Organic Reaction Mechanisms 2019 E-Book

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

Seitenzahl: 1550

Veröffentlichungsjahr: 2023

Beschreibung

Organic Reaction Mechanisms 2019, the 55th annual volume in this highly successful and unique series, surveys research on organic reaction mechanisms described in the available literature dated 2019. 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 * Radicals 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

Cover

Title Page

Copyright

Contributors

Preface

1 Reactions of Aldehydes and Ketones and Their Derivatives

Formation and Reactions of Acetals and Related Species

Reactions of Glucosides

Reactions of Ketenes and Related Cumulenes

Formation and Reactions of Nitrogen Derivatives

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

Other Addition and Related Reactions

Reactions of Enols, Enolates, and Related Reactions

Oxidation of Carbonyl Compounds

Reduction of Carbonyl Compounds

Miscellaneous Cyclizations

Other Reactions

References

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

Intermolecular Catalysis and Reactions

Intramolecular Catalysis and Neighbouring Group Participation

Biologically Significant Reactions

References

3 Oxidation and Reduction

Reviews and Accounts

Oxidation/Reduction/Catalysis by Metal Ions

Group VIII Metals: Iron, Palladium, Rhodium, Ruthenium, and Osmium

Oxidation/Reduction by Non‐metallic Elements

Ozonolysis and Ozonation

Peracids and Peroxides

References

4 Carbenes and Nitrenes

Reviews

Generation, Structure, and Reactivity

Carbenes in Coordination Chemistry

Addition–Fragmentation Reactions Involving Carbenes

Insertion–Abstraction Reactions Involving Carbenes

Rearrangements of Carbenes

Nucleophilic Carbenes—Carbenes as Organocatalysts

Nitrenes

Heavy‐Atom Carbene Analogues

References

5a Nucleophilic Aromatic Substitution

General

Reactions of Arenediazonium Ions

The

S

N

Ar Mechanism

Meisenheimer and Related Complexes

Benzyne and Related Intermediates

Transition Metal‐Catalysed Carbon–Carbon Bond Formation

References

5b Electrophilic Aromatic Substitution

General Introduction

Protonation and Deuteration

Halogenation

Fluorination

Chlorination

Bromination

Iodination

Nitration and Nitrozation

Hydroxylation/Acyloxylation

Amination and Amidation

Borylation and Silylation

Sulfonation and Sulfanylation

Photochemical Processes

Metallation (General)

C—C Bond‐Forming Reactions

Metallation (C–H Insertion)

Acylation

Alkenylation

Arylation

Radical Reactions

Miscellaneous FGIs

References

6 Carbocations

Introduction

Vinyl, Allyl, and Propargyl Cations

Benzyl Cations

Arenium Ions

Oxonium, Sulfonium, Phosphonium, and Iminium Cations

New Cations and Synthetic Methods

Nonclassical Carbocations

Carbocation Rearrangements

Carbocations in Biosynthesis

References

7 Nucleophilic Aliphatic Substitution 2019

Introduction

Nucleophilic Substitutions

Substrates

Leaving Group Behaviour

Nucleophile Behaviour

Reactions

Metal‐Mediated Processes

References

8 Carbanions and Electrophilic Aliphatic Substitution

Carbanion Reactions

Miscellaneous

References

9 Elimination Reactions

E

1

cB

and

E

2 Mechanisms

Solvolytic Reactions

Elimination Reactions in Synthesis

Other Reactions

References

10 Addition Reactions: Polar Addition

Reviews

Electrophilic Additions

Nucleophilic Additions

Acronyms

References

11 Addition Reactions: Cycloaddition

2 + 2‐Cycloaddition

2 + 3‐Cycloaddition

2 + 4‐Cycloaddition

Miscellaneous Cycloadditions

References

12 Molecular Rearrangements

Pericyclic

Named Reactions

Metal Catalysed

Other

References

13 Ligand‐Promoted Catalysed Reactions

Reactions Not Involving C—H Bond Activation

Reactions Involving C—H Bond Activation

References

14 Radical Reactions

Generation and Trapping

Functional Group Interconversion

Intermolecular Additions

Cyclizations

Cascade Reactions

Radical Cations

Miscellaneous Reactions

References

Author Index

Subject Index

End User License Agreement

List of Illustrations

Chapter 2

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Guide

Cover

Table of Contents

Title Page

Copyright

Contributors

Begin Reading

Author Index

Subject Index

End User License Agreement

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Organic Reaction Mechanisms ⋅ 2019

An annual survey covering the literature dated January to December 2019

Edited by

Mark G. MoloneyUniversity of OxfordEngland, UK

This edition first published 2023

© 2023 John Wiley & Sons Ltd.

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Library of Congress Cataloging-in-Publication Data has been applied for

Hardback: 9781119608271

Contributors

C. T. BEDFORD

Department of Chemistry, University College London, London, UK

M. L. BIRSA

Faculty of Chemistry, “Al. I. Cuza” University of Iasi, Iasi, Romania

I. BOSQUE

Instituto de Síntesis Orgánica and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Alicante, Spain

S. CHASSAING

Laboratoire de Synthèse, Réactivité Organique et Catalyse, Institut de Chimie, Université de Strasbourg, Strasbourg, France

J. M. COXON

University of Canterbury, Christchurch, New Zealand

M. R. CRAMPTON

Department of Chemistry, University of Durham, Durham, UK

N. DENNIS

Stretton, Queensland, Australia

J. C. GONZALEZ‐GOMEZ

Instituto de Síntesis Orgánica and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Alicante, Spain

E. GRAS

Laboratoire d'Hétérochimie Fondamentale et Appliquée, Université Toulouse III, Toulouse, France

S. R. HUSSAINI

Department of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK, United States

P. KOČOVSKÝ

Department of Organic Chemistry, Charles University, Czech Republic

and

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Czech Republic

R. N. MEHROTRA

Formerly of Department of Chemistry, Jai Narain Vyas University, Jodhpur, India

J. G. MOLONEY

Department of Chemistry, University of Oxford, UK

M. G. MOLONEY

Department of Chemistry, University of Oxford, UK

V. M. MOREIRA

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

and

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Portugal

and

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

B. A. MURRAY

Department of Science, Technological University of Dublin (TU Dublin), Dublin, Ireland

G. W. WEAVER

Department of Chemistry, Loughborough University, Loughborough, UK

Preface

The present volume, the 55th in the series, surveys research reporting organic reaction mechanisms described in the available literature dated 2019. The general format for ORM 2019 follows the adjustments made for ORM 2018, and I remain grateful to all authors for their continued support and attention to detail, as well as for completing this work during the main global pandemic of 2020.

