organic reaction mechanisms · 2013-07-23 · organic reaction mechanisms · 2010 an annual survey...

ORGANIC REACTION MECHANISMS

EDITORA. C. KNIPE

2010

ORGANIC REACTION MECHANISMS · 2010

ORGANIC REACTIONMECHANISMS · 2010An annual survey covering the literature

dated January to December 2010

Edited by

A. C. KnipeUniversity of Ulster

Northern Ireland

An Interscience® Publication

A John Wiley & Sons, Ltd., Publication

This edition first published 2012© 2012 John Wiley & Sons, Ltd

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Contributors

K. K. BANERJI Faculty of Science, National Law University, Mandore,Jodhpur 342304, India

C. T. BEDFORD Department of Chemistry, University College London,20 Gordon Street, London, WC1H 0AJ, UK

M. L. BIRSA Faculty of Chemistry, “Al. I. Cuza” University of Iasi,Bd. Carol I, 11, Iasi 700506, Romania

A. BRANDI Dipartimento di Chimica Organica “U. Schiff”, Univer-sita’ degli Studi di Firenze-Polo Scientifico, Via dellaLastruccia 13 1-50019 Sesto Fiorentino (Fl), Italy

J. M. COXON Department of Chemistry, University of Canterbury,Christchurch, New Zealand

M. R. CRAMPTON Department of Chemistry, University of Durham, SouthRoad, Durham, DH1 3LE, UK

N. DENNIS 3 Camphor Laurel Court, Stretton, Brisbane, Queensland4116, Australia

M. GENSINI Department of Chemistry, Menarini Ricerche S.p.A., ViaSette Santi, 3, 50131 Florence, Italy

E. GRAS Laboratoire de Chimie de Coordination, CNRS, 205Route de Narbonne, 31077 Toulouse Cedex 4, France

A. C. KNIPE Faculty of Life and Health Sciences, University ofUlster, Coleraine, Northern Ireland

P. KOCOVSKY Department of Chemistry, The Joseph Black Building,University of Glasgow, Glasgow G12 8QQ, UK

R. A. McCLELLAND Department of Chemistry, University of Toronto, 80 StGeorge Street, Toronto, Ontario M5S 1A1, Canada

B. A. MURRAY Department of Science, Institute of Technology Tallaght(ITT Dublin), Dublin 24, Ireland

K. C. WESTAWAY Department of Chemistry and Biochemistry, LaurentianUniversity, Sudbury, Ontario P3E 2C6, Canada

v

Preface

The present volume, the forty-sixth in the series, surveys research on organic reactionmechanisms described in the available literature dated 2010. In order to limit the sizeof the volume, it is necessary to exclude or restrict overlap with other publicationswhich review specialist areas (e.g. photochemical reactions, biosynthesis, enzymo-logy, electrochemistry, organometallic chemistry, surface chemistry and heterogeneouscatalysis). In order to minimize duplication, while ensuring a comprehensive coverage,the editor conducts a survey of all relevant literature and allocates publications toappropriate chapters. While a particular reference may be allocated to more than onechapter, it is assumed that readers will be aware of the alternative chapters to whicha borderline topic of interest may have been preferentially assigned.

In view of the considerable interest in application of stereoselective reactions toorganic synthesis, we now provide indication, in the margin, of reactions which occurwith significant diastereomeric or enantiomeric excess (de or ee).

Some changes of authorship will be apparent as Sue Armstrong (Molecular Re-arrangements: Pericyclic) and Bob Coombes (Electrophilic Aromatic Substitution)have found it necessary to step down, having previously made excellent contributionsto ORM for eight and twenty years respectively. Hopefully they will be reassured tofind that their chapters are now in the safe hands of continuing members of the team.

Steps taken to reduce progressively the delay between title year and publicationdate have continued to bear fruit, as evidenced by the publication of recent annualORM volumes at nine-month intervals. Consequently we hope to regain our optimumproduction schedule soon.

I wish to thank the staff of John Wiley & Sons and our expert contributors for theirefforts to ensure that the review standards of this series are sustained, particularlyduring a period of substantial reorganization of production procedures.

A. C. K.

vii

CONTENTS

1. Reactions of Aldehydes and Ketones and their Derivativesby B. A. Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and theirDerivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

3. Oxidation and Reduction by K. K. Banerji . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794. Carbenes and Nitrenes by E. Gras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555. Nucleophilic Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . 1756. Electrophilic Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . 1917. Carbocations by R. A. McClelland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2138. Nucleophilic Aliphatic Substitution by K. C. Westaway . . . . . . . . . . . . . . . . 2299. Carbanions and Electrophilic Aliphatic Substitution by M. L. Birsa . . . 265

10. Elimination Reactions by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28511. Addition Reactions: Polar Addition by P. Kocovsky . . . . . . . . . . . . . . . . . . 29912. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . 36313. Molecular Rearrangements: Part 1. Pericyclic Reactions

by J. M. Coxon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39314. Molecular Rearrangements: Part 2. Other Reactions by A. Brandi

and M. Gensini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

ix

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

B. A. Murray

Department of Science, Institute of Technology Tallaght (ITT Dublin),Dublin, Ireland

Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . 2Reactions of Glucosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Reactions of Ketenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . 5

Synthesis of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5The Mannich Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Addition of Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . 7Other Arylations, Alkenylations, and Allylations of Imines . . . . . . . . . . 8Reduction of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Iminium Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Other Reactions of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Oximes, Hydrazones, and Related Species . . . . . . . . . . . . . . . . . . 13

C−C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . 16Reviews of Organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . 16Asymmetric Aldols Catalysed by Proline and its Derivatives . . . . . . . . . 16Other Asymmetric Aldols . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Mukaiyama and Vinylogous Aldols . . . . . . . . . . . . . . . . . . . . . . 20Other Aldol and Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . 21The Henry (Nitroaldol) Reaction . . . . . . . . . . . . . . . . . . . . . . . 23The Baylis–Hillman Reaction and its Morita-variant . . . . . . . . . . . . . 24Allylation and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . 25The Horner–Wadsworth–Emmons Reaction and Other Olefinations . . . . . 26Alkynylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Benzoin Condensation and Pinacol Coupling . . . . . . . . . . . . . . . . . 27Michael Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Miscellaneous Condensations . . . . . . . . . . . . . . . . . . . . . . . . . 31

Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Addition of Organozincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Arylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Addition of Other Organometallics, Including Grignards . . . . . . . . . . . 35The Wittig Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Hydrocyanation, Cyanosilylation, and Related Additions . . . . . . . . . . . 37Hydrosilylation, Hydrophosphonylation, and Related Reactions . . . . . . . 39

Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 40α-Halogenation, α-Alkylation, and Other α-Substitutions . . . . . . . . . . . 40

Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . 41Regio-, Enantio-, and Diastereo-selective Reduction Reactions . . . . . . . . 41Other Reduction Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Organic Reaction Mechanisms 2010, First Edition. Edited by A. C. Knipe.© 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

1

2 Organic Reaction Mechanisms 2010

Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Atmospheric Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Formation and Reactions of Acetals and Related Species

A series of pyridinium cations with electron-withdrawing substituents on the ringcatalyse acetalization of aldehydes and other protection reactions, such as the forma-tion of dithianes, dithiolanes, dioxanes, and dioxolanes.1 The best catalyst works at0.1 mol%, outperforming a Brønsted acid with a pKa of 2.2.

DFT has been used in the development of a general equation relating the acti-vation energy of an intramolecular proton transfer to r (the distance between thereacting centres) and α (the hydrogen-bonding angle).2 The equation has been appliedto intramolecular general acid catalysis of five of Kirby’s acetals (e.g. 1; X = NH,O). Reaction rates correlate with r2 and sin (180◦ − α); that is, acetals with short r

values and α close to 180◦ (forming a linear hydrogen bond) are more reactive.3

(2)(1) (3)

XN

HOOOMeO

O

Ar

OH

O

CO2RRO2C O OR

Cyclic hemiacetals (2) have been prepared stereoselectively in a 2 : 1 reaction of4-formylbenzoates and aromatic enals (trans-Ar–CH=CH–CHO), using catalysis byN -heterocyclic carbenes (NHCs).4 de©

A dual acid-catalyst system has been employed for enantioselective addition ofalkenyl and aryl boronates to chromene acetals (3).5 The Lewis–Brønsted combination ee©of a lanthanide triflate and a tartaric acid monoamide gives ee up to 97%.

The gas-phase elimination kinetics of several β-substituted acetals have been mea-sured in the range 370–441 ◦C and in the presence of a radical inhibitor.6 Two differentconcerted four-membered transition states are proposed, leading to either the alcoholand vinyl ether (the latter decomposing to alkene and aldehyde) or alkane and alkylester.

Methylenecyclopropylcarbinols such as (4) react with acetals to give 3-oxabicyclo-[3.1.0]hexanes (5); an intramolecular Prins-type mechanism is proposed.7 de©

Iron(III) chloride or bromide has been used to catalyse Prins cyclization/halogenation of alkynyl acetals, using an acetyl halide as halogen source.8

1 Reactions of Aldehydes and Ketones and their Derivatives 3

(5)

OH

HPh OPh

EtO

Ph

(4)

PhCH(OEt)2

Sc(III), cat.

Deacetalization of acetals, R1CH(OR2)2, in the presence of trifluoroacetic acid hasbeen shown to be viable without water.9 Although water is a by-product, alcoholsare not, and a hemiacetal is not an intermediate. Rather, a hemiacetal TFA ester[R1–CH(OR2)–OCOCF3] is formed, followed by carbonyl production with two TFAester byproducts, F3CCO2R2. The latter process renders the reaction irreversible. Thetwo esters are produced at separate points in what is essentially a cascade mechanism.All intermediates have been identified by NMR. The new reaction has been dubbed‘acidolysis’ to distinguish it from the more familiar acid-catalysed hydrolysis.

Reactions of Glucosides

4,6-O-Benzylidene acetals of glycopyranosides (6) have been oxidatively cleavedto the corresponding hydroxy-benzoates (7a/b) using dimethyldioxirane under mildconditions, and in high yield.10 Appropriate choice of the neighbouring protectinggroup gives regioselectivity, with a preponderance of (7a) or (7b) of >99%, as desired.The balance of electronic and steric effects in the best groups – chloroacetyl and TBS(t-butyldimethylsilyl) – is discussed.

(7b)

(6; R = ClCH2CO, TBS)

O

NPhthRO

O

NPhth

OH

BzO

OO

Ph

OMe

O

NPhth

OBz

OHO

O

ClOMe

OMe

O O

acetone/5 °C

(7a)

TBSO

The stereo- and regio-selectivity of Lewis-acid-catalysed reductive ring-opening of4,6-O-benzylidene acetals have been studied by kinetics, including primary and sec-ondary isotope effects, leading to identification of a range of mechanisms in solventsof varying polarity, and in protocols with Brønsted acid additives.11 It is hoped that de©this will lead to new reducing agents, where reactivity and selectivity can be fine-tunedby choice of borane, solvent, Lewis acid, and temperature.


Glycoside hydrolases can give 1017-fold rate enhancements, and estimates of theirdissociation constants from their transition states are as low as 10−22 mol dm−3. Suchaffinity has encouraged mimicry, and a number of criteria have now been advancedto assess whether a natural or man-made glycosidase inhibitor is a true TS mimic.12

A new dicyanohydrin-β-cyclodextrin acts as an artificial glycosidase, hydrolyz-ing aryl glycosides up to 5500 times faster than the uncatalysed reaction.13

Michaelis–Menten parameters are reported and compared with other modifiedcyclodextrins.

An investigation of nucleophilic substitutions of 2-deoxyglycosyl donors indicatesthat the more nucleophilic the oxygen nucleophile used, the less stereo-selective thereaction becomes.14 This erosion of stereo-chemical control is attributed to the rate de©of the stereochemistry-determining step approaching the diffusion limit, when the twofaces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afforda statistical mixture of diastereomers.

