Organic Reactions, Volume 70

Published by John Wiley & Sons. Inc., Hoboken, New Jersey Copyright €> 2008 by Organic Reactions. Inc. All rights reserved. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate pcr-copy fee to the Copyright Clearance Center. Inc., 222 Rosewood Drive. Danvers. MA 01923. (978) 750-8400. fax (978) 750-4470. or on the web at www.copyright.com. Requests for permission need to be made jointly to both the publisher. John Wiley & Sons, Inc.. and the copyright holder. Organic Reactions, Inc. Requests to John Wiley & Sons, Inc., for permissions should be addressed to the Permissions Department. John Wiley & Sons. Inc., 111 River Street, Hoboken. NJ 07030. (201) 748-6011. fax (201) 748-6008, or online at http://www.wilcy.com/go/pcimission. Requests to Organic Reactions, Inc.. for permissions should be addressed to Dr. Jeffery Press, 22 Bear Berry Lane. Brewster. NY 10509, E-Mail: [email protected]. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Catalog Card Number. 42-20265 ISBN 978-0-470-25453-0 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

CONTENTS

CHAPTER

1.

2.

PAGE

THE CATALYTIC ASYMMETRIC STRECKER REACTION Masakatsu Shibasaki, Motomu Kanai, and Tsuyoshi Mita . . . . . . . .

1

THE SYNTHESIS OF PHENOLS AND QUINONES VIA FISCHER CARBENE COMPLEXES Marcey L. Waters and William D. Wulff . . . . . . . . . . . . . . . . . . . 121

CUMULATIVE CHAPTER TITLES BY VOLUME . . . . . . . . . . . . . . . . . . . . . . . 625 AUTHOR INDEX, VOLUMES 1–70 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 CHAPTER AND TOPIC INDEX, VOLUMES 1–70 . . . . . . . . . . . . . . . . . . . . . . 645

ix

CHAPTER 1

THE CATALYTIC ASYMMETRIC STRECKER REACTION MASAKATSU SHIBASAKI, MOTOMU KANAI, and TSUYOSHI MITA Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . MECHANISM AND STEREOCHEMISTRY SCOPE AND LIMITATIONS . . . . . . . . . . . . Imine Synthesis . . . . . . . . . . . . . Catalytic Enantioselective Strecker Reaction of Aldimines . . . . . Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Organocatalysts . . . . . . . . . . . . Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Metal Complexes . . . . . . . . . . . . Catalytic Enantioselective Strecker Reaction of Ketimines . . . . . Catalytic Enantioselective Reissert Reaction . . . . . . . . APPLICATIONS TO SYNTHESIS . . . . . . . . . . . COMPARISON WITH OTHER METHODS . . . . . . . . . . Chiral Auxiliary-Controlled Asymmetric Strecker Reaction . . . . . Catalytic Asymmetric Hydrocyanation of Hydrazones . . . . . . Catalytic Asymmetric Hydrogenation . . . . . . . . . Catalytic Asymmetric Introduction of the Side Chain through C–C Bond Formation . . . . . . . . . . . . . . Asymmetric Phase-Transfer-Catalyzed Reactions . . . . . . Asymmetric Allylic Substitution Catalyzed by Chiral Transition Metal Complexes Reactions . . . . . . . . . . Catalytic Asymmetric Addition to Imino Esters . . . . . . . Oxazole as a Glycine Enolate Equivalent . . . . . . . . Catalytic Asymmetric Electrophilic Amination of Enolates . . . . . . . . . . . . . . . . EXPERIMENTAL CONDITIONS Toxicity of Cyanide Compounds . . . . . . . . . . Isolation of Amino Acids . . . . . . . . . . . EXPERIMENTAL PROCEDURES . . . . . . . . . . . Allyl-(4-tert-butylbenzylidene)amine [General Procedure for Preparation of Simple Amine-Derived Aldimines] . . . . . . . . .

[email protected] Organic Reactions, Vol. 70, Edited by Larry E. Overman et al.  2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 1

PAGE 3 3 10 10 12 .

12

.

15 19 20 23 27 28 30 30 31 31

.

32 34 37 38 39 39 39 40

.

40

2

ORGANIC REACTIONS

N -(2-Isopropylcyclopent-2-en-1-ylidene)-P,P-diphenylphosphinic Amide [General Procedure for Preparation of N-Phosphinoyl Ketimines] . . . . . Cyclohexanecarboxaldehyde N-(Mesitylenesulfonyl)imine [General Procedure for Preparation of N-Sulfonyl Imines] . . . . . . . . . N-allyl-N-((4-tert-butylphenyl)(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Urea-Based Catalyst] . . . . . . . . . . . N-(Mesitylenesulfonyl)-α-(cyano)cyclohexylmethylamine [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Phase-Transfer Catalyst] . . . . . . . . . . . . . . Chiral (Salen)Al(III) Complex [Catalyst Preparation] . . . . . . (S)-N -Allyl-N -(phenyl(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst] . . . . . . . . . . . . . . N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition A] . . . . . . . . . . . . . N -(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition B] . . . . . . . . . . . . . N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Solid-Supported Aluminum Catalyst] . . . . . . . . . . . . . . 2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Zirconium Catalyst] . . . . . . . . . . . . . . 1-(2-Hydroxy-6-methylphenyl)aminononane-1-carbonitrile [General Procedure for the Catalytic Enantioselective Three-Component Strecker Reaction Using a Zirconium Catalyst] . . . . . . . . . . . . . . 2-Benzhydrylamino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction Using a Titanium Catalyst] . . . . 2-Benzylamino-2-(4-bromophenyl)propionitrile [General Procedure for Asymmetric Strecker Reaction of Ketimines Using a Urea Catalyst] . . . . . N-[1-Cyano-2-isopropylcyclopent-2-en-1-yl]-P ,P -diphenylphosphinic Amide [General Procedure for the Asymmetric Strecker Reaction of Ketimines Using a Gadolinium Catalyst] . . . . . . . . . . . . . . 4-(4-Chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one [General Procedure for the Catalytic Enantioselective Strecker Reaction of Ketimines Using a Gadolinium Catalyst: Combination of TMSCN and HCN] . . . . . . . N -(2-Furoyl)-2-cyano-6,7-dimethoxy-1,2-dihydroquinoline [General Procedure for the Catalytic Enantioselective Reissert Reaction of Quinolines] . . . . 1-Cyano-1-phenyl-1,2-dihydroisoquinoline-2-carboxylic Acid Vinyl Ester [General Procedure for Generating Quaternary Stereocenters by Catalytic Enantioselective Reissert Reaction of Isoquinolines] . . . . . . . . . 2-Cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 9H -Fluoren-9-ylmethyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives] . . . . . . . . 4-Chloro-2-cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 2,2-Dimethylpropyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of a Halide-Substituted Pyridine Derivative] . . . . . . . . . ADDITIONAL CONTRIBUTIONS AFTER MANUSCRIPT SUBMISSION . . . . . . . . . . . . . TABULAR SURVEY Chart 1. Catalysts and Ligands Used in Tables . . . . . . . Table 1. Catalytic Enantioselective Strecker Reactions of Aldimines . . .

40 41

42

43 43

44

44

45

45

46

47 47 48

48

50 51

52

52

53 54 58 59 62

THE CATALYTIC ASYMMETRIC STRECKER REACTION Table 2. Catalytic Table 3. Catalytic Table 4. Catalytic Aug. 2007 . Table 5. Catalytic Aug. 2007 . . REFERENCES

Enantioselective Enantioselective Enantioselective . . . Enantioselective . . . . . .

Strecker Reactions of Ketimines . . Reissert Reactions . . . . . Strecker Reactions of Aldimines: Nov. 2006 to . . . . . . . . . Strecker Reactions of Ketimines: Nov. 2006 to . . . . . . . . . . . . . . . . . .

3 . .

88 95

.

99

. .

110 115

INTRODUCTION

α-Amino acids are important building blocks for proteins, peptides, and pharmaceuticals. Among a wide variety of methods to synthesize optically active α-amino acids,1 – 6 the Strecker reaction7 is one of the simplest and the most powerful. This reaction consists of three steps (Eq. 1): (1) condensation of an aldehyde or a ketone with an amine to produce an imine, (2) nucleophilic attack of cyanide on the imine to produce an amino nitrile, and (3) hydrolysis of the amino nitrile to the corresponding α-amino acid. These three steps can be conducted in one pot. Conversion of the nitrile group to amide, amine, or aldehyde functionalities is also possible. + H2NR3

O R

1

R

2

– H2 O

N R

1

R3 R

2

asymmetric catalyst CN

–

hydrolysis and deprotection

R3NH

CN

R1

* R2 H 2N

(Eq. 1) CO2H

R 1 * R2

The catalytic promotion and enantiocontrol of cyanide addition to imines is the main focus of the catalytic asymmetric Strecker reaction. Therefore, isolated and purified imines are normally used as substrates. The catalyst turnover efficiency and enantioselectivity of this step are intimately related to the electronic and steric characteristics of the substrate imines, with the nitrogen substituent greatly contributing to these factors. However, since optically active α-amino acids are generally the synthetic target of a catalytic asymmetric Strecker reaction, the accessibility of the starting imines and ease of final deprotection of the product are also important considerations. Due to the importance of catalytic enantioselective Strecker reactions, there have been several reviews on this topic to date.8 – 10 This chapter focuses on catalytic enantioselective Strecker reactions (and Reissert reactions) and the Tables cover all of the references through August 2007. For enzymatic reactions, the reader is directed elsewhere.11 MECHANISM AND STEREOCHEMISTRY

Many of the catalysts for the asymmetric Strecker reaction (and the Reissert reaction) appear to promote the reaction through dual activation12 – 15 of the

4

ORGANIC REACTIONS

electrophilic imine and the nucleophilic cyanide, either trimethylsilyl cyanide (TMSCN) or hydrogen cyanide (HCN).16 This type of asymmetric catalysis was initially postulated in the closely related catalytic asymmetric cyanosilylation of aldehydes. A dual activation mechanism was first proposed for chiral tin (II)–cinchonine catalyst 1.17 In this reaction, the alkoxytin triflate and the tertiary amine of the quinuclidine are believed to act as a Lewis acid to activate the aldehyde, and as a Lewis base to activate TMSCN, respectively. Although high enantioselectivity (90% ee) was obtained, the catalyst turned over only twice (catalyst loading = 30 mol%, product yield = 63%), and the result for only one substrate (cyclohexanecarboxaldehyde) was reported. H TfOSnO N

N H

O

SiMe3

H

R

CN

1

A synergistic combination catalyst was reported for an enantioselective cyanosilylation of aldehydes. Magnesium bisoxazoline 2 acted as a chiral Lewis acid to activate the aldehyde, and uncomplexed bisoxazoline 3 as a Brønsted base to activate HCN as shown in complex 4.18 HCN was generated in a catalytic amount from TMSCN and moisture, and regenerated after TMS trapping of the intermediate cyanohydrin by TMSCN. Only aliphatic aldehydes produced high enantioselectivities in this report. Ph O

N + H N O

Mg

H – N C

O R

O N

Cl

Ph

CN N O

Ph 2

Ph 3

4

Extensive mechanistic studies of an asymmetric cyanosilylation of aldehydes and ketones catalyzed by a salen–titanium complex revealed that the actual catalyst is a bimetallic complex bridged by a µ-oxo atom (5).19,20 One titanium atom acts as a Lewis acid to activate the substrate, while the other titanium atom

THE CATALYTIC ASYMMETRIC STRECKER REACTION

5

generates titanium cyanide (or isocyanide) via transmetalation with TMSCN. It was proposed that the reaction proceeds through an intramolecular cyanide transfer from one titanium to the substrate activated by the other titanium (5).21,22 Only aromatic aldehydes led to high enantioselectivity.

+ N

t-Bu t-Bu t-Bu t-Bu

N Ti O O +N C−

O O

Bu-t Bu-t

O

Ph

Ti

N O

N

H

5

Asymmetric catalyst 6 (prepared from Et2 AlCl and the corresponding BINOLderived ligand) promotes cyanosilylation of aromatic and aliphatic aldehydes with excellent enantioselectivities (Eq. 2).23,24 This catalysis is believed to occur via a dual activation mechanism, in which the aluminum provides a Lewis acidic site to activate the aldehyde and the internal phosphine oxide acts as a Lewis base to activate TMSCN as in intermediate 7. The additive phosphine oxide (R
3 PO) coordinates to the aluminum, and modulates the Lewis acidity and geometry of the aluminum to be optimal for the dual activation pathway. This mechanism was supported by the following: (1) the reaction rate increased according to the electron density of the internal phosphine oxide (a nucleophile activator) at the 3,3
-positions of the BINOL scaffold, (2) an IR absorption derived from the activated ionic cyanide was observed (ν = 2057 cm−1 ; cf. TMSCN, ν = 2192 cm−1 )25 when the bifunctional catalyst 6 was mixed with TMSCN, while a monofunctional Lewis acid aluminum catalyst (generated from BINOL and Et2 AlCl) did not produce this absorption, and (3) a control reaction with a monofunctional catalyst containing diphenylmethyl groups at the 3,3
-positions of BINOL, instead of the Lewis basic phosphine oxide, produced the enantiomer of the products that were obtained using the bifunctional catalyst 6. Catalyst 6 was later applied to a catalytic enantioselective Strecker reaction.26,27 Based on the mechanism of the catalytic enantioselective cyanosilylation of aldehydes using 6, the Strecker reaction was proposed to proceed through a dual activation mechanism illustrated by intermediate 8. These models (7 and 8) can explain the absolute configuration of the products.

6

ORGANIC REACTIONS

O R

6 (9 mol%), R'3P(O) (36 mol%)

+ TMSCN

OTMS (86-100%) 83-99% ee

CH2Cl2, –40°

H

R

CN

P(O)Ph2 O Al Cl O P(O)Ph2 6

Ph

Ph P

O O

Me3 R Si

O O

(Eq. 2)

P

H O

Al Cl

Me3 Si CN

Ph

Ph CN

O

O R''

H N R

Al Cl

(O)PR'3 7

P(O)Ph2

8

P(O)Ph2

A dual activation mechanism illustrated by complex 9 was proposed for the catalytic enantioselective Strecker reaction of aldimines using a titanium–peptide complex.28,29 This transition state model was based on the mechanistic information obtained from kinetic studies, observation of a kinetic isotope effect, measurement of the activation enthalpy and entropy, and molecular modeling studies.30 The titanium acts as a Lewis acid to activate the imines, while the terminal amide carbonyl oxygen acts as a Brønsted base to activate HCN, which is generated in situ from TMSCN and the additive i-PrOH. Specifically, the observed large negative entropy of activation (S= = −45.6 ± 4.1 kcal/K•mol) supports the notion that the reaction proceeds through the highly ordered transition state 9. Ph

H

C N H R N Ph t-Bu O H NBu N N + H Ti O O OBu-t i-PrO OPr-i 9

Chiral organocatalysts now provide an important class of reagents for asymmetric catalysis.31 Two significant asymmetric organocatalysts for the Strecker reaction have been reported, and both of these studies presented mechanistic proposals. One of the organocatalysts is the chiral thiourea catalyst 10, which is one

THE CATALYTIC ASYMMETRIC STRECKER REACTION

7

of the most useful asymmetric catalysts for the Strecker reaction of aldimines and ketimines.32 – 35 Detailed NMR and molecular modeling studies of the catalyst–imine complex demonstrated that the E- and Z-imine geometrical isomers of acyclic imines rapidly interconvert in the presence of the thiourea catalyst, and that the reaction proceeds from the Z-imine complexed to the thiourea moiety of the catalyst through hydrogen bonding as in 11 (Y = S).36 In accord with this pre-transition-state model, a cyclic Z-imine (3,4-dihydroisoquinoline) is an excellent substrate for the Strecker reaction, producing the product in quantitative yield with 89% ee. The absolute stereoinduction from the cyclic Z-imine is identical to that of all of the Strecker adducts derived from acyclic imines that exist predominantly as E isomers. In addition, high-level calculations suggested that the catalyst binds to the starting imine more strongly than to the product; the energy of formation of the thiourea catalyst–imine complex is 10.0 Kcal/mol, while that of the catalyst–product complex is 6.3 Kcal/mol. Thus, product inhibition is unlikely to occur. RL t-Bu S Ph

O O

N H

N

N H

N

HO

RS H N

H t-Bu N

t-Bu

Y

OCOBu-t

10

O

HO

O (Y = O or S)

Ph

OCOBu-t

N

H

t-Bu

11

The other useful organocatalyst for the Strecker reaction is the chiral C-2-symmetric bicyclic guanidine catalyst 12.37 This catalyst was proposed to promote the Strecker reaction through a dual activation mechanism as shown in intermediate 13. The nucleophile HCN is deprotonated by the basic guanidine, while the substrate imine undergoes hydrogen bonding to the protonated guanidine catalyst. A proximal phenyl group of the catalyst can undergo π-stacking with one of the benzhydryl phenyls of the imine. This well-organized pre-transition state model defines the approach of cyanide to the activated imines, and can explain the absolute configuration of the product.

N

Ph N

N

Ph N H

Ph

N +

12 N

N H

H – C

Ph 13

N H

Ph

8

ORGANIC REACTIONS

Ketimines are generally much less reactive than aldimines. Therefore, an asymmetric catalyst with higher activity is required to promote the enantioselective Strecker reaction of ketimines. Chiral thiourea catalyst 10 can promote this type of reaction38 through a similar mechanism to that shown in complex 11. Chiral gadolinium catalyst 18 can promote the asymmetric Strecker reaction of N -diphenylphosphinoyl ketimines.39 – 41 The active catalyst was generated from Gd(OPr-i)3 and D-glucose-derived chiral ligand 14 in a 1 : 2 ratio (Scheme 1). Protic additives such as 2,6-dimethylphenol or HCN dramatically accelerated the reaction, as well as improved the enantioselectivity. Based on ESI-MS studies, the active catalyst was proposed to be a 2 : 3 complex (18) of gadolinium and 14, which was generated through reaction of initially formed alkoxide complex 16 with TMSCN giving compound 17, followed by protonolysis. The Strecker reaction should proceed through an intramolecular transfer of a cyanide to the activated imine by the second Lewis acidic gadolinium (19). The proton in the asymmetric catalyst should accelerate the dissociation of the product from the catalyst (from 19 to 16), and thus accelerate the catalytic cycle. Regeneration of the active catalyst 18 from 16 requires TMSCN. Direct conversion of 16

O Gd(OPr-i)3

+

P Ph2 HO

O

14: X = F 15: X = Cl

O

X

HO

X

(Gd:14 or 15 = 1:2) O H N PPh2

NC R1

R2

O O O

Gd O

O O O

O

Gd O H

O

= 14 or 15 O O Gd O O

16

O

O Gd O CN O O PPh2 N

R1

N R1

O O O

O PPh2 R2

O

Gd

O O Gd O

O CN NC O TMS

R2

19

2 TMSCN (cat.)

O O O

O

Gd O H

O O Gd O

CN 18

Scheme 1

O

HCN 2 TMSCN (cat.)

TMS

17

THE CATALYTIC ASYMMETRIC STRECKER REACTION

9

to 18 through protonolysis by HCN did not occur, and no reaction proceeded in the absence of a catalytic amount of TMSCN. When HCN was used as the additive in combination with a catalytic amount of TMSCN, TMSCN was regenerated at the protonolysis step (17 to 18). Therefore, only a catalytic amount of TMSCN (and a stoichiometric amount of HCN) is required. Labeling studies using TMS13 CN and kinetic studies revealed that the actual nucleophile is not TMSCN, but rather the gadolinium cyanide generated through transmetalation from TMSCN.42 A catalytically active species was crystallized and its structure was elucidated by X-ray crystallography using the dichlorocatechol-containing ligand 15.43 The crystal, however, was not the 2 : 3 complex 16 (active catalyst prepared in situ), but a 4 : 5 complex (20) of gadolinium and 15. Although both polymetallic complexes contain the chiral ligands with the same absolute configuration, crystal 20 (4 : 5 complex) produced the enantiomers of the Strecker products compared to those obtained by using the in situ prepared 2 : 3 complex (16) (Eq. 3). These results demonstrated the importance of the higher order assembly structure of the polymetallic asymmetric catalyst for its function. Due to the structural complexity of the catalysts, three-dimensional models for enantioinduction have yet to be clarified. O O O

Gd O

ligands with the same chirality

O

O O Gd

O

S-isomer

O

16 (2:3 complex) 3D structure unknown

but complex with different assembly state

R-isomer

20 (4:5 complex) elucidated by x-ray crystallography

(Eq. 3)

The Reissert reaction44 is an acyl cyanation of N -heteroaromatic compounds using a combination of an acylating reagent (such as acyl halide or halo carbonate) and a cyanating reagent (such as TMSCN or NaCN). This reaction is very important for the synthesis of biologically active compounds containing N -heterocycles.45,46 The reaction proceeds through an initial N -acylation followed by a dearomatizing cyanation (Eq. 4). Because the amide bond of the N -acylated heteroaromatic intermediates 21 (such as acylquinoliniums, acylisoquinoliniums, and acylpyridiniums) are conformationally flexible, it is essential to define the positions of both the electrophile and the nucleophile by the asymmetric

10

ORGANIC REACTIONS

catalyst to realize high enantioselectivity. All the reported catalytic enantioselective Reissert reactions47 – 50 to date have utilized Lewis acid–Lewis base bifunctional aluminum complexes similar to 6 as the catalysts. In a typical proposed transition-state model (22), the N -acylquinolinium intermediate is activated by the aluminum, and the TMSCN is activated by the phosphine oxide of the catalyst. Due to steric factors, the reaction via the s-trans N -acylquinolinium 22 should be more favorable than that via the s-cis isomer 23. Thus, the reactive conformer with regard to the amide bond is influenced by the asymmetric catalyst.

4

RCOCl TMSCN

6

+ N

N

Cl–

N O

*

2

R

O

CN

R

21

Ar Ar

P

O

Ar Ar

O O

O

Me3 Si CN

Me3 Si CN + N Cl– R

Al

+ N

O O

Cl–

R

O O

Cl P(O)Ar2

P

Al Cl

22

P(O)Ar2

23

(Eq. 4) The catalytic enantioselective Reissert reaction of pyridine derivatives presents additional difficulties. There are three similarly electrophilic carbon centers on the acyl pyridinium intermediate (C-2, 4, and 6 of 21). Therefore, an asymmetric catalyst needs to facilitate one specific pathway out of a possible six (three positions × two faces) to produce one specific regioisomer with high enantioselectivity. As will be discussed below, a finely tuned bifunctional asymmetric catalyst is able to elegantly solve this problem.50 SCOPE AND LIMITATIONS

Imine Synthesis There are mainly two types of imines that have been utilized in catalytic enantioselective Strecker reactions: (1) simple amine-derived imines such as N -allyl, N -benzyl, N -benzhydryl, and N -fluorenyl imines, and (2) activated imines containing electron-withdrawing groups on the nitrogen atom, such as N -phosphinoyl and sulfonyl imines. Simple amine-derived aldimines are the most readily prepared by mixing the aldehydes and amines in the presence of desiccant. Many of

THE CATALYTIC ASYMMETRIC STRECKER REACTION

11

these simple amine-derived imines are labile to purification using silica gel column chromatography or during distillation at high temperature; therefore, imines purified by recrystallization are preferred. The substrate purity is generally very important for catalytic enantioselective reactions, because trace amounts of impurities might have detrimental effects on the asymmetric catalyst. There is, however, an example of using in situ-generated aldimines as substrates for the catalytic enantioselective Strecker reaction (see the chiral Zr-catalyzed threecomponent reaction).51 On the other hand, N -phosphinoyl imines and N -sulfonyl imines require multistep syntheses from the corresponding aldehydes or ketones. Although N -phosphinoyl aldimines have not been utilized as substrates for the catalytic asymmetric Strecker reaction, N -phoshinoyl ketimines are excellent substrates.39 – 43 N -Phosphinoyl ketimines can be synthesized in two steps from the corresponding ketones (Eq. 5)52 via oxime formation followed by treatment with R2 PCl. The reaction of ketoximes with R2 PCl at low temperature produces unstable O-phosphinyl oximes 24 as the initial products, which undergo rearrangement to give N -phosphinoyl imines 25 at higher temperature through a radical-cage mechanism.53,54 Interestingly, E/Z geometrical isomerization of phosphinoyl ketimines is very fast even at low temperature based on NMR studies.39 This characteristic is important for the induction of high enantioselectivity from substrates having a wide variety of substituents, because imine geometrical isomers (with regard to the C=N bond geometry) produce enantiomeric products. The cyanation should proceed from the more reactive imine geometry, and so the thermodynamic stability of (E) and (Z) N -phosphinoyl imines (E/Z ratio of imines) is not related to the enantioselectivity. Although N -phosphinoyl imines are more electrophilic than simple aminederived imines, they are generally quite stable to silica gel purification. In addition, many of the aromatic ketone-derived phosphinoyl imines are crystalline.

O R1

NOH

H2NOH R2

R1

R2

N

Ph2PCl Et3N

R1

R2 24

OPPh2

OPPh2

N R1

N R2

R1

O PPh2 R2

25

(Eq. 5) N -Sulfonylimines are the most activated (electron-deficient) imines. N Sulfonylimines derived from aromatic aldehydes or aliphatic aldehydes bearing no enolizable α-protons are relatively easy to prepare. For example, condensation of an aldehyde with a sulfonamide in the presence of a Lewis acid (e.g. TiCl4 , BF3 •OEt2 , (EtO)4 Si)55,56 or a Brønsted acid (e.g. p-TsOH, amberlyst-H+ , HCO2 H)57 affords the target imines. Aliphatic N -sulfonyl aldimines have been prepared in situ without purification in two steps (Eq. 6):58 (1) condensation of an aldehyde, an arenesulfinic acid sodium salt, and a sulfonamide in the presence of formic acid and water to form the corresponding sulfonamide sulfone 26, then (2) treatment of the isolated sulfone with a mild base such as sodium bicarbonate.

12

ORGANIC REACTIONS

Due to their lability, the aliphatic N -sulfonylimines are used in further reactions without purification. O R

NHSO2Ar

HCO2H

+ p-TolSO2Na + ArSO2 NH2

H2O

H

SO2Tol-p

R 26

(Eq. 6)

NSO2Ar

NaHCO3 H2O/CH2Cl2

R

H

Catalytic Enantioselective Strecker Reaction of Aldimines The catalytic enantioselective Strecker reaction of aldimines can be categorized into two classes: (1) reactions promoted by chiral organocatalysts and (2) reactions promoted by chiral metal catalysts. Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Organocatalysts. The first example of a catalytic enantioselective Strecker reaction was reported using organocatalyst 27,59 which was developed based on the structure of a previously reported asymmetric catalyst that promotes cyanosilylation of aldehydes.60 – 63 Catalyst 27, containing guanidine and (S)-phenylalanine moieties, can promote Strecker reactions of aromatic aldimines with high to excellent enantioselectivity (Eq. 7). Heteroaromatic and aliphatic imines afforded products with only low enantioselectivities (up to 32% ee). The products can be converted to optically active α-amino acids via a one-step acid hydrolysis. N R

CHPh2

27 (2 mol%), HCN (2 eq) MeOH, –75° to –25°

H

H N

O

NH2 NH

HN Ph

HN R

CHPh2 CN

(71-97%) <10 to >99% ee

(Eq. 7)

NH O 27

A more general asymmetric organocatalyst class for the Strecker reaction was developed using urea or thiourea as the activating moiety of imines, giving thiourea catalysts 28–30. Optimization of each structural module of the catalyst by a combinatorial approach led to the identification of catalysts that produce excellent enantioselectivity and catalyst activity with a wide range of aldimines containing aromatic and aliphatic substituents (Eq. 8).32,33 The enantioselectivity is not affected by the size of the nitrogen protecting group, and allylamine-derived and benzylamine-derived imines produced comparable enantioselectivity. This tendency can be explained based on model 11. Resin-bound asymmetric catalyst 30 is as effective as the soluble catalysts 28 and 29. Additional advantages of using

THE CATALYTIC ASYMMETRIC STRECKER REACTION

13

catalyst 30 are facile catalyst recovery and product isolation by simple filtration. The filtered catalyst was reusable for at least ten cycles without any loss of enantioselectivity or catalyst activity. The products were converted to enantiomerically pure α-amino acids through protection of the nitrogen atom with a formyl group, recrystallization, nitrile hydrolysis to a carboxylic acid, deformylation, and removal of the N -benzyl group. A typical conversion process is shown in Eq. 9. N R

R1

cat. 28-30 (1–4 mol%), HCN toluene, –78°, 15–20 h

H

R3 t-Bu Y N R2 N N H H O

HN

R1 (65-99%) 77-99% ee CN

R

R = aryl, alkyl R1 = benzyl, allyl

(Eq. 8) 28: R2 = PhCH2, R3 = H, Y = O 29: R2 = R3 = Me, Y = S 30: R2 = polystyrene–CH2, R3 = H, Y = S

N

HO t-Bu

OCOBu-t

O HN t-Bu

Ph CN

1. Ac2O, formic acid

H

2. recrystallization

N

Ph

t-Bu 1. H2SO4, (65% w/v) 45°, 20 h

>99% ee

CN

(Eq. 9)

NH2•HCl

2. HCl (conc), 70°, 12 h 3. H2, Pd/C, MeOH

t-Bu

CO2H

(84% overall from imine) >99% ee

Although substrate generality is not as broad as for the thiourea catalysts 28–30, chiral C-2-symmetric guanidine 12 is a simple yet highly enantioselective organocatalyst for the Strecker reaction of N -benzhydryl aldimines.37 The sterically bulky N -benzhydryl group is essential for high enantioselectivity. Aromatic aldimines produced high enantioselectivity, while aliphatic aldimines produced less satisfactory results (Eqs. 10a & 10b). The enantioselectivity reversed depending on the substrates, with aromatic imines affording products in the R-configuration and aliphatic imines affording S-configurational products. The absolute configuration of the products from aromatic ketimines can be explained using model 13. N

CHPh2 H

Ar

12 (10 mol%), HCN (2 eq) toluene, –40°, 20 h

N 12 N R

CHPh2 H

R = alkyl

Ar

CHPh2 (80-99%) 50-88% ee CN

(Eq. 10a)

N

Ph

HN

Ph N H

12 (10 mol%), HCN (2 eq) toluene, –40°, 22 h

HN R

CHPh2 CN

(~95%) 63-84% ee

(Eq. 10b)

14

ORGANIC REACTIONS

Chiral ammonium salt 31 is an effective catalyst for the asymmetric Strecker reaction of N -allyl aromatic aldimines (Eq. 11).64 The reaction was proposed to proceed through the attack of cyanide on the imine, which is activated by hydrogen bond formation to the ammonium proton of the catalyst. The reaction should occur in the U-shaped pocket constructed by the three aromatic groups of the catalyst. Bulky substrates containing N -benzyl or N -benzhydryl protecting groups produced less satisfactory enantioselectivities. In addition, aliphatic aldimines were poor substrates in this reaction. 1. 31 (10 mol%), HCN (2 eq), CH 2Cl2, –70°, 24-48 h

N Ar

HN

2. (CF3CO)2O

H

Ar

CN

(86-98%) 79 to >99% ee

OMe

(Eq. 11)

N N

H +N

H O

N N

H

O

N

CF3CO2– 31

BINOL-derived chiral phosphates are versatile Brønsted acid organocatalysts.65,66 A highly enantioselective catalytic Strecker reaction was reported using catalyst 32 (Eq. 12).67 Only aromatic imines produced high enantioselectivities. The activation of the substrate aldimine occurs in the chiral environment through protonation by the phosphate. N Ar

Bn H

32 (10 mol%), HCN (1.5 eq) toluene, –40°, 48–72 h

O O P O OH

HN Ar

Bn CN

(59-97%) 85-99% ee

(Eq. 12)

32

Chiral quaternary ammonium salt 33 is a useful asymmetric phase-transfer catalyst for the Strecker reaction of aliphatic N -sulfonyl aldimines (Eq. 13).68 Inexpensive and easy-to-handle KCN can be used as a cyanide source. Generally, enantioinduction from aliphatic aldimines is more difficult than from aromatic

THE CATALYTIC ASYMMETRIC STRECKER REACTION

15

aldimines. This phase-transfer-catalyzed reaction, however, is notable because aliphatic aldimines produced better results than aromatic aldimines. N R

SO2Mes

33 (1 mol%), 2 M aq. KCN (1.5 eq)

HN

toluene–H2O, 0°, 2-8 h

H

R = alkyl Mes = 2,4,6-Me3C6H2

SO2Mes CN

R

(81-98%) 88-97% ee

Ar

Ar Me + N

(Eq. 13) I–

Me Ar Ar 33: Ar = 4-CF3C6H4

Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Metal Complexes. The (salen)aluminum(III) complex 34 is an excellent catalyst for the enantioselective Strecker reaction between aromatic aldimines and HCN (Eq. 14).69 Aliphatic imines afford products with moderate enantioselectivities (37–57% ee). The reaction is best performed at very low temperature (−70◦ ) to avoid competing background reactions. Catalyst 34 is easily prepared on a large scale and appears to have an indefinite shelf-life even when stored under ambient conditions.70 The products can be converted to enantiomerically pure α-amino esters through methanolysis of the cyanide followed by N deprotection (Eq. 15). 1. 34 (2–5 mol%), HCN (1.2 eq), toluene, –70°

N Ar

CF3

2. TFAA

H

O

Ar

N t-Bu

(91-99%) 79-95% ee

N CN

(Eq. 14)

N

Al O Cl O Bu-t

Bu-t

t-Bu 34

HN

MeOH/HCl, reflux, 8 h CN

78%

HN CO2Me

93% ee dimethylbarbituric acid, Pd(PPh3)4 (5 mol%) CH2Cl2, rt, 3 h

NH2•HCl CO2Me (60%), >99% ee recrystallized

(Eq. 15)

16

ORGANIC REACTIONS

Asymmetric bifunctional catalyst 6 was developed as a general catalyst for the Strecker reaction of aldimines, and high enantioselectivities have been observed using this catalyst with both aromatic and aliphatic substrates.26,27 Catalyst 6 acts in a bifunctional manner: aluminum activates the imine as a Lewis acid, and the phosphine oxide activates TMSCN as a Lewis base (8 in Eq. 2).71 The N -protecting group of the substrate has a large effect on the enantioselectivity, and N -fluorenylimines gave optimal results. Slow addition of a catalytic amount (20 mol%) of phenol into the reaction mixture containing a stoichiometric amount of TMSCN dramatically increased the reaction rate (condition A), and the reaction was completed in less than 68 hours. Alternatively, a more atom-economic combination of a catalytic amount of TMSCN and a stoichiometric amount of HCN can be used (condition B). Both conditions produced comparable enantioselectivity. The N -fluorenyl group of the product could be removed through oxidative treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or manganese dioxide to generate the corresponding fluorenone-derived imine, followed by acidic hydrolysis (Eq. 16). A recyclable, solid-supported asymmetric catalyst 35 was developed by connecting catalyst 6 to JandaJ EL72 (Eq. 17).73 Catalyst 35 produced slightly lower enantioselectivity than the soluble catalyst 6, and the catalyst activity decreased significantly after the fourth recycle. A: 6 (9 mol%), TMSCN (2 eq), PhOH (20 mol%), slow addition over 17 h or B: 6 (9 mol%), TMSCN (20 mol%), HCN (1.2 eq), slow addition over 24 h CH2Cl2, –40°, 24-68 h

N R

H 1. HCl, H2CO2H 2. DDQ, THF 3. 1 N HCl 4. Amberlyst A-21

NH2 R

CONH2

(91%) 4 steps, R = Ph

HN R

CN (66–98%) 70–96% ee

1. MnO2, CH2Cl2 2. HCl, THF 3. 12 N HCl

NH2•HCl R

CO2H

(79%) 3 steps, R = t-Bu

P(O)Ph2 O Al Cl O P(O)Ph2 6

(Eq. 16)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

35 (10 mol%), TMSCN (4 eq), t-BuOH (1.1 eq) CH2Cl2, –50°, 41-66 h

N R

(96-100%) 83-87% ee

HN CN

R

H

(Eq. 17)

O

Ph2(O)P

3

3

17

JandaJEL

O Cl Al O Ph2(O)P 35

Corey’s oxazaborolidine14 catalyst was utilized in the catalytic enantioselective Strecker reaction of aldimines. Enantioselectivity was, however, only moderate (up to 71% ee, Eq. 18).74 N R

Ph H

oxazaborolidine catalyst (20 mol%), HCN (1.5 eq) toluene, –25° H Ph N

HN

Ph (82-95%) 39-71% ee

R

CN

Ph

O

B Me oxazaborolidine catalyst

(Eq. 18)

Other metals that are utilized in catalytic enantioselective Strecker reactions of aldimines are the Group 4 metals titanium and zirconium. The complex generated from Zr(OBu-t)4 , 6,6
-dibromo-1,1
-bi-2-naphthol (36) or 3,3
-dibromo-1,1
-bi2-naphthol (37), and N -methylimidazole (NMI) is a general asymmetric catalyst that produced high enantioselectivity in the reactions between aldimines and (n-Bu)3 SnCN (Eq. 19).51,75 The structure of the asymmetric catalyst was proposed as 38 based on NMR studies. The free phenolic group of the imine is essential for high enantioselectivity as well as high chemical yield. This reaction was extended to a three-component catalytic enantioselective Strecker reaction. Thus, the Strecker products were obtained with high enantioselectivity from a mixture of aldehydes, o-hydroxyaniline derivatives, and HCN in the presence of 1–5 mol% of the chiral Zr catalyst (Eq. 20).51,76 The products were converted to amino acid derivatives through methylation of the phenolic OH, conversion of the nitrile to the methyl ester, and oxidative removal of the N -protecting group.

18

ORGANIC REACTIONS

HO +

N

(n-Bu3Sn)CN (1.1 eq)

Zr(OBu-t)4 (10 mol%), (R)-6-Br-BINOL (36: 10 mol%), (R)-3-Br-BINOL (37: 10 mol%), NMI (30 mol%)

HN

toluene/benzene (1/1) –65° to 0°, 12 h

H

R

HO

CN R (72-98%) 74-92% ee

Br

Br

(Eq. 19)

Br

OBu-t O O Zr O L

L O

Zr

O

O OBu-t

Br

Br

Br

38 HO

HO RCHO +

38 (1–5 mol%)

+ HCN

H 2N

CH2Cl2, –45°, 12 h R1

R1 CN

R

1. MeI, K2CO3 2. HCl/MeOH

(76-100%) 84-94% ee

HN

(Eq. 20)

NH2•HCl (24-38%) 4 steps

3. Ce(NH4)2(NO3)6, TFAA 4. HCl/MeOH

CO2Me

R

Titanium catalysts derived from peptide 39 promoted the enantioselective Strecker reaction of N -benzhydryl aldimines and TMSCN (Eq. 21).28 – 30 The catalyst can be systematically tuned, and the optimal catalyst structure is different depending on the substrate. Slow addition of i-PrOH to the reaction mixture dramatically accelerated the reaction rate. The protic additive generated the actual nucleophile, HCN, in situ from TMSCN, and also facilitated the catalyst turnover step. The reaction was proposed to proceed through a dual activation mechanism as depicted in model 9. Ph Ph

N R

H

+ TMSCN

Ti(OPr-i)4 (10 mol%), peptide ligand 39 (10 mol%)

Ph HN

i-PrOH, slow addition for 20 h, toluene, –20° to 4° t-Bu Ar

N O

H N

R

O N H O OBu-t

OMe

Ph

(93-100%) 76-97% ee

CN

(Eq. 21)

39 Ar (e.g.) = 2-HO-5-MeOC6H3, 2-HO-3,5-Br2C6H2 , 2-HO-3,5-Cl2C6H2, 2-HO-1-naphthyl

A chiral titanium complex generated from an easily accessible N -salicylβ-aminoalcohol 40 can also promote a highly enantioselective Strecker reaction of aromatic aldimines (Eq. 22).77

THE CATALYTIC ASYMMETRIC STRECKER REACTION

Ti(OPr-i)4 (10 mol%), ligand 40 (10 mol%)

Ph Ph + TMSCN

N Ar

19

Ph HN

i-PrOH (1 eq), toluene, 0°

H

Ar

Ph

(80-85%) 83 to >98% ee

CN

Ph N H OH 40

OH

(Eq. 22)

Catalytic Enantioselective Strecker Reaction of Ketimines α,α-Disubstituted amino acids are important chiral building blocks for biologically active compounds, such as enzyme inhibitors and conformationally restricted peptide mimetics.78 The catalytic enantioselective Strecker reaction of ketimines is a very useful reaction for the synthesis of enantiomerically enriched α,α-disubstituted amino acids. Normally, ketimines are much less reactive than aldimines. In addition, differentiation of the two substituents (aryl vs. aryl, aryl vs. alkyl, or alkyl vs. alkyl groups) on the prochiral carbon of ketimines is much more difficult compared to those on aldimines (aryl or alkyl vs. hydrogen). Therefore, asymmetric catalysts that can promote the Strecker reaction of ketimines need to be more active and enantioselective than those promoting reactions of aldimines. Chiral urea 28 and its solid-supported derivative are efficient catalysts for enantioselective Strecker reactions of aryl methyl ketimines (Eq. 23).38 Aliphatic ketimines and ethyl-substituted ketimines react with moderate (41–69% ee) enantioselectivity. N Ar

Ph

+ HCN

Me H Bn

28 (2 mol%)

NC

toluene, –75°, 24-90 h

Ar

t-Bu

N O

N H

NHBn

(45-100%) 42-95% ee

O N H

(Eq. 23) N

HO t-Bu

OCOBu-t

28

Chiral titanium catalyst 41 derived from BINOL79 and heterobimetallic catalyst 4280 have been shown to promote the asymmetric Strecker reaction of an acetophenone-derived ketimine (Eq. 24). However, this was the only substrate studied in these reactions.

20

ORGANIC REACTIONS Ph

N Ph

+ TMSCN

catalyst 41 or 42 (10 mol%)

NC

toluene, –20°

Ph

Me

NHBn

41, 1 h: (80%) 56% ee 42, 9 h: (>95%) 88% ee i-PrO O Ti O i-PrO

(Eq. 24)

Li

Me2 N

O

N Me2

O

O Sc

41

O 42

A synthetically useful catalyst for the enantioselective Strecker reaction of ketimines is a gadolinium complex derived from ligand 14 (Scheme 1).39 – 41 This catalyst was prepared from Gd(OPr-i)3 and 14 in a 1 : 2 ratio. Excellent enantioselectivities were obtained from a wide range of N -diphenylphosphinoyl ketimines (aromatic, heteroaromatic, and aliphatic) in the presence of minimal catalyst loadings (0.1–2.5 mol%). The reaction can be performed either in the presence of a stoichiometric amount of TMSCN and 2,6-dimethylphenol40 or the combination of a catalytic amount of TMSCN and a stoichiometric amount of HCN (Eq. 25).41 Using the latter combination, excellent catalyst turnover (up to 1000) was observed. The N -diphenylphosphinoyl group was easily removed under acidic conditions.

N R1

O PPh2 R2

Gd(OPr-i)3 (1-2.5 mol%)–14 (2-5 mol%), TMSCN (1.5 eq), 2,6-dimethylphenol (1 eq), EtCN, –40°, 2.5–67 h or Gd(OPr-i )3 (0.1-1 mol%)–14 (0.2-2 mol%), TMSCN (2.5-5 mol%), HCN (1.5 eq), EtCN, –40°, 3-54 h

O NC HN PPh2 R1

R2

(73-99%) 80-99% ee

(Eq. 25) O

P Ph2 HO

O

O

F

HO

F

14

Catalytic Enantioselective Reissert Reaction The catalytic enantioselective Reissert reaction is very useful for the synthesis of biologically active compounds containing N -heterocycles. The reaction requires the use of strong electrophiles such as acyl chlorides. In addition, TMSCl is generated during the course of the reaction when TMSCN is used as a cyanide source. Therefore, an asymmetric catalyst should be tolerant toward these strong electrophiles. The catalytic enantioselective Reissert reaction of quinolines was developed using BINOL-derived Lewis acid–Lewis base bifunctional catalyst 43 (Eq. 26).47,48 The use of 2-furoyl chloride and methylene chloride/toluene mixed

THE CATALYTIC ASYMMETRIC STRECKER REACTION

21

solvent gave the best results with the fewest side-products. In addition, ligand 43 containing di(o-tolyl)phosphine oxide as a Lewis base to activate TMSCN produced slightly improved enantioselectivity compared to the original bifunctional catalyst 6 containing diphenylphosphine oxide. Generally, quinolines containing electron-donating substituents resulted in higher yields and enantioselectivities as compared to those containing electron-withdrawing substituents. This tendency is consistent with the following results obtained from mechanistic studies: (1) the rate-determining step of the Reissert reaction is the catalyst-independent acyl quinolinium formation, and (2) the catalyst-independent background cyanation of an acyl quinolinium intermediate is faster for electron-deficient substrates. The reaction was conducted using the JandaJ EL-supported catalyst 44; the enantioselectivity, however, was slightly lower than with the soluble catalyst 43. The solid-supported catalyst 44 was recyclable and the aluminum was retained, although the enantioselectivity decreased with each run (from 86% ee in the first run using 44 to 64% ee in the fourth run). Z Z

W

Y X

43 (1-9 mol%), 2-furoyl chloride (2-4 eq), TMSCN (2-4 eq)

Y

CH2Cl2–toluene, –40°, 40-112 h

X

N R

W

N O O (57-99%) 67-96% ee

P(O)(tol-o)2 O Al Cl O

CN

(Eq. 26)

P(O)(tol-o)2 43: R = H 44: R = (CH2)3CH=CH(CH2)3OCH2–JandaJEL

Taking advantage of the multifunctionality of the quinolinium products, several subsequent useful transformations were possible. An enantiomerically enriched tetrahydroquinoline-2-carboxylate derivative 46 was synthesized from the Reissert product 45 via rhodium-catalyzed hydrogenation followed by hydrolysis and methyl esterification, without any loss of enantiopurity (Eq. 27). In addition, epoxidation of cyanoquinoline derivative 47 proceeded selectively from the side opposite to the nitrile (Eq. 28). After conversion of the nitrile to an amide, regioselective epoxide ring-opening with water using ceric ammonium nitrate (CAN) followed by cleavage of the N -furoyl amide produced functionalized tetrahydroquinoline 48 containing three contiguous stereocenters. 1. LiO2H, H2O–MeOH

H2, Rh/C N Ph

CN O

45

AcOEt 71%

N Ph

CN O

2. 6 N HCl 3. CH2N2

N CO2Me H 46 (58%) 3 steps

(Eq. 27)

22

ORGANIC REACTIONS O m-CPBA

CN

N

N

CH2Cl2, 15 h (71%)

O O

O CN

O

aq. H2O2, Na2CO3, (n-Bu)4HSO4

N

CH2Cl2, 1.5 h (62%)

O

O

47

O

OH

OH

OH

OH

sat. NH3

CAN (10 mol%) N

aq. MeCN, 1 h (66%)

CONH2

CONH2 O

i-PrOH, 40°, 6 h (73%)

N H 48

O

CONH2

(Eq. 28) The catalytic enantioselective Reissert reaction was applied to the synthesis of quaternary stereocenters by tuning the bifunctional catalyst (Eq. 29).49 To overcome the attenuated reactivity of substrate 49, catalyst 50 containing an enhanced Lewis acidity was developed. The Lewis acidity of aluminum in complex 50 should be higher than in the previous catalysts 6 or 43 due to the electronwithdrawing bromine substituents on the BINOL core and the electronegativity of the triflate anion. Excellent enantioselectivity was obtained from a number of highly substituted isoquinolines. The reaction was utilized as a key step in the catalytic asymmetric synthesis of several biologically active compounds (see “Applications to Synthesis”). R1 N

R1 R

50 (1-2.5 mol%), CH2=CHOCOCl (1.8 eq), TMSCN (2 eq) CH2Cl2, –40° to –60°, 48 h

49 Br

P(O)Ph2

R1 N

R1 R

O

CN O

(62-98%) 73-95% ee

(Eq. 29)

O Al OTf O P(O)Ph2

Br 50

Chiral piperidines are among the most important building blocks for biologically active compounds. The catalytic enantioselective Reissert reaction of pyridine derivatives can produce such chiral building blocks. An asymmetric catalyst prepared from Et2 AlCl and chiral ligand 51 in a 1 : 2 ratio promotes the enantioselective Reissert reaction of nicotinamide derivatives 54 with excellent regio- and enantioselectivity (Eq. 30).50 The electron-withdrawing amide functional group at the 3-position of the substrates is essential for high conversion and enantioselectivity, and the configuration of the sulfoxides at the 3,3
-positions of

THE CATALYTIC ASYMMETRIC STRECKER REACTION

23

the ligand is also critical for the observed high selectivity. The aluminum complexes derived from the C-2-symmetric ligands 52 and 53 are poor catalysts in terms of catalyst activity, enantioselectivity, and regioselectivity. On the basis of structural studies of the active catalyst using mass spectroscopy, a 2 : 3 complex of aluminum and ligand 51 is proposed to be the active enantioselective catalyst. Proper configurational matching between the axial chirality of the BINOL core and central chiralities of the two sulfoxides is essential for the stabilization of the active bimetallic catalytic species, and thus for the high regio- and enantioselectivity. Ligands 52 and 53 did not generate the corresponding 2 : 3 complexes. A different type of enantioselective bifunctional catalyst, generated from Et2 AlCl and phosphine sulfide-containing ligand 55 in a 1 : 1 ratio, was the optimal catalyst for slightly different substrates 56 containing a halogen substituent at the 4-position of the pyridine core (Eq. 31).50 O

Et2AlCl (5 mol%), 51 (10 mol%), FmocCl (1.4 eq), TMSCN (2 eq)

O NR2

CH2Cl2, –60°, 5 h

NC

N 54 R = Me or i-Pr

NR2

+ Z S Y OH OH + Z' S Y'

N Fmoc

(89-98%) 93-96% ee

51: Z, Y' = Ph; Z', Y = O– 52: Z, Z' = O–; Y, Y' = Ph 53: Z, Z' = Ph; Y, Y' =O –

(Eq. 30) X

O N(Pr-i)2

N 56 X = Cl or Br

Et2AlCl (10 mol%), 55 (10 mol%), neopentyl–OCOCl (1.4 eq), TMSCN (2 eq)

X

O N(Pr-i)2

N

NC

CH2Cl2, –60°, 27-36 h

t-Bu P(S)Ar2 OH OH

O

O

(89-92%) 86-91% ee

P(S)Ar2 55: Ar = 2-EtC6H4

(Eq. 31)

APPLICATIONS TO SYNTHESIS

The importance of catalytic enantioselective Strecker and Reissert reactions is demonstrated by their effective use in the synthesis of biologically active compounds. The catalytic enantioselective three-component Strecker reaction of aldehyde 57, aniline derivative 58, and HCN using 2.5 mol% of chiral zirconium catalyst

24

ORGANIC REACTIONS

38 produced the corresponding product 59 in 80% yield with 91% ee. This product was converted to D-pipecolic acid methyl ester (60) in three steps (Eq. 32).51 HO CHO

TBSO

HCN, 38 (2.5 mol%)

+

CH2Cl2, –45°

H2N

57

58

(Eq. 32)

HO NH HN TBSO

CO2Me 60

CN 59 (80%) 91% ee

Sorbinil (63) is a highly potent aldose reductase inhibitor, considered to be a pharmaceutical lead for the treatment of diabetic neuropathy.81 Sorbinil contains a spirohydantoin structure with a quaternary stereocenter. A concise catalytic enantioselective synthesis of sorbinil was achieved using the catalytic enantioselective Strecker reaction of ketimine 61 as the initial key step (Eq. 33).40 Product 62 was obtained in quantitative yield with 98% ee using 1 mol% of the gadolinium complex derived from ligand 14. Enantiomerically pure 62 was obtained through one recrystallization. Synthesis of 63 was completed in three steps from intermediate 62.

N F

O PPh2

Gd(OPr-i)3 (1 mol%), 14 (2 mol%), TMSCN (1.1 eq), 2,6-dimethylphenol (1 eq) F

EtCN, –40°, 83 h

O

O 61

O H N PPh2

NC

62 (100%) 98% ee (93%) >99% ee, recryst. from CHCl3-hexane HN F

O NH

O O 63

(Eq. 33)

Lactacystin (66) is a potent and selective proteasome inhibitor isolated from Streptomyces by Omura and coworkers.82 It contains a quaternary stereocenter in a highly substituted γ -lactam ring. Due to its challenging structure, many synthetic chemists have studied and achieved the total synthesis of lactacystin.83 – 85 The catalytic enantioselective Strecker reaction using a gadolinium catalyst was applied to construct the quaternary stereocenter (C-5) of lactacystin starting from N -phosphinoyl imine 64 (Eq. 34).86 The catalyst prepared from Gd[N(TMS)2 ]3 and ligand 14 in a 1 : 1.5 ratio gave the best results. The reaction was completed

THE CATALYTIC ASYMMETRIC STRECKER REACTION

25

in two days using 2.5 mol% of catalyst, and produced chiral product 65 in quantitative yield and 98% ee. The chiral catalyst prepared from Gd(O-Pr-i)3 and 14 in a 1 : 2 ratio as used in Eq. 33 produced less satisfactory results. Three of the other stereogenic centers (C-6, 7, and 9) of lactacystin, except for the one derived from cysteine, were controlled by the configuration of the quaternary stereocenter at C-5 with excellent stereoselectivity.

N

O PPh2

Gd[N(TMS)2]3 (2.5 mol%), 14 (3.75 mol%), TMSCN (2 eq), 2,6-dimethylphenol (1 eq) i-Pr

EtCN, –40°, 48 h

i-Pr

O H N PPh2

NC

64

65 (>99%) 98% ee HO2C

NHAc

(Eq. 34)

O NH

7 6

5

S O

9

Pr-i

HO HO 66

L-689,560 (70) is a potent NMDA (N -methyl-D-aspartate) receptor antagonist identified by the Merck group.87 The synthesis involved the catalytic enantioselective Reissert reaction of quinoline 67 using 1 mol% of aluminum catalyst 43 (Eq. 35).48 When the Reissert reaction was complete, intermediate enamine 68 was reduced in situ by subsequent addition of NaBH3 CN, AcOH, and MeOH. This one-pot catalytic enantioselective Reissert reaction–reduction protocol selectively (>20 : 1) produced 69, with the cyanide trans to the amine, in 91% yield and 93% ee. Subsequent functional group transformations and enantioenrichment by recrystallization furnished 70 in enantiomerically pure form. Solid-supported catalyst 44 was also utilized in the Reissert reaction of 67; the enantioselectivity was 86% ee using 3 mol% of 44. Cl Cl

N(allyl)2

CH2Cl2, –40°, 40 h Cl

N(allyl)2

43 (1 mol%), TMSCN (2 eq), 2-furoyl chloride (2 eq) Cl

N

N

CN O

67

O 68 Cl

N(allyl)2

NaBH3CN AcOH–MeOH

Cl

N O O 69 (91%) 93% ee

(Eq. 35)

O Cl HN

NHPh

N H

CO2H

CN Cl

70

26

ORGANIC REACTIONS

MK801 (dizocilpine, 73), which contains a quaternary stereocenter,88 is another highly potent NMDA receptor antagonist. The synthesis of this agent involved the catalytic enantioselective Reissert reaction of isoquinoline 71 using 2.5 mol% of the enantiomer of catalyst 50 (ent-50) to form 72 in 62% yield and 95% ee.49 Subjecting 72 to radical cyclization conditions using (n-Bu)3 SnH and AIBN produced the tetracyclic core. Synthesis of MK801 was completed through a series of functional group transformations (Eq. 36). ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)

N Br

N

O

CN O

CH2Cl2, –40°, 48 h

Br 71

72 (62%) 95% ee

(Eq. 36)

O O (n-Bu)3SnH

HN

N

AIBN 73

NC (85%)

Anticonvulsant phenytoin analogues 78 and 7989 were synthesized using the catalytic enantioselective Reissert reaction of compounds 74 and 75, respectively (Eq. 37).49 Thus, the Reissert reaction of these two substrates in the presence of catalyst ent-50 produced the corresponding products 76 and 77 with high enantioselectivity. These compounds were converted to the target molecules 78 and 79 through hydrogenation and hydrolysis of the nitrile.

N R 74: R = Me 75: R = Ph

ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)

N

CH2Cl2, 48 h

R

Temp –60° –40°

O

CN O

76: (88%) 89% ee 77: (95%) 95% ee

N R

(Eq. 37)

O

NH

O 78: R = Me 79: R = Ph

The catalytic enantioselective Reissert reaction of isoquinoline 80 was utilized as a key step for the synthesis of biosynthetic intermediate 8190 of a dopaminederived alkaloid salsolinol (Eq. 38).49 The Reissert reaction of 80 proceeded with excellent yield and enantioselectivity using ent-50 as the catalyst.

THE CATALYTIC ASYMMETRIC STRECKER REACTION

PhCO2

ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)

PhCO2

CH2Cl2, –60°, 48 h

PhCO2

N

PhCO2

27

O

N CN O (94%) 94% ee

80 HO + NH Cl– 2

HO

CO2H 81

(Eq. 38)

An asymmetric formal synthesis of a dopamine D4 − receptor-selective antagonist CP-293,019 (85)91 was achieved using the catalytic enantioselective Reissert reaction of pyridine derivative 82 as a key step (Eq. 39).50 The Reissert reaction of 82 using a catalyst derived from Et2 AlCl and a chiral sulfoxide-containing ligand 51 in a 1 : 2 ratio produced the corresponding product 83 in 98% yield with 91% ee. The known key intermediate 84 was synthesized from 83 in several steps.

NMe 2 N

O

Et2AlCl (5 mol%), 51 (10 mol%), MeOCOCl (1.4 eq), TMSCN (2 eq)

O

NMe 2

CH2Cl2, –60°, 5 h

NC

N Fmoc 83 (98%) 91% ee

82

F OH

O

N

N

BocN

N

N 84 F

N

85

(Eq. 39)

COMPARISON WITH OTHER METHODS

Due to the importance of α-amino acids in a variety of fields, a number of excellent stereoselective methods have been developed for their synthesis.1 – 6 As shown in Scheme 2, there are mainly four types of retrosynthetic bond disconnection. Any non-stereoselective reactions for the synthesis of α-amino acids can theoretically be extended to asymmetric synthesis using the chiral auxiliary method. Asymmetric synthesis of α-amino nitriles through the chiral auxiliary method is the main focus of this section. However, given the importance of and current emphasis on developing catalytic enantioselective reactions, three other types of catalytic enantioselective methods for chiral α-amino acid synthesis are also discussed in some detail.

28

ORGANIC REACTIONS

alkylation Mannich-type reaction etc.

R1 H2N

hydrogenation (R2 = H)

R2 CO2H

amination

Strecker reaction

Scheme 2

Chiral Auxiliary-Controlled Asymmetric Strecker Reaction It is possible to control the stereochemistry of the Strecker reaction by introducing a chiral auxiliary to the amine moiety of substrates. There are two main features of this methodology: (1) the diastereoinduction is reliable and predictable, and (2) the enantiomeric purity of the target compounds can be easily enriched through separation of the intermediate diastereomers even if the initial stereoselectivity is not completely satisfactory. Disadvantages of the chiral auxiliary method are that a stoichiometric amount of a chiral source is always required, and that chiral auxiliaries normally decompose during the deprotection of the nitrogen atom to obtain final target amino acids. Therefore, the use of inexpensive chiral auxiliaries is essential. Imines derived from 1-phenylethylamine (or its analogues)81,92 – 105 and chiral N -sulfinyl imines106 – 111 are two representative chiral substrates used in the asymmetric Strecker reaction. The diastereoselectivity of 1-phenylethylamine-derived imines is normally moderate (ca. 1.5 : 1 to 4 : 1),93,94,95,100 with some exceptions. When high diastereoselectivity was obtained (Eq. 40), reversible cyanide addition occurred concomitantly with fractional crystallization.81 The desired diastereomer 87 was obtained from 86 as a single isomer in 82% yield. The product is a key synthetic intermediate of an aldose reductase inhibitor. N

Ph HCN, EtOH, 0°

F

F

Ph

O 86

H N

NC

(82%) single isomer

O 87

(Eq. 40)

Chiral N -sulfinyl ketimines afford high diastereoselectivity in the Strecker reaction (Eq. 41).108 The chiral auxiliary is removed under acidic conditions, and α,α-disubstituted amino acid derivatives are obtained with high enantiomeric purity.

THE CATALYTIC ASYMMETRIC STRECKER REACTION

p-Tol

O S

Et2AlCN (1.5 eq), i-PrOH (1 eq)

N

p-Tol

THF, –78°

O S

NH

t-Bu

Bu-t

29

(95%) 99:1

CN

(Eq. 41) To highlight the utility of the chiral auxiliary-controlled method, two recent examples of the asymmetric Strecker reaction of trifluoromethyl ketone-derived imines are described. A diastereoselective Strecker reaction of chiral oxazolidine 88 containing a phenylglycinol auxiliary proceeded with moderate to low selectivity in the presence of 1.5 eq of BF3 •OEt2 (Eq. 42).112 The resulting diastereomers 89 and 90 were separable by silica gel column chromatography. The diastereomerically pure 89 was converted to trifluoromethylalanine hydrochloride (91) through acid hydrolysis in 60% yield.

HN CF3

Ph

TMSCN (1.5 eq), BF3•OEt2 (1.5 eq)

Ph

CH2Cl2

O

HN CF3

88

OH

HN +

CN 89

89

Ph OH

CF3

(91%) 89:90 = 54:46

CN 90

NH2•HCl

conc. HCl, reflux, 14 h CF3

CO2H

91 (60%)

(Eq. 42)

Highly diastereoselective Strecker reactions of trifluoromethyl-substituted N -sulfinyl imine 92 have been reported (Eq. 43).113 Imine 92 can be synthesized through condensation between trifluoromethylketones and the corresponding enantiomerically pure sulfonamide in the presence of an excess amount (1.5 eq) of Ti(OPr-i)4 .114,115 Trifluoromethyl-substituted sulfinyl amides 92 are not very stable, and should be generated and purified quickly prior to use. The diastereoselectivity of this Strecker reaction was strongly dependent on the solvent. When non-coordinating hexane was used as a solvent, isomer 93 was obtained as the major diastereomer. However, the other isomer 94 was the major product when highly coordinating DMF was used as a solvent. The authors attributed this dramatic solvent effect to the switch of the transition state from cyclic (in hexane) to acyclic (in DMF). In hexane, the oxygen atom of the sulfinyl amide acts as a Lewis base to activate TMSCN. On the other hand, the oxygen atom of DMF activates TMSCN, thus liberating the oxygen atom of the sulfinyl amide from coordination to silicon. Isolated diastereomer 94 was converted to amino acid 95 via acid hydrolysis. Currently, there is no

30

ORGANIC REACTIONS

catalytic enantioselective Strecker reaction that is effective with trifluoromethylsubstituted aldimines and ketimines. Therefore, the diastereoselective methods are the only asymmetric approaches to access chiral trifluoromethyl-substituted amino acids. O S

N CF3

TMSCN

Bu-t

HN

(69-92%)

R 92

O S

R

HN

Bu-t +

CN CF3

CF3

93

Solvent Temp hexane rt DMF –35°

R

O S

Bu-t

CN 94

(Eq. 43)

93:94 = 7:1 to 99:1 93:94 = 1:6 to 1:19 NH2

conc. HCl 94

CF3

CO2H R 95 R = Ph

(80%)

Catalytic Asymmetric Hydrocyanation of Hydrazones Hydrazones can be considered to be stable surrogates for imines. Despite the existence of several examples of racemic cyanation of hydrazones,116,117 including a Lewis acid catalyzed reaction,118 there is only one catalytic enantioselective variant reported (Eq. 44).119 An ErCl3 –PhPyBox (96) complex was used as an asymmetric catalyst (5 mol%). Hydrazones derived from aromatic aldehydes afforded high enantioselectivity (76–97% ee). Aliphatic substrates and ketone-derived hydrazones, however, produced only moderate enantioselectivity. O N R1

O

Ph NH

96 (5 mol%), TMSCN (2 eq) MeOH (2 eq), CHCl3, 0°

R2

HN Ph NC NH R1

O

96

(Eq. 44)

O

N N ErCl3

Ph

R2

(85-100%) 31-97% ee

N Ph

Catalytic Asymmetric Hydrogenation Asymmetric hydrogenation of dehydroamino acids 97 by chiral rhodium or ruthenium catalysts is one of the most general and reliable methods for the synthesis of α-amino acid derivatives (Eq. 45). Because this reaction is fundamental

THE CATALYTIC ASYMMETRIC STRECKER REACTION

31

and has been extensively reviewed,120 – 128 it will not be discussed here in detail. Excellent catalyst turnover rates, catalyst turnover numbers, and enantioselectivities are generally obtained. This method is used practically for large-scale syntheses of chiral α-amino acids. α,α-Disubstituted amino acids, however, cannot be synthesized using this method. CO2R1

R

NHCOR2 97

chiral catalyst + H2

R

1 * CO2R

NHCOR2

(Eq. 45)

A potentially important but much less studied catalytic asymmetric hydrogenation route to chiral α-amino acids is the reductive amination of α-keto acids 98. A catalytic enantioselective hydrogenative amination of 98 in the presence of N -benzylamine and 1 mol% of a chiral rhodium complex derived from 99 proceeded with moderate to excellent enantioselectivity (Eq. 46).129 The reaction conditions were tolerant of the carboxylic acid functional group.

O R

CO2H 98

+ BnNH2

[Rh(COD)2]BF4 (1 mol%), 99 (1.1 mol%), H2 (60 bar) MeOH, rt, 3-24 h

NHBn R

CO2H

(19-99%) 19-98% ee

PPh2 BnN PPh2 99

(Eq. 46)

Catalytic Asymmetric Introduction of the Side Chain through C–C Bond Formation Asymmetric Phase-Transfer-Catalyzed Reactions. The asymmetric alkylation of glycine-derived Schiff base ester 100 using chiral phase-transfer catalysis is an alternative approach to chiral α-amino acids.5,130,131 Phase-transfer catalysis generally offers the following advantages: (1) mild reaction conditions, (2) simple reaction procedures, and (3) the use of safe and inexpensive reagents and solvents. Thus, the reaction can be easily conducted both on small and large scales. Chiral phenylglycine derivatives, however, cannot be synthesized using the phase-transfer methodology. Since the first report of catalytic enantioselective alkylation of 100 using cinchona alkaloid-derived phase-transfer catalyst 101,132 the efficiency has been significantly improved by modifying the catalyst structure (Eq. 47). Specifically, N -9-anthracenylmethyl catalyst 102133,134 and a catalyst containing two cinchona alkaloid moieties (103)135 are highly effective asymmetric catalysts.

32

ORGANIC REACTIONS Ph N Ph

Ph

catalyst CO2Bu-t

N

R-X, base

Ph

100 R = Bn Catalyst mol% Solvent Temp 101 rt CH2Cl2 10 102 –78° 10 CH2Cl2 103 1 toluene-CH2Cl2 0° 104 0° 0.2 toluene

H

+ N Br– R1 OR2

Time 9h 23 h 10 h 12 h

CO2Bu-t R

Yield (75%) (87%) (95%) (81%)

% ee 64 94 97 98

101: R1 = benzyl, R2 = H 102: R1 = 9-anthracenylmethyl, R2 = allyl 103: R1 =

(Eq. 47)

, R2 = allyl

N Ar Br – N+

Ar 104: Ar = 3,5-Ph2C6H3 105: Ar = 3,4,5-F3C6H2

The most useful asymmetric phase-transfer catalysts in terms of enantioselectivity, substrate generality, and catalyst activity are the binaphthyl-derived quaternary ammonium salts 104 and 105.136,137 It is noteworthy that the method can be applied to a catalytic asymmetric synthesis of α,α-dialkyl-substituted amino acids using sterically less crowded prenucleophile 106 (Eq. 48). The absolute configuration of the quaternary stereocenter can be controlled by the order of addition of the alkylating reagents. Br (1 eq), CsOH•H O (5 eq), 2 toluene, –10°, 3.5 h 2. PhCH2Br (1.2 eq), 0°, 30 min 1.

Ar

N

CO2Bu-t

106 + 105 (1 mol%) Ar = 4-ClC6H4

H2N

CO2Bu-t Ph

3. 10% citric acid (80%) 98% ee

(Eq. 48) Asymmetric Allylic Substitution Catalyzed by Chiral Transition Metal Complexes. The catalytic asymmetric allylic substitution by azlactone 107

THE CATALYTIC ASYMMETRIC STRECKER REACTION

33

produces enantiomerically enriched precursors of α,α-disubstituted amino acids. Two kinds of constitutional isomers can be formed selectively, depending on the asymmetric catalyst used (Eqs. 49 and 50). Using the palladium catalyst containing chiral diphosphine ligand 108, substitution occurs at the C-1 position having the acetoxy leaving group.138,139 Using a molybdenum catalyst derived from ligand 109, the substitution occurs at C-3.140 High enantio- and diastereo selectivities are obtained in both reactions. The product azlactone was solvolyzed in basic methanol to give the amino acid derivative 110 in quantitative yield.

Ph

1

2

OAc

[Pd(η3-C3H5)Cl]2 (2.5 mol%), 108 (7.5 mol%), NaH (2 eq)

O

OAc

3

+ R

O

DME, 0° to rt, 2-24 h

N

OAc O O

Ph R N

Ph 107 (2.25 eq) R = alkyl

Ph (60-91%) 83-99% ee dr = 4.4:1 to >19:1 O

O NH

HN

PPh2 Ph2P 108

OCO2Me + 1

3

Ar

2

C7H8Mo(CO)3 (10 mol%), 109 (15 mol%), NaH (2 eq)

O R

(Eq. 49)

O

Ar

O

THF, 65˚, 3-6 h

N

O

R N

Ph 107 (2.25 eq) R = alkyl

Ph (76-92%) 85-99% ee dr = 97:3 to >98:2 Ar

K2CO3, MeOH

R

O

O

OMe NH2 110

(100%)

O NH HN

N

N 109

(Eq. 50)

An asymmetric allylic substitution by zinc enolates (such as 111) derived from N-protected glycine esters catalyzed by a chiral palladium complex and ligand 112 has been reported (Eq. 51). The substrate generality of this reaction is not very broad.141

34

ORGANIC REACTIONS OCO2Me

+

Ph

Ph

CF3OCN Zn O

[Pd(η3-C3H5)Cl]2 (1.2 mol%) OBu-t

112 (3 mol%), THF

CF3CONH

CO2Bu-t

Ph Ph (62%) 94% ee dr = 95:5

111 O N

PPh2

112

(Eq. 51)

Catalytic Asymmetric Addition to Imino Esters. Imino esters (113, 118, or 121) are reactive electrophiles, and they have been used in various catalytic asymmetric carbon–carbon bond-forming reactions (e.g. the Mannich-type reactions) using diverse nucleophiles. Enol silyl ethers react with 113 in the presence of the chiral cationic palladium catalyst 116 with high enantioselectivity (Eq. 52).142 The binuclear µ-hydroxo complex 116 was prepared from ˚ the mononuclear dicationic palladium complex 114 through treatment with 4 A molecular sieves in acetone. The dicationic complex 114 did not induce any enantioselectivity in the Mannich-type reaction shown in Eq. 52. This reaction was recently extended to the direct addition of β-ketoesters to imino esters using dicationic 115 as an asymmetric catalyst (Eq. 53).143 Interestingly, binuclear complex 117 was an unsatisfactory catalyst for this reaction. A three-component reaction involving a glyoxalate, an amine, and a β-ketoester was also reported in which the enantioselectivity was high, but the diastereoselectivity was moderate. Similarly, addition of nitroalkanes was developed with high diastereo- and enantioselectivity from imino ester 113 using cationic copper (II)–chiral bisoxazoline complexes.144,145

N i-PrO2C

Ar + H

113 Ar = 4-MeOC6H4

2

OTMS

116 (3-5 mol%), DMF

R

28°, 17-24 h

2 eq

Ar Ar OH2 4 Å MS P Pd ++ 2 BF4– acetone P Ar OH2 –2 H2O, –2 BF4– Ar 114: Ar = p-TolC6H4 115: Ar = Ph

Ar

NH O

i-PrO2C R (62-95%) 53-90% ee 2 BF4– Ar Ar Ar H Ar P P O Pd+ Pd+ O P P Ar H Ar Ar Ar 116: Ar = p-TolC6H4 117: Ar = Ph

(Eq. 52)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

N EtO2C

Ar

CO2Bu-t

+ Ac

H

Ar

115 (5 mol%) THF, rt, 35 h

NH CO2Bu-t

EtO2C

Ar = 4-MeOC6H4

35

Ac

(70%) 86% ee/55% ee dr = 74:26

(Eq. 53)

N -Acyl imino esters 118 can be synthesized through elimination of HBr from the corresponding 2-bromoglycine derivative using a polymer-supported amine. The chiral copper(II) triflate–diamine complex 119 catalyzed the asymmetric addition of enol silyl ethers (Eq. 54),146,147 alkyl vinyl ethers,145 and acyl enamides148 to 118. Reactions using propionate-derived enol silyl ethers also proceeded with high enantio- and diastereoselectivity. Syn-isomer 120 was produced from both E- and Z-enolates. The catalytic asymmetric Mannich-type reactions149 and allylation reactions150 proceeded in aqueous media (H2 O/THF = 1 : 9) using more stable N -acylhydrazono esters as substrates. A combination of zinc fluoride (50 mol%), chiral diamine (related to 119), and triflic acid (1 mol%) was used as the catalyst. The hydrazine moiety of the products was converted to the amine by reduction with samarium diiodide.

N

+

R1 O

R2OC

COR2

OTMS R3

R4

Cu(OTf)2–119 (10 mol%) CH2Cl2, 0° to –78°, 12-18 h

O 118 Ph

Ph

NH O

R 1O

R4

R3 O 120 (44-97%) 42-96% ee

NH HN 119

(Eq. 54)

N -Tosylimino esters 121 should be more electrophilic than N -acylimino esters, considering the strong electron-withdrawing ability of the tosyl group. The chiral cationic copper(I) complex derived from Tol-BINAP and copper(I) perchlorate is a useful asymmetric catalyst for Mannich-type reactions using enol silyl ethers, ene reactions using alkenes, and allylation reactions using allylsilanes and substrate 121.151 More recently, a catalytic asymmetric Staudinger-type β-lactam formation (Eq. 55) was reported.152 A ketene generated in situ from an acid chloride and proton sponge was nucleophilically activated by benzoylquinine (122). Addition of 10 mol% of indium triflate, acting as a Lewis acid to activate imine 121, dramatically accelerated the reaction without affecting the excellent diastereo- and enantioselectivity.

36

ORGANIC REACTIONS

N

Ts

Cl

122 (10 mol%), In(OTf)3 (10 mol%), proton sponge (1 eq)

O

+

EtO2C

toluene, –78°, 16 h

R

O N

EtO2C R (91-98%) 96-98% ee dr = 9:1 to 60:1

1 eq

121

Ts

OMe

(Eq. 55)

N N OBz 122

Organocatalysts can promote direct asymmetric Mannich-type reactions of ketones or aldehydes to imino esters.153 – 163 Generally, proline-catalyzed or dinuclear zinc-catalyzed164 direct asymmetric Mannich-type reactions between imino esters and α-substituted ketones or aldehydes result in syn products with excellent diastereo- and enantioselectivity. Through logical consideration of the transition state structure, an anti-selective direct asymmetric Mannich-type reaction between imino esters and aldehydes producing 124 was developed using 3-pyrrolidinecarboxylic acid derivative 123 as a catalyst (Eq. 56).165 N

Ar

Ar

CHO

+

DMSO

R

EtO2C Ar = 4-MeOC6H4

NH O

123 (1-5 mol%)

2 eq CO2H

EtO2C

H R 124 (57-92%) 97 to >99% ee dr = 95:5 to 98:2

(Eq. 56)

N H 123

The organocatalyzed direct asymmetric Mannich-type reaction was extended to the synthesis of quaternary stereocenters using a special keto imino ester 125 as a substrate (Eq. 57).166 The proline-derived diamine 126 produced high diastereoand enantioselectivity in the reactions between 125 and aldehydes. O O R1

O N CO2Et

CHO

+ R

126 (5 mol%)

O R1

Et2O, 0°, 20 h

R2

R2 R3

125

2 eq

NH CO2Et CHO R

(Eq. 57)

R3 N H

N

(72-99%) 83-98% ee dr = 4:1 to >20:1

126

The catalytic enantioselective nucleophilic alkylation of imino esters is much less studied than Mannich-type reactions. N -Benzyloxycarbonyl (Cbz) imino esters

THE CATALYTIC ASYMMETRIC STRECKER REACTION

37

127 can react with electron-rich aromatic compounds through a Friedel-Crafts type alkylation under the catalysis of a cationic copper(I)-chiral phosphine complex (Eq. 58).167,168 This reaction directly generates enantiomerically enriched N -Cbzprotected α-aryl amino esters, which are common intermediates for peptide synthesis. Catalytic enantioselective addition of dialkylzinc to imino esters has been recently reported.169 The enantioselectivity, however, was in the moderate range. O N

EDG OBn

+

CuPF6-(R)-Tol-BINAP (5-20 mol%)

Cbz

CH2Cl2 or THF, –78°

EtO2C

NH

EDG

(Eq. 58)

EtO2C EDG = electron donating group

127

(44-88%) 52-98% ee

Oxazole as a Glycine Enolate Equivalent. Oxazole derivatives can be utilized as a glycine enolate equivalent.170,171 Two catalytic enantioselective variants have been reported. First, the chiral nucleophilic pyridine derivative 128 catalyzed the enantioselective rearrangement of O-acylated azlactone 129 to α,α-disubstituted amino acid derivatives 130 with excellent enantioselectivity and broad substrate generality (Eq. 59).172 The products were directly converted to protected dipeptides (e.g., 131) in high chemical yield. Second, chiral aluminum catalyst 132 promoted the addition of 133 to aromatic aldehydes in the presence of a catalytic amount of lithium perchlorate, and the subsequent one-pot rearrangement of 134 afforded cis-β-hydroxy-α-amino acid derivatives 135 with excellent diastereo- and enantioselectivity (Eq. 60).173 When R=H, the products were isomerized to trans-136 by treatment with 5% 1,8-diazabiclo[5.4.0]undec7-ene (DBU), allowing for the synthesis of both syn- and anti-β-hydroxy-α-amino acid derivatives. In addition, application to α,α-disubstituted amino acid synthesis was possible using a dicationic copper-bisoxazoline complex as a catalyst and methyl-substituted 137 as a nucleophile. O BnO R

O

O

128 (2 mol%), t-amyl alcohol 0°, 2-6 h

O

N Ar 129 Ar = 4-MeOC6H4

O

BnO

O R N Ar

H2N

CO2Me

130 (93-95%) 88-91% ee O BnO2C N CO2Me R NH H COAr 131 (95%) R = Me

N N

128

Fe

(Eq. 59)

38

ORGANIC REACTIONS MO R Ar'

N

3 Å MS, toluene, rt, 20 h

OMe

O

Ar

132 (5-10 mol%), LiClO4 (20 mol%)

N

ArCHO +

Ar'

133: R = H 137: R = Me Ar' = 4-MeOC6H4 N

CO2Me

R O Ar 135: R = H (58-100%) 91 to >99% ee dr = 73:27 to >99:1

OMe O + 134 M = metal

N

5% DBU

Ar'

R

CO2Me

Ar'

R=H

O

Ar 136

t-Bu

Bu-t N + O Al O N

SbF6– Bu-t

132

t-Bu

(Eq. 60)

Catalytic Asymmetric Electrophilic Amination of Enolates Azodiacarboxylates are excellent nitrogen electrophiles in catalytic asymmetric amination of enolate derivatives. Direct organocatalytic asymmetric α-amination of aldehydes has been reported (Eq. 61).174 – 176 Excellent enantioselectivity is achieved from a wide range of aldehydes using L-proline as catalysts. The products are converted to amino acid derivatives by oxidation of the aldehyde and reduction of the hydrazine using Raney nickel. The proline-catalyzed asymmetric amination of aldehydes was applied to the syntheses of biologically active pharmaceutical leads.177,178

R1 O2 C

N N

CO2R1

CHO

+ R

L-proline (10 mol%)

CH2Cl2, rt

R1O2C 1

R O2C

NH CHO N

R (57-92%) 89-95% ee

1.5 eq

1. KMnO4 2. TMSCHN2 3. TFA 4. H2, Raney Ni 5. Boc2O, DMAP

R1O2C

H N

CO2Me R

(Eq. 61)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

39

Chiral cationic copper(II)–bisoxazoline complex 138 catalyzes a general and highly enantioselective α-amination of α-substituted β-ketoesters (Eq. 62).179 – 181 Enantiomerically enriched α,α-disubstituted amino acid derivatives can be synthesized using this reaction. An asymmetric organocatalyzed synthesis of quaternary stereocenters is also possible using α-cyanoacetates as nucleophilic substrates.182,183

N N

O

CO2Bn

BnO2C 1.2 eq

+

O

R1

OR3 R2

Cu(OTf)2 (0.2-0.5 mol%), 138 (0.2-0.5 mol%)

BnO2C

CH2Cl2, 16 h

BnO2C

O

O N Ph

138

NH CO2R3 N

COR1 R2 (70-98%) 87-99% ee

N Ph

(Eq. 62)

EXPERIMENTAL CONDITIONS

Toxicity of Cyanide Compounds Cyanide compounds (TMSCN, HCN, and KCN) used in the Strecker reaction are highly toxic, and should be handled very carefully in a well-ventilated hood.184 The toxicity of cyanide is attributed to its extremely high affinity to the iron(III) ion of the mitochondrial cytochrome oxidase enzyme (50% inhibitory concentration = 10−8 M). Through the inhibition of this enzyme, the reduced form of cytochrome c, a key electron transporting membrane protein, cannot be converted to the oxidized form, and the respiratory system of cells is blocked. The fatal concentration of HCN for humans after 10 minutes of exposure is 0.2 mg/L, and concentrations over 0.3 mg/L cause instantaneous death. To prevent any exposure to cyanide, use of appropriate personal protective equipment (gloves, eye glasses, respirator, and HCN gas detector) is indispensable. All solutions containing cyanide should be kept and treated under basic pH. The cyanide waste should be discarded by a special facility, or after oxidative treatment with sodium hypochlorite solution (available chlorine >5%) overnight. If the latter method is used, the remaining cyanide concentration in the treated waste solution should be confirmed by commercial CN− test paper to be below the detection limit before that solution is discarded. Isolation of Amino Acids Due to their high polarity, free amino acids synthesized after acid hydrolysis of the Strecker products are generally difficult to isolate and purify using silica gel column chromatography. Taking advantage of the ionic feature of amino acids, however, they can be isolated relatively easily using ion-exchange column chromatography.40 The crude mixture after acid hydrolysis of the Strecker products usually contains the target amino acid, a residue derived from the nitrogen protecting group, and ammonium chloride. This mixture is loaded onto an acidic

40

ORGANIC REACTIONS

resin (such as acidic Dowex), and the non-charged organic byproduct derived from the nitrogen protecting group is first eluted using methanol. Next, the target amino acid is eluted from the column as the corresponding ammonium salt by changing the eluent to aqueous ammonia. During evaporation of the eluent, the ammonia that is generated through equilibration of the weak acid (carboxylic acid) with the weak base (ammonia) salt is eliminated. Thus, the free amino acid can be obtained. EXPERIMENTAL PROCEDURES

Preparation of the catalysts referred to in the preceding text and in the experimental procedures may be found by consulting information within references cited. O H

+

NH2

N

3 Å MS

(—)

H

t-Bu

t-Bu

Allyl-(4-tert-butyl benzylidene)amine [General Procedure for Preparation of Simple Amine-Derived Aldimines].33 To a flame-dried 50-mL round˚ molecular sieves (2 g) and CH2 Cl2 bottom flask, were added activated 3 A (20 mL, freshly distilled from CaH2 ). To this solution, the substrate benzaldehyde (20 mmol) was added followed by a syringe addition of allylamine (1.3 eq, 26 mmol). After 4 hours, the sieves were removed by filtration and washed with CH2 Cl2 (2 × 10 mL). The filtrate was collected and the solvent was removed in vacuo. Further purification was accomplished by vacuum distillation to yield the target aldimine. IR (thin film) 2955, 1650, 1462, 1372 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 8.28 (s, 1H), 7.71 (d, J = 10.4 Hz, 2H), 7.45 (d, J = 10.4 Hz, 2H), (s, 1H), 6.06 (ddd, J = 5.6, 10.3, 17.1 Hz, 1H), 5.24 (dappq, J = 1.5, 17.1 Hz, 1H), 5.16 (dappq, J = 1.5, 10.3 Hz, 1H), 4.26 (dappq, J = 1.5, 5.6 Hz, 2H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl3 ) δ 161.7, 153.9, 135.9, 133.4, 127.9, 125.4, 115.6, 63.4, 34.7, 31.1; HRMS (m/z): [M+ ] calcd for C14 H19 N, 201.1517; found, 201.1528.

O i-Pr

N

1. pyridine, NH2OH•HCl, 4˚ 2. 60°, 12 h

i-Pr

OH

Ph2PCl, Et3N –40° to rt

(79%)

N

O PPh2 (55%)

i-Pr 64

N -(2-Isopropylcyclopent-2-en-1-ylidene)-P,P-diphenylphosphinic Amide [General Procedure for Preparation of N-Phosphinoyl Ketimines].39,52,86 Pyridine (20.8 mL, 0.26 mol) and hydroxylamine hydrochloride (16.8 g, 0.24 mol) were added to the starting ketone (20 g, 0.16 mol) in EtOH (268 mL)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

41

at 4◦ . After stirring for 15 minutes at 4◦ , the reaction mixture was warmed to 60◦ and stirred for 12 hours. Concentration and purification by flash column chromatography (EtOAc/hexane = 1 : 10 to 1 : 5) afforded the corresponding oxime (17.7 g, 79%) as a white solid. To a solution of Et3 N (18.4 mL, 0.13 mol) and the oxime (16 g, 0.12 mol) in CH2 Cl2 (96 mL) and hexane (96 mL), chlorodiphenylphosphine (27.1 g, 0.13 mol) in CH2 Cl2 (38 mL) was added slowly over 1 hour at −40◦ . The reaction mixture was warmed gradually to room temperature, CH2 Cl2 (100 mL) was added, and the insoluble salt was removed by filtration through a celite pad. The filtrate was concentrated in vacuo. The solid residue was purified by flash column chromatography (CH2 Cl2 /MeOH = 50 : 1 to 20 : 1; EtOAc/MeOH = 20 : 1) to afford the target ketimine (37.4 g) as a white solid. Toluene (75 mL) was added to 64 (37.4 g) and the solution was warmed to 70◦ , at which point hexane (75 mL) was added. The solution was gradually cooled to room temperature, and the resulting precipitate was collected by filtration to afford pure title compound (25.7 g, total yield 55%) as a white solid, mp 133–134◦ ; IR (neat) = 2959, 1634, 1609, 1192 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 7.89–7.94 (m, 4H), 7.36–7.43 (m, 6H), 6.99–7.00 (m, 1H), 2.95–2.97 (m, 2H), 2.86 (sept, J = 7.0 Hz, 1H), 2.50–2.51 (m, 2H), 1.16 (d, J = 7.0 Hz, 6H); 13 C NMR (125 MHz, CDCl3 ) δ 194.2 (d, J = 4.9 Hz), 154.2, 154.1, 152.1, 135.7, 134.7, 131.5, 131.5, 131.4, 131.4, 131.1, 131.1, 128.3, 128.3, 128.2, 128.2, 34.3 (d, J = 4.9 Hz), 29.4, 25.3, 21.5; 31 P NMR (CDCl3 ) δ 20.7; LRMS–FAB (m/z): 324 [M + H]+ ; HRMS–FAB (m/z): [M + H]+ calcd for C20 H23 NOP+ , 324.1512; found, 324.1524. MesSO2NH2, p-TolSO2Na

O H

HCO2H, H2O, rt, 12 h (Mes = 2,4,6-Me3C6H2)

HN

SO2Mes NaHCO3 SO2Tol-p

(96%)

N

SO2Mes H

(67%)

Cyclohexanecarboxaldehyde N-(Mesitylenesulfonyl)imine [General Procedure for Preparation of N-Sulfonyl Imines].58,68 A mixture of cyclohexanecarboxaldehyde (363 µL, 3.0 mmol), mesitylenesulfonamide (598 mg, 3.0 mmol) and sodium p-toluenesulfinate (481 mg, 3.0 mmol) in HCO2 H (4.5 mL) and H2 O (4.5 mL) was stirred for 12 hours at room temperature. The resulting white precipitate was filtered off, and washed with H2 O and hexane. The precipitate was then recrystallized from EtOAc/hexane to obtain the intermediate N -(mesitylenesulfonyl)-α-(p-toluenesulfonyl)cyclohexylmethylamine (301 mg, 2.01 mmol, 67%) as a crystalline material; IR (thin film) 3401, 3285, 3028, 2928, 2855, 1599, 1566, 1450, 1331, 1302, 1155, 1123, 1082, 903, 853, 814, 733 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.52 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 6.81 (s, 2H), 5.27 (d, J = 10.7 Hz, 1H), 4.53 (dd, J = 3.0, 10.7 Hz, 1H), 2.50–2.40 (m, 1H), 2.42 (s, 6H), 2.34 (s, 3H), 2.29 (s, 3H), 2.11 (d, J = 12.3 Hz, 1H), 1.81–1.60 (m, 4H), 1.38–1.28 (m, 2H), 1.19-1.02

42

ORGANIC REACTIONS

(m, 3H); 13 C NMR (100 MHz, CDCl3 ) δ 144.4, 141.7, 137.5, 135.7, 134.2, 131.6, 129.3, 128.3, 77.5, 37.5, 30.7, 27.2, 26.2, 25.8, 25.7, 22.9, 21.7, 21.0. The sulfonamide sulfone obtained above (901 mg, 2.01 mmol) was dissolved in CH2 Cl2 (2 mL). Then, saturated aqueous sodium bicarbonate solution (1 mL) was added and the mixture was stirred for 1 hour. Phases were separated and the aqueous phase was extracted with CH2 Cl2 . The combined organic phase was dried over sodium bicarbonate and concentrated under vacuum to yield the target imine (566 mg, 1.93 mmol, 96%); IR (thin film) 3026, 2930, 2853, 1624, 1603, 1566, 1450, 1319, 1155, 1057, 853, 797, 777, 750 cm−1 ; 1 H NMR (400 MHz, CD2 Cl2 ) δ 8.40 (d, J = 4.0 Hz, 1H), 6.98 (s, 2H), 2.58 (s, 6H), 2.43 (m, 1H), 2.31 (s, 3H), 1.88-1.66 (m, 5H), 1.38–1.20 (m, 5H); 13 C NMR (100 MHz, CD2 Cl2 ) δ 179.8, 143.7, 140.4, 132.1, 131.9, 44.0, 28.9, 26.2, 25.6, 23.1, 21.2; HRMS–ESI–TOF (m/z): [M + H]+ calcd for C16 H24 NO2 S, 294.1522; found, 294.1522. O N

t-Bu

CF3

1. 28 (2 mol%), HCN, –70° H

2. (CF3CO)2O

N

(89%) 97% ee CN

t-Bu

N-allyl-N-((4-tert-butylphenyl)(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Urea-Based Catalyst].33 In a flame-dried 5-mL round-bottom flask equipped with a stirring bar, catalyst 28 (5 mg, 2 mol%, 0.008 mmol) and toluene (1.6 mL) were combined. The substrate (0.4 mmol, 200 mM final concentration) was added by syringe. The reaction mixture was stirred at ambient temperature until the catalyst completely dissolved. The reaction flask was cooled to −70◦ by means of a constant temperature bath and then a toluene solution of HCN (1.54 M, 340 µL, 0.52 mmol, 1.3 eq) was added slowly by syringe. After 20 hours, the reaction mixture was left to warm to ambient temperature and quenched with trifluoroacetic anhydride (103 µL, 0.73 mmol, 1.5 eq). The solvents were removed under vacuum and the resulting residue was purified by flash chromatography (hexanes/CH2 Cl2 = 3 : 2) to afford the Strecker adduct as a clear oil (89% yield, 97% ee); HPLC (Chiralcel AD, 0.6% i-PrOH/hexane, 1 mL/min) tr = 9.0 min (major), tr = 11.4 min (minor); [α]23 D −61.4◦ (c 1.0, CH2 Cl2 ); IR (thin film) 2966, 1704, 1213, 1154 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.47 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.60 (s, 1H), 5.69 (m, 1H), 5.21 (d, J = 10.4 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 4.16 (dd, J = 4.7, 17.0 Hz, 1H), 3.92 (dd, J = 6.2, 17.0 Hz, 1H), 1.33 (s, 9H); 13 C NMR (100 MHz, CDCl3 ) δ 157.7 153.5, 131.2, 127.7, 127.0, 126.3, 120.1, 117.4, 115.4, 49.5, 48.4, 34.7, 31.1; HRMS (m/z): M+ calcd for C17 H19 F3 N2 O, 324.1449; found, 324.1436.

THE CATALYTIC ASYMMETRIC STRECKER REACTION

N

SO2Mes

HN

33 (1 mol%), 2 M aq. KCN (1.5 eq) H

SO2Mes CN

toluene–H2O, 0°

43

(89%) 95% ee

N-(Mesitylenesulfonyl)-α-(cyano)cyclohexylmethylamine [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Phase-Transfer Catalyst].68 A mixture of the starting imine (58.7 mg, 0.20 mmol), chiral ammonium iodide catalyst 33 (2.6 mg, 0.002 mmol) in toluene (1 mL), and H2 O (3 mL) was cooled to 0◦ and an aqueous KCN solution (2 M, 150 µL, 0.3 mmol) was added dropwise. The reaction mixture was stirred vigorously at this temperature for 2 hours, saturated aqueous NH4 Cl solution was added, and the mixture was extracted with CH2 Cl2 . The combined extracts were dried over Na2 SO4 . Evaporation of solvents and purification of the crude products by flash column chromatography on silica gel (EtOAc/hexane = 1 : 4) gave the title compound (57.0 mg, 0.178 mmol, 89% yield, 95% ee); HPLC (Daicel Chiralpak AD-H, 2-propanol/hexane = 1 : 10, 0.5 mL/min, λ = 254 nm), tr = 13.3 min (R) and 14.7 min (S); [α]29 D − 18.9◦ (c 1.00, CHCl3 , 95% ee); IR (thin film) 3275, 3028, 2930, 2855, 2253, 1602, 1566, 1450, 1330, 1157, 1091, 1057, 904, 852, 731 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.99 (s, 2H), 5.37 (d, J = 9.1 Hz, 1H), 3.92 (dd, J = 6.7, 9.1 Hz, 1H), 2.65 (s, 6H), 2.31 (s, 3H), 1.86-1.67 (m, 6H), 1.29–1.06 (m, 5H); 13 C NMR (100 MHz, CDCl3 ) δ 143.0, 139.0, 132.7, 132.1, 116.5, 49.5, 41.2, 29.0, 28.4, 25.7, 25.4, 25.3, 23.0, 21.1; HRMS–ESI–TOF (m/z): [M + Na]+ calcd for C17 H24 N2 O2 SNa, 343.1454; found, 343.1451. Bu-t

Bu-t

t-Bu

t-Bu OH N OH N

t-Bu

O N Cl Al O N

Et2AlCl CH2Cl2, toluene, 2 h

(95%)

t-Bu

Bu-t

Bu-t 34

Chiral (Salen)Al(III) Complex [Catalyst Preparation].69 In a flame-dried 100-mL round-bottom flask equipped with a stir bar were combined and stirred salen ligand (1.52 g, 2.78 mmol) and CH2 Cl2 (20 mL, freshly distilled from CaH2 ). A toluene solution of diethylaluminum chloride (1.8 M, 1.54 mL, 2.78 mmol) was added slowly to the stirring solution at ambient temperature. After stirring for 2 hours, the solvents were removed under vacuum and the resulting yellow solid was rinsed with 50 mL of hexane. The solid was dried

44

ORGANIC REACTIONS

under vacuum to yield catalyst 34 (1.59 g, 95% yield) as a yellow solid, mp >350◦ (dec); IR (KBr) 2966, 2953, 2867, 1640, 1544, 848 cm−1 ; 1 H NMR (400 MHz, C6 D6 ) δ 7.84 (s, 2H), 7.77 (s, 2H), 7.61 (s, 2H), 3.51 (m, 2H), 1.91 (s, 18H), 1.39 (s, 18H) 1.36 (m, 4H), 0.59 (m, 4H); 13 C NMR (100 MHz, CD2 Cl2 ) δ 162.7, 141.2, 139.3, 131.4, 128.7, 128.4, 118.7, 64.6 (broad), 35.9, 34.4, 31.6, 30.0, 28.2, 24.1. Anal. Calcd for C36 H52 AlClN2 O2 : C, 71.20; H, 8.42; Al, 4.44; Cl, 5.84; N, 4.61. Found: C, 71.05; H, 8.63; Al, 4.49; Cl, 5.73; N, 4.56. 1. 34 (2–5 mol%), HCN (1.2 eq), toluene, –70°

N Ph

CF3

2. (CF3CO)2O

H

O N Ph

(91%) 95% ee CN

(S )-N -Allyl-N -(phenyl(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst].69 In a flame-dried 5-mL round-bottom flask equipped with a stir bar, 34 (12 mg, 5 mol%, 0.02 mmol) and toluene (1.4 mL) were combined. The reaction mixture was stirred at ambient temperature until the catalyst had completely dissolved. The reaction flask was cooled to −70◦ by means of a constant-temperature bath, and a toluene solution of HCN was added (0.85 M, 690 µL, 0.59 mmol, 1.2 eq). After 5 minutes, N-allyl benzylimine (71 mg, 0.49 mmol) was added in one portion by syringe. After 15 hours, the reaction was quenched with trifluoroacetic anhydride (103 µL, 0.73 mmol, 1.5 eq) and left to warm to ambient temperature. The solvents were removed under vacuum, and the resulting residue was purified by flash chromatography (hexane/CH2 Cl2 = 3 : 2) to afford the title product as a clear oil (119 mg, 91% yield, 95% ee); Chiral GC (γ TA, 112◦ for 23 min, 3◦ /min to 123◦ ) tr = 21.5 min (major), tr = 23.9 min (minor); [α]23 D 57.7◦ (c 1.0, CH2 Cl2 ); IR (thin film) 2936, 2249, 1701 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.45 (m, 5H), 6.65 (s, 1H), 5.66 (m, 1H), 5.19 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 4.15 (dd, J = 4.7, 17.0 Hz, 1H), 3.91 (dd, J = 6.0, 17.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3 ) δ 157.9 (q, J = 38 Hz), 131.1, 130.1, 130.0, 129.4, 127.8, 120.3, 117.5, 115.2, 49.8, 48.6; HRMS (m/z): [M + NH4 ]+ calcd for C13 H11 F3 N2 O, 286.1167; found, 286.1163. A: 6 (9 mol%), TMSCN (2 eq), PhOH (20 mol%), slow addition over 17 h CH2Cl2, –40°

N Ph

H

HN Ph

CN

(92%) 95% ee

N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition A].26,27 The chiral substituted BINOL ligand precursor (13 mg, 18 µmol) was placed in a flame-dried flask and dissolved in CH2 Cl2

THE CATALYTIC ASYMMETRIC STRECKER REACTION

45

(0.5 mL). To this solution was added a hexane solution of diethylaluminum chloride (0.96 M, 17 µL, 16 µmol) under argon. The resulting mixture was stirred at room temperature for 1 hour to give a clear solution of the BINOL-derived catalyst 6. To the thus-prepared catalyst solution, a solution of the starting fluorenyl imine (0.17 mmol) in CH2 Cl2 (0.6 mL) was added at −40◦ , followed by the addition of TMSCN (45 µL, 0.34 mmol). After 30 minutes, a solution of phenol (3 µ, 34 µmol) in CH2 Cl2 (0.2 mL) was slowly added over 17 hours. The reaction mixture was stirred for an additional 44 hours. The reaction was quenched with aqueous saturated NaHCO3 , and the mixture was diluted with Et2 O. The organic layer was separated, and the water layer was extracted with Et2 O. The combined organic layers were washed with water and dried over Na2 SO4 . Further purification was performed by flash column chromatography on silica gel to afford the target fluorenyl aminonitrile (92% yield, 95% ee); HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 90 : 10, 1.0 mL/min) tr = 13.3 min and 25.0 min; [α]24 D − 14.0◦ (c 1.0, CHCl3 ); 1 H NMR (CDCl3 ) δ 7.78–7.68 (m, 3H), 7.53–7.26 (m, 10H), 5.14 (s, 1H), 4.57 (s, 1H), 2.34 (bs, 1H); 13 C NMR (CDCl3 ) δ 143.6, 143.5, 141.1, 140.7, 135.8, 129.01, 128.98, 128.9, 128.8, 127.6, 127.4, 125.7, 125.0, 120.2, 120.1, 119.6, 62.2, 50.3. B: 6 (9 mol%), TMSCN (20 mol%), HCN (1.2 eq), slow addition over 24 h CH2Cl2, –40°

N Ph

H

HN Ph

CN

(92%) 95% ee

N -(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition B].26,27 To a CH2 Cl2 solution (1.0 mL) of catalyst 6 (33 µmol) prepared as described above, a solution of the starting imine (0.352 mmol) in CH2 Cl2 (1.0 mL) and TMSCN (70 µmol) were added at −40◦ . To this mixture, a solution of HCN (0.422 mmol) in CH2 Cl2 (0.26 mL) was slowly added over 24 hours. After 12 hours (total 36 hours), the reaction was worked up as described above to yield the title compound in 92% yield and 95% ee. 35 (10 mol%), TMSCN (4 eq), TMSCN (4 eq), t-BuOH (1.1 eq) CH2Cl2, –50°

N Ph

H

HN Ph

CN

(98%) 87% ee

N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Solid-Supported Aluminum Catalyst].73 To the corresponding swollen polymersupported ligand (19.1 mg, loading level = 0.52 mmol/g, 10 mmol) in CH2 Cl2

46

ORGANIC REACTIONS

(0.4 mL), a hexane solution of diethylaluminum chloride (0.95 M, 10 µL, 9.5 mmol) was added at ambient temperature, and the mixture was stirred for 1 hour to prepare catalyst 35. The catalyst mixture was cooled to −50◦ , then the starting imine (27 mg, 0.1 mmol) in CH2 Cl2 (0.25 mL), TMSCN (54 µL, 0.4 mmol), and tert-butanol (0.11 mmol) in CH2 Cl2 (0.25 mL) were added successively with 10 minute intervals between additions. After 60 hours, saturated aqueous NaHCO3 (1 mL) was added. The usual workup and purification by silica gel column chromatography afforded pure title compound in 98% yield and 87% ee. Catalyst recycling experiments were performed as follows: Instead of quenching the reaction with NaHCO3 , after the reaction was completed, dry Et2 O (five times the volume of CH2 Cl2 ) was added and the reaction mixture was left for 3 hours. The supernatant containing the Strecker product was then decanted by syringe, and catalyst 35 was washed with dry Et2 O five times under an inert atmosphere. After drying the catalyst under reduced pressure for 30 minutes, CH2 Cl2 , imine, TMSCN, and tert-butanol were added at −50◦ to start the new cycle. HO

HO 38 (5 mol%), NMI (30 mol%) + (n-Bu)3SnCN

N Ph

H

toluene–benzene (1:1), –65° to 0°

HN Ph CN (92%) 91% ee

2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Zirconium Catalyst].51,75 To Zr(OBu-t)4 (0.04 mmol) in toluene (0.25 mL) was added (R)-6-Br-BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and N -methylimidazole (NMI; 0.12 mmol) in toluene (0.75 mL) at room temperature. The mixture was stirred for 1 hour, and then cooled to −65◦ to generate catalyst 38. A benzene solution (1.0 mL) of the imine (0.4 mmol) and tributyltin cyanide (0.44 mmol) were added. The mixture was stirred and warmed from −65◦ to 0◦ over 12 hours, and then saturated aqueous NaHCO3 was added to quench the reaction. The aqueous layer was extracted with CH2 Cl2 . After the usual workup, the crude product was chromatographed on silica gel to give the desired adduct (92%, 91% ee); HPLC (Daicel Chiralcel OD, hexane/isopropyl alcohol = 9 : 1, 1.0 mL/min) tr = 40.0 min (major) and 49.7 min (minor); 1 H NMR (CDCl3 ) δ 7.61–7.43 (m, 6H), 6.93–6.72 (m, 4H), 5.40 (d, 1H, J = 7.2 Hz), 4.43 (br, 1H); 13 C NMR (CDCl3 ) δ 144.5, 134.0, 133.3, 129.5, 129.3, 127.2, 121.5, 120.7, 118.4, 114.9, 114.2, 50.6. Since some of the products from this method were unstable, they were characterized after methylation of the phenolic OH group as follows: The product was treated with 20% MeI–Me2 CO (5 mL) and K2 CO3 (200 mg). After the mixture was stirred at room temperature for 6 hours, saturated aqueous NH4 Cl was added to quench the reaction. After extraction of the aqueous layer with CH2 Cl2 , the crude product was purified by chromatography on silica gel to afford the corresponding methylated product (quantitative yield).

THE CATALYTIC ASYMMETRIC STRECKER REACTION HO

HO C8H17CHO +

38 (1 mol%) + HCN

H2N

47

CH2Cl2, –45°

HN C8H17

CN

(86%) 84% ee

1-(2-Hydroxy-6-methylphenyl)aminononane-1-carbonitrile [General Procedure for the Catalytic Enantioselective Three-Component Strecker Reaction Using a Zirconium Catalyst].51 To a CH2 Cl2 solution (3.0 mL) of (R)-6Br-BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and N -methylimidazole (0.12 mmol) was added a CH2 Cl2 solution (1.0 mL) of Zr(OBu-t)4 (0.04 mmol) at room temperature. After the mixture was stirred for 1 hour, a CH2 Cl2 solution (0.2 mL) of HCN (0.8 mmol) was added at 0◦ , and the mixture was further stirred for 3 hours at the same temperature. The resulting solution was then added to a mixture of nonaldehyde (0.4 mmol) and 2-amino-3-methylphenol (0.4 mmol) in CH2 Cl2 (1 mL) at −45◦ . After the mixture was stirred for 12 hours, HCN was added if the reaction was not yet completed. Saturated aqueous NaHCO3 was then added to quench the reaction, and after the usual workup, the crude product was purified by chromatography on silica gel to give the desired adduct (86%, 84% ee); HPLC (Daicel Chiralpak AD, hexane/isopropyl alcohol = 19 : 1, 1.0 mL/min) tr = 10.4 min (major) and 13.0 min (minor); 1 H NMR (CDCl3 ) δ 6.93–6.70 (m, 3H), 4.00 (t, J = 7.3 Hz, 1H), 2.33 (s, 3H), 1.92 (dt, J = 7.3, 7.7 Hz, 2H), 1.70-1.20 (m, 12H), 0.89 (t, J = 6.7 Hz, 3H); 13 C NMR (CDCl3 ) δ 150.1, 134.5, 130.6, 125.2, 123.0, 120.4, 113.4, 49.7, 34.2, 31.7, 29.1, 29.0, 25.6, 22.6, 17.7, 14.0; HRMS (m/z): M+ calcd for C17 H26 N2 O, 274.2047; found, 274.2045. Ph

Ph N Ph

Ph H

+ TMSCN

Ti(OPr-i)4 (10 mol%), 39 (10 mol%) i-PrOH, slow addition for 20 h, toluene, 4°

HN Ph

Ph CN

(99%) 97% ee

2-Benzhydrylamino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction Using a Titanium Catalyst].28 The reaction was set up inside of a glove box under a nitrogen atmosphere. Chiral ligand 39 (49 mg, 0.10 mmol) was placed into a flame-dried round-bottomed flask, and dissolved in toluene (5 mL). The flask was charged with a toluene solution of Ti(OPr-i)4 (0.5 M, 0.2 mL, 0.1 mmol), and the yellow solution was stirred for 10 minutes at 22◦ . Subsequently, N-diphenylmethylbenzalimine (271 mg, 1.0 mmol) was added. The reaction vessel was capped with a septum, sealed with teflon tape, removed from the glove box, and placed in a room maintained at 4◦ . TMSCN (267 µL, 2.0 mmol) was added to the stirred solution. Isopropyl alcohol (153 µL, 2.0 mmol) in toluene (2 mL) was added over 20 hours with additional stirring for 10 hours. The crude reaction mixture was passed through a plug of silica with CH2 Cl2 (5 mL) and concentrated under vacuum. The crude reaction mixture showed 99% conversion and 97% ee by HPLC

48

ORGANIC REACTIONS

(Chiralpak AD). The pale yellow solid was recrystallized from hexane/CH2 Cl2 (5 : 1) to afford the title compound (228 mg, 82%, >99% ee); [α]24 D − 64.2◦ (c 5.0, CHCl3 ); IR (CCl4 ) 3327, 3087, 3069, 3031, 2848, 2231, 1948, 1879, 1810, 1608, 1501, 1451, 1187, 929 cm−1 ; 1 H NMR (CDCl3 , 400 MHz) δ 7.58–7.20 (m, 15H), 5.24 (s, 1H), 4.59 (d, J = 12.0 Hz, 1H), 2.14 (d, J = 12.0 Hz, 1H); 13 C NMR (CDCl3 , 100 MHz) δ 243.4, 242.7, 235.6, 129.7, 129.6, 129.4, 128.6, 128.4, 128.1, 127.9, 127.7, 119.4, 66.2, 53.0; HRMS (m/z): [M + H]+ calcd for C21 H18 N2 , 299.1548; found, 299.1549. Anal. Calcd for C21 H18 N2 : C, 84.53; H, 6.08; N, 9.39. Found: C, 84.22; H, 6.19; N, 9.28. N

Ph +

HCN

NC

28 (2 mol%)

NHBn (99%) 93% ee

toluene, –75° Br

Br

2-Benzylamino-2-(4-bromophenyl)propionitrile [General Procedure for Asymmetric Strecker Reaction of Ketimines Using a Urea Catalyst].38 A 10-mL round-bottom flask equipped with a stir bar was charged with catalyst 28 (3.7 mg, 0.006 mmol, 0.02 eq), toluene (2 mL), and the starting ketimine (0.3 mmol). The reaction mixture was cooled to −75◦ by means of a constant temperature bath. In a separate 2-mL flask equipped with a stir bar, toluene (1 mL) and TMSCN (50 µL, 1.25 eq) were combined. After cooling the solution to 5◦ , MeOH (15 µL, 1.25 eq) was added. The solution was stirred for 2 hours at 5◦ , cooled to −78◦ , and then added to the reaction flask by syringe. When conversion of the starting material exceeded 99% as monitored by either 1 H NMR or HPLC, the solvents were removed under vacuum. The crude product was obtained as a solid (quantitative as a mixture with catalyst, 93% ee). Recrystallization from hexanes afforded pure title product as white needles (76% overall yield, >99.9% ee), mp 79.9–80.1◦ ; HPLC (Chiralcel OD, i-PrOH/hexanes (3%), 1 mL/min) tr = 15.9 min (major), tr = 19.5 min (minor); [α]23 D −58.6◦ (c 1.0, CH2 Cl2 ); IR (thin film) 3323, 2224 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.65 (d, J = 6 Hz, 2H), 7.59 (d, J = 6 Hz, 2H), 7.42–7.26 (m, 5H), 3.93 (d, J = 10 Hz, 1H), 3.58 (m, 1H), 2.02 (d, J = 5 Hz, 1H), 1.80 (s, 3H); 13 C NMR (400 MHz, CDCl3 ) δ 139.4, 139.1, 132.4, 128.9, 128.6, 127.8, 127.8, 123.0, 121.2, 60.4, 49.8, 31.5; EI–HRMS (m/z): M+ calcd for C16 H15 BrN2 , 314.0418; found, 314.0414.

N i-Pr

O PPh2

Gd[N(TMS)2]3 (2.5 mol%), 14 (3.75 mol%), TMSCN (2 eq), 2,6-dimethylphenol (1 eq) EtCN, –40°

NC

O H N PPh2

i-Pr (94%) 98% ee

N-[1-Cyano-2-isopropylcyclopent-2-en-1-yl]-P,P -diphenylphosphinic Amide [General Procedure for the Asymmetric Strecker Reaction of Ketimines Using a Gadolinium Catalyst].86 A solution of tris[N ,N -bis(trimethylsilyl)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

49

amide]gadolinium in THF (0.2 M, 2.0 mL, 0.40 mmol) was added to a solution of ligand 14 (276 mg, 0.6 mmol) in THF (16 mL) at 4◦ , and the mixture was stirred at 50◦ for 1 hour. The solvent was evaporated, and the residue was dried under vacuum for 2 hours at room temperature. The resulting amorphous material was dissolved in propionitrile (18.7 mL), cooled to −40◦ , and TMSCN (4.3 mL, 32 mmol) and 2,6-dimethylphenol (1.95 g, 16 mmol) in THF (6 mL + 2 mL for wash) were added. The mixture was stirred for 0.5 hours at −40◦ , the imine substrate (5.2 g, 16 mmol) was added, and the reaction mixture was stirred for about 2.5 days at −40◦ . Silica gel (50 g) was added at −40◦ to quench the reaction. (Caution! HCN generation! The reaction was quenched in a well-ventilated hood, and the generated HCN was trapped into a saturated NaHCO3 bubbler.). The slurry was filtered and the solid washed with a mixture of CH2 Cl2 (400 mL) and MeOH (20 mL). The combined filtrate was concentrated under vacuum. The solid residue was partially purified by flash column chromatography (EtOAc/hexane = 2 : 1 to EtOAc/MeOH = 20 : 1) to afford the expected product as a white solid (5.9 g) containing chiral ligand 14. To remove ligand 14, toluene (117 mL) was added to the mixture (5.9 g), the mixture was warmed to 80◦ , and to the resulting solution hexane (47 mL) was added. The solution was cooled gradually to room temperature, and the precipitate was filtered off to afford the pure amide product (4.6 g) as a white solid. The filtrate was concentrated under vacuum and toluene (30 mL) was again added at 80◦ , followed by the addition of hexane (12 mL). After gradually cooling to room temperature, the precipitate was filtered to afford an additional crop of amide product (0.7 g). These two crops were combined, and the pure title product was obtained as a white solid [5.3 g, 94% yield, 98% ee (unaffected by the washing process)], mp 132−133◦ ; [α]23 D + 12.9◦ (c 0.51, CHCl3 ); IR (neat) 2230, 1590, 1437, 894 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 7.99 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.56–7.44 (m, 6H), 5.77 (m, 1H), 3.24 (d, J = 5.8 Hz, 1H), 2.73–2.69 (m, 1H), 2.59 (sept, J = 8.2 Hz, 1H), 2.47–2.44 (m, 1H), 2.40–2.34 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ) δ 149.5, 133.6, 132.5, 132.5, 132.4, 132.2, 131.4, 131.3, 131.1, 129.8, 128.8, 128.7, 128.7, 128.6, 120.4, 62.2, 40.2, 29.4, 26.9, 22.9, 22.7; 31 P NMR (CDCl3 ) δ 20.9; LRMS–FAB(m/z): [M + Na]+ 373; HRMS–FAB (m/z): [M + H]+ calcd for C21 H24 N2 OP, 351.1621; found, 351.1635. Chiral ligand 14 was recovered as follows: The filtrate solution containing the ligand was evaporated, and concentrated aqueous HCl (20 mL) was added to the residue. The mixture was heated at 100◦ for 5 hours and poured into water (50 mL). Ligand 14 was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (30 mL), dried (Na2 SO4 ), and concentrated. Pure ligand 14 was recovered in 90% yield through silica gel column chromatography (EtOAce/hexane = 1 : 1).

50

ORGANIC REACTIONS

NC

O H N PPh2

O

1. conc. HCl 2. PhCOCl, pyridine, DMAP

i-Pr

Ph (—) 98% ee

N

O i-Pr

The enantiomeric excess of the Strecker product was determined by its conversion to the corresponding oxazoline according to the scheme above. Concentrated HCl (1 mL) was added to the cyclopentenyl amide product (10 mg), and the mixture heated at 100◦ for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. Pyridine (0.5 mL), benzoyl chloride (20 µL), and 4-N ,N -dimethylaminopyridine (DMAP, 5 mg) were added at room temperature. After stirring for 1 hour, the reaction mixture was poured into saturated aqueous NH4 Cl (5 mL). The products were extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried (Na2 SO4 ), and concentrated. Purification by silica gel preparative TLC (EtOAc/hexane = 1 : 4) gave the oxazoline in 98% ee. The enantiomeric excess was determined by chiral HPLC (Daicel Chiralcel OJ-H, i-PrOH/hexane = 1 : 99, 1.0 ml/min) tr = 6.3 min (minor) and 7.2 min (major); [α]23 D +1.5◦ (c 0.95, CHCl3 ); IR (neat) 3436, 2965, 1813, 1650 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 8.03–7.99 (m, 2H), 7.58–7.45 (m, 3H), 5.92 (brt, J = 2.3 Hz, 1H), 2.68–2.55 (m, 2H), 2.44–2.37 (m, 1H), 2.35–2.28 (m, 1H), 2.18–2.09 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 180.6, 160.4, 148.2, 132.7, 130.5, 128.8, 127.9, 126.0, 81.4, 36.8, 30.6, 27.5, 22.2, 22.2; LRMS–ESI (m/z): [M + Na]+ 278.0.