Interestingly, the challenges of the current pandemic have not directly affected the volume of scientific output relevant to organic reaction mechanisms; the size of this volume is in keeping with those of recent years. Perhaps in the following years, this may become leaner due to laboratory shutdown, which will therefore impact primary research output. It is interesting to see if this is eventually occurs.

M. G. Moloney

1Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

School of Chemical and BioPharmaceutical Sciences, Technological University of Dublin (TU Dublin), Dublin, Ireland

CHAPTER MENU

Formation and Reactions of Acetals and Related SpeciesReactions of GlucosidesReactions of Ketenes and Related CumulenesFormation and Reactions of Nitrogen DerivativesImines: Synthesis, and General and Iminium ChemistryMannich and Mannich‐type ReactionsStereoselective Hydrogenation of Imines, and Other Reductive ProcessesCyclizations of IminesOther Reactions of IminesOximes, Oxime Ethers, and Oxime EstersHydrazones and Related SpeciesC—C Bond Formation and Fission: Aldol and Related ReactionsReviews of Aldols, and General Reviews of Asymmetric CatalysisThe Asymmetric AldolThe Morita–Baylis–Hillman ReactionOther Aldol and Aldol‐Type ReactionsAllylation and Alkynylation ReactionsThe Michael AdditionOther Addition and Related ReactionsArylationsThe Wittig and Other OlefinationsHydroboration and Hydroacylationα−Aminations and Related ReactionsMiscellaneous AdditionsReactions of Enols, Enolates, and Related ReactionsTautomerismEnol Ethers, Enol Esters, and Enolatesα−Halogenation, α−Alkylation, and Other α−SubstitutionsOxidation of Carbonyl CompoundsOxidation of Aldehydes to AcidsCross‐dehydrogenative and Related C–C Coupling Processes, and C()‐H ActivationsOther Oxidations and Oxidative ProcessesReduction of Carbonyl CompoundsMiscellaneous CyclizationsOther ReactionsReferences

Formation and Reactions of Acetals and Related Species

A hemiacylal‐type species (1, from Ph—CH2—O—CHMe—CO2H) was formed in a study of photocatalytic decarboxylative acetoxylation of aliphatic carboxylic acids, employing copper(II) catalysis and a hindered acridinium cation in a single electron transfer (SET) process.1

Some preliminary results in trithioester exchange with thiols, and in metathesis between trithioesters, have been described. The reactions are discussed in terms of their potential, as tools for dynamic covalent chemistry.2 Acetal metathesis is also described, particularly in the context of making polyacetals via acetal metathesis polymerization (AMP).3

C‐Alkynyl‐N‐Boc N,O‐acetals, R1—C≡C—CCH(OR2)NHBoc, have been reacted with oxonium ylides (generated in situ from α−diazoketones) to give polyfunctional propargyl‐amines. A rhodium(III)/chiral Bronsted acid catalyst system gives high yields/des/ees.4

Reactions of Glucosides

A short tutorial/review (55 references) describes advances in stereo‐ and regio‐selective glycosylation with protection‐less sugar derivatives.5 A review (38 references) describes the development of glucose transport inhibitors, which are potentially useful for selective attack on cancer cells (due to their altered metabolism and enhanced glucose demand), and other medical conditions.6 Synthetic strategies for regio‐ and stereo‐selective fluorinations of sugars have been reviewed (73 references), focusing on reaction mechanisms and biological applications.7

The possibility of inosine tautomerism in water has been investigated by computation, including an exploration of relevant conformational space, inosine‐water clusters, hydrogen bonding, and comparisons with the gas phase. The 6‐enol tautomer appears to be accessible via an asynchronous concerted route.8

An unusual 1,5‐ or 1,6‐alkyl transposition has been reported along with acetalization of 3‐deoxy glycals, using TMSOTf as Lewis acid. Although the mechanism has not yet been pinned down, the transformation opens up routes to 2‐C‐branched bicyclic acetals of various deoxy‐sugars, and to 2‐C‐branched levoglycosans.9

In a total synthesis of saffloneoside, an unusual para‐hydroxycinnamylcyclopentenone C‐glucoside, a stereospecific acyloin contraction was found to be controlled by the glucose moiety.10

A glycosyl fluoride has been activated for glycosylation using indium(III) triflate. This mild, nontoxic catalyst allows the process to occur under ambient conditions, stereoselectively, without pre‐activation or additives, and with simple workup.11

Unprotected mono‐ and di‐saccharidic carboxamides undergo transamidations with primary and secondary arylic, heterocyclic, and aliphatic amines without solvent or catalyst, producing only ammonia as by‐product. A known epimerization at the α−position is a limitation of the method.12

A new route to trifluorinated glucopyranose analogues has been developed, starting from inexpensive levoglucosan and using a Chiron approach. The dominant conformation was established for each. Lipophilicities were then measured, using 19F‐NMR spectroscopy to determine log P: significant variations were seen, with four isomers varying between −0.64 and −0.18.13

β−D‐Glycosaminosides have been prepared via a 2,4‐nitrobenzenesulfonamide‐directed SN2‐type displacement with good stereoselectivity. Examples from the gluco‐ and galacto‐series are reported.14

Novel triazole‐fused iminocyclitol‐δ−lactams have been prepared and tested as glycosidase inhibitors.15

