Ph

Ph P

Ph

Ph P N

Ph R

Ph Ph P N Ph

- N2

R

R R1

H2O

H2N R1

R1

DISCONNECTION : NH2 R

N3

R1

R

R1

NOTES :

The conversion of organic azides with phosphines or phosphates to iminophosphoranes and their hydrolysis to amines. Kosower et al. has published a detailed mechanistic study about how the sequence of reactants alters the course of the reaction.

REFERENCES : March : 1219

1624

Smith – March : 1555 Houben – Weyl : E8a, 962; E15, 872, 2349; E16a, 1279

1) H. Staudinger; J. Meyer, Helv. Chim. Acta, 1919, 2, 635. 2) Yu.G. Gololobov; I.N. Zhmurova; L.F. Kasukhin, Tetrahedron, 1981, 37, 437. 3) R.D.G. Cooper; B.W. Daugherty; D.B. Boyd, Pure Appl. Chem., 1987, 59, 485. 4) E.F.V. Scriven; K. Trumbull, Chem. Rev., 1988, 88, 297. 5) J. Barluenga; F. Palacios, Org. Prep. Proced. Int., 1991, 23, 1. 6) A. Koziara; A. Zwierzak, Synthesis, 1992, 1063. 7) Yu.G. Gololobov; L.F. Kasukhin, Tetrahedron, 1992, 48, 1353. 8) D.E. Shalev; S.M. Chiacchiera; A.E. Radkowsky; E.M. Kosower, J. Org. Chem., 1996, 61, 1689. 9) E. Saxon; C.R. Bertozzi, Science, 2000, 287, 2007. 10) O. David; W.J.N. Meester; H. Bieräugel; H.E. Schoemaker; H. Hiemstra; J.H. van Maarseveen, Angew. Chem., Int. Ed., 2003, 42, 4373.

11) W.Q. Tian; Y.A. Wang, J. Org. Chem., 2004, 69, 4299. 12) M. Basato; F. Benetollo; G. Facchin; R.A. Michelin; M. Mozzon; S. Pugliese; P. Sgarbossa; S. Mazzega Sbovata; A. Tassan, J. Organomet. Chem., 2004, 689, 454. 13) Y. He; R.J. Hinklin; J. Chang; L.L. Kiessling, Org. Lett., 2004, 6, 4479.

COMMENTS :

STAUDINGER KETENE ADDITION EXAMPLE :

CH3

Cl CH3 CH3

O

H3C +

Cl Cl

Cl Cl

Cl ZnCu, POCl3 Et2O

1625

O

H

MECHANISM :

O

O R

R1

R

R

R1

R2

R3

+

O

R1 R2

R3

R3 H R2

DISCONNECTION :

R

O

O

R1

R4 R2 R3

R

R2

R

+

R = R1 = H, alkyl, aryl R1 R2 = H, alkyl, aryl, vinyl, -OR, -N(R)2 R3 = H, alkyl, aryl, -Cl, -Br R4 = alkyl, aryl, -Cl, -Br, -OR

R3

O

O N

R1

R

R4

N

R2

+

R1

R = alkyl, benzyl, aryl R1 = H, alkyl, aryl R2 = alkyl, aryl R3 = H, alkyl R4 = alkyl, -OR, -N(R)2

R2 R3

R3

O

R4 R2 R3

R4

O

O O R1

R4

R1 R1 = H, alkyl, aryl R2 = H, alkyl, aryl, vinyl R3 = H, alkyl, -Cl, -Br R4 = alkyl, aryl, -Cl, -Br -OR, -SiMe3

R2

+ R3

R4

NOTES :

The thermal [2+2] cycloaddition reaction between ketenes and carbon-carbon, carbon-oxygen and carbon-nitrogen double bonds. The reaction of ketenes with alkenes is assumed to occur via a concerted mechanism, the path of approach between the reactants is orthogonal.

1626

REFERENCES : March : 856, 858 Smith – March : 1077 Smith : 1183 Smith 2nd : 979 Org. React. : 45, 159 Org. Synth. : 4, 39; 20, 47; 21, 13, 64; 33, 29; 45, 50; 55, 32; 68, 32 Org. Synth. Coll. Vol. : 1, 330; 3, 164, 356, 508; 4, 348; 5, 679; 6, 210; 8, 82

1) H. Staudinger, Ber. Dtsch. Chem. Ges., 1907, 40, 1145. 2) H. Staudinger; H.W. Klever, Ber. Dtsch. Chem. Ges., 1907, 40, 1149. 3) G. Quadbeck, Angew. Chem., 1956, 68, 361. 4) W.T. Brady, J. Org. Chem., 1966, 31, 2676. 5) E. Ziegler, Chimia, 1970, 24, 62. 6) K.N. Houk, Acc. Chem. Res., 1975, 8, 361. 7) H.R. Seikaly; T.T. Tidwell, Tetrahedron, 1986, 42, 2587. 8) R.K. Orr; M.A. Calter, Tetrahedron, 2003, 59, 3545.

COMMENTS :

STEGLICH – HASSNER ESTERIFICATION EXAMPLE :

O

O H H3C

H N

Ph COOH

+ PhCH2OH

DCC, DMAP DCM

1627

Ph OCH2Ph

N

H3C O

MECHANISM :

R

OH

+

N C N

R

O

R

O

O H N N C N H

+

O

N R

R O H N

O

O H N

O H+

O N H

N

R O H N

H O

R1 O H N C N H O

N H

R - H+

R + O

R1 O H

R1 O

O

DISCONNECTION :

R

OR1 RCOOH + R1OH

O

NOTES :

The direct room temperature esterification of carboxylic acids with alcohols, including tert-alcohols with the help of dicyclohexylcarbodiimide (DCC) and 4-dialkylaminopyridine (DMAP) catalysts. The intramolecular version uses an additional reagent DMAP.HCl and is called the Keck macrolactonisation. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-

closure, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi, and Yamamoto macrolactonisation reactions.

1628

REFERENCES : March : 395 Smith – March : 485 Org. Synth. : 63, 183 Org. Synth. Coll. Vol. : 7, 93

1) W. Steglich; G. Höfle, Angew. Chem., Int. Ed. Engl., 1969, 8, 981. 2) A. Hassner; L.R. Krepski; V. Alexanian, Tetrahedron, 1978, 34, 2069. 3) E.P. Boden; G.E. Keck, J. Org. Chem., 1985, 50, 2394. 4) B.J. Balcom; N.O. Petersen, J. Org. Chem., 1989, 54, 1922. 5) D. Barker; M.D. McLeod; M.A. Brimble; G.P. Savage, Tetrahedron Lett., 2001, 42, 1785.

COMMENTS :

STENHOUSE CLEAVAGE EXAMPLE :

H3CO

H O

+ 2 PhNH2 O

O 1) HCl, Et2O 2) CH3OH, NaHCO3 H

N Ph

MECHANISM :

H

H O

+ 2 ArNH2 O

H N

HCl, Et2O

Ar

N HO

Ar

Ph

H N O

Cl

N H Ph

1629

DISCONNECTION :

H

H N

Ar

H

N HO

Cl Ar

+ 2 ArNH2

O

O

NOTES :

This reaction includes the cleavage of 2-furaldehydes (other aldehydes can also be used) in the presence of acid and aromatic amines to yield anils. These salts also react with piperidines, dimethyl malonate anions and methanol. The intermediate salts are called Stenhouse salts. Some of the Stenhouse salts show reverse photochromism.

REFERENCES :

1) J. Stenhouse, Liebigs Ann. Chem., 1870, 156, 197. 2) C.V. Brouillette; W.M. Foley; H. McKennis, J. Am. Chem. Soc., 1954, 76, 4617. 3) K. Honda; H. Komizu; M. Kawasaki, J. Chem. Soc., Chem. Commun., 1982, 253. 4) B.R. Darcy; K.G. Lewis; C.E. Mulquiney, Aust. J. Chem., 1985, 38, 953. 5) G. Piancatelli; M.D. D’Auria; F. Donofrio, Synthesis, 1994, 867. 6) P. Safar; F. Povazanec; N. Pronayova; P. Baran; G. Kickelbick; J. Kozisek; M. Breza, Coll. Czech. Chem. Commun., 2000, 65, 1911.

COMMENTS :

STEPHEN ALDEHYDE SYNTHESIS EXAMPLE :

O C

N

1) HCl, Et2O 2) SnCl2 3) H2O

1630

H

MECHANISM :

R C N

Cl R C NH2

HCl Et2O

Cl

H R N · SnCl4 H H

SnCl2

Cl

H

O

H N

R

H Cl

H2O, - NH3

R

H

DISCONNECTION :

O R

R

H

N

R = alkyl, aryl, heteroaryl

NOTES :

This synthesis comprises the production of aldehydes from nitriles by treatment with anhydrous stannous chloride dissolved in diethyl ether saturated with hydrogen chloride. The resulting aldimine – SnCl4 complex is hydrolysed with warm water. See also Sonn – Müller reaction.

REFERENCES : March : 919 Smith – March : 1204 Smith : 470 Smith 2nd : 406 Houben – Weyl : 7/1, 301; E3, 485 Org. React. : 8, 246 Org. Synth. : 23, 63 Org. Synth. Coll. Vol. : 3, 626

1) H. Stephen, J. Chem. Soc., 1925, 127, 1874. 2) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 3) L. Turner, J. Chem. Soc., 1956, 1686. 4) C.G. Stuckwisch, J. Org. Chem., 1972, 37, 318. 5) N. Suzuki, Chem. Pharm. Bull., 1980, 28, 761. 6) J.S. Cha; S.W. Chang; O.O. Kwon; J.M. Kim, Synlett, 1996, 165. 7) P. Kasak; M. Putala, Collect. Czech. Chem. Commun., 2000, 65, 729. 8) J.S. Cha; S.H. Jang; S.Y. Kwon, Bull. Korean Chem. Soc., 2002, 23, 1697.

1631

COMMENTS :

STEPHENS – CASTRO SYNTHESIS EXAMPLE :

I 6 1) Cu+, NH4OH 2) pyridine,heat

MECHANISM :

CuII(NH3)42+

CuI(NH3)2+

HONH3Cl +

R

+

CuC CR

CuI(NH3)2+

H

R

Cu

I pyridine

XH

R + CuI X

DISCONNECTION :

Ar

R

ArI + R

1632

Cu

NOTES :

The reaction between unactivated cuprous acetylides and aryl halides. See also Cadiot – Chodkiewicz – Eglington, Rosenmund – von Braun and Sonogashira – Hagihara reactions.

REFERENCES : March : 662 Smith – March : 868 Smith 2nd : 1124 Org. React. : 22, 253 Org. Synth. : 52, 128; 72, 104 Org. Synth. Coll. Vol. : 6, 916; 9, 117 Science of Synthesis : 10, 20

1) R.D. Stephens; C.E. Castro, J. Org. Chem., 1963, 28, 3313. 2) H.A. Staab; K. Neunhoffer, Synthesis, 1974, 424. 3) J. Kabbara; D. Schinzer; C. Hoffmann, Synthesis, 1995, 299. 4) M.S. Yu; L. Lopez de Leon; M.A. McGuire; G. Botha, Tetrahedron Lett., 1998, 39, 9347. 5) F. von der Ohe; R. Bruckner, New. J. Chem., 2000, 24, 659.

COMMENTS :

STETTER 1,4-DICARBONYL SYNTHESIS EXAMPLE : O PhCHO +

N NaCN DMF

1633

Ph

CN

MECHANISM :

O

O R

OH

R

H

C N

H

R

CN

CN

H O

R1 H

X

O

OH

HO R1 +

R CN

NC H

H R1

O H

X

HO O R1

X CN

+

O

O R X

NC H

CH2Ph HO

R1

H

R

N

CH2Ph

Base

N

Cl

HO

S

S

CH3(CH2)5CHO

CH2Ph

CH2Ph N HO S

N

OH

HO

C

S O

CH3 Tautomerisation - Thiazole

X

R

H3C

O O

1634

O OH

DISCONNECTION :

O R2

R R1 O

RCHO +

O

R2 O

H OH

R

R1

2 RCHO

R

NOTES :

The Michael addition (benzoin condensation) of aromatic or heterocyclic aldehydes (via cyanohydrins) to α,βunsaturated systems in aprotic solvents. Also the addition of aliphatic aldehydes catalysed by thiazolium ylids. Highly enantioselective catalytic intramolecular Stetter reactions are reported in the literature.

REFERENCES : March : 471, 806, 970 Smith – March : 1243 Houben – Weyl : E5, 453 Org. React. : 40, 407 Org. Synth. : 62, 170; 65, 26 Org. Synth. Coll. Vol. : 7, 95; 8, 620

1) H. Stetter; M. Schreckenberg, Angew. Chem., Int. Ed. Engl., 1973, 12, 81. 2) H. Stetter; H. Kuhlmann, Synthesis, 1975, 379. 3) H. Stetter; P.H. Schmitz; M. Schreckenberg, Chem. Ber., 1977, 110, 1971. 4) S. Hünig, Chimia, 1982, 36, 1. 5) H. Wynberg; J. Metselaar, Synth. Commun., 1984, 14, 1. 6) D. Enders; K. Breuer; J. Runsink; J.H. Teles, Helv. Chim. Acta, 1996, 79, 1899. 7) M.S. Kerr; J. Read de Alaniz; T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298. 8) A.E. Mattson; A.R. Bharadwaj; K.A. Scheidt, J. Am. Chem. Soc., 2004, 126, 2314. 9) A.R. Bharadwaj; K.A. Scheidt, Org. Lett., 2004, 6, 2465. 10) A.G.M. Barrett; A.C. Love; L. Tedeschi, Org. Lett., 2004, 6, 3377. 11) S.M. Mennen; J.T. Blank; M.B. Tran-Dubé; J.E. Imbriglio; S.J. Miller, Chem. Commun., 2005, 195.

COMMENTS :

1635

STETTER CARBOXYLIC ACID SYNTHESIS EXAMPLE :

O

O

O

Bu

HO 1) Et3N 2) BuBr 3) H+, H2O 4) Wolff - Kishner reduction

MECHANISM :

O

O O

R O

1) Et3N 2) RX

H+, H2O

O

O R

HO

O Wolff - Kishner reduction

R

HO

DISCONNECTION : O O R

+ RX

OH

O

NOTES :

The synthesis of carboxylic acids using C-alkylation of 1,3-cyclohexanedione in the 2-position, followed by acidic treatment and reduction of the ketone group to afford the carboxylic acid.

REFERENCES :

1) H. Stetter; W. Dierichs, Chem. Ber., 1952, 85, 61. 2) H. Stetter; H. Figge, Chem. Ber., 1954, 87, 869. 3) H. Stetter; H. Meisel, Chem. Ber., 1957, 90, 2928.

COMMENTS :

1636

STEVENS REARRANGEMENT EXAMPLE :

CH3 H N

H3C H3C

H

H3C

NaNH2

CH3 CH3 N H O

O

Br

MECHANISM :

Br

R H H3C N H3C H O

R H3C N H3C H O

base

R

R H3C

H3C N

H3C

N H3C

H O

O

H

or CH3 H3C N H

R

H3C N

R H3C

O

H

O

DISCONNECTION :

R2 R1

Y

R3

R1 Y = NR, S

Y R3

R2

NOTES :

Quaternary ammonium or sulfonium salts give amino ketones or sulfides on treatment with base. The reaction proceeds through hydrogen abstraction from the ammonium salt to the ylid. A N -> C 1,2-benzyl shift occurs via a carbanionic intermediate to give the rearranged amine. It is still under debate if the reaction proceeds though a ion pair or radical pair in the solvent cage. A third possibility (a concerted 1,2-shift) is mentioned in Smith – March. See also Meisenheimer, Sommelet – Hauser and [1,2]-Wittig rearrangement reactions.

1637

REFERENCES : March : 673 Smith – March : 878, 1419, 1454 Smith : 809 Smith 2nd : 324, 677 Houben – Weyl : 13/1, 230; E5, 816; E7b, 179, 750; E8b, 855; E11, 1414, 1457; E16d, 1149; E19b, 271, 1582 Org. React. : 8, 271; 18, 403

1) T.S. Stevens; E.M. Creighton; A.B. Gordon; M. MacNicol, J. Chem. Soc., 1928, 3193. 2) G. Wittig, Angew. Chem., 1954, 66, 14. 3) W.H. Puterbaugh; C.R. Hauser, J. Am. Chem. Soc., 1964, 86, 1394. 4) Y. Sato; Y. Yagi; M. Koto, J. Org. Chem., 1980, 45, 613. 5) I. Markó, Comp. Org. Syn., 1991, 3, 913. 6) G.L. Heard; B.F. Yates, Aust. J. Chem., 1994, 47, 1685. 7) Y. Maeda; Y. Sato, J. Chem. Soc., Perkin Trans. 1, 1997, 1491. 8) M.P. Doyle; D.G. Ene; D.C. Forbes; J.S. Tedrow, Tetrahedron Lett., 1997, 38, 4367. 9) A. Padwa; L.S. Beall; C.K. Eidell; K.J. Worsencroft, J. Org. Chem., 2001, 66, 2414. 10) M. Harada; T. Nakai; K. Tomooka, Synlett, 2004, 365. 11) G.J. Rowlands; W.K. Barnes, Tetrahedron Lett., 2004, 45, 5347.

COMMENTS :

STIEGLITZ REARRANGEMENT EXAMPLE :

HO

CH3 N Cl

O Ag+

1638

N

CH3

MECHANISM :

Ar3C

N H

Ar

OH

Ar

PCl5

Ar Ar

O PCl4

N

- POCl3

H

Ar

Cl

Ar

H2O Ar

N H

Ar

Ar

Ar H

Ar

N Cl

H

Ar

N O

Ar

H

- PhNH3 Cl

Ar O

DISCONNECTION :

R

R N R2 R1

R1

R3, R4 = H, Br, Cl, OH, N3

R3 N

R2

R4

NOTES :

The rearrangement or ring enlargement of amines, normally containing aromatic residues, via nitrenes using phosphorous pentachloride or lead tetraacetate. See also Beckmann rearrangement, Curtius rearrangement, Hofmann rearrangement, Lossen rearrangement, Schmidt rearrangement, Tiemann rearrangement and Wolff

reaction.

REFERENCES : March : 1097 Smith – March : 1416

1) J. Stieglitz; P.N. Leech, Ber. Dtsch. Chem. Ges., 1913, 46, 2146. 2) L.A. Pinck; G.E. Hilbert, J. Am. Chem. Soc., 1937, 59, 8. 3) S.S. Berg; V. Petrov, J. Chem. Soc., 1952, 3713. 4) A.J. Sisti; S.R. Milstein, J. Org. Chem., 1974, 39, 3932. 5) R.V. Hoffman; D.J. Poelker, J. Org. Chem., 1979, 44, 2364. 6) A.R. Renslo; R.L. Danheiser, J. Org. Chem., 1998, 63, 7840.

1639

COMMENTS :

STILES – SISTI FORMYLATION EXAMPLE :

OH

O

CH3 N CH3

H

N2

H

SO3H

MECHANISM :

OH

H MgBr +

NMe2 O O

H SO3H

N H

N2

NMe2

H+

+ N

SO3H

N

DISCONNECTION : O R

R Br

H

NOTES :

The synthesis of aldehydes by formylation of Grignard reagents with p-dimethylaminobenzaldehyde and a diazonium salt.

1640

REFERENCES : Org. Synth. : 44, 4 Org. Synth. Coll. Vol. : 5, 46

1) M. Stiles; A.J. Sisti, J. Org. Chem., 1960, 25, 1691. 2) A.J. Sisti; J. Burgmaster; M. Fudim, J. Org. Chem., 1962, 27, 279.

COMMENTS :

STILL – GENNARI REACTION EXAMPLE :

H O

+

O

H3CO2C

P

F3CH2CO

H3CO2C

KN(SiCH3)2, 18-crown-6, THF, - 78 oC

OCH2CF3

MECHANISM :

O CO2R1 RO P OR

KN(TMS)2 18-crown-6

O CO2R1 RO P H OR R2

O RO RO P O

CO2R1

R2

R2

1641

CO2R1

O

DISCONNECTION :

R2

O CO2R1 + RO P OR

CO2R1

R2

H O

NOTES :

This is the structural variant of the Horner – Wadsworth – Emmons reaction. It makes cis-substituted acrylic esters and Z-substituted methacrylic esters accessible. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Takeda, Tebbe and Wittig

reactions.

REFERENCES :

1) W.C. Still; C. Gennari, Tetrahedron Lett., 1983, 24, 4405. 2) S.-H. Chen; R.F. Horvath; J. Joglar; M.J. Fisher; S.J. Danishefsky, J. Org. Chem., 1991, 56, 5834. 3) M.G. Banwell; M.D. McLeod; P. Rajaratnam; G.W. Simpson, Aust. J. Chem., 2000, 53, 659. 4) X. Franci; S.L.X. Martina; J.E. McGrady; M.R. Webb; C. Donald; R.J.K. Taylor, Tetrahedron Lett., 2003, 44, 7735.

COMMENTS :

STILL – WITTIG REARRANGEMENT EXAMPLE : OH

BnO Bn2N + n

O SnBu3

BuLi - 78 oC

BnO

1642

NBn2

OH

BnO

NBn2

MECHANISM :

O

OH R1

R2

1) KH 2) ICH2SnBu3 THF

R2

SnBu3

R1

n

BuLi THF, - 78 oC

R2

R1

OH

DISCONNECTION : OH R1

OH R1

R2

R2

NOTES :

The general [2,3]-sigmatropic rearrangement has been studied extensively, providing detailed accounts of how substitution of the allyclic ether precursor determines the stereochemical outcome of the rearrangement in a predictable way. While (E)- or (Z)-alkene selectivity of [2,3]-sigmatropic rearrangements can be predicted by conformational analysis of the expected transition state, little has been demonstrated regarding solvent effects. See also [2,3]-Wittig rearrangement.

REFERENCES : Org. React. : 46, 105

1) W.C. Still; A. Mitra, J. Am. Chem. Soc., 1978, 100, 1927. 2) R.W. Hoffmann, Angew. Chem., Int. Ed. Engl., 1979, 18, 563. 3) M.M. Midland; Y.C. Kwon, Tetrahedron Lett., 1985, 26, 5013. 4) T. Nakai; K. Mikami, Chem. Rev., 1986, 86, 885. 5) A.G. Wee; L. Zhang, Synth. Commun., 1993, 23, 325. 6) J.A. McKinney; D.F. Eppley; R.M. Keenan, Tetrahedron Lett., 1994, 35, 5985. 7) K. Fujii; Y. Fujita; Y. Sakagami, Tetrahedron Lett., 1996, 37, 389. 8) A.K. Ghosh; Y. Wang, J. Org. Chem., 1998, 63, 6735. 9) S.A. Hart; C.O. Trindle; F.A. Etzkorn, Org. Lett., 2001, 3, 1789.

COMMENTS :

1643

STILLE – KELLY COUPLING EXAMPLE :

Br Br OH

Me3Sn SnMe3 OH Pd(Ph 3P)4, dioxane 100 - 105 oC

OH OH

MECHANISM : X R1

R R1

n

X

X

R n

Ln Pd PdIILn

LnPdo

R1

R1

R

R

n

n

X Sn(R3)3 Sn(R3)3 Sn(R3)3 X

(R3)3Sn

PdIILn

R1

Sn(R3)3

R R1

n

X

Sn(R3)3

n

R1

X

R n

X

DISCONNECTION :

Ar

Ar

Hal-Ar

1644

R

Ar-Hal

PdLn

Sn(R3)3 X

NOTES :

This is the palladium-catalysed intramolecular aryl dihalide cyclisation (also other aromatic compounds like thiophenes react in a similar way.) using ditin compounds. The mechanism consists of two connected catalytic cycles. See also Grigg and Stille – Migita – Kosugi reactions.

REFERENCES :

1) T.R. Kelly; Q. Li, Tetrahedron Lett., 1990, 31, 161. 2) S.A. Hitchcock; D.R. Mayhugh; G.S. Gregory, Tetrahedron Lett., 1995, 36, 9085. 3) S.P. Stanforth, Tetrahedron, 1998, 54, 263. 4) J.A. Marshall, Chem. Rev., 2000, 100, 3163. 5) Y. Fukuyama; M. Kodama; Y. Asakawa, J. Synth. Org. Chem. Jpn., 2000, 58, 654. 6) T. Mori; M. Kodama; H. Yaso; Y. Fukuyama; H. Minami; H. Takahashi, Heterocycles, 2001, 54, 259.

COMMENTS :

STILLE – MIGITA – KOSUGI COUPLING EXAMPLE :

OTf 1) Pd(II) 2) LiCl 3) Bu3Sn

1645

MECHANISM :

reductive elimination

R1 X

Pd0Ln

oxidative addition

R1 R2

X PdIILn

R2 PdIILn

R1

R1

M R2

X M

R2 M II

X Pd Ln R1 transmetallation

R2 R1

R1

0 X + Pd

Sn(CH3)3 R1

+ Pd0

R2

via (CH3)3Sn-PdIIH (CH3)3SnX

(CH3)3SnH

Na2CO3

ROCO2Sn(CH3)3

"SiO"

NaX

PMHS

DISCONNECTION :

R R1

R X

+

R1 M

2

R, R1 = sp -hybridised X = I, OSO2CF3, Br, Cl M = Sn, B, Zr, Zn

NOTES :

The coupling of organotin (expensive and highly toxic) reagents (and Pd catalyst) with aryl or vinyl halides or triflates, acyl chlorides or allyl acetates. Tandem hydrostanylation and Stille coupling provide a way to make the reaction catalytic in tin. The reaction has an exceptional tolerance of functional groups. The transmetallation step is supposed to be the rate-determining step. Dramatic rate enhancements have been observed with readily dissociable ligands, like AsPh3 and P(furyl)3. Fu et al. has developed the use of aryl chlorides in the Stille – Migata – Kosugi coupling.

1646

For more on the mechanism see Espinet and Echavarren. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi

(Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Kelly, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : Smith – March : 931 Smith : 1364 Smith 2nd : 1122, 1127 Org. React. : 50, 1 Org. Synth. : 67, 86; 71, 97, 125; 77, 135 Org. Synth. Coll. Vol. : 8, 268; 9, 553, 741; 10, 2376 Science of Synthesis : 1, 801; 9, 258, 370, 527

1) W.J. Scott; G.T. Crisp; J.K. Stille, J. Am. Chem. Soc., 1984, 106, 4630. 2) J.K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508. 3) V. Farina; S.R. Baker; D. Benigni; C. Sapino, jr., Tetrahedron Lett., 1988, 29, 5739. 4) L. Del Valle; J.K. Stille; L.S. Hegedus, J. Org. Chem., 1990, 55, 3019. 5) A. Godard; F. Marsais; N. Plé; F. Trécourt; A. Turck; G. Quéguiner, Heterocycles, 1995, 40, 1055. 6) S. Marumoto; H. Kogen; S. Naruto, J. Org. Chem., 1998, 63, 2068. 7) A.F. Littke; G.C. Fu, Angew. Chem., Int. Ed., 1999, 38, 2411. 8) W.P. Gallagher; I. Terstiege; R.E. Maleczka, jr., J. Am. Chem. Soc., 2001, 123, 3194. 9) H. Tang; K. Menzel; G.C. Fu, Angew. Chem., Int. Ed., 2003, 42, 5079. 10) S.P.H. Mee; V. Lee; J.E. Baldwin, Angew. Chem., Int. Ed., 2004, 43, 1132. 11) P. Espinet; A.M. Echavarren, Angew. Chem., Int. Ed., 2004, 43, 4704. 12) W.P. Gallagher; R.E. Maleczka, jr., J. Org. Chem., 2005, 70, 841. 13) A. Herve; A.L. Rodriguez; E. Fouquet, J. Org. Chem., 2005, 70, 1953.

COMMENTS :

1647

STILLE CARBONYL SYNTHESIS EXAMPLE :

H3CO

I

+ CO + nBu3SnH

H3CO

CHO

(Ph3P)4Pd CO

MECHANISM :

OTf

O

. LiCl

L

SiMe3

Pd L

O LiOTf L L Pd Cl O

O

L Pd

CO

L

SiMe3

O n

Bu3SnCl

SiMe3

Bu3Sn O

O

L

O

L Pd Cl L

CO

Pd L Cl

DISCONNECTION : Ar

O Ar

I

Ar OTf

R

1648

L Pd L Cl

NOTES :

The synthesis of aryl ketones or aldehydes from aryl triflates or iodides and organo stannanes in the presence of CO and a palladium catalyst. See also Yamamoto ketone synthesis.

REFERENCES : Org. Synth. : 68, 116 Org. Synth. Coll. Vol. : 8, 97

1) V.P. Baillargeon; J.K. Stille, J. Am. Chem. Soc., 1983, 105, 7175. 2) A.M. Echavarren; J.K. Stille, J. Am. Chem. Soc., 1988, 110, 1557. 3) V. Jeanneret; L. Meerpoel; P. Vogel, Tetrahedron Lett., 1997, 38, 543. 4) E-i. Negishi; B. Liao, Heterocycles, 2000, 52, 1241. 5) C.S. Elmore; D.C. Dean; D.G. Melillo, J. Labelled Compd. Radiopharm., 2000, 43, 1135. 6) S.R. Dubbaka; P. Steunenberg; P. Vogel, Synlett, 2004, 1235.

COMMENTS :

STOBBE CONDENSATION EXAMPLE :

O EtO

O O

+

H3C

H3C CH3

OEt

1649

base

H3C

CO2Et CO2Et

MECHANISM :

O

O

O O

EtO

O

EtO H

OEt

R

R1

OEt

B O

B

H O

EtO

OEt

R R1

R

EtOOC R

O

R1

O

O

H+

R1

CO2Et CO2Et

DISCONNECTION :

R1

COOH

O

CO2R

+ R2

R1

COOH

R2

COOH

NOTES :

The base-catalysed condensation of aldehydes or ketones with an ester of succinic acid to give alkylidenesuccinic acids. If the ketone has an α-hydrogen atom an alkenylsuccinic acid may be obtained. The method enables a propionic acid residue to be introduced at the site of a carbonyl group in a molecule. See also Claisen – Geuther and Haworth reactions.

REFERENCES : March : 944 Smith – March : 1224 Smith : 901 Smith 2nd : 753 Houben – Weyl : 5/1b, 865; 5/1c, 536; E3, 645; E5, 412, 726; E6a, 953; E6b, 111 Org. React. : 6, 1; 8, 67 Org. Synth. : 9, 38; 30, 18 Org. Synth. Coll. Vol. : 1, 252; 4, 132 Science of Synthesis : 10, 67, 479, 719

1) H. Stobbe, Ber. Dtsch. Chem. Ges., 1893, 26, 2312. 2) W.S. Johnson; A.L. McCloskey; D.A. Dunnigan, J. Am. Chem. Soc., 1950, 72, 514. 3) R. Baker; P.H. Briner; D.A. Evans, J. Chem. Soc., Chem. Commun., 1978, 410. 4) F.A. Yassin; G.A. Ahmed; H.Y. Mostafa, J. Indian Chem. Soc., 1996, 73, 620. 5) J.W. Huffman; S. Yu, Bioorg. Med. Chem., 1998, 6, 2281. 6) A.M.A. Asiri; A. Cleeves; H.G. Heller, J. Chem. Soc., Perkin Trans. 1, 2000, 2741.

1650

7) J. Liu; N.R. Brooks, Org. Lett., 2002, 4, 3521.

COMMENTS :

STOERMER DEALKYLATION EXAMPLE :

OH O

48% aq. HBr AcOH, reflux

MECHANISM :

(R)2O + HBr + R1COOH

RBr + ROH + H2O O

ROH + R1COOH R1

OR

DISCONNECTION :

ROH + R1Br ROR1 R1OH + RBr

NOTES :

The dealkylation of alkylaromatic and dialkyl ethers is effected by the action of hydrogen bromide in acetic acid. See also Gustus cleavage, Mann dealkylation and Prey reaction.

REFERENCES : March : 433 Smith – March : 465, 519

1) R. Stoermer, Ber. Dtsch. Chem. Ges., 1908, 41, 321.

1651

2) R.L. Burwell, jr., Chem. Rev., 1954, 54, 615. 3) M.V. Bhatt; S.U. Kulkarni, Synthesis, 1983, 249. 4) M. Tiecco, Synthesis, 1988, 749.

COMMENTS :

STOLLÉ – BECKER SYNTHESIS EXAMPLE :

COOH Ph N H

N

1) (COCl)2, heat 2) NaOH

N

N

MECHANISM :

O

O

N H

N N

N

O O

O N

O

N

heat

(COCl)2

H+ NaOH

Cl

HOOC OH HN N

- H2O

1652

N

N

DISCONNECTION :

COOH Ar R N

R

N

+ NH2

R1

H O

NOTES :

Benzaldehyde-phenylhydrazone on treatment with oxalyl chloride yields an oxalylhydrazine which at 150 oC cyclises to N-(benzylidene-amino)-isatin. The latter on treatment with aqueous sodium hydroxide yields 3-phenylcinnoline-4carboxylic acid. See also Borsche – Koelsch, Neber – Bossell, von Richter cinnoline and Widman – Stoermer reactions.

REFERENCES :

1) R. Stollé; W. Becker, Ber. Dtsch. Chem. Ges., 1924, 57, 1123. 2) K. Schofield; J.C.E. Simpson, J. Chem. Soc., 1945, 512.

COMMENTS :

STOLLÉ SYNTHESIS EXAMPLE :

H CH3 O H N CH3

+

H Cl

Cl

1) HCl 2) AlCl3

1653

CH3 O

N CH3

MECHANISM :

AlCl3 R2

O

R1

O H

Cl

Cl

R1

HCl

Cl

Cl

R2

N R

H R1 R2

AlCl3 - HCl

Cl

R1 R2

N R

O

H R1

R2 O

O N R

N R

DISCONNECTION :

R1 +

O N R

N R

H

COOH

R1 X

NOTES :

In the presence of dry aluminium chloride aniline reacts with α-halogenocarboxylic acid chlorides to afford oxindoles. If oxalyl chloride is used, the intermediate can be cyclised in the presence of a Lewis acid to afford the isatin. See also von Baeyer oxindole, Brunner, Friedel – Crafts and Hinsberg reactions.

REFERENCES : Smith : 1346 Smith 2nd : 1107

1) R. Stollé, Ber. Dtsch. Chem. Ges., 1913, 46, 3915. 2) W.C. Stumpter, Chem. Rev., 1944, 34, 393. 3) W.C. Stumpter, Chem. Rev., 1945, 37, 443. 4) A.H. Beckett; R.W. Daisley; J. Walker, Tetrahedron, 1968, 24, 6093. 5) G. Loloiu; O. Maior, Rev. Roum. Chim., 1997, 42, 67. 6) J.F.M. da Silva; S.J. Garden; A.C. Pinto, J. Braz. Chem. Soc., 2001, 12, 273.

1654

COMMENTS :

STONE – WALES REARRANGEMENT EXAMPLE :

CH3I, 400 oC

MECHANISM :

NOTES :

The essence of this rearrangement is the transposition of two sp2-hybridised carbon atoms within a framework of other sp2-hybridised atoms.

REFERENCES :

1) R.W. Alder; G. Whittaker, J. Chem. Soc., Perkin Trans. 2, 1975, 712. 2) A.J. Stone; D.J. Wales, Chem. Phys. Lett., 1986, 128, 501. 3) B.R. Eggen; M.I. Heggie; G. Jungnickel; C.D. Latham; R. Jones; P.R. Briddon, Science, 1996, 272, 87. 4) P.I. Dosa; A. Schleifenbaum; K.P.C. Vollhardt, Org. Lett., 2001, 3, 1017. 5) Y. Kumeda; D.J. Wales, Chem. Phys. Lett., 2003, 374, 125. 6) R.W. Alder; J.N. Harvey, J. Am. Chem. Soc., 2004, 126, 2490.

COMMENTS :

1655

STORK – NISHIYAMA RADICAL CYCLISATION EXAMPLE :

H

H

1) H3C

O OH

H3C

Cl

O

Si OH

CH2Br

OH

Et3N 2) nBu3SnH AIBN heat, 4 h, C6H6 3) 30% H2O2 NaHCO3 MeOH, THF reflux

MECHANISM :

H

H H3C OH

H n

Cl Si

H3C Et3N

H

Br

Br Si

O

Bu3SnH AIBN heat 4 h, C6H6

H

O

Si

30% H2O2 NaHCO3 MeOH, THF reflux

H

OH OH

DISCONNECTION :

H

OR

OH H

OH

OH OR

NOTES :

(Bromomethyl)dimethylsilyl allylic ethers cyclise by treatment with n-tributyltin hydride in a free-radical process. Oxidation with hydrogenperoxide will give 1,2 or 1,3-diols with high stereoselectivity (Kumada – Tamao – Fleming oxidation). See also Kumada – Tamao – Fleming stereoselective hydroxylation.

1656

REFERENCES :

1) H. Nishiyama; T. Kitajima; M. Matsumoto; K. Itoh, J. Org. Chem., 1984, 49, 2298. 2) G. Stork; M. Kahn, J. Am. Chem. Soc., 1985, 107, 500. 3) G. Stork; P.M. Sher, J. Am. Chem. Soc., 1986, 108, 303. 4) M. Crimmins; R. O’Mahoney, J. Org. Chem., 1989, 54, 1157. 5) J. Lejeune; J.Y. Lallemand, Tetrahedron Lett., 1992, 33, 2977. 6) V. Pedretti; J.M. Mallet; P. Sinay, Carbohydr. Res., 1993, 244, 247. 7) P.R. Jenkins, Pure Appl. Chem., 1996, 68, 771.

COMMENTS :

STORK – UENO REACTION EXAMPLE :

Br n

EtO

O

Bu3SnH, AIBN 80 oC

EtO O

MECHANISM :

EtO

EtO

Br

O

O

H

O

H

OEt

H

n

Bu3SnH AIBN

H

EtO

EtO

O

O

H

EtO O

H +

1657

DISCONNECTION :

O H

O

OR

n

OR

n

H

Br

H

NOTES :

The free-radical cyclisation of bromoacetals to construct acetals and bicyclic lactones.

REFERENCES :

1) Y. Ueno; K. Chino; M. Watanabe; O. Moriya; M. Okawara, J. Am. Chem. Soc., 1982, 104, 5564. 2) G. Stork; R. Mook; S.A. Biller; S.D. Rychnovsky, J. Am. Chem. Soc., 1983, 105, 3741. 3) G. Stork; P.M. Sher; H.-L. Chen, J. Am. Chem. Soc., 1986, 108, 6384. 4) Y. Ueno; K. Chino; M. Watanabe; O. Moriya; M. Okawara, J. Chem. Soc., Perkin Trans. 1, 1986, 1351. 5) G. Stork, Bull. Chem. Soc. Jpn., 1988, 61, 149. 6) G. Stork, Bull. Soc. Chim. Fr., 1990, 127, 675. 7) F. Villar; O. Equey; P. Renaud, Org. Lett., 2000, 2, 1061.

COMMENTS :

STORK CYANOHYDRIN ALKYLATION EXAMPLE :

O

O

H O

EtO

1) KCN 2) 3)

OEt O

1658

CN

MECHANISM :

CN H O

CN

H 1) KCN 2) OEt

C6H13

C6H13

O OEt

1) LDA 2) C6H13Br

+

O

H

O

OEt

DISCONNECTION :

H

R O

O

NOTES :

The conversion of aldehydes to ketones via cyanohydrin derivatives by alkylation or Michael addition; also used with silyl ethers, dialkylaminonitriles. See also Stetter reaction.

REFERENCES : Org. React. : 31, 1

1) G. Stork; L. Maldonado, J. Am. Chem. Soc., 1971, 93, 5286. 2) S. Hünig; M. Öller, Chem. Ber., 1981, 114, 959. 3) J.D. Albright, Tetrahedron, 1983, 39, 3207. 4) G. Stork, Med. Res. Rev., 1999, 19, 370.

COMMENTS :

1659

STORK ENAMINE ALKYLATION AND ACYLATION EXAMPLE :

N N

O CN

1)

dioxane 2) H+

MECHANISM :

R X R N

H R

+

N

H3O

-X

R

H N OH2

R

H

O

N OH H

DISCONNECTION :

R R2

R1

N

R1 R2

O

NOTES :

α-Alkylation and acylation of ketones via enamines or imines and the Michael addition via enamines.

REFERENCES : March : 601 Smith – March : 787 Smith : 951 Smith 2nd : 792 Houben – Weyl : 7/2a, 473 Org. Synth. : 53, 59; 54, 39 Org. Synth. Coll. Vol. : 6, 592, 1014

1660

1) G. Stork; R. Terrell; J. Szumskovicz, J. Am. Chem. Soc., 1954, 76, 2029. 2) G. Stork; H. Landesman, J. Am. Chem. Soc., 1956, 78, 5128. 3) A. Doutheau; J. Gore, Tetrahedron Lett., 1972, 13, 4545. 4) J.K. Whitesell; M.A. Whitesell, Synthesis, 1983, 510. 5) J.J. Li; B.K. Trivedi; J.R. Rubin; B.D. Roth, Tetrahedron Lett., 1998, 39, 6111. 6) G. Stork, Med. Res. Rev., 1999, 19, 370. 7) B. Kempf; N. Hampel; A.R. Ofial; H. Mayr, Chem. Eur. J., 2003, 9, 2209.

COMMENTS :

STORK RADICAL CYCLISATION EXAMPLE :

EtOOC

EtOOC

COOEt

COOEt

+

n

Bu3SnH AIBN, hν

Br

EtOOC

COOEt

MECHANISM :

Br MeO2C MeO2C

CO2Me

NaOCH3 CH3OH

MeO2C

CH3

MeO2C

CH3 MeO2C

CH3

H

H H3C

H3C NaH THF

H

CO2Me CO2Me

Br CO2Me

H3C

H

H3C CO2Me n

Bu3Sn

MeO2C

n

Bu3SnH AIBN

Bu3Sn

CO2Me

MeO2C SiO2, DCM

1661

CO2Me

CH3

H

H

DISCONNECTION :

R

R

X

X

X n

n

R

NOTES :

The free radical cyclisation with preferential formation of cyclopentanes. The free radical reactions are synthetically useful as alternatives for producing C-C bonds. Vinyl radicals are valuable in the ring forming reactions since they place a double bond in a predictable position. They are compatible with many unprotected functional groups.

REFERENCES : Smith 2nd : 472 Org. Synth. : 66, 75 Org. Synth. Coll. Vol. : 8, 381

1) G. Stork; N.H. Baine, J. Am. Chem. Soc., 1982, 104, 2321. 2) G. Stork; R. Mook, jr., J. Am. Chem. Soc., 1987, 109, 2829. 3) G. Stork; F. West; H.Y. Lee; R.C.A. Isaacs; S. Manabe, J. Am. Chem. Soc., 1996, 118, 10660.

COMMENTS :

STORK REDUCTIVE CYCLISATION EXAMPLE :

O

OH CH2 THF

1662

MECHANISM :

O

O

R

O

R

R

OH

CH

R

CH2

THF H

H

DISCONNECTION :

OH CH2

O

H

R R

NOTES :

The cyclisation of acetylenic ketones to allyl alcohols by one electron reduction with Li in ammonia; also electrochemically (Shono) or by SmI2 (Molander) or with naphthalene anion radicals (Pradhan). See also Kagan – Molander reaction.

REFERENCES :

1) G. Stork; S. Malhotra; H. Thompson; M. Uchibayashi, J. Am. Chem. Soc., 1965, 87, 1148. 2) S.K. Pradhan; T.V. Radhakrishnan; R. Subramanian, J. Org. Chem., 1976, 41, 1943. 3) G. Stork; R.K. Boeckmann, jr.; D.F. Taber; W.C. Still; J. Singh, J. Am. Chem. Soc., 1979, 101, 7107. 4) G. Molander; C. Kenny, J. Am. Chem. Soc., 1989, 111, 8236.

COMMENTS :

1663

STORY MACROCYCLE SYNTHESIS EXAMPLE :

O

O +

1) H2O2 2) CuSO4 3) O

14

14

O

MECHANISM :

O O O O

2 H2O2

OOH OOH

O O

1) CuSO4 2) O

O

O O

O +

14

14

- H2O

O

DISCONNECTION :

k-2

O

k+l+m-3

+

O O O

O k+l+m-2

O

O O

l-2

m-2

NOTES :

The synthesis of large ring alkanes and lactones from smaller ring ketones via peroxides. The products have 3 and 2 carbon atoms less than the starting peroxide. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi

(Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

1664

REFERENCES : March : 1048 Smith – March : 1355

1) P.R. Story; D.D. Denson; C.E. Bishop; B.C. Clark; J.-C. Farine, J. Am. Chem. Soc., 1968, 90, 817. 2) P.R. Story; P. Bush, Adv. Org. Chem., 1972, 8, 67. 3) J.R. Sanderson; K. Paul; D.D. Denson; J.A. Alford, Synthesis, 1975, 159.

COMMENTS :

STRECKER AMINO ACID SYNTHESIS EXAMPLE :

O Et

H2N Et

1) NaCN, NH4Cl 2) NH4OH, H2O MeOH, 60 oC 3) H2O, HCl, heat 4) Pb(OH)2

1665

Et

COOH Et

MECHANISM :

O NH3 +

R

NH2 O + HCN

R

H

H

OH

2 H2O, - NH3 H+ or HOOH H R N H H

OH R

C N H

R NH3, - H2O

NH2 C N H

- H2O HCN R

H

R N

H

N

H

H

DISCONNECTION :

R2

N

R

R3

O R

CN

H

H R2

N

R

H + R2 N

R3

O

R3

R

CN

R1

R1

NOTES :

This is a special case of the Mannich reaction. Aldehyde-ammonia compounds are condensed with hydrogen cyanide and the resulting amino-nitrile is hydrolysed. The synthesis has been applied in a variety of forms to which special names (Tiemann) are sometimes applied. The Lewis acid asymmetric hydrocyanation is gaining special reverence since it provides rapid access to a library of valuable chiral building blocks. See also Bruylants, Bucherer, Corey – Link, Mannich, Tiemann, Ultee, Urech and Zelinsky – Stadnikoff reactions.

REFERENCES : March : 965 Smith – March : 1240 Smith : 678

1666

Smith 2nd : 575 Houben – Weyl : E5, 534, 543, 1425; E16d, 550, 1073, 1243 Org. Synth. : 4, 47; 9, 4; 11, 4; 22, 13, 23; 24, 9; 32, 50; 58, 101 Org. Synth. Coll. Vol. : 1, 21, 355; 2, 29; 3, 66, 84, 88; 4, 274; 6, 334

1) A. Strecker, Liebigs Ann. Chem., 1850, 75, 27. 2) E. Ware, Chem. Rev., 1950, 46, 403. 3) C. O’Connor, J. Chem. Soc., Quat. Rev., 1970, 24, 553. 4) F.A. Davis; R.E. Reddy; P.S. Portonovo, Tetrahedron Lett., 1994, 35, 9351. 5) M.S. Iyer; K.M. Gigstad; N.D. Namdev; M. Lipton, J. Am. Chem. Soc., 1996, 118, 4910. 6) E.J. Corey; M.J. Grogan, Org. Lett., 1999, 1, 157. 7) D. Enders; J.P. Shilvock, Chem. Soc. Rev., 2000, 29, 359. 8) W.H.J. Boesten; J.-P.G. Seerden; B. de Lange; H.J.A. Dielemans; H.L.M. Elsenberg; B. Kaptein; H.M. Moody; R.M. Kellogg; Q.B. Broxterman, Org. Lett., 2001, 3, 1121. 9) D. Enders; M. Moser, Tetrahedron Lett., 2003, 44, 8479. 10) U. Meyer; E. Breitling; P. Bisel; A.W. Frahm, Tetrahedron: Asymmetry, 2004, 15, 2029. 11) K. Matsumoto; J.C. Kim; H. Iida; H. Hamana; K. Kumamoto; H. Kotsuki; G. Jenner, Helv. Chim. Acta, 2005, 88, 1734.

COMMENTS :

1667

STRECKER DEGRADATION EXAMPLE :

O COOH H3C NH2 H

H3C

O

+

N H

H O

MECHANISM :

COOH R

O COOH R NH2 H

N H O

+ O

N H

N H R H

decarboxylation - CO2

H2N

N H

R

HO

hydrolysis

N H

O

+

HO N H

DISCONNECTION :

R

H

R

O

COOH NH2 H

NOTES :

Interaction of an α-amino acid with a carbonyl compound (Strecker used alloxan, an oxidation product of uric acid) in aqueous solution or suspension to give carbon dioxide and an aldehyde or ketone containing one less carbon atom. Inorganic oxidising agents can also be used to bring about the reaction. See also Herbst – Engels reaction.

REFERENCES : Houben – Weyl : 11/2, 322; E3, 533

1) A. Strecker, Liebigs Ann. Chem., 1862, 123, 363. 2) Th. Wieland, Angew. Chem., 1942, 55, 147. 3) A. Schönberg; R. Moubasher, Chem. Rev., 1952, 50, 261.

1668

4) T. Nyhammar; K. Olsson; P.A. Pernemalm, Acta Chem. Scand., 1983, B37, 879. 5) J. Koch; M. Pischetsrieder; K. Polborn; T. Severin, Carbohydr. Res., 1998, 313, 117.

COMMENTS :

STRECKER SULFITE ALKYLATION EXAMPLE :

H3C

I + (NH4)2SO3

NaI

H3C SO2O NH3

MECHANISM :

R CH2l + Na2SO3

R CH2SO3 Na + NaCl

NaI

DISCONNECTION :

RSO3 M + MX

RX + M2SO3

NOTES :

The sulfite alkylation of primary and sometimes secondary alkyl halogens with alkylsulfonic acids using a catalytic amount of sodium iodide. See also Kolbe reaction.

REFERENCES : March : 410 Houben – Weyl : 9, 372 Org. Synth. : 10, 96; 37, 55 Org. Synth. Coll. Vol. : 2, 558; 4, 529

1) A. Strecker, Liebigs Ann. Chem., 1868, 148, 90. 2) R.M. Reed; H.V. Tartar, J. Am. Chem. Soc., 1935, 57, 570.

1669

3) H.J. Backer; J. Strating; J.F.A. Hazenberg, Recl. Trav. Chim. Pays-Bas, 1953, 72, 813.

COMMENTS :

STRUKOV SYNTHESIS EXAMPLE :

NH2 CH2Cl + 2

O

N

1) H2O 2) KOH, Et2O

O

O

MECHANISM :

CH2Cl RNH2 + 2

H2O

O

Cl

R N HO

R N

OH

O

KOH, Et2O

Cl

O

DISCONNECTION :

R N

O

CH2Cl

RNH2 + O

O

NOTES :

Epichlorhydrin reacts with an arylamine hydrochloride in aqueous solution at room temperature to give the di(chlorohydroxy)amine, which on treatment with powdered alkali hydroxide in diethyl ether yields N,N-di-(2,3-epoxy-npropyl)arylamine.

REFERENCES :

1) T. Strukov, Khim. Farm. Prom., 1934, 11. (Chem. Abs., 1934, 28, 5421.)

1670

2) W. Davis; J.L. Everett; W.C.J. Ross, J. Chem. Soc., 1950, 1331. 3) R.F. Homer, J. Chem. Soc., 1950, 3690. 4) F.L. Rose; J.A. Hendry; A.L. Walpole, Nature, 1950, 165, 993.

