Organic Reaction Mechanisms 2012: An annual survey covering the literature dated January to December 2012

Organic Reaction Mechanisms 2012, the 48th annual volume in this highly successful and unique series, surveys research on organic reaction mechanisms described in the available literature dated 2012. 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 compiled these reviews, ensuring the quality of selection and presentation.

• Language: English
• Publisher: Wiley
• Release date: Apr 16, 2015
• ISBN: 9781118930762

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This edition first published 2015

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Print ISBN: 978-1-118-36259-4

Contributors

Preface

The present volume, the 48th in the series, surveys research on organic reaction mechanisms described in the available literature dated 2012. In order to limit the size of the volume, it is necessary to exclude or restrict overlap with other publications which review specialist areas (e.g., photochemical reactions, biosynthesis, enzymology, electrochemistry, organometallic chemistry, surface chemistry, and heterogeneous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editor conducts a survey of all relevant literature and allocates publications to appropriate chapters. While a particular reference may be allocated to more than one chapter, it is assumed that readers will be aware of the alternative chapters to which a borderline topic of interest may have been preferentially assigned.

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

We are pleased to have retained for ORM 2012 our current team of experienced authors who have contributed to ORM volumes for periods of 7 to 34 years.

However, it is unfortunate that intervention of the editor to avoid an anticipated delay between title year and publication date for this volume was thwarted by unusually late arrival of a particularly long chapter. Nonetheless, we hope soon to regain our optimum production schedule.

I wish to thank the staff of John Wiley & Sons and our expert contributors for their efforts to ensure that the review standards of this series are sustained, particularly during a period of substantial reorganisation of production procedures.

A. C. K.

Chapter 1

Reactions of Aldehydes and Ketones and their Derivatives

A.C. Knipe

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

Formation and Reactions of Acetals and Related Species

Reactions of Glucosides and Nucleosides

Reactions of Ketenes and Ketenimines

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, Tautomerism, and Catalysis

The Mannich and Nitro-Mannich reactions

Addition of organometallics

Other alkenylations, allylations, and arylations of imines

Oxidation and reduction of imines

Iminium species

Imine cycloadditions

Other reactions of imines

Oximes, Hydrazones, and Related Species

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

Reviews of Organocatalysts

Asymmetric Aldols Catalysed by Proline, Its Derivatives, and Related Catalysts

Other Asymmetric and Diastereoselective Aldols

Mukaiyama and Vinylogous Aldols

Other Aldol and Aldol-type Reactions

The Henry (Nitroaldol) Reaction

The Baylis–Hillman Reaction and Its Morita Variant

Allylation and related reactions

Alkynylations

Michael Additions

Miscellaneous Condensations

Other Addition Reactions

Addition of Organozincs

Arylations

Addition of Other Organometallics, Including Grignards

The Wittig Reaction

Hydrocyanation, Cyanosilylation, and Related Additions

Hydrosilylation, hydrophosphonylation, and related reactions

Miscellaneous additions

Enolization and Related Reactions

Enolization

α-Alkylation, α-Halogenation, and Other α-Substitutions

Oxidation and Reduction of Carbonyl Compounds

Regio-, Enantio-, and Diastereo-selective Reduction Reactions

Other Reduction Reactions

Oxidation Reactions

Cycloadditions

Other Reactions

References

Formation and Reactions of Acetals and Related Species

Mechanisms and energetics for Brønsted-acid-catalysed glucose condensations, dehydration, and isomerization reactions have been reviewed.¹ Recent developments in the asymmetric synthesis of spiroketals have been reviewed and the potential for further application of transition metal catalysis and organocatalysis has been highlighted.² c1h001

Hemiacetal formation from formaldehyde and methanol has been studied by intrinsic reactivity analysis at the B3LYP/6-311++G(d,p) level and the beneficial combined assistance of watermolecules and Brønsted acids has been quantified.³ Theoretical study of hemiacetal formation from methanol with derivatives of CH3CHO (X = H, F, Cl, Br, and I) has shown that the energy barrier can be reduced by a catalytic molecule (MeOH or hemiacetal product).⁴

A combined experimental and density functional theory (DFT) study of the thermal decomposition of 2-methyl-1,3-dioxolane, 2,2-dimethyl-1,3-dioxolane, and cyclopentanone ethylene ketal, in the gas phase, has established that acetaldehyde and the corresponding ketone are formed by a unimolecular stepwise mechanism; concerted nonsynchronous formation of a four-centred cyclic transition state is rate determining and leads to unstable intermediates that then decompose rapidly through a concerted cyclic six-centred transition state.⁵

Real-time ultrafast 2D NMR observations of an acetal hydrolysis at ¹³C natural abundance have enabled observation of the reactive hemiacetal intermediate.⁶ Mutual kinetic enantioselection (MKE) and enantioselective kinetic resolution (KR) have been explored for aldol coupling reactions of ketal- and dithioketal-protected β-ketoaldehydes expected to have high Felkin diastereoface selectivity with a chiral ketone enolate.⁷ c1h001

The quantitative transacetalization of 2-formylpyrrole found in RONa/ROH may involve highly reactive azafulvene intermediates.⁸ c1h001

Baldwin's rules can account for the unprecedented ring expansion, whereby polyoxygenated eight- and nine-membered rings are formed regioselectively by rhodium-catalysed reaction of cyclic acetals with α-diazo β-ketoesters and diketones under mild conditions.⁹

It has been found that if an acetal OR group is first displaced to form a pyridinium-type salt, then the resulting electrophile can be reacted with various nucleophiles under mild (non-acidic) conditions.¹⁰

An intermediate 1-methoxyfulvene is believed to form through a cyclization–cycloaddition cascade on reaction of allenyl acetals with nitrones catalysed by a gold complex and a silver salt (Scheme 1).¹¹

c1h001

Scheme 1

A kinetic study of intermolecular hydroamination of allylic amines by N-alkylhydroxylamines has revealed a first-order dependence on aldehyde catalyst. This is a consequence of advantageous formation of a mixed aminal intermediate, which is able to undergo intramolecular Cope-type hydroamination, thereby leading to high yield of the required hydroamination product (Scheme 2).¹²

c1h002

Scheme 2

Coupling of alkenyl ethers (Ene–OR) with ketene silyl acetals R¹R²C=C(OR³)OSiMe3, catalysed by GaBr3, forms α-alkenylated esters Ene–C (R¹R²)CO2R³.¹³

Reactions of Glucosides and Nucleosides

Recent advances in transition-metal-catalysed glycosylations have been reviewed.¹⁴, ¹⁵ Plausible transition states for such reactions have been discussed¹⁶ and primary ¹³C isotope effects have been determined as a guide to the mechanism of formation of α-manno- and gluco-pyranosides.¹⁷ The influence of protecting groups on the reactivity and selectivity of glycosylation chemistry of 4,6-O-benzylidene-protected mannopyranosyl donors and related species has been reviewed.¹⁸

A commentary on diastereoselectivity in chemical glycosylation reactions has dismissed molecular orbital explanations that invoke stereoelectronic effects analogous to the anomeric effect in kinetically controlled reactions.¹⁹ c1h001

A reversal of the usual anomeric selectivity for glycosidation methods with thiols as acceptors has been observed for O-glycosyl trichloroacetimidates as donors and PhBF2 as catalyst; the reaction proceeds without anchimeric assistance to form mainly β-thioglycosides, apparently through direct displacement by a PhBF2–HSR adduct.²⁰ α-Glycosylation of protected galactals to form 2-deoxygalactosides, promoted by a thiourea organocatalyst, occurs by syn-addition.²¹ Cyclopropenium-cation-promoted α-selective dehydrative glycosylations have been initiated using 3,3-dibromo-1,2-diphenylcyclopropene to generate 2-deoxy sugar donors from stable hemiacetals.²² The yield obtained on α-glycosidation of α-thioglycosides in the presence of bromine is undermined by partial anomerization of the intermediate β-bromide to the unreactive α-isomer.²³ c1h001

High diastereoselectivity, giving α- and β-C-glycosides, respectively, has been reported for reaction of C-nucleophiles with 2-O-benzyl-4,6-O-benzylidene-protected 3-deoxy gluco- and manno-pyranoside donors. This does not parallel the preferential formation of β-O-glycosides on reaction with alcohols, for which nucleophilic attack by Osp3 on oxocarbenium ions should be less sterically hindered than for Csp2 attack by a typical carbon nucleophile.²⁴ c1h001