Recent advances in understanding mechanisms of chemical O-glycosylation havebeen reviewed.15 pH-rate profiles have been constructed and analysed for glycosylationreactions of a range of aromatic amines.16

Oxime formation from sugars can be slow, but nucleophilic catalysis by aniline(at 100 mM) can increase rates up to 20-fold, and glycosylamine formation has to bewatched.17

A DFT method has been applied to scan the potential energy surface of fura-nosyl oxocarbenium ions.18 The results suggest that the preferred oxocarbenium ion de©conformation is not a consistent predictor of product stereochemistry.

A chiral Brønsted acid, a BINOL-phosphoric acid, activates trichloroacetimidateglycosyl donors with β-selectivity.19

de©An account describes the mechanistic investigations that have led to a fuller under-

ee©standing of the use of the 4,6-O-benzylidene acetal as a control element in glycosy-lation, giving direct access to β-mannopyranosides in high yield and selectivity.20

de©A rhodium(II)-carbene-promoted activation of the anomeric C−H bond of carbohy-

drates has been used to provide a stereospecific entry to α- and β-ketopyranosides.21de©

Three unnatural methyl α-septanosides (8), with the 3- and 5-hydroxyls ax–eq,eq–ax , and eq–eq have been synthesized, and their rates of hydrolysis measured by1H NMR at 50 ◦C in 0.5 mol dm−3 DCl.22 The hydroxyl orientation affects the rate, de©with equatorial being more electron withdrawing than axial. Comparison with ratesfor analogous methyl α-pyranoside structures shows that, while the inherently lessstable seven-membered sugars react about two orders of magnitude faster, the rankordering is the same.

(8)

O

OH

TBSO

OMe

OMeOH

HO


Reactions of Ketenes

Keto-ketenes (R1R2C=C=O) homodimerize to β-lactones (e.g. 9), thereby providingan important way of accessing such compounds. Catalysis by tributylphosphine hasbeen investigated by NMR, and evidence for tetravalent phosphonium enolate inter-mediates (10) is presented: they can be trapped as their TMS ethers or by reactionwith 4-chlorobenzaldehyde (to give a β-lactone). Such enolates may prove useful inother synthetic methodologies. There was no evidence for pentacovalent phosphorusintermediates.23 de©

(10)(9)

OO

R2R1

R2

R1

O−Bu3+P

R1 R2

DFT investigation of Staudinger 2 + 2-cycloaddition of a ketene and an imine,catalysed by NHCs, favour the ‘ketene-first’ mechanism, that is, it is the ketenethat is initially activated by the NHC. This mechanism persists even when varia-tion in the electrophilicity of the imine leads to stereodivergence in the experimen-tal results.24 NHCs also promote the chlorination of unsymmetrically disubstitutedketenes, R1R2C=C=O; the products are typically α-halo esters [R1R2C∗(Cl)–CO2R3]under the conditions employed. With chiral NHCs, modest ees of up to 61% are seen.25

ee©Dimerization and trimerization reactions of thioformaldehyde and dimerization of

thioketene have been studied by computation.26

Formation and Reactions of Nitrogen Derivatives

Synthesis of Imines

The affinities of a wide-ranging array of imines for hydride, proton, and electron havebeen measured by titration colorimetry and by electrochemical methods, in acetoni-trile.27 Thermodynamic ‘characteristic graphs’ are then introduced, linking the energiesof the processes for each imine: each graph is intended to give the ‘molecular ID’ ofthe imine, facilitating prediction of likely reactions and mechanisms thereof.

The mechanism of Schiff base formation between pyridoxal analogues and aldehy-des has been studied by DFT.28

P –N–P ‘pincer’ complexes of ruthenium catalyse a new imine synthesis, from analcohol and an amine, with evolution of hydrogen.29

Formylpyridines react with tris(hydroxymethyl)aminomethane [(HOCH2)3CNH2,‘TRIS’], to give 1,3-oxazolidines (e.g. 11), which can equilibrate with their acyclictautomers, that is, Schiff bases. Anomeric and hydrogen-bonding effects have beenstudied in these systems, including the adduct derived from pyridoxal.30 Oxazolidinessuch as (12) – derived from TRIS and a benzaldehyde – have been prepared and then


(11; Ar = 4-Py; 12; Ar = Ph-X)

(13)

O

HN Ar

HO

HO NH

SN

R1

R2

R3

ring-opened under acetylating conditions. X-ray crystal data and computations indicatea strong endo anomeric effect stabilizing a conformation that leads to regioselectivering opening to give imine (rather than N -acetyloxazolidine). Imine-oxazolidine equi-libria are also reported, and a per-O-acetylated imine, (AcOCH2)3–C−N=CHAr, inthe para-nitro case.31

An alkyl or aryl group, R1, in a 2-iminothiazole (13) can be exchanged with that inan isothiocyanate, R4–N=C=S, in toluene at 105 ◦C.32 The position of equilibriumin this reversible reaction is mainly dependent on the electronic properties of theexchanging groups (i.e. R1 and R4) and has been used to empirically compare theelectrophilicity of various isothiocyanates.

2-Substituted benzimidazoles have been prepared by condensation of various alde-hydes with 1,2-phenylenediamine, using copper(II) triflate catalyst, in refluxing ace-tonitrile.33

The Mannich Reaction

Organocatalytic asymmetric Mannich reactions have been reviewed, focussing on pro- ee©line derivatives,34 as have Mannich preparations of alkyl- and cycloalkyl-amines.35

de©The autocatalysis previously seen in enantioselective Mannich reactions catalysed

ee©by l-proline and related species has been reinvestigated, using both the productsthemselves and close structural mimics.36 de©

The 1-ethyl-3-methylimidazolium salt of (S)-proline acts as an ionic liquid (IL), ee©which gives ‘three 99s’ performance (yield/de/ee) in a one-pot three-component Man-nich reaction.37 The reaction shows excellent chemo- and regio-selectivities, the pre- de©cursors are cheap, the process tolerates moisture, and it can often be conducted at−20 ◦C.

