Organic Reaction Mechanisms 2013 E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Organic Reaction Mechanisms
• Sprache: Englisch

Seitenzahl: 1310

Veröffentlichungsjahr: 2016

Beschreibung

Organic Reaction Mechanisms 2013, the 49th annual volume in this highly successful and unique series, surveys research on organic reaction mechanisms described in the available literature dated 2013.

The following classes of organic reaction mechanisms are comprehensively reviewed:

• Reaction of Aldehydes and Ketones and their Derivatives
• Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives
• Oxidation and Reduction
• Carbenes and Nitrenes
• Nucleophilic Aromatic Substitution
• Electrophilic Aromatic Substitution
• Carbocations
• Nucleophilic Aliphatic Substitution
• Carbanions and Electrophilic Aliphatic Substitution
• Elimination Reactions
• Polar Addition Reactions
• Cycloaddition Reactions
• Molecular Rearrangements

An experienced team of authors compile these reviews every year, so that the reader can rely on a continuing quality of selection and presentation.

Leseprobe

Table of Contents

Title Page

Copyright

Contributors

Preface

Chapter 1: Reactions of Aldehydes and Ketones and Their Derivatives

References

Chapter 2: Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and Their Derivatives

Intermolecular Catalysis and Reactions

Intramolecular Catalysis and Neighbouring Group Participation

Association-Prefaced Catalysis

Biologically Significant Reactions

References

Chapter 3: Oxidation and Reduction

References

Chapter 4: Carbenes and Nitrenes

References

Chapter 5: Aromatic Substitution

References

Chapter 6: Carbocations

References

Chapter 7: Nucleophilic Aliphatic Substitution

References

Chapter 8: Carbanions and Electrophilic Aliphatic Substitution

References

Chapter 9: Elimination Reactions

References

Chapter 10: Addition Reactions: Polar Addition

References

Chapter 11: Addition Reactions: Cycloaddition

References

Chapter 12: Molecular Rearrangements

References

Author Index

Subject Index

End User License Agreement

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Guide

Table of Contents

preface

Begin Reading

List of Illustrations

Chapter 2: Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and Their Derivatives

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Chapter 3: Oxidation and Reduction

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Chapter 4: Carbenes and Nitrenes

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Chapter 5: Aromatic Substitution

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Chapter 8: Carbanions and Electrophilic Aliphatic Substitution

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Chapter 9: Elimination Reactions

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Chapter 10: Addition Reactions: Polar Addition

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Chapter 11: Addition Reactions: Cycloaddition

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Chapter 12: Molecular Rearrangements

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Organic Reaction Mechanisms . 2013

An annual survey covering the literature dated January to December 2013

Edited by

A. C. Knipe

University of Ulster

Northern Ireland

This edition first published 2017

© 2017 John Wiley & Sons, Ltd

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Library of Congress Catalog Card Number 66-23143

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A catalogue record for this book is available from the British Library

Print ISBN: 978-1-118-70786-9

Contributors

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

S. CHASSAING

Centre National de la Recherche Scientifique, Université de Toulouse, Toulouse, France

Centre Pierre Potier, ITAV, Université de Toulouse, F-31106 Toulouse, France

INSA, F-31400 Toulouse, France

J. M. COXON

Department of Chemistry, University of Canterbury, Christchurch, New Zealand

M. R. CRAMPTON

Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

N. DENNIS

3 Camphorlaurel Court, Stretton, Brisbane, Queensland 4116, Australia

E. GRAS

Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique, 205 Route de Narbonne 31077, Toulouse Cedex 4, France

D. A. KLUMPP

Department of Chemistry, Northern Illinois University, DeKalb, IL 60115, USA

A. C. KNIPE

Faculty of Life and Health Sciences, University of Ulster, Coleraine, Northern Ireland

P. KOČOVSKÝ

Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm SE 10691, Sweden

Department of Organic Chemistry, Charles University, 12843 Prague 2, Czech Republic

R. N. MEHROTRA

Department of Chemistry, Jai Narain Vyas University, A-85 Saraswati Nagar, Jodhpur 342005, India

B. A. MURRAY

Department of Science, Institute of Technology, Tallaght (ITT Dublin), Dublin D24 FKT9, Ireland

K. C. WESTAWAY

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada

Preface

The present volume, the forty-ninth in the series, surveys research on organic reaction mechanisms described in the available literature dated 2013. In order to limit the size of the volume, it is necessary to exclude or restrict overlap with other publications which review specialist areas (e.g. photochemical reactions, biosynthesis, enzymology, electrochemistry, organometallic chemistry, surface chemistry and heterogeneous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editor conducts a survey of all relevant literature and allocates publications to appropriate chapters. While a particular reference may be allocated to more than one chapter, it is assumed that readers will be aware of the alternative chapters to which a borderline topic of interest may have been preferentially assigned.

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

We welcome Prof Doug Klumpp as author of the carbocation chapter. He replaces Prof Bob McClelland who has provided expert reviews of this area since ORM 2000 and now deserves some well-earned respite. We are naturally pleased to have retained members of our current team of experienced authors for all other chapters of ORM 2013.

Although every effort has again been made to reduce the delay between title year and publication date, circumstances beyond the editor's control resulted in late arrival of a substantial chapter which made it impossible to regain our optimum production schedule.

I wish to thank the staff of John Wiley & Sons and our expert contributors for their efforts to ensure that the review standards of this series are sustained. We are aware of demands of informatic evolution which require periodic adjustment of our procedures and are not always helpful!

