Organic Reaction Mechanisms 2015: An annual survey covering the literature dated January to December 2015

Organic Reaction Mechanisms 2015, the 51st annual volume in this highly successful and unique series, surveys research on organic reaction mechanisms described in the available literature dated 2015. 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.

• Language: English
• Publisher: Wiley
• Release date: Feb 20, 2019
• ISBN: 9781119125075

Book preview

Contributors

Preface

The present volume, the 51st in the series, surveys research on organic reaction mechanisms described in the available literature dated 2015. 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.

All the chapters have been written by the members of a team of experienced ORM contributors who have submitted authoritative reviews over many years. We are naturally pleased to benefit from such commitment and consequent awareness of developing trends in the title area. Particularly noteworthy in recent years has been a major impact on directed organic synthesis through mechanistic studies which enable optimization of ligand design for highly selective transition metal catalysts.

In view of the considerable interest in the 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).

Although every effort was made to reduce the delay between the title year and the publication date, circumstances beyond the editor's control again resulted in the late arrival of a substantial chapter which made it impossible to regain our optimum production schedule. Steps have been taken to reduce the knock‐on effect of this occurrence.

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.

A. C. K.

CHAPTER 1

Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

Department of Science, 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 and Azirines

Alkylations, Arylations, Allylations, and Additions of Other C‐Nucleophiles

Miscellaneous Additions to Imines

Oxidation and 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

The Mukaiyama Aldol

The Baylis–Hillman Reaction and its Morita Variant

Other Aldol and Aldol‐type Reactions

Allylation and Related Reactions

Alkynylations

The Stetter and Benzoin Reactions

Michael Addition and Miscellaneous Condensations

Other Addition Reactions

Addition of Organozincs

Arylations

Addition of Other Organometallics, Including Grignards

The Wittig, Julia–Kocienski, Peterson, and other Olefinations

Hydrosilylation, Hydrophosphonylation, Hydroboration, and Addition of Isocyanide

Miscellaneous Additions

Enolization, Reactions of Enolates, and Related Reactions

Oxidation and Reduction of Carbonyl Compounds

Oxidation of Aldehydes to Acids

Oxidation of Aldehydes to Amides, Esters, and Nitriles

Baeyer–Villiger Oxidation

Miscellaneous Oxidative Processes

Reduction Reactions

Stereoselective Reduction Reactions

Other Reactions

References

Formation and Reactions of Acetals and Related Species

Lutetium(III) triflate catalyses acetalization of acetone with glycerol, (HOCH2)2−CH(OH), giving a regioselective preference for the 1,3‐dioxolane product (1, ‘solketal’), as against the six‐membered‐ring 1,3‐dioxane alternative. Density functional theory (DFT) studies have identified a constrained hemiacetal intermediate to explain the selectivity.(1)

To assist in using glycerol by‐product from biodiesel manufacturing, a quantum mechanics (QM) study of its acetalization with acetone has been undertaken, using benzenesulfonic acid as catalyst.(2)

Nucleophilic substitutions of acetals such as (2) with a remote benzyloxy group can be highly diastereoselective, an effect which increases as the reactivity of the nucleophile is increased, in violation of the reactivity/selectivity principle. The result has been explained in terms of multiple conformers of a reactive intermediate leading to the product.(3)

Acetophenones undergo mild one‐step α‐haloacetalization in ethylene glycol, using 1,3‐dihalo‐5,5‐dimethylhydantoins (3; X = Cl or Br). Temperature and solvent effects have been investigated.(4)

A kinetic study of acetal hydrolysis has examined the effect of 4‐alkoxy groups, with appropriate control of stereochemistry. For example, several acetal series (4) have been prepared with varying ring size (n = 1–4), and either endocyclic oxygen (X = H, Y = O) or exocyclic (X = OBn, Y = CH2), with appropriate non‐cyclic controls such as 4‐benzyloxy‐butanal dimethylacetal. Hydrolysis rate enhancements are of the order of 20‐fold, perhaps 200‐fold when controlled for inductive destabilization. However, rates of solvolysis of related tosylates show much larger effects, including a factor of nearly

10⁶ going from five‐ to eight‐membered rings. It is concluded that neighbouring‐group participation operates in the tosylate solvolysis, but not in the acetal hydrolysis.(5)

Using an amine as a nucleophile carrier, R2N−CH2Nu, a range of progressively more hindered α‐cyanoamines, R2N−CH2−CN (R = Me, Et, i‐Pr, and CyHx), have been tested as cyanating agents of acetals. The congested dicyclohexyl compound proved best: using 2 equiv, together with 2 equiv of trichlorosilane triflate in DCM at 0 °C for 30 min, benzaldehyde dimethyl acetal gave 95% yield of PhCH(OMe)CN. Similar results were obtained for a wide range of acetal types, and indeed for orthoesters (to give the cyanoacetal). Investigation by nuclear magnetic resonance (NMR) spectroscopy helped identify an oxocarbenium ion intermediate, Ph−CHO+−Me (as the triflate), upon addition of Cl3SiOTf, and addition of (CyHx)2N−CH2−CN rapidly gave the product, together with an iminium cation, (CyHx)2N+ CH2.(6)

Regioselective monoalkylation of diols is often achieved via dialkylstannylene acetal intermediates. Though slow to form, addition of nucleophiles helps, especially fluoride. The reaction of a fluoride salt (5) with bromomethane has now been studied at several levels of theory in the gas phase, and in DMF solution. In solution state most closely related to experiment, fluorinated monomers and monofluorinated dimers showed similar activation energies. A widely considered ‘Sn−O bond cleavage first’ mechanism did not feature, with C−O bond formation actually well advanced over Sn−O cleavage in the TS. Comparing gas phase with DMF, solvation effects significantly lower the energy of fluoride ion to form (5), but the tetramethylammonium cation stays close to the F atom.(7)

A series of dialkyl acetals, Me2N−CH(OR)2, derived from DMF have been screened for their ability to N‐alkylate 8‐oxoadenosine and guanosine at N(7). Comparative kinetic experiments have been used to explore the mechanism and side‐reaction possibilities.(8)

ortho‐Alkynylbenzaldehyde acetals and thioacetals (6) undergo a range of divergent cyclizations catalysed by palladium(II) or platinum(II) halides. While metal‐triggered C−X cleavage was previously proposed, DFT calculations now point to electrophilic activation of the alkyne as the initiating step. Terminal and non‐terminal alkyne cases are contrasted, and the nature of the heteroatom's effect on the route taken was also studied. The DFT results have led to some literature assignments being challenged, with new experiments reported that validate the new assignments.(9)

Hemithioacetal enantiomers (7) contain an unstable quaternary chiral centre and can equilibrate through their open‐chain ketone–enethiol form (8). Variable temperature and exchange spectroscopy (EXSY) NMR techniques have been used to measure the rates and barriers for the interconversion, in toluene solvent. A DFT study was also undertaken, but the toluene solvent severely constrains the possibilities in terms of acid–base and hydrogen‐bonding chemistry. A computed barrier of 40 kcal mol−1 is at odds with half that found by NMR. But an alternative path was found to resolve the discrepancy: a ‘solvent molecule’ is available … in the form of another hemithioacetal, which – through a dimer complex – assists the proton transfers.(10)

‘Fmox’, a 3‐Fmoc‐(1,3)‐oxazinane moiety, has been developed as a base‐labile aldehyde‐protecting group. For the example of the doubly protected 3‐aminopropanal (9), deprotection is 100% effected with 1% piperidine in 2 h, while leaving the amine protection intact. The group, like many others, is acid‐labile to the extent of 6% in 20% acetic acid and 93% in 10% TFA, though it survives in 0.1% TFA for 10 min. Protection of the aldehyde (10) requires N‐Fmoc‐3‐amino‐propanol/Na2SO4/HCl(cat.)/50 °C.(11)

Enantiomerically enriched β ²‐amino acids have been accessed in the form of their N,N‐diprotected esters (11) via dual activation of an enal (trans‐R−CHCH−CHO) and an N,O‐acetal (Bn2N−CH2−OMe), the activations being achieved by an N‐heterocyclic carbene (NHC) and an in situ‐generated Brønsted acid, respectively. The enal is converted to an azolium enolate, and the acetal to an iminium ion (Bn2N+ CH2) and methanol. Typical conditions are mild base at ambient temperature, giving ee up to 90%.<ee> The essence of the process is an aminomethylation of the enal α‐carbon, via an internal redox process.(12)

Isatin‐derived N‐Boc imines have been converted to the corresponding N,O‐aminals in up to 96% yield and 92% ee, using a cinchonidine–urea catalyst.(13) <ee>

