name reactions homologations€¦ · pinacol rearrangement pummerer rearrangement schmidt...

Name Reactions for Homologations

Part I1

Edited by

Jie Jack Li Bristol-Myers Squibb Company

Foreword by E. J. Corey

Harvard University

@3 WILEY

A JOHN WILEY & SONS, INC., PUBLICATION

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Name Reactions for Homologations Part I1

Name Reactions for Homologations

Part I1

Edited by

Jie Jack Li Bristol-Myers Squibb Company

Foreword by E. J. Corey

Harvard University

@3 WILEY

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright 0 2009 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey. 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 per-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 to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 11 1 River Street, Hoboken, NJ 07030, (201) 748-601 1, fax (201) 748-6008, or online at http://www.wiley.comlgo/permission

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Library of Congress Cataloging-in-Publication Data:

Name reactions for homologations / edited by Jie Jack Li ; foreword by E. J. Corey. v. cm.

Includes index. ISBN 978-0-470-08507-3 (pt. 1 : cloth) -ISBN 978-0-470-46498-4 (pt. 2 : cloth)

1. Organic compounds-Synthesis. 2. Chemical reactions. 3. Chemical tests and reagents I. Li, Jie Jack.

QD262.N363 2009 547 ' .24c22 2008055902

Printed in the United States of America

1 0 9 8 7 6 5 4 3 2 1

http://www.wiley.comlgo/permissionhttp://www.wiley.comhttp://www.copyright.com

V

Dedicated to

Prof. E. J. Corey

On occasion of his eightieth birthday

vi

Foreword

Part of the charm of synthetic organic chemistry derives from the

vastness of the intellectual landscape along several dimensions.

First, there is the almost infinite variety and number of possible target structures that lurk in the darkness waiting to be made.

Then, there is the vast body of organic reactions that serve to

transform one substance into another, now so large in number as to be beyond credibility to a non-chemist. There is the staggering

range of reagents, reaction conditions, catalysts, elements, and

techniques that must be mobilized in order to tame these reactions

for synthetic purposes. Finally, it seems that new information is

being added to that landscape at a rate that exceeds the ability of a

normal person to keep up with it. In such a troubled setting any

author, or group of authors, must be regarded as heroic if through

their efforts, the task of the synthetic chemist is eased.

These two volumes on methods for the extension of carbon

chains by the use of coupling reactions brings to the attention of

practicing synthetic chemists and students of chemistry a wide

array of tools for the synthesis of new and usefbl molecules. It is a

valuable addition to the literature by any measure and surely will

prove its merit in years to come. The new knowledge that arises

with its help will be impressive and of great benefit to humankind.

E. J. Corey October 1,2008

vii

Preface

This book is the fourth volume of the series Comprehensive Name Reactions, an ambitious project conceived by Prof. E. J. Corey of Harvard University in the summer of 2002. Volume 1, Name Reactions in Heterocyclic Chemistry, was published in 2005 and was warmly received by the organic chemistry community. Volume 2, Name Reactions for Functional Group Transformations was published in 2007. After publication of the current Volumes 3 and 4 on homologations in 2009, we plan to roll out Volume 5, Name Reactions on Ring Formation in 2010; and Volume 6, Name Reactions in Heterocyclic Chemistry-2, in 201 1, respectively.

Continuing the traditions of the first two volumes, each name reaction in Volume 4 is also reviewed in seven sections: I . Description; 2. Historical Perspective; 3. Mechanism; 4. Variations and Improvements; 5. Synthetic Utility; 6. Experimental; and 7. References.

I also introduced a symbol [R] to highlight review articles, book chapters, and books dedicated to the respective name reactions.

I have incurred many debts of gratitude to Prof. E. J. Corey. What he once told me - “The desire to learn is the greatest g f t from God’ - has been a true inspiration. Furthermore, it has been my great privilege and a pleasure to work with a collection of stellar contributing authors from both academia and industry. Some of them are world-renowned scholars in the field; some of them have worked intimately with the name reactions that they have reviewed; some of them even discovered the name reactions that they authored in this series. As a consequence, this book truly represents the state-of-the-art for Name Reactions for Homologations.

