Progress in Heterocyclic Chemistry. Volume 13

PROGRESS IN HETEROCYCLIC CHEMISTRY V o l u m e 13 PROGRESS IN HETEROCYCLIC CHEMISTRY V o l u m e 13 Related Ti...

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PROGRESS IN

HETEROCYCLIC

CHEMISTRY

V o l u m e 13

PROGRESS IN

HETEROCYCLIC

CHEMISTRY

V o l u m e 13

Related Titles of Interest

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CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBI~: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions and Unnamed Reactions KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2 nd Edition LEVY & TANG: The Chemistry of C-Glycosides LI & GRIBBLE: Palladium in Heterocyclic Chemistry McKILLOP: Advanced Problems in Organic Reaction Mechanisms MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries PELLETIER: Alkaloids: Chemical and Biological Perspectives SESSLER & WEGHORN: Expanded, Contracted and Isomeric Porphyrins WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works

BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations SAINSBURY: Rodd's Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals

BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) JOURNAL OF SUPRAMOLECULAR CHEMISTRY PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS

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PROGRESS IN

HETEROCYCLIC CHEMISTRY V o l u m e 13 A critical review of the 2 0 0 0 literature p r e c e d e d by two c h a p t e r s on c u r r e n t heterocyclic topics Editors

GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and

THOMAS L. GlLCHRlST Department of Chemistry, University of Liverpool, Liverpool, UK

2001

PERGAMON An Imprint of Elsevier Science Amsterdam - London

- NewYork - Oxford - Paris - Shannon - Tokyo

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V

Contents Foreword Editorial Advisory Board Members Chapter 1: The Junjappa-Ila (J1)-Heteroaromatic Annulation

vii ...

vzzz

I

H. Ila, H. Junjappa and P. K. Mohanta, Indian Institute of Technology, India

Chapter 2: The Synthesis of Fused 7-Azanorbornanes

25

Ronald N. Warrener, Central Queensland University, Australia

Chapter 3: Three-Membered Ring Systems

5;

S. Shaun Murphree, Allegheny College, Meadville, PA, USA and Albert Padwa, Emory University, Atlanta, GA, USA

Chapter 4: Four-Membered Ring Systems L. K. Mehta and J. Pamck, Brunel University, Uxbridge, UB8 3PH, UK

71

Chapter 5: Five-Membered Ring Systems Part 1. Thiophenes & Se, Te Analogs Erin T. Pelkey, Stanford University, Stanford, CA, USA

87

Part 2. Pyrroles and Benzo Derivatives Daniel M. Ketcha, Wright State University, Dayton, OH, USA

111

Part 3. Furans and Benzofurans Xue-Long Hou, The Chinese Academy of Sciences, China, Zhen Yang, Haward Medical School, Boston, MA, USA and Henry N. C. Wong, The Chinese University of Hong Kong, China and The Chinese Academy of Sciences, China

130

Part 4. With More than One N Atom Lany Yet, Albany Molecular Research, Inc., Albany, N E USA

167

Part 5. With N & S (Se) Atoms David J. Wilkins, Key Organics Ltd., Cornwall, UK and Paul A. Bradley, The Broadlands, Hillside Road, Radcliffe-on-Trent, Nottingham, UK

I88

Part 6. With 0 & S (Se, Te) Atoms R. Alan Aitken, The University of St Andrews. UK

205

Part 7. With 0 & N Atoms Stefan0 Cicchi, Franca M. Corder0 and Donatella Giomi, Universita di Firenze, Italy

217

vi Chapter 6: Six-Membered Ring Systems Part 1. Pyridines and Benzo Derivatives D. Scott Coffey, Scott A. May and Andrew M. Ratz, Eli Lilly & Company, Indianapolis, IN, USA

238

Part 2. Diazines and Benzo Derivatives Brian R. Lahue, Grace H.C. Woo and John K. Snyder, Boston University, Boston, MA, USA

261

Part 3. Triazines, Tetrazines and Fused Ring Polyaza Systems Carmen Ochoa and Pilar Goya, Instituto de Quimica Mgdica (CSIC), Madrid, Spain

296

Part 4. With 0 andlor S Atoms John D . Hepworth, University of Hull, Hull, UK and B. Mark Heron, University of Leeds. Leeds. UK

317

Chapter 7: Seven-Membered Rings

340

John B. Bremner, University of Wollongong, Australia

Chapter 8: Eight Membered and Larger Rings

3 78

George R. Newkome, The University ofAkron, Akron, OH, USA

Index

394

vii

Foreword This is the thirteenth annual volume of Progress

in Heterocyclic Chemistry and

covers literature published during 2000 on most of the important heterocyclic ring systems. References are incorporated into the text by a system of journal codes as in

Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. In this volume there are two specialized reviews. The first, by H. Ila, H. Junjappa and P.K. Mohanta, covers their work on annulation using -oxoketene dithioacetals, a synthetic method that provides useful routes to an impressively wide range of fused heterocycles. The second, by Ronald N. Warrener, is on the synthesis of fused 7-azanorbornanes. The 7-azanorbornane structural unit is incorporated into a series of elegant polycyclic molecules with rigid geometry. The remaining chapters cover the published literature on the common heterocycles systematically according to ring size and the heteroatoms present. We are delighted to welcome several new contributors to this volume and we thank all the authors for their expert coverage. We are also grateful to Adrian Shell of Elsevier Science for supervising the publication of the volume, and especially for his efforts to reduce the production time. These volumes are intended to provide a convenient and efficient means of keeping up to date with the literature in heterocyclic chemistry and with important advances in the area. We welcome suggestions for improving the coverage and will be glad to receive offers of specialized reviews on developing topics.

Gordon W. Gribble Tom Gilchrist

viii

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2001 - 2002

PROFESSORY. YAMAMOTO(CHAIRMAN)

Tokyo University, Sendai, Japan

PROFESSOR D. P. CURRAN

University of Pittsburg, USA

PROFESSORA. DONDONI

University of Ferrara, Italy

PROFESSOR C.J. MOODY

University of Exeter, UK

PROFESSORK. FUJI

Kyoto University, Japan PROFESSOR T.C. GALLAGHER

University of Bristol, UK

PROFESSORA.D. HAMILTON

Yale University, C T, USA

PROFESSOR M. IHARA

Tohoku University Sendai, Japan

PROFESSORG.R. NEWKOME

University of Akron, OH, USA

PROFESSOR a. PRAGER

Flinders University South Australia

PROFESSORR.R. SCHMIDT

University of Konstanz, Germany

PROFESSORS.M. WEINREB

Pennsylvania State University University Park, PA, USA

ix Information about membership and activities of the International Society of Heterocyclic Chemistry can be found on the World Wide Web; the address of the Society's Home Page is: http ://e u ch 6f. chem. e m o ry. ed u/h etsoc, htm I

This Page Intentionally Left Blank

Chapter 1 The Junjappa-Ila (JI)-Heteroaromatic Annulation: A New General ~-Oxoketene Dithioacetals Mediated Inverse Method for the Synthesis of Benzo/Condensed Heterocycles and Related Heteroaromatization Processes H. Ila,* H. Junjappa* and P.K. Mohanta

Department of Chemistry, lndian Institute of Technology, Kanpur-208 O16, lndia e-mail: [email protected], Fax: 91-0512-597436, 91-0512-590260

1.1

INTRODUCTION

The classical methods for the synthesis of five and six membered benzoheterocycles generally involve a sequential construction of heterocyclic component over the preconstructed regiospecifically substituted benzene ring. This conventional benzoheterocyclic chemistry has been extensively investigated and still continues to be an active area of research. The required substitution pattern in the benzene ring of these heterocycles is generally achieved by subjecting the aromatic compounds to a series of stepwise electrophilic or nucleophilic substitution reactions. These efforts have evolved into elegant heteroaromatic chemistry from which a vast range of benzo-fused heterocycle compounds has emerged. However the synthesis of highly substituted benzene derivatives demands multistep reaction sequences which face difficulties of ortho, meta and para orientation resulting in the formation of isomeric mixtures and consequently poor yields of target molecules which negates the abundance of fossil resources. Some of these limitations are so prominently rigid that many of the substitution patterns still remain unexplored. Modem methods for the synthesis of substituted aromatic compounds involve highly convergent annulation routes in which the aromatic system is assembled from acyclic precursors in a single step. Particularly noteworthy aromatic annulation reactions developed in recent years include methods based on Diels Alder chemistry, Robinson annelation <76S777> and transition metal mediated Fischer carbene complexes <91COS(5)1065>. However these annulation methods have found limited applications for benzoheterocycle synthesis i.e. construction of a benzene ring on to preconstructed heterocycles and the only transformations of potential general scope which fall under this category are [4 + 2] cycloaddition of heterocyclic o-quinodimethanes <99CRV3199> or benzoannulation with Fischer type heteroaryl carbene complexes. Recently [3 + 3] benzoannulation reactions <99T8263> have become the subject of intense investigation primarily due to easy availability of three component synthons and high degree of regiocontrol observed in these reactions. Among many other variations of this category, [3 + 3] benzoannulation of cx-oxoketene dithioacetals with allyl anions and its hetero variants developed in our laboratory (1984) have emerged as versatile

2

H. Ila, H. Junjappa and P.K. Mohanta

general methods for the construction of a wide range of substituted aromatic and heteroaromatic compounds which we now call "The Junjappa-Ila (JI) aromatic and heteroaromatic annulation". The JI aromatic annulation has been reviewed <90T5423; 94MI35; 99T8263; 01JOM(624)34> but the present review covers only the JI heteroaromatic annulations.

1.2

SYNTHESIS OF BENZOHETEROCYCLES" INVERSE APPROACH

1.2.1 Allyl Anions Derived from Five and Six Membered Heteroeyeles (1,3Binucleophilic Components) In principle, a wide variety of five and six membered heterocycles bearing a ring C-C double bond with an exocyclic methyl group can be used as allyl anion precursors T a b l e 1. L i s t o f ~ - O x o k e t e n e D i t h i o a c e t a l s 6 U s e d in t h e P r e s e n t W o r k

6

6

R1

R2

Reference

6.1 6.2 6.3 6.4

Me Me Me Et

H Me n-Bu Me

6.5 6.6 6.7

CH(Me)2 CH(OMe)2 C6H5

H H H

62BSF2182 62BSF2187 62BSF2187 62BSF2187 73TL4207 81JOC5031 98TH47 97T14737 10CB1252 59BSF1398 62CB2861 82JOC3027 76T1911 73TIA207 73TIA207 81ZC69 82JOC3027 81ZC69 82JOC3027 88TH58 82JOC3207 94TH212

6.8 6.9 6.10 6.11

4-MeOC6H4 4-C1C6H4 2-Furyl

Me H H H

6.12

2-Thienyl

H

6.13 6.14 6.15

C6H5

13-Naphthyl 2-Pyridyl ~

H H H

6

R1

R2

Reference

H H H H

88TH48 88TH58 88TH58 88TH48

H

88TH48

H

88TH48

H H

85S163 85S163

A r ~ 6.16 6.17 6.18 6.19 6.20

Ar = C6H5 Ar = 2-C1C6H4 Ar =4-NO2C6H4 Ar =4-MeOC6H4 Ar = 3,4(-CH20-)2C6H3 6.21 Ar = 3,4,5(MeO)3C6H2

6.22 6.23

6.24 6.25 6.26 6.27

Ar =C6H5 Ar =4-OMeC6H4

Ar = C6H5 Me Me MeO

H MeCO CO2Et CO2Me

88TH48 70ACS 1191 70ACS1191 62CB2861

The Junjappa-Ila (J1) Heteroaromatic Annulation

3

Table 1 (Contd.) Cyclic tx-Oxoketene Reference Dithiacetals

Cyclic ct-Oxoketene Reference Dithiacetals

O

n(~SlVle SMe

6.28 ; n - 1 6.29 ; n ---2

6.30 ; n - 3 6.31; n--4

O SMa 62BSF2194 62BSF2194 73TL3817 73TIA207 81JOC5031 62BSF2194 62BSF2194

O 6.32

Me O SMa R ~ ~ n

6.33; R = H, n = 1 6.34; R = OMe, n = 1 6.35; R = H, n = 2 o

6.36;

84JCS(P1)921

SMa 76T1779 73TL4207 78JCS(P1)549

~02Ph

79JCR(S)268 79JCR(M)3001 6.38 ; R = H, n =1, X = S 79JCR(S)268 79JCR(M)3001 6.39; R = Me, n = 2, X = S 79JCR(S)268 79JCR(M)3001 O 6.40

~ S ~ ~ ~ ' MeMo 99T11563

6.41

SMo ~_~SMa

66YZ1152

6.42

~ o S ~

68CA2869p

O

.s~

~ S M o

6.37; R - H, n =2, X = O

79JCR(S)268 79JCR(M)3001

~

S

6,,43 MeO-VV

Me Me 95S841

for benzoheterocycles. The required heterocycles can either be bought or they can be prepared by reported procedures. Theoretically possible anions from various five or six membered heterocycles are depicted in Scheme-1 (Type I-V). Thus the heteroaUyl anions la-b (Type-I), 2a-b (Type-II) and 3a-b (Type-III) can be generally prepared either by Grignard reaction or by metallation. The reaction of 1 a-b and 2a-b with 6 generally yields the corresponding carbinol dithioacetals 7a-b and 9a-b in nearly quantitative yields following the expected 1,2-addition mode. These carbinol acetals can be cycloaromatized in the presence of Lewis acid to yield the corresponding benzoheterocycles 8a-b and 10a-b in high yields. However, when ring atom X = >C=O, the allyl anions 3a-b may react with 6 to afford the intermediates l la-b involving 1,4-addition-elimination sequence (Type-III) and follow direct insitu cycloaromatization (or acid assisted) to afford the corresponding angularly substituted and fused benzoheterocycles 12a-b in high yields. In the Type IV and Type-V category, the exocyclic methyl group carries an electron withdrawing group (EWG, CN or SO2Ph) in place of one of the hydrogen atoms and the corresponding anions 4a-b and $a-b are generally derived under mild basic conditions which on reaction with 6

4

H. lla, H. Junjappa and P.K. Mohanta

I Scheme - 1 ~J

Tvoe__ I

SMe

y;~,,C~~MMeS."~R2-

~ 1,2addition>

~/

/X' r'R2" )

Acid

M e s ~ R 2 " , . ~ ,'

O'~RI"'

la-b

SMe

SMe

\z~.~.R 8a SMe

n ~ O H RI

6

7a-b

8a: n = 1" x, y, z = either C,N,O or S etc. (5 membered ring) la,lb, 7a,7b,8b: n = 2; x, y, z = either C,N or N, C etc. (6 membered ring) T v D e II --

|

~n~

y/X

~1:~-, i,

-~1

Lz ' R . r

|

addition

y_X /~?HR1,

Ty,e III

RI" - "~

3a-b

6

O

O

~ R2SMe Y~z

>

R1"

x

+

6

- %

1, 4 addition x O "~ I elimination "- Y z

~ I

R 1"

Acid SMe

>

e

-,,

H 12b

_ R 1" "~

~

\z...~,,,.~,%.SM e

z- " ~ "SMe EWG

EWG

EWG 4a-b 13a-b 14a 4a, 13a, 14a: n = 1" x, y, z = either C,N,O or S etc. (5 membered ring) 4b, 13b, 14b" n = 2; x, y, z = either C,N or N, C etc. (6 membered ring) TvDe V __

Y

/

EWG + 6

elimination-. . 15a-b

.

.

EWG

x~ > I.,

5a-b

14b

EWG Aci~

.

.

.

R]

. 16a

5a, 15a, 16a n = 1; x, y, z = either C,N,O or S etc. (5 membered ring) 5b, 15b, 16b: n = 2; x, y, z = either C,N or N, C etc. (6 membered ring)

R 1" - ' '

~ ] [ ~ i ~

H 11a-b 12a 3a, 11a, 12a: n = 1" x, y, z = either C,N,O or S etc. (5 membered ring) 3b, 11b, 12b" n = 2; x, y, z = either C,N or N, C etc. (6 membered ring)

__

|

Acid

O~~o~R2,.,n elimination ~ y~z~',,,.,,/~SMe

Tw)e IV

y/-~

'

SMe lOb

RI"-"~

1, 4 addition M

-

RI

Acid

SMe SMe 9a-b lOa 2a, 9a, 10a: n = 1" x, y, z = either C,N,O or S etc. (5 membered ring) 2b, 9b, 10b: n = 2; x, y, z = either C,N or N, C etc. (6 membered ring)

+

-

8b

+ 6

Oy~

I.

J .

y/X

SMe

L

2 16b

The Junjappa-Ila (J1) Heteroaromatic Annulation

5

afford the corresponding 1,4-addition-elimination adducts 13a-b and 15a-b in excellent yields. These intermediates undergo facile acid assisted cyclization to afford the corresponding angularly substituted and fused benzoheterocycles 14a-b and 16a-b respectively in high yields. The synthetic strategies depicted in the Scheme 1 provide an overall view of the scope and potential of JI-heteroaromatic annulation protocol to yield benzoheterocycles with full regiocontrol on all the four positions of the newly formed benzene ring.

1.2.2

The t~-Oxoketene Dithioaeetals: (1,3-Biseleetrophilie C o m p o n e n t s )

The ct-oxoketene dithioacetals 6 (6.1-6.43) employed in this work as three carbon 1,3-biselectrophilic components have been drawn from various active methylene ketones and are described in the Table-1. The corresponding ct-oxoketene N,S- and O,S-acetals (17.1- 17.15) which are usually derived from ct-oxoketene dithioacetals are described in Table-2. These examples are only a representative groups to demonstrate the general application of the new JI-heteroaromatic annulation methodology

R2 T a b l e 2. T h e L i s t o f

N, S- and O, S- Aeetals 17 Used in t h e P r e s e n t W o r k X"

"SMe

17

17

R~

R2

X

Reference

17.1

Me

H

. .r'-N --NX...~ 98TH100

17.9 2-furyl

17.2

Me

H

--Nr"XO 98TH100

17.10

~~_.~J

--Nr"-~ 88TH99

17.3

C6H5

H

--N~

17.11

~J

NMe2 94TH235

17.4

C6H5

H

--N~-~O 85IJC466

R~

R2

--~-"~O 94TH142

17.6

H

-N~

82S203

17.7 4-MeOCrH4H

-N~

94TH142

17.8

-N~

94TH235

Reference

_Nf~

94TH235

Me

17.12 Ph

H

--N" 94TH235 "Ph

17.13

Ph

H

NEt2

17.14

Me

Me

OMe

97T14737

H

OMe

93S245

17.15 C6H5 2-thienyl H

H

X

85IJC466

17.5 4-C1C6H4 H C6H5

17

94TH235

6

H. Ila, H. Junjappa and P.K. Mohanta

1.2.3 Reaction of 3-Methyl-5-1ithiomethylisoxazole 18 with cx-Oxoketene dithioacetals 6: A New General Method for the Synthesis of Substituted and Fused 1,2-Benzisoxazoles (Type I, l a Model)

3-Methyl-5-lithiomethylisoxazole 18 prepared as reported in the literature <70CJC2006> was reacted with various cz-oxoketene dithioacetals 6 (6.1-6.2, 6.7-6.13) which followed 1,2- addition mode (type I) to afford the corresponding carbinol acetals 19 in excellent yields. All the carbinol acetals 19 were cyclized with BF3.Et20 in refluxing benzene to yield the corresponding benzisoxazoles 20 <88TL501> in 54-81% overall yields. Similarly the linearly fused benzisoxazoles 21a-b, 23a-c, 24 and 25 were obtained in overall 57-81% yields by reacting 18 with appropriate cz-oxoketene dithioacetals 6 <93S241>. Apparently the intermediate carbinol thioacetals 19 underwent ring closure through C4-C5 double bond following elimination of SMe group. The reported methods for the synthesis of 1,2-benzisoxazoles <84CHEC(6)114> have largely been the elaboration of a functionalized benzene ring over which isoxazole is constructed. Therefore the present method is the first report of utilizing the inverse approach to synthesize wide variety of substituted and condensed benzisoxazoles in high yields.

MeN II ~ + I N..O 18

SMe SMe [~ R l ~ Me ~ /Me 6.1-6.2, THF/'78=C "-'- ' SMe/T'~'N A ._._ ( iI 6.7-6.13 1, 2 - addition , . R 2 ~ O / r ,,..R1~,,,"'~,Ao.,N

Li

R2~I I

OH

A : BF3.Et20 / C6H6 / A

19

20 (54 - 81%)

SMe

SMe ~ ~ j ~ ~ i /IN/Me

../Me

18 + 6.29-6.30

n O" 21a, n = 1 (65-67%) b,n=2 SMe ,. ~.,..,~~ , . . /Me n~r) T / -II ,I

~

6.33- 6.35 R

o..N

"~

SMe

~ s

6.39

~ ~

23a, n= 1, R = H

b, n = 1, R = OMe (57-78%) c,n=2, R=H

0

~

SMe

!"

II

/Me ,I

-'N

24 (81%)

Me

~L~

6.166, 6.19- 6.24

0 22 (57%)

/Me

-- r @ O25, 'nl=.1,2,3 (55-68%);

1.2.4 Reaction of 1-N-Carboxy-2-1ithiomethylindole Dianion 26 with 6: A New General Method for the Synthesis of 2,3- Substituted and Fused Carbazoles (Type-I, 1 a Model)

It was considered of interest to utilize dianion 26 <89PHC(1)1 > as a potential three carbon allyl anion fragment to react with 6 with a view to develop a new synthesis of 2,3substituted and fused carbazoles 28 involving protection, activation and deprotection of the

The Junjappa-Ila (JI) Heteroaromatic Annulation

7

N-H group in a one pot reaction. The dianion 26 was generated according to the method of Katritzky and Akutagawa <86JA6808> and reacted with 6.1, 6.7, 6.8 and 6.30 to afford insitu the 1,2-adduct carbinols 27. These carbinols were directly cyclized in the presence of orthophosphoric acid to yield the corresponding carbazoles 28 in overall high yields with simultaneous loss of carbon dioxide during cyclization <98TL2029>. In most other carbazole syntheses the NH group is generally protected by a group which requires special reagents and additional steps for its removal. The method was also applied to prepare other condensed carbazoles 29a and 29b by reacting 26 with 6.33 and 6.35 respectively. They were further desulfurized with Raney Ni to obtain the sulfur free carbazoles in overall good yields. Interestingly dithioacetal 6.43 derived from estrone methyl ether <95S841> reacted with 26 to yield optically active 2,3- fused carbazole 30 in 70% yield. The optical rotation of 30 was found to be [tx]250 +47~ (c = 1, dioxane).

I[~

,~ I 1, 2 addition..-

or o,U 26

6.33

SMe MeS R2,~

27 ) n 6.43

29a, n = 1

(64_68%)

b,n=2 X = SM~-_...I RaneyNi x= H ~

H3PO4~ / ]~/R~I,~

oAo,

X ]

X

H 28

~

MeS

I

H

~

(62-70%) _

OMe

30 (70%)

(58-61%)

1.2.5 Reaction of 3-Lithiomethyl-2-methyl-l-phenylpyrazolin-5-one with 6: A New General Method for the Synthesis of 1,2-Disubstituted Indazolones and Their Condensed Analogs (Type III, 3a Model)

The hitherto unreported 3-1ithiomethyl-2-methyl-l-phenylpyrazolin-5-one 31 was prepared <95T10941> by the lithiation of 2,3-dimethyl-l-phenylpyrazolin-5-one (antipyrine) with LDA at-78~ The anion 31 was reacted with 6.1 and 6.9-6.11 and 6.13 at -78~ to afford the corresponding addition-elimination ketones 32 which were found to undergo partial ring closure during chromatographic purification over silica gel to yield the corresponding indazolones 33. The intermediate adducts were thus directly cyclized with BF3.Et20 to give 28 in high yields <95T10941>. The versatility of the method was demonstrated by the synthesis of condensed indazolones 33, 35 and 36 from the appropriate tx-oxoketene dithioacetals 6 and 31 as described earlier. The regiochemistry of the reaction was confirmed by subjecting a few indazolones (33, 35a) to Raney Ni dethiomethylation to yield the corresponding sulfur free indazolones. The characteristic ~H NMR chemical shifts and coupling constants of the vicinal protons in the desulfurized aromatic ring of 34 confirmed the regiochemistry of product indazolones. This heteroannulation strategy was also utilized for the synthesis of 6-aminoindazolones 37 by

8

H. Ila, H. Junjappa and P.K. Mohanta

reaction of 31 with N, S-acetals 17.3 and 17.5. We have thus achieved for the first time an efficient one step synthesis of substituted indazolones <78S633; CHEC84(5)274; 93JCS(P1)ll19> and their condensed variants by JI-annulation of a substituted benzene ring onto a pyrazolone ring. The anion 31 is in conjugation with ring carbonyl group and thus follows the orbital controlled 7-1,4-addition-elimination sequence with 6. O

+ 6.1, 6.9-6.11, THF .._ N~ph 6.13, 17.3, 17.5 . 780C "Li

",R1

,'

Me

1~2.~=

1,4 addition

31

Oy~ 62-69%

[

O

,o-~.

"R1

O

N~pI.

MeS

N..ph

Me

ph

32

I

Me

A" BF3.Et20 / C6H6 / A

28(64-92%)

X = SMe 7 Raney Ni

~ N ~ M e

X= H~

6.29, 6.31 n = 1, 3 > ( t , ~ . . ~

I X 33, n= 1,2; X= SMe---1 n = l 34, n 1, 2; X H ~ _ - I Raney Ni

(91- 99%)

"

6.37

> O

~

N'Me SMe 36 (91%)

~Me

6.35 - 6.36 X

N..ph

(88-92%)

X = -CH 2- or O

35a, R = H, OMe; X = SMe--- l R = H

b, R = H, OMe; X = H < - ~ J

Raney Ni

37 (78-98%)

1.2.6 Reaction of 6-Lithiomethyl-l,3-dimethyluracil 38 with 6 (Type III, 3b): One Pot New General Synthesis of Substituted Quinazolones The hitherto unknown anion 38 was generated for the first time in our laboratory by deprotonating 1,3,6-trimethyluracil with LDA at -78~ <92TL6173>. The anion 38 when reacted with 6, underwent direct cyclization to afford the corresponding quinazolones 40 in overall high yields. The intermediate conjugate adduct 39 appears to follow base O

6.1, 6.7, +

~"

"R1

l"

0

THF .._

6.11

LDA

"

Li

Me

38

41 (82%)

Me

RI

O

I

N

"'S

1,4 addition

0 Me

39

~

40 (73-86%)

n

42 Me

The Junjappa-Ila (J1) Heteroaromatic Annulation

9

catalyzed intramolecular cyclization to afford 40. However by curtailing the reaction time (15 min) and quenching the reaction mixture, it was possible to isolate uncyclized 1,4addition-elimination product 39. The reaction was found to be otherwise general except when 38 was reacted with 6.33 which failed to afford the corresponding condensed quinazolone 42 probably due to intramolecular steric crowding. The reaction of 38 with less hindered 6.29 yielded the corresponding fused quinazolone 41 in good yield <92TL6173>. 1.2.7 Reaction of 1-Methylpyrrole-2-acetonitrile 43 with 6: New Efficient Synthesis of Highly Substituted Indoles (Type-IV, 4a Model)

Despite the availability of numerous synthetic methods for the synthesis of indoles <99JCS(P1)1045>, there have been very few methods leading to the synthesis of 2,3unsubstituted indoles, which are important precursors for the synthesis of the corresponding tryptamines, tryptophans (gramine route) and a number of alkaloids,<84CHEC(4)313>. All these intermediates can be transformed into 13-carbolines which are precursors of many indole alkaloids. We therefore selected 43 as a readily available starting material for the synthesis of indoles. Thus 43 reacted with 6 in the presence of NaH/DMF to afford the corresponding 1,4-addition-elimination products 44 in nearly quantitative yields following type-IV, 14a model. These intermediates 44 underwent smooth cyclization in the presence of PTSA in refluxing benzene to afford the corresponding 3,4-substituted indoles 45 (four examples) <97T14737> in overall high yields. The method was equally versatile when 43 was reacted with 6.28-6.30 to yield the corresponding 4,5-cycloalkanoindoles 46. Similarly 4,5-condensed indoles 47 were obtained in overall good yields by reacting 43 with 6.32-6.33 and 6.35 under identical conditions. The ketene dithioacetal 6.43 from estrone methyl ether also reacted with 43 to yield the corresponding angularly fused optically active 48 [13s = + 49 ~ (c = 0.48, [

~.- -.%

.R1

]

(

j-- -- %

44

43

OMe

e=8-e3o os" y -N-jj 6.32, e.3s 6.33,

17.1, 17.3, 17.4,

17.14,17.15

["

.., .,. %

il~

CN Me 47 n = 1,2,3

R]

(65-87%)

._ ~ , . 2 ~

6.43

-- x.. ~,,...IN,IJ CN

CN Me 45(65-88)%

"I I.I

CN Me

46 n = 1,2,3 (68-78%)

R1

Me

49, X= OMe,--N~ ,--CO (65-85%)

CN Me 48 (74%)

10

H. Ila, H. Junjappa and P.K. Mohanta

dioxane) in 74% yield. The method was particularly useful for the synthesis of biologically important 6-amino/alkoxyindoles when reacted with N,S- and O,S-acetals 17. A few of these indoles 45 were subjected to Raney Ni dethiomethylation to give sulfur free derivatives with simultaneous conversion of cyano to methyl group. The new indole synthesis is an efficient JI inverse approach from readily available 1-methyl-2cyanopyrrole 43. This model has great potential for synthesis of many regioisomers of indoles proposed in Scheme 1.

1.2.8 Reactionof Indole-3-acetonitrilewith 6: A New EfficientGeneralMethodfor the Synthesisof 1,2- SubstitutedandCondensedCarbazoles(Type-V, 5a Model) Indole-3-acetonitriles 50a-b were reacted with 6 and 17 (12 examples) to afford the corresponding 1,4-addition elimination products 51 in nearly quantitative yields as described earlier. The open chain adducts 51 were cyclized to afford the corresponding carbazoles 52 in overall high yields <97TL3119>. Interestingly, carbazole aldehyde 53 was obtained by reacting 50a with pyruvaldehyde dithioacetals 6.6 under identical reaction conditions. The 1,2-condensed carbazoles 54 and 55 were prepared by reacting 50 with 6.28-6.30 and 6.32-6.35 in high yields under identical reaction conditions. The ketene dithioacetal 6.43 from estrone methyl ether also yielded with 50 the corresponding angularly fused optically active [CX]n6D= +49 ~ (C = 1, dioxane) 1,2-condensed carbazole 56 in excellent yields. It was therefore possible to synthesize both optically active regioisomeric [1,2-b]- (56) and [2,3-b]- (30) carbazoles in excellent yields. We consider CN

CN

CN

6.1-6.2, 6.5-6.8, Nail / ~ 6.15,17.3, 17.4 D M F / 0 o ~ 17.7, 17.14,17.15

N I

R

51

50a; R = Me

b; R = PhCH 2

SN~

...

52

X= SMe, O M e , - - N ~ , - - O

CN

~

6.28-6.30 ~

TsOH / CrH6 "-

Me 6.6----~

n

=

54 n = 1 , 2 , 3 (78-92%) CN

1

A

.Sie

6.32-6.35

6.43

Cj.

L~ 1 ~ R3

.

(62-96%) ,--C

~

CN

Me

Me CHO CN 53 (69%) ..L .SMe

55, n= 1,2,3 R3 = H, OMe (78-92%) OMe

.

The Junjappa-Ila (JI) Heteroaromatic Annulation

11

the present method as a versatile carbazole synthesis derived from the JI-heteroaromatic annulation protocol, which provides better regiocontrol on all 1,2,3,4 carbon atoms of carbazole. It still remains to explore other regioisomers that can be conceived on the basis of Scheme 1 as well as natural products belonging to the carbazomycin series.

1.2.9 Reaction of Thiophene-2-acetonitrile 57 and Thiophene-3-acetonitrile 59 with 6 (Type IV, 4a and Type-V, 5a Model): An Efficient New General Synthesis of Highly Substituted Benzo[b]thiophenes The versatility of JI-heteroaromatic annulation has been further established by its application to the synthesis of isomeric benzo[b]thiophenes 58 and 60 <00T8153>. Both 2-cyanomethyl- (57) and 3-cyanomethyl- (59) thiophenes isomers have been reacted with various oxoketene dithioacetals 6 to obtain wide range of 4,5- (58) and 6,7- (60) substituted and condensed benzothiophenes <81AHC171; 90JCSP(I)2909> in excellent

CN

t.,

59 ~ 2. TsOH / C6H6 / A

S ...s

~

CN

6.1, 6.2, 6.5, 6.7, 6.8, 17.2, 17.3,17.15

[

/ "" -

/ Nail/DMF 2. TsOH / C8H6 / A

>

~.

'R1

~2 S" CN

60 (63-78%)

58 (60-72%)

yields. Thus both regioisomeric 4,5- (61) and 6,7- (62) cycloalkanobenzothiophenes could be obtained in excellent yields by reaction of 6.28 and 6.29 with either 57 or 59 respectively. Similarly the other condensed benzothiophenes 63 and 64 were synthesized by cyclization of 57 and 59 with 6.32 and 6.33 derived from benzocyclic ketones. These examples amply demonstrate the formation of the proposed regioisomers as depicted in Scheme 1. The other two anions of Type I (la) and Type II (2a) model leading to linearly substituted/fused benzothiophenes are still unexplored but we hope to investigate them in the near future. CN c.

59 n{9..~ CN MeS,,v ~

6.28 6.29

>

Me

S ~j

CN 61 n = 1,2 (60-66%)

n-1 2

62 (61-71%)

CN 59

6:32

> Me

S ~j CN

64 n = 1, 2; (62-65%)

63 n = 1, 2; (56-62%)

12

H. Ila, H. Junjappa and P.K. Mohanta

1.2.10 Synthesis of Benzoheterocycles Oxoketene Dithioacetal Precursors

from

Heterocyclic

Ketone

Derived

r

The above examples represent JI-heteroaromatic annulation involving the reaction of allyl anions whose double bond is a part of the heterocyclic ring system (Scheme 1). The corresponding tx-oxoketene dithioacetals (1,3-electrophilic component) were generally derived from nonheterocyclic carbonyl precursors. Alternatively the JI-heteroaromatic annulation can also be employed to ot-oxoketene dithioacetals derived from heterocyclic ketones (1,3-bielectrophile) and hetero/nonheteroallyl anions (1,3-binucleophile). These reactions are described below.

1.2.10.1 Reaction of a Dithioacetal Derived from Indoxyl with Allyl and Stabilized Benzyl Anions

The t~-oxoketene dithioacetal 6.40 is derived from indoxyl (1,2-dihydroindol-3one), a heterocyclic carbonyl precursor, and its reaction with simple allyl anions will also yield the corresponding JI-annulation product. Thus when 6.40 was reacted with allyl anions 65 the corresponding carbinol acetals 66 formed insitu underwent smooth BF3.Et20 assisted cyclization to afford the corresponding carbazoles 67 in high yields <99T11563>. Fe

R , , ~ , , , ~ MgX

HO

R1 I .R2 e

Me SMe 6.40

Me

SMe

66

65, 67 a; R 1 = R2 = H, X= SMe (63%) b; R I = H ; R 2=Me;x=SMe(68%)

R1 ..~.L,,,~. R2

,N

--

Me X A: BF3.E20.C6H61A 67

65, 67 r R 1 = Me; R 2 = H; X= SMe (65%) 67d; R I = R 2 = H = x = H ( 9 4 % )

Similarly the stabilized benzyl anions from 68 and 70 also reacted with 6.40 following Type IV (4b) reactivity patterns to afford the corresponding 3,4-annulated carbazoles 69 and 71 respectively in moderate yields <99T11563>.

6.40 Me

SMe

71 (41%)

2. H3PO4 / A

I NaH I D I ~

2. H3PO4 / A

Me

SMe

N

69(59%)

1.2.10.2 Reaction of a Dithioacetal Derived from Indoxyl with Heteroarylallyl Anions (Type IV and Type V )

a-Oxoketene dithioacetal 6.40 when reacted with N-methylpyrrole-2-acetonitrile 43 under the earlier described conditions, proceeded by the Type IV 4a reactivity model and the intermediate on treatment with HaPO4 yielded the pyrrolo[2,3-c]carbazole 72 in high

The Junjappa-Ila (J1) Heteroaromatic Annulation

13

yield. Similarly the corresponding indolo[3,2-a]carbazole 73 was obtained in 70% yield by reaction of 6.40 with indole-3-acetonitrile. Both 2- and 3-thiopheneacetonitriles 57 and 59 reacted with 6.40 to afford the corresponding isomeric 3,4-thienocarbazoles 74 and 75 respectively in overall high yields <99T11563>. The synthesis of these examples amply demonstrates the structural flexibility of JI-heteroaromatic annulation. The synthesis of thienocarbazoles would certainly involve difficult synthetic pathways possibly with multistep reaction sequences with little hope of good yields. By JI-annulation, these compounds can be prepared in high yields within two steps in high purity. Oq

~ /

N I ~/~ N

"-Me 4 3 ~

Me SMe 72 (73%) /

CN

H3PO4/ A

6.40

H3PO4/ A

CN ~

s"" c

N

59

HaPO4 / A

6.40

N Me SMe 73 (70%)

H3PO4 / '~

Me SMe 75 (62%)

N

CN

Me SMe 74(67%)

Interestingly the heteroallyl anion 26 from antipyrine displayed unusual 1,2-mode Type 1 (la) reactivity with 6.40 instead of Type III (3a) reactivity as generally observed in the preceding examples. The carbinol acetal 76 thus formed by 1,2-addition mode was cyclized with BF3.Et20 to afford the corresponding linearly annulated carbazole 77 in 73% yield <99T11563>.

Li

Me

6.40

OH

Me

l~l.N-Ph

Me

N"'Ph 26

o

Ne SMe 76

A: BF3.Et20/ C6He/ A

Me ~( '0 77 (73%) X = SMe-- ! Raney Ni X = H ~t.-J 93%

1.2.10.3 Reaction of N-Benzenesulfonyl-3-[bis(methylthio)methylene]-2,3dihydro-lH-quinoline-4-one 6.36 with Allyl and Benzyl Anions: A New Regiospecific Synthesis of Phenanthridines and Benzolj]phenanthridines The reaction of 6.36 with allyl and benzyl anions was examined with a view to develop an efficient method for the synthesis of phenanthridines and their benzo[/]derivatives. The dithioacetal 6.36 when reacted with allyl anions yielded the corresponding

14

H. Ila, H. Junjappa and P.K. Mohanta

N-benzenesulfonyl-dihydrophenanthridines 78 in high yields. These intermediates 78 underwent deprotection and dehydrogenation in the presence of phase transfer catalyst to afford the desired phenanthridines 79 in excellent yields <98T10169>. Interestingly

0

1. B . ~ 5 MgX

SMe

"

6.36

SMe

X

78 (82-86%)

R = H, Me

79(84.97%)

X = SMe-..1 Raney Ni X = H ~1 (62-78%)

P = C6H5SO2A = BF3.Et20/C6Hjz~; B = BLkNOH/Toluene/z~

various benzyl Grignard reagents 80a-e reacted with 6.36 in 1,2-fashion to afford the corresponding N-protected dihydrobenzo[j]phenanthridines 81a-e in excellent yields. These dihydro derivatives were deprotected and dehydrogenated to afford the corresponding phenanthridines 82 in excellent yields. The benzo[j]phenanthridines were virtually unexplored due to the lack of appropriate methodology in the literature. The only method reported in the literature <56JHC15> involves the rearrangement of the oxime of the fluorenone to yield the isomeric phenanthridine from which only 12% of benzo[j]phenanthridine was isolated. The JI-heteroaromatic annulation therefore provides the first versatile synthetic methodology for benzo[j]phenanthridines <98T10169>. The hitherto unreported basic skeleton 84 of naphtho[2,1-j]phenanthridine was also synthesized in high yield by reacting 83 with 6.36 under the described reaction conditions.

Rl " ~ ~ l V I g

CI

R2" y "R4 1. 80 R3 / Et20 / THF 6.36

~'

R2

R4

a; R 1 = R 2 = R3 = R4 = H

b ; R I = R 3 = R 4 = H , R2=OMe c; R1 = R4 = H; R2 = R3 = OMe d; R 1 = R4 = H; R2 = R3 = -(OCH20)e;R I = R 2 = O M e ; R3 = R 4 = H

SMe 6.36

"1

R3~~~,,IN"p

2. A

MeS

II

SMe 81

R4

IVlgCI

2. A 3. B 4. Raney Nil EtOH

8 4 ( 6 9 %) |

|

X

88-98% 82 X = SMe'-] X H~RaneyNi

63-79%

A: BF3Et20 / C6H6/A; B: Bu4NOH / Toluene

The Junjappa-Ila (J1) Heteroaromatic Annulation 1.3 HETEROAROMATIC ANIONS

ANNULATION

15

THROUGH

HETEROALLYL

In the preceding examples we have shown that the reaction of selected allyl anions derived from cyclic heterocycles with a-oxoketene dithioacetals 6 (Table 1) affords the corresponding benzoheterocycles. Benzoannulation was also observed when all carbon allyl and benzyl anions were reacted with 6 derived from heterocyclic ketones. However if the allyl anion contains either one or two nitrogen atoms the annulation with 6 generally proceeds through the terminal nitrogen so that the newly formed heterocycle is also one containing either one or two nitrogen atoms. The list of azaallyl systems or their anions are described in Table 3 (85.1-85.18). Table-3. List of Azaallyl Anions Used in the Present Work

R2.,,~SMe SMe 6

| Li R3-CH-CN 85.1, R3 : H 85.2, R3 = Me H_

CN

[i 85.3, 85.4,

85.5, 85.6, 85.7, 85.8, 85.9,

R3 = Me R3 = Et

+

| ~!~, 1~~ |

,~

"~~

or

R1~ ~ _ ~ '

X

85

X

86

87

X= SMe, H ~

CH2LI

85.11

85.12 M e O ~

CH2LI

R3 = -CH2OMe l" l] ] R3 = C6H5 MeO~.~N R3 = 4-MeOCsH4 85.13 CH2M R3 = 2-thienyl R3 = 2-furyl

85.10, R3 = ~ ' ~

R1

.,j~~R LiCH~" "S 85.14 LiCH2~S 85.15

NH H2N'~"-NH2 85.18

[F'-'~..

LiCH2""~N/NCO2Li 85.16 H2N,~=N ~N H 85.17

1.3.1 Reaction of Lithioacetonitriles 85.1-85.2 and [~-Lithioamino-[3-substituted acrylonitriles 85.3-85.10 with 6: A New General Synthesis of Pyridines and their Condensed Variants The lithioacetonitriles < 76S391; 68JOC3402> 85.1-85.2 (Table-3) underwent 1,2addition with 6 to give the carbinols 88 in nearly quantitative yields, which on phosphoric acid assisted cyclization through a nitrogen terminal following a Ritter type reaction yielded the pyridine derivatives 92 <88TL6633> in 54-68% overall yields involving intramolecular 1,3-SMe shift. Similarly 4,5-annulated pyridines 93 and 94 were obtained

16

H. Ila, H. Junjappa and P.K. Mohanta

by reacting anions 85.1 and 85.2 with oc-oxoketene dithioacetals 6.29-6.30, 6.32-6.35 and 6.38-6.39 respectively. The method was found to be general with 17 examples examined <90T2561>. -"

I s

(" "'R 1

s

%

R1

[

~ i ~ M O e a3caLiCN~-- ~ 2 ~ U 6.1-

RI

MeS~ "N ~ ~SMe

Reaction

[ -"-",R1 1,3< -MeS Shift 1 ~ 2 ~ R3

MeSf ~N" ~SMe

R3

92

MeS'~LN ~|

91

SMe 90 SMe

~ S M e 6.29-6.30

> ,1,, IJ i~1 kn ~ . , " ' ~ " 93,

R3

891 Pdtter

~' R1 <54.82"He% ~ 2 ~ R 3

R2~R3

R1

MeS" "SUe-"~l

88

6.16-6.18

"-%

R3 a3PO4/A~ ~ 2 ~

"780C/ THF MeS,,~SUe C 6.4, 6.7, 6.11-6.13

~,.'* -

R3 6.32-6.35 6.38-6.39

N~

n = 1, 2 (58-79%)'-

SMe

SMe n = 1,2 R3 = H, Me (70-76%)

R" ~

"X'~/n

94,R = H, OMe, Me R3 = H, Me; n = 1,2 X = S, CH2 (58-79%;

However when 3 equivalents of acetonitrile were treated with 1.5 equivalents of nBuLi the corresponding 13-1ithioamino-I]-methyl acrylonitrile 85.3 was formed. The anion 85.3 reacted with 6 in 1,4-addition- elimination fashion to afford the corresponding 3cyanopyridine 96a in high yield <90T3703>. A number of 13-1ithioamino-13-substituted acrylonitriles 85.3 and 85.6-85.9 were prepared by adding lithioacetonitrile to various aryl nitriles which were reacted in situ with 6 to afford the corresponding 3-cyano-4methylthiopyridines (96a-e) and their condensed analogs 97-98 in high overall yields <90T3703>. SMe SMe c

6.1, 6.8-6.13, MeCN(3 eqv.)/ n-BuLi (1.5 eqv.) ,._ 6.23

,. R1

N

r

or n-BuLi (1.5 eqv.)/ MeCN(1.5 eqv.)/ L

LiCH2CN + R3CN H. CN

HNLR 3

1,4 addition

I

ki 85.3, 85.6-85.9 6.28-3.29

'"

R3

Rlf~N/~R3

H" "Li

95 95,96 a; R3 = Me,

96

d; R3 = 2-thienyl,

b; R3 = C6H5,e; R3 = 2-furyl, c; R3 - 4-MeOC6H4

SMe

~ ~ L _~ f f , . ~ y C N

57-82% n~',N-~",-R3 n=1,2 97

6.33-6.35

6.37-6.39 83- 8

SMr CN

x

R3 98

R= Me; X= S, O; n = 1, 2

The Junjappa-Ila (J1) Heteroaromatic Annulation

17

The method was efficiently extended to N,S-acetals by reacting 85.3, 85.6-85.9 with various N,S-acetals 17 to afford the corresponding 3-cyano-4-aminopyridines 99 (8 examples) <91S889>. Cyclohexanone ketene N,S-acetal 17.11 reacted with 13-1ithioamino crotononitrile 85.3 to afford the corresponding tetrahydroisoquinoline 100.

I I

N~CN 1 H R

t

R3,N, R2 < 99

"""" 1~3N.R2

H~

85.3, 85.6-85.9

NMe2

SMe

NMe2

~ ' ~

c"

SMe 85.3 ... 0.5 h / -78~ / THF RV" ~'O v ~"O 0.5 h / -78~ / THF 48 - 92% 17.3, 17.4, 17.6, 17.11 29 % 17.8-17.9, 17.12-17.13 ,..._

Me 100

1.3.2 Reaction of Azaallyl Anions with 6.40 and 6.41: A New General Efficient Synthesis of (x-, 13- and ;5- Carbolines

The azaallyl anions 85.3-85.7 and 85.10 reacted with 6.40 following the initial 1,4addition elimination step and in situ cyclization to afford the corresponding ~5-carbolines 101 (6 examples) in excellent yields <99T11563; 00TH142>. In the absence of satisfactory methods for the synthesis of 8-carbolines in the literature, the present method provides an important route for these compounds. Similarly the isomeric 6.41 reacted with 85 to afford the a-carbolines 102 (7 examples) in high yields <01 T781 >. When lithioacetonitrile 85.1 was reacted with 6.40 the corresponding 13-carboline 103 was formed in 51% yield. Guanidine also reacted with 6.40 to afford the corresponding pyrimidoindole 104 in good yield. Thus the methodology is efficient for the high yield synthesis of cx, 13 and 5carbolines. MoS

SMe N Me

R

SMe

C78*C / THF 66-78 %

CN H Li

102 85.3-85.8, R = Me, Et, -CH2OMe,Ph, 4-MeOC6H4, 2-thienyl, ~ v

r:' ' ~ ,

R

-780C/ THF "79 %

85.10

CN Me SMe 101 R = Me, Et, -CH2OMe,Ph, 4-MeOCeH4, 2-thienyl

-N

Me NH I , " " N ~ NH2 H2NJ'I"NH2

~ " " N ' ~~Ae N , . , ~Me v 104

SMe

1. LiCH2CN/ THF / -78~ ~

~aH/DMF/or NaOMe / MeOH6"40 2. H3PO4/4; 51%

~SMe

~' ~ L , , . N M e . ~S ~ 103

18

H. Ila, H. Junjappa and P.K. Mohanta

1.3.3 Heteroaromatic Annulation with Cyclic Azaallyl Anions: Synthesis of Bridgehead Nitrogen Heterocycles The azaallyl anions 85.11-85.17 derived from cyclic nitrogen heterocycles generally react with 6 to afford the corresponding bridgehead nitrogen heterocycles. Some of the examples studied by our group are described below.

1.3.3.1. Reaction of 2-Lithiomethylpyridine 88.11, 1-Lithiomethylisoquinoline 85.12, 2-Lithiomethylthiozole 85.14/thiazolidine 85.15, 3-Aminopyrazole 85.17 with 6: A New General Method for Bridgehead Heterocycles The 2-1ithiomethylpyridine 85.11 reacted with 6 and 6.40 to afford the corresponding carbinol acetals 105 in excellent yields which underwent BF3.Et20 assisted cyclization to afford the corresponding quinolizinium fluoroborate salts 106 (13 examples) and 107 in high yields <87TL3023>. Similarly 1-1ithiomethylisoquinoline 85.12 reacted with 6 to afford the corresponding condensed bridgehead products 108 <90TH141 >. When 2-1ithiomethylthiazole 85.14 was reacted with 6, the corresponding thiazolopyridinium fluoroborates 109 were formed in 42-68% overall yields <90T4295>. Similarly 2lithiomethylthiazolidine 85.15 reacted with 6.33-6.35 and 6.39 to yield the corresponding fluoroborate salts of 110 in high yields <90T4259>. ~~N

CH2Li

OH

O - ~ R I ' , THF/-15~

+ MeS, , , , ~ R 2 i 1,2-addition 73 - 85% 85.11 SMe

106 X=SMe A = BF3.Et20/ C6H6/A; X = H

|@

II~-IN

107 (74%) [-

BF4 X

105

6.7, 6.9, 6.11-6.13, 6.29, 6.30, 6.33, 6.34, 6237, 6.39 6.40

|

SMe

17 exampleL

85.12

R1

108

1~2

O

MeS

e

1. THF/-15~

+

6.1, 6.7, 6.9, 6.11-6.13, 6.16 6.19, 6.22

X'-(-'0 n SMe 6.33-6.35, 6.39

S

1,2-addition 85.14

R 2. BF 3.Et20/C6C 6 / 42-68% Lli s Rl

O RI__~~SM

RI

e

R 109

1. ,T;" ~,N_~/ THF 85.15/ _15oc " ~ ~ 2. BF 3.Et20/C6H6/A

41-69%

A

~X~,~~N~

':"n

S1

T | 0 R SMe BF4

110

The Junjappa-Ila (J1) Heteroaromatic Annulation

19

The 3-aminopyrazole 85.17 also reacted with 6 to yield the corresponding pyrazolo[a] pyrimidines 111 (19 examples) exclusively as sole regioisomers in excellent yields. Similarly the condensed variants 112 and 113 were prepared in high yields <90T577>.

R3

" H

+

I:~ NH2 85.17

N--N

R3

6.1, 6.3-6.4

6.8-6.12

Piperidine.._ AoOH

68 - 93%

"

n_~~.S R3,~N'~N"H _., 6.28-6.30 Me-'n=l'2'3

113 (48 - 81~

R4

N~.N

R3--"<'_.'I"

~1

R2

"~'~"~"~'N SMe 1~4111 R

6.38-6"32" 6.396"35' >

NH2 n=l,2R3

~ X

N~N..,.J,~)n

R3=R4=H;R 3=SMe,R4=C6H5 R4

1.3.3.2

N

SMe

112 (82-86%)

Reaction of 5-Lithiomethyl-3-methylpyrazole-l-lithiocarboxylate with 6: A New General Method for Pyrazolo[1,5-a]pyridines

The dianion 85.16 was prepared for the first time following the method of Katrizky and co-workers <86JA6808> and reacted with various tx-oxoketene dithioacetals which followed 1,2-addition mode to afford the corresponding carbinol acetals 114. These carbinols when cyclized in the presence of orthophosphoric acid yielded the corresponding pyrazolo[1,5-a]pyridines 117, 118 and 119 <99T7645> in overall high yields. It is interesting to note that the cyclization of 114 followed through the ring nitrogen to afford pyrazolopyridines 117 rather than indazoles 115. The course that the reaction took in giving 117, 118 and 119 was established by an X-ray analysis of one of the products.

+ 6.1- 6.2

l1,2 addition.._ Me

MeS

SMe R2

6.7, 6.9

85.16 -COy

r, H20~A~ Me~~AJ~I.

Me~RI"~

? ~ V I ~ S ~ . ~ R2"' SMe 116

NS"-.~ ~R2,' SMe 117 (72-82%) 6.28

6.29 6.31

M > e ~ n=1,2,4

Me\

n

SMe 118 (67-80%)

6.33-6.35

SMe ~/R2

li "T

N , ,. N ~ , R,1 H 115

M ~ > ~ ~ ~ n

n = 1, 2

SMe 119 (63-68)

R

20

H. Ila, H. Junjappa and P.K. Mohanta

1.3.3.3 Cycloannulation of 13-Oxodithioates 120 with 1-Methyl-3,4-dihydro-6,7dimethoxyisoquinoline Derived Anion 85.13: An Efficient Synthesis of 2,3Disubstituted and Fused Benzo[a]quinolizine-4-thiones The 13-oxodithioates 120 are precursors of a-oxoketene dithioacetals 6 and are prepared in high yields by one of our published methods <82S693>. When 1-methyl-2,3dihydroquinoline 85.13 was reacted with 13-oxodithioates 120 in refluxing benzene (12 h) in the presence of triethylamine the corresponding benzo[a]quinolizine-4-thiones 121 (10 examples) were formed in 45-80% overall yields <01OL229>. The corresponding sulfur free oxo compounds 123 were prepared by alkaline hydrolysis of methylthioquinolizinium iodides 122 which were intum obtained by treating 121a-b and 121g and 121i with methyl iodide. The quaternary salts 122 were also reduced with sodium borohydride to afford the corresponding tetrahydrobenzo[a]quinolizines 124 and 125 in 81 and 76% yields respectively. M e O ~

""§ § CH3

O

S

Et3N / C6H6 / ..~ MeO"~h~ "~ ~

R1 SMe ,,,.._.." 1~2 120

A

""- M e O " ~ ' ~ ~ N " ~ lzl

S R-'

120, 121, R1 = R2 = - (CH2)3 - (45%) g, R1 = R2 =-(CH2)4- (70%) b, R1 = C6H5, R2 = H (80%) h, R1 = -(CH2-CH2-N-CH2)-(46%) c, R1 = 4-MeOC6H4, R2 = H (71%) / CH2C6H5 d, R1 = CH3, R2 = CH3 (60%) e, R1 = CsH5, R2 = CH3 (72%) i, R1 = R2 = [ i ~ - " j(65%)

120, 121a, R1 = CH3, R2 = H (66%)

v

121a-b, 12g, 121i

Mel/C6H~//MeO~ | RT ".,~ j.,J,~ ~ / Sie MeO'~'~' y

v

/ M e O ~ aq.NaOH ._ RT/2h " - M e O ~ N - ~ 82%

O

123R ~ ~ I R~ I

MeO M e O ~

NaBH4/MeOH

MeO'~

81%

76%

124

125

~

The Junjappa-Ila (JI) Heteroaromatic Annulation

21

1.4 A NEW GENERAL SYNTHESIS OF SUBSTITUTED AND ANNULATED PYRIDO[2,3-b]INDOLES A novel efficient method of considerable synthetic value has been developed for the synthesis of 2,3- substituted and annulated tx-carbolines 128, 129 and 132. Thus 2oxoindole 126 was reacted with various t~-oxoketene dithioacetals 6 in the presence of sodium hydride in DMF to afford the corresponding dicarbonyl intermediates 127 (11 examples) in 89-91% overall high yields. These intermediates 127 when heated with ammonium acetate in acetic acid, yielded the corresponding t~-carbolines 129 in 51-79% overall yields <99TL3797>. Similarly the condensed t~-carbolines 128 were obtained by reacting the cyclic dithioacetal 6.33 (from 1-tetralone) with 126. Also 13-methylthienone 130 derived from quinolone mercaptal 6.36 reacted with 126 to afford first the corresponding dihydro product 131 in 50% yield along with 15% of deprotected and dehydrogenated condensed carboline 132. However 131 on treatment with a phase transfer catalyst in boiling toluene yielded 132 in high yield.

SMe [~

,,~O ~ 6.1-6.2,6.5 Nail / DMF 6.7- 6.12, 6.14, 0~ - RT N 1 6.26 1,4-addition H 126

H 51-79% 127 I

SMe N

NH4OAc/ AcOH/ A 9 (11 examples)

RI"

h

128

51-79%

SMe 126

H

130

SMe

MeSO ~

',"

>

~N~I

~

6.33

131

I

(50%) |174

iii

i. Nail / DMF/ ii.9 NH4OAc/ AcOH/ A; iii. Bu4NOH/ Toluene/

132~

22 1.5

H. Ila, H. J u n j a p p a a n d P.K. M o h a n t a

CONCLUSION

W e have briefly described the JI-heteroaromatic annulation constituting a new general inverse method for the synthesis of benzoheterocycles and related heteroaromatic ring forming reactions. The examples are drawn from a few selected heterocycles to demonstrate the general application of the methodology as proposed in Scheme 1. Thus the application of this methodology to the vast majority of heterocycles remains to be explored; we hope that this review will be a catalyst for further investigations. W e have not explored the anions from seven m e m b e r e d and higher heterocycles to build the corresponding benzo derivatives but these are being planned as a part of our current programme.

1.6

ACKNOWLEDGMENT

W e gratefully thank Dr. Gilchrist for his kind invitation to contribute this work. W e are grateful to Dr. Okram Barun and Mr. S. Peruncheralathan for their help in preparing this manuscript. W e also thank our entire graduate and postdoctoral fellows without whose efforts this work would not have been possible. W e profusely thank all those whose names have appeared in the references. W e also thank DST New Delhi, CSIR New Delhi, D A E B o m b a y , U N E S C O , I N F A R India Ltd. Calcutta, M a y and Baker England who have generously helped us financially.

1.7

REFERENCES

10CB 1252 56JHC15 59BSF1398 62BSF2182 62BSF2187 62B SF2194 62CB2861 66YZ1152 68CA2869p 68JOC3402 70ACS 1191 70CJC2006 B-70MI1 73TL3817 73TL4207 76S391 76S777 76T 1779 76T1911 78JCS(P1)549 78S633 79JCR(S)268

C. Kelber,. Ber. 1910, 43, 1252. L.H. Klemm, A. Weisert, J. Heterocycl. Chem. 1956, 2, 15. A. Thuillier, J. Vialle, Bull. Soc. Chim.Fr. 1959, 1398. A. Thuillier, J. Vialle, Bull. Soc. Chim.Fr. 1962, 2182. A. Thuillier, J. Vialle, Bull. Soc. Chim. Ft. 1962, 2187. A. Thuillier, J. Vialle, Bull. Soc. Chim. Fr. 1962, 2194. R. Gomper, W. Topfl, Chem. Ber. 1962, 95, 2861. G. Kobayashi, S. Furukawa, Y. Matsuda, Yakugaku Zasshi 1966, 86, 1152. T. Teshigawara, G. Kobayashi, Y. Matsuda, Chem. Abstr. 1968, 69, 2869p. E. M. Kaise, C. R. Hauser, J. Org. Chem. 1968, 33, 3402. J. Sandstrom, I. Wennerbeck, Acta. Chem. Scand. 1970, 24, 1191. R. G. Micetich, Can. J. Chem. 1970, 48, 2006. R. J. Sundberg, "The Chemistry oflndoles", Academic Press, New York, 1970 P1. E. J. Corey, R. H. K. Chen. Tetrahedron Lett. 1973, 3817. I. Shahak, Y. Sassan, Tetrahedron Lett, 1973, 4207. A. Debal, T. Cuvigny, M. Larcheveque, Synthesis 1976, 391. R. E. Gawley, Synthesis 1976, 777. S. M. S. Chauhan, H. Junjappa, Tetrahedron 1976, 32, 1779. S. M. S. Chauhan, H. Junjappa, Tetrahedron 1976, 32, 1911. R. R. Rastogi, A. Kumar, H. Ila, H. Junjappa J. Chem. Soc,. Perkin Trans 1 1978, 549. Review on Indazolone: L. Baiocchi, G. Corsi, G. Palazzo, Synthesis 1978, 633. A. Kumar, H. Ila, H.Junjappa, J. Chem. Res.(S) 1979, 268.

The Junjappa-Ila (J1) Heteroaromatic Annulation

79JCR(M)3001 81AHC171 81JOC5031 81ZC69 82JOC3027 82S203 82S693 84CHEC(4)313 84CHEC(5)274 84CHEC(6) 114 84JCS(P1)921 84TL5095 85IJC466 85S163 86JA6808 87TL3023 88TH48 88TH58 88TH99 88TL501 88TL6633 89PHC(1)l 90C406 90JCS(P1)2909 90PAC1967 90T577 90T2561 90T3703 90T4295 90T5423 90TH141 91COS(5)1065 91S889 92TL6173 93IJC(B) 1173 93JCS(P1)l 119 B-93MI257 93S241 93S245

23

A. Kumar, H. Ila, H. Junjappa, J. Chem. Res (M) 1979, 3001. R. M. Scrowston in "Advances in Heterocyclic Chemistry", A. R. Katritzky, (Ed.) Academic Press, New York, 1981, 29, 171. R. K. Dieter, J. Org. Chem. 1981, 46, 5031. N. B. Mansour, W. - D. Rudorf, M. Augustin, Z. Chem. 1981, 21, 69. K. T. Potts, M. J. Cipullo, P. Ralli, G. Theodoridics, J. Org. Chem. 1982, 47, 3027. W. Schroth, R. Spitzner, B. Koch Synthesis 1982, 203. G. Singh, S. S. Bhattacharjee, H. Ila, H. Junjappa, Synthesis 1982, 693. R.J. Sundberg in "Comprehensive Heterocyclic Chemistry" Eds., A.R. Katritzky, C.W. Rees, C.W. Bird, G.W.H. Cheeseman, Pergamon Press, Oxford, 1984, Vol. 4., pp 313. A. R. Katritzky, C. W. Rees "Comprehensive Heterocyclic Chemistry", Pergamon Press, Volume 5, Ch. 4. 04, p. 274. S. A. Lang, Jr., Y.- I Lin in "Comprehensive Heterocyclic Chemistry", K. T. Potts, Eds., Pergamon Press, Volume 6, Part 4B, Ch. 4.16, pp. 48-50 and 114-120. S. Apparao, Apurba Dutta, H. Ila, H. Junjappa Jr. Chem. Soc. Perkin Trans 1 1984, 921. G. Singh, H. Ila, H. Junjappa, Tetrahedron Lett. i984, 25, 5095. J. N. Vishwakarma, S. Apparao, H. Ila, H. Junjappa Indian J. Chem 1985, 24B, 466. C. V. Asokan, H. Ila, H. Junjappa Synthesis 1985, 163. A. R. Katritzky, K. Akutagawa, J. Am.Chem. Soc. 1986, 108, 6808. M. P. Balu, H. Ila, H. Junjappa, Tetrahedron Lett. 1987, 28, 3023. C. V. Asokan, Ph.D. Thesis, North Eastern Hill University, Shillong, India 1988, p. 48-62. Apurba Dutta, Ph. D. Thesis, North Eastern Hill University, Shillong India 1988, p. 58-61. Apurba Dutta, Ph.D. Thesis, North Eastern Hill University, Shillong India 1988, p. 99100. M. P. Balu, D. Pooranchand, H. Ila, H. Junjappa, Tetrahedron Lett. 1988, 29, 501. A. K. Gupta, H. Ila, H. Junjappa, Tetrahedron Lett. 1988, 29, 6633. A. R. Katritzky, J. N. Lam, S. Sengupta, G. W. Rewcastle, "Progress in Heterocyclic Chemistry", Pergamon Press, 1989, Vol. 1, p. 1. U. Pindur, Chimia 1990, 44, 406. P. M. Jackson, C. J. Moody, P. Shah J. Chem. Soc. Perkin Trans I 1990, 2909. J. Bergman, B. Pelcman, Pure Appl. Chem, 1990, 62, 1967. A. Thomas, M. Chakraborty, H. Ila, H. Junjappa, Tetrahedron 1990, 46, 577. A. K. Gupta, H. Ila, H. Junjappa, Tetrahedron, 1990, 46, 2561. A. K. Gupta, H. Ila, H. Junjappa, Tetrahedron 1990, 46, 3703. A. Thomas, H. Ila, H. Junjappa, Tetrahedron 1990, 46, 4295. H. Junjappa, H. Ila, C. V. Asokan, Tetrahedron 1990, 46, 5423. A. K. Gupta, Ph.D. Thasis, North Eastern Hill University, Shillong India 1990, p. 141-183. W. D. Wulff in "Comprehensive Organic Synthesis" B. M. Trost, I. Flemming, Eds., Pergamon Press, Vol. 5, p. 1065-1113. J. Satyanarayan, H. Ila, H. Junjappa, Synthesis 1991, 889. J. Satyanarayan, K. R. Reddy, H. Junjappa, H. Ila, Tetrahedron Lett. 1992, 33, 6173. S. K. Sharma, R. T. Chakrasali, H. Ila, H. Junjappa, Indian J. Chem. Sect.B, 1993, 1173. V. J. Aran, J. L. Asensio, J. R. Ruiz, M. Stud, J. Chem. Soc. Perkin Trans.1 1993, 1119. D.P. Chakraborty, in "The Alkaloids ", G. A. Cordell (Ed.), Academic Press, New York, Vol. 44, 1993, pp 257. D. Pooranchand, J. Satyanarayan, H. Ila, H. Junjappa, Synthesis 1988, 241. M. L. Purkayastha, M. Chandrasekharan, J. N. Vishwakarma, H. Ila, H. Junjappa, Synthesis 1993, 245.

24

H. Ila, H. Junjappa and P.K. Mohanta

H. Junjappa, H. Ila, B. Patra, CH. S. Rao, Indian J. Chem.,1994, 501. H. Junjappa, H.Ila, Phosphorous, Sulfur, Silicon, 1994, 95-96, 35. K. R. Reddy, Ph.D. Thesis, North Eastern Hill University, Shillong, Meghalaya 1994, 142-144. K. M. Yadav, Ph.D. Thesis, North Eastern Hill University, Shillong, Meghalaya, India 94TH212 1994, p. 212-214. J. Satyanarayana, Ph. D. Thesis, North Eastern Hill University, Shillong, Meghalaya, 94TH235 India 1994, p. 235-239. H.-J. Knolker in "Advances in Nitrogen Heterocycles ", C. J. Moody (Ed), JAI Press, B-95MI71 Greenwich(CT). Vol. 1, 1995, p 71. A. K. Gupta, K. MaUik Yadav, B. Patro, H. Ila, H. Junjappa, Synthesis 1995, 841. 95S841 K. R. Reddy, A. Roy, H. Ila, H. Junjappa, Tetrahedron 1994, 51, 10941. 95T10941 P. K. Patra, J. R. Suresh, H. Ila, H. Junjappa, Tetrahedron Lett. 1997, 38, 3119. 97TL3119 J. R. Suresh, P. K. Patra, H. Ila, H. Junjappa, Tetrahedron 1997, 53, 14737. 97T14737 J. R. Suresh, Ph.D. Thesis, North Eastern Hill University, Shillong, Meghalaya, 1998, p. 98TH100 100-101. P.K. Patra, J. R. Suresh, H. Ila, H. Junjappa, Tetrahedron, 1998, 54, 10169. 98T10169 U. K. Syam Kumar, P. K. Patra, H. Ila, H. Junjappa, Tetrahedron Lett. 1998, 39, 2029. 98TL2029 J. L. Segura, N. Martin Chem. Rev. 1999, 99, 3199. 99CRV3199 99JCS(P1)1045 G. W. Gribble, J. Chem. Soc., Perkin Trans I 1999, 1045 and references therein. K. Kishore, K. R. Reddy, J. R. Suresh, H. Ila, H. Junjappa, Tetrahadron 1999, 55, 7649 99T7645 A. R. Katritzky, J. Li, L. Xie, Tetrahedron 1999, 55, 8263. 99T8263 M. V. Basaveswara Rao, U. K. Syam Kumar, H. Ila, H. Junjappa, Tetrahedron, 1999, 55, 99T11563 11563. O. Bantu, P. K. Patra, H. Ila, H. Junjappa, Tetrahedron Lett. 1999, 40, 3797. 99TL3797 J. R. Suresh, O. Barun, H. Ila, H. Junjappa, Tetrahedron 2000, 56, 8153. 00T8153 U. K. Syamkumar, Ph.D. Thesis, Indian Institute of Technology, Kanpur, India, 2000, p. 00TH142 142. 01JOM(624)34 H. Ila, H. Junjappa, O. Barun, J. Organomet. Chem. 2001, 624, 34. A. Roy, S. Nandi, H. Ila, H. Junjappa, Org. Lett. 2001, 3, 229. 01OL229 J. R. Suresh, U. K. Syam Kumar, H. Ila, H. Junjappa, Tetrahedron 2001, 57, 781. 01T781 94IJC501 94MI35 94TH142

25

Chapter 2 The Synthesis of Fused 7-Azanorbornanes Ronald N. Warrener

Centre for Molecular Architecture, Central Queensland University, North Rockhampton, Queensland, 4702, Australia e-mail: [email protected]

2.1 INTRODUCTION The medicinal value of alkaloids containing N-bridged alicyclic ring systems have been recognised for some time and exploited commercially. This class of compound is typified by the tropane alkaloids which contain the 8-azabicyclo[3.2.1]octane ring system (e.g. tropine 1, Figure 1). By contrast, a role for 7-azanorbomane (7-azabicyclo[2.2.1] heptane) which has one less methylene group in the largest ring, had to wait until the 1990's for its discovery in nature <92JA3475>. Epibatidine 2, found in only small amounts in a rare South American frog <00NPR131>, displayed strong non-opioid analgesic activity, a property which initiated substantial research interest in the synthesis of the natural product and its analogues. A spin off of this research has been heightened awareness of the chemistry of 7-azanorbornanes which has taken them from relative obscurity to a high point in synthetic endeavors to obtain analogues that mimic the biological activity of epibatidine <98JPE777>. tCI

kl tropine

X 2

epibatidine

R

~N 3a

Y

X

R N/

Y

3b

XNY-[n]polynorbornane (tridents)

Figure 1 Alicyclic compounds with more than one 7-azanorbomane subunit are rare and none with more than two fused 7-azanorbornane units were known prior to our study<98SL588>. The presence of aza-bridges introduces new properties into the carbocyclic [n]polynorbomane ring systems, including H-bonding centres and acid solubility. Further, the topology of the azabridged [n]polynorbomane frame can be modified by changing the nature of the N-substituent. Finally, the conformational mobility of the N-substituents introduces dynamic features unique to this class of [n]polynorbomanes. As pointed out in this review, we have developed efficient routes to make aza-bridged [n]polynorbomanes containing only N-bridges (up to 5-bridges) as well as hybrid systems containing 7-azanorbornane units combined with norbomanes, 7oxanorbomanes and 7-modified norbomanes (up to 10 bridges). Trident systems 3 in which the N-bridge are flanked by different combinations of sentinel bridges (X, Y = C, N, O bridges) have allowed a comprehensive study (VT and 15N NMR) of through-space effects on bridge nitrogen hybridisation for the first time. This type of conformational mobility involved N-

R.N. Warrener

26

substituent motion 'in the long plane' associated with the invertomerisation between 3a and 3b (Figure 1), whereas N-acyl or N-Z substituents underwent 'out of plane' rotational isomerisation (see, Section 2.10) and provided the first examples of stable atropisomers capable of isolation in these systems. All these features are discussed in this chapter as well as the new methodology developed for the synthesis of fused the 7-azanorbomanes. This presentation has focused on the use of 1,3-dipolar cycloaddition methods for the production of the fused 7-azanorbornanes. Alternative Diels-Alder approaches to the production of diazasesquinorbornadienes using pyrrole and isoindole cycloadditions are mentioned only briefly since these reactions have been covered by us elsewhere <00EJO3363>. For a earlier review of 7-azanorbornane chemistry, see Trudell <96CRVl179>.

22

1,3-DIPOLAR CYCLOADDITION ROUTES TO 7-AZANORBORNANES

2.2.1 The Role of Azomethine Ylides in Heteroalicyclic Synthesis Ring-opening of aziridines to form azomethine ylides such as 4 to 5, and their trapping with dipolarophiles (alkenes, alkynes or hetero n-bonds) has become an established route to produce pyrrolidines or related heterocyclic systems, e.g. reaction of maleic anhydride 6 with 5 to form fused pyrrolidine 7 (Scheme la) <66JOC3924>); for other examples, see <00TJC59, 96JOC9072, 95Sl147, 81Hl131, 73BSF3437, 71JA1777, 94CJC2108>. Applications of this type of cycloaddition to the synthesis of 7-azanorbomanes by reaction of dipolarophiles with cyclic azomethine ylides are known, but rare. Thus, irradiation of divinylamines 8 in the presence of electron-deficient alkenes is reported to form 7-azanorbomanes 10 with ester groups at the bridgehead by addition to the dipolar intermediate 9, while the related 7-azanorbomenes were formed with 1,2-dicyanoacetylene or dimethyl acetylenedicarboxylate, e.g. 10 (R=E=CO2Me) (Scheme lb) <83JHCl>. Generation of the parent N-benzyl azomethine ylide 9 (R=H) by double desilylation of 11 has been reported and used for the construction of 7-aza norbomanes <93TL7301>. Larger bicyclic systems such as aza-bridged bicyclo[3.2.1]octanes and bicyclo[4.2.1]nonanes have been prepared via the ring-opening and trapping of bicyclic aziridines, e.g. formation of 14 by addition of norbomene to the 1,3-dipole 13 (Scheme l c) <83JOC4968>.

NPh A ,, P b)

E

4 R'

YY 8

c) II

~

+k%-Nph

o .I 12

5 _E

hv

R

<83JH1~1> E=CO2Me

R

~

IX

\~/

E ~

9

R=CO2Me, H

<83JOC4968>

O

N

o

L,,;NR

-

pfi

t

R

-

E

T

O TMS

"X(E)

R 10

R' NR

Ph

94%

60

'TY

,

<06J003024>

+

11 TMS 0..~..,,~.~

.,,r

,~

60%

R = 4-CI-Ph

R'= Ph

O

14

Scheme 1 Ring-opening routes to azomethine ylides and trapping with alkenes

The Synthesis of Fused 7-Azanorbornanes

27

An intramolecular version of the bicyclo[3.2.1]octane-forming reaction has been reported involving tethered substrates 15 which open to dipoles 16 prior to intramolecular cyclisation<98T2289> (Scheme 2). Different length silicon-containing tethers were used to control regioselectivity, e.g. formation of endo-re isomer 17 v endo-si isomer 18, and such tethers had the advantage of being removable following cycloaddition. O

Me N

O

Me N

Ph NMe I

_

+

Y

-

15

16

N

Y

N

endo-re 17

Scheme 2

.J endo-si 18

22.2 Ring-Opening and Trapping of Fused 5-Aza and 5-Oxabicyclo[2.1.0]pentanes

Our first entry to the synthesis of hetero-bridged norbomanes 21 using 1,3-dipolar chemistry involved formation of 7-oxanorbomanes by the trapping of carbonyl ylides 20 formed by ringopening of norbornane-fused 5-oxa[2.1.0]pentanes 19 (ACE reaction, Scheme 3a) <97CC1023>. The ACE reaction has proved to be an extremely versatile method for producing 7-oxa norbomanes and attaching effector groups to extended-frame O-bridged [n]polynorbomanes. It has been successfully applied to the production of molecular frames containing up to 10 alternating syn-fused norbomane and 7-oxanorbomane rings. The characteristic curved topology of such [n]polynorbomane frames has been exploited in the preparation of cavity biscrown ethers <99OL203>. More recently, a photochemical variant of the ACE reaction has been described for introduction of 1,4-dimethoxynaphthalene chromophores into scaffolds <00OL4003> and methods for the control of scaffold hydrophilicity and lipophilicity have also been reported <00TL4671>. a) ACE Reaction X

0

19

X

Z

X

~

X = CO2Me, CO2H CONR 2, Ph

X

Z

20

X

21 X

b) AzaACE Reaction

NR 22

E

= E = C02Me R Me, CH2Ph Ph, CH2OMe

NR 23

E

...} 24 E

Z

Scheme 3

A key finding, and the basis for this review chapter, is that it has been possible to develop a nitrogen equivalent of the ACE reaction (aza-ACE reaction) in which the epoxide was replaced by an aziridine (Scheme 3b) <98SL566>. This finding opened the way to produce a new class of fused 7-azanorbornanes 24 having various combinations of C, N, O-bridges. The aza-ACE reaction proceeded via generation of cyclic 1,3-dipoles of type 23 by ring-opening of esteractivated aziridinocyclobutanes 22 and trapping them with alkenes, especially norbomenes and

28

R.N. Warrener

hetero-bridged norbomenes, to access aza-bridged [n]polynorbomanes 24. Electron-deficient alkenes react in a similar way to furnish 7-azanorbomenes. The aza-ACE reaction proceeded under much milder conditions (85 ~ than its oxygen counterpart (140 ~ and was more synfacially stereoselective. The initial results were reported in 1998 <98SL588> and while some newer aspects have appeared subsequently <99TL4111, 00OL721, 00OL725>, much of the work described herein is unpublished or in press.

2.3 THE SYNTHESIS OF FUSED AZIRIDINOCYCLOBUTANES (5-AZABICYCLO[2.1.0]PENTANES) The N-substituted aziridinocyclobutanes 28 essential as building block (BLOCK <97CC1519>) reagents for the aza-ACE reaction were produced in a two step sequence starting from cyclobutene-l,2-diesters 25 (Scheme 4). This process involved 1,3-dipolar cycloadditions of aryl or alkyl azides 26 to cyclobutene-l,2-diesters 25 using thermal or high-pressure conditions to form the related triazolines 27, followed by photochemical ejection of dinitrogen to afford the aziridine reagent 28 (Scheme 4). E

{ ~

+

RN3

25

E = CO2Me

- L / ~l ~E[ % ~ N

26

-

I E 28

27

Scheme 4

a)

b)

OAc

o

0

29

OAc

34

35

I

E = CO2Me

46

i O/~c

31/32 36

37

38 39 40

+ R-C-'-C-R 47 R = CF3 32 R =CO2Me

~

E-C~C-E32

30

L~Z

O'

!•

RuCOH2(PPh3)3 31-

X O NCO2Bn C=CMe2 CH2

<1

49

48 R = CF3 49 R =CO2Me Scheme 5

E

33

E 41 42 43 44 45

31/32_ E ~ E E [E=CO2Me]

E 50

The Synthesis of Fused 7-Azanorbornanes

29

Cyclobutene-l,2-diesters 25 had already served as starting materials in the formation of cyclobutene epoxides in ACE chemistry, accordingly, many of the bridged systems had already been prepared. Typically, fused cyclobutene-l,2-diesters such as 33 and 41-45, were readily formed by the Ru-catalysed addition of dimethyl acetylenedicarboxylate (DMAD) 32 to the appropriate benzonorbomenes 30, 38-40 or their hetero-bridged varients 36, 37 <00OL721> (Scheme 5a,b). An entry to cyclobutene-l,2-diesters which avoided the use of metal catalysts could be achieved using the thermal reaction of perfluorobut-2-yne (PFB) 47 or DMAD 32 with quadricyclane 46 to form the bis-alkenes 48 or 49 respectively <66JA4273> <95JFC61>. As reported elsewhere <79JOC4492>, the norbornene component present in 49 has been further transformed to bis(cyclobutene-l,2-diesters) 50 using the Ru-catalysed addition of DMAD 32 (Scheme 5c). Another convenient entry to fused cyclobutene-l,2-diesters was via site selective modification of the norbornene n-bond in Smith's bis-alkene 49, e.g. treatment with 3,6-di(2'pyridyl)-s-tetrazine 51 followed by DDQ oxidation afforded the cyclobutene-derivative 53 <97AAl19>, while direct coupling with 3,5-bis(trifluoromethyl)-l,3,4-oxadiazole 54 furnished the bis(cyclobutene-l,2-diester) 55 (Scheme 6) <97SL196>.

NZ-N__ Py2

|,.=.i

N,,~N

_N2

Py2 51 E = C02Me; Py2 = 2-pyridyl

.Py2

.F~/2 DDQ

N

N

Py2

Py2

52

CF3

E 53

CF3

+ 54N~__OCF3 ~N~J~ 140~

E E ~ E E Scheme 6

Addition of benzyl azide 56 to ester-activated cyclobutenes can be achieved under thermal conditions (no solvent, RT, several days) or better still under high-pressure (8-15 kbar, RT, DCM or THF).

E

E

E

E

50 140

E BnN3

+

56

BnN~NBn E

57a

E

58

I 300 nm Bn

E

N N ffZ~*N ' N ~ N ' B

,>

0C

E

E

T--

E

N,

+

E I

Bn~ E

Bn

~-isomer

57b

E

C2-isomer Scheme 7

,N N

R.N. Warrener

30

In molecules containing two cyclobutenes, addition of organic azides 26 yielded two adducts, e.g. reaction with 50 with benzyl azide 56 produced the or-isomer 57a in which the N-benzyl substituents were syn-aligned and the C2-isomer 57b in which they were anti-orientated (Scheme 7). The structure of syn-isomer 57a was confirmed by X-ray (Figure 2). The fact that both isomers yielded the same bis-aziridine 58 upon photolysis made separation of the individual triazoline isomers unnecessary. X-ray structure of 57a

~ c(29)

~0(23) .-,. 0c22'~~ c(2s'

;k

T ~ 0(27}~

(~C(26}

C{9) I _~'t,~0(24) C(IOI~a~~,~,~~N(6'

C(33) C ' ~ C ( 4 3 ) C(42)~ C , 4 4 , '

~

(

4

~ _ (~&~C(35'~ C(40' 6''*'~''

'

0(371 ~

C(39'

Figure 2

Ejection of dinitrogen from the triazoline adducts to form the related aziridines was promoted by ultraviolet irradiation (300 nm, benzene) and usually proceeded in excellent yield. An exception was found in the irradiation of the triazoline substrate 59, where cleavage of the cyclobutane ring occurred as the dominant reaction pathway to form the pyridazino norbomadiene 61 (and secondary photoproducts derived therefrom), together with the triazole4,5-diester 62. A role for the pyridazine ring and the 2-pyridyl substituents in stabilising the diradical intermediate 60 has been proposed for this abnormal outcome (Scheme 8). .Py2 I

II (

Py2

,-- ,Bn I

I

F

Py2

"L

P~

Bn

Py2

Bn

,N

S9

80

E = C02Me; Py2 = 2-pyridyl

Scheme 8

Py2 61

62

The Synthesis of Fused 7-Azanorbornanes

31

2.4 ALKENE CYCLOADDITIONS TO RING-OPENED AZIRIDINOCYCLOBUTANES The aza-ACE coupling reaction involved the generation of a 1,3-dipole 66 from ring-opening of the aziridine 65 and the reaction of this intermediate with an alkene reagent to form the 7-aza norbomane. As norbomane sub-structures could be present in both the aziridine and the alkene reagents and a 7-azanorbornane subunit was formed in the coupling process, so knowledge of reagent stereochemistry and the stereoselectivity of the coupling step were required to predict product stereostructures. In this respect, the stereoselectivity of the steps leading to the preparation of the aziridine required validation. Formation of the starting cyclobuten-l,2-diester 63 by [2+2]addition of DMAD at the norbomene n-bond had been established by Mitsudo to occur with exo-stereochemistry (Scheme 9) <79JOC4492>. The azide addition step was highly stereoselective and formed the anti-fused products 64, the structure of which was supported Xray data (Figure 2). This anti-fused geometry was retained in the photoconversion of 64 to the aziridine 65, a step that involved ejection of dinitrogen. Disrotatory ring-opening of the aziridine ring is considered to produce the exo-fused 5-membered 1,3-dipole 66 as a transient intermediate. The dipolar structure of the intermediate was supported by reversible colour formation upon heating the aziridine 67 alone in toluene. This colour was reversible quenched by cooling but rapidly and irreversibly quenched by addition of maleic anhydride. Attack of the dipolarophile always occurred from the under-side ((z-face) of the 1,3-dipole to form the 7azanorbomane in which the N-bridge was syn-related to the X-bridge originating from the aziridine reagent. This stereoselectivity was also found to occur when the methano-bridge in the aziridine was replaced by heterobridges (O,NR) or modified by isopropylidene or spirocyclopropyl substituents.

N+R _

9

k , . . ~ aN3 63 E = C02Me

64

,-

65

E/

66 J attack by dipolarophile

Scheme 9

The facial-selectivity was confirmed in the methano-bridged series by spectral examination of the syn-fused 7-azanorbomene 68 formed exclusively in the 1,3-dipolar cycloaddition of DMAD 32 (in excess) to the N-benzylaziridine 67 (R=Bn) (Scheme 10a). The down-field shift of the Ha methano-bridge proton (Ha 3.60) in 68 is indicative of steric shielding by the proximate N-bridge, thereby confirming the syn-facial stereochemistry. A similar downfield shift is observed in the corresponding O-bridged ACE products, a feature that has been employed earlier as a diagnostic for syn-facial stereochemistry <99OL199>. In the reaction of fused aziridines with alkene dipolarophiles, the opportunity for stereoselectivity as well as facial selectivity arises since exo- or endo-isomers can be formed (Scheme 10). In practice, maleic anhydride 6, N-methyl maleimide and N-phenyl maleimide each reacted exo-stereoselectively with N-benzyl aziridine 69 to form adducts of type 71 (Scheme 10b), the stereochemistries of which were confirmed by NOE measurement between Hb and Hc. Similar reaction of the N-phenyl aziridine 67 with N-Ph maleimide gave a 1:1 mixture of endo-adduct 72 and exo-adduct 73 (Scheme 10c). Adducts 68, 71-73 all exhibited a low-field methano-bridge proton (Ha) in the range 5 3.06-3.60 confirming the syn-facial stereochemistry of the two bridges. Norbomene-type dipolarophiles offered yet another stereochemical consideration owing to the facial selectivity posed by the dipolarophile. While no examples of endo-face attack on

R.N. Warrener

32

norbomene dipolarophiles have been uncovered in reactions with aziridine reagents, the bridge component of the dipolarophile did play a role in the stereoselectivity of the addition. A second factor also contributes to the stereoselectivity, notably the nature of the substituent on the aziridine nitrogen. 5 1.80 5 3.60 a) HsNlf/Ha N/CH2Ph

E -~...~z'='~=~{=~"- NR 67

R=l~n

~

68

Hbl~

/~cO/

b)

69 r

R

~ R=Me, Ph or 6

70 O

5 1.80 5 3.42 Ph Hs,,,,~/Ha ~ /OAc/~L,," I~,E

70, R=Ph ] 6--~hI ratio " 1:1

+

~

;

"E

Hs/Hb

t,,-- 5 1.40 6 3.30 . . . . X=NPh Hs. Ha ~,n2r~,

O Bn

W coupling

p

NR 71

Hb Hbsingle products

5 1.47 5 3.06 Ph Hs .Ha I N .O/~j~ ~X .E

h

,.(3

N P h + ~ O/~ 73 exo-isomer

9 Scheme

10

The stereochemical outcomes could be rationalised by reference to the two types of transition state (TSA and TSB) which arose in the attack of the 1,3-dipole onto the exo-face of the norbornene reagent (Figure 3). In particular, the interaction between R and X was crucial in determining the stereochemical outcome and was further influenced by the aziridine substituent (N-R). This mechanism indicated that the exo-products 73 were preferred except when X and/or R are bulky, and this premise was found to hold experimentally. While no participation of the Y-bridge of the 1,3-dipole was detected in our initial studies, the fact that the stereoselectivity in additions of the N-Z-bridged dipolarophile 37 to the N-Z-bridged bis-aziridine 106 (see Section 2.5) gave mixed adducts involving TSB, indicated that such interactions might also apply.

Transition State A (TSA)

(extended frame product)

.; N~R

-

~

R I

Y

N E

~ 75 exo, exo-isomer

N.---R

Transition State B (TSB)

(bent frame product)

I

a) X=CH2 b) X is C=CMe2

I

p - 74a,b

R i N E

Y E

endo, exo-isomer

Figure 3 Transition states for the reaction of 1,3-dipole 23 with norbomadienes 74a (X=CH2) and 7-isopropylidenenorbomadiene 74b (X is C=CMe2).

33

The Synthesis of Fused 7-Azanorbornanes

Transition state energies have been determined by computation (PM3 and AM1) for the reaction of norbomadiene 74a (X=CHa) and 7-isopropylidenenorbomadiene 74b (X is C=CMe2) with the 1,3 dipoles 23 formed from ring-opening of the N-phenyl and N-benzyl derivatives of aziridine 22 (see, Table 1). These data demonstrate the preference for formation of exo, exoisomers 75 with norbomadiene in the N-benzyl series, however the energy difference between the transition states for the N-phenyl series is much closer and accords with the drop in stereoselectivity. Introduction of the isopropylidene substituent into the 7-position of the dipolarophile favours formation of the bent-frame isomers 76, especially in the N-phenyl series. These predictions accord well with the stereoselectivities observed experimentally. R=Bn

X CH2

AM1 31.6

C=CMe 2

30.2

R=Ph

X CH2 C=CMe2

I

AM1 33.0

linear PM3 36.1

AM1 34.0

34.5

30.8

linear

I ,o i PM3

AM1

38.9

29.4

bent

AAHact AM1 PM3 2.4 1.5

PM3 37.6 33.6

bent

PM3 33.7

0.6

-0.9

AAHact AM1 PM3

,411,,-3.6

04

-5.2

Table 1 Activation Energies in kcal/mol. Reaction of norbomadiene 74 (in excess) with N-benzyl aziridine 67 formed exclusively the all-synl:l-adduct 77. This stereochemistry, confirmed by NOE between Ha and Hb, resulted from attack at the underface of the dipole by the exo-face of the dipolarophile. Similarly, reaction of N-benzyl aziridine 67 with the diacetoxybenzonorbomadiene 30 gave a single adduct 78 (Scheme 11), the symmetrical structure of which was clearly apparent in the 1H NMR spectrum. These stereochemical outcomes demonstrated that the transition state (TSA), in which the methano-bridge was adjacent to the N-substituent, was favoured in the N-benzyl series (X and R small), and in accord with the semiempirical calculations. CH2Ph

CH2Ph

I

I

i o, i +

___ 74a

AcO

77

Ha'-

Hb

Scheme 11

Whereas N-benzyl aziridine 69 reacted with the methano-bridged dipolarophile 39 to give exclusively TSA-product 79, use of the bulkier isopropylidene bridged dipolarophile 38 afforded substantial amounts of the TSB-adduct 84 as well as some of the TSA-product 80, an outcome attributed to unfavourable X)(NR TSA interaction in the latter reaction (X large, R small) (Scheme 12a). N-phenyl aziridines were clearly more sterically demanding than their N-benzyl aziridine counterparts as benzonorbomadiene 39 gave bent-frame product 82, of TSB origin, exclusively on reaction with N-phenyl aziridine 81 (X small, R large) (Scheme 12b). Not surprisingly, 7isopropylidenebenzonorbomadiene 38, which already gave significant amounts of the bentframe adduct 84 on reaction with the N-benzylaziridine 78, gave exclusively the bent-frame adduct 83 on reaction with the N-phenylaziridine 81 (X and R large).

34

R.N. Warrener

a)

~

Bn

NE

Me Me'ff"~

38 ~

E ~

N

B

80 (+84)

b)

E

3

9

.

.

_

NE

38

E

~'--" ~

N

~

n 79

69

R_

Bn

P

Ph

E

39

h

Scheme 12

2.5 TRIDENT FORMATION AND N-BRIDGE HYBRIDISATION 2.5.1 Trident Synthesis

The aziridine-coupling reaction had the ability to introduce bridge-substituents X or Y on either side of the N-bridge in fused 7-azanorbomanes 87 and allowed a rare opportunity to study through-space effects on N-bridge hybridisation and N-alkyl invertomerisation in fused 7-aza norbomanes. x

N

I I I

Y

85

[3]polynorbornane X

X

+

e

NRE

.!

trident86 Y

~ EE

E

NN 91

:

+

R 90

Scheme 13

88

89

The synthesis of XNY-[3]polynorbomanes 85, referred to collectively as tridents owing to their profile resembling a trident 86 (see cartoon at top of Scheme 13) <98MI03>, can be approached in two parity related fashions<00SL98>. In the dibenzo-fused series 87, the Xbridge could be incorporated into the aziridine 88 and reacted with the Y-bridged benzonorbomadiene 89 (Scheme 13, RHS retrosynthesis). Altematively, the Y-bridge could form part of the aziridine reagent 90 and the X-bridge incorporated into the dipolarophile 91 (Scheme 13, LHS retrosynthesis). The N-benzyl aziridines 69, 92-95 which differ only in the nature of the norbomane bridge (CH2, spirocyclopropyl, isopropylidene, oxygen, substituted nitrogen) (Scheme 14), have been prepared and reacted with each of the corresponding benzonorbomadienes 36-40 from which they were derived. All 25 reactions were conducted to produce 14 of the possible 15 different

The Synthesis of Fused 7-Azanorbornanes

35

XNY trident system (ANA not formed). Parity considerations reduce the number of different products from 25 to 15, and some parity combinations were found to be more fruitful than others. The yields of the tridents are summarised in Table 2. It should be noted that the reactions conducted in the absence of solvent (the melt method) have not been conducted for all reactions, but early results indicate that this method gives improved yields of trident.

A. Carbon-bridged R ~

E N

~

E

~

~

Bn

Me Me Bn

69 R -----H

Bn

92

B. Heteroatom-bridged

E

I E= CO2MeI

~

B

n

Z

~

94

B

E

n

95

Seriesa) R=Me Seriesb) R=Bn Seriesc) R=CH2OMe Seriesd) R=Ph Scheme

14

H2

Bn

V

Z

C ~

0 0 0% melt 4% melt

6

CH2 MeTMe

26% melt

NCO2Bn 0

6

N

O

9 + 34*

26

74

22+ 11"

44

51

8 + 24*

67

94

8 + 0.5*

42 62

46 43

12 + 18*

* yield of bent-frame isomer. ** symmetrical XNX compounds are on diagonal and boxed in bold. Table 2 Yields are for isolated products formed by the benzene reflux method (all reactions) or the melt method (no solvent; few reactions attempted). A key factor in the success of these aza-ACE coupling reactions was related to the stability of the intermediate 1,3-dipole. Those containing O-, N-R or isopropylidene bridges were less stable and underwent a competing fragmentation process leading to the formation of isobenzofuran, isoindoles or 6,6-dimethylisobenzofulvene respectively (Scheme 15a). In such cases, the isobenzo systems so generated were isolated as cycloadducts, together with varying amounts of the expected trident (the dipolarophilicity of the 2n reagent was a contributing factor also; the more reactive heterobridged dipolarophiles giving more of the trident product). An important result from the isopropylidene series, was the isolation of an unprecedented adduct 101 derived from the reaction of the 1,3 dipole 96 (X is C=CMe2) with its fragmentation product, 8,8-dimethylisobenzofulvene (IBF) 100 (Scheme 15b). This reaction was a rare example of a [6+4] cycloaddition involving a 1,3-dipole as the 4n reagent. Further, the result added support for the existence of the 1,3-dipolar intermediate 96 and indicated that it had a finite lifetime prior to fragmentation, sufficient to allow reaction with isobenzofulvene 100, itself a transient species that is too short lived to be detected in solution <81AJC628,

36

R.N. Warrener

82AJC757>. This reaction is a curious example of an transient intermediate reacting with a transient product of its own making!

E

~ 93b-95b

~

E NBn E

xiso

~

XisNR

96b

97X=0

+

=.

Me

Me,,~/

NBn 99E +

X is C=CMe2~ M e 100

Me

E

,..

99

Bn N E Me

[6+4]

1,3-dipole 96 X is C=CMe2

H ,iM e

100 Scheme 15

2.5.2 N-Invertomerisation

J Oynamic 102

102'

~ AG$3050 -(kJ/m~ t ~"""""'~"~'~-~ 30- !- ~

ONO

115 110 (AM1) = 9 o~ (av)angle X-Ray CNC

Figure 4 The N-benzyl XNY tridents formed two classes of invertomers. In those cases where X and Y were identical, the N-benzyl substituent was dynamic and oscillated between the two degenerate invertomers 102/102' in solution, a situation which was retained even when cooled to -100 ~ The angle c~ which represents the offset from trigonal nitrogen <98TL7877> became smaller as the steric size of X increased and the N-bridge geometry tended towards planar nitrogen (sp2 hybridisation) (see diagram, Figure 4). A different situation existed when X and Y were not the same since two individual invertomers 87a and 87b were possible. In all cases studied, one invertomer was dominant (Figure 5). The invertomer preference was established using a combination of VT NMR and NOE spectroscopy. A bridge-substituent hierarchy was established in the N-benzyl series in

The Synthesis of Fused 7-Azanorbornanes

37

which the substituent preferred to be positioned proximate to the bridge of least steric demand, i.e., to the RHS of the list CH2 > A > C=CMe2 > O --, NR. In all cases, the invertomer preference that was established by NMR in solution, corresponded to the invertomer of lower energy of the pair as determined by AM1 computation. Additionally, this same invertomer preference corresponded to that found in the solid state by X-ray crystallography (5 structures were available for comparison <00OL721>).

i

-CH2-Ph

Ph ~'CH2

87a favoured invertomer IX

87b unfavoured invertomer

CH2 > C3H4 > C=CMe2 > O / NR ~ y J

Figure 5 The change in N-hybridisation of these various tridents has been studied by 15N-labelling of the N-benzyl bridge where it was established that increased planarity of the N-bridge shifted the 15N-resonance to higher field <01MI01>. 2.6 MULTI-AZA-BRIDGED [n]POLYNORBORNANES The high stereoselectivity exhibited by the CH2-bridged aziridine 69 and the NZ-bridged aziridine 95 in their aza-ACE reaction with N-Z 7-azabenzonorbornadiene 37 to form the synfacial adducts 102 and 103 respectively (Scheme 17), set the scene for the production of extended-frame poly(7-azanorbomanes) using the dual extension approach. a) C48 C49

(339 C47

C46

C44~I~ " ~

, 08

~, ~ 3

C32 C3~A

b)

C381~ , i 04 E~

c24 oiN2.'

os~.,,~2,

pc35 ~12

~

clo~"

N1

-06

~2 . . . . c4't~

C18~

~ 7 c~6

C40

103

C5~C 7 C5" ~ C 6C7

c3oA 0 ( 3 ~ ........ " / '" . ,..~,.

~

(

1

~c.23~

~.T C(24,

4

1

(,4

o(33~ ".~(,. .InQk 1 U i::JD

c{6)-N,~c(lo) -- ]~;~..'" c(71'~C(~(9)

Figure 6 X-ray structures of NNN-trident 103 (note disorder in the position of one of the benzyl groups) and ON3(O)-[5]polynorbomane 108b

The exo, exo-stereoselectivity of the coupling process was confirmed by X-ray crystallography of the NNN-trident adduct 103 (Figure 6a), which substantiated the syn-facial stereochemistry. The same exo, exo-stereoselectivity of the coupling process was also evident in

38

R.N. Warrener

the dual aza-ACE reaction of the N-Z dipolarophile 37 with the methano-bridged bis-aziridine 58 which formed the NaCNZ-[5]polynorbomane 105 as the only isolated adduct in 54% yield. The Z-protecting groups (but not the N-benzyl group) in these adduct can be removed by hydrogenolysis (Pd/C), e.g. 104 yielded the mono N-Bn trident 107 in 96% yield. Somewhat disappointingly, the stereoselectivity of the aza-ACE reaction dropped off when the N-Z bridged bis-aziridine 106 was employed in coupling reactions with either the O-bridged dipolarophile 36 or the N-Z bridged dipolarophile 37. Three stereoisomers were produced in each case and these were separated by chromatography into individual products 107a,b, 108a,b and 109a,b (Scheme 17). The structure of the least 'symmetrical' stereoisomer 108b in the ON30-[5]polynorbornane series was determined by X-structure analysis (Figure 6b). Significantly, the outer N-Z bridges are non-planar (one inward and one outward facing), whereas the central N-Z bridge is planar. In contrast, all three N-bridges are non-planar in the NNN-trident 103. There is good precedent for non planar geometry in N-Z bridges in 7-aza norbornanes and related alicyclic structures.<98TL865> ~ N E

Bn

Z N so,e t

102 Z

I~nE

,o%o0% 0 0

Z

H

103

54%

BnN~

E ~

Z N N

E

B

Bn Z N/E N

^ 105

E

E

sole adduct

X

Bn I NE

X

36 or 37

Hal, I

NE

Z

N

Bn I N

Z

N

X

85 ~

n

106

Bn

H

104

Bn Z \N=

E

BnE

Bn

NOEJ

I

N.E

major product Product ratio 107:108:109 S e r i e s a ( X = N Z )

ratio 1 " 2 " 1 "

Hb 107 Bn I N. E

Z ,

Ph ~'-Hc N/~ . E Hd NOE

Series b (X= O) ratio 1 " 5 " 1

Scheme 17

The structures of the [5]polynorbomanes were assigned on the basis of VT NMR spectroscopy to distinguish the formal 'symmetrical' forms e.g., syn-facial product 107a and cavity structure 109a, from the hnsymmetrical' isomer 108a. The interesting feature of adducts 107a-109a was the fact that the central N-Z group was locked into one atropisomeric position by the flanking N-Bn bridges and remained so until monitoring was stopped at 90 ~ Accordingly, all the 'symmetric' products were unsymmetrical about the short axis of the molecular frame and the 'unsymmetrical'product 108a was further asymmetrised. The broadening and complexity of

The Synthesis of Fused 7-Azanorbornanes

39

the NMR specra at room temperature was associated with the restricted rotation of the N-Z substituents at the termini and these became more 'symmetrised' as the temperature was increased. This allowed structural assignments to be defined on the basis of VT NOE measurements, in particular the interrelation between the endo-protons Ha and Hb in 107a (two such correlations) and between the benzylic methano protons Hc with the exo-proton Hd in the cavity structure 109a.

2.7 THE PREPARATION OF POLAROFACIAL [n]POLYNORBORNANES The incorporation of O-bridges or N-bridges into [n]polynorbomanes afforded molecules which had the potential to display unusual polarity since the top face that contained the heterobridges exhibited hydrophilic properties and the endo-face retained the lipophilic properties of the [n]polynorbomane. There were distinct synthetic advantages when combinations of O-bridges and N-bridges were required in the target molecule, since alternative dipolar cycloaddition approaches could be utilised. The aza-ACE approach employed the addition of O-bridged dipolarophile 36 with NR-aziridine 94 to form ONO-trident 110 (Scheme 18, Type A). The other method utilised the ACE reaction whereby the N-Z 7-azanorbornadiene 37 (or 114) was reacted with the O-bridged cyclobutene epoxide 113 to form the bridge-inverted OON-trident 111 (or 112) (Scheme 18, Type B). The ACE method had the advantage of providing direct access to terminal N-H derivatives by employing the NH 7-azabenzonorbornadiene 114. While the Z-protecting group could be removed by hydrogenolysis, an all NH-bridged system has yet to be developed. The aza-ACE approach yielded products in which the central N-bridge contained either an N-alkyl or N-aryl substituent. Attempts to circumvent this by preparing N-Z aziridines was thwarted since addition of azidoformate esters to cyclobutene-l,2-diesters failed (see, Section 2.3), although such compounds can be used to prepare 5-azabicyclo[2.1.0] pentanes by photo-induced addition of carbomethoxy nitrene to unsubstituted cyclobutenes <96CC1519>. An approach using the Nmethoxymethyl protecting group offered partial success (see, Section 2.10). Type A

Type B

110

Position Isomers

R

111 R=Z; 112 R=H

I R=Bn, Me

IR=Z,H

o

36

N

aziridinecoupling 94 (azaACE reaction)

113

epoxidecoupling 37 R=Z (ACE reaction) 114 R=H

Scheme 18

The stereoselectivity established for the trident series, was tested using the C-bridged bisaziridine 58 which produced the ONCNO-[5]polynorbomane 115 by reaction with the Obridged dipolarophile 36 (two equivalents) in 70% yield (Scheme 19). However, as noted above, replacing the central C-bridge with the N-Z bridge caused loss in stereoselectivity. Accordingly the type B approach was preferred.

R.N. Warrener

40

Bn

Bn

N

r-ffl

36

=

70%

115

Scheme19

In a route designed to make more extended heterobridged [n]polynorbomanes, the bisaziridine 118 was prepared from the dioxasesquinorbomadiene anhydride 116 <97T3975>. The related bis-epoxide 121 was secured, in the N-methoxyethyl succinimide series, from the biscyclobutene 120 that was derived from 119 (Scheme 20) using the standard protocols described earlier. It is noteworthy that only the aziridine protocol tolerates the anhydride group. j.x,,...~ O ~3x..~

~ O

E

Ru[0]

O

DMAD

E

O

E

E BnN3

Bn 118

117

O

E

E

BnN~

hv

~

116

i) MeOCH2CH2NH2 ii) NaOAc/Ac20 O

O

~

E

tBu O-

E

9

tBuO2H

OC i NCH2CH 9 2OMe 119

OCt, i

~'NCH2CH2OMe 120

121

Scheme20

NCH2CH2OMe

The two internally-positioned O-bridges present in these reagents were introduced to achieve extended-frame dipolarofacial systems. Their potential to achieve syn-facial coupling was established by reaction of bis-aziridine 118 with norbomadiene 74a to produce the CNOZNC [6]polynorbomadiene 122 in 35% yield (Scheme 21). Again our efforts to incorporate Nbridges into the frame using N-Z 7-azabenzonorbornadiene dipolarophile 37 to react with bisaziridine 120 were compromised to some extent by the loss in stereoselectivity in the cycloaddition protocol. This resulted in the production of all three stereoisomers 123-125, however the desired syn-facial product 123 was the major isomer.

Aza-ACECouplingl~~

+ ,~~

35o; o ~

"

74a IE = CO2Me j

25%

C02 Bn

ratio

37

E Z N

~

Bn N E

123:124:125 ~

N

Bn

N E

124

O

O

O

Bn

Bn

N E

N E

ZN

O

u

Bn N

Z N

123 OC,.~

= 4.3:3.7;1 Z

O ,~

122

Scheme21

O

125

O

N E

The Synthesis of Fused 7-Azanorbornanes

41

The low yields of isolated products in this series was attributed to the presence of the anhydride functionality which precluded purification by chromatography. Accordingly, the anhydride was converted to the related imide for other applications. As discussed above, the Type B coupling involving ACE reaction between N-bridged dipolarophiles and cyclobutene epoxides was a more reliable stereoselective approach to achieve exo, exo-coupling. In keeping with this evidence, reaction of the O-bridged bis-epoxide 126 with 7-azabenzonorbomadiene 114 afforded the syn-facial NO3N-[5]polynorbomane 127 as the exclusive product (Scheme 22). Furthermore, thermal cycloaddition of the dual O-bridged bisepoxide 121 with N-Z 7-azabenzonorbomadiene 37 fumished the syn-facial NO4N[6]polynorbomane 128, the longest dipolarofacial system yet produced by direct coupling. Similarly, reaction of 121 with the trident dipolarophile 77 furnished the CNCO4CNC[10]polynorbomane 129, again in record length. ACE Coupling E

E

+~L~-~~

o.

.

.

.