COMMENTS :

STRYKER REGIOSELECTIVE REDUCTION EXAMPLE :

O H

OSiMe2Ph 3 mol% CuH·PPh3 1.3 PhMe2SiH toluene, RT

MECHANISM :

6 CuCl + 6 NaOtBu + 6 PPh3

H

O R

6 H2, Benzene RT, 24 h

[(Ph3P)CuH]6 + 6 NaCl + 6 tBuOH

LnCu R1

cat. CuH·PPh3 silane

O

O

SiLm O H R

CuH·PPh3

R1

O

CuH·PPh3 O OTMS

H CuH·PPh3 TMSCl

1671

+

R

SiLm R1

DISCONNECTION :

O R

SiR3 O R1

R

O SiR3

R1

RCHO

R

NOTES :

The regioselective conjugate reduction and reductive silylation of α,β-unsaturated ketones, esters, and aldehydes using stable copper(I)hydride cluster [(Ph3P)CuH]6 with or without a silane.

REFERENCES :

1) W.S. Mahoney; D.M. Brestensky; J.M. Stryker, J. Am. Chem. Soc., 1988, 110, 291. 2) D.M. Brestensky; D.E. Huseland; C. McGettingen; J.M. Stryker, Tetrahedron Lett., 1988, 29, 3749. 3) T.M. Koenig; J.F. Daeuble; D.M. Brestensky; J.M. Stryker, Tetrahedron Lett., 1990, 31, 3237. 4) P. Chiu; B. Chen; K.F. Cheng, Tetrahedron Lett., 1998, 39, 9229. 5) B.H. Lipschutz; W. Chrisman; K. Noson, J. Organomet. Chem., 2001, 624, 367. 6) P. Chiu; Z. Li; K.C.M. Fung, Tetrahedron Lett., 2003, 44, 455. 7) W.K. Chung; P. Chiu, Synlett, 2005, 55. 8) D-w. Lee; J. Yun, Tetrahedron Lett., 2005, 46, 2037.

COMMENTS :

STUFFER – BACKER DISULFONE HYDROLYSIS EXAMPLE :

O S O

O S O

NaOH

O Na S O

1672

+

O S O

CH2OH

MECHANISM :

O S O

O S O

O S O

O +

Na S O

CH2OH

OH

O H H R S Y O X H

RSO2H

X

H

H

Y

+

DISCONNECTION :

O NaS O

R(R1) +

O (R)R1 S

CH2OH

R1

O

O

O

X

H

H

Y

O

S

S O

R

O H H R S Y O X H

RSO2H +

NOTES :

γ-Disulfones when treated with alkali yield a hydroxysulfone and a sulfinate. If one of the 2 carbon atoms attached to the SO2 group has an electron withdrawing group on the α-poition and the β-carbon atom has acidic hydrogens elimination takes place.

REFERENCES : Houben – Weyl : 9, 257

1) R. Otto; H. Damköhler, J. Prakt. Chem., 1884, 30, 171. 2) E. Stuffer, Ber. Dtsch. Chem. Ges., 1890, 23, 3226. 3) H.J. Backer, Recl. Trav. Chim. Pays-Bas, 1950, 70, 92.

COMMENTS :

1673

SUÁREZ – HEUSLER – KALVODA REACTION EXAMPLE :

CO2Et O

OH O

EtO2C O

O

1) 3 PhIO, I2 benzene reflux 2) Ph3SnH

O

O HO

MECHANISM :

O

O

OH

EtO2C O

I

O

EtO2C

I

3 PhIO, I2 benzene reflux

O

O

I

O

O

CO2Et

OH

EtO2C

O O

O

O

O HO

2 RCOOH

(RCO2)IPh

2 RCO2I

2 RI + 2 CO2

DISCONNECTION :

R O

R OH

NOTES :

This reaction is the photoinduced conversion of hydroxyl-containing substrates with hypervalent iodine to the corresponding oxygen-centered radical. Heusler – Kalvoda used Pb(OAc)4, I2, CaCO3, light, while Suárez used diacetoxyiodobenzene, I2 and light. See also Hunsdiecker reaction.

REFERENCES :

1) K. Heusler; J. Kalvoda, Angew. Chem., Int. Ed. Engl., 1964, 3, 525. 2) J. Kalvoda; K. Heusler, Synthesis, 1971, 501.

1674

3) J.I. Concepción; C.G. Francisco; R. Hernández; J.A. Salazar; E. Suárez, Tetrahedron Lett., 1984, 25, 1953. 4) A. Martín; J.A. Salazar; E. Suárez, J. Org. Chem., 1986, 51, 402. 5) C.M. Hayward; M.J. Fisher; D. Yohannes; S.J. Danishefsky, Tetrahedron Lett., 1993, 34, 3989. 6) J.L. Courtneidge; J. Lusztyk; D. Pagé, Tetrahedron Lett., 1994, 35, 1003. 7) A. Kittaka; H. Kato; H. Tanaka; Y. Nonaka; M. Amano; K.T. Nakamura; T. Miyasaka, Tetrahedron, 1999, 55, 5319.

COMMENTS :

SUGASAWA INDOLE SYNTHESIS EXAMPLE :

NH2

1) ClCH2CN BCl3, AlCl3 heat 2) NaBH4 dioxane, H2O

N H

MECHANISM :

O Cl ClCH2CN BCl3, AlCl3 heat

NH2

NaBH4 dioxane H2O

NH2

OH

OH Cl H N H

NH2

1675

- H2O

N H

DISCONNECTION :

R

R N H

NH2

R = H, CH3, OBn, Cl, F, OCH3

NOTES :

Arylamines undergo Friedel – Crafts acylation ortho to the nitrogen atom. Up to 2 Lewis acids can be used. The ringclosure takes place after reduction of the ketone to a hydroxyl. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman

indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : Science of Synthesis : 10, 438

1) T. Sugasawa; M. Adachi; K. Sasakura; A. Kitagawa, J. Org. Chem., 1979, 44, 578. 2) M. Nimtz; G. Häflinger, Liebigs Ann. Chem., 1987, 765. 3) K. Sasakura; M. Adachi; T. Sugasawa, Synth. Commun., 1988, 18, 265.

COMMENTS :

1676

SUGASAWA INDOXYL SYNTHESIS EXAMPLE :

O

O

Cl N H

Ac

NaH DME 0 oC

N Ac

MECHANISM :

O

O

O Br

H N SO2Ph

CuBr2, CHCl3 EtOAc, heat

Et3N, 0 oC

H N SO2Ph

N SO2Ph

DISCONNECTION :

O

O X

R1 N R

R1 R = Ac, COCF3 R1 = H, Cl, OCH3

N H

R

NOTES :

The simple intramolecular displacement of a halide by the amino group will give indoxyls. Base affects the ringclosure.

REFERENCES : Science of Synthesis : 10, 621

1) T. Sugasawa; M. Adachi; K. Sasakura; A. Kitagawa, J. Org. Chem., 1979, 44, 578. 2) S.C. Conway; G.W. Gribble, Heterocycles, 1990, 30, 627.

1677

COMMENTS :

SUGASAWA REACTION EXAMPLE : O Cl

Cl NH2

Ph

1) BCl3 2) PhCN AlCl3

NH2

MECHANISM :

R Cl N B Cl Cl H

R X

N

BCl3

H

R1

R1CN MClx O

Cl N B Cl N R H

X

X

X

R1

MCl(X+1)

NH2

DISCONNECTION :

O X

R1

X

NH2

H N R

NOTES :

Ortho acylation of anilines by nitriles in the presence of BCl3 and a second Lewis acid appear to proceed through an

intermediate "supercomplex" including all four components. Yield improvements were obtained based on recognition that chloride affinity of the second Lewis acid governs supercomplex formation. Aniline protonation was found to be the cause of incomplete reaction.

1678

REFERENCES :

1) T. Sugasawa; T. Toyoda; M. Adachi; K. Sasakura, J. Am. Chem. Soc., 1978, 100, 4842. 2) M. Adachi; K. Sasakura; T. Sugasawa, Chem. Pharm. Bull., 1985, 33, 1826. 3) A.W. Douglas; N.L. Abramson; I.N. Houpis; S. Karady; A. Molina; L.C. Xavier; N. Yasuda, Tetrahedron Lett., 1994, 35, 6807.

4) I.N. Houpis; A. Molina; A.W. Douglas; L. Xavier; J. Lynch; R.P. Volante; P.J. Reider, Tetrahedron Lett., 1994, 35, 6811. 5) J.W. Coe; M.G. Vetelino; M.J. Bradlee, Tetrahedron Lett., 1996, 37, 6045.

COMMENTS :

SUNDBERG INDOLE SYNTHESIS EXAMPLE : N3 N3 toluene, 160 oC sealed tube

N3

N H

MECHANISM :

N3 toluene, 160 oC sealed tube

N3

N3

N3 N H

N

DISCONNECTION :

R R1

R1

R N H

N3

1679

NOTES :

The thermolysis of ortho-azidostyrenes and resulting cyclisation of the nitrene will afford indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman

indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

1) R.J. Sundberg; H.F. Russell; W.V. Ligon, jr.; L.-S. Lin, J. Org. Chem., 1972, 37, 719. 2) P. Kaszynski; D.A. Dougherty, J. Org. Chem., 1993, 58, 5209. 3) P. Molina; J. Alcántara; C. López–Leonardo, Tetrahedron, 1996, 52, 5833. 4) E.T. Pelkey; G.W. Gribble, Tetrahedron Lett., 1997, 38, 5603.

COMMENTS :

SURZUR – TANNER REARRANGEMENT EXAMPLE :

CH3 O H3C

CH2 O O

H

CCl3 CuCl, bpy (1:1, 2 eq.) DCE, reflux

1680

Cl

O

CH3 CH3

MECHANISM :

OAc

OAc

O

O AcO

Br

AcO

t

AcO

Bu3Sn

AcO

OAc

OAc

OAc

O

O AcO

OAc

OAc

t

Bu3SnH

AcO

OAc

AcO

AcO

DISCONNECTION :

X O

O X

O

R O

R

NOTES :

This is the intramolecular 1,2-suprafacial migration of the acyloxy group in β-acyloxyalkyl radicals. See also Schenck rearrangement.

REFERENCES : Org. Synth. : 69, 66 Org. Synth. Coll. Vol. : 8, 583

1) J.-M. Surzur; P. Teisser, C.R. Séances Acad Sci., Ser. C, 1967, 264, 1981. 2) D.D. Tanner; F.C. Law, J. Am. Chem. Soc., 1969, 91, 7537. 3) B. Giese; K.S. Gröninger; T. Witzel; H.-G. Korth; R. Sustmann, Angew. Chem., Int. Ed. Engl., 1987, 26, 233. 4) D. Crich; A.L.J. Beckwith; G.F. Filtzen; R.W. Longmore, J. Am. Chem. Soc., 1996, 118, 7422. 5) A.L.J. Beckwith; D. Crich; P.J. Duggan; Q. Yao, Chem. Rev., 1997, 97, 3273. 6) R.N. Ram; N.K. Meher, Org. Lett., 2003, 5, 145.

1681

COMMENTS :

SÜS REACTION EXAMPLE :

OH

COOH NH2 1) HNO2 HCl 2) hν

N

N H

MECHANISM :

OH

O NH2

N

N HNO2 HCl

O

N

N

N

O

O

N

N

- N2

N O C

COOH

H2O

N

DISCONNECTION :

OH

COOH

NH2 N H

N

NOTES :

The ring-contraction of 6-membered 1,2-amino alcohols. See also Wolff rearrangement.

REFERENCES :

1) O. Süs, Liebigs Ann. Chem., 1944, 556, 65. 2) R. Huisgen, Angew. Chem., 1955, 67, 459.

1682

N

N H

3) O. Süs; K. Möller, Liebigs Ann. Chem., 1955, 593, 91. 4) L. Horner; K.H. Weber, Chem. Ber., 1962, 95, 1227.

COMMENTS :

SUZUKI – MIYAURA VINYL COUPLING EXAMPLE :

HOOC

HOOC

Br B(OH)2

+

N

Pd(PPh3)4, Na2CO3 aq. CH3CN, 90 oC

N

MECHANISM :

R1 X reductive elimination

Pd0Ln

oxidative addition

R1 R2 X PdIILn

R2 PdIILn

R1

R1

M R2 X M

X PdIILn R1 transmetallation

1683

R2 M

DISCONNECTION :

R R1

R BY2

+

R1 X

BY2 = B(OR)2, 9_BBN X = I, Br, Cl, OSO2(CnF2n+1), n = 0, 1, 4 R = Ar, Alk, Alkenyl R1 = Ar, Alk, Alkenyl, Alkynyl, Allyl, Benzyl

NOTES :

Trialkylboranes resulting from the addition of 9-BBN to terminal alkenes or alkynes can be combined with aryl-X or alkenyl-X compounds (X = Br, I, OTf) via palladium catalysed Suzuki coupling. This reaction is less expensive and less toxic alternative to the Stille coupling. Depending on the leaving group, the oxidative addition can be the rate determining step. The reaction is performed under basic conditions (Na2CO3, NaOEt, Et3N, TlOH). There are watersoluble Suzuki catalysts known. Recently palladium has been substituted for nickel. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Liebeskind – Srogl, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi, Yamamoto

macrolactonisation and Yamamoto ketone reactions.

REFERENCES : Smith – March : 868 Smith 2nd : 476, 1123 Org. Synth. : 68, 130; 71, 89; 75, 53, 61, 69, 129; 77, 176 Org. Synth. Coll. Vol. : 8, 532; 9, 107 Science of Synthesis : 9, 257, 373, 527; 10, 420, 735

1) N. Miyaura; K. Yamada; A. Suzuki, Tetrahedron Lett., 1979, 20, 3437. 2) A. Suzuki, Pure Appl. Chem., 1991, 63, 419. 3) N. Miyaura; A. Suzuki, Chem. Rev., 1995, 95, 2457. 4) A. Godard; F. Marsais; N. Plé; F. Trécourt; A. Turck; G. Quéguiner, Heterocycles, 1995, 40, 1055. 5) A.N. Cammidge; K.V.L. Crépy, Chem. Commun., 2000, 1723. 6) B. Zhishan; A.D. Schlűter, Chem. Eur., 2000, 6, 3235. 7) S.A. Frank; H. Chen; R.K. Kunz; M.J. Schnaderbeck; W.R. Roush, Org. Lett., 2000, 2, 2691. 8) A.-S. Castanet; F. Colobert; T. Schlama, Org. Lett., 2000, 2, 3559. 9) S. Sakamuri; C. George; J. Flippen–Anderson; A.P. Kozikowski, Tetrahedron Lett., 2000, 41, 2055. 10) P. Lloyd–Williams; E. Giralt, Chem. Soc. Rev., 2001, 30, 145. 11) T.E. Pickett; C.J. Richards, Tetrahedron Lett., 2001, 42, 3767. 12) S. Kotha; K. Lahiri; D. Kashinath, Tetrahedron, 2002, 58, 9633.

1684

13) M.D. Smith; A.F. Stephan; C. Ramarao; P.E. Brennan; S.V. Ley, Chem. Commun., 2003, 2652. 14) J.T. Singleton, Tetrahedron, 2003, 59, 1837. 15) A.-E. Wang; J. Zhong; J.-H. Xie; K. Li; Q.-L. Zhou, Adv. Synth. Catal., 2004, 346, 595. 16) C.J. Mathews; P.J. Smith; T. Welton, J. Mol. Catal. A: Chem., 2004, 214, 27. 17) V. Percec; G.M. Golding; J. Smidrkal; O. Weichold, J. Org. Chem., 2004, 69, 3447. 18) S. Kotha; K. Mandal; K.K. Arora; V.R. Pedireddi, Adv. Synth. Catal., 2005, 347, 1215.

COMMENTS :

SUZUKI (KYODAI) REACTION EXAMPLE :

NO2

NO2, O3 - 78 oC

MECHANISM :

NO3

NO2, O3 O

NO2 O

O CH3

OH

CH3

CH3 NO3

OH

1685

NO2

OH

NO2 + O3

NO3 + O2

ArH + NO3

ArH

ArH

+

+

+ NO3-

Ar(H)NO2+

+ NO2

NO3 + NO2

- H+

N2O5

+

H

ArNO2 NO2+ + HNO3

DISCONNECTION :

RNO2

RH R = Ar

NOTES :

Nitrogen dioxide is activated in the presence of ozone and joins mainly aromatic moieties as a nitro group at low temperature.

REFERENCES : Smith – March : 696

1) H. Suzuki; T. Murashima; K. Shimizu; K. Tsukamoto, Chem. Lett., 1991, 817. 2) T. Mori; H. Suzuki, Synlett, 1995, 383. 3) H. Suzuki; J. Murashima, J. Chem. Soc., Perkin Trans. 1, 1994, 903. 4) H. Suzuki; N. Nonoyama, Chem. Commun., 1996, 1783.

COMMENTS :

1686

SUZUKI REDUCTION EXAMPLE :

CN NaBH4, CoCl2 EtOH

NH2

DISCONNECTION :

RCH2NH2

RCN

NOTES :

The reduction of nitriles, amides, nitro compounds by sodium borohydride in the presence of cobalt dichloride to the corresponding primary amines. It is not clear what the exact nature is of the reducing species.

REFERENCES : March : 918 Smith – March : 1204

1) T. Satoh; S. Suzuki; Y. Suzuki; Y. Miyaji; Z. Imai, Tetrahedron Lett., 1969, 10, 4555. 2) A-u. Rahman; M. Ghazala; N. Sultana; M. Bashir, Tetrahedron Lett., 1980, 21, 1773. 3) S.W. Heinzmann; B. Ganem, J. Am. Chem. Soc., 1982, 104, 6801. 4) J.P. Williams; D.R. St. Laurent; D. Friedrich; E. Pinard; B.A. Roden; L.A. Paquette, J. Am. Chem. Soc., 1994, 116, 4689. 5) L.W. Deady; C.L. Smith, Aust. J. Chem., 2001, 54, 135.

COMMENTS :

1687

SWARTS REACTION EXAMPLE :

3 CCl4

1) 2 SbF3 2) 6 HF

3 CF2Cl2

MECHANISM :

3 CCl4 + 2 SbF3

2 SbCl3 + 3 CCl2F2

6 HF + 2 SbCl3

2 SbF3 + 6 HCl

DISCONNECTION :

RCClF2 RCCl3

RCCl2F

RCHClF

RCHCl2

NOTES :

C-F bonds can be formed by the stoichiometric reaction of SbF3 with activated C-Cl bonds. Trace amounts of SbF5 are required. See also Gryszkiewicz – Trochimowski – McCombie reaction.

REFERENCES : Org. React. : 2, 49

1) F. Swarts, Bull. Acad. Royal Belg., 1892, 24, 309. 2) H.W. Daudt; M.A. Youker, U.S. Patent, 1935, 2005705. (Chem. Abs., 1935, 29, 5123.) 3) T. Midgley, jr.; A.L. Henne; R.R. McNary, U.S. Patent, 1935, 2007208. (Chem. Abs., 1935, 29, 5459.) 4) A.L. Henne; A.M. Whalley; J.K. Stevenson, J. Am. Chem. Soc., 1941, 63, 3478.

COMMENTS :

1688

SWERN OXIDATION EXAMPLE :

CH3

CH3 TFAA - 50 oC, DMSO

OH

O

MECHANISM :

CH3 H3C

(CH3)2SO

S O

CO2Cl2

Cl O

Cl

O

(CH3)2SCl + Cl + CO + CO2

R R1

R R1

OH

R

O

CH3 S H CH 3

base

R1

O

O

CH2 S H CH 2

R1

R

DISCONNECTION :

R

R1

R

O

R1 OH

NOTES :

The oxidation of alcohols using DMSO and oxalyl chloride or trifluoroacetic anhydride to aldehydes or ketones in the presence of other groups. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Sarett

and Uemura reactions.

REFERENCES : March : 1194

1689

Smith – March : 1516 Smith : 239 Smith 2nd : 204, 540, 550 Houben – Weyl : E6b, 877 Org. React. : 39, 297; 53, 1 Org. Synth. : 64, 164; 66, 14; 70, 120; 76, 110; 77, 64 Org. Synth. Coll. Vol. : 7, 258; 8, 501; 9, 692

1) K. Omura; D. Swern, Tetrahedron, 1978, 34, 1651. 2) A.J. Manusco; S.-L. Huang; D. Swern, J. Org. Chem., 1978, 43, 2480. 3) D. Keirs; K. Overton, Chem. Commun., 1987, 1660. 4) T.T. Tidwell, Synthesis, 1990, 857. 5) L. Gentilucci; Y. Grijzen; L. Thijs; B. Zwanenburg, Tetrahedron Lett., 1995, 36, 4665. 6) J.M. Harris; Y. Li; S. Chai; M.D. Andrews; J.C. Vederas, J. Org. Chem., 1998, 63, 2407. 7) D. Crich; S. Neelamkavil, J. Am. Chem. Soc., 2001, 123, 7449. 8) D. Crich; S. Neelamkavil, Tetrahedron, 2002, 58, 3865. 9) K. Nishide; S.-I. Ohsugi; M. Fudesaka; S. Kodama; M. Node, Tetrahedron Lett., 2002, 43, 5177.

COMMENTS :

SZARVASY – SCHÖPF CARBOMETHOXYLATION EXAMPLE :

Ph

CH3 +

Ph

O

CO2 OCH3

N O

O H3CO Mg

1690

H N H

Ph Ph O

MECHANISM : O Mg

(MeO)2Mg

MeOH heat

H3 C

CO2 DMF

O

Mg O

O

CH3

Mg O R

O CH3

R

O H3C

Mg O

O

O

O

O

N R

O H

CH3

O

O

O N H

R

R N H

- CO2

O

O

O

DISCONNECTION :

O n

N H

O n

R n = 0, 1

N

+

R

CH3

NOTES :

The carboxylation of activated CH groups with MMMC (methoxy magnesium methyl carbonate) (Szarvasy) and addition of the resulting activated ketones to C=N bonds (Schöpf).

REFERENCES :

1) E. Szarvasy, Ber. Dtsch. Chem. Ges., 1897, 30, 1836. 2) C. Schöpf; A. Komzak; F. Braun; E. Jacobi, Liebigs Ann. Chem., 1948, 559, 1. 3) C. Schöpf, Angew. Chem., 1949, 61, 31. 4) C. Schöpf; H. Arm; H. Krimm, Chem. Ber., 1951, 84, 690. 5) C. Schöpf; F. Braun; K. Burkhardt; G. Dummer; H. Müller, Liebigs Ann. Chem., 1959, 626, 123. 6) J.M. Grisar; G.P. Claxton; K.T. Stewart, Synthesis, 1974, 284. 7) W.H. Parsons; R.H. Schlessinger; M.L. Quesada, J. Am. Chem. Soc., 1980, 102, 889.

COMMENTS :

1691

1692

TIEMANN REARRANGEMENT · 1718 TIFFENEAU – DEMJANOV RING ENLARGEMENT · 1719

E

TIFFENEAU SYNTHESIS · 1721 TIMMIS PTERIDINE SYNTHESIS · 1722

EVANS – TISCHTSCHENKO REDUCTION · 1726

TIPSON – COHEN OLEFINATION · 1723 TISHCHENKO – CLAISEN REACTION · 1725 T

TOLLENS ADDITION · 1726 TORGOV SYNTHESIS · 1728

TABOURY SYNTHESIS · 1694

TRAHANOVSKY ETHER OXIDATION · 1731

TAFEL REARRANGEMENT · 1695

TRAUBE PURINE SYNTHESIS · 1732

TAKEDA REACTION · 1696

TREIBS ALLYLIC OXIDATION · 1733

TANIGAWA REACTION · 1698

TROFIMOV PYRROLE SYNTHESIS · 1735

TANIGUCHI REACTION · 1699

TROST – CHEN DECARBOXYLATION · 1737

TÄUBER SYNTHESIS · 1700

TROST CYCLOPENTANATION · 1738

TAYLOR SYNTHESIS · 1702

TROST DESYMMETRISATION · 1740

TEBBE OLEFINATION · 1703

TROST OXIDATIVE DECARBOXYLATION · 1741

TEUBER QUINONE SYNTHESIS · 1705

TSCHUGAEFF (CHUGAEV) OLEFIN SYNTHESIS · 1743

THIELE – DIMROTH SYNTHESIS · 1708

TSUGE REACTION · 1744

THIELE – WINTER QUINONE ACETOXYLATION · 1709

TSUJI – TROST ALLYLATION · 1746

THIELE FULVENE SYNTHESIS · 1710

TSUJI – WACKER OLEFIN OXIDATION · 1747

THOMAS REACTION · 1712

TSUJI – WILKINSON REACTION · 1750

THORPE – ZIEGLER REACTION · 1713

TWITCHELL PROCESS · 1751

THYAGARAJAN INDOLE SYNTHESIS · 1715

TYRER SULFONATION PROCESS · 1752

TIEMANN AMINATION · 1716

1693

TABOURY SYNTHESIS EXAMPLE :

ArMgX +

Ar

Se

Se Ar

1) Et2O 2) aq. HCl

ArSeH

MECHANISM :

ArMgX + Se

ArSeMgX Et2O

HX

ArSeH + MgX2

DISCONNECTION :

ArSeX

ArMgX

NOTES : An aromatic Grignard compound is treated in diethyl ether with selenium to give an aryl selenium magnesium halide, which with a hydrohalic acid yields the selenophenol. See also Grignard reaction.

REFERENCES : Houben – Weyl : 9, 958 Org. Synth. : 24, 89 Org. Synth. Coll. Vol. : 3, 771

1) M. Taboury, Bull. Soc. Chim. Fr., 1903, 29, 761. 2) H. Wuyts, Bull. Soc. Chim. Fr., 1906, 35, 166. 3) D.G. Foster; S.F. Brown, J. Am. Chem. Soc., 1928, 50, 1184. 4) T. Jayachandran; T. Manimaran; V.T. Ramakrishnan, Indian J. Chem., 1984, 23B, 328. 5) R.V. Bonnert; P.R. Jenkins, J. Chem. Soc., Perkin Trans. 1, 1989, 413.

1694

COMMENTS :

TAFEL REARRANGEMENT EXAMPLE :

Et

O

Et

Et

Pr O

O CH3

Pb reduction

H

H

MECHANISM :

H3C

H3C

O OEt

O

O OEt

Pb-electrode

H3C Pb-electrode

H

CH3

CH3 O

CH3 OEt

DISCONNECTION :

R

H3C

O

R1 CH3 R

R1

H3C

H

R O

EtO

R1

NOTES : Substituted acetoacetic acid and similar ketonic compounds when submitted to cathodic (lead) reduction give hydrocarbons with rearranged carbon skeletons. Both the oxo and carboxyl groups are reduced to methylene and methyl groups.

1695

REFERENCES : Houben – Weyl : 5/1a, 280, 471

1) J. Tafel; H. Hahl, Ber. Dtsch. Chem. Ges., 1907, 40, 3312. 2) J. Tafel; W. Jürgen, Ber. Dtsch. Chem. Ges., 1909, 42, 2548. 3) J. Tafel, Ber. Dtsch. Chem. Ges., 1912, 45, 437. 4) H. Stenzl; F. Fichter, Helv. Chim. Acta, 1934, 17, 669. 5) H. Stenzl; F. Fichter, Helv. Chim. Acta, 1936, 19, 392. 6) H. Stenzl; F. Fichter, Helv. Chim. Acta, 1937, 20, 846.

COMMENTS :

TAKEDA REACTION EXAMPLE :

PhS Ph

O

SPh H

+

EtO

Ph

Ph

Ph OEt

2 (CH3O)2P Ti P(OCH3)2

MECHANISM :

RS R3

R4

- Cp2Ti=O

R3

R4

SR 2 Cp2Ti(P(OEt)3)2 - Cp2Ti(SR)2 R2

R4

R1

R3

Cp2Ti

R3

O R1

1696

Cp2Ti O R2

R4 R2 R1

RS

SR

R3

R4

2 Cp2Ti(P(OEt)3)2 - Cp2Ti(SR)2

SR Cp2Ti

SR TiCp2 O

R3 R4 R1

- (RSCp2Ti)2O

R2

R4

R1

R3

RS

R1 Cp2 Ti O

R2Cp2 Ti SR R4 R3

R2

DISCONNECTION :

R2

R4

RS

SR

R1

R3

R1

R2

O +

R3

R4

NOTES : The Takeda reaction solves the problems of the Nozaki – Hiyama – Kishi (Takai – Utimoto) reaction. The major drawback is the difficult access to substituted dihalomethane compounds. Dithioacetals however are very easily accessible. The reaction proceeds smoothly with aldehydes, ketones, esters but also with olefins, which are cyclopropanated and symmetrically disubstituted alkynes to afford trisubstituted 1,3-dienes. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Tebbe and Wittig reactions.

REFERENCES : 1) T. Takeda; H. Shimokawa; Y. Miyachi; T. Fujiwara, Chem. Commun., 1997, 1055. 2) Y. Horikawa; M. Watanabe; T. Fujiwara; T. Takeda, J. Am. Chem. Soc., 1997, 119, 1127. 3) Y. Horikawa; T. Nomura; M. Watanabe; T. Fujiwara; T. Takeda, J. Org. Chem., 1997, 62, 3678. 4) B. Breit, Angew. Chem., Int. Ed., 1998, 37, 453.

COMMENTS :

1697

TANIGAWA REACTION EXAMPLE :

CH2OH

1) NaH, DMF 2) Ph3P+N(CH3)PhI-, C4H9NCH3, DMF

N CH3 Bu

MECHANISM :

Ph3P_NR1R2 I

Ph3

RO

HNR3R4 - HNR1R2

NR3R4 I P NMe2 O

NMe2 H NR3R4

Ph3P_NR3R4 I HCONMe2

R3R4NCHNMe2

NMe2 RO H OR

HNR3R4

I

RONa - NaI

RNR3R4

DISCONNECTION :

RNR3R4

Ph3P_NR1R2 I

+ HNR3R4

NOTES : The Tanigawa reaction has been widely cited in numerous reviews and textbooks. Unfortunately, there has been no report by any worker that has made any amine by this method since the originally work was published. This is because this reaction does not work under the reaction conditions reported by Tanigawa et al.

REFERENCES : March : 414 Smith – March : 502

1698

1) Y. Tanigawa; S.L. Murahashi; I. Moritani, Tetrahedron Lett., 1975, 16, 471. 2) P. Frøyen; J. Skramstad, Tetrahedron Lett., 1998, 39, 6387.

COMMENTS :

TANIGUCHI REACTION EXAMPLE :

N H 4

N H

N

N

1) HCHO K2CO3 2) DDQ

H N

MECHANISM :

N H

2 HCHO K2CO3 5 oC, 7 days

excess

N H

HO

OH N H 0.15 equiv. HCl < 5 oC, 30 min

N H N

N N H

N H

N 1) H HO

N H

H N OH

BF3, MeOH, RT 2) 2,3,5,6-tetrachloro-p-benzoquinone 30 min, reflux

1699

DISCONNECTION :

N H N

N

N H

H N

NOTES : The reaction between 2,5-bis(hydroxymethyl)pyrrole and pyrrole in the presence of hydrochloric acid affords tripyrrane, which gives porphyrins by the standard [3+1] MacDonald condensation. See also Adler – Longo, Lindsey, MacDonald, and Rothemund reactions.

REFERENCES : S. Taniguchi; H. Hasegawa; M. Nishimura; M. Takahashi, Synlett, 1999, 73.

COMMENTS :

TÄUBER SYNTHESIS EXAMPLE :

H2N

NH2 NH2

NH2

18% HCl 180 - 190 oC

1700

NH2

H2N N H

MECHANISM :

H2N

NH2 NH2

- NH3

NH2

H2N N NH3 H

NH2 H+

H2N

NH2 N H

DISCONNECTION :

H2N

H2N

NH2 N H

NH2 NH2

NH2

NOTES : Carbazoles are obtained by heating 2,2’-diaminodiphenyls with mineral acid or phosphoric acid at 180 – 190 oC. See also Borsche – Drechsel, Bucherer carbazole and Graebe – Ullmann reactions.

REFERENCES : Houben – Weyl : E6a, 932 Science of Synthesis : 10, 710

1) E. Täuber, Ber. Dtsch. Chem. Ges., 1890, 23, 3266. 2) F.E. King; F.J. King, J. Chem. Soc., 1945, 824. 3) H. Leditschke, Chem. Ber., 1953, 86, 522. 4) T. Yamamoto; C. Hideshima; K. Suehiro; M. Tashiro; G.K.S. Prakash; G.A. Olah, J. Org. Chem., 1991, 56, 6248.

COMMENTS :

1701

TAYLOR SYNTHESIS EXAMPLE :

O

O

O NH2

H2N

CH3

+

1) AcOH, RT 2) NH

N OH

CN

H H2N

2

H2N

N

N N

CH3

N O

NH

CH3OH, DMF heat

MECHANISM :

N

C

NH2 C N

O

NC

Cl

N OH

RCHO Et3N CHCl3

2-propanol - H2O NC

N

H2N

N O

H2N

N

PPh3 DMF

N O

R H

Cl

PCl3 THF RT

NC

N

H2N

N

NC

N

H2N

N O

P(Ph)3Cl

R H

H2N

N

H

NH2

NH2

H2N

R

N

N N

N

H

DISCONNECTION : NH2 N

N H2N

R NC

N

N

NH2 R H + O CN

N

OH

NOTES : Another pteridine synthesis using 2-malononitrile and 2-oxoalkanal oximes as reagents. See also Blicke – Pachter, Boon – Polonovski, Isay and Timmis reactions.

1702

REFERENCES : 1) E.C. Taylor; T. Kobayashi, J. Org. Chem., 1973, 38, 2817. 2) E.C. Taylor; R.F. Abdulla, Tetrahedron Lett., 1973, 14, 2093. 3) E.C. Taylor; R.C. Portnoy; D.C. Hochstetter; T. Kobayashi, J. Org. Chem., 1975, 40, 2347. 4) H. Bader; A. Rosowsky, J. Org. Chem., 1991, 56, 3386. 5) A. Rosowsky; R.A. Forsch; V.E. Reich; J.H. Freisheim; R.G. Moran, J. Med. Chem., 1992, 35, 1578. 6) A. Rosowsky; R.A. Forsch; R.G. Moran, J. Heterocycl. Chem., 1996, 33, 1355.

COMMENTS :

TEBBE OLEFINATION EXAMPLE :

CH2

O H3C

OEt

H2 C Cp2Ti AlMe2 Cl toluene, pyridine

H3C

OEt

MECHANISM :

Cp2TiCl2 + 2 AlMe3 toluene, RT - CH4, - AlMe2Cl t

Bu t

Bu O

O

H2 C Cp2Ti

H2 C Cp2Ti AlMe2 Cl

Cp2Ti

AlMe2 Cl

t

Bu

1703

Cp2Ti

DISCONNECTION : CH2

O R

R

R1

R1

NOTES : This is the synthesis of terminal olefins from ketones or esters via a titanium methylene transfer reagent. Takai and Lombardo published a still undefined reagent that accomplishes methylation and alkylidenation of carboxylic acid derivatives including silyl esters. The catalyst is also used for olefin metathesis. See also Corey – Kwiatkowski, Eastwood, Horner – Wadsworth – Emmons, Julia – Paris – Kocienski – Lythgoe, Krief – Reich – Chow, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Paquette, Petasis reaction, Peterson, Ramberg – Bäcklund, Still – Gennari, Takeda and Wittig reactions.

REFERENCES : March : 933 Smith – March : 1237 Smith : 813 Smith 2nd : 679 Org. React. : 43, 1 Org. Synth. : 65, 81; 69, 72 Org. Synth. Coll. Vol. : 8, 386, 512

1) F.N. Tebbe; G.W. Parshall; G.S. Reddy, J. Am. Chem. Soc., 1978, 100, 3611. 2) K. Takai; Y. Hotta; K. Oshima; H. Nozaki, Tetrahedron Lett., 1978, 19, 2417. 3) L. Lombardo, Tetrahedron Lett., 1982, 23, 4293. 4) S.E. Kelly, Comp. Org. Syn., 1991, 1, 743. 5) S.H. Pine; G.S. Shen; H. Hoang, Synthesis, 1991, 165. 6) C.P. Ball; A.G.M. Barrett; A. Commercon; D. Compere; C. Kuhn; R.S. Roberts; M.L. Smith; O. Venier, Chem. Commun., 1998, 2019. 7) R.C. Hartley; G.J. McKiernan, J. Chem. Soc., Perkin Trans. 1, 2002, 2763. 8) M.E. Jung; J. Pontillo, Tetrahedron, 2003, 59, 2729. 9) X. Lu; G. Arthur; R. Bittman, Org. Lett., 2005, 7, 1645. 10) D.J. Chambers; G.R. Evans; A.J. Fairbanks, Tetrahedron, 2005, 61, 7184.

COMMENTS :

1704

TEUBER QUINONE SYNTHESIS EXAMPLE : OH

O CH3

H3C

CH3 H3C

(KSO3)2NO NaOH

CH3

CH3 O

MECHANISM :

NH2 R1

R

ON(SO3K)2 - HON(SO3K)2

NH R1

NH R

R1

NH R

R1

R

H NH

NH

R1

R

R1

R

- HN(SO3K)2

ON(SO3K)2 H

ON(SO3K)2

O R1

R

H2O O

1705

O

OH

R

ON(SO3K)2 - HON(SO3K)2

O

O

O

R

R

H

R

R=H ON(SO3K)2

ON(SO3K)2

O

O H ON(SO3K)2

H ON(SO3K)2

R

- HN(SO3K)2

- HN(SO3K)2

O

O O

O

R

1706

DISCONNECTION :

O R1

NH2

R

R1

R

O O

OH O O R

O

NOTES : The oxidation of phenols and anilines derivatives to quinones using potassium nitrosodisulfonate (Fremy’s salt). See also Adler phenol oxidation.

REFERENCES : March : 1171 Smith – March : 1518 Smith : 256 Smith 2nd : 221 Org. Synth. : 52, 83, 88 Org. Synth. Coll. Vol. : 6, 480, 1010

1) H.-J. Teuber; G. Jellinek, Chem. Ber., 1952, 85, 95. 2) H.-J. Teuber; W. Rau, Chem. Ber., 1953, 86, 1036. 3) H. Zimmer; D.C. Lankin; S.W. Horgan, Chem. Rev., 1971, 71, 229. 4) A.P. Kozikowski; K. Sugiyama; J.P. Springer, J. Org. Chem., 1981, 46, 2426. 5) J.A. Hadfield; A.T. McGown; J. Butler, Molecules, 2000, 5, 82.

COMMENTS :

1707

THIELE – DIMROTH SYNTHESIS EXAMPLE :

H2N

HCl 170 - 180 oC

NH2

N H

MECHANISM :

H

NH2

H2N

N HCl 170 - 180 oC

NH2

+

NH2

N H

DISCONNECTION : R

R1

H2N

NH2

(R1)R N H

NOTES : A mixture of equimolecular amounts of 2,2’-diaminostilbene and its anhydrous dihydrochloride, when heated at 170 – 185 oC yields indole and aniline. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : J. Thiele; O. Dimroth, Ber. Dtsch. Chem. Ges., 1895, 28, 1411.

1708

COMMENTS :

THIELE – WINTER QUINONE ACETOXYLATION EXAMPLE : OAc

O

OAc

O Ac2O BF3.Et2O

OAc

MECHANISM :

O

O

O

H Ac2O

H+ O

OH

OH H

O H3C OH

O H

H3CO

H3C O

CH3

O O

O

H O OH

O

Ac2O O

OH

O

OCH3 O

DISCONNECTION :

O

OAc OAc R

R

O

OAc

1709

NOTES : The synthesis of triacetoxyaryl derivatives from quinones and derivatives catalysed by sulfuric acid or boron trifluoride. See also Hinsberg sulfone reaction.

REFERENCES : Houben – Weyl : 4/2, 40; E5, 55 Org. React. : 19, 199

1) J. Thiele, Ber. Dtsch. Chem. Ges., 1898, 31, 1247. 2) J. Thiele; E. Winter, Liebigs Ann. Chem., 1900, 311, 341. 3) H. Erdtman, proc. Roy. Soc., Ser. A, 1934, 143, 177. 4) J.M. Blatchly; J.F.W. McOmie, J. Chem. Soc., 1963, 5311. 5) M. Hirama; S. Ito, Chem. Lett., 1977, 627. 6) D. Villemin; N. Bar; M. Hammadi, Tetrahedron Lett., 1997, 38, 4777.

COMMENTS :

THIELE FULVENE SYNTHESIS EXAMPLE :

H3C Ph +

H3C

H3C

O H3C

NaOH EtOH

1710

Ph

MECHANISM :

H

R1 H

H

H NaOEt

R1

O

R2

R1

R2

O OH R2

NaOEt

R1

R2

- OH

DISCONNECTION :

R1

R2

H

H +

R1

R2 O

NOTES : 1,3-Cyclopentadiene reacts with aldehydes and ketones in the presence of sodium ethoxide or sodium hydroxide in ethanol. The base not only deprotonates but also catalyses the dehydration of the primary adduct via the substituted cyclopentadienide. See also Nesmanjanov fulvene reaction.

REFERENCES : 1) J. Thiele, Ber. Dtsch. Chem. Ges., 1900, 33, 666. 2) J. Thiele; H. Balhorn, Liebigs Ann. Chem., 1906, 348, 1. 3) J. Thiec; J. Wiemann, Bull. Soc. Chim. Fr., 1956, 177. 4) J. Thiec; J. Wiemann, Bull. Soc. Chim. Fr., 1960, 1066. 5) R.D. Little; K.J. Stone, J. Org. Chem., 1984, 49, 1849. 6) I. Erden; F.-P. Xu; A. Sadoun; W. Smith; G. Sheff; M. Ossun, J. Org. Chem., 1995, 60, 813. 7) K. Chajara; H. Ottoson, Tetrahedron Lett., 2004, 45, 6741.

COMMENTS :

1711

THOMAS REACTION EXAMPLE :

Bu3Sn

HO

OBn 1) SnCl4 2) PhCHO

CH3

OBn Ph

CH3

MECHANISM :

CH3

Bu3Sn

OBn

Cl3Sn OBn Cl H

CH3

Cl O

R Cl Sn OBn Cl Cl

RCHO H OH

H2O

CH3

Bu3Sn

SnCl4

H

Cl Sn Cl H OBn

Cl O

R

H

CH3

Cl Sn Cl H OBn CH3

OBn

H

H

R

CH3

DISCONNECTION :

OH

R2

Bu3Sn

R

R3

R

R3CHO + R2

R1

R1

NOTES : Alk-2-enylstannanes with heteroatom substituents at the 4-, 5-, and 6-positions undergo stereoselective transmetallation (under kinetic control) on treatment with tin(IV) halides to generate allyltin trihalides which react with aldehydes and imines with useful levels of 1,5-, 1,6- and 1,7-asymmetric induction. 1,8-Asymmetric induction has also been reported by Thomas. See also Duthaler – Hafner, Ibuka – Yamamoto, Matteson and Roush – Hoffmann – Yamamoto reactions.

REFERENCES : 1) S.V. Mortlock; E.J. Thomas, Tetrahedron Lett., 1988, 29, 2479. 2) A.H. McNeil; E.J. Thomas, Tetrahedron Lett., 1990, 31, 6239.

1712

3) A.H. McNeil; E.J. Thomas, Synthesis, 1994, 322. 4) E.J. Thomas, Chem. Commun., 1997, 411. 5) E.-M. Moffatt; E.J. Thomas, Tetrahedron, 1999, 55, 3723. 6) N.H. Taylor; E.J. Thomas, Tetrahedron, 1999, 55, 8757. 7) P. Kumar; E.J. Thomas; D.R. Tray, J. Braz. Chem. Soc., 2001, 12, 623. 8) N. Martin; E.J. Thomas, Tetrahedron Lett., 2001, 42, 8373.

COMMENTS :

THORPE – ZIEGLER REACTION EXAMPLE :

N C

OCH3

N C

O

1) NaOEt 2) hydrolysis 3) decarboxylation

O

MECHANISM :

C N

C N (CH2)n-1

(CH2)n-1 C C N H2

Na N

Na

CH3

C N Ph

H O C

C N Na (CH2)n-1

hydrolysis

(CH2)n-1

- CO2 COOH

C N H

H

(CH2)n

O

1713

DISCONNECTION : N O N

NOTES : The intermolecular reaction is called the Thorpe reaction. The intramolecular reaction is called the Thorpe – Ziegler reaction. The synthesis involves the cyclisation of α,ω-dinitriles with metal amines, in high dilution to yield iminonitriles, which are hydrolysed, and decarboxylated to the ketones. For 5-, 6-, 7-, 8- and 18-membered rings the yields are high. For 9-, 10-, 11-, and 12- membered rings the yields are moderate. It is also possible to make larger oxygen containing rings. See also Corey – Nicolaou, Dieckmann condensation, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ruggli, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 963 Smith – March : 1219, 1238 Smith : 899 Smith 2nd : 752 Houben – Weyl : 4/2, 758; E6a, 335, 618; E7a, 321; E8a, 674, 723 Org. React. : 15, 1; 31, 1 Org. Synth. : 53, 98 Org. Synth. Coll. Vol. : 6, 932

1) H. Baron; F.G.P. Remfry; J.F. Thorpe, J. Chem. Soc., 1904, 85, 1726. 2) K. Ziegler; H. Eberle, H. Ohlinger, Liebigs Ann. Chem., 1933, 504, 94. 3) K. Ziegler, Chem. Ber., 1934, 67, 139. 4) H.J. Nitzchke, Angew. Chem., 1951, 63, 491. 5) H.J. Nitzchke; H. Dudka, Chem. Ber., 1955, 88, 264. 6) E.C. Taylor; A. McKillop, Adv. Org. Chem., 1970, 7, 1. 7) D.P. Curran; W.D. Liu, Synlett, 1999, 117. 8) L. Kovacs, Molecules, 2000, 5, 127. 9) R. Malassene; L. Toupet; J.-P. Hurvois; C. Moinet, Synlett, 2002, 895.

1714

COMMENTS :

THYAGARAJAN INDOLE SYNTHESIS EXAMPLE :

HO CH3 N

O 2 N CH3

mCPBA DCM, RT

N H3C

O

MECHANISM :

CH3 N

H3C 1) mCPBA benzene 2) HCl (g)

CH2R

H3C

OH N

Cl aq. K2CO3

CH2R

CH2R

CH3 + H N O

CH3 N O CH2R

H

CH3 R N

CH3 N OH R

O O H O

Cl

O N

O

1715

Cl

CH2R

DISCONNECTION :

CH2R1

R2 R1 N R

N R

NOTES : The formation of indole by sequential [2,3]- and [3,3]-sigmatropic rearrangements from the N-oxide of the aryl propynylamine. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) B.S. Thyagarajan; J.B. Hillard; K.V. Reddy; K.C. Majumdar, Tetrahedron Lett., 1974, 15, 1999. 2) J.B. Hillard; K.V. Reddy; K.C. Majumdar; B.S. Thyagarajan, J. Heterocycl. Chem., 1974, 11, 369. 3) T. Balasubramanian; K.K. Balasubramanian, J. Chem. Soc., Chem. Commun., 1994, 1237. 4) K.C. Majumdar; G.H. Dana; U. Das, Chem. Commun., 1996, 517. 5) K.C. Majumdar; G.H. Dana; U. Das, J. Chem. Soc., Perkin Trans. 1, 1997, 1229.

COMMENTS :

TIEMANN AMINATION EXAMPLE :

H3C

H

H O

1) HCN 2) NH3

1716

H3C

NH2 CN

MECHANISM :

R O

H

H

H

R HCN

OH CN

NH2

R

NH3 - H2O

CN

DISCONNECTION :

H R

R

NH2 CN

H O

NOTES : The cyanohydrin amination of aldehydes. See also Bucherer – Bergs, Corey – Link, Strecker amino acid, Ultee, Urech and Zelinsky – Stadnikoff reactions.

REFERENCES : March : 964 Smith – March : 1239 Houben – Weyl : 8, 280 Org. Synth. : 11, 4; 22, 13, 23 Org. Synth. Coll. Vol. : 2, 29; 3, 66, 84

1) A. Strecker, Liebigs Ann. Chem., 1850, 75, 27. 2) F. Tiemann, Ber. Dtsch. Chem. Ges., 1880, 13, 381. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189.

COMMENTS :

1717

TIEMANN REARRANGEMENT EXAMPLE :

N Ph

OH N H

C6H11

Ph

PhSO2Cl pyridine dioxane

H N

C6H11 N H O

MECHANISM :

N Ph

OH N H

N

C6H11

Ph

PhSO2Cl pyridine dioxane

H+ SO2Ph O N H

Ph

C6H11

N N H

C6H11

O S OH O H+ Ph

N

O N O S OH Ph

C6H11

- PhSO2H

Ph

C6H11 N H

H N O

DISCONNECTION :

NH2 R

N H

R

O

NH2 NOH

NOTES : The Beckmann rearrangement of amidoximes to urea derivatives in the presence of acids (benzene sulfonyl chloride). See also Beckmann rearrangement, Curtius rearrangement, Hofmann rearrangement and Lossen reactions.

REFERENCES : Org. React. : 3, 337

1718

1) F. Tiemann, Ber. Dtsch. Chem. Ges, 1891, 24, 4162. 2) L.A. Paquette; J.P. Freeman, J. Org. Chem., 1970, 35, 2249. 3) J. Garapon; B. Sillion; J.M. Bonnier, Tetrahedron Lett., 1970, 11, 4905. 4) R. Richter; B. Tucker; H. Ulrich, J. Org. Chem., 1983, 48, 1694. 5) S.A. Bakunov; A.V. Rukavishnikov; A.V. Tkachev, Synthesis, 2000, 1148.

COMMENTS :

TIFFENEAU – DEMJANOV RING ENLARGEMENT EXAMPLE :

CH2NH2

O

OH

HONO

MECHANISM :

2 HONO

O

- H2O O

HO

N NH2

O

N

N

O

N

O O H N N OH

O

HO H+

- HONO

H H+ O N N H

NO2

HO

N

N N

OH2

O

HO

N - H2O

- N2, H+

1719

DISCONNECTION :

O

HO

CH2NH2 n

n

n = 1, 2, 3, 4, 5

NOTES : Amino alcohols, of the type 1-hydroxy-1-cycloalkylmethylamine obtained, e.g. by the reduction of a cyanohydrin, undergo deamination and rearrangement to cycloalkylones with one more carbon atom in the ring when treated with nitrous acid. There is also a halogenohydrin rearrangement. Tert-β-iodoalcohols rearrange when treated with silver or mercuric salts to yield carbonyl compounds, C.R. Séances Acad. Sci., 1907, 145, 593. See also Demjanov rearrangement.

REFERENCES : March : 1074 Smith – March : 1399 Smith : 1293 Smith 2nd : 1068 Houben – Weyl : 4/2, 793; E19c, 400 Org. React. : 11, 157

1) N.J. Demjanov, J. Russ. Phys. Chem. Ges., 1903, 35, 375. 2) M. Tiffeneau; P. Weill; B. Tchoubar, C.R. Séances Acad. Sci., 1937, 205, 54. 3) A. Nickpon; G. Stern, Tetrahedron Lett., 1985, 26, 5915. 4) H. Stach; M. Hesse, Tetrahedron, 1988, 44, 1573. 5) H.N.C. Wong; M.-Y. Hon; C.-W. Tse; Y.-C. Yip, Chem. Rev., 1989, 89, 165. 6) D. Fattori; S. Henry; P. Vogel, Tetrahedron, 1993, 49, 1649. 7) L. Chow; M. McClure; J. White, Org. Biomol. Chem., 2004, 2, 648.

COMMENTS :

1720

TIFFENEAU SYNTHESIS EXAMPLE : CH3

MgCl 1) HCHO 2) H2O

CH2OH

MECHANISM :

H

R O

Mg O

MgCl xs RCHO

H R R

R

H

H

CH2

CH2

Mg

Mg H

H

O R

H

O R

R H CH3

CH2 Mg H

OH

H2O

O R

R

DISCONNECTION :

CH3

MgCl

OH

+ RCHO

R

NOTES : o-Methylbenzyl alcohols are obtained by treatment of the Grignard compound formed from benzyl chlorides with paraformaldehyde.