I welcome your critique.

Jack Li October 1,2008

... Vlll

Contributing authors:

Dr. Nadia M. Ahmad Takeda Cambridge 4 18 Cambridge Science Park Cambridge CB4 OPA United Kingdom

Dr. Marudai Balasubramanian Research informatics Pfizer Global Research & Development Eastern Point Rd Groton, CT 06340

Dr. Marco A. Biamonte Medicinal Chemistry BIOGEN IDEC 5200 Research Place San Diego, CA 92 122

Prof. Sherry Chemler 6 18 Natural Sciences Complex Department of Chemistry University at Buffalo The State University of New York Buffalo, NY 14260-3000

Dr. Daniel P. Christen Transtech Pharma 4 170 Mendenhall Oaks Pkwy, Suite 1 10 High Point, NC 27265

Dr. Timothy T. Curran Chemical Development Vertex Pharmaceuticals 130 Waverly Street Cambridge, MA 02139

Dr. Paul Galatsis Department of Chemistry Pfizer Global Research & Development Eastern Point Rd Groton, CT 06340

Prof. Brian Goess Department of Chemistry Plyler Hall Furman University Greenville, SC 296 13

Prof. Gordon W. Gribble Department of Chemistry 6 128 Burke Laboratory Dartmouth College Hanover, NH 03755

Dr. Paul Humphries Department of Chemistry Pfizer Global Research & Development Eastern Point Rd Groton, CT 06340

Prof. Richard J. Mullins Department of Chemistry Xavier University 3800 Victory Parkway Cincinnati, OH 45207-422 1

Prof. Subbu Perumal School of Chemistry Madurai Kamaraj University Madurai 62502 1, India

ix

Dr. Jeffrey A. Pfefferkom Pfizer Global Research & Development Eastern Point Rd Groton, CT 06340

Dr. Jeremy M. Richter Discovery Chemistry Bristol-Myers Squibb Company 3 11 Pennington-Rocky Hill Road, Pennington, NJ 08534

Prof. Christian M. Rojas Department of Chemistry Barnard College 3009 Broadway New York, NY 10027

Prof. Kevin M. Shea Department of Chemistry Clark Science Center Smith College Northampton, MA 01063

Prof. David R. Williams Department of Chemistry Indiana University 800 East Kirkwood Avenue Bloomington, IN 47405-7 1020

Prof. John P. Wolfe Department of Chemistry University of Michigan 930 N. University Ave. Ann Arbor, MI 48 109

Dr. Yong-Jin Wu Discovery Chemistry Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492

Dr. Ji Zhang Process Research & Development Pharmaceutical Research Institute Bristol-Myers Squibb Princeton, NJ 08543-4000

X

Table of Contents

Foreword Preface Contributing Authors

Chapter 1.

Section 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 1.1.7 1.1.8 1.1.9 1.1.10

Section 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6 1.2.7

Section 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.3.8

Rearrangements

Concerted rearrangement Alder ene reaction Claisen and related rearrangements Cope and related rearrangements Curtius rearrangement Hofmann rearrangement Lossen rearrangement Overman rearrangement [ 1,2]-Wittig rearrangement [2,3]-Wittig rearrangement Wolff rearrangement

Cationic rearrangement Beckmann rearrangement Demj anov rearrangement Meyer-Schuster rearrangement Pinacol rearrangement Pummerer rearrangement Schmidt rearrangement Wagner-Meerwein rearrangement

Anionic rearrangement Benzilic acid rearrangement Brook rearrangement Favorskii rearrangement Grob fragmentation Neber rearrangement Payne rearrangement Smiles rearrangement Stevens rearrangement

vi vii viii

1

2 2 33 88 136 164 200 210 226 24 1 257

2 74 274 293 305 319 334 353 373

395 395 406 43 8 452 464 474 489 516

x1

Chapter 2.