N

O PPh2

Gd(OPr-i)3 (0.1 mol%), 14 (0.2 mol%), TMSCN (2.5 mol%), HCN (1.5 eq)

NC

O H N PPh2

EtCN, –40° Cl

Cl

O 1. conc. HCl

O N

2. PHCOCl, pyridine, DMAP

(99%) 93% ee

Ph (—) 93% ee

Cl

4-(4-Chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one [General Procedure for the Catalytic Enantioselective Strecker Reaction of Ketimines Using a Gadolinium Catalyst: Combination of TMSCN and HCN].41 A THF solution of gadolinium triisopropoxide (0.2 M, 18.8 µL, 3.8 µmol) was added to a solution of ligand 14 (3.5 mg, 7.6 µmol) in THF (75 µL) in an ice bath. The mixture was stirred for 40 minutes at 45◦ , and then the solvent was evaporated. After drying the resulting pre-catalyst under vacuum (5 mmHg) for 1 hour, the substrate ketimine (1.33 g, 3.8 mmol) was added as a solid in one portion. Propionitrile (1 mL) was added at −40◦ , and after 30 minutes, TMSCN (12.5 µL,

THE CATALYTIC ASYMMETRIC STRECKER REACTION

51

0.094 mmol) was added. After 5 minutes, a propionitrile stock solution of HCN (4 M, 1.4 mL, 5.6 mmol) was added to start the reaction. After 54 hours at −40◦ the reaction was complete, and silica gel was added. The mixture was carefully concentrated until no HCN gas remained as determined by monitoring with an HCN sensor. The silica gel was removed by filtration, and the filtrate was washed with MeOH/CHCl3 (1 : 9). The combined liquids were removed by evaporation, and the resulting residue was purified by silica gel column chromatography to give the diphenylphosphinic amide intermediate (99% yield). The enantiomeric excess of the product was determined to be 93% after converting to the corresponding oxazoline, 4-(4-chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one, as described above. HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 499 : 1, 1.0 ml/min) tr = 18.7 min (minor) and 22.4 min (major); [α]22 D +120.5◦ (c 1.37, CHCl3 ); IR (neat) 1820, 1656, 1007 cm−1 ; 1 H NMR (CDCl3 ) δ 8.09 (d, J = 8.3 Hz, 2H), 7.62–7.50 (m, 5H), 7.36 (d, J = 8.5 Hz, 2H), 1.86 (s, 3H); 13 C NMR (CDCl3 ) δ 178.8, 160.4, 137.3, 134.3, 133.0, 128.8, 128.1, 126.9, 125.7, 70.2, 27.3; EIMS (m/z): M+ 285; EI–HRMS (m/z): M+ calcd for C16 H12 ClNO2 , 285.0557; found, 285.0564.

43 (9 mol%), 2-furoyl chloride (2 eq), TMSCN (2 eq)

MeO MeO

N

MeO MeO

N

CH2Cl2–toluene, –40°

CN O

O (—) 91% ee

N -(2-Furoyl)-2-cyano-6,7-dimethoxy-1,2-dihydroquinoline [General Procedure for the Catalytic Enantioselective Reissert Reaction of Quinolines].47,48 Diethylaluminum chloride in hexane (30 µL, 0.029 mmol) was added at ambient temperature to a solution of the corresponding ligand (22 mg, 0.029 mmol) in CH2 Cl2 (2.5 mL) and the resulting solution was stirred for 1 hour. This catalyst solution of 43 was cooled to −40◦ , and a solution of 6,7-dimethoxyquinoline (60.5 mg, 0.32 mmol) in CH2 Cl2 (0.5 mL) was added, followed by the addition of 2-furoyl chloride (63 µL, 0.64 mmol). After adding toluene (2.5 mL), TMSCN (85 µL, 0.64 mmol) in toluene (0.5 mL) was added slowly over 24 hours at −40◦ . A saturated aqueous solution of NaHCO3 was added after 40 hours, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated NaCl and dried over Na2 SO4 . Evaporation of the solvent and purification of the resulting crude product by silica gel column chromatography (EtOAc/hexane = 1 : 4) gave pure title compound in 91% ee; HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 70 : 30, 1.0 mL/min) tr = 15.7 and 20.8 min; [α]23 D +267◦ (c 1.0, CHCl3 ); IR (KBr) 3447, 2234, 1655 cm−1 ; 1 H NMR (CDCl3 ) δ 7.41 (m, 1H), 6.92 (d, J = 3.4 Hz, 1H), 6.78–6.72 (m, 2H), 6.47 (m, 1H), 6.43 (brs, 1H), 6.10 (d, J = 6.7 Hz, 1H), 5.96 (dd, J = 6.7, 9.1 Hz, 1H), 3.91 (s, 3H), 3.62 (s, 3H); 13 C NMR (CDCl3 ) δ 158.2, 148.9, 147.4, 146.3, 145.1, 129.2, 127.3, 112.8, 117.7, 116.0, 111.9, 109.4, 107.7, 56.2, 56.0, 42.5;

52

ORGANIC REACTIONS

EIMS (m/z): M+ 310; EI–HRMS (m/z): M+ calcd for C17 H14 N2 O4 , 310.0943; found 310.0957.

N Ph

50 (1 mol%), CH2=CHOCOCl (1.8 eq), TMSCN (2 eq) CH2Cl2, –50°

N Ph

O

CN O

(88%) 95% ee

1-Cyano-1-phenyl-1,2-dihydroisoquinoline-2-carboxylic Acid Vinyl Ester [General Procedure for Generating Quaternary Stereocenters by Catalytic Enantioselective Reissert Reaction of Isoquinolines].49 To a CH2 Cl2 solution (3 mL) of ligand 50 (13.1 mg, 0.015 mmol), a hexane solution of trimethylaluminum (0.98 M, 15.3 µL, 0.015 mmol) was added at ambient temperature and the resulting solution was stirred for 1 hour. A CH2 Cl2 solution of freshly distilled triflic acid (0.0585 M, 250 µL, 0.146 mmol, 97.5 mol% to trimethylaluminum) was then added and the mixture was stirred for 30 minutes. To the catalyst solution was added a solution of 1-phenylisoquinoline (308 mg, 1.5 mmol) in CH2 Cl2 (2.5 mL) at −50◦ , followed by TMSCN (400 µL, 3.0 mmol) and vinyl chloroformate (230 µL, 2.7 mmol). After 48 hours, 5% aqueous NH3 was added. The solution was extracted with CH2 Cl2 and purified by silica gel column chromatography (hexane/EtOAc) to give the title product (88%, 95% ee); HPLC (Daicel Chiralpak AD, hexane/2-propanol = 98 : 2, 1.0 mL/min) tr 12.1 min and 14.3 min; [α]25 D +195◦ (c 0.60, CHCl3 ); IR (neat) 1737, 1652, 1495, 1453, 1382, 1323, 1259, 1194, 1143, 943, 876, 762, 695 cm−1 ;1 H NMR (CDCl3 ) δ 7.62–7.60 (m, 2H), 7.37–7.28 (m, 3H), 7.22–7.03 (m, 5H), 5.83 (d, J = 8.2 Hz, 1H), 4.86 (d, J = 13.4 Hz, 1H), 4.55 (dd, J = 6.6, 2.1 Hz, 1H); 13 C NMR (CDCl3 ): δ 149.5, 142.2, 141.2, 130.3, 129.3, 128.8, 128.7, 128.4, 128.1, 126.9, 125.7, 125.0, 123.4, 117.7, 105.3, 98.2, 62.9; EIMS (m/z): M+ 302; EI-HRMS (m/z): M+ calcd for C19 H14 N2 O2 , 302.1055; found, 302.1055.

N(Pr-i)2 N

O

Et2AlCl (5 mol%), 51 (10 mol%), FmocCl (1.4 eq), TMSCN (2 eq)

O

CH2Cl2, –60°

N(Pr-i)2 NC

N Fmoc (98%) 96% ee

2-Cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 9H Fluoren-9-ylmethyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives].50 Ligand 51 (0.02 mmol) was dried under reduced pressure for 1 hour, and dissolved in CH2 Cl2 (0.5 mL). A hexane solution of diethylaluminum chloride (0.98 M, 10.2 µL, 0.01 mmol) was added and the mixture stirred at room temperature for 1 hour. The resulting mixture was cooled to −60◦ , and a CH2 Cl2 solution of N ,N -diisopropylnicotine amide (0.4 M, 0.5 mL, 0.2 mmol), 9-fluorenylmethoxycarbonyl chloride (FmocCl,

THE CATALYTIC ASYMMETRIC STRECKER REACTION

53

2.8 mmol), and TMSCN (53.3 µL, 4.0 mmol) were added successively. After the reaction was completed, water was added. The products were extracted three times with CH2 Cl2 . The organic phase was washed with brine, dried over Na2 SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title product (98%, 96% ee); HPLC (Daicel Chiralpak AD–H, hexane/2-propanol = 9 : 1, 1.0 mL/min, λ 254 nm) tr = 38.5 min, tr = 42.1 min (minor); [α]20 D −153.33◦ (c 0.93, CHCl3 ); IR (neat) 3462, 3092, 2958, 1736, 1653, 1624, 1442, 1371, 1297, 1255, 1211 cm−1 ; 1 H NMR (DMSO-d6 , 50◦ ) δ 7.86 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 6.4 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 6.53 (brd, 1H), 6.26 (d, J = 8.9 Hz, 1H), 5.98 (d, J = 5.8 Hz, 1H), 5.77 (t, J = 8.9 Hz, 1H), 4.74 (brd, 1H), 4.64 (brd, 1H), 4.40 (t, J = 5.8 Hz, 1H), 3.71 (m, 2H), 1.21 (brd, 12H); 13 C NMR (CDCl3 ) δ 166.7, 152.0, 142.9, 142.8, 141.3, 128.0, 127.3, 124.7, 124.6, 120.2, 120.1, 115.7, 69.3, 46.8, 42.8, 21.0, 20.8; ESI–MS (m/z): [M + H]+ 456, [M + Na]+ 478; HRMS–FAB (m/z): [M + H]+ calcd for C28 H30 N3 O3 , 456.2287; found, 456.2285. Cl

N(Pr-i)2 N

Cl

Et2AlCl (10 mol%), 55 (10 mol%), neopentyl–OCOCl (1.4 eq), TMSCN (2 eq)

O

CH2Cl2, –60°

O N(Pr-i)2

NC t-Bu

N O

O

(92%) 91% ee

4-Chloro-2-cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 2,2-Dimethylpropyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of a Halide-Substituted Pyridine Derivative].50 Ligand 55 (0.02 mmol) was dried under reduced pressure for 1 hour, and dissolved in CH2 Cl2 (1.5 mL). A hexane solution of diethylaluminum chloride (0.98 M, 20.4 µL, 0.02 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was cooled to −60◦ , and 4-chloro-N ,N -diisopropylnicotinamide in CH2 Cl2 (0.4 M, 0.5 mL, 0.2 mmol), neopentyl chloroformate (2.8 mmol), and TMSCN (53.3 µl, 4.0 mmol) were added successively. After the reaction was completed, water was added. The products were extracted three times with CH2 Cl2 . The organic phase was washed with brine, dried over Na2 SO4 , and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title compound (92% yield, 91% ee); HPLC (Daicel Chiralpak OD–H, hexane/ i-PrOH = 20 : 1, 1.0 mL/min, λ 254 nm) tr = 24.4 min (major), tr = 17.3 min (minor); [α]23 D −175.0◦ (c 0.68, CHCl3 ); IR (neat) 3452, 2076, 1634, 759 cm−1 ; 1 H NMR (DMSO-d6 , 50◦ ) δ 6.92 (s, 1H), 6.15 (d, J = 6.9 Hz, 1H), 5.97 (d, J = 6.9, 1H), 4.1-3.5 (brd, 2H), 4.0 (d, J = 10.3 Hz, 1H), 3.9 (d, J = 10.3 Hz, 1H), 1.27 (s, 12H), 0.96 (s, 9H); 13 C NMR (DMSO-d6 ) δ 162.7, 151.5, 128.8, 126.0, 123.5, 116.1, 112.0, 76.5, 50.8, 45.2, 44.4, 31.2, 25.9, 20.0; ESI–MS (m/z): [M + Na]+ 304; HRMS–FAB (m/z): [M + H]+ calcd for C19 H29 ClN3 O3 , 382.1897; found 382.1893.

54

ORGANIC REACTIONS ADDITIONAL CONTRIBUTIONS AFTER MANUSCRIPT SUBMISSION

Due to high interest in the catalytic asymmetric Strecker reaction, several important papers have been published after this manuscript was submitted. In this section, the latest contributions in this field (from November 2006 to August 2007) are surveyed.185 Quinine-derived quaternary ammonium salt 139 catalyzed an asymmetric Strecker reaction using α-amido sulfones 140 as aldimine precursors and acetone cyanohydrin as a cyanide source (Eq. 63).186 Highly reactive aliphatic N -Boc imines were generated in situ in the presence of a stoichiometric base (aqueous K2 CO3 ). Aliphatic substrates, including unstable linear aliphatic substrates, resulted in moderate to high enantioselectivity. Analogous reactions involving aromatic substrates, however, were not described. HN

Boc +

R

HO

CN

139 (10 mol %)

HN

aq. K2CO3–toluene, –20°, 42 h

SO2Tol-p 140

Boc CN

R

(85-95%) 50-88% ee Br–

H HO

N

(Eq. 63)

+ CF3

MeO N 139

A similar approach was reported using chiral phase-transfer catalyst 33 and KCN (1.05 eq) was used as a cyanide source (Eq. 64).187 Chemical yields and enantioselectivities improved compared to the reactions starting from the preformed aldimines.68

HN R

SO2Mes

33 (1 mol%), 2 M aq. KCN (1.05 eq)

SO2Tol-p

toluene–H2O, 0°, 1-2 h

HN R

SO2Mes CN

(93-99%) 85-99% ee

Ar

(Eq. 64) Ar Me + N

I–

Me Ar Ar 33: Ar = 4-CF3C6H4

THE CATALYTIC ASYMMETRIC STRECKER REACTION

55

Jacobsen’s chiral thiourea catalyst (ent-29) was applied to a catalytic asymmetric acylcyanation of N -benzyl aldimines using acylcyanide (141) as acyl and cyanide sources.188 This reaction was later extended to a three-component reaction involving in situ imine generation from aldehydes and amines (Eq. 65).189 Both aromatic and aliphatic substrates resulted in excellent enantioselectivities. Whether the reaction proceeds through initial acylation of the imine by acylcyanide followed by enantioselective cyanation, or initial enantioselective cyanation of the imine by a trace amount of contaminated HCN followed by trapping the resulting amine with acyl cyanide to regenerate HCN, is not clear. The fact that the same enantiomer was produced as the Jacobsen’s Strecker reaction32,33 suggests mechanistic similarities between these two reactions. O O R

1

+ H

R2NH2

O

+ R3

(1 eq)

ent-29 (5 mol%)

R3

CH2Cl2, 5 Å MS, –40°, 36 h

CN

141 (1 eq)

Me t-Bu S N Me N N H H O

N R1

R2

(46-97%) 74-94% ee

CN

N

HO t-Bu ent-29

OCOBu-t

(Eq. 65)

Chiral urea catalyst 142, related to 28 and 29, was synthesized from glucosamine and applied to a catalytic asymmetric Strecker reaction of aromatic aldimines and a ketimine (Eq. 66).190 Enantioselectivity and substrate generality, however, are less satisfactory than with 28 and 29. N Ar

R2

142 (2 mol%), HCN (2 eq)

NC HN R2

toluene, –50°, 24 h

R1 Ar (60-98%) 50-95% ee

R1

OAc AcO AcO

O

H N

N HO O

H N

O

Bu-t Bu-t

N H

Ph

(Eq. 66)

OPiv 142

A significant protecting group effect was observed in the asymmetric Strecker reaction of N -sulfonyl aldimines catalyzed by Mg(OTf)2 –box 143 complex (Eq. 67).191 Although N -p-tosylimines afforded no enantioselectivity, enantioselectivity increased up to 84% by using N -(2-pyridylsulfonyl)imines 144.

56

ORGANIC REACTIONS

The marked difference was attributed to the two-point binding of imine 144 to magnesium with the pyridine nitrogen and sulfonyl oxygen atoms. O N

O S

N

Mg(OTf)2 (10 mol%), 143 (11 mol%), TMSCN (1.3 eq)

O HN

ClCH2CH2Cl, rt

N

CN Ar (99%) 73-84% ee

Ar 144 O

O S

(Eq. 67)

O N

N

Ph

Ph 143

Chiral vanadium–salen complex 145, which was proven to be an efficient catalyst for cyanosilylation of aldehydes, can promote the Strecker reaction of aromatic aldimines and a ketimine with moderate enantioselectivity (Eq. 68).192 N

145 (10 mol%), HCN (1.2 eq)

Ph

Ar

NC HN R2

toluene, –40°, 4 h

R1

t-Bu t-Bu

N O N V+ O O O H H

Ar

R1

(48-100%) 41-81% ee

EtOSO3–

(Eq. 68)

Bu-t Bu-t

145

Although the enantioselectivity and substrate generality are not comparable to those obtained using chiral thiourea catalysts 28 or 29 and the chiral gadolinium catalyst derived from 14, two organocatalysts that promote asymmetric Strecker reactions of ketimines have been reported recently. First, chiral phosphate 146 can activate simple amine-derived ketimines through hydrogen bond formation. The Strecker reaction proceeded at −40◦ giving the corresponding products with moderate enantioselectivity (Eq. 69).193 Only results for aromatic substrates were described. N Ar

Ph

146 (5 mol%), HCN (1.5 eq) toluene, –40°, 3 d

HN Ar

Ph CN

(69-95%) 56-80% ee

CF3

O O P O OH

146

CF3

(Eq. 69)

THE CATALYTIC ASYMMETRIC STRECKER REACTION

57

Bis(pipecolic acid)-derived N -oxide catalyst 147 promotes an enantioselective Strecker reaction of N -phosphinoyl ketimines with high enantioselectivity (Eq. 70).194 A dual activation transition state model is proposed, in which oxygen atoms of the N -oxide act as Lewis bases to activate TMSCN and an amide hydrogen atom acts as a Brønsted acid to activate the imine. A related organocatalyst 148 has been developed for a catalytic enantioselective Strecker reaction of N -tosyl ketimines (Eq. 71).195 The enantioselectivity of catalyst 148 was in the moderate range.

N R1

O PPh2

147 (5 mol%), TMSCN (1.5 eq) toluene, –20°

O NC HN PPh2 R1

R2

(90-99%) 72-92% ee

R2

(Eq. 70) O

HN

NH + N

O−

−

O

+ N O

147

N R1

Ts

148 (5 mol%), 2,5-di-(1-adamantyl)hydroquinone (20 mol%)

NC

R2 R (90-99%) 61-91% ee

TMSCN (1.5 eq), toluene, -20°

R2

O

O + N

NH

HN

O−

NHTs

1

(Eq. 71)

+ N

−O

148

Jacobsen’s catalytic asymmetric Strecker reaction was applied to the synthesis of several isoquinoline alkaloids, such as (−)-calycotomine, (−)-salsolidine, and (−)-carnegine. The chiral stereogenic center was constructed in high efficiency using the catalytic asymmetric Strecker reaction (Eq. 72).196 MeO MeO

N

1. 29 (5 mol%), HCN (1 eq), toluene, –70°, 40 h

MeO

2. TFAA, –60°, 2 h

MeO

N

CF3

CN O 86%, 95% ee MeO MeO

MeO NH

HO (–)-calycotomine

MeO

MeO NH

(–)-salsolidine

MeO

NMe

(–)-carnegine

(Eq. 72)

58

ORGANIC REACTIONS TABULAR SURVEY

The literature has been surveyed up to August 2007. The reactions in the Tables are arranged in order of increasing carbon number of the imines, excluding the protecting group of the nitrogen atom. The reactions of aldimines are listed in Table 1. The reactions of ketimines are listed in Table 2. The catalytic enantioselective Reissert reactions are listed in Table 3. The catalytic enantioselective Strecker reactions of aldimines and ketimines reported in the literature disclosed after submission of this manuscript (from November 2006 to August 2007) are listed in Table 4 and Table 5, respectively. Yields of the products are included in parentheses; (—) indicates that the yield was not reported. Enantiomeric excesses (ee) of the products are also listed. The following abbreviations have been used in the Tables: BINOL BINAP Bn Boc DAHQ Flu Fm fur FmocCl HMDS Mes Mtr Mts naph Ph PMB TADDOL t-Bu Tf TFAA TMS TMSCN Tol Ts

binaphthol 2,2
-bis(diphenylphosphino)-1,1
-binaphthyl benzyl tert-butoxycarbonyl 2,5-di-(1-adamantyl)hydroquinone 9-fluorenyl fluorenylmethyl furyl 9-fluorenylmethoxycarbonyl chloride hexamethyldisilazide mesityl (2,4,6-trimethylphenyl) 4-methoxy-2,3,6-trimethylbenzenesulfonyl 2,4,6-trimethylphenylsulfonyl naphthyl phenyl p-methoxybenzyl [5-(hydroxydiphenylmethyl)-2,2-dimethyl[1,3]dioxolan-4-yl]-diphenylmethanol tert-butyl trifluoromethanesulfonyl trifluoroacetic anhydride trimethylsilyl trimethylsilyl cyanide tolyl p-toluenesulfonyl

59 O

H N N H O

Ph2(O)P

O

8

3

5d: Ar = 2-HO-1-naphthyl

5c: Ar = 2-HO-5-MeOC6H3

O

N H

Y

t-Bu

HO

N H N

3

OMe

O JandaJEL

t-Bu t-Bu

N

6

HN

t-Bu

Ph

O Cl O

N Al

OCOBu-t

2c: R1 = polystyrene–CH2, R2 = H, Y = S

5b: Ar = 2-HO-3,5-Cl2C6H2

Cl Al

O

t-Bu

2b: R1 = R2 = Me, Y = S

OBu-t

O

N

2a: R1 = PhCH2, R2 = H, Y = O

R

1

5a: Ar = 2-HO-3,5-Br2C6H2

t-Bu

P(O)Ph2

Al Cl

N

Ph2(O)P

Ar

1

O

O

P(O)Ph2

R2

O

O

Bu-t

3

NH

H N

CHART 1. CATALYTS AND LIGANDS USED IN TABLES

NH

9

O

O

P

Ph

NH2

OH

O

N 7

N N H

Ph

4: Ar = 4-CF3C6H4

Ar

Ar

Ar Me +N I– Me

Ar

60

HO

P Ph2

O O P(O)(Tol-o)2

Al Cl

P(O)(Tol-o)2

F

HO 13

F

O

O

OH

N

CF3CO2–

16b: R = (CH2)3CH=CH(CH2)3OCH2–JandaJEL

16a: R = H

R

O

10

OH

N H

Ph

Br

Br

+ N O

11

H

H

17

14

Ti

O

O

O i-PrO

O

P(O)Ph2

N Me2

Me2 N

N

P(O)Ph2

Al OTf

N

H

i-PrO O

N N

OMe

CHART 1. CATALYTS AND LIGANDS USED IN TABLES (Continued)

15

12

Sc

Li

+ S

OH

OH

Ph

O–

O–

Ph

P(S)Ar2

P(S)Ar2

OH + S

OH

O

O

18: Ar = 2-EtC6H4

O

O

61

MeO

Ph

O N

HO

22

19

N

H

N

+

Ph

O

N CF3

Br–

t-Bu

O

25

O

O

23

P

–O

OH

O

+ N

O

CF3

Bu-t

EtOSO3–

CF3

Bu-t

+ N

20

H

O

HN

O–

H

O

NH

t-Bu

O

N O N V+

AcO AcO

+ N

O

O–

H N

24

21

OPiv

HO O

NH

N

O

OAc

O + N –O

HN

O

Bu-t Bu-t

H N N H

Ph

62

C4

C3

N

N

N

N

N

N

H

Bn

H

SO2Mes

H

Flu

H

CHPh2

H

Bn

H

Flu

Aldimine

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene–H2O, 0°, 3 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

Conditions

CF3

CN

Bn

I

CN

NHFlu

CN

NHCHPh2

N

O

HN

N

CN

Bn

CN

SO2Mes

I (92), 71

CF3

O

CN

NHFlu

(89), 91

(85), 93

(89), 72

(81), <10

(74), 79

(84), 70

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES

33

68

26, 27

26, 27

59

33

26, 27

Refs.

63

C5

t-Bu

R

N

t-Bu

H

H

CHPh2

H

CHPh2

N

H

H

Bn

SO2Mes

N

N

N

toluene, –78°, 15 h; then Ac2O, formic acid

polymer-supported catalyst 2c (4 mol%),

HCN (1.3 eq),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene–H2O, 0°, 3 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene, –20°

Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),

n-BuOH (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

toluene, –20°

Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),

n-BuOH (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

O

t-Bu

H

O

N

CN

CN

CN

Bn

CN

Bn

N

CN

t-Bu

CF3

R

HN

N

N

SO2Mes

t-Bu

CF3

O

t-Bu

CF3

O

CN

NHCHPh2

CN

NHCHPh2

(82), 88

(94), 94

(98), 93

(88), 96

i-Bu

t-Bu

R

(75), 95

(69), 37

(80), 95

(84), 85

33

33

68

33

69

29

29

64

C5

R

O

t-Bu

t-Bu

t-Bu

H

N

N

N

H

Flu

H

+

CHPh2

H

Bn

H2N

HO

Aldimine Ph

O (20 mol%), B Me

N-methylimidazole (15 mol%), CH2Cl2, –45°

(R)-3-BINOL (5 mol%),

(R)-6-BINOL (5 mol%),

HCN (2.0 eq), Zr(OPr-n)4 (5 mol%),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

1,1,1-trichloroethane, 4°

Ti(OPr-i)4 (10 mol%), ligand 5a (10 mol%),

n-BuOH (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

toluene, –40°, 22 h

HCN (2.0 eq), catalyst 7 (10 mol%),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, –25°, 24 h

HCN (1.5 eq),

N

H Ph

Conditions

I

CN

NHCHPh2

CN

Bn

I

CN

R

HN

HO

CN

I (98), 77

t-Bu

NHFlu

I (100), 85a

I (95), 84

t-Bu

t-Bu

HN

i-Bu

t-Bu

R

(97), 78

(80), 17

(82), 39

(94), 91

(quant), 88

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

51

26, 27

26, 27

28

37

59

74

Refs.

65

O

O

O N

N

N

N

H

CHPh2

H

Bn

H

Flu

H

CHPh2

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

CH2Cl2, –50°, 66 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

toluene, –20°

Ti(OPr-i)4 (15 mol%), ligand 5b (15 mol%),

n-BuOH (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

I

CN

Bn

I

CN

NHCHPh2

I (82), 91

O

O

HN

I (97), 86

I (92), 87

O

CN

NHFlu

CN

NHCHPh2

(94), 32

(84), 89

(92), 90

(86), 94

77

59

67

73

26, 27

26, 27

29

66

C6

C5

R

H

O

N

HO

S

S

S

O

N

N

N

N

N

H

Bn

H

Flu

H

CHPh2

H

Bn

H

Flu

Aldimine

Bn

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene–benzene, –65° to 0°

O

CN

(85), 92

—

HN

12 h 2-thienyl

N-methylimidazole (30 mol%),

HN

Time

(90), 89

(83), 98

i-Bu CN

CN

NHFlu

CN

(77), 95

(93), 79

R

R

CN

Bn

NHCHPh2

HN

CN

(R)-3-BINOL (10 mol%),

HO

S

S

S

O

NHFlu

(89), 92

(79), 83

Product(s) and Yield(s) (%), % ee

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

catalyst 1 (9 mol%), CH2Cl2, –40°, 58 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

Conditions

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

67

51, 76

26, 27

77

67

26, 27

Refs.

67

C7

t-Bu

N

N

N

N

H

H

Bn

H

N

N

H

CHPh2

H

Bn

CHPh2

CH2Cl2, –70°, 36 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene, –20°

Ti(OPr-i)4 (15 mol%), ligand 5c (15 mol%),

n-BuOH (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

N

O

O

N

I

N

CF3

O

I (95), 92

CF3

CF3

t-Bu

CF3

N

CN

Bn

CN

CN

(74), 95

(91), 95

(95), 89

(69), 78

(85), 90

(86), <10

NHCHPh2

N

CN

O

CN

Bn

CN

NHCHPh2

64

33

69

29

33

33

59

68

C7

N

N

N

N

PMP

H

Flu

H

CHPh2

H

H

Bn

Aldimine

N

O (20 mol%), B Me

Ph

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

toluene, –40°, 20 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

MeOH, –25°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –25°, 24 h

HCN (1.5 eq),

H Ph

Conditions

CN

CN

Bn

PMP

I

CN

NHFlu

CN

NHCHPh2

I (85), 96

I (99), 97b

I

CN

NHCHPh2

HN

HN

(92), 95

(96), 86

(97), >99

(87), 89

(94), 71

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

26, 27

37

77

28

59

67

74

Refs.

69

F

F

O

N

HO

N

N

H

H

H

CHPh2

H

+ H 2N

HO

toluene, –40°, 23 h

HCN (2.0 eq), catalyst 7 (10 mol%),

CH2Cl2, –70°, 24 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

N-methylimidazole (30 mol%), CH2Cl2, –45°

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

CH2Cl2, –50°, 60 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

F

F

CF3

I (80), 86

O

I

HN

HO

I (98), 87

I (92), 95

CN

CN

NHCHPh2

N

CN

(97), 86

(96), 89

(92), 91

37

64

51

51, 75

73

26, 27

70

C7

Cl

Cl

Cl

Cl

Cl

N

N

N

N

N

H

Flu

H

CH2Cl2, –50°, 59 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

toluene, –20°, 20 h

HCN (2.0 eq), catalyst 7 (10 mol%),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

Conditions

I (98), 85

Cl

Cl

Cl

Cl

Cl

Cl

CF3

I

N

CN

PMP

CN

NHFlu

CN

NHCHPh2

CN

NHCHPh2

HN

CN

Bn

CN

(92), 95

(88), 81

(94), >99

(60), 86

(69), 85

(92), 81

Product(s) and Yield(s) (%), % ee

HN

O

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

PMP

CHPh2

H

H

Bn

H

Aldimine

73

26, 27

37

59

67

67

69

Refs.

71

Br

Cl

Cl

Cl

N

N

H

H

N H

CHPh2

H

CHPh2

N

HO

CH2Cl2, –70°, 40 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene-benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

I

CF3

CF3

O N

N

CN

O

Cl

I (88), 85

Br

Br

CN

CN

I

CN

(80), >99

(90), 88

(89), 89

(93), 79

(96), 93c

NHCHPh2

CN

NHCHPh2

I (84), 97

Cl

Cl

HN

HO

64

33

69

77

28

59

51, 75

72

C7

F

F

NO2

Br

N

Br

N

Br

N

N

N

H

H

Bn

CHPh2

H

CHPh2

H

H

Aldimine

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

toluene, –70°, 36 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

Conditions

O

I

F

O2N

F

CN

N CN

HN

Br

CN

CN

Bn

CN

(87), 90

(59), 98

(71), <10

(99), 94d

(88), 95

NHCHPh2

NHCHPh2

Br

N

CF3

I (80), >98

CF3

Br

O

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

67

59

77

28

33

33

Refs.

73 O

N

N

N

N

H

H

+ H 2N

HO

SO2Mes

H

CHPh2

H

Bn

H

N-methylimidazole (30 mol%), CH2Cl2, –45°

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),

toluene–H2O, 0°, 2 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, –40°, 22 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

CF3

CF3

CF3

CN

Bn

CN

CN

HN CN

CN

NHSO2Mes

CN

NHCHPh2

N

N

N

HO

O

O

O

(95), 94

(89), 95

(95), 76

(85), 87

(88), 86

(77), 57

51

68

37

33

33

69

74

C8

C7 N

N

H

Bn

H

N

N

N

H

Flu

H

Flu

H

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

catalyst 1 (9 mol%), CH2Cl2, –40°, 24 h

phenol (50 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

CH2Cl2, –40°, 24 h

TMSCN (2.0 eq), catalyst 1 (9 mol%),

toluene, –40°, 22 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

Conditions

N

CF3

O

I (75), 81

CF3

O

I

N

I

CN

Bn

CN

CN

NHFlu

CN

NHFlu

CN

(95), 63

(66), 86

(80), 80

(99), 94

NHCHPh2

(90), 91

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

CHPh2

Aldimine

69

26, 27

26, 27

26, 27

37

33

Refs.

75 N H

N

N

N

H

Flu

H

CHPh2

H

Bn

CH2Cl2, –70°, 40 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

CH2Cl2, –50°, 64 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

toluene, –40°, 20 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

CH2Cl2, –70°, 36 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

CF3

CF3

N

O

CN

Bn

CN

N

N

CN

CN

CN

NHFlu

CN

NHCHPh2

HN

O

I (94), 87

CF3

O

(98), >99

(97), 96

(100), 83

(96), 80

(55), 87

(99), 95

64

33

73

37

67

64

33

76

C8

PMP

N H

N

HO

N

N

H

H

H

CHPh2

Aldimine

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

CH2Cl2, –70°, 40 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, –40°, 12 h

HCN (2.0 eq), catalyst 7 (10 mol%),

Conditions

O

N

N

I

N

HN

HO

O

PMP

CF3

CF3

CF3

O

CN

CN

CN

CN

CN

NHCHPh2

CN

NHCHPh2

(93), 91

(96), 89

(86), 89

(96), 95

(84), 98

(88), 50

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

69

51, 75

64

33

77

37

Refs.

77

PMP

PMP

N

N

H

CHPh2

H

Bn

N

Ph

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

toluene, –40°, 28 h

HCN (2.0 eq), catalyst 7 (10 mol%),

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

O (20 mol%), B Me

H Ph

toluene, –25°, 24 h

HCN (1.5 eq),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

CH2Cl2, –70°, 36 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

I

I

CN

I (85), 91

CN

NHCHPh2

I (99), 94

PMP

PMP

CN

NHCHPh2

I (95), 40

PMP

HN

CN

Bn

N

I (95), 90

PMP

CF3

O

(99), 84

(90), 96

(97), 93

(98), 95

77

28

37

59

74

67

64

33

78

C8

N

HO

OMe

OMe

PMP

PMP

N

N

N

H

H

H

CHPh2

H

Flu

Aldimine

MeOH, –75°

HCN (2.0 eq), catalyst 3 (2 mol%),

CH2Cl2, –70°, 40 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

CH2Cl2, –50°, 41 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

Conditions

I

MeO

MeO

MeO

PMP

CF3

O

O

CN

CN

CF3

HN

HO

I (98), 83

PMP

NHFlu

CN

CN

CN

NHCHPh2

N

N

(97), 76

(93), 93

(82), 80

(96), >99

(99), 93

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

59

64

33

51, 75

73

26, 27

Refs.

79

O

O

CF3

CF3

NC

H

H

N

N

N

N

H

Bn

H

H

Bn

H

CHPh2

OMe

N

OMe

N

PMP

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

CH2Cl2, –70°, 24 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

O

O

CF3

CF3

NC

CF3 CN

O N

HN

HN

HN

OMe

CN

CN

Bn

CN

CN

Bn

CN

NHCHPh2

OMe

N

CF3

O

PMP

(88), 93

(53), 96

(75), 97

(92), 80

(84), 83

(93), 77

67

67

67

64

77

33

80

C9

C8

Ph

Ph

O

O

N

HO

N

N

N

H

H

H

SO2Mes

H

CHPh2

H

N

HO

Aldimine

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

toluene–H2O, 0°, 2 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, –40°, 16 h

HCN (2.0 eq), catalyst 7 (10 mol%),

CH2Cl2, –70°, 48 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

Conditions

Ph

Ph

O

O

CF3 CN

CN

HN

HO

CN

CN

SO2Mes

CN

NHCHPh2

N

HN

O

HN

HO

(55), 83

(81), 90

(96), 79

(88), 90

(89), 80

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

51, 75

68

37

64

51, 75

Refs.

81

Ph

Ph

Ph

NO2

N

N

O +

N

H

Flu

H

H2N

H

CHPh2

CHPh2

H

HO

toluene, –20°, 24 h

Ti(OPr-i)4 (10 mol%), ligand 5a (10 mol%),

2-propanol (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

CH2Cl2, –50°, 66 h

polymer-supported catalyst 8 (10 mol%),

TMSCN (4 eq), t-BuOH (1.1 eq),

CH2Cl2, –40°, 36 h

TMSCN (20 mol%), catalyst 1 (9 mol%),

HCN (1.2 eq, slow addition for 24 h),

catalyst 1 (9 mol%), CH2Cl2, –40°, 41 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

toluene, 4°, 24 h

Ti(OPr-i)4 (10 mol%), ligand 5d (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

N-methylimidazole (15 mol%), CH2Cl2, –45°

(R)-3-BINOL (5 mol%),

(R)-6-BINOL (5 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (5 mol%),

NO2

I (96), 83

I (78), 92

Ph

Ph

Ph

CN

I

CN

NHCHPh2

CN

NHFlu

CN

NHCHPh2

HN

HO

(>98), 90f

(80), 96

(>98), 84e

(85), 94

29

73

26, 27

26, 27

29

51

82

C9

n-C8H17

n-C8H17

O

N

HO

N

N

N

H

H

H 2N

H

SO2Mes

H

+

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene-H2O, 0°, 2 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

N-methylimidazole (6 mol%), CH2Cl2, –45°

(R)-3-BINOL (2 mol%),

(R)-6-BINOL (2 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (2 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

Conditions

CF3

n-C8H17

n-C8H17

N

CN

N O

CN

CF3

SO2Mes

CN

CN

CN

HN

O

HN

HO

HN

HO

(88), 91

(88), 97

(65), 90

(86), 84

(72), 74

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

HO

Aldimine

33

68

33

51

51, 75

Refs.

83

C11

C10

Ph

OMe

N

H

CHPh2

H

N

N

H

Bn

H

SO2Mes

N

N

Ph

O (20 mol%), B Me

H Ph

toluene, –25°, 24 h

HCN (1.5 eq),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –20°, 1 h

HCN (2 eq), catalyst 12 (10 mol%),

CH2Cl2, –70°, 40 h; then TFAA

HCN (2.0 eq), catalyst 11 (10 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene–H2O, 0°, 8 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, 4°, 24 h

Ti(OPr-i)4 (10 mol%), ligand 5d (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

I

CF3

I (93), 68

I

I (95), 79

Ph

HN

OMe

N

HN

HN

O

CN

SO2Mes

CN

Bn

CN

Bn

CN

CN

(94), 78g

(71), 85

(80), 86

(93), 93h

(95), 98

NHCHPh2

74

67

80

64

69

68

29

84

C11

N

N

N

H

H

toluene, 0°

Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),

TMSCN (2.0 eq), 2-propanol (1.0 eq),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

toluene, –20°, 12 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

toluene, –70°, 15 h; then TFAA

HCN (1.2 eq), catalyst 6 (5 mol%),

toluene, 4°

Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),

2-propanol (1.5 eq, slow addition for 20 h),

TMSCN (2.0 eq),

Conditions

CN

CN

Bn

I

CN

NHCHPh2

CN

NHCHPh2

HN

N

I (91), 98

CF3

O

CN

NHCHPh2

(93), 90j

(90), 76

(85), 99

(95), 93

(100), 93i

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

CHPh2

CHPh2

H

Bn

H

N

Aldimine

77

28

37

67

69

28

Refs.

85

t-Bu

t-Bu

N

HO

O

N

HO

N

N

N

H

H

H

H

Flu

H2N

H

CHPh2

H

+

HO

toluene, –40°, 72 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –70°, 20 h; then TFAA

HCN (1.3 eq), catalyst 2a (2 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

N-methylimidazole (30 mol%), CH2Cl2, –45°

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),

toluene–benzene, –65° to 0°, 12 h

N-methylimidazole (30 mol%),

(R)-3-BINOL (10 mol%),

(R)-6-BINOL (10 mol%),

(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),

catalyst 1 (9 mol%), CH2Cl2, –40°, 68 h

phenol (20 mol%, slow addition for 17 h),

TMSCN (2.0 eq),

t-Bu

t-Bu

CF3

O

HN

HO

HN

HO

HN

HO

CN

CN

(80), 85

(89), 97

(85), 87

(83), 85

(98), 91

(95), 89

NHCHPh2

N

CN

CN

CN

CN

NHFlu

37

33

51, 75

51

51, 75

26, 27

86

C13

C12

C11

TBSO

MeO

TBSO

Me2N

N

3

O

H

N

N

H

+ H 2N

HO

H

CHPh2

H toluene, –40°, 38 h

HCN (2.0 eq), catalyst 7 (10 mol%),

toluene, –40°

HCN (1.5 eq), catalyst 9 (10 mol%),

N-methylimidazole (15 mol%), CH2Cl2, –45°

(R)-3-BINOL (5 mol%),

(R)-6-BINOL (5 mol%),

HCN (2.0 eq), Zr(OBu-t)4 (5 mol%),

toluene-H2O, 0°, 8 h

2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),

toluene, –20°, 24 h

Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),

n-BuOH (1.5 eq, slow addition for 10 h),

TMSCN (2.0 eq),

Conditions

TBSO

MeO

TBSO

Me2N

HN

CN

Bn

HN

HO

CN

(80), 91

(93), 76

(98), 88

(70), 94

CN

(98), 97

NHCHPh2

HN

CN

SO2Mes

CN

NHCHPh2

Product(s) and Yield(s) (%), % ee

TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)

CHPh2

H

Bn

SO2Mes

N

Aldimine

37

67

51

68

29

Refs.

87

After recrystallization from hexanes, the product yield was 55%, >99% ee.

After recrystallization, the product yield was 87%, >99% ee.

j

g

After recrystallization, the product yield was 80%, >99% ee.

After recrystallization, the product yield was 61%, 97% ee.

f

i

After recrystallization, the product yield was 87%, 97% ee.

e

h

After recrystallization, the product yield was 93%, >99% ee.

After recrystallization, the product yield was 80%, 97% ee.

d

After recrystallization, the product yield was 82%, >99% ee.

After recrystallization, the product yield was 85%, >99% ee.

c

After recrystallization, the product yield was 97%, 85% ee.

b

a

88

C6

C5

t-Bu

S

N

S

O

N

P(O)Ph2

P(O)Ph2

P(O)Ph2

Bn

N

N

N

P(O)Ph2

Ketimine

toluene, –75°, 15 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 10 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 3 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

HCN (1.5 eq), TMSCN (5 mol%),

CH3CH2CN, –40°, 21 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 6 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 2.5 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

Conditions

t-Bu

I

S

CN

NHBn

NC NHP(O)Ph2

I (99), 99

S

NC NHP(O)Ph2

O

NC NHP(O)Ph2

NC NHP(O)Ph2

(98), 70

(94), 96

(93), 93

(98), 98

(91), 80

Product(s) and Yield(s) (%), % ee

TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES

38

40

41

40

40

40

Refs.

89

C8

C7

N

N

N

N

P(O)Ph2

Bn

P(O)Ph2

N

toluene, –20°, 9 h

TMSCN (2 eq), catalyst 12 (10 mol%),

toluene, –20°, 1 h

TMSCN (2 eq), catalyst 14 (10 mol%),

toluene, –75°, 24 h

HCN (1.25 eq), catalyst 2a (2 mol%),

toluene, –75°, 30 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 0.25 h

Gd(OPr-i)3 (5 mol%), ligand 13 (10 mol%),

HCN (1.5 eq), TMSCN (20 mol%),

CH3CH2CN, –40°, 16 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 43 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

I

I (>95), 88

I

I (99), 94

N

CN

NHBn

CN

NHBn

CN

NH

NC NHP(O)Ph2

(80), 56

(97), 90

(97), 85

(90), 95

NC NHP(O)Ph2 (73), 90

80

79

38

38

41

40

40

90

C8

Cl

O2 N

N

N

N

N

CH3CH2CN, –40°, 54 h

ligand 13 (0.2 mol%),

Gd(OPr-i)3 (0.1 mol%),

HCN (1.5 eq), TMSCN (2.5 mol%),

CH3CH2CN, –40°, 13 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 80 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 19 h

ligand 13 (0.2 mol%),

Gd(OPr-i)3 (0.1 mol%),

HCN (1.5 eq), TMSCN (5 mol%),

CH3CH2CN, –40°, 30 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°

HCN (1.25 eq), catalyst 2a (2 mol%),

Conditions

I (97), 90

I (99), 93

Cl

O2N

CN

N

CN

NHBn

I

Time 36 h 50 h 30 h 40 h

R OMe CF3 t-Bu Br

(93), 95

(quant), 93b

(94), 92

R

NC NHP(O)Ph2

I

NC NHP(O)Ph2

H

Product(s) and Yield(s) (%), % ee

TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)

R

P(O)Ph2

Bn

P(O)Ph2

Ketimine

(95), 92a

(95), 89

(95), 92

(97), 93

41

40

38

41

40

38

Refs.

91

Br

Br

N

N

Br

N

N

Bn

P(O)Ph2

P(O)Ph2

Bn

Bn

N

CH3CH2CN, –40°, 2 days

ligand 13 (3.75 mol%),

Gd(HMDS)3 (2.5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (2.0 eq),

CH3CH2CN, –40°, 3 days

Gd(OPr-i)3 (5 mol%), ligand 13 (10 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 52 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 90 h

HCN (1.25 eq), catalyst 2a (2 mol%),

toluene, –75°, 60 h

HCN (1.25 eq), catalyst 2a (2 mol%),

toluene, –75°, 80 h

HCN (1.25 eq), catalyst 2a (2 mol%),

Br

I

NC NHP(O)Ph2

(quant), 93c

(94), 96

(99), 97

(45), 42

(97), 91

NC NHP(O)Ph2

CN

NHBn

CN

NHBn

Br

I (99), 98

Br

CN

NHBn

86

86

40

38

38

38

92

C9

CF3

MeO

N

N

N

N

Bn

Bn

P(O)Ph2

N

N

P(O)Ph2

Bn

Ketimine

CH3CH2CN, –40°, 31 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 17 h

HCN (1.25 eq), catalyst 2a (2 mol%),

toluene, –75°, 65 h

HCN (1.25 eq), catalyst 2a (2 mol%),

toluene, –75°, 60 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 38 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 80 h

HCN (1.25 eq), catalyst 2a (2 mol%),

Conditions

CF3

MeO

NC NHP(O)Ph2

CN

NH

CN

NHBn

CN

NHBn

NC NHP(O)Ph2

CN

NHBn

(97), 95

(96), 69

(quant), 95a

(98), 88

(89), 87

(98), 91

Product(s) and Yield(s) (%), % ee

TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)

40

38

38

38

40

38

Refs.

93

C10

Ph

Ph

F

N

N

P(O)Ph2

N P(O)Ph2

O

N

P(O)Ph2

N

P(O)Ph2

CH3CH2CN, –40°, 38 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 17 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 48 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 1.3 h

ligand 13 (1 mol%),

Gd(OPr-i)3 (0.5 mol%),

HCN (1.5 eq), TMSCN (5 mol%),

CH3CH2CN, –40°, 83 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.1 eq),

CH3CH2CN, –40°, 8 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

Ph

Ph

CN

NH

NHP(O)Ph2

O

NC NHP(O)Ph2

NC

I

NC NHP(O)Ph2

I (96), 93

F

(93), 96

(98), 41

(98), 97

(100), 98d

NC NHP(O)Ph2 (94), 88

40

38

40

41

40

40

94

C12

C10

N

P(O)Ph2

P(O)Ph2

CH3CH2CN, –40°, 16 h

Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

toluene, –75°, 65 h

HCN (1.25 eq), catalyst 2a (2 mol%),

CH3CH2CN, –40°, 67 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

CH3CH2CN, –40°, 22 h

Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),

2,6-dimethylphenol (1.0 eq),

TMSCN (1.5 eq),

After recrystallization from hexanes, the product yield was 79%, >99.9% ee.

After recrystallization from hexanes, the product yield was 76%, >99.9% ee.

After recrystallization from CHCl3–hexane, the product yield was 93%, >99% ee.

b

c

d

After recrystallization from hexanes, the product yield was 75%, >99.9% ee.

N

N

P(O)Ph2

Conditions

NC NHP(O)Ph2

CN

NH

(73), 53

(97), 89

(99), 86

(92), 92

NC NHP(O)Ph2

NC NHP(O)Ph2

Product(s) and Yield(s) (%), % ee

TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)

a

N

Ketimine

40

38

40

40

Refs.

95

C10

C9-10

C8

C7

O

O

R

N

N

4.0 4.0 2.0

Br MeO CH2Cl2–toluene

CH2Cl2

CH2Cl2–toluene

CH2Cl2–toluene

40 h

112 h

64 h

64 h

Time

CH2Cl2–toluene, –40°, 64 h

2-furoyl chloride (2.0 eq),

2. Catalyst 16a (9 mol%),

1. TMSCN (2.0 eq), slow addition for 12 h

4.0

Cl

Solv

2-furoyl chloride (x eq), –40˚

TMSCN (x eq), catalyst 16a (9 mol%),

CH2Cl2, –60°, 5 h

ligand 15 (10 mol%), ROCOCl (1.4 eq),

TMSCN (2.0 eq), Et2AlCl (5 mol%),

H

N

Me

CH2Cl2, –60°, 5 h

ligand 15 (10 mol%), FmocCl (1.4 eq),

x

N

Me

N

OMe

TMSCN (2.0 eq), Et2AlCl (5 mol%),

Conditions

O

O

R

NC

NC

O

N

N

OR

O

(74), 89

(63), 67

(57), 67

N

N

O

CN

CN

Me

O

O Me

OMe

OCH2Flu

(91), 85

O

O

N

O

(89), 93

(98), 91

(77), 83

Fm

Me

R

(85), 57a

Product(s) and Yield(s) (%), % ee

TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS

R

O

O

Substrate

47, 48

47, 48

50

50

Refs.

96

C11

C10

Me2N

MeO

MeO

N

N

N

N

N

Substrate

CH2Cl2–toluene, –40°, 40 h

2-furoyl chloride (2.0 eq),

2. Catalyst 16a (9 mol%),

1. TMSCN (2.0 eq), slow addition for 12 h

CH2Cl2–toluene, –40°, 40 h

2-furoyl chloride (2.0 eq),

2. Catalyst 16a (9 mol%),

1. TMSCN (2.0 eq), slow addition for 12 h

CH2Cl2, –60°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (2.5 mol%),

CH2Cl2, –78°, 24 h

acetyl chloride (1.1 eq),

TMSCN (2.0 eq), catalyst 16a (9 mol%),

CH2Cl2–toluene, –40°, 40 h

2-furoyl chloride (2.0 eq),

TMSCN (2.0 eq), catalyst 16a (9 mol%),

Conditions

MeO

MeO

MeO

O

O

O

O

N

N

O

O

O

CN

CN O

N

N

O

CN

N

CN

CN

(73), 75

(71), 54

(72), 89

(99), 91

(88), 89

Product(s) and Yield(s) (%), % ee

TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS (Continued)

47, 48

47, 48

49

47, 48

48

Refs.

97

C15

C12

C11-12

Cl

N

X

N

Cl

O

O

R

N

N(allyl)2

N(Pr-i)2

N(Pr-i)2

R

N

N

CH2Cl2, –40°, 40 h

2-furoyl chloride (4.0 eq),

polymer-supported catalyst 16b (3 mol%),

TMSCN (4.0 eq),

CH2Cl2, –40°, 40 h

2-furoyl chloride (2.0 eq),

TMSCN (2.0 eq), catalyst 16a (1 mol%),

CH2Cl2, –60°, 27 h

neopentyl-OCOCl (1.4 eq),

ligand 18 (10 mol%),

TMSCN (2.0 eq), Et2AlCl (10 mol%),

CH2Cl2, –60°, 5 h

ligand 15 (10 mol%), ROCOCl (1.4 eq),

TMSCN (2.0 eq), Et2AlCl (5 mol%),

CH2Cl2, –60°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (2.5 mol%),

CH2Cl2, –60°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (2.5 mol%),

O

O

Cl

N

X

N

I (92), 86

Cl

NC

NC

R

R

O N(Pr-i)2

N(Pr-i)2

O

O

O

N

I

O

CN

N(allyl)2

OCH2Bu-t

R

O

CN O

N

CN O

N

(88), 87

(80), 84

(84), 73

(98), 88

36 h

27 h

Time

(91), 93

Br

Cl

X

Fm

(89), 86

(92), 91

(98), 96

neopentyl (98), 93

R

Me

H

R

CH2OMe

Et

R

48

48

50

50

49

49

98

C24

C16

C15

a

Ph

N

N Br

N CH2Cl2, –60°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (2.5 mol%),

CH2Cl2, –60°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (2.5 mol%),

CH2Cl2, –40°, 72 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (1 mol%),

CH2Cl2, –50°, 48 h

vinyl chloroformate (1.8 eq),

TMSCN (2.0 eq), catalyst 17 (1 mol%),

Conditions

PhC(O)O

PhC(O)O

Ph

Ph

CN O

N

CN O Br

N

CN O

N

O

O

O

N CN O

O

(95), 92

(59), 93

(88), 95

(94), 94

Product(s) and Yield(s) (%), % ee

TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS (Continued)

After recrystallization, the product yield was 42%, >99% ee.

PhC(O)O

PhC(O)O

Ph

N

Substrate

49

49

49

49

Refs.

99

C5

C4

C3

C2

t-Bu

SO2Tol-p

Boc

HN

O + PhCH2NH2

SO2Tol-p

Boc

H

H

N Bn

SO2Tol-p

HN Mts

HN

SO2Tol-p

Boc

SO2Tol-p

Boc

HN

HN

Substrate

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene–H2O, 0°, 1.5 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

Conditions

I

N

CN

Bn

CN

Mts

t-Bu

CN

NHBoc

I (92), 92

O

HN

CN

NHBoc

CN

NHBoc

CN

NHBoc

(85), 88

(87), 95

(99), 97

(92), 82

(88), 80

(85), 78

Product(s) and Yield(s) (%), % ee

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007

186

189

188

187

186

186

186

Refs.

100

C5

N

O + PhCH2NH2

Ph

SO2Tol-p

Boc

H

H

H

H

N Bn

SO2Tol-p

HN Mtr

SO2Tol-p

HN Mts

HN

n-Bu

i-Bu

i-Bu

i-Bu

t-Bu

t-Bu

t-Bu

N Bn

Substrate

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene, –40°, 4 h

HCN (1.2 eq), catalyst 20 (10 mol%),

toluene, –40°, 36 h

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

Conditions

N

N

N

HN

HN

n-Bu

CN

CN

Bn

CN

Bn

Ph

CN

Bn

CN

Mtr

CN

Mts

CN

NHBoc

HN

O

i-Bu

i-Bu

i-Bu

t-Bu

t-Bu

O

t-Bu

O

(76), 94

(99), 93

(96), 91

(90), 68

(85), 16

(46), 94

(62), 96

Product(s) and Yield(s) (%), % ee

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)

188

187

187

186

192

189

188

Refs.

101

C7

C6

C5

t-Bu

t-Bu

n-Bu

O

O

H

O

SO2Tol-p

Boc

H

H

N Bn

N

H

+ PhCH2NH2

+ PhCH2NH2

N Bn

H

HN

O

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene, –40°, 36 h

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –70°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°, 36 h

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

N

I

N

CN

NHBoc

CN

Bn

CN

CN

Bn

CN

Bn

HN

O

O

O

O

N

I (97), 92

t-Bu

n-Bu

O

(95), 50

(87), 96

(87), 50

(94), 89

(75), 88

187

189

188

190

188

189

102

C7

H

N Bn

H

N Bn

H

N Bn

HN SO2Tol-p

Boc

Substrate

SO2Tol-p

HN Mts

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene–H2O, 0°, 1.5 h

KCN (1.05 eq), catalyst 4 (1 mol%),

Conditions

N

O

O

N

N

HN

O

HN

CN

Bn

CN

Bn

CN

Bn

CN

Bn

CN

Mts

(94), 96

CN

NHBoc

(82), 98

(60), 47

(88), 92

(99), 97

(95), 72

Product(s) and Yield(s) (%), % ee

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)

188

186

188

190

188

187

Refs.

103

Ph

Ar

Ar

O

N

N

H

N

O

H

H

Bn

N

+ PhCH2NH2

+ RNH2

H

S

O

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

n-C6H13COCN (1.5 eq),

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

22 (11 mol%), ClCH2CH2Cl, rt

TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),

toluene, 24 h

catalyst 21 (2 mol%),

HCN (2 eq),

toluene, –40°, 4 h

catalyst 20 (10 mol%),

HCN (1.2 eq),

Ph

Ph

5

O

O

CN

CN

Bn

N

CN

R

HN

N

HN

O

Ar

Ar

HN

CN

Bn

CN

S

O

(95), 94 (93), 94 (92), 94 (83), 80

4-MeOC6H4CH2 4-ClC6H4CH2 1-naphCH2 2-furCH2

(76), 74

(88), 88

(67), 0

4-O2NC6H4

–50°

n-C5H11

allyl

R

(77), 84

4-BrC6H4

–50°

(99), 75

(83), 74

3-BrC6H4

–50°

(84), 88

N

(69), 72

(72), 84

Ph 2-BrC6H4

Ph

–50° –50°

(86), 95

Ar

(48), 41

4-ClC6H4

–70°

(76), 57

3-ClC6H4

Temp

(88), 75

Ph

Ar

189

189

191

190

192

104

C7

Cl

Cl

Cl

Cl

H

N Bn

N

O

O

N

H

S

H

H

Bn

O N

+ PhCH2NH2

Substrate

O

O

Ph

Ph

Ph

OH OH

Ph

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

22 (11 mol%), ClCH2CH2Cl, rt

TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

TADDOL =

toluene, –40°, 3 d

HCN (1.5 eq), TADDOL (10 mol%),

Conditions

Cl O

O

N

CN

Bn

HN

I

O

Cl

N

I (78), 92

Cl

Cl

HN

O

CN

S

CN

Bn

CN

Bn

(86), 98

N

(87), 98

(—), 32

(99), 72

Product(s) and Yield(s) (%), % ee

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)

188

191

189

188

193

Refs.

105

C8

R

Ph

Ph

Ph SO2Tol-p

Boc

SO2Tol-p

6

N

O

N

H

S

H

Bn

SO2Tol-p

HN Mtr

6

HN Mts

O

SO2Tol-p

HN Mtr

SO2Tol-p

HN Mts

HN

N

22 (11 mol%), ClCH2CH2Cl, rt

TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), TADDOL (10 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

R

Ph

Ph

Ph

6

HN

6

HN

CN

Mtr

CN

Mts

HN

O

HN

CN

Mtr

CN

Mts

HN

HN

CN

NHBoc

O

CN

S

CN

Bn

N

(68), 30

(96), 89

(96), 84

(86), 86

(93), 85

(95), 79

(99), 72 (99), 84

Me MeO

R 191

193

187

187

187

187

186

106

C8

Ar

Ar

N

N

MeO

MeO

MeO

H

H

Ph

O

N

N

H + PhCH2NH2

H

Bn

H

Bn

Substrate

toluene, –40°, 4 h

HCN (1.2 eq), catalyst 20 (10 mol%),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°, 3 d

HCN (1.5 eq), TADDOL (10 mol%),

Conditions

Ar

Ar

HN

HN

CN

CN

I (88), 92

MeO

MeO

Ph

I

O N

HN

CN

Bn

CN

Bn

(98), 64 (96), 66 (79), 82

2-MeOC6H4 3-MeOC6H4 4-MeOC6H4

(46), 52 (70), 59 (50), 51 (65), 31

3-MeOC6H4 4-MeOC6H4 3-CF3C6H4

(77), 74 3-MeC6H4 2-MeC6H4

(65), 70 4-MeC6H4

Ar

(83), 75

(93), 78

3-MeC6H4 4-MeC6H4

(81), 69

2-MeC6H4

Ar

(95), 96

(93), 22

Product(s) and Yield(s) (%), % ee

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)

192

190

189

188

193

Refs.

107

C9

Ph

Ph

Ph

Ph

Ph

Ph

SO2Tol-p

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

Cbz

O

N

H

H

Bn

+ PhCH2NH2

SO2Tol-p

HN Mts

SO2Tol-p

HN Mtr

SO2Tol-p

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

toluene–H2O, 0°, 2 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

toluene–H2O, –20°, 42 h

catalyst 19 (10 mol%),

Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),

SO2Tol-p

Boc

HN Mts

HN

HN

N

HN

HN

O

CN

CN

Bn

CN

Mts

CN

Mtr

CN

Mts

CN

NHCbz

HN

I (82), 92

Ph

Ph

Ph

Ph

Ph

NHBoc

(83), 94

(99), 98

(98), 96

(99), 94

(79), 40

(95), 68

189

188

187

187

187

186

186

108

C11

Ar

N

O

H

S

N

O

H

N

N

N

O

N

H

H

H

H

Bn

+ PhCH2NH2

Ph

Substrate

toluene, –50˚, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

22 (11 mol%), ClCH2CH2Cl, rt

TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),

toluene, –40˚, 4 h

HCN (1.2 eq), catalyst 20 (10 mol%),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –40°, 36 h

catalyst ent-2b (5 mol%),

Acetyl cyanide (1.5 eq),

toluene, –40°

catalyst ent-2b (1 mol%),

Acetyl cyanide (1.5 eq),

Conditions

Ar

HN

O

O

I

N

CN

N

HN CN

CN

CN

Bn

Ph

(78), 80

1-naph (99), 75

2-naph (99), 73

Ar

(46), 72

(73) , 76

(92), 96

Product(s) and Yield(s) (%), % ee

HN

HN

CN

S

I (92), 94

O

TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)

190

191

192

190

189

188

Refs.

109

C14

C12

Cbz

MeO

MeO

MeO

t-Bu

N

N

N

H

H

Bn

N

H

Ph

SO2Tol-p

HN Mts

N

toluene–H2O, 0°, 1 h

KCN (1.05 eq), catalyst 4 (1 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), TADDOL (10 mol%),

2. TFAA

toluene, –70°, 40 h

1. HCN (1.5 eq), catalyst 2b (5 mol%),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –40°, 4 h

HCN (1.2 eq), catalyst 20 (10 mol%),

Cbz

MeO

MeO

MeO

MeO

MeO

t-Bu

N

HN

O

CN

Bn

CN

Mts

CN

N

NH

CN

Ph

CN

HN

CN

HN

HN

(86), 95

(99), 99

(93), 22

CF3

(97), 86

(82), 84

(82), 34

187

193

196

190

190

192

110

C8

C7

C6

Ph

Ph

N

t-Bu

t-Bu

N

N

S

O

N

N

N

N

N

P(O)Ph2

Ts

P(O)Ph2

Ph

Ts

P(O)Ph2

Br

Substrate

toluene, –40°, 4 h

HCN (1.2 eq), catalyst ent-20 (10 mol%),

toluene, –50°, 24 h

HCN (2 eq), catalyst 21 (2 mol%),

toluene, –20°, 196 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 120 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 70 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 108 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

Conditions

Ph

Ph

HN

CN

NHBn

CN

(63), 50

(91), 72

(92), 81

(92), 77

(95), 77

(98), 80

(92), 43

Br

NC HN P(O)Ph2

S

NC HN Ts

O

NC HN P(O)Ph2

N

t-Bu

NC HN Ts

t-Bu

NC HN P(O)Ph2

Product(s) and Yield(s) (%), % ee

TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007

192

190

194

195

194

195

194

Refs.

111

C9

Br

X

Ph

Ar

N

N

N

Ts

N

PMB

Ts

PMB

N

N

Ts

PPh2

O

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –20°, 68 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 68 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°

TMSCN (1.5 eq), catalyst 23 (5 mol%),

NHP(O)Ph2

Br

X

Ph

(92), 91 (95), 88 (94), 88 (98), 81

4-BrC6H4 3-ClC6H4 3-O2NC6H4 2-FC6H4

(88), 68

(90), 76

(99), 85

NC HN PMB

NC HN Ts

NC HN PMB

Br

Cl

(90), 71

(91), 71

(98), 89

4-ClC6H4

X

(95), 90

(91), 90

4-FC6H4

Ph

Ar

(99), 85

NC HN Ts

NC HN Ts

Ar

NC

193

195

193

195

195

194

112

C9

O

O

MeO

MeO

R

N

N

N

N

Ts

PMB

PPh2

O

N

N

PPh2

O

Ts

Substrate

Br

toluene, –20°

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –20°

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

Conditions

O

O

MeO

MeO

R

NHP(O)Ph2

NC

NHP(O)Ph2

NC HN Ts

(89), 70

(97), 92

(91), 89

(92), 76

(92), 56

Me

MeO (93), 89

R

Br

(94), 61

NC HN PMB

NC

NC HN Ts

NC HN

Product(s) and Yield(s) (%), % ee

TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007 (Continued)

194

195

193

194

195

193

Refs.

113

C10

MeO

MeO

MeO

MeO

Cl

N

N

N

P(O)Ph2

P(O)Ph2

Ts

N

Ts

P(O)Ph2

Ts

N

N

P(O)Ph2

N

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 196 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 196 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 70 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

toluene, –20°, 144 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –20°, 72 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

NC HN Ts

NC HN P(O)Ph2

(99), 61

(91), 78

(96), 65

(99), 88

(95), 91

NC HN P(O)Ph2

NC HN Ts

MeO

MeO

MeO

NC HN Ts

(97), 76

(91), 90

HN P(O)Ph2

NC HN P(O)Ph2

MeO

Cl

NC

195

194

195

194

195

194

194

114

C12

Ph

Ph N

N

N

N

N

PMB

P(O)Ph2

PMB

Ts

Substrate

Br toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –20°, 168 h

TMSCN (1.5 eq), catalyst 23 (5 mol%),

toluene, –40°, 3 d

HCN (1.5 eq), catalyst 25 (5 mol%),

toluene, –20°, 80 h

catalyst 24 (5 mol%),

TMSCN (1.5 eq), DAHQ (20 mol%),

Conditions

Ph

Ph NC HN

NC HN PMB

(90), 92

Br

(95), 72

NC HN P(O)Ph2

(82), 60

(98), 71

NC HN PMB

NC HN Ts

(69), 80

Product(s) and Yield(s) (%), % ee

TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007 (Continued)

193

193

194

193

195

Refs.

THE CATALYTIC ASYMMETRIC STRECKER REACTION

115

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92 93 94 95 96 97 98

99 100 101 102 103 104

105 106 107 108 109 110 111

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136 137 138 139 140 141 142 143

144

145

146 147

148 149 150 151

152

153

154

155 156

157 158

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Koenig, M. D. In Asymmetric Synthesis, Vol. 5 ; Morrison, J. D. Ed; Academic Press: New York, 1985; pp 71–98. Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37. Noyori, R. Adv. Synth. Catal. 2003, 345, 15. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; B¨orner, A. J. Org. Chem. 2003, 68, 4067. O’Donnel, M. J. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; pp 727–755. O’Donnell, M. J. Acc. Chem. Rec. 2004, 37, 506. O’Donnell, M. J.; Bennett, W. D. J. Am. Chem. Soc. 1989, 111, 2353. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem., Int. Ed. 2002, 41, 3036. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36, 2635. Trost, B. M.; J¨akel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438. Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256. Weiß, T. B.; Helmchen, G.; Kazmaier, U. Chem. Commun. 2002, 1270. Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525. Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. Engl. 2001, 40, 2992. Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143. Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679. Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640. Hamada, T.; Manabe, K. Kobayashi, S. Angew. Chem., Int. Ed. 2003, 42, 3927. Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. France, S.; Shah, M.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206. C´ordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1842. C´ordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866. Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III Org. Lett. 2004, 6, 2507. Notz, W.; Watanabe, S.; Chowdari, N. S.; Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F., III Adv. Synth. Catal. 2004, 346, 1131. Kano, T.; Yamaguchi, U.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 16408. Franz´en, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.

THE CATALYTIC ASYMMETRIC STRECKER REACTION 161

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166 167 168 169 170 171 172 173 174

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Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077. Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., III Org. Lett. 2006, 8, 811. Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 1040. Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476. Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 4114. Saaby, S.; Bay´on, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352. Basra, S.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 2659. Steglich, W.; H¨ofle, G. Tetrahedron Lett. 1970, 4247. Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040. Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40, 1884. Bøgevic, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. List, B. J. Am. Chem. Soc. 2002, 124, 5656. For an example of metal-catalyzed asymmetric electrophilic amination, see: Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452. Chowdari, N. S.; Barbas, C. F., III Org. Lett. 2005, 7, 867. Suri, J. T.; Steiner, D. D.; Barbas, C. F., III Org. Lett. 2005, 7, 3885. Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367. Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Commun. 2005, 5115. Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658. Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. Hartung, R. In Patty’s Industrial Hygiene and Toxicology; Clayton, G. D., Clayton, F. E., Eds.; Wiley: New York, 1994; Vol. II, Part D, Chapter 33. For the latest review of catalytic asymmetric addition to imines, see: Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006, 71, 9869. Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.; Maruoka, K. Tetrahedron Lett. 2007, 48, 1337. Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007, 46, 612. Pan, S. C.; List, B. Org. Lett. 2007, 9, 1149. Becker, C.; Hoben, C.; Kunz, H. Adv. Synth. Catal. 2007, 349, 417. Nakamura, S.; Nakashima, H.; Sugimoto, H.; Shibata, N.; Toru, T. Tetrahedron Lett. 2006, 47, 7599. Blacker, J.; Clutterbuck, L. A.; Crampton, M. R.; Grosjean, C.; North, M. Tetrahedron: Asymmetry 2006, 17, 1449. Rueping, M.; Sugiono, E.; Moreth, S. A. Adv. Synth. Catal. 2007, 349, 759. Huang, J.; Liu, X.; Wen, Y.; Qin, B.; Feng, X. J. Org. Chem. 2007, 72, 204. Huang, X.; Huang, J.; Wen, Y.; Feng, X. Adv. Synth. Catal. 2006, 348, 2579. Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett 2006, 1595.

CHAPTER 2

THE SYNTHESIS OF PHENOLS AND QUINONES VIA FISCHER CARBENE COMPLEXES MARCEY L. WATERS Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599 WILLIAM D. WULFF Department of Chemistry, Michigan State University, East Lansing, Michigan 48824

CONTENTS ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . INTRODUCTION MECHANISM AND OVERVIEW . . . . . . . . . . . . . . . . . SCOPE AND LIMITATIONS Benzannulation . . . . . . . . . . Product Isolation . . . . . . . . . Regioselectivity . . . . . . . . . . Alkenyl, Aryl, and Alkynyl Chromium Complexes . . . Alkyne Components . . . . . . . . . Heteroatom Stabilizing Substituents . . . . . . Reaction Media and Conditions . . . . . . . Metal and Ligand Complement . . . . . . . Diastereoselectivity . . . . . . . . . Intramolecular Reactions . . . . . . . . Heteroannulation . . . . . . . . . . Cyclohexadienone Annulation . . . . . . . Two-Alkyne Annulation . . . . . . . . Ortho-Benzannulation/Cyclization of Doubly Unsaturated Complexes . . . . . . . . APPLICATIONS TO SYNTHESIS . . . . . . COMPARISON WITH OTHER METHODS . . . . . . . PREPARATION OF CARBENE COMPLEXES . . . . . . . . EXPERIMENTAL CONDITIONS . . . . . . . . EXPERIMENTAL PROCEDURES

[email protected] Organic Reactions, Vol. 70, Edited by Larry E. Overman et al.  2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 121

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PAGE 123 123 124 131 131 131 135 140 150 160 164 170 173 175 179 181 185 188 192 199 204 207 208

122

ORGANIC REACTIONS

2-Butyl-4-methoxy-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)naphthalen-1-ol (Benzannulation with an Alkynylborane). . . . . . . . . 2,3-Diphenyl-1,4-naphthoquinone (Comparison of Thermal Reaction in THF Solution with Solid-Phase Reaction on Silica Gel). . . . . . . . . {tert-Butyl-[2-tert-butyl-4-(2-isopropyl-5-methylcyclohexyloxy)naphthalen-1yloxy]dimethylsilanyloxy}tricarbonylchromium(0) (Asymmetric Benzannulation of O-Menthyloxy Complexes). . . . . . . . . . . 2,3-Diethyl-4,4,5-trimethoxy-4H -naphthalen-1-one (Oxidative Workup to Quinone Monoacetals). . . . . . . . . . . . . . 4-Methoxy-2-phenylphenanthren-1-yl Acetate (Benzannulation and In Situ Protection as an Aryl Acetate). . . . . . . . . . . . . 2-Acetyl-11-hydroxy-6,7-dimethoxy-2,3,4,4a,12,12a-hexahydro-1H -naphthacen-5-one and 8-Acetyl-7,8,9,10-tetrahydro-11-hydroxy-1-methoxytetracene-5,12-dione (One-Pot Benzannulation/Friedel-Crafts Reactions Followed by Oxidation). . Tricarbonyl[6-(tert-butyldimethylsilanyloxy)-2
-(tert-butyldimethylsilanyloxymethyl)-3methoxy-2,5-dimethylbiphenyl]chromium(0) (Simultaneous and Stereoselective Creation of Axial and Planar Elements of Chirality). . . . . . . {tert-Butyl[4-methoxy-2-methyl-6-(1-trityloxyethyl)phenoxy]dimethylsilanyloxy} tricarbonylchromium(0) (Central to Planar Chirality Transfer from a Chiral Propargyl Ether). . . . . . . . . . . . . 4-Methoxy-6-methyl-6-(3-methylbut-3-enyl)-2-(3-methyl-1-trityloxyhepta-2,6dienyl)cyclohexa-2,4-dienone (1,4-Asymmetric Induction in Cyclohexadienone Formation). . . . . . . . . . . . . . {[2-(4-Benzenesulfonylbutyl)-4-methoxy-6,7-dimethyl-5,8-dihydronaphthalen-1-yloxy]tert-butyldimethylsilanyloxy}tricarbonylchromium(0) (Tandem Diels-Alder/ Benzannulation Reaction). . . . . . . . . . . . 7-Methoxy-10-oxospiro[4.5]deca-6,8-diene-1-carbonitrile and 5-(tertButyldimethylsilanyloxy)-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (Tandem Benzannulation/Aromatic Nucleophilic Substitution). . . . . Methyl 5-{1-[(tert-Butyldimethylsilyl)oxy]ethyl}-6-ethoxy-4-hydroxy-7-methoxyindole and its Acetate (Benzannulation of a Heteroaryl Carbene Complex). . . . N-{3-[1-Methoxy-4a-(2-methoxymethoxyethyl)-9-methyl-4-oxo-4a,9-dihydro4H-carbazol-3-yl]propyl}benzamide (Cyclohexadienone Annulation of an Aryl Carbene Complex). . . . . . . . . . . . . Ethyl 3,4-Diethyl-2-hydroxy-5-(1-pyrrolidinyl)benzoate (Phenol Formation from an Activated Aminocarbene Complex). . . . . . . . . . {[4-(tert-Butyldimethylsilanyloxy)-2-methyl-5-propylphenyl] dimethylamino}tricarbonylchromium(0) (Generation of an Aniline Chromium Tricarbonyl Complex). . . . . . . . . . . . 2-Hydroxymethyl-3,6-dimethyl-1,4-naphthoquinone (Intramolecular Benzannulation with an In Situ Generated Tether). . . . . . . . . . 5,17-Dimethyl-11,23,26,28-tetramethoxy-25,27-dihydroxycalix(4)arene (Calix[4]arene Formation via a Triple Annulation). . . . . . . . . . 6-Methyl-4-(trimethylsilanyl)indan-5-ol (Regioselective Two-Alkyne Phenol Annulation). . . . . . . . . . . . . . 3-(tert-Butyldimethylsilanyloxy)-12-methyl-7,15,16,17-tetrahydro-6H cyclopenta[a]phenanthren-11-ol (Tandem Diels-Alder Two-Alkyne Phenol Annulations). . . . . . . . . . . . . . N-Benzyl-1-heptyl-4-methoxy-2-methyl-9H -carbazol-3-ol (Photoinduced ortho-Benzannulation). . . . . . . . . . . . . . . . . . . . . . . . . TABULAR SURVEY Table 1. Phenyl(alkoxy)chromium Carbene Complexes with Internal Alkynes . Table 2. Phenyl(alkoxy)chromium Carbene Complexes with Terminal Alkynes . Table 3. Aryl(alkoxy)chromium Carbene Complexes with Internal Alkynes . .

209 209

210 211 211

212

214

215

216

217

217 219

220 220

221 222 223 223

224 225 225 228 261 283

THE SYNTHESIS OF PHENOLS AND QUINONES Table 4. Aryl(alkoxy)chromium Carbene Complexes with Terminal Alkynes . Table 5. Alkenyl(alkoxy)chromium Carbene Complexes with Internal Alkynes Table 6. Alkenyl(alkoxy)chromium Carbene Complexes with Terminal Alkynes Table 7. Heteroaryl(alkoxy)chromium Carbene Complexes with Internal Alkynes Table 8. Heteroaryl(alkoxy)chromium Carbene Complexes with Terminal Alkynes Table 9. Amino and Imino Chromium Carbene Complexes with Internal Alkynes Table 10. Amino and Imino Chromium Carbene Complexes with Terminal Alkynes . . . . . . . . . . . . . Table 11. Sulfur-Stabilized Chromium Carbene Complexes with Alkynes . Table 12. Arylmolybdenum Carbene Complexes with Internal Alkynes . . Table 13. Arylmolybdenum Carbene Complexes with Terminal Alkynes . Table 14. Alkenylmolybdenum Carbene Complexes with Internal Alkynes . Table 15. Alkenylmolybdenum Carbene Complexes with Terminal Alkynes . Table 16. Aryltungsten Carbene Complexes with Internal Alkynes . . . Table 17. Aryltungsten Carbene Complexes with Terminal Alkynes . . Table 18. Alkenyltungsten Carbene Complexes with Internal Alkynes . . Table 19. Alkenyltungsten Carbene Complexes with Terminal Alkynes . . Table 20. Carbene Complexes of Non-Group VI Metals with Alkynes . . Table 21. Carbene Complexes with Tethered Alkynes . . . . . Table 22. Non-Heteroatom-Stabilized Carbene Complexes with Alkynes . Table 23. Cyclization of Doubly Unsaturated Complexes . . . . Table 24. Miscellaneous Reactions of Carbene Complexes . . . . . . . . . . . . . . . . . REFERENCES

123 . . . . . .

312 345 375 434 443 454

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472 487 491 494 498 501 503 508 511 513 517 524 557 568 597 612

ACKNOWLEDGMENTS

We express our gratitude to our coworkers at Michigan State University for assistance in proofreading this chapter. We also thank the many students and postdoctoral fellows who have contributed over the years to much of the original research that we cite. We are grateful to the National Science Foundation and National Institutes of Health for financially supporting the study of the chemistry of carbene complexes conducted in our laboratories over the last twenty-three years. Finally, we certainly extend our thanks to Bob Joyce (now deceased) and Linda Press for their invaluable help in assembling the tables, and to Scott E. Denmark for his patience, encouragement, and professional oversight of this chapter. INTRODUCTION

Fischer carbene complexes can be broadly defined as those transition-metal carbene complexes that have a low oxidation state, have an electrophilic carbene carbon, and usually have a heteroatom-stabilizing substituent on the carbene carbon. The reactivity of Fischer complexes of the type 1 is consistent with the resonance structures 1a and 1b (Scheme 1). These complexes were first prepared by E. O. Fischer and were, in fact, the first examples of any type of transitionmetal carbene complexes to be reported.1 The reaction of a Fischer carbene complex with an alkyne was first reported by D¨otz and was found to give a chromium tricarbonyl complexed 4-alkoxy-substituted phenol (Scheme 1).2 The

124

ORGANIC REACTIONS OH (CO)5Cr

OMe R2 R3

+

R

S

L

R =H

R3 RS (CO)3Cr OMe 2

1

(CO)5Cr

R3 1a

R1

RL

R

R1

OMe R2

R1

2

(CO)5Cr

OMe R2 R3 1b

R1

R1

O C

R3 OMe

RL

RS

Scheme 1

outcome was unexpected because the reaction was anticipated to give a cyclopropene by transfer of the carbene ligand to the alkyne.3 The reaction of Fischer carbene complexes with alkynes is facile, occurring just above ambient temperature, and resulting in the assembly of a benzene ring from the three carbons of the α,β-unsaturated carbene complex, the two carbons of the alkyne, and the carbon of a carbon monoxide ligand (Scheme 1). The synthetic value of this reaction stems from its broad scope, the generally high yields for the process, and the fact that the products can function as intermediates for the synthesis of a variety of aromatic compounds including para-quinones. It is the most synthetically valuable of the large number of reactions of Fischer carbene complexes that have been developed for applications in synthetic organic chemistry. Most of the previous reviews of the reactions of Fischer carbene complexes with alkynes have appeared as part of larger reviews on the applications of Fischer carbene complexes in organic synthesis that include a number of different reactions.4 – 41 The first major review was published only a few years after the discovery of the reaction,10 and shortly thereafter a detailed review appeared which focused on the work of a single research group.16 The literature on the reaction of Fischer carbene complexes with alkynes up to 1988 is roughly contained in three reviews that cover all reactions of Fischer carbene complexes.10,16,20 A comprehensive review has appeared that includes the reaction of Fischer carbene complexes with alkynes for the period 1988 to 1993.24 This chapter is the first comprehensive review that is limited to the synthesis of phenols and quinones from the reactions of Fischer carbene complexes with alkynes. The literature is covered as cited in Chemical Abstracts up to September, 2004. MECHANISM AND OVERVIEW

The mechanism by which (4-alkoxyphenol)chromium tricarbonyl complexes 2 are produced from the reaction of Fischer carbene complexes is not known in complete detail. A summary of the current understanding of the reaction of α,βunsaturated Fischer carbene complexes 1 with alkynes is presented in Scheme 2.

THE SYNTHESIS OF PHENOLS AND QUINONES

(CO)5Cr

OMe R2 R3

– CO

R1 1

R R1 β α

R3

R

S

R

L

R1 3

3

1 R2 R

OMe

R2

RS

O • RL

(CO)4Cr

OMe 2 α βR

Cr(CO)3

(E)-5

R3 R1 β α 3 OMe S R2 L 2 R R 1 Cr(CO)4 (E)-4 OH

O

R3

RL

OMe RS Cr(CO)3 6

125

2

R =H

R1

RL

R3 (CO)3Cr

RS OMe 2

Scheme 2

The first and rate-limiting step of the reaction was long ago proposed on the basis of kinetic studies to be a carbon monoxide dissociation from the starting carbene complex to give the 16-electron unsaturated species 3.42 Subsequent reaction with the alkyne is suggested to give the η1 ,η3 -vinyl carbene-complexed intermediate (E)-4. Recently, this view has been called into question by a theoretical study that concluded that the first step is an insertion of the alkyne to give a pentacarbonyl species and then a rate limiting loss of CO to give the unsaturated vinyl carbene complex (E)-4.43 This report is controversial44 because it is inconsistent with kinetic studies that demonstrated that the first step of the reaction is loss of CO, and that the second step depends on the alkyne concentration.42 The η1 ,η3 -vinyl carbene-complexed intermediate (E)-4 has been suggested to exist in a number of different forms. Most early mechanistic proposals include a [2 + 2] cycloaddition of the alkyne and carbene complex to give a metallacyclobutene intermediate that undergoes subsequent electrocyclic ring opening to give an η1 -vinyl carbenecomplexed intermediate related to (E)-4 (see structure (E)-17 in Scheme 6) but not having the chromium coordinated to carbons 2 and 3.5,9 It was suggested in 1987 that the η1 -complex (E)-17 is coordinatively unsaturated and may prefer to exist as the 18 e− (η1 ,η3 -vinyl)carbene complex (E)-4.13 Subsequently, extended H¨uckel calculations found that the η1 - and η1 ,η3 -vinyl carbene complexes are of comparable energy and also ruled out a metallacyclobutene intermediate as a precursor to (E)-4.45,46 The intermediate 4 must have an E-configuration about the C2-C3 double bond to enable phenol formation, and evidence suggests that this configuration is favored by the electron-releasing methoxy group.47 One recent density functional theory calculation (DFT) found that the η1 ,η3 -complex (E)4 is more stable,48 while another recent DFT study found that the η1 complex (E)-17 (Scheme 6) is more stable.49,50 It has been experimentally shown that the η1 ,η3 and η1 forms can interconvert.51,52 A third isomeric form of (E)-4 has been proposed recently on the basis of spectroscopic evidence in which the chromium is coordinated to a carbon-carbon double bond originally present in an alkenyl carbene complex.53,54 The intermediacy of this species in the formation of phenols has been supported by DFT calculations that find this configuration to

126

ORGANIC REACTIONS

be the most stable of the isomers of 4.49,50,55 An η1 ,η3 -vinyl carbene-complexed intermediate has been isolated from the reaction of a cationic tungsten carbene complex bearing a Cp ligand.56 The insertion of CO was originally proposed to give the (η4 -vinyl) ketene complex (E)-5 which upon electrocyclic ring closure and tautomerization gives the observed phenol complexes 2.57 DFT studies support the intermediacy of vinyl ketene complex (E)-5 for aryl complexes.48 However, for the same studies on alkenyl carbene complexes there is no local minimum for the vinyl ketene complex but rather CO insertion and electrocyclic ring closure occur in the same step.48 – 50 The isolation of (η4 -vinyl) ketene complexes has been reported for the reaction of alkynes with carbene complexes that do not have an α,β-unsaturated substituent.58,59 The last step in the reaction is proposed to be the tautomerization of cyclohexadienone complex 6, and support for this intermediate comes from the isolation of a non-tautomerized (R2 = H) complex from a molybdenum carbene complex.60 Metal-free and metal-complexed cyclohexadienones can be obtained from these reactions if tautomerization is not possible (R2 , R1 = H).61,62 Information about the rates and reversibility of these processes has been difficult to obtain because a rate-limiting CO dissociation is followed by rapid conversion into product, which also explains the inability to detect reaction intermediates.63,64 One DFT study suggests that both the alkyne insertion and CO insertion steps should be irreversible.48 Another DFT study finds that the alkyne insertion should be irreversible, but information on the CO insertion step was not provided.49,50 A detailed study of the reaction of a (2-furyl) carbene complex with 1-pentyne concludes that at least one of these steps must be irreversible.65 More recent studies on the reaction of a 2-methoxyphenyl complex finds that the constitutional isomers of the vinyl carbene complex (E)-4 (see structures 4 and 7, Scheme 3) undergo interconversion faster than CO insertion although it could not be determined if this interconversion takes place by reversible insertion of the alkyne or some other mechanism.66 Unsymmetrical acetylenes react with α,β-unsaturated Fischer carbene complexes to give two constitutionally isomeric phenol products as represented by compounds 2 and 8 (Scheme 3). In most reaction scenarios, the predominant product can be predicted on the basis of the steric bulk of the alkyne substituents such that the major product has the largest substituent of the alkyne incorporated adjacent to the hydroxy group of the phenol.67 – 70 With internal alkynes, mixtures of isomers that vary with the sizes of the substituents are observed. With terminal alkynes the reaction generally proceeds with greater than 100 : 1 selectivity, but lower selectivities are occasionally observed (10 : 1). The source of the steric influence of the alkyne substituents on regioselectivity has been suggested to result from the interaction of these substituents with carbon monoxide ligands in the η1 ,η3 -vinyl carbene complexed intermediate (Scheme 3, 4 vs. 7). Extended H¨uckel calculations reveal that the substituent ˚ closer to its nearest CO ligand at the 2-position of this intermediate is at least 1 A than the substituent on the 1-position.46 It is not clear whether the preference for isomer 4 over 7 is a result of kinetic or thermodynamic control. Perturbation of

THE SYNTHESIS OF PHENOLS AND QUINONES

R1 R

L

S

R

2

R

R3

3

OMe 2

RL 1

RS

OH R2

=H

OC Cr CO OC CO OMe R2

(CO)4Cr

R3

R1 R1

3 RS

RL

R2

R3

3

RS 1

2

R

RL

2 major product OH

OMe 2

RL

OC Cr CO OC CO (E)-7 R1

R1

R3 RS (CO)3Cr OMe

(E)-4

RL larger than RS

127

R3

R2 = H

R1

RS

R3 RL (CO)3Cr OMe 8 minor product

OMe RL +

RS – OC Cr CO OC CO (E)-4a

Scheme 3

the regioselectivity by electronic effects has been reported rarely. To date, only ketone71 and tributylstannyl72,73 substituents on the alkyne are known to influence regioselectivity to the point that electronic factors predominate over steric factors. The source of these electronic effects have been interpreted in terms of the resonance structure (E)-4a for the η1 ,η3 -vinyl carbene complexed intermediate. A recent report describes the regioselective reaction with internal boryl alkynes, which may be due to electronic rather steric effects.74,75 Even if the key intermediates in the reaction are those shown in Scheme 2, this information is usually not sufficient to predict the product distribution. The reactions are quite sensitive to solvent, temperature, concentration, the nature of the metal and its ligands, and on any functionalities present in either the carbene complex or the alkyne. The optimal conditions for a given carbene complex and alkyne are best determined experimentally with the aid of the known set of reactions that are presented in the Tabular Survey. One of the main problems in the reaction of α,β-unsaturated Fischer carbene complexes with alkynes is the large number of chemical structures that are possible products. The chemoselectivity, or the selectivity for a certain product type, has been carefully examined and the number of products that have been reported for this reaction are too numerous to list here, but are included in the Tabular Survey. However, for those reactions targeting phenols, the most common structures observed as co-products are furans,65,76,77 vinylcyclopentadienones,78

128

ORGANIC REACTIONS

cyclobutenones,76,13 indenes (cyclopentadienes),76,79 and two-alkyne phenols, which are phenols derived from the carbene carbon, a carbon monoxide ligand, and two equivalents of the alkyne.80,81 The mechanistic origin of each of these side-products will be briefly discussed below to the extent that such information is known. A mechanistic accounting for the formation of the vinylcyclopenten-1,3-dione product 10 and the furan product 13 is presented in Scheme 4. These products result from the insertion of the alkyne to give the Z-isomer of the η1 ,η3 -vinyl carbene complexed intermediate 4. The alkyne normally inserts to give the Eisomer of 4 and this preference has been shown to be a result of the electronic influence of the methoxy group.47 Consequently, the vinylcyclopenten-1,3-dione 10 and furan product 13 are usually observed in less than 20% combined yield, although under certain circumstances they are the major products of the reaction. Furan formation results from insertion of a carbon monoxide ligand to give the Z-isomer of the vinyl ketene complex 5, and then attack of the methoxy group on the ketene to give the zwitterion 11. Carbon-oxygen bond fragmentation gives the non-stabilized carbene-complexed intermediate 12, which is not observed but is presumably attacked rapidly by the carbonyl oxygen with subsequent loss of chromium to give the furan.65,77 Although two reasonable possibilities have

OMe R2

(CO)4Cr

R3 3

RL

R1

3

R

L

R3

R1 R

R

S

RS

O RS

R3

R2

(Z)-5

O

R RL (Z)-5 O

RL

RL OMe

R2 RS

R1

O RS

RL

RS 11

Cr(CO)n

R2

R3

R1

10

R1 R2

RS

Cr(CO)3

9 3 Me R O

RL

S

O •

Cr(CO)4

(CO)n M RL OMe

R1

MeO

2

(Z)-4 RL

RS

Cr(CO)4 (E)-4

MeO

RS

OMe

R2 R L

R3 RL

R3

R1

RS

R3 O

MeO RL

R2 Cr(CO)n RS

12

Scheme 4

R1

R3 O

MeO RL

R1 RS

13

R

2

THE SYNTHESIS OF PHENOLS AND QUINONES

129

been suggested for the formation of the vinylcyclopenten-1,3-dione 10, the most likely pathway is thought to involve a reductive coupling of the carbon-carbon double-bond of the ketene with a second molecule of the alkyne to give metallacyclopentenone 9. Subsequent CO insertion and reductive elimination would render the observed product 10.78,60 For many reactions of interest, the formation of the indene product can be the most detrimental, decreasing the yields of the desired phenol product. The indene product results from the failure of carbon monoxide to insert into the vinyl carbene-complexed intermediate (E)-4 to produce the vinyl ketene complexed intermediate (E)-5 (Scheme 5). Instead, cyclization occurs to give a five-membered ring (14), which upon loss of the metal gives the cyclopentadiene 15. This product is actually rarely seen with alkenyl-substituted chromium carbene complexes and is usually only observed as a side-product in the reaction of aryl complexes, where it is often isolated as the metal-free indene 16. The phenol to indene (cyclopentadiene) ratio is more favorable for phenol formation with chromium than with molybdenum and tungsten complexes.60,63,71,82 Phenol formation is also more often seen with electron-poor complexes than with electron-rich complexes,79,83 and in less polar solvents rather than in more polar

R3

R1

R1

RS

R2

R2 RL (E)-4

R3

OMe

OMe

R1

RS L

R

Cr(CO)4

R2

Cr(CO)4

14

OMe

R2 RL

R

R

S

RS

R1

O R1

R3

RL •

RS

RL Cr(CO)3

3 O R

RL

R1 R2

OMe RS

RS

RL

RL R3

RS Cr(CO)4

20 R1

R1

RS

RS

R2

21 R1

R3

R3 OMe

R2 O •

OH R3 RL

RL

RL

19

(E)-4

RS

18

RS

MeO

RL 16

R2

Cr(CO)4 (E)-17 R2

RS

RL 15

MeO L

O

R2 OMe

RS RL Cr(CO)3 (E)-5

Scheme 5

OMe

R4

OMe RS

R3

R1 (E)-4

R3

RL

RS 22

130

ORGANIC REACTIONS

solvents.13 Concentration and temperature can also influence this ratio such that lower temperatures and higher concentrations favor phenol formation.84 The two-alkyne phenol product 21 results from the incorporation of two equivalents of the alkyne. It is believed that the formation of this product begins with the decomplexation of the double-bond in the saturated 18-electron η1 ,η3 vinyl carbene complexed intermediate (E)-4 to give the unsaturated 16-electron η1 -analog (E)-17 (Scheme 5).80 Calculations have shown that these two intermediates are nearly identical in energy and that the barrier to their interconversion is quite low45,46 This observation has been confirmed experimentally.51,52 The site of unsaturation in (E)-17 makes possible the reaction with a second alkyne to give the η1 ,η3 -vinyl carbene complexed intermediate 18 that has two equivalents of the alkyne incorporated. CO insertion would give the vinyl ketene complex 19 and electrocyclic ring closure would give the cyclohexadienone 20, which can sometimes be isolated but is usually reduced in situ by chromium(0) to give phenol 21. This mechanism suggests that the formation of two-alkyne phenols is concentration dependent and experiments reveal that the phenol 21 is most often significant as a side-product at high concentrations and with sterically unencumbered alkynes. Just as the η1 ,η3 -vinyl carbene complexed intermediate (E)-4 can decomplex from the double bond to give the η1 -vinyl carbene complexed intermediate (E)-17 and then insert an alkyne, so can the η1 ,η3 -vinyl carbene complexed intermediate 18. This process is presumably the mechanism by which Group 6 carbene complexes, especially those of tungsten, can cause oligomerization and polymerization of alkynes.85 Finally, the cyclobutanone product 22 is thought to be the result of an electrocyclic ring closure of the vinyl ketene complex (E)-5. The formation of this product is often maximized in acetonitrile where coordination of the solvent to the metal may foster cyclization.13 It has not been determined whether the two-alkyne phenol product 21 and the cyclobutanone product 22 can be formed from the E-η1 ,η3 -vinyl carbene complexed intermediate 4, or formed from the Z-isomer, or from both. The formation of the phenol product can often be sensitive to the concentration of the reactants. Extensive investigation revealed that this dependency is linked to the concentration of the alkyne and not to that of the carbene complex.13,60,84 Increased concentration of the alkyne leads to increased proportions of the phenol product relative to the indene (cyclopentadiene) product. An explanation was put forth that involves the coordination of a molecule of the alkyne to the metal center in the 16 electron η1 -vinyl carbene complexed intermediate (E)-17, which already has a molecule of the alkyne incorporated. Because an alkyne can be either a 2or 4-electron donor ligand, the coordination of alkyne 23 is proposed to facilitate the insertion of a carbon monoxide ligand (Scheme 6). The alkyne can switch from a 2-electron donor in 24 to a 4-electron donor in 25, and thus maintains a saturated, 18-electron metal center during the CO insertion step. Electrocyclic ring closure and loss of the acetylene would then produce the phenol chromium tricarbonyl complex 2 as the product. This alkyne-promoted enhancement of phenol formation is termed the “allochemical effect”84 if the alkyne 23 is the

THE SYNTHESIS OF PHENOLS AND QUINONES R3

R1 2

R R

L

Cr(CO)4

R1

R

23

OMe

R2 (CO)4Cr

RS

R

Cr(CO)4 (E)-17

OMe

1 R2 R

O

RS RL

4

R5 24

R3

25

OH 2

R =H

RS

RL Cr(CO)3 5

R2

R3

R1

R5

R3

R2 O • R4

R4

OMe RL

RS

(E)-4

R3

R1 OMe

131

RL

OMe RS

Cr(CO)3

6

R1

RL

R3 (CO)3Cr

RS OMe 2

Scheme 6

same as the first alkyne that has already been incorporated into (E)-17, and the “xenochemical effect”86 if the two alkynes are different. This allochemical effect and the process that leads to the formation of the 2-alkyne phenol product 21 (Scheme 6) are closely related. In the former the alkyne coordinates to the metal of (E)-17 but does not insert and in the latter the alkyne inserts into (E)-17 to give the intermediate 18. SCOPE AND LIMITATIONS

Benzannulation Product Isolation. The primary product of the reaction between an alkyne and an α,β-unsaturated Fischer carbene complex (e.g., 26) is an arene chromium tricarbonyl complex with the chromium coordinated to the newly formed benzene ring. The phenoxy function present in these products renders the molecule sensitive to air and special precautions are needed to isolate these complexes. The arene complex 27 is isolated in 45% yield by purification on silica gel at −15◦ under an inert atmosphere (Eq. 1).87 However, this result does not represent the actual yield because naphthol 28 can be isolated in 66% yield after oxidation in air60 and quinone 29 is obtained in 73% yield after an oxidative workup with ceric ammonium nitrate (Eq. 2).13 The lower yield of complex 27 is due to air oxidation which occurs despite the precautions taken. Most arene chromium tricarbonyl complexes from this reaction are quite air-sensitive and will lose the metal within minutes upon exposure to atmospheric conditions. This air-sensitivity is in contrast to that of Fischer carbene complexes, which are normally stable to air and only undergo extensive air oxidation when left in solution for a day or more. Relatively air-stable arene chromium tricarbonyl complexes are obtained from reactions of carbene complexes with acetylenes

132

ORGANIC REACTIONS

bearing large substituents as illustrated in the isolation of complex 30 in 79% yield (Eq. 3).68 Many such arene complexes with hindered substituents adjacent to the phenol are quite stable to air and some will survive chromatography on silica gel at room temperature in the presence of air with little or no decrease in yield.88 OH 1. Cr(CO)5

Pr-n

Pr-n, n-Bu2O, 45°

(Eq. 1)

2. silica gel, N2, –15°

OMe 26

(CO)3Cr OMe 27 (45%) OH Pr-n

THF, 80° 2. air Cr(CO)5

1.

OMe

Pr-n

28 (66%) O

OMe 26

(Eq. 2) Pr-n

THF, 45° 2. CAN O 29 (73%) OH 1. Cr(CO)5

OMe 26

Bu-t

Bu-t , n-Bu2O, 45°

(Eq. 3)

2. silica gel, N2, –15° (CO)3Cr OMe 30 (79%)

The reaction of complex 26 with diphenylacetylene at 45◦ produces the arene complex 31 with the chromium tricarbonyl group on the newly formed benzene ring.2 This product results from kinetic control because heating this complex to 70◦ results in migration of the chromium tricarbonyl group to the other ring of the naphthalene nucleus giving complex 32. This observation requires that the chromium remains bound to the organic fragment during the entire course of the reaction. Complex 31 is also used to demonstrate a method for removal of the chromium tricarbonyl unit from the product that does not involve an oxidation of the metal. Ligand displacement with carbon monoxide can effectively provide the metal-free phenol 33 in good yield (Eq. 4).76 A related ligand displacement method with triphenylphosphine has been reported.90 Another important aspect of deprotection with CO in addition to the mild conditions is that this method sequesters the chromium as its hexacarbonyl complex in high yield, thus providing for a convenient recycling of the chromium (chromium hexacarbonyl is the starting material from which most Fischer carbene complexes are produced).

THE SYNTHESIS OF PHENOLS AND QUINONES

133

Because chromium hexacarbonyl is relatively insoluble in ether, it can be recovered by simple filtration. OH Ph Bu2O, 70° Ph

OH

(CO)3Cr

Ph

OMe 32

Ph

(Eq. 4)

OH

(CO)3Cr OMe

Ph

50 atm CO

31

+ Cr(CO)6

Et2O, 70°

Ph OMe 33 (80%)

In most synthetic applications the metal-free organic product is desired and the method of workup is chosen to provide a clean and rapid removal of the metal as well as to provide the product in a particular oxidation state or particular form of functional group differentiation, as illustrated in the reaction of the cyclohexenyl complex 34 with diethylacetylene (Scheme 7).69 Oxidative workup with ferric chloride-DMF removes the metal from complex 35 but does not oxidize the hydroquinone mono-ether, resulting in product 36. Pyridine N -oxide has also been used for this purpose.91 Oxidation with ceric ammonium nitrate removes the metal and oxidizes the product to the quinone 37. Cerium(IV) oxidation in methanol gives the quinone mono-acetal 38. Other oxidants that have been

OH Et

FeCl3-DMF complex

Et OMe 36 (64%) O

OH Et Cr(CO)5 OMe 34

Et

Et

THF, 45°

Et

CAN

Et

Et O 37 (65%)

(CO)3Cr OMe 35

O Et

CAN/MeOH

Et MeO OMe 38 (59%)

Scheme 7

134

ORGANIC REACTIONS

used include lead oxide,92 nitric acid,76 silver oxide,93 and iodine.67 The ferric chloride-DMF complex is not selective in the oxidation of naphthol chromium tricarbonyl complexes, removing the metal and oxidizing the product to a naphthoquinone. Other than air, no oxidant has been reported that will selectively remove the metal from a naphthol chromium tricarbonyl complex without also oxidizing the naphthol to a naphthoquinone. Air oxidation is usually effective for obtaining naphthols from naphthol complexes but exposure to air for extended times, or additional irradiation with ultraviolet light may be required for certain complexes. Ligand displacement with CO can be a useful alternative for the clean isolation of naphthols. In general, it has been possible to efficiently protect the phenoxy function while retaining the chromium tricarbonyl group in products from the reactions of alkenyl complexes. However, this process has not been as successful for the reactions of aryl complexes, probably because of the increased lability of naphthol chromium tricarbonyl complexes toward ligand displacement compared to that of phenol chromium tricarbonyl complexes. For example, the reaction of phenyl complex 26 with 1-hexyne in the presence of acetic anhydride and triethylamine gives the acetylated product 39, which has lost the metal (Eq. 5).94 In contrast, cyclohexenyl complex 34 undergoes benzannulation with 1-pentyne followed by in situ acylation to give tricarbonyl(O-acetoxyarene)chromium complex 40 in 64% yield (Eq. 6).95 O-Acetyl complexes can sometimes be obtained from aryl carbene complexes if the naphthyl chromium tricarbonyl complexes are first isolated.73 Whereas O-acetoxynaphthalene chromium tricarbonyl complexes cannot be obtained by the one-pot method, the in situ acylation of these products is useful because O-acylated naphthols are often less sensitive to air oxidation than their corresponding naphthols. For this reason, in situ acylation is often used to produce acylated products from both alkenyl and aryl complexes and the transformation indicated in Eq. 5 has been developed as an Organic Syntheses procedure.94 With alkenyl complexes, the metal-free O-acylated products are obtained from a tandem process in which the benzannulated product is exposed to air before the acylating reagents are added.

OH Bu-n

Bu-n, THF, reflux Cr(CO)5 OMe 26

Ac2O, Et3N, DMAP (CO)3Cr OMe

(Eq. 5)

OAc Bu-n

OMe 39 (68%)

THE SYNTHESIS OF PHENOLS AND QUINONES

135

OAc Pr-n

Pr-n, THF, 50° Cr(CO)5

(Eq. 6)

AcBr, (i-Pr)2NEt

OMe

(CO)3Cr OMe 40 (64%)

34

Several other methods for derivatization of the phenoxy function have been reported for the direct preparation of differentially-protected (hydroquinone)chromium tricarbonyl complexes. The silylated chromium tricarbonyl complex 4295 and the triflated complex 4396 have both been prepared from carbene complex 41 and 1-pentyne (Eq. 7). The yields of these complexes are approximately the same for both one-step and two-step processes. Silylated complexes can also be obtained from aryl complexes in a one-pot process with certain alkynes.73,97 Other electrophiles that have been used include triisopropylsilyl triflate and methoxymethyl chloride.95 Two reports of functionalization of the phenol by an intramolecular Mitsunobu reaction have been described.98,99 In the reaction of the octalin carbene complex 44, the metal is retained in product 45, which is formed as a single diastereomer (Eq. 8).99 OTBS Pr-n

THF, 50° 2. TBSCl, Et3N, rt Cr(CO)5

1.

(CO)3Cr OMe

Pr-n

42 (65% )

OMe

(Eq. 7)

OTf

41

Pr-n

CH2Cl2, 50° 2. Tf2O, (i-Pr)2NEt, rt (CO)3Cr OMe 43 (66% )

(CO) 5Cr

OEt

EtO

Cr(CO)3 (CH2)4OH

44

Cr(CO)3

DEAD

(CH2)4OH OH

THF, 60° H

EtO

H

O

Ph3P H 45 (50%)

(Eq. 8) Regioselectivity. In general, the regioselectivity of the reaction is controlled by steric effects and the level of regioselectivity is related to the difference in steric bulk of the two alkyne substituents.67 – 70 The major isomer derives from the incorporation of the larger substituent into the position adjacent to the phenolic hydroxy group. The largest difference in substituent sizes occurs when one of them is hydrogen, and thus the highest selectivities are found with these alkynes.

136

ORGANIC REACTIONS

The regioselectivity with terminal alkynes is almost always extremely high with both aryl and alkenyl complexes alike. This high selectivity is illustrated by the reaction of phenyl complex 26 with phenylacetylene, which gives at least a 179 : 1 selectivity for phenol 46 in preference to phenol 47 (Eq. 9).100 Likewise, reaction of cyclohexenyl complex 34 with 1-pentyne gives phenol 48 in preference to phenol 49 with at least 250 : 1 selectivity (Eq. 10).101 OH 1. Cr(CO)5

OH Ph +

Ph, THF, 45°

2. air

Ph

OMe

OMe

26

(Eq. 9)

OMe

46

47 (87%) 46:47 ≥ 179:1 OH

OH 1.

Cr(CO)5

Pr-n +

Pr-n, THF, 50°

2. FeCl3-DMF

Pr-n

OMe

(Eq. 10)

OMe OMe 48 49 (55%) 48:49 ≥ 250:1

34

The pair of reactions of carbene complexes 41 and 50 with 1-pentyne provides a direct comparison of the regioselectivity of these complexes with the same alkyne because these two reactions share the same set of two possible isomeric quinones (but not phenols) (Eq. 11).69 Interestingly, whereas the trans1-propenyl complex 50 gives the typically high regioselectivity observed with terminal alkynes, the 2-propenyl complex 41 only gives a 93 : 7 selectivity for quinones 51 and 52. This ratio represents the lowest regioselectivity that has been observed in the reaction of an alkenyl complex with a non-electronically perturbed terminal alkyne and no explanation for it has been offered. The regioselectivity of this reaction can be increased to 97 : 3 if the reaction is performed with 1-tributylstannyl-1-pentyne.72 Cr(CO)5

+

Pr-n

OMe 41 Cr(CO)5

O

O Pr-n

1. THF, 45°

+

2. CAN +

Pr-n O 51

Pr-n

O 52

(Eq. 11)

OMe 50

Complex 41 50

51 + 52 (51%) (75%)

51:52 93:7 1:99

The effect of the difference in steric size of the two alkyne substituents on the regioselectivity of the reaction is illustrated in Eq. 12.67 2-Pentyne gives a 1.5 : 1 mixture of the isomeric quinones 54 and 55 upon reaction with the

THE SYNTHESIS OF PHENOLS AND QUINONES

137

2-methoxyphenyl complex 53 (Eq. 12). This ratio is increased to 4.8 : 1 with 4-methyl-2-pentyne. On the basis of the difference in the size of the two substituents, higher regioselectivity was expected for the reaction with 1-phenylpropyne and the value of 41 : 1 has been recorded for this reaction.66 This selectivity drops to 18 : 1 when the temperature is increased from 45◦ to 90◦ . This is the only example in which regioselectivity as a function of temperature has been reported.

O OMe MeO

1.

O R

R, THF, 45°

+

2. CAN

R

Cr(CO)5

MeO

53

O 54

R Et i-Pr Ph Ph

Temp 45° 45° 45° 90°

MeO

O 55

(Eq. 12)

54:55 1.5:1 4.8:1 41.0:1 18.0:1

Regioselectivity is rarely influenced by electronic perturbations of the alkyne. Very small differences in the regioselectivity of the reaction of complex 26 with substituted diphenylacetylenes 56 are found where nearly equal ratios of phenol complexes 57 and 58 are observed despite significant electronic differences in the two arene rings of 56 (Eq. 13).42 Electronic factors can, under some circumstances, exert a strong influence on regioselectivity.71 – 73 If the alkyne is substituted by a stannyl group, the regioselectivity of incorporation of the alkyne occurs as if the stannyl group were not present. Occasionally the regioselectivity is enhanced over that observed for the terminal alkyne. For example, the reaction of complex 41 with 1-tributylstannyl-1-pentyne gives, after oxidative workup, a 97 : 3 mixture of quinones 51 and 52 (Eq. 11).72 The reaction of tributylstannylacetylene with complex 59 followed by in situ protection with tert-butyldimethylsilyl triflate gives the stannyl-substituted chromium tricarbonyl complex 60 in 40% yield, and the destannylated complex 61 in 27% yield (Eq. 14).72 The major product 60 has the stannyl group incorporated adjacent to the methoxy group (3-position). This orientation is opposite to the regioselectivity previously seen with all terminal acetylenes. Minor product 61 could have resulted from loss of the stannyl group in either the 2- or 3-position. The reaction with 2-deuterio-1-tributylstannylacetylene proceeds with a 2 : 1 selectivity in favor of the “abnormal” isomer 60. The origin of this effect is attributed to β-stabilization of the positive charge on C1 of the vinyl carbene complexed intermediate (E)-4a when the stannyl group is on C2 of (E)-4a (Scheme 3). Although silicon has a lesser ability to stabilize β-carbocations than does tin,102

138

ORGANIC REACTIONS

it is nonetheless surprising that a similar electronic effect has not been observed for silicon.69,72,73 +

Cr(CO)5

R2

OMe

26

Bu2O, 45°

R1 56 R

OH

1

R2

OH

+

(Eq. 13) (CO)3Cr

OMe

(CO)3Cr OMe

R2

57

R1

58 R1 H H Me

R2 Me CF3 CF3

57 + 58 57:58 (52%) 0.82:1.00* (66%) 1.22:1.00* (62%) 1.17:1.00

* constitution not assigned OTBS TMS

1. Cr(CO)5

Sn(Bu-n)3, THF, 50°

2. TBSOTf, Et3N

OMe 59

OTBS

+ TMS Sn(Bu-n)3 TMS (CO)3Cr OMe (CO)3Cr OMe 60 (40% ) 61 (27%)

(Eq. 14) A disubstituted alkyne with a ketone function in conjugation with the alkyne reacts with high regioselectivity to give products in which the ketone function is introduced into the phenol adjacent to the methoxy group (Eq. 15).71 Reaction of complex 62 with hex-3-yn-2-one gives products 63 and 64, both as a result of the same regiochemical incorporation of the alkyne. Compound 64 is formed via cyclization of the vinyl ketene in a crossed fashion. Ester functions do not impart a strong enough effect when conjugated with an alkyne to influence the regioselectivity and as a result mixtures of isomers are observed.47,70 It is curious that a ketone, which is separated from the alkyne by two methylenes, has an effect on the regioselectivity, albeit to a lesser extent than is observed with conjugated ketones (Eq. 47).103 A recent report on the regiochemical outcome of the reactions of internal boryl alkynes may involve electronic control of the regioselectivity by boron.74,75 OH Et OMe

O

Cr(CO)5 62

THF, 50°

O

Et

Ac

+ O

Ac

OMe 63 (33%)

O Et

O OMe 64 (32%)

(Eq. 15)

THE SYNTHESIS OF PHENOLS AND QUINONES

139

Site selectivity in reactions of unsymmetrically substituted phenyl carbene complexes has been examined to some extent. In all of the reactions of 3-substituted phenyl carbene complexes 65, the major isomer 66 results from cyclization away from a meta substituent (Eq. 16).67 A very curious observation is that the magnitude of the site-selectivity observed with the 3-methoxy complex 65b is highly dependent on whether a terminal or internal alkyne is used.67 The reaction with 3-hexyne is four times less selective than the reaction with 1-pentyne. An explanation for this behavior has not been advanced. The electronic nature of the meta substituent also has a strong effect. The 3-trifluoromethylphenyl complex 65c is ten times as selective as the 3-methoxy complex 65b. The same reaction with the 3-methyl complex 65a gives a 1.2 : 1 mixture of 66a and 67a. Because the trifluoromethyl group is not significantly different in size than a methyl or methoxy group, it is clear that a strongly electron-withdrawing group directs the cyclization to the more remote para position. Two isomers are also possible in the cyclization of the 2-naphthyl complex 68. However, reaction with diphenylacetylene affords only a single isomer, namely a phenanthrene rather than an anthracene (Eq. 17).104 The actual chemical yield of this reaction is likely to be quite high and the low yield of 69 is likely a consequence of the air instability of this arene chromium tricarbonyl complex containing an unprotected phenolic hydroxy group. Cyclization to the 1-position of the naphthalene is a typical reactivity pattern for various types of cyclizations of 2-substituted naphthalenes because this option disrupts the aromaticity in only one of the naphthalene rings. This direction of cyclization of 2-substituted naphthyl carbene complexes has been confirmed in a different system by X-ray crystal structure analysis.105 OMe

(CO)5Cr

O 1. Et

R

65 65a 65b 65c

R Me OMe CF3

66 + 67 (79%) (81%) (55%)

Ph

Ph

Bu2O, 45° 68

Et

Et MeO OMe 66

Et MeO OMe 67

(Eq. 16)

66:67 1.2:1 2.1:1 25.5:1

Ph

Cr(CO)5 OMe

O

+

2. CAN/MeOH R

R Et

Et, THF, 45°

HO

Ph OMe Cr(CO)3

(Eq. 17)

69 (19%)

The normal site selectivity of the reaction of Fischer carbene complexes with alkynes can be reversed if the alkyne is tethered through the heteroatomstabilizing substituent. Either isomer of the quinone from the reaction of 4-methylphenyl carbene complex and 3-butynol can be obtained cleanly as shown

140

ORGANIC REACTIONS

in Eqs. 18 and 19.86 Carbene complex 70 and the free alkyne give the expected quinone isomer in 76% yield. The regiochemical outcome is reversed for the tethered complex 71 because the vinyl carbene complexed intermediate 72 in this reaction has the unsubstituted end of the alkyne at the C1 position. Note that in the absence of a tether, a terminal alkyne will preferentially be incorporated to give vinyl carbene intermediate (E)-4 rather than (E)-7 (Scheme 3) for the reasons discussed above. It is interesting to note that the intramolecular reaction of complex 71 gives high yields only in the presence of ten equivalents of diphenylacetylene. This phenomenon is observed for a number of intramolecular examples and is termed the xenochemical effect.86 The xenochemical effect is related to the allochemical effect84 in that the product distribution is a function of the alkyne concentration, but it differs in that the distribution is a function of the concentration of an alkyne that does not become incorporated into the product (Scheme 6). 1. Cr(CO)5 OMe 70

Cr(CO)5 O 71

O

(CH2)2OTHP, hexane, reflux

2. CAN 3. MeOH, HCl

O OH (76%)

(Eq. 18)

O

1. Ph Ph (10 eq), hexane, reflux

O (60%)

2. CAN

OH

Si Me2

O R3

R1

O

(Eq. 19)

R2 OC

Cr CO OC CO 72

Alkenyl, Aryl, and Alkynyl Chromium Complexes. The only alkenyl chromium carbene complex that will not react with alkynes to give useful yields of annulated products is the unsubstituted parent vinyl carbene complex 73 (Scheme 8). The reaction of complex 73 with 1-pentyne gives approximately a 13% yield of phenol 74.106 The origin of the failure of this reaction is not understood but it is known that complex 73 is unstable with respect to polymerization and can only be isolated in pure form below its melting point (15◦ ).107 – 109 The α-silyl-substituted vinyl complex 59 (Scheme 8) has been developed as a synthetic equivalent for the parent vinyl complex.110 The reaction of 59 with 1-pentyne followed by exposure to air and trifluoroacetic acid affords phenol 74 in 60% yield. Both the 2-propenyl and trans-1-propenyl complexes react with alkynes to give useful yields of the cyclized product (Eq. 11). The cis-1-propenyl

THE SYNTHESIS OF PHENOLS AND QUINONES

141

OH Cr(CO)5 OMe

Pr-n

Pr-n

(~13%)

CH2Cl2, 50°

73

OMe 74 OH

TMS Cr(CO)5 OMe 59

1.