A 2,4-O-di-t-butylsilylene group induces strict β-controlled glycuronylations, without classical neighbouring group participation, by hindering approach of ROH to intermediate oxocarbenium ion.²⁵

A kinetic study of acid hydrolysis of methyl α- and β-d-glucopyranosides has revealed direct participation by the counterion (Br− or Cl−), which becomes more pronounced as the proportion of 1,4-dioxane is increased.²⁶

Cyclodextrins carboxymethylated at the secondary rim have been evaluated as chemzymes for glycoside hydrolysis.²⁷

A DFT investigation of the mechanism of alkaline hydrolysis of nitrocellulose dimer and trimer in the gas phase and in bulk water has indicated that, following a C(3) to C(6) to C(2) denitration route, peeling-off will be preferred to ring cleavage of the ring C–O bond.²⁸ A DFT study of the kinetics and thermodynamics of N-glycosidic bond cleavage in 5-substituted-2′-deoxycitidines has provided insight into the role of thymine DNA glycolase in active cytosine demethylation.²⁹ A real-time ¹H NMR study of the acidic hydrolysis of various carbohydrates has revealed that for insulin the activation energy decreases with chain length.³⁰ Concentrated aqueous ZnCl2 is found to convert carbohydrates into 5-hydroxymethylfurfural.³¹

Reactions of Ketenes and Ketenimines

The thriving chemistry of ketenimines has been reviewed³² and an overview of the development of silyl ketene imines and their recent applications in catalytic, enantioselective reactions has also been summarized.³³ c1h001

Asymmetric synthesis of trans-β-lactams from disubstituted ketenes and N-tosyl arylimines has been catalysed by (R)-BINAPHANE with up to 98% ee and dr ≥ 90 : 10.³⁴ However, the Staudinger cycloaddition method can be unsuitable if the reactants (ketones + imines) bear electron-withdrawing substituents as β-lactams undergo base-induced isomerization to the azacyclobutene followed by electrocyclic ring opening to the corresponding α,β-unsaturated alkenamide.³⁵ c1h001 c1h001

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, Tautomerism, and Catalysis

A restricted Hartree–Fock study of formation of Schiff base (N-[(Z)-furan-2-ylmethylidene]-4-methoxyaniline) from aromatic amine and furaldehyde has revealed that an auxiliary water molecule enables proton transfer in the carbinolamine-forming step.³⁶ The temperature-dependent kinetics of second-order formation of N-salicylidene aniline in ethanol has been interpreted.³⁷ Mechanistic analysis with the aid of DFT calculations has enabled easy formation of triarylmethanimines from Ph2CO and PhNH2 under mild conditions catalysed by a Lewis acid–base pair (AlCl3–Et3N).³⁸

An unprecedented highly enantioselective catalytic isomerism of trifluoromethylimines (2) has been promoted by a chiral organic catalyst (1) and thereby provided a new approach to optically active alkyl and aryl trifluoromethylated amines (3).³⁹ c1h001

chemical structure image

Infrared spectra and structures have been reported for nitrile imines generated photochemically and thermally in Ar matrices at cryogenic temperature. The results are consistent with theoretical predictions, and the isomerization of both propargylic and allenic forms to the corresponding carbodiimides could be reversed by flash vacuum thermolysis.⁴⁰

The kinetics and thermodynamics of the formation of E and Z enamines between aldehydes with α-stereocentres and pyrrolidine-based catalysts that lack an acidic proton have been studied as a guide to the probable diastereo- and enantio-selection towards electrophiles when introduced.⁴¹ c1h001 c1h001

Fifty years of established views of the Ugi reaction have been challenged by results of a theoretical study which suggests, for example, that the intermediate imine is not in equilibrium with its isocyanide adduct.⁴² An asymmetric three-component Ugi reaction has applied chiral cyclic imines in synthesis of morpholino- or piperazine-keto-carboxamide derivatives.⁴³ c1h001

The Mannich and Nitro-Mannich reactions

The Bignelli reaction of aldehydes, β-ketoester, and urea catalysed by (2R,3R)-tartaric acid has been confirmed, by DFT calculations, to proceed by attack of the C-nucleophile on a protonated imine intermediate.⁴⁴ c1h001

Three-component Mannich reactions of cyclohexanone and anilines with aromatic aldehydes, in the presence of H2O, have been promoted by amphiphilic isosteviol–proline organocatalysts with excellent de and ee.⁴⁵ DFT calculations indicate that the proline-catalysed single and double Mannich reactions between acetaldehyde and N-Boc imines, to give (S) and (S,S)-conformation products, respectively, are stereochemically controlled by hydrogen bonding.⁴⁶ High enantioselectivity has been reported for l-proline-catalysed addition of aldehydes to 2-aryl-3H-indol-3-ones,⁴⁷ and chinchona alkaloid-directed Mannich reaction of malononitrile with imines to give β-amino malonoitriles,⁴⁸ and azlactones with aliphatic imines to give α,β-diamino acid derivatives.⁴⁹ The aza-Mannich reaction of azlactones with imines has also been catalysed by a powerful synergistic ion pair combination of a chiral phosphate ion and Ag+, resulting in excellent diastereo- (up to 25:1 dr) and enantio-selectivity (ee ≤ 99%).⁵⁰ c1h001 c1h001 c1h001 c1h001 c1h001 c1h001 c1h001 c1h001

Bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond have been redesigned to effect highly enantioselective Mannich reactions between malonates and aliphatic and aromatic imines.⁵¹ c1h001

β-Amino α-cyanosulfones are formed with high stereoselectivity on reaction of α-cyano α-sulfonyl carbanions with N-Boc imines catalysed by chiral 1,2,3-triazolium ions that have anion-recognition ability.⁵² c1h001

Reactions of sulfonylimidates (4) with Boc-protected imines (5) have been found to exhibit an induction period, and proceed with high anti selectivity, in the presence of an organosuperbase (7) that works as an initiator (Scheme 3).⁵³ c1h001

c1h003

Scheme 3

Highly efficient asymmetric anti selectivity has also been reported for reactions of carbonyl compounds with N-carbamoyl imines catalysed by a series of amino-thiourea organocatalysts.⁵⁴ Mannich reaction of glycinate Schiff bases (Ar2C=NCH2CO2Bu-t) with aliphatic imines (RCH=NTs) generated in situ from α-amidosulfones(RCH(Ts)NHTs) is highly diastereo- and enantio-controlled by Cu(I)-Fesulfos catalyst; typically syn/anti >90:<10, ee > 90%.⁵⁵ Syn-adducts were also obtained in up to 99% ee from reaction of imino esters Ph2C=NCH2CO2R′ with sulfonyl imines catalysed by N,N,N-tridentate bis(imidazolidine) pyridine–Cu(OTf)2 complex.⁵⁶ Direct asymmetric (ee ≤ 95% and 13 : 1 dr) vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimines (ArCH=NTs) catalysed by quinine provides a route to γ-substituted amino butyrolactones.⁵⁷ Up to 93 : 7 dr has been achieved for the formation of β-aryl-β-trifluoromethyl-β-aminoarones through reaction of ketone enolates with chiral aryl CF3-substituted N-t-butanesulfinyl ketimines R′(CF3)C=NSO2Bu-t.⁵⁸ c1h001 c1h001 c1h001 c1h001 c1h001 c1h001 c1h001 c1h001

Imidazoline-anchored phosphine ligand–Zn(II) complexes promote asymmetric Mannich-type reaction of F2C=C(R³)OTMS with hydrazones (R¹CH=NNHCOR²) under mild conditions.⁵⁹ c1h001

The spontaneous emergence of limited enantioselectivity in an uncatalysed Mannich reaction has been discussed⁶⁰ and a rare example of a Brønsted base-catalysed Mannich reaction of unactivated esters has been reported.⁶¹ c1h001

In contrast to its intermolecular counterpart, an intramolecular Borono–Mannich reaction (Petasis condensation) has been found to proceed with exclusive anti stereoselectivity.⁶² The aza-Cope/Mannich reaction has been reviewed.⁶³ c1h001

Unprecedented nucleophilic tribromomethylation of N-t-butanesulfinylimines by bromoform enables the synthesis of enantiomerically pure α-tribromomethyl amines and 2,2-dibromoaziridines.⁶⁴ c1h001