2.1 2.2 2.3 2.4

Chapter 3.

3.1 3.2 3.3 3.4 3.5 3.6

Appendixes

Appendix 1,

Appendix 2,

Appendix 3,

Appendix 4,

Appendix 5,

Asymmetric C-C bond formation

Evans aldol reaction Hajos-Wiechert reaction Keck stereoselective allylation Roush allylboronation

Miscellaneous homologation reactions

Bamford-Stevens reaction Mannich reaction Mitsunobu reaction Parham cyclization Passerini reaction Ugi reaction

53 1

532 554 5 83 613

641

642 653 67 1 749 765 786

Table of Contents for Volume 1 : 807 Name Reactions in Heterocyclic Chemistry Table of Contents for Volume 2: 810 Name Reactions for Functional Group Transformations Table of Contents for Volume 3: 812 Name Reactions for Homologations-I Table of Contents for Volume 5: 814 Name Reactions for Ring Formations Table of Contents for Volume 6: 816 Name Reactions in Heterocyclic Chemistry-11

Subject index 819

Chapter 1. Rearrangements 1

Section 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 1.1.7 1.1.8 1.1.9 1.1.10

Section 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6 1.2.7

Section 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.3.8

Concerted rearrangemen t Alder ene reaction Claisen and related rearrangements Cope and related rearrangements Curtius rearrangement Hofmann rearrangement Lossen rearrangement Overman rearrangement [ 1,2]-Wittig rearrangement [2,3]-Wittig rearrangement Wolff rearrangement

Ca tionic rearrangemen t Beckmann rearrangement Demjanov rearrangement Mey er-S chus ter rearrangement Pinacol rearrangement Pummerer rearrangement Schmidt rearrangement Wagner-Meerwein rearrangement

Anionic rearrangement Benzilic acid rearrangement Brook rearrangement Favorskii rearrangement Grob fragmentation Neber rearrangement Payne rearrangement Smiles rearrangement Stevens rearrangement

2 2 33 88 136 164 200 210 226 24 1 257

274 274 293 305 319 334 353 373

395 395 406 43 8 452 464 474 489 517

2 Name Reactions for Homologations-2

1.1.1 Alder-Ene Reaction

Timothy T. Curran

1.1.1.1 Description

heat, light, ,X LA cat., organo-

Y Y metallic cat., etc. Ene, 1 Enophile, 2

X = CR, 0, N Y = CR, 0, N

+ I l l

Z = H, metal, transferable

group

h -P. I 1 :

R Cyclic TS, 3 Ene-Adduct, 4

The Alder-Ene reaction is the indirect substitution addition of a compound containing a double or triple bond which also has an allylic, transferable group (typically a hydrogen-ene, 1) with another multiple bond containing compound (enophile, 2). The reaction leads to an allylic shift of one double bond and the transfer of the allylically-positioned, transferable group and formation of a new bond.

exo TS endo TS 5 6

In the all carbon and hydrogen instance, the Alder-Ene reaction is considered to be concerted and is thermally allowed based on Woodward- Hoffman rules. Thus, the Alder-Ene reaction is proposed to be a six-electron process, like the Diels-Alder reaction, having transition states (endo and exo) analogous to the Diels-Alder reaction. However, the Alder-Ene reaction is easily modulated by steric effects as secondary electronic stabilizing effects have yet to be clearly identified. For example, Berson reported cis-2-butene reacted with maleic anhydride to provide about a 4:l ratio of endo:exo adducts 5:6, while trans-2-butene provided little selectivity at 43:57 ratio of 5:6. In the reaction of maleic anhydride with trans-2-butene, the exo-TS encounters a steric interaction that the endo-TS does not. Steric effects are


observed for the thermal reaction of cis-2-butene and trans-2-butene with diethyl azodicarboxylate (DEAD) wherein the trans-compound reacts 3.7 times faster. These observations are steric in nature and lack electronic- stabilizing data for the endo-TS in comparison to the Diels-Alder reaction.’’2