REFERENCES : 1) M. Tiffeneau; Delange, C.R. Séances Acad. Sci., 1903, 137, 573. 2) J. Schmidlin; A. Garcia–Banύs, Ber. Dtsch. Chem. Ges., 1912, 45, 3193. 3) H. Gilman; J.E. Kirby, J. Am. Chem. Soc., 1927, 49, 1825.

1721

4) H. Gilman; J.E. Kirby, J. Am. Chem. Soc., 1929, 51, 3475. 5) H. Gilman; J.E. Kirby, J. Am. Chem. Soc., 1932, 54, 345. 6) W.G. Young; S. Siegel, J. Am. Chem. Soc., 1944, 66, 354. 7) S. Siegel; S.K. Coburn; D.R. Levering, J. Am. Chem. Soc., 1951, 73, 3163. 8) B. van Zanten; W. Nauta, Recl. Trav. Chim. Pays-Bas, 1960, 79, 1211.

COMMENTS :

TIMMIS PTERIDINE SYNTHESIS EXAMPLE :

H2N H2N

N N

N O H2N

NH2

N

Cl

+

N

NH2 N N

O HO

MECHANISM :

H+

H2N O N

H

N NH2 N

HN

H2N

H+

N NH2 N H2N

N

N N

NH2

1722

OH N

NH2

N H

N

N NH2

DISCONNECTION :

NH2 N R

H2N N

N

N

N

NH2

O N NH2

R = NH2, OH

N H2N

NOTES : 7-Amino and 7-hydroxy-pteridines and its derivatives are synthesised by the reaction of 4-amino-5-nitrosopyrimidines with phenylacetonitriles or phenylacetyl chlorides. In the case of the phenylacetonitriles, the use of sodium alkoxides as catalyst is necessary. See also Blicke – Pachter, Boon – Polonovski, Isay, and Taylor reactions.

REFERENCES : 1) G.M. Timmis, Nature, 1949, 164, 139. 2) R.G.W. Spickett; G.M. Timmis, J. Chem. Soc., 1954, 2887. 3) T.S. Osdense; G.M. Timmis, J. Chem. Soc., 1955, 2032. 4) T.S. Osdense; G.M. Timmis, J. Chem. Soc., 1955, 2036. 5) T.S. Osdense; G.M. Timmis, J. Chem. Soc., 1955, 2038.

COMMENTS :

TIPSON – COHEN OLEFINATION EXAMPLE :

Ph

O O TsO

Ph O

O O

OCH3

H OTs H

NaI, Zn DMF, reflux

1723

H

O

OCH3 H

MECHANISM :

Ph

Ph

OTs

O

O

O

O

O

OCH3 I

O

OCH3 H

H

Ph O

O OCH3

O I Zn

O O S O

Ph

H

O O

O OCH3 H

CH3

DISCONNECTION :

TsO I

NOTES : The formation of enes from α-diols, in which derived α-disulfonates (two adjacent secondary tosylates) are treated with sodium iodide and zinc in refluxing DMF or butanone.

REFERENCES : Org. React. : 30, 457

1) R.S. Tipson; A. Cohen, Carbohydr. Res., 1965, 1, 338. 2) B. Fraser–Reid; B. Boctor, Can. J. Chem., 1969, 47, 393. 3) T. Yamazaki; K. Matsuda; H. Sugiyama; S. Seto; N. Yamaoka, J. Chem. Soc., Perkin Trans. 1, 1977, 1981. 4) B.K. Radatus; I.S. Clarke, Synthesis, 1980, 47. 5) L.M. Engelhardt; M. Mocerino; R.V. Stick; A.H. White, Aust. J. Chem., 1990, 43, 1111. 6) L.H.B. Baptistella; A.Z. Neto; H. Onaga; E.A.M. Godoi, Tetrahedron Lett., 1993, 34, 8407.

1724

COMMENTS :

TISHCHENKO – CLAISEN REACTION EXAMPLE :

O

2 CH3CH2CH2CHO

i

2% Al(O Pr)3 CCl4

O

MECHANISM :

O

Al(OR1)3

R

O

O R

H

H

R

R

Al(OR1)3

O

Al(OR1)3

Al(OR1)3 O

H O

H

- Al(OR1)3

R2

H

R

R1

O R2

R1 O R2

H R1

DISCONNECTION :

R

R

O

2 RCHO

O

NOTES : The conversion of aldehydes to esters in the presence of metal alcoholates. One molecule of aldehyde is oxidised while the other is reduced. Crossed reactions are possible. The samarium promoted reduction is sometimes called

1725

the Evans – Tishchenko reduction. Other transition metals like ruthenium and zirconocenes are also being used. See also Cannizzaro, Meerwein – Ponndorf – Verley reduction, Nord and Oppenauer oxidation reactions.

REFERENCES : March : 1235 Smith – March : 1565 Houben – Weyl : E5, 658

1) L. Claisen, Ber. Dtsch. Chem. Ges., 1887, 20, 648. 2) W. Tishchenko, J. Russ. Physik. Chem. Ges., 1906, 38, 355. 3) P.R. Stapp, J. Org. Chem., 1973, 38, 1433. 4) D.A. Evans; A.H. Hoveyda, J. Am. Chem. Soc., 1990, 112, 6449. 5) S.-Y. Onozawa; T. Sakakura; M. Tanaka; M. Shiro, Tetrahedron, 1996, 52, 4291. 6) K.M. Gillespie; I.J. Munslow; P. Scott, Tetrahedron Lett., 1999, 40, 9371. 7) I. Simpura; V. Nevalainen, Tetrahedron Lett., 2001, 42, 3905. 8) A.B. Smith III; D. Lee; C.M. Adams; M.C. Kozlowski, Org. Lett., 2002, 4, 4539. 9) C.A. Fan; X.D. Hu; Y.Q. Tu; B.M. Wang; Z.L. Song, Chem. Eur. J., 2003, 9, 4301. 10) J. Mlynarski; M. Mitura, Tetrahedron Lett., 2004, 45, 7549. 11) C. Schneider; K. Klapa; M. Hansch, Synlett, 2005, 91.

COMMENTS :

TOLLENS ADDITION EXAMPLE :

H

O +

2 H

H

H3C O

aq. Ca(OH)2

1726

HO

H

HO

O

MECHANISM :

H

O + H

H

H

H2C

H

O

O

H2O

O

HO

O

- OH H

H + HO

HO

+ H2O

O

HO O

H + HO

O

O

H

H

O

H

HO

O

H2O

HO

H

HO

O

DISCONNECTION :

HO

HO

R

R H R1

R1 OH

O

NOTES : The aldol addition of one, two, three or four equivalents of formaldehyde to an aldehyde or ketone in the presence of a weak base. See also Cannizzaro and Mannich reactions.

REFERENCES : March : 955 Smith – March : 1219, 1230 Houben – Weyl : 7/1, 89 Org. Synth. : 4, 53; 31, 101 Org. Synth. Coll. Vol. : 1, 425; 4, 907

1) B. Tollens; P. Wigand, Liebigs Ann. Chem., 1891, 265, 316. 2) M. Apel; B. Tollens, Ber. Dtsch. Chem. Ges., 1894, 27, 1087. 3) T.J. Prosser, J. Org. Chem., 1961, 26, 242. 4) I.D. Jenkins, J. Chem. Educ., 1987, 64, 164. 5) S. Munoz; G.W. Gokel, J. Am. Chem. Soc., 1993, 115, 4899. 6) S. Huang; A.W.H. Mau, J. Phys. Chem. B, 2003, 107, 3455.

COMMENTS :

1727

TORGOV SYNTHESIS EXAMPLE :

H3C O

H H

H3CO

1)

MgBr

2)

THF, Et2O O

HO

CH3 O HOAc, xylenes 3) H2, Pd/CaCO3 toluene 4) HO OH p-TsOH toluene 5) Li, NH3 6) H+, H2O 7) Pyridine.HCl, heat

1728

H

O

MECHANISM :

O

For Lewis acid catalysed step see next scheme

OH MgBr THF, Et2O

H3CO

O H3CO CH3 O HOAc, xylenes

O

H3C

H2, Pd/CaCO3 toluene

H3CO

O

H3C

H

HO

H3CO

OH

p-TsOH toluene H3C O O

H3C O O

H Li, NH3

H

H

H+, H2O

H

H3CO

H3CO H3C

O

H3C H

H H

H

H

Pyridine.HCl, heat HO

H3CO

1729

H

O

O

O

O

O

H3CO

H3CO X

H

O L Ti O X

O

H3C

H3C

O

H O

OH

O L Ti X O X

H3CO

H3C

H3CO

O

H3C

OH

O

- H2O

H3CO

H3CO

DISCONNECTION :

H3C

O O

H H

H

H3CO

HO

NOTES : The main cyclisation step in the synthesis of estrone. The reaction can be Lewis acid mediated to give an asymmetric Torgov cyclisation in a Prins-type of fashion. See also Prins reaction.

REFERENCES : 1) S.N. Anachenko; I.V. Torgov, Dokl. Akad. Nauk SSSR, 1959, 127, 553. 2) C.H. Kuo; D. Taub; N.L. Wendler, J. Org. Chem., 1968, 33, 3126. 3) I.V. Torgov, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1982, 31, 271. 4) S. Jayaraman; K. Rajagopalan, Indian J. Chem., 1989, 28B, 61. 5) J.-C. Blazejewski; M. Haddad; C. Wakselman, Tetrahedron Lett., 1994, 35, 2021.

1730

6) V.S. Enev; J. Mohr; M. Harre; K. Nickisch, Tetrahedron: Asymmetry, 1998, 9, 2693.

COMMENTS :

TRAHANOVSKY ETHER OXIDATION EXAMPLE :

Ph

Ph

O O

O Ph

Ce(NH4)2(NO3)6 CH3CN

Ph

MECHANISM :

H3C H3C

OCH3 CH3

HO* H3C

OCH3 CH3

4+ * CH3 2 Ce + 2 H2O - 2 H+, - 2 Ce3+ OCH3

H3C HO*

CH3 OCH3

O* H3C - CH3OH

H3C

NOTES : The oxidation of aromatic ethers to carbonyl compounds with cerium ammonium nitrate.

REFERENCES : 1) W.S. Trahanovsky; L.B. Young, J. Chem. Soc., 1965, 5777. 2) W.S. Trahanovsky; D.B. Macaulay, J. Org. Chem., 1973, 38, 1497. 3) T.-L. Ho, Synthesis, 1973, 347. 4) P. Jacob III; P.S. Callery; A.T. Shulgin; N. Castagnoli, jr., J. Org. Chem., 1976, 41, 3627. 5) J. Laduranty; L. Lepage; Y. Lepage, Can. J. Chem., 1980, 58, 1161. 6) L. Lepage; Y. Lepage, Synthesis, 1983, 1018.

1731

CH3 CH3 O*

COMMENTS :

TRAUBE PURINE SYNTHESIS EXAMPLE :

OH O

NH2

EtO

NH2

N

N

+

O

N

1) EtONa 2) HNO2 (NH4)2S 3) HCOOH

HO

N

N H

MECHANISM :

H+ O

O O

EtO NH2

.

H

CN

HCl H2N

HN EtONa

NH2

+

HCl.H2N

N

N N

H2N

NH2

N

Cl

H2N

HNO2 (NH4)2S

NH2

N

H2N

OH NH2 O N H

N

OR

N

N H2N

OR

OH N H

N

DISCONNECTION :

OH

HX

O N

N

RO

R N

N H

X = O, NH

1732

N H OH

+ CN

H2N

NH2 X

NH H+

NH2

N

OH

O

HCl.H2N

OH

OH

HCl.H2N

N H

NH2

N

N

NH2

NOTES : The pyrimidine synthesis from guanidine or urea and cyanoacetic ester, followed by reaction with nitrous acid and condensation with formic acid afford purines. See also Behrend – Roosen, Fischer and Horbaczewski reactions.

REFERENCES : Org. Synth. : 32, 45; 37, 15 Org. Synth. Coll. Vol. : 4, 245, 247

1) W. Traube, Ber. Dtsch. Chem. Ges., 1900, 33, 1371. 2) A.R. Katritzky, J. Chem. Soc., Quat. Rev., 1956, 10, 397. 3) A.R. Katritzky, Pure Appl. Chem., 1961, 11, 178. 4) M. Melguizo; M. Nogueras; A. Sanchez, Synthesis, 1992, 491. 5) A. Rybar; J. Alfoldi; I. Smondrkova, Monatsh. Chem., 1994, 125, 565. 6) K.A. Ismail; A.A. Eltombary; A. Omar; O.M. Abouwafa; N.I. Madi, Eur. J. Med. Chem., 1995, 30, 423.

COMMENTS :

TREIBS ALLYLIC OXIDATION EXAMPLE :

O

O

Hg(COOCF3)2 AcO

AcO

OH

1733

MECHANISM :

HgOAc OAc

HgOAc

OAc HgOAc

- H+

HgOAc

HgOAc

- Hg0, - OAc

OAc

HgOAc

OAc

- Hg0, - OAc

OAc

OAc

OAc OAc

OAc

OAc

OAc

OAc

1734

DISCONNECTION :

R R2 H

R

R2

R1

R3

OH R1 R3

NOTES : The allylic oxidation of alkenes using mercuric trifluoroacetate, allylic rearrangement is possible although mercury normally stabilises the formed cation.

REFERENCES : March : 759 Smith – March : 993 Smith : 179 Smith 2nd : 150

1) W. Treibs, Naturwissenschaften, 1948, 35, 125. 2) W. Treibs; H. Bast, Liebigs Ann. Chem., 1949, 561, 165. 3) K.B. Wiberg; S.D. Nielsen, J. Org. Chem., 1964, 29, 3353. 4) G. Massiot; H.-P. Husson; P. Potier, Synthesis, 1974, 722. 5) R.A. Broad; J.R. Hanson; P.B. Reese, J. Chem. Res., 1987, 5, 172.

COMMENTS :

TROFIMOV PYRROLE SYNTHESIS EXAMPLE :

NOH

H H KOH, DMSO pressure

1735

N H

MECHANISM :

R1

R1

R1 R

R + N

R2

base DMSO heat

OH

N

H

O

R1

R1

R [3,3]-sigmatropic rearrangement

R

R2

R2 N

O

R2

R2 - H2O

NH O

R

N H

DISCONNECTION :

R1

R1

R2

R +

R

N

N H

R2

OH

NOTES :

Another synthesis of pyrroles derived from hetaryl alkyl ketoximes and acetylenes via a [3,3]-sigmatropic rearrangement. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert and Zav’yalov reactions.

REFERENCES :

1) B.A. Trofimov, Adv. Heterocycl. Chem., 1990, 51, 177. 2) B.A. Trofimov; A.I. Mikhaleva, Heterocycles, 1994, 37, 1193. 3) A.M. Vasil’tsov; A.B. Zaitsev; A.I. Mikhaleva; E.Yu. Schmidt; A.V. Afo–nin, Mendeleev Commun., 2001, 11, 74. 4) A.M. Vasil’tsov; A.B. Zaitsev; A.I. Mikhaleva; E.Yu. Schmidt; A.V. Afo–nin, Chem. Heterocycl. Comp., 2002, 415, 66.

5) E.Yu. Schmidt; N.V. Zorina; A.B. Zaitsev; A.I. Mikhaleva; A.M. Vasil’tsov; P. Audebert; G. Clavier; R. Méallet– Renault; R.B. Pansu, Tetrahedron Lett., 2004, 45, 5489. 6) A.B. Zaitsev; R. Méallet–Renault; E.Yu. Schmidt; A.I. Mikhaleva; S. Badré; C. Dumas; A.M. Vasil’tsov; N.V. Zorina; R.B. Pansu, Tetrahedron, 2005, 61, 2683.

1736

COMMENTS :

TROST – CHEN DECARBOXYLATION EXAMPLE :

O

O OCH3 O

OCH3 (Ph3P)2Ni(CO)2

O

O

MECHANISM :

O

O

H3C

H3C O H3C

[Ph3P]Ni(CO)2

H3C

O

O

O Ni L L

- CO

O H3C H3C

O

O O Ni L L

H3C

O Ni L H L

H2C

H3C H3C

O Ni L L

H3C H3C

CH3

H3C

1737

CH3

DISCONNECTION : O R

R

X R1

X = O, S

R1

O

NOTES :

The nickel complex catalyses the decarboxylation of dicarboxylic acid anhydrides or thioanhydrides to form alkenes.

REFERENCES :

1) J.D. Rose; F.S. Statham, J. Chem. Soc., 1950, 69. 2) B.M. Trost; F. Chen, Tetrahedron Lett., 1971, 12, 2603. 3) T.C. Flood; A. Sharhangi, Tetrahedron Lett., 1977, 18, 3861. 4) G.L. Grunewald; D.P. Davis, J. Org. Chem., 1978, 43, 3074.

COMMENTS :

TROST CYCLOPENTANATION EXAMPLE :

MOMO

OMOM H

SiMe3 +

SO2Ph

OAc

Pd(OAc)2 P(OiPr)3

SO2Ph

MECHANISM :

SiCl3

Cl Cl

Cl3SiH Et3N, CuCl

Cl

SiMe3 CH3MgBr - 78 oC

1738

Cl

SiMe3 KOAc 55 oC

OAc

R1 TMS

OAc

PdL2

R

EWG

R1

H

R

L

R1

EWG

Pd[Ph3P]4

+

Pd

R

R1 EWG H

L

H R1 H

EWG

R

L

Pd

EWG

R

L

DISCONNECTION :

TMS R

OAc

+

R

R1

R1

NOTES :

The formation of methylenecyclopentane starting from siloxymethylallylsilane or acetoxymethylallylsilane with Michael acceptor olefins and palladium catalysts (via trimethylene methane equivalent). The geometry of (E)-olefins is retained in the products. The mechanism is or [3+2]-concerted or is step-wise but collapse of the intermediate enolate is faster than σ-bond rotation. (Z)-Olefins give syn and anti mixtures.

REFERENCES :

1) B.M. Trost; D.M.T. Chan, J. Am. Chem. Soc., 1979, 101, 6429. 2) B.M. Trost; D.M.T. Chan, J. Am. Chem. Soc., 1983, 105, 2315. 3) B.M. Trost; P. Seoane; S. Mignani; M. Acemoglu, J. Am. Chem. Soc., 1989, 111, 7487. 4) H.W. Frühauf, Chem. Rev., 1997, 97, 523.

1739

COMMENTS :

TROST DESYMMETRISATION EXAMPLE :

BnO

BnO

O

OH

HO

1) TsNCO 2) cat. Pd0

O Ph2P

O

N Ts

O N

N

PPh2

H H

MECHANISM :

chiral backbone

linker

linker O *

L =

N

N H

O

H

P P Ph2 Ph2

AcO AcO

Nu

OAc Pd(L*)2 Pd * L L*

1740

AcO

Nu

NOTES :

A palladium-catalysed desymmetrisation using a nitrogen nucleophile (azide or amine). Where the palladium complex is derived from a chiral ligand and π-allylpalladium chloride. This will afford an enantiomerically pure, azide or amine containing five or six membered ring. The primary chirality of the stereogenic centres of the backbone gets translated via the linker units into a secondary chirality at the phosphines. See also Bäckvall reaction.

REFERENCES :

1) B.M. Trost; D.L. van Vranken; C. Bingel, J. Am. Chem. Soc., 1992, 114, 9327. 2) B.M. Trost; R.C. Bunt, J. Am. Chem. Soc., 1994, 116, 4089. 3) S.R. Pulley; B.M. Trost, J. Am. Chem. Soc., 1995, 117, 10143. 4) B.M. Trost, Acc. Chem. Res., 1996, 29, 355.

COMMENTS :

TROST OXIDATIVE DECARBOXYLATION EXAMPLE :

CH3

CH3

O

COOH 1) 2 LDA, CH3SSCH3, - 20 oC, THF 2) NCS, EtOH 3) aq. HCl

1741

MECHANISM :

H

R

SCH3 OH

R OH

R1

2 LDA, CH3SSCH3 THF

O

R1

R O

O

R1

Cl SCH3 O O

N Cl O R

R - CO2

R R1

SCH3

OR O R

ROH

R1

R - ROR

R1

SCH3 ROH - SCH3

OR

R1 O

DISCONNECTION :

R

R

R1

R1

O

H OH O

NOTES :

The conversion of a carboxylic acid to a ketone with the loss of one carbon atom using dimethyl disulfide as sulfenylating agent and N-chlorosuccinimide as oxidising reagent. See also Barbier – Locquin – Wieland degradation, Gallagher – Hollander, Hoehn – Mason degradation, Krafft, Miescher degradation and Wieland – Dane degradation reactions.

REFERENCES :

B.M. Trost; Y. Tamaru, J. Am. Chem. Soc., 1975, 97, 3528.

COMMENTS :

1742

TSCHUGAEFF (CHUGAEV) OLEFIN SYNTHESIS EXAMPLE :

H H3C

CH3 CH3 O CH3 S CH3 S

heat

H3C

CH3

H3C

CH3

MECHANISM :

H

S R

S

O + R S

O

COS + RSH

SH

DISCONNECTION : R1

H

R1

H

R

H

R

OH

NOTES :

The intramolecular syn-elimination of an alcohol into an olefin by the thermal decomposition of the xanthate prepared from the alcohol. It proceeds through a six-membered transition state. See also Cope – Mamlock – Wolffenstein reaction.

REFERENCES : March : 1014 Smith – March : 1330 Smith : 167 Smith 2nd : 140 Org. React. : 12, 57 Org. Synth. : 64, 57 Org. Synth. Coll. Vol. : 7, 139

1) L. Tschugaeff, Ber. Dtsch. Chem. Ges., 1899, 32, 3332. 2) G.L. O’Connor; H.R. Nace, J. Am. Chem. Soc., 1952, 74, 5454. 3) G.L. O’Connor; H.R. Nace, J. Am. Chem. Soc., 1953, 75, 2118. 4) R.F.W. Bader; A.N. Burns, Can. J. Chem., 1961, 39, 348. 5) C.H. DePuy; R.W. King, Chem. Rev., 1960, 60, 431.

1743

6) A. De Groot; B. Evenhuis; H. Wynberg, J. Org. Chem., 1968, 23, 2214. 7) G. Cernigliano; P. Kocienski, J. Org. Chem., 1977, 42, 3622. 8) X. Fu; J.M. Cook, Tetrahedron Lett., 1990, 31, 3409. 9) P.S. Ray; M.J. Manning, Heterocycles, 1994, 33, 1361. 10) T. Kumamoto; N. Tabe; K. Yamaguchi; H. Yagishita; H. Iwasa; T. Ishikawa, Tetrahedron, 2001, 57, 2717.

COMMENTS :

TSUGE REACTION EXAMPLE :

O N Ph

H3CO

N O

1)

N O N Ph O RT, 10 min

2)

OH N

Cl

OCH3 RT, 60 min

1744

O

N

O

Ph

O

Ph

MECHANISM :

N

EWG

R R1

EWG

H

H

N

R1 R

EWG

EWG R1

N Ar

C

Ar

O

R1

N

R

R

N O

N

DISCONNECTION :

EWG R Ar N O

R1

N

R

N

R2

R2

NOTES :

Pyridinium or isoquinolinium methylides undergo highly stereo- and regioselective cycloadditions with olefinic dipolarophiles to form unstable tetrahydroindolizine derivatives. One of the double bonds will react further with nitrile oxides to give isoxazole-fused tetrahydroindolizines in a good stereo- and regioselective fashion.

REFERENCES :

1) O. Tsuge; S. Kanemassa; S. Takenaka, Bull. Chem. Soc. Jpn., 1985, 58, 3137. 2) O. Tsuge; S. Kanemassa; S. Takenaka, Bull. Chem. Soc. Jpn., 1986, 59, 3631. 3) A.J. Bicknell; N.W. Hird; S.A. Readshaw, Tetrahedron Lett., 1998, 39, 5869. 4) P. Brooking; M. Crawshaw; N.W. Hird; C. Jones; W.S. MacLachlan; S.A. Readshaw; S. Wilding, Synthesis, 1999, 1986.

COMMENTS :

1745

TSUJI – TROST ALLYLATION EXAMPLE :

OCO2CH3

O

O

+

OCH3

Pd2(dba)3 O

MECHANISM :

Pd Ph2PCH2PPh2

PdCl2, NaCl CuCl2, NaOAc 60 oC

H3CO

H3CO H

Ph2P

CO2CH3 CO2CH3

Pd PPh2

H3CO

H3CO

OCH3 O

H3CO

O

DISCONNECTION :

X

Nu

NuH = malonates, β-diketones, β-ketoesters, enamines, β-keto sulfones, bis-sulfones X = Br, Cl, OCOOR, SO2R, OCOR, OCONR2, OPO(OR)2, NO2

NOTES :

The direct C-allylation of ketones or of tin enol ethers with Pd(0) catalysts. These transformations require rather sophisticated conditions depending mainly on the nature of the catalytic species. They allow control of regio-, diastereo-, and even enantioselectivity. Bimetallic systems containing rhodium(I) are used to activate the pronucleophiles by coordination to a cyano group. Other metals can catalyse allylic alkylations, e.g. molybdenum, tungsten, iridium and rhodium. See also Bäckvall reaction.

REFERENCES :

1) J. Tsuji; H. Takahashi; M. Morikawa, Tetrahedron Lett., 1965, 6, 4387. 2) J. Tsuji, Acc. Chem. Res., 1969, 2, 144.

1746

3) B.M. Trost; T.J. Fullerton, J. Am. Chem. Soc., 1973, 95, 292. 4) B.M. Trost, Acc. Chem. Res., 1980, 13, 385. 5) B.M. Trost; D.P. Curran, J. Am. Chem. Soc., 1980, 102, 5699. 6) C.G. Frost; J. Howarth; J.M.J. Williams, Tetrahedron: Asymmetry, 1992, 3, 1089. 7) M. Sawamura; M. Sudoh; Y. Ito, J. Am. Chem. Soc., 1996, 118, 3309. 8) B. Nay; J.F. Peyrat; J. Vercautern, Eur. J. Org. Chem., 1999, 2231. 9) M. Kimura; Y. Horino; R. Mukai; S. Tanaka; Y. Tamaru, J. Am. Chem. Soc., 2001, 123, 10401. 10) V. Branchadell; M. Moreno–Mañas; R. Pleixats; S. Thorimbert; C. Commandeur; C. Boglio; M. Malacria, J. Organomet. Chem., 2003, 687, 337.

11) C. Chevrin; J. Le Bras; F. Hénin; J. Muzart, Tetrahedron Lett., 2003, 44, 8099. 12) N. Nomura; K. Tsurugi; T.V. RajanBabu; T. Kondo, J. Am. Chem. Soc., 2004, 126, 5354. 13) B.M. Trost, J. Org. Chem., 2004, 69, 5813. 14) D.A. Singleton; C.F. Christian, Tetrahedron Lett., 2005, 46, 1631.

COMMENTS :

TSUJI – WACKER OLEFIN OXIDATION EXAMPLE :

O

PdCl2, CuCl, O2 H2O, DMF

1747

O

O

MECHANISM :

R Cl

H2O PdII Cl

H2O

H2O

Cl

PdII Cl

.5 O2 + 2 HCl

R OH2

2 CuCl

Cl

H2O

R

PdII H2O

Cl

2 CuCl2

OH2

LnPd0 HCl HCl H2O PdII

H

H2O PdII H2O

Cl

H

R OH

Cl

H

H2O

R

PdII HO

Cl

R OH

O R

DISCONNECTION : O R

CH3

R

O R

H

NOTES :

The oxidation of olefins to ketones by a palladium(II) catalyst. The unique feature is the invention of the in situ redox system of PdCl2 – CuCl2. The formation of aldehydes is also possible see Kiers et al. Water soluble palladium complexes have been reported by Sheldon et al. There are two mechanistic possibilities for the hydroxypalladation,

1748

syn or anti, deuterium-labelling study has shown that it proceeds through a palladium-nucleophile anti-addition. See

also Uemura oxidation.

REFERENCES : Smith – March : 1538 Smith 2nd : 278, 1110 Houben – Weyl : E3, 340; E18, 1088 Science of Synthesis : 1, 322, 333; 10, 417

1) F.C. Philips, Amer. Chem. J., 1894, 16, 255. 2) J. Tsuji; H. Nagashima; K. Hori, Chem. Lett., 1980, 257. 3) J. Tsuji; H. Nagashima; K. Hori, Tetrahedron Lett., 1982, 23, 2679. 4) D.G. Miller; D.D.M. Wagner, J. Org. Chem., 1990, 55, 2924. 5) N.H. Kiers; B.L. Feringa; H. Kooijman; A.L. Spek; P.W.N.M. van Leeuwen, J. Chem. Soc., Chem. Commun., 1992, 1169. 6) N.H. Kiers; B.L. Feringa; P.W.N.M. van Leeuwen, Tetrahedron Lett., 1992, 33, 2403. 7) P. Compain; J. Gore; J.M. Vatele, Tetrahedron, 1996, 52, 10405. 8) G.J. ten Brink; I.W.C.E. Arends; G. Papadogianakis; R.A. Sheldon, Chem. Commun., 1998, 2359. 9) G.J. ten Brink; I.W.C.E. Arends; G. Papadogianakis; R.A. Sheldon, Appl. Catal. A: Gen., 2000, 194-195, 435. 10) T. Nishimura; N. Kakiuchi; T. Onoue; K. Ohe; S. Uemura, J. Chem. Soc., Perkin Trans. 1, 2000, 1915. 11) D.J. Nelson; R. Li; C. Brammer, J. Am. Chem. Soc., 2001, 123, 1564. 12) M. Gaunt; J. Spencer, Org. Lett., 2001, 3, 25. 13) J.M. Takacs; X-t. Jiang, Curr. Org. Chem., 2003, 7, 369. 14) T. Hayashi; K. Yamasaki; M. Mimura; Y. Uozumi, J. Am. Chem. Soc., 2004, 126, 3036. 15) A.L. Maksimov; T.S. Buchneva; E.A. Karakhanov, J. Mol. Catal. A: Chem., 2004, 217, 59. 16) T.J. Sommer, Synthesis, 2004, 161.

COMMENTS :

1749

TSUJI – WILKINSON REACTION EXAMPLE :

CH3 CHO

CH3 0.8 RhCl(PPh3)3 PhCN, reflux

H

MECHANISM :

Ph3P

PPh3 Rh

Cl

Ph3P

- PPh3, S

PPh3

-S

+

Rh Cl

R X PPh 3 Rh OC Cl PPh3

Ph3P X S Rh R Cl PPh3 O

O

S

R

PPh3

X

Ph3P

R X +

OC

X Rh Cl

DISCONNECTION :

O R X

R

O R

X(H) O

R1

R1

R O

R = alkyl, aryl, alkenyl X = H, Cl, Br, CN, CO-alkyl, CO-aryl, CH2CO2CH3 R1 = alkyl, aryl, alkenyl

NOTES :

Aldehydes, acyl halides or 1,2-diketones can be decarbonylated using Wilkinson’s catalyst.

REFERENCES :

1) J. Tsuji; K. Ono, Tetrahedron Lett., 1965, 6, 3969. 2) J. Tsuji; K. Ono, Synthesis, 1969, 157. 3) J.K. Stille; F. Huang; M.T. Regan, J. Am. Chem. Soc., 1974, 96, 1518. 4) S. Murahashi; T. Naota; N. Nakajima, J. Org. Chem., 1986, 51, 898. 5) T. Hansson; B. Wickberg, J. Org. Chem., 1992, 57, 5370.

1750

6) F.E. Ziegler; M. Belema, J. Org. Chem., 1997, 62, 1083. 7) M. Murakami; Y. Ito, Top. Organomet. Chem., 1999, 3, 97.

COMMENTS :

TWITCHELL PROCESS EXAMPLE :

CH2OCOC18H36 CHOCOC18H36 + 3 H2O CH2OCOC18H36

CH2OH CHOH CH2OH

H2SO4 Heat

MECHANISM :

O CH2OCC18H36 CHOCOR CH2OCOR

H2SO4

R1 R1

OH CH2OCC18H36 CHOCOR CH2OCOR

OH CH2OCC18H36 CH HOH CH2

H2O

repeat process

R1 R1

OH CH2OCC18H36 CH OH2 CH2

CH2OH CHOH CH2OH

DISCONNECTION :

CH2OCOR CHOCOR CH2OCOR

CH2OH CHOH CH2OH

NOTES :

The hydrolysis of fatty acids with 30% sulfuric acid to afford the free fatty acid and glycerine. See also Claisen hydrolysis.

1751

REFERENCES : March : 378 Smith – March : 469

1) E. Twitchell, J. Am. Chem. Soc., 1900, 22, 22. 2) E. Twitchell, J. Am. Chem. Soc., 1906, 28, 196. 3) O.T. Joslin, Ind. Eng. Chem., 1909, 1, 654. 4) A.C. Langmuir, Ind. Eng. Chem., 1917, 9, 195. 5) V. Mills; H.K. McClain, Ind. Eng. Chem., 1949, 41, 1982. 6) T.A. Patil; D.N. Butala; T.S. Raghunathan; H.S. Shankar, Ind. Eng. Chem. Res., 1988, 27, 727.

COMMENTS :

TYRER SULFONATION PROCESS EXAMPLE :

SO3H + H2SO4

170 - 180 oC

MECHANISM :

H2SO4

H2O + SO3H

H+ H

SO3H

SO3H

SO3H - H+

1752

DISCONNECTION :

SO3H

NOTES :

The sulfonylation of benzene with sulfuric acid.

REFERENCES : Houben – Weyl : 9, 452 Org. React. : 3, 141

1) D. Tyrer, U.S. Patent, 1917, 1210725. 2) A.W. Harvey; G. Stegeman, Ind. Eng. Chem., 1924, 16, 842.

COMMENTS :

1753

1754

ULLMANN – HORNER PHENAZINE SYNTHESIS · 1761 ULLMANN – LA TORRE ACRIDINE SYNTHESIS · 1763

G

ULLMANN – UKITA – BUCHWALD – LI REACTION · 1765 ULLMANN DIARYL CONDENSATION · 1764

GRAEBE – ULLMANN FLUORENE SYNTHESIS · 1768

ULLMANN DIARYL ETHER SYNTHESIS · 1766 ULLMANN FLUORENONE SYNTHESIS · 1767 U

ULTEE CYANOHYDRIN SYNTHESIS · 1768 URECH CYANOHYDRIN METHOD · 1770

UEMURA OXIDATION · 1756

URECH HYDANTOIN SYNTHESIS · 1771

UGI CONDENSATION · 1757

UTZINGER ALDEHYDE SYNTHESIS · 1772

ULLMANN – FETVADJIAN ACRIDINERING CONDENSATION · 1760

1755

UEMURA OXIDATION EXAMPLE :

O CH2OH

H

5 mol % Pd(OAc)2 pyridine, toluene, 80 oC O2, 3 A MS

MECHANISM :

Pd(OAc)2Py2 R2 R1

HO H AcOH H2O + .5 O2 L2(AcO)Pd

MS 3 A

O H

H2O2

R2 R1

O R1

H2O2 R2

R2 HO

HO

HPd(OAc)L2

R1

R1

R2

H

H O2

HOOPd(OAc)L2

DISCONNECTION :

OH R

O

R1

R

R1

NOTES : The aerobic oxidation of primary and secondary alcohols to the corresponding carbonyl derivatives using palladium acetate and pyridine as rate accelerant. The original conditions developed for the asymmetric oxidation (Pd(OAc)2, (-)-sparteine) were rather sluggish. The Stolz and Sigman group reported that addition of tert-butanol and caesium carbonate increases the reaction rate. The change of solvent to chloroform allows the reaction to be preformed at

1756

room temperature and under ambient air. Both homogeneous and heterogeneous catalysts have been reported. See also Anelli, Ball – Goodwin – Morton, Collins, Corey – Kim, Corey – Schmidt, Corey – Suggs, David – Thieffry, Delépine, Dess – Martin, Einhorn oxidation, Fétizon, Jones oxidation, Ley, Maurer – Drefahl, Mukaiyama oxidation, Nicolaou, Oppenauer, Parikh – von Doering, Pfitzner – Moffatt, Pinnick, Sarett and Swern reactions.

REFERENCES : 1) T. Nishimura; T. Onoue; K. Ohe; S. Uemura, Tetrahedron Lett., 1998, 39, 6011. 2) T. Nishimura; T. Onoue; K. Ohe; S. Uemura, J. Org. Chem., 1999, 64, 6750. 3) D.R. Jensen; J.S. Pugsley; M.S. Sigman, J. Am. Chem. Soc., 2001, 123, 7475. 4) E.M. Ferreira; B.M. Stolz, J. Am. Chem. Soc., 2001, 123, 7725. 5) S.K. Mandal; D.R. Jensen; J.S. Pugsley; M.S. Sigman, J. Org. Chem., 2003, 68, 4600. 6) J.T. Bagdanoff; E.M. Ferreira; B.M. Stolz, Org. Lett., 2003, 5, 835. 7) B.M. Stolz, Chem. Lett., 2004, 33, 362. 8) R.M. Trend; B.M. Stolz, J. Am. Chem. Soc., 2004, 126, 4482. 9) R.J. Nielsen; J.M. Keith; B.M. Stolz; W.A. Goddard III, J. Am. Chem. Soc., 2004, 126, 7967. 10) B.A. Steinhoff; I.A. Guzei; S.S. Stahl, J. Am. Chem. Soc., 2004, 126, 11268.

COMMENTS :

UGI CONDENSATION EXAMPLE :

H

H3C

Ph COOH +

H3C

H

N

Cbz

Ph N

Cbz

H3C O

H3C

+ N

Ph

O

C

9 Kbar, 14 d

H

Ph

N N

Ph

CH3 O Ph H N

O OCH3 O

1757

MECHANISM :

O

O

H

O

O

+ R

O R

R1

OH

H

R

O

O

O

O

H

R2 NC

+

R

R1

R1

H O

O

R1 O

R1

R

H N

O

N R2

O

O R

H

R

N

R

R1 NH2

+

N

O

H N

R

+

R1

R R2

R1 H N

OH

O +

R1

R2 N

O +

R1

R2

+

O

R2

R N R1

R3 N

R3 R

O

R3 NC

HN

R2 O

O

O

R1

H

O

DISCONNECTION :

O R

R1

H N

O

O

O R2

R

OH

+

R1

H

+

R2 NC

O

O R2

R N R1

R3 N

O

O H

R

H

O

1758

+

R1 NH2 +

R2

OH

+ R3 NC

R2

NOTES : The peptide synthesis via a three, four or five component condensation (carboxylic acid, imine, isocyanide). The mechanism is still a subject of uncertainty. Simple starting reagents can give access to tetrazole derivatives, hydantoinimide

derivatives,

thiohydantoinimide

derivatives,

α-acylaminocarboxamide

derivatives,

α-amino

carboxamide derivatives and α-acyloxyaminocarboxamide derivatives. See also Passerini reaction.

REFERENCES : March : 980 Smith – March : 1251 Houben – Weyl : E3, 457; E5, 1652; E16d, 568, 740, 1243

1) R.H. Baker; D. Stanonis, J. Am. Chem. Soc., 1951, 73, 699. 2) I. Ugi; R. Meyr, Chem. Ber., 1961, 94, 2229. 3) I. Ugi, Angew. Chem., Int. Ed. Engl., 1962, 1, 8. 4) G. Skorna; I. Ugi, Angew. Chem., Int. Ed. Engl., 1977, 16, 259. 5) T. Yamada; T. Yanagi; Y. Omote; T. Miyazawa; S. Kuwata; M. Sugiura; K. Matsumoto, J. Chem. Soc., Chem. Commun., 1990, 1640. 6) T.A. Keating; R.W. Armstrong, J. Am. Chem. Soc., 1995, 117, 7842. 7) T.A. Keating; R.W. Armstrong, J. Org. Chem., 1996, 61, 8935. 8) T.A. Keating; R.W. Armstrong, J. Org. Chem., 1998, 63, 867. 9) S.J. Park; G. Keum; S.B. Kang; H.Y. Koh; Y. Kim; D.H. Lee, Tetrahedron Lett., 1998, 39, 7109. 10) N. Shibata; B.K. Das; Y. Takeuchi, J. Chem. Soc., Perkin Trans. 1, 2000, 4234. 11) I. Ugi; B. Werner; A. Dömling, Molecules, 2003, 8, 53. 12) V. Nair; C. Rajesh; A.U. Vinod; S. Bindu; A.R. Sreekanth; J.S. Mathen; L. Balagopal, Acc. Chem. Res., 2003, 36, 899. 13) H. Tye; M. Whittaker, Org. Biomol. Chem., 2004, 2, 813.

COMMENTS :

1759

ULLMANN – FETVADJIAN ACRIDINERING CONDENSATION EXAMPLE :

NH2

+ CH2O

+

N

250 oC

N N

HO

MECHANISM :

H H2N OH

NH2 O

O

H

N

HO H

- 2 H2O

H

H

H N

O O H+ H+

N

N

N H H OH OH

N

- 2 H2O

DISCONNECTION :

+ CH2O

N

NH2

+ HO

NOTES : The synthesis of polynuclear pyridines (acridines) from anilines, phenols and formaldehyde. See also Bernthsen acridine, Mayer and Ullmann – la Torre reactions.

REFERENCES : 1) F. Ullmann; A. Fetvadjian, Ber. Dtsch. Chem. Ges., 1903, 36, 1027. 2) Ng.Ph. Buu-Hoï, J. Chem. Soc., 1949, 670. 3) Ng.Ph. Buu-Hoï, J. Chem. Soc., 1950, 1146.

1760

4) Ng.Ph. Buu-Hoï, J. Chem. Soc., 1951, 2871. 5) Ng.Ph. Buu-Hoï, J. Chem. Soc. (C), 1967, 213.

COMMENTS :

ULLMANN – HORNER PHENAZINE SYNTHESIS EXAMPLE :

CH3 NH2 + OH OH

N

N

CH3

N

NH2

o

N

150 C, melt NH2

OH

1761

MECHANISM :

NH

NH2

K+ + HOC(CH3)3

2

+ KOC(CH3)3

2

NH

NH H

2

+ K2O2

O2

H H N

2 KOC(CH3)3 O2

H N

HN

H2N

N

N

HN

H HN + K2O2 + 2 HOC(CH3)3

N

N K2O2

N H H

+ 2 KOH N

DISCONNECTION :

N

CH3

N

NH2

X = NH2, OH

X

NOTES : The synthesis of phenazine. The Ullmann method react 2-naphthol derivatives with 1-phenylazo-2-napthylamine derivatives. While the Horner method is the autoxidation of 1-aminonapthalene.

1762

REFERENCES : 1) F. Ullmann; J.S. Ankersmit, Ber. Dtsch. Chem. Ges., 1905, 38, 1811. 2) L. Horner; J. Dehnert, Chem. Ber., 1963, 96, 786.

COMMENTS :

ULLMANN – LA TORRE ACRIDINE SYNTHESIS EXAMPLE :

H3C N H

N

PbO reflux

MECHANISM :

NH2 +

H N

H2N

PbO, reflux

I2, reflux

CH3

N

CH3

- NH3

DISCONNECTION :

NH2

N

+

H2N

CH3

NOTES : o-Methyldiarylamines cyclise with anilines in the presence of lead(II) oxide to afford acridines. See also Bernthsen acridine, Mayer and Ullmann – Fetvadjian reactions.

1763

REFERENCES : 1) F. Ullmann; A. La Torre, Chem. Ber., 1904, 37, 2922. 2) Ng.Ph. Buu-Hoï, J. Chem. Soc., 1949, 670. 3) N. Motohashi; J. Emrani; R. Meyer; M. Kawase, Org. Prep. Proced. Int., 1993, 25, 259.

COMMENTS :

ULLMANN DIARYL CONDENSATION EXAMPLE :

OCH3 OCH3

OCH3 I OCH3

1) nBuLi CuI 2) OCH3

OCH3 OCH3

I OCH3 pyridine, heat

MECHANISM :

R

X

R R1

R

R

+ Cu

Cu

R1

X

DISCONNECTION :

R

R

X

+

X R1

R1

-

1764

NOTES : Diaryl derivatives are formed by the condensation of aromatic halides with itself or with other aromatic halides in the presence of metals. A large variety of conditions have been reported by several authors. There are several name reactions derived from the original Ullmann reaction, the most recent one Ullmann – Ukita – Buchwald – Li reaction. See also Gattermann, Kondo – Uyeo and Mayer reactions.

REFERENCES : March : 655 Smith – March : 871 Smith : 1437 Smith 2nd : 1185 Houben – Weyl : 6/3, 86; E8b, 401 Org. React. : 2, 224; 63, 265 Org. Synth. : 20, 45 Org. Synth. Coll. Vol. : 3, 339 Science of Synthesis : 9, 259, 371; 10, 134, 140, 309, 350, 497

1) F. Ullmann; P. Sponagel, Ber. Dtsch. Chem. Ges., 1905, 38, 2211. 2) P.E. Fanta, Chem. Rev., 1946, 38, 139. 3) H.E. Ungnade, Chem. Rev., 1946, 38, 405. 4) P.E. Fanta, Chem. Rev., 1964, 64, 613. 5) P.E. Fanta, Synthesis, 1974, 9. 6) M. Tashiro, Synthesis, 1979, 933. 7) T. Yamamoto; Y. Kurata, Can. J. Chem., 1983, 61, 86. 8) A.J. Paine, J. Am. Chem. Soc., 1987, 109, 1496. 9) A.I. Meyers; J.J. Willemsen, Chem. Commun., 1997, 1573. 10) M. Sugahara; T. Ukita, Chem. Pharm. Bull., 1997, 45, 719. 11) G. Harada; M. Yoshida; M. Iyoda, Chem. Lett., 2000, 160. 12) G.Q. Lin; R. Hong, J. Org. Chem., 2001, 66, 2872. 13) A. Hameurlaine; W. Dehaen, Tetrahedron Lett., 2003, 44, 957. 14) P.-S. Wang; C.-K. Liang; M-k. Leung, Tetrahedron, 2005, 61, 2931.

COMMENTS :

1765

ULLMANN DIARYL ETHER SYNTHESIS EXAMPLE :

Cl

OH

O

+ CuI heat pyridine

MECHANISM :

Y

X

L2CuII X

-

L2CuIII X

L2CuIII Y

e

- e-

L2CuII Y

X Y X2CuIIX2 X

CuIXL2

2L CuIIX2

Cu0 2L

X

Z

CuIX

DISCONNECTION :

OH

O R

R1

R

X +

R1

X = Cl, Br

NOTES : This reaction has traditionally been carried out under harsh conditions, usually at high temperature in pyridine as solvent. Low to moderate yields are common and the reactions between electron-rich aryl halides and electron deficient phenols typically do not work well. Milder reaction conditions have been reported by several groups.

REFERENCES : March : 655

1766

Smith – March : 863 Org. Synth. : 14, 66; 26, 50 Org. Synth. Coll. Vol. : 2, 445; 3, 566

1) F. Ullmann, Ber. Dtsch. Chem. Ges., 1904, 37, 853. 2) F. Ullmann; P. Sponagel, Ber. Dtsch. Chem. Ges., 1905, 38, 2211. 3) R.W. Turner; E.I. Amma, J. Am. Chem. Soc., 1963, 85, 4046. 4) A.A. Moroz; M.S. Shvartsberg, Russ. Chem. Rev., 1974, 43, 679. 5) J. Lindley, Tetrahedron, 1984, 40, 1433. 6) D.L. Boger; S.M. Sakya; D. Yohannes, J. Org. Chem., 1991, 56, 4204. 7) M. Wolter; G. Nordman; G.E. Job; S.L. Buchwald, Org. Lett., 2002, 4, 973.

COMMENTS :

ULLMANN FLUORENONE SYNTHESIS EXAMPLE :

O

O

NH2

CH3

NaNO2, HCl CH3

MECHANISM :

O

NH2

O

CH3

NaNO2 HCl

N2+Cl-

1767

O

CH3

- N2, - HCl CH3

DISCONNECTION :

O

O

NH2

CH3

CH3 O

O

NO2 NO2 NH2

NOTES : A 2-aminobenzophenone is diazotised to afford fluorenone. This reaction is very similar to the Graebe – Ullmann reaction and is sometimes called the Graebe – Ullmann fluorenone synthesis. See also Gomberg – Bachmann – Hey, Larock fluorene and Pschorr reactions.

REFERENCES : 1) C. Graebe; F. Ullmann, Ber. Dtsch. Chem. Ges., 1894, 27, 3484. 2) F. Ullmann; Ed. Mallet, Ber. Dtsch. Chem. Ges., 1898, 31, 1694. 3) W.C. Lothrop; P.A. Goodwin, J. Am. Chem. Soc., 1943, 65, 363. 4) D.F. Detar; S.V. Sagmanli, J. Am. Chem. Soc., 1950, 72, 966. 5) A.J. Nunn; K. Schofield; R.S. Theobald, J. Chem. Soc., 1952, 2797. 6) D.F. Detar; D.I. Relyea, J. Am. Chem. Soc., 1954, 76, 1680.

COMMENTS :

ULTEE CYANOHYDRIN SYNTHESIS EXAMPLE :

H3C

CH3 + HCN O

KOH

1768

CH3 H3C OH CN

MECHANISM :

CN H3C

CH3

H3C

CH3 OH CN

R

R1

O H+

DISCONNECTION :

R1 R

OH O

CN

NOTES : The cyanohydrin synthesis in the presence of a base by addition of water-free hydrogen cyanide to carbonyls and ketones. See also Bouveault – Locquin amino acid, von Braun amino acid synthesis, Bucherer – Bergs, Corey – Link, Darapsky, Herbst – Engel, Knoop – Oosterlin, O’Donnell, Schöllkopf, Sorensen, Strecker amino acid, Tiemann amination, Urech and Zelinksy – Stadnikoff reactions.

REFERENCES : March : 964 Smith – March : 1239 Smith : 678 Smith 2nd : 575 Houben – Weyl : 8, 275

1) A.J. Ultee, Ber. Dtsch. Chem. Ges., 1906, 39, 1856. 2) A.J. Ultee, Recl. Trav. Chim. Pays-Bas, 1909, 28, 1. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189. 4) S.L. Shapiro; I.M. Rose; E. Roskin; L. Freedman, J. Am. Chem. Soc., 1959, 81, 386. 5) H. Plieniger; J. Kurze, Liebigs Ann. Chem., 1964, 680, 60.

COMMENTS :

1769

URECH CYANOHYDRIN METHOD EXAMPLE :

H3C

H

H KCN CH3COOH

O

H3C

OH CN

MECHANISM :

CN H3C

CH3 H3C OH CN

CH3 O H+

DISCONNECTION :

R NC

R1

R

OH

R1 O

NOTES : The cyanohydrin synthesis by addition of alkali cyanide to ketones and aldehydes in the presence of acetic acid. See also Bouveault – Locquin amino acid, von Braun amino acid synthesis, Bucherer – Bergs, Corey – Link, Darapsky, Herbst – Engel, Knoop – Oosterlin, O’Donnell, Schöllkopf, Sorensen, Strecker amino acid, Tiemann amination, Ultee and Zelinksy – Stadnikoff reactions.

REFERENCES : Houben – Weyl : 8, 274 Org. Synth. : 13, 56; 15, 1; 27, 41; 33, 7 Org. Synth. Coll. Vol. : 2, 7, 387; 3, 436; 4, 58

1) F.L. Winckler, Liebigs Ann. Chem., 1832, 4, 246. 2) F. Urech, Liebigs Ann. Chem., 1872, 164, 255. 3) D.T. Mowry, Chem. Rev., 1948, 42, 189. 4) Yu.N. Ogibin; D.S. Velibekova; E.T. Troyanskii; G.I. Nikishin, Izv. Akad. Nauk. SSSR Ser. Khim., 1981, 633. (Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.), 1981, 30, 475.) 5) K. Mori; T. Ebata; S. Takechi, Tetrahedron, 1984, 40, 1761.