Addition of organometallics

Addition of lithiated alkoxy ethynyl anion with chiral N-sulfinyl imines proceeds with dr > 95 : 5, which can be reversed in the presence of BF3.⁶⁵ Excellent diastereoselectivity has been reported for zinc-mediated addition of methyl and terminal alkynes to chiral N-t-butanesulfinyl ketimines (to form 3-amino oxindoles).⁶⁶ Zinc–BINOL complexes have been used to achieve enantioselective addition of terminal alkynes to N-(diphenylphosphinoyl)imines (up to 96% ee)⁶⁷ and terminal 1,3-diynes to N-arylimines to trifluoropyruvates (up to 97% yield and 97% ee).⁶⁸ c1h001 c1h001 c1h001

A complete reversal of α- to γ-regioselectivity in the allylzincation of imines has been achieved by fine-tuning of the N-side-chain.⁶⁹ c1h001

Enantioselective synthesis of homopropargyl amines can be effected through copper-catalysed reaction of an allenyl boron reagent with aldimines.⁷⁰ The first nucleophilic allylation of π-electrophiles by allylboron reagents has been achieved enantioselectively using a chiral rhodium catalyst (Scheme 4);⁷¹ an allylrhodium intermediate has been implicated. Similar additions of R¹CH=CR²BF3K have also been reported.⁷² c1h001 c1h001

c1h004

Scheme 4

A metal complex has also been used to promote enantioselective arylation of α-imino esters by Ar2B(OH)2 and provide direct access to chiral arylglycine derivatives (Scheme 5).⁷³ c1h001

c1h005

Scheme 5

Allylation of imines R¹CH=NR² by CH2=CHCH2SnBu3 in tetrahydrofuran (THF) has been achieved enantioselectively (ee ≤ 98%) using a newly developed π-allylpalladium catalyst that incorporates (−)-β-pinene bearing an isobutyl side-chain;⁷⁴ a menthane-based complex was less effective.⁷⁵ c1h001

A rhenium-catalysed regio- and stereo-selective reaction of terminal alkynes with imines forms N-alkylideneallylamines rather than the expected propargylamines. The β-carbon of the alkynyl rhenium is believed to attack the imine carbon to give a vinylidene rhenium intermediate (Scheme 6).⁷⁶

c1h006

Scheme 6

Asymmetric arylation of aldimines has been performed using organoboron reagents as the aryl transfer reagents in the presence of ruthenium catalysts along with known chiral phosphane ligands and an NHC-type chiral ligand.⁷⁷ Aryl transfer from arylboroxines (ArBO)3 to cyclic N-sulfonyl ketimines has been promoted in the presence of a rhodium catalyst bearing a chiral diene ligand, to create a triaryl-substituted carbon centre with 93–99% ee.⁷⁸ c1h001 c1h001

Other alkenylations, allylations, and arylations of imines

Vinylogous niitronate nucleophiles generated from β,β-disubstituted nitroolefins have been used for highly stereoselective aza-Henry reactions base catalysed by chiral ammonium betaines; high α-selectivity with 95–99% ee has been reported for the nitroallyl addition.⁷⁹ c1h001

The first example of olefinic C–H addition to N-sulfonylaldimines and aryl aldehydes has been achieved through olefinic C–H bond activation by a rhodium complex.⁸⁰ C–H bond functionalization by Rh(III) catalysts has also been used to achieve arylation of N-protected aryl aldimines by 2-arylpyridine⁸¹ and benzamide;⁸² mechanistic studies have provided insight for further development of this means of creating α-branched amine functionality. A cobalt-N-heterocyclic carbene (NHC) catalyst has also directed arylation of aromatic aldimines through C–H bond functionalization of 2-arylpyridines.⁸³

Oxidation and reduction of imines

A DFT study of Rh(II)-catalysed asymmetric transfer hydrogenation of acetophenone N-benzylimine has indicated why (S,S)-TsDPEN ligand promotes the formation of (S)-amine, whereas (R)-amine is normally obtained from endocyclic imines.⁸⁴ DFT studies of the role of a base in such hydrogenations have revealed a correlation between basicity and diastereoselectivity.⁸⁵ A further study of chiral cationic Ru(diamine) complexes in hydrogenation has explored the counterion and solvent effects and substrate scope for N-alkyl and N-aryl ketimines.⁸⁶ Catalysis based on Ru(II) having an achiral aminoalcohol ligand has been used for hydrogenation of chiral N-(t-butylsulfonylimine); DFT calculations have rationalized the diastereoelectivity of the amines obtained (on desulfination).⁸⁷ c1h001 c1h001 c1h001

Hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines has been promoted by an Ir–diphosphine complex with up to 96% ee.⁸⁸ c1h001

Bifunctional rhenium complexes [Re(H)(NO)(PR3)(C5H4OH)] (R = Cy, i-Pr) have effected the transfer hydrogenation of ketones and imines; DFT calculations suggest a secondary-coordination-sphere mechanism for the former.⁸⁹

A mechanistic study has enabled enantioselective (up to 87% ee) hydrosilylation of various imines for the first time using a novel frustrated Lewis pair (FLP) metal-free catalyst (Scheme 7).⁹⁰ c1h001

c1h007

Scheme 7

A selectivity determining hydride transfer identical to that for a related B(C6H5)3-catalysed carbonyl reaction has been proposed for hydrosilylation of imines by a silane reactant catalysed by an axially chiral borane (Scheme 8).⁹¹ c1h001

c1h008

Scheme 8

An N-pivaloyl-l-prolineanilide promotes high-yield imine hydrosilylation by HSiCl3 with up to 93% ee.⁹² α-Deuterated amines have been formed with up to 99% ee by chiral phosphoric-acid-catalysed enantioselective transfer of deuterium from 2-deuterated benzothiazoline to ketimines; the isotope effect suggests that C–D bond cleavage is rate determining.⁹³ c1h001 c1h001

Enantioselective epoxidations (ee ≤ 98%) of N-alkenyl sulfonamides and N-tosyl imines have been catalysed by chiral Hf(IV)-bishydroxamic acid complexes.⁹⁴ c1h001

Iminium species

The mechanism of geometric and structural isomerization of enammonium and iminium cations derived from captodative trifluoromethylated enamines has been studied by MP2/6-311+G(dp) calculations.⁹⁵ c1h001

Nucleophile-specific parameters N and sN of enamides have allowed their rates of reaction with various electrophiles to be predicted and thereby reveal the stepwise nature of iminium-activated reactions of electrophilic α,β-unsaturated aldehydes with enamides and the inadvisability of using strong acid co-catalysts.⁹⁶

As a consequence of direct observation of enamine intermediates, it has been concluded that the failure to achieve organocatalytic aza-Michael additions of imidazoles to enals is due to unfavourable proton transfer within the adduct from the imidazolium fragment to the enamine unit.⁹⁷

α-Amination of ketone-derived nitrones by an imidoyl chloride has been found to occur via [3, 3]-rearrangement (Scheme 9).⁹⁸

c1h009

Scheme 9

Imine cycloadditions

Imines derived from (R)-α-methyl benzyl amine have been aziridinated by reaction with ethyldiazoacetate and secondary diazoacetamides promoted by both (R)- and (S)-VANOL boroxinate catalysts (VBCs); the high diastereoselectivity achieved is summarized in Scheme 10.⁹⁹ c1h001

c1h010

Scheme 10

Organocatalysts derived from cinchona alkaloids promote [2 + 2] asymmetric cyclization reactions of allenoates with electron-deficient imines; the range of products obtained from alkenes has also been discussed.¹⁰⁰ c1h001

A DFT study of 1,3-dipolar cycloadditions of azomethine imines with electron-deficient dipolarophiles CH2=CH–CN, CH2=CHCO2Me, and dimethyl maleate has successfully predicted the regioselectivity and reactivity and found little evidence of charge transfer in the transition states.¹⁰¹

Asymmetric 1,3-dipolar cycloadditions of azomethine imines with terminal alkynes have been catalysed by 11 chiral ligand (8) coordinated metal amides to form N,N-bicyclic pyrazolidinone derivatives. Mechanistic studies have established the factors that determine the regioselectivity of the stepwise reaction.¹⁰² Novel phosphoramidite ligands (9) coordinated with palladium have been used to effect enantioselective synthesis of pyrrolidines by 3 + 2-cycloaddition of trimethylenemethane (from 2-trimethylsilylmethyl allyl acetate) to a wide range of imine acceptors (Scheme 11).¹⁰³ c1h001 c1h001

c1h011

Scheme 11

Dinitrogen-fused heterocycles have been formed in high yield by thermal 3 + 2-cycloadditions of two types of azomethine imines with allenoates.¹⁰⁴ Rhodium-catalysed formal 3 + 2-cycloadditions of racemic butadiene monoxide with imines in the presence of a chiral sulfur–alkene hybrid ligand have furnished spirooxindole oxazolidines and 1,3-oxazolidines stereoselectively.¹⁰⁵ Formation of 1,2-disubstituted benzimidazoles on reaction of o-phenylenediamine with aldehydes is promoted by fluorous alcohols that enable initial bisimine formation through electrophilic activation of the aldehyde.¹⁰⁶ c1h001