Reduction of O,O‐, N,O‐, and S,S‐acetals to ethers has been reviewed.(14)

In a highly diastereoselective synthesis of diaziridines (12), an aldehyde or ketone (R¹COR²) is combined with an amine (R³NH2). Compound (12) is simultaneously a hydrazine and an aminal, with three chiral centres from achiral reactants: with ring strain and lone pair repulsion, stereochemistry is automatically anti at the nitrogens. The reaction is catalysed by hydroxylamine‐O‐sulfonic acid, which exists in zwitterionic form, H3N+−O−S(O)2−O−. NMR studies at low temperature indicate initial imine formation, and conversion over time to diaziridine. No non‐chiral intermediates were observed during the second process, indicating that the diastereoselective step may be concerted.(15) <de>

Propargylic acetals (e.g. 13) undergo asymmetric gold(I)‐catalysed 3 + 2‐cycloaddition with aldehydes to give functionalized 2,5‐dihydrofurans in yield/ee up to 84/95%. A new gold(I)‐catalysed cycloaddition of a secondary propargylic acetal (derived from a ketone) with nitrones is also reported.(16) <ee>

An acylrhodium(III) species may be a key intermediate in the rhodium(III)/copper(II)‐catalysed cyclization of phthalaldehyde with alcohols to give 3‐alkoxyphthalides (14). Replacing the alcohol with various 1,3‐dicarbonyls gives 3‐alkyl‐phthalides with side‐chain functionality.(17) <de>

Reactions of Glucosides

A palladium‐catalysed reaction of a 3‐O‐picoloyl glucal (15) allows α‐ versus β‐selectivity based on the nature of the nucleophile: harder nucleophiles (ROH and ArO− Na+) follow an inner‐sphere pathway to give β‐products, while phenols give α‐products, via an outer‐sphere route, which is slower.(18) <de>

Appropriately ortho‐substituted benzyl‐protecting groups allow control of stereoselective formation of a 1,2‐trans‐glycosidic linkage, essentially acting as armed participating groups. Nitro and cyano are particularly effective: compound (16) shows how it sets up the oxocarbenium ion intermediate for β‐face attack by the incoming nucleophile. The results and conclusions are supported by DFT calculations.(19) <ee>

Gold(III) and gold(I) chlorides both act as powerful catalysts of O‐glycosidation with O‐glycosyl trichloroacetimidates as glycosyl donors. A dual‐activation Lewis acid/base mechanism is outlined, with gold forming a catalyst–acceptor adduct which then binds to the donor.(20) <ee>

The mechanisms of glycoside bond formation in monosaccharides and glycosides have been reviewed.(21)

Formose chemistry explores plausible prebiotic routes to convert formaldehyde to sugars. Deuterium kinetic isotope effects (KIEs) have been measured for one such reaction: isomerization of glyceraldehyde to dihydroxyacetone, under base catalysis. Evidence for significant quantum‐mechanical tunnelling is presented.(22)

Recent advances in the mechanisms of glycosylation have been reviewed.(23)

The reactivity of a series of ring‐substituted S‐glycosyl phenylcarbamothioates has been assessed in comparative glycosidations. Significant differences between para‐methoxy and para‐nitro substituents may be exploitable in selective activation strategies for oligosaccharide synthesis.(24)

6‐Deoxy‐α‐D,L‐altropyranose derivatives (17) have been prepared in up to 99% yield under thermodynamic control, using a domino aldol–aldol–hemiacetal cascade starting from an indium(III) enolate (18) and benzaldehyde. The enolate, in turn, is formed from α‐methoxy‐acetophenone (PhCOCH2OMe) and lithium diisopropylamide (LDA); several other Group 13 metals besides indium also work. A trace of product forms at −20 °C, while at 0 °C, small amounts of 6‐deoxy‐galactose and ‐allose by‐products show up, plus ca 50% of aldol intermediate. Raising the temperature gives progressively more altrose (17), reaching 99% at 67 °C. This switchover from kinetic control was seen as a good test of modern DFT methods, and calculations at the B3LYP/6‐31(G)/LANL2DZ level at 25 and 67 °C reproduced the change in experimental behaviour.(25) <de>

Molecular dynamics and metadynamics have been used to model hydrolysis of cellulose in two solvents: water and the ionic liquid (IL), 1‐ethyl‐3‐methylimidazolium acetate. The IL makes hydrolysis easier, breaking intramolecular hydrogen bonds and favouring more reactive non‐chair conformers.(26)

As part of an investigation of natural selection of nucleobases in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), rates of hydrolytic deglycosylations of modified, alternative, and native nucleosides were measured at pH 1 over a range of temperatures, allowing extraction of thermodynamic parameters and comparisons of structure at 37 °C. Contemporary nucleosides exhibited the slowest rates, supporting their ‘hydrolytic fitness’ as nature's selected structures.(27)

As a model for formation of cyclic boronic esters or boronate ions with saccharides, a DFT study examined the rates and mechanisms of reaction of boronic acids with diols.(28)

Kinetics of the reaction of D‐fructose with diphenylborinic acid, Ph2BOH, has been studied in aqueous solution.(29)

A DFT study of the Brønsted‐acid‐catalysed dehydration of glucose has been presented alongside a kinetic and isotopic tracing NMR spectroscopic investigation. The main products are hydroxymethylfurfural, levulinic acid, and formic acid. The rate‐limiting step was identified as the first dehydration of protonated glucose with most consumption of glucose proceeding via the furfural. Formic acid is mainly produced at high levels of glucose conversion and/or high temperature, and arises from a retro‐aldol at C(6).(30)

In perchloric acid medium, kinetics of oxidation of D‐xylose by vanadium(V) is first order in both, with iridium(III) and hydronium ion also being efficient catalysts. A study from 35 to 50 °C afforded thermodynamic parameters.(31) Kinetics of silver(I)‐catalysed oxidation of maltose by vanadium(V) in perchloric acid has been studied over a range of temperatures.(32)

Gas‐phase oxidation of D‐fructose by iodine has been studied by computation.(33)

Levoglucosenone (19) is a valuable anhydrosugar derived from pyrolysis of cellulose/biomass. To elucidate the mechanism of formation, DFT was used to study how it forms from both β‐D‐glucopyranose and cellobiose. The results tend to rule out levoglucosan (20) as an essential intermediate. The likely pathway from both glucose and cellobiose involves 1,2‐dehydration, six‐membered hydrogen transfer, and enol–keto steps, the last being rate determining.(34)

Such fast pyrolysis of biomass can be an efficient route to fuel. Pyrolysis of ¹³C‐labelled cellobioses has been studied by MS. Several products including levoglucosan (20) arise from fragmentation of the reducing end, leaving the non‐reducing end intact in these products … at variance with previously proposed mechanisms.(35)

Reactions of Ketenes

NHC‐catalysed reaction of aryl–alkyl ketenes, Ar(R)CCO, with chloral (trichloroacetaldehyde) can give either asymmetric chlorination (in up to 94% ee) or formal 2 + 2‐cycloaddition to give β‐lactones in up to 76% de/94% ee. Steric effects are critical: 2‐substitution of the aryl or R = i‐Pr favours the α‐chloroester (21), while 4‐substitution or R = n‐alkyl yields more lactone (22).(36) <de> <ee>

Electro‐ and nucleo‐philicity indices have been used to study the formation of β‐lactams from 2 + 2‐cycloaddition of substituted ketenes and imines.(37)

DFT methods have been used to explore the mechanism of the ketene–imine Staudinger reaction, identifying an initial attack of the imine lone pair on the central carbon of the ketene (generating a zwitterionic intermediate), followed by a rate‐ and stereo‐selectivity‐determining ring closure.(38)

N‐Ditriflylimidazole reacts with bis‐(TMS)ketene acetals, R¹R²CC(OTMS)2, to give 2,3‐dihydroimidazolylcarboxylic acids (23) in DCM at −78 °C. New bicyclic δ‐lactones can then be formed by bromolactonization with NBS.(39)

Torquoselective effects have been investigated in Nazarov reactions of allenyl‐vinyl ketones, mediated by boron trifluoride etherate.(40)

Sulfonyl‐ketimines (24) are proposed as key intermediates in the preparation of selenocyanates (25) from nitriles (R¹−CN) and sulfonyl azides (N3−SO2−R²). This three‐component coupling reaction is catalysed by copper(I) iodide via the copper acetylide, which presumably reacts with the azide to form a triazole, the ring opening of which gives (24) after loss of dinitrogen. Trapping by KSeCN yields the N‐(alkyl‐ or aryl‐sulfonyl)alkaneimidoyl selenocyanate derivative (25). The whole sequence occurs at ambient temperature in DMF, using Et3N base.(41)