1770

6) R.S. Randad; G.H. Kulkarni, Indian J. Chem., 1985, 24B, 225. 7) A.J. Sutherland; J.K. Sutherland; P.J. Crowley, J. Chem. Soc., Perkin Trans. 1, 1996, 349.

COMMENTS :

URECH HYDANTOIN SYNTHESIS EXAMPLE :

NH2 H COOH + KOCN CH3

H3C

H N

O

N H

O HCl

MECHANISM :

NH2.HOCN H COOK CH3

NH2 H COOH + KOCN CH3 H3C

H N

rearrangement

O

O OH

NH2

HCl - H2O

H3C

H N

O

N H

O

DISCONNECTION :

R

H N H

O O

N H

NH2 COOH R

NOTES : An α-amino acid reacts with potassium cyanate to afford an hydantoin. See also Bucherer – Bergs, Johnson 2thiohydantoin and Schlack – Kumpf reactions.

1771

REFERENCES : 1) F. Urech, Liebigs Ann. Chem., 1873, 165, 99. 2) W.T. Read, J. Am. Chem. Soc., 1922, 44, 1746. 3) E. Ware, Chem. Rev., 1950, 46, 403. 4) F.W. Gubitz; W.B. McKeon, jr., J. Med. Chem., 1962, 5, 168. 5) K. Sobczyk; I.Z. Siemion, Pol. J. Chem., 1980, 54, 1833. 6) R.N. Comber; R.C. Reynolds; J.D. Friedrich; R.A. Manguikian; R.W. Buckheit; J.W. Truss; W.M. Shannon; J.A. Secrist, J. Med. Chem., 1992, 35, 3567.

COMMENTS :

UTZINGER ALDEHYDE SYNTHESIS EXAMPLE :

Cl

+

H

OH N

H 1) KMnO4 acetone 2) H2O

O

MECHANISM :

R

Cl

O N R

H

OH N

OH N

R - HCl

R H2O

KMnO4 acetone

H O

DISCONNECTION :

R

H O

R Hal = Cl, Br, I

1772

Hal

NOTES : Alkyl and aromatic halides react in water or in ethanolic pyridine with phenylhydroxylamine to yield a substituted phenylhydroxylamine, which is oxidised by potassium permanganate in acetone, to the nitrone. The latter may be quantitatively hydrolysed to the aldehyde. See also Kröhnke – Ortoleva – King reaction.

REFERENCES : Houben – Weyl : 7/1, 203

1) G.E. Utzinger, Liebigs Ann. Chem., 1944, 556, 50. 2) H.D. Hartough, J. Am. Chem. Soc., 1947, 69, 1355.

COMMENTS :

1773

1774

VASELLA – BERNET REACTION · 1777 VEDEJS HYDROXYLATION · 1779

H

VENKATARAMAN – WAGLE REACTION · 1780 VIGNEAUD du SERINE SYNTHESIS · 1782

HILBERT – JOHNSON – RIST REACTION · 1790

VILSMEIER – HAACK – VIEHE REACTION · 1783 VOIGHT AMINATION · 1785 N

VOLHARD – ERDMANN CYCLISATION · 1786 VORBRÜGGEN – KROLIKIEWICZ REACTION · 1787

NISHIMURA – CRISTESCU N-GLYCOSIDATION · 1790

VORBRÜGGEN NUCLEOSIDE SYNTHESIS · 1789 VORLÄNDER SYNTHESIS · 1790

V VARRENTRAPP OLEIC ACID REACTION · 1776

1775

VARRENTRAPP OLEIC ACID REACTION EXAMPLE :

O ONa 300 oC O

ONa

MECHANISM :

O

H3C O

H2C CH CH2

HC CH CH3

O

- H2O + H2O

O

O O

+ HO-

H2C CH CH2

O O

- H2O + H2O

HC CH CH2

O O

NOTES : When oleic acid is heated in an alkali melt at 300 oC a migration of the double bond to the α,β-position occurs to afford palmitinic acid and acetic acid. Linoleic and stearolic acid give myristic acid, together with small amounts of palmitinic acid, on treatment with molten potassium hydroxide. Similar reactions occur with other olefinic acids.

1776

REFERENCES : Houben – Weyl : E5, 456

1) F. Varrentrapp, Liebigs Ann. Chem., 1840, 35, 196. 2) J.J.A. Blekkingh; H.J.J. Janssen; J.G. Klepper, Recl. Trav. Chim. Pays-Bas, 1957, 76, 35. 3) R.G. Ackman; P. Linstead; B.J. Wakefield; B.C.L. Weedon, Tetrahedron, 1960, 8, 221. 4) R.G. Ackman; R.A. Dytham; B.J. Wakefield; B.C.L. Weedon, Tetrahedron, 1960, 8, 239. 5) R.G. Ackman; B.C.L. Weedon, Tetrahedron, 1960, 8, 246. 6) R.G. Ackman; M.A. Bannerman; M.E. Retson; F.A. van den Heuvel, Can. J. Chem., 1961, 29, 1730.

COMMENTS :

VASELLA – BERNET REACTION EXAMPLE :

Br BnO BnO

OBn OBn O O OCH3

1) Zn, aq. EtOH, reflux 2) H H3C

N

1777

OH

OBn N CH3

OBn

MECHANISM :

Br

ZnBr

OBn O

BnO BnO

Zn, BuOH reflux

OCH3

OBn O

BnO BnO

- OCH3 OCH3 CH3

H BnO BnO

OBn

N O

BnO

O OBn H3C

H N

O N H3C

BnO

OBn OBn

OBn

OH

DISCONNECTION :

Br

OR RO O

O

OR1 R1O

N CH3

OR2

OR2

OCH3

NOTES : The formation of cyclopentane derivatives derived from the monosaccharides, glucose, mannose, galactose and 6deoxy-6-halo-hexono-1,5-ortholactones. The crucial steps in these syntheses are the reductive fragmentation of the 6-bromo-6-deoxy-glycosides affording the unsaturated aldehydes and the intramolecular cycloaddition of the corresponding nitrones.

REFERENCES : 1) B. Bernet; A. Vasella, Helv. Chim. Acta, 1979, 62, 1990. 2) B. Bernet; A. Vasella, Helv. Chim. Acta, 1979, 62, 2400. 3) B. Bernet; A. Vasella, Helv. Chim. Acta, 1979, 62, 2411. 4) B. Bernet; A. Vasella, Helv. Chim. Acta, 1984, 67, 1328.

COMMENTS :

1778

VEDEJS HYDROXYLATION EXAMPLE :

O

O

OH

Ph

1) LDA, - 22 oC Ph 2) MoOPH, 15 min 3) aq. Na2SO3

Ph

Ph

MECHANISM :

O

Ph

Ph Ph

O

O Bu

Pr

Ph

LDA

Pr O

O Pr

Pr

Ph O MoOPH

MoO4L2

OMoO4L2

H2O H+ O

O

O Pr

Ph

OH

Ph

H2O

Ph Ph

Pr O

MoO4L2

Pr

- MoOPH

Pr OH OH

- 2 H2O Pr Ph

O O

Pr

Ph

Pr

O

Ph

DISCONNECTION :

O R1

O R OH

R1 = CR2, OR3

1779

R1

R

NOTES : The oxidation of enolates of ketones, esters and lactones to α-hydroxy derivatives using MoOPH (MoO3.Py.HMPA) reagent. Several side reactions under the typical conditions can take place as shown in the mechanism scheme. See also Hassner – Rubottom α-hydroxylation reaction.

REFERENCES : Smith – March : 915 Smith 2nd : 738 Org. Synth. : 64, 127 Org. Synth. Coll. Vol. : 7, 277

1) E. Vedejs; D.A. Engler; J.E. Telschow, J. Org. Chem., 1978, 43, 188. 2) K. Krohn; H. Riger; K. Khanbabaee, Chem. Ber., 1989, 122, 2323. 3) L.N. Mander; R.P. Robinson, J. Org. Chem., 1991, 56, 3595. 4) S. Hanessian; J.Y. Sanceau, Can. J. Chem., 1996, 74, 621. 5) O. Hara; J. Takizawa; T. Yamatake; K. Makino; Y. Hamada, Tetrahedron Lett., 1999, 40, 7787. 6) D.B. Weibel, Synlett, 2000, 1076.

COMMENTS :

VENKATARAMAN – WAGLE REACTION EXAMPLE :

H N

NH2 CH3COOH +

CH3

Et3N, N

Cl N

Cl N

Cl

1780

O

MECHANISM :

Cl N

Cl

Cl

N N

+ RCOOH + Et3N

N Cl

Cl Cl

N R O

+ Et3NH

O

Cl

N N

Cl

N

N

+ Et3N +

R

Cl O

OH

DISCONNECTION :

R

Cl O R1 N

R

H

RCOOH

O R

OR1 O

O

O HO(CH2)nCOOH

(CH2)n

NOTES : The use of cyanuric chloride in the conversion of carboxylic acids into acid chlorides, esters, amides and peptides. The reaction is also used in the macrolactonisation of ω-hydroxy carboxylic acids. See also Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Vorbrüggen – Krolikiewicz, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : 1) K. Venkataraman; D.R. Wagle, Tetrahedron Lett., 1979, 20, 3037. 2) K. Venkataraman; D.R. Wagle, Tetrahedron Lett., 1980, 21, 1893.

1781

COMMENTS :

du VIGNEAUD SERINE SYNTHESIS EXAMPLE :

OH NH2

1) Br2 2) NaOEt 3) NH4OH 4) aq. HBr

EtO2C

EtO2C

MECHANISM :

Br CO2Et

Br2

EtO

Br CO2Et

Br CO2Et

NH4OH

HO

EtO H2N

NaOEt

H2N

aq. HBr

CO2Et

CO2Et

DISCONNECTION :

NH2 HO

CO2Et

CO2Et

NOTES : Ethyl acrylate is brominated to yield α,β-dibromopropionate, which on treatment with one mole of sodium ethoxide is converted into ethyl α-bromo-β-ethoxypropionate. The latter with ammonium hydroxide gives ethyl α-amino-βethoxypropionate, which with aqueous hydrogen bromide yields dl-serine. See also von Braun amino acid synthesis and Leuchs – Bergmann reactions.

1782

REFERENCES : 1) V. du Vigneaud; J.L. Wood, J. Biol. Chem., 1940, 134, 413. 2) H. Bretschneider; N. Karpitschka; G. Piekarski, Monatsh. Chem., 1953, 84, 1084.

COMMENTS :

VILSMEIER – HAACK – VIEHE REACTION EXAMPLE :

O

DMF, POCl3

N H

H

N H

MECHANISM :

H3C

CH3 N O H

O Cl N O P H3C H Cl Cl

O P Cl Cl Cl

R2N R2N

H3C

O H O P Cl N Cl H3C CH3

- H+

O aq. H+, - HN(CH3)2, - HOPOCl2

R2N H

1783

- Cl

R2N

H3C

CH3 N O H Cl

O O P Cl Cl N CH3 H3C

O P

Cl

DISCONNECTION :

O R

R H H R = aromatic, heterocyclic, an activated ethylene

NOTES : Formamides react with aromatic, heterocyclic and activated ethylenic compounds in the presence of phosphorous oxychloride to produce intermediates, which on hydrolysis in acid solution yield aldehydes. Me2N+=CHCl Cl(Vilsmeier – Haack), Me2N+=CCl2 Cl- (Viehe). See also Friedel – Crafts, Gattermann, Gattermann – Koch and Meth–Cohn quinoline reactions.

REFERENCES : March : 542 Smith – March : 715, 785 Smith : 1328 Smith 2nd : 327, 1093 Houben – Weyl : 7/1, 29; E6a, 95, 438; 758, 977; E6b, 256, 1042, 1050, 1065, 1069, 1098; E7b, 231; E8a, 608, 750, 833, 845, 987; E8b, 263; E19c, 360 Org. React. : 49, 1; 56, 355 Org. Synth. : 20, 11; 33, 27; 64, 144 Org. Synth. Coll. Vol. : 3, 98; 4, 331; 7, 323 Science of Synthesis : 9, 239, 351, 438, 509; 10, 72, 450, 509, 511, 537, 601, 683, 717, 726

1) O. Dimroth; R. Zoeppritz, Ber. Dtsch. Chem. Ges., 1902, 35, 995. 2) A. Vilsmeier; A. Haack, Ber. Dtsch. Chem. Ges., 1927, 60, 121. 3) L.N. Ferguson, Chem. Rev., 1946, 38, 227. 4) A. Vilsmeier, Chem.-Ztg, 1951, 75, 133. 5) H.G. Viehe, Angew. Chem., Int. Ed. Engl., 1971, 10, 575. 6) E.M. Becalli; A. Marchesini; H. Molinari, Tetrahedron Lett., 1986, 27, 627. 7) C.M. Marson, Tetrahedron, 1992, 48, 3659. 8) O. Meth–Cohn, Heterocycles, 1993, 35, 539. 9) S. Paul; M. Gupta; R. Gupta, Synlett, 2000, 1115. 10) Y. Liu; D. Dong; Q. Liu; Y. Qi; Z. Wang, Org. Biomol. Chem., 2004, 2, 28. 11) J.-P. Lellouche; V. Kotlyar, Synlett, 2004, 564. 12) A.D. Thomas; J. Asokan; C.V. Asokan, Tetrahedron, 2004, 60, 5069. 13) D. Dong; Y. Liu; Y. Zhao; Y. Qi; Z. Wang; Q. Liu, Synthesis, 2005, 85.

1784

COMMENTS :

VOIGHT AMINATION EXAMPLE :

Ph

OH

Ph Ph + BuNH2

O

H

H Ph

Bu N

o

1) P2O5, 200 C 2) H+

H O

MECHANISM :

H

H

H2N 200 oC - H2O

OH O

H

OH N

H+

OH N H

DISCONNECTION :

H

H

Ar

Ar

Ar + R NH2

Ar OH N H R

OH O

NOTES : N-substituted 1,2-diaryl amino alcohols are obtained by the interaction of benzoins and primary amines. Phosphorous pentoxide or hydrochloric acid may be used as a condensing agent for aliphatic amines.

1785

REFERENCES : 1) K. Voight, J. Prakt. Chem., 1886, 34, 1. 2) R.E. Lutz; J.A. Freek; R.S. Murphey, J. Am. Chem. Soc., 1948, 70, 2015. 3) R.E. Lutz; J.W. Baker, J. Org. Chem., 1956, 21, 49. 4) U. Müller; H.-J. Timpe; E. Küstermann; K. Urban, Z. Chem., 1981, 21, 224. 5) B.B. Makaparra; B. Patel; D. Satyanarayana; S.K. Pujari, Acta Chim. Hung., 1983, 114, 217.

COMMENTS :

VOLHARD – ERDMANN CYCLISATION EXAMPLE :

NaO2C

CO2Na

P2S3 heat

S

MECHANISM :

O

O

O

P2S3

O O Na+

HO

O S

- 2 H2O reduction

OH

Na+

S

DISCONNECTION :

R

R1

R

R1

O S

O O O

NOTES : The action of diphosphorous trisulfide on sodium succinate or a substituted sodium succinate yields a thiophene. See also Baumann – Fromm, Bogert – Herrera, Fiesselmann, Hinsberg thiophene, Paal – Knorr and Willgerodt – Kindler reactions.

1786

REFERENCES : Org. React. : 6, 9 Org. Synth. : 12, 72; 34, 73 Org. Synth. Coll. Vol. : 2, 578; 4, 671

1) J. Volhard; H. Erdmann, Ber. Dtsch. Chem. Ges., 1885, 18, 454. 2) H. Scheibler; M. Schmidt, Ber. Dtsch. Chem. Ges., 1921, 54, 139. 3) H. Scheibler; F. Rettig, Ber. Dtsch. Chem. Ges., 1926, 59, 1194. 4) F.F. Blicke, Heterocyclic Compounds, 1950, 1, 212. 5) K.E. Schulte; J. Reisch; L. Hörner, Chem. Ber., 1962, 95, 1943.

COMMENTS :

VORBRÜGGEN – KROLIKIEWICZ REACTION EXAMPLE :

CH3 Et CH3COOH +

H2N

O

OH

2 CCl4, 2 PPh3 4 Et3N, CH3CN

N Et

MECHANISM :

PPh3Cl2 + Cl2

PPh3 + CCl4 R

R

OH PPh3Cl2

O R

Cl

R

O

OH Et3N

O

OH O N

H2N

- H2O

H

1787

N

DISCONNECTION :

R X

HX

N n

R1

NH2 n

X = N, O, S n = 1,2

R1

+ R1COOH

NOTES : Carboxylic acids react readily with amino alcohols, amino mercaptans, diamines and o-aminophenols in the presence of triphenylphosphine- or tributylphosphine dichloride (generated in situ from the reaction of the phosphines with hexachloroethane or CCl4) and triethylamine in acetonitrile to form the corresponding Δ2-oxazolines, Δ2-oxazines, Δ2thiazolines, Δ2-imidazolines, 2-substituted benzoxazoles and 2-oxazolidinones. See also Appel, Corey – Nicolaou, Diels – Alder, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Keck macrolactonisation, Kita, Masamune, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Thorpe – Ziegler, Venkataraman – Wagle, Wittig, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : 1) H. Vorbrüggen; K. Krolikiewicz, Angew. Chem., Int. Ed. Engl., 1977, 16, 876. 2) H. Vorbrüggen; K. Krolikiewicz, Tetrahedron Lett., 1981, 22, 4471. 3) H. Vorbrüggen; K. Krolikiewicz, Tetrahedron, 1993, 49, 9353. 4) T.H. Kim; G.-J. Lee, J. Org. Chem., 1999, 64, 2941. 5) G. Madhusudhan; G. Om Reddy; J. Ramanatham; P.K. Dubey, Tetrahedron Lett., 2003, 44, 6323.

COMMENTS :

1788

VORBRÜGGEN NUCLEOSIDE SYNTHESIS EXAMPLE :

O

N Me3SiO

H

OSiMe3 OCH3

O

BzO

O

OAc

+ N

OCH3

N

BzO

Me3SiSO3CF3 NaHCO3

OBz

OBz

O

OBz OBz

MECHANISM :

OTMS BzO

O

BzO

Cl

TMSO

OTMS

AgClO4 benzene

N

O

N

OTMS

ClO4

N O

TMS

BzO

O

N

BzO

OBz

OBz R1

H2O

O N BzO

BzO

O

O

- TMSCl or - TMSClO4

Cl BzO

O O

BzO

N BzO

ClO4

O

N

+

OBz

BzO

N

N H

R2

H R1

N

R2

O N BzO

OBz

BzO

1789

O

N

OBz

O

Ph

NOTES : The synthesis of nucleosides by condensation of sugars with silyl heterocycles and Lewis acids such as SnCl4, BF3.Et2O or trimethyl triflate. In the literature also known as the Hilbert – Johnson – Rist reaction, although several other names show up. See also Nishimura – Cristescu N-glycosidation.

REFERENCES : Org. React. : 55, 1

1) G.E. Hilbert; T.B. Johnson, J. Am. Chem. Soc., 1930, 52, 4489. 2) G.E. Hilbert; C.E. Rist, J. Biol. Chem., 1937, 117, 371. 3) U. Niedballa; H. Vorbrüggen, Angew. Chem., Int. Ed. Engl., 1970, 9, 461. 4) H. Vorbrüggen; B. Bennua, Tetrahedron Lett., 1978, 19, 1339. 5) H. Vorbrüggen; K. Krolikiewicz; B. Bennua, Chem. Ber., 1981, 114, 1234. 6) N. Ikemoto; S.L. Schreiber, J. Am. Chem. Soc., 1990, 112, 9657. 7) B. Bennua–Skalmowski; K. Krolikiewicz; H. Vorbrüggen, Tetrahedron Lett., 1995, 36, 7845. 8) S. Sun; J.A. Piccirilli, Nucleosides, Nucleotides, 1997, 16, 1543. 9) Z. Wang; C.J. Rizzo, Tetrahedron Lett., 1997, 38, 8177. 10) N.A. Al–Masoude, Tetrahedron Lett., 1999, 40, 4795. 10) M. Nomura; T. Sato; M. Washinosu; M. Tanaka; T. Asao; S. Shuto; A. Matsuda, Tetrahedron, 2002, 58, 1279.

COMMENTS :

VORLÄNDER SYNTHESIS EXAMPLE :

OMe

OMe 2 NH2 COOH

1) HNO2 2) Cu+

HOOC HOOC OMe

1790

MECHANISM :

OMe

OMe

OMe

2

2 NH2 COOH

HNO2

N2+ClCOOH

HOOC HOOC

+

Cu - N2

OMe

DISCONNECTION :

R 2 R NH2

R

NOTES : Diphenyl dicarboxylic acids are obtained by diazotisation and subsequent reduction of a derivative of anthranilic acid by ammoniacal cuprous hydroxide. Other types of diaryl derivatives can be similarly prepared.

REFERENCES : Houben – Weyl : 10/3, 163; E16d, 52

1) D. Vorländer; F. Meyer, Liebigs Ann. Chem., 1902, 320, 122. 2) G.H. Beaven; D.M. Hall; M.S. Lesslie; E.E. Turner; G.R. Bird, J. Chem. Soc., 1954, 131. 3) J.I.G. Cadogan; P.G. Hibbert; M.N.U. Siddiqui; D.M. Smith, J. Chem. Soc., Perkin Trans. 1, 1972, 2555.

COMMENTS :

1791

1792

WEYGAND – LÖWENFELD REDUCTION · 1834 WHARTON FRAGMENTATION · 1836

B

WHARTON OLEFIN SYNTHESIS · 1835 WHITING – NAYLER REACTION · 1836

BUU–HOÏ MODIFICATION · 1871

WIBAUT – ARENS SYNTHESIS · 1838 WICHTERLE REACTION · 1839 H

WIDEQVIST CYCLOPROPANE SYNTHESIS · 1841 WIDMAN – STOERMER SYNTHESIS · 1842

HUANG-MILON MODIFICATION · 1875

WIDMANN SYNTHESIS OF INDOLES · 1843 WIELAND – DANE DEGRADATION · 1844

S

WIELAND TRIPHENYLMETHYL RADICAL REARRANGEMENT ·

SCHLOSSER MODIFICATION · 1865

WILKE REACTION · 1847

SCHWENK MODIFICATION · 1849

WILLGERODT – KINDLER REDOX AMINATION · 1849

1845

WILLIAMS – BEN–ISHAI AMINO ACID SYNTHESIS · 1851 WILLIAMSON ETHER SYNTHESIS · 1852

W

WINTERFELDT OXIDATION · 1854 WAGNER – MEERWEIN REARRANGEMENT · 1795

WISLICENUS SYNTHESIS · 1855

WAGNER–JAUREGG ADDITION · 1794

WISSNER α-FUNCTIONALISED METHYL KETONE SYNTHESIS · 1855

WAKAMATSU SYNTHESIS · 1796 WAKATSUKI – YAMAZAKI – BÖNNEMANN REACTION · 1799

WITT DIAZOTATION · 1857

WALKER – HAUSER SYNTHESIS · 1801

WITTE – SEELIGER REACTION · 1858

WALLACH IMIDAZOLE SYNTHESIS · 1802

WITTIG – GILMAN REACTION · 1859

WALLACH REARRANGEMENT · 1803

WITTIG – WITT LITHIUM EXCHANGE · 1859

WASSERMANN – BORMANN MACROCYCLIC LACTAM

WITTIG [1,2]-REARRANGEMENT · 1860 WITTIG [2,3]-REARRANGEMENT · 1861

SYNTHESIS · 1805 WATANABE HETEROCYCLISATION · 1806

WITTIG PHENANTHRENE SYNTHESIS · 1863

WATANABE INDOLE SYNTHESIS · 1808

WITTIG REACTION · 1864

WAWZONEK – YEAKEY REARRANGEMENT · 1809

WOHL – AUE REACTION · 1866

WEERMAN DEGRADATION · 1811

WOHL – MARCKWALD SYNTHESIS · 1867

WEERMAN SYNTHESIS OF INDOLE · 1812

WOHL – ZIEGLER BROMINATION · 1869

WEIDENHAGEN IMIDAZOLE SYNTHESIS · 1813

WOHL DEGRADATION · 1872

WEIL SYNTHEIS OF ARYL ALDEHYDES · 1814

WÖHLER UREA SYNTHESIS · 1873

WEINREB ACYLATION · 1815

WOLFF – KISHNER REDUCTION · 1874

WEISS ANNULATION · 1817

WOLFF REARRANGEMENT · 1876

WEITZ – SCHEFFER REACTION · 1818

WOLFFENSTEIN – BÖTERS REACTION · 1878

WELDE SYNTHESIS OF DIXANTHATES · 1820

WOLFRAM – SCHÖRNIG – HANSDORF CARBOXYMETHYLATION · 1880

WENDER CYCLOHEPTENE SYNTHESIS · 1823 WENDER INDOLE SYNTHESIS · 1821

WOLFRAM SYNTHESIS OF CYCLONITE · 1881

WENDER REACTION · 1825

WOLFROM – KARABINOS REDUCTION · 1882

WENKER RING–CLOSURE · 1826

WOODWARD CIS-HYDROXYLATION · 1883

WENZEL – IMAMOTO REDUCTION · 1827

WOODWARD PEPTIDE SYNTHESIS · 1884

WERNER SYNTHESIS · 1828

WRIGHT – WEST GERMYL MIGRATION · 1886

WESSELY – MOSER REARRANGEMENT · 1829

WURTZ – FITTIG REACTION · 1887

WESTPHAL CONDENSATION · 1830

WURTZ REACTION · 1888

WESTPHALEN – LETTRÉ REARRANGEMENT · 1831

WUYTS SYNTHESIS · 1889

WETTSTEIN OXIDATION · 1833

1793

WAGNER–JAUREGG ADDITION EXAMPLE :

O O

+ 2 Ph

1) AcOH, HI 2) Zn, Ba(OH)2

O

Ph

MECHANISM :

O

O

O

O

O

O

O O

O

O

O O

O

O

O

COOH COOH Zn, Ba(OH)2 - 2 CO2

AcOH, HI

DISCONNECTION :

R1

R3

O

R2 R2

R3 O

X = O, NR4

X

+

R1

X O

O

NOTES : The Diels – Alder reaction between an asymmetrical substituted styrene and maleic anhydride yields bis-adducts, which can be converted into aromatic ring systems. See also Diels – Alder reaction.

REFERENCES : Org. React. : 4, 1

1794

1) T. Wagner–Jauregg, Ber. Dtsch. Chem. Ges., 1930, 63, 3213. 2) F. Bergmann; J. Szmuszkowicz; G. Fawaz, J. Am. Chem. Soc., 1947, 69, 1773. 3) B.R. Stranix; G.D. Darling, J. Org. Chem., 1997, 62, 9001. 4) R.L. Bindu; C.P.R. Nair; K.N. Ninan, J. Appl. Polym. Sci., 2001, 80, 737.

COMMENTS :

WAGNER – MEERWEIN REARRANGEMENT EXAMPLE :

H3C OH H3C H H3C CH3

H+

H3C

CH3

H3C

CH3

MECHANISM :

H3C H H3C OH R CH3

H3C H H3C R CH3

H+, - H2O

H3C

H

H3C

R

CH3

- H+

H3C H3C

H3C

CH3

H3C

R

H R

DISCONNECTION :

R2

R

R1

R2

or R

R3

if R2 = H

R1 R2 R1

R3

R4

R

OH R3 R4

if R has an α−H

1795

CH3

NOTES : This is a retro-pinacolic rearrangement involving certain alkyl carbinols. These undergo heterolytic removal of an anion, or addition of a proton to form a carbonium ion, which suffers a 1,2-rearrangement to form a compound of greater stability. See also von Baeyer – Villiger, Criegee, Demjanov rearrangement, Nametkin, von Ragué Schleyer adamantisation and Wallach reactions.

REFERENCES : March : 1068 Smith – March : 1384, 1393 Smith : 1296 Smith 2nd : 892, 1069 Houben – Weyl : E5, 298, 316; E19c, 3, 72, 398; E15, 2524

1) G. Wagner, J. Russ. Phys. Chem. Ges., 1859, 31, 680. 2) H. Meerwein; K. van Emster, Ber. Dtsch. Chem. Ges., 1922, 55, 2500. 3) A. Streitwieser, jr., Chem. Rev., 1956, 56, 571. 4) T.S. Sorensen, Acc. Chem. Res., 1976, 9, 257. 5) L.A. Paquette; L. Waykole; H. Jendralla; C.E. Cottrell, J. Am. Chem. Soc., 1986, 108, 3739. 6) S.M. Starling; S.C. Vonwiller; J.N.H. Reek, J. Org. Chem., 1998, 63, 2262. 7) L. Birladeanu, J. Chem. Educ., 2000, 77, 858. 8) B. Guizzardi; M. Mella; M. Fagnoni; A. Albini, J. Org. Chem., 2003, 68, 1067. 9) A. Majchrzak; G. Mlostoń; A. Linden; H. Heimgartner, Helv. Chim. Acta, 2004, 87, 790.

COMMENTS :

WAKAMATSU SYNTHESIS EXAMPLE :

H3C

N + H2O + (CH3CO)2O

H3C CO, H2 Co2(CO)8

1796

COOH CH3 N H O

MECHANISM :

NH2

O

H

+

O

H N

R

H

N

O

O OH

R

+

H

OH

O

H

H

O

N H

R

R

[Co(CO)4]

O H+

- H+ CO

[HCo(CO)4] H

H

H2O N

O Co(CO)2

R

O

O

Co(CO)3 N H

O

1797

H

R

X R

O

O +

N H

[PdL2]

R

N H X

R

L

X Pd L

N

O H

- HX

L O R

O R

O

X Pd

CO

L O

N H

O

X

R

N H

H2O

N

H2O

O

OH O

R

N H

DISCONNECTION :

O R1

COOH H N R1 H

R1CHO + RCONH2 + CO

1798

O

H2O - HX

NOTES : Cobalt-catalysed amidocarbonylation is generally carried out at 70 – 160 oC with synthesis gas pressures of 50-200 bar in solvents such as dioxane, THF, DME, ethyl acetate, acetone or benzene. Co2(CO)8 is used in amounts of 1 – 5 mol%. Milder reactions conditions are used for the amidocarbonylation with a palladium catalyst. Temperatures of 70 – 130 oC and CO pressures of 10 – 60 bar are used. In this case the presence of halide ions are essential. For an excellent review on the subject see Beller and Eckert. See also Arndtsen, Asinger, Biginelli, Mannich and Strecker reactions.

REFERENCES : 1) H. Wakamatsu; J. Furukawa; N. Yamakami, Bull. Chem. Soc. Jpn., 1971, 44, 288. 2) H. Wakamatsu; J. Uda; N. Yamakami, J. Chem. Soc., Chem. Commun., 1971, 1540. 3) J.-J. Parnaud; G. Campari; P. Pino, J. Mol. Catal., 1979, 6, 341. 4) M. Beller; M. Eckert, Angew. Chem., Int. Ed., 2000, 39, 1010. 5) Y.-S. Lin; H. Alper, Angew. Chem., Int. Ed., 2001, 40, 779.

COMMENTS :

WAKATSUKI – YAMAZAKI – BÖNNEMANN REACTION EXAMPLE :

Pr Pr 2 Pr

Pr + CH3CN

CpCo(CO)2

1799

Pr

Pr N

CH3

MECHANISM :

H H H

H

CpCo

H

H

CpCo

Cp Co R N

Cp

RCN

Co N R

DISCONNECTION :

R2 R2 R

R1 N

R1 R CN + R1

R1 R1 R

R1 +

R2

R2

R2 N

R2

NOTES : Pyridine is obtained from two alkynes and a nitrile with cobalt complexes, with or without phosphane-modified cobaltcomplexes. Although the method is very effective, mainly a mixture of two regio isomers will be obtained. A way around this is to react first one of the alkynes with the nitrile to give an azametalacyclopentadiene. This is reacted with the second alkyne. See also Bohlmann – Rahtz, Chichibabin pyridine, Gattermann – Skita, Guareschi – Thorpe, Hantzsch – Beyer, von Meyer – Mohr, Petrenko – Kritschenko and Riehm pyridine reactions.

REFERENCES : 1) Y. Wakatsuki; H. Yamazaki, J. Chem. Soc., Chem. Commun., 1973, 280. 2) Y. Wakatsuki; T. Kuramitsu; H. Yamazaki, Tetrahedron Lett., 1974, 15, 4549. 3) H. Bönnemann, Angew. Chem., Int. Ed. Engl., 1978, 17, 505. 4) Y. Wakatsuki; H. Yamazaki, J. Chem. Soc., Dalton Trans., 1978, 1278.

1800

5) H. Hoberg; G. Burkhart, Synthesis, 1979, 525. 6) C.A. Parnell; K.P.C. Vollhardt, Tetrahedron, 1985, 41, 5791. 7) M. Lautens; W. Klute; W. Tam, Chem. Rev., 1996, 96, 49. 8) A.W. Fatland; B.E. Eaton, Org. Lett., 2000, 2, 3131. 9) T. Takahashi; F.-Y. Tsai; Y. Li; H. Wang; Y. Kondo; M. Yamanaka; K. Nakajima; M. Kotera, J. Am. Chem. Soc., 2002, 124, 5059.

COMMENTS :

WALKER – HAUSER SYNTHESIS EXAMPLE :

Ph

Ph

Cl 1) EtOMgCH(CO2Et)2 2) H2O, H+

O

CH3 O

MECHANISM :

R

Cl O

R

CO2Et +

OEt EtO2C

Mg

R

CO2Et

O

CH3

+

CO2Et

H2O, H

O

DISCONNECTION :

R

R

CH3

Cl O

O

NOTES : This synthesis involves the acylation of the sodium- or preferably the magnesium-ethoxy-derivative of diethyl malonate with the appropriate acid chloride followed by hydrolysis and decarboxylation of the two ester groups of the resulting diethyl acyl-malonate in the presence of acid.

REFERENCES : Org. Synth. : 30, 70

1801

Org. Synth. Coll. Vol. : 4, 708

H.G. Walker; C.R. Hauser, J. Am. Chem. Soc., 1946, 68, 1386.

COMMENTS :

WALLACH IMIDAZOLE SYNTHESIS EXAMPLE :

O CH3CH2

N H

CH2CH3 N H

CH2CH3 N CH3 N

1) PCl5 2) HI

O

MECHANISM :

H H RCH2 N O

CH2R N R N

Cl

N CH2R PCl5 - 2 H2O

O

HI

CH2R N R N

DISCONNECTION :

CH2R N R N

H H RCH2 N O

N CH2R O

NOTES : The Wallach synthesis uses N,N-dialkyloxamides with phosphorous pentachloride to yield 5-chloro-Nalkylglyoxalines, which on treatment with hydriodic acid give the N-alkylimidazoles. See also Akabori – Neuberg – Fischer, Brackeen, Bredereck, Debus – Radziszewski, Maquenne and Weidenhagen reactions.

1802

REFERENCES : Houben – Weyl : E8c, 9, 13, 97

1) O. Wallach, Liebigs Ann. Chem., 1877, 184, 1. 2) O. Wallach; E. Schulze, Ber. Dtsch. Chem. Ges., 1881, 14, 420. 3) A. Mukherjee; S. Kumar; A.P. Bhaduri, Indian J. Chem., 1989, 28B, 1. 4) R.A. Egolf; N.D. Heindel, J. Heterocycl. Chem., 1991, 28, 577. 5) T. Benincori; E. Brenna; F. Sannicolo, J. Chem. Soc., Perkin Trans. 1, 1993, 675. 6) D.J.K. Crawford; J.L. Maddocks; D.N. Jones; P. Szawlowski, J. Med. Chem., 1996, 39, 2690.

COMMENTS :

WALLACH REARRANGEMENT EXAMPLE :

N N N O

H2SO4, heat

N

HO

MECHANISM :

Ph N N O

Ph

Ph H2SO4, heat

Ph

Ph

N N H2O

Ph N N

OH

OH N N

H2O

OH

- H2O

H

N

1803

N

DISCONNECTION :

OH Ph

Ph

N N O

Ph N N

NOTES : The acid-catalysed rearrangement of azoxybenzenes to para-hydroxyazobenzenes. Ortho-rearrangement may occur as a side reaction. The mechanism of this reaction has not been fully understood. There is also a photo-chemical Wallach rearrangement known affording an ortho-hydroxyazo compound.

REFERENCES : March : 1155 Smith – March : 1464 Houben – Weyl : E16d, 121

1) O. Wallach; L. Belli, Chem. Ber., 1880, 13, 525. 2) H.E. Bigelow, Chem. Rev., 1931, 9, 117. 3) C.S. Hahn; H.H. Jaffé, J. Am. Chem. Soc., 1962, 84, 946. 4) H. Kolck, Z. Chem., 1989, 29, 18. 5) E. Buncel; K.S. Cheon, J. Chem. Soc., Perkin Trans. 2, 1998, 1241. 6) G.R. Hodges; J.R.L. Smith; J. Oakes, J. Chem. Soc., Perkin Trans. 2, 1999, 1943. 7) A. Lalitha; K. Pitchumani; C. Srinivasan, J. Mol. Catal. A: Chem., 2000, 160, 429.

COMMENTS :

1804

WASSERMANN – BORMANN MACROCYCLIC LACTAM SYNTHESIS EXAMPLE : O O N Ph

N

+ H

1) heat 2) NaBH3CN HOAc

H3CO

Ph

H N

N

MECHANISM :

N H

N

N

N Ph

O

O

O heat OCH3

Ph

Ph

NH OCH3

O

O

N Ph

NaBH3CN HOAc

N

N H

H N

N

Ph

DISCONNECTION :

R2

O

R N

R3 R1 R

N

n

n = 3, 4 and 5

R1 R2

O NH

R3

N

+ H3CO

n

NOTES : The ring-expansion sequence of lactams by reaction with cyclic imino ethers followed by reductive ring-opening to a macrocyclic lactam.

REFERENCES : 1) D. Bormann, Chem. Ber., 1970, 103, 1797. 2) H.H. Wasserman; H. Matsuyama, J. Am. Chem. Soc., 1981, 103, 461. 3) H.H. Wasserman; R.P. Robinson, Tetrahedron Lett., 1983, 24, 3669.

1805

COMMENTS :

WATANABE HETEROCYCLISATION EXAMPLE : NH2

OH +

HO

Ph Ph

RuCl2(PPh3)3 180 oC, 50 h

N H

MECHANISM :

(ArNH2)RuLn

RCH2OH

ArNH2 H RCH2O Ru(ArNH2)Ln

RuLn (RCHO)RuH2(ArNH2)Ln

ArNHCH2R (ArN=CHR)RuH2Ln

1806

- H2O

ArN(CH2R)2 (RCH=N(Ar)CH2R)RuH2Ln

(RCHO)RuH2(ArNHCH2R)Ln

RuLn H RCH2O Ru(ArNHCH2R)Ln

ArNHCH2R RCH2OH

(ArNHCH2R)RuLn

DISCONNECTION :

R3 R2

R N R1

R2 R

R N

R N R1

R1

N R1

H

R1

NOTES : The ruthenium-catalysed N-alkylation or N-benzylation of aminoarenes with alcohols. Quinoline, indole and its derivatives can be prepared.

1807

REFERENCES : 1) Y. Watanabe; Y. Tsuji; Y. Ohsugi; J. Shida, Bull. Chem. Soc. Jpn., 1983, 56, 2452. 2) Y. Watanabe; Y. Tsuji; J. Shida, Bull. Chem. Soc. Jpn., 1984, 57, 435. 3) Y. Watanabe; Y. Tsuji; H. Ige; Y. Ohsugi; T. Ohta, J. Org. Chem., 1984, 49, 3359. 4) Y. Tsuji; K.-T. Huh; Y. Ohsugi; Y. Watanabe, J. Org. Chem., 1985, 50, 1365. 5) Y. Tsuji; K.-T. Huh; Y. Watanabe, J. Org. Chem., 1987, 52, 1673.

COMMENTS :

WATANABE INDOLE SYNTHESIS EXAMPLE :

Cl

N NMe2

3 mol% Pd(dba)2 4.5 mol% PtBu3 NaOtBu, Xylene 120 oC

N NMe2

MECHANISM :

Cl

N

N

NMe2

Pd P

NMe2 Cl

base - HCl

P Pd0 Pd P

N NMe2

1808

N

NMe2

DISCONNECTION :

R

R N NMe2

Cl

N NMe2

NOTES : A palladium-catalysed synthesis of 1-amino indoles. It is assumed that the reaction proceeds via the mechanism shown. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Weerman indole, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : M. Watanabe; T. Yamamoto; M. Nishiyama, Angew. Chem., Int. Ed., 2000, 39, 2501.

COMMENTS :

WAWZONEK – YEAKEY REARRANGEMENT EXAMPLE :

O H3C N CH3 H3C N

O H3C heat

1809

CH3 N N CH3

MECHANISM :

O CH3 CH3 H3C N N H

CH3 H3C N

O N

H

CH3

Br

NO2

HO-

Br O2N

O CH3 H3C N N

CH3

CH3 H3C N

O N

heat, vacuum

CH3

O2N O2N

DISCONNECTION :

O H3C

O

CH3 N N CH3 R

H3C

CH3 N CH3 N R

NOTES : Aminimides with benzyl groups rearrange in a similar fashion to that observed with the corresponding sulfilimines.

REFERENCES : 1) A.S.F. Ash; F. Challenger, J. Chem. Soc., 1952, 2792. 2) S. Wawzonek; E. Yeakey, J. Am. Chem. Soc., 1960, 82, 5718. 3) S.-B. Lee; H. Jung; K.W. Lee, Bull. Korean Chem. Soc., 1996, 17, 362.

COMMENTS :

1810

WEERMAN DEGRADATION EXAMPLE :

O

OH

CH2OH

H2N

OH OH

OH

O

OH

CH2OH

H

HOCl Na2CO3

OH OH

OH

MECHANISM :

NH2

COOH 1) SOCl2 2) NH3

S

S

KOCl, MeOH

O

O

S

N H

OCH3

(COOH)2 EtOH, 100 oC

S H

O

DISCONNECTION : O R

O OH

R

H

NOTES : The synthesis of lower homologue aldehydes from α,β-unsaturated carboxamides (Hofmann degradation). Initially used for the degradation of aldonic acid amides. Later expanded to ethylenic amides. See also Hofmann degradation.

REFERENCES : Org. React. : 3, 267

1) R.A. Weerman, Liebigs Ann. Chem., 1913, 401, 1. 2) R.A. Weerman, Recl. Trav. Chim. Pays-Bas, 1918, 37, 1. 3) C.D. Mason; F.F. Nord, J. Org. Chem., 1951, 16, 1869. 4) P.S. O’Colla; J.J. O’Donnell; J.A. Mulloy, Proc. Chem. Soc., 1961, 300.

1811

COMMENTS :

WEERMAN SYNTHESIS OF INDOLE EXAMPLE :

O NH2 1) KOCl, CH3OH 2) Fe, AcOH 3) KOH

NO2

N H

MECHANISM :

O

H N

NH2 KOCl, CH3OH

NO2 H N

CO2CH3 Fe, AcOH

NO2

CO2CH3 KOH

NH2

N H

DISCONNECTION :

O R

NH2

R N H

NO2

NOTES : o-Nitrocinnamide is converted by methanol and potassium hypochlorite into the methyl carbamate, which is reduced by iron in acetic acid to the corresponding o-amino compound. The latter is cyclised to the indole by heating with alkali. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Hofmann degradation,

1812

Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman, Wender, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) R.A. Weerman, Recl. Trav. Chim. Pays-Bas, 1910, 29, 18. 2) R.A. Weerman, Liebigs Ann. Chem., 1913, 401, 1.

COMMENTS :

WEIDENHAGEN IMIDAZOLE SYNTHESIS EXAMPLE :

N

H3C

H3C O

+

N H

OH

H3C

N

N

NH3, H2CO Cu(OAc)2

H

H3C

MECHANISM :

OH H3C

O

OH N H

+

H3C

O N CH3

O H3C H2N H2N

OH

OH N CH3

NH3

H2CO

H N N

NCu

H3C

H3C

H3C

Cu(OAc)2 NH4OH

N

H3C

1813

N H3C

N

O N CH3 H3C

DISCONNECTION :

R H N

O N

RCHO + NH3 + R1

HO R1

NOTES : This is a modification of the Debus – Radziszewski reaction. See also Akabori – Neuberg – Fischer, Brackeen, Bredereck, Debus – Radziszewski, Maquenne and Wallach imidazole reactions.

REFERENCES : Houben – Weyl : E8c, 9, 13, 97 Org. Syn. : 24, 64 Org. Syn. Coll. Vol. : 3, 460

1) R. Weidenhagen, R. Herrmann, Ber. Dtsch. Chem. Ges., 1935, 68, 1953. 2) C.F. Huebner, J. Am. Chem. Soc., 1951, 73, 4667.

COMMENTS :

WEIL SYNTHESIS OF ARYL ALDEHYDES EXAMPLE :

OH CO2Na

OH 1) Na(Hg), H3BO3, NaHSO3 2) H2SO4

1814

H O

MECHANISM :

OH

OH

OH OH

CO2Na Na(Hg), H3BO3, NaHSO3

H

H

H2SO4

SO3Na

O

DISCONNECTION : OH

OH

H

COOH

O

NOTES : The sodium salt of an aromatic acid is reduced by sodium amalgam in the presence of sodium hydrogen sulfite and boric acid to yield the bisulfite addition compound, which on boiling with sulfuric acid is decomposed to araldehyde. The reaction mainly applies to o-hydroxyaldehydes.

REFERENCES : 1) H. Weil, Ber. Dtsch. Chem. Ges., 1908, 41, 4147. 2) H. Weil; H. Ostermeier, Ber. Dtsch. Chem. Ges., 1921, 54, 3217.

COMMENTS :

WEINREB ACYLATION EXAMPLE :

O Ph

O

O Ph

2 LDA H3CO N H3C

O

1815

O

O

MECHANISM :

O R

R

CH3

N OCH3

LDA, Nu

O

Li N

Nu

O O CH3

H+

R

Nu

CH3

DISCONNECTION :

O

O R

Nu

R

+ Nu

CH3 N OCH3

+ RLi or RMgBr

O

O R1

CH3 N OCH3

R

R1

NOTES : Weinreb amides are acylation reagents. The formed intermediate is stable until it is protonated upon aqueous workup. See also Chattaway acylation, Einhorn acylation, Galat – Elion, Lumière – Barbier and Schotten – Baumann reactions.

REFERENCES : 1) S. Nahm; S.M. Weinreb, Tetrahedron Lett., 1981, 22, 3815. 2) W.L. Whipple; H.J. Reich, J. Org. Chem., 1991, 56, 2911. 3) M. Sibi, Org. Prep. Proced. Int., 1993, 25, 15. 4) M.R. Seong; J.N. Kim; H.R. Kim; R.K. Ryu, Synth. Commun., 1998, 28, 139. 5) A.K. Ghosh; Y. Wang, Tetrahedron Lett., 2000, 41, 4705. 6) L. De Luca; G. Giacomelli; M. Taddei, J. Org. Chem., 2001, 66, 2534. 7) J. Ruiz; N. Sotomayor; E. Lete, Org. Lett., 2003, 5, 1115.

COMMENTS :

1816

WEISS ANNULATION EXAMPLE :

O O

H3CO H3C

O

H3CO

OCH3

O

+ H3C

O

O

O

OCH3 O

aq. NaHCO3

O

H3CO

OCH3

O O

MECHANISM :

R

O 2 H3CO2C

+ R

CO2CH3 O

HO NaHCO3

CO2CH3

R

O

O OH CO2CH3 R H O

NaHCO3

R OH

R

O

CO2CH3 R

H3CO2C NaHCO3 O

HO H3CO2C H3CO2C

R

O

O R OH

H3CO2C

- H2O

CO2CH3 O

O R

H CO2CH3

CO2CH3 R

H3CO2C

O

R

R +

CO2CH3

CO2CH3

CO2CH3

H3CO2C - H2O

O

H3CO2C

CO2CH3

CO2CH3 O

NaHCO3 H3CO2C

R

CO2CH3

DISCONNECTION :

R2 R

R4

O

R +

O

O R3

R1 R 5

O

1817

R1

R4/R2

R3/R5 O

NOTES : The synthesis of fused cyclopentanones (bicyclo[3.3.0]octadiones) or of propellanes from α-dicarbonyl compounds via the double aldol condensation with β-ketoesters.

REFERENCES : Org. Synth. : 64, 27 Org. Synth. Coll. Vol. : 7, 50

1) U. Weiss; J.M. Edwards, Tetrahedron Lett., 1968, 9, 4885. 2) G. Kubiak; J.M. Cook, Tetrahedron Lett., 1985, 26, 2163. 3) A.K. Gupta; X. Fu; J.P. Snydert; J.M. Cook, Tetrahedron, 1991, 47, 3665. 4) X. Fu; J.M. Cook, Aldrichimica Acta, 1992, 25, 43. 5) R.V. Williams; V.R. Gadgil; A. Vij; J.M. Cook; G. Kubiak; Q. Huang, J. Chem. Soc., Perkin Trans. 1, 1997, 1425.

COMMENTS :

WEITZ – SCHEFFER REACTION EXAMPLE :

O

O CH3

O CH3

OOH Ph R toluene

MECHANISM :

O

O

t

CH3 H3C

O

CH3

OOH

KOH, - 40 oC

1818

Bu

Ph H O

H3C H K

H3C

Re face attack

O H3C

Ph H3C H O H3C H3C O H

O H

CH3 Ph

DISCONNECTION :

O

R

O

R1

O R2

R = EWG

R1 R

R2

NOTES : The epoxidation of electron-deficient olefins like α,β-enones with hydroperoxides. The asymmetric version of this reaction has gained considerable attention over the last few years using optically active hydroperoxide and metal ions. See also Buchner – Curtius – Schlotterbeck, Corey – Chaykovsky, Jacobsen – Katsuki, Juliá – Colonna, Katsuki – Sharpless, Mukaiyama – Yamada, Prileschajew and Shi reactions.

REFERENCES : 1) E. Weitz; A. Scheffer, Ber. Dtsch. Chem. Ges., 1921, 54, 2327. 2) H. Pluim; H. Wynberg, J. Org. Chem., 1980, 45, 2498. 3) S. Colonna; A. Manfredi, Tetrahedron Lett., 1986, 27, 387. 4) E.J. Corey; F.-Y. Zhang, Org. Lett., 1999, 1, 1287. 5) W. Adam; P. Bheema Rao; H.-G. Degen; C.R. Saha–Möller, J. Am. Chem. Soc., 2000, 122, 5654. 6) A. Lévai; T. Patonay; A. Székely; E.B. Vass; W. Adam; J. Jekő, J. Heterocycl. Chem., 2000, 37, 1065. 7) W. Adam; P. Bheema Rao; H.-G. Degen; C.R. Saha–Möller, Tetrahedron: Asymmetry, 2001, 12, 121. 8) W. Adam; P. Bheema Rao; H.-G. Degen; C.R. Saha–Möller, Eur. J. Org. Chem., 2002, 630. 9) W. Adam; P. Bheema Rao; H.-G. Degen; A. Levai; T. Patonay; C.R. Saha–Möller, J. Org. Chem., 2002, 67, 259. 10) D.R. Kelly; E. Caroff; R.W. Flood; W. Heal; S.M. Roberts, Chem. Commun., 2004, 2016.

COMMENTS :

1819

WELDE SYNTHESIS OF DIXANTHATES EXAMPLE : CH3

CH3 S S

N2

S EtO

OEt

SK

MECHANISM :

S S EtO

S

S

OEt Cl

S

Cl

S OEt

S

OEt S

DISCONNECTION :

S Ar

Ar

OEt

S

N2

S R

S

R Cl

OEt

NOTES : Dixanthates are obtained by the action of alkali xanthate on alkyl dihalides in ethanol at temperatures of 20 – 50 oC. Similar reaction is possible on diazonium salts.