Also, as shown in this example and similar to the Diels-Alder reaction, the “normal” or “traditional mode” of reaction is for the lowest unoccupied molecular orbital (LUMO) of the electron-deficient enophile to react with the highest occupied molecular orbital (HOMO) of the electron- rich ene. However, there are some carbon and hydrogen containing systems that have been proposed to proceed via radical or stepwise pathways. For example, allenyl alkynes 7 and 8 were thermally cyclized using PhMe under relatively mild conditions to provide 10 and 11 in good yield. The authors suggested a radical mechanism for this transformation via the fblvene biradical intermediate 9.3

In addition, with the implementation of metals and the use of a variety of enophiles (RCHO, 0 2 , PTAD, RNO, SeOz, R3COR4, benzyne, etc.), there is evidence for many of these reactions to be stepwise and oftentimes very difficult to distinguish concerted reactions from stepwise reactions. The broader definition of a radical, stepwise or concerted process of the Alder-Ene reaction will be utilized here.

1.1.1.2 Historical Perspectiw

Until recently, the Alder-Ene reaction was more underdeveloped than other pericyclic reactions like the Diels-Alder reaction. Alder’s initial 1943 report on the study of the reaction that bears his name, described reactions of maleic anhydride with simple enes using an autoclave and temperatures in excess of 200 0C.4 One of the reasons for the slow development may be attributed to the relatively harsh conditions used to promote the reaction thermally and the lack of high selectivity. While intramolecular reactions served to allow the


temperature for cyclization to be reduced in some instances, the reaction still lacked selectivity as illustrated in the thermal cyclization of P-citronella1 (12) forming isopulegol 13 as the major product.2

12 13 14 15 16

6 0 o/o 20% 1 5% 5% P-citronella1 isopulegol neoisoputegol iso-isopulegol neoiso-isopulegol

By the time of Hoffmann's first review on the subject in 1969, a variety of enophiles had been used including allenes, alkynes, benzyne, diazodicarboxylates, enones and enoates, ketones with and without electron- withdrawing groups (EWG), aldehydes, triazoline-dione (TAD), singlet oxygen ( l 0 2 ) , sulphur trioxide and selenium dioxide. Shortly after Hoffmann's review, a review describing enol formation for the ene component and intramolecular reaction with an enophile (Conia type ene reaction) a~pea red .~ Subsequent to that review, Oppolzer and Snieckus reviewed the intramolecular Alder-Ene reaction.6 They noted energetic differences between the intramolecular and intermolecular Alder-Ene reactions and suggested that the participation of non-activated enophiles in the intramolecular ene process is due to the less negative AS: (-18 to -19 kcal/mol compared to the intermolecular case -36 to 4 5 kcal/mol) which compensates for the higher AHt (31-32 kcal/mol for the intramolecular case and 18-22 kcal/mol for the intermolecular case). As shown, the reaction was typically thermally promoted under relatively harsh conditions, and mixtures of products were oftentimes reported.* The conversion of keto-alkyne 17 into an 85: 15 mixture of 20:21 was reported in high yield at 260 "C via the enol intermediate 18 followed by ene reaction providing 19. Alkene migration provided the two products.

260 OC,

98%

17 18 19

- & + & 20 21


Similar to the Diels-Alder reaction, Lewis acid-catalyzed approaches were applied to intra- and intermolecular ene reactions, which served to diminish the temperatures required to promote the reaction and improved the selectivity. For example, reaction of 2-Me-2-propene with methyl propiolate provided a mixture of 24 and 25 at 220 "C, but proved higher yielding and more regioselective providing exclusively 24 when a Lewis acid was used.'

JjlJo2+Me 24 Meu 25 C02Me Me C02Me - Me 22 23

220 "C, 45% 93 7 AICl3, rt, 61% 100 0

With continued study of a variety of Lewis acids, not only was the selectivity improved but was frequently changed. Yamamoto and co-workers developed bis-phenoxy-methyl aluminum catalysts which proved to change the selectivity and provide high stereoselectivities for the Alder-Ene p r o d ~ c t . ~ In the instance cited, the stereoselectivity was changed due to use of the bulky Lewis acid MABR, 29 which provided mainly tvans-28. In comparison, MeZAlC1 provided predominantly the cis product 27.