Pentasubstituted pyridines (26) have been prepared regioselectively in up to 88% yield at ambient temperature, using CuI/Et3N in acetonitrile. In a four‐component one‐pot reaction, sulfonyl‐ketenimine (24) is reacted with a conjugated guanidine adduct [(27), generated from tetramethylguanidine (28) and a dialkyl acetylenedicarboxylate (29)] to give dialkyl 5‐aryl(alkyl)‐4‐[aryl(alkyl)sulfonamide]‐6‐(dimethylamino)pyridine (26).(42)

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, and General and Iminium Chemistry

N‐Tosyl‐4‐iminoquinolizines (31) have been prepared from pyridyl alkynes (30) in a process that requires air. A copper(I)‐catalysed azide–alkyne cycloaddition (CuAAC) route is proposed, with tosyl azide converting the alkyne group to give an N‐sulfonyl ketenimine in situ. Attack on the pyridine nitrogen closes the ring, and subsequent base‐promoted oxidation gives the N‐tosyl‐4‐iminoquinolizines (31).(43)

DFT has been used to study the mechanism of the one‐pot preparation of 2‐(para‐tolyl)‐1H‐benzo[d]imidazole (32) from ortho‐phenylenediamine, isothiocyanatomethane, and para‐methylbenzaldehyde.(44)

A computational investigation of Paal–Knorr syntheses of furan, pyrrole, and thiophene has identified specific mechanisms involving water assistance.(45) The mechanism of Schiff base formation from glycine and formaldehyde has been studied by a variety of computational approaches.(46) Solvent(water)‐catalysed reactions of phenylpropanone and ethylamine have been studied by a variety of computational methods.(47)

Mechanisms of imine exchange reactions in organic solvents have been reviewed, especially imine formation, transimination, and imine metathesis.(48)

Non‐stabilized azomethine ylides, − :CH2−N+(R¹)CH2, generated in situ from N‐(methoxymethyl)‐N‐(trimethylsilylmethyl)benzylamine, MeOCH2N(Bn)−CH2SiMe3, or (methylamino)acetic acid, react with aromatic ketones (R³−C6H4−COR²) to give 5‐aryloxazolines (33). HCl treatment ring opens (33) to give 2‐alkylamino‐1‐arylethanols (34), via demethylenation.(49)

Stable N,N′‐ and C,N‐cyclic azomethine imines based on pyrazolidine‐3‐one (e.g. 35) and 3,4‐dihydroisoquinoline undergo 1,3‐dipolar addition to give N‐arylitaconimides regioselectively.(50) <de>

The cycloaddition of 1,4‐dithiane‐2,5‐diol (36) with cyclic azomethine imines (37) in the presence of DABCO in methanol has been studied by B3LYP and M06‐2X functionals. The domino process consists of cleavage of (36) to give free mercaptoacetaldehyde, followed by 3 + 3‐cycloaddition with imine (37). The first step is catalysed by a methanol dimer‐mediating proton transfer. Calculations then suggest that DABCO deprotonates the free thiol, followed by nucleophile attack of the thiolate anion on the imine (37), and intramolecular cyclization to produce diastereomeric products (38), with de being mainly determined by hydrogen‐bonding effects.(51) <de>

Pyrazolidinones have been prepared via a formal 1,3‐dipolar cycloaddition of azomethine imines with mixed anhydrides. The Lewis‐base‐catalysed process exhibits high de and ee.(52) <de> <ee> In a study of iminium ion activation, addition of uncharged nucleophiles to iminium salts derived from MacMillan's first‐generation catalyst has been examined for evidence of cation‐π interactions. Calculated quadrupole moments were found to linearly correlate with enantioselectivity.(53) <ee>

A computational and kinetic study of the mechanism of prolinol‐silyl‐ether catalysis of the reaction of α,β‐unsaturated aldehydes with cyclopentadiene has highlighted subtle differences between the diphenyl catalyst (39) and its trifluoromethyl‐substituted analogue (40). Proceeding via iminium ions, the reactions can be Michael type, or cycloaddition. The LUMO of the iminium ion derived from (40) is lower in energy than that derived from (39), favouring the Diels–Alder cycloaddition type. In contrast, the Michael type is favoured for (39) as it forms the iminium ion quicker. While acid promotes iminium ion formation, it also protonates anionic nucleophiles, so Michael reaction requires careful choice of appropriate acid.(54) <de> <ee>

An investigation of the formation of pyridine‐2(1H)‐one (41) from a vinamidinium salt (42) and cyanoacetamide (43, shown as its conjugate base) has identified, isolated, and characterized 2‐cyano‐5‐(dimethylamino)‐4‐phenylpenta‐2,4‐dienamide (44) as an intermediate, formed by loss of dimethylamine from the initially formed adduct (45).(55)

A review has examined the progress in green transition‐metal‐catalysed C−H and C−C activation for the case of propargylic amines, that is C(sp ³)−H and C(sp ³)−C(sp) activation, typically via iminium intermediates.(56)

A formal C(sp ³)−H activation seen in rhodium(I)‐catalysed direct C−H alkylation of benzylic amines with alkenes has been shown to be a C(sp ²)−H mechanism, that is via an imine intermediate. A benzylic aminopyridine, 2‐Py−NH−CH2−Ph, reacts with an alkene, H2CCHR, to give C‐alkylated product, 2‐Py−NH−CH(CH2−CH2−R)−Ph. A primary KIE of 4.3 is seen at the benzylic C−H, together with reversible H−D exchange.(57)

A review of guanylation reactions of amines and carbodiimides discusses four types of mechanisms that have been well characterized.(58) A short review highlights the unique properties of hafnium(IV) triflate as a Lewis acid, focussing on its applications in Friedel–Crafts acylation, and in Mannich‐type reactions of imines, hydrazones, and N,O‐acetals.(59)

E,Z‐Isomerization of imines, (R¹)2CNR², has been investigated by DFT for a wide range of C‐ and N‐substituents.(60)

3a‐Hydroperoxitryptophan, an intermediate in photodynamic cancer treatment, can exist in an indolenine form (46) or the tautomeric pyrroloindoline structure (47). Computation has identified two mechanisms of interconversion close to the isoelectric point, one involving protonation of the side‐chain nitrogen and proton transfer to the other nitrogen, with the second starting with attack of the side‐chain amino on the C(2) of the indole. The former predominates at low pH, and the latter at high pH.(61)

Rearrangement of 5‐oxymethyl‐1,3‐oxathiolane‐2‐imine (48) to thiiran‐2‐ylmethyl‐carbonate (49) was modelled by DFT.(62)

Mannich, Mannich‐type, and Nitro‐Mannich Reactions

Asymmetric detrifluoroacetylative Mannich addition reactions between 2‐fluoro‐1,3‐diketones (or their hydrates, e.g. 50) and chiral N‐sulfinylimines (51) give C−F quaternary α‐fluoro‐β‐ketoamines (52) in high yields and de. Many ring types work (X = CH2, CH2CH2, O, O−CH2), and a range of fluoroalkyl substituents (Rf) have been used in the imine. (Not shown is the deprotecting step to give free amine, but this is mild, high‐yielding, and shows ee > 99.5%).(63) <de> <ee>

β‐Amino nitriles with congested vicinal tetrasubstituted stereocentres have been obtained from Mannich reaction of silyl ketene imines with isatin‐derived ketimines. Using a chiral N,N‐dioxide/Zn(II) catalyst, yields/des/ees of up to 98/90/99% were achieved.(64) <de> <ee> 3‐Substituted benzofuran‐2(3H)‐ones undergo Mannich reaction with isatin N‐Boc ketimines with yield/de/ee up to 99/90/98%, using a biscinchona catalyst.(65)

A range of imidazolidine‐2‐thiones (53) derived from L‐amino acids have been investigated as chiral auxiliaries in titanium‐mediated Mannich reactions, using triphenylphosphine as an additive. The high de and anti‐stereochemistry of the products are explained in terms of a non‐chelated TS with the titanium enolate bound to the phosphine. Methanolysis can then be used to cleave (and recover) the auxiliary.(66) <de>

An asymmetric synthesis of azabicyclo[3.3.1]nonanes (54) reacts chiral derivatives of 2‐oxocyclohexanecarboxylic acid with bis(aminol) ethers, R–CH2N(CH2OEt)2, in a double‐Mannich process.(67) <de>