Other reactions of imines

Synthesis of 1,2-aminoalcohols via cross-coupling of imines with ketones or aldehydes can be achieved using Ti(OPr-i)4/c-C5H9MgCl in Et2O, although some ketones form cis-2,3-dialkyl aziridines predominantly.¹⁰⁷

NHCs have been used to promote reactions of enals with N-substituted isatinimines¹⁰⁸, ¹⁰⁹ and oxindole-derived α,β-unsaturated imines¹¹⁰ to form spirocyclic γ-lactam oxindoles. Asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with N-Boc-protected aryl imines to form RCOCH(Ar)NHBoc have also been NHC catalysed.¹¹¹ c1h001

The ambivalent role of metal chlorides, which may act as Lewis acids or electron donors, in ring-opening reactions of 2H-aziridines by imines, enaminones, and enaminoesters to form imidazoles, pyrroles, and pyrrolinones has been discussed.¹¹²

Experimental and theoretical mechanistic studies of the Davis–Beirut reaction, whereby 2H-indazolenes are obtained from o-nitrosobenzaldehydes and primary amines, implicate o-nitrosobenzylidine imine as a pivotal intermediate in the N,N-bond formation.¹¹³

The mechanism of Schiff base hydrolysis continues to receive attention.¹¹⁴–¹¹⁷ Direct spectroscopic observation of the decay of two protonated imines, N-methylisobutylidene and N-isopropylethylidene, has enabled kinetic monitoring of the carbinolamine as a non-steady-state intermediate.¹¹⁴ The kinetics and activation parameters for hydrolysis of the N-salicylidenes of m-methylaniline¹¹⁵ and p-chloroaniline¹¹⁶ have been monitored in the pH range 2.86–12.30 and 293–308 K; a mechanism has been suggested to account for the rate minimum in the pH range 5.21–10.22 and subsequent plateau (found at pH >10.73 and >11.15, respectively).

The mechanism of action of a type I dehydroquinate dehydratase has been explored theoretically by MD and DFT methods.¹¹⁷

Enantioselective addition of primary amides to aromatic aldimines (Ar¹CH=NCO2CH2Ar²) has been catalysed by chiral 1,1′-binaphthyl-2,2′-disulfonate salts and found to occur in high yield (75–99%) with 71–92% ee.¹¹⁸ c1h001

Synthesis of 2,3-dihydroquinazolinones has been achieved with 80–98% ee through intramolecular amidation of imines catalysed by Sc(II)-inda-pybox (Scheme 12).¹¹⁹ c1h001

c1h012

Scheme 12

The bisaziridination reaction of symmetric (E-s-trans-E)-α-diimines (10) with ethyl nosyloxycarbamate as aminating agent occurs diastereospecifically as the aza-anion attacks opposite faces of the conjugated system to form (11) (Scheme 13).¹²⁰ c1h001

c1h013

Scheme 13

Highly reactive o-quinone methides are proposed intermediates of reaction of 2-hydroxymethylphenols with Lawesson's reagent.¹²¹

Enantioselective hydrocyanation of a range of N-benzyloxycarbonyl aldimines by HCN has been promoted with 92–99% ee by Ru[(S)-phgly]2[(S)-binap] systems; the imine-to-catalyst molar ratio required was 500–5000.¹²² c1h001

Strecker reactions of ethyl cyanoformate with cyclic (Z)-aldimines (indoles and thiazines) catalysed by chinchona alkaloid derivatives,¹²³ and with various aromatic and aliphatic N-benzhydrylimines catalysed by a chiral polyamide (12),¹²⁴ proceed with excellent ee values. c1h001

chemical structure image

Oximes, Hydrazones, and Related Species

A statistical study for prediction of pKa values of substituted benzaldoximes has been based on quantum chemical methods.¹²⁵

The kinetics of oxidative deoximation (in AcOH) of N-methyl-2,6-diphenyl piperidin-4-one oximes by acid dichromate¹²⁶ and of 3,5-dimethyl-2,6-diaryl piperidin-4-one oximes by pyridinium chlorochromate¹²⁷ have been determined and are found to be consistent with polar mechanisms, first order in each reactant and subject to acid catalysis.

Biodegradable imidazolium-based ionic liquid solvents have been applied effectively to cyanuric-chloride-catalysed Beckmann rearrangement of ketoximes.¹²⁸ Conflicting views of the mechanism of aldoxime to amide rearrangements catalysed by metals have been reviewed and whether or not a universal mechanism applies has been discussed in the light of new evidence.¹²⁹

Double (umpolung) nucleophilic N-alkylation of α-oxime-esters by Grignard reagents, as a route to N,N-dialkyl α-amino acids, is dependent on an (E)-configuration for the oxime that may bear electron-donating or -withdrawing groups on nitrogen.¹³⁰

The cyclization step, whereby Pt(IV)-mediated nitrile–amidoxime coupling leads to 1,2,4-oxadiazoles (14), is promoted by strong acceptor substituents R′ and unaffected by the metal centre (Scheme 14).¹³¹

c1h014

Scheme 14

A detailed DFT study has been made of the mechanisms involved in a multiple-step cascade synthesis of substituted 4-amino-1,2,4-triazol-3-one from Huisgen zwitterion and aldehyde hydrazone.¹³² Metal–carbene migratory insertion is proposed to account for N-tosylhydrazone reactions involving the formation of a Csp2–Csp3 bond in Pd-catalysed oxidative coupling with allyl alcohols.¹³³ and a Csp–Csp3 bond in Cu-catalysed coupling with trialkylsilylethynes.¹³⁴

The mechanism of addition of oxime derivatives to alkynyl Fischer carbene complexes has been studied experimentally and by DFT methods.¹³⁵

Conjugate addition of donor–acceptor hydrazones (EDG-NH–N=CH-EWG) to α,β-unsaturated aldehydes, catalysed by a proline derivative through a formal diaza–ene reaction, gives access to 1,4-dicarbonyl compounds with up to 99% ee.¹³⁶ c1h001

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

Reviews of Organocatalysts

Reviews have featured recent applications of organocatalysts to asymmetric aldol reactions,¹³⁷ including particular focus on catalysis by small molecules.¹³⁸ The effects of introduction of a diaryl (oxy)methyl group into chiral auxiliaries, catalysts, and dopants have been discussed¹³⁹ and applications of amidine-, isothiourea-, and guanidine-based nucleophilic catalysts for a range of reactions of carbonyl compounds have been highlighted.¹⁴⁰ c1h001

Asymmetric Aldols Catalysed by Proline, Its Derivatives, and Related Catalysts

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol condensation of propionaldehyde in water have revealed that the stereoselectivity can be attributed to differences in transition-state solvation patterns.¹⁴¹ The hydrogen bond concept has been applied to design new proline-based organocatalysts.¹⁴² 4-Hydroxyproline derivatives bearing hydrophobic groups in well-defined orientations have been explored as catalysts in water; an advantage of aromatic substituents syn to the carboxylic acid moiety has been attributed to a stabilizing transition-state hydrophobic interaction and this is supported by quantum mechanics (QM) calculations.¹⁴³ Catalysts and solvents were screened for reaction between cyclohexanone and p-nitrobenzaldehyde.