A diastereoselectivity switch has been engineered in the direct Mannich reac-tion of glycine imines, R1O2C−CH2–N=CR2R3, with N -(8-quinolyl)sulfonyl imines ee©(14).38 Steric and electronic tuning of the R groups of the glycine imine switches the de©selectivity from syn-α,β-diamino acids (for benzophenone-type imines) to anti - (forelectron-rich aldimines). An Fe-sulfos-Cu(I) chiral catalyst gives ees of 99% in manycases.

An anti -selective reaction of aldehydes with N -sulfonyl imines exploits hydrogenbonding involving a 4-hydroxypyrrolidine catalyst and an external Brønsted acid.39

de©DFT methods have been used to study diastereoselective reactions of ketimine with

aldehyde, using both l-proline and (S)-1-(2-pyrrolidinylmethyl)pyrrolidine, catalysts ee©that give opposite diastereoselectivities.40

de©Ferrocenyl cation, as its PF6

− salt, catalyses Mannich reaction of benzaldehyde,aniline, and cyclohexanone to give β-aminoketone (15), with some anti -preference,


(15)(14)

N

S

N

O

O

Ar

H

NHPh O

under solvent-free conditions.41 Tests of two-reactant combinations indicate that the de©reaction proceeds initially via imine rather than aldol formation.

Bench-stable α-amido sulfones have been used to generate N -Boc amino-protectedimines, which then undergo in situ Mannich reactions with glycine Schiff-bases,using a cinchonidine–thiourea catalyst, to give α,β-diamino acid derivatives withee/de close to 100%.42 In a similar strategy, a highly diastereo- and enantio-selective

ee©de©

aminocatalytic Mannich reaction of aldehydes with N -carbamoyl imines involves theirgeneration in situ from such α-amido sulfones.43

ee©de©

DFT-calculated ees and des compare well with observed values for anti -Mannichand syn-aldol reactions catalysed by axially chiral amino sulfonamides.44

ee©de©

While chiral phosphoric acids such as 3,3′-disubstituted BINOLs have been knownto catalyse direct Mannich-type reaction of aldimines with 1,3-dicarbonyls, such cata-lysts can be contaminated by group I/II metal cations. Deliberate introduction of suchcations, especially calcium, confirms that the metal salts may be the ‘true’ catalysts,giving higher yields and ees in some cases.45

ee©Enantioselective Mannich reactions of diethyl fluoromalonate with N -Boc aldimines

using chiral bifunctional organocatalysts give (β-aminoalkyl)fluoromalonates in93–97% ee,46 and bifunctional amine–thiourea catalysts derived from rosin give

ee©high ee and de in reaction of lactones with such imines.47

ee©de©

N -Sulfonylcarboxamides of proline catalyse Mannich reaction of cyclic ketoneswith N -protected iminoglyoxylate, with de/ee up to 94/99%. Enamine intermediateshave been examined by DFT.48

ee©de©

The first catalytic, enantioselective vinylogous Mannich reaction of acyclic silyldienolates (17) has been reported. Using protected imines (16), ees up to 98% havebeen achieved (R1 = H), and more highly substituted products (18, R1 = Me) canbe prepared diastereoselectively. A second-generation BINOL-based phosphoric acidcatalyst developed for the process has been studied by NMR, and a crystal structureof the imine-bound catalyst was obtained, shedding light on the facial selectivity ofthe reaction.49

ee©de©

A Yb/K heterobimetallic catalyst and a chiral amide ligand promote nitro-Mannich(aza-Henry) reactions in up to 86% ee.50

ee©Addition of Organometallics

Advances in copper-catalysed enantioselective addition of dialkylzincs to imines havebeen reviewed back to 2000.51 ee©


(18)(17)

R1

OR2

OTBSOR2

O

Ar

NH

R1

Pg

N

HAr

Pg

+

(16)

Nickel(II) and a spiro-chiral phosphine catalyse the three-component coupling ofimines, diethylzinc, and aromatic alkynes with ee up to 98%, and with good chemos-electivity, to give useful allylic amines.52

ee©Diimines (19; R = Ph, 2-pyrrolyl, 2- and 4-pyridinyl, 2,2′-bithiophen-5-yl) have

been prepared from (R,R)-1,2-diaminocyclohexane and aromatic aldehydes.53 Addi- de©tion of organolithiums and allylzinc proceeds in high yield and de (except for the2-pyridine case), giving diamines with four chiral centres. The latter have also beentested as enantioselective catalysts for the Henry reaction.

(19)

N N

RRCl

Ar

NS

But

(20)

O

Quantitative structure–reactivity relationships (QSSR) have been used to examineenantioselectivity in the addition of organolithiums to imines.54

ee©Chiral α-chloro N -t-butanesulfinyl ketimines (20) react with Grignards to give

chiral aziridines with de/ee up to 96/98%; the stereoselectivity is opposite to that foundfor imines without the α-chloro substituents, presumably due to chlorine coordinationof the incoming Grignard.55

ee©de©

The reactions of Grignard reagents with imines have been contrasted for catalyticand stoichiometric amounts of titanium alkoxide reagents.56 The former favours alky-lation, while the latter gives reductive coupling, with distinctive mechanisms for each,as shown by studies using deuterium-labelled substrates.

Chiral phosphinoylimines have been prepared in high yield and good de by additionof Grignards to new P -chirogenic N -phosphinoylimines.57

de©For more references to Grignards and imines, see under ‘Addition of Other

Organometallics, Including Grignards’ below .

Other Arylations, Alkenylations, and Allylations of Imines

Rhodium-diene complexes catalyse arylation of N -tosyl ketimines by addition ofsodium tetraarylborates. Using a chiral diene renders the process highly enantiose-lective.58 ee©


Enantioselective formal alkenylations of imines, catalysed by axially chiral BINAPdicarboxylic acids, have been carried out using vinylogous aza-enamines.59 As the lat- ee©ter can be oxidized to nitriles, the route can allow access to enantiomerically enrichedγ -amino α,β-unsaturated nitriles, and thus to synthetically useful chiral γ -amino acids.

In the triphenylphosphine-catalysed reaction of alkyl propiolates with N -tosylimines, a stable phosphonium-enamine zwitterion (21) of proven importancein the mechanism has been isolated and characterized by X-ray crystallography.60

Deuterium-labelling experiments have identified several hydrogen-specific processes,none of which limit turnover, but they are highly medium dependent.