Pyrolysis of holocellulose produces carboxylic acids and alcohols. Acetic acid and glycerol were selected as representative compounds in a DFT study of secondary reactions arising from such species during pyrolysis. Glycerol can produce vinyl alcohol, acrolein, acetaldehyde, and acetol by various paths, and can also catalyse reactions of acetic acid.16

Such pyrolysis also allows isomerizations between isomers of monosaccharides to occur, and a computational study of the rates and equilibria of such processes indicates that barriers are significantly lowered if a hydroxy group within the monosaccharide participates, or an external R–OH group, including that of water. The equilibrium constants calculated indicate that higher temperatures favour furanoses, and also linear aldehyde forms.17

Stereoselectivity in glycosylation with deoxofluorinated glucos‐ and galactos‐azide thiodonors has been investigated by low‐temperature NMR for the case of the Tf2O/Ph2SO promoter system, with the formation of covalent α−triflate and both anomers of oxosulfonium triflate being observed. The selectivity depends on the configuration of the glycosyl donor and on the reactivity of the acceptor: reactive ones favour 1,2‐trans‐β−glycosides for both D‐gluco and D‐galacto donors, while poorer acceptors favoured 1,2‐cis‐α−glycosides with D‐galacto donors (but were unselective with D‐gluco donors).18

4‐O‐Glycosylated 2‐pyrones have been synthesized by a gold(I)‐catalysed intermolecular rearrangement of glycosyl alkynoic β−ketoesters.19

A pyrrolidine salt converts 2‐deoxyribofuranoses to 2‐deoxyribofuranosides via a furanosyl oxocarbenium ion, trapped with various alcohols: α−selectivity varies from complete to non‐existent, and the reasons are discussed. An unexpected β−selectivity in the case of 2‐cyanoethanol is explained in terms of a nitrile effect.20

C‐Glycosides have been prepared by a carbonylative Negishi‐type coupling of 2‐iodoglycals and alkyl or aryl halides, using catalysis by palladium and base.21

Cascade aldol reactions of aldopentoses with methyl ketones have been studied by QM simulation, using both L‐ and D‐proline as catalysts, and identifying matched and mismatched cases. The mechanism identified includes Mannich, proline hydrolysis, retro aza‐Michael, and oxa‐Michael steps.22

A range of anthocyanidins (e.g. 2) and anthocyanins (glycosides of anthocyanidins) have been prepared and tested as inhibitors of α−glucosidase. Some proved quite potent: (2) exhibits IC50 = 14.4 µM, holding out potential application for diabetes. Fluorescence quenching and in silico studies have been used to characterize the binding.23

Similar studies have been undertaken for compounds isolated from the bark of Quercus coccifera, a folk medicine used to treat diabetes and other conditions. Several are inhibitors of α−glucosidase, and also of tyrosinase.24

Another antidiabetic study examined the inhibition of three different α−glucosidases by furofuran lignans: these molecules possess one or two catechol (ortho‐dihydroxybenzene) moieties.25

Gold(III)‐catalysed glycosylation has been effected using phenylpropiolate glycosides: the method benefits from phenylpropiolic acid (Ph—C≡C—CO2H) being an easily separable and reusable leaving group, the reagents are stable and the conditions mild, and good anomeric selectivity was found for mannosyl and rhamnosyl donors.26

The significant reactivity difference between hexoses and N‐acetylhexosamines under the conditions of MS collision‐induced dissociation(CID) has been studied by experiment and computation.27

Reactions of Ketenes and Related Cumulenes

The reaction of ketene with hydroxyl radical is of growing interest, partly because of its implication in combustion of fuels. A computational study has estimated rate coefficients and their dependence on temperature and pressure: formation of CH2OH and CO by OH addition to the olefinic carbon is the dominant process under all conditions.28

Inline reaction monitoring of the acetylation of benzyl alcohol was conducted using a microfluidic stripline NMR experiment, and—in the case of catalysis by tertiary amines—shows ketene as an intermediate.29

The formation of ketene from acetic acid as catalysed by LaMnO3 has been studied for strontium‐substituted catalysts, La1−xSrxMnO3: Sr substitution accelerates the reaction, apparently by increasing surface oxygen vacancies.30

β−Ketothioesters have been prepared by acid‐catalysed hydrolysis of ketene N,S‐acetals with an amine as the leaving group.31

Succinimides with N‐ and C‐substitution (3, R2 typically α−keto) have been prepared by reaction of ketene N,S‐acetals with glyoxal (ethanedial, as a 40% aqueous solution).32

Heterocyclic ketene aminals (4, n = 1, 2) undergo a tandem cycloaddition/auto‐oxidation with diazo‐esters in air to give epoxypyrrolidines in up to 98% ee.33

A new metal‐free synthesis of benzazepinones (5) involves an intramolecular cyclization involving ketene iminium intermediates, starting from an ortho‐vinyl‐anilino‐amide. The factors that favour the reaction over a competing formation of a cyclobutaniminium salt were also explored.34

α−Chiral esters have been prepared by a photocatalysed Wolff rearrangement of α−diazoketones in up to 95% ee, with additional catalysis by a chiral benzotetramisole.35

A 3 + 2 cyclization of siloxyalkynes, R1—C≡C—OSiR23, with suitably substituted isocyanides, EWG—CH2—N+≡C:−, yields oxazoles (6) in good yield, with the siloxyalkyne supplying the C—O unit for ring formation: it is more typically a C≡C contributor. Promoted by tetrabutylammonium fluoride, a ketene intermediate is proposed. However, while fluoride promotes displacement of silicon to yield an ynolate anion, it is not essential that it is stoichiometric: tetrabutylammonium hydroxide can serve as a catalyst for a later step.36

A dichloroketene 2 + 2 cycloaddition has been employed in a synthesis of the natural product, Haouamine A.37

A scandium phosphonioketene complex has been reported and characterized.38

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, and General and Iminium Chemistry