A. C. K.

Chapter 1Reactions 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

Reactions of Glucosides

Reactions of Ketenes

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, and General and Iminium Chemistry

Mannich, Mannich-type and Nitro-Mannich Reactions

Other ‘Name’ Reactions of Imines

Synthesis of Azacyclopropanes from Imines

Alkylations and Additions of Other

C

-Nucleophiles to Imines

Arylations, Alkenylations and Allylations of Imines

Miscellaneous Additions to Imines

Reduction of Imines

Other Reactions of Imines

Oximes, Hydrazones and Related Species

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

Reviews of Aldols and General Reviews of Asymmetric Catalysis

Asymmetric Aldols Catalysed by Proline and Its Derivatives

Asymmetric Aldols Catalysed by Other Organocatalysts

The Mukaiyama Aldol

Other Asymmetric Aldols

The Henry (Nitroaldol) Reaction

The Baylis–Hillman Reaction and Its Morita-variant

Other Aldol and Aldol-type Reactions

Allylation and Related Reactions

The Horner–Wadsworth–Emmons Reaction and Related Olefinations

Alkynylations

Stetter Reaction, Benzoin Condensation and Pinacol Coupling

Michael Additions

Miscellaneous Condensations

Other Addition Reactions

Addition of Organozincs

Arylations

Addition of Other Organometallics

The Wittig Reaction

Hydrocyanation, Cyanosilylation and Related Additions

α

-Aminations and Related Reactions

Miscellaneous Additions

Enolization, Reactions of Enolates and Related Reactions

α

-Halogenation,

α

-Alkylation and Other

α

-Substitutions

Oxidation and Reduction of Carbonyl Compounds

Oxidation of Aldehydes to Acids

Oxidation of Aldehydes to Amides, Esters and Related Functional Groups

Baeyer–Villiger and Other Oxidation Reactions of Ketones

Miscellaneous Oxidative Processes

Reduction Reactions

Stereoselective Reduction Reactions

Other Reactions

References

Formation and Reactions of Acetals and Related Species

Equilibria for the formation of hemiacetals from eight isomeric hexanals have been measured in methanol, and compared with the steric environment around the aldehyde.1 Kinetic studies have also been carried out, and these suggest an early TS.

Catalytic asymmetric acetalization of aldehydes has been demonstrated, using large chiral BINOL-derived phosphoric acid catalysts: these are proposed to generate confined chiral microenvironments.2

A new enantioselective arylation of enecarbamates (1) has been developed, using a quinone imine acetal (2) as a functionalized surrogate aromatic, and an axially chiral BINAP-dicarboxylic acid catalyst.3 The useful α-amino-β-aryl ether products (3) are formed in up to 99% ee, and des often >90%, and are further transformable into chiral β-aryl amines and α-aryl esters. Mechanistically revealing observations include: (i) trans-enecarbamate switches the sense of asymmetric induction; (ii) the NH in (1) is critical, presumably for hydrogen bonding to catalyst: the NMe starter fails; and (iii) crossover experiments fail, implicating an intramolecular route. The proposed first step is a highly stereoselective C–C bond formation followed by aromatization (with elimination of R3-OH), then re-addition of R3-OH to the sidechain.

A stable N,N′-diamidocarbene has been used to activate molecules with X–X homonuclear single bonds (where X = Br, O, S, C).4 Br2 yields a substituted tetrahydropyrimidinium salt, benzoyl peroxide yields diamidoacetal product, and various sulfides give the corresponding diamidothioacetals. For X = C, insertion into the (O)C–C(O) bond of diones was observed, and for cyclopropenone, insertion into the (O)–C–C bond occurred.

meta- and para-Substituted benzaldehyde acetals, X-C6H4–CH(OBu)2, have been oxidized by N-bromosuccinimide in acetonitrile, to give the corresponding esters (and alkyl bromide).5 Rates have been measured by the iodometric method, over a range of temperature. A primary kinetic isotope effect, kH/kD, is observed, indicating rate-determining C–H cleavage; a Hammett σ value of 1 · 4 and activation parameters are given.

Kinetics of the oxidation of a range of aromatic acetals by N-chloronicotinamide have been measured in acetonitrile.6

The combination of triethylsilyltriflate with either 2,6-dimethylpyridine (2,6-lutidine) or 2,4,6-trimethylpyridine (2,4,6-collidine) effectively deprotects acetals of aldehydes under mild, neutral conditions, while leaving those of ketones unaffected.7 Pyridinium-type salt intermediates are proposed.

The Prins reaction has been modelled using DFT (density functional theory), using an alkene (RCH=CH2, R = Me or Ph), a formaldehyde dimer, and a proton-water cluster, H3O+(H2O)13. Both alkenes feature a concerted path to give the 1,3-diols. An unprecedented hemiacetal intermediate, HO–CH2–O–CH(R)–CH2CH2–OH, was then identified: it undergoes ring closure to the 1,3-dioxane product.8 Gas-phase Prins reaction of formaldehyde dimer with alkene has been studied computationally: it proceeds via a π-complex (without formation of any intermediate σ-complex).9

DFT calculations have been used to study the kinetic and thermodynamic parameters of the oligomerization of formaldehyde in neutral aqueous solution: linear and cyclic oligomers up to tetramer were examined, and implications for enolization and aldol reactions were also examined.10

A series of new naphtha[1,3]oxazino[2,3-α]isoquinolines (4, R1 = H, Me, Ph, Ar; R2 = H, OMe) have been prepared from 1-aminomethyl-2-naphthols and 3,4-dihydro-isoquinolines.11 The predominant diastereomer is trans- (at the 7a- and 15-positions), but a surprising inversion at nitrogen can be observed by NMR (nuclear magnetic resonance). Computations support ring-opening at the C(7a)-oxygen bond, giving an iminium-phenolate intermediate.

For other reports of acetals, see the section titled ‘Miscellaneous Oxidative Processes’ later.

Reactions of Glucosides

Proton affinities and pKas have been calculated for various tautomers of d-glucose and d-fructose, and compare favourably with experimental measurements of the pH's of sugar solutions in water.12

A review surveys the catalysts and mechanistic approaches to alter the reactivity of hydroxyl groups in carbohydrates, thus facilitating regioselective manipulation.13

exo-Glycals [e.g., (Z)-5 and (E)-5] are glycosides with an exocyclic enol ether next to the oxygen of the ring, are useful synthons, and some have biochemical applications in their own right. However, the (E)-isomers have been inaccessible to date. In a treatment of the (Z)-species with strong base (aimed at further functionalization), t-BuLi at −78 °C surprisingly gave 34% conversion to the (E)-exo-glycal [(E)-5] with no by-products. A vinyl anionic intermediate was confirmed. Optimum isomerization employed 3 mol LiHDMS at ambient temperature for 10 min (to deprotonate), followed by −100 °C for 2 h, which favours the (E)-isomer.14

Several formic acid derivatives of a protected glucose have been prepared: O-perbenzoylated C-(β-d-glucopyranosyl)-formimidate [6, R = C(=NH)OEt], -formamidine [R = C(=NH)–NH2], -formamidrazone [R = C(=NH–NHX)–NH2, X = H or Ts] and -formyl chloride (R = COCl).15 Designed to lead to 1,2,4-triazole derivatives of the sugar, they unexpectedly also gave 1,3,4-oxadiazole derivatives. DFT calculations have been used to investigate the alternative ring-forming pathways.