Structurally diverse chiral spiro[imidazolidine‐2‐thione‐4,3′‐oxindole] derivatives (e.g. 55) have been prepared via a domino‐Mannich/cyclization of the corresponding 3‐isothiocyanate oxindoles with N‐tosyl aldimines, R−CHNTs. Commercially available quinine catalysts give yields/des/ees up to 99/98/97%.(68) <de> <ee>

N‐(Benzothiazolyl)imines undergo an NHC‐catalysed domino‐Mannich/lactamization with α‐chloroaldehydes, giving pyrimidinones in yield/de/ee up to 78/95/99%.(69) <de> <ee>

Inspired by classic three‐component Mannich syntheses of β‐aminoketones, a novel Mannich‐type reaction combines an imide source (saccharin, 56) and acetophenone or acetylheteroarene (57), using DMSO as solvent and also as a ‘carbon bridge’ … in some ways, a formaldehyde surrogate. Selectfluor™ was essential, and – although transition metallic species were not required – best yields of the β‐aroyl saccharin products (58) were achieved with an RuCl3/Na2CO3 combination. Evidence for initial reaction of saccharin (56) with DMSO, and for C−S bond cleavage as the rate‐limiting step (k H/k D = 4.0), has helped narrow down the likely mechanisms.(70)

Mannich‐type reactions of the addition of lithium enolates derived from esters, ketones, and aldehydes to nitrones have been studied by DFT. α‐Methoxy and α‐methyl enolates react stepwise, with initial nucleophilic attack of the enolate on the carbon of the nitrone followed by nucleophile attack of the oxygen of the nitrone to the formed carbonyl group. However, the calculations show α‐unsubstituted enolates reacting in a highly asynchronous one‐step process, with C−O bond formation lagging well behind the formation of the (first) C−C bond.(71)

Fluorinated β‐amino acid derivatives (59; ‘F’ = F, CF3, and other Rf) have been made by Mannich‐type reaction of appropriately fluorinated 7‐azaindoline amides with aldimines, RCHN–PG, with yield/de/ee up to 96/95/99%, using a chiral diphosphine catalyst.(72) <de> <ee>

N‐(Diphenylthiophosphinoyl)imines, Ph−CHN−P(S)Ph2, undergo direct catalytic Mannich‐type reactions with benzyl isocyanide (Ph−CH2−N + C:− ), using a copper(I) catalyst as soft Lewis acid, a chiral phosphine ligand, and potassium t‐butoxide in toluene at ambient temperature. The 1,2‐diphenyl products (60) were obtained in good yield, fair ee, and moderate de (predominantly trans‐). To access free 1,2‐diarylethylenediamines requires aqueous HClO4 at 65 °C (to remove the thiophenylphosphine), followed by basic hydrolysis of the imidazoline with aqueous Ba(OH)2 at 80 °C.(73) <de> <ee>

β‐Keto esters (R¹−CO−CHR²–CO2R³) undergo diastereoselective Mannich‐type reactions with chiral trifluoromethyl aldimines [e.g. F3C−CHN−CH(Ph)−Me], catalysed by zirconium tetrachloride. The reaction proceeds at ambient temperature in <30 min, without solvent, producing a highly functionalized product (61) with three chiral centres as a single anti‐diastereomer, in 68–80% yield.(74) <de>

Asymmetric Mannich‐type reactions of N‐Boc imines use an alkyl ketone as an enolate equivalent. A zinc phenolate catalyst with diphenylprolinol ligands pendant in the ortho‐positions gives yield/de/ee performance of up to 99/95/99% in THF.(75) <de> <ee>

Indolines (63) have been prepared in good to excellent yields with de/ee up to 95/99% from appropriate aldimines (62). The process is auto‐inductive, and is phase‐transfer initiated (as against phase‐transfer‐catalysed), with most steps occurring in the organic phase. The cyclization is a kinetically controlled 5‐endo‐trig process. The mechanistic conclusions are supported by kinetic, NMR, and DFT studies.(76) <de> <ee>

In situ‐generated N‐Boc imines have been prepared under both acidic and basic conditions from N‐Boc‐aminals, R−CH(NHBoc)2, with a wide variety of R groups: aryl, alkyl, E‐ and Z‐alkenyl, and alkynyl. The novel precursors have been demonstrated in asymmetric Mannich‐type reactions under phase‐transfer conditions.(77) <de> <ee>

Azlactones undergo Mannich‐type reaction with aldimines, R¹−CHN−SO2Me, to give azlactone derivatives (64) with two contiguous chiral centres. Using a buttressed BINOL‐phosphoric acid catalyst, yield/de/ee up to 74/90/98% was achieved.(78) <de> <ee>

In an unusual reductive nitro‐Mannich cyclization, an ‘unreactive’ lactam with a tethered nitro group (65) undergoes chemoselective partial reduction to a ‘reactive’ iminium, followed by a diastereoselective nitro‐Mannich cyclization to bicyclic product (66). Two equivalents of a silane [(Me2HSi)2O] and Vaska's catalyst [IrCl(Co)(PPh3)2] followed by HCl give yields/des up to 80/94% in toluene at ambient temperature. NMR evidence for an enamine is presented, followed by iminium ion on addition of HCl.(79) <de>

trans‐2‐Aryl‐ or trans‐2‐alkyl‐3‐nitro‐tetrahydroquinolines (68) with two contiguous chiral centres have been prepared from ortho‐(β‐nitroethyl)anilines (67) via an intramolecular aza‐Henry (nitro‐Mannich) reaction. Using a chiral thiourea catalyst derived from a quinine alkaloid, good yields, des, and ees were obtained across a wide range of aldehydes and aniline substituents.(80) <de> <ee>

α‐Substituted vinylogous nitronates have been generated catalytically from α,β‐unsaturated nitroolefins, setting up a highly stereoselective aza‐Henry reaction with N‐Boc aldimines.(81) <de> <ee>

Inexpensive cinchonidinium acetate catalyses aza‐Henry reaction of an N‐Boc imine (Ph−CHN−Boc) with arylnitromethanes to give cis‐stilbenediamines (in masked form) in good de and ee. Key to the catalysis is the formation of the kinetic syn‐product without causing epimerization of the highly acidic α‐nitro stereocentre.(82) <de> <ee>

In a similar vein, aryl N‐Boc imines, Ar¹−CHN−Boc, undergo highly stereoselective aza‐Henry reactions with α‐aryl nitromethanes, Ar²−CH2NO2, using chiral BINAP‐betaine catalysts. The β‐nitro‐N‐Boc‐amine products, after reduction and deprotection, yield non‐racemic anti‐1,2‐diarylethylenediamines, anti‐Ar¹−*CH(NH2)−*CH(NH2)−Ar².(83) <de> <ee>

A chiral 1,2‐cyclohexyldiamine bearing quinolyl groups catalyses aza‐Henry reaction of nitromethane and N‐Boc phenylaldimine. DFT studies have identified deprotection of the nitromethane as rate‐limiting step, while C−C bond formation is enantio‐determining. As well as being a Brønsted base, the catalyst activates both nucleophile and electrophile via hydrogen bonding.(84) <ee>

3‐Ethylacetate‐substituted 3‐amino‐2‐oxindoles (69) have been prepared in high ee using a cinchona‐alkaloid catalyst. Starting with isatin‐derived N‐Boc imine (70), a Mannich reaction is carried out with ethyl nitroacetate (71), followed by denitration. The nitro group thus acts as a traceless activating and directing group.(85) <ee>

Malonic acid half thioesters (‘MAHT’s, HO2C−CH2−COSR¹) undergo enantioselective decarboxylative Mannich reaction with cyclic N‐sulfonyl ketimines (72).

Using cinchona‐alkaloid catalysts, yields/ee of up to 99/92% are reported. NMR evidence points to the initial nucleophilic addition of (72) to the MAHT, followed by decarboxylation.(86) <ee>

An MS charge‐tag strategy has revealed key intermediates in the Petasis Borono‐Mannich multi‐component reaction. One such intermediate was isolated and characterized by single crystal X‐ray diffraction.(87)

A BINOL‐derived phosphoric acid catalyses asymmetric Pictet–Spengler reaction of tryptamine with (2‐oxocyclohexyl)acetic acid to give a β‐carboline (73). DFT and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations have now been employed to explain the de/ee observed.(88) <de>

A Mukaiyama–Mannich reaction of N‐Boc isatin ketimines(185) is described in the ‘Aldols’ section.