A series of l-proline amides with 2-aminoamidazoles have promoted inter- and intra-molecular aldol reactions in high yields, ee ≤ 98% and de 98/2, in the presence of tetrafluoroacetic acid (TFA) catalyst.¹⁴⁴ c1h001 c1h001

Aldol reactions between cyclic ketones and aldehydes have been used to evaluate the excellent diastereo- and enantio-selectivities found using a multifunctional catalyst (15) featuring a prolinamide moiety, a gem-diamine unit, and a urea group.¹⁴⁵ This model has also demonstrated that the choice of the anion of an achiral triazabicyclo[4.4.0]dec-5-ene-derived guanidinium salt, used as a cocatalyst for proline, allows preparation of either anti- or syn-aldol with a very high ee value.¹⁴⁶ c1h001 c1h001 c1h001

chemical structure image

Chiral imidazolium salts (16) derived from trans-l-hydroxyproline have catalysed aldol reaction in [Bmim]NTf2 as solvent with near quantitative yield, dr 99 : 1 and ee ≤ 89%; the origins of the selectivity have been discussed with reference to salts having different H-bonding potentials.¹⁴⁷ c1h001 c1h001

Di[3,5-(trifluoromethyl)phenyl]prolinol has been used to effect enantioselective formation of γ-oxo-β-hydroxy-α-substituted aldehydes with anti selectivity.¹⁴⁸ Homoboroproline bifunctional catalysts have been fine-tuned for asymmetric aldol reactions in DMF by adjusting the Lewis acidity of boron through in situ esterification with mildly sigma-electron-withdrawing diols. NMR study of the more stable five-ring boronate esters has shed light on their mode of action; (17) was particularly effective.¹⁴⁹ c1h001 c1h001

The counterion of Zn–prolinamide complexes in aldol condensation has also been found to exert modulation of the Lewis acidity of zinc cation and thereby affect the reactivity and stereoselectivity of these complexes.¹⁵⁰

A desymmetrizing aldol reaction of 3-substituted cyclobutanones with aryl aldehydes in CH2Cl2 has been promoted with dr up to 99 : 1 and ee ≤ 99% stereodirected by N-phenylsulfonyl (S)-proline.¹⁵¹ Proline-based di-¹⁵² and tri-amides¹⁵³ have also been used effectively to catalyse asymmetric aldol condensation and the importance of each chiral centre of the catalyst has been discussed. c1h001 c1h001

The efficacies of prolinamide bearing a carbohydrate group on nitrogen,¹⁵⁴ six β-cyclodextrin conjugates with proline,¹⁵⁵ and two with the enantiomers of proline-derived 2-aminomethylpyrrolidine¹⁵⁶ have been reported for aldol reactions in water. The performance of new pyrrolidine-based organocatalysts derived from tartaric and glyceric acids proved to be disappointing.¹⁵⁷ c1h001

A computational study using DFT methods has rationalized selectivity, reported previously,¹⁵⁸ for proline-catalysed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds.¹⁵⁹ Steric effects are relatively unimportant and the several contributing controlling factors are quite different to those for 6-enolexo aldolizations known to be much less sensitive to experimental conditions. c1h001 c1h001

Stereoselectivities of aldol additions catalysed by histidine have been shown to contrast with those for proline.¹⁶⁰ Quantum mechanical calculations suggest that the imidazolium and CO2H functionalities of histidine stabilize the cyclic aldolization transition state through hydrogen bonding and that stereoselectivity is a consequence of minimization of gauche interactions around the forming C–C bond. Extensive computations have been used to support rules that enable prediction of the outcome for asymmetric cross-aldol additions between enolizable aldehydes catalysed by histidine.¹⁶¹ c1h001 c1h001 c1h001

Other Asymmetric and Diastereoselective Aldols

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed¹⁶² and their modularly designed thioamide derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones,¹⁶³ reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor,¹⁶⁴ and C(1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones.¹⁶⁵ Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-trans-α,β-unsaturated methyl ketones has also been promoted by a cinchona-based bifunctional Brønsted acid–Brønsted base catalyst with moderate enantioselectivity.¹⁶⁶ c1h001 c1h001

A fluorous chiral organocatalyst (18) promotes the formation of the anti-aldol product (with up to 96% ee) on reaction between aromatic aldehydes with ketones in brine.¹⁶⁷ The enantioselectivity achieved on promotion of aldol and Mannich reactions by another cis-diamine-based catalyst (19) can be reversed by the addition of an achiral acid and is to be the subject of further mechanistic investigation.¹⁶⁸ c1h001 c1h001

chemical structure image

DFT calculations, focusing on the C–C bond forming steps, have been used to rationalize the high regio- and stereo-selectivities found for direct aldol reactions of aliphatic ketones (propanone, butanone, and cyclohexanone) with a chiral primary–tertiary diamine catalyst (trans-N,N-dimethyl diaminocyclohexane).¹⁶⁹

A chiral bifunctional pyrrolidinylsilanol catalyst is able to direct enantioselective (88% ee) reaction of ethanal with isatin by silanol activation of the electrophile and enantiocontrol through hydrogen bonding.¹⁷⁰ c1h001

Cross aldehyde reaction between simple ketones has been promoted enantioselectively by chiral 1,1′-binaphthyl 2,2′-(POPh2) (BINAPO), with SiCl3OTf/i-Pr2NEt.¹⁷¹ c1h001

A reversal of diastereoselectivity from syn to anti is found on reducing the temperature from room temperature to −78 °C for enolboration–aldolization reaction of methylphenylacetate with RCHO promoted by Chx2BOTf/i-Pr2NEt in CH2Cl2; the converse temperature dependence applies in nonpolar solvents.¹⁷² c1h001

Biomimetic decarboxylative aldol reaction of β-ketoacids with RCOF3 has been promoted enantioselectively by a chiral tertiary amine (Scheme 15).¹⁷³ c1h001

c1h015

Scheme 15

The creation of chiral oxazolidones with a tetrasubstituted chiral centre has been attributed to memory of chirality by an axially chiral enolate intermediate of the aldol reaction involved (Scheme 16).¹⁷⁴ c1h001

c1h016

Scheme 16

Vinylic esters are able to act simultaneously as the enol precursor and acylating agent in stereoselective aldol reaction when catalysed by nucleophilic ammonium betaines, as illustrated in Scheme 17.¹⁷⁵ c1h001 c1h001

c1h017

Scheme 17

The highly chemoselective Lewis acid/hard Brønsted base cooperative chiral catalyst used to promote anti-selective direct asymmetric aldol reaction of N-protected thiolactams permits the use of enolizable aldehydes as the aldol acceptor.¹⁷⁶ c1h001

Preference for the formation of the anti aldol diastereomer, with increasing steric constraints of the reactants, is a feature of such couplings of 3-aryl-1-alkyl dihydrothiouracils.¹⁷⁷ In contrast, the origin of syn preference found on coupling zincated 3-chloro-3-methyl-1-azaallylic anions with aromatic aldehydes, in the presence of LiCl and THF, has been attributed by DFT to a highly ordered bimetallic six-membered twist-boat-like transition state.¹⁷⁸ A syn preference has also been found for asymmetric reaction of α-sulfanyl lactones with aldehydes, catalysed by an AgPF6/(R)-biphep-type ligand/DPU complex.¹⁷⁹ c1h001 c1h001

A DFT study of the origins of stereoselectivity in the aldol reaction of bicyclic amino ketones (20) with aromatic aldehydes has been reported (Scheme 18).¹⁸⁰

c1h018

Scheme 18

Base-catalysed direct aldolization of α-alkyl-α-hydroxy trialkyl phosphonoacetates with aldehydes proceeds via a fully substituted glycolate enolate intermediate formed by a [1,2]-phosphonate–phosphate rearrangement.¹⁸¹ High enantioselectivity can be achieved by the application of chiral iminophosphorane catalysts. c1h001

Mukaiyama and Vinylogous Aldols

Organocatalytic vinylogous aldol reactions have been reviewed¹⁸² and a protocol for syn-selective vinylogous Kobayashi reaction, rather than the usual anti-diastereoselectivity, provides further options in polyketide synthesis.¹⁸³, ¹⁸⁴ c1h001

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form β-ketoalcohols, have been promoted by new chiral lanthanide-containing complexes¹⁸⁵ and a chiral Fe(II)–bipyridine complex¹⁸⁶ with outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselectivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the α-carbon of the silyl ether, and the aldehyde.¹⁸⁷ The relative steric effects of the Lewis acid and trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with β,γ-unsaturated α-ketoesters has been reported for the first time and studied extensively.¹⁸⁸ c1h001 c1h001 c1h001

The Yamamoto vinylogous aldol reaction, in which bulky aluminium-based Lewis acids activate the aldehyde and also become part of the enolate, is stereodirected by 2,3-syn and 2,3-anti disubstitution of the aldehydes; bulky β-substituents favour 1,3-syn diol formation, whereas alkynyl groups lead to 1,3-anti products.¹⁸⁹ The reaction of α-branched enals with isatins may switch from vinylogous aldolization to a pericyclic pathway depending on the nature of the α-branch.¹⁹⁰ c1h001

Other Aldol and Aldol-type Reactions

The excellent 1,5-syn stereoinduction (e.g., Scheme 19) found for aldehyde reactions with boron enolates of methyl ketones bearing a bulky ether group (e.g., TBSO) at the β-position has been rationalized by DFT analysis.¹⁹¹ c1h001

c1h019

Scheme 19

Formation of RCH(OH)CH2CN by NHC-catalysed cyanomethylation of aldehydes with Me3SiCH2CN in DMF can be achieved in high yield (≤89%).¹⁹²

¹³C-Labeling studies and semiempirical MO calculations for condensation of 2-aroyl-cyclohexanones with 2-cyanoacetamide in ethanol have explained the circumstances under which formation of the regioisomeric tetrahydroquinoline can compete with target tetrahydroisoquinoline 4-carbonitriles.¹⁹³ There is a clear relationship between the product ratios and Hammett σ values, and also the corresponding LUMOs, of the aryl-substituted electrophiles.