Pr-n

Pr-n

CH2Cl2, 50°

2. air/CF3CO2H

74 (60%)

TMS (CO)3Cr OMe 75

Scheme 8

complex also reacts with alkynes to give phenol products but the cis- and trans1-propenyl complexes could not be compared since the former isomerizes to the trans complex at a rate competitive with the reaction with 1-pentyne.69 Interestingly, β,β-disubstituted complexes do not isomerize during their reactions with alkynes.111 The β-silyl-substituted complex 76 can also serve as a synthetic equivalent for the parent and has the additional advantage that the silicon migrates to the phenolic oxygen both obviating the need for protodesilylation and producing an air-stable arene chromium tricarbonyl complex directly from the reaction (Eq. 20).110 This process occurs because migration of silicon to oxygen is faster than tautomerization of the hydrogen in intermediate 78. Benzannulation of a β-silyl-substituted carbene complex can be coupled with a Diels-Alder reaction of an alkynyl carbene complex as illustrated in the one-step preparation of the dihydronaphthyl complex 81 (Eq. 21).95,112 In this process, the diene reacts with alkynyl complex 79 faster than with the alkyne to give the Diels-Alder adduct 80, which then reacts with 1-pentyne with silyl migration to give the arene complex 81 in 80% yield.

Pr-n

Cr(CO)5

TBS

OMe

OTBS Pr-n

CH2Cl2, 50° (CO)3Cr OMe

76

77 (72%) O Pr-n

TBS

(CO)3Cr OMe 78

(Eq. 20)

142

ORGANIC REACTIONS

OMe (CO)5Cr + 79

+

THF, 50°

Pr-n

TMS Pr-n

OMe (CO)5Cr

TMS

MeO

(Eq. 21)

OTMS

(CO)3Cr 80

81 (80% )

A wide range of substituents on the phenyl ring in an aryl carbene complex can be tolerated in the reaction. The introduction of a methyl group at the 2-position (82) has very little effect on the yield of quinone product (Eq. 22 vs. Eq. 23).84 However, the methyl substituent does have some effect on the reaction run at lower concentration and higher temperatures where both quinone and indene products are observed. A methoxy group at this position has an even greater effect (Eq. 24).84 Even if the reaction of the 2-methoxyphenyl complex 53 is run at high concentration and low temperature to maximize the six-membered ring product, indenes 84 and 85 are still formed in a combined 23% yield. More dramatically, at low concentrations and high temperatures only a trace of the quinone is observed. The yield of quinone 83 can be improved (77–91%) by utilizing a large excess of alkyne or employing a less coordinating solvent (benzene or 2,5-dimethyltetrahyrofuran).84

Cr(CO)5 OMe 26 [26] 0.1 M 0.005 M

1. Et Et, THF, temp

+

Temp 45° 110°

OMe

(88%) (87%)

(Eq. 22)

(≤0.3%) (≤1.0%)

O

Et Et +

2. CAN

Et O

Temp 45° 110°

Et

Et O

OMe 82 [82] 0.5 M 0.005 M

Et Et

2. CAN

1. Et Et, THF, temp Cr(CO)5

O

(87%) (58%)

Et OMe

(≤1.0%) (16%)

(Eq. 23)

THE SYNTHESIS OF PHENOLS AND QUINONES O

1. Et Et, THF, temp

OMe Cr(CO)5

Et

Et

Et +

2. CAN

Et

Et

OMe 53

OMe OMe 84

OMe O 83

[53] 0.5 M 0.005 M

143

Temp 45° 110°

(61%) (trace)

(18%) (65%)

+

Et OMe O 85 (5%) (10%)

(Eq. 24) The effect of the methoxy group at the 2-position may be due to a combination of coordination, electronic, and steric effects. Interestingly, the 4-methoxyphenyl complex 86 displays a different sensitivity to concentration and alkyne substitution than the does the 2-methoxyphenyl complex 53 and thus the effects of the methoxy group cannot be strictly electronic (Eq. 25).84 The 4-methoxy complex reacts with 1-pentyne to give a 30% yield of quinone 87 along with indene 88 and keto ester 89, whereas, the reaction of the 2-methoxyphenyl complex under the same conditions gives the quinone as the predominant product (not shown).84 The keto ester 89 is not a primary product of the reaction but rather results from air oxidation of furan 90, which is often seen as a by-product in this reaction but is usually difficult to isolate.65,76,77 The influence of the 4-methoxy group can only be electronic and the degree of its effect is significant because the reaction of the unsubstituted phenyl complex 26 gives a 73% yield of the quinone 29 (Eq. 2) and the 4-acetoxy complex 91 gives a 61% yield of the quinone 92 (Eq. 26).84 1.

MeO Cr(CO)5

Pr-n, THF, 45°

O

Pr-n MeO

Pr-n

MeO

+

+

2. CAN

OMe

OMe

O 87 (30%)

86 (0.5 M)

88 (37%) O O

MeO n-Pr

OMe 89 (9%)

OMe MeO

O

n-Pr 90

(Eq. 25)

144

ORGANIC REACTIONS 1.

AcO Cr(CO)5

Pr-n, THF, 45°

O Pr-n

AcO

(Eq. 26)

2. CAN

OMe

O 92 (61%)

91 (0.5 M)

Almost all of the substituent effect studies that have been carried out on the reaction of substituted phenyl complexes involve alkyl or alkoxy groups. Complexes bearing electron-withdrawing groups have rarely been studied because they are not available by the standard methods of synthesis. Fischer carbene complexes are typically prepared by reaction of chromium hexacarbonyl with the corresponding aryllithium compounds. Thus, functionality that is not compatible with an organolithium reagent cannot be easily introduced into an arylcarbene complex. A recent study provides one of the few direct comparisons of the effects of electron-withdrawing and electron-donating groups on the reactions of phenyl carbene complexes (Eqs. 27 and 28).113 Reactions of a number of para-substituted complexes with 1-pentyne were examined in benzene. The complex bearing the electron-releasing methoxy group gives low yields of quinone product and an equal amount of the indanone product (the distribution is slightly different in benzene and THF; Eqs. 25 vs. 27). The effect of the bromo substituent is negligible, whereas the trifluoromethyl group has a dramatic effect, affording a 95% yield of the quinone. The observation of a positive effect of an electron-withdrawing group was anticipated from published mechanistic studies.47 However, the yield from the 4-acetylphenyl complex is not consistent with these studies and this may be because of the instability of this complex. The reaction of the phenyl complex bearing a trifluoromethyl group in the 2-position with 1-pentyne gives a much reduced yield of quinone.113 In fact, all 2-substituted phenyl complexes give reduced yields independent of the electronic nature of the substituent. The larger the substituent the more the yield decreases (methyl vs. iso-propyl).113 The reduced yields observed with 2-substituted complexes could be the result of steric destabilization of the planar conformation of the vinyl ketene complex (E)-5 that is necessary for cyclization (Scheme 2).

1.

R Cr(CO)5 OMe 0.1 M

Pr-n, benzene, 80°

O R

Pr-n Pr-n

R +

2. CAN R OMe H Br Ac CF3

O

O (36%) (78%) (75%) (63%) (95%)

(Eq. 27) (40%) (1%) (—) (—) (—)

THE SYNTHESIS OF PHENOLS AND QUINONES 1. OMe

O

Pr-n, benzene, 80°

145 Pr-n

Pr-n +

2. CAN R Cr(CO)5 0.1 M

R

R H OMe CF3 Me i-Pr

O

R

(78%) (60%) (64%) (66%) (49%)

O

(Eq. 28)

(1%) (—) (—) (—) (11%)

The reactions of a number of internally coordinated tetracarbonyl carbene complexes have been investigated but the effects of such coordination on product distribution have not been carefully determined in many systems. Given the sensitivity of the reactions of the 2-methoxy-substituted phenyl carbene complex 53 to concentration, temperature, and solvent (Eqs. 24 and 28), it is necessary that comparisons be made with full awareness of the exact reaction conditions. One system in which a comparison under precise control of conditions has been made is the reaction of the 2-methoxy-4-acetoxyphenylcarbene complex 94 (Eq. 29).84 The chelated complex 94 can be generated in high yield by heating 93 in THF. The reaction of both complexes at 110◦ , and at 0.005 M in carbene complex with 1.5 equivalents of alkyne gives an essentially identical profile of the three products. From this experiment it can be concluded that it makes no difference whether 2-O-substituted phenyl carbene complexes are used as either the pentacarbonyl or the coordinated tetracarbonyl complexes. Often, the transient formation of an internally coordinated complex can be observed during the course of a reaction of a non-coordinated complex with an alkyne. AcO

1.

AcO Cr(CO)5

or

OMe MeO

OMe OMe 93

2. CAN

Cr(CO)4

94 O AcO

Pr-n

OMe O (41%) (41%)

AcO

AcO

Pr-n +

93 94

Pr-n THF, 110°

Pr-n

+ OMe O (12%) (14%)

OMe O O

OMe

(18%) (14%)

(Eq. 29) Although the reactions of complexes 93 and 94 demonstrate that the product distribution is not dependent on whether the methoxy group is coordinated prior to the reaction, the results in Eqs. 24 and 30 suggest that coordination by the methoxy group at some point in the reaction may take place. The chromium should be much less able to coordinate to a tert-butoxy group than to a methoxy

146

ORGANIC REACTIONS

group. Thus, if coordination of the methoxy group is responsible for the differences in the reactions of phenyl complex 26 and the 2-methoxyphenyl complex 53 (Eqs. 22 and 24), then the reaction of the 2-tert-butoxyphenyl complex 95 (Eq. 30) should have a product distribution more similar to that of 26 than to that of 53. On the other hand, if the effect is strictly electronic, then the two oxygenated complexes 53 and 95 should produce the same distribution. The result is intermediate between these extremes. It is clear that hindered protecting groups on the oxygen substituent allow preferential formation of the quinone product. The reaction of 2-tert-butoxyphenyl complex 95 with 3-hexyne at 0.5 M and 45◦ affords a 96% yield of the quinone with less than 1% of the indene (Eq. 30), whereas under the same conditions the 2-methoxyphenyl complex 53 affords only a 61% yield of the quinone and 23% of the indene (Eq 24).84 Note that the data in Eq. 28 predict that the yield of quinone from the reaction of complex 95 would be less than that for 53 (Eq. 24) given the size of the 2-substituent. However, the reactions in Eq. 28 are performed in a different solvent and are carried out on a terminal alkyne. Internal and terminal alkynes can have quite different product distributions (see below).

OMe

O

1. Et Et, THF, temp

+

2. CAN t-BuO

Cr(CO)5 95 [95] 0.5 M 0.005 M

Et Et

Et t-BuO

Temp 45° 110°

Et Et

O

(96%) (7%)

t-BuO

OMe

(≤1%) (54%)

+ t-BuO

Et O

(—) (8%)

(Eq. 30) The sulfur-coordinated complex 97 has been prepared and its reaction with 4-pentyn-1-ol has been compared with that of the non-coordinated complex 96 (Scheme 9).91 The reactions are carried out by adsorption on silica gel and the internally coordinated complex gives a 39% yield of the phenol 98, double that of the non-coordinated complex. No other products are reported for this reaction and the fate of the remainder of the substrate is not known. The coordinated complex is more stable than the non-coordinated complex, and thus the increased yield may be due to competing decomposition of complex 96. It is likely that the loss of sulfur arises from an in situ reduction of the cyclohexadienone 99 by chromium(0) to give 98.80 A variety of heteroaryl Fischer carbene complexes give good yields of annulated phenols and quinones. The reaction of the 2-furyl complex 100 with 3hexyne provides the quinone 101 in 85% yield after oxidative workup with CAN (Eq. 31).114 The reaction of the 3-furyl complex 102 gives the same quinone in 77% yield with no detectable amount of an isobenzofuran that would result from the alternate siteselectivity in the cyclization.104,114 The furan complex 100 reacts with the functionalized alkyne 104 in the presence of acetic anhydride to give

THE SYNTHESIS OF PHENOLS AND QUINONES

147

OMe (CO)5Cr O

S Ph 96

1. 45o, benzene (76%)

OH

(CH2)3OH silica gel, 80°

OH

2. pyridine N-oxide

O OMe

OMe

98 (19%) from 96 (39%) from 97

(CO)4Cr O

S Ph

Ph S O

97

OH O OMe 99

Scheme 9

the benzannulated product 105 (Eq. 32).115 The same reaction of the 2-pyrrolyl complex 103 is more efficient, providing the highly functionalized indole 106 in 62% yield.115,116

O

Cr(CO)5 O

1. Et Et, THF, 70°

OMe 100

Et

2. CAN O

O

Et

(Eq. 31)

O

Cr(CO)5

101 (85%) from 100 (77%) from 102

OMe 102

OAc OTBS X

Cr(CO)5 OMe

100 X = O 103 X = NMe

OTBS

+ EtO

THF, 65° Ac2O, NEt3

104

X

OEt OMe 105 X = O (43%) 106 X = NMe (62%)

(Eq. 32)

The site selectivity of the annulation of a 3-pyrrolyl carbene complex can be reversed by blocking the 2-position. This was demonstrated in the reaction of the 2,5-dimethyl-3-pyrrolyl complex 107 with diphenylacetylene to give a substituted isoindolequinone (Eq. 33).117 The synthetic utility of indole-substituted

148

ORGANIC REACTIONS

carbene complexes is illustrated in the reaction of the 2-indolyl complex 108, which reacts with 3-hexyne to give a carbazoloquinone in 81% yield (Eq. 34).62 Pyridylcarbene complexes have proved difficult to make118 – 120 and for this reason dihydropyridyl complexes of the type 109 were developed as synthetic equivalents for 2-pyridyl complexes (Eq. 35).121 Subsequent to annulation with an alkyne, the pyridine ring may be reoxidized with trityl tetrafluoroborate, which also oxidizes the hydroquinone ring to give substituted quinolinoquinones. 1. Ph Ph, toluene, 95°

Me N Cr(CO)5

O Ph Me N

2. air

OMe 107

Cr(CO)5 N Me

OMe

O (44 %) O

1. Et Et, THF, 50°

OMe

N Boc Cr(CO)5 109

Pr-n, THF, 60°

2. air

Et

(Eq. 34)

Et

2. CAN

N O Me (81%)

108 1.

(Eq. 33)

Ph

OH

O Pr-n

N Boc OMe (58%)

Pr-n

Ph3C+ BF4– N O (70%)

(Eq. 35) There have been occasional reports of the benzannulation of Fischer carbene complexes bearing heteroatoms at a position beta to the carbene carbon. Examples already discussed include the β-silyl substituted complexes 76 and 80 (Eqs. 20 and 21)112,110 and a β-thio ether complex 96 (Scheme 9).91 The sulfone complex corresponding to 96 also undergoes benzannulation with loss of the sulfone to give phenolic products related to 98 where the sulfur is lost in the aromatization.91 Only two examples of cyclization of complexes bearing β-oxygen substituents are known. In the first, the β-methoxyalkenyl complex 110 reacts with 1-pentyne to give phenol 111 in 64% yield (Eq. 36).122 The loss of the methoxy group from the cyclohexadiene complex 112 is likely a result of reduction by chromium(0) to give a chromium(II) phenolate complex.80 The second example is the reaction of the internally coordinated naphthyl complex 113 with the alkyne 114 to give the substituted phenanthrene 115 (Eq. 37).105 This example demonstrates the strong preference for cyclization of a 2-naphthyl complex to the α-position. With complex 113, this preference is strong enough to force cyclization to occur ipso to the methoxy despite the fact that the other ortho position is unsubstituted. An amino group in the β-position leads to the exclusive formation of cyclopentadiene products. This reaction has been examined extensively and is illustrated by the

THE SYNTHESIS OF PHENOLS AND QUINONES

149

reaction of complex 116 which gives the cyclopentadiene 117 in 77% yield (Eq. 38).123 Depending on the conditions and substrates, a variety of products have been observed from the reaction of β-amino complexes.30

MeO

β

1.

α

Cr(CO)5

OH

Pr-n, MeCN, 50°

Pr-n

2. air

OMe 110

OMe MeO

(Eq. 36)

111 (64%)

O Pr-n

(CO)3Cr OMe 112 OMe OMe + OMe MeO

OMe

1. t-BuOMe, 50° CO2Me 2. PPh3, acetone, CO2Me Ac 2O, NEt3

Cr(CO)4

113

114

AcO

115 (44%)

CO2Me CO2Me

(Eq. 37) NMe2

NMe2

Pr-n n-Pr

EtO

(Eq. 38)

THF, 52° Cr(CO)5 116

OEt 117 (77%)

Cyclization occurs onto an α,β-unsaturated carbene complex that bears a β-halogen substituent. The two known examples involve fluorine and chlorine substituents. The β-chloroalkenyl complex 120 reacts with phenylacetylene to give a significantly higher yield of the quinone 119 than the corresponding unchlorinated complex 118 (Eq. 39).124 The α,β-difluoro complex 121 reacts in a similar fashion to afford (after cyclization and reductive cleavage of the fluorine) phenol 122 in 35% yield (Eq. 40).125 Cyclization does not occur if the βfluoro substituent is on a benzene ring.126 The reaction of the 2,6-difluorophenyl complex 123 with diphenylacetylene affords the cyclobutenone 124 as the major product (Eq. 41).126 A second product, 125, results from cyclization, not onto the phenyl group of the carbene complex, but onto the phenyl group of the alkyne. Both products from this reaction are obtained as chromium tricarbonyl complexes but in each case it was not determined which of the aryl rings is coordinated.

150

ORGANIC REACTIONS Cr(CO)5 O

BnO

OEt

Ph, SiO 2, 80°

O O

BnO

2. CAN

R

BnO

1.

BnO

BnO 118 R = H 120 R = Cl

Cr(CO)5

n-Bu

OMe 121

F MeO

F 123

(Eq. 39)

OH

1. Ph Ph, t-BuOMe, 55°

n-Bu

Ph

F

Ph

2. FeCl3-DMF

(Eq. 40)

OMe 122 (35%)

1. Ph Ph, n-Bu2O, 100°

O

OMe

F • Cr(CO)3

2. air

(CO)5Cr

O

119 (19%) from 118 (48%) from 120

F

F

Ph BnO

Ph

+

Ph F 124 (30%)

(Eq. 41) F

F OMe Ph

• Cr(CO)3

125 (—)

The benzannulation of α-alkynyl complexes has been reported and is illustrated in Scheme 10.127 Mechanistically, this reaction must be quite distinct from that of alkenyl- and arylcarbene complexes (Scheme 1). Intramolecular reaction of the pendant alkyne in complex 126 and carbon monoxide insertion is proposed to give an alkynyl-substituted vinyl ketene complex of the type 127. Cyclization of this vinyl ketene complex then gives a diradical intermediate, which upon hydrogen abstraction gives a benzannulated product. Note that the indoline 129 obtained from thermolysis of complex 126 is the same product that could be produced from the alkenyl complex 131 by the normal mechanism. However, complexes of the type 131 do not give phenols but rather cyclize without CO insertion to give a cyclopentadiene unit that is embedded into an azabicyclo[3.3.0]octane.128 The indoline 129 cannot be isolated as its chromium tricarbonyl complex. However, if the reaction of 126 is carried out in the presence of triethylsilane as hydrogen donor, the silyloxyindolinylchromium tricarbonyl complex 130 is isolated in 41% yield. Recently, an alternative entry to diradical intermediates of the type 128 from saturated carbene complexes has been reported, and the synthetic utility of these intermediates has been further explored.129,130 Alkyne Components. The reactions of α,β-unsaturated Fischer carbene complexes with alkynes will tolerate a broad range of functional groups present in the alkyne. Less tolerant are alkynes that are conjugated to strongly electronwithdrawing or electron-donating groups and also alkynes that are very bulky.

THE SYNTHESIS OF PHENOLS AND QUINONES

γ-terpinene, Ac2O, NEt3

(CO)5Cr N Me

Ph

O

.

• N Me Cr(CO)3

THF, 85° Ph

126

151

O

.

Ph

127

128

Et3SiH THF, 85°

H source

Et3SiO

AcO

(CO)5Cr N Me Cr(CO)3

Ph

N Me Cr(CO)3

N Me

Ph

130 (41%)

Ph

131

N Me

129 (53%)

Scheme 10

Coordination of functional groups on the alkyne to the metal can lead to sideproduct formation. Functional groups on the alkyne that survive under the reaction conditions include alkenes, alkynes (hindered), halides, silanes, stannanes, ethers, thio ethers, seleno ethers, acetals, epoxides, ketones, esters, amides, nitriles, nitro groups, sulfoxides, and sulfones. Alcohols can be tolerated by the reaction in some instances (see below). The reaction of Fischer carbene complexes with acetylene fails to give useful amounts of the normal benzannulation product. For example, the reaction of complex 26 with two equivalents of acetylene affords a 1% yield of naphthol 132 and a 36% yield of the two-alkyne phenol 133 (Eq. 42).131 The two-alkyne phenol results from incorporation of the carbene carbon, a carbon monoxide ligand, and two equivalents of the alkyne. The primary product is the cyclohexadienone complex of the type 134, which is reduced by chromium(0) to the phenol.80 The yield of the two-alkyne phenol drops sharply with substituted alkynes. The reaction of 26 with propyne provides useful yields of the naphthols and only 4% of the two-alkyne phenol corresponding to 133.131 OH OH

(2 eq) Cr(CO)5

+

THF, 45°

OMe

OMe 132 (1%)

26 O

OMe Ph

(CO)3Cr 134

133 (36%)

(Eq. 42)

152

ORGANIC REACTIONS

Trimethylsilylacetylene can serve as a synthetic equivalent for acetylene because it affords high yields of the normal benzannulated product and can be subject to clean proto-desilylation (Eq. 43, Scheme 8).69,101,110 Bulky silylsubstituted alkynes can lead to the isolation of vinyl ketenes that are stabilized by the α-silyl substituent.57,61,132 – 134 Thus, reaction of phenyl complex 26 with phenyl(triisopropylsilyl)acetylene gives the vinyl ketene in 88% yield (Eq. 44).134 Whereas stannyl-substituted alkynes do not yield stable vinyl ketenes, they have been reported to cause a reversal in the site selectivity of alkyne incorporation into phenolic products (Eq. 14).72,73 OH

R2 R1

R2

TMS

OMe

OH TMS

R2

+

H

(Eq. 43)

R1

Cr(CO)5

R1 OMe

OMe O

Cr(CO)5

Ph

TIPS

Ph

benzene, 80°

OMe

TIPS

•

(Eq. 44)

(88%)

OMe Cr(CO)3

26

The efficiency of phenol formation from unfunctionalized alkynes is quite different for internal and terminal alkynes. The reactions of 4-substituted phenyl carbene complexes in benzene with 3-hexyne (Eq. 45) are compared to the same reactions with 1-pentyne (Eq. 27).113 Reactions with 3-hexyne produce greater than 90% yields of quinone products for all 4-substituted phenyl complexes including those with electron-deficient as well as electron-donating substituents. The yields are also generally higher for reactions of ortho-substituted complexes with 3-hexyne compared to 1-pentyne (Eq. 46 and Eq. 28). However, as in the reaction of 1-pentyne (Eq. 27), the yields from reactions of 3-hexyne with orthosubstituted complexes are also suppressed relative to those of the unsubstituted phenyl complex (Eqs. 45 and 46). There are two reports of the reactions of cyclic alkynes, and the example shown in Eq. 47 is of interest because it reveals that a carbonyl group separated from an alkyne function by two methylenes can influence the regioselectivity.103,135 R OMe

1. Et Et, benzene, 80°

O R

R OMe H Br CF3

R +

2. CAN Cr(CO)5

Et Et

Et

Et O

O

(93%) (96%) (93%) (96%)

(—) (<0.7%) (<1%) (—)

(Eq. 45)

THE SYNTHESIS OF PHENOLS AND QUINONES

OMe

O

1. Et Et, benzene, 80°

Et Et +

2. CAN R

Et

Et

Cr(CO)5

R

R H OMe CF3 Me

153

R

O

O

(Eq. 46)

(<0.7%) (7%) (—) (—)

(96%) (77%) (74%) (58%)

O O

R

Cr(CO)5

O

1. THF, 45°

OMe +

O +

2. CAN O

R

O

R H OMe CF3

R

I I + II (89%) (69%) (42%)

O

II

(Eq. 47)

I :II (—) 2.3:1.0 1.5:1.0

Although alkenes react with Fischer carbene complexes to produce cyclopropanes,136 they do so too slowly to compete with the benzannulation reaction. Thus, the reaction of Fischer carbene complex 34 with (Z)-1-methoxybut-1-en-3yne results in a good yield of the phenol (Eq. 48).69 The compatibility of alkenes with the benzannulation reaction has also been demonstrated in an intermolecular competition experiment. The yield of the quinone from the reaction of complex 53 and 3-hexyne (Eq. 24) is unchanged (58%) when carried out in the presence of four equivalents of ethyl vinyl ether137 even though, in the absence of 3-hexyne, ethyl vinyl ether gives good yields of cyclopropane.138 MeO Cr(CO)5 OMe 34

OH

O

(2 eq),

TsOH

(Eq. 48)

OMe

THF, 45° OMe (68%)

OMe (70%)

Conjugated 1,3-diynes react with one equivalent of a Fischer carbene complex to provide the benzannulated product in which one of the alkynes has been incorporated in a process that is unaffected by the presence of the other alkyne. After decomplexation of the metal from the phenol 135 by exposure to air, a second benzannulation can be carried out to give biaryl product 136 in good yield (Eq. 49).100 Interestingly, product 136 cannot be obtained by direct reaction of the diyne with an excess of the carbene complex. It thus appears that the presence of a chromium tricarbonyl group on the mono-annulated product 135 hinders subsequent reaction with a second equivalent of carbene complex. The reactions

154

ORGANIC REACTIONS

of conjugated 1,3,5-triynes are complicated by the ability of a carbene complex to react either with the central alkyne unit or with one of the two terminal alkyne units. Steric interactions predict that the reaction would be selective for the central alkyne. The cyclohexenyl complex 34 reacts at the central alkyne with 1,3,5-triynes that are capped with triisopropylsilyl groups. Surprisingly, the triyne capped with a phenyl group gives rise to exclusive incorporation of a terminal alkyne unit (Eq. 50).139 1. Ph THF, 66° Cr(CO)5

OH

Ph,

Ph

1. 34, THF, 70°

2. air

2. air

OMe

OMe 135 (67%)

34

Ph

(Eq. 49)

OH Ph

Ph OMe

MeO

HO

136 (56%)

Cr(CO)5 OMe 34

1. R THF, 55°

R

2. air OH R

OH

R

OMe

R

(Eq. 50)

or OMe R (43%) R = Ph

(70%) R = TIPS

Heteroatom-substituted alkynes do not always react with Fischer carbene complexes to give phenolic products. Ynamines are reactive towards Fischer carbene complexes and react below room temperature to give simple non-cyclized insertion products.140,141 This reaction occurs by a mechanism that is different from that for simple alkynes. The reaction is first order in both carbene complex and ynamine.141 The insertion products undergo a thermally induced cyclization that leads to indene products and not to phenols, presumably due to the electronrich nature of α,β-unsaturated complexes of type 137 (Eq. 51).142 In contrast to ynamines, alkoxy-substituted alkynes such as 104 do react with carbene complexes to give phenols (Eq. 32). Terminal alkoxy acetylenes also yield insertion products analogous to 137.143 Alkynyl thio ethers do not react with chromium carbene complexes in the same way as either ynamines or alkoxy acetylenes, but rather give very unusual dienyne products that are unprecedented in all

THE SYNTHESIS OF PHENOLS AND QUINONES

155

the reactions of carbene complexes with alkynes (Eq. 51).144 Tungsten complexes react with thioalkynes to give insertion products analogous to 137.145 Haloacetylenes react with Fischer carbene complexes to generate complex mixtures of products.72,146 MeO n-Bu

Bu-n

Ph

SMe

(39%)

Ph

hexane, 80˚ n-Bu

MeO

OMe

(Eq. 51)

Cr(CO)5 Ph 26

NEt2

NEt2

(CO)5Cr

Ph

hexane, 20° 137

(70%)

OMe

The presence of an alcohol function on the alkyne can sometimes be tolerated, but can also lead to intramolecular trapping of the complexed vinyl ketene intermediate to give lactones. This behavior is dependent on the length and substitution of the tether between the alkyne and the alcohol function and on the nature of the carbene complex. A dramatic example of this dependence is the reaction of the two propargylic alcohols shown in Eqs. 52 and 53. Propargyl alcohol gives only the phenol (Eq. 53),147 whereas substituted propargylic alcohols give β-lactones as the exclusive products (Eq. 52).148 This divergence has been attributed to the Thorpe-Ingold effect.148 Interestingly, alkynes similar to 138 that contain a 4-membered ring can afford either ring-expanded or cyclobutenone products.149 OH

Ph +

(CO)5Cr

O

O THF, reflux

Ph

Ac2O, NEt3

OMe 26

138

(52%)

(Eq. 52)

OMe

OH OH Cr(CO)5 OMe 26

+

OH

t-BuOMe

(Eq. 53)

45° OMe (60%)

Homopropargylic alcohols afford substantial amounts of lactone product with aryl complexes but not with alkenyl complexes.147 Whereas the reaction of 4methylphenyl complex 70 affords naphthol 139 in only 17% yield along with the lactone 140 in 33% yield (Eq. 54a), the reaction of alkenyl complex 141 with 3-butyn-1-ol affords phenol 142 in good yield (Eq. 54b).147 Lactone 140 is depicted as the Z-enol ether rather than as the E-enol ether that was originally reported. Subsequent work established that the enol ether from the reaction

156

ORGANIC REACTIONS

of 4-pentyn-1-ol with complex 70 was assigned incorrectly as the E-enol isomer and thus it is considered likely that the enol ether configuration of 140 was also incorrectly assigned as the E-isomer.65 The Z-isomer of the complexed vinyl ketene intermediate 143 cannot cyclize to the naphthol 139. Because the E-isomer of 140 is not observed, it can be assumed that for the E-isomer of ketene complex 143, intramolecular trapping of the ketene by the hydroxy group cannot compete with cyclization to phenol 139. Longer-chain alcohols give much less of the ketene-trapped product. The reactions of complex 70 with 4-pentyn-1-ol and 5-hexyn-1-ol give the corresponding naphthols in 44 and 75% yields, respectively.147

OH

OH

OH +

Cr(CO)5

t-BuOMe, 45°

OMe

OMe 70

O O

OMe 139 (17%)

140 (33%)

(Eq. 54a) OH

OH OH

Cr(CO)5 t-BuOMe, 45°

OMe

OMe

141

142 (76%)

(Eq. 54b)

Cr(CO)3 Cr(CO)3

MeO • O (E)-143

OH OMe

• O

OH

(Z)-143

The presence of a propargyl ether function can be detrimental to benzannulation especially for the reaction of electron-rich aryl carbene complexes. Whereas the tert-butyldimethylsilyl ether of 1-hexyn-3-ol reacts with complex 144 to give only the naphthol product 145, the corresponding methyl ether gives a mixture of naphthol 145 and furan 146 (Eq. 55).150 These examples suggest that coordination of the propargyl oxygen to chromium during the reaction is somehow responsible for the formation of furans. An increase in the level of substitution at the propargylic position is also detrimental to the reaction but not as a result of furan formation. For example, the indene product 147 is formed in 28% yield from the reaction of complex 144 with the quaternary TBS-protected propargyl ether prepared from 3-methyl-1-hexyn-3-ol.150 This steric effect is also observed for alkynes that do not bear propargylic oxygen substituents.84

THE SYNTHESIS OF PHENOLS AND QUINONES R1

OMe Cr(CO)5

157

Pr-n

OR2

OMe

THF, 60° OMe 144

R1 Pr-n

OMe OH OR2 R1 Pr-n +

R2O MeO

OMe

OMe

(Eq. 55)

O

146 R1 H H Me

R2 Me TBS TBS

OR2

+ OMe OMe

OMe OMe 145

R1 Pr-n

OMe 146 (16%) (—) (—)

145 (24%) (46%) (30%)

147 147 (—) (—) (28%)

Propargyl ether functions can lead to high yields of naphthol products if the oxygen carries a tert-butyldimethylsilyl group and the aryl ring of the carbene complex is not electron-rich. This behavior is illustrated in the reaction of phenyl complex 26 with bis-propargyl ether 148, which provides the naphthol 149 in 85% yield (Eq. 56).151 The phenol functionality is not acetylated, but if acetic anhydride is not present the reaction falls. Alkenyl complexes are much less susceptible to side product formation with propargyl ethers. The reaction of carbene complex 76 with propynal diethyl acetal gives a 53% yield of the chromium tricarbonyl complex 150 (Eq. 57).110 Complexation of the propargyl ether oxygen is not a problem for the reaction of trans-1-propenyl complex 50 as it is for the reaction of the aryl complex 144 (Eq. 55) given that an 82% yield of the phenol complex 151 is produced in this reaction (Eq. 58).88 Homopropargyl ether functions can also interfere with the benzannulation reaction.152 TBSO OBn Cr(CO)5

OTBS OH

Ac2O

+

OBn OTBS

heptane, 80°

OMe 26

148

OMe OTBS 149 (85%)

(Eq. 56) TBSO TBS

Cr(CO)5 OMe 76

OEt +

CH2Cl2, 50°

OEt OEt

OEt

(53%)

(CO)3Cr OMe 150

(Eq. 57)

158

ORGANIC REACTIONS OMe

TBSO Cr(CO)5

OMe

CH2Cl2, 50°

+

(82%) dr = 85:15

TBSOTf, 2,6-lutidine

OMe 50

(CO)3Cr OMe 151

(Eq. 58)

Propargylsilanes react to give phenols but only if they are unsubstituted at the propargylic carbon. The reaction of the phenyl complex 26 with 1-trimethylsilyl2-propyne gives the normal phenol product in 62% yield (Eq. 59).153 However, phenols are not observed if an additional substituent is present in the 1-position of the propyne.154,155 These propargylsilanes stereoselectively produce only the E,Edienes. This type of product may be formed when the normal cyclization process is thwarted by a β-silyl elimination from the intermediate η1 ,η3 -vinyl carbene complexed intermediate 152 with subsequent reductive elimination resulting in the formation of a carbon-silicon bond. R

R Cr(CO)5

TMS

TMS

solvent, reflux

OMe 26

Solvent dioxane dioxane THF

OH R

MeO TMS

+ OMe

R Ph n-Pr H

(82%) (75%) (—)

TMS

Ph

(—) (—) (62%)

(Eq. 59)

OMe Cr(CO)4

R 152

Reactions of alkynes that are conjugated to ketone or ester groups do give phenol products but in diminished yields when compared to unfunctionalized alkynes. The reaction of phenyl complex 26 with 3-butyn-2-one affords the naphthol product in 42% yield (Eq. 60).70 No other products are reported from this reaction. The reaction of the same complex with ethyl propynoate affords the naphthol in 41% yield.70 These are the highest yields reported to date with any alkoxy carbene complex having a terminal alkynone or alkynoate ester; however, there is a high-yielding reaction of ethyl propynoate and an amino complex.156,157 Higher yields of naphthols can be obtained from conjugated alkynyl esters if the alkyne is internal.70 The ester functionality has little influence on regioselectivity when the alkyne is internal. The reaction of conjugated alkynyl ketones in an internal alkyne also gives higher yields but of two predominant products, as illustrated by the reaction of 62 where an unusual tricyclic lactone 64 is produced along with the normal product 63 (Eq. 15).71 Both products are formed by the same regiochemistry of incorporation of the alkyne. The reaction of complex 53

THE SYNTHESIS OF PHENOLS AND QUINONES

159

with alkyne 153 illustrates that the presence of non-conjugated ketone and ester groups is usually tolerated (Eq. 61).158 OH O

O Cr(CO)5

+

R

THF

R

65° OMe

R Me (42%) OEt (41%)

(Eq. 60)

OMe

26

OH

OMe

Ac

Cr(CO)5

+

45°

MeO2C

OMe

Ac

benzene CO2Me OMe (81%)

153

53

(Eq. 61) Alkynyl borate esters participate in the benzannulation reaction. The reaction of phenyl complex 26 with alkynylborate 154 affords a single isomer of the naphthol 155 along with a small amount of the protiodeboronated product 156 (Eq. 62).74,75 This reaction has considerable synthetic potential because it represents an example of a regioselective insertion with an internal alkyne. Moreover, the pinacol boronate products are suitable for Suzuki cross-coupling reactions. OH

n-Bu Cr(CO)5

B O O

+

THF B O OMe O

45°

OMe 26

OH

Bu-n

154

Bu-n + OMe 156 (15%)

155 (73%)

(Eq. 62) The benzannulation reaction is also compatible with a number of groups that could coordinate to the metal and interfere with the reaction such as thio ethers91,114,159 (Scheme 9) and nitriles. Interestingly, the reaction of the cyclohexenyl complex 34 with the 6-cyano-1-hexyne (Eq. 63)12,159 occurs to give a slightly higher yield of the desired product than does the reaction of this complex with 1-pentyne (Eq. 10). OTIPS Cr(CO)5 + OMe 34

(CH2)4CN

CN

TIPSOTf, 2,6-lutidine CH2Cl2, 50° (CO)3Cr OMe 157 (76%)

(Eq. 63)

160

ORGANIC REACTIONS

Heteroatom Stabilizing Substituents. The most thoroughly studied class of non-oxygen-stabilized carbene complexes is that of the amino carbene complexes. These complexes are more electron-rich and as a consequence have stronger bonds to the carbon monoxide ligands, which in turn leads to decreased proportions of products that incorporate carbon monoxide. The reactions of amino carbene complexes with alkynes in DMF have been developed as an efficient method for the synthesis of indenes.79 The effect of solvent on this reaction is illustrated in the combination of the morpholine complex 158 with 1-hexyne. In THF, the phenol and indanone products are formed in 18% and 43% yields, respectively, whereas in DMF the latter is favored over the former by a factor of 13 : 1 (Eqs. 64a and 64b).160 The indanone is a secondary product of the reaction that results from hydrolysis of the indene 159 upon purification on silica gel. The highest yield of the naphthol (50%) is obtained when the reaction is run in hexane. The efficiency of indene formation is highly dependent on the nature of the substituents on nitrogen. Reaction of the pyrrolidino complex 160 with 1-hexyne in DMF gives the indanone in 49% yield (Eq. 64b),79 whereas reaction of the dimethylamino complex corresponding to 160 with 1-pentyne in DMF gives only a 32% yield of the indanone product.83 Internal alkynes usually give higher proportions of indenes than do terminal alkynes. However, with morpholino carbene complex 158 there is not much difference. The reaction of this complex with 1hexyne in DMF gives a 90% yield of the indenone product (Eq. 64a) and under the same conditions it gives a 96% yield of indanone product with 3-hexyne.79 OH Cr(CO)5

Bu-n

N

+

120°

+ N

O O 158

Solvent DMF MeCN THF hexane

O

Bu-n

Bu-n

N O O

O (7%) (9%) (18%) (50%)

(90%) (71%) (43%) (13%)

Bu-n

(—) (3%) (7%) (12%)

(Eq. 64a)

Bu-n

N O 159

Bu-n Cr(CO)5 N

Bu-n

(49%)

DMF, 120° O

160

(Eq. 64b)

THE SYNTHESIS OF PHENOLS AND QUINONES

161

Phenols can be obtained from the reaction of amino carbene complexes bearing non-aromatic substituents.54,83 Reaction of the cyclohexenyl complex 161 with 1-pentyne in benzene affords the phenol 162 in 66% yield with no detectable amount of the five-membered ring product 163 (Eq. 65).83 The formation of phenols from aminoalkenyl complexes is limited to terminal alkynes. The reaction of complex 161 with 3-hexyne gives a complex mixture of products, none of which is the expected phenol.83 Reactions of amino complexes with alkynes can give a number of unusual products that are derived from internal trapping of the vinyl ketene complex by the amino group.22 This trapping leads to zwitterionic species of the type 165, which can be isolated from the reaction of complex 164 with diphenylacetylene in refluxing cyclohexane (Eq. 66).161 Many other reactions of this type lead to products that result from a Stevens-type rearrangement of this zwitterionic intermediate that gives rise to lactams. This rearrangement is usually seen with groups of greater migratory propensity than methyl. An example is the reaction of the pyrrolidino carbene complex 160 with 1-phenylpropyne to give the bicyclic lactam 166 in 38% yield (Eq. 67).77 OH Cr(CO)5

Pr-n

Pr-n

Pr-n

+

solvent, 80°

NMe2 161

162 Solvent benzene THF DMF

162 (66%) (57%) (25%)

O

NMe2

163

163 (≤2%) (12%) (13%) Me O

(CO)5Cr Ph NMe2

(Eq. 65)

Me

N

Ph

Ph

C6H12, 80°

(Eq. 66)

Ph Cr(CO)3

164

165 (55%) Ph Cr(CO)5 N

Ph

N

benzene, reflux

O

(Eq. 67)

(CO)3Cr 160

166 (38%)

The propensity of amino complexes to give indenes instead of phenols can be alleviated by installing a carbonyl group on the nitrogen162,163 or by incorporating the nitrogen atom into a pyrrole.164 Both of these modifications attenuate the electron-donating capacity of the nitrogen atom to the carbene carbon. The tertbutyl carbamate complex 167 reacts with 3-hexyne to give predominantly the

162

ORGANIC REACTIONS

phenol-derived product 168 in 56% yield along with an 11% yield of the indene 169 (Eq. 68)162 Similar reaction of the methoxy complex 26 gives the quinone in 88% yield (Eq. 22).84 Although the reaction of an N ,N -dialkylamino complex corresponding to 167 has never been investigated under these conditions with 3-hexyne, no N ,N -dialkylamino aryl carbene complex has ever been reported to react with an internal alkyne in any solvent to give a phenol. Alternatively, electron density can be removed from an amino complex through the carbon substituent to give enhanced yields of phenols. The alkenyl amino complex 170 bearing an ester group gives good to excellent yields of phenols even with internal alkynes as illustrated by the formation of phenol 171 in 75% yield (Eq. 69).156,157 In the absence of electron-withdrawing groups, alkenylamino complexes fail to give phenols with internal alkynes.83 In contrast to the carbamate complex 167, certain N -acyl complexes react with alkynes to give pyrroles. Complex 172 reacts with methyl propiolate to give the pyrrole 174 in a process that has been shown to involve a [3 + 2] cycloaddition of the alkyne with in situ generated munchnone 173 (Eq. 70).165 (CO)4Cr

N Bn

OAc

1. Et Et, toluene, 55°

O

Et

Et

Et

+

OBu-t 2. Ac O, Et N 2 3 3. FeCl3-DMF

Et N CO Bu-t 2 Bn 169 (11%)

N Bn CO2Bu-t 168 (56%)

167

(Eq. 68) OH EtO2C

Cr(CO)5 N

1. Et Et, THF, 60°

EtO2C

Et

(Eq. 69)

Et

2. SiO2

N

170 171 (75%) O

O

(CO)4Cr

N Me 172

Ph

THF, rt

CO2Me O

CO (30 psi) Ph

N Me 173

CO2Me Ph

Ph

N Me

Ph

(Eq. 70)

174 (80%)

A limited number of reports have described the reactions of sulfur-stabilized Fischer carbene complexes with alkynes. Although it has been reported that this reaction can proceed without the assistance of a Lewis acid,166 most of the studies have employed boron trifluoride etherate to afford the best, albeit still low, yields.167,168 The thiomethyl phenyl complex 175 reacts with 3-hexyne in the presence of five equivalents of boron trifluoride etherate and five equivalents of acetic anhydride to give the acetylated phenol 176 in 13% yield (Eq. 71).167 The reaction of 175 with 1-hexyne under the same conditions is more efficient, giving the acetylated phenol 177 in 45% yield.167 It is interesting to note that

THE SYNTHESIS OF PHENOLS AND QUINONES

163

the reaction of the thioethyl analog of 175 with 3-hexyne in THF affords a 46% yield of the naphthol in the absence of Lewis acids.166 OAc Et

Et

Et

(13%) Et

Cr(CO)5

SMe 176

Ac2O, Et3N, BF3•OEt2

(Eq. 71)

THF, 65°

SMe

OAc Bu-n

n-Bu

175

(45%) SMe 177

The benzannulation of alkoxy carbene complexes has been carried out almost universally on either methoxy or ethoxy complexes. There is little data available on the effect of the alkoxy group on either the yield or the product distribution from reactions with alkynes. When the same reaction has been reported with two different alkoxy groups, the results often conflict.88,91,100,159 In the only systematic study on the effect of the size of the alkoxy group, it was found that the yields of quinone product are higher for isopropoxy groups compared to methoxy groups in reactions of aryl complexes with 1-pentyne (Eq. 72).113 This effect was not general because no difference is seen for electron-donating substituents in the 4-position or for any type of substituent in the 2-position. The deleterious consequences of 2-substitution in an aryl complex (Eq. 28) cannot be offset by substitution of isopropoxy for methoxy.113 The benzannulation of aryloxy carbene complexes provides yields similar to those of alkoxy complexes, however, there has been no direct comparison.47,169 1.

R2 Cr(CO)5 R1 Me i-Pr Me i-Pr

OR1 R2 H H Br Br

Pr-n, benzene, 80°

R2

O R

2

Pr-n

n-Pr

O

+

2. CAN

R 1O O (78%) (90%) (75%) (91%)

O

Pr-n

(Eq. 72)

(7.5%) (<5%) (5%) (<5%)

Given the thermal instability of acetoxy complexes,170,171 it is surprising that complex 179,172 in this example generated from complex 178, reacts with 1-hexyne (Eq. 73) to give the same yield of the benzannulation product as does the reaction of the corresponding methoxy complex 26 (Eq. 5).94 Other acetoxy complexes fail to provide any cyclized product upon reaction with alkynes.114 The only class of complexes that has two carbon substituents on the carbene

164

ORGANIC REACTIONS

carbon and which are isolable are those bearing two aryl groups. The reactions of these complexes generally give low yields of phenols upon reaction with alkynes.47,87,143 In contrast, the dibenzocycloheptatriene complex 180 reacts with 1-hexyne to give a 55% yield of the benzannulation product after protection as its TBS ether (Eq. 74).173,174

AcCl

Cr(CO)5 O–

NMe4

Cr(CO)5

+

O

1. Bu-n, THF, 65°

Bu-n (71%)

2. CAN

OAc

178

O

179 (35%)

(Eq. 73) 1.

Bu-n, t-BuOMe, 20°

(55%)

(Eq. 74)

2. TBSCl, Et3N Cr(CO)5

TBSO Bu-n

180

Reaction Media and Conditions. The nature of the solvent can have a significant effect on the product distribution from reactions of Fischer carbene complexes with alkynes. This effect is most often observed for the reaction of aryl alkoxy carbene complexes and is rarely seen for alkenyl alkoxy carbene complexes, although the reactions of alkenyl amino carbene complexes are sensitive to the nature of the solvent (Eq. 65).83 The general observation of the correlation between efficiency of phenol formation and the nature of the solvent is that the highest chemoselectivity for phenol formation is found in non-polar and/or non-coordinating solvents.12,13,60,84 The effects of solvent on the benzannulation reaction is usually more pronounced for internal alkynes than for terminal alkynes. As an example, the reaction of phenyl complex 26 with 3-hexyne gives higher yields of the naphthol in THF and in benzene than in acetonitrile, in which an indene is formed as a mixture of double-bond isomers in 25% yield along with a cyclobutenone in 7% yield (Eq. 75).60 The use of polar solvents in combination with other changes can lead to reactions that give high selectivity for products other than phenols. For example, reactions of amino carbene complexes in DMF can give synthetically useful yields of indenes (Eq. 64a).79,160 OH Cr(CO)5 OMe 26

Et

+

solvent, 80°

MeO Et

Et OMe

Solvent THF MeCN benzene

Et Et

Et

(97%) (32%) (97%)

OMe (1.3%) (25%) (≤0.7%)

+

O

Ph Et

Et (—) (7%) (—)

(Eq. 75)

THE SYNTHESIS OF PHENOLS AND QUINONES

165

Reactions of 2-methoxyphenyl complex 53 are much more sensitive to the solvent than those of the unsubstituted phenyl complex 26. The product distribution from the reaction of complex 53 with 3-hexyne is especially responsive to the ability of the solvent to coordinate to the metal during the course of the reaction (Eq. 76).84 Non-coordinating solvents such as hexane and benzene give significantly higher yields of the quinone than does THF. Furthermore, the yield of the quinone drops precipitously in acetonitrile where the cyclobutenone is the major product and is isolated in 78% yield. An indication of the importance of the coordination of the solvent to the metal during the reaction can be seen in the data from the reaction in 2,5-dimethyltetrahydrofuran (DMTHF) in which the yield of quinone is significantly higher than it is in THF. 1. Et Et, solvent, 45°

OMe

2. CAN OMe Cr(CO)5 53

O

Et Et + Et

Solvent DMTHF hexane benzene THF MeCN

OMe O

Et Et +

OMe OMe

(88%) (83%) (77%) (61%) (6%)

(6%) (—) (2%) (18%) (5%)

MeO Et

+

OMe O

O

Ar

(Eq. 76)

Et Et Ar = 2-MeOC6H4

(—) (—) (5%) (5%) (6%)

(—) (—) (—) (—) (78%)

The rule that non-polar and non-coordinating solvents give the highest chemoselectivity for phenols is rarely violated. One exception is the reaction of the 2,5-dimethoxyphenyl complex 144 with 1-pentyne, which gives a 76% yield of phenol in acetonitrile and only a 59% yield in THF (Eq. 77).175 Even more surprising is the drop in yield to 14% when the reaction is performed in hexane. Another exception is the reaction of the phenyl complex 26 with diphenylacetylene, which in heptane76 gives an equal mixture of phenol and indene products, but in THF84 affords the phenol almost exclusively. The solvent can also have profound effects on the intramolecular reactions of carbene complexes with alkynes leading to products not seen in intermolecular reactions.176 OMe

1. OMe

OMe Cr(CO)5 144

Pr-n, solvent, 45°

OMe OH Pr-n

2. air Solvent hexane THF MeCN

OMe OMe (14%) (59%) (76%)

(Eq. 77)

166

ORGANIC REACTIONS

Reactions of Fischer carbene complexes with alkynes have also been examined without solvent.177,178 As an example, the reaction of phenyl complex 26 with 1.5 equivalents of diphenylacetylene is performed by dissolving the two reactants in ether, adding silica gel, and removing the solvent to leave a dry powder which is heated under nitrogen at 40–50◦ for 3 hours (Eq. 78). The yield of the quinone 181 after oxidation is comparable to the yield reported for the same reaction in THF.84 The reaction of complex 26 with 1.5 equivalents of phenylacetylene carried out in the same manner gives the quinone 182 in 81% yield, which is comparable to the yield reported for this reaction in THF where the corresponding naphthol 46 was isolated (Eq. 9).100 This technique has not been widely examined; however, a few dry-state reactions on silica gel give improved yields of phenolic products compared to the same reactions performed in solution,91,98,124,179 whereas it is less effective for other reactions.75,180 O Ph

Ph

Ph

(86%) 40-50°

Cr(CO)5 OMe 26

Ph O 181

1. alkyne, SiO2, heat 2. CAN

(Eq. 78)

O Ph

Ph

(81%)

60-65° O 182

The distribution of products from the reaction of Fischer carbene complexes with alkynes can be dependent on the concentration such that the preference for the phenolic product increases at higher concentrations.13,60,84 The sensitivity of the product distribution on the concentration is greater for aryl complexes than for alkenyl complexes, and greater for internal alkynes than for terminal alkynes. One system that is particularly sensitive to concentration is the reaction of the 2-methoxyphenyl complex 53 with 3-hexyne.84 At 1.0 M in alkyne the distribution between phenol and indene products is not particularly sensitive to the concentration of the carbene complex (Eq. 79).84 However, the distribution is strongly dependent on the concentration of the alkyne as can be seen from the data at 0.005 M in carbene complex where a 100-fold increase in the concentration of the alkyne increases the yield of quinone from 5% to 81%. An additional increase in concentration of the alkyne to 8.8 M (neat 3-hexyne) affords the quinone as the exclusive product. A careful analysis of the concentration dependence of the reaction of a molybdenum complex also reveals that the product distribution is a function of the concentration of the alkyne and not of the carbene complex.60 This phenomenon has been termed the allochemical effect and is explained by an alkyne-assisted insertion of carbon monoxide into the vinyl carbene intermediate to give the vinyl ketene intermediate (Scheme 6).84 The η1 ,η3 -vinyl carbene complexed intermediate (E)-4 is an 18-electron complex and coordination of an

THE SYNTHESIS OF PHENOLS AND QUINONES

167

alkyne must be preceded by a dissociation of the double-bond to generate the η1 vinyl carbene intermediate (E)-17 (Scheme 6). An alkyne can be either a 2- or 4electron donor and because carbon monoxide insertion results in the formation of an unsaturated complex, it has been proposed84 that the alkyne ligand in complex 24 can accelerate the CO insertion if it switches from a 2- to a 4-electron donor during the process such that 25 is a saturated 18-electron complex (Scheme 6).

OMe Cr(CO)5

MeO 53

1. Et Et, THF, 45° 2. CAN O

Et

Et

MeO

Et +

Et +

Et

Et OMe O [53] 0.005 0.05 0.005 0.05 0.5 0.05

[Alkyne] 0.01 0.1 1.0 1.0 1.0 8.8

(5%) (46%) (81%) (84%) (61%) (91%)

OMe OMe (66%) (42%) (5%) (5%) (18%) (<1%)

OMe O (9%) (1%) (<1%) (1%) (5%) (<1%)

+

O

Ar Et Et Ar = 2-MeOC6H4 (—) (3%) (5%) (2%) (—) (—)

(Eq. 79) A related phenomenon, termed the “xenochemical effect”, has been observed in which the yield of phenolic product from reaction with an alkyne is dependent on the concentration of a second added alkyne that does not become incorporated into the product.86 This is schematically indicated in Scheme 6. The xenochemical effect is a special case of the allochemical effect where the alkyne R4 CCR5 is not the same as the alkyne that has already been incorporated (RL CCRS ). Thus far it has only been observed in intramolecular reactions, and a dramatic example is in the reaction of complex 183 to give the quinone 184 and indanone 185. The yield increases from 33 to 83% if 10 equivalents of diphenylacetylene are added to the reaction mixture (Eq. 80). The yield of quinone 184 could be increased somewhat by employing 3-hexyne as the xenochemical agent. However, competition is seen with the intermolecular benzannulation of 3-hexyne at the expense of the intramolecular benzannulation. Examples have also been reported for an intramolecular reaction of manganese carbene complexes (see Eq. 89 in the following section).181,182 One might expect to find intermolecular examples of the xenochemical effect if the two alkynes were of much different reactivity. Finally, concentration is also an important factor in the distribution between phenolic products and products resulting from the incorporation of more that one alkyne. Examples include the formation of two-alkyne phenols (21 in Scheme 5),80,81 vinylcyclopentenediones (10 in Scheme 4),60,78 and polyacetylene.85

168

ORGANIC REACTIONS

Cr(CO)5 Me2Si

O

O

1. additive, hexane, reflux, 1 h

OH OH

2. CAN

+ O

O 184

O 183 Additive none Ph Ph (10 eq) Ac2O (1.5 eq)

184 (33%) (83%) (26%)

185

(Eq. 80)

185 (—) (3%) (2%)

Another interesting additive effect that has not been widely reported, but which nonetheless could be synthetically quite important, is the effect of added acetic anhydride.116,183 This effect is illustrated by the reaction of complex 26 with alkyne 186, which fails to give any of the phenolic product in refluxing heptane, but in the presence of one equivalent of acetic anhydride affords the expected product in 66% yield (Eq. 81). Note that the product is not acetylated. Acetic anhydride does not have any effect on the yield of quinone from the intramolecular reaction of 183.86 The effect of acetic anhydride has only been reported for a small number of reactions and while it certainly does not work in all reactions,84 or may not even work on a majority of reactions, when it does work the effect can be substantial and thus should be considered when optimizing a benzannulation reaction. An even less well studied additive is carbon monoxide. Small increases in the yield of quinone product can be observed for some complexes when the reaction is performed under a carbon monoxide atmosphere,184 as has been observed for 2-alkoxyaryl carbene complexes (10-15% increase). OH OTBS OTBS Cr(CO)5 OMe 26

+ TBSO

additive, heptane 80°

186

Additive none Ac2O (1.5 eq)

OMe OTBS (—) (66%)

(Eq. 81) The effect of temperature on chemoselectivity has been examined for some reactions. The reaction of complex 53 with 3-hexyne over a 135◦ temperature range reveals that, whereas the mass balance is fairly consistent over this range, the proportion of phenolic product varies dramatically (Eq. 82).84 In these studies, phenolic products are favored at lower temperature and are increasingly replaced by indene products as the temperature is raised. The unsubstituted phenyl complex 26 and the 2-methylphenyl complex 82 are not as sensitive to changes in temperature, but the latter is sensitive to a combination of temperature and concentration (Eqs. 22 and 23).84 The effects of temperature on the reactions of alkenyl complexes have not been extensively studied.60 The effect of temperature on the regioselectivity of the reaction of Fischer carbene complexes with

THE SYNTHESIS OF PHENOLS AND QUINONES

169

alkynes has only been examined in one example and it was found that the level of the regioselectivity drops by a factor of two for a 45◦ increase in temperature (Eq. 12).66

OMe

1. Et Et, benzene, temp

O

53

Et OMe O

Temp 45° 110° 180°

Et Et +

+

2. CAN OMe Cr(CO)5

Et Et

(77%) (29%) (16%)

OMe OMe (2%) (6%) (12%)

Et OMe O

(Eq. 82)

(5%) (37%) (44%)

Although lower temperatures favor the formation of phenols compared to indenes, there is a limit to which the temperature can be lowered to achieve reasonable rates. The rate-limiting step is the loss of a CO ligand (Scheme 2).42 For most pentacarbonyl chromium carbene complexes, a reasonable rate for the thermal reaction can only be achieved at temperatures no lower than approximately 40–50◦ . Reactions of amino carbene chromium complexes79 and alkoxy carbene tungsten complexes60,63 require higher temperatures than those of alkoxy carbene chromium complexes and both give a greater proportion of indene. This phenomenon has been attributed to the slower initial CO dissociation for amino complexes.48 This shift in product distribution to indenes for these reactions may be due to a combination of electronic effects in the carbene complexes and the temperature of the reaction, but these effects have not been sorted out. Molybdenum complexes react faster than chromium complexes and also give a higher proportion of indene products.185,60 Thus, for molybdenum complexes it is clear that the increased propensity for indene formation is due to the nature of the metal. Other methods for facilitating the loss of CO include photolysis, ultrasound irradiation, and microwave irradiation, and all three have been examined for the reaction of carbene complexes with alkynes. Photolysis has been used to probe for reactive intermediates in this reaction for both chromium and tungsten complexes.63,64 The effect of photolysis of chromium carbene complexes on the yield of phenol products is variable. The reaction of complex 26 with 3-hexyne is mediated by irradiation with a 450 Watt Hg lamp and occurs at reasonable rates at 15◦ and at −78◦ , but the highest reported yield of the quinone is 54% at 15◦ (Eq. 83).13 It is clear that ultraviolet irradiation can do more than just lower the barrier of CO dissociation since the photo-induced reaction of the 2methoxyphenyl complex 53 with 3-hexyne gives no trace of phenolic product and instead the indene product is obtained in 49% yield. This result is in contrast to the thermally-induced reaction in the same solvent (Eq. 79).13 Much higher yields of phenolic products have been reported from the photolysis of heteroaryl complexes and heteroaryl-substituted alkenyl complexes.186 The photo-induced reaction of complex 187 with 3-hexyne affords the phenolic product in 81% yield and is important because reactions of complexes of this type provide the only known

170

ORGANIC REACTIONS

examples of a successful photo-induced benzannulation of a chromium complex in which the corresponding thermal reaction fails (Eq. 84).187,188 Photolysis is also known to greatly facilitate or make possible the benzannulation reactions of manganese complexes in inter- and intramolecular reactions.181,182 The photolysis of β,β-disubstituted iminocarbene complexes in the presence of alkynes leads to the formation of 2H -pyrroles.189,190 1. Et Et, 450-W Hg lamp, vycor, THF, 15°, 3 h

OMe

O +

2. CAN

Et

Et

Cr(CO)5

R

Et Et

R

26 R = H 53 R = OMe

OMe

R

O (54%) (—)

(—) (49%)

(Eq. 83) Ph

Ph Et (CO)5Cr

125-W Hg lamp, quartz, THF, –20°, 2 h

O 187

OH

Et

(81%) O

Et

(Eq. 84)

Et

There are also a few examples of ultrasound-promoted reactions, an illustration being the reaction of complex 34 with 1-pentyne (Eq. 85).177 This reaction provides the quinone product in essentially the same yield as the corresponding thermal reaction,13 but the time and temperature are greatly reduced. Other reports include improvement in yields and rate for the benzannulation of aryloxy complexes169 and similar improvements in the key step in the synthesis of parvaquone.191 1. OMe

Pr-n ultrasound, n-Bu2O, rt, 10 min

O Pr-n (75%)

2. CAN Cr(CO)5 34

(Eq. 85)

O

The synthesis of phenols from the reactions of Fischer carbene complexes with alkynes has also been facilitated with microwave irradiation in a commercial reactor at 130◦ for 5 minutes.192 Despite the relatively high temperatures employed, the reactions give yields comparable to the corresponding thermal reactions. Other agents that have been reported to mediate the reaction of carbene complexes with alkynes include [(COD)RhCl]2 ,which has been reported to facilitate the reaction of β-aminovinyl complexes with alkynes,193 – 195 and boron trifluoride etherate, which has been reported to facilitate the benzannulation of thio carbene complexes (Eq. 71).167,168 Metal and Ligand Complement. Fischer carbene complexes are known for a large number of transition-metals and the reactions of many of these have been

THE SYNTHESIS OF PHENOLS AND QUINONES

171

investigated with alkynes. However, of the Group 6 metals, chromium remains the metal of choice for the synthesis of phenols and quinones. The reactions of tungsten and molybdenum carbene complexes with alkynes are much less chemoselective for the phenolic product60,63,82,185 as exemplified by the reaction of unsubstituted phenyl complexes 188 and 189 with 1-pentyne (Eq. 86).60 The situation can be quite different with alkenyl complexes. For example, higher yields of the phenols can be obtained for certain molybdenum and tungsten alkenylcarbene complexes than with the corresponding chromium complexes.60 One disadvantage of molybdenum complexes is that they are less stable than the chromium complexes. Nonetheless, molybdenum complexes can be employed without special precautions if used immediately after preparation. Tungsten complexes are more stable than the chromium complexes but suffer from the fact that alkyne polymerization63,85 can be a serious side-reaction, thus requiring significant excesses of the alkyne. The reactions of tungsten and molybdenum alkenyl complexes with internal alkynes are not as chemoselective for phenols as are their reactions with terminal alkynes and thus these reactions usually give mixtures of products.60

OMe

Pr-n benzene, 80°

M(CO)5 OH

Pr-n

Pr-n

Pr-n + OMe 26 M = Cr 188 M = Mo 189 M = W

(59%) (3%) (6%)

+ OMe (1%) (80%) (60%)

Ph

n-Pr

O Pr-n OMe

+ O

(8%) (3%) (5%)

(Eq. 86)

OMe O

Ph

(6%) (3%) (6%)

A few non-Group 6 Fischer carbene complexes have been investigated for their reactivity with alkynes but none provide for a synthesis of phenols that is as general as that of chromium complexes. Iron tetracarbonyl carbene complexes such as 190 give only phenols upon reaction with dimethyl acetylenedicarboxylate (Eq. 87).196 The more typical outcome of the reaction of iron complexes with alkynes is the production of furans196,197 or the formation of pyrones (Eq. 87).198 A ruthenium Fischer carbene complex has been reported to give a quinone.199 The reaction of stannyl tricarbonyl cobalt carbene complexes (e.g., 191) with alkynes gives 2-alkoxyfurans as the only observable products as in the reaction of stannyl complex 191 with 3-hexyne (Eq. 88). This process has been used in the synthesis of bovolide.200 Cyclopentadienyl dicarbonyl manganese carbene complexes will only react with alkynes upon ultraviolet irradiation and then only with non-carbon groups on the oxygen substituent of the carbene carbon. The intramolecular reaction of the siloxycarbene complex 192 gives a quinone upon photolysis and oxidative workup (Eq. 89). However, if the siloxy group is

172

ORGANIC REACTIONS

replaced by a methyl group, no quinone formation is detected either by thermolysis or photolysis.181,182 Note that intramolecular benzannulation of the manganese complex 192 is facilitated by the xenochemical effect (Scheme 6). The yields are approximately doubled by the addition of 5 equivalents of diphenylacetylene. O Ph

O

(100%)

CH2Cl2, 55 psi CO, 70°

OEt

(Eq. 87)

Fe(CO)4 OH

OEt

MeO2C

190

CO2Me

CO2Me

(21%)

THF

CO2Me OEt

OMe Ph3Sn(CO)3Co Ph

Et

benzene, 50°

Et

Et

Et

Ph

O

(Eq. 88)

OMe

191 (93%) Mn(CO)2(η5C5H4CH3) O Me2Si O 192

1. Ph Ph (5 eq), CH2Cl2, 150-W xenon lamp

O

2. CAN

OH

(Eq. 89)

O (56%)

Replacing one of the carbon monoxide ligands of a Fischer carbene complex with a phosphine affects the benzannulation reaction with alkynes.87,13,201 Only a small effect is seen in the reaction of phenyl complex 26 with 3-hexyne when a CO ligand is replaced with a tri-n-butylphosphine (Eq. 90).201 In a related study with diphenylacetylene, replacement of a CO ligand by either the electron-rich tri-n-butylphosphine or with the electron-poor tris-(para-fluorophenyl)phosphine also has only a minor effect on the outcome of the reaction.201,87 In contrast, a trin-butylphosphine ligand greatly affects the reaction of the phenyl molybdenum complex 188 with 3-hexyne (194, Eq. 90).133,201 The major product changes from the indene with the pentacarbonyl complex 188 to the quinone with the tri-n-butylphosphine complex 194. The origin of this effect has not been determined, but this is one of only three known examples of phenol formation from an aryl molybdenum carbene complex.60,82,185,201 In principle, the use of phosphine ligands could provide a method to lower the temperature requirement of the benzannulation reaction. It has been demonstrated that a triphenylphosphine (but not trialkylphosphine) dissociates faster than CO from a Fischer carbene complex.202 Although there are no known examples of the benzannulation

THE SYNTHESIS OF PHENOLS AND QUINONES

173

of tetracarbonyl(triphenylphosphine) aryl or alkenyl complexes, the two-alkyne annulation reaction has been reported for an alkyl carbene complex with a triphenylphosphine ligand and a rate acceleration was observed (see section on Two-Alkyne Annulation).133 L M(CO)4 OMe M 26 Cr 193 Cr 188 Mo 194 Mo

1. Et Et, THF, 80°

O +

2. CAN

L CO (n-Bu3)P CO (n-Bu3)P

Et Et Et

O (97%) (79%) (9%) (43%)

Et + Ph OMe (1.3%) (≤3 %) (67%) (≤1 %)

Et

Et OMe

O (≤1%) (8%) (5%) (2%)

(Eq. 90) There are many more examples in which a carbon monoxide ligand has been replaced by an oxygen or sulfur donor atom as the result of the coordination of an alkoxy group, a thio ether, or a carbonyl oxygen. Some examples include the methoxy-chelated complexes 94 (Eq. 29)84 and 113 (Eq. 37),105 the thioetherchelated complex 97 (Scheme 9),91 and the carbonyl-chelated complexes 167 and 172 (Eqs. 68 and 70).162,165 Only one example is known in which a carbon monoxide ligand is replaced by an isonitrile ligand, and an indene product results from reaction of this complex with an alkyne.203 Diastereoselectivity. A new stereogenic element is formed when the arene chromium tricarbonyl group is created. There are three modes of stereoinduction involving diastereoselective installation of the chromium tricarbonyl group. These three possibilities arise when the stereocenter of the arene chromium tricarbonyl group is created in the presence of stereocenters that already exist either on the alkyne, on the oxygen substituent of the carbene carbon, or on the carbon substituent of the carbene carbon. The development of stereoselective benzannulation procedures is dependent on the invention of a general method for the protection of the phenol function and the resulting production of air-stable arene chromium tricarbonyl complexes.95 The only success that has been achieved with a carbene complex bearing a chiral alcohol is illustrated by the reaction of the phenyl [(−)-menthyloxy]carbene complex 195 with 3,3-dimethyl-1-butyne to give a 10 : 1 mixture of the diastereomers 196 and 197 (Eq. 91).97,204 Although this reaction does give a similar selectivity with 3-hexyne,73 it gives low selectivity with 1-pentyne.205 The corresponding reactions of alkenyl [(−)-menthyloxy]carbene complexes fail to give significant stereoselectivity with a number of acetylenes including tertbutylacetylene.97,205

174

ORGANIC REACTIONS

Cr(CO)5 O

1.

Bu-t, t-BuOMe, 55°, 45 min

2. TBSCl, NEt3

OTBDMS Bu-t

OTBDMS Bu-t

195

(Eq. 91)

+ (CO)3Cr O

(CO)3Cr O

196 (50%)

197 (5%)

Another mode of stereocontrol involves asymmetric induction from a stereogenic center on the alkyne to the newly formed planar element of chirality. Very high asymmetric induction is observed for the reaction of certain alkenyl carbene complexes with propargyl ethers. The reaction of the β-substituted vinyl carbene complex 50 with alkyne 198 (R = CPh3 ) gives the arene chromium tricarbonyl complex 199 in 68% yield and ≥96 : 4 stereoselectivity (Eq. 92).88 The high stereoselectivities observed may have a stereoelectronic origin as revealed by variations in the ether substituent of the propargyl ether 198 and by the fact that the alkyne 200 gives nearly an equal mixture of diastereomers upon reaction with complex 50.88,206 This stereoinduction is limited to β-substituted alkenyl carbene complexes. The same reaction with alkenyl carbene complexes bearing an α-substituent gives low stereoselectivity. The third mode for stereoinduction in the benzannulation reaction involves chiral carbene complexes that have a stereogenic center in the carbon substituent of the carbene carbon. This reaction has been examined for cyclohexenyl complexes bearing substituents in the 3- and 6-positions and the diastereoselectivity varies from low to modest.207 High diastereoselectivity has been observed from the reaction of complex 44 with 5-hexyn-1-ol which gives a single diastereomer of 45 after an intramolecular Mitsunobu cyclization (Eq. 8).99 Other examples of this mode of stereoselection include the use of the benzannulation reaction in the formation of cyclophanes,208 chiral biaryls,209 annulenes,98 and carbohydratederived carbene complexes.210 TBSO

R Cr(CO)5 OMe 50

i-Pr2NEt, TBSCl, CH2Cl2, 60°

OTr (68%) ≥96:4 dr

(CO)3Cr OMe

198 R = OCPh3 (OTr) 200 R = Bu-t

(Eq. 92)

199

Asymmetric induction is also observed in reactions where the chromium tricarbonyl unit is not retained in the newly formed arene ring. In a study directed

THE SYNTHESIS OF PHENOLS AND QUINONES

175

to the synthesis of allocolchicinoids, the reaction of the carbene complex 201 with 1-pentyne selectively gives the benzannulated product 203 in which there is central to axial stereoinduction leading to the preferential formation of one of the two possible atropisomers 202 and 203 (Eq. 93).211 Another example of this type of asymmetric induction is presented in the next section (Eq. 98).100 MeO MeO

OMe 201

MeO MeO

Pr-n

MeO MeO

Pr-n

Cr(CO)5 benzene, 55-58° 36 h

OH

MeO

OMe MeO

Pr-n

202 +

MeO MeO MeO

OH OMe

MeO 202 + 203 (73%) 202:203 7:93

203

(Eq. 93) Asymmetric induction can also be achieved from the newly formed plane of chirality of the arene chromium tricarbonyl complex to an axis of chirality formed in the same reaction. The combination of α,β-unsaturated carbene complexes with 2-substituted aryl acetylenes simultaneously generates planar and axial elements of chirality.212 As an example, if the reaction of complex 50 and aryl propyne 204 is carried out in toluene at 50◦ in the presence of tert-butyldimethylsilyl chloride and (i-Pr)2 NEt, the arene chromium tricarbonyl complex 206 is obtained in an 89 : 11 mixture of syn- to anti-isomers (Scheme 11). This diastereoselectivity can be reversed to give a 97 : 3 ratio in favor of the anti-isomer if the benzannulation and silylation steps are carried out sequentially. These observations are consistent with a kinetic formation of the syn-phenoxy complex 205. Under simultaneous silylation conditions the phenol is silylated before rotation about the chiral axis can occur to give the anti-phenoxy complex 205. Under sequential silylation conditions, complete isomerization to the anti-phenoxy complex can occur if the first step is performed at 80◦ (the two step reaction at 50◦ gives a 95 : 5 mixture of anti:syn isomers). Subsequent silylation then yields the silylated complex anti206. The reactions of aryl acetylenes of the type 204 with a chiral substituent replacing the methyl group on the benzene can give rise to asymmetric induction from the stereocenter in the alkyne to a newly formed axis of chirality in the benzannulated product.213 Intramolecular Reactions. The most thoroughly studied intramolecular reactions of α,β-unsaturated Fischer carbene complexes involve those in which the alkyne is tethered through the heteroatom substituent (Type A). The thermolysis of the complexes 207 provides good yields of fused cyclic aryl ethers for the generation of dihydrobenzofurans, dihydrobenzopyrans, and

176

ORGANIC REACTIONS

Cr(CO)5 OMe 50

OC CO OC Cr HO

204

rotation

OC CO OC Cr HO

TBSCl, i-Pr2NEt, toluene MeO syn-205

MeO anti-205

TBSCl

TBSCl

OC CO OC Cr EO

OC CO OC Cr EO

MeO

MeO

syn-206

E = TBS syn + anti (63%) (62%)

one pot, 50° TBSCl, i-Pr2NEt added in 2nd step, 80°

anti-206

syn:anti 89:11 3:97

Scheme 11

tetrahydrobenzoxepins, respectively (Eq. 94).214 The extension to formation of eight-membered rings has not been reported. There are a few examples of intramolecular cyclizations wherein the alkyne is tethered to an alkenyl or aryl substituent of the carbene carbon (Type B).215,216 These reactions do not always give the normal phenolic products, but often good yields of the phenol can be obtained (Eq. 95). If the alkyne is tethered to the β-carbon of an alkenyl complex as in 208, the product of the reaction is a metacyclophane.215 The yield of the phenol is modest for the cyclophane with an eight-methylene bridge (43%), but above that, the yield increases and levels off at 60%. If the alkyne is connected to the α-carbon, and if it is sufficiently long, then paracyclophanes are formed, but the strain introduced with shorter tethers can lead to the formation of products that are unprecedented in intermolecular reactions including bicyclo[3.1.0]hexenones and m-alkoxyphenols.217,176 OMe

OMe

O

R

R1

(CO)5Cr

R1

R

O (CO)5Cr

R2 R1

R2

R OH

Type A Intramolecular Benzannulation

R1 R

OH

Type B Intramolecular Benzannulation

THE SYNTHESIS OF PHENOLS AND QUINONES

O n

n

n 0 1 2

THF, 35°

O (CO)5Cr

OH

207

177

(81%) (62%) (62%)

(Eq. 94)

OMe OMe (CO)5Cr

n 0 2 5 9

THF, 100° OH

n+8

208 n

(43%) (58%) (65%) (60%)

(Eq. 95)

A significant difference between the two modes of intramolecular cyclization (especially with terminal alkynes) is that the regiochemistry is reversed in Type A but is normal in Type B reactions. A consequence is that terminal alkynes do not give as high yields of phenols for the Type A process as for Type B. These low yields can be overcome by capping the alkyne with a trimethylsilyl group.114 Intramolecular benzannulation with alkynes attached through removable tethers has been used to control the regiochemistry of reactions of internal alkynes (Eq. 19). A synthesis of deoxyfrenolicin featured the intramolecular benzannulation of carbene complex 209, which upon oxidative workup gives a naphthoquinone, and upon workup involving a ligand displacement gives a naphthol (Eq. 96).86,90,218 An intermolecular reaction with a similarly functionalized alkyne gives the opposite constitutional isomer.90 MeO

O

1. THF, 35° MeO

O

O

Pr-n

OH

O Pr-n

2. DDQ

(51%)

O

(Eq. 96)

Cr(CO)5 MeO 209

O

O

1. THF, 35° Pr-n

2. (n-Bu)3P, acetone

(48%)

OH

Intramolecular benzannulations also impact the chemoselectivity of the reaction. For intermolecular reactions, alkenyl amino carbene complexes and alkynes can sometimes yield phenolic products (Eq. 65),83 but aryl amino carbene complexes rarely afford phenols as the major product and instead usually afford indenes.79,160 However, as illustrated by the reaction of complex 210, the intramolecularity of a benzannulation reaction can cause a switch from indenes to phenols for amino carbene complexes (Eq. 97).219 Other examples of intramolecular

178

ORGANIC REACTIONS

reactions of amino complexes give phenolic products,23,128,220,221 whereas others give indene products.128,222 O Ph

H N

OH Ph

benzene

Ph +

reflux

Cr(CO)5

(Eq. 97)

N (54%)

210

N (23%)

Intramolecular benzannulations have also been demonstrated in the reactions of bis(carbene) complexes with bis(alkynes). The first benzannulation from the reaction of the bis(carbene) complex 211 and 1,4-diphenylbutadiyne is intermolecular but the second step must be intramolecular (Eq. 98).100 The intramolecularity of the second step leads to the formation of a C2 -symmetric product unlike that observed for the product from the intermolecular reaction (Eq. 49).100 Despite the low yields observed for the reaction of complex 211, this reaction has potential for the asymmetric synthesis of chiral biaryls given that only a single diastereomer of the binaphthol 212 is formed (Eq. 98). A bis(carbene) complex can also be employed in a double-benzannulation of a non-conjugated diyne as a route to calix[4]arenes. The reaction of bis(carbene) complex 213 with diyne 214 gives calix[4]arene 215 in 41% yield in a process in which two of the benzene rings of the calixarene are made at the same time as the macrocycle. (Eq. 99).223

(CO)5Cr

Cr(CO)5 O

O Ph

Ph

Ph

OH

Ph Ph

HO Ph

O

THF, 75°

O

H

211

H

(Eq. 98)

212 (23%) one diastereomer

Ph OMe

Ph OMe

(CO)5Cr

+

Cr(CO)5 OMe 213

OMe 214 MeO

Ph Ph

OMe

THF, 100°

HO MeO

OMe OH

215 (41%)

(Eq. 99)

THE SYNTHESIS OF PHENOLS AND QUINONES

179

Heteroannulation Heteroaromatic rings containing a hydroxyl function have been produced from the reaction of α,β-unsaturated carbene complexes by two routes (Scheme 12). In reactions with carbene complexes of type 216, substitution of one of the triplybonded carbon atoms of the alkyne with a heteroatom leads to the heterocycles 217. Alternatively, heterocycles 219 can be formed by the reactions of alkynes with carbene complexes of the type 218 in which the α-carbon of the α,βunsaturated substituent has been replaced by a heteroatom. Although the latter approach has been proven so far to be the more general, the following discussion will begin with the reactions of “hetero-alkynes.” OH

R2 R

Cr(CO)5

R1

3

Y

R2

R3 Y

R1

OMe

OMe 217

216

OH

R2

R3 Y

R4

R2

Cr(CO)5

R3 Y

R1 218

R4 R1 219

Scheme 12

Reaction of aryl carbene complexes with nitriles do not produce functionalized isoquinolines. Instead, imidatocarbene complexes such as 220 result from the insertion of the nitrile function into the chromium-carbon bond of the starting carbene complex (Scheme 13).224,225 At higher temperatures (138◦ ) the only products formed are the oxazole 221 and the alkene 222.226,227 The latter is likely due to thermal decomposition of phenyl complex 26, which is formed by expulsion of benzonitrile from complex 220.228 OH Ph

Ph

N

Cr(CO)5

N

OMe 26

26

Ph

OMe

Ph

N

benzene, 80°

MeO

Ph N

n-Bu2O Cr(CO)5

138°

220 (85%)

Scheme 13

MeO

O N

Ph 221 (12%)

Ph

Ph

Ph

+ MeO

OMe

222 (12%)

180

ORGANIC REACTIONS

Whereas the reaction of carbene complexes with nitriles does not produce six-membered heterocycles, these products can result from reactions of carbene complexes with phosphaalkynes.229 – 231 Reaction of the 1-naphthyl carbene complex 223 with 2,2-dimethylpropylidynephosphane gives a phosphabenzene chromium tricarbonyl complex in 82% yield (Eq. 100).229,231 The metal can be removed in quantitative yield by ligand exchange with toluene. Despite the high yield observed for this reaction, significant yields of phosphaarenes could not be obtained with other carbene complexes. The predominant product from most of these reactions are oxaphospholes. (CO)5Cr

MeO

OMe t-Bu

P

Bu-t

MeO

P

Bu-t

toluene

P OH Cr(CO)3

t-BuOMe, 50°

OH

140-170°

(82%)

223

(Eq. 100)

(100%)

Although thermolysis of complex 220 does not produce a six-membered heterocycle (Scheme 13), its reaction with alkynes gives 3-hydroxypyridines.226,232 The 3-hydroxypyridine 224 is produced in 51% yield along with the non-CO inserted pyrrole 226 (Eq. 101).232 A third product (225) is formed by cyclization to the phenyl group on the carbene carbon in 220 rather than to the imino group. This complication does not exist for complex 227; however, its reaction with 1pentyne only gives five-membered ring products containing nitrogen (Eq. 102).226 The naphthalene product from this reaction results from extrusion of tert-butyl nitrile to give phenyl complex 26, which then undergoes reaction with 1-pentyne. This reaction is carried out in tert-butyl nitrile as solvent to suppress extrusion. The same reaction in THF gives only the naphthalene product.233 Extrusion of tert-butyl nitrile from complex 228 would give a non-stabilized carbene complex and this apparently disfavors extrusion since a naphthalene is not observed from the reaction of complex 228 with 1-pentyne (Eq. 103).232 The observation that the more electron-deficient complex 228 gives a six-membered ring product incorporating a CO ligand while the more electron-rich complex 227 only gives non-CO inserted products is consistent with the differences observed for reactions of alkoxy- and aminocarbene complexes. OH OH

OMe N

Ph (CO)5Cr

Ph

Pr-n hexane, 70°

Pr-n Pr-n +

N

N

Ph

OMe

(CO)5Cr 227

N H

t-BuCN, 70°

+ Ph

Ph

(Eq. 101)

226 (4%) OH

n-Pr Pr-n Bu-t

Ph

OMe 225 (31%)

224 (51%)

N

Ph

Ph

220

Ph

n-Pr

+

Bu-t N H (54%)

n-Pr MeO Ph

Pr-n + N (23%)

Bu-t (18%)

OMe

(Eq. 102)

THE SYNTHESIS OF PHENOLS AND QUINONES OH

OAc Pr-n

N

Ph (CO)5Cr

Ph

181

Pr-n

n-Pr

Pr-n

+

+

hexane, 70°

N

Bu-t

Ph

Bu-t N H (26%)

Bu-t (37%)

228

Ph

Bu-t N H (13%)

(Eq. 103) The imino complex 229 (Eq. 104) gives a higher proportion of 3-hydroxypyridine product than does the imidato complex 228 (Eq. 103).232 – 236 Chromium imino complexes of the type 229 produce mixtures of 3-hydroxypyridines and pyrroles, whereas the tungsten analogs give only pyrroles in a highly chemoand regioselective synthesis of these heterocycles (Eq. 104).234 The reaction of β,β-disubstituted imino complexes of the type 229 (obtained from ketones) with alkynes has been reported to give 2H -pyrroles under photolytic conditions.189,190 The only examples of heteroannulation onto a heterocylic substituent of a carbene complex involve the reactions of pyrazole complexes of the type 230 (Eq. 105).237 Moderate yields of pyrazolopyridinoquinones are obtained upon reaction with alkynes. The intramolecular assembly of a 3-hydroxypyridine from the complex 231 affords a 53% yield of a ring-fused 3-hydroxypyridine (Eq. 106).232 OH N

Pr-n

(CO)5M 229 M = Cr M=W

hexane, 70°

Ph

Ph

Pr-n + N

OMe hexane, rt

Ph

N H (9%) (≤1%)

OMe TMSCHN2

+ Ph

(51%) (—)

(CO)5Cr

Pr-n

n-Pr

(CO)5Cr NH N

(40%) (74%)

1. Et Et THF, 45° 2. CAN

Et Et

(Eq. 105)

OH

OMe

(CO)5Cr

O N N O (45%)

230 (76%)

Ph

(Eq. 104)

N H

hexane, 70°

N

Ph N

(53%)

(Eq. 106)

231

Cyclohexadienone Annulation Cyclohexa-2,4-dienones can be the predominant products from the reactions of alkynes with α,β-unsaturated carbene complexes of the type 232 that bear two carbon substituents in the β-position (Scheme 14).61 Complexes of the type 232 with YR = R3 Si give silylated phenols of the type 233 in high yield, often as their chromium tricarbonyl complexes (Eqs. 20 and 21).95,110,112,159 These products result from the carbon to oxygen migration of the silicon substituent in

182

ORGANIC REACTIONS

R2 R1

OP

YR Cr(CO)5

RL

RS

YR = H, TMS

OMe 232

OH

R2

RL

R1 RS (CO)3Cr OMe 233

P=H

R2

RL

R1

RS OMe 237

P = H, TMS

232

R

L

R

S

YR = R3

R3

O RL

R2 R1

RS

OMe 234 R3 = alkyl, aryl

232

RL

RS

R1

R2 NR2 RL

YR = NR2 RS

MeO 235

232

RL

RS

YR = OR, SR, F

RY R2

O RL 237

R1 RS (CO)3Cr OMe 236

Scheme 14

intermediate 236. If the carbene complex bears an oxygen, sulfur, chlorine, or fluorine substituent in the β-position, phenol 237 is produced by cleavage of the carbon-YR bond in intermediate 236 shown in Scheme 14 (Scheme 9,91 Eq. 36,122 Eq. 37,105 Eq. 39,124 Eq. 40125 ). The reactions of complexes bearing β-amino substituents do not give phenols or cyclohexadienones but rather yield predominantly cyclopentadienes of the type 235 (Scheme 14).123,30 Given the higher reduction potential of carbon-carbon bonds and the lower migratory propensity of carbon versus silicon or hydrogen, the reaction of complexes of the type 232 with YR as a carbon substituent usually give the cyclohexadienone product 234, although carbon migration may occur (see below). The reactions of complexes 238, 241, and 242 illustrate the versatility of the cyclohexadienone annulation (Eqs. 107–109). The reaction of hindered complex 238 with keto alkyne 239 gives the decalindienone 240 in 70% yield (Eq. 107).238 The quaternary carbon that is produced in the cyclohexadienone annulation becomes a spirocyclic center if the carbene complex is derived from a methylidenecycloalkane such as complex 241 (Eq. 108).239 The tetracyclic cyclohexadienone 243 is constructed from simple starting materials utilizing a

THE SYNTHESIS OF PHENOLS AND QUINONES

183

Diels-Alder reaction of a Fischer carbene complex as well as the cyclohexadienone annulation (Eq. 109).240 O O OMe

OBu-t

+

O OBu-t

THF, 50° Pr-i

Pr-i

Cr(CO)5 238

OMe 240 (70%)

239

(Eq. 107) OMe (CO)5Cr

+

TMS

TMS

THF, 50°

O (71%)

(Eq. 108)

MeO

241 OEt

Cr(CO)5

(CO)5Cr

OEt

Ph OEt

rt Pr-c

(Eq. 109)

THF, 50°

Pr-c

c-Pr O

Ph

243 (33%)

242

The cyclohexadienone annulation reaction can produce a new stereogenic center at the quaternary carbon if the two β-substituents of the carbene complex are not the same, as illustrated in Eq. 109.240 In such reactions the potential exists for relative asymmetric induction between the preexisting stereocenters in either the carbene complex or the alkyne and the newly formed stereocenter in the cyclohexadienone. Although the stereoselectivity of these reactions has not been extensively examined, examples of both types of induction can be found in the literature. Reaction of the 2,6-dimethylcyclohexenyl complex 244 gives a 90 : 10 selectivity for the trans-configured cyclohexadienone (Eq. 110),61 in contrast to the reaction of the 2,3-dimethylcyclohexenyl complex 245, which renders a nearly equal mixture of isomers (Eq. 111).207 A proposal to account for this difference in stereoselectivity has been presented. Significant levels of 1,4-asymmetric induction are observed for reactions with propargyl ethers (Eqs. 112 and 113).111 This reaction is stereospecific as demonstrated by the reaction of the Z- and E-isomers of carbene complex 246. The E-isomer gives a 92 : 8 mixture of diastereomers, whereas the Z-isomer gives a 9 : 91 mixture of the same cyclohexadienones. This result requires that the Z- and E-isomers of the β,β-disubstituted carbene complex 246 do not isomerize under the reaction conditions, which is surprising in light of the fact that the cis- and trans-1-propenyl carbene complexes have been found to isomerize under the reaction conditions.69 O OMe Cr(CO)5 244

O Bu-n

Bu-n

Bu-n +

(Eq. 110)

THF, 50° OMe

OMe (78%) 90:10

184

ORGANIC REACTIONS O

O Pr-n OMe

Pr-n

Pr-n +

hexane, 60°

Cr(CO)5 245

(Eq. 111)

OMe

OMe (83%) 56:44

O

OTr

Et OMe

OTr

Cr(CO)5

OMe

(E)-246

O

OTr

Et OMe

OTr

(Eq. 112)

(73%) 92:8

OTr

Et

OMe

O

OTr

+

Et

heptane, 55°

O

+

Et

heptane, 90°

Et

Cr(CO)5 (Z)-246

OMe

(Eq. 113)

(66%) 9:91

OMe

The reactions of aryl carbene complexes that have all-carbon substituents in positions beta to the carbene carbon often do not give cyclohexadienone products. For example, the reaction of the 2,6-dimethylphenyl carbene complex 247 with diphenylacetylene gives a 96% yield of the indene product, which is isolated as a mixture of the metal-free indene and its chromium tricarbonyl complex (Eq. 114).241,242 Although this reaction does not give a naphthol in which the methyl group has migrated to oxygen, this reaction does give an indene in which the methyl group has undergone a 1,5-sigmatropic rearrangement. Part of the driving force for this migration is the restoration of the aromaticity of the benzene ring that was lost when cyclization occurred to give the intermediate 249 (R = H, Eq. 115). A recent study finds that the 1,5-sigmatropic migration of methyl can be prevented by a keto-enol tautomerization in intermediate 249 (R = OH).243 An example of this tautomer-arrested annulation is the reaction of complex 248 with 3-hexyne, which affords the highly functionalized indenone 250 in 75% yield (Eq. 115). Some intramolecular variants of these reactions lead to CO insertion and the formation of vinyl ketene intermediates, which upon cyclization give cyclohexadienone products.243 Ph Ph Cr(CO)5

Ph

Ph

benzene, 110° (CO)3Cr

OMe 247

Ph +

OMe

Ph

(96%) 45:55

Et

HO

R Et Cr(CO)5 OMe 248

(Eq. 114)

OMe

Et

benzene, 110°

Et O

Et Cr(CO)3 OMe 249 R = OH

Et OMe 250 (75%)

(Eq. 115)

THE SYNTHESIS OF PHENOLS AND QUINONES

185

Cyclohexadienones can be obtained in good yields from other β,β-blocked aryl carbene complexes. Both 2-indolyl and 3-indolyl carbene complexes that have carbon substituents beta to the carbene complex give moderate to high yields of cyclohexadienone annulation products.62 As an example, the 2-indolyl complex 251 reacts with alkyne 252 to give the 4H -carbazol-4-one 253 in 59% yield (Eq. 116). The only example of an asymmetric cyclohexadienone reaction involving a chiral auxiliary on the carbene complex has been reported for an indolyl carbene complex. The reaction of chiral carbene complex 254 with 1pentyne gives the 4H -carbazol-4-one 255 with a greater than 96 : 4 selectivity for the diastereomer shown (Eq. 117).244 OMOM

MOMO

O

NHBz OMe N Me

Cr(CO)5

NHBz

252

(Eq. 116)

benzene, 50°

N Me

251

OMe

253 (59%)

Me N

MeN

O N (CO)4Cr Me N

Ph

Pr-n MeCN, 45-50°, 24 h

O Me N

N

Ph (61%) dr = ≥ 96:4

(Eq. 117)

Pr-n O

254

255

Two-Alkyne Annulation The original discovery of the formation of phenols from the reaction of Fischer carbene complexes with acetylenes involved the incorporation of only one molecule of alkyne. However, phenolic products can also be formed from the reaction of a Fischer carbene complex with two molecules of an alkyne. This structural type was first observed as a minor product in the cyclohexadienone annulation.61 An example of the competition between the formation of the two different phenolic products is presented in the reaction of phenyl complex 26 with propyne to give naphthol 256 along with phenol 257, which is derived from two molecules of propyne (Eq. 118).131,245 The yield of the “two-alkyne” phenol 257 initially increases with the number of equivalents of alkyne employed in the reaction and then falls off, presumably because of competing polymerization of the alkyne. The two-alkyne phenol is the major product with acetylene under all conditions (Eq. 42).131 The unsaturated substituent of the carbene complex is not incorporated into the two-alkyne phenol and thus alkyl-substituted carbene complexes such as 258 can also give “two-alkyne” phenol products. The

186

ORGANIC REACTIONS

latter reacts with propyne to give the phenol 259, which is likely formed via the intermediate vinylcarbene complex 260 into which a second molecule of alkyne inserts (Eq. 119).131 A more thorough presentation of the mechanistic path to the two-alkyne phenol product can be found in Scheme 5. OH

OH

(x eq) Cr(CO)5

+

THF, 45°

OMe

OMe 256

26 x 2 40 neat

256 (45%) (10%) (0.3%)

257

(Eq. 118)

257 (4%) (44%) (28%)

OH OMe Cr(CO)5

(10 eq) THF, 45°

258 OMe

259 (33%)

(Eq. 119)

Cr(CO)4 260

The utility of the intermolecular “two-alkyne phenol” annulation is limited by typically poor yields as indicated in Eqs. 118 and 119. Furthermore, this variant is limited to small alkynes such as propyne or acetylene (Eq. 42). More success has been achieved with intramolecular variations of this process (Eqs. 120–123). The possibilities for intramolecular reaction are three-fold: (1) the tethering of the carbene complex to one of the alkynes, (2) the tethering together of the two alkynes, and (3) the tethering of both alkynes to the carbene complex. The first combination is limited in its ability to produce the two-alkyne phenol product as illustrated by the formation of phenol 262 from the reaction of complex 261 with 1-pentyne (Eq. 120).246 This particular intramolecular variation in benzene can produce good to moderate yields of 2-vinylcyclopentenedione 263, a rather complex product derived from the incorporation of two equivalents of alkyne and two equivalents of carbon monoxide (Scheme 4).78 Also observed in this reaction is the isomeric “two-alkyne phenol” 264, which results from incorporation of the carbon monoxide into the benzene ring para to the carbon derived from the carbene carbon. Increased amounts of this para “two-alkyne phenol” are observed at lower substrate concentrations78,246 and with amino carbene complexes.58

THE SYNTHESIS OF PHENOLS AND QUINONES OMe 1.

(CO)5Cr

Pr-n (10 eq), solvent, 80°

OH

Pr-n

O

n-Pr +

n-Pr

187

OMe +

2. TiCl3, LiAlH4

HO

O 261

262 Solvent THF benzene MeCN

262 (7%) (8%) (15%)

263

263 (23%) (41%) (≤1 %)

264

264 (≤0.3%) (2.0%) (≤0.5%)

(Eq. 120) Synthetically useful yields of “two-alkyne phenols” can be obtained from the reaction of Fischer carbene complexes with diynes. This feature is illustrated by the reactions of complexes 258 and 268 with 1,6-heptadiyne (265) which, depending on the solvent, gives mixtures of the phenol 266 and the cyclohexadienone 267 (Eq. 121).80,133 The cyclohexadienone 267 can be reduced to the phenol 266 by chromium(0), supporting the mechanism proposed for phenol formation (Scheme 5). The phenol is the major product in THF, but in acetonitrile increased amounts of the cyclohexadienone are isolated. This outcome is thought to be attributable to the ability of acetonitrile to sequester the chromium(0). Good yields of the cyclohexadienone product can be obtained with the phosphine-substituted complex 268, which can react with the diyne without the need for heating. In a related process, phenols of the type 266 can also be produced by the reaction of diynes and Fischer carbyne complexes.81 The double intramolecular reaction of carbene complexes bearing tethered diynes can give good yields of tricyclic phenols as illustrated by the thermolysis of complex 269 in acetonitrile (Eq. 122).245,247 1. OMe

, solvent, temp

OH

O

265

(CO)4Cr

2. silica gel

L

266 258 258 268

L CO CO Ph3P 267

OMe

+

Solvent THF MeCN MeCN

Temp 70° 70° 22°

(CO)5Cr-THF

267

(Eq. 121)

266 267 (57%) (0%) (39%) (26%) (6%) (54%)

266 (47%)

OMe OH

(CO)5Cr 1. MeCN, 70° 2. silica gel

O +

(72%) 43:57 269

OMe

(Eq. 122)

188

ORGANIC REACTIONS

A tandem Diels-Alder/“two-alkyne annulation” has been developed as a strategy for the synthesis of steroid analogs.245,247 Diels-Alder reaction of endiynyl carbene complex 270 with 2-methoxybutadiene proceeds at room temperature to give the cycloadduct 271 in 84% yield (Eq. 123). The tungsten complex is employed because the double intramolecular two-alkyne annulation of chromium complexes gives lactone side products, the amount of which is dependent on the geometric constraints of the tether. Tungsten complexes require higher temperatures for reaction but, nonetheless, give good yields of two-alkyne phenols. Thermolysis of 271 in THF produces the cyclohexadienone in 72% yield as a 3 : 1 mixture of diastereomers.245 W(CO)5

(CO)5W

MeO

TMS

TMS OMe

MeO rt, 23 h

(84%)

MeO

270

271 TMS O H

THF, 110°

TMS +

O H

R MeO

R MeO

H (72%) 72:28

H

R = OMe

(Eq. 123) Ortho-Benzannulation/Cyclization of Doubly Unsaturated Complexes The penultimate intermediate in the formation of phenols from the thermal reaction of Fischer carbene complexes with alkynes is a doubly unsaturated ketene complex of the type 274 (Scheme 15). The typical reaction involves the carbene complex 272 and an alkyne to give the 4-methoxyphenol 275. On the basis of the extensive photochemical studies of Fischer carbene complexes,248,249,37 it was anticipated that an alternative method for access to ketene complex 274 would be the photolysis of the doubly unsaturated carbene complex 273.250,251 Photolysis should promote a CO insertion to give ketene complex 274, and subsequent cyclization would then lead to the 2-methoxyphenol 276. These two methods would thus be complementary as to the substitution patterns in the phenol product. Recently, the thermal conversion of certain types of complex 273 into phenols 276 has been observed.252,253 Photo-induced ortho-benzannulation of carbene complex 278 (prepared by a Diels-Alder reaction of alkynyl complex 277 with cyclopentadiene) gives the ring-fused 2-methoxynaphthol 279 in 18% yield (Eq. 124).250,251 The yield of this reaction is dramatically improved (93%) when the reaction is carried out in a Pyrex vessel under an atmosphere of carbon monoxide.254 2-Methoxyanilines

THE SYNTHESIS OF PHENOLS AND QUINONES

R5

R5 R1

MeO

189

O •

R2

R4 Cr(CO)5

R1 (CO)3Cr

272

OH R4 R3

R1 R3 = OMe

R5

R2

R2

R4 OMe

274

275 OH

OMe R5

(CO)5Cr

R5

MeO

hn or heat 274

R2

R4

R2

R3

R4 R3 276

273

Scheme 15

and 2-methoxyaminonaphthalenes are produced by thermal reaction of doubly unsaturated carbene complexes with isonitriles.255 This reaction presumably proceeds via the iminoketene analog of 274 (Scheme 15). For example, complex 280 reacts with tert-butyl isonitrile to give the aminonaphthalene 281 in 89% yield, and with ethyl 2-cyanoacetate to give 282 in 80% yield, in contrast to photo-induced CO insertion into 280, which gives the naphthol 283 in 42% yield (Eq. 125). OMe

Cr(CO)5

(CO)5Cr

OMe OH

THF, hν OMe

rt Ph

Ph 277

278 (98%)

279 (18%) (93%, CO atm, Pyrex filter)

(Eq. 124) OMe NHR

CNR rt-65°

Ph

Cr(CO)5

281 R = t-Bu 282 R = CH2CO2Et

OMe

(89%) (80%)

Ph 280

OMe hn

OH

CO Ph 283 (42%)

(Eq. 125)

190

ORGANIC REACTIONS

The photo-induced ortho-benzannulation reaction is not generally extendable to dialkylamino-substituted carbene complexes. The photolysis of complex 284 in the presence of CO does not give any detectable amount of the amino naphthol 285 (Eq. 126).256 However, if the amino group of the carbene complex is incorporated as a carbamate, photolysis of complexes such as 286 give amino naphthols like 287 (Eq. 127).256 A similar observation has been made for the scope of the thermal benzannulation of amino complexes with alkynes (Eq. 68).162,163 The most general method for the synthesis of 2-amino phenols from this reaction is the thermolysis of isonitriles.255,257 For example, the amino carbazole 289 is obtained in 86% yield from thermal reaction of indole carbene complex 288 with tert-butyl isonitrile,258 compared to the 65% yield of alkoxy carbazole 290 that was obtained from the photolysis of 288 in the presence of CO (Eq. 128). Both the CO and isonitrile insertion/cyclization products from indolyl carbene complexes of the type 288 were used in the total synthesis of carbazoquinocin C.258 Cr(CO)5

hn, CO

NMe2

NMe2 OH

284 (CO)4Cr

(Eq. 126)

Ph

Ph 285 O N Bn

O O-Bu-t

hn

t-BuO

N

Bn

(Eq. 127)

OH

CO

Ph

Ph 286

287 (33%)

MeO

NHBu-t

t-BuNC MeO

Cr(CO)5

THF, reflux

C7H15-n N Bn 288

C7H15-n N Bn 289 (86%) MeO

OH

(Eq. 128)

hn CO, THF

N Bn

C7H15-n

290 (65%)

The formation of ortho-alkoxy phenols from doubly unsaturated carbene complexes can be effected thermally in good yield with certain complexes.252,253 Whereas thermolysis of complex 278 in refluxing heptane affords only the o-methoxyphenol 279 in 29% yield (Eq. 124),254 thermolysis of complex 291

THE SYNTHESIS OF PHENOLS AND QUINONES

191

in THF produces the o-methoxyphenol 292 in 93% yield (Eq. 129). This thermal reaction was found to be synthetically viable only for a variety of cyclobutenylcarbene complexes, presumably because of the strain in the four-membered ring.253 These cyclobutenyl complexes are also unique in that their reactions with alkynes produce eight-membered ring compounds like 293.54 MeO OH

O

(93%)

MeO Cr(CO)5

O

292

THF, reflux

(Eq. 129)

MeO 291

Ph

O

Ph

O

(71%)

293

An alternative entry into dienyl ketenes of the type 274 (Scheme 15) involves reactions of Fischer carbene complexes with alkynes that are conjugated to doubly unsaturated groups.51,129,130,259,260 The reaction of complex 258 with (Z)-4-phenyl-3-buten-1-yne gives the naphthalene derivative 297 in 80% yield (Scheme 16).51 In these reactions, the vinyl ketene intermediate 295 is formed by addition of the carbene complex 258 to the terminal alkyne function to give the new complexed vinyl carbene intermediate 294. Subsequent CO insertion to give 295 followed by cyclization affords phenol 296, which is isolated as cyclized product 297.51

MeO

O •

(CO)4Cr Cr(CO)5

dioxane, reflux, 4 h

MeO

MeO

258

(CO)3Cr 295

294 MeO

OMe O

OH

297 (80%)

296

Scheme 16

192

ORGANIC REACTIONS APPLICATIONS TO SYNTHESIS

A large number of reactions of Fischer carbene complexes have been employed in organic synthesis and undoubtedly the reaction that has been most widely used in organic complex molecule synthesis is the benzannulation reaction with alkynes. The benzannulation reaction has been used in the total syntheses of a variety of natural products including vitamins K3 and K1(20) ,261 vitamins in the K1 and K2 series,262 vitamin E,263 nanaomycin A and deoxyfrenolicin,86,90,152,218 7-ethoxyprecocene,69 khellin,264,115 sphondin,114 thiosphondin,114 heratomin,114 angelicin,114,265 visnagan,167 12-O-methylroyleanone,266 5-lipoxygenase inhibitors,267 fredericamycin A,151,183,268,269 egonol,270 parvaquone,191 calphostins A, B, C, and D,271,272 shikonin,273 – 275 7-methoxyeleutherin,276 bis-N -dimethylmurryquinone,75 carbazoquinocin C,258 and landomycinone.277 The benzannulation reaction has also been used for the synthesis of the anthracyclinone antitumor antibiotics including the formal synthesis of daunomycinone278,12,112 and 11-deoxydaunomycinone158,279 – 281 . An alternate strategy for the formal synthesis of daunomycinone and 4-demethoxydaunomycinone has also been reported,279,281 – 284 but subsequently this synthesis has been called into question.105 Strategic models have been examined for the synthesis of several natural products including frenolicin and granaticin,214 olivin and chromomycinone,285,286,113,265 aspidosperma alkaloids,62,242 mitomycin A,287 taxodione,238 nogalarol,288 11-ketosteroids,245,247 oxasteroids,289 gilvocarcins,290 anthracyclines,159 angucyclinone SF 2315A,103 berberine alkaloids,291 indolocarbazole natural products,292,293 benzocarbazole natural products,220 modified carbohydrates,294,124 C-arylglycosides,295,296 menogaril,175,297 rubromycin,298 and allocolchicinoids.299,211 A selected set of total syntheses that feature the reaction of Fischer carbene complexes with alkynes is presented below and in each example the presentation begins with the key benzannulation step. The synthetic target is usually a natural product, but one example highlights benzannulation in the synthesis of a ligand for use in asymmetric catalysis. The examples were chosen to illustrate the utility of the benzannulation of alkenyl, aryl, and heteroaryl complexes, the intramolecular benzannulation, and the ortho benzannulation. The syntheses of 12-O-methylroyleanone266 and vitamin K1(20) 262 result directly from the benzannulation of alkenyl complex 299 and phenyl complex 26, respectively (Eqs. 130 and 131). Decalenyl complex 299 is prepared from the hydrazone 298 upon in situ generation of the corresponding vinyllithium. The reaction of this complex with 1-methoxy-3-methyl-1-butyne gives the target quinone 300 in 37% overall yield from 298. The synthesis of vitamin K1(20) is actually quite straightforward once the phytyl chain is appended to the proper alkyne function. The reaction of alkyne 301 with the phenyl carbene complex 26 gives a 56% yield of vitamin K1(20) after oxidation of the 4-methoxyphenol product with silver oxide.262 The same alkyne can be used in the synthesis of vitamin E.300

THE SYNTHESIS OF PHENOLS AND QUINONES

N

NHSO2Ar

EtO

1. n-BuLi (2.2 eq), –78° to –20° 2. Cr(CO)6 3. Et3O+ BF4–

H

Cr(CO)5

193

1. MeO Pr-i THF, reflux 2. CAN/H2O

H 299

298

MeO O

Pr-i

(Eq. 130)

O H 300 (37%) from 298 12-O-methylroyleanone 1. Cr(CO)5

R, t-BuOMe, 50°, 1 h 301

2. Ag2O, Et2O

OMe 26

R=

(Eq. 131)

3

O

O

(56%) vitamin K1(20)

Alkenyl and aryl carbene complexes have both been used in the synthesis of anthracycline antitumor antibiotics. Daunomycinone and 11-deoxydaunomycinone are aglycones of members of the anthracycline family of antitumor antibiotics, which include agents that are among the clinically most important compounds in cancer chemotherapy (Eqs. 132 and 133). The syntheses of daunomycinone278,12 and 11-deoxydaunomycinone158 via Fischer carbene complexes are illustrative of the power of the benzannulation reaction to solve two of the most significant problems related to the synthesis of this family of compounds: (1) the control of the relative orientation of the A vs. D rings, and (2) a convergent method to both the 11-oxy and 11-deoxy members of the anthracycline family.301 The construction of the tetracyclic quinone 305 from carbene complex 302 and alkyne 303 represents a formal synthesis of daunomycinone because its synthesis from 305 has been previously reported.302 This reaction gives a single constitutional isomer of 304 and locks in the correct relative regiochemistry of two ends of the tetracyclic target 305. The regioselectivity is expected to be quite high because the related reaction of the cyclohexenyl complex 34 with 1-pentyne gives greater than 250 : 1 selectivity (Eq. 10).

194

ORGANIC REACTIONS

OH

O O

MeO

O

1. THF, 45°

+

O

O

2. FeCl3-DMF

OMe O

(CO)5Cr 302

OMe O

303 O

O OMe

304 (72-74%)

OH

O

OH

B

C

O

O A

OMe O OH 305 (61-65%)

MeO

D

OH

O OH OH daunomycinone

(Eq. 132) The synthesis of 11-deoxydaunomycinone is accomplished with an inverted strategy compared to that for daunomycinone in that it incorporates the aromatic A-ring in the carbene complex and the saturated D-ring in the alkyne (Eq. 133).158 A tetracyclic intermediate can be made in a one-pot process involving a tandem benzannulation/Friedel-Crafts sequence of carbene complex 53 and alkyne 306. Benzannulation is carried out in benzene and after completion, the reaction mixture is opened to air to oxidatively liberate product 307 from the metal. Triflic anhydride and sodium acetate are added to protect the phenol and then triflic acid is added to effect the Friedel-Crafts cyclization. Final adjustments to the oxidation state give the tetracyclic target 308 in 61% overall yield from alkyne 306. Intermediate 308 has been previously converted into 11-deoxydaunomycinone in four steps.303 The complete synthesis of 11-deoxydaunomycinone, including the four additional steps from intermediate 308, is achieved in 8.5% overall yield from commercially available starting materials. This synthesis clearly demonstrates the efficiency of the benzannulation reaction of Fischer carbene complexes in organic synthesis. OH

O OMe OMe Cr(CO)5

O

1. C6H6, 75°

+

2. air, 10 min

O

O OMe OMe

OBu-t 306

53 O

OBu-t

307 O

O

O OH

OMe O

OH

308 (61% from 306)

MeO

O

OH OH

11-deoxydaunomycinone

(Eq. 133)

THE SYNTHESIS OF PHENOLS AND QUINONES

195

The synthesis of fredericamycin A is a formidable task not only due to the complexity of the molecule but also because a highly oxygenated aryl carbene complex is required (Eq. 134). Depending on the substitution pattern and the nature of the substituents, these complexes can be problematic in the benzannulation reaction.151,183,268,269 The 2,3,5-trioxygenated phenyl carbene complex 309 is no exception. In fact, the importance of the “acetic anhydride” effect (Eq. 81)116 was made apparent in the course of this synthesis. The key benzannulation in the synthesis of fredericamycin A is the reaction of complex 309 with alkyne 310 to give the desired phenol 311 in 35% yield. In the absence of acetic anhydride no product is observed. OTBS MOMO MeO

Cr(CO)5 OMe

+

TBSO BnO

Ac2O (1-2 eq) n-heptane, 50°, 48 h

EtO MOMO 309

N

310

MOMO MeO

OMe OTBS

MOMO

OH OTBS BnO

O

OH

O

O OH HO

MeO

EtO 311 (35%)

N

O

O

N H fredericamycin A (28% from 311)

(Eq. 134) The synthesis outlined in Eq. 135 is not of a natural product, but rather of a compound that was designed and synthesized for the purpose of serving as the chiral ligand VAPOL for catalytic asymmetric synthesis. The synthesis begins with the benzannulation reaction of the 1-naphthylcarbene complex 312 and phenylacetylene,89 which is carried out on a 250-gram scale to give a 72% yield of phenanthrene 313 after acetylation of the phenol.304 Cleavage of the methyl ether occurs with simultaneous reduction of the acetoxy group to give 2-phenyl4-phenanthrol (314) in 81% yield. Heating 314 in the presence of air at 185◦ gives the VAPOL ligand directly as a product of oxidative phenolic coupling. The racemic VAPOL can be resolved into its enantiomers by salt formation of a cyclic phosphoric acid derivative with (−)-cinchonidine. VAPOL has found general use in asymmetric catalysis.305 – 309

196

ORGANIC REACTIONS 1.

(CO)5Cr

OMe

Ph THF, 60°, 17 h

AcO

2. Ac2O, Et3N, THF, 60°, 24 h

Ph

312 250-g scale

185°

Ph Ph

neat, air

AlCl3, n-PrSH

resolution

OH OH

Cl(CH2)2Cl, rt, 12 h Ph

OMe 313 (72%)

Ph Ph

(±)-VAPOL (80-89%)

OH 314 (81%)

OH OH

(S)-VAPOL

(Eq. 135) The structural features of deoxyfrenolicin are sufficiently seductive to have inspired one formal and two total syntheses utilizing the benzannulation reaction. Since deoxyfrenolicin has a naphthalene core that is substituted in both the 2- and 3-positions, retrosynthesis to an aryl carbene complex requires a benzannulation reaction with an internal alkyne, a reaction known not to be regioselective. The first total synthesis solved the regiochemistry problem by tethering the alkyne 316 to the aryl carbene complex 315 via a β-alkoxyethoxy group that serves as the heteroatom stablizing group (Eq. 136).90,214,218 The key intermediate is the carbene complex 317, which upon thermolysis and oxidative workup gives naphthoquinone 318 as a single constitutional isomer. –+ ONMe4

1. AcCl, –20° 2. 316

OMe Cr(CO)5 315

MeO

O

O

O 317 (88%)

O

O

2. DDQ Pr-n

O CO2H

Pr-n OMe O

1. Et2O, 35°

Cr(CO)5

Pr-n OH

OMe O

318 (51%)

OH

OMe O deoxyfrenolicin

319

HO

O

O

Pr-n

316

(Eq. 136)

THE SYNTHESIS OF PHENOLS AND QUINONES

197

This synthesis can be shortened and improved in overall efficiency by employing the silicon tether in carbene complex 321, generated in situ from complex 315 and chloro(alkynyloxy)silane 320. Complex 321 is heated in hexane to give the key intermediate 319, which undergoes several subsequent steps to complete a formal synthesis of deoxyfrenolicin (Eq. 137).86 Note that in this intramolecular reaction the product can be liberated from the silicon tether without oxidation at the alcohol function. A second total synthesis of deoxyfrenolicin has been reported in which the problem of regiochemistry is circumvented by employing a terminal alkyne. The substitutent in the 3-position is introduced by an oxa-Pictet-Spengler reaction.152

–+ ONMe4

320

1. n-hexane, reflux

Cr(CO)5

CH2Cl2, –23°

MeO

OMe Cr(CO)5 315

2. CAN

O Si Me Me Pr-n O

321 (100%) O

O

CO2H O

Pr-n OMe O

OH OMe O 319 (49%)

deoxyfrenolicin

ClMe2SiO Pr-n 320

(Eq. 137)

The total synthesis of sphondin has been achieved by both an inter- and intramolecular benzannulation. The intramolecular approach involves the 3-furyl carbene complex 322 that has the alkyne tethered through the oxygen substituent of the carbene complex (Eq. 138).114,265 Thermolysis of 322 leads to in situ formation of the arenechromium tricarbonyl complex 323, which is methylated, proto-desilylated, and finally oxidatively liberated from remaining metal fragments to afford the benzofuran 324 in yields that range from moderate to excellent. The presence of the trimethylsilyl group in the intramolecular benzannulation is critical because extremely poor yields are observed for this reaction with terminal alkynes.90,114,214 A more efficient synthesis of sphondin can be achieved by an intermolecular benzannulation of the 2-furyl complex 100 and alkyne 325 to generate the benzofuran 326 in 55% yield (Eq. 139).114 Oxidation of 326 with DDQ produces sphondin in 40–57% yield.

198

ORGANIC REACTIONS

SPh

TMS O (CO)5Cr

SPh

O

2. MeI, K2CO3

1. THF, 75-85°

3. TFA 4. FeCl3-DMF

O TMS (CO)3Cr OH

O 322

323 O

SPh

O

O

O

O OMe

OMe sphondin (40%)

324 (56-92%)

(Eq. 138) 1.