Other ‘Name’ Reactions of Imines

An organocatalysed asymmetric tandem reaction of cyclic N‐sulfonylimines with α,β‐unsaturated aldehydes yields tricyclic piperidines with yield/de/ee up to 93/95/99.7% via a Michael‐type process.(89) <de> <ee>

The use of N‐substituted maleimides as nucleophiles in aza‐Morita–Baylis–Hillman (MBH) reactions of ketimines derived from isatin has been described, giving 3‐substituted‐3‐amino‐oxindoles (74) in up to 99% ee.(90) <ee>

ortho‐Diphenylphosphinobenzaldehyde reacts with N‐tosyl‐1,2‐phenylenediamine to give the product of intramolecular Wittig reaction, N‐[2‐{2‐(diphenylphosphoryl)‐benzylamino}phenyl]‐4‐methyl‐benzenesulfonamide. The product was characterized by NMR and IR, and the mechanism was explored using DFT.(91)

Nickel(II) complexed with a chiral bis(imidazolidine)pyridine catalyses addition of methanol or organic peroxides to an isatin‐derived N‐Boc imine to give chiral quaternary N,O‐acetals (e.g. 75) in high yields and ees.(92) <ee>

The Povarov reaction combines an N‐aryl imine (76) with an electron‐rich alkene to give a formal [4 + 2] cycloadduct (77), followed by an aromatizing 1,3‐hydrogen shift to a tetrahydroquinoline (78). The first step, an aza‐Diels–Alder, is traditionally catalysed by Lewis acid, but more recently Brønsted acids have been used to activate the imine. Such a reaction between N‐phenyl‐C‐methoxycarbonyl imine (Ph−NCH−CO2Me) and diphenyl‐methylene–cyclopropane has now been studied by DFT. Protonation of the imine allows it to react with the alkene in an intramolecular Friedel–Crafts‐type reaction.(93)

Whether Staudinger reactions of chloro‐cyano‐ketene with unsaturated imines give δ‐ or β‐lactones has been studied by DFT; the former product is favoured in the absence of countervailing steric effects.(94)

Synthesis of Azacyclopropanes and Azirines

Nucleophilic addition to >CO and >CN bonds to produce epoxides and aziridines has been reviewed from 1991 to date.(95)

Chiral ammonium ylide precursor (79) undergoes epoxidation under mild conditions in good yields with de typically >98% for a range of R groups: aromatic, aliphatic, and alicylic. Replacement of the aldehyde with an N‐protected aldimine gives the corresponding aziridine.(96) <de>

UV methods and DFT have been used to examine the reaction of a simple imine, MeCHNEt, with R−NHBr to give 1,2,3‐trialkyldiaziridines.(97)

3‐Phenylazirine (81) reacts with butane‐1,2,4‐tricarbonyls to give functionalized pyrroles via transition‐metal‐catalysed reactions, yielding mixtures of the 3‐(1,2‐dioxyethyl) and 2,3‐dicarbonyl products via an azirine–metal complex intermediate.(98)

Alkylations, Arylations, Allylations, and Additions of Other C‐Nucleophiles

α‐N‐Acyloxyiminoesters (82) have proved to be highly versatile precursors to a wide range of substituted α‐amino esters (84, 85). Attack by Grignard reagent gives N‐substituted imino‐ester (83, previously inferred, now isolated). Another Grignard can react again at nitrogen (to give 84), and subsequent oxidation and a further Grignard gives (85). So the starting material allows access to N‐alkyl, N,N‐dialkyl, and N,N,C‐trialkyl products.(99)

Borane has been used as a directing group for addition of organolithiums to N‐phosphanylimines. Coordination of a P‐stereogenic N‐phosphanylimine with borane (e.g. 86), followed by 1,2‐addition of R²−Li, gives the corresponding phosphanylamine in up to 98% de. Changing from non‐coordinating DCM to THF reverses the selectivity.(100) <de>

α‐Aminoacetonitriles, protected as their diphenylmethylidene derivatives (87), undergo enantioselective reaction with aromatic aldimines to give highly functionalized diastereomeric products (88), using chiral palladium catalysts and silver(I) co‐catalyst. Yields/des/ees of up to 95/98/99% were obtained. A palladium ketenimide intermediate, Ph2CN–CHCN–Pd*, is proposed, which then reacts with the aldimine; MS and DFT evidence is provided.(101) <de> <ee>

α,α‐Diaryl‐α‐amino acid esters, Ar¹Ar²C*(NH2)−CO2R, have been accessed via a rhodium‐catalysed asymmetric addition of arylboronic acids to cyclic aromatic N‐sulfonyl ketimines, followed by deprotection.(102) <ee>

A new mechanism has been proposed for the enantioselective phenylation of (E)‐N‐propylidene–tosylsulfonimide, (E)‐Et−CHN−Ts, catalysed by a rhodium(I) species, Rh(OH)(diene*)2. Phenylboronic acid is found to play a dual role as aryl source and proton donor. The DFT study rules out a role for water and indicates that the phenylboronic acid–phenylboroxin equilibrium is not relevant.(103)

A chiral ferrocenyl‐palladacycle catalyses enantioselective arylation of N‐sulfonylimines by arylboroxines.(104) <ee>

A palladium(II)‐catalysed asymmetric arylation of cyclic N‐sulfonyl ketimine esters by arylboronic acids gives yield and ee up to 99%. The mechanism was explored by DFT.(105)

Isatin‐derived ketimines undergo indium‐promoted Barbier‐type addition of γ‐substituted allylic halides to give 3‐allyl‐3‐amino‐oxindoles. The mild and convenient conditions – THF/water at 30 °C, using indium powder – have been used to assemble β‐amino acid derivatives.(106) <de>

A high‐yielding asymmetric allylation of chiral N‐t‐butanesulfinyl aldimines with near‐100% des exploits dual stereocontrol, via the sulfur chirality and a chiral bulky binaphthyl phosphoramidite ligand for the copper(I) catalyst employed. Extension to ketimines also worked, but with the opposite diastereoselectivity, probably because the CN and SO bonds are pseudo‐trans, as against pseudo‐cis in the aldimine substrates.(107) <de> <ee>

Ruthenium‐catalysed hydrogen transfer from 4‐aminobutanol to 1‐substituted‐1,3‐butadiene produces 4‐aminobutanal generating in situ cycloimine (89), which undergoes alkylation at carbon, giving the product of imine anti‐crotylation (90) in up to 95% de. This redox‐triggered imine addition, with a carbonyl or imine reactant derived from the primary alcohol level of oxidation, avoids stoichiometric use of pre‐metallated carbanions and thus avoids stoichiometric metallic by‐products.(108) <de> A related reaction of alkynes is described in the ‘Allylation’ section.

Zinc‐BINOL complexes catalyse enynylation of N‐sulfonyl aldimines (e.g. PhCHNTs), adding terminal 3‐en‐1‐ynes to produce enynylated carbinamines (e.g. the series 91) in up to 96% yield and 95% ee.(109) <ee>

Miscellaneous Additions to Imines

Isatin‐derived N‐Cbz ketimines (92) undergo organocatalysed conjugate addition with monothiomalonates (93) to give oxindoles with adjacent tetrasubstituted stereocentres (94; PMB = para‐methoxybenzyl, PMP = para‐methoxyphenyl). Using well‐established chiral amino‐urea and amino‐thiourea catalysts at 2 mol% loading at −15 °C in toluene, either epimeric product can be obtained in good to excellent yields with de often >95% and ee up to 99%.(110) <de> <ee>

Metal‐free β‐boration of α,β‐unsaturated imines (formed in situ from an enone and an amine) has been carried out using a diboron adduct, [MeO → Bpin–Bpin]− (95). The products are easily convertible to 1,3‐aminoalcohols. The use of a chiral phosphine renders the reaction enantioselective.(111) <ee>

N‐Aryl imines (96) – formed in situ from the corresponding aniline and an aldehyde (R²CHO) – undergo copper(I)‐catalysed regioselective amination with TMS–azide and oxidant t‐butyl hydroperoxide (TBHP), in a convenient one‐pot multi‐component preparation of substituted benzimidazoles (97). A radical route is involved (TEMPO suppresses it), and an isotope experiment with an ortho‐deuterated aniline suggests that C−H bond cleavage is not involved in the product‐determining step. MS evidence suggests that azide is transferred onto imine‐complexed copper and thence onto the benzene ring, with N2 loss associated with closure of the new ring. Many functional groups are tolerated.(112)

Mechanistic variations have been identified in the reaction of isocyanides with imines, under Lewis acid catalysis. Typically, two molecules of isocyanide attack the >CN bond, leading to a four‐membered ring.(113)

A high‐valent mono‐oxo‐rhenium hydride, Re(O)HCl(PPh3)2, catalyses hydrosilylation of imines. A DFT study has identified finely balanced mechanistic alternatives with a switchover depending on the steric hindrance around the CN bond.(114)