REFERENCES : Org. React. : 12, 2 Org. Synth. : 27, 81; 72, 265 Org. Synth. Coll. Vol. : 3, 809; 9, 72

1) H. Welde, J. Prakt. Chem., 1877, 15, 43. 2) J. Leuckart, J. Prakt. Chem., 1890, 41, 179. 3) Ed. Bourgeois, Recl. Trav. Chim. Pays-Bas, 1899, 18, 426. 4) D. Lefort; G. Hugel, Bull. Soc. Chim. Fr., 1952, 172.

1820

COMMENTS :

WENDER INDOLE SYNTHESIS EXAMPLE :

Br N O

H CF3

1) CH3Li 2) tBuLi 3) CeCl3, Cl O 4) KOtBu, tBuOH, THF 5) KOH, CH3OH 6) TFA

1821

N H

MECHANISM :

N O

H R

2 nBuLi

HO

Li N O

Li

Cl

R

O

1) tBuOK 2) H2O

N H O

R

N H

t

BuLi CH3Li Br N O

H R

DISCONNECTION :

R1 O N H

N H

R

+

R1

Cl O

NOTES : This reaction starts with the ortho-lithiation of N-phenylamides. The formed dianion is reacted with α-haloketones, ring-closure followed by dehydration will give the indole. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Widman, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

1822

REFERENCES : 1) P.A. Wender; A.W. White, Tetrahedron, 1983, 39, 3767. 2) P. Hewawasam; N.A. Meanwell, Tetrahedron Lett., 1994, 35, 7303. 3) K. Smith; G.A. El–Hiti; G.J. Pritchard; A. Hamilton, J. Chem. Soc., Perkin Trans. 1, 1999, 2299. 4) K. Smith; G.A. El–Hiti; A.P. Shukla, J. Chem. Soc., Perkin Trans. 1, 1999, 2305. 5) K. Smith; G.A. El–Hiti; A.C. Hawes, Synlett, 1999, 945.

COMMENTS :

WENDER CYCLOHEPTENE SYNTHESIS EXAMPLE :

MeO2C MeO2C

CH3

MeO2C 0.5 mol% RhCl(PPh3)3 0.5 mol% AgOTf toluene, 110 oC, 20 min

1823

MeO2C H

MECHANISM :

H PPh3 X

Rh PPh3

H R PPh3 Rh PPh3

X

oxidative coupling

PPh3 PPh3 Rh

X

H

ring expansion

R

Ph3P PPh3 Rh

H

X

reductive elimination - [LnRh]

H

X H

DISCONNECTION :

R

R X R1

X

R

R H X X H

NOTES :

The rhodium-catalysed (AgOTf, modified Wilkinson’s catalyst or [RhCl(CO)2]2, AgOTf) inter- and intramolecular [5+2]-cycloaddition of cyclopropanes with alkynes or alkenes to afford cycloheptenes (cis-fused product). Vinylcyclopropanes behave like dienes because of significant p-orbital character in the strained σ-bond.

REFERENCES :

1) P.A. Wender; H. Takahashi; B. Witulski, J. Am. Chem. Soc., 1995, 117, 4720. 2) P.A. Wender; C.O. Husfeld; E. Langkopf; J.A. Love, J. Am. Chem. Soc., 1998, 120, 1940. 4) P.A. Wender; C.O. Husfeld; E. Langkopf; J.A. Love; N. Pleuss, Tetrahedron, 1998, 54, 7203.

1824

5) S.R. Gilbertson; G.S. Hoge, Tetrahedron Lett., 1998, 39, 2075. 6) P.A. Wender; F. Glorius; C.O. Langkopf; J.A. Love, J. Am. Chem. Soc., 1999, 121, 5348. 7) P.A. Wender; F.C. Bi; M.A. Brodney; F. Gosselin, Org. Lett., 2001, 3, 2105. 8) P.A. Wender; T.J. Williams, Angew. Chem., Int. Ed., 2002, 41, 4550.

COMMENTS :

WENDER REACTION EXAMPLE :

O

OH KH 18-Crown-6 THF, RT

OCH3

OCH3

MECHANISM :

OH

O KH

O

DISCONNECTION :

O

OH

NOTES :

The anionic oxy-Cope rearrangement is followed by a second Cope rearrangement. It is argued that a [5,5]sigmatropic rearrangement directly leads to the 14-membered ring product. See also Cope rearrangement.

1825

REFERENCES : Smith : 1237 Smith 2nd : 1020

1) P.A. Wender; S.McN. Sieburth, Tetrahedron Lett., 1981, 22, 2471. 2) P.A. Wender; S.McN. Sieburth; J.-J. Petraitis; S.K. Singh, Tetrahedron, 1981, 37, 3967. 3) P.A. Wender; D.A. Holt, J. Am. Chem. Soc., 1985, 107, 7771. 4) P.A. Wender; R.J. Ternansky; S.McN. Sieburth, Tetrahedron Lett., 1985, 26, 4319. 5) P.J. Parsons; C.S. Penkett; A.J. Shell, Chem. Rev., 1996, 96, 195.

COMMENTS :

WENKER RING–CLOSURE EXAMPLE :

H2N

OH

1) H2SO4 2) NaOH

H N

MECHANISM :

H2N

OH

H3N

H N

OSO3

H2SO4

NaOH

DISCONNECTION : R N H

R1

1826

R N

R1 OH

NOTES :

Ethanolamine when treated with sulfuric acid gives β-aminoethylsulfuric acid, which with hot alkali yields ethylenimine. See also Blum, Hassner azide aziridine, Gabriel – Marckwald – Cromwell ethylenimine method, Hoch – Campbell, Mansuy – Evans and Scheiner reactions.

REFERENCES :

1) H. Wenker, J. Am. Chem. Soc., 1935, 57, 2328. 2) S.J. Brois, J. Org. Chem., 1962, 27, 3532. 3) V.R. Gaertner, Tetrahedron Lett., 1968, 9, 5919. 4) V.R. Gaertner, J. Org. Chem., 1970, 35, 3952. 5) H.M.I. Osborn; J. Sweeney, Tetrahedron: Asymmetry, 1997, 8, 1693. 6) J-i. Park; G. Tian; D.H. Kim, J. Org. Chem., 2001, 66, 3696. 7) J. Xu, Tetrahedron: Asymmetry, 2002, 13, 1129.

COMMENTS :

WENZEL – IMAMOTO REDUCTION EXAMPLE :

LaNi5H6

NOTES :

The selective reductions of C=C, aldehydes and ketones with LaNi alloy. After the hydrometallation a reductive elimination takes place.

REFERENCES :

1) H. Wenzel, Int. Met. Rev., 1982, 27, 140. 2) T. Imamoto; T. Mita; M. Yokoyama, J. Chem. Soc., Chem. Commun., 1984, 163. 3) T. Imamoto; T. Mita; M. Yokoyama, J. Org. Chem., 1987, 52, 5695.

COMMENTS :

1827

WERNER SYNTHESIS EXAMPLE :

Ph

H N

H N

Ph + (CH3CO)2O

Ph N

heat

S

S

MECHANISM :

Ph

H N

H N

O Ph

O

O S + CH3COOH +

Ph N

O

S

N H

Ph

DISCONNECTION :

Ar

N

S

Ar

H N

H N

Ar

S

NOTES :

Aryl isothiocyanates are obtained by heating N,N’-diarylthioureas with acetic anhydride followed by fractional distillation of the resulting mixture. See also Hugershoff reaction.

REFERENCES : Org. Synth. : 36, 56 Org. Synth. Coll. Vol. : 4, 700

1) E.A. Werner, J. Chem. Soc., 1891, 59, 396. 2) Ng.Ph. Buu–Hoï; Ng.D. Xuong; Ng.H. Nam, J. Chem. Soc., 1955, 1573.

COMMENTS :

1828

WESSELY – MOSER REARRANGEMENT EXAMPLE :

OH O

O HI, 175 oC

H3CO O

HO

OH

OH

O

OH

MECHANISM :

OH

OH

O HI, 175 oC rotation

H3CO O

OH

HO

OH

OH

O

OH

O

R

O HO

OH O

OH

DISCONNECTION : OR2 O

R

O

R1 R = Ar, H, Alk R1 = H, OH, Ar R2 = H, Alk

HO OH

R1 OR2 O

NOTES :

5,8-Dialkoxy- or dihydroxy-flavones rearrange on treatment with hydriodic (or sulfuric) acid, through the intermediate diaroylmethanes, to yield the corresponding 5,6-dihydroxyflavones. The rearrangement has been found to occur with other pyrone derivatives, e.g. isoflavones, flavonols, chromones, chromonols and xanthones.

REFERENCES : Houben – Weyl : E7b, 55

1) F. Wessely; G.H. Moser, Monatsh. Chem., 1930, 56, 97. 2) E.M. Philbin; J. Swirski; T.S. Wheeler, J. Chem. Soc., 1956, 4455. 3) J.L. Suschitzky, J. Chem. Soc., Chem. Commun., 1984, 2275.

1829

4) M. Hauteville; P. Gaillard; M. Kaouadji; M.C. Duclos, Liebigs Ann. Chem., 1996, 1217. 5) K. Shinomiya; Y. Hano; T. Nomura, Heterocycles, 2000, 53, 877. 6) D. Ishiyama; Y. Kanai; H. Senda; W. Iwatani; H. Takahasi; H. Konno; S. Kanazawa, J. of Antibiotics, 2000, 53, 873.

COMMENTS :

WESTPHAL CONDENSATION EXAMPLE :

CH3

H3C +

N Br

CH3

CH3

O

N

Bu2NH reflux

O

CO2Et

CH3

Br

MECHANISM :

Y N Z

Y

Y

N

base

N Z

Z

O

R

O

R

N

- 2 H2O

DISCONNECTION : Y R1

N

YH2

R R1

X

R

X = CCOOR; Y = CAlk X=Y=N X = N; Y = CAlk

1830

N

O

R

O

R

+ XH2

Y

R

Z

R

NOTES :

This is one of the easiest methods for preparing bicyclic systems with a bridgehead quaternary nitrogen atom. The reaction can be done on solid-phase support.

REFERENCES :

1) O. Westphal; K. Jann, Liebigs Ann. Chem., 1957, 605, 8. 2) O. Westphal; K. Jahn; W. Heffe, Arch. Pharm. (Weinheim, Ger.), 1961, 294, 37. 3) M.P. Matia; J.L. García–Navío; J.J. Vaquero; J. Alvarez–Builla, Liebigs Ann. Chem., 1992, 777. 4) A. Diaz; M.P. Matia; J.L. Garcia–Navio; J.J. Vaquero; J. Alvarez–Builla, J. Org. Chem., 1994, 59, 8294. 5) F. Delgado; M.L. Linares; R. Alajarín; J.J. Vaquero; J. Alvarez–Builla, Org. Lett., 2003, 5, 4057.

COMMENTS :

WESTPHALEN – LETTRÉ REARRANGEMENT EXAMPLE :

Me Me

Me Me

O

Me 1) Ac2O 2) NaHSO4

H3CO O

HO

F

H3CO O

1831

H3C

F

O

MECHANISM :

Me Me

Me Me

O Me

Me H+

H3CO HO

O

O

H3CO

- H2O H2O

O

F Me Me

F Me Me

O

O

Me H3CO

H3CO O

F

O

H3C

F

DISCONNECTION :

Me Me

Me Me

O

O

Me H3CO

H3CO O

H3C

Hal

O

HO

Hal

NOTES :

This is the carbocation rearrangement of steroidal tert-alcohols. The position next to the formed carbocation ion has to be a halogen atom. See also Wagner – Meerwein rearrangement.

REFERENCES :

1) T. Westphalen, Ber. Dtsch. Chem. Ges., 1915, 48, 1064. 2) H. Lettré; M. Müller, Chem. Ber., 1937, 70, 1947. 3) J.S. Mihina, J. Org. Chem., 1962, 27, 2807. 4) J.W. Blunt; A. Fischer; M.P. Hartshorn; F.W. Jones; D.N. Kink; S.W. Yoong, Tetrahedron, 1968, 21, 1567. 5) V. Pouzar; P. Drasar; P. Kočovský; M. Havel, Coll. Czech. Chem. Commun., 1982, 47, 96. 6) A. Kasal; M. Budesinsky, Coll. Czech. Chem. Commun., 1996, 61, 276. 7) A. Kasal; J. Polman; M. Budesinsky, Coll. Czech. Chem. Commun., 1998, 63, 1549.

1832

COMMENTS :

WETTSTEIN OXIDATION EXAMPLE :

HO

Al(OtBu)3 BQ, toluene reflux

O

MECHANISM :

HO

Al(OtBu)3 O BQ, toluene Oppenauer oxidation

O

DISCONNECTION :

O

O HO

NOTES :

3β-Hydroxy-5-enic steroids (steroidal allylic alcohols), e.g., preg-5-en-3β-ol-20-one are oxidised by the Oppenauer method with aluminium tert-butoxide, using benzoquinone in boiling toluene as a hydrogen acceptor, to yield a 4,6dien-3-one, e.g., 6-dehydroprogesterone. The reaction can give low yields. Sondheimer et al. published a similar route using manganese dioxide. See also Oppenauer reaction.

1833

REFERENCES :

1) A. Wettenstein, Helv. Chim. Acta, 1940, 23, 388. 2) F. Sondheimer; C. Amendolla; G. Rosenkranz, J. Am. Chem. Soc., 1953, 75, 5930. 3) F. Sondheimer; C. Amendolla; G. Rosenkranz, J. Am. Chem. Soc., 1953, 75, 5933.

COMMENTS :

WEYGAND – LÖWENFELD REDUCTION EXAMPLE : F

NOH

OH HO

OH

NO2

HO

+

OH

O

OH OH

OH OH

NO2

MECHANISM :

F NOH H

OH

H+

NO2 O2N

+ - HF

R

H R

NO2

NO2 OH

N

NO2 H

H N O HO

H

+

OH R

R O

NO2

DISCONNECTION : NOH H

R

H

OH R

O

1834

+ HCN

NOTES :

The sugar oxime degradation with 2,4-dinitrofluorophenol (Sanger reagent) in bicarbonate solution. See also Wohl reaction.

REFERENCES :

1) F. Weygand; R. Löwenfeld, Ber. Dtsch. Chem. Ges., 1950, 83, 559. 2) F. Weygand; O. Trauth; R. Löwenfeld, Ber. Dtsch. Chem. Ges., 1950, 83, 563. 3) F. Weygand; H. Wolz, Ber. Dtsch. Chem. Ges., 1952, 85, 256.

COMMENTS :

WHARTON OLEFIN SYNTHESIS EXAMPLE :

H3C

O

CH3

H3C

CH3 1) NH2NH2 2) Base

O

CH3 CH3

OH

MECHANISM :

O

O

H2NNH2 heat - H2O

N H N H

O H+ B

- N2

OH

1835

N N H

OH

DISCONNECTION :

R

OH R2 R

R1

R3

R1

R2 O

H

R3 N

NH

NOTES :

The conversion of α-haloketones to olefins using hydrazine. Also the reduction α,β-epoxy ketones to allyl alcohols. This reaction can be considered an eliminative Wolff – Kishner reduction. Some authors call this reaction the Wharton fragmentation reaction, this fragmentation is the base-induced fragmentation of cyclic 1,3-diol monosulphate

esters to give medium-sized cyclic alkenes. See also Eschenmoser – Tanabe, Grob, Marshall – Minnaard fragmentation and Wolff – Kishner reactions.

REFERENCES :

1) P.S. Wharton; D.H. Bohlen, J. Org. Chem., 1961, 26, 3615. 2) P.S. Wharton, J. Org. Chem., 1961, 26, 4781. 3) G.V. Nair; G.D. Pandit, Tetrahedron Lett., 1966, 7, 5097. 4) G. Stork; P.G. Williard, J. Am. Chem. Soc., 1977, 99, 7067. 5) S. Takano; K. Inomata; M. Takahashi; K. Ogasawara, Synlett, 1991, 636. 6) K-i. Yamada; T. Arai; H. Sasai; M. Shibasaki, J. Org. Chem., 1998, 63, 3666. 7) M. DiFilippo; F. Fezza; I. Izzo; F. De Riccardis; G. Sodano, Eur. J. Org. Chem., 2000, 3247. 8) J. Liu; R.P. Hsung; S.D. Peters, Org. Lett., 2004, 6, 3989.

COMMENTS :

WHITING – NAYLER REACTION EXAMPLE :

1) EtMgBr CHO 2) 3) LiAlH4 4) Hydrolysis

1836

MECHANISM :

OH

1) LiAlH4 2) Hydrolysis

HO

DISCONNECTION :

R1 R

R

R1 HO HO R

OH

HO OH

H R

R1

R1

NOTES :

Alkenes and alkynyls are normally not reduced by lithium aluminium hydride however propargylic alcohol derivatives are an exception. See also Favorskii – Babayan and Isler reaction.

REFERENCES : Smith : 358 Smith 2nd : 319

1) P. Nayler; M.C. Whiting, J. Chem. Soc., 1954, 4006. 2) O. Isler; M. Montavon; R. Rüegg; P. Zeller, Helv. Chim. Acta, 1956, 39, 454. 3) H.R. Pfaendler; F.K. Maier; S. Klar, J. Am. Chem. Soc., 1986, 108, 1338. 4) B.M. Trost; D.C. Lee, J. Org. Chem., 1989, 54, 2271. 5) J. Mulzer; M. Scharp, Synthesis, 1993, 615.

COMMENTS :

1837

WIBAUT – ARENS SYNTHESIS EXAMPLE :

CH3 1) (CH3CO)2O 2) Zn, heat

N

N

MECHANISM :

O 2

O N

+ (RCO)2O

N

R

N R

O

Zn, heat

N R

R

N R

O

DISCONNECTION :

R

+ N

(RCO)2O

N

R = Alk

NOTES :

Certain 4-alkylpyridine derivatives are formed by the treatment of dry pyridine with an acid anhydride and zinc dust. See also Comins and Friedel – Crafts reactions.

REFERENCES : Houben – Weyl : E7b, 674

1838

1) J.P. Wibaut; J.F. Arens, Recl. Trav. Chim. Pays-Bas, 1941, 60, 119. 2) W. Solomon, J. Chem. Soc., 1946, 934. 3) J.P. Wibaut; D. van der Vennen, Recl. Trav. Chim. Pays-Bas, 1947, 66, 236. 4) I.P. Kutney; T. Tabata, Can. J. Chem., 1963, 41, 695.

COMMENTS :

WICHTERLE REACTION EXAMPLE : CH3

H3C

Cl

CH3

+ H

O

Cl

HClO4, HCOOH heat

O

MECHANISM :

H3C Cl

H

H3C H2SO4

R O - HCl

H3C

OH H

H

Cl

R

H R

1839

H2O, - H+

H3C Cl

R

R

R Cl

n

n

O

Cl

OH

H2O R R

Cl n

+

O

R

CH3 n

H

Cl

Cl

n

O

O

R

R n

Cl

O

n

H2O

O

O

DISCONNECTION :

R

R n

O

Cl n

n = 1 and 2

O

CH3

+ H

Cl

NOTES :

The modification of the Robinson annulation in which 1,3-dichloro-cis-2-butene is used instead of methyl vinyl ketone. In general the Wichterle reaction is the conversion of vinylic halides to ketones with the possibility of additional cyclocondensation. The mechanism is still a matter of speculation. See also Robinson – Mannich annulation.

REFERENCES :

1) O. Wichterle; J. Procházka; J. Hofmann, Coll. Czech. Chem. Commun., 1948, 13, 300. 2) M. Kobayashi; T. Matsumoto, Chem. Lett., 1973, 957. 3) H. Yoshioka; K. Takasaki; M. Kobayashi; T. Matsumoto, Tetrahedron Lett., 1979, 20, 3489. 4) R.W. Conrow; J.A. Marshall, Synth. Commun., 1981, 11, 419. 5) M. Hudlický, Coll. Czech. Chem. Commun., 1993, 58, 2229.

1840

COMMENTS :

WIDEQVIST CYCLOPROPANE SYNTHESIS EXAMPLE :

H3C

CH3

NC

H + 2

CN

NC

O

H3C 1) H+ 2) I-

Br

H3C

CN CN NC

MECHANISM :

N H3C

HO

CH3

NC

O

H3C H3C Br

CN Br

N

+

H

NC H3C

H3C C(CN)2 - HOBr

base H

H3C NC

H3C

CN CN NC

CN Br

DISCONNECTION :

NC R1

CN

R

CN

R

R1 O

NC

H + 2 NC

CN Br

NOTES :

Tetracyanocyclopropane is prepared from bromomalonitrile and ketones. The name is sometimes also spelled as Widequist.

1841

REFERENCES :

1) L. Ramberg; S. Wideqvist, Arkiv. Kemi. Mineral. Geolog., 1937, 12A, 8. 2) S. Wideqvist, Arkiv. Kemi. Mineral. Geolog., 1941, 14B, 13. 3) R.M. Scibner; G.N. Sausen; W.W. Pritchard, J. Org. Chem., 1960, 25, 1440. 4) H. Hart; Y.C. Kim, J. Org. Chem., 1966, 31, 2784.

COMMENTS :

WIDMAN – STOERMER SYNTHESIS EXAMPLE :

CH3

CH3 H

H HNO2, HCl

NH2

N

N

MECHANISM :

R

R

R NH2

R1

R1

R1

HNO2, HCl

N

N N

N

DISCONNECTION :

R1

R1 R

N

R

N

NH2

NOTES :

Cinnolines are obtained by the diazotisation and cyclisation of o-amino-arylethylenes. See also Borsche – Koelsch, Neber – Bossel, Pschorr and von Richter cinnoline reactions.

1842

REFERENCES :

1) O. Widman, Ber. Dtsch. Chem. Ges., 1884, 17, 722. 2) R. Stoermer; H. Fincke, Ber. Dtsch. Chem. Ges., 1909, 42, 3115. 3) N.J. Leonard, Chem. Rev., 1945, 37, 269. 4) K. Schofield; J.C.E. Simpson, J. Chem. Soc., 1945, 512. 5) J.W. Barton; N.D. Pearson, J. Chem. Soc., Perkin Trans. 1, 1987, 1541.

COMMENTS :

WIDMAN SYNTHESIS OF INDOLES EXAMPLE :

CH3 CH2 HOOC

CaO

NO2

N H

NOTES :

Indoles are obtained in low yield by dry distillation of o-nitrophenylalkenes with calcium oxide. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe

indole, Weerman indole, Wender, Yamamoto indole-1, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES :

O. Widman, Ber. Dtsch. Chem. Ges., 1882, 15, 2547.

COMMENTS :

1843

WIELAND – DANE DEGRADATION EXAMPLE :

COOH COOH O CH3 HOOC HOOC

H3C 1) Br2 2) KOH 3) KMnO4 4) Br2 5) KOH 6) KMnO4 7) HNO3

H H

H

MECHANISM : COOH

COOH

COOH

O

O

HOOC O H H3C

HO

H3C

H

H3C H 1) Br2 2) KOH

H

H

H

KMnO4 H

H

COOH

COOH H3C HOOC

HOOC CH3 O OH H3C 1) Br2 2) KOH

H

HOOC

O

KMnO4

H H

H COOH CH3 HOOC HOOC H

1844

CH3

HNO3

DISCONNECTION :

COOH O

COOH H3C

CH3 HOOC HOOC

H H

H

NOTES :

A complex series of reactions by which, e.g. 12-ketocholanic acid is converted into a trans-tricarboxylic acid. The result of this degradation enables a trans configuration to be assigned to the CD rings of the bile-acid and determines the position of the angular methyl group at C(13). See also Barbier – Locquin – Wieland degradation, Miescher degradation, Hoehn – Mason degradation and Trost oxidative decarboxylation reactions.

REFERENCES :

H. Wieland; E. Dane, Hoppe Seylers Z. Physiol. Chem., 1933, 216, 91.

COMMENTS :

WIELAND TRIPHENYLMETHYL RADICAL REARRANGEMENT EXAMPLE :

Ph + 2

Ph Ph

O O Ph

Ph O O

1845

MECHANISM :

O

O 2 Ph3C

+ 2

2

Ph

O

O

R Ph3C

R

R

+

O C(Ph)3

Ph

C(Ph)3 O

or (PhCO2)2 - C6H5COOH

DISCONNECTION :

R

R Ph3C

+

C(Ph)3

NOTES :

A triphenylmethyl radical attacks aromatic substrates in the presence of benzoylperoxyde.

REFERENCES : Smith – March : 241

1) H. Wieland, Ber. Dtsch. Chem. Ges., 1911, 44, 2550. 2) H. Wieland; A. Meyer, Liebigs Ann. Chem., 1942, 551, 249. 3) J.E. Leffler, Chem. Rev., 1949, 45, 387. 4) G.S. Hammond; J.T. Rudesill; F.J. Modic, J. Am. Chem. Soc., 1951, 73, 3929. 5) R.A. Benkeser; W. Schroeder, J. Am. Chem. Soc., 1958, 80, 3314.

COMMENTS :

1846

WILKE REACTION EXAMPLE :

+ 0.46% NiAlL

H3C

N

PPh2 OPPh2

L= OPPh2

MECHANISM :

X Ni

Ni X

PR3, Y ,

Y

Ph

H Ni PR3

Ph

Y Ph

Ni PR3

Ph

Y Ni H

Y Ph

Ni Y PR3

Ph

Ni PR3

Y = non- or weakly coordinating counter ion.

1847

PR3

DISCONNECTION :

R R R

NOTES :

The enantioselective hydrovinylation of olefins is highly atom economic, requires low catalyst loading and low pressure. The classical Wilke reaction uses Ziegler-type catalysts made from tetrabutyltitanate and triethylaluminium. In later versions nickel and palladium are used as metals.

REFERENCES :

1) H. Martin, Angew. Chem., 1956, 68, 306. 2) G. Wilke, Angew. Chem., 1956, 68, 306. 3) G. Wilke, Angew. Chem., Int. Ed. Engl., 1963, 2, 105. 4) W. Ring; J. Gaube, J. Chem. Ing. Tech., 1966, 36, 1041. 5) B. Bogdanovic; P. Heimbach; M. Kroner; G. Wilke; E.G. Hoffmann; J. Brandt, Liebigs Ann. Chem., 1969, 727, 143. 6) G. Wilke, Angew. Chem., Int. Ed. Engl., 1988, 28, 186. 7) G.W. Parshall; W.A. Nugent, CHEMTECH, 1988, 18, 314. 8) G. Wilke; A. Eckerle, Applied Homogeneous Catalysis Organometallic Compounds, 1996, 1, 358. 9) A. Wegner; W. Leitner, Chem. Commun., 1999, 1583. 10) H. Park; T.V. RajanBabu, J. Am. Chem. Soc., 2002, 124, 734. 10) S. Tobisch, J. Am. Chem. Soc., 2004, 126, 259.

COMMENTS :

1848

WILLGERODT – KINDLER REDOX AMINATION EXAMPLE : O O

CH3

NH2

S8 NH4OH pyridine, 160 oC

MECHANISM :

Ph

OH

HNRR1

CH3

Ph

O

Ph

R S

CH3

Ph

R HNRR1

Ph

N

Ph

N

Ph

H2O

R1

R

R1 Ph

R HS N R1

SH

- HNRR1 CH3

N

R1 -S

Ph

SH S

S

R

CH3 N

SH

H2S

Ph

S SH R - H2S

SH

N

Ph

S

R1 S

R1 O

DISCONNECTION : R1 R2 N R O n

R3 R R = Alk, Ar R1, R2, R3 = H, Alk

n

O

NOTES :

The rearrangement of aromatic and aliphatic ketones to amides by heating with sulfur (Kindler modification, Willgerodt used (NH4)2Sx) and ammonia or amines. For volatile amines the corresponding hydrogen chloride salts

can be used. The Schwenk modification is based on the Kindler variation of the Willgerodt reaction, the carbonyl compound is treated with morpholine and sulfur to yield the morpholide of the corresponding thio-acetic acid. This may be hydrolysed with alkali to yield an arylacetic acid. There are several mechanisms proposed in the literature, the most interesting one is the mechanism by Carmack. See also Asinger, and Pummerer reactions.

1849

REFERENCES : March : 1236 Smith – March : 1567 Houben – Weyl : E3, 635; E5, 1232; E8a, 18, 1084; E15, 2029; E6a, 208; E8b, 988 Org. React. : 3, 83; 6, 439 Org. Synth. : 74, 257 Org. Synth. Coll. Vol. : 9, 99 Science of Synthesis : 9, 539

1) C. Willgerodt, Ber. Dtsch. Chem. Ges., 1887, 20, 2467. 2) K. Kindler, Liebigs Ann. Chem., 1923, 431, 193. 3) E. Schwenk; E. Bloch, J. Am. Chem. Soc., 1942, 64, 3051. 4) E. Schwenk; D. Papa, J. Org. Chem., 1946, 11, 798. 5) R.N. Hurd; G. DeLaMater, Chem. Rev., 1961, 61, 45. 6) E.V. Brown, Synthesis, 1975, 358. 7) S.W. Schneller, Int. J. Sulfur Chem., 1976, 8, 591. 8) J.O. Amupitan, Synthesis, 1983, 730. 9) M. Carmack, J. Heterocycl. Chem., 1989, 26, 1319. 10) M.R. Kanyonyo; A. Gozzo; D.M. Lambert; D. Lesieur; J.H. Poupaert, Bull. Soc. Chim. Belg., 1997, 106, 39. 11) L. Skulski; P. Wroczynski, B. Pol. Acad. Sci., Chem., 1999, 47, 231. 12) J.H. Poupaert; K. Bouinidane; M. Renard; D.M. Lambert; M. Isa, Org. Prep. Proced. Int., 2001, 33, 335. 13) M.M. Alam; S.R. Adapa, Synth. Commun., 2003, 33, 59. 14) H.R. Darabi; K. Aghapoor; M. Tajbaksh, Tetrahedron Lett., 2004, 45, 3981.

COMMENTS :

1850

WILLIAMS – BEN–ISHAI AMINO ACID SYNTHESIS EXAMPLE :

Ph

O H3N CO 2

Ph

O

OH

EtO 1) NH2OH.HCl Pd/C, H2 L-Glu 2) BrCH2CO2Et, Et3N (Boc)2O, NaHCO3 p-TsOH, PhH, heat 3) NBS, CCl4

H

CH3 O Si CH3 t Bu OEt

4)

ZnCl2, THF 5) Pd/C, H2

MECHANISM :

H Ph Ph O

Ph OH

H

H Ph NBS, CCl4

Boc

N H

OH

H NH2

NH2OH.HCl Pd/C, H2 resolution with L-Glu Ph

Ph

Ph

H OH

Ph

H NH2

BrCH2CO2Et, Et3N (Boc)2O, NaHCO3 p-TsOH, PhH, heat

Ph H

H Ph

O O Br

N CH3 Boc O Si CH3 EtO2CH2C t Bu OEt ZnCl2, THF

1851

Boc

N

Ph H

O O

Ph H

O H3N CO 2

O Pd/C, H2 O H

EtO

H

DISCONNECTION :

H3N

H

O O

Ph

R H3N

H

Ph O

OH O

O R

NOTES :

Optically active oxazin-2-ones serve as an electrophilic glycine template for the asymmetric synthesis of amino acids.

REFERENCES :

1) D. Ben–Ishai; I. Satari; Z. Berler, J. Chem. Soc., Chem. Commun., 1975, 349. 2) D. Ben–Ishai; Z. Berler; J. Altman, J. Chem. Soc., Chem. Commun., 1975, 905. 3) P.J. Sinclair; D. Zhai; J. Reibenspeis; R.M. Williams, J. Am. Chem. Soc., 1986, 108, 1103. 4) R.M. Williams; P.J. Sinclair; D. Zhai; D. Chen, J. Am. Chem. Soc., 1988, 110, 1547.

COMMENTS :

WILLIAMSON ETHER SYNTHESIS EXAMPLE :

HO HO

H3CO O

Ph

CH3I, KOH Toluene, heat

1852

H3CO

O

Ph

MECHANISM :

R1 X

R1-OR

OR

DISCONNECTION :

R OH

R O R1

+

R1 X

NOTES :

Ethers are synthesised by the interaction of an alkyl halide and an alkali alkoxide. See also Robertson – Robinson and Ullmann diaryl reactions.

REFERENCES : March : 386 Smith – March : 477 Smith : 132 Smith 2nd : 106, 227, 543 Houben – Weyl : 6/3, 24; E6b, 62 Org. Synth. : 25, 9 Org. Synth. Coll. Vol. : 3, 140

1) A.W. Williamson, Liebigs Ann. Chem., 1851, 77, 37. 2) O.C. Dermer, Chem. Rev., 1934, 14, 385. 3) H.-O. Kalinowski; G. Crass; D. Seebach, Chem. Ber., 1981, 114, 477. 4) R.C. Beier; B.P. Mundy; G.A. Strobel, Carbohydr. Res., 1983, 121, 79. 5) A. Katoh; T. Lu; B. Devadas; S.P. Adams; J.L. Gordon; G.W. Gokel, J. Org. Chem., 1991, 56, 731. 6) Y. Doi; A. Hayashi; F. Mikuchi; H. Masada, Nippon Kagaku Kaishi, 1995, 164. 7) A. Weisberg; A. Dahan; M. Portnoy, J. Comb. Chem., 2001, 3, 154. 8) R.G. Stabile; A.P. Dicks, J. Chem. Educ., 2003, 80, 313.

COMMENTS :

1853

WINTERFELDT OXIDATION EXAMPLE :

O O N

N H

CF3

N

O O

4 KO2 18-crown-6 DMF

CF3

O

N H

O O

O

O

DISCONNECTION :

O N N H

N H

N

NOTES :

In the classic example substituted indole derivatives are oxidised on treatment with potassium tert-butylate followed by oxygen. Nowadays potassium superoxide is used and is more superior.

REFERENCES :

1) E. Winterfeldt, Liebigs Ann. Chem., 1971, 745, 23. 2) J. Warneke; E. Winterfeldt, Chem. Ber., 1972, 105, 2120. 3) M. Boch; T. Korth; J.M. Nelke; D. Pike; H. Radunz; E. Winterfeldt, Chem. Ber., 1972, 105, 2126. 4) J.-F. Carniaux; C. Kan–Fan; J. Royer; H.-P. Husson, Tetrahedron Lett., 1997, 38, 2997. 5) W. Jiang; Z. Sui; X. Chen, Tetrahedron Lett., 2002, 43, 8941. 6) X. Zhang; W. Jiang; Z. Sui, J. Org. Chem., 2003, 68, 4523. 7) W. Jiang; X. Zhang; Z. Sui, Org. Lett., 2003, 5, 43. 8) W. Jiang; V.C. Alford; Y. Qiu; S. Bhattacharjee; T.M. John; D. Haynes–Johnson; P.J. Kraft; S.G. Lundeen; Z. Sui, Bioorg. Med. Chem., 2004, 12, 1505.

COMMENTS :

1854

WISLICENUS SYNTHESIS EXAMPLE :

2 ICH2CH2COOH

Ag powder Heat

HOOC

COOH

DISCONNECTION :

R R

2 RI

NOTES :

In the classic example aliphatic dibasic acids are obtained by action of metals (Ag, Ce, Al, U) on halogeno mono basic acids. See also Fittig and Wurtz reactions.

REFERENCES :

1) J. Wislicenus, Liebigs Ann. Chem., 1869, 149, 215. 2) J. Wislicenus, Liebigs Ann. Chem., 1874, 174, 285. 3) J.B. Lal; S. Dutt, J. Indian Chem. Soc., 1932, 9, 570.

COMMENTS :

WISSNER α-FUNCTIONALISED METHYL KETONE SYNTHESIS EXAMPLE :

O

O Cl

OH OSiMe3 OSiMe3 OSiMe3

1855

MECHANISM :

XCH2CO2R

H

LiN[Si(CH3)3]2 THF

+ OSiR3

O Li+

H

OR

TMSCl

O

OR

X

X

R1

R1 Cl

R3SiO

X

OSiR3

H

OR

X CO2R

H+

O

O CO2R

R1 X

R1 hydrolysis and decarboxylation - CO2

X

DISCONNECTION :

O

O

R1

R1

Cl

X

NOTES :

The conversion of acyl chlorides to functionalised (OH, OCH3, OPh, SCH3) ketones using silylated ketene acetals.

REFERENCES :

1) A. Wissner, Tetrahedron Lett., 1978, 19, 2749. 2) A. Wissner, J. Org. Chem., 1979, 44, 4617. 3) A. Wissner; J.E. Birnbaum; D.E. Wilson, J. Med. Chem., 1980, 23, 715.

COMMENTS :

1856

WITT DIAZOTATION EXAMPLE :

N2+

NH2 2

K2S2O5 4 HNO3

2

MECHANISM :

NH2

N

2

K2S2O5 4 HNO3

N

2

DISCONNECTION :

N

N

NH2

R

R

NOTES :

The diazotation of aromatic amines in concentrated nitric acid with a reducing agent. See also Balz – Schiemann, Cadogan arylation, Craig exchange, Demjanov rearrangement, Gattermann diazo, Gattermann sulfinic acid, Griess deamination, Knoevenagel diazotation, Körner – Contardi, Meerwein arylation, Sandmeyer diazonium and Schwechten reactions.

REFERENCES : March : 635 Smith – March : 816 Smith 2nd : 167, 1057 Org. React. : 2, 262

O.N. Witt, Ber. Dtsch. Chem. Ges., 1909, 42, 2953.

COMMENTS :

1857

WITTE – SEELIGER REACTION EXAMPLE :

OH t

OH t

t

Bu

t

Bu

Bu

CH3

Bu

H3C + H2N

cat. ZnCl2 C6H5Cl

OH

O

N

CN

CH3 H3C

MECHANISM :

R OH R1

R N

O

N

- NH3

NH2

R1

DISCONNECTION :

R O

R2 R3 N

R3

R

N

+

R1

R1 R4 H2N OH

R4 R2

NOTES :

The formation of 2-oxazolines from nitriles and amino alcohols using zinc chloride as catalyst. In addition, oxazines can be prepared this way. See also Vorbrüggen – Krolikiewicz reaction.

REFERENCES :

1) H. Witte; W. Seeliger, Liebigs Ann. Chem., 1974, 996. 2) C. Bolm; K. Weickhardt; M. Zehnder; T. Ranff, Chem. Ber., 1991, 124, 1173. 3) A. Scheurer; P. Mosset; W. Bauer; R.W. Saalfrank, Eur. J. Org. Chem., 2001, 3067.

1858

COMMENTS :

WITTIG – GILMAN REACTION EXAMPLE :

H3CO

H3CO

OCH3

Br

Br

PhLi

OCH3

Br

Li

MECHANISM :

R Li + R1 X

R X + R1 Li

NOTES :

An organo lithium species (R1-Li) reacts reversibly with an alkyl halide (mostly Br, I) to produce a new organo lithium species (R-Li) via a metal-halogen exchange. There are several mechanisms proposed, but the equilibrium favours the organo lithium species possessing the best group to stabilise the carbanionic center. This reaction is also known as Wittig – Witt lithium exchange. See also Wurtz coupling.

REFERENCES : Smith : 724 Smith 2nd : 611 Houben – Weyl : 4/2, 783; E7b, 622 Org. React. : 6, 339

1) G. Wittig; U. Pockels; H. Dröge, Chem. Ber., 1938, 71, 1903. 2) H. Gilman; W. Langham; A.L. Jacoby, J. Am. Chem. Soc., 1939, 61, 106. 3) G. Wittig; H. Witt, Ber. Dtsch. Chem. Ges., 1941, 74, 1474. 4) M. Schlosser; K.F. Christman, Angew. Chem., Int. Ed. Engl., 1964, 3, 636. 5) W.F. Bailey; E.R. Punzalan, J. Org. Chem., 1990, 55, 5404. 6) L. Green; B. Chauder; V. Snieckus, J. Heterocycl. Chem., 1999, 36, 1453.

1859

COMMENTS :

[1,2]-WITTIG REARRANGEMENT EXAMPLE :

H3C

H

CH3

O n

OH

BuLi, TMEDA THF

MECHANISM :

R

O

R1

R2H +

R2Li

R

R

O

R1

H OH

O R

R1

O H

H

H+

R1

R

H R1

DISCONNECTION :

OH R

R

H

O

R1

R1

NOTES :

The non-concerted rearrangement of ethers with alkyl lithium to an atom with a lone pair of electrons to yield alcohols via a [1,2]-shift. The reaction can also be samarium diiodide induced. See also Meisenheimer and Stevens

rearrangement reactions.

1860

REFERENCES : March : 1102 Smith – March : 1421

1) G. Wittig; L. Löhmann, Liebigs Ann. Chem., 1942, 550, 260. 2) G. Wittig, Experientia, 1958, 14, 389. 3) U. Schöllkopf, Angew. Chem., Int. Ed. Engl., 1970, 9, 763. 4) V. Rautenstrauch, J. Chem. Soc., Chem. Commun., 1970, 4. 5) R.W. Hoffmann, Angew. Chem., Int. Ed. Engl., 1979, 18, 563. 6) T. Nakai; K. Mikami, Chem. Rev., 1986, 86, 885. 7) K. Tomooka; H. Yamamoto; T. Nakai, Liebigs Ann. Chem., 1997, 1275. 8) K. Tomooka; T. Inoue; T. Nakai, Chem. Lett., 2000, 418. 9) L. Lemiègre; T. Regnier; J.-C. Combret; J. Maddaluno, Tetrahedron Lett., 2003, 44, 373. 10) O. Miyata; T. Koizumi; H. Asai; R. Iba; T. Naito, Tetrahedron Lett., 2004, 45, 3893.

COMMENTS :

[2,3]-WITTIG REARRANGEMENT EXAMPLE :

O

OH n

BuLi HMPA

MECHANISM :

R

R

R1 O

R2

LDA

R

R1

O

R2

H

H+

HO

R

R1

R2

1861

R1 O

R2

DISCONNECTION :

R

R1 HO

R2

R R2 = alkynyl, alkenyl, Ph, COR, CN

R1 O

R2

NOTES :

Certain benzyl and allyl ethers rearrange ([2,3]-sigmatropic rearrangement) on treatment with a base (LDA, nBuLi, NaNH2) to yield secondary and tertiary alcohols. Aza-[2,3] rearrangements have also been published. See also Meisenheimer, Mislow – Evans and Sommelet – Hauser reactions.

REFERENCES : Smith – March : 558, 1453 Houben – Weyl : 12/1, 120 Org. React. : 46, 105 Science of Synthesis : 9, 270

1) G. Wittig; L. Löhmann, Liebigs Ann. Chem., 1942, 550, 260. 2) G. Wittig; P. Davis; G. Koenig, Chem. Ber., 1951, 84, 627. 3) S. Trippett, J. Chem. Soc., Quat. Rev., 1963, 17, 406. 4) N. Sayo; E. Nakai; T. Nakai, Chem. Lett., 1985, 1723. 5) K. Mikami; O. Takahashi; T. Kasuga; T. Nakai, Chem. Lett., 1985, 1729. 6) K. Kakinuma; H.Y. Li, Tetrahedron Lett., 1989, 30, 4157. 7) D.S. Keegan; M.M. Midland; R.T. Werley; J.I. McLoughlin, J. Org. Chem., 1991, 56, 1185. 8) K. Fujimoto; T. Nakai, Tetrahedron Lett., 1994, 35, 5019. 9) D. Enders; D. Backhaus, Synlett, 1995, 631. 10) C. Vogel, Synthesis, 1997, 497. 11) A. Kawachi; H. Maeda; H. Nakamura; N. Doi; K. Tamao, J. Am. Chem. Soc., 2001, 123, 3143. 12) G. McGowan, Aust. J. Chem., 2002, 55, 799. 13) J.C. Anderson; S. Skerratt, J. Chem. Soc., Perkin Trans. 1, 2002, 2871. 14) I.M. Barrett; S.W. Breeden, Tetrahedron: Asymmetry, 2004, 15, 3015.

COMMENTS :

1862

WITTIG PHENANTHRENE SYNTHESIS EXAMPLE :

CH3

H3C CH3 O EtO O EtO

CH3

1) LiAlH4 2) PBr3 3) HN(CH3)2 4) CH3I

MECHANISM :

CH3

CH3 H3C

H3C

CH3

PBr3

LiAlH4 O

OR O RO

CH2OH

CH3

H3C

CH2OH

- H+ CH2

H2C

N H3C CH3

CH2Br

CH3 H3C

HN(CH3)2 H2C

CH N

CH3

H3C CH3

CH3

CH3

CH3

CH3I N(CH3)2

DISCONNECTION :

CH3

H3C

H3C CH3

CH3

O RO O RO

1863

CH2Br

NOTES :

The synthesis of phenanthrene via ylide-isomerisation of a quaternary cyclic ammonium salt. See also Haworth polynuclear aromatics reaction.

REFERENCES :

1) G. Wittig; H. Zimmermann, Chem. Ber., 1953, 86, 629. 2) G. Wittig, Angew. Chem., 1954, 66, 15. 3) A.J. Floyd; S.F. Dyke; S.E. Ward, Chem. Rev., 1976, 76, 509.

COMMENTS :

WITTIG REACTION EXAMPLE :

O

CH2

CH3Br, PPh3 THF

MECHANISM :

R2

R2 H +

X

Ph3P

PPh3

H R1 X

R1

R1

R2

R2

Ph3P

Ph3P

R1

R1

R R

R2

R

R1

1864

R2 R

O R

PPh3 O R

DISCONNECTION :

O R4

R2

R3

R1

R4

X R3

+

R1

O

X = halide R1

R2 X

R2

+

R3

R4

NOTES :

Triphenylphosphine methylene and derivatives substituted in the methylene group react with aldehydes and ketones, whereby the carbonyl oxygen is exchanged for the methylene group to yield triphenylphosphine oxide and the corresponding unsaturated compound. In the Schlosser variant a salt is used as base in which the cation can block the oxygen atom. Then tert-butyl alcohol is added, this protonates the oxygen atom and ring-closure cannot take place and the more favourable conformation is formed (trans). In the aza-Wittig reaction an iminophosphorane formed in a Staudinger reaction is reacted with the ketones. Solvent-free Wittig reactions have also been reported. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Horner – Wadsworth – Emmons, Hunsdiecker ring-closure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Nysted, Petasis reaction, Peterson, Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Staudinger, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Yamaguchi and Yamamoto macrolactonisation reactions.

REFERENCES : March : 956 Smith – March : 1231 Smith : 782 Smith 2nd : 656 Houben – Weyl : 12/1, 120; E15, 2523 Org. React. : 14, 270 Org. Synth. : 40, 66; 75, 153 Org. Synth. Coll. Vol. : 5, 751 Science of Synthesis : 9, 146, 479, 488, 537

1) H. Staudinger; J. Meyer, Helv. Chim. Acta, 1919, 2, 619. 2) G. Wittig; M. Rieber, Liebigs Ann. Chem., 1949, 562, 187. 3) W.J. Gensler, Chem. Rev., 1957, 57, 191. 4) K.C. Nicolaou; W.E. Barnette; P. Ma, J. Org. Chem., 1980, 45, 1463. 5) E. Vedejs; T. Fleck; S. Hara, J. Org. Chem., 1987, 52, 4637. 6) P.J. Murphy; J. Brennan, Chem. Soc. Rev., 1988, 17, 1.

1865

7) B.E. Marynoff; A.B. Reitz, Chem. Rev., 1989, 89, 863. 8) K. Hornfeldt; B. Langstrom, Acta Chem. Scand., 1994, 48, 665. 9) K. Tago; M. Arai; H. Kogen, J. Chem. Soc., Perkin Trans. 1, 2000, 2073. 10) W.M. Dai; C.W. Lau, Tetrahedron Lett., 2001, 42, 2541. 11) T. Rein; T.M. Pedersen, Synthesis, 2002, 579. 12) G. Cami–Kobeci; J.M.J. Williams, Chem. Commun., 2004, 1072. 13) T. Thiemann; M. Watanabe; Y. Tanaka; S. Mataka, New. J. Chem., 2004, 28, 578. 14) P.M. Fresneda; P. Molina, Synlett, 2004, 1.

COMMENTS :

WOHL – AUE REACTION EXAMPLE :

H2N N +

KOH powder Benzene, heat

NO2

N O

MECHANISM :

H

H2N N O

O

NH base

N O O

H N N O O

N

N - H2O

N O

OH

H+

1866

N O

DISCONNECTION :

N

R R

+

N O

H2N

NO2

NOTES :

Phenazine-N-oxide is synthesised from anilines and nitrobenzene. For a more exact and detailed reaction mechanism see Yoshioka et al.

REFERENCES :

1) A. Wohl; W. Aue, Chem. Ber., 1901, 34, 2442. 2) S. Maffei, Gazz. Chim. Ital., 1946, 76, 239. 3) I.J. Pachter; M.C. Kloetzel, J. Am. Chem. Soc., 1951, 73, 4958. 4) S.B. Serebryanyǐ, Ukrain Khim. Zhur., 1955, 21, 350. (Chem. Abs., 1955, 49, 14773h.) 5) I. Yoshioka; H. Otamasu, Hoshi Yakka Daigaku Kiyô, 1957, 6, 44. (Chem. Abs., 1958, 52, 1171h.)

COMMENTS :

WOHL – MARCKWALD SYNTHESIS EXAMPLE :

EtO CH3 H NH2 + CH3NCS EtO H

CH3 N S H3C

1867

N H

H

S +

N H3C

N

CH3

MECHANISM :

EtO CH3 H NH2 EtO H

H CH3 CH3 N C EtO N S H H EtO H

+ CH3NCS

H CH3 CH3 N C EtO N SH H

H CH3 CH3 N C EtO N S H H

HO H

HO H

CH3 N

EtO

EtO

H3C

H

N

N H

H3C

N

CH3

H

- EtOH

- EtOH

CH3 N

H

S

S

N

N H

H3C

H

S

S

H3C

N

CH3

DISCONNECTION :

R N S R1

R1

N H

H

R1

S

O

H

N

NH2 + RNCS H N R

1868

NOTES :

An α-amino aldehyde (an acetal can also be used) or ketone reacts with potassium thiocyanate or alkyl- or arylisothiocyanate to give a substituted thiourea which with acid yields a glyoxazoline-2-thiol. The 2-thiol group can be removed by oxidation. In certain instances substituted α-amino-acetals yield thiazolines or mixtures of glyoxalines, thiazolines and thiazoles. See also Debus, Maquenne, Radziszewski, Wallach and Weidenhagen reactions.

REFERENCES :

1) A. Wohl; W. Marckwald, Ber. Dtsch. Chem. Ges., 1889, 22, 568. 2) R. Burtles; F.L. Pyman; J. Roylance, J. Chem. Soc., 1925, 581.

COMMENTS :

WOHL – ZIEGLER BROMINATION EXAMPLE :

O N Br O

H +

H R

H

H H

H

benzoyl peroxide, CCl4

1869

H

Br R

H

H

MECHANISM :

O

O

N Br

N

initiator

O Br

Br

O

Br

initiator

H

2 Br

H

H R

H

H

H

Br

+

H R

+

H H O

O N Br

N H

Br2 +

+ HBr

O

O H

H

H + Br2

R

+

Br

H H

H

R

H

H

H Br

+ R

H

H

Br

H

R

H

H

Br2

2 Br

DISCONNECTION :

R R1

R

R2

R1

Br R3

1870

R2 H

H

R3

H

Br

NOTES :

The use of N-haloamides, especially N-bromosuccinimide (NBS) as brominating agents, e.g., for the bromination of olefins. The method is of value in the production of α-bromoketones. In some cases dehydrobromination occurs to introduce a new double bond. Certain applications of the reaction require the use of catalysts, e.g. light, benzoyl peroxide, metal chlorides. The Buu–Hoï modification uses N-chlorosuccinamide to chlorinate aliphatic compounds in the presence of peroxybenzoyl. NBS can also be used to brominates non-olefinic substrates.