O

OMe

CO2Me

O

325 THF, 85°

O

(Eq. 139)

2. air, 85°, 3 Å MS Cr(CO)5 100

O OMe 326 (55%)

The calphostin family of natural products are potent inhibitors of protein kinase C. The synthesis of calphostin A illustrates a situation where the thermal isonitrile insertion/cyclization is superior to the photo-induced CO insertion/cyclization procedure (Eq. 125).255 The presence of adjacent oxygenated carbons in one of the rings in these molecules suggested an approach utilizing the ortho-benzannulation of a Fischer carbene complex (Eq. 140).271,272 The key intermediate for this synthesis is the 2-alkenyl substituted aryl complex 327. The central disconnection in the retrosynthetic analysis leads to the ortho-quinone intermediate 329. The photo-induced ortho-benzannulation fails to provide a synthetically viable synthesis since photolysis of complex 327 gives low yields of the ortho-methoxy phenol 330. However, the alternative procedure involving the thermal reaction of complex 327 with an isonitrile gives the o-methoxynaphthylamine 328 in 60% yield. After protection of the alcohol function, 328 is oxidized to the o-quinone 329 in 87% yield. Quinone 329 is dimerized with trifluoroacetic acid in the presence of oxygen to give an intermediate, which upon deprotection affords calphostin A. The synthetic strategy developed for the synthesis of calphostin A has also been applied to the synthesis of calphostins B, C, and D.271,272

THE SYNTHESIS OF PHENOLS AND QUINONES MeO

Cr(CO)5

MeO

OMe OTIPS

OMe NHBu-t OH

1. t-BuNC 2. TBAF

MeO

199

1. BzCl, pyr 2. DDQ

MeO 327

328 (60%) OH O

MeO

OMe OBz

O O

MeO MeO

OBz

(Eq. 140)

MeO

OBz OMe

329 (87%) OH O calphostin A MeO

OMe OH OTIPS

MeO 330

COMPARISON WITH OTHER METHODS

The synthesis of phenols and quinones by the reaction of Fischer carbene complexes with alkynes is broadly applicable, and provides good to excellent overall synthetic efficiency for a range of substituted phenols, naphthols, and higher polycyclic phenols. There are many other methods for construction of aromatic ring systems in general, and also for phenols and quinones in particular.310 A few of these methods are closely related mechanistically to the benzannulation of carbene complexes in that they involve electrocyclic ring closure of a dienyl ketene intermediate that, however, is not coordinated to a metal center. Most of these processes involve the generation of cyclobutenones of the type 331, and their electrocyclic ring opening to a dienyl ketene and subsequent cyclization (Eq. 141). R1

O O R5

R2

R3 331

R4

heat or light

R1

OH

• R5

R2 R3

R4

R1

R5

R2

R4

(Eq. 141) R3

Many of the methods for the construction of cyclobutenones involve the [2 + 2] cycloaddition of a ketene with an alkyne (332 to 331, Scheme 17). This reaction can be synthetically useful with stable ketenes such as diphenylketene,311,312 but not generally with simple alkynes and ketenes. One example involves the reaction of phenylacetyl chloride with phenylacetylene.313 Thermally induced elimination of HCl at 180◦ produces phenylketene, which undergoes cyclization to the cyclobutenone 334. Under the reaction conditions, 334 undergoes ring

200

ORGANIC REACTIONS R5

N2 R3

R

light

4

O O

R5

R5

O

base

•

R4

R4

Cl O

R5

R3

R4

R3 332 heat or light

R1

Y

R1

R2 X R2

O R5 R3 R 333

332

4

– HY

R1

R2

R1

O

R2

R3

R5 R4

331 R1

O Cl

R2

+

R3Sn

R5 R4

R3 Ph

CH2COCl

Ph

180°, 16 h

Ph

O

KOH 335 (56%)

Ph

O

Ph 334

OH 335

Ph

O 336

Scheme 17

opening and then cyclization to afford naphthol 335, which in the presence of the acid chloride is acylated to provide ester 336. Hydrolysis gives a 56% yield of naphthol 335. The limitation of the [2 + 2] cycloaddition of ketenes with alkynes can be overcome in a two-step process involving the [2 + 2] cycloaddition of a ketene with an enol ether to provide 333 (Y = OR), followed by elimination of an alcohol to generate the phenol precursor 331.314,315 An alternative approach to cyclobutenones of the type 331 is the installation of the unsaturated substituent on the sp3 carbon by a Stille coupling reaction of chlorocyclobutenones.316 A synthetically reliable synthesis of phenols via cyclobutenones has been developed on the basis of the [2 + 2] cycloaddition of ketenes with alkynyl ethers, thio ethers, and ynamines.317,318 This process involves the cascade of

THE SYNTHESIS OF PHENOLS AND QUINONES

201

four pericyclic reactions and has been utilized in syntheses of a number of natural products. The synthesis of royleanone outlined in Eq. 142 involves a cascade of three pericyclic reactions beginning with the [2 + 2] cycloaddition of alkyne 338 with a ketene generated from the Wolff rearrangement of the diazo ketone 337.319 This reaction affords phenol 339 in 64–67% yield and subsequent silyl deprotection and oxidation completes the synthesis of royleanone. This synthesis is to be compared with the synthesis of O-methyl royleanone from carbene complex 299 (Eq. 130).266 The synthetic route to the methyl ether via the carbene complex is a few steps shorter and proceeds with somewhat higher overall yield.319 Pr-i

N2 O

i-Pr

OTIPS

TIPSO

TIPSO Pr-i

O

338 OH

hn 337 339 (64-67%)

(Eq. 142)

OH O

Pr-i

1. TBAF 2. Fremy's Salt

O

royleanone (49%)

A flexible synthesis of 4-alkoxyphenols and quinones grew out of the synthesis of phenols from cyclobutenones as outlined in Scheme 18.320 – 325 Alkoxyphenols would be the expected products when R3 in cyclobutenone 331 is an alkoxy group, that is, when cyclobutenones of the type 340 are employed (Scheme 18). Cyclobutenones 340 bearing an alkoxy substituent on the sp3 carbon tend to give higher yields of phenols upon thermolysis because the alkoxy group has a propensity for outward rotation in the electrocyclic ring opening. Thus, the unsaturated substituent preferentially undergoes inward rotation to give the ketene intermediate 341 having the correct geometry for cyclization to phenol 342.326 Cyclobutenones of the type 340 are best prepared from squaric acid.327,328 One of the key advantages of this quinone synthesis is the regiocontrolled construction of quinones as exemplified in the synthesis of quinone 344 in an overall yield of 90% from the intermediate 343 (Scheme 19).329 The synthesis of the same quinone from the reaction of a 4-methylphenyl-substituted Fischer carbene complex with 2-heptyne would give a mixture of isomers in which quinone 344 would be expected as the minor isomer. Thus, although this quinone synthesis is longer than the one involving Fischer carbene complexes, it offers a much higher level of regiochemical control that is not possible with Fischer carbene complexes. Much of the work on methods for quinone synthesis involving cyclobutenones and cyclobutenediones described above grew out of an earlier method that featured an oxidative addition of a transition-metal to a cyclobutenedione to give a metalla-cyclopentadienone followed by coupling with an alkyne to produce

202

ORGANIC REACTIONS HO

O

HO

O

i-PrOH

i-PrO

O

i-PrO

O (86%)

R5

Li

R1

R4

O R

2. MeX

O

i-PrO

O

2. 12 N HCl

benzene

1.

R1

1. R1Li

i-PrO

OMeR

R1

1. R2Li

5

R5

2. TFA

4

R2

O R1

O

OR R 340

4

OH

•

R2

R5

R1

R4

R2

OR

R5 R4 OR 342

341

Scheme 18

i-PrO

O

i-PrO

O

i-PrO

(72%) i-PrO

O (89%)

OMe

OH

O n-Bu

O

1. Li 2. MeX

2. 12 N HCl

1. n-BuLi 2. TFA

O

1. MeLi

O

140° xylene

OMe

CAN n-Bu

n-Bu OMe

O 344 (90%) from 343

343 (55%)

Scheme 19

quinones (Eq. 143).330,331 This method can be extended to cyclobutenones where, depending on the nature of the metal, either metallacyclopentenones332 or vinyl ketene complexes of the type 346 can be isolated (Eq. 144).333 Subsequent reaction of complex 346 with an alkyne gives a mixture of constitutionally isomeric phenols. R1

O

MLn

R1

O

O R3

R4

R1

R4

R2

R3

ML(n-1) R2

O

R2 O 345

O

(Eq. 143)

THE SYNTHESIS OF PHENOLS AND QUINONES

203

OH O R1

(C9H7)Co(PPh3)2

O

R2

•

R3

Co

R3 +

COD (2 eq), 100°

R2

OH R4

R4 R1

R1

R3 R2

R1

R4 R2

346

(Eq. 144) The reaction can also be performed catalytically with substoichiometric amounts of bis(cyclooctadiene)nickel resulting in facile formation of the same phenols at much reduced temperatures (Eq. 145).334 Reactions of the isolated vinyl ketene complexes 346 with alkynes give good to moderate yields of phenols (Eq. 144). However, the regioselectivity is low as indicated in the reaction of 347 with 1hexyne, which gives a 2.5 : 1 mixture of phenols 348 and 349 (Eq. 146).333 OH O

R

R

OH R3

R4

4

R1

R1

R3

•

R4

R2

R2

OH O

(Eq. 145)

+

Ni(COD)2 (10-20 mol%), 0°

R2

R1

3

Co

Bu-n

OH Bu-n +

(Eq. 146)

COD (2 eq), 100° Ph Bu-n 349 (45%)

Ph Ph

348 (18%)

347

Reactions of cyclobutenones with alkynes catalyzed by Ni(0) fail to give phenolic products with terminal alkynes, but afford good to high yields with internal alkynes. The steric difference between the two substituents of the alkyne has essentially no impact on regioselectivity as noted in the reaction of cyclobutenone 350 with 4-methyl-2-pentyne, which gives an equal mixture of the two possible isomeric products (Eq. 147).334 O Ph

Ni(COD)2 (10-20 mol%) 350

OH

OH Pr-i

Pr-i Ph

(40%) + Ph

(40%)

(Eq. 147)

Pr-i

The most widely studied of the organometallic-based quinone syntheses is that involving metallacyclopentenediones of the type 345 derived from cyclobutenediones (Eq. 143). Application of this process to the synthesis of an intermediate for the natural product royleanone is illustrative (Eq. 148).335 Reaction of cyclobutenedione 351 with tris(triphenylphosphine)chlorocobalt gives the corresponding metallacycle in 46% yield. Replacement of the phosphine ligands in the metallacycle with dimethylglyoxime produces the more reactive (toward alkynes)

204

ORGANIC REACTIONS

complex 352.336 The key step in the synthesis is the reaction of complex 352 with alkyne 353 to give the quinone 354 as a 5 : 1 mixture of constitutional isomers. i-Pr

O

MeO

O

O i-Pr

Cl Co PPh3 PPh3 MeO O (46%)

ClCo(PPh3)3

351

O

O i-Pr

DMG

OH N

Co

pyridine

MeO

N L O OH 352 (86%) L = pyridine

(Eq. 148)

OH

OMe O

OTBS 353

Cl

Pr-i

Pr-i

CoCl2•6H2O

O

O OTBS 354 (81%) 5:1 mixture of constitutional isomers

H royleanone

PREPARATION OF CARBENE COMPLEXES

The most widely used method for the synthesis of Fischer carbene complexes remains the original method reported by Fischer, which involves the addition of an organolithium reagent to a metal carbonyl complex (Scheme 20).1 The alkoxy complexes 356 can be obtained directly from the metal acylate 355 by in situ alkylation with trialkyloxonium salts,337 alkyl fluorosulfonates,338 or alkyl trifluoromethanesulfonates.339 The carbon monoxide ligands in lithium acylates will rapidly exchange with free carbon monoxide and also with the acyl carbon, thus providing an efficient method for the preparation of isotopically-labeled compounds.340 The reactions of acylate complexes 355 with less reactive electrophiles such as methyl iodide are not generally useful, although the direct preparation of complexes 356 with alkyl iodides in a two-phase system has been developed.341 Reactivity toward a given electrophile can be increased by conversion of the lithium acylate 355 to the tetraalkylammonium acylate 359. This enhancement is illustrated by the reaction of 359 with acid halides to generate the acyloxy complexes 360.170 These complexes are not generally stable to isolation under ambient conditions, but their reactivity can be utilized in the preparation of a variety of complexes by substitution reactions with alcohols, amines, and thiols.171 The preparation of complexes of the type 356 via the acyloxy complexes 360 is more efficient when the latter are generated with an acid halide from the ammonium salt 359 than from the lithium salt 355. Fischer was the first to demonstrate that amino and thio complexes of the type 357 could be prepared by the direct treatment of alkoxy complexes with amines and thiols.9 The alkylation of 355 with dimethyl sulfate is slow and inefficient. However, high yields have been reported with this inexpensive alkylating agent from the reaction of the potassium acylate generated in situ from the hydroxy complex 358 and potassium

THE SYNTHESIS OF PHENOLS AND QUINONES O C OC

O C

H+

OH (CO)5M

Cr CO

C O C O

R1

358 R1Li

OLi (CO)5M

R1

355

CH2N2 or K2CO3/Me2SO4 R2Y + or R2I, Et4NBr–/H2O

+ O– (R3)4 N R1 359

OR2 HXR3

(CO)5M

R1

356

+ (R3)4 NBr–

(CO)5M

205

YR3 (CO)5M

R1 357 YR3 = SR3, N(R3)2

HOR2 O

R4COY

O (CO)5M

HYR3

R4

R1 360

Scheme 20

carbonate.89 Alkylation of the hydroxy complex with diazomethane was, in fact, the first method by which a Fischer carbene complex was produced.1 A number of “non-Fischer” methods for the synthesis of Group 6 pentacarbonyl carbene complexes have been developed and, while a comprehensive discussion of these methods is not possible here, a few select examples are shown (Eqs. 149–151). The most important of these involves the reaction of the pentacarbonyl Group 6 metal dianions with acid halides342 and amides,343 which can lead to efficient synthesis of alkoxy and amino carbene complexes (Eq. 149). Although these methods were originally developed with disodium salts, the dipotassium salt is the preferred choice because of the ease of purification of the resulting carbene complex.344 Fischer carbene complexes can be prepared efficiently by the reaction of diazo compounds with metal pentacarbonyl derivatives of the type 361 that have an easily dissociable ligand (Eq. 150).345 This method does not appear to be applicable to the preparation of complexes that have oxygen substituents on the carbene carbon.346 Although Grignard reagents and other organometallic reagents less reactive than organolithiums do not provide useful yields of carbene complexes by the Fischer procedure, these reagents can potentially lead to Fischer complexes by addition to the more reactive metal precursors of the type 361 that have a labile ligand. Such a process has been reported for organozinc compounds.347 After the addition of diphenylzinc to 361 (L = THF), the resulting chromium pentacarbonyl monoanion is exposed to an atmosphere of CO, presumably leading to the formation of the zinc acylate corresponding to 355, which upon subsequent alkylation gives phenyl complex 26 (Eq. 150). Finally, a rather interesting synthesis of the stablized complex 363 has

206

ORGANIC REACTIONS

been reported from the reaction of the vinyllithium derivative 362 and complex 361 (L = PPh3 ) in which the addition product suffers a conjugate elimination of triisopropylsiloxide to give the α,β-unsaturated complex 363 (Eq. 151).143 O (R3)2N

R1

TMSCl

N(R3)2 (CO)5M

M(CO)6

2 M (0)

R1

357

1

(Eq. 149)

(M1)2M(CO)5 O

M1 = Li, Na, K Cl

R1

OR2

R2X

(CO)5M

R1

356

OMe C6H4OMe-4 N2 C6H4OMe-4 L = cyclooctene M(CO)6

L

(CO)5Cr

L M(CO)5

hn

3. Me3O+ BF4– L = THF

OMe

(66%)

1. Ph2Zn 2. CO (1 atm)

361

(Eq. 150)

OMe (CO)5Cr

26 (35%) OTIPS

OTIPS L M(CO)5

+

TIPSO

M = Cr O

L = PPh3

361 TIPSO

Li 362

TIPSO

O

(Eq. 151)

Cr(CO)5 363 (56%)

Another important route to α,β-unsaturated Fischer carbene complexes is the conversion of one carbene complex into another. It is not possible to even summarize the large number of classes of reactions in this category. The examples provided illustrate the types of transformations resulting in α,β-unsaturated Fischer carbene complexes that could serve in the preparation of phenols and quinones (Eqs. 152–155). The first method (Eq. 152) involves the Diels-Alder reaction of an alkynyl carbene complex that provides cycloadduct 80, which has been used to produce a benzannulated product (Eq. 21).112 Certainly one of the most important reactions in this category is the aldol condensation of alkyl carbene complexes to give trans-1-alkenyl complexes as is illustrated by the synthesis of complex 364 (Eq. 153).348 A number of useful procedures for this process have been developed over the years.156,239,348 – 351 The carbene complex 366 obviously could not be directly prepared by the standard Fischer procedure

THE SYNTHESIS OF PHENOLS AND QUINONES

207

starting with 4-bromobenzaldehyde (Eq. 154).113 The metal-halogen exchange in the 4-bromophenyl carbene complex 365 is only successful if the isopropoxy group is present to prevent attack on the carbene carbon.352 Finally, the metathesis reaction of electron-rich alkenes can be a useful method for the synthesis of either amino-353 or alkoxy-substituted354 Fischer carbene complexes (Eq. 155). TMS

TMS Cr(CO)5

Cr(CO)5

50°, 4 h

(Eq. 152)

OMe

OMe 79

80 (89%)

OMe (CO)5Cr

1. n-BuLi 2. C(CH2)6CHO /SnCl4

OMe (CO)5Cr

3. MsCl, Et3N

258

364 (57%)

(Eq. 153) OPr-i

OPr-i 1. n-BuLi

(CO)5Cr

2. DMF

(CO)5Cr

(Eq. 154)

Br

CHO

365

366 (49%)

O N O

OMe

OMe N

(CO)5Cr

(69%)

(Eq. 155)

+

THF, 66° (CO)5Cr 26

EXPERIMENTAL CONDITIONS

The reactions of Fischer carbene complexes with alkynes are best performed in non-polar solvents at temperatures of 45−80◦ under an inert atmosphere. Lower concentrations are usually required for intramolecular reactions and also to inhibit certain side-products in intermolecular reactions. However, most side-processes can be avoided by higher reaction concentrations. Many of the published procedures include deoxygenation of the reaction mixture by the freeze-thaw method. This procedure is usually taken for precautionary reasons when exploring a new reaction and looking for all primary products. For example, the 2-alkoxyfuran side-products are quite sensitive to air and often do not survive prolonged exposure. Deoxygenation by the freeze-thaw method is usually not needed for most reactions. Instead, flushing the flask with nitrogen is sufficient. In many reactions

208

ORGANIC REACTIONS

where the yields have been compared with and without careful deoxygenation, only slight if any differences have been noted. This observation is particularly important in the development of large-scale reactions where deoxygenation by the freeze-thaw method would be impractical (see the experimental procedure for the preparation 4-methoxy-2-phenylphenanthren-1-yl acetate). Most Fischer chromium carbene complexes are only slightly sensitive to air and can be purified by chromatography on silica gel in the presence of air with negligible losses. In large-scale preparations, purification can be accomplished by crystallization because many complexes are solids. Crystallized complexes can be stored in a refrigerator in a vial or bottle flushed with nitrogen for indefinite periods, sometimes up to several years. For some of the more air-sensitive complexes, reactions are most successful if the complex is purified just prior to use by chromatography on silica gel in the presence of air. It is extremely rare to encounter a complex that is so air sensitive that chromatography on silica gel under an inert atmosphere is required. Air oxidation of chromium carbene complexes produces chromium(III) and even trace amounts can cause broadening in the NMR spectra. Filtration through a short plug of silica gel with CDCl3 directly into an NMR tube removes the contaminant sufficiently enough to produce high quality spectra even when the filtration is done in air. Some complexes produce trace amounts of chromium(III) upon reaction with CDCl3 and thus C6 D6 is the preferred solvent in that event. CAUTION: Although chromium is an essential element in the +3 oxidation state, high levels of chromium(III) are toxic. In addition, the reaction of chromium carbene complexes with alkynes can produce chromium hexacarbonyl as a product of the reaction. This compound is a toxic and relatively volatile solid. Thus, these reactions should be carried out in ventilated hoods taking the normal precautions for handling toxic materials.

EXPERIMENTAL PROCEDURES

The following set of experimental procedures was chosen to illustrate a number of facets of the reactions of Fischer carbene complexes with alkynes. Methods for product isolation, of particular importance in most applications of the procedure, are reviewed in the section on Scope and Limitations. As is more fully illustrated by the following Experimental Procedures, there is a range of experimental protocols available for the production of a diverse set of functionalized products from these reactions including phenols, protected phenols, quinones, quinone acetals, arene chromium tricabonyl complexes, and cyclohexadienones. The reaction of Fischer carbene complexes with alkynes can be a very complicated reaction that can lead to a vast array of products, potentially detracting from its synthetic utility for generating phenols and quinones. The identity of the products reflects both the choice of reaction conditions and the actual protocol employed. In most of the following procedures, the procedure and conditions have been optimized for the normal benzannulation product.

THE SYNTHESIS OF PHENOLS AND QUINONES O B O THF, 45°, 16 h

OH

1. n-Bu Cr(CO)5

209

OH

Bu-n B O OMe O

2. air

OMe

Bu-n +

OMe (15%)

(73%)

2-Butyl-4-methoxy-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)naphthalen-1-ol (Benzannulation with an Alkynylborane).75 To a solution of pentacarbonyl(methoxyphenylmethylene)chromium (102 mg, 0.327 mmol) in THF (6.4 mL) was added 2-(hex-1-ynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (204 mg, 0.980 mmol) via syringe under nitrogen. The reaction mixture was stirred at 45◦ for 14 hours and concentrated by rotary evaporation. Purification of the resulting residue by silica gel chromatography provided 4-methoxy-2n-butyl-1-naphthol (11 mg, 15%) and the title compound (85 mg, 73%). The latter was crystallized from hexanes to provide an amber solid, mp 116–116.5◦ : IR 3445, 2991, 2977, 1662, 1142 cm−1 ; 1 H NMR (250 MHz, CDCl3 ) δ 0.96 (t, J = 7.3 Hz, 3H), 1.42 (s, 12H), 1.47–1.72 (m, 4H), 2.73 (app t, J = 7.9 Hz, 2H), 3.91 (s, 3H), 4.93 (br s, 1H), 7.39–7.53 (m, 2H) 7.95–8.03 (m, 1H), 8.05–8.13 (m, 1H); 13 C NMR (62.9 MHz, CDCl3 ) δ 14.1, 24.7, 24.9, 30.2, 33.0, 63.5, 84.0, 121.6, 122.0, 124.3, 125.2, 125.9, 126.6, 144.4, 153.9. Anal. Calcd for C21 H29 BO4 : C, 70.80; H, 8.20. Found: C, 70.67; H, 8.36. O Cr(CO)5

1. Ph

Ph

Ph

2. CAN/H2O

OMe Method A (solid state) Method B (solution)

Ph O (86%) (94%)

2,3-Diphenyl-1,4-naphthoquinone (Comparison of Thermal Reaction in THF Solution with Solid-Phase Reaction on Silica Gel).84,177 Method A. A suspension of pentacarbonyl(methoxyphenylmethylene)chromium (65 mg, 0.208 mmol), silica gel (2.58 g), and diphenylacetylene (46 mg, 0.258 mmol) in hexane or Et2 O was stirred for 5 minutes at room temperature and the solvent was removed in vacuo. The round-bottomed flask containing the resulting orange powder was purged with nitrogen, immersed in a heated oil bath, and the contents were stirred at 40–50◦ until all the complex had been consumed (as indicated by TLC analysis of extracts of small aliquots of solid mixture, 3 hours). On completion of the reaction, the adsorbent was extracted with Et2 O and the extracts filtered through a pad of Kieselguhr. The resulting crude phenol product was taken up in Et2 O (10 mL) and treated with an aqueous cerric ammonium nitrate solution (8 eq) for 30 minutes at room temperature. The quinone was purified on a silica gel column with a 3 : 2 mixture of petroleum ether/CH2 Cl2 as eluent. 2,3-Diphenyl-1,4-naphthoquinone was obtained as a yellow crystalline

210

ORGANIC REACTIONS

solid (56 mg, 86%), mp 139–140◦ (lit.355 mp 141–142◦ ): FTIR (CH2 Cl2 )1670, 1601 cm−1 ; 1 H NMR (CDC13 ) δ 7.10 (m, 4H), 7.23 (m, 6H), 7.81 (m, 2H), 8.21 (m, 2H). Method B. A solution of pentacarbonyl(methoxyphenylmethylene)chromium (0.156 g, 0.500 mmol) and diphenylacetylene (0.178 g, 1.00 mmol) in THF (1.0 mL) was deoxygenated by the freeze-thaw method and heated at 70◦ for 12 hours under an argon atmosphere. The reaction mixture was diluted with THF (10 mL) and water (10 mL) and then ceric ammonium nitrate (1.8 g) was added. After 20 minutes the aqueous layer was extracted twice with Et2 O and the combined organic fractions were washed with water and brine, then dried over Mg2 SO4 . The crude reaction mixture was chromatographed on a silica gel column with a mixture of Et2 O, CH2 Cl2 , and hexanes (1 : 1 : 10) to give 0.146 g (0.47 mmol) of the title compound as a yellow solid in 94% yield. OTBS Cr(CO)5 O +

Bu-t

1. t-BuOMe (0.4 M), 55°, 55 min Bu-t 2. silica gel 3. TBSCl (4 eq), Et3N (4 eq), rt, 3 h

(CO)3Cr O

(55%)

{tert-Butyl-[2-tert-butyl-4-(2-isopropyl-5-methylcyclohexyloxy)naphthalen-1-yloxy]dimethylsilanyloxy}tricarbonylchromium(0) (Asymmetric Benzannulation of O-Menthyloxy Complexes).97 A solution of pentacarbonyl [[[(1S,2R,5S)-5-methyl-2-(1-methylethyl)cyclohexyl]oxy]phenylmethylene] chromium (2 mmol) and of 3,3-dimethyl-1-butyne (8 mmol) in tert-butyl methyl ether (5 mL) was degassed in three cycles and warmed at 55◦ for 55 minutes. After cooling to room temperature and filtration over silica gel, (tertbutyl)chlorodimethylsilane (8 mmol) and triethylamine (8 mmol) were added and the solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether/CH2 Cl2 = 5 : 1, −10◦ ) to give 0.66 g (1.1 mmol, 55%) of the title arene complex as a red solid: Rf = 0.27 (petroleum ether/CH2 Cl2 = 5 : 1); dr = 91 : 9 (based on 1 H NMR signals for H-3: 5.71 (s)/5.60 (s) ppm); [α] = −690◦ (c = 0.9, CHCl3 ); IR (petroleum ether) 1958, 1890, 1877 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 0.34, 0.53 (s, 6H), 0.80, 0.93, 1.01 (d, J = 7.0 Hz, 3H), 1.09 (s, 9H), 1.52 (s, 9H), 1.15–1.70 (m, 3H), 1.75 (m, 2H), 2.11 (qd, J = 7.0, 2.6 Hz, 1H). 2.65 (m, 1H), 4.00 (ddd, J = 10.6, 9.8, 5.3 Hz, 1H), 5.60 (s, 1H), 7.33 (ddd, 1H, J = 9.1, 6.5, 1.0 Hz, 1H), 7.45 (ddd, J = 8.9, 6.5, 1.0 Hz, 1H), 8.05 (m, 2H); 13 C NMR (100 MHz, CDCl3 ) δ −1.0, 0.4, 16.9, 20.8, 22.2, 19.9, 23.6, 26.0, 27.0, 30.9, 31.5, 34.2, 34.9, 39.3, 48.1, 76.9, 79.7, 99.0, 101.0, 108.6, 123.4, 125.4, 126.6, 127.8, 128.9, 130.6, 234.4; MS (70 eV) m/z (% relative intensity): 604 (5, M+ ), 548 (1, M+ −2 CO), 520 (100, M+ −3 CO), 468 (1, M+ −Cr(CO)3 ). Anal. Calcd for C33 H48 O5 SiCr: C, 65.53; H, 8.00. Found: C, 65.43; H, 7.91.

THE SYNTHESIS OF PHENOLS AND QUINONES

MeO

O

1. Et Et, THF, 45°, 24 h

Cr(CO)5

211

Et (72%)

2. CAN / MeOH

OMe

Et MeO OMe OMe

2,3-Diethyl-4,4,5-trimethoxy-4H -naphthalen-1-one (Oxidative Workup to Quinone Monoacetals).12 A solution of pentacarbonyl[methoxy(2-methoxyphenyl)methylene]chromium (0.690 g, 2.02 mmol) and 3-hexyne (0.207 g, 2.52 mmol) in THF (20 mL) was deoxygenated by the freeze-thaw method (−196◦ /0◦ , 3 cycles). The mixture was stirred under argon at 45◦ and monitored by TLC. The crude mixture was poured into a solution of ceric ammonium nitrate (7.5 eq) in anhydrous MeOH (100 mL) and stirred over powdered anhydrous Na2 CO3 (1 g). After 30 minutes the solution was diluted with of 2% aqueous Na2 CO3 (200 mL) then extracted with several portions of Et2 O. After removal of the volatiles the crude product was purified by chromatography on activity IV basic alumina with a mixture of Et2 O/CH2 Cl2 /hexanes (1 : 1 : 4, Rf = 0.13) to give the title compound in 72% yield as a white solid, mp 88–89.5◦ (ether/hexane); 1 H NMR (CDCl3 ) δ 1.14 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H), 2.51 (q, 2H), 2.57 (q, 2H), 2.92 (s, 6H), 3.94 (s, 3H), 7.15 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H); 13 C NMR (CDCl3 ) δ 13.3, 14.0, 19.4, 20.0, 51.2, 56.1, 99.5, 115.2, 118.5, 125.l, 130.0, 134.4, 142.1, 154.8, 157.3, 183.2; MS m/z (% relative intensity): 290 (18, M+ ), 275 (16), 261 (100), 259 (52), 231 (78), 135 (78), 115 (85), 91 (60), 77 (88). OAc Cr(CO)5 MeO

1.

Ph

Ph, THF, 55°, 4 h

(72%)

2. Ac2O, Et3N, THF, 55°, 17 h OMe

4-Methoxy-2-phenylphenanthren-1-yl Acetate (Benzannulation and In Situ Protection as an Aryl Acetate).304 An oven-dried, 3-L, three-necked, roundbottomed flask equipped with a mechanical stirrer, a reflux condenser, and a septum was charged with pentacarbonyl(methoxy-1-naphthalenylmethylene)chromium (250 g, 0.69 mol). To this was added dry THF (1.4 L) via cannula under an inert nitrogen atmosphere. The resulting dark-red solution was purged with nitrogen for 30 minutes. The septum was replaced by a pressure-equalizing dropping funnel containing a nitrogen purged solution of phenylacetylene (91 mL, 0.83 mol) and dry THF (29 mL). The flask and its contents were heated to 55◦ with a heating mantle and then the phenylacetylene solution was added dropwise over a 3-hour period. The reaction mixture was stirred at 55◦ for an additional 1 hour or until TLC indicated that the chromium carbene complex was totally consumed. At this point triethylamine (289 mL, 2.07 mol) and acetic anhydride (196 mL, 2.07 mol) were added to the flask and the resultant mixture was stirred at 55◦ for 17 hours. The dark brown reaction mixture was cooled to ambient

212

ORGANIC REACTIONS

temperature, decanted into a 2-L round-bottomed flask, and the volume reduced to 1/4 of the original volume under reduced pressure (rotary evaporator). The greenish yellow precipitate was collected by filtration on a 13-cm B¨uchner funnel under reduced pressure and washed with EtOAc (3 × 200 mL) to afford the first crop of the yellow product. The green solid remaining in the 3-L flask was washed with EtOAc (3 × 100 mL) and the solvent decanted. The solid residue remaining was discarded, the decanted EtOAc washings were combined with the filtrate from the first crop, and the combined organic layers washed with 1 L of water and 1 L of brine. The organic layer was suction filtered through a 3-cm bed of wet packed silica gel in a 12-cm diameter B¨uchner funnel to remove the green chromium residue. The brown filtrate was reduced to 1/4 of its original volume under reduced pressure and the resultant precipitate was collected by filtration and washed with EtOAc (3 × 50 mL) to afford a second crop of the product as a yellow solid. The filtrate was then further concentrated to afford a third crop. The three crops were combined to provide the title compound as a light yellow solid (171 g, 72% yield based on the carbene complex). The product was further purified by flash column chromatography using EtOAc/hexane (1 : 9) to give a white solid, mp 160–161◦ ; Rf = 0.23 (EtOAc/hexane = 1 : 9); IR (neat) 3056, 2929, 2844, 1762, 1598, 1498, 1451, 1367, 1213, 1196, 1174, 1157, 1100, 1049, 815, 745, 700 cm−1 ; 1 H NMR (CDCl3 ) δ 2.19 (s, 3H), 4.14 (s, 3H), 7.13 (s, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53–7.63 (m, 4H), 7.70 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 9.62 (d, J = 8.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 20.7, 56.0, 109.6, 119.5, 120.9, 126.3, 126.9, 127.5, 127.6, 128.3, 128.4, 128.6, 129.1, 129.3, 130.1, 131.9, 132.5, 137.3, 138.0, 156.6, 169.7; MS m/z (% relative intensity): 342 (8, M+ ), 300 (100), 285 (46), 268 (8), 255 (6), 239 (10), 226 (12), 191 (2), 155 (27), 126 (18); exact mass (m/z) calcd for C23 H18 O3 , 342.1256; found, 342.1253. Anal. Calcd for C23 H18 O3 : C, 80.68; H, 5.30. Found: C, 80.76, H, 5.42. O Cr(CO)5 MeO

+

O

OMe

OBu-t

OH

1. benzene, 75°, 12 h 2. air, 15 min, rt 3. TFAA, NaOAc, 1 h 4. TFA, 2 h, rt 5. 2 N NaOH, rt

O

O

O

1. AgO, HNO3

MeO MeO

O (56%)

2. O2, DMF, 100°, 3 h (75%)

MeO

O

OH

2-Acetyl-11-hydroxy-6,7-dimethoxy-2,3,4,4a,12,12a-hexahydro-1H -naphthacen-5-one and 8-Acetyl-7,8,9,10-tetrahydro-11-hydroxy-1-methoxytetracene-5,12-dione (One-Pot Benzannulation/Friedel-Crafts Reactions Followed by Oxidation).158 A solution of pentacarbonyl[methoxy(2-methoxyphenyl)

THE SYNTHESIS OF PHENOLS AND QUINONES

213

methylene]chromium (0.176 g, 0.516 mmol) and tert-butyl 4-acetyl-2-(prop-2ynyl)cyclohexanecarboxylate (0.163 g, 0.619 mmol) in benzene (6 mL) was deoxygenated by the freeze-thaw method (−196◦ to room temperature, 3 cycles). The reaction mixture was heated under an argon atmosphere at 60◦ for 30 hours and then opened to air for 15 minutes. A major spot on TLC (Rf = 0.34, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1) indicated the presence of the benzannulated product. NaOAc (98.0 mg, 0.715 mmol) was added and the mixture was stirred at room temperature for 5 minutes before trifluoroacetic anhydride (2.0 mL) was introduced. The acetylation reaction was complete in one hour after stirring at room temperature (Rf = 0.42, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). Trifluoroacetic acid (3 mL) was added and the resulting mixture was stirred at room temperature for 2 hours to effect the Friedel-Crafts cyclization. Only one spot was present on TLC (Rf = 0.29, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). To hydrolyze the trifluoroacetate, NaOH solution (4 M) was slowly added until the solution became basic (pH > 11). After the mixture was stirred at room temperature for a half hour, HCl was added to neutralize the reaction mixture (Rf = 0.13, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). The mixture was extracted with Et2 O (6 × 30 mL) and the organic phases were combined and dried over MgSO4 . After removal of the volatiles, 2-acetyl-2,3,4,4a,12,12a-hexahydro-11-hydroxy6,7-dimethoxytetracen-5(1H )-one was isolated by flash chromatography (CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1) in 56% overall yield. The tetracenone intermediate was not characterized, but rather directly oxidized by treatment with silver oxide (1.28 g, 10.3 mmol) and nitric acid (2.0 N, 10.3 mL, 20.6 mmol) in acetone (20 mL) at room temperature for 30 minutes (Rf = 0.14). After addition of buffer solution (pH 7, 10 mL) and CH2 Cl2 (50 mL), the organic phase was washed with brine and water, and dried over MgSO4 . Evaporation of the volatiles under reduced pressure gave an orange residue which was aromatized by a gentle purge with oxygen in DMF (10 mL) at 100◦ for 2 hours. After removal of the DMF by heating under reduced pressure, the product was purified by flash chromatography (CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1, Rf = 0.44) to give the title compound (0.109 g, 0.311 mmol, 75% yield) as an orange solid and as the sole product; mp 222–225◦ (lit.356 mp 222–225◦ ). If the tetracenone intermediate is not purified, the final product was isolated in 61% overall yield from the alkyne in a one-pot seven step process. IR (neat) 2957, 2921, 2854, 1701, 1665, 1622, 1585, 1460, 1436, 1415, 1384, 1353, 1287, 1269, 1260, 1249, 1235, 1213, 1176, 1053 cm−1 ; 1 H NMR (CDCl3 ) δ 1.71–1.82 (m, 1H), 2.23–2.31 (m, 1H), 2.27 (s, 3H), 2.69–2.84 (m, 2H), 2.95–3.08 (m, 3H), 4.06 (s, 3H), 7.33 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 13.35 (s, 1H); 13 C NMR (CDCl3 ) δ 22.8, 24.5, 28.2, 31.5, 46.8, 56.7, 114.0, 118.0, 119.5, 120.1, 120.9, 129.7, 132.7, 135.6, 135.9, 144.2, 160.8, 160.8, 182.7, 188.8, 210.1; MS m/z (% relative intensity): 350 (100, M+ ), 335 (6), 308 (30), 307 (97), 306 (12), 304 (25), 291 (12), 290 (12), 289 (15), 275 (5), 189 (6), 178 (4), 166 (4), 115 (5), 77 (4), 69 (5); exact mass (m/z) calcd for C21 H18 O5 , 350.1154; found, 350.1169.

214

ORGANIC REACTIONS

OMe (CO)5Cr

TBSO

(CO)3Cr

TBSO

(CO)3Cr

OTBS

+ MeO

Method A Method B

OTBS

syn + anti (53%) (58%)

syn

OTBS MeO

anti

syn:anti >99:1 6:94

Tricarbonyl[6-(tert-butyldimethylsilanyloxy)-2
-(tert-butyldimethylsilanyloxymethyl)-3-methoxy-2,5-dimethylbiphenyl]chromium(0) (Simultaneous and Stereoselective Creation of Axial and Planar Elements of Chirality).212 Method A. A magnetic stir bar was placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was back-filled with argon. N ,N -diisopropylethylamine (0.162 g, 1.25 mmol, distilled from KOH and freshly filtered through basic alumina) was added via syringe. Pentacarbonyl[(2Z)-1-methoxy-2-butenylidene]chromium (0.102 g, 0.37 mmol, freshly purified or freshly prepared) was added to the reaction flask followed by a solution of (2-(prop-1-ynyl)benzyloxy)(tert-butyl)dimethylsilane (0.065 g, 0.25 mmol) in toluene (1.0 mL) and then (tert-butyl)chlorodimethylsilane (0.113 g, 0.75 mmol) was added via syringe. The septum was replaced by the threaded stopcock and the reaction mixture was deoxygenated using the freeze-thaw method (three cycles). The reaction flask was left to warm to room temperature, after which it was back-filled with argon, sealed with the stopcock, covered with aluminum foil, and heated to 50◦ for 24 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator and subjected to silica gel chromatography. Elution with a mixture of pentane and CH2 Cl2 (3 : 1) gave the title compound (88 mg, 53% yield) as a yellow oil which was determined by 1 H NMR to be ≥99 : 1 syn:anti. 1 H NMR (CD2 Cl2 , 400 MHz) δ−0.64 (s, 3H), −0.17 (s, 3H), 0.17 (s, 6H), 0.80 (s, 9H), 0.97 (s, 9H), 1.86 (s, 3H), 2.22 (s, 3H), 3.78 (s, 3H), 4.97 (d, J = 7.8 Hz, 1H), 5.34 (d, J = 7.8 Hz, 1H), 5.72 (s, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H). Method B. A magnetic stir bar was placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was back-filled with argon. Pentacarbonyl[(2Z)-1-methoxy-2butenylidene]chromium (105 mg, 0.38 mmol) was added together with a solution of (2-(prop-1-ynyl)benzyloxy)(tert-butyl)dimethylsilane (65 mg, 0.25 mmol) in toluene (1.0 mL). The septum was replaced by the threaded stopcock and the reaction mixture was deoxygenated using the freeze-thaw method (−196◦ to room temperature, three cycles). At the end of the third cycle (room temperature), the reaction flask was back-filled with argon, sealed with the stopcock,

THE SYNTHESIS OF PHENOLS AND QUINONES

215

covered with aluminum foil, and heated in an oil bath at 50◦ for 48 hours. After cooling to room temperature, the reaction flask was placed under a positive flow of argon, and N ,N -diisopropylethylamine (0.218 mL, 1.25 mmol) and (tert-butyl)chlorodimethylsilane (0.113 g, 0.75 mmol) were added to the reaction flask. The flask was deoxygenated by the freeze-thaw method (−196◦ to room temperature, two cycles) and heated for an additional 24 hours at 50◦ . After being cooled to room temperature, the reaction mixture was concentrated on a rotary evaporator and the product was purified by silica gel chromatography (pentane/CH2 Cl2 = 3 : 1) to provide the title compound as a yellow oil (92 mg, 58%). The product was determined by 1 H NMR to be a 96 : 4 mixture of anti to syn diastereomers. The same ratio was found in the 1 H NMR of the crude reaction mixture. The diasteromers are not separable by TLC or silica gel chromatography. Anti-isomer: IR (neat) 2930, 2857, 1955, 1880, 1463, 1409, 1255, 1159, 1119, 1077, 914, 837, 778 cm−1 ; 1 H NMR (CD2 Cl2 , 400 MHz) δ −0.49 (s, 3H), −0.04 (s, 3H), −0.03 (s, 3H), 0.04 (s, 3H), 0.73 (s, 9H), 0.85 (s, 9H), 1.80 (s, 3H), 2.20 (s, 3H), 3.70 (s, 3H), 4.28 (d, J = 13.6 Hz, 1H), 4.56 (d, J = 13.6 Hz, 1H), 7.40 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H). TBSO OMe (CO)5Cr

OTr +

TBSCl, (i-Pr)2NEt,

(68%) dr ≥ 96:4

CH2Cl2, 60°, 12 h (CO)3Cr

OTr

OMe

{tert-Butyl[4-methoxy-2-methyl-6-(1-trityloxyethyl)phenoxy]dimethylsilanyloxy}tricarbonylchromium(0) (Central to Planar Chirality Transfer from a Chiral Propargyl Ether).88 Pentacarbonyl[(2Z)-1-methoxy-2-butenylidene] chromium (0.263 mmol) and a small magnetic stir bar were placed in a flamedried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock (Kontes No. 826610). The stopcock was replaced with a rubber septum and the flask was evacuated and back-filled with argon. One half of the volume of anhydrous CH2 Cl2 required for a 0.05 M solution of the carbene complex, optically pure (S)-(but-3-yn2-yloxy)triphenylmethane (1.9 eq), N ,N -diisopropylethylamine (5.0 eq, freshly distilled or passed through a pipette-size basic alumina column), (tert-butyl)chlorodimethylsilane (3.0 eq), and the remaining solvent were added via syringe. The septum was replaced with the threaded stopcock, and the reaction mixture was degassed using the freeze-thaw method (three to four cycles). Then the reaction flask was back-filled with argon, sealed with the stopcock, and the reaction mixture was heated at 60◦ for 6–20 hours or until all the carbene complex was consumed. After cooling to room temperature, the reaction mixture was analyzed by TLC (CH2 Cl2 /hexane = 1 : 1, UV/PMA), concentrated under reduced pressure, and subjected to column chromatography (gradient elution from 0–75% CH2 Cl2 in hexane or pentane, column size 1.5 × 30 cm) to give the title compound (239.7 mg, 68% yield) as a yellow waxy foam,

216

ORGANIC REACTIONS

Rf = 0.42 (CH2 Cl2 /hexane = 1 : 1). The diastereomeric purity was determined to be greater than 96 : 4 by 1 H and 13 C NMR analysis with the aid of samples of each diastereomer. [α]20 436 −298.3◦ (c 5.70 × 10−5 , CH3 OH); [α]20 D −114.0◦ (c 5.70 × 10−5 , CH3 OH); IR (neat) 2928, 2855, 1941, 1858, 1452, 1429, 1235, 1153, 1041, 1026, 893, 829 cm−1 ; 1 H NMR (CDCl3 ) δ 0.14 (s, 3H), 0.15 (s, 3H), 0.76 (s, 9H), 1.51 (d, J = 6.3 Hz, 3H), 2.05 (s, 3H), 3.52 (s, 3H), 4.82 (d, J = 2.5 Hz, 1H), 4.85 (q, J = 6.3 Hz, 1H), 5.51 (d, J = 2.5 Hz, 1H), 7.12 (t, J = 7.0 Hz, 3H), 7.16 (t, J = 7.7 Hz, 6H), 7.36 (d, J = 7.5 Hz. 6H); 13 C NMR (CD2 Cl2 ) δ −2.9, 17.7, 18.8, 25.8, 26.7, 56.2, 66.3, 81.6, 83.3, 88.3, 99.1, 114.1, 127.5, 127.6, 128.0, 128.1, 129.1, 129.3, 136.0, 144.6, 235.5; EIMS m/z (% relative intensity): 675 (11, M+ + 1), 590 (56), 538 (10), 347 (3), 330 (4), 289 (3), 243 (100), 228 (3), 207 (3), 183 (9), 165 (34), 126 (5), 105 (28); exact mass (m/z) calcd for isomer C38 H42 CrO6 Si: 674.2156, found 674.2143.

OTr

O

Cr(CO)5 OMe

MeCN, 55°, 14 h

OMe

OTr

(88%) dr 98:2

4-Methoxy-6-methyl-6-(3-methylbut-3-enyl)-2-(3-methyl-1-trityloxyhepta2,6-dienyl)cyclohexa-2,4-dienone (1,4-Asymmetric Induction in Cyclohexadienone Formation).357 Pentacarbonyl[methoxy-1-(2,5-dimethylhexa-1,5-dienyl)methylene]chromium (0.552 mmol) and ((E)-5-methylnona-4,8-dien-1-yn3-yloxy)triphenylmethane (0.28 g, 0.718 mmol, 1.3 eq) were placed in a 100-mL, flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was evacuated and back-filled with argon. To this flask was added MeCN (50 mL), the septum was replaced by the threaded stopcock, and the reaction mixture was deoxygenated by the freezethaw method (three cycles). The flask was back-filled with argon, sealed with the stopcock at room temperature, and heated to 55◦ for 14 hours. After cooling to room temperature, the reaction mixture was opened to the air, the solvent was changed to Et2 O, and the solution was stirred for 3 hours in air. The crude mixture was concentrated, and the product purified by column chromatography (silica gel, hexane/CH2 Cl2 = 1 : 1) to yield the title compound (0.28 g, 88% yield) as a light yellow solid, dr = 98 : 2 as determined by 1 H and 13 C NMR analysis with the aid of a sample of a mixture of diastereomers. Rf = 0.31 (hexane/CH2 Cl2 = 1 : 1); IR (neat) 1646, 1598, 1448, 1384 cm−1 , 1 H NMR (CDCl3 ) δ 0.94 (s, 3H), 1.32 (m, 3H), 1.53 (s, 3H), 1.59 (s, 3H), 1.81 (m, 1H), 2.01 (m, 2H), 2.13 (m, 2H), 3.48 (s, 3H), 4.46 (s, 1H), 4.55 (s, 1H), 4.69 (d, J = 3 Hz, 1H), 4.93 (d, J = 10.1 Hz, 1H), 5.01 (d, J = 16.8 Hz, 1H), 5.07 (d, J = 9 Hz, 1H), 5.33 (d, J = 9 Hz, 1H), 5.77 (m, 1H), 6.66 (d, J = 3 Hz, 1H), 7.71 (m, 9H), 7.47 (d, J = 8 Hz, 6H); 13 C NMR (CDCl3 ) δ 17.0, 22.4, 27.1, 32.2, 32.3, 39.0, 41.2, 48.5, 54.5, 66.9,

THE SYNTHESIS OF PHENOLS AND QUINONES

217

87.8, 109.3, 109.5, 114.4, 125.3, 127.0, 127.6, 128.8, 136.0, 136.2, 138.3, 138.5, 144.6, 145.4, 150.4, 202.8.

TBS Cr(CO)5

3

,

OTBS

SO2Ph

SO2Ph (74%)

THF, 50°, 4 d

OMe

(CO)3Cr OMe

{[2-(4-Benzenesulfonylbutyl)-4-methoxy-6,7-dimethyl-5,8-dihydronaphthalen-1-yloxy]-tert-butyldimethylsilanyloxy}tricarbonylchromium(0) (Tandem Diels-Alder/Benzannulation Reaction).95 Pentacarbonyl[3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propynylidene]chromium (0.388 g, 1.037 mmol) and 1-(hex-5-ynylsulfonyl)benzene (0.166 g, 1.55 mmol) were combined in a mixture of THF (10 mL) and 2,3-dimethylbutadiene (3.5 mL). The solution was degassed (four cycles), and heated at 50◦ under argon for six days. Concentration and chromatographic purification on silica gel (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 6) gave the title compound as a yellow solid (0.409 g, 0.764 mmol, 74% yield), mp 136.5 − 138.0◦ : Rf = 0.23 (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 4); IR (neat film) 1946, 1860, 1463, 1355, 1306, 1257, 1150, 1133 cm−1 ; 1 H NMR (CDCl3 ) δ 0.28 (s, 3H), 0.34 (s, 3H), 0.94 (s, 9H), 1.65 − 1.85 (m, 4H), 1.73 (s, 3H), 1.75 (s, 3H), 2.24 (dt, J = 13.8, 7.0 Hz, 1H), 2.61 (dt, J = 13.8, 7.0 Hz, 1H), 3.07−3.13 (m, 5H), 3.20−3.30 (m, 1H), 3.67 (s, 3H), 4.87 (s, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.87 (d, J = 7.1 Hz, 2H); 13 C NMR (CDCl3 ) δ −3.1, −2.1, 18.4, 18.5, 18.7, 22.4, 25.9, 28.9, 29.8, 30.8, 32.5, 55.8, 56.0, 73.8, 96.8, 102.0, 103.6, 121.4, 122.0, 125.9, 127.9, 129.3, 133.8, 136.2, 138.9, 234.7; MS m/z (% relative intensity): 650 (10, M+ ), 566 (45), 514 (100), 457 (100), 372 (20), 331 (20), 317 (75). Anal. Calcd for C32 H47 CrO7 SSi: C, 59.06; H, 6.50. Found: C, 58.67; H, 6.14. O TBS

Cr(CO)5 OMe

1.

OTBS

CN or

2. LDA

Method A Method B

CN OMe (50%) (—)

OMe CN (—) (46%)

7-Methoxy-10-oxospiro[4.5] deca-6,8-diene-1-carbonitrile and 5-(tert-Butyldimethylsilanyloxy)-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (Tandem Benzannulation/Aromatic Nucleophilic Substitution).159 Method A. Pentacarbonyl[(2E)-3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propenylidene]chromium (0.2125 g, 0.565 mmol), 6-cyano-1-pentyne (0.0666 g, 0.621 mmol), and a small stir bar were placed in a 100-mL flask that had been modified by replacement of the 14/20 joint with a 10-mm

218

ORGANIC REACTIONS

threaded high-vacuum stopcock. The contents of the flask were dissolved in anhydrous CH2 Cl2 (11.3 mL) and deoxygenated by the freeze-thaw method. The flask was back-filled with argon at room temperature, the stopcock was replaced, and the flask sealed and heated at 65◦ under argon for 20 hours. The reaction flask was cooled to 0◦ and opened to high vacuum to strip the volatiles, followed by 2 hours at room temperature under high vacuum. The crude benzannulated product was taken up into THF (30 mL), then the flask was degassed and back-filled with argon. Under an argon stream, the threaded stopcock was replaced with a rubber septum. The flask was then cooled to −78◦ . A deoxygenated THF solution of lithium diisopropylamide (0.847 mmol, 1.5 eq) was cooled to −78◦ and added by cannula. The reaction mixture was stirred at −78◦ for 1.5 hours. A −78◦ degassed THF solution of iodine (1.15 g, 4.52 mmol, 8.0 eq) was added to the reaction mixture. After stirring the resulting solution for 1 hour at −78◦ , the cold bath was removed. After 2.5 hours of stirring at room temperature, the mixture was poured into Et2 O/10% aqueous Na2 S2 O3 . The aqueous layer was extracted once with Et2 O. The combined organic layers were dried with brine and MgSO4 , filtered, and concentrated. Chromatography on silica gel (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 6) gave two separable diastereomers of the spirocyclic title compound in a combined yield of 50%; major (0.0298 g, 0.147 mmol) and minor (0.0234 g, 0.115 mmol). If the arene chromium tricarbonyl complex produced by the benzannulation reaction was first purified (69%) and then subjected to the aromatic nucleophilic addition in a second step, then the major diastereomer of the spirocyclic product was obtained in 33% overall yield and the minor in 17% overall yield. The major isomer was isolated as a colorless solid, mp 88−90◦ : Rf = 0.19 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 4); IR (neat film) 2240, 1670, 1641, 1582, 1453, 1408, 1250, 1032, 824 cm−1 ; 1 H NMR (CDCl3 ) δ 1.83 (quint, J = 6.3 Hz, 1H), 1.94−2.00 (m, 2H), 2.04−2.16 (m, 2H), 2.39−2.46 (m, 1H), 3.31 (t, J = 9.1 Hz, 1H), 3.66 (s, 3H), 5.27 (d, J = 2.5 Hz, 1H), 6.09 (d, J = 10.1 Hz, 1H), 6.90 (dd, J = 10.1, 2.7 Hz, 1H); 13 C NMR (CDCl3 ) δ 23.9, 30.8, 39.6, 40.8, 55.1, 57.9, 105.9, 119.7, 126.6, 142.3, 150.9, 201.7; MS m/z (% relative intensity): 203 (70, M+ ), 188 (15), 175 (25), 171 (10), 161 (30), 147 (90), 137 (100), 133 (50), 122 (40), 117 (40), 105 (50), 91 (65), 77 (90); exact mass (m/z) calcd for C12 H13 NO2 , 203.0946; found 203.0915. The minor isomer was isolated as an amber oil: Rf = 0.14 (Et2 O/CH2 Cl2 / hexane = 1 : 1 : 4); IR (neat film) 2240, 1669, 1642, 1585, 1464, 1408, 1242 cm−1 ; 1 H NMR (CDCl3 ) δ 1.74 − 1.78 (m, 1H), 1.83−1.91 (m, 1H), 2.12− 2.19 (m, 2H), 2.21−2.29 (m, 1H), 2.38−2.46 (m, 1H), 2.76 (t, J = 9.5 Hz, 1H), 3.63 (s, 3H), 4.93 (d, J = 2.6 Hz, 1H), 6.04 (d, J = 10.1 Hz, 1H), 6.83 (dd, J = 10.2, 2.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 23.4, 30.1, 38.5, 40.5, 55.0, 58.5, 107.6, 119.5, 126.7, 141.5, 151.3, 202.0; MS m/z (% relative intensity) 203 (45, M+ ), 188 (10), 175 (15), 171(5), 161 (25), 147 (25), 137 (90), 121 (25), 107 (40), 91 (45), 77 (100); exact mass (m/z) calcd for C12 H13 NO2 , 203.0946; found 203.0948.

THE SYNTHESIS OF PHENOLS AND QUINONES

219

Method B. Pentacarbonyl[(2E)-3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propenylidene]chromium (0.1555 g, 0.414 mmol) and 6-cyano-1-pentyne (0.071 g, 0.66 mmol) were combined as described in Method A and heated at 65◦ for 21 hours. The procedure for the nucleophilic addition was the same as for the one-pot conversion to spirocycle, except that (1) the annulation residue was taken up into only 8.5 mL of THF (∼0.05 M), and (2) 10 minutes after the addition of lithium diisopropylamide to the reaction mixture, the dry ice/acetone bath was replaced with an ice-water bath. After 1 hour at 0◦ , a deoxygenated solution of iodine (0.79 g, 3.11 mmol, 7.5 eq) in THF (5 mL) was added at 0◦ . The mixture was stirred at room temperature for 3 hours prior to workup as described above. Chromatography (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 10) yielded the tetrahydronaphthalene title compound in 38% yield (0.0497 g, 0.157 mmol). If the arene chromium tricarbonyl complex from the benzannulation reaction was first purified (69%) and then subjected to the aromatic nucleophilic addition in a second step, the tetrahydronaphthalene product was obtained in 46% yield for the two steps. The product was a colorless solid, mp 72−74◦ : Rf = 0.52 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 4); IR (neat film) 2237, 1594, 1476, 1252, 1090, 905, 861 cm−1 ; 1 H NMR (CDCl3 ) δ 0.22 (s, 3H), 0.23 (s, 3H), 1.02 (s, 9H), 1.80–1.84 (m, 1H), 1.88–1.94 (m, 1H), 1.95–2.04 (m, 1H), 2.25 (br d, J = 13.0 Hz, 1H), 2.47 (ddd, J = 17.7, 11.4, 5.7 Hz, 1H), 2.86 (br d, J = 17.4 Hz, 1H), 3.84 (s, 3H), 4.06 (br s, 1H), 6.59 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H); 13 C NMR (CDCl3 ) δ −4.2, 18.2, 19.1, 23.6, 25.0, 25.7, 26.1, 55.7, 107.6, 117.1, 119.9, 121.7, 129.3, 147.2, 151.3; MS m/z (% relative intensity) 317 (65, M+ ), 261 (20), 233 (100), 218 (10), 159 (15), 144 (5), 129 (5), 115 (10); exact mass (m/z) calcd for C18 H27 NO2 Si, 317.1811; found 317.1828. TBSO (CO)5Cr

MeO

OTBS N Me

+

EtO

OR

Ac2O (1.1 eq) THF, 65°, 5 h EtO R=H R = OAc

N OMe Me (26%) (41%)

Methyl 5-{1-[(tert-Butyldimethylsilyl)oxy]ethyl}-6-ethoxy-4-hydroxy-7methoxyindole and its Acetate (Benzannulation of a Heteroaryl Carbene Complex).115,116 A solution of pentacarbonyl[methoxy(1-methyl-1H -pyrrol2-yl)methylene]chromium (1.0 g, 3.2 mmol), (4-ethoxybut-3-yn-2-yloxy)(tertbutyl)dimethylsilane (1.5 g, 4.8 mmol), and acetic anhydride (0.3 mL, 3.2 mmol) in THF (150 mL) was heated at 65◦ under argon for 5 hours. The mixture was cooled, and the solvent was removed by rotary evaporation to give a black oil. Purification by flash column chromatography (silica gel, 250 g, Et2 O/hexanes = 3 : 7) gave the title compound as a brown oil (309 mg, 26% yield) and its corresponding acetate as a brown oil (553 mg, 41% yield). Spectral data for the 4-acetoxyindole: IR (neat) 3334, 1637, 1494, 1324, 1288, 1056 cm−1 ; 1 H NMR

220

ORGANIC REACTIONS

(CDCl3 ) δ −0.07 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.41 (t, J = 7.0 Hz, 3H), 1.51 (d, J = 6.3 Hz, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.09 (q, J = 7.0 Hz, 2H), 5.45 (q, J = 6.3 Hz, 1H), 6.49 (d, J = 3.1 Hz, 1H), 6.78 (s, J = 3.1 Hz, 1H), 8.86 (s, 1H); MS m/z: 379 (M+ ), 363, 247, 218. Anal. Calcd for C20 H33 NO4 Si: C, 63.28; H, 8.76; N, 3.69. Found: C, 63.25; H, 8.81; N, 3.52. OMOM

MOMO

(CH2)3NHBz

O

(CH2)3NHBz Cr(CO)5 N Me

(59%)

benzene, 50°, 17 h N Me

OMe

OMe

N-{3-[1-Methoxy-4a-(2-methoxymethoxyethyl)-9-methyl-4-oxo-4a,9-dihydro-4H-carbazol-3-yl]propyl}benzamide (Cyclohexadienone Annulation of an Aryl Carbene Complex).62 Pentacarbonyl[methoxy[3-[2-(methoxymethoxy)ethyl]-1-methyl-1H -indol-2-yl]methylene]chromium (121 mg, 0.27 mmol) was combined with N -(pent-4-ynyl)benzamide (76.8 mg, 0.41 mmol) in benzene (27.0 mL). The mixture was deoxygenated by the freeze-pump-thaw method and then was stirred at 50◦ under argon for 17 hours. Once cool, the flask was opened to air and stirred for 1 hour at room temperature. The solution was concentrated and the residue was chromatographed on 60 mL of silica gel (Et2 O/hexane = 9 : 1). The principal deep purple band was collected to afford the title compound (77 mg, 0.16 mmol, 59% yield) as a viscous oil: IR (CHCl3 ) 2929, 2851, 1653, 1609, 1580, 1547, 1488, 1464, 1363, 1101, 993, 913 cm−1 ; 1 H NMR (CDCl3 ) δ 1.73 −1.87 (m, 2H), 2.09 (br t, J = 6.8 Hz, 2H), 2.33–2.42 (m, 2H), 3.21 (s, 3H), 3.33 (t, J = 6.8 Hz, 2H), 3.34–3.50 (m, 2H), 3.50 (s, 3H), 3.64 (s, 3H), 4.39 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 6.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.96 (s, 1H), 7.03 (br s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H); 13 C NMR (CDCl3 ) δ 25.6, 29.4, 31.2, 38.6, 46.4, 55.1, 60.9, 61.5, 63.2, 96.3, 107.0, 120.2, 122.3, 125.1, 126.9, 127.3, 128.2, 128.3, 128.4, 129.5, 131.0, 134.7, 141.8, 146.7, 167.2, 201.6; Anal. Calcd for C28 H32 N2 O5: C, 70.57; H, 6.77; N, 5.88. Found: C, 70.26; H, 7.03; N, 5.76. OH Cr(CO)5

EtO2C N

1. Et Et, THF, 60°, 48 h

EtO2C

Et Et

2. air

(75%)

N

Ethyl 3,4-Diethyl-2-hydroxy-5-(1-pyrrolidinyl)benzoate (Phenol Formation from an Activated Aminocarbene Complex).156 – 157 To a solution of pentacarbonyl[(2E)-4-ethoxy-4-oxo-1-(1-pyrrolidinyl)-2-butenylidene]chromium

THE SYNTHESIS OF PHENOLS AND QUINONES

221

(74 mg, 0.2 mmol) in THF (7 mL) was added an excess of diethylacetylene. The mixture was stirred at 60◦ for 48 hours and then cooled to room temperature and stirred with silica gel (1 g) for 30 minutes. The solid was filtered off and the solvent and excess alkyne were removed under reduced pressure. The resulting residue was subjected to flash chromatography on silica gel (hexane/EtOAc = 3 : 1) to yield the title compound (44 mg, 75% yield) as a yellow oil: 1 H NMR (CDC13 ) δ 1.22 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H), 1.93 (m, 4H), 2.77 (m, 4H), 3.00 (m, 4H), 4.40 (q, J = 7.1 Hz, 2H), 7.52 (s, 1H), 10.94 (s, 1H); 13 C NMR (CDC13 ) δ 14.1, 14.3, 15.3, 19.5, 21.3, 24.5, 53.9, 61.0, 109.4, 118.3, 131.2, 141.1, 147.7, 156.5, 170.5. Anal. Calcd for C16 H21 NO5 : C, 62.53; H, 6.89; N, 4.56. Found C, 62.69; H, 6.72; N, 4.53.

Cr(CO)5 NMe2

Pr-n TBSCl, (i-Pr)2NEt, benzene, 80°, 18 h

OTBS Pr-n (65%) (CO)3Cr NMe2

{[4-(tert-Butyldimethylsilanyloxy)-2-methyl-5-propylphenyl]dimethylamino}tricarbonylchromium(0) (Generation of an Aniline Chromium Tricarbonyl Complex).83 Pentacarbonyl[1-(dimethylamino)-2-methyl-2-propenylidene]chromium (75.0 mg, 0.26 mmol) and a small magnetic stir bar were placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock (Kontes No. 826610). The stopcock was replaced with a rubber septum and the flask was evacuated and back-filled with argon. One-half of the total amount of anhydrous benzene (1.0 mL) required for a 0.25 M solution of the carbene complex, 1pentyne (48.5 µL, 0.49 mmol, 1.9 eq), N ,N -diisopropylethylamine (135.3 µL, 0.78 mmol, 3.0 eq, freshly distilled and/or passed through a pipette-size basic alumina column), (tert-butyl)chlorodimethylsilane (78.1 mg, 0.52 mmol, 2.0 eq), and the remaining solvent were added via syringe. The septum was replaced with the threaded stopcock, and the reaction mixture was deoxygenated using the freeze-thaw method (−196◦ to room temperature, three to four cycles). The reaction flask was back-filled with argon at the end of the last cycle, sealed with the stopcock, and heated at 80◦ for 17 hours. After cooling to room temperature, the reaction mixture was analyzed by TLC (CH2 Cl2 /hexane = 1 : 1, UV/PMA), concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (10-50% CH2 Cl2 in hexane) to give the title compound as a yellow solid (74.8 mg, 65% yield), mp 74−75◦ . Recrystallization from Et2 O:pentane gave yellow needles: Rf = 0.43 (CH2 Cl2 /hexane = 1 : 1); IR (neat) 2959, 2932, 2861, 1951, 1868, 1473, 1364, 1266, 1172, 945, 862, 842, 784 cm−1 ; 1 H NMR (CD2 Cl2 ) δ 0.31 (s, 3H), 0.41 (s, 3H), 1.02 (s, 9H), 1.03 (t, J = 7.5 Hz, 3H), 1.59 (m, 2H), 2.19 (m, 1H), 2.24 (s, 3H), 2.61 (s, 6H), 2.63 (m, 1H), 5.05 (s, 1H), 5.50 (s, 1H); 13 C NMR (CD2 Cl2 ) δ −4.2, −3.8, 14.3, 18.4, 18.6, 24.8, 25.8, 32.7, 45.1, 86.1, 89.5, 102.0, 106.1, 126.5, 135.8, 236.0;

222

ORGANIC REACTIONS

EIMS m/z (% relative intensity): 443 (46, M+ ), 387 (25), 359 (100), 307 (64), 250 (9), 120 (14); exact mass (m/z) calcd for C21 H33 CrNO4 Si, 443.1584; found, 443.1566. Anal. Calcd for C21 H33 CrNO4 Si: C, 56.86; H, 7.50; N, 3.16; Cr, 11.73. Found C, 56.64; H, 7.84, N, 3.05; Cr, 11.56.

1. Me2SiCl2 2. vacuum 3. OH

Cr(CO)5

O

O– Me4N+

4. Ph Ph (3 eq), hexane, 69°, 1 h 5. CAN/H2O

(83%) O

OH

2-Hydroxymethyl-3,6-dimethyl-1,4-naphthoquinone (Intramolecular Benzannulation with an In Situ Generated Tether).86 2-Butyn-1-ol (500 mg, 7.1 mmol) was added dropwise at room temperature to neat dichlorodimethylsilane (9.10 g, 70.5 mmol). Immediate removal of HCl and excess dichlorodimethylsilane in vacuo provided (but-2-ynyloxy)chlorodimethylsilane in quantitative yield and requiring no additional purification. The in situ preparation of pentacarbonyl[[[(2-butynyloxy)dimethylsilyl]oxy](4-methylphenyl)methylene] chromium was accomplished by dropwise addition of a solution of (but-2-ynyloxy)chlorodimethylsilane (84 mg, 0.52 mmol) in CH2 Cl2 (3 mL) to a stirred solution of [tetramethylammonium][(4-(1-methylphenyl)oxidomethylene]pentacarbonyl chromium (200 mg, 0.52 mmol) in CH2 Cl2 (20 mL). After several minutes, tetramethylammonium chloride was removed by filtration and the solvent was removed in vacuo to give the siloxy carbene complex in quantitative yield. This complex was taken up in hexane (50 mL, [Cr] = 0.01 M) and diphenylacetylene (922 mg, 5.2 mmol, 10.0 eq) was added. The reaction mixture was heated to reflux with stirring and monitored by IR spectroscopy until the carbonyl ligand stretching bands of the starting siloxycarbene complex disappeared (∼1 hour). The reaction mixture was left to cool to room temperature under an inert atmosphere after which the solvent was removed by rotary evaporation in air. The residue was taken up in Et2 O (40 mL) and treated with a solution of ceric ammonium nitrate (0.5 M, 10 mL) in 0.1 N aqueous nitric acid (10 eq). The combined aqueous and organic layers were stirred vigorously for 10 minutes. The aqueous phase was then extracted with Et2 O (3 × 25 mL), and the combined organic extracts were dried over MgSO4 and concentrated. The products were separated by flash chromatography (petroleum ether/EtOAc = 65 : 35). The excess diphenylacetylene eluted rapidly and was recovered quantitatively. Further elution gave the title compound (93 mg, 83% yield): IR (CDCl3 ) 1665, 1622, 1602 cm−1 ; l H NMR (CDCl3 ), δ 2.21 (s, 3H), 2.46 (s, 3H), 4.72 (s, 2H), 6.76 (br s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 12.2, 21.8, 58.0, 126.4, 126.9, 129.4, 131.8, 134.5, 141.9, 144.7, 145.2, 185.4, 186.0. Anal. Calcd for C13 H12 O3 : C, 72.21; H, 5.59. Found: C, 72.14; H, 5.91.

THE SYNTHESIS OF PHENOLS AND QUINONES

OMe

MeO

223

+ Cr(CO)5

(CO)5Cr OMe

OMe OMe

MeO ClCH2CH2Cl

(36%)

100° HO MeO

OMe OH

5,17-Dimethyl-11,23,26,28-tetramethoxy-25,27-dihydroxycalix(4)arene (Calix[4]arene Formation via a Triple Annulation).223 1,3-Bis-[2
-propenyl (methoxy)methylene pentacarbonylchromium (0)]-2-methoxy-5-methylbenzene (0.188 g, 0.28 mmol) and 2-methoxy-5-methyl-1,3-di(prop-2-ynyl)benzene (0.055 g, 0.28 mmol) were dissolved in 1,2-dichloroethane (112 mL) in a flamedried, 250-mL Schlenk flask under argon. The solution was deoxygenated by the freeze pump thaw method (−196◦ to room temperature, three cycles) and then backfilled with argon at ambient temperature. The flask was sealed with a threaded high-vacuum Teflon stopcock and heated to 100◦ for 20–40 minutes during which time the deep red solution turned yellow. The yellow solution was stirred overnight exposed to air to facilitate demetalation of the arene chromium tricarbonyl complex. The solvent was removed under vacuum, the residue dissolved in EtOAc (50 mL), and the solution filtered through a short pad of silica gel. Further washing of the silica gel pad with EtOAc and evaporation of the solvent gave the crude calixarenes. Purification was accomplished by flash chromatography on silica gel (EtOAc/hexanes = 1 : 3), giving the title calix(4)arene (0.054 g, 0.101 mmol, 36% yield) as a white solid and as a single conformer. This compound was crystallized from acetonitrile and subjected to single crystal X-ray diffraction analyses that revealed that it exists as the cone conformer, mp >298◦ (dec.) Rf = 0.32 (EtOAc/hexanes = 1 : 3); IR (CH2 Cl2 ) 3297, 3055, 2988, 2937, 2835, 1600, 1481, 1433, 1285, 1228, 1124, 1055, 1009 cm−1 ; 1 H NMR (CDCl3 , 300 MHz) δ 2.03 (s, 6H), 3.27 (d, J = 13.2 Hz, 4H), 3.74 (s, 6H), 3.93 (s, 6H), 4.27 (d, J = 12.9 Hz, 4H), 6.61 (s, 4H), 6.72 (s, 4H), 7.59 (s, 2H,); 13 C NMR (CDCl3 , 75 MHz) δ 20.9, 31.5, 55.8, 63.5, 113.7, 129.1, 129.7, 132.7, 134.3, 146.9, 151.3, 152.2; HRMS (m/z): calcd for C34 H36 O6 , 540.2512; found 540.2512. Anal. Calcd for C34 H36 O6 : C, 75.53; H, 6.71. Found: C, 75.62; H, 6.60.

Cr(CO)5 OMe

TMS +

TMS 1. THF, 70° 2. air

HO

(73%)

6-Methyl-4-(trimethylsilanyl)indan-5-ol (Regioselective Two-Alkyne Phenol Annulation).80 A deoxygenated solution of pentacarbonyl[methoxy(methyl) methylene]chromium (164 mg, 0.67 mmol) and (hepta-1,6-diynyl)trimethylsilane

224

ORGANIC REACTIONS

(108 mg, 0.66 mmol) in THF (7 mL) was heated at 50◦ for 20 hours. The mixture was then stirred in air at room temperature for 1 hour followed by filtration through a bed of Celite. After removal of the volatiles from the filtrate, the crude product was purified by chromatography on silica gel (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 50) to first give the recovered carbene complex (14 mg) and then the title compound (106 mg, 0.48 mmol, 73% yield): IR (CHCl3 ) 3600, 2970, 1560, 1400 cm−1 ; 1 H NMR (CDCl3 ) δ 0.37 (s, 9H), 2.02 (m, 2H), 2.20 (s, 3H), 2.78 (t, J = 7.3 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H), 4.73 (s, 1H), 7.01 (s, 1H); MS m/z (% relative intensity) 220 (30, M+ ) 205 (30), 204 (100), 189 (50); exact mass (m/z) calcd for C13 H20 OSi, 220.1283; found 220.1287. Anal. Calcd for C13 H20 OSi: C, 70.88; H, 9.09. Found: C, 71.20; H, 9.23. TBSO OMe (CO)5W

1.

OMe , 1 atm CO, MeCN, rt, 16 h

HO (62%)

2. 110°, 23 h TBSO

3-(tert-Butyldimethylsilanyloxy)-12-methyl-7,15,16,17-tetrahydro-6H cyclopenta[a]phenanthren-11-ol (Tandem Diels-Alder Two-Alkyne Phenol Annulations).245 A 100-mL, single-necked flask equipped with a threaded highvacuum stopcock was charged with pentacarbonyl(1-methoxy-2,6,11-tridecatriynylidene)tungsten (0.147 g, 0.28 mmol), ((E)-4-methoxybuta-1,3-dien-2-yloxy) (tert-butyl)dimethylsilane (0.0902 g, 0.42 mmol), and MeCN (5.6 mL). The solution was deoxygenated three times via the freeze-thaw method, the flask was back-filled with 1 atm of carbon monoxide and sealed, and the contents of the flask were stirred at room temperature for 16 hours. The flask was opened and the reaction mixture was diluted with MeCN (50.6 mL). The solution was degassed twice using the freeze-thaw method, and then the flask was back-filled with one atmosphere of carbon monoxide at room temperature, sealed, and placed in an oil bath at 110◦ for 23.5 hours. The crude reaction mixture was filtered through Celite, and after removal of solvents, the product was purified by flash chromatography on silica gel (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 30, then 1 : 1 : 4) to give the title compound as a colorless oil (0.0635 g, 0.17 mmol, 62% yield); Rf = 0.38 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 16); IR (neat) 3567, 3028, 2952, 2894, 2857, 1608, 1495, 1471, 1419, 1287, 1247, 1224, 1169, 1073, 999, 969, 852, 839, 781 cm−1 ; 1 H NMR (CDCl3 ) δ 0.25 (s, 6H), 1.02 (s, 9H), 2.10 (quintet, J = 7.5 Hz, 2H), 2.23 (s, 3H), 2.65 (m, 2H), 2.68 (m, 2H), 2.88 (quintet, J = 7.5 Hz, 4H), 5.20 (s, 1H), 6.74 (m, 1H), 6.76 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H); 13 C NMR (CDCl3 ) δ −4.1, 12.6, 18.2, 24.6, 25.7, 26.5, 30.0, 31.3, 32.2, 117.8, 118.2, 119.3, 119.9, 126.4, 126.6, 132.0, 132.7, 140.7, 142.8, 149.2, 154.0; MS m/z (% relative intensity): 380 (100, M+ ), 339 (14), 323 (36), 161 (8), 75 (29), 57 (14); exact mass (m/z) calcd for C24 H32 O2 Si, 380.2173; found, 380.2162. Anal. Calcd for C24 H32 O2 Si: C, 75.74; H, 8.48. Found: C, 75.36; H, 8.58.

THE SYNTHESIS OF PHENOLS AND QUINONES MeO

C7H15-n N Bn

MeO

Cr(CO)5

225

OH

hn

(65%)

CO, THF N Bn

C7H15-n

N-Benzyl-1-heptyl-4-methoxy-2-methyl-9H-carbazol-3-ol (Photoinduced ortho-Benzannulation).258 A solution of pentacarbonyl[[2-(1-ethylideneoctyl)1-(phenylmethyl)-1H -indol-3-yl)methoxymethylene]chromium (472 mg, 0.815 mmol) in THF (150 mL) in a quartz photoreactor was purged with nitrogen for 15 minutes and then purged with carbon monoxide for another 15 minutes. The solution was irradiated with a 450 W medium-pressure mercury lamp for 30 minutes at room temperature. The resulting solution was kept under a carbon monoxide atmosphere for 12 hours. The solvent was then evaporated to give a red oily residue. The residue was purified by column chromatography (EtOAc/hexanes = 3 : 97) to give the title compound (223 mg, 65% yield) as a light brown solid, mp 102−104◦ : IR (CH2 Cl2 ) 3544, 2959, 2928, 2857 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 0.91 (t, J = 6.9 Hz, 3H), 1.20–1.40 (m, 8H), 1.42–1.64 (m, 2H), 2.38 (s, 3H), 2.74–2.84 (m, 2H), 4.06 (s, 3H), 5.65 (s, 1H), 5.66 (s, 2H), 7.04 (d, J = 6.8 Hz, 2H), 7.19–7.30 (m, 5H), 7.34–7.40 (m, 1H), 8.20 (dd, J = 7.8, 1.3 Hz, 1H); 13 C NMR (125 MHz, CDCl3 ) δ 12.0, 14.1, 22.6, 28.2, 29.1, 29.8, 31.8, 31.8, 48.7, 60.5, 108.8, 114.7, 119.2, 121.0, 122.1, 123.0, 124.3, 125.4, 127.1, 128.8, 134.2, 138.7, 138.8, 140.6, 142.1; EIMS m/z (% relative intensity) 415 (65), 330 (20), 240 (80), 91 (100). Anal. Calcd for C28 H33 NO2 : C, 80.93; H, 8.00; N, 3.37. Found C, 81.23; H, 7.84; N, 3.48. TABULAR SURVEY

The literature coverage includes that cited in Chemical Abstracts up to midSeptember of 2004, but some additional references past this time have been included. All reactions in the literature that involve the reaction of an α,βunsaturated Fischer carbene complex with an alkyne are included whether or not a phenol or quinone product was formed in the reaction, i. e., every example is included where a phenol or quinone product could have been produced. Not all reactions of saturated alkyl carbene complexes with alkynes are included; only those where reaction occurs to give a phenol product or phenol-derived product. The reactions of alkyl carbene complexes that give phenol products are largely the two-alkyne phenol products, which are to be found in Table 24 on miscellaneous reactions, or in Table 21 on carbene complexes with tethered alkynes. The product distribution from the reactions of carbene complexes with alkynes can often be very sensitive to the concentration and, thus, for purposes of comparison, the concentration of the carbene complex and the number of equivalents of alkyne are given in the tables when they are reported. Most of the tables are organized by the carbon number of the alkyne that appears in the first column and then by the carbon number of the carbene complex that appears in the second

226

ORGANIC REACTIONS

column. Tables 21 and 23 are organized by the carbon number of the carbene complex which appears in the first column. In some instances, the carbene complex that participates in the reaction is generated in situ and the organization is by the carbon number of the precursor carbene complex. The tables are subdivided by the nature of the metal, whether the alkyne is terminal or internal, and by the type of heteroatom-stabilizing group on the carbene complex. Thus the reactions of chromium, tungsten, and molybdenum complexes occur in separate tables. The reactions of chromium complexes are also separated into oxygen-, aminoand imino-, and sulfur-stabilized complexes. The exceptions to this organization are the tables on intramolecular reactions (Table 21), non-heteroatom-stabilized complexes (Table 22), and doubly unsaturated complexes (Table 23), where all examples of different metals and/or heteroatom complexes appear. The yields for the reactions are given in parentheses, followed by a ratio of product if applicable. A dash (—) indicates that no yield is reported in the reference. The following abbreviations have been used in the tables: Ad Bn Boc Bz CAN CC COD Cp Cp
DBU de DEAD DDQ DMAP DME DMF DMTH dr ds EE HMPA LAH MEM MOM naphth N-morph PMB PMP

adamantyl benzyl tert-butoxycarbonyl benzoyl ceric ammonium nitrate carbene complex 1,5-cyclooctadiene cyclopentadienyl methylcyclopentadienyl 1,8-diazabicyclo[5.4.0]undec-7-ene diastereomer excess diethylazodicarboxylate 2,3-dichloro-5,6-dicyano-f-benzoquinone N ,N -dimethylaminopyridine 1,2-dimethoxyethane N ,N -dimethylformamide 2,5-dimethyltetrahydrofuran diastereomeric ratio diastereomer selectivity 2-ethoxylethyl hexamethylphosphoric triamide lithium aluminum hydride methoxyethoxymethyl methoxymethyl naphthyl N -morpholino p-methoxybenzyl p-methoxyphenyl

THE SYNTHESIS OF PHENOLS AND QUINONES

pyr TBAF TBS TBDPS Tf THF THP TIPS TMS Tol Tr tr Ts

pyridine, pyridinyl tetrabutylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl trifluoromethanesulfonyl (triflyl) tetrahydrofuran 2-tetrahydropyranyl triisopropylsilyl trimethylsilyl tolyl triphenylmethyl (trityl) trace p-toluenesulfonyl

227

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C4

Refs.

OH Cr(CO)5 Ph excess

(n-Bu)2O, 45°, 2 h

OMe 0.27 M

(68)

87

(CO)3Cr OMe O

C5 Cr(CO)5

Et Ph 1.7 eq

OMe 0.3 M

O Et

1. Solvent, 45°

+

I

II

2. CAN, MeOH

67

Et MeO OMe

MeO OMe Time

I + II

I :II

2h

(51)

2.2:1

(n-Bu)2O 24 h

(70)

2.0:1

THF

(66)

2.2:1

Solvent (n-Bu)2O

228

24 h

OH Cr(CO)5 1.5 eq Ph

Et (n-Bu)2O, 45°, 2 h

(60)

358

OMe 0.33 M

(CO)3Cr

OMe OH

Cr(CO)5

1.5 eq Ph

OH Et

t-BuOMe, 45-50°, 2-5 h

OMe 0.2 M

+

I

II

68

Et (CO)3Cr

OMe

(CO)3Cr

OMe

I + II (56), I:II = 2.2:1 NMe2

Cr(CO)5 NMe2

Hexane, rt, 1 h Ph

1 eq

(CO)5Cr

Ph

OMe 0.3 M

(2-65) E:Z = 45:1

359, 142

OMe

OMe Cr(CO)5 1. Hexane, rt, 1 h Ph 1 eq

OMe

2. Decane, 125°, 3 h

0.3 M

O

(CO)3Cr OH

Cr(CO)5

2 eq

OMe

(CO)3Cr

(24)

C6

Ph

(—)

(CO)3Cr

(20)

O

Me

(n-Bu)2O, 40-60°, 2 h

0.33 M

142

+

93

OMe OH Pr-n

Cr(CO)5 Ph

229

1.25 eq

OMe

(n-Bu)2O, 45°, 2 h

0.27 M

(CO)3Cr

I (58)

87

I (80)

68

OMe

OH Pr-n(Me)

Cr(CO)5 t-BuOMe, 45-50°, 2-5 h

1.5 eq

Ph

OMe

Me(Pr-n)

0.2 M

(CO)3Cr

OMe

OH Cr(CO)5 Et

Et Ph 1-4 eq

OMe 0.3-0.3 M

Et (n-Bu)2O or t-BuOMe,

(65-72)

45-55°, 1-2 h

Et (CO)3Cr

OMe

87, 73

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) O

C6 Et

Et

Cr(CO)5

Et

OMe

Et

I +

Et Ph

Refs.

Et II

+

OMe

O Et

Ph

O Et

III

OMe

+ Et

O

IV

+

Et OH

Et

Et

Et V

230

Ph

O

+

VI

OMe

Et OMe

Alkyne (eq)

CC (M)

3.0

0.12

1. THF, 45°, 16-24 h

I

II

III

IV

V

VI

(88)

(≤0.3)

(≤0.3)

(0)

(—)

(—)

13, 84

(97.4)

(1.3)

(0)

(0)

(≤1)

(—)

60

(44)

(—)

(—)

(—)

(—)

(—)

13

(54)

(—)

(—)

(—)

(—)

(—)

13

(96.6)

(1.7)

(0)

(0)

(1.3)

(—)

60

(87)

(≤1)

(≤1)

(0)

(—)

(—)

60

(96)

(—)

(—)

(—)

(—)

(—)

67

(96.5)

(≤0.7)

(0)

(0)

(≤1)

(—)

60

(95.7)

(≤0.6)

(0)

(0)

(<0.9)

(—)

60

(84)

(—)

(—)

(—)

(—)

(—)

13

(57)

(tr)

(—)

(23)

(—)

(—)

84

(38)

(14)

(—)

(23)

(≤1)

(—)

84

(—)

(25)

(—)

(7)

(≤2)

(32)

60

(37)

(5)

(5)

(24)

(—)

(—)

84

(24)

(14)

(15)

(19)

(—)

(—)

84

(—)

(65)

(—)

(11)

(1)

(12)

60

2. CAN 2.0

1. THF, 80°, 47 h

0.1

2. CAN 2.0

1. THF, –78°, 13.5 h

0.021

UV photolysis 2. CAN, –78° 2.0

1. THF, –15°, 13.5 h

0.021

UV photolysis 2. CAN 2.0

1. THF, 80°, 34 h

0.005

2. CAN 2.0

1. THF, 110°, 1-2 h

0.005

2. CAN

1.5

0.3

1. THF, 50°, 20 h 2. CAN

1.9

0.1

1. Benzene, 80°, 46 h 2. CAN

1.9

0.005

1. Benzene, 45°, 64 h 2. CAN

3.0

0.1-0.2

1. Hexane, 45°, 24 h 2. CAN

2.0

0.5

1. MeCN, 45°, 16-24 h 2. CAN

2.0

0.1

1. MeCN, 45°, 17 h 2. FeCl3-DMF

2.0

1. MeCN, 80°, 20 h

0.1

2. Air/SiO2 2.0

0.05

1. MeCN, 45°, 16-24 h

231

2. CAN 2.0

0.005

1. MeCN, 45°, 44 h 2. CAN

2.0

0.005

1. MeCN, 80°, 48 h 2. Air/SiO2

(n-Bu)3P

Cr(CO)4

Ph

OMe

Alkyne (eq)

CC (M)

2.2

0.05

I + II + III + IV + V + VI

1. THF, 50°, 20 h

I

II

III

IV

V

VI

(64)

(—)

(—)

(—)

(—)

(—)

133

(79)

(<3)

(—)

(—)

(8)

(—)

201

2. CAN 1.9

0.1

1. THF, 80°, 20-40 h 2. CAN

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C6 Ac2O (1.1 eq),

Cr(CO)5 Et

Ph 2.8 eq

Et

NEt3 (1.1 eq),

Et OMe 0.03 M

THF, 65°, 2 h

(75)

267, 360

(94)

73

Et OMe OTBS Et

1. t-BuOMe, 55°, 1 h

Cr(CO)5

2. TBSCl (4 eq),

4 eq Ph

OMe

Et

Et3N (4 eq), rt, 4 h

0.4 M

(CO)3Cr

OMe O

Et 1.5 eq

Et

232

+ Bu-n 1.5 eq

Ph

O Et

Cr(CO)5

1. Benzene, 40°, 22 h

OMe

I

2. CAN

Bu-n II

+

361

Et

0.1 M

O

O I + II (78), I:II = 4:96 Ph

Cr(CO)5 Et

THF, –20° to rt, 15 h

Et Ph 1.9 eq

(≤5)

Ph

Ph

(≤5)

+

OAc

+

114

(<5)

+

Ph

0.14 M Ph

Ph

+

(≤5)

Ph

Ph (≤5) +

OAc

O Ph

+

(<5)

Ph

Ph

Ph (≤5)

Ph (CO)3Cr

O

Et Et

Cr(CO)5 2 eq

Benzene, 80°, 16 h Ph

(97)

OPr-i

+

Et (≤0.5)

0.1 M

O

O O

Et 1.5 eq

Et

+ Bu-n 1.5 eq

O Et

Cr(CO)5 Ph

113

Et

1. Benzene, 40°, 22 h

OPr-i

Bu-n I

2. CAN

+

II

361

Et O

0.1 M

I + II (75), I:II = 1:99

O

OTBS (CO)5Cr

Et

Ph 1. t-BuOMe, 55°, 4 h

O

233

Et

Et

Et

2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h

(CO)3Cr

(44) 85% de

73

O

0.4 M

4 eq R1O

OR1

R1O

OR1

1. TBSCl (5 eq), Et3N (10 eq), R2O THF, 55°, 3h R2O 2. CAN

6 eq

OR2 362

(80) OR2 TBSO

Ph

Et

R2 =

R1 = (CO)5Cr

Et

0.022 M OH MeO2C 1 eq

CO2Me

CO2Me

Cr(CO)5

(7)

THF, 65°, 3 h Ph OMe 0.03 M

CO2Me OMe

183

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C7

Refs.

Et

Cr(CO)5 (n-Bu)2O, 40-60°, 2 h

Et

Ph 2 eq

(—)

93

OMe 0.33 M

OMe

(CO)3Cr

OH

OH Bu-t

Cr(CO)5 t-BuOMe, 45-50°, 2-5 h

Bu-t Ph

0.2 M

1.5 eq

I

OMe

+

(CO)3Cr OMe

II Bu-t

68

II (23)

13

(CO)3Cr OMe

I + II (59), I:II = 98:2 O

234

1.5 eq OMe

2. FeCl3-DMF

OMe

t-Bu

0.1-0.2 M "

Ph

I (32) +

1. Hexane, 45°, 24-48 h Ph

O

Bu-t

Cr(CO)5

O 1. THF, 45°, 24-48 h

I (26) +

II (14)

13

2. FeCl3-DMF "

1. MeCN, 45°, 24-48 h

II (27)

13

2. FeCl3-DMF OH Pr-n(Et)

Cr(CO)5 Et

t-BuOMe, 45-50°, 2-5 h

Pr-n Ph

(CO)3Cr OMe

OAc Cr(CO)5 2 eq

OAc Pr-n

1. THF, 55°, 12 h

OMe 0.1 M

Et I

2. Ac2O, NaOAc, Ph

68

Et(Pr-n)

0.2 M

1.5 eq

(62) one isomer

OMe

+

II

Et

THF, 55°, 12 h

363

Pr-n

OMe

OMe I + II = (96), I:II = 52:48

OAc Cr(CO)5 Et

CO2Et

OAc Et

Ac2O (2.5 eq), Et3N (2 eq),

CO2Et I

THF, 65°, 5 h Ph

OMe

+

II

CO2Et OMe

0.03 M

70

Et OMe

I + II (38), I:II = 1.1:1 Ph n-Bu

Cr(CO)5 n-Bu

SMe

OMe

Hexane, 79°, 16 h

235

Ph

OMe

(39) MeO

144

Bu-n Ph NEt2

Cr(CO)5 NEt2

Ph

1 eq

OMe

Hexane, rt, 0.5 h

(CO)5Cr

Ph

0.3 M

"

I (62-70) E:Z = 14.5:1

Octane, 30.2°

140, 359 142, 141

OMe

I (—)

364 O

C8

Pr-n

Cr(CO)5

n-Pr

(35)

1. (n-Bu)2O, 40-60°, 2 h Ph 2 eq

OMe 0.33 M

2. O2/SiO2 O

93

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C8

Refs.

Me

Cr(CO)5 (85)

t-BuOMe, 45-55°, 1 h Ph

(CO)3Cr

0.29 M

1.15 eq

262

OMe OMe OH Bu-t

Cr(CO)5 Et

Bu-t

Ph

1.5 eq

OMe

t-BuOMe, 45-50°, 2-5 h

(66)

0.2 M

(CO)3Cr OMe O

236

Pr-i Ph

2 eq

OMe

Pr-i Pr-i

Cr(CO)5 i-Pr

68

Et

1. Solvent, heat

+

I

Pr-i II

84

Pr-i

2. CAN

O II

O CC (M)

I

Solvent Temp

0.5

THF

45°

(78)

(<1)

0.5

heptane

45°

(71)

(<1)

0.5

THF

110°

(65)

(<1)

0.005

THF

110°

(45)

(21)

O Cr(CO)5

1.5 eq

OMe

2. CAN O OH

0.2 M

OMe

Cr(CO)5

OMe

Heptane, 80°, 84 h Ph

TMS 1.8 eq

135

(49)

1. THF, 66°, 5 h Ph

OMe

(0)

183

(0)

183

TMS

0.4 M

OMe

OAc OMe

Cr(CO)5 2.1 eq Ph

OMe

Ac2O (1.5 eq), Et3N (1.5 eq), heptane, 80°, 19 h

TMS

0.4 M

OMe O

Cr(CO)5 TMS

TMS Ph 1.25 eq

OMe 0.4 M

•

O

TMS

(n-Bu)2O, 50°, 2 h

(52)

Ph

TMS

+

Cr(CO)3

•

TMS

OMe

C9

TMS Ph

(20)

57, 132 365

OMe

OH Cr(CO)5 n-Pr

Bu-n

Ph

1.5 eq

OMe 0.2 M

Bu-n(Pr-n) (62) single isomer

t-BuOMe, 45-50°, 2-5 h

68

Pr-n(Bu-n) (CO)3Cr

OMe

237

OH Ph

Cr(CO)5 t-BuOMe, 45-50°, 2-5 h

Ph

Ph

0.2 M

1.5 eq

(73) single isomer

OMe (CO)3Cr

68, 42

OMe O

Cr(CO)5 5 eq

Ph

OMe 0.05 M Cr(CO)5

1. Microwave,

Ph

OMe 0.05 M

I (70)

192

2. CAN O 1. Microwave, THF, 130°, 300 s

5 eq

Ph

(n-Bu)2O, 130°, 300 s

2. CAN

I (86)

192

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C9

O

Cr(CO)5 t-Bu

CO2Et

Product(s) and Yield(s) (%)

OMe

1. THF, 65°, 6 h Ph

1.5 eq

OMe 0.06 M

2. Air

Refs.

Ph

t-Bu

(93)

70

(33)

93

CO2Et OH Bu-n

Cr(CO)5

n-Bu Ph 2 eq

OMe 0.33 M

1. (n-Bu)2O, 40-60°, 2 h 2. Air, silica gel OMe OH

O

Cr(CO)5

B

THF, 45°, 2-16 h

238

O

Ph

3 eq

C10

B

OMe

(53)

O

75

OMe O

0.05 M

OAc Bu-n

Cr(CO)5 n-Bu

Bu-n

Ph

2 eq

OMe

Ac2O (2 eq), NEt3 (2 eq),

(48)

THF, 65°, 10 h,

267

Bu-n OMe

0.03 M O

OH

O

Cr(CO)5 Ph

MeO2C

OMe

151, 183

(0)

THF, 65°, 24 h CO2Me

0.2 M

1.5 eq

OMe

O Cr(CO)5 1. THF, 45°, 24 h Ph

O

OMe 0.3 M

1 eq

Ph n-Bu

Ph

OMe

O

MeO THF, 65°, 4 h

149

(—)

OH n-Bu

0.12 M

0.83 eq

OMe

Cr(CO)5 (16) +

Ac2O (2 eq), Et3N (2 eq),

EtO

Ph

OMe

Ph

O

OAc

HO

O

(21)

148, 191

OEt

THF, reflux, 16 h

OEt OMe

239

1.2 eq

OAc Cr(CO)5 n-C5H11

103

O

Cr(CO)5

OH

(89)

O

2. CAN

CO2Et

Ph

OMe

Ac2O (2.5 eq), Et3N (2 eq),

I

THF, 65°, 5 h

CO2Et +

II

CO2Et

0.03 M

1.5 eq

OAc C5H11-n

70, 267

C5H11-n

OMe

OMe

I + II (49-60), I:II = 1.6-2.0:1 NEt2

Cr(CO)5 Et2N

NEt2

Ph

OMe

Hexane, 14°, 4 d

(CO)5Cr

Ph

Et2N

(52)

366, 367

OMe

0.13 M

3 eq

NEt2

Cr(CO)5 1 eq

(n-Bu)2O, 70°, 4 h Ph

(CO)4Cr

Ph

OMe 0.33 M

Et2N

OMe

(39)

366, 367

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C10

Refs.

NEt2 Cr(CO)5 Et2N

NEt2 Ph 1 eq

OMe 0.33 M (step 1)

1. (n-Bu)2O, 70°, 4 h

NEt2

(23)

367

(0)

183

(0)

183

2. Decane, 125°, 2 h (CO)3Cr

OMe

0.09 M (step 2)

C11

O

OH

O

Cr(CO)5 Ph

TMS

OMe

Heptane, 80°, 17 h TMS

1.4 eq

0.4 M

OMe OH

O

O

240

Cr(CO)5 Hexane, 45°, 17 h Ph MeO

OMe OMe

0.02 M

1.5 eq

OMe

MeO Ph

OAc CO2Et

Ph

1.5 eq

OMe 0.03 M

CO2Et

Ph

Cr(CO)5 Ph

Ph

+

(22)

Ac2O (1.2 eq), Et3N (1.3 eq), THF, 65°, 6 h

O

O

(50)

70

Ph

CO2Et OMe

CO2Et Ph OH

MeO

Cr(CO)5

n-Bu

O OH

THF, 65°, 4 h Ph 0.83 eq

OMe

149

(—)

n-Bu

OMe 0.12 M

C12

OAc OTBS OTBS

Cr(CO)5

1.5 eq

OMe 0.033 M

70, 115

(54)

Ac2O (1.5 eq), Et3N (1.5 eq), Ph

EtO

THF, 65°, 3 h

OEt OMe OAc OTBS

OH

OTBS

Cr(CO)5 1.5 eq

Ac2O (1.1 eq), Ph

OMe

+

THF, 65°, 4 h

115

OEt

0.03 M

OEt

OMe

OMe

I (12)

II (52)

Cr(CO)5 1.5 eq

Ph

OMe

AcOH (1 eq),

I (0), II (50)

115

THF, 65°, 6 h

0.033 M

241

MeO Cr(CO)5 1.5 eq

Ph

OMe 0.03 M

EtO Et3N (1.0 eq),

OH I (29)

O

THF, 65°, 4 h

115

OEt OMe Cr(CO)5 1.5 eq

Ph

OMe 0.03 M

THF, 65°, 4 h

I (88)

115, 368

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C12 R

Refs.

R

O Cr(CO)5 1. Silica gel, 100°, 2 h Ph

n-Bu

OMe

2. CAN

I

369

I

369

Bu-n

1.2 eq O R

I

NH2

(38)

NO2

(0)

Cl

(71)

O Cr(CO)5

242

n-Bu

Ph

R

OMe

1. Silica gel R Bu-n

2. CAN

1.2 eq

O R

Temp

Time

I

NO2

125°

12 h

(0)

Cl

100°

2h

(79)

OH Cr(CO)5 n-Bu

Ph

NH2

OMe

Silica gel, 100°, 2 h

369

(13) NH2 Bu-n

1.2 eq

OMe OH Bu-n O

n-Bu

Cr(CO)5

B Ph

O 3 eq

THF, 45°, 2-16 h

75

(73)

O

B

OMe 0.05 M

OMe O

C13 OH Cr(CO)5 t-BuOMe, 45-55°, 1 h Ph

(91)

OMe 0.29 M (CO)3Cr

1.15 eq

262

Me OMe O

Cr(CO)5 1. Silica gel Ph n-Bu 1.2 eq

OMe

R

I

O

243

Temp

Time

I

Me

100°

2h

(64)

OMe

80°

20 h

(57)

CHO 100°

2h

(0)

CHO

Cr(CO)5 Ph

n-Bu

R

O

CHO

369

R Bu-n

2. CAN

OMe

1. Silica gel, 120°, 20 h

(24)

2. CAN

369

Bu-n

1.2 eq

O

C14

OH Ph

Cr(CO)5 Ph

Ph

Ph

1 eq

OMe 0.31 M

(n-Bu)2O, 45°, 3 h

(62)

2

(53)

360

Ph (CO)3Cr

OMe OAc Ph

Cr(CO)5 1.8 eq

Ph

OMe 0.04 M

Ac2O (1 eq), Et3N (1 eq), Ph

THF, 45°, 2 h OMe

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

OH

OH (20) +

Heptane, 80°, 0.5 h

Ph 1 eq

Ph

Ph

Cr(CO)5 Ph

Refs.

Ph OMe 0.33 M

(18)

(CO)3Cr OMe

OMe

(CO)3Cr

Ph

Ph

OMe

244

Ph

Ph

O

Ph

OMe

Ph

I

Ph

O

(—)

+

Ph

Ph Ph

1. THF, 45°, 24-48 h

O

OMe

Ph

Ph

Ph

III +

O

0.1-0.2

II

+

OMe

O

CC (M)

+

Ph

Ph

Ph

Cr(CO)5

3.0

•Cr(CO)3 (2) OMe

OMe

+

(10) OMe

O

Alkyne (eq)

+

(CO)3Cr

C23H18O2•Cr(CO)3

Ph

Ph (4)

Ph (26) +

+

Ph

76

Ph

Ph

IV

I

II

III

IV

(59)

(—)

(—)

(—)

13

(65)

(—)

(—)

(—)

177

(94)

(—)

(3)

(3)

84

(89)

(—)

(8)

(3)

84

(94)

(—)

(6)

(—)

84

(64)

(—)

(24)

(7)

84

(41)

(—)

(38)

(4)

84, 13

(—)

(19)

(—)

(51)

13

(36)

(—)

(—)

(21)

13

(86)

(—)

(—)

(—)

177, 178

(77)

(—)

(—)

(—)

177, 178

(15)

(—)

(—)

(—)

177, 178

(—)

(83)

(—)

(—)

79

2. CAN 1.5

1. (n-Bu)2O, 5°, 0.33 h

0.04

ultrasound 2. CAN 2.0

1. THF, 70°, 12 h

0.5

2. CAN 2.0

1. THF, 70°, 15 h

0.005

2. CAN 2.0

1. THF, 110°, 0.5 h

0.5

2. CAN 2.0

1. THF, 110°, 4 h

0.005

2. CAN 3.0

1. Heptane/hexane, 45°, 24 h

0.16

245

2. CAN 3.0

1. MeCN, 45°, 24 h

0.16

2. CAN 3.0

1. Benzene, 45°, 24 h

0.16

2. CAN 1.2

1. Silica gel, 40-50°, 3 h

—

2. CAN 1.0

1. MgSO4, 50°, 1.5 h

—

2. CAN 1.2

1. Al2O3, 60-65°, 10 min

—

2. CAN —

DMF, 90°

— (n-Bu)3P

Cr(CO)4

Ph

OMe

1.0 eq 0.04 M

1. (n-Bu)2O, 90°, 3 h 2. CAN

I (48) + II (—) + III (6) + IV (—)

133

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C14

Ph Ph

(CO)5Cr Ph

1. THF, 45°, 36 h

Ph

Br

O

2 eq

(93)

Ph

2. Air, 30 min

O

169

Br

0.03 M

OH Ph (CO)5Cr 2-3 eq

Ph

R 1. THF, 45°, 36 h

O

2. Air, 30 min

246

0.02 M

OMe (86)

Ph

t-Bu

O

169

(70)

R R OH

L Cr(CO)4

1 eq

Ph

Ph (n-Bu)2O, heat, 2.5 h

87

•Cr(CO)3

OMe

Ph

0.05-0.08 M

OMe Temp

L (4-FC6H4)3P

60°

(61)

(n-Bu)3P

90°

(11)

OH Cr(CO)5 Dioxane, 100°, 26 h Ph

n-Bu 1.2 eq

OMe

(57)

260

I

369

Bu-n

0.015 M

OMe

O Cr(CO)5 R

n-Bu

Ph

OMe

1. Silica gel, heat, time

R Bu-n

2. CAN O

1.2 eq

R

R

Temp

Time

I

Ac

120°

12 h

(0)

CO2Me

100°

2h

(0)

R

O

R

Cr(CO)5 Ph

n-Bu

OMe

(54)

1. Silica gel, 80°, 20 h

Ac

2. CAN

CO2Me (56)

Bu-n

1.2 eq

369

O OTBS

247

Ph Cr(CO)5

OTBS Ph

1. t-BuOMe, 55°, 1.5 h

Ph +

2. CH2Cl2, TBSCl, Et3N, Ph 2 eq

CO2Et

OMe

rt, 3 h

(CO)3Cr

CO2Et

(35) O Cr(CO)5 Ph

Benzene, 80°, 12-24 h

TBS 1.2 eq

Ph

(CO)3Cr

OMe

0.33 M

370 OMe (8.5)

CO2Et

TBS •

(CO)3Cr

TBS Ph

Ph

+

OMe OMe (55)

OMe

(CO)3Cr (19)

134

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

O

Refs. O

Ph O Ph

Cr(CO)5

B Ph

O 3 eq

OMe 0.5 M

Ph

1. THF, 45°, 16 h 2. CAN

O

B

74

+

O

O

O (12)

(57) OH Ph Cr(CO)5

3 eq Ph

THF, 45°, 14 h OMe O

0.5 M

C15

248 Ph Ph

1.2 eq

Ph

t-BuOMe, 45°, 6 h

42, 68

+

OMe

Ph

0.26 M

OH

R

OH

R Cr(CO)5

75

(64)

O

B

OMe

(CO)3Cr

(CO)3Cr

OMe

R

OMe I

II

R

I + II

I:II

CF3

(66)

55:45 (not assigned)

Me

(52)

53:47 (not assigned)

O R

Cr(CO)5 1. Silica gel, 80°, 20 h Ph

R

Ph

OMe

2. CAN

R

Ph

1.2 eq

Me

(65)

OMe

(57)

369

O

O Cr(CO)5 Ph

OMe

CH(Me)OMe

n-Bu

1. Silica gel, 50°, 2 h

CH(Me)OMe Bu-n

2. CAN

1.2 eq

213

(76) 0% de

O OH

O

O

Cr(CO)5 (0)

THF, 65°, 24 h Ph TBSO

1.5 eq

i-PrO

O

0.03 M

OMe OTBS O i-PrO

Cr(CO)5 Pr-n i-PrO

151, 183

OMe

Pr-n (72)

1. THF, reflux, 4 h Ph

OH

OMe

2. HCl (cat), CH2Cl2, rt

372, 149

O

i-PrO

249

O Ph

0.12 M

0.83 eq OH

Ph

Ph Ph

Cr(CO)5

O Ph

Ph 3 eq

Ph (39) +

Dioxane, reflux, 6 h OMe

(16)

Ph

0.26 M

OMe

OMe

+ Ph C16

Ph

(5)

OH p-Tol

Cr(CO)5

Ar Ph 1.2 eq Ar =

CF3

OMe 0.26 M

OH Ar

t-BuOMe, 45°, 6 h

Tol-p 42, 68

+ Tol-p (CO)3Cr

371

OH

OMe I

Ar (CO)3Cr

I + II (62), I:II = 46:54

OMe II

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C16 O Cr(CO)5

(42)

1. Silica gel, 100°, 2 h

n-Bu

O

Ph

O

OMe

369

CHO Bu-n

2. CAN O

1.2 eq OH

OTBS

OTBS OAc

Cr(CO)5

+

THF, 65°, 24 h MeO2C

Ph

OMe 0.3 M

1.5 eq

250

Cr(CO)5

1.5 eq Ph

OMe

151

CO2Me CO2Me

OMe I (22)

OMe

II (0)

Ac2O (1.5 eq), Et3N (1.5 eq), I (10) + II (8)

151, 183

heptane, 80°, 19 h

0.1 M

TBSO

HO TBSO O

O

O

O

Cr(CO)5 Ac2O (1.1 eq), Et3N (1.1 eq), Ph

EtO

OMe

THF, 65°, 5 h

0.03 M

1.5 eq

(45)

115

(45)

70

OEt OMe

AcO TBSO

O

O

Cr(CO)5 Ac2O (1.5 eq), Et3N (1.5 eq),

1.5 eq Ph

OMe 0.03 M

THF, 65°, 7 h

OEt OMe

O Ph

Cr(CO)5 Ph

(42)

1. THF, 105°, 2 h

Ph Ph 1.0 eq

OMe

100

2. CAN

0.21 M

O

Ph

OH

O

Cr(CO)5 1.0 eq

Ph

THF Ph

+

I

II

OMe

Ph

Ph

251

CC (M)

Temp

Time

I

II

0.03

60°

24 h

(20)

(21)

0.03

70°

23 h

(44)

(—)

0.5

70°

24 h

(16)

(—)

0.21

105°

3h

(12)

(—)

0.21a

105°

3h

(—)

(—)

O

O (53)

1. THF, 50°, 17 h OBu-n

+

(21)

O

Ph

Ph

OH Solvent, 70°, 24 h Ph

O I

+

II Ph

OBu-n 0.03 M

OBu-n Ph

Ph

Cr(CO)5 1.0 eq

100

Ph

2. CAN

0.03 M

OBu-n Ph

Ph

Cr(CO)5 Ph

100

Ph

OMe

1.0 eq

OMe

Ph

OBu-n Solvent

Ph

Ph

I

II

THF

(61)

(—)

benzene

(40)

(—)

hexane

(31)

(—)

100

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C16

Ph

O

O

OH

THF

Ph (CO)5Cr

Ph Ph

HO

Ph

Ph

+

I

100

Cr(CO)5 O

0.9 eq

O Ph Ph

HO

II O

O

252

CC (M)

Temp

Time

I

II

0.005

80°

16 h

(12)

(21)

0.024

80°

16 h

(23)

(13)

0.029

105°

4h

(19)

(25)

0.16

45°

16 h

(19)

(7)

0.20

105°

4h

(7)

(13)

0.84 eq (CO)5Cr

O

O

Ph Ph

HO

Ph

Ph

OH (23)b

THF, 75°, 17 h

100

Cr(CO)5 O O Ph Ph

HO 0.03 M +

O

+

O

Ph

(21)b

Ph

Ph Ph

Ph THF, 75°, 5 h

(CO)5Cr

O

O

Cr(CO)5

O

(22)b Ph

O

Ph (29)

0.84 eq

O

O

100

O

0.03 M

C17

O Cr(CO)5 Ph

Benzene, 80°, 12-24 h

TIPS Ph

•

TIPS

(CO)3Cr

(88)

134

OMe

1.2 eq

OMe

O Cr(CO)5

253

Ph

OMe

2. CAN

CH(Pr-i )OMe

n-Bu

213

O

1.2 eq

C18

(68) 0% de CH(Pr-i)OMe Bu-n

1. Silica gel, 75°, 2 h

O Cr(CO)5 n-Bu

O

O

Ph

OMe

(39) 0% de

1. Silica gel, 125°, 2 h

213

CHO Bu-n

2. CAN O

1.2 eq

O Cr(CO)5 213

1. Silica gel, temp, 2 h Ph

OMe

CH(t-Bu)OMe Bu-n

2. CAN

CH(t-Bu)OMe

n-Bu

O

1.2 eq Temp

% de

75°

(60)

47

50°

(40)

52

213

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C18

Refs.

OH Cr(CO)5 n-Bu

Ph

SOPh

OMe

1. Silica gel, 75°, 2 h

SOPh Bu-n

2. Air

1.2 eq

(44) 67% de

213

(—)

213

OMe

OH Cr(CO)5 1. Silica gel, 75°, 2 h n-Bu

Ph

SO2Ph

OMe

SO2Ph Bu-n

2. Air

1.2 eq

OMe

254

OTBS

Ph

OTBS Ph

Cr(CO)5

Ph

1. t-BuOMe, 55°, 1.5 h +

2. TBSCl, Et3N,

(CO)5W

OMe Ph 0.33 M

OMe

CH2Cl2, rt, 3 h

(CO)3Cr

(CO)5W

2 eq

370 (CO)3Cr

OMe

OMe

(CO)5W

OMe

(28)

OMe

(7)

OH

Ph

Ph Cr(CO)5 Benzene, 90°, 24 h Ph 1 eq

Ph

(3)

373

OMe OMe

0.04 M

Ph

O

C19 Cr(CO)5 1. Silica gel, 100°, 2 h n-Bu

CON(Pr-i)2

Ph

OMe

CON(Pr-i)2 Bu-n

2. CAN

1.2 eq

(44)

369

O O Cr(CO)5 1. Silica gel, 100°, 2 h Ph

NHBz

n-Bu

OMe

(44)

NHBz Bu-n

2. CAN

369

O

1.2 eq

NHBz

O

NHBz Cr(CO)5

(34)

1. Silica gel, 100°, 2 h Ph

OMe

n-Bu

2. CAN

369

Bu-n

255

O

1.2 eq

H

C20 HO

H Cr(CO)5 t-BuOMe, 45-55°, 1 h 3

Ph

3

OMe

0.29 M

1.15 eq

(CO)3Cr

(90)

262

Me OMe O

Cr(CO)5 Ph CH(OMe)Ph

n-Bu 1.2 eq

OMe

1. Silica gel, 100°, 2 h

CH(OMe)Ph Bu-n

2. CAN O

(0)

213

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C20

Refs.

O Cr(CO)5 1. Silica gel, 100°, 2 h n-Bu

N(Me)Bz

Ph

OMe

369

(50) N(Me)Bz Bu-n

2. CAN

1.2 eq

O NMeBz

O

NMeBz Cr(CO)5

(72)

1. Silica gel, 100°, 2 h Ph

OMe

n-Bu

2. CAN

369

Bu-n O

1.2 eq C21

O

256

Cr(CO)5 1. Silica gel, 80°, 12 h Ph

CON(Pr-i)2

Ph

OMe

2. CAN

Ph

CON(Pr-i)2

(0)

369

O 1.2 eq OH Sn(Bu-n)3

Sn(Bu-n)3

Cr(CO)5

TBSO

Ph 1.9 eq

183

(0)

THF, 65°, 4 h OMe

OTBS

0.03 M

OMe OH

OTBS

OTBS

OH

Cr(CO)5 I +

Additives, solvent, Ph TBSO

0.7-3.0 eq

OMe

II

151, 183

heat, 3-24 h

0.3 M

OMe OTBS

OMe OTBS

I

II

heptane

80°

1.0

0

(66)

(—)

heptane

80°

1.0

1.0

(68)

(—)

heptane

80°

1.0

1.0

(67)

(—)

heptane

80°

1.0

1.0

(63)

(—)

heptane

80°

1.0

1.0

(65)

(—)

heptane

80°

1.0

1.0

(66)

(—)

heptane

80°

1.0

1.0

(67)

(—)

heptane

80°

0

1.0

(30)

(17)

heptane

80°

0

0

(—)

(74)

heptane

40°

0

0

(48)

(—)

THF

65°

1.0

0

(29)

(—)

acetone

55°

0

0

(24)

(—)

heptane,

54°

1.5

1.5

(44)

(—)

56°

0

0

(51)

(26)

Temp Ac2O (eq) Et3N (eq)

Solvent

ultrasound

257

heptane, ultrasound C23

HO Cr(CO)5 Ph 3

1.15 eq

t-BuOMe, 45-50°, 1 h

+

3

OMe

0.29 M

(CO)3Cr

I

OMe HO

(CO)3Cr

3

OMe II

I + II (92), I:II = 63:37

262, 68

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C23

Refs.