H N

0

114

126

~

127

Z

37 77

O EO

,~cO

Bn

N E

0 E

0

0

0 E

O=N

H

E

Bn N

Ac

A

Longest syn-facial N-bridged polynorbornane yet produced

Scheme22

2.8 INTERNAL N-BRIDGED CAVITY SYSTEMS In Section 2.6 and 2.7, the synthesis of the internally N-bridged cavity systems 109a, 109b and 125 were reported, but always as a minor product admixed with other stereoisomers. To overcome this problem, the reaction sequence outlined in Scheme 23 was devised to produce 'southern' cavity 134, exclusively as a single product. The sequence featured two stereoselective steps and commenced with the reaction of cyclopentadiene 131 with N-benzoyl 7-azabenzonorbornadiene 130 which produced the exo, endo adduct 132. This is a general reaction that worked equally well with O-bridged norbomenes <99OL203>. Having positioned the N-bridge on the under face of the norbomene ring in dipolarophile 132, the second stereoselective step, ACE coupling of norbomene 132 with bis-epoxide 133, geometrically positioned the N-benzoyl bridges so that they were inwardfacing in the coupled product 134. The structure of the product 134 was confirmed by X-ray analysis (Figure 7). The geometry of the N-bridges are planar in 134 and the phenyl rings are outward facing away from one another to produce a single atropisomer. In solution, however, the conformational rotation of the benzoyl groups is too rapid to observe individual atropisomes by 1H NMR at normal probe temperature.

R.N. Warrener

42 ~OPh

H~ 5.84, 6.27

130

131

E

+

h 'j

Hd

E

132

132

curved frame, see X-ray Figure 7

30% 135 ~

133 E=CO2Me

" N-bridged norbornene

Hb He

134

dual epoxide

Scheme 23

C(61) (~60)

c~ss,I ~

0(55) (:~

C(39}

~

0(c~4 7' ' ~ ('~ 0(51)

c(46),~(~4~'w

cc~ oc593.~/~,~ ~ccl~l~1201~K~cts0~

C(331,~L.~ ~t,~

~

~

.....

r

C(65)0(63, ~

C(7L/I 4 ,

C1741

c,~;~ ~, * 'c,,,, C(101

Figure 7 X-Ray structure of N-bridged cavity 134 <01TIA65> The synthesis of cavity systems of the altemative horthem' type, outlined in Scheme 24, involved the Diels-Alder addition of tetrafluoroisoindole 136 to the cavity bis-(cyclobutene-l,2diester) 135 <97T3975> to produce the cavity structure 137. The stereoselectivity of the DielsAlder step, established in model compound reactions <98TL3083>, ensured that the N-bridges were positioned with inward-facing geometry. Molecular modelling (AM1) indicated that the bridge hetero-atom separations in 137 were as follows: N-N = 8~, N-O = 4.6.,~, O-O = 2.7 ,~. In addition, the invertomer preference of the Nbenzyl groups position them over the aromatic rings thereby ensuring that the lone pairs on the heteroatoms are concentrated within the cavity section of the molecule. F4

NBn

136 OC"=giCH2CH2OMe 135

Bn

..

14 kbar 1 week 45%

~'~,=/I E

o

o

/,,,[-'k E

137 O , INCH2CH2OMe

Scheme 24

The Synthesis of Fused 7-Azanorbornanes

43

2.9 MOLECULAR MODELLING While there are several compounds in this presentation for which X-ray structures have been determined, it was important that a knowledge of the geometry of structures could be obtained and assessed against design criteria, even prior to preparation. Molecular modelling became a regular feature of our study once it was acertained that modelled structures were good guides as assessed against X-ray derived data. Modelling was performed at the AM1 level and usually conducted on ring systems devoid of the ester groups attached to the frame of the [n]polynorbornane since the rotational freedom of these groups made calcuations lengthy and more prone to be trapped in localised energy minima.

L

NCN

Figure 8 Molecular modelled structures (AM 1) for representative [9]polynorbornadienes The syn-fused isomers in the [n]polynorbomane series exhibited a curved structure which was most pronounced in the parent system and attributed to H)(H interactions between adjacent methano-bridges (Figure 8). Removal of such H)(H-interaction by replacement of alternate methano-bridges with oxygen-bridges considerably reduced the interaction and the curvature of the frame was shown to straighten. Further straightening was observed when all the methanobridges were replaced by oxygen, but even then, some curvature was retained. Replacement of the methano-bridges with NH-bridges also affected some straightening while introduction of substituents onto the N-bridge reintroduced frame curvature. Modelling studies indicated that the nature of the N-substituents (NBn>NMe>NH) could be used to induce controlled frame curvature into the aza[n]polynorbomanes. Modelling studies were employed to find norbomane-related BLOCKs of suitable geometry to be used in coupling protocols to provide rod-like molecular frames. Dual alkenes 138-140 (Figure 9) were identified as suitable alkene BLOCKs and the bis-epoxide 141 derived from the dehydro-sesquinorbomadiene 138 has already found use as a reagent in ACE coupling protocols <98TL5277>. The ethano-linked system 139 was less successful as the bridgehead substituents

44

R.N. Warrener

reduced access to attack at the n-bonds <99MI02>. The third member 140 has yet to be investigated in detail.

,~~ E

138

E

N N 139

E ~ O E

E

140

Figure 9 Building BLOCKs with rod-like structure The CO[n]polynorbomane frames have found use in the preparation of cavity bis-(crown ether) systems and modelled structures of the frames used in that study are shown in Figure 10. The curvature of the frame remained constant in the three systems, however the phenylene rings attached at the termini changed relative orientations as the frame size lengthened such that the centre to centre distance between the aromatic rings varied only slightly while their orientation moved from highly divergent in [7]polynorbomane 142, towards parallel in [ll]polynorbomane 144. The [9]polynorbomane 143 was of intermediate geometry.

a)

b)

142

18.7

143

144

20.7 A

Figure 10

Modelled (AM1) geometry of CO-bridged [N]polynorbornanes a) O(CO) 3[7]polynorbomane 142, b) O(CO)4-[9]polynorbomane 143, c) O(CO)5-[ll]polynorbomane 144

2.10 TRANSANNULAR INTERACTIONS IN N-METHOXYMETHYL 7-AZANORBORNANES In experiments designed to allow access to NH-compounds by controlled removal of the Nsubstituent in 7-azanorbomanes, the use of the N-methoxymethyl group has been investigated <01SL202>. The required N-methoxymethyl aziridines were prepared via the addition of Nmethoxymethyl azide to cyclobutene-l,2-diesters, followed by photo-induced loss of dinitrogen. In the methano-bridged series, reaction of benzonorbomadiene 39 with the C-bridged Nmethoxymethyl aziridine 145 yielded a symmetrical product 149 devoid of the N-substituent following chromatographic work-up (Scheme 25). Inspection of the crude reaction product by 1H NMR confirmed that the N-methoxymethyl group was intact at that stage, thereby indicating that hydrolysis of the initially-formed adduct 147 to the NH-product 149 occurred during the chromatography, possibly via an intermediate of type 148. A similar NH-bridged ONO-trident 151 was formed from the reaction of 7-oxabenzo norbomadiene 36 with the O-bridged N-methoxymethyl aziridine 146. However, in light of the bridged products discussed below, the mechanism for formation of the NH-compound may implicate neighbouring group participation of the O-bridge and a cyclic intermediate such as 150.

The Synthesis of Fused 7-Azanorbornanes

X

~~

' ~ N I

45

?H2OMe

E

column Si02

39

145 X=CH2 146 X=O

CH2

H

148

isolated product 149

F

0

0

N~"~0 +

H ~ .E 0

isolated product 151 Scheme 25

When the N-Z 7-azabenzonorbomadiene 37 acted as the dipolarophile in the reaction with the methano-bridged aziridine 145, the reaction yielded a novel class of product 154, in which the two N-bridges were linked by a new methano bridge (Scheme 26). Several features were noteworthy in this process, a) the preferred invertomer of trident 152 positioned the Nmethoxymethyl group proximate to the adjacent N-Z group; b) the N-Z group adopted a nonplanar configuration promoted by the steric interaction with the methoxymethyl group (the Xray structure of the related N-benzyl Na-[3]polynorbomane 103 provided the precedent for this premise); c) the lone pair electrons of the nitrogen in non-planar N-Z systems were not delocalised by resonance and acted as the nucleophile for C-N bond formation; d) the charge on the quaternary ammonium bridge facilitated the loss of the Z-group by nucleophilic attack at the CO and generated the N-methano-N product 154 as a neutral species.

1~~

1O037 ~

r l

~

MeO\ ~k-"'-CH2 -Z N" EL":N/

hydrolysis_ ~ L

-]

1

E 154

153 Scheme 26

Neighbouring group attack on the N-methoxymethyl group could also involve C=C nucleophiles resulting in CNC-bond formation. Thus, reaction of the isopropylidene-bridged Nmethoxymethyl aziridine 155 with 7-isopropylidene benzonorbomadiene 38 gave an isomeric mixture of products 158 and 159, neither of which retained the N-methoxymethyl group (Scheme 27). Again formation of dipolar adducts 156 and 157 is presumed to occur first.

R.N. Warrener

46

Me

MeP

EE ~ENcH20M

Mef

100 ~

e

?H2~M.~.ef'

1

38

155

156

+

bent-frame isomer 157'

Me

Me~ I]

N/~,/~-Me

158

Scheme 27 These isomers resulted from the non-stereoselectivity of the initial coupling process typical of the aza-ACE reactions of the 7-isopropylidene-bridged dipolarophile 38, while molecular weight measurements and the presence of an isopropenyl group in the 1H NMR of each product supported C,N-methano-bridge formation. Such products were considered to arise via the bond reorganisation depicted by the arrows in adduct 156 in which one of the isopropylidene n-bonds acted as the nucleophile to attack the methylene carbon of the adjacent N-methoxymethyl group. An interesting situation arose when the N-Z bridged dipolarophile 39 was reacted with the isopropylidene-bridged N-methoxymethyl aziridine 155. In this case, the primary adduct 160 (Scheme 28) containing the N-methoxymethyl group was flanked by different neighbouring groups; an isopropylidene group potentially yielding 161 and a N-Z-bridge potentially yielding 162. The practical outcome of this reaction was the exclusive formation of the C-N linked product 161.

~

N

CH Me ~ 3 NE 162

~ ~

Z ~

OMe pu.-H /(~H2Me~""2 observed NI E , ~,~ 160

Z N

NE

Me

161

Scheme 28

2.11 ATROPISOMERISM IN BIS-(7-AZANORBORNANES) The restricted rotation of tertiary amides and carbamates is a well-recognised property <78T13277>. Such CO-NR2 rotations, which have energy barriers in the 40-70 kJ/mol range, are clearly manifested in their 1H NMR spectra since the resonances are often broad at normal probe temperatures. The restricted rotation of N-acyl 7-azanorbomanes has been reported <98TL865, 85JCS(P1)1277> as well as N-sulfonyl <98TL7877>and N-NO <00TL3637> derivatives. When two such groups are present in the same molecule the opportunity exists for syn- and anti-atropisomers to be formed. A case of such atropisomerism was first detected by our group in the N-benzoyl series by reaction of the N-benzoyl-bridged aziridine 163 with the Nbenzoyl 7-azabenzonorbomadiene 130 to form trident 164 (Scheme 29) <01TL465>.

The Synthesis of Fused 7-Azanorbornanes COPh

N

~

I

N

163 Ph

-o~"

E

1O0 Bn

47

COPh Bn I I N N =

oC

COPh I N

130

164 Ph 0-o1~ Bnl Phlf' +N N ,- N+

Ph

~ -o.~

syn-isomer 164a

anti-isomer 164b

Scheme 29 VT NMR showed that N3-[3]polynorbomane 164 existed as an equilibrium mixture of the

syn-atropisomer 164a and anti-atropisomer 164b (ratio 1: 1.7). NMR spectroscopy allowed distinction between the isomers on the basis of symmetry. The syn-isomer 164a exhibited two well-separated ester methyl resonances (5 3.67, 4.05) as predicted for the isomer with Cssymmetry, whereas the anti-isomer 164b displayed a single ester methyl resonance (5 3.85) in accord with that expected for a compound with C2-symmetry. It was not possible to isolate the separate atropisomers in this system since the energy barriers governing rotation were too low. More success was obtained in the NZ, NZ-diazasesquinorbomane series where it was possible to lock the N-Z isomers in conformations that were stable in solution to well above 100 ~ Thus, reaction of the N-Z 7-azanorbomadiene-2,3-anhydride 165 with N-Z pyrrole 166 yielded a single stereoisomer 167 in which the N-Z bridges were syn-facially related (Scheme 30). 1H NMR spectroscopy indicated that the N-Z groups were undergoing rotation in solution at room temperature and provided evidence for syn- and anti-atropisomers being present at lower temperature. C02Bn CPD131

~N

NI

:c:O o

0

Bn

C02Bn ?02Bn N

,,~176 0%/

165

-

_C02Bn

-O '

OBn

-O '

O13n

N

167

CPD 131 75%

OBn O -Or 131IOr

o%, 17'0

syn-atropisomer 168 Scheme 30

anti- atropisomer 169

Reaction of adduct 167 with excess cyclopentadiene 131 occurred with high exo, endostereoselectivity to furnish isomeric 2:l-adducts 168 (syn-isomer) and 169 (anti-isomer) (ratio 1:5), which could be separated by chromatography. These isomers contained the same ring structure and differed only by the relative geometry of the N-Z groups. Each N-Z bridge was

R.N. Warrener

48

flanked by an etheno-bridge on one side and an N-Z bridge on the other that locked the N-Z groups into a fixed conformation. The structures of these adducts were assigned on the basis of their symmetry as evaluated by 13C NMR. The syn-atropisomer 168 had a mirror plane and the carbonyl groups of the anhydride appeared as separate resonances (5 170.52, 170.78) whereas the anti-atropisomer 169 had a C2 axis and a single CO resonance (6 170.50). While the structure of these atropisomers rested on spectral evidence alone, the structure of the related single NZ-bridged adduct 170 flanked by two etheno-sentinel bridges was confirmed by X-ray structure analysis (Figure 11). Adduct 170 was formed by addition of cyclopentadiene 131 (in excess) to anhydride 165. Significantly, the N-Z group which is flanked on both sides by an etheno-bridge had adopted planar geometry (sp2-hybridised N), precisely that expected to be present in the atropisomers 168 and 169. In both atropisomers, the N-Z groups were locked in a single configuration and stable up to 100 ~ Further, the geometry of the N-Z group was manifested in the wide separation of the proximate etheno-bridge proton resonances. C(31)

~

~

C130)

, , ~ _ . . , z , , , , ~ c(29)

C(281

~c,,o,k( 6 )lc, , I.

C(13)

~(17, C(14, t;'~l' /C(2) I .... ~' C(16) / I C(20)~ ~ ) 0 ( 2 1 ) 0(22) 0(19) Figure 11 X-ray structure of adduct 170 In completing this survey, we report the first synthesis of an NH,NH-diazasesquinorbomane 173 has been achieved and its structure confirmed by X-ray crystallography (Figure 12). The synthesis involved addition of perfluorobut-2-yne 47 to N-Z pyrrole 166 under thermal conditions to produce the 7-azanorbomadiene 171 (Scheme 31). (~O2Bn

166

.CF3

47

Reaction conditions: i) heat 90~

C02Bn I N

171

60 ~

166

?02Bn ?02 Bn N N

172

H I N

H I N

173

sealed tube, 6h; ii) 166, 14 kbar, RT, 4 d; iii) EtOH, 10% Pd/C, 30 psi, 3d

Scheme 31 Further reaction of 7-azanorbomadiene 171 at room temperature with NZ pyrrole 166 under high pressure, followed by removal of the Z-protecting groups by hydrogenolysis yielded the deprotected diazasesquinorbornane 173. The last step required prolonged treatment with Pd/C (10%) in ethanol at room temperature and moderate pressure (30 psi) for 3 days, conditions that

The Synthesis of Fused 7-Azanorbornanes

49

also caused hydrogenation of the alkene groups. More forcing thermal conditions could not be employed because of the instability of 172 towards regeneration of the starting materials 166 and 171 in a retro Diels-Alder reaction 00.5 at 60 ~ = 103 min).

C(37) C136)(~~C1381 ~ , C(261 0(35)~~C(39} ._..%(401 0 ( 2 8 ],~~C(25}C(24)~..._,.,jr' c(34, ~''*u' C(29) ~ _j~),221& .~ 0(33, 0'23)~C(21,0(32~ 0(31,

H(12)

,~ c(s) "~(41 I

R171

~~)

H(ll}

c(81~) :(7)

~ F1161

~

/.f~~(91

c(io)

F{201

-"Fi20;-"/u,2) [ ~.,Em~C(S)

~E.-ZC(17)_.~ C(13)'~F'(lS)

Figure 12 X-ray structures for adduct 172 and the derived NH,NH-diazasesquinorbomane 173 2.12 CONCLUSION This survey confirmed that the 7-azanorbomanes have a rich chemistry especially when incorporated into [n]polynorbomane scaffolds. The synthetic versatility of the aza-ACE reaction to produce such systems has now been placed on a firm footing, and when complemented with the related ACE coupling reaction, formed an unparalleled entry to a wide variety of structural types. The ability to control the stereoselectivity of the aza-ACE coupling protocol by variation of N-substituent on the aziridine together with the more subtle changes in frame curvature available by variation of C-, N- and O-bridges has immediate application to the controlled production of new molecular architectures. The discovery of stable atropisomers in NZ-bridged diazasesquinorbomanes is new and has the potential to be applied to N-bridged [n]polynorbomanes, Further, the ability to make XNY-tridents and their use to study through space effects on the hybridisation of 7-alkyl-7-azanorbomanes confirmed the power of polyalicyclic model structures to help understand fundamental problems such as Nhybridisation. Neighbouring group participation between adjacent bridges has opened yet another avenue for the preparation of new ring structures. The use of [n]polynorbomane molecular frames to hold effector groups at definitive separations and angular relationships has an important role to play in the study of the mechanism for energy and electron transfer, the preparation of molecular switches, the design of hosts for guest encapsulation, the preparation of bioactive bis-intercalators and the ground-breaking preparation and applications of alicyclophanes.

50

R.N. W a r r e n e r

2.12 A C K N O W L E D G E M E N T S I wish to thank Professor Doug Butler for the stimulating conversations and ideas that flowed between us during the course of this research and much that we developed in partnership over the many years of our collaboration. Dr John Malpass deserves special mention since he made several trips to the CMA in Australia and spent much time helping with the important areas of physical organic chemistry, and also for his early guidance of Guangxing Sun. Dr Martin Johnston is also singled out for mention because of his unstinting willingness to help the group at the CMA and especially for his NMR expertise, while still conducting a vigorous research program in porphyrin chemistry. Dr Davor Margetic is another stalwart who has the rare talent of being both a 'green-fingered' synthetic chemist as well as a top class computational scientist. Special thanks are reserved for Dr Guangxing Sun (PhD student 1997-2000) and Malcolm Hammond (honours and former PhD student 1998-1999) who conducted the majority of the experimental work. Dr Alan Lough, Toronto University, Canada is thanked for the X-ray structure detterminations. Funding support from the Australian Research Council and Central Queensland University was an important factor in the work presented becoming a reality, rather than another idea destined to remain scribbled on the back of an envelope or locked in an unsuccessful grant application. 2.13 R E F E R E N C E S 66JOC3924 66JA4273 71JA1777 79JOC4492 81Hl131 81AJC628

H.W. Heine, R. Peavy and A. J. Durbetaki, J. Chem. Soc. 1966, 31,3924. C.D. Smith, J. Amer. Chem. Soc. 1966, 88, 4273. R. Huisgen and H. Maeder, J. Amer. Chem. Soc. 1971, 93,1777. T. Mitsudo, K. Kokuryo, T. Shinsugi, Y. Nakagawa, Y. Watanabe and Y. Takegami J. Org. Chem. 1979, 44, 4492. R. Huisgen, K. Matsumoto and C. H. Ross, Heterocycles 1981,15, 1131. R.N. Warrener, M. N. Paddon-Row, R. A. Russell and P. L. Watson, Aust. J. Chem. 1981, 34,397.

82AJC757 83JOC4968 83JHC1 85JCS(P1)1277 92JA3475 93TL7301 94CJC2108 95JFC61 95Sl147 96CC1519 96CRVl179 96JOC9072 97AAl19 97CC1023 97SL196 97T3975

R.N. Warrener, D. A. C. E. Evans and M. N. Paddon-Row, Aust. J. Chem. 1982, 35,757. K. Maruyama and T. Ogawa, J. Org. Chem., 1983, 48, 4968. T. Zaima, Y. Matsunaga and K. Mitsuhashi, J. Heterocycl. Chem. 1983, 20,1. M.G.B. Drew, A. V. George, N. S. Isaacs and H. S. Rzepa,,J. Chem. Soc., Perkin Trans. 1,1985, 1277. T.F. Spand, H. M. Garraffo, M. W. Edwards and J. W. Daly, J. Am. Chem. Soc. 1992, 114, 3475. G. Pandey, G. Lakshmaiah and A. Ghatak, Tetrahedron Lett. 1993, 34, 7301. K. Matsumoto, H. Iida, U. Hirokazu; T. Uchida, Y.Yabe, A. Kakehi and J. W. Lown, Can. J. Chem., 1994, 72, 2108. M.G. Barlow, N. N. E. Suliman and A. E. Tipping, J. Fluor. Chem. 1995, 73, 61. I. Coldham, A. J. Collis, R. J. Mould and D. E. Robinson, Synthesis, 1995,1053. R.N. Warrener, A. S. Amarasekara and R. A. Russell, J. Chem. Soc., Chem. Commun. 1996,1519. Z. Chen and M. L. Trudell, Chem. Rev. 1996, 96,1179. J.A. Leonetti, T. Gross and R. D. Little, J. Org. Chem. 1996, 61,9072. R.N. Warrener. and D. N. Butler, Aldrichim. Acta 1997, 30, 119. R.N. Warrener, A. C. Schultz, D. N. Butler, S. Wang, I. B. Mahadevan and R. A. Russell, J. Chem. Soc.,Chem. Commun. 1997,1023. R.N. Warrener, D. Margetic, E. R. T. Tiekink and R. A. Russell, Synlett, 1997,196. R.N. Warrener, S. Wang and R. A. Russell, Tetrahedron, 1997, 53, 3975.

The Synthesis o f F u s e d 7-Azanorbornanes 98JPE777

98MI03

98SL566 98SL588 98T2289 98TL7877 98TL5277 98TL3083 98TL865 99OL199 99OL203 99MI02 99TL4111 00EJO3363 00NPR131 00OL721 00OL725 00OL4003 00SL98 00TJC59 00TL4671 00TL3637 01SL202 01TL465 01MI01

51

D. L. Donnelly-Roberts, P. S. Puttfarcken, T. A. Kuntzweiler, C. A. Briggs, D. J. Anderson, J. E. Campbell, M. Piattoni-Kaplan, D. G. McKenna, J. T. Wasicak, M. W. Holladay, M. Williams and S. P. Americ, J. Pharmacol. Exp. Theor. 1998, 285,777. R. N. Warrener, D. Margetic and R.A. Russell, Article 014, Electronic Conference on Heterocyclic Chemistry 98" 1998, H.S. Rzepa and O. Kappe (Eds), Imperial College Press, ISBN 981-02-3594-1. (http://www.ch.ic.ac.uk/ectoc/echet98/pub/O14/index.htm) R. N. Warrener, D. N. Butler and R. A. Russell Synlett, 1998, 566. D. N. Butler, J. R. Malpass, D. Margetic, R. A. Russell, G. Sun and R. N. Warrener, Synlett, 1998, 588. D. R. Gauthier, Jr., K. J. Zandi and K. J. Shea, Tetrahedron, 1998, 54, 2289. T. Ohwada, I. Okamoto, K. Shudo and K. Yamaguchi, Tetrahedron Lett. 1998, 39, 7877. D. Margetic, M. R. Johnston, E. R. T. Tiekink and R. N. Warrener, Tetrahedron Lett., 1998, 39, 5277. J. R. Malpass, J. Fawcett, G. Sun and R. N. Warrener, Tetrahedron Lett. 1998, 39, 3083. T. Ohwada, T. Achiwa, I. Okamoto and K. Shudo, Tetrahedron Lett. 1998, 39,865. R. N. Warrener, D. Margetic, A. S. Amarasekara, D. N., Butler, I. D. Mahadevan and R. A. Russell, Org. Lett., 1999,1,199. R. N. Warrener, D. Margetic, A. S. Amarasekara and R. A. Russell, Org. Lett., 1999,1, 203. D. Margetic, M. R. Johnston and R. N. Warrener, Third Internat Electronic Conference on Synthetic Organic Chemistry, 1999, no 16. R. N. Warrener, D. Margetic, G. Sun, A. S. Amarasekara, P. Foley, D. N. Butler and R. A. Russell, Tetrahedron Lett. 1999, 40, 4111. R. N. Warrener, Eur. J. Org. Chem. 2000, 3363. J. W. Daly, M. H. Garraffo, T. F Spande, M. W. Decker, J. P. Sullivan and M. Williams Nat. Prod. Rep. 2000,17, 131 (review). D. N. Butler, M. L. A. Hammond, M. R. Johnston, G. Sun, J. R. Malpass, J. Fawcett and R. N. Warrener, Org. Lett. 2000, 2,721. J. R. Malpass, D. N. Butler, M. R. Johnston, M. L. A. Hammond and R. N. Warrener, Org. Lett. 2000, 2,725 D. Margetic, R. A. Russell and R. N. Warrener Org. Lett. 2000, 2, 4003 D. N. Butler, D. Margetic, P. J. C. O'Neill and R. N. Warrener, Synlett 2000,10, 98. O. Dogan and P. P. Garner, Turk. J. Chem. 2000, 24, 59. R. N. Warrener, D. N. Butler, D. Margetic, F. M. Pfeffer and R. A. Russell, Tetrahedron Lett. 2000, 41, 4671. M. Miura, S. Sakamoto, K. Yamaguchi and T. Ohwada, Tetrahedron Lett. 2000, 41,3637. R. N. Warrener, D. Margetic, D. N. Butler and G. Sun, Synlett 2001, 2002. R. N. Warrener and G. Sun, Tetrahedron Lett. 2001, 42,465. J. R. Malpass, R. N. Warrener and D. N. Butler, 2001, unpublished results.

52

Chapter 3

Three-Membered Ring Systems S. Shaun Murphree

Allegheny College, Meadville, PA, USA [email protected] Albert Padwa

Emory University, Atlanta, GA, USA [email protected]

3.1

INTRODUCTION

The controlled generation and predictable reactivity of the three-membered heterocycles constitutes one of the most fruitful fields of synthetic organic chemistry. Few other areas can boast the generality of application, the significance of contribution, and the diversity of methods that continue to appear on this topic in the current literature. Recognizing the vitality of this subject, we seek here not to provide a comprehensive overview, but rather to highlight some of the last year's salient contributions with regard to synthetic application. The organization of this chapter is similar to that of previous years.

3.2

EPOXIDES

3.2.1 Preparation of Epoxides The protocol developed by Jacobsen and Katsuki for the salen-Mn catalyzed asymmetric epoxidation of unfunctionalized alkenes continues to dominate the field. The mechanism of the oxygen transfer has not yet been fully elucidated, although recent molecular orbital calculations based on density functional theory suggest a radical intermediate (2), whose stability and lifetime dictate the degree of cis/trans isomerization during the epoxidation <00AG(E)589>.

short- _ P~R'

cis-3

Mn

trans-3

lived I

Mn

Three-Membered Ring Systems

53

The lifetime of the proposed radical intermediate is dependent upon several factors, including reaction medium and salen substrate structure. In addition, a novel counterion effect has been reported, in which complexes with ligating counterions (i.e., 4, X = CI-, B r , AcO-) lead to extensive isomerization during the epoxidation of phenyl-substituted cisalkenes 5, while non-ligating counterions (BF4", PF6-, SbF6") allow for minimal isomerization. This phenomenon has been rationalized on the basis of an alteration in the triplet-quintet energy gap of the radical intermediate by the axial ligand <00EJOC3519>.

4

R Ph

,~R

R X = BF4, PF6, SbF6

cis-6

Ph

X = CI, Br, AcO"

5

Ph trans-6

More subtle arguments have been invoked to rationalize the dichotomous behavior of so-called "second-generation" Mn-salen catalysts of type 7 toward unfunctionalized and nucleophilic olefins. For example, higher yields and ee's are obtained with the (R,S)-complex for the epoxidation of indene (8). However, N-toluenesulfonyl-l,2,3,4-tetrahydropyridine (10) gave better results using the (R,R)-configuration. An analysis of the transition-state enthalpy and entropy terms indicates that the selectivity in the former reaction is enthalpy driven, while the latter result reflects a combination of enthalpy and entropy factors <00TL7053>.

(R,S)-7

~

(R,R)-7

O l h(R'S)-7 P r..- ~ ~ 8

9

57% yield; 96% ee

O

(R'R)'7 PhlO --O~ I Ts

10

I Ts

61% yield; 94% ee

11

S.S. Murphree and A. Padwa

54

These Mn-salen catalysts are tolerant to a broad palette of terminal oxidants, including molecular oxygen, DMD, and hydrogen peroxide. Recently, the asymmetric epoxidation of simple cis-disubstituted and trisubstituted alkenes has been reported using the readily available organic-soluble ammonium and phosphonium monopersulfates derived from Oxone, along with N-methylmorpholine N-oxide as proximal ligand. Thus, epoxidation of 6,7dihydro-5H-benzocycloheptene (13) under these conditions provided the corresponding epoxide 14 in 72% yield and 90% ee <00T417>.

PWh 12

,,,,,Q

C HaCN 12

14

:

Considerable effort is being directed at developing efficient strategies for catalyst recovery. Toward this end, the catalytic moiety has been immobilized by attaching a tether to either the ethylenediamine portion <00CC615> or the salicylaldehyde subunit <00JA6929> to give solid-supported catalysts of type 15 and 16, respectively. These are the first gel-type resins to give results rivaling solution-phase counterparts. Other approaches for easily recyclable catalyst systems involve the use of perfluoroalkyl-substituted catalysts (e.g., 17) in a fluorous biphasic system <00CC2171> and a traditional Jacobsen catalyst (e.g., 4) in the air- and moisture-stable ionic liquid [bmim][PF6] (18) <00CC837>. Enantioselectivities in the former case tend to be modest.

t-

p-o-g- t. u

*

o

o

_ % n~ 0/ I"0

t-Bu

16

~--~t-~u ~ t - ~ -~ 15

/~N

/ N ~

C8F 17

CaFlz

18

17

Another interesting asymmetric epoxidation technique using metal catalysis involves the vanadium complexes of N-hydroxy-[2.2]paracyclophane-4-carboxylic amides (e.g., 19), which serve as catalysts for the epoxidation of allylic alcohols with t-butyl hydroperoxide as

Three-Membered Ring Systems

55

the terminal oxidant. Enantioselectivity tends to be modest, although ee's as high as 71% have been reported (e.g., 20 ~ 21) <00SL899>.

Me 20

19

~

VO(Oi-Pr)3,TBHP

P

~

o

H

21 85%yield;71%ee

R = Adamantyl 19

A conveniently prepared amorphous silica-supported titanium catalyst exhibits activity similar to that of Ti-substituted zeolites in the epoxidation of terminal linear and bulky alkenes such as cyclohexene (22) <00CC855>. An unusual example of copper-catalyzed epoxidation has also been reported, in which olefins are treated with substoichiometric amounts of soluble Cu(II) compounds in methylene chloride, using MCPBA as a terminal oxidant. Yields are variable, but can be quite high. For example, cis-stilbene 24 was epoxidized in 90% yield. In this case, a mixture of cis- and trans-epoxides was obtained, suggesting a step-wise radical mechanism <00TL1013>. O 22

PII~ 24

SiO2-supportedTi H202/ CH2C12

Cu(CH3CN)4PF6= Ph MCPBA/ CH2CI2

{~O 23

p~ 25

Ph

There are also many examples of epoxidations in the absence of a transition metal catalyst. Particularly interesting is the action of Oxone on olefins in the presence of simple amines. For example, triene 26 is selectively converted to epoxide 28 by a mixture of Oxone, pyridine, and a 2-pyrrolidine derivative (27) in a medium of aqueous acetonitrile. The mechanism is believed to proceed via a single electron transfer (SET) process involving radical cation intermediates <00JA8317>. Water-soluble alkenes can be epoxidized in remarkably high yields using bicarbonate-activated hydrogen peroxide (BAP). Thus, epoxide 30 was obtained in >95% yield. Diol formation is a competing side reaction with some substrates <00JA3220>.

56

S.S. Murphree and A. Padwa

~~27 ph h

61%

Oxone / pyndine NaHCO3

26

28

N

NaHCO3 H20

N

29

30

Dioxirane technology continues to represent a powerful methodology for epoxide preparation. Practically unrivaled in efficiency and ease of use, dimethyldioxirane (DMD) can be generated in situ in an appropriate buffer. Thus, the dropwise addition of an aqueous solution of Oxone to a stirred mixture of cis-carveol (31), sodium bicarbonate, and acetone at 0~ led to the selective formation of epoxide 32 in 92% yield <00TL5021>. When chiral dioxirane precursors are used, such as ketones 33 and 34, good to excellent enantioselectivities can be realized, as exemplified by the epoxidation of the trisubstituted alkene 35 <00JAIl551>. In the case of fluorinated dioxiranes, B3LYP/6-31G(5) molecular orbital calculations suggest a stereoelectronic preference in the epoxidations, in which the transition state finds the fluorine anti to the dioxirane oxygen that becomes the carbonyl oxygen and syn to the alkene <00JA6297>.

oxone

92%

acetone NaHCO3 31

~~

32

33

33

P 35

34

'-P

Oxone DME / DMM

75% yield, 95% ee (+)-36

The epoxidation of electron-deficient alkenes, particularly ct,13-unsaturated carbonyl compounds, continues to generate much activity in the literature, and this has been the subject of a recent concise review <00CC1215>. Additional current contributions in this area include a novel epoxidation of enones via direct oxygen atom transfer from hypervalent oxido-X3iodanes (38), a process which proceeds in fair to good yields and with complete retention of

Three-Membered Ring Systems

57

the olefin stereochemistry <00OL2923>. A wide variety of enones can be epoxidized in high yield using hydrogen peroxide in the presence of basic hydrotalcite catalysts. For example, 3methyl-2-cyclohexen-l-one (40) gives the corresponding epoxide (41) in 90% yield. The catalytic activity of the hydrotalcites appears to be proportional to the basicity of their surfaces. In the case of less reactive substrates, epoxidation is accelerated by the addition of a cationic surfactant <00JOC6897>. ONa 0

0

DMF

37

O

66% yield

M0

H,24003

39

O

H20 2 / methanol 90% yield 40

41

A variety of methods are also known for the asymmetric epoxidation of electrondeficient alkenes. For example, the Julifi-Colonna method, which utilizes polyamino acids as chiral catalysts, has become recognized as a reliable method for the asymmetric epoxidation of enones, with particularly high induction for chalcone (42). Ohkata and co-workers have studied this reaction using organic-soluble catalysts with defined degrees of polymerization prepared by a stepwise elongation process. The yield and enantioselectivity increases with the number of amino acid units. Effective asymmetric induction requires an unprotected amine moiety at the N-terminus, and is sensitive to reaction solvent <00BCJ2115, 00CL366>. 0

oligo-L-leucine catalyst

P ~ P h 42

30% aq. H202 / NaOH toluene

0 p

Ph 43

Electrophilic olefins can also be asymmetrically epoxidized using chiral oxygen donors, such as (S)-(-)-(1-phenyl)ethyl hydroperoxide (45) <00JA5654> or the chiral dioxirane 47 <00OL3531>, or through the use of an on-board chiral auxiliary, as in the case of proline-derived cinnamamides. Diastereomeric ratios in the latter case were very sensitive to the proline amide substituent, with the best results being obtained from the prolineanilides (e.g., 48) <00CC495>.

S.S. Murphree and A. Padwa

58

OOH

base / CHaCN 44

46

p -

t-BuO2H

P h H N ~ ,0 47

11.n-BuU 48% yield, >99% de

PhHN~,

48

0

49

Finally, chiral epoxides can be prepared from ot,13-unsaturated carbonyl ~ompounds through an entirely different approach, in which the epoxide oxygen is derived from the carbonyl moiety. For example, trans-aryl-vinyl epoxides 52 can be synthesized from conjugated aldehydes 50 and chiral sulfonium salts 51, with excellent ee's. The protocol is especially effective for substrates which bear a p-methoxy group on the aryl substituent <00TL7309>. R3

R1

R3 50

3.22

51

R2-,h~ /

R1

52

Reactions of Epoxides

Ring-opening with heteroatomic nucleophiles is certainly among the most thoroughly studied behavior of epoxides, and this reaction continues to be a versatile workhorse of synthetic utility. This is exemplified in the recent literature by the examples of the 13cyclodextrin-catalyzed aminolysis of simple epoxides by aniline derivatives (i.e., 53 ~ 54) <00SL339> and the synthesis of oxa-azacrown ethers through the treatment of bis-epoxides 55 with diamines 56. Yields in the latter synthesis are sensitive to the size of the macrocycle and substitution on the bis-epoxide <00TL1019>.

Three-Membered Ring Systems

53

BnO.__~O~_. (~O

59

OH

PhNH2 13-cyclodextrin

78% '~"-'tNHPh 54

H2N(CH2)3NH2H 20 1,~ B n O - - - ~ ~ ~ 90%yield OH 56

55

Alcoholysis of epoxides is also well-known, and a particularly mild and selective method has been reported using catalytic amounts of ferric perchlorate. Thus, the reaction of optically active styrene oxide (57) with methanol in the presence of 1 mol% of Fe(C104)3 provides the hydroxy ether 58, corresponding to attack of the nucleophile at the more substituted epoxide carbon, with practically complete inversion of stereochemistry <00SC2967>. Another mild and high-yielding hydrolytic method involves the treatment of epoxides with ammonium molybdate and hydrogen peroxide, a system which promotes the smooth formation of ~-hydroxy ketones (e.g., 60), presumably through the intermediacy of 1,2-diols; however, competitive generation of ct-hydroxy aldehydes has not been observed in these reactions <00CL844>.

,• p

*

(-)-57

,• R

59

cat. Fe(CIO4)3 MeOH

'~

OMI~ O

H

P (-)-58

(NH4)6MoTO24.4H20 O THF 9 RJ""jOH 60

For 1,2-disubstituted epoxides, the regiochemical outcome of nucleophilic attack becomes less predictable. However, in the case of epoxy ethers chelation control can be used to deliver the nucleophile preferentially to the epoxide carbon away from the ether moiety. Thus, treatment of epoxy ether 61 with an imido(halo)metal complex, such as [Cr(N-tBu)C13(dme)], leads to the clean and high-yielding production of the chlorohydrin 64. The regioselectivity is rationalized in terms of initial formation of a chelated species (62), followed by attack at C-3 to form the more stable 5-membered metallacyclic alkoxide 63 <00SL677>.

S.S. Murphree and A. Padwa

60

~ [ ~ ) ' ' ~O Bn 61

[Cr(N-t-Bu)Cl3(dme)]j,. ~ ~ , , : , ~ 3 0H2012 Bn 62 I

~ O B n

95%yield

.~~Bn

64

63

Some clever functional group transformation methodology has been developed using a tandem process which involves the initial nucleophilic ring-opening of an epoxide. For example, trimethyl- and dimethylphenysilylepoxides (e.g., 65) react with lithium phenylsulfide to give regio- and stereodefined vinyl sulfides resulting from a-ring opening and Peterson elimination <00TLllll>. Unfunctionalized epoxides (e.g., 68) can be transformed into allylic alcohols 71 through an initial epoxide ring-opening with a thiol in hexafluoroisopropanol (HFIP) and in situ oxidation to the sulfoxide (70), followed by pyrolysis in the presence of potassium carbonate <00TL2895>. Epoxy ketones (72) can be deoxygenated to the corresponding enones (74) by the action of sodium iodide in acetone in the presence of an Amberlyst 15 resin catalyst. This methodology represents an interesting protocol for protection/deprotection of a conjugated double bond <00T1733>.