REFERENCES : March : 694 Smith – March : 911 Smith : 156 Smith 2nd : 126 Houben – Weyl : 5/4, 221; 8, 657; E8d, 80 Org. Synth. : 38, 8; 42, 26; 46, 81; 56, 49 Org. Synth. Coll. Vol. : 4, 108; 5, 145; 6, 462

1) A. Wohl, Ber. Dtsch. Chem. Ges., 1919, 52, 51. 2) K. Ziegler; A. Späth; E. Schaaf; W. Schumann; E. Winkelmann, Liebigs Ann. Chem., 1942, 551, 80. 3) C. Djerassi, Chem. Rev., 1948, 43, 271. 4) Ng.Ph. Buu–Hoï; P. Demerseman, J. Org. Chem., 1953, 18, 649. 5) R. Filler, Chem. Rev., 1963, 63, 21. 6) M. Pinza; G. Pfferi, J. Pharm. Sci., 1978, 67, 120. 7) S. Harusawa; H. Ohishi; H. Osaki; S. Tomii; R. Yoneda; T. Kurihara, Chem. Pharm. Bull., 1992, 40, 2185. 8) W. Lowe; S. Bratter; C. Dietrich; M. Weber; P. Luger, J. Heterocycl. Chem., 1997, 34, 1173. 9) S.M. Ma; B. Xu; S.M. Zhao, Synthesis, 2000, 139.

COMMENTS :

1871

WOHL DEGRADATION EXAMPLE :

H

O

H H H H H

OH OH OH OH OH

1) H2NOH, H+ 2) Ac2O, NaOAc 3) Ag2O, NH3 4) HCl, H2O

H

O

H H H H

OH OH OH OH H

H

MECHANISM :

H

N

O

H H

OH OH

H2NOH, H+ +

- H3O

H

N OH

H H

OH OH

R

H

R

Ac2O, NaOAc - 2 H2O

H H

OAc OAc R

Ag2O, NH3 - HCN

Ac N

H H

NHAc OH R

HCl, H2O - 2 H2NAc

H

O

H

OH R

DISCONNECTION :

H

O

H

O

H

OH

H H

OH OH

R

R

NOTES :

An aldose oxime is acetylated to yield the nitrile of the corresponding acetylated aldonic acid, which with ammoniacal silver oxide or ammonia yields the diacetimido compound of the aldose containing one carbon less than the original aldose. The diacetimido compound is then hydrolysed to the lower aldose. The method is nowadays of limited value. See also Kiliani – Fischer, Ruff – Fenton, Weerman degradation and Zemplén reactions.

1872

REFERENCES : Org. Synth. : 20, 74 Org. Synth. Coll. Vol. : 3, 690

1) A. Wohl, Ber. Dtsch. Chem. Ges., 1893, 26, 730. 2) G. Zemplén, Ber. Dtsch. Chem. Ges., 1926, 59, 1254. 3) F. Weygand; H. Wolz, Chem. Ber., 1952, 85, 256. 4) E.G. Gros; V. Deŭlofeŭ, J. Org. Chem., 1964, 29, 3647. 5) W.W. Wendall, Tetrahedron Lett., 1970, 11, 3439.

COMMENTS :

WÖHLER UREA SYNTHESIS EXAMPLE :

O C N K

H2 N aq. NH3

NH2 O

MECHANISM :

R N

O

R1NH2

H

R N

R1 N

H

O

H+

DISCONNECTION :

R

H N

H N

R1

R1 NH2 + R N

O

1873

O

NOTES :

The classical formation of urea from an aqueous solution of ammonia to a salt of isocyanate. See also Bosch – Meiser reaction.

REFERENCES : Smith – March : 1191 Org. Synth. : 17, 16; 21, 83; 28, 89; 31, 8; 36, 8; 37, 52; 45, 89; 56, 95 Org. Synth. Coll. Vol. : 2, 79; 3, 617, 735; 4, 49; 180; 213; 515; 700; 5, 801; 6, 951

1) F. Wöhler, Pogg. Ann., 1828, 12, 253. 2) L. Jannelli, Gazz. Chim. Ital., 1958, 88, 443. 3) G. Richet, Am. J. Neph., 1995, 15, 528. 4) G. Kauffman; S. Chooljian, Chem. Ind. (London), 2000, 23, 774.

COMMENTS :

WOLFF – KISHNER REDUCTION EXAMPLE :

O HOOC

COOH

1874

NH2NH2 KOH

HOOC(CH2)9COOH

MECHANISM :

O R

R

base

R2C N NH2 NH2NH2 - H2O - H+

H-solvent

R2C N N H

R2C N NH

R2C N N H

- N2

R2C N NH H

R2CH H-solvent

R2CH2

DISCONNECTION :

O RCH2R1

R

R1

NOTES :

The carbonyl group in aldehydes and ketones can be reduced to a methylene group by heating the azine, hydrazone or semicarbazone with an alkaline catalyst, e.g. potassium hydroxide or sodium ethoxide. α,β-Unsaturated carbonyl compounds react abnormally. Certain hydroxy and amino-ketones may undergo elimination to yield an olefin (Kishner reduction elimination). In the original procedure, the carbonyl was heated with hydrazine hydrate and a base. This method has been almost completely replaced by the Huang–Milon modification, where the reaction is carried out in refluxing diethylene glycol. See also Clemmensen, Schwenk, and Wolfrom – Karabinos reactions.

REFERENCES : March : 1209 Smith – March : 1547 Smith : 473 Smith 2nd : 411, 1094, 1136 Houben – Weyl : 5/1a, 251; E6a, 407, 719; E8a, 904; E8b, 525; E14b, 596 Org. React. : 4, 378 Org. Synth. : 43, 34 Org. Synth. Coll. Vol. : 5, 533 Science of Synthesis : 10, 322, 340, 619, 737, 783

1) N. Kishner, J. Russ. Phys. Chem. Ges., 1911, 43, 582. 2) L. Wolff, Liebigs Ann. Chem., 1912, 394, 1912. 3) Huang–Milon, J. Am. Chem. Soc., 1946, 68, 2487.

1875

4) H.H. Szmant; C.M. Harmuth, J. Am. Chem. Soc., 1964, 86, 2909. 5) T. Momose; O. Muraoka, Tetrahedron Lett., 1978, 19, 1125. 6) C. Crestini; R. Saladino, Synth. Commun., 1994, 24, 2835. 7) Q. Lin; E. Parquet, J. Chem. Educ., 1997, 74, 1225. 8) K. Mlinarić–Majerski; G. Kragol, Eur. J. Org. Chem., 1999, 1401. 9) C.G. Bashore; I.J. Samardjiev; J. Bordner; J.W. Coe, J. Am. Chem. Soc., 2003, 125, 3268. 10) M.E. Furrow; A.G. Myers, J. Am. Chem. Soc., 2004, 126, 5436.

COMMENTS :

WOLFF REARRANGEMENT EXAMPLE :

O

Cl

CO2Et

1) CH2N2 2) PhCO2Ag EtOH

MECHANISM :

H

H

O

R Cl

H

CH2N2

O

O

R N N

H H

R

C H

C

O

H

O

H

OH

R H2O

1876

- N2

R

CH

DISCONNECTION : H

O

H

O

H

Cl

R

R H

OH

NOTES :

α-Diazoketenes can be converted by heating in solvents with or without heterogeneous or homogeneous catalysts, into nitrogen and a ketene, or into products that would be formed from the ketene by reaction with such hydroxy- and amino-compounds as are present in solution. Amines and silver oxide, Raney nickel, silver benzoate dissolved in triethylamine, and ultra-violet light are among the catalysts employed. See also Arndt – Eistert, Clibbens – Nierenstein, Curtius, Lossen, Schmidlin and Süs reactions.

REFERENCES : March : 201,1083 Smith – March : 1250, 1405 Smith : 1453 Smith 2nd : 1199 Houben – Weyl : E6a, 702; E11, 241, 1334, 1415; E14b, 1371; E15, 2393, 2578; E16b, 463, 538, 597, 934; E19b,

1055, 1232, 1431, 1679 Org. React. : 1, 39 Org. Synth. : 52, 53 Org. Synth. Coll. Vol. : 6, 840 Science of Synthesis : 9, 27, 71, 505

1) L. Wolff, Liebigs Ann. Chem., 1912, 394, 25. 2) F. Arndt; B. Eistert, Ber. Dtsch. Chem. Ges., 1935, 68, 200. 3) J. Meinwald; P.G. Gassman, J. Am. Chem. Soc., 1960, 82, 2857. 4) K.B. Wiberg; B.A. Hess, jr., J. Org. Chem., 1966, 31, 2250. 5) R.J. McMahon; O.L. Chapman; R.A. Hayes; T.C. Hess; H.-P. Krimmer, J. Am. Chem. Soc., 1985, 107, 7597. 6) T. Lippert; A. Koskelo; P.O. Stoutland, J. Am. Chem. Soc., 1996, 118, 1551. 7) J. Podlech; M.R. Linder, J. Org. Chem., 1997, 62, 5873. 8) H. Yang; K. Foster; C.R.J. Stephenson; W. Brown; E. Roberts, Org. Lett., 2000, 2, 2177. 9) W. Kirmse, Eur. J. Org. Chem., 2002, 2193. 10) P.H. Dussault; C. Xu, Tetrahedron Lett., 2004, 45, 7455. 11) J.R. Davies; P.D. kane; C.J. Moody; A.M.Z. Slawin, J. Org. Chem., 2005, 70, 5840.

1877

COMMENTS :

WOLFFENSTEIN – BÖTERS REACTION EXAMPLE :

OH O2N

NO2

HNO3 Hg(NO3)2 100 oC

NO2

MECHANISM :

N2NO3

NO

HgNO3

Hg(NO3)2

dil. HNO3

N2O4

conc. HNO3

NO2

H2O

HO

OH

HNO3 NO2

O2N

HNO3 NO2

O2N

NO2 HNO3 NO2

HO

1878

NO2

HO NO2

DISCONNECTION :

NO2 HO O2N

NO2

HO O2N

NO2

HO NO2

NOTES :

The hydroxynitration of aromatic compounds to nitrophenols with nitric acid or higher oxides of nitrogen in the presence of a mercury salt as catalyst. See also Zincke halogenphenol nitration.

REFERENCES : Houben – Weyl : 10/1, 815

1) O. Böters; R. Wolffenstein, U.S. Patent, 1909, 923761. 2) O. Böters; R. Wolffenstein, Ber. Dtsch. Chem. Ges., 1913, 46, 586. 3) T.L. Davies, J. Am. Chem. Soc., 1922, 44, 1588. 4) F.H. Westheimer; E. Segel; R. Schramm, J. Am. Chem. Soc., 1947, 69, 773.

COMMENTS :

1879

WOLFRAM – SCHÖRNIG – HANSDORF CARBOXYMETHYLATION EXAMPLE : COOH +

OH

Cl

Fe3O4, KBr

O

MECHANISM : O

O

Cl Cl

OH

n O

O

O

KBr

O

+ n-1 HCl

OH n

active species

DISCONNECTION :

COOH

R

R

+

OH

Cl O

NOTES :

The carboxymethylation of aromatics in the presence of oxidants or thermally or by photochemical means to afford aromatic acetic acids. See also Kolbe – Schmitt and Reimer – Tiemann reactions.

REFERENCES :

1) A. Wolfram; L. Schörnig, German Patent, 1929, 562391. 2) E. Hansdorf, U.S. Patent, 1934, 1951686. 3) Y. Ogata; J. Ishiguro; Y. Kitamura, J. Org. Chem., 1951, 16, 239. 4) P.L. Southwick, Synthesis, 1970, 628.

COMMENTS :

1880

WOLFRAM SYNTHESIS OF CYCLONITE EXAMPLE :

H

H

O2N + 3 H2NSO3K

N

HNO3 SO3

O

N

NO2

N NO2

MECHANISM :

K H

H

O3S

N

N

O2N

SO3 K

+ 3 H2NSO3K

HNO3 SO3

N SO3 K

O

N

N

NO2

N NO2

DISCONNECTION : O2N

N

N

NO2 H

N NO2

H

+ H2NSO3K

O

NOTES :

Formaldehyde reacts with potassium sulfamate to yield tripotassium 1,3,5-triazocyclohexane-1,3,5-trisulfonate that is nitrated to cyclonite using absolute nitric acid and sulfur dioxide. See also Ebele – Schiessler – Ross, Hale and Knoffler – Bachmann reactions.

REFERENCES :

1) W.P. Binnie; H.L. Cohen; G.F. Wright, J. Am. Chem. Soc., 1950, 72, 4457. 2) C.J. McHugh; W.E. Smith; R. Lacey; D. Graham, Chem. Commun., 2002, 2514.

COMMENTS :

1881

WOLFROM – KARABINOS REDUCTION EXAMPLE :

H3C

CH3

H H +

HS

O

SH H H

H3C 1) H+ 2) Raney Ni H2

H

CH3 H

MECHANISM :

R

R1

H H SH

+ HS

O

H+

R

R1

S

S Raney Ni, H2 EtOH - C2H6, - H2S

H2O

H H

R

R1

H

H

DISCONNECTION : R

R1

H

H

R

R1 O

NOTES :

The carbonyl groups of aldehydes and ketones can be reduced to the hydrocarbon stage by the hydrogenolysis of their thioacetals with Raney nickel in dilute ethanolic solution. See also Clemmensen, Corey – Seebach and Wolff – Kishner reactions.

REFERENCES : Houben – Weyl : 5/1a, 327 Org. React. : 8, 229

1) M.L. Wolfrom; J.V. Karabinos, J. Am. Chem. Soc., 1944, 66, 909. 2) M.L. Wolfrom; J.V. Karabinos, J. Am. Chem. Soc., 1945, 67, 500. 3) H. Hauptmann, J. Am. Chem. Soc., 1947, 69, 562. 4) F. Sondheimer; S. Wolfe, Can. J. Chem., 1959, 37, 1870. 5) H. Hauptmann; W.F. Walter, Chem. Rev., 1962, 62, 347.

1882

COMMENTS :

WOODWARD CIS-HYDROXYLATION EXAMPLE :

I2, AgOAc aq. CH3COOH

HO

OAc

MECHANISM :

I

I2, AgOAc - AgI

-I I

OAc

O O CH3

H+ O

O

aq. CH3COOH

O H3C

CH3

O HO

O H

OAc

DISCONNECTION :

R1 HO

R2

R1

R2

OAc

H

H

NOTES :

An olefinic compound is cis-hydroxylated by treatment with iodine and silver acetate in wet acetic acid followed by alkaline hydrolysis of the mixed mono- and di-acetates first formed. See also Bäckvall, Birnbaum – Simonini, Brown, Milas, Prévost and Sharpless dihydroxylation reactions.

REFERENCES : Smith – March : 1050

1883

Smith 2nd : 255

1) S. Winstein; R.E. Buckles, J. Am. Chem. Soc., 1942, 64, 2780. 2) R.B. Woodward, U.S. Patent, 1954, 2687435. 3) W. Lwowski, Angew. Chem., 1958, 70, 490. 4) R.B. Woodward; F.V. Brutcher, jr., J. Am. Chem. Soc., 1958, 80, 209. 5) W.R. Mayberry, J. Microbiol. Methods, 1984, 2, 177. 6) H.H. Jensen; M. Bols, J. Chem. Soc., Perkin Trans. 1, 2001, 905.

COMMENTS :

WOODWARD PEPTIDE SYNTHESIS EXAMPLE :

EtO2C H

H COOH + HN O Ph

H2N

H2N

CO2Et

O O

Et3N,CH3CN, 20 oC

O

HN

O N Et

O O

O

SO3

1884

H2N

N H

Ph

MECHANISM :

R1 R1 R N

R

OH O

Et

H

N

O

N H H

SO3

O O

Et N

R O

N H

H N O

H3N

+ Et3NH

O

Et3N, CH3CN 0 oC R1

SO3

O OR3

+

Et

R2

H N

SO3 O

+ Et3NH

O

OR3 R2 Et3N, CH3CN 0 oC

DISCONNECTION :

R1 R

N H

H N O

O

R1

+

OR3 R2

O

OH

R N

O H

H2N

OR3 R2

NOTES :

The peptide synthesis mediated by N-ethyl-5-phenylisoxazolium-3’-sulphonate (Woodward reagent K).

REFERENCES : Org. Synth. : 56, 88 Org. Synth. Coll. Vol. : 6, 263

1) O. Mumm, Dissertation, Kiel Germany, 1902. 2) R.B. Woodward; R.A. Olofsen, J. Am. Chem. Soc., 1961, 83, 1007. 3) R.B. Woodward; R.A. Olofsen; H. Mayer, J. Am. Chem. Soc., 1961, 83, 1010. 4) I.A. Pikuleva; A.G. Lapko; V.L. Chashchin, J. Biol. Chem., 1992, 267, 1438. 5) M. Bodsanszky, Peptide Res., 1992, 5, 134.

1885

COMMENTS :

WRIGHT – WEST GERMYL MIGRATION EXAMPLE :

H3C tBu H3C Si S CH3

HS 1) tBuLi, THF 2) aq. H+

H3C t Bu Si CH3

MECHANISM :

R1

R2 Y X R3 H R4

R

R

strong base

R1

R2 Y X R3 R4

R +

H

R1 Y H R2 X R3 R4

DISCONNECTION : R R R2 R1 Y H R1 Y X R3 R2 X R3 X = C, Si, Ge; Y = O, S H R4 R4

NOTES :

The transformation of silyl and germyl ethers or sulfides into their isomeric alcohols or thiols. These reactions, similar to the Wittig rearrangement, take place through electrophilic rearrangements in the presence of excess strong base. See also Brook rearrangement and [1,2]-Wittig rearrangement.

REFERENCES :

1) A. Wright; R. West, J. Am. Chem. Soc., 1974, 96, 3214. 2) A. Wright; R. West, J. Am. Chem. Soc., 1974, 96, 3222. 3) A. Wright; R. West, J. Am. Chem. Soc., 1974, 96, 3227. 4) P. Antoniotti; G. Tonachini, Organometallics, 1996, 15, 1307. 5) P. Antoniotti; G. Tonachini, Organometallics, 1999, 18, 4538.

1886

COMMENTS :

WURTZ – FITTIG REACTION EXAMPLE :

Br

CH3 + 2 CH3I

Br

Na, Et2O

H3C

MECHANISM :

R Y X

R

- NaY

2 Na, - NaX

Na+

DISCONNECTION :

R

X R = alkyl X = halide

NOTES :

This is the Wurtz reaction carried out on a mixture of alkyl and aryl halides.

REFERENCES : March : 449 Smith – March : 535 Houben – Weyl : 5/1a, 480; E19a, 876 Org. Synth. : 25, 11; 51, 55 Org. Synth. Coll. Vol. : 3, 157; 6, 133

1) A. Wurtz, Ann. Chim. (Paris), 1855, 44, 275. 2) B. Tollens; R. Fittig, Liebigs Ann. Chem., 1864, 131, 303.

1887

3) A.A. Morton; I. Hechenbleikner, J. Am. Chem. Soc., 1936, 58, 2599. 4) T.L. Kwa; C. Boelhouwer, Tetrahedron, 1969, 25, 5771. 5) G. Nagendrappa; S. Hariprasad, Indian J. Chem., 1997, 36B, 1016. 6) K. Miyoshi; T. Nishio; A. Yasuhara; M. Moriata, Chemosphere, 2000, 41, 819.

COMMENTS :

WURTZ REACTION EXAMPLE :

H

H Cl Cl

Cl

CuCl2, DMSO

Cl H

MECHANISM :

R Na + NaX

RX + 2 Na

R Na

R1 X

R R1 + NaX

or by an alternative reaction mechanism R + R1 + MX

RX + R1M

DISCONNECTION :

R R1

RX + R1X(M)

1888

R R1

NOTES :

The synthesis of alkyl hydrocarbons by the interaction of alkyl halides with sodium or finely divided silver or copper. Tetraphenylethylene has been used as catalyst. The reaction has been extended to silicon and tin compounds. The reaction has had limited utility due to many side reactions. See also Wislicenus, Wurtz – Grignard and Wurtz – Fittig reactions.

REFERENCES : March : 449 Smith – March : 535 Smith : 726 Smith 2nd : 613 Houben – Weyl : 5/1b, 451; E19a, 101, 876

1) A. Wurtz, Liebigs Ann. Chem., 1855, 96, 364. 2) H. Nozaki; T. Shirafuji; Y. Yamamoto, Tetrahedron, 1969, 25, 3461. 3) J.F. Garst; P.W. Hart, J. Chem. Soc., Chem. Commun., 1975, 215. 4) E. Erdik, Tetrahedron, 1984, 40, 641. 5) D.C. Billington, Comp. Org. Syn., 1991, 3, 413. 6) R. Giovannini; T. Stüdemann; G. Dussin; P. Knochel, Angew. Chem., Int. Ed., 1998, 37, 2387. 7) R.G. Jones; W.K.C. Wong; S.J. Holder, Organometallics, 1998, 17, 59. 8) M. Ceylan; Y. Budak, J. Chem. Res. (S), 2002, 416.

COMMENTS :

WUYTS SYNTHESIS EXAMPLE :

SH + S

CH3

H

NH2

O

N

1889

MECHANISM :

R

N

H N

H H N NH2

S RMgX + CS2

R

N

H N

R

O

SH

+ H2S + S

H2N

N H

R

H

HCl H2O

NH2

H

O +

O

NH2

O +

H2N

N H

NH2.HCl

DISCONNECTION :

R

H RMgX O

NOTES :

Aromatic

aldehydes

are

obtained

from

the

corresponding

dithio-acids

and

N,N-methylphenylhydrazine,

semicarbazide, or hydroxylamine followed by hydrolysis. The dithio-acid is prepared by the action of carbon disulfide on a Grignard reagent. See McFadyen – Stevens reaction.

REFERENCES :

1) H. Wuyts, Bull. Soc. Chim. Belg., 1929, 38, 195. 2) H. Wuyts, Bull. Soc. Chim. Belg., 1930, 39, 58. 3) L.I. Smith; J. Nichols, J. Org. Chem., 1941, 6, 489.

COMMENTS :

1890

1891

YAMAMOTO INDOLE-2 SYNTHESIS · 1901 YAMAMOTO KETONE SYNTHESIS · 1903

Y

YAMAMOTO MACROLACTONISATION · 1905 YAMADA PEPTIDE COUPLING · 1893

YAMAZAKI – CLAUSEN GUANINE SYNTHESIS · 1906

YAMAGUCHI – HIRAO REACTION · 1894

YAMAZAKI CYANOANILINE SYNTHESIS · 1908

YAMAGUCHI REACTION · 1895

YANG CYCLISATION · 1909

YAMAMOTO ALLYLATION · 1897

YUROVSKAYA INDOLE SYNTHESIS · 1911

YAMAMOTO INDOLE-1 SYNTHESIS · 1899

1892

YAMADA PEPTIDE COUPLING EXAMPLE :

O COOH +

H2N(CH2)3CH3

O N C P OEt OEt

N H

CH3

Et3N, DMF, 0 oC

MECHANISM :

O R

OH

+

N3

O

O P OPh OPh

R

Et3N

O P(OPh)2 O N3

O R

N H

R1

R1 N H H

DISCONNECTION :

H N

R

RCOOH + R1NH2

R1

O

NOTES : The use of diphenylphosphoryl azide (DPPA) or diethylphosphoryl cyanide (DEPC) as an efficient coupling reagent for the amide bond formation of peptides from carboxyl and amino components. See also Kita reaction.

REFERENCES : 1) T. Shioiri; K. Ninomiya; S-i. Yamada, J. Am. Chem. Soc., 1972, 94, 6203. 2) S-i. Yamada; Y. Kasai; T. Shioiri, Tetrahedron Lett., 1973, 14, 1595. 3) T. Shioiri; Y. Hamada, J. Org. Chem., 1978, 43, 3631. 4) A. Guzman; E. Diaz, Synth. Commun., 1997, 27, 3035. 5) M. Mizuno; T. Shioiri, Tetrahedron Lett., 1998, 39, 9209. 6) C.S. Elmore; D.C. Dean; Y. Zhang; C. Gibson; H. Jenkins; A.N. Jones; D.G. Melillo, J. Labelled Compd. Radiopharm., 2002, 45, 29.

1893

COMMENTS :

YAMAGUCHI – HIRAO REACTION EXAMPLE : OH

O BnO

CH3

BnO

1 mol% (CH3)3Ga H3C Li toluene

MECHANISM :

H

F H

R

1) nBuLi THF, - 78 oC 2) BF3.Et2O

B

R

F

H3C

CH3 O

R

H3C

CH3 OH H

H+

DISCONNECTION :

OH R2

R2 R

R1

+

H

R

O

R1

NOTES : The alkylation of lithioacetylides by substituted epoxides using BF3.Et2O. The use of BF3.THF affords higher yields. Trimethylgallium has also been used to catalyse this reaction.

1894

REFERENCES : 1) M. Yamaguchi; I. Hirao, Tetrahedron Lett., 1983, 24, 391. 2) K. Utimoto; C. Lambert; Y. Fukuda; H. Shiragami; H. Nozaki, Tetrahedron Lett., 1984, 25, 5423. 3) A.B. Evans; D.W. Knight, Tetrahedron Lett., 2001, 42, 6947.

COMMENTS :

YAMAGUCHI REACTION EXAMPLE :

O

O HOOC H3C OH

OCH2OCH3

O

OCH2OCH3 H3C Cl

O

1) Cl Cl

Cl

2) DMAP, toluene 70 oC

1895

, Et3N

O

MECHANISM :

Cl

Cl

O

R

O

Cl RCOOH + Cl

O

O

Et3N THF

Cl

Cl

+ Et3N.HCl

Cl N

H3C Cl

O O

Cl

Cl

N CH3 N CH3

Cl

R

O O

Cl

CH3

R

O C6H6

N

O

+

Cl

N

HOR1

R CH3

N CH3

- DMAP

OR1 O

DISCONNECTION :

R

OR1

RCOOH + R1OH

O

NOTES : The rapid and mild esterification or macrolactonisation method using 2,4,6-trichlorobenzoyl chloride as coupling reagent. The reaction has a high reaction rate and lacks any by-products. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Hunsdiecker ringclosure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Petasis reaction, Peterson, Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig and Yamamoto macrolactonisation reactions.

REFERENCES : Smith 2nd : 527, 540

1896

1) J. Inanaga; K. Hirata; H. Saeki; T. Katsuki; M. Yamaguchi, Bull. Chem. Soc. Jpn., 1979, 52, 1989. 2) E. Haslam, Tetrahedron, 1980, 36, 2409. 3) J.A. Porco, jr., F.J. Schoenen; T.J. Stout; J. Clardy; S.L. Schreiber, J. Am. Chem. Soc., 1990, 112, 7410. 4) M. Bartra; J. Vilarrasa, J. Org. Chem., 1991, 56, 5132. 5) Q. Meng; M. Hesse, Top. Curr. Chem., 1992, 161, 107. 6) M. Berger; J. Mulzer, J. Am. Chem. Soc., 1999, 121, 8393. 7) Y. Kobayashi; H. Okui, J. Org. Chem., 2000, 65, 612. 8) A.K. Ghosh; Y. Wang; J.T. Kim, J. Org. Chem., 2001, 66, 8973. 9) P.R. Blakemore; C.C. Browder; J. Hong; C.M. Lincoln; P.A. Nagornyy; L.A. Robarge; D.J. Wardrop; J.D. White, J. Org. Chem., 2005, 70, 5449.

COMMENTS :

YAMAMOTO ALLYLATION EXAMPLE :

N

Bn H +

H

SiMe3

Cl 5 mol%

Pd 2

0.5 TBAF Hexane, THF

1897

N

Bn

MECHANISM :

Ph OH

Ph

PhCHO

Pd PPh3

OSnBu3

- PPh3

+ PPh3

Pd H

O SnBu3

Ph

Pd O Ph

DISCONNECTION :

R R2

R OH

R1

X

+ R2CHO

X

+

R1

R1 R2 H

R N

R X = SnBu3, SiMe3

R2

N

R3

R1

R3

NOTES : The asymmetric allylation of imines and aldehydes catalysed by chiral π-allylpalladium. See also Hiyama coupling.

1898

REFERENCES : 1) H. Nakamura; H. Iwama; Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 6641. 2) H. Nakamura; K. Nakamura; Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 4242. 3) K. Nakamura; H. Nakamura; Y. Yamamoto, J. Org. Chem., 1999, 64, 2614. 4) M. Bao; H. Nakamura; Y. Yamamoto, Tetrahedron Lett., 2000, 41, 131.

COMMENTS :

YAMAMOTO INDOLE-1 SYNTHESIS EXAMPLE :

Et

Et O + NH2

H

Pd(OAc)2, nBu3P THF, 100 oC

1899

N H

MECHANISM :

R2

R1 R1

R2

PdOAc N

HPdOAc

R3

N

Carbopalladation

H

R3

Oxidative addition

R2 R1

R2 H

H

R1

H

H

PdOAc

R3

N PdOAc

N

R2 - HPdOAc

R1

- HPdOAc

H R3 N

R2 R1

H R3 N H

DISCONNECTION :

H R1

R1 H

H

R N H

N

1900

R

R3

NOTES : The three component coupling for the synthesis of indole. The palladium-catalysed intramolecular cyclisation of an alkyne and imine on an aromatic ring will afford 3-alkenylindoles. Also tandem copper-catalysed tandem reaction between imines and alcohols to afford indoles. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-2 and Yurovskaya reactions.

REFERENCES : 1) A. Takeda; S. Kamijo; Y. Yamamoto, J. Am. Chem. Soc., 2000, 122, 5662. 2) S. Kamijo; Y. Sasaki; Y. Yamamoto, Tetrahedron Lett., 2004, 45, 35.

COMMENTS :

YAMAMOTO INDOLE-2 SYNTHESIS EXAMPLE :

Pr O N

+

OCO2CH3 1 mol% [Pd(PPh3)]4 4 mol % CuCl THF, 100 oC, 1 h

1901

Pr N CO2CH3

MECHANISM :

Pd0

OCO2R1

R N O

R1O

CO2

ClCu

ClCu

R

Pd OR1

N Pd

N R1O

R

R1O

O Pd

O

or alternatively Pd

R R

N CuCl R1O

O

O

N

DISCONNECTION :

R O

R

+

OCO2R2

N N CO2R1 R = Pr, cyclopentyl, Ph, p-CH3OC6H4, p-CF3C6H4 R1 = CH3, iPr, tBu, Ph, Bn

NOTES : The coupling of 2-alkynylphenylisocyanates and allylic carbonates using a palladium-copper(I) bimetallic catalyst to afford indoles. The role of CuCl is not fully understood but it is believed that it behaves as a Lewis acid to activate the alkynyl function. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin,

1902

Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1 and Yurovskaya reactions.

REFERENCES : 1) S. Kamijo; Y. Yamamoto, Angew. Chem., Int. Ed., 2002, 41, 3230. 2) S. Kamijo; Y. Yamamoto, J. Org. Chem., 2003, 68, 4764.

COMMENTS :

YAMAMOTO KETONE SYNTHESIS

EXAMPLE :

O Ph

O O

O Ph

+ PhB(OH)2

2 mol% Pd(PPh3)4

1903

Ph

Ph

MECHANISM :

O O R1

R2

O

0

Pd Ln

O

R1

O

R1

LnPd

O

R1

R1

LnPd

O

R2 R1

R1

O O

OH B OH

O

R2B(OH)2

DISCONNECTION :

O R1

O R2

O +

R1

O

R1

R2B(OH)2

NOTES :

The treatment of a carboxylic anhydride or ester with organoboron compounds in the presence of a palladium catalyst affords ketones. See also Suzuki – Miyaura reaction.

REFERENCES :

1) A. Yamamoto, Adv. Organomet. Chem., 1992, 34, 111. 2) K. Nagayama; F. Kawataka; M. Sakamoto; I. Shimizu; A. Yamamoto, Chem. Lett., 1995, 367. 3) K. Nagayama; I. Shimizu; A. Yamamoto, Chem. Lett., 1998, 1143. 4) K. Nagayama; I. Shimizu; A. Yamamoto, Bull. Chem. Soc. Jpn., 2001, 74, 1803. 5) R. Kakino; I. Shimizu; A. Yamamoto, Bull. Chem. Soc. Jpn., 2002, 75, 137.

1904

COMMENTS :

YAMAMOTO MACROLACTONISATION EXAMPLE :

O O HO(CH2)5COOH

20 mol% Sc(OTf)3 2 (p-NO2C6H4CO)2O CH3CN : THF 168:10 reflux

MECHANISM :

possible intermediate

OH Sc(OTf)3 O

O O

NO2

DISCONNECTION :

O O (CH2)n

HO(CH2)nCOOH 5>n>15

1905

NOTES :

Scandium trifluoromethanesulfonate is a practical and useful Lewis acid for the selective macrolactonisation of ωhydroxy carboxylic acids. The exact mechanism is not fully understood. See also Corey – Kwiatkowski, Corey – Nicolaou, Diels – Alder, Eastwood, Hanessian macrolactonisation, Hansley – Prelog – Stoll, Hunsdiecker ring-

closure, Julia – Paris – Kocienski – Lythgoe, Keck macrolactonisation, Kita, Krief – Reich – Chow, Masamune, McMurry, Michael condensation, Mitsunobu, Mukaiyama macrolactonisation-1, Mukaiyama macrolactonisation-2, Murai rearrangement, Nagarajan – Kumar – Rao, Nozaki – Hiyama – Kishi (Takai – Utimoto), Petasis reaction, Peterson, Raphael, Roush, Ružička large ring synthesis, Schmidt macrolactonisation, Spassow, Staab, Stacey, Steglich – Hassner, Still – Gennari, Stille – Migita – Kosugi, Story, Suzuki – Miyaura, Takeda, Tebbe, Thorpe – Ziegler, Venkataraman – Wagle, Vorbrüggen – Krolikiewicz, Wittig and Yamaguchi reactions.

REFERENCES :

1) K. Ishihara; M. Rubota; H. Kurihara; H. Yamamoto, J. Am. Chem. Soc., 1995, 117, 4413; J. Am. Chem. Soc., 1995, 117, 6639 (corrections). 2) K. Ishihara; M. Rubota; H. Kurihara; H. Yamamoto, J. Org. Chem., 1996, 61, 4560. 3) K.C. Nicolaou; A. Ritzén; K. Namoto; R.M. Buey; J.F. Díaz; J.M. Andreu; M. Wartmann; K.-H. Altmann; A. O’Brate; P. Giannakakou, Tetrahedron, 2002, 58, 6413.

COMMENTS :

YAMAZAKI – CLAUSEN GUANINE SYNTHESIS EXAMPLE :

O

O H2N H2N

H

N N H

1) KOH H2N 2) HCl, DMF 3) PhCONCS, acetone 4) K2CO3, aq. MeOH, acetone 5) 35% H2O2, Na2WO4 aq. NaOH

1906

N

N N

N H

MECHANISM :

O

O

O N

H2N

1) KOH 2) RX, DMF

N H

H2N

H2N

N

H2N

N R

H2N

O

N N R NH

HN

Ph

NCS

S

acetone

O H2N

H

N

H

K2CO3 aq. MeOH acetone

Hg2+, aq. NaOH

N R NH2

N

S

N

N

N R

N

H2N

O

O

O N

H2N

1) KOH 2) RX, DMF

H2N

H2N

N

H2N

N H

H2N

N R

O

N

HN

Ph

NCS

S

acetone

O

H2N

CH3I

H3C

H2N

N N

S

N O

H

N R

NH3

N

H2N

N O

Ph

N R

NaOH - NH3 - PhCOOH

Ph

N

N

H2N

N

N R

DISCONNECTION : O H H2N

Ph

N

O H

N R NH

O

O

H

Ph

O

O

O N

N N

H2N

N R

H2N

1907

N N H

NOTES :

The simple and efficient synthesis of 9-substituted guanines starting from 5-aminoimidazole-4-carboxamide.

REFERENCES :

1) A. Yamazaki; I. Kumashiro; T. Takenishi, J. Org. Chem., 1967, 32, 1825. 2) A. Yamazaki; M. Okutsu, J. Heterocycl. Chem., 1978, 15, 353. 3) M.P. Groziak; J.W. Chern; L.B. Townsend, J. Org. Chem., 1986, 51, 1065. 4) B. Alhede; F.P. Clausen; J. Juhl–Christensen; K.K. McCluskey; H.F. Preikschat, J. Org. Chem., 1991, 56, 2139.

COMMENTS :

YAMAZAKI CYANOANILINE SYNTHESIS EXAMPLE :

CN NO2 + N

NH2

OEt N

1) KOH 2) 10% HCl

O

N

MECHANISM :

NO2

O +

N

CH3 base

O

CH3 N

CN

O O

EtOOC CN

O N

H

OEt N

+

H

CN

O

NH2 10% HCl

1908

DISCONNECTION : CN NH2

NO2

X

X

NOTES :

The synthesis of o-aminoarylnitriles from nitroquinolines, nitronapthalenes, and m-substituted (CF3, COCH3, and COPh) nitrobenzenes. The exact mechanism has not yet been established.

REFERENCES :

1) Y. Tomioka; A. Mochiike; J. Himeno; M. Yamazaki, Chem. Pharm. Bull., 1981, 29, 1286. 2) Y. Tomioka; J. Miyake; M. Yamazaki, Chem. Pharm. Bull., 1982, 30, 851. 3) Y. Tomioka; K. Ohkubo; M. Yamazaki, Chem. Pharm. Bull., 1985, 33, 1360. 4) A. Halama; J. Kaválek; V. Macháček; T. Weidlich, J. Chem. Soc., Perkin Trans. 1, 1999, 1839. 5) A. Halama; V. Macháček, J. Chem. Soc., Perkin Trans. 1, 1999, 2495.

COMMENTS :

YANG CYCLISATION EXAMPLE :

H

N

Ac

H3C

Tol

H3C CH

3

O

hν benzene

1909

H3C H

H CH3 N Ac OH H Tol

MECHANISM :

O* H

H

O

R

hν

R

H

HO

HO

O R

anti

gauche

intersystem crossing HO R OH + R

DISCONNECTION : O H

HO

R

R

NOTES :

The Yang cyclisation is the formation of cyclobutanols from 1-hydroxytetramethylene biradicals, which are produced via photochemical γ-hydrogen abstraction. From one chiral molecule up to 8 diastereoisomers can be formed. Norrish type I and type II fragmentation products are observed. See also Norrish type 1 and type 2 reactions.

REFERENCES :

1) N.C. Yang; D.-D. H. Yang, J. Am. Chem. Soc., 1958, 80, 2913. 2) J.C. Scaiano, Acc. Chem. Res., 1982, 15, 252. 3) L.J. Johnston; J.C. Scaiano, Chem. Rev., 1989, 89, 521. 4) A.E. Dorigo; M.A. McCarrick; R.J. Loncharich; K.N. Houk, J. Am. Chem. Soc., 1990, 112, 7508. 5) P.J. Wagner; B.-S. Parl, Org. Photochem., 1991, 11, 227. 6) R.R. Sauers; L.A. Edberg, J. Org. Chem., 1994, 59, 7061. 7) A.G. Griesbeck; H. Heckroth; J. Lex, Chem. Commun., 1999, 1109. 8) A.G. Griesbeck; H. Heckroth, Res. Chem. Intermed., 1999, 25, 599. 9) A.G. Griesbeck; H. Heckroth, J. Am. Chem. Soc., 2002, 124, 396. 10) A.G. Griesbeck; P. Cygon; J. Lex, Lett. Org. Chem., 2004, 1, 313. 11) S. Saphier; Y. Hu; S.C. Sinha; K.N. Houk; E. Keinan, J. Am. Chem. Soc., 2005, 127, 132.

1910

COMMENTS :

YUROVSKAYA INDOLE SYNTHESIS EXAMPLE :

H

H

H3C

NO2

H3C

CH3 N CH3 X

N

+ H3C

CH3 H

H3C CH3 N

H3C H

1911

CH3

MECHANISM :

R

R5

R

H N

NO2

R4

N R1 CH3 X

R

R2

R5

N R1 CH3 H+

R2

H N

NO2

R

R3 N R1 CH3

R4

R4

R3

H

R2

O N O

R

H N

R4 H3C

R

R3

N

H N R1

H3C N

CH3

H R2 R3

R3

N

R1

R1

R5

- H+

R2

R N H R5

R3

R4 H3C R1

N

R4

H H

R2

R N

R2

R5

R3

H+

O N O

R5

CH3

R2 H

- H+

HN

N

H

N R1 CH3

R1

R4 H3C

NO2

R3 N R1 CH3

H R4

R5

R1 R5

R4

R2

NO2

N

O R2 N OH

H N

R3

R2

H N

NO2

R4

H N R5

R

R5

R

R3

R3

R5

R

H

R2

H N

R3 R1 N R

R4

1912

R4 R5

- NO2-

DISCONNECTION :

R2

R2 R3

N

R1

R5

N

R4 R5

R3

R

R

NO2

+ R4

R1 N CH3 X

NOTES :

The formation of indoles by the reaction of 3-nitropyridinium salts with N-alkyl-2-ketimines. The more alkyl substituents on the pyridinium the better the yield of the indole. See also von Baeyer – Emmerling, von Baeyer – Jackson, Bailey – Liebeskind, Bartoli, Bischler – Möhlau, Cadogan – Sundberg, Couture, Engler, Feldman

indole, Fischer indole, Foulds – Robinson, Fukuyama, Fürstner, Gassman indole, Grandberg, Hegedus, Hemetsberger – Knittel, Inanaga, Iwao, Japp – Murray, Julia, Kihara, Larock indole, Leimgruber – Batcho, Lipp, Madelung indole, Magnus, Martin, Montevecchi, Mori – Ban, Murphy, Naito, Natsume, Nenitzescu indole, Piloty – Robinson, Pschorr – Hoppe, Reissert indole, Saegusa indole, Schmid, Smith, Sugasawa indole, Sundberg, Thiele – Dimroth, Thyagarajan, Watanabe heterocyclisation, Watanabe indole, Weerman indole, Wender, Widman, Yamamoto indole-1 and Yamamoto indole-2 reactions.

REFERENCES :

M.A. Yurovskaya; A.Z. Afanasyev; F.V. Maximova; Y.G. Bundel, Tetrahedron, 1993, 49, 4945.

COMMENTS :

1913

1914

ZIEGLER ALKYLATION · 1928 ZIEGLER ALUMINIUMALKYL OXIDATION · 1929

C

ZIEGLER TERTIARY HIGHER FATTY ACIDS SYNTHESIS · 1930 ZIMMER REARRANGEMENT · 1931

CLAYTON – JENSEN REACTION · 1947

ZIMMERMAN REACTION · 1933 ZINCKE – KÖNIG PYRIDINIUM SALTS · 1934 Z

ZINCKE – SUHL CYCLOHEXADIENONE SYNTHESIS · 1936 ZINCKE DIARYLMETHANE SYNTHESIS · 1937

ZAGOUMENNY DIPHENYL CARBINOL SYNTHESIS · 1916

ZINCKE DISULFIDE CLEAVAGE · 1938

ZAV’YALOV PYRROLE SYNTHESIS · 1916

ZINCKE HALOGENPHENOL NITRATION · 1940

ZEISEL SYNTHESIS · 1918

ZININ REACTION · 1941

ZEISS KETONE TRANSFER · 1919

ZININ REARRANGEMENT · 1942

ZELINSKY – STADNIKOFF AMINONITRILE SYNTHESIS · 1922

ZINKE – CORNFORTH MODIFICATION · 1945

ZELINSKY ALDEHYDE SYNTHESIS · 1921

ZINKE – ZIEGLER SYNTHESIS · 1944

ZEMPLÉN SUGAR DEGRADATION · 1923

ZINNER SYNTHESIS · 1946

ZIEGLER – HAFNER AZULENE SYNTHESIS · 1925

ZINOVEV – SOBOROVSKI REACTION · 1947

ZIEGLER – NATTA POLYMERISATION · 1926

1915

ZAGOUMENNY DIPHENYL CARBINOL SYNTHESIS EXAMPLE :

O

OH CH3

2

Na2CO3, EtOH, 160 oC

NOTES : Diphenyl carbinol is obtained by heating benzophenone, ethanol and alkali in a sealed tube at 160 °C for five hours. In addition, zinc can be used. See also Hammick picolinic acid decarboxylation.

REFERENCES A. Zagoumenny, Liebigs Ann. Chem., 1876, 184, 174.

COMMENTS :

ZAV’YALOV PYRROLE SYNTHESIS EXAMPLE : K

O O

O N

H

Ac2O heat, 2 h

1916

N Ac

MECHANISM :

O

O O

R

O

N H

O R O

COOH H

O

R

CH3 N

N O

Ac2O, heat

O

O

O CH3

R

N

- CO2

O

DISCONNECTION :

R1 R

R

R1 N Ac

N

R2

O H O K

R2 O

NOTES : The potassium salts of amino acid derived alkenones are heated in acetic anhydride. The pyrrole ring is formed after decarboxylation and dehydration. See also Barton – Zard, Clauson–Kaas, Fischer – Fink, Grob – Camenisch, Hantzsch pyrrole, Harries pyrrole, Kenner, Knorr pyrrole, Miller – Plöchl, Paal – Knorr, Padwa, Piloty – Robinson, Schwanert and Trofimov reactions.

REFERENCES : 1) S.I. Zav’yalov; I.F. Mustafaeva; N.I. Aronova; N.N. Makhova, Izv. Akad. Nauk. SSSR, Ser Khim., 1973, 2572. (Proc. Acad. Sci. USSR (Eng., 1973, 2505.) 2) N.J. Bach; E.C. Kornfeld; N.D. Jones; M.O. Chaney; D.E. Dorman; J.W. Paschal; J.A. Clemens; E.B. Smalstig, J. Med. Chem., 1980, 23, 481. 3) D. Berney, Helv. Chim. Acta, 1982, 65, 1694. 4) V. Cecchetti; A. Fravolini; F. Schiafella, J. Heterocycl. Chem., 1982, 19, 1045. 5) M.A. Ansari; J.C. Craig, Synth. Commun., 1991, 21, 1971. 6) C.D. Gabutt; J.D. Hepworth; B.M. Heron; M.R.J. Elsegood; W. Clegg, Chem. Commun., 1999, 289. 7) K.-M. Cheung; P.M. Shoolingin–Jordan, Synthesis, 2001, 1627.

1917

COMMENTS :

ZEISEL SYNTHESIS EXAMPLE :

O

OH + CH3I

+ HI reflux

CH3

DISCONNECTION :

R OR1 R1

I

O R

OR1

NOTES : The removal of alkyl groups from methoxy and ethoxy compounds with boiling hydrogen iodide or TMS-iodide. See also Appel – Robinson, Gustus cleavage, Herzig – Meyer, Jung – Olah – Voronkov, Mann dealkylation, Prey, and Stoermer dealkylation reactions.

REFERENCES : Houben – Weyl : 2, 404

1) S. Zeisel, Monatsh. Chem., 1885, 6, 989. 2) S. Zeisel, Monatsh. Chem., 1886, 7, 406. 3) S. Zeisel; R. Fanto, Z. Anal. Chem., 1903, 42, 549. 4) H.J. Backer, Recl. Trav. Chim. Pays-Bas, 1952, 71, 740. 5) J. Haslam; J.B. Hamilton; A.R. Jeffs, Analyst, 1958, 83, 66. 6) T.G. Miller; R.J. Hronek, Anal. Chem., 1985, 57, 2091. 7) A.M.T. Magalhaes; P.M. Chalk, Analyst, 1986, 111, 77.

1918

COMMENTS :

ZEISS KETONE TRANSFER EXAMPLE :

CH3

CH3 CH3

H3C

O

1) PhCHO, NaOH 2) Al(OiPr)3, heat 3) O3

H

CH3

H3C

O

MECHANISM :

CH3 H3C

O

CH3

CH3

H3C PhCHO aq. EtOH NaOH

H

Ph

O

Al(OiPr)3 xylene reflux

H

CH3 H3C

CH3

CH3

CH3

H3C O3, EtOAc O

Ph

1919

CH3

CH3

CH3 CH3

H3C

LiAlH4

1) SOCl2 2) NaN3 Hofmann degradation

HOOC CH H 3

OCN CH H 3 CH3

CH3 CH3

H3C

CH3

H3C

CH3

H3C

Ag2O heat

CH3I H

H3C

N CH H 3 CH3

N CH H 3 CH3

H2CO HCOOH

CH3

CH3

CH3

H3C

CH3

H3C O3

H CH2

O

H

DISCONNECTION :

CH3

CH3 H3C

O

CH3

H3C

CH3

HOOC CH H 3

H

NOTES : The basic transformation is the movement of the A-ring carbonyl function to an adjacent ring carbon atom in steroidal systems.

REFERENCES : 1) H.H. Zeiss; W.B. Martin, jr., J. Am. Chem. Soc., 1953, 75, 5935. 2) J.W. Huffman; R.F. Stockel, J. Org. Chem., 1963, 28, 506. 3) C.R. Bennett; R.C. Cambie; T.J. Fullerton, Aust. J. Chem., 1968, 21, 2473. 4) A.W. Burgstahler; J.N. Marx, J. Org. Chem., 1969, 34, 1562.

1920

5) E.E. van Tamelen; J.P. Demers; E.G. Taylor; K. Koller, J. Am. Chem. Soc., 1980, 102, 5424. 6) A. Abad; C. Agulló; M. Arnó; L.R. Domingo; R.J. Zaragoźa, Org. Prep. Proced. Int., 1991, 23, 323.

COMMENTS :

ZELINSKY ALDEHYDE SYNTHESIS EXAMPLE :

Et

CH3CH2MgBr + HCO2H

H2O

H O

MECHANISM :

R

RMgX + HCO2H

H

H

O MgX

R

H O

O H O

H

DISCONNECTION :

R

H

HCOOH

O

NOTES : Aldehydes are obtained by the hydrolysis of the complex formed by the interaction of a Grignard reagent and formic acid. See also Bodroux – Chichibabin reaction.

REFERENCES : Org. Synth. : 6, 22 Org. Synth. Coll. Vol. : 1, 188

1921

1) N. Zelinsky, Chem. -Ztg., 1904, 28, 303. 2) L.I. Smith; J. Nichols, J. Org. Chem., 1941, 6, 489. 3) F. Sato; K. Oguro; H. Watanabe; M. Sato, Tetrahedron Lett., 1980, 21, 2869. 4) M. Bogavac; L. Arsenijevic; S. Pavlov; V. Arsenijevic, Tetrahedron Lett., 1984, 25, 1843.

COMMENTS :

ZELINSKY – STADNIKOFF AMINONITRILE SYNTHESIS EXAMPLE :

H3C

H

H 1) NH4Cl KCN 2) aq. HCl 3) NH4OH

O

CH3 NH2 CN

MECHANISM :

O

H2N H

H

NaCN, NH4Cl H2O, MeOH H2N

ClH.H2N

CN aq. HCl

COOH H

COOH H

NH4OH

DISCONNECTION : R H

R

H

NH2 O

CN

NOTES : This reaction forms in situ NH3 and HCN. These reactants react with the carbonyl group and afford α–amino acids after hydrolysis. See also Bouveault – Locquin amino acid, von Braun amino acid synthesis, Bucherer – Bergs,

1922

Darapsky, Herbst – Engel, Knoop – Oosterlin, O’Donnell, Schöllkopf, Sorensen, Strecker amino acid, Tiemann amination, Ultee and Urech reactions.

REFERENCES : Houben – Weyl : 8, 280 Org. Synth. : 9, 4; 11, 4; 22, 13, 23; 24, 9 Org. Synth. Coll. Vol. : 1, 21; 2, 29; 3, 66, 84, 88

1) N. Zelinsky; G. Stadnikoff, Ber. Dtsch. Chem. Ges., 1906, 39, 1722. 2) D.T. Mowry, Chem. Rev., 1948, 42, 189.