Stereoselectivities of aldol reactions of trimethoxysilyl enol ethers catalysed by lithium binaphthoate are greatly affected by the presence of water, which may induce a change from anti- to syn-adduct formation for those derived from cyclohexanone, for example.¹⁹⁴ Direct anti- and regio-specific aldol reactions of cyclododecanone with benzaldehyde in NaOH/MeOH have provided building blocks for helical construction of supramolecules.¹⁹⁵ c1h001

Intramolecular acid-catalysed aldol cyclization of 2,3,7-triketoesters forms 1,2-anti- and 1,2-syn-tetrasubstituted cyclopentanones with high diastereoselectivities under kinetic control, when catalysed by Lewis and Brønsted acid catalysts, respectively.¹⁹⁶ c1h001

A plausible stepwise mechanism proposed for DABCO-mediated [4 + 2] annulation of but-3-yn-2-one (23) and activated ketones (22) to form 2,3-dihydropyran-4-ones (24) is under further investigation.¹⁹⁷

chemical structure image

A six-membered hydrogen-bonded transition state apparently enables AcOH-catalysed nucleophilic addition of benzylic C of 2-methyl azaarenes to aldehydes.¹⁹⁸

Tertiary enamides and enecarbamates undergo nucleophilic intramolecular Csp2 addition to an N-CH2CH2CHO group to form 4-hydroxytetrahydropyridine derivatives; the enantioselective reaction is promoted by a BINOL–Ti complex.¹⁹⁹ c1h001

The Henry (Nitroaldol) Reaction

Biocatalytic approaches to the formation of β-nitroalcohols by the Henry reaction have been reviewed.²⁰⁰

QM/MM calculations and experimental kinetic study have explored the effects of solvation on the transition states for reaction between nitromethane and formaldehyde and between nitropropane and benzaldehyde.²⁰¹ Asymmetric reactions of nitromethane with various aldehydes have been promoted by Cu(II) coordinated with amino alcohols,²⁰² imidazolium/pyrrolidinium-tagged Indabox,²⁰³ and imidazolium-tagged bis(oxazoline)-based²⁰⁴ chiral ligands. The Henry reaction has also been promoted by Mn(OAc)2/Schiff bases bearing a triazole structure, with up to 99% yield,²⁰⁵ and by phosphonium ionic ligands MeP+(octyl)3 ROCO2− without solvent.²⁰⁶ c1h001

A bifunctional chiral phase-transfer 1,1-binaphthyl catalyst has promoted aldol reaction of α-substituted nitroacetates with aqueous HCHO under neutral conditions.²⁰⁷

Aza-Henry reaction of N-protected imines (R′CH=NPg) with bromonitromethane to yield nitroamines and bromonitroamines has been promoted by SmI2 and NaI, respectively, in THF.²⁰⁸ c1h001

The Baylis–Hillman Reaction and Its Morita Variant

A review of the Morita–Baylis–Hillman (MBH) reaction has covered mechanism, activated olefins and electrophiles as substrates, multicomponent and intramolecular reactions, and the use of ionic liquid reaction media.²⁰⁹

MBH reactions of benzaldehyde with cyclic enones²¹⁰ have been promoted by a bicyclic imidazolyl bifunctional catalyst, and reactions with acrylate esters have been catalysed by a glucose-based chiral phosphino thiourea,²¹¹ hydrogen bonding organocatalysts incorporating a pyrrolidine ring,²¹² and bifunctional β-isocupreidine derivatives.²¹³ The first example of asymmetric MBH reaction of aromatic aldehydes with acrolein (CH2=CHCHO) has achieved 81% ee by application of Hatakeyama's catalyst (β-isocupreidine 25) in the presence of 2,6-dimethoxybenzoic acid.²¹⁴ A remote activation effect on diastereoface selection in MBH alkylation at C(2) of a cyclic enone derived from d-glucose has been discussed.²¹⁵ c1h001 c1h001

Kinetic studies have revealed the complex Baylis–Hillman reaction of 3-methoxy-2-nitrobenzaldehyde with CH2=CHCOMe²¹⁶ and a second-order dependence on aldehydes for BH reactions in ionic liquids featuring EtSO4−.²¹⁷

DFT-based mechanistic studies and free energy computations have explained why enhanced rates of MBH reactions of heterocyclic aldehydes depend on the position of a formyl group.²¹⁸

chemical structure image

4-(N,N-dimethylamino)pyridine (DMAP) is an efficient catalyst for MBH reactions of isatins (26) with allenoates (27) (Scheme 20).²¹⁹

c1h020

Scheme 20

Aza-MBH reaction between acrylonitrile (30) and imines (29) has been achieved with 98% ee using chiral phebim/Pd(II) complexes (32) to form α-methylene-β-aminonitriles (31).²²⁰ Aza-MBH reactions of ArCH=NTs with electronically and sterically deactivated Michael acceptors can be achieved by the use of electron-rich phosphanes (PAr3) and pyridines (33) as catalysts (Scheme 21).²²¹ Nucleophilic and steric influences, respectively, are exerted by new multifunctional chiral phosphines and BINOL derivatives used to cocatalyse aza-MBH reactions of 5,5-disubstituted cyclopent-2-enone and RCH=NTs in THF, with 99% yield and 85% ee.²²² c1h001

c1h021

Scheme 21

Allylation and related reactions

The first example of enantioselective (ee ≤ 92%) allylation of aldehydes (by allyl-SnBu3) using a chiral B(III) complex has been developed using Bi(OTf)3 with Trost's (R,R)-ProPhenol ligand.²²³ c1h001

Allylborations of aldehydes have included enantioselective reactions with pinacol allylboronates, catalysed by 1,1′-spirobiindane-7,7′-diol (SPINOL)-based phosphoric acids,²²⁴ and with chiral B-(3,3-difluoroallyl)diisopinocampheylborane to form 1,1-difluorinated homoallylic alcohols with 91–97% ee.²²⁵ c1h001

Intermolecular ¹³C kinetic isotope effects (KIEs) determined for Rouse allylboration of p-anisaldehyde (Scheme 22) are indicative of a rate-limiting cyclic transition state but are much higher than expected. A heavy-atom tunnelling explanation is supported by multidimensional calculations.²²⁶

c1h022

Scheme 22

Asymmetric allylations of ArCHO with allyltrichlorosilane in CH2Cl2 to form homoallylic alcohols has been Lewis base catalysed by chiral bisformamide-type catalysts (with ee ≤ 83%)²²⁷ and by (R)-methyl p-tolyl sulfoxide.²²⁸ Mechanistic study of the latter reaction supports a dissociative pathway via an octahedral cationic complex with two sulfoxides. The greater stereoselectivity of N-oxide-catalysed allylations, compared to propargylations, has been explained by a simple electrostatic model that should enable design of suitable catalysts for both reactions.²²⁹ c1h001

A study of the orientation of the reacting double bonds in the transition state of the allylsilane–aldehyde addition to model compounds (34) and (36) has revealed low and high synclinal preference, respectively, which has been attributed to stereoelectronic factors as there should be no intrinsic steric bias for double bond alignment (Scheme 23).²³⁰

c1h023

Scheme 23

Vinyl silacyclopropanes generated in situ add to aldehydes with formation of seven-membered-ring trans-oxasilacycloheptenes with high diastereoselectivity.²³¹ High diastereoselectivity has been reported for the formation of tertiary homoallylic alcohols on addition of allyltitanocenes to α-chiral ketones.²³² c1h001 c1h001