Chemo- and regio-selective functionalization of non-protected carbohydrates has been developed, allowing selective thiocarbonylation, acylation and sulfonylation of a particular carbohydrate in the presence of structurally similar carbohydrates, for example, anomers.16 For example, sugar anomers (7) can be functionalized in the 6-position in up to 99% yield and 99% β-selectivity, using Me2SnCl2 as catalyst. Just switching the catalyst to Bu2SnCl2 gives comparable yields and α-selectivities in the 2-position. The mechanisms are discussed in terms of the steric approaches of the catalysts at the 1,2- versus 4,6-sites.

A DFT study of the acid catalysis of the mutarotation of erythrose and threose has looked at reaction in the gas phase, and in a continuum water model.17 Sodium cation can act as an inhibitor, whereas borane acts as a Lewis acid catalyst. Brønsted acids H+ and H3O+ are particularly effective, with the activation energy being further lowered using H3O+ with one bridging H2O.

MP2 and B3LYP methods have been used to examine the mechanisms of the Lewis acid-catalysed isomerization and epimerization of xylose to xylulose and lyxose, respectively.18

myo-Inositol 1,3,5-orthoesters (8, R = Me, Pr, Ph, but not H) exclusively afford the corresponding 2-O-acyl myo-inositol products (10) via a 1,2-bridged five-membered ring dioxolanylium ion intermediate (9) observed by NMR.19 If the orthoester (8, R = CH3) is equilibrated in TFA-d, the R group becomes deuterated; however, if the free hydroxyls (either axial or equatorial) are benzylated, the benzyl CH2s are not exchanged. Complete mechanisms are proposed for these processes.

Activation of O-glycosyl trichloroacetimidates as glycosyl donors typically requires moderately strong acids, such that a simple N,N′-diarylthiourea, ArNHC(=S)NHAr [e.g., Ar = 3,5-bis(trifluoromethyl), pKa = 8 · 5], would not be expected to catalyse the process.20 However, it can act as a co-catalyst with simple Brønsted acids such as benzoic (pKa = 4). The system gives significant rate and yield enhancements, and good selectivity for the β-anomer. A multiply hydrogen-bonded complex of reactants and catalysts is proposed.

An α/β-stereo- and diastereo-selective glycosylation method employs a glucosyl α-trichloroacetimidate and a chiral BINOL-derived phosphoric acid catalyst: the system selects the R-enantiomer of a racemic mixture of secondary alcohols.21

A mechanistic study of glycosylation using a prop-1-enyl donor in the presence of N-iodosuccinimide and triflic acid highlights one of the possible roles of TfOH: it could produce IOTf in situ to activate the prop-1-enyl group.22

Highly stereospecific formation of O-alkyl glycosides has been achieved by ‘native chemical ligation’, in which a pendant alcohol at the anomeric centre is used to steer the reaction.23

DFT has been used to identify a neighbouring-group participation step in a BF3-catalysed glycosylation of a galactosyl donor.24

Glycosidase-like activity is reported for a cyclodextrin with one or two cyanohydrins incorporated on its secondary rim, with a rate acceleration of up to 1770.25

Studies of Grignard reactions and hydride reductions of epi- and scyllo-inososes (11) indicate that the diastereoselectivity is determined by the orientation of the β-hydroxyl group (or its derivative).26

The rates of hydrolysis of N-acetyl-d-glucosamine (the monomer of chitin) have been measured in hydrochloric, perchloric and phosphoric acids: they depend on proton concentration, without counterion effects.27

Acid-catalysed hydrolysis of sucrose to glucose and fructose has been investigated by DFT, using a catalytic cluster, H3O+(H2O)13.28 Considering protonations of the three ethereal oxygens, that at the bridging oxygen is relevant to the mechanism, but the calculations only find a slight preference for cleavage on the fructosyl side (over the glucosyl side).

Conversion of glucose, fructose and cellulose into S-hydroxymethylfurfural was studied under hydrothermal conditions, with both acid and base catalyses, with DFT calculations helping to scope out mechanistic possibilities.29

In situ13C-NMR spectroscopy has been used to investigate the kinetics and mechanism of the conversion of d-fructose into 5-hydroxymethyl-2-furaldehyde (12), and subsequent hydrolysis to formic and levulinic acids.30 Following a study in three solvents [water, methanol and DMSO (dimethyl sulfoxide)] and temperatures from 30 to 150 °C, the production of the two useful acids is predicted to be favoured by hydrothermal methods.

The kinetics of oxidation of d-galactose by cerium(IV) in the presence of catalytic rhodium(III) have been measured in acid in the range 308–333 K.31

The rate of oxidation of galactose by N-bromophthalimide in the presence of acid has been measured at 308 K, and the effects of salts, phthalimide, mercury(III) and a cationic surfactant have been used to explore the mechanism.32

The carbon-Ferrier rearrangement, in which appropriately functionalized glycols react with a variety of C-nucleophiles at the anomeric carbon with loss of a C(3) substituent, has been reviewed.33

For the use of carbohydrates catalytically activated as acyl anions to act as formaldehyde equivalents, see the section titled ‘Stetter Reaction’ below.

Reactions of Ketenes

Synthesis of β-lactams via transition metal promoted Staudinger [2+2] cycloaddition of a ketene and an imine has been reviewed (63 references).34

Staudinger reaction of ketene and imine gives β-lactam, via [2+2] cycloaddition.35 Six-membered rings can potentially be formed using a second equivalent of ketene or of imine, via [2+2+2] processes. DFT has been used to probe annuloselectivity in forming such (N,O), (N,O,O) or (N,N,O) ring systems for a range of seven reactants with substituents which are EWG, EDG or bulky.

The Staudinger synthesis is catalysed by NHCs (N-heterocyclic carbenes), via Ye's possible ‘ketene-first’ or ‘imine-first’ mechanisms.36a To test these alternatives, four zwitterionic NHC adducts have been prepared: two using N-tosyl benzaldimine and two using diphenylketene.36b All four adducts had 1:1 stoichiometry and have been extensively characterized by 1H- and 13C-NMR, X-ray crystallography and catalytic tests. The imine-derived zwitterions proved poor catalysts, whereas those derived from diphenylketene replicated the free carbene catalysts, strongly supporting the ‘ketene-first’ route.