COMMENTS :

ZEMPLÉN SUGAR DEGRADATION EXAMPLE :

H

O

H HO H H H

OH H OH OH OH H

H

1) NH2OH 2) Ac2O, AcONa 3) NaOCH3

1923

O

HO H H H

H OH OH OH H

MECHANISM :

H

H

O

H HO H H H

OH H OH OH OH

H2N H HO H H H

NH2OH

H

O OH H OH OH OH

H HO H H H

OH H OH OH OH H

H

Ac2O, AcONa - H2O

OH

H

N H AcO H H H

HN

OAc H OAc OAc OAc

NaOCH3 MeOH

O

HO H H H

H OH OH OH H

H O via

O

CH3

O

OH + CH3O

MeOH

CH3O

DISCONNECTION :

OH H

HO H

disaccharide

H

disaccharide H

O

H OH O

NOTES : This method is developed for the degradation of disaccharides. Hydrolysis with NH3 and Ag2O (Wohl degradation) to form diacetamide compounds is not possible due to hydrolysis of the disaccharides at the same time. The acetylated nitrile is converted directly to the aldose by the alkoxide. See also Wohl reaction.

1924

REFERENCES : 1) G. Zemplėn, Ber. Dtsch. Chem. Ges., 1926, 59, 1254, 2402. 2) G. Zemplėn; G. Braun, Ber. Dtsch. Chem. Ges., 1926, 59, 2230. 3) E. Restelli di Labriola; V. Denlofen, J. Org. Chem., 1947, 12, 726. 4) D. Keglevic; A.E. Derome, Carbohydr. Res., 1989, 186, 63. 5) Z. Szurmai; A. Liptaka; G. Snatzke, Carbohydr. Res., 1990, 200, 201. 6) D. Crich; H.M. Li, J. Org. Chem., 2000, 65, 801. 7) E. Osz; K. Czifrak; T. Deim; L. Szilagyi; A. Benyei; L. Somsak, Tetrahedron, 2001, 57, 5429.

COMMENTS :

ZIEGLER – HAFNER AZULENE SYNTHESIS EXAMPLE :

CH3

CH3 + H3C

O

CH3

NaOEt THF

CH3

H3C

ClO4

MECHANISM :

H

H3C H

EtO EtOH

HH H

O H+

H3C N

Ph

H3C Ph N H heat

- PhNHCH3

1925

- H2O

N

Ph

DISCONNECTION :

NOTES : The first step is the deprotonation to form the cyclopentadienyl anion, followed by condensation with the carbonyl of the Zincke aldehyde. The thermal cyclisation is followed by elimination of the secondary amine.

REFERENCES : Org. Synth. : 44, 94; 62, 134 Org. Synth. Coll. Vol. : 5, 1088; 7, 15

1) K. Ziegler; K. Hafner, Angew. Chem., 1955, 67, 301. 2) K. Hafner, Angew. Chem., 1958, 70, 419. 3) R.W. Alder; G. Whittaker, J. Chem. Soc., Perkin Trans. 2, 1975, 714. 4) L.T. Scott; M.A. Kirms, J. Am. Chem. Soc., 1981, 103, 5875.

COMMENTS :

ZIEGLER – NATTA POLYMERISATION EXAMPLE :

H

H

H

H

n

Al(propyl)3 TiCl4

1926

*

n

MECHANISM :

H2C CH2 R + C2H4

[Ti]

[Ti] R

[Ti] CH2CH2R

H2C CH2 [Ti] C2H4

[Ti] (CH2CH2)2R

CH2CH2R

propagation R C CH2 + [Ti]H H

[Ti] C2H4

CH2CH3

propagation

NOTES : Ethene is polymerised by trialkylaluminium compounds and traces of a transition metal belonging to group 4, 5, or 6. The polymerisation takes place at room temperature and at normal pressure. According to the Cossee – Arlman mechanism, propagation of the polymer occurs exclusively at the titanium centre. The exact nature of the propagation step was controversial for some time. Recent studies show that α-agostic species are important. The use of vanadium-based catalysts allows for the preparation of high-molecular-weight polymers with narrow molecular-weight distributions, although the activity of these catalysts is inferior to other known systems.

REFERENCES : Houben – Weyl : 14/1, 578

1) K. Ziegler; E. Holzkamp; H. Breil; H. Martin, Angew. Chem., 1955, 67, 426. 2) K. Ziegler; E. Holzkamp; H. Breil; H. Martin, Angew. Chem., 1955, 67, 541. 3) G. Natta, Angew. Chem., 1956, 68, 398. 4) P. Cossee, Tetrahedron Lett., 1960, 1, 12. 5) P. Cossee, Tetrahedron Lett., 1960, 1, 17. 6) E.J. Arlman; P. Cossee, J. Catal., 1964, 3, 99. 7) L. Fan; D. Harrison; T.K. Woo; T. Ziegler, Organometallics, 1995, 14, 2018. 8) J. Huang; G.L. Rempel, Prog. Poly. Sci., 1995, 20, 459. 9) M.C. Murray; M.C. Baird, Can. J. Chem., 2001, 79, 1012. 10) H.G. Cho; G.Y. Han; G. Ahn, Kor. J. Chem. Eng., 2001, 18, 561. 11) H. Hagen; J. Boersma; G. van Koten, Chem. Soc. Rev., 2002, 31, 357. 12) L.L. Böhm, Angew. Chem., Int. Ed., 2003, 42, 5010. 13) Y. Zhang; L.R. Sita, J. Am. Chem. Soc., 2004, 126, 7776.

1927

COMMENTS :

ZIEGLER ALKYLATION EXAMPLE :

1) PhLi 2) O2

N

N

Ph

MECHANISM :

H N Li

N Li

Bu

toluene, heat

N

Bu

Bu

DISCONNECTION :

N

R

N

NOTES : The alkylation of heterocyclic nitrogen compounds. The unshared pair of electrons on the nitrogen combines with the lithium, so the extra pair of ring electrons has a place to go; it becomes the new unshared pair on the nitrogen.

REFERENCES : March : 666 Smith – March : 871 Org. Synth. : 18, 70 Org. Synth. Coll. Vol. : 2, 517

1928

1) K. Ziegler; H. Zeiser, Ber. Dtsch. Chem. Ges., 1930, 63, 1847. 2) R.A. Abramovitch; G.A. Poulton, J. Chem. Soc., Chem. Commun., 1967, 274. 3) C.S. Giam; J.L. Stout, J. Chem. Soc., Chem. Commun., 1969, 142. 4) H. Vorbrüggen; M. Maas, Heterocycles, 1988, 27, 2659. 5) D.R. Armstrong; R.E. Mulvey; D. Barr; R. Snaith; D. Reed, J. Organomet. Chem., 1988, 350, 191.

COMMENTS :

ZIEGLER ALUMINIUMALKYL OXIDATION EXAMPLE :

AlMe3 + 1.5 O2

3 CH3OH

1.5 H2O

MECHANISM :

Al(OR)3

AlR3 + 1.5 O2

H2O

HOR

DISCONNECTION : AlR3

HOR R = alkyl

NOTES : The oxidation of trialkylaluminium compounds with air followed by hydrolysis to afford primary alcohols. This is due to the fact that only terminal double bonds react.

REFERENCES : 1) K. Ziegler, Angew. Chem., 1952, 64, 323. 2) K. Ziegler; H.-G. Gellert; H. Martin; K. Nagel; J. Schneider, Liebigs Ann. Chem., 1954, 589, 91.

1929

COMMENTS :

ZIEGLER TERTIARY HIGHER FATTY ACIDS SYNTHESIS EXAMPLE : Bu OH H3C C N

Bu

1) 3 nBuBr, NaNH2 2) 80% H2SO4 3) NaNO2, H2SO4

Bu O

MECHANISM :

H H

Bu C N

Bu 3-times

H Bu

Bu

Bu NH2

C N 80% H2SO4

Bu

Bu O

NaNO2 H2SO4

Br

NH2

Bu

Bu N

Bu O

Bu

N H2O - N2

Bu OH

Bu O

DISCONNECTION :

R

OH

R

O

H N + RBr

H

R

H

NOTES : An alkyl nitrile is alkylated with an alkyl halide in the presence of sodamide. The resulting tertiary nitrile is hydrolysed with 80% sulfuric acid to give the amide, which yields the tertiary fatty acid on treatment with sodium nitrite in sulfuric acid. Compare with the Haller – Bauer reaction. See also Haller – Bauer reaction.

1930

REFERENCES : 1) K. Ziegler; H. Ohlinger, Liebigs Ann. Chem., 1932, 495, 84. 2) N. Sperber; D. Papa; E. Schwenk, J. Am. Chem. Soc., 1948, 70, 3091.

COMMENTS :

ZIMMER REARRANGEMENT EXAMPLE :

H

H N

O H3C

H3C O N OH

hν

Ph

1931

O

O

O Ph

MECHANISM :

H

H

O

O

O

hν

NH2

O N O H H

N H

O

O NH2

- H2O

N

O

OH

NOTES : This is the (photolytic) rearrangement from α-methylenelactones, -lactams and thiolactones. A wide variety of compounds can be obtained including carbostyril, dihydrocoumarin and quinolines.

REFERENCES : 1) D.H. Marrian; P.B. Russell, J. Chem. Soc., 1946, 753. 2) H. Zimmer; J. Rothe, J. Org. Chem., 1959, 24, 28. 3) H. Zimmer, Angew. Chem., 1961, 73, 149. 4) R. Walter; T.C. Purcell; H. Zimmer, J. Heterocycl. Chem., 1966, 3, 235. 5) H. Zimmer; D.C. Armbuster; S.P. Kharida; D.C. Lankin, Tetrahedron Lett., 1969, 10, 4053. 6) R.G. Gailey; H. Zimmer, Tetrahedron Lett., 1970, 11, 2839. 7) H. Wamhoff; F. Korte, Synthesis, 1972, 151.

COMMENTS :

1932

ZIMMERMAN REACTION EXAMPLE :

O

NO2

O +

H3C

H3C

EtOH NaOEt

NO2

H3C

NO2

H3C

H3C

O2N

H3C

MECHANISM :

O

NO2

O

H3C

H3C

H3C

H3C

base

H3C

H3C O H3C

H3C H3C

O N O

+ O H

H

H3C

alkali

NO2

N O

O2N O

O

H3C H3C

O2N

NO2

H3C H3C H3C

O2N

DISCONNECTION :

O R

R

NO2 R1

R1 O

O2N

NOTES : The reaction that occurs between methylene ketones and aromatic polynitro compounds in the presence of an ethanolic solution of sodium ethoxide (Janovsky used aqueous sodium hydroxide). When applied to 17-oxosteroids, the coloured compounds formed can be used for the quantitative determination of 17-oxosteroids. See also Meisenheimer – Janovsky reaction.

1933

REFERENCES : 1) W. Zimmermann, Z. Physiol. Chem., 1935, 233, 257. 2) M. Ishidate; T. Sakaguchi, J. Pharm. Soc. Japan, 1950, 70, 444. 3) O. Neunhoeffer; K. Thewalt; W. Zimmermann, Z. Physiol. Chem., 1961, 323, 116. 4) R. Foster; R.K. Mackie, Tetrahedron, 1962, 18, 1131. 5) H. Hoffmeister; C. Rufer, Chem. Ber., 1965, 98, 2376. 6) C.S. Feldkamp; R. Watkins; R.J. Thibert; E. Epstein; B. Zak, Microchem. J., 1977, 22, 201.

COMMENTS :

ZINCKE – KÖNIG PYRIDINIUM SALTS EXAMPLE :

N

CH3

1) H N

Ph 2) KOH

1934

O

N Ph

CH3

MECHANISM :

H3C N Ph

N +

Cl

N

NO2

NO2

O2N

H

Cl NO2

H CH 3 N Ph NO2

N

N O2N

CH3 N O2N

NO2

NO2

N

CH3 Ph N H

H3C

N Ph Ph

NH2

N Ph

CH3

O2N

CH3

O2N H+,

N Ph

O

-

HO CH3 - Ph N H

N Ph

CH3

NO2

DISCONNECTION :

N NO2

+

Cl

NO2

N O2N

Cl NO2

NOTES : Instead of 1-bromo-2,4-dinitrobenzene (used by Zincke), methyl aniline or bromocyanide (used by König) can be used. The initial formed salts are called the Zincke salts. See also Allan – Loudon reaction.

REFERENCES : Houben – Weyl : E3, 86

1) Th. Zincke, Liebigs Ann. Chem., 1904, 330, 361.

1935

2) W. König, J. Prakt. Chem., 1904, 70, 19. 3) W. König, J. Prakt. Chem., 1904, 69, 105. 4) Th. Zincke, Liebigs Ann. Chem., 1905, 339, 193. 5) A. Diez; L. Vilaseca; I. Lopez; M. Rubiralta; C. Marazano; D.S. Grierson; H.P. Husson, Heterocycles, 1991, 32, 2139. 6) D. Gnecco; C. Marazano; R.G. Enriquez; J.L. Terán; M. Del Rayo Sánchez S.; A. Galindo, Tetrahedron: Asymmetry, 1998, 9, 2027. 7) M. Rehwald; P. Bellmann; T. Jeschke; K. Gewald, J. Prakt. Chem., 2000, 342, 371. 8) M. Eda; M.J. Kurth, Tetrahedron Lett., 2001, 42, 2063. 9) W.-C. Cheng; M.J. Kurth, Org. Prep. Proced. Int., 2002, 34, 585.

COMMENTS :

ZINCKE – SUHL CYCLOHEXADIENONE SYNTHESIS EXAMPLE :

CH3

H3C

CCl3

+ CCl4 AlCl3 O

OH

MECHANISM :

HO

CH3

CCl4, AlCl3

O

Cl Al Cl

CH3 Cl Cl

Cl Cl

H3C

CCl3

O AlCl3

H3C

CCl3

O

1936

AlCl3

DISCONNECTION :

R

R

CCl3

R = Alk OH

O

NOTES : p-Alkylated phenols react with carbon tetrachloride in the presence of aluminium chloride to yield 4,4-disubstituted cyclohexadienones. See also Friedel – Crafts reaction.

REFERENCES : 1) Th. Zincke; R. Suhl, Ber. Dtsch. Chem. Ges., 1906, 39, 4148. 2) M.S. Newman; A.G. Pinkus, J. Org. Chem., 1954, 19, 978, 985. 3) M.S. Newman; L.L. Wood, jr., J. Am. Chem. Soc., 1959, 81, 6450. 4) S.V. Sergeev; V.A. Nikanorov; V.I. Rozeberg; O.A. Reutov, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 37, 790.

COMMENTS :

ZINCKE DIARYLMETHANE SYNTHESIS EXAMPLE :

+

Cl Zn

1937

MECHANISM :

Cl

ZnCl Zn

DISCONNECTION : R

R

Cl

+ R1

R, R1 = H, CH3 R1

NOTES : This method is exemplified by the reaction of benzene and benzyl chloride, when heated in the presence of zinc dust or other metallic catalyst, gives diphenylmethane.

REFERENCES : Org. Synth. : 14, 34 Org. Synth. Coll. Vol. : 2, 232

Th. Zincke, Liebigs Ann. Chem., 1871, 159, 367.

COMMENTS :

ZINCKE DISULFIDE CLEAVAGE EXAMPLE :

S S Cl2 CCl4

1938

2

S Cl

MECHANISM :

S CH3

Cl S CH3

Cl2

Cl

+ CH3SCl

Cl

DISCONNECTION :

2 ArSX

ArSSAr

ArSH + X2

ArSX + HX + X2

ArSX + HX + ArS

X

NOTES : The reaction of chlorine or bromine on aryldisulfides, thiophenols or arylbenzylsulfides to afford aromatic and aliphatic sulfenylhalogenides. Ortho or para nitro groups suppress halogenation of the phenyl ring.

REFERENCES : Houben – Weyl : 9, 268 Org. Synth. : 11, 455; 15, 55 Org. Synth. Coll. Vol. : 2, 455, 471

1) Th. Zincke, Ber. Dtsch. Chem. Ges., 1911, 44, 769. 2) Th. Zincke, Liebigs Ann. Chem., 1912, 391, 55. 3) N. Kharasch; S.J. Potempa; H.L. Wehrmeister, Chem. Rev., 1946, 39, 269. 4) E. Kühle, Synthesis, 1970, 561.

COMMENTS :

1939

ZINCKE HALOGENPHENOL NITRATION EXAMPLE :

Br F

Br OH

F

OH

NaNO2 CH3COOH

Br

NO2

MECHANISM :

Br Br

O

OH

O2N

HNO3 - 10 oC

HNO3 25 oC

O2, H2O

O2N

OH

DISCONNECTION :

Hal

NO2 O2N

Hal

OH

OH

Hal = Br, I Hal

NO2

NOTES : The replacement of o- and p-bromine or iodine atoms (not fluorine or chlorine) in phenols by nitro groups using nitrous acid or a nitrite in acidic acid. See also Wolffenstein – Böters reaction.

REFERENCES : Houben – Weyl : 10/1, 821

1940

1) Th. Zincke, J. Prakt. Chem., 1900, 61, 561. 2) L.C. Raiford, Am. Chem. J., 1910, 43, 393. 3) H.H. Hodgson; J. Nixon, J. Chem. Soc., 1932, 273. 4) L.C. Raiford; A.L. LeRosen, J. Am. Chem. Soc., 1944, 66, 1872.

COMMENTS :

ZININ REACTION EXAMPLE :

NO2

NH2

(NH4)2S, H2O

MECHANISM :

4

NO2

2-

6S

4 + 7 H2O

NH2 + 3 S2O32- + 6 HO-

DISCONNECTION :

Ar NH2

Ar NO2

NOTES : This is the reduction of nitro compounds to amines using sulfides or polysulfides. See also Béchamp reduction.

REFERENCES : March : 1216 Smith – March : 1553 Org. React. : 20, 455

1941

1) N. Zinin, J. Prakt. Chem., 1842, 27, 140. 2) K. Brand, J. Prakt. Chem., 1906, 74, 449. 3) M. Hojo; Y. Takagi; Y. Ogata, J. Am. Chem. Soc., 1960, 82, 2459.

COMMENTS :

ZININ REARRANGEMENT EXAMPLE :

H N

N H

H+ H2O, EtOH

H2N

NH2

MECHANISM :

H N

H2N N H

2 H+

H

H2N

NH2

NH2 - 2 H+

H

H2N

NH2

DISCONNECTION :

R(R1) H2N

R1(R)

H N

NH2 R1

1942

R N H

NOTES : 1,2-Diphenyl hydrazine is converted to 4,4’-diaminobiphenyl under acidic conditions. The mechanism involves a [5,5]sigmatropic rearrangement. Even with the para position occupied the rearrangement can still take place. This reaction is maybe better known as the benzidine rearrangement.

REFERENCES : March : 1144 Smith – March : 1455 Houben – Weyl : 4/2, 58; 11/1, 839

1) N. Zinin, J. Prakt. Chem., 1845, 36, 93. 2) P. Jacobsen, Liebigs Ann. Chem., 1922, 428, 76. 3) M.J.S. Dewar, J. Chem. Soc., 1946, 777. 4) G.A. Olah; K. Dunne; D.P. Kelly; Y.K. Mo, J. Am. Chem. Soc., 1972, 94, 7438. 5) H.J. Shine; H. Zmuda; K.H. Kwart; A.G. Horgan; C. Collins; B.E. Maxwell, J. Am. Chem. Soc., 1981, 103, 955. 6) H.J. Shine, J. Chem. Educ., 1989, 66, 793. 7) K.H. Park; J.S. Kang, J. Org. Chem., 1997, 62, 3794. 8) E. Buncel, Can. J. Chem., 2000, 78, 1251. 9) A.C. Benniston; W. Clegg; A. Harriman; R.W. Harrington; P. Li; C. Sams, Tetrahedron Lett., 2003, 44, 2665.

COMMENTS :

1943

ZINKE – ZIEGLER SYNTHESIS EXAMPLE :

4

+ 4 HCHO

OH OH HO HO

HO-

OH

MECHANISM :

O

R

H H+ O

H O

H+

R

R

H

H HO

OH OH

OH

R

H+ HO

R

OH H2O

R

H

- H2O

1944

HO

OH

DISCONNECTION :

R R CH2 OR1

n

OR1

NOTES : The synthesis of calixarenes from formaldehyde and phenols or resorcinols under basic conditions. The shapes range from baskets to wheels. There is a synthetic modification better known as the Zinke – Cornforth modification. See also Baekeland, von Baeyer aldehyde and Lederer – Manasse reactions.

REFERENCES : March : 84 Smith – March : 106 Org. Synth. : 68, 234 Org. Synth. Coll. Vol. : 8, 75, 77

1) A. Zinke; E. Ziegler, Chem. Ber., 1941, 74, 1729. 2) A. Zinke; G. Zigeuner; K. Hössinger; G. Hoffmann, Monatsh. Chem., 1948, 79, 438. 3) J.W. Cornforth; P. D’Arcy Hart; G.A. Nicholls; R.J.W. Rees; J.A. Stock, Br. J. Pharmacol., 1955, 10, 73. 4) C.D. Gutsche; B. Dhawan; K.H. No; R. Muthukrishnan, J. Am. Chem. Soc., 1981, 103, 3782. 5) C.D. Gutsche, Acc. Chem. Res., 1983, 16, 161. 6) C.D. Gutsche, Top. Curr. Chem., 1984, 123, 1. 7) C.D. Gutsche; M. Iqbal; D. Stewart, J. Org. Chem., 1986, 51, 742. 8) I. Alam; C.D. Gutsche, J. Org. Chem., 1990, 55, 4487. 9) P. Timmerman; W. Verboom; D.N. Reinhoudt, Tetrahedron, 1996, 52, 2663. 10) R.J. Bernardino; B.J.C. Cabral, J. Phys. Chem. A, 1999, 103, 9080.

1945

COMMENTS :

ZINNER SYNTHESIS EXAMPLE : CH3

CH3 ClO2S

SO2ONH2

CH3 + HON OEt

1) Et3N 2) HClO4

MECHANISM :

CH3 HON

CH3 +

ArO2SON

ArSO2Cl

OEt

OEt

[ArSO2ONH2.HX]

70% HClO4 0 oC

ArSO2ONH2

DISCONNECTION :

CH3 RONH2

HON OEt

NOTES : The preparation of O-aryloyl-, O-carbalkoxy-, O-arylsulfonyl-, and O-nitrophenyl hydroxylamines starting with ethylhydroxamate. Zinner’s method has been improved by Tamura et al.

1946

REFERENCES : 1) G. Zinner, Angew. Chem., 1957, 69, 204. 2) G. Zinner, Angew. Chem., 1957, 69, 480. 3) G. Zinner, Chem. Ber., 1958, 91, 302. 4) Y. Tamura; J. Minamikawa; K. Sumoto; S. Fujii; M. Ikeda, J. Org. Chem., 1973, 38, 1239. 5) G. Zinner; E.-U. Ketz, Synthesis, 1973, 165.

COMMENTS :

ZINOVEV – SOBOROVSKI REACTION EXAMPLE :

O H3C

CH3

PCl3, O2

H3C

P

Cl Cl

MECHANISM :

PCl3 + O2

PCl3O2 RPOCl2 + HCl + POCl3

PCl3O2 + RH + PCl3

DISCONNECTION :

O R P Cl Cl

R-H

NOTES : It involves the synthesis of dichloroanhydrides or of alkylphosphonic acids by oxidative phosphorylation of hydrocarbons. With long chain hydrocarbons, branching takes place. This reaction is also known under the name of Clayton – Jensen reaction. See also McBride reaction.

1947

REFERENCES : 1) J.O. Clayton; W.L. Jensen, J. Am. Chem. Soc., 1948, 70, 3880. 2) W.L. Jensen; R.C. Noller, J. Am. Chem. Soc., 1949, 71, 2384. 3) L.S. Soborovski; Yu.M. Sinovev; M.A. Englin, Ber. Akad. Wiss. USSR, 1950, 73, 333. 4) R. Graf, Chem. Ber., 1952, 85, 9. 5) G. Geiseler; F. Asinger; M. Fedtke, Chem. Ber., 1960, 93, 765.

COMMENTS :

1948

A ABRAMOV PHOSPHONYLATION REACTION · 13 ACHMATOWICZ PYRANONE REACTION · 14 ADAMS DECARBOXYLATION · 16 ADAMS MODIFICATION · 684 ADKINS – PETERSON FORMALDEHYDE REACTION · 17 ADLER – LONGO PORPHYRIN REACTION · 18 ADLER PHENOL OXIDATION · 19 AHMED – STRONG SYNTHESIS · 21 AKABORI – MOMOTANI AMINO ALCOHOL SYNTHESIS · 22 AKABORI – NEUBERG – FISCHER AMINO ACID REACTION · 23 AKABORI HYDRAZINOLYSIS · 24 ALDER – RICKERT REACTION · 25 ALDER ENE REACTION · 26 ALGAR – FLYNN – OYAMADA FLAVANONE REACTION · 28 ALLAN – LOUDON QUINOLINE SYNTHESIS · 30 ALLEN – MILLAR – MATHEY REARRANGEMENT · 32 ALLEN REACTION · 33 ALPER CARBONYLATION · 35 ALPHEN – HÜTTEL PYRAZOLE REARRANGEMENT · 37 AMADORI REARRANGEMENT · 38 ANDERSON – FUCHS REACTION · 40 ANDO MANDELIC ACID SYNTHESIS · 41 ANDO MODIFICATION · 855 ANDREASCH THIAZOLE SYNTHESIS · 43 ANDRUSSOV OXIDATION · 44 ANELLI OXIDATION · 45 ANGELI – RIMINI SYNTHESIS · 46 ANGELI FURAZAN OXIDE REARRANGEMENT · 47 ANGELI MODIFICATION · 1511 ANGELO’S D’ ASYMMETRIC MICHAEL ADDITION · 49 ANSCHÜTZ – SCHOLL HYDROXYACETOPHENONE SYNTHESIS · 50 ANSCHÜTZ ANTHRACENE SYNTHESIS · 51 ANSCHÜTZ HYDROXYCOUMARIN SYNTHESIS · 52 APPEL – ROBINSON OXIDATION · 54 APPEL REACTION · 55 ARBUZOV REACTION (MICHAELIS – ARBUZOV) · 56 ARENS – van DORP SYNTHESIS · 58 ARNDT – EISTERT SYNTHESIS · 60 ARNDTSEN MÜNCHNONE REACTION · 61 ARNOLD VARIATION · 375 ASINGER REACTION · 63 ASSCHER – VOFSI REACTION · 64 ATHERTON – OPENSHAW – TODD SYNTHESIS · 66 AUWERS von – INHOFFEN REARRANGEMENT · 67 AUWERS von FLAVONOL SYNTHESIS · 68 AUWERS von INDANE-1-ONE SYNTHESIS · 70 AUWERS von REARRANGEMENT · 72

1949

BARTON DECARBOXYLATION · 149 BARTON PHENYLATION · 150

B

BARTON REACTION · 152 BÄCKVALL ACETOXYLATION REACTION · 77

BAUDART ACYLOIN SYNTHESIS · 153

BADDELEY REARRANGEMENT · 79

BAUDART SYNTHESIS · 154

BAEKELAND POLYCONDENSATION · 81

BAUDISCH REACTION · 155

BAER – FISCHER SYNTHESIS · 83

BAUM BENZOYLATION · 157

BAEYER von – DREWSEN INDIGO SYNTHESIS · 85

BAUMANN – FROMM SYNTHESIS · 158

BAEYER von – DREWSEN QUINOLINE SYNTHESIS · 86

BAYLIS – HILLMAN – MORITA REACTION · 160

BAEYER von – EMMERLING INDOLE SYNTHESIS · 88

BÉCHAMP ARSONYLATION · 162

BAEYER von – JACKSON INDOLE SYNTHESIS · 89

BÉCHAMP REDUCTION · 164

BAEYER von – PICCARD REACTION · 91

BECKMANN REARRANGEMENT · 165

BAEYER von – PICTET CONVERSION OF PYRYLIUM SALTS

BECKMANN – CHAPMAN REARRANGEMENT · 344 BEDOUKIAN REACTION · 167

(KATRITZKY PYRYLIUM – PYRIDINIUM METHOD) · 91 BAEYER von – VILLIGER REARRANGEMENT · 92

BÉHAL – SOMMELET SYNTHESIS · 168

BAEYER von – VILLIGER TRITYLATION · 94

BEHN REACTION · 641

BAEYER von ALDEHYDE CONDENSATION · 95

BEHREND – ROOSEN SYNTHESIS · 169

BAEYER von CONVERSION OF PYRONE · 97

BEHREND REARRANGEMENT · 170

BAEYER von OXINDOLE SYNTHESIS · 98

BELLUŠ – CLAISEN REARRANGEMENT · 171

BAILEY – LIEBESKIND INDOLINES SYNTHESIS · 100

BELOUSOV – ZHABOTINSKY REACTION · 173

BAILEY CYCLOADDITION · 101

BENARY REACTION · 174

BAILEY PEPTIDE SYNTHESIS · 102

BENET SYNTHESIS · 175

BAKER – OLLIS SYNTHESIS · 103

BENKESER REACTION · 176

BAKER – VENKATARAMAN REARRANGEMENT · 105

BENKESER REDUCTION · 178

BALABAN – NENITZESCU – PRAILL SYNTHESIS · 106

BERCHTOLD REACTION · 180

BALBIANO OLEFIN OXIDATION · 108

BERGIUS PROCESS · 600

BALBIANO PYRAZOLE SYNTHESIS · 109

BERGMAN – MASAMUNE CYCLISATION · 181

BALL – GOODWIN – MORTON OXIDATION · 110

BERGMANN – SCHOTTE REACTION · 183

BALLY – SCHOLL SYNTHESIS · 112

BERGMANN – ZERVARS CARBOBENZOXY METHOD · 184

BALSOHN ADDITION · 113

BERGMANN ANTHRACENE REACTION · 186

BALZ – SCHIEMANN REACTION · 115

BERGMANN AZLACTONE PEPTIDE SYNTHESIS · 187

BAMBERGER – GOLDSCHMIDT SYNTHESIS · 116

BERGMANN DEGRADATION OF PEPTIDES · 188

BAMBERGER – HEY DIARYL SYNTHESIS · 118

BERNTHSEN ACRIDINE SYNTHESIS · 190

BAMBERGER ARYLNITRAMINES REARRANGEMENT · 119

BERNTHSEN PHENOTHIAZINE SYNTHESIS · 192

BAMBERGER BENZOTRIAZINE SYNTHESIS · 121

BERSON – WILLCOTT REARRANGEMENT · 193

BAMBERGER IMIDAZOLE REARRANGEMENT · 122

BERTRAM – WALBAUM SYNTHESIS · 194

BAMBERGER REARRANGEMENT · 123

BESTMANN REACTION · 195

BAMFORD – STEVENS REACTION (CAGLIOTI – SHAPIRO

BETTI REACTION · 196 BEYER’S MODIFICATION · 495

REACTION) · 125 BANERT CASCADE REACTION · 127

BIELLMANN ALKYLATION · 198

BARBIER – LOCQUIN – WIELAND DEGRADATION · 129

BIGINELLI PYRIMIDONE SYNTHESIS · 200

BARBIER REACTION · 130

BINGEL REACTION · 201

BARDHAN – SENGUPTA PHENANTHRENE SYNTHESIS · 132

BINKLEY TRIFLATE DISPLACEMENT · 202

BARGELLINI REACTION · 133

BIRCH – HAAS REACTION · 205

BARGELLINI RING-CLOSURE · 134

BIRCH REDUCTION · 207

BARGER DEMETHYLATION · 135

BIRCKENBACH – GOUBEAU – WATERS REACTION · 209

BARRY REACTION · 136

BIRNBAUM – SIMONINI SYNTHESIS · 210

BART (BART – SCHMIDT) REACTION · 138

BISCHLER – MÖHLAU INDOLE SYNTHESIS · 211

BARTLETT – CONDON – SCHNEIDER REACTION · 139

BISCHLER – NAPIERALSKI REACTION · 213

BARTOLI INDOLE SYNTHESIS · 140

BISCHLER CYCLISATION · 215

BARTON – KELLOGG OLEFINATION · 142

BISCHLER TRIAZINE SYNTHESIS · 216

BARTON – McCOMBIE DEOXYGENATION · 144

BLAISE – GUERIN (BLAISE –LeSUEUR) DEGRADATION · 217

BARTON – ZARD PYRROLE SYNTHESIS · 146

BLAISE – MAIRE KETONE SYNTHESIS · 218

BARTON DEAMINATION · 147

BLAISE KETOESTER REACTION · 219

1950

BRAUN von – RUDOLPH MODIFICATION · 1609

BLANC – QUELLET CHLOROMETHYLATION /

BRECKPOT REACTION · 288

CHLOROALKYLATION REACTION · 221 BLANC REACTION · 223

BREDERECK IMIDAZOLE SYNTHESIS · 290

BLICKE – PACHTER SYNTHESIS · 224

BREDERECK MODIFICATION · 1012

BLOMQUIST REACTION · 225

BROOK SILAKETONE REARRANGEMENT · 291

BLUM AZIRIDINE SYNTHESIS · 226

BROWN HYDROBORATION · 293

BOBBIT MODIFICATION · 1391

BROWN REACTION · 295

BOBBIT REACTION · 228

BROWN REARRANGEMENT · 296

BODROUX – CHICHIBABIN ALDEHYDE SYNTHESIS · 229

BRUNNER OXINDOLE RING–CLOSURE · 299

BODROUX REACTION · 230

BRUYLANTS AMINATION · 300

BOECKMANN PROCEDURE · 1300

BUCHERER – BERGS REACTION · 301

BOEKELHEIDE REACTION · 232

BUCHERER – GROLÉE SYNTHESIS · 303

BÖESEKEN – BALLIO SYNTHESIS · 233

BUCHERER – LE PETIT REACTION · 304

BÖESSNECK – HÉBERT REACTION · 234

BUCHERER CARBAZOLE SYNTHESIS · 306

BOGER – PANEK PYRIDINE SYNTHESIS · 235

BÜCHNER – CURTIUS – SCHLOTTERBECK REACTION · 308

BOGERT – COOK REACTION · 237

BÜCHNER METHOD OF RING ENLARGEMENT · 310

BOGERT – HERRERA SYNTHESIS · 238

BUCHWALD – HARTWIG REACTION · 312

BOHLMANN – RAHTZ REACTION · 239

BUCHWALD ZIRCONOCENE REACTION · 314

BOHN – SCHMIDT REACTION · 240

BUNNETT REACTION · 315

BOHN SYNTHESIS · 242

BURTON – WIEMERS TRIFLUOROMETHYLATION · 317

BONE – SPRANKLING SYNTHESIS · 243

BUTLEROW SUGAR SYNTHESIS · 318

BOON – POLONOVSKI PTERIDINE REACTION · 244

BUU–HOÏ MODIFICATION · 1871

BOORD OLEFIN SYNTHESIS · 245 BORCH REDUCTION · 246 BORSCHE – BEECH AROMATIC ALDEHYDE SYNTHESIS · 248 BORSCHE – BERKHOUT SYNTHESIS · 249 BORSCHE – DRECHSEL CYCLISATION · 250 BORSCHE – KENNER SYNTHESIS · 252 BORSCHE – KOELSCH CINNOLINE SYNTHESIS · 253 BORSCHE – RIED MODIFICATION · 643 BOSCH – MEISER UREA PROCESS · 255 BOTT – HELLMANN REACTION · 255 BÖTTINGER – MICHAELIS REACTION · 257 BOUGAULT SYNTHESIS · 258 BOUIS SYNTHESIS · 259 BOULTON – KATRITZKY REARRANGMENT · 261 BOUVEAULT – BLANC REDUCTION · 262 BOUVEAULT – LOCQUIN ACYLOIN SYNTHESIS · 263 BOUVEAULT – LOCQUIN AMINO ACID SYNTHESIS · 265 BOUVEAULT – WAHL SYNTHESIS · 267 BOUVEAULT ALDEHYDE SYNTHESIS · 268 BOUVEAULT HYDROLYSIS OF AMIDES · 269 BOWMAN DEBENZYLATION · 271 BOWMAN REACTION · 274 BOYD – ROBINSON 4-HYDROXYCOUMARINS SYNTHESIS · 276 BOYLAND – SIMS ORTHO-HYDROXYANILINE SYNTHESIS · 277 BRACKEEN SYNTHESIS · 278 BRACKMAN – SMITH MODIFICATION · 1511 BRADSHER CYCLOADDITION REACTION · 279 BRADSHER REACTION · 281 BRANDI – GUARNA REARRANGEMENT · 282 BRANDT ALDEHYDE SYNTHESIS · 283 BRAUN von AMIDE DEGRADATION · 284 BRAUN von AMINO ACID SYNTHESIS · 287 BRAUN von CYANOGEN BROMIDE REACTION · 286

1951

COLEMAN SYNTHESIS · 387 COLLINS OXIDATION · 389

C

COLVIN SYNTHESIS · 391 CACCHI COUPLING · 1611

COMBES ACETYLACETONE SYNTHESIS · 392

CADIOT – CHODKIEWICZ REACTION· 695

COMBES QUINOLINE SYNTHESIS · 394

CADOGAN – CAMERON–WOOD CYCLISATION · 324

COMINS ADDITION · 395

CADOGAN – SUNDBERG INDOLE SYNTHESIS · 325

CONANT – FINKELSTEIN HALOGEN EXCHANGE · 397

CADOGAN ARYLATION · 326

CONIA CYCLISATION · 398

CAMPS QUINOLINE SYNTHESIS · 328

CONRAD – LIMPACH SYNTHESIS · 399

CANNIZZARO REACTION · 329

COOK – HEILBRON THIAZOLE SYNTHESIS · 401

CARBONI – LINDSEY SYNTHESIS · 331

COOK – LEVY PEPTIDE SYNTHESIS · 403

CARGILL REARRANGEMENT · 333

COOPER – FINKBEINER HYDROMAGNESIATION · 404

CARROLL METHYLENE ADDITION (KIMEL – COPE

COPE – MAMLOCK – WOLFFENSTEIN OLEFIN SYNTHESIS (COPE ELIMINATION) · 405

REARRANGEMENT) · 334 CASON (GILMAN – NELSON) SYNTHESIS · 336

COPE REARRANGEMENT · 407

CAVA REARRANGEMENT · 337

COREY – CHAYKOVSKY EPOXIDATION · 408

CHAN – LAM COUPLING · 338

COREY – FUCHS REACTION · 410

CHAN REARRANGEMENT · 340

COREY – HOUSE REACTION · 411

CHAN REDUCTION OF ACETYLENES · 341

COREY – ITSUNO – BAKSHI – SHIBATA ENANTIOSELECTIVE BORANE REDUCTION · 413

CHAPMAN REARRANGEMENT · 342 CHARDONNET de CELLLOSE ESTERIFICATION · 344

COREY – KIM OXIDATION · 415

CHARETTE CYCLOPROPANATION · 344

COREY – KWIATKOWSKI REACTION · 416

CHATTAWAY ACETYLATION · 346

COREY – LINK REACTION · 418

CHATTAWAY REARRANGEMENT · 347

COREY – NICOLAOU MACROLACTONISATION · 419

CHENEY SYNTHESIS · 349

COREY – SCHMIDT OXIDATION · 421

CHICHIBABIN PYRIDINE SYNTHESIS · 350

COREY – SEEBACH PROCEDURE · 423

CHICHIBABIN PYRROCOLINE (INDOLIZINE) SYNTHESIS · 351

COREY – SEMMELHACK MODIFICATION · 425

CHICHIBABIN REACTION · 353

COREY – SUGGS OXIDATION · 426

CHRÉTIEN – LONGI NITROSATION · 354

COREY – WINTER ALKENE SYNTHESIS · 428

CIAMICIAN – DENNSTEDT REARRANGEMENT · 355

CORNFORTH REARRANGEMENT · 430

CIAMICIAN PHOTO COUPLING · 356

COUTURE INDOLE SYNTHESIS · 431

CIAMICIAN PHOTO DISPROPORTIONATION · 358

CRABBÉ SYNTHESIS · 433

CLAISEN – GEUTHER CONDENSATION · 359

CRAIG EXCHANGE · 434

CLAISEN – HAASE ENOL ESTER TRANSFORMATION · 361

CREIGHTON PROCESS · 436

CLAISEN – MAUTHNER – BOUVEAULT SYNTHESIS · 362

CRIEGEE GLYCOL CLEAVAGE · 436

CLAISEN – SCHMIDT CONDENSATION · 363

CRIEGEE OSMIUM TETROXIDE REACTION · 438

CLAISEN – SHADWELL SYNTHESIS · 365

CRIEGEE REARRANGEMENT · 439

CLAISEN – WISLICENUS CONDENSATION · 366

CROSS – BEVAN – BEADLE REACTION · 441

CLAISEN CARBONATE ALKYLATION · 368

CRUM BROWN – WALKER ELECTROLYSIS · 442

CLAISEN CINNAMIC ESTER SYNTHESIS · 369

CURATOLO SYNTHESIS · 443

CLAISEN HYDROLYSIS · 371

CURTIUS REARRANGEMENT · 444

CLAISEN ORTHO ESTER REARRANGEMENT · 367 CLAISEN REARRANGEMENT (CLAISEN – IRELAND REARRANGEMENT) · 372 CLAR REDUCTION · 375 CLAUSON–KAAS REACTION · 376 CLAY – KINNEAR – PERREN PHOSPHONYL CHLORIDE SYNTHESIS · 378 CLEMMENSEN REDUCTION · 379 CLEMO SYNTHESIS · 381 CLIBBENS – NIERENSTEIN SYNTHESIS · 383 CLOKE – WILSON CYCLO PROPYL KETONE REARRANGEMENT · 384 COHEN – DANIEWSKI PROCESS · 386

1952

D DAKIN – WEST REACTION · 449 DAKIN AZLACTONE REACTION · 451 DAKIN OXIDATION OF BUTYRIC ACID · 452 DAKIN PHENOL ALDEHYDE OXIDATION · 454 DANHEISER ANNULATION · 456 DANHEISER CYCLOPENTENE ANNULATION · 457 DANISHEFSKY REACTION · 459 DARAPSKY AMINO ACID REACTION · 460 DARZENS – ERLENMEYER – CLAISEN CONDENSATION · 462 DARZENS METHOD · 463 DARZENS SYNTHESIS OF TETRALIN · 465 DAVID – THIEFFRY OXIDATION · 466 DAVIDSON OXAZOLE SYNTHESIS · 467 DEACON REACTION · 468 DEBUS – RADZISZEWSKI IMIDAZOLE SYNTHESIS · 469 DECKER – FORSTER AMINATION · 470 DELÉPINE AMINE SYNTHESIS · 471 DELÉPINE OXIDATION · 473 DEMJANOV REARRANGEMENT · 474 DEMOLE SYNTHESIS · 475 DESS – MARTIN PERIODINANE REACTION · 476 DIECKMANN – KOMPPA MODIFICATION · 480 DIECKMANN – MEISER SYNTHESIS · 479 DIECKMANN CONDENSATION · 480 DIELS – ALDER REACTION · 481 DIELS – REESE REACTION · 483 DIELS DEHYDRATION · 485 DIMROTH REARRANGEMENT · 486 DIONNEAU METHOD · 487 DISCHE REACTION · 488 DJERASSI – RYLANDER OXIDATION · 489 DODDS – ROBINSON SYNTHESIS · 491 DOEBNER – von MILLER SYNTHESIS · 492 DOEBNER MODIFICATION · 496 DOEBNER QUINOLINE SYNTHESIS · 494 DOERING von – LA FLAMME – MOORE ALLENE SYNTHESIS · 497 DONDONI HOMOGOLATION · 499 DORNOW – WIEHLER ISOXAZOLE REACTION · 500 DÖTZ HYDROQUINONE SYNTHESIS · 502 DOUGLAS – FARAH REACTION · 504 DOWD – BECKWITH REACTION · 506 DOYLE – KIRMSE REACTION · 505 DREIDING – SCHMIDT REACTION · 508 DUFF REACTION · 509 DUTHALER – HAFNER ALLYLATION · 511 DUTT – WORMALL REACTION · 512

1953

E EABORN – CHVALOVKSÝ REACTION · 516 EABORN REACTION · 517 EASTWOOD REACTION · 518 EBELE – SCHIESSLER – ROSS CYCLONITE SYNTHESIS · 519 ECKEY PROCESS · 520 EDER REACTION · 520 EDMAN DEGRADATION · 521 EGLINGTON - GALBRAITH REACTION · 695 EHRLICH – SACHS REACTION · 522 EHRLICH PYRROLE REACTION · 524 EIJKMAN ADDITION · 525 EINHORN – BRUNNER REACTION · 527 EINHORN – TSCHERNIAC AMIDOMETHYLATION · 528 EINHORN ACYLATION · 530 EINHORN OXIDATION · 531 EISLEB AMINOALKYLATION · 532 ELBS PERSULFATE OXIDATION · 533 ELBS REACTION · 535 ELTEKOFF KETONE SYNTHESIS · 536 ELTEKOFF METHYLATION · 537 EMDE DEGRADATION · 538 EMMERT – ASENDORF REACTION · 540 ENDERS REACTION · 541 ENGLER INDOLE SYNTHESIS · 543 ERLENMEYER – FRÜSTÜCK SYNTHESIS · 544 ERLENMEYER – PLÖCHL AZLACTONE SYNTHESIS · 546 ESCHENMOSER – MEERWEIN – CLAISEN REARRANGEMENT · 547 ESCHENMOSER – TANABE RING CLEAVAGE · 549 ESCHENMOSER METHENYLATION · 551 ESCHENMOSER SULFIDE CONTRACTION · 552 ESCHWEILER – CLARKE REACTION · 554 ÉTARD REACTION · 555 EVANS – TISCHTSCHENKO REDUCTION · 1726 EVANS REACTION · 558

1954

FREUDENBERG – SCHÖNBERG XANTHATE REARRANGEMENT · 636

F

FREUND REACTION · 637 FAVORSKII – BABAYAN SYNTHESIS · 563

FRIEDEL – CRAFTS – KARRER REACTION · 638

FAVORSKII ACETYLENE REARRANGEMENT · 564

FRIEDEL – CRAFTS REACTION · 640

FAVORSKII REARRANGEMENT · 565

FRIEDLÄNDER QUINOLINE SYNTHESIS · 642

FEIST – BÉNARY FURAN SYNTHESIS · 568

FRIEDMAN SYNTHESIS · 644

FEIST CARBOXYLIC ACID SYNTHESIS · 569

FRIES REARRANGEMENT · 645

FELDMAN INDOLE SYNTHESIS · 571

FRITSCH – BUTTENBERG – WIECHELL REARRANGEMENT · 648

FELDMAN SYNTHESIS · 573 FELKIN CYCLISATION · 575

FRITSCH – KLING CHLORINATION · 649

FENTON REACTION · 577

FUJIMOTO – BELLEAU REACTION · 650

FERINGA CHIRAL BUTENOLIDE SYNTHESIS · 578

FUJIWARA LANTHANIDE REACTION · 652

FERRARIO – ACKERMAN REACTION · 580

FUKUYAMA – MITSUNOBU REACTION · 1212

FERRIER REARRANGEMENT I · 582

FUKUYAMA INDOLE SYNTHESIS · 653

FERRIER REARRANGEMENT II · 584

FUKUYAMA REDUCTION · 655

FÉTIZON OXIDATION · 585

FÜRSTNER INDOLE SYNTHESIS · 657

FICINI – CLAISEN REARRANGEMENT · 587

FÜRSTNER PROCEDURE · 1300

FIESSELMANN THIOPHENE SYNTHESIS · 588

FURUGAWA MODIFICATION · 1583

FINEGAN TETRAZOLE SYNTHESIS · 589 FISCHER – ACH URIC ACID SYNTHESIS · 590 FISCHER – DILTHEY CONDENSATION · 591 FISCHER – FINK PYRROLE SYNTHESIS · 593 FISCHER – HEPP REARRANGEMENT · 594 FISCHER – NOURI MODIFICATION · 830 FISCHER – SPEIER ESTERIFICATION · 595 FISCHER – STECHE SYNTHESIS · 597 FISCHER – TROPSCH SYNTHESIS · 598 FISCHER – ZACH REACTION · 600 FISCHER – ZERWECK PYRROLE ALDEHYDE SYNTHESIS · 602 FISCHER ACETAL SYNTHESIS · 603 FISCHER ARYLHYDRAZINE SYNTHESIS · 604 FISCHER GLYCOSIDATION · 605 FISCHER INDOLE SYNTHESIS · 607 FISCHER INDOLENINES SYNTHESIS · 609 FISCHER OXAZOLE SYNTHESIS · 610 FISCHER PEPTIDE SYNTHESIS · 611 FISCHER PHENYLHYDRAZINE AND OXAZONE REACTION · 615 FITTIG – EGBERT REARRANGEMENT · 616 FITTIG – ERDMANN SYNTHESIS · 617 FITTIG PINACOLONE REARRANGEMENT · 619 FLEMING – MAH ANTHRACENE SYNTHESIS · 620 FLOOD REACTION · 622 FONKEN – JOHNSON SYNTHESIS · 623 FORSTER – DECKER REACTION · 624 FORSTER REACTION · 625 FOULDS – ROBINSON INDOLE / QUINOLINE SYNTHESIS · 627 FOWLER SYNTHESIS · 629 FRANCHIMONT DICARBOXYLIC ACID SYNTHESIS · 630 FRANCHIMONT NITRAMINE REACTION · 631 FRANKEL – SHIBASAKI REARRANGEMENT · 632 FRANKLAND – DUPPA REACTION · 633 FRANKLAND SYNTHESIS · 634 FREDENHAGEN PROCESS · 635

1955

GRIGNARD – COLONGE SYNTHESIS · 718 GRIGNARD DEHALOGENATION · 719

G

GRIGNARD REACTION · 720 GABRIEL – COLMAN REARRANGEMENT · 661

GROB – CAMENISCH SYNTHESIS · 722

GABRIEL – ISAY REACTION · 889

GROB FRAGMENTATION · 723

GABRIEL – MARCKWALD – CROMWELL AZIRIDINE METHOD ·

GROVENSTEIN – ZIMMERMANN REARRANGEMENT · 725 GROVES SYNTHESIS · 726

662 GABRIEL SYNTHESIS · 663

GRUBBS REACTION · 727

GALAT – ELION ACYLATION · 665

GRUNDMANN ALDEHYDE SYNTHESIS · 729

GALLAGHER – HOLLANDER DEGRADATION · 666

GRYSZKIEWICZ–TROCHIMOWSKI – McCOMBIE METHOD · 730

GANEM OXIDATION · 1027

GUARESCHI – THORPE CONDENSATION · 731

GAREGG – SAMUELSSON OLEFIN SYNTHESIS · 667

GUARESCHI HYDROLYSIS · 732

GARIGIPATI SYNTHESIS · 669

GUERBET REACTION · 733

GASSMAN INDOLE SYNTHESIS · 670

GUSTAVSON CYLISATION · 734

GASSMAN OXINDOLE SYNTHESIS · 672

GUSTUS CLEAVAGE · 735

GASTALDI PYRAZINE SYNTHESIS · 673

GUTKNECHT PYRAZINE SYNTHESIS · 737

GATTERMANN – CANTZLER SYNTHESIS · 675

GUY – LEMAIRE – GUETTE REACTION · 738

GATTERMANN – EHRHÁRDT ACYLATION · 676

GUYOT – GRY – BOUVEAULT SYNTHESIS · 739

GATTERMANN – KOCH REACTION · 677 GATTERMANN – MAFFEZZOLI SYNTHESIS · 679 GATTERMANN – SKITA SYNTHESIS · 680 GATTERMANN DIARYL SYNTHESIS · 681 GATTERMANN DIAZO REACTION · 682 GATTERMANN FORMYLATION · 683 GATTERMANN SULFINIC ACID SYNTHESIS · 685 GAULTIER – GUILLEMARD REARRANGEMENT · 686 GERLACH MODIFICATION · 421 GEWALD HETEROCYCLE SYNTHESIS · 687 GIBBS – WOHL PHTHALIC ANHYDRIDE PROCESS · 689 GIESE REDUCTIVE MERCURY REACTION · 690 GILMAN – SPEETER REACTION · 692 GILMAN – van ESS SYNTHESIS · 691 GLADSTONE – TRIBE SYNTHESIS · 694 GLASER – HAY REACTION · 695 GLASER COUPLING (CADIOT – CHODKIEWICZ – EGLINGTON COUPLING) · 695 GODCHOT – MOUSSERON RING CONTRACTION · 696 GOGTE SYNTHESIS · 697 GOMBERG – BACHMANN – HEY REACTION · 699 GOMBERG FREE RADICAL REACTION · 700 GOMBERG SYNTHESIS · 701 GOULD – JACOBS REACTION · 702 GRAEBE – PICTET SYNTHESIS · 704 GRAEBE – ULLMANN CARBAZOLE SYNTHESIS · 705 GRAEBE – ULLMANN FLUORENE SYNTHESIS · 1768 GRAHAM REACTION · 706 GRÄNACHER CONDENSATION · 707 GRANDBERG TRYPTAMINE SYNTHESIS · 709 GRIBBLE INDOLE REDUCTION · 710 GRIBBLE REDUCTION · 712 GRIECO CONDENSATION · 713 GRIECO SELENIDE REACTION · 714 GRIESS DEAMINATION · 715 GRIGG COUPLING · 717