O Cr(CO)5 OMe

Ph 3

1. t-BuOMe, 60°, 1 h

261

(48)

3

2. Ag2O/Et2O, 1 h

0.17 M

O

2.5 eq

O Cr(CO)5 OMe

Ph CH(Me)OTIPS

n-Bu

1. Silica gel, 100°, 2 h

(43) 60% de

CH(Me)OTIPS Bu-n

2. CAN

213

O

1.2 eq

O

258

Cr(CO)5 N(Bu-t)Bz

n-Bu

OMe

Ph

1. Silica gel, 100°, 2 h

369

O

1.2 eq C24

(0)

N(Bu-t)Bz Bu-n

2. CAN

TIPS

TIPS

TIPS

Cr(CO)5 THF, 90°, 24 h TIPS 0.05 M

1.0 eq

(69)

373

OMe

Ph

Ph

OMe

O

C25 OH

Ph

Ph Ph

HO Cr(CO)5

Ph MeO

Benzene, 80°, 24 h

(16)

OMe

Ph

MeO

0.05 M

3 eq

OMe

HO

Ph Ph

HO

Cr(CO)5

OMe

THF, 80°, 24 h OMe

Ph 3 eq

+

I MeO

100

100

HO

HO

Ph II MeO

+

OMe Ph

OH Ph Ph MeO O

III

Ph OMe

259

Alkyne (M)

I

II

III

0.1

(35)

(11)

(16)

0.05

(17)

(8)

(29)

0.006

(19)

(23)

(32)

C26 OH OTBDPS Cr(CO)5 Ph

MeO2C

OMe

OAc +

Et3N (1.5 eq), heptane, 80°, 19 h

151

CO2Me OMe

0.1 M

1.5 eq

OTBDPS

Ac2O (1.5 eq),

Ph2P

(7)

OMe

CO2Me (6)

Cr(CO)4

Cr(CO)5 Ph2P

Octane, 90°, 4 h

PPh2 Ph 1.2 eq

PPh2

OMe 0.06 M

OMe

(78)

374

TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C30

Product(s) and Yield(s) (%)

Refs.

O Cr(CO)5 n-Bu

CH(Me)OTBDPS

Ph

OMe

1. Silica gel, 100°, 2 h

CH(Me)OTBDPS Bu-n

2. CAN

1.2 eq

(67) 50% de

213

O

OH

Cr(CO)5

OBn

Heptane, 80°

BnO

Ph

TBSO

OTBS

OTBS

OMe 0.3 M

1 eq

Time

151, 183

OMe OTBS

260

Ac2O (1 eq)

3h

(85-89)

—

20 h

(0) R

C54

O

R Cr(CO)5 1. THF, 60° 2 d OMe Ph 0.008 M

n-Bu 1.25 eq

p-Tol

N

N

N

N

R=

Tol-p

p-Tol a

The carbene complex was added slowly.

b

Only one diastereomer was observed.

3-R (73)

2. PbO2, CH2Cl2

Bu-n O

4-R (75)

375, 376

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

C2

Product(s) and Yield(s) (%)

Refs.

OH OH

Cr(CO)5 THF, 45° Ph

I

OMe

0.07-0.13 M

OMe

Alkyne

Ph

+

I

II

2 eq

(1)

(36)

20 eq

(1)

(27)

1 atm

(2)

(34)

C3

OH

OH Ph

Cr(CO)5 Solvent, 45° Ph

131

II

+

I

131, 377,

II

OMe

245

261

0.07-0.2 M Alkyne

OMe I

II

(45)

(4)

Solvent

2 eq

THF

40 eq

THF

(10)

(44)

neat

—

(0.3)

(26-28)

O Cr(CO)5 saturated solution Ph

C4

OMe 0.25 M

1. (n-Bu)2O, 55°, 2 h

(66) O OH

O

261

2. AcOH, HNO3, 0.5 h

O

Cr(CO)5 (28-42)

THF, 65°, 5 h Ph 1.5 eq

OMe 0.03 M

70, 183

OMe

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C4 O

Cr(CO)5 OMe

OMe

THF, 65°, 6 h Ph

1.25 eq

Et

OMe 0.27 M

(n-Bu)2O, 45°, 2 h

Cr(CO)5 OEt Ph

262

4 eq

183

OMe OH

Cr(CO)5 Et Ph

(32)

OMe 0.08 M

1.5 eq

Refs.

O

OEt 0.25 M

Et2O, 0-4°, 24 h

(35) (CO)3Cr OMe OEt Ph (CO)5Cr

87

E:Z = 10:1

(48)

378

OEt OH OH

Cr(CO)5

OH

(0) + (CO)5Cr

1. THF, reflux, 16 h Ph 3 eq

OEt

O (38) 289

2. Air OEt OH

C5 O OEt 1.1-1.5 eq

Additive (1.1-1.5 eq), THF, Ph

OMe

Ph

CO2Et

Cr(CO)5

I

60-65°, 4-6 h

0.03-0.05 M

OMe

+

MeO RO2C

CO2R' II

I

R

R1

II

none

(41)

Et

Et

(9)

—

70

EtOH

(0)

Et

Et

(83)

6:1

379

t-BuOH

(0)

t-Bu

t-Bu

(16)

4:1

379

t-BuOH

(0)

Et

t-Bu

(35)

4:1

379

t-BuOH

(0)

Et

Et

(18)

3:1

379

(i-Pr)2NH

(0)

Et

N(Pr-i)2 (50)

Z >> E

379

Additive

E:Z

OH Cr(CO)5

Pr-n 1.2-1.5 eq

Pr-n

(n-Bu)2O or t-BuOMe,

(45)

45-50°, 2-5 h

Ph OMe 0.2-0.27 M

68, 87

(CO)3Cr OMe O

1. See table

Cr(CO)5

Pr-n

2. CAN Ph

OMe

I

Alkyne (eq)

CC (M)

Solvent hexane

O

Temp Time 45° 24-48 h

0.1-0.2 0.04

3

0.1-0.2

2

—

5

0.05

(n-Bu)2O 130°

5

0.05

THF

130°

263

3 1-1.5

(n-Bu)2O

rt

15 min

—

(80)

13

ultrasound

(67)

177

THF

45° 24-48 h

—

(73)

13

—

60°

silica gel

(51)

177, 178

300 s

microwave

(91)

192

300 s

microwave

(68)

192

10 min

n-Pr O

Ph

Cr(CO)5

1. MeCN, 45°, 24-28 h

3 eq Ph

OMe

O

I (53) +

O

(45)

Pr-n

13

2. CAN

0.1-0.2 M O Pr-n Cr(CO)5

1. Benzene, 80°, 16 h

3 eq Ph

2. CAN

OR

O n-Pr

I

+

Pr-n OR III

+

II O

CC (M)

R

Ph

O

I

II

III (11)

0.005

Me

(82)

(—)

0.1

Me

(78)

(1)

(8)

0.1

i-Pr

(90)

(<1)

(<5)

113

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

OH

Pr-n Pr-n

Cr(CO)5 Ph

OR 0.1 M

+

+

1. Benzene, 80°, 16 h

Pr-n 2 eq

Refs.

113

2. Air II

I OR

OR

O n-Pr

R

Pr-n OR

I

II

III

Me

(76)

(1)

(8)

i-Pr

(90) (≤1) (<5)

Ph

O III OR

264

I: R = H MeO O II: R =

Pr-n

Cr(CO)5 1. Solvent, 45-80°, 20-70 h

1.5-1.9 eq Ph

OMe

Ph

+

2. Air Pr-n

OMe O

OH

MeO O +

III

Pr-n O

+

n-Pr

V OMe

Pr-n

+ Ph Ph VI OMe

OMe Ph

+ OMe

O VII OH

Ph

Pr-n

O

IV

O

O n-Pr

+

MeO

O Pr-n

Ph

Pr-n

+ VIII

IX Pr-n

CC (M)

Solvent

I

II

III

IV

V

VI

VII VIII

IX

0.1

MeCN

(48)

(31)

(5)

(0)

(4)

(2)

(0)

(0)

(0)

13

0.1

THF

(84) (<1.5) (0)

(0)

(2)

(0)

(10)

(0)

(0.5)

60

0.005

THF

(62)

(0)

(0)

(12) (0)

(7)

(0)

(0.5)

60

0.1

benzene

(64) (<1.5) (0)

(0)

(1)

(0)

(4)

(10)

(1)

60

0.005

benzene

(59)

(0)

(0)

(0)

(1)

(0)

(8)

(5)

(3)

60

0.1

MeCN

(60)

(12)

(0) (<1.5) (9) (0.5) (19)

(0)

(2)

60

0.005

MeCN

(76) (<1.5) (0) (<1.5) (3)

(0)

(5)

60

—

hexane

(80)

(—) (—) (—) (12) (—)

78

(0)

(—)

(—)

(—)

(3)

OTBS

OTBS Pr-n

(CO)5Cr O Ph

4 eq

(1)

Pr-n

1. t-BuOMe, 58°, 2.5 h Cr(CO)3

+

2. TBSCl (4 eq), O

Et3N (4 eq), rt, 12 h

205

O

265

0.4 M I (17)

II (25) dr = 6.4:1

(CO)5Cr O

4 eq Ph

I (32) + II (25) dr = 6.1:1

TBSCl (2 eq),

205

EtN(Pr-i)2 (3 eq), CH2Cl2, 58°, 2.5 h

0.05 M O O

Cr(CO)5

HO

Et3N (x eq) Ph

Ph

OMe I

OMe

x

Solvent

Temp Time

I

Isomer ratioa

Ac2O (2 eq)

3

THF

reflux

7h

(26)

2:1

148

Ac2O (2 eq)

2

THF

reflux

7h

(40)

3:1

148

ultrasound

3

benzene

—

1.5

(35)

4:1

380

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

OH OEt OH

(CO)5Cr

OH 1. THF, 60°, 15 h

Ph

3 eq

(50)

289

2. Air OEt OH

O TMS

Cr(CO)5 (n-Bu)2O, 50°, 1.5 h

TMS Ph 1.7 eq

(76)

OMe 0.37 M

•

TMS

+

OMe (4)

+

57

•Cr(CO)3 Ph

OMe O

•

TMS OMe

266

Ph

(2)

Cr(CO)3

OTBS Cr(CO)5 4 eq

TMS

1. t-BuOMe, 55°, 1 h 2. TBSCl (4 eq),

Ph

OMe 0.4 M

(92)

73

(61)

169

Et3N (4 eq), rt, 3 h (CO)3Cr

OMe OH TMS

Cr(CO)5 4 eq

1. THF, 45°, 24 h Ph

OPh 0.04 M

2. Air OPh OH

Cr(CO)5 THF, 65°, 16 h OMe 2.8 eq

Ph

OMe 0.2 M

OMe OMe

(0)

183

OAc Cr(CO)5 OMe 2.3 eq

Ph

OMe 0.2 M

Ac2O (1.5 eq), Et3N (1.5 eq), heptane,

183

(43)

OMe

80°, 21 h OMe OH

C6

Bu-n

Cr(CO)5 (n-Bu)2O, 45°, 2 h

Bu-n Ph 1.25 eq

OMe 0.27 M

(45) (CO)5Cr

87

OMe OH Bu-n

Cr(CO)5 1.0 eq

(94)

THF, 65°, 2 h Ph

OMe 0.03 M

267

OMe

267

OR Cr(CO)5

Ac2O (1.1 eq),

I: R = Ac

Bu-n

Et3N (1.1 eq),

1.5 eq Ph

OMe

II: R =

O

+

OMe

381

THF, 65°, 3 h Bu-n Ph

OMe Bu-n

MeO

n-Bu

O

O

H

+

Pr-n

Pr-n

I (65), II (18), III (0), IV (0) Cr(CO)5

1. THF, 65°, 1 h 2. Ac2O (1.1 eq),

Ph

OMe

Et

O

III

OMe

1.5 eq

OAc

IV

OMe

I (56), II (0), III (10), IV (10)

381

pyridine, rt

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

Refs.

OAc Cr(CO)5 Bu-n

Ac2O (2.2 eq), Et3N (1.1 eq),

Bu-n

DMAP (0.16 eq), Ph

1.5 eq

OMe 0.1 M

I (68)

94

THF, 65°, 1 h OMe

Cr(CO)5 2.7 eq Ph

OMe 0.04 M

Ac2O (1 eq), Et3N (1 eq),

I (82)

267, 360

THF, 60°, 1 h O

Bu-n +

1.5 eq

1. Benzene, 40°, 22 h Et 1.5 eq

Et

O Bu-n

Cr(CO)5 Ph

OMe 0.1 M

I

Et +

II

361

Et

2. CAN O

O

268

I + II (78), I:II = 96:4 Cr(CO)5 1. Benzene, 40°, 22 h Ph

OPr-i 0.1 M

2. CAN

Cr(CO)5

1. THF, rt, 20 h

Bu-n

I + II (75), I:II = 99:1 O Bu-n

2. 50°, 2 h Ph

3 eq

OAc 0.1 M

361

(71)

172

(60)

169

3. CAN O OH Bu-n

Cr(CO)5 1. THF, 45°, 24 h

2 eq Ph

OPh 0.05 M

2. Air, 30 min OPh

OH Bu-t

Cr(CO)5 t-BuOMe, 45-50°, 2-5 h

Bu-t

Ph

1.5 eq

148

(79)

OMe 0.2 M (CO)3Cr

OMe OTBS

Cr(CO)5 4 eq

1. Solvent, 55°, 55 min

OTBS Bu-t

Bu-t

2. TBSCl (4 eq), Ph

OR* 0.4 M

I

+

II

204, 97

Et3N (4 eq), rt, 2 h (CO)3Cr

(CO)3Cr

OR*

OR*

269

R*

Solvent

I + II

dr

de

(–)-menthyl

t-BuOMe

(55)

10:1

82

(–)-menthyl

benzene

(50)

5.6:1

70

(–)-menthyl

pet ether

(52)

3.7:1

57

(+)-menthyl

t-BuOMe

(55)

1:9.2

80

(–)-8-phenylmenthyl

t-BuOMe

(65)

3:1

50

endo-(–)-bornyl

t-BuOMe

(65)

2.3:1

40

endo-(+)-fenchyl

t-BuOMe

(80)

7:1

75

(±)-1-phenylethyl

t-BuOMe

(71)

3:1

53

(±)-naphthylethyl

t-BuOMe

(51)

2.3:1

40

(±)-1-phenyl-2-methylpropyl

t-BuOMe

(45)

3:1

50

O HO

Cr(CO)5 Ph

i-Pr

OMe

O

Ac2O (2 eq), Et3N (3 eq), THF, reflux

Ph

I (33)b

148

i-Pr OMe

Cr(CO)5 Et3N (3 eq), ultrasound, Ph

OMe

I (20)c > 2 isomers

380

benzene, 1.5 h

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C6

Product(s) and Yield(s) (%)

Refs.

OH

3 eq

OH

Cr(CO)5

OH

1. THF, 60°, 15 h Ph

OEt

(40)

289

2. Air OEt OH

Cr(CO)5 TMS

TMS

1. THF, reflux Ph

0.83 eq

OMe 0.12 M

2. Air

Cr(CO)5

1. THF, rt, 20 h

C5H11-n

2. 50°, 2 h

270

Ph 3 eq

OAc 0.1 M

153

OMe O

C7 C5H11-n

(62)

(58)

172

3. CAN O OH

Cr(CO)5 t-BuOMe, 45-55°, 1 h Ph 1.2 eq

OMe 0.3 M

(60)

262

(CO)3Cr OMe OH Ph

Cr(CO)5 +

THF, 70°, 1.5 h 1.2 eq

Ph

OH OMe O

C8 Cr(CO)5 C6H13-n 3 eq

OAc 0.1 M

(24)

(41)

C6H13-n

1. THF, rt, 20 h

(47)

2. 50°, 2 h Ph

16

OMe

3. CAN O

172

O

Ph

C6H11-c

1. See table

Cr(CO)5

C6H11-c

191

2. CAN

OR O

Alkyne (eq)

R

Temp

Time

1.8

Me

(n-Bu)2O

70°

14 h

(72)

2.8

Me

silica gel

50°

4h

(68)

1.4

Me

ultrasound, THF,

—

25 min

(83)

1.8

Et

silica gel

60°

2h

(51)

1.4

Et

ultrasound, THF

—

40 min

(91) OAc Ph

1. Ac2O (2.2 eq),

Cr(CO)5 Ph

Et3N (2) eq),

271

Ph 2.7 eq

OMe 0.5 M

(93)

2. THF, 60°, 4 h

OMe OH *

Cr(*CO)5 2 eq

OH

OMe 0.1 M

*C =

13

*

Ph

THF, 45°, 21 h Ph

89

THF, 45°, 12 h

I

+

II

100

Ph

C OMe

OMe

I + II (87), I:II 179:1

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C8

Product(s) and Yield(s) (%)

Refs.

O Cr(CO)5

1. Microwave, solvent,

Ph

130°, 300 s

Ph Ph

OMe

192

2. CAN O

272

Alkyne (eq)

CC (M)

1

0.01

(n-Bu)2O

(68)

1

0.05

(n-Bu)2O

(88)

1

0.5

(n-Bu)2O

(65)

5

0.05

(n-Bu)2O

(91)

210

0.05

(n-Bu)2O

(47)d

1

0.01

THF

(70)

1

0.05

THF

(73)

1

0.5

THF

(64)

5

0.05

THF

(78)

1

0.05

toluene

(58)

1

0.05

CH2Cl2

(36)

1

0.05

MeOH

(50)

1

0.05

EtOH

(54)

1

0.05

HO(CH2)2OH

(58)

1

0.05

H2O

(0)

1

0.05

THF

(73)

1

0.05

Et2O

(82)

1

0.05

(n-Bu)2O

(88)

Solvent

I

Cr(CO)5 1. See table Ph

OMe

I

2. CAN

Alkyne (eq)

CC (M)

Time

I

3.0

0.1-0.2

—

THF

45°

24-48 h

(67)

13

3.0

0.1-0.2

—

hexane

45°

24-48 h

(57)

13

1-1.5

0.04

ultrasound n-Bu2O

—

10 min

(66)

177

2.0

—

silica gel

—

60-65° 90 min

(81)

177, 178

2.0

—

MgSO4

—

60-70° 90 min

(18)

177, 178

Solvent Temp

OMe Ph

Cr(CO)5 1 eq

1. THF, 48°, 12 h Ph

OMOM 0.2 M

(58)

100

(88)

169

2. NaH, Me2SO4 OMOM

273

OH Ph

Cr(CO)5 2 eq

1. THF, 45°, 24 h Ph

OPh

2. CAN

0.04 M

OPh

Cr(CO)5

O

THF, 60°, 12 h O

OMe

Ph

O

MeO

OH OMe

+

OMe

Ph

150 O

1 eq

OMe

OMe

(38)

(38)

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8

Refs.

O

OH

O

Cr(CO)5 Ph

OMe

Ph

Ac2O (2 eq), Et3N (3 eq),

(52) 3:2 mixture of isomersa

148

THF, reflux, 2.5 h OMe

I Cr(CO)5 Et3N (3 eq), ultrasound, Ph

OMe

I (36) 9:1 mixture of isomersa OH

O

380

benzene, 1.5 h O

Cr(CO)5 (0)

Hexane, 45°, 3 h

183

Ph OMe 0.1 M OMe

1.5 eq

274

OH Cr(CO)5

O

THF, 45°, 2-16 h

B Ph

O 3 eq

O B

O

(50)

75

OMe

0.05 M OMe

C9 TMS

TMS Ph

Cr(CO)5 Dioxane, 100°

n-Pr

Ph

OMe

OMe

I + 2 isomers (II and III)

154

n-Pr I + II + III (75), I:II:III = 56:25:19 OH

CF3

Cr(CO)5

1. Photolysis, 3-methylpentane, 95 K

Ph

OMe

CF3

(—)

2. 200-235 K (CO)3Cr

OMe

64

O Cr(CO)5

1. Microwave, solvent,

Solvent

130°, 5 min Ph 2 eq

OMe

2. CAN

0.05 M

THF

(75)

(n-Bu) 2O

(73)

192

O

C10

OH C8H15-n

Cr(CO)5 C8H15-n Ph 1.5 eq

OMe

(59)

t-BuOMe, 45-50°, 2-5 h

0.2 M

(CO)3Cr

OMe OR

OTBS

68

OTBS

Cr(CO)5 Ac2O (1.5 eq), Et3N (1.5 eq), Ph

OMe

0.3 M

1.5 eq

R = Ac (74)

I

183

heptane, 80°, 1 h

275

OMe

Cr(CO)5 1.5 eq

Heptane, 80°, 43 h

I R = H (0)

183

Ph OMe 0.3 M OH

C11

Ph

Cr(CO)5 Benzene, 45°, 12 h Ph OMe 2 eq

0.05 M

382

(76)

OMe

OMe OMe OAc

OAc Ph

Cr(CO)5 Ph OMe 2 eq

Ac2O (2.5 eq), Et3N (5 eq), OCD3

OMe

Ph

+

0.05 M

OCD3

382

OCD3

benzene, 45°, 12 h OMe

I

II

I + II = (53), I:II = 1:1

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) Cl

OH

Cl

Refs.

Cr(CO)5 Benzene, 45°, 12 h Ph OMe

+

I

382

OMe

OCD3 0.05 M

OCD3

2 eq

OH

Cl

Ph II OCD3 OMe

I + II (68), I:II = 1:1

OH

O

276

Cr(CO)5 Ph

OMe

Ph +

(25)

Dioxane, reflux

(45)

51

O

0.29 M

OMe

1.1 eq OMe

MeO

OMe OH

Cr(CO)5

O

O

O

O +

THF, 60°, 12 h Ph

OMe

O

OAc OMe

Ph

288

MeO

OAc

OAc 1.0 eq

O

O (34)

(43)

Ph Ph MeO2C CO2Me 1.3 eq

Cr(CO)5 O–Li+ 0.7 M

THF, reflux, 12 h

(66)

O MeO2C

CO2Me

383

C12 Cr(CO)5

OAc

O

OAc

OAc

OAc Ph

TMS

1. THF, 50-55°, 16-36 h

OMe

295

OMe TMS Ph Dioxane, 100°

Ph

(low)

CH2Cl2, rt, 16-24 h

Cr(CO)5 Ph

OAc

O

2. Ac2O, pyr, DMAP,

I + 2 isomers (II and III)

OMe

OMe

154

I + II + III (82), I:II:III = 63:20:17

Ph O

Cr(CO)5 Fe

Fe

1. THF, 65°, 2 d Ph OMe 0.58 M

1 eq

(71)

92

2. PbO2, CH2Cl2 O

C13

Ph

277

Cr(CO)5 Ts

N Ph 0.83 eq

OEt

1. MeCN, 70°, 1 h

(79)

O

2. 10% HCl

384

Ts N H

0.12 M O Cr(CO)5 Se

Ph

Se

See table. OR

179

NO2

NO2 O R

Solvent

Temp Time

Me

—

THF

heat

—

(18)

Et

—

THF

heat

—

(22)

Me

ultrasound

benzene

—

—

(0)

Et

ultrasound

benzene

—

—

(0)

Me

silica gel

—

55°

—

(27)

Et

silica gel

—

55°

—

(23)

Me

silica gel

—

rt

3d

(51)

Et

silica gel

—

rt

3d

(66)

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

Ph

C14

O Cr(CO)5 Ph Ph

OMe

(78)

Dioxane, reflux

51

0.29 M 1.1 eq O

Ph

OMe

O Cr(CO)5 Ph Ph

O Dioxane, 100°, 26 h

+

O

OMe 0.007 M

260 (2)

(52)

1.1 eq

278

OAc OTBS OTBS

Cr(CO)5 Ph

1.4 eq

OMe

Ac2O (1.5 eq), (47)

Et3N (1.5 eq),

151, 183

heptane, 80°, 1 h

0.3 M

OMe O

3

1.8 eq

CO2Et Ph

Cr(CO)5 OMe 0.11 M

3

1. THF, 45°, 24 h 2. CAN O

CO2Et

(25)

385

O

Ph Ph

Cr(CO)5 Ts

1. MeCN, 70°, 41 h

N

Ph OEt 0.12 M

2. 10% HCl

O

+

O Ts N

Ts N

(32)

0.83 eq

+

384

(25)

Ts N (12)

O OH Sn(Bu-n)3

Cr(CO)5 THF, 45°, 4 h

Sn(Bu-n)3 Ph 1.5 eq

(0)

183

OMe 0.4 M OMe

279

OTBS Cr(CO)5 4 eq

OTBS Sn(Bu-n)3

1. t-BuOMe, 55°, 1 h +

2. TBSCl (4 eq), Ph

OMe 0.4 M

+

73

Sn(Bu-n)3

Et3N (4 eq), rt, 3 h (CO)3Cr

(CO)3Cr OMe

OMe

(45)

(6)

OH

(15) Sn(Bu-n)3 (CO)3Cr Ph

C19 Ts

Ph

Cr(CO)5 1. MeCN, 70°, 41 h

N

Ph

OEt 0.12 M

OMe

Ts N

(69)

O

2. 10% HCl

384

0.83 eq

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

EtO

C21

Ph Ts

Ph

N

Ph

Cr(CO)5 1. Solvent, heat, 17-30 h OEt 0.12 M

Ts N

2. [FeCl4][FeCl2(DMF)3]

Ph +

O

+

Ts N

OEt

386, 387

II

I Ph

0.33 eq

O Ts

O

N

III

280

Solvent

Temp

I

II

III

THF

reflux

(22)

(9)

(22)

EtOH

70°

(21)

(14)

(21)

MeCN

70°

(14)

(16)

(7)

CH2Cl2

reflux

(27)

(0)

(22)

benzene

70°

(19)

(5)

(18)

toluene

70°

(0)

(17)

(27)

DMF

70°

(0)

(23)

(0)

i-PrOH

70°

(13)

(12)

(20)

70°

(13)

(3)

(12)

reflux

(20)

(0)

(20)

acetone THF, PPh3 (0.39 eq) C24

OAc OTBDPS OTBDPS

Cr(CO)5

Ac2O (1.5 eq), (32)

Et3N (1.5 eq), Ph 1.5 eq

OMe 0.1 M

heptane, 80°, 3 h OMe

151, 183

C49

R

O

R

Cr(CO)5 (72)

1. THF, 60°, 2 d Ph 1.25 eq

OMe 0.008 M

375, 376

2. PbO2, CH2Cl2 O O

Cr(CO)5

R

1. THF, 60°, 2 d R

Ph

1.25 eq

OMe 0.008 M

2. PbO2, CH2Cl2

375, 376

(74) p-Tol

O N

N

N

N

R=

Tol-p

281

p-Tol C52

R O N

N

Cr(CO)5

R

R N

Ph

N

OMe 0.04 M

Por (69)

1. THF, 60°, 2 d

376

2. DDQ, MeOH, reflux, 1 h O

4

R 0.8 eq

N

N

N

N

Por =

R=

TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C56

Refs.

OTBDPS OTBDPS Cr(CO)5

OTBDPS OTBDPS

O

Ph

OMe

1. THF, 50-55°, 16-36 h

OTBDPS

OAc

2. Ac2O, pyr, DMAP,

OTBDPS

O

(low)

295

CH2Cl2, rt, 16-24 h OMe OTBDPS

OTBDPS Cr(CO)5

OTBDPS O

OTBDPS

Ph

OMe

1. THF, 50-55°, 16-36 h 2. Ac2O, pyr, DMAP,

O

CH2Cl2, rt, 16-24 h

282

OMe a

Isomers were not specified.

b

Only one isomer of unreported configuration was obtained.

c

More than two isomers were obtained as products from this reaction.

d

The starting alkyne provided the solvent for this reaction.

OTBDPS

OAc

OTBDPS

(62)

295

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C4

Refs.

O OMe

1. THF, 45°, 24 h

1.5 eq

(68)

13

2. CAN

OMe Cr(CO)5

MeO

0.1-0.2 M

O O

OMe

3 eq

+

(3)

1. MeCN, 45°, 24 h

(9) +

2. CAN

OMe Cr(CO)5

MeO

0.1-0.2 M

OMe

MeO

O MeO O

+

(30)

283

OMe

(11) OMe

MeO C5

13

O

O Et

OMe

Et

1. THF, 45°, 24 h

OMe Cr(CO)5 0.3 M

1.5 eq

+

I

II

67

Et

2. CAN MeO

O

MeO

O

I + II (81), I:II = 1.5:1 O

MeO MeO OMe

OEt 4.3 eq 0.1 M

OMe Cr(CO)5

276

(22)

1. THF, 62°, 34 h OEt

2. CAN MeO

O

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

O

F

Refs.

O

Et Et

Et 1.5 eq

Cr(CO)5

F

OMe

0.3 M

1. THF, 45°, 24 h 2. CAN, MeOH

Et +

I F

Et

II

67

+

84

Et

MeO OMe

MeO OMe

I + II (70), I:II = 7.5:1 O

Et Et

2.0 eq

Cr(CO)5

1. THF, heat

I

Et

+

II

Et

2. CAN

OMe

OMe

O Et

284

III

Et O CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(87)

(<1)

(<1) (<1)

0.5

110°

30-40 min

(77)

(<1)

0.005

110°

1-2 h

(58)

(16)

(1)

0.001

110°

14 h

(37)

(17)

(<1)

R 2.0 eq

Cr(CO)5

1. Benzene, 80°, 16 h 2. CAN

OR 0.1 M

I + III

I

III

Me

(58)

(—)

i-Pr

(59)

(6)

113

O

Et Et

Cr(CO)5 CF3

1. Benzene, 80°, 16 h

+

I

2. CAN

OR

Et

II

+

113

Et CF3

0.1 M

O

Et CF3

O

CF3

Et

III R

OR

I

II

III

Me

(74) (—) (—)

i-Pr

(36) (20) (26)

O

Et Et

Cr(CO)5 OMe OMe

Et

+

1. Solvent, heat, additive Et

2. CAN

285

MeO

I

OMe

MeO

O Et

MeO

III

O

O

+

Et

+ II

MeO MeO

Et

IV

Et

Alkyne (eq)

CC (M)

Temp

Time

Additive

I

II

III

IV

2.0

0.5

THF

45°

24 h

—

(61)

(18)

(5)

(—)

84, 13

2.0

0.5

THF

45°

24 h

—

(70)

(—)

(—)

(—)

13

2.0

0.5

THF

45°

24 h

—

(72)

(—)

(—)

(—)

67

1.5

0.2

THF

45°

24 h

—

(55-65)

(18-26)

(4)

(<3)

67

3.4

0.1

THF

55°

34 h

—

(52)

(27)

(4)

(—)

13

3.4

0.1

THF

55°

48 h

PPh3 (1 eq)

(33)

(48)

(9)

(—)

13

1.7

0.1

THF

55°

48 h

PMe2Ph (1 eq)

(27)

(4)

(—)

(—)

13

2.0

0.1

THF

55°

43 h

OPPh3 (1 eq)

(32)

(50)

(6)

(—)

13

Solvent

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C6

Et

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Et

Refs.

I + II + III + IV (continued from previous page)

286

Alkyne (eq)

CC (M)

Solvent Temp

Time

Additive

I

II

III

IV

2.0

0.1

THF

55°

55 h

OPPh3 (1 eq)

(27)

(30)

(5)

(—)

13

2.0

0.1

THF

55°

48 h

Me2S (1 eq)

(39)

(43)

(4)

(—)

13

2

0.05

THF

45°

11 h

—

(46)

(42)

(1)

(3)

84

20

0.05

THF

45°

11 h

—

(84)

(5)

(1)

(2)

84

176

0.05

neat

45°

12 h

—

(91)

(<1)

(<1)

(—)

84

2

0.005

THF

45°

48 h

—

(5)

(66)

(9)

(—)

84, 13

200

0.005

THF

45°

37 h

—

(81)

(5)

(<1)

(5)

84

4

0.1-0.2

THF

45°

40 h

EtOCH=CH2 (4 eq) (58)

(—)

(—)

(—)

137

2

0.5

THF

110°

30 min

—

(29)

(53)

(10)

(—)

84

2

0.5

THF

110°

20 min

—

(26)

(54)

(10)

(—)

84

2

0.5

THF

110°

40 h

CO (1 atm)

(28)

(47)

(<1)

(—)

84

2

0.05

THF

110°

1h

—

(9)

(68)

(11)

(—)

84

20

0.05

THF

110°

1h

—

(38)

(46)

(7)

(—)

84

2

0.005

THF

110°

2h

—

(tr)

(65)

(10)

(—)

84

2

0.005

THF

110°

2h

CO (1 atm)

(8)

(62)

(10)

(—)

84

2

0.005

THF

110°

—

C5H6 (200 eq)

(0)

(73)

(12)

(—)

84

2

0.005

THF

110°

—

isoprene (200 eq)

(0)

(55)

(16)

(—)

84

200

0.005

THF

110°

12 h

—

(45)

(31)

(8)

(—)

84

2

0.5

THF

180°

5 min

—

(13)

(38)

(18)

(—)

84

2

0.5

DMTHF 45°

36 h

—

(88)

(6)

(tr)

(—)

84

2

0.005

DMTHF 45°

58 h

—

(28)

(52)

(2)

(—)

84

2

0.5

benzene 45°

24 h

—

(77)

(2)

(5)

(—)

84

2

0.005

benzene 45°

48 h

—

(21)

(—)

(37)

(—)

84, 13

2

0.5

benzene 110°

30 min

—

(29)

(6)

(37)

(—)

84

2

0.05

benzene 110°

13 h

—

(5)

(8)

(53)

(—)

84

287

2.0

0.005

benzene

110°

2h

—

(<1)

(3)

(68)

(—)

84

2.0

0.5

heptane

45°

—

—

(81)

(<2)

(<4)

(—)

84

2.0

0.5

heptane

110°

50 min

—

(54)

(9)

(35)

(—)

84

2.0

0.5

heptane

110°

25 min

—

(60)

(1)

(38)

(—)

84

2.0

0.5

heptane

110°

25 min

Ac2O (1.5 eq) (36)

(tr)

(30)

(—)

84

1.5

0.1-0.2

hexane

45°

24 h

—

(83)

(—)

(—)

(—)

13

2

0.5

MeCN

45°

24 h

—

(6)

(5)

(6)

(78)

84

2

0.05

MeCN

45°

24 h

—

(3)

(24)

(12)

(44)

84

2

0.005

MeCN

45°

48 h

—

(tr)

(31)

(25)

(25)

84

1.5

0.12

MeCN

45°

24 h

—

(<2)

(17)

(—)

(43)

13

3

0.1-0.2

CH2Cl2

45°

24 h

—

(65)

(—)

(—)

(—)

12,13

2

0.5

isoprene

45°

24 h

—

(80)

(—)

(4)

(—)

84

1.5

0.1-0.2

dioxane

45°

24 h

—

(70)

(—)

(—)

(—)

13

1.5

0.1-0.2

MeNO2

45°

24 h

—

(60)

(—)

(—)

(—)

13

1.5

0.1-0.2

MeOHa

45°

24 h

—

(51)

(20)

(—)

(—)

13

1.5

0.1-0.2

HMPA

45°

24 h

—

(12)

(21)

(—)

(29)

13

(16) +

13

O

O

Et Et

Cr(CO)5

3 eq

OMe OMe 0.1-0.2 M

1. DMF, 45°, 24 h

O MeO

+

(12)

Et

Et

2. CAN MeO

MeO

O Et (12)

Et O

MeO

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OTBS

C6

Et

Cr(CO)5

Et 4 eq

OMe OMe 0.4 M

Et

1. t-BuOMe, 55°, 1 h 2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h

Et

(63)

73

MeO OMe (CO)3Cr Et

3 eq

Cr(CO)5 OMe OMe 0.1-0.2 M

Et

1. DMF, 45°, 24 h

MeO MeO

O +

I

II

OMe

MeO

Et

Et

I

II

air

(5)

(25)

air, S8

(19)

(28)

Oxidant

288

Et

CO2Me

1. UV photolysis, Cr(CO)5

1.5 eq

OMe OMe

13

2. Oxidant

THF, 15°, 2 h

Et +

I (49) +

MeO

13

2. Air, silica gel MeO

0.02 M

(2)

(2)

Et

Et Et +

+ MeO

Et MeO

(5)

O (4)

O Et OMe

1.2 eq MeO

Cr(CO)4

(58)

1. THF, 45° Et

2. CAN MeO

O

13

O

R

O

Et 1.5 eq

Cr(CO)5

R

+

I

2. CAN, MeOH

OMe

0.3 M

Et

1. THF, 45°, 24 h R

II

Et MeO OMe

MeO OMe

R

I + II

I:II

Me

(79)

1.2:1

OMe

(81)

2.1:1

CF3

(55)

25.5:1

(70)

7.5:1

F

O

OMe O Et

2 eq

Cr(CO)5

MeO

1. THF, heat

Et +

I

2. CAN

MeO

II

289

O I:II

O Temp

84

Et

Et

OMe CC (M)

67

Et

Time

I + II

0.5

45°

16-24 h

(94)

2:1

0.5

110°

30-40 min

(94)

1.6:1

0.005

110°

1-2 h

(94)

1.3:1

O

R2 R2 Cr(CO)5

2 eq

113

2. CAN

OR1

0.1 M

Et

1. Benzene, 80°, 16 h Et O

R1

R2

Me

Br

(93)

i-Pr Br

(98)

Me

CF3

(96)

i-Pr CF3

(99)

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C6

Carbene Complex

Conditions

Product(s) and Yield(s) (%) O

RO Et

Et Et

RO

Et

Cr(CO)5

+

1. Solvent, heat 2. CAN

1.5-2 eq

RO +

Et

Et

OMe

O

OMe

I Et

RO Et III R

Refs.

Et

OMe

Et

O

II

+

O

OR IV

290

CC (M)

Solvent

Temp

Time

I

II

III

IV

Me

0.12

hexane

45°

1-2 d

(80)

(—)

(—)

(—)

13

Me

0.12

MeCN

45°

1-2 d

(44)

(19)

(—)

(4)

13

Me

0.5

THF

110° 3-40 min

(85-93)

(—)

(—)

(—)

84, 13

Me

0.5

THF

110° 3-40 min

(88)

(—)

(—)

(—)

84

Me

0.005

THF

110°

1-2 d

(64)

(—)

(—)

(—)

84

Ac

0.5

THF

45°

16-24 h

(94)

(—)

(—)

(—)

84

Ac

0.5

THF

110° 30-40 min

(80)

(—)

(—)

(—)

84

O

Et Et

Cr(CO)5

2 eq MeO

OMe

1. THF, heat

Et

+

2. CAN

+

84

Et MeO

O

OMe I

MeO Et Et O

MeO

II Et

III

+

Et OMe

IV

CC (M)

Temp

Time

I

II

III

IV

0.5

45°

16-24 h

(74)

(tr)

(—)

(—)

0.5

110°

30-40 min

(59)

(17)

(—)

(9)

0.005

110°

1-2 h

(6)

(37)

(16)

(5)

O Et 2 eq

Cr(CO)5

MeO

OMe OMe CC (M)

+

1. THF, heat MeO

2. CAN Temp

I

OMe O II

0.5

45°

16-24 h

(45)

(14)

0.5

110°

30-40 min

(37)

(—)

0.005

110°

1-2 h

(<4)

(—)

OMe

OMe 84

Et

Time

OMe

O

O Et

I

Et

II

OTBS Et

1. t-BuOMe, 55°, 1 h

291

4 eq

Cr(CO)5

MeO

OMe OMe 0.4 M

2. TBSCl (4 eq),

(70)

Et3N (4 eq), rt, 3 h

MeO

73

Et OMe OMe Cr(CO)3 O

MeO MeO Cr(CO)5 OMe OMe

Et MeO

Et

1. THF, heat 2. CAN

+

Et

I

II

Et

OMe

OMe O

O

84

Et

MeO Et

+

CC (M)

Temp

Time

I

OMe II

OMe

0.5

45°

16-24 h

(83)

(<2)

(<2)

0.5

110°

30-40 min

(15)

(19)

(34)

0.005

110°

1-2 h

(<2)

(54)

(<2)

III

III

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C6

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

MeO Et

Et

OMe

2-3 eq MeO

1. Solvent, 45°

I + II + III

2. CAN

Cr(CO)4

CC (M)

Solvent

0.03

t-BuOMe

0.005

THF

Time

I

II

III

8h

(20)

(—)

(—)

276

48-72 h

(24)

(31)

(<2)

84

O

AcO Cr(CO)5

2 eq

OMe OMe

Et AcO

Et

AcO

Et

+

1. THF, heat

84

Et

2. CAN

292

OMe

I

OMe O

O

II

Et AcO +

Et III OMe

CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(60)

(tr)

(10)

0.5

110°

30-40 min

(35)

(8)

(42)

0.005

110°

1-2 h

(—)

(12)

(70)

OMe

OTBS Et

1. t-BuOMe, 55°, 1 h 4 eq

Cr(CO)5 OMe 0.4 M

(92)

2. TBSCl (4 eq), Et

Et3N (4 eq), rt, 3 h OMe

Cr(CO)3

73

OMe

OMe OH

OMe

1. THF, heat

2 eq

Cr(CO)5

Et

Et +

I

2. Oxidant

Et

OMe OMe

OMe OMe

OMe

Et

Et

Et III +

Temp

Time

0.5

45°

16-24 h

0.005

45°

48-72 h

Et

OMe

OMe CC (M)

0.5

IV

II

III

air

(52)

(<2)

(<2)

(9)

air

(<4)

(<7)

(20)

(43)

293

(11)

(tr)

(31)

(46)

FeCl3-DMF

(<1)

(<1)

(34)

(54)

1-2 h

OMe

IV

OMe

OMe

I

Oxidant

110° 30-40 min FeCl3-DMF 110°

84

O

OMe

OMe

0.005

+

II

Et

OMe OTBS Et

1. t-BuOMe, 55°, 1 h 4 eq

Cr(CO)5 OMe OMe

(67)

2. TBSCl (4 eq),

73

Et

Et3N (4 eq), rt, 3 h

0.4 M

OMe OMe Cr(CO)3 Et

Et 2 eq

Cr(CO)5 OMe

Et I

1. Benzene, 110°, 13 h 2. Air

(CO)3Cr

OMe

1.0 M

Et

+

II

242

OMe

I + II (100), I:II = 65:35 OTBS

Cr(CO)5 MeO

4 eq

OMe 0.4 M

MeO

1. t-BuOMe, 55°, 1 h

MeO

Et

MeO

Et

(73)

2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h

73

OMe Cr(CO)3

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C6

Carbene Complex

Conditions

Refs.

Et

HO Et

Product(s) and Yield(s) (%)

O

Et

Cr(CO)5

2 eq

Benzene, 110-125°

OMe

(75)

243

Et

(37)

243

OMe

0.5-1.0 M O

HO 2 eq

Et

Cr(CO)5

O

(i-Pr)2NEt (0.1 eq), MeCN, 60°, 29 h OMe

OMe

0.5-1.0 M

Et

O

Et Et

294

Cr(CO)5

2 eq R

+

Et

2. CAN

OMe

Et

+

1. THF, heat R

O

I

OMe

R

II

Et Et R

O

O

OMe

Et

Et

R

+ III

IV

CC (M)

Temp

Time

I

II

III

IV

CH2CH2OMe

0.5

45°

16-24 h

(82)

(—)

(—)

(—)

84

CH2CH2OMe

0.5

110°

30-40 min

(76)

(tr)

(—)

(—)

84

CH2CH2OMe

0.005

110°

1-2 h

(50)

(22)

(4)

(—)

84

OBu-t

0.5

45°

16-24 h

(96)

(<1.3)

(—)

(—)

84

OBu-t

0.5

110°

30-40 min

(52)

(21)

(6)

(—)

84

OBu-t

0.005

110°

1-2 h

(7)

(54)

(8)

(—)

84

OBu-t

0.12

45°

1-2 d

(72)

(<6)

(—)

(—)

13

R

Cr(CO)5

2 eq t-BuO

0.12 M

OMe

1. MeCN, 45°, 1-2 d

I (24) + II (18) + III (—) + IV (23)

Bu-n OAc

OAc Et

Ac2O (1.1 eq), 2.8 eq

Cr(CO)5

n-Bu 0.03 M

OMe

13

2. FeCl3-DMF

Et +

(26)

Et3N (1.1 eq), Et

THF, 65°, 5 h

n-Bu

OMe TMS

(9)

12

II

84

Et

Et

Cr(CO)5

267

OMe

OTMS

TMS

(26) Et

THF, 45°

Et

+

(0) Et

OMe OMe

OMe

OMe OMe

OMe

295

O

Et Et

Cr(CO)5

2 eq t-BuO

OMe

1. THF, heat

Et

I +

2. CAN

Et OMe

O

t-BuO

t-BuO Et

+

III

Et OMe

CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(87)

(—)

(—)

0.5

110°

30-40 min

(71)

(—)

(—)

0.005

110°

1-2 h

(44)

(13)

(8)

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

Et

HO Et

Refs.

O OMe

Et 2 eq

Et

Benzene, 90°, 4 h

Cr(CO)5

(60)

243

(58)

98

(41)

98

(44)

98

OMe

0.5 M

(CO)5Cr

Et

OMe

1.8 eq

MeO

Et

1. THF, 60°, 20 h OH

2. O2, Et2O, rt 0.05 M

296

(CO)5Cr

Et

OMe

O

Et

1. THF, 60°, 9 h

1.6 eq

O

2. CAN 0.05 M (CO)5Cr

Et

OMe

1.5 eq

O

Et

1. Silica gel, 60°, 5 h

O

2. CAN Br (CO)5Cr

Br OMe

2 eq

MeO

Et

Et2O, rt 2. FeCl3-DMF

Et

+

2. Ac2O, Et3N, DMAP,

0.1 M

(CO)3Cr Et MeO

Et 1. THF, 60°, 5 h

OAc (59)

98 OAc (6)

(CO)5Cr

Et

OMe

MeO

1. THF, 60°, 5 h

Et (63)

2. Ac2O, Et3N, DMAP,

2 eq

Et2O, rt 0.2 M

98

OAc

3. FeCl3-DMF

Br

Br Et (CO)5Cr

MeO

OMe

Et OH

10 eq

1. Silica gel, 60°, 6 h

(31)

HO

98

2. O2, Et2O, rt (CO)5Cr

Et

OMe

OMe Et

297

(CO)5Cr OMe

OTBS OTBS

1. t-BuOMe, 50° 2. TBSCl (10 eq),

3 eq

O

Et

O

Et

+

388

Et3N (10 eq), rt, 12 h

O

Et Et

0.04 M

(CO)3Cr

OMe

(30)

OMe

(39)

O Et

Cr(CO)5 10 eq Me Me

(48)

1. Hexane, reflux, 1 h Si

O

86

Et

2. CAN O

OBu-n

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C6 Et

MeO

Cr(CO)5 Et

Et

1. THF, 55°, 3 h

Et OMe

4 eq

(34)

208

OTBS

2. TBSCl, Et3N, rt, 3 h (CO)3Cr

0.05 M (CO)3Cr MeO +

Et Et

(18)

OTBS Et OMe

1.3-1.5 eq

298

MeO

Et

Toluene, 70°, 0.75-3 h

203

Cr(CO)3 0.04 M

CNR

(CO)2(RNC)Cr

OMe

OMe

R 2,6-Me2C6H3

(68) (48) Et TBSO

Cr(CO)5

Et Cr(CO)5

OMe OMe 5 eq

OMe

OMe OMe

1. THF, 66°, 2 h

OMe 0.1 M

Cr(CO)5

(29) 1.4:1 mixture of isomers

OMe

2. TBSCl, Et3N, rt, 2 h

OMe Cr(CO)5 TBSO

Et Et

209

Et O

Cr(CO)5

Et

OMe

O

OMe

1. THF, reflux, 2 h

OMe

OMe

2. CAN

OMe

OMe

209

O

Cr(CO)5

0.1 M

(56)

O

Et Et O

O R

1. THF, 45°, 24 h

R

Cr(CO)5 1.5 eq

+

I

2. CAN

13, 67

II R

0.3 M

299

OMe OMe

OMe O

OMe O

R

I + II

I:II

n-Pr

(64)

2.9:1

i-Pr

(61)

4.8:1

O

O OMe

Cr(CO)5

OMe

1. Hexane, reflux, 1 h

+

2. CAN

MeO

O

CF3

C7

86

OMe O I I + II (79), I:II = 1:2.5

II

CF3 NEt2

Et2N

Hexane, 20°, 0.5 h 1 eq MeO

(67)

Cr(CO)5

Cr(CO)5

141

MeO

0.075 M

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8

EtO2C

CO2Et

OMe

(CO)5Cr

MeO

CO2Et

CO2Et (2)

1. THF, 60°, 17 h

2.1 eq

Refs.

0.04 M

98

OH

2. Air, Et2O, rt O

Pr-i Pr-i

i-Pr

Cr(CO)5

Pr-i

Pr-i

+

1. THF, 45°, 70-115 h Pr-i I

2. CAN

OMe OMe

MeO

O

OMe

MeO

Pr-i

300

Pr-i O

MeO

III

O

+

84

II

MeO MeO

+ i-Pr

Pr-i

Alkyne (eq)

CC (M)

I

II

III

IV

20

0.05

(29)

(36)

(9)

(11)

2

0.5

(21)

(43)

(8)

(12)

IV

O MeO

MeO Cr(CO)5

2 eq 0.5 M

OMe

Pr-i (83)

1. THF, 45°, 44 h

84

Pr-i

2. CAN O Pr-i

Cr(CO)5

2 eq

OMe 0.5 M

Pr-i

1. Benzene, 110-130°, 34 h 2. FeCl3-DMF

OMe

(79)

242

HO TMS

Pr-i

HO

Pr-i

Cr(CO)5

2 eq

2,6-di-tert-butylpyridine (1 eq),

(51)

243

benzene, 110-125°

OMe

O

0.5 M

O

O

• OMe TMS

TMS

TMS

TMS

n-Bu2O, 2 h, 50°

(CO)5Cr

1.25 eq

• TMS

MeO

R

0.4 M

TMS

+

57. 365

MeO I

R

R

(CO)3Cr R

I

II

CF3

(0)

(41)

Me

(43)

(27)

OMe

(—)

(—)

301

C9

II

O Ph Cr(CO)5

Ph 1.5 eq

OMe OMe

1. THF, 45°, 24 h

(78)

67

2. CAN OMe O

0.3 M

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C9

O Ph

1. Solvent, heat, 2-24 h OMe

Ph 2 eq

MeO

Cr(CO)4

Refs.

O

additive

+

IA

IB

+

OMe O

OMe O

Ph

Ph IIB +

IIA + OMe Ph

OMe

OMe

OMe

Ph IIIB +

IIIA +

302

O

OMe

OMe

Ph

O

IV

MeO MeO O CC (M)

Solvent

66

Ph

2. CAN

Temp Additive

I

A:B

A:B

III

A:B

IV

0.5

THF

45°

none

(70)

38:1

(13) 1.1:1

II

(1)

1.0:1

(7)

0.005

THF

45°

none

(23)

49:1

(53) 1.1:1

(11)

1.1:1

(0)

0.5

THF

45°

PPh3 (2 eq)

(29) ≥27:1

(24) 1:1.5

(4)

1.6:1

(15)

0.005

THF

45°

PPh3 (2 eq)

(13) ≥35:1

(67) 1.2:1

(6)

1.2:1

(2)

0.05

DMTHF

90°

none

(34)

18:1

(59) 1.3:1

(3)

1:1.1

(—)

0.005

DMTHF

90°

none

(5)

18:1

(74) 1.4:1

(9)

1:1.1

(—)

0.05

DMTHF

90°

PPh3 (2 eq)

(17)

16:1

(69) 1.3:1

(2)

1:1.1

(—)

0.005

DMTHF

90°

PPh3 (2 eq)

(8)

19:1

(81) 1.3:1

(5)

1:1.6

(—)

O 1. Microwave, (n-Bu)2O, 2 eq

Cr(CO)5

Ph

130°, 300 s

(54)

192

2. CAN

OMe

O

0.05 M

Ph

HO

O

O Cr(CO)5

Ph

+

Benzene, 110-125°

OMe

OMe

OMe (17)

(61)

0.5-1.0 M

OMe

OMe OMe

243

HO Cr(CO)5

Benzene, 100°, 8 h

O

HO +

TMS

243 TMS

OMe

TMS

303

2 eq

0.5-1.0 M

(40)

OMe

R1

R2

R1

O

1. Solvent, 45°, 24 h Cr(CO)5

O

O

+

O

O

103

2. CAN

R2 OMe 0.2-0.4 M

1.5-2 eq

(4)

OMe

R1

R1

R2

Solvent

CF3

H

OMe

H

OMe

O

R2

I I

II

THF

(25)

(17)

THF

(48)

(21)

H

benzene

(53)

(25)

OMe

H

n-heptane

(57)

(20)

OMe

H

DMTHF

(56)

(24)

OMe

OMe

THF

(27)

(—)

O

II

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C10

Pr-i i-Pr

Pr-i Cr(CO)5 1 eq

Me

Cr(CO)5

2 eq

100

Pr-i

OR

OR 0.03 M

C5H11-n

(53)

n-Bu (65)

C5H11-n

1. Benzene, 110-145°, TMS

R

THF, 50°, 16 h

TMS

33-39 h 2. FeCl3-DMF

OMe 0.5 M

TMS

(78)

OMe

C5H11-n

+ OMe

R1

HO 2 eq

Cr(CO)5

304

+ R2 (8)

benzene, 110-125°

0.5 M

OMe

pentyl-n

HO

O 2,6-Di-tert-butylpyridine (1 eq),

243 (63) O

OMe

C11

242

(6)

1 : 1 mixture R1 = TMS (n-C5H11); R2 = n-C5H11 (TMS) TMS

Cr(CO)5

Ph

1. THF, 45°

Complex mixture

146

2. CAN

OMe OMe

O Ph Me3Sn

Cr(CO)5

Ph

1. THF, 45°

(20)

146

2. CAN

OMe OMe

t-Bu OMe O

C12

O

Bu-t n-BuO

Cr(CO)5 t-Bu

Bu-t 1 eq

t-Bu

1. THF, 50°, 16 h OBu-n

+

2. CAN

Bu-t

0.03 M (6)

O

100 O (72)

C13 Cr(CO)5 O OMe

TMS O OMe

0.94 eq

1. Dioxane, 60°, 32 h

(47)

O O F Ph

F Ph

OMe

0.025 M

C14

Cr(CO)5

Ph 1.2 eq

F

270

O

2. Iodine

F •Cr(CO)3 Ph +

(n-Bu)2O, 100°, 1 h

OMe

126

F MeO

OMe 0.2 M

•Cr(CO)3

F Ph

O (30)

(—)

OH

R

R Cr(CO)5

1.6 eq

R

Ph

(n-Bu)2O, 45-60°, 2 h

305

Ph

OMe

Me

(40)

CF3

(25)

104

(CO)3Cr OMe

0.1-0.2 M

O Ph

1. Ultrasound, (n-Bu)2O, Cr(CO)5

1-1.5 eq

177

Ph

2. CAN

OMe 0.04 M

O

Cr(CO)5

1.4 eq

I (69)

20 min

1. Silica gel, 50°, 3 h

I (70)

177, 178

2. CAN

OMe

OH Ph Cr(CO)5

3 eq

1. THF, 45°, 36 h

(76)

OPh 0.02 M

169

Ph

2. Air, 30 min OPh

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

Ph Ph

Cr(CO)5

Ph 2 eq

OMe

Ph

Ph

Solvent, 100-110°, 2-20 h

0.5 M

OMe

+ OMe Cr(CO)3

I

Solvent

I + II

I:II

(n-Bu)2O

(52)

65:35

benzene

(96)

55:45

2 eq

Cr(CO)5 OMe

Ph

HO

O Solvent, 100-125°

II 241, 242

Ph

HO

Refs.

Ph

Ph

+

Ph

243

additive OMe

OMe

I

0.5-1.0 M

306

Solvent

Additive

I + II

I:II

benzene

none

(88)

49:51

THF

none

(64)

38:62

MeOH

none

(74)

46:54

benzene

2,6-di-tert-butylpyridine (76)

72:28

benzene

pyridinium tosylate

(39)

92:8

II

OH Ph 1.1 eq Cr(CO)5 OMe

Cr(CO)3 Ph

(n-Bu)2O, 70°, 2.5 h

Cr(CO)5

OMe Ph

OMe (n-Bu)2O, 60°, 2.5 h

Cr(CO)3 (19) Ph

0.3 M

104

OMe

0.3 M

1.3 eq

(21.5)

OH

104

(CO)5Cr

Ph

OMe

MeO

Ph X

1. THF, 65°, 16 h

1.8 eq

OH

2. O2, Et2O, rt

H

(50)

Br

(32)

98

0.07 M

X

X

(CO)5Cr

OMe 1. THF, 60°, 4 h

2 eq

Ph

MeO

Ph

2. Ac2O, Et3N, DMAP, 0.1 M (CO)5Cr

98

(39)

389

(51)

98

3. FeCl3-DMF Ph

OMe

O

1 eq

Ph

1. (n-Bu)2O, 45°, 4 h O

2. HNO3

307

(50) OAc

Et2O, rt

0.1 M (CO)5Cr

Ph

OMe

O

1.4 eq

Ph

1. Silica gel, 60°, 6 h

O

2. CAN Br

Br (CO)5Cr

1.1 eq

OMe O

Ph Cr(CO)3 Ph

HO

(30)

1. (n-Bu)2O, 50°

0.2 M

+

OMe

2. TBSCl, Et3N, rt

TBSO

O

Ph Cr(CO)3 Ph

388 (1)

OMe O

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C14

Ph

Ph

EtO Cr(CO)5

2.2 eq

OH

OEt

(CO)5Cr THF, 45°, 3.5 h

Ph

(CO)5Cr

(42) (CO)3Cr

OEt

0.09 M

391

Ph

OEt

OEt

OEt Ph

(CO)5Cr

OH

(s-Bu)2O, 50°, 2.5 h

2.0 eq

Ph

Ph OEt

0.08 M

(CO)3Cr

OH

391

Ph (CO)3Cr

308

Cr(CO)5 OMe Cr(CO)5

(51)

OMe

OEt

OEt

OEt Ph 1.2 eq

(32) β:α = 1.9:1.0

1. Heptane, 76-80°, 1 h

MeO2C

MeO2C

0.08 M

(CO)3Cr Cr(CO)5 Ph

OMe

TBS OMe

390

Ph

2. Air, 40 h

O TBS

• Benzene, 80°, 12-24 h

+

TBS OMe

MeO

Ph MeO OMe

(57)

(12)

134

C14

(CO)3Cr

O

MeO Ph

TBS

• Cr(CO)5

TBS

MeO +

TBS

Benzene, 80°, 12-24 h MeO

OMe

Ph OMe

(CO)3Cr OMe

(53)

(18)

O Ph

O

Ph

O B

Cr(CO)5

1. THF, 65°

O 3 eq

B

2. CAN

OMe

Ph +

O

75

O

O (45)

0.05 M

134

O

(15)

OMe (CO)5Cr

309

1. Dioxane, reflux, 24 h TMS

O

CO2Me

(40)

O

270

O

2. Iodine

O

CO2Me

O 0.05 M

0.84 eq C15

O

OH

O Cr(CO)5

OMe 3 eq

(40)c one isomer

1. THF, 55°, 14 h

90

2. CAN

OMe OMe 0.02 M

OMe O OH

C16

Ph Ph

Cr(CO)5

Ph 1 eq

R

THF, 50°, 16 h

0.03 M

OR

OR

Me

(61)

n-Bu

(82)

100

Ph

TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C16

Carbene Complex

OTBS

Conditions

Product(s) and Yield(s) (%)

OBn

OBn OH

(53) OBn OMe OTBS (CO)3Cr

C17

TIPS

O •

(CO)5Cr Ph

R TIPS

Benzene, 80°, 12-24 h

MeO

298

MeO

0.17 M OBn Cr(CO)5

OTBS

OTBS

Ac2O (1 eq), THF, 50°, 17 h

OMe

MeO

3 eq

Refs.

3-MeO (84)

R MeO C23

134

4-MeO (87) R

310

HO OH

(CO)5Cr

Pr-i

Pr-i Pr-i

OMe

OMe

THF, 75°, 40 h OMe 1 eq C26

Pr-i

PPh2 1.2 eq

100

0.03 M Ph2P

R Ph2P

(32)

MeO HO

R Cr(CO)5 OMe

Cr(CO)4 PPh2

Octane, 90°, 4 h

R Me

(85)

CF3 (74) OMe

374

C26

Ph2P

OEt (CO)5Cr Ph2P

PPh2

EtO

MeO

PPh2

Cr(CO)4

1. Heptane, reflux, 4 h 2. Air

1.2 eq

MeO

(7)

MeO

+

(30)

390

CO2Me CO2Me

0.03 M

C32

CO2Me OH

OH

Ph

Cr(CO)5 OBu-n

Ph

Ph OBu-n

1. THF, 67°, 3 d OBu-n

0.04 M

311

BnO MOMO

TBSO

MOMO

Cr(CO)5

MeO 0.5 eq

MOMO

OMe

N

80°, 2 d

0.2 M

(48)

MOMO

EtO MOMO

MeO MOMO

a

OMe OTBS

R

BnO TBSO Cr(CO)5 OMe

0.34 eq R=

Oxidation was carried out using FeCl3-DMF.

b

The product was a single isomer.

c

The carbene complex was recovered in 30% yield.

0.5 M

N

BnO HO TBSO

Heptane, 50°, 47 h Additive Ac2O (1.5 eq) —

268

MeO

OMOM

OTBS

BnO HO TBSO

Ac2O (1.5 eq), heptane,

OTBS EtO

100

Ph

0.77 eq

C 42

(48)c

OBu-n

2. 85°, 1 d

269 MeO MOMO

OMe OTBS

(35) (0)

3:1 mixture of diastereomers

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C3

Refs.

OH Cr(CO)5

OH 2 eq 0.22 M

OH

t-BuOMe, 45°, 2-4 h

(60)

147

OMe OMe OMe

OMe OMe Cr(CO)5

1.5 eq

Ac2O (2 eq), Et3N (3 eq),

OMe OMe 0.009 M

I (45) one isomer

O

OMe

THF, reflux, 4.5 h

148

O

OMe Cr(CO)5

312

2.2 eq

I (41) one isomer

O

OMe

Et

1. THF, rt, 20 h Et

Cr(CO)5

3 eq

2. 50°, 2 h

(35) OMe O OMe

OMe Cr(CO)5 OH

Ac2O (2 eq), Et3N (3 eq), THF, reflux, 3.5 h

OMe OMe

OMe OMe O

0.01 M

(48) >2 isomers

148

>2 isomers

380

O

OMe

OMe Cr(CO)5

2.2 eq

172

3. CAN

OAc 0.01 M

1.5 eq

380

benzene, 3 h

OMe OMe 0.01 M

C4

Ultrasound, Et3N (3 eq),

Ultrasound, 1-4 h

OMe OMe 0.01 M

OMe OMe O

313

Solvent

Ac2O

Et3N

THF

0 eq

0 eq

(55)

THF

0 eq

3 eq

(0)

THF

1.5 eq

0 eq

(0)

THF

2 eq

3 eq

(0)

(n-Bu)2O

0 eq

0 eq

(29)

(n-Bu)2O

0 eq

3 eq

(27)

(n-Bu)2O

1.5 eq

0 eq

(0)

(n-Bu)2O

2 eq

3 eq

(25)

benzene

0 eq

0 eq

(20)

benzene

0 eq

3 eq

(89)

benzene

1.5 eq

0 eq

(0)

benzene

2 eq

3 eq

(72)

O

OH

2.0 eq

O

OH

OH

Cr(CO)5

t-BuOMe, 45°, 2-4 h

+

0.22 M OMe

p-Tol

(17)

OMe

O

MeO

+ O

Cr(CO)5

147

(33)

(—)

O Cr(CO)5 OMe t-BuOMe, 45°, 2-4 h

2.0 eq

O

MeO

MeO

MeO

(46)

0.22 M

+ O

OMe OMe

Cr(CO)5

(—)

147

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) O

C5

Refs.

Pr-n Pr-n

Cr(CO)5

Pr-n

1. THF, heat

2 eq

+

I

2. CAN

OMe

II

+

84

O

O

CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(59)

(—)

(—)

0.5

110°

30-40 min

(55)

(—)

(—)

0.005

110°

1-2 h

(77)

(—)

(7)

O

O

III OMe

n-Pr

314

Cr(CO)5

2 eq

I +

+

II

113

Pr-n O

2. CAN

OR R

1. Benzene, 80°, 16 h

IV

CC (M)

I

II

Me

0.1

(66)

(—)

(3)

i-Pr

0.1

(66)

(—)

(—)

Me

0.005

(78)

(4)

(—)

OR

IV

OH Cr(CO)5

2 eq

1. Benzene, 80°, 16 h 2. Air

Pr-n Pr-n

I + IV

+

OR 0.1 M

113 OR

OR V I

IV

Me

(3)

(3)

i-Pr

(19)

(—) (48) (—)

R

VI V

VI

(62) (—)

O Pr-n Cr(CO)5

2 eq

1. Benzene, 80°, 16 h

CF3

CF3

113

O O Pr-n

1. Microwave, (n-Bu)2O, Cr(CO)5

2 eq 0.05 M

(64)

i-Pr (60)

OR

0.1 M

R Me

2. CAN

OMe

130°, 5 min

(85)

192

2. CAN O O

Pr-n

OH 3 eq

Cr(CO)5

315

OMe OMe 0.1-0.2 M

OMe Pr-n

1. MeCN, 45°, 24 h

O Pr-n

+

2. CO (650 psi),

MeO

THF, rt, 36 h OMe OMe (57)

OMe OMe

(18-23)

13

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) O

C5

Refs.

Pr-n Pr-n

Cr(CO)5

Pr-n

1. Solvent, heat

I

+

OMe O

+

II

2. CAN

OMe OMe

O

OMe

MeO O O

III

MeO Alkyne

CC (M)

2 eq

0.5

3 eq

n-Pr

316

Temp

Time

I

II

III

THF

45°

16-24 h

(64)

(—)

(11)

84

0.1

THF

45°

24 h

(74)

(—)

(—)

13

2 eq

0.5

THF

110° 30-40 min

(57)

(—)

(11)

84

2 eq

0.005

THF

110°

1-2 h

(23)

(41)

(6)

84

3 eq

0.1

CH2Cl2

45°

24 h

(71)

(—)

(—)

13

1-1.5 eq

0.04

(n-Bu)2O, ultrasound —

5 min

(61)

(—)

(—)

177

2 eq

0.5

benzene

45°

16-24 h

(60)

(—)

(tr)

84

3 eq

0.1-0.2

benzene

45°

24 h

(90)

(—)

(—)

13

2 eq

0.5

benzene

110° 30-40 min

(52)

(—)

(—)

84

2 eq

0.5

n-heptane

45°

16-24 h

(56)

(—)

(—)

84

3 eq

0.1-0.2

n-hexane

45°

24 h

(88)

(—)

(—)

13

3 eq

0.1-0.2

MeCN

45°

24 h

(—)

(—)

Solvent

(57-69) OTBS

13 OTBS

Pr-n Cr(CO)5

1.5 eq

amine (2.5 eq), 45°

OMe OMe 0.05 M

Pr-n +

TBSX (1.5 eq), I

II

OMe OMe X

Amine

Solvent

Cl

Et3N

Cl

Et3N

OMe OMe I

II

THF

only

(—)

n-heptane

(—)

(34)

(86)

(tr)

OTf 2,6-lutidine CH2Cl2

O

OMe O Pr-n

2 eq

Cr(CO)5

MeO

OMe

95

•Cr(CO)3

1. THF, heat

Pr-n +

I

II +

MeO

2. CAN

O

OMe

O

O O MeO

III

n-Pr CC (M)

Temp

Time

I + II

I:II

0.5

45°

16-24 h

(74)

11.3:1

(7)

84

0.3

45°

24 h

(76)

10.5:1

(—)

67

0.5

110°

30 min

(80)

5.6:1

(9)

84

0.005

110°

1-2 h

(84)

5.0:1

(—)

84

III

O

317

CF3

CF3 Cr(CO)5

2 eq 0.1 M OR

Pr-n

Me

2. CAN

i-Pr (98)

CF3 Cr(CO)5 OR

Pr-n

Me

2. Air

i-Pr (98)

Br

0.1 M OR

(96)

113

OR O

Cr(CO)5

R

1. Benzene, 80°, 16 h

0.1 M

2 eq

113

(95)

O OH

CF3 2 eq

R

1. Benzene, 80°, 16 h

1. Benzene, 80°, 16 h

Br

Br

O

Pr-n +

2. CAN O

113 RO n-Pr II O

I R

I

II

Me

(75)

(5)

i-Pr

(91) (≤5)

Pr-n

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C5

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

Br

Br

Pr-n

Cr(CO)5

2 eq

O

Pr-n +

1. Benzene, 80°, 16 h

113 RO n-Pr

2. Air

OR

Refs.

Br

OR

I

0.1 M

II R

I

II

Me

(72)

(5)

i-Pr

(90)

(≤5)

O

MeO Cr(CO)5

2 eq

318

OMe

O

Pr-n

MeO

1. Additive (1.5 eq),

Pr-n

MeO

Pr-n +

solvent, heat

+

84

2. CAN I

II

O

O

O O MeO

OMe III

n-Pr Temp

Time

I

II

THF

45°

16-24 h

(30)

(37)

(9)

none

THF

110°

30 min

(41)

(39)

(13) (—)

Additve

Solvent

0.5

none

0.5 0.5

CC (M)

III

TBSCl

THF

110°

25 min

(46)

(28)

0.005

none

THF

110°

1-2 h

(41)

(25)

(7)

0.5

none

benzene

45°

16-24 h

(36)

(40)

(Tr)

0.5

none

benzene

110°

30 min

(50)

(23)

(2)

0.5

none

heptane

110°

0.5 h

(50)

(23)

(2)

0.5

TBSCl

heptane

110°

0.5 h

(55)

(26)

(2)

0.5

TMSCl

heptane

110°

0.5 h

(52)

(22)

(—)

0.5

Ac2O

heptane

110°

0.5 h

(26)

(12)

(9)

0.5

BF3•OEt2

heptane

110°

0.5 h

(56)

(20)

(—)

MeO 1. Benzene, 45°, 16 h

2 eq

Cr(CO)5 0.5 M

2. CAN

I (29) + II (59)

113

OPr-i OH

MeO

MeO Cr(CO)5

Pr-n (46) + II (28) +

Hexane, 45°

OMe

78

OMe MeO

O (15) MeO n-Pr

Pr-n O

OH

HO

319

1. Tf2O, pyridine, benzene Cr(CO)5

2 eq 0.1 M

OR

TfO

Pr-n +

2. Alkyne, benzene, 80°, 16 h

O

113

Pr-n

3. Air

OR O

OR TfO

Pr-n

OR R Me

I

II

(80) (≤5)

i-Pr (82)

(6)

OTf

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

O

Pr-n Pr-n

Cr(CO)5

Pr-n 2 eq

MeO

1. THF, heat

+

I

II +

2. CAN

OMe

O

MeO

84

O MeO O O

MeO

III

n-Pr

MeO

320

CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(56)

(—)

(—)

0.5

110°

30-40 min

(63)

(<6)

(7)

0.005

110°

1-2 h

(59) (<18)

(5)

O

AcO Cr(CO)5

2 eq

OMe

0.5 M

Pr-n

AcO

1. THF, heat

84

2. CAN Temp

Time

45°

16-24 h

(61)

110°

30-40 min

(50)

O

OH

AcO

Pr-n

AcO Cr(CO)5

2 eq OR

0.1 M

R

1. Benzene, 80°, 16 h

Me

(60)

2. Air

i-Pr

(60)

113

OR

O

Ac

Ac Cr(CO)5

2 eq

Pr-n (63)

1. Benzene, 80°, 16 h

113

2. CAN

OMe

O

0.1 M

O

Pr-n Pr-n

2 eq

Cr(CO)5

MeO

OMe OMe

+ MeO

1. THF, heat MeO

2. CAN

+ OMe O II

OMe O I

O

MeO

O

OMe

OMe

321

Pr-n CC (M)

Temp

Time

I

II

III

0.5

45°

16-24 h

(60)

(—)

(10)

0.5

110°

0.5 h

(53)

(tr)

(9)

0.005

110°

1-2 h

(39)

(10)

(10)

III

84

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

O

MeO

Pr-n

MeO Cr(CO)5

Pr-n 2 eq

OMe OMe

MeO

Pr-n

+

1. Solvent, heat

+ OMe O II

OMe O I MeO

MeO O

O

O

+

MeO

OMe O n-Pr

OMe

IV

322

Temp

Time

I

II

III

IV

16-24 h

0.5

THF

45°

(46)

(<16)

(<10)

(<2)

0.5

THF

110° 30-40 min

(43)

(12)

(3)

(—)

0.005

THF

110°

1-2 h

(<6)

(43)

(<2)

(—)

0.5

benzene

45°

16-24 h

(47)

(14)

(<2)

(10)

0.5

benzene

110°

40 min

(35)

(8)

(4)

(—)

0.5

hexane

45°

16-24 h

(49)

(7)

(<2)

(16)

OMe

OMe OH

Cr(CO)5

OMe

OMe

Pr-n

Pr-n +

1. Solvent, heat

Pr-n O

Pr-n

III Solvent

CC (M)

84

2. CAN

Pr-n +

+

2. Air

OMe OMe

OMe OMe I

O

OMe

OMe III

II

OMe

OMe

OMe +

Pr-n

Pr-n +

OMe O IV

OMe OMe V OMe

O

O

MeO OMe VI Solvent

Temp

Time

I

II

III

IV

V

VI

0.5

THF

45°

16-24 h

(71)

(2)

(—)

(<1)

(—)

(<2)

84

0.5

THF

110° 30-40 min

(52)

(—)

(17)

(8)

(—)

(10)

84

0.005

THF

45°

2-3 d

(65)

(13)

(—)

(4)

(—)

(<3)

84

0.005

THF

110°

1-2 h

(15)

(—)

(36)

(—)

(20)

(—)

84

0.5

THF

45°

24 h

(59)

(—)

(—)

(—)

(—)

(—)

175

0.5

hexane

45°

24 h

(14)

(—)

(—)

(—)

(—)

(—)

175

0.5

MeCN

45°

24 h

(76)

(—)

(—)

(—)

(—)

(—)

175

CC (M)

323

OH

HO

1. Tf2O, pyridine, benzene Cr(CO)5

2 eq

OMe OMe 0.5 M

TfO

Pr-n (62)

2. Alkyne, benzene, 45°, 16 h OMe OMe

OMe

OMe O Br

Br Cr(CO)5 OMe OMe 0.5 M

113

3. Air

OMe 2 eq

Pr-n

Br Pr-n O

+

1. THF, 45°, 24 h 2. CAN OMe O (24)

(23)

175

O

OMe

OMe n-Pr

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

O

Refs. Pr-n

Pr-n Cr(CO)5

Pr-n 2 eq

1. Benzene, 80°, 16 h

+

(49)

(11)

113

2. CAN

Pr-i OMe 0.1 M

Pr-i

O

Pr-i

O O

AcO

Pr-n

AcO Cr(CO)5

2 eq

OMe OMe

AcO

Pr-n +

1. THF, heat

+

84

2. CAN O

OMe

OMe O I

II

AcO

AcO

324

O

Pr-n

O

OMe

OH

+ OMe

OMe Pr-n

III

IV

CC (M)

Temp

Time

I

II

III

IV

0.5

45°

16-24 h

(67)

(<2)

(<15)

(<2)

0.5

110°

30 min

(41)

(12)

(18)

(—)

0.5

110°

30 mina

(52)

(9)

(13)

(—)

0.005

110°

1-2 h

(25)

(24)

(12)

(—)

Pr-n

AcO OMe

2 eq

Cr(CO)5

MeO

I + II + III + IV

1. Solvent, heat

Temp

Time

I

II

III

IV

0.5

Solvent THF

45°

16-24 h

(68)

(<2)

(<15)

(<2)

0.5

THF

110°

40 min

(41)

(14)

(14)

(—)

0.005

THF

110°

1-2 h

(37)

(24)

(23)

(—)

0.5

benzene

45°

16-24 h

(51)

(10)

(26)

(—)

0.5

benzene

110°

30 min

(47)

(11)

(14)

(—)

CC (M)

Pr-n

HO

O Cr(CO)5

2 eq 0.5-1.0 M MeO

(9)

Benzene, 110-125°

OMe

Cr(CO)5

t-BuOMe, 55°, 0.5 h

(57)

MeO

MeO OMe OMe

TMS

TMS

325

OMe OMe 0.25 M OMe

2 eq

93

Cr(CO)3

OMe OH

Cr(CO)5 OMe OMe 0.5 M

O

243

OMe OH MeO OMe Pr-n

OMe

1.1 eq

3 eq

84

2. CAN

OMe Cr(CO)5

175

2. Air Solvent

OMe OMe

hexane

(20)

THF

(46)

MeCN

(42)

1. t-BuOMe, 50° 0.04 M

Pr-n

1. Solvent, 45°, 24 h

2. TBSCl (10 eq),

OTBS O

O Pr-n

+ OMe

Et3N (10 eq), rt, 12 h (CO)3Cr

OMe (15)

TBSO Pr-n (15)

388

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

O

C5 1. THF, 45°, 36 h Cr(CO)5 1.5 eq

2. CAN, MeCN/H2O,

(52)

218, 90

rt, 0.5 h

OMe OMe 0.1 M

OMe O OH

Cr(CO)5

1.5 eq

OMe

O OMe OMe (46) O

326

Cr(CO)5

1.5 eq

+

1. THF, 45°, 36 h 2. Silica gel

OMe OMe 0.1 M

90

OMe (20)

(54)

1. THF, 45°, 36 h

218

2. DDQ, MeOH, 0°, 2 h

OMe OMe 0.1 M

MeO MeO OMe OH Cr(CO)5

OH 2 eq

OH

t-BuOMe, 45°, 2-4 h

147, 65

+ O

OMe OMe (44)

0.25 M

Cr(CO)5

(18) O +

O OMe (20)

Cr(CO)5

MeO 3 eq

MeO

OH

1. THF, 60°, 17 h 0.05 M

Cr(CO)5

MeO

98

MeO

1. THF, 60°, 4 h 2. DEAD, PPh3,

2 eq

(41)

OH

2. O2, Et2O, rt

(29)

O

THF, rt, 18 h

98

0.5 M OMe

OMe Cr(CO)5 OH

Et3N (3 eq) OMe OR

0.01 M

OMe OR

O O Isomer Ratio b

R

Additive

Me

Ac2O (2 eq)

THF, reflux

(58)

4:1

148

Et

Ac2O (2 eq)

THF, reflux

(72)

3:1

148

Me

none

benzene, ultrasound

(67)

3:1

380

O •

327

Cr(CO)5

TMS 2 eq

OMe 0.09 M MeO

(69)

61

(61)

98

MeO

Cr(CO)5

MeO

TMS

1. THF, 50°, 6 h

2 eq

TMS

THF, 45°, 64 h

OH

2. O2, Et2O, rt 0.1 M O

C6

Bu-n

1. THF, rt, 20 h Cr(CO)5

Bu-n 3 eq

OMe OAc 0.1 M

2. 50°, 2 h

(80)

3. CAN OMe O

172

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C6

Bu-n Bu-n

Cr(CO)5

2 eq

Ac2O (2 eq), Et3N (2 eq),

(44)

267

THF, 65°, 4 h

OMe 0.03 M

OMe O

MeO

Bu-n

MeO OMe

2.3 eq MeO 0.1 M

Cr(CO)4

MeO

Bu-n (6)

1. THF, 45°, 12 h

(19)

+

276

2. CAN OMe

OMe O

O

OAc Bu-n

328

2 eq

Cr(CO)5

n-Bu

OMe

0.03 M

(51)

Ac2O (2 eq), Et3N (2 eq), THF, 65°, 4 h

267

n-Bu OMe OAc Bu-n

2 eq

Cr(CO)5

Ac2O (2 eq), Et3N (2 eq),

OMe 0.03 M

267

(19)

98

OMe O

Cr(CO)5

MeO

(51)

THF, 65°, 20 h

Bu-n

1. THF, 60°, 9 h

1.8 eq

O

2. CAN 0.07 M

Bu-n O

Cr(CO)5 OMe OMe 5 eq

OMe

O OMe

1. THF, 66°, 2 h

OMe 0.1 M

(36)

OMe

2. CAN

209

O

Cr(CO)5

O Bu-n

OMe

R

OMe OH

OMe

R R

Cr(CO)5

1 eq

OMe

329

OMe OMe

OMe OMe I

R

O

+

THF, 60°, 12 h

I

OMe

II

150

II

(67) (3)

s-Bu

(82) (9)

t-Bu OTBS

Bu-t OR

Bu-t 4 eq

MeO

Cr(CO)5

1. t-BuOMe, 55°, 1 h

Cr(CO)3

(48) dr = 9.5:1

OMe OR

0.4 M R = (–)-menthyl

OH

OH Bu-t

Cr(CO)5

1.5 eq

73

2. TBSCl (4 eq), Et3N (4 eq)

Bu-t +

THF, 60°, 17 h

89

OMe

Cr(CO)3 OMe

OMe

0.5 M (78)

(13)

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C6

OH

1. t-BuOMe, 50° O

Bu-t

2. TBSCl (10 eq),

5 eq

Bu-t

(23) +

(20) OMe

Et3N (10 eq), rt, 12 h

OMe 0.4 M

O

O

Cr(CO)5

(CO)3Cr

388

TBSO

OMe

Bu-t 1. THF, 50°, 2 h

MeO

2. Et3N (4 eq), TBSCl (4 eq),

4.4 eq OMe

Bu-t

THF, rt, 2 h

(50)c

208

OTBS (CO)3Cr

330

(CO)5Cr 0.05 M OH

OH

Cr(CO)5

OH

t-BuOMe, 45°, 2-4 h

(75)

147

OMe

2 eq

OMe

0.22 M

OMe

OMe

OH

Cr(CO)5

Et3N (3 eq), 3.5 h

0.01 M

O

OMe OR

OMe OMe

O Additive Ac2O (2 eq)

THF, reflux

(77)d

148

none

benzene, ultrasound

(77)d

380

C7

O C5H11-n

1. THF, rt, 20 h Cr(CO)5

C5H11-n 3 eq

OMe OAc 0.1 M

(51)

2. 50°, 2 h OMe O

MeO OMe OH

OMe OMe

1 eq

Pr-n

OMe Pr-n

Cr(CO)5

Pr-n

172

3. CAN

THF, 60°, 12 h

OMe OMe

+

O

(24)

150

(16)

OMe OMe

OMe OMe

OMe MeO OMe OH

OMe OMe

Et

331

Cr(CO)5

Et 1 eq

THF, 60°, 12 h

OMe OMe

+

O

OMe OMe (11)

OMe OMe

OMe

OMe

+

150

(12)

OMe Et

+

(41)

OMe

OMe

OMe OH

OMe

Et

OMe

OMe CO2Me

CO2Me 1 eq

Cr(CO)5 OMe OMe

+

THF, 60°, 12 h

150

CO2Me OMe OMe (65)

OMe

OMe (5)

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C7

Refs.

OH R

OR 1. t-BuOMe, 45-65° CO2Me

1.3 eq

Cr(CO)5

RO 0.2 M

2. PPh3, acetone, rt, 15 h

CO2Me

RO

Me

(53)

Ac

(47)

105

OMe

OMe

MOMO

MOMO

O

OH

O O O

Cr(CO)5 MOMO

See table

275

OMe

MOMO

OMe

332

Temp

Time

THF

50°

14 h

(36)

hexane

55°

64 h

(30)

—

CH2Cl2

70°

4h

(39)

0.05

—

heptane

90°

12 h

(33)

1.2

0.05

ultrasound THF

—

—

(23)

5

0.05

ultrasound hexane

—

—

(31)

2.6

0.5

—

CH2Cl2

70°

3h

(20)

2.4

0.3

—

hexane

50°

20 h

(28)

Alkyne (eq)

CC (M)

Solvent

1.2

0.05

—

1.2

0.05

—

1.2

0.05

1.2

OMe

O

OMe OH

O Cr(CO)5

See table

275

OMe OMe

OMe OMe

Alkyne (eq)

CC (M)

1.2

0.05

THF

50°

12 h

(18)

2.2

0.05

THF

50°

12 h

(34)

3.5

0.1

THF

50°

12 h

(42)

2.2

0.05

CH2Cl2

70°

1h

(23)

10

0.05

CH2Cl2

70°

1h

(59)

20

0.05

CH2Cl2

70°

1h

(76)

Solvent Temp Time

C7

OMe OTBS Cr(CO)5 CN 2 eq

OMe OTBS +

2,6-lutidine, TBSOTf, heptane or CH2Cl2, 45°

OMe OMe 0.3 M

95

(22)

(tr)

OMe OMe CN

OMe OMe CN •Cr(CO)5

O

C8

C6H13-n

1. THF, rt, 20 h

333

Cr(CO)5

C6H13-n 3 eq

172

3. CAN

OMe OAc 0.1 M MeO

(33)

2. 50°, 2 h OMe O

O

Cr(CO)5

C6H13-n

1. Silica gel, 60°, 4 h

1.5 eq

O

O

+

C6H13-n

98

2. CAN (30)

(7) O Ph

1. Microwave, (n-Bu)2O, Ph 5 eq

Cr(CO)5 0.05 M OMe

130°, 300 s

(52)

2. CAN O

192

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C8

OAc Cr(CO)5

Ph 1.2-2.0 eq

Ph Ph

1. Solvent, 60°, 17 h

+

2. Ac2O (2 eq), Et3N (3 eq),

89

I

solvent, 60°, 17 h

OMe

II

OMe CC (M)

Solvent

E-II

Z-II

THF

(79)

(<1.2)

(—)

0.03

THF

(65)

(8)

(—)

0.05

THF

(66)

(<13)

(—)

0.5

THF

(38)

(32)

(—)

0.5

THF

(74)

(8)

(<0.5)e

0.5

benzene

(36)

(25)

(<1.7)

0.5

MeCN

(22)

(18)

(<2.8)

334

I

0.005

1. THF, 60°, 17 h

OMe

Ph

2. Ac2O (2 eq), Et3N (3 eq), Cr(CO)5

1.2 eq

THF, 60°, 24 h

(69)

3. AlCl3, EtSH,

OMe

89

OMe

CH2Cl2, rt, 12 h O

Cr(CO)5

MeO

Ph R

1.5 eq

O

1. Silica gel, 60°, 5 h

R MeO

R MeO

Cr(CO)5

1.8 eq

(50)

OH

98

2. O2, Et2O, rt

Cr(CO)5

MeO

98

Ph

1. THF, 60°, 21 h 0.07 M

H (22) Br (24)

2. CAN

MeO

Ph

1. THF, 60°, 5 h 2 eq

2. Ac2O, Et3N, 0.2 M

OAc

3. FeCl3–DMF

Cr(CO)5

Et3N (3 eq) O

OMe OR

OMe OR

O Z:E

0.01 M Additive

R

98

OMe

OMe

OH

(25)

DMAP, Et2O, rt

Me

Ac2O (2 eq) THF, reflux

(74) 3:1

148

Et

Ac2O (2 eq) THF, reflux

(77) 7:3

148

Me

—

(79) 7:3

380

benzene, ultrasound

OMe

OMe

335

Cr(CO)5

Silica gel, 50-60°, 3 h

OMe OMe

(71)

380

OMe OMe

C9

O 1. Microwave, (n-Bu)2O, Cr(CO)5 5 eq

130°, 300 s

(57)

0.05 M

O O OH

1. Hexane Cr(CO)5

OTHP

192

2. CAN

OMe

2. CAN

(76)

86

3. MeOH, HCl (1 M)

OMe

O OH OMe O 1.5 eq

O

1. t-BuOMe, 40°, 1 h

O

MeO

Cr(CO)4

2. CO (75 bar), O

CH2Cl2, 70°, 48 h 0.1 M

279 (75)

OMe OMe

280 281

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C9 OH O

Cr(CO)5

O

O

O

O

150

OAc OMe

1 eq

O

+

THF, 60°, 12 h

OAc OMe

O

(30-50)

OMe (—)

OAc OMe

OMe OH 1. t-BuOMe, 50°, 1 h

CO2Me OMe

CO2Me 1.1 eq

(76)

CO2Me

Et2O, 70°, 72 h MeO 0.2 M

282, 283,

CO2Me

2. CO (75 bar),

Cr(CO)4

281, 279, 284

OMe OMe

336

O OMe O

1. t-BuOMe, 50°, 16 h 1.1 eq

OMe

CO2Me

2. CO (82 bar),

(20)

105

Et2O, 70°, 84 h MeO

MeO

Cr(CO)4

OMe

0.2 M OMe 1.1 eq

OR

OMe

2. See table MeO

CO2Me

1. t-BuOMe, 50°, 16 h MeO

Cr(CO)4

0.2 M

105

CO2Me OMe

Step 2

R

NaOMe (9 eq), MeOH, rt, 2 h

OH

Ac2O (3.2 eq), Et3N (9.5 eq),

OAc (44)

(27)

PPh3 (7.5 eq), acetone

OMe

OMe OH 1. t-BuOMe, 50°, 1 h

1.1 eq

OMe

CO2Me

2. CO (75 bar), CH2Cl2, 70°, 72 h

MeO MeO 0.2 M

C10

Cr(CO)4

OMe OMe OMe O

MeO

MeO OMe

OTHP 2 eq

281, 279

(79)

CO2Me

MeO

Cr(CO)4

1. Hexane, 50°, 3.5 h

OH

2. CAN

(10)

+

276 O

OMe O

0.11 M

MeO

O H

(22)

OMe O O

337

Cr(CO)5

CO2Bu-t 1.5 eq

OMe OMe 0.3 M

CO2Bu-t

1. THF, 45°, 24 h

(66)

67

(66)

12

2. CAN OMe O OH

Cr(CO)5

1.5 eq

OMe OMe

CO2Bu-t

1. THF, 45°, 24 h 2. Air OMe OMe

0.2 M 1. CH2Cl2, 40°, 36 h

OH

2. Air, rt, 15 min 1.5 eq

Cr(CO)5 OMe OMe 0.18 M

(64)

3. (CF3CO)2O, NaOAc 5. NaOH

12, 13, 265

4. CF3CO2H, 45 min OMe OMe O

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C10

Conditions

Product(s) and Yield(s) (%)

RO

RO

1. Solvent, 45°, 24 h OMe

CO2Bu-t

1.5 eq

Me

0.01 M

hexanes

1.2 eq

Ac

0.5 M

CH2Cl2

OMe OMe

Solvent

Cr(CO)5

CONHBu-t

(47) O

(67) CONHBu-t (70)

1. THF, 45°, 24 h

67

2. CAN

OMe OMe

OMe O

0.3 M

C11

286

CH2Cl2, rt, 14 h

MeO R

Cr(CO)4

CO2Bu-t

2. TF2O, pyridine,

Alkyne

1.5 eq

Refs.

OTf

338

OH O

O

1. t-BuOMe, 40°, 1 h OMe

O O

MeO 1.5 eq

O

2. CO (75 bar),

Cr(CO)4

279, 280,

(76)

O

CH2Cl2, 70°, 48 h

281

OMe OMe

0.1 M

O CN

CN Cr(CO)5 OEE

R

OMe

OMe O

O

Cr(CO)5 R1

OAc

12

R2 OMe

2

R2 O

(76)

OEE

2. CAN

OMe OMe 0.3 M

1.5 eq

1. THF, 45°, 36 h

O

O

OH

OMe

O +

THF, 60°, 12 h

O

R1

OAc OMe R

1 eq

1

O

AcO

OMe I

II

OMe

OMe R2 O

R1

R2

OMe OAc OAc

OAc

OAc R1

I

II

III

OMe

(—)

(24)

(24)

(—)

H

(—)

(—)

(—)

(30-50)

OAc

(16)

(30)

(—)

(21)

OMe

O

+

III

MeO R1

O

OH

O +

C12

OMe 150, 288

OMe OH

OTBS

OMe

IV

IV

OTBS Pr-n

Cr(CO)5

Pr-n 1 eq

150

(46)

THF, 60°, 12 h

339

OMe OMe

OMe OMe

OMe

OMe OH

TBSO

OTBS

MeO

Et

OTBS Cr(CO)5

Et 1 eq

Et

THF, 60°, 12 h

OMe OMe

OMe OMe

(30)

+

(28)

150

OMe

MeO

OTBS SO2Ph 1 eq

SO2Ph Cr(CO)5 OMe OMe

TBSCl, Et3N,

(—)

95

heptane, 45° OMe OMe O

Fe

Cr(CO)5 OMe OMe

Fe

1. THF, 65°, 48 h 2. PbO2, CH2Cl2 OMe O

(63)

92

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C12

Conditions

R2

R1

Product(s) and Yield(s) (%) R1

Refs.

R2 O

1. THF, reflux, 19-25 h

Fe OMe 1.2 eq

(57)

Fe

392

2. PbO2, CH2Cl2

0.05 M OMe Cr(CO)5 R1, R2 = CH2

OMe O

R1 = CH2OMe, R2 = Me MeO OH

C13 MeO Cr(CO)5

Heptane, 70°, 10 h

OMe OMe 0.1 M

340

CO2Me 1.5 eq

(43)

OMe OMe OH

OMe

OMe Cr(CO)5

1. Solvent, 50°, 48 h 2. Air

MeO2C

OMe OMe 0.08 M

0.85-1.2 eq

OMe

Cr(CO)5

MeO MeO2C 1.1 eq

OMe

0.5 M

+

I

II

MeCN

(53)

(—)

hexane

(34)

(—)

benzene

(54)

(9)

benzene

(60)

(10)

OMe OMe O OMe MeO2C II

OMe OH OMe

TMS 1. MeCN, 45°, 36 h

(66)

2. Air

Ac Cr(CO)5

1. Solvent, 45°, 24 h 2. Air, silica gel

OMe OMe 0.1 M

1.1 eq

341

OMe

1.1 eq

MeO Cr(CO)4 0.1 M

C14

175

MeO2C OMe OMe OH

Ac MeO2C

297

MeO2C OMe OMe I

Solvent

OMe

TMS

290

CO2Me

Solvent

I

II

MeCN

(74)

(0)

benzene

(81)

(9)

1. Benzene, 50°, 48 h

158, 393

+ MeO2C OMe OMe I Ac

OMe O OMe MeO2C II

I (73) + II (10)

158, 393

2. Air, silica gel

MOMO

MOMO

OH

OTBS

OTBS Cr(CO)5 MOMO

t-BuOMe, 55-60°, 10-24 h

OMe

(—) MOMO

C15

274

OMe OH OBn

OBn Cr(CO)5 OR OMe OMe

1. Solvent, 60°, 15 h

OR

2. Air, silica gel OMe OMe

R

Solvent

OMOM

THF

(25)

OMOM

benzene

(22)

OAc

THF

(74)

152

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C16

Conditions

OMe

Product(s) and Yield(s) (%) OMe OH

OTBS

OMe

TBSO

THF, 60°, 12 h

Cr(CO)5

OMe 1 eq

R

OMe OMe

OMe

(15)

OMe OMe

Ac

(40)

150

OMe

OMe

OMe O

OH

2. Air, 10 min, rt Cr(CO)5

t-BuO2C

3. (CF3CO)2O, NaOAc

1.2 eq

(56)

5. NaOH

OMe OMe O

342

OMe OH

OMe OBn

Cr(CO)5 OMe OMe

(62)

1. MeCN, 45°, 24 h 2. Air

O OMe OMe

0.5 M MOMO

MOMO

OTBS

OBn

TMS

TMS

1.1 eq

158

4. CF3CO2H, 1.5 h, rt

OMe OMe 0.1 M

C19

MeO2C

R

+

OMe

R= 1. Benzene, 75°, 12 h

Refs. OTBS

175

OMe

OH OTBS

OAc

Cr(CO)5 2.8 M OMe

1.0 eq MOMO

OTBS

THF, 55°, 12 h MOMO MeO MOMO

MOMO

1.0 eq OAc

Cr(CO)5 3.2 M OMe

MOMO

277

(38)

OAc

O

OTBS

(35-40)

1. Heptane, 55°, 14 h

277

2. CAN MOMO

O

OAc

C21 O

1. Tf2O, pyridine, CH2Cl2 O

Cr(CO)5 OMe OMe 0.14 M

OTBS

OMe

OAc

HO OMe

O O

TfO

(40)

2. Alkyne (1.05 eq),

113

OTBS

CH2Cl2, 45°, 24 h 3. Ac2O, DMAP

OMe OMe

C23 OMe

1. CH2Cl2, 45°, 22 h

O

MeO2C

OPMB

OMe Cr(CO)4

MeO 0.5 M

1.04 eq

O (42) MeO2C OMe OMe TBSO OTBS

OMe

343 O

OMe Cr(CO)5

O

O O

THF, 60°, 12 h

OMe OMe

OMe

1 eq

O

(40)

150

OMe

OH

OMe

OMe Cr(CO)5

CO2CHPh2

285

OPMB

DMAP, rt, 5 h

O TBSO

O

AcO

3. Ac2O, (i-Pr)2EtN,

C25 OTBS

OMe

OAc

AcO

O

OMe OMe

(56-60)

MeCN, 50°, 15 h OMe OMe

CO2CHPh2

12

TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C49

Refs.

R

O R Cr(CO)5

0.8 eq

1. THF, 60°, 2 d

375, 376

(75)

2. PbO2, CH2Cl2

OMe OMe

OMe O

0.01 M Tol

N

N

N

N

R=

Tol

Tol

R

O

344

Br Br Cr(CO)5

0.8 eq 0.01 M

OMe

(76)

1. THF, 60°, 2 d

375, 376

2. PbO2, CH2Cl2 O O

Cr(CO)5 R 0.8 eq

a

OMe OMe 0.01 M

R

1. THF, 60°, 2 d 2. PbO2, CH2Cl2

The reaction mixture was not deoxygenated.

b

Isomers were not specified.

c

Only one isomer of unreported configuration was obtained.

d

More than two isomers were obtained as products from this reaction.

e

Alkyne added via syringe pump.

OMe O

(74)

375, 376

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C4 Cr(CO)5

t-BuOMe, 40-60°, 2-4 h

OMe 0.2 M

1.2 eq

(68) (CO)3Cr

NMe2

OMe

R

NMe2

R Pyridine

x eq

300

(CO)5Cr OEt

OEt

x

y

3

0.05

R Me

Temp Time

4

0.1

n-Pr 55°

80° 1.5 h (56)

394

78 h (95)

yM Br

Br NMe2

NMe2

345

3 eq

Pyridine, 70°, 72 h

(79)

394

(36)

395

(CO)5Cr OEt

OEt

0.05 M Me

Me

N

N O

2-4 eq

O

OH

1. Pyridine, 80°, 6 d 2. HCl, DME, 80°, 14 h

(CO)5Cr

O

OEt 0.05 M O

O

R NMe2

O 2-4 eq

R

O

R

NMe2

Pyridine, 80°, 3 d (CO)5Cr OEt

0.05 M

H

(87)

Me

(75)

395

OEt

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C4

Carbene Complex

Conditions

TBSO

Product(s) and Yield(s) (%) TBSO

NMe2

NMe2

Pyridine, 80°, 1.5 h 3 eq

Refs.

(91)

(CO)5Cr

394

OEt

OEt 0.05 M O O

NMe2

O

NMe2

Pyridine, 80°, 3 d

O

1:1 mixture

(72)

398

of isomers (CO)5Cr OEt

OEt

346

O

O

O

O

NMe2

O

NMe2

Pyridine, 80°, 3 d

O +

398 Me2N

(CO)5Cr (38)

OEt

O

NBn2 Pr-n

C5

Pr-n

[(Naphthalene)Rh(cod)]-

Z:E = 64:36

397

CO2Me

[SbF6] (10 mol%), O 1.5 eq

(78)

O OMe

MeO

OEt

OEt

(CO)5Cr O

(27)

NBn2

THF, 50-55°, 4 d

OEt

(CO)5Cr

OEt

CH2Cl2, rt, 12-36 h 0.05 M

(81) O

396

C6

O Et

Cr(CO)5 Et

Et

1. THF, 45-60° OMe

(<5)

110, 399

(~10)

110, 399

Et

2. CAN O OH

Et

Cr(CO)5 1. CH2Cl2, 45-60° OMe

Et

2. Air OMe

OTBS Cr(CO)5

1.5 eq

Et

1. THF, 50°

(59)

2. TBSCl (1.5 eq), OMe

(CO)3Cr

0.05 M

95

Et

Et3N (2.5 eq), rt, 6-12 h

OMe

347

O Et

Cr(CO)5 1.5 eq

Solvent

1. Solvent, 45-55°, 24 h OMe

Et

2. Air

0.1 M

THF

(39)

MeCN

(42)

61

OMe OH THF, –-20°, photolysis, 2 h

5 eq Cr(CO)5

O

OMe

1.5 eq

Et

O

Et

O

Et

1. THF, 45°, 24 h 2. CAN

O

187

O

Cr(CO)5 O

(35)

Et O

(58)

69

O

0.3 M

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

O

C6

OMe Et

Et

Et

Cr(CO)5

(37)

1. THF, 45°, 24 h

1.5 eq

69

Et

2. CAN O

0.3 M

O Et 1.5 eq

OMe

O

Cr(CO)5

Solvent

1. Solvent, 45°, 24 h 2. CAN

Et

O O

THF

(73)

hexane

(79)

benzene (73)

0.3 M

MeCN

(64)

OH

348

1.5-2.0 eq

OMe

O

Cr(CO)5

69, 13

Et Et

1. THF, 45-50°, 24-96 h

I

2. Air O

+

Et

Et

II

O O

OMe CC (M)

I

II

0.3

(80)

(—)

69

0.5

(73)

(<0.1)

60

0.005

(75)

(<1.0)

60

OTBS Et

1. THF, 50° 1.5-2.0 eq

Cr(CO)5

TMS

OMe 0.05 M

(38)

2. TBSCl (1.5 eq), Et3N (2.5 eq), rt, 6-12 h

TMS (CO)3Cr

Et OMe

95

OH Et 1.5 eq

Cr(CO)5

TMS

TMS

2. Air

OMe

(33)

1. THF, 50°, 26 h

95

Et

0.05 M

OMe OH

Et Et

Cr(CO)5

1.5-2.0 eq

+

1. Solvent, 45-50°, 18-42 h

OMe

I Solvent

CC (M)

Et

Et

2. Conditions

II

OMe

Conditions

I

O

II

349

0.5

THF

air, TsOH, H2O/THF

(67)

(≤3)

60

0.3

THF

FeCl3-DMF

(64)

(—)

69

0.005

THF

air, TsOH, H2O/THF

(60)

(≤1)

60

0.5

n-heptane

air, TsOH, H2O/THF

(58)

(≤0.1)

60

0.005

n-heptane

air, TsOH, H2O/THF

(73)

(≤0.1)

60

0.5

MeCN

air, TsOH, H2O/THF

(41)

(≤1)

60

0.005

MeCN

air, TsOH, H2O/THF

(23)

(22)

60

O Et Cr(CO)5

1.5 eq

Et

2. CAN

OMe

Solvent

1. Solvent, 45°, 24 h

THF

(65)

MeCN

(56)

69, 13

O O

0.3 M

Et Cr(CO)5

1.5 eq

1. THF, 45°, 24 h

(59)

69

Et MeO OMe

2. CAN/MeOH

OMe 0.3 M

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

Refs.

OTBS Et

1. THF, 50° Et

Cr(CO)5

Et 1.5 eq

2. TBSCl (1.5 eq), (CO)3Cr

0.05 M

95

(65) Et

Et3N (2.5 eq), rt, 6-12 h

OMe

OMe O

P(Bu-n)3 Cr(CO)4

5 eq

Et 1. THF, 60°, 12 h

133

(33) Et

2. CAN

OMe

O O

0.1 M TBS

Cr(CO)5

350

OMe

O

TBS

Et

Et

1. THF, 45-60°

(<6)

2. CAN

+

(<6)

Et

110

Et

O

O OTBS

TBS

Et

Cr(CO)5 CH2Cl2, 65°, 15 h

1.5 eq

(43)

OMe (CO)3Cr

0.05 M

OMe OTBS

TBSCl (2 eq), Cr(CO)5

1.9 eq

OMe 0.05 M

110

Et

(i-Pr)2NEt (3 eq), CH2Cl2, 60°, 10-12 h

OTBS Et

Et (48) +

Et OMe Cr(CO)3

(35) Et OMe Cr(CO)3

207

OH

1. 2,3-Dimethyl-1,3-buta-

TMS Cr(CO)5

1.5 eq

OMe

0.03 M

Et

diene (80 eq),

112

(52)

THF, 70°, 48 h Et

2. Air OMe

O

O NMe2

O

O 2-4 eq

NMe2

Pyridine, 80°, 4 d

(78)

Et

395

(CO)5Cr OEt

Et

OEt

Ph

OH

Ph 5 eq

Photolysis, THF, –20°, 2 h

Et

351

Cr(CO)5 O 0.05 M

187

(36)

188

Et Ph OH

Ph Photolysis, THF,

5 eq Cr(CO)5

O

(81)

O

Et

O

–20°, 0.5 h

Et Bu-n

n-Bu

OH Et

1. THF, 60°, 42 h

Cr(CO)5

N Boc

Et

Boc

OMe O

O

OMe O

O

NMe2

O

121

(12) N

2. Air

O

NMe2

Pyridine, 80°, 3 d

Et

+

Et

(CO)5Cr OEt

398

Me2N Et

(37)

Et

OEt

OEt (18)

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

C6

Conditions

Product(s) and Yield(s) (%)

OBn MeO Et

Et

MeO

Cl

MeO Cr(CO)5

O

2.2 eq

THF, 80°

Et Et

O

OEt

OEt

TIPSO

OTIPS

OH

TIPSO

O

Et

t-BuOMe, 55°, 7 h O

O

Cr(CO)5

O

124

(42)

MeO

O 10 eq

Refs.

OH

O

Et

+

Et 210, 400

O

O Et (CO)3Cr OMe

OMe

OMe 0.07 M

OH

O

(33)

352

(46) 3:1 mixture of isomers

OTIPS

TIPSO

TIPSO

TIPSO

OH

TIPSO

10 eq

Cr(CO)5

O OTIPS 0.07 M

Et

OH

TIPSO +

Et

THF or t-BuOMe, OTIPS

OMe

O

Et

O

50-55°, 2.5-6 h

Et

143, 294, 210, 400

OMe OTIPS (CO)3Cr

OMe (30-31)

(39-40)

OH

OH Pr-n

Pr-n 1.2 eq

Cr(CO)5

t-BuOMe, 40-60°, 2-4 h

(52)

+

0.2 M

(13) Pr-n

OMe (CO)3Cr OMe

(CO)3Cr OMe

300

O Pr-i MeO

Cr(CO)5

Pr-i

OMe

3 eq

1. THF, reflux, 4 h

(≥28)

266

(≥37)

266

OMe

2. CAN O O

Pr-i

H

Cr(CO)5

3 eq

OMe

H

1. THF, reflux, 4 h

OMe

2. CAN O OH

Ac

Cr(CO)5

Et

THF, 50°

353

1.5-2 eq

+

(18)

(39) OMe

OMe OH

Cr(CO)5

O

Solvent, heat

R 0.05 M

+

I

R

R R

Solvent

OMe OMe 1-morpholino

II

O

Et

Ac

O

H

O

O

Et 1.5-2 eq

71

Et

Ac

OMe 0.05 M

H

O

O

Et

Temp

I

II

THF

50°

(33)

(32)

71

MeCN

50°

(35)

(31)

71

THF

70°

(18)

(63)

401

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C6

O

Et

O

Cr(CO)5

O Ac

Et

O

1. Solvent, 50°, 14-15 h

O

O

2. FeCl3-DMF

2 eq

O

Et

+

Ac

Refs.

47 O

I

II

0.05 M

R

R

Solvent

CF3 CF3

R

R

354

I + II

I:II

THF

(56)

71:29

benzene

(67)

74:26

CF3

MeCN

(37)

68:32

CF3

CH2Cl2

(51)

72:28

Cl

THF

(57)

65:35

H

THF

(63)

49:51

OMe

THF

(59)

53:47

NMe2

THF

(51)

39:61

OH CO2Me MeO2C

Cr(CO)5

CO2Me 1.5 eq

1. THF, 45°, 24 h

(8) OMe

C7

Et2N Ph

Cr(CO)5

Et2N OEt 1.5 eq

0.5 M

69

CO2Me

2. Iodine

OMe 0.3 M

Pet ether/hexanes (1:1), 0-20°

Ph

(30) + OEt

EtO

Cr(CO)5 Ph

Cr(CO)5 (29)

NEt2

402

NEt2

Ph 1 eq

Ph

(CO)5Cr 0.05 M

Hexane, rt, 3 h

Ph

(CO)5Cr

(64)

Ph

403

OMe

OMe OH

Ac

Cr(CO)5

TMS 1.5-2 eq

THF, 50°

(25)

OH

OH Pr-n

MeO2C

Pr-n

Cr(CO)5

O

1.5-2 eq

O

(33) O

OMe

0.05 M

355

C8

CO2Me

(35) + CO2Me

THF, 50°

OMe

71

OMe

OMe

0.05 M

H

+ TMS

(8) Ac

OMe

O

O

TMS

47

Pr-n OMe

O O

NMe2 O

O

NMe2

Pyridine, 80°, 4 d

(65)

395

(CO)5Cr OEt

2-4 eq 0.05 M

OEt

Ph

N Ph

3 eq

N

Pyridine, 80°, 1.5 h

(51)

(CO)5Cr

394

OEt OEt

0.05 M

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

C8

Conditions

Product(s) and Yield(s) (%)

R (CO)5Cr

NBn2

R

Z:E

n-Pr

THF, 50-55°, 4 d

OEt

(75) 67:33

OEt OH Pr-n

Cr(CO)5

TMS

TMS (56) +

1. THF, 45°, 24 h TMS

2. FeCl3-DMF

OMe

397

c-C3H5 (62) 90:10

R OH

n-Pr

Refs.

O

NBn2

(20)

101

(23)

72

Pr-n

OMe

OMe

OH

OH Pr-n

Cr(CO)5

1.5 eq

(48) +

1. THF, 50°, 18 h

356

Pr-n

2. TFA, CH2Cl2, rt, 0.5 h

OMe 0.05 M

OMe

OMe

O

O

1. THF, 50°, 16 h n-Pr

Cr(CO)5

SnMe3 1.5 eq

Pr-n

2. HCl (aq)

I O

I + II (—), I:II = 34.3:1

O

Pr-n

TMS

THF, 50-55°, 4 d

OEt

72

(0)

Pr-n TMS

O

NBn2

TMS

(CO)5Cr

II Pr-n

NBn2 TMS

+

3. CAN

OMe 0.07 M

397

OEt OH Ph

Ph

I

O

Cr(CO)5 OMe

(0)

THF, 60° I

O OMe

146

C9

HO

Cl TBS

Cr(CO)5

OMe

TBS

SiO2, 80°

OMe

O

(39)

404

(31)

404

O

OEt

OEt HO

Cl Cr(CO)5

TBS

THF, 80° OMe

O OMOM

O OMOM OH Ph

H Ph 1.5-2 eq

O

Cr(CO)5

O

THF, 50°

357

OMe 0.05 M

O

Cr(CO)5

–20°, 0.5 h

Ph +

187 O C7H15-n (10) Ph

Ph

Ph

OH

OH +

Photolysis, THF, O

Cr(CO)5

–20°, 0.5 h

71

OH

C7H15-n O (30)

5 eq

(62)

OMe

OH

Photolysis, THF, O

+

(4)

Ph

Ph

n-C7H15 5 eq

H H

OMe O

Ph

C10

H

O

O

O

C7H15-n

O

188 O

(28)

(7)

C7H15-n

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C10 Cr(CO)5

TBSCl (3 eq),

(CO)3Cr

TBSO

(CO)3Cr +

TBSO 212

(i-Pr)2NEt (5 eq), OMe 0.25 M

1.5 eq

toluene, 50°, 24 h

I

MeO

MeO

II

I + II (63), I:II = 89:11 1. Toluene, 80°, 24 h Cr(CO)5 1.5 eq

212

I + II (62), I:II = 3:97

toluene, 80°, 24 h

0.25 M

358

Cr(CO)5

1.5 eq

2. TBSCl (3 eq), (i-Pr)2NEt (5 eq),

OMe

TBSCl (3 eq),

(CO)3Cr

TBSO

TBSO

(i-Pr)2NEt (5 eq),

212 I

toluene, 50°, 3 h

OMe

(CO)3Cr +

II MeO

MeO

0.25 M

I + II (61), I:II = 22:78 1. Toluene, 120°, 24 h Cr(CO)5

1.5 eq

2. TBSCl (3 eq),

I + II (63), I:II = 2:98

toluene, 120°, 24 h

0.25 M

(CO)3Cr

TBSO

(CO)3Cr +

Cr(CO)5

TBS

212

(i-Pr)2NEt (5 eq),

OMe

TBSO

Toluene, 50°, 24 h

1.5 eq

212

OMe 0.25 M

I MeO I + II (73), I:II≤ 3:97

MeO

II

1.5 eq

HO

(CO)3Cr t-Bu

Cr(CO)5

t-Bu

+

Toluene, heat, 24 h

HO

(CO)3Cr t-Bu

212

OMe MeO

0.25 M

Cr(CO)5

I + II

I:II

50°

(69)

65:35

120°

(60)

1:99

TfO

(CO)3Cr

TfO

(CO)3Cr

2. Tf2O (3 eq),

+

(i-Pr)2NEt (5 eq), OMe

II

MeO

Temp

1. Toluene, 80°, 24 h 1.5 eq

I

toluene, 80°, 24 h

I

MeO

0.25 M

212 II

MeO

I + II (86), I:II ≤1:99

359

TBSCl (3 eq), Cr(CO)5

1.5 eq

(CO)3Cr

TBSO

II

MeO

Temp

I + II

I:II

50°

(77)

21:79

80°

(66)

23:77

Temp

Time

I + II

I:II

50°

24 h

(75)

14:86

(i-Pr)2NEt (5 eq),

50°

48 h

(66)

≤1:99

toluene, heat, 24 h

80°

24 h

(74)

2:98

1. Toluene, heat, time

OMe 0.25 M

212

I

MeO

Cr(CO)5

TBSO

+

(i-Pr)2NEt (5 eq), toluene, heat, 24 h

OMe 0.25 M

1.5 eq

(CO)3Cr

2. TBSCl (3 eq),

I + II

212

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C10 (CO)3Cr

TBS Cr(CO)5

2,3-Dimethyl-1,3-butadiene, MeO

Ac

O

O

(73)

THF, 50° OMe

1.5-2 eq

71

Ph OMe

0.05 M

OH Ph Cr(CO)5

1.5-2 eq

212

(29)

0.07 M Cr(CO)5

Ph

TBSO

THF, 50°, 14 d

OMe 1.5 eq

H

O

O (5) +

THF, 50°

(70)

Ac

360

OMe 0.05 M

OMe

OMe Ph

O

Cr(CO)5

(6) + Ac

O

71

O (62) ≥98% ds

THF, 70°

47

Ph

OMe 0.05 M

OMe

Cr(CO)5 O 1.5 eq

(87)

OMe

OMe

Cr(CO)5

CO2Me

O Ph

O 1.5-2 eq

H

O

O

THF, 50°

OMe 0.05 M

71

Ph

OH

1.5-2 eq

Refs.

OMe

[(Naphthalene)Rh(cod)]-

O (85)

[SbF6] (10 mol%), CH2Cl2, rt, 12-36 h

CO2Me

0.05 M O

396

C11

O Ph

Cr(CO)5 Ph

TMS

1. THF, 45-60°, 19-38 h OMe

2 eq

(70)

146

TMS

2. CAN

0.044 M

O O Ph

2 eq

Cr(CO)5

O

1. THF, 45-60°, 19-38 h

OMe 0.044 M

O O Ph

Cr(CO)5

Ph 2 eq

Ph

1. THF, 45-60°, 19-38 h OMe

361

O OH Ph

CO2Et

Cr(CO)5

O

1.5-2 eq

THF, 50°

EtO O

O (43) +

OEt

O

OMe

Cr(CO)5

[(Naphthalene)Rh(cod)]-

71

OMe

O

Ph (75)

[SbF6] (10 mol%), OMe

(27)

O

OMe O

O

H

Ph

0.05 M

1.5 eq

146

(60) TMS

2. CAN

0.044 M

Ph

146

(66) TMS

O

2. CAN

CH2Cl2, rt, 12-36 h

396

CO2Et

0.05 M O

TBSCl (3 eq), Cr(CO)5 CO2Me

TBSO R

(CO)3Cr

TBSO

+

(i-Pr)2NEt (5 eq),

212

R

I

toluene, 50°, 24 h

OMe

1.5 eq

(CO)3Cr

II

MeO MeO I + II = (74), I:II <2:98 R = CO2Me

0.25 M

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C12

Cr(CO)5

(CO)3Cr

TBSO Pr-i

I MeO I + II = (56), I:II = 94:6

MeO 1. Toluene, 120°, 24 h 2. TBSCl (3 eq), (i-Pr)2NEt (5 eq),

OMe 0.25 M

212

II

I + II = (33), I:II ≤1:99

212

toluene, 120°, 24 h Cr(CO)5

362

1. Pyridine, 80°, 60 h 2. H2O NMe2 0.05 M

2 eq

TBSO i-Pr

toluene, 50°, 12 h

Cr(CO)5

EtO

(CO)3Cr +

(i-Pr)2NEt (5 eq),

OMe 0.25 M

Pr-i 1.5 eq

TBSCl (3 eq),

O (47)

405

Me2N

OMe

O

Cr(CO)5 THF, 50°, 36 h

O OMe 1.5 eq

Ph

(8) O

O

0.04 M

+

Ph

401

(37)

O OMe

Ph

C12-14

R OH

R

n-Pr

Pr-n O

2 eq

O

Cr(CO)5

1. THF, 50°, 14-15 h 2. FeCl3-DMF

OMe

R +

O OMe O

0.05 M I

O

47

O O

n-Pr II

OMe

R

I + II

I:II

CF3

(70)

37:63

Cl

(56)

51:49

H

(67)

61:39

OMe

(68)

74:26

NMe2

(75)

79:21

O

C13

Ph Ph

TMS

Cr(CO)5

O

1. THF, 60°, 28 h

OMe

TBSCl (3 eq), Cr(CO)5

363

1.5 eq

+

Bu-t

212

II

MeO I + II = (75), I:II 57:43

1. Toluene, 120°, 24 h 2. TBSCl (3 eq),

I + II = (67), I:II ≤1:99

212

(i-Pr)2NEt (5 eq),

OMe

toluene, 120°, 24 h

0.25 M

Cr(CO)5

TBSCl (3 eq),

(CO)3Cr

TBSO

(CO)3Cr +

(i-Pr)2NEt (5 eq),

TBSO 212

toluene, 50°, 24 h

OMe 0.25 M

1. Toluene, 120°, 24 h 2. TBSCl (3 eq),

OMe 0.25 M

II

I MeO I + II = (57), I:II = 89:11

MeO

Cr(CO)5 1.5 eq

146

TBSO

I

MeO

Cr(CO)5

1.5 eq

(CO)3Cr

(i-Pr)2NEt (5 eq),

0.25 M

1.5 eq

Bu-t

TBSO (CO)3Cr

toluene, 50°, 24 h

OMe

complex mixture

TMS

O

0.05 M

Bu-t

+

(5) O

2. CAN

I + II = (47), I:II ≤1:99

212

(i-Pr)2NEt (5 eq), toluene, 120°, 24 h

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

Refs.