Gas-phase reaction of ketene and water to produce acetic acid – both uncatalysed and with catalysis by an additional water molecule – has been studied computationally: the reaction is found to be likely to occur in high-temperature combustion of biomass, but is negligible under ambient atmospheric conditions.37

Hydration of ketene to give acetic acid has been studied under atmospheric conditions, over a range of humidities.38

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, and General and Iminium Chemistry

A DFT mechanistic study of the formation of Schiff bases from acetaldehyde in water has looked at two amines of biological importance: glycine and phosphatidylethanolamine, with an amine-phospholipid monolayer model being incorporated in the latter.39 The rate-determining step was found to be dehydration of the carbinolamine intermediate in both cases. Relative free energies of the intermediates and transition states were lower (compared to butylamine as a reference amine), these effects being ascribed to the carboxylic group and phospholipid environment, respectively.

Amines react with primary alcohols to give imines under the influence of a ‘pincer’ complex, ruthenium(II)-PNP [PNP = 2,6-bis(di-t-butylphosphanylmethyl)pyridine].40 DFT has been used to identify the mechanistic steps, and in particular the factors that favour imine as product, as closely related complexes yield amides.

Imine metathesis is often carried out at high temperature using a metal-based catalyst.41 However, amine–imine exchange reactions of sterically unhindered reactants have been shown to proceed rapidly in non-aqueous organic solvent systems without such catalysts, or acids. Ab initio gas-phase calculations suggest that such transiminations involve nucleophilic addition to the C=N bond in concert with proton transfer from the amine NH bond to the imine nitrogen in a highly imbalanced TS. Primary amines are highly efficient catalysts, and reported kinetic data is fully consistent with the mechanism outlined.

A kinetic and mechanistic study of the transaldimination of amino acids and aromatic amines with pyridoxal considers the geometric constraints on the aminal and Schiff base intermediates with respect to the pyridine ring plane of pyridoxal, and especially the influence of its ortho-hydroxy and -methylol substituents.42

Mayr has extended his electrophilicity scale to benzaldehyde-derived iminium ions through measurement of rate constants for their reactions with C-nucleophiles such as enamines, silylated ketene acetals and enol ethers.43 With an E value of −9.27 for Ph–CH=NMe2+ (in a range from −8.34 to −10.69 for para-CF3 and para-OMe, respectively), these iminium ions are 10 orders more reactive than the parent aldehydes. However, the values are restricted to C-nucleophiles: the iminium ions react 103–105 times faster with water and amines than these E values would predict. Such reactions benefit from the anomeric stabilization of O,N-acetals and N,N-aminals.

For more on such parameters, see DDQ (140) under the section titled ‘Miscellaneous Additions’ below.

The use of chiral organocatalysts to produce enantioselective transformation of N-acyliminium ions has been reviewed.44

Vilsmeier–Haack formylations of acetophenones are slow in acetonitrile, even at elevated temperatures, but are markedly accelerated by Cu(II), Ni(II), Co(II) and Cd(II).45 Second-order kinetics are observed. A ternary precursor, MII:substrate:Vilsmeier reagent, is proposed.

Mannich, Mannich-type and Nitro-Mannich Reactions

The use of Mannich and aza-Henry reactions to synthesize β-nitroamines has been reviewed.46

Readily available chiral cyclopropenimine (13) catalyses Mannich reactions of N-Boc-aldimines (14) and glycine imines (15), with yields/de/ee up to 97/98/95%.47 The vicinal diamino stereoarray of the products (16) allows access to many useful derivatives, and the t-butyl ester of the product (16, R2 = But) is amenable to acidic deprotection. In the proposed mechanism, the congestion caused by the cyclohexyl substituents in catalyst (13) is suggested to lock the stereocentre therein.

A simple gold(I) NHC, 1,3-bis(diisopropylphenyl)imidazol-2-ylidene]AuNTf2, catalyses Mannich reactions of N-protected imines with 1,3-dicarbonyls under mild conditions (DCM/ambient).48 Using N-sulfonylimines, R4-CH=N–PG, the reaction works in good yields for both β-ketoesters and β-diketones, affording protected β-amino-dicarbonyls, R1-CO–CR2(–CHR4–NH–PG)–CO-R3, in up to 62% de.

An N-Boc sulfone derivative has been used for in situ generation of an α-keto imine, which undergoes an asymmetric Mannich reaction, using a diarylprolinol silyl ether (17) as organocatalyst.49

The proposed intermediates in proline-catalysed Mannich reactions have been studied computationally; enamines, iminium ions and oxazolidinones have been examined, and the transition states involved in their interconversion.50

Highly substituted γ-lactams with three stereogenic centres, including one quaternary centre (e.g., 18), have been prepared in good de from an imine and an anhydride (in this case, from N-methylbenzaldimine and cyanosuccinic anhydride).51a Computations suggest a Mannich reaction between the E-imine and the enol of the anhydride, followed by a transannular acylation. The results do not support an earlier iminolysis route.51b The stereoselectivity is determined by the Mannich step, with stabilizing C–H···O and hydrogen-bonding interactions being identified.

An asymmetric one-pot sequential Mannich/hydroamination sequence involves a three-catalyst system: a chiral organocatalyst, BF3 and a gold complex.52 It converts an indole-imine into privileged spiro[pyrrolidin-3,2′-oxindole] structures in up to 91/97% yield/ee.

Treating enolizable cyclo-1,3-diketones with acyclic nitrones, R-CO-CH=N(Me)-O−, allows access to β-enamino diones (19) in up to 99% yield, via a self-catalysed Mannich-type reaction, followed by a spontaneous intramolecular reorganization.53 The proposed mechanism is supported by a DFT analysis.

A Mannich-type reaction of β-keto ester with C-alkynyl imines generated in situ delivers asymmetric synthesis of propargylamines with two adjacent stereocentres organocatalytically.54

The potential for chiral silane-gem-diols to act as anion-binding catalysts has been explored in the case of acyl Mannich reactions.55

Spirodiketones have been prepared in >99% ee via a redox-pinacol-Mannich cascade.56 Controlling both the reversibility of the Mannich step and background catalysis by gold complexes are critical to minimizing racemization: low-temperature conditions and rapid isolation are essential in this regard.