26

Me2AICI or MABR, -78 OC

Me,AICI MABR R Yield %. ratio 27:28 Yield %, ratio 27:2f

Me 65, 9:l 82, 1:32

i-Pr 70, 33:l 85, 1:17

Ph 95. 26:l 98, 1:62

-

+ HO "Ja 28

j MABR, 2 9 K I . . . . . . . . . . . . . . . . . . . . . . .

These reactions were, of course, limited to instances in which the enophile could be activated with a Lewis acid. Nevertheless, this was an excellent advancement toward promoting the utility of the Alder-Ene reaction and an asymmetric, Lewis acid-promoted ene reaction was reported by Whitesell using a chiral auxiliary.*


SnCI4, -78 :C &:% 92% OH

0 32, > 99% de

&:


transition metals have successfully been applied to promoting this transformation. An early example of this reaction was catalyzed by palladium at a lower temperature than could be achieved therrnally and provided 41 in good yield."

* PhH, 65 O C * * Bn N 2 (Ph3P)2Pd(OAc)2 BnN 41 70% 40

1.1.1.3 Mechanism

There has been much study and some argument on the mechanism of the Alder-Ene reaction. For carbon and hydrogen substrates, the reaction is typically accepted to be a six-electron, concerted process. For other substrates like oxalates, it has been suggested that the reaction is stepwise in particularly in Lewis acid-catalyzed reactions. Other enophiles like ' 0 2 , TAD or RNO are all suggested to go through a cyclic intermediate (peroxirane or aziridinium intermediate) and be stepwise. For the transition metal Alder-Ene reactions, a mechanism has been proposed and has been sufficient to explain product ratios. Overall, due to the complexity in discerning a particular mechanism which may be operable for certain types of reactants, it has been difficult to develop the Alder-Ene reaction.

Thermally-Promoted Reactions

An early report suggesting a concerted or highly ordered transition state (TS) for the Alder-Ene reaction was described for the reaction of optically enriched 3-Ph-butene 42 and maleic anhydride 43. In this reaction, optical activity was maintained in the product, and the optical rotation suggested a predominance of compound 44. The endo-TS was suggested as the predominate conformation leading to product. l1

Me x/ + 4o 0

210 OC - o-DiCIPh


Further evidence for a highly ordered transition state comes from the observation that entropies of activation (-125 to -170 J/mol.K) are comparable to that of the Diels-Alder reaction or other pericyclic processes. l2 Additionally, high pressure chemistry studied on Alder-Ene reactions with mesoxalate showed a large negative volume of activation (-36 to -48 mL/mol), similar to the Diels-Alder reaction. One would expect the biradical process to be about 10 mL/mol less than the pericyclic process.

A very interesting deuterium labelling study was done by Arnold and co-workers using pinene. l 3 When compound 45 containing 100% OD label was allowed to partially react at 275 "C, it regenerated mono-deuterated p- pinene containing 88% of the mono-deuterated material 46, other thermally rearranged products, and ester 47. Furthermore, reaction of isolated 46 at 165 "C regenerated 45 in a 70:30 0D:OH mixture. This shows a reasonable degree of selectivity for the Alder-Ene reaction. During their study, it was also recognized that the ene reaction of 47 with p-pinene was not dependent on solvent polarity.

COZMe

0 9- I c - 45 - I c. )$+ PhKCOzMe OD:OH, 70:30 46 88% 47

mono-deuterated

Use of azodicarboxylate as an enophile has also been investigated and results suggest that the reaction is not stepwise. On reaction of optically enriched 48 with methyl diazodicarboxylate 49, a mixture of 50 and 51 was obtained. Both 50 and 51 were optically enriched and an isotope effect was observed (kH/kD -3). Additionally, this ratio matches well with the ratio of enantiomers (also -3) and thus the reaction is reported to proceed as a concerted mechanism with 94% transfer of chirality. ',14

PhCl DN-C09Me

48 49 COZMe

50

A 51

The reaction of mesoxolate esters has been studied using both temperature and deuterium studies. While the authors concluded that


reaction of diethyloxomalonate with ally1 benzene showed a temperature- independent isotope effect which supported a cyclic transition state, this has been challenged by others on theoretical grounds.