N

Ar CO2R

Ts PPh3

N

N

OO

N

Ph Ph

NR1 R2

Ar

NS

But

Cl(23)(21) (22)

O

+−

N -protected α-imino esters, for example, Pg-N=CH–CO2Et, have been alkynylatedwith terminal alkenes using copper(I) triflate and a PYBOX ligand (22).61 Surprisingly, ee©excess ligand does not raise the ee, but excess copper does, and a switch in metal-to-ligand ratio alone can reverse the ee. A modest positive non-linear effect wasobserved, and it is suggested that changing the metal-to-ligand stoichiometry mayalter the coordination geometry at copper, and thus the transition state.

Enantioselective addition of terminal alkynes to imines and their derivatives hasbeen reviewed, including in situ examples, that is, three-component reactions of ter-minal alkynes, aldehydes, and amines.62

ee©Chiral phosphinoylimines undergo highly diastereoselective alkynylation with alu-

minium acetylides, but lithium or magnesium alkynes give poor results.63de©

An alkylzinc-mediated enantioselective synthesis of N -tosyl-(E)-(2-en-3-ynyl)-amines has been developed, working well with various N -tosylaldimines.64 ee©

A review covers diastereo- and enantio-selective alkynylation of imines and iminiumions.65

ee©de©

Reduction of Imines

Chiral 1,3-diamines have been accessed by diastereoselective reduction of enantiopureN -t-butanesulfinylketimines (23, prepared from the corresponding diaryl ketone).66

de©The reduction can be 99 : 1 diastereoselective in either direction, depending on sub-strate and conditions. X-ray crystallography of reactants and products and NOESY-NMR studies point to unusual directing effects of the ortho-substituent in controllingthe selectivity.


A chiral phosphoramidite ligand has been used to achieve good enantioselectivityin iridium-promoted hydrogenation of benzophenone N–H imines, Ar–C(=NH)–Ph,affording chiral diarlmethylamines without the need for N -protection.67 Several ortho- ee©substituted substrates gave particularly high ee.

Advances in enantioselective reduction of C=N bonds have been reviewed,focussing on the use of metal-free chiral organocatalysts with Hantzsch esters ashydride source.68

ee©Reductive amination of carbonyl compounds – via transfer hydrogenation of their

imine derivatives – has been achieved with cyclometalated iridium complexes.69ee©

Ammonia–borane (H3N–BH3) has been employed in a mild, metal-free trans-fer hydrogenation of imines.70 A concerted double-hydrogen-transfer mechanism isproposed, backed up by deuterium kinetic isotope effects, Hammett correlations,and ab initio calculations. Hydrogenation of other unsaturated systems is being fol-lowed up.

Iminium Species

Kinetics of the reactions of iminium ions (pre-generated from cinnamaldehyde and sec-ondary amines) with cyclic ketene acetals were studied by UV–visible spectroscopy.71

Second-order rate constants have been used to derive values of the electrophilicityparameter, E (−10 < E < −7), and these have been analysed using a correlationequation, log10k = S(E + N), where S and N are nucleophilicity parameters. Theequation is then found to predict rate constants for reactions of the iminium ions witha range of other species, such as pyrroles, indoles, and sulfur ylides.

The intermediacy of an iminium ion, Me2N+=CH2, in the nitrosative cleavageof triethylamine to N -nitrosodimethylamine (Me2N–NO) has been explored in aDFT study designed to elucidate how carcinogenic N -nitrosamines form from tertiaryamines.72

Reaction of dimethyl sulphate with DMF gives methoxymethylene-N ,N -dimethyliminium salt, Me2N+=CH(OMe) −O4S–Me.73 It acts as an acid promoter ofStaudinger synthesis of 2-azetidinones (β-lactams) from imines and substituted aceticacids. Under base catalysis, the carboxylate is proposed to react with the iminiumsalt to produce an activated ester, which breaks down (again with base catalysis) toyield the corresponding ketene, which is the immediate reactant with the imine.

A review surveys the development and potential of iminium ion catalysis, usingions formed by the condensation of chiral secondary or primary amines with α,β-unsaturated aldehydes or ketones, in a variety of cyclo- and conjugate-addition reac-tions.74

ee©de©

Other Reactions of Imines

Palladium(II) and rhodium(I) catalysts and chiral disphosphane ligands allow additionof phenylboronic acid, and of phenylboroxine, to N -tosylimines, in up to 99% ee.75

ee©Azomethine imines (24) undergo 1,3-dipolar cycloaddition to homoallylic alco-

hols, giving trans-pyrazolidines (25) with excellent regio-, diastereo-, and enantio-selectivities and good yields.76 A tartrate auxiliary and a Grignard in excess complete ee©


(25)

N−

N OH

R

N NOH

O

R

(24)

OH+

the protocol, with generation of the chloromagnesium salt of the homoallylic alcoholbeing essential to the mechanism.

An unexpected reaction of aromatic aldimines (26) with a difluoroenoxysi-lane gives access to 2,2-difluoro-3-hydroxy-1-ones (28) – the Mukaiyama aldol-typeproduct – via an amine (27).77 Zinc triflate promotes the reaction, and 18O-labellingand other experiments suggest that water is required to form the product (28).

(28)

N

Ar1

Ar2

(27)(26)

NH

Ar1

Ar2

Ph

O

F F

OH

Ar1 Ph

O

F F

F

F OTMS

Ph

3,4-Dihydroisoquinoline (29) undergoes aza-Henry reaction with excess nitro-methane at ambient temperature to give the corresponding 1-(nitromethyl)tetrahydro-isoquinoline (30), an unstable species that is trapped by acylation or alkylation,leading to Reissert-like products via an overall one-pot three-component reaction.78

Evidence for reaction via the methyleneazinic acid tautomer of nitromethane (31) ispresented.