The nitro-Mannich reaction has been reviewed (266 references), covering a variety of its manifestations: simple nitroalkane versus more functionalized nitro compounds, non-catalytic, metal ion- and organo-catalytic, conjugate and cycloadditions and so on.57

New chiral modular bifunctional iminophosphorane superbase organocatalysts allow metal-free enantioselective addition of nitromethane to otherwise unreactive ketone-derived imines.58 The readily scalable reaction yields β-nitroamines (20) with a fully substituted carbon atom, in up to 95% ee.

The Kabachnik–Fields (phospha-Mannich) reaction has been reviewed, including evidence for imine intermediates via in situ FT-IR studies.59 Solvent-free microwave conditions are particularly effective, with little call for catalysts.

Functionalized 2,5-dihydrofurans (21) have been prepared by a Petasis borono-Mannich reaction, using a 4-substituted 1,2-oxaborol-2(5H)-ol and salicylaldehyde.60 The amine-catalysed process combines a boronic-acid-based Mannich reaction with an intramolecular SN2 cyclization.

Other ‘Name’ Reactions of Imines

A review examines the use of carbohydrates as versatile starting materials for chiral auxiliaries in glycosylation, Mannich-type, stereoselective Strecker condensation and Ugi reactions.61

A theoretical investigation of a cinchona-alkaloid-catalysed Strecker reaction using Ti(OPri)4 indicates that the rate-determining step is the isomerization of HCN to HNC, while the stereodetermination occurs at C–C bond formation.62

β-Amino-α-methylene carbonyl compounds have been prepared in up to 92% ee via an aza-Morita–Baylis–Hillman reaction.63N-Tosyl imines of β,γ-unsaturated α-ketoesters have been reacted with acrolein in the presence of two catalysts: β-isocupridine (a chiral quinolol containing a DABCO moiety) and a bifunctional BINOL (or a 3° amine-thiourea). NMR and MS evidence supports a self-assembly of the catalysts, giving a multi-functional supramolecular catalyst.

The kinetics of the aza-Morita–Baylis–Hillman reaction have been studied for a range of imine substrates in various solvents, using triphenylphosphine as catalyst, and p-nitrophenol as a Brønsted acid co-catalyst.64 The effects of varying the phosphine:phenol catalyst ratio on the rate indicate interdependence between them. This and the solvent effects support reversible protonation of zwitterionic intermediates within the mechanism. 31P-NMR and quantum calculations also support such a route.

An asymmetric aza-MBH reaction of isatin-derived N-Boc ketimines with methyl vinyl ketone has been developed, giving 3-amino-2-oxindoles bearing quaternary stereogenic centres (22), using chiral amine or phosphine catalysts.65

The l-threonine-derived phosphine-sulfonamide (23) is one of the best catalysts for the enantioselective aza-Morita–Baylis–Hillman reaction.66 A DFT study has identified a key intramolecular N–H···O hydrogen-bonding interaction between the sulfonamide and enolate groups of the phosphonium enolate intermediate. This helps stereochemical control in both the enolate addition to imine and in the subsequent proton transfer step.

NHCs catalyse a one-pot synthesis of hydroxamic esters, via reaction of nitrosobenzenes, aldehydes and enals in an aza-benzoin-type process, followed by an internal redox esterification.67

An enantioselective aza-benzoin reaction of enals with activated ketimines employs an NHC catalyst: incorporation of appropriate steric hindrance in the catalyst blocks competing reaction through the homo-enolate route.68

Sulfonimines (24) with a pendant ortho-Michael acceptor (Z = COR, CHO, NO2, SO2R) undergo nucleophilic addition (Nu = Ar, heteroAr, CN, allyl, propargyl, enolate; adduct = 25); subsequent intramolecular aza-Michael reaction (IMAMR) yields 1,3-disubstituted isoindolines (26) in good yield and de.69Cis- and trans-products can be selected kinetically or thermodynamically, sometimes by choice of base. The products can be readily desulfonated.

A multi-component aza-Henry reaction of an aldehyde (R1CHO), aniline and a nitroalkane (R2R3CHNO2) yields β-nitroamines (27) in high de, ee, and yield in brine, with an optimal rate at pH 5.5, using a hydrogen-bond donor (a chiral thiourea or squaramide), and a tertiary amine as Lewis base.70

Synthesis of Azacyclopropanes from Imines

Terminal aziridines have been prepared in modest ee by methylene transfer to an N-sulfonylimine, using a simple chiral sulfonium salt (28) and a strong organic base.71

N-Sulfinyl imines (29) undergo highly enantioselective Payne-type oxidation to give oxaziridines (30) in high yields, using hydrogen peroxide and trichloroacetonitrile under mild conditions.72 A P-spiro chiral triaminoiminophosphorane provides the asymmetry. The roles of the amide, Cl3CCONH2, and of the related anions, Cl3C–C(=NH)–O− and Cl3C–C(=NH)–O–O−, in the mechanism are discussed.

A new method for enantioselective oxaziridination of aryl aldimines uses meta-chloroperbenzoic acid and a cinchona alkaloid derivative.73

Alkylations and Additions of Other C-Nucleophiles to Imines

A novel migration-addition sequence has been found for enantioenriched N-t-butylsulfinyl iminoacetate (31) with functionalized benzylzinc bromide reagents, producing t-leucine derivatives (32) in up to 96% de.74 Desulfurization and N-protection to give (33) can then be carried out in >98% ee.

Imines (34) have been C-alkylated to give amines (35), in an unusual alkyl transfer arising from C–C cleavage.75 Hantzsch ester analogues such as (36) can act as hydride-transfer agents, but they have now been used to transfer alkyl groups, using Brønsted or Lewis acid catalysts. Benzyl-substituted dihydropyridines (i.e., 36, with R1 = Bn) are particularly efficient. Evidence for a concerted transfer process is discussed.

The alkylation of ambident enolates of a methyl glycinate Schiff base has been studied computationally.76 Although the E- and Z-enolates have similar energy and geometry, and similar transition states with ethyl chloride, the E-enolate is substantially more stabilized by lithium cation.

The direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines, Ar–CH=N–P(=S)Ph2, proceeds at 50 °C, using Barton's base [(Me2N)2–C=N–But], copper(I) and a Taniaphos chiral ligand; that is, using a soft Lewis acid-hard Brønsted base cooperative catalysis. Although the yield and ee are modest, the corresponding nitrile derivatives of amines, Ar–*CH(CH2–C≡N)–NH–P(=S)Ph2, are obtained.77 Subsequent treatment with 4 M HCl in dioxane at 60 °C cleaves the thiophosphinoyl group (without racemization) to give the β-aminonitrile, Ar–*CH(CH2–C=N)–NH2.

Arylations, Alkenylations and Allylations of Imines

Enantioselective arylation of ketimines has been carried out using rhodium catalysis with chiral sulfur-olefin ligands: arylboronic acids are added in up to 99/99% yield/ee.78

3-Aryl-3-hydroxyisoindolin-1-ones (37) can be further arylated at the 3-position with an arylboroxine and rhodium(I) catalysis: reaction proceeds via dehydration to give a cyclic N-carbonyl ketimine in situ, followed by addition.79

Enantioselective production of quaternary centres has been carried out in high yields via palladium-catalysed addition of arylboronic acids to cyclic ketimines.80

A range of cyclic ketimines (38, X = CH2, O, NR) undergo rhodium-catalysed asymmetric arylation to give gem-diaryl sulfamidates or sulfamides (39) in up to 99% ee.81 The products can be converted into α-tertiary chiral amine derivatives without loss of enantiomeric purity.

N-Alkyl-α,α-dichloroaldimines, for example, N-propyl (40), undergo Lewis-acid-catalysed vinyl transfer, using a terminal alkyne as vinyl donor, yielding geometrically pure allylic β,β-dichloroamines (41).82 The reaction features the acetylenic hydrogen unsurprisingly ending up cis- to the phenyl, but the other vinyl hydrogen in the product is derived from the N-alkyl group acting as a sacrificial hydrogen donor, with an unusual cleavage of an unactivated C–N bond.

Miscellaneous Additions to Imines

The lithium enolate of t-amyl acetate exists as a doubly chelated dimer in the presence of TMEDA (N,N,N′,N′-tetramethylethylenediamine).83 Reaction with a simple aldimine such as para-F–C6H4–CH=N–Ph gives an N-lithiated β-amino ester as a monomer, observed by 6Li- and 15N-NMR. Kinetic studies by 19F-NMR give a reaction order consistent with a TS of stoichiometry [(ROLi)2(TMEDA)2(imine)], supported by DFT calculations. That such aza-aldol condensations involve dimeric mechanistic routes runs counter to many claims that monomers are more reactive.

Dialkylformamides and LDA (lithium diisopropylamide) react to give ‘carbamoyl anions’ (42, with contributions from C-lithiated anion and O-lithiated carbene forms).84 Addition of such anions to chiral N-sulfinyl ald- and ket-imines provides α-amino amides. The method avoids the ‘unmasking’ of the nucleophile found in other approaches. 13C-NMR confirms the unusual nature of the carbon of the anion (42).

3,5-Disubstituted N-acyl-1,4-benzoquinone monoamines exhibit significant steric strain in the C=N–C fragment, in contrast to their N-arylsulfonyl analogues.85 This results either in the bond angle exceeding 130° or in twisting of the double bond and loss of quinoid planarity. The increase in reactivity allows 1,2-addition of alcohols.

Lithiated ynamides react stereoselectively with chiral N-sulfonyl imides without Lewis acid catalysts.86 Boron trifluoride etherate completely reverses the selectivity: a switch from a chelated to an open TS is proposed.

A C(2)-selective nucleophilic addition of indoles to sulfonimines is catalysed by a CoIII(C6H6)(Cp–Me5) complex.87

Lewis acids catalyse regio- and diastereo-selective additions of silyl dienolates to fluorinated sulfinylimines, RF–CH=N–S(=O)–But, allowing access to new chiral α-fluoroalkyl amines.88

Solution-phase DFT methods have been used to identify the source of the diastereoselectivity in sulfur ylide additions to chiral N-sulfinyl imines, which – upon ring-closure – yield terminal aziridines.89 Ring closure is fast and irreversible, and the control due to the sulfur configuration is augmented by a favourable interaction between the sulfinyl oxygen and iminyl hydrogen.

The stereochemistry of the addition of dialkyl phosphonates to the azomethine bond of pyridine-2,6-dicarboxaldimines and of isophthalaldimines, to give the corresponding aminophosphonates, has been studied, with the latter giving higher de.90 For bis(trimethylsilyl)phosphonate, the pyridine substrate gives comparable or better de.

N-Phosphinoyl and N-thiophosphinoyl ketimines, Ph–C(Me)=N–P(=X)Ph2 (X = O and S), have been hydrophosphonylated in high yield and ee using a copper(I) catalyst liganded with a chiral diphosphino ethane.91 In the case of the sulfur substrates, facile differentiated removal of the thiophosphinoyl group affords α-amino phosphonic acid derivatives, Ph–*C(Me)(NH2)–P(=O)(OEt)2, that is, phosphonic acid analogues of enantio-enriched α,α-disubstituted α-amino acids. The reaction also accommodates alkyl, cycloalkyl and alkenyl substituents in place of the phenyl.

A multi-component reaction of a terminal alkyne, sulfur, electrophile (E–X) and carbodiimides, R1R2CH–N=C=N-R3, produces 1,2-dihydrothiopyrimidines and 2,3-dihydropyrimidinthiones (43, R4 derived from alkyne, E = H, alkyl).92 The expected N=C cleavage of the diimide is accompanied by an unexpected C(sp3)–H cleavage, such that the carbodiimide acts as sources of ‘H’ + ‘R1R2-C–N’ + ‘C=N-R3’, with subsequent reorganization to give products.

Reduction of Imines

An achiral iridium catalyst gives high yields in hydrogenation of imines derived from acetophenone, and also imines of aliphatic ketones.93 An enantioselective version has been developed, using a chiral phosphoric acid as Brønsted acid. This gives ees up to 98%, but at the expense of the reaction rate, slowed by the bulk of the BINOL-type phosphoric acid.