LiSPh ,••TMS M O

~~~0

65

~Ph R ~' Li TMS 66

PhSH~..~ s H HFIP

Ph

~

d H

~/

SPh

67

H202~,.~ 3 H

K2C03 ~,. ~ "OH ,, ,,,Ph 1700C 0 70 71 n

68

69 Nal

Amberlyst15 acetone 72

73

X

74

Epoxide ring-opening reactions can also be used for carbon-carbon bond formation. For example, epoxyketones (75) undergo nucleophilic attack by trialkylaluminum reagents to give hydroxycarbonyl compounds (76) with inversion of configuration about the carbon undergoing nucleophilic attack. In the case of epoxy alcohols (77), reaction occurs with net retention of configuration, a result which has been rationalized by invoking a Lewis acid coordinated carbocation intermediate (78), which allows delivery of the alkyl group from the face previously occupied by the oxirane moiety <00JCS(P1)2455>. When no adjacent

Three-Membered Ring Systems

61

functionality is present, an extemal Lewis base is necessary to activate the organoaluminum reagent. Thus, when dimethylepoxide (80) is treated with triethylaluminum alone, no reaction occurs; however, in the presence of 5 mol% triphenylphosphine the alcohol 81 is produced in 81% yield <00TL3043>.

Ph~H H 75

Ph~H,,o H-

O

Ph

R3AI >. C~I

Ph. . . . . H'~--R

H 76

H Me3A/

O

M~ ...sMe"] =(f/"'~/-- MeI ph~H~ /

Me" ~ "Ph HO H

H"

77

Ph

79

78

cat PPh3 Me,,/" 81

80

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00Tl149>. o,

H

83 82

[~e 85

TiCI4

Et2AICH2CO2tBu 86

84

~CO2t-Bu Moe" 87'

Vinyl epoxides undergo somewhat more facile ring opening and tend to give products derived from nucleophilic attack at the allylic epoxide carbon. For example, boron trifluoride etherate catalyzes the regiospecific opening of vinyl epoxides with alcohols to provide 13hydroxy allyl ethers 91 in good yield <00TL3829>. Rhodium catalysts promote similar reactivity in the presence of alcohols and aromatic amines under neutral conditions at room temperature to give trans-l,2-addition products 93. The rhodium-catalyzed mode of addition

S.S. Murphree and A. Padwa

62

is complementary to that typically observed with analogous palladium-promoted ring openings <00OL2319>. Carbon-centered nucleophiles also add at the allylic position, as exemplified by the alkyllithium-boron trifluoride ring-opening reaction, to give homoallylic alcohols 95, free from the products of SN2' addition <00JCS(P1)3352>.

'3He H =Me

90 BF3"OEt2

89

O

9

C9H 19 O ~ / 91 ~t-Bu

[Rh(CO)2CI]2~

MeO

MeOH / THF 89%

92

MeO" ~)Me 93

RLi

R

BF3.OEt2 94

95

Kinetic resolution of meso-epoxides (e.g., 96 ---> 97) continues to be a very useful protocol for the preparation of optically pure funcfionalized alcohols. The predominant approach in this regard tends to center around asymmetric ring opening reactions catalyzed by metal salen complexes (e.g., 4), and this has been the t@ic of some timely review articles <00ACR421, 00COC869>. These catalysts are also active in room temperature ionic liquids, such as 1-butyl-3-methylimidazolium salts (e.g., 18), which facilitate recovery and recycling of the catalyst <00CC1743>. In addition to salen complexes, other catalytic systems that have been reported include gallium heterobimetallic multifunctional complexes (98) <00JA2252>, (pybox)lanthanide complexes (99) <00OL1001>, and titanates equipped with novel 1,7-dioxaspiro[5.5]undecane ligands (100) <00T507>.

O 96

Catalytic System

R" " ~

"~

~ 98

catalytic s y s t e m nucleophilic precursor

~.,~~H 97

u

Nucleophilic

% yield

% ee

Precursor p-MeO-Ph-OH

48

93

Three-Membered Ring Systems

63

TMSCN

96

47

TMSN3

51

41

100

Kinetic resolution can also be accomplished via eliminative pathways. Thus, the enantiomerically enriched allylic alcohol 102 can be prepared from the meso epoxide 96 with up to 96% ee by the action of LDA in the presence of the chiral diamine 101 and 1,8diazabicyclo-[5.4.0]undec-7-ene (DBU). The DBU is believed to function as an aggregation modifier, and the active catalyst is theorized to be a heterodimer of the lithium amide (deprotonated 101) and DBU, although some nonlinear effects have been observed at low DBU concentrations <00JA6610>. Dipyrrolidino derivatives (e.g., 104) have also demonstrated utility with regard to kinetic resolution <00H1029>.

~ N I ~ I

[~O

101 t-Bu

96 ~.N/,.., I Li 104

(rac)-103

II-DBU/ THF

101 ~. LDA (2 eq.) DBU (5 eq.)

THF

&o t-Bu

(+)-103

~OH 102

t-Bu +

(-)-105

An interesting and synthetically useful functional group transformation involves the rearrangement of epoxides to carbonyl derivatives. Aryl and aliphatic-substituted epoxides possessing a tertiary epoxide carbon undergo smooth rearrangement in the presence of 10-50 mol% of bismuth(III) oxide perchlorate. The products of the reaction can be rationalized as resulting from the migration of the substituent with higher aptitude to the locus of the more stabilized incipient carbocation (e.g., 106 --->107) <00TL1527>. In a similar vein, bicyclic epoxides can undergo rearrangement to carbonyl derivatives with either ring contraction (e.g., 108 --> 109) <00SC3327> or ring expansion, which can be induced by Lewis acid (e.g., 110 --->111) <00OLl193> or lithium iodide (e.g., 112 --> 113) <00SL749>.

S.S. Murphree and A. Padwa

64

CH2CI2 70% yield

106

Bn O , , , . ~ ' { O

BF3

O 107

BnO,..~CHO

108

SO~ H

TM

109

Me e

BF3.OEt2

110

/CO2Me 1"CO2Me

@MeDH Q

Me

111

Lil DMSO ;._

CO2Me

O2Me "CO2Me

112

113

Epoxides can also serve as precursors to other interesting heterocyclic rings. For example, cyclic ethers of various ring sizes can be obtained by the transetherification of hydroxy epoxides, a process which is can be promoted by a variety of reagents, including protic acids such as CSA and TFA <00TL3805>, (Bu3Sn)20 in the presence of a Lewis acid <00TL7701>, or Lewis acid alone, as exemplified by the biomimetic tandem oxacyclization of the triepoxide 114 in the presence of boron trifluoride etherate which gives the bis-oxepane 115 <00OL2917>. Tetrahydrofuran derivatives have also been prepared via a novel titanocene catalyzed cyclization of alkynyl epoxides 116 <00SL1357>. M-

J-I Me Me

t-Bu

Mr ~

_["1 .[de

BCH2CI2 "O o, H " Me

114

115

CP2TiCI2 Zn 116

H 117

Oxazolines can be obtained by the Lewis acid catalyzed epoxide ring opening of glycidic esters or amides (e.g., 118) with acetonitrile <00TL5357>. Oxazolidines are available from the palladium-catalyzed cycloaddition of vinyl epoxides with imines <00H885> or the samarium-promoted reaction of ketimines (e.g., 120) with unfunctionalized

Three-Membered Ring Systems

65

epoxides <00TL3389>. Finally, cyclic sulfides have been produced by the nickel(II)mediated electroreduction of thioacetates 123 <00TL2621>.

,,~,c/le 118

BF3"OEt2 CH3CN O2Me 90%

Me,..~o~N~ Me

Me02C~

119 gn

Me n

5 mol%Sml~ THF 88%

+

Me/ 120

/

Me,,. r 1 1 ~ Me Me/~O/ "Me

121

122

O

e Ni(bae)~ DMF 84%

Ph OH

123

3.3

124

AZIRIDINES

3.3.1 Preparation of Aziridines The synthesis of aziridines from acyclic precursors generally falls into one of two categories: addition of a carbon center onto an imine bond (C + C=N) or addition of a nitrogen center onto an olefin (N + C=C). In terms of the former approach, trimethylsilydiazomethane (126) smoothly reacts with N-sulfonylaldimines (125) to give 2substituted N-sulfonyl-3-trimethylsilylaziridines (127) with high cis-selectivity <00TL9455>. Ethyl diazoacetate is also a frequently encountered carbon donor in the [C + C=N] approach, a reaction which can be catalyzed by InC13 <00TL6245> or by iridium complexes. In the latter case, the aldimines can be generated in situ in a one-pot, three component procedure to give ethoxycarbonyl aziridines (131) in generally good yield <00CC625>.

N~RH R102S/

Me3SiCHN 2126 2

~

125

,•,••HO 128

+ t-Bu"--NH2 129

R~__..~iMe3 H I]1 H SO2R~ 127

N2CHCO2Et 130 [Ir(c~ CI]2 THF 83%

.t-Bu

Pr-~O2E t 131

In an anionic approach, the sodium salt of the chiral chloroallyl phosphonamide 132 engages in nucleophilic addition onto oximes and gives the optically pure N-alkoxy aziridines

66

S.S. Murphree and A. Padwa

134. The chiral auxiliary can be removed by oxidative cleavage of the double bond with ozone <00TL787>.

Me L , ~ ....~ ~ 1 f''"Y~l~lO Me 132

+ R.lOy,,~/0R2NaHMDS ~ THF 0 133

I /7N.~ , ~ ~R2 ?Me '" M~-e OR1 134

In the area of [N + C=C] methodology, cyclic and acyclic enol derivatives 136 can be asymmetrically aziridinated with (N-tosylimino)iodobenzene (137) using a chiral copper catalyst prepared in situ from [Cu(MeCN)4]PF6 and the optically active ligand 135. Collapse of the aminal (i.e., 138) leads to the formation of enantiomerically enriched m-amino carbonyl compounds 139, although ee's to date are modest <00EJOC557>. Similarly, dienes can be selectively aziridinated using the chiral Mn-salen complex 140 to give vinyl aziridines 142 in scalemic form <00TL7089>.

~

13

0

136

~

~-

~-Bu 141

138

e

.u

pyridineN-oxide TsN j Ts20/ pyr CH2CI2

139

.~-Bu 142

Aziridination of electron-deficient olefins usually proceeds by a conjugate addition pathway. Thus, benzylamine adds to 2-(5H)-furanon-3-yl methanesulfonate (143) to give a Michael adduct 144 which ring closes to form the corresponding aziridine (145) <00TL3061, 00TL6393>. Ring-closure strategies have also been used in other systems not constructed directly from electron- deficient olefins. For example, the chloroamino ester 148, derived from the action of alanine dehydrogenase on keto acid 146, undergoes base-catalyzed ring closure to form an aziridine<00CC245>, as does the 13-alkylamino phenylselenide 150, which is prepared from an tx-phenylselanyl imine <00TL663>. Similarly, chiral aziridinoalcohols 154 are readily obtained from the reaction of racemic methyl 2,3-dibromopropionate (152) and optically pure 2-phenylglycinol (153) <00SC1303>.

Three-Membered Ring Systems

~i

)

BnNH2/Et3N,_ ~"D"~O MeOH/ THF~ ~ "IL s BnHNf 13Ms

143

~ , ~ C

H O

5/

~ O

-'=

N Bn

144

alanine _LklH2 ~ CLv~/OH dehydrogenaseI I O

146

145

NHTr 1. SOCI2/ROH C L v ~ O R 2. TrCI/ Et3N ~"

147

RI• PhS~

148

NHR2 1. Me30+BF4-> vco 2Et

2. 1NNaOH

150

152

33.2

T~NL~ O R 149

?2 /N\

RI~.~-.~CO2Et 151

BF

B~,,~OMe 0

~

+ H O / / ~ Ph NH2 153

Et20~'EtaN

HO~

./\N

Ph

Me02C"'

154

Reactions of Aziridines

The most familiar behavior of aziridines is associated with their ring-opening reactivity. For example, a variety of N-activated aziridines (155) are efficiently cleaved by water, primary, allylic, and propargyl alcohols at room temperature in the presence of catalytic amounts of tin triflate and boron trifluoride etherate <00TL4677>. Aziridines can also be ring-opened by trimethylsilyl compounds (158) and tetrabutylammonium fluoride to give cyano-, azido-, and chloramines in simple and efficient fashion <00JOC1344>. Silylsubstituted aziridines 160 are attacked by hydrogen halides to furnish the corresponding haloamine compound (161) <00JCS(P1)439>.

68

S.S. Murphree and A. Padwa ,,NHR'

ROH J" Sn(OTf)2 BF3OEt2

N~R' 155

156

R1~ 3

~.;.r~ n2

Me3SiX

R1 B,3.~j . .HTs

TBAF

+ (x :N~,c.,cl rH---"~

157

RS""x

158

(r3H7

159

L

P!-I,, ~ ,. ,. t. ~. ~ , SHiMe3

HCI~

I

C 3 H 7~z- N - ~ i M:kkCI e3 161

160

Sulfinyl aziridines (162) were found to undergo a clean metallation by ethyl Grignard with loss of the sulfoxide moiety to give the aziridinyl anions 163, which in turn can be alkylated in the presence of copper(I) iodide to give new elaborated products (164) with the heterocyclic nucleus intact <00TL6495>. At' Tol

At' H

162

BrMgv

Ad ~H

163

Cul

R2Hz~3"

~H 164

Vinyl and alkynyl aziridines exhibit particularly interesting chemistry in the presence of palladium catalysts. Thus, 2-vinylaziridines undergo cycloaddition reactions with various heterocumulenes in the presence of [Pd(OAc)2] and triphenylphosphine to give new fivemembered heterocycles 167 in moderate to high yields. The mechanism is believed to involve a ri3-rll-rl3 interconversion of a 0t-allyl)palladium intermediate <00JOC5887>. Conversely, treatment of 3-alkyl-2-ethynyl-aziridines 168 with indium iodide in the presence of Pd(PPh3)4 and water gives intermediate allenylindium reagents which can undergo in situ addition onto aldehydes to afford 2-ethynyl-l,3-amino alcohols 169 bearing three chiral centers <00OL2161>.

,, p2

69

T h r e e - M e m b e r e d R i n g Systems

+ X::C---Y

[Pd (OAc~2] PPh3

166

R1

R1

165

167

H R2 168

3.4

Pd(0) /Inl H20 / RCHO

R1

R

R21NH

OH 169

REFERENCES

00ACR421 00AG(E)589 00BCJ2115 00CC245 00CC495 00CC615 00CC625 00CC837 00CC855 00CC1215 00CC1743 00CC2171 00CL366 00CL844 00COC869 00EJOC557 00EJOC3519 00H885 00H1029 00JA2252 00JA3220 00JA5654 00JA6297 00JA6610 00JA6929 00JA8317 00JAIl551 00JCS(P1)439 00JCS(P1)2455 00JCS(P1)3352

E. N. Jacobsen, Acc. Chem. Res. 2000, 33,421. L. Cavallo, H. Jacobsen, Angew. Chem., Int. Ed. Engl. 2000, 39,589. R. Takagi, T. Manabe, A. Shiraki, A. Yoneshige, Y. Hiraga, S. Kojima, K. Ohkata, Bull. Chem. Soc. Jpn. 2000, 73, 2115. Y. Kato, K. Fukumoto, Chem. Commun. 2000, 245. O. Meth-Cohn, D. J. Williams, Y. Chen, Chem. Commun. 2000, 495. C. E. Song, E. J. Roh, B. M. Yu, D. Y. Chi, S. C. Kim, K.-J. Lee, Chem. Commun. 2000, 615. T. Kubo, S. Sakaguchi, Y. Ishii, Chem. Commun. 2000, 625. C. E. Song, E. J. Roh, Chem. Commun. 2000, 837. M. C. Capel-Sanchez, J. M. Campos-Martin, J. L. G. Fierro, M. P. de Frutos, A. P. Polo, Chem. Commun. 2000, 855. M. J. Porter, J. Skidmore, Chem. Commun. 2000, 1215. C. E. Song, C. R. Oh, E. J. Roh, D. J. Choo, Chem. Commun. 2000,1743. M. Cavazzini, A. Manfredi, F. Montanari, S. Quici, G. Pozzi, Chem. Commun. 2000, 2171. R. Takagi, A. Shiraki, T. Manabe, S. Kojima, K. Ohkata, Chem. Lett. 2000, 366. N. Ismail, R. N. Rao, Chem. Lett. 2000, 844. G. R. Cook, Curr. Org. Chem. 2000, 4,869. W. Adam, K. J. Roschmann, C. R. Saha-M611er,Eur. J. Org. Chem. 2000, 557. W. Adam, K. J. Roschmann, C. R. Saha-M611er,Eur. J. Org. Chem. 2000, 3519. J. -G. Shim, Y. Yamaoto, Heterocycles 2000, 52,885. M. Asami, S. Sato, K. Handa, S. Inoue, Heterocycles 2000, 52, 1029. S. Matsunaga, J. Das, J. Roels, E. M. Vogl, N. Yamaoto, T. Iida, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 2000,122, 2252. H. Yao, D. E. Richardson, J. Am. Chem. Soc. 2000,122, 3220. W. Adam, P. B. Rao, H.-G. Degen, C. R. Saha-M611er,J. Am. Chem. Soc. 2000,122, 5654. A. Armstrong, I. Washington, K. N. Houk, J. Am. Chem. Soc. 2000,122, 6297. M. J. S6dergren, S. K. Bertilsson, P. G. Andersson, J. Am. Chem. Soc. 2000, 122, 6610. T. S. Reger, K. D. Janda,J. Am. Chem. Soc. 2000,122, 6929. M. F. A. Adamo, V. K. Aggarwal, M. A. Sage,J. Am. Chem. Soc. 2000,122, 8317. H. Tian, X. She, L. Shu, H. Yu, Y. Shi,J. Am. Chem. Soc. 2000,122,11551. A. R. Bassindale, P. A. Kyle, M. -C. Soobramanien, P. G. Taylor, J. Chem. Soc., Perkin Trans. 1 2000, 439. L. Carde, D. H. Davies, S. M. Roberts,J. Chem. Soc., Perkin Trans. 1,2000, 2455. A. Alexakis, E. Vrancken, P. Mangeney, F. Chemla, J. Chem. Soc., Perkin Trans. 1 2000, 3352.

70 00JOC1344 00JOC5887 00JOC6897 00OL1001 00OL1193 00OL2161 00OL2319 00OL2917 00OL2923 00OL3531 00OL3555 00SC1303 00SC2967 00SC3327 00SL339 00SL677 00SL749 00SL899 00SL1357 00T417 00T507 00Tl149 00T1733 00TL663 00TL763 00TL787 00TL1013 00TL1019 00TL1111 00TL1527 00TL2621 00TL2895 00TL3043 00TL3061 00TL3389 00TL3805 00TL3829 00TL4677 00TL5021 00TL5357 00TL6245 00TL6393 00TL6495 00TL7053 00TL7089 00TL7309 90TL7701 30TL9455

S.S. Murphree and A. Padwa J. Wu, X.-L. Hou, L.-X. Dai, J. Org. Chem. 2000, 65,1344. D. C. D. Butler, G. A. Inman, H. Alper, J. Org. Chem. 2000, 65, 5887. K. Yamaguchi, K. Moil, T. Mizugaki, K. Ebitani, K. Kaneda, J. Org. Chem. 2000, 65, 6897. S. E. Schaus, E. N. Jacobsen, Org. Lett. 2000, 2, 1001. S. W. Baldwin, P. Chen, N. Nikolic, D. C. Weinseimer, Org. Lett. 2000, 2, 1193. H. Ohno, H. Hamaguchi, T. Tanaka, Org. Lett. 2000, 2, 2161. K. Fagnou, M. Lautens, Org. Lett. 2000, 2, 2319. F. E. McDonald, X. Wang, B. Do, K. I. Hardcastle, Org. Lett. 2000, 2, 2917. M. Ochiai, A. Nakanishi, T. Suefuji, Org. Lett. 2000, 2923. A. Solladi6-Cavallo, L. Bou~rat, Org. Lett. 2000, 2, 3531. T. -H. Chuang, K. B. Sharpless, Org. Lett. 2000, 2, 3555. L. Orea F., A. Galindo, D. Gnecco, R. A. Toscano, R. G. Enriquez, Synth. Commun. 2000, 30, 1303. P. Salehi, B. Seddighi, M. Irandost, F. K. Bahbahani, Synth. Commun. 2000, 30, 2967. M. G. Constantino, P. M. Donate, D. Frederico, T. V. Carbalho, L. E. Cardoso, Synth. Commun. 2000, 30, 3327. L. R. Reddy, M. A. Reddy, N. Bhanumathi, K. R. Rao, Synlett 2000, 339. W. -H. Leung, T. K. T. Wong, J. C. H. Tran, L. -L. Yeung, Synlett 2000, 677. D. Bouyssi, M. Cavicchioli, S. Large, N. Monteiro, G. Balme, 2000, 749. C. Bolm, T. Kiihn, Synlett 2000, 899. A. Gans~iuer, M. Pierobon, Synlett 2000, 1357. P. Pietik~iinen, Tetrahedron 2000, 56,417. D. Patra, L. Yang, N. I. Totah, Tetrahedron 2000, 56,507. S. K. Taylor, Tetrahedron 2000, 56,1149. G. Righi, P. Bovicelli, A. Sperandio, Tetrahedron 2000, 56,1733. S. Boivin, F. Outurquin, C. Paulmier, Tetrahedron Lett. 2000, 41,663. G. Lalic, Z. Petrovski, D. Galonic, R. Matovic, R. N. Saicic, Tetrahedron Lett. 2000, 41,763. S. Hanessian, L. -D. Cantin, Tetrahedron Lett. 2000, 41,787. M. B. Andrus, B. W. Poehlein, Tetrahedron Lett. 2000, 1013. M. F. Sebban, P. Vottero, A. Alagui, C. Dupuy, Tetrahedron Lett. 2000, 41, 1019. P. Cuadrado, A. M. Gonz~ilez-Nogal, Tetrahedron Lett. 2000, 41, 1111. A. M. Anderson, J. M. Blazek, P. Garg, B. J. Payne, R. S. Mohan, Tetrahedron Lett. 2000, 41,1527. S. Ozaki, E. Matsui, H. Yoshinaga, S. Kitagawa, Tetrahedron Lett. 2000, 41,2621. V. Kesavan, D. Bonnet-Delpon, J. -P. B6gu6, Tetrahedron Lett. 2000, 41,2895. C. Schneider, J. Brauner, Tetrahedron Lett. 2000, 41, 3043. C. de Saint-Fuscien, R. H. Dodd, Tetrahedron Lett. 2000, 41, 3061. T. Nishitani, H. Shiraishi, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 2000, 41, 3389. I. C. Gonz~ilez, C. J. Forsyth, Tetrahedron Lett. 2000, 41,3805. G. Prestat, C. Baylon, M.-P. Heck, C. Mioskowski, Tetrahedron Lett. 2000, 41,3829. B. A. B. Prassad, G. Sekar, V. K. Singh, Tetrahedron Lett. 2000, 41,4677. H. M. C. Ferraz, R. M. Muzzi, T. de O. Vieira, H. Viertler, Tetrahedron Lett. 2000, 5021. J. L. Garcia Ruano, C. Garcia Paredes, Tetrahedron Lett. 2000, 41,5357. S. Sengupta, S. Mondal, Tetrahedron Lett. 2000, 41, 6245. C. de Saint-Fuscien, A. Tarrade,P. Dauban, R. H. Dodd, Tetrahedron Lett. 2000, 41, 6393. T. Satoh, R. Matsue, T. Fuji, S. Morikawa, Tetrahedron Lett. 2000, 41,6495. T. Nishida, A. Miyafuji, Y. N. Ito, T. Katsuki, Tetrahedron Lett. 2000, 41, 7053. M. Nishimura, S. Minakata, S. Thongchant, I. Ryu, M. Komatsu, Tetrahedron Lett. 2000, 41, 7089. A. Solladi6-Cavallo, L. Bou6rat, M. Roje, Tetrahedron Lett. 2000, 41, 7309. R. Matsumura, T. Suzuki, K. Sato, K. -I. Oku, H. Hagiwara, T. Hoshi, M. Ando, V. P. Kamat, Tetrahedron Lett. 2000, 41, 7701. R. Hori, T. Aoyama, T. Shioiri, Tetrahedron Lett. 2000, 41,9455.

71

Chapter 4

Four-Membered Ring Systems L.K. Mehta and J. Parrick Brunel University, Uxbridge, UB8 3PH, UK E-mail: L ina.Mehta@bruneL ac. uk and John.Parrick@brunel. ac. uk

4.1

INTRODUCTION

The overall impression this year is of the amount of work being devoted to the development of stereoselective syntheses particularly, of course, in the area of 13-1actam chemistry but also in other areas. A review which includes the formation of four-membered rings among a range of other heterocycles has appeared <99MI637>. 4.2

AZETINES AND AZETIDINES

Fluorinated azetines 1 and 2 are obtained by treatment of perfluoro-2-methylpent-2-ene with heteroaromatic amines (e.g. 6-bromobenzothiazole) and with the more nucleophilic aliphatic amines (e.g. isopropylamine), respectively <00MI99>.

1

2

The enantioselective preparation of trans-2,4-disubstituted azetidines 4 by treatment of 3 with methanesulfonyl chloride and triethylamine followed by benzylamine at 45 ~ has been reported. N-Arylation of the debenzylated 4 has given 5 in yields of 32-96% by use of racBinap and moderate reaction temperatures to suppress racemization of the amines <00EJOC1815>. Azetidines can also be formed from certain oxetanes (see 4.2.3) <00JOC2253> and from 13-1actams (see 4.3 and 4.6) <99JOC9596>.

72

L.K. Mehta and J. Parrick

OH

PhH2C,,?I~R

OH

R

4.3

~

~

Ar\?.~R

,..."

R

4

.,.,, 5

BENZO[b]THIETES, THIETANES, OXETANES AND OXETANONES

The catalysed macrocyclization of thietanes by metal carbonyl complexes has been reviewed <00ACR171>. Electronically stabilized thiones have been shown to undergo [2+2] cycloaddition with benzyne to give 2H-benzo[b]thietes, for example 6 <00BCJ155>. Reviews which include mention of oxetanes or oxetanones include <00JCS(P1)1291> and <99RHAl17>. Conversion of 2-unsubstituted 1,3-disubstituted propane-l,3-diols 7 (R 2 = H) to oxetanes 8 with overall retention of configuration has been reported <00JCS(P1)711>. When R 2 = Me, the process did not give a product with retention of configuration, presumably due to crowding on one face of the ring. OHOH

ut

Ar

R1

R3

6

R1 .....

"~

R3

7

8

Photocyclization of benzophenone with chiral allylic alcohols, 9 (R = Me, Et, W, and

Bu t) is hydroxyl group-directed to give regioselectivity and threo-diastereoselectivity in the formation of mainly 10 <00JA2958>. OH

OH

R

Ph2CO, hv "----

Ph

O--'- ----L,,,, R Me -t--

Ph

Ph Me

9

OH

0 ....

-t-

Ph

Ph

Ph Me

10

OH

Me

High facial diastereoselectivity has been reported in the [2+2] photocycloaddition of aromatic aldehydes with a chiral enamide to give the cis-2,3-disubstituted oxetanes 11 and 12 with only minor amounts of the trans-oxetanes <99TL9003>. The same group of workers have investigated the photocycloaddition of m-substituted benzaldehydes to 3,4-dihydro-lHpyridin-2-ones to give mainly 13 <99JA10650>. Ph

Ac

N~ ....

11

ut

Ph

Ac

12

ut

0 o

13

RO

Biphenyl catalyses the reductive ring opening of oxetanes with lithium metal under aprotic conditions to give alcohols 14 <00TL1073>.

Four-Membered Ring Systems

R~ ~0

I

Li, THF 'biphenyl(cat)

73

Ry-..../OH R

14

The oxetane tertiary amides 15 on treatment with methyl triflate in anhydrous nitrobenzene at 150 ~ undergo ring expansion to the cyclic acetals 16 and, if the groups R~and R z are sufficiently bulky, the acetals undergo a ring contraction to form the azetidines 17 <00JOC2253>.

/

Me

,~~-"ONS~.._

o,lC. N. co l

.'

~ - - - O

15

-

._.~e

R2"--NI

16

CH202CR1

17

Treatment of a 13-t-butoxycarboxylic acid 18 with thionyl chloride gave an intermediate 13-hydroxyacid chloride 19 which underwent intramolecular cyclization to oxetanone 20 <00T3921>.

BuoOOH

o jeO E

No.coo

Me" \CO2Et

Me \CO2E t

18

19

20

The zinc chloride-mediated tandem Mukaiyama aldol-lactonization reaction of aldehydes 21 and thiopyridylketene acetals 22 gave mainly the trans isomer 23. However, if the catalyst is stannic chloride and the reaction is carried out at-78 ~ then the cyclization is highly diastereoselective and yields the cis-isomer 24 <99OL1197>.

O

21

-I-- R3 R2 ~

=

22

O--~ O R1,"J

23

/IO-~ O

R2

R1."

24

R2

Metal catalysed or photochemically promoted reactions of diazo compounds with diketene gave cyclopropanespiro-13-1actones 25 and 26 <00JCS(P1)2109>. Commercially available lipase PS has been used to obtain kinetic resolution of racemic 4-substituted oxetan-2-ones <00JOC1227, 00JCS(P1)71> and 3- and 3,4-disubstituted oxetan2-ones in organic solvents <00JCS(P1)71>. The enzyme appears to be relatively insensitive to the substituents on the lactone or to the nature of the ring opened products.

o

,

25

§

26

74

L.K. Mehta and J. Parrick

4A

THIAZETIDINES AND THIAZETIDINONES

Regioselective hydrolysis of the diester 27 gave the 1,3-thiazetidine 28 where the thiazetidine ring is fused to a quinolone nucleus <99CPB1765>. Derivatives of the tricyclic system, e.g. 29, showed activity against gram-positive bacteria including quinolone-resistant MRSA <99H(51)2915>.

Ph. Me

0 F ~ ~CJO ~ 2Et~/ ~--F"

C l Y ......~ F

t ~ ~ ~ _

CO2H

"N ~S 28

27

0

29

The oxidative rearrangement of 2-vinyl-l,3-thiazetidines 30 (X = CH=CH) with MCPBA gave ring expanded thiazine sulfones 31 (X = CH=CH, Y = SO2). However, the action of trifluoroperacetic acid on 30 (X = CH2CH2) gave the corresponding thiazine 31 (X = CH2CH2,Y = S) <99JCS(P1)3569>.

EtO2~~'l---~ // MCPBA,,. EtO2~~l'/Y"~ N ~ "O ~ CIO2EtMe CHCI3 ~7/N'~~" Me O CO2Et 30

31

A short review of heterobond cleavage and sequential reactions of 1,2-thiazetidinones (13-sultams) has appeared <99PS193>. The first data for optically active 13-sultams 33 have been reported. The precursor of 33 was the sulfonamide 32 which was obtained by use of a chiral tricarbonyl(rl6-arene)chromium(0) complex <99T14089>.

R

~ H

CH2SO2NHBu t OH

,,"CsHAR

~ o.~1 I

O"'S-- N"But

32

4.5

33

SILICON AND PHOSPHORUS HETEROCYCLES

The spirocompounds 34 (M = Ti or Zr) have been prepared <00OMl198>. Studies of the thermolysis of pentacoordinate 1,2-oxasiletanides 35, potential intermediates in both the Peterson reaction and the homo-Brook rearrangement of [3-hydroxyalkylsilanes with bases, in the presence of a proton source afforded the olefin, RCH=C(CF3) 2 and/or the alcohol, (CF3)2CHOH <99CL1139>.

Four-Membered Ring Systems

R

75

F3C

co l_ L 34

R

CF3

R

CF 3

35

OF3

The phosphetane ring is a useful synthon in the preparation of optically active ligands. Chiral 1,2-bis(phosphetano)benzenes 38 are easily prepared from dilithiophenylphosphine 36 by reaction with a cyclic sulfate 37 <00T95>.

PHLi

0~,~0 0tb~ 0

PHLi + 36

v

R~"~R 38

37

R

The same group of workers has prepared ferrocene derivatives 39 as chiral ligands for asymmetric catalysis. Again, cyclic sulfates of optically pure 1,3-diols were used as reagents in the preparation <99SL1975>. Novel 1,3-diphosphetene derivatives 41 (X = S or Se) have been obtained from di(isopropyl)aminophosphaethyne 40 <00T27>.

R

PI~2N-C=p 40

39

.+

P

.

~ Pr'2N==::~ X~-NPr~2 -X,'P,yX 41

R

Irradiation causes ring closure by valence isomerization of 1,3-diphosphacyclobutane2,4-diy142 (R = 2,4,6-tri(tert-butyl)phenyl) to 2,4-diphosphabicyclo[ 1.1.0]butane 43 which on thermolysis yielded the gauche-l,4-diphosphabutadiene 44 <99AG(E)3028>. The same group of workers have isolated the carbene 45 (R as above) as the lithium salt of a trimethylalane complex 46 <99AG(E)3031>. A review of the chemistry of compounds containing a phosphorus-chalcogen bond includes mention of dithiadiphosphetanes <00YGK208>. The first stable pentacoordinate 1,2thiaphosphetene 47 has been described <99PS119> and 1,2-thiaphosphole-2-sulfides 48 have

76

L.K. Mehta and J. Parrick

been obtained by the action of Lawesson's <98PS(133)119>. H R--P

), Y

reagent on a,13-unsaturated nitriles

~-P~P-~

P--R

SiMe a 42

~ ~-% ~P-~

SiMe 3

44

43

SiMe 3

--P~P--"J["('HF'n'+ L"--PyP--"J["('H~+ AIMe3 46

45

Z

/13

47

R

NHAr NHAr

TN

CN I S--P--Ar II S 48

Spiro-l,2-oxaphosphetes 50 can be obtained in good yield by the [2+2] cycloaddition of the cyclic phosphine oxide 49 with dimethyl acetylenedicarboxylate <00T4823>.

T

~r'o'~

CO2Me 49

COMe CO2M e

50

The pentacoordinate oxazaphosphetidines 53 (Tip = tri(isopropyl)phenyl) are related to intermediates in the aza-Wittig reaction. Thermolysis of 53 shows that the compound displays two types of reactivity: as an azaphosphetidine to give 51 and 52 and as an oxaphosphetane to yield 54 and 55 <00TL5237>. R1R2C=NPh 51 +

--~

-;p..

Tip 52

R1R2C=O F3C

O

R2 R 53

54 -t-

--~,]%p, 55

7'/

Four-Membered Ring Systems 4.6 MONOCYCLIC 2-AZETIDINONES ([3-LACTAMS) AND 2,3-AZETIDINEDIONES

Several reviews of 13-1actam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions <00EJOC563>, enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of 13-1actams <99MI955>. The two-step Staudinger reaction has been investigated in depth and 1,3-azadienes 56 have been isolated in some cases. The evidence suggests that the enol ether group is crucial in the stabilization of the diene and also plays an important role in promoting the conrotatory ring closure process <00EJOC2379>. Changing the protecting group from benzyl to benzoyl in glycolic acid derived ketenes is a simple way of switching the substituents on the [3-1actam product from a cis to a trans orientation <99TL8495>. The ketene from 57 added to imines to give 3-butadienyl substituted 13-1actams 58 but the relative stereochemistry of the 3- and 4-substituents depended upon the nature of R 1 and R 2 <00H(52)603>. The presence of benzoylquinine in Staudinger reaction medium gave cis-l,3,4-trisubstituted [3-1actams in good yield and ee > 99:1 <00JA7831>. An alternative approach is to attach the chiral auxiliary to one of the reactants. Using this approach and (+)-3-carene as an available starting material the ketene precursor 59 yielded 13lactams with some stereoselectivity. A zinc-mediated cleavage of the ether link gave enantiomerically pure 3-hydoxy-cis-fS-lactams 60 <00TA1477>. Indium has been used to obtain 3-unsubstituted azetidin-2-ones from imines and ethyl bromoacetate <00JCS(P1)2179>. Thioamide S-oxides 61 have been used as starting materials for the preparation of 13lactams carrying a 4-silylsulfenate group 62 <99PS389>. Phosphonium salts 63 can be used as precursors for ketene in the Staudinger reaction <99IJC(B)l121>. Reactions induced by microwave irradiation have been studied and the results compared with those obtained using conventional heating techniques <00M85>. The microwave procedure is eco-friendly because the volumes of solvent are small <00T5587> and, indeed, solid-phase microwave reactions give very high yields <00SC989>.

Sill 3 56

57

58

O ,-,

,-,

PhCNHR 1 +I--Oi

59

60

61

R3 S.OSiR23 R4

N

O

P,-,

"R 1 62

78

L.K. Mehta and J. Parrick

Lithium ester enolate addition to imines has been used for the construction of optically active 13-1actams, e.g. 64 <00H(52)1001> and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide 13-1actams in good to excellent yield <00TL5943>.

+

_

Me M e / ( p h

ArCH2CO2PPh3 CFzSOa 63

0

/~-N

OMe

Ph

Ph

64

Ph Bu

65

OLi _t_

Bu

"~1-78~ N\. Fos

Ph

~Ni/ ~ O

Tos

Studies of the intramolecular cyclization of 13-amino acids have included the use of camphor-derived oxazoline N-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, 00EJOC1595>. A diastereoselective synthesis of a ll3-methylcarbapenem intermediate utilises a cyclization of a 13-amino acid <99CC2365>. The unsaturated amides (RCH=CHCONH2, where R = aryl or heteroaryl) in the presence of sodium acetate and NBS gave 3-bromoazetidin-2-ones 67 in moderate yield, probably by cyclization of 68 <99JCS(P1)2435>. The mesylate 69 cyclized in the presence of base to 70 and, after deprotection, the racemic 13-1actam was subjected to lipase-mediated resolution to yield 71 (R = Et, ee 99%) and the amino acid 72 (R = Et, ee 98%) <00JOC4919>.

Me .Me Me~_..~~/~

Br.

(R

~,Br +

O

-d 66

R MesO

67

/NHPMP 69

O

68

~ 70

PMP

+ R

71

R

CO2H NH2

72

Intramolecular attack of the tertiary amide anion 73 on the epoxide yielded a 13-1actam <00T3209>.

79

Four-Membered Ring Systems

Radical cyclizations of 2-azabutadienes <00OL1077> and enamides in solution to give 13-1actams have been reported <00OIA01>. Photocyclization of enamides as guests in inclusion crystals with an optically active host have been investigated <00JOC2728>. The unexpected formation of 13-1actams 74 from thermocatalytic decomposition of sodium trichloroacetate in the presence of a quaternary salt and the imine Ph2C=NCHR1CO2R2 has been investigated and a reaction mechanism proposed <99MI707>. Rhodium-mediated cyclization of ct-amino-ct'-diazomethyl ketones (RICH2NHCR2R3COCHN2) gave 3azetidinones 75 in high yield <00OL1657>. 0

o

CI Ph

73

74

75

3-Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-13-1actams <00OL1411>. Two groups of workers have studied the reaction of 13-1actams with dimethyl titanocene to give 2-methyleneazetidines <00TL1975, 00TL5607>. Reduction of 13-1actams with chloroalane gave azetidines in high yield <99JOC9596>. Thermal isomerization of certain cis-l,3,4-trisubstituted azetidin-2-ones 76 provided the trans isomer in good yield <00JOC4453>. Bases caused the isomerization of cis-3substituted-4-formylazetidin-2-ones <00JOC3453> and of sulfonic acid derivatives of 3aminoazetidin-2-ones during the formation of a Schiff base <00T3985>. 4-Acyloxy-N-oazidobenzoyl-f~-lactams underwent ring expansion to produce 1,3-oxazin-6-ones 77 <00OL965>.

Ro Ar 2

0

4.7

76

"R 1

77

BI-, TRI- AND TETRA-CYCLIC [~-LACTAMS

Substitution at the 2-position of carbapenems by use of stannanes of the heterocycle has been explored and found to have some advantages over the conventional Stille cross-coupling which employs aryl stannanes and carbapenem triflates <00TL2995>. Efforts to develop carbapenems with activity against methicillin-resistant Staphylococcus aureus (MRSA) <99BMCL3225, 99BMCL2973, 00BMCL109, 00OL1081, 00JAN314> and to find orally active carbapenems <00CPB126, 00BMCL333, 00JOC517> have continued.

80

L.K. Mehta and J. Parrick

[3+2] Cycloaddition of the azomethine ylides 79, readily produced from 78 which is available in two steps from clavulanic acid, opens a route to a range of fl-lactam based heterocycles, e.g. 80, through a regio- and stereo-selective reaction <99JHC1365, 00T5579>. Acylketenes, derived from Meldrum's acid, add to esters of (R)-4,5-dihydrothiazolin-4carboxylic acid to give 81 <00OL2065>. A solid-phase synthesis of 2[~-methyl substituted penam derivatives utilises a tether through an ester group <99TA3893>. A review describes how penicillins and cephalosporins having S-aminosulfenamine side-chains at the 6- and 7-positions, respectively, may act as 13-1actamase-dependent prodrugs either as antibiotics or in antibody-directed enzyme prodrug therapy (ADEPT) in the treatment of cancer <00T5699>. H

/,~0~ o

0

z~

/~]N~

C02PMB 78

Se=CBu'2

H

-~Se But

2PM

C02PMB

79

80

Studies using PM3 calculations of the alkaline hydrolysis of bicyclic 13-1actam structures 82 (X = NNHCHO, O, S) have shown that cleavage of the X-CO bond is the energetically favoured pathway both in the gas and solution phase <99MI287>. Another route is available for the preparation of the important intermediate 83, which is used in the synthesis of both penicillins and cephalosporins <00S289>. Microwave irradiation has been used to convert 3-acetoxymethyl substituents on the cephem nucleus into 3-(hetero-arylthiomethyl) groups 99IJC(B)993>. A new cephem derivative has activity against Helicobacter pylori <99BMCL3123>. Some cephem antibiotics produce clathrate compounds with naphthalenes where the cephem and water molecules form the host. The guest naphthalene molecules are capable of inducing deviations in the host structure <00JCS(P2)1425>.

Ph

0

81

C02Me

O/2---N--./ 82

83

The 3-trifluoromethylsulfonyloxy-3A-cephem 84 is converted to the norcephalosporin 85 at 130 ~ and 3-nor-2A-cephalosporin 86 at 0 ~ by the action of copper(I) hydride, formed from tributyltin hydride and copper(I) chloride in N-methylpyrrolidone <99JCS(P1)3463>.

Four-Membered Ring Systems

RI~ 0 84

81

S

OTf CO2R2

85

RI~

S

CO2R 2

86

CO2R 2

Cyclization of 87 in the presence of a chiral rhodium catalyst gave good diastereoselectivity and allowed the required 3-oxacepham 88 to be isolated <00H(52)875>. The stereoselectivity obtained in three approaches to 1-oxacephams have been compared <00T5553>. Me Me _

87

88

The action of N-methylhydroxylamine on enantiopure 4-formylazetidin-2-ones beating an N-tethered alkynyl group 89 has been studied and products formed by 1,3-dipolar cycloaddition and reverse Cope elimination isolated, e.g. 90 <00TL1647>. .

~L--N~

eNHOH

n:l

H

H

0

89

I

~.0-

Me

90

Larger fused rings can be constructed from suitably 1,3,4-substituted 13-1actams by tandem Ireland-Claisen rearrangement and ring closing alkene metathesis. In this way 91 was used as the starting material for the preparation of 92 and 93 (X = OCH2, SCH2, NTosCH2 or CH2, R 2 = Et or PNB)<00JOC3716>.

91

92

CO2R 2

93

CO2R 2

FVP of isatoic anhydride at 550 ~ gave benzazetinone 94 in 80% yield but 94 is not stable above -20 ~ <99TL9271>. The stereoselective synthesis of 'classical' trinems (fused tricyclic systems having the azetidin-2-one nucleus fused through the N-C4 bond) <98MI347> and the chemistry of 'nonclassical' polycyclic 13-1actamshave been reviewed <00T5743>.

82

L.K. Mehta and J. Parrick

Recent approaches to the formation of the trinem system 95 have used a phosphonate as the condensing agent <00T5639> and another similar process used triethyl phosphite <00CPB716>. Other workers have prepared trinems having a central six-membered ring by forming an acetonide bridge across a phenolic OH and the NH of the 13-1actam group <99EJOC3067> or by using intramolecular Diels-Alder reactions of suitably disubstituted 13lactams <00JOC3310>. The number of fused rings in reported 13-1actams continues to increase. The phosphonate cyclization technique has been used to produce a classically fused five-ring compound <00CJC772>. Non-classically fused tricyclic 13-1actams have been synthesised <00TL3261, 00TA1927>. The Baylis-Hillman reaction of N-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised 13-1actams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. O

R

OR 2 C02AII 94

95

The preparation of unfunctionalised 96 (R 1 = R 2= H, R 3= TBDMS) and a functionalised lactenediyne 96 (R 1 = OMe, R E = OH, R 3 = (CHE)EOTBDMS) have been reported. The unfunctionalised compound was obtained through a pinacol coupling of the dialdehyde 97 by use of a Pedersen vanadium reagent <00EJOC939>. The substituted derivative was designed and prepared as a potentially useful agent in antibody-directed enzyme prodrug therapy (ADEPT) or the corresponding gene-directed approach (GDEPT) to cancer treatment <00TL6523>. CHO

96

4.8

CHO

97

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00JOC2253

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00JOC2728

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00JOC1227

Four-Membered Ring Systems

00JOC3310

85

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00JOC3453

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00JOC3716

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86

00TL5237 00TL5607 00TL5943 00TL6523 00YGK208

L.K. Mehta and J. Parrick

N. Kano, X. J. Hua, S. Kawa, T. Kawashima, Tetrahedron Lett. 2000, 41,5237. I. Martinez, A. R. Howell, Tetrahedron Lett. 2000, 41,5607. M. Shindo, S. Oya, R. Murakami, Y. Sato, K. Shishido, Tetrahedron Lett. 2000, 41,5943. L. Banfi, G. Guanti, Tetrahedron Lett. 2000, 41, 6523. K. Toyata, M. Yoshifuji, Yuki Gosei Kagaku Kyokaishi 2000, 58,208.

87

Chapter 5.1 Five-Membered Ring Systems: Thiophenes & Se, Te Analogs Erin T. Pelkey

Stanford University, Stanford, CA, USA email: [email protected]

5.1.1 INTRODUCTION Reports detailing the chemistry and syntheses of thtophenes, benzo[b]thiophenes, and related ring systems that have appeared during the past year (Jan-Dec 2000) are the primary focus of this review. Different aspects of chemistry that involve thiophenes have been reviewed during the past year <00AM481, 00BCSJ1, 00CR2537, 00CSR109, 00PAC1645>. 5.1.2 THIOPHENE RING SYNTHESIS One general strategy for preparing the thiophene ring system is to add sulfur to activated four carbon units. For example, treatment of the zirconocene-based oligomer 1 with sulfur chloride gave the thiophene-based oligomer 2 by replacement of the zirconium moieties with sulfur <00AC2870>. The synthesis of a thieno[3,4-c]thiophene involved the addition of sulfuryl chloride to a 3,4-dicyanomethylthiophene <00TL8843>. The central thiophene ring of the structurally interesting thiahelicene 4 was prepared by dilithiation of 3 with LDA followed by double displacement of bis(phenylsulfonyl) sulfide <00AC4481>. Additional examples of thiophene ring synthesis involving the treatment of 1,4-dicarbonyl compounds with Lawesson's reagent appeared including a synthesis of a terthiophene <00JMAT107> and a novel fluorophore <00CC939>.

$2CI2 1

2

Br ~ T M S TMS~ ~ 3

s~TMS 1.LDA,ether ~ r~T 2.(PhSO2)2S Br MS 4

One of the most common strategies for the preparation of thiophenes involves the intramolecular condensation of ~-thioglycolates (and related a-substituted thiols) onto adjacent carbonyls. One prominent example involved the synthesis of naturally occurring

E.T. Pelkey

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anthrathiophene pigment 7 <00OL2351>. A novel addition-elimination of tosylate 5 with methyl thioglycolate gave 6, which was treated with sodium methoxide to effect an intramolecular cyclization giving 7. This synthesis helped ensure that the correct structure 7 had been assigned to the natuaral product. The preparation of the peri-substituted thieno[2,3b]thiophene 10 was also achieved using this type of condensation with diester 9 <00SC1695>. The latter was prepared by treating 8 with carbon disulfide and ethyl bromoacetate. Related reaction sequences have been utilized to prepare a variety of thiophenes including benzo[b]thiophene-2-carboxylates <00TIA973, 00TL5415>, a 2-acetylbenzo[b]thiophene <00H(53)1175>, 2-trifluoromethyl-thiophenes <00S1078>, and benzothiazole-substituted thiophenes <00HC94>. A related cyclization reaction of thioacetamides with activated bromides was used to prepare cyanovinyl-substituted thiophenes <00EJOC1327>, thiopheneot-carboxylates, <00EJOC3273> and a-amine-substituted thiophenes <00JCS(P1)4316>.

C.O2Me O

OTs

OH O

OH

HS~CO2Me

0 LS

OH O

5

Ar Ar KF, CS 2 j ~ v ~ O grCH2eO2Et 0 ' 8

Me02C"~----S

OH

6

7

AF~AF '/~r , ~]S~OS O NaOEt, I EtO2C CO2Et

Ar

Ar

Et02C

9

C02 10

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare ct-aminothiophene 11 <00TL1597>. An alternate method for preparing aminosubstituted thiophenes involved the treatment of ketene S,N-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. O

CO2Etmorpholine M e \ 9 O2Et " ~ O I~CN EtOH, A/7~ MeO/ $8 MeO" "S~ NH2 11

jJ~P(O)(OEt)2 NHMe S NHMe 13 h ~ ph~.,,~SMe Hg(OAc)2" P P(O)(OEt)2 12 14

Another method of thiophene synthesis involves either acid- or base-mediated cyclization of acyclic prcecursors. An acid-catalyzed cyclization was utilized to prepare benzo[b]thiophenes that were evaluated as retinoic acid receptor (x agonists <00JMC2929>. Treatment of alkynyl sulfide 15 with potassium tert-butoxide gave 2,3-dihydrothiophene 16, perhaps via a 5-endodig cyclization of a terminal alkyne intermediate arising from a rearrangement <00TL5637>. Treatment of thiol 17 with sodium hydride gave 2-fluoro-4,5-dihydrothiophene 18 by a 5-endo-

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

89

trig cyclization of the resulting sulfide onto a gem-difluoroalkene <00CC1887>. An important new thiophene synthesis involved the palladium-mediated cyclization of enyne thiol 19 giving thiophene 20 <00OL351>. Importantly, this reaction occurs under neutral conditions, while similar thiophene ring forming reactions are usually performed under strongly basic conditions (vide infra). A similar cyclization of alkynyl thiols mediated by group VI metals (Cr, Mo, W) gave dihydrothiophenes <00S970>.

F•Ph

~___,~sfMe t-BuOK ~ CH3CN

FHS'J

15

16

Me __~~ PdI2'KI'DMA ~ Et ' " Et 19

Me Me

~ M NaH Ph e F" "S"

17

18

~-~H (R*O)2

20

hv'AIBN

(R*O)2

)~

R*-OH--menthol

21

22

Radical cyclization reactions have been utilized to prepare tetrahydrothiophenes. For example, ultraviolet irradiation of thiol 21 in the presence of AIBN gave tetrahydrothiophene 22, importantly with no epimerization <00OL3757>. Radical cyclizations of 13-thioacrylates were utilized to prepare a variety of 5- and 6-membered ring sulfur heterocycles including tetrahydrothiophenes <00T3425>. A novel radical cascade reaction approach was utilized to prepared fused thiophenes. Treatment of 23 and diazonium salt 24 with base gave 26 presumably via intermediate 25 <00JOC8669>. Finally, a novel cyclization of sulfur-tethered bis-allenes gave thiophenes via a diradical intermediate <00TL2675>.

NCS+B 23

N 24

L

25

S J

26

Syntheses of thiophenes using 1,3-dipolar cycloadditions have been studied. The cycloaddition between 2-aminothioisomiinchnone 28 and arabinose-derived alkene 27 gave a mixture of dihydrothiophene diastereomers 29 and 30 <00JOC5089>. A computational-based rationale for the facial selectivity was offered. Additional research on the same reaction with 2-aminothioisomiinchnones and achiral alkynes gave either thiophenes or pyridones depending on the substituent on the thiazolium nitrogen <00T1247>. A thiophene product was obtained with a 1,3-dipolar cycloadditon of a 1,3-dithiole and alkynes <00HC434>. Theoretical calculations for [5+2] cycloadditions giving products containing tethered tetrahydrothiophenes were reported <00JOC5480>.

E.T. Pelkey

90

Ph. N

Ph "N

NII

Ph

I~

OE)

eh-(,

R*

I~

"

R* = chiral sugar M~

H

+ Bn ~ l , ph "N~S~CONHPh Mc~

29

28

R* :

Bn ~ C O N H P h "N~ ~ " ~Ph Md

"[[,R.§ BO,N.. ,sNp , 27

Ph. N

30

Another approach to synthesizing thiophenes and additional heterocycles involves the extrusion of sulfur from the corresponding sulfur heterocycles. Treatment of highly fluorinated 31 with sulfur and iodine gave a small yield of thiophene 34 via intermediates dithietene 32 and 1,4-dithiin 33 <00JFC323>. Interestingly, 34 was irradiated to give Dewar thiophene 35 en route to an attempted preparation of a fluorinated tetrahedrane. Finally, an extensive study was recently reported on the synthesis and chemistry of 1,2-dithiins, useful thiophene precursors via sulfur extrusion <00JA5052>.

Rf. Rf - - .,Rf Rf= CF2CF2CI 31

2

R

32

S''Rf

---~R

33

Rf

34

Rf

' Rf~~;

35

5.1.3 THIOPHENE RING SUBSTITUTION The unsubstituted a-positions of the thiophene ring system continue to be elaborated using standard electrophilic aromatic substitution reactions including bromination (NBS) <00CC877, 00CC1631, 00CC2487, 00JA1820, 00JA6746, 00JMAT1777, 00JMC1293, 00P5681>, iodination (12, Hg II) <00AC3481, 00CC877, 00JCS(P1)1211>, and Friedel-Crafts acylation (trifluoroacetaldehyde imine, BF3) <00SL1058>. The fluorination of thiophene with gaseous SF3 has been studied using MS experiments <00JOC3920>. The treatment of thiophene 36 with chlorosulfonic acid gave thiophene-4-sulfonyl chloride 37 which was utilized to prepare biotin conjugate 38 <00CCl199>. The regioselectivity of the formylation of 3methylthiophene (39) has been studied and the highest selectivity (41/40; 46:1) was achieved using Rieche conditions (MeOCHC12, TiCI4) <00TL2749>. The hydroxymethylation of bis(thiophene) 42 with formaldehyde in the presence of diamine 43 (double Mannich reaction) gave macrocycle 44 <00JCS(P1)1877>. Finally, the synthesis and chemistry of 2silyloxythiophenes continues to be studied <00JOC2048> and has been reviewed <00CSR109, 00PAC1645>. o

~

O

O

o

36

o

SO2C'

37

O ,,

O

~CF3~S-N o

~

H

HN-J( .[ ,,NH

N ~ I I ~ . / ~ . . |....k / ~

38

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

Me

Me

o42

Me

c.o Q o

AcOH

+

m

HH 39

40

91

N N

41 43

Ph

44

The synthesis and chemistry of iodonium thiophene derivatives have been studied <00AM133, 00TL5393>, for example, the preparation of 46 involved the ipso substitution of 2-stannylthiophene 45 <00CC649>. A similar ipso substitution of 2-stannylbenzo[b]thiophene 47 with tetranitromethane gave 2-nitrobenzo[b]thiophene (48) <00JOMC187>.

G 45

PhI(OH)OTs SnBu3 ' ~ 1 ~ Q @OTs

C(NO2)4, DMSO ~ [~SLSnMe3

46

47

NO2 48

Oxidation of the sulfur of thiophene to either thiophene-l-oxide (49) or thiophene-l,1dioxide (50) modifies the electronic structure (aromaticity, polarizability) and these effects have been studied using theoretical methods <00CC439, 00JMS203>. Sulfur oxidized thiophenes are susceptible to nucleophilic addition, for example, the addition of amines to 2,5disilylthiophene-l,l-dioxides has been studied <00EJOC3139>. The conversion of thiophene1-oxide 51 to the corresponding thiophene-l-imide 52 was achieved by activation with trifluoroacetic anhydride followed by the addition of tosylamide <00TL8461>. Nucleophilic addition of sodium ethoxide to 52 gave 2-ethoxythiophene 53 via a Michael addition and subsequent loss of tosylamide (Pummerer-like reaction) <00CL744>. Cycloadditions of thiophene-l-oxides with methylenecyclopropanes have been studied <00JCS(P1)2968>.

y

t-Bu

o 49

50

t-Bu 1.(0F300)20 t-Bu

t-Bu NaOEt t- Bu

p

t-

Bu

>

0

NTs

51

52

53

Nvcleophilic substitution of thiophene can also be enabled by the presence of electron withdrawing groups (e.g.,-CHO <00SC1359>,-COMe <00T7573>,-NO2 <00JCS(P1)1811>) on carbon. The regioselectivity of the addition of amine nucleophiles onto 3,5dibromothiophene-2-carboxaldehyde (54) has been studied and found to be independent of reaction conditions (para product 55 favored over ortho product 56) <00SIA59>.

. ~ Br 54

Br

Br

N3morpholine tE ~ CHO ..D, ~/'N O"v')

. ~ CHO + Br

55

56

~'---~ CHO

E.T. Pelkey

92

One of the more common methods for functionalizing the thiophene ring involves (xlithiation <00AC4481, 00CC1631, 00CM1508, 00JA1820, 00JA6746, 00JMAT1777, 00SM89, 00T3255>. The cc-cuprate formed by a-lithiation of 57 followed by treatment with copper iodide was treated with iodide 58 to give phosphonate 59 <00TL617>. Treatment of polycyclic thiophene 60 with n-butyllithium and TMEDA followed by iodomethane gave the cz-lithiation product 61 rather than the product resulting from directed ortho metalation (ortho to the methoxy group) <00SC3569>. The preparation of the novel azulene-fused thiophene 64 involved the cx-lithiation of benzo[b]thiophene 62 to prepare 2-cycloheptatrienylthiophene 63 <00JHC1363>. C6H.13

1. n-BuLi 3.

C6H.13

1. n-BuLi

O

II I~P(OEt)2

06H13

O~

57

58

S"

C6H13

MeO"

~

2. Mel

S

Me

MeO"

59

60

61 COMe

~s,f

Br

1. LDA 2. CFHF+BF,,

~

jBr

63

62

~

64

Directed ortho metalation can be utilized to regiospecifically lithiate the thiophene ring. For example, the directed lithiation of 2-amidothiophene 65 with tert-butyllithium followed by treatment with acetaldehyde gave 3-(cz-hydroxyethyl)thiophene 66 <00SL1788>. The lithiation of dicarbamate 67 has been studied <00T2985>. Interestingly, treatment of 67 with three equivalents of n-butyllithium followed by quenching with allyl bromide gave thieno[3,4d]imidazolone 68 after an unexpected, regiospecific intramolecular cyclization. O 1. tert-BuLi

OH

2. CH3CHO ,.NEt 2 , 65

O

BocHN

NHBoc 1. n-BuLi (3 equiv)

NEt 2 66

O

67

2. allyI-Br

L.

68

Another method that is often utilized to regiospecifically functionalized the thiophene ring involves the halogen-metal exchange of halogenated thiophenes <00H(52)761, 00JA6746, 00JCS(P 1) 1211, 00JCS(P2) 1453, 00T7205>. The lithiation of 2-bromothiophene 69 followed by treatment with dichloro-diisopropylsilane gave 2-silylthiophene 70, a building block for the synthesis of oligothiophenes <00JOC352>. The lithiation of 3-bromothiophene (71) followed by treatment with bis-electrophile, N,N-dimethylcarbamyl chloride (72), gave ketone 73 <00S1253>.

Five-Membered Ring Systems: Thiophene & Se, Te, Analogs

1 n-BuLi

9

9

Br

~

2. CI2Si(i-Pr)2

0 1. n-B,,.~Li

2.

69

71

93

0

CI

72

NMe2

73

The organometallic cross-coupling of metallated thiophenes continues to be an effective technique for the preparation of highly functionalized thiophenes. Metallated thiophenes that have been utilized in cross coupling reactions include thiophene-2-borates <00CC1649, 00CC2487, 00JOC3883, 00S 1229, 00TL3197>, thiophene-3-borates <00OL3417, 00TL2185 >, thiophene-2-magnesium bromides <00P5681>, thiophene-2-stannanes <00AM668, 00AC4547, 00JA1820, 00JMAT1777, 00SL963, 00TL5521>, and thiophene-2-zincates <00CC1631, 00SM33>. A novel solid-phase synthesis of regioregular oligothiophenes (tetrathiophenes to dodocathiophenes) has been reported <00JCS(P1)1211> utilizing cross-coupling reactions. For example, the palladium-catalyzed cross coupling of borate 75 with iododithiophene 74 gave tetrathiophene 76. A novel one step synthesis of piperazinone 80 involved the multicomponent reaction of thiophene 77, diamine 78, and glyoxylic acid (79) <00TL9607>. C6H13 061"1,13

C6H13 7s

74

06H13

.

CsF, Pd (PPh3)4

0

C61"~13

C61"~13

7'6

B(OH)2 + MeHN 77

06]"1,13

NHMe + H 78

o 79

0

oMi 80

N tvlle

The organometallic cross-coupling reaction of halogenated thiophenes is another related method for the preparation of highly functionalized thiophenes. Halogenated thiophenes that have been utilized in palladium-catalyzed cross coupling reactions include ct-bromothiophenes <00BMCIA15, 00CC2487, 00JA6746, 00JHC281, 00JMAT1303, 00SC2281, 00SM47, 00T2985>, 13-bromothiophenes <00BMCIA15, 00EJOC2357, 00JMC1293>, and cxiodothiophenes <00JOC352>. The synthesis of the novel bis-cyclobutene 83 was achieved by a Stille coupling of 2,5-diiodothiophene (81) and stannane 82 <00T4249>. Palladiumcatalyzed Sonogashira coupling reactions and related variants have been utilized to prepare alkyne-substituted thiophenes <00AC3481, 00HCA3043, 00T2985, 00TL3607, 00TL5151>. Palladium-catalyzed aminations of halothiophenes have been utilized to synthesize aminothiophenes <00CC133>. For example, 13-aminothiophene 85 was prepared from 13-

E.T. Pelkey

94

bromothiophene 84 by a palladium-catalyzed amination with n-butylamine <00TL7731>. Treatment of 81 with sulfide 86 in the presence of palladium and copper gave the S-arylation product, o~-thiothiophene 87, via a novel depropargylation reaction <00TL7259>. The perfluorohexyl-dithiophene 89 was prepared utilizing a copper-catalyzed coupling reaction of dithiophene 88 with perfluorohexyl iodide <00AC4547>. Other metals that have been reported in coupling reactions with halothiophenes include nickel <00P423, 00TL5039> and indium, the latter (with palladium) was utilized in a novel Barbier-type allylation reaction <00CC645>. Bu3Sn\

I

I

l

Br

Pd(PPh3)4

C02Me

81

81

83

[~

NHTs

84

~NHTs

86 si~ ~,

NHBu

5 mol%

PdNIba3

02Me

85

1. Cu-bronze

S,~ff~ i

Pd (PPh3)2CI2 Cu, Et3N

BuNH2

cs co

#~_/S~B

r 2. C6F13I

88

87

89

Photochemical substitution reactions of thiophene <00T9383> and electron-deficient (-NO2) diiodo-thiophenes <00JCS(P1)3513> have been reported during the previous year. Irradiation of a-iodothiophene 90 in the presence of methyl acrylate gave a mixture of the addition product 91 and the substitution product 92 <00EJOC1653>. Photodecarboxylation of thiophene-2-acetic acid in the presence of nitrogen aromatic compounds (e.g., acridine) gave the corresponding o~-(arylmethyl)thiophenes <00T6845>. ~C02Me hv, CH3CN

9O

Me

"S" "CHO

91

OMe H

93

I" v

OMe

+ MeO2C'~S~CHO

92

OMe 0

CI3CC02H . . 94

S 95

The side-chain functionalization of thiophenes have been reported including Wittig olefinations <00CCl139, 00EJOC1703, 00EPJ2005, 00TL5521>, the nucleophilic addition of n-butyllithium to the tosylhydrazone of thiophene-2-carboxaldehyde <00TL2667>, and the nucleophilic addition of amines to 2-ethynyl-5-nitrothiophene <00OL2419>. The preparation of chiral thiophene alcohols from thiophene-2-carboxaldehydes has been accomplished by the asymmetric addition of diethylzinc performed in the presence of chiral tryptophan-derived

95

l~ive-Membered Ring Systems: Thiophene & Se, Te, Analogs

ligands <00TA2315> and by asymmetric reduction mediated by a chiral ruthenium complex <00OL1749>. Finally, the attempted reduction of ethyl 3-methoxythiophene-2-carboxylate to thiophene-2-methanol 93 with lithium aluminum hydride led primarily to a by-product, dithenylmethane 94 <00JCS(P1)3020> which inspired further investigation. Interestingly, treatment of 93 with trichloroacetic acid gave 94 and the spiro product 95, the latter by acidcatalyzed condensation of additional 93 with 94. 5.1.4 RING ANNELATION ON THIOPHENE The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[b]thiophene 101 mediated by boron trifluoride-etherate <00JOC3883>.

N~X'N~Tr

~H

TMSOTf 0

N

MeS

CN p-TsOH, M e S ~

97

L-~

jL ~-~ ,BF3-ether 100

~

~OMe

~1

S , ~ 0~1 "(3Me

The synthesis of complex thiophene-containing polycyclic hydrocarbons has been achieved utilizing intramolecular photocyclization reactions of f~-chlorobenzo[b]thiophenes, and recent examples include dibenzo[f,h]benzothieno[2,3-c]quinolin-lO(9H)-one 102 <00JHC997> and naphtho[2',l':4,5]thieno[2,3-c]naphtho[1,2-f]quinolin-6(5H)-one 103 <00JHC171>. The photocyclization of 3-styrylthiophenes to fused thiophenes has been studied <00JHC959, 00TL1951>. An interesting photorearrangement involving a [1,9] hydrogen shift occurs upon irradiation of electron-rich stilbenes (e.g., 104 --->105) <00JA8575>. o

S 102

s 0

104

Me

105

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96

A copper-mediated cyclization of metallated thiophenes has been utilized to prepare polycyclic thiophenes and thiophene cyclophanes. Treatment of dibromide 106 in succession with n-butyllithium (halogen-metal exchange), zinc chloride (transmetallation), and copper chloride gave 7H-cyclopenta[1,2-b;4,3-b']dithiophene (107) <00H(52)761>. This conversion has also been achieved using a palladium-mediated cyclization performed in the presence of hexamethylditin <00H(52)761>. Copper-mediated cyclizations hhve also been applied to the syntheses of cyclopenta[2,1-b;3,4-b']dithiophen-4-one (108) (three steps from 73) <00S1253> and cyclophane 109 <00CC2329>.

S

1. n-BuLi 2. ZnCI2

Br Br

S

O

106

107

108

109

Cyclometallation of thiophene imine 110 with platinum complex 111 proceeded to give metallacycle 112 via an intramolecular C-H insertion on the thiophene ring <00JOMC22>. BnN

~

C)SbCI6

Pt2Me4(SMe2)2 ~

110

M N---Bn

"S~" Pt-L..SMe2 Me" 112

,~~OH MeO

pyr

S + ~Me NHPhth 116 113

Me ~ ~ 1 ~ ~ ~ s

Me S =0

Md

Me

118

+

113

Me M

~--Ph

Ph

9 M(

C)SbCI6 114

115

~O~../S,,~~OMe -'-MeO- ''r

"S"~S M~e " 117

PhOC __ COPh i,

Me Me S ~[ ~ ~ "~~/ [~/ ~ C O P' hr " ~N"~'~ / -"i~/-"L'co Ph Me

119

I~le

Treatment of 2-methylthiophene (113) with nitrilium ion 114 gave the novel heterobicyclic ring system, 3-azo-6-thiabicyclo[3.2.1]octa-3-ene 115, via an ene-like reaction <00JOC3569>. The cycloaddition between the o-thioquinone derivative 116 and 113 gave the 2:1 cycloadduct, [1,4]oxathiin 117 <00SL61>. Cycloadditions of thiophenes <00TL5005>, thiophene-l-oxides <00H(52)1215>, and thiophene-l,l-dioxides <00H(52)365> with dienophiles give benzenoid products after extrusion of the sulfur moieties from the bicyclic cycloadducts. For example, treatment of thiophene-l-oxide 118 with dibenzoylacetylene gave fused benzene 119 <00H(52)1215>. Finally, thiophene-based and other heterocyclic quinodimethanes have been investigated using theoretical methods <00JOC7971>.

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

97

5.1.5 THIOPHENE INTERMEDIATES IN SYNTHESIS The thiophene ring system can be utilized as a synthetic scaffold for the preparation of nonthiophene materials as the sulfur moiety can be removed by reduction (desulfurization) or extrusion (loss of SO2). The extrusion of sulfur dioxide from 3-sulfolenes (2,5dihydrothiophene 1,1-dioxides) give dienes (butadienes or o-quinodimethanes) that can be utilized to prepare six-membered rings by cycloaddition chemistry. For example, thermolysis of 3-sulfolene 120 provided tricyclic pyrazole 122 via an intramolecular cycloaddition of the oquinodimethane 121 that results by extrusion of sulfur dioxide <00JOC5760>. Syntheses of 3sulfolenes 123 <00JCCS83> and 124 <00S507> have recently been reported.

N.-...,

A _ ~ ' ~ "-"

SOPh

9

Oi

CO2Me

123

122

124

The reductive extrusion of sulfur from thiophene derivatives using Raney nickel has been utilized to prepare a variety of materials. For example, treatment of 125 with Raney nickel gave ester 126 <00OL3719>. Hydrolysis of 126 with aqueous lithium hydroxide gave 8hydroxyhexadecanoic acid (127), an inhibitor agent of spore germination. Treatment of 128 with excess Raney nickel proceeded to give alcohol 129 by reductive desulfurization the dithiane and tetrahydrothiophene with concomittant removal of the benzyl protecting group <00S 1863>. Finally, the thiophene ring can be considered an "n-butyl synthon" as reduction of thiophene 130 gave C-butyl glycoside 131 <00TA4463>.

1. RaneyNi 2. aq. LiOH

CH3(CH2 ) 7 ~ C O 2 M e OH 125

R=H

Raney Ni

S

D

O """O 130

Me Me 129

128

M'~~'*OM e

R

126 R = Me 127

OBn

MeO

CH3(CH2)7~CO2 OH

Raney

Ni

MeO'~~~"l~ Me(~ ~Vle 131

OH Me

E.T. Pelkey

98

The addition of cuprate 133 to benzo[b]thiophene-l-oxide 132 unexpectedly led to the ringopened product 134 <00JOC8811>. The reaction proceeded via an unprecedented 1,2-addition onto the sulfur moiety rather than via the expected 1,4-addition pathway giving the 3substituted benzo[b]thiophene. The corresponding thiol of 134 (prepared by reduction of the sulfoxide) was found to be an inhibitor of tubulin polymerization. Finally treatment of sulfur ylide 135 with cesium fluoride led to a mixture of ring enlarged benzothiocine 136 ([2,3]sigmatropic rearrangement product) and thiol 137 (Hoffman elimination product) <00JOC7055>. A mechanistic model involving the cis-trans isomerization of 135 is proposed to explain the formation of both products. When this reaction was performed in DMSO, the aromatized product derived from 136 was also obtained.

/ Br

MeO J Jtt'S (~

t MeO ~ Me~e ~ CuU 133

v "OMe

~ O M e

2

MeO"":11 "OMe OMe 134

L

1

132

_..,.,.TMS

CsF.

+

| cl04@ 135

136

137

5.1.6 BIOLOGICALLY IMPORTANT THIOPHENE DERIVATIVES A number of biologically active thiophene-containing compounds have been designed, synthesized, and evaluated. One of the more common scaffolds utilized in medicinal chemistry is the benzo[b]thiophene moiety, and examples of which include thrombin inhibitor 138 <00BMCLl199, 00BMCL2347, 00JMC649> and protein tyrosine phosphatase 1B inhibitor 139 <00JMC1293>. Additional biologically active benzo[b]thiophenes that been synthesized and/or evaluated include an inhibitor of urokinase-type plasminogen activator (structural study) <00CB299>, dual inhibitors of thromboxane A2 synthase and aromatase <00JMC1841>, adrenoceptor agonists <00JMC765>, analgesics <00CCC280>, and anti-inflammatory agents <00CCC1082>. OH

138

99

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

The biological activity of a variety of fused thiophene analogues have been synthesized and evaluated, and examples of which include phosphodiesterase 7 inhibitors (e.g., benzo[b]thieno[3,2-a]thiadiazine 140) <00JMC683> and antioxidants (e.g. thieno[3,2-c] carbazole 141)<00JMC1762>. Additional examples of biologically active fused thiophenes include antimicrobial agents (benzo[b]thieno [2,3:6,5 ]pyrimidino [6,1 -f]pydridazines) <00HC403>, antidepressant agents (pyrazolo[2,1]benzothiazepines) <00JHC389>, adrenoceptor antagonists (benzo[b]thieno[3,2-d]pyrimidines) <00JMC1586>, and DNAbinding agents (imidazo-[4',5':4,5]thieno[3,2-d]pyrimidin-5(6H)-ones) <00JMC4877>. The synthesis and evaluation (mutagenicity) of the carcinogenic metabolite, acenaphtho[1,2-b] benzo[d]thiophene 142, was reported <00JOC8134>. O

~ S

Me 140

Me...N ~

S

o

CO2Et

~

[

141

~ 142

Finally, the biologically activity of non-fused thiophenes have been synthesized and evaluated, and examples of which include progesterone receptor antagonist 143 <00BMCL415>, anti-trypanosomal agent 144 <00CB733>, and mercaptocarboxylate inhibitor 145 (structural study) <00B4288>. Additional examples of biologically active non-fused thiophenes include carbonic anhydrase inhibitors <00BMC2145>, adenosine A1 receptor antagonists <00DDR227> and agonists <00JOC8114>, cyclooxygenase (COX) inhibitors <00EJMC499>, dopamine receptor agonists <00EJP255>, antibacterial agents <00JAB546>, and antitumor agents <00JMC167>. Glycopolythiophenes have been synthesized using solidphase methods and evaluated as novel detectors of Influenza Virus <00BCC777>. Finally, the synthesis and biological evaluation of tetrahydrothiophene derivatives (bioisosteric replacements ofpyrans) has been reported <00JMC1264> and reviewed <00S1637>.

CF3 Me

NC

P,h

MeO

,.,

e 143

"N H " "Me

144

H ff-~

' N, N ,, ,.

CF3

N SH O

I~,'N

,~,/N.. N" CO20 145

5.1.7 NOVEL THIOPHENE DERIVATIVES The unique electronic and physical properties of thiophenes make it a useful building block for a variety of novel materials. The preparation of thiophene-containing porphyrins and related higher order macrocyclic materials have been reported including water-soluble thiophene-modified porphyrin 146 (photodynamic therapy) <00JMC2403>, heptaphyrin 147 (a novel 30n aromatic system) <00OL3829>, calix[n]thieno[n]pyrroles <00TL2919>, thiophenemodified porphyrin pentamers <00TL3709>, dioxadithiaporphycenes <00TL10277>, and thiophene-substituted phthalocyanines <00CC 1649, 00T4085>.

100

E.T. Pelkey

R

R

R

146 R = S03Na

147 R = mesityl

In addition to modified porphyrin derivatives, a variety of novel thiophene-containing macrocycles have been prepared including dehydrothieno[18]annulene 148 <00CC1733>, mixed cyclooligothiophenediacetylenes (structurally related to 148) and cyclo[n]thiophenes <00AC3481>, thiophene-containing cyclophanes (e.g., 109) <00CC2329>, and a pyridinethiophene cyclophane <00CC2465>. The novel oligothiophene cyclophane, [2.2]quinquethiophenophane 149, was synthesized and evaluated as a 7t-dimer model <00OIA197>. S

148

149

The unique electronic properties of the thiophene ring system are often utilized to manipulate the electronic and optical properties of various materials including dyes, light emitting diodes, and molecular devices. A variety of thiophenes conjugates to other interesting organic materials have been prepared including ferrocene complexes (e.g., 150 <00SC2281>) <00AM599, 00OM1008, 00OM1035, 00PH291>, chromium complex 151 <00TL3607>, and derivatives of C6o (e.g., 152 <00CC2487>) <00AM908, 00JPC5974>. Syntheses of complex thiophene-containing helicenes (e.g., 4 <00AC4481>), potentially important materials in the field of molecular recognition, have been reported <00CC97, 00CCl139, 00JCS(P2)2492, 00JHC1009>. Thiophenes with push-pull substitution have been synthesized and/or evaluated <00AC556, 00JAIl54, 00SM213> including dithiophene 153 <00S1229>, ~-nitrothiophene 154 <00OL2419>, and thioindigo 155 <00TL2983>. A number of thiophenes with interesting optical <00AM978, 00AM1587, 00CC939, 00CM284, 00CM1508, 00HCA3043, 00JAIl021, 00JOC2900, 00OL2979> and/or structural properties (e.g., liquid crystals) <00AM1336, 00JA585, 00JMAT1303> have been prepared and evaluated. Finally, the transformation of open cyclopentene 156 to closed cyclopentene 157 by irradiation of a single crystal has been studied using x-ray crystallography <00BCSJ2179>. The photochromic properties of closely related systems <00AM1597, 00CLl188, 00CL1340, 00JA3037, 00JA8309, 00OL2749> have been widely studied during the past year.

101

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

Me

s

o

N-Me

N02

SMe

154

SMe

:.~ ~M Me

~e eM 156

F Me

EE F F F F

360nm 650nm (singlecrystal)

Me

Me

157

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of 13-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>.

Ph2N ,-~

Me Me~PPh

2

Me~s~/~Ph2 Me 158

~~/~PPh2 ~L~~ ~---PPh2

P

h

~

Ph2N

159

2

N

NPh2 ~

~.(" _ NPh2 160

Ph2

Finally, novel thiophene-containing dendrimeric materials have been prepared <00CC507, 00CM2372, 00JCS(P2)1976> including C6-symmetric dendrimer 160 <00AM668>. 5.1.8 THIOPHENE OLIGOMERS AND POLYMERS The thiophene ring is a common building block for novel oligomeric and polymeric materials. The synthesis of monodisperse thiophene oligomers conti,lues to be widely studied and the preparation of one class of oligomers, oligothienylenevinylenes <00CEJ1698,

E.T. Pelkey

102

00CM2581, 00TL5521>, was reviewed <00ACR147>. The conformational properties of simple thiophene oligomers have been studied utilizing theoretical methods <00JHC847>. The synthesis and/or evaluation of monodisperse thiophene oligomers that have appeared include: dithiophenes <00JA6746> (e.g., 161 <00AM563>), trithiophenes <00CC1005, 00JA6746, 00MAC4628> (e.g., palladium-incorporated dimer 162 <00JA10456>), tetrathiophenes <00AC2680, 00JA6746, 00JCS(P 1) 1211, 00TL5521> (e.g., 163 <00JOMC8>), sexithiophenes <00AC4547, 00CC383, 00JA1820>, octathiophenes <00CC81, 00JCS(P1)1211>, dodecathiophenes (from 76) <00JCS(P1)1211>, and heptadecathiophenes (!) <00JA7042>. Syntheses of thiophene oligomers containing thiophene-l,l-dioxide moieties have also been reported <00JA9006, 00SM47, 00SM83, 00SM235>. Various mixed thiophene co-oligomers have been prepared including silole/thiophene 164 <00AC1695>, phosphole/thiophene 165 <00AC1812>, and phenylene/thiophene 2 <00AC2870>. Additional examples of thiophene co-oligomers include furan/vinylene/thiophenes <00EPJ2005>, phenylene/thiophenes <00JHC25, 00JHC281>, and pyrrole/thiophenes <00JMAT107>.

S

H H

v

~

,J ' I-'N-CI2H25

o

~d" 15d" 2

161

Me a'-a

~'~s

Ph

S

C6H13 "C6H13 163

~S

162

Ph S

S

ph 2

164

Ph 165

The synthesis and evaluation of thiophene polymers continues to be widely studied. Monolayers of electrostatically charged thiophene polymer 166 complexed with a biotinylated material have been studied in avidin-based assays <00CC1847>. The self-assembly properties of amphilic polymer 167 has been studied using Langrnuir-Blodgett films <00JA5788>. The preparation of green electroluminescent <00CC1631>, copper-entwined <00CEJ1663>, and radical-containing <00MAC8211> thiophene polymers have been reported. Many additional studies of thiophene polymers have been appeared during the last year <00AM567, 00AM589, 00AM1594, 00CC877, 00CM2996, 00JA5788, 00MAC5481, 00P423, 00P3147, 00P5681, 00P9147, 00SM133, 00SM305, 00SM433>. Examples of co-polymers of thiophenes with other materials that have been studied include 1,3,4-oxadiazole/thiophene co-polymer 168 <00JOC3894>, fluorophenylene/thiophene co-polymer 169 <00SM33, 00SM151>, and cobaltsalen/thiophene co-polymer 170 <00CM872>. Additional examples of thiophene-containing co-polymers include bipyridine/thiophenes <00CM1611>, fluorene/thiophenes <00CM1931>, crown ether/thiophenes <00JMAT263>, phenylene/thiophenes <00JMAT927, 00MAC2462>, ethylene glycol/thiophenes <00JMAT 1777>, pyrrole/thiophenes <00JMAT 1785>, quinoxaline/thiophenes <00PB231 >, and divinylphenylene/thiophenes <00SM437>.

103

Five-Membered Ring Systems: Thiophene& Se, Te, Analogs

.08H17

003~

__~oH17

Me S 166

_

)

167

(~03S

n

L

"

N--N

N-N J n

168

~O__/__OM e

F F

0/'-"'~0

~N~N__ ~o

"~ F

""

o

~ I~

1

170

169

5.1.9 SELENOPHENES AND TELLUROPHENES A modest number of reports on the chemistry of selenophenes and tellurophenes appeared during the past year. The preparation of selenophene 172 was accomplished by treatment of titanocycle 171 with selenium diselenocyanate <00JA5052>. The formation of 172 could also be achieved by irradiation of 1,2-diselenin 1 7 3 . An interesting synthesis of dihydroselenophenes involved the thermolysis of 1,2,3-diselenadiazole (denitrogenation) in the presence of ethyl acrylate <00JOMC488>. This reaction was accompanied by the formation of 1,4-diselenins. A Pummerer-related synthesis of benzo[b]selenophenes involved the oxidation of 2-benzo[b]selenopyrans <00H(52)1021>. The preparation of selenophene-containing porphyrin 176 (note inverted pyrrole ring) was achieved by treatment of diol 174 and tripyrrole 175 with boron trifluoride-etherate <00JOC8188>. Additional syntheses of selenophene-modified porphyrin materials have also appeared <00EJOC1353, 00JCS(P2)1788>. The laser photolysis of selenophene and tellurophene has been reported <00AOC715, 00JOC2759>.

t_BUT.~it_BuSe(SeCN)2 t_Bu.~~et_Buhv /-PRO~ "Oi-Pr 171

172

t-Bu~-Bu 173

104

E.T. Pelkey

OH

,~ H

~

.,Me

,~

Me

BF3-ether

+

,

h

chloranil ~~-OH

~

M

174

e

Me

176

175

The synthesis of ditellurophenes and mixed selenophene/tellurophene trimers has been reported <00H(52)159>. The structul'e of 1,1-diiodotetrahydrotellurophenes and related compounds has been studied <00JOMC96>. Finally, the synthesis of the novel benzo[c]tellurophene (179) has been achieved <00JOC5413>. Treatment of 177 with tellurium and sodium iodide followed by silver trifluoroacetate gave 178. The base-mediated double elimination of the trifluoroacetates of 178 proceeded smoothly to give 179. The cycloaddition and lithiation chemistry of 179 was investigated, for example, the double a-lithiation with nbutyllithium followed by quenching with ethyl chloroformate gave diester 180.

1. Te, Nal CI 2. CF3CO2Ag ~ II Cl ~

~~I~

9

.I 178

177

/OCOCF3 Et3N- [ ~ ~ ~ T e me, OCOCF3 179

1. n-BuLi C02 Et 2"ClCO2Et, ~ ~ / T e 180

CO2Et

5.1.10 R E F E R E N C E S 00ACR147 00AM133 00AM481 00AM563 00AM567 00AM589 00AM599 00AM668 00AM908 00AM978 00AM1336 00AM1587 00AM1594 00AM1597 00AC556 00AC1695 00AC1812

Roncali, J. Acc. Chem. Res. 2000, 33, 147. Tykwinski, R. R.; Kamada, K.; Bykowski, D.; Ohta, K.; McDonald, R. Adv. Mater. 2000, 12, 133. Groenendaal, L. B.; Jonas, F.; Freitag, D.; Pielartzik, H.; Reynolds, J. R. Adv. Mater. 2000, 12, 481. Rep, D. B. A.; Roelfsema, R.; van Esch, J. H.; Schoonbeek, F. S.; Kellogg, R. M.; Feringa, B. L.; Palstra, T. T. M.; Klapwijk, T. M. Adv. Mater. 2000, 12, 563. Storsberg, J.; Ritter, H.; Pielartzik, H.; Groenendaal,L. Adv. Mater. 2000, 12, 567. Meskers, S. C. J.; Peeters, E.; Langeveld-Voss, B. M. W.; Janssen, R. A. J. Adv. Mater. 2000, 12, 589. Wolf, M. O.; Zhu, Y. Adv. Mater. 2000, 12, 599. Wu, I.-Y.; Lin, J. T.; Tao, Y.-T.; Balasubramaniam, E. Adv. Mater. 2000, 12, 668. Apperloo, J. J.; Langeveld-Voss, B. M. W.; Knol, J.; Hummelen, J. C.; Janssen, R. A. Adv. Mater. 2000, 12, 908. Cornil, J.; Calbert, J.-P.; Beljonne, D.; Silbey, R.; Br6das, J.-L. Adv. Mater. 2000, 12, 978. Zhang, H.; Shiino, S.; Shishido, A.; Kanazawa, A.; Tsutsumi, O.; Shiono, T.; Ikeda, T. Adv. Mater. 2000, 12, 1336. Yoshida, Y.; Tanigaki, N.; Yase, K.; Hotta, S. Adv. Mater. 2000, 12, 1587. Apperloo, J. J.; Janssen, R. A.; Nielsen, M. M.; Bechgaard, K. Adv. Mater. 2000, 12, 1594. Tian, H.; Tu, H.-Y. Adv. Mater. 2000,12, 1597. Hartmann, H.; Eckert, K.; Schr~Sder,A. Angew. Chem., Int. Ed. 2000, 39, 556. Yamaguchi, S.; Goto, T.; Tamao, K. Angew. Chem., Int. Ed. 2000, 39, 1695. Hay, C.; Fischmeister, C.; Hissler, M.; Toupet, L.; R6au, R. Angew. Chem., Int. Ed. 2000, 39, 1812.

F i v e - M e m b e r e d Ring Systems: Thiophene & Se, Te, Analogs

00AC2680 00AC2870 00AC3481 00AC4481 00AC4547 00AOC715 00B4288 00BCC777 00BMC2145 00BMCIA15 00BMCLll99 00BMCL2347 00BCSJ1 00BCSJ2179 00CB299 00CB733 00CC81 00CC97 00CC133 00CC383 00CC439 00CC507 00CC645 00CC649 00CC877 00CC939 00CC1005 00CCl139 00CCl199 00CC1631 00CC1649 00CC1733 00CC1847 00CC1887 00CC2329 00CC2465 00CC2487 00CCC280

105

Mena-Osteritz, E.; Meyer, A.; Langeveld-Voss, B. M. W.; Janssen, R. A. J.; Meijer, E. W.; B/iuefle, P. Angew. Chem., Int. Ed. 2000, 39, 2680. Suh, M. C.; Jiang, B.; Tilley, T. D. Angew. Chem., Int. Ed. 2000, 39, 2870. Kr6mer, J.; Rios-Carreras, I.; Fuhrmann, G.; Musch, C.; Wunderlin, M.; Debaerdemaeker, T.; Mena-Osteritz, E.; B~iuefle, P. Angew. Chem., Int. Ed. 2000, 39, 3481. Rajca, A.; Wang, H.; Pink, M.; Rajca, S. Angew. Chem., Int. Ed. 2000, 39, 4481. Facchetti, A.; Deng, Y.; Wang, A.; Koide, Y.; Sirringhaus, H.; Marks, T. J.; Friend, R. H. Angew. Chem., Int. Ed. 2000, 39, 4547. Pola, J.; Bastl, Z.; Subrt, J.; Ouchi, A. Appl. Organomet. Chem. 2000,14,715. Concha, N. O.; Janson, C. A.; Rowling, P.; Pearson, S.; Cheever, C. A.; Clarke, B. P.; Lewis, C.; Galleni, M.; Fr6re, J.-M.; Payne, D. J.; Bateson, J. H., Abdel-Meguid, S., S. Biochemistry 2000, 39, 4288. Baek, M.-G.; Stevens, R. C.; Charych, D. H. Bioconjugate Chem. 2000,11,777. lilies, M.; Supuran, C. T.; Scozzafava, A.; Casini, A.; Mincione, F.; Menabuoni, L.; Caproiu, M. T.; Maganu, M.; Banciu, M. D. Bioorg. Med. Chem. 2000, 8, 2145. Zhi, L.; Tegley, C. M.; Pio, B.; West, S. J.; Marschke, K. B.; Mais, D. E.; Jones, T. K. Bioorg. Med. Chem. Lett. 2000,10,415. Takeuchi, K.; Kohn, T. J.; Harper, R. W.; Lin, H.-S.; Gifford-Moore, D. S.; Richett, M. E.; Sail, D. J.; Smith, G. F.; Zhang, M. Bioorg. Med. Chem. Lett. 2000,10,1199. Takeuchi, K.; Bastian, J. A.; Gifford-Moore, D. S.; Harper, R. W.; Miller, S. C.; Mullaney, J. T.; Sail, D. J.; Smith, G. F.; Zhang, M.; Fisher, M. J. Bioorg. Med. Chem. Lett. 2000,10, 2347. Nakayama, J. Bull. Chem. Soc. Jpn. 2000, 73,1. Yamada, T.; Kobatake, S.; Irie, M. Bull. Chem. Soc. Jpn. 2000, 73, 2179. Katz, B. A.; Mackman, R.; Luong, C.; Radika, K.; Martelli, A.; Sprengeler, P. A.; Wang, J.; Chan, H.; Wong, L. Chem. Biol. 2000, 7, 299. Du, X.; Hansell, E.; Engel, J. C.; Caffrey, C. R.; Cohen, F. E.; McKerrow, J. H. Chem. Biol. 2000, 7, 733. Langvelde-Voss, B. M. W.; Janssen, R. A. J.; Spierin, A. J. H.; van Dongen, J. L. J.; Vonk, E. C.; Claessens, H. A. Chem. Commun. 2000, 81. Yamada, K.-i.; Kobori, Y.; Nakagawa, H. Chem. Commun. 2000, 97. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem. Commun. 2000, 133. Kilbinger, A. F. M.; Cooper, H. J.; McDonnell, L. A.; Feast, W. J.; Derrick, P. J.; Schenning, A. P. H. J.; Meijer, E. W. Chem. Commun. 2000, 383. Bongini, A.; Barbarella, G.; Zambianchi, M.; Abrizzani, C.; Mastragostino, M. Chem. Commun. 2000, 439. Sebastian, R.-M.; Caminade, A.-M.; Majoral, J.-P.; Levillain, E.; Huchet, L.; Roncali, J. Chem. Commun. 2000, 507. Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan, V. Chem. Commun. 2000, 645. Martin-Santamafia, S 9Carroll, M. A.; Carroll, C. M.; Carter, C. D.; Pike, V. W.; Rzepa, H. S.; Widdowson, D. A. Chem. Commun. 2000, 649. Kowalik, J.; Tolbert, L. M. Chem. Commun. 2000, 877. Raimundo, J.-M.; Blanchard, P.; Brisset, H.; Akoudad, S.; Roncali, J. Chem. Commun. 2000, 939. Skabara, P. J.; Roberts, D. M.; Serebryakov, I. M.; Pozo-Gonzalo, C. Chem. Commun. 2000, 1005. Caronna, T.; Sinisi, R.; Catellani, M.; Malpezzi, L.; Meille, S. V.; Mele, A. Chem. Commun. 2000,1139. Taki, M.; Murakami, H.; Sisido, M. Chem. Commun. 2000,1199. Pei, J.; Yu, W.-L.; Huang, W.; Heeger, A. J. Chem. Commun. 2000,1631. Muto, T.; Temma, T.; Kimura, M.; Hanabusa, K.; Shirai, H. Chem. Commun. 2000,1649. Sarker, A.; Haley, M. M. Chem. Commun. 2000,1733. Kumpumbu-Kalemba, L.; Leclerc, M. Chem. Commun. 2000, 1847. Ichikawa, J.; Fujiwara, M.; Wada, Y.; Okauchi, T., Minami, T. Chem. Commun. 2000,1887. Kabir, S. M. H.; Iyoda, M. Chem. Commun. 2000, 2329. Hanton, L. R.; Richardson, C.; Robinson, W. T.; Tumbull, J. M. Chem. Commun. 2000, 2465. Cravino, A.; Zerza, G.; Maggini, M.; Bucella, S.; Svensson, M.; Andersson, M. R.; Neuebauer, H.; Sariciftci, N. S. Chem. Commun. 2000, 2487. Rfidl, S.; Hezky, P.; Urb~inkov~i,J.; V~ichal, P.; Krejci, I. Coil. Czech. Chem. Commun. 2000, 65, 280.

106

00CCC1082 00CEJ1663 00CEJ1698 00CL744 00CLl188 00CL1340 00CM284 00CM872 00CM1508 00CM1611 00CM1931 00CM2372 00CM2581 00CM2996 00CR2537 00CSR109 00DDR227 00EJMC499 00EJOC1327 00EJOC1353 00EJOC1653 00EJOC1703 00EJOC2357 00EJOC3139 00EJOC3273 00EJP255 00EPJ2005 00HCA3043 00HC94 00HC403 00HC434 00H(52)159 00H(52)365 00H(52)761 00H(52)1021 00H(53)1175 00H(52)1215 00JA585 00JA1154 00JA1820 00JA3037 00JA5052

E.T. P e l k e y

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F i v e - M e m b e r e d R i n g Systems: Thiophene & Se, Te, Analogs

00JA5788 00JA6746 00JA7042 00JA8309 00JA8575 00JA9006 00JA10456 00JA11021 00JAB546 OOJCS(P1)1211 OOJCS(P1)1811 OOJCS(P1)1877 OOJCS(P1)2968 00JCS(P1)3020 00JCS(P1)3513 00JCS(P1)4316 00JCS(P2)1453 00JCS(P2)1788 00JCS(P2)1976 00JCS(P2)2492 00JCCS83 00JFC323 00JHC25 00JHC171 00JHC281 00JHC363 00JHC389 00JHC847 00JHC959 00JHC997 00JHC1009 00JHC1363 00JMAT107

107

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00JMAT263 00JMAT927 00JMAT1303 00JMAT1777 00JMAT1785 00JMC167 00JMC649

Bouachrine, M.; I_Are-Porte, J.-P.; Moreau, J. J. E.; Serein-Spirau, F.; Torreilles, C. J. Mater. Chem. 2000,10,263. L6re-Porte, J.-P.; Moreau, J. J. E.; Serein-Spirau, F.; Torreilles, C.; Righi, A.; Sauvajol, J.-L.; Brunet, M.J. Mater. Chem. 2000,10,927. Matharu, A. S.; Grover, C.; Komitov, L.; Andersson, G.J. Mater. Chem. 2000,10,1303. Kilbinger, A. F. M.; Feast, W. J.J. Mater. Chem. 2000,10, 1777. Ryder, K. S.; Schweiger, L. F.; Glidle, A.; Cooper, J. M.J. Mater. Chem. 2000,10,1785. Zhang, S.-X.; Feng, J.; Kuo, S.-C.; Brossi, A.; Hamel, E.; Tropsha, A.; Lee, K.-H. J. Med. Chem. 2000, 43,167. Sall, D. J.; Bailey, D. L.; Bastian, J. A.; Buben, J. A.; Chirgadze, N. Y.; Clemens-Smith, A. C.; Denney, M. L.; Fisher, M. J.; Giera, D. D.; Gifford-Moore, D. S.; Harper, R. W.; Johnson, L. M.; Klimkowski, V. J.; Kohn, T. J.; Lin, H.-S.; McCowan, J. R.; Palkowitz, A. D.; Richett, M. E.; Smith, G. F.; Snyder, D. W.; Takeuchi, K.; Toth, J. E.; Zhang, M. J. Med. Chem. 2000, 43, 649.

108

00JMC683 00JMC765 00JMC1264 00JMC1293 00JMC1586 00JMC1762 00JMC1841 00JMC2403 00JMC2929 00JMC4877 00JMS203 00JOC352 00JOC2043 00JOC2048 00JOC2759 00JOC2900 00JOC3569 00JOC3690 00JOC3883 00JOC3894 00JOC3920 00JOC5089 00JOC5413 00JOC5480 00JOC5760 00JOC7055 00JOC7971 00JOC8114 00JOC8134 00JOC8188 00JOC8669 00JOC8811 00JOMC8 00JOMC22 00JOMC96 00JOMC187 00JOMC488 00JPC5974

E.T. Pelkey

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Five-Membered Ring Systems: Thiophene & Se, Te, Analogs 00MAC2462 00MAC4628 00MAC5481 00MAC8211 00OL351 00OL1749 00OL2351 00OL2419 00OL2749 00OL2979 00OL3417 00OL3719 00OL3757 00OL3829 00OL4197 00OM1008 00OM1035 00PH291 00P423 00P3147 00P5681 00P9147 00PB231 00PAC1645 00SL61 00SL459 00SL963 00SL1058 00SL1470 00SL1788 00SC1359 00SC1695 00SC2281 00SC3569 00SM33 00SM47 00SM83 00SM89 00SM133 00SM151 00SM213 00SM235 00SM305 00SM433 00SM437 00S507 00S970 00S1078 00S1229

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110

00S1253 00S1637 00S1863 00T1247 00T2985 00T3255 00T3425 00T4085 00T4249 00T6845 00T7205 00T7573 00T8153 00T9383 00TA2315 00TA4463 00TL617 00TL1597 00TL1951 00TL2185 00TL2667 00TL2675 00TL2749 00TL2919 00TL2983 00TL3197 00TL3607 00TL3709 00TL4973 00TL5005 00TL5039 00TL5151 00TL5393 00TL5415 00TL5521 00TL5637 00TL7259 00TL7731 00TL8461 00TL8843 00TL9607 00TL10277

E.T. Pelkey

Lucas, P.; E1 Mehdi, N.; Ho, H. A.; B61anger, D.; Breau, L. Synthesis 2000, 1253. Yokoyama, M. Synthesis 2000,1637. Karlsson, S.; H6gberg, H.-E. Synthesis 2000,1863. Ar6valo, M. J.; Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B 9Jim6nez, J. L.; Light, M. E.; L6pez, I.; Palacios, J. C. Tetrahedron 2000, 56, 1247. Brugier, D.; Outurquin, F.; Paulmier, C. Tetrahedron 2000, 56, 2985. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.; Temperini, A.; Tomassini, C.; Santi, C. Tetrahedron 2000, 56, 3255. Bilokin, Y. V.; Melman, A.; Niddam, V.; Benham6, B.; Bachi, M. D. Tetrahedron 2000, 56, 3425. Cook, M. J.; Jafari-Fini, A. Tetrahedron 2000, 56, 4085. Feng, J.; Szeimies, G. Tetrahedron 2000, 56, 4249. Koshima, H.; Matsushige, D.; Miyauchi, M.; Fujita, J. Tetrahedron 2000, 56, 6845. Heerklotz, J.; Linden, A.; Hesse, M. Tetrahedron 2000, 56, 7205. Abdou, W. M.; Kamel, A. A. Tetrahedron 2000, 56, 7573. Suresh, J. R.; Barun, O.; Ila, H.; Junjappa, H. Tetrahedron 2000, 56, 8153. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. Tetrahedron 2000, 56, 9383. Dai, W.-M.; Zhu, H.-J.; Hao, X.-J. Tetrahedron Asymm. 2000,11,2315. Krishna, P. R.; Lavanya, B.; Ilangovan, A.; Sharma, G. V. M. Tetrahedron Asymm. 2000, 11, 4463. Wang, C.; Dalton, L. R. Tetrahedron Lett. 2000, 41,617. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41,1597. Song, K.; Wu, L.-Z.; Yang, C.-H.; Tung, C.-H. Tetrahedron Lett. 2000, 41, 1951. Nakamura, H.; Aizawa, M.; Takeuchi, D.; Murai, A.; Shimoura, O. Tetrahedron Lett. 2000, 41, 2185. Chandrasekhar, S.; Reddy, M. V.; Reddy, K. R.; Ramarao, C. Tetrahedron Lett. 2000, 41,2667. Braverman, S.; Zafrani, Y.; Gottlieb, H. E. Tetrahedron Lett. 2000, 41,2675. Meth-Cohn, O.; Ashton, M. Tetrahedron Lett. 2000, 41,2749. Jang, Y.-S.; Kim, H.-J.; Lee, P.-H.; Lee, C.-H. Tetrahedron Lett. 2000, 41,2919. Aqad, E.; Ellem, A.; Shapiro, L.; Khodorkovsky, V. Tetrahedron Lett. 2000, 41,2983. Ford, E.; Brewster, A.; Jones, G.; Bailey, J.; Sumner, N. Tetrahedron Lett. 2000, 41,3197. Tranchier, J.-P.; Chavignon, R.; Prim, D.; Auffrant, A.; Plyta, Z. F.; Rose-Munch, F.; Rose, E. Tetrahedron Lett. 2000, 41, 3607. Ravikanth, M. Tetrahedron Lett. 2000, 41,3709. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett. 2000, 41, 4973. Watson, J. A.; Pascal, R. A.; Ho, D. M.; Kilway, K. V. Tetrahedron Lett. 2000, 41,5005. Gosmini, C.; N6d~lec, J. Y.; P6richon, J. Tetrahedron Lett. 2000, 41,5039. Kabalka, G. W.; Wang, L.; Namboodiri Tetrahedron Lett. 2000, 41,5151. Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetrahedron Lett. 2000, 41,5393. Gallagher, T.; Pardoe, D. A.; Porter, R. A. Tetrahedron Lett. 2000, 41,5415. Turbiez, M.; Fr6re, P.; Blanchard, P.; Roncali, J. Tetrahedron Lett. 2000, 41,5521. McConachie, L. K.; Schwan, A. L. Tetrahedron Lett. 2000, 41,5637. Nandi, B.; Das, K.; Kundu, N. G. Tetrahedron Lett. 2000, 41,7259. Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D. R. Tetrahedron Lett. 2000, 41, 7731. Otani, T.; Sugihara, Y.; Ishii, A.; Nakayama, J. Tetrahedron Lett. 2000, 41, 8461. Amaresh, R. R.; Lakshmikantham, M. V.; Geng, R.; Cava, M. P. Tetrahedron Lett. 2000, 41, 8843. Petasis, N. A.; Patel, Z. D. Tetrahedron Lett. 2000, 41, 9607. Dai, W.-M.; Mak, W. L. Tetrahedron Lett. 2000, 41, 10277.

111

Chapter 5.2 Five Membered Ring Systems: Pyrroles and Benzo Derivatives

Daniel M. Ketcha

Wright State University, Dayton, OH, USA daniel ketcha @wright. edu

5.2.1

INTRODUCTION

The subjects of pyrroles, indoles, and related heterocycles were amply reviewed during the reporting period of this chapter. Most notably, Gribble published a review on recent developments in indole ring synthesis - methodology and applications which covered the period of 1994-1999 <JCS(P1)1045>, while a more general review on the synthesis of heterocycles by radical cyclizations also appeared <00JCS(P1)I>. In the area of natural products, there appeared reviews on pyrrolizidine <00NPR455> and indolizidine alkaloids <00NPR579>, as well as an overview of pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids <00NPR435>. Bonjoch reviewed synthetic approaches to strychnine <00CR3455> and Lounasmaa reported on simple indole alkaloids and those with a nonrearranged monoterpenoid unit <00NPR175>. In the broader context of heterocyclic natural products, Winterfeldt examined biomimetic syntheses of alkaloids <00NPR349> while Faulkner provided a survey of marine natural products <00NPR7>. A review coveting the synthetic utility of furan-, pyrrole- and thiophene-based 2-silyloxydienes was prepared by Casiraghi <00CSR109>, and a review on the mechanisms of pyrrole electropolymerization also appeared <00CSR283>. In a study of the synthesis and NMR characteristics of 1arylpyrroles, good correlations were observed between the chemical shift values of the [3-H and the 13-Cofpyrroles and the Hammett o <00JHC15>.

5.2.2

SYNTHESIS OF PYRROLES

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>.

TBDMSOI,,~

TBDMSo/,H~"~ R-NH2,, H R~N 2

112

D.M. Ketcha

The Paal-Knorr reaction was also employed by Steglich in likely biomimetic approaches to the marine alkaloids lamellarin L <00CEJ1147> as well as purpurone and ningalin C <00TL9477>. The overall approach employed herein involved initial oxidative coupling of two arylpyruvic acids followed by condensation of the resulting 1,4-diketones with suitable 2-arylethylamines. Ferreira developed a novel method for the preparation of masked 1,4-dicarbonyl derivatives for utilization in the Paal-Knorr synthesis of pyrroles <00SC3215>. In this process, the reaction between diazocompound 3 and n-butyl vinyl ether using dirhodium tetraacetate as catalyst provides dihydrofurans 4 which are easily converted into substituted 3-acylpyrroles 5 upon reaction with amines.

M"

\~) N2

IILOBu-n

n-BuO ~ \ 0 / -'Me

XN/-'Me

3 4 ~2 5 Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5dimethylfuran with magnesium monoperoxyphthalate to cis-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 7 131.O2

O

DBU " MeCN

6

O 40 psi

R basic AI203

8

9

1~2 10

Akiyama developed a novel [3+2] cycloaddition reaction of alkenyl Fischer carbene complexes 11 with simple imines 12 in the presence of a catalytic amount of GaC13 to produce 3-alkoxy-2,5-disubstituted-3-pyrroline derivatives 13 <00JA11741 >. (oc

=~~OR3 )hCr 11

+

RI

~'~

R30

GaCI3 CICH2CH2CI reflux, lh

R2

R4 12 i~~ 13 Merlic demonstrated the direct, non-photochemical insertion of carbon monoxide from acylamino chromium carbene complexes 14 to afford a presumed chromium-complexed ketene 15 <00JA7398>. This presumed metal-complexed ketene leads to a munchnone 16 or munchnone complex which undergo dipolar cycloaddition with alkynes to yield the pyrroles 17 upon loss of carbon dioxide. O O R4 R5 (CO)hCr O RI,~N.JLR3 14

"~-~R 4

N R2/ IJ

~: O ~ (OC)4Cr-'~Ri/~N/~R 3u 15

~NO@

> R1

~R 3

16

CO

R4 _ _

R5 ~" R1

R3 17

Domino reactions of imines with difluorocarbene in the presence of electron-deficient alkynes lead to 2-fluoropyrroles. For instance, reaction of N-benzylideneaniline (18) with difluorocarbene yields an intermediate azomethine ylide 19 capable of undergoing 1,3-

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

113

dipolar cycloaddition with electron-deficient alkynes leading to 2-fluoropyrroles 20 upon dehydrofluorination <00JCS(P1)231>. This manuscript also discloses a new modification of the difluorocarbene generation protocol, using active lead obtained by reduction of aqueous lead acetate with sodium borohydride instead of lead powder. Ph p./---Nn

:CF2

I

OPh

]

CO2R

F I Ph Katritzky developed a facile synthesis of ],2-diaryl(heteroary])pyrroles in a two-step procedure from N-al]ylbenzotriazo]es via intramolecular oxidative cyclization in the presence of a Pd(II) catalyst <00JOC8074>. Thus, treating N-a]lylbenzotfiazole (2]) with nbury]lithium followed by addition of a diary]imine yielded the (2-benzotnazolyl-l-arylbut-3en)anilines 22 which were subsequently heated in the presence of the system Pd(OAc)2-PPh3CuC12-K2CO3 to undergo intermolecular amination with simultaneous oxidation of the intermediate 3-pyrroline to the pyrroles 23. 18

Ph~OCF2

R'

19

I. n-BuLi

Bt ~

, 2. Arl-CH=N-Ar2

21

Ph

20

Art__ "...r~N-H Bt~ /

Pd(OAc)2/PPh3 ~ CuCl2, K2CO3

22

r1

~kr2 23

Grigg has examined the Pd-catalyzed cyclization of enamines containing 13-vinyl bromide functionalities <00CC873>. Thus, treatment of the amine 24 with mono- or disubstituted alkynes (e.g., 25) affords the enamines 26 which upon treatment with Pd(OAc)2/PPh3 and K2CO3 leads to cyclization to the pyrroles 27. At present it is unclear whether the palladium(II) serves as a Lewis acid lowering the pKa of the N-H group leading to cyclization via nucleophilic attack on the vinyl bromide moiety or rather involves the oxidative addition of Pd(0) into the C-Br bond leading to a palladacycle. Br

+ NH2

24

R --

002 R1

25

DMF rt

Br ~ ' ~ N H 26

CO2R1

R

Pd(OAc)2, PPh3 K2CO3, DMF, 85~

'X,,~/cO2R1 H 27

Hewson reports an improvement on his earlier pyrrole synthesis via intramolecular Wittig reaction of (z-amido ketones 28 affording 4-phenylthio-3-pyrrolines <95Sl151>. In the original version, oxidation to the sulfone 29 was followed by reduction of the amide and aromatization resulting in a pyrrole bearing N-benzyl and 3-sulfone moieties, both of which are not easily removed. The simple extension of treating the 3-pyrroline with potassium tertbutoxide leads directly to the 2,3-disubstituted pyrrole 31 presumably by deconjugation to the 2-pyrroline 30 followed by elimination of benzenesulphinic acid <00TL8969>. This author also utilized this reaction as a key step in a synthesis of the necine base (-)-supinidine <00JCS (P 1)3599>. R O 1. Nail ,. R $O2Ph R SO2Ph R R1 28

2. P NH PPh3 I COPh 3. MCPBA

R'

KOButr R' = COPh

29

I COPh 30

I COPh 31

Katritzky offers a general one-pot alternative approach to polysubstituted pyrroles utilizing disubstituted olefins of which a wider variety is commercially available compared to acetylenes <00JOC8819>. Thus, thioamides 32 were subjected to Mannich condensation with aldehydes and BtH to yield functionalized thioamides 33 which were then treated with base

114

D.M. Ketcha

followed by MeI to afford the corresponding S-methylthioamidate intermediates 34. Conversion into the desired pyrroles was achieved by an additional 3 equiv of t-BuOK and an activated olefin (ester, amide, sulfone, cyano). Quenching the reaction mixture with acyl chlorides or alkyl halides led to the N-acylated or N-alkylated products 35.

S BtH ~ S Bt r Mes Bt 1. R2-CH=CHX X R,,~ NH2 .R30HO R,,,J~N.,,~R3 THF6o~el t-BuOK -- [ R,,,.,~.~N~,,.R3 t-BuOK . ~ 32 PhCH3 H 2. Nail, R4-• " R1 33

34

R2 R3

IR4 35

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of tert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX2LiC1 (X =-C1, -CN) to afford ot-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to o~,[3-alkynylketones affording ml3-enones 37, which upon treatment with PhOH/TMSC1 undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 <00OL2283>.

R

a2

R1

L..J

1. sec-BuLi

2. CuCN-2LiCl

I

3. R 2

Boc

--

R

"

COR 3

36

R~

~ O L;O c '152 ' 153 37

PhOH = TMSCl

R I . . ~ N ~.,..R3 R

J

38

Trofimov has extended his previously reported heterocyclization of ketoximes 39 with acetylene to propyne or its isomer allene in superbase systems (MOR/DMSO" M = K, Cs, R = H, t-Bu) to afford a facile synthesis of substituted pyrroles 40 and 41 <00S1585>. Due to a fast propyne to allene protropic isomerization under the reaction conditions, the product is the same regardless of which species is employed. R2

R~~I 39

N~.OH

+ ---- ~ Me I,

R2

MOR/DMSO ~ 115-125~ R1

40

Me

I

H

+

R2

R'

Me 41 ~

Petrillo reports that the reaction of 1,4-diaryl-2,3-dinitrobutadienes 42 with representative primary amines leads to N-alkyl-3-alkylamino-2,5-diaryl-4-nitropyrrolidines 43 presumably via a "disfavored" 5-endo-trig ring closure <00EJOC903>. Acid catalyzed elimination of the amine led to the corresponding trans-2,5-diaryl-3-nitro-3-pyrrolines 44 which could be dehydrogenated to the corresponding pyrroles 45.

r ~ A O2 N 42

NO2

Ar

O2N

.,,NH R

RNH2 ~ A CH2CI2/MeOI-~Arw" I

R 43

O2N

O2N

PPTs ~A r 0H2012 -" ArW'

DDQ " ~ A r PhMe,A Ar

R 44

R 45

I

I

r

A facile synthesis of 5-substituted 3-aminopyrrole-2-carboxylates has been developed wherein condensation of diethyl aminomalonate with ot-cyano ketones 46 was facilitated by prior formation of the p-toluenesulfonyl enol ether 47 <00JOC2603>. Addition of the amine component is followed by cyclization and decarboxylation to afford the pyrroles 48.

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

NC. R2 NCo/~,,'R2 ,~ TS20, Et3N=TsOL R1 R1 CH2CI2

.NH2.HCI NaOEt " EtO2C'~CO2Et

115

H2N R2 ~ff~ EtO2C R1

46 47 48 The reaction of tosylmethyl isocyanide (TosMIC) with chalcones was employed in the synthesis of 3-aroyl-4-arylpyrroles which were demonstrated to represent a new class of COX-I/COX-2 inhibitors <00EJMC499>. As pointed out by Lash, the Barton-Zard synthesis of pyrroles often fails with nitro aromatic compounds since the precursor nitroarene must possess sufficient nitroalkene character to allow nucleophilic attack by the enolate anion derived from the isocyanoacetate ester <00SL213>. To this end, this author utilized a phosphazene base 51 to allow hitherto unreactive nitroaromatic compounds to condense with ethyl isocyanoacetate to give annelated pyrroles. Interestingly, 3-nitropyridine (49) reacted under these conditions to afford the novel tricyclic heterocycle 50. Likewise, Murashima, Ono and coworkers also utilized the reaction of dinitrobenzene derivatives with isocyanates in the presence of DBU or phosphazene base for the preparation of stable 2H-isoindoles <00JCS(P1)995>, while Ono employed the Barton-Zard reaction for the preparation of 4formylpyrrole-2-carboxylates enroute to cycloalkano-oligopyrroles <00JCS(P 1)2977>.

'NO2 49

H2 ~ N . ..C(VH3)3 CN-C-CO2Et H ~ I~ Base EtO2C---~'N" -'~ Base= L...../P-P-pN,~J ~1~..~./ CO2Et p, 50

f ' "/

51 The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B <00JOC2479>. Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55.

MeO---~'~ - )_=., ,=

OMe ~k/--OMe

MeO ~

MeO OMe MeO MeO ~ Zn M e O - - ~ ~

OMO

_

N=N ~ ~ OMOM MeO2C---~\ /~)--CO2Me MeO2C---~\//~-CO2Me N-N N-N 53

5.2.3

OMe

54

OMOM MeO2C/~N/~CO2Me H 55

REACTIONS OF PYRROLES

Although the most characteristic reaction of the pyrrole nucleus is the predominant addition of electrophiles to the C-2 position, it is interesting to note that contrary to previous assumptions, sulfonation of pyrrole and its 1-methyl derivative with sulfur trioxide-pyridine complex affords mainly the 3-sulfonated pyrroles <00TL6605>. As Mizuno wisely points out, it is likely that some of the pyrrole-2-sulfonates reported previously are actually pyrrole3-sulfonates. Donohoe reports a novel and unprecedented reductive aldol process involving the Birch reduction of furans and pyrroles (e.g., 62) which presumably generates a dianion 63 and subsequently (after protonation at C-5 by ammonia) an enolate 64. After quenching excess

116

D.M. Ketcha

electrons with isoprene, the enolate was treated with a series of aldehydes yielding the aldol products 65 <00TL989>. Although the reaction was not stereoselective, the pyrrolines could be oxidized and then reduced with NaBH4 to provide syn-aldol adducts with high levels of stereoselectivity. 2 Li ~ HO [O . ~ O P ? 1 ~ ~ ~ r ,,OP? is~ ~ c R c02Pr j Li, NH3 ~ NH3= O2P~ ' = THF,-78~ / 13oc O (~) 13oc O O then RCHO Boc Boc 62

"-

63

64

65

Additionally, it was found that the double reductive alkylation of the 2,5-diester 66 could be achieved under Birch conditions (Li/NH3) to produce the 3-pyrroline 67. On the basis of a mechanistic postulate that such reductions do not involve transfer of a proton from ammonia, the authors discovered that the same reduction could be performed in THF (no ammonia) with lithium metal and catalytic amounts of naphthalene as an electron shuttle, thereby making this reaction more practicable on a large scale <00TL1327>.

EtO2C

I

CO2Et

Boc 66

(i) Li (10 equiv.), THF, -78~ , . ~ ~

" EtO2C'~N _~_/~CO2Et Boc

(8 mol%)

(ii) Mel

67

In the case of mono-ester substituted pyrroles (e.g., 68) wherein relatively unstable dianions likely to deprotonate ammonia might be produced, the authors instead utilized an excess of (MeOCH2CH2)2NH as a substitute for ammonia. It was felt that upon in situ formation of (MeOCH2CH2)2NLi, this base would be unable to protonate the dianion <00TL1331>. Remarkably, quenching the reduction reactions with benzoyl chloride affords 13-keto esters (e.g., 69, R = COPh), a reaction that does not occur when conducted in liquid ammonia.

I Boc

CO2Pri

(i) Li (15 equiv.), THF,-78~ ~ ~ (5 equiv.) (MeOCH2CH2)2NH (5 equiv.)

68

-=

/-~,,R k,N ~CO2Et i Boc 69

(ii) R-X

An interesting approach to the pyrrolizidine skeleton was devised wherein pyrrole-2carboxaldehyde (70) underwent N-allylation under basic conditions and subsequent olefination with ethyl p-tolylsulfinylmethanephosphonate to produce the pyrrolyl alkene 71 <00TL1983>. Intramolecular Heck reaction of the iodo species then produced the 1-ptolylsulfinyl- 1,3-diene 72.

c.o 1 . , . 2 0 . H 70

'

2. LDA, THF, -78~ (EtO)2OPvSOTol

' 'SOTo' pdpp,3, -

%., II

71

50uC

SOT~ 72

A facile approach to 3-aryl pyrroles was devised from commercially available 1-benzyl 3-pyrrolidinone (73) <00TL3423>. Preparation of the corresponding vinyl triflate 74 by trapping the regioselectively generated enolate with the triflating agent, N-phenyltrifluoromethanesulfonimide (Tf2NPh), followed by Suzuki coupling with aryl boronic acids occurred with concomitant dehydrogenation afforded the aryl pyrroles 75.

Five-Membered Ring Systems: Pyrrolesand BenzoDerivatives

~o

~OTf

1.NaHMDS i 2.Tf2NPh " Bn

i Bn

73

117

Ar

ArB(OH)2 _.dioxane,KOAc i Pd(PPh3)4 Bn

74

75

Wong has devised a remarkably versatile and highly regioselective synthesis of 3,4disubstituted pyrroles employing the ipso-directing property of a trimethylsilyl group <00JOC3274>. As a key starting material in this process, the known 3,4-bis(trimethylsilyl)pyrrole was protected with carefully chosen groups, namely tert-butoxycarbonyl, N,Ndimethylaminosulfonyl, p-toluenesulfonyl, and triisopropylsilyl. A highly regioselective mono- iodination of these N-protected pyrroles 76 was then achieved by reaction with iodinesilver trifluoroacetate affording 77. Subsequent palladium-catalyzed cross-coupling reactions afforded 4-substituted-3-trimethylsilyl derivatives 78, which again underwent further ipsoiodination and Pd-catalyzed cross-coupling (e.g., Sonogashira) to provide the unsymmetrical 3,4-disubstituted pyrroles 79. This approach was also utilized by Wong in a formal total synthesis of lukianol A <00JOC3587>. The Suzuki reaction was also employed by Ono in conjunction with the nitro arene Barton-Zard reaction described earlier for the preparation of dimers containing pyrrolobenzothiadiazole units <00JCS(P1)2761 >. a !

Me3Si~''~ ,,,~_/,SiMCF3CO2Ag12 e3rq Me3Si~l,. I~l~"'~ 2MPMe3Si d(PPh3)4A~rBArNa2CO3 (OH)2 IodinatiOncross.~and Ar R I

76

THF,lh

R

MeOH-PhMe R

77

coupling

78

R I

79

ot-Diazoketones derived from pyrrolyl- (80a,80b) or indolyl-carboxylic acids were prepared (using diazomethane and carbodiimide coupling reagents) and their Rh2(OAc)4 catalyzed decomposition resulted in the alkylation of the heteroaromatic system by the ketocarbenoid <00T8063>. Whereas decomposition of 80a gave 4,6-dihydrocyclopenta[b]pyrrol-5(1H)-one (81) as the sole product, the isomeric diazoketone 80b underwent both C-H and N-H insertion to afford a mixture of S1 and the 1H-pyrrolizin-2(3H)-one 82. R

80a: 80b:

Rh2(OAc)4= R= CH2COCHN 2andR'=H R=HandR'=CH2COCHN2 H R'

+ H1

Petrillo reported that the bis-acetoxymethylpyrrole 83 undergoes a sequential Diels-Alder reaction of the in situ generated 2,3-dimethylpyrrole with carbodienophiles (such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate) to afford the octahydrocarbazoles 84 which can be oxidized with DDQ to the corresponding carbazole derivatives <00OL73>. Bn Bn I I

' ~ AcO 83

OAc

dienophile (6eq) mesitylene,reflux

.

R--,~~R R

84

R

118

5.2.4

D.M. Ketcha

SYNTHESIS OF INDOLES

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20dioxane) at 180~ in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of N-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2:1 sodium bisulfite-sodium sulfite mixture <00JHC1293>.

NH2

R~~ R4 ~a3 ~R2I~'85 ) X~

COR2 NaHSO3/Na2SO 3 R 3 ~ H20/ROAc/A 9 R1 86 H

Witulski introduced a novel protocol for crossed alkyne cyclotrimerizations of systems such as 87 mediated by Grubb's catalyst to produce 4,6-disubstituted indolines 88 <00CC1965>. Interestingly, use of Wilkinson's catalyst [RhCI(PPh3)3] allows for the regioselective synthesis of the corresponding 4,5-substituted isomers. Ra

+ H ~ N ~

Ts 87

R1 [RuCI2(=CHPh)(PCy3)2]

H

"

Ts

88

R1

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-N-allylanilines in the presence of (-)sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of tBuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent.

[~

Br~, N

2.2 t-BuLi ,. n-C5H12-Et20 "78~

89

[~

Li/,

~CH3 1. (-)-sparteine ,. 2. temp,time ~~N 3. MeOH

N

~ 90

91

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,Ndisubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of ptBu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = C1, this cyclizative process can be coupled with other Pdcatalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring.

[Pd(dba)2]33 mol% 92

"NMe2

ptBu3,4.5 mol% base,o-xylene 120~

~"'ptBu2 93

NMe2

~ ~

94

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of N-aryl enaminones 97, this reaction could be applied in a tandem

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

119

fashion by combining C-N bond formation with an intramolecular Heck reaction to achieve a one pot synthesis of indoles (e.g., 98) utilizing 1,2-dibromobenzene (95) <00OL1109>. O O O

Br

+

. ~

Br H2N

95

Pd2(dba,3,80~ THF 0S2003,

I~I~B[.~

biarylphosphine

96

N H

Heck =~

i ~

N

97

H

98

In a process starting with the stereospecific Horner-Wadsworth-Emmons reaction of phosphonoglycinates 99 with 2-iodobenzaldehydes to afford the corresponding (Z)didehydro-phenylalanine derivatives 100, Brown similarly utilized an intramolecular palladium-catalyzed amination of 100 (Y = 2-chloro-3-pyridyl, Ph, OBn) to form the Nsubstituted indole carboxylates 101 <00TL1623>. H J~.'PO(OMe)2 MeO.~~~CHO MeO2C..~N MeO~

MeO2C/-...NH..~_ 99

Y

-U

~ .., DBU

Meo

,I Y Y P

~'Y~T"~, O 100

0 ,)cat.

KOAc,90ocDMF

101

Y

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. R3

O HN"R O H 102

R3

O

R3

CH3NO2

O

FA HO

R2

I

R"

103

104

R 105

Grigg has devised a chemo- and regio-specific palladium-catalyzed four component process initiated by oxidative addition of Pd(0) with aryl iodides 106 followed by sequential incorporation of CO (1 atm), a polymer supported allene 107 and an amine to provide oxindoles 108 with three points of diversity <00CC2241>. Alternatively, this author also reported a novel synthesis of oxindoles by Pd(0) catalyzed cyclization of 3-carbamoyl chlorides onto proximate alkene or alkyne groups <00CC2239>, while Jones prepared 3methylene oxindoles related to mitomycins by the radical cyclization of acetylenic amides from 2-bromoaniline and propiolic acids <00JCS(P 1)763>. Et, /Et

J 106

iPr2NEt

107

I] fl

piperidine toluene,50~

~

Sl(

0

lO8

Nicolaou reported a selenium-based approach for the solid-phase synthesis of indolines wherein o-allyl anilines 109 are "cycloloadded" onto a polystyrene-based selenyl bromide resin via a 5-exo-trig cyclization to afford the resin-bound indoline scaffolds 110 <00JA2966>. Such resin bound indoline scaffolds can be further elaborated and tracelessly cleaved providing access to 1-methylindolines. Moreover, the ability of this selenium tether to generate a carbon-centered radical also allows for a novel cleavage approach whereby

120

D.M. Ketcha

additional ring systems can be formed. For instance, coupling the indoline nitrogen to a series of olefinic acceptors via either amide or alkyl linkages to form derivatives of type 111 allowed for cleavage (Bu3SnH, AIBN) with concomitant cyclization to provide polycyclic indolines 112.

R

2

R1 ~

R ~I--SeBr R

R3~~R4 "NH2 109

~

Q

S e

SnCI4 R3~.,,,,.,,~.-...N CH2Cl2 /4 H 110

X

111

X 112

Zhang reported a solid-phase approach to indoles involving the palladium catalyzed heteroannulation of 2-iodoanilines with terminal alkynes. Unlike the analogous reaction with internal alkynes, activation of the amine in this case is required and to this end the authors ingeniously employ a resin-based traceless sulfonyl linker which serves the dual purposes of facilitating the indole cyclization and can afterwards be easily removed <00OL89>. Thus, reaction of commercially available PS-TsC1 113 resin with the iodoanilines 114 afforded the resin-bound precursors 115, which were treated with the terminal alkynes in the presence of Pd(PPh3)2 (10 mol%), CuI (20 mol%) and Et3N in DMF at 70~ to yield the resin-bound indoles 116. Whereas cleavage of arylsulfonyl indoles can normally be effected using alcoholic KOH, the resin-bound indoles were found resistant to such conditions but could be cleaved using tetrabutylammonium fluoride (TBAF) in THF at 70~

"~" 113

&

CI

+

114

H2

"

H ~Ar-SO2 115 '

R

[Pd]

~

'

Ar-SO2 116

K.nochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KOtBu or CsOtBu as well as KH in N-methylpyrrolidinone (NMP) for promoting the 5-endodig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of oalkynyltrifluoroacetanilides with the addition ofbenzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(1-alkynyl)-Nalkylideneanilines 117 give 2-substituted-3-(1-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>.

RI

~R R3

117

RI

2

Pd(OAc)2(5 mol~ ~ nBu3P (20 mol%) dioxane, 100~

R ~ N 118

R2 3

H

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of 2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These Nunprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles.

Five-Membered Ring Systems: Pyrrolesand BenzoDerivatives

[CO2Me 119

CO2Me [i O2Me

n-Bu3SnH,AIBN ,. 12 CH3CN' 100~ ~[~L'~N/~--SnBu3

NO

120

""~"--N

H

121

121

I

H

Rainier devised a variant of the 5-exo-dig radical cyclization of 2-alkynylisocyanides 122 wherein thiols were utilized to both initiate the radical cascade as well as act as nucleophiles in the reaction with the indolenine intermediate 123 yielding the indoles 124 <00JOC6213>. When R = TMS, elimination of the C-10 thioether can be effected in a gramine-like fashion so as to add nucleophiles (e.g., malonate anion) in the presence of Bu3P allowing for the preparation of more highly functionalized indoles.

i ~ 122

NC

F RN' S RR.

R'SH .. AIBN. 100~

SR' 124

123

H

Murphy previously reported a tetrathiafulvalene-mediated radical polar crossover reaction as a key step in a total synthesis of aspidospermidine <99JCS(P1)995>. This author now describes an alternative iodoazide radical cascade cyclization strategy as a key step in a formal synthesis of this alkaloid wherein aryl iodide 125 is selectively attacked by organosilyl radicals [from tris(trimethylsilyl)silane, TTMSS] in the presence of an alkyl azide to yield the desired skeleton 126 <00OL3599>. Moreover, this author also demonstrated the effectiveness of N-ethylpiperidine hypophosphite as a replacement for organotin reagents in the radical cyclization of similar substrates to hexahydrocarbazoles <00TL1833,00JCS(P1)2395>. It is noted by the author that the low cost of the phosphorus reagents and their ease of separation from reaction products heralds a new era where radical reactions forming C-C bonds are becoming both economical and convenient.

~h I

Ms

125

TTMSS AIBN. C6H6 reflux

Ms

126

Heathcock reported a novel intramolecular cascade reaction in which monocyclic precursor 127 undergoes a tricyclization to form 128 containing the B, C and D rings of aspidospermidine <00JOC2642>. Moreover, in this synthetic effort the authors disclosed a facile method of closing the E ring in high yield using silver triflate in what had been a hitherto difficult process due to steric impedence about the pseudopentacoordinate transition state. O

NHBoc OHC,,,,Et H ~ N , ~ ' , . C l 0

127

TFA-CH2cl2 0 H

128

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine

122

D.M. Ketcha

(131) <00OL1625>. The synthesis was then completed by invoking Stork's classic Fischer indolization strategy to afford the target molecule. ~

TiCl4 ,

NHH 131

130

129

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. OAc

[/~~

'CH2OTBS

",,,,,~O,,

L~/~'~

_~,NMe

132'~'

1. AgOTf CH3CN

2. BnNMe3NCN

133

134 oAc

C~

y--NN~I~NMe

5.2.5

NMe

/"',. I

/-orBs

O

" L

NMe

=

NMe O

137

=

[ ~ ~ - - ~ CH2OTBs (~ CN OI~"(~)N~N

136

135

Me

REACTIONS OF INDOLES

As described earlier, Wong introduced the N,N-dimethylaminosulfonyl (DMAS) moiety as a useful N-protecting group for pyrroles which is amenable to cleavage with TBAF or M ~ e O H <00JOC3274>. However, when employed for the protection of indoles, Dodd and coworkers found such conditions afforded inconsistent results and cleavage was found to be markedly substituent dependent <00TL9403>. To this end, Dodd reports that controlled potential electrolysis has proven to be an efficient solution to this problem, wherein the DMAS-group could be cleaved selectively in the presence of other reducible functional groups such as nitrile, ester, chloride and carboxamide. In terms of methodologies for the preparation of N-arylindoles 140, Buchwald reported improved conditions for the palladium-catalyzed coupling of aryl chlorides, bromides, iodides and triflates 138 with a variety of 2-, 7- and polysubstituted indoles 139 utilizing novel electron-rich biaryl(dialkyl)phosphine ligands in combination with Pd2(dba)3 <00OL1403>. Alternatively, Watanabe reports similar N-arylations of pyrrole, indole and carbazoles with aryl bromides and chlorides using Pd(OAc)2/P(t-Bu)3 in xylene at 120~ <00TL481 >.

X Rl.~~~ " 138

+

R 2 ~ 139 H

Pd2(dba)3 ligand base,toluene 60"120~

R 2 ~ 140

R1

Indolylborates 142 (Z = Me, Boc, OMe), available via regioselective C-2 lithiation of indoles 141, are capable of undergoing palladium-catalyzed carbonylative cross-coupling

123

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

with vinyl triflates to afford indol-2-yl ketones 143 and this process was utilized enroute to the synthesis of yuehchukene and analogs <00H(53)2201>.

1. tert-BuLi/THF 2. BEt3

t3

T ,. PdCI2(PPh3)2 z 143 141 142 CO (10 atm) Gribble reports a convenient one-pot synthesis of 2,3-diarylindoles via a bis-Suzuki palladium-catalyzed cross-coupling of 2,3-dihalo-l-(phenylsulfonyl)indoles 144 with arylboronic acids 145 <00TL8717>. Deprotection of the resulting indoles 146 can then be effected with Mg/MeOH to afford the corresponding N-unsubstituted analogs. The Suzuki arylation of 2-bromoindoles was also conducted on the solid-phase utilizing a carbamate indole linker for the synthesis of 2,3-disubstituted indoles and led to the discovery of a novel, high-affinity, selective h5-HT2a antagonist <00BMCL2693>. Z

X =Y= I X ==IY. Y==Br X Br X = Br, Y = I

[~7 ~

If"IY ,,~t,,,, N x ~ SO2Ph

Z

+

144

.B(OH)2

0

Pd(OAc)2(10 mol%)

P(o-tol)3,K2CO3

Z

"

aq. acetone (or DMF)

PhO2 L j 'z

145

146

Yoshino reports a novel and general method for the C-3 acylation of indoles with acyl chlorides in the presence of dialkylaluminium chloride which obviates the need for prior Nprotection <00OL1485>. Interestingly, as described in this preliminary communication, the unprotected indoles 147 are first treated with the Lewis acids prior to addition of the acid chlorides, yielding the desired 3-acyl derivatives 148. In reactions more typical of indoles under acidic conditions, Nakatsuka determined the structures of the dimers and trimers of 1trimethylacetylindole produced in the presence of aluminium chloride <00TL1059>.

X ~ 147

I

Et2AICI

or Me2AICI .. R'COCI

Ox-~7~N

R

148

R'

I

R

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from 1-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the 1-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. R

~ ~ N ~ 149

~ ,

R

Bu3SnSnBu3 methyl acrylate " ~ ~ N ~

06H6,80~ sun lamp

i

150

9,CO2Me [O]

=

R

~

CO2Me

151

In an altemate mode of radical cyclization, indolyl-2-radicals generated from the corresponding 2-bromo derivatives 152 (n=l-3) undergo intramolecular reactions with appended aromatic rings to afford fused [ 1,2-a]indoles 153 <00TL4209>.

124

D.M. Ketcha

CHO ( ~ 152

Bu3SnH,AIBN MeCN -~ syringepump

Br

~

~

~

CHO n

153

Molander has introduced a new generation of lanthanide metallocenes [CpTMS2y([.t-Me)]2 for the cyclization/silylation of 1-ally-2-vinyl-lH-indoles and -pyrroles <00JOC3767>. In this process, the active catalyst for the reaction, "CpTMS2YH'" undergoes initial olefin insertion at the vinyl group of 154, and the resulting intermediate 155 then undergoes cyclization onto the remaining alkene and subsequent silylation by an a-bond metathesis reaction, affording the fused-ring products 156.

[CpTMS2y(I~-Me)]2 154

~

PhSiH3

155

~

156

SiH2Ph

The intramolecular cycloaddition of nitrones derived from N-allyl-2-indolecarbaldehyde was used to an entry to pyrrolo- and pyrido[1,2-a]indole skeletons <00JOC8924>. For instance, the cinnamyl-substituted aldehyde 157 upon treatment with benzylhydroxylamine affords to the nitrone 158, which upon heating in refluxing toluene leads to mainly the cycloadduct 159. Ph

CliO

157

Ph~NHOH-HC/ Toluene,NaHCO3 ~~"~" Ph AI203,z~

-O 158

=

~Ph

~

N

~

159

O Ph

Gribble examined the cycloadditions of 3- and 2-nitroindoles 160 with unsymmetrical munchnones 161 (generated in situ from N-acylamino acids and diisopropylcarbodiimide) in a process which loses the elements of nitrous acid and carbon dioxide to afford pyrrolo[3,4b]indoles 162 <00T10133>. Surprisingly, the expected regioselectivity predicted from consideration of frontier molecular orbital theory is not observed, but rather the major products derive from the presumed positive end of the 1,3-dipole bonding with the electrondeficient indole C-3 position and the presumed negative site of the dipole bonding to the electron-rich indole C-2 position. R NO2

CO2Et 160

+

R

R1

THF A "

~

Bn 161

N

1 R

CO2Et 162

In terms of the asymmetric Pictet-Spengler (P-S) route to tetrahydro-[3-carbolines, Cook reported an improved procedure for the large scale synthesis of Nb-benzyl D-tryptophan methyl ester and its utilization in total syntheses of the sarpagine related indole alkaloids talpinine and talcarpine as well as alstonerine and anhydromacrosalhine-methine <00JOC3174>. Additionally, in furtherance of the concept that a bulky substituent on the Nbnitrogen is the only requirement to achieve 100% diastereoselectivity in the P-S reaction of carbonyl compounds with tryptophan alkyl esters, Cook also utilized the aforementioned Nbbenzyl ester to achieve the first enantiospecific total synthesis of (-)-corynatheidine as well as enantiospecific syntheses of corynantheidol, geissoschizol and geissoschizine <00JA7827>.

125

Five-Membered Ring Systems: Pyrroles and Benzo Derivatives

Other notable use of the P-S reaction for the synthesis of natural products include the synthesis of (-)-suaveoline by Bailey <00JCS(P1)3566,3578>, and yohimbine analogs by Brown <00TL5627,5631>. Interestingly, Singh reported a flexible variant of the P-S reaction employing oxazines and oxazolidines as synthetic equivalents of non-available carbonyl compounds <00TL4977>. Finally, the P-S condensation of a resin-bound tryptophancontaining fragment was employed as a key step in the synthesis of a tetrahydro-13-carbolinecontaining peptidomimetic library <00OL3075>. Tietze adopted a somewhat more indirect route to enantiopure tetrahydro-13-carbolines 166. This approach begins with P-S reaction of tryptamine with aldehydes or ot-keto acids to yield the carbolines 163, which upon oxidation to the corresponding imines 164 subsequently undergo enantioselective hydrogenation with the catalyst 165 in a 5:2 formic acid/triethylamine mixture in acetonitrile <00EJO2247>.

QTos ~ ] ~/

,~N KMn04" ~ / N / [ ~ N N H THF,-10~ H R R 163 164

cFU' ~/ TogNI~I~"1 ~ 165 -9 HCO2H/Et3N

}~r N H 166

H

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 <00OL953>. A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton <00OL675>.

9 ~ TMSCI I + N, Z 0H2012'"30~,,

167

Me

168

, Me

N,, Z

MeHN. O,..,,, iv,~~ --~ 0 q ~ N i ~i_i e 169

Me

Omura devised an efficient asymmetric synthesis of the 3a-hydroxyfuroindoline ring system required for the total synthesis of madindoline A (172) and B <00JA2122>. Thus, Sharpless asymmetric oxidation of tryptophol (170) led to the desired product 171 in 99% ee in a fashion consistent with the Sharpless epoxidation mnemonic <80JA5976>.

~ N H 170

OH (+)-DIPT ~ N Ti(O-i-Pr)4 t-BuOOH

H

171

HO ,

-

H~N

I~

NO 0

Ito has disclosed that the rhodium complex generated from Rh(acac)(cod) and PPh3 is a good catalyst for the hydrogenation of five-membered heteroaromatic compounds <00CL428>. This author further reports the rhodium catalyzed asymmetric hydrogenation of a variety of 2-substituted indoles 173 to the corresponding indolines 174 in enantiomeric excesses up to 95% by use of a trans-chelating chiral bisphosphine ligand, (S,S)-(R,R)PhTRAP (175) <00JA7614>.

126

D.M. Ketcha

[Rh(nbd)2]SbF 6(1.0mol%) R~

R 173

Ph2P\ "~ Me

Cs2CO 3(10mo1%)

,~c

~

R~

i-PrOH, H2 (5 MPa), 60~

R 174

,.

,~c

.~pph 2

M e"A

175

In miscellaneous oxidative processes of indoles, two methods for the preparation of 3hydroxyindoles have been reported. The first approach involves initial Vilsmeier-Haack reaction of indole-2-carboxylates 176 to afford the corresponding 3-formyl analogs 177. Activation of the aldehyde with p-toluenesulfonic acid (PTSA) and Baeyer-Villiger oxidation with m-chloroperoxybenzoie acid (m-CPBA) then affords high yields of the 3-hydroxy compounds 178 <00TL8217>

CHO

R

HCON(CH3)C6H 5R CICH2CH2CI,A

176

H

OH

Et

PTSA R

177

H

Et

178

Alternatively, diazotization of ethyl indole-2-carboxylate (179) leads to formation of 2carboethoxy-3-diazo-3H-indole (180) which undergoes rhodium-catalyzed alcohol O-H insertion reactions leading to 3-alkoxyindoles 181 <00TL6905>.

~ ~

Et

H

NaNO2/HCI ~ (

179

N2

180

OR O ROH ~ O Et Rh2(OAc)4 Et H 181

Some interesting chemistry of indoles has been uncovered utilizing fluorinating agents. For instance, treatment of 3-substituted indoles with commercially available Selectfluor in acetonitrile/water furnished 3-substituted-3-fluorooxindoles <00OL639>. An unusual diethylaminosulfur trifluoride (DAST)-mediated rearrangement of (3S,4S)-3-hydroxy-4-(2phenyl-lH-indol-3-yl)-l-piperidine-l-carboxylic acid benzyl ester 182 occurs presumably via initial formation of a reactive spirocyclopropyl-3H-indole 183 to give stereospecifically the product 184 <00JOC4984>.

HO,,,~.~Cbz

~b~

DAST,.r ' / ~ ~L~L..N/~-Ph Et5OoA ~ ~[~~N//~'-Ph 182

5.2.5

H

183

~NCbz ~L,,.~~N,2~Ph 184

H

PYRROLE AND INDOLE ALKALOIDS

The antitumor agent vinblastine sulfate was crystallized by the hanging drop vapor diffusion method and its structure determined by X-ray crystallography <00JCS(P1)2079>. The total synthesis of spirotryprostatin B was achieved by Ganesan <00JOC4685> and Danishefsky <00AG(E)2175> in studies which confirmed the proposed structure of this natural product. Synthetic approaches to diazonamide A were reported by Nicolaou <00AG(E)3473>, Moody <00TL6893,6897,6901>, Magnus <00TL831,835>, Vedejs <00OL1033>, Wood <00OL3521> and Harran <00AG(E)937,1156>. The intense synthetic interest in this metabolite of the colonial ascidian Diazona chinensis arises from its structural

F i v e - M e m b e r e d R i n g Systems: Pyrroles and Benzo Derivatives

127

complexity, which as pointed out by Nicolaou, "exemplifies an unprecedented molecular architecture encompassing a cyclic dipeptide backbone as well as an admirably complex and strained halogenated heterocyclic core trapped as a single atropisomer harboring a quaternary center at the epicenter." Williams reported the synthesis of VM55599 by intramolecular Diels-Alder cycloaddition of a reverse isoprene moiety across an azadiene <00JA1675>. Smith reported the synthesis of (-)-penitrem D <00JA11254> and utilized a Lewis acid biomimetic polyene cyclization route to achieve the first synthesis of the indole diterpene (+)emindole <00TL9419>. Ishikura utilized the Pd-catalyzed carbonylative cross-coupling reaction of indolylborates with vinyl triflates as the key step in the synthesis of yuehchukene <00H(53)2201>. Omura reported the synthesis of madindoline A and B, selective inhibitors of interlukin 6 <00JA2122>. The synthesis of the indolocarbazole antitumor antibiotic AT2433-A1 was reported by Van Vranken <00JOC7541>, while routes to arcyriaflavin A were reported by Bergman utilizing an intramolecular coupling of indole-3-acetic acid derivatives <00JCS(P1)2609>, and Lobo and Prabhakar <00TL9835> by a novel intramolecular sulfur-extrusion reaction. Other examples of notable indole alkaloid syntheses include the preparation of (-)-vindoline <00SL883>, (+)-chimonanthine by Overman <00AG(E)213>, lahadinine by Magnus <00TL9369>, and normalindine by Ohba <00T7751>. In addition to the syntheses of pyrrole natural products mentioned earlier, Hiemstra reported an enantioselective formal total synthesis of roseophilin <00OL1157,00JCS(P 1)345>. Other notable syntheses of pyrrole containing natural products include the tricyclic (+)-myrmicarin <00JOC2824>, the antimitotic rhazinilam <00JA6321>, and B-norrhazinal <JCS(P 1) 1497>.

5.2.6

REFERENCES

80JA5976 00A~(E)213 00AG(E)937 00AG(E)1156 00AG(E)2175 00AG(E)2488 00AO(E)2501 00AG(E)3473 00BMCL2693 00CC1965 00CC873 00CC1965 00CC2239 00CC2241 00CEJ1147 00CL428 00CSR109 00CSR283 00CR3455 00EJMC499 00EJO903 00EJO2247 00H(53)2201 00H(53)2415 00JA1675 00JA2122 00JA2966

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128 00JA3801 00JA5401 00JA5662 00JA6787 00JA6789 00JA7398 00JA7614 00JA7827 00JA11254 00JAIl741 00JCS(P1)I 00JCS(P1)231 00JCS(P1)345 00JCS(P1)763 00JCS(P1)995 00JCS(P1)1045 00JCS(P1)1497 00JCS(P1)2079 00JCS(P1)2069 00JCS(P1)2395 00JCS(P1)2671 00JCS(P1)2977 00JCS(P1)3389 00JCS(P1)3566 00JCS(P 1)3578 00JCS(P1)3599 00JHC15 00JHC1293 00JOC2603 00JOC2642 00JOC2824 00JOC3173 00JOC3274 00JOC3587 00JOC3767 00JOC4685 00JOC4984 00JOC6213 00JOC7541 00JOC8074 00JOC8819 00JOC8924 00NPR7 00NPR175 00NPR349 00NPR435 00NPR455 00NPR579 00OL73 00OL89 00OL639 00OL675

D.M. K e t c h a

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F i v e - M e m b e r e d Ring Systems: Pyrroles and Benzo Derivatives 00OL953 00OL1033 00OL 1109 00OL 1157 00OL1403 00OL1485 00OL1625 00OL2283 00OL3075 00OL3599 00S429 00S 1585 00SC3215 00SL213 00SL391 00SL394 00SL883 00T7751 00T8063 00T10133 00TL481 00TL831 00TL835 00TL989 00TL1059 00TL1327 00TL1331 00TL1623 00TL 1811 00TL1833 00TL1983 00TL3243 00TL4209 00TLA367 00TL4977 00TL5627 00TL5631 00TL6253 00TL6605 00TL6893 00TL6897 00TL6901 00TL6905 00TL8217 00TL8717 00TL8969 00TL9369 00TL9403 00TL9419 00TL9477 00TL9835 00TL1018

129

M. Nakagawa, M. Kawahara, Org. Len. 2000, 2,953. E. Vedejs, D.A. Barda, Org. Lett. 2000, 2, 1033. S.D. Edmondson, A. Mastracchio, E.R. Payne, Org. Lett. 2000, 2, 1109. S.J. Bamford, T. Luker, W.N. Speckamp, H. Hiemstra, Org. Lett. 2000, 2, 1157. D.W. Old, M.C. Harris, S.L. Buchwald, Org. Lett. 2000, 2, 1403. T. Okauchi, M. Itonaga, T. Minami, T. Owa, K. Kitoh, H. Yoshino, Org. Lett. 2000, 2, 1485. R. Iyengar, K. Schildknegt, J. Aube, Org. Lett. 2000, 2, 1625. R.K. Dieter, H. Yu, Org. Lett. 2000, 2, 2283. X. Li, L. Zhang, W. Zhang, S.E. Hall, J.P. Tam, Org. Lett. 2000, 2, 3075. B. Patro, J.A. Murphy, Org. Lett. 2000, 2, 3599. H. Tokuyama, Y. Kaburagi, X. Chen, T. Fukuyama, Synthesis 2000, 429. B.A. Trofimov, O.A. Tarasova, A.I. Mikhaleva, L.M. Sinegovskaya, J. Henkelmann, Synthesis 2000, 1585. A.C. Cunha, L.O.R. Pereira, R.O.P. de Souza, M. Cecilia, B.V. de Souza, V.F. Ferreira, Synth. Commun. 2000, 30, 3215. T.D. Lash, M.L. Thompson, T.M. Werner, J.D. Spence, Synlett 2000, 213. R. Ballini, L. Barboni, G. Bosica, M. Petrini, Synlett 2000, 391. A. Arcadi, S. Cacchi, G. Fabrizi, F. Marinelli, Synlett 2000, 394. S. Kobayashi, T. Ueda, T. Fukuyama, Synlett 2000, 883. M. Ohba, H. Kubo, H. Ishibashi, H., Tetrahedron 2000, 56, 7751. M. Salim, A. Capretta, Tetrahedron 2000, 56, 8063. G.W. Gribble, E.T. Pelkey, W.M. Simon, H.A. Trujillo, Tetrahedron 2000, 56, 10133. M. Watanabe, M. Nishiyama, T. Yamamoto, Y. Koie, Tetrahedron Lett. 2000, 41,481. P. Magnus, E.G. Mclver, Tetrahedron Lett. 2000, 41, 831. F. Chan, P. Magnus, E.G. Mclver, Tetrahedron Lett. 2000, 41,835. T.J. Donohoe, K.W. Ace, P.M. Guyo, M. Helliwell, J. McKenna, Tetrahedron Lett. 2000, 41, 989. N. Tajima, T. Hayashi, S. Nakatsuka, Tetrahedron Lett. 2000, 41, 1059. T.J. Donohoe, R.R. Harji, R.P.C. Cousins, Tetrahedron Lett. 2000, 41, 1327. T.J. Donohoe, R.R. Harji, R.P.C. Cousins, Tetrahedron Lett. 2000, 41, 1331. J.A. Brown, Tetrahedon Lett. 2000, 41, 1623. C.S. Cho, J.H. Kim, S.C. Shim, Tetrahedron Lett. 2000, 41, 1811. C. G. Martin, J.A. Murphy, C.R. Smith, Tetrahedron Lett. 2000, 41, 1833. M. Mar Segorbe, J. Adrio, J.C. Carretero, Tetrahedron Lett. 2000, 41, 1983. C.-W. Lee, Y.J. Chung, Tetrahedron Lett. 2000, 41, 3423. A. Fiumana, K. Jones, Tetrahedron Lett. 2000, 41, 4209. B. Dudot, J. Royer, M. Servin, P. George, Tetrahedron Lett. 2000, 41, 4367. K. Singh, P.K. Deb, Tetrahedron Lett. 2000, 41, 4977. R.T. Brown, S.B. Bratt, P. Richards, Tetrahedron Lett. 2000, 41, 5627. F. Binns, R.T. Brown, B.E.N. Dauda, Tetrahedron Lett. 2000, 41,5631. D.M. Ketcha, L.J. Wilson, D.E. Portlock, Tetrahedron Lett. 2000, 41, 6253. A. Mizuno, Y. Kan, H. Fukami, T. Kamei, K. Miyazaki, S. Matsuki, Y. Oyama, Tetrahedron Lett. 2000, 41, 6605. F. Lach, C.J. Moody, Tetrahedron Lett. 2000, 41, 6893. M.C. Bagley, S.L. Hind, C.J. Moody, Tetrahedron Lett. 2000, 41, 6897. M.C. Bagley, C.J. Moody, A.G. Pepper, Tetrahedron Lett. 2000, 41, 6901. J.G. Kettle, A.W. Faull, S.M. Fillery, A.P. Flynn, M.A. Hoyle, J.A. Hudson, Tetrahedron Lett. 2000, 41, 6905. Z.L. Hickman, C.F. Sturino, N. Lachance, Tetrahedron Lett. 2000, 41, 8217. Y. Liu, G.W. Gribble, Tetrahedron Lett. 2000, 41, 8717. I. Burley, B. Bilic, A.T. Hewson, J.R.A. Newton, Tetrahedron Lett. 2000, 41, 8969. P. Magnus, N. Westlund, Tetrahedron Lett. 2000, 41, 9369. M. Largeron, B. Farrell, J.-F. Rousseau, M.-B. Fleury, P. Potier, R.H. Dodd, Tetrahedron Lett. 2000, 40, 9403. J.D. Rainier, A.B. Smith III, Tetrahedron Lett. 2000, 41, 9419. C. Peschko, W. Steglich, Tetrahedron Lett. 2000, 41, 9477. M.M.B. Marques, M.M.M. Santos, A.M. Lobo, S. Prabhakar, Tetrahedron Lett. 2000, 41, 9835. L.D. Miranda, R. Cruz-Almanza, M. Pavon, Y. Romero, J.M. Muchowski, Tetrahedron Lett. 2000, 41, 10181.

130

Chapter 5.3 Five-Membered Ring Systems Furans and Benzofurans Xue-Long Hou

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. email: [email protected] Zhen Yang

Institute of Chemistry and Cell Biology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115-5731, U.S.A. email: zhen_yang @hms.harvard.edu and College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China (after October 2001). Henry N.C. Wong

Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. email: [email protected] and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. email: [email protected]

5.3.1 I N T R O D U C T I O N Furans and benzofurans continue to play an important role in the field of heterocyclic chemistry because their skeletons are present in many naturally occurring molecules, and they serve also as extremely useful precursors or intermediates towards the realization of many complex molecules. The authors of the present chapter have placed their attention on the more interesting applications and syntheses of these families of compounds, instead of executing an exhaustive literature search of all the relevant papers that were recorded in 2000. Several new furan-containing natural products were reported. The structures of five new furanocembrenoids 1-5, isolated from the venom of the Brazilian ant Crematogaster brevispinosa ampla, were established by NMR studies <00TL633>. The relative stereochemistry of two furanosesquiterpenes 6 and 7 from Commiphora sphaerocarpa has been determined and confirmed by NMR and X-ray crystallography as l(lO)E,2R*,4R*)-2-methoxy-8,12epoxygermacra-1 (10),7,11-trien-6-one and 1(10)E,4E-8,12-epoxygermacra-1 (10),4,7,11-tetraen6-one, respectively <00TL9875>.

Five-Membered Ring Systems: Furans and Benzofurans O

1 R 1 = R 2 = CO-n-Pr

I

131

MeO,,~ ~ ] ~

a R 1 = CO-n-Pr, R 2 = COMe OR 2 3 R 1 = COMe, R 2 = CO-n-Pr 4 R 1 = CO-n-Pr, R 2 = H

H~

_O

''~ r .

-

5 I:! 1 = H, R 2 = CO-n-Pr

~].,,,,"~,~.

O\

1i~ ,~

OII

\

6

7

The new tsitsikammafuran 8 was isolated from a South African Dysidea sponge. The structure of 8 was unequivocally substantiated by its synthesis from thymol <00T9391>. 12Acetoxypseudopterolide 9 was isolated from the non-polar fraction of the MeOH extracts of Pseudopterogorgia elisabethae Bayer collected from the Florida Keys <00H(53)717>. Interestingly, a structurally related bisfuranopseudopterane ether, namely biskalloide A 10, was shown to be one of the constituents of the West Indian alcyonacean Pseudopterogorgia bipinnate (Verrill, 1864), The structure elucidation of 10 was mainly based on 1D and 2D NMR and MS spectral studies, and was confirmed by a total synthesis <00JOC3192>.

:.k. 0

H

,,H

on 8

o 9

o

O

"I

o

10

Three new prieurianin-type tetranortriterpenoids dysoxylumins A 11, B 12 and C 13 were found from the EtOH extracts of the bark of Dysoxylum hainanense Merr., whose structures were established on the basis of 1D and 2D NMR studies <00H(53)2225>. Another family of naturally occurring secolimonoids with anti-feedant property, namely nimbolinins A 14, C 15 and D 16, were isolated by Nakatani from the unripe fruits of a Chinese meliaceae plant Melia toosendan. Again, their structures were determined by spectroscopic methods <00H(53)689>. Nakatani also identified other secolimonoids containing 3-substituted furan moieties from the stem bark of a meliaceous plant Khaya senegalensis <00H(53)2233> <00CL876>.

'Pr O. O-I-O

A

H C O 2 ~..,,,,'~=:

~

O

R

Aoo,"-W C

t " OAc

2

11 R = COCH(Me)Et 1 2 R = COCH(OAc) /-Pr 13 R = COCH(OH) /-Pr

I ~'--C~

OR

2

1 4 R 1 = Ac, R 2 = Bz, R 3 = H 15R 1 = Cin, R 2 = H, R 3= Me 16R 1 = H, R 2= Bz, R 3= Me

The structures of sclerophytins A 17 and B 18, isolated from the soft coral Sclerophytum capitalis, were revised on basis of spectroscopic re-evaluation <00OL1879>. Two unusual

flavonoid tetrahydrofuranyl skeletons, namely tephrorin A 19 and B 20, were identified from Tephrosia purpurea <00OL515>. An alkaloid cartormin 21 was isolated and identified from Carthamus tinctorius, a plant used widely as a traditional Chinese medicine, <00TL1955>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

132

IIHH

I,,o" ":.~OR

Ho~O~' OAc ,""

17R=H 18R=Ac

19

0

OH OH

~.0

HO

H

0

O

HOHO~ O H~-"-~'.,,,-O "

'

20

H

A ~ OH

~

21

Guided by in vitro cytotoxicity test against the KB cancer cell line, three novel 1,7dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-one derivatives, namely aculeatins A 22, B 23 and C 24 have been isolated from the petroleum ether extracts of rhizomes of Amomum aculeatum <00HCA2939>. A new styryllactone, namely cardiopetalolactone 25, was isolated from the stem bark extracts of Goniothalamus cardiopetalus (annonaceae). The absolute configuration of 25 was solved by employing the Mosher ester method <00T9985).

,,,I(CH2)12Me HO 22

,,~OH

Me(CH2)12 23

oU 0 "~0

24

25

The structure of amabiose 26, a new disaccharide skeleton obtained from the rhizomes of Hemsleya amabilis, was confirmed by an X-ray crystallographic study <00T7433>. Two highly oxygenated norbisabolane derivatives, namely phyllanthusols A 27 and B 28, have been isolated from the roots of Phyllanthus acidus <00JOC5420>.

Five-Membered Ring Systems: Furans and Benzofurans

133

HOHO OH

HO.

HO H H O

Ho I;

HOD

NO

.o

26

OH The structures of four new potentially allelopathic spiroditerpenoids, namely (+)breviones B 29, C 30, D 31 and E 32, have been identified from extracts of semisolid fermented Penicillium brevicompactum Dierckx <00JOC9039>.

R O

O 29

..0" O ~

R=H

30 31

AcO

R = OH

32

(+)-Tephrosone 33, a flavonoid belonging to the tephrorin family (vide supra), was found to possess a dihydrobenzofuran framework <00OL515>. Moreover, a metabolite of Penicillium brevicompactum, namely brevione A 34 was found to contain a spiro system <00TL2683>. Neomarinone 35, another metabolite from a marine actinomycete, constitutes an intriguing sesquiterpenoid skeleton <00TL2073>.

0

33

0

0 34

H

35

A new class of secondary metabolites tyrolobibenzyls A 36 and B 37 were isolated from

Scorzonera humilis (Asteraceae) of Tyrolean origin. Compounds 36 and 37 were shown to possess a unique phenylethylbenzofuran skeleton <00HCA2920>. The structure of the dimeric coumarin 38 was confirmed by an X-ray diffraction study, as well as by a photochemical synthesis from its co-occurring monomer bergapten <00H(53)441>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

134

OH

~

r"

.o

MeO

OH OH

o.

MeO

H , , ~ ~ .,~

~OH

36R=H 37 R = OH

"-O

38

5.3.2 R E A C T I O N S 5.3.2.1 Furans

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2:1 mixture of diastereomers via amidofuran cycloadditionrearrangement methodology, which serves as a key intermediate in the total synthesis of (+)dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile <00OL3233>.

0

tBuO2C ' N v V

Heat ],.

],,. 39

(•

Me"

An electron-withdrawing group on the alkenyl double bond has been shown to greatly facilitate the Diels-Alder cycloaddition with furan as depicted below < 00TL9387>. SMe

SMe ,oc,

O

CO2Me

.

O

Cycloaddition of furans followed by a subsequent transformation is still adopted as a useful strategy to prepare fluorine-containing benzene derivatives <00OL3345> and isoquinoline compounds <00SL550>. The cycloaddition adduct can also be converted to a trifluoromethyl substituted cyclohexanone compound via hydrogenation and hydrolysis. Examples of these transformations are illustrated below.

135

Five-Membered Ring Systems: Furans and Benzofurans

a3

~

a2"~

a3

a3 Br

(Me3Si)2NLi~ R 2 R 1 ~ t ~ ~ N

Reduction

R3

CF3

Ill

Heat ~

RX

CF3

XR

0 ~ C F

X=NH, O

3

87-92%

R1~ R3 R2 ~ y

"CF3

X=O 10% Pd/C R = SiMe3 H2 94% O ~ 0.2% HCI THF-H20 M e 3 S i O ~ CF3 80% cg3

OH

XR

+

OH

CF3 ~CF3

,~CF3 '~CF3

0

The cycloaddition-isomerization procedure can be accomplished in the presence of a catalytic amount of a transition metal salt. The reactions proceed at room temperature, neither air nor water needed to be excluded. The presence of an electron-withdrawing group is not necessary to activate the dienophile as the example below shows that gold coordination increases the electrophilicity of the triple bond. The presence of a terminal alkyne should also be important. In the case of a disubstituted alkyne no reaction can be observed <00JA11553>.

R1

R1 2 mol%AuCI3 ~ _ ~ / G MeCN,20~ R2 65-97% OH R2 G = CH2, O, NTs,C(CO2Me)2,NCH2Ts. The cycloaddition-isomerization strategy has also been applied to the synthesis of hydrindanone. Thus, by using a modified Kanematsu's procedure, the keto aldehyde 40, a hydrindanone of the steroid C-D ring type, can be synthesized from a substituted furan via a cycloaddition-isomerization procedure and is followed by subsequent transformations <00HAC755>.

~

e2

I,

t-BuOK t-BuOH

~.~1NMe2

~NMe2

[ ~

80o/o. 0 = ,~,,~

~'~,,,.0

CliO

40

Similar to gold(III) chloride, Diels-Alder cycloaddition can also be catalyzed by indium trifluoromethansulfonate. As can be seen below, the reaction proceeds when the mixture is irradiated with microwave. Although the same reaction could take place on standing for several days, the present one is solvent free and the yield is high. Also, the catalyst can be recovered and reused <00TL8639>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

136

AF !

O ~ R~

N Ar

10 mol% In(OT,)3 Microwave

R = H, CI, NO2

0~,~

O••NAr

Rs

R 80-90%

8-12%

A complexation-initiated reaction was realized for the first time as depicted below. Thus, the octacarbonyldicobalt complex of furan is subjected to silica gel and gives rise to the adduct with a seven-membered ring owing to bending of the triple bond to a structure with an angle of around 140 ~ when the alkyne is allowed to react with Co2(CO)8 at room temperature <00OL871 >. O

O~~~~,,,"~R

O

002(00)8

~

O .,,I",~~~R

Silicagel ~

J~O R "-W"

Co2(CO)8

Reaction of furan with a modified vinyl sulfoxide type dieneophile, namely (Z)-3-ptolylsulfinylacrylonitriles, has been carried out with high reactivity and stereoselectivity <00JOC7938>. In addition to the [4+2] cycloaddition, intramolecular [2+2] photocycloaddition was also successfully used as a main procedure in the synthesis of (+)-ginkgolide B <00JA8453>. The studies on the model reactions and molecular mechanics calculation show that the stereochemistry of the substituents at C6 and C8 should influence severely the reaction diastereoselectivity. When syn-diastereomer 41 is subjected to irradiation the reaction gives a single diastereomer 42 in a quantitative yield since two substituents at C6 and C8 would be in pseudo-equatorial orientation in the chair-like transition state.

EtO O~ zco2et 0 Et3SiO CMe3 41

__ e t 3 s i o 0 ~ ---CMe3

hv

> 350 nm 100%

Q~ .C02Et Et3SiO~'"V'qCMe3 42

The regio- and stereo-chemistries of the intermolecular photocyclization of furans with carbonyl compounds were studied. The reaction of the triplet state of ketones with 2-siloxyfurans gives rise to adduct 43 in high regioselectivity while the reaction of the singlet one provides two products 43 and 44 with no regioselectivity. Similar reactions of aldehydes afford lower regioselectivity although all reactions deliver the exo-adducts in high stereoselectivity <00JOC3426>.

R1 R2 O~

R1 p2 R4 R-4 R1 R2 .~ hv(> 290 am) .'~o,R 3 R~,, , O N / ~ + R4 R3 MeCN,0~ ~ + OSiR3 quantitatively ~ C)SiR3 44 OSiR3 R1, R2 = H, Me; R3 = Ph, npr, Me; R4 = H, Me, Ph

137

Five-Membered Ring Systems: Furans and Benzofurans

Cha reported an enantioselective synthesis of (-)-colchicine, free from isocolchicine by utilizing a [4+3]cycloaddition of an oxyallyl cation to a 2,3-disubstituted furan 45. The regio- and enantio-controlled formation of the colchicine precursor 46 is a result of the N-Boc derivative which serves as a poor hydrogen bond donor in the [4+3]cycloaddition procedure. It has been found that N-acetamide protection leads to a wrong regio-precursor due to the formation of hydrogen bond with the oxyallyl species <00T10175>. A potential precursor of analogs of Cglycosides of neuraminic acid, namely 2,6-anhydro-5-azido-3,5-dideoxy-2-C-hydroxymethyl-Lallo-heptose, has been prepared from furfuryl alcohol via also a [4+3]cycloaddition route <00TA4661>.

Me3SiO MeO''2 M e O ~ MeO" ~

~

MeO

M e O ~ "~CH(OMe)2 .',NHBoc D,- .LLP.L ~L~0

45

OSiMe3 Me3SiOTf MeO" y EtNO2 .78o ~ .60oc 45%

M e O ~

)""

~

46

MeO" y

(~MeO

>""

(-)-Colchicined)MeO

1,3-Dipolar cycloaddition of 2-methylfuran with hydroxamic acid, the nitrile oxide precursor, is able to give a key intermediate with a lower diastereoselectivity for the synthesis of (+)-furanomycin <00AG(E)910>. The double [4+3]cycloaddition of 2,2'-methylenedifuran in CF3CH(OH)CF3 provides a 45:55 mixture of meso- and (+_)-threo-adducts. The former has been adopted as a starting material in the synthesis of long-chain polyols 47, the compounds of biological interest <00CEJ4091>. The intramolecular version of this reaction has also been used in the synthesis of racemic lasidiol, a sesquiterpenoid with a carotane skeleton <00TL 1375>.

O

1. CI2HCCOCHCI2-Et3N CF3CH(OH)CF3 2. Zn/Cu-NH4CI MeOH 55%

PivO

0 (•

-_ OR 0

O

)~

4T

_OH OH OR OH

Conversion of furfuryl alcohol derivatives 48 to pyranones 49 (Achmatowicz oxidative ring expansion) is employed in the synthesis of spiroketal moiety of a natural product <00OL863> and cyclopentenones <00T8953> <00TL6879>.

48

OH

1 H+ 9 NBS 2. Ac20 NaOAc

O ~[~

R

49 OAc A palladium catalyst is used in the transformation of a siloxyfuran to a phenyl substituted furanone <00JCS(P1)3350>. Similar products, furan-2(5H)-one derivatives, are afforded through the reaction of tetra-n-butylammonium fluoride with the corresponding substituted 2-siloxyfuran <00S 1878>, as well as the oxidation of 3,4-disubstituted furans by singlet oxygen <00JOC6153>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

138

~OSiMe

3

Ph2Sb(OAc)2 PdCI2 (5 mol%) DME, CH3CN ~ 82%

Pt'r~'O'''l~O

Synthesis of (+_)-untenone A from 5-substituted furylacetate 50 by using bromine oxidation in MeOH followed by acidic hydrolysis, an approach based on a likely biogenetic pathway, has appeared <00TL3467>.

H3301

50

MeOH CO2Me 96%

2. 1.0M NaHCO3 62%

HO~ y - - - - o CO2Me (• A

Stereoselective reduction of chiral 2-furoic amides has been studied in detail and used as a key step in the synthesis of (+)-nemorensic acid <00JCS(P1)3724> <00CC465>. OMe

1.

OMe

Na -78~

/~ o "'/~ ~" /,. ),~'~ 3q. ) o.

R = Me, Et, CH2=CHCH2,/-Bu, Bn, H Yield:57- 98%

Addition of carbon nucleophiles to furfural tosylhydrazone provides 5-substituted 2E,4Epentadienyls in good yields <00TL2667>. The ab initio calculations at the RHF/3-21G* level have been utilized to study the origins of diastereoselectivity of the vinylogous Mannich reaction of 2-methylfuran with pyrrolinium ion <00OL3445>. A simple procedure for isomerization of 2furylcarbinols to cyclopentenones under neutral condition was reported and a new mechanism was proposed <00H(52) 185>.

5.5.2.2 Di- and Tetrahydrofurans Tetrabutylammonium peroxydisulfate-mediated oxidative cycloaddition was recently discovered to be a convenient method for the realization of fused acetal derivatives. It is believed that the reactive intermediate is the cyclic enol ethers of the 1,3-diketones. An example is presented below <00S 1091>. 0 9

0 O

MeCN r.t., 2 hr 82%

H

.

In a program directed towards the total synthesis of (+_)-arthrinone and related natural compounds, the commercially available 2,3-dihydrofuran was employed as the starting material. As shown in the following scheme, 2,3-dihydrofuran is transformed by a oxyselenenylationoxidative deselenenylation sequence, and is finally converted to the pivotal alcohol 51 in a diastereoselective manner via a [2,3]Wittig rearrangement route <00TL10013>. The hydroboration of 2,3-dihydrofuran has also been studied <00JCS(P1)4505>.

139

Five-Membered Ring Systems: Furans and Benzofurans

1. PhSeCI 0H2012 .78o0 , ~ 2. Me3SiC_--CCH2OH -78~~ -50~ 94% n-BuLi THF -78oc 95%

.,SePh

30% H202 NaHCO3 O EtOAc-THF 0~~ r.t. L~.~.... SiMe3 86% OH O

HO,,..

/'~

~.~.~.... SiMe3

~ O o H

MeO

OH m

51

(•

Tochtermann reported the addition of dichlorocarbene to the racemic glycal 52, whose cyclopropyl-allyl rearrangement leads to the 2H-pyran. The synthesis of the optically pure (+)(2S,3R,7S) and (-)-(2R,3S,7R)-glycal precursors has also been achieved. As pointed out, optically pure glycals are versatile precursors for carbohydrate synthesis <00EJO 1741>.

MeO,

50% aq. KO, FMeO ,,H -O

'

c,c,~./

n'~~ ' ~ O ' J oL~

~';;'~c,I

]

<~co~

MeO ~"..~1~' ~I,,O Me

~eO"'o0%

0'

"

52 R = CH2OMe 5.3.2.3 Benzo[b]furans and Related Compounds In the process directed towards the total synthesis of diazonamide A, several interesting benzofuran's scaffolds have been synthesized. Dirhodium (II) caprolactamate [Rh2(cap)4] promotes cyclopropanation of the starting a-diazoester 53 to afford the cyclopropane. Hydrolysis of the lactone followed by a BF3oEt20 promoted rearrangement gives the 2,3-disubstituted benzo[b]furan 54. Interestingly, treatment of 2-methoxybenzofuran substrate 55 with Rh2(cap)4 gives a cyclopropane product in 89% yield, which undergoes a rearrangement to the tetracyclic product 56 in 76% yield upon treatment with LiOMe <00OL3521>.

N2.~o_~

o~

Rh2
LOMeTHF

53

r "

L

~o~-3 v~o

~CO2Me

H

,~

88%

HO

~o~

68o/~ '~ ~ C O 2 M e 54

140

X.-L. Hou, Z. Yang, and H.N.C. Wong

Rh2(caP)489% ~M OO oO~ o M

M~~z-OMe

e

F

LOeTH

eJ

55

MeO2C,,,,~ 76% ~'"M ~ ~ 56

e

Photochemical [2+2]cycloaddition between benzo[b]furan and 3-cyano-2-alkoxypyridines in benzene has been reported to follow a very interesting mechanism supported also by Frontier-MO calculations using the PM3 Hamiltonian. It is believed that the singlet excited state of the pyridine and the ground state benzofuran react to form a [2+2] adduct and is followed by ring opening to the cyclooctatriene, which cyclizes to the secondary endo- and exo-isomers shown below <00CC1201>.

CN

ON

hv ~ e ~ ~ ~ . . _

06H6 M 59% ~-Conversion Md" N~-.~ H OMe

+

endo

~

~

0

Me

OMe

NO UO,.. ~,~ Me" N-~ H OMe exo

32%

25%

2-Substituted benzo[b]furan can be oxidatively converted to the lactone 57 in 81% yield, which is allowed to react with chloroformate containing a chiral trans-(1R,2R)-2phenylcyclohexyl group (R*) to give the benzo[b]furan-based enol carbonate. When the carbonate is treated with DMAP, nearly complete conversion to the new benzo-fused ~,-lactone 58 is observed in dichloromethane or in THF with a diastereomeric ratio of 3:1 <00OL1031>.

TrocHN~/CO2Me ~ H"~~OM

TrocHN CO2Me H

Br e

TrocHN H MeCO3H ~ CH2CI2 81%

Br Me

DMAP ~CO2R, 86%

~ Br ~:=oOMe 57

)-

TrooHN~/CO2Me H~'[ R*O2C, 58

CICO2R* Et3N

Br OMe

Five-Membered Ring Systems: Furans and Benzofurans

141

2-Allyl-benzo[b]furans 59 can be effectively synthesized in good yields by palladiumcatalyzed hydrofurylation of alkylidenecyclopropanes at 120 ~ without solvent <00JA2661>.

5% mol% Pd(PPh3)4 10 mol% P(OBu)3~ ~ , . ~ , t . ~ . ~ No solvent 120~

a1

FR1 2

Condensed benzo[b]furan molecules can be prepared by inter- or intra-molecular DielsAlder reactions from furo[3,4-b]benzofurans, and some interesting intermolecular examples are listed below. As can be seen, the furo[3,4-b]benzofuran 60 underegoes Diels-Alder reactions with naphtho-1,4-quinone in the presence of ZnI2 as a Lewis acid to form the aromatized cycloadduct. When the diene precursor reacts with benzo-l,4-quinone in the absence of ZnI2, the product is obtained as an endo-exo mixture <00JCS(P1)1387>. O

O

O

o

~ O

o

MeO2C OMe

10%

OMe 60

~ O

79%

OMe

Very few reports are available in the literature on heteroaryl singlet carbenes. Recently, it was reported by Sheridan that the 2-benzofurylchlorocarbene 61 can be slowly produced upon irradiation of the diazirine at 436 nm at 10 K in an N2 matrix. The carbene is quite photolabile and short exposure of which to 313 nm light gives the quinone methide, which can be further converted to the intriguing didehydrobenzopyran at 404 nm. The identity of the didehydrobenzopyran can be substantiated by comparing its MP2/6-31" calculated IR spectrum with the experimental one, as well as through its conversion to the benzopyrylium chloride by warming with the HCl-doped N2 matrix at 32 K <00JA8585>.

~

CI hv N 436 nm 10 K N2

~ C I

313 nm

61

CI

H 4o4nm

"CI

32 K

+

CI CI"

The chemistry of benzo[c]furans (isobenzofurans) will be discussed in Section 5.3.3.4 due to their reactive diene properties. 5.3.3 SYNTHESIS 5.3.3.1 Furans

Direct metallation of 2-substituted furan can be realized when 2-furancarboxamide is allowed to react with t-BuLi in the presence of TMEDA. Treatment of the lithiated 2furancarboxyamide with acetaldehyde provides the corresponding 2,3-disubstituted furan in 52% yield <00SL1788>. 3-Trialkylsilyl-2-furancarboxamide can also be afforded in high yield if 2-

X.-L. Hou, Z. Yang, and H.N.C. Wong

142

furancarboxamide is allowed to react with vinylsilanes catalyzed by 6 mol% of Ru3(CO)12 or RuHCI(CO)(PPh3)3 <00CL750>. Reaction of 3-furancarboxamide with LDA provides difuranfused quinone <00JOC2577>. Heck reaction of 2,5-dihydro-2,5-dimethoxyfuran followed by treatment of the intermediates with HC104 on the other hand delivers 3-arylbutenolides, which can be reduced to 3-arylfurans with DIBAL <00H(52)67>. 2,5-Disubstituted furans 62 are obtained from a gold-catalyzed cycloisomerization/dimerization pathway involving terminal allenyl ketones and cq3-unsaturated ketones <00AG(E)2285>. a2

+R R Auc'3 - > R

R

35-88%

5-51%

o .R

"

1 mol% AuCI 3

R = Me, Ar, ArCH 2

R,

R1, R2 = Me, Et, H 46-74%

2,4-Disubstituted- and 2,3,4-trisubstituted-furans are provided by oxidation or oxidation/acid-induced cyclization of the corresponding 2-butene-l,4-diols. These methods have been successfully employed for the synthesis of hibiscone C <00SL363> and cristatic acid <00OL2467>. OH

H

O

O

.,~COOH

DMSO ~

HO~ T

(0001)2

"OH

85~

~~...v~~~ Hibiscone C

Cristatic acid

An intermolecular version of a [4+2] cycloaddition-retrofragmentation of alkyne-oxazoles can be adapted to the synthesis of 2,3,4-trisubstituted furan in high regioselectivity if acetylenic aldehydes are used as starting materials. The product of this reaction is a pivotal intermediate for the synthesis of (-)-teubrevin G <00JA9324>. Ph

.*... O

H

..~o

TBSO---~ OTBS

~ooc S2yo

single isomer

H

k/==O

d,

"

~

~

t

, ~

Y

~-

~co

o ,.

O

(-)-Teubrevin G

2-Aryl-3,4-fused furans 63 are synthesized in moderate to good yields from propargyl nucleophiles and a-sulfonyl a,13-unsaturated ketones under palladium catalysis conditions <00JOC3223>.

Five-Membered Ring Systems: Furans and Benzofurans

143

o

RSO2S~,,,J[,.R2 PdCI2(PPh3)2t.BuOKR . . J \ R + 11, X H R1 45_600/0 ~ x ~ R 1 R = Me, H; R1 = Ar, cyclohexyl 63 R2 = Ar,/-Pr. X = O, BnN, MeN I~

R2

Substituted furan formation by an indirect cyclization of 1,4-dicarbonyl derivatives has also been adopted as a key step in the synthesis of 3-oxa-guaianolides. Although 1,4-dicarbonyl compounds have been traditionally considered as the direct precursors for furans, treatment of 1,4-dicarbonyl compounds having a tertiary acetoxy group with p-toluenesulfonic acid leads to only 11% yield of an alkenylfurans as derived from a cyclization/acetoxy-elimination route. The following scheme shows an alternative multi-step conversion of the 1,4-dicarbonyl that leads to a more acceptable yield of the acetoxyfuran <00T6331>.

HH'~C 0

~

1. LiAIH4

;

/,~~Ac

3. DBU

( ~ . . . ,..... O

O

4. hv, 0 2, methylene blue

5. SiO2 Total yield: 30%

...... O

An efficient access to 3-carboxy-2,5-disubstituted furans 64 has been developed. 13-Keto esters are found to undergo an acid- or a base-catalyzed enolization and a subsequent intramolecular 1,4-addition to afford the desired furans in excellent yields. The carbonyl substituent can be further transformed to a vinylic substituent with a desired substitution pattem <00TL 1347>

CO2Me MeO2C\ / \ SiO2MeO2CN 1. LiN(SiMe3)2MeO2C~ /~ O/)' ~ 95 Y o ~ THF-HMPA),. ~ Pd(PPh3)4 ~ O~t / or Et3N"-- "O~ 7-'~T'~NTf9 - "O" ]l Me2Zn O- II -- ',C5Hll 99% 99% C5Hl1"/~O ~" N TfO'J'L'C5H11 64 Me"JI'C5H11 92%

,__?

3-Acetyl-1-aryl-2-pentene-1,4-diones 65 formed from the reaction of arylglyoxal with 2,4pentanedione in the presence of BF3.Et20 are converted to tri- and tetra-substituted furans <00TL3149>. H-O

9,

Ar,,a,,,W,H AcCH2Ac BF3~ I I O

A

Ac

r ~ O

Ac 65

AcCH2Ac,.. BF3~ Ar

O -

O~'H (]

Ar~-\Of~ 8-59%

Under cathodic reduction condition, 2-bromo-2-cyanoacetophenone is transformed into 5amino-4-benzoyl-3-phenylfuran-2-carbonitrile in good yield <00H(53)1337>. Cyanoketones react with glycolate under Mitsunobu conditions to produce vinyl ethers which give rise to 3-

X.-L. Hou, Z. Yang, and H.N.C. Wong

144

aminofuran-2-carboxylate esters 66 in good yields on treatment with Nail. 4-Pyridylcarbinol and 4-nitrobenzyl alcohol can also react with cyanoketone to provide 3-aminofurans <00OL2061>.

R,,~O + HO,,~OEto ~CN

O PPh3:~ R ~ O ' ~ O E t l l DEAD I~CN

NH2 ~.,NaH

R

COOEt

66

A divergent protocol for a solid-phase synthesis of 3-substituted 2,5-biarylfurans was reported. Thus, reaction of furan zincate A with polymer bound aryl bromide or iodide provides resin intermediates 67. Subsequent bromination-Suzuki coupling reaction followed by further transformations gives rise to structurally diverse 2,3,5-trisubstituted furans 68 in good overall yields and chemical purities <00TL5447>.

1. n-BuLi 2. ZnCI2

+

CIZn""%OJ

ZnCI

A

~ i - - Ar-X X= Br.I THPO"~ (~

B

Ar1B(OH)2 A THPO"'~ NBS THPO."~ Pd2(dba)~ "- ~i__ Ar.,./~O,,~ Pd(OAc)2 Br PPh3 As2Ph3 ~)'--Ar"/'~O~ 67 Ph3PBr2

ID

Br

1. HYR Ar1 2. TFA or

Ar--KO,,;,'-,,,Arl

11~ A

NaOH

Ar1

68 Y = S, NR2

Alkylation of tert-butylacetoacetate with ~-haloketones followed by treatment of the intermediate with TFA leads to substituted 2-hydroxy-3-acetylfurans 69 in high yields. A second alkylation of the intermediate followed by treatment with TFA affords trisubstituted furans 70 <00OL3535>.

a2 o

O

-O

CF3CO2H Nail

~-R1

60-95%

,

69 67-87%

l BrBn or BrCH2CO2Me, Nail

(R2= H)

~ 1 7 6

CF3CO R1.,I~O 56-89%

R1 70 67-71%

An effective synthesis of 2-methylthio-5-amidofurans 71 involves a Pummerer induced cyclization of imidodithioacetals, which can be prepared by a mixed aldol reaction of the N-

145

Five-Membered Ring Systems: Furansand Benzofurans

trimethylsilyl protected 8-valerolactam. The furan products can serve as precursors for a convergent synthesis of hexahydro-pyrroloquinolinone derivatives through an intramolecular Diels-Alder cycloaddition <00TL9387>. AcOL '~~

~N_ ~

LDA

SMe

~AcO ~ , , , ~ SMe

SMe

r " J ' y "~

DMTSF

" SM~,,,I e

.... O

t~',MeS,2CH2CHv ~ ~-vR SiMe3 Ac20- RCOCI rl 0

.... O R

-AoOH

0

R

71 0 R = (CH2)nCX=CH2, X = H, CO2Me, aryl 70-82%

DMTSF = dimethyl(methylthio)sulfonium tetrafluoroborate

Reaction of cis-2,3-bis(trimethylsilyl)cyclopropanone with 13-ketophosphorus ylide gives 2-trimethylsilyl-3-trimethylsilylmethyl-5-methylfuran and 2-methyl-4-trimethyl-silylmethylfuran in a ratio of 77:23 <00TL3399>. ~,-Hydroxyketal 72 undergoes acidic decomposition to afford the corresponding furan derivatives <00CEJ2887>.

.O

MeO ?--(X

C(.;U

SiO2 dil. H2SO4 OMe

OMe

72

2,3,5-Trisubstituted furans can be realized from hydrofurylation of alkylidenecyclopropanes 73 <00JA2661>. R4

5 mol% Pd(PPh3)4

R3

R~ 73

a novel

palladium-catalyzed R4

no solvent 35-77%

R3

R1, R2 = Bu, Bu; Me PhCH2CH2; H, PhCH2CH2; Me, cyclohexyl; -(CH2)5Me, n-pentyl, COOEt; R 4 = H; 2,3-furan = benzofuran

R3 =

Reaction of propargylic dithioacetals 74 with organocopper reagent followed by treatment with an aldehyde and then with acid provides 2,3,5-trisubstituted furans in moderate to good yields <00JA4992>. 1. Bu2CuLi

/~S

2. ArCHO .. R2

R1

74

3. Acid "25-73%

~ R2

R1 Ar

3-Trifluoroethylfurans can be obtained from (Z)-2-alkynyl-3-trifluoromethyl allylic alcohols 75 through palladium-catalyzed cyclization-isomerization procedures <00JOC2003>.

146

X.-L. Hou, Z. Yang, and H.N.C. Wong R1 F3C,~ HO I

R

+

m

F3C ~

R1 Pd(PPh3)4 CuI'Et3N 53-91%

75

R = n-Pr, Ph p-MeOC6H4, H R 1 = n-C6H13, SiMe 3, Ph, p-MeOC6H 4

R

PdCl2(MeCN)2 F3C'~k~.ma 64.77O/o

J"

R/,/~O ~

HO

Polysubstituted furans can be obtained in good to excellent yields via the reactions of properly substituted 1,2-allenylketones 76 with organic halides under catalysis with Pd(0) and Ag2CO3 <00CC117> <00OL941>. R4

R2

R3

~ 6 0 ~

R

+ 1

5 m~176176 Pd~PPh3)4 IP

R3X

Et3N, 10 mol YoAg2CO 3 51-97% R4

R2 R1

R 1, R2 = Alkyl, H; R4= Ph, alkyl, H R3X = Aryl iodide, methyl 3-iodopropenoate, substituted allyl bromide

An one-pot reaction of propargyl alcohols 77 with Grignard reagents followed by treatment with electrophiles producing polysubstituted furans has been described <00TL17>.

R ~ 77

(' OH

~.-

R R2 N~--a/

R3CN or DMF M

R1

25-92%

k--

R3

R = Ph, SiMe3; R1 = Ph,/-Pr, H; R2= Ph, CH2=CH; R3= Ph, H (DMF as reagent).

-Xo

R1

Unexpected transformations of 5-(phenylthio)pent-2-en-4-ynal and 5-(methylthio)pent-2en-4-ynal to 2-bis(phenylthio)- and 2-bis(methylthio)methylfurans respectively in the presence of a slight excess of HC1 have been recorded. The transformations are expected to involve a pyran to furan ring-contraction sequence <00HCA1191>. Reaction of 1,3-dicarbonyl compounds with vinyl sulfides gives the corresponding medium- and large-sized ring substituted furans 78 in moderate to good yields. In addition to cyclohexane-l,3-diones, 4-hydroxycoumarins and 4-hydroxyquinone can also be used as 1,3dicarbonyl components <00OL1387>. O R1

O

A02co3 O

+

Celite

SPh

R = H, Me; R 1 = H, Me, CHMe2 n = 1,2,3,7,10

45-69%

n

D,- R 1 R

78

Cyclic 2-diazo-l,3-diketones have also been utilized to react with diketene to afford the corresponding methylfurans in moderate yields <00JCS(P 1)2121 >.

147

Five-Membered Ring Systems: Furans and Benzofurans

5.3.3.2 Di- and Tetrahydrofurans The use of alkynyliodonium salts in the synthesis of 2,3-disubstituted 4,5-dihydrofurans was reported by Feldman. In this conversion, the addition of p-toluenesulfinate to ethers of 1hydroxybut-3-ynyl(phenyl)iodonium triflates 79 induces a series of reactions that afford eventually 2-substituted 3-p-toluenesulfonyl-4,5-dihydrofurans 80 <00JOC8659>.

SitBuMe2 O

SitlBuMe2

Alkylidene carbene

SitBuMe2

iPhoTfP.MeC6 H65%4SO2 @ SO2C6H4-P"Me CH2CI 2 Na __~~ O2C6H4-P"Me formation - Phi -42~ -" IPh *~ tBuMe2SI _ [1'2]'Shift ~ . ~ SiMe2tBu Stevens '~ SO2C6H4.P.Merearrangement 80 SO2C6H4-P-Me

The preparation of 2,3,5-trisubstituted 4,5-dihydrofurans 81 with complete regio-control can be realized by an one-pot transformation involving epoxidation of 2-alkenyl-l,3-dicarbonyls by in situ generated dimethyldioxirane, and is followed by a 5-exo-tet intramolecular nucleophilic cyclization under the same basic condition <00TL10127>.

Ph

h

Oxone ,. P acetone-H20 Na2CO317.O 70~ 36 hr ~

Ph

,. 96% "-

HO

h 81

The Cu(I)-catalyzed cyclization for the formation of ethyl (_+)-tetrahydro-4-methylene-2phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(~-substituted Ntosylaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>.

PhO2S CO2Et Na+ "~ III CO2Et Ph '1~ '~SO2Ph Cul(PPh3)386O/o kONa O Ph

Nail XOH

THF

k/..soPhPhyZnCI.MgC,B / (CO Et Ph

9 CO2Et

\O/'~Ph 82

Pd(PPh3)4 v

THF-Et20 20oc

85%

\O F ' " Ph

X.-L. Hou, Z. Yang, and H.N.C. Wong

148

Chiral 2,5-dihydrofuran can be prepared through the HC1 gas promoted cyclization of the corresponding optically active allenic hydroxy-ester 83 with almost complete axis chirality (87% ee) to center chirality (85% ee) transfer <00TL9613>. H CO2Et tB~"~ " Me

83

8 7 % ee

.CI

tBu, ,,i~~.,,H

0"013 ~ 68%

M~ ~J s 8 5 % ee

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and nonenolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of 1-bromo-2-chloroethane. In this way, the more basic ~,carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>.

CI

CN

+

o

R

CN NaOH

H

Phase Transfer Catalyst

R = Ar, PhCH=CH

R 84

1.2.3 equiv. LDA THF O

O

14 hr ,~.. NEt2 2. ClCH2CH2Br CONEt

reflux ~ ~14, hr. 80%

ONEt 2 85 E ' Z = > 9 8 " 2

More complex molecules can also be synthesized employing the Williamson procedure. Thus, on treatment with Nail, the mesylate 86 provides the tetrahydrofuran in excellent yield and stereo-control <00OL1529>. In a similar manner, tosylate 87 undergoes the same reaction to lead to the bis-tetrahydrofuran <00EJO 1889>. ....OH

O~\

,(]Me

/--~0 0~~-- N, Me Me Me

'----"

Me

...OH NaH ,.-- M 99%

O~\

QMe e

Md

~

~

O

Me

86

HO HO TsO

OTs OH OH 87

NaH THF 0oc 92%

P

O H

H

A much more elaborate synthesis of 4-aryl-2-(benzyloxy)carbonyl-3-hydroxy tetrahydrofurans 88 from aryl epoxides requires the use of benzyl diazoacetate. This methodology can now be extended to a highly stereoselective synthesis of chiral tetrahydrofurans starting from optically active epoxides. The mechanism is believed to involve a Williamson-type cyclization as illustrated below <00TL8059>.

149

Five-Membered Ring Systems: Furans and Benzofurans

IOn.

,,OSiEt3 ]

~[

~CO2Bn[

65~

+ J

O

N2CHCO2Bn

OSlEt3 BF3oEt20 Et3si

H

O,,,.,

,OH

.."

.

Et3Sio~CO2Bn +N2 H

~CO2Bn 88

Several substituted 1-oxaspiro[4.5]dec-6-enes have been prepared by employing a mild amberlyst-15-catalyzed SN2' oxaspirocyclization. As can be seen below, the tertiary <00TL3411> and secondary <00TL3415> allyl alcohols 89 serve as the n-allyl cation precursors and the other hydroxy groups function as nucleophiles.

HQ R1 ~

R2 R3

R1 Amberlyst-15

~ O

CHCI3 ~ ~ R -20~ R1, R2, R3 = H, Me

89

R2

3

Hydroxy groups have been utilized commonly as nucleophiles for the opening of epoxides. An example of this reaction illustrated below involves the in situ asymmetric epoxidation of the allyl alcohol 90 and the concomitant intramolecular opening of the epoxide by the secondary hydroxy group to form an anti-tetrahydrofuran framework <00TL4127>. Further examples of similar reactions have been employed as key steps in the synthesis of peptidomimetics as potential HIV-1 protease inhibitors <00TL10121>, in the enantioselective synthesis of the squalene-derived pentaTHF polyether glabrescol <00JA4831> <00JA7124> <00JA9328>, in the total synthesis of a novel neuroexcitotoxic amino acid (-)-dysiherbaine <00TL3923>, and in the synthesis of the common C8-C18 fragment of pectenotoxins <00SL1733>.

tBuPh2SiO~./~.~

Ti(Oipr)4 (R,R)-(+)-DET [tBuPh2SiO'~k O,,

l

90

CH2CI2 -20~ 2 hr tBu P h 2 S i O~t~ 82% ~ ~- n.CsHl,~,~O ~ - ~ -OH ~ OH In Carter's studies toward the total synthesis of azaspiracid, the construction of "fragment B" requires the conversion of the y-lactone 91 into a furan acetal. In this connection, it has been uncovered that the desired furan acetal can indeed be formed in 64% yield under methanolic acidic conditions <00OL3913>.

150

X.-L. Hou, Z. Yang, and H.N.C. Wong

H HO..~. H H H p-TsOHj,. sF~~~OMe imidazole~o-, ~0~.~ MeCN ,, OMe J...y 90~ H 64% MeO2C "'" 97% FragmentB

O~ _0 H OH 91

O

Overman reported the synthesis of highly enantiopure 3-acyltetrahydrofurans with C5 substituents from formaldehyde acetals of allylic diols <00TL9431>. An example of Overman's procedure is depicted below, which involves the generation of a formaldehyde oxonium ion intermediate 92 before the cyclization. O

xo

PI~~~

OMOM

[3.3]

XO[~ + ~ H

]

AldoI I " ~

C.H~o(~2L'~O+~HHHJ 67% 92

Phi.../

v

Efficient and stereoselective routes are provided for the realization of 13hydroxytetrahydrofurans from the 5-endo-iodoetherification of 3-alkene-l,2-diol derivatives 93 <00TL4447>. A precursor towards the total synthesis of alasmomycin was obtained by the same authors employing this strategy <00TL4453>. A similar method was devised in which a mixture of NalO4 and NaHSO3 was found to provide another entry to tetrahydrofurans through an iodoetherification reaction of 3-alken- 1-ols <00TL 10223>.

HO

12

O,~._Bn nB Me u 93

NaHCO3 MeCN

HO ~ ~ Me

I

HO

,,I

,,~ '~nBu + Me

63%

nBu

80:20

The aforementioned iodoetherization design has been applied to the conversion of pyranoside precursors to the bis-tetrahydrofuran core of an acetogenin, namely rolliniastatin. As can be seen below, the treatment of the trityl-trifluoroethyl bispyranoside 94 with iodonium dicollidine perchlorate (IDCP) in wet CH2C12 afforded the cis-tetrahydrofuran-iodide 95 exclusively. It was reasoned that the trityl pyranoside is a stereo-directing and activating aglycone while the trifluoroethyl pyranoside is a deactivating aglycone <00T9203>. Fe(CO)4-mediated ring closing cycloetherification has also been employed to the preparation of optically active functionalized tetrahydrofurans. The reactions were found to proceed with chirality transfer <00S2092>.

BnQ

~OBn

9

,

i

CF3CH2

CPh3 94

IDCP CH2CI2-H20 79%

BnO,

~OBn CF3CH2

CHO 95

In Morimoto's total synthesis of (+)-eurylene and (+)-14-deacetyleurylene, the pivotal steps are the construction of trans- and cis-tetrahydrofuran rings via a hydroxy-directed syn oxidative cyclization of acyclic bishomoallylic alcohols promoted by Re(VII) and Cr(VI) oxides, respectively. As depicted below, the trans-THF is achieved by treatment of the triol with the oxorhenium(VII) complex, and the cis-THF is constructed by the use of PCC <00AG(E)4082>.

Five-Membered Ring Systems: Furans and Benzofurans

151

(CF3CO2)ReO3-2MeCN (CF3CO)20. CH2CI2-MeCN -40~ 1.5 hr 84% PCC CH2CI2 r.t., 30 min 47%

R=H R=Ac

(+)-14-deacetyleurylene - - ] Ac20 ' C5H5N / r.t., 40 hr, 80% eurylene ~ .......

Yang reported a procedure in which a regioselective intramolecular oxidation of phenols or anisoles by dioxiranes generated in situ would also lead to tetrahydrofuran formation for ketones with electron-withdrawing groups COCF3, COCO2Me or COCH2C1 tethered to the ary! rings with a C2 linker. The proposed mechanism of this reaction is shown in the following scheme. <00JOC4179>. X

R10

, 1,.R2 Na2,,EDTA R10 MeOH-H20

Y

R ~ ~X[ ~ O..~ 24-55%

X

Oxone NaHCO3

iv

X R -2 .....

R1

o- T

Y

Y

2

R I = H , Me

OH

R2 = CF3, CO2Me, CH2CI X = H, Me Y = H, Me, Br

O y

A straightforward stereoselective catalytic hydrogenation of furans to tetrahydrofurans has been reported by Ye, who demonstrates that the desired tetrahydrofuran rings are obtained from dimethyl 2-arylfuran-3,4-dicarboxylates 96 through their smooth catalytic hydrogenation over 4-5 mol% Pd-C catalyst under 100 MPa of hydrogen atmosphere at 100~ without hydrogenation of the aryl ring <00S2069>. The THF rings serve as precursors for lignan synthesis. MeO2C\

,~O2Me R1

H2 (100 Pd-C MPa) ...... ~

MeO2C ~

100~ 71-91% 96

~3

.~CO2Me R O" O

~ ~ 3 R2 R

R1 = R2 = R3 = H R1 = H, R2-R3 = OCH20 R1 = H, R2 = R3 = OMe R1 =R 2 = R 3=OMe

1 MeO2C + ~

Ratio

.CO2Me R O" O

1

~ ~ 3 R2 R

100:0 72 : 28 67 : 33 67:33

Anodic oxidation reactions have been utilized to reverse the polarity of enol ethers and to initiate radical cation cyclizations. As shown below, the ketene acetal 97 is oxidized on a

X.-L. Hou, Z. Yang, and H.N.C. Wong

152

reticulated vitreous carbon (RVC) anode using an 8 F/mol of charge electrolytic condition, leading to the formation of the tetrahydrofuran 98 in 74% yield <00JA5636>. In the stereoselective total synthesis of (_+)-sesamin, a radical-induced cyclization reaction is also 9bserved for an epoxide using dicyclopentadienyltitanium chloride (prepared in situ from dicyclopentadienyltitanium dichloride and Zn dust in THF) as the radical initiator <00TL9337>.

Me3Si~OMe

Me3Si,,,,trOMe RVC anode li + Hn ~,.~CH2Ph H O O C H 2 Ph Pt cathode 0.~"MEt4N--"-'OT~s ' " ~ / / 97 MeOH 2.6-1utidine OMe 8 mA Me3Si-,~OMe

-e MeOH

Me3SiTMe - H+ .~. O ~

CH2Ph

O/~.,~CH2Ph

%_./ 98

Iodoetherification (vide supra) of (E)-allyl alcohols 99 followed by transannular radical cyclization in a 5-exo-trig mode was reported to provide cis-fused bicyclic acetals with high diastereoselectivities. To illustrate, an example is given below <00SL1193>.

OMe

NIS CH2CI2

H

~ 3 M e

n-Bu3SnH Et3B

99

H OMe

H ..OMe

+ 13.5%

H OMe

+ 6.0%

" 1.9%

HOMe

O + 0.6%

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(rt-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of Ostannyl ketyls and allylic O-stannyl ketyls onto electron-rich or electron-poor alkenes <00TL8941 >.

"e,[ofo i e 100

n-Bu3SnH AIBN 75%

Me3SiuCO2Me

In Semmelhack's synthetic approach to plakortones, a palladium(II)-promoted intramolecular alkoxycarbonylation was used as a key step to form the tetrahydrofuran-fused ~,lactone framework 101 <00TL3567>.

Five-Membered Ring Systems: Furansand Benzofurans

~.o~OH tBuMe2SiO.,,~. " ~ """ OH ~

Pd(OAc)2 O CO BuMe2Si THF D,86%

153

~

0

O

H 101

Rhodium-catalyzed enyne cycloisomerizations were utilized by Zhang to prepare alkylidenyltetrahydrofurans with 1,4-diene patterns. Appropriate conditions for the cyclization was assessed and it was reported that high yields and clean transformations were achieved using 10 mol% [Rh(dppb)C12]2 with AgSbF6 in 1,2-dichloroethane <00JA6490>. As can be seen in the following scheme, the cis-alkene gives the tetrahydrofuran 102 in 84% yield. In a similar manner, highly enantioselective Rh-catalyzed enyne cycloisomerization was also reported by Zhang, who obtained chiral tetrahydrofurans in 65-98% ee and in 24-99% chemical yield by using [Rh(diphos)C1]2 as catalyst together with optically active ligands such as (R,R)-Me-DuPhos, (R,R,R,R)-BICP and (R,R,R,R)-BICPO <00AG(E)4104>. The same strategy has also been extended to include dienynes and cyclopropylalkenynes <00TL8041>. Ph

[Rh(dppb)Cl]2 O ~ / AgSbF6 ClCH2CH2Cl 84% 102

O~_. - Ph

Treatment of terminal alkynes containing a remote leaving group with a base was reported to afford tetrahydrofurans fused with five-membered rings. An example of this conversion is shown in the following scheme. The key steps involve an alkylidene carbene formation, which is followed by an intramolecular C-H insertion, yielding in the process a tetrahydrofuran ring <00OL1855>.

Ph.

Ph,

~

X

Alkylidene carbene formation

THF 60-76%

H

X

- MX

Ph Intramolecular / ~ ~ P h IP

C-H insertion

Base= NaN(SiMe3)2, LiNPr2

X = OSO2C6H4-P-CI,I

Domino olefin metathesis has also been used to convert the endoxide 103 to the synthetically useful cis-fused 2,6-dioxa[4.3.0]nonane skeleton. An example of this domino reaction is shown below in which a ring opening metathesis is followed consecutively by a cross metathesis and a ring closing metathesis <00TL9777>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

154

~OAc (~),,,. CI2(PCY3)2Ru=CHPh//,',...(,'0"~I ..... [Ru] f ' ~ ' ~ . Ph .~ ~ ~ Ph~--J " "1" ~ "OAc (3" ~.,~...,,~ 103 H P".F~

,,

-

, . / / f....- 'O7 .,,'k OAc

--

?o c

5.3.3.3 Benzo[b]furans and Related Compounds The synthesis of benzo[b]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting f~-blockers in the treatment of various cardiovascular diseases <00JMC1525>. An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[b]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>.

Clay Microwave 76-92%

R2

104

R1~ ~ - - " ' ~ ~

R2

2,3-Disubstituted benzo[b]furans can be constructed by a new synthetic method involving a [3,3]sigmatropic rearrangement through an O-arylsulfoxonium intermediate 105. The reaction pathway allows the starting sulfoxide and a substituted phenol to be joined in the presence of trifluoroacetic anhydride and rearranged in one operation at or below room temperature, creating articulated dihydrobenzo[b]furans or benzo[b]furans in several examples <00OL2729>.

CF3

O'H"1~1r

"Ph "CF3OO2H O

105 SP

PhsH~"

O

CF3CO2" R-

A novel cyclofragmentation pathway has been developed for the synthesis of 3-substituted benzo[b]furans. In this transformation, the initial generated alkoxide 106 undergoes a 5-exo-trig cyclization, then collapses to 3-substituted benzo[b]furan by the concomitant expulsion of both formaldehyde and a phenylsulfinate anion under very mild conditions. Further applications of this pathway on a traceless thiophenyl solid support give a large number of 3-substitited benzo[b]furans with high purities <00AG(E)1093>.

Five-Membered Ring Systems: Furans and Benzofurans S02 Ph

155

F s02 Ph

~ I"0 "~PhKO-t-Bu

THF.DM~E 0~ 55%

Ph

Ph h

~

2P

[H2C=O] { ~ [PhS02"]

106

The sulfide derivative of furocoumarin based natural products can be synthesized by treatment of a thiadiazole 107 with KO-t-Bu and an organohalide in an one-pot operation. This process presumably involves the generation of a phenolate 108 and is followed by an intramolecular proton shift and a rearrangement to give an alkynethiolate 109, which undergoes a sequence of intramolecular proton shift, cyclization and alkylation to lead to the furocoumarin product. The thiadiazole, in turn, can be prepared by reaction of the corresponding acetyl precursor with carbethoxyhydrazine, followed by treatment with thionyl chloride <00S 1529>.

Me

S N-"N

.e~,N~NHOO~~~Ot~u/_ ~OC~, .~Ho" y s-.~

Me

-o" --o

Me

Ho~o-~o Me 107

Me

H

-~" " T "o" ",-o Me 109

Me

.eCN -I

~~

F/I,~,,N~.N

Me 108 Me

L

~" " T " ~ 1 7 6 Me

Me

J

Me

o

o

Another interesting application of thiadiazole chemistry is the synthesis of thiacrown ether. To this end, the precursor thiadiazole is treated with K2CO3 in the presence of 1,11dichloro-3,6,9-trioxaundecane to give 1,11-bis(5-hydroxybenzofuran-2-sulfanyl)-3,6,9trioxaundecane, which can be transformed into thiacrown ether 110 by treatment with tetraethylene glycol bis-tosylate and bases <00T3933>.

OH

~'~O~~

c, o c, co

Tso ?oTs

~O~O~O~ o

o

0 0

M_J M._/M_J k__/ 110

3-Pyridyl-2-hydroxybenzo[b]furans have been obtained by an unexpected Truce-Smiles type rearrangement of 2-(2'-pyridyloxy)phenylacetic esters 111. Yields of these conversions were not recorded <00TL4541 >.

156

X.-L. Hou, Z. Yang, and H.N.C. Wong

N

N

Rq(~~CO2Me N;

N~)" ~ # M L ) "

MeO

111

~ O H

Na +

A two-step procedure as illustrated below for the synthesis of C2-symmetric 3,8diaryldifurano[2,3-a:2',3'-f]naphthalenes 112 has been developed. In this route, one equivalent of 1,5-dihydroxynaphthalene is allowed to react with 2 equivalents of o~-bromoarylketone to produce the intermediary naphthalene 1,5-diethers in fair to good yields. The final products are eventually obtained by treatment of the 1,5-diethers with anhydrous methanesulfonic acid in hot CH2C12 <00JOC8783>. Other condensations of phenols and a-bromoacetophenone <00IJC(B)112> or o~chloroacetates <00T8769> in the quest of benzo[b]furans have also been reported. 2-Aryloxy-l,1diethoxyethanes can also form benzo[b]furans upon treatment with amberlyst-15 in chlorobenzene at 90~ <00S2131>. R2

OH

qb t + R1

HO

R2

O~J~coa 1 K2003 ~-

R2

Br

O R1

MeSO3H

MeCN

CH2Cl 2

R1

1

R2

R2

112

The synthesis of a new benzo[b]furan-containing cyclophane has been achieved by irradiation of the starting diketone 113 via a 8-hydrogen abstraction from the oalkoxybenzophenone. X-ray analysis shows that the cyclophane has a well-defined rectangular cavity <00TL1393>.

y-o,, #-y

A

CoH0HOWL .~:Yo.

HGI

U

CH - ,4

Coumestrol has been prepared via a photocyclization of the glyoxylate ester shown below through consecutive 6-hydrogen abstraction and cyclization processes, and is followed by

Five-Membered Ring Systems: Furans and Benzofurans

157

treatment of the generated dihydrobenzo[b]furan with hydrochloric acid and BBr3 <00JOC5644>. A palladium-catalyzed carbonylative ring closure strategy has also been employed for the total synthesis of coumestrol <00JCS(P1)4339>. In addition to the use of irradiation, the hindered nonionic phosphazene base P4-t-Bu has been found to deprotonate o-arylmethoxybenzaldehydes to also form benzo[b]furans in 47-78% yields <00OL2409>.

CO2Me

O

Oco .e MeO~Q OMOMh_~vl"(~'~J'~.--(r~_ OMe2' g g r ~ ~ o ~ - - - O M e MeO~OoMo v

~--/

MeO~ v

-u -Coumestrol

"OMe

A novel synthetic approach for the synthesis of benzo[b]furan derivatives through the coupling of conjugated dienynes 114 with Fischer carbene complexes has been developed. This single-pot synthesis involves a simultaneous construction of both the furan and benzene rings, and generates three carbon-carbon bonds and one carbon-oxygen bond <00TL8687>.

R1

~" 114

Cr(CO)5 ~

R1 Me O

1. Me"~OMe '1~ 2. 12 R2 61-84%

R2

A short five-step synthesis of a bifuran, namely (_)-2,2'-bis(diphenylphosphino)-3,3'binaphtho[2,1-b]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate <00OL2817>. Another way in which a benzofuranone can be converted into benzo[b]furan is by treatment of the former with i-Bu2A1H at -78~ followed by an acidic work up <00TL5803>.

1. Low-valenttitanium ),. 2. DDQ

O

O ~,-_

PPh2 PPh2

"BINAPFu

A highly effective co-catalysis system (PdI2-thiourea and CBr4) was developed for the carbonylative cyclization of both electron-rich and electron-deficient o-hydroxyarylacetylenes to form the corresponding methyl benzo[b]furan-3-carboxylates 115 at 45~ under balloon pressure of CO as depicted in the following scheme <00OL297>. 2-Phenyl-3-benzo[b] furanmethanol can be prepared in 83% yield from o-t-butyldimethylsiloxy- diphenylacetylene and a hydroxymethylene equivalent such as paraformaldehyde with n-Bu4NF and 4A molecular sieves in THF at 50~ This approach has been employed to the synthesis of vibsanol, a benzofuran-type lignan isolated from Viburnum awabuki <00H(52)643>. An intermolecular palladium-catalyzed approach towards ~-aryl-l,2-benzofuranmethanamines utilizing o-iodophenol and terminal acetylenes has also been recorded <00TA1681>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

158

R2

Pdl2.thiourea CBr4 ~ 0s2003 MeOH, CO 45~

R1

CO2Me R1

R2 115

A solid phase synthesis of 2-substituted benzo[b]furans has been accomplished with a traceless linker. The polymer-supported esters are smoothly converted into enol ethers using titanocene alkylidene, which is generated by treatment of 2-t-butyldimethyl silyloxybenzaldehyde diphenyldithioacetal with the low valent titanium species Cp2Ti[P(OEt)3]2. After treatment with n-Bu4NF, the enol ether gives phenols, and the latter are released from the Wang resin by CF3CO2H and then cyclize to 2-substituted benzo[b]furans 116 under the same acid conditions in overall yields of 38-83% <00TL4987>.

Mg P(OEt)3 Cp2TiCl2 ~ ~ 4AMS THF

O (~~O,,~R

PhS~SPh R1 RlI~- R2 Cp2Ti[P(OEt)2]2 ~ ' ~ Cp2Ti%2

CP2Ti[P(OEt)3]2 ~CH(SP~)2 ~ V

[~

Titanocenealkylidene sitguMe2_

O'~R

OH

n BTHNF ~

R

-ositBuMe2

CF3CO2H .~,H20 CH2CI2

R 116

Dihydrobenzo[b]furans can be synthesized by using Pd(dba)2/Ph5FcP(t-Bu)2 as an efficient catalyst at room temperature, and some interesting discussions related to this catalyst discovery are also addressed <00JA10718>. Buchwald also shows that bulky, electron-rich obiarylphosphines are effective in Pd(OAc)2-catalyzed cross-coupling reactions for the generation of 2,3-dihydrobenzo [b]furans <00JA 12907>.

~ O H

R

Pd(dba)2 Ph5FoP(t'Bu)2 ~ M e ~,PhMe r.t.

R = H 59% R = Me 77%

Five-Membered Ring Systems: Furans and Benzofurans

159

A simple lithium procedure can also lead to the formation of dihydrobenzo[b]furan frameworks. Thus, an excess of n-BuLi would generate a bis-lithium species 117 that will follow a Williamson etherification route, forming a dihydrobenzo[b]furans with concomitant functionalization of the benzene ring <00TL2269>. Active magnesium also reacts with arylbromides to give a Grignard reagents that cyclize with O-allyllic systems via presumably a radical condition to give dihydrobenzo[b]furans <00OL2303>.

MeO.~~Br Br" v

equiv"MeO~ A. L, 9. ~ l M e O ~ CI2-3n-BuLi y('-')y,~(

-O#

T'HF L i f O , , , ' 40~ 117

1. DMF .. --.-40~

Li,,,~~'O 2.H 3 0 + O H C ~ O " 75%

A novel approach towards the construction of the morphine skeleton is the total synthesis of (+_)-desoxycodeine-D. One of the key steps for this palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic construction of the polycyclic ring systems has provided an efficient access pentacyclic skeleton of morphine <00TL915>.

'I"~I/~N

Et3N "MeCN -CO2Et 120-130~

~ ~ N

_CO2Et

(•

demonstrated by synthesis is the strategy for the to the complete

/k~_~k~,,,N. Me

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[b]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. H

MeO

SltBuMe2 Pd(OAc)2._ ositBuiMe2 MeO ~ SitBuMe2 MeO dope "~l'~/J'~/OSitBuMe2 "~l~i" L('~JLv ~ T M e 50% dope = 1,2-bis(dicyclohexylphosphino)ethane (-)-Galanthamine

An asymmetric synthesis of the dihydrobenzo[b]furan segment of epheradine C has been achieved by a novel debenzylation and concomitant intramolecular cyclization with iodotrimethylsilane. The mechanism of this transformation as shown below involves the attachment of two Me3Si groups to the oxygen atoms of the hydroxyl group and the benzyl ether of the precursor 118 with the release of HI to afford the bis-Me3Si intermediate 119. The latter then facilitates the cleavage of the benzyl group, forming benzyl iodide. The released HI then protonates the oxygen atom of the Me3Si ether in the resulting intermediate and as a result promotes the cleavage of the C-O bond with the loss of trimethylsilanol to give a resonancestabilized benzyl carbocation 120. Ring closure can occur with an attack on the cation by the Me3Si ether aided by the iodide ion, to form Me3SiI as well as the thermodynamically more stable trans-dihydrobenzo[b]furan 121 <00JCS(P1)893>.

X.-L. Hou, Z. Yang, and H.N.C. Wong

160

Ph

BrO , ~ ~ O M e + 2 Me3Sil / L N ~ , 0 ~I,,~_____~OM e -HI ~SiMe3 ,,~,,,,,,Ocd~SiMe3 r I

B

r

I'~I Ph Me3Si,,I"~ ~ , , . / s ~o,,SiMe3

-

~

Br~ ~ ~ ~ ~ . ~ ~

~

+HI - PhCH21 r

~

-

Me3SiO ~H

-

SiMe3 I"

% B

OMe

~L-N'~ 0 ~ O M e "

OMe

r

~

OMe

~N~%0 ~I~___----~OM e

~ O ~ OMe Br" v - ~ "~. 71% O~ ~O OMe Me3S~ ~__N " O r , ) ....'("/ 121 X Diastereoselective syntheses of dihydrobenzo[b]furans have been accomplished by a rhodium-catalyzed regioselective and enantiospecific intermolecular allylic etherification of oiodophenols as a key step, providing the corresponding aryl allyl ether 122, which leads to a dihydrobenzo[b]furan by treatment of the intermediate aryl iodide with tris(trimethylsilyl)silane and triethylborane at room temperature in the presence of air <00JA5012>.

Meal

OH

BnO,, ~"~~7 OCO2Me,M e + l Rh(PPh3)3C/ P(OMe)3 THF 0~ to r.t. 122 84%

BnO~

Me (Me3Si)3SiH ._,._ / ..... 02 BnO Et3B 73%

Me

A sulfinyl group on phenol has been employed recently to achieve a ligand exchange reaction in which an ipso-substitution of the sulfur functionality by a carbon substituent can be realized in the synthesis of dihydrobenzo[b]furan neolignans. Thus, treatment of the psulfinylphenol 123 with (CF3CO)20 triggers the aromatic Pummerer-type reaction to form presumably a quinone thionium intermediate which reacts with the styrene to form the dihydrobenzo[b]furan. Oxidation of the sulfide with MCPBA leads to the sulfoxide 124 which can undergo a ligand exchange procedure to afford the synthetically useful benzo [b]furanaldehyde <00OL2279>.

Five-Membered Ring Systems: Furans and Benzofurans

i~

+

161

Me~~e, O Me /-~--~ JDMe Me(0F300)20 PhSy , ' ~ - ~ ~ M

MeCN -40oc

~+o-

Ph 123

~

~[.~____~O~

OMe

81%

Me ,OMe

Q"

MOPBA,.. Ph"S 94%

124

Me ,OMe

OHC,~ ~ ~ ,--4' OMe 1.n-BaLi ]'(~'~'3--'('('~OMe 2. DMF ~ O ~/ 61%

5.3.3.4 Benzo[c]furans Benzo[c]furans (isobenzofurans) are reactive molecules usually employed as reactive dienes in the synthesis of more complex molecules. In the synthesis of spiro compounds related to fredericamycin A, Kumar generated the trimethylsiloxytrimethylsilylbenzo[c]furan 125 from phthalide via two consecutive deprotonations and silylations of the resulting anions. Diels-Alder reaction of the isobenzofuran as shown below with a spiroenedione leads to the formation of an endo-exo mixtures that can be smoothly converted to the dihydroxydione <00IJC(B)738>.

O

1. LDA -78oc 2. Me3SiCI

OSiMe31. LDA .78oc 2. Me3SiCI

OSiMe3

125

40 O THF 58%

CF3CO2H. O II,-

Me3SiO n O

CHCI3 reflux 65%

H

SiMe3

~ OH

O

The generation and trapping of 5,6-bis(trimethylsilyl)benzo[c]furan 126 was reported by Wong utilizing Warrener's s-tetrazine methodology. The trapping of the silylated isobenzofuran with N-phenylmaleimide is illustrated below. A number of other dienophiles such as dimethyl acetylenedicarboxylate, benzoquinone, naphthoquinone and anthra-l,4-quinone have also been used <00TL5957>.

-Ph +

CHCl3M e 3 S i ~

0

126

M e 3 S i ~ ~-- .,Jf~,~)J,~(~. ~ N-Ph

X.-L. Hou, Z Yang, and H.N.C. Wong

162

Another way in which an isobenzofuran can be generated is by reaction of an acetal with a base. In this manner, 1-arylisobenzofurans 127 where Ar = Ph and o-MeC6H4 are prepared and trapped with dienophiles. An example is shown below <00OL923>.

OMe 2 equiv. [~0 n-BuLi i ~ O ~ , . Et20 Ar 127 Ar

/

CO2Me SePh 1~ [~ph~epCO toluene 2Me 80~= ph2 hr

A more elaborate organochromium method for the generation of 1-substituted isobenzofurans was also reported. As can be seen below, treatment of the o-alkynylbenzaldehyde with the Fischer chromium carbene complex provides the isobenzofuran-Cr(CO)3 complex 128 which can be trapped by the electron-deficient N-phenylmaleimide with excellent exo-selectivity. <00OL1267>.

g u

OMe

Cr(CO)5 ~ M e N-phenyl Me"JL'oMe maleimide~ dioxane Cr(CO)3 % 100~ 128

OMe Me -Ph n O

5.3.4 M I S C E L L A N E O U S

Ab initio and density functional calculations (DFT) on a number of cyclohexane derivatives containing spiro(THF) units reveal that they all favor the all-O-equatorial conformation, due to the gauche effect of the di-O-equatorial arrangement, as well as to the high energetic cost for arranging the alkoxy substituents axially on the same face. As an example, the hexaspiro(THF)cyclohexane 129 is calculated to prefer the all-O-equatorial conformer by 22.0 kcal/mol. The aforementioned effects are so pronounced that even the energy-lowering effect caused by metal complexation is insufficient to drive the all-O-equatorial conformation to the allO-axial conformation <00JOC9180>.

•@•

O.

129 O-equatorial The development of a natural way to monitor the early events in protein folding has been investigated. The strategy involves formation of a small loop from N-terminals of a protein to an internal amino acid side chain using 3'-(carboxymethoxy)benzoin (CMB) (due to its high quantum yields, good water solubility, and fast photolysis rates) as a trigger to initiate the protein folding. This unique device, after integrating into the small c~-helical villin headpiece subdomain, can transfer the photo-sensitive benzoin into an inert photo-product 2-phenylbenzo[b]furan 130 after irradiation. As a result, this irreversible triggering event allows Chan to monitor the entire protein refolding process <00JA11567>.

163

F i v e - M e m b e r e d Ring Systems: Furans and Benzofurans

~~ OvCO2tBu

HO2C y s ~ .J4.,.../O

~L 2CLC

Ph

~

I/~

130

Acknowledgment: H.N.C.W. wishes to thank the Croucher Foundation (Hong Kong) for a Croucher Senior Research Fellowship (1999-2000).

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F i v e - M e m b e r e d Ring Systems: Furans and Benzofurans 00OL2303 00OL2409 00OL2467 00OL2729 00OL2817 00OL3233 00OL3345 00OL3445 00OL3521 00OL3535 00OL3913 00S 1091 00S 1529 00S 1878 00S2069 00S2092 00S2131 00SL363 00SL550 00SL743 00SL 1163 00SLl193 00SL1273 00SL1733 00SL1773 00SL1788 00T2967 00T3933 00T6331 00T7433 00T8769 00T8953 00T9181 00T9203 00T9985 00T9391 00T10175 00TA 1681 00TA4661 00TL17 00TL633 00TL915 00TL1347 00TL1375 00TL 1393 00TL1955 00TL2073 00TL2269 00TL2667 00TL2683 00TL3149 00TL3399 00TL3411 00TL3415 00TL3467 00TL3567

165

N. Bodineau, J.-M. Mattalia, V. Thimokhin, K. Handoo, J.-C. N6grel, M. Chanon, Org. Lett. 2000, 2, 2303. G.A. Kraus, N. Zhang, J.G. Verkade, M. Nagarajan, P.B. Kisanga, Org. Lett. 2000, 2, 2409. A. Ftirstner, T. Gastner, Org. Lett. 2000, 2, 2467. J.B. Hendrickson, M.A. Walker, Org. Lett. 2000, 2, 2719. N.G. Andersen, M. Parvez, B.A. Keay, Org. Lett. 2000, 2, 2817. A. Padwa, M. Dimitroff, B. Liu, Org. Lett. 2000, 2, 3233. G.-D. Zhu, M.A. Staeger, S.A. Boyd, Org. Lett. 2000, 2, 3345. S.K. Bur, S.F. Martin, Org. Lett. 2000, 2, 3445. D.E. Fuerst, B.M. Stoltz, J.L. Wood, Org. Lett. 2000, 2,3521. F. Stauffer, R. Neier, Org. Lett. 2000, 2, 3535. R.G. Carter, D.J. Weldon, Org. Lett. 2000, 2, 3913. F.-E. Chen, H. Fu, G. Meng, Y. Cheng, Y.-L. Hu, Synthesis 2000, 1091. M.A. Abramov, W. Dehaen, Synthesis 2000, 1529. N. Kanoh, J. Ishihara, Y. Yamamoto, A. Murai, Synthesis 2000, 1878. W.-W. Pei, J. Pei, S.-H. Li, X.-L. Ye, Synthesis 2000, 2069. D. Enders, D. Nguyen, Synthesis 2000, 2092. H.-J. Kn61ker, W. Fr6hner, Synthesis 2000, 2131. G. A. Kraus, Z.-W. Wan, Synlett 2000, 363. C. Bozzo, M.D. Pujol, Synlett 2000, 550. P. Langer, I. Karim6, Synlett 2000, 743. C. Pilger, B. Westermann, U. Fl6rke, G. Fels, Synlett 2000, 1163. H. Nagano, A. Tada, Y. Isobe, T. Yajima, Synlett 2000, 1193. H.M. Meshram, K. Chandra Sekhar, Y.S.S. Ganesh, J. S. Yadav, Synlett 2000, 1273. D. Awakura, K. Fujiwara, A. Murai, Synlett 2000, 1733. M. Makosza, J. Przyborowski, R. Klajn, A. Kwast, Synlett 2000, 1773. T. Grimaldi, M. Romero, M.D. Pujol, Synlett 2000, 1788. W.-P. Deng, A.-H. Li, L.-X. Dai, X.-L. Hou, Tetrahedron 2000, 56, 2967. M.A. Abramov, W. Dehaen, B.D'hooge, M.L. Petrov, S. Smeets, S. Toppet, M. Voets, Tetrahedron 2000, 56, 3933. G. Blay, L. Cardona, B. Garcfa, L. Lahoz, B. Monje, J. R. Pedro, Tetrahedron 2000, 56, 6331. Y.-K. Yang, M.-H. Chiu, C.-W. Gao, R.-L. Nie, Y. Lu, Q.-T. Zheng, Tetrahedron 2000, 56, 7433. D. Bogdal, M. Warzala, Tetrahedron 2000, 56, 8769. S. Caddick, S. Khan, L.M. Frost, N.J. Smith, S. Cheung, G. Pairaudeau, Tetrahedron 2000, 56, 8953. I.R. Nascimento, L.M.X. Lopes, L.B. Davin, N.G. Lewis, Tetrahedron 2000, 56, 9181. Z.-M. Ruan, D. Dabideen, M. Blumenstein, D.R. Mootoo, Tetrahedron 2000, 56, 9203. A. Hisham, A. Harassi, W. Shuaily, S. Echigo, Y. Fujimoto, Tetrahedron 2000, 56, 9985. K.L. McPhail, D.E.A. Rivett, D.E. Lack, M.T. Davies-Coleman, Tetrahedron 2000, 56, 9391. J.C. Lee, J.K. Cha, Tetrahedron 2000, 56, 10175. F. Messina, M. Botta, F. Corelli, C. Villani, Tetrahedron: Asymmetry 2000, 11, 1681. F. Carrel, P. Vogel, Tetrahedron: Asymmetry 2000, 11,4661. P. Forgione, P. D. Wilson, A.G. Fallis, Tetrahedron Lett. 2000, 41, 17. S. Leclercq, J.C. de Biseau, D. Daloze, J.-C. Braekman, Y. Quinet, J.M. Pasteels, Tetrahedron Lett. 2000, 41,633. J.-P. Liou, C.-Y. Cheng, Tetrahedron Lett. 2000, 41,915. J.A. Marshall, D. Zou, Tetrahedron Lett. 2000, 41, 1347. G. Kreiselmeier, B. F6hlisch, Tetrahedron Lett. 2000, 41, 1375. K.K. Park, H. Seo, J.-G. Kim, I.-W. Suh, Tetrahedron Lett. 2000, 41, 1393. H.-B. Ye, Z.-S. He, Tetrahedron Lett. 2000, 41, 1955. I.H. Hardt, P.R. Jensen, W. Fenical, Tetrahedron Lett. 2000, 41, 2073. M. Plotkin, S. Chen, P.G. Spoors, Tetrahedron Lett. 2000, 41, 2269. S. Chandrasekhar, M.V. Reddy, K.S. Reddy, C. Ramarao, Tetrahedron Lett. 2000, 41, 2667. F.A. Macfas, R.M. Varela, A.M. Simonet, H.G. Cutler, S.J. Cutler, S.A. Ross, D.C. Dunbar, F.M. Dugan, R.A. Hill, Tetrahedron Lett. 2000, 41, 2683. S. Onitsuka, H. Nishino, K. Kurosawa, Tetrahedron Lett. 2000, 41, 3149. T. Takanami, A. Ogawa, K. Suda, Tetrahedron Lett. 2000, 41, 3399. J.-J. Yung, L.-J. Jung, K.-M. Cheng, Tetrahedron Lett. 2000, 41,3411. J.-J. Yung, L.-J. Jung, K.-M. Cheng, Tetrahedron Lett. 2000, 41 3415. S. A1-Busafi, R.C. Whitehead, Tetrahedron Lett. 2000, 41, 3467. M.F. Semmelhack, P. Shanmugam, Tetrahedron Lett. 2000, 41, 3567.

166

00TL3923 00TL4447 00TL4453 00TL4541 00TL4987 00TL5447 00TL5803 00TL5957 00TL6879 00TL8041 00TL8059 00TL8639 00TL8687 00TL8941 00TL9337 00TL9387 00TL9431 00TL9613 00TL9777 00TL9875 00TL 10013 00TL10121 00TL10127 00TL10223

X.-L. Hou, Z. Yang, a n d H.N.C. W o n g

M. Sasaki, T. Koike, R. Sakai, K. Tachibana, Tetrahedron Lett. 2000, 41, 3923. S.P. Bew, J.M. Barks, D.W. Knight, R.J. Middleton, Tetrahedron Lett. 2000, 41, 4447. S.P. Bew, D.W. Knight, R.J. Middleton, Tetrahedron Lett. 2000, 41, 4453. W.R. Erickson, M.J. McKennon, Tetrahedron Lett. 2000, 41,4541. E.J. Guthrie, J. Macritchie, R.C. Hartley, Tetrahedron Lett. 2000, 41, 4987. Y.-X. Han, A. Roy, A. Giroux, Tetrahedron Lett. 2000, 41, 5447. P.J. Coleman, J.H. Hutchinson, C.A. Hunt, P. Lu, E. Delaporte, T. Rushmore, Tetrahedron Lett. 2000, 41, 5803. C.-Y. Yick, S.-H. Chan, H.N.C. Wong, Tetrahedron Lett. 2000, 41, 5957. S. Caddick, S. Cheung, L. M. Frost, S. Khan, G. Pairaudeau, Tetrahedron Lett. 2000, 41, 6879. B. Wang, P. Cao, X. Zhang, Tetrahedron Lett. 2000, 41, 8041. S.R. Angle, S.L. White, Tetrahedron Lett. 2000, 41, 8059. D. Prajapati, D.D. Laskar, J.S. Sandhu, Tetrahedron Lett. 2000, 41, 8639. J.W. Herndon, Y. Zhang, H. Wang, K. Wang, Tetrahedron Lett. 2000, 41, 8687. D. Bebbington, J. Bentley, P.A. Nilsson, A.F. Parsons, Tetrahedron Lett. 2000, 41, 8941. K.K. Rana, C. Guin, S.C. Roy, Tetrahedron Lett. 2000, 41, 9337. J.D. Ginn, S.M. Lynch, A. Padwa, Tetrahedron Lett. 2000, 41, 9387. C.M. Gasparski, P.M. Herrinton, L.E. Overman, J.P. Wolfe, Tetrahedron Lett. 2000, 41,9431. N. Krause, M. Laux, A. Hoffmann-R6der, Tetrahedron Lett. 2000, 41, 9613. O. Arjona, A.G. Cs~ik~, M.C. Murcia, J. Plumet, Tetrahedron Lett. 2000, 41, 9777. A. Dekebo, E. Dagne, L.K. Hansen, O.R. Gautun, A.J. Aasen, Tetrahedron Lett. 2000, 41, 9875. M. Uchiyama, Y. Kimura, A. Ohta, Tetrahedron Lett. 2000, 41, 10013. T.K. Chakraborty, S. Ghosh, M.H.V. Ramana Rao, A.C. Kunwar, H. Cho, A.K. Ghosh, Tetrahedron Lett. 2000, 41, 10121. R. Antonioletti, G. Righi, L. Oliveri, P. Bovicelli, Tetrahedron Lett. 2000, 41, 10127. Y. Okimoto, D. Kikuchi, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 2000, 41, 10223.

167

Chapter 5.4 Five Membered Ring Systems: With More Than One N Atom

Larry Yet Albany Molecular Research, Inc., Albany, NY, USA larryy@albmolecular, com

5.4.1

INTRODUCTION

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives continued in 2000. Solid-phase combinatorial chemistry of pyrazoles and benzimidazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. Notably, metal-promoted and cross-coupling reactions of all classes seemed to be a dominant theme in 2000. Applications of pyrazole-, imidazole-, and 1,2,3-benzotfiazole-containing reagents to a wide array of synthetic applications remained active. 5.4.2

P Y R A Z O L E S AND RING-FUSED DERIVATIVES

Tris(pyrazolyl)methanesulfonates have been prepared as a novel class of watersoluble ligands to be used as enzyme models <00ACIE2464>. Unusually stable pyrazolatebridged dialuminum complexes, containing bridging methyl groups, have been disclosed <00JACS9338>. The kinetics and activation parameters of the thermolysis of hexasubstituted-4,5-dihydro-3H-pyrazoles were reported <00HC299>. The neighboring effect of pyrazole rings has been investigated in the regio- and stereoselective WagnerMeerwein rearrangement in electrophilic addition reactions of norbornadiene-fused pyrazoles <00JCS(P 1)2731 >. The synthesis of the pyrazole core structure in 2000 has been approached from many angles. The classical method involves the reaction of 1,3-difunctional species with hydrazine derivatives. Thus, chiral tx-acetylenic ketones 1 reacted with hydrazines to yield pyrazolyl oxazolidine derivatives 2, which were further elaborated to novel enantiomerically pure pyrazolyl-[3-amino alcohols 3 <00TA2483>. Similarly, optically active pyrazolyl a-amino acids were prepared from chiral tx-acetylenic ketones <00S1295>. Isomeric AE-pyrazolines were synthesized from 2'-hydroxy-5'-chlorochalcones <00SC3241>. ot,13-Unsaturated ketones 4 were condensed with arylhydrazines to yield dihydropyrazoles 5, which were further alkylated and oxidized to 1,3,5-triaryl-4-aklylpyrazoles 6 which are novel ligands for the estrogen receptor <00OL2833>. tx-Halogenoketone hydrazones 7 reacted with isocyanides in the presence of sodium carbonate to give 5-aminopyrazoles 8 <00SL489>. Addition of hydrazines to 13-hydroxy acylsilanes 9 afforded 3-trimethylsilyl pyrazoles 10 <00TL9791>.

168

L. Yet

O O/"~ /~N

"Boc

R1 RNHNH2, DMF K2CO3, 0 ~ ~1

2

0

"

h

1. TFA, MeOH, 0 ~ R1 2. Boc20, NaHCO3 ~ dioxane, 0 ~

/Ar3 N-N Arl''J~'~Ar2

Ar3NHNH2.HCI DMSO, 80 ~

1. LDA; RI 2. DDQ or MnO2

HO

R1

HN4 \N"N"R Boc 3

N-N Arl

5

Ar 3 r2

R 6

N~NHR2 R1 i ~ j X 7

1~2 R3NC, Na2CO3 N'N ,'~NHR3 0H2012 " ~ R1 8

OH O R~.~.

R1 TMS

R1NHNH Et20 2 " __ R~/-~ ~" NT-MN~.S~--- _..._ 10

9

Acid- and base-promoted methods have also been used in the syntheses of pyrazoles. Hydrogenation of methyl 2-Cbz(hydrazine)-3-hydroxy-4,4-dimethoxybutanoate 11 followed by cyclization in the presence of trifluoroacetic acid afforded the first asymmetric synthesis of the (4S,5R)-5-carbomethoxy-4-hydroxy-A2-pyrazoline 12 <00TL8795>. Reaction of 2nitrobenzyl triphenylphosphonium ylide (13) with aryl isocyanates afforded 2-aryl-2Hindazoles 14 <00TL9893>. Base-promoted reaction of nitrobenzenes 15 with aryl imines 16 afforded aryl pyrazoles 17 <00OIA13>. OH Me(o~'~CO2Me 1" H2' Pd/C' MeOH' 25 ~ Me 2. TFA Cbz/ "NHCBz 11

-'/~'PPh3 "NO2

ArNCO,MeCN Nail or DBU

13

+ O2N

H 12

"/C02Me

~N-Ar

14 NNH2

15

OH N,N/~I

=

H 16

HN-N Nail, DMF ,

NO2 17

Thermolysis reactions have also been investigated as methods for preparing pyrazoles. Thermolysis of azido imines 18 led to 2-substituted-4,6-dinitro-2H-indazoles 19 <00S 1474>. High temperature intramolecular cyclization of N,N-diethyl-N'-(4-substituted-2-

169

Five-Membered Ring Systems: With More Than One N Atom

ethynylphenyl)triazenes (20) under neutral conditions provided both 5-substituted isoindazoles 21 and 6-substituted cinnolines 22, respectively <00OL3825>. Microwaveassisted cycloaddition of pyrazolylimines with aromatic and aliphatic nitroalkenes afforded pyrazolo[3,4-b]pyridines <00T1569>. Thermolysis of N-(acryloyloxy)alkylated pyrazole-3sulfolenes 23 gave the intermediate pyrazole-o-quinodimethanes 24, which underwent typetwo intramolecular Diels-Alder reactions to afford tricyclic pyrazoles 25 <00JOC5760>. Cyanopyrazole heterocycles were prepared in a facile manner from thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines or tetrazolo[1,5-a]pyridines <00TL2699>. _@N-RNO2 O2N

150-180~ 18

NEt2

~~,.NO2

N3

~ "~N N ~ N - B

O2N

19

,NEt2

H

~N-N

17Cl02oPh =_ R

20

R

,,0oc

23