A chiral H‐phosphonate, derived from a readily available TADDOL, adds to (S)‐N‐t‐butylsulfinyl aldimines with de >90%, giving α‐aminophosphonates. Removal of both chiral auxiliaries gives α‐aminophosphonic acids.(115) <de>

1,4‐Benzoquinone monoamines bearing amide functionality have been thiocyanated.(116)

Fluoroacetate esters, with or without C‐alkyl groups (i.e. FHR¹C−CO2R²; R¹ = H, alkyl), have been converted to their metal α‐fluoroenolates using LiHMDS and added diastereoselectively to N‐t‐butylsulfinyl aldimines, R³CHN−*S(O)−t‐Bu, to give α‐fluoro‐β‐amino acids, R³−CH(NH2)−CF(R¹)−CO2H (after deprotection). Product stereochemistry differed from non‐fluoro‐ or bromo‐ or chloro‐enolate cores, suggesting an open TS.(117) <de>

Oxidative γ‐carbon addition of an enal (98) to imine (99) allows enantioselective access to tricyclic sulfonyl amides (100), using a chiral NHC catalyst and a quinone oxidant (101). A kinetic investigation suggests that the slow step is the formation of the

Breslow intermediate between the enal and the NHC, with subsequent steps (oxidation, γ‐carbon deprotection, and nucleophilic addition of γ‐carbon to imine) being facile. In addition, the deprotonation of the γ‐carbon of the enal–NHC adduct is irreversible (in the absence of external base).(118) <ee>

Oxidation and Reduction of Imines

Hydrogenation of imines has exploited catalysis by FLPs (frustrated Lewis pairs). Classically, arenes such as B(C6F5)3, have sufficient Lewis acidity to heterolytically split H2, albeit using elevated temperatures and pressures under dry conditions. Now mesoionic borenium catalysts such as 1,3,4‐triphenyl‐triazolylidene‐5‐(9‐borabicyclo[3.3.1]nonane) (102) have been prepared and characterized. A variety of aldimines, ketimines, and N‐heterocycles undergo up to 100% reduction with 1 atmosphere of H2 in DCM at ambient temperature, at a faster rate than that observed with isosteric NHC–borenium ions.(119)

Oxidation of Schiff bases (103 (120) and 104 (121)) by cerium(IV) in aqueous sulfuric acid has been studied kinetically, with solvent, salt, and temperature effects also examined.

Direct asymmetric hydrogenations of acyclic and cyclic imines catalysed by iridium species have been reviewed.(122) <ee>

A hindered pyridinium salt (105; R = 2,6‐Me2−C6H3) can be ortho‐deprotected by strong base to give a pyridylidene, the carbenoid centre of which can react directly with molecular hydrogen to give a 1,2‐dihydropyridine (106), which can act as reducing agent towards organic electrophiles. This activation of dihydrogen has been exploited to reduce the N‐phenylimine of phenyl trifluoromethyl ketone, Ph−C(CF3)N−Ph, to the corresponding amine, Ph−CH(CF3)−NHPh. Coupling the steps in this way allows the pyridinium salt (105) to be used catalytically.(123)

An NHC–borane (107) reduces t‐butanesulfinyl ketimines in up to 95% yield and up to 99% de, in methanol at −10 °C, in the presence of para‐toluenesulfonic acid.(124) <de>

A kinetic investigation of FLP hydrogenation and deuteration of N‐benzylidene–t‐butylamine, Ph−CHN−t‐Bu, has examined the effect of lowering the Lewis acidity, comparing three BAr3 catalysts: the pentafluoro, 2,4,6‐trifluoro, and 2,6‐difluoro. The weaker two displayed auto‐induced catalysis. Surprisingly, reduction of imine by D2 was faster than by H2, due to a primary inverse equilibrium isotope effect.(125)

1‐Aryl‐substituted dihydroquinolines have been converted in high yields and ee to the corresponding tetrahydro compounds by transfer hydrogenation with formic acid and triethylamine, using a chiral ruthenium(I) catalyst.(126) <ee>

Transfer hydrogenation of imines by formic acid using a single‐site iridicycle catalyst has been studied by DFT, NMR, and kinetics. The reaction was found to be rate limited by the hydride‐formation step, and this step and the subsequent transfer step are both favoured by methanol, through hydrogen bonding.(127)

Vicinal diamines, Ar¹−NH−*CH(Ar²)−*CH(Ar)²−NH−Ar¹, have been prepared from anilines and benzaldehydes via a mild one‐pot reaction catalysed by BiCl3/Zn. The reaction proceeds via the aldimines and shows good to excellent yields and modest des.(128) <de>

H2 hydrogenation of N‐benzylidene‐methylamine (H2CN−Bn) catalysed by thiolate complexes of rhodium(III) has been modelled by DFT.(129)

A DFT study has examined the role of halogen bonding in an organocatalytic approach to hydrocyanation of imines, using Ph−CHN−Me as a model imine, and four monodentate catalyst candidates.(130)

Glyoxal‐derived α‐imino ketones, ArC(O)−CHNR, undergo chemoselective addition of (difluoromethyl)trimethylsilane, F2HC−SiMe3, at the carbonyl; reduction of the surviving imine by borohydride gives α‐aminoalcohols, F2HC−C(OH)(Ar)−CH2−NHR. A similar reaction occurs for aromatic α‐diones such as benzil (PhCOCOPh): one carbonyl reacts to give the alcohol, F2HC−C(OH)(Ph)−C(O)−Ph. Borohydride reduction of the second carbonyl gives diastereoselective diols, that is syn/anti‐F2HC−C(OH)(Ph)−C(OH)Ph.(131)

Other Reactions of Imines

Chiral guanidine bisthioureas catalyse enantioselective 1,2‐type Friedel–Crafts reactions of phenols (108) with N‐Boc aryl aldimines (109). The origin of the stereodiscrimination has been probed by measuring ΔΔS≠ , the differential activation entropy, a parameter which is found to be maximal around ambient temperature. It is also significantly solvent‐tunable.(132) <ee>

S‐Chiral N‐sulfinyl ketimines derived from isatin undergo Friedel–Crafts reaction at C(3) of N‐substituted indoles to give tetrasubstituted 3‐indolyl‐3‐amino‐oxindoles (110) in yields/des up to 99/96%, under bismuth(III) triflate catalysis in DCM at −78 °C. Both the N‐sulfinyl and isatin‐protecting groups are readily removable with retention of enantioselectivity at isatin's C(3).(133) <de> <ee>

Chiral NHCs catalyse 3 + 3‐cyclocondensation of α‐bromoenals with N‐tosyl aldimines to give dihydropyridinones (e.g. 111) in good yields and ees typically in the high 90s.(134) <ee>

β,γ‐Unsaturated ketones react with imines in a tandem dimerization/oxy‐2‐azonia Cope rearrangement, catalysed by tin(IV) chloride, giving homoallylic amides and lactams. A DFT study has helped characterize the mechanism, and in particular the origin of the (E/Z)‐ and enantio‐ and diastereo‐selectivities observed.(135) <de> <ee>

The factors affecting annuloselectivity in reactions of diacyl chlorides ClCO(CH2) m COCl (m = 3–7) with aromatic aldimines, Ar−CHN−R, have been explored with the major products being bis‐β‐lactams (via a [2 + 2] annulation) or 2,3‐dihydro‐1,3‐oxazin‐4‐ines (112, n = 1,2; i.e. m = 4,5), via cascade annulations.(136)

α‐(N‐Sulfonyl)aminoamides (113) have been prepared in benzene at 60 °C, without catalyst, from N,N‐dimethylcarbonyl(trimethyl)silane, Me3Si−CONMe2, and N‐sulfonylimines, R¹−CHN−SO2R².(137)

A DFT approach (M06‐2X/6‐311++G**) has been taken to the reaction of aroylimines (e.g. 115, Ar = Ph, mesityl) with diaminocarbenes (114, R typically = i‐Pr). Earlier proposals that compound (114) can act electrophilically are not borne out in this case: direct formation of the carbonyl ylide by attack on the aroyl oxygen has a high activation energy. Two alternatives were considered: (a) attack on the imino nitrogen followed by rearrangement to give the urea (116) and nitrile ylide (117) or (b) formation of a

five‐membered cyclic intermediate (not shown). Compound (117) can react with a second molecule of carbene (114) to give α′,β′‐unsaturated imine (118). Substrates less sterically crowded than those described can follow pathway (b).(138)

α‐Hydroxyphosphonates have been rearranged to vinylphosphates, and the course of the reaction sheds light on the corresponding α‐hydroxyphosphonate formation from aldehyde and phosphite observed in the Pudovik reaction.(139)