An important advancement in highly regioselective and enantioselective allylation of β-diketones has been enabled using their enol form to provide the necessary Brønsted-acid activation for t-carbinol formation.²³³ c1h001

Alkynylations

Schiff base ligands derived from (1R)- and (1S)-camphor are excellent catalysts for the addition of phenyl acetylene to give propargylic alcohols in high yields (≤99%) with ee ≤ 92%.²³⁴ Computational studies suggest that asymmetric propargylation of aldehydes by an allenic boronic pinacol ester is promoted by a chiral phoshoric acid through activation of the ester rather than the aldehyde.²³⁵ Asymmetric Barbier-type propargylations of aldehydes and ketones by organoindium reagents derived in situ from propargyl bromide have been promoted by (1S,2R)-(+)-2-amino-1,2-diphenylethanol with ≤ 90% yield and ≤ 95% ee.²³⁶ c1h001 c1h001

Zircanocene complexes with silyl- or t-butyl-substituted 1,3-butadienes undergo two syn-SN2′ reactions with various aldehydes to yield cis-[3]cumulenic diols with a high de value.²³⁷ c1h001

Michael Additions

A C2-symmetric pyrrolidine-based tetraamine promotes additions of ketones to nitroolefins and chalkones with respective yields of ≤ 99% and ≤ 91% and relative ee values of ≤ 91% and ≤ 93%.²³⁸ Excellent enantioselectivities have been reported for conjugate addition of ketones to nitroalkenes catalysed by chiral pyrrolidine sulfamides; incorporation of an additional chiral centre in the side-chain is of negligible advantage.²³⁹ Additions of ketones to nitroolefins have also been promoted by a chiral amino-naphthalene-derived prolinamide.²⁴⁰ c1h001 c1h001

Axially chiral binaphthyl-based secondary amines have been screened for the promotion of asymmetric Michael reactions of aldehydes with nitroalkenes; syn/anti ratios up to 99 : 1 and ee ≤ 99% have been achieved.²⁴¹ Perhydroindolic acids have performed likewise.²⁴² c1h001

A Michael–Henry cascade organocatalysed by a quinidine derivative has enabled the formation of spiroindoles having four consecutive stereocentres (Scheme 24).²⁴³ c1h001

c1h024

Scheme 24

Michael additions to 2-aryl nitroalkenes organocatalysed by proline derivatives have been used to form hexahydroxanthenes having three contiguous stereocentres,²⁴⁴ and enantiopure tetrahydro-pyrans and -furans.²⁴⁵ c1h001 c1h001

Asymmetric conjugate addition of aldehydes to acrylate esters has been achieved through catalysis by a bifunctional enamine-metal Lewis acid²⁴⁶ and by an axially chiral amino diol.²⁴⁷ c1h001

c1h001 Bifunctional squaramide-derived chiral catalysts have promoted the addition of cyclic diketones to β,γ-unsaturated α-ketoenols with ee ≤ 99% (Scheme 25).²⁴⁸ c1h001

c1h025

Scheme 25

Excellent yields, de, and ee have been achieved by tuning a bulky group (R) on a chiral diamine catalyst (38) for the addition of substituted rhodamines to α,β-unsaturated ketones (Scheme 26).²⁴⁹ c1h001 c1h001 c1h001

c1h026

Scheme 26

Cinchona-alkaloid-catalysed conjugate cyanation of enones has enabled the synthesis of trifluoromethyl-substituted diarylpyrroles with ee ≤ 96%.²⁵⁰ Thiochromanes have been formed by asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with α,β-unsaturated N-acylpyrazoles.²⁵¹ Asymmetric organocatalysed oxy-Michael addition to γ-hydroxy α,β-unsaturated thioesters on reaction with t-BuCHO has been used to form β-hydroxy carbonyl compounds HOCH2C*H(OH)CH2CO.SAr via cyclic hemiacetal intermediates.²⁵² c1h001 c1h001

Triazolium salt-based NHCs have been used to promote asymmetric intra-²⁵³ and inter-molecular²⁵⁴ Stetter reactions of cyclohexadienones and simple acrylates, respectively, resulting in umpolung addition of aldehydic carbon.

Acyl azoliums generated from enals have been converted to cyclopropyl carboxylic esters with ee ≤ 99% by reaction with sulfur ylides.²⁵⁵ Some FLPs have been found to react by conjugate P/B addition to unsaturated ketones and esters, whereas 1,2-addition to corresponding aldehydes is usual.²⁵⁶ c1h001

Miscellaneous Condensations

The mechanism of formation of α,α′-dihydroxy ketones by tertiary amine-catalysed reaction of aldehydes with lithium hydroxypyruvate proceeds with opportunity for facial stereodifferentiation as an intermediate adds to the aldehyde and can be achieved with up to 50% ee if catalysed by a quinine ether.²⁵⁷ c1h001

Three-component condensation of silicylaldehyde and two different CH acids to give 2-amino-4H-chromenes, catalysed by base-functionalized ionic liquids, has been investigated experimentally and theoretically.²⁵⁸ Mechanisms of formation and reaction of camphor-derived amino ketones have been discussed.²⁵⁹

Kinetic isotope measurements for the cyclocondensation step of the Knorr pyrrole synthesis suggest that two protic solvent molecules participate in a rate-determining ketone protonation before cyclization and dehydration.²⁶⁰ Chiral SPINOL-phosphoric acids (39) promote asymmetric Pictet–Spengler reactions (Scheme 27).²⁶¹

c1h027

Scheme 27

The Knoevenagel condensation of formaldehyde with methylene dicyanide catalysed by alkali metal chlorides has been studied theoretically.²⁶² c1h001

Atropoisomeric α,α′-binaphthyl (P,N) ligands have been used to effect Pd-catalysed asymmetric intramolecular α-arylation of α-branched aldehydes (Scheme 28).²⁶³ c1h001

c1h028

Scheme 28

Other Addition Reactions

Addition of Organozincs

Linear homoallylic alcohols are obtained α-regioselectively on zinc/DMPU-mediated reaction of crotyl bromide with aldehydes and ketones.²⁶⁴ Enantioselective alkylations of aldehydes by dialkyl zincs have been catalysed by (−)-2-exo-morpholinoisoborne-10-thiol²⁶⁵ and (S)-1-alkyl-2-(arylamino)methylpyrrolidine²⁶⁶ with ee values up to 99% and 94%, respectively. c1h001

A quantitative correlation between enantiomeric product ratios and the size of N-substituents on chiral 1,2-aminophosphoramide ligands has been found for the reactions of Et2Zn with benzaldehyde.²⁶⁷ c1h001

The 99% enantioselectivity found for t-alcohol formation on autocatalysed reaction of i-Pr2Zn with a pyrimidine-5-carbaldehyde, initiated by (2S,3S)-butane-2,3-diol, reverses from (S) to (R) if an achiral phenol is also present.²⁶⁸ c1h001

A transient alkoxyacetal intermediate formed by 1 : 2 combination of (40) and (41) has been observed by ¹H NMR for reaction of i-Pr2Zn with (40) promoted by Soai asymmetric autocatalysis by (41) (Scheme 29).²⁶⁹ c1h001

c1h029

Scheme 29

Ketone olefination occurs on reaction with organozinc reagents in the presence of diphenylphosphite, which causes dehydration of the intermediate alcohol via a six-centred transition state.²⁷⁰ Arylzinc reagents have been added to sugar-derived aldehydes with dr up to >20 : 1.²⁷¹ c1h001

Arylations

Rh(I)/chiral sulfoxide phosphine complexes catalyse enantioselective addition of arylboronic acids to NH isatins.²⁷² α-Hydroxyketones have been formed by Rh(I)-catalysed aryl addition from arylboronic acids to α-diketones under the influence of an enantioselective sulfur–alkene ligand (42) (Scheme 30).²⁷³ c1h001

c1h030

Scheme 30

Similar conditions have promoted five-, six-, and seven-membered ring formations by intramolecular cyclization of arylboron compounds onto ketones (Scheme 31).²⁷⁴

c1h031

Scheme 31

Biaryl methanols can be obtained from aryl aldehydes by Rh-catalysed addition of an aryl ring bearing an N-directing group ortho to the activated C–H.²⁷⁵ Cyclization reactions of (2-iodoanilino)carbonyl compounds (43) promoted via a palladacycle intermediate (44) can be directed towards α-arylation versus nucleophilic addition by choice of additives and conditions (Scheme 32).²⁷⁶

c1h032

Scheme 32

The first example of enantioselective addition of in situ generated pyridylmagnesiate to aldehydes has relied on (R,R)-TADDOLate ligand.²⁷⁷ c1h001