~~~

C NO 21

R

_.-

24

22

)n

25

O

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. N-Aryl-N-(o-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2H-indazoles 27 <000L519>. Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. ~Br R

/ AF N NH2

26

Pd(OAc)2, d p p f NaOt-Bu,PhMe 90 ~

~N--Ar R ~ N" 27

/ N-N ~OH 28

Pd(PPh3)4(5 tool%), K2CO3 (2 eq) Dimethylallene(3 eq), CO (1 atm) Arylhydrazine,PhMe,45 ~

OH

(

ArX + 30

31

Ph

1. Pd(PPh3)2CI2,Cul Et3N, THF, 65 ~ 2. MeNHNH2

29

Me

N-N

Art~-~ph 32

AF

170

L. Yet

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates <00TA1975>. N-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecarboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <00JHC1309>.

[ ~ N ~ NN @/> Me2N CIQ 33

Pr~.N R 34

R2

THF, 25 ~ - genzotriazole

N ~'--Pr CI LT) [ H-~(~ ~N.Mei / R R2 Me J 35

NH2NH2"H20 - HNMe2.HCI - PrNH2

N-N H~T " R1

R2 36

Synthetic elaboration of pyrazole core structures have been investigated. Selective Nmethylation of pyrazolone was accomplished with methanol as a methylating agent in the liquid phase with zirconium(IV) oxide as catalyst <00SL809>. Reaction of iodopyrazole 37 with iso-propylmagnesium bromide provided the intermediate magnesiated pyrazole, which was converted to functionalized pyrazoles 38 with various electrophiles <00JOC4618>. 3Aryl-5-ethylpyrazoles or 3-alkoxylmethyl-5-ethylpyrazoles 39 underwent a highly regioselective arylation on the N-1 atom with 4-fluoronitrobenzene in the presence of base to yield the corresponding 1-(4-nitrophenyl)pyrazoles 40 <00TL5321, 00OL3107>. An asymmetric synthesis of densely functionalized pyrazolidines was accomplished from diastereoselective additions of silyl ketene acetals, allyl tributylstannane, and trimethylsilyl cyanide to N-acyl pyrazolines <00OL4265>. Ethyl 1-pyrazoloacetate reacted with carbon disulfide and iodomethane to afford pyrazolo[5,1-b]thiazole <00SC763>. 5,5-Dimethyl-2(indenyl-2)-3-pyrazolidinone reacted with acetylene dicarboxylates to yield pyrrolo[1,2a]pyrimidinones <00OL423>. I

Me

E

Me

~N.N 1. i-PrMgBr, CH2CI2, -25 ~ :=~ O "Me 2. Electrophile " O N-N'-Me I I Ph Ph 37 38

~N.N R H 39

F

NO2

KOt-Bu, DMSO, 70 ~ R = Ar, R1CHOR2

,.

R 40

NO2

The cross-coupling reaction of 1-aryl-5-bromopyrazoles with alkynes, vinyltin reagents and arylboronic acids promoted by palladium catalyst afforded unsymmetrical 3,5disubstituted 1-arylpyrazoles 41 <00TL4713>. 3-Iodoindazole (42) underwent combined N1- and C3-arylations with boronic acids in a one-pot palladium-catalyzed reaction to give 1,3-diarylindazoles 43 <00TL9053>. 3-Iodoindazole (42) also participated in a Heck crosscoupling reaction with methyl acrylate to give indazoles 44, which are useful precursors to 2azatryptamines <00TL4363>. 7-Iodopyrazolo[1,5-a]pyridines 45 underwent palladium-

171

Five-Membered Ring Systems: With More Than One N Atom

catalyzed cross-coupling reactions to afford 7-substituted pyrazolo[1,5-a]pyridines 46 <00S1727>.

Br R1

R3

R2

Reagents, THF, 65 ~ =- R1

R2

41

AF

ArB(OH)2 (3 eq), DME,Cu(OAc)2(1.5 eq) NaHCO3(3 eq), Pd(PPh3)4 (5 mol%),80 ~

y I

~ N 42

Xr

43

'N H ~

~

1. Boc20, DMAP,Et3N,CH3CN 2. PdCI2(dppf) (20 mol%), Et3N,Bu4NI,DMF Methyl Acrylate, 50 ~ 3. NaOMe,MeOH,25 ~

R I

Pd(PPh3)4( 5 mol%), PhMe R1SnBu3, 110 ~ =

44

~

H

R R1

45

CO2Me

46

Bis(pyrazolyl)borate copper complex 47 has been employed as a catalyst in the homogeneous and heterogeneous styrene epoxidation reactions <00JCS(CC)1653>. Pyrazole palladacycles 48 have proven to be stable and efficient catalysts for Heck vinylations of aryl iodides <00JCS(CC)2053>. An asymmetric borane reduction of ketones catalyzed by Nhydroxyalkyl-l-menthopyrazoles has been reported <00JHC983>.

H .,,,,H

/~...~ B%Q N CuO 47

R3~ v

"1:142

48

Several solid-phase combinatorial approaches to the pyrazole core have been reported in 2000. 1,3-Dipolar cycloaddition of polymer-supported (z-silylnitrosoamides 49 with dimethyl acetylenedicarboxylate gave pyrazole derivatives 50 without the necessity of a cleavage operation <00TL691>. Condensation of aromatic or aliphatic esters with resinsupported acetyl carboxylic acids 51, followed by cyclization With hydrazines, activation with trimethylsilyldiazomethane, and cleavage using amines provided highly substituted, isomeric pyrazoles 52 and 53 <00OL2789>. A parallel solution phase synthesis of Nsubstituted 2-pyrazoline libraries 56 were obtained from hydrazine addition to chalcones 54 to give the unstable pyrazoline 55, which were trapped with various electrophiles in the presence of polymer-bound base <00TL2713>. New germanium-based linkers 57 have been

172

L. Yet

utilized for the preparation of regioisomeric polymer-supported pyrazoles 58 and 59, which were cleaved upon reaction with hydrazines to pyrazoles 60 and 61 <00JOC5253>.

O

R

MeO2C

~No/L'SiMe3

DMAD PhMe, 80 ~

R~N~ N H

49

02 O O ( ~ ' S " N ' ~ R ~ Me 51

O RI" ~" 54

Me M e l i ~ 57

x ''~

50

1. R2CO2Me 2. NH2NHR3-HCl 3. TMSCHN2 = 4. R4NHR4

NH2NH2.H20 -R2 EtOH,70 ~

H N\ N

RI.~NN_R 3 + R3 O,~ O.~R, I.~N N R4/N.R4L ~ R4/N.R4 LL~ 52 R2 R2 53

N\N R1 R1

,E E,ectroph,,e

~N(i-Pr)2

Me Me ~

RNHNH2-HCI,100~ ,. n-BuOH,HOAc NMe2 X = H , Br

I~N 58

x~N

R2 56

... ~.JVle Me

Go

TFA, 16 h or Br2, CH2CI2, 15 min E=H, Br

X

+

60

5A.3

CO2Me

+

..~

59

__.~j~"N-R

X

~.N,N_R

61

IMIDAZOLES AND RING-FUSED DERIVATIVES

A series of 1,3-di(ferrocenylmethyl)imidazolium and 1-ferrocenylmethyl-3alkylimidazolium salts were synthesized from ferrocene <00SC1865>. Nuclear magnetic resonance studies of the coordinating behavior of 2,6-bis(benzimidazole-2'-yl)pyridine metal ions were performed <00HC392>. The structural features of the pyrido[1,2-a]benzimidazole (PBI) chemical series of high-affinity GABA-A receptor ligands were studied by a variety of NMR spectroscopic techniques and by AM-1 semi-empirical force-field calculations <00T8809>. Hydrolysis of multicyclic guanines under basic conditions led to isolable trisubstituted imidazoles <00TL5025>. The persistent carbenes of 4,5-dialkynylimidazol-2ylidenes have been synthesized and characterized by low temperature NMR spectroscopy <00JCS(CC)919>. General procedures for the synthesis of the imidazole core have been published in 2000. Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles 64 from aldehydes 62 and 1,2-dicarbonyl compounds 63 in the presence of ammonium acetate and alumina has been reported <00TL5031>. N-protected or-amino glyoxals 65 were utilized as potential chiral educts for the synthesis of amino acid-derived imidazoles 66 <00TL1275>.

Five-Membered Ring Systems: WithMore

173

Than One N A t o m

Traditional imine-forming reactions employing virtually any amine 67 and aldehyde 68 followed by addition of tosylmethyl isocyanides 69 delivered 1,4,5-trisubstituted imidazoles 70 with predictable regiochemistry <00JOC1516>. ct-Anilino-tx-methoxyacetates 71 cyclized in the presence of (p-tolylsulfonyl)methyl isocyanide to yield 1-arylimidazole-5carboxylates 72 <00TL5453>. A novel preparation of imidazol-2-ones in four steps from quinolines via an oxidative ring rearrangement was reported <00TL6387>.

R R1CHO +

R2COCOR2

62

CbzH~

R2

Microwaves " NyNH

63

R

R1

64

~kk~ ~=1=/ R2

RNH2 + R1CHO + 67

68

H

O

R1CHO R

NH4OAc~"

H"N

OMe 71

R1

66

S02T~ K2003 = NC DMF

R~N ..R 70

/~r os ,c

OEt

"'-NH

65

69

,•r O

NHCbz

K2003,

EtOH

O

"

Et 72

1,2-Diamines have been useful precursors for the syntheses of imidazoles and benzimidazoles. 2-Alkylbenzimidazoles 74 were prepared from o-phenylenediamine (73) in the presence of carboxylic acids with natural bentonite clay as the acid catalyst and using infrared light as the energy source <00SC2191>. o-Phenylenediamine (73) reacted with (E)2-ethoxy-l-(trifluoromethylacetyl)ethylene (75) to give benzimidazole 76 <00SC677>. Easily prepared N-(2-propenylideneaminophenyl)ketenimines underwent intramolecular [4+2] cycloadditions to afford pyrido[1,2-a]benzimidazole derivatives <00TL7029>. Reactions of nitriles 77 with 1,2-diaminoethanes 78 in the presence of phosphorus pentasulfide afforded 2-aryl-A2-imidazolines 79, which were dehydrogenated with dimethylsulfoxide or 10% palladium on carbon to give 2-aryl-lH-imidazoles 80 <00S1814>.

~OCF 3 ~ ~ . NH2 aOO2H' 'R 9 ~ -,~ -NH2 BentoniteClay 73

:\~---R 74

ArCN 77

+

H2N R ~ H2N

78

H

P2S5 ,

[~~~i

EtO/ 75 EtOH,70~

73

9

N R2 Ar---~ ~ N

H 79

9[ ~

:\~._.CF3

76

DMSO or

lO%Pd/C

~

H

._..~/~~,,,R2 Ar H 80 I

Imidazole-containing reagents have found useful applications in a variety of organic transformations. A second generation of ruthenium-based olefin metathesis catalysts

174

L. Yet

coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligand 81 have been utilized in the synthesis of bis- and oligo-gem-difluorocyclopropanes <00OL1431>, in improved yneene-cross metathesis reactions <00TL5465, 00OL2271>, in cross-metathesis reactions <00OL3153>, and in stereoselective macrocyclic ring-closing olefin metathesis <00OL2145>. The use of ruthenium benzylidine 82, bearing the 1,3-dimesitylimidazol-2ylidene ligand, has widened the scope of the ring-closing metathesis reactions of various hindered heterodynes, which did not cyclize with the original Grubbs' catalyst <00OL1517, 00JOC2204>. These catalysts have proven to be more air- and water-tolerant than the earlier ruthenium-based catalysts and their ring-closing metathesis activity has greatly exceeded the previous analogs. Catalyst 82 has been utilized in the ring-closing metathesis reaction to synthesize conduritol derivatives <00T2195> and 2-substituted chromenes <00TL5979>. Ruthenium alkylidene catalyst 83 has been used in the synthesis of functionalized olefins by cross and ring-closing metatheses reactions <00JACS3783>. Polymer-bound "boomerang" catalyst 84 has been utilized in several ring-closing metathesis reactions <00SL1007>. A phosphine-free 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium complex has been developed for ring-closing and cross metathesis reactions <00TL9973>.

PCy3 Mes--N

.N-Mes

CI ,,,"R~, __/ CIf

9

I~Cy3

Mes--N.

CI,,,, . CIf

81

N-Mes .

.

PCy3

.

.

Mes--N .

.

.N-Mes

....

c, =Ru---~ v

Me CI4 " I~Cy3 k ~ M e .

82

83

u ,,,CI

/'c,

MeS..N~N..Mes 84

Bulky imidazolium salts 85 and 86 were found to greatly accelerate the amination of aryl chlorides using palladium catalysts <00OL1423> as well as to provide efficient nickelcatalyzed cross-coupling of aryl chlorides with aryl Grignard reagents <00ACIE1602>. Imidazolium salt 85 participated in the efficient cross-coupling reactions of aryl chlorides and bromides with phenyl- or vinyltrimethoxysilanes <00OL2053>. General and efficient Suzuki cross-coupling reactions of aryl chlorides with arylboronic acids~were promoted by palladium complex with bisimidazolium salt 87 <00TL595>. \,

XO

X=CI 86 X=BF4

85

Me,

~

/ - - N ~ N'Mes --Me

2CI @

.Mes

87

L-Valinol and L-phenylalaninol-derived 2-imidazolidinones 88 have been utilized as chiral auxiliaries for asymmetric aldol reactions <00TL1505>. Imidazolidone 89 has been used in enantioselective Diels-Alder cycloadditions <00JACS4243> and in enantioselective [3+2] cycloadditions between nitrones and a,13-unsaturated systems <00JACS9874>. N'butyryl-2-imidazolidinone auxiliaries have been reported to give unusual enhancement in diastereocontrolled methylation reactions <00TL8533>. Imidazole phosphine 90 was used in a novel Staudinger reaction with azides for the formation of amide bonds <00OL2141>. The ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (91, [bmim][BF4]) has been utilized in palladium-catalyzed Suzuki cross-coupling reactions <00CC1249>,

175

Five-Membered Ring Systems: With More Than One N Atom

tetraallylstannane additions to Weinreb amides <00TL8147>, and in lipase-catalyzed transesterifications and ammoniolysis reactions of esters <00OIA189>. Similarly, ionic phosphine 92 has been utilized in palladium-catalyzed cross-couplings of aryl- and benzylzinc halides with aryl iodides <00SL1613> and nickel-catalyzed cross-couplings of aryl halides to give biaryls <00TL10319>. 1-Cyanoimidazole (93) has been utilized as a mild electrophilic cyanating agent in the high-yielding N-acylation of amines, sulfur, and with carbanion nucleophiles <00OL795>. 1-(Methyldithiocarbonyl)imidazole (94) has been employed as a useful thiocarbonyl transfer reagent for synthesis of substituted thioureas <00T629>. Iminic glycinimides of 1,5-dimethyl-4-phenylimidazolidin-2-one (95) have proven to be useful reagents for the practical asymmetric synthesis of or-amino acids <00JOC7310>.

J,L~ Ph~N" ~NH 'k~-~R 88

R = i-Pr,

Bn

o. N'Me Me r~NNkMe Ph H.HCl 89

'x~QMe Ph2P,%~N INI ...~ 90

BF4Q MeINvN'n-Bu 91 O

/-~ PF60 Me~N.~N~n_Bu PPh2 92

~N--~ (~N

93

S ~N,~NH N.~,,,N.~SMe Me v=_/ Me"" "Ph 94

95

Several metal-promoted cross-coupling reactions of imidazoles have been published in 2000. Copper-catalyzed N-phenylation of imidazoles with diphenyliodonium tetrafluoroborate (96) afforded N-phenylimidazoles 97 <00SL1022>. Arylboronic acids 98 reacted efficiently with imidazoles in the presence of a novel diamine-copper complex to give a variety of N-arylimidazoles 99 <00OL1233>. p-Tolylboronic acid (100) has been found to arylate benzimidazole in the presence of copper(II) acetate and pyridine to afford benzimidazole 101 <00SL674>. Hypervalent aryl siloxanes 102 underwent efficient copperpromoted cross-coupling reactions with benzimidazole in the presence of tetrabutylammonium fluoride to yield arylimidazoles 103 <00JACS7600>. Copper-catalyzed formation of N-arylimidazoles 106 from aryllead(IV) precursors 104 and imidazoles 105 were prepared with complete N-1 regiocontrol <00OL3055>. 3-Iodoimidazo[1,2-a]pyridines 107 underwent facile Suzuki cross-coupling reactions to afford benzimidazoles 108 <00JOC6572>.

00 Ph21BF4 96

Cu(acac)2,K2CO3 PhMe,50oc ~ NRE../../N_ ~ ph N~ R{ LT~/NH 97 R

[Cu(OH),TMEDA]2CI2 B(OH)2 0H2012'02, 25oC= ~ - ~ N / ~ , N HN-"%N R(J'/'`~/ ~-\J 98 ~_l__j 99 R2 R2

L. Yet

176

Cu(OAc)2 (1.5 eq), 4/%,MS Pyridine (2 eq), CH2CI2, 25 ~

Me---~--B(OH)2

101

100

H Cu(OAc)2 (1.1 eq), TBAF (2 eq) Pyridine (2 eq), CH2CI2, 25 ~

ArSi(OMe)3

Ar--N/~ ~N 103

H

~ ~

R2 + Pb(OAc)3

HN~ ~

104

105

R I ~ N ~ IN"-/~R2 107

I

R1

Cu(OAc)2(10 mol%) CH2Cl2, 25~ 106

"R1

R I ~ N R3B(OH)2,Pd(PPh3)4 (5 m o ' % ) ~ lNf/~R2 Na2CO3 (2 eq), DME, 80 ~ 108 R3

The imidazole core structure itself has been utilized for several synthetic operations. Base-promoted alkylations of imidazoles have resulted in new structural entities. For example, fused ring imidazoles 110 were obtained from two successive condensations of a dihalide from 4,5-diphenylimidazole 109 <00SL710>. An efficient synthesis of substituted benzimidazole-2-ones 112 from benzimidazole-l-carboxyate 111 was achieved using polymer-supported thiophenol to remove excess alkylating agent. Lateral metallation at C2(ct) of 1-tert-butoxycarbonyl-2-methyl-2-imidazoline (113), followed by reaction with a range of electrophiles and deprotection with trifluoroacetic acid afforded N(1)-unsubstituted 2-substituted-2-imidazolines (114) in good yields <00T2061>. Reaction of iodoimidazole 115 with iso-propylmagnesium bromide provided an intermediate magnesiated imidazole, which was converted to functionalized imidazoles 116 with various electrophiles <00JOC4618>. A highly regioselective N-alkylation of 4-formylimidazole (117) with methyl acrylate to give Michael adduct 118 was observed <00SC3383>.

Ph H 109

1. X(CH2)nX Me KOH Ph --" 2. LDA

i~'...~l~k_._ N ~ t4 ~ x"'-'kC' '2/n 110

111

H

" O 2. PS-thiophenol,DMF 3. K2CO3, EtOH

H

112 h

177

Five-Membered Ring Systems: With More Than One NAtom

Boc 1. sec-BuLi, -78 ~ ~~/~---Me 2" Electr~ ~ 3. TFA, 25 ~ 113

H ~~/yE 114

I .CO2Et N ~N~/OEt ~ Me 115

0

1. i-PrMgBr 0H2CI2'-25 ~ 2. Electrophile

E~CO2Et N,~' h l ~ OEt Me 116

O

DBU' MeCN,25 ~ = H~I

~~\~-R H 117

~"CO2Me

~\~F_._a ~ j C O 2 Me 118

Addition of nucleophiles to imidazoles has been reported for several applications. Addition onto imidazole (119) with silyl enol ethers in the presence of alkyl chloroformates provided 2-substituted imidazolines 120 <00T4383>. Amines reacted with 4hydroxymethylimidazole (121) in refluxing water to give 4-aminomethylimidazoles 122 <00TL2777>. Imidazoles 123 were acylated by ruthenium carbonyl-catalyzed direct carbonylation reactions to give imidazoles 124 <00JOC4039>. N-Acylated-2-methylthio-2imidazoline derivatives 125 reacted with various aryl amines in acidic ethanol to afford 2arylamino-2-imidazolines 126 <00TL6563>.

H

1. CICO2R1,Et3N

002R1

R~R4:gTMS

119

~ O CO2R1 120

R3

R1 R2

z--OH

~R

123

R2

100 oC

H 121

FI~

R'~ O

124 O

R

/'---NR 2

N"-I 125

H 122

1. ArNH2,HOAc 2. reflux

Ar/ H'N'J 126

Imidazole nitrones 127 reacted with dimethyl acetylenedicarboxylate to yield imidazo[1,5-b]isoxazoles 128, which in the presence of base afforded imidazoles 129 <00TL5407>. Chiral imidazoline nitrone 130 participated in a [3+2] cycloaddition reaction with various dienophiles to furnish imidazoisoxazoles 131 <00SL967>. A convenient synthesis of N,N,N'-trisubstituted ethylenediamine derivatives from 2-methyl-2-imidazoline has beenreported <00SC3307>. Dehydrogenation of 1,3-di- and 1,2,3-trisubstituted imidazolidines afforded 1H-4,5-dihydroimidazolium salts <00SC3369>

Ph Ar--N/"~~uv''~(~

127

Ph CO2Me DMADA= A r - - N ~ . . CO2Me 128

PipeMecNridine

Ar--N""~ Ph~N 129

178

L. Yet

Bn ,

R

N

p

Bn ' H

R

~/ Et3N, PhMe, 60 ~

p

h~NNo~R

130

131

R

Several solid-phase combinatorial approaches to the benzimidazole core have been developed in 2000. Solid-supported 1,2-benzenediamines have been useful precursors for many of these reactions. For example, 1,2,5-substituted 7-azabenzimidazoles 133 were prepared from polymer-supported pyridine diamines 132 <00TL5383>. 3,6-Substituted 2aminomethylbenzimidazoles 135 were obtained from polymer supported benzenediamine 134 <00TL5419>. Soluble polymer-supported diamines 136 were employed in the synthesis of benzimidazoles 137 from trimethyl orthoformate followed by basic cleavage <00SL591>. Resin-bound benzimidazoles 141) were prepared from resin-bound aldehydes 139 with 1,2benzenediamines 138 in a catalytic Fe(III)/Fe(II) redox cycling approach <00S1380>. Benzimidazoles 142 were efficiently prepared from polymer-bound o-nitroanilines 141 in a one-pot nitro reduction-cyclization protocol <00TL9871>.

N al

O

NH2 ~N/"~NHR2

"R3OHOH ' OAc DMA, 100 ~

O R1HN

2. TEA, CH2CI2

"~N/~N

132

t~.~

~ O O

.~r/NHR1

134

NH2

R3 133

1. FmocNHCHR2CO2H,PyBroP, i-Pr2NEt, NMP 2. HOAc, 90 ~ 3. PIPeridine, NMP, 20 ~ 4. R3CO2H,DIC, HOBt, i-Pr2NEt DCP, NMP 5. TFA, CH2CI2, 20 ~

9

R2

..~"-.,./I~

0

135

0

O 1. CH(OMe)3,TFA,CH2CI2 2. NaOMe, MeOH

137

136

[o] Fem OHC--~I 138

R~

139

Fe"

DMF, 120 ~

140

H

h

HN---~

R3

179

Five-Membered Ring Systems: With More Than One N Atom

1

~'~ ~ O ~ N o O 141 I

I

NHR1 1. SnCI2.2H20, R2CHO, DMF, 60 ~ 2 2. TFA, CH2CI2, 25 ~

.o. o

142

Other methods of preparing imidazoles from solid-supports were disclosed. The solid-phase synthesis of N-alkyl-N-(13-keto)amides 144, obtained using a traceless cleavage strategy from 143 based on benzylic acylammonium chloride reactivity, provided 1,2,4,5tetrasubstituted imidazoles 145 <00OL323>. Traceless solid-phase synthesis of 5,6,7,8tetrahydro-lH-imidazo[4,5-g]quinoxalin-6-ones with three points of diversity has been disclosed <00TL7>. A three-component synthesis of 3-aminoimidazo[1,2-a]pyridine derivatives has been developed <00TL1495>. The palladium-catalyzed coupling reaction of immobilized iodobenzoate 146 with N-methylimidazole (147) gave coupled methyl ester 148, after cleavage with sodium methoxide <00OL3111>. Reactions of resin-bound carbodiimides 149 with primary amines or secondary amines afforded trisubstituted 2aminoimidiazolinones 150 and 151, respectively, from a cyclization-cleavage process <00TL6989>.

R3

0"~~--~

R2~O

R.~ O

~ . ~

R2

R1 R4

Cl@ O

" O~N.R1 R4

143

(~P-O

R1/N,,,,~,

DMF, 90 ~

144

+ O

NH4OAc,HOAc ." R2"~N

M

~e

146

"

145

PPh3 (20 mol%), DMF 2. NaOMe, MeOH,THF

"

M e O ~ O

147

/

o R

149

(R1)2NH

Me 148

O RI'N~ff,,," L~ 2 ''''R ArHN/ ~'N 150

R1NH2

~AF

R4

~.

0 Ar\N'~

(R1)2N-'~N'~''

,IR

151

5.4.4

1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES

The first experimental determination of a singlet-triplet energy gap (AEst) for an organic nitrenium ion was made for the 1,3-dimethylbenzotriazolium ion <00OL2451>. A powerful ligand, 4,5-bis(diphenylphosphinoyl)-l,2,3-triazole, has been synthesized and found to possess two different modes of chelation <00ACIE3321>.

L. Yet

180

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 13-(N-1,2,3-triazolyl)substituted (x,13-unsaturated (x amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,2,3-triazoles 157 <00HC387>. 2-Aryl-2H,4H-imidazo[4,5-d][1,2,3]triazoles 159 were prepared from the reaction of triethyl N-l-ethyl-2-methyl-4-nitro-lH-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>.

..,-,-

~

~"~N/~I "R N.. NH2 152

O:~/N~Ph

~

PhI(OAc)2,-~~-~N~R CH2012 N=N 153

~ NC

NH

NC

O/~/N~Ph

iso-PentylNitrite NH2

HOAc'25 ~

= N-N .~~ NC CN

154

. ~N

o

x

2--Ar

[ ~ --N 156H

.3

dioxane,80~ X ---~,,~2

N=-(k

~

Et

Ar

~N=P(OEt)3

N"N"N ~ 157

155

~

Me---~ ] N~'~"~NO2

"X

158

ArNCO

Et

N

;~N

,r

159

Benzotriazole-based methodologies continued to be dominant in 2000. Hexahydro1H-pyrrolo[1,2-a]imidazoles were readily prepared from succindialdehyde, benzotriazole, and N-phenylethylenediamine <00JOC3683>. A benzotriazole-mediated synthesis of some 5-alkyldihydro-4H-1,3,5-dithiazines has been reported <00SC779>. Catalytic use of benzotriazole was critical in a stereoselective route to polysubstituted tetrahydroquinolines by condensation of aliphatic aldehydes and aromatic amines <00JOC3148>. Facile routes to 2substituted N-Boc pyrrolidines <00TL9691> and 1,5-disubstituted pyrrolidine-2-ones <00JOC4364> were obtained from benzotriazole-mediated processes. N-Acylbenzotriazoles reacted with aryl isocyanates to form, depending on the type of acyl group, compounds based on five different classes of polycyclic heteroaromatics <00JOC8069>. N-Allylbenzotriazoles were utilized in the preparation of 1,2-diaryl(heteroaryl)pyrroles via intramolecular oxidative cyclization in the presence of Pd(II) catalyst <00JOC8074>. Lewis acid-catalyzed czamidoalkylation of enolizable aldehydes with N-((x-benzotriazolyl-(x-arylalkyl)amides followed by intramolecular Friedel-Crafts cyclization provided a convenient route to 2substituted-l-amidoindenes <00JOC8066>. Vilsmeier type reagent 160 was employed in the direct and efficient synthesis of dimethylformamidrazones from hydrazines <00JOC2246>. 2-Benzotriazolyl-l,3-dioxolane (161) has been utilized as a novel formyl cation equivalent <00JOC1886>. 1Acylbenzotriazoles 162 are efficient C-acylation reagents for the regioselective conversion of ketone enolates into 13-diketones <00JOC3679>. Diethyl(1-benzotriazolmethyl)phosphinate (163) was found to be a convenient reagent for the stereoselective preparation of (E)-I-(1alkenyl)benzotriazoles <00SC1413>. The novel three-carbon synthon 1-(1H- 1,2,3-

181

Five-Membered Ring Systems: With More Than One NAtom

benzotriazol-l-yl)-3-chloroacetone (164) has been used for the synthesis of benzothiazoles, pyrido [ 1,2-a ] indoles, sty ryl-substituted indolizines, and imidazo [ 1,2-a ]py ridines <00JOC8059>. A variety of functionalized N-allylamines and N-allylsulfonamides were synthesized by Pd(II)-catalyzed intermolecular amination of the corresponding Nallylbenzotriazoles 165 <00JOC8063>. 1-(Hydroxymethyl)benzotriazole (166) reacted with thioamides in an efficient one-pot synthesis of polysubstituted pyrroles <00JOC8819>.

N

N

O~ Me2N CI@ 160

N

/~"'O

N

~==O

161 Ox,~J

~---e(o)(OEt)2

162 R

N

163

N

Benzotriazole-containing resin 167 reacted with aldehydes and amines to give resinbound Mannich adducts 168, which reacted with Grignard and organozinc reagents to afford tertiary amines 169 <00JCC173>.

N N..N 167

5A.5

H

THF, 60 ~

:

\N.. N R4MgXor RI~].,,,N THF, 65 ~ "R3 I 168 R2

:

R4 169

1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES

A kinetic study of thermolysis reactions of N-crotyl substituted 1,2,4-triazoles was performed at temperatures in the range of 260-350 qC <00JHCl135>. Thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo[1,5-a]pyridines allowed easy ring contraction to a facile preparation of cyanopyrazole heterocycles <00TL2699>. Microwave-assisted rate acceleration of reactions between 2-aminothiadiazoles 170 with oxadiazoles 171 on alumina support afforded thiadiazolyl substituted 1,2,4-triazoles 172 <00SC3031>. Reaction of aromatic nitriles 173 with hydrazine dihydrochloride in the presence of hydrazine hydrate in ethylene glycol under microwave irradiation gave 3,5disubstituted 4-amino-l,2,4-triazoles 174 <00TL1539>. Condensation of semicarbazide hydrochloride 175 with orthoester 176 resulted in a simple synthesis of chlorotriazolinone 177, and the method was applied to the convergent synthesis of an NK1 antagonist <00TL8661>. Triazines 178 were effectively cyclized to 1,3,5-trisubstituted 1,2,4-triazoles 179 in the presence of silver carbonate <00T8071>. Reactions of benzamidrazone hydroiodide with various sugars were reported as a new approach to the synthesis of

182

L. Yet

nucleosides of 1,2,4-triazole <00JCS(PI)829>. Cyclic amides were used as common templates to react with acyl hydrazines to yield 1,2,4-triazolopyridines, which are constrained tertiary amides <00TL4533>. N-N

N-N Rl~"S H 2~'~'" ' N -NN

R2.-~N ~/~--.SH

R2--'J(,O~,~SH 171 R~1~ Alumina, Microwaves 1S"%N/

170

EthyleneGlycol ArCN 173

NH2

NH2NH2-H20 : Ar...~N-N NH2N H2~ r N/~ 1 7 4A

172 H2N CI o/~NH .HCI + MeO..,,J 'NH2 MeO">[" OMe 175

MeOH,20~ 3d "

H NgN-~CI O=:~ N H 177

176

AF

N-I~ Ph---(/ '14 NH

Ag2CO3, MeCN

R2~/178

"

N. Ar Ph-~2 "N" N~~,R2

179

A novel one-step synthesis of thiazolo[3,2-b]l,2,4-triazoles 182 was reported from the reaction of chalcones 180 with bis(1,2,4-triazolyl)sulfoxide 181 <00OL429>. 1,2,4Triazoline-3,5-dione 184 underwent an ene reaction with olefins 183 to yield trialkylated allylic urazoles 185, which were further elaborated into allylic amines 186 <00OL1297>. DBU has been found to be a mild and convenient base for the alkylation of 1,2,4-triazole with various alkyl halides in the high yielding syntheses of 1-substituted-l,2,4-triazoles <00TL1297>.

0 ff'N"S" N"~,N

O RI.~'-,~-~ R2

N-_,

180

R~~

R3

R1

183

5.4.6

R2

coco

181

HN-NH

O"~N'~O ' Me184 CH2CI2,20 ~

R2 (2N..N..~/, j - k'%.___ffO

PhMe

.

R4~

182

R3

R j~-2 5,,~ ~N_NH R, O ~ N ~ O 185

1. NaH

2. BrCH2COPh 3. aq. KOH

Me

R4~ ' r / R 3 R5,,~R2 I NH2 R1 186

TETRAZOLES AND RING-FUSED DERIVATIVES

A review on the alkylation and related electrophilic reactions at endocyclic nitrogen atoms in the chemistry of tetrazoles has been published <00H(53)1421>. Several approaches to tetrazoles have been published in 2000. In medicinal chemistry, the tetrazole functionality is an increasingly popular isoteric replacement for the

183

Five-Membered Ring Systems: With More Than One N Atom

carboxylic acid group in drug discovery research and thus much current research is geared toward its synthesis. Addition of azides to nitriles is a common method to tetrazoles. Tetrazole analogue 188 of '~-aminobutyric acid (GABA) was prepared from aminonitrile 187 with azidotributyltin followed by deprotection <00SC1587>. Commercially available FmocL-4-cyanophenylalanine (189) was treated with azidotrimethyltin 4-(tetrazol-5-yl)phenylalanine 191) for use in Fmoc-based solid-phase peptide synthesis <00TL6555>. A variety of 2-allylated-5-substituted tetrazoles 194 were prepared regiospecifically from the reaction of alkyl- and arylidenemalononitriles 191, allyl acetates 192, and trimethylsilyl azide (193) in the presence of palladium catalyst <00TL4193>. The effect of the 5-substituent on the tetrazole-azide isomerization in tetrazolo[1,5-a]pyridines was investigated by ab initio calculations <00T8775>.

Bocl Boc/N~CN 187

1. n-Bu3SnN3 2. HCI (g), MeNO2

Q O N-N CIH3N.. ~ --/J4~ 'N" "~ v N" H 188 N=N

N~/CN

~

N'NH

1. MeaSnNa, PhMe, 80 ~

Fmoc..

2. aq. HCI H

ON

Fm~

189

H

H

R3 192

191

~ \ ^ 0" 0 2

193

Pd(PPh3)4 (5 mol%) THF, 60 ~ 24 h

190

R1 ~

CN / N~.; IN

_ H3

R2

194

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 <00OL3237>. A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 21)0 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 21)1, with sodium azide afforded aryl tetrazoles 21)2 <00JOC7984>.

RI~N.H i R2 195

S R3NCS ~ RI~N/ILN.R 3 CH2CI2 i I R2 H 196

N-N NAN3,HgCI2 = RI~N~N. N'' Et3N DMF ' i ' R2 R3 197

184

L. Yet

o

R4

H

R I ' ~ R 2 , R3NH2

MeO2C/~NC

TMSN 3, MeOH

198

N-N

R1 N.- N R2 - - 7 ~ , ,2' ..-N IJ

R3~N~ 'N RI~R2"N"

=-

R:.~CO2Me

- MeOH" 6'

199

Br

1. Zn(CN)2, Pd(PPh3)4 DMF, 60 W Microwaves

R/

2. NaN 3, NH4CI, DMF 20 W Microwaves

201

200

R4

HN-N ,~..~N,~N ll=

R 202

5-Substituted tetrazoles reacted with 4,5-dichloro-l,2,3-thiazolium chloride (Appel salt) to give 1,3,4-thiadiazole oligomers <00TL9407>. 2-Benzyloxymethyl-5(tributylstannyl)tetrazole (203) was found to be a versatile reagent for the conversion of aryland heteroarylhalides to 5-aryl- and 5-heteroaryl-lH-tetrazoles 204 <00TL2805>.

1. ArX, Pd(PPh3)a (5 mol%)

N=N Bu3Sn"~N -~1"BOM 203

N-N

El % Arf\N,,', H

Cul (10 mol%), PhMe, 110 ~ 2. HCI or H2, Pd(OAc)2

204

Solid-supported e0-chloroalkyl tetrazoles 205 were reacted with a variety of nucleophiles followed by acidic cleavage to give tetrazoles 206 <00JCC19>.

"~"

205

N-N ~"N ~

1 KI 9 ' K2CO3, Nuc ; 2. TFA

i~..N

Nuc

H 206

5.4.7 R E F E R E N C E S 00ACIE1253 00ACIE1602 00ACIE2464 00ACIE3321 00H(53)1421 00HC299 00HC387 00HC392 00JACS3783 00JACS4243 00JACS7600

T.JJ. Miiller, M. Ansorge, D. Aktah,Angew. Chem. Int. Ed. 2000, 39,1253. V.P.W. B6hm, T. Weskamp, C.W.K. Gst6ttmayr, W.A. Herrmann, Angew. Chem. Int. Ed. 2000, 39,1602. W. Kliiui, M. Berghahn, G. Rheinwald, H. Lang, Angew. Chem. Int. Ed. 2000, 39, 2464. A.L. Rheingold, L.M. Liable-Sands, S. Trofimenko, Angew. Chem. Int. Ed. 2000, 39, 3321. V.A. Ostrovskii, A.O. Koren, Heterocycles 2000, 53,1421. P.C. Vasquez, D.C. Bennett, K.K. Towns, G.D. Kennedy, A.L. Baumstark, Heteroatom Chem. 2000,11,299. B. Liu, M.-X. Wang, L.-B. Wang, Z.-T. Huang, Heteroatom Chem. 2000,11,387. A.E. Ceniceros-G6mez, A. Ramos-Organillo, J. Hernfindez-Diaz, J. Nieto-Martinez, R. Contreras, S.E. Castillo-Blum, Heteroatom Chem. 2000,11,392. A.K. Chatterjee, J.P. Morgan, M. Scholl, R.H. Grubbs, J. Am. Chem. Soc. 2000, 122, 3783. K.A Ahrendt, C. J. Borths, D.W.C. MacMillan,J. Am. Chem. Soc. 2000,122, 4243. 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.

Five-Membered Ring Systems: With More Than One NAtom 00JACS9338 00JACS9874 00JCC19 00JCC173 00JCS(CC)919 00JCS(CC)1249 00JCS(CC)1653

00JCS(CC)2053 00JCS(PI)829 00JCS(P1)2731 00JHC175 00JHC983 00JHCl135 00JHC1209 00JHC1309 00JOC1516 00JOC1886 00JOC2204 00JOC2246 00JOC3148 00JOC3679 00JOC3683 00JOC4039 00JOC4364 00JOC4618 00JOC5253 00JOC5760 00JOC6572 00JOC7310 00JOC7984 00JOC8059 00JOC8063 00JOC8066 00JOC8069 00JOC8074 00JOC8819 00OL323 00OL413 00OL423 00OL429 00OL519 00OL795 00OL1233 00OL1295 00OL1423 00OL1431

185

Z. Yu, J.M. Wittbrodt, M.J. Heeg, H. B. Schlegel, C. H. Winter, J. Am. Chem. Soc. 2000,122, 9338. W.S. Jen, J.J.M. Wiener, D.W.C. MacMillan,J. Am. Chem. Soc. 2000,122, 9874. D.P. Matthews, J.E. Green, A.J. Shuker, J. Comb. Chem. 2000, 2,19. A.R. Katritzky, S.A. Belyakov, D.O. Tymoshenko,J. Comb. Chem. 2000, 2,173. R. Faust, B. G6belt,J. Chem. Soc., Chem. Commun. 2000, 919. C.J. Mathews, P.I. Smith, T. Welton,J. Chem. Soc., Chem. Commun. 2000,1249. M.M Diaz-Requejo, T.R. Belderrain, P.J. P6rez, J. Chem. Soc., Chem. Commun. 2000, 1653. X. Gai, R. Grigg, M.I. Ramzan, V. Sridharan, S. Collard, J.E. Muir, J. Chem. Soc., Chem. Commun. 2000, 2053. E.S.H. El Ashry, L.F. Awad, M. Winkler, J. Chem. Soc., Perkin Trans. I 2000, 829. T. Kobayzashi, Y. Uchiyama, J. Chem. Soc., Perkin Trans. I 2000, 2731. C.B. Vicentini, M. Mazzanti, C.F. Morelli, M. Manfrini, J. Heterocyclic Chem. 2000, 37,175. C. Kashima, Y. Tsukamoto, K. Higashide, H. Nakazono, J. Heterocyclic Chem. 2000, 37, 983. P.H.J. Carlsen, K.B. Jorgensen, J. Heterocyclic Chem. 2000, 37,1135. B. Le Bourdonnec, E Meulon, S. Yous, R. Houssin, J.-P. H6nichart, J. Heterocyclic Chem. 2000, 37,1209. A.R. Katritzky, A. Denisenko, S.N. Denisenko, J. Heterocyclic Chem. 2000, 37,1309. J. Sisko, A.J. Kassick, M. Mellinger, J.J. Filan, A. Allen, M.A. Olsen, J. Org. Chem. 2000, 65,1516. A.R. Katritzky, H.H. Odens, M.V. Voronkov, J. Org. Chem. 2000, 65,1886. A. Fiirstner, O.R. Thiel, L. Ackermann, H.-J. Schanz, S.P. Nolan, J. Org. Chem. 2000, 65, 2204. A.R. Katritzky, T.-B. Huang, M.V. Voronkov,J. Org. Chem. 2000, 65, 2246. S. Talukdar, C.-T. Chen, J.-M. Fang, J. Org. Chem. 2000, 65, 3148. A.R. Katritzky, A. Pastor, J. Org. Chem. 2000, 65, 3679. A.R. Katritzky, G. Qui, H.-Y. He, B. Yang, J. Org. Chem. 2000, 65, 3683. N. Chatani, T. Fukuyama, H. Tatamidani, F. Kakiuchi, S. Murai, J. Org. Chem. 2000, 65, 4039. A.R. Katritzky, S. Mehta, H.-Y. He, X. Cui, J. Org. Chem. 2000, 65, 4364. M. Abarbri, J. Thibonnet, L. B6rillon, F. Dehmel, M. Rottl~inder, P. Knochel, J. Org. Chem. 2000, 65, 4618. A.C. Spivey, C.M. Diaper, H. Adams,J. Org. Chem. 2000, 65, 5253. T. Chou, H.-C. Chen, W.-C. Yang, W.-S. Li, I. Chao, S.-J. Lee, J. Org. Chem. 2000, 65, 5760. C. Enguehard, J.-L. Renou, V. Collot, M. Hervet, S. Rault, A. Gueiffier, J. Org. Chem. 2000, 65, 6572. G. Guillena, C. N~ijera,J. Org. Chem. 2000, 65, 7310. M. Alterman, A. Hallberg, J. Org. Chem. 2000, 65, 7984. A.R. Katritzky, D.O. Tymoshenko, D. Monteux, V. Vvedensky, G. Nikonov, C.B. Cooper, M. Deshpande,J. Org. Chem. 2000, 65, 8059. A.R. Katritzky, J. Yao, O.V. Denisko, J. Org. Chem. 2000, 65, 8063. A.R. Katritzky, O.V. Denisko, S. Busont,J. Org. Chem. 2000, 65, 8066. A.R. Katritzky, T.-B. Huang, M.V. Voronkov, J. Org. Chem. 2000, 65, 8069. A.R. Katritzky, L. Zhang, J. Yao, O.V. Denisko, J. Org. Chem. 2000, 65, 8074. A.R. Katritzky, T.-B. Huang, M.V. Voronkov, M. Wang, H. Kolb, J. Org. Chem. 2000, 65, 8819. H.B. Lee, S. Balasubramanian, Org. Lett. 2000, 2,323. T. Kawakami, K. Uehata, H. Suzuki, Org. Lett. 2000, 2,413. C. Turk, J. Svete, B. Stanovnik, L. Golic, A. Golobic, L. Selic, Org. Lett. 2000, 2,423. A.R. Katritzky, A. Pastor, M. Voronkov, P.J. Steel, Org. Lett. 2000, 2,429. J.J. Song, N.K. Yee, Org. Lett. 2000, 2,519. Y.-q. Wu, D.C. Limburg, D.E. Wilkinson, G.S. Hamilton, Org. Lett. 2000, 2,795. J.P. Collman, M. Zhong, Org. Lett. 2000, 2,1233. W. Adam, A. Pastor, T. Wirth, Org. Lett. 2000, 2,1295. S.R. Stauffer, S. Lee, J.P. Stambuli, S.I. Hauck, J.F. Hartwig, Org. Lett. 2000, 2,1423. T. Itoh, K. Mitsukura, N. Ishida, K. Uneyama, Org. Lett. 2000, 2,1431.