(30)(29)

NHN

NO2

OH

NO−

(31)

+

A vinylogous imine intermediate (33), generated in situ from an arylsulfonylindole (32), undergoes enantioselective Michael addition to malonitrile, using a chiralthiourea catalyst, to give useful 3-indolyl derivatives (34).79

ee©DFT has been used to study aziridination of diazoacetate with syn- and anti -imines

in the presence of a chiral bisoxazoline-copper(I) catalyst.80de©

trans-2,3-Disubstituted aziridines (36) have been prepared from N -sulfinylaldimines(37) and 2-(para-tolylsulfinyl)benzyl iodide (35) in high ee/de. Whether the inter-mediates are benzyl halocarbenoids or benzyl carbanions has been examined usingDFT.81

ee©de©

The previously reported reaction of diarylmethyl imines with diazoacetates to givecis-aziridines (using chiral VANOL or VAPOL ligands) has now been complemented


(34)(33)(32)

NH

R1

R2

SO2Tol

NR1

NH

R1

R2R2

CN

CN

base

(35) (36)

R2 H

NS

O

Tol

SO

Tol

I

N

S

(37)

R1

H R2

H

O• •• •

by conversion of diazoacetamides to the corresponding trans-aziridines, again withhigh de, ee, and yield.82

ee©de©

Systematic investigation of aziridination of benzhydryl-type imines, R–CH=N–CHAr2, has been undertaken, varying the imine aryls and using VANOL-and VAPOL-derived chiral boroxinates.83 Typical ees of 96–97% were obtained

ee©de©

using 2,4-dimethyl-3-methoxy as the Ar groups, and for these substrates their highactivity allowed the conventional diazoacetate ester reagent to be replaced by adiazoacetamide, an option that is not really viable for simple benzhydryls (i.e. Ar= Ph). While varying the aryls varies the aziridine products, the latter are easilyconverted to N–H aziridines.

2-Methylazaarenes such as 2,6-lutidine (38) undergo palladium-catalysed benzylicaddition with N -sulfonyl aldimines, showing a powerful C−H activation effectand giving access to heteroarylethylamines (39); a stereoselective version is beingexplored.84

(39)(38)

Ph NTs

NN

Ph

NHTsPd(II)/120 °C

(40)R2

∗∗HN

OOR3

R1

Organocatalytic asymmetric Strecker reactions have been reviewed.85ee©

Chiral BINOLs and amino alcohols have both been used as enantioselective cat-alysts for Strecker reaction of achiral N -phosphinoyl imines with diethylaluminiumcyanide.86

ee©Enantioselective titanium-catalysed cyanation of imines has been carried out rapidly

at room temperature.87ee©


Chiral mono- and di-meric manganese(III) salen complexes catalyse Strecker addi-tion of TMSCN to N -benzylimines at −55 ◦C in the presence of 4-phenylpyridine-N -oxide.88 The dimeric auxiliary is more effective (ee > 99%), and the catalysts are ee©recyclable.

Hydrolysis of the Schiff base, N -salicylidene-meta-chloroaniline, has been studiedfrom pH 3 to 12 at 303 K and also at other temperatures to yield thermodynamicparameters.89

Chiral phosphoric acids catalyse asymmetric peroxidation of imines, R2–CH=N–R1, to give amine-peroxides with the chiral centre between the functional groups(40), using organic hydroperoxides, R3–OOH.90

ee©Recent interest in the intermolecular carbon radical addition to the C=N double

bond of imines, hydrazones, and oxime ethers has been reviewed, including stereos-elective approaches.91

ee©de©

A catalytic asymmetric exo ′-selective [3 + 2] cycloaddition of iminoesters (41) tonitroalkenes yields highly functionalized proline esters (42).92

ee©de©

NH

CO2R2R1

O2N R3R1 N CO2R2

R3NO2

+R3

O

Ph O N

R1

R2

(41)

(42) (43)

For a homocoupling of aromatic imines, see under ‘Benzoin Condensation andPinacol Coupling’ below . For a nucleophilic perfluoroalkylation of imines, see under‘Addition of Organozincs’ below .

Oximes, Hydrazones, and Related Species

FT-ICR mass spectrometry has been used to measure gas-phase acidities of ring-substituted (E)-acetophenone oximes.93 Substituent trends are the same as in DMSOsolution, indicating that solvation stabilization has a consistent effect, but that thereis no specific solvent effect on any particular substituent.

The use of O-substituted hydroxylamines and oximes as electrophilic amino-transferagents has been reviewed.94

2-Isoxazolines have been prepared enantioselectively by conjugate addition ofoximes to α,β-unsaturated aldehydes, with anilinium catalysis.95

ee©(O)-2-(Acyl)vinylketoximes (43) have been made as their (E)-isomers by

regio- and stereo-specific addition of ketoximes (R1R2C=NOH) to acylacetylenes(Ph–C≡C−COR3) under mild conditions (DCM/r.t./10 mol% Ph3P).96 Slow build-upof the (Z)-material over time indicates that the (E)-isomer is a kinetic product.

A gold complex catalyses cyclization of O-propioloyl oximes (44), giving goodyields of 4-benzylideneisoxazol-5(4H )-ones (45) after transfer of the arylidene


(45)(44)

ON

H Ph

O

Ph

NO

O

Ph

H

PhAu(PPh3)NTf2

MeCN/25 °C

(46)

NN

N

NR2

R1

group, but crossover experiments indicate that the arylidene ‘migration’ is in factintermolecular.97

Triphenylphosphine and carbon tetrachloride, together with catalytic DBU andBu4NI, effect oxime ether formation (from oxime and alcohol) in refluxing acetoni-trile.98

Among reports involving Beckmann rearrangement, N -imidoylbenzotriazoles (46)have been prepared in one pot in high yield from ketoximes, R1–C(R2)=NOH, byreaction with mesyl chloride in the presence of a base and subsequent addition ofbenzotriazole.99 A kinetic study of the rearrangement of cyclohexanone oxime toε-caprolactam in aprotic solvents has been carried out, using trifluoroacetic acid ascatalyst.100 Bromodimethylsulfonium bromide (Me2S+Br Br−) catalyses rearrange-ment of ketoximes in refluxing acetonitrile, in the presence of zinc chloride.101 Ratesof rearrangement of cyclohexanone oxime para-toluenesulfonate in eleven solventshave been described by a three-parameter linear correlation involving polarizabil-ity, electrophilicity, and solvent molar volume.102 Rearrangement of cyclododecanoneoxime into ω-laurolactam has been followed by an ‘in situ’ multinuclear solid-stateNMR method, and in a batch reactor process, using IL media.103