A short review (18 references) describes NHC‐catalysed umpolung reactions of imines and their role in achieving enantioselectivity.39

The use of benzophenone Schiff bases of glycine derivatives as versatile starting materials for synthesizing amino acids and their derivatives under phase‐transfer conditions has been reviewed (115 references). The related use of aldimine derivatives of monosubstituted amino acid esters is also covered.40

DFT has been used to probe the origin of the chemo‐ and stereo‐selectivities of the addition of saturated esters to iminium ions, as catalysed by isothioureas.41

Hemigossypol (7) and gossypol (a related ‘dimer’ diad) are natural products of medicinal interest, as are Schiff bases derived from them. Several of the latter are the subject of a DFT study of their tautomers: for bis‐Schiff bases of gossypol, this includes imine‐imine, enamine‐enamine, and imine‐enamine forms.42

N‐Hydroxyanilines (Ar‐NHOH) react with diazo compounds (R1R2C=N2) to give imines, R1R2C=N—Ar, via a ‘rebound hydrolysis’ mechanism.43

As part of a route to produce (thiophenyl)pyrazolyl‐β−lactams, 2‐acetylthiophene has been condensed with phenylhydrazine (PhNHNH2) to give the corresponding hydrazone, 2‐thiophenyl‐CMe=N—NHPh, which—on reaction with phosphorus oxychloride/DMF—gives 1‐phenyl‐3‐(1′‐thiophen‐2′‐yl)‐1H‐pyrazole‐4‐carbaldehyde (8, X = O). Subsequent treatment with amines, RNH2, gives a series of corresponding imines (8, X = N–R), which can easily be converted to β−lactams by cyclization with a suitable ethanoyl chloride.44

Protected tetrahydroquinolines (9, R1 = H) react in a transition‐metal‐free oxidative cross‐coupling with triorganoindiums, (R1)3In, to give 1‐substituted products [R1 = (hetero)aryl, alkyl, and alkynyl]; iminium ion intermediates are implicated, with a 1H‐NMR signal being observed at 9.5 ppm for the H–C=N+–Cbz moiety, generated from the starter (9) using trityl tetrafluoroborate, Ph3CBF4.45

C,N‐Cyclic azomethine imines (10) undergo a (3+1) annulation/rearrangement cascade with 3‐chloro-oxindoles to give hexahydro-indeno[2,1‐c]pyrazole spiro‐oxindoles (11). Modest des were obtained, but racemization was observed over time, possibly due to the process being reversible.46

The reaction of an α−cyclopropyl N‐acyliminium ion (12), derived from the hemiaminal, with indoles can involve 1,2‐addition or homoconjugate addition. A synthetic and DFT study has probed the factors involved, finding the 1,2‐addition to be kinetically controlled: destabilizing the 1,2‐adduct makes its formation reversible and allows the thermodynamically preferred homoconjugate addition to predominate. Other electron‐rich arenes were also tested.47

An intramolecular iminium cyclization features simultaneous generation of planar, central, and axial chiralities on a ferrocene backbone, as confirmed by NOESY, variable‐temperature NMR, and X‐ray diffraction.48

Bicyclic isoxazolidines (13) have been accessed in good de and up to 99% yield via 3 + 2 cycloaddition of oxaziridines and cyclic allylic alcohols, apparently via a carbonyl imine intermediate [R2—N−—+O=CH—R1] derived from the oxaziridine, and an allyl cation.49

To improve our understanding of rhodium‐organic cooperative catalysis, DFT has been used to estimate Rh—C bond dissociation enthalpies of (iminoacyl)rhodium(III)hydride and (iminoacyl)rhodium(III)alkyl.50

Novel‐five‐membered N‐tosyl cyclic α,β−unsaturated iminium ions (14) have been generated from stable precursors, and applied in iminium Diels–Alder cycloadditions, Mukaiyama–Michael reactions, and intramolecular cyclizations.51

Mannich and Mannich‐type Reactions

A new and unusual route to indolizines (15) reacts 2‐mercaptopyridine with a nitroallylic acetate in the presence of base, via a domino SN2/Michael addition sequence followed by removal of the sulfur moiety.52

An organocatalytic asymmetric Mannich addition of 3‐fluoro‐oxindoles to dibenzo[b.f][1,4]oxazepines (16) allows a highly enantioselective synthesis of quaternary C–F stereocentres. Using a bifunctional thiourea catalyst derived from a Cinchona alkaloid, yields/ee/de of up to 88/99/95% were obtained.53

An investigation of labile imino‐substituted ethano Tröger bases has identified a reversible Mannich reaction as the cause of the racemization.54

A Mannich reaction between an O‐triethylsilylated hemiaminal, Et3SiOCH2NMe2, and a substituted aniline can generate a wide variety of diamine, triamine, imine, or 1,3,5‐triazine products, depending on the nature of the aniline's substituent(s).55

Enone (17) has been converted to a β−amino diaryldienone (18) by reaction with a secondary amine and paraformaldehyde, via a double Mannich/β−elimination sequence.56

Spiro-indolenines, acting as ω−indol‐3‐yl α,β−unsaturated ketones (19), have been employed for enantio‐ and diastereo‐selective synthesis of 3‐(indolyl)‐pyrrolidines via a Michael/retro‐Mannich/Mannich sequence, employing a BINOL‐derived chiral phosphoric acid (CPA).57

Such CPAs are often buttressed and electronically modified with 3,3′‐substituents. The structural space around such catalysts and the effect of such substituents on the CPA's Bronsted acid catalysis have been investigated by NMR and DFT studies for the case of CPA/imine complexes.58

Stereoselective Hydrogenation of Imines, and Other Reductive Processes

Chiral β−fluoroalkyl β−amino acid derivatives (20, Rf = CF3 or CF2H, R = ester or amide) have been prepared in excellent ee from the corresponding enamines (which may tautomerize to the imines), using palladium(II) catalysis with chiral ligands. Deuterium labelling and NMR experiments support the route via the imine tautomer.59