186 00OL1517 00OL2053 00OL2141 00OL2145 00OL2271 00OL2451 00OL2789 00OL2833 00OL3055 00OL3107 00OL3111 00OL3153 00OL3237 00OL3825 00OL4265 00OL4189 00S1295 00S1380 00S1474 00S1727 00S1814 00SC417 00SC677 00SC763 00SC779 00SC1413 00SC1587 00SC1865 00SC2191 00SC2863 00SC3031 00SC3241 00SC3307 00SC3369 00SC3383 00SL489 00SL591 00SL674 00SL710 00SL809 00SL967 00SL1007 00SL1022 00SL1613 00T629 00T1569 00T2061 00T2195 00T4383 00T8071 00T8775 00T8809 00TA1975

L. Yet A. Briot, M. Bujard, V. Gouvemeur, S.P. Nolan, C. Mioskowski, Org. Lett. 2000, 2, 1517. H.M. Lee, S.P. Nolan, Org. Lett. 2000, 2, 2053. E. Saxon, J.I. Armstrong, C.R. Bertozzi, Org. Lett. 2000, 2, 2141. C.W. Lee, R.H. Grubbs, Org. Lett. 2000, 2, 2145. J.A. Smulik, S.T. Diver, Org. Lett. 2000, 2, 2271. S. MclIroy, C.J. Cramer, D.E. Falvey, Org. Lett. 2000, 2, 2451. D.-M. Shen, M. Shu, K.T. Chapman, Org. Lett. 2000, 2, 2789. Y.R. Huang, J.A. Katzenellenbogen, Org. Lett. 2000, 2, 2833. G.I. Elliott, J.P. Konopelski, Org. Lett. 2000, 2, 3055. X.-j. Wang, J. Tan, L. Zhang,, Org. Lett. 2000, 2, 3107. Y. Kondo, T. Komine, T. Sakamoto, Org. Lett. 2000, 2, 3111. J.P. Morgan, R.H. Grubbs, Org. Lett. 2000, 2, 3153. R.A. Batey, D.A. Powell, Org. Lett. 2000, 2, 3237. D.B. Kimball, A.G. Hayes, M.M. Haley, Org. Lett. 2000, 2, 3825. F.M. Guerra, M.R. Mish, E.M. Carreira, Org. Lett. 2000, 2, 4265. R.M. Lau, F. van Rantwijk, K.R. Seddon, R.A. Sheldon, Org. Lett. 2000, 2, 4189. L. De Luca, G. Giacomelli, A. Porcheddu, A.M. Spanedda, M. Falomi, Synthesis 2000, 1295. M.P. Singh, S. Sasmal, W. Lu, M.N. Chatterjee, Synthesis 2000,1380. A.M. Kuvshinov, V.I. Gulevskaya, V.V. Rozhkov, S.A. Shevelev, Synthesis 2000, 1474. T. Aboul-Fadl, S. L6ber, P. Gmeiner, Synthesis 2000,1727. M. Anastassiadou, G. Baziard-Mouysset, M. Payard, Synthesis 2000,1814. O. Prakash, H.K. Gujral, N. Rani, S.P. Singh, Synth. Commun. 2000, 30,417. Q. Chu, Y. Wang, S. Zhu, Synth. Commun. 2000, 30,677. Z. Wang, J. Ren, Z. Li, Synth. Commun. 2000, 30,763. N. Peerzada, I. Neely, Synth. Commun. 2000, 30,779. H. Qian, X. Huang, Synth. Commun. 2000, 30,1413. Y. Rival, C.G. Wermuth, Synth. Commun. 2000, 30,1587. J. Howarth, J.-L. Thomas, K. Hanlon, D. McGuirk, Synth. Commun. 2000, 30,1865. G. Penieres, I. Bonifas, J.G. L6pez, J.G. Garcia, C. Alvarez, Synth. Commun. 2000, 30, 2191. M. Polak, B. Vercek, Synth. Commun. 2000, 30, 2863. M. Kidwai, P. Misra, K.R. Bhushan, B. Dave, Synth. Commun. 2000, 30,3031. M.M. Ali, A.G. Doshi, P.B. Raghuwanshi, Synth. Commun. 2000, 30, 3241. C. Xia, C. Kang, B. Zhao, J. Chen, H. Wang, P. Zhou, Synth. Commun. 2000, 30, 3307. A. Salerno, C. Caterina, I.A. Perillo, Synth. Commun. 2000, 30, 3369. Q. Su, J.L. Wood, Synth. Commun. 2000, 30, 3383. V. Atlan, C. Buron, L.E. Kaim, Synlett 2000, 489. Y.-C. Chi, C.-M. Sun, Synlett 2000, 591. P.Y.S. Lain, C.G. Clar, S. Saubem, J. Adams, K.M. Averill, D.M.T. Chan, A. Combs, Synlett 2000, 674. J.R. McClure, J.H. Custer, H.D. Schwarz, D.A. Lill, Synlett 2000, 710. S. Shinoda, S. Shima, T. Yamakawa, Synlett 2000, 809. R.C.F. Jones, J.N. Martin, P. Smith, Synlett 2000, 967. M. Ahmed, T. Amauld, A.G.M. Barrett, D.C. Braddock, P.A. Procopiou, Synlett 2000, 1007. S.-K. Kang, S.-H. Lee, D. Lee, Synlett 2000,1022. J. Sirieix, M. O[3berger, B. Betzemeier, P. Knochel, Synlett 2000,1613. P.K. Mohanta, S. Dhar, S.K. Samal, H. Ila, H. Junjappa, Tetrahedron 2000, 56,629. A. Diaz-Oritz, J.R. Carrillo, F.P. Cossfo, M.J. G6mez-Escalonilla, A. de la Hoz, A. Moreno, P. Prieto, Tetrahedron 2000, 56,1569. R.C.F. Jones, P.. Dimopoulos, Tetrahedron 2000, 56, 2061. L. Ackermann, D.E. Tom, A. Fiirstner, Tetrahedron 2000, 56, 2195. T. Itoh, M. Miyazaki, K. Nagata, A. Ohsawa,, Tetrahedron 2000, 56, 4383. K. Paulvannan, T. Chen, R. Hale, Tetrahedron 2000, 56, 8071. M. Kanyalkar, E.C. Coutinho, Tetrahedron 2000, 56, 8775. A.B. Reitz, D. A. Gauthier, W. Ho, B.E. Maryanoff, Tetrahedron 2000, 56, 8809. G. Broggini, G. Molteni, T. Pilati, Tetrahedron: Asymmetry 2000,11,1975.

F i v e - M e m b e r e d R i n g Systems: With More Than One N Atom

00TA2483 00TL7 00TL691 00TL595 00TL1275 00TL1297 00TL1495 00TL1505 00TL1539 00TL2483 00TL2699 00TL2713 00TL2777 00TL2805 00TL4363 00TL4193 00TL4533 00TL4713 00TL5025 00TLS031 00TL5321 00TL5383 00TL5407 00TL5419 00TL5453 00TL5465 00TL5979 00TL6387 00TL6555 00TL6563 00TL6989 00TL7029 00TL7129 00TL8147 00TL8533 00TL8661 00TL8729 00TL8795 00TL9053 00TL9407 00TL9691 00TL9791 00TL9871 00TL9889 00TL9893 00TL9973 00TL10319

187

G. Cabarrocas, M. Ventura, M. Maestro, J. Mahia, J.M. Villalgordo, Tetrahedron: Asymmetry 2000,11,2483. A. Mazurov, Tetrahedron Lett. 2000, 41, 7. K.-I. Washizuka, K. Nagai, s. Minakata, I. Ryu, M. Komatsu, Tetrahedron Lett. 2000, 41,691. C. Zhang, M.L. Trudell, Tetrahedron Lett. 2000, 41,595. M. Groarke, M.A. McKervey, M. Nieuwenhuyzen, Tetrahedron Lett. 2000, 41,1275. P.G. Bulger, I.F. Cottrell, C.J. Cowden, A.J. Davies, U.-H. Dolling, Tetrahedron Lett. 2000, 41,1297. C. Blackburn, B. Guan, Tetrahedron Lett. 2000, 41,1495. T.H. Kim, G.-J. Lee, Tetrahedron Lett. 2000, 41, 1505. F. Bentiss, M. Lagren6e, D. Barby, Tetrahedron Lett. 2000, 41,1539. M. Ermann, N.M. Simkovsky, S.M. Roberts, D.M. Parry, A.D. Baxter, J.G. Montana, Tetrahedron Lett. 2000, 41, 2483. D. Simoni, R. Rondanin, G. Fum6, E. Aiello, F.P. Invidiata, Tetrahedron Lett. 2000, 41,2699. U. Bauer, B.J. Egner, I. Nilsson, M. Berghult, Tetrahedron Lett. 2000, 41,2713. J.E. Macor, L.A.M. Cornelius, J.Y. Roberge, Tetrahedron Lett. 2000, 41,2777. B.C. Bookser, Tetrahedron Lett. 2000, 41,2805. V. Collot, D. Varlet, S. Rault, Tetrahedron Lett. 2000, 41,4363. Y.S. Gyoung, J.-G. Shim, Y. Yamamoto, Tetrahedron Lett. 2000, 41,4193. E.C. Lawson, B.E. Maryanoff, W.J. Hoekstra, Tetrahedron Lett. 2000, 41,4533. X.-j Wang, J. Tan, K. Grozinger, Tetrahedron Lett. 2000, 41,4713. D.Gala, M.S. Puar, M.Czamiecki, P.R. Das, M. Kugelman, J.J. Kaminski, Tetrahedron Lett. 2000, 41,5025. A.Y. Usyatinsky, Y.L. Khmelnitsky, Tetrahedron Lett. 2000, 41,5031. X.-j Wang, J. Tan, K. Grozinger, R. Betageri, T. Kirrane, J.R. Proudfoot, Tetrahedron Lett. 2000, 41,5321. E. Farrant, S.S. Rahman, Tetrahedron Lett. 2000, 41,5383. N. Coskun, F.T. Tat, t3.0 Giiven, D. 131k,C. Arici, Tetrahedron Lett. 2000, 41,5407. J.P. Kilbum, J. Lau, R.C.F. Jones, Tetrahedron Lett. 2000, 41,5419. B.-C. Chen, M.S. Bednarz, R. Zhao, J.E. Sundeen, P. Chen, Z. Shen, A.P. Skoumbourdis, J.C. Barrish, Tetrahedron Lett. 2000, 41,5453. R. Stragies, U. Voigtmann, S. Blechert, Tetrahedron Lett. 2000, 41,5465. R. Doodeman, F.P.J.T. Rutjes, H. Hiemstra, Tetrahedron Lett. 2000, 41,5979. S. Wendebom, T. Winkler, I. Foisy, Tetrahedron Lett. 2000, 41,6387. J.S. McMurray, O. Khabashesku, J.S. Birtwistle, W. Wang, Tetrahedron Lett. 2000, 41, 6555. S.R. Mundla, L.J. Wilson, S.R. Klopfenstein, W.L. Seibel, N.N. Nikolaides, Tetrahedron Lett. 2000, 41,6563. D.H. Drewry, C. Ghiron, Tetrahedron Lett. 2000, 41,6989. M. Alajafin, A. Vidal, F. Tovar, Tetrahedron Lett. 2000, 41, 7029. R. Grigg, A. Liu, D. Shaw, S. Suganthan, M.L. Washington, D.E. Woodall, G. Yoganathan, Tetrahedron Lett. 2000, 41,7129. A. McCluskey, J. Garner, D.J. Young, S. Caballero, Tetrahedron Lett. 2000, 41,8147. A.A.-M. Abdel-Aziz, J. Okuno, S. Tanaka, T. Ishizuka, H. Matsunaga, T. Kunieda, Tetrahedron Lett. 2000, 41,8533. C.J. Cowden, R.D. Wilson, B.C. Bishop, I.F. Cottrell, A.J.Davies, U.-H. Dolling, Tetrahedron Lett. 2000, 41,8661. T. Nixey, M. Kelly, C. Hulme, Tetrahedron Lett. 2000, 41,8729. O. Poupardin, C. Greck, J.P. Genet, Tetrahedron Lett. 2000, 4l, 8795. V. Collot, P.R. Bovy, S. Rault, Tetrahedron Lett. 2000, 41,9053. V.-D. Le, C.W. Rees, S. Sivadasan, Tetrahedron Lett. 2000, 41,9407. A.R. Katritzky, Z. Luo, Y. Fang, Tetrahedron Lett. 2000, 41,9691. S. G6rard, R. Plantier-Royon, J.-M. Nuzillard, C. Portella, Tetrahedron Lett. 2000, 41, 9791. Z. Wu, P. Rea, G. Wickham, Tetrahedron Lett. 2000, 41,9871. A. Taher, S. Eichenseher, G.W. Weaver, Tetrahedron Lett. 2000, 41,9889. A. Taher, S. Ladwa, S.T. Rajan, G.W. Weaver, Tetrahedron Lett. 2000, 41,9893. S. Gessler, S. Randl, S. Blechert, Tetrahedron Lett. 2000, 41, 9973. J. Howarth, P. James, J. Dai, Tetrahedron Lett. 2000, 41, 10319.

188

Chapter 5.5 Five-Membered Ring Systems" With N & S (Se) Atoms

David J. Wilkins

Key Organics Ltd., Highfield Industrial Estate, Camelford, Cornwall, PL32 9QZ, UK. Paul A. Bradley

The Broadlands, Hillside Road, Radcliffe-on-Trent, Nottingham, NG12 2GZ, UK. e-mail: [email protected], paul bradley [email protected]

5.5.1 I S O T H I A Z O L E S Irradiation of isothiazoles (1; R = X = C1) and (1; R = Me, X = Br) with UV light gave excellent yields of 3,7-disubstituted bisisothiazolo[4,5-b:4',5'-e]pyrazines 2 with smaller amounts of diazene 3 when CC14 was used as the solvent. However, when CH2C12 was used as solvent none of the tricycle 2 or the diazene 3 was isolated <99RCB1339>. Reaction of the corresponding phenyl substituted isothiazole (1; R = Ph, X = Br) gave low yields of both the pyrazine (2; R = Ph; 15%) and the diazene (3; R = Ph, X = Br; 14%) <00RCB956>.

S- N Br2N\

/

X . ~ S .11 N

UV CCl 4

R

N~N~-S N~ N R 2

X ~'~~R

N

+

R~~T~X N

S

R = CI, Me, Ph; X = CI, Br Photochemical reactions of both 3- and 5-phenylisothiazoles were described in the literature giving in each case, low yields of a mixture of phenylthiazoles <00JOC3626>. An unusual thermal rearrangement of 3-allyloxy-l,2-benzisothiazole 1,1dioxides 4 was described by Cristiano et al. Heating in a non-polar solvent, such as toluene at 85 ~ C gave the N-allyl derivative 5 which was proposed to have formed via a [3,3] sigrnatropic shift. In polar solvents, at similar temperatures, the compound

Five-Membered Ring Systems: With N & S (Se) Atoms

189

formed by a [1,3] rearrangement the homoallyl derivative 6 predominated. IH NMR studies also revealed that, on extended heating S gave 6. Also, prolonged heating of 4 at 135 ~ C, eventually gave 6 as the only product <99JCR(S)704>. O

O

[3,3]

~N

O

~ , 3 ]

O

R

4

O 6

R = H, Me, Ph

Oxidation of the substituted isothiazolium-2-imines 7 with H202 in AcOH gave stable 3-hydroperoxy-2-benzoylaminohexahydro- 1,2-benzisothiazole 1sulfoxide rac cis 8 and the sultam 9. The sultam 9 could then be converted into novel hydroxysultams 10 by reduction with Na2SO3/H20 in excellent yields. If necessary, 10 could be reoxidised to 9 with H202 <00JPR291>.

~

R

[~~ S.IN+..N-~~ I 7 O [ ~

H L"OH

s.N,

s '0

10

H

H202/AcOH _--

H ..pOOH I o S,. N. N~

1

Na2SO3/H20 9

,

H202/AcOH

---

, o?

HvOOH

L,,.,,-&.S,,,N, N.~ R S (O H ~ 9

R = H, 4-Me, 2-CI, 3-CI, 4-CI, 2-NO2, 3-NO2, 4-NO2, 3-CF3

190

P.A. Bradley and D.J. Wilkins

Bicyclic isothiazolium salts [11; X (CH2)2 and (CH2)3] on treatment with anilines form isomeric salts 12. The actual yields of 12 were greatly influenced by the substituents in the aryl ring of the aniline. Thus, reaction of 11 with unsubstituted or electron-donating anilines gave excellent yields of 12 whereas use of an electronwithdrawing substituents on aniline (e.g. 4-chloroaniline) gave very poor yields of 12. However, when X = CH2 only isothiazole ring opened products were obtained when 11 was treated with anilines. These new isothiazolium salts 12 on reaction with H202 in AcOH gave alkanoic acids 13 via a Criegee type rearrangement <00JPR675>. =

R--O-N"2

X~~~L.S..

x

J ~ l..S "~

_ClO4

-ClO4 11 12

HO2C(CH2)n+I 0

N'S=O I

0

~H20/AcOH

13

R = H, Me, CI Bassin et al. reported a convenient synthesis of 3-methylsulphonamido-l,2benzisothiazole-l,l-dioxide 15 from 14 via initial condensation with ammonia followed by an internal Michael reaction <00JHC181>.

MeO~~~~ MeO/

~

jS02CI "S02CI

14

NH3

..... M e O ~ O0 15

5.5.2 T H I A Z O L E S A modification of the Hantzsch synthesis of thiazoles has been reported. The reaction of alkoxyoxiranes 16 with N-arylthioureas 17 affords thiazoles such as 20. The mechanism involves the initial [3-cleavage of the oxirane to give the hemiacetal

Five-Membered Ring Systems: WithN & S (Se) Atoms

191

18 which then loses methanol to give the ketone 19. 19 then readily undergoes intramolecular ring closure to give the aminothiazole 20. The reaction of alkoxyoxiranes with NN'-diarylthioureas or N,N'ethylenethiourea fail to undergo the final dehydration step and the corresponding hydroxydihydrothiazoles are produced <99RJOC741>.

,/~OMe CF3

Ph

O- OMe ~/ S

S -I- PhNH.~,,NH2

16

Ph

17

=-MeOH

F3C

Ph I

Ph

y.

NH2 Br-

18

syNH o

Ph I NH

NH

F3C _H20

=

Ph

19

NHPh 20

Fairly complex approaches have been used to construct thiazoles substituted with an enamine group. The cyclocondensation of 1-tosyl-2,2-dichloroethenyl isothiocyanate 21 with various enamines such as 22 affords enamino substituted thiazoles such as 23 in high yields <00MI109>.

NCS

o

(o3 TOS~N

Cl~Tos

Ph

CI

21

22

23

A novel type of heterocyclisation reaction involving the dipolar cycloaddition of N,N-dialkylamino substituted thioisomunchnones and azodicarboxylates giving 1,2,4-triazine derivatives has been reported. The cycloadduct 26 is initially formed from the isomunchnone 24 and the azodicarboxylate 25, it then undergoes a selective fragmentation to give the 1,2,4-triazine 27 <99TL8675>.

P.A. Bradley and DJ. Wilkins

192

Ph

J

~

~N / S/~N +-Ph Ph

,,CO2Et NII EtO2C/N

0

m

Ph

Ph'N~NICO2Et 0 -/Ph N C02Et

24

26

25

Ph

\NJ

m

\J

m

N" Ph~N--~ N

PhxN.~N+-CO2Et Ph

Ph

Ph ~\CO2Et

g

27 The traceless cleavage of a rink amide resin has been used to prepare a library of thiazoles. The rink amide resin is initially coupled with a range of carboxylic acids 28 to give the corresponding amides 29 which are then converted into thioamides 3t1 using Lawesson's reagent. Treatment of the resin bound thioamide 31) with a range of ~-bromoketones 31 in refluxing THF for 16 hours causes cleavage of the resin with concomitant formation of the thiazole 32 in excellent purity and yield <00TL4965>.

O R"~OH

couple NH2 resin

O Lawesson's S reagent R"~NHI ~ R'~NHI resin resin

28

29

B r - ~ IR1 O

30

R1

31

THF, reflux, 16 h 32

F i v e - M e m b e r e d Ring Systems: With N & S (Se) Atoms

193

A new method for the construction of thiazoline rings has been reported. Nacylcysteamine derivatives 33 have been cyclised using phosphorus pentachloride under mild conditions to give a range of 2-alkyl and 2-aryl thiazolines 34. This method is particularly useful for the construction of sterically hindered thiazoline analogs, and has been used to construct micacocidin 35, a unique anti mycoplasma antibiotic <99T10271>. 4

SR

o

l~J~

R

N H

R2

R1 ~

S_ .

i~2

33

R3

34

H H

s~ ~

s~

N ?

HO2C....

OH

~jS

35

A useful method for the preparation of functionalised thiazoles has been described. Palladium catalysed cross coupling reactions between 4-thiazolyl-5-acetyl triflates 36 and alkynes afforded 4-alkynyl-5-acetylthiazoles 37 in good yields (5682%). If 37 is then treated with ammonia in methanol, thiazolo[5,4-c]pyridines 39 are formed, probably via the intermediate imine 38 which then undergos a regioselective 6-endo dig cyclisation <99EJOC3117>.

194

P.A. Bradley and D.J. Wilkins

1 R R

f

R1 H

R~.~N~f~

Cul, Et3N,Pd(PPh3) DMF, rt 4

~

~ 0

37

36

1

NH3, MeOH R

~N

~..~~R

120oC, 12 h

38

39

Phosphonothiazolylmethanes 40 react with carbonyl compounds to give the expected alkene products via Knoevenagel or Homer-Wadsworth Emmons reactions. When they are treated with c~-haloketones, pyrrolothiazoles 42 are obtained in a two stage process via the quaternary salt 41 <98PSS251>.

0

(P i rOS~ , S~"N

Y 40

0

0

0

H

i,p~ /

..~Br (iPrO,2..l~~yO ~ ~

S" "N

Y

41

Br

(iPrO, ~

S

Y

N-

42

Novel C-4 thiazole kainoid analogues have been synthesised from kainic acid 43. This was converted into the ~-bromoketone 44 in three steps, which reacted with thioamides and thioureas to form thiazole and aminothiazole heterocycles 45. All the synthesised thiazole kainic acid derivatives exhibited strong binding to the kainate receptors <00BMCL309>.

195

Five-Membered Ring Systems: With N & S (Se) Atoms

"•,,.

Br

..,,-'~CO2H

O~

3 steps

~/-~CO2 H H

,~CO2tBu "~CO2tB

u

44

43

R 1. RCSNH=2

S ~,,,,..

2.6M HCI

.."'~ CO2H

~CO2H H R = Me. Ph. NH2 and NHMe 45

An asymmetric synthesis of phosphonylated thiazolines has been described. The phosphonodithioacetate 46 was aminated with a chiral amino alcohol 47 to give the phosphonylated thioamide 48 in good yield. This was then cyclised using a Mitsunobu procedure to give the chiral thiazoline phosphonate 49 in good yields under mild conditions. Homer-Wadsworth-Emmons reaction of these phosphonylated thiazolines gave chiral vinylic thiazolines 50 <00S 1143>.

S

(EtO)2P

R SEt

46

OH

H2N

O -~ (EtO)2P

S

R N H

47

48

0 PPh3, DEAD

(EtO)2P,,,v,,~ N

.~

R R2

49

50

OH

196

P.A. Bradley and D.J. Wilkins

N-Thiazolyl ct-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of o~-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an c~-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields N-thiazolyl m-amino acids 56 <00T3161>.

_R

I

H2N~CO2Me 51

o

o

~L'~'~BrNasC N ~ N C S O2N

HN'~~O

el

1 "= R~

R1NCS

R

CO2M 52

53

.

H2N"~OO2M~~N~

O~N" 54

55

56

A new stable sulfenylating reagent 3-phenylsulfenyl-2-(N-cyanoimino)thiazolidine 57 has been described. It reacts with amines or thiols to give sulfenamides or disulfides in excellent yields, t~-Sulfenylation of carbonyl compounds also proceeds smoothly and if an optically active 4-diphenylmethyl substituent is attached to the thiazolidine ring (58), the cyclic 13-ketoester 59 can be sulfenylated in high yield with an ee of 96% to give the sulfide 60 <00SL32>.

Phs..N~r[,.S NCN R=H 58; R = CHPh2 57;

O [ ~ C O 2 M e Nail,58 = THF, -78 oC 59

O

S~h CO2Me

60

2-Phenylaminothiazolines 63 have been synthesised from N-(2-hydroxyethyl)N'-phenylthioureas 62 in a one pot procedure using p-toluenesulfonylchloride. The synthesis starts from the corresponding 1,2-aminoalcohols 61 which form the thioureas on reaction with phenylisocyanate. The final cyclisation was performed in the presence of a base, sodium hydroxide was found to be the most effective giving the phenylaminothiazolines in moderate to high yields (29-94%) <99TL8201>.

e

Five-Membered Ring Systems: With N & S (Se) Atoms

.H PhN N~ HO~/ \

PhNCS S"~NH --- HO - - . ~

61

197

Ph, .H TsCl NaOH

S~ N ~_~

62

63

Two groups have reported the total synthesis of epithilone A <00OL2575, 00AG(E)209>. The synthesis of (-)-epithilone B <99EJC2492>, an improved synthesis of epithilone B <99OL1431> and the total asymmetric synthesis of (-)mycothiazole <00OL2149> have also been reported.

5.5.3 THIADIAZOLES 5.5.3.1 1,2,3-Thiadiazoles The most common, convenient and versatile synthesis of 1,2,3-thiadiazoles is undoubtedly the Hurd-Mori cyclisation of semicarbazones with thionyl chloride. This reaction was again widely reported in the literature during 2000 (e.g. <00ASJC687, 00JHC1325, 00T3933>. A series of 4-(o-hydroxyphenyl)-l,2,3-thiadiazoles (64; Z = OH) were prepared by the Hurd-Mori procedure and when treated with K2CO3 and a primary halide gave 2-benzofuranthiolates (65; Y = O) via a base catalysed ring cleavage mechanism. The corresponding 4-(o-aminophenyl)-l,2,3-thiadiazole (64; Z = NH2) system gave 2-methylsulphanylindole (65; Y = NH), in excellent yield, on reaction with t-BuOK and then AcOH/MeI <00T3933>. R~

R2

Base, R3X

64

~ ~ - ~ S R 3

65

Y = O, NH; Z = OH, NH2; R~= H, OH; R2 = H, OH; R3 = Me, Bn, n-hexadecyl Attempted hydrolysis of the ester group in the thienothiadiazine 66 using H2SO4 and AcOH at 100 °C gave a moderate yield of the ring-contracted thieno[2,3d]-l,2,3-thiadiazole 67 and none of the required carboxylic acid. Compotmd 67 was

198

P.A. Bradley and D.J. Wilkins

proposed to have formed by way of an acid-catalysed decomposition / recyclisation of the ester 66 and enables relatively easy access to this bicyclic heterocycle. The only other reported synthesis of 67 involves 8 steps with the final reaction requiring a chromatographic separation <00JI-IC191>.

I ~ s " O ' ~ c O2Me

H2SO4,AcOH 100°C, 4 h 67

66

Bakulev et aL reported the synthesis of 5H-[1,2,3]triazolo[5,1-b] [1,3,4]thiadiazines starting from 5-N-nitrosylamino-l,2,3-thiadiazole 68. Reduction of 68 with SnC12and 1MHC1 and then subsequent reaction with a ketone gave the imine 69. Treatment of 69 with thionyl chloride at -80 °C led to the formation of the isolable triazolothiazine 70 which on further reaction with thionyl chloride at room temperature gave the corresponding chloro derivative 71 <00MC 19>.

N,, ~ cO2Et (a) SnC,2, 1M HCl . N-S.-~.N.NO H (b) ArCOMe,1M HCI 68

Et4NCI

CO2Et N.N\~FAr

NS-~

Me 69

I SOCl -80 °C EtO2C

S .Cl /"~'H N~N.N-N¢~t~Ar 71

rt E t O 2 C ~ s HH SO012. N.N.N.N/~Ar 70

5.5.3.2 1,2,4-Thiadiazoles

Iwakawa et aL studied the reaction of 3-acetonyl-5-cyano-l,2,4-thiadiazole 72 with a series of 4-substituted phenylhydrazine hydrochlorides. When electrondonating substituents were used (e.g., methyl and methoxy) in the phenyl ring of the hydrazine, the reaction proceeded via a Fischer-indole mechanism to give indoles 73 as the sole product. In contrast, reaction of 72 with phenylhydrazine and 4chlorophenylhydrazine gave only small amounts of indole 72, but much higher yields of the pyrazole 74. The authors described in detail the respective reaction mechanisms

F i v e - M e m b e r e d Ring Systems: With N & S (Se) Atoms

199

and ascribed the different reaction pathways to the different electron-donating and withdrawing properties of the substituents in the phenyl ring of the hydrazine <00CPB 160>.

f Me HI

.

"eO N' LON

.-

NTcN NC

MeOH, Reflux, 3 h ~

Me

~N]S

72

N-N-.C~Me R = H, CI, Me. MeO

R 74 The mechanism of formation of various 1,2,4-thiadiazoles by self condensation of aromatic thioamides and of N-substituted thioureas was studied by Forlani et al. Typically, condensations were performed in the presence of DMSO and an acid such as hydrochloric acid <00JHC63>. A new, simple, high yielding synthetic route to 3,5-disubstituted 1,2,4thiadiazoles 75 was described by Passmore and co-workers which involved the reaction of nitriles with S.(AsF6)2 in liquid SO2 <99CC 1801 >.

2RCN

liquid SO 2

N - S,"~- R

75 R = Ph, Me; n = 4,8

The novel mesoionic 1,2,4-thiadiazole 78 was reported to be the unexpected byproduct in the reaction of the triazole 76 with ferric chloride (the bicyclic compound 77 also gave the same result). Besides spectroscopic and X-ray diffraction evidence, a preparative proof for the structure of 78 was also provided <00JHC261 >.

200

P.A. Bradley and D.J. Wilkins

MIe

S

S . ~ N- N~'--Ar H2N -N. N

OR Ar

R

/~N.)~--NH H 77

FeCI3

76

Ar'~N'N'Me

CI-

S~N+----N H

78

5.5.3.3 1,2,5-Thiadiazoles Reaction of tetrasulphur tetranitride antimony pentachloride complex (S4Nn.SbC15) with a series of primary 13-enaminones and [3-enamino esters 79 in toluene at 100 °C gave reasonable yields of 3,4-disubstituted 1,2,5-thiadiazoles 80. The formation of 80 was explained by the same mechanism as that proposed for the formation of 1,2,5-thiadiazoles from 3,5-disubstituted isoxazoles with S4Na.SbC15 complex <00H159>. NH z O R1'

S4N4.SbCIs R2

Toluene, 100" C

0

R1 ~

R2

N.s.N

79

80

R 1 = aryl, alkyl, heteroaryl; R2 = aryl, OEt Ueda et al. reported the synthesis of the novel diazepines (82; X = NMe) and oxepines (82; X = O) starting from the pyrimidin-3,5-dione 81 <00JHC1269>. 0

0

Me-.N.J~N,s

X"J~N.

,

Me 81

O

Me 82

S

201

F i v e - M e m b e r e d Ring Systems: With N & S (Se) Atoms

5.5.3.4 1,3,4-Thiadiazoles The stepwise condensation of 2-amino-5-ethyl-l,3,4-thiadiazole 83 with a mixture of salicylic aldehyde and acetylacetone in ethanol in a reagent mixture of 1:1:1 gave compound 84 in 36% yield <99RJOC624>. Me.

~[~OH NH2 CHO

N--N

Et

S

~%-

.Me

o o

//

\\

Et.,~S I.~N Me-'~ OH Me O

83

84

Tetramethylthiuram disulphide (TMTD) has proved to be a useful reagent for the thiocarbamoylation of amine containing compounds. Thus, reaction of a series of hydrazones of aromatic aldehydes with TMTD in a 1:1 ratio gave amongst other products, 4,4-dimethylthiosemicarbazide 86 and 5-dimethylamino-l,3,4-thiadiazole2-thiol 85. It was confirmed that 86 was an intermediate in the synthesis of 85 as treatment of 86 with TMTD gave 85 in 85% yield <00RCB344>.

XCsH4CH=NHNH2 N--N

4-

S

HS

S

S

S NMe2 Me2N

85

Me2N"JL'S-SANMe2

NHNH2 86

TMTD Kidwai and co-workers reported a series of insertion reactions of the thiadiazoles 87 with oxadiazoles 88 on a solid support using microwaves. This produced the triazoles 89 in much higher yield and in much shorter reaction times than conventional heating <00SC3031 >.

N--N

R

S 87

+

NH 2

N--N

AcidicAlumina

R'~I~OI~sH

MWl

88

N--N .~ I~

SII~N 89

202

P.A. Bradley and D.J. Wilkins

Tashtoush and Talib reported an unexpected reaction of propanodihydrazide and butanodihydrazide with carbon disulphide giving 2,5-dimercapto-l,3,4thiadiazoles in good yield <99IJC1374>. 5.5.4 SELENAZOLES AND SELENADIAZOLES

A

'one pot' procedure for the preparation of 1,3-selenazoles has been reported. The method, a variation on the Hantzsch synthesis, involves the a-tosylation of ketones 90 with [hydroxy(tosyloxy)iodo]benzene followed by treatment with selenoamides to give 1,3-selenazoles 91 in moderate to high yields <00S1219>.

R ~O, ~ R1

1. PhI(OH)OT)S Ar~Sex,~R 1 2. ArC(Se)NH2 \~N~ , R

90

91

The synthesis of 1,3-selenazoles from N-phenylimidoyl isoselenocyanates has been reported. N-phenylimidoyl isoselenocyanates 94 are prepared from Nphenylbenzamides 92. Treatment of 92 with thionyl chloride affords Nphenylbenzimidoyl chlorides 93, which yield imidoyl isoselenocyanates 94 on reaction with potassium isoselenocyanate. The imidoyl isoselenocyanates 94 were transformed into selenoureas 95 with either ammonia or primary or secondary amines. Reaction of 95 with an activated bromomethylene compound such as bromoacetophenone in the prescence of a base gave the 1,3-selenazole 97 via the salt 96 <00HCA1576>.

/H"Ph

SOC'~2N } "

"Ph KSeCN }" ~ N ' p h

o

ci

N'ph HN"~=:Se H2N 95

Br/~Pho ~ )

"~Se

94

93

92

NH3 }"

N.%..

N' IH+ph Br N'~-Se O H2N ~ Ph 96

}. /~ PSe~

O Ph

H2N 97

203

F i v e - M e m b e r e d Ring Systems: With N & S (Se) Atoms

The preparation of 2-amino-5-arylselenazoles 99 and 3,5-diaryl-l,2,4selenadiazoles 101 has been described. Starting from readily available c~-arylsulfonylc¢-bromoacetophenones 98 reaction with selenourea gave 2-amino-5-arylselenazoles 99 in good yield. Reaction of 98 with selenobenzamide 100 did not give the expected selenazole; the 3,5-diaryl-l,2,4-selenadiazole 101 was obtained in moderate yield. Compound 101 is a known oxidation product of selenobenzamide and a mechanism for its formation is proposed <99JHC901>.

Se

O

Ph'~SO2PhBr

Ph H2N~.se~-~SO2Ph

H2N/U~NH2~-

98

99

Se Ph

..Sd'~'-ph 101 The synthesis of 1,2,3-selenadiazole derivatives has been reported. The reaction of aroyl chlorides such as 102 with potassium isoselenocyanate and ethyl diazoaeetate yielded 5-(aroylimino)-2,5-dihydro-l,2,3-selenadiazole-4-carboxylate esters such as 104. A reaction mechanism via the initial formation of the corresponding aroyl isoselenocyanate 103 followed by a 1,3-dipolar cycloaddition of the diazo compound with the C=Se bond is proposed <00HCA539>.

N COzEto O O N2CHCO2E L //"~... H ph/[/...Ci + KSeCN -ph/JJ...NCSe N.se.~N/~Ph 102

103

104

P.A. Bradley and D.J. Wilkins

204

5.5.5 R E F E R E N C E S 98PSS251

B. A. Baimashev, N. A. Polezhaeva and E. N. Klimovitskii,Phosphorus, Sulfur and

Silicon, 1998, 251.

99CC1801 99EJC2492 99EJOC3117 99IJC1374 99JCR(S)704 99JHC901 99OL1431 99RCB1339 99RJOC624 99RJOC741 99TL8201 99TL8675 99T10271 00AG(E)209 00ASJC687 00BMCL309 00CPB160 00H159 00HCA539 00HCA1576 00JHC63 00JHC181 00JHC191 00JHC261 00JHC1269 00JHC1325 00JOC3626 00JPR291 00JPR675 00MC19 00MI109 00OL2149 00OL2575 00RCB344 00RCB956 00S 1143 00S1219 00SC3031 00SL32 00T3161 00T3933 00TL4965

T. S. Cameron, A. Decken, M. Fang, S. Parsons, J. Passmore and D. J. Wood, Chem. Commun. 1999, 1801. D. Schinzer, A. Bauer and J. Schieber, Eur. J. Chem., 1999, 2492. A. Arcadi, O. A. Attanasi, B. Guidi, E. Rossi and S. Santeusanio,Eur. J. Org. Chem., 1999, 3117. M. A. Talib and H. Tashtoush, Ind. J. Chem., 1999,1374. M. L. S. Cristiano, A. F. Brigas, R. A. W. Johnstone, R. M. S. Loureiro and P. C. A. Pena, J. Chem. Res(S), 1999, 704. A. Shafiee, M. A. Ebrahimzadeh and A. Maleki,J. Heterocycl. Chem., 1999, 36,901. J. D. White, K. F. Sundermann and R. G. Carter, Org. Lett., 1999, 1, 1431. S. G. Zlotin, A. V. Bobrov and K. S. Chunikhin, Russ. Chem. Bull., 1999, 1339. B.B. Umarov, M.M. Ishankhodzhaeva, K. Sh. Khusenov, N.A. Parpiev, S. A. Talipov and B. T. Ibragimov,Russ. J. Org. Chem., 1999, 624. V. S. Karavan and V. A. Nikiforov, Russian J. Org. Chem., 1999, 741. T. H. Kim, J. K. Min and G-J. Lee, Tetrahedron Lett., 1999, 40, 8201. M. J. Arevalo, M. Avalos, R. Babiano, P. Cintas, M. B. Hursthouse, J. L. Jimenez, M. E. Light, I. Lopez and J. C. Palacios, Tetrahedron Left., 1999, 40, 8675. A. Ino and A. Murabayashi, Tetrahedron, 1999, 55, 10271. D. Sawada and M. Shibasaki, Angew. Chem., Int. Ed. Engl., 2000, 39,209. A. V. Naidu and M. A. Dave,Asian. J. Chem., 2000, 687. J. E. Baldwin, A. M. Fryer and G. J. Pritchard,Biorg. Med. Chem. Lett., 2000, 309. T. Iwakawa, H. Nakai, G. Sugimori and A. Murabayashi, Chem. Pharm. Bull., 2000, 160. S. H. Bae, K. Kim and Y. J. Park, Heterocycles, 2000, 52,159. Y. Zhou and H. Heiragartner, Helv. Chim. Acta, 2000, 83,539. Y. Zhou, A. Linden and H. Heimgartner, Helv. Chim. Acta, 2000, 83, 1576. L. Forlani, A. Lugi, C. Boga, A. B. Corradi and P. Sgarabotto,J. HeterocycL Chem., 2000, 37, 63. J. P. Bassin, K. A1-Nawwar and M. J. Frearson,J. Heterocycl. Chem., 2000, 83,181. C. E. Stephens and J. W. Sowell Sr, J. Heterocycl. Chem., 2000, 37, 191. G. Argay and A. Kalman,.L Heterocycl. Chem., 2000, 37,261. T. Ueda, W. Doi, S. Nagai and J. Sakakibara, J. Heterocycl. Chem., 2000, 37, 1269. A. Shafiee, A.R. Jalilian and M. Rezaei, J. Heterocycl. Chem., 2000, 37, 1325. J. W. Pavlik and P. Tongcharoensirikul, J. Org. Chem., 2000, 65, 3626. A. Kolberg, S. Kirrbach, D. Selke, B. Schulze and S. Morozkina, J. Prakt. Chem., 2000, 291. A. Noack, I. Rohlig and B. Schulze, J. Prakt. Chem., 2000, 675. Y. Y. Morzherin, T. V. Glukhareva, I. N. Slepukhina, V. S. Mokrushin, A. V. Tkachev and V. A. Bakulev, Mendeleev Commun., 2000, 19. A. A. Tolraachev, V. S. Zyabrev, N. V. Lysenko and B. S. Drach, Chem. Het. Cpds., 2000, 109. H. Sugiyama, F. Yokokawa and T. Shioiri, Org. Lett., 2000, 2, 2149. B. Zhu and J. S. Panek, Org. Lett., 2000, 2, 2575. L. V. Boi and V. Floria,Russ. Chem. Bull., 2000, 344. S. G. Zlotin and A. V. Bobrov, Russ. Chem. Bull., 2000, 956. N. Leflemme, P. Marchand, M. Gulea and S. Masson, Synthesis, 2000, 1143. P-F. Zhang and Z-C Chen., Synthesis, 2000, 1219. M. Kidwai, P. Misra, K. R. Bhushan and B. Dave,Synth. Commun., 2000, 30, 3031. T. Tanaka, T. Azuma, X. Fang, S. Uchida, C. Iwata, T. Ishida, Y. In and N. Maezaki, Synlett., 2000, 32. J. Rudolph, Tetrahedron, 2000, 56, 3161. M. A. Abramov, W. Dehaen, B.D'hooge, M.L. Petrov, S. Smeets, S. Toppet and M. Voets, Tetrahedron, 2000, 56, 3933. J-F. Pons, Q. Mishir, A. Nouvet and F. Brookfield, Tetrahedron Lett., 2000, 41, 4965.

205

Chapter 5.6 Five-Membered Ring Systems: With O & S (Se, Te) Atoms

R. Alan Aitken

University of St. Andrews, UK e-mail." [email protected]

5.6.1

1,3-DIOXOLES AND DIOXOLANES

New methods for reaction of carbonyl compounds with ethanediol to give 1,3-dioxolanes include microwave irradiation under solvent free conditions with either cadmium iodide <99CL1283> or a mixture of silica and sodium hydrogen sulfate <00SL701>. The latter method is selective for aldehydes over ketones. Reaction of propylene oxide with supercritical CO 2 to give 4-methyl-l,3-dioxolan-2-one has been described <00MI589-1> while treatment of glycidol with phosgene in the presence of triethylamine gives 4-chloromethyl-l,3dioxolan-2-one in 65% yield <99MI2086>. The enol ethers 1 react with either EtMgBr or Bui2A1H followed by benzaldehyde to give hydroxyalkyldioxolanes 2 <00SL257>. An industrial scale synthesis of the substituted benzodioxoles 3 has been patented

R1 O

~,-

R2

Ph

1

2

/--~

L / ~ J " ~ - , , , ' ' ~ - c~ R'

LA

q'r R~-m'~R O

8 -C02M e

3

~

_jo...¢ °-~o.J "

4

10

R2

HO

R1

R- v

R1

Me-- " o + O / -

5

~._2""( '-'-',o..J

0/~--~.0 Me F F 11

HQ .Me

7

l,-

r"'F %0 ~

~,~,,. ~ ,,...,/"'-0 12

Me

%..1

206

R.A. Aitken

<00MIP40575> and anodic oxidation of benzodioxoles to give the cyclic trimers 4 has been described <00TL4769>. The spiro dioxolane 5 has been prepared by reduction of a Meisenheimer complex and its X-ray structure and conformation determined <99MI1691>. The conformation of the butanedione trimer 6 and similar compounds has been examined by NMR methods at -90 oC <00T1005>. Anodic fluorination of dioxolanones 7 gives mainly 8 in CH2CI 2 but mainly 9 in dimethoxyethane <00CC1617>. In the presence of oxygen, radical addition of 2-substituted 1,3-dioxolanes to methyl acrylate gives 10 <00CC2457> and similar addition to a fluorinated acrylate affords 11 <00JFC(102)345>. The benzotriazolyldioxolane 12 acts as a synthetic equivalent of the 1,3-dioxolane 2-cation by addition of organozinc reagents <00JOC 1886>. There has been continued interest in the use of chiral dioxolanes in asymmetric synthesis. Good selectivity has been achieved in the metal-catalysed conjugate addition of functionalised alcohols to 13 <99MI629> and asymmetric aziridination of the esters 14 has been examined <00T4515>. The dioxolane 15 is the key starting material in the first synthesis of the natural product fugomycin 16 <00SL1070> and addition of glycine to glyceraldehyde acetonide catalysed by the enzyme L-threonine aldolase affords the product 17 in 33 % d.e. <00SL1046>. Kinetic resolution of the racemic dioxolanone 18 using porcine pancreatic lipase may be used to produce either enantiomeric diol in good yield and e.e. <00T9281> and a stereoselective synthesis of the cyanodioxolanes 19 has been reported <00S220>.

Me

Me

Me%l"-O / ~,,H ~ X 13 X

Me"~ 0 H gr

= NO 2

--~.-

O~Br

OH --~-

15

16

14 X = CO2R OH

Me~l--t-,'

Me

NH2

(CH2)7OCH2Ph NC~'--O Me

17

18

19

Reductive cleavage of dioxolanes to give products 20 may be achieved with Bui2AIH and catalytic ZrC14 <99MI1530> while zinc chloride in aqueous THF provides a mild method to cleave 14 to the corresponding 1,2-diol <00MI95>. Highly stereoselective addition of allylsilane to isopropylidene protected carbohydrates 21 to give 22 has been described <00AG(E)2727> and the regioselectivity of TiC14 mediated addition of allylsilane to 2-hexyl4,4-dimethyl-l,3-dioxolane is completely altered by changing the order of addition of reagents: adding TiC14 first gives 23 while adding allylsilane first gives 24 <00H(52)583>.

R1 0.~ R2~HOJ 20

M~0~.0~ ~ N ~ , HO~o~ R

Me

Et

22

21

Hex ,j~Me HeH% ./~.,,,v~o / ~.~ ~ ~,,,J<.Me //- v "0 Me 23

/OH

24

25

i

l, 26

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

207

Addition of 2-ethylphenyllithium to dioxolane 25 in the presence of the alkaloid sparteine gives the chiral product 26 in up to 80% e.e. <00OL2845>. Further applications of chiral 4,5-bis(diarylhydroxymethyl)-2,2-dimethyl-l,3-dioxolanes (TADDOLs) in asymmetric catalysis include the use of a copper(I) thiol complex to catalyse Michael addition of a Grignard reagent to cyclic enones <00AG(E)153> and a zirconium complex to catalyse asymmetric cyanohydrin formation from aldehydes <00SLl133>. TADDOL titanium complexes immobilised on silica can catalyse addition of Et2Zn to benzaldehyd¢ and 1,3-dipo!ar cych~addilion <00AG(E)I63> while similar polymer suppol~ed catalysts give reversed selectivity in the Diels Alder reaction according to the nature of the polymer support <00AG(E)1503>. A chiral bis(diferrocenylphosphinomethyl)-dioxolane has been introduced as a ligand for rhodium catalysed double bond hydrogenation <00CCC717>. New applications of dioxolanes include evaluation of compounds such as 27 in perfumery <99MI77>, synthesis of N-hydroxypyrimidine derived nucleoside analogues such as 28 as potential antiviral agents <00CC2311> and use of 29 as a fungicide <00MIP43390>.

o

CI,.,~

CI

oO~-'JR ,

Me3Si 27 O-S 28 5.6.2

29

1,3-DITHIOLES AND D I T H I O L A N E S

Indium tribromide acts as a selective catalyst for formation of 1,3-dithiolanes from aldehydes in the presence of ketones which do not react <00TL9695>. The mechanism of reaction of diarylthioketones with diazomethane to give 1,3-dithiolanes 30 has been examined in detail <00EJOC1685> and regiospecific cycloaddition of Ph2C=S+-CH2 - to thiones to give products 31 has been reported <00EJOC1695>. Following an earlier report on the corresponding reaction with selenium, treatment of 1,3-di-t-butylcyclopentadiene with KOBu t and sulfur to give products such as 32-34 has now been described <00ICA(304)184>.

208

R.A. Aitken

Ar'~ Ar" ~r S

Ph~'~S~s

30

31

R But

32

But

But

33

But

A1C1435 [ ~ T e ~ _R T e

But

36 RzN--~ f

Br-----2~

34

But

(S~/~Br

37 38 39 A new route to the tetrahydroTTF system is provided by reaction of oxalyl chloride with ethanedithiol followed by dehydration to give 35. When this is treated with aluminium chloride the salt 36 is formed and its X-ray structure is reported <00ZN(B)597>. The preparation of new simple benzoditelluroles 37 has been described <00MI1127>. Treatment of allyl dithiocarbamates 38 with bromine affords the 2-amino-l,3-dithiolanylium salts 39 <97MIP112282, 98MIP113243>. The poor yields sometimes encountered in TTF synthesis using the phosphonate anion 40 have been explained by competitive ring-opening to the carbene form 41 which may then dimerise <99TL7219>. Reaction of 1,3-dithiolane-2-thione with dibenzoylacetylene in the presence of ZnC12 gives thiopyranthione 42 whose X-ray structure is presented and the mechanism of the process is discussed <00JCS(P1)1467>. Treatment of dithiolanes 43 with Nail in DMSO results in tandem fragmentation-cyclisation to give dihydrothiapyranones 44 <00SL1804>. The preparation and properties of dithiole 45 have been described <00CHE18> and the X-ray structure of 46 shows short S-S contacts <99MI719>. Cycloaddition of simple alkenes with 47 affords a new synthesis of 48 <00ZN(B)231> while the diselenone analogue of 47 adds to DMAD to give 49 <00CEJ1153>. New routes to compounds 50 have been described <99TL6635> and treatment of 51 with P2S5 to give 52 is the key step in the synthesis of the fused TTF derivative 53 <00CC2039>.

209

F i v e - M e m b e r e d Ring Systems: With 0 & S (Se, Te) Atoms

°Et

-~-"

~ s - "" ° E t

R2

41

40

--"

44 [~I~]~sS~ O

43

Me'~sk/~=(CN Me'~S45 ~)

42

R2

R S,,""~,

H46

NMe2 S=='(~ -- ~" S===(~S ~- R -s~/Se~/CO2MeR~sS ~ O/S S S",,i S=:=~S.~Se~-~C02Me 47

48

Ph

49

50

-

51

o

52

Ph

o

53

The high level of interest in tetrathiafulvalene (TrF) derivatives has continued and there have been reviews on new applications of functionalised TTFs <00MI589>, TTFs as building blocks in supramolecular chemistry <99PS(153-4)99, 00CSR153>, selenium containing organic conductors , and salts of bis(ethylenedithio)tetraselenafulvalene as molecular magnetic superconductors <00CSR325>. The acid fluoride TTF-COF has been introduced as an important intermediate for synthesis of substituted TTFs <99TL8611> and the preparation and properties of salts 54 have been described <00EJOC737>. The hexaTTF system 55 has been prepared and its X-ray structure and electrochemistry examined <00CC331> and the photochromic TTF derivative 56 has been reported <99CL 1071 >. M

54

%

~__~',~Me~lVlse +

M

S55 S SMd6

_..1/Me

M e

/ Me Me Me 56 Me

New results in the area of ring-fused TTFs include an improved synthesis and the first Xray structure of 57 <00CCl117> and the first synthesis of the parent dipyrroloTTF 58 <99OL1291>. Metallic conductivity has been reported for radical cation salts of 59 <00CL680> and 60 has been introduced as a new donor <99AM1527>. The aldehyde containing TTFs 61 and 62 have been reported <99TL8819> and the synthesis, X-ray structure and conductivity of the dibenzoTTF complex 63 has been described <00MI372>. New TTF-thioindigo donor-acceptor systems such as 64 have been prepared <00TL2983>.

210

R.A. Aitken

57 58 5 9 X = Br,CI Me~,....S, ,S~.~.Te'k- -S- o S S- CHO Me-"J'L'S')=~SATe) ~ S,~ S~k/~'SZSy ( i ~ ~ ~S 60

61

63

CHO

62

64

0

New extended and bisTTF systems include 65 <00CL842>, 66 <00MI1273>, 67 <00NJC919>, 68 <00OL1585> and 69 <00OL2217>. A variety of new extended derivatives based upon the system 70 have also been reported <00EJOC51, 00EJOCll99, 00TL2091>. Unusual electrochemical behaviour has been found for a series of extended TTF derivatives <00CEJ1199>. Significant progress has been made in the synthesis and study of Tl'F-containing cyclophanes and macrocycles <00S824, 00EJOC2135, 99CHE795, 00JOC4120, 99EJOC3335> as well as TrF-containing catenanes and rotaxanes <00JOC1924>. Molecular recognition of Na + and Ag + by TTF-containing crown ethers has been described <00CC295> and use of a TTF derivative as a sensor for Ag + has been reported <00JCS(P2)189>. Electrochemical polymerisation of a Tl'F-containing terthienyl has been examined <00CC 1005>. Several studies on systems incorporating TI'F and C60 have appeared including the formation of a BEDT-TTFoI3oC60 complex <00CC2357>, covalently bound TTF-C60 compounds <00JOC1978, 00CC113> and a C60-TTF-crown ether triad <00EJOC1157>.

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

\

67

MeS SMe

70

5.6.3

13-OXATHIOLES AND OXATHIOLANES

The Lewis acid catalysed reaction of cyclic thiones with epoxides to give spiro 1,3oxathiolanes such as 71 has been reported <99HCA7316>. Reaction of 1,4-oxathiins 72 with singlet oxygen proceeds by a novel rearrangement to give a mixture of isomeric oxathiolane S-oxides 73 <000L1205>. Treatment with N-bromosuccinimide in aqueous acetone is reported to cleave 1,3-oxathiolanes to the corresponding carbonyl compounds while leaving 1,3-dioxolanes unaffected <00SL1798>. Antiv~ralactivity has been reported for hindered 1.3benzoxathiolanones such as 74 <99MI366>.

5.6.4

1,2-DITHIOLES AND DITHIOLANES

The synthesis, X-ray structure and solid state NMR of 4,4-dimethyl-l,2-ditellurolane75 have been reported <98PS(136-8)291>. Chemoselective oxidation of 1,2-dithiole derivatives using dimethyldioxirane to give products such as 76 has been described <00SUL169>. Cycloaddition of dihydroquinoline-fused 1,2-dithiole-3-thiones 77 with DMAD gives the spiro 1,3-dithioles 78 <99CHE587>. Dicationic thiatelluroles such as 79 have been prepared <00AG(E)1318>, anti cancer properties have been claimed for the simple dithiolopyrrolones

212

R.A. Aitken

80 <00USP6020360> and self-assembled monolayers of 81 on a gold surface are capable of recognising Na + and K + <00CC141>.

Me,x~'~Te Ph~ O Me/ ~ T e (~S-S 75

~'~S S S S Me e 77R1 ~

76

~ i "

Ph e~-SMe ~'/S'ph 2 CF3SO379

MeO2C\ - CO2Me ~:SL.,,,,~ CO2Me MeO2~o/l "l R~. L ...,J~Me NR2R3 ~ NR1 "Me O 78 al 80

0

2

81 5.6.5

1,2-OXATHIOLES AND O X A T H I O L A N E S

The 1,2-oxaselenolanes 82 are useful reagents for the oxidation of sulfides to sulfoxides and treatment with RTe(CH2)3OH gives 83 by an exchange reaction <00SC979>. A review of the synthesis and stereoselective reactions of enantiomerically pure sulfuranes 84 and their selenium and tellurium analogues has appeared <00PS(157)225>. Reaction of alkenes with PhCH2SO2CI, Et3N and 2,4,6-collidine N-oxide affords the 1,2-oxathiolane S,S-dioxides 85 in a process possibly involving the hitherto unknown c~-sultones <00CC189>. In a most unusual process, treatment of the propargyl iron complexes Cp(CO2)Fe-CH2C---C-R with SO 2 or SO 3 results in cyclisation to give 86 and by reaction with Me2CuLi these can be converted into the metal-free heterocycles 87 <00JOM(598)150>.

O 82

83

R ~q

onO 85

8 6 n = 1,2

8 7 n = 1,2

84 X = S, Se, Te 5.6.6

THREE HETEROATOMS

Stable 1,2,4-trioxolanes such as 88 <99JOU628> and 89 <00MIll03> have been isolated from ozonolysis of the corresponding alkenes and characterised by 1H and 13C NMR. Ozonolysis of cycloalkenes in the presence of a carbonyl compound R2C=O gives the "cross ozonides" 90 <00EJOC335> and treament of the ozonide of an alkene, RCH=CH 2, with Ph3P=CHCO2Et leads directly to formation of the c~,[3-unsaturated ester R-CH=CH-CO2Et <00T9269>. A review of cyclic sulfites and sulfates in organic synthesis includes many examples of 1,3,2-dioxathiolane S-oxides and S,S-dioxides <00T7051>. Reaction of cyclic sulfates such as

213

F i v e - M e m b e r e d Ring Systems." With 0 & S (Se, Te) Atoms

91 with R2PLi has been used to prepare new bidentate diphosphine ligands <00AG(E)564>. T h e cycloaddition of thioketone S-ylides to N-sulfinylamines results not only in addition across the N=S bond to give dithiazolidines but also addition across the S=O bond to give 1,2,4-oxadithiolane S-imides such as 92 < 9 9 H A C 6 6 2 > . The synthesis, structure and ringinversion of the strained 1,2,3-trithiolane 93 has been studied < 9 9 H A C 6 3 8 > . T h e planarchiral sulfoxides 94 and 95 have been obtained by Sharpless oxidation of the corresponding benzotrithiole and are found not to interconvert <99CL1305>. Reaction of t-butyl p-tolyl ketone with P2S5 gives a mixture of the two isomeric 1,2,4-trithiolanes 96 and 97 both of w h o s e X-ray structures have been determined <00CC1535>. M i x e d 1,3,2-dioxaborole / 1,3,2dithiaborole c o m p o u n d s such as 98 have been prepared <00NJC 115>.

CI° L,

o-s o

OMe

.F,,,/O. A Ok/F

06F13O F

88

OMe~M IO-']s,Me" Me .

89

N-Ts

~ ~

O-" R Me.. . . . q

o'so

90

91

"~S"~SS/s"""~'~S 94

95

S

S

92

aut~s~~?But But"~s_~Ar ~ - O ~ --BkS~ 96

5.6.7

97

98

REFERENCES

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216

OOMI1103 00MIl127 00MI1273 00MIP40575 00MIP43390 00NJCI15 00NJC919 00OL1205 00OL1585 00OL2217 00OL2845 00PS(157)225 00S220 00S824 00SC979 00SL257 00SL701 00SL1046 00SL1070 00SL1133 00SL1798 00SL1804 00SUL169 00T4515 00T7051 00T9269 00T9281 00T1005 00TL2091 00TL2983 00TL4769 00TL9695 00USP6020360 00ZN(B)231 00ZN(B)597

R.A. Aitken V. N. Odinokov, V. R. Akhmetova, R. G. Savchenko, M. V. Bazunova, E. A. Paramonov and L. M. Khalilov, Russ. Chem. Bull., 2000, 49, 1103. P. I. Gadzhieva and I. D. Sadekov, Russ. Chem. Bull., 2000, 49, 1127. D. E. John, A. J. Moore, M. R. Bryce, A. S. Batsanov, M. A. Leech and J. A. K. Howard, J. Mater. Chem., 2000, 10, i273. V. Borzatta and D. Brancaleoni, PCT Int. Appl. WO 40 575 (2000) [Chem. Abstr., 2000, 133, 89531]. B. T. Kim, S. Y. Han and C. S. Pak, PCT Int. Appl. WO 43 390 (2000) [Chem. Abstr., 2000, 133, 120337]. M. J. G. Lesley, N. C. Norman, A. G. Orpen and J. Starbuck, New J. Chem., 2000, 24, 115. C. Carcel, J.-M. Fabre, B. Garreau de Bonnevol and C. Coulon, New Z Chem., 2000, 24, 919. F. Cermola, F. De Lorenzo, F. Giordano, M. L. Graziano, M. R. Iesce and G. Palumbo, Org. Lett., 2000, 2, 1205. R. Gomez, J. L. Segura and N. Martin, Org. Lett., 2000, 2, 1585. M. Iyoda, K. Hara, Y. Kuwatani and S. Nagase, Org. Lett., 2000, 2, 2217. P. MUller and P. Nury, Org. Lett., 2000, 2, 2845. J. Zhang and T. Koizumi, Phosphorus Sulfur Silicon Relat. Elem., 2000, 157, 225. P. Hutin and M. Larchev6que, Synthesis, 2000, 220. D. E. John, A. S. Batsanov, M. R. Bryce and J. A. K. Howard, Synthesis, 2000, 824. J. Zhang and T. Koizumi, Synth. Commun., 2000, 30, 979 [Chem. Abstr., 2000, 132, 308432]. P. Maier and H. Redlich, Synlett, 2000, 257. J. S. Yadav, B. V. Subba Reddy, R. Srinavas and T. Ramalingam, Synlett, 2000, 701. M. Fujii, T. Miura, T. Kajimoto and Y. Ida, Synlett, 2000, 1046. M. Braun, J. Rahematpura, C. BUhne and T. C. Paulitz, Synlett, 2000, 1070. T. Ooi, K. Takaya, T. Miura, H. Ichikawa and K. Maruoka, Synlett, 2000, 1133. B. Karimi, H. Seradj and M. H. Tabaei, Synlett, 2000, 1798. R. Samuel, S. K. Nair and C. V. Asokan, Synlett, 2000, 1804. S. L. Tardif and D. N. Harpp, Sulfur Lett., 2000, 23, 169. A. Fazio, M. A. Loreto, P. A. Tardella and D. Tofani, Tetrahedron, 2000, 56, 4515. H.-S. Byun, L. He and R. Bittman, Tetrahedron, 2000, 56, 7051. Y.-S. Hon, L. Lu, R.-C. Chang, S.-W. Lin, P.-P. Sun and C.-F. Lee, Tetrahedron, 2000, 56, 9269. M. Shimojo, K. Matsumoto and M. Hatanaka, Tetrahedron, 2000, 56, 9281. A. V. Patel, I. Alexandropoulou and T. A. Crabb, Tetrahedron, 2000, 56, 1005. N. Gautier, M. Cariou, A. Gorgues and P. Hudhomme, Tetrahedron Lett., 2000, 41, 2091. E. Aqad, A. Ellern, L. Shapiro and V. Khodorkovsky, Tetrahedron Lett., 2000, 41, 2983. S. R. Waldvogel and D. Mirk, Tetrahedron Lett., 2000, 41, 4769. M. A. Ceschi, L. de A. Felix and C. Peppe, Tetrahedron Lett., 2000, 41, 9695. J. M. Webster, J. Li and G. Chen, US Pat., 6 020 360 (2000) [Chem. Abstr., 2000, 132, 93329]. G. C. Papavassiliou, G. A. Mousdis and A. Papadima, Z Naturforsch., Teil B, 2000, 55, 231. H. Bock, A. Seibel, M. Sievert and Z. Havlas, Z. Naturforsch., Teil B, 2000, 55, 597.

217

Chapter 5.7 Five-Membered Ring Systems: With 0 & N Atoms

Stefano Cicchi, Franca M. Cordero, Donatella Giomi Universit~ di Firenze, Italy

email." giomi@chimorg, unifi.it

5.7.1

ISOXAZOLES

Cyclocondensation processes of 13-dicarbonyl derivatives or their analogues are still widely employed for the synthesis of new isoxazoles. Non-proteinogenic heterocyclic substituted ~amino acids have been synthesised using the alkynyl ketone functionality as a versatile building block: ynone 2, derived from protected L-aspartic acid 1, reacted with hydroxylamine hydrochlofide affording the isoxazole 3 with enantiomeric purity greater than 98% ee <00JCS(P 1)2311 >. O

NHBoc

OtBu

HO 1

O

O

NHBoc

74-100%

O O O'/

4

/O~N

OIBu

2

RCOCI H pyridin~-e-

O

O

,

53-91%

R

8

OH

2. (COCI)2 RNHOH

76-99% R1 O

9

~R OH OH

N-R

"

DEAD,THF 78-92% X

OH " R

6

X

O

HCI

Ni "OB°c

1. AcCl, CO2H

3

O,oc

5

X

OtBu

EtOH,A

O

HN-OBoc Boc A "

NHBoc

10

7

~~L,.

~

~ c ~ N R2

11

Although the synthesis of 3-isoxazolots from 13-ketoesters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum's acid 4 followed by aminolysis gave rise to 13-keto hydroxamic acids 6 that cyclised to the corresponding 5-substituted 3-isoxazolols 7 without formation of any byproduct <00JOC1003>. Cyclisation of N-substituted salicylhydroxamic acids 9 under

218

S. CicchL F.M. Cordero and D. Giomi

Mitsunobu conditions is the key step in the synthesis of N-substituted 1,2-benzisoxazolin-3ones 10 <00TL2295>. Starting from 1,2-bis(o-haloaryl)ethanones, 4,5-bis(ohaloaryl)isoxazoles were efficiently prepared and then converted via intramolecular Stilletype biaryl coupling to phenanthro[9,10-d]isoxazoles 11 in high overall yields <00JOC6398, 00SL1028>. Reductive cyclisation of 2-nitro-substituted acylbenzenes or iminobenzenes in the presence of 2-bromo-2-nitropropane and indium in aqueous media afforded 2,1benzisoxazoles in excellent yields <00TL2137>. HO--Nx

N- O MeO2C/~--~OB n

N- O

~ O B n

"

95%

12

=

O- Nk~..~ -O OBn

80%

OH ('~n

•

Br

Het

14

OH 15

N~O BocHN~ =

gr

NaOCl

13

N-OH Het"~// + --

/

72-90%

""

N~N NH e t / ~ - - ~ O ~ O B

CO2Et

n

x in

17

16

~CO2H

,

HO'"'~.......I~IH

/......~CHO -

TBSO'"'%I~I.pNZ

" TBSO'"'N ~ . p N Z

18

HOH H "

HOH H "

". o

22

~

CO2PNB

21

23 CO2PNB K

I

I

,

o-N

/

CO2E,

o~N

1,3-Dipolar cycloadditions (1,3-DC) of nitrile oxides continue to be a useful source of new isoxazoles and isoxazolines. Methyl 3-(p-nitrobenzoyloxy)acrylatebehaves with substituted benzonitrile oxides as a methyl propiolate equivalent with reverse regioselectivity affording 3aryl-4-methoxycarbonylisoxazoles <00JHC75>; 4-stannyl isoxazoles were regioselectively obtained from nitrile oxides and stannyl alkynes <00SL223>. 1,3-DC of benzyl propargyl ether afforded isoxazole 12, which was converted into the oxime 13. The in situ generated nitrile oxide reacted with propargyl bromide affording C3,C3'-diisoxazole 14 which gave rise to the tetraheterocyclic, triisoxazole-containing products 16 by coupling with alcohols 15 <00JOC2225>. The orthogonally protected 3-(1-aminoalkyl)isoxazole-4-carboxylicacid 17

Five-Membered Ring Systems." With 0 & N A toms

219

has been prepared by cycloaddition of ec-aminonitrile oxide with an enaminoester dipolarophile: deprotection and coupling with amino acids independently at either the C- or N- terminus produced pseudopeptide segments as peptide mimetics with a cis-amide bond replacement <00TA3273>. Formylpyrrolidine 19 and vinylpyrrolidine20, coming from trans4-hydroxy-L-proline 18, were employed in 1,3-DC processes as 1,3-dipole precursor and dipolarophile, respectively, affording in several steps isoxazole derivatives 21. Treatment of the enolphosphate 22 with thiols 21 gave rise to ll)-methylcarbapenems 23 containing 5'isoxazolopyrrolidin-3'-ylthio derivatives as C-2 side chain which exhibited potent antibacterial activity <00BMC95>.

H2N/k_.~__,k25 0 ~

CHO

Ri

H

CHCI3,rt 68-82%

N Ri

24

NH 2

ffffff~ 26

TFA,rt

N

49-86%

~-I --/

8Z%oT

Rib =

BzO OBz

Rib 27

X

HO2C-R1 ( ~ ? 02 DIEA, ~=O DM/~P ~S-N,,'[LR, 0200 L H2N DIC,

R2CO2Me

O

O

O

O

28 I NH2OH NR2 N-O

O2 OII

NR2 O-N

N-O

Jl

2. NHR 2

31

30

+ isomer

29

Ring-opening of 5-ribofuranosylisoxazole-4-carbaldehyde 24 with 1,2-diaminobenzenes 25 led to 3-cyano-l,5-benzodiazepine C-nucleosides 27 through the Schiff's bases 26 <00CAR681 >. Condensation of aromatic or aliphatic esters with resin-supported acetyl carboxylic acids 28 followed by cyclisation with hydroxylamine, activation of the linker, and cleavage using amines, provided highly substituted isoxazoles 30 and 31. This general method gave products in excellent yields and purities in which the regioisomers ratio can be easily controlled <00OL2789>. 5.7.2

ISOXAZOLINES

Nitrile oxides generated under neutral conditions by thermal fragmentation ofnitrolic acids 32, were trapped in situ with alkenes to afford isoxazolines 33 in 53-97% yields <00TL1191>. Nitrile oxides were also produced by treating O-silylated hydroxamic acids 34 with triflic anhydride and TEA <00OL539>.

220

S. CicchL F.M. Cordero and D. Giomi

NOH

70 °C

R"I~'NO2R'HC=CHW' 32

R R" Tf20,TEA O N~O~-~ -40 °C -0 °C R.,,~N~OTBDPS

53-97%

33

R' R'HC=CHR"

H

54-85%

34

The penam nitrile oxide 36 underwent 1,3-DC reactions with various alkenes and alkynes to give cycloadducts of general formula 37. The corresponding acids (37 R=H) exhibited potent 13-1actamaseinhibitory activity <00OL3087>.

~ S ~ , H~,, / O o (Bu3Sn)2? +~

HON ~ H

Cl n/~-N- ~ \ O 35 CO2R

-H-H~"~0 1

_

/15

-

~CO2RJ

036

.HO ' ~o

A.H

-

37

CO2R

High diastereomeric ratios were observed in the 1,3-DC of various nitrile oxides to the chiral acryloylhydrazide 38. For example benzonitrile oxide afforded the isoxazoline 40 in 98% de <00TL1453>. The levels of facial selectivity obtained in the same 1,3-DC with the chiral 3-acryloyl-2-oxazolidinone39 was very low (dr 43:57), but in the presence of MgBr2 (1 equiv) the reaction proceeded with high diastereoselectivity to give preferentially the isoxazolidine 41 in 92% de <00TL3131 >.

".,rxA&2c,2~..yx

O 40 (98% de)

97%

O 38(X=XA) 39(X=XB)

0,20;= ' - o - ~ x= 86%

41 O (92% de)

,,

O

,,yo

,

Ph XAH

0

XBH

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The Ralcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold <00JOC8527>. The achiral hydantoin- and isoxazolinesubstituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, 00CC1835>.

~ 43o ,

42

Bo

.

45

PhNCO

~--oAc

BocHN v b~N 46

=

44

R'/N--0

47

oAc

Five-Membered Ring Systems: With 0 & N Atoms

221

Treatment of isoxazoline-fused [60]fullerene 48 with NaOMe in the presence of MeOH gave the 13-hydroxy nitrile derivative 49 in good yield <00SL361>. The synthesis of the enantiomericallypure cyclopropane amino acid 51 covalently attached to a fulleroisoxazoline has been achieved <00JOC6246>.

//X•

N i) NaOMe O H MeOl--I C6o ii) HCI C6 CN 48 71% 49

NOH NCS, TEA O- N HC" NHBoc C6° ,. /, ..Boc ""~7
Propargylic N-hydroxylamines 52 underwent intramolecular cyclisation catalysed by ZnI2 and DMAP (10 mol%) to give 2,3-dihydroisoxazoles 53 in high yields (82-97%) <00OL2331 >.

Bn

HO':/%

Znl2

__ 52

5.7.3

R

R' cDHMAI~Bn_N.o'~R, 53

ISOXAZOLIDINES

A variety of enantiomericallypure isoxazolidines have been synthesised by intramolecular 1,3-DC reactions of chiral nitrones. Selective exo addition of the camphor-derived oxazoline N-oxide 54 to the trisubstituted alkene 55 gave the isoxazolidine 56 which was a key intermediate in a formal synthesis of carbapenem (+)-Carpetimycin A <00OL1053>. The anti-exo adducts were preferentially obtained from the chiral (E)-geometry fixed ct-alkoxycarbonylnitrone (5R)-57 with various alkenes. The isoxazolidine 58 was transformed into the optically pure amine 59 by hydrogenolysis <00JOC8544>. Enantiomerically pure pyrroline N-oxides 60-61 and 62-63 reacted selectively with maleic acid and buten-2-ol derivatives to afford, after a few simple transformations of the primary adducts, functionalised pyrrolizidines and indolizidines, respectively. These methodologies are exemplified by the synthesis of (-)-croalbinecine (66) <00EJO3633>, and indolizidines 68 <00TL1583> and 71 <00OL2475>. The pyrrolo[1,2-b]isoxazolidine 70, having the [3a,4]-cis configuration, was selectively achieved through an intramolecular 1,3-DC of a nitrone generated in situ by retrocycloaddition from the isoxazolidine 69. Some different stereoselective approaches to isoxazolidinyl nucleosides such as 72 have been reported <00JOC5575, 00TL9239, 00TA1543>. Enantiomerically pure nitrones generated from aldehydes 73 underwent diastereoselective intramolecular 1,3-DC to afford pyrrolo [3,4-c]isoxazolidines 74 <00S365>. Spirocyclopropane isoxazolidines 75, obtained from alkylidenecyclopropane nitrones, underwent thermally induced selective rearrangement to pyrrolo[3,4-b]pyridinones 76 <00TA897>. The same adducts 75 in the presence of a protic acid afforded exclusively 13lactams 77 (57-60% yield) accompanied by ethylene extrusion <00JA8075>. The one step domino cycloaddition-rearrangement process of N-aryl nitrones 78 to BCP (79) afforded spirocyclopropane-annelated pyridones 81 and benzazocinones 82 in good overall isolated yields <00SL1034>.

222

S. CicchL F.M. Cordero and D. Giomi

~N~+.~

+ H2NNr ~

CO2Me

"~7

O H2N- - C ' O2Me 56

Ph''

O O

O_ (5R)-57

88%

Ph"

~O~

"~'0

150 °C

69

."

..... \ -~" /

PhNHOHQN/N~N

40-97% Bn / >96%de ph/N~IH~R R ' " - N SO2Ph I (R)-73 74 76

78

V

,,,OH O MeO2C.

OH

ff~l~lH

B°cHNB n N - ~~N~'~O _

(-)-71

72

NTs~ene

~ R

toluene 110 *C (R'=H)

77

R

O

Ar/N...~ 80

NTsTFA /N--~

1400C / R (R'=H, Me) 75

Ph

xylenes Ph

+ ' ~ 100o-~-~" 79

O_ 62: X=NHR,Y=OR' 63: X=OR', Y=NHR

H2C=CH2

0OPh

Ph

-

RO

,V

H (4R)-59 (>99%ee)

TBDMSO. H

i) MsCI,TEA

70

R

-

61: X=Y=OR

B o c H N ~ ii)Pd/C.%o,H: B o c H N ~ - ~ 67 Hd 65% 68 O O CO2Et

f Nf ' O ~ -~

60: X=H, Y=OR

tBuO H CO2Me HO H F OH Mo(CO)6 ~( I ),,,'OH i) LiAIH4 ( I ),,"OH CH3CN/H20 ~ N - ~ ii) TFA N/N-..J 65% 65 ~) 80%o 66

TBDMSO H

O

O_

\

H2 H2N~

Pd(OH)2-C - AcOH O >90%

(9R)-58

tBuO H COeMe ~CO2Me

O~

+

81 (40-57%)

82 (20-27%)

5-Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-O bond reduction. Addition of N-acryloyl-(2R)-bornane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85:15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline N-oxide to chiral pentenoates using (-)-trans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The

223

Five-Membered Ring Systems: With 0 & N Atoms

reaction of C-aryl-N-phenylnitrones with 16-dehydropregnenolone acetate was highly regioand stereoselective and afforded cycloadducts 86 in 74-85% yield <00TL7551>. High regioand stereoselectivity was also observed in the 1,3-DC of cyclic nitrones 60-61 to peptidomimetic maleic diamide 87. The adducts showed a significant ability to bind tachykinin NK-2 receptor <00JOC4003>. The 1,3-DC reaction of heterocyclic nitrones such as 88 and 89 to different dipolarophiles has been reported <00SL967, 00T7229>. The intramolecular 1,3-DC of norbomadienetethered nitrones occurred with high regio- and stereoselectivity, for example the single cycloadduct 91 was obtained by treatment of aldehyde 90 with MeNHOH. A poorer selectivity was observed when a longer tether was inserted <00CC863>. Alkenyl nitrones, generated from bis(alkenyl) ketoximes through regioselective electrophile induced cyclisation, underwent stereoselective intramolecular 1,3-DC. This cascade reaction, applied to the unsymmetrical ketoxime 92, afforded the single adduct 93 in 61% yield <00T10087>.

~N

H

"Bnx * o' ' ~. &+ 90% 70% de O

0

O

0

Zn/AcOHHO~ N~,R~-/ + ~ S f NH O-N 83 84 "R 85 (86%) O H (X'H02 ,92%) R' _ +)---,, : II P,.e O-N N-R H ~ H Ar O/~NJ'Z'.,:: 88: n=0, R=Bn,R'=Ph AcO H87 89: n=l, R=R'=H Et i) PhSeBr, CH2Cl2 ~ N O~ . ~ MeNHOH~I~H~X Etii)K2003, CH2CI2 SePh n=1,2 iii) 80 *C, CH3CN ~ . ~ . , , / 0 O-~n 60-71% L"-O'~9); 90

x"

92

61%

F-I 93

Highly diastereo- and enantioselective catalytic 1,3-DC of cyclic nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. For example the exo adduct 96 was obtained in 82% yield and 85% ee in the presence ofa chiral BINOL-A1Me3 complex (20 mol%) <00JOC9080>. BINOL-Box-Scandium complexes catalysed asymmetric 1,3-DC of acyclic nitrone 97 to 98 to give the isoxazolidine 99 in high yield with high diastereo- and enantioselectivity <00JOM6>. An overview of catalytic enantioselective 1,3-DC reactions of nitrones has been reported <00CC 1449>. An enantioselective organocatalytic 1,3-DC reaction, based on the activation of cx,flunsaturated aldehydes through the reversible formation of iminium ions with chiral imidazolidinones 100, was described. Good levels of asymmetric induction and diastereocontrol were achieved (up to 94% ee and 94:6 dr) <00JA9874>. Conjugate addition of N-benzylhydroxylamine to pyrrolidinone cinnamate 101 catalysed by Mg(C104)2 and bisoxazoline ligand 103 gave the isoxazolidinone 102 in 80% yield and 96% ee <00OL3393>. The lipase-catalysed resolution of racemic 105 in the presence of vinyl acetate afforded isoxazolidines 105 and their corresponding acetates in 52-82% ee. A higher optical purity

224

S. CicchL F.M. Cordero and D. Giomi

(>90% ee) was obtained by kinetic resolution of the alcohol 104, followed by base induced cyclisation <00SC1467>.

~ N

I1~ 95, AIMe3 =, 9 6 ~ ~ O 82% N, "O- OEt 85%ee 94 "bEt Bn..O ..... oo ,, ".., Bn,N+,O + ~"'~-'~NAO Sc(OTf)~ , , ~ y +

IILph 97 O O A

Ph

Mg(ClO4)2

N

~/"

CI

[

" ~

O 104

RO2C

OH

,,,OH

R

95

~/ 79% PH 98 83%ee 99O O 390a Bn..O./.O

O

RH, H~N~., . .HX k---]

O X

N /~ ~ ~ Pli I..02 , 101 BnNHOH,oo,o, .... ,oee, O

~,,R

+

100

Q

~/' I ~ "IT" "~..,.~ r ~,~N N,,,< ]

O

OH ROH ~"~,,~ O~/ f05

5.7.4 OXAZOLES 4-Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from arylsubstituted tosylmethyl isocyanides and aldehydes <00JOC1516>. Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>.

Ts 10%Na-Hg 4 eq. NaHPO4 N-~ TsvNC 1. BuLi,THF,-78°C N-~ R 2. RCOCI K'OA"~'R EtOH/THF)))) 106 107 (53-85%) 108 (51-10O%)

~: 109

BDMS LiCH2NCHOO~'"'OTBDMS. THF,-78°C

~'~---N 110 (66%)

OTBDMS

"MeO2(~ ~-N 111 (46%)

150oc

[M O~.

HO.... MeO2

O ~

~

"

(-)-114 (55%)

0

MeO~

N

113 (37%)

OTBDMS]

eO2C/'X"~N 112

J

225

F i v e - M e m b e r e d Ring Systems: With 0 & N Atoms

A short multigram synthesis of oxazole was realised starting from ethyl isocyanoacetate according to the Sch611kopf procedure <00H(53)1167>. Analogously, the homochiral 7butyrolactone 109 was readily converted to the oxazole alcohol 110 with cz-lithiated methyl isocyanide: the key intermediate 111 afforded the monoterpene alkaloid (-)-plectrodorine (114) through intramolecular oxazole-olefin Diels-Alder reaction <00TL10251>. Following the same strategy, the first synthesis of enantiomerically pure (-)-normalindine (115) was performed <00T7751>. N2

O'~CO2Me ZHN--~M ZHN-~ R 117 R=Me ZHN"~N o~NH 2 Rh2(OAc)4 " , O'k/~CO2H " 116 19-35% R 118 119

HN--
.

X=H'RI=H'R2=CO2Me]12'Ph3P'Et3N91% O H O

~CN

O H

ZHN~x/.~N

N--.~"COeMe

Rh2(OAc)4

121

122 (95%)

-~ CO2Me -~CO2Me ._~OH DPPA BooHN~ O OH B°cHN"~"CO2H + HCI'H2N CO2Bn Et3N95% HO~OB n 123

124

,~-OBn O

65%

125

CO2Me N---~ R1 ZHN~O,/~"N/L-CO2M e i~2 H 128

CO2Me ,.B°cHN~-/-~

Ar Me02C 0 200oc ,,~ MeO2C~NY"Ar or cat. CuXn,r~ N O + Ar3Bi BiAr3 MeO2C CO2Me 129 130

126

2 ,""~N H

HN'~O ....

127

/

The indole bis-oxazole 120, a potential intermediate for the synthesis of the marine natural product diazonamide A, has been synthesised starting from valinamide 116 and

226

S. CicchL F.M. Cordero and D. Giomi

diazoketoesters 117. Rhodium (II)-catalysed carbenoid insertion into the primary N-H bond and subsequent cyclodehydration gave the oxazole derivatives 118; conversion to the ctacylamino ketones 119 allowed the construction of the second oxazole ring <00TL6897>. 5-Fluoroalkyl substituted oxazoles were also obtained in fair to good yields from ethyl 2-diazofluoroalkylacetoacetate and nitriles in the presence of catalytic Rh2(OAc)4 <00JFC139>. Epoxy diazomethyl ketone 121 behaved as a nonracemic epoxy transfer agent to afford with propionitrile the epoxyoxazole 122 <00OL2393>. Under microwave irradiation in the presence of Hg(OTs)2, aromatic ketones and nitriles gave polysubstituted oxazoles in very short reaction times and 47-86% yields <00TL5891>. Oxazole 126, coming from the acid 123 and protected L-threonine 124 through the acylamino alcohol 125, resulted an useful building block for the synthesis on gram scale of the functionalised pseudopeptide molecular platform 127 as a template molecule in supramolecular chemistry <00TL5013>. Optically active amino acids 128 were conveniently synthesised and directly assembled onto peptidomimetic chains <00EJO3217>. Thermolysis or copper-catalysed decomposition of stabilised bismuthonium ylides 129 afforded trisubstituted oxazoles 130 <00JOM89>.

O~N /~

RCOH. O~N2 ~ CBHB,hv ~ H

131

132

OTBS "~N

+ R

R

OTBS

~_ CO2Et

H*.

~'J ?

O ..~..NH2 HO~'~ 133

OTBS ~ CO2Et CN

CO2Et

BnMe3N÷ CN

~

~.

O~.H TfO ~NBn R=CH2CH2SO2P h "~~ilBn

134 OBz

O"IOF"N" ?HNBn "-. OBz

135 OBz lO2Et

136

OTBSCOEt

NBn 0

138

~

137

z

The photocycloaddition of aliphatic and aromatic aldehydes with 2,4,5-trimethyloxazole (131) gave bicyclic oxetanes 132 in almost quantitative yields; hydrolitic cleavage led selectively to erytro et-amino-13-hydroxymethyl ketones 133 <00CC589>. The oxazolium salt 134 was converted to the azomethine ylide 136 via electrocyclic ring opening of the oxazoline 135. Intramolecular cycloaddition afforded 137 in 66% overall yield which was transformed into the aziridinomitosene derivative 138 <00JOC5498>.

227

Five-Membered Ring Systems: With 0 & N Atoms

1,3-DC of unsymmetrical 1,3-oxazolium-5-olates with 2- and 3-nitroindoles gave rise to pyrrolo[3,4-b]indoles in good to excellent yields <00T10133>; trifluoroacetyl miinchnones and amidines led to 5-trifluoroacetylimidazoles<00CPB410>. Azomethines 139 reacted with alkylating reagents to afford optically active 2-(tx-aminoalkyl)oxazoles 140; with dihaloalkanes the alkylation product could be cyclised to give optically active 2-oxazolyl-Nheterocycles such as 141 that was converted to the naturally occurring 4,5-dihydroxypipecolic acid 142 <00S2051>. Ph

~

Ph

" "2N N.,.~0~-~ Ph 2. RX 3. citric acid/H20/THF I~ 139 140

Ph

R= Br Ph

H

..r'"'T'c°2H.c, HOf ' ' ~ : 6H

5.7.5

H .

"

0 _~ +6

142

I .o~Ph

.....

141

OXAZOLINES

Several new chiral ligands containing one or more oxazolinyl moieties were synthesised and used for various kinds of metal-catalysed enantioselective reactions. The reactions that have been studied include asymmetric cyclopropanation <00JOC3326, 00OL2045, 00OL3905, 00TL1023, 00TL7135>, nucleophilic addition of dialkylzinc reagents <00SC1627, 00SL239, 00SL1512, 00TL9351>, allylic substitution <00CC285, 00CCl195, 00CH299, 00OL3695, 00TA1495, 00TA4027>, allylic oxidation <00SC1627, 00T5775, 00TL3941> and Michael addition <00T2879>. Diethylaminosulfur trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) were found to be useful reagents for the synthesis of enantiomerically pure oxazolines 144 by dehydrative cyclisation of [3-hydroxy amides 143 (36-90% yield) <00OL1165>. The same reaction was performed using the Vilsmeier reagent in pyfidine (2995% yield) <00JOC9223>. Chiral 2-alkynyloxazolines were synthesised in two steps from 2alkynoic acids and 2-amino alcohols <00TA4407>. The BF3.OEtz catalysed ring-opening of oxiranes 145 with CH3CN afforded oxazolidines 146 in 65-92% yield <00TL5357>.

R3

% R, .orb.

R'

H N ~ _R2 N~\R2 143 144 a: DAST or Deoxo-Fluor(R2 = CO2R, 36-90%) +

b: Me2N=CHCICI-, Py (29-95%)

1

R3 0 R1 R2'~COX

BF3.0Et2 2N-,,--0 1 CH3CN R 3 " j ~ ' R

145

65-92% R i 4 6 COX

X = NH2, OR; R1 = Alkyl

228

S. CicchL F.M. Cordero and D. Giomi

Chiral acetamido selenides 147, obtained from alkenes with camphorselenenyl sulfate, underwent intramolecular substitution in the presence of PhSeOTf or SO2C12 to afford enantiomerically pure oxazolines 148 <00EJO3451>.

NHAc PhSeOTf R,,,,~R' or _~Oy 147

SeR* SO2CI2 55-98%

R'

148

Amido methanesulfonate 149 was transformed to cis-oxazoline 150, with a clean inversion of configuration at the (x-centre, with K2CO3 in acetone/H20. When 149 was treated with DBU in refluxing CHC13 the trans-oxazoline 151 was mainly obtained. The trans isomer 151 was more reactive than 150 toward ring-opening reactions <00OL1243>.

._~? --.T,"CO2/Pr KHCO3 .NHAc O~.~CO2/'Pr NHAc .J Acetone ph....J-~CO2/Pr DBU "--'(k ..~.. XH . ph~CO21P r "CHCI~ N "Ph 78-90% N ""Ph H20 OMs X 62% 76% 150 149 151 XH = HN3,PhSH,AcSH 4-Spirocyclopropane oxazolines 153 were formed from cyclopropylideneacetates 152 and carboxamides under basic conditions through a domino process involving a Michael addition followed by an intramolecular nucleophilic substitution <00JOC3850>. The carbonylation of lithium derivatives of aryloxazolines 154 afforded the oxazolo[2,3-a]isoindolinones 155 in high yields (84-91%) <00JOC7944>. The oxazoline 156 was used as a key intermediate in the total synthesis of the potent antifungal agent (+)-preussin (157) <00OL4041 >.

CI]~ CO2Me R'CONH2NaH R - - ~ ' O R' R 152

CH3CN 6-77%

CO2Me 153

t~..~v.~ 154

ii)CO (1 atm) N--(-..~iii) aq. NH4CI R | 84-91%

~,~O---~,Bn O "~r-~"OH 1) H2/Pd(OH)2 II Ph .... "'"~C9H19 2) HCHO C9H19'. . . . . . Bn 156 NaBH3CN I (+)-Preussin 157

The natural product westiellamide (158) and other unnatural cyclopeptide alkaloids were synthesised by cyclooligomerisation reactions <00T9143>. The benzene-based tripodal tris(oxazolines) 159 were developed as new selective receptors toward alkylammonium ions <00CEJ3399>.

229

Five-Membered Ring Systems: With 0 & N Atoms

..

O ~ N

R4

R2

Oxl~"N R'

......

R1 N'R2 R

R~,,L o'

,,,,"

Westiellamide 158 5.7.6

R3

~R4

159

OXAZOLIDINES

New methods for the synthesis of the oxazolidine ring were published. Several Sm(II) and Sm(III) derivatives catalyse the reaction of imines with epoxides to obtain highly substituted oxazolidines 160 <00TL3389>. Imines are used also in the reaction with vinyl oxiranes catalysed by a palladium complex to afford regioselectively 4-vinyl-l,3-oxazolidines 161 <00H(53)885>. Solid phase supported 1,3-oxazolidines 162 were synthesised and subsequently cleaved with DDQ <00TL5069>. Treatment of azetidinium salts, derived from c~-aminoaldehydes, with primary amines afforded 5-substituted-l,3-isoxazolidines <00TL1231>. Compound 163 was a key intermediate in the synthesis of aminoderivatives of 1-deoxynojirimycin <00JOC7208>. 3-Aminooxazolidinopiperidin-2-one 164 was synthesised and studied as type II' 13-turn mimetics <00JOC6992>. Compound 165 was synthesised in both enantiomeric forms and tested for antihypertensive activity <00BMC319>.

R~ al"~U"a3

O + R4~?L~ R5

Sml2 (50/0) --'THF, r.t., 5h 50-88%

o i . > ~~

~o

-I- /=N

~Ts

RI Ph/,

R3 .~1 . R1

Pd(dba)2 DPPE 75-97%

~,,

~ " "y..R~ a 4 ~ O 160 R1

'r-. 7s

O,,~R2 //'161

9~ ,x 162

OH 163

164

165

Some new observations were published on the peculiar reactivity of the phenyloxazolopiperidine 166 which acts as an equivalent of an enamine, reacting with methyl vinyl ketone in a Michael reaction and with diethyl acetylenedicarboxylate in a [2+2] cycloaddition reaction <00JOC3209>.

230

S. CicchL F.M. Cordero and D. Giomi

The cyano derivative 169, through treatment with alkyllithium and reduction, afforded 3aminoazepane 170 <00TL1179>. Ph. :/ - - X

Ph,,

Ph,,:

o

o.

EtO2C~""~ / / 168

93% Ph,,,

NC,~,,~..'.O

63%

166

1Phi R~ N RLi . ~ . ~

.

"OH

LIAIH4 65-91%

169

H

,

He

170

PI~

Oxazolidine derivatives have found several applications as chiral auxiliaries. Polymer supported oxazolidine aldehydes 171 were obtained and used for the stereoselective synthesis of 13-1actams <00TL8621 >. Chiral oxazolidine auxiliary 172 can steer the diastereoselectivity and the regioselectivity in singlet-oxygen ene reactions through hydrogen bonding <00JA7610>. Vinyloxazolidine derivatives were used for the synthesis of unnatural aminoacids via Suzuki cross-couplings reactions which afforded 173 as intermediate <00OL 1089>. Allylic alcohol 174 was used in Claisen rearrangements <00TL8301 >. With an analogous procedure bicyclic thiolactam 175 was used in a thio-Claisen rearrangement <00TL815>. The use of different oxidising reagents with oxazoline 176 resulted in opposite selectivity in the formation of the correspondent epoxide <00OL1019>. Phosphinooxazolidine 177 was synthesised and tested with excellent results in Pd-catalysed asymmetric allylation reactions <00TA1193>. RI

171

' ~ N'R

Ph 172

Jo~ OH Boc

174

R

Ph

O S

175

"~~Nh~ 176

173 Ph

~

H"

PPh2

177

A very simple and straightforward access to enantiopure substituted pyrrolidines and piperidines was obtained by reaction of phenylglycinol 178 with to-chloroketones 179. The intermediate oxazolidines 180 were then easily converted into the desired compounds <00EJO1719>. Compound 182 was obtained by reaction of the correspondent oxazolidine with a complex alkyllithium derivatives and was the intermediate for the synthesis of

231

F i v e - M e m b e r e d R i n g Systems: with 0 & N Atoms

enantiopure substituted derivatives of pipecolic acid <00JOC4435>. Again by reaction of an organoaluminium reagent with an oxazolidine, compound 183 was obtained.<00JOC6423> R

OH

O(~)

CHCl3'NEt3 .t.r

Ph"" n NH2 178 179o

60-92% de 60-92%

[~ON~

Ph"" 180 HO

:~ =

)n

H 181

)

n

~~.jSiMe3

183

182 ,,,0 ~"'~/'~-- O "~O ~ N

OH (TMS)2NNa ~ " ~ O THF, r.t. 88%

/P(Cy)3 Cl.. C," IRu--"~Ph. P(Cy)3

185 0

o

CH2012 99%

ojO

O~LN3 [FeCI2],TMSCI 0*C, EtOH ~

H

l=

70%

Hi

[Pd(C3Hs)CI]2,dppf

R R' )~'(" + CO + (1/2)O2 " O. NH HO NH2 -H20 ~O 193 50-100% 194 Pdl2, KI

I

I

R1 195

197

198

'ph190

Asymmetric R1 Aminohydroxylation 2

? H iOi NaCIO,OH'[ OH i..O TrO..v.-'L.v.~ NH2 TrO~.....~ N~c =

O

'~XN_ R 192 0-~ 0

R-NH2,60-70%

191 R'

.H

= THF:DMSO (10:1) 90~ 72% |H~"

MeO2CO'~~'~OCO2Me

R

CI

,BX

189 ~

OH

Base "

R2

g.yo O O

90~ TrO..~.~J NH 199

232

S. CicchL F.M. Cordero and D. Giomi

Several new syntheses of the oxazolidinone ring have been published. Treatment of ~poxyurethane 184 with a strong base induced the cyclisation to oxazolidinone 185 which, trough an olefine methathesis afforded 186 <00OL93>. Treatment with iron salt of acyl azide 187 afforded an aziridine, which, upon nucleophilic attack of a chloride ion, was transformed in the final oxazolidinone 188 <00CC287>. Addition to a double bond is involved in the transformation of urethane 189 into 190, mediated by IBX (o-iodoxybenzoic acid). A radical centred on the nitrogen atom is proposed to be the reacting species <00AG(E)625>. Dicarbonate 191, upon treatment with palladium complex and primary amines, affords N-alkylated-5-vinyloxazolidinones 192 <00TL6785>. Another palladium complex acts as catalyst in the oxydative carbonylation of 2-amino-1alkanols 193 under pressure of CO and 02 <00OL625>. A direct route to enantiopure oxazolidinones has been published, starting from a simple olefin 195 through an asymmetric aminohydroxylation <00OL2821>. Treatment of amide 197 with sodium hypochlorite afforded isocyanate 198 which cyclised in situ to the enantiopure oxazolidinone 199 <00TA4429>. Enantiopure oxazolidinones are largely used in organic synthesis as chiral auxiliaries and new examples of this class of compotmds have been synthesised and used in asymmetric synthesis. N-acylselones 201 have been synthesised starting from oxazoline 200 and used in asymmetric alkylation reaction <00JA386>. 3-Methylthiomethyl substituted enantiopure oxazolidinone 202 was proposed for the synthesis of enantiopure diols <00OL1501>. Solid phase supported N-acyl oxazolidinone 203 has been synthesised and used in 1,3-DC reactions with nitrones and nitrile oxides <00TL1265>. New enantiopure oxazolidinones built on a carbohydrate skeleton, 205 and 206, have been described <00TA423, 00TA371> as well as a new water soluble ligand 204 <00TA1455>. 1 ) LiHMDS

O

2) Se

Se

N~'.....~ 3)Propionylchloride,. ~N20~/1.Ph.. .o h200

o O"J~N~SMe

"~~O

o~~ /--o 204 H

MeOw,OMe

MeO--1 OMe 0.,. -OH MeO_..I I I 0 206

~

Ph 0-1~ ~

The literature presents a large number of examples concerning the use of known oxazolidinones as chiral auxiliaries in many kinds of reactions. Rare is the use of N-amino derivatives of oxazolidinones, which were used to synthesise new N-acylhydrazones 207. Radical addition reactions occurred with high diastereoselectivity <00JA8329>. The use of glycolate oxazolidinones 210 proved to be efficient for the enantioselective preparation of ot-alkoxy carboxylic acid derivatives <00OL2165>. Photochemical reaction of vinyl

233

Five-Membered Ring Systems: With 0 & N A to ms

oxazolidinones with chromium carbene complexes afforded cyclobutanone 209 with excellent selectivity <00JOC2096>. cx-Bromoacetyl-2-oxazolidinone 212 was used in an asymmetric samarium-Reformatsky reaction with aldehydes <00JOC1702>. Enantiopure oxazolidinones were also key intermediates in the total synthesis of epothilone B <00TL7635>, (-)-reveromycin B <00OL191> and in the synthesis of lignans <00JOC464>.

Bu3Sn

R1~ 207 ~ p h

O ROv'J~ . . N"tlxo _O_

EtaB 30-83% de 90-98% NaN(SiMs3)2

208

R1

O

O . ~ ....,, 209 = O O

O

Xo

.

R1

30-80% de98%

210

o

o

II

R 211

12

Oxazolidinones have also been used as intermediates in simple transformations utilising their peculiar reactivity. The absolute configuration of N-Boc-13-aminoalcohol 213 can be easily inverted via SN2 cyclisation to oxazolidinone 214 <00TL10071>. Treatment with Olah's reagent (HF-Pyridine) of 4-alkyl-5,5-diphenyl-oxazolidinones 216 afforded the corresponding a-(fluorodiphenylmethyl)alkylamines 217 <00TA2033>.

~Nt-Boc ,,~Ph

213 OH

~...Ph CH3SO2Cl IN4~oO 100%= 21

LiAIH, 100%"

~_N/ ......'~. Ph 2150 H

_ Ph_ph ph h I'HN~ O HF-Pyridine,. R ~ P 216 '~)

HN'~O RI''R2LRL~ R3 218

29-77%

NH2 217 0 HI~~

Pd cat.,CO EtOH R1'"' 57-87% R" 219

R3

The palladium-catalysed decarboxylative carbonylation of 5-vinyloxazolidin-2-ones 218 caused, unexpectedly, a ring enlargement process to ~-lactams 219 <00JA2944>. The conjugate addition of 4-phenyloxazolidin-2-one to a nitroalkene was used for the synthesis of diastereoisomers of dethiobiotin <00EJO3575>. Attempted deprotection of the O-TBDMS

234

S. CicchL F.M. Cordero and D. Giomi

group in an L-serine derived isoxazolidinone caused the migration of the Boc group from nitrogen to the hydroxymethyl group <00TL7577>.

5.7.7

OXADIAZOLES

The decomposition reaction of oxadiazole derivatives was studied under various conditions. Thermal treatment of 5,5-dimethyl-2,2-diphenoxy-A3-1,3,4-oxadiazoline (220) in the presence o f D M A D afforded a mixture o f triester 221 and bicyclo[1.1.0]butanes 222 and 223 <00OL3501>. 1,2,4-Oxadiazole-4-oxides 224 underwent clean thermal cleavage in refluxing chlorobenzene or xylene to nitriles and nitrosocarbonyl intermediates 226, which either are trapped with suitable olefins to afford ene adducts or dimerise <00TL2019>. Treatment o f tx-nitro-oximes 227 with acidic alumina afforded 1,2,5-oxadiazoles N-oxides 228 <00TL8817>. Compound 229 was synthesised to evaluate the barrier for nitrogen inversion in 1,3,4-oxadiazolidines using N M R techniques <00AG(E)2938>.

PhO OPh 1100C PhO2C N,"~.O DMAD ~ ~II = E

220 ' ~

221

Ar'k

,(3-

N,O,,~-...Ar

Ph E

H0~ N

R~ 227

5.7.8

E" 222

Ph

+

PhO

AI203(acidic) CH3CN R 600C

OPh "

E" 223

Ar,.ON.[Ar ,. O]

224

R' NO2

+

OPh qO PhO. _ ~ , , ,,EE OPh

226

225 ,,(3. -~OR'

22yR-'RN-N'"

228

REFERENCES

00AG(E)625 00AG(E)2938 00BMC95 00BMC319 00CAR681 00CC285 00CC287 00CC589 00CC863 00CC 1195 00CC1449 00CC1835

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236

00JOC9080 00JOC9223 00JOM6 OOJOM89 00OL93 00OL191 00OL539 00OL625 00OL1019 00OL1053 00OL1089 00OLl165 00OL1243 00OL1501 00OL2045 00OL2165 00OL2331 00OL2393 00OL2475 00OL2789 00OL2821 00OL3087 00OL3393 00OL3501 00OL3695 00OL3905 00OL4041 00S365 00S2051 00SC1467 00SC1627 00SL223 00SL239 00SL361 00SL967 00SL1028 00SL1034 00SL1512 00T2879 00T5775 00T7229 00T7751 00T9143 00T10087 00T10133 00TA371 00TA423 00TA 1193 00TA897 00TA1455 00TA1495

S. CicchL F.M. Cordero and D. Giomi

K. B. Jensen, M. Roberson, and K. A. Jergensen, J. Org. Chem., 2000, 65, 9080. P. G. M. Wuts, J. M. Northuis, T. A. Kwan J. Org. Chem. 2000, 65, 9223. H. Kodama, J. Ito, K. Hori, T. Ohta, and I. Furukawa, J. Organomet. Chem., 2000, 603, 6. Y. Matano, H. Nomura, H. Suzuki J. Organomet. Chem. 2000, 611, 89. R. Martin, A. Moyano, M. Peric/ts, A. Riera Org. Lett. 2000, 2, 93. A. N. Cuzzupe, C.A. Hutton, M. J. Lilly, R. K. Mann, M. A. Rizzacasa, S. C. Zammit Org. Lett. 2000, 2, 191. D. Mud, J. W Bode and E. M. Carreira, Org. Lett., 2000, 2, 539. B. Gabriele, G. Salerno, D. Brindisi, M. Costa, G.P. Chiusoli Org. Lett. 2000, 2, 625. W. Adams, A. Pastor, K. Peters, E.-M Peters Org. Lett. 2000, 2, 1019. M. Mauduit, C. Kouklovsky, Y. Langlois, and C. Riche, Org. Lett., 2000, 2, 1053. M. Sabat, C. R. Johnson Org. Lett. 2000, 2, 1089. A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams Org. Lett. 2000, 2, 1165. S.-H. Lee, J. Yoon, K. Nakamura, Y.-S.Lee Org. Lett. 2000, 2, 1243. C. Gaul, D. Seebach Org. Lett 2000, 2, 1501. M. Glos, O. Reiser Org. Lett. 2000, 2, 2045. M. T. Crimmins, K. A. Emmitte, J. D. Katz Org. Lett. 2000, 2, 2165. P. Aschwanden, D. E.; Frantz and E. M. Carreira, Org. Lett., 2000, 2, 2331. M. Groarke, M. A. McKervey, H. Miel, M. Nieuwenhuyzen Org. Lett. 2000, 2, 2393. F. M. Cordero, M. Gensini, A. Goti, and A. Brandi, Org. Lett., 2000, 2, 2475. D.-M. Shen, M. Shu, K. T. Chapman Org. Lett. 2000, 2, 2789. N.S. Barta, D.R. Sidler, K.B. Somerville, S.A. Weissman, R.D., Larsen, P.J. Reider Org. Lett. 2000, 2, 2821. V. P. Sandanayaka and Y. Yang, Org. Lett., 2000, 2, 3087. M. P. Sibi, and M. Liu, Org. Lett., 2000, 2, 3393. X. Lu, J. Warkentin Org. Lett. 2000, 2, 3501-3503. R. Shintani, M. M.-C. Lo, G. C. Fu Org. Lett. 2000, 2, 3695. M. I. Burguete, J. M. Fraile, J. I. Garcia, E. Garcia-Verdugo, S. V. Luis, J. A. Mayoral Org. Lett. 2000, 2, 3905. K.-Y. Lee, Y.-H. Kim, C.-Y. Oh, W.-H. Ham Org. Lett. 2000, 2, 4041. Md. J. Uddin, M. Kikuchi, K. Takedatsu, K.-I. Arai, T. Fujimoto, J. Motoyoshiya, A. Kakehi, R. Iriye, H. Shirai, and I. Yamamoto, Synthesis, 2000, 365. M. Thierne, E. Vieira, J. Liebscher Synthesis 2000, 2051. E. Buchalska, and J. Plenkiewicz, Synth. Commun., 2000, 30, 467 T.-H. Chuang, J.-M. Fang, C. Bolrn Synth. Commun. 2000, 30, 1627. T. N. Mitchell, A. E1-Farargy, S.-N. Moschref, E. Gourzoulidou Synlett 2000, 223. Y. Imai, S. Matsuo, W. B. Zhang, Y. Nakatsuji, I. Ikeda Synlett 2000, 239. A. Yashiro, Y. Nishida, K. Kobayashi and M. Ohno, Synlett, 2000, 361. R. C. F. Jones, J. N. Martin, and P. Smith, Synlett, 2000, 967. R. Olivera, R. SanMartin, E. Dominguez Synlett 2000, 1028. F. M. Cordero, I. Baffle, A. Brandi, S. I. Koshushkov, and A. de Meijere, Synlett, 2000, 1034. W. B. Zhang, H. Yoshinaga, Y. Irnai, T. IOda, Y. Nakatsuji, I. Ikeda Synlett 2000, 1512. I. H. Escher, A. Pfaltz Tetrahedron 2000, 56, 2879. M. B. An&us, D. Asgaff Tetrahedron 2000, 56, 5775. M. I. M. Wazeer, H. P. Perzanowski, S. I. Qureshi, M. B. A1-Murad, and Sk. A. All, Tetrahedron, 2000, 56, 7229. M. Ohba, I. Kubo, H. Ishibashi Tetrahedron 2000, 56, 7751. P. Wipf, C. P. Miller, C. M Grant Tetrahedron 2000, 56, 9143. H. A. Dondas, R. Grigg, M. Hadjisoteriou, J. Markandu, W. A. Thomas, and P. Kennewell, Tetrahedron, 2000, 56, 10087. G. W. Gribble, E. T. Pelkey, W. M. Simon, H. A. Trujillo Tetrahedron 2000, 56, 10133. Stover, A. Lutzen, P. Koll Tetrahedron: Asymmetry 2000, 11,371. R. Saul, J. Kopf, P. KeN Tetrahedron: Asymmetry 2000, 11,423. Y. Okuyama, H. Nakano, H. Hongo Tetrahedron: Asymmetry 2000, 11, 1193. F. Pisaneschi, F. M. Cordero, A. Goti, R. Paugam, J. Ollivier, A. Brandi, and J. Salaiin, Tetrahedron: Asymmetry, 2000, 11,897. S. Lee, C. W. Lira, D.C. Kim, J. K. Lee Tetrahedron: Asymmetry 2000, 11, 1455. S.-L. You, X.-L. Hou, L.-X. Dai Tetrahedron: Asymmetry 2000, 11, 1495.

F i v e - M e m b e r e d R i n g Systems: leith 0 & N Atoms

00TA1543 00TA2033 00TA3273 00TA4027 00TA4407 00TA4429 00TL815 00TL1023 00TL 1179 00TLll91 00TL 1231 00TL1265 00TL1453 00TL1583 00TL2019 00TL2137 00TL2295 00TL3131 00TL3389 00TL3941 00TL5013 00TL5069 00TL5357 00TL5891 00TL6785 00TL6897 00TL7135 00TL7551 00TL7577 00TL7635 00TL8301 00TL8621 00TL8817 00TL9239 00TL9351 00TL10071 00TL 10251

237

P. Merino, E. M. del Alamo, S. Franco, F. L. Merchan, A. Simon, and T. Tejero, Tetrahedron: Asymmetry, 2000, 11, 1543. D. O'Hagan, f. Royer, M. Tavasli Tetrahedron: Asymmetry 2000, 11, 2033. R. C. F. Jones, S. J. Hollis, J. N. Iley Tetrahedron: Asymmetry 2000, 11, 3273. G. Chelucci, G. A. Pinna, A. Saba, R. Valenti Tetrahedron: Asymmetry 2000, 11, 4027. A. Cevallos, R. Rios, A. Moyano, M. A. Peric/ts, A. Riera Tetrahedron: Asymmetry 2000, 11, 4407. G. Wang, R.I. Hollingsworth Tetrahedron: Asymmetry 2000, 11, 4429. D. J. Watson, C. M. Lawrence, A. I. Meyers Tetrahedron Lett. 2000, 41,815. R. Boulch, A. Scheurer, P. Mosset, R. W Saalfrank Tetrahedron Lett. 2000, 41, 1023. S. Cutri, M. Bonin, L. Micouin, O. Froelich, J.-C. Quirion, H.-P. Husson Tetrahedron Lett. 2000, 41, 1179. C. Matt, A. Gissot, A. Wagner and C. Mioskowski, Tetrahedron Lett., 2000, 41, 1191. J.M. Concellbn, P.L. Bemad, J. A. P&ez-Andr6s Tetrahedron Lett. 2000, 41, 1231. G. Faita, A. Paiolo, P. Quadrelli, F. Rancati, P. Seneci Tetrahedron Lett. 2000, 41, 1265. K.-S. Yang,; J.-C. Lain, C.-H. Lin and K. Chert, Tetrahedron Lett., 2000, 41, 1453. S. Cicchi, P. Ponzuoli, A. Goti, and A. Brandi, Tetrahedron Lett., 2000, 41, 1583. P. Quadrelli, G. Campari, M. Mella, P. Caramella Tetrahedron Lett. 2000, 41, 2019. B. H. Kim, Y. Jin, Y. M. Jun, R. Hart, W. Baik, B. M. Lee Tetrahedron Lett. 2000, 41, 2137. G. Shi Tetrahedron Lett. 2000, 41, 2295. H. Yamamoto, S. Watanabe, K. Kadotani, M. Hasegawa, M. Noguchi and S. Kanemasa, Tetrahedron Lett., 2000, 41, 3131. T. Nishitani, H. Shiraishi, S. Sakaguchi, Y. Ishii Tetrahedron Lett. 2000, 41, 3389. Y. Kohmura, T. Katsuki Tetrahedron Lett. 2000, 41,3941. G. Haberhauer, L. Somogyi, J. Rebek Jr. Tetrahedron Lett. 2000, 41, 5013. H.S. Oh, H.-G. Hahn, S.H. Cheon, D.-C Ha Tetrahedron Lett. 2000, 41, 5069. J. L. G. Ruano, C. G. Parades Tetrahedron Lett. 2000, 41, 5357. J. C. Lee, I.-G. Song Tetrahedron Lett. 2000, 41, 5891. S. Tanimori, M. Kirihata Tetrahedron Lett. 2000, 41, 6785. M. C. Bagley, S. L. Hind, C. J. Moody Tetrahedron Lett. 2000, 41, 6897. K. Alexander, S. Cook, C. L. Gibson Tetrahedron Lett. 2000, 41, 7135. N. K. Girdhar, and M. P. S. Ishar, Tetrahedron Lett., 2000, 41, 7551. S. P. Bew, S.D. Bull, S.G. Davies Tetrahedron Lett. 2000, 41, 7577. J. Mulzer, G. Karig, P. Pojarliev Tetrahedron Lett. 2000, 41, 7635. C. Agami, F. Couty, G. Evano Tetrahedron Lett. 2000, 41, 8301. K. Gordon, M. Bolger, N. Khan, S. Balasubramanian Tetrahedron Lett. 2000, 41, 8621. M. Curini, F. Epifanio, M. C. Marcotullio, O. Rosati, R. Ballini, G. Bosica Tetrahedron Lett. 2000, 41, 8817. P. Merino, E. M. del Alamo, M. Bona, S. Franr F. L. Merchan, T. Tejero, and O. Vieceli, Tetrahedron Lett., 2000, 41, 9239. G. Jones, D. C. D. Butler, C. J. Richards Tetrahedron Lett. 2000, 41,9351. F. Benedetti, S. Norbodo Tetrahedron Lett. 2000, 41, 10071. M. Ohba, R. Izuta, E. Shimizu Tetrahedron Lett. 2000, 41, 10251.