NiCl2·6H2O catalyses coupling of aldoximes with amines to give amides; the oximecan be prepared in situ from the corresponding aldehyde. 18O-Labelling studies havebeen used to probe the mechanism: a label in the oxime is not incorporated into theamide.104

The combination of triflic anhydride and a 30% excess of triphenylphosphinedehydrates aldoximes to nitriles at 0 ◦C in high yield in minutes, using 2 equiv. of tri-ethylamine base in DCM. 1H, 13C, 19F, and 31P NMR studies indicate that the reagentcombination equilibrates to a mixture of (Ph3P+) OTf Tf− and (Ph3P+)2O·2Tf−, withthe former acting as oxygen activation and dehydration reagent.105

Indium trichloride catalyses hydration of nitriles to amides: in refluxing toluene,acetaldoxime can be used as a water surrogate.106 The by-product – acetonitrile – isalready known to be required for some amide-to-nitrile protocols.

Reports of oxidative deoximation back to carbonyl include an account of the kineticsof deoximation of a series of oximes of 3-alkyl-2,6-diphenylpiperidin-4-one (47) bypyridinium fluorochromate, which indicate steric crowding as the major influence.107

Rates of deoximation of aldoximes and ketoximes by morpholinium chlorochromatehave been measured in DMSO, showing first-order dependence on both substrate andoxidant; for acetaldoxime, 19 solvents were examined.108 Quinolinium fluorochromatedeoximates ketoximes in aqueous acetic acid, with a first-order dependence on bothsubstrate and oxidant.109 Oximes have also been deoximated by aerial oxidation, using


(49)(47)

Ph NH

(48)

O

R

Ph

N

ON

R1

R2

O

a

R4R3

R2R1

manganese(I) porphyrins as catalysts and benzaldehyde as oxygen acceptor, in tolueneat 50 ◦C. A radical trap stops the reaction, and the presence of a manganese-oxoporphyrin was confirmed by UV–vis spectra. The oximes of 2-nitrobenzaldehyde andpyridine-2-carboxaldehyde gave nitrile product; that is, ‘benzaldehydes’ with electron-withdrawing groups in the ortho-position divert in this way.110

Organoceriums have been added diastereoselectively to chiral aldehyde hydrazonesderived from 1-aminoprolines; resulting hydrazines can be cleaved to give enantiomer-ically enriched amines in protected form.111 The advantages of organoceriums over

ee©de©

Grignards or organolithiums are discussed.Chiral N -amino cyclic carbonate hydrazones (‘ACC’ hydrazones, e.g. (48), with

a rigid carbamate derived from camphor) undergo α-alkylation via deprotonation byLDA.112 DFT has identified the features of the azaenolate intermediate that give rise

ee©de©

to stereoselectivity. The calculations predict higher stereoselectivity than previouslyreported by experiment, and a modified experimental method has now yielded thehigher values.

Indium and a chiral ammonium catalyse allylation of N -benzoylhydrazones togive homoallylic amines in high yield and up to 99% ee, at room temperature inmethanol.113 ee©

Tetrasubstituted alkenes (49) have been accessed by coupling of N -arylsul-fonylhydrazones with aryl halides, using palladium(II) catalysis.114

Arylation of α-chiral ketones has been achieved by converting them to tosylhydra-zones, then cross-coupling them with aryl halides, using palladium(0).115 Enantiopurity ee©is maintained, avoiding the epimerization problems found with many other approaches.

Chiral α-hydrazino acids (50) have been accessed by asymmetric hydrocyanationof hydrazones with TMSCN; an O-silylated BINOL-phosphate formed in situ acts asauxiliary, giving α-hydrazinonitriles in a Strecker-like process, with subsequent acidhydrolysis yielding (50).116

ee©

(51)(50)HO2C R

HNNH2

NH

NO−Ph

PhO

HN

Het

+


A range of α-amido-α-aminonitrones (51) can react to form three classes ofproducts – 1,2,5-oxadiazin-4-ones, amidines, and dibenzo[d,f ][1,3]diazepines – allof which retain the core structure. The products were identified by X-ray crys-tallography, which also pointed out unusual features, such as an exceptionallylong Csp2 –Csp2 single bond (arrowed), up to 1.54 A, and a very high ‘trigonal’angle of 131◦ for Nsp3 –Csp2 –Nsp2 , as well as NH· · ·O and NH· · ·N intramolecularhydrogen-bond-like interactions. These features, together with DFT calculations,have been used to help elucidate the operative mechanisms.117

For oxime formation from carbohydrates, see under ‘Reactions of Glucosides’above.

C−C Bond Formation and Fission: Aldol and Related Reactions

Reviews of Organocatalysts

General reviews include coverage of chemoselectivity in reactions involvingasymmetric aminocatalysis,118 the roots of asymmetric aminocatalysis over the past

ee©century, championing the seminal contributions of Knoevenagel in the 1890s,119

ee©current approaches to improving asymmetric organocatalysts via supramolecularinteractions,120 and recent developments in aldolase-type organocatalytic direct

ee©de©

reactions in water.121

ee©de©

Chiral BINOL-phosphoric acid catalysis has been reviewed,122 as has the emergingee©

field of chiral phosphine oxides as organocatalysts of, for example, reductive aldols.123ee©de©The use of NHC catalysts in aldehyde reactions has been reviewed,124 as has been

the regio- and stereo-chemistry of the aldol, with a survey of methodologies up to thepresent.125 ee©

de©No Barrier Theory and Marcus Theory have been applied to the rates of aldol addi-tion reactions of representative aldehydes and ketones.126 The use of kinetic isotopeeffects in probing the mechanisms of stereoselective reactions has been surveyed (84references).127

ee©Many slow reactions not considered suitable for continuous flow processing tech-