Aryl imines, activated with N‐diphenylphosphinoyl (or N‐tosyl) groups, have been enantioselectively hydrogenated using an unsymmetrical iron(II)–P–NH–P′ catalyst, with DFT calculations suggesting that the NH of the catalyst plays a key role: it activates and orients the imine towards hydride attack by hydrogen bonding to the PO (or SO) group on the imine nitrogen, rather than to the imine nitrogen itself.60

A DFT investigation of the reduction of quinoline by the Hantzsch ester with iodo-imidazolinium catalysis seeks to tease out contributions of halogen bond catalysis versus Bronsted acid catalysis, noting the complication that such a catalyst can itself be reduced by the Hantzsch ester, generating a Bronsted acid as a by‐product!61

n‐Butyllithium catalyses hydroboration of aldimines with HBpin (pinacolborane) at ambient temperature, a method which also works for hydroboration of alkynes (with trans‐selectivity), though there is a high selectivity for the imine function over the alkyne. For the imine product, treatment with silica at 50 °C removes boron to give free secondary amine.62

Cyclizations of Imines

Enantioselective copper(II)‐BOX‐catalysed spiroannulation of N‐Boc‐imino‐oxindoles (21) with allylsilanes shows a nonlinear effect (NLE): the significantly positive effect observed has been explained in terms of a heterochiral ML2 species detected by ESR.63

A computational study has probed the mechanism of the mild, caesium carbonate‐catalysed reaction of a simple N‐protected aldimine, Ph—CH=N—Boc, with a quaternary ammonium amide, Me3N+–CH2CONMe2 Br−, to give the trans‐aziridine (22). The ammonium salt is deprotonated to the ylide, and this is then proposed to react with the imine to give a betaine‐like intermediate, which subsequently loses trimethylamine.64

Pyridine‐fused heterocycles have been prepared via a 6π‐aza‐electrocyclization of imino‐alkyne derivatives. For example, N,O‐dipropargylaldimine (23, prepared from the corresponding aldehyde and propargyl amine) undergoes a 2 + 4 cycloaddition (the 6π‐aza‐electrocyclization) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) to give tricycle (24), which aromatizes via a 1,5‐hydrogen shift to chromenopyridine (25). If an ortho‐hydroxy group is included in the imine, (benz)oxazepane derivatives can be prepared. Several other heterocycles are similarly described.65

3,4‐Dihydro‐2H‐1,3‐benzoxazines (26) have been prepared via a one‐pot, three‐component cyclization of an O‐Boc salicylaldehyde, an aldimine (R2—CH=N—R3), and a Grignard (R4MgCl). An ortho‐quinone methide intermediate has been implicated.66

3,4‐Dihydroquinolines (27) undergo aza‐Navarov cyclizations with α,β−unsaturated acid chlorides to give α−methylene‐γ−lactams as single diastereomers.67

Imidazopyridines (28) have been prepared from formimidamide pyridinium salts (made from 2‐aminopyridine starters) in a new alternative to classical α−haloketone chemistry.68

Arylcyanoacetylenes, Ar1—C≡C—CN, undergo highly regioselective phosphine‐catalysed 2 + 2 + 2 annulations with N‐tosylaldimines, Ar2—CH=N—Ts, to give 1,2‐dihydropyridine‐3,5‐dicarbonitriles (29); the closely related ‘1,6’‐isomer (30) was not observed.69

SnAP [tin (Sn) amine protocol) reactions involve an aminocyclopropane with pendant ether and tin atoms (31) undergoing imine formation with aldehydes (or ketones), followed by copper(II)‐catalysed cyclization to give N,O‐heterocycles. Detailed investigations tend to confirm the initial assignment of the cyclization mechanism as being radical‐based.70

A diastereoselective aziridination of olefins via an organocatalytic nitrene transfer from [N‐(p‐toluenesulfonyl]imino]phenyliodinane (PhINTs) is catalysed by an iminium salt.71

DFT has been used to probe the mechanism of an NHC‐catalysed oxidative α−C(sp3)‐H activation of aliphatic aldehydes and subsequent cascade 2 + 2 cycloaddition with ketimines (e.g. 32). In the example, the cycloaddition involves an azolium enolate intermediate reacting with the C=N bond of (32) rather than with the C=O bond.72

Sulfamate‐derived cyclic imines undergo phosphine‐catalysed 3 + 2 cycloaddition with β−sulfonamido‐substituted enones, to give imidazoline derivatives in high de.73

Cyclic enamides have been prepared in up to 99% ee via a chemo‐ and regio‐selective catalytic umpolung cascade reaction of α−imino‐amides with enals.74

Other Reactions of Imines

A review deals with the development of a three‐component reaction to yield highly substituted β−keto‐enamides (33). Dubbed ‘LANCA’ after the components, it features a lithiated methoxyallene (34, ‘LA’) reacting with pivalonitrile (‘N’) to give an intermediate allenyl‐imine (35), which reacts with a carboxylic acid (‘CA’, TFA), under very mild conditions (−78 °C, then 0 °C → RT). The resulting β−keto‐enamides (33) are very useful for making functionalized pyridines, pyrimidines, oxazoles, and quinoxalines.75

The mechanism of the tributylphosphine‐catalysed 1,4‐dipolar addition of an allene ester, H2C=C=CMe–CO2Et, and an imine, trans‐Me—CH=N—Ts, to give a tetrahydropyridine (36) has been investigated at the M06‐2X/6‐311++G(d,p) level of theory.76

The first catalytic asymmetric alkenylation of isatin imines has been reported.77 An N‐trifluoroethyl imine derived from isatin (37, R1 = H) reacts with cinnamyl methyl carbonate (Ph—CH=CH—CH2—OCO2Me) in a formal net C‐alkenylation to give chiral imine derivatives (37, R1 = CH2—CH=CH—Ph) in high yield and ee. The iridium‐catalysed reaction involves an umpolung allylation followed by a 2‐aza‐Cope rearrangement.78