238

Chapter 6.1 Six-Membered Ring Systems: Pyridines and Benzo Derivatives

D. Scott Coffey, Scott A. May and Andrew M. Ratz

Chemical Process Research & Development, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN, USA email:[email protected], [email protected] [email protected]

6.1.1 INTRODUCTION The synthesis of pyridines, quinolines, isoquinolines, and piperidines has long been an area of intense interest for organic chemists. This is, in part, due to the presence of these scaffolds within the framework of numerous biologically interesting natural products. Furthermore, the pharmaceutical industry has taken its cue from nature and made these groups commonplace within structure-activity relationship (SAR) studies in the search for new medicines. The intent of this chapter is not to survey all existing methodologies for synthesis of these compounds, but rather to report the significant advances in the year 2000. The most popular strategies for the synthesis of these groups this past year include transition metal-mediated, radical, and cycloaddition reactions. 6.1.2 PYRIDINES

6.1.2.1 Preparation of Pyridines Methods for the synthesis of substituted pyridines remains an intense topic of research. One of the most popular approaches to substituted pyridines remains cycloaddition reactions. While this strategy is not new and many examples are in the current literature <00TL10251>, the state-of-the-art has been expanded. Weinreb and co-workers have reported the regioselective synthesis of pyridines (3) via intramolecular oximino malonate hetero DielsAlder reactions (1 ---, 2) <00OL4007>. Similarly, the intramolecular [4 + 2] cycloaddition of

N I~

NC I~CO2Et Ph 1

=

I CN Ph 2

N0

0s2003

N "O

A

2Et

= Ph

2Et

3

chloropyrimidine 4 affords pyridine 5 after fragmentation. This methodology was applied by Dehaen and co-workers in a recent total synthesis of cerpegin (6) <00SL625>. Dfaz-Ortiz recently expanded the scope of microwave mediated [4+2] reactions between pyrazolylimines

239

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

and nitroalkenes <00T1569>. Additionally, Hart and co-workers report dipolar cycloaddition reactions to form tetrahydropyridine moieties <00SC3203>.

MeO

O~

O

MeO

CI

=

O

N~

N~/N 4

O

O

=

5

6

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloroN,N-dimethyl-aminotrimethinium hexafluorophosphate afforded 8 in 97% yield <00JOC8415>. Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. CI

H2N/-=(k_=-O Pa~

~ 0.,~,..,, ~

7

SO2Me

path b

pat

/

MsOH72% " ~ 1. LiHMDS CI Cl~-O 2. NH4OAc 58%

O2Me (31 ~"

/:

2. i CI I .N ~.1~ i~ pFS~ 6 3. AcOH, TFA 4. NH4OH, 97% ," Scheme 1

Novel transition metal-mediated strategies were also well represented this past year. Takahashi and co-workers reported a ~,.nickel-catalyzed reaction between azaziconacyclopentadienes (9) and alkynes to form pyridines (10) of varying substitution patterns <00JA4994>. This methodology, a formal cyclotrimerization, is also noteworthy since two different alkynes can be used. In similar fashion, Eaton reported an aqueous, cobalt(II) catalyzed cyclotrimerization between two identical acetylenes and one nitrile to afford substituted pyridines <00OL3131>.

240

D.S. Coffey, S,4. May and A.M. Ratz

Et CP2ZrEt2 Et + =.

Et ZrCp2

M

MeCN

Pr ~ Pr EtEe~~j~ Pr NiCl2(PPh3)2 Pr

M

66% 9

10

A popular approach to pyridine and dihydropyridine formation continues to be formation of azadienes via condensation followed by 6~t electrocyclization <00T6319>. A microwavemediated condensation/electrocyclization reaction was also reported by Boruah and coworkers <00TL3493>. Novel methods for 1-azadiene formation include the reaction of 4nitro-l-(2-phenethylamino)-l,3-butadiene (11) with aldehydes to form azadiene 12, which cyclizes to dihydropyridine 13 <00CPB436> (Scheme 2). Benzo[b]thieno[3,2-b]pyridines have also been synthesized via reaction between iminophosphoranes and aldehydes <00T1517>. Pyridine formation resulting from solvent-free aldol and Michael reactions have also been reported <00CC2199>. Pyridines (16) have also been accessed via electrocyclization of 3-azadienes. Clerici and co-workers have recently reported the formation of pyridines via 3-azadienes obtained through conjugate addition reactions between 14 and propiolate ester derivatives <00T4817>.

P

NTH

+

;

NO2

NO2

11

12

MeO. OMe MeO~

NO2

NEt2

CO2Me CO2Me

13

MeO .OMe Et2NI ~ ~

A

= MeO2C'~N ~ O M e CO2Me

14

C02Me MeO"~.. CO2Me Meo~N2

15

16

Scheme 2

Smith and co-workers have recently expanded the scope of the [4+1] radical annulation reaction between isonitriles and 1-iodoalkynes to include vinylisonitriles <00JCS(P1)641>. Thus, vinylisonitrile 17 and iodide 18 afford annulated pyridine 19.

Ph

19

17 18 The oxidation of Hantzsch 1,4-dihydropyridines has been a long standing method for preparation of pyridines. The development of mild oxidants that do not affect other functional groups about the ring has been a specific point of interest. Yadav and co-workers

241

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

report oxidation of Hantzsch 1,4-dihydropyridines with iodine in methanol <00S1532>. Yadav found that the addition of base dramatically accelerates the reaction. For example, the addition of potassium hydroxide generally results in complete oxidation within 30 minutes while control reactions run in absence of base require 5-10 hours. Likewise, Zolfigol and coworkers report heterogeneous conditions [Mg(HSO4)2, NaNO2, wet SiO2] for mild, costeffective oxidation of dihydropyridines <00SC3919>. A detailed mechanistic study on the oxidation of Hantzsch 1,4-dihydropyridines was also reported <00JOC3853>.

6.1.2.2 Reactions of Pyridines The use of transition metals across all areas of organic chemistry has become commonplace and reactions involving pyridines, in particular, have been extensive. The synthesis of organometallics of pyridines via metallation was recently reviewed <00JHC615>. Metal-mediated intermolecular coupling reactions remain a popular method for both C-C <00NJC425, 00TL1653> as well as C-N bond formation <00TL2875>. Murai reported a ruthenium catalyzed [2+2+1] coupling of pyridyl imines (20) as a novel route to functionalized ),-butyrolactones (21) <00S925>.

Q

Ru3(CO)I 2 (2.5mol%) ethylene (2 atm)

20

NAr

Ar = p-MeOCsH4

A~rN

CO (5 atm) toluene,160~ 20h 97%

21

O

An alternative to the typical lithiation-based <00JCS(P1)1983> preparation of enantiopure 2-(hydroxyalkyl)pyridines has been reported via non-BINAP reduction of pyridyl ketones <00TL9277>. Thus catalyst 24 effectively promotes the enantioselective reduction of pyridyl ketone 22 to provide 23 in excellent yield and e.e.. Other metalmediated work includes dehalogenation of monohalopyridines by metallocene reagents <00BKCS211>. The use of chromium and tungsten pyridinium ylides as reagents for cyclopropanation and cascade multi-insertions of olefins, alkynes and carbon monoxide has also been detailed <00T5001>.

Q

2,

O 22

HCOOH,Et3N 97%yield 95% e.e.

o %U.c,

OH 23

[

..

24

An interesting double nucleophilic addition reaction was recently reported by Zhang <00TL3025>. This reaction sequence effects both C-C and C-N bond formation allowing for preparation of substituted pyridyl hydrazines 25. Another example of C-N bond formation was published by Kotsuki who reported a high-pressure-promoted reaction between various amines and 4-chloropyridine <00SLll6>. The ring transformation of pyridines by Cnucleophiles has also been recently reviewed <00H1607>.

242

D.S. Coffey, S~A. May and A.M. Ratz

+

0

1

1 tBuO/[L'-N'-'N~1],,-OtBu 9 O =-

= Li

N

"NH2

2. TFA

25

Workers at Pfizer report a total synthesis of (_)-cytisine via the intramolecular cyclization of 2-methoxypyridine 26 <00OIA201>. H

A 2 "s

1. Toluene,A y

Bn

NN4OAc, NeON

26

27

Lithiation of pyridines and reaction with various electrophiles has been a common transformation this past year. Fort and co-workers report an unusual lithiation of 2chloropyridines with BuLi-Me2N(CH2)2OLi. This unique "superbase" promotes regioselective lithiation at C-6 without effecting reaction with chlorine <00OL803>. In contrast to this work, the reaction of 3-chloropyridines with strong base is known to provide highly reactive pyridynes (29). Hegarty reports an efficient cycloaddition reaction between 2-substituted 3,4-pyridynes (28 ---, 30) with various dienophiles <00JCS(P1)1245>. The substitution at the 2-position with an electron donating group is critical for efficient reaction.

~ 28

Cl OEt

tBuLi I ~

flJran

OEt 29

71%

~ E t 30

Photochemistry has also been a prominent theme this past year. Intermolecular photocyclization reactions involving pyridones have been reported <00JOC1972>. An unusual photocyclization between 1-cyanonaphthalene and substituted pyridines was also reported <00JA8141>. In similar fashion the reaction between benzofurans and substituted pyridines was reported by Sakamoto <00CC1201>. 6.1.2.3 Pyridine N-Oxides and Pyridinium Salts

The preparation of pyridine N-oxides has been reported from oxidation of the corresponding pyridines via molecular sieve catalysis <00CC1577> and trifluoroacetic acid in combination with hydrogen peroxide-urea complex <00TL2299>. Several methods for deoxygenation of pyridine N-oxides to form pyridines have also been reported. Indium metal under neutral aqueous conditions <00TL2663>, lithium chloride/sodium borohydride <00SC3511>, alkanesulfonyl chlorides <00H1471>, and oxygen transfer to triphenylphosphine catalyzed by rhenium <00OL3525> have all been reported this past year as effective reducing protocols. Finally, the reaction of pyridine N-oxides (31) with the

243

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

Tebbe reagent to form 2-methyl pyridine products (32) has recently been reported by Nicolaou <00AG(E)2529>.

Ph

Ph CP2Ti=CH2 ~.

O

83%

31.

32

The direct preparation of pyridinium salts (35) from acyclic starting materials 33 and 34 was reported by Adamczyk and co-workers <00TA2289>. Pyridinium salts have also been used to form other heterocyclic ring systems such as imidazolo[1,2-a]pyridines as reported by Katritzky <00JOC9201>. A final report worthy of comment is the preparation of chiral 2,6disubstituted tetrahydropyridines via chiral pyridinium salts <00EJOC1391>.

~NH 2 OH 33

1) K2CO3, MeCN,Air

=

2) TFA 42%

N(BOC)2 tBuO2C~~]~'~ O 34

_NH2 ~CO2H

NH2

H O e C ~

OH

Br

OH

35

6.1.3 QUINOLINES

6.1.3.1 Preparation of Quinolines Methods utilizing organometallic reagents continue to be used to prepare quinoline derivatives. An efficient method for the preparation of 2(1H)-quinolinones from alkynalides using 1-3 mol% Pd(OAc)2 and trifluoroacetic acid at room temperature was reported <00SCI1992, 00JOC7516>. Palladium(0)-catalyzed carbonylation of o-iodoanilines followed by allene insertion and nucleophilic capture of the resulting :t-allyl palladium(II) species afforded 3-methylene quinolones in good yields. Subsequent nucleophilic addition and stereoselective reduction, prior to isolation, afforded ~,-aminoalcohols 38 in moderate yields <00TL7125>. An interesting domino reaction provided disubstituted quinolines directly via rhodium-catalyzed amination of styrenes with anilines <00CEJ2513>. Furthermore, 2,3-dialkyl substituted quinolines were prepared by a ruthenium-catalyzed reaction between anilines and trialkylamines <00CC1885>. The vapor phase synthesis of quinoline from aniline and glycerol over mixed oxide catalysts was also reported <00JMCA289>.

[~i

pd(PPh3)4, O K2CO3,D.{ ~ HTs CO, allene

36

37

Ts

OH

1)HNR2 ~ [ ~

'""N .R2

2) LiAIH4 38

Ts

244

D.S. Coffey, S.4. May and A.M. Ratz

A variety of approaches to quinoline derivatives utilized cycloaddition reactions. Nmethyleneamine equivalents were generated by treating 1,3,5-triphenylhexahydro-l,3,5triazines with various Lewis acids and used in cycloaddition reactions with 1,2bistrimethylsiloxycyclobutene to afford tetrahydroquinoline derivatives <00JOC8384>. Aldimines derived from anilines and aromatic aldehydes were also shown to undergo cycloaddition reactions with allyl silane in the presence of a Lewis acid to afford cis-2,4tetrahydroquinolines <00H529>. Benzotriazole was shown to promote the condensation of two molecules of anilines and two molecules of phenylacetaldehyde to afford 1,2,3,4tetrahydroquinolines stereoselectively. Furthermore, benzotriazoles 39, derived from anilines and (R)-glyceraldehyde, were shown to disassociate in the presence SmI2 and undergo cycloaddition reactions to afford optically active tetrahydroquinolines 40 (Scheme 3) <00JOC3148>. Intramolecular Diels-Alder reaction of N-arylimine 41 afforded dihydroquinoline derivative 42 as a single diastereomer (Scheme 3) <00TL5715>. In a similar fashion, treatment of the hydrochloride salt of dimethylaniline with formaldehyde and cyclopentadiene also afforded an angularly substituted dihydroquinoline derivative as a single diastereomer <00SL209>. Bismuth (III) chloride and triflate were shown to be excellent catalysts for hetero Diels-Alder reactions between aromatic imines and the appropriate dienophiles to prepare tetrahydroquinoline derivatives <00SLll60>. A convenient preparation of (2/4)-quinolinones via an electrocyclization reaction of o-isocyanatostyrenes prepared by MCPBA oxidation of the corresponding o-isocyanostyrenes was also reported <00CL798>. Several quinoline derivatives were also prepared by the reaction of aryl isocyanates with N-acylbenzotriazoles <00JOC8690>.

Sml2= R1

R

R2 38

40

tBu tBu .Si

Bu

TfOH

tBu ~BuI~ ;

80%

Bd

42, R = Hex

t

41, R = Hex Scheme 3

Nitroaromatic compounds are often used as starting materials for the synthesis of quinoline derivatives. Acrylates 43 were reported to undergo a tandem reduction-Michael addition affording tetrahydroquinolines 44 (Scheme 4) <00JOC2847>. Baylis-Hillman adducts of o-nitrobenzaldehydes 45 react with trifluoroacetic acid to afford 3ethoxycarbonyl-4-hydroxyquinoline N-oxides 46 <00OL343>. Furthermore, carbohydrate nitro enones react with anilines to give N,O-acetals. Subsequent treatment with benzaldehyde produces dihydroquinones which can be oxidized to the corresponding quinoline derivatives <00JCS(P1)753>.

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

~"~"'1 ~------~ 115 ~ NO2 (~OzEt

O2Et

43, R = H or Me

OH

~

Xn NO"

245

44, R = H or Me

OH ~/CO2Et

CO2Et CF3CO2H

~

Xn

45

46 (~ -

Scheme 4

Anilines and substituted anilines have long been used as building blocks for the construction of the quinoline scaffold. An improved version of the Doebner-Miller synthesis of quinoline derivatives utilizing a two-phase solvent system was reported <00TL8523>. A one-pot synthesis of quinolines from anilines and alkyl vinyl ketones on the surface of silica gel in the presence of indium chloride under microwave irradiation was also reported <00TL531>. Cyclocondensation of 2-amino thiophenol 47 with chiral acetylenic ketone 48 afforded benzo[b][1,4]thiazepine derivatives 49. Subsequent sulfur extrusion afforded enantiomerically pure 2,4-disubstituted quinolines 5t) <00SL595>. Free radical cyclizations of alkylsulfonyl anilides were also utilized for the preparation of quinolinone derivatives <00T6209>. In addition, tetrahydroquinoline derivatives were prepared by the diastereoselective addition of a-aminoalkyl radicals to (5R)-5-mentholoxy-2-[5H]-furanone <00JOC8690>. The alkaloid toddaquinoline was prepared by a cobalt mediated radical addition to a pyridine derivative <00TL6681>.

,,,NBoc

47

49 48

o

R 50

Rearrangement reactions provide yet another entry into the quinoline ring system. Tetrahydroquinoline was prepared in good yield via reduction of 1-indanone O-TBS oxime with borane-THF <00TL6567>. Quinoline derivatives were also prepared by the treatment of pyrrolo and pyrido[2,1-c][1,4]benzodiazepines with POC13 <00T1361>. The intramolecular Schmidt reaction of azides and carbocations was used to prepare benzo-fused indolizidines. A formal synthesis of gephyrotoxin was accomplished by treatment of alkyl azide 51 with TfOH followed by reduction of the resultant iminium ions to afford Schmidt reaction products which were converted, without purification, to the desired benzo-fused indolizidine 52 in 45% yield and its regioisomer 53 in 10% yield. Several other examples of this intramolecular Schmidt reaction, along with a mechanistic discussion, were also reported <00JOC7158>.

246

D.S. Coffey, S,4. May and A.M. Ratz OMe

1) TfOH

B ~ N 3 Br

OMe

OMe

2) L-Selectride 3) Bu4NOAc ~ 4) LiAIH4

51

,,H +

N

52 45%

53 10%

6.1.3.2 Reactions of Quinolines Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and 1-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained <00OL433>. Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. X

TMSCN/RCOCI

X "

y

'"CN

Y

(67-91% ee) 55

,54 I-CI

Z = P(O)(o-tol)2

Quinoline derivatives often serve as building blocks for the synthesis of more elaborate substrates. Highly enantioselective, intramolecular [2 + 2] photocycloadditions of substituted 2-quinolones in the presence of a chiral host compound were reported <00AG(E)2302>. The first enantioselective synthesis of the pyrroloquinolone 58, representing the heterocyclic core of the martinellines, was achieved by condensation of quinolone with R-(-)-phenylglycinol and further elaboration <00OL1395>. The 3-aza-Grob fragmentation of tetrahydrofuranyl and tetrahydrothienyl protected 3,4-dihydro-2(1H)quinolinones using hydride reagents was also described <00JOC4208>.

o 9o .

56

.~

P.

HO.,,~NH2

Ph ,,H

0

"

77% (single isomer)

> 57

~,

58

H

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

247

The reactivity of quinoline derivatives was also examined. Trifluoroacetylation of the pyridine ring of quinolines was reported. Treatment of 4-dimethylaminoquinoline with 1trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate afforded 3-trifluoracetyl-4dimethylaminoquinoline, which was shown to undergo nucleophilic N-N exchange reactions with various amines <00CL50>. Quinolincarboxaldehydes were shown to undergo condensation reactions with arenes in the presence of triflic acid <00S1117>. Regioselective lithiation of 5-(t-Boc)-7-methoxy-l,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline at C6 was accomplished with s-BuLi (3.0 equiv.) in the presence of water (1.0 equiv). Under conventional conditions, the quinoline derivative was not regioselectively lithiated <00TL5225>. A novel and efficient synthesis of 2,3-dichloroquinoline was also reported <00SC427>. 6.1.4

ISOQUINOLINES

6.1.4.1 Preparation of Isoquinolines The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with LiAlH4/Me3Al afforded the trans-l,3 derivative, and

H Me~N.._s.-p-Tolyl M e O ~ , ~ ~ (3 1) MeLi MeO~ " ~ "ON MeO 59

2) HCI LIAIH4/Me3AI~ (93%) >95%ee~/

MeO\~NHMe

/

Me

L~-i-/~ N MeO Me 60

NaBH4 (91%) >95%ee MeO~~HMe MeO Me

MeO Me

62

61

Scheme 5 reduction with NaBH4 afforded the cis 1,3 derivative <00OL3901>. An enantioselective synthesis of isoquinolines using the Pomeranz-Fritsch-Bobbitt methodology, by the enantioselective addition of MeLi to imines in the presence of chiral oxazoline ligands, was reported <00TA2359>. Additionally, a highly efficient asymmetric addition of MeLi to an N-naphthalenylimine in the presence of a chiral ligand followed by cyclization and removal of the N-naphthalenyl group resulted in a facile asymmetric synthesis of (+)-salsolidine. This methodology provided higher enantioselectivities than previously reported methods describing organolithium additions to N-p-methoxyphenyl imines <00TL5533>. All four possible stereoisomers of 1,3-dimethyl-l,2,3,4-tetrahydroisoquinoline were also prepared in enantiomerically pure form utilizing a Pummerer reaction as a key step <00CPB91>.

D.S. Coffey, S,4. May and A.M. Ratz

248

The use of organometallic reagents in the synthesis of isoquinoline derivatives continues to be explored. Isoquinoline 64 was prepared in moderate yield from aryl iodide 63 and benzaldehyde using a termolecular Pd-In queuing process <00CC933>. Tetrahydroisoquinoline-3-carboxylic acid derivatives 66 were prepared by a [2+2+2] cycloaddition reaction in the presence of Rh and Co catalysts <00BMCL1413> (Scheme 5). The intramolecular Heck reaction of aryl iodides and Z-allylsilanes in the presence of chiral ligands was utilized in the enantioselective preparation of 4-substituted tetrahydroisoquinolines <00CC583>. The palladium-catalyzed coupling of 2-(1-hexynyl)benzonitrile with aryl iodides gave substituted isoquinolines <00TL1215>. Hydrogenation of Cl-substituted 1,2-dihydroisoquinolines using a chiral Rh catalyst gave Cl-substituted tetrahydroisoquinolines in >97% ee <00EJC2247>.

OH 1 ~ O

N\

Ph

1) Pd(0) 2) allene 9 3) PhCHO,In

63 64

R II

R

+ ~%-'/~ fCO2Et (Ph3P)3RhCI= R ~NTs 65

or CpCo(CO)2

O ~

CO2Et

RAL'%~'-.../NTs 66

Scheme 6

Strategies for the preparation of isoquinoline derivatives utilizing cyclization reactions were explored. Cyclization of the ~t-bond onto the thio-N-acyliminium ion formed by treatment of thioamide 67 with bromoacetyl chloride afforded N,S-ketal 68, which was converted to the corresponding tetrahydroisoquinoline derivative by treatment with Raney Ni <00JOC2684>. Similarly, thionium ion promoted Mannich cyclization of amide 69 by treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) provided tetrahydroisoquinoline 70 in 99% yield <00JOC235> (Scheme 7). A stereo- and regiocontrolled aryl enamide photocycloaddition reaction was used to prepare a tetrahydroisoquinolinone derivative used in a total synthesis of (+)-pancratistatin <00JA6624>. Tetrahydroisoquinoline derived enamines were prepared by a cyclization reaction of the corresponding polarized N,S-ketene acetals <00SL653>. Diastereodivergent approaches to thiazolo[4,3-a]isoquinoline systems were reported. The 1,10b-cis derivatives were prepared by an acyliminium cyclization reaction while the 1,10b-trans derivatives were prepared by a tandem Parham cyclization-hydroxyl reduction protocol <00SL101>. A tandem Pummererht-aromatic cyclization of an ot-acyliminium ion for the preparation of a thioepoxyareno-bridged isoindoloisoquinolinone was also reported <00OL1201>.

Six-Membered Ring Systems: Pyridines and Benzo Derivatives M e O ~

BrCH2COC/ MeO 98%

MeO

N

67 ' Me/

OMe

SMe

DMTSF

"v~'~~ 0

69

O

68

SMe

~ N

249

OMe

~ O M e

99%"

~ O M e

/N..~J 0

70

Scheme 7

Diels-Alder reactions were utilized to prepare isoquinoline derivatives. Various tetrahydroisoquinoline-3-carboxylic acid derivatives were prepared by an enyne metathesis followed by a Diels-Alder reaction. For example the enyne 71 was treated with Grubb's catalyst to afford diene 72 in 65% yield. Subsequent Diels-Alder reaction and oxidation gave tetrahydroisoquinoline 73 in 93% yield <00CC503>. Dihydrosoquinoline 75 was prepared

. co2EtGru00,s.. TMS/

~ , ~ ' v "NTs 71

.co2Et -- R R

catalyst ~-..~..~L.,.~NTs 72

-

R

OO2Et

~' z ~ ~ v . . N T s 73 R = C02Me

OTBS v 76

-.~ "Ph OTBS

OTBS 2) PhSO2N=CHPh 68%

74

TBS 2) T s ~ N 73%

75

Ts OTBS

Scheme 8

by a Diels-Alder reaction between benzocyclobutane 74, via a 1,2-quinone dimethide, and toluenesulfonyl cyanide. Similarly, tetrahydroisoquionline 76 was prepared by a Diels-Alder reaction between 74 and N-benzylidenephenylsulfonamide <00AG(E)1937>. In another example, the Diels-Alder reaction of a hetero homophthalic anhydride with an ct-sulfinylsubstituted enone was reported. The sulfinyl group promoted the cycloaddition and undergoes an in-situ elimination to afford an isoquinoline derivative which was a key intermediate in the asymmetric total synthesis of fredericamycin A <00JOC89>. Anhydrolycorinone, an isoquinoline containing natural product, was also prepared by sequential inverse electron demand Diels-Alder reactions of an unsymmetrical N-acyl-6amino-l,2,4,5-tetrazine <00JOC9120>. A regioselective route to benzo[g]isoquinolines via hetero-Diels-Alder reactions of benzoquinones and a nitrogen-containing diene was also reported <00T5147>.

250

D.S. Coffey, SA. May and A.M. Ratz

6.1.4.2 Reactions of Isoquinolines The reactions of 3,4-dihydroisoquinoline N-oxides (cyclic nitrones) were investigated. The catalytic asymmetric addition of dialkylzinc to the C-N double bonds of 3,4dihydroisoquinoline N-oxides using a catalytic amount of the 2-magnesium 3-zinc salt of dicyclopentyl (R,R)-tartrate afforded 1-alkyl-2-hydroxytetrahydroisoquinolines with moderate to high enantioselectivities. For example, treatment of 77 with Et2Zn in the presence of the 2-magnesium 3-zinc salt of dicyclopentyl (R,R)-tartrate afforded 78 in 93% yield and 94% ee <00BCJ447> (Scheme 9). A similar tartrate auxiliary was utilized in the asymmetric addition of a Reformatsky-type reagent derived from Et2Zn and an iodoacetic acid ester to 3,4-dihydroisoquinoline N-oxides affording 1-alkyl-2-hydroxytetrahydroisoquinolines in up to 86% ee <00TA733>. Furthermore, the addition of the lithium carbanion of a chiral sulfoxide to 3,4-dihydroisoquinoline N-oxide derivatives afforded 1alkyl-2-hydroxytetrahydroisoquinolines with high diastereoselectivities <00PSS(161)181>. In addition the reduction of a homochiral 15-sulfinyl nitrone tetrahydroisoquinoline derivative afforded 1-substituted tetrahydroisoquinoline derivatives with high diasteroselectivities <00H557>. Cyclic nitrones also participate in 1,3-dipolar cycloaddition reactions with electron rich alkenes. A highly diastereo-and enantioselective 1,3-dipolar cycloaddition reaction of nitrone 79 with vinyl ethers in the presence of chiral Lewis Acids (3,3'-aryl BinolA1Me complexes) was reported. The exo isomer 80 was obtained with >90% de and up to 85% ee <00JOC9080>.

M e O w +

Et2Zn

Meo~N,o

M e O ~

- CpenO2C~CO2open -" MeO/~JL-,,I/N,oH

77

BrMgO

OZnMe

78 Et

9 3 % yield 9 4 % ee

OR +

"079

~.

+

Cat. 80, (exo)

z

bR

- "(3 :-.____/ z

81, (endo) bR

Scheme 9 Isoquinoline derivatives are often further elaborated by various cyclization reactions. A variety of alkoxy-substituted indolo[2,1-a]isoquinolines 83 were prepared by treatment of 1(2'-bromobenzyl)-3,4-dihydroisoquinolines 82 with K2CO3 in boiling DMF <00OL1799> (Scheme 10). Interestingly, when 1-(2'-bromobenzyl)-3,4-dihydroisoquinolines were treated with n-Bu3SnH and AIBN, mixtures of aporphines and alkoxy-substituted indolo[2,1-a] isoquinolines were obtained from the radical cyclization <00OL307>. The intramolecular radical addition to the 3-position of a 2-isoquinolinone derivative was also reported <00OL2535>. In addition the radical translocation/cyclization reactions of 1-alkynyl-2-(oiodobenzoyl) tetrahydroisoquinolines were examined <00H571>. Additionally, the 3-azaCope rearrangement reactions of benzo[a]quinolizine and pyrrolo[2,1-a]isoquinoline derivatives were examined. The rearrangements proceeded with 90-98% stereospecificity. For example, benzo[a]quinolizine 84 underwent a [3,3] rearrangement to afford 85 with >98% stereospecificity. Subsequent reduction gave 86 as a single isomer <00JOC4938>.

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

MeO~

K2CO3,DMF

BnO~

N Br

['82

231

MeO

reflux -"

' ~ R

1

82-83%yield

R2 Ph rt

NaBH 4

S c h e m e 10

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H20 and NHaC1 afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee <00OL2185>. The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>.

Ph ~ O o H 87

Ph

Ph H 1)n-BuLi~ O o H

Ph H = ~ N

NH4CI 88, 97%dePh

89, >97% ee

"]N 1)n-BuLi,TMEDA ~ N "~tBu 2' .,~ L 90 Me 0

Ph

N

H

Ph

91

92,

"~T/tBu

Me 0

(90-95%)

83-86% ee

S c h e m e 11

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at C1 of the intermediate 2tosylaminoacylisoquinolinium salt <00TL5479>.

252

6.1.5

D.S. Coffey, S,4. May and A.M. Ratz

PIPERIDINES

6.1.5.1 Preparation of Piperidines A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiralpool, chiral auxiliaries, and catalytic asymmetric methodology. The ring-closing metathesis reaction (RCM) continues to evolve as a major tool for the preparation of substituted piperidines in synthetic strategies for natural products <00OL1847, 00CPB1593, 00CC1027, 00TL4113> and conformationally restricted amino acids (analogues of pipecolic acid) <00JOC1222, 00SL1031, 00CC699>. An interesting double RCM reaction involving amino acid derived tetraene 93 provided spirocyclic piperidine 94 in good yield and high diastereoselectivity <00TL2027>. A tandem RCM and ring-opening metathesis of 95 gave 96 in excellent yield <00S893>. This methodology was also showcased in the synthesis of indolizidine and quinolizidine alkaloids <00OL3971, 00CC1501>.

~N,~~,,/RO/,,,,,,~

RuCI2(PCy3)2=CHPh74-87% D,

/

O~ /

"i's

R = Me, iPr, iBu, CH2Ph

93

is

94

OAc OAc

RuCI2(PCY3)2=CHPh

.~,...~ N~Ts CO2Me 95

95%

MeO2C~'~, N . , " L v ' L ~ / Ts

96 Scheme 12

The hetero Diels-Alder reaction has long been recognized as a method of choice for the synthesis of substituted dihydropiperidines <00SL242>. Chiral imines derived from tartaric acid were shown to react with Danishefsky's diene in the presence of Lewis acids to provide 2,3-dihydropiperidin-4-ones in excellent yield and selectivity <00H137>. Reactions of 1amino-3-siloxy-l,3-butadiene with activated and unactivated imines were shown to procede under mild thermal conditions without the need for Lewis acid catalysis <00OL3321>. A novel multicomponent reaction featuring a tandem aza [4+2]/allylboration process was achieved by reaction of hydrazonodiene 97 with N-phenylmaleimide and benzaldehyde to produce piperidine derivative 98 in good yield and high diastereoselectivity <00OL3715>. An aqueous intramolecular Diels-Alder reaction featuring acylnitroso derivative 99 was reported as the key step in the enantioselective total synthesis of lepadin B (Scheme 13) <00OL2955>. Intra- and intermolecular 1,3-dipolar cycloadditions of nitrones and alkenes to provide substituted piperidines in moderate to good yields were also reported <00SL1034, 00OL2475>.

253

Six-Membered Ring Systems: Pyridines and Benzo Derivatives Me

Me

Me-~Me O'B'O

O

0 + PhCHO

I

Me

0

_N J....Me ~~~"OMe

Tol, 80 ~

Ph

55 % " > 95%de

T..

"~O

OH ~__~C(Me)2OM e 98

97

BnO.y.....-.~

OMOM

OBn O

99

H

nPr4NIO4

N..OH

H20/DMF

,.

90 %

i

i

i

i

'~_~1~N.~L~d ,

= r_ LepadinB

O

~.jOMOM 100

Scheme 13 Intramolecular allylmetal cyclization reactions have been explored for the synthesis of substituted piperidines. For example, addition of an allylsilane to an iminium ion derived from (S)-phenylglycinol and glyoxal provided efficient access to a variey of enantiomerically pure pipecolic acid derivatives <00JOC4435>. Hydroformylation of an allyl substitutedaminoallylboronate 101 provided good yield of 102 and 103 <00HI21>. Additionally, the utility of the intramolecular Mannich reaction has been utilized in the synthesis of a variety of piperidine alkaloids <00JCS(P1)353, 00TA2221, 00TL9797> and polyhydroxylated piperidines <00JOC7208>.

A,~B~O Cbz 101

Me

~~Me M~ Me

H2/CO

,,

Rh(CO)2acac BIPHEPHOS 66 %

_ (~bz

HO (~bz

102

103

Radical cyclizations have become popular methodologies for the preparation of piperidines. Photoinduced electron transfer (PET) generated ct-trimethylsilylmethyl amine radical cation cyclization onto an internal alkyne provided a new route to isofogamine <00TL8821>. Reductive photocyclization of dienamides allowed efficient access to 2substituted piperidines such as (S)-pipecoline and (S)- and (R)-coniine <00TL8769>. Similarly, a variety of metal mediated radical processes for the synthesis of polysubstituted piperidines appeared including SmI2 <00JCS(P2)1375>, Mn(III) <00JOC7257>, and Cu(I) <00S1561, 00JCS(P1)671>. Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1deoxymannojirimycin <00OL2427>. A new synthetic entry into the 2azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields <00OL2225>. A palladium catalyzed decarboxylative carbonylation of 5-vinyl

D.S. Coffey, S,4. May and A.M. Ratz

254

oxazolidinones 104, prepared in two steps from protected ct-aminoaldehydes and ketones, was reported as a new route to 3,6-dihydro-lH-pyridin-2-ones 105 <00JA2944>. Ruthenium has been exploited as a catalyst for the cycloisomerization of 1,7-enynes to provide good yields of 3,4-disubstituted piperidines <00JA714> and as a catalyst for carbonylative [5+1] cycloadditions of cyclopropyl imines to provide ?,a-unsaturated piperidones. 0

0

HN"JJ~'O

Pd(Ph3P)2(OAc)2

Ht~

CO, EtOH

R1~''"

R2 104

R2 105 57-87%

R1 = iPr, Bn, Ph R2 = H, Me

6.1.5.2 Reactions of Piperidines Alkylations of N-acyliminium ions continue to be reported as powerful methods for the construction of C-2 substituted piperidines. Stereoselective alkylation of the iminium ion derived from lactam 106 with racemic 3-trimethylsilyl-l-decene gave rise to a 6 : 1 mixture of olefins 108 and 109. Both olefin isomers are derived from an axial alkylation pathway. Simple reduction of the lactam carbonyls provided the first total synthesis of piclavine A1 and A2 <00TL5411, 00TL275>. Likewise, addition of propargyl trimethylsilane <00TL5307> and alkyl Grignard reagents <00TL6167> to other bicyclic acyliminium ions provided excellent yields and high selectivities of the C-2 addition products. An interesting methodology was studied for the formation of the N-acyliminium ion derived from pipecolic acid via a one-pot radical decarboxylation-oxidation sequence <00TL2899>.

SiMe3 MeOX.,.L..v.J 106

+

C7H15 107

C7H15~ x , , , . L , . , v ~ TiCI4 108 ,. CH2CI2 + 60%,6"10

1~-~

C7H15

LiAIH4 ,. Piclavine A1 and A 2 73 %

H

109

Scandium triflate was demonstrated as an efficient catalyst for the addition of silylenolates to 2,3-diaryloxypiperidines <00SL989>. This methodology was highlighted as a potential route to fibrifungine derivatives. Enantioselective reduction of tetrahydropyridine 111 with (S)-BINAP-RuCI2 provided (S)-N-Boc-pipecolic acid 112 in 95 % yield and 96 % ee <00OL155>. Approaches to a variety of 2-substituted and 2,6-disubstituted piperidines including (-)-coniine, (-)-solenopsin A, and (-)-dihydropinidine from diastereoselective lithiation-substitution reactions were also outlined.

255

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

~

OMe

1. s-BuLi

~

2. CO2 80 %

130c 110

(S)-BINAP-RuCI2 Boc 111

CO2H

H2, MeOH

CO2H

Boc 112

95 %

Diastereoselective synthesis of 2-aryl-3-aminoazepanes has been achieved via a novel ring enlargement process (Scheme 14) <00TLl179>. Conversely, treatment of 3methoxypiperidines with BBr3 facilitated formation of an intermediate bicyclic aziridinium ion which is opened regioselectively with bromide ion to give ring contracted products <00TL2507>. Tetrahydropyridinium bromides also give ring contracted products upon treatment with base via a [3+2] sigmatropic rearrangement <00SL1208>. An unusual DASTmediated rearrangement was reported involving piperidine-substituted indole derivative 116 providing 117 in near quantitative yield <00JOC4984>.

P~ ~O N(1~,C4kJN\,~

PhLi ~

N.~-Ph ph~N/L L ~ 114

113

H Ph. N LiAIH4 ,.~ 91% ,,. RHN~' 115

Cbz

~__N,ebz

HO\,' ~ N ph

DAST

F

99 %

~ ~ N

H

ph

H

116

117

Scheme 14

The use of dihydropyridones as dienophiles in intermolecular Diels-Alder reactions to provide partially reduced isoquinolines continue to be studied <00T4027>. Reaction of 118 with a mixture of dienes 119 provided the spirocyclic lactam 120 in > 19 : 1 selectivity, an advanced intermediate for the synthesis of (-)-gymnodimine <00OL763>. The observed selectivity suggests that a formal Diels-Alder reaction proceeding through a stepwise double Michael reaction is operating. Piperidone enol ethers have also been shown to undergo Lewis acid directed cyclocondensation reactions with 2-methoxy-4-(N-sulfonyl)-l,4benzoquinoneimine to provide oxygenated carbolines regioselectively <00JOC2444>. 0

Ts"N~ 118

OTBS Me~~

119

Me

Et2AICI

Ts,, =

N

0

~

III

I Me 120

OTBS Me

256

D.S. Coffey, S,4. M a y a n d A.M. R a t z

Single electron transfer photoinduced oxidation of N-arylaminopiperidines 121 in the presence of T M S C N and catalytic methylene blue (MB) have been shown to yield the C2cyanosubstituted piperidine 122 <00JCS(P2)l147>. Continued photooxidation in the presence of water provided the lactams in good yield. Alternatively, conducting the initial photooxidation in the presence of alcohols or water provided ring opened products in moderate to good yield <00T2975>.

R.CL

h .O2. MB 121

N'N"'JJTMSCN, MeCI~ H 96 %

hv, 02, MB H20, MeCN 81%

h .O2. MB R 122

N" H CN

H20, MeCI~I 75 %

N" 123

O

~N'-'N~cHO 124

6.1.6

REFERENCES

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S i x - M e m b e r e d R i n g Systems: Pyridines and Benzo Derivatives

00CPB436 00CPB1593 00EJC1391 00EJC2247 00H121 00H137 00H529 00H557 00H571 00H1471 00H1607 00JA714 00JA2944 00JA4994 00JA6327 00JA6624 00JA8141 OOJCS(P1)353 OOJCS(P1)641 OOJCS(P1)671 OOJCS(P1)753 OOJCS(P1)1245 OOJCS(P1)1893 OOJCS(P1)2898 OOJCS(P2)1375 00JCS(P2)1147 00JHC615 00JMCAC289 00JOC89 00JOC235 00JOC907 00JOC1222 00JOC1972 00JOC2444 00JOC2684 00JOC2847 00JOC3148 00JOC3853

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00JOC4208 00JOC4435 00JOC4938 00JOC4984

Six-Membered Ring Systems: Pyridines and Benzo Derivatives

00Sl117 00S1532 00S1561 00S1781 00S1992 00SC427 00SC3203 00SC3511 00SC3919 00SCI1992 00SL101 00SLl16 00SL209 00SL242 00SL595 00SL625 00SL653 OOSL801 00SL989 OOSLI031 00SL1034 00SLl160 00SL1208 00SL1640 00T1361 00T1517 00T1569 00T2975 00T4027 00T4817 00T5001 00T5147 00T6209 00T6319 00TA733 00TA2221 00TA2289 00TA2359 00TL275 00TL531 00TLl179 00TL1215

239

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260

00TL1653 00TL2027 00TL2299 00TL2507 00TL2663 00TL2875 00TL2899 00TL3025 00TL3493 00TL4113 00TL5225 00TL5307 00TL5411 00TL5479 00TL5533 00TL5715 00TL6167 00TL6567 00TL6681 00TL7125 00TL8523 00TL8769 00TL8821 00TL9277 00TL9797 00TL 10251

D.S. Coffey, S,4. M a y a n d A . M . R a t z

S.L. Hargreaves; B.L. Pilkington; S.E. Russell; P.A. Worthington Tetrahedron Lett. 2000, 41, 1653-1656. D.J. Wallace; C.J. Cowden; D.J. Kennedy; M.S. Ashwook; I.F. Cottrell; U.-H. Dolling Tetrahedron Lett. 2000, 41, 2027-2029. S. Caron; N.M. Do; J.E. Sieser Tetrahedron Lett. 2000, 41, 2299-2302. K.A. Tehrani; K. Van Syngel; M. Boelens; J. Contreras; N. De Kimpe; D.W. Knight Tetrahedron Lett. 2000, 41, 2507-2510. J.S. Yadav; B.V.S. Reddy; M.M. Reddy TetrahedronLett. 2000, 41, 2663-2665. C. Desmarets; R. Schneider; Y. Fort Tetrahedron Lett. 2000, 41, 2875-2879. A. Boto; R. Hernandez; E. Suarez Tetrahedron Lett. 2000, 41, 2899-2902. L.-H. Zhang, Z. Tan Tetrahedron Lett. 2000, 41, 3025-3028. U. Sharma; S. Ahmed; R.C. Boruah Tetrahedron Lett. 2000, 41, 3493-3495. C. Agami; F. Couty; N. Rabasso Tetrahedron Lett. 2000, 41, 4113-4116. Y. Moro-oka; S. Iwakiri; T. Fukuda; M. Iwao Tetrahedron Lett. 2000, 41, 5225-5228. C. Guo; S. Reich; R. Showalter; E. Villafranca; L. Dong Tetrahedron Lett. 2000, 41, 53075311. H. McAlonan; D. Potts; P.J. Stevenson; N. Thompson TetrahedronLett. 2000, 41, 5411-5414. O. Surygina; M. Ehwald; J. Liebscher Tetrahedron Lett. 2000, 41, 5479-5481. D. Taniyama; M. Hasegawa; K. Tomioka Tetrahedron Lett. 2000, 41, 5533-5536. T. Shimizu; K. Tanino; I. Kuwajima Tetrahedron Lett. 2000, 41, 5715-5718. J.R. Harrison; P. O'Brien Tetrahedron Lett. 2000, 41, 6167-6170. M. Ortiz-Marciales; D. Figueroa; J.A. Lopez; M. De Jesus; R. Vega Tetrahedron Lett. 2000, 41, 6567-6570. D.C. Harrowven; M.I.T. Nunn; N.J. Blumire; D.R. Fenwick Tetrahedron Lett. 2000, 41, 66816683. R. Grigg; A. Liu; D. Shaw; S. Suganthan; D.E. Woodall; G. Yoganathan Tetrahedron Lett. 2000, 41, 7125-7128. M. Matsugi; F. Tabusa; J.-I. Minamikawa Tetrahedron Lett. 2000, 41, 8523-8525. F. Bois; D. Gardette; J.-C. Gramain Tetrahedron Lett. 2000, 41, 8769-8772. G. Pandey; M. Kapur Tetrahedron Lett. 2000, 41, 8821-8824. K. Okano; K. Murata; T. Ikariya Tetrahedron Lett. 2000, 41, 9277-9280. S. Rougnon Glasson; J.L. Canet; Y. Troin Tetrahedron Lett. 2000, 41, 9797-9802. M. Ohba; R. Izuta; E. Shimizu Tetrahedron Lett. 2000, 41, 10251-10255.

261

Chapter 6.2 Six-Membered Ring Systems" Diazines and Benzo Derivatives Brian R. Lahue Boston University, Boston, MA, USA [email protected] Grace H.C. Woo Boston University, Boston, MA, USA [email protected] John K. Snyder Boston University, Boston, MA, USA jsnyde r@ chem. bu. edu

6.2.1 I N T R O D U C T I O N In recent years, diazines and their derivatives have become extremely important to the field of chemistry as well as to the general population in terms of their invaluable biological activities. In 2000 alone, there were hundreds of publications on the syntheses and important reactions of these heterocycles. This review is comprised of the most significant of these reports.

6.2.2 PYRIMIDINES 6.2.2.1 Preparations of Pyrimidines The most common method for the preparation of the fully aromatized pyrimidine skeleton is the condensation of an amidine with an a,13-unsaturated carbonyl compound. For example, Palanki and co-workers reported that the reaction of amidines 1 with a,13-unsaturated carbonyl compounds 2 produced pyrimidines 3 <00JMC3995>.

O H2NLNH

+

1

O OEt

R1

39-88%

CO2Et

N~N Re

1

2

3

Similarly, one of several new chiral ligands bearing pyrimidine rings was prepared through the bis-condensation of chiral amidine 5 with di ~t,13-unsaturated carbonyl compound 4 <00T8489>. The use of the dimethylamino functionality as a leaving group led to 6 in high yield.

262

B.R. Lahue, G.H.C. Woo and J.K. Snyder

Me2N~~~/~ O

NMe2 4

O

EtONa/EtOH 88%

HCI~HN ~ ~ , . H2N v.,,,l~ 5

Miiller and co-workers reported the three-component one-pot synthesis of various pyrimidines through the in situ generation of ~,13-unsaturated carbonyl compounds. The palladium catalyzed coupling of aryl halides bearing electron withdrawing substituents 7 with propargyl alcohols 8 produced ct,13-unsaturated carbonyl compounds 9 after isomerization, which condensed with amidines 10 to form triaryl pyrimidines 11 <00OL1967>.

EWG-Ar2-X 7+ (Ph3P)2PdCl2, Cul, Et3N ..._ I EWG"A~~"~k~O I ~<~r H

"-

8

Ar'

~ r3 -HCI H2Nlt) NH EWG"Ar~~i/Ar 2 1 41-70% ~

N.....~ NAr 3 11

9

4-Iminopyrimidines 14 and 15 were prepared with nearly complete regioselectivity through the conjugate addition of amidines 13 to cyanoalkynes 12 followed by ring closure onto the nitrile <00OL3389>. In the absence of base, 14 is the dominant product, while the addition of HMDS reverses the selectivity of the reaction yielding almost entirely the regioisomer 15.

R2

Ar - 12

NH CN + HNR.~I 13

Ar..,.,.[~~NH Ar-~~.~NH 5% MeCN/THF .._ 5-65% "- R21NR~IN + N'~N'R2R 1 14

No Base up to 98:2 NaHMDS(2eq) up to 1:99

15

In a similar closure onto a nitrile, activation of the cyano functionality of intermediates 16 with TMSC1 (17) resulted in ring closure of the urea nitrogen to the nitrile carbon to form pyrimidones 18 following basic hydrolysis <00H347>.

263

Six-Membered Ring Systems: Diazines and Benzo Derivatives

o

R2~N~Ic'~N O"~ NH

,.TM,1

HMDS,TMSCI 0

16

o

NaHCO3 16-92% ~ O"/~ NLNH2

17

18

Ureas are commonly employed in the syntheses of 2-hydroxypyrimidines. An example is the reaction of 1,3-dicarbonyl compounds 19 with urea (20) in the presence of HC1 to produce pyrimidines 21 though no yields were given <00JMC3995>.

o o o al./JL..~CO2Et + H2N..~NH2 19

RI-..~'~/CO2Et

HCI

N~.~.N OH 21

20

Guanidines, the nitrogen analogs of ureas, are typically used to generate 2aminopyrimidines. Molina and co-workers utilized this methodology in their synthesis of the biologically active marine natural products known as the meridianin alkaloids 23 <00TL4777>. The reaction of vinylogous amides 22 with guanidine produced the pyrimidine ring of the target molecules with concomitant removal of the N-tosyl group from the indole nitrogen in good yields.

NMe2 0 ~ R

H2N NH HCI 9 H2N"JJ~NH2 K2003 72-82% ~"

"Ts

R2~~'-~ R4

R3 R"

R3

22

H 23

MeridianinC,D,E Similarly, Hafez and co-workers <00JCR(S)13>, as well as A1-Afaleq <00SC1985>, prepared 2-aminopyrimidines 26 from the conjugate addition of guanidine 25 to enaminones 24 followed by ring closure and aromatization.

H CN F /Ar~NMe2

o Ar@'NMe2

CN 24

+

NH

H2N-'J'L-NH2~ 25

/ L

0 NH HN/JJ~NH2

Ar~ 80%

-H20 " -HNMe2

CN

N.,.~N NH2 26

264

B.R. Lahue, G.H.C. Woo and J.K. Snyder

The widespread use of pyrimidine-containing compounds as anticancer drugs has led to the development of numerous pyrimidine preparations, such as the opening of lactone 27 with guanidine 28 to give pyrimidone 29 <00JMC3837>. This methodology was utilized by Gangjee and co-workers in their design and synthesis of dual inhibitors of thymidylate synthase and dkhydrofolate reductase for use as antitumor agents. , C @ ~ CH3

+

NH

Et3N, EtOH

H2N/ILNH2

69%

27

CH3

N ~ O

~

H

H2N~J"N" "0 H

28

29

Aside from the pyrimidine preparations which follow well-established strategies, several new pathways have been developed. In model studies for the synthesis of cylindrospermopsin, Weinreb and Keen reported a novel route to N-hydroxydihydrouracil 33 from 0t,13-unsaturated ester 30 followed by aromatization to give pyrimidone 34 <00TIA307>.

OMOM CO2iPr

1) NH4OH PhOCOCI,Et3N 2) 65%

H OMOM TMs"N"oTMS"- ~ ~ 0 68% "-

30

31

OMOM

OMOM

OH

O _..CICH2CH2CI 81%

34

OMOM

O

O

O

PhO'~o

33

32

Ariga and co-workers reported the novel ring transformation of nitropyrimidone 35 with ketones or aldehydes 36 in the presence of ammonia or ammonium acetate to produce pyrimidines 37 along with nitropyridones 38 <00JCS(P1)27>. It was noted that the substitution of the less nucleophilic reagent NHnOAc for NH3 improved the yields of pyrimidines 37 at the expense of pyridones 38. A detailed and lengthy mechanism was provided to explain these results.

O O2N~ j l . 35

Me +

O RI..-'~R 2 36

NH3 0r6_95%NH4OAc~"

R~NO 2 R2"~"2"~,,,~j + R1 R1AN/"-~O H 37

38

265

Six-Membered Ring Systems: Diazines and Benzo Derivatives

6 2 . 2 2 Reactions of Pyrimidines

Nucleophilic substitution reactions (SNAr) of pyrimidines are among the most common transformations of these heterocycles. Direct displacement of a variety of leaving groups is well known, although regioselectivity between multiple leaving groups is still actively being explored. For example, Wagner, Mioskowski, and co-workers reported the regioselective displacement of one chloride from trichloropyrimidine 39 with sodium carbamates to provide pyrimidines 40 and 41 in a single step <00TL1757>. It was noted that under most conditions, regioisomer 40 was the major product, but the regioselectivity was lower, or even reversed by altering the base, solvent, and reaction time.

o R2~N~OR1 base H 33-99% ~"

cI N.~N ClI S ~ ~ C I 39

cI N~ N

o RLN~OR '

CI"'~-~N "R2 O-'~OR,

+

N'~N CiI.-'~--~Ci

95:5 to 32:68

40

41

The intramolecular displacement of the pyrimidine chloride by a tethered pyridine, as in substrate 42 or various other nitrogen-containing heterocycles, was reported by Volovenko and co-worker to produce a variety of condensed pyridopyrimidines such as compound 43 <00T5185>.

N~~N__~SO2CH3 Et3N, dioxanereflux

ON N. N

~,-

~N

SO20H3

CN

42

43

Similarly, Dang and co-workers reported the displacement of one chloride from pyrimidine 44 with various amines to give diaminopyrimidines 45 <00TL6559>. These compounds were then subjected to a FeC13-SiO2-promoted cyclocondensation with various aldehydes to produce trisubstituted purines 46 in moderate to good yields as potential adenosine regulating agents.

c,

N~NH2 II~.N~CI 44

H2NR1.."-

N

CI

NH 2

II~N//LNH 45

R2CHO,FeCI3-SiO2 ~ 48-88%

N

C

N,

~"R 2

46

In another example of a tandem displacement/annulation sequence, Neidlein and coworkers reported the reaction of ethyl 2-mercaptoacetate with chlorocyanopyrimidine 47 <00S255>. Thienopyrimidine 48 was produced in high yield through this one-pot procedure.

266

B.R. Lahue, G.H.C. Woo and J.K. Snyder

Me2N,,,,~N ~ C I

HSCH2CO2Et, K2CO3 93% ~.

N " ~ ON NH2

Me2NvN~IS II '[ /~/---CO2Et N ~ NH2 NH2

47

48

As sulfones are known to be readily displaced from electron deficient nitrogen-containing heterocycles, Bessard noted significant rate enhancements as well as improved yields in the displacement of the chloride on pyrimidine 49 by alcohols, through the use of sodium methylsulfinate as a catalyst <00T4739>. The production of trialkoxypyrimidines 51 as potential herbicides, presumably formed from the displacement of methysulfinate from intermediate 50 by the various alcohols, required a less than a stoichiometric amount of sodium methylsulfinate (typically 0.10-0.25 equivalents).

N?N

MeSO2Na,base D.

c,

.OH

/ N. N / k

=

N..T~N

SO MeJ

49

O.

50

51

Similarly, Cocco and co-workers reported the direct displacement of the thiomethyl group from pyrimidines 52 with hydrazine to produce 53, along with varying amounts of the dihydrazide, a result of the displacement of both the thiomethyl group as well as "X" (X = alkylamine) <00JHC707>. After optimization, 53 could be produced selectively and then cyclized by heating in butanol to form 54 in excellent yields.

SCH3 NC-..~ N X

N

H2NNH2.H20

NHNH2 NC-..~ N

NH2

NH2

52

,uoH_

80-87%'-

.2\ I N

H

53

NH2 54

An alternative to displacement of a leaving group from the pyrimidine skeleton is the regioselective addition of a nucleophile to an unsubstituted position on the pyrimidine ring, with C4 typically being the site of addition. An example reported by Fort and co-workers was the addition of C6-1ithiated 2-chloropyridine, formed through deprotonation of 55, to pyrimidine to form adduct 56 after rearomatization, though in only 25% yield <00OL803>.

1) BuLi-Me2N(CH2)2OLi CI 55

N....~N 25%

~"

CI

N...~N 56

267

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Similarly, heterocyclic amines such as imidazole were added to pyrimidines 57 with moderate to high regioselectivity to produce mainly 4,5-disubstituted pyrimidines 58 after a 1,3-hydride shift along with small amounts of the 2,5-disubstituted isomers 59 <00JOC9261 >.

OMs

Nu

R~N/JI

Nail Null~

R

57

N 58

59

47-64%

5-17%

Iodopyrimidines 60 could be converted to their Grignard derivatives by the action of iPrMgC1, which then react with various electrophiles <00T265>. Qu6guiner and co-workers reported the synthesis of pyrimidines 61 bearing alcohols, aldehydes, and esters through this methodology.

Y X

E(Y)

N

2) Electrophile 27-69%

IP,

(X) E

N

X=l, Y=OCH3 X=SCH3,Y=I

60

61

In a similar reaction, Knochel and co-workers synthesized allylpyrimidine 63 through a magnesium-iodine exchange with iodopyrimidine 62, followed by copper (I) promoted coupling with allylbromide <00JOC4618>.

1) i-PrMgBr, CuCNo2LiCI /,

Br

I

81%

D,.

Br 63

62

As the 2-aminopyrimidine moiety is found in various biologically important natural products, a variety of reactions involving these substituted heterocycles have been reported. For example, Grubb employed the cyclocondensation of a-bromoaldehyde 64 with diaminopyrimidone 65 in their total synthesis of queuine (66), also known as Q Base, found in tRNA <00T9221>.

Br Ns O~~" ~ " /H" N' (~~~) 64

+

.~N~~..... HN j H2N

NH2 65

1) deprotection NaOAc 2) ~ 17%, 4 steps

HN O

/~N(~~"

H2N

H 66

OH

268

B.R. Lahue, G.H.C. Woo and J.K. Snyder

Similarly, aminopyrimidine 67 was treated with a-bromoketone 68 to produce 69, an intermediate used by Laneri and co-workers in subsequent studies of the Vilsmeier reaction in the synthesis of various imidazopyrimidines <00JHC1265>.

H3C,,~N ]~.NH 2 wN

O

H3C-...,~N-,.T~N

EtOH 80%

+ ~~--Br

OH

OH

67

68

69

Aminopyrimidines are also known to undergo Michael additions to ct,13-unsaturated carbonyl compounds. This methodology was utilized by Insuasty and co-workers using triaminopyrimidines 70 with conjugated ketones 71 to produce a variety of pyrimidine-fused diazepines 72 <00JHC193, 00JHC401>.

NH2 I

Ia 2

.NH2 I ~

~

RI,,~.N~.,NH2

+

35-81%

R2

R3

70

R1

71

N

72

Cox and co-workers reported the cyclization of polymer-supported aminopyrimidines formed by the reduction of nitropyrimidines 73 to produce cyclized pyrimidines 74 after cleavage from the resin <00TL8177>. O

H

N,,,,~ N 73

O ~T~R 2

1) SnCl2eH20

NO2 H

R2

2) TFA 61-95%

,.~ ~~ O H N "- H O ~ NH

14

R'

II

I

N.,,,~N

74

Often, it is difficult to regioselectively alkylate 2-aminopyrimidines as a mixture of endocyclic and exocyclic nitrogen alkylation occurs. Alvarez-Builla and co-workers reported methodology which deters the alkylation of a pyrimidine ring nitrogen through an intramolecular hydrogen bond in starting material 75 to produce 2-alkylaminopyrimidines 77 with high regioselectivity after reductive removal of the pyridine moiety from alkylated intermediate 76 <00T2481>. Similar methodology was also applied to 2-aminopyrazines (Section 6.2.7.2).

269

Six-Membered Ring Systems: Diazines and Benzo Derivatives

~H

(5)N~NI ~N

R-Br,acetone,.~Br ~ (~) "-

75

R~NX~NI ?N

Zn/AcOHor H Pt/C,HCO2H,Et3N R.-N-.ff-N<7 65-76% N~

76

77

Pyrimidones may also function as substrates for further annulation.- For example, Bhat and co-workers reported the reaction of uracil 78 with tosylmethylisocyanide to give condensed product 79 in their concise synthesis of pyrrolopyrimidione 80 <00H205>.

O

O

I Bn

I Bn

Bn,,N.~I Bn,,N~ HCO2NH4, O.,~N3 NaH,TosMIC O~,,.N/~/NH Pd/C ~ 78

O

"JJ~~N HN__ H

79

80

Ganjee and co-workers produced another series of potential dihydrofolate reductase inhibitors 84, initiating the cyclocondensation of pyrimidine 81 with ketone 82 in DMF at room temperature to give 83 in 53% yield <00JHC935>. AF

H2N NI z OH+ C I ~ C I

DMF53% "-H2N

82

81

-~2N 83

84

Recent developments in palladium-catalyzed coupling reactions have arisen in the pyrimidine field as well. The Sonogashira coupling of bromopyrimidine 85 with alkynes 86 produced pyrimidines 87, important intermediates reported by Hart and co-workers in their approach to the cylindrospermopsin substructure <00JOC5668>.

Br~OMe N.,~N OMe 85

\

+ 86

R

(Ph3P)2PdCl 2, Cul ,.~ 75-90% "-

R ~ O M e N.~N OMe 87

The traditional Stille-type cross coupling of stannane 88 with bromopyrimidine 89 was reported by Fort and co-workers to provide pyrimidine 90 in 80% yield <00OL803>. This illustrates a novel route to heterocyclic chlorobiaryls.

270

B.R. Lahue, G.H.C. Woo and J.K. Snyder

Bu3Sn'~

cl

+ (\~~Br

88

Pd(PPh3)4 ~

/

~

~

_ J

89

90

Similarly, Lehn and co-workers reported the Stille coupling of stannane 91 with bromoanthracene 92 to provide aminopyrimidine 93 after deprotection <00T6701>. These 2aminopyrimidines were utilized in molecular recognition studies.

SnMe3 N.~.N O~o

1) Pd(PPh3)4 2) MeNHNH2 HI ~ 79% ~ H2N m

+ Br

91

92

93

Yoon and co-workers reported a methodology that yielded pyridopyrimidones 97 and 98 through the palladium-catalyzed coupling of iodouracil 94 with alkenes 95 and 96, respectively <00SC81>. It was noted that when the alkenes of type 95 (X = acetyl, ester, or nitrile) were employed, demethylated products 97 resulted, otherwise, the deaminated products 98 were favored. No mechanistic explanation of these results was supplied by the authors. O

O Me~Nfi~'J'l Me O"~ NLN~-~NMe2 I Me 94

X

+

Pd(OAc)4, K2CO3

65-88% 95 X=CO2Me,COMe,CN

fii~-------1 R 96

Pd(OAc)4,K2CO3

80-94%

Me"N~ O~"N" "N" NMe 2 I Me 9"1

Me..N

Or

O

Ar

I

Me 98

The cross-coupling reaction of thiomethylpyrimidines 99 with organozinc compounds 100 in the presence of palladium was found to produce pyrimidines 101 in good to excellent yields <00SL905>.

271

Six-Membered Ring Systems: Diazines and Benzo Derivatives

SMe

Ar

NJ%N I R L2~ R1

+

99

Pd(PPh3)4 -71-90% .--

ArCH2ZnBr

NIN R1

100

101

In work reminiscent of earlier studies by van der Plas <89T803, 89T5"611>, Dehaen and co-workers illustrated how the electron deficient pyrimidine ring can be exploited in the intramolecular inverse electron demand Diels-Alder reactions of pyrimidine-tethered alkynes 102 <00SL625>. Under thermal conditions, pyridines 103 were produced in modest to excellent yields.

o x_y Cl~Cl N....~N

nitrobenzeno, A ~ -ClCN, 20-94%

X=O,NH Y=CH2, CH2CH2, CMe2

102

CI

N~'~P"'R 103

Novel pyrimidine enediynes 104 prepared by Russell and co-workers undergo Bergman cyclization to give tricyclic products 105 <00OL3761>. Pyrimidines 104 were also shown to cleave dsDNA under appropriate conditions.

or A 10-93% hv

H3CO

-N-

OCH3

X.

H OO/

104

105

Soai and co-workers reported the oxidative cleavage of the pyrimidine ring in pyrimidines 106 to produce chiral acetamides 107 along with amides 108 with excellent retention of optical purity <00HI51>. This is claimed to be the first such oxidative cleavage of the pyrimidine ring.

R

~OAc H20, CCI4, MeCN

M .106

O

NH ~y-CH3 +

107 59-80% 89-95%ee

DAc NH2 108 11-17% 91-95%ee

B.R. Lahue, G.H.C. Woo and J.K. Snyder

272

6 2,.3 QUINAZO LINES

6.23.1 Preparations of Quinazolines Quinazolines, the benzo derivatives of pyrimidines, were prepared in a variety of ways, from methods analogous to those for synthesizing pyrimidines to vastly different condensation schemes. In analogous fashion to many pyrimidine preparations, Yang and coworkers reported the condensation of polymer-tethered amidines 109 with cyclic anhydrides 110 to yield a library of 2-amino-4(3H)-quinazolinones 111 after cleavage from the resin <00TL7005>. 0

~I~js,

HR + NH eHCI

X~ ~ N . ~

O

0 O

i-Pr2NEt 53-88% =

H N"R • rI~'~"N N~"

H

109

H

110

111

Through similar chemistry, quinazolinones 114 were formed from the reaction of chlorinated lactones 112 with aminothiazoles 113 <00JHC725>. This type of condensation is quite general, as Abdel-Hamide reported a very similar pathway to quinazolinones 117 starting with iodolactone 115 <00IJHC59>. It was noted that the initial product, ring-open diamide 116, could be cyclized by thionyl chloride to give 117 with concurrent conversion of the alcohol to the corresponding chloride. N-Unsubstituted quinazolinones 119 were produced in analogous fashion through the reaction of formamide with lactone 115. o

o

CIx'-~~N~L Me + 112

I

O

H2N'~N/~ $I~-' R

p29-55% yridine

113

C,x - ~ ~ N ~

HN

O

M~e /N

114

..OH

NH2CH2CH2OH~ Ph 61% I

S~,R

SOCI2 ~ I 52% I

II N l p h

COPh 116

115

HCONH2 84%

117

0

Ph 119 Azizian, Mehrdad, and co-workers reported a novel route to quinazolinones 123 through a Baeyer-Villiger pathway starting from isatin derivatives 120 <00TL5265>. The initial

273

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Baeyer-Villiger products 121 were thought to undergo ring cleavage to isocyanates 122, which upon cyclization form products 123.

~

N

N"Ar /

..~1~r

m-CPBA~

120

~~"

121

N'Ar

1

~ .

~

122

N"Ar

123

In analogous fashion to isocyanate chemistry, isothiocyanates like 125 can be utilized to produce the corresponding quinazoline-2-thioxo-4-ones. Makino and co-workers reported the solid phase synthesis of quinazoline derivatives 126 through the reaction of polymerbound primary amines 124 with isothiocyanates 125 <00TL8333>.

I~I~o"R'NH2

+

124

N~ 125

C OMe

NMP

r

Oo LL, -'R, N

S

O

H

126

Carbon disulfide, the "all sulfur" equivalent of isothiocyanates, was found to react with benzimidazole 127 very rapidly under microwave irradiation to produce 128 <00TL5857>.

HH2N

HS,2-~N

127

128

The intramolecular conjugate addition of ureas 129 to form quinazolinones 130 was reported by Xin and co-workers <00TLl147>. Ureas 129 were reported to be the major byproducts of Molina's carbodiimide methodology for making quinazolinones <94Sl197>, which according to this work, can now be further transformed to the desired product.

~o v

0

NH

O'~"NHR2 129

" R1

0

NaOH,THF ,._ 62-99% ..-

I"~O" R1 ~.,~,...,,I,~ . / y .N..R2 H 130

274

B.R. Lahue, G.H.C. Woo and J.K. Snyder

Bergrnan and co-worker reported the two-step cyclocondensation beginning with aminoamide 131 and acyl chlorides 132 to form diamide intermediates 133, which cyclized upon treatment with sodium hydroxide to give quinazolin-4-ones 134 <00T7245>. O NH2 2

131

.~

I I+ 0

77-88%

CI'~~CI R '

~NH2 O

(Br)

0 NaOH 75-99%

"=/ NH 0

~ . . . ~ R1 (Br)

133

134

132 In a similar sense, the intramolecular aza-Wittig reaction of azide 135 resulted in quinazolinone-containing product 136 in good yield <00H1765>. Compound 136 then underwent acid-promoted cleavage through intermediate 137 to yield fused quinazolinones 138 after tautomerization.

0 [~N 3

Bu3P 75%

o 135

136

m

m

40-97% DMB/N'~cH3 O 138

H DMI3 ~ "CH3 O 137

Van Muijlwijk-Koezen and co-workers utilized the reaction sequence beginning with the deprotonation of aminonitrile 139, which when trapped with various nitriles produced aminoquinazolines 140 upon acid-promoted cyclization, in their preparation of numerous aminoquinazoline as antagonists for the human adenosine A3 receptor <00JMC2227>.

275

Six-Membered Ring Systems: Diazines and Benzo Derivatives

~

1) base 2) R-CN 3) H+/H20

NH2

v

"CN

~ N ~ R N

16-86%

NH2

139 6232

140

Reactions of Quinazolines

Quinazolines undergo many of the same reactions as pyrimidines, such as the modification of an amino group. Gangjee and co-workers reported the reductive alkylation of diaminoquinazolinones 141 with various aryl carbonyl compounds 142, which regioselectively produced quinazolinones 143 <00JHC1097>.

O H/j,.~~/NH H2N

2

+

141

Ar

~

O R

Raney Ni/H2 or Et3N/BH3 10-62% "

O ...j.,~N~ HN H2N

142

H N

"~ R

Ar

143

The SN2 reaction of quinazolinone 147 with phenylhydrazine was followed by rearrangement of the tautomerized intermediate 148 <00T7987>. The loss of both ammonia and aniline was followed by the addition of a second equivalent of phenylhydrazine to the resulting imine to produce quinazolinone hydrazone 149. Subsequent Fischer indolization of 149 followed by condensations with aldehydes led to 7-azarutacarpines. m

N ~

Br

N'NH 2 0

147

PhNHNH2 81%

HN H ~"NH

[

~N'NH2 O 148

PhNHNH2 - PhNH2 - NH3

N..NH -.~N'NH O

2

149

E1-Hiti reported an in-depth study of the regioselective lithiation of numerous substituted quinazolines and subsequent trapping of these nucleophiles with an array of electrophiles <00H1839>. As a representative example, lithiation of dichloroquinazoline 150 gave rise to further substituted quinazolines 151.

276

B.R. Lahue, G.H.C. Woo and J.K. Snyder

OMe ~ N ~ j CI N CI

1) 2.2 eq LTMP 2) Electr~ ~ 3) HCI 88-99%

150

OMe . C I.' ~ N E

N~'j

CI 151

6.2.4 PYRIDAZINES

6.2.4.1 Preparations of Pyridazines A common method to synthesize pyridazines remains the inverse electron-demand DielsAlder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 <00RCB355>. This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R 1 and R 2 on the tetrazine. Ph ~OC4H

N=N N-N

152

o

9

--_~I--U~NH2

41-93%

N=N

R I ~ ~ '~ R2 153

Similarly, [4 + 2]-cycloadditions were used to prepare the pyridazine moiety in fused tetraheterocyclic azepine 155 syntheses. In this reaction, the 1,2,4,5-tetrazines 154 function both as the 47t-components and the oxidizing agents thereby requiring four equivalents of tetrazine for optimal yield. <00JOC9265>.

27'/

Six-Membered Ring Systems: Diazines and Benzo Derivatives

R

R

R"---~NN.

N' N R

~

N~~

N,J.NN

RCN

154

tetrazinet [o] R

R

R N~ N

R

[O]

tetrazine 38-45%

155

R

R N~ N

N~ N tetrazine

R

Condensations with hydrazine also yield pyridazines. For example, Shvartsberg and coworkers treated peri-acetylenic naphthoquinones 156 with hydrazine to give the sixmembered pyridazine ring 158 after cyclization <00TL771>.

O

C-CPh

H2N, N

NH2NH2 ,. O

156

N,.N~ CH2Ph .N. ~-"1~

C=CPh 6O%

O

157

~. O

158

Aryl hydrazones have also been utilized as starting materials for preparing targeted condensed pyridazone ring systems. For example, diazotized 2-aminothiophene 159 coupled readily with vinylogous amide 160 to yield hydrazone 161 after hydrolysis of the dimethylamino moiety. These hydrazones condensed with malononitrile to give 163 via intermediate 162, though no yields were reported <00JCR(S)154>.

278

B.R. Lahue, G.H.C. Woo and J.K. Snyder

O

~J~

/CO2Et

sZ c,|

R,'~~'~ NMe2 160

N

[ ~ ~

161

159

CO2Et N_N=:~"CHO H COIl

X = CN, COPh O L~NNp~I

O2Et X 162

X

S

~ COR

163

~ COR

Yoon and co-workers prepared perchlorinated pyridazines via chlorination of pyridazone 164 <00JHC1049>. They reported that the chlorination of 164 using phosphorus oxychloride gave only 165 in 81% yield. However, a solution of phosphorus pentachloride and cyclohexane provided only 166 in 81% yield. Furthermore, other reaction conditions gave a mixture of 165 and 166 in varying ratios depending upon the solvent, temperature, and reaction time. CI

CI CI~CI

O ~ N -N H 164

POCI3 No solvent 81%

CI..~CI CI..-'%N.-N 165

PCI5 cyclohexane 81%

CI'~/-=N

N-N

c, ~ ' a ~ _ ~ ~ C, CI~-~I~o CI ~ Cl 166

6.2.4.2 Reactions of Pyridazines As has long been known, reductive ring construction of pyridazines is an efficient methodology to produce pyrrole derivatives <99JACS54>. Activated pyridazines 167 were converted to the corresponding functionalized pyrroles 169 by an electrochemical reduction process, proceeding through a 1,2-dihydro intermediate 168 <00TL647>.

279

Six-Membered Ring Systems: Diazines and Benzo Derivatives

2

CO2Me

[- 2

I ~

CO2Me

C:PR"

CO2Me

R2 \

2e + 2H+ 60-70% MeO2C L

H

CO2Me

167

168

R1 / CO2Me

169

C.P.R = Controlled potential reduction Similar to reactions of iodopyrimidines previously mentioned in Section 6.2.2.2 (60 --* 61), the Grignard reagent 171, efficiently prepared from halopyridazine 170, was quenched with electrophiles such as acetaldehyde, ethyl cyanoformate, DMF or phenylsulfide to give 172 in acceptable yields <00T265>. OMe

OMe 1 equiv. RMgX

OMe

N,,~

.

OMe

OMe

170

171

electrophile overall: 35-70% .

N ,,E N,,~ OMe 172

New tri- and tetracyclic compounds containing the pyridazine moiety were synthesized in a multistep reaction sequence from commercially available pyridazine 173 <00AP231>. Acid chloride 173 reacted-readily with 174 to yield 175. Cyclized product 176 was then produced by treatment of tethered pyridazine 175 with sodium hydride in an intramolecular SNAr displacement. 0 C l ~ c N, N/~r

I I

O H C l a N .

H2N~ +

HO I ~ - - ' R

173

"

174

I~..N~CI H O I ~ - R 175

O Nail

1,4-dioxane

N--N

0~ ~

R

176 6.2.5

CINNOLINES

6.2.5.1 Preparations of Cinnolines Cinnolines, one of the two benzo derivatives of pyridazines, attracted considerable attention due to the variety of pharmacological activities exhibited by these heterocycles.

280

13.R. Lahue, G.H.C. Woo and J.K. Snyder

Cinnoline syntheses frequently utilize palladium catalyzed coupling reactions. In the following example, 2-iodoaniline 177 was coupled with trimethylsilylacetylene to yield intermediate 178, followed by diazotization and ring closure to hydroxycinnoline 179 in good yield <00T5499>. Chlorination of 179 followed by cross-coupling reactions under Suzuki conditions of various substituted arylboronic acids with 4-chlorocinnoline 180 led to heterobiaryls 181. Similar couplings of 4-chloroquinazolines and 4-aryl-8-iodoquinazolines were also reported. These heterobi- and triaryls showed significant nonlinear optical properties.

[~'N

H = SiMe3 PdCI2(PPh3)2/Cul/NEt3 H2 95%

177

/SiMe3

~

1.NaNO2/HCI/H2O ~ N 2. A 73% -"

178

OH

179

c,

POCI3 77%

,. ~ N ,

N

180

X-PhB(OH)2/Pd(PPh3)4 ~ ~ N ~ N DME/aq.K2CO3/A 181

x =p-CF3 85% X =m-NO2 88% X =p-OCH3 86%

One of the most convenient ways to form benzocinnolines 183 is the intramolecular reductive coupling of 2,2'-dinitrobiphenyls 182 exemplified by the work of Kaszynski and Sandhu <00JCS(P1)67>. The reaction is general, effected by most typical reducing agents with good to excellent yields <00JOC6388>.

NO2 ,NO2

R

~ 182

R

1.Zn/CaCI2,95%EtOH,N 2 2. air N=N 3.95%EtOHor 79% = R ~ R Bi-KOH 85-95%

183

Dialkyltriazenes ortho to an acetylene substituent on an aryl ring as in 184, undergo ring closure in modified Richter-type cyclizations, forming substituted cinnolines 185 and isoindazoles 186 in fair to very good yields <00OL3825>.

281

3'ix-Membered Ring Systems: Diazines and Benzo Derivatives

NEt2~ N~N

NEt2 o-CI2Ph A

R

+ R 90-99%

184

185

R 14-63% 186

6.2.5.2 Reactions of Cinnolines

As with other haloaromatic systems, Barbier reactions are also suitable for heterocyclic systems. For example, the lithio derivatives formed in situ from iodide 187 upon sonication reacted immediately with electrophiles such as benzaldehyde, hexanal and diphenyl disulfide, to give good yields of 188 <00T3709>. Similar chemistry was also successful with pyrazines, pyrimidines, and pyridazines. I

E

~ O M e

1. 2.2 eq. Li, 1.1 eq.,)))Electrophile i ~ ~ ~ O M e

~N;N

2. EtOH

35 - 72%

187

6.2.6

t~_p...N, N 188

PHTHALAZINES

6.2.6.1 Preparations of Phthalazines

As with pyridazines, phthalazines, the other benzopyridazines, were also prepared most frequently through the condensation of hydrazines with carbonyl-containing compounds, typically phthalate derivatives. Recently, Napoletano and co-workers demonstrated the condensation of hydroxylactone 189 and hydrazine to afford phthalazones 190. After POC13 chlorination, advanced intermediates for a novel series of PDE4 inhibitor I, phthalazines 191 were prepared <00BMC2235>.

Ri

OH

J O ~

O O

189

R NH2NH2 "EtOH 72%

/O'~/~N t L ~ " ~ NH O 190

R 95-98%PO0=13~ O ' ~ ' ~ N t~X~N 191

CI

Similar chemistry was used to synthesize pyridyl(methyl)phthalazines, 193, inhibitors of the VEGF receptor tyrosine kinase. The active inhibitors 193 were formed by condensation of 192 with hydrazine, followed by POC13 chlorination. <00JMC2310>. Furthermore, a simple substitution reaction withp-chloroaniline gave anilinophthalazine 194.

282

B.R. Lahue, G.H.C. Woo and J.K. Snyder CI

R21 NH2NH2 9 4 '%

HO

CI

CI i iI R1 ~ N H

2. POCI3,82-92% N~ ~ J ~ R

2

20-52%

N~J

192

R = NO2, Me

NH -

R1

N'/ "~ ~ T I~/ I~

R2

194

N~.~

193

R1= NH2, R 2 = H R1, R2 = Me or H (1:1 mixture) Propanophthalazine 200 was synthesized by a novel cycloaddition pathway. This synthesis was thought to proceed by a Diels-Alder reaction of the thiophene subunit of 197 to form intermediates 198 and 199, with the loss of ammonia, and not hydrogen sulfide elimination. Unfortunately, no yields were given <00JCR(S)20>.

S

ArN2QcIQ

H2

NNHR AcOH/HCI S ~

S H2

195

RI=R2=CO2Et

196

N

198

R2

1,4-dioxane

O

197 Rl=2-thienoyl, R2=NMe2 RI=NO2, R2=ph

~

I R I ~ N L H2N 0

H2N

R1~ /

N H

N 1 , . / ~ . . ~__, ~

NH

-NH3

~

N NH

R1

FI H2N ~ 199

200

6.2.6.2 Reactions of Phthalazines

Morozov and co-workers electrochemically demonstrated the pyridazine ring fragmentation induced by electron transfer agents. This reaction proceeded by elimination of chloride ions, cleavage of the pyridazine ring, and the formation of phthalonitrile 202 from 201 <00MC34>.

283

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Cl N

+2e

N

-2C1

C~N

CI

201

202

Hu and co-workers reported a facile synthesis of pyrrolo[2,1-a]phthalazine 205 by a 1,3dipolar cycloaddition of phthalazium N-ylides generated from 203 with electron deficient alkenes to give 204, followed by treating 204 with tetrakispyridine cobalt(II) dichromate [Py4Co(HCrO4)2, TPCD] to complete the aromatization <00JHCl165>. BrQ

~tL....~k....~ ' N

~

'

NEt3/EtOAc

"

R2

R2

TPCD/DMF

~%...~-q....~ ' N

203

R1

= ~q.....~_..x....~ ' N

204

205

R l = COPh, CO2Et, 4-NO2Ph

overall yield = 46 - 81%

R2= CN, CO2Me, COMe, COPh, CO2Et

6.2.7

PYRAZINES

6.2.7.1 Preparations of Pyrazines One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyl compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The Nprotected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. a 1

_ CbzNH

CbzNH

:

R~/O O

H

~

R

N2 O

CbzNH H

=_ R

~ H2N

O O

206

H

_NHCbz N

NH2 ~ R

28-55%

N

R 1 = H, OH 3, CO2CH 3

207

R1

Another method for pyrazine preparation is the cycloaddition of oxadiazinones with dienophiles. The oxadiazinone 208 undergoes cycloadditions with electron rich dienophiles such as 2,3-dihydrofuran to produce lumazines 209 <00JHC419>.

284

B.R. Lahue, G.H.C. Woo and J.K. Snyder

O

O

~N'~N"o o.~L,,.N7J..~N,~O I

+

-CO2 13-74%

~R

~ ~ N N . /R O.~',,,.N,,~N ~l"

"

I

208

209

The imidazo[1,5-a]pyrazine system is one of the lesser known members of the azaindolizine family. The greatest challenge to prepare this system involves closure of the pyrazine ring. Ver6ek and co-workers reported a novel one-pot approach to the imidazo[1,5a]pyrazine system. Treatment of oxazolone 210 with triethyl orthoformate gave imidazole 211. Ethyl ester 212 was produced by refluxing 211 in ethanol, which was subsequently transformed by further heating either in ethanol or triethyl orthoformate to the desired product 213. The 1H NMR spectra of 213 showed that it existed in solution as mixture of imino and amino tautomers in ratios varying from 1:5 (imino:amino in DMSO-d6) to 5:1 (CDC13) depending upon the solvent <00SL1458>.

Ph // O

-.~-

A, 81%

N 0

2111

CN ~ N..Z/

CN 70%

EtOOC.~.~ N..~/

211

212 I EtOH, A, 81% or

HC(OEt)3, A, 76%

PhCONH CN

PhCON

CN

EtOOC~N--~

EtOOCI~/N---.~ 214

213

6.2.72 Reactions of Pyrazines

Pyrazines undergo many of the same reactions as pyridazines and pyrimidines including Grignard formation from halopyrazines. Pyrazines 215, after conversion to their Grignard derivatives, reacted with electrophiles to produce adducts 216 <00T265>. Electrophiles similar to those used with pyrimidyl Grignard reagents (Section 6.2.2.2) and pyridazinyl Grignard reagents (Section 6.2.4.2) Were employed.

N 215

I

1. RMgCI 2. Electrophile 35-70%

N 216

E

285

Six-Membered Ring Systems: Diazines and Benzo Derivatives

The reaction of deprotonated 217 with n-butylisothiocyanate followed by n-butyl iodide quench gave 218 in 72% yield. In this reaction, the higher reactivity of the isothiocyanate compared with the corresponding isocyanate gave the bispyrimidopyrazine, and subsequent n-butylation of the thiocarbonyl groups gave 218. Hydrolysis of 218 in the presence of sulfuric acid proceeded smoothly to give 219 in good yield <00JHCll51>.

NC~N/~NH2 H2N N/~,~.CN + n-BuNCS

NaH DMF :-

217

0

NH n-Bul BU..N.~N~ N~ SBn 72% B uS..~N./I~. N/~~NT. Bu NH 218

BU~NJ,L N~ H. i0

6N H2SO4,n-PrOH 87%

219

O

The reaction of 220 with primary alkylamines in benzene yielded, after ring-closure, the novel heterocycles 222. It was assumed that 220 reacted with primary amines to first yield the corresponding 3-amino derivatives 221 which subsequently added to the carbonyl group to give the ring-closed amina1222 <00JHC1299>.

NC.. N ~ O . ~

NO N; C,

RNH2

NC.. N~

220

Nc. I

- NC N N OH

221

222

As noted in Section 6.2.2.2 for 2-aminopyrimidines, alkylations of 2-aminopyrazines can be directed to the exocyclic amino group using nitride species 223, where the exocyclic nitrogen anion is stabilized by the pyridinium moiety <00T2481>. The endocyclic nitrogen of the pyrazine is blocked by the intramolecular hydrogen bond, making the alkylation regioselective to give 224, followed by reduction to release the alkylated aminopyrazine 225.

_H (~N Iq "~ /~

RBr = acetone 47-50%

QI ~

BrQ

R" N'~N~

N

N

223

224

Zn/AcOHor Pt/C, HCO2H, Et3N 55-79%

H R..N N "~ N

225

286

B.R. Lahue, G.H.C. Woo and J.K. Snyder

6.2.8 PHENAZINES 6.2.8.1 Preparations of Phenazines

Naturally occurring phenazines, though relatively rare, have attracted considerable attention because of their interesting biological activities <88HCA2058, 92JOC740, 96TL9227>. Phenazines are also widely employed as metal-binding components in all aspects of coordination chemistry, and in applications to areas such as supramolecular chemistry and bioinorganic chemistry <84JPC5709>. Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A.

CO2CH3

0020H3 Br2,NaHCO3. OCH3 CHCI3,0~

NH2

226 Pd (OAc)2 BINAP CseCO~ PhMe, 100~

Ph

91%

OCH3

Ph

227

0020H3

I

k l ~

OCH3 Ph

228

O

NH2 Br

I•O20H3

100%

N

Ph

3:1

229

Another novel synthesis of phenazines was introduced by Vagg and co-workers <00JHC151>. The key step was the reaction of dicarboxylic acid 230 with various 1,2diamines to give 231,232, and 233. Each was a potential polydentate ligand capable of interacting with DNA via their extended phenanthroline or phenazine components.

287

Six-Membered Ring Systems: Diazines and Benzo Derivatives

I ~ / N CO2H N

230

H3C'~'~ NH2 H3C" ~ "NH2

CO2H

66%

1

H3C,~~ N/~~ CO2H ,,, H3C-" -...7 "N" ~ \'N 231

H2N/---~NH2 78%

~NH2

~

--NH2

..-'~~CO2H

[~.~CO2H

~'~CO2H ~Ny,,'~N

232

I~~CO2H

[ ~ ~ '~ CO2H

233

Hasegawa and co-workers illustrated the syntheses of substituted phenazine-5,10-dioxides 236 by a dehydrative condensation between benzofuroxan 234 and dihydroxybenzene derivatives 235 catalyzed by molecular sieves at room temperature <00H2151>. OH Moecuarseves

+

0 234

87%

D.

OH 235

236

6.2.8.2 Reactions of Phenazines

Methanophenazine 239 functions as an electron carrier in the cytoplasmic membrane. The etherification of 2-hydroxyphenazine 237 with mesylate 238 was a key step in a total synthesis of 239 <00AC(E)2470>.

288

B.R. Lahue, G.H.C. Woo and J.K. Snyder N..~

1OH

MsO

~

23"1 KOH, aliquot, THF, 90%

~

~

238

239 aliquot = methyltrioctylammonium chloride

6.2.9

QUINOXALINES

6.2.9.1 Preparations of Quinoxalines

A number of quinoxaline derivatives show antifungal and anticancer activities <85H2025>. Moreover, several quinoxaline derivatives showed antidiabetic, antiallergic, angiotensin II receptor antagonistic properties as well as adenosine binding and benzodiazepine receptor binding activities <94JMC2846>. Therefore, these heterocycles continue to attract the attention of synthetic chemists. The traditional method to the construct the pyrazine ring of quinoxalines proceeds by the condensation between an o-phenylenediamine with a 1,2-dicarbonyl compound. For example, the reaction of diamine 240 and glyoxal afforded the pyridoquinoxalines 241 in excellent yields <00H423>.

~

H

O

NH2 NH2 R

240

R = H, CI (90%, 86%)

~/~-.N R 241

~

Similar chemistry was applied by Heeg and co-workers in their synthesis of substituted quinoxalines 244, which were prepared by condensation of diamine 243 with 1,2-dicarbonyl compounds <00JHC1273>. Vagg utilized analogous chemistry to synthesize phenazines as well as quinoxalines (Section 6.2.8.1).

289

Six-Membered Ring Systems: Diazines and Benzo Derivatives

F..~~NO2

cSnnCcl2,HC, F.....~~NH2

H3c..N~N/"~'~-NH2 NaOH ~r~ N,..-q..~__-~NH2 242

:~~

F.. ~

.N..z R

EtOH "I-."'~'N~ ' ~ / N ~ R

243

244

Invidiata and co-workers developed another method to synthesize quinoxalines. Diketones 246 reacted with o-phenylenediamine to give 248, though in low yield. Interestingly, an alternative approach to the quinoxaline derivatives was devised employing the dioximes 247 which are easily prepared from monooximes 245. When 247 reacted with o-phenylenediamine in the presence of concentrated hydrochloric acid, product 248 was obtained in higher overall yield <00JHC355>. Direct conversion of 245 to 248 was also successful.

NH2OH/

/

oH3~ N //-~-~/.R H3C.~~]~N:N--/~ N'OH R = H, 3-CI,4-NO2 245

oH3C%~N H3C~~-~ NN~~___~ O 246 ~ 1 -phenyl ~ nc. HCI enedi(62%) amine N~3C~~IN~ o-phenylenediamine conc.HCI(77%) N~Cs 248

NH2OH~

.~o-phenylenediamine conc.HCI (70'~) o

HO"NH3C N

II "Y~ "N / = ~ ,

H3C'~'~II ~N" N'OH 247

Analogously, the reaction of trifluoroacetaldehyde dimethylhydrazone 249 with TFAA gave 250, which condensed in situ with o-phenylenediamine to afford quinoxaline 251 in good yield <00TL9267>.

H3C. H3c'N-N~cF3 249

TFAA H3/N_ NC,, (CH3)2NEt -"H3C 250

CF3 CF3

74%

= 251

290

B.R. Lahue, G.H.C. Woo and J.K. Snyder

6 2 . 9 2 Reactions of Quinoxalines

Due to interest in the significant biological activities of quinoxalines, several methods for derivatization of these heterocyclic skeleta have been reported. Many of the reactions involving quinoxalines are analogues to those of the other heterocycles discussed earlier. Boger and Lee reported the synthesis of azatriostin A, (253), an analogue of triostin A which exhibits DNA bisintercalation binding properties <00JOC5996>. The precursor 252 was acylated with quinoxaline-2-carboxylic acid using the coupling reagent combination 1ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI) and 1-hydroxy-7-azabenzotriazole (HOAt) to provide the desired product 253 in 34% yield.

O Me 0 " ~ " N / ~ I~1Y~" N , , ,H HN...] Me ~'~S O O%,,,NH2 BocNHe't'~ O Q S"11 Mek"-NH2 HN~ . ~ Nv _C~ O 2 H 252

O ~

1. EDCI, HOAt 2. HCI, EtOAc 3. Qxc-OH, EDCI, HOAt 34%

\/ Y

0

Me -

o HN.~ Me "S O O~.~,,,N-g~N ""

Azatriostin A 253

O //=-...

Paglietti and co-workers performed nucleophilic displacements on chloroquinoxalines 254 with substituted benzylamines to afford 256 and 257, although yields were not given <00IF77>.

291

Six-Membered Ring Systems: Diazines and Benzo Derivatives

R

R

R2

H2N'~~~--

R

R3 ,,

CI

/--NH

CO2Et

2

254

R

/---NH CO2Et 2

R2

256

257

Kim and Okamoto also demonstrated a nucleophilic displacement of the chloro substituent on chloroquinoxaline N-oxide 258 with substituted hydrazines to afford 259 <00JHC791>. Furthermore, the additional pyridazine ring in 260 was constructed by treating 259 with dimethyl acetylenedicarboxylate. The additional fused pyridazine ring could also be formed by condensing diethyl acetonedicarboxylate with quinoxaline 259 in good yield. They hypothesized that this ring is formed via hydrazone intermediate 261 to give dihydropyridazino[3,4-b]quinoxalines 262 <00JHC1257>.

X ~

L>L

!~.~6E~2~i . o/R ,. X" ~ ~ ! ~

X=H, CI 258

259

MeO2C - - CO2MeX ~ N H'CO2"~CO2Me e N.NH2 63-77% EtOH ~ ' x ~ N"'/k"N"N R R 260

~tEtO2Cv~CO2Et -

|

H

X " ~ ~ N~]~ c o 2 e ~N//~N

_

-

o

O O~oEt

261

I

R

-N

t

80%

,. X . ~ ~ N

H CO2Et

CO2Et

~.~--~N/.-'~N.N R I

262

2,3-Bis(bromomethyl)quinoxalines 263 was treated with aldehydes 264 to obtain 265 <00T897>. Macrocyclization to 266 was completed by cyclocondensation of the aldehydes 265 with the appropriate diaminoalkanes. Elwahy used this chemistry to synthesize new macrocyclic ligands containing the quinoxaline subunit.

292

B.R. Lahue, G.H.C. Woo and J.K. Snyder

R3.OH RN~N /~ Br

R3R2

R2/R.,.~I .CHO 264

R

N,,,:

1. KOH-MeOH 2. DMF 64-73% Br

263

N

O

CHO

a3

R~ H2%

CHO MeOH O~R1 ~.,~i~~R2

O IJ /1 /J.

X

--,,.~-N- ",. I rN-" O'.~N1

"~. ~R2

266

265

R1

R3

Ford and co-workers reported regioselective substitutions of 2,3-dichloro-6-aminoquinoxaline 270 with various dialkylamines to study the biological properties of substituted quinoxalines <00TL3197>. For example, 2,3-dichloro-6-aminoquinoxaline 270 reacted with nucleophiles to give the opposite regioisomer to that seen with 2,3-dichloro-6nitroquinoxalines 267.

O2N~N~CI

HNR1R202N~N~r...CI

SnCI2,H2oH2N"[~~ N'~ CI

.N/J',,,CI 76% = ~ N / J ' - , , N R 1 R 2 73% 267

268

~N~--,NR1R 2 269

SnCI2,H20 97% H 2 N ' ~ ~ N / ~ "CI ~- -N/J'-,,CI 270

HNR1R2 65%

H2N~N~ v

NR1R2 -N~CI

271

6.2.10 REFERENCES 70CC1423 84JPC5709 85H2025 88HCA2058 89T803 89T5611 92JOC740 94JMC2846 94S 1197 97JOC1264

F.G. Holliman, S.R. Challand, R.B. Herbert, Chem. Commun. 1970, 1423. A. Yamagishi, J. Phys. Chem., 1984, 88, 5709. K. Makino, G. Sakata, K. Morimoto, Y. Ochiai, Heterocycles 1985, 23, 2025. W. Keller-Schierlein, A. Geiger, H. Zachner, M. Brandl, Helv. Chim. Acta 1988, 71, 2058. A.E. Frissen, A.T.M. Marcelis, H.C. van der Plas, Tetrahedron 1989, 45, 803. A.E. Frissen, A.T.M. Marcelis, D.G. Buurman, C.A.M Pollmann, H.C. van der Plas, Tetrahedron 1989, 45, 5611. C. Pathirana, P.R. Jensen, R. Dwight, W. Fenical, J. Org. Chem. 1992, 57, 740. D. Catarzi, L. Cecchi, V. Colotta, F. Melani, G. Filacchioni, C. Martini, L. Giusti, A. Lucacchini, J. Med. Chem. 1994, 37, 2846. P. Molina, M.J. Vilaplana, Synthesis 1994, 1197. J. P. Wolfe, S. L. Buchwald, J. Org. Chem., 1997, 62, 1264.

Six-Membered Ring Systems: Diazines and Benzo Derivatives 97TL9227 99JACS54 00AC(E)2470 00AP231 00BMC2235 00H151 00H205 00H347 00H423 00H1765 00H1839 00H2151 00IF77 00IJHC59 00JCR(S) 13 00JCR(S)20 00JCR(S) 154 00JCS(P 1)27 00JCS(P 1)67 00JCS (P 1)381 00JHC 151 00JHC 193 00JHC355 00JHC401 00JHC419 00JHC707 00JHC725 00JHC791 00JHC935 00JHC 1049 00JHC 1097 00JHC 1151 00JHC 1165 00JHC 1257 00JHC1265 00JHC 1273 00JHC1277 00JHC 1299 00JMC2227

Y. Hosoya, H. Adachi, H. Nakamura, Y. Nishimura, H. Naganawa, Y. Okami,T. Takeuchi, Tetrahedron Lett. 1996, 37, 9227. D.L. Boger, C.W. Boyce, M.A. Labroli, C.A. Sehon, Q. Jin, J. Am. Chem. Soc., 1999, 121, 54 U. Beifuss, M. Tietze, S. Baumer, U. Deppenmeier, Angew Chem. Int. Ed. 2000, 37, 2470. G. Heinish, B. Matuszczak, K. Planitzer, Arch. Pharm. Pharm. Med. Chem. 2000, 231. M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G. Morazzoni, P. Ferlenga, L. Pradell, Bioorg. Med. Chem. Lett. 2000, 10, 2235. S. Tanji, Y. Kodaka, T. Shibata, K. Soai, Heterocycles 2000, 52, 151. M.N. Zimmerman, N.H. Nemeroff, C.W. Bock, K.L. Bhat, Heterocycles 2000, 53, 205. F. Fulle, C.E. MOiler, Heterocycles 2000, 53, 347. P. Sanna, A. Carta, G. Paglietti, Heterocycles 2000, 53, 423. E. Caballero, C. Avendafio, J.C. Men6ndez, Heterocycles 2000, 53, 1765. G.A. E1-Hiti Heterocycles 2000, 53, 1839. T. Takabatake, T. Miyazawa, M. Kojo, M. Hasegawa, Heterocycles 2000, 53, 2151. P. Corona, G. Vitale, M. Loriga, G. Paglietti, IL FARMACO 2000, 55, 77. S.G. Abdel-Hamide Indian J. Heterocycl. Chem. 2000, 10, 59. K.M. A1-Zaydi, M.A.A. A1-Shiekh, E.A.-A. Hafez J. Chem. Res.(S) 2000, 13. F. A1-Omran N. A1-Awadhi, A.A. Elassar, A.A. E1-Khair, J. Chem. Res. 2000, 20. K.M. A1-Zaydi, E,A, Hafez, M.H. Elnagdi, J. Chem. Res. 2000, 154. N. Nishiwaki, T. Adachi, K. Matsuo, H.-P. Wang, T. Matsunaga, Y. Tohda, M. Ariga, J. Chem. Soc., Perkin Trans. 1 2000, 27. D.D. Laskar, D. Prajapati, J.S. Sandhu, J. Chem. Soc., Perkin Trans. 1 2000, 67. P. Varkins, M. Groarke, M.A. McKervey, H.M. Moncrieff, N. McCarthy, M. Nieuwenhuyzen, J. Chem. Soc., Perkin Trans 1 2000, 381. A.M.S.Garas, R.S. Vagg, J. Heterocycl. Chem. 2000, 37, 151. B. Insuasty, A. P6rez, D. Gonz~ilez, J. Quiroga, H. Meier, J. Heterocycl. Chem. 2000, 37, 193. F.P. Invidiata, S. Aiello, G. Furno, E. Aiello, J. Heterocycl. Chem. 2000, 37, 355. B. Insuasty, H. Insuasty, J. Quiroga, C. Saitz, C. Jullian, J. Heterocycl. Chem. 2000, 37, 401. N. Sato, M. Ono, J. Heterocycl. Chem. 2000, 37, 419. M.T. Cocco, C. Congiu, V. Onnis, J. Heterocycl. Chem. 2000, 37, 707. C. P~irk~inyi, D.S. Schmidt, J. Heterocycl. Chem. 2000, 37, 725. Y. Okamoto, H. S. Kim, J. Heterocycl. Chem. 2000, 37, 791. A. Gangjee, N.P. Dubash, S.F. Queener, J. Heterocycl. Chem. 2000, 37, 935. Y.J. Kang, W.S. Lee, H.K. Kim, Y.J. Yoon, J. Heterocycl. Chem. 2000, 37, 1049. A. Gangjee, M. Kothar6, R.L. Kisliuk, J. Heterocycl. Chem. 2000, 37, 1097. K. Shirai, K. Fukunishi, J. Htereocycl. Chem. 2000, 37, 1151. J. Zhou, Y. Hu, H.W. Hu, J. Heterocycl. Chem. 2000, 37, 1165. Y. Okamoto, H. S. Kim, J. Heterocycl. Chem. 2000, 37, 1257. S. Laneri, A. Sacchi, E. Abignente, J. Heterocycl. Chem. 2000, 37, 1265. P. Heeg, R.J. Alder-Jalil. R.A. AI-Qawasmeh, W. Voelter, J. Heterocycl. Chem. 2000, 37, 1273. H.S. Kim, G. Jeong, H.C. Lee, J.H. Kim, Y.T Park, J. Heterocycl. Chem. 2000, 37, 1277. K. Shirai, D.F. Hou, K. Fukunishi, M. Matsuoka, J. Heterocycl. Chem. 2000, 37, 1299. J.E. van Muijlwijk-Koezen, H. Timmerman, H. van der Goot, W.M.P.B. Menge, J.F. von Drabbe Ktinzel, M. de Groote, A.P. IJzerman, J. Med. Chem. 2000, 43, 2227.

293

294 OOJMC2310 00JMC3837 00JMC3995 00JOC4618 00JOC5668 00JOC5996 00JOC6388 00JOC9261 00JOC9265 00MC34 00OL803 00OL1967 00OL3389 00OL3761 00OL3825 00RCB355 00S255 00SC81 00SC1985 00SL625 00SL905 00SL1458 00T265 00T897 00T2481 00T3709 00T4739 00T5185 00T5499 00T6701 00T7245 00T7987 00T8489 00T9221 00TL355 00TL647 00TL771 00TL 1147 00TL 1757 00TL3197

B.R. Lahue, G.H.C. Woo a n d J.K. S n y d e r G. Bold, J. Med. Chem. 2000, 43, 2310. A. Gangjee, J. Yu, J.J. McGuire, V. Cody, N. Galitsky, R.L. Kisluik, S.F. Queener, J. Med. Chem. 2000, 43, 3837. M.S.S. Palanki, P.E. Erdman, L.M.Gayo-Fung, G.I. Shelvin, R.W. Sullivan, M.J. Suto, M.E. Goldman, L.J. Ransone, B.L. Bennett, A.M. Manning, J. Med. Chem. 2000, 43, 3995. M. Abarbri, J. Thibonnet, L. B6rillion, F. Dehmel, M. Rottl~inder, P. Knochel J. Org. Chem. 2000, 65, 4618. J.F. Djung, D.J. Hart, E.R.R. Young, J. Org. Chem. 2000, 65, 5668. D.L. Boger, J.K. Lee, J. Org. Chem. 2000, 65, 5996. V. Benin, P. Kaszynski, J. Org. Chem. 2000, 65, 6388. H. Sard, M.D. Gonzalez, A. Mahadevan, J. McKew, J. Org. Chem. 2000, 65, 9261. R.E. Sammelson, M.M. Olmstead, M.J. Haddadin, M.J. Kurth, J. Org. Chem. 2000, 65, 9265. B.I. Buzykin, V.V. Yanilkin, V.I. Morozov. N.I. Maksimyuk, R.M. Eliseenkova, N.V. Nastapova, Meendeleev Commun. 2000, 34. S. Choppin, P. Gros, Y. Fort, Org. Lett. 2000, 2, 803. T.J.J. MOiler, R. Braun, M. Ansorge, Org. Lett. 2000, 2, 1967. J.A. McCauley, C.R. Theberge, N.J. Liverton, Org. Lett. 2000, 2, 3389. N. Choy, B. Blanco, J. Wen, A. Krishan, K.C. Russell, Org. Lett. 2000, 2, 3761. D.B. Kimball, A.G. Hayes, M.M. Haley, Org. Lett. 2000, 2, 3825. G.L. Rusinov, R.I. Ishmetova, N.I. Latosh, I.N. Ganebnych, O.N. Chupakhin, V.A. Potemkin, Russ. Chem. Bull. 2000, 49, 355. Z. Wang, R. Neidlein, C. Krieger, Synthesis 2000, 255. Y.H. Roh, J.W. Bae, G.S. Nam, J.H. Kim, S.H. Kim, C.M. Yoon, Synth. Commun. 2000, 30, 81. E.I. A1-Afaleq, Synth. Commun. 2000, 30, 1985. E.V. Tarasov, A. Henckens, E. Ceulemans, W. Dehaen, Synlett. 2000, 625. M.E. Angioletti, A.L. Casalnuovo, T.P. Shelby, Synlett. 2000, 905. T. Trcek, A. Meden, B. Vercek, Synlett. 2000, 10, 1458. A. Lepr~,tre, A. Turck, K. PI6, P. Knochel, G. Qu6guiner, Tetrahedron 2000, 56, 265. A.H.M. Elwahy, Tetrahedron 2000, 56, 897. V. Martfnez-Barrasa, F. Delgado, C. Burgos, J.L. Garcfa-Navfo, M.L. Izquierdo, J. Alvarez-Builla, Tetrahedron 2000, 56, 2481. A. Lepretre, A. Turck, N. Pie, G. Queguiner, Tetrahedron 2000, 56, 3709. Y. Bessard, R. Crettaz, Tetrahedron 2000, 56, 4739. Y.M. Volovenko, E.V. Blyumin, Tetrahedron 2000, 56, 5185. V.G. Chapoulaud, N. Pie, A. Turch, G. Queguiner, Tetrahedron 2000, 56, 5499. M.J. Kische, J.-M. Lehn, M. Kyritsakas, J. Fischer, E.K. Wegelius, K. Rissanen, Tetrahedron 2000, 56, 6701. A. Witt, J. Bergman, Tetrahedron 2000, 56, 7245. ,~,. Kiss, J. K0k0si, R. Rotter, I. Hermecz, Tetrahedron 2000, 56, 7987. F. Pezet, L. Routaboul, J.-C. Daran, I. Sasaki, H. Ai't-Haddou, G.G.A. Balavoine, Tetrahedron 2000, 56, 8489. C.J. Barnett, L.M. Grubb, Tetrahedron 2000, 56, 9221. T. Emoto, N. Kubosaki, Y. Yamagiwa, T. Kamikawa, Tetrahedron Lett. 2000, 41,355. G.T. Manh, R. Hazard, J.P. Pradere, A. Tallex, E. Raoult, D. Dubreuil, Tetrahedron Lett. 2000, 41,647. M.S. Shvartsberg, I.D. Ivanchikova, Tetrahedron Lett. 2000, 41, 771. Z. Xin, Z. Pei, T. von Geldem, M. Jirousek, Tetrahedron Lett. 2000, 41, 1147. M. Zanda, P. Talaga, A. Wagner, C. Mioskowski, Tetrahedron Lett. 2000, 41, 1757. E. Ford, A. Brewster, G. Jones, J. Bailey, N. Summer, Tetrahedron Lett. 2000, 41, 3197.