OH Ph Ph

Cr(CO)5

Ph 1.1 eq

(n-Bu)2O, 70°, 1.5 h

(26)

104

Ph

OMe 0.14 M

(CO)3Cr OMe OH Ph

Cr(CO)5

1.5 eq

1. (n-Bu)2O, 70°

(36)

69

(66)

13

(67)

69

Ph

2. FeCl3-DMF

OMe 0.3 M

OMe OH Ph

1.5 eq

Cr(CO)5

364

O

1. Hexane, 45°, 24 h O

2. FeCl3-DMF

OMe

Ph OMe

0.3 M

OH OEt

Ph Cr(CO)5

1.5 eq

1. THF, 45°, 24 h 2. FeCl3-DMF

OMe

Ph

EtO OMe

0.3 M E:Z = 1.6:1.0 O TMS 1.5 eq

O Ph

Cr(CO)5 1. THF, 50°, 46 h

0.03 M

OMe

TMS (25) +

Ph (27)

Ph

2. CAN

406

Ph

O

O O

TMS

Cr(CO)5 THF, 50°, 46 h

1.5 eq 0.03 M

Ph TMS

OMe Ph

OMe

(11)

406, 110

OH F n-Bu

1.5 eq

Cr(CO)5 F

n-Bu

Ph

F

Ph

(35)

1. t-BuOMe, 55°, 18 h 2. FeCl3-DMF

OMe

125

OMe OH Ph Cr(CO)5

1.5 eq

1. THF, 45°, 24 h

Me2N

Cr(CO)5

4 eq

13

OMe

Pr-n

Me2N

(89) Ph

2. FeCl3-DMF

OMe 0.3 M

Pyridine, 55°, 78 h

OEt

Pr-n

Ph

(80)

Ph

0.1 M

394

OEt

365

OH Ph

Cr(CO)5

Ph

Ph

t-BuOMe, 40-60°, 2-4 h

1.2 eq

(90)

OMe

300

Ph

0.2 M

OMe

(CO)3Cr

O Cr(CO)5

TBS

1. THF, 50°, 46 h

1.5 eq

O

TBS

Ph

OMe

Ph (35)

2. CAN

+

(17)

Ph

0.05 M

O

O

OTBS TBS

110

Ph

O Ph

Cr(CO)5

1.5 eq

Ph (26) +

CH2Cl2, 50° OMe

TBS

(8)

110

Ph

0.05 M

(CO)3Cr

Ph

OMe

OMe

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Me

C14

N

R Ph

Ph 2-4 eq

Conditions Ph

R

N Ph

2. HCl, DME, 80°, time 2

O R Cr(CO)5

4 eq

OEt

20 h (42)

395

R

R

Ph Ph

H

Time Time 5d

(81)

Me 4 d

(51)

395

OEt

OEt

366

(CO)5Cr

1. Pyridine, 80°, 60 h

2 eq NMe2 0.05 M

O

Ph

Ph Cr(CO)5

O

(0)

405

2. H2O Ph

Me2N

OH

O

MeO

36 h (50)

3d

O

Me2N Pyridine, 80°, time

0.05 M

1.5 eq

7d

n-Pr

O

O Me2N

Time 1 Time 2

Me OH

O

OEt 0.05 M

Refs.

Me

R

O 1. Pyridine, 80°, time 1

(CO)5Cr

Product(s) and Yield(s) (%)

O

Toluene, 70°, 5 h

Ph

Ph

(52)

407

Ph

0.2 M

OMe OH

Ph

Ph Cr(CO)5

5 eq O

Ph

Photolysis, THF, –20°, 0.5 h

(14) Ph O

188

NMe2 Pyridine, 80°, 3 d (CO)5Cr

O

O Me2N

(46)

Et

O

OEt

398

O Et

EtO O Cr(CO)5

R

THF, 50-55°, 4 d

NBn2

Ph

Ph

TIPSO

367

OMe

O OTIPS

(0)

OH Ph

Cr(CO)5

OH

Ph

Ph

O

CO2Me

+

Photolysis, THF, –20°, 2 h Cr(CO)5

210

OTIPS OMe (CO)3Cr (46)

OMe (7)

Ph

Ph

O

OH

CO2Me

OH Ph

Ph

OTIPS

C13

5 eq

—

+ O

Ph

397

TIPSO

t-BuOMe, 55°, 3.5 h

0.2 M Ph

75:25

TIPSO

TIPSO

2 eq

(68)

c-C3H5 (59) >95:<5

OEt

OTIPS

Z:E

n-Pr

R

NBn2 OEt

TIPSO

R

Ph

Ph

(44)

O

187

(22)

O

CO2Me C14 Cr(CO)5

O

THF, 50° 0.05 M

Ph

(50)

O

OMe

O

Ph

1.5-2 eq

71

OMe

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) O

C14

O

Ph

Ph

O B

Cr(CO)5

Ph

O 0.05 M

3 eq

OMe

1. THF, 45°, 14 h

B

2. CAN

+

O

75

O

O

O

(83)

C15 TBSCl (3 eq), Cr(CO)5 OTBS

OMe

1.5 eq

RO RO

(CO)3Cr

(CO)3Cr +

(i-Pr)2NEt (5 eq),

(14)

RO 212

I

toluene, 50°, 24 h

0.25 M

Refs.

II

RO MeO

MeO

I + II = (70), I:II <1:99 R = TBS

368

OH

Cl

OMe MeO

Sn(Bu-n)3

Cr(CO)5

O

O OEt

Ph

OEt OH

OMe

Ph

0.83 eq

OMe i-PrO

Cr(CO)5 OMe

THF, reflux, 6 h

O Pr-n

i-PrO

Pr-n

+ OMe i-PrO

i-PrO O

OH

371

(8) Ph

O O

Ph

+

Ph

0.26 M

Pr-n i-PrO

MeO (48)

Dioxane, reflux, 6 h

O

i-PrO

OH Ph

Cr(CO)5

0.77 eq

404

(20)

SiO2, 80°

OMe O

0.1 M (39) 2.8:1 mixture of isomers

(21) E:Z = 2.5:1

372, 149

C16

OH

OH

Ph

Ph Ph

Cr(CO)5

Ph

+

55-70°, 10-30 h

OMe OMe Alkyne (eq)

CC (M)

1.0

100

I

Solvent

Additive

0.05

THF

1.0

0.5

1.0

0.05

0.4

1.2

II

Ph

Ph

OMe I

II

none

(73)

(2.4)

THF

none

(73)

(2.8)

benzene

none

(44)

(<1.3)

THF

(n-Bu)3P (3 eq)

(74)

(<1.3)

OH Ph Cr(CO)5

0.4 eq

THF, 66-70°

Ph OMe

+

I

OMe HO

369

OMe 1.2 M

Time

I

9h

(67)

(4)

60 h

(5)

(0.6)

100 III

III

Cr(CO)5

EtO

O

Ph

1. Pyridine, 80°, 72 h

2 eq NMe2 0.05 M

2. H2O

405

(60) Me2N Ph OMe

OMe O

1. Dioxane, 85° 2. MeO2C

(CO)5Cr

CO2Me ,

0.75 eq Ph

CO2Me

Ph

0.02 M

408

(61)

O

dioxane, 85°, 1-2 h

CO2Me

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C16 Cr(CO)5

TBSCl (3 eq),

Product(s) and Yield(s) (%) (CO)3Cr

TBSO R

(CO)3Cr

1.5 eq

OMe 0.25 M

Cr(CO)5

toluene, 50°, 24 h

C17

I + II = (58), I:II 6:94

Sn(Bu-n)3

Cr(CO)5

R = CH2OTBS

212

toluene, 50°, 24 h O Pr-n

1. THF, 50° 2. HCl (aq)

+

370

I

3. CAN

OMe

R = CH2OTBS

(i-Pr)2NEt (5 eq), O

n-Pr

II

MeO

I + II = (53), I:II = >99:1

1. Toluene, 50°, 48 h

212

R

I

MeO

2. TBSCl (3 eq), OMe 0.25 M

TBSO

+

(i-Pr)2NEt (5 eq), CH2OTBS

Refs.

Pr-n

O

72

II

O

I + II = (68), I:II = 34.1:1 OH OH Pr-n

Cr(CO)5

I +

1. CH2Cl2, 50° OMe

I

2. I2

72

I

Pr-n

II

OMe OMe I + II = (50), I:II > 20:1 OH

OH Pr-n

Cr(CO)5 OMe

+

1. Hexanes, 50°, 18 h 2. HCl (aq)

I OMe OMe I + II = (77), I:II > 99:1

72 Pr-n

II

Ph

Cr(CO)5

EtO

O

Ph

1. Pyridine, 80°, 56 h CO2Et 2 eq

NMe2 0.05 M

405

(66) Me2N

2. H2O

CO2Et

C18

OH OH

Ph

Ph

Ph Cr(CO)5

Ph

1. THF, 55°, 24 h

+

2. Air Ph

OMe Ph

I

II

CC (eq)

I

II

1

2

(29)

(32)

1

5

(0)

(69)

5

1

(43)

(0)

371

Alkyne (eq)

Ph

EtO

O

Ph

2. H2O

NMe2 0.05 M

Ph (48)

Ph MeO

OMe

TMS OMe

TMS

1. Dioxane, 85° 2. MeO2C

(CO)5Cr

CO2Me ,

0.02 M

CO2Me

+

O

dioxane, 85°, 1-2 h Ph 0.75 eq

405

Me2N

TMS

O

MeO

Cr(CO)5 1. Pyridine, 80°, 56 h

2 eq

OH 139

OMe

OMe 0.1 M

Ph

408

O

CO2Me

CO2Me

CO2Me (5)

Ph (62)

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

C19

Carbene Complex

Conditions n-Bu

Bu-n OMe

n-Bu

2. MeO2C

CO2Me ,

Ph

OMe

(3) MeO n-Bu

1. Dioxane, 85° 2. MeO2C

(CO)5Cr

CO2Me ,

372

CO2Me

CO2Me (56)

O

(19)

O

1. Dioxane, 85° 2. MeO2C

Ph

OMe

n-Bu OMe

408

O

CO2Me

Ph

0.02 M

CO2Me

+

O

dioxane, 85°, 1-2 h

(CO)5Cr

Ph

OMe

n-Bu

0.75 eq

CO2Me

CO2Me (76)

0.02 M

408

O

CO2Me

Ph

0.75 eq

CO2Me

+

O

dioxane, 85°, 1-2 h 0.75 eq

Refs.

MeO

1. Dioxane, 85°

(CO)5Cr

O

Product(s) and Yield(s) (%) OMe

CO2Me ,

0.02 M

408

(39)

O

dioxane, 85°, 1-2 h

CO2Me

Ph

CO2Me C21 OMe (CO)5Cr

O Ar

0.02 M

Ar = O

n-Bu

1. Dioxane, 85° 2. MeO2C

CO2Me , Ar

CO2Me

+

O

dioxane, 85°, 1-2 h 0.75 eq

MeO

OMe

n-Bu

Bu-n

CO2Me CO2Me (45)

O CO2Me Ar

(30)

408

OH

C23 Cr(CO)5 R

OH R

t-BuOMe, 47°, 3.5 h

+

R

263, 409

OMe

1.1 eq

(CO)3Cr

0.23 M R=

OMe (41)

(CO)3Cr

OMe (18)

2

C24 TIPS

TIPS

OH

OMe (CO)5Cr

Solvent 1. Solvent, 55°, 24 h

THF

(70)

2. Air

toluene

(81)

TIPS

TIPS

1.1 eq

139

OMe

0.1 M

C25

OH

373

OH Ph

Ph OMe

THF, 70-74°, 12 h

(CO)5Cr OMe

Ph

OMe

(56)

100

MeO HO

Ph

0.37 eq

1.7 M O Ph

OMe 0.37 eq

Ph O

1. Benzene, 70-74°, 12-34 h

(CO)5Cr

2. CAN

O

CC (M)

100

O

0.016

(16)

0.16

(42)

1.7

(60)

TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C26 OH R

R Cr(CO)5

1 eq

R

OMe

(41)

1. THF, 55°, 24 h 2. Air

+

139

OMe

0.1 M

R OH R

R=

R OH

OMe

374

MeO

(23)

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C2

OH Cr(CO)5 1 atm

THF, 50°

(15)

OMe 0.22 M

+

(33)

131

OMe

C3

O Cr(CO)5 1. THF, 45-55°, 24 h OMe

I (59)

0.1 M

1.5 eq

61

2. Air OMe

Cr(CO)5 1.5 eq

1. MeCN, 45-55°, 24 h OMe

I (62)

61

2. Air

375

0.1 M

O

1.5 eq

Cr(CO)5

OH

1. THF, 45°, 24 h

+

(44)

(7)

61

2. Air OMe 0.1 M

OMe

trans:cis = 91:9

O 2.4 eq

Cr(CO)5

O (26)

Hexane, 60°, 24 h

OMe

+

(20)

OMe

+

207

OMe

0.05 M

OH (1-2)

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C4

Conditions

OEt

MeO

(CO)5Cr

2.5 eq

Product(s) and Yield(s) (%)

Refs.

MeO NHBn

THF, 70°, 12 h

(CO)5Cr

N Bn

Bu-n

0.1 M

(46)

410

Bu-n O

O

N Cr(CO)5

N Ph

OEt

Ph (76)

RhCl3•3H2O (2 mol%), THF/MeOH (4:1), 20°

194

MeO

0.25 M

OEt OH OH Cr(CO)5

376

OH 2 eq

OMe 0.22 M

1.5 eq

OMe

O

O

CH2Cl2, rt, 12-36 h

147

OMe

[(Naphthalene)Rh(cod)][SbF6] (10 mol%),

O

(76) (CO)3Cr

Cr(CO)5 Ac

t-BuOMe, 45°, 2-4 h

(64)

396

(22)

69

Ac

0.05 M OH Cr(CO)5

CO2Me

OMe 1.5 eq

CO2Me 1. THF, 45°, 24 h 2. Iodine OMe CO2Me

0.3 M [(Naphthalene)Rh(cod)]-

1.5 eq

O

OMe

Cr(CO)5 0.05 M

[SbF6] (10 mol%), CH2Cl2, rt, 12-36 h

(89) O O

396

O 1.5 eq

R

[(Naphthalene)Rh(cod)]-

Cr(CO)5

R

OMe 0.05 M

[SbF6] (10 mol%),

Ph

(75)

CH2Cl2, rt, 12-36 h

p-MeOC6H4

(81)

2-furyl

(88)

ferrocenyl

(71)

n-Bu

(70)

C5

R

CO2Me

396

OH Pr-n

Cr(CO)5 n-Pr

CH2Cl2, 50°

(~13)

110, 399

OMe OMe O

O Pr-n

Cr(CO)5

1.5 eq

1. THF, 50°, 24 h

377

Pr-n (66)

2. Tf2O (1.5 eq), (i-Pr)2NEt (2.5 eq), CH2Cl2, rt, 24 h

0.05 M

96

Cr(CO)3

OMe

OTBS Cr(CO)5

Pr-n

TBSOTf (1.5 eq), base (2.5 eq), 50°, 18-22 h

OMe

69

O

1. CH2Cl2, 50°, 1 d

OMe

1.5 eq

(4) Pr-n

O OTf

Cr(CO)5

1.5 eq

+

(47)

2. CAN

OMe 0.3 M

0.05 M

Cr(CO)3

OMe

Solvent

Base

THF

2,6-lutidine

(73)

CH2Cl2

2,6-lutidine

(77)

THF

(i-Pr)2NEt

(55)

95

OTBS Cr(CO)5

1.5 eq

Pr-n

1. THF, 50°, 18-22 h 2. TBSCl (1.5 eq),

(65)

Et3N (2.5 eq),

OMe 0.05 M

THF, rt, 6-12 h

95

Cr(CO)3

OMe

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OTBS

C5 (i-Pr)2NEt (3 eq),

R1 =

OR* R3 =

Ph R2 =

R4 =

378

Ph Cr(CO)5 1.5 eq OMe

Pr-n +

I

CH2Cl2, 60°, 14-19 h

OR* 0.05 M

1.9 eq

Pr-n

TBSCl (2 eq),

Cr(CO)5

n-Pr

II

Cr(CO)3 I

II

dr I

R1

(69)

(23)

60:40

R2

(83)

(—)

50:50

R3

(68)

(—)

58:42

R4

(77)

(—)

55:45

OH Pr-n (60)

2. (n-Bu)3P, rt, 36 h

69

3. MeOH, CCl4 OMe O

O Pr-n

Cr(CO)5 1. THF, 50°, 24 h OMe

205

OR*

R*

1. THF, 50°, 24 h

0.3 M

1.5 eq

Refs.

OTBS

I

+

II Pr-n

2. CAN

0.3 M

O

69

O I + II (75), I:II≥ 99:1

O Pr-n

Cr(CO)5 1. THF, 50°, 24 h

1.5 eq OMe 0.3 M Z:E = 2.2:1.0

(—)

2. CAN O

69

OTBS Cr(CO)5

Pr-n

TBSOTf (1.5 eq), 2,6-lutidine (2.5 eq),

1.5 eq OMe

(74)

CH2Cl2, 50°, 18-22 h

0.05 M

OMe

95

Cr(CO)3

OTBS Pr-n Cr(CO)5 O

1.5 eq

TBSCl (2 eq), Cr(CO)3

(i-Pr)2NEt (3 eq),

(82)

O

CH2Cl2, 60°, 14 h

205

57:43 mixture of diastereomers

0.05 M OH Pr-n Cr(CO)5

379

1.2 eq

t-BuOMe, 40-60°, 2-4 h

(75)

OMe OMe

0.2 M

300

Cr(CO)3 OH

5 eq

Photolysis, THF, –20°, 2 h Cr(CO)5

O

0.2 M MeO

187

(24)

Pr-n O OH Pr-n

Cr(CO)5 MeCN, 50°, 24 h

(64)

122

OMe OMe O

O 1.5 eq

O OMe

O

Cr(CO)5

Pr-n

1. THF, 45°, 24 h

69

(38) O

2. CAN

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

O

C5 EtO

Pr-n Cr(CO)5

n-Pr 1.5 eq

OMe 0.3 M E:Z = 1.6:1.0

1. THF, 45°, 24 h 2. CAN

(40)

69

EtO O OH Pr-n

Cr(CO)5

1.5 eq

OMe 0.3 M

1. THF, 45°, 24 h

60. 69

(54)

2. FeCl3-DMF complex OMe OH

O

n-Pr

Pr-n

Pr-n Cr(CO)5

1.5 eq

380

OMe 0.3 M

OMe (51)

1. Hexane, 45°, 24 h

+

2. Air, TsOH, THF/H2O

(9)

60, 246

O OMe OH

Pr-n Pr-n

2 eq

Cr(CO)5

O

OMe 0.005 M

(57)

1. THF, 50°, 21 h 2. Air, TsOH, THF/H2O

+

(≤0.2)

60

O

O

O

OMe O Pr-n

1.5 eq

Cr(CO)5

O

(67)

1. THF, 45°, 24 h

OMe 0.3 M

2. CAN

Cr(CO)5

1. CH2Cl2, 50°

69, 13

O O OH

TMS

Pr-n

OMe

(60)

2. Air, CF3CO2H OMe

110

OTf TMS

1. CH2Cl2, 50°, 24 h Cr(CO)5

Pr-n (81)

2. Tf2O, (i-Pr)2NEt CH2Cl2, rt, 12-15 h

OMe

TMS

96

Cr(CO)3 OMe OTBS

TMS

Pr-n Cr(CO)5

50°, 18-22 h

0.05 M

TMS Cr(CO)5

OMe I

Base

Solvent

TBSCl

Et3N

THF

(44)

TBSCl

(i-Pr)2NEt

THF

(37)

TBSOTf

2,6-lutidine CH2Cl2

Silane

95, 72

I TMS

OMe

1. THF, 50°, 18-22 h

Cr(CO)3

(79)

I (60)

95

381

2. TBSCl, Et3N

OMe 0.05 M

O

TMS

Pr-n Cr(CO)5

2 eq

1. Heptane, 50°, 24 h

95

(76) TMS

2. CAN

OMe

O

0.05 M

OH

Pr-n Pr-n

Cr(CO)5

1.5-2 eq

OMe

1. Solvent, 45-50°, 18-24 h

+

I

II

2. Oxidant, solvent O

OMe CC (M)

Solvent 1

Oxidant, Solvent 2

I

II

0.5

THF

air, TsOH, THF/H2O

(69)

(≤2)

60

0.005

THF

air, TsOH, THF/H2O

(65)

(≤6)

60

MeOH

FeCl3-DMF complex

(72)

(—)

13

0.3

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

OH

Refs.

OH Pr-n

Cr(CO)5

n-Pr

THF, 45°, 24 h

+

I

II

101

Pr-n

OMe OMe

OMe I + II (55), I:II≥250:1

OE

OH Pr-n

Pr-n Cr(CO)5

EX, (i-Pr)2NEt, 50°, 24 h

Cr(CO)3 OMe I

OMe

OMe

II OMe

EX

Solvent

Tf2O

CH2Cl2

(43)

(23)

96

AcBr

THF

(64)

(—)

95

382 Cr(CO)5

+

I

1. THF, 50°

I

2. EX, base

II

EX

Base

I

TBSCl

Et3N

(65)

95

MEMCl (i-Pr)2NEt (68) O Pr-n

Cr(CO)5

1.5 eq

OMe

1. Solvent, conditions 2. CAN O Solvent

Conditions

0.3

THF

45°, 24 h

(61)

69

0.3

MeCN

45°, 24 h

(69)

13

0.08

(n-Bu)2O ultrasound, rt,

(75)

177

CC (M)

10 min

OTBS Cr(CO)5

1.9 eq

CH2Cl2, 60°, 10-12 h

OMe

Pr-n +

I

(i-Pr)2NEt (3 eq), OMe

II

Cr(CO)3

OMe

207

Cr(CO)3

I + II (65), I:II = 60:40

0.05 M

OTBS

R Cr(CO)5

R

Pr-n +

I

(i-Pr)2NEt (3 eq), CH2Cl2, 60°, 10-12 h

OMe

OTBS

R Pr-n

TBSCl (2 eq), 1.9 eq

OTBS Pr-n

TBSCl (2 eq),

OMe

0.05 M

II

Cr(CO)3

OMe

R

I + II

I:II

Me

(50)

76:24

OMe

(48)

94:6

207

Cr(CO)3

OH

383

Pr-n Cr(CO)5

1.5 eq

(66)

1. THF, 45°, 24 h

69

2. FeCl3-DMF complex

OMe 0.3 M

OMe EtO

Cr(CO)5

R 3.5-7 eq

EtO

THF, 52°, 14 h R

Pr-n

NMe2

R NMe2 I

0.04 M EtO

i-Pr

(14)

c-Pr

(77)

411, 412

Pr-i THF, 52°, 14 h

3.5-7 eq (CO)4Cr

I R = i-Pr (30)

411

NMe2

0.04 M

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C5

Conditions

Product(s) and Yield(s) (%) EtO

Cr(CO)5 EtO

n-Pr

NMe2

n-Pr

NMe2

NMe2

n-Pr +

Pr-n +

See table.

n-Pr

Refs.

O

Pr-n

EtO

n-Pr

I O

NMe2 III

Pr-n + OEt III O

NMe2

n-Pr

+

O

n-Pr Pr-n

Et OEt

NMe2

IV

V

384

Alkyne (eq)

CC (M)

Solvent

Time

Temp

Additive

I

II

III

IV

V

4.5

0.01

hexane

90 h

55-60°

none

(11)

(0)

(10)

(0)

(0)

412

4

0.1

hexane

20 h

55-60°

none

(26)

(tr)

(27)

(0)

(0)

412

34

0.1

hexane

20 h

55-60°

none

(24)

(tr)

(25)

(0)

(0)

412

101

0.1

1-pentyne 20 h

55-60°

none

(22)

(tr)

(24)

(0)

(0)

412

4

0.1

THF

60 h

55-60°

none

(20)

(tr)

(47)

(0)

(0)

412

34

0.1

THF

22 h

55-60°

none

(22)

(tr)

(37)

(0)

(0)

412

3.5-7

0.04

THF

14 h

52˚

none

(9)

(—)

(—)

(—)

(—)

411

4

0.1

DMF

144 h

55-60°

none

(27)

(tr)

(0)

(0)

(28)

412

34

0.1

DMF

48 h

55-60°

none

(25)

(tr)

(0)

(0)

(27)

412

4

0.1

MeCN

72 h

55-60°

none

(40)

(14)

(0)

(26)

(0)

412

34

0.1

MeCN

14 h

55-60°

none

(13)

(2)

(1)

(45)

(0)

412

4

0.1

DMF

90 h

55-60°

Ph3P (1 eq)

(42)

(10)

(0)

(6)

(6)

412

4

0.1

DMF

72 h

55-60°

Ph3P (10 eq)

(50)

(12)

(0)

(0)

(0)

412

60

0.1

DMF

60 h

55-60°

Ph3P (1 eq)

(21)

(5)

(0)

(0)

(24)

412

4

0.1

pyridine

88 h

55-60°

none

(68)

(11)

(0)

(3)

(0)

412

1.5

0.05

pyridine

7h

80°

none

(78)

(15)

(0)

(0)

(0)

412

4

0.1

hexane

7h

55-60°

MeCN (1.8 eq)

(6)

(tr)

(13)

(59)

(0)

412

O

O Pr-n

1.9 eq

Cr(CO)5

Pr-n +

Solvent, 60°, 24 h

+

207

I OMe 0.05 M

III

OMe

OMe OH

I

II

III

THF

(27)

(25)

(—)

hexane

(46)

(37)

(<3)

MeCN

(43)

(17)

(—)

Solvent

n-Pr

III

Pr-n

O Cr(CO)5

Pr-n

THF, 50°, 24 h

OMe

(47)

112

(65)

95

MeO

0.05 M

385

OTBS TBS

Pr-n

2,3-DimethylCr(CO)5

1.5 eq

butadiene (50 eq), THF, 50°, 7 d

OMe

Cr(CO)3 OMe

0.07 M O Cr(CO)5

TBS

O

TBS

Pr-n

1. THF, 45-60° 2. CAN

OMe

Pr-n +

(<5) O

OTBS Pr-n

Cr(CO)5

110

O

OH TBS

(<5)

Pr-n +

(0)

CH2Cl2, 50°

(72)

110

OMe OMe

OMe

Cr(CO)3

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

C5

Carbene Complex

Conditions

n-Pr

EtO

3.5-7 eq

t-Bu

Product(s) and Yield(s) (%) OEt n-Pr

EtO

(CO)5Cr

Pr-n (0)

THF, 52°, 14 h to 7 d NMe2

0.04 M

t-Bu

Refs.

+

(43)

NMe2

411, 413

Bu-t

O n-Pr

O Pr-n Cr(CO)5

(67)

THF, 50°, 24 h

112

0.05 M

OMe

OMe O

O

TBS TBS

Cr(CO)5

Pr-n

1. THF, 45°, 24 h

(<5)

2. CAN

386

OMe

O

THF, 55°

Pr-n (CO)5Cr

OEt

(63) E:Z = 2:1

412

Pr-n 0.1 M

OEt O

Pr-n

O

n-Pr

See table

Pr-n

N-morph Alkyne (eq)

95

N

n-Pr

OEt (CO)5Cr

(<62) O

O

N 4 eq

Pr-n +

N-morph Solvent

Temp Time

6

DMF

55°

36 h

(52)

3

THF/H2O (99:1)

80°

3h

(54)

414

O

N-morph 4 eq

(CO)5Cr

Pr-n

THF, 80°, 3 h

O

N-morph

n-Pr

+

Pr-n

OEt

OEt (13)

O 3 eq

DME, 65°, 15 h (CO)5Cr

414, 412

OEt (56) Pr-n

N-morph

n-Pr

N-morph

n-Pr

(66)

Pr-n

415

N-morph OEt

OEt 0.05 M O

Pr-n 3 eq

(CO)5Cr

N-morph

THF/MeCN (9:1), 65°, 15 h

N-morph

n-Pr

(82)

OEt

415

OEt

387

0.05 M N-morph

c-Pr

N-morph n-Pr 4.5 eq

(CO)5Cr

Pr-c

412

(67)

THF, 55°

OEt

OEt

0.05 M n-Pr

OEt (CO)5Cr

NHMe

N Me

(CO)5Cr

THF, 65° OTBS

OEt 8 eq

416

OTBS n-Pr

OEt

(CO)5Cr

(25)

EtO (66)

THF, 52°, 7 d O

NMe2

OEt

n-Pr

0.05 M

413

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

C5

Carbene Complex

Conditions

(CO)5Cr

Refs.

n-Pr OEt

n-Pr 8 eq

Product(s) and Yield(s) (%) EtO

THF, 52°, 7 d

413

O n-Pr

EtO

OH

Ph Ph

Pr-n

Photolysis,

5 eq O

(17)

OEt

0.05 M

Me2N

(37)

187

THF, –20°, 0.5 h

Cr(CO)5

O OH

Cr(CO)5

388

TMS OMe MeO

Pr-n

THF, 50°, 24 h

(56)

112

0.05 M MeO MeO OMe OH

OMe

Pr-n 1.1 eq

OEt MeO MeO

t-BuOMe, 55°, 30 min MeO OMe OMe n-Pr

(CO)5Cr OEt Me2N

+

Ph

n-Pr

OTMS

Pr-n Ph

n-Pr

(21)

THF, 55°, 36 h O

0.05 M n-Pr

(0)

411, 413

NMe2 Pr-n

OEt Me2N

OEt Me2N

EtO (19)

O

(CO)5Cr 4 eq

Cr(CO)3

OEt

THF, 52°, 14 h to 7 d 0.04 M

Ph

279

0.25 M

Cr(CO)4

3.5-7 eq

417, 418, (57)

OEt

+

OTMS

(38) 416 Cr(CO)3

OH

Ph

Ph Cr(CO)5

5 eq

Pr-n

THF, –20°, 0.5 h

(30)

188

photolysis

O

O OTMS

TMS

Pr-n

OMe

1.5 eq

(97)

THF, 45°, 24 h

12, 95, 112

0.05 M Cr(CO)5

OMe

(CO)3Cr

OH 1. THF, 45°, 24 h

Cr(CO)5

Pr-n

2. Silica gel

389

TMS OMe 0.05 M

(95)

112

MeO

O

OH

O 1. THF, 45°, 12 h

O

Cr(CO)5

Pr-n (64)

O

2. Air

12

OMe

OMe O

TMSO

O OMe

Pr-n (33)

THF, 50°, 24 h

OMe Cr(CO)5 0.05 M

112

OMe OH Pr-n 1. THF, 60°, 42 h

Cr(CO)5

N Boc

(60)

121

N

2. Air OMe

Boc

OMe

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

C5

Carbene Complex

Conditions

Product(s) and Yield(s) (%) TBSO

OTBS

OTBS

n-Pr

CH2Cl2, 60°, 10-12 h

0.05 M

OMe

OTBS Pr-n

+

(i-Pr)2NEt (3 eq),

Cr(CO)5

1.9 eq

TBSO Pr-n

TBSCl (2 eq),

Refs.

(CO)3Cr

207

I

(CO)3Cr

OMe

II OMe

OTBS Pr-n +

I + II (<2); III (79) (CO)3Cr

TBSO

OTBS

III OMe

O

O Pr-n

390

1.9 eq

(47)

1. CH2Cl2, 60°, 10-12 h

Cr(CO)5

(11)

207

2. CAN

0.05 M

OMe

Pr-n +

O

O

OH Pr-n 3 eq

1. Hexanes, 50°, 24 h Cr(CO)5 OMe OMe

(65)

299

(58)

121

2. Air OMe OMe

0.15 M

OH Pr-n 1.5 eq N Boc

Cr(CO)5 OMe

0.04 M

1. THF, 60°, 42 h 2. Air

N Boc

OMe

O

OEt (CO)5Cr

6 eq

Ph

DMF, 55°, 45 h

O

n-Pr

(39)

Ph

N-morph

414

N-morph OH 1. 2-Trimethysiloxy-1,3-

TMS 1.5 eq

O

Pr-n

butadiene (15 eq),

Cr(CO)5

(58)

THF, 50°, 36 h OMe

0.03 M

2. Silica gel, air

OEt

OMe Me2N

(CO)5Cr

4 eq

OTBS

Hexanes, 55°, 24 h

OTBS

n-Pr

NMe2

0.1 M

391

Cr(CO)5

0.04 M

394

OH

O

O

(92)

OEt

O 1.2 eq

112

1. THF, 45°, 48 h

Pr-n (60)

O

12

2. FeCl3-DMF OMe

TMS OMe

Bu-n

n-Bu

OH Pr-n

1.5 eq

Cr(CO)5

N Boc

(47)

1. THF, 60°, 42 h

OMe

Boc

OMe

R

R

Me2N

R

NMe2

n-Pr

n-Pr Pyridine, 80°, 3 d

OEt

121

N

2. Air

+

(41)

Cr(CO)5

(21)

Me2N

OEt

398

OEt

R= O

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C5

Conditions

Product(s) and Yield(s) (%) 1

R 1O

Refs.

1

OR OH

OR OH Pr-n

(CO)5Cr

n-Pr 3 eq

+

1. Benzene, 55-58°, 36 h

1.0 M

OMe OMe

MeO

392 OMe

0.33 M

OMe

R2

I + II

I:II

Me

Me

(40)

II only

Me

Et

(43)

II only

Me

i-Pr

(47)

II only

Me

t-Bu

(50)

II only

Et

Me

(73)

1:13.2

i-Pr

Me

(72)

1:12.5

OMe

MeO

OMe OH Pr-n

Pr-n

+

I

OR2

II

OMe

OMe OH Cr(CO)5 1. Benzene, 55-58°, 36 h 2. Air

OR1

MeO

R1

MeO

3 eq

OR2 OMe

I

OMe

OMe

MeO

211

OR2 OMe

2. Air

R2O MeO

Pr-n

2 OR1 OR

II 2 OR1 OR

R1

R2

I + II

I:II

Me

Me

(53)

3.0:1

Me

Et

(45)

2.4:1

Me

i-Pr

(51)

2.4:1

Me

t-Bu

(48)

2.0:1

Et

Me

(45)

2.1:1

i-Pr

Me

(45)

2.1:1

i-Pr

t-Bu

(48)

3.4:1

211, 299

OEt 4 eq

O

OTBS

(CO)5Cr

THF/H2O (99:1), 80° 3 h

O

n-Pr OTBS

N-morph OEt N-morph DME, 65°, 15 h

3 eq 0.05 M

4

OTBS

(62)

415

4

OTBS OEt OTBS Pr-i CH2Cl2, 65°, 20 h

OMe

i-Pr 2 eq

Cr(CO)5 R

0.1 M

(68) (CO)3Cr

393

Pyridine, 80°, 3 d Cr(CO)5 R= O

R + Me2N

(24)

(20)

OEt

398

OEt

O c-Pr Hexane, 55°, 24 h

EtO

NMe2

c-Pr (95)

0.1 M

Cr(CO)5 R

110

i-Pr

i-Pr

NMe2

c-Pr

OMe NMe2

R

NMe2

EtO

4 eq

N-morph

n-Pr

TBS

c-Pr

414

N-morph O

(CO)5Cr

(50)

OEt R

NMe2 Pyridine, 80°, 3 d

EtO

394

Cr(CO)5

R

NMe2

c-Pr(H) (36) H(c-Pr)

+

c-Pr Me2N

(24)

OEt

398

OEt

R= O

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C5

(CO)5Cr OMe 1.5 eq

1. THF, 45°, 24 h

Cr(CO)5

2 eq

1. Pyridine, 80°, 45 h 0.05 M NMe2 R2N

2. H2O

O

(73)

OEt

394

0.25 M Cr(CO)5

Ph

RhCl3•3H2O (2 mol%), OEt

N-morph Ph +

THF, 60°, 12 h

OMe 0.05 M

193

(10)

N-morph

OEt TBSO

MeO 1.9 eq

(74) NR2 = morpholine

N-morph Ph

Cr(CO)5

194

(76) NR2 = NMe2

THF/MeOH (4:1), 20°

Ph EtO (CO)5Cr

405

Me2N R 2N

Ph

1.5 eq

69

OMe

0.3 M EtO

1.5 eq

(57)

2. FeCl3-DMF

(25)

OEt TBSO

OMe

2,6-Lutidine, TBSOTf,

OMe

+

CH2Cl2, 60°, 12-24 h

(70) (CO)3Cr OMe OH

(CO)3Cr OMe

88 (12)

OMe Cr(CO)5

1.5 eq

OMe 0.3 M

1. THF, 45°, 24 h

OMe

2. SiO2, air OMe

(68)

12, 69

OH

Cl

OH

OEt

HO

Silica gel, 80°

(20)

404

(32)

404

O

O Cr(CO)5

3 eq

OH

Cl

OH

OEt

O

I

OEt

Silica gel, 80° O

Cr(CO)5

OEt O 1. THF, reflux

OEt

(41)

2. Ph3P, DEAD,

395

Cr(CO)5

289

THF, 20° (CO)3Cr OEt

SPh OEt

8 eq

1. Silica gel, 80°

O Cr(CO)5

I (19)

91

I (39)

91

2. Pyridine-N-oxide

Ph S 8 eq

Cr(CO)4 O

1. Silica gel, 80° 2. Pyridine-N-oxide

OEt O H

OEt

3 eq

1. THF, reflux

OH

H

(≥34)

2. CAN Cr(CO)5

289

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

O 1. THF, reflux

H

OEt

HO Cr(CO)5

3 eq

2. PPh3, DEAD, THF, 20°

(≥7)

H

289

3. Air, benzene, hn OEt

OEt

O

(CO)5Cr 1. THF, reflux 3 eq

(≥31)

2. PPh3, DEAD, THF, 20° 3. Air, benzene

O O

O O O

396

O

O

Cr(CO)5

O

1. MeCN, 45-55°, 24 h

O OMe 1.5 eq

(55)

61

2. Air

0.1 M

OMe OH Cr(CO)5

1.5 eq

289

OEt

OMe 0.3 M

O O (33)

1. THF, 45°, 24 h

69

2. FeCl3-DMF OMe O TMS

Cr(CO)5 TMS

Solvent, 45-55°, 24 h 1.5 eq

OMe 0.1 M

OMe

Solvent THF

(50)

MeCN

(73)

61

OH

Cl

TMS OEt

Silica gel, 80°

(36)

404

O

O Cr(CO)5

OEt OTBS

TMS

TMS Cr(CO)5

1.5 eq

1. THF, 50°, 22 h 2. TBSCl, Et3N, rt, 16 h

OMe 0.05 M

TMS (CO)3Cr

(40)

72

(71)

69, 13

(71)

239

OMe OH TMS

Cr(CO)5

1.5 eq

1. THF, 45°, 24 h 2. Air

397

OMe 0.05 M

OMe O TMS

Cr(CO)5 THF, 50°, 36 h OMe OMe

OAc 1. THF, 50-55°, 16-36 h Cr(CO)5

O

OMe

TMS

O

2. Ac2O, pyr, DMAP,

(—)

295

CH2Cl2, rt, 16-24 h OMe

Me2N

Me2N

Pr-n OEt

2 eq

Pr-n

TMS MeCN, 80°, 8 h

(53)

Cr(CO)5

394

OEt

0.05 M

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

O

O TMS

Cr(CO)5

TMS 1.5 eq

Refs.

TMS +

THF, 45°, 24 h

61

OMe 0.1 M

I

OMe

II

OMe

I + II (75), I:II = 92:8 H

O

O

H OMe

(37) 2:1 mixture of isomers O

H

Cr(CO)5

H

398

OMe 2.2 eq

TMS

MeO +

THF, 80°

124

O OMe

Cr(CO)5

OMe

OMe OH

MeO OEt

O

419

OMe OMe OH

Cl

MeO

TMS

THF, 55°, 24 h

O I

OMe

OEt

TMS II

OEt

I + II (28) O O O

O

O

R

NMe2

2-4 eq

Pyridine, 80°, 4 d

O

NMe2

R TMS

NMe2

R

+

395

EtO Cr(CO)5 0.05 M

TMS

OEt I

OEt II

R

I

II

H

(40)

(9)

Me

(45)

(9)

MeN n-Pr O

2-4 eq

Me N

n-Pr

O Pyridine, 80°, 40 h

O

TMS

(56)

O

EtO Cr(CO)5 0.05 M Ph

395

OEt Ph

Ph

O

O 3 eq

+ TMS

THF, reflux O

OMe

O

MeO

420

Cr(CO)3

(13) (50) 1.4:1 mixture of isomers

0.07 M OEt

O

N-morph

399

THF/MeCN (9:1), 75°

N-morph OTBS

TMS

(—)

415

OEt

TBSO OTBDPS

OTBDPS

TBDPSO

TBDPSO

OAc

1. THF, 55°, 28 h 3 eq

TMS

MeO

Cr(CO)5

(CO)5Cr

O

2. Ac2O, pyr, DMAP,

O OMe

OTBDPS

TBDPSO

TMS

O

(—)

295

CH2Cl2, rt, 16-24 h

Cr(CO)5

OMe

C6

O OMe

Bu-n

(CO)5Cr

n-Bu

0.1 M

1.5 eq

Solvent

Solvent, 45-55°, 24 h

THF

(60)

MeCN

(80)

61

OMe

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

O

O Bu-n

Cr(CO)5

n-Bu 1.5 eq

Refs.

THF, 45°, 24 h

Bu-n I

+

II

61

OMe OMe

0.1 M Cr(CO)5

Bu-n

OEt

THF, 60°, 2 h

(66) Ph

NH2

Ph

OMe OH Cl

2.2 eq

MeO

400

OEt

O

Bu-n

THF, 80°

(42) OMe

OEt R

Cr(CO)5

Cr(CO)5

Bu-n OEt

2.5 eq Ph

124

O

Cr(CO)5

OMe

410

N

OMe MeO

OMe

I+II (78), I:II = 90:10

THF, 70°, 12 h Ph

NHR 0.1 M

N R

Me

(54)

i-Pr

(48)

Ph

(42)

Bn

(46)

410

Cr(CO)5

Cr(CO)5

Bu-n OEt

2.5 eq

THF, 70°, 12 h

(71) n-Bu

n-Bu NHBn 0.1 M

O

SO2Ph 8 eq

O

OMe

Bu-n 1. Silica gel, 70° 2. CAN

Cr(CO)5

410

N Bn

(37) O O

91

H O 3 eq

(70)

THF, reflux OMe

O 0.07 M

O

Bu-n

Cr(CO)5

420

3:1 mixture of isomers

MeO

Ph

Ph O

3 eq

THF, reflux

0.07 M

420

(57) O

OMe

O

Bu-n

5:1 mixture of isomers

MeO

Cr(CO)5

H O 3 eq

THF, reflux

401

OMe

MeO

OMe THF, reflux OMe

MeO OMe

15:1 mixture of isomers

MeO

OMe MeO

3 eq

Bu-n

Cr(CO)5

0.07 M

420

(53) MeO

MeO

O

MeO

Bu-n

420

(52) OMe MeO

Cr(CO)5

0.07 M Ar 3 eq

O

Ar OMe

O

Bu-n

Ar

THF, reflux

Ph O

Cr(CO)5

0.07 M

420

(45)

PMP (62) OMe

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C6

Conditions

Product(s) and Yield(s) (%)

R

R2

R1 t-Bu

Refs.

OTBS

2

Bu-t

A: TBSCl (2 eq),

O

(CO)5Cr

R1

(i-Pr)2NEt (3 eq),

1.9-4.0 eq

Cr(CO)3 O

CH2Cl2, 60°, 14 h B: 1. t-BuOMe, 55°, 55 min R1

R2

CC (M)

Me

H

0.4

H

Me

0.05

Method

2. Filter through SiO2 3. TBSCl (4 eq), NEt3 (3 eq), rt, 3 h

% de

(63)

57:43

14

97

A

(78)

52:48

4

205

—(CH)4—

0.05

A

(90)

55:45

10

205

—(CH)4—

0.4

B

(59)

58:42

16

97

402

O

Cr(CO)5 OEt Me2N

THF, 60°, 20 h

Pr-i

Pr-i

Me2N

Pyridine, 80°, 2 d

t-Bu Pr-i (9)

0.05 M

O

OEt Ph N-morph

DMF/H2O (99:1), 55°, 36 h

Cr(CO)3 Pr-i

N Me (11)

(15) R = NMe2 O O

Pr-i

(CO)5Cr

+ t-Bu

R (47) R = OEt

OEt

2 eq

OEt

O

t-Bu

Cr(CO)5

6 eq

dr

B

t-Bu

421

O

+

Pr-i

421

N Me

OEt

(60)

O

t-Bu Ph N-morph

(54)

414

O

OEt 3-6 eq

(CO)5Cr

Pr-n N-morph

Solvent/H2O (99:1),

O

Solvent

t-Bu Pr-n

55-80°, 3-36 h

THF

(51)

DMF

(30)

414

N-morph O 1. THF, reflux

H

OEt

HO

Cr(CO)5

2. PPh3, DEAD,

(50)

H

Cr(CO)3

OEt

5 eq OMe MeO

OMe OH Cl

2.2 eq

MeO OEt

O

403

OMe

99

THF, –10° to –20°

THF, 80°

OH (16)

MeO

+

124

O

Cr(CO)5

OEt OMe MeO

Cl

O H

MeO

(18)

O

O OEt

O

Cl

OH

1. THF, 80°, 16 h

OEt

O

2. PPh3, DEAD

Cr(CO)5

2 eq Me2N

OEt

MeCN, 80°, 8 h

(53)

394

Pr-n

TMS

0.05 M Cr(CO)5

2 eq

404

OEt Me2N

Pr-n

TMS

(33) O

OEt

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C7

Conditions

Product(s) and Yield(s) (%)

SO2Ph n-C5H11

O

C5H11-n

1. Silica gel, 70°

OEt

8 eq

Refs.

O

2. CAN

(49)

91

O

Cr(CO)5

O OH

OEt Cr(CO)5

1.5 eq

(23)

1. THF, 45°, 24 h 2. Air

OMe

69

EtO OMe

0.3 M EtO

Cr(CO)5 O (43)

404

1. Pyridine, 80°, 60 h 2 eq

2. H2O

NMe2 0.05 M

Me2N

TBSO EtO

OEt

Cr(CO)5

TBS

OEt CH2Cl2, 65°, 20 h

EtO 2 eq

405

(53)

110

OMe 0.05 M

OMe

Cr(CO)3

TBSO

OTMS

TBSO

OTMS

Cr(CO)5 +

(i-Pr)2NEt, TBSCl, TMSO 1.9 eq

OMe 0.05 M

CH2Cl2, 60°, 12-24 h (CO)3Cr OMe

I

(CO)3Cr OMe

I + II (75), I:II = 90:10

88 II

Me2N O

Cr(CO)5

Me2N Me2N

Pyridine, 80°, 2 d 2 eq

Pr-i

OEt

Pr-i

(58)

421

(76)

95

(47)

95

N

0.05 M

Me O CN

Cr(CO)5 NC

2. CAN

OMe 0.5 M

2 eq

1. Heptane, 50°, 24 h O OTf CN

Cr(CO)5

1.5 eq

Tf2O, 2,6-lutidine, CH2Cl2, 50°

OMe

OMe

0.05 M

Cr(CO)3

405

OTBS Cr(CO)5

1.5 eq

CN

TBSOTf (1.5 eq),

Me

CH2Cl2, 50-65°, 15-24 h

OR

R

2,6-lutidine (2.5 eq),

159, 95

c-C6H11 (75)

Cr(CO)3

OR

0.05 M

(73)

OTBS 1. THF, 50° 1.5 eq

Cr(CO)5

CN

2. TBSCl (1.5 eq),

(67)

Et3N (2.5 eq), rt, 6-12 h

OMe 0.05 M

OMe

95

Cr(CO)3

O CN Cr(CO)5

2 eq

1. Heptane, 50°, 24 h

(57)

95

2. CAN

OMe 0.5 M

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OR

C7 Cr(CO)5

CN

ROTf (1.5 eq), 2,6-lutidine (2.5 eq),

NC 1.5 eq

OMe 0.05 M

R TBS

CH2Cl2, 50-65°, 15-24 h OMe

(73)

159, 95

TIPS (68)

Cr(CO)3

OTBS Cr(CO)5

CN

1. THF, 50° 2. TBSOTf (1.5 eq),

1.5 eq OMe

(22)

Et3N (2.5 eq), rt, 6-12 h

0.05 M

OMe

95

Cr(CO)3

OE CN

406

1.5 eq

Cr(CO)5 OMe 0.05 M

EX (1.5 eq), base (2.5 eq),

159, 95

solvent, 50-65°, 15-24 h OMe

Cr(CO)3

EX

Solvent

Base

TBSOTf

CH2Cl2

2,6-lutidine

(72)

TIPSOTf

CH2Cl2

2,6-lutidine

(76)

AcBr

THF

(i-Pr)2NEt

(55)

OE CN

1. Solvent, 50° 1.5 eq

Cr(CO)5 OMe 0.05 M

159, 95

2. EX (1.5 eq), base (2.5 eq), rt, 6-12 h OMe

Cr(CO)3

Solvent

EX

THF

TBSCl

Et3N

(65)

CH2Cl2

TIPSOTf

2,6-lutidine

(72)

THF

Ac2O

Et3N

(31)

Base

OTBS TMS

CN

1. THF, 50° Cr(CO)5

1.5 eq

2. TBSCl (1.5 eq), Et3N (2.5 eq), rt, 6-12 h

OMe 0.05 M

(52) TMS OMe

95

Cr(CO)3

OTBS CN

Cr(CO)5

TBS 2 eq

CH2Cl2 or THF, OMe 0.05 M

(68-69)

45-65°, 11-24 h OMe

110

Cr(CO)3 OH

OTBS

TBS Cr(CO)5

TBS

159, 95,

4 CN

THF, 45°, 24 h

OMe OMe

4

(<5) +

Cr(CO)3

OMe

CN

(43)

95

Cr(CO)3

407

OTBS TBS

CN Cr(CO)5

1.5 eq

2,3-Dimethyl-

(68)

butadiene (50 eq), OMe 0.07 M

C8

THF, 50°, 6 d

OMe O

Cl n-C6H13

95

Cr(CO)3

C6H11-n

1. Silica gel, 80°

OEt

O

2. CAN

Cr(CO)5

404

(52)

404

O O

Cl

C6H11-n

1. Silica gel, 80°

OEt

O

(31) O

2. CAN

O

Cr(CO)5

O

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C8

Conditions

Product(s) and Yield(s) (%)

SPh n-C6H13

C6H11-n

OEt

O

Refs.

O I (9)

1. Silica gel, 80° 2. CAN

Cr(CO)5

91

O O

PhS Cr(CO)4

O

1. Silica gel, 80°

I (18)

91

2. CAN

OEt

TBSO

Bu-t

Cr(CO)5

t-Bu

(i-Pr)2NEt, TBSCl,

408

1.9 eq

OMe 0.05 M

CH2Cl2, 60°, 12-24 h

(79) 55:45 mixture of isomers

88

(CO)3Cr OMe TBSO

TBS

Cr(CO)5 CH2Cl2, 65°, 19 h

(40)

110

OMe 2 eq

0.05 M

(CO)3Cr OMe

Me2N

Cr(CO)5 O OEt

2 eq

1. Pyridine, 80°, 60 h 2. H2O

(40)

405

Me2N

0.05 M R2N R2N

Ph NR2

Cr(CO)5 RhCl3•3H2O (2 mol%),

1.5 eq Ph 0.25 M

OEt

THF/MeOH (4:1), 20°

NMe2 OEt

(72)

N-morpholino (73)

194

N-morph Ph

N-morph (CO)5Cr

1.5 eq

Pr-i OEt

THF, 60°, 12 h

(26)

Pr-i

Ph

193

OEt O Ph

Cr(CO)5 Ph OMe

THF

(55)

2. Air

MeCN

(81)

0.1 M

1.5 eq

Solvent

1. Solvent, 45-55°, 24 h

61

OMe O Ph

4 eq

OEt

O

Medium

1. Medium, 70° O

2. CAN

Cr(CO)5

Silica gel

(2)

THF

(2)

91

O

409

OH Ph OMe

1.5 eq

1. THF, 45°, 24 h

(76)

69

2. FeCl3-DMF

Cr(CO)5 0.3 M

OMe NMe2

NMe2 Ph 3.5-7 eq

(2)

THF, 52°, 14 h Cr(CO)5

EtO

411

OEt

0.04 M O Ph 2 eq

1. THF, 50°, 9 h

OMe

O

2. CAN

(60)

146

O

Cr(CO)5

O

0.04 M

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8

Refs.

O Ph

1. (n-Bu)2O, 130°, 300 s, OMe

Ph 2 eq

microwave

c-Pr 3.5-7 eq

NMe2

192

I (62)

411

O NMe2

c-Pr

EtO

THF, 52°, 14 h Cr(CO)5

(75)

2. CAN

0.05 M Cr(CO)5

Ph

0.04 M

OEt

c-Pr NMe2 3.5-7 eq

THF, 52°, 14 h Cr(CO)4

410

EtO

I (72)

i-Pr

i-Pr NMe2

3.5-7 eq

THF, 52°, 14 h Cr(CO)4 EtO t-Bu

3.5-7 eq

411

0.04 M NMe2

Ph

(27)

0.04 M

OEt

NMe2

t-Bu

EtO

411

THF, 52°, 14 h to 7 d

Ph

OEt

Ph

NMe2 (0)

+

(52)

0.04 M Cr(CO)5

OEt

(CO)5Cr Ph

R 3-6 eq

EtO

EtO Me2N

Ph R

Ph

R

Ph

EtO

TMS

Ph R R

Ph

+

THF, 55°, 4 d R

NMe2

422, 423 R

Ph I

411, 413

Bu-t

O

NMe2 Ph

R

I + II

I:II

H

(62)

1.8:1

D

(64)

1.8:1

II

O

O Ph

OMe

1.5 eq

(3)

OMe

OMe

OMe

O

H

Ph

THF, 55°, 16 h

(21) 2.5:1 mixture of isomers O

Cr(CO)5

H

1.5 eq

O

TBS

Cr(CO)5

Ph

Ph

1. THF, 65°, 17 h 0.02 M OMe

424

OMe O

TBS

61

2. Air

Cr(CO)5 0.1 M

O

Ph (55) +

1. THF, 45°, 24 h

+

(<5)

(54)

110

2. CAN O

O

411

OTBS Ph

Cr(CO)5

TBS 1.5 eq

CH2Cl2, 65°, 19 h

(44)

110

OMe 0.05 M

(CO)3Cr

OMe

(CO)5Cr R1 2.5 eq

Ph

Cr(CO)5 THF, 70°, 12 h

NHR2 OMe

R1

0.1 M

(CO)5Cr

R2

Ph

Me

(34)

Ph

Bn

(19)

n-Bu Bn

(57)

R THF, 52°, 7 d

OEt 0.05 M

410

OEt

Ph

R

8 eq

N R2

R1

O

OEt

OEt

Ph

OEt

(27)

NMe2

(51)

413

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

C8

Carbene Complex

Conditions Ph

OEt

(CO)5Cr

Product(s) and Yield(s) (%)

Ph

THF, 52°, 7 d OEt 0.05 M NMe 2

8 eq

3 eq Pr-n

(41)

413

Ph O THF/MeCN (9:1),

(CO)5Cr

OEt

O

N-morph

OEt

Refs.

OEt

65°, 15 h

N-morph

Ph

(97)

415

Et

0.05 M OEt n-Pr 2 eq

N

n-Pr MeCN, 80°, 8 h

412

EtO

(95)

0.05 M

(CO)5Cr

OEt

OEt

Ph

THF, 50°, 20 h

Cr(CO)5

(33)

240

EtO O

Y

Ph OR

O

394

Pr-c O

Pr-c

8 eq

N

Ph

1. Medium, 70-80°

Cr(CO)5

2. CAN

91 O

I O

R

Y

Medium

Et

SPh

silica gel

Et

SPh

THF

(0)

Et

SO2Ph

silica gel

(47)

Me

SO2Ph

silica gel

(69)

(21)

SPh 8 eq

Cr(CO)4

O

1. Medium, 70-80°, 2. CAN

OEt

2 eq

1. Pyridine, 80°, 68 h

OEt Me2N 0.05 M

Cr(CO)5

I

silica gel

(68)

THF

(45)

O

91

(88)

Me2N

Ph

Ph

NMe2

405

OEt

Ph

Ph

EtO

(0) +

THF, 52°, 14 h to 7 d 0.04 M

Cr(CO)5

Ph

411, 413

(24) O

OEt

NMe2

Ph

413

1.5 eq

Medium

2. H2O

NMe2

Ph 3.5-7 eq

I

Ph

Ph

NMe2

Ph

EtO

(73)

RhCl3•3H2O (2 mol%), 0.25 M

Cr(CO)5

THF/MeOH (4:1), 20°

194

OEt

H O 3 eq

(71)

THF, reflux OMe

O

Ph

0.07 M

(CO)5Cr

OEt 1.5 eq

O MeO

morph-N

Ph Pr-i

(CO)5Cr

420

1.2:1 mixture of isomers

THF, 60°, 12 h

Ph

Ph

Pr-i

N-morph

(34)

193

OEt

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C8

Conditions

Product(s) and Yield(s) (%)

OBn BnO

R

Ph

BnO 1. Silica gel, 80°

OEt

O

Ph O O

OAc

1. Silica gel, 80° 2. Pyridine N-oxide, CH2Cl2, 20°

Cr(CO)5

(28) O

N-morph

TBS

414

THF/MeCN (9:1), (CO)5Cr

N-morph

TBS

(72)

415

65°, 15 h OEt

0.05 M O OEt 3 eq

91

O

O OEt 3 eq

124

O

OMe

O

(19)

Cl (48)

Cr(CO)5 SO2Ph

AcO

R H

BnO

2. CAN

OBn

Refs.

OBn O

N-morph OTBS

(CO)5Cr

4

THF/MeCN (9:1),

N-morph

TBS 3

65°, 15 h

0.05 M

(69)

OTBS

415

OEt

O O O

O NMe2

2-4 eq

Pyridine, 80°, 4 d

O NMe2 (42)

TBS

O +

NMe2 (6)

EtO Cr(CO)5 0.05 M

OEt

TBS

OEt

395

O OEt

R

3 eq (CO)5Cr

N-morph

THF/H2O (99:1),

R R

80°, 12-20 h

N-morph

C9

Me2N

O

TBS

n-Pr

(62)

Ph

(48)

414

O OEt

1. Pyridine, 80°, 60 h 2. H2O

405

(26) Me2N

Cr(CO)5 0.05 M

2 eq

TBSO Cr(CO)5

TBS

CH2Cl2, 65°, 20 h

(57)

OMe

415

I 1.5 eq

110

I

0.05 M

(CO)3Cr

OMe PMP

PMP EtO

Cr(CO)5

TMS PMP

PMP

EtO

PMP

(26) +

THF, 55°, 4 d NMe2 OEt

(11)

NMe2

3-6 eq

422, 423

NMe2

PMP

PMP

H O

TBSO

THF, reflux OMe

O

1.3:1 mixture of isomers

Cr(CO)5 3 eq

420

(59) O OTBS

MeO

0.07 M NMe2

NMe2 EtO

3 eq

Pyridine, 80°, 1.5 h

NMe2 +

(86)

TBSO

Cr(CO)5 0.05 M

(7)

TBSO

OEt

394

OEt

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C9

O i-Pr

Refs.

O

O OMe

THF, 50°, 24 h

Cr(CO)5 0.05 M

1.5 eq

O OMe

OMe OH O Ph

1. THF, 45°, 24 h

(17)

2. I2

Ph 1.5 eq

Cr(CO)5

O

O

OMe

416

OH

THF, 50°, 24 h OMe

O 238 Pr-i MeO

(49)

OH

(8)

O

O OBu-t

O

+

Pr-i

Cr(CO)5 0.05 M

1.5 eq

TMS

O

OH

O

1.5 eq

69

OMe

0.3 M i-Pr

238

(66)

Pr-i

OBu-t OMe

N

(43)

1. THF, 60°, 42 h 2. Air

Boc Cr(CO)5 0.04 M

121

N Boc

OMe

OMe

OMe (70)

THF, reflux, 6 h Cr(CO)5

Pr-n

Pr-n TMS

E,E is major

OMe

OMe Cr(CO)5

155

5.1:1:1 mixture of isomers;

(72)

THF, reflux, 6 h Pr-n TMS

155

11.5:4.2:1 mixture of isomers; E,E is major

OMe O

OMe

O

Pr-n

Cr(CO)5

TMS

0.01 M

C10

Cr(CO)5

1.9 eq

Ph

(i-Pr)2NEt, TBSCl,

(74) 55:45 mixture of isomers

CH2Cl2, 60°, 12-24 h

OMe 0.05 M

88

(CO)3Cr OMe Ar OEt

Ar

EtO

NMe2

Ar

Ar

(CO)5Cr

EtO

Ar

(30) +

THF, 55°, 4 d

3-6 eq

155

E,E is major

TBSO Ph

(79) 5.25:1 mixture of isomers;

THF, reflux, 6 h

TMS

(18)

NMe2 Ar

Ar = 3,5-Me2C6H3

422, 423

NMe2 Ar

417 NMe2 OEt

1. Pyridine, 80°, 52 h 2. H2O

EtO

405

(50) Me2N

0.05 M

2 eq

O

Cr(CO)5

OEt OMe O

OMe Ph 1.1 eq

(80)

Dioxane, reflux

(CO)5Cr

51

0.03 M O

1. THF, reflux 2. TBAF (1 eq), THF, 20°

TBSO OEt

3. Ph3P, DEAD, THF, 20°

Cr(CO)5

(≥9)

289

4. Photolysis, air, OEt

benzene, 20°

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C10

Conditions

Product(s) and Yield(s) (%) O

1. THF, reflux OTBS

2. TBAF (1 eq), THF, 20°

H

OEt Cr(CO)5

3. Ph3P, DEAD, THF, 20°

H

( 7) OEt TBSO

TBSO

OTBS

OTBS

Cr(CO)5

OTBS

(i-Pr)2NEt, TBSCl, OR 0.05 M

88

+

CH2Cl2, 60°, 14 h

I

(CO)3Cr OR

418

I + II

I:II

Me

(70)

91:9

i-Pr

(80)

91:9

Cr(CO)5

TBSO

OTBS

(i-Pr) 2NEt, TBSCl,

OTBS

+

CH2Cl2, 60°, 14 h

OMe 0.05 M

II

(CO)3Cr OR

R

TBSO 1.9 eq

289

4. Photolysis, air, benzene, 20°

1.9 eq

Refs.

(CO)3Cr OMe

I

88 (CO)3Cr OMe

II

I + II (41), I:II = 57:43 TBSO OMe

1.9 eq

Cr(CO)5 0.05 M

OTBS

TBSO

OTBS

+

(i-Pr) 2NEt, TBSCl, CH2Cl2, 60°, 14 h (CO)3Cr OMe

I

88 (CO)3Cr OMe

I + II (87), I:II = 72:28

II

OH

t-Bu

OH

OTBS

t-Bu OMe

1.9 eq

(i-Pr) 2NEt, TBSCl, 0.05 M

Cr(CO)5

OTBS

t-Bu +

CH2Cl2, 60°, 14 h

I

(CO)3Cr OMe

88 II

(CO)3Cr OMe

I + II (74), I:II = 91:9 O

Ph OMe

1.3 eq

Additive (3 eq),

OTBS

Ph

II

OMe

OMe

Additive

I + II

I:II

none

(73)

82:18

(n-Bu)3P

(49)

66:34

O

419

O

OEt

OMe OEt

Cr(CO)5

1.5 eq

THF, 50°, 24 h 0.05 M

238

(68)

Pr-i OMe O

i-Pr

111

I

O i-Pr

OTBS

+

heptane, 90°, 18 h

Cr(CO)5

O

Ph

O OMe

O OMe

THF, 50°, 24 h

Cr(CO)5

1.5 eq

OMe

C11

O

NMe2 Pr-n

1. Pyridine, 80°, 64 h

EtO 0.05 M

2 eq

238

(62)

Pr-i

0.05 M

OMe

(87)

405

Me2N

2. H2O

Cr(CO)5

Pr-n

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C11 EtO

Ar 3 eq

THF, 60°, 7 d

Me2N

Ar = 2,4,6-Me3C6H2

TBSO

Ar

OTBS

R

NMe2

(22)

R

NMe2

421

NMe2

R Pyridine, 80°, 1.5 h

EtO

+

(77)

0.05 M

(8)

R OEt R = (CH2)3OTBS

Cr(CO)5

3 eq

Cr(CO)3 TMS

N Me

TMS

3

OH OMe

OCD3

420

OMe

OCD3

+

Benzene, 45°, 48 h

Cr(CO)5 0.05 M

394

OEt

OH

2 eq

Refs.

OEt

Cr(CO)5

52 I

OCD3

OCH3

II

I + II (77), I:II = 1:1; E:Z I = 1:3, E:Z II 1:3 OMe OH

OMe OMe O

O

1. THF, 45°

O

O

(39)

Cr(CO)5

OMe O 1.1 eq

O 0.1 M

16

2. FeCl3-DMF

1. Solvent, 45-50°, 18 h OMe Cr(CO)5

2. FeCl3-DMF

O

O

Solvent THF MeCN

OMe OH

O

OMe (72-76) (69)

O

278, 12

OMe

OMe 1. 2-TMSO-1,3-butadiene

(CO)5Cr

OH

O

(15 eq), THF, 50°, 72 h

1.5 eq

O

O

O

2. Me2C(CH2OH)2, TMSCl

112

(23)

TMS

0.03 M

OMe OH

Cl

MeO2C

OEt

O

CO2Me

Silica gel, 80°

Cr(CO)5

(40)

MeO2C CO2Me

O

404

OEt O CO2Me

Cl

O

n

OEt

O

421

MeO2C

CO2Me

1. Silica gel, 80° 2. DBU, THF

Cr(CO)5

n

n

O

1

(38)

2

(48)

404

OEt R OEt

Pyridine, 80°, 1.5 h

Br MeO2C

CO2Me

NMe2

(CO)5Cr

3 eq

NMe2

n-Pr

Br MeO2C

CO2Me

1-Ad OEt 1-Ad

O

O

Pr-i

Pr-i

Pyridine, 80°, 2 d (CO)5Cr

2 eq

NMe2

N Me

0.05 M

(69)

394

(CH2)3OTBS (51)

OEt

0.05 M

C12

R

R

+

O

1-Ad Pr-i

421

OEt (19)

(50)

OTIPS SPh OMe

PhS

Cr(CO)5 0.05 M

TIPSOTf, 2,6-lutidine,

(65)

THF, 50° OMe

95

Cr(CO)3

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C12

O

Cl

n

n

OEt

O

OTs

Refs.

Cr(CO)5

n

1. Silica gel, 80° 2. Cs2CO3, DMF

1 (25)

O

404

2 (26) OEt O

SO2Ph

1. Silica gel, 80°

OEt

O

Cr(CO)5

2. Pyridine N-oxide, CH2Cl2, 20°

(26)

91

O

2. Cs2CO3, DMF, 20°

OEt O

Ph S

422

OTs 8 eq

O

Cr(CO)4

(49)

1. Silica gel, 80° 2. Pyridine N-oxide

91

O

OEt

O OTBS

TBS

SO2Ph Cr(CO)5

SO2Ph

OMe 0.07 M

1.5 eq

O 1.2 eq

butadiene (50 eq), OMe

THF, 50°, 4 d

TMS

OMe

OAc

Cr(CO)5 0.05 M

1. THF, 55°, 18 h O

2. Ac2O, pyr, DMAP, CH2Cl2, rt, 16-36 h

TMS OMe

95

Cr(CO)3

OAc

OAc OAc

(74)

2,3-Dimethyl-

OAc (59)

295

OAc

O 1.2 eq

OMe

TMS

2. CAN

Cr(CO)5

OAc

O

1. THF, 55°, 18 h

(61)

295

TMS

0.05 M

O O

CO2Et CO2Et NHAc

OMe

O

CO2Et CO2Et

1. THF, 45°, 24 h

69

O

0.3 M

1.5 eq

(71)

NHAc

O

2. CAN

Cr(CO)5

O

Fe

423

OMe

1. THF, 65°, 2 d

Cr(CO)5 0.06 M

2. PbO2, CH2Cl2

O

1 eq

(55)

Fe O O

Ph

Ph OMe

1 eq

1. THF, 65°, 2 d

Cr(CO)5

92

O TBSO

OSiMe2R

(62)

Fe

2. PbO2, CH2Cl2

0.06 M

TBSO

OSiMe2R

(i-Pr)2NEt, TBSCl,

OMe Cr(CO)5

OSiMe2R

+

CH2Cl2, 60°, 14 h 1.9 eq

92

O

(CO)3Cr OMe I

88

I + II

(CO)3Cr OMe II I:II

Ph

(40)

85:15

C6F5

(32)

62:38

PMP

(56)

88:12

0.05 M R

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C13

TBSO

OTIPS

TBSO

Refs. OTIPS

OTIPS OMe Cr(CO)5

1.9 eq

+

(i-Pr)2NEt, TBSCl, CH2Cl2, 60°, 14 h

I

(CO)3Cr OMe

0.05 M

88

(CO)3Cr OMe

II

I + II (87), I:II = 95:5 O OEt Br

OTBS

(CO)5Cr

OTBS 3 eq

THF/MeCN (9:1), 80°, 1.5 h

4

Br

3

OTBS

424

MEMO O

(78)

415

OTBS

OEt

0.05 M

O

MeO

N-morph

N-morph

OMe

O

O

OMe

1. CH2Cl2, 50°

(65)

95

2. MEMCl, (i-Pr)2NEt, rt

Cr(CO)5

MeO Cr(CO)3 O O

O OBu-t

Pr-i OMe

t-BuO 1.5 eq

THF, 50°, 24 h

O Pr-n

Br EtO2C 3 eq

CO2Et

238

OMe

OEt (CO)5Cr

(70)

Pr-i

Cr(CO)5 0.05 M

N-morph

THF (1% H2O), 80°, 7 h

O Pr-n

Br EtO2C

CO2Et

N-morph

(26)

414

Me2N

NMe2

R

R OEt

2-4 eq

Pyridine, 80°, 3 d

0.05 M Cr(CO) 5

(48)

Br EtO2C

CO2Et

395

OEt

O

R = (CH2)2

C14

O TMS

Ar

NMe2

EtO

OEt

Ar 3 eq Ar = 4-PhC6H4

Ar

THF, 55°, 4 d

395, 423

(34) NMe2

Cr(CO)5

4.5:1 mixture of isomers

Ar OTBS

(n-Bu)3Sn

OMe

TMS

1.5 eq

0.07 M

425

Me2N TMS

MeO2C CO2Me 3 eq CO2Et

TMS (CO)3Cr

rt, 16 h

Me2N

(27) TMS (CO)3Cr

OMe

Pr-n OEt

+

(40) Sn(Bu-n)3

2. TBSOTf, Et3N,

Cr(CO)5

72

OMe

Pr-n

Pyridine, 80°, 1.5 h

(81)

394

MeO2C CO2Me

TMS

0.05 M Cr(CO) 5

OEt OH

Z

Z

3

OMe

Y

0.9 eq

OTBS

1. THF, 50°, 22 h

3

Benzene, 70°, 2 h Y

Cr(CO)5 0.003 M Y Z

I

II

O

O

(38)

(3)

O

CH2

(41)

(3)

CH2

CH2

(53)

(3)

+

385

H

I

OMe

CO2Et

OMe Y

CO2Et

Z II

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

Refs.

OH CO2Et 3

0.9 eq C15 OTBS Ph

OMe

TMS

Cr(CO)5

1.9 eq

OMe TBSO OTBS Ph

(i-Pr)2NEt, TBSCl, CH2Cl2, 60°, 14 h

I

(CO)3Cr OMe

0.05 M

TIPSO

426

1.9 eq

(46)

385

TBSO

OTBS Ph

+

88

(CO)3Cr OMe

II

I + II (81), I:II = 71:29

Pr-n

OMe

(i-Pr)2NEt, TIPSCl,

Cr(CO)5

CH2Cl2, 60°, 14 h

0.05 M

TIPSO

OTIPS

OTIPS Pr-n

CO2Et

TMS

Cr(CO)5 0.003 M

OMe

3

Benzene, 70°, 2 h

I

(CO)3Cr OMe

OTIPS Pr-n

+

88 II

(CO)3Cr OMe

I + II (68), I:II = 93:7 MeO

OMe 1. Dioxane, 85° O

OMe Cr(CO)5

Ph

2. MeO2CC CCO2Me,

CO2Me

Ph

CO2Me (72) OH O

O

CO2Me

+

O

dioxane, 85°, 1-2 h

408

O CO2Me Ph

(9)

Solvent OMe O OMe NEt2

Cr(CO)5

1. Solvent, 45°

O

2. Iodine OMe

NEt2 OMe

THF

(17)

MeCN

(30)

278

C17 O

Me2N OEt 2 eq

Pr-n

1. Pyridine, 80°, 60 h 2. H2O

405

(15)

Me2N

Cr(CO)5 0.05 M

Pr-n OR R

OMe Cr(CO)5 0.05 M

SPh OMe 1.3 eq

ROTf, 2,6-lutidine, CH2Cl2, 50-65°, 15-24 h

(76)

TIPS

(77)

OAc

OMe R

OMe

427

(67)

TBSO

OTr

CH2Cl2, 60°, 12-24 h

I

(CO)3Cr OMe

0.05 M

OTr

+

(i-Pr)2NEt, TBSCl,

Cr(CO)5

1.9 eq

OH

OMe TBSO

OMe

139

R

C23 OTr

R=

MeCN, 55°, 24 h

Cr(CO)5 0.12 M

OMe 0.5 eq

159

SPh OMe

(CO)3Cr OMe

OAc

TBS

88 II

(CO)3Cr OMe

I + II (89), I:II = 55:45 TBSO OMe

1.9 eq

OTr

TBSO

(i-Pr)2NEt, TBSCl,

Cr(CO)5

88

+

CH2Cl2, 60°, 12 h

I

(CO)3Cr OMe

0.05 M

OTr

II

(CO)3Cr OMe

I + II (68), I:II ≥ 96:4

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

C23

Conditions

Product(s) and Yield(s) (%) TBSO

TBS

TBSO

OTr

Refs. OTr

OTr OMe

OMe

428

R1

+

R1 Heptane, additive (3 eq),

R2 +

OMe E:Z

Additive

Temp

I + II

I:II

Et

≥98:2

none

90°

(73)

92:8

Et

Me

≤2:98

none

55°

(66)

91:9

Me

Ph

≥98:2

none

90°

(72)

90:10

Me

Ph

≥98:2

(n-Bu)3P

90°

(68)

80:20

Me

Ph

60:40

none

90°

(65)

68:32

Cr(CO)5 0.05 M

1. THF, 55°, 22 h CH2Cl2, rt, 16-24 h

O TMS OMe

111 II

OBn

OAc 2. Ac2O, pyr, DMAP,

OTr

OMe

Me

OMe

O

R1

I

0.01 M R2 R1

OBn

1.2 eq

88 II

(CO)3Cr OMe

OTr

R2

Cr(CO)5

O

O

16-18 h

TMS

OTr

I + II (88), I:II = 58:42

OMe

OBn

TBSO

I

(CO)3Cr OMe

0.05 M

1.3 eq

OTr

CH2Cl2, 60°, 14 h

Cr(CO)5

R2

II

(CO)3Cr OMe (CO)3Cr OMe I + II (65), I:II = 69:31 TBSO

1.9 eq

88

I

Cr(CO)5 0.05 M

1.9 eq

+

CH2Cl2, 60°, 14 h

OBn (53)

295

TIPSO

C25

Pr-n 1.9 eq

TIPSO

OTr

OTr

Pr-n

OMe

TIPSCl, (i-Pr)2NEt,

Cr(CO)5

CH2Cl2, 60°, 14 h

Pr-n

+

I

(CO)3Cr OMe

0.05 M

OTr

(CO)3Cr OMe

+

88

II

I + II (72), I:II = ≥ 96:4 OH

OTr Pr-n

(13)

III

OMe C29 O

OTr

OTr O

429

OMe

+

See table.

Cr(CO)5

OTr 357

OMe

0.01 M

OMe II

I Solvent

Temp

I + II

I:II

MeCN

55°

(88)

98:2

MeCN

90°

(72)

95:5

heptane

90°

(60)

94:6

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OBn

C36 OBn

BnO OH

Ph OBn

BnO

R O 2 eq

t-BuOMe, 60°, 26 h

Ph

O

OBn Cr(CO)5 0.15 M

R

R O O

(88) O

O

O O O

430

O

(85)

O

O

O O O O

O

O

(76) O

O

O O

O

O

(67)

O O

O O O O

O

O

OBn

(80)

OBn

425

C36-56

OBn BnO OAc

OBn OBn

BnO

OMe

TMS OBn

O

Cr(CO)5

1. THF, 55°, 16 h 2. Ac2O, pyr, DMAP,

OBn

O

(54)

295

CH2Cl2, rt, 16-24 h TMS

0.27 M

1.1 eq

OBn

OMe

C49 R

O

Ph Ph OMe R

Cr(CO)5

1. THF, 60°, 2 d

375, 376

(71)

375, 376

O

0.008 M

1.25 eq

(73)

2. PbO2, CH2Cl2

431 O

Ph Ph OMe Cr(CO)5

R

2. PbO2, CH2Cl2 O

0.008 M

1.25 eq

R

1. THF, 60°, 2 d

p-Tol

N

N

N

N

R=

Tol-p

p-Tol

TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

C52

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

R Ph

Ph N

O

N

R

R N

N

OMe Cr(CO)5

1. THF, 60°, 2 d

376

O

2. DDQ, MeOH, reflux, 1 h

0.04 M R 0.8 eq

O

O

N

N

N

N

Ph

R=

432

Ph

O

O

O O

Ph (68)

C56 OTBDPS TBDPSO OTBDPS O

OMe (CO)5Cr

OTBDPS

O

295

CH2Cl2, rt, 16-24 h

TMS

1.1 eq

1. THF, 55°, 22 h 2. Ac2O, pyr, DMAP,

OTBDPS

OTBDPS

OAc

TMS

0.05 M

OMe (32) 7:1 mixture of β:α anomers OTBDPS

TBDPSO OTBDPS O

433

1.05 eq

OMe (CO)5Cr

OTBDPS TMS 0.05 M

OTBDPS

OAc

1. THF, 55°, 24 h 2. Ac2O, pyr, DMAP,

O

CH2Cl2, rt, 16-24 h TMS OMe

OTBDPS

(56)

295

TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C4

Refs.

OAc MeO

N 4 eq

OMe

Ac2O (1 eq), Et3N (1 eq), N

THF, 70°, 6 h

Cr(CO)5

287

(—)

287

OMe

0.1 M

C5

(—) OMe

OAc EtO

N 4 eq 0.1 M

OMe

Ac2O (1 eq), Et3N (1 eq), N

THF, 70°, 6 h

Cr(CO)5

OEt OMe

C6

OH

O

Et

434

Et

Et

OMe

O

2. Air, silica gel

Cr(CO)5 0.08 M

1.5 eq

(82) +

1. THF, 85°, 10 h O

(4)

Et

Et

I OMe MeO

1.5 eq

OMe

O

1. MeOH, 85°, 10 h

+

I (82)

Cr(CO)5 0.08 M

(3)

Et

65

Et

O

MeO2C

2. Air, silica gel

O

MeO

65

Et

O Et

1.6 eq

OMe

O

1. THF, 75°, 18 h 2. CAN

Cr(CO)5 0.17 M O

1. THF, 75°, 18 h

114

Et O

OMe

1.6 eq

(85) O I

I (77)

114

2. CAN

Cr(CO)5 0.17 M

O

OAc

1.0 eq

CH2Cl2, –20° to rt, 1 h

O

(3)

O

0.22 M Cr(CO)5

114

OAc Et

2-4 eq

OMe

N

Ac2O (2 eq), Et3N (2 eq),

Me Cr(CO)5 0.03 M

THF, 65°, 3 h

N Me

H N N

(45)

237

Et

1. THF, 45°, 18 h

OMe

116, 360

OMe O

N N

1.5 eq

(42-48) Et

Et

2. CAN 0.1 M Cr(CO)5

O O Et

435

1.5-2.5 eq

N Me

1. Solvent, 50°, 24 h

OMe

Me

Cr(CO)5 CC (M)

Cr(CO)5 OMe N Me

I

O

0.2

THF

(81)

0.01

hexane

(79)

0.2

benzene

(79)

0.01

MeCN

(29)

1. Hexane, 80°, 9-20 h

I (78)

62

2. CAN 0.01 M Me

N

1. Hexane, 50°, 24 h OMe

0.01 M

Et

Solvent

Me 1.1 eq

62 N

2. CAN

Cr(CO)5

O Et

N

(76)

2. Air

Et OMe

62

TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

O

Refs. O

Et Et

Et

OMe

N

1.1 eq

Me 0.01 M

N

2. Air

Me

Cr(CO)5

Et

(75) + Et

1. Hexane, 50°, 24 h

(20) 62 Et OMe Cr(CO)4

N Me

OMe OH CO2Me

MeO2C

CO2Me

OMe

N Me

2.4 eq

(36)

THF, 65°, 5 h N

Cr(CO)5

Me

0.04 M

116

CO2Me OMe OAc

OAc TMS

TMS

OMe

N

436

4 eq

Cr(CO)5

Ac2O (1 eq), Et3N (1 eq),

+

(32) N

THF, 70°, 6 h

N

0.1 M

OMe OAc

C7

(tr) TMS

287

(20) Bu-n

116

OMe OAc

Bu-n n-Bu

OMe

N

Me Cr(CO)5 0.04 M

2.4 eq

Ac2O (1.5 eq), Et3N (1 eq), THF, 65°, 5 h

+

(31) N

N

Me

Me

OMe O

OMe

Pr-n EtO

Pr-n

OMe

N

3.2 eq

1. Hexane, 50°, 24 h N

2. Air

Me 0.01 M

Me

Cr(CO)5

(49)

62

(78)

62

OEt OMe O TMS

EtO

TMS

OMe

N

2.5 eq

N

2. CAN

Me 0.2 M

H N

1. THF, 50°, 24 h OEt

Me

Cr(CO)5

O

O 1. THF, 45°, 48 h

N

1.5 eq

OMe

N

N (16)

2. CF3CO2H, 0.5 h

Ph

Cr(CO)5

Ph

O

0.1 M

C8-9

R

2

R

Fe

R2

+

R1

Fe

Fe

R2

O 426

Alkyne (eq)

II

I

II (15)

n-Pr n-Pr

1.5

(0)

n-Pr n-Pr

2.5

(18) (21)

Ph

Me

1.5

(13)

Ph

Me

2.5

(29) (10)

437

C8

R1

R2

I

0.05 M R1

O

OMe Dioxane, 100°, 5 h

OMe

OMe

O

Cr(CO)5 1

237

OEt

3. CAN

(0)

O Y

Y

Y OMe

1.5 eq

0.2 M

Cr(CO)5

1. THF, 66°, 5 h

S

2. CAN

NMe (28)

(56)

135

O O

C9

Ph

1. (n-Bu)2O, 130°, 300 s, Ph

OMe

O 2 eq

microwave 2. CAN

Cr(CO)5 0.05 M

(64)

192

O O O

O B O 3 eq

N Me 0.05 M

OMe

1. THF, 45°, 16 h 2. CAN

Cr(CO)5

N Me

B O

O

O

(64)

75

TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C10

OH

Refs. Bu-n

Bu-n n-Bu

Bu-n

O

1.5 eq

OMe Cr(CO)5

Bu-n

+

1. DMF, 120°, 5 h O

2. 1 N HCl, MeOH

O

(37)

OMe

427

O

Bu-n

(34)

Bu-t O

Bu-t

OMe Cr(CO)5

1.5 eq

1. DMF, 120°, 5 h

427

(72) O

2. 1 N HCl, MeOH

O

C11

OH

Ph Ph

O

438

Ph

OMe Cr(CO)5

1.5 eq

+

1. DMF, 120°, 5 h

427

O

2. 1 N HCl, MeOH

O O (36) trans:cis = 2.6:1 Ph

(14)

OMe OH

C12

Ph Ph

Bu-n

O

1.5 eq

OMe Cr(CO)5

Bu-n

+

1. DMF, 120°, 5 h O

2. 1 N HCl, MeOH

O (51) trans:cis = 1:2.6

(15)

OMe

427

O

Bu-n OH Ph

O

OMe Cr(CO)5

1. THF, 65°

427

(51) O

2. 1 N HCl, MeOH

Bu-n OMe Bu-t

O O

O Bu-t

OMe Cr(CO)5

1.5 eq

O

1. DMF, 125°, 5 h

427

(60)

O

2. 1 N HCl, MeOH

O

OAc OTBS x

TBSO OEt 1.5 eq

O

OMe

Cr(CO)5 0.03 M

Ac2O (2 eq), Et3N (x eq), O

THF, 65°, 10 h

OEt OMe OH

2

(43)

0

(36)

115, 264

OAc OTBS

OTBS

Ac2O (x eq), Et3N (y eq), N

OMe

Me Cr(CO)5 0.03 M

+

AcOH (z eq), N

THF, 65°, 5-10 h

115, 116 N

OEt

Me

Me

I I

OMe

y

z

1.1

0

0

(26) (41)

1.1

1.1

0

(0)

(46)

2.4

1.5

1.5

0

(0)

(62)

1.5

0

0

1

(19) (—)

Alkyne (eq)

x

1.5 1.5

439

OMe

N Me

OMe Cr(CO)5

Et3N (x eq),

O

THF, 65°, 4-5 h

OH

MeO

0.03 M

Me N x

N

Me

II

OMe

II

EtO 1.5 eq

OEt

1.0

(13)

0

(68)

115

OEt O

O Bu-n

O B O

Bu-n 3 eq

O

OMe

Cr(CO)5 0.03 M

1. THF, 65°, 16 h

O

O

B

2. CAN

Bu-n (47) +

O

O

(30)

74, 75

O O

OH

C14

Ph Ph

Ph 1.1 eq

O

OMe

Cr(CO)5 0.17 M

(n-Bu)2O, 80°, 2.5 h

(19) O (CO)3Cr OMe

Ph

104

TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C14

Ph Ph

R Ph

Refs.

Ph

OMe

O

Cr(CO)5

1.5 eq

1. DMF, 120°, 5 h

R

R

+ O

2. 1 N HCl, MeOH

Ph O

I OMe

R

I

H Me

427

O

Ph II

II

cis:trans II

(8) (61)

1.5:1

(9) (56)

1.3:1

O Ph 1.3 eq

OMe

O

Medium

1. Medium, 50-80°, 2-3 h O

2. CAN

Cr(CO)5

Ph

silica gel

(74)

MgSO4

(43)

177, 178

O

440

OH O

Ph

O OMe

1.25 eq

(n-Bu)2O, 70°, 2 h

(62)

104

(28)

104

Ph

Cr(CO)5 0.2 M

(CO)3Cr OMe OH Ph (n-Bu)2O, 80°, 1.5 h

1.3 eq OMe

S

S

Ph

(CO)3Cr OMe

Cr(CO)5 0.18 M

OAc Ph 2-4 eq

OMe

N Me

Cr(CO)5 0.04 M

Ac2O (1-2 eq), Et3N (1-2 eq),

(22-24) N

THF, 65°, 2-24 h

116, 267,

Ph

Me

360

OMe

C14

O Ph Ph

Ph

Ph

N

OMe

1. Toluene, 95°, 15 h

Ph

N

(44)

2 eq

Cr(CO)5

0.1 M H N

O O

N

Ph

N N

1.5 eq

R

1. THF, 45°, 18 h

OMe R

117

Ph

2. Air

Ph

2. CAN Cr(CO)5 0.1 M

R

Me

(41)

237

O

Me

Ph

N OMe

(51)

Ph

O

N 1.5 eq

Me

1. Hexane, 50°, 24 h

(52)

62

Ph

2. CAN

441

Cr(CO)5

O

0.01 M O

Cr(CO)5 1.5 eq

Fe

OMe

(n-Bu)2O, 80°, 4 h

Fe Ph

OMe (45)

Ph Cr(CO)3

428

0.11 M O

Ph

O

Cr(CO)5 Fe

Alkyne (eq)

OMe

0.05 M

+

Dioxane, 100°, 5 h Fe

OMe 426

Fe

OMe Ph I

Ph

I

II

1.5

(38)

(—)

2.5

(43)

(20)

Ph II

TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

O

O

Ph O B

Ph

OMe

O

O 3 eq

Cr(CO)5 0.05 M

1. THF, 65°, 16 h

O

B

2. CAN

Ph (35) +

O

(42)

74, 75

O

O

O

Refs.

O

C14-17 O Ph

R

OMe

O

1.2 eq

Benzene, 80°, 12-24 h

•

R

R

(CO)3Cr O

Cr(CO)5

TBS

(36)

TIPS

(62)

134

OMe

C16 AcO TBSO

442

OTBS O O

OEt

OMe

O

Cr(CO)5

1.0 eq

THF, 65°, 72 h

O

N

(28)

264, 115

(38)

115

OEt OMe HO TBSO

Me

O

Ac2O (2 eq), Et3N (2 eq),

0.03 M

1.5 eq

O

OMe

Cr(CO)5 0.03 M

O

Ac2O (1.1 eq), Et3N (1.1 eq), THF, 65°, 8 h

N Me

OEt OMe

O

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C4

HO

O

O OMe

Y

THF, 65°, 20 h Y

x eq

x

y

Time

O

—

—

20 h (13)

264, 115,

0.03

4 h (39)

116

OMe

yM

C5

Y

NMe 2.4

Cr(CO)5

Refs.

O Pr-n n-Pr

1. THF, 75°, 18 h

OMe

O

2. CAN

1.5 eq

(51) O

Cr(CO)5 0.17 M

114

I O

1. Ultrasound, (n-Bu)2O, OMe

O

443

1.3 eq

rt, 25 min

I (45)

177

I (72)

192

2. CAN

Cr(CO)5 0.1 M

1. Microwave, (n-Bu)2O, OMe

O

2 eq

130°, 300 s 2. CAN

Cr(CO)5 0.05 M

OH Pr-n OMe

Y

x eq

Y

(n-Bu)2O, 70°, 2 h Y

Cr(CO)5

Cr(CO)3

yM

x

y

Temp Time

O 1.1 0.35

70°

S

80°

1.2 0.5

2h

(23)

104

1.5 h (40)

OMe

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C5

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

O

H N N

Pr-n

N N

n-Pr

OMe

1.5 eq

0.01

(10)

2. CAN

0.1

(31)

1.0

(27)

Cr(CO)5

xM

x

1. THF, 45°, 18 h O

237

OAc

H N N

Pr-n

N N

1.5 eq

Ac2O (1.5 eq),

OMe

(11)

237

THF, 45°, 36 h Cr(CO)5

OMe

0.1 M

O

O

444

Pr-n 1.1-1.5 eq

1. Hexane, 50°, 24 h N

OMe

Me 0.01 M

Cr(CO)5

2. CAN

+

62

N

N

Me I

Me

Pr-n

Me

O

I + II (68), I:II ≥ 350:1

II

O

N 2 eq

OMe

1. Hexane, 80°, 9-20 h

I + II (73), II:I ≥110:1

62

2. CAN Cr(CO)5 0.1 M O Pr-n 1.1 eq

N

OMe

Me 0.01 M

Cr(CO)5

1. Hexane, 50°, 24 h 2. Air

(85) N Me

OMe

62

Me

O

Me

N

Pr-n

N OMe

1.1-1.5 eq

1. Hexane, 50°, 24 h

62

(48)

2. Air Cr(CO)5

0.1 M

OMe OTBS

OTBS

O Pr-n 1.1 eq

1. Hexane, 55°, 1.5 h N

OMe

Me 0.01 M

Cr(CO)5

(53)

2. Air

Me

OMe

OTBS

1.1 eq

OTBS

O Pr-n

1. Hexane, 55°, 48 h

445

OMe

N Me

242

N

(38)

242

N

2. Air

Me

Cr(CO)5

OMe

0.01 M OH H OMe

O

HO 1.2 eq

Cr(CO)5

1. Solvent, 80°, 14 h

+

I

O

65

OMe II

OMe

Solvent

O

O

O

2. Air

0.1 M

I

(Z)-II (E)-II

THF

(22)

(48)

(0)

MeCN

(32)

(20)

(5)

H

O OMe

S EtO

OH

3

1.5 eq

Cr(CO)5 0.05 M

EtOH (1.5 eq),

CO2Et

S

THF, 60° , 4-6 h

(81) E:Z = 1:2

379

OMe CO2Et

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C5

H

O OMe

O EtO

Refs.

O

1.5 eq

Cr(CO)5 0.05 M

OEt

EtOH (x eq), THF, 60-65, 3-20 h

OMe CO2Et OMe I

II I

N

II (E:Z)

(—) (80)

1:1.2

0

(21) (20)

—

446

Cr(CO)5

264, 115

H +

N

OMe

CO2Et

N Me

OMe CO2Et

Me I

0.05 M

379

CO2Et

EtOH (x eq), THF, 60-65°, 3-6 h

Me

II

1.5

O 2-4 eq

CO2Et

O

O

x

OMe

+

II

x

I

1.5 0

II

II (E:Z)

(—) (87) E only

379

(51)

116

(5)

—

C6

MeO

Bu-n n-Bu

Y

OMe Cr(CO)5

Additives (1.1 eq), THF, 60-65°, 6-24 h

Bu-n

Y

OR +

O

OMe

O Bu-n

Y Y

I

II OMe

Alkyne (eq)

Y

Additive

R

I

II

1.5

O

none

H

(33)

(35)

381

2.6

O

none

H

(76)

(—)

360

1.5-2.5

O

Ac2O, Et3N

Ac

(68)

(—)

381, 267,

1.5

S

none

H

(33)

(10)

381

1.5

S

none

H

(44)

(—)

360

1.5

S

Ac2O, Et3N

Ac

(66)

(—)

381, 360

360

OAc Bu-n

1. THF, 85°, 20 h 1.5 eq

OMe

O

2. Ac2O, NaOAc,

O (29)

65

O

THF, 85°, 6 h

Cr(CO)5 0.08 M

O

MeO +

(60)

n-Bu OMe OH

447

Bu-n Cl

3 eq

O

O

Conditions O

1. THF, 53°, conditions

Cl

2. Air, 30 min

O

40 h

(42)

ultrasound, 2 h

(59)

169

Cr(CO)5 0.03 M OAc Bu-n 2.4 eq

OMe

N Me

Cr(CO)5

Ac2O (1.5 eq), Et3N (1 eq),

(34)

116

N

THF, 65°, 2 h

Me

OMe OAc Bu-n

4 eq

OMe

N

Cr(CO)5

Ac2O (1 eq), Et3N (1 eq),

287

(22) N

THF, 70°, 6 h

0.1 M

OMe

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C6

Bu-n n-Bu

OMe

N 4 eq 0.1 M

Cr(CO)5

Ac2O (1 eq), Et3N (1 eq),

287

(18) N

THF, 70°, 6 h

OMe O OH O

R MeO2C 1.0-2.1 eq

O

OMe Cr(CO)5

1. Solvent, 78-85°, 12-20 h

114, 65

+

+ O

2. Workup

I

0.08-0.17 M

O

OMe

II OMe

O

MeO

448

O R

+

III R

O MeO R

O MeO

+

O

O R

CO2Me

IV

V

O R = (CH2)2CO2Me

OMe

Solvent

Workup

I

II

III

IV

V

THF

air, SiO2

(15)

(37)

(22)

(—)

(—)

THF

TsOH, benzene, 85°

(—)

(55)

(—)

(—)

(—)

hexane

air, SiO2

(6)

(39)

(15)

(—)

(—)

MeOH

air, SiO2

(47)

(—)

(—)

(24)

(—)

benzene

(n-Bu)3P, acetone

(30)

(—)

(30)

(—)

(—)

MeCN

air, SiO2

(12)

(—)

(—)

(—)

(42)

1. MeOH, 85°, 18 h OMe

1.1 eq

O

CO2Me

OH

O

O

O

2. (n-Bu)3P, acetone,

(51)

O

+

(8)

Cr(CO)5

OMe

OMe

S

O

1. THF, 85°, 10 h 2. Air, SiO2

Cr(CO)5 0.17 M

OMe O

CO2Me

OH 1.5 eq

114

rt, 1 h

+

(5)

114

(37)

S

S OMe

OMe MeO

+

O S

(30)

MeO2C

449

O O 1. MeOH, 85°, 2 h 2. Cl3CCO 2H, benzene,

O

O

114

(35) O

reflux

Cr(CO)5

O

0.1 M O

C8

Ph

1. Microwave, (n-Bu)2O, Ph

OMe

O 2 eq

130°, 300 s

(29)

192

(73)

169

O

2. CAN

Cr(CO)5 0.05 M

O OH Ph

1.2 eq

1. THF, 45°, 36 h

OPh

O

2. Air, 30 min

Cr(CO)5 0.02 M

O OPh

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8

Refs.

OAc Ph Ph

OMe

N 2.4 eq

Me H N

Cr(CO)5

Ac2O (2 eq), Et3N (2 eq),

(45) Me

N

OMe O Ph

N N

1.5 eq

OMe R

116

N

THF, 65°, 4 h

R

1. THF, 45°, 18 h

Me

(22)

2. CAN

TMS

(10)

Cr(CO)5

R

237

O

0.1 M

O Ph

450

1. Benzene, 50°, 24 h

2.5 eq

N

OMe

Me 0.2 M

Cr(CO)5

(61)

2. CAN

62

N Me

O O Ph

1. Hexane, 50°, 24 h

1.1 eq

OMe

N Me

2. Air

(80)

62

(0)

192

N Me

Cr(CO)5

OMe

0.01 M C9

O 1. Microwave, (n-Bu)2O, O 2 eq

OMe

Cr(CO)5 0.05 M

130°, 300 s 2. CAN

O O

OH

C10

OBn BnO

Cl O

O 1.2 eq

1. THF, 55°, conditions

O

Conditions

Cl

2. Air, 30 min

O

33 h

(25)

ultrasound, 5 h

(55)

169

Cr(CO)5 0.03 M

C11

O TsO OMe

N

Me

Cr(CO)5

0.01 M

C12 CO2Et

OMe

HO OMe

O

62

N

2. K2CO3, NaI, 80°, 6 h

Me

1.1-1.5 eq

(42)

1. Hexane, 50°, 24 h

CO2Et

Benzene, 70°, 2 h

(37)

385

451

I

O

Cr(CO)5

OMe THF, 100°, 2 h

OMe

O

I (10)

385 O

Cr(CO)5 MeO2C

OMe

O

3. Air, SiO2

O

MeO (23) +

2. (n-Bu)3P, acetone

Cr(CO)5

1.1 eq

SPh

O

1. Toluene, 85°, 18 h

SPh

O (8)

MeO2C

O

114

PhS OMe Boc OH N

O

O OPh

O

N Boc

1. THF, 50-55°, conditions 2. Air, 30 min

Cr(CO)5 0.03-0.05 M

169 O

Conditions

OPh

1.5

21 h

(53)

3.0

ultrasound, 2 h

(59)

Alkyne (eq)

TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C12

OH

O NHBoc

EtO

1. THF, 45°, 17-36 h 2. Air, 30 min

Cr(CO)5 1.2 -2.0 eq

O OEt

OAr

O

NHBoc

O

ArO II I

II

2-ClC6H4

(34)

(—)

2-MeOC6H4

(26)

(—)

4-IC6H4

(43)

(—)

3-CF3C6H4

(35)

(—)

OMOM

452

OMOM

O

O

1. Benzene, 50°, 17 h OMe

N Me

169

O

OAr I

0.01-0.05 M

O N H 1.5 eq

Boc

N

+

O

Ar

Ph

Refs. OEt

O

N H

2. Air

Ph

(59)

62

N Me

Cr(CO)5

OMe

0.01 M C13

BnO

O

O

O

Et N H

1.5 eq

N Me 0.05 M

OMe

1. Xylenes, 55°, 1.5 h 2. 140°, 1 h

Cr(CO)5

Et N Me

OMe

N H

OBn (61)

242

C14

OH CO2Et 3

OMe

O

Cr(CO)5 0.83 eq

3

Benzene, 70°, 2 h

CO2Et

(52)

O OMe

0.0025 M

H

+

OMe O

CO2Et

(10)

385

453

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C4 NH2 1.3 eq

MeO

Argon (5 bar), MeCN, 80°, 15 min

Cr(CO)4

OMe H

0.24 M

NHMe

1.3 eq MeO

Argon (5 bar), MeCN, 80°, 15 min

Cr(CO)4

(48)

431

(73)

431

N Cr(CO) 5

N Me Cr(CO)4

MeO

0.24 M H N

Ph

454

5 eq

Benzene, reflux, 12 h

(52)

429

(CO)4Cr O

(CO)3Cr (CO)5Cr

N

Ph THF or cyclohexane,

1.5 eq Ph

Ph

0.33 M H N 3.2 eq

Cr(CO)4

Argon (5 bar),

(51)

N

THF, 70°, 1 h

N Me2 NMe2

NH2 Benzene, 20°, 2 h

(CO)5Cr

1.0 eq

Ph

0.3 M

432

Cr(CO)4

0.08 M

Me2N

235, 236

Ph

N Me2 C5

(48)

Ph

N H

80°, 1-3 h

N

(79)

Et

(CO)5Cr

Et

C6 Et

Cr(CO)5

Et 2 eq

Benzene, 80°, 18 h

NMe2

Et +

Et NMe2

0.25 M

(10)

Et Et +

Et

(10)

(5)

NMe2

EtO2C

Cr(CO)5 N

Et

THF, 60°, 48 h

156, 157

(75)

Et N

0.03 M

Et Ph

NMe2

83

OH

EtO2C 4 eq

430

Ph

Et

Cr(CO)5

3 eq

Et

Solvent, 2.5-5 d

Et +

+

13

NMe2 0.1 M

455

I Solvent

NMe2

O II

Temp

I

II

III

THF

95°

(13)

(46)

(15)

THF

115°

(31)

(22)

(14)

toluene

95°

(2)

(2)

(19)

toluene

115°

(22)

(14)

(22)

5 eq

O

Et

N Me

Ph

III

Et

H N

Ph

Et

Et

Benzene, reflux, 6 h

(71)

429

(CO)4Cr

1.5-2.0 eq

Et

Cr(CO)5

Ph N

O

(CO)3Cr

0.08 M

Et

1. DMF, 120-125°, 5 h 2. 90-95°, 15 h O

(52)

79

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

Et

C6 Cr(CO)4

Ph Et

1. DMF, 120-125°, 5 h

Et

Et

2. 90-95°, 15 h

N-morph

79

(59)

432

(67)

162, 163

N-morph Et

1.5-2.0 eq H N

Ph

1.2 eq

Et THF, 70°, 1 h

Cr(CO)4

N

N Me2

Cr(CO)4 N Me2 OAc

0.1 M

456 2 eq

N

Bn

2. Ac2O, Et3N, DMAP,

Et

rt, 3.5 h

O

3. FeCl3-DMF, 20 min

OBu-t

0.1 M

Et

1. Toluene, 55°, 4 h

Cr(CO)4

N

Bn

O OBu-t OH

O

Pr-n

Et

N 2 eq

(96)

n-Pr

N

n-Pr

Toluene, 100°

N

p-Tol

p-Tol

Et

Et

Et

+

(17)

Cr(CO)4

Et

Et

(14)

OH

433

p-Tol

0.25 M Et H N

Et

Tol-p

1.2 eq

Toluene, 70°, 1 h

Cr(CO)4

Et

(CO)3Cr

N Me2

(36)

(5) NMe2

OAc

Et p-Tol

Et

Cr(CO)4

R

N

1. Solvent, 55-60°, 2-3 h

O

Et +

2. Ac2O, Et3N, DMAP, rt, 0.5-2 h

OBu-t

R

Solvent

Workup

R

I

II

THF

none

H

(54)

(—)

0.26

toluene

FeCl3-DMF

Bn Et

(11)

(56)

Ph N

Hexane, 85-90°, 24 h

Cr(CO)5

Et

R

457

3 eq

Ph

O II

232

Et R

Hexane, 70-90°, 1-3 d

Cr(CO)5

N

(84)

Ph

N H

0.014 M

N

OBu-t

0.05

Et

R

I

OBu-t

162, 163

Et

O

N

3. Workup

CC (M)

3 eq

432 NH

NMe2

0.09 M

2 eq

Et

+ (CO)3Cr

N

0.014 M

Ph

N H

R

Ph

(97)

Me

(81)

t-Bu

(85)

232

N NH 0.05 M

(n-Bu)2O, 90°, 3 h

(40)

208

(66)

392

Et Et

Cr(CO)5

Cr(CO)3

Et 2.2 eq

DMF, 120°, 3 h

Et

N-morph OMe Cr(CO)5 0.06 M

OMe

N-morph

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

CO2Me

C6 Cr(CO)4

MeO2C

(CO)4Cr

CO2Me

CO2Me

CH2Cl2, –20°, 24 h N-morph 0.1 M

1 eq

N-morph

Cr(CO)5

RO2C

R CO2Me

THF, 60°, 16 h

N

458

Cr(CO)5

N 0.005 M

hexane, rt, 4-11 h

157

CO2Me (23)

Ph

Photolysis (pyrex),

(81)

(1R,2S,5R)-menthyl (67)

MeO2C

Ph Ph

Et

N

0.03 M

10 eq

54

CO2Me

RO2C

1.2 eq

(73)

189, 190

N

Ph

CO2Me R1

Cr(CO)4

1 eq

CH2Cl2, –20°, 24 h R2

N-morph

CO2Me R1 R2

N-morph

MeO2C

CO2Me

0.1 M O 2 eq

Ph

Cr(CO)4

N Me

R1

(CO)4Cr

CO (30 psi), THF, rt, 25 h

Ph

Ph

(54)

—CH2CH2CH2O—

(95)

CH2OMe

Me

54, 53

(69)

I (90)

Ph

N Me

R2

—CH2CH2CH2—

165

0.03 M Cr(CO)5

O 2 eq

CO (30 psi), THF, rt, 5 d

Ph

N Me

Ph

165

I (78)

0.03 M

1. n-BuLi, THF, –78°, 10 min Cr(CO)5

R

MeO2C

CO2Me

R

Ph

R

2. PhCOCl, –78 to 0°,

2 eq

15 min

NHMe 0.17 M

N Me

3. Alkyne (2 eq),

Ph

(72)

Me

(23)

165

CO (30 psi), rt, 2 d CO2Me

O

(CO)4Cr Cr(CO)5

1 eq

NR2

0.05 M

Photolysis, THF,

NR2 CO2Me

O

–40° to rt, 12 h

NH2

(9)

NHMe

(10)

54

NR2 CO2Me

O

(CO)4Cr

1. Photolysis, THF, –40° Cr(CO)5

1 eq 0.05 M

NMe2

2. Alkyne (1 eq),

CO2Me

O

54

(35)

–40° to rt, 12 h NMe2

459

CO2Me Cr(CO)5

R 1 eq

1. Photolysis, THF, –40°

CO2Me

2. Alkyne (1 eq), N-morph 0.05 M

–40° to rt, 12 h

Et

Ph

3 eq

N 0.014 M

R

Cr(CO)5 R

Hexane

Pr-n 3 eq

0.014 M

(50)

54

Ph Temp

Time

Me

80°

24 h

Ph

70°

2-3 d

N H

Cr(CO)5

Hexane, 80°, 24 h

Ph

II Ph

R I

II

(95)

(≤1)

(98)

(0)

N H

EtO

OEt (73) N H

O

+

I

n-Pr N

(55)

2-furyl

Et

Et

O

C7 Ph

Ph

N-morph R

O

EtO

R

(CO)4Cr

+

Ph

234, 232

R

Pr-n (≤1) N H

234

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C7

Product(s) and Yield(s) (%) EtO

EtO

Pr-n

Hexane, 70°, 2-3 d Ph 0.014 M

3 eq

Pr-n

Cr(CO)5

N

Ph

Ph

Benzene, 20°, 2 h Ar

0.3 M

232

NEt2

(CO)5Cr 1 eq

(94)

Ph

N H

NH2 Et2N

Refs.

Ar

N Et

(CO)5Cr Ar

Ph

(81)

4-ClC6H4

(96)

430, 435

NEt2 (CO)4Cr

Cr(CO)5 1 eq

Benzene, 60°, 2 h Ph

MeHN

Me

0.3 M

460

(63)

403

(26)

235, 236

N Ph NEt2

Ph THF or hexanes, Ph

N

Cr(CO)5

80°, 1-3 h

Ph

Ph

N H I

NEt2 Ph 1 eq

THF, 20°, 1 h Ph

N

Ph

+

I (16)

N

+

(33)

434

Cr(CO)5

0.33 M Ph

NEt2 +

(34) Ph

N

Cr(CO)5

NEt2 Ph

(10)

Ph

N

Cr(CO)3

OEt

Et2N Et2N

Ph

4 eq

THF, 80°, 30 min Ph

N

NEt2 O

EtO

(tr) +

(CO)2Cr

Cr(CO)5

0.33 M

Et2N

(15)

436

+

227

Cr(CO)3

NEt2 EtO

+

Ph

N

Ph

O

(86) Ph

N

Ph

NEt2

NEt2 O

O O N

2 eq

Ph

O

+

Et2O, 20°, 1 h

Ph

(CO)5Cr

N

O

N

O

Ph Ph

(CO)5Cr

Ph Ph

Ph

0.33 M

Ph

(28)

(16) NEt2

461

NEt2 (CO)5Cr

(CO)5Cr

Ph O

O N

N H (8) C8 (CO)4Cr

MeO2C

Bu-n

2 eq

Ph

N Me 0.03 M

Ph

CO (30 psi), THF, rt, 25 h Ph

N Me

R 1.2 eq

N

165

(36)

R CO2Et

THF, 60°, 16 h N

0.03 M

Ph

(16) Ph

R

EtO2C

EtO2C

Ph

Cr(CO)5

EtO2C

O

Ph

Bu-n

MeO2C

O

Ph

+

CO2Et

(77)

n-Pr

(61)

157

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C9 Ph

Ph

(CO)4Cr

+

Benzene, reflux, 6 h

Ph N H

Ph 5 eq

O

(CO)3Cr

0.08 M

O

(CO)3Cr

Ph

(CO)5Cr 1.9 eq

429 (22)

(30)

Benzene, reflux, 12 h

N

Ph

N

Ph (CO)3Cr

0.1 M

Ph +

N

Ph

(38)

O

77 (—)

O

462

OH EtO2C

Cr(CO)5

EtO2C 4 eq

Ph 156, 157

(70)

THF, 60°, 48 h

N

N

0.03 M

R1 R1

Cr(CO)5

Ph

R2 1.5-2 eq

R1 R2

1. DMF, 120-125°, 5 h 2. 90-95°, 15 h

N-morph

R2

+ I

79 II

N-morph

O

R1

R2

Ph

Me

(41) (52)

Bu-t

CO2Et

(31) (58)

I

II

Bu-t EtO2C

Bu-t

+ CO2Et

DMF, 120°, 3 h N-morph

2.1 eq 0.05 M

OMe Cr(CO)5

O

OMe

(54)

392 H (6)

OMe O

C9-11

Ph

R

DMF, 120°, 3 h

R

0.05 M

SMe

392

Ph

N-morph

2.1 eq

OMe Cr(CO)5

O

OMe

(3) (low)

TMS C10

463

Bu-n Ph n-Bu

Bu-n

Bu-n

1. DMF, 120-125°, 5 h N-morph

1.5-2 eq

Bu-n

Cr(CO)5 Bu-n

+

(28) O

C11

(67)

Cr(CO)5

Ph

N

CO2Et

THF, 60°, 16 h

(70)

157

N

1.2 eq

0.03 M n-Bu

C12 Ph

N-morph

Ph

EtO2C EtO2C EtO2C

79

2. 90-95°, 15 h

Bu-n

O

1.5 eq

Cr(CO)5 NMe2

0.08 M

Ph

DMF, 120°, 5 h O O

NMe2

(21)

427

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C12

Fe

DMF, 120°, 3 h

Fe

392

(50)

N-morph 1.5 eq

0.05 M

OMe Cr(CO)5

O

OMe

C14

OH Ph Ph

Cr(CO)5

Ph

Benzene, reflux, 15 h

2 eq

437

(15.4) Ph

N

N

464

Ph

O NMe2

1.5 eq

DMF, 120-125°, 5 h

Ph

O

Ph

O N-morph

1.5 eq

1. DMF, 120°, 5 h

Ph

Ph

O

Ph

+

N-morph

O

2. 1 N HCl, MeOH

Cr(CO)5

427

(44)

NMe2

O

Cr(CO)5

427

O

(20)

(27)

O

cis:trans = 1:1 S 1.1 eq

N

1. Benzene, reflux, 12 h

Cr(CO)5

2. Pyridine, reflux, 6 h

S

Ph

N +

(44)

S

(46) 77 N

Ph Ph

Ph

0.1 M

O

Ph

1.1 eq

Ph

Ph

N

S

N

1. Benzene, reflux, 12 h Cr(CO)5

2. Pyridine, reflux, 6 h

+

(1)

S (44) 77

Ph

N

S

0.1 M

O OH EtO2C

Cr(CO)5

EtO2C 1.5 eq

N

Ph

THF, 60°, 48 h

156, 157

(57)

Ph

0.03 M

N

Cr(CO)3 Ph

Cr(CO)5

Ph 1.2 eq

Ph

Benzene, reflux, 12 h

465

NMe2

– O

Ph Ph

(55)

161

(59)

438

Ph N Me + Me Ph

Cr(CO)5

1.2 eq

Cyclopentadiene (10 eq), NMe2

O

Ph

N

benzene, reflux, 24 h

Me Ph Ph 2 eq

(CO)5Cr

N

1. Benzene, reflux, 12 h

Ph

Ph

Ph (24) +

N O Ph

Cr(CO)5

Ph N

N

(2)

77

Ph Ph

2 eq

Ph

2. Pyridine, reflux, 6 h

0.12 M

Benzene, reflux, 2 h

N

Ph (CO)3Cr

Ph O

Ph

(18-23)

439, 440a

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C14 Ph

Ph Ph

Ph 2 eq

N

S

Cr(CO)5

Ph

O O +

Benzene, reflux, 12 h S

N

N

S

Ph

O (42)

Ph

Ph

(7)

Ph

Ph Ph

+ O

(7) Ph 1.9 eq

N

Cr(CO)5

Ph

+ (11) O

Ph

Ph Benzene, reflux, 12 h

Ph

Ph

466

Ph (CO)3Cr

0.1 M

(42)

77

O

Ph

Ph +

N

+

(14)

Ph

N

77

Ph

N

Ph

(16)

O Ph 1.9 eq

N

Ph

Ph Cr(CO)5

Benzene, reflux, 12 h

Ph

Ph

+

N Ph

Ph

O

(0-2) Ph

+

N

77, 440a

(50-62)

Ph

Ph

N

(CO)3Cr O (0-33)

OH Ph

Ph Ph

Cr(CO)5

0.9 eq

Ph

1. THF, reflux

N

(57) +

Ph

2. Air

(13)

164

N

N 0.03 M c-Pr 1.25 eq

N

Me Cyclohexane, Cr(CO)5

Ph

reflux, 12 h

c-Pr + Me N Ph – Ph

0.07 M

+

O Ph

c-Pr

Ph

1.5-2.0 eq

Ph 161, 441

+

Ph

Cr(CO)3 O

Cr(CO)3 (14)

(21) Ph

1. DMF, 120-125°, 5 h Ph

2. 90-95°, 15 h

467

N-morph

Ph

Ph

N

Cr(CO)3 (42-47) Ph Cr(CO)5

Ph

Me

O

Ph

+

79

3. Acid N-morph

I

II N-morph Ph

Acid I no

II

III Ph

+

(34) (55) (0)

yes (34) (0) (52) (CO)5Cr 2.0 eq

Ph

Ph Bu-s N H

1. Toluene, reflux, 18 h 2. Pyridine, 6 h

HN H

1. Benzene, reflux, 12 h 2. Pyridine, 6 h

441

N Bu-s Me

Cr(CO)5

O

(32) 1:1 mixture of isomers Ph

Ph 2.0 eq

III

Ph

O

N

Ph Ph (23)

a

H Ph

Ph

Ph

+ Ph

O Ph (41)

+ O

(11)

441

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C14 Ph

Cr(CO)5 Ph

Ph

Ph

1. Benzene, reflux, 8 h

N

Ph

Ph

Ph

(—) +

N

Ph

Ph

(—)

N

440a

2. Pyridine, reflux O

0.17 M

O Me

Me

Me

N

O

N

Ph

1. Benzene, reflux, 48 h

1.5 eq Ph

(CO)5Cr

+

2. Pyridine, reflux, 12 h

Ph

Ph

440b

Ph

Ph (7)

(62)

468

Me

N

Ph

O Cyclohexane, reflux

(CO)5Cr

Ph

Me + Ph N Ph –

Ph

Ph

N

O

(—)

442

Ph

Cr(CO)3 Ph

Cr(CO)5

Ph

N

THF, 80°, 1-3 h

Ph

Ph

Ph

N

1.5 eq Ph

Cyclohexane, reflux

Cr(CO)5 0.1 M

+ N

O

(41)

235, 236

(65)

440b

Ph

N H

Ph

– Ph

Ph

Cr(CO)3

n

1.2 eq N

Benzene, reflux, 22 h

n

N

O

Ph

n

N

O

+

Ph

437

+

(CO)5Cr Ph

Ph

Ph

Ph

I

Ph

N

Ph

II

Cr(CO)3

n

Ph

N

Ph

Ph

Ph

Ph

III

IV

Ph

Ph Ph

469 V

Ph

+

O

VI

O Ph

Ph

Ph

Ph +

+

N

N

n

IX

VIII

VII I

II

III

IV

(47) (0.7) (0)

V

VI

VII VIII

IX

(9.7)

(0)

(0)

(0)

(0)

2 (10) (32.6) (0.6) (1.5) (23)

(0) (17.9) (3.9)

3 (11) (37.4) (0)

(0)

(0)

4

(0) (11.3) (3.9) (1.9)

(0)

N

(CO)3Cr

n

n

1 (6.7)

+

Ph

Ph

n

+

n

O

+

(31)

(0)

(8)

(0)

(4.6) (5.2) (5.8) (0) (12.3)

TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

C14

(CO)4Cr Ph

Ph

Product(s) and Yield(s) (%)

O

N Me 0.03 M

CO (30 psi), THF, rt, 25 h

Ph

Ph

165

(12)

Ph

N Me

OH

Ph

Ph

Cr(CO)5

2 eq

Refs.