An ortho‐nitrosobenzaldimine intermediate is critical to a photochemical Davis–Beirut synthesis of N‐aryl 2H‐indazoles: previously generated under basic conditions, a new method uses a Bronsted acid catalyst.79

A one‐pot Knoevenagel–Chan–Evans–Lam coupling of a salicylaldehyde with malononitrile (NC—CH2—CN) in the presence of triethylamine produces, initially, an unsubstituted 2‐imino‐2H‐chromene‐3‐carbonitrile (38, R1 = H), which—on the addition of an arylboronic acid and copper(II)—converts to the N‐aryl derivative (38, R1 = Ar).80

A cyclic silyl enol ether undergoes an α−alkenyl addition to an isatin‐derived N‐Boc imine to give a protected amine retaining the silyl enol ether moiety (39). A silyl shift had been expected after the addition (to give the protected amine with pendant cyclopentanone, i.e. the Mukaiyama–Mannich product), but a proton shift intervened. Control experiments suggest that the Si‐ and H‐shifts are in competition. Using a chiral zinc(II) catalyst, the tandem addition/shift process is rendered enantioselective. The product is easily converted to give a β−fluoroamine with two vicinal tetrasubstituted carbons.81

2‐Aryl benzenesulfonimides, ortho‐Ar2—Ar1—CH=N—SO2—Ph, undergo a mild tandem annulation/aromatization to yield 6H‐phenanthridines (40) in a process catalysed by copper(0) and Selectfluor.82

2‐Cyano‐N‐benzylidene-imine has been reacted with a thiol in the presence of Cinchona‐based alkaloids to desymmetrize it; a dynamic kinetic resolution is achieved via an organocatalytic heterocyclization. Mechanistic investigations clearly show how hydrogen bonding effects can explain the enantioselectivity, and the route provides an enantiopure tertiary isoindolinone N,S‐acetal for the first time.83

A polarity‐reversed addition of enol ethers to glyoxalate aldimines in the presence of TMS‐azide yields γ−azido amino acids. The redox‐neutral, metal‐free process is activated by visible light, and likely involves an oxyalkyl radical intermediate.84

Michael addition of 2‐chloromalonate esters to conjugated imines gives chiral α,β−dehydro‐α−aminoesters enantioselectively. The configuration of the double bond in these enamines can be chosen by the catalyst, and in particular, its metal: La(OTf)3 gives Z‐, while Ca(OTf)2 gives E‐.85

A DFT study has examined the imine‐type intermediates implicated in the addition of organometallics to nitriles.86

A catalytic asymmetric synthesis of γ−lactams has been developed, using cycloaddition between enolizable anhydrides (such as succinic anhydride) and imines, with a simple bisurea catalyst. A DFT‐generated model shows how the enolate and iminium components are likely to bind.87

Intramolecular cyclization of iminyl radicals has been investigated by QM and a numerical simulation for evidence of a neophyl‐like (ring contraction) rearrangement.88

Chiral oxazaborolidinium ions catalyse enantioselective Strecker and allylation reactions of N-aryl aldimines in yields/ee up to 98/99%, allowing access to α-aminonitriles and homoallylic amines.89

A magnesium-aluminium hydroxide acts as a heterogeneous catalyst for preparation of azetidine-2-ones from aldimines as acid chlorides in a greener approach to this reaction. However, an unexpected C—N cleavage of the azetidine-2-ones was detected in some cases, giving an enamide. The catalyst was characterized by N2-adsorption/desorption, X-ray diffraction, SEM, and high-resolution transmission electron microscopy (HR-TEM).90

Rhodium(III) catalyses formation of 3‐amino‐4‐arylisoquinolinones from 4‐diazo‐isochroman‐3‐imines and N‐methoxybenzamides.91

The bicyclic amidines, DBU and 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN), undergo ring‐opening reactions with benzaldehydes, to yield the corresponding benzaldimines with a γ−pendant lactam, using 1,2‐dimethyl‐3‐ethylimidazolium iodide (41) as catalyst, an ‘NHO’ species (N‐heterocyclic olefin).92

A fluorinated iminoyl chloride, Ar—N=C(CF3)—Cl, acts as a four‐atom building block, facilitating construction of benzazepines via 4 + 3 annulation with MBH (Morita–Baylis–Hillman) carbonates.93

DFT has been used to examine hydrogen bond bifunctional catalysis in the dipolar cycloaddition of azamethylene imines to nitroalkenes catalysed by Takemoto's catalyst, with a particular focus on activation by intramolecular hydrogen bonds and its effects on reactivity and enantioselectivity.94

Chiral cyclic ureas such as trans‐2‐imidazolinones have been prepared from a range of nitrones, Ph—N+(—O−)=CHR, and isocyano‐acetate esters in good yields, fair de, and up to 99% ee, using as catalysts a chiral bifunctional Bronsted acid and Ag+ as a Lewis base.95

Carbodiimides, RN=C=NR, have been monohydroborated with pinacol borane (HBpin), using commercial 9‐borabicyclo[3.3.1]nonane dimer (H‐BBN dimer) as a metal‐free catalyst. Based on studies of stoichiometry and kinetics, and DFT calculations, a heterocyclic amidinate intermediate is proposed.96

Oximes, Oxime Ethers, and Oxime Esters

Hydrogen bonding effects in the Beckmann rearrangement of diphenyl‐ketoxime on protonated amino‐functional mesoporous silica have been studied in a range of solvents.97

In a new enamide synthesis, a simple oxime such as that of acetophenone is converted to its acetate ester (with acetic anhydride), and then reduced by KI/Na2S2O4 with iron(II) catalysis to give the N‐acetyl enamide, Ph—C(=CH)—NHAc, possibly via the intermediate radical, Ph—C(Me)=N⋅.98

The use of oximes and hydroxamic acids as α−nucleophile compounds which can act as catalytic scavengers of toxic organophosphates is described in an account which focuses in particular on N‐methylpyridinium oximes (2‐, 3‐, and 4‐isomers).99