S i x - M e m b e r e d Ring Systems: Diazines and Benzo Derivatives

00TL4307 00TL4777 00TL5265 00TL5857 00TL6559 00TL7005 00TL8177 00TL8333 00TL9267

S.P. Keen, S.M. Weinreb, Tetrahedron Lett. 2000, 41, 4307. P.M. Fresneda, P. Molina, S. Delgado, J.A. Bleda, Tetrahedron Lett. 2000, 41, 4777. J. Azizian, M. Mehrdad, K. Jadidi, Y. Sarrafi, Tetrahedron Lett. 2000, 41, 5265. M. Soukri, G. Guillaumet, T. Besson, D. Aziane, M. Aadil, E.M. Essassi, M. Akssira, Tetrahedron Lett. 2000, 41, 5857. Q. Dang, B.S. Brown, M.D. Erion, Tetrahedron Lett. 2000, 41, 6559. R.-Y. Yang, A. Kaplan, Tetrahedron Lett. 2000, 41, 7005. A.D. Baxter, E.A. Boyd, P.B. Cox, V. Loh Jr., C. Monteils, A. Proud, Tetrahedron Lett. 2000, 41, 8177. S. Makino, N. Suzuki, E. Nakanishi, T. Tsuji, Tetrahedron Lett. 2000, 41, 8333. Y. Kamitori, Tetrahedron Lett. 2000, 41, 9267.

295

296

Chapter 6.3

Six-Membered Ring Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems Carmen Ochoa and Pilar Goya

Instituto de Qufmica Mddica (CSIC), Madrid, Spain. e-mail: [email protected], [email protected]

6.3.1. TRIAZINES Tris[3-hydroxy-l,2,3-benzotriazin-4(3H),one]iron(III) complex has been described as a source of activated N2 upon visible wavelength ligand-to-metal charge transfer (LMTC) excitation <00CC69>. Substituted 1,3,5-triazines have been used as chiral solvating agents for chiral discrimination <00TA1555, 00TA3901, 00TA2067>. 1H- and 13C-NMR <00MRC504> and circular-dichroism <00EJOC1767> studies on different melamine (2,4,6t riamino-1,3,5-t riazine) derivatives have been reported. Combination of hexa(chloromethyl)melamine (HCMM) and zinc chloride has been found to be a multifunctional initiator system for the living cationic polymerization of isobutyl vinyl ether <00MI472>. Covalent linkage of three calix[4]arene units (containing two units of melamine) in hydrogen-bonded assemblies via a threefold ring closing metathesis (RCM) reaction quantitatively converts the dynamic assemblies into covalent systems (123membered macrocycles containing six units of melamine) <00CC367>. Guest-templated selection and amplification of a receptor, constituted by a calix[4]arene containing two units of melamine linked to two opposed zinc-porphyrin moieties, by non covalent combinatorial synthesis has been achieved using 1,3,5-tris[4-pyridyl]benzene as template <00AG(E)755>. An X-ray study on 1,3,5-triazine-2,4,6-triaminehexaacetic acid and its calcium salt reveals the existence of novel channel type cavities and helical packing organizations in the crystals <00CC1351>. Cyanuric acid forms a 2:1 hydrogen-bonded adduct with 4,4'-bipyridyl when co-crystallized from a methanol solution and a 1:1 adduct from an aqueous solution <00MI87>. Methyl rearrangement of 2,4,6-trimethoxy-l,2,3-triazine in the solid and liquid state has been investigated <00T6887>.

6.3.1.1. Synthesis 3-Substituted derivatives of 1-(tetrahydrobenzo[b]thiophen-2-yl-3-carboxylate)-5-phenyl6-thio-l,2,4-triazin-4-one have been synthesized by heterocyclization reactions of different hydrazones obtained from 2-amino-tetrahydrobenzo[b]thiophene-3-carboxylate with phenyl isothiocyanate <00PS275>. Reaction of S-methyl isothiosemicarbazide with c~-amino acid vicinal tricarbonyl reactive substrates 1 and 2 yields 1,2,4-triazine substituted a-amino acids, as an equimolar mixture of regioisomers 3a/3b and 4a/4b, respectively <00JCS(P1)299>.

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems MeS,,~ N~-C02 But O

O

NBoc2

B u t O ~

"

OBut

O'H20

O

eSy Jn

Boc2N. T/CO2But

N-N~]n

N" N//~'-CO2But

ButO2C/"NBoc2

3b, 4b

3a, 4a

1,n =1,2, n =2 i: H2NHN(CSMe)NH-HI, pri2NEt, DCM, reflux

297

3a/b, n = 1 (87%), 4a/b, n = 2 (76%)

Ring closure of 2-oxohydrazones 5a and 5b in refluxing dioxane occurs through an unusual intramolecular nucleophilic attack of the semicarbazide amino group to the keto function. The resulting 1,2,4-triazine carboxylates 6a (unequivocally assigned by X-ray analysis) and 6b provide 5-methoxy derivatives 7a and 7b upon reflux in methanol <00JOC2820>. R1, ~ O

H N " N Y NH2 O

dioxane reflux "

5a, R l= C02Me 5b, R2 = C02Et

H O , ~ N R1 HN ~ OH "N Me

H MeOH O , ~ / N , , ~ 1 I'OMe reflux " - HN'I~-A~ Me

6a (8 h, 79%) 6b (12 h, 70%)

7a (48 h, 68%) 7b (8 h, 79%)

An unexpected production of 2,4,6-triphenyl-l,3,5-triazine in the electroreduction of 3,4diphenyl-l,2,5-thiadiazole 1-oxide has been reported <00TL3531>. Synthesis of 1,3-diyne derivatives of 2,4-diamino-l,3,5-triazine, 9a and 9b, has been accomplished by reaction of biguanidine with mono- and di-esters 8a and 8b, respectively <00T1233>. NH2 R1 ~

~

R2

biguanidine MeOH, 40~

8a, R 1 = n-C10H21, R 2 = CO2Et

8b, R1 = R2 = (CH2)sCO2Et

R3 ~

--

(CH2)n-~

N

N=(

NH2

9a, R3 = n-C1oH21,n = 0 (59%) NH2 9b, R3 =-(CH2)8--(N--~N, n=8(21%)

N=(

NH2

Spatially addressed synthesis of amino and amino-oxy substituted 1,3,5-triazine arrays on polymeric membranes used for the preparation of a combinatorial library of 8000 compounds has been reported <00MI361>. The quantitative synthesis of perhydro-l ,3 ,5tris(alkylpolyalkyloxy)-l,3,5-triazines has been described <00JHCl157>. New hexahydro1,3,5-triazine-2-thione derivatives have been prepared by aminomethylation of thiourea with formaldehyde and primary amines <00MI442>. A family (12) of conjugated diamino-l,3,5triazine-functionalized chemosensors for flavine has been synthesized. Reaction of the corresponding nitriles 10 with cyanoguanidine provides diaminotriazines 11 which by acylation with isobutyryl chloride yield receptors 12a -12d. Triazine 12e is obtained by ammonia treatment of the triacylated derivative <00JCS(P2)1309>.

298

C. Ochoa and P. Goya

CN

H2N I . ~ ~ . . . N H 2

N

H2N"~ N"CN H

O I

KOH

X2

pyridine

Xl X2

X 2 "~

y

Xl

10

Xl

11

a) X 1= X 2 = H; b) X 1 = CI, X2 = H; c)

X1 =

12

OMe, X2 = H; d)

X1=

OMe, X2 = OMe; e) X 1 = NMe2, X2 = H

Condensation of N-perchloroethenylbenzimidoyl chlorides 13 with S-alkylisothiuronium iodides leads to the formation of 4,6-disubstituted 2-alkylthio-l,3,5-triazines 14 in high yields. Their N-alkyl isomers 15 are synthesized by successive treatment of chlorides 13 with strong basic primary amines and sodium thiocyanate <99MI996>. CI RI'Y~ CI RI'~'~

CI

CI

R1~

-

CIi y ~ c i'

CI

~

.~.

13. RI= H. Me. Et

,-#-c,

N.~N

SR2

SR2

14, R2= Me, Et

a) R2NH2 J b) NaSCN R1

R1 " " 1 " ~

R2/

CI

CI

R2..N~s N 15

Interaction of N-pentafluorophenylcarbonimidoyl dichloride with benzonitrile and aluminium trichloride leads to 1-pentafluorophenyl-4,6-diphenyl-l,3,5-triazin-2-one along with urea derivatives <00JFC(103)63>. Reaction of perfluoro-5-azanon-4-ene with a range of bidentate nitrogen nucleophiles (urea, substituted amidine hydrochlorides and guanidine), in the presence of triethylamine or potassium hydroxide, effectively provides fluorinated 1,3,5triazines 16-19 <00JFC(103)105>. R

16

17

18

R = (CF2)2CF3

19

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems

299

In the reduction reaction of the methylpyridinium salt 20, with a variety of reagents, the novel piperidine spiro triazine derivative 21 together with thiazole derivative 22 is obtained, the spiro compound 21 being the major reaction product <00EJOC675>.

~N,,,~N~O I

Me

BH4Na

Pr-.

Et

I~~.NN~

Pr

r

Pr

Me/ 'Me Me

20

21

22

A novel route to synthesize 1,3,5-triazine-2,4(1H,3H)-diones through the desulfurization of thiocarboamides, such as 1,3-disubstituted 2-thioureas, trisubstituted thioureas and Nsubstituted thioamides by silver cyanate has been reported <00H(53)929>. Treatment of urazole 23 with one equivalent of sodium hydride under anhydrous conditions, followed by addition of dimethyl sulfate, leads to 1,3,5-triazine-2,4-dione 24 in 80% yield <00OL1295>.

~ N_N/~COP h O

N O I Me

Nail

COPh

Me2SO4~- L " , , ~ N - ' ~ N ' M e

Ar, 30 min

Ar, 12 h

O

23

Ni O Me 24

The synthesis and crystal structure of the peptide nucleic acid (PNA) monomer 25 having cyanuric acid as nucleobase have been described. Monomer 25 can be directly used for the solid phase synthesis of PNA oligomers <00OL2825>.

O H2NCONHCONHNO2---'-~

H2N-JI"NH

iii

.•

HN

H,,N,,'~ O

L

" CO2Bn

/) glycinebenzyl estertoluene-4-sulfonate, EtaN,DMF, 80~ 6 h; ii) carbonyldiimidazole, pyridine, reflux, 30 min; , iii) aqueous KOH, MeOH, reflux, 45 min; iv) ethyl N-(2-Boc-aminoethyl)glycinate,HOBT, 0~ DCC, DMF.

O NH

iv

HN "jl" NH

LCOH

Boct- N ~ H

Nv~U2tt 25

Reactions of arylchloromethyl-p-tolyl sulfoxides with tetrasulfur tetranitride ($4N4) yield 3,5-diaryl-l,2,4,6-thiatriazine 1-oxides <00T7153>. [4+2] Cycloadditions of thiazyl derivatives 26a and 26b to the 1,3-diazabutadiene 27 give the corresponding 2,5-dihydro1,2,4,6-thiatriazines 28a and 28b respectively <00JFC(103)337>.

300

C. Ochoa and P. Goya /OF3

N---S-R +

ph//<"N CF3 Me~ Me

26a, R = F

26b, R = ON(CF3)2

CF3,,><.CF3 SO 2

27

6.3.1.2. Reactions

Interaction of 5-methoxy-l,2,4-triazines with ureas in the presence of acylating agents has been reported as a new route to 6-azapurines <00MC58>. A new synthesis of pyrazolo[4,3e]-[1,2,4]triazines via acid-promoted ring-closure of the phenylhydrazones of 5-acyl-l,2,4triazines has been described <00H(53)2175>. A new entry for short and regioselective synthesis of 1,2,4-triazolo[4,3-b][ 1,2,4]-triazin-7-ones from 1,2,4-triazin-3-yl-thiomethylene derivatives has been investigated <00JPR599>. A novel one-pot synthesis of annulated 2,2'bipyridine ligands by inverse electron demand Diels-Alder reaction of 5,5'-bis-[(3,3'-dimethylthio)-l,2,4-triazines] has been reported <00TL3657>. 5-Cyano-l,2,4-triazines undergo Ritter reaction with secondary and tertiary alcohols to form N-alkylated-l,2,4triazine-5-carboxamides <00MCll7>. A new route to functionalized 3-aminopyridazines by ANRORC (addition of nucleophile-ring opening- ring closure) type ring transformation of 1,2,4-triazines with carbon nucleophiles has been reported <00JHC879>. Condensation of acetic acid hydrazides 29 with carbonyl compounds yields the corresponding acetic acid hydrazides 30 which are transformed into several heterobicyclic systems among which 1,2,4triazine derivatives 31 and 32 are found <00IJC(B)36>.

N-N

FeCI3/EtOH Ph.. :,,N..N/"~-~ O R1COR2 Ph. >N,N/~.O

RI=H

31

" \~O NH2 29

30

RII~R 2

ph/~N~o

NaOEt R1 = CH(Ph)OH

N--~O O~--NH ph/

ph/

"R 2

32

Regiocontrolled alkylations of chiral 4,5-dihydro-l,2,4-triazin-6-ones using sodium hydride in DMF has been reported. By this approach different Nl-alkyl, N1,N4-dialkyl and N4-alkyl dihydrotriazinones could be obtained in good yields with conservation of their optical activity <00TL671>. A novel class of dioxolane 1,2,4-triazine and 1,3,5-triazine nucleoside analogues have been prepared, in several steps, by reaction of 4-acetoxy-2benzyloxymethyldioxolane and the corresponding silylated triazines <00MI603>, <00BMCL2145>. A novel ring contraction of 6-azauracils yields imidazole derivatives <00T5909>. Azauracil-5-yl-isatin 33 is converted through its thiosemicarbazone 34 to 6-(6-azauracil-5-

Six-Membered Ring Systems: Triazines,Tetrazinesand Fused Ring Polyaza Systems

301

yl)-2,3-dihydro-5H-1,2,4-triazino[5,6-b]indol-3-thione 35. Reaction of the potassium salt of isatinic acid 36 with thiosemicarbazide yields the bis-(6-azauracil-5-yl)-anilino derivative 37. Cyclocondenstion of 37 in acetic acid medium affords a mixture of the two regioisomers 35 and 38 in a 10/3 ratio <00JHCll5>. o

N HN'-I~-NH O

O

~CO KOH~. N ~ O

NH2NHCSNH2

NH2

HN',IF'NH O

33

H

,N,,cS

COOK

~oNH T NH2

NH2NHCSNH2oH_ ~ N"'~'~i~0

HN'-II/NH O

36

37

Na2C03 or DMP

H 0 $

N~

••_...•N-

N~==S

--o.-

0

reflux~

HN~II,'NH O 34

HN~rF-NH O

0

35

38

Reaction of hydrazonoyl halides 40 with 4-amino-2,3-dihydro-6-substituted-3-thioxo1,2,4-triazinones 39 gives 1,2,4-triazino[4,3-b ][ 1,2,4,5]tetrazine derivatives 41 <00JPR96>.

R1I ~ N " N H 2 N. N,~S H 39

R2

N" H

0 H 40

R3

R2

Et3N EtOH R3

41

When 1,3,5-triazine is allowed to react with dinitrogen pentoxide and quenched with methanol the cis and trans isomers of 1,3,5-trinitro-2,4,6-trimethoxy-hexahydrotriazine are obtained. Nitration of the triazine in deuterated nitromethane at -10 ~ affords the mixture of cis and trans 2,4,6-trinitrato-l,3,5-trinitro-hexahydro-l,3,5-triazines which are decomposed at room temperature <00JOC4743>. Hexahydro-l,3,5-triaryl-l,3,5-triazines cyclorevert upon exposure to HC1 gas to give solid arylmethylene iminium chlorides as new versatile reagents

302

C. Ochoa and P. Goya

<00JPR269>. 1,3,5-Triallyl-hexahydro-l,3,5-triazine has been used in the preparation of a C4 unsubstituted azetidinone which is the starting material for the synthesis of penems and cephams <00S289>. A novel method for the preparation of N,N'-disubstituted-N" nitroguanidines via 2-nitroimino-hexahydro-l,3,5-triazine derivatives has been studied <00TL7187>. Nucleophilic aromatic substitution of cyanuric fluoride (2,4,6-trifluoro-l,3,5-triazine) yields four 1,3,5-triazine derivatives with donor groups, 4-N,N-diethylaminophenyl and 4N,N-diethylaminophenylethynyl, as substituents. These triazines are the most active twodimensional (2D) chromophores found so far <00AG(E)1436>. Several reactions of cyanuric chloride have been reported. Cyanuric chloride has been the starting material for nanostructure polymer duplexes <00JA5006>, for dendrimers based on melamine <00OL843> and for the two new triazine derived macrocycles 42 (00PJC837) and 43 <00TL1837>. 7o

NHR 2

o

NH

NH

42

43

Reaction of cyanuric chloride with the sodium salt of hydroxyaryl compounds under microwave irradiation afforded 2,4,6-triaryloxy-l,3,5-triazines <00SC1719>, with Grignard reagents followed by amination gave 2-(alk-l'-ynyl)-l,3,5-triazines and 2-alkyl-4,6dialkylamino-l,3,5-triazines in one-pot reactions <00T9705> and with diarylamines provided 2,4,6-tri(diarylamino)-l,3,5-triazines, the cationic states of which have been analyzed <00OL171>. The first example of an isocyanurate-containing fullerene has been provided by cycloaddition of 5-[5'-(azidopentyl)]-1,3-diallyl-1,3,5-triazine-2,4,6-trione to C60 <00MC61>. The salt formed from 2-chloro-4,6-dimethoxy-l,3,5-triazine and Nmethylmorpholine (DMTMM) is an effective coupling agent for solid phase peptide synthesis <00SL275>. Naphthalene-catalyzed lithiation of 2-chloro-4,6-dimethoxy-l,3,5-triazine in the presence of different electrophiles yields, after hydrolysis, the expected functionalized 2substituted-4,6-dimethoxy-l,3,5-triazines <00T4043>. Reactions of 1,3-disubstituted 5-(0)bromoalkyl)hexahydro-l,3,5-triazin-2,4,6-triones with bis(2-hydroxy-ethyl)amine and with thionyl chloride <99MI1817> and thiourea <99MI1827> have been reported. H

Me '

Me"'~ i-N'S~" Me + MeSi(OMe)2-(CH2)3SH Me/N'sr "N"Me Me" "H 44

45

Me,

RhCl(Ph3P) 3

C6H6

iP-

Me

R...Si- "Si- Me Me/N'sr"N"Me Me" "R 46

R = S(CH2)2Si(OMe)2Me Dehydrocoupling of polyhydrosiloxane 44 with thiol 45 proceeds smoothly in the presence of Wilkinson 's catalyst to furnish polythioether 46 in high yield <00TL1127>.

303

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems

6.3.2. TETRAZINES The conformation of a diaryl-dialkyl-hexahydro-l,2,4,5-tetrazine crystallographic analysis has been reported for the first time <00SL137>. 6.32.1.

by

X-ray

Synthesis

A procedure for the preparation of 3,6-bis(4-hydroxyphenyl)-l,2,4,5-tetrazine (48) from phenol 47 and hydrazine has been described <00SC1083>. +

NH2CI-

H O / ~

OMe

NH NH

dioxane

=,- HO

~

47

HN- NH

OH

48

Reaction of dichlorobenzaldazine (49) with sodium azide and 1-propanethiol gives the unprecedented ylide 50, as the main product, confirmed by X-ray analysis <00JA2087>.

Cr~N Cl,~a Ph

I

Ph NaN3/TEBAC N"~b~/I~'S~ Et ~ I II PrSH/Et3N a,~,, a Ph

49

50

Phenylhydrazones 51a and 51b have been converted into 1,2,4,5-dihydrotetrazines 52a and 52b by reflux in acetonitrile in the presence of ammonium acetate <00S 1166>.

r-O B RJ~N_NHP h 51a, R = CN

51b, R = COPh

, N..O c

MeCN ~

Ph,

R

4 , ~ I~1,, Ph R

52a, R = CN 52b, R = COPh

Perhydro-l,2,4,5-tetrazines 54 and 57 have become accessible via novel azomethine/azomethine cycloadditions starting from rigid N=N/N=N systems 53 and 55, respectively <00EJOC763>.

304

C. Ochoa and P. Goya N

a) i ~

is

N''~'~

b) ii

Me

Me 54

53

.N~ae ,~ e ~ ~ ""' ~ -N ' MM~

H2/Pd~ MM MeOH

~N

HN NH HN' bMeN~ ^ ~

55

N,~Me "

a) i

b) iii 57

56

i: Me3OBF4/CH2CI2;//: K2CO3/H20, N2; iii,

Mel, K2CO3, Ar

6.3.2.2. Reactions 1,2,4,5-Tetrazines acting as oxidant and reactant with DBU have afforded the unexpected formation of a novel fused tetraheterocyclic azepine <00JOC9265>. Thermal Diels-Alder reactions between C60 and 3,6-diaryl-l,2,4,5-tetrazines yield monoadducts possessing a diaryldihydropyridazine function nested atop the fullerene <00OL3091>. Sequential inverse electron demand Diels-Alder reactions of an unsymmetrical N-acyl-6-amino-l,2,4,5-tetrazine have been used for the preparation of Lycorine alkaloids <00JOC9120>. The inverse electron demand Diels-Alder reaction between 3,6-diaryl-l,2,4,5-tetrazines 58 and imidazolidine 59 yield the dispiro derivatives 62 but not their regioisomers. When the reaction is performed at low temperature zwitterions 60a, 60b, 61b and 61c can be detected as intermediates depending on the nature of the aryl substituent (60a + 61a; 60b/61b, 33/67; 60c/61c, 0/100). On heating, compounds 60a and 60b yield the dispiro derivatives 62a and 62b, respectively, while the regioisomers 61b and 61c afford starting tetrazines 58b and 58c instead of the corresponding regioisomers of 62 <00T4213>.

'P~

.,,

,.

N.,~N

Ar

Me +

Me/

Ph

Me +P

t <-10~

58

59

N..~N 60

Me

.P~

~

.N., N:,N1e |

Me

Ar

61

,N

+ N

-N2

e

Ar 62

N

y

Ar

58

a, Ar = Ph; b, Ar = 2-Me.C6H4; r Ar = 2,4,6-Me3.C6H2 The heterocyclic azadiene Diels-Alder strategy to convert 1,2,4,5-tetrazine-3,6dicarboxylate into 1,2-diazine and then into pyrrole has been used for an efficient total synthesis of ningalin B <00JOC2479>. 1,2,4,5-Tetrazines and 1,2,4-triazines tethered to tryptamine via the ethylamine side chain undergo intramolecular inverse electron demand cycloadditions to produce adducts with the [ABazaCE]-ring skeleton of the aspiroderma alkaloids <00T1165>. The fact that the 3,5-dimethylpyrazol-l-yl moieties of 1,2,4,5-tetrazine 63 are good leaving groups in nucleophilic displacements has been used for the synthesis of azotetrazine 66, a novel high-nitrogen energetic material <00AG(E)1791>.

N

305

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems

Me Me Me~,~N 0.5 NH2NH2~ Me~ _..~N ~ N- N/u ~N"- " ' N~ ~ N - ~ ' ~ / N-N N ~ ~ =1~1 nl Me iprOH = N=N N~-" Me Me

Me

63

64 (79%)

/

N-N N-N H2N-~ k~"N=N--'~ NI~'-"NH2 ,i NH3 N=N N=N DMSO

Me,.,,,~N

MeCN~ NBS N-N N-N

Br/ ~

N=N

Me

66 (44%)

N=N

Me

}~...jBr "N-~'~Me

65 (98%)

63.3. FUSED [6]+[5] POLYAZA SYSTEMS Structure-activity studies in the pyrazolo[1,5-a]-l,3,5-triazine series have provided a potent, orally bioavailable CRF1 receptor antagonist <00JMC449>. Anilide derivatives of an 8-phenylxanthine carboxylic congener have been reported as potent and selective antagonists at human A(2B)adenosine receptors <00JMCl165>. Novel 6-cyclohexylmethyloxyguanines have been identified as cyclin-dependent kinase inhibitors <00JMC804>, and purine-based peptidomimetics as vitronectin receptor antagonists <00AG(E)2874>. Chemiluminescence and bioluminiscence properties of imidazopyrazines bearing an azido group have been studied <00BCJ465>. Applications of (15N) labelled 1,2,5-oxadiazolo[3,4-d]pyrimidine-1oxides as a useful tool for mechanistic investigations have been described <00JOC6670>. 63.3.1. Synthesis The synthesis of pyrazolo[4,3-d]-l,2,3-triazine starting from a pyrazolo-3-carbaldehyde derivative has been reported <00JIC168>. Azolo-l,2,4-triazine derivatives have been prepared via the reaction of functionalized thiazole derivatives with several heterocyclic diazonium salts <00JCR(S)206>. The reaction of 1,2,4-triazolium salt 67 with alkene 68 gives the pyrrolo[2,1-f][1,2,4]triazine 69 <00H(53)213>. N--.N-I~~Br-CH2CO2Et + M e S ~ _ H

Bn 67

MeS 68

K2CO3 ~

N~/N"L~NO2

NO2 CHCI3/EtOH Brf" O~ ~SMe 69 (44%)

The solid phase synthesis of various substituted purines starting from 4,6-dichloro-5nitropyrimidine using Rink amide resin has been described <00MI249>. 6,8,9-Trisubstituted purine analogues are efficiently synthesized via cyclization of 6-chloro-4,5diaminopyrimidines and various aldehydes promoted by FeCI3-SiO2, this mixture having a dual role of dehydration and oxidation agent <00TL6559>. The synthesis and antiviral properties of guanine derivatives as novel acyclovir analogs have been described <00FES104>.

306

C. Ochoa and P. Goya

The synthesis of some novel acyclonucleosides involving pyrrolo[2,3-c]pyridazine and a 4-hydroxybutyl side chain has been reported <00H(53)5>. New pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent, as potent and selective inhibitors of lck (an src-family tyrosine kinase), have been synthesized and tested <00BMCL2171>. Dicyanomethylenethiadiazine 70 reacts with SC12 in the presence of benzyltriethylammonium chloride to give cyanopyrrolo[2,3-c][1,2,6]thiadiazine 71 <00J CS(P 1) 1089>.

NC~I CN c,.~c,

NC_% /CI so,2 ,~ c , ~ . ~ BnEt3N+CF/CH2012 Nxs.N

N\s.N

71 (20%)

70

An efficient one-pot synthesis of some novel azolo[1,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[1,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of c~-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal <00EJOC1661>. A rapid synthesis of trisubstituted 1,2,4-triazolo[4,3-b]pyridazines has been devised to give selective variation of the three substituents through combinations of silicon-directed anion formation, palladium-catalyzed couplings and SNAr displacements <00TL781>. The synthesis of new 1,2,4-triazolo[1,5-a]pyrimidines <00MI435>, 1,2,3-triazolo[4,5-d] pyrimidine isonucleosides <00HCA1398>, 1,2-bis(1,2,4-triazolo[3,4-b]thiadiazino-3-yl) ethanes <00FES354>, 1,2,4-triazolo [3,4-c]pyrimidines and 1,2,3,4-tetrazolo[4,5-c] pyrimidines <00JHC707> have been reported. 6.3.3.2. Reactions

Several methods for the functionalization of the 4-position of imidazo[4,5-d][1,2,3]triazin4-one to afford 9-ribofuranosyl derivatives of 2-azapurines have been investigated <00MI39>. Alkylation of purine derivative 72 yields an N-7/N-9 regioisomer (73/74) mixture which can be purified using aluminium oxide/H + to provide the N-9 isomer selectively as a parallel or chemoselective high-throughput purification <00TL3573>.

OBn I~~N~ H2N~ Ik~r'N 72

i:

+

RCH21~

i

OBn /----R OBn OBn N N H § N~ N ~ N~N/~ .~NINe:\) Alumina:N~~~[~N~ H2 H2N ~i._a H ~--a +

73

74

74

2-tert-Butylimino-2-diethylamino-l-(4-polystyrylmethyl)-3-methylperhydro-1,3,2-diazaphosphori / MeCNne

307

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Potyaza Systems

Reaction of 6-halopurines with Michael acceptors under Heck conditions gives N-Isubstituted hypoxanthine derivatives <00CCC797>. Reactions of a series of 1aminobenzimidazoles and 1-amino-3-methylbenzimidazolium chlorides with 2,4pentanediones afford pyridazino[1,6-a]benzimidazoles and 2-pyrazolylanilines, the product ratio depending on conditions and on the electronic character of the substituents at the benzene moiety <00BMC37>. Cyclization reactions of adenine derivative 75 with different amines or hydrazine afford tricyclic polyaza compounds 76 <00CCC1109>. ,NH2

N.H2

~CH2)4Cl 75

R = H, Me, Pr, cyclopropyl, NH2

76

Reaction of 8-mercaptohypoxanthine with dihaloalkanes in liquid ammonia yields the corresponding symmetric dithioether derivative <00MI160>. A series of 6-alkyl- and 6arylamino-9-(tetrahydro-2-pyranyl)purines have been prepared in three steps in 35 to 45% overall yield from 6-methylthiopurine via 6-methylsulfonylpurine <00MI1005>. Starting from guanine the regioselective synthesis of various prodrugs of ganciclovir has been accomplished <00TLll31>. The NMR data for these pro rugs has been reported <00MRC696>. Solvent-free transformation of xanthines into thioxanthines by Lawesson's reagent using microwave irradiation has been described <00H(53)2275>. Substitution reactions in xanthines <00JMC1223>, theophylline <00T7685> and different purines <00JCS(P1)2015, 00T4589, 00JMC1817, 00JMC1282, 00MIl193, 00TL7211> have been described. The glutamic moiety of TNP-351, a pyrrolo[2,3-d]pyrimidine glutamic acid derivative, and related compounds have been transformed into their N-co-masked omithine analogs which show remarkable antifolate activity <00CPB1270>. The reaction of the heterocyclic enamine 77 with tosyl azide leads to the tosylimino derivative of 1,2,4-triazolo[1,5a]pyrimidine 79. Extrusion of nitrogen from the primary adduct 78 is followed by a 1,2-shift of a methyl group to yield 79 <00JHC195>.

.Ph

LN

Me I

77

TsN3 Et20/AcOEt

Me

48 h, r.t.

N~N k

N Ie 78

- N2~

TS~

N ~ N ~

Me

I~le 79 (67%)

The 4-hydrazino-pyrazolo[3,4-d]pyrimidine derivative 80 yields pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidinones 82 through hydrazone derivatives 81 <00JCS(P1)33>, these compounds being a new class of potential xanthine oxidase inhibitors.

308

C. Ochoa and P. Goya NHNH2

C

NHN=CHR

N

RCHO

]D

DMF, r.t.

H

Cl

N~N

N

70% HNO3

DMF, 100~

H

iv

81 (63-95%)

SO

N H

H

82 (60-85%)

6.3.4. FUSED [6]+[6] POLYAZA SYSTEMS 6.3.4.1. Synthesis The Staudinger reaction of N-substituted o-azidobenzamides 83 with triphenylphosphine yields phosphazides 84 which react with isocyanates to give, unexpectedly, the corresponding 1,2,3-benzotriazinone derivatives 85 <00T4079>. CONHR 1 "N 3

PPh3

~'~

CH2Cl2

~

CONHR 1 "I~-N=N- P(Ph)3 +

83

"c~

R2NCO

Ik..~N~N

84

85

A strategy has been described for the synthesis of 2-ethylthio-6-(3-hydroxy-l,2-Oisopropylidenepropyl)pteridin-4(3H)-one 90 which can be used as a useful intermediate for the conversion of neopterin to biopterin. Diaminopyrimidinone 86 reacts with D-arabinose phenylhydrazone 87, the obtained diastereomeric mixture 88 is converted into its isopropylidene derivative 89 which under oxidation conditions yields 90 <00H(53)1551>. ~,NNHPh HN

NH2

EtS

NH2

H%~O H +

HO /Xg,H HOH2C" OH

86 o

N/J 90

i: 50% MeOH (aq.), 5N HCI,

iii" 02, pH 10, r.t.

EtS

HN

,,,0 -~

EtS

H 89

~

OH

88

87

N.-T/'h,,'~ 2" CH2OH

HN EtS

. .L. •N•

H HQ-H N ~ O H

HN

(~) H H OH HN.'~..f N - . ~ , , , O H

" sts.J-,'-N l o.J 88

HS(CH2)2OH,N2, reflux, 1 h.; ii: 2,2-dimethoxypropane,p-TsOH, DMF, r.t., 16 h.;

Solid-phase synthesis of dihydropteridinones has been achieved from 4,6-dichloro-5nitropyrimidine <00TL8177>. A series of ethyl 7-aminopteridine-6-carboxylate derivatives has been prepared in one step from the reaction of vicinal diamines as 1,3-dialkyl-5,6diamino-2-thiouracils with diethyl (E)-2,3-dicyanobutenedioate <99JHC1317>. The relative binding affinities to human dihydrofolate reductase of new 2,4-diaminopteridine derivatives

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems

309

have been estimated by free energy perturbation (FEP) simulations. The more promising derivative has been synthesized by standard solution-phase chemistry combined with solidphase synthesis <00JMC3852>. New lipophilic methotrexate-lipoaminoacid conjugates coupled with amide or ester linkages have shown antitumor activity <00MI237>. Cyclocondensation of 4-cyano-5-methoxycarbonyl-6-phenyl-3(2H)-pyridazinone with hydrazine hydrate provides an efficient method to obtain the pyridazino[4,5-d]pyridazine ring system <00TL2863>. A double retro Diels-Alder reaction has been applied for the preparation of a pyrimido[1,2-b]pyridazine <00SL67>. High-throughput organic synthesis of bicyclic diketopiperazines, as peptide 13-turn mimetics, using Merrifield resin-bound piperazine-2-carboxylic acid has been described. A combinatorial library of six compounds has been obtained <00TL4841>. A facile synthesis of bicyclic diketopiperazines as conformationally restricted reverse turn mimetics has been described <00OL301>. New substituted pyrido[2,3-d]pyridazines have been prepared in one step from the corresponding arylidene substituted Meldrum's acid <00T2473>. The synthesis of pyridopyrimidines via palladium-catalized reaction of iodouracil with acetylenes<00TL5899> and with olefins <00SC81> has appeared in the literature. An elegant approach towards the regioselective synthesis of pyrido[2,3-d]pyrimidines through nucleophile induced ring transformations of cyanopyran-2-ones has been described <00S541>. Different pyridopyrimidines as antiviral and cytotoxic agents <00JMC2915>, tyrosine kinase inhibitors <00JMC1380> and antibacterials <00IJC(B)210, 00H(53)1129> have been synthesized and tested. 6.3.4.2. Reactions

Substitution reactions on benzotriazinone yield new 3-acyl and amidoyl derivatives with local anesthetic activity <00EJMC1043>. Analogs of the potent antifolate PT523 have been prepared from 2,4-diamino-6-bromoethylpteridine <00JMC1620>. Various 6-substituted pteridines and tetrahydropterins bearing photolabile functions at the side chain have been synthesized from pterin and 6-phenylpterin <00HCA2738>. Development of an efficient pteridine intermediate for the synthesis of folate ),-conjugated and its application for the synthesis of folate-nucleoside conjugates have been described <00JOC5016>. Substitution of 1,3-dimethyl-2,4-pteridinedione 6-triflate by copper acetylide proceeds regioselectively on the 7-position to give the corresponding 7-alkynylpteridine 6-triflate whose triflate group can be subsequently replaced by various nucleophiles <00H(53)1259>. The hydration of triple bonds is usually not regioselective, but substrate 91 gives acetonyllumazine 92 as unique product. Compounds 95 have been prepared by cross-coupling reaction of 6-bromo derivatives 93 with 1-ethoxyprop-l-enyltin 94 in the presence of a palladium catalyst and copper iodide <00JCS(P1)89>.

310

C. Ochoa and P. Goya

Me,,,NL

oJ'-N I

Me

i:

'~

HgSO4,H20,TFA.

O~.N~N ~ Me I

91

92 (100%)

MeoN ,iy Br

EtO

+ ~ BuaSn/

I

R 93

R=H, Me

N /CH2COCH3

ii:

Me

Me,,N L

ii

N~/TCO2Et

reflux)'.

,~N/[LN//' O i R 94 95 Pd(Ph3P)2CI2,Cul, Et3N,MeCN. R = H (77%); R = Me (96%)

Selective reduction of the 7-oxo group in pyrido[2,3-d]pyrimidine-4,7-diones has been described as a new synthetic approach to 5,10-dideazatetrahydrofolic acid <00H(53)1207>. Cycloaddition of pyrimido[4,5-c][1,2,5]oxadiazine 96 with 2,3-dihydrofuran affords a new synthesis of dimethyllumazine derivative 97 which undergoes a ring-opening reaction to give pyrazine derivative 98 <00JHC419>. o

o

M , OH2OH

OZSNLO+&_. O''Nt' I

Me 96

I

Me

MeHN .CH2OH

4..e

97

J

98

A report dealing with the bronchodilator activity and transamination reactions of 4-aminopyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides has been published <00JMC4219>. 6.3.5. MISCELLANEOUS FUSED RING POLYAZA SYSTEMS Several reports have dealt with structures which can be referred to under this heading, and only examples including the triazine ring will be highlighted. 6.3.5.1. Synthesis Several ring closure reactions of amino-substituted heterocyclic condensed systems, such as thiazolo[3,2-a]pyridines <00FES109>, thiazolo[2,3-b]quinazolines <00FES249>, thieno[2,3-b]pyridines <00PS53>, cyclopenta[e]thieno[2,3-b]pyridines <00PHA577> and thieno[2,3-b]thiophenes <00PS65>, with nitrous acid have been carried out to obtain the corresponding polycyclic heterocycles condensed to the 1,2,3-triazine ring formed in the reaction. A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane has been demonstrated by the synthesis of a variety of novel pyridotriazines (99), isoquinolinotriazines (100), benzimidazolotriazines (101) and benzothiazolotriazines (102) <00TL5613>.

Six-Membered Ring Systems: Triazines,Tetrazines and Fused Ring Polyaza Systems R1

311

ICH212 R2

~'

MeCN

N

NH2 R1 = H, CI, Br; R2= H, Br, OPh I-

99

I-

Me

I-

Me 101

100

102

The synthesis of new 1,2,4-triazinobenzimidazoles <00IJC(B)202>, <00JMC96>, 1,2,4triazinopyrazolo[3,4-d]pyrimidines <00AP(333)99>, 1,2,4-triazino-azaazulenes <00H(53)323> and 1,2,4-triazinoquinolines <00OL413> have been reported. The preparation of a novel heterocyclic ring system, the indazolotriazinopurine 1117, by the condensation of 8-hydrazinotheophylline (11)3) with 5-substituted isatins 11)4, via the hemiaminal 11)5 and hydrazone 11)6 intermediates, has been described <00JHC373>. R o

MeN

o

j

O&N ~/~NHNH2

+

R

"

I

O

EtO/refux

16-24 h m

H

Me 103

. , ~J. , ~N / ~-' N H N H O

I

Me

104 (R = H, F, NO2)

O

105 (95-99%)

H

~

220~C, 30 rain !

Me 107 (18-54%)

R

O i

Me

O

106 (77-90 %)

Phenyl isocyanate reacts, at room temperature, with substituted 3,4-dihydroquinazoline 11)8 to give the 1,3,5-triazinoquinazoline 11)9 by the expected [2+2+2] cycloaddition. However, at higher temperatures, the unexpected cycloadducts 111), and 111 are formed from these substrates <00EJOC2105>.

312

C. Ochoa and P. Goya

R1

~.~c___o~ A .

~,~

R1 R2 N

R1 R2 N

N" R2

N"Ph

,'"

OJ'~,~O

Ph

O

Ph

108

R1= H, Me; R2= Me, 4-Me.C6H4

Ph

109

110

Ph 111

6.3.5.2. Reactions

Upon treatment with a base the zwitterionic triazine derivatives 112 undergo a valence bond isomerization yielding 1,2,3-triazolo[4,5-d]pyridazine derivatives 113 <00CC1785>.

~~.~N,~ Me I

N~~Ph

K~CO~ ~ % ' N ' N ~L~

toluene

N,,N

Me I

N,~/~ph

a'N--N

,

R 112 R = 4-CI.C6H4,4-NO2.C6H4, 4-MeO.C6H4

113

Naphtho[1,8-de][1,2,3]triazine 114 can be alkylated with a variety of alkyl halides and lithium diisopropylamide (LDA) to give alkylated derivatives 115. Reduction of 115 with aluminium amalgam cleaves the naphthotriazine moiety to afford substituted cz-aminoacids 116 in good overall yields <00TL6665>. r~+CO2Et

R',T~CO2Et

-N~N,.N

- N~k+N b) (i/)

114 i: LDA, THF,-78 ~ C, 1 h ii: R-X, r.t., 2-4 h

115 (58-88%)

iii: AI-Hg, 90% THF/H20, 12-24 h

fii

R--CH-CO2Et ~4H2 116 (70--80%)

R = Me, n-Bu, allyl, p-xylyl,p-NO2.CH2Cd-14, EtO2C(CH2)2, X(CH2)4

X=I, Br

In a similar manner, starting from 2-methylchloride-naphtho[1,8-de][1,2,3]triazine and magnesium, via a novel sonication-promoted Barbier reaction, an cz-aminomethyl carbanion equivalent is generated which reacts in situ with a variety of carbonyl compounds. Subsequent catalytic hydrogenolysis of the triazine moiety yields the corresponding amines <00TIA685>. Sterically controlled regiospecific cyclization of aldose-5-ethyl-l,2,4-

S i x - M e m b e r e d R i n g Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems

313

triazino[ 5,6-b]indol-3-yl-hydrazones to linearly annelated 3-polyhydroxyalkyl- 10-ethyl- 1,2,4triazolo[4',3'/2,3]-[ 1,2,4]triazino[5,6-b]indoles has been described <00M487>.

6.3.4. REFERENCES 99IJC(B)1075 99JHC1317 99MI996 99MI1817 99MI1827 00AG(E)755 00AG(E)1436 00AG(E)1791 00AG(E)2874 00AP(333)99 00BCJ465 00BMC37 00BMCL2145 00BMCL2171 00CC69 00CC367 00CC1351 00CC1785 00CCC797 00CCC 1109 00CPB1270 00EJMC1043 00EJOC675 00EJOC763 00EJOC1661 00EJOC1767 00EJOC2105 00FES104 00FES109 00FES249 00FES354 00rt(53)5

00H(53)205 00H(53)213 00H(53)323 00H(53)929 00H(53)1129 00H(53)1155 00H(53)1207 00H(53)1551

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314

00H(53)1259 00H(53)2175 00H(53)2275 00H(53)2643 00HCA1398 00HCA2738 00IJC(B)36

00IJC(B)202 00IJC(B)210

00JA2087 00JA5006 00JCR(S)206 00JCS(P1)33 00JCS(P1)89 00JCS(P1)299 00JCS(P1)1089 00JCS(P2)1309 00JCS(P1)2015 00JFC(103)63

00JFC(103)105 00JFC(103)337 00JHC 115 00JHC195 00JHC373 00JHC419 00JHC707 00JHC879 00JHCl157 00~C168 00JMC96 00JMC449 00JMC804 00JMCll65 00JMC1223 00JMC1282 00JMC1380 00JMC1620 00JMC1817 00JMC2915 00JMC3852 00JMC4219 00JOC2479

C. O c h o a a n d P. Goya

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Six-Membered Ring Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems 00JOC2820 00JOC4743 00JOC5016 00JOC6670 00JOC9120 00JOC9265 00JPR96 00JPR269 00JPR599 00M487 00MC58 OOMC61 00MCl17 00MI39 OOMI160 00MI87 00MI237 00MI249 00MI361 00MI435 00MI442 00MI472 00MI603 00MI979 00MI1005 00MI 1193 00MRC504 00MRC696 00OL171 00OL301 00OL413 00OL843 00OL1295 00OL2825 00OL3091 00OL4841 00PHA577 00PJC837 00PS53 00PS65 00PS275 00S289 00S541 00Sl166 00SC81 00SC1083 00SC1719

315

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316 00SC1985 00SL67 00SL137 00SL275 00Tl165 00T1233 00T2473 00T4043 00T4079 00T4213 00T4589 00T5909 00T6887 00T7153 00T7685 00T9705 00TA1555 00TA2067 00TA3901 00TL671 00TL781 00TLl127 00TLl131 00TL1837 00TL2863 00TL3531 00TL3573 00TL3657 00TL4589 00TL4685 00TL4841 00TL5613 00TL5899 00TL6559 00TL6665 00TL7187 00TL7211 00TL7379 00TL8177 00ZN(B)321

C. Ochoa and P. Goya E. I. Alafaleq, Syn. Commun. 2000, 30,1985. F. Miklos, G. Stajer, P. Sohar, Z. Bocskei, Synlett 2000, 67. G. H. Merriman, D. M. Fink, B. S. Freed, B. E. Kurys, S. Pavlek, J. Varriano, E. F. Paulus, Synlett 2000,137. A. Falchi, G. Giacomelli, A. Porcheddu, M. Tadei, Synlett 2000, 275. S. C. Benson, L. Lee, L. Yang, J. K. Snyder, Tetrahedron 2000, 56, 1165. W. E. Lindsell, C. Murray, P. N. Preston, T. A. J. Woodman, Tetrahedron 2000, 56,1233. B. Pita, E. Sotelo, M. Sufirez, E. Ravifia, E. Ochoa, Y. Verdecia, H. Novoa, N. Balton, C. Deranter, O. M. Peeters, Tetrahedron 2000, 56, 2473. I. G6mez, E. Alonso, D. J. Ram6n, M. Yus, Tetrahedron 2000, 56, 4043. M. D. Velasco, P. Molina, P. M. Fresneda, M. A. Sanz, Tetrahedron 2000, 56, 4079. K. P. Hartmann, M. Heuschmann, Tetrahedron 2000, 56, 4213. R. Freer, G. R. Geen, T. W. Ramsay, A. C. Share, G. R. Slater, N. M. Smith, Tetrahedron 2000, 56, 4589. H. Wojtowiczrajchel, J. Szczepkowskasztolcman, A. Katrusiak, K. Golankiewicz, Tetrahedron 2000, 56, 5909. E. Handelsman-Benoroy, M. Botoshansky, M. Greenberg, V. Shteiman, M. Kaftory, Tetrahedron 2000, 56, 6887. Y. C. Kong, K. Kim, Y. J. Park, Tetrahedron 2000, 56, 7153. S. Kozai, K. Ogimoto, T. Maruyama, Tetrahedron 2000, 56, 7685. R. Menicagli, S. Samaritani, V. Zucchelli, Tetrahedron 2000, 56, 9705. A. Iuliano, G. Ucello-Barreta, P. Salvadori, Tetrahedron-Asymmetry 2000,11,1555. H. Sugimoto, Y. Yamane, S. Inoue, Tetrahedron-Asymmetry 2000,11, 2067. G. Ucello-Barreta, S. Samaritani, R. Menicagli, P. Salvadori, Tetrahedron-Asymmetry 2000, 11, 3901. L. Saniere, M. Schmitt, J. J. Bourguignon, Tetrahedron Lett. 2000, 41,671. I. Collins, J. L. Castro, L. J. Street, Tetrahedron Lett. 2000, 41,781. B. P. S. Chauhan,P. BBoudjouk, Tetrahedron Lett. 2000, 41,1127. H. W. Gao, A. K. Mitra, Tetrahedron Lett. 2000, 41,1131. D. W. P. M. Lowik, C. R. Lowe, Tetrahedron Lett. 2000, 41, 1837. E. Sotelo, B. Pita, E. Ravifia, Tetrahedron Lett. 2000, 41,2863. S. L. Aimone, M. V. Mirifico, J. A. Caram, D. G. Mitnik, O. E. Piro, E. E. Castellano, E. J. Vasini, Tetrahedron Lett. 2000, 41,3531. W. McComas, L. Chen, K. Kim, Tetrahedron Lett. 2000, 41,3573. A. Rykowski, D. Branowska, J. Kielak, Tetrahedron Lett. 2000, 41,3657. R. Freer, G. R. Geen, T. W. Ramsay, A. C. Share, G. R. Slater, N. M. Smith, Tetrahedron Lett. 2000, 41,4589. S. Chandrasekhar, M. Sridhar, Tetrahedron Lett. 2000, 41, 4685. J.G. Sanjayan, V. R.Pedireddi, K. N. Ganesh, Tetrahedron Lett. 2000, 41,4841. M. J. Haddadin, J. M. Kurth, M. M. Olmstead, Tetrahedron Lett. 2000, 41,5613. J. W. Bae, S. H. Lee, Y. J. Cho, Y. J. Yung, H. J. Hwang, C. M. Yoon, Tetrahedron Lett. 2000, 41,5899. Q. Dang, B. S. Brown, M. D. Erion, Tetrahedron Lett. 2000, 41,6559. R. Anilkumar, S. Chandrasekhar, M. Sridhar, Tetrahedron Lett. 2000, 41,6665. P. Maienfisch, H. Huedimann, J. Haettenschwiler, Tetrahedron Lett. 2000, 41,7187. K. Alarc6n, A. Martelli, M. Demeunynck, J. Lhomme, Tetrahedron Lett. 2000, 41,7211. O. N. Chupakhin, V. N. Kozhevnikov, A. M. Prokhorov, D. N. Kozhevnikov, V. L. Rusinov, Tetrahedron Lett. 2000, 41,7379. A. D. Baxter, E. A. Boyd, P. B. COx, V. Loh, C. Monteils, A. Proud, Tetrahedron Lett. 2000, 41, 8177. I. S. A. Hafiz, Z. Naturforsch. (B) 2000, 55,321.

317

Chapter 6.4 Six-Membered Ring Systems: With O and/or S Atoms

John D. Hepworth

University of Hull, Hull, UK B. Mark Heron

Department of Colour Chemistry University of Leeds, Leeds, UK email: ccdbmh@ leeds.ac.uk

INTRODUCTION Reviews of saturated oxygen heterocycles <00JCS(P1)1291>, routes to 2,2-dimethyl-2H[ 1]benzopyrans <00H(53) 1193> and pyranonaphthoquinone antibiotics <00T 1937>, HIV- 1 active Calophyllum coumarins <00H(53)453> and of the application of 13-halovinylaldehydes in heterocyclic synthesis <00H(53)941> have appeared. Convergent syntheses of the trans-fused tetracyclic tetrahydropyran system have been described; both involve alkynic triflate coupling as a key step <00TL507, 903>. A two directional construction of tricyclic ethers involves a double ring closing metathesis (RCM) sequence applied to allylic, alkynyl and enol ethers <00AG(E)372>. These developments should facilitate the synthesis of biologically potent, naturally occurring polycyclic ethers. Amongst marine natural products, efficient, stereocontrolled routes to the C1-C28 sector <00OL679>, the spiroacetal CD rings <00TL2649> and the highly substituted pyran F ring <00EJO2195> of spongistatin 1 have been published. Further work on the brevetoxin-B system <00OL231; 00TL7673; 00TL7677; 00TL7681>, ciguatoxin <00T5391; 00TL1425> and halichondrin B <00JOC4070> has been reported. Total syntheses of (-)-polycavernoside A <00JA619>, mycalamide A <00OL859> and bryostatin 3 have been achieved <00AG(E)2290> and simplified analogues of the bryostatins have been made and evaluated <00TL1007>. Syntheses of mycalamide B and theopederin D utilise common building blocks, a lithiated dihydropyran and a dihydropyran-4-one, and illustrate a general approach to the pederins <00JCS(P1)2357>. A total synthesis of everninomicin 13,384-1, a powerful antibiotic, has been accomplished <00CEJ3095; 00CEJ3116; 00CEJ3149; 00CEJ3166> as has that of some nicandrenones <00JA9044> and the cytotoxic penostatins A and B <00JOC8490>. Amongst studies of natural products containing a spiroacetal unit reported this year are an enantioselective synthesis of the spiroketal core of spirofungin A and B <00TL3141>, reveromycin A <00OL207> and a total synthesis of reveromycin B <00OL191>. Naphthoquinone-based spiroacetals discussed include the rubromycins <00EJO729; 00JCS(P1)2681> and analogues of griseusin A <00JCS(P1)697>. An oestrone-derived exocyclic enol ether offers access to a number of steroidal spiroacetals through a hetero-Diels-

318

J.D. Hepworth and B.M. Heron

Alder (hDA) reaction <00CEJ3755> and the electrochemical oxidation of 03-hydroxyalkyl tetrahydropyrans offers a different approach to spiroketals <00TL4383>. The synthesis and stereochemistry of insect derived spiroacetals has been reviewed <00S 1956>. Syntheses of natural products based on the benzopyran nucleus include stigmatellin A <00CEJ1302>, ravidomycin <00TL1063>, hongoquercin A <00EJO297> and quassin <00JOC7059>. Alternative routes to coumestrol <00JOC5644> and to analogues of forskolin <00CC 1737> have been published. 6.4.1

HETEROCYCLES CONTAINING ONE OXYGEN ATOM

6.4.1.1

Pyrans

The Pd-catalysed cyclisation of (E)-3-alkynyl-3-trifluoromethyl allylic alcohols 2, derived from a cross coupling reaction between terminal alkynes and the 3-iodo alcohols 1, yields the pyrans 3 rather than the expected furan derivatives (Scheme 1). It appears that the electronwithdrawing properties of the CF3 group assist the 6-endo-dig cyclisation <00TL7727>.

I

HO

(i)

nC3H7

F3C. -~ R

1

nC3H7

(ii)

2

Reagents: (i) terminal alkyne, Pd(PPh3)4, Cul, Et3N, 50 ~

CF3

R = Ph (77%)

R = nC6H13 (63%) nC3H7 R = 4-MeOC6H4 (66%) 3

(ii) PdCI2(MeCN)2, THF, 70 ~

Scheme 1

Cyclodehydration of 1,5-bis(acylsilanes) 4, accessible through dithiane chemistry, affords 2,6-bis(trialkylsilyl)-4H-pyrans (Scheme 2) <00S843>. O R3Si

O R

R 4-TsOH _ ~ . SIR'3 0.05 mbar, heat R3Si

4

7 examples, SIR'3 (50 - 94%)

Scheme 2

The base-catalysed anionic cyclisation of hexynones 5 results in the 4H-pyran 6 and a mixture of E- and Z-dihydropyrans 7 (Scheme 3) <00EJO527>.

CO2Me 5

DMF, N2

/ ,46o o

CO2Me 6

E-isomer (18%) Z-isomer (14%)

O-..ff"

Scheme 3

7

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from ct-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2H-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS (P 1)2916>.

Six-Membered Ring Systems: With 0 and~or S Atoms

002 R2 RI.-J"..OH

319

.a.,.

allyl bromide ,,~L~ ~RI~ Grubbs' catalyst,, THF, 65 ~ O 002 R2 CH2CI2, 20 ~

8

002R2

9

Scheme 4

10

The 1,7-dioxaspiro[4,5]deca-3,9-diene 11 can be prepared by both a double RCM and by sequential single RCMs (Scheme 5) <00JOC5817; 00T2421>.

-~

II',oll TBDMS(i)

~O~.,/R (ii).

~ R .

(iii)

~ R

.

.

(i)

~ . u0/~R/

(iv) II~.O~.,/R ~.~],O

..~ 11 Reagents: (i) Grubbs' catalyst, CH2Cl2,20 ~ (ii) TBAF, THF, rt; (iii) Nail, allyl bromide, THF, 65 ~ (iv) Grubbs' catalyst, PhMe, heat Scheme 5

Tetrahydropyran epoxides 12, the synthesis of which involves a RCM, undergo a baseinduced rearrangement to 3,4-dihydro-2H-pyran-4-ols 13. These compounds are converted stereospecifically to 3,6-dihydropyrans 14 on treatment with allyltrimethylsilane (Scheme 6) <00EJO3145>.

O[.•

LDA or LITMP THF (38 - 89%)

- R4

~O I~1R2/=~ 12

~

HO R3

13

_R3 R4 (i)allyltrimethylsilane, [I R4 (ii) BF3.OEt2, CH2CI2 ~,,." \O.,.-=_-~. R 2 R2 (2 steps 49 - 87%) A1

14

Scheme 6

Ill.f:

Fluorinated dihydropyrans 16 are readily derived from aldehydes via the homoallyl alcohols 15. A second allylation is a prelude to a RCM (Scheme 7) <00CC607>.

RCHO

(i)

~H

(ii),,IFI.,.. ,. ~-----~[~F O.....k..R

15

(iii)o~F' "

4(56_examples,97%)

16

Reagents: (i) H2C=CHCF2Br, In, DMF, sonication, rt; (ii) allyl bromide, NaOH, 0H2012, Bu4NHSO4, rt; (iii)5 mol% Grubbs' catalyst, 0H2012, rt Scheme 7 Further examples of the use of the hDA reaction in dihydropyran synthesis include the formation of the fused pyrans 18 from vinylallenes 17 and aldehydes (Scheme 8) <00TL6781> and a trans-fused dihydropyran containing a phosphonate group 19 <00JOC4326>. A total synthesis of the l l-oxa steroid system is based on an intramolecular Diels-Alder reaction involving an orthoquinodimethane derived from a benzocyclobutene (Scheme 9) <00TL 1767 >.

320

J.D. Hepworth and B.M. Heron

R

O + IL

BF3.OEt 2

R'

17

. H

Scheme 8

O ii /POEt2

6 examples, (36- 70%) i

18

19

OH ~

OH :

heat, 12h MeO

.."

(55%)

Scheme 9

MeO

A highly enantioselective dihydropyran synthesis results from the use of bis(oxazoline) copper(II) complexes as catalysts <00JA1635; 00JA7936> and the value of this approach to carbohydrate synthesis has been noted <00JOC4487>. The reaction between benzylidenepyruvic esters and vinyl ethers has been adapted to solidphase conditions with significant improvement in yield but with little change in the endo/exo ratio <00EJO639>. The diastereoselectivity of the high pressure promoted hDA reactions shown in Scheme 10 is changed in the presence of pyridine. It is postulated that transient Michael addition of pyridine to the starting (E)-diene occurs allowing isomerisation to the more reactive (Z)-diene <00CC1191>. +

Ar~P(OMe)20" x py-

PY

frO

~

r

I P(OMe)

P(OMe)2

0/ ~

II

EtO/ 11 kbar

trans:cis trans:cis

Scheme 10

Ar 0

(OMe)2

EtO" "O" 75:25 (95%) no pyridine 30:70 (93%) with pyridine

Highly substituted 4-methylenetetrahydropyrans can be obtained from the allyl alcohol via its carbamate 20. Reaction of the derived allyllithium with aldehydes affords the (Z)enolcarbamates 21 which undergo an intramolecular Sakurai cyclisation to the pyran as a single diastereoisomer (Scheme 11) <00TL7225>.

==~~CON(iPr)2 MS 20

(i)- (iii) _-. A

TMS

R,/I,,,oHOCON(iPr) 2

(iv)

.~OCON(iPr)2 R1~O/,'%R2 (78- 91%)

21

Reagents: (i) sBuLi, TMEDA, Et20; (ii) Ti(OiPr)4, R1CHO, Et20; (iv) R2CHO, BF3.OEt2, CH2CI2 Scheme 11 An intramolecular alkylation of the bromoacetals 22 gives a mixture of two tetrahydropyran diastereomers 23 from which the dihydropyran 24 is readily available (Scheme 12) <00TL9753>.

321

Six-Membered Ring Systems: With 0 and~orS Atoms

SO2Ph SO2Ph (i) 4-TsOH, MeOH SO2Ph B~~OI~ LHMDS,THF,-78~ ~.~ (ii) NaI, TMSCI,MeCN ~ , . (98%) (iii) [(Me)3Si]2NH Et EtO" "O" "~ (80%) 22

23

24

Scheme 12

Prolonged reaction of the triols 25 with trimethyl orthoacetate and a weakly acidic catalyst affords a mixture of the 5- and 6-membered oxacycles from which the tetrahydropyran is obtained on equilibration (Scheme 13). By selection of the reaction conditions, it is possible to obtain either ring system exclusively <00CC1781>.

~ O H o H (3H

(i) P h S ~ O A c

PhS~,,~

(ii) P h S , ~ ~

25 26:74 (98%) (86%) Reagents: (i) (MeO)3CMe,py+TsO',0H2012,rt; (ii) 4-TsOH, 0H2012,40 ~ Scheme 13 The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) <00TL2171>, whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the cis-2,6-disubstituted tetrahydropyran (Scheme 16) <00JOC4523>.

Ph

O~O

Me3Si-OTf 1 1 silica (iPr)2NEt~" L_ ~ gel "O" Ph (77%) Scheme 14 Ph L~ SO2Ph

Ph ~ O 26

(TMS)3SiH,Et3B= Phil

f

Bu3SnH AIBN,(65%) Scheme 15

27

+

SO2Ph SO2Ph Scheme 16 rt 6:1 (90%);heat 3:1 (95%)

An oxidative Prins cyclisation of the aUylsilane-tethered a-stannyl ethers offers a route to tetrahydropyrans avoiding the need for catalysis by a Lewis acid (Scheme 17) <00JOC3252>.

Bu3Sn...7....Of

Ce(NBu4)2(NO3)6, mol. sieve MeCN, CH2CI2, 25 ~ Scheme 17

R = iBu (85%) R Bn (74%) (74%) R == cyclohexyl

Transformation of the 7-oxo-2-enimides 28, available from chiral syn-aldols by a Cope rearrangement, into enantiopure tetrahydropyrans involves reduction of the aldehyde function followed by a fast intramolecular oxa Michael addition. The stereochemical course of the

322

J.D. Hepworth and B.M. Heron

cyclisation is reversed when the hydroxyenoates are used in place of the enimides, when the reaction is under thermodynamic control and exhibits excellent stereoselectivity (Scheme 18) <00EJO73>.

Ph ~

,O,

Bn KOtBu,THF OH Ph "

9

c

-

(83%) --0~-.0

Ph KOtBu,THF ~ ~ L .

O -

x

-

0~

-

28 Scheme 18

(72o/o)

OEt

The conversion of anomerically linked enol ethers 29 into either the cis- or transsubstituted pyranyl ketones with high diastereoselectivity and yield involves a Lewis acidpromoted O ---, C rearrangement (Scheme 19) <00JCS(P1)2385>. Under similar conditions, homoallylic ethers 30 ring open and the oxonium ions then recyclise to new pyran derivatives 31. Whilst the product is a mixture of alkene isomers, catalytic hydrogenation occurs with excellent diastereoselectivity (Scheme 20) <00JCS(P 1) 1829>.

R1

R2

0H2012 -78 ~

1 R

O

R2

0H2012 rt

1 R

R2

29

Scheme 19 1 eq. TfOH

30

6.4.1.2

H2,

0H2CI2 HO (CH2)

Pd/C

MeOH HO (CH2)

mixture of isomers (80%) Scheme 20

(93%, 80% d.e.)

[1]Benzopyrans (Chromenes)

A selenium-functionalised resin converts o-prenylated phenols into resin-bound dihydrobenzopyrans from which benzopyrans are released on treatment with hydrogen peroxide. Manipulation of the benzopyran scaffold is readily accomplished (Scheme 21) <00AG(E)734; 00AG(E)739>. The 2,2-dimethyl-2H-[1]benzopyran moiety has been used as the privileged natural product template for the construction of a combinatorial library because of its wide occurrence and the diverse structural and pharmacological features associated with both natural and man-made products. Using split-and-pool technology involving the above solid-phase selenium-based cyclisation and loading (cyclo-loading) methodology, a 10,000 member library has been constructed and this has been extended by a parallel solution-phase approach <00JA9939; 00JA9954; 00JA9968>. A high-throughput structure verification based on 2D NMR has been successfully applied to a library of 96 4-phenylchromans synthesised from phenols, 0t,13-unsaturated aldehydes and secondary amines <00AG(E)3816>. A solidphase synthesis of some cyclopenta[c]-4H-chromenes utilises a fulvene hetero [6+3]cycloaddition <00OL2647>.

Six-Membered Ring Systems: With 0

resin + I SeBr

R

,~

.

a ~ ~ - - " " ~ . resin i ~Se . ~ . .

(i)

323

and~or S Atoms

(ii)

R

R = H (92%)

R = OMe (93%) R = NO2 (91%)

Reagents: (i) EtOH, 25 ~ (ii) 30% H202, THF, 25 ~ Scheme 21 2,2-Dimethylchromene has also proven to be a useful substrate for the assessment of various transition metal complexes as epoxidation catalysts. Chiral Mn(llI)-salen complexes are efficient <00CC615; 00T417> and can be recycled when used in an ionic liquid <00CC837>. The enantioselective aziridination of a chromene has been achieved using a chiral biaryldiamine-derived catalyst (Scheme 22) <00JA7132>.

o

O

~ 5 % [ C u ( L ) ( M e C N )~2 ] BPF 4 C hH2CI l 2 N " T

cI ~

s

,

~

CI

L= C I ~ / I N ' * ~ 4 C I ~ (83%)

Scheme 22

A neat variation of the Iwai-Ide chromene synthesis is outlined in Scheme 23. The alkynols derived from the Boc-protected 1-aminobenzotriazole 32 by a Sonogashira coupling are partially reduced to the allylic alcohols 33, whereupon intramolecular trapping of the benzyne generated by deprotection and treatment with N-iodosuccinimide leads to iodochromenes 34. Complete reduction to the arylpropanols 35 offers an analogous route to chromans 36 (Scheme 23) <00JCS(P1)2343; 00T1013>. When applied to 3-hydroxyxanthones, the Claisenrearrangement methodology leads to a mixture of linear and angular pyranoxanthones <00H(53)93> and photochromic naphthopyrans have been obtained from naphthols when the reaction is carried out in the solid state <00OL2133>. Several naphthopyrans exhibit crystalline state photochromism <00CC 1339>. ,i,i, N

(i) .~

I

32

NHBoc

=

klHBoc

R1

R

OH

OH ~

R

(ii)

~

-'N"

R1

33

N

I 34

"~N (iv), (v) N = NHBoc

= R1 R

~

35

~

R1 136

Reagents: (i) alkynol, Pd(PPh3)4, Cul, THF, Et3N, heat; (ii) H2, 10% Pd-C, MeOH; (iii) Rieke zinc, THF, MeOH, H20; (iv) TFA, CH2CI2, 20 ~ (v) NIS, CH2012,20 ~ Scheme 23 3-Fluorochromenes result from the reaction of the Cs salts of salicylaldehydes with the phosphonium triflate 37 (Scheme 24) <00JCS(P1)103> and 3-acylchromenes are formed from salicylaldehydes and alkyl vinyl ketones in a chemoselective Baylis-Hillman reaction (Scheme 25) <00JCS(P1)1331>.

324

J.D. Hepworth and B.M. Heron

~~

.CHO

v

"OH

P+Ph3OTf-DMF,CsF, Si(OEt)4 ~ I F + ===( 9 F 130 ~ 40h 37 Scheme 24

(34%)

OH O

O

~"~OH

examples, (54 -87%)

Reagents: (i) DABCO, CHCI3, H20, N2, rt Scheme 25

Chromene acetals 39 are accessible from 2-vinyl-substituted phenols via the allylic acetals 38 through oxypalladation of benzyloxypropa-l,2-diene and a subsequent Ru-catalysed RCM. 2-Substituted chromenes can be derived from the acetals 39 by conversion into the 1-benzopyrylium salts which are then trapped by nucleophiles (Scheme 26) <00TL5979>. In a like manner, 2-alkoxychromans have been converted into various 2-substituted chromans by sequential treatment with SnCI4 and a silyl enol ether <00TL7203>.

R1

R1

R1

R1

R 38

(iii)

OBn

39

R

OBn

R2

Reagents: (i) benzyloxyallene, 5 mol% Pd(OAc)2,dppp, Et3N, MeCN; (ii) Grubbs' catalyst, 0H2012, rt;

(iii) BF3.OEt2, 0H2012, 0 ~ then nucleophile (R2).

Scheme 26

The allylic alcohols 41 derived from the propynols 40 by either a regioselective Pdcatalysed hydroarylation or hydrovinylation are readily cyclised to 4-aryl or 4-vinyl 2H-chromenes in high yield (Scheme 27) <00EJO4099>.

R1 ~R 2

OR3 ~

~OH

~ (i)

R4

9

~ al R2

40

41

(ii) (iii)

9

R4

M e ~

Reagents: (i) Arl or vinyl triflate, nBu3N, HCO2H,Pd(OAc)2, P(Ar)3, DMF, N2, 60 ~ (ii) NaHCO3, MeOH; (iii) 1,2-DCE, ZnCI2, heat Scheme 27 6.4.1.3

: H N

1 42

Dihydro[1]benzopyrans (Chromans)

2-Substituted chromans of high enantiomeric purity can be obtained from 2-bromophenols and 3-halopropanols using sequential Mitsunobu coupling and Parham cyclisation procedures <00TL8655>. The synthesis of the chiral pyrrolidine-2,3'-chroman 42 from L-proline features a Mitsunobu reaction to generate the benzopyran unit <00JOC914>. Cyclisation of the enynes 43, derived from salicylaldehydes and 2'-hydroxyacetophenones using Mitsunobu and Wittig methodology, to isomeric cyclopenta[c]chromans is catalysed by Co2(CO)8 (the Pauson-Khand reaction) and promoted by molecular sieves (Scheme 28) <00JOC3513>.

43

17 examples ,, 0- ~

R

Reagents:(i) mol.sieve,Co2(CO)8,PhMethen Me3NO,-10~ Scheme28

The product 46 from the Rh(I)-catalysed [2+2+2] cycloaddition of the diynyl ether 44 to the substituted iodobenzene 45 undergoes a Pd-catalysed cyclisation to the fused chromans 47 <00TL3003>.

o(

o

. --~-. 44

IL ! ~ O '+~

ICHO

OMe 45

(i)

o

Io"~

/CHO

O +

('i)

OMe

O

CHOo

Me

MeO

46

47

Reagents:(i) Rh(PPh3)3CI,PhMe,heat(64%);(ii) Pd(OAc)2,PPh3, TI2CO3,PhMe,heat(82%) Tethered alkenes feature in the synthesis of benzofuran-fused <00JCS(P 1) 1387> through intramolecular cycloadditions.

{~

CHO H O ? (MeO)3CH,4-TsOH OH + Phil, rt 23h ~'SPh Scheme29

O H_ Ph

chromans

R- v ~ u

majorisomer

48

'-' 48

The pyrano[3,2-c][1]benzopyran system is available from the reaction between salicylaldehyde and 5-phenylthio-4-penten-l-ols which proceeds by an intramolecular cycloaddition of an o-quinone methide; desulfurisation is facile (Scheme 29) <00TL2643>. Mild conditions have been established for the synthesis of (-)-hexahydrocannabinol 50 from the olivetol derivative 49 which also involves a quinone methide (Scheme 30) <00SC1431>.

~EE A cat. PPTS ~ ,"';-r/'~'OH"~, MeOH RAL~~oEE I ' / ~ CHCl3 R 49

OH

R = C5Hll (73%) Scheme30

50

The two saturated tings of the cannabinoid nucleus are formed with the correct stereochemistry at C-6, C-6a and C-10a but without selectivity at C-9 in a single acidcatalysed cyclisation step from the phenol 51. Stabilisation of a cationic intermediate by the alkyne group is proposed to account for the facile cyclisation <00JOC6576>.

326

J.D. Hepworth and B.M. Heron

OH

OH TFA

06H13

~ O O H

,,

CHCI3,0 ~

C6H13~,'-~.,,,,,-~O~

TBDMSO 51

52

(76%) TBDMSO

The stable chromanyl hydroperoxide 52 is formed through a hydroperoxide rearrangement of the 1-methylindanol in 65% yield <00JOC1873>. There is considerable interest in amino derivatives of chroman and hydrogen bromide has been found to promote a stereoselective hydrogenation of an ~t-hydroxyoxime enabling the S,S-aminochromanol 53 to be obtained in over 30% yield from chroman-4-one on a multi-kilo scale (Scheme 31) <00TL8021>.

HO.. N

~ 6.4.1.4

,,,OH

Pd/C-HBr, H2 0 - 5 ~ MeOH

_NH2 9 ~,,,OH

Scheme31

= 25:1 (94%)

cis:trans

53

[2]Benzopyrans and dihydro[2]benzopyrans (Isochromenes and isochromans)

A tandem enolate-arylation-allylic cyclisation, in which an essential t-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-lH-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) <00CC933>.

Q~Br

j

-- ~ t B u 54 Reagents: (i) LiHMDS,Pd2(dba)3,dppf, PhMe,THF, 100 ~ (67%). Scheme32 + ~'~tBu

I'l

L v

allene, PhCHO indium powder 10 mol%Pd(OAc)2 20 mol%P(2-furyl)3 DMF, 84 ~ Scheme33

O~ [(

(52%)

CH2CH(OH)Ph 55

Benzocyclobutene reacts with a range of heterodienophiles under mild conditions through the intermediacy of an o-quinone dimethide; the reaction with aldehydes gives high yields of

327

Six-Membered Ring Systems: With 0 and~or S Atoms

isochromans 56 (Scheme 34) <00AG(E)1937>. In the presence of a Yb complex, naphtho[b]cyclopropene 57 undergoes an [8+2]-cycloaddition with tropones to produce fused isochromans 58 and 59 (Scheme 35) <00H(53)2601>.

OTBS

.OTBS ~/~~~"~O TBS

[ ~ ~

=

(92%)

PhCHO Phil 50 ~

~ /

OTBS Scheme 34

O

+

OTBS

~Me

yb(fod)3 ),. CHCI3

57

OTBS 56

+

(56%) ~ / 58 Scheme 35

59

6.4.1.5 Pyranones Pyran-2-ones are formed in high yield through the Pd-catalysed annulation of allenyl stannanes by 13-iodo vinylic acids. The reaction, which probably involves a Stille cyclisation sequence, exhibits good selectivity (Scheme 36) <00CC1987>.

RI~oH I

O

R2

a1 Pd(OAc)2, PPh 3, Na2CO3

nBu4Br, DMF, rt

+ Bu3Sn"~~

Scheme 36

R2,,,,.y,~ 11 examples,

R~ ~ v

.1..(79 86%)

"(3" ~O

A cascade process involving a Ni-catalysed coupling, carbonylation, cyanation and heterocyclisation results in the rapid, efficient conversion of propynyl halides and alcohols into 5-cyanopyran-2-ones in aqueous conditions (Scheme 37) <00JCS(P1)1493>.

'I

Br

Scheme 37

o

Ar

Scheme 38

r

Substituted unsymmetrical biaryls can be readily obtained from 6-aryl-3-cyanopyran-2-ones on treatment with acetone and a base. Initial nucleophilic attack at C-2 is followed by a C-C cyclisation (Scheme 38)<00JCS(P1)3719>. Detailed NMR assignments for a range of bispyranones and some dihydro derivatives have followed their unambiguous syntheses through the Lewis acid-mediated reaction between 4-hydroxypyranones and a,13-unsaturated acids, a reaction which has potential in natural product synthesis (Scheme 39) <00TL1901>.

328

J.D. Hepworth and B.M. Heron

O O OH

HO ,~ O POCI3,ZnCI2 heat (57%)

12,NaOAc,AcOH-heat (68%)

O

Scheme 39

The Pd-catalysed carbonylation of alkynyl epoxides 60 and alkynyldioxolanones 61 leads to the allenes 62 which can then be converted to the same pyranones through a tandem conjugate addition-cyclisation (Scheme 40) <00JCS(P1)3188>. Carbonylation of allenyl alcohols is catalysed by Ru3(CO)12 and yields 5,6-dihydropyran-2-ones <00OL441>.

RI R=o ~176

R3

3

(ii) = R 2 " ~

R3

6 examples, R1/~O..-'.~O (53- 60%)

R2 oH,2 R'

Reagents: (i) 1 mol % Pd(PPh3)4,CO, MeOH, rt; (ii) Me2CuLi,Et20,-78 ~ Scheme 40 The furans 63 are a convenient source of functionalised cyclopentenones 65 through sequential ring expansion to the 2,6-dihydropyran-3-ones 64 and base-catalysed isomerisation; the choice of amine base and solvent is important (Scheme 41) <00TL6879>.

~ R

(i)'(ii) ' OH

63

6.4.1.6

~~- - ~ O , AcO

(iii) , "-- R

R

. ~ OO

tBuO

):v i (

"-- tBuO""

R

HO

64

Reagents: (i) H+, NBS; (ii) Ac20, NaOAc; (iii) SnCI4,tBuOH; (iv) Et3N,DMF 70 ~ Scheme 41

65

Coumarins

Coumarins are formed by the intramolecular hydroarylation of an activated alkyne. The basic starting materials for this fast, efficient and general Pd-catalysed reaction are phenols and alkynoic acids (Scheme 42). An intermolecular version in which electron-rich phenols react with 4-methoxycinnamic acid leads to high yields of 3,4-dihydrocoumarins <00JOC7516>. R

R~ ,

R

[~O1~ Pd(OAc)2 R ~ O ~ O TFA, CH2CI2 O 10 examples, Scheme 42 (60 - 91%)

R

[~~

CO, cat. Pd(0) [ ~ ~ l H R --

R

Scheme 43

O

12 examples, (9 - 78%)

A three-component coumarin synthesis involves the Pd-catalysed coupling of o-iodophenols with alkynes and subsequent insertion of carbon monoxide. With internal alkynes, pyridine is the crucial base for successful annulation; the regioselectivity with unsymmetrically substituted alkynes is only moderate (Scheme 43) <00OL3643>.

Six-Membered Ring Systems: With 0

329

and~or S Atoms

Michael addition of di- and tri-hydric phenols to N-cinnamoylimidazoles followed by a lactonisation offers a route to 4-aryl-3,4-dihydrocoumarins and their [f]-benzologues <00S123>. The lactonisation of the naphthoquinone derivative 66 is sensitive to the acidic cyclising medium and it is possible to obtain the thermodynamically less stable o-quinone derivative exclusively (Scheme 44) <00TL3007>. Some related quinones have been obtained from 1-benzylisoquinolines via an arylnaphthoquinone <00T6023>. I

(iii) (95%)

O

~eO

o

.,

(ii)

(i)

(91%)

.

(92%)

OMeO OMeO 66 OMeO Reagents: (i) TFA, CH2CI2, -78 ~ (ii) MeSO3H,CH2CI2, -78 ~ (iii) TMSOTf,CH2CI2,25 ~ Scheme44 There are a number of examples of the use of derivatives of 7-hydroxycoumarin in fluorescent probes <00AG(E)4067; 00CEJ4154; 00JCS(P 1) 1541 >. The choice of catalyst controls the intramolecular cyclisation of 2-(1-alkynyl)benzoic acids, with AgNO3 effecting efficient formation of 3-substituted isocoumarins, but Ag powder favouring a 5-exo-dig-cyclisation to the phthalide (Scheme 45) <00T2533>.

v

AgNO3(20 mo2~ Me2CO 24 h, 20 ~

-CO2H

3H7

+

~ O

Scheme45

O molar ratio 6:94, 83%

In a total synthesis of coriandrin 68, the isocoumarin unit is generated by the thermal rearrangement of an indenone epoxide 67, the first application of a cycloreversion route to isocoumarin synthesis (Scheme 46) <00TL3677>.

MeO

O

Reagents:

(i)

MoO

67

0

(ii) ~ MeO

0

[ ~ 0

68

(i) Et3N,H202,Me2CO(40%);(ii) FVP (88%). Scheme 46

69

Lateral metallation is the key step in the synthesis of the peri-fused isocoumarin 69 from 5,6,7,8-tetrahydro-l-naphthoic acid <00S 1113>. 6.4.1.7

Chromones

An improvement in the Baker-Venkataraman route to flavonols (2-aryl-3hydroxychromones) which avoids a final oxidation step of the flavone involves formation of

J.D. Hepworth and B.M. Heron

330

the 2-bromoacetophenone 70. Subsequent displacement of the halogen by an aryl carboxylate introduces the 3-oxygen atom of the final product (Scheme 47) <00JOC583>.

O

O OAr (i)

R.\~."~

O "Br (ii)

R\.

I

O

(iii)

OBz

R

I

OBz

70 Reagents: (i) PhMeaN+Br3, THF, rt (75 - 85%); (ii) RCO2K, MeCN, rt (68- 84%); (iii) Nail, THF, 65 ~ then 5~176 NaOH, EtOH/H20, 60 ~ (75 - 91%). Scheme 47

An efficient synthesis of flavones, which occurs without formation of the corresponding aurone, involves the carbonylative cyclisation of o-acetoxyiodophenols and arylalkynes (Scheme 48) <00OL1765>. A large scale, one-pot synthesis of isoflavones has been described <00SC469>.

-~O R--

Ac

+

PO(PhaP)2CI2 thiOurea'dppp 9 CO, Et2NH, DBU

'1' Ar

O ~~ A R---

(8 examples' 68-92%) r

Scheme 48

A [3+2+l]-cycloaddition cascade involving the Pd-catalysed insertion of CO into an iodophenol and addition of the resulting complex to an allene leads finally to a 3-methylenechroman-4-one through an intramolecular nucleophilic attack. A wide range of these s-cis-enones have been obtained in good yields <00TL7125> and shown to behave as 2rt and 4rt components in various cycloaddition processes offering access to fused heterocycles (Scheme 49) <00TL7129>. The ring expansion of phthalides to isochroman-4-ones also involves a Pd-catalysed sequence of reactions <00H(52)85>.

O O

'0 (i) [~RR H

(ii) = ~ R O R ,

.Ph N

(iii) (iv) _~ O " O~

OEt O

o Me

Reagents: (i) allene, Pd(PPh3)4, K2003, 00, PhMe (R = Me, 70%); (ii) phenyl chlorooxime, EtzN, Et20, 0H2012 (R = Me, 88%); (iii) ethyl vinyl ether, hydroquinone, ZnGI2 (R = Me, 77%); (iv) Danishefsky's cliene, PhMe then HGI (R = H, 63%) Scheme 49 An improved version of the Knoevenagel reaction between acetophenones and aldehydes allows direct access to trans-2,3-disubstituted chroman-4-ones, examples of which show high anti-estrogenic activity <00T1811>. Reduction of flavanones by NaBH4 leads to the 2,4-cisflavan-4-ols from which 4-methoxyflavans can readily be obtained; detailed 1H and 13C NMR data are provided <00T6047>.

331

Six-Membered Ring Systems: With 0 and~or S Atoms

The methanochromanone 71 is converted with high trans-selectivity into the furo[2,3-b]chromanone 72 by reaction with symmetric ketones (Scheme 50) <00H(53)657>.

O ~'J~OO2Me ~"~,,'''O / 71

6.4.1.8

R2CO 10 mol% SnCI4 CH2Cl2

002 Me

~ ~

Scheme 50

~1 H CO2Me 2Me (6 examples, O 67 - 99%) \O/1~O R H 72

Xanthones

The reaction of the O-alkylated cyclohexan-l,3-diones 73 with p-substituted anilines in the presence of acetic acid is influenced by the nature of R in 73, yielding 4-anilinoxanthones 74 when R = H, but the condensed 3,-lactams 75 when R = Me (Scheme 51) <00T5947>.

O O O

MeO

R= H MeO,~( Me R

73

4.MeOC6H4NH2 AcOH,heat a=Me,.

~

(

NHAr

" ~ )- v 74

(20~176 Me

'X~---NAr / \ 5 0 % )

MeO~ . ~ ~ - . 0 ~.~~--Me Scheme 51

Me

75

Vinylchromones undergo a [4+2]-cycloaddition with pyrrolidine enamines, generated in The reaction proceeds by way of a methylidene tetrahydroxanthone 76 (Scheme 52) <00JCS(P1)3732>. situ, leading to xanthones substituted in the C-ring.

OMe O

OMe O

Ph

~'-

"
"O" v "Ph 76 (24%) Scheme 52

6.4.2

HETEROCYCLES CONTAINING ONE SULFUR ATOM

6.4.2.1

Thiopyrans and analogues

(59%)

j Ph

The formation of dihydrothiopyrans using Diels-Alder methodology continues to attract attention. Thioacyl silanes [Me(C=S)SiMe3], generated using benzotriazole methodology, behave as dienophiles and react with dimethylbutadiene to afford 2-trimethylsilyl-3,6-dihydro2H-thiopyrans in good yield <00JOC9206>. A detailed study of the behaviour of 0t,13-unsaturated thiocarbonyl compounds has shown that they can act as both heterodiene and dienophile and yield 1,2- and 1,3- dithiins and dihydrothiopyrans as dimeric products. In the reaction with norbornadiene, they function as heterodienes but as the dienophile towards cyclopentadiene, leading to 77 and 78, respectively (Scheme 53) <00JOC6601>.

332

J.D. Hepworth and B.M. Heron

= 7 ~

(Me2AI)2S

~s

(48%)

H

CHO THF,PhMe

9

S7/ 7 8 ~ 0

77 (70%)

Scheme 53 The first example of an intramolecular, asymmetric Diels-Alder reaction involving an a,13-unsaturated thioketone exhibits high diastereoisofacial selectivity and leads to bornenefused dihydrothiopyrans (Scheme 54) <00H(53)1685>. The reaction of a,13-unsaturated thioesters containing a phosphonate group with enol ethers offers a high-yielding route, though with varying diastereoselectivity, to phosphono-substituted dihydrothiopyrans <00T3909>.

PhMeheat 9

H~O Scheme54

+

exo:endo

H

91:9(90%)

In a quite different approach, the 1,3-oxathianes 79 undergo a tandem [4++2]-cycloadditionelimination with alkenes yielding 3,4-dihydrothiopyrans; a preference for the cis-isomer was noted (Scheme 55). The oxathianes, which are readily synthesised, thus serve as ~t,13-unsaturated thioaldehydes <00TL371 >.

R2

R1

ic,4

R1 CH2CI2'-78 ~ 79

O ~ S O 2

2

10 examples, (31 - 88%)

Scheme55

O 80

Cyclisation of a sulfone acetal prepared from 1,4-dimethoxynaphthalene produces the 2-sulfone analogue of pentalongin 80 <00TL755>. Formation of the 10n-electron cyclopenta[b]thiopyran moiety appears to be the driving force in the thermal rearrangement of the cyclohepta-l-thiaspiro[4.4]nonatriene 81 into the deep blue cycloheptathialene 82 <00TL8255>. tBu

tBu

hMe

Bu3SnH

heatw 81

t

82

(44%)

83

O

Phil, heat (80%) Scheme56

84

O

The enone 83 and related compounds undergo a Bu3SnH-catalysed intramolecular cyclisation to trans-fused thiopyran 84 (Scheme 56) <00TL2279>.

333

Six-Membered Ring Systems: With 0 and~or S Atoms

CH3(CH2)43

_CI PhCHO,InCI3 " (CH2)4CH 3 S Bz S D. [ ' ~ ir[ cat. ZnCI2 Bz Bz L SH A, + ; ~SJ",ph (75%) S S PhMe,heat Bz Bz Bz 85 (33%) Scheme57 Scheme58

Homoallyl mercaptans react with aromatic aldehydes in an InC13-mediated Prins cyclisation to give substituted tetrahydrothiopyrans 85 with good diastereoselectivity (Scheme 57) <00TL 1321 >. Simple large scale syntheses of 4-hydroxythiocoumarin and 2-methylthiochromone from 2-mercaptobenzoic acid have been devised <00SCl193> and efficient syntheses of various simple and fused thiopyran-4-ones and 4-thiones have been achieved through the reaction of ethylene trithiocarbonate and dibenzoylacetylene (Scheme 58) <00JCS(P1)1467>. The 2-thiobenzopyrylium salt 86 behaves as an electron-deficient diene undergoing [4++2] polar cycloadditions with electron-rich alkenes to give the benzo-fused bicyclo[2.2.2]thiaheterocycles 87 (Scheme 59) <00TL2161>.

{~~/S

CH+_ MeOH,2=CHAr =-rt

86 BF4

Scheme59

X~~==~_-

87 SOMe

~

X

O 88

tBu

tBu

Infrared-absorbing dyes 88 have been prepared from croconic acid and 4-methylchalcogenopyrylium salts. Red shifts of ~nax are noted as the size of the heteroatom increases and range from 845 nm for (88; X = O) to 1081 nm for (88; X = Te) <00JOC2236>. 6.4.3

HETEROCYCLES CONTAINING TWO OR MORE OXYGEN ATOMS

6.4.3.1

Dioxins

The keto endoperoxide 90 has been synthesised from 1,4-cyclohexadiene through its photooxygenation, reduction of the resulting diastereoisomeric mixture of endoperoxides 89 and subsequent oxidation (Scheme 60). Some chemistry of 90 is described <00JOC5926>.

O

(i)

/ ~ ~PO O H

(ii)

~~OH

(iii)

P

" ~0

89 90 Reagents:(i) 02, TPP,hv, CHCI3;(ii) PPh3,20 ~ (75%);(iii) PCC,CH2CI2(52%) Scheme60

Functionalised cyclopropanes can be prepared from 1,2-dioxines by reaction with stabilised phosphorus ylides <00JCS(P1) 1319; 00JOC5531>. The 5-triflate of 1,3-dioxin undergoes a variety of facile Pd-catalysed cross coupling reactions affording 5-substituted 1,3-dioxins from which acrolein can be thermally generated in high yield by a retrocycloaddition. In particular, this approach leads to a new class of 2-acylacroleins (Scheme 61) <00T10275>.

334

J.D. Hepworth and B.M. Heron

(60%)

OiBu Scheme 61

Oxidation of the aminonaphthols 91 gives the quinone spiroketals 92, analogues of palmarumycin <00TL9105>. The first total synthesis of (+)-diepoxin ~ 93 has been achieved from a naphthoquinone <00JOC6319>.

0

NH2 Mn02, Phil

0

O

(70 8o%)

O-~k j , . - O H

91

92

93

Cyclopenta-l,4-dioxanes 95 are formed in high yields through the acid-catalysed rearrangement of the dioxolanes 94 in which electrocyclisation of a hydroxypentadienyl carbocation, akin to a Nazarov cyclisation, is involved (Scheme 62) <00CEJ4021>. tBu

FeCI3, SiO2- tBu '~

O

(85%)

94

Scheme 62

OH

OH 95

Pd2(dba)3 +

R-Binap -"

R2/~OCO2Me

O ,,~

O

2

Scheme 63

An enantioselective synthesis of 2-alkylidene-l,4-dioxanes is based on the Pd-catalysed heteroannulation of alkynyl carbonates to benzene-l,2-diol in the presence of chiral diphosphine ligands (Scheme 63) <00OL527>. 6.4.3.2

Trioxins

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345; 00JCS(P1)1265; 00JMC2753; 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 6.4.4

HETEROCYCLES CONTAINING TWO OR MORE SULFUR ATOMS

6.4.4.1

Dithianes

Treatment of the 1,2-bis(benzylthio)benzene S-oxide 96 with triflic anhydride is thought to generate benzodithiete 97 which can be trapped by alkynes to give substituted 1,4-benzodithiins 98. On the basis of the stereochemistry of the products from trapping with alkenes, a stepwise mechanism is favoured (Scheme 64) <00CC1667>.

335

Six-Membered Ring Systems: With 0 and~or S Atoms

0

R1

SATol-p

Tf20

/ ~ . , ~ ~ S 2~ .R-

R2

97 Scheme 64

96

5 examples, (18 - 64%)

98

The value of 2-acyl-l,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of 13-hydroxy-q,-ketoesters through ester enolate aldol reactions <00JOC6027>. 6.4.4.2

Trithianes

Oxidation of the hexathiaadamantane 99 can lead to a variety of products, but the tetrasulfone 100 is unexpectedly, but regioselectively, formed when an excess of oxidant is used <00JCS(P2) 1777>.

Ss "'s

-Igo I

Ar,~Ar

S,S dsXS~R

2e-oxn ___ S"%"'S

103

~ - / "SO2 99

1 O0

101

102

104

The pale yellow 2-diarylmethylene derivative of 1,3,5-trithiane 101 exhibits electrochromism, changing to the deep blue dication 102 upon electrochemical oxidation <00JOC5514>. 6.4.4.3

Tetrathianes

Oxidation of the dithiabicyclo[3.3.1]heptane with Oxone T M leads to a mixture of the cisand trans-l,2,4,5-tetrathianes; the former exists in a twist 103 and the latter in a chair 104 conformation <00BCJ729>. 6.4.5.

H E T E R O C Y C L E S CONTAINING BOTH OXYGEN AND SULFUR IN THE SAME RING

6.4.5.1

Oxathianes

The unsaturated sulfinyl compound 105 can be converted into the iodooxathiane 107 either directly by N-iodosuccinimide or via the sulfoxide 106, providing the first example of an iodonium-promoted Pummerer rearrangement <00H(52)465>.

heatNS

O~'SBn 105

~

xylene OHoISBn 106

O'- 1

O.,..~S Ph 107

~

108

,BnNEt3,MoS4

L,,,Br MeCN, rt ~ Scheme 65

(75%)

336

J.D. H e p w o r t h a n d B.M. H e r o n

Benzyltriethylammonium tetrathiomolybdate, [BnNEt3]2MoS4, is a useful sulfur transfer reagent which has now been shown to effect a one-pot, three-step sequence of S - t r a n s f e r m r e d u c t i o n m M i c h a e l addition. The intramolecular version successfully produces 1,4-oxathianes from the bromoenone 108 (Scheme 65). In like manner, the bicyclo[3.3.1]nonane skeleton incorporating a thiopyran ring can be constructed <00AG(E)4316>. The 0t,0t'-dioxothione 109 can be generated from indan-l,2,3-trione using potassium thiotosylate as the sulfur transfer reagent and has been trapped as its [4+2]-cycloadduct 110 (Scheme 66). A 1,3-sulfinate migration from S ~ O is involved <00OL2519>. o

o

O

O 109

~oTSSK+~strans'cycl~176

(63%)

=

S O

Scheme 66

110

Hetero-Diels-Alder reactions in which o-thioquinones behave as the 4~ component towards pentafulvenes lead to 1,4-benzoxathianes (Scheme 67) <00TL6919>. + SNPhth

py, sealed tube R

2

CHCI 3, 70 ~ Scheme 67

6.4.6

"

5 examples, (61 -82%)

S R1

R2

REFERENCES

00AG(E)372 00AG(E)734 00AG(E)739 00AG(E) 1937 00AG(E)2290 00AG(E)3816 00AG(E)4067 00AG(E)4316 00BCJ729 00CC607 00CC615 00CC837 00CC933 00CCl191 00CC1339 00CC1675 00CC1667 00C C 1737 00CC 1781 00CC1987 00CEJ1302 00CEJ3095 00CEJ3116

J. S. Clark, O. Hamelin, Angew. Chem. Int. Ed. Engl., 2000, 39, 372. K. C. Nicolaou, J. A. Pfefferkorn, G.-Q. Cao, Angew. Chem. Int. Ed. Engl., 2000, 39, 734. K. C. Nicolaou, G.-Q. Cao, J. A. Pfefferkorn, Angew. Chem. Int. Ed. Engl., 2000, 39, 734. M. F. Hentemann, J. G. Allen, S. F. Danishefsky, Angew. Chem. Int. Ed. Engl., 2000, 39, 1937. K. Ohmori, Y. Ogawa, T. Obitsu, Y. Ishikawa, S. Nishiyama, S. Yamamura, Angew. Chem. Int. Ed. Engl., 2000, 39, 2290. H. Schrtider, P. Neidig, G. Ross6, Angew. Chem. Int. Ed. Engl., 2000, 39, 3816. F. Badalassi, D. Wahler, G. Klein, P. Crotti, J.-L. Reymond, Angew. Chem. Int. Ed. Engl., 2000, 39, 4067. K. R. Prabhu, P. S. Sivanand, S. Chandrasekaran, Angew. Chem. Int. Ed. Engl., 2000, 39, 4316. A. Ishii, T. Omata, K. Umezawa, J. Nakayama, Bull. Chem. Soc. Jpn., 2000, 73, 729. J. M. Percy, S. Pintat, Chem. Commun., 2000, 607. C. E. Song, E. J. Roh, B. M. Yu, D. Y. Chi, S. C. Kim, K.-J. Lee, Chem. Commun., 2000, 615. C. E. Song, E. J. Roh, Chem. Commun., 2000, 837. U. Anwar, R. Grigg, V. Sridharan, Chem. Commun., 2000, 933. H. A1-Badri, N. Collignon, J. Maddaluno, S. Masson, Chem. Commun., 2000, 1191. J. Hobley, V. Malatesta, R. Millini, W. Giroldini, L. Wis, M. Goto, M. Kishimoto, H. Fukumura, Chem. Commun., 2000, 1339. R. Mutter, E. M. Martin de la Neva, M. Wills, Chem. Commun., 2000, 1675 K. Kobayashi, E. Koyama, M. Goto, C. Noda, N. Furukawa, Chem. Commun., 2000, 1667. M. Leclaire, R. Levet, F. Ferreira, P.-H. Ducrot, J.-Y. Lallemand, L. Ricard, Chem. Commun., 2000, 1737. D. J. Fox, D. House, F. Kerr, S. Warren, Chem. Commun., 2000, 1781. S. Rousset, M. Abarbri, J. Thibonnet, A. Duchene, J.-L. Parrain, Chem. Commun., 2000, 1987. D. Enders, G. Geibel, S. Osborne, Chem. Eur. J., 2000, 6, 1302. K. C. Nicolaou, R. M. Rodrfguez, H. J. Mitchell, H. Suzuki, K. C. Fylaktakidou, O. Baudoin, F. L. van Delft, Chem. Eur. J., 2000, 6, 3095. K. C. Nicolaou, H. J. Mitchell, K. C. Fylaktakidou, R. M. Rodrfguez, H. Suzuki, Chem. Eur. J., 2000, 6, 3116.

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00CEJ4021 00CEJ4154 00EJO73 00EJO297 00EJO527

K. C. Nicolaou, H. J. Mitchell, R. M. Rodrfguez, K. C. Fylaktakidou, H. Suzuki, S. R. Conley, Chem. Eur. J., 2000, 6, 3149. K. C. Nicolaou, K. C. Fylaktakidou, H. J. Mitchell, F. L. van Delft, R. M. Rodriguez, S. R. Conley, Z. Jin, Chem. Eur. J., 2000, 6, 3166. L. F. Tietze, G. Schneider, J. W61fling, A. Fecher, T. N/3bel, S. Petersen, I. Schuberth, C. Wulff, Chem. Eur. J., 2000, 6, 3755. B. Iglesias, A. R. de Lera, J. Rodriguez-Otero, S. L6pez, Chem. Eur. J., 2000, 6, 4021. R. P6rez Carl6n, N. Jourdain, J.-L. Reymond, Chem. Eur. J., 2000, 6, 4154. C. Schneider, A. Schuffenhauer, Eur. J. Org. Chem., 2000, 73. H. Tsujimori, M. Bando, K. Mori, Eur. J. Org. Chem., 2000, 297. T. Nicola, R. Vieser, W. Eberbach, Eur. J. Org. Chem., 2000, 527.

/"~/~t~, T / ' ~ , " ~ n

i~ T

00CEJ3149 00CEJ3166 00CEJ3755

o~nt

~

I'),1i r c l i n

t7 R r n * , , n

Ft,r I Oro Chain

~OOO 6qO

338

J.D. Hepworth and B.M. Heron

00JCS(P 1)3188 J. G. Knight, S. W. Ainge, C. A. Baxter, T. P. Eastman, S. J. Harwood, J. Chem. Soc., Perkin Trans. 1, 2000, 3188. 00JCS (P 1)3719 V. J. Ram, M. Nath, P. Srivastava, S. Sarkhel, P. R. Maulik, J. Chem. Soc., Perkin Trans. 1, 2000, 3719. 00JCS (P 1)3732 A. S. Kelkar, R. M. Letcher, K.-K. Cheung, K.-F. Chiu, G. D. Brown, J. Chem. Soc., Perkin Trans. I, 2000, 3732. 00JCS (P 1 )4279 W-M. Wu, Y-L. Wu, J. Chem. Soc., Perkin Trans. 1, 2000, 4279. 00JCS(P2) 1777 G. P. Miller, I. Jeon, A. N. Faix, J. P. Jasinski, A. J. Athans, M. C. Tetreau, J. Chem. Soc., Perkin Trans. 2, 2000, 1777. 00JMC2753 J. L. Vennerstrom et al., J. Med. Chem., 2000, 43, 2753. 00JOC583 A. Fougerousse, E. Gonzales, R. Brouillard, J. Org. Chem., 2000, 65, 640. 00JOC914 S. Usse, G. Guillaumet, M.-C. Viaud, J. Org. Chem., 2000, 65, 914. 00JOC 1873 H.-J. Hamann, J. Liebscher, J. Org. Chem., 2000, 65, 1873. 00JOC2236 T. P. Simard, J. H. Yu, J. M. Zebrowski-Young, N. F. Haley, M. R. Detty, J. Org. Chem., 2000, 65, 2236. 00JOC3252 C. Chen, P. S. Mariano, J. Org. Chem., 2000, 65, 3252. 00JOC3513 L. P6rez-Serrano, J. Bianco-Urgotti, L. Casarrubios, G. Domfnguez, J. P6rez-Castells, J. Org. Chem., 2000, 65, 3513. 00JOC4070 S. D. Burke, K. W. Jung, W. T. Lambert, J. R. Phillips, J. L. Klovning, J. Org. Chem., 2000, 65, 4070. 00JOC4326 R. Kouno, T. Tsubota, T. Okauchi, T. Minami, J. Org. Chem., 2000, 65, 4326. 00JOC4487 H. Audrian, J. Thorhauge, R. G. Hazell, K. A. Jorgensen, J. Org. Chem., 2000, 65, 4487. 00JOC4523 P. A. Evans, T. Manangan, J. Org. Chem., 2000, 65, 4523. 00JOC5514 T. Suzuki, T. Yoshino, J. Nishida, M. Ohkita, T. Tsuji, J. Org. Chem., 2000, 65, 5514. 00JOC5531 T. D. Avery, D. K. Taylor, E. R. T. Tiekink, J. Org. Chem., 2000, 65, 5531. 00JOC5644 G. A. Kraus, N. Zhang, J. Org. Chem., 2000, 65, 5644. 00JOC5817 B. Schmidt, H. Wildemann, J. Org. Chem., 2000, 65, 5817. 00JOC5926 W. Adam, M. Balci, H. Kiliq, J. Org. Chem., 2000, 65, 5926. 00JOC6027 J. L. Garcia Ruana, D. Barros, M. C. Maestro, A. M. Z. Slawin, P. C. Bulman Page, J. Org. Chem., 2000, 65, 6027. 00JOC6319 P. Wipf, J.-K. Jung, J. Org. Chem., 2000, 65, 6319. 00JOC6576 P. E. Harrington, I. A. Stergiades, J. Erickson, A. Makriyannis, M. A. Tius, J. Org. Chem., 2000, 65, 6576. 00JOC6601 G. M. Li, S. Niu, M. Segi, K. Tanaka, T. Nakajima, R. A. Zingaro, J. H. Reibenspies, M. B. Hall, J. Org. Chem., 2000, 65, 6601. 00JOC7059 T. K. M. Shing, Q. Jiang, J. Org. Chem., 2000, 65, 7059. 00JOC7516 C. Jia, D. Piao, T. Kitamura, Y. Fujiwara, J. Org. Chem., 2000, 65, 7516. 00JOC8490 B. B. Snider, T. Liu, J. Org. Chem., 2000, 65, 8490. 00JOC9206 A. Degl'Innocenti, A. Capperucci, D. C. Oniciu, A. R. Katritzky, J. Org. Chem., 2000, 65, 9206. 00OL 191 A. N. Cuzzupe, C. A. Hutton, M. J. Lilly, R. K. Mann, M. A. Rizzacasa, S. C. Zammit, Organic Letters, 2000, 2, 191. 00OL207 K. E. Drouet, T. Ling, H. V. Tran, E. A. Theodorakis, Org. Lett., 2000, 2,207. 00OL231 J. D. Rainier, S. P. Allwein, J. M. Cox, Org. Lett., 2000, 2, 231. 00OL441 E. Yoneda, T. Kaneko, S.-W. Zhang, K. Onitsuka, S. Takahashi, Org. Lett., 2000, 2, 441. 00OL527 J.-R. Labrosse, P. Lhoste, D. Sinou, Org. Lett., 2000, 2,527. 00OL679 D. Zuev, L. A. Paquette, Org. Lett., 2000, 2,679. 00OL859 W. R. Roush, L. A. Pfeifer, Org. Lett., 2000, 2, 859. 00OL1765 H. Miao, Z. Yang, Org. Lett., 2000, 2, 1765. 00OL2011 C.-K. Sha, Z.-P. Zhan, F.-S. Wang, Org. Lett., 2000, 2,2011. 00OL2133 K. Tanaka, H. Aoki, H. Hosomi, S. Ohba, Org. Lett., 2000, 2, 2133. 00OL2519 W. Adam, B. Fr6hling, Org. Lett., 2000, 2, 2519. 00OL2647 B.-C. Hong, Z.-Y. Chen, W.-H. Chen, Org. Lett., 2000, 2, 2647. 00OL3643 D. V. Kadnikov, R. C. Larock, Org. Lett., 2000, 2, 3643. 00S 123 G. Speranza, C. F. Morelli, P. Manitto, Synthesis, 2000, 123. 00S843 J.-P. Bouillon, D. Saleur, C. Portella, Synthesis, 2000, 843. 00S 1113 B. A. Kowalczyk, Synthesis, 2000, 1113. 00S 1956 Y. Q. Tu, A. HUbener, H. Zhang, C. J. Moore, M. T. Fletcher, P. Hayes, K. Dettner, W. Franke, C. S. M. P. McErlean, W. Kitching, Synthesis, 2000, 1956. 00SC469 S. Balasubramanian, M. G. Nair, Synth. Commun., 2000, 30, 469. 00SC 1193 J.-C. Jung, J.-C. Kim, O.-S. Park, Synth. Commun., 2000, 30, 1193.

Six-Membered Ring Systems: With 0 and~or S Atoms 00SC 1431 00T417 00T1013 00T1811 00T 1937 00T2421 00T2533 00T3909 00T5391 00T5947 00T6023 00T6047 00T 10275 00TL371 00TL507

339

T. Wang, J. P. Burgess, P.H. Reggio, H. H. Seltzman, Synth. Commun., 2000, 30, 1431. P. Pietikfiinen, Tetrahedron, 2000, 56, 417. M. A. Birkett, D. W. Knight, P. B. Little, M. B. Mitchell, Tetrahedron, 2000, 56, 1013. R. W. Draper, B. Hu, R. V. Iyer, X. Li, Y. Lu, M. Rahman, E. J. Vater, Tetrahedron, 2000, 56, 1811. M. A. Brimble, M. R. Nairn, H. Prabaharan, Tetrahedron, 2000, 56, 1937. B. Schmidt, M. Westhus, Tetrahedron, 2000, 56, 2421. F. Bellina, D. Ciucci, P. Vergamini, R. Rossi, Tetrahedron, 2000, 56, 2533. H. A1-Badri, N. Collignon, J. Maddaluno, S. Masson, Tetrahedron, 2000, 56, 3909. T.-Z. Liu, M. Isobe, Tetrahedron, 2000, 56, 5391. B. Chandrasekhar, S. R. Ramadas, D. V. Ramana, Tetrahedron, 2000, 56, 5947. E. Martfnez, L. Martfnez, M. Treus, J. C. Est6vez, R. J. Est6vez, L. Castedo, Tetrahedron, 2000, 56, 6023. C. Pouget, C. Fagnere, J.-P. Basly, H. Leveque, A.-J. Chulia, Tetrahedron, 2000, 56, 6047. S. P. Fearnley, R. L. Funk, R. J. Gregg, Tetrahedron, 2000, 56, 10275. K. Nishide, S. Ohsugi, M. Node, Tetrahedron Lett., 2000, 41, 371. K. Fujiwara, H. Morishita, K. Saka, A. Murai, Tetrahedron Lett., 2000, 41,507.