Conia-type reactions have recently been reported using gold catalysis. l 5 Deuterium labelling experiments showed that the deutero-enol reacts with an Au-alkyne complex, illustrated by 53, to provide the Alder- Ene product 54 with 90% of the D-incorporated syn to the keto-ester.

\,AgOTf (1 mol%) \ CH2CI2, rt

52

Ye 1

Special Case Enophiles

As mentioned, TAD, nitroso and ' 0 2 reactants have been shown to proceed through a 3-membered ring intermediate 55, 56a,b, and 57, These cyclic intermediates and the approach necessary to form them impacts the selectivity of the reaction. While all go through a 3-membered transition state, it has been suggested that the nitroso-Alder-Ene reaction proceeds through an aziridine intermediate 56a converting to a polarized diradical56b. The polarized diradical 56b was suggested to explain the relatively small kinetic isotope effect (KIE), thereby being the rate determining step in the process. Alternatively, others suggested that the aziridine intermediate 56a proved sufficient to explain the observed isotope effects and regioselectivies of the reaction.

6+ b-

aziridine aziridine polarized peroxirane intermediate intermediate biradical intermediate

55 56a 56b 57

Lewis Acid-Promoted Alder-Ene Reaction

The SnCl4-promoted reaction of cis- and trans-2-butene with glyoxalate esters was suggested to be stepwise due to the observation that cis-2-butene


isomerized to trans prior to cyclization. More recently, this was shown in the use of Yb(OTf)3 in TMSOTf.19 While, these conditions are sufficient for the promotion of the Alder-Ene reaction of 58 and tosylimine 59 providing homoallyl-tosylamide 60, deuterium experiments revealed scrambling of the olefinic hydrogens on 61 under slightly more rigorous conditions providing 62.

H 'NTS

Yb(OTf)3, zt.su + JTS TMSOTf A.J../t-B"

Ph CHZC12, THF Ph 58 59 I?, 68% 60

?

Me+ p d Z:E = 1 2:88

Yb(OTf)3, CH(D)3 45'/0-d Ph TMSOTf

H(D) 62

CD3 (CH&l)z, THF

M € ? A

reflux Z:E = 9614 61

2 Computational, H, and 13C isotope effects on the reaction of 2- methyl-2-butene with formaldehyde catalyzed by Et2AlCl support a ste wise mechanism with either the first or second step being rate-limiting! A carbocationic process for the Lewis acid-catalyzed ene reaction may occur when the optimum geometry for a cyclic transition state is not accessible or the cationic intermediate is initially generated by the use of a strong Lewis acid.

Transition Metal- Catalyzed Alder-Ene Reaction

The use of transition metals to catalyze this process has been explored and pioneered by Trost, Oppolzer, Negishi, and others. Trost has proposed mechanisms and published scope and limitations on the reactions in which

After formation of the metallocycle 65, the course of the reaction is dependent upon the comparative, energetic accessibility of Hb in comparison to Ha. If the metallocycle 65 can get into a geometry in which syn elimination can occur, then competition is set-up between the P-hydride abstraction of Ha or Hb. Thus, reductive elimination of 66 or 68 leads to products 67 or 69, respectively. A similar mechanism has been suggested for other metals shown to provide Alder-Ene products.

While the proposed mechanism for the transition-metal catalyzed Alder-Ene reaction is much different than the traditional Alder-Ene reaction, the overall transformation typically does produce an ene-type product.

the selectivity is largely governed by sterics. 10,2 1,22


Metals used to catalyze such a process have been Pd, Pt, Ni, Fe, Co, Ru, Ir, and Rh.