α−Sulfonyl ketones, R1—CO—CH2—SO2Tol, undergo α−methylsulfonylation by DMSO, to give the α,α−bis‐derivatives, R1—CO—CH(SO2Me)—SO2Tol. This substitution is achieved using hydroxylamine/HCl, i.e. an umpolung route via the oxime.100

Chromones (42, X = CH or N) have been prepared from ortho‐bromoaryl ynones and benzaldoxime via sequential C—O bond formation. The oxime acts as a source of hydroxide, with this oxygen ending up in the ring, and 1,3‐diketone intermediates are implicated.101

In a new green protocol for nitrile oxides, R—C≡N+—O−, they have been generated from aldoximes (RCH=NOH) using Oxone (potassium peroxymonosulfate) and sodium chloride to first form the hydroximoyl chloride [RC(Cl)=NOH]. Both of these species are isolable and observable by NMR, and a base (sodium carbonate) is required to perform the dehydrochlorination. To test the usefulness of the method, an alkene was added to allow 1,3‐dipolar cycloaddition to give isoxazolines. Indeed, the whole protocol was successfully converted to a one‐pot, three‐component reaction by mixing aldehyde, hydroxylamine, and alkene, with addition of NaCl, Oxone, and Na2CO3 in acetonitrile for comparable yields.102

Allyloximes (43) undergo an alkoxy‐oxygenation in a reaction promoted by iodosobenzene diacetate, Ph‐I(OAc)2, to give isoxazoline products (44).103

2‐Aroylthienothiazoles (46) have been prepared via C—H/N—O bond functionalization of α,β−unsaturated ketoximes (45), using an acetophenone (or heterocyclic analogue) and octasulfur. Evidence for a radical process is presented, and for the intermediacy of 3‐aminobenzothiophene (from the oxime and S8) and of phenylglyoxal (ArCOCHO, from acetophenone forming a carbon radical, which gets oxidized).104

In a similar process, vinyl or aryl methylketoxime acetates participate in a three‐component bis‐heteroannulation with ortho‐chloro or ‐bromobenzaldehydes and octasulfur to give thieno[3,2‐c]isoquinolines or benzo[4,5]thieno[3,2‐c]isoquinolines (47). The reaction is catalysed by copper(I) and requires lithium carbonate as base in DMSO at 140 °C.105

para‐Methoxybenzyl cycloketoxime ethers (PMB oxime ethers) ring‐open in reaction with electron‐deficient terminal alkenes, H2C=CR4‐EWG, to give nitriles (48, n = 1, 2; Y = C, O, N), via a radical C—C bond cleavage/addition cascade. The reaction is promoted by photogenerated iminyl radicals under metal‐free conditions.106

The 2‐aminopyridine moiety features in many drugs and is also a starting point for many more elaborated heterocycles. A new synthesis cyclizes a simple ketoxime, R—CMe=NOH, with tetracyanoethene (TCNE) to yield 3,4‐dicyano‐substituted 2‐aminopyridines (49) using copper(I) chloride as catalyst in toluene at 120 °C. A radical mechanism is proposed, and addition of TEMPO is found to completely kill the reaction.107

A defluorinative ipso‐functionalization of (trifluoromethyl)alkenes (50) is reported, in which an oxime (51) reacts to give an O‐(1,1‐difluoroallyl) oxime ether (52) via a single C(sp3)—F bond activation in a CF3 group. The reaction is carried out in DMF with caesium carbonate as base, under nitrogen at 90 °C for 12 hours. The γ−selective product (i.e. reaction at the other end of the alkene) is not observed. Radical traps have no effect, but oxime ethers are unreactive, suggesting the need to deprotonate the oxime OH. Indeed, the mechanism is proposed to involve the conjugate base of the oxime reacting in an SN2‐like process with the CF3 carbon.108

Spirocyclic NH‐azetidines (e.g. 2‐substituted‐1‐azaspiro[3.5]nonanes, 53) have been synthesized from oxime ethers (in this case, from CyHx=NOR1) using a Grignard reagent, R2—CH2—CH2—MgBr, and titanium(IV) mediation. A Kulinkovich‐type reaction is proposed, with a titanacyclopropane intermediate acting as a 1,2‐dianion equivalent which inserts into the 1,2‐dielectrophilic oxime ether. An alternative route, using a terminal alkene instead of the Grignard, is also explored.109

C1‐Substituted unsymmetrical oxabenzonobornadienes (54) undergo ring‐opening reactions with oximes to give either naphthols (if R is donating) or 1,2‐dihydronaphthols (diastereoselectively), the latter arising from oxime addition at C(2), but the isomer arising from reaction at C(3) is not observed. Palladium(II)/Lewis acid co‐catalysis is employed.110

Aromatic ketoxime ethers, Ar—C(R)=N—OMe, undergo C—H amination in the ortho‐position in rhodium(III)‐catalysed reaction with benzenesulfonamides. Potassium acetate was found to be essential for the process.111

In another reaction of aromatic ketoxime ethers, Ar—C(Me)=N—OMe, a pendant ketone can be placed in the ortho‐position via rhodium(III)‐catalysed oxidative coupling with a cyclopropanol. DFT studies indicate that ring‐opening of the cyclopropanol occurs first, followed by C—H activation, with an outer‐sphere mechanism involving N→Rh binding to set up the oxime's directing role and concerted metallation–deprotonation.112

Samarium(II) iodide promotes reductive cleavage of the N—O bond in oxime ethers to produce an iminyl radical. If the oxime ether has an appropriately placed pendant bromine, intramolecular cyclization provides a five‐membered cyclic imine.113

A photoredox benzyl activation involving C(sp3)—C(sp3) bond dissociation of 1‐aryl acetone oxime esters, Ar—CHR—C(Me)=N—OPG, under irradiation by visible light has been developed: subsequent benzyl C—O and C—N formation via coupling with alcohols or amines yields useful ether and amine derivatives, Ar—CHR—X (X = O, N). Control experiments, electrochemical investigations, and in situ NMR spectroscopy have been used to probe the mechanistic manifold.114