340

Chapter 7

Seven-Membered Rings

John B. Bremner

Director Institute for Biomolecular Science Department of Chemistry University of Wollongong Wollongong, NSW 2522, Australia e-mail: [email protected]

7.1

INTRODUCTION

The past year was an active one in the area of seven-membered heterocycles, particularly with regard to fused seven-membered systems. Activity in the fused ring system area is powered largely by the range of pharmacological activities shown by different members of this class. Another feature worthy of mention is the increasing impact of the elegant ring closing metathesis reaction on heterocyclic synthesis, including seven-membered rings. This is a trend likely to continue and expand in its applications. Some major reviews including seven-membered heterocyclic systems have been published on saturated oxygen heterocycles <00JCS(P1)1291>, quatemary ct-amino acids <00TA645>, glycosidase inhibitors <00PHA331>, seven-membered ring lactones and lactams <00SL161>, and artimisinin drugs <00MI05>. This Chapter is structured largely along previous lines, with divisions based on the number of ring heteroatoms. However, more fused ring and bridged structures incorporating seven-membered rings have been included to broaden the base and to reflect current trends. Also a section on systems of pharmacological interest are included together with a brief comment on future directions.

Seven-Membered Rings

7.2

341

SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM

Systems of this type are still dominated by those containing a nitrogen atom, particularly with one or more rings fused to the seven-membered ring. The following material is divided into non-fused and fused examples. 7.2.1 Azepine and derivatives Rearrangement reactions have provided access to some interesting azepinone or azepine dione systems. Curtius rearrangement followed by a [3,3] sigmatropic reaction on intermediate carbonyl azides gave azepin-2-one derivatives, for example 2, in fair to moderate yield. The precursor intermediates for this sequence were made, in turn, by treatment of 2siloxysubstituted 2-alkenylcyclopropanecarboxylic acids (for example, 1) (Scheme 1) with diphenylphosphorazidate and triethylamine <00SL725>.

TBSON,j / ~ ~,,,

1. (PhO)2OPN3 NEt 3 [COOH

2.80~

TBsA I

1

R

HO

NH

2

3

Scheme 1 Thermal ene reactions of 3-(alk-2-enyl)benzylamino-2-(methoxycarbonyl) acrolein derivatives have been reported to give the substituted 4,5-dihydro-lH-azepines 3 (R = H, Me, Ph, 2-furyl, CO2Et) in good yield <00T1299>. A neat regio- and stereoselective ring enlargement strategy has been employed to access the optically pure azepanes 4 (eg. R = Ph) based on cyanophenyloxazolo piperidine and a reduction-ring enlargement process <00TLl179>. Ring cyclisation methodologies have been used to make the polyhydroxylated azepane 5 (via a double reductive amination of a manno-l,6-dialdehyde derivative) <00JCS(PI)1157>, and the N-(1-phenylethyl)azepane 6 (via a rhodium-catalysed reaction of N-(1-phenylethyl)pent-4-enamine with H2/CO) <00AJC835>. The ring closing metathesis reaction with Grubbs' catalyst has also been used to make a tetrahydroazepine derivative in moderate yield <00CC1771>.

342

J.B. Bremner

H H

OH

H2

PhFH(CH3)

HO 4

5

6

Trihydroxyazepanes (trideoxy-l,6-iminohexitols) have also been prepared from carbohydrate precursors and activities as inhibitors of selected glycosidase enzymes assessed <00CAR22>. An altemative approach (Scheme 2) to polyoxyfunctionalised azepines (eg. 9) involves cyclooctatetraene as a starting material via its 1~, 2~, 5ct, 6c~ -diepoxy-3[3,413-diol 7, and subsequent amine nucleophilic attack to give 8 followed by ozonolysis with reductive work up to afford 9 <00TL5483>. ~0. .,'.$

M~ OMe

g,"

HOH2C

~OMe

N

OH / k ~--OM~

~OMe

0

HOH2C-k\'- " v ~ _ _

HO ~ OMe

7

MeO

8

o Me

9

Scheme 2 A ring contraction approach (Scheme 3) to seven-membered rings involves the use of the Ramberg-B~icklund rearrangement, for example with the thiaazacyclooctane 10, which gave the azepine 11 in good yield, with stereoselective double bond formation, on reaction with potassium t-butoxide <00JOC8367>. Boc

I

Boc

"Ot',

i

66% 10

11 Scheme 3

The first synthesis of a 2-azatropone, eg. 13 (R = t-Bu) has been described by Takami and co-workers. Although the yield was poor, the product itself has some novelty. It resulted (Scheme 4) from selenium dioxide oxidation of the 3H-azepine 12 (R = t-Bu) <00JOC6093>.

Seven-Membered Rings

343

O SeO 2

R.

R

R

12

13 Scheme 4

7.2.2

Fused azepines and derivatives

A large amount of work covering these systems was reported in the past year. References to this work are organised in terms of benzo-fused derivatives, then dibenz-fused, heteroaromatic ring-fused, and combinations of benz- and heteroaromatic ring-fused systems. A particularly elegant combination of directed ortho metalation and ring closing metathesis methodologies has been described by Lane and Snieckus to access the benzazepine 15 in 80% yield, with Grubbs' ruthenium catalyst (C12Ru(PCy3)2CHPh)) being used in the ring closing metathesis step from 14. The general strategy is summarised in Scheme 5 below <00SL1294>. In this scheme, DMG is the directed metallation group, Z is a carbon or heteroatom, G is a substituent group, and m, n = 1, 2, 3.

~

~ D M

MG

Li

[)m

~G Boc

I

Boc

I

Ru cat. 14

Scheme 5

15

N-Silylaldimine condensation with the lithiated intermediate 16 (Scheme 6), after working up the reaction under acidic conditions, produced an amino alcohol that can then be dehydrated to the benzo[d]azepine system 17 (R = Ph) <00JHC1061>.

344

J.B. Bremner

OLi

~ ~b..

~

b

~

Li

H R

16

17 Scheme 6

The chiral (R)-benzazepine derivative 20 is a key intermediate in the synthesis of a non-peptide AVP V2-agonist. Efficient production of this intermediate was thus required, and this has been achieved by highly enantioselective asymmetric hydrogenation of the easily made acids 18 (E and Z) and 19, using Ru(II) complex catalysts <00CHIR425>.

HCOOH

Ts 18

H2COOH

~'H2COOH

Ts 19

Ts 20

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then N-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>.

I

R

21 A diastereoselective imine alkylation and a palladium-catalysed biaryl coupling were important steps in the diastereoselective synthesis of 6,7-dihydro-5H-dibenz[c,e]azepines (Scheme 7) starting from (R)-l-(2-methoxyphenyl)ethylamine. Selection for the atropisomeric conformer having aS chirality and pseudo equatorial groups was influenced by the benzylic stereogenic centres of the (5R,7R)-azepine nucleus <00SL483>.

345

Seven-Membered Rings

Me

(R) Me

Me

Me .Me @

O

H

~

Me _.l~Ie c ~ ~ 98%

N R~ Tf

(R,R)

Me H

d,e 64%

Tf

Me (R,R)

d k___.... (R,R) R-H

90%

(R,R) R=COCF3

a. MeLi b. A1Br3 c. 4-NO2PhOTf

d. (CF3CO)20 e. (Me3Sn)2,Pd(PPh3)4, LiCI f. K2CO3,NaBH4

Scheme 7

Pyrroloazepine derivatives, and other azole fused analogues, have also attracted a good deal of attention. Typical of the papers in this area is the synthesis of a series of 7aminoalkylpyrrolo[2,3-c]azepine derivatives for evaluation as ~l-adrenergic and 5-HT2 receptor antagonists. The compound 24 made from 22 via 23 after a standard polyphoshoric acid-catalyzed cyclisation (Scheme 8), showed potent blocking activity at both receptors <00CPB 1129>. OH /

Hoo

\

R

Et

Et

O 22

23

Scheme 8

v 24

R=(CH2)3_N , L_._J

~

F

346

J.B. Bremner

Related work described the synthesis of pyrrolo[3,2-c] azepines (eg. 25) as 5-HT2 antagonists and their antiplatelet aggregation activity <00CPB623>. R

jNA?F m

Et

OH 25

The synthesis of the previously undescribed 4,6,7,8-tetrahydropyrrolo[2,3-d]azepine ring system has been reported, based on pyrroles or azepinedione derivatives. For example, reaction of the azepinedione shown below with benzylamine in the presence of ptoluenesulfonic acid gave the fused derivative 26 <00MI04>. O

Et

.C

o

_

/~.....

COzEt

PhH2C~~'~~xCH2Ph

Phil

26 The unexpected ring enlargement of the 3,4-dihydroisoquinolinium ring system to give the pyrazolone-annelated benzazepines 28 (R = H, MeO) has been described on treatment of compounds 27 (R = H, MeO) with hydrazine hydrate. Presumably the oximino hydrazide is an intermediate in this process followed by internal hydrazide attack at the 1position <00MC36>. Me

Me

R

R

Me

Me

C(:NOH)COzEt 27

H 28

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused 1-azabicyclo[m.n.0]alkanes, the perhydrobenzo[/]pyrrolo[1,2-a] azepine 29 was prepared in 72% yield <00JOC7158>.

Seven-Membered Rings

347

29 Ring expansion of 4,5,6,7-tetrahydro-4-indolone oximes also underpinned the synthesis of the 3H-azeto[1,2-a]pyrrolo[3,2-c]azepin-8-ones 30 (eg. R = H, Me) in good yield <00H(53)557>. OPh

30

The pyrrolo[3',4':2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-[3-carbolines did not occur under the conditions <00JHC1177>. The previously unknown pyrazolo[3,4-d]pyrido[3,2-b]azepine ring system has been described by Albright and co-workers, based on the known 5H-pyrido[3,2-b]azepine derivative 31 and using 3-(dimethylamino)acrolein as a modestly successful substitute for the difficult to access, propynal. A key further step was the introduction of keto functionalisation at the 9-position in the 7-membered ring (via rearrangement of the pyridine-N-oxide and later oxidation of a secondary alcohol) to give 32. The fused pyrazole ring was then introduced by standard methodology <00JHC 41>. Pyrazolo[3,4-d]thieno[3,2-b]azepines have also been made by this group with a view to evaluating antagonistic activity at the arginine vasopressin receptor <00BMCL695>. N

r H 31

Ts/ 32

H 33

There is considerable interest in imino-sugars and analogues as glycosidase enzyme inhibitors. The synthesis of a "homonojiritriazole" derivative 35 has now been reported

348

J.B. Bremner

involving a tetrahydro-4H-1,2,3-triazolo[1,5-a]azepine system. This derivative was prepared in high yield from the azido compound 34 (accessed turn from a 5-azido-5-deoxy-Dglucofuranose derivative) by a thermal intramolecular 1,3-dipolar cycloaddition reaction followed by hydrogenolysis of the benzyl ether protecting groups. Unfortunately, 35 showed only weak inhibitory activity with two enzymes, E.coli ot-galactosidase and baker's yeast isomaltase <00SL1837>.

BnOH2q

no-...~

,~

onO

I-K)~

N3

BnO

///

o.

/t,r==N,,,

HOHo

OH

~

OH

34

35

A concise method for the synthesis of the 5-substituted azepino[3,4-b]indol-l-ones 37 (eg. R = Bn, R 1 = Ph) has been described, based on the Pd-mediated cross coupling reactions of azepino[3,4-b]indol-5-yl trifluoromethanesulfonates eg. 36. These latter compounds were accessed in turn from the corresponding azepino[3,4-b]indole-l,5-dione <00T4491>. TfQ

~

R1

N

N~ R

~N \

Me

\

Me

36

37

An interesting annelation reaction of allene-derived 1,3-dipoles with 3-(Naryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel N-aryl-2,3-dihydro-4ethoxycarbonylchromano[2,3-b]azepin-6-one system 39 (for example, R = Me, R 1 = C1) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023> o R~

A

/

o ~

~

N

/Ar

+ +PPh3

~,

COOEt ~

38

~

~i~

39 Scheme9

< R1

Seven-Membered Rings

349

In a new reaction of the pyrano[2,3-c]azepines 40 with hydrazine hydrate, the first derivatives of the pyridazino[4,3-c]azepine system 42 (for example R 1 = R 2 = Me) have been described (Scheme 10). The rearrangement probably involves initial ring opening to the intermediate 41. Aromatisation of this system was achieved by further oxidation with thallium (III) nitrate or copper(II) acetate <00SL254>.

a2

R1

R1 a2 \

0

H N~

N2H4 xH20

CONHNH2

H2 0

0 40

42

a1

R2~OH j~ONHN H2 HN%

"~

~NH2

0 41 Scheme 10

In other somewhat related work, the synthesis of pyrano[2,3-c]azepines (and pyrido[2,3-c]azepines has been described. Reaction of hydrazoic with N-(5,6,7.8-tetrahydro2,5-dioxo-2H- 1-benzopyran-3-yl)benzamide (or 8-hydrazono) derivatives afforded pyrano[2,3-c]azepines, which in tum can be transformed to pyrido[2,3-c]azepines <00H(53)1111>. 7.2.3

Oxepines and derivatives

A new procedure for the stereoselective preparation of cis-3-hydroxy-2-ethynyl oxepane derivatives, exemplified by 43, based on 5,6-epoxy-7-octyn-l-ols via endo cyclization mediated by Co2(CO)8 has been described. The procedure is not stereospecific however <00JOC6761>. OH o(CO) 3

43

ph//v-C~

J.B. Bremner

350

Disubstituted oxepanes have also been synthesised by (Bu3Sn)20/Zn(OTf)2-promoted cyclization of hydroxy epoxides via an SN2 process with exo mode selectivity <00TL7697> and <00TL7701>. Reductive nucleophilic cleavage of the 1-alkoxymethyl-6,8-dioxabicyclo[3.2.1]octanes 44 catalysed by TIC14 leads to the formation of the oxepane derivatives 45 (eg. R = Me) in good yield <00T1065>. 20 Me

~

44

~CH2 ~ Me

45

Baeyer-Villiger oxidation of cyclohexanone can be accomplished with a Dowex 50Wsupported, mixed Ni(II) and Fe(II) catalyst, in the presence of oxygen to give tetrahydroazepin-2-one <00JCR(S)196>. Another classical approach to seven-membered rings, but involving ring formation rather than ring interconversion, has been described by Walsh and co-workers. Thus reaction of 2,4-hexadiene-l,6-diols with butyl lithium and ptoluenesulfonylchloride gives dihydro-lH-oxepins <00H(53)897>. Stereochemical aspects of the bromination reactions of 2,7-dialkyl-3-hydroxyoxepanes have been investigated in connection with eventual total syntheses of brominated marine natural products (Scheme 11). Brominations with various R3P-Br2 complexes were assessed and bicyclic oxonium ion intermediates proposed. Thus reaction of 46 with DPPE-2Br2 in DCM at 23~ gave the brominated oxepane 47 (R = CH2CH2Ph) in 81% yield with retention of configuration, while the diastereomer 48 under virtually the same conditions gave the corresponding oxepane 49 (71% yield) together with the ring contracted product 50 in 24% yield <00SLl187>.

~ 0/

"q/R

~

46

~ 0/

"~R

47

DPPE-2Br 2 ~\xx"" ~ 0 / 48

-'~R 49

50

R=CH2CH2Ph Scheme 11

Seven-Membered Rings

351

The oxepane and oxepanone derivatives 51 and 52 respectively, were made by allylindation of, or allylmagnesium bromide addition to, acyclic tetrakis(tetrahydrofuranyl) dialdehydes. The solid state conformation of 52 was determined by X-ray diffraction analysis <00JOC4303>. CH 2

O

51

7.2.4

52

Fused oxepines and derivatives

The stems of the plant Perilla frutescens var. acuta have yielded two new prenyl 3benzoxepine derivatives, perilloxin 53 and dehydroperilloxin 54, whose structures were established by spectroscopic means. An in vitro cyclooxygenase-1 bioassay was used to guide the separation of these natural products, which possessed moderate inhibitory activities against this enzyme (ICs0 values for 53 and 54 were 23.2M and 30.4M respectively) <00JNP403> OMe

OMe 0

.S 53

54

The first enantioselective total synthesis of the sesquiterpenoid heliannuol D 56 has been reported by Shishido and co-workers. The key step was a base-mediated (NaOH) intramolecular cyclisation of the phenolic epoxide mixture 55 (R 1 = MOM, R 2 = H and R 1 = H, R 2 = MOM). Heliannuol D (and the eight-membered congener, heliannuol A) is an allelopathic agent isolated from cultivated sunflowers (Helianthus annuus L.SH-222) <00JCS(P 1) 1807>.

352

J.B. Bremner

H

R1

O

Me

55

56

An elegant general method for the catalytic formation of benzo-fused oxygen heterocycles, including seven-membered rings, is featured in the work of Buchwald et al. The key reaction involved the palladium-catalysed cyclisation of hydroxyalkyl-substituted halides, 57 and 58, in the presence of a binaphthyl di-t-butylphosphine ligand; yields of the reduced 1-benzoxepines 59 and 60 were moderate to good <00JA12907>.

57

59

~~~'/OHx=Br X

Me

58

X=C1 60

Me

A further application of ring-closing metathesis in seven-membered heterocyclic ring formation is in the synthesis of the trans-fused oxpane systems. This process involved tandem RCM/allylstannane-aldehyde cyclizations and interaction of the process provides access to trans-fused polyoxepanes <00S883>. Ciguatoxin, the potent marine neurotoxin, continues to attract synthetic attention. It is a polycyclic ether which contains four fused, reduced oxepine ring systems. The fused oxepane ring moiety (ring K) has been prepared on the basis of a cobalt complex-mediated cyclization as indicated in the conversion of 59 (obtained from the substituted acetylene by reaction with Co2(CO)8) to 60, and then ultimately to 61 in good overall yield (Scheme 12). The stereochemistry of 62 was confirmed by NOESY and other NMR experiments; this synthetic strategy was then applied in a neat elaboration of the (HIJ)K-ring fragment of ciguatoxin <00SL587>.

Seven-Membered Rings

/SO2Ph /:t

i)n-Bu3SnH,A n)Na-Hg

/ SO2Ph H---

_H

H -

H 59

353

BF3"EI20 ~ ~

OMe

.OBn R= .~,,/A.x..~OR'

2

R'=TBDPS

H 6O

.Me

Zt

.H-

I

I

A o oy2

)" ~ O H ~

'

..OBn i)TBAFbii)Ac20

h_o ,

61

~"IK"O~ <.OBn H - i~I ~ . . ( "

Scheme 12

In a related area, a novel 1,3-dipolar cycloaddition strategy involving 1,2isopropylidene furanoside-fused oxepane derivatives and 4-O-allyl nitrone or nitrile oxide species to give chiral oxepinopyran and oxepinooxepane systems has been described <00TL10135>. The non-dynamic kinetic resolution of configurationally stable biaryl lactones, including the seven-membered ring case, by reduction with a chiral oxazaborolidine-BH3 complex was studied using calculations based on the semiempirical AMI method and good agreement with experimental findings was obtained <00JOC2517>. 7.2.5

Thiepins and derivatives

Reaction of the diyne 63 with $2C12 resulted in cyclization in nearly quantitative yield to the 4H, 5H-thiepin 64 (Scheme 13) <00TL8349>. H3C CH3 u CH~ CH3(CH3)2C-~=-C(CH3)2-C(CH3)2---~:-C(CH3)2CH3 ~

j

/~----C1

(H30)2~" \S"~_.. 63

CH 3 Scheme 13

C(CH3)2CH3 64

When the dioxalane-fused thiepane 65 was converted to the anion by reaction with butyl lithium in THF at -20~ this anion then was converted to the butyl-substituted thiepane 66 in fair yield <00S 1756>.

354

J.B. Bremner

BUs

65

66

Cyclization of 1,6-dibromo-2,4-dienes with sulfide ion results in the formation of dihydro-lH-thiepins, which were characterised in turn as their sulfones <00H(53)897>. Stereospecific contraction of the seven-membered nucleus was observed on treatment of the dimesylated thiepanetetrol derivatives 67 (obtained in turn from d-sorbitol) with sodium azide to give a 5:1 mixture of the bis(azido)tetrahydrothiophenes 68 and 69. Intramolecular nucleophilic displacement of either mesylate group initiates this ring contraction <00TA1389>. .~OMe MeO

SO2M e

MeO/,,,,

"

[,,,,....j) '"'OMe

R

,r

MeO,,,,,,Ik/,,

MeOw,

~"

";~ N3

5

OMe

67

68

69

Representatives of the bridged sulfone system 70 have been subjected to ruthenium catalysed ring-closing metathesis reactions (Grubbs' catalyst) and shown to afford, in low yields, a few selected cyclic dimers and trimers, of all the possibilities available. The diastereoselectivities observed were rationalised in terms of kinetic control involved with internal ruthenium/sulfonyl oxygen coordination <00JA3391>.

~

/ Hzln

[H2C]n~/ 70 7.2.6

Fused thiepins and derivatives

The enantioenriched sulfoxide intermediate 72 (R = CH2OH), obtained by asymmetric S-oxidation with a chiral oxaziridine (89:11 enantiomeric ratio), has provided a highly enantioselective synthesis of the benzothiepin derivative 71 (4R, 5R). The aldehyde intermediate 72 (R = CHO) was cyclized asymmetrically to 71 (4R, 5R) with >98:2 enantiomeric ratio. Base treatment (t-BuOK,-10~ THF) of the racemic benzothiepin 73

Seven-Membered Rings

355

(RI= H, R2= OH) and its epimer gave a 77:23 mixture of stereoisomers favouring 73 (R 1 = H, R2 = OH), indicative of a thermodynamic process with diastereoselectivity controlled by the configuration of the sulfoxide <00JOC2711>.

Me2N

Bu Bu "OH F

~

MeO 71

R

~

B

u Bu

Bu F

~

MeO

MeO

72

73

1R

The properties of the chiral dibenzo[c,e]thiepin, 1,11-dimethyl-5,7dihydrodibenzo[c,e]thiepin, and its S-oxide, and S,S-dioxide, together with a doubly bridged analogue, were studied by chromatography, CD spectroscopy, X-ray crystallography, and empirical force-field and CNDO/S calculations. Unlike its S-oxide or S,S-dioxide, the dibenzothiepin could not be resolved into enantiomers by chromatography on triacetylcellulose. In the case of the sulfoxide, the barrier to rotation was shown to be >167 kJmo1-1 <00HCA479>. The crystal structure of dinaphth [2,1-c:l~2'-e]thiepin-3(5H)-thione has also been reported <00MI06>. Pyridine- and pyran-fused benzothiepin-S,S-dioxide derivatives of types 74 and 75 (X = SOE) have been prepared by standard annelation procedures from the benzothiepin ketone derivatives. A number of the bis-fused derivatives showed good anti-cancer and moderate anti-HIV activity <00ZN(B)417>. R

x

X

/ / ' ~

NH2 NH2

CN

CN R1 74

75

356

7.2.7

J.B. Bremner

Miscellaneous systems with one heteroatom

A convenient, though low yield, route to dihydro-lH-phosphepin oxide has been described based on the reaction of 1,6-dibromo-2,4-di-tert-butylhexa-2,4-diene with PhPC12 in the presence of sodium <00H(53)897>. A number of benzo- or dibenzo-fused seven membered phosphorus heterocyclic systems have also been studied. These include the benzo-fused oxa-bridged phosphaalkene 76 prepared by thermolysis of 2,3-diphenylindenone 2,3-epoxide (as a source of the carbonyl ylide 1,3-dipole intermediate) in the presence of t-butylphosphaalkyne. This bridged phosphaalkene is unusually stable even without inert gas blanketing <00EJOC2219>. Reaction of 76 with sulfur or grey selenium stereoselectively affords the thia- or selenaphosphiranes 77 (X = S, Se respectively). <00T6259> Ph

Ph But

/I O

O

76

77

. i h Bu-t

Standard cyclisation methodology was used to access the cyclic monophosphinic acid derivative 78 by reaction of ammonium phosphonate and ethyldiisopropylamine, followed by the addition of chlorotrimethylsilane, with 2,2'-bis (bromomethyl)-l,l'-biphenyl. Silane reduction of 78 gave the secondary phosphine. The secondary phosphine borane complex 79 could be used in alkylation or Michael addition reactions. For example the Michael adduct 80 was produced in high yield by treatment of 78 with a Nail suspension in THF followed by the addition of diethylvinylphosphonate <00EJOC3497>.

OEt OH O

78

BH3 H

79

P ~ C ~ C ~ ~'-~-~O H2 H2 OEt

80

The 1-benzoborepines 82 (R = C1, Ph), representative of a previously unknown heterocyclic ring system, have been made by sequential reaction of the 1-benzostannepine 81 (R = n-Bu) with BC13 and then PhBC12. The 1-benzostibepines 83 (R = Ph, Me, n-Bu) could also be prepared from 82 <00JCS(P1)1965>.

Seven-Membered Rings

Bu t

R

81

357

/ R

Bu t

82

Bu t

83

In a particularly significant achievement, the first cyclic n-conjugated silylium ion has been described. The silatropylium ion 85 annelated with bicyclo[2.2.2]octene groups was prepared from the dichlorosilepin 84 (R 1 = R 2 = C1) on treatment first with mesityllithium at room temperature, and then with LiA1H4 at 40~ (to give 84, R 1 = H, R 2 = mesityl), followed by stirring of this mesityl derivative with trityl tetrakis(pentafluorophenyl)borate in CD2C12 in a sealed tube at -50~ The presence of the ion 85 was evidenced by 29Si and 13C NMR spectroscopy, which showed it was aromatic and that the aromatic stabilisation reduced the solvent-silylium ion interaction. Calculations on the simplest silylium ion 86 at the B3LYP/6-31G* level were done to estimate the degree of interaction between dichloromethane and the silatropylium ion. The synthesis of an isolable and solvent free silatropylium ion moiety is now awaited with interest <00JA9312>. Me

Me 84

O

/

~/

85 i--H

86

7.3

SEVEN M E M B E R E D SYSTEMS CONTAINING T W O H E T E R O A T O M S

7.3.1

Diazepines and fused diazepines and derivatives

The cyclization of N-arylcarbamoyl alkenes promoted by o-iodoxybenzoic acid led to the synthesis of the bridged 1,3-diazepinone derivative 87 in good yield. It has been proposed tentatively that this novel reaction methodology may proceed via an amide-centred free radical intermediate <00AG(E)625>. As part of a project on the biomimetic synthesis of muscarinic antagonists, the bridged 1,4-diazepane derivative 88 (RR 1 = O(CH2)40) was prepared via enamine formation from an amino aldehyde <00OL643>.

358

J.B. Bremner

~N..~O

/

CN___ph

87

Me

A ~ ~ N M e

I! "1

Me~ . / ~ I . . - N . . 0 . . . ~ , ~

88

N~ J

R

Cyclic ureas incorporating a 1,3-diazepinone skeleton continue to be of pharmacological interest. The N,N-disubstituted system 89 has been prepared and shown to be a potent inhibitor of factor Xa in vitro and to have an improved pharmacokinetic profile in the rabbit. The binding model for this series of compounds was confirmed by an X-ray crystallographic analysis of one analogue in the series <00BMCL301>.

HO/•-•

~OH

+NH2C1

HNx

T

/NH

NOH

Bu~ N 89

9O

The guanidino analogue 90 of the 7-membered cyclic urea system was prepared, enantiomerically pure, from D-mannitol. The derivative 90 selectively inhibits bovine kidney ct-L-fucosidase at 2.8~tM <00BMC307>. In a correction to previous work, the cyclization of 4-ureidobutyric acids with thionyl chloride has been shown (by NMR spectroscopy) to result in pyrrolidinone carboxamide derivatives and not aryl perhydro-l,3-diazepine-2,4-diones <00JHClll>. Optimization of the geometry of 1-(o-nitrophenyl)-2-phenyl-lH-4,5,6,7-tetrahydro-l,3-diazepine has been undertaken using computer-based molecular modelling, and correlations made with theoretical and experimental UV spectra <00MOL483>. The pyridyl substituted 1,4-diazepinone derivative 91 was prepared by photolysis of 2,6-bispyridyl-4-azidopyridine, and it represents a new class of ligand for metal ion complexing <00HCA384>.

359

Seven-Membered Rings

H

0

~ N

91

CF3

92

Condensation of ethylenediamine with 4-ethoxy-l,l,l-trifluoro-3-buten-2-one occurs readily to give the simple 2,3-dihydro-lH-1,4-diazepine 92 in good yield <00SC677>. Much of the diazepine chemistry reported in 2000 has focussed on ring fused derivatives. Some pertinent examples illustrative of new chemistry in this area include the following. The 1,4-benzodiazepines 95 and 96 have been prepared by ring expansion methodology. The precursors required were made from the 2-alkyl-l-methylquinazolinium hexafluorophosphates 93 (R 1 = H, Me; R2 = H, Me, Ph), which were then deprotonated by sodium or potassium hydride to afford solutions of the 2-alkylidenedihydroquinazolines 94. Trapping of 94 with methanesulfonyl azide in situ, or subsequent treatment with trifluoromethanesulfonyl azide, gave mixtures of the N-sulfonylimino-l,4-benzodiazepines 95 (R3 = Me, CF3) and 96 plus other products <00EJOC1577>. 'h

Ph N

N

N~..-ZR PF6 [Me 93

R

R/1 94

Ph

Me

R

Ph

N--q'7-R2 95

Me

Me R1

96

Novel 1,2-diazepino[3,4-b]quinoxalines of type 98 have been reported to result from 1,3-dipolar cycloaddition of the quinoxaline 4-oxides 97 (R -- Ph, C6Ha-p-Me, and C6H4-pOMe) with 2-chloroacrylonitrile; compounds of type 97 could also be converted to 99. Reaction of compounds 98 with selenium dioxide resulted in ring contraction to the pyridazino[3,4-b]quinoxalinones 100 <00MI03>.

360

J.B. Bremner

~)-

N

CI~+N~I,,~

C I ~ N/N~'~,/R

~

Me

97

/OH ~'-

-N/~",, Me/

98

R

H

H MeO

Me/

H

Me

99

100

Other 3-(2-thienyl)-l,2-diazepino[3,4-b] quinoxalines have been made by a similar nitrone cycloaddition process, and these compounds have algicidal activity <00JHC1277>. Analogues 101 of the non-competitive AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4yl)propionic acid) antagonist have been prepared. Compounds 101 (R - MeCO; MeNHCO) had comparable activity to the prototype antagonist GYK152466, 102, but other derivatives were less active <00BMCL899>. Me

Me

H2N

O ) ( ~ H2N 101

C1

I~NN~

HEN 102

Me 103

Further new competitive AMPA antagonists include the imidazo-fused 2,3benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson's disease <00BMC2127>. An efficient synthesis of fluorine-containing 1H-1,4-diazepino[6,5h]quinolines has been described based on N,N-dimethyl-5,7-bis(trifluoroacetyl)-8quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>.

Seven-Membered Rings

361

An alternative pathway for the reaction of an imidazo[4,5-c]isoxazole with dimethyl acetylenedicarboxylate has been discovered, leading to ring expansion and the formation of the first example, 104, of a [1,4]diazepino[2,3-c]isoxazole <00TL9319>. Me

/

COOMe

MeOOC~~N/O MeOOC 104

A high yield approach to the hexahydropyrrolo[3,2-e][1,4]diazepine-2,5-diones, 105 and their tetrahydrofuro analogues, 106, based on rearrangements of cyclopropylketimines and the cyclopropylketones, derived by acid hydrolysis, have been described. Thermolysis followed by DDQ oxidation of the unstable dihydro intermediates then gave compounds 105 (eg. R 1 = Me, R2 = i-Bu) and 106 (eg. R = 4-CI(C6Ha)CH2) <00OL4249>. R1

R ~

O~

O

2R NH O

O

105

106

A range of azole-fused 1,4-diazepine derivatives have also been reported, for example the [ 1,2,5]selenadiazolo[3,4-e] [1,4]diazepines 107 (eg. R = H) <00JHC1269>.

R__~ ~ 0

X~Nse I Me 107

The reaction of 4-amino-3-aryl-5-(benzylamino) pyrazoles with ketoamines with the structure 4-RC6HaCOCH2CH2NMe2 (R = H, C1, Br, NO2, MeO) in ethanol with acetic acid has been reported to afford a series of 1-benzyl-4,6-diaryl-2,3-dihydropyrazolo [3,4b][1,4]diazepines <00HC231>. Sequential condensations with 2-bromo-2-bromomethylcyclopropane-l-carboxylate and an imidazole derivative, and then guanidine gave the novel ring-expanded 108 with a 6Himidazo[4,5-e][1,3]diazepine-4,8-dione skeleton <00JHC951>. Another 6-amino-2-phenyl derivative of this ring system has also been reported <00MOLl64>.

362

J.B. B r e m n e r

O

0 108

"~H

,coN.(

NH2

Interest continues in the preparation of pyrimido-fused diazepines. In this context, a number of new 6-amino and 6,8-diamino-4-aryl-2,3-dihydropyrimido[4,5-b][1,4]diazepines were synthesised by the highly regioselective condensation of 4,5,6-triaminopyrimidine and 2,4,5,6-tetraaminopyrimidine respectively with 3-dimethylaminopropiophenones <00JHC401>. Some new spirothiadiazolepyrazolo[ 1,5,4-el][ 1,5] benzodiazepines have been reported by Rakilo et al. They are prepared by a regioselective 1,3-dipolar cycloaddition of a nitrile imine with pyrazolo[1,5,4-ef] [ 1,5]benzodiazepine-thione <00H(53)571>. Treatment of the chlorobutyl derivative 109 with iodide in acetone afforded the new 1H, 2H, 3H, 4H, 5H-[1,3]diazepino[2,1-b][1,3]benzoxazol-6-ium ring system 110 via intramolecular nucleophilic displacement <00T8567>. Me

109 7.3.2

110 I-

Dioxepines and fused dioxepines and derivatives

There are relatively few entries in the non-fused dioxepin area, and most of these focus on reactions of these systems. For example the triflic acid-initiated polymerisation of 1,3-dioxepane in the presence of acetic acid and hexanedicarboxylic acid has been studied and mechanistic aspects discussed <00JPS(A)1232>. Biodegradable microspheres for the controlled delivery of drugs have been made from copolymers and homopolymer blends of Llactide and 1,5-dioxepan-2-one <00PP1628>. Ring contraction of 5-methylene-l,3dioxepanes (eg. 111) on reaction with trimethylsilyl trifluoromethanesulfonate in the presence of base afforded the exo tetrahydropyrans, in good yields <00TL2171>.

Seven-Membered Rings

363

Ph 111 Synthetically, 5-chloro-2,2,5-trimethyl-l,2-dioxepane can be accessed by TiC14mediated cyclization of an unsaturated monoperoxyacetal through a 7-endo/endo pathway in modest yield <00JOC8407>. The bridged 1,4-dioxepanones 112 (R = TBMS; X = H, Me) were prepared, unexpectedly, in moderate yield by radical deoxygenation of capuramycin derivatives. These products were rationalised in terms of a novel intramolecular radical glycosylationlactonization reaction <00H(52)133>.

. . ~ . . . ~ _~

ov "*o-c~

112

o~'--./

I OR I

MeO

Two new strobilurins O, 113 and P, 114, containing benzodioxepin skeletons, were isolated from the mushroom Mycena galericulata and characterised spectroscopically <00JAN297>.

364

J.B. Bremner

Me+ H 113

Me "o--4 \

M-

/ MeO~OMe I0I

Me

Me~O.~_.~( ~ ~ ~ / M e 114 0"-'~ / M~~,,IOM e 0 A highly regio- and stereo-regulated synthesis of the (Z)-l,4-benzodioxepin-5-ones 115 (Ar = Ph, 4-MeOC6H4; X = O) has been reported, and involved, at the penultimate stage, cyclization of disubstituted alkynes on treatment with copper (I) iodide. <00JCS(P1)775>.

LO

Ar

115 Small ring fusions to 1,3- or 1,4-dioxepane systems have been reported in two papers. In the first case, the seven-membered ring bridged 2,5-dichloro Dewar benzene 116 was synthesised and used as a building block for O-phenylene-based acetylenic macrocycle construction <00JOC4385>. In the second, the precursor 117 was photolysed in pentane or decane at temperatures from 195-423 K and the alkoxyketene carbene insertion intermediate underwent a stereocontrolled [2 + 2] cycloaddition to give only the (1R, 6R)-l,4-dioxepanefused isomer 118 in low yields, independent of temperature. Significantly, the reaction demonstrates the validity of entropy control as a new principle of asymmetric synthesis <00JA2128>.

365

Seven-Membered Rings

C1

~

0

C1 116

117

118

A number of new depsidones have been reported, including 2-hydroxyvirensic acid 119 <00AJC233> from the lichen Sulcaria sulcata, the cytotoxic prenylated derivative 120

<00JNP1361> from Garcinia parvifolia, and dehydrocollatolic acid from the lichen Parmotrema nilgherrense <00AJC891>. Me

Me

M

H

Me

2Lo

Me

H O ~ Z . O ~ ~ X

HO~o~ ~ clio

__/ Me

,,

Me~M

CO2H

119

e

OH

OH

120

The seven-membered ring containing chiral bisphosphine 121 (n = 1) was made as part of a series of bisphosphines (n = 1-6) to study the influence of ligand dihedral angles on the enantioselectivity of Ru-catalysed asymmetric hydrogenation of 13-ketoesters <00JOC6223>.

n(HzC)

1

121

PPh2 PPh2

J.B. Bremner

366

A 1,4-dioxepin fused derivative 122 of the anticancer agent acronycine was prepared by lead tetraacetate oxidation of cis-l,3-dihydroxy-l,2-dihydroacronycine followed by treatment with sodium borohydride <00NPL183>. Mo

I

-,

Mo O

122

OH

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R 1 = CH2COMe) from dihydroartemisinin acetate, and of type 124 (eg. R 2 = a-OH, R 3 - Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin <00JMC4228>.

M Me

M

e

o

O R1 123

Me

Me ,,,, R 2

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126; some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of l l azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>.

Seven-Membered Rings

M

e

367

M

H

Me

H

/___ ~ R 0" 125 ~ - - R Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = O(CH2)3NR1R2 where NRIR 2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. M ~ i v i e

Me

R

127 73.3

Miscellaneous derivatives with two heteroatoms

The X-ray crystal structure of 6-chloro-2,3-dihydro-7-methyl-5-methylene-2H, 3H, 5H- 1,4-dithiepin-l,l,4,4-tetraoxide has been published and a short intermolecular contact across an inversion centre noted <00AX(C)el09>. An experimentally direct and efficient approach to 1,3-dithiepins has been reported using 1,n-alkyldihalides and carbon disulfide and sodium borohydride, to generate the sulfide nucleophile <00OLl133>. Enantioselective desymmetrization of the seven-membered meso-cyclic disulfide 128 (n = 3, R = Me) by desulfurization with a chiral tert-aminophospine, gave 129 (n = 3, R = Me) in modest yields with up to 30% ee <00JCS(P1)1595>.

s.~CO2R

/~02P-

~(CH2)n

~ _(CH2)n_

CO2R 128

CO2R 129

368

J.B. Bremner

The new heterocyclic derivative 130 has been shown to be an efficient chiral auxilliary for asymmetric desymmetrization of cyclic meso-l,2-diols via diastereoselective acetal cleavage <00JOC3284>.

(

0 "v. y "

"s.....

130 Three new spirans, including 131 and 132, incorporating a 1,5-benzodithiepin system have been synthesised from methyl benzynes. The structure of 131 was confirmed by X-ray crystallography, and the seven-membered ring was shown to have a chair conformation and the five-membered ring an envelope conformation <00OL425>.

131

132

The reduced pyrido[4,3-g][1,4]benzothiazepine 133 has been detected by HPLC as a novel metabolite in some human urine samples. It arises from Pictet-Spengler condensation of 5-S-cysteinyldopa with formaldehyde. This chemistry also underpins a facile synthesis of the 2,3,4,5-tetrahydro[1,4]benzothiazepine 134 via reaction of formaldehyde with a cysteinylcatechol <00JOC4269>.

H

/__~C02H

HO 133

CO2H

OH 134

The synthesis of new thiazepinobenzimidazoles has been described by Chimirri and co-workers <00H(53)613>. The ring contraction of the 1,4-thiazepine derivatives 135 and 136

369

Seven-Membered Rings

(eg. R 1 = R2 = R3 = Ph) to racemic 2-thiazolidine acetic acid derivatives 137 and 138 in fair to good yields on treatment with ceric ammonium nitrate (CAN) (Scheme 14) has been reported <00SL1831>. The ready thermal extrusion of sulfur from benzo[b][1,4]thiazepines formed a key step in another ring contraction sequence which lead to a stereoselective synthesis of novel quinolyl glycines <00SL595>. Cl H

\+

R1

~

N.-. 3R

~

I" Re l ~ S

1 H +, EtOH, A

\

"- R 2 ~ ~ /

O 135[ CAN ~ CH3CN-H20 , A R2

O

O 136

CAN CH3OH , A

R 1~ ,CH2COOMe

N ~ CHzCONHR3

O~138

J137 Scheme 14

Racker et al. have developed an interesting new combinatorial method for the synthesis of [1,4]oxazepin-7-ones (eg 139, R = Ph) from aldehydes and or-amino alcohols with the Baylis-Hillman reaction being a key step <00JOC6932>.

R

O

139

Photolysis of the azide 140 gave the tetrahydro-l,3-oxazepine derivative 141 in moderate yield. The rearrangement involved migration (with retention of configuration) of the endocyclic carbon atom attached to the anomeric centre, independent of the anomeric configuration. When the nitrile group was replaced either by a carboxamido or a tetrazolyl group, complex mixtures of products resulted <00TA533>.

370

J.B. Bremner

UoOC

140

141

O-Alkylation of N-(phenacyl)- and N-(pivaloylmethyl)-derivatives of N-(benzhydryl)(2R,3R)-cis-2,3-epoxybutyramide gave 4,5,6,7-tetrahydro-4-aza-oxepin-5-ones by SNi reactions under basic conditions <00T3209>. A ring enlargement process was used effectively to access the enantiopure pyrrolo [1,2-d][1,4]oxazepine-9a(7H)-carboxylate derivatives 142 and 143 . The sequence involved copper (II)-catalysed decomposition of an tx-diazocarbonyl derivative attached to a chiral morpholinone, and a carbenoid, spiro-[5,6]-ammonium ylide, Stevens [1,2] rearrangement sequence. The Stevens and related rearrangements have considerable further potential for novel heterocyclic syntheses <00TA3449>. O 142 143 ~) R _

R=~COOEt R . . . . . ~ICOOEt

Ph

Baeyer-Villiger oxidation of the anti-tumour alkaloid acronycine and its 2-nitro derivative, led to the chromeno[5,6-b][4,1]benzoxazepin-8-one 144 (R = H) and 144 (R = NO2) respectively <00NPL183>. O

Me/

~ R

M

e Me

144 Amongst other fused seven-membered ring systems, the synthesis of novel [1,2,5]selena (and [1,2,5]thia)diazolo[3,4-e][1,4]oxazepines from fused pyrimidine precursors has been described by Ueda and co-workers <00JHC1269>.

371

Seven-Membered Rings

7A SEVEN MEMBERED HETEROATOMS

SYSTEMS

CONTAINING

THREE

OR

MORE

7.4.1 Systems with N, S and/or O A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. H ~,,."N,,,'" N'~ N

0 H

H 145

H 146

The new heterocyclic system represented by compounds of type 147 (eg. R = C1), and containing a bis-fused [1,3,4]thiadiazepine moiety, was prepared by cyclocondensation of 1aminobenzimidazole-2-thione with 6-chloropyrimidine-5-carboxaldehydes. Some representatives of the system (e.g. 147, R = NMe2) showed anti-HIV activity <00SC3719>.

R

N/~-'--S

,

SMe

147 A facile route to 1,3,4-oxadiazepin-2-ones has been developed by Komatsu et al. involving acid-catalysed cyclisation of carbazate derivatives derived from the reaction of N, N-di-tert-butyldiaziridinone and ot-hydroxy ketones with B F3.Et20 catalysis <00H(52)541>. Two significant papers by Nakagawa et al. describe synthetic work on the structurally fascinating tunicate natural products, the eudistomins 148, containing the oxathiazepine ring system. Formation of this ring system was achieved by, for example, acid-catalysed (TsOH) cyclisation of the S-oxide 149 (P = Boc; COOMe) to give 150, which could then be deprotected to give (-)-debromoeudistomin L (148, X = Y = Z = R = H, c~-NH2); (-)debromoeudistomin L (148, X = Y = Z = R = H, 13-NH2) was accessed from Nhydroxytryptamine and D-cysteinal <00JCS(P1)3477>. Extension of this work to the synthesis of (-)-eudistomins C, E, F, K and L (148, X = H, Br; Y = H, Br, OH; Z = H, Br; R =

J.B. Bremner

372

H, COOMe) from the appropriately substituted N-hydroxytryptamine was also completed <00JCS(P1)3487>. X S

S(O)Me

z

s

148

149

150

7.4.2 Miscellaneous systems The single-crystal structures of 1,2,4,5-tetrathiepane-3,3-carboxylates 151 (R,R = Me;Et) have been determined by x-ray diffraction analysis <00EJOC2583>. Reaction of 1,2benzenedisulfenyl chloride with [(CpzTiC1)aS3] gave the known 1,2,3,4,5-benzopentathiepin 152 in moderate yield <00EJIC921>. OOR

[

\siS

S /

151 7.5

-coop.

152

SEVEN MEMBERED SYSTEMS OF PHARMACOLOGICAL SIGNIFICANCE

Many seven-membered ring heterocyclic derivatives show pharmacological activity, and many, for example the benzodiazepines, nevirapine (anti-HIV), trineptine (antidepressant) and artemisinin derivatives (anti-malarial) are used clinically. The number of papers reporting pharmacological activity of new compounds or pharmacological mode of action studies continues at a significant rate. Amongst the examples of seven-membered heterocyclic ring compounds of interest in this context are the following: 1,4-thiazepin-5-ones as protein tyrosine kinase c-Src inhibitiors <00MI01>, pyridazino [3,4-b][1,5]-benzoxazepin-5(6H)-ones as antimycobacterial agents <00AP231 >, pyridazino [4,5-b] 1,5-oxazepinones, thiazepinones and diazepinones as memory enhancing and neuroprotection agents <00MI02>, 5H-dibenz[b,f]azepine derivatives as cardioselective M2 muscarinic receptor antagonists <00CPB1611>, <00EJP93>, and as potential neurotoxic/neuroprotective agents <00EJP191>, and as steroid 5ot-reductase inhibitors <00CPB552>, a tetrahydro[5,4,3-cd]azepinoindole as a CNS active agent <00HC9>, dihydro-benzo[c]azepino[2,1-a]indoles as melatonin analogues <00JMC1050>, azepino-and diazepinoindoles as dopamine receptor ligands <00AP287), and PDE4 enzyme inhibitors <00BMCL35>, a pharmacophore for benzodiazepine-induced hyperphagia <00MI07>, 1,5-benzodiazepine derivatives as cholecystokinin-B receptor antagonists

Seven-Membered Rings

373

<00JMC3596>, an imidazo[4,5-d][1,3]diazepin-8-ol as an AMP deaminase inhibitor <00JMC1508>, the antimalarial mode of action of artemisinin <00FEBSL238>, and finally dithiepin-l,l,4,4-tetroxides as non-peptidic human galanin receptor antagonists <00BMC1383>. The behavioural effects of two antidepressants with opposite molecular actions, ie. tianeptine (a serotonin reuptake enhancer) and fluoxetine (a serotonin reuptake blocker) have been assessed and it was concluded that, apart from the effects on serotonin reuptake, these drugs have other mechanisms playing an important role in the anti-depressant action <00AF5>. 7.6

FUTURE DIRECTIONS

The synthetic power of the ring closing metathesis methodology is still not fully realised in heterocyclic synthesis and many further applications of the methodology, either alone or combined with other methods, are predicted, including applications in sevenmembered heterocyclic ring synthesis. Opportunities also exist for the application of ylide rearrangement technology and free radical cyclisations. While some new spirocyclic and bridged seven-membered heterocyclic systems were reported in 2000, the scope in these two areas is significant, particularly with respect to the design of pharmacologically active compounds with new molecular architectures. Further developments in these areas are thus expected.

7.7

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00AF5 00AG(E)625 00AJC233 00AJC835 00AJC891 00AP231 00AP287 00AX(C)el09 00BBR359 00BMCL35 00BMCL301 00BMCL695 00BMCL899

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00JOC6761

C. Mukai, S. Yamaguchi, Y.-i. Sugimoto, N. Miyakoshi, E. Kasamatsu and M. Hanaoka,

J. Org. Chem. 2000, 65, 6761.

00T4491 00T6259 00T8567 00TA533 00TA645 00TA1389

R. Raecker, K. Doering and O. Reiser, J. Org. Chem. 2000, 65, 6932. W.H. Pearson and W.-k. Fang,J. Org. Chem. 2000, 65, 7158. D. I. MaGee and E.J. Beck, J. Org. Chem. 2000, 65, 8367. P.H. Dussault, I.Q. Lee, H.-J. Lee, J. Richard, Q. J. Niu, J. A. Schultz and U. R. Zope, J. Org. Chem. 2000, 65, 8407. Y. Xu and C. Pan, J. Polym. Sci., Part A: Polym. Chem. 2000, 38,1232. Y. V. Shklyaev, V. A. Glushkov, V. V. Davidov, V. I. Sokol and V. S. Sergienko, Mendeleev Commun. 2000, 36. D. Benard, P. Deprez, D. Lesuisse, E. Mandine and A. Ugolini. PCTInt.Appl.; (Chem.Abstr., 2000,132, 137 416). F. Andrasi, A. Angyal, P. Berzsenyi, S. Boros, L. Harsing, K. Horvath, P. Matyus, I. Moravcsik, A. Papp, A. Simay, E. Szabo, K. Szabo, I. Tamawa and I. Varga. PCTInt. Appl.; (Chem.Abstr., 2000,132,334 478). H. S. Kim, S. U. Lee, G. Jeong, M. K. Li and Y. Kurasawa, Yakhak Hoechi. 2000, 44(4), 325; (Chem. Abstr., 2000,133,335 219). M. A. Waly, Chin. Pharm. J. (Taipei) 2000, 52,179. R. N. Price, Expert Opin. Invest. Drugs 2000, 9,1815. K. Peters, E.-M. Peters, J. Hinrichs and G. Bringmann, Z. Krystallogr. 2000, 215,395. M. Filizola, D. L. Harris and G. H. Loew, J. Biomol. Struct. Dyn. 2000,17, 769. H.-M. Chen and R. S. Hosmane, Molecules 2000, 5,164. M. E. Hedrera, A. Robinsohn and I. A. Perillo, Molecules 2000, 5,483. P. Magiatis, S. Mitaku, A.-L. Skaltsounis, F. Tillequin, A. Pierre and G. Atassi, Nat. Prod. Lett. 2000,14, 183. J. Baranska, J. Grochowski, J. Jamrozik and P. Serda, Org. Lett. 2000, 2,425. B. B. Snider and H. Lin, Org. Lett. 2000, 2,643. Y. Wan, A. N. Kurchan, L. A. Barnhurst and A. G. Kutateladze, Org. Lett. 2000, 2,1133. K. Kumar, K. Rajiv, A, Kapur and M. P. S. Ishar, Org. Lett. 2000, 2, 2023. E. S. H. E1Ashry, N. Rashed and A. H. S. Shobier, Pharmazie 2000, 55,331. I. Brouard, L. Hanxing and J. D. Martin, Synthesis 2000, 883. S. Carini, V. Cere, F. Peri and S. Pollicino, Synthesis 2000,1756. Q. Chu, Y. Wang and S. Zhu, Synth. Commun. 2000, 30,677. H. Abdel-Ghany, A. Khodairy and H. M. Moustafa, Synth. Commun. 2000, 30, 1257. A. Brukstus, D. Melamedaite and S. Tumkevicius, Synth. Commun. 2000, 30, 3719. B. El Ali and H. Alper, Synlett 2000,171. S. Kafka, P. Trebse, S. Polanc, K. Slovenko and M. Kocevar, Symlett 2000, 254. L. A. Saudan, G. Bernardinelli and E. P. Kundig, Synlett 2000, 483. T.-Z. Liu, B. Kirshbaum and M. Isobe, Synlett 2000, 587. G. Cabarrocas, S, Rafel, M. Ventura and J. M. Villagordo, Synlett 2000, 595. G. Bottcher and H.-U. Reissig, Synlett 2000, 725, K. Fujiwara, M. Kobayashi, D. Awakura and A. Murai, Synlett 2000,1187. C. Lane and V. Snieckus, Synlett 2000,1294. B. Zaleska and D. Ciez, Synlett 2000,1831. K. Tezuka, P. Compain and O. R. Martin, Synlett 2000,1837. K. Fujiwara, A. Amano, T. Tokiwano and A. Murai, Tetrahedron 2000, 56,1065. M. Noguchi, H. Yamada, S. Takamura, K. Okada, A. Kakehi and H. Yamamoto, Tetrahedron 2000, 56,1299. B.-L. Deng, M. Demillequand, M. Laurent, R. Touillaux, M. Belmans, L. Kemps, M. Ceresiat and J. Marchand-Brynaert, Tetrahedron 2000, 56, 3209. L. Chacun-Lefevre, B. Joseph and J.-Y. Merour, Tetrahedron 2000, 56, 4491. S. G. Ruf, J. Dietz and M. Regitz, Tetrahedron 2000, 56, 6259. A. I. Khalaf, R. G. Alvarez, C. J. Suckling and R. D. Waigh, Tetrahedron 2000, 56, 8567. J.-P. Praly, C. D. Stefano and L. Samsak, Tetrahedron: Asymmetry 2000,11,533. C. Cativiela and M. D. Diaz-De-Villegas, Tetrahedron: Asymmetry 2000,11,645. A. Arcelli, V. Cere, F. Peri, S. Pollicino and P. Sabatino, Tetrahedron: Asymmetry 2000,

00TA3449 00TL2171

G. Chelucci, A. Saba, R. Valenti and A. Bacchi, Tetrahedron: Asymmetry 2000,11,3449. K. Okuma, T. Hayano, K. Shioji, H. Matsuyama, Tetrahedron Lett. 2000, 41(13), 2171.

00JOC6932 00JOC7158 00JOC8367 00JOC8407 00JPS(A)1232 00MC36 OOMI01 00MI02 OOMI03 00MI04 00MI05 00MI06 00MI07 00MOLl64 00MOL483 00NPL183 00OL425 00OL643 00OLl133 00OL2023 00PHA331 00S883 00S1756 00SC677 00SC1257 00SC3719 00SL161 00SL254 00SL483 00SL587 00SL595 00SL725 00SLl187 00SL1294 00SL1831 00SL1837 00T1065 00T1299 00T3209

11,1389.

S e v e n - M e m b e r e d Rings

00TL5483 00TL7697 00TL7701 00TL8349 00TL9319 00TL10135 00ZN(B)417

377

J. Armbruster, F. Stelzer, P. Landenberger, C. Wieber, D. Hunkler, M. Keller and H. Prinzbach, Tetrahedron Lett. 2000, 41,5483. R. Matsumara, T. Suzuki, K. Sato, T. Inotsume, H. Hagiwara, T. Hoshi, V. P. Kamat and M. Ando, Tetrahedron Lett. 2000, 41,7697. R. Matsumara, T. Suzuki, K. Sato, K.-i. Oku, H. Hagiwara, T. Hoshi, M. Ando and V. P. Kamat, Tetrahedron Lett. 2000, 41,7701 J. Nakayama, K. Takahashi, T. Watanabe, Y. Sugihara and A. Ishii, Tetrahedron Lett. 2000, 41,8349. A. Taher, A. M. Z. Slawin and G. W. Weaver, Tetrahedron Lett. 2000, 41,9319. A. Pal, A. Bhattacharijya and R. Mukhopadhyay, Tetrahedron Lett. 2000, 41, 10135. A. E. G. Hammama, N. A. A. E1-Hafeza, W. H. Wanda, and M. Mikolajczyk, Z. Naturforsch., Teil B. 2000, 55,417.

378

Chapter 8

Eight-Membered and Larger Rings George R. Newkome The University of Akron, Akron, OH, USA e-maih [email protected]

8.1 INTRODUCTION In the nineties, there has been a continuing trend from synthetic studies of classical "crown ethers" towards polyazamacromolecules and the introduction of multiple heteroatoms, including most recently metal atom centers. As we start a new millennium, the introduction of nanoscale constructs into the marketplace will demand the synthesis and understanding of large structurally perfect materials to meet specific needs, thus there will be an increasing emphasis to be more imaginative in the design and formation of larger macrocycles and macromolecules. The utilization of readily available, or off-the-shelf, compounds and their mere modification will force new synthetic paradigms. In that I have reviewed the macroheterocyclic family for numerous years the introduction of stable macrocycles possessing metal centers is but one subtle transformation. The inclusion of crystal engineering starts to focus us on the intermolecular interactions of macromolecules, which bridges the nanoscale r6gime. Numerous reviews, concepts, highlights, accounts, and perspectives have appeared throughout the year that are of interest to the macroheterocyclic scientist and those delving into supramolecular chemistry <00PT(R)431> at the molecular level, as well as those in supermolecules and crystal engineering: templates, "wheeled reagents", and rotaxanes by anion complexation <00CEJ21>; hydraphiles <00CCI>; macrocyclic complexes with pendant arms for biological models <00CCR125>; macrocyclizations of thietanes and thiiranes by metal carbonyl complexes <00AA39, 00ACR171>; giant porphyrinoids (nanomolecular cavities) <00AG(E)1763>; N-functionalization of tetraazacycloalkanes <00SL561>; conjugated polymer-based chemical sensors <00CR2537>, sensor functionalities <00AM1315, 99OPIC317> and fluorescent chemosensors <00EJIC2143>; heavy metal chemistry of linked heteromacrocycles <98CCR327, 00JACll3>; synthetic receptors <00JCS(P1)3155>; calixarenes, heteroatoms-bridged <00EJIC2303>, detection- removal of cesium ion <00IECR3605>, crystallographic and modeling studies <00JIPMC375>, and general separations <00ACS(SS)2>; lanthanide-containing functional assemblies <00CSR347,00CCR53>; dinuclear metallo-phosphodiesterase models <00CSR75>; organic conductors <00MI267>; nonsteroidal anti-inflammatory drugs <00CDI21>; new extractants <00MPEMR89, 00JIPMC1, 00IECR3442, 00VMU3>; chiral recognition <00KtK495>, separation <00FKX328, 00IECR3582>, and optical applications <00MRC795>; electron transfer for signaling <00CCR41>; combinatorial supramolecular chemistry

Eight-Membered and Larger Rings

379

<00JCS(D)2483>; molecular entanglements <00CCR5>; cation separations <00CCR3>; cyanine dyes <00H1821> and functionalized phthalocyanines <00JPP454>; sulfur-containing crowns <99MI31, 99MI24>; cycloetherification <99MMM293>; molecular recognition <00FKX82>; new effective synthesis of crowns and cryptands <99UKZ17>; P-crowns <99PSSRE457>; high performance electrodes with crown ethers<99NKK629>; functional nanostructures <00HNMN277> and a short survey of bicyclic diamines <00JCS(P2)175>. Because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic tings are reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated. The introduction of a systematic nomenclature of catenanes, rotaxanes, and derived assemblies has recently appeared <00JPC437>; this should have appeared two decades ago, but is still timely in futuristic point of view. 8.2

C A R B O N - O X Y G E N RINGS

Numerous simple macrocyclic crown ethers possessing diverse subunits, for example: (+)(18-crown-6)-2,3,11,12-tetracarboxylic acid <00JOC1243>, perfluoro-[60]crown-20 and [30]crown-10 <00CC2139>, 16-crown-5 containing both a carboxylic acid unit and electrondonating sidearm on a pivot center <00JA6307>, and benzocrowns functionalized with phthalocyanines <00OL1057>, buta-l,3-diyne <00JCS(P1)2805>, arylurea unit for anion association studies <00OL3099>, meso-meso coupled diporphyrin <00TL8527>, bis(naphthyl)crownophanes, possessing an isobutenyl group and different ring sizes <00TL9261>, exoligands based on an [1.1.1.1]-metacyclophane backbone incorporating either 2,2'-bipyridine or bisquinoline subunits <00TL9043>, transmembrane polyether active in lipid bilayers <00OL3161>, an achiral 30-crown-12 polyacetal from a-cyclodextrin <00CEJ3366>, [n](2,7)pyrenophanes, where n = 7-9 <00JOC5360>, a cyclyne (1), possessing 1,3-diethynylbenzene and ether components <00JA7404>, cyclic ethers with functional methallyl 2,3-dimethylhydroquinone diether subunits <00TL5895>, and related systems

O

O

1

2;n=0or 1

<00CL1364>, new cyclophanes containing two benzo[b]furan rings <00TL1393>, and cyclic ethers that are responsive to two chemical inputs (2) <00AG(E)2167> have been reported. Polymeric pseudocrown ether networks have been generated in situ by the photopolymerization of poly(ethylene glycol) diacrylate transition metal complexes <00CM633>, and the effect of metal ion templation was evaluated. The 1,6,13,18tetraoxa[6.6]paracyclophane-3,15-diyne (termed: pyxophanes) was prepared from hydroquinone and 1,4-dichlorobut-2-yne; it forms size-selective z-complexes with alkali metal cations <00CC2377>. Dibenzo[n]crown-m have been used in numerous elegant studies in which they were the "needles" that were threaded by diverse reagents; the resultant

380

G.R. Newkome

[n]pseudorotaxanes have been characterized and evaluated for supramolecular properties; for example see: <00CEJ3558, 00CEJ2274, 00OL2943, 00OL1221, 00JA6252, 00JA5831>. Calix[n]arenes continue to play an important role in supramolecular chemistry, since they possess a convenient platform for the assembly of convergent loci. Numerous capping processes have tailored their cavity and highly preorganized architecture, but bridging the open ends has been of on-going interest. The syntheses of the cone and partial cone calix[4]arenes possessing an 1,3-alternate-crown-6 <00JOC8283, 00TL9167, 00CC833> and larger crown ethereal <00OL839> or a bis-l,3-alternate-crown-6 <00TL8221> bridges have been reported. A related series of neutral hosts generated from the head-to-head linkage of two calix[4]arene-bis(crown-3) moieties attached on the rigid cone conformation has appeared <00EJOC2325>. A new class of calix[4]arene crown ethers with one or two bipyridine units to the polyether ring have been created and shown to form highly luminescent Eu 3+ and Tb 3+ complexes <00CEJ1026>. Cone and 1,2,3-alternate isomers of 37,40-diallyloxy-(38,42),(39,41)-bis-crown-4 calix[6]arene were prepared by bridging the dialkylated calix[6]arene with triethylene glycol di-p-tosylate <00JA1486>. The related ptert-butylcalix[6]-l,4-2,5-bis-crowns has been synthesized and shown to exhibit high complexation selectivity towards n-PrNH3 + <00TL1571, 00CL1208>. Larger crowned calix[8]arenes were obtained by direct alkylation of p-tert-butylcalix[8]arene with poly(ethylene glycol) ditosylate in the presence of base; with Cs2CO3, mainly the 1,5-isomer was formed, whereas with Nail, the 1,4-bridge was favored <00JOC5143>. Numerous furan-based porphyrins have been reported, such as tetraoxa[4n+2]porphyrin dications with 187t-, 227t-, or 26rt-electron systems <00AG(E)ll01>. The McMurry reaction of the (all-E)-5,5'-([2,2'-bifuran]-5,5'-diyl)bis[penta-2,4-dienal] only occurs intramolecularly to afford mixtures of diepoxy[18]annulenes(10.0); isomers were isolated and studied <00HCA592>.

8.3

CARBON-NITROGEN RINGS

A convergent preparation of hexahomotriazacalix[3]arene utilized the coupling of an appropriate triamine with 2,6-bis(chloromethyl)4-methylphenol in 9 0 95 % yield <00JOC8297>. The synthesis and characterization of 1,4,7,10-tetraaza[12](2,6)phenolphane as well as the related pentamer have recently been reported <00IC2156>. Aza-bridged bis1,10-phenanthroline was synthesized in one-step from the chloromethyl precursor <00TL8565> and the related compound 3, prepared in a single step from 6,6'-dibromo-2,2'dipyridine, was shown to possess color-switching properties <00JA12174>. The 1,4,8,11tetraazabicyclo[6.6.2]hexadecane ligands, including the N,N'-dialkyl and the N,N'-bispendant derivatives, have been synthesized via a simple, short approach <00JA5831>. A large bifunctional chelating agent was generated by a bimolecular cyclization of an iminoester and a polyamine using a molar equivalent of NaOMe <00TL7207>. The synthesis of opposing bisbipyridine-bridged shape-persistent macrocycles was constructed by a Hagihara/Sonogashira cross-coupling procedure <00CEJ2362> and the [44](2,6)- and [46](2,6)pyridinophanes have been generated in a stepwise coupling procedure <00OL3265>. Alkyl derivatives of 1,8-diazacyclotetradeca-3,5,10,12-tetrayne have been accomplished in a simple one-step procedure <00EJOC2291>, whereas related N-substituted cyclic enediynes have been synthesized by a Pd(0)-catalyzed ene-yne coupling, followed by alkylation <00JCS(P1)1955>. A series of "multi-layer" polyamines (e.g., 4) has appeared and several were found to be potential anti-HIV agents <99CL1273>. A well-known macrocycle,

Eight-Membered and Larger Rings

381

muscopyridine, was asymmetrically prepared from (R)-(+)-citronellal using a ring closing olefin metathesis route <00JOC7231>. Polyamine cryptands, incorporating either bipyridine or phenanthroline, have always struck interest with heterocyclic chemists interested in the internal directed N-electrons; numerous examples of polyamine bridge relatives has appeared <00JOC7686, 00CC561>. Numerous interesting macropolycyclic cages have been prepared by a traditional ring-forming process by treatment of diamines and bis(bromomethyl) derivatives <00JOC3708>. Treatment of 1,4,7-triazacyclononane with tris(3-chloropropyl)amine generated the inside monoprotonated form of 1,4,8,12-tetraazatricyclo[6,6,3,24'lZ]nonadecane in 38% yield <99JCS(P2)2701>. A series of novel fluorine-containing aza-cyclophanes has been reported <00EJOC141, 00CEJ2334>. Cages possessing a bridged 2,6-phenol moiety have been shown to selectively encapsulate the lithium ion <00EJIC51>, whereas, others have incorporated a cysteine unit to give facile entry to chiral calixarene analogues <00JOC8361>. A one-pot creation of a new series of diazabicyclophanes (e.g., 5) has been reported <00OL609>, and the bisalkynes in related bridged alkynes have been converted into the CpCo-cyclobutadiene complex and described as a new type of superphane <00JCS(D)685>. The unnatural porphyrin family still fascinates the imagination. This year, to give a flavor for the diversity, there has appeared hybrid calixphyrins <00OL3103>, doubly N-confused porphyrins <00JOC4222, 00JA803>, unsymmetrical porphyrins attached to a modified 5,10,15,20-tetrakis(4-(2-trimethylsilylethynyl)phenyl]-21-23-dithiaporphyrin <00TL3709>, CO2R

CN

RO20~~~002

X.-..

II

CN 3

R

II

R 0 -2 C. ~ , / /

~ C 0I 2~R

5

002 R

4; X = CH, C-CN, or N R = n-C8H17 and new porphyrinoid structures <00AG(E)1105>. The formation of helical cycloocta- and cyclododecapyrroles put yet another twist to macrocycles possessing the pyrrole subunit <00JOC8709>.

G.R. Newkome

382 8.4

CARBON-SULFUR RINGS

When 2,7-dibromotropone and 1,3-bis(mercaptomethyl)benzene were condensed, the desired 2:2 condensate, 2,6,8,12-tetrathia- 1(2,7),7(2,7)-ditropona-4(1,3),10(1,3)-dibenzenacyclododecaphane was formed in 46% yield; the X-ray structure was obtained and this material formed a complex with Hg(lI) <00CL180>. The first tetrathiafulvalene (TTF)containing cuppedophane (6) has been reported <00OL2471>. A series of double-bridged TTFphanes with different alkylenedithio-bridges has been synthesized as models of interactive dimeric TTFs <00CM2196>, and the related doubled bridged tetra selenafulvalenophanes have also appeared <00EJOC3013>. A [2.2]quinquethiophenophane has been prepared and suggested to be the first oligothiophenophane that has typical dimeric n-stacking of a layered cyclophane <00OIA 197>. The cyclization of dilithium acetylide with dithiacyanatoalkanes afforded a series of tetrathiacyclodiynes in overall moderate yields; the use of trimethylsilyl protection gave rise to a more efficient stepwise route to same <00EJOC2479>. The treatment of {Co2(CO)6 }2{grlz:~t-rlZ-(HOCHzC-C)2} with HBF4-OEt2 a t - 7 8 ~ followed by addition of (HSCHzCH2)2S afforded the novel complex {C02(C0)5}-{C02(C0)6}{~t-rl2-C-CCHzSCH2CH2)2S} <00CC1411>. A new class of conjugated macrocycles, designated as a-cyclo[n]thiophenes (7), which afford tunable cavities in the nanometer regime, has been reported <00AG(E)3481>. Very large cyclophanes [C132H920884 and C172H1200884] have been gu

RS

SR

RS SR ~ / ~t S~ S

Bu

BL

~S~7

1

L S~BuJ n

I(I Bu

6

Bu

7; m andn = 1 or 2

prepared in a five-step route from commercial compounds <00JOC7711>. Treatment of 4,4'sulfonylbis(benzenethiol) with 4,4'-dichlorodiphenylsulfone and "pseudo"-high-dilution conditions gave [-S-Ar-SOz-Ar]n, where Ar = 1,4-phenylene) <00CEJ4285>. 8.5

C A R B O N - S E L E N I U M RINGS

The synthesis and molecular structures of 6,7,13,14-dibenzo-l,5,8,12-tetraselenacyclotetradecane and 1,5,9-triselenacyclododecane have been reported and they have been shown to adopt conformations which maximize the number of possible gauche [C-Se-C-C] bond torsion angles; a series of complexes has also been demonstrated <00IC2558>.

Eight-Membered and Larger Rings 8.6

383

CARBON-PHOSPHORUS RINGS

The first synthesis by macrocyclization of the corresponding bis-chloride via metallation followed by the addition of aryldichlorophosphine afforded the 1-phenylphosphacycloundeca-3,9-diyne; related members in the family were also formed and subsequently transformed to the corresponding P-sulfide <00TL4075>. The oxidative coupling (the Eglinton reaction) of diethynyl(2,4,6-tri-tert-butylphenyl)phosphane afforded a mixture of the family of 15-, 20-, 25-, and 30-membered macrocycles <00CEJ3806>. The simple one-pot reaction of a bis-phenol with PC13 afforded (15% of the mixture) a novel series of isomeric phosphite cryptands [8 depicts the major (5%) out-out structure; the in-in was formed in 2.9% and the in-out in 4.4%] <00CEJ3043>.

8.7

CARBON-NITROGEN-OXYGEN RINGS

Several procedures to aza-crown ethers have appeared, which can make their construction potentially easier <99AJCl109, 99AJCl139, 00TL3345, 00TL2373>. Gokel et al. have constructed and studied a series of hydraphiles channels which are constructed of aliphatic bridged azacrown ethers <00CC2371, 00CC2375>, several have shown "dramatic" enhancement in sodium ion transport across a phospholipid bilayer relative to other members in the family <00CC2373>. Synthesis of unsymmetrical chiral triaza-18-crown-6 and the related diaza-12-crown-4 with pendant groups has appeared <00JOC7225>. Two new C2 and D2 symmetrical dioxatetraaza 18-membered macrocycles were synthesized in enantiomerically pure form by a chemoenzymatic method starting from (+)-transcyclohexane-l,2-diamine <00CEJ3331>. The formation of triazolephthalocyanines with azocrown ether substituents has been reported <00EJOC2767>. A very novel supramolecular assembly based on exocyclic functional groups of azo-crown ethers resulted in "leaflet" structures <00JA1558>. Polyazacrown ethers possessing one, two, or four naphthyl or anthracenyl units have appeared; the photophysical properties were also investigated <00EJOC2041>. Diaza-18-crown-6 ethers containing two [1,4-related] 2,2'-bipyridinyl moieties have been reported and complexed affording a Ru(II)-azacrown-Re(I) complex <00JCS(D)1783>. Three types of triphenylmethane leuconitrile derivatives incorporating 1 to 3 monoaza-15-crown-5 moieties have been designed <00JA5448>. The reduction of a new series of macrocyclic Schiff-bases, prepared by cyclocondensation of 01,07-bis(2 formylphenyl)-l,4,7-trioxaheptane with either ol,07-bis(2-aninyl)-l,4,7-trioxaheptane or tris(2-aminoethyl)amine, afforded the corresponding cyclic amine <00EJIC1015>. Interestingly, The Rh(I)-catalyzed hydroformylation of dienes in the presence of primary amines or secondary-a,m-diamines has been used to generate 12- to 36-membered polyheterocyclic tings in up to 56% yield; cryptand ring systems (e.g., 9) have also been created by this procedure <00EJOC2367>. N-l,10-Pentacosadiynoyl azacrown ethers have been shown to undergo facile polymerization upon irradiation <00CLl128>. p-tertButylcalix[4]arene-azacrowns, bridged with an aza-etherea! bridge, were prepared by initial amidation, followed by reduction; there appears to be Hg 2+ selectivity <00CL1422>.

G.R. Newkome

384

oJ%o

I N- - ~ o

1 oo

8

9

Macrocyclic ethereal materials possessing subheterocyclic units continue to stimulate the imagination of chemists as demonstrated by a few selected examples. Sauvage et al. have constructed molecular novelties that push the molecular frontier and shown by the incorporation of both porphyrin and 1,10-phenanthroline to generate new rotaxane assemblies <00JA11834, 00JA3526>. Their use of the same simple phenanthroline subunit has led to linear rotaxane dimers, which as they suggested give insight to synthetic molecular muscles <00AG(E)3284>, as well as other novel doubly threaded assemblies <00AG(E)1295> and new trefoil knots <00CEJ2129>. Sauvage et al. also reported the unexpected synthesis of an 8-shaped macrocycle rather then the anticipated catenane <00IC5169>. Others have also used this phenanthroline moiety to form a directed ligating site, such use has led to three-strand conducting ladder polymers <00AG(E)608>, and interesting concave reagents <99SL1826>. Simpler azo-subunits have been instilled: the pyridylmethyl derivative of the 14-membered, NzOz-macrocycle has been formed and complexed <00JCS(D)ll91>, dipyrido[24]crown-8 has been synthesized and converted into a [2]pseudorotaxane <00OL2947>, exocyclic thiophene-containing aza-crown ethers have been reported <00TL6223>, and acridine-18crown-6 ligands have appeared <00NJC781>. Several examples of meso-alkylporphyrinogen-like cyclic oligomers possessing both furan and pyrrole subunits have been reported <00OL3115, 00AG(E)1496>. Corroles and coremodified corroles have been formed using a [2+2]condensation of different heterocomponents <00TL697>. The convenient one-step approach of bis-diazo crown ethers porphyrins has opened a new family of interesting modes of engulfing the face of the porphyrin moiety <00TL8289>. 8.8

[ C A R B O N - N I T R O G E N - ( O X Y G E N and/or SULFUR)] n (n > 1) RINGS

(CATENANES) Artifical photosynthetic reaction centers have continued to peak the interest of scientists over the years and this year is no exception. One such catenane-type example contains a ruthenium tris(2,2'-bipyridine) center, as the sensitizer, which is linked with cyclobis(paraquat-p-phenylene), as the acceptor, and covalently linked with a protoheme or Zn-protoporphyrin, as the donor, located in the myoglobin pocket <00JA241>. A related assembly and on a Au-particle has appeared which possesses a Ru(II)-tris(2,2'-bipyridine)-

Eight-Membered and Larger Rings cyclobis(paraquat-p-phenylene) catenane or Zn(II)-protoporphyrin I X -

385

bis(N-methyl-N'-

undecanoate-4,4'-bipyridinium) as molecular cross-linkers for the generation of the Aunanoparticle arrays <00JAIl480>. Numerous catenane papers have appeared and each attempts to address varied aspects of their supramolecular properties: template-directed synthesis of a self-complementary [2]catenane and the formation of a supramolecular homodimer composed of two mutually interpenetrating [2]catenanes <00AG(E)148, 00CEJ2262>, molecular machines <00JA3542>, and neutral p-associated [2]catenanes <00CEJ608, 00OIA49>. Synthesis of two coordinating catenates, possessing the ability to undergo surface-confined chemistry, in which one ring has a 2,9-diphenyl-l,10-phenanthroline moiety and a disulfide linker that is capable of gold attachment, has appeared <00OL1991>. [2]Catenanes possessing a central tetrathiafulvalene (TTF) donor have been incorporated into the traditional catenane skeleton comprised of a cyclobis(paraquat-p-phenylene) cyclophane and the arylether component with the TTF subunit <00JOC1924>.

8.9

CARBON-SULFUR-OXYGEN RINGS

Polyhydroxylated symmetrical C,X,O-macrocycles have been prepared by the 1:1 condensation of several bis-epoxides with bis-nucleophiles, specifically the bis-thiol to give the desired (X = S) ring <00TL1019>. The S204-crown annulated derivatives of 9,10-bis(1,3dithiol-2-ylidene)-9,10-dihydroanthracene have been demonstrated to voltammetrically and spectroscopically recognize Na + and Ag + ions <00CC295>, and the self-assembled monolayers of related compounds on both gold and platinum surfaces have been reported <00JOC8269>. Charge transfer complexes of bis(methylthio)tetrathia-fulvalene bisannulated macrocycles with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquino-dimethane were generated; the magnitude of intramolecular 7t-Ttoverlap is related to ring size <00CL132>. A series of TTF and dithia-crown-TTF derivatives attached with one or two TTF disulfides were formed and subsequently self assembled as monolayers of a gold surface <00JOC3292>. Face-to-face overlapped quadruple-bridged bisTTFs (dimeric TTFs) have been prepared by an efficient few-step protocol <00JA9486>. The trisTTF macrocycles 10a and 10b with a large end cavity were prepared from tetrakis(cyanoethylthio)TTF with selective deprotection and realkylation followed by an intramolecular coupling procedure <00CEJ 1947>. A cyclophane generated from one 1,5-dioxynaphthalene and one TTF moiety and bridged by-SCH2CH20- linkages has been formed <00JOC4120>. S-cage molecules were constructed by capping the upper rim of homooxacalix[3]arene, which then showed very high Cs + selectivity <00TL1807>. 8.10 CARBON-NITROGEN-SULFUR RINGS The synthesis of [3-substituted 5,10,15,20-tetraphenyl-21,23-dithiaporphyrins from 3phenyl-4-nitropyrrole and 2,5-bis(a-hydroxyphenylmethyl)thiophene and its characterization have been reported <00CI_A80>. A series of 2,2'-bithiazole-containing macrocycles was formed by the coupling of the corresponding [2,2'-bithiazole]-5,5'-dicarbaldehyde and 2,2'(1,4-phenylene)bis[thiazole-5-carbaldehyde in a simple two-step procedure <00HCA1161>. The creation of 2,10-dithia[3](2,6)pyridino[3](2,5)-thiophenophanes (11) from 2,6bis(chloromethyl)-pyridine and 2,5-bis(methylsulfanyl)-thiophene or, in slightly better yields, from 2,5-bis(bromomethyl)thiophene and 2,6-bis(methylsulfanyl)pyridine affords a ligand

G.R. Newkome

386

that binds strongly to Cu(I) via the S-thiophene, N-pyridine, and a thioether, leaving the remaining S-donor available for an exodentate linkage to generate an infinite Cu(I) polymer <00CC2465>. New meso aryl 307t heptaphyrins have been accomplished and shown to possess an inverted structure <00OL3829>.

s/

/s

L1~S

S~ s

s

~L2"

10a; L 1 = (CH2CH20)2CH2CH 2 L2 = CH2CH2OCH2CH2 10b; L 1 = (CH2CH20)2CH2CH 2 L 2 = (CH2)3

8.11 C A R B O N - N I T R O G E N - S E L E N I U M R I N G The 5,10,15,20-tetraaryl-2-aza-21-carba-22-selenaporphyrin possessing an inverted pyrrole ring has been prepared by the [3+1] condensation of 2,5-bis(phenylhydroxymethyl)selenophene and 5,10-ditolyltripyrrin <00JOC8188>. 8.12

CARBON-SILICON

RING

Crown-like silaalkanes (12) have been synthesized in good yields (74-82%) by the hydrogenation of the corresponding cyclic oligosilaalkynes <00CL1416>. Treatment of (ipr)2Si(O-p-C6H4-C-CMe)2 with Mo(CO)6 and 4-chlorophenol at 140 ~ gave the corresponding cyclotrimer and cyclotetramer <00CC87>.

Cs,

Ph 2 / ~ k

Ph2Si

Ph 2 S'iPh2

/Ph2 ~ - - / Ph2) n

12; n =0 (74%)orn = 1 (82%)

0

(o

0 5 cis/trans

S-J

13; R =CH 3 or n-C8H~3

Eight-Membered and Larger Rings

387

8.13 CARBON-NITROGEN-SULFUR-OXYGEN RINGS Synthesis of TTF-phenanthroline macrocycles (e.g., 13) were accomplished in a simple multi-step sequence; the macrocyclization procedure was from the 2,9-di(p-hydroxyphenyl)1,10-phenanthroline with TTF-diiodide under high dilution conditions in the presence of C s 2 C 0 3 <00CC215>. 8.14 CARBON-PHOSPHORUS-METAL RINGS Novel triply-bridged disilver complexes [Ag2(g2-dppa-P,P')3(anion)2] (14) form selectively and are stabilized by the numerous aromatic interactions <00CC617>. A monomer, rectangular dimer, and triangular (15) macrocycles have been prepared from [RuCl(tpy)]based moieties and the rigid PhzP-C=C-C-C-PPh2 <00AG(E)1826>. 8.15 CARBON-PHOSPHORUS-OXYGEN (AND S U L F U R ) - M E T A L RINGS Very large organogold rings (16), as well as the related dimeric [2]catenane, have been generated by the self-assembly of complex digold(I) diacetylide with a diphosphane ligand <00AG(E)3819>. 8.16 CARBON-NITROGEN-METAL RINGS Bowl-shaped coordination compounds have been assembled spontaneously from 10 small components, such as six (en)Pd 2+ units and four 2,4,6-tri(3-pyridinyl)triazene moieties; the overall structure approaches 30A <00JA2665>. A different construct was derived from the 4pyridinyl isomer and Pt(bpy) 2+ and shown to facilitate self-assembly within the coordination p

Ph3P.,, + - Ij'~g--PPh3

eh3P ,":%,

I

Ph3

Ph 14

(tpy)CI Ph2P~Au--PkPh2 / k~ Ph2P, Cl(tpy)~,, \ Ph2P

/ Ph2i

PPh2 / / Ru(tpy)CI PPh2 15

Au - -

-

"O

/O

Au' 16

cage <00JA6311>. A strain-free platinotriangle was created using 1,2-phenylene diisocyanide as the ligand to instill the critical 60 o angles at the comers and trans-Pt(C6Fs)2 as the linear connector <00CC915>. The formation of "Pt(II)Br-Pt(IV)" mixed valence complexes gave rise to square compounds, e.g., [(en)M(4,4'-bpy)]4(NO3)8, which were converted into higher ordered infinite complexes <99BCSJ2603>. 8.17 CARBON-NITROGEN-OXYGEN/SULFUR-METAL RINGS The placement of four pyridyl groups on the upper rim of the resorcin[4]arene cavitands was followed by the addition of Pd(II) ions to generate a monomeric molecular receptor with hydrophobic binding sites <00TL3113>. The treatment of 2,4,6-tris[(4-pydrinyl)methylsulfanyl]-l,3,5-triazene (tpst) with silver(I) to form a single-stranded one-dimensional coordination polymer, [Agv(tpst)(C104)z(NO3)5(dmf)2],,, which contains nanotubes

388

G.R. N e w k o m e

<00AG(E)2468>. The application of distinct self-assembly processes to form grid-type and double-helical structures has potential in understanding and controlling molecular information; an interesting discussion has been presented <00CEJ2103>.

8.18 CARBON-NITROGEN-PHOSPHORUS-METAL RINGS Metallocryptands, based on trigonally coordinated Pt(0) or Pd(0) with 2,9b i s ( d i p h e n y l p h o s p h i n o ) - l , l O - p h e n a n t h r o l i n e possessing P3Pd bridge-heads, binds Pb(II) within the structure <00CC 1413>. At the end of the millennium, chemists have become more adventuresome as they prepare and characterize nanoscopic materials and probe the macroscopic regime. There is little doubt that as confidence continues to grow, coupled with the creation of new instrumentation, the next century will unveil unnatural constructs of perfect, predictable nanostructures with molecular weights of currently unprecedented magnitude.

8.19 REFERENCES

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390 00CEJ3331 00CEJ3366 00CEJ3558

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Eight-Membered and Larger Rings 00JA241 00JA803 00JA1486 00JA1558 00JA2665 00JA3526 00JA3542 00JA5448 00JA5831 00JA6252 00JA6307 00JA6311 00JA7404 00JA9486 00JAl1480 00JA11834 00JA12174 00JCS(D)685 00JCS(D)1191 00JCS(D)1783 00JCS(D)2483 00JCS(P1)1955 00JCS(P1)2805 00JCS(P1)3155 00JCS(P2)175 00JIPMC1 00JIPMC375 00JOC1243 00JOC1924 00JOC3292 00JOC3708 00JOC4120

00JOC4222 OOJOC5143 00JOC5360 00JOC7225

391

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394

INDEX Acenaphtho[1,2-b]benzo[d]thiophene, 99 Acetogenins, 150 Acronycine, 366 Aculeatins, 132 N-Acyliminium, 254 Adenosine A1 receptor antagonists, 99 Adrenoceptor agonists, 98 Adrenoceptor antagonists, 99 Alasomycin, 150 Alkoxyoxiranes, 190 Allylboration, 252 Alstonerine, 124 Amabiose, 132 Amidines, 261 Amidothiophene, 92 Aminothiophene, 88, 93 Analgesics, 98 Anhydrolycorinone, 249 [18]Annulene, 100 Anthrathiophene, 88 Antidepressant agents, 99 Anti-HIV agents, 381 Anti-inflammatory agents, 98 Antimicrobial agents, 99 Anti-trypanosomal agents, 99 Arcyriaflavin A, 127 Artemisinins, 366 Arylboronic acids, 171,175 Aspidospermidine, 121 Asymmetric aldol reactions, 175 Asymmetric epoxidation, 54 Asymmetric reduction, 95,171 Asymmetric ring opening reactions, 62 Asymmetric synthesis, 101 AT2433-A1,127 Azabicyclo[2.1.0]pentanes, 27 3-Aza-Cope rearrangement, 250 Azadiene Diels-Alder, 115 Azadienes, 240 Azaindolizine, 284 7-Azanorbomanes, 25-50 Azaphosphetidines, 76 Azaspiracid, 149 Azathiaoctane, 342 Azatriostin A, 290 2-Azatropone, 342 Aza-Wittig reaction, 76,274 Azepanes, 341 Azepines, 341 Azetidines, 71 Azetidinones, 77 Azetines, 71 Aziridines, 65-69

Aziridinocyclobutanes, 28 Azomethine ylides, 26, 80, 122 Baeyer-Villiger oxidation, 126,273,350, 370 Barbier reaction, 94,281 Barton-Zard reaction, 115,117 Baylis-Hilman adducts, 245 Beak deprotonation, 114 BenthocyaninA, 286 Benzazepines, 343 Benzazetinones, 81 Benzimidazoles, 172-9 Benzisoxazoles, 6 1,2-Benzisoxazolin-3-ones, 218 1-Benzoborepines, 356 1,3-Benzodioxoles, 205,206 1,3-Benzoditelluroles, 208 Benzodithiepanes, 368 Benzo [a ]quinolizine, 250, 251 Benzo[a]quinolizine 4-thiones, 20 Benzo[b][1,4]thiazepine, 245 Benzo[b]furans, 139-41,154-60 Benzo[c]furans, 160 Benzo[g]isoquinolines, 250 1,2,3,4,5-Benzopentathiepin, 372 Benzo[/]phenanthridines, 13,14 [1]Benzopyrans, 322-4 [2]Benzopyrans, 326 Benzo[b]selenophenes, 103 Benzo[b]selenopyrans, 103 Benzo[c]tellurophene, 104 1,2-Benzothiatellurolium salts, 210 Benzothiepins, 354 Benzo[b]thietes, 72 Benzo[b]thiophene-2-carboxylates, 88 Benzo[b]thiophene 1-oxide, 98 Benzo[b]thiophenes, ll, 87, 92, 95 Benzotrithiole 1-oxides, 213 1,3-Benzoxathiol-2-ones, 210 Benzotriazoles, 181 Bergman cyclization, 271 Birch reduction, 116 Brevetoxin B, 317 Breviones, 133 Bromothiophene, 92, 93 Bryostatins, 317 C-Butyl glycoside, 97 Calixarenes, 378,380 Calixphyrins, 381 Carbapenems, 79,219 Carbazoles, 6, 7,10,13 Carbolines, 17 Carbonylative cycloadditions, 254 Cardiopetalolactone, 132

Index

Cartormin, 131 Catenane, 385,387 Cephems, 80 Cerpegin, 238 Chemical sensors, 378 Chimonanthine, 127 Chiral auxiliary, 57, 65 Chiral oxazoline ligands, 247 Chiral ruthenium complex, 95 Chromans, 324--6 Chromenes, 322-4 Chromium reagents, 241 Chromones, 329-31,348 Ciguatoxin, 352 Cinnolines, 279-81 Cobalt addition, 245 Cobalt(II) catalyzed cyclotrimerization, 239 (-)-Colchicine, 136 Coniine, 253,254 Copper (I) promoted coupling, 267 Copper-catalyzed coupling, 94 Copper-catalyzed epoxidation, 55 Copper-catalyzed reactions, 175 Copper-mediated cyclizations, 96 Coriandrin, 329 Corroles, 384 Corynantheidol, 124 Coumarins, 133,328 Coumestrol, 156 COX inhibitors, 99,115,239 Criegee type rearrangement, 190 Cyanine dyes, 378 Cyclo[n]thiophenes, 100 [4+3] Cycloadditions, 136,137,348 [2+2] Cycloadditions, 229 [5+2] Cycloadditions, 89 [3-Cyclodextrin catalysis, 58 Cyclophanes, 96, 100,382,385 Cyclopropanation, 241 Cyclyne, 379 Cylindrospermopsin, 264,270 Cytisine, 242 Danishefsky's diene, 252 DAST, 227 Dendrimer, 101 Deoxymannojirimycin, 254 Depsidones, 365 Desulfurization, 97 Dewar thiophene, 90 Diazepanes, 157 Diazepines, 199,357 Diazines, 261 DiazonamideA, 126,225 Dibenz[b f]azepine, 344 Dibenz[c,e]azepine, 344

395

Dibenzothiepins, 355 Diels-Alder reactions, 115,117, 141,142,160, 169,175,238,244,249,250,252,255,271,276, 277,282,304 Dihydrofolate reductase inhibitors, 264,269 Dihydrofurans, 138,146-53 Dihydroimidazoisoquinolinones, 251 Dihydropinidine; 255 Dihydropyrans, 318-22 Dimethyldioxirane, 56 1,3,2-Dioxaboroles, 213 1,3,2-Dioxathiolane 2,2-dioxides, 212 1,3,2-Dioxathiolane 2-oxides, 212 1,3-Dioxepanes, 321 Dioxepanes, 364 Dioxepines, 362 Dioxins, 333 Dioxiranes, 151 1,3-Dioxolan-2-ones, 205,206 1,3-Dioxolanes, 205-7 1,3-Diphosphetenes, 75 1,3-Dipolar cycloadditions, 26, 80, 89,113,137, 171,177 191,202,218,239,250,253,353 Diradical intermediate, 89 Directed ortho metalation, 92 Diselenins, 103 1,2-Ditellurolanes, 211 Ditellurophenes, 104 1,3,2-Dithiaboroles, 213 Dithiadiphosphetanes, 75 Dithianes, 334 Dithietene, 90 1,4-Dithiin, 90 1,2-Dithiolanes, 211 1,3-Dithiolanes, 207,208 1,2-Dithioles, 211 1,3-Dithioles, 89,207 1,3-Dithiole-2-thiones, 208 1,2-Dithiole-3-thiones, 211 1,3-Dithiol-2-ones, 208 Dithiophenes, 96,102 DNA binding agents, 99 DNA bisintercalation, 290 Dodecathiophenes, 102 Doebner-Miller synthesis, 245 Dopamine receptor agonists, 99 Dysokylumins, 131 Eglinton reaction, 383 Electrochemical reduction, 278 Electrocyclization, 240,244 Electrolysis, 122 Emindole, 127 Enantioselective Heck reactions, 101 Enantioselective reduction, 241 5-endo-dig Cyclization, 120,121

396

6-endo-dig Cyclization, 193 5-endo-trig Cyclization, 89,119,144 EpheradineC, 159 Epithilone, 203 Estrogen receptor, 167 Eudistomins, 371 (+)-Eurylene, 150 Ferrocene, 100 Fibrifungine, 254 Fischer carbene complexes, 112,157 Fischer indolization, 121,197,276 Fluorene, 102 Fluorinated dioxiranes, 56 Fluorophore, 87 FredericamycinA, 249 Free radical cyclizations, 245 Friedel-Crafts reactions, 90, 95,180,246 Frontier Molecular Orbital theory, 124 Fullerenes, 221,302,304 Furanocembrenoids, 130 Furans, 102, 134--8,141-6 Furocoumarins, 155 Fusedthiophenes, 95 GABA-A receptor ligands, 172 (-)-Galanthamine, 159 Gallium complexes, 62 Ganciclovir, 307 Geissoschizine, 124 Geissoschizol, 124 Gephyrotoxin, 246 Germanium-based linkers, 172 (_+)-Ginkgolide B, 136 Grignard organozinc reagents, 181 Grignard reagents, 174,267,279,284 Grob fragmentation, 246 Grubb's catalyst, 118, 174,249,341,343 Guanidines, 263 Gymnodimine, 255 Halichondrin B, 317 Hantzsch synthesis, 190, 195,196,201,241 Heck reaction, 116,119,157,158,171,248 Heliannuol, 351 Helicenes, 87,100 Heptadecathiophenes, 102 Heptaphyrins, 386 Horner-Wadsworth-Emmons reaction, 119,194, 195 Human adenosine A3 receptor antagonists, 275 Hurd-Mori cyclisation, 203 Hydraphiles, 378,383 Hydrindanone, 135 Hydroformylation, 253 Hydrotalcite catalysts, 57 Hypervalent aryl siloxanes, 175 Imidazo[1,5-b]isoxazoles, 177

Index

Imidazoles, 172-9 Imidazo[1,5-a]pyrazine, 284 Imidazolo[1,2-a]pyfidines, 243 Imidazo [4,5-d] [1,2,3]triazin-4-one, 306 Indazoles, 169 Indazolones, 7 Indoles, 9, 10,118-26 Indolizidine alkaloids, 111 Indolizidines, 246 Indolo[3.2-a]carbazole, 12 Indolo[2,1-a]isoquinolines, 250 Iododithiophene, 93 Iodonium derivatives, 91 Iodothiophene, 94 Isobenzofurans, 160 Isochromans, 326 Isochromenes, 326 Isofogamine, 253 Isomiinchnone, 191 Isonitriles, 240 Isoquinolines, 134,247-51 Isothiazoles, 188 Isothiazolium salts, 190 Isothiazolium-2-imines, 189 Isoxazoles, 217-9 Isoxazolidines, 221--4 Isoxazolines, 219-21 Jacobsen catalyst, 54 Julifi-Colonna method, 57 Kainic acid derivatives, 194 Kinetic resolution, 62, 63 Knoevenagel reaction, 194 13-Lactams, 77 Ladder polymers, 384 Lahadinine, 127 Lamellarin L, 112 Langmuir-Blodgett films, 102 Lanthanide metallocenes, 124 Lawesson's reagent, 87,192 Lepadin B, 253 Light emitting diodes, 100 Liquid crystals, 100 Lithiation, 92,242,247 Lukianol A, 117 Lumazines, 283 Madindoline, 125,127 Mannich reactions, 90, 114, 181,248,253 Martinellines, 246 McMurry reaction, 380 Meridianin alkaloids, 263 Metallocryptands, 388 Metallo-phosphodiesterase models, 378 Metathesis reactions, 153 Micacocidin, 193 Michael addition, 91,176,190,240,245,255,268

Index

Microwave assisted synthesis, 77,169,173,181183,200,239,240,245,274 Mitosenes, 122 Mitsunobu procedure, 195 Mn-salen catalysts, 53 Molecular devices, 100 Molecular machines, 385 Molecular Orbital calculations, 52, 56 Molecular recognition, 100,270 Molecular sieve catalysis, 242 Morphine, 158 Miinchnones, 89, 112, 124,227 MycalamideA, 317 Mycothiazole, 203 Myrmicarin, 127 Nanostructures, 379,388 Naphtho [2,1-j]phenanthridinjes, 14 Naphtho [1.8-de] [1,2,3]triazine, 312 Nenitzescu indole synthesis, 119 Neomarinone, 133 Nickel(II)-mediated electroreduction, 65 Nickel-catalyzed reaction, 239 NingalinB, 304 NingalinC, 112 Nitrobenzo[b]thiophene, 91 NK 1 antagonist, 182 (-)-Normalindine, 127,225 B-Norrhazinal, 127 Octathiophenes, 102 Olefin metathesis, 174,381 Oligomers, 101,102 Oligothiophenes, 92 Oxabicyclo[2.1.0]pentanes, 27 1-Oxacephems, 81 Oxadiazepines, 371 Oxadiazoles, 102,234 1,3,4-Oxadiazoles, 29 1,2,4-Oxadithiolanes, 213 1,2-Oxaphosphetes, 76 Oxaphosphetidines, 76 1,2-Oxaselenolanes, 212 1,2-Oxatellurolanes, 212 Oxathianes, 335 [1,4]Oxathiin, 96 1,2-Oxathiolane 2-oxides, 212 1,3-Oxathiolane 3-oxides, 211 12-Oxathiolanes, 212 1,3-Oxathiolanes, 213 1,2-Oxathiole 2,2-dioxides, 212 Oxazepines, 369 Oxazoles, 142,224-7 Oxazolidines, 229-34 Oxazolines, 78,227-9 Oxepanes, 350 Oxepines, 199,349

397

Oxetanes, 72,226 Oxetanones, 72 Oxiranes, 52-65 a-Oxoketene dithioacetals, 1-22 Oxone, 54-56 Paal-Knorr reaction, 111,112 Palladium catalysts, 68, 93,174, 183 Palladium-catalyzed amination, 181 Palladium-catalyzed cross-coupling reactions, 89, 93, 96,113,117,118,119,120,122,169,171,175, 179,193,243,248,253,254,262,270,271,280 Palladium-catalyzed cycloaddition, 65 Palladium-mediated cyclization, 89, 96,352 Palladium-promoted ring openings, 62 Pancratistatin, 248 Parham cyclization, 248 PDE4 inhibitor I, 281 Penams, 220 Penitrem D, 127 Perilloxin, 351 Peterson elimination, 59 Phenanthridines, 13 Phenazines, 286-8 Phenylisothiazoles, 188 Phosphepins, 356 Phosphodiesterase 7 inhibitors, 99 Phospholes, 102 Photochemical reactions, 94,188 Photochromic properties, 100 Photocyclization reactions, 95,242 Photocycloadditions, 246,248 Photodecarboxylation, 94 Photodynamic therapy, 99 Photoinduced electron transfer, 253 Photooxidation, 256 Photorearrangement, 95 Phthalazines, 281-3 Phthalocyanines, 99,378,379 Physostigimine, 125 Piclavine, 254 Pictet-Spengler reaction, 124 Pipecolic acid, 231 Pipecoline, 253 Piperidines, 230,252--6 Platinum complex, 96 (-)-Polycavernoside, 317 Polycyclic thiophenes, 96 Polymer-bound "boomerang" catalyst, 174 Polymers, 102 Polymer-supported aminopyrimidines, 268 Polymer-supported diamines, 178 Polymer-supported pyrazoles, 172 Polymer-tethered amidines, 272 Pomeranz-Fritsch-Bobbitt methodology, 247 Porphyrin derivatives, 99,100

398

(+)-Preussin, 228 Progesterone receptor antagonist, 99 Protein tyrosine phosphatase 1B inhibitor, 98 Protoporphyrin, 385 Pteridines, 308 Pummerer reactions, 91,144,248,249 Purines, 305,307 Purpurone, 112 Pyrano[2,3-c]azepines, 349 Pyranones, 327 2H-Pyrans, 139,318-22 4H-Pyrans, 318-22 Pyrazines, 283-5 Pyrazoles, 167-72 Pyrazolophanes, 170 Pyrazolo[1,5-a]pyridines, 19,171 Pyrazolo[a]pyrimidines, 19 Pyrazolo[5 ,1-b]thiazole, 170 Pyrazolo [ 1,5-a ]- 1,3,5-triazines, 305 Pyridazines, 276-9 Pyridazino[1,6-a]benzimidazoles, 307 Pyridines, 15,140,238-43 Pyrido[2,3-c ]azepines, 349 Pyrido[1,2-a]benzimidazole, 173 Pyrido [2,1 -c ] [ 1,4]benzodiazepines, 245 Pyrido[2,3-b ]indoles, 21 Pyrido[2,3-d]pyrimidines, 310 Pyrimidines, 261-71 Pyrrole electropolymerization, 111 Pyrroles, 102, 103,111-7 Pyrrolidines, 230 Pyrrolidinones, 222 Pyrrolizidine alkaloids, 111 .Pyrroloazepines, 345 Pyrrolo[2,1-c] [1,4]benzodiazepines, 245 Py rrolo [2,3-c]carbazole, 12 Pyrrolo[3,4-b]indoles, 124,227 Pyrrolo[2,1-a]isoquinoline, 250 Pyrrolothiazoles, 194 Pyxophanes, 379 :~uinazolines, 272-6 :~uinazolones, 8 :~uinodimethanes, 96, 97,319 :~uinolines, 243-7 :~uinolizinium salts, 18 ~uinone methides, 141 :~uinoxalines, 103,288-92 Radical addition, 245 Radical cyclizations, 89,120, 123,152,253 Radical polar crossover reaction, 121 Radical reaction, 240 Raney nickel, 97 1,3]Rearrangement, 189 ~eformatsky reagent, 250 .~eissert reaction, 246

Index

Resin-bound carbodiimides, 179 Retinoic acid receptor a agonists, 88 Reveromycins, 317 Rhazinilam, 127 Rhodium catalysts, 61, 62, 79, 81,139,153,226 Rhodium-catalyzed amination, 243 Richter-type cyclizations, 280 Rieche conditions, 90 Ring-closing olefin metathesis, 174,252,341,343 Ring-opening metathesis, 252 Rink resin, 192 Rolliniastatin, 150 Roseophilin, 111,127 Rotaxanes, 378 Rubromycins, 317 Ruthenium-catalyzed reactions, 241,243 Salen-Mn catalyzed asymmetric epoxidation, 52 Salsolidine, 248 Schmidt reaction, 121,246 Sclerophytins, 131 1,2,3-Selenadiazoles, 202 Selenazoles, 202 Selenophenes, 104 (_)-Sesamin, 152 Sexithiophenes, 102 Sharpless asymmetric oxidation, 125 [2,3]-Sigmatropic rearrangement, 98,255 [3,3]-Sigmatropic shift, 188,341 Silaalkanes, 386 Silatropyliumlon, 357 Siloles, 102 Silyloxythiophenes, 90 Silylthiophene, 92 Single electron transfer, 256 Solenopsin A, 255 Solid-phase combinatorial methods, 171,178 Solid-phase synthesis, 93, 99, 119,120,273 Sonication, 281 Sonogashira coupling, 93,117,270,380 Spirofungins, 317 Spirotryprostatin B, 126 Spongiostatins, 317 Stannylbenzo[b]thiophene, 91 Stannylthiophene, 91 Staudinger reaction, 175 Stille cross-c oupling, 93,270 Strobilurins, 363 Strychnine, 111 Suaveoline, 124 a-Sulfenylation, 196 Sulfinimine, 247 Sulfolenes, 97 13-Sultams, 74 Superbase, 242 Superphane, 381

Index

Supinidine, 113 Suzuki cross-coupling reactions, 117,120,123, 174,175,280 Talcarpine, 124 Talpinine, 124 Tebbe reagent, 243 Tellurophenes, 104 (+)-Tephrosone, 133 Tetrahydrofurans, 138,146-53 Tetrahydroisoquinolines, 17 Tetrahydropyrans, 319 Tetrahydrothiophenes, 89 Tetramethylthiuram disulfide, 200 Tetrasulfur tetranide antimony pentachloride complex, 199 Tetrathiafulvalenes, 208,209 Tetrathianes, 335 Tetrathiepanes, 372 Tetrathiophenes, 102 1,2,4,5-Tetrazines, 29,161,303-5 Tetrazoles, 182 Tetrazolo[1,5-b]pyridazines, 181 Tetrazolo[1,5-a]pyridines, 181,183 Tetrazolo[1,5-a]pyrimidines, 181 2,1,3-Thiadiazines, 306 1,2,3-Thiadiazoles, 155,197,203 1,2,4-Thiadiazoles, 198 1,2,5-Thiadiazoles, 200 1,3,4-Thiadiazoles, 201 1,2,4,6-Thiatriazine 1-oxides, 299 Thiazetidines, 74 Thiazetidinones, 74 Thiazoles, 190 Thiazolidines, 18 Thiazoline, 193 Thiazolo [4,3-a]isoquinoline, 248 Thiazolo [5,4-c]pyridines, 193 Thiazolo[3,2-b] 1,2,4-triazoles, 182 Thienocarbazoles, 13 Thieno[3,4-d]imidazolone, 92 Thienopyrimidine, 266 Thienothiadiazine, 203 Thieno [2,3-d]- 1,2,3-thiadiazole, 203 Thieno[2,3-b]thiophene, 88 Thieno[3,4-c]thiophene,87 Thiepanes, 353 Thiepins, 353 Thietanes, 72,378 Thiiranes, 378 Thioisomiinchnones, 89,191 Thiophenes, 11, 87-104 Thiophene-2-borates, 93 Thiophene-3-borates, 93 Thiophene 1,1-dioxides, 91, 96,102 Thiophene 1-imide, 91

39

Thiophene 1-oxides, 91, 96 Thiophene-2-stannanes, 93 Thiophene-2-zincates, 93 Thiopyrans, 331 Thrombinlnhibitor, 98 Thromboxane A2 synthase inhibitors, 98 Thymidylate synthase inhibitors, 264 Titanium catalyst, 55 Titanocene catalyzed, 64 Toddaquinoline, 245 TosMIC, 224 Traceless solid-phase synthesis, 179 Trefoil knots, 384 Triazepines, 370 1,2,3-Triazines, 296, 312 1,2,4-Triazines, 296-302 1,3,5-Triazines, 296-302 1,2,3-Triazoles, 179 1,2,4-Triazoles, 181 1,2,3-Triazolines, 28 1,2,4-Triazolium salts, 305 1,2,3-Triazolo[1,5-a]azepines, 348 1,2,4-Triazolo[4,3-b]pyridazines, 306 5H- [1,2,3]Triazolo [5,1-b] [1,3,4] thiadizines, 197 Triazolothiazine, 197 Trifluoromethylthiophenes, 88 Trinems, 81 Trioxins, 334 1,2,4-Trioxolanes, 212 Trithianes, 335 1,2,3-Trithiolanes, 213 1,2,4-Trithiolanes, 213 Trithiophenes, 102 Tropane alkaloids, 111 Tubulin polymerization inhibitor, 98 Tungsten reagents, 241 Ugi reaction, 183 Uracils, 8 Vanadium complexes, 55 VEGF receptor tyrosine kinase inhibitors, 281 Vilsmeier reagent, 170 Vilsmeier-Haack reaction, 126 Vinblastine, 126 Vindoline, 127 VM55599, 127 Wagner-Meerwein rearrangement, 167 Westiellamide, 228 Wilkinson 's catalyst, 118 Williamson ether synthesis, 148 Wittig reaction, 94,113 Wittig rearrangement, 138 Xanthones, 331 X-ray crystallography, 100 Yuehchukene, 123,127

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