Addition of Other Organometallics, Including Grignards

Aggregation between lithiated dipolar entities throughout a catalytic cycle for enantioselective hydroxyalkylation of an aldehyde by cat*-RLi has been studied.²⁷⁸ Up to 90% ee has been achieved for alkylation of ArCHO by RLi/Ti(i-PrO)4 in the presence of a 1,1-binaphthyl ligand featuring OH and R-(CH(OH)Ph) at 2- and 2′-positions.²⁷⁹

DFT computations for BuLi addition to PhCHO in the presence of chiral N,P-amides R′NHC*H(R)CH2PPh2 derived from amino acids have reproduced the enantioselectivities observed.²⁸⁰ c1h001

Addition of organolithiums to thioketones might be expected to proceed, as for ketones, via the lithium salt of the t-alcohol. However, a computational study has shown that this is a relatively minor route and that the variety of products obtained can be attributed to slower addition to C=S, as a consequence of small bond angles preferred by divalent sulfur, combined with lower activation energies for thioketone reduction.²⁸¹ c1h001

1,2-Addition of R²MgBr to XC6H4COR¹ catalysed by Cu(I) bearing a chiral ferrocenyl diphosphine ligand occurs with up to 90% yield and ee ≤ 98%.²⁸²

Anti- and syn-homoallylic alcohols are obtained by the reaction of E- and Z-allylic sulfides, respectively, with ketones in the presence of [Cp2Ti(III)]; allyltitanocene intermediates are generated by initial desulfurizative titanation (Scheme 33).²⁸³ c1h001

c1h033

Scheme 33

The degree of diastereoselection achieved for addition of allyltitanocenes (45) to five- to seven-membered cyclic enones increases with ring size and the syn- versus anti-stereochemistry depends on R (Scheme 34).²⁸⁴ c1h001

c1h034

Scheme 34

The Wittig Reaction

A reexamination of the preferential formation of Z-olefin on reaction of nonstabilized ylides with aldehydes has concluded that this is driven only by steric influences on the two cis/trans oxaphosphetane intermediates with the oxygen atom in equatorial position.²⁸⁵ The higher than expected proportion of Z-alkene obtained from o-substituted benzaldehydes on reaction with Ph3P-derived keto-stabilized ylides is further increased by greater steric bulk at the α′-position of the ylide and can be rationalized within the 2 + 2-cycloaddition mechanism.²⁸⁶ It has also been found that there is consistently increased selectivity for cis-oxaphosphetane and its derived products (Z-alkene and erythro-β-hydroxy phosphonium salt) in reactions involving β-heteroatom-substituted aldehydes, whether aliphatic or aromatic and whether the resulting ylide is nonstabilized, semistabilized, or stabilized.²⁸⁷ This supports a common mechanism for all Li-salt-free Wittig reactions and can be most easily explained by the 2 + 2-cycloaddition mechanism to form oxaphosphetane followed by syn-cycloreversion to give alkene and phosphine oxide; this also explains the cooperative effect found for ortho-substituents in the case of semistabilized ylides. It is concluded that with very limited exceptions no Li-salt-free Wittig reaction is reversible and that OPAs are the first formed and only intermediates; however, the mechanism is as yet unknown for Wittig reactions conducted in the presence of Li salts. c1h001 c1h001

DFT calculations of substituent effects on aza- and arsa-Wittig reactions (HM=PH3 + O=CHX forming HM=CHX + O=PH3, where M = N, As; X = H, F, Cl, Me, OMe, NMe2, CMe3) have established that differences between singlet–triplet splitting of the reactants influence the reaction kinetics and thermodynamics.²⁸⁸ The greater the ylidic character of HM=PH3 the smaller the activation energy and larger the exothermicity.

Hydrocyanation, Cyanosilylation, and Related Additions

2-Formylarylketones are readily isomerized in dimethyl sulfoxide (DMSO) to 3-substituted phthalides by photolysis or by a Cannizarro–Tishchenko-type nucleophilic catalysis by NaCN.²⁸⁹

A study of the addition of Me3SiCN to aldehydes catalysed by four Lewis bases (Et3N and Bu4N+X, where X = CN, N3, or SCN) has revealed three different reaction mechanisms; there was spectroscopic evidence of formation of a hypervalent silicon species by each of the ammonium salts.²⁹⁰ Asymmetric trifluoromethylation of aromatic aldehydes by Me3SiCF3 is catalysed cooperatively by (IPr)CuF and a quinidine-derived quaternary ammonium salt.²⁹¹ c1h001

Hydrosilylation, hydrophosphonylation, and related reactions

Catalyst development and mechanistic insights have been reviewed for rhodium-catalysed hydrosilylation of ketones,²⁹² and P/S ligands derived from phosphinite thioglycosides have been designed for this purpose using Ar2SiH2 as reactant.²⁹³

Asymmetric reductions of ketones via hydrosilylation have been promoted by ZnEt2 with pybox or pybim ligands and polymethylhydrosiloxane (PMHS);²⁹⁴ zinc Schiff base complexes and (EtO)3SiH in THF-t-BuOH;²⁹⁵ Ni(II)-dipyridylphosphine and PhSiH3 in toluene; and²⁹⁶ Cu(II)-(S)-Xyl-P-Phos and PMHS in toluene.²⁹⁷ c1h001

The origins of enantioselectivity in hydrosilyation of acetophenones by SiH4 over chiral diphosphine-ligated CuH have been investigated by DFT computations.²⁹⁸ CuH addition to C=O via a four-membered transition state is stereocontrolling and precedes rate-determining reaction with SiH4 to form the silyl ether and regenerate ligated CuH. c1h001

A new family of Lewis basic 2-pyridyl oxazolines has been developed for Cl3SiH reduction of prochiral aromatic ketones and ketimines in CHCl3 with up to 94% ee and 89% ee, respectively.²⁹⁹

Hydroboration of aldehydes and ketones by pinacolborane is aided by a pre-catalyst cycle involving a heteroleptic magnesium alkyl complex and the ketone.³⁰⁰ c1h001

Recent developments in metal-catalysed asymmetric addition of phosphorus nucleophiles, with the formation of P–C bonds, have been reviewed; the metals and electrophiles have been discussed widely.³⁰¹ DFT study of salicylaldehyde–Al(III)-catalysed hydrophosphonylation of benzaldehyde by diethylphosphonate (DEPH) reveals that P–H activation by the formation of Al-phosphite species is followed by rate-determining C–P bond formation, which determines the predominant (S) configuration (with 99% ee) of the α-hydroxyl phosphonate ester on regeneration of the salicylaldehyde–Al(III) complexes.³⁰² Reduction of activated carbonyl groups by alkylphosphanes can proceed either through path a or path b (Scheme 35), as evidenced experimentally and theoretically.³⁰³ c1h001 c1h001

c1h035

Scheme 35

Miscellaneous additions

Enantiopure vic-fluorohydrins (48) and α-fluorobenzylketones (49) have been obtained from the product (47) of nucleophilic monofluorobenzylation of a range of aldehydes directed anti-diastereoselectively by an o-sulfoxide group (Scheme 36).³⁰⁴ c1h001

c1h036

Scheme 36

Nucleophilic fluoroalkylations of α,β-unsaturated carbonyl compounds with α-fluorinated sulfones have been shown to form 1,2- and 1,4-adducts under kinetic control in LiHMDS/THF.³⁰⁵

Direct introduction of –CF2I and –CF2Br groups by nucleophilic addition is undermined by competing conversion to difluorocarbene. However, formal addition of these groups to carbonyl C has been achieved via desulfinative halogenation of in situ generated sulfinate intermediates from the base-promoted Julia–Kocienski reaction of ketones with 2-pyridyl SO2CF2H.³⁰⁶

Conversion of aldehydes to terminal epoxides has been achieved with 95% ee, through methylene transfer from a chiral sulfonium ylid.³⁰⁷ c1h001

Umpolung behaviour has been achieved, whereby direct thioesterification of aldehydes (other than aliphatic) and enals by direct nucleophilic attack of carbonyl C on disulfides is promoted by an NHC and DBU/DEAD.³⁰⁸

Enolization and Related Reactions

Enolization

A quantitative structure–property relationship (QSPR) developed for predicting acidities of ketones promises to enlighten understanding of their chemical