Enantioselective hydrogenation of imines has been achieved via a cooperative catalysis involving an iridium(I) organometallic and an organocatalyst, with low-temperature nOe- and DoSy-NMR techniques being used to characterize a key ternary complex.94

A cyclometallated iridium(III) catalyst (44) bearing an imine ligand catalyses hydrogenation of imines, typically in an hour at 0.05 mol% loading/20 atm H2/75 °C.95 It is selective for imines, is air-stable, and is probably turnover-limited by the hydride formation step.

A new Ru-η6-arene complex (45) acts as a C-based Lewis acid catalyst for the hydrogenation of aldimines at ambient temperature via a ‘frustrated Lewis pair’ mechanism: with 102 atm H2 in DCM at 25 °C, 1 mol% catalyst gives up to 99% amine in 8 h.96 The catalyst and its mechanism have been extensively characterized by X-ray crystallography and NMR, including deuteration experiments with D2 which prove that exchange is occurring ortho- and para- to the boron.

In another frustrated Lewis pair route, a highly enantioselective metal-free hydrogenation of imines uses a BINAP-derived diene as a ‘ligand’: hydroboration of the alkenes in situ with HB(C6F5)2 generates a chiral bis-borane catalyst.97

Reduction of ald- and ket-imines, and α-imino esters, has been carried out by transfer hydrogenation using Hantzsch ester: molecular iodine is an efficient catalyst.98

2-Arylbenzothioazolines (46) are efficient reducing agents for the transfer hydrogenation of ketimines and α-imino esters: in the presence of a chiral BINOL-phosphoric acid catalyst, it affords the corresponding amines in high ee, following a similar mechanism to (but superior than) using Hantzsch ester.99 A DFT study has clarified the reasons for the high ee, which are mainly steric in origin, but including the scope for tuning the benzothiazoline's aryl substituent. The phosphoric acid's Brønsted site activates the imine, while its basic site coordinates benzothiazoline.

Other Reactions of Imines

Two series of N-pyrrolyl-2-methylene-aniline Schiff bases (47; R1 = H, Me; R2 = H, Me, OMe, OEt, Cl, Br) have been hydrolysed over a wide range of pH (−4 to +14), and pH-rate profiles generated: these are bell shaped, and mechanistic explanations are offered for each pH domain.100

The kinetics of oxidation of a Schiff base, 5-chloro-2-hydroxy-4-methyl-acetophenoneanil, by cerium(IV) in aqueous sulfuric acid has been reported.101

Aromatic N-TMS-ketene imines undergo efficient aldol-type reaction with O-protected α-hydroxy aldehydes, giving syn-selectivity at ambient temperature, reversing at −78 °C to anti-.102 Transfer of the TMS group from the ketene imine prevents retro-reaction.

Pyrroles (48; R = H, Me) undergo Friedel–Crafts aminoalkylation with cyclic α-perfluoroalkylated imines (49; RF = CF3, C2F5; n = 1, 2, 3) to give α- and β-substituted pyrroles (50α, 50β).103 Catalysed by Lewis acids, the most high-yielding and regioselective results were obtained using boron trifluoride etherate in DCM at 0 °C over 5 days, giving 9% 50α to 87% 50β (RF = CF3; n = 1). The preference is thermodynamic, as a sample of pure 50α converts into 50β in the presence of BF3 · Et2O. DFT studies identify the steric bulk of the trifluoromethyl group, as well as its specific electronic properties, as the main factors giving β-selectivity.

The recently reported insertion of N-sulfonylaldimines into aryl C–H bonds, catalysed by rhodium(III), has been examined to determine the mechanism.104 Key intermediates were isolated and their structures determined by X-ray crystallography.

The Povarov cascade reaction of an aniline, two moles of formaldehyde and two moles of styrene gives tricyclic (51).105 Calix[4]- and calix[6]-arene sulfonic acids have been employed as catalysts, giving good yields and fair des in a range of solvents, including water. MS evidence is provided for an iminium ion intermediate formed from the aniline and formaldehyde, as well as a later iminium ion, after the first styrene and second formaldehyde have been incorporated.

Rhodium(I) catalyses a dynamic kinetic asymmetric [3+2] annulation of aryl ketimines with racemic allenes, with good E/Z-selectivity and up to 98% ee.106

cis-Homoenolate equivalents have been generated from cis-enals using NHC catalysis: they react with α,β-unsaturated imines to form chiral cyclic ketone products.107 Their reactivities and stereoselectivities contrast with the better known trans-enals.

Ugi multi-component reactions of an amine, aldehyde, carboxylic acid and isocyanide (or the three-component variant with preformed imines) involve a Mumm rearrangement of an imidate in the final step, often considered the stereoselective step.108 However, experimental and computational evidence for kinetic control has now been reported in Ugi reactions of a d-pentose-derived pyrroline (52). The selective step is the formation of the imidate by the addition of isocyanide to the intermediate iminium ion, with the conformation of the latter determined by its substitution pattern.

A new ‘split-Ugi’ reaction is the subject of a short review (37 references).109 The classical four-component reaction of aldehyde, primary amine, carboxylic acid and isocyanide has been modified using a secondary amine instead. This allows the Mumm-like rearrangement step to be avoided, freezing the reaction at the imino-anhydride intermediate, which is susceptible to alternative nucleophilic trapping.

Oximes, Hydrazones and Related Species

Neighbouring halogen participation effects have been investigated for peri-chloro- and peri-bromo-substituted O-tosyl oximes under acid-catalysed Beckmann rearrangement conditions.110 Evidence for stabilization of a nitrogen cation by nearby halogen is presented, including diversion of expected pathways.

A DFT study of organo-mediated Beckmann rearrangements recharacterizes the species as initiators, rather than true catalysts.111 A self-propagating mechanism has been identified and shown to be energetically more favourable than previous proposals involving Meisenheimer complexes.

The oxime derived from the triterpenoid, oleanolic acid, has been studied under Beckmann rearrangement conditions.112

α-Imino aldehydes (53) based on benzophenone have been prepared by coupling benzophenone oxime with a trans-alkenyl boronic acid [R-CH=CH–B(OH)2] followed by thermal [1,3]-rearrangement.113 Evidence for a dissociative rearrangement is presented, and the products (53) can be used in Horner–Wadsworth–Emmons olefinations to produce γ-imino-α,β-unsaturated esters.