1956

HERZIG – MEYER N-ALKYL GROUP DETERMINATION · 806 HEUMANN INDIGO SYNTHESIS · 807

H

HEWITT REACTION · 809 HILBERT – JOHNSON – RIST REACTION · 1790

HABER – WEISS REACTION (HABER – WILLSTÄTTER

HILL REDUCTION · 810

REACTION) · 744

HILLMAN REACTION · 812

HADDADIN – ISSIDORIDES QUINOXALINE SYNTHESIS (BEIRUT

HINKEL MODIFICATION · 684

REACTION) · 745

HINSBERG OXINDOLE SYNTHESIS · 813

HAJOS – PARRISH – EDER – SAUER – WIECHERT

HINSBERG REACTION · 815

CYCLISATION · 746 HAKOMORI REACTION · 748

HINSBERG SULFONE SYNTHESIS · 816

HALBERKANN VARIANT · 1369

HINSBERG THIOPHENE SYNTHESIS · 818

HALE CYCLONITE SYNTHESIS · 749

HIYAMA AMINOACRYLATE SYNTHESIS · 819

HALLER – BAUER REACTION · 750

HIYAMA COUPLING · 820

HAMMICK PICOLINIC ACID DECARBOXYLATION · 752

HO DEHALOGENATION · 822

HANESSIAN – HULLAR REACTION · 753

HOCH – CAMPBELL AMINO ALCOHOL SYNTHESIS · 823

HANESSIAN MACROLACTONISATION · 754

HOCK – LANG OXIDATION · 825

HANSLEY – PRELOG – STOLL SYNTHESIS · 756

HOCKET – HUDSON OXIDATION · 1489

HANTZSCH – BEYER PYRIDINE SYNTHESIS · 758

HODGES – VEDEJS REACTION · 826

HANTZSCH PYRROLE SYNTHESIS · 760

HOEHN – MASON DEGRADATION · 828

HANTZSCH TETRAZOLE SYNTHESIS · 762

HOESCH – HOUBEN SYNTHESIS · 829

HANTZSCH THIAZOLE SYNTHESIS · 763

HOFER – MOEST REACTION · 831

HARGAR REACTION · 447

HOFMANN – LÖFFLER – FREYTAG REACTION · 832

HARLAY AMINATION · 764

HOFMANN – MARTIUS REARRANGEMENT (REILLY – HICKINBOTTOM) · 833

HARLEY–MASON MODIFICATION · 86 HARRIES OZONIDE REACTION · 766

HOFMANN – SAND OXYMERCURATION · 835

HARRIES PYRROLE SYNTHESIS · 767

HOFMANN DEGRADATION · 836

HASS – BENDER CARBONYL SYNTHESIS · 768

HOFMANN ISONITRILE SYNTHESIS · 838

HASS CYCLOPROPANE PROCESS · 770

HOFMANN REARRANGEMENT · 839

HASS PROCESS · 771

HOLLEMANN PINACOL SYNTHESIS · 840

HASSNER – GHERA – LITTLE RING– CLOSURE · 772

HOMO-FAVORSKII REARRANGEMENT · 566

HASSNER – RUBOTTOM α-HYDROXYLATION · 773

HONZL – RUDINGER PEPTIDE SYNTHESIS · 842 HOOGEWERFF – VAN DORP SYNTHESIS · 843

HASSNER AZIDE AZIRIDINE SYNTHESIS · 774

HOOKER REACTION · 844

HAUSER – BEAK ORTHO-LITHIATION · 776

HOPPE HOMOALDOL REACTION · 846

HAUSER – KRAUS ANNULATION · 778

HORBACZEWSKI SYNTHESIS · 847

HAWORTH METHYLATION · 779

HOREAU – ORMANCEY SYNTHESIS · 849

HAWORTH POLYNUCLEAR AROMATICS SYNTHESIS · 781

HORENSTEIN – PÄHLICKE ESTERFICATION · 850

HAY REACTION · 695

HORNER – KNOWLES – KAGAN ASYMMETRIC

HAYASHI – ITO REACTION · 783

HYDROGENATION · 851

HAYASHI REARRANGEMENT · 784

HORNER – WADSWORTH – EMMONS REACTION · 854

HECK – FUJIWARA – MIZOROKI COUPLING · 786

HORNING REACTION · 856

HEGEDUS – MORI – HECK INDOLE SYNTHESIS · 791

HOSOMI – MIYAURA BORYLATION · 857

HEGEDUS INDOLE SYNTHESIS · 790

HOSOMI – SAKURAI ALLYLATION · 859

HEINE REACTION · 791

HOUBEN – FISCHER SYNTHESIS · 861

HEINISCH – MATUSZCZAZOV – MERETEIRA REACTION · 792

HOULIHAN MODIFICATION · 1123

HELFERICH ETHERIFICATION · 794

HOUSE – BABAD METHOD · 481

HELFERICH METHOD · 795

HUA REACTION · 863

HELL – VOLLHARD – ZELINSKY HALOGENATION · 796

HUANG-MILON MODIFICATION · 1875

HEMETSBERGER – KNITTEL INDOLE SYNTHESIS · 798

HUDSON – JACKSON OXIDATION · 864

HENKEL PROCESS · 1413

HUGERSHOFF REACTION · 865

HENRY REACTION (KAMLET REACTION) · 799

HUGERSHOFF SYNTHESIS · 866

HENZE – HUMPHREYS AMINE SYNTHESIS · 801

HUISGEN – WHITE REACTION · 867

HERBST – ENGEL AMINO ACID SYNTHESIS · 802

HUISGEN REACTION · 869

HERSHBERG SYNTHESIS · 803

HUNSDIECKER – BORODINE REACTION · 870

HERZ REACTION · 805

HUNSDIECKER RING–CLOSURE · 872

1957

HURD – MORI REACTION · 873 HURTLEY REACTION · 875

1958

I IBUKA – YAMAMOTO 1,3-CHIRALITY TRANSFER · 879 IMAMOTO ALKYLATION · 880 INANAGA INDOLE SYNTHESIS · 881 ING – MANSKE PROCEDURE · 883 INHOFFEN ALDEHYDE SYNTHESIS · 884 IPATIEW – SENDERENS OLEFIN SYNTHESIS · 885 IPATIEW CYCLOPROPANE SYNTHESIS · 886 IRVINE – PURDIE SUGAR METHYLATION · 887 ISAY PTERIDINE REACTION · 889 ISLER SYNTHESIS · 890 IVANOV REACTION · 893 IWAO INDOLE SYNTHESIS · 894

1959

J JACOBSEN – KATSUKI EPOXIDATION · 899 JACOBSEN REARRANGEMENT · 901 JACOBSON INDAZOLE SYNTHESIS · 903 JAPP – KLINGEMANN REACTION · 904 JAPP – MURRAY INDOLE SYNTHESIS · 906 JAPP OXAZOLE SYNTHESIS · 907 JÉGER THF SYNTHESIS · 908 JOHNSON – CLAISEN REARRANGEMENT · 910 JOHNSON – McINTOSH – Mc NELIS α-IODINATION · 911 JOHNSON 2-THIOHYDANTOIN SYNTHESIS · 913 JOHNSON ALKYNYLATION · 914 JOHNSON ANGULAR METHYLATION · 915 JOHNSON POLYENE CYCLISATION · 917 JONES – WEEDON SYNTHESIS · 918 JONES HYDROXYPYRAZINE SYNTHESIS · 920 JONES OXIDATION · 921 JOURDAN – ULLMANN – GOLDBERG SYNTHESIS · 923 JULIA – BRUYLANTS CYCLOPROPYL CARBINOL REARRANGEMENT · 927 JULIÁ – COLONNA REACTION · 925 JULIA – JOHNSON CYCLOPROPYL CARBINOL REARRANGEMENT · 926 JULIA – PARIS – KOCIENSKI – LYTHGOE SYNTHESIS · 927 JULIA INDOLE SYNTHESIS · 930 JUNG – OLAH – VORONKOV ETHER CLEAVAGE · 931 JUST SYNTHESIS · 932

1960

KNORR PYRAZOLE SYNTHESIS · 1003 KNORR PYRROLE SYNTHESIS · 1004

K

KNORR QUINOLINE SYNTHESIS · 1005 KABACHNIK – FIELDS REACTION · 937

KNUNYANTS FLUORO ALKYLATION · 1007

KABBE CHROMANONE SYNTHESIS · 938

KOCH – HAAF REACTION · 1008

KAGAN – MODENA REACTION · 940

KOCHI DECARBOXYLATION · 1009

KAGAN – MOLANDER REACTION · 941

KOCHI REACTION · 1010

KAHNE – RYU – CURRAN HYDROXYMETHYLATION · 943

KOENIGS – KNORR SYNTHESIS · 1012

KAHNE GLYCOSIDATION · 944

KOHLER ISOXAZOLE-N-OXIDE SYNTHESIS · 1013

KAISER – JOHNSON – MIDDLETON DINITRILE CYCLISATION ·

KOLBE – SCHMITT REACTION · 1015 KOLBE ALDEHYDE SYNTHESIS · 1016

945 KAISER TRIAZOLE SYNTHESIS · 947

KOLBE CYANIDE ALKYLATION · 1017

KAKIS – KIKUCHI REARRANGEMENT · 948

KOLBE ELECTROLYTIC SYNTHESIS · 1018

KALB – GROSS SYNTHESIS · 949

KONDAKOFF OLEFIN REACTION · 1019

KALUZA ISOTHIOCYANATE SYNTHESIS · 950

KONDO – UYEO SYNTHESIS · 1020

KAMETANI – TSUJI AMINE OXIDATION · 951

KÖNIG BENZOXAZINE SYNTHESIS · 1022

KANEMASA REACTION · 953

KOPETSCHNI CONVERSION · 1023

KAPP – KNOLL SYNTHESIS · 954

KORNBLUM – DELAMARE REARRANGEMENT · 1023

KARRER SYNTHESIS · 956

KORNBLUM – RUSSELL REACTION · 1024

KATO – YAMABE REACTION · 957

KORNBLUM ALDEHYDE SYNTHESIS · 1026

KATOH SYNTHESIS · 958

KÖRNER – CONTARDI REPLACEMENT · 1028

KATSUKI – SHARPLESS EPOXIDATION · 959

KOSER TOSYLATION · 1029

KAUFFMANN DIMERISATION · 962

KOST – SAGITULLIN REARRANGEMENT · 1031

KAWASE REARRANGEMENT · 963

KOSTANECKI von (ALLAN – ROBINSON) ACYLATION · 1032

KECK ALLYLATION · 964

KOTALI – TSOUNGAS REACTION · 1034

KECK MACROLACTONISATION · 1628

KOWALSKI ESTER HOMOLOGATION · 1036

KEKULÉ SYNTHESIS · 965

KRAFFT DEGRADATION · 1037

KEMP ELIMINATION · 966

KRAPCHO DECARBOXYLATION · 1038

KENDALL – MATTOX REACTION · 968

KRIEF – REICH – CHOW OLEFINATION · 1040

KENNEDY OXIDATIVE CYCLISATION · 969

KRIEWITZ – PRINS ADDITION · 1041

KENNER MODIFICATION · 254

KRÖHNKE – ORTOLEVA – KING ALDEHYDE SYNTHESIS · 1043

KENNER SYNTHESIS · 971

KRÖHNKE PYRIDINE SYNTHESIS · 1044

KERK VAN DER – SCHLESINGER REACTION · 972

KUHN – ROTH OXIDATION · 1046

KERP REDUCTION · 973

KUHN – WINTERSTEIN REACTION · 1047

KHARASCH – CURRAN REACTION · 974

KUHN MODIFICATION · 888

KHARASCH – KLEIMANN SYNTHESIS · 976

KULINKOVICH REACTION · 1048

KHARASCH – SOSNOVSKY REACTION · 977

KUMADA – TAMAO – CORRIU CROSS–COUPLING · 1049

KHARASCH – URRY REARRANGEMENT · 979

KUMADA – TAMAO – FLEMING STEREOSELECTIVE HYDROXYLATION · 1052

KIHARA INDOLE SYNTHESIS · 980 KILIANI – FISCHER SYNTHESIS · 982

KUMADA REARRANGEMENT · 1054

KILIANI REDUCTION · 983

KURSANOV – PARNES IONIC HYDROGENATION · 1056

KIMPE de SYNTHESIS · 985

KUTSCHEROFF – DENIGÈS HYDRATION · 1057

KINDLER SYNTHESIS · 986 KINUGASA REACTION · 987 KISHNER CYCLOPROPANE SYNTHESIS · 988 KITA ESTERIFICATION · 990 KNOCHEL REACTION · 992 KNOEVENAGEL AMINE SYNTHESIS · 994 KNOEVENAGEL CONDENSATION · 995 KNOEVENAGEL COUMARIN SYNTHESIS · 997 KNOEVENAGEL CYCLOHEXENONE SYNTHESIS · 998 KNOEVENAGEL DIAZOTATION · 999 KNOFFLER – BACHMANN CYCLONITE SYNTHESIS · 1001 KNOOP – OESTERLIN AMINO ACID SYNTHESIS · 1001

1961

L LADENBURG – VYSHNEGRADSKIÎ HYDROGENATION · 1061 LADENBURG CONIINE SYNTHESIS · 1062 LADENBURG REARRANGEMENT · 1063 LADENBURG RING-CLOSURE · 1064 LANDAUER – RYDON SYNTHESIS · 1065 LANDER REARRANGEMENT · 1066 LAPWORTH CONDENSATION (BENZOIN CONDENSATION) · 1067 LAROCK FLUOREN-9-ONE-2 SYNTHESIS · 1071 LAROCK FLUORENE SYNTHESIS · 1069 LAROCK INDOLE SYNTHESIS · 1073 LAWESSON THIOCARBONYLATION · 1075 LEBEDEV BUTADIENE PROCESS · 1077 LEBEDEV METHOXYMETHYLATION · 1077 LEDERER – MANASSE REACTION · 1078 LEHMSTEDT – TANASESCU REACTION · 1080 LEHN CRYPTAND SYNTHESIS · 1081 LEIMGRUBER – BATCHO ENAMINE / INDOLE SYNTHESIS · 1083 LEMIEUX – JOHNSON CLEAVAGE · 1085 LEMIEUX – von RUDLOFF OXIDATION · 1085 LESPIEAU – BOURGEL SYNTHESIS · 1086 LESSER – WEIβ SYNTHESIS · 1087 LETTS NITRILE SYNTHESIS · 1088 LEUCHS (LEUCHS – BERGMANN) PEPTIDE SYNTHESIS · 1089 LEUCHS ALKYLATION · 1090 LEUCKART – PICTET – HUBERT (MORGAN – WALLS) REACTION · 1092 LEUCKART – WALLACH REACTION · 1093 LEUCKART THIOPHENOL REACTION · 1095 LEUSEN van OXAZOLE SYNTHESIS · 1096 LEVINSTEIN PROCESS · 1098 LEY OXIDATION · 1099 LIEBEN IODOFORM REACTION · 1100 LIEBESKIND – SROGL REACTION · 1102 LIEBIG BENZYLIC ACID REARRANGEMENT · 1103 LIEPA COUPLING · 1105 LIMAYE SYNTHESIS · 1106 LINDSEY PORPHYRIN SYNTHESIS · 1107 LIPP INDOLE SYNTHESIS · 1109 LOBRY de BRUIN – van EKENSTEIN TRANSFORMATION · 1111 LOSSEN REARRANGEMENT · 1112 LUCHE ALLYLATION · 131 LUCHE REDUCTION · 1114 LUMIÈRE – BARBIER ACETYLATION · 1115 LÜTTRINGHAUS REARRANGEMENT · 1116

1962

METH–COHN QUINOLINE SYNTHESIS · 1180 MEDZIHRADSKY METHOD · 842

M

MEYER – HARTMANN SYNTHESIS · 1182 MEYER – SCHUSTER REARRANGEMENT (RUPE REACTION) ·

MACDONALD – FISCHER SUGAR DEGRADATION · 1120

1185

MACDONALD PORPHYRIN SYNTHESIS · 1121 MADELUNG INDOLE SYNTHESIS · 1122

MEYER ALKYLATION REACTION · 1187

MAGNUS INDOLE SYNTHESIS · 1124

MEYER NITROALKANE REACTION · 1188

MAILLARD REACTION · 39

MEYER REACTION · 1189

MAITLAND – JAPP REACTION · 1125

MEYER von – MOHR SYNTHESIS · 1183

MAJETICH ANNULATION · 1127

MEYER von PYRIMIDINE SYNTHESIS · 1190

MAKAROV–ZEMLYANSKIĬ – PROKIN SYNTHESIS · 1128

MEYERS ALDEHYDE SYNTHESIS · 1191

MĄKOSZA VICARIOUS NUCLEOPHILIC SUBSTITUTION · 1128

MICHAEL CONDENSATION · 1193

MALAPRADE REACTION · 1130

MICHAEL GLYCOSIDATION · 1195

MANN ETHER DEALKYLATION · 1131

MICHAELIS – BECKER – NYLÉN PHOSPHONYLATION · 1196

MANNICH REACTION · 1133

MIDLAND REDUCTION · 1197

MANSUY – EVANS REACTION · 1135

MIESCHER DEGRADATION · 1199

MAQUENNE SYNTHESIS · 1136

MIGITA – SANO SYNTHESIS · 1200

MARASSE MODIFICATION · 1015

MILAS HYDROXYLATION OF OLEFINS · 1202

MARBET – SAUCY MODIFICATION · 1138

MILLER – PLÖCHL SYNTHESIS · 1203

MARSCHALK AROMATIC ALKYLATION · 1139

MILLER – SNYDER ARYL CYANIDE SYNTHESIS · 1204

MARSHALL – MINNAARD FRAGMENTATION · 1141

MILLER SYNTHESIS · 1206

MARTIN – SHERMAN MODIFICATION · 381

MILLS SYNTHESIS · 1207

MARTIN INDOLE SYNTHESIS · 1142

MINISCI AROMATIC AMINATION · 1208

MARTINET SYNTHESIS · 1143

MISLOW – BRAVERMAN – EVANS REARRANGEMENT · 1209

MASAMUNE MACROLACTONISATION · 1145

MITSUNOBU REACTION · 1211

MASCARELLI FLUORENE SYNTHESIS · 1146

MOEDRITZER – IRANI REACTION · 1213

MATHEWS DRY HYDROLYSIS · 1147

MONTEVECCHI INDOLE SYNTHESIS · 1214

MATSUDA VARIANT · 788

MORI – BAN INDOLE SYNTHESIS · 1216

MATTESON REACTION · 1149

MORIN REARRANGEMENT · 1217

MAURER – DREFAHL SYNTHESIS · 1151

MOUREAU – MIGNONAC REACTION · 1219

MAYER SYNTHESIS · 1152

MOUSSERON – FRAISSE – McCOY CYCLOPROPANATION · 1220

MAYO de REACTION · 1153 McBRIDE REACTION · 1154

MOZINGO DESULFURISATION · 1222

McCLUSKEY FRAGMENTATION · 1156

MUKAIYAMA – MICHAEL REACTION · 1230

McCORMACK – KUKHTIN – RAMIREZ PHOSPHOLE SYNTHESIS

MUKAIYAMA – YAMADA EPOXIDATION · 1223 MUKAIYAMA MACROLACTONISATION - 1 · 1224

· 1157 McFADYEN – STEVENS REACTION · 1158

MUKAIYAMA MACROLACTONISATION - 2 · 1226

McLAFFERTY REARRANGEMENT · 1159

MUKAIYAMA OXIDATION · 1227

McMURRY OLEFINATION · 1161

MUKAIYAMA REACTION · 1229

McNELIS REARRANGEMENT · 1162

MÜLLER – ROCHOW SYNTHESIS · 1233

MEER ter REACTION · 1164

MÜLLER–CUNRADI CONDENSATION · 1231

MEERWEIN – PONNDORF – VERLEY REDUCTION · 1165

MUMM REARRANGEMENT · 344

MEERWEIN ARYLATION · 1166

MURAHASHI ALLYLIC ALKYLATION · 1234

MEERWEIN METHYLATION · 1168

MURAHASHI CROSS-COUPLING REACTION · 1235

MEINWALD REACTION · 1169

MURAI C-C BOND FORMATION · 1237

MEINWALD REARRANGEMENT · 1170

MURAI COUPLING · 1238

MEISENHEIMER – JACKSON REACTION · 1172

MURAI REARRANGEMENT · 1240

MEISENHEIMER – JANOVSKY SYNTHESIS · 1172

MURPHY INDOLE SYNTHESIS · 1242

MEISENHEIMER REARRANGEMENT · 1173

MYERS – MOORE – SAITO – SCHMITTEL CYCLISATION · 1243

MENCKE – LASZLO NITRATION OF PHENOLS · 1175

MYERS REDUCTIVE COUPLING · 1246

MENDIUS REDUCTION · 1176 MENSCHUTKIN REACTION · 1177 MENTZER PYRONE SYNTHESIS · 1178 MERLING – von DOERING SYNTHESIS · 1179

1963

N NAGARAJAN – KUMAR – RAO MACROLACTONISATION · 1250 NAGATA HYDROCYANATION · 1251 NAITO INDOLE SYNTHESIS · 1253 NAMETKIN REARRANGEMENT · 1254 NATSUME INDOLE SYNTHESIS · 1256 NAZAROV CYCLISATION · 1257 NEBER – BOSSEL CINNOLINE / OXINDOLE SYNTHESIS · 1259 NEBER REARRANGEMENT · 1261 NEF REACTION · 1262 NEF SYNTHESIS · 1264 NEGISHI COUPLING · 1265 NENCKI MODIFICATION · 641 NENITZESCU ACYLATION · 1267 NENITZESCU INDOLE SYNTHESIS · 1269 NERDEL CYCLOPROPANE SYNTHESIS · 1271 NESMANJANOV FULVENE SYNTHESIS · 1272 NESMANJANOV METALLATION · 1273 NEWMAN – BEAL MODIFICATION · 60 NEWMAN – KARNES – KWART REARRANGEMENT · 1274 NEWMAN SYNTHESIS · 1275 NICHOLAS SYNTHESIS · 1277 NICKL SYNTHESIS · 1279 NICOLAOU OXIDATION · 1280 NIEMENTOWSKI von QUINAZOLONE REACTION · 1281 NIEMENTOWSKI von QUINOLINE SYNTHESIS · 1283 NIEUWLAND HYDRATION · 1284 NISHIMURA – CRISTESCU N-GLYCOSIDATION · 1285 NOLLER SYNTHESIS · 1286 NORD SYNTHESIS · 1288 NORDLANDER MODIFICATION · 213 NORRISH TYPE 1 REARRANGEMENT · 1290 NORRISH TYPE 2 REARRANGEMENT · 1291 NOYORI ANNULATION · 1293 NOYORI HYDROGENATION · 1295 NOYORI REARRANGEMENT · 1297 NOZAKI – HIYAMA – KISHI (TAKAI – UTIMOTO) REACTION · 1298 NUGENT – RAJANBABU EPOXIDE HOMOLYSIS · 1301 NYSTED REACTION · 1302

1964

O O’DONNELL AMINO ACID SYNTHESIS · 1306 OGLIALORO MODIFICATION · 1359 OHIRA – BESTMANN PROCEDURE · 1562 OHLE CLEAVAGE · 1309 OHSHIRO – HIRAO REDUCTION · 1310 OLAH CROWDED OLEFIN SYNTHESIS · 1312 OLEKSYSZYN AMINOPHOSPHONIC ACID SYNTHESIS · 1314 OPPENAUER OXIDATION · 1315 OPPOLZER ALLYL ALCOHOL SYNTHESIS · 1317 ORTON HALOANILINE REARRANGEMENT · 1318 OSTROMYSLENSKI REACTION · 1320 OVERMAN PYRROLIDINE SYNTHESIS · 1321 OVERMAN REARRANGEMENT · 1322 OXY – COPE REARRANGEMENT · 408

1965

POLONOVSKI REACTION · 1388 POMERANZ – FRITSCH REACTION · 1391

P

PONZIO REACTION · 1392 PAAL – KNORR FURAN SYNTHESIS · 1326

POSNER TRIOXANE SYNTHESIS · 1393

PAAL – KNORR PYRROLE SYNTHESIS · 1326

POVAROV REACTION · 1395

PADBURY – LINDWALL MODIFICATION · 1327

PRÉVOST REACTION · 1396

PADWA ANNULATION · 1328

PREY REACTION · 1398

PAOLINI de REACTION · 1330

PRILESCHAJEW REACTION · 1399

PAQUETTE OLEFIN SYNTHESIS · 1331

PRINS REACTION · 975

PARHAM CYCLIC ALKYLATION · 1332

PRINS REDUCTION · 264

PARIKH – DOERING von OXIDATION · 1334

PSCHORR – HOPPE SYNTHESIS · 1400

PARNES GEMINAL DIMETHYLATION · 1335

PSCHORR SYNTHESIS · 1402

PASSERINI REACTION · 1336

PUDOVIK REACTION · 1403

PASTO – MATTESON REARRANGEMENT · 1338

PUMMERER REARRANGEMENT · 1404

PATERNÒ – BÜCHI REACTION · 1339

QUASI-FAVORSKII REARRANGEMENT · 566

PAULY – LOCKEMANN SYNTHESIS · 1340 PAUSON – KHAND REACTION · 1342 PAYNE REARRANGEMENT · 1344 PECHMANN von – DUISBERG SYNTHESIS · 1345 PECHMANN von PYRAZOLE SYNTHESIS · 1347 PECHMANN von synthesis · 1346 PEDERSEN COUPLING · 1348 PEDERSEN CROWN ETHER SYNTHESIS · 1349 PELLIZZARI BENZIMIDAZOLE SYNTHESIS · 1351 PELLIZZARI REACTION · 1352 PELOUZE SYNTHESIS · 1353 PERKIN ALICYCLIC SYNTHESIS · 1354 PERKIN BENZOFURAN SYNTHESIS · 1355 PERKIN COUMARIN REARRANGEMENT · 1356 PERKIN COUMARIN SYNTHESIS · 1356 PERKIN REACTION · 1358 PERKOW REACTION · 1360 PERRIER MODIFICATION · 641 PETASIS – FERRIER REARRANGEMENT · 585 PETASIS MODIFICATION · 585 PETASIS REACTION · 1361 PETASIS SYNTHESIS · 1363 PETERSON OLEFINATION REACTION · 1364 PETRENKO – KRITSCHENKO PIPERIDONE SYNTHESIS · 1366 PEW REDUCTION · 1368 PFITZINGER – BORSCHE REACTION · 1369 PFITZNER – MOFFATT OXIDATION · 1370 PHILLIPS – LADENBURG RING–CLOSURE · 1372 PICTET – GAMS ISOQUINOLINE SYNTHESIS · 1373 PICTET – SPENGLER ISOQUINOLINE SYNTHESIS · 1375 PILOTY – ROBINSON SYNTHESIS · 1377 PILOTY ALLOXAZINE SYNTHESIS · 1378 PINNER IMINOETHER SYNTHESIS · 1379 PINNER TRIAZINE SYNTHESIS · 1381 PINNICK OXIDATION · 1382 PIRIA REACTION · 1383 PISHCHIMUKA REARRANGEMENT · 1385 PLANCHER REARRANGEMENT · 1386 PLÖCHL REACTION · 1387

1966

ROSENMUND – SAYTZEFF REDUCTION · 1479 ROSENMUND – von BRAUN SYNTHESIS · 1480

R

ROSENMUND REACTION · 1481 RADZISZEWSKI AMIDE SYNTHESIS · 1409

ROTHEMUND REACTION · 1482

RADZIEWANOWSKI MODIFICATION · 641

ROUSH – HOFFMANN – YAMAMOTO STEREOSELECTIVE ALLYLATIONS · 1484

RAECKE PROCESS · 1410 RAGUÉ SCHLEYER von ADAMANTISATION · 1525

ROUSH COUPLING · 1485

RAMBERG – BÄCKLUND REACTION · 1413

ROUSH MACROLACTONISATION · 1486

RANJORWA SYNTHESIS · 1415

ROWE REARRANGEMENT · 1487

RAPHAEL MACROLACTONISATION · 1619

RUFF – FENTON DEGRADATION · 1488

RAPHAEL SYNTHESIS · 1416

RUFF REACTION · 1490

RAPP – STOERMER CONDENSATION · 1418

RUGGLI SYNTHESIS · 1491

RAPSON TRIPHENYLENE REACTION · 1420

RÜHLMANN VARIATION · 757

RASCHIG PHENOL PROCESS · 1421

RUPE REARRANGEMENT · 1492

RASODA SYNTHESIS · 1422

RUPPERT FLUOROALKYLATION · 1493

RATHKE ESTER SYNTHESIS · 1423

RUSSIG – LAATSCH REACTION · 1494

RAUHUT – CURRIER REACTION · 1424

RUŽIČKA LARGE RING SYNTHESIS · 1496

RAUTENSTRAUCH REARRANGEMENT · 1426

RUŽIČKA OLEFINIC ACID SYNTHESIS · 1497

REED REACTION · 1428

RUŽIČKA REARRANGEMENT · 1498

REETZ TITANIUM ALKYLATION · 1429

RYCHNOVSKY POLYOL SYNTHESIS · 1500

REEVE SYNTHESIS · 1431 REFORMATSKY REACTION · 1432 REGITZ DIAZO TRANSFER · 1434 REIMER – TIEMANN REACTION · 1435 REINDERS – RINGER DISPLACEMENT · 1437 REISSERT – GROSHEINTZ – FISCHER SYNTHESIS · 1438 REISSERT – HENZE REACTION · 1440 REISSERT INDOLE REACTION · 1442 REMFRY – HULL SYNTHESIS · 1443 REPPE ACETYLENE SYNTHESIS · 1444 REPPE BUTADIENE SYNTHESIS · 1445 REPPE CARBONYLATION · 1447 REPPE POLYMERISATION · 1449 REPPE VINYLATION · 1450 REVERDIN REACTION · 1451 RICHMAN – ATKINS SYNTHESIS · 1452 RICHTER von CINNOLINE SYNTHESIS · 1454 RICHTER von REACTION · 1455 RIECHE FORMYLATION · 1457 RIEHM PYRIDINE SYNTHESIS · 1458 RIEHM QUINOLINE SYNTHESIS · 1459 RIEMSCHNEIDER THIOCARBAMATE SYNTHESIS · 1461 RIGBY – TROST DEHYDROGENATIVE SULFENYLATION · 1462 RILEY – SHARPLESS OXIDATION · 1463 RITTER REACTION · 1465 ROBERT CHLORINATION · 1466 ROBERTSON – ROBINSON METHYLATION · 1468 ROBINSON – GABRIEL SYNTHESIS · 1469 ROBINSON – MANNICH ANNULATION REACTION · 1470 ROBINSON – ROBINSON KETO-ESTER METHOD · 1472 ROBINSON – SCHÖPF REACTION · 1473 ROBINSON DEHYDROGENATION · 1475 ROELEN CARBONYLATION · 1476 ROGER SYNTHESIS · 1478

1967

SEYFERTH – GILBERT HOMOLOGATION · 1561 SEYFERTH – HILBERT REACTION · 1562

S

SHAPIRO REACTION · 1563 SHARPLESS ASYMMETRIC AMINOHYDROXYLATION

SABATIER – MAILHE SYNTHESIS · 1505

(OXYAMINATION) · 1564

SABATIER – SENDERENS REACTION · 1506 SAEGUSA INDOLE SYNTHESIS · 1507

SHARPLESS DIHYDROXYLATION · 1566

SAEGUSA REACTION · 1508

SHEEHAN – FRANK SYNTHESIS · 1569

SAKAI REACTION · 1509

SHERADSKY REARRANGEMENT · 1571

SANDMEYER DIAZONIUM REACTION · 1510

SHESTAKOV HYDRAZINE SYNTHESIS · 1572

SANDMEYER DIPHENYLUREA ISATIN SYNTHESIS · 1512

SHEVERDINA – KOCHESHKOV AMINATION · 1574

SANDMEYER ISONITROSOACETANILIDE ISATIN SYNTHESIS ·

SHI EPOXIDATION · 1575 SHIBASAKI CYCLISATION · 1577

1514 SARETT OXIDATION · 1515

SHILOV REACTION · 1579

SAWDEY REARRANGEMENT · 1517

SIEGRIST STILBENE SYNTHESIS · 1580

SAYTZEFF SYNTHESIS · 1519

SIMCHEN SYNTHESIS · 1582

SCHEINER AZIRIDINE SYNTHESIS · 1520

SIMMONS – SMITH REACTION · 1583

SCHELLER MODIFICATION · 138

SIMONIS CHROMONE CYCLISATION · 1585

SCHENCK REACTION · 27

SKATTEBØL DIHALOCYCLOPROPANE REARRANGEMENT · 1586

SCHENCK REARRANGEMENT · 1521 SCHIFF REACTION · 1522

SKRAUP – PRIGLINGER SYNTHESIS · 1587

SCHLACK – KUMPF REACTION · 1523

SKRAUP QUINOLINE SYNTHESIS · 1589

SCHLITTLER – MÜLLER RING-CLOSURE · 1526

SLYKE van DETERMINATION · 1590

SCHLOSSER MODIFICATION · 1865

SLYKE van OXIDATIVE DECARBOXYLATION · 1591

SCHMID INDOLE SYNTHESIS · 1527

SMILES REARRANGEMENT · 1593

SCHMIDLIN – BERGMAN – WILSMORE KETENE SYNTHESIS ·

SMITH – MIDDLETON – ROZEN FLUORINATION · 1594 SMITH – TIETZE COUPLING · 1597

1529 SCHMIDT – RUTZ SYNTHESIS · 1530

SMITH INDOLE SYNTHESIS · 1599

SCHMIDT GLYCOSIDATION · 1531

SNIECKUS REARRANGEMENT · 1600

SCHMIDT MACROLACTONISATION · 1533

SOAI AUTOCATALYSIS · 1602

SCHMIDT MODIFICATION · 138

SOMEI – KAMETANI REACTION · 1604

SCHMIDT REARRANGEMENT · 1535

SOMMELET – HAUSER REACTION · 1605

SCHMITZ DIAZIRIDINE SYNTHESIS · 1537

SOMMELET ALDEHYDE REACTION · 1607

SCHOELLER MODIFICATION · 1087

SONN – MÜLLER ALDEHYDE SYNTHESIS · 1608

SCHOLL REACTION · 1538

SONN EXTENSION OF THE HOESCH REACTION · 1610

SCHÖLLKOPF AMINO ACID SYNTHESIS · 1540

SONOGASHIRA – HAGIHARA COUPLING · 1611

SCHOLTZ INDOLIZINE SYNTHESIS · 1541

SORENSON AMINO ACID SYNTHESIS · 1612

SCHÖNBERG ADDITION · 1543

SPASSOW ESTERIFICATION · 1614

SCHORIGIN – WANKLYN REACTION · 1544

SPECKAMP RING-CLOSURE · 1615

SCHOTTEN – BAUMANN REACTION · 1545

SPENGLER – PFANNENSTIEL OXIDATION · 1616

SCHROEDER MODIFICATION · 1013

ST. PFAU – PLATTNER SYNTHESIS · 1617

SCHWANERT SYNTHESIS · 1546

STAAB ACYLATION · 1618

SCHWARTZ HYDROZIRCONATION · 1548

STACEY ESTERIFICATION · 1619

SCHWECHTEN REACTION · 1550

STADEL – RÜGHEIMER PYRAZINE SYNTHESIS · 1622

SCHWEIZER ALLYL AMINE SYNTHESIS · 1551

STADLER – ZIEGLER REACTION · 1621

SCHWEIZER REARRANGEMENT · 1552

STARKEY MODIFICATION · 138

SCHWENK MODIFICATION · 1849

STAUDINGER – PFENNINGER THIIRANE DIOXIDE SYNTHESIS · 1623

SCRETTAS – YUS METHOD · 1553 SEEBACH – FRÁTER ALKYLATION · 1554

STAUDINGER AZIDE REDUCTION · 1624

SEEBACH SELF-REGENERATION · 1555

STAUDINGER KETENE ADDITION · 1625

SEMMLER – WOLFF – SCHROETER REACTION · 1557

STEGLICH – HASSNER ESTERIFICATION · 1627

SENDERENS DIETHYL ETHER SYNTHESIS · 1558

STENHOUSE CLEAVAGE · 1629

SENDERENS KETONE SYNTHESIS · 1559

STEPHEN ALDEHYDE SYNTHESIS · 1630

SERINI REACTION · 1560

STEPHENS – CASTRO SYNTHESIS · 1632

SESHADRI MODIFICATION · 29

STETTER 1,4-DICARBONYL SYNTHESIS · 1633 STETTER CARBOXYLIC ACID SYNTHESIS · 1636

1968

STEVENS REARRANGEMENT · 1637 STIEGLITZ REARRANGEMENT · 1638 STILES – SISTI FORMYLATION · 1640 STILL – GENNARI REACTION · 1641 STILL – WITTIG REARRANGEMENT · 1642 STILLE – KELLY COUPLING · 1644 STILLE – MIGITA – KOSUGI COUPLING · 1645 STILLE CARBONYL SYNTHESIS · 1648 STOBBE CONDENSATION · 1649 STOERMER DEALKYLATION · 1651 STOLLÉ – BECKER SYNTHESIS · 1652 STOLLÉ SYNTHESIS · 1653 STONE – WALES REARRANGEMENT · 1655 STORK – JUNG – ROBINSON ANNULATION · 1471 STORK – NISHIYAMA RADICAL CYCLISATION · 1656 STORK – UENO REACTION · 1657 STORK CYANOHYDRIN ALKYLATION · 1658 STORK ENAMINE ALKYLATION AND ACYLATION · 1660 STORK RADICAL CYCLISATION · 1661 STORK REDUCTIVE CYCLISATION · 1662 STORY MACROCYCLE SYNTHESIS · 1664 STRECKER AMINO ACID SYNTHESIS · 1665 STRECKER DEGRADATION · 1668 STRECKER SULFITE ALKYLATION · 1669 STRUKOV SYNTHESIS · 1670 STRYKER REGIOSELECTIVE REDUCTION · 1671 STUFFER – BACKER DISULFONE HYDROLYSIS · 1672 SUÁREZ – HEUSLER – KALVODA REACTION · 1674 SUGASAWA INDOLE SYNTHESIS · 1675 SUGASAWA INDOXYL SYNTHESIS · 1677 SUGASAWA REACTION · 1678 SUNDBERG INDOLE SYNTHESIS · 1679 SURZUR – TANNER REARRANGEMENT · 1680 SÜS REACTION · 1682 SUZUKI – MIYAURA VINYL COUPLING · 1683 SUZUKI (KYODAI) REACTION · 1685 SUZUKI REDUCTION · 1687 SWARTS REACTION · 1688 SWERN OXIDATION · 1689 SZARVASY – SCHÖPF CARBOMETHOXYLATION · 1690

1969

T TABOURY SYNTHESIS · 1694 TAFEL REARRANGEMENT · 1695 TAKEDA REACTION · 1696 TAKAI – UTIMOTO REACTION · 1300 TANIGAWA REACTION · 1698 TANIGUCHI REACTION · 1699 TÄUBER SYNTHESIS · 1700 TAYLOR SYNTHESIS · 1702 TEBBE OLEFINATION · 1703 TEUBER QUINONE SYNTHESIS · 1705 THIELE – DIMROTH SYNTHESIS · 1708 THIELE – WINTER QUINONE ACETOXYLATION · 1709 THIELE FULVENE SYNTHESIS · 1710 THOMAS REACTION · 1712 THORPE – ZIEGLER REACTION · 1713 THYAGARAJAN INDOLE SYNTHESIS · 1715 TIEMANN AMINATION · 1716 TIEMANN REARRANGEMENT · 1718 TIFFENEAU – DEMJANOV RING ENLARGEMENT · 1719 TIFFENEAU SYNTHESIS · 1721 TIMMIS PTERIDINE SYNTHESIS · 1722 TIPSON – COHEN OLEFINATION · 1723 TISHCHENKO – CLAISEN REACTION · 1725 TOLLENS ADDITION · 1726 TORGOV SYNTHESIS · 1728 TRAHANOVSKY ETHER OXIDATION · 1731 TRAUBE PURINE SYNTHESIS · 1732 TREIBS ALLYLIC OXIDATION · 1733 TROFIMOV PYRROLE SYNTHESIS · 1735 TROST – CHEN DECARBOXYLATION · 1737 TROST CYCLOPENTANATION · 1738 TROST DESYMMETRISATION · 1740 TROST OXIDATIVE DECARBOXYLATION · 1741 TRUCE – SMILES REARRANGEMENT · 1593 TSCHUGAEFF (CHUGAEV) OLEFIN SYNTHESIS · 1743 TSUGE REACTION · 1744 TSUJI – TROST ALLYLATION · 1746 TSUJI – WACKER OLEFIN OXIDATION · 1747 TSUJI – WILKINSON REACTION · 1750 TWITCHELL PROCESS · 1751 TYRER SULFONATION PROCESS · 1752

1970

U UEMURA OXIDATION · 1756 UGI CONDENSATION · 1757 ULLMANN – FETVADJIAN ACRIDINERING CONDENSATION · 1760 ULLMANN – HORNER PHENAZINE SYNTHESIS · 1761 ULLMANN – LA TORRE ACRIDINE SYNTHESIS · 1763 ULLMANN – UKITA – BUCHWALD – LI REACTION · 1765 ULLMANN DIARYL CONDENSATION · 1764 ULLMANN DIARYL ETHER SYNTHESIS · 1766 ULLMANN FLUORENONE SYNTHESIS · 1767 ULTEE CYANOHYDRIN SYNTHESIS · 1768 URECH CYANOHYDRIN METHOD · 1770 URECH HYDANTOIN SYNTHESIS · 1771 UTZINGER ALDEHYDE SYNTHESIS · 1772

1971

V VARRENTRAPP OLEIC ACID REACTION · 1776 VASELLA – BERNET REACTION · 1777 VEDEJS HYDROXYLATION · 1779 VENKATARAMAN – WAGLE REACTION · 1780 VIGNEAUD du SERINE SYNTHESIS · 1782 VILSMEIER – HAACK MODIFICATION · 641 VILSMEIER – HAACK – VIEHE REACTION · 1783 VOIGHT AMINATION · 1785 VOLHARD – ERDMANN CYCLISATION · 1786 VORBRÜGGEN – KROLIKIEWICZ REACTION · 1787 VORBRÜGGEN NUCLEOSIDE SYNTHESIS · 1789 VORLÄNDER SYNTHESIS · 1790

1972

WISSNER α-FUNCTIONALISED METHYL KETONE SYNTHESIS · 1855

W

WITT DIAZOTATION · 1857 WAGNER – MEERWEIN REARRANGEMENT · 1795

WITTE – SEELIGER REACTION · 1858

WAGNER–JAUREGG ADDITION · 1794

WITTIG – GILMAN REACTION · 1859

WAKAMATSU SYNTHESIS · 1796

WITTIG – WITT LITHIUM EXCHANGE · 1859

WAKATSUKI – YAMAZAKI – BÖNNEMANN REACTION · 1799

WITTIG [1,2]-REARRANGEMENT · 1860

WALKER – HAUSER SYNTHESIS · 1801

WITTIG [2,3]-REARRANGEMENT · 1861

WALLACH DEGRADATION · 566

WITTIG PHENANTHRENE SYNTHESIS · 1863

WALLACH IMIDAZOLE SYNTHESIS · 1802

WITTIG REACTION · 1864

WALLACH REARRANGEMENT · 1803

WOHL – AUE REACTION · 1866

WALTHER MODIFICATION · 1369

WOHL – MARCKWALD SYNTHESIS · 1867

WASSERMANN – BORMANN MACROCYCLIC LACTAM

WOHL – ZIEGLER BROMINATION · 1869 WOHL DEGRADATION · 1872

SYNTHESIS · 1805 WATANABE HETEROCYCLISATION · 1806

WÖHLER UREA SYNTHESIS · 1873

WATANABE INDOLE SYNTHESIS · 1808

WOLFF – KISHNER REDUCTION · 1874

WAWZONEK – YEAKEY REARRANGEMENT · 1809

WOLFF REARRANGEMENT · 1876

WEERMAN DEGRADATION · 1811

WOLFFENSTEIN – BÖTERS REACTION · 1878

WEERMAN SYNTHESIS OF INDOLE · 1812

WOLFRAM – SCHÖRNIG – HANSDORF CARBOXYMETHYLATION · 1880

WEIDENHAGEN IMIDAZOLE SYNTHESIS · 1813 WEIL SYNTHEIS OF ARYL ALDEHYDES · 1814

WOLFRAM SYNTHESIS OF CYCLONITE · 1881

WEINREB ACYLATION · 1815

WOLFROM – KARABINOS REDUCTION · 1882

WEISS ANNULATION · 1817

WOODWARD CIS-HYDROXYLATION · 1883

WEITZ – SCHEFFER REACTION · 1818

WOODWARD PEPTIDE SYNTHESIS · 1884

WELDE SYNTHESIS OF DIXANTHATES · 1820

WRIGHT – WEST GERMYL MIGRATION · 1886

WENDER CYCLOHEPTENE SYNTHESIS · 1823

WULFF CYCLISATION · 504

WENDER INDOLE SYNTHESIS · 1821

WURTZ – FITTIG REACTION · 1887

WENDER REACTION · 1825

WURTZ AMINE SYNTHESIS · 447

WENKER RING–CLOSURE · 1826

WURTZ REACTION · 1888

WENZEL – IMAMOTO REDUCTION · 1827

WUYTS SYNTHESIS · 1889

WERNER SYNTHESIS · 1828 WESSELY – MOSER REARRANGEMENT · 1829 WESTPHAL CONDENSATION · 1830 WESTPHALEN – LETTRÉ REARRANGEMENT · 1831 WETTSTEIN OXIDATION · 1833 WEYGAND – LÖWENFELD REDUCTION · 1834 WHARTON FRAGMENTATION · 1836 WHARTON OLEFIN SYNTHESIS · 1835 WHITING – NAYLER REACTION · 1836 WIBAUT – ARENS SYNTHESIS · 1838 WICHTERLE REACTION · 1839 WIDEQVIST CYCLOPROPANE SYNTHESIS · 1841 WIDMAN – STOERMER SYNTHESIS · 1842 WIDMANN SYNTHESIS OF INDOLES · 1843 WIELAND – DANE DEGRADATION · 1844 WIELAND TRIPHENYLMETHYL RADICAL REARRANGEMENT · 1845 WILDS – MEADER MODIFICATION · 60 WILKE REACTION · 1847 WILLGERODT – KINDLER REDOX AMINATION · 1849 WILLIAMS – BEN–ISHAI AMINO ACID SYNTHESIS · 1851 WILLIAMSON ETHER SYNTHESIS · 1852 WINTERFELDT OXIDATION · 1854 WISLICENUS SYNTHESIS · 1855

1973

Y YAMADA PEPTIDE COUPLING · 1893 YAMAGUCHI – HIRAO REACTION · 1894 YAMAGUCHI REACTION · 1895 YAMAMOTO ALLYLATION · 1897 YAMAMOTO INDOLE-1 SYNTHESIS · 1899 YAMAMOTO INDOLE-2 SYNTHESIS · 1901 YAMAMOTO KETONE SYNTHESIS · 1903 YAMAMOTO MACROLACTONISATION · 1905 YAMAZAKI – CLAUSEN GUANINE SYNTHESIS · 1906 YAMAZAKI CYANOANILINE SYNTHESIS · 1908 YANG CYCLISATION · 1909 YUROVSKAYA INDOLE SYNTHESIS · 1911

1974

Z ZAGOUMENNY DIPHENYL CARBINOL SYNTHESIS · 1916 ZAV’YALOV PYRROLE SYNTHESIS · 1916 ZEISEL SYNTHESIS · 1918 ZEISS KETONE TRANSFER · 1919 ZELINSKY – STADNIKOFF AMINONITRILE SYNTHESIS · 1922 ZELINSKY ALDEHYDE SYNTHESIS · 1921 ZEMPLEN – HELFERICH MODIFICATION · 1012 ZEMPLÉN SUGAR DEGRADATION · 1923 ZIEGLER – HAFNER AZULENE SYNTHESIS · 1925 ZIEGLER – NATTA POLYMERISATION · 1926 ZIEGLER ALKYLATION · 1928 ZIEGLER ALUMINIUMALKYL OXIDATION · 1929 ZIEGLER TERTIARY HIGHER FATTY ACIDS SYNTHESIS · 1930 ZIMMER REARRANGEMENT · 1931 ZIMMERMAN REACTION · 1933 ZINCKE – KÖNIG PYRIDINIUM SALTS · 1934 ZINCKE – SUHL CYCLOHEXADIENONE SYNTHESIS · 1936 ZINCKE DIARYLMETHANE SYNTHESIS · 1937 ZINCKE DISULFIDE CLEAVAGE · 1938 ZINCKE HALOGENPHENOL NITRATION · 1940 ZININ REACTION · 1941 ZININ REARRANGEMENT · 1942 ZINKE – CORNFORTH MODIFICATION · 1945 ZINKE – ZIEGLER SYNTHESIS · 1944 ZINNER SYNTHESIS · 1946 ZINOVEV – SOBOROVSKI REACTION · 1947

1975

About the author Elbertus Kruiswijk was born in Utrecht, the Netherlands in 1968 and studied Chemistry at the University of Utrecht. He graduated in the Metal-mediated organic synthesis group of Gerard van Koten in 1996. He later moved to the University of Wales in Cardiff where in 1999 he received his PhD in Organic Chemistry under the supervision of Mark Elliott. He then spent a year as a post-doctoral Research Assistant in Ben Feringa’s group at Groningen, The Netherlands. From March 2001 until August 2004, he has been involved as a post-doctoral Research Associate on a combined project between DSTL, Porton Down and the Bacterial Toxins group School of Crystallography, School of Biological and Chemical Sciences (David Moss and Howard Carless) at the University of London, Birkbeck College. In July 2005, Bert graduated as a secondary school teacher from Swansea Institute of Higher Education.

Other books: Thin Layer Chromatography Visualisation Reagents, 1st Edition. Available as E-book or ring bound. Prices £15.00 and £20 +P&P. Student Workbook Organic Chemistry AS and A2-level, 1st Edition, ring bound. Price £3.99 + P&P.

ISBN : 0-9544302-1-2

1976