/ Abstraction 4

68 non-ene product 69

ene-product 67

The mechanism of the Alder-Ene reaction is therefore considered to be duplicitous in that both concerted and stepwise processes may be operating in both the thermal and Lewis acid-catalyzed cases depending on the enophile and particular conditions. A concerted process should maximize allylic resonance by turning the axis of the breaking C-H bond parallel to the x-orbitals of the neighbouring alkene. The stepwise process may occur provided the optimum geometry of the TS is not accessible or if an intermediate radical, biradical or cation is formed and properly stabi1izeds2 The transition metal-catalyzed reaction is mechanistically different, while formally providing the Alder-Ene product.

1.1.1.4 Regioselectivity and Stereoselectivity

The regioselectivity of the migrating group of the ene component in the Alder-Ene reaction is dependent upon a few factors: 1) the ability to adopt a proper conformation adequate for the reaction, 2) the steric accessibility of the migrating group, and 3) the electronic nature of the carbon containing the migrating group.

Intramolecular reactions provided the best examples for requiring the proper conformation for a successful Alder-Ene reaction to occur. Oftentimes, a chiral template has been used to induce chirality into the Alder-Ene reaction. Retro-Diels-Alder reaction formed 71, which revealed the enophile, followed by cyclization to 72. Notably, reactions with the E- alkenes were very slow and poor yielding, while the Z-alkenes which underwent reaction via the exo-TS led to product; the E-alkene required the endo-TS. The authors suggested that due to the highly strained endo-TS, the Z-alkenes reacted more smoothly.23


Ph20, reflux - %O retro-ene

R1

70 [CHz] Zor E

71

R

- & 0 H 72

R Ratio of 71 :72 Yield B1 - - Z-(CH2)2CH=CHCH3 H 33:67 74%

.€-(CH2)2CH=CHCH3 H 56:44 43%

Z-(CH2)2CH=CHCH2TMS TMS >1:


Perhydrobenzoxazine 73 was reported as being a chiral auxiliary used to control the stereoselectivity of a thermally induced Alder-Ene reaction. In this instance, both endo- or em-transition states seemed plausible to provide the observed products. Both TS minimize non-bonding steric interactions and were used to explain the selectivity observed.24 Ultimately, 74 was used to prepare cis-3,4-disubstituted pyrrolidines. For the conversion of 73 into 74, it should be noted that the enophile was the rqp-unsaturated amide and that the new C-C bond formed was alpha to the carbonyl. This appeared counter-intuitive for a LUMO enophile controlled reaction.

An intramolecular cyclization of an ene with a Lewis acid-activated carbonyl also took advantage of low-energy conformers to obtain high selectivity in the reaction. The optically-enriched ketones 75 and 77 underwent Lewis acid promoted cyclization via a “chair-chair” transition state, which minimized steric interactions and provided quantitative yield of the optically-enriched alcohols 76 and 78, respectively. In this instance, the OTIPS group served as a conformational anchor to result in the stereoselectivity in the cy~l iza t ion .~~

OTIPS Me2AICI, ___t

‘//OBn CH2C12, rt

75

QTIPS

Me2AICI,

OTBS 76 QTIPS

1

TBSO’ 6 77

L H‘ 78 OTBS

A study conducted with a range of butenes and pentenes with diethyl azodicarboxylate showed that hydrogen on primary carbons was abstracted more readily than secondary and much faster than tertiary hydrogem2 An electron-withdrawing group (EWG) on the carbon with the migrating group diminishes the transferability of the group. The EWG could merely be a heteroatom or a group. Snider published this observation in a study on the reaction of cis-alkenes with formaldehyde and EtAlC12. The observed product ratio was claimed to be due to formation of the carbenium ion furthest from the EWG.26 Notably, the inductive effect drops off as carbons were added for the addition of formaldehyde to alkene 79.