Ph

Ph

Ph

2 eq

Conditions

Benzene, reflux, 10 h

N

CN

Ph

Ph

+

(53.3)

(19.4)

437

Ph N Ph

Ph

H N

Ph

470

1.0 eq

Toluene, 75°, 1 h (CO)4Cr

(CO)3Cr

Ph

Ph Ph

1. Benzene, reflux, 12 h

(3)

Ph (3.6) +

+

O O

O Me

Ph

N

O

Ph Ph

Ph

Ph Photolysis (pyrex), Cr(CO)5

N

hexane, rt, 4-5 h

0.005 M

Me

(42.6) +

Ph

O

Ph

Ph

N

Ph H

Ph

(4.1)

Ph

R

Ph

Me (51) N

Ph Me

N

R

Ph (5.8) +

Ph

Ph

Ph Ph

10 eq

Ph

(0.7) +

O

Ph

440b

2. Pyridine, reflux, 12 h

Ph

Ph

NH NMe2 (10)

Ph

N

(CO)5Cr

432

(CO)3Cr

NMe2 (42)

Me 2.3 eq

N

N Me2

0.1 M

Ph +

R

189, 190

Ph (49)

Ph DMF, 120°, 3 h

1.5 eq

Ph

N-morph OMe Cr(CO)5

OMe

(85)

392

N-morph

0.05 M MeO

C15

(CO)4Cr

(CO)5Cr Ph MeO

471

2 eq a

Ph

O N Me

Ph Ph

Cr(CO)5

CO (30 psi), THF, rt, 2.25 h

0.03 M

This product was formed with retention of configuration of the s-butyl group.

(65) Ph

N Me

Ph

165

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C3

DMF, 120°, 1 h

392

(50)

N-morph 0.05 M

OMe Cr(CO)5

O

OMe CN

Cr(CO)5

Ph NC

1. Photolysis, THF, –40° 2. Alkyne (1 eq),

N-morph 0.05 M

C4

–40° to rt, 12 h

(CO)4Cr Ph

472

(73)

190

(38-55)

235, 236

N-morph

Ph Photolysis (pyrex), Ph

54

OEt

EtO 10 eq

(22)

Cr(CO)5

N 0.005 M

hexane, rt, 5 h

Ph N

Ph MeO

Ph

MeO

THF, MeCN or C6H12, Ph

N

Cr(CO)5

80°, 1-3 h

Ph

0.3 M

1.5 eq

N H

Ph

N

Ph

MeO Ph

Ph THF, 80°, 1.5 h

1.5 eq BzO

N

Cr(CO)5

BzO

(11)

236

Bz

0.3 M OH

CO2Me

O

Cr(CO)4

MeO

CH2Cl2, –20°, 24 h

N-morph 0.1 M

1 eq

(25)

54

(36)

236

Cr(CO)3 N-morph

MeO2C Ph 1 eq

THF or MeCN, 80°, 1-3 h Ph N 0.3 M

Cr(CO)5

Ph

N H

Ph

N

Ph

MeO2C Ph

Ph 1 eq

THF, 80°, 1.5 h Cr(CO)5

N

BzO

BzO

Ph

N Me 0.03 M

CO (30 psi), THF, rt, 13 h

Ph

Ph

N Me

C4-5

OH EtO2C

473

1.5 eq

Ph

165

O

EtO2C

Cr(CO)5 N

R

(80)

MeO2C

Cr(CO)4

O

O

236

Bz

0.3 M

2 eq

(18)

R

R Me

THF, 60°, 48 h

0.03 M

156, 157

OMe (89)

N

OEt

C5

(63) (94)

OH Pr-n Cr(CO)5

n-Pr

Benzene, 80°, 24 h

(57)

83

(65)

83

NMe2 2 eq

NMe2

0.25 M

OTBS Pr-n Cr(CO)5

3 eq

NMe2 0.25 M

TBSCl, (i-Pr)2NEt, benzene, 80°, 17 h Cr(CO)3

NMe2

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OTBS

C5

Pr-n Cr(CO)5

n-Pr 2 eq

TBSCl, (i-Pr)2NEt, benzene, 80°, 14 h

NMe2 0.25 M

(42)

83

(57)

83

Cr(CO)3 NMe2 OH Pr-n

Cr(CO)5 2 eq

Benzene, 80°, 16 h NMe2 0.25 M

NMe2 OTBS

R4

474

2 eq

R4

Cr(CO)5 N

R2

R1 0.05 M

TBSCl, (i-Pr)2NEt, benzene, 80°, 14-18 h

OTBS R4

Pr-n +

R3O

205

R3O

Cr(CO)3

N

Pr-n

N

anti R1 = H, R2 = CH2OR3 syn R1 = CH2OR3, R2 = H

II

I

R3

R4

anti:syn

I

II

dr

% de

Me

Me

≤17:83

(49)

(—)

55:45

10

Me

Me

≥83:17

(34)

(—)

55:45

10

Me

Ph

26:74

(40)

(13)

52:48

4

TBS

Me

14:86

(51)

(—)

55:45

10

TBS

Me

86:14

(48)

(—)

59:41

18

Cr(CO)5 N

2 eq

Ar—Cr(CO)3

Ar

N

N

+

TBSCl, (i-Pr)2NEt, benzene, 80°, 20 h

O 0.05 M

OTBS Pr-n Ar =

O

205

O (12)

(51) dr = 55:45

OH R

EtO2C

EtO2C

Pr-n R

Cr(CO)5

1.5 eq

N

THF, 60°, 48 h

R N

0.03 M

H

(72)

D

(72)

OH

156, 157

Pr-n Pr-n

Cr(CO)5

4 eq

NMe2

1. Solvent, 80°, 36-47 h

I

+

II

83

2. HX, THF/H2O O

NMe2

475

CC (M)

Solvent

I

II

0.5

heptane

(66)

(<2)

0.5

benzene

(64)

(<1)

0.5

THF

(57)

(12)

0.005

THF

(<22)

(19)

0.5

CH2Cl2

(18)

(<7)

0.5

MeCN

(<5)

(13)

0.5

DMF

(25)

(13)

OTBS Pr-n 4 eq

Cr(CO)5 NMe2

TBSOTf, 2,6-lutidine,

83

80°, 42-64 h NMe2

CC (M)

Solvent

0.5

heptane

(50)

0.5

benzene

(40)

0.05

CH2Cl2

(33)

Cr(CO)3

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

OTf Pr-n

1. Benzene, 80°, 84 h Cr(CO)5

n-Pr 4 eq

NMe2

0.5 M

2. Tf2O, (i-Pr)2NEt,

83

(25)

rt, 1 d NMe2

Cr(CO)3

OH

O Pr-n

Cr(CO)5

2 eq

1. Solvent, 80°, 20 h

Pr-n +

2. Oxidative workup NMe2

+

NMe2 I

0.25 M

83

II

O

Pr-n

O

O

Pr-n

Pr-n

476

O

MeN

+

+

III

Ph

IV

NMe2

V O

Ph

Solvent

Workup

I

II

III

IV

V

benzene

CAN

(—)

(<4)

(—)

(25)

(<4)

THF

none

(—)

(<2)

(12)

(15)

(19)

THF

CAN

(—)

(<2)

(—)

(—)

(—)

DMF

none

(<1)

(—)

(<1)

(<1)

(32)

OTBS

OTBS Pr-n

Cr(CO)5

1.9 eq

NMe2

Pr-n (21) +

TBSCl, (i-Pr)2NEt, benzene, 80°, 10-12 h NMe2

0.25 M

(20)

Cr(CO)3

NMe2

OTBS

Cr(CO)3

OTBS Pr-n

1.9 eq

Cr(CO)5

TBSCl, (i-Pr)2NEt,

NMe2

NMe2

(4)

+

Cr(CO)3

NMe2

OTBS

OR

OR

Pr-n (35)

benzene, 80°, 10-12 h

OR

Cr(CO)5

Cr(CO)3

Pr-n +

TBSCl, (i-Pr)2NEt, benzene, 80°, 10-12 h

I

NMe2

NMe2

0.25 M

207

OTBS

Pr-n 1.9 eq

207

+

Cr(CO)3

II

NMe2

207

Cr(CO)3

OTBS Pr-n

R

I

II

(32)

(2)

(9)

TBS (25)

(4)

(29)

Me III

477

NMe2

Cr(CO)3

III

O Pr-n OMe

n-Pr

HO 1. THF, 70°, 4 d

2 eq Ph

N

Cr(CO)5

2. Air/silica gel

0.16 M

(21) Ph

+

OMe (18) 406 N

N

Ph Pr-n

n-Pr

Pr-n R 3 eq

Solvent, 70-80°, 24 h Ph

N

Cr(CO)5

0.014 M

Ph

R

N H I

+

Ph

N H II

R

Solvent

I

II

III

Me

hexane

(40)

(9)

(51)

Ph

hexane

(64)

(—)

(28)

t-Bu

hexane

(94)

(≤1)

(5)

t-Bu

MeCN

(20)

(61)

(14)

R

+

HO 234, 232 Ph

N III

R

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5 OR1

R2

n-Pr

Hexane, 70° Ph

N

Cr(CO)5

1

R

Me

Ph

Ac

Ph

Ac

t-Bu

R

Ph

+

R2

N H I

Refs. Pr-n

n-Pr

Pr-n

Ph

R2

I

N H II II

(0)

(4)

(51)

(0)

(9)

(31)

(13)

(26)

(37)

2

HO + Ph

234 N III

R

2

III

O Pr-n

OMe Bu-t 2 eq

1. THF, 70°, 24 h Ph

N

Cr(CO)5

0.08 M

478

(41)

224, 233

(38)

224

2. CAN O OH Pr-n

OMe Bu-t 1. THF, 70° Ph

Cr(CO)5

N

2. Air OMe OH

Cr(CO)5

Ph

OH

Ph

2 eq

Pr-n

Ph

NMe2

2. Workup

II

NMe2

NHMe I

Workup

(39) (—)

air, benzene

(23)

(8)

O

N

Pr-n

O N (CO)4Cr

Ph

N

MeCN, 45-50°, 24 h

244, 205

(40-61) >96% de

Me

0.005 M

N

Me

II

air, silica gel

Me

N O Ph N Me

Me

O

N

Pr-n

O N 1.5 eq

83

I

0.25 M

1.5 eq

Pr-n

+

1. Benzene, 84°, 17 h

(CO)4Cr

Ph Me N

N

MeCN, 45-50°, 24 h

244, 205

(22-33) >96% de

Me

N O Ph

0.005 M

479

N Me TMS Ph

HO

TMS

(60) +

THF or MeCN, 80°, 1-3 h Ph

Cr(CO)5

N

Ph

0.3 M

1.5 eq

TMS

N

Ph

Ph

N H

Ph

(10)

236

O O

Ph

Cr(CO)5

1. Photolysis, THF, –40° 2. Alkyne (1 eq),

Me2N

N-morph 0.05 M

–40° to rt, 12 h

NMe2 (CO)4Cr

(54)

Ph N-morph

54

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C6

n-Bu 4 eq

EtO2C

Cr(CO)5

EtO2C

Bu-n

THF, 60°, 16 h

N

N

0.03 M

Ph 1.5-2 eq

156, 157

(88)

Bu-n

Cr(CO)5 1. DMF, 120-125°, 5 h

N

(49)

2. 90-95°, 15 h

79

O OH

Bu-n

480

1.0 eq

Bu-n +

+

1. Solvent, temp, 4 h N-morph

2. 90-95°, 15 h I

N-morph

Solvent

Temp

I

II

III

DMF

120°

(7)

(90)

(—)

MeCN

120°

(9)

(71)

(3)

THF

120°

(18)

(43)

(7)

hexane

90°

(50)

(13)

(12)

1. DMF, 120-125°, 5 h N-morph

Ph

160 N-morph

III

II (95)

79

2. 90-95°, 15 h Bu-n

Ph

n-Bu

HO THF or MeCN, 80°, 1-3 h

Ph

N

(30)

O

+

Cr(CO)5 Ph

Ph

O

II

O

Cr(CO)5

Ph

2 eq

O

Bu-n

Cr(CO)5

Ph

Ph

N Me

Ph

N H

Ph

(56)

236

n-Bu

Cr(CO)4

N Me 0.03 M

N

Ph

CO (30 psi), THF, rt, 13 h

Ph

Ph

165

(27)

Bu-t

t-Bu

(n-Bu)2O, 90°, 3 h

NH

O Cr(CO)3

Cr(CO)5

R 2-4 eq

208

(40)

4 eq

Bu-t DMF, 120-125°, 3-3.5 h

O N

R H

(53)

Me

(20)

392

R

481

OMe Cr(CO)5 0.04-0.06 M

OMe

OMe

O

OMe Bu-t

2 eq

O

(8)

DMF, 125°, 3 h

392

N OMe Cr(CO)5

OMe

O

0.09 M OH EtO2C TMSO 4 eq

N 0.03 M

EtO2C

Cr(CO)5

OTMS

THF, 60°, 16 h

(73) N

156, 157

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C7

Refs.

OAc

N

n-C5H11

OBu-t

OAc

C5H11-n

1. Toluene, 55°, 2.5 h

Bn

C5H11-n

2. Ac2O, Et3N, DMAP,

+

rt, 3.5 h O

(CO)4Cr

2 eq

3. FeCl3-DMF, 20 min

N

Bn

O

0.03 M

(46)

162, 163

(19) C5H11-n

OBu-t R C5H11-n

1.2-2 eq

DMF, 120-125°, 3 h R

482

OMe Cr(CO)5

0.05 M

O

OMe

NH2

(17)

NHMe

(22)

NMe2

(51)

N-aziridinyl

(0)

N-pyrrolidinyl

(7)

N-piperidinyl

(75)

392

(17)

N C7 OH EtO2C

THF, 60°, 16 h

N 4 eq

EtO2C

Cr(CO)5

156, 157

(82) N

0.03 M

C8 C6H13-n (CO)4Cr

n-C6H13

(n-Bu)2O/THF (10:1), N H

Ph

(45)

443

90°, 1 h O

(CO)3Cr

OH EtO2C

Cr(CO)5

EtO2C 4 eq

C6H13-n

THF, 60°, 16 h

N

1.2 eq

N

Tol-p 1. Toluene, 120°, 1 h

R 0.06 M

O

MeO2C

H N

MeO2C

156, 157

(66)

0.03 M

Cr(CO)5

R

N

2. rt, 20 h p-Tol

O

MeO2C C6H13-n

+

R

p-Tol

I

R

I + II

I:II

Me

(45)

58:42

Bn

(26)

—

OH

C6H13-n

N

444

II

Ph

483

Ph Cr(CO)5

Ph 2 eq

I (42)

THF, 66°, 1 h

+

II (40)

54

N-morph

Cr(CO)4

2 eq

N-morph

N-morph

0.05 M

THF, 66°, 1 h

I (20) + II (20)

54

N-morph 0.05 M N-morph Cr(CO)4

2 eq

N-morph 0.05 M

(CO)5Cr CH2Cl2, rt, 1 h

(46)

54

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8

Refs.

OH

R

Ph

Ph R

THF, 60°, 16 h

N

4 eq

EtO2C

Cr(CO)5

EtO2C

R

0.03 M

N

H

(95)

D

(80)

156

OTBS

Ph

Ph (70)

1. THF, 60°, 16 h

N 4 eq

EtO2C

Cr(CO)5

EtO2C

2. TBSCl, Et3N

0.03 M

156

Cr(CO)3

N

484 Ph Ph

Ph

HO THF, MeCN or cyclohexane,

1.5 eq Ph

N

Cr(CO)5

80°, 1-3 h

0.3 M

Ph

N

Ph

Ph

10 eq

Photolysis (pyrex), N

Cr(CO)5

hexane, rt, 4-5 h

0.005 M

Ph

Ph

(41)

235, 236

189, 190

(43) N

Ph Ph

Ph

THF, 80°, 1-3 h BzO

Ph

Ph

1.5 eq N

Cr(CO)5

BzO

Ph (38)

N

+

Ph

Bz

0.3 M

Me

(CO)4Cr

Ph

(12)

236

Ph

O N

N H

O

N

1.5 eq

N H

Ph

Ph Ph

+

(0-12)

Ph Me N

N

MeCN, 45-50°, 24 h

(40) >95% de

Me

N

244

O

Ph N Me

0.01 M

C9

OH

THF, 60°, 16 h

N 4 eq

EtO2C

Cr(CO)5

EtO2C

156, 157

(58) N

0.03 M

485 Ph

N

Ph

Ph

Ph

4 eq

THF or MeCN, 80°, 1-3 h N

Ph

Cr(CO)5

(15)

HO

H N

Ph (43)

236

p-Tol

p-Tol C11

+

O

TsO 4 eq

N 0.03 M

EtO2C

Cr(CO)5

EtO2C

(68)

THF, 60°, 16 h N

156, 157

TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C12 EtO2C

Cr(CO)5

EtO2C

Fe N

Fe

(85)

THF, 60°, 16 h

0.03 M

156, 157

N

4 eq

DMF, 120°, 3 h

1.5 eq

Fe

N-morph

486

0.05 M

OMe Cr(CO)5

OMe

O

(50)

392

TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C5 Ph

Cr(CO)5

n-Pr

2. Air

SEt 0.02 M

2 eq

Pr-n 1. THF, 46°, 48 h

(36)

377

(32)

377

SEt OH Pr-n SEt

2 eq

1. THF, 46°, 48 h 2. Air

MeO Cr(CO)5 0.02 M

SEt OAc

MeO

C6

Bu-n

BF3•OEt2 (5 eq), n-Bu

SMe

O

487

Cr(CO)5

2 eq

THF, 65°

O

(48)

167

O n-Bu SMe OAc

0.03 M Cr(CO)5

Ph

O

MeS

(28) +

Ac2O (5 eq), Et3N (5 eq),

Bu-n

BF3•OEt2 (5 eq), Ac2O (5 eq), Et3N (5 eq),

2 eq SMe

(45)

167

(21)

168

(41)

167

THF, 65° SMe OH

0.03 M

Bu-n SPr-n

1.9 eq

BF3•OEt2 (5 eq), toluene, 65°

MeO

Cr(CO)5

SPr-n OAc

MeO

0.18 M

Et

BF3•OEt2 (5 eq), Et

Et

SMe

O

2 eq

Cr(CO)5 0.03 M

Ac2O (5 eq), Et3N (5 eq), THF, 65°

O

Et SMe

TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C6 Cr(CO)5

Ph Et

Et

Et

BF3•OEt2 (5 eq), Ac2O (5 eq), Et3N (5 eq),

2 eq

SMe 0.03 M

2 eq SEt

SEt Cr(CO)5

Cr(CO)5

NEt2 Petroleum ether

n-PrS

488

1 eq

377, 166

Et

2. Air

0.02 M

Et2N

(46)

Et 1. THF, 46°, 48 h

C7

167

SMe OH

Cr(CO)5

Ph

(13) Et

THF, 65°

n-PrS

0.1 M Y

Y O

(58)

S

(54)

168

Y R

Cr(CO)5 Cr(CO)5 Et2O, 20°

2 eq Ph

Et2N

SR 0.5 M

SR

Ph

Cr(CO)5 Cr(CO)5 1 eq RS

Ar RS

0.1 M

C8

NEt2

Petroleum ether Ar

allyl

(82)

t-Bu

(75)

Ph

(79)

c-C6H11 (79) R

Ar

n-Pr

Ph

(67)

Me

4-MeC6H4

(60)

n-Pr

4-MeOC6H4 (63)

Ph

O 2 eq

SMe

Ph

Cr(CO)5 0.03 M

THF, 65°

Ph

Ph

(32) +

Ac2O (5 eq), Et3N (5 eq),

(32)

O SMe

168

O

OAc BF3•OEt2 (5 eq),

445

O

SMe

167

OAc Ph

Ph

BF3•OEt2 (5 eq),

Cr(CO)5

Ac2O (5 eq), Et3N (5 eq),

2 eq SMe 0.03 M

(42)

167

(45)

377

THF, 65° SMe OH

Ph

Ph

Cr(CO)5

2 eq

1. THF, 46°, 48 h SEt 0.02 M

2. Air SEt OAc Bu-t

BF3•OEt2 (5 eq), MeO2C

Bu-t

SMe

O

Ac2O (5 eq), Et3N (5 eq), THF, 65°

Cr(CO)5

2 eq

O

167

(25)

167

SMe

0.03 M

489

(55) CO2Me

C9

OAc Ph

BF3•OEt2 (5 eq), Ph

SMe

O 2 eq

Ac2O (5 eq), Et3N (5 eq), THF, 65°

Cr(CO)5

O SMe

0.03 M

OAc Ph

Ph

BF3•OEt2 (5 eq),

Cr(CO)5

Ac2O (5 eq), Et3N (5 eq),

2 eq SMe

(9)

167

THF, 65°

0.03 M

SMe OAc BF3•OEt2 (5 eq),

TMSO OEt

SMe

O

Ac2O (5 eq), Et3N (5 eq), THF, 65°, 96 h

Cr(CO)5

2 eq

(33) O

167

OEt SMe

0.03 M

TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OAc

C11

Ph

BF3•OEt2 (5 eq), EtO2C

Ph

SMe

O

Ac2O (5 eq), Et3N (5 eq), THF, 65°

Cr(CO)5 0.03 M

2 eq

O

(52)

167

(43)

167

CO2Et SMe OAc

Ph

Ph

BF3•OEt2 (5 eq),

Cr(CO)5

Ac2O (5 eq), Et3N (5 eq),

2 eq SMe

CO2Et

THF, 65°

0.03 M

SMe

C12 OMe

OMe O

490

BF3•OEt2 (5 eq), Et3N (5 eq),

Fe SEt 2 eq

0.03 M

(3)

392

Fe

THF, reflux, 19 h

OMe Cr(CO)5

OMe O

C14 OAc Ph

BF3•OEt2 (5 eq), Ph

Ph 2 eq

O

SMe Cr(CO)5 0.03 M

Ac2O (5 eq), Et3N (5 eq), THF, 65°

(23) O

Ph SMe

167

TABLE 12. ARYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

OH Et

O

1. Additive (2 eq), solvent,

L Mo(CO)4 Et

80°, 20-50 h Ph

OMe

Refs.

2. Workup

Et

Et +

Et +

Et

Et

OMe

Et + OMe

O I

II

III

Et Et Et

Et

+ Ph

O

Ph

+ OMe

O V

OMe

IV

OMe

Et

Et VI

491

Alkyne (eq)

CC (M)

L

Solvent Additive Workup

I

II

III

IV

V

VI

1.9

0.1

CO

THF

none

air

(9)

(—)

(66)

(1)

(5)

(—)

60

1.9

0.005

CO

THF

none

air

(3)

(—)

(71)

(0)

(2)

(—)

60

1.9

0.1

(n-Bu)3P

THF

none

CAN

(—)

(43)

(—)

(—)

(—)

(—)

201

1.9

0.1

(n-Bu)3P

THF

none

air

(—)

(—)

(<1)

(—)

(2)

(—)

201

7.8

0.056

(n-Bu)3P

THF

none

CAN

(—)

(36)

(—)

(—)

(—)

(—)

201

7.8

0.056

(n-Bu)3P

THF

none

air

(—)

(—)

(≤1)

(—)

(4)

(—)

201

1.9

0.1

CO

THF

(n-Bu)3P CAN

(—)

(≤5)

(0)

(—)

(0)

(—)

201

1.9

0.1

CO

benzene none

air

(6)

(—)

(74)

(0)

(15)

(—)

60

1.9

0.005

CO

benzene none

air

(5)

(—)

(66)

(0)

(8)

(—)

60

7.8

0.1

CO

MeCN

none

air

(—)

(—)

(—)

(—)

(6)

(16)

60

7.8

0.1

CO

MeCN

none

CAN

(—)

(39)

(>5)

(1)

(—)

(—)

60

7.8

0.005

CO

MeCN

none

air

(—)

(—)

(—)

(—)

(6)

(3)

60

7.8

0.005

CO

MeCN

none

CAN

(—)

(67)

(>5)

(1)

(—)

(—)

60

TABLE 12. ARYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C6

Et

Et

p-Tol

1.2 eq

Et

O

(CO)4Mo

OBu-t

N

1. Solvent, temp, 1 h

p-Tol

Temp

R

I

II

60°

H

(11)

(—)

toluene

80°

Bn

(—)

(13)

Et

p-Tol

492

N

Solvent, temp, 2-3 h

R

p-Tol N HO R I

I

II

n-Pr

(18)

(—)

toluene

80°

Bn

(9)

(10)

(CO)5Mo

Ph

OMe

O

433

(63)

359

(83)

430

OMe

NEt2 Benzene, 20, 2 h

Ph

N

NEt2 Hexane, rt, 1 h

(CO)5Mo 0.3 M

Et

R II R

NH2 1 eq

p-Tol

60°

Ph (CO)5Mo

+

O

Temp

C7

0.3 M

Et

Et

THF

Solvent

1 eq

163

N

0.06 M

NEt2

OR

CO2Bu-t II

THF

R

Et

N

I Solvent

1.2 eq

p-Tol

CO2Bu-t

0.06-0.1 M

(CO)4Mo

+

O

N

2. Air, 3-12 h

R

Et

Et

N (CO)5Mo

Et Ph

C8-9 OMe R1

OMe

O

(CO)5Mo

O O OMe

R2

Dioxane, 100°, 5 h

2.5 eq

0.05 M

R2

Fe

Fe

Fe

R1 I

R1

R2

n-Pr

n-Pr

(10) (17)

Me

Ph

(40) (19)

I

II

426 R1

R2

II

C14 O Ph

HN

Ph 1.2 eq

Ph

Benzene, reflux, 3 h

N Mo(CO)4

Ph

N

N

(40)

446

(27)

426

Ph

Ph

493

0.1 M OMe Alkyne (eq)

O

Ph

(CO)5Mo

1.5

Dioxane, 100°, 5 h

2.5

Fe 0.05 M

Fe

OMe Ph

(37)

TABLE 13. ARYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

OH

Pr-n Ph

+

+

1. Solvent, 80°, 26-60 h OMe

1.9 eq

Pr-n

Pr-n

Mo(CO)5

n-Pr

Refs.

Ph

2. Air, silica gel

I

II

OMe

OMe

60

OH

O n-Pr

OMe

O III

Pr-n

Ph

OMe

Pr-n

+

Ph O Ph

IV

MeO + CO2Me Ph

MeO O + Ph

O

O

O

494

Pr-n

Pr-n

Pr-n

VII

VI Solvent

V

Pr-n

OMe

VIII

I

II

III

IV

V

VI

VII

VIII

0.1

THF

(21)

(5)

(25)

(0)

(20)

(20)

(0)

(0)

0.005

THF

(27)

(12)

(27)

(0)

(6)

(11)

(0)

(0)

0.1

benzene

(62)

(4)

(2)

(1.3)

(21)

(2.5)

(0)

(0)

0.005

benzene

(80)

(3)

(3)

(3)

(6)

(1)

(0)

(0)

0.1

MeCN

(10)

(18)

(16)

(0)

(4)

(30)

(3)

(0)

0.005

MeCN

(3)

(9)

(2)

(0)

(2)

(1)

(2)

(27)

0.1

MeOH

(19)

(2)

(0.2)

(0)

(25)

(41)

(0)

(0)

CC (M)

O TMS Mo(CO)5

TMS

OMe

1.3 eq

(69)

1. Toluene, 90°, 5 min

82, 185

2. CAN O

0.07 M

C6

Bu-n OMe

n-Bu 1.3 eq 0.07 M

Mo(CO)5

1. Toluene, 90°, 5 min

(53)

82, 185

(27)

185

2. CAN O O Bu-n

1.3 eq

O

OMe Mo(CO)5 0.07 M

1. Toluene, 90°, 90 min 2. CAN

O O Bu-t

OMe

t-Bu

Mo(CO)5

1.3 eq

O O OMe

+

1. Toluene, 90°, 5 min 2. CAN O

0.07 M

185

Bu-t (34)

(15)

Bu-t

495

O OMe

1.3 eq

Mo(CO)5

+

1. Toluene, 90°, 5 min 2. Air

(17)

O

0.07 M R

Bu-t

R O OMe

1.3 eq

Mo(CO)5

OMe

1. Toluene, 90°, 5 min 2. Air

OMe

Bu-t

185 (55)

R H

(33)

185

OMe (34)

0.07 M C6H13-n

C8 OMe

n-C6H13 1.3 eq

Mo(CO)5 0.07 M

1. Toluene, 90°, 5 min

(69)

2. Air O

185

TABLE 13. ARYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C6H13-n

C8 OMe

n-C6H13 1.3 eq

Mo(CO)5

1. Toluene, 90°, 5 min

82, 185

(60)

2. CAN

O

0.07 M O

C6H13-n OMe

O

1.3 eq

Mo(CO)5

1. Toluene, 90°, 90 min O

0.07 M

C9 Ph

TBSO

OTBS

OMe

Ph

Benzene, 100°, 1.5 h Mo(CO)5

496

1.7 eq

185

(35) O

2. CAN

(66)

447

OMe

0.04 M

C12 EtO2C

OH OMe

O

CO2Et

See table

0.9 eq

+

385

O

Mo(CO)5

I

OMe

0.003 M

H

H CO2Et

CO2Et +

OMe

OMe

O

O

II

III

Temp

Time

I

II

III

THF

55°

4h

(tr)

(12)

(—)

THF

67°

0.33 h

(—)

(10)

(—)

THF

67°

2h

(—)

(40)

(—)

THF

100°

2h

(tr)

(42)

(—)

benzene

25°

56 h

(19)

(8)

(17)

benzene

70°

4h

(12)

(8)

(16)

benzene

100°

2h

(17)

(5)

(10)

1,4-dioxane 102°

2h

(tr)

(34)

(—)

Solvent

C14

H EtO2C 3

497

0.9 eq

OMe

O

1,4-Dioxane, reflux, 2 h

Mo(CO)5 0.003 M

OMe

CO2Et

OMe

CO2Et

(42)

385

O H

Mo(CO)5 0.83 eq

(33)

THF, reflux, 2 h Ph

OMe

0.003 M

+

385

Ph H (17) OMe Ph

CO2Et

TABLE 14. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

OH Et

Et

O

OMe Mo(CO)5

Et

+

1. Additive, solvent, temp 2. Air, TsOH, THF/H2O

Et

H

Et O

O

Et

H

OMe I

Refs.

+

60

O

II H

O Et

O

Et Et

OMe Et

Mo Et

CO Et III

498 Alkyne (eq)

CC (M)

I

II

III

2

0.5

THF

rt

none

(49)

(12)

(3-5)

Solvent Temp Additive (eq)

499

2

0.05

THF

rt

none

(31)

(33)

(3-5)

20

0.05

THF

rt

none

(58)

(16)

(3-5)

2

0.05

THF

60°

none

(16)

(36)

(—)

2

0.05

THF

110°

none

(6)

(25)

(—)

3

0.05

THF

rt

MeCN (10)

(10)

(59)

(—)

2

0.05

THF

rt

MeCN (100)

(tr)

(6)

(—)

2

0.05

THF

60°

Ph3P (1)

(14)

(47)

(—)

2

0.05

THF

60°

(n-Bu)3P (1)

(—)

(—)

(—)

2

0.05

THF

60°

(MeO)3P (1)

(—)

(—)

(—)

2

0.05

THF

60°

CO (1 atm)

(33)

(11)

(—)

2

0.005

THF

rt

none

(8)

(59)

(—)

200

0.005

THF

rt

none

(36)

(10)

(—)

2

0.005

THF

rt

MeCN (100)

(7)

(58)

(—)

2

0.5

n-heptane rt

none

(69)

(<3)

(—)

2

0.05

n-heptane rt

none

(68)

(<5)

(—)

2

0.005

n-heptane rt

none

(69)

(<1)

(—)

2

0.05

benzene

rt

none

(65)

(—)

(—)

2

0.05

benzene

rt

MeCN (2)

(54)

(6)

(—)

3

0.05

benzene

rt

MeCN (4)

(24)

(34)

(—)

3

0.05

benzene

rt

MeCN (10)

(16)

(33)

(—)

3

0.05

benzene

rt

MeCN (38)

(7)

(46)

(—)

3

0.05

benzene

rt

MeCN (114)

(7)

(43)

(—)

2

0.05

CH2Cl2

rt

none

(53)

(—)

(—)

2

0.05

DMTHF

rt

none

(28)

(36)

(—)

3

0.05

MeCN

rt

none

(5)

(25)

(—)

2

0.05

DME

rt

none

(57)

(14)

(—)

2

0.05

DMF

rt

none

(9)

(14)

(—)

2

0.05

MeOH

rt

none

(11)

(40)

(—)

2

0.05

MeNO2

rt

none

(<10)

(<10)

(—)

OH

H

Et 2 eq

OMe Mo(CO)5

+

1. Solvent, temp, 8-19 h 2. Air, TsOH, THF/H2O

Solvent

Et

Et I

CC (M)

H

OMe

II

Temp

I

II

0.5

THF

50°

(48)

(22)

0.005

THF

50°

(6)

(64)

0.5

n-heptane

50°

(33)

(7)

0.005

n-heptane

50°

(33)

(9)

MeCN

25°

(5)

(27)

0.1

Et

O

60

TABLE 14. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C6

OH

OH

Refs. O

Et

O Et

OMe

O

+

Solvent, rt O

Mo(CO)5

1.5-2 eq

+ Et

O

I OMe O

0.05 M

OMe H

I

II

III

THF

(23)

(—)

(44)

MeCN

(<10) (26)

(7)

Solvent

O O

O

III Et

C10

OMe

OH

H Ph

O

OMe

500

Ph

(11) +

THF, 50°

C14

Ph Photolysis (pyrex), Ph 10 eq

N 0.005 M

Mo(CO)5

hexane, rt, 7 h

Ph Ph

(59)

71

OMe

Ph

Ph Ph

O Ph

OMe O

0.05 M

Ph

O

Mo(CO)5

1.5-2 eq

71

II

(21) N

190

TABLE 15. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

Refs.

OH Pr-n OMe

n-Pr 2 eq

Mo(CO)5 0.1 M

(80)

1. THF, rt, 14 h

60

2. Air, TsOH, THF/H2O OMe OH

2 eq

OMe

O

Mo(CO)5

+

1. THF, rt, 24-28 h 2. Air, acid, THF/H2O

60 O

O

H

OMe I

501

Acid

I

II

0.05

TsOH

(51)

(10)

0.005

none

(35)

(14)

OH

Mo(CO)5

+

1. Solvent, temp, 15-45 h

60

2. Air, TsOH, THF/H2O

H

OMe I

CC (M)

Solvent

0.5

THF

0.005

THF

Pr-n

H

Pr-n OMe

O

II

CC (M)

2 eq

Pr-n

H

Pr-n

O

II

Temp

I

II

rt

(86)

(<0.2)

rt

(77)

(—)

0.5

n-heptane

50°

(72)

(<0.8)

0.005

n-heptane

50°

(80)

(<3)

TABLE 15. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

C14 3

1 eq

OMe

O

THF, 67°, 2 h

O

Mo(CO)5 0.003 M

0.7 eq

OMe

O

THF, 67°, 2 h

CO2Et O

502

0.01 M

CO2Et

THF, 100°, 2 h TMS

Mo(CO)5

(34)

385

3.4:1 mixture of isomers

OMe OH OMe

385

O

0.004 M

TMS

(72)

H

Mo(CO)5

1 eq

Refs.

OMe

EtO2C

O

EtO2C

Product(s) and Yield(s) (%)

385

(30) OMe OH

0.9 eq

OMe

CO2Et

THF, 67°, 12 h (24)

Mo(CO)5 0.003 M

OMe

+

CO2Et (35) O

3:1 mixture of isomers

385

TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C4 W(CO)5

Ph

Photolysis, toluene, rt

+ polymer

(<10)

63

OMe OMe C6

OH Et

Et Et

W(CO)5

Ph

1. THF, 80°, 42-75 h

Et

Et

+

2. Air, silica gel

OMe

60

Et I OMe Et

1.9 eq

OMe

II Et

Et

+

Et

+ Ph

O

O

503

III

Ph

Et

OMe

O IV

Et

+ Bz

CO2Me

V

CC (M)

I

II

III

IV

V

0.1

(6)

(53)

(—)

(33)

(—)

0.005

(8)

(57)

(17)

(—)

(9)

OH

Et Et

W(CO)5

Ph

1. MeCN, 80°, 62 h

1.9 eq

Et (7) +

+

(4)

2. Air, silica gel

OMe

60

Et

0.005 M

OMe

OMe Et

MeO

Et +

(2) Ph

OMe

O

O

Ph

(3)

Et

Et

TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Ph

C6 Et

Et

Ph

3 eq

Et

N

W(CO)5

Hexane, 80°, 24 h

(86) Ph

0.014 M

234

Ph

N H O

Ph

W(CO)5

1.9 eq

Et Et

1. Benzene, 80°, 42-73 h

Et

+

2. Workup

OMe

Refs.

Et

+

60

Et I

II

O

O

Et Et Et

Ph

504

III Workup

CC (M)

Et

+

O

O

OMe

IV

I

II

III

IV

0.1

air, silica gel

(—)

(—)

(—)

(6)

0.1

CAN

(3)

(42)

(44)

(—)

0.005

air, silica gel

(—)

(—)

(—)

(1)

0.005

CAN

(2)

(31)

(36)

(—)

Et OMe

4 eq

W(CO)5

Et

1. Benzene, 80°, 46 h 2. Silica gel

(40)

448

O

0.1 M

C7

O

NEt2 O Petroleum ether, 20°, 2 h

NEt2 1 eq

(CO)5W

(72)

(CO)5W SC3H5 0.1 M

SC3H5

168

NEt2

NH2 1 eq

N

Benzene, 20°, 2 h

(CO)5W

(91)

Et

(CO)5W

Ph

430

Ph

0.3 M R

R

R NEt2

1 eq

Hexane, 20°, 2 h

(CO)5W

(CO)5W

OMe I

OMe 0.33 M

I

E:Z

OMe

(61)

10:1

Me

(78)

100:0

H

(74)

100:0

Br

(45)

5:1

CF3

(69)

100:0

359, 141

O NEt2

SR (CO)5W

2 eq

(CO)5W

Et2O, 20°

Ph

Ph

SR

I

0.5 M

+

+ II

505

O

S

445

W(CO)5

R

O + SR

III R

IV

I

II

III

IV

allyl

(82)

(4)

(0)

(0)

Ph

(69)

(0)

(3)

(1)

CH2Ph

(70)

(0)

(22)

(7)

TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C7

NEt2

Ph

(CO)5W

(CO)5W

NEt2 1 eq

Ph +

Pet ether/ether, 20°, 0.5 h

N

+

N

Ph

0.22 M

Refs.

NEt2

Ph

(82)

(10)

NEt2 Ph

N

Ph NEt2

Ph +

(CO)5W

Ph N Ph

W(CO)5 (3) C9-14

434

N

(3)

Ph Ph

506

Ph

W(CO)5

R

R

Toluene or benzene

63

OMe R

OMe Recovered CC

Temp Time

Me

photolysis

Me

—

Ph

photolysis

Ph

—

rt

72 h

(—)

(50)

100°

18 h

(>90)

(—)

rt

6-10 d

(<10)

(—)

100°

3h

(90)

(—) Ph

C9 Ph

Ph

OR

R=

Toluene, 110°, 1.5 h

(60) (CO)3W

C10

1 eq

(CO)5W 0.25 M

(n-Bu)2O, 90°, 6 h OMe

+

OR

(30) (CO)3W

449

OR

NEt2

Ph NEt2

NEt2

Ph

W(CO)5

(CO)4W Et2N

Ph OMe

(19)

366

H N

C14 Ph

O N

N

Ph

Ph

N

(51)

1. THF, 45°, 18 h

OMe

1.5 eq

237

Ph

2. CAN W(CO)5 0.1 M OMe (CO)5W

O O p-Xylene, 138°, 5 h

0.05 M

OMe

O +

OMe Ph

Fe

Fe

Ph

426

Ph

Fe Ph

(34)

(30)

Ph OMe

4 eq

Ph

Benzene, 80°, 66 h

W(CO)5

(19)

448

OMe

507

0.1 M Ph (CO)3W

EtO (CO)5W 2.2 eq

Ph

EtO

Toluene 2

+

(CO)5W

I

Ph (CO)3W

0.06 M Temp

Time

I

II

70°

3h

(30)

(46)

75°

4h

(0)

(70)

391

OEt Ph

EtO OEt II

Ph Ph OMe

C26

(CO)4W

OMe Ph2P

PPh2

(CO)5W

1 eq

Ph Hexane, 100°, 4 h

Ph

Ph

Ph2P W(CO)4

0.085 M MeO

PPh2

(78)

374

TABLE 17. ARYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne

Carbene Complex

C3

Conditions

Product(s) and Yield(s) (%)

Refs.

OMe (CO)5W

40°, 45 h

OEt

OEt

C4 EtO

(CO)5W 2 eq

85

Polymer (44)

Ph

100 eq

(CO)5W

Et2O, 0-4°, 24 h

0.25 M

OEt

Ph

(80) E:Z = 9:1

Ph OH

C5 Ph

378

Pr-n Pr-n

Pr-n

W(CO)5

n-Pr

+

1. Solvent, 80°, 30-240 h OMe

2. Air, silica gel

I

+ Ph II

OMe

OMe

OMe

OH

508

O n-Pr

60 O III

Pr-n

+

Ph

OMe

Pr-n

+

+

Ph O

Pr-n V

IV

OMe Ph

MeO CO2Me Pr-n

O

O

Ph

VI

Pr-n

VII

Alkyne (eq)

CC (M)

I

II

III

IV

V

VI

VII

30

0.1

THF

(6)

(6)

(37)

(0)

(10)

(18)

(0)

3.8

0.005

THF

(10)

(9)

(38)

(0)

(7)

(20)

(4)

20-30

0.1

benzene

(7)

(57)

(12)

(1.2)

(19)

(2)

(0)

3.8

0.005

benzene

(6)

(60)

(5)

(6)

(14)

(1)

(0)

3.8

0.005

MeCN

(10)

(9)

(5)

(0)

(1)

(5)

(5)

Temp, 18-22 h

Polymer

C6-8

Solvent

+

OMe (CO)5W

R

85, 63

Ph Alkyne (eq)

Temp

50

40°

R n-Bu

(45)

100

60°

t-Bu

(28)

50

40°

Ph

(55)

Polymer

C8 OMe Cycloalkene (100 eq),

(CO)5W

Ph

Ph

Ph

450, 451

Ph

50°, 21-312 h n

m

509

Alkyne (eq)

Cycloalkene

n

10

cyclopentene

1

(19)

3

cyclopentene

1

(4.9)

2.25

cyclopentene

1

(4.2)

1.75

cyclopentene

1

(7)

1

cyclopentene

1

(15.8)

0.75

cyclopentene

1

(20.3)

0.3

cyclopentene

1

(36.7)

10

cycloheptene

3

(16)

1

cycloheptene

3

(16)

10

cyclooctene

4

(7)

1

cyclooctene

4

(8) Ph

OMe

4 eq

W(CO)5 0.1 M

1. Benzene, 80°, 96 h 2. Silica gel

(40) O

448

TABLE 17. ARYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C16 OMe (CO)5W

Toluene, 75°, 18-24 h

452

Ph

CC (M)

Alkyne (eq) 1

0.05

(50)

100

0.001

(31)

C17 OMe (CO)5W

Toluene, 75°, 18-24 h

E:Z = 22:78

452

(24)

452

510

Ph E:Z = 44:56 Alkyne (eq)

CC (M)

1

0.05

(41)

100

0.001

(26)

C18 OMe (CO)5W

Toluene, 75°, 18 h Ph

0.001 M 100 eq

TABLE 18. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C6

Refs.

Et Et

Et

Et

O

2 eq

OMe

2. Air, TsOH, THF/H2O

Et

+

1. THF, 90°, 24-48 h

W(CO)5

OMe

60

O

Et

O

O

I

CC (M)

I

II

0.5

(58)

(<3)

0.05

(65)

(<3)

0.005

(77)

(<2)

OH

II

Et Et

2 eq

511

OMe

1. Solvent, 90°, 18-32 h

W(CO)5

2. Air, TsOH, THF/H2O

O

I

OMe Solvent

CC (M)

Et

+

I

II (7)

0.1

THF

(45)

0.005

THF

(56)

(8)

0.1

n-heptane

(51)

(23)

0.005

n-heptane

(50)

(38)

0.1

MeCN

(24)

(24)

0.005

MeCN

(8)

(47)

OH Et

O OMe

Et

II

H

O

O (36) +

THF, 80°

(20) 71 Et

W(CO)5

1.5-2 eq

60

Et

OMe

OMe O

0.05 M

TABLE 18. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne

Carbene Complex

C7

Conditions

Product(s) and Yield(s) (%) NEt2

OEt (CO)5W

Et2N 1 eq

Cyclohexane, 0° 0.5 M

NEt2

Ph

(CO)5W (37) +

(CO)5W

Refs.

OEt (1)

OEt

Ph

Ph OEt

OEt +

(CO)5W Ph

(CO)4W (22) +

Et2N

NEt2

Ph

OEt (CO)5W

512

+

Ph (16)

Et2N

(1)

402

TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne C4

Carbene Complex R 2N

Conditions

Product(s) and Yield(s) (%) R2N

Ph Catalyst (2-2.5 mol%),

MeO

OEt 1.5 eq

THF/MeOH (4:1),

MeO

20°, 36 h

W(CO)5

Catalyst

Ph

OEt

0.25 M

OEt

morph-N R1

(CO)5W

THF/EtOH (5:1), R2

NR2

[(COD)RhCl]2 NEt2

(63)

[(COD)RhCl]2 N-morph

(61)

[(CO)2RhCl]2

NEt2

(77)

[(CO)2RhCl]2

N-morph

(74)

RhCl3•3H2O

NEt2

(77)

RhCl3•3H2O

N-morph

(77)

194

R1

[(COD)RhCl]2 (2.4 mol%),

1.5 eq

Refs.

R2

MeO

193

20°, 36-38 h OEt

N-morph 0.25 M

513

R1

R2

1-cyclohexenyl Me

(53)

Ph

Me

(63)

Ph

i-Pr

(59)

Ph

(70) n-Pr

Pr-n

C5

R n-Pr

Hexane, 80°, 24 h W(CO)5

N

Ph 3 eq

Ph

0.014 M

+

R

N H I

Ph

Pr-n OMe W(CO)5 0.005 M

1. THF, 80°, 61 h

I

II

Me

(74)

(<1)

Ph

(76)

(0)

R

OH 2 eq

234

R

N H II

(87)

60

2. Air, TsOH, THF/H2O OMe

TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

OH

H

Pr-n

n-Pr 8 eq

OMe

O

1. THF, 80°, 108-120 h 2. Air, TsOH, THF/H2O

W(CO)5

Refs.

Pr-n

+

60 O

O I OMe

CC (M)

I

II

0.5

(43)

(≤0.4)

0.005

(54)

(—)

H II

O

O Pr-n OMe

4 eq

W(CO)5

1. THF, 80-90°, 38-64 h

60

2. CAN O

514

CC (M) 0.1

(88)

0.005

(96)

R 2N

Ph Catalyst (2-2.5 mol%), OEt W(CO)5

1.5 eq

0.25 M

R2N

Ph

NR2

Catalyst

NMe2

[(COD)RhCl]2

(53)

THF/MeOH (4:1),

N-morph [(COD)RhCl]2

(58)

20°, 36 h

NMe2

[(CO)2RhCl]2

(74)

N-morph [(CO)2RhCl]2

(75)

NMe2

RhCl3•3H2O

(78)

NEt2

RhCl3•3H2O

(74)

N-morph RhCl3•3H2O

(76)

NHMe

[(CO)2RhCl]2

(0)

NHEt

[(CO)2RhCl]2

(0)

NHMe

RhCl3•3H2O

(0)

NHEt

RhCl3•3H2O

(0)

OEt

194

N-morph R1

OEt R1

(CO)5W

[(COD)RhCl]2 (2.4 mol%),

1.5 eq

R2

THF/EtOH (5:1), R2

193

(59)

20°, 28-36 h OEt

N-morph 0.25 M R1

R2

1-cyclohexenyl Me

(59)

Ph

Me

(68)

Ph

i-Pr

(68)

Ph

(71)

C8 R 2N

Ph OEt

Ph

THF/MeOH (4:1),

194

20°, 36 h

515

W(CO)5

1.5 eq

R2N

Catalyst (2-2.5 mol%),

0.25 M

OEt

Catalyst

NR2

[(COD)RhCl]2

NEt2

(61)

[(COD)RhCl]2

N-morph

(60)

RhCl3•3H2O

NMe2

(73)

RhCl3•3H2O

NEt2

(71)

RhCl3•3H2O

N-morph

(71)

N-morph Ph

OEt (CO)5W

[(COD)RhCl]2 (2.4 mol%),

Ph

1.5 eq R

R R

THF/EtOH (5:1), 20°, 30-32 h

Me

(62)

i-Pr

(59)

193

OEt

N-morph 0.25 M

TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C8

Carbene Complex R 2N

Product(s) and Yield(s) (%) R2N

Ph RhCl3•3H2O (2 mol%), OEt

Ph 1.5 eq

Conditions

(CO)5W

Refs.

Ph NR2

Ph

THF/MeOH (4:1),

NMe2

(76)

20°, 36 h

NEt2

(77)

OEt

194

0.25 M Ph

OEt 2.5 eq

NHMe

(CO)5W

THF, 70°, 12 h

NMe

(CO)5W

Ph

0.1 M

morph-N [(COD)RhCl]2 (2.4 mol%),

516

1.5 eq

THF/EtOH (5:1),

Ph OEt

(CO)5W

410

Ph

R

morph-N

(53)

0.25 M

Ph

Ph

193

R

20°, 36 h OEt

R Me

(69)

i-Pr

(71) (69)

C11 TMSO

morph-N

morph-N Ph (CO)5W

1.5 eq

0.25 M

Ph

[(COD)RhCl]2 (2.4 mol%),

OEt

THF/EtOH (5:1), 20°, 38 h

(61)

TMSO OEt

193

TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C4

Refs.

Ph H

PF6–

Cp(CO)2Fe 3 eq

+

+

CH2Cl2, –78° to rt

Ph

PF6– I

+ Cp(CO)2Fe CH2Ph (—)

Cp(CO)2Fe PF6–

I + II = (75)

453

II

O Ph

10 eq

(89)

198

EtO

Fe(CO)4

EtO

Ph

O

CH2Cl2, 78°, 1 h

Fe(CO)3

O

Fe(CO)4 4.9 eq

60°, 1 h

517

Ph

Ph

NMe2 0.2 M

NMe2

O

Ph

O

+

I

II +

197

Me2N Fe(CO)3

O O

Fe(CO)3

+

III

IV

Me2N (OC)3Fe

Ph Fe(CO)3 Atmosphere

Solvent

I

II + III

III

CO (55 psi)

CH2Cl2

(47)

(13)

(0)

(20)

(47)

(0)

CO (650 psi) (CH2)2Cl2 Ar (40 psi)

CH2Cl2

(73)

(0)

(21)

Ar (15 psi)

THF

(62)

(0)

(4)

CO2Et N

EtO2C

Ph

2 eq

Ph

N

Photolysis, Et2O, 20°

(79)

454

Ph

Ph

(CO)3Fe

(CO)3Fe

0.01 M

TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne C4

Carbene Complex Ph3Sn

Conditions

Product(s) and Yield(s) (%)

Co(CO)3 Benzene, 50°, 6 h

Ph 2.5 eq

Refs.

Ph

OMe 0.007 M

(75)

200

(33)

198

OMe

O O

Fe(CO)4 Et

Ph

O CO (55 psi),

EtO

Ph

CH2Cl2, 70°, 1 h

10 eq

EtO Et Fe(CO)3 MeO2C

Fe(CO)4 MeO2C

CO2Me

THF EtO

Ar

I EtO

4.9 eq

O

+

Ar

518

Ar

I

II

Ph

(15)

(4)

2-MeOC6H4

(78)

(0)

3-MeOC6H4

(22)

(1)

4-MeOC6H4

(42)

(11)

CO2Et N

2 eq (CO)3Fe

CO2Et

Ph Photolysis, Et2O, 20° Ph

N Fe(CO)3

Ph

Ar

O

Ph

CO2Et

Ph

N

(38) MeO2C

+

Ph MeO2C

CO2Et Ph N+

0.01 M +

455

II EtO

Ph

O (CO)3Fe CO2Me

(11)

(44)

454

C5 n-Pr Ph

ClCH2CH2Cl, 60°, 1 h

NMe2

4.9 eq

n-Pr

n-Pr

Fe(CO)4

Ph

0.2 M

+

(64) NMe2

O

(4) Ph

197

Pr-n

O Fe(CO)4 MeO2C

EtO

Ph

O CO (55 psi), CH2Cl2,

Ph

(15) Fe(CO)3

MeO2C

Ar

THF

OEt

519

Ar

I

II

Ph

(25)

(42)

2-MeOC6H4

(0)

(79)

3-MeOC6H4

(30)

(19)

4-MeOC6H4

(0)

(80)

455

OEt

O

CO2Me (73)

ClCH2CH2Cl, 60°, 1 h

NMe2 0.2 M

Ph

Et

197

NMe2

O Et

Fe(CO)4 Et

II Ar

OEt

O

Fe(CO)4

C6

+

I Ar

4.9 eq Ph

MeO2C

CO2Me

Fe(CO)4 4.9 eq

198

EtO

70°, 1 h

10 eq

Et

Solvent, 60°, 1 h Ph

4.9 eq

NMe2

Ph3Sn

NMe2

O

Solvent

0.2 M

2.5 eq

197 Ph

THF

(45)

ClCH2CH2Cl

(74) Et

Co(CO)3

Et (93)

Benzene, 50°, 6 h Ph

Ph OMe 0.007 M

200

OMe

O

TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

R2

C6

1. Photolysis, pyrex filter, n-Bu

R2

+

520

Et Et

181

I

2. CAN O

II

O

R2

R 1O R1

R2

I

II

Me

H

(0)

(5-10)

TiCp2Cl

H

(30)

(5-10)

TiCp2Cl

Me

(28)

(5-10)

OC

R2

O

Bu-n

THF, 20°, 5 h MnCp'(CO)2

5 eq

Refs.

O

Ph

OC

Ru OMe H B B Cl B H Co

O Bu-n (18)

1. Toluene, reflux, 3 h

199

2. CAN O

0.04 M

MeO2C 4.9 eq

OEt

CO2Me

CO2Me

MeO2C

CO2Me

MeO2C

CO2Me

+

THF CO2Me

R

R

CO2Me

OH

Fe(CO)4

OEt

455 CO2Me

I

R

R in I

H 2-OMe

I

II

H

(21)

(9)

5-OMe

(5)

(5)

3-OMe

6-OMe

(33)

(2)

4-OMe

7-OMe

(93)

(<1)

II

CO2Me

C6

MeO2C

Fe(CO)4 MeO2C

CO2Me NMe2

Ph Solvent

CO2Me CO2Me

II

CH2Cl2

(50)

(0)

ClCH2CH2Cl

(35)

(24)

THF

(16)

(13)

Ph Ph Photolysis, Et2O, 20°

N

E*

Ph

Ph (62)

(11)

+

E*

Ph

E

E

E

II

Ph

E*

N

Ph

(CO)3Fe

MeO2C I

CO2Et N

CO2Me 197

NMe2

O I

0.2 M

2 eq

MeO2C +

Solvent, 60°, 1 h Ph

4.9 eq

CO2Me

0.01 M

454

E

N

521

+

Ph

O (CO)3Fe NEt2

Ph Et2N

Cp'(CO)2Mn 1 eq

Hexane, 70°, 22 h

Cp'(CO)2Mn

Ph

OMe

0.4 M

Benzene, 80°, 2 h NH2

430

Et

Cp'(CO)2Mn

NEt2

NH2 Benzene, 20°, 2 h Ph

0.3 M

(66)

N Ph

(CO)5Mn(CO)4Mn

1 eq

456

NEt2

Ph 0.3 M

(76) E:Z = 10:1

OMe

Cp'(CO)2Mn

1 eq

E* = CO2Et

E

E

C7

E = CO2Me

(7)

N

(83)

Et

(CO)5Mn(CO)4Mn

430

Ph

TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

O

C8 Fe(CO)4 Ph

Ph

O CO (55 psi), CH2Cl2,

EtO

10 eq

Ph

70°, 1 h

(74) EtO Ph

Fe(CO)3 Ph

Ph

Fe(CO)4 4.9 eq

+

Solvent, 60°, 1 h Ph

198

NMe2

Ph

197

NMe2

O

Ph

I

II

O Ph

Ph

522 N

2 eq (CO)3Fe

III

Solvent

I

II

III

IV

CH2Cl2

(18)

(0)

(0)

(0)

ClCH2CH2Cl

(16)

(15)

(0)

(30)

THF

(12)

(13)

(18)

(0)

EtO2C

Ph

N

Ph

IV

Ph

Photolysis, Et2O, 20°

(74) Ph

Ph

Ph

+ Ph

CO2Et

Ph

Me2N

+

Ph OH

454

Ph Fe(CO)3

0.01 M C10

OBu-t t-BuO

Fe(CO)4 t-BuO 4.9 eq

OBu-t Ph

NMe2 0.2 M

OH OBu-t

CH2Cl2, 60°, 1 h

(6) t-BuO

OBu-t OBu-t

t-BuO

Ph

t-BuO

(5) 197 OBu-t

+

OBu-t

C13 OMe MeO2C

OMe Cp'(CO)2Mn

MeO2C

CH2Cl2, 60°, 1 h Ph

MeO2C

Ph (68)

457

(93)

198

MeO2C

C14

O Fe(CO)4 Ph

Ph 10 eq

EtO

70°, 1 h

Ph

Ph3Sn 1.2 eq Ph

Ph

O

CO (55 psi), CH2Cl2, EtO

Ph Ph Fe(CO)3

Ph Co(CO)3 OMe

0.007 M

Ph

Heptane, 50°, 6 h

(58) Ph

O

OMe

200

523

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C13

R

OH

R1

1. RC CH (3 eq),

(CO)5Cr

MeO

R

R

benzene, 70°, 12-24 h

+

78

+

2. Silica gel

0.005 M

Refs.

OH I

O III

II O

R1

R

OMe OMe

I

II

III

IV

H

(9) (10) (8)

(34)

Me

(6)

(54)

(2)

(3)

R

OMe

+ O

IV

OH

C13-16

Pr-n

1. n-PrC CH (x eq),

524

solvent, 60-85°, 4-24 h

+

I + II + IV R = n-Pr +

2. Workup

VI

V 1

CC (M)

x

Solvent

Workup

I

II

IV

V

VI

OMe

0.005

3

benzene

silica gel

(3)

(15)

(55)

(—)

(—)

OMe

0.005

3

benzene

Zn/HOAc

(2)

(12)

(—)

(—)

(—)

OMe

0.005

3

benzene

silica gel

(—)

(—)

(54)

(—)

(—)

OMe

0.5

3

benzene

TiCl3/LAH

(7)

(5)

(—)

OMe

0.5

3

benzene

silica gel

(—)

(—)

(14)

(—)

(—)

OMe

0.05

3

benzene

TiCl3/LAH

(5)

(11)

(—)

(<0.1)

(0.6)

OMe

0.05

3

benzene

silica gel

(—)

(—)

(38)

(—)

(—)

OMe

0.005

3

benzene

TiCl3/LAH

(2)

(13)

(—)

OMe

0.005

3

benzene

silica gel

(—)

(—)

(53)

OMe

0.05

10

benzene

TiCl3/LAH

(8)

(2)

(—)

OMe

0.05

10

benzene

Silica gel

(—)

(—)

(41)

(—)

(—)

OMe

0.05

10

THF

TiCl3/LAH

(7)

(<0.3)

(—)

(<0.1)

(<1)

OMe

0.05

10

THF

silica gel

(—)

(—)

(23)

(—)

(—)

OMe

0.05

10

MeCN

TiCl3/LAH

(15)

(<0.5)

(—)

OMe

0.05

10

MeCN

silica gel

(—)

(—)

(<1)

(—)

(—)

OMe

0.08

3

MeCN

silica gel

(41)

(—)

(—)

(—)

(—)

OMe

0.005

2.5

MeCN

silica gel

(17)

(—)

(—)

(—)

(—)

OMe

0.08

2

hexane

silica gel

(4)

(—)

(43)

(—)

(—)

OMe

0.01

2

hexane

silica gel

(10)

(9)

(56)

(—)

(—)

OMe

0.005

2

hexane

silica gel

(10)

(10)

(57)

(—)

(—)

OMe

0.004

1.2

hexane

silica gel

(2)

(2)

(24)

(—)

(—)

N-pyrrolidinyl

0.05

10

THF

TiCl3/LAH

(2)

(16)

(—)

(<1.0)

(7)

N-pyrrolidinyl

0.05

10

THF

silica gel

(—)

(—)

(16)

(—)

(—)

N-pyrrolidinyl

0.05

10

benzene

TiCl3/LAH

(2.4)

(14)

(—)

(<0.2)

(3)

N-pyrrolidinyl

0.05

10

benzene

silica gel

(—)

(—)

(17)

(—)

(—)

N-pyrrolidinyl

0.5

10

benzene

TiCl3/LAH

(3)

(11)

(—)

(<1.0)

(5)

N-pyrrolidinyl

0.5

10

benzene

silica gel

(—)

(—)

(11)

(—)

(—)

N-pyrrolidinyl

0.05

10

MeCN

TiCl3/LAH

(<0.3)

(<0.2)

(—)

N-pyrrolidinyl

0.05

10

MeCN

silica gel

(—)

(—)

(<1)

R

58, 246 OH

Pr-n

(<0.8) (<1.2)

(<0.3) (<1.0) (—)

(—)

(<0.2) (<0.6)

(<0.5) (<0.5)

525

(<0.2) (<0.3) (—)

(—)

C13 OMe (CO)5Mo

1. n-PrC CH (3 eq), benzene, 60-85°, 4-24 h

I + II + IV + V + VI R = n-Pr

58, 246

2. Workup CC (M)

Workup

I

II

IV

0.5

TiCl3/LAH

(36)

(<0.4)

(—)

0.5

silica gel

(—)

(—)

(1)

0.05

TiCl3/LAH

(43)

(<0.5)

(—)

0.05

silica gel

(—)

(—)

(5)

0.005

TiCl3/LAH

(48)

(<0.5)

(—)

0.005

silica gel

(—)

(—)

(20)

V

VI

(<0.4) (<0.4) (—)

(—)

(<0.5) (<0.4) (—)

(—)

(<0.5) (<1.0) (—)

(—)

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C13 OMe (CO)5W

1. n-PrC CH (3 eq), benzene, 60-85°, 4-24 h

I + II + IV + V + VI R = n-Pr

58, 246

2. Workup Workup

I

II

0.5

TiCl3/LAH

(17)

(<0.5)

CC (M) 0.5

silica gel

(—)

(—)

0.05

TiCl3/LAH

(27)

(<3.0)

526

0.05

silica gel

(—)

(—)

0.005

TiCl3/LAH

(29)

(<1.0)

0.005

silica gel

(—)

(—)

OMe

1. n-PrC CH (3 eq), MeOH (x eq), benzene,

(CO)5Cr

60-85°, 12-24 h 0.005 M

IV

V

(<0.5) (—) (<0.5) (—)

(—)

(—) (<1.0) (<2.0) (0.2)

(—)

(—)

OMe O I + II + IV R = n-Pr +

246

VII OMe

2. Silica gel x

I

II

IV

VII

0

(2)

(12)

(54)

(—)

5

(—)

(—)

(41)

(1)

10

(—)

(—)

(42)

(4)

20

(4)

(9)

(35)

(8)

50

(2)

(4)

(34)

(9)

100

(1)

(3)

(11)

(49)

200

(3)

(3)

(12)

(49)

500

(3)

(1)

(4)

(74)

OMe

1. RC CH (3 eq),

O

R +

MeOH, 45°, 36-42 h I CC (M)

R

246

OMe

2. Silica gel II

I

II

III

0.21

n-Pr

(18)

(18)

(11)

0.07

n-Bu

(21)

(27)

(13)

0.005

n-Pr

(9)

(12)

(45)

R OMe O

+ OMe III

OH

O

1. TMSC CH (3 eq), 0.005 M

(—)

(—) (<0.5) (<0.5)

OH OMe (CO)5Cr

VI

(—) (<0.5) (<0.5)

TMS

TMS

OMe

(8) +

benzene, 70°, 12-24 h

(46)

78

(27)

78

2. Silica gel O

527

MeO

1. EtC CEt (3 eq), 0.005 M

Et

O Et

Et

benzene, 70°, 12-24 h 2. Silica gel

OMe

+

(11)

Et

O

O O 1. RC 0.005 M

3

CH (3 eq),

benzene, 70°, 12-24 h 2. Silica gel

O OH

1. PhC CH (3 eq),

MeO

Ph

solvent, 15-36 h

H

(36)

TMS

(39)

Ph

OMe

+

458, 78, 246

O I

II

Temp

I

THF

45°

(7)

benzene

70°

(16) (20) (54)

MeCN

45°

(43) (—) (—)

II

III

(—) (—)

78

CO2Bu-t (41) O

Ph

+

2. Silica gel Solvent

R

OMe R

O

III

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C13

OH OMe

1. n-BuC CH (3 eq),

(CO)5W

Refs.

Bu-n Bu-n

THF, 85°, 48 h

+

(26)

(42)

458

+

246

Bu-n

2. Silica gel n-Bu OH OMe

1. R1C CPh (2-3 eq),

(CO)5Cr

OMe R1

Ph

R2OH, 45°, 48 h

OR2

R1

2. Silica gel I

0.07 M

II

2

I

II

III

H

Me

(36)

(40)

(12)

H

i-Pr

(37)

(14)

(<1)

Ph

Me

(5)

(<1)

(41)

R

1

R

528

1. RC CPh (3 eq),

(CO)5W

Ph

OMe O OR2 III

OH OMe

O

+

Ph

O

Ph +

solvent, 85°, 48 h 2. Silica gel

Ph

+

O

458

R I

0.07 M

II

Ph

Solvent

R

I

II

III

THF

H

(50)

(24)

(—)

MeCN

H

(8)

(—)

(40)

THF

Ph

(7)

(—)

(—)

C14

Ph

R

III

O OMe

1. n-PrC CH (3 eq),

(CO)5Cr

n-Pr

OMe

benzene, 70°, 12-24 h

+

(37)

(30) O

2. Silica gel

78

OMe

O

0.005 M

C15 O

1. THF, 75°, 14 h

O

2. (n-Bu)3P, acetone, 50°, 5 h

(CO)5Cr

(12-14)

3. MeOH, CCl4

114

O

O 0.5-0.005 M

OH

O (CO)5Cr

1. CH2Cl2, –20°

O

2. –20° to 25°

(tr) O

114

O

O C16-17

O

O O SiMe2

1. PhC CPh (10 eq),

R1

2. CAN

R3

hexane, reflux, 1 h

(CO)5Cr

86

529

R2

OH O

R1 2-propenyl 2-furyl

CC (M)

R2

R3

—

Me

H

0.01l

—OCH=CH—

C16-19

OAc R O

(CO)5Cr

1. Et2O, 25-35°, 20-44 h 2. PPh3, Ac2O, Et3N

Ph 0.04 M

n

R

O

n

(62) (75) R

n

H

1

(16)

H

2

(18)

H

3

(38)

Me

1

(81)

Me

2

(62)

Me

3

(62)

214, 90

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C16-18

3 R1 R

R1

H N (CO)5Cr

R2 R3

H

Toluene, 110°, 2-2.5 h

C17

222, 221 N

R2

MeO 0.03 M

Refs.

OMe

R1

R2

R3

H

H

H

H

Me

H

(0)

Me

H

H

(50)

Et

H

H

(50)

Me

H

D

(—)a

Cr(CO)3

(0)

530

OMe

OMe

O

O

(CO)5Cr

Benzene, 70°, 16-24 h

245, 247

(41)

0.005 M C17-20

OH

OMe

245, 247

Solvent, 110°, 16-24 h

(CO)5W m

0.005 M

m

n

n

m

n

Solvent

1

1

benzene

(30)

1

1

MeCN

(48)

1

2

MeCN

(61)

1

3

MeCN

(38)

2

2

MeCN

(36)

2

3

MeCN

(—)

OMe

C17-28 (CH2)n

MeO

OMe

OMe (CO)5Cr Solvent, 16-24 h

(CH2)n

OH HO OH

(CH2) n OH OH

+

(CH2)n

(CH2) n +

n

0.005 M

I

OMe

II (CH2) n

OMe

OH +

III

OMe

531

n

Solvent

Temp

I

II

III

6

hexane

60°

(4)

(10)

(—)

6

benzene

60°

(4)

(14)

(—)

6

CH2Cl2

60°

(14)

(26)

(—)

6

MeCN

60°

(19)

(27)

(—)

6

THF

60°

(9)

(36)

(—)

6b

THF

60°

(9)

(19)

(—)

6

THF

100°

(18)

(39)

(—)

8

THF

100°

(2)

(15)

(43)

10

THF

100°

(—)

(5)

(58)

13

THF

100°

(—)

(—)

(65)

17

THF

100°

(—)

(—)

(60)

215, 459

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C17-27 (CH2)n

OMe (CO)5Cr

OH

O

Solvent, 12-22 h

+

n

+

I

0.002 M

(CH2)n

(CH2)n

OH

+

II

OMe

176, 217

III

OMe

OMe (CH2)n

(CH2)n

OH MeO

HO

IV

(CH2)n

532

OMe

C17-18

OMe

+

HO

V

n

Solvent

Temp

I

II

III

IV

V

6

THF

100°

(—)

(—)

(—)

(—)

(36)c

6

benzene

100°

(—)

(—)

(—)

(—)

(28)c

10

THF

70°

(8)

(31)

(30)

(—)

(10)

10

THF

100°

(4)

(42)

(15)

(tr)

(8)

10

MeCN

100°

(17)

(11)

(24)

(—)

(5)

10

CH2Cl2

100°

(22)

(—)

(<2)

(17)

(12)

10

hexane

100°

(22)

(—)

(—)

(29)

(8)

10

benzene

100°

(40)

(—)

(tr)

(21)

(12)

13

THF

65°

(1)

(40)

(20)

(—)

(6)

13

THF

100°

(5)

(38)

(16)

(2)

(10)

13

benzene

100°

(14)

(—)

(—)

(18)

(26)

16

THF

100°

(56)

(2)

(1)

(—)

(10)

16

benzene

100°

(48)

(—)

(—)

(2)

(9)

OAc

Me N

γ-Terpinene (100 eq),

(CO)5Cr

0.02 M

R

TMS

(—)

THF, 85°

t-Bu

(31)

N

R

C18

R

Ac2O (3 eq), Et3N (4 eq),

127

Me OH

O

1. THF, 75°, 14 h

(CO)5Cr TMS

O (76)

2. (n-Bu)3P, acetone, 50°, 5 h

114

3. CCl4, MeOH, rt, 16 h 0.2 M

O

O

O O O SiMe2

R2

533

(CO)5Cr R1

Ar 0.01 M

R1

1. Solvent, reflux, 1 h

86

OH

2. CAN O

R1

Ar

Solvent

Additive

R2

Me

Ph

THF

none

H

(24)

Me

Ph

hexane

none

H

(34)

H

4-MeC6H4

THF

none

Me

(14)

H

4-MeC6H4

hexane

PhC CPh (10 eq)

Me

(40) OMe

OMe

R

OMe

R

(CO)5Cr +

t-BuOMe, 55°, 2 h

460

R R

R

(CO)3C r

OMe

OMe

R n-Pr

(30)

(30)

TMS

(—)

(—)

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C19 Bu-t

OMe OMe

(CO)5Cr t-BuOMe, 55°, 2 h

(38)

461

MeO

t-Bu t-Bu

O

O O

(CO)5Cr

O +

(20)

Benzene, 60°, 1.5 h

(51)

O

243

O

OH

534

OAc

O

1. Additive (10 eq),

(CO)5Cr

solvent, reflux, 1 h 2. PPh3 0.01 M

3. Ac2O, pyridine

O

TBSO

OMe (CO)5Cr

1.

Solvent

Additive

THF

none

(38)

hexane

none

(40)

hexane

PhC CPh

(39)

HO

HO

, OMe MeCN, rt, 16 h, CO (1 atm)

245, 247

+ (10)

(52)

2. 110°, 23 h HO H

86

TBSO TMS

TMS N

(CO)5Cr

Benzene, 87°, 12 h

(40)

128

(22)

128

N

0.25 M (E:Z = 1:1)

(CO)5Cr

OH

H

Ph

N (CO)5Cr

Benzene, 85°, 12 h 0.25 M Ph

(E:Z = 3.5:1)

H

O O SiMe2

N O OH

1. Additive (x eq), solvent,

(CO)5Cr

reflux, 1 h

OH

2. CAN

+

+

I

O

86

II

O

O

0.01-0.3 M

R1 + O

III

R2 IV

535

Additive

x

Solvent

I

II

III

IV

O R1

none

—

THF

(17)

(8)

(10)

(0)

—

—

none

—

benzene

(19)

(2)

(16)

(0)

—

—

none

—

hexane

(33)

(0)

(0)

(0)

—

—

2,6-di-tert-butylpyridine

—

hexane

(28)

(0)

(0)

(0)

—

—

Ac2O

1.5

hexane

(26)

(2)

(0)

(0)

—

—

diphenylacetylene

10

THF

(26)

(—)

(—)

(—)

—

—

diphenylacetylene

2

hexane

(50)

(6)

(—)

(—)

—

—

diphenylacetylene

5

hexane

(70)

(8)

(—)

(—)

—

—

diphenylacetylened

5

hexane

(61)

(4)

(—)

(—)

—

—

diphenylacetylene

10

hexane

(83)

(3)

(—)

(—)

—

—

diphenylacetylened

10

hexane

(85)

(3)

(—)

(—)

—

—

diphenylacetylene, CO (1 atm) 10

hexane

(45)

(6)

(—)

(—)

—

—

1-hexyne

10

hexane

(31)

(4)

(—)

(24)

n-Bu H

3-hexyne

2

hexane

(39)

(6)

(—)

(22)

Et

Et

3-hexyne

5

hexane

(48)

(4)

(2)

(21)

Et

Et

3-hexyne

10

hexane

(51)

(11)

(4)

(19)

Et

Et

R2

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C19

O O SiMe2

Conditions

Product(s) and Yield(s) (%) O

Refs.

O

1. Additive, solvent,

(CO)5Cr

Et +

reflux, 1 h 2. CAN

0.01-0.3 M

I

Additive

Solvent

none none

86

OH

Et

II

O

O

536

I

II

THF

(23)

(0)

benzene

(24)

(0)

none

hexane

(26)

(0)

2,6-di-tert-butylpyridine

hexane

(22)

(0)

diphenylacetylene (2 eq)

benzene

(22)

(0)

diphenylacetylene (10 eq)

hexane

(60)

(0)

3-hexyne (10 eq)

hexane

(41)

(14)

OAc 1. THF, reflux, 1 h 2. TBAF, Et2O

0.01-0.3 M

(33) OAc

3. TMSCl, MeOH 4. Ac2O, pyridine

O O SiMe2

+

OAc (6)

86

O

OAc O MeO

(CO)5Cr 1. CH2Cl2, reflux

Ar Ar = 4-MeOC6H4

86

(26) OH

2. CAN O O 1. PhC CPh (10 eq), hexane, reflux, 1 h

Ar = 2-MeOC6H4

(41)

86

OH

2. CAN MeO

O

O O SiMe2

O 1. Additive (10 eq), hexane,

(CO)5Cr

MeO

MeO +

reflux, 1 h 0.01-0.03 M

+

I O

II

OH

O

OMe

O Additive

O O SiMe2

Et

MeO

I

II

III

none

(21)

(tr)

(0)

PhC CPh

(39)

(tr)

(0)

EtC CEt

(29)

(tr)

(14)

Et III O

O Additive

1. Additive (10 eq), hexane,

(CO)5Cr

none

reflux, 1 h

(38)

86

PhC CPh (62)

2. CAN

MeO

86

OH

2. CAN

537

0.01 M

MeO

O

OH

O O O SiMe2

OH 1. Solvent, reflux, 1 h

(CO)5Cr

+

2. Workup Ph

0.01 M

I

O

86 II

OH

Solvent

Workup

I

II

THF

CAN

(27)

(6)

benzene

TBAF, HCl, CAN

(25)

(3)

OH

O

OMe (CO)5Cr

Benzene, 70°, 16-24 h 0.005 M

O

(24) +

O O (19)

245, 247

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%) OH

C19-20

MeO

OMe (CO)5Cr

+

Solvent, 70°, 16-24 h

Refs.

O

245, 247

n

0.005 M

n

n

n

Solvent

I

II

1

benzene

(57)

(—)

1

(n-Bu)2O

(50)

(5)

1

THF

(61)

(7)

1

MeCN

(31)

(41)

1

DMF

(10)

(16)

2

benzene

(33)

(0)

538

C20-23 O

1. PhC CPh (5 eq),

O n O SiMe2

R

150 W Xe Arc

Cp'(CO)2Mn

(345 nm filter),

n

O

2. CAN R

182

OH

CH2Cl2, 20°

R

n

H

1

(30)

Me

1

(20)

Me

2

(22)

Me

3

(23)

C20 O O

OMe

(39)

Benzene, 70°, 16-24 h

(CO)5Cr

245, 247

0.005 M O O SiMe2 (CO)5Cr

O 1. Additive (10 eq), solvent, reflux

86 OH

2. CAN O 0.01-0.3 M

539

Additive

Solvent

none

THF

(15)

PhC CPh

hexane

(48) OAc

O O (CO)5Cr Ph

1. Et2O, 35°, 20 h

(65)

2. PPh3, Ac2O, Et3N, 17.5 h O

O

214

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C20

O O SiMe2

Conditions

Product(s) and Yield(s) (%)

Refs.

O OH

1. Additive (x eq),

(CO)5Cr 0.01-0.03 M

+

+

solvent, reflux

86

OH

2. CAN I

O

II

O

O

R1 R2 III O

540

Additive none none nonee none none diphenylacetylene diphenylacetylene diphenylacetylene 1-hexyne 3-hexyne 3-hexyne

x — — — — — 5 10 10 10 5 10

Solvent THF benzene benzene toluene hexane THF benzene hexane hexane hexane hexane

II (4) (5) (5) (—) (0) (6) (—) (5) (0) (10) (0)

I (30) (27) (25) (25) (27) (29) (55) (65) (54) (61) (75)

III (0) (0) (0) (0) (0) (0) (0) (0) (15) (6) (9)

R1

R2 — — — — — — — — H Et Et

— — — — — — — — n-Bu Et Et

OAc OAc

1. Solvent, reflux +

2. TBAF, Et2O

86

OAc

3. TMSCl, MeOH I

4. Ac2O, pyridine Solvent

II

OAc I

II

THF

(38)

(7)

hexane

(40)

(4)

O O SiMe2

O

O

HO

MeO

1. Additive (10 eq),

(CO)5Cr

MeO

OH

+

+

solvent, reflux

86

2. CAN I OMe

Additive

O O SiMe2

Solvent

II

O I

II

O O

III

none

THF

(20)

(6)

(0)

none

hexane

(31)

(0)

(0)

PhC CPh

hexane

(55)

(0)

(0)

EtC CEt

hexane

(40)

(4)

(7)

MeO

Et Et III O

O 1. PhC CPh (10 eq),

(CO)5Cr

hexane, reflux

541

MeO

86

(59) OH

2. CAN OMe O O O SiMe2

O MeO

(CO)5Cr 1. THF, reflux

OH

(30)

86

2. CAN O OMe OMe

OH

N (CO)5Cr

Ph

Hexane, 70°

(53) N

462

Ph

Ph 1. PhC CPh (10 eq),

N (CO)5Cr

Ph

benzene, reflux 2. Air, silica gel Ph

N

Ph

(31) +

Ph

CN

(48)

219

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

Me

C20

N

OH

(CO)5Cr

Solvent

1,4-Cyclohexadiene (100 eq), N

solvent, 80°

0.01 M

Ph

Me

Ph

THF

(25)

toluene

(15)

MeCN

(6)

127

OAc

Hydrogen source, Ac2O (3 eq), Et3N (4 eq),

127 N

THF, 85° Hydrogen Source

CC (M)

Ph

Me

1,4-cyclohexadiene (100 eq)

(43)

0.01

1,4-cyclohexadiene (10 eq)

(34)

0.01

1,4-cyclohexadiene (100 eq)

(63)

0.02

1,4-cyclohexadiene (100 eq)

(49)

0.02

γ-terpinene (100 eq)

(53)

542

0.005

(CO)3Cr 0.02 M

OSiEt3

HSiEt3 (100 eq),

(41) N

THF, 85°, 13 h

127

Ph

Me (CO)3Cr 0.02 M

(CO)3Cr

OSiEt3 (7)

DSiEt3 (100 eq), N

THF, 85°, 13 h

OSiEt3

+

(2.2) N

Ph

Me

Me

127

Ph D

Me N

γ-Terpinene (100 eq),

(CO)5Cr

R = 1-cyclohexenyl

OAc

Ac2O (3 eq), Et3N (4 eq),

(41) N

THF, 85° 0.02 M

C21

Me

R

O O SiMe2 Cp'(CO)2Mn

127

R

1. PhC CPh (5 eq),

O

150 W Xe Arc (345 nm filter),

(45)

OAc

CH2Cl2, 20° 2. CAN

182

O

3. Acetylation OMe

OMe

(CO)5M

M

(CO)4M Photolysis, Et2O, –44°

Ph

Ph

OMe

Cr

(—)

W

(51)

463

OMe

(CO)5Mo

(CO)4Mo 10–3

mbar, 45°

543

Ph

463

(—) Ph OMe Ph

OMe (CO)5Cr 1. t-BuOMe, 55°, 2 h Ph

463

(55)

2. Air Ph OMe O O SiMe2

(CO)5Cr MeO

O 1. PhC CPh (10 eq), hexane, reflux

OH

2. CAN OMe O

(65)

86

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C21 O O SiMe2

O 1. Additive (10 eq),

(CO)5Cr

O

R

R

Et

86

OH

2. CAN

R

I

O

Et

Additive

Me

PhC CPh

(50)

(0)

Me

EtC CEt

(25)

(14)

OMe

PhC CPh

(37)

(0)

I

O

II

R

O O SiMe2

Et

+

hexane, reflux

II

O 1. EtC CEt (10 eq),

(CO)5Cr

hexane, reflux

+

Et

+ Et

544

2. CAN OH

O

(53)

(17)

86

O

O Et Et (9)

Et

O

O O SiMe2

1. PhC CPh (10 eq), hexane, reflux

(CO)5Cr

+

(73)

Et

Et

2. CAN MeO

MeO H

O

O

MeO

OH

(4)

86

O

TMS

TMS N

(CO)5Cr

Benzene, 88°, 12 h

Ph

(57)

128

N Ph

0.25 M

Cr(CO)5

TMS TMS Benzene, 80°, 12 h

N H

Ph

(60)

128

N

(CO)5Cr

Cr(CO)5 Ph

0.25 M C21-22 OMe (CO)5Cr

Y

Y

OH THF, 65°, 3 h Y 0.02 M

O

(25)

NMe

(20)

CH2

(38)

464, 216

(CO)3Cr OMe

545

C21-26 O O SiMe2

O

1. PhC CPh (5 eq), 150 W Xe Arc

Cp'(CO)2Mn R2

R1

R2

(345 nm filter),

OH

CH2Cl2, 20° R1

O

2. CAN

C22

R1

R2

H

Me

(75)

H

Et

(51)

H

Ph

(60)

Me

Me

(75)

Me

Et

(79)

Me

TMS

(32)

OMe

Me

(48)

182

OMe (CO)5Cr 1. (n-Bu)2O, 90°, 2 h

O (40)

2. CAN 0.04 M O

216

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C22

Refs.

OH

H

Ph

N (CO)5Cr

TMS (29)

Benzene, 85°, 12-17 h

128

TMS Ph 0.25 M E:Z = 1:15.5

H

N

C23

O

OH

H

Ph N

Ph

Benzene, reflux, 12 h

(CO)5Cr

+

(54)

(23)

219

Ph

Ph

N

546

O O SiMe2

N O

1. PhC CPh (5 eq), 150 W Xe Arc

Cp'(CO)2Mn

(345 nm filter), O

2. CAN

C23-24

182

(56) OH

CH2Cl2, 20° n-Pr OH N

R

Pr-n +

Solvent, 105°, 1 h

(CO)5Cr

I

R

C23-26

Pr-n

R

H

R

Solvent

H Me

465 II

N

H

H

I

II

(n-Bu)2O

(34)

(14)

(n-Bu)2O

(39)

(10)

H

toluene

(21)

(18)

Me

toluene

(23)

(16)

Ar

N

OH Ar

H

Ar

Toluene, 110°, 2 h

N (CO)5Cr

N H

Ph

(19)

4-MeC6H4

(18)

2,4,6-Me3C6H2

(17)

220

C24 5

(CO)5Cr

Cr(CO)5

OMe 0.005 M

MeO

HC C(CH2)6C CH,

MeO

OH

HO

OMe

(31)

215

THF, 100°, 0.2-4 h

PhS O

SPh

1. THF, 80°, 8 h

547

O

2. FeCl3-DMF

(CO)5Cr TMS

3. TFA/AcOH (1.5:1) CCl4, rt, 15 min

O

(51)

114, 265

(56-94)

114

O OH

0.13 M 1. THF, 80°, 8 h

O

SPh

2. MeI, K2CO3, Me2CO 0.13 M

3. TFA/AcOH (1.5:1), CCl4, rt, 15 min

O

4. Air or FeCl3-DMF

OMe OH

O O (CO)5Cr MeO 0.05 M

n-Pr

1. Et2O, 35-37°, 64 h

Pr-n

2. PPh3, acetone MeO

O

O

(48)

218, 90

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C24

Conditions

Product(s) and Yield(s) (%) O

O O

1. Et2O, 35-37°, 64 h

n-Pr

(CO)5Cr

(51)

O

2. DDQ, MeCN/H2O

MeO

Refs.

0.05 M

MeO

Pr-n

O

Pr-n

218, 90

OH

HO

O

O O SiMe2

1. Additive (10 eq), hexane, reflux

(CO)5Cr

Pr-n

+

OH

Pr-n

+

86

2. CAN MeO

MeO

O

Pr-n

O

MeO

I

II I

II

III

none

(40)

(9)

(40)

PhC CPh

(53)

(3)

(—)

EtC CEt

(51)

(4)

(40)

Additive

548 C24-25

O O SiMe2

O R

1. Additive (10 eq),

(CO)5Cr

solvent, reflux, 1 h

R

OH

2. CAN O

III

R

Additive

Solvent

Ph

none

THF

(25)

Ph

none

hexane

(19)

Ph

PhC CPh

hexane

(43)

n-C7H15 none

hexane

(48)

n-C7H15 PhC CPh n-C7H15 EtC CEt

hexane

(51)

hexane

(56)

86

C24-30 OMe

OH

OH

(CO)5Cr

R

THF, 100°, 0.2-4 h 13

0.005 M

+

R R I

OMe

R

I + II

I:II

H

(>65)

(<1:30)

TMS

(31)

(39:61)

Ph

(66)

(80:20)

215

II

OMe

OH

Ph

Me

Ph N

Ph TMS

+

(30)

Benzene, reflux, 12 h

(CO)5Cr Ph

Me

(17)

(CO)3Cr

N

Me OH

OH TMS

H N (CO)5Cr

219

N

TMS

Cr(CO)3

See table N

(CO)3Cr

I

H TMS

+

+ N

II

H •

23

O TMS

•

O

+

549

N

N

H (CO)3Cr

H

III

Solvent

Temp

Time

I

II

III

IV

hexane

reflux

3h

(13)

(10)

(43)

(0)

MeCN

reflux

0.5 h

(0)

(0)

(0)

(71)

toluene

70°

2h

(0)

(0)

(80)

(10)

t-Bu •

t-Bu

IV

O

Ar

H

Solvent, 85°, 1 h

465

N

N

(CO)5Cr

H Ar

Ar

Solvent

Cr(CO)3

Ph

(n-Bu)2O

(70)

4-MeC6H4

(n-Bu)2O

(82)

Ph

toluene

(20)

4-MeC6H4

toluene

(57)

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

Et

C25 O O

O

1. PhC CPh (5 eq),

SiMe2

150 W Xe Arc

Cp'(CO)2Mn

(345 nm filter),

182

(51)

Et

CH2Cl2, 20° OH

O

2. CAN O O SiMe2

O MeO

(CO)5Cr C7H15-n

C7H15-n

1. Hexane, reflux

86

(36)

OH

2. CAN O

550

OMe O O SiMe2

O C7H15-n

1. Additive (10 eq),

(CO)5Cr

hexane, reflux

C7H15-n

OH

2. CAN

MeO

Additive none

(55)

PhC CPh

(49)

86

O

MeO

OH

H

Ph

N (CO)5Cr

Ph

Benzene, 85°, 12-17 h

(59)

128

Ph Ph

H

0.25 M E:Z = 11:1

N Ph O

Ph N

f

(CO)5Cr

1. Benzene, reflux

NC

2. Air, silica gel

+

(16)

N

(7)

Cr(CO)3

C26

TMS

OMe

TMS

O

(CO)5W

H

+

(43)

THF, 110°, 20 h

(17)

MeO MeO

OMe

O

H

CO (1 atm), TMS

219

Ph

245

MeO MeO

H

H

O H

CO (1 atm),

O (19)

MeCN, 110°, 20 h MeO TMS H N

Toluene, 110°, 2 h

•

O

Ph

(29)

551

H (CO)3Cr

Ph Ar

OH Ar

H

Toluene, 90°, 2 h N N

(CO)5Cr

H

Ph C26-33

220

N

(CO)5Cr

C26-29

TMS

H

TMS

245

t-Bu

R

t-Bu

n-(Bu)2O, 85° N

(CO)5Cr Tol-p

•

Ar Ph

(28)

4-MeC6H4

(24)

2,4,6-Me3C6H2

(65)

2,6-(MeO)2C6H3

(42)

3,4,5-(MeO)3C6H2

(43)

220

O R

p-Tol N R (CO)3Cr

H

(82)

Me

(85)

Bn

(63)

465

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C27-30

Conditions

Product(s) and Yield(s) (%)

Refs.

Ar OH Ar

H N

See table

(CO)5Cr

+

I

II = I-Cr(CO)3

220

N H

552

Ar

Solvent

Temp

Time

I

II

Ph

toluene

90°

1h

(26)

(—)

4-MeC6H4

toluene

90°

1h

(25)

(—)

2,4,6-Me3C6H2

toluene

90°

1h

(70)

(—)

2,4,6-Me3C6H2

t-BuOMe

55°

4.5 h

(25)

(22)

2,4,6-Me3C6H2

THF

68°

3h

(57)

(15)

2,4,6-Me3C6H2

MeCN

82°

40 min

(63)

(0)

2,4,6-Me3C6H2

(n-Bu)2O

75°

1h

(45)

(28)

2,4,6-Me3C6H2

(n-Bu)2O

85°

35 min

(49)

(30)

2,6-(MeO)2C6H3

toluene

90°

1h

(43)

(—)

3,4,5-(MeO)3C6H2

toluene

90°

1h

(45)

(—)

C28-38

R2

R1

OMe

OMe

(CO)5Cr

R1

MeO

R3

OMe

Cr(CO)5

R3

0.0025 M

223 R4 (1.0 eq), 1,2-dichloroethane,

OH

100°, 20-40 min

R2

HO

R4

553

R1

R3

R

2

R4

Me

Ph

Me

Ph

(35)

Me

n-C6H13

Me

n-C6H13

(22)

Me

OMe

Me

OMe

(36)

Ph

OMe

Ph

OMe

(41)

Me

OMe

Me

Ph

(31)

Ph

OMe

Me

Ph

(35)

Me

OMe

Me

n-C6H13

(22)

Me

n-C6H13

Ph

OMe

(35)

Me

OMe

Ph

OMe

(40)

C29-30

O

R HO

(CO)5Cr

O

1. Benzene, temp, 18-19 h

MeO

+

247, 245

2. Workup TBSO

OTBS 0.005 M

R

Temp

I I

II

OMe

75°

air

(30)

(23)

NMe2

120°

TiCl3/LAH

(10)

(—)

OMe

O

(CO)5Cr CO (1 atm),

MeO

MeCN, 80°, 27 h 0.005 M

II

TBSO

Workup

OTBS

TBSO

O (28)

245

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C29

Conditions

Product(s) and Yield(s) (%)

Refs.

OMe HO

(CO)5W

HO

Additive,

+

247, 245

solvent, 110°, 19 h I

TBSO

OTBS

II

THF

(53)

(0)

benzene

(51)

(0)

none

heptane

(48)

(0)

0.005

none

MeCN

(63)

(0)

0.05

none

MeCN

(50)

(0)

0.005

CO (1 atm)

MeCN

(47)

(31)

Additive

Solvent

0.005

none

0.005

none

0.005

II

HO

I

CC (M)

554

Pr-n C33 O

Pr-n

H N

N

(CO)5Cr

H (n-Bu)2O, 85°, 1.5 h

MeO

466

(7)

MeO

0.06 M

OMe

OMe

C36-43 R O

OBu-n

H N

R

N (n-Bu)2O, 85°, 1.5 h

R

N

H

(CO)5Cr

H

+

MeO

466

MeO

MeO

II

I

OMe 0.05 M

OMe

R

555

C37

OMe I

II

TMS

(14)

(—)

Ph

(8)

(7)

ferrocenyl

(16)

(8)

2-pyridinyl

(3)

(3)

t-Bu O

O

OBu-n

OH

H N

N

Bu-t

Solvent, 85°, 1.5-2 h

MeO

Bu-t

N

H

(CO)5Cr

+

MeO

H 466

MeO I

OMe 0.02-0.05 M

Solvent (n-Bu)2O toluene

OMe

II

I

II

(low)

(0)

(0)

(17)

OMe

TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex

C38

Conditions

Product(s) and Yield(s) (%)

Refs.

n-C5H11 O H N

N

C5H11-n

H

(CO)5Cr (n-Bu)2O, 85°, 2 h

(44)

MeO

MeO

OMe 0.04 M

556

a b c d

OMe

There was greater than 90% deuterium incorporation in the product. The concentration of the starting carbene complex was equal to 0.025 M. A trimer was also isolated in 9-13% yield. The concentration of the starting carbene complex was equal to 0.001 M.

e

The concentration of the starting carbene complex was equal to 0.006 M.

f

This product was a mixture of two diastereomers.

466

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

OH

C2 Cr(CO)5

Ph

Et2O, rt, 2 h

(9)

87

Ph

1.6 eq

(CO)3Cr

Ph

C3 W(CO)5

Ph

Alkyne (100 eq), Ph

Polymer (75)

85

40°, 22 h OH

C4 Cr(CO)5

Ph

Et2O, rt, 2 h

(12)

87

Ph

1.6 eq

557

(CO)3Cr + BF – 4

1. CO (1 atm), CH2Cl2, –78°

H

S

Ph OH

2. Air

W(CO)2Cp

(33)

467

S

0.006 M + BF – 4

OH

1. CO (1 atm), CH2Cl2, –78°

H

56, 467

(62)

2. Air W(CO)2Cp 0.006 M + BF – 4

O WCp(CO) 2

+ BF – 4

CO (1 atm),

H

(73) dr = 1.2:1

56

CH2Cl2, –10° W(CO)2Cp 0.006 M

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

C4

Conditions

H (CO)5W

EtO

Product(s) and Yield(s) (%)

CH2Cl2, –78° to –25°

(CO)5W

(21)

Ph

18 eq

Refs.

OEt 468

Ph Cr(CO)5

Cr(CO)5 OEt 1 eq

CH2Cl2, –20°, 2 h

(47)

345

(41)

345

0.05 M Cr(CO)5 Cr(CO)5 OEt 1 eq

CH2Cl2, –20°, 2 h

558

O O

0.05 M

Cr(CO)5 Cr(CO)5 OEt

1 eq

CH2Cl2, –20°, 2 h

(36)

0.05 M

C5 Ph

E:Z = 1.6:1

345

OH Pr-n

Cr(CO)5

n-Pr

Et2O, rt, 2 h

(11)

87

Ph 1.5 eq

(CO)3Cr + BF – 4

R

H

OH R

CH2Cl2, –78° 2. Air, 24 h

W(CO)2Cp 0.006 M

Ph

1. CO (1 atm),

R

n-Pr

(34)

i-Pr

(67)

467

Cr(CO)5 1. t-BuOMe, 20°, 1-2 h

(CO)5Cr

HO

+

2. TBSCl, Et3N, 20°, 2 h

4 eq 0.1 M

+

O

(46)

O

173

(59)

(<5)

TBSO (CO)5Cr

4 eq

O

O

1. t-BuOMe, 40°, 1-2 h

(68)

173

2. TBSCl, Et3N, 20°, 2 h TBSO

0.1 M

TBSO

559

(CO)5Cr

4 eq

Cr(CO)5

(CO)3Cr

1. t-BuOMe, 20°, 1-2 h

+

2. TBSCl, Et3N, 20°, 2 h

0.1 M

173

O

(33)

TBSO (46) Me3P (1 eq),

H (CO)5W

CH2Cl2/pentane (1:2), Ph

1.1 eq

PMe3 (CO)5W Ph

(11)

469

(—)

469

–50°, 3-5 min

0.02 M SMe

H

(CO)5W

(CO)5W CH2Cl2/pentane (1:2),

MeS

–50°, 30 min

1.1 eq

0.02 M

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

MeO

n-Bu

(CO)5Cr

1. t-BuOMe, 20°, 1-2 h

4 eq

Refs.

OTBS

OMe

C6

Bu-n

(62)

(CO)3Cr

173

2. TBSCl, Et3N, 20°, 2 h 0.1 M

OMe

OMe

OMe

OTBS

OTBS MeO 4 eq

+

1. t-BuOMe, 20°, 1-2 h

560

(CO)5Cr

Bu-n Bu-n 173

(CO)3Cr

(CO)3Cr

2. TBSCl, Et3N, 20°, 2 h

0.1 M

(40)

(25) OMe

4 eq

(CO)5Cr

1. t-BuOMe, 20°, 1-2 h

(78)

173

2. TBSCl, Et3N, 20°, 2 h 0.1 M OTBS

OTBS

n-Bu 4 eq

(CO)5Cr

O

(42) +

1. t-BuOMe, 40°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h

0.1 M

Bu-n

O

(26) 174, 173 O

Cr(CO)3

(CO)3Cr (CO)5Cr

4 eq

1. t-BuOMe, 20°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h

0.1 M

174, 173

(55) n-Bu TBSO

(CO)3Cr (CO)5Cr

4 eq

+

1. t-BuOMe, 20°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h

0.1 M

173 n-Bu

n-Bu

RO

TBSO (27) + BF – 4

561

t-Bu

R = H (26) R = TBS (<5)

OH 1. CO (1 atm), CH2Cl2, –78°

H

(49)

2. Air, 24 h

Bu-t

W(CO)2Cp

0.006 M

467

Ph (CO)5W

100 eq

40°, 15 h

85

Polymer (15)

Ph + BF – 4 R

OH

OH

1. CO (1 atm),

R

CH2Cl2, –78°

H

+

467

2. Air, 24 h

R

W(CO)2Cp

0.006 M

R

I

I

II

n-Pr

(28)

(33)

i-Pr

(16)

(49)

II

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

C6

+ BF – 4 Et

Et

Conditions

Product(s) and Yield(s) (%) OH

1. CO (1 atm),

Et

CH2Cl2, –78°

H

(34)

2. Air, 24 h 0.006 M NMe2

NMe2

(CO)5W

CH2Cl2, –50° Ph

C7 Cp'(CO)2Mn 1 eq

W(CO)5

+

(CO)5W Me2N

Cp'(CO)2Mn

Ph

Ph

0.4 M

(8)

(25)

470a

Ph

NEt2 Hexane, 70°, 22 h

(52)

456

Ph

562

NEt2

Ph 1 eq

NMe2

(CO)5W Me2N

Ph Et2N

467

Et

W(CO)2Cp H

Me2N

Refs.

(CO)5W

Hexane, –60° to rt

(CO)5W

Ph

Ph

359

(50)

Ph

0.7 M NEt2 (CO)5Cr 1 eq

(CO)5Cr

CH2Cl2, –60°, 5 min

(51)

345

(52)

345

0.05 M

NEt2 (CO)5Cr (CO)5Cr 1 eq 0.05 M

O

CH2Cl2, –60°, 5 min

O

NEt2 (CO)5Cr 1 eq

CH2Cl2, 20°, 1 h

(CO)5Cr

345

(27) syn/anti = 4.6

0.05 M NEt2

Ar (CO)5Cr

1 eq

CH2Cl2, –20°, 1 h

(CO)5Cr

PMP

0.05 M

Ar

Ar

Ph

(58) E:Z = 5.6:1

345

PMP (65)

PMP NEt2 (CO)5Cr

(CO)5Cr 1 eq

CH2Cl2, –60°, 5 min

(73) E:Z = 3.4:1

345

563

0.05 M

C8 (CO)5W

H (CO)5W Ph 0.02 M

1.1 eq

NMe2

1. CH2Cl2/pentane (1:2), –40°

(14)

469

2. MeC CNMe2 (1.2 eq)

OH Ph

Cr(CO)5

Ph Ph

(27)

Et2O, rt, 2 h

87

Ph

1 eq

Cr(CO)3

Ph Ph (CO)5W

50 eq

40°, 46 h

Polymer (49)

85

Ph

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8 H (CO)5W

Ph

Ar

1 eq

H

Ph CH2Cl2, –80° to –10°

Refs.

Ar

(CO)5W

(—) +

(CO)5W

(—) Ph

470b

Ar

Ph Ar

H

+

(CO)5W

TMS

TMS

(CO)5Cr

(—)

Ar = Ph, 4-MeC6H4

W(CO)4

t-BuOMe, 20°, 1-2 h

(82)

+ O

(<5)

173

4 eq

564

0.1 M TMS

TMS

Cr(CO)5 t-BuOMe, 40°, 1-2 h

4 eq

(44)

O

173

O

0.1 M

O •

Cr(CO)5 TMS t-BuOMe, 20°, 1-2 h

4 eq

TMS

(—)

173

0.1 M NEt2

H

Et2N

(CO)5W

CH2Cl2/pentane (1:2), Tol-p

1.1 eq

0.02 M

–40°, 30 min

(CO)5W

(78) Tol-p

469

C10 1. CH2Cl2/pentane (1:2),

H (CO)5W

–50°, 1.5 h Ph

1.0 eq

Ph

Ph NEt2

(CO)5Cr

Hexane/benzene (3:1), Ph

rt, 30 min

0.2 M

1.5 eq

Ph

(10)

469

2. Me3P (1 eq)

0.02 M

Et2N

+ PMe3

– (CO)5W

O

Ph

471

(16)

Et2N

NEt2 OH

C11 EtO2C

Ph

Cr(CO)5

Ph Ph

Et2O, rt, 2 h

(7)

Ph

87

CO2Et

1 eq

(CO)3Cr Ph OMe

C12

565

MeO OH

MeO O

Cr(CO)5

Ph

MeO

OMe

1. THF, 20°, 1 h Ph

MeO

OMe

O

296

2. Silica gel, 10°

OMe

(30) dr = 1.25:1

(CO)3Cr

Ph

C14 + BF – 4 Ph

H

Ph 1 eq 0.006 M

+ BF – 4

Tol-p

(89)

CO (1 atm), CH2Cl2, –78°

W(CO)2Cp

56

Ph

Cp(CO)2W

Ph

TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C14

Refs.

OH

Ph

Ph

Ph

(CO)5Cr Ph

(n-Bu)2O, 40°, 2 h O

1.4 eq

Ph

(22)

104

(20)

87

(CO)3Cr O

0.1 M OH

Ph

Cr(CO)5

Ph

Et2O, rt, 2 h

1 eq Ph

Ph (CO)3Cr Ph OH

566

CF3

CF3 Cr(CO)5

1.2 eq

(18)

104

Ph

Tol-p

0.4 M

Ph

(n-Bu)2O, rt, 2 h (CO)3Cr

Tol-p OH Ph

OH

CF3 Cr(CO)5

1.5 eq

1. (n-Bu)2O, rt, 2 h

CF3

Ph +

2. Air Tol-p (14)

(4) CF3

OH Ph

Cr(CO)5

2-naphth

(n-Bu)2O, rt, 1 h

1.2 eq

(11)

Ph 0.25 M

47

Ph

Tol-p

0.05 M

Ph

Ph (CO)5Cr

naphth-2

104

C16 W(CO)5

Ph

(18)a

Toluene, 50°, 16 h

452

Ph 0.001 M I

100 eq W(CO)5

Ph 1.0 eq

Toluene, 50°, 16 h

I (51)

452

Ph 0.05 M

C17

W(CO)5

Ph

(19)a

Toluene, 50°, 16 h

452

Ph 0.001 M

567

I

100 eq W(CO)5

Ph 1 eq

Toluene, 50°, 16 h

I (40)

452

Ph 0.05 M

C18

W(CO)5

Ph

Toluene, 50°, 16 h Ph 0.001 M 100 eq a

The yield was based on starting alkyne.

(24)a

452

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES Carbene Complex or Precursor Complex

C13

Conditions

Product(s) and Yield(s) (%)

Refs.

OMe OMe

N-morph

(CO)5Cr +

THF, rt, 12 h

morph-N

O

(38)

O

472

morph-N

C14 OMe (CO)5Cr MeO

OMe

1. CNBn (2 eq),

+

THF, rt, 15 min 2. Silica gel

(52)

473

NHBn

O OMe

C15

568

OEt

EtO

(CO)5W +

R2PH

EtO

O

+

Pentane, 0° PR2

(CO)5W

+ PR2

(CO)5W I

R

I

(CO)5W

474 PR2

II III

IV

t-Bu

I + II + III (80)

II

(0)

c-C6H11

(30)

III EtO +

(7) (22) (36) IV

(CO)5W PR2 OH

OMe (CO)5Cr

OMe

Photolysis, CO, THF

(0)

254

Ph

OMe

OMe

(CO)5W +

+

(10)

Neat, 50°, 4 h

(5)

475, 472

Ph OMe

Ph

Ph

OMe

(CO)5W +

MeCN, rt, 72 h MeO

Ph

(51)

475, 472

MeO

C15-16 OMe (CO)5W

O +

+

THF, rt

569

morph-N R

OMe

O

I

475, 472

morph-N

R

Time

I

II

Cl

12 h

(36)

(0)

H

10 min

(0)

(95)

Me

15 min

(0)

(90)

2d

(0)

(95)

R

OMe

R

OMe

OMe OMe

(CO)5W +

(CO)5W

Ph

THF, rt, few min

(95) OMe

morph-N Ph

II

N-morph

472

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

C15-16

Conditions

Product(s) and Yield(s) (%)

OMe

OMe (CO)5W + Ar

THF, rt

472 morph-N

morph-N

Ar

R

Time

R

Ph

5 min

H

(95)

4-MeC6H4

15 min

Me

(97)

OMe

(94)

4-MeOC6H4

Refs.

OMe OMe

8h

OMe +

THF, rt

472

570

morph-N

morph-N

R

Time

R

15 min

H

(92)

15 min

Me

(95)

OMe

(96)

10 h C15

OTMS OMe

OTMS

OMe (CO)5W + Ph

(83)

THF, rt, 10 min

472

O

morph-N

OMe (CO)5Cr +

O

O

1. THF, rt, 10 min 2. TsOH, toluene, 110°

morph-N

Ph

OMe

472

(58) morph-N

OMe

N-morph

(CO)5Cr +

THF, –10°, 6 d morph-N

Ph

(34)

472

morph-N

OMe (CO)5Cr

OMe

OMe +

THF, rt, 3 d

OMe

OMe 3 eq

+

OMe

(59)

571 +

OMe

THF, rt, 2 d morph-N

+

MeO

OMe

(85)

472

morph-N

morph-N

C3H5O

OC3H5 THF, rt, 4 d morph-N

472

OMe

THF, rt, 6 d

+

(86) morph-N

OMe

2 eq

472

TMSO

OMe

2 eq

OMe

THF, rt, 3 d TMSO

2 eq

472

(64) TMSO

TMSO

1 eq

OMe

OMe

OMe (54)

O

472

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

C15

Conditions

Product(s) and Yield(s) (%)

OMe

OMe

(CO)5Cr

OMe

O

O

+

Refs.