Amino-oxygenation of alkenes has been achieved using O‐acylhydroxylamines, with catalysis by copper(II): the method can be applied to the use of oximes, carbonyls, thio‐carboxylic acids, and alcohols as nucleophiles, which have broad functional group tolerance.115

Cycloketone oxime esters with ring sizes of 4–7 react in DMF at 70 °C with enaminothiones, R1—C(=S)—CH=C(NHR2)–SMe (α−thioxo ketene N,S‐acetals), to give 2‐cyanoalkyl‐3‐aminothiophenes (55). The copper(I)‐catalysed process involves radical C—C bond cleavage and 4 + 1 annulation.116

A similar C(sp3)–N cross‐coupling reaction of cyclobutanone oxime esters with anilines—again catalysed by copper(I)—yields 4‐(arylamino)butanenitriles,117 and O‐Boc cyclobutane‐ and cyclopentane‐ketoximes yield ω−trifluoromethyl nitriles on treatment with a Zn(CF3)2 complex.118

Cyclobutylketoxime aryl esters react with anilines in a SET‐induced C(sp3)–N coupling via a C—C bond cleavage catalysed by copper(II) triflate, with loss of the ester functionality, yielding an aniline with an ω−cyano function, Ar—NH—(CH2)3—CN. In some cases, the product's secondary aniline can react again. A radical pathway is indicated, and photoredox catalysis is also effective.119 Another report describes a similar cyclobutylketoxime aryl ester substituting a cyanopropyl group on the 3‐position of a coumarin (56), on carbon in (2H)‐indazoles (57),120 and also on carbon in quinoxal‐2(1H)‐ones (in this case, for an oxime ether, and with photocatalysis).121

Acetophenone O‐acetyl oximes have been annulated via a redox‐neutral ortho‐C—H activation with allenoates to produce isoquinolines, using rhodium(III) catalysis.122

A copper‐catalysed iminohalogenation of unactivated alkenes of γ,δ−unsaturated oxime esters (58, Z = CH2, CMe2, NR) was achieved using copper(I) and halide salts (KX), yielding functionalized 2‐halomethyl pyrrolines (59, X = I, Br, or Cl). Iminyl radical intermediates are proposed.123 The method has been extended to imino‐sulfonylation, imino‐cyanogenation, and imino‐thiocyanation to give the corresponding pyrrolines.124

The ester derivative is not essential for such processes: the simple γ,δ−unsaturated ketoxime, Ph—C(=NOH)—CR2—CH2—CH=CH2, reacts with para‐iodochlorobenzene to give in some cases a carbonitronylation product, the 5‐membered cyclic nitrone (60, R = Me), or in other cases a carboetherification product, the 5,6‐dihydro‐4H‐oxazine (61, R = H).125

Oxime acetates undergo a copper(I)‐catalysed 3 + 3 cycloaddition with fluorinated enones, trans‐F5C2—CH=CH—COR, to yield 4‐(pentafluoroethyl)pyridines in a mild, redox‐neutral process. A copper(II)‐enamine intermediate is proposed.126

O‐Propargylic glyoxylate‐derived oximes, trans‐R1O2C—CH=N—O—CH(R2)—C≡C—R3, are cyclized and rearranged to give 2‐isoxazolines (62), using gold(I) catalysis.127

An oxime reagent (63) brings about a remarkable one‐pot deacetylative amination, converting acetophenones (Ar–Ac) and aliphatic methyl ketones (R–Ac) to primary amines (Ar–NH2, R–NH2). The domino transoximation/Beckmann rearrangement/Pinner process is catalysed by a Bronsted acid in methanol solvent. Ambient temperature works for the arenes, while the alkyl cases require reflux.128

Hydrazones and Related Species

While exchange at hydrazones via transamination processes has been exploited in dynamic combinatorial chemistry, the fact that the optimal rate occurs at c. pH 4.5 limits their use for biological targets. A DFT study has been undertaken with a view to identifying suitable substitutions that could nudge this towards pH 7. One strategy identified is to place N‐ or O‐hydrogen‐bond acceptors on the ‘carbonyl’ side. The use of a benzodihydropyran substituent looks promising.129

Regioselective syntheses of 1,3‐disubstituted and 1,3,4‐trisubstituted pyrazoles have been reported, using copper(II)‐catalysed cascade reactions of saturated ketones with hydrazines or aldehyde hydrazones. An enone intermediate is proposed to undergo 3 + 2 annulation.130

3,5‐Substituted pyrazoles have been prepared from phenylethyne, hydrazine, and O2 as oxidant, via a cascade of Glaser coupling and annulation. Promoted by visible light, the mechanism is proposed to include hydrogen atom abstraction and enamine‐imine tautomerization.131

2‐Aryl‐1,2,3‐triazoles (64) have been prepared from bis‐hydrazones via intramolecular N—N bond formation.132

β,γ−Unsaturated hydrazones (65) undergo a copper(II)‐catalysed aerobic 6‐endo‐trig cyclization to yield pyridazines (66). Changing the conditions to somewhat milder acetonitrile reflux gives the corresponding 1,6‐dihydropyridazine, suggesting that the latter is an intermediate in the formation of the aromatic (66) in the acetic acid condition.133

While E‐oxime ether azatrienes are inert to 6π‐electrocyclization (to give pyridine derivatives), their Z‐isomers proved inert. Switching to the more geometrically labile hydrazones solved the problem.134

1,3,4‐Oxadiazol‐2(3H)‐ones (67, R = alkyl or aryl) have been prepared from aldehydes (R–CHO), arylhydrazines, and carbon dioxide, in a reaction promoted by hypoiodite generated in situ. The first step is presumed to be formation of the hydrazone, which is then iodinated at carbon, followed by base‐catalysed ring closure.135

N′‐Alkyl benzohydrazides (68