A [3+3]-type condensation of O-acetyl ketoximes and α,β-unsaturated aldehydes yields pyridines;114 for example, Ph–(Me)C=N–OAc and trans-cinnamaldehyde (trans-Ph–CH=CH–CHO) give 2,4-diphenylpyridine (54) using copper(I) iodide as catalyst and a salt of a secondary amine; only a trace of the 2,6-product is observed. A synergistic copper/iminium catalysis is proposed: the oxime reacts with the copper iodide to give an iminyl copper species, Ph–(Me)C=N–Cu-X (i.e., N–O reduction), which tautomerizes to a copper(II) enamide, Ph–C(=CH2)–NH–CuX, which then acts as a nucleophile towards the iminium ion (formed from the aldehyde and 2° amine).

Imidazo[1,2-a]pyridines (55) have been prepared from an (R1-)substituted pyridine and a ketone oxime ester, R3-CH2C(R2)=N–OAc, via a copper-catalysed aerobic dehydrogenative cyclization.115 The best yields were obtained with copper(I) iodide in the presence of lithium carbonate and air, in DMF at 95 °C.

Oximes (56) and α,β-unsaturated aldehydes (57) undergo a redox esterification to oxime esters (58) catalysed by a triazolium salt.116 A wide variety of oxime and enal types are tolerated.

DFT has been used to investigate the mechanism of enantioselective borane reduction of E-acetophenone O-methyl oxime, using a stable chiral spiroborate ester.117

The Neber rearrangement of oxime O-sulfonates to 2H-azirines (or α-amino ketones, after aqueous acid workup) has been reviewed, together with the ‘modified Neber’, involving N,N,N-trimethylhydrazonium iodides.118 With an excess of base, the α-amino acetal can be formed from the 2H-azirine via the unstable 2-alkoxy aziridine.

Oxyma [59, ethyl 2-cyano-2-(hydroxyimino)acetate] has been O-sulfonated, and the sulfonate ester (60) is an excellent catalyst for dehydration of oximes to nitriles.119

A kinetic study of nitrile-forming elimination from (E)-2,4-dinitrobenzaldehyde O-aryloximes has been carried out in acetonitrile, with catalysis by tertiary amines.120 The Brønsted β value for this dehydration ranges from 0.83 to 1.0, with |βlg| = 0.41−0.46. The results are consistent with a highly E1cb-like TS.

Oxidative deoximation of aldo- and keto-oximes by tetraethylammonium chlorochromate in DMSO is first-order in oxime and oxidant, and the kinetic study was extended to 19 organic solvents.121 Similar kinetic behaviour was found for imidazolium fluorochromate;122 in the case of acetaldoxime, the same solvent survey was performed. Pyridinium fluorochromate as oxidant was also studied in DMSO.123

Iodine catalyses the condensations of 2-aminobenzohydrazide with aldehydes and ketones, to give hydrazones and quinazolines, respectively.124

Formaldehyde hydrazones (61a ↔ 61b), prepared by reaction of formaldehyde and N,N-dialkylhydrazones, can act as C- or N-nucleophiles.125 Their reactivities have been measured by reaction with a range of benzhydryl cations, Ar2CH+, as reference electrophiles with known E values. Kinetic reaction of the carbocations at the (terminal) nitrogen is followed by slower thermodynamic reaction at carbon, with second-order rate constants derivable for both processes. The results rationalize why Mannich salts, Vilsmeier reagents and nitrostyrenes react freely with hydrazones, whereas weaker electrophiles such as enones and aldehydes require catalytic activation.

N-Iminopyridinium ylides (62) undergo direct C–H bond alkylation by cross-coupling with N-tosylhydrazones, using unliganded copper(I) iodide and lithium t-butoxide.126 DFT calculations suggest a Cu carbene migratory insertion. Direct Cu carbene C–H insertion was ruled out by a diphenyldiazomethane control reaction which only gave (63) if the requisite base was present (the direct carbene process does not need base).

A three-component cross-coupling of N-tosylhydrazones, terminal alkynes and allyl halides yields allyl allenes, using copper(I) catalysis: a copper carbene migratory insertion is proposed.127

A series of bis(guanylhydrazone) derivatives of the pentacycloundecane and adamantane skeletons (e.g., 64) have been studied in the gas phase via ESI-MS/MS.128 Elimination of neutral guanidine is a major fragmentation pathway, via cage opening of the hydrocarbon skeleton leading to carbocations. In some cases, elimination of CH2N2 is preferred. The results are interpreted in terms of a neighbouring-group effect, with close contact of two guanidines being crucial to determining the preferential pathway and suppressing dication formation.

Formaldehyde t-butyl hydrazone, H2C=N–NH–But, has been used as a formyl anion equivalent: it reacts with isatins to give functionalized 3-hydroxy-2-oxindoles. BINAM-derived organocatalysts which provide dual activation – hydrogen-bond donor and acceptor – render the reaction which is high yielding and highly enantioselective.129

An enantioselective Strecker-type transformation of aliphatic N,N-dibenzylhydrazones, R-CH=N–NBn2, to the corresponding hydrazino nitriles, R-CH(CN)–NH–NBn2, uses a t-leucine-derived bifunctional thiourea catalyst, and the combination of TMSCN and phenol for in situ generation of HCN as cyanide source.130

α,β-Alkynic hydrazones (e.g., 65) undergo an unusual cyclization-carbonylation-cyclization reaction in the presence of CO to give a bis-heterocyclic ketone (66), using a bis(oxazolinyl)palladium(II) complex to catalyse the coupling and para-benzoquinone (1.5 equiv) in methanol.131

trans-Enals (trans-R-CH=CH–CHO) have been reacted with various diazo compounds, X–C(=N2)–CO2–Y, to give N-acylhydrazones, R-CH=C(=O)–NH–N=C(X)–CO2–Y, in up to 91% yield.132 The reaction is NHC-catalysed and proceeds via an acyl anion pathway (and not via the competing homoenolate, enol or acyl azolium pathways). DFT calculations indicate that this fully regioselective reaction is under orbital control, whereas charge control would give homoenolate products.

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

Reviews of Aldols and General Reviews of Asymmetric Catalysis

The applications of primary and secondary amine-ureas and -thioureas in asymmetric organocatalysis have been reviewed (138 references),133