Di‐t‐butyl peroxide (DTBP) N‐methylates diarylsulfoximines, Ar¹Ar²S(O)NH, with the methyl group being derived from the t‐butyl group. Copper(II) acetate catalyses the reaction (in DMSO at 110 °C), and it has been extended to N‐ethylation with the use of bis(1,1‐dimethylpropyl)peroxide, [Me2C(Et)−O−]2. DMSO was ruled out as methyl source, as d 6 ‐DMSO gives no D‐incorporation. TEMPO inhibits the reaction and traps methyl. It is proposed that copper(II) cleaves and disproportionates DTBP, generating a t‐butoxy anion and a t‐butoxy radical, the latter generating a methyl radical by release of acetone: both acetone and t‐butanol were picked up by GC–MS.(140)

ortho‐Pyridyl C−H bonds can be aminomethylated by 1,2‐insertion into a simple imine, R¹−CHN−R². The α‐aminopyridine product (119), derived from ortho‐R³‐pyridine, is formed in good yield in toluene at 100 °C, using a lanthanide triamido complex, Ln[N(SiMe3)2]3, as catalyst, with gadolinium and yttrium being particularly effective.(141)

α‐Nitro‐δ‐keto esters (120) react with 1,2‐diaminoethane to give enantiomeric diazabicyclo compounds (121) with an α‐nitrolactam moiety. The highly functionalized starters (120) are prepared by reaction of ethyl nitroacetate with enones, Ar¹CO−CHCHAr². A pseudo‐intramolecular process is outlined to explain the efficient formation of an imine intermediate from the ketone and amine. Larger ring analogues are formed using 1,3‐diaminopropane and 1,4‐diaminobutane.(142) <de>

Oximes, Hydrazones, and Related Species

γ‐Phosphonyloximes react with Lawesson's reagent to give new 1,2,5‐oxazaphospholines regioselectively.(143) <de>

α,β‐Unsaturated N‐aryl nitrones (122) have been prepared under metal‐free conditions from the corresponding oximes and diaryliodonium salts, Ar2−I−OTf, in basic media at ambient temperature. O‐Arylation can alternatively occur. If the iodine reagent bears two different aryl groups, the more electron‐deficient one reacts. The process readily tolerates ortho‐substituted aryls and heteroaryls. DFT calculations suggest that N‐arylation proceeds via [1,3]‐phenyl migration of an O‐coordinated oximate complex via a four‐membered TS, while the O‐arylation process involves such a migration of an N‐coordinated oximate complex.(144)

Catalytic rearrangement of aldoximes to primary amides has been reviewed, highlighting how metal catalyses have helped the reaction ‘catch up’ with the better‐known Beckmann rearrangement to secondary amides. In situ protocols are also featured, involving aldehyde and hydroxylamine, as well as cases starting right back at an appropriate primary alcohol. Examples of tandem processes to prepare N‐substituted amides are also surveyed.(145)

Anhydrous cerium(IV) sulfate deoximates oximes back to the parent carbonyl compounds. For substituted benzaldoximes, a Hammett ρ value of −1.94 was reported. The oxygen source in the carbonyl product was sulfate, implicating a sulfate ester of the oxime as an intermediate.(146)

Ruthenium(III) chloride catalyses efficient deoximation of ketoximes and aldoximes without the use of acceptors, to give ketones and nitriles, respectively.(147)

A range of 3,4,5‐tetrasubstituted 1H‐pyrazoles (123) have been synthesized by cross‐dehydrogenative coupling (CDC) of benzaldehydes (R²−C6H4−CHO) with acetophenone hydrazones [R³−C6H4−C−(CH2R¹)N−NH2]. Elemental sulfur is used as hydrogen acceptor and is also found to promote the reaction.(148)

With the growing pharmaceutical interest in organic carbamates, a three‐component coupling has been developed to deliver them. As an example, heterocyclic carbamates (124; R¹, R² = H, Me, Ar, Py, etc.) have been prepared from pyrrolidine, carbon dioxide (at 4 MPa), and an N‐tosylhydrazone, R¹R²CN−NHTs, using potassium carbonate as base in aqueous acetonitrile at 120 °C for 24 h. Other secondary amines can be employed, the reaction has widespread scope, and workup is easy. A one‐pot version, starting from the appropriate ketone and tosyl hydrazide (TsNHNH2), has also been developed. Preliminary evidence for carbocation intermediates is presented.(149)

The mechanism of the Shapiro reaction – the conversion of tosyl hydrazones by alkyllithiums to give alkenes – has been investigated by DFT.(150)

Tin powder promotes a one‐pot reaction of α‐methylene‐γ‐lactams (125) from an aldehyde or ketone (R¹CHO or R¹COR²), a hydrazide (R³CONHNH2), and ethyl 2‐(bromomethyl)acetate. Cyclic ketones give α‐methylene‐γ‐spirolactams.(151)

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

Reviews of Aldols, and General Reviews of Asymmetric Catalysis

‘Deconstructing Covalent Organocatalysis’ (100 references) is a short review drawing parallels between recent developments in the field and the intramolecularization inherent in many enzyme catalyses, often accompanied by conformational changes in the catalyst. While not comprehensive, the examples covered such as proline‐catalysed aldols, organocatalytic Michael additions, iminium activation, and NHCs are highly representative. The cross‐fertilizations of enzymatic and organometallic catalysis, and of the tools of structural biology and spectroscopy, are also highlighted.(152) <de> <ee>

A short review, ‘Aminocatalysis: Beyond Steric Shielding and Hydrogen Bonding’, highlights the recent cases where the stereochemical outcome can be explained by electrostatic interactions between the catalyst‐bound substrate and the reagent in the TS.(153) <de> <ee>

Other short reviews cover the application of both Lewis‐ and Brønsted‐acidic disulfonimides in enantioselective organocatalysis (122 references),(154) <de> <ee> recent development of chiral iminophosphoranes as superbase organocatalysts,(155) <de> <ee> and the use of β‐keto thioamides, R¹−COCH2C(S)−NHR², in the synthesis of heterocycles.(156)

Kinetic and DFT evidence has been presented for the role of hydrogen‐bond acceptors in organo‐enamine catalysis of a variety of common reactions.(157)

DFT has been used to probe the mechanism of the gas‐phase reaction of acetone with methylene, which is found to be concerted but asynchronous. The study was extended to the effect of fluorine substituents on the rate.(158)

Ab initio models have been used to study the reaction of simple carbonyl compounds with a range of X2YIV ZIV species (YIV, ZIV = Ge, Si; X = H, Me, F, Cl, Br, and Ph), typically giving spiro‐ZIV‐heterocyclic products. Cases examined include formaldehyde with X2GeSi,(159) acetone with X2GeGe,(160) and acetaldehyde with X2SiSi.(161)

Asymmetric Aldols

Simple cyclic hemiacetals, 2‐hydroxytetrahydro‐furan and ‐pyran, undergo aldol reaction with a variety of aldehydes in varying yields, fair des, but good to excellent ees, using L‐proline as catalyst.(162) <de> <ee>

cis‐ and trans‐4,5‐Methano‐L‐prolines give high yields and ee in a test aldol addition of acetone to para‐nitrobenzaldehyde.(163) <ee> cis‐4,5‐Methano‐L‐proline catalyses this benchmark aldol with yield/ee up to 98/99% in DMF at 0 °C, superior to proline itself for this reaction. Benzoic acid helped raise the yield and ee, and a wide range of aldehyde types worked.(164) <ee>

A comparison of cis‐ and trans‐4‐fluoro‐prolines as enantioselective catalysts of five representative organic transformations showed little improvement over proline itself.(165) <ee>

New homochiral‐L‐prolinamido‐sulfonamides catalyse model aldols at ambient temperature, with yields/ees up to 97/90%. DFT has been used to determine why.(166) <ee>

Unnatural proline esters (e.g. 126) have been prepared and tested as catalysts of the aldol reaction of cyclohexanone and pentafluorobenzaldehyde, conveniently monitored by ¹H and ¹⁹F NMR, including direct observation of the iminium intermediate (127) and enamines (not shown). Rate measurements and KIEs, together with DFT calculations and molecular dynamics simulations, paint a picture of subtle and remote effects on the diastereo‐ and enantio‐selectivities.(167) <de> <ee>

Covalent attachment of proline to β‐cyclodextrin via a urea link gives a water‐soluble catalyst for aldols, resulting in good yields and ees up to 99% at ambient temperature.(168) <ee>