79 80

B Yield% ratio 80:81

OH (1) 43 1oo:o

OAc (1) 59 1oo:o

OH (2) 63 80:20

OAc (2) 64 82: 18

OH (3) 50 67:33

H (3) 75 44~56

Selectivity of Certain Enophiles

HO Y-( CH 2, nR 81

Ene reactions using Me2Si=C(TMS)2, Me2Sn=C(TMS)2, and Me2Ge=C(TMS)2 as enophiles have been reported with the more reactive being sila-ethene. These ene reactions were proposed to be concerted. In all cases, when reacted with propene, a C-Si, C-Sn or C-Ge bond formed, and the carbon bearing the two TMS groups forms a C-H bond.27 Likewise, reaction with Se02 takes place via an Alder-Ene reaction.28

Some Alder-Ene products remain quite reactive; therefore, trapping of the initial product may be required. Alder-Ene reactions of SO2 have been reported with subsequent trapping of the sulfinate ester with an amine to provide sulfonamides. In this case, the TMS group serves as the transferring group, but 83 was not suitable for isolation, and the amide 84 was prepared in good yield for this Conia-type Alder-Ene reaction.29

r 1

SO2 (excess)

82 CH&12,'-78 OC ' 1 83

Et2NH - -20 OC Ph n

U

65% 84


As mentioned in the mechanistic section, TAD, ‘ 0 2 , and RNO reactions have been shown to be special enophiles. Reactions using these enophiles have been well studied and characterized. For example, ‘ 0 2 manifests a “cis-effect,” which is characterized by H-abstraction from the more substituted side of the alkene, forming a 1:l mixture of 86 and 87. Furthermore, the hydrogen removed displays a preference for removal from the lone carbon as shown in structure 88.’6,30 Most of the explanations for the transition state are consistent with the idea that the two allylic hydrogens stabilize the transition state.

Models have been developed to explain the selectivity displayed between which of the two alkyl groups, twix or lone, will undergo H- abstraction in the ‘ 0 2 reaction. Typically, steric effects impact the selectivity unless there is an EWG attached to one of the two cis-allylic carbons.

OOH ~ C H , 5 [v] 4-

H3C CH3

50% 50% 86 87 cis-effect

i H d H lone ~ ; twin twix

____________________. 85

88 ,

I _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ I

Several models of selectivity are shown. Models 89-91 depict the peroxide bond being formed away from the large, sterically encumbering group. When an EWG is attached directly to the alkene (e.g., 92), there is a driving force to form the double bond in conjugation with the EWG. There may be steric interactions to consider as well as electronic repulsion or attraction of the perepoxide with other functionality.

89 1- 92. R = CHO. H

CN, COzH, ~ ’ C02Mer SOPh

YU Y l


Reactions using phenyl or methyl triazolinediones (PTAD or MTAD) have also been rigorously studied. TAD has been shown to have a “gem- preference” for H-abstraction, which is H-abstraction from one of the two geminal carbons which is attached the larger substituent with the new C-N bond formed away from the large substituent. Examples of selectivity for PTAD reactions are shown in structures 93-95. H-abstraction occurred close to the larger substituent with C-N bond formation away from the larger group.16

93 94 95

Of course, there are always exceptions to the rule as reported for the conversion of 96 into 97 using PTAD, in which the only product was 97. The inversion of regioselectivity was rationalized by positive charge build-up in the transition state.

. ... . I \

96 WMS Nitroso compounds and their reaction with alkenes have been very

well characterized. Reactions of aryl or acyl nitroso compounds have demonstrated synthetic utility. Interestingly, reaction of aryl nitroso compounds did not display analogous selectivity to TAD nor ‘ 0 2 but instead displayed a selectivity of its own. Reaction of p-nitro-nitrosobenzene manifested a selectivity for abstraction from the twix group (see 88). An example of this was the conversion of 98 into 100, the only compound reported to form.30

r 1

N Ar\

H 3 C y C H 3 +nL g - M e . H4 /

L I r r A& 6- CH3 02N

name reactions homologations€¦ · pinacol rearrangement pummerer rearrangement schmidt...

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