niques are now being reassessed under high-temperature/pressure conditions.128

Asymmetric Aldols Catalysed by Proline and its Derivatives

Reviews of asymmetric aldol reactions include an account of those proceeding viaenamines using organocatalysts,129 their application to total synthesis of natural prod-

ee©de©

ucts in the last 5 years,130 and a survey of direct asymmetric aldols (357 references), ee©which covers both organocatalytic and metal-based catalysts, noting the still low reac-tivity of many of the catalysts developed to date.131

ee©In reports of proline-catalysed aldol reactions, the central role of enamine interme-

diates has been underlined by their direct observation by NMR. E-Configured s-transenamines (52) are detected: in DMSO, EXSY-NMR shows them arising from oxa-zolidinones rather than from iminium-type intermediates. The oxazolidinone-enamineequilibrium is not affected by additional water (in small amounts) or by the amountof catalyst.132 A computational study has compared the enamine (Houk–List) and


(53)(52) (54)

N

R

OH

O

NH HN

O

NH HN

O

NH

EWGR

oxazolidinone (Seebach) mechanisms, with the latter being found to be inadequatefor predicting the stereochemical outcome.133 Another DFT study has focussed on

ee©de©

the scope for oxazolidinone intermediates,134 and this method has also been used to ee©investigate further the enamine mechanism for reactions involving acetone.135 A coher- ee©ent mechanistic rationale has been put forward for differences in kinetic behaviourin enamine reactions such as aldol, amination, and aminoxylation, with a particularfocus on auto-inductive effects and on the catalytic effects of additives.136 DFT has ee©also been used to identify the origin of the enantioselectivity in the aldol reaction ofbenzaldehyde and acetone as catalysed both by proline derivatives and by 2-azetidinecarboxylic acid.137

ee©New prolinamide catalysts of the aldol reaction of para-nitrobenzaldehyde

with acetone have been reported.138 Calix[4]arene-prolinamide organocatalysts ee©give yields/ee/de up to 99/97/70% in direct aldols of aromatic aldehydes withcyclohexanone.139

ee©de©

List’s proline-catalysed stereoselective intramolecular aldols of 1,7-dicarbonyl com-pounds have been studied by DFT, with a polarizable continuum model employed forsolvent effects. The enantioselectivity is found to arise from a key electrostatic contactbetween the forming alkoxide and the proline. The origin of the diastereoselectivityis typically more complex, especially for dialdehydes.140

ee©de©

The application of reaction progress kinetic analysis to the proline-catalysed aldolhas been described.141 ee©

The possible roles of imidazolidinone intermediates or by-products in aldol reactionscatalysed by prolinamides (53; R = H, NO2) has been studied by NMR and X-raycharacterization of these species.142

ee©Four prolinamides (54) have been designed with enhanced acidity (EWG = Ac, Ms,

Tf, and Ts) and the potential for multiple N–H· · ·O hydrogen bonding. The mesylategave the best performance in terms of yield/de/ee in a test aldol: 94/94/>98%, whilethe tosylate may involve an aryl-stacking stabilization of the transition state.143

ee©de©

Two new catalysts (alcohol 55, and the corresponding ketone) have been developedfor direct aldol addition in the presence of water.144 Prepared from trans-4-hydroxy-

ee©de©

l-proline and the steroid isosteviol, the strategy involves a hydrophilic catalytic group(the acid of proline), a lipophilic pocket (the isosteviol skeleton), and an assistingfunctional group (the remote alcohol/ketone). With only 1 mol% loading, yield/de/eeof up to 99/98/99% has been achieved for a cyclohexanone–araldehyde aldol at roomtemperature. Effects of solvent, water, temperature, and substrate structure have beenstudied.


NH OH

O

NH HN

O

SO2

C12H25

O

O

OH

(56)

(55)

Ethylene and propylene carbonate, readily prepared from epoxides and carbondioxide, are effective solvents for proline-catalysed aldols, giving yields/de/ee up to99/100/99%. Choice of carbonate solvent and whether or not to use water co-solventhas to be matched to substrates, and in particular to their polarity.145

ee©de©

Intramolecular aldols of cyclic diketones are catalysed by proline, and List’s studiesof the effect of incorporation of a 4-fluoro substituent in the cis- or trans-positionhas been studied by DFT. It finds that fluorine changes pathways as well as transitionstates: a low energy epimerization (after the C−C bond forming process) affectsproduct distribution.146

ee©de©

N -(para-Dodecylphenylsulfinyl)-2-pyrrolidinecarboxamide (56) is one of the bestanti -aldol catalysts to date, with yields/ee/de up to 98/99/98%, low catalyst loading,mild conditions, and convenient solvents (or none). A DFT study has now identifiedthe origins of the diastereoselectivity in non-classical hydrogen bonds between thesulfonamide, the electrophile, and the catalyst enamine that favour the anti -Re aldoltransition state.147

ee©de©

An l-prolinethioamide catalyses aldols in water at 0 ◦C, with yields/ee up to98/99%.148 ee©

Strong non-linear effects are observed in proline-catalysed aldols when an achiralthiourea catalyst is also employed in non-polar solvents: with an ee as low as 5%for the proline, 40% ee and 94% de are observed in the products.149 The role of the

ee©de©

thiourea co-catalyst in such reactions has been investigated. Examining the reactionof acetone with 4-substituted benzaldehydes, non-linear effects are observed (%eealdol

versus %eeproline), but these are markedly dependent on the nature of the aromatic sub-stituent. Results from 1H-NMR and ESI-MS suggest that the main role of the thioureais not that of producing a soluble proline-thiourea hydrogen-bonded complex.150

ee©IL-tagged amino acid derivatives – 1,2,3-triazolium salts linked to lysine or

proline – give high yields/ee/de in direct aldols: the lysine surprisingly outperformedthe proline.151

ee©de©

(S)-Prolinamides with a trans-4-ester moiety bearing an IL group give excellentyields, des and ees in aldol reactions in water.152

ee©de©

organic reaction mechanisms · 2013-07-23 · organic reaction mechanisms · 2010 an annual survey...

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