A pyrrolidine–diaminomethylenemalononitrile (128) promotes direct aldols, without solvent, in yield/de/ee up to 100/98/99%. Like its urea analogues, compound (128) presumably acts as a double hydrogen‐bond donor.(169) <de> <ee>

Amide and ester derivatives of dipeptides have been tested in the acetone/para‐nitrobenzaldehyde model aldol reaction. Pro‐Gly‐Ot‐Bu gave the best results in acetonitrile, while Pro‐Gly‐NHBn worked well in brine. Both catalysts were then extended to a wider range of ketones and aldehydes, giving de up to 86% and ee up to 99%, often with quantitative yield.(170) <de> <ee> Tests on t‐butyl esters of other peptides show Pro‐Glu(Ot‐Bu)−Ot‐Bu giving the best yield/de/ee of those studied. The secondary amine is designed to activate ketones via enamine formation, with the amide proton activating the electrophile.(171) <de> <ee>

Enantiopure thiazolines, derived by cyclization of L-amino acids with either acetone or formaldehyde, catalyse direct aldols with de/ee of up to 95/99%.(172) <de> <ee>

In one of the several reports on the privileged isatin structure, cross‐aldol reaction of isatin (129) with acetone catalysed by L-leucinol to give α‐hydroxy‐γ‐keto amide (130) has revealed that the isatin itself is catalytic. Indeed, it not only catalyses its own reaction with the leucinol to produce an oxazolidine ‘resting state’, its hydrogen‐bond donor/acceptor abilities allow it speed up the rate‐determining formation of a syn‐enamine. This contrasts with proline's formation of an anti‐enamine. Conclusions are supported by kinetics, isotope effects, and DFT studies.(173) <ee>

Phenylalanine sodium salt catalyses aldol reactions of isatin with acetone, with yields/ees up to 97/90%.(174) <ee> A chiral 2‐aminopyrimidin‐4(1H)‐one catalyses aldol reaction of isatins with aldehydes with yield/ee up to 92/94%.(175) <ee>

A 1° amino organocatalyst (131) shows enhanced reactivity on addition of water. A new experimental and computational study has further clarified water's role, and in particular that of proton relays via mediation by two water molecules. Indeed, appropriate diols such as cis‐2‐butene‐1,4‐diol (132) are superior to water in this respect.(176) <ee>

In a study of direct cross‐aldols catalysed by simple chiral diamines, calculations at the B3LYP/6‐31G* level gave a poor match for experimental de and ee values, but better results were obtained with M06‐2X.(177) <de> <ee>

Stereoselective direct aldol addition of S‐phenyl thioesters and aromatic aldehydes has been achieved using promotion by tetrachlorosilane, with a chiral phosphine oxide Lewis base. syn‐β‐Hydroxy thioesters are the major products with de/ee up to 98/92%.(178) <de> <ee>

A zinc‐templated bifunctional organocatalyst has been assembled from zinc chloride and simple chiral pyridine ligands in situ in a dynamic mixture. In the benchmark aldol reaction of cyclohexanone and para‐nitrobenzaldehyde, conversion up to 99% and de/ee of up to 90/92% are reported. Three equivalents of water were added, both to achieve full dissolution and because it further enhanced the enantioselectivity. The approach looks very promising for rapid screening of new catalysts for particular reactions.(179) <de> <ee>

The Mukaiyama Aldol

How far can you push vinylogy? Catalytic enantioselective hypervinylogous Mukaiyama‐aldol reaction (HVMAR) has been reported for a series of multiply unsaturated 2‐silyl‐oxyindoles (133) reacting with benzaldehyde to give alcohols (134). Using tin tetrachloride as Lewis acid and a chiral Lewis base, the versions achieved include ε‐selective (n = 1), η‐selective (n = 2), and ι‐selective (n = 3), with several examples showing high levels of regio‐, enantio‐, and diastereo‐selectivity, as well as geometric selectivity (E/Z).(180) <de> <ee>

Base‐catalysed Mukaiyama‐type reaction of trimethylsilyl enolates with aldehydes can be complicated by by‐products dependent on the base used and the medium. A new study aimed at understanding the factors involved has identified mild Brønsted bases with inbuilt hydrogen‐bonding sites, which proved to be both efficient and clean catalysts.(181)

A chiral europium(III) complex (135) achieves high stereoselectivity in the aqueous Mukaiyama‐aldol reaction, despite being fluxional. An automatic exploration tool, GRRM (global reaction root mapping), was used to identify the three lowest energy conformations, all of which coexisted in the reaction. All related TSs were calculated, allowing the observed ees and des to be reproduced, which also points towards how they could be increased by appropriate rigidification of the catalyst system.(182) <de> <ee>

DFT and AFIR (artificial force‐induced reaction) methods have been applied to the mechanism of an asymmetric Mukaiyama aldol in aqueous media, catalysed by a chiral iron(III) complex.(183) <de> <ee> An N‐(perfluorooctanesulfonyl)thiophosphoramide on a buttressed BINOL scaffold acts as a Brønsted acid for asymmetric Mukaiyama aldols, with de/ee up to 98/99%. It also catalyses Hosomi–Sakurai allylation in up to 96% ee.(184) <de> <ee>

A gold‐catalysed Mukaiyama–Mannich reaction has been reported, in which N‐Boc isatin ketimines add difluoroenol silyl ethers to give highly functionalized products (136), using Ph3PAuOTf (generated in situ from Ph3PAuCl and AgOTf). While use of Au(I) as a π‐acid is well known, this use as a σ‐acid for C−C bond formation is novel. Extension to the mono‐fluoroenol silyl ether gives good ee, and the non‐fluoro substrate also works. (185) <de>

A computationally designed point‐chiral seven‐membered cyclic guanidine has been synthesized: it catalyses vinylogous aldols, giving γ‐butenolides in up to 80/94% de/ee.(186) <de> <ee>

The Baylis–Hillman Reaction and its Morita Variant

O‐ and S‐Functionalized 1,2,3‐triazoliums (137; X = BnO or PhS) have been prepared and tested as catalytic ILs for the Baylis–Hillman (BH) reaction. They can separately be used to prepare rhodium(I), gold(I), or palladium(I) complexes, by deprotonation at C(5) and subsequent metallation with Rh(COD)Cl, Pd(allyl)Cl, or AuCl(SMe2).(187) In another reaction conducted in several ILs, a linear solvation energy relationship (LSER) indicates a notable sensitivity to the nature of the anion of the IL.(188)

(E)‐α‐Cinnamaldehydes (138) have been converted into the corresponding functionalized amides (139). The three‐component coupling proceeds via NHC‐catalysed regioselective introduction of C‐ and N‐nucleophiles into BH enals. Amides (139) can be cyclized to δ‐lactams in high yields and des.(189) <de>

The utility of the current computational approaches for elucidating the mechanism of the alcohol‐mediated MBH reaction has been severely criticized. The authors argue that simple acid–base chemistry adequately describes the aldol steps, based on experimental data such as KIEs, as against the ‘proton‐shuttle’ mechanism invoked in multiple computational studies. They caution against ‘functional shopping’ and ‘computational model shopping’, and allege an inbuilt but unsustainable bias towards computationally tractable mechanisms over less tractable ones.(190)

MBH reactions of nitroalkenes with ethyl glyoxylate (OHC−CO2Et) have been studied with a range of hypernucleophilic catalysts such as DMAP, 4‐pyrrolidinopyridine, azajulolidine (140; X = CH2; ‘Azajul’), and super‐DMAP (140; X = N‐Bn; ‘s‐DMAP’), with s‐DMAP giving 93% conversion for β‐nitrostyrene in chloroform at ambient temperature, on a loading of 0.05 mol%. A detailed analysis of the individual steps in the mechanism from a physical‐organic standpoint is most revealing. The initial nucleophilic attack on the nitroalkene to give a zwitterion was analysed in terms of the nucleophilicity and electrophilicity parameters of the reactants. Estimates of equilibrium constants suggest that s‐DMAP favours zwitterion formation by a factor of ca 4 over DMAP. The next step – reaction with the ethyl glyoxylate – suffers from parasitical polymerization of nitroalkene, one of the main reasons that simple aldehydes do not work: they are just too slow. Appropriate addition order can help minimize polymerization. This step also benefits from the catalyst acting to depolymerize the linear polyacetal form in which ethyl glyoxylate mainly exists. The final deprotonation step with release of catalyst does not appear to be rate determining in this case.(191)

Tunable bifunctional phosphine squaramides (e.g. 141) promote MBH reaction of N‐alkyl isatins with acrylates in yields of up to 93% and ees of up to 95%.(192) <ee>

MBH reactions of dibenzofuran‐2‐ and ‐4‐carbaldehydes