(87)

THF, rt, 12 h

472

morph-N

morph-N 2 eq

OMe

N-morph +

2 eq

OMe

THF, rt, 12 h

+

(57) morph-N

morph-N

472

MeO MeO

Cr(CO)5

(9)

572 morph-N OMe

OMe

OMe

+

1 eq

OMe

THF, rt, 3 d

TMSO

(90)

472

(76)

472

TMSO

OMe

OMe

OMe

+

1 eq

OMe

OMe

OMe

THF, 40°, 2 d

morph-N

morph-N

C15-16 OMe

OR2

(CO)5M +

OMe

OMe

OR2 Toluene or benzene, 45°

+

OR2 R1

C16

476 R1

1

R

M

R1

R2

Cr

H

TBS

Cr

H

W

H

Cr

OMe

OR2 I

OR2 I

II

(73)

(25)

TMS

(9)

(80)

TBS

(35)

(55)

TBS

(65)

(5)

II

OMe (CO)5Cr Photolysis, THF, CO

(23)

OH

254

573

OMe C17-18 NHR

CO2Me

CO2Me

(CO)4Cr CO2Me

O

H O

0.1 M

C17

CO2Me

(35)

54

Me (44)

NHR

OMe

O

R

CH2Cl2, rt, 8 h

N2 purge, THF, reflux, 9 h

(79)

252, 253

OH

O OMe

W(CO)5 0.02 M H

OEt

OEt R

(CO)5M

Et2O, 20°, 12-14 h NMe2

W (89) (CO)5M –

NMe2 +

Cr (85)

474

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C17 O

O Photolysis, CO, THF

Cr(CO)5

(65)

477

OH OMe

OMe

O CNBu-t (3 eq),

(78)

255

NHBu-t

toluene, reflux OMe O

O

574

CNR, solvent,

Cr(CO)5

reflux, 12-24 h

NHR

Solvent

R

toluene

t-Bu

(72)

THF

CH2CO2Et

(64)

255, 257

OMe

OMe OMe

OMe

(CO)5M +

THF, rt, 20-30 min

OMe 472

(95)

Ph

Ph

morph-N morph-N

2 eq Ph M = Cr, W OMe

MeO

(CO)5M +

MeO

OMe

O (30)

THF, rt, 2.5 min

2 eq Ph

472

Ph

Ph O

morph-N

M=W

OMe M = Cr 1 eq

+ morph-N

N

CCl3

OMe

OMe

Cr(CO)5

OMe

THF, rt, 48 h

Ph

(85)

472

morph-N

1. CNBu-t (2 eq),

N

OMe

CCl3

THF, 60°

N 478

(60)

N

NHBu-t

2. Silica gel OMe

OMe C18 Ph OMe

CNBu-t (2 eq),

(90)

ether, reflux

Cr(CO)5

255

NHBu-t OMe

575 1. N2 purge, THF, reflux, 4-9 h OMe

O 0.02 M

2. Workup

O

OH

THF, reflux, 6 h OMe R 0.02 M

2. Air, sunlight, 12 h

1. N2 purge,

0.02 M

OMe W(CO)5

none

Me

MeO

OH

252, 253

(77)

2. Air, sunlight, 12 h

(72)

253

OMe (0)

OMe

O

THF, reflux, 6 h O

air, sunlight, 12 h (56)

W

R R

Cr(CO)5

O

Workup

Cr OMe

M(CO)5

1. N2 purge, MeO

M

(65) O

OH OMe

253

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C18 M CNBn (2 eq), OMe

O

THF, rt, 15-60 min

O

NHBn

CNBu-t (2 eq),

(86)

473

NHBu-t

MeO

OMe

Cr(CO)5 OMe

OMe

576

(CO)5W +

THF, rt, 4 d morph-N

2 eq

473

(85)

THF, rt, 15 min OMe

0.05 M

(78)

Cr

OMe

0.05 M M(CO)5

MeO

W

OMe 472

(67)

Ph

Ph morph-N

Ph OMe

OMe

OMe +

2 eq

THF, rt, 1 d morph-N

N

CCl3

1. CNBu-t (2 eq), N

OMe Ph

M(CO)5

morph-N

N

CCl3

2. Silica gel

Sealed tube, THF, 80°, 18 h

(93)

472

M NHBu-t

Ph

OMe

W

(72)

Cr

(68)

478

N

CCl3 M = Cr

O

N

THF, 60°, 12 h

Ph

Ph

MeO

478

(70)

N OMe

C18

N-morph

N-morph CO2Me

CO2Me

CH2Cl2, rt, 8 h

54

(68)

0.1 M (CO)4Cr

CO2Me

CO2Me

C19 R R

R OMe Ph

Photolysis, THF, CO OH

Cr(CO)5

H

(90)

OH

(78)

254

OMe Ph R=H

O

CNBu-t (2 eq),

NHBu-t

ether, reflux

577

(CO)5Cr THF, reflux, 36 h

(90)

479

OMe Cr

OMe

Time

R

CNR, reflux Ph

255

OMe O C OC

OMe

(85)

Cr(CO)5 NHR

t-Bu

t-BuOMe

48 h

(71)

CH2Ts

ZnCl2, THF

5h

(84)

257

OMe

1. N2 purge, THF, reflux, 6 h O 0.02 M

OMe Cr(CO)5

2. Air, sunlight, 12 h

(46) O

OH OMe

252, 253

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

R

C19 (CO)5Cr

OMe R

R

Photolysis, solvent, CO

OH R

Solvent

F Cl

+

477 OH

I

OMe

OMe

I

II

THF

(11)

(55)

THF

(6)

(83)

OH

THF

(30)

(35)

F

toluene

(<2)

(58)

Cl

toluene

(<3)

(89)

OH

toluene

(63)

(12)

II

578 1. Conditions, time O 0.02 M

M(CO)5

252, 253

2. Workup, 12 h

OMe M

Conditions

O OMe Workup

Time

Cr

THF, reflux, N2 purge

8h

air, sunlight, 12 h

(72)

Cr

THF, reflux

12 h

air, sunlight, 12 h

(26)

Cr

THF, 40°

28 h

air, sunlight, 12 h

(20)

Cr

hexane, reflux

24 h

air, sunlight, 12 h

(25)

Cr

MeCN, 65°

8h

air, sunlight, 12 h

(25)

Cr

THF, reflux, CO atm

9d

air, sunlight, 12 h

(—)

W

THF, reflux, N2 purge

9h

none

(59)

W

THF, reflux

20 h

none

(58)

W

THF, 40°

48 h

none

(15)

W

hexane, reflux

48 h

none

(19)

W

MeCN, 65°

10 h

none

(32)

1. N2 purge,

O

OH

O

THF, reflux, 4 h OMe

O 0.02 M

253

(67) O

2. Air, sunlight, 12 h

OH OMe

Cr(CO)5 O CNBu-t (2 eq),

0.05 M

473

(78) O

THF, rt, 15 min

NHBu-t OMe

C20 Ph OMe

See table OH

Cr(CO)5

579

OMe Conditions

Temp

photolysis, THF

—

(18)

251

photolysis, THF, CO

—

(93)

254

reflux

(29)

254

heptane, CO

80°

(75)

480

THF

80°

(41)

480

THF, CO

80°

(87)

480

benzene

80°

(51)

480

benzene, CO

80°

(92)

480

heptane

Ph Photolysis, MeOH, CO

CO2Me

(6)

+

(67) OH

OMe

OMe

254

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C20 Ph CNR1

OMe

255, 257 NHR2

Cr(CO)5

OMe

580

R1

Solvent

Temp

t-Bu

Et2O

reflux

8h

t-Bu

(83)

n-Bu

t-BuOMe reflux

12 h

n-Bu

(70)

Bn

THF

rt

21 h

Bn

(85)

CH2CO2Et

THF

reflux

8h

CH2CO2Et

(81)

2,6-Me2C6H3

CH2Cl2

reflux

8h

2,6-Me2C6H3

(86)

TMS

THF

rt

2h

H

(56)

CH=CHMe

THF

reflux

1h

H

(68)

Time

Ph OMe

O

Photolysis, THF, CO

(50) O

Cr(CO)5

254

OH OMe R

R

R

Photolysis, solvent, CO

+

477

OH

Cr(CO)5

OH

OMe OMe

OMe I

II

Solvent

R

I

II

THF

OMe

(9)

(61)

THF

Me

(39)

(32)

THF

CHO

(30)

(41)

THF

CF3

(<2)

(69)

toluene

Me

(7)

(89)

toluene

CHO

(22)

(66)

Ph

Ph CNBu-t (2 eq), OMe

(44)

NHBu-t

t-BuOMe, reflux

255

OMe

Cr(CO)5 n-Pr 1. CNBu-t (2 eq), MeO

MeO

Pr-n

THF, reflux, 40 h

581

Cr(CO)5

(73)

O

2. CAN

272

OMe O

OMe OMe

1. THF, reflux, 9-12 h OMe

O

2. Air, sunlight, 12 h

(69) with N2 purge OH

O OMe

Cr(CO)5

OMe OMe

Cr(CO)5

253

(44) without N2 purge

1. N2 purge, THF, reflux, 3 h 2. Air, sunlight, 12 h

(95) OMe

OH OMe

253

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C20 OMe

OMe

1. N2 purge,

MeO

MeO

THF, reflux OMe

MeO OMe

2. Air, sunlight, 12 h

(0) MeO OMe

Cr(CO)5

253

OH OMe

OMe

OMe

MeO

MeO CNBu-t (2 eq), OMe

MeO OMe

THF, rt, 15 min

(85) MeO OMe

Cr(CO)5 O

582

OMe

OMe

473

NHBu-t OMe O

MeO

MeO

(97)

CNBu-t (2 eq), OMe

MeO OMe

THF, rt, 15 min

MeO OMe

Cr(CO)5

473

NHBu-t OMe

O

O CNBn (2 eq), OMe

O

(67) O

THF, rt, 15 min

473

NHBn OMe

Cr(CO)5 O C OC

NMe2 (CO)5Cr Dioxane, reflux, 52 h

NMe2 Cr

(29)

479

H O Photolysis, CH2Cl2

(45)

256

Ph OEt

OEt

(CO)5Cr

OEt O

Pr-c

N

THF, 50-55°

Pr-c N

R

Pr-c

R

+

0.03 M

Pr-c

R

N

Pr-c

I R

583

(CO)4Cr

I

II

n-Pr

(22)

(63)

c-Pr

(0)

(81)

t-Bu

(0)

(92)

Ph

(21)

(45)

CH2Cl2, rt, 8 h

CO2Me

N-morph 0.1 M (CO)4Cr

(74)

54

N-morph CO2Me

CO2Me CO2Me

O

II

CO2Me

CO2Me CO2Me

481

Pr-c

CH2Cl2, rt, 8 h

O

N-morph

CO2Me

(62)

54

N-morph

0.1 M MeO

(CO)4Cr

CO2Me N-morph 0.1 M

N-morph

CO2Me

CO2Me

CH2Cl2, rt, 8 h MeO

CO2Me

(65) 60:40 mixture of isomers

54

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Ph

Conditions

CN

Ph 1. THF, rt, 9 h

(20)

2. Air, sunlight N-morph

54

N-morph

0.05 M

M

1. CO (1 atm),

W

THF, 65°, 6 h O

O

Refs.

OH

CN

(CO)4Cr

Product(s) and Yield(s) (%)

2. Air, sunlight, 12 h

O O

M(CO)5

253

(49)

Cr (55) O

0.02 M C21

584

OMe

OMe

(CO)5Cr Ph

HO Photolysis, THF, CO

(42)

254

Ph OMe CNR

R2HN

1

255, 257 Ph

O

R1

Solvent

t-Bu

t-BuOMe

Temp

Time

R2

32°

12 h

CH2CO2Et

t-Bu

(89)

THF

reflux

8h

CH2CO2Et

(80)

TMS

THF/PhMe

reflux

24 h

H

(32)

CH=CHMe

Et2O

reflux

2h

H

(76)

1. N2 purge, O

THF, reflux, 3 h OMe

O 0.02 M

2. Air, sunlight, 12 h

O

(77)

252, 253

OH OMe

Cr(CO)5 1. N2 purge,

(70)

THF, reflux, 9 h OMe OMe

2. Air, sunlight, 12 h OMe

W(CO)5

253

OH OMe

0.02 M OMe

OMe MeO

CNBn (2 eq), OMe

585

MeO OMe

THF, rt, 15 min

MeO (76) MeO OMe

Cr(CO)5

473

NHBn OMe

Ph Photolysis, CO, THF, 8 h

(75)

255, 256

(92)

54

(32)

54

Cr(CO)5 Me2N

Ph

Me2N

(CO)4Cr

OH

OH

CO2Me

CO2Me

Ph 1. THF, rt, 9 h

N-morph

2. Air, sunlight N-morph

0.05 M

OH

1. MeLi (1 eq), THF, –80° 2. H3O+, –60°

Ph

CO2Me

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

C21

Conditions

Product(s) and Yield(s) (%) H

OEt

Refs.

OEt

(CO)5M

M Et2O, 20°, 5 h N

MeO

(CO)5M –

OEt (CO)5M

N +

OMe

W

(92)

Cr

(86)

OEt

H

474

OEt

H

NHPh +

Toluene, 50°, 4 h H

H

N

M(CO)5

Ph

(CO)5M

I

586

O

OBu-t

I

II

W

(30)

(59)

Cr

(44)

(45)

474

II

OH N(Me)CO2Bu-t

NMe

(CO)4Cr

N Ph

M

Photolysis, THF, CO

256

(81)

O

O

CH(OMe)2

C22

CH(OMe)2 Cr(CO)5

CH(OMe)2

Photolysis, solvent, CO

+

477

OH

OMe

OH

I

OMe Solvent

I

II

OMe

II

THF

(30) (44)

toluene

(<4) (92)

Ph Ph

1. N2 purge, OMe

O

2. Air, sunlight, 12 h 0.02 M

M R = OH

THF, reflux, 7-12 h O

R

I

W

(89)

Cr

(72)

252, 253

OMe

M(CO)5

M CNBu-t (2 eq),

0.05 M

I R = NHBu-t

THF, rt, 15 min Ph

W

(88)

Cr

(94)

Ph 1. THF, reflux, 7-12 h

OMe

O 0.02 M

2. Air, sunlight, 12 h

(56) with N2 purge O

OH

587

1. N2 purge,

M

THF, reflux, 3-12 h OMe 0.02 M

2. Air, sunlight, 12 h

OMe

M(CO)5 Ph

O OMe

O

252, 253

(32) without N2 purge

OMe

Cr(CO)5

OMe

473

CNBu-t (2 eq),

OH

(83)

Cr

(90)

253

OMe

O

Ph

O

NHBu-t

THF, rt, 15 min

W

(98)

473

OMe

Cr(CO)5 0.05 M

CNBn (2 eq), OMe

TMSO OMe 0.05 M

Cr(CO)5

THF, rt, 15 min

(59) TMSO OMe

NHBn OMe

473

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

C22

O

Conditions

OMe CNBu-t (2 eq), OMe

THF, rt, 15 min

(92)

MeO

Cr(CO)4

NHBu-t

morph-N

Ph

THF, rt, 9 h

CONMe2

Cr(CO)5

588

Se

OEt

(CO)3Fe THF, reflux, 2.5 h

Se

(CO)3Fe

Se

Cr(CO)3

EtO

(24)

CH2Ph

Se

482

Ph

Cr(CO)5 (CO)3Fe

(CO)3Fe

Se

Ph

Se

54

(45)

OH

CONMe2

0.05 M

473

OMe

Cr(CO)5 Ph

(CO)3Fe

MeO

OMe

morph-N

(CO)3Fe

O

OMe

MeO

OEt

(CO)3Fe THF, reflux, 2 h

(CO)3Fe

Se

Cr(CO)3

EtO +

(25)

CH2Ph

Se

Ph

483

Ph

0.13 M

(CO)3Fe

Se

(CO)3Fe

Se

Ph OEt Se Fe(CO)3 EtO

Se

Ph (CO)3Fe

(CO)3Fe

OEt

Se

THF, 85°, 3 h

(CO)3Fe

Cr(CO)5

Se (15)

+

Se

(CO)3Fe

Se

(CO)3Fe

Se

(18)

O

(CO)3Fe

Se

(CO)3Fe

Se

(19)

Se Fe(CO)3

Ph (CO)3Fe

Refs.

O

O

MeO

OMe

Product(s) and Yield(s) (%)

484

OH OEt

(70)

Toluene, reflux, 3 h

484

OH OEt

S

(CO)3Fe

Ph (CO)3Fe

(CO)3Fe

OEt

Se

THF, 85°, 3 h

S

(CO)3Fe

Se

Cr(CO)5

Toluene, 85°, 3 h S

(CO)3Fe

Te

Se

484 OH

I (23) OEt 484

589

(CO)3Fe

S

(CO)3Fe

Te

Ph

THF, reflux, 2 h

Cr(CO)5

0.09 M

(CO)3Fe

I (34)

Ph OEt

S

O

(11)

(CO)3Fe

(CO)3Fe +

OEt

+

(17)

(CO)3Fe

S

(CO)3Fe

Te

483 Ph OEt Te Fe(CO)3 (9) EtO Ph

(CO)3Fe

S

(CO)3Fe

Te

S

Fe(CO)3

Solvent

Solvent, reflux, 2 h OH

THF

(21)

toluene

(38)

484

OEt Ph Cr(CO)4 Photolysis, THF, CO MeN

O OBu-t

(83) OH N(Me)CO2Bu-t

256

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C23 OMe (CO)5Cr Photolysis, solvent, CO

+

(76)

(7)

477

OH OH

OMe OMe

Ph Ph

1. N2 purge, OMe

O

M

THF, reflux, 6-12 h O

2. Air, sunlight, 12 h

OH

W

(60)

Cr

(55)

252, 253

OMe

M(CO)5 Ph 1. N2 purge,

590

O OMe

O

O

Ph

O

OH

THF, reflux, 6 h 2. Air, sunlight, 12 h

Ph

OMe

(82)

473

Ph

MeO

MeO CNBn (2 eq), OMe

MeO

473

OMe

Cr(CO)5 OMe

(72)

THF, rt, 15 min

MeO

NHBn

OMe 0.05 M Cr(CO)5

OMe

N-morph

N-morph

CO2Me

OMe

CO2Me

CH2Cl2, rt, 8 h

(52) 71:29 mixture of isomers

54

Ph (CO)4Cr

CO2Me

Ph

CO2Me Ph

0.1 M 1. MeLi (1 eq), THF, –80° 2. H3O+

MeO2C

(71)

OH

54

CO2Me

C23 OEt

Ph

(CO)5W

Petroleum ether, 20°, 3 d

– W(CO)5

+ Et2N

NEt2

(—)

Ph

NEt2

485

OEt – W(CO)5

Ph

(CO)5W

Petroleum ether, 20°, 3 d

EtO

Ph

OEt

(66)

485

(82)

485

NEt2 + O

Ph

1. Toluene, 45°, 5 h NEt2

2. aq HCl C23-26

591

OEt (CO)5Cr

Ph N Pr-c

0.05 M

R

Ph

N

R

Pr-c

THF, 50-55°, 16-24 h

R

OEt

C24

n-Pr

(88)

c-Pr

(97)

t-Bu

(85)

Ph

(62)

481

Ph Ph

1. N2 purge, OMe OMe

THF, reflux, 2 h 2. Air, sunlight, 12 h

OMe

Cr(CO)5

(90)

253

(—)

253

OH OMe

1. N2 purge, THF, reflux, 2 h O

OBn Cr(CO)5

2. Air, sunlight, 12 h

O

OH OBn

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C24 (t-Bu)2P

Cr(CO)5

(t-Bu)2P

CNR (2 eq), Ph

OEt

(96) R = t-Bu, c-C6H11

cyclohexane, 60°, 1 h

486

NHR

0.16 M

OEt M(CO)5

M(CO)5

(t-Bu)2P

(t-Bu)2P

(t-Bu)2P

M(CO)5

(t-Bu)2P

+

Pyridine (0 or 1 eq), 3-35 h Ph

+

486

OEt EtO

592

M

Solvent

Temp

Cr

benzene

60°

no

Cr

benzene

80°

no

Cr

benzene

80°

W

heptane

W

heptane

W

heptane

EtO

I

Pyridine

EtO

II II

III

(>90)

(0)

(0)

(0)

(>90)

(0)

yes

(0)

(0)

(>90)

55°

no

(91)

(0)

(0)

80°

no

(0)

(86)

(0)

80°

yes

(0)

(0)

(>90)

I

III

C25 Cr(CO)4 Photolysis, THF, CO

256

(28)

OH

O

BnN

N(Bn)CO2Bu-t OBu-t C25-27 Conditions R1

R2

MeO

OMe

(CO)5Cr

A: Photolysis, toluene, CO or B: CNBu-t, toluene,

NR1

N Me

NR1

reflux, 5 h

N Me

R2

A

Me

OH

(51)

A

allyl OH

(58)

B

Me

B

allyl NHBu-t (58)

292, 293

NHBu-t (89)

C26 Cr(CO)5 (c-C6H11)2P

Ph

Cr(CO)5

(c-C6H11)2P OEt

(c-C6H11)2P +

Heptane, 2 h

Cr(CO)5

EtO

486 EtO

I

Temp

I

II

80°

(>80)

(>10)

100°

(0)

(>90)

II

Ph Ph CNBu-t (2 eq), OMe

MeO TMSO

THF, rt, 15 min

(65) TMSO OMe

Cr(CO)5

473

NHBu-t OMe

0.05 M

593

C26-29 Ph R

Ph R

N

N

Ph Ph

THF, 50-55°, 15-18 h OEt

OEt Cr(CO)5 0.05 M

C28

R n-Pr

(88)

c-Pr

(96)

t-Bu

(99)

Ph

(80)

481

N-morph [(COD)RhCl]2 (2.5 mol%),

Ph

N-morph Ph

THF, 20°, 36 h OEt OEt W(CO)5

(76)

195

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C28-30 MeO

OMe

(CO)5Cr

OH R

Photolysis, toluene, CO N R

293

allyl (63)

N

N

MOM

Boc

N

R

(71)

MOM

MeO

NHBu-t R 292, 293

allyl (74)

CNBu-t, toluene, reflux, 5 h N R

C29

Boc

N

(68)

MOM

Cr(CO)5

594

MeO

MeO MeO OTIPS

Photolysis, CO, OTIPS

271, 272

(36)

OH

THF or toluene

OMe OMe

0.03 M

OMe

MeO 1. CNBu-t (2 eq), THF, OH NHBu-t

reflux, 24 h

0.75 M

2. TBAF

(60)

271, 272

OMe OMe TIPSO

MeO

MeO

1. CNBu-t (2 eq), THF, OTIPS

reflux, 16 h

+

271, 272

O

2. CAN

OMe O I

CC (M) 0.4 0.1

I

II

(82)

(0)

OMe O II

(57-62) (20-25)

Ph Cr(CO)4

Atmosphere Photolysis,

O

BnN

atmosphere, THF

OH

OBu-t

C30

(40)

CO

(62)

256

N(Bn)CO2Bu-t

Me

Me

Ph

N

N2

N

Ph

Photolysis, CO, THF

OMe

Ph

(51)

165

(33)

256

OH

Ph

Cr(CO)5

Ph

OMe

C31 Ph Ph Cr(CO)4

595

Photolysis, CO, THF

OH

O

BnN

N(Bn)CO2Bu-t OBu-t C31-36 W(CO)5 EtO [(COD)RhCl]2 (2.5 mol%),

R1 R3 R2

toluene, 70°, 12 h

N Me

R3 R2

R1

N Me OEt

0.1 M E:Z = 95:5 R1

R2

R3

Ph

Me

Me

(71)

Ph

Me

H

(74)

Ph

Ph

H

(76)

cyclohex-1-enyl

Ph

H

(73)

195

TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C32-33 C7H15-n

R

C7H15-n

R

N

R

N Photolysis, CO, THF

Bn

Cr(CO)5

OH

C7H15-n

Bn

C7H15-n

Bn

N

R

N CNBu-t (7 eq), Cr(CO)5

596

OR

258

OMe

0.005 M

MeO

(65)

PMB (62)

Me NHBu-t

THF, 75°, 18 h

(86)

258

MOM (72)

OR

1.2 M

C39 RhCl(COD) EtO Toluene, 70°, 4 h

Ph Ph

N Me

0.1 M E:Z = 95:5

Ph Ph

N Me OEt

(63)

195

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES Alkyne

Carbene Complex

C2

Conditions

Product(s) and Yield(s) (%)

OEt (CO)4W

Refs.

OH 487

(8)

Hexane, rt, 2 d

105 Pa 0.07 M C4

H

Ph

(CO)5W

9 eq

W(CO)5

H

Ph

CH3

CH2Cl2, 20°, 6 h

+

(CO)5W

Ph 488, 489

W W (CO)3 (CO)3

W(CO)4 (28)

(23)

+ poly-2-butyne (—)

597

H (CO)5W

excess

Pentane, –78° to rt

(CO)5W

Ph

+ Ph

Ph

+ Me2C2[C(H)Ph]a

+ n-C H 5 11

Ph

489

Me2C2[C(H)Ph]2a

+

+ (Me2C2)2(CO)[C(H)Ph]a OH

C5 t-Bu

Bu-t

Argon (4 bar), t-BuOMe,

P

Cr(CO)5

1.1 eq

(extremely low)

100°, 2 h

231

P

OMe 0.1 M

(CO)3Cr OMe

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5

OH t-Bu

P

Argon (4 bar), t-BuOMe,

+

(minor)

P

70°, 7 h

1.1 eq

OMe Cr(CO)5

Argon (9 bar), DME, 90°, 3 h

MeO

598

OEt Cr(CO)5 0.04 M

Argon (9 bar), Et2O, 90°, 3 h

(4)

P

S (CO)3Cr

231

t-Bu

Bu-t S

O O

OH 1.3 eq

(43)

+

OMe

0.08 M

231

P

(9)

P

O

(22)

t-Bu

Bu-t O

231

O

OMe OH

1.3 eq

(5)

•

OMe 0.25 M

Cr(CO)5 OMe P

t-Bu

Bu-t Cr(CO)5

Refs.

P +

EtO

O S

OEt OH

1.2 eq

Argon (5 bar), DME, OMe 0.02 M

t-Bu

Bu-t

Cr(CO)5

Ph

P

(6)

80°, 5 h

+ MeO

P O

(35)

231

Ph

OMe

t-Bu (CO)4Cr 1.2 eq

MeO

OMe

P Argon (5 bar), CH2Cl2, rt, 8 h

0.02 M

MeO O

OMe (60)

230, 231

OH

MeO 1.2 eq

MeO Cr(CO)5

MeO 0.08 M

+

(25)

P

MeO

70°, 4 h

OMe

Bu-t

Argon (5 bar), DME,

OMe

231

t-Bu P

OMe (50)

MeO

O OMe

t-Bu

OMe

(CO)4Cr

P MeO EtO

1.3 eq

Cr(CO)3

Argon (5 bar), Et2O,

EtO

230, 231

(77)

O

70°, 1 h

Cr(CO)3

0.04 M OH

599

1.4 eq

Bu-t

Bu-t

Cr(CO)5

2-naphth

OMe

P

+

Argon (5 bar), t-BuOMe, P

50°, 5 h

0.17 M

230, 231

2-naphth

(CO)3Cr OMe (19)

OMe

O (9)

(CO)5Cr

Bu-t P

+ 2-naphth

(8) OMe

O

OH Cr(CO)3

OH

Bu-t Cr(CO)5

1.0 eq

Argon (5 bar), t-BuOMe, P

50°, 2 h

Bu-t +

II

OR 0.4 M

229, 231

P

I

OR

OR

R

I

II

Me

(82)

(7)

Et

(72)

(0)

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C5-6

OH Cr(CO)3 t-Bu

OH Bu-t

Bu-t

P Cr(CO)5

+ t-Bu

OEt 1:1

Refs.

Alkyne (1 eq), argon (5 bar),

+

P

P

231

Et2O, 60°, 2 h OEt

OEt I

0.19 M

II

OH Bu-t

I + II + III (—), OEt

C5

Cr(CO)3

I:II:III = 27:3:5

III t-Bu (CO)4Cr

600 t-Bu

P

OMe

OMe

P MeO

MeO

O

Argon (5 bar), t-BuOMe,

(11)

231

70°, 3 h 0.06 M OMe C6

OMe

H (CO)5W

t-Bu

Alkyne (excess)

polymer (—)

489

Ph OMe (CO)5Cr

(3)

THF, 50°, 41 h

1.2 eq

1.2 eq

490

OH I

Br(CO)4M

Toluene, –10° to rt, 10 min

I

M

I

Cr

(12)

W

(16)

81

OH

OMe O

(CO)5Cr

O

THF, 70°, 9 h

(31)

80

0.0044 M

1.1 eq C7

OH

OMe (CO)5Cr 1.2 eq

THF, 70°

80

I

CC (M)

Time

0.0044

6.5 h

(57)

0.1

2h

(20)

0.1

84 hb

(52) O

OMe (CO)5Cr

1.2 eq

I (39) +

MeCN, 70°, 6.5 h

(26)

80

OMe

II

0.0044 M

601

OMe (CO)4Cr

Solvent, 2-12 h

I + II

133

L 0.006 M L

Solvent

Temp

I

II

2.8

(n-Bu)3P

THF

70°

(48)

(0)

3.2

(n-Bu)3P

MeCN

70°

(49)

(0)

2.0

Ph3P

THF

21°

(61)

(0)

0.8

Ph3P

MeCN

22°

(8)

(55)

Alkyne (eq)

OMe (CO)5Cr

OH THF, 70°, 6 h

1.2 eq

(71)

491

0.0044 M

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

C7

Conditions

Product(s) and Yield(s) (%) OH

OMe (CO)5Mo 3.5-4 eq

+

Solvent, 70°, 1-4 h

80

I

0.0044 M

OMe

II I

II

THF

(62)

(5)

MeCN

(29)

(10)

Solvent

Refs.

O

OMe (CO)5W

See table

0.0044 M

I + II

80

Time

I

II

5

—

THF

95°

59 h

(56)

(0)

5

—

MeCN

95°

44 h

(8)

(23)

rt

4h

(56)

(0)

95°

133 hb

(71)

(0)

Alkyne (eq)

Solvent Temp

602

2.5

photolysis THF

6

—

THF

OH

OMe 7 eq

THF, 95°, 65 hb

(CO)5W

(71)

Bu-n 0.0044 M

OH 1.2 eq

Br(CO)4M

R

Toluene, –10° to rt, 10 min R

0.1 M

(CO)5W

–78° Ph

R

M

Me

Cr

(50)

Me

W

(54)

Ph

W

(18)

81

NEt2

H Et2N

80

Bu-n

(CO)5W

(57) Ph

489

C6H13-n

C8 n-Bu

n-Bu

Mo(CO)5

n-C6H13 OMe

C5H11-n (5)

(20) +

Benzene, 100° n-Bu

C6H13-n

447

MeO

OH OH Ph Cr(CO)5 Ph

(n-Bu)2O, 80°, 1 h OMe 2.2 eq

(12)

492

(CO)3Cr

0.5 M OMe OH

Ph

Ph

O Cr(CO)5 2.2 eq

Ph

+

Hexane, 70-80°, 8-20 h

+

603

OH (22)

0.05 M

OMe (7)

Hexane, 80°, 24 h Ph

N

M(CO)5

Ph

0.014 M

(12)

Ph

Ph 2.2 eq

406

Ph

OMe

+ N H I

Ph

+ N H II

I

II

III

Cr

(20)

(25)

(18)

W

(65)

(≤1)

(0)

OMe

HO 234 N III

Ph

M

OMe Ph

OH

(CO)5Cr

(n-Bu)2O, 70°, 6 h

(61)

246

Pr-n 1.1 eq

Pr-n

0.006 M

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

C8 Br(CO)4M

M

OH

Toluene, –10° to rt, 10 min

0.1 M

Refs.

Cr

(46)

W

(52)

81

1.2 eq OH

OMe (CO)5M

M

THF, 50-95°, 32-50 h

0.0044 M

Cr

(32)

W

(50)

80

1.2-4 eq OMe

OMe

n-Pr

(40)

THF, reflux, 6 h

(CO)5Cr

TMS

n-Pr

Ph

155

Ph

TMS

604

10:3.3:1 mixture of diastereomers; E,E-major

C10 TMS OMe (CO)5M

OH THF, 70-95°

TMS 1.2-10 eq

M Cr

(73)

W

(61)

80

0.0044 M

Ph

OMe (CO)5Cr 1.1 eq

O

Dioxane, reflux, 6 h

OMe

(80)

51

0.02 M OMe OMe (CO)5Mo

OMe

OMe

Benzene, 60°, 4.5 h Bu-n

OH Bu-n

(9)

493

C11 MeO2C Br(CO)4M MeO2C

Toluene, –10° to rt,

M

MeO2C

10 min

0.1 M

OH

MeO2C

Cr

(52)

W

(60)

81

1.2 eq C12 OMe (CO)5Cr Pr-n

0.83 eq

1. PhCl, 100° 24 h

0.05 M

C13

Ph Ph Br(CO)4M . 0.1 M

1.2 eq

+

(2)

O

(10)

O

130

2. Iodine

M

OH

Toluene, –10° to rt, 10 min

Cr

(31)

W

(42)

81

Cl

605

OMe (CO)5Cr

1. Solvent, reflux

+

O

2. TsOH, rt

+ O

I

129

II

Bu-n Solvent

I

II

III

dioxane

(34)

(0)

(26)

dioxane/CDCl3 (49:1)

(29)

(7)

(26)

III O

OMe (CO)5Cr

0.83 eq

1. Solvent, 100°, 24 h

O

I + II +

0.05 M

130

IV

O

2. Iodine Solvent

I

II

IV

PhCl

(60)

(0)

(5)

PhCl/CCl4 (9:1)

(20)

(45)

(0)

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

OMe (CO)5Cr

Conditions

Product(s) and Yield(s) (%)

1. Dioxane, reflux

129

+

+

2. TsOH, rt

Refs.

O

O

O (13)

(54)

(4)

Bu-n OMe (CO)5Cr Bu-n

1. Dioxane, reflux, 26 h

O

(71)

259

O

(84)

259

2. Iodine

0.03 M

0.83 eq

606

Bu-n OMe (CO)5Cr

1. Dioxane, reflux, 26 h 2. Iodine

0.03 M

n-Bu

0.83 eq OMe

EtO2C (CO)5M

OH

EtO2C

THF

EtO2C

80

EtO2C 0.0044 M Alkyne (eq)

M

Temp

Time

1

Cr

70°

15.5 h

(57)

5.5

W

95°

65 h

(72) CO2Me

MeO2C N

MeO2C (CO)5Cr 1.3 eq

0.7 M

Toluene, 120°, 1 h

MeO2C CO2Me

(48) O

O

494

CO2Me MeO2C Toluene, 120°, 1 h

N

MeO2C 1.3 eq

494

MeO2C CO2Me

(CO)5Cr

O

(59)

O

0.7 M OEt Ts

N

solvent, 65-80°, 1-4 h

(CO)5Cr

OH

1. Additive (4 eq), Ts

N

291

2. FeCl3-DMF 1 eq

607

CC (M)

CC (eq)

Solvent

Addtive

0.13

1.0

MeCN

none

(17)

0.13

1.0

benzene

none

(31)

0.13

1.0

THF (sealed tube)

none

(59)

0.13

1.0

THF

none

(40)

0.013

1.0

THF

none

(56)

0.006

1.0

THF

none

(57)

0.006

2.0

THF

none

(60)

0.006

2.0

THF

Ph3P

(71)

0.006

1.0

benzene/hexane (1:1)

Ph3P

(74)

0.006

2.0

THF

DMAP

(19)

0.006

2.0

THF

(PhO)3P

(71)

0.006

2.0

THF

(n-Bu)3P

(27)

C14 Ph

R

OMe (CO)5Cr

Me (61)

Dioxane, reflux, 6 h R

O

0.02 M

1.1 eq

51

c-Pr (68) OMe

R

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C14 Ph O

Ph

OMe (CO)5Cr

Solvent, 100°

+

I

R

II

260

O

0.02 M

OMe

O

1.1 eq R

Solvent

Me c-Pr

OMe

R

I

II

dioxane

(22)

(26)

dioxane/H2O (99:1)

(26)

(50)

Bu-n OMe (CO)5Cr

1. PhCl, 100°, 24 h

608

0.05 M

Bu-n 0.83 eq TMS

TMS

OMe 1. Dioxane, reflux

OH

2. TsOH, rt

OEt N 1 eq

Ts

(CO)5Cr

2. FeCl3-DMF

OEt (CO)5Cr

1 eq

1. THF, reflux

0.006 M

N

0.006 M

130

n-Bu

(CO)5Cr

Ts

(14)

O

2. Iodine

(20)

155

OH Ts

(71)

N

OH 1. THF, reflux 2. FeCl3-DMF

Ts

Ts +

N (25)

291

OH

N

291 (25)

C15 Ph OMe (CO)5Cr

Dioxane, reflux, 6 h

(54)

51

O 0.02 M

1.1 eq

OMe

OMe (CO)5Cr

(30)

1. PhCl, 100°, 24 h

0.05 M

130

O

2. Iodine

0.83 eq CO2Me

CO2Me

609

OMe (CO)5Cr

1. Dioxane, reflux, 26 h

0.03 M

Bu-n

259

(61)

O

2. Iodine n-Bu

0.83 eq OH

OEt Ts

N

(CO)5Cr

1. THF, reflux

N

(0)

291

2. FeCl3-DMF

0.006 M

1 eq

Ts

C15-16 R OEt Ts

N

(CO)5Cr R

1. THF, reflux 2. FeCl3-DMF

0.006 M

1 eq

R

OH Ts

N

CO2Me

(16)

TMS

(84)

291

TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne

Carbene Complex

Conditions

Product(s) and Yield(s) (%)

Refs.

C17 OMe (CO)5Cr

+

1. PhCl, 100°, 24 h

0.05 M

2. Iodine

O

1. PhCl, 100°, 24 h

O

130 O

(50)

(5)

0.53 eq 6

OMe (CO)5Cr

(40)

130

2. Iodine

0.05 M 0.53 eq C18

610

Ph

OMe Ph

(CO)5Cr

1. PhCl, 100°, 24 h

(31)

O

130

2. Iodine

0.05 M 0.53 eq C19

Ph

Ph OMe (CO)5Cr Bu-n

1. Dioxane, reflux, 26 h

O

(81)

259

(63)

259

2. Iodine

0.03 M

n-Bu

0.83 eq Ph Ph

OMe (CO)5Cr

1. Dioxane, reflux, 26 h

O

2. Iodine Bu-n 0.83 eq

0.03 M

n-Bu

CO2Me CO2Me

6

OMe

(CO)5Cr

1. PhCl, 100°, 24 h

(35)

O

130

2. Iodine

0.05 M 0.53 eq

TMS TMS Ts

N

OH

OEt (CO)5Cr

1. THF, reflux

TMS

N

(10)

291

2. FeCl3-DMF

0.006 M

1 eq

Ts

TMS Ph OEt

Ts

N

(CO)5Cr

1. THF, reflux

Ph

2. FeCl3-DMF

1 eq

(83)

291

611

Ts

Ts

N

N

OEt OMe

(CO)5Cr 0.006 M

1 eq

OMe

OMe

1. THF, reflux OMe

2. FeCl3-DMF

(34)

OH

These products arise from the coupling of 2-butyne with one or two C(H) Ph fragments, or two 2-butyne molecules with one C(H)Ph fragment and one CO

molecule. b

N

0.006 M

C23

a

OH Ts

The alkyne was added slowly.

291

612

ORGANIC REACTIONS REFERENCES

1

Fischer, E. O.; Maasb¨ol, A. Angew. Chem., Int. Ed. Engl. 1964, 3, 580. D¨otz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644. 3 D¨otz, K. H., Rheinische Friedrich-Wilhelms-Universit¨at Bonn, D-53121, Bonn, Germany. Personal communication. 4 Brown, F. J. Prog. Inorg. Chem. 1980, 27, 1. 5 Casey, C. P. In Reactive Intermediates; Jones, M.; Moss, R. A., Eds.; Wiley-Interscience: New York, 1981; Vol. 2, pp 135–174. 6 Semmelhack, M. F. Pure Appl. Chem. 1981, 53, 2379. 7 Semmelhack, M. F., Sato, T.; Bozell, J.; Keller, L., Wulff, W.; Zask, A.; Spiess, E. In Current Trends in Organic Synthesis; Nozaki, H., Ed.; Pergamon: New York, 1982; p 303. 8 D¨otz, K. H. Pure Appl. Chem. 1983, 55, 1689. 9 D¨otz, K. H.; Fischer, H.; Hofmann, P.; Kreissl, F. R.; Schubert, U.; Weiss, K. Transition Metal Carbene Complexes; Verlag Chemie: Deerfield Beach, FL, 1983; p. 153. 10 D¨otz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. 11 Casey, C. P. In Reactive Intermediates; Jones, M.; Moss, R. A., Eds.; Wiley-Interscience: New York, 1985; Vol. 3, pp 109–150. 12 Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S. R. Tetrahedron 1985, 41, 5813. 13 Chan, K.-S.; Peterson, G. A.; Brandvold, T. A.; Faron, K. L.; Challener, C. A.; Hyldahl, C.; Wulff, W. D. J. Organomet. Chem. 1987, 334, 9. 14a D¨otz, K. H. In Organometallics in Organic Synthesis: Aspects of a Modern Interdisciplinary Field; tom Dieck, H. ; de Meijere, A., Eds.; Springer: Berlin, 1988; p 85. 14b Schore, N. E. Chem. Rev. 1988, 88, 1081. 15 D¨otz, K. H. In Advances in Metal Carbene Chemistry; NATO ASI Ser., Ser. C, 1989; Vol. 269, p 199. 16 Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, pp 209–393. 17 Harrington, P. J. Transition Metals in Total Synthesis; Wiley: New York, 1990; p 346. 18 D¨otz, K. H. Nouv. J. Chem. 1990, 14, 433. 19 McQuillin, F. J.; Parker, D. G., Stephenson, G. R. Transition Metal Organometallics for Organic Synthesis; Cambridge University Press: Cambridge, 1991. 20 Wulff, W. D. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, p 1065. 21 Mulzer, J.; Altenbach, H.-J.; Braun, M.; Krohn, K.; Reissig, H.-U. Organic Synthesis Highlights; VCH: Weinheim, 1991; p 186. 22 Rudler, H. Chem. Soc. Rev. 1991, 186. 23 Grotjahn, D. B.; D¨otz, K. H. Synlett 1991, 381. 24 Wulff, W. D. In Comprehensive Organometallic Chemistry II ; Abel, E. W., Stone, F. G. H., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, pp 469–576. 25 Harvey, D. F.; Sigano, D. M. Chem. Rev. 1996, 96, 271. 26 Wulff, W. D. Organometallics 1998, 17, 3116. 27 D¨otz, K. H., Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187. 28 Herndon, J. W. Coord. Chem. Rev. 1999, 181, 177. 29 D¨orwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH: New York, 1999. 30 de Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964. 31 Herndon, J. W. Coord. Chem. Rev. 2000, 206–207, 237. 32 Sierra, M. A. Chem. Rev. 2000, 100, 3591. 33 Barluenga, J. Pure Appl. Chem. 2002, 74, 1317. 34 D¨otz, K. H.; Stendel, J. Jr. In Modern Arene Chemistry, Didier, A., Ed.; Wiley-VCH: New York, 2002; pp 250–296. 35 Sola, M.; Duran, M.; Torrent, M. Catalysis by Metal Complexes 2002, 25, 269. 36 Barluenga, J.; Fananas, F. J. Tetrahedron 2000, 56, 4597. 2

THE SYNTHESIS OF PHENOLS AND QUINONES 37

38

39

40

41 42 43 44 45 46 47

48 49 50 51 52 53

54

55 56

57 58 59

60

61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77

78

613

Hegedus, L. S. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 157. Wu, Y.-T.; de Meijere, A. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 21. Minatti, A.; D¨otz, K. H. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 123. Barluenga, J.; Rodriguez, F.; Fananas, F. J.; Florez, J. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer, New York: 2004; p 59. Barluenga, J.; Santamaria, J.; Tomas, M. Chem. Rev. 2004, 104, 2259. Fischer, H.; M¨uhlemeier, J.; M¨arkl, R.; D¨otz, K. H. Chem. Ber. 1982, 115, 1355. Torrent, M.; Duran, M.; Sola, M. Organometallics 1998, 17, 1492. Fischer, H.; Hofmann, P. Organometallics 1999, 18, 2590. Hofmann, P.; H¨ammerle, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 908. Hofmann, P.; H¨ammerle, M.; Unfried, G. Nouv. J. Chem. 1991, 15, 769. Waters, M. L.; Brandvold, T. A.; Isaacs, L.; Wulff, W. D.; Rheingold, A. L. Organometallics 1998, 17, 4298. Gleichmann, M. M.; D¨otz, K. H., Hess, B. A. J. Am. Chem. Soc. 1996, 118, 10551. Torrent, M.; Duran, M.; Sola, M. Chem. Commun. 1998, 999. Torrent, M.; Duran, M.; Sola, M. J. Am. Chem. Soc. 1999, 121, 1309. Herndon, J. W.; Hayford, A. Organometallics 1995, 14, 1556. Waters, M. L., Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. Barluenga, J.; Aznar, F.; Martin, A.; Garcia-Granda, S.; Perez-Carreno, E. J. Am. Chem. Soc. 1994, 116, 11191. Barluenga, J.; Aznar, F.; Gutierrez, I.; Martin, A.; Garcia-Granda, S.; Llorca-Baragano, M. A. J. Am. Chem. Soc. 2000, 122, 1314. Torrent, M.; Sola, M.; Frenking, G. Chem. Rev. 2000, 100, 439. Garrett, K. E.; Sheridan, J. B.; Pourreau, D. B.; Feng, W. C.; Geoffroy, G. L.; Staley, D. L.; Rheingold, A. L. J. Am. Chem. Soc. 1989, 111, 8383. D¨otz, K. H.; F¨ugen-K¨oster, B. Chem. Ber. 1980, 113, 1449. Anderson, B. A.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 8615. Chelain, E.; Parlier, A.; Rudler, H.; Daran, J. C.; Vaissermann, J. J. Organomet. Chem. 1991, 419, C5. Wulff, W. D.; Bax, B. M; Brandvold, T. A.; Chan, K.-S.; Gilbert, A. M.; Hsung, R. P.; Mitchell, J.; Clardy, J. Organometallics 1994, 13, 102. Tang, P.-C.; Wulff, W. D. J. Am. Chem. Soc. 1984, 106, 1132. Bauta, W. E.; Wulff, W. D.; Pavkovic, S. F.; Zaluzec, E. J. J. Org. Chem. 1989, 54, 3249. Foley, H. C.; Strubinger, L. M.; Targos, T. S.; Geoffroy, G. L. J. Am. Chem. Soc. 1983, 105, 3064. Knorr, J. R.; Brown, T. L. Organometallics 1994, 13, 2178. McCallum, J. S.; Kunng, F.-A.; Gilbertson, S. R.; Wulff, W. D. Organometallics 1988, 7, 2346. Waters, M. L.; Bos, M. E.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 6403. Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Soc. 1981, 103, 7677. D¨otz, K. H.; M¨uhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247, 187. Wulff, W. D.: Chan, K.-S.; Tang, P.-C. J. Org. Chem. 1984, 49, 2293. Yamashita, A.; Toy, A. Tetrahedron Lett. 1986, 27, 3471. Brandvold, T. A.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 1645. Chamberlin, S.; Waters, M. L.; Wulff, W. D. J. Am. Chem. Soc. 1994, 116, 3113. D¨otz, K. H.; Szesni, N.; Nieger, M.; N¨attinen, K. J. Organomet. Chem. 2003, 671, 58. Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. Chem. Commun. 1999, 2107. Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525. D¨otz, K. H. J. Organomet. Chem. 1977, 140, 177. Parlier, A.; Rudler, M.; Rudler, H.; Goumont, R.; Daran, J.-C.; Vaissermann, J. Organometallics 1995, 14, 2760. Xu, Y.-C.; Challener, C. A.; Dragisich, V.; Brandvold, T. A.; Peterson, G. A.; Wulff, W. D.; Willard, P. G. J. Am. Chem. Soc. 1989, 111, 7269.

614 79 80 81 82 83 84

85 86 87 88 89

90

91 92 93 94 95 96 97 98 99 100

101

102 103 104 105

106 107 108

109

110 111

112 113 114 115 116 117 118

119 120 121

ORGANIC REACTIONS

Yamashita, A. Tetrahedron Lett. 1986, 27, 5915. Wulff, W. D.; Kaesler, R. W.; Peterson, G. A.; Tang, P. C. J. Am. Chem. Soc. 1985, 107, 1060. Sivavec, T. M.; Katz, T. J. Tetrahedron Lett. 1985, 26, 2159. D¨otz, K. H.; Larbig, H. J. Organomet. Chem. 1991, 405, C38. Wulff, W. D.; Gilbert, A. M.; Hsung, R. P.; Rahm, A. J. Org. Chem. 1995, 60, 4566. Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J. Am. Chem. Soc. 1991, 113, 9293. Katz, T. J.; Lee, S. J. J. Am. Chem. Soc. 1980, 102, 422. Gross, M. F.; Finn, M. G. J. Am. Chem. Soc. 1994, 116, 10921. D¨otz, K. H.; Dietz, R. Chem. Ber. 1977, 110, 1555. Hsung, R. P.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1994, 116, 6449. Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392. Semmelhack, M. F.; Bozell, J. J.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803. Painter, J. E.; Quayle, P.; Patel, P. Tetrahedron Lett. 1995, 36, 8089. Chan, K.-S.; Zhang, H. Synth. Commun. 1995, 25, 635. D¨otz, K. H.; Pruskil, I. Chem. Ber. 1980, 113, 2876. Timko, J. M.; Yamashita, A. Org. Synth. 1992, 71, 72. Chamberlin, S.; Wulff, W. D.; Bax, B. Tetrahedron 1993, 49, 5531. Gilbert, A. M.; Wulff, W. D. J. Am. Chem. Soc. 1994, 116, 7449. D¨otz, K. H.; Stinner, C. Tetrahedron: Asymmetry 1997, 8, 1751. Neidlein, R.; G¨urtler, S.; Krieger, C. Helv. Chim. Acta 1994, 77, 2303. Beddoes, R. L.; King, J. D.; Quayle, P. Tetrahedron Lett. 1995, 36, 3027. Bao, J.; Wulff, W. D.; Fumo, M. J.; Grant, E. B.; Heller, D. P.; Whitcomb, M. C.; Yeung, S.-M. J. Am. Chem. Soc. 1996, 118, 2166. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 258. Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954. Gordon, D. M.; Danishefsky, S. J.; Schulte, G. K. J. Org. Chem. 1992, 57, 7052. D¨otz, K. H.; Dietz, R. Chem. Ber. 1978, 111, 2517. Semmelhack, M. F.; Ho, S.; Cohen, D.; Steigerwald, M.; Lee, M. C.; Lee, G.; Gilbert, A. M.; Wulff, W. D.; Ball, R. G. J. Am. Chem. Soc. 1994, 116, 7108. Chan, K. S.; Ph.D. Dissertation, The University of Chicago, 1986. Wilson, J. W.; Fischer, E. O. J. Organomet. Chem. 1973, 57, C63. Macomber, D. W.; Hung, M. H.; Liang, M.; Verma, A. G.; Madhukar, P. Macromolecules 1988, 21, 1187. Wulff, W. D.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.; Miller, R. A.; Murray, C. K.; Yang, D. C. J. Am. Chem. Soc. 1990, 112, 3642. Chamberlin, S.; Wulff, W. D. J. Org. Chem. 1994, 59, 3047. Hsung, R. P.; Quinn, J. F.; Weisenberg, B. A.; Wulff, W. D.; Yap, G. P. A.; Rheingold, A. L. Chem. Commun. 1997, 615. Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565. Liptak, V. P.; Wulff, W. D. Tetrahedron 2000, 56, 10229. Wulff, W. D.; McCallum, J. S.; Kunng, F.-A. J. Am. Chem. Soc. 1988, 110, 7419. Yamashita, A.; Toy, A.; Scahill, T. A. J. Org. Chem. 1989, 54, 3625. Yamashita, A.; Scahill,T. A.; Toy, A. Tetrahedron Lett. 1985, 26, 2969. D¨otz, K. H.; Gl¨anzer, J. Z. Naturforsch. B: Chem. Sci. 1993, 48, 1595. Kalinin, V. N.; Shilova, O. S.; Petrovskii, P. W.; Kovredov, A. L. Organomet. Chem. (USSR) 1989, 2, 520. Barluenga, J.; Tomas, M.; Lopez-Pelegrin, J. A.; Rubio, E. Tetrahedron Lett. 1997, 38, 3981. Aumann, R.; Yu, Z.; Fr¨olich, R. J. Organomet. Chem. 1997, 549, 311. Peterson, G. A.; Wulff, W. D. Tetrahedron Lett. 1997, 38, 5587.

THE SYNTHESIS OF PHENOLS AND QUINONES 122

123 124 125 126 127 128 129 130 131

132 133 134 135 136

137 138 139 140 141 142 143 144 145 146 147 148

149 150 151 152 153 154 155 156 157 158 159 160 161

162 163

164 165 166

167 168

615

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620 355 356 357 358 359 360 361 362 363

364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380

381 382

383 384 385 386 387 388 389 390 391 392 393 394 395

396

397

398 399 400 401 402

ORGANIC REACTIONS

Beringer, F. M.; Galton, S. A. J. Org. Chem. 1963, 28, 3250. Hauser, F. M.; Mal, D. J. Am. Chem. Soc. 1983, 105, 5688. Liu, Y.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. D¨otz, K. H.; Dietz, R.; von Imhof, A.; Lorenz, H.; Huttner, G. Chem. Ber. 1976, 109, 2033. D¨otz, K. H. Chem. Ber. 1977, 110, 78. Yamashita, A.; Johnson, H. G. U.S. Patent 4,737,519 (1988); Chem. Abstr. 1989, 110, 23565. Wulff, W. D.; Wu, C., Michigan State University, East Lansing, MI, unpublished results. Quast, L.; Nieger, M.; D¨otz, K. H. Organometallics 2000, 19, 2179. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 219. Schneider, K. J.; Neubrand, A.; van Eldik, R.; Fischer, H. Organometallics 1992, 11, 267. D¨otz, K. H.; M¨uhlemeier, J. Angew. Chem., Int. Ed. Engl. 1982, 21, 929. D¨otz, K. H.; Kreiter, C. G. Chem. Ber. 1976, 109, 2026. D¨otz, K. H.; Neugebauer, D. Angew. Chem., Int. Ed. Engl. 1978, 17, 851. Yamashita, A.; Scahill, T. A.; Chidester, C. G. Tetrahedron. Lett. 1985, 26, 1159. Anderson, J. C.; Cran, J. W.; King, N. P. Tetrahedron Lett. 2002, 43, 3849. Kretschik, O.; Nieger, M.; D¨otz, K. H. Organometallics 1996, 15, 3625. Zora, M.; Herndon, J. W. Organometallics 1994, 13, 3370. Zora, M.; Herndon, J. W. J. Org. Chem. 1994, 59, 699. Jiang, M. X.-W.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 5970. D¨otz, K. H.; Pruskil, I.; Schubert, U.; Ackermann, K. Chem. Ber. 1983, 116, 2337. Chan, C.-S.; Mak, C. C.; Chan, K. S. Tetrahedron. Lett. 1993, 34, 5125. Chan, C.-S.; Tse, A. K.-S.; Chan, K. S. J. Org. Chem. 1994, 59, 6084. Peterson, G. A., Ph. D. Thesis, University of Chicago, IL, 1987. Aumann, R.; Hinterding, P. Chem. Ber. 1991, 124, 213. Yamashita, A.; Scahill, T. A. Tetrahedron Lett. 1982, 23, 3765. Caldwell, J. J.; Harrity, J. P. A.; Heron, N. M.; Kerr, W. J.; McKendry, S.; Middlemiss, D. Tetrahedron Lett. 1999, 40, 3481. Yamashita, A.; Timko, J. M.; Watt, W. Tetrahedron Lett. 1988, 29, 2513. Waters, M. L.; Wu, C.; Wulff, W. D., Michigan State University, East Lansing, MI, unpublished results. Hoye, T. R.; Rehberg, G. M. J. Am. Chem. Soc. 1990, 112, 2841. Watanuki, S.; Mori, M. Organometallics 1995, 14, 5054. Harvey, D. F.; Grenzer, E. M.; Gantzel, P. K. J. Am. Chem. Soc. 1994, 116, 6719. Watanuki, S.; Ochifuji, N.; Mori, M. Organometallics 1994, 13, 4129. Watanuki, S.; Ochifuji, N.; Mori, M. Organometallics 1995, 14, 5062. Jahr, H. C.; Nieger, M.; D¨otz, K. H. J. Organometal. Chem. 2002, 641, 185. Neidlein, R.; Rosyk, P. J.; Kramer, W.; Suschitzky, H. Synthesis 1991, 123. Cambie, R. C., Rutledge, P. S.; Tercel, M.; Woodgate, P. D. J. Organomet. Chem. 1986, 315, 171. Huy, N. H. T.; Lefloch, P. J. Organomet. Chem. 1988, 344, 303. Woodgate, P. D.; Sutherland, H. S.; Rickard, C. E. F. J. Organometal. Chem. 2001, 627, 206. Xu, Y.-C., Ph. D. Thesis, The University of Chicago, IL, 1988. Flynn, B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995, 1007. Schirmer, H.; Funke, F. J.; M¨uller, S.; Noltemeyer, M.; Flynn, B. L.; de Meijere, A. Eur. J. Org. Chem. 1999, 2025. Barluenga, J.; Vicente, R.; Lopez, L. A.; Rubio, E.; Tomas, M.; Alvarez-Rua, C. J. Am. Chem. Soc. 2004, 126, 470. Duetsch, M.; Vidoni, S.; Stein, F.; Funke, F.; Noltemeyer, M.; de Meijere, A. J. Chem. Soc., Chem. Commun. 1994, 1679. Milic, J.; Schirmer, H.; Flynn, B. L.; Noltemeyer, M.; de Meijere, A. Synlett 2002, 875. Chan, K. S.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. D¨otz, K. H.; Jakel, C.; Haase, W.-C. J. Organomet. Chem. 2001, 617, 119. Brandvold, T. A.; Wulff, W. D. J. Am. Chem. Soc. 1991, 113, 5459. Aumann, R.; Heinen, H.; Hinterding, P.; Str¨ater, N.; Krebs, B. Chem. Ber. 1991, 124, 1229.

THE SYNTHESIS OF PHENOLS AND QUINONES 403

621

D¨otz, K. H.; F¨ugen-K¨oster, B.; Neugebauer, D. J. Organomet. Chem. 1979, 182, 489. Eastham, S. A.; Herbert, J.; Painter, J. E.; Patel, P.; Quayle, P. Synlett 1998, 61. 405 Wu, Y.-T.; Schirmer, H.; Noltemeyer, M.; de Meijere, A. Eur. J. Org. Chem. 2001, 2501. 406 Challener, C. A.; Wulff, W. D.; Anderson, B. A.; Chamberlin, S.; Faron, K. L.; Kim, O. K.; Murray, C. K.; Xu, Y.-C.; Yang, D. C.; Darling, S. D. J. Am. Chem. Soc. 1993, 115, 1359. 407a Christoffers, J.; D¨otz, K. H. J. Chem. Soc., Chem. Commun. 1993, 1811. 407b Christoffers, J.; D¨otz, K. H. Chem. Ber. 1995, 128, 157. 408 Luo, Y.; Herndon, J. W.; Cervantes-Lee, F. J. Am. Chem. Soc. 2003, 125, 12720. 409 Dotz, K. H. German Patent 3,221,506 (1983). 410 Aumann, R.; Hinterding, P. Chem. Ber. 1992, 125, 2765. 411 Duetsch, M.; Lackmann, R.; Stein, F.; de Meijere, A. Synlett 1991, 5, 324. 412 Flynn, B. L.; Schirmer, H.; Duetsch, M.; de Meijere, A. J. Org. Chem. 2001, 66, 1747. 413 Stein, F.; Duetsch, M.; Lackmann, R.; Noltemeyer, M.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1991, 30, 1658. 414 Flynn, B. L.; Funke, F. J.; Noltemeyer, M.; de Meijere, A. Tetrahedron 1995, 51, 11141. 415 Flynn, B. L.; Silveira, C. C.; de Meijere, A. Synlett 1995, 10, 812. 416 Stein, F.; Duetsch, M.; Noltemeyer, M.; de Meijere, A. Synlett 1993, 7, 486. 417 D¨otz, K. H.; Popall, M.; M¨uller, G.; Ackermann, K. Angew. Chem., Int. Ed. Engl. 1986, 25, 911. 418 D¨otz, K. H.; Popall, M.; M¨uller, G.; Ackermann, K. J. Organomet. Chem. 1990, 383, 93. 419 Faron, K. L.; Wulff, W. D. J. Am. Chem. Soc. 1988, 110, 8727. 420 Barluenga, J.; Aznar, F.; Palomero, M. A. Angew. Chem., Int. Ed. 2000, 39, 4346. 421 Schirmer, H.; Labahn, T.; Flynn, B.; Wu, Y.-T.; de Meijere, A. Synlett 1999, 2004. 422 Schirmer, H.; Duetsch, M.; Stein, F.; Labahn, T.; Knieriem, B.; de Meijere, A. Angew. Chem., Int. Ed. 1999, 38, 1285. 423 Schirmer, H.; Flynn, B. L.; de Meijere, A. Tetrahedron 2000, 56, 4977. 424 Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 329. 425 Janes, E.; Nieger, M.; Saarenketo, P.; D¨otz, K. H. Eur. J. Org. Chem. 2003, 2276. 426 Zora, M.; Gungor, E. U. Tetrahedron Lett. 2001, 42, 4733. 427 Yamashita, A.; Toy, A.; Watt, W.; Muchmore, C. R. Tetrahedron Lett. 1988, 29, 3403. 428 D¨otz, K. H.; Dietz, R.; Neugebauer, D. Chem. Ber. 1979, 112, 1486. 429 Alvarez, C.; Parlier, A.; Rudler, H.; Yefsah, R.; Daran, J. C.; Knobler, C. Organometallics 1989, 8, 2253. 430 D¨otz, K. H. Chem. Ber. 1980, 113, 3597. 431 D¨otz, K. H.; Rau, A. J. Organomet. Chem. 1991, 418, 219. 432 D¨otz, K. H.; Rau, A.; Harms, K. J. Organomet. Chem. 1992, 439, 263. 433 D¨otz, K. H.; Kroll, F.; Harms, K. J. Organomet. Chem. 1993, 459, 169. 434 Aumann, R.; Heinen, H.; Goddard, R.; Kr¨uger, C. Chem. Ber. 1991, 124, 2587. 435 D¨otz, K. H. J. Organomet. Chem. 1976, 118, C13. 436 Aumann, R.; Heinen, H.; Kr¨uger, C.; Betz, P. Chem. Ber. 1990, 123, 599. 437 Lafolle-Bezzenine, S.; Parlier, A.; Rudler, H.; Vaissermann, J.; Daran, J.-C. J. Organomet. Chem. 1998, 567, 83. 438 Bouancheau, C.; Rudler, M.; Chelain, E.; Rudler, H.; Vaissermann, J.; Daran, J.-C. J. Organomet. Chem. 1995, 496, 127. 439 Denise, B.; Parlier, A.; Rudler, H.; Vaissermann, J. J. Organomet. Chem. 1995, 494, 43. 440a Rudler, H.; Parlier, A.; Yefsah, R.; Denise, B.; Daran, J.-C.; Vaissermann, J.; Knobler, C. J. Organomet. Chem. 1988, 358, 245. 440b Rudler, H.; Parlier, A.; Rudler, M.; Vaissermann, J. J. Organomet. Chem. 1998, 567, 101. 441 Bonancheau, C.; Parlier, A.; Rudler, M.; Rudler, H.; Vaissermann, J.; Daran, J.-C. Organometallics 1994, 13, 4708. 442 Rudler, H.; Parlier, A. Goumont, R.; Daran, J.-C.; Vaisserman, J. J. Chem. Soc., Chem. Commun. 1991, 1075. 443 D¨otz, K. H.; Erben, H.-G.; Harms, K. J. Chem. Soc., Chem. Commun. 1989, 692. 444 D¨otz, K. H.; Weber, R. Chem. Ber. 1991, 124, 1635. 404

622 445

ORGANIC REACTIONS

Aumann, R.; Schr¨oder, J.; Heinen, H. Chem. Ber. 1990, 123, 1369. Denise, B.; Dubost, P.; Parlier, A.; Rudler, M.; Rudler, H.; Daran, J. C.; Vaissermann, J.; Delgado, F.; Arevalo, A. R.; Toscano, R. A.; Alvarez, C. J. Organomet. Chem. 1991, 418, 377. 447 Harvey, D. F.; Neil, D. A. Tetrahedron 1993, 49, 2145. 448 Neidlein, R.; G¨urtler, S.; Krieger, C. Synthesis 1995, 11, 1389. 449 Barluenga, J.; Trabanco, A. A.; Florez, J.; Garcia-Granda, S.; Llorca, M.-A. J. Am. Chem. Soc. 1998, 120, 12129. 450 Katz, T. J.; Lee, S. J.; Nair, M.; Savage, E. B. J. Am. Chem. Soc. 1980, 102, 7940. 451 Katz, T. J.; Lee, S. J.; Nair, M. J. Am. Chem. Soc. 1980, 102, 7942. 452 Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737. 453 Brookhart, M.; Humphrey, M. B.; Kratzer, H. J.; Nelson, G. O. J. Am. Chem. Soc. 1980, 102, 7802. 454 Aumann, R.; Trentmann, B.; Kr¨uger, C.; Lutz, F. Chem. Ber. 1991, 124, 2595. 455 Rehman, A.; Schnatter, W. F. K.; Manolache, N. J. Am. Chem. Soc. 1993, 115, 9848. 456 D¨otz, K. H.; Pruskil, I. J. Organomet. Chem. 1977, 132, 115. 457 Hoye, T. R.; Rehberg, G. M. Organometallics 1990, 9, 3014. 458 Wulff, W. D.; Xu, Y.-C. Tetrahedron Lett. 1988, 29, 415. 459 Wang, H.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. 460 Hohmann, F.; Siemoneit, S.; Nieger, M.; Kotila, S.; D¨otz, K. H. Chem. Eur. J. 1997, 3, 853. 461 D¨otz, K. H.; Siemoneit, S.; Hohmann, F.; Nieger, M. J. Organometal. Chem. 1997, 541, 285. 462 Wulff, W. D. In Comprehensive Organometallic Chemistry II ; Abel, E. W., Stone, F. G. H., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, p 509. 463 D¨otz, K. H.; Sch¨afer, T.: Kroll, F.; Harms, K. Angew. Chem., Int. Ed. Engl. 1992, 31, 1236. 464 D¨otz, K. H.; Mittenzwey, S. Eur. J. Org. Chem. 2002, 39. 465 Leese, T.; D¨otz, K. H. Chem. Ber. 1996, 129, 623. 466 Woodgate, P. D.; Sutherland, H. S. J. Organomet. Chem. 2001, 629, 131. 467 Garrett, K. E.; Feng, W. C.; Matsuzaka, H.; Geoffroy, G. L.; Rheingold, A. L. J. Organomet. Chem. 1990, 394, 251. 468 Casey, C. P.; Polichnowski, S. W.; Shusterman, A. J.; Jones, C. R. J. Am. Chem. Soc. 1979, 101, 7282. 469 Fischer, H.; Volkland, H.-P.; Stumpf, R. Anal. Quim. Int. Ed. 1996, 92, 148. 470a Hartbaum, C.; Mauz, E.; Roth, G.; Weissenbach, K.; Fischer, H. Organometallics 1999, 18, 2619. 470b Fischer, H.; Hofmann, J.; Mauz, E. Angew. Chem., Int. Ed. Engl. 1991, 30, 998. 471 D¨otz, K. H.; Dietz, R. J. Organomet. Chem. 1978, 157, C55. 472 Barluenga, J.; Aznar, F.; Barluenga, S.; Fernandez, M.; Martin, A.; Garcia-Granda, S.; PineraNicolas, A. Chem. Eur. J. 1998, 4, 2280. 473 Barluenga, J.; Aznar, F.; Palomero, M. A. Chem. Eur. J. 2002, 8, 4149. 474 Aumann, R.; Fr¨ohlich, R.; Prigge, J.; Meyer, O. Organometallics 1999, 18, 1369. 475 Barluenga, J.; Aznar, F.; Barluenga, S. J. Chem. Soc., Chem. Commun. 1995, 1973. 476 Barluenga, J.; Fernandez-Rodriguez, M. A.; Aguilar, E. Org. Lett. 2002, 4, 3659. 477 Merlic, C. A.; Roberts, W. M. Tetrahedron Lett. 1993, 34, 7379. 478 Barluenga, J.; Lopez, L. A.; Martinez, S.; Tomas, M. Synlett, 1999, 219. 479 Merlic, C. A.; Xu, D.; Khan, S. I. Organometallics 1992, 11, 412. 480 Lian, Y.; Wulff, W. D., Michigan State University, East Lansing, MI, unpublished results. 481 Funke, F.; Duetsch, M.; Stein, F.; Noltemeyer, M.; de Meijere, A. Chem. Ber. 1994, 127, 911. 482 Mathur, P.; Ghosh, S., Sarkar, A.; Rheingold, A. L.; Guzei, I. A. Organometallics 1998, 17, 770. 483 Mathur, P.; Ghosh, S.; Sarkar, A.; Rheingold, A. L.; Guzei, I. A. J. Organomet. Chem. 1998, 566, 159. 484 Mathur, P.; Ghosh, S.; Sarkar, A.; Rheingold, A. L.; Guzei, I. A. Tetrahedron 2000, 56, 4995. 485 Aumann, R.; Heinen, H.; Dartmann, M.; Krebs, B. Chem. Ber. 1991, 124, 2343. 486 Aumann, R.; Jasper, B.; Fr¨ohlich, R. Organometallics 1995, 14, 231. 487 Parlier, A.; Rudler, H.; Platzer, N.; Fontanille, M.; Soum, A. J. Chem. Soc., Dalton Trans. 1987, 1041. 488 Fischer, H.; Schmid, J.; Riede, J. J. Organomet. Chem. 1988, 355, 219. 446

THE SYNTHESIS OF PHENOLS AND QUINONES 489 490

491

492 493 494

623

Fischer, H.; Schmid, J. J. Mol. Catal. 1988, 46, 277. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 354. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 356. Dietz, R.; D¨otz, K. H.; Neugebauer, D. Nouv. J. Chem. 1978, 2, 59. Harvey, D. F.; Lund, K. P.; Neil, D. A. J. Am. Chem. Soc. 1992, 114, 8424. Hoye, T. R.; Rehberg, G. M. Organometallics 1989, 8, 2070.

AUTHOR INDEX, VOLUMES 1-70

Volume number only is designated in this index

Adam, Waldemar, 61, 69 Adams, Joe T., 8 Adkins, Homer, 8 Agenet, Nicolas, 68 Agcr, David J., 38 Albertson, Noel F., 12 Allen, George R., Jr., 20 Angyal, S. J., 8 Antoulinkis, Evan G., 57 Apparu, Marcel, 29 Archer. S., 14 Arseniyadis, Simeon. 31 Aubcrt, Corinnc, 68 Bachmann, W. E., 1,2 Baer. Donald R.. 11 Banfi. Luca. 65 Baudoux, Jerome. 69 Baxter. Ellen W.. 59 Beauchemin, 58 Behr, Lyell C , 6 Behrman. E. J., 35 Bergmann, Ernst D., 10 Berliner, Ernst, 5 Biellmann, Jean-Francois, 27 Birch, Arthur J., 24 Blatchly, J. M., 19 Blatt. A. H.. 1 Blickc, F. F., 1 Block, Eric, 30 Bloom, Steven H., 39 Bloomfield, Jordan J., 15, 23 Bonafoux. Dominique, 56 Boswell, G. A., Jr., 21

Brand, William W., 18 Brewster, James H., 7 Brown, Herbert C , 13 Brown, Weldon G., 6 Bruson, Herman Alexander, 5 Bublitz. Donald E.. 17 Buck, Johannes S.. 4 Bufali, Simone, 68 Buisine, Olivier, 68 Burke, Steven D., 26 Butz. Lewis W., 5 Cahard, Dominique, 69 Caine, Drury, 23 Cairns, Theodore L., 20 Carmack, Marvin. 3 Carpenter, Nancy E., 66 Carreira, Eric M.. 67 Carter. H. E., 3 Cason, James, 4 Castro, Bcrtrand R., 29 Casy. Guy, 62 Chamberlin, A. Richard, 39 Chapdelaine, Marc J.. 38 Charette, Andre" B., 58 Chen, Bang-Chi, 62 Cheng, Chia-Chung. 28 Ciganek, Engelbert, 32, 51, 62 Clark, Robin D., 47 Confalone, Pat N., 36 Cope, Arthur C , 9, 11 Corey, Elias J., 9 Cola, Donald J.. 17 Cowden, Cameron J., 51

Organic Reactions, Vol. 70, Edited by Larry E. Ovemian et al. © 2008 Organic Reactions. Inc. Published by John Wiley & Sons. Inc. 639

640

AUTHOR INDEX. VOLUMES 1-70

Crandall, Jack K., 29 Crich, David, 64 Crimmins, Michael T., 44 Crouch, R. David, 63 Crounse, Nathan N., 5 Daub, Guido II.. 6 Dave, Vinod, 18 Davies, Huw M. L., 57 Davis, Franklin A., 62 Denmark. Scott E., 45 Denny, R. W.. 20 DeLucchi, Ottorino, 40 DeTar, DeLos R, 9 Dickhaut, J., 48 Djerassi, Carl, 6 Donai lima. L. Guy, 11 Drake, Nathan L., 1 DuBois. Adrien S., 5 Ducep, Jean-Bernard, 27 Dunogues, Jacques, 37 Eliel, Ernest L., 7 Emerson, William S., 4 Engel, Robert, 36 England, D. C. 6 Fan, Rulin, 41 Farina, Vittorio, 50 Ferrier. Robert J., 62 Fettes, Alec, 67 Fieser, Louis F., I Fleming, Ian, 37 Folkers, Karl, 6 Fuson. Reynold C, 1 Gadamasctti, Kumar G., 41 Gandon, Vincent, 68 Gawley, Robert E., 35 Geissman, T. A.. 2 Gensler, Walter J.t 6 Giese, B., 48 Gilman, Henry, 6, 8 Ginsburg, David, 10 Gobcl, T., 48 Govindachari, Tuticorin R.. 6 Grieco, Paul A., 26

Grierson, David, 39 Gschwend, Heinz W., 26 Gung, Benjamin W., 64 Gutsche, C. David. 8 Habermas, Karl L., 45 Hageman, Howard A., 7 Hamilton. Cliff S., 2 Hamlin, K. E., 9 Hanford, W. E., 3 Hanson, Robert M., 60 Harris. Constance M., 17 Harris, J. F., Jr., 13 Harris, Thomas M, 17 Hartung, Walter H., 7 Hassan, C. H., 9 Hauser, Charles R., 1,8 Hayakawa, Yoshihiro, 29 Heck, Richard F., 27 Heldt, Walter Z., 11 Heintzelman, Geoffrey R., 65 Henne, Albert L., 2 Hofferberth. John E.. 62 Hoffman, Roger A., 2 Hoiness, Connie M., 20 Holmes. H. L., 4, 9 Houlihan, William J., 16 House. Herbert O., 9 Hudlicky\ MiloS, 35 Hudlicky\ Tom«, 33, 41 Hudson, Boyd E., Jr., 1 Hughes, David L., 42 Huie, E. M., 36 Hulce, Martin, 38 Huyscr, Earl S.. 13 Hyatt. John A., 45 Idacavage. Michael J., 33 Ide, Walter S.. 4 Ingersoll. A. W., 2 Itsuno, Shinichi, 52 Jackson, Ernest L., 2 Jacobs. Thomas L., 5 Jahangir, Alam, 47 Jakka, Kavitha, 69 Johnson. John R., 1 Johnson. Roy A., 63 Johnson, William S.. 2. 6

AUTHOR INDEX, VOLUMES 1-70

Jones. Gurnos. 15, 49. 56 Jones, Reuben G., 6 Jones, Todd K., 45 Jorgenson, Margaret J., 18 Kanai, Motomu, 70 Kappe, C. Oliver, 63 Katsuki, Tsutomu, 48 Kende, Andrew S., 11 Kloetzel, Milton G„ 4 Knochel, Paul, 58 Kobayashi, Shu. 46 Kochi, Jay K., 19 K op pi nil. B., 48 Kornblum, Nathan, 2, 12 Kosolapoff, Gennady M., 6 Kreider, Eunice M.. 18 Krimcn, L. I., 17 Krishnamurthy, Vcnkat, 50 Krow, Grant R., 43 Kuhlmann, Heinrich, 40 Kulicke. K. J.. 48 Kulka, Marshall, 7 Kutchan, Toni M., 33 Kylcr, Keith S., 31

Lane, John F., 3 Leffler, Marl in T., 1 Letavic, Michael A., 66 Lim, Linda B. L.. 64 Link, J. TM 60 Little, R. Daniel, 47 Lipshutz, Bruce 11.. 41 Luzzio, Frederick A., 53 Malacria, Max, 68 McCombie, Stuart W., 66 McElvain, S. M., 4 McKeever, C. H., 1 McLoughlin, J. I., 47 McMurry, John E., 24 McOmie, J. F. W., 19 Maercker. Adalbert, 14 Magerlein, Barney J., 5 Mahajan, Yogesh R., 65 Malek. Jaroslav, 34. 36 Mallory, Clelia W., 30 Mallory, Frank B., 30

Manske, Richard H. F., 7 Marcinow, Zbigniew, 42 Marti, Christianc, 67 Martin, Elmore L., 1 Martin, Victor S., 48 Martin, William B., 14 Masjedizadeh, Mohammad R.. 47 Meigh, Ivona R., 65 Meijer, Egbert W.. 28 Melikyan. G. G., 49 Mikami, Koichi, 46 Miller. Joseph A., 32 Millot, Nicolas, 58 Miotti, Umberto, 40 Mita, Tsuyoshi, 70 Modena, Giorgio, 40 Molander, Gary, 46 Moore, Maurice L., 5 Morgan, Jack F., 2 Moriarty, Robert M.. 54, 57 Morton, John W., Jr., 8 Mosettig, Erich, 4, 8 Mozingo, Ralph, 4 Mukaiyama, Teruaki, 28, 46

Nace, Harold R., 12 Nagata, Wataru, 25 Nakai, Takeshi, 46 Nakamura, Eiichi, 61 Naqvi, Saiyid M., 33 Negishi. Ei-Ichi, 33 Nelke, Janice M.. 23 Nelson, Todd D., 63 Newman, Melvin S., 5 Nickon, A., 20 Nielsen, Arnold T.. 16 Noe. Mark C , 66 Noyori, Ryoji, 29

Ohno, Masaji, 37 Ojima, Iwao, 56 Otsuka, Masami, 37 Overman, Larry E., 66 Owsley, Dennis G, 23 Pappo. Raphael, 10 Paquette. Leo A.. 25. 62 Parham, William E., 13

641

642

AUTHOR INDEX, VOLUMES 1-70

Parmerter, Stanley M., 10 Pasto, Daniel J., 40 Paterson, Ian, 51 Pettit, George R., 12 Phadke, Ragini, 7 Phillips, Robert R., 10 Pierini, Adriana B., 54 Pigge, F. Christopher, 51 Pine, Stanley R, 18,43 Pinnick, Harold W., 38 Porter, H. K., 20 Posner, Gary H., 19, 22 Prakash, Om, 54, 57 Price, Charles C, 3

Rabideau, Peter WM 42 Rabjohn, Norman. 5, 24 Rathke, Michael W., 22 Raulins, N. Rebecca, 22 Raynolds, Peter W., 45 Reed. Josephine W., 41 Reich, Hans J., 44 Reinhold, Tracy L., 44 Reitz, Allen B., 59 Rhoads, Sara Jane, 22 Rickborn, Bruce, 52, 53 Rigby. James H., 49, 51 Rinehart, Kenneth L., Jr., 17 Ripka, W. C, 21 Riva, Renata, 65 Roberts, John D., 12 Rodriguez, Alain L., 58 Rodriguez, Herman R., 26 Roe. Arthur, 5 Rondcstvcdt, Christian S., Jr., 11,24 Rossi, Roberto, 54 Ruh-Polenz. Carmen, 55 Rytina, Anton W., 5 Saha-Moller, Chantu R., 61 Santiago, Ana N., 54 Saner. John C, 3 Schaefer, John P., 15 Schore, Neil E., 40 Schulenberg, J. W., 14 Schweizer, Edward E., 13 Scott, William J., 50

Scribner, R. M.. 21 Seeberger, Peter H., 68 Semmelhack, Martin F., 19 Sengupta, Saumitra, 41 Sethna, Suresh, 7 Shapiro, Robert R, 23 Sharts. Clay M., 12, 21 Sheehan, John C, 9 Sheldon, Roger A., 19 Sheppard, W. A., 21 Shibasaki, Masakatsu. 70 Shirley, David A., 8 Shriner. Ralph L., 1 Simmons, Howard E., 20 Simonoff, Robert, 7 Slowinski, Franck, 68 Smith, Lee Irvin, 1 Smith, Peter A. S., 3. 11 Smithers, Roger, 37 Snow, Sheri L., 66 Spielman, M. A., 3 Spoerri, Paul E., 5 Stacey. F. W., 13 Stadler, Alexander, 63 Stanforth, Stephen P., 49, 56 Stetter, Hermann, 40 Struve, W. S., 1 Suter, C. M.. 3 Swamer, Frederic W., 8 Swern, Daniel, 7

Takai, Kazuhiko, 64 Tarbell. D. Stanley, 2 Taylor, Richard J.K., 62 Taylor, Richard T., 40 Thoma, G., 48 Tidwell, Thomas T., 39 Todd, David. 4 Touster, Oscar, 7 Trach, F., 48 Truce, William E., 9, 18 Trumbull, Elmer R., 11 Tsai, Chung-Ying. 56 Tucker. Charles E., 58 Tullock, C. W., 21 Tzamarioudaki, Maria, 56

Ucmura, Motokazu, 67

AUTHOR INDEX, VOLUMES 1-70

van Leusen, Albert M., 57 van Leusen, Daan, 57 van Tamelen, Eugene E., 12 Vedejs, E., 22 Vladuchick, Susan A., 20 Vorbriiggen, Helmut, 55 Wadsworth, William S., Jr., 25 Walling, Cheves, 13 Wallis, Everett S., 3 Wallquist, Olof, 47 Wang, Chia-Lin L., 34 Warnhoff, E. W., 18 Waters, Marcey L., 70 Watt, David S., 31 Weinreb, Steven M., 65 Weston, Arthur W., 3, 9 Whaley, Wilson M., 6 Wilds, A. L., 2 Wiley, Richard H., 6

Williamson, David H., 24 Wilson, C. V., 9 Wilson, Stephen R., 43 Wolf, Donald E., 6 Wolff, Hans, 3 Wollowitz, Susan, 44 Wood, John L., 3 Wulff, William D., 70 Wynberg, Hans, 28 Yam ago, Shi gem. 61 Yan, Shou-Jen, 28 Yoshioka, Mitsuru, 25 Zaugg. Harold E., 8, 14 Zhao, Cong-Gui, 61,69 Zhou, Ping, 62 Zubkov, Oleg A., 62 Zweifel, George, 13, 32

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Many chapters contain brief discussions of reactions and comparisons of alternative synthetic methods related to the reaction that is the subject of the chapter. These related reactions and alternative methods are not usually listed in this index. In this index, the volume number is in boldface, the chapter number is in ordinary type. Acetoacetic ester condensation, 1, 9 Acetylenes: cotrimerizations of, 68, 1 oxidation by dioxirane, 69, 1 reactions with Fischer carbene complexes, phenol and quinone formation, 70, 2 synthesis of, 5, 1; 23, 3; 32, 2 Acid halides: reactions with esters, 1, 9 reactions with organometallic compounds, 8, 2 α-Acylamino acid mixed anhydrides, 12, 4 α-Acylamino acids, azlactonization of, 3, 5 Acylation: of esters with acid chlorides, 1, 9 intramolecular, to form cyclic ketones, 2, 4; 23, 2 of ketones to form diketones, 8, 3 Acyl fluorides, synthesis of, 21, 1; 34, 2; 35, 3 Acyl hypohalites, reactions of, 9, 5 Acyloins, 4, 4; 15, 1; 23, 2 Alcohols: conversion to fluorides, 21, 1, 2; 34, 2; 35, 3 conversion to olefins, 12, 2 oxidation of, 6, 5; 39, 3; 53, 1

replacement of hydroxy group by nucleophiles, 29, 1; 42, 2 resolution of, 2, 9 Alcohols, synthesis: by allylstannane addition to aldehydes, 64, 1 by base-promoted isomerization of epoxides, 29, 3 by hydroboration, 13, 1 by hydroxylation of ethylenic compounds, 7, 7 by organochromium reagents to carbonyl compounds, 64, 3 by reduction, 6, 10; 8, 1 from organoboranes, 33, 1 Aldehydes, additions of allyl, allenyl, propargyl stannanes, 64, 1 Aldehydes, catalyzed addition to double bonds, 40, 4 Aldehydes, synthesis of, 4, 7; 5, 10; 8, 4, 5; 9, 2; 33, 1 Aldol condensation, 16; 67, 1 catalytic, enantioselective, 67, 1 directed, 28, 3 with boron enolates, 51, 1 Aliphatic fluorides, 2, 2; 21, 1, 2; 34, 2; 35, 3 Alkanes, by reduction of alkyl halides with organochromium reagents, 64, 3 oxidation of, 69, 1

Organic Reactions, Vol. 70, Edited by Larry E. Overman et al.  2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 645

646

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Alkenes: arylation of, 11, 3; 24, 3; 27, 2 asymmetric dihydroxylation, 66, 2 cyclopropanes from, 20, 1 cyclization in intramolecular Heck reactions, 60, 2 from carbonyl compounds with organochromium reagents, 64, 3 dioxirane epoxidation of, 61, 2 epoxidation and hydroxylation of, 7, 7 free-radical additions to, 13, 3, 4 hydroboration of, 13, 1 hydrogenation with homogeneous catalysts, 24, 1 reactions with diazoacetic esters, 18, 3 reactions with nitrones, 36, 1 reduction by alkoxyaluminum hydrides, 34, 1 Alkenes, synthesis: from amines, 11, 5 from aryl and vinyl halides, 27, 2 by Bamford-Stevens reaction, 23, 3 by Claisen and Cope rearrangements, 22, 1 by dehydrocyanation of nitriles, 31 by deoxygenation of vicinal diols, 30, 2 from α-halosulfones, 25, 1; 62, 2 by palladium-catalyzed vinylation, 27, 2 from phosphoryl-stabilized anions, 25, 2 by pyrolysis of xanthates, 12, 2 from silicon-stabilized anions, 38, 1 from tosylhydrazones, 23, 3; 39, 1 by Wittig reaction, 14, 3 Alkene reduction by diimide, 40, 2 Alkenyl- and alkynylaluminum reagents, 32, 2 Alkenyllithiums, formation of, 39, 1 Alkoxyaluminum hydride reductions, 34, 1; 36, 3 Alkoxyphosphonium cations, nucleophilic displacements on, 29, 1 Alkylation: of allylic and benzylic carbanions, 27, 1 with amines and ammonium salts, 7, 3 of aromatic compounds, 3, 1 of esters and nitriles, 9, 4

γ -, of dianions of β-dicarbonyl compounds, 17, 2 of metallic acetylides, 5, 1 of nitrile-stabilized carbanions, 31 with organopalladium complexes, 27, 2 Alkylidenation by titanium-based reagents, 43, 1 Alkylidenesuccinic acids, synthesis and reactions of, 6, 1 Alkylidene triphenylphosphoranes, synthesis and reactions of, 14, 3 Allenylsilanes, electrophilic substitution reactions of, 37, 2 Allylic alcohols, synthesis: from epoxides, 29, 3 by Wittig rearrangement, 46, 2 Allylic and benzylic carbanions, heteroatom-substituted, 27, 1 Allylic hydroperoxides, in photooxygenations, 20, 2 Allylic rearrangements, transformation of glycols into 2,3-unsaturated glycosyl derivatives, 62, 4 Allylic rearrangements, trihaloacetimidate, 66, 1 π-Allylnickel complexes, 19, 2 Allylphenols, synthesis by Claisen rearrangement, 2, 1; 22, 1 Allylsilanes, electrophilic substitution reactions of, 37, 2 Aluminum alkoxides: in Meerwein-Ponndorf-Verley reduction, 2, 5 in Oppenauer oxidation, 6, 5 Amide formation by oxime rearrangement, 35, 1 α-Amidoalkylations at carbon, 14, 2 Amination: of heterocyclic bases by alkali amides, 1, 4 of hydroxy compounds by Bucherer reaction, 1, 5 Amine oxides: Polonovski reaction of, 39, 2 pyrolysis of, 11, 5 Amines: from allylstannane addition to imines, 64, 1

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

oxidation of, 69, 1 synthesis from organoboranes, 33, 1 synthesis by reductive alkylation, 4, 3; 5, 7 synthesis by Zinin reaction, 20, 4 reactions with cyanogen bromide, 7, 4 α-Aminoacid synthesis, via Strecker Reaction, 70, 1 α-Aminoalkylation of activated olefins, 51, 2 Aminophenols from anilines, 35, 2 Anhydrides of aliphatic dibasic acids, Friedel-Crafts reaction with, 5, 5 Anion-assisted sigmatropic rearrangements, 43, 2 Anthracene homologs, synthesis of, 1, 6 Anti-Markownikoff hydration of alkenes, 13, 1 π-Arenechromium tricarbonyls, reaction with nitrile-stabilized carbanions, 31 η6 -(Arene)chromium complexes, 67, 2 Arndt-Eistert reaction, 1, 2 Aromatic aldehydes, synthesis of, 5, 6; 28, 1 Aromatic compounds, chloromethylation of, 1, 3 Aromatic fluorides, synthesis of, 5, 4 Aromatic hydrocarbons, synthesis of, 1, 6; 30, 1 Aromatic substitution by the SRN 1 reaction, 54, 1 Arsinic acids, 2, 10 Arsonic acids, 2, 10 Arylacetic acids, synthesis of, 1, 2; 22, 4 β-Arylacrylic acids, synthesis of, 1, 8 Arylamines, synthesis and reactions of, 1, 5 Arylation: by aryl halides, 27, 2 by diazonium salts, 11, 3; 24, 3 γ -, of dianions of β-dicarbonyl compounds, 17, 2 of nitrile-stabilized carbanions, 31 of alkenes, 11, 3; 24, 3; 27, 2 Arylglyoxals, condensation with aromatic hydrocarbons, 4, 5 Arylsulfonic acids, synthesis of, 3, 4 Aryl halides, homocoupling of, 63, 3

647

Aryl thiocyanates, 3, 6 Asymmetric aldol reactions using boron enolates, 51, 1 Asymmetric cyclopropanation, 57, 1 Asymmetric dihydroxylation, 66, 2 Asymmetric epoxidation, 48, 1; 61, 2 Asymmetric Strecker reaction, 70, 1 Atom transfer preparation of radicals, 48, 2 Aza-Payne rearrangements, 60, 1 Azaphenanthrenes, synthesis by photocyclization, 30, 1 Azides, synthesis and rearrangement of, 3, 9 Azlactones, 3, 5 Baeyer-Villiger reaction, 9, 3; 43, 3 Bamford-Stevens reaction, 23, 3 Barbier Reaction, 58, 2 Bart reaction, 2, 10 Barton fragmentation reaction, 48, 2 B´echamp reaction, 2, 10 Beckmann rearrangement, 11, 1; 35, 1 Benzils, reduction of, 4, 5 Benzoin condensation, 4, 5 Benzoquinones: acetoxylation of, 19, 3 in Nenitzescu reaction, 20, 3 synthesis of, 4, 6 Benzylic carbanions, 27, 1; 67, 2 Biaryls, synthesis of, 2, 6; 63, 3 Bicyclobutanes, from cyclopropenes, 18, 3 Biginelli dihydropyrimidine synthesis, 63, 1 Birch reaction, 23, 1; 42, 1 Bischler-Napieralski reaction, 6, 2 Bis(chloromethyl) ether, 1, 3; 19, warning Borane reduction, chiral, 52, 2 Borohydride reduction, chiral, 52, 2 in reductive amination, 59, 1 Boron enolates, 51, 1 Boyland-Sims oxidation, 35, 2 Bucherer reaction, 1, 5 Cannizzaro reaction, 2, 3 Carbenes, 13, 2; 26, 2; 28, 1 Carbene complexes in phenol and quinone synthesis, 70, 2

648

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Carbenoid cyclopropanation, 57, 1; 58, 1 Carbohydrates, deoxy, synthesis of, 30, 2 Carbo/metallocupration, 41, 2 Carbon-carbon bond formation: by acetoacetic ester condensation, 1, 9 by acyloin condensation, 23, 2 by aldol condensation, 16; 28, 3; 46, 1; 67, 1 by alkylation with amines and ammonium salts, 7, 3 by γ -alkylation and arylation, 17, 2 by allylic and benzylic carbanions, 27, 1 by amidoalkylation, 14, 2 by Cannizzaro reaction, 2, 3 by Claisen rearrangement, 2, 1; 22, 1 by Cope rearrangement, 22, 1 by cyclopropanation reaction, 13, 2; 20, 1 by Darzens condensation, 5, 10 by diazonium salt coupling, 10, 1; 11, 3; 24, 3 by Dieckmann condensation, 15, 1 by Diels-Alder reaction, 4, 1, 2; 5, 3; 32, 1 by free-radical additions to alkenes, 13, 3 by Friedel-Crafts reaction, 3, 1; 5, 5 by Knoevenagel condensation, 15, 2 by Mannich reaction, 1, 10; 7, 3 by Michael addition, 10, 3 by nitrile-stabilized carbanions, 31 by organoboranes and organoborates, 33, 1 by organocopper reagents, 19, 1; 38, 2; 41, 2 by organopalladium complexes, 27, 2 by organozinc reagents, 20, 1 by rearrangement of α-halosulfones, 25, 1; 62, 2 by Reformatsky reaction, 1, 1; 28, 3 by trivalent manganese, 49, 3 by Vilsmeier reaction, 49, 1; 56, 2 by vinylcyclopropane-cyclopentene rearrangement, 33, 2 Carbon-fluorine bond formation, 21, 1; 34, 2; 35, 3; 69, 2 Carbon-halogen bond formation,

by replacement of hydroxy groups, 29, 1 Carbon-heteroatom bond formation: by free-radical chain additions to carbon-carbon multiple bonds, 13, 4 by organoboranes and organoborates, 33, 1 Carbon-nitrogen bond formation, by reductive amination, 59, 1 Carbon-phosphorus bond formation, 36, 2 Carbonyl compounds, addition of organochromium reagents, 64, 3 Carbonyl compounds, α,β-unsaturated: formation by selenoxide elimination, 44, 1 vicinal difunctionalization of, 38, 2 Carbonyl compounds, from nitro compounds, 38, 3 in the Passerini Reaction, 65, 1 oxidation with hypervalent iodine reagents, 54, 2 reductive amination of, 59, 1 Carbonylation as part of intramolecular Heck reaction, 60, 2 Carboxylic acid derivatives, conversion to fluorides, 21, 1, 2; 34, 2; 35, 3 Carboxylic acids: synthesis from organoboranes, 33, 1 reaction with organolithium reagents, 18, 1 Catalytic enantioselective aldol addition, 67, 1 Chapman rearrangement, 14, 1; 18, 2 Chloromethylation of aromatic compounds, 2, 3; 9, warning Cholanthrenes, synthesis of, 1, 6 Chromium reagents, 64, 3; 67, 2 Chugaev reaction, 12, 2 Claisen condensation, 1, 8 Claisen rearrangement, 2, 1; 22, 1 Cleavage: of benzyl-oxygen, benzyl-nitrogen, and benzyl-sulfur bonds, 7, 5 of carbon-carbon bonds by periodic acid, 2, 8 of esters via SN 2-type dealkylation, 24, 2

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

of non-enolizable ketones with sodium amide, 9, 1 in sensitized photooxidation, 20, 2 Clemmensen reduction, 1, 7; 22, 3 Collins reagent, 53, 1 Condensation: acetoacetic ester, 1, 9 acyloin, 4, 4; 23, 2 aldol, 16 benzoin, 4, 5 Biginelli, 63, 1 Claisen, 1, 8 Darzens, 5, 10; 31 Dieckmann, 1, 9; 6, 9; 15, 1 directed aldol, 28, 3 Knoevenagel, 1, 8; 15, 2 Stobbe, 6, 1 Thorpe-Ziegler, 15, 1; 31 Conjugate addition: of hydrogen cyanide, 25, 3 of organocopper reagents, 19, 1; 41, 2 Cope rearrangement, 22, 1; 41, 1; 43, 2 Copper-Grignard complexes, conjugate additions of, 19, 1; 41, 2 Corey-Winter reaction, 30, 2 Coumarins, synthesis of, 7, 1; 20, 3 Coupling reaction of organostannanes, 50, 1 Cuprate reagents, 19, 1; 38, 2; 41, 2 Curtius rearrangement, 3, 7, 9 Cyanation, of N-heteroaromatic compounds, 70, 1 Cyanoborohydride, in reductive aminations, 59, 1 Cyanoethylation, 5, 2 Cyanogen bromide, reactions with tertiary amines, 7, 4 Cyclic ketones, formation by intramolecular acylation, 2, 4; 23, 2 Cyclization: of alkyl dihalides, 19, 2 of aryl-substituted aliphatic acids, acid chlorides, and anhydrides, 2, 4; 23, 2 of α-carbonyl carbenes and carbenoids, 26, 2 cycloheptenones from α-bromoketones, 29, 2 of diesters and dinitriles, 15, 1

649

Fischer indole, 10, 2 intramolecular by acylation, 2, 4 intramolecular by acyloin condensation, 4, 4 intramolecular by Diels-Alder reaction, 32, 1 intramolecular by Heck reaction, 60, 2 intramolecular by Michael reaction, 47, 2 Nazarov, 45, 1 by radical reactions, 48, 2 of stilbenes, 30, 1 tandem cyclization by Heck reaction, 60, 2 Cycloaddition reactions, of cyclenones and quinones, 5, 3 cyclobutanes, synthesis of, 12, 1; 44, 2 cyclotrimerization of acetylenes, 68, 1 Diels-Alder, acetylenes and alkenes, 4, 2 Diels-Alder, imino dienophiles, 65, 2 Diels-Alder, intramolecular, 32, 1 Diels-Alder, maleic anhydride, 4, 1 [4 + 3], 51, 3 of enones, 44, 2 of ketenes, 45, 2 of nitrones and alkenes, 36, 1 Pauson-Khand, 40, 1 photochemical, 44, 2 retro-Diels-Alder reaction, 52, 1; 53, 2 [6 + 4], 49, 2 [3 + 2], 61, 1 Cyclobutanes, synthesis: from nitrile-stabilized carbanions, 31 by thermal cycloaddition reactions, 12, 1 Cycloheptadienes, from divinylcyclopropanes, 41, 1 polyhalo ketones, 29, 2 π-Cyclopentadienyl transition metal carbonyls, 17, 1 Cyclopentenones: annulation, 45, 1 synthesis, 40, 1; 45, 1 Cyclopropane carboxylates, from diazoacetic esters, 18, 3

650

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Cyclopropanes: from α-diazocarbonyl compounds, 26, 2 from metal-catalyzed decomposition of diazo compounds, 57, 1 from nitrile-stabilized carbanions, 31 from tosylhydrazones, 23, 3 from unsaturated compounds, methylene iodide, and zinc-copper couple, 20, 1; 58, 1; 58, 2 Cyclopropenes, synthesis of, 18, 3

Darzens glycidic ester condensation, 5, 10; 31 DAST, 34, 2; 35, 3 Deamination of aromatic primary amines, 2, 7 Debenzylation, 7, 5; 18, 4 Decarboxylation of acids, 9, 5; 19, 4 Dehalogenation of α-haloacyl halides, 3, 3 Dehydrogenation: in synthesis of ketenes, 3, 3 in synthesis of acetylenes, 5, 1 Demjanov reaction, 11, 2 Deoxygenation of vicinal diols, 30, 2 Desoxybenzoins, conversion to benzoins, 4, 5 Dess-Martin Oxidation, 53, 1 Desulfurization: of α-(alkylthio)nitriles, 31 in alkene synthesis, 30, 2 with Raney nickel, 12, 5 Diazo compounds, carbenoids derived from, 57, 1 Diazoacetic esters, reactions with alkenes, alkynes, heterocyclic and aromatic compounds, 18, 3; 26, 2 α-Diazocarbonyl compounds, insertion and addition reactions, 26, 2 Diazomethane: in Arndt-Eistert reaction, 1, 2 reactions with aldehydes and ketones, 8, 8 Diazonium fluoroborates, synthesis and decomposition, 5, 4 Diazonium salts: coupling with aliphatic compounds, 10, 1, 2

in deamination of aromatic primary amines, 2, 7 in Meerwein arylation reaction, 11, 3; 24, 3 in ring closure reactions, 9, 7 in synthesis of biaryls and aryl quinones, 2, 6 Dieckmann condensation, 1, 9; 15, 1 for synthesis of tetrahydrothiophenes, 6, 9 Diels-Alder reaction: intramolecular, 32, 1 retro-Diels-Alder reaction, 52, 1; 53, 2 with alkynyl and alkenyl dienophiles, 4, 2 with cyclenones and quinones, 5, 3 with imines, 65, 2 with maleic anhydride, 4, 1 Dihydrodiols, 63, 2 Dihydropyrimidine synthesis, 63, 1 Dihydroxylation of alkenes, asymmetric, 66, 2 Diimide, 40, 2 Diketones: pyrolysis of diaryl, 1, 6 reduction by acid in organic solvents, 22, 3 synthesis by acylation of ketones, 8, 3 synthesis by alkylation of β-diketone anions, 17, 2 Dimethyl sulfide, in oxidation reactions, 39, 3 Dimethyl sulfoxide, in oxidation reactions, 39, 3 Diols: deoxygenation of, 30, 2 oxidation of, 2, 8 Dioxetanes, 20, 2 Dioxiranes, 61, 2; 69, 1 Dioxygenases, 63, 2 Divinyl-aziridines, -cyclopropanes, -oxiranes, and -thiiranes, rearrangements of, 41, 1 Doebner reaction, 1, 8 Eastwood reaction, 30, 2 Elbs reaction, 1, 6; 35, 2 Electrophilic fluorination, 69, 2 Enamines, reaction with quinones, 20, 3

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

651

Enantioselective aldol reactions, 67, 1 Ene reaction, in photosensitized oxygenation, 20, 2 Enolates: Fluorination of, 69, 2 α-Hydroxylation of, 62, 1 in directed aldol reactions, 28, 3; 46, 1; 51, 1 Enone cycloadditions, 44, 2 Enzymatic reduction, 52, 2 Enzymatic resolution, 37, 1 Epoxidation: of alkenes, 61, 2 of allylic alcohols, 48, 1 with organic peracids, 7, 7 Epoxide isomerizations, 29, 3 Epoxide formation, 61, 2 migration, 60, 1 Esters: acylation with acid chlorides, 1, 9 alkylation of, 9, 4 alkylidenation of, 43, 1 cleavage via SN 2-type dealkylation, 24, 2 dimerization, 23, 2 glycidic, synthesis of, 5, 10 hydrolysis, catalyzed by pig liver esterase, 37, 1 β-hydroxy, synthesis of, 1, 1; 22, 4 β-keto, synthesis of, 15, 1 reaction with organolithium reagents, 18, 1 reduction of, 8, 1 synthesis from diazoacetic esters, 18, 3 synthesis by Mitsunobu reaction, 42, 2 Ethers, synthesis by Mitsunobu reaction, 42, 2 Exhaustive methylation, Hofmann, 11, 5

Gattermann aldehyde synthesis, 9, 2 Gattermann-Koch reaction, 5, 6 Germanes, addition to alkenes and alkynes, 13, 4 Glycals, fluorination of, 69, 2 transformation in glycosyl derivatives, 62, 4 Glycosides, synthesis of, 64, 2 Glycosylating Agents, 68, 2 Glycosylation on polymer supports, 68, 2 Glycosylation, with sulfoxides and sulfinates, 64, 2 Glycidic esters, synthesis and reactions of, 5, 10 Gomberg-Bachmann reaction, 2, 6; 9, 7 Grundmann synthesis of aldehydes, 8, 5

Favorskii rearrangement, 11, 4 Ferrocenes, 17, 1 Fischer carbene complexes, 70, 2 Fischer indole cyclization, 10, 2 Fluorinating agents, electrophilic, 69, 2 Fluorination of aliphatic compounds, 2, 2; 21, 1, 2; 34, 2; 35, 3; 69, 2 of carbonyl compounds, 69, 2 of heterocycles, 69, 2

Halides, displacement reactions of, 22, 2; 27, 2 Halide-metal exchange, 58, 2 Halides, synthesis: from alcohols, 34, 2 by chloromethylation, 1, 3 from organoboranes, 33, 1 from primary and secondary alcohols, 29, 1

Fluorination: by DAST, 35, 3 by N-F reagents, 69, 2 by sulfur tetrafluoride, 21, 1; 34, 2 Formylation: by hydroformylation, 56, 1 of alkylphenols, 28, 1 of aromatic hydrocarbons, 5, 6 of aromatic compounds, 49, 1 of non-aromatic compounds, 56, 2 Free radical additions: to alkenes and alkynes to form carbon-heteroatom bonds, 13, 4 to alkenes to form carbon-carbon bonds, 13, 3 Freidel-Crafts catalysts, in nucleoside synthesis, 55, 1 Friedel-Crafts reaction, 2, 4; 3, 1; 5, 5; 18, 1 Friedl¨ander synthesis of quinolines, 28, 2 Fries reaction, 1, 11

652

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Haller-Bauer reaction, 9, 1 Halocarbenes, synthesis and reactions of, 13, 2 Halocyclopropanes, reactions of, 13, 2 Halogen-metal interconversion reactions, 6, 7 α-Haloketones, rearrangement of, 11, 4 α-Halosulfones, synthesis and reactions of, 25, 1; 62, 2 Heck reaction, intramolecular, 60, 2 Helicenes, synthesis by photocyclization, 30, 1 Heterocyclic aromatic systems, lithiation of, 26, 1 Heterocyclic bases, amination of, 1, 4 in nucleosides, 55, 1 Heterodienophiles, 53, 2 Hilbert-Johnson method, 55, 1 Hoesch reaction, 5, 9 Hofmann elimination reaction, 11, 5; 18, 4 Hofmann reaction of amides, 3, 7, 9 Homocouplings mediated by Cu, Ni, and Pd, 63, 3 Homogeneous hydrogenation catalysts, 24, 1 Hunsdiecker reaction, 9, 5; 19, 4 Hydration of alkenes, dienes, and alkynes, 13, 1 Hydrazoic acid, reactions and generation of, 3, 8 Hydroboration, 13, 1 Hydrocyanation of conjugated carbonyl compounds, 25, 3 Hydroformylation, 56, 1 Hydrogenation catalysts, homogeneous, 24, 1 Hydrogenation of esters, with copper chromite and Raney nickel, 8, 1 Hydrohalogenation, 13, 4 Hydroxyaldehydes, aromatic, 28, 1 α-Hydroxyalkylation of activated olefins, 51, 2 α-Hydroxyketones: rearrangement, 62, 3 synthesis of, 23, 2 Hydroxylation: of enolates, 62, 1 of ethylenic compounds with organic peracids, 7, 7

Hypervalent iodine reagents, 54, 2; 57, 2 Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2; 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Isocyanides, in the Passerini reaction, 65, 1 sulfonylmethyl, reactions of, 57, 3 Isoquinolines, synthesis of, 6, 2, 3, 4; 20, 3 Jacobsen reaction, 1, 12 Japp-Klingemann reaction, 10, 2 Katsuki-Sharpless epoxidation, 48, 1 Ketene cycloadditions, 45, 2 Ketenes and ketene dimers, synthesis of, 3, 3; 45, 2 α-Ketol rearrangement, 62, 3 Ketones: acylation of, 8, 3 alkylidenation of, 43, 1 Baeyer-Villiger oxidation of, 9, 3; 43, 3 cleavage of non-enolizable, 9, 1 comparison of synthetic methods, 18, 1 conversion to amides, 3, 8; 11, 1 conversion to fluorides, 34, 2; 35, 3 cyclic, synthesis of, 2, 4; 23, 2 cyclization of divinyl ketones, 45, 1 synthesis from acid chlorides and organo-metallic compounds, 8, 2; 18, 1 synthesis from organoboranes, 33, 1 synthesis from α,β-unsaturated carbonyl compounds and metals in liquid ammonia, 23, 1 reaction with diazomethane, 8, 8 reduction to aliphatic compounds, 4, 8 reduction by alkoxyaluminum hydrides, 34, 1

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

reduction in anhydrous organic solvents, 22, 3 synthesis from organolithium reagents and carboxylic acids, 18, 1 synthesis by oxidation of alcohols, 6, 5; 39, 3 Kindler modification of Willgerodt reaction, 3, 2 Knoevenagel condensation, 1, 8; 15, 2; 57, 3 Koch-Haaf reaction, 17, 3 Kornblum oxidation, 39, 3 Kostaneki synthesis of chromanes, flavones, and isoflavones, 8, 3 β-Lactams, synthesis of, 9, 6; 26, 2 β-Lactones, synthesis and reactions of, 8, 7 Leuckart reaction, 5, 7 Lithiation: of allylic and benzylic systems, 27, 1 by halogen-metal exchange, 6, 7 heteroatom facilitated, 26, 1; 47, 1 of heterocyclic and olefinic compounds, 26, 1 Lithioorganocuprates, 19, 1; 22, 2; 41, 2 Lithium aluminum hydride reductions, 6, 2 chirally modified, 52, 2 Lossen rearrangement, 3, 7, 9 Mannich reaction, 1, 10; 7, 3 Meerwein arylation reaction, 11, 3; 24, 3 Meerwein-Ponndorf-Verley reduction, 2, 5 Mercury hydride method to prepare radicals, 48, 2 Metalations with organolithium compounds, 8, 6; 26, 1; 27, 1 Methylenation of carbonyl groups, 43, 1 Methylenecyclopropane, in cycloaddition reactions, 61, 1 Methylene-transfer reactions, 18, 3; 20, 1; 58, 1 Michael reaction, 10, 3; 15, 1, 2; 19, 1; 20, 3; 46, 1; 47, 2 Microbiological oxygenations, 63, 2 Mitsunobu reaction, 42, 2 Moffatt oxidation, 39, 3; 53, 1

653

Morita-Baylis-Hillman reaction, 51, 2 Nazarov cyclization, 45, 1 Nef reaction, 38, 3 Nenitzescu reaction, 20, 3 Nitriles: formation from oximes, 35, 2 synthesis from organoboranes, 33, 1 α,β-unsaturated: by elimination of selenoxides, 44, 1 Nitrile-stabilized carbanions: alkylation and arylation of, 31 Nitroamines, 20, 4 Nitro compounds, conversion to carbonyl compounds, 38, 3 Nitro compounds, synthesis of, 12, 3 Nitrone-olefin cycloadditions, 36, 1 Nitrosation, 2, 6; 7, 6 Nucleosides, synthesis of, 55, 1 Olefins, hydroformylation of, 56, 1 Oligomerization of 1,3-dienes, 19, 2 Oligosaccharide synthesis on polymer support, 68, 2 Oppenauer oxidation, 6, 5 Organoboranes: formation of carbon-carbon and carbon-heteroatom bonds from, 33, 1 isomerization and oxidation of, 13, 1 reaction with anions of α-chloronitriles, 31, 1 Organochromium reagents: addition to carbonyl compounds, 64, 3; 67, 2 addition to imines, 67, 2 Organohypervalent iodine reagents, 54, 2; 57, 2 Organometallic compounds: of aluminum, 25, 3 of chromium, 64, 3; 67, 2 of copper, 19, 1; 22, 2; 38, 2; 41, 2 of lithium, 6, 7; 8, 6; 18, 1; 27, 1 of magnesium, zinc, and cadmium, 8, 2; of palladium, 27, 2 of tin, 50, 1; 64, 1 of zinc, 1, 1; 20, 1; 22, 4; 58, 2

654

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Osmium tetroxide asymmetric dihydroxylation, 66, 2 Overman rearrangement of allylic imidates, 66, 1 Oxidation: by dioxiranes, 61, 2; 69, 1 of alcohols and polyhydroxy compounds, 6, 5; 39, 3; 53, 1 of aldehydes and ketones, Baeyer-Villiger reaction, 9, 3; 43, 3 of amines, phenols, aminophenols, diamines, hydroquinones, and halophenols, 4, 6; 35, 2 of enolates and silyl enol ethers, 62, 1 of α-glycols, α-amino alcohols, and polyhydroxy compounds by periodic acid, 2, 8 with hypervalent iodine reagents, 54, 2 of organoboranes, 13, 1 of phenolic compounds, 57, 2 with peracids, 7, 7 by photooxygenation, 20, 2 with selenium dioxide, 5, 8; 24, 4 Oxidative decarboxylation, 19, 4 Oximes, formation by nitrosation, 7, 6 Oxochromium(VI)-amine complexes, 53, 1 Oxo process, 56, 1 Oxygenation of arenes by dioxygenases, 63, 2 Palladium-catalyzed vinylic substitution, 27, 2 Palladium-catalyzed coupling of organostannanes, 50, 1 Palladium intermediates in Heck reactions, 60, 2 Passerini Reaction, 65, 1 Pauson-Khand reaction to prepare cyclopentenones, 40, 1 Payne rearrangement, 60, 1 Pechmann reaction, 7, 1 Peptides, synthesis of, 3, 5; 12, 4 Peracids, epoxidation and hydroxylation with, 7, 7 in Baeyer-Villiger oxidation, 9, 3; 43, 3 Periodic acid oxidation, 2, 8 Perkin reaction, 1, 8 Persulfate oxidation, 35, 2

Peterson olefination, 38, 1 Phenanthrenes, synthesis by photocyclization, 30, 1 Phenols, dihydric from phenols, 35, 2 oxidation of, 57, 2 synthesis from Fischer carbene complexes, 70, 2 Phosphinic acids, synthesis of, 6, 6 Phosphonic acids, synthesis of, 6, 6 Phosphonium salts: halide synthesis, use in, 29, 1 synthesis and reactions of, 14, 3 Phosphorus compounds, addition to carbonyl group, 6, 6; 14, 3; 25, 2; 36, 2 addition reactions at imine carbon, 36, 2 Phosphoryl-stabilized anions, 25, 2 Photochemical cycloadditions, 44, 2 Photocyclization of stilbenes, 30, 1 Photooxygenation of olefins, 20, 2 Photosensitizers, 20, 2 Pictet-Spengler reaction, 6, 3 Pig liver esterase, 37, 1 Polonovski reaction, 39, 2 Polyalkylbenzenes, in Jacobsen reaction, 1, 12 Polycyclic aromatic compounds, synthesis by photocyclization of stilbenes, 30, 1 Polyhalo ketones, reductive dehalogenation of, 29, 2 Pomeranz-Fritsch reaction, 6, 4 Pr´evost reaction, 9, 5 Pschorr synthesis, 2, 6; 9, 7 Pummerer reaction, 40, 3 Pyrazolines, intermediates in diazoacetic ester reactions, 18, 3 Pyridinium chlorochromate, 53, 1 Pyrolysis: of amine oxides, phosphates, and acyl derivatives, 11, 5 of ketones and diketones, 1, 6 for synthesis of ketenes, 3, 3 of xanthates, 12, 2 Quaternary ammonium N-F reagents, 69, 2 salts, rearrangements of, 18, 4

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Quinolines, synthesis of, by Friedl¨ander synthesis, 28, 2 by Skraup synthesis, 7, 2 Quinones: acetoxylation of, 19, 3 diene additions to, 5, 3 synthesis of, 4, 6 synthesis from Fischer carbene complexes, 70, 2 in synthesis of 5-hydroxyindoles, 20, 3

Ramberg-B¨acklund rearrangement, 25, 1; 62, 2 Radical formation and cyclization, 48, 2 Rearrangements: allylic trihaloacetamidate, 66, 1 anion-assisted sigmatropic, 43, 2 Beckmann, 11, 1; 35, 1 Chapman, 14, 1; 18, 2 Claisen, 2, 1; 22, 1 Cope, 22, 1; 41, 1, 43, 2 Curtius, 3, 7, 9 divinylcyclopropane, 41, 1 Favorskii, 11, 4 Lossen, 3, 7, 9 Ramberg-B¨acklund, 25, 1; 62, 2 Smiles, 18, 2 Sommelet-Hauser, 18, 4 Stevens, 18, 4 [2,3] Wittig, 46, 2 vinylcyclopropane-cyclopentene, 33, 2 Reduction: of acid chlorides to aldehydes, 4, 7; 8, 5 of aromatic compounds, 42, 1 of benzils, 4, 5 of ketones, enantioselective, 52, 2 Clemmensen, 1, 7; 22, 3 desulfurization, 12, 5 with diimide, 40, 2 by dissolving metal, 42, 1 by homogeneous hydrogenation catalysts, 24, 1 by hydrogenation of esters with copper chromite and Raney nickel, 8, 1 hydrogenolysis of benzyl groups, 7, 5 by lithium aluminum hydride, 6, 10

655

by Meerwein-Ponndorf-Verley reaction, 2, 5 chiral, 52, 2 by metal alkoxyaluminum hydrides, 34, 1; 36, 3 of mono- and polynitroarenes, 20, 4 of olefins by diimide, 40, 2 of α,β-unsaturated carbonyl compounds, 23, 1 by samarium(II) iodide, 46, 3 by Wolff-Kishner reaction, 4, 8 Reductive alkylation, synthesis of amines, 4, 3; 5, 7 Reductive amination of carbonyl compounds, 59, 1 Reductive cyanation, 57, 3 Reductive desulfurization of thiol esters, 8, 5 Reformatsky reaction, 1, 1; 22, 4 Reimer-Tiemann reaction, 13, 2; 28, 1 Reissert reaction, 70, 1 Resolution of alcohols, 2, 9 Retro-Diels-Alder reaction, 52, 1; 53, 2 Ritter reaction, 17, 3 Rosenmund reaction for synthesis of arsonic acids, 2, 10 Rosenmund reduction, 4, 7 Samarium(II) iodide, 46, 3 Sandmeyer reaction, 2, 7 Schiemann reaction, 5, 4 Schmidt reaction, 3, 8, 9 Selenium dioxide oxidation, 5, 8; 24, 4 Seleno-Pummerer reaction, 40, 3 Selenoxide elimination, 44, 1 Shapiro reaction, 23, 3; 39, 1 Silanes: addition to olefins and acetylenes, 13, 4 electrophilic substitution reactions, 37, 2 oxidation of, 69, 1 Sila-Pummerer reaction, 40, 3 Silyl carbanions, 38, 1 Silyl enol ether, α-hydroxylation, 62, 1 Simmons-Smith reaction, 20, 1; 58, 1 Simonini reaction, 9, 5 Singlet oxygen, 20, 2 Skraup synthesis, 7, 2; 28, 2

656

CHAPTER AND TOPIC INDEX, VOLUMES 1–70

Smiles rearrangement, 18, 2 Sommelet-Hauser rearrangement, 18, 4 SRN 1 reactions of aromatic systems, 54, 1 Sommelet reaction, 8, 4 Stevens rearrangement, 18, 4 Stetter reaction of aldehydes with olefins, 40, 4 Strecker reaction, catalytic asymmetric, 70, 1 Stilbenes, photocyclization of, 30, 1 Stille reaction, 50, 1 Stobbe condensation, 6, 1 Substitution reactions using organocopper reagents, 22, 2; 41, 2 Sugars, synthesis by glycosylation with sulfoxides and sulfinates, 64, 2 Sulfide reduction of nitroarenes, 20, 4 Sulfonation of aromatic hydrocarbons and aryl halides, 3, 4 Swern oxidation, 39, 3; 53, 1 Tetrahydroisoquinolines, synthesis of, 6, 3 Tetrahydrothiophenes, synthesis of, 6, 9 Thia-Payne rearrangement, 60, 1 Thiazoles, synthesis of, 6, 8 Thiele-Winter acetoxylation of quinones, 19, 3 Thiocarbonates, synthesis of, 17, 3 Thiocyanation of aromatic amines, phenols, and polynuclear hydrocarbons, 3, 6 Thiophenes, synthesis of, 6, 9 Thorpe-Ziegler condensation, 15, 1; 31 Tiemann reaction, 3, 9 Tiffeneau-Demjanov reaction, 11, 2 Tin(II) enolates, 46, 1 Tin hydride method to prepare radicals, 48, 2 Tipson-Cohen reaction, 30, 2 Tosylhydrazones, 23, 3; 39, 1 Tosylmethyl isocyanide (TosMIC), 57, 3 Transmetallation reactions, 58, 2 Tricarbonyl(η6 -arene)chromium complexes, 67, 2

Trihaloacetimidate, allylic rearrangements, 66, 1 Trimethylenemethane, [3 + 2] cycloaddition of, 61, 1 Trimerization, co-, acetylenic compounds, 68, 1 Ullmann reaction: homocoupling mediated by Cu, Ni, and Pd, 63, 3 in synthesis of diphenylamines, 14, 1 in synthesis of unsymmetrical biaryls, 2, 6 Unsaturated compounds, synthesis with alkenyl- and alkynylaluminum reagents, 32, 2 Vilsmeier reaction, 49, 1; 56, 2 Vinylcyclopropanes, rearrangement to cyclopentenes, 33, 2 Vinyllithiums, from sulfonylhydrazones, 39, 1 Vinylsilanes, electrophilic substitution reactions of, 37, 2 Vinyl substitution, catalyzed by palladium complexes, 27, 2 von Braun cyanogen bromide reaction, 7, 4 Vorbr¨uggen reaction, 55, 1 Willgerodt reaction, 3, 2 Wittig reaction, 14, 3; 31 [2,3]-Wittig rearrangement, 46, 2 Wolff-Kishner reaction, 4, 8 Xanthates, synthesis and pyrolysis of, 12, 2 Ylides: in Stevens rearrangement, 18, 4 in Wittig reaction, structure and properties, 14, 3 Zinc-copper couple, 20, 1; 58, 1, 2 Zinin reduction of nitroarenes, 20, 4