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ORGANIC REACTION MECHANISMS ⋅ 2012

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ORGANIC REACTION
MECHANISMS ⋅ 2012
An annual survey covering the literature
dated January to December 2012

Edited by

A. C. Knipe
University of Ulster
Northern Ireland

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This edition first published 2015
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1 2015

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Contributors

K. K. BANERJI

Faculty of Science, National Law University, Mandore,
Jodhpur 342304, India

C. T. BEDFORD

Department of Chemistry, University College London,
20 Gordon Street, London, WC1H 0AJ, UK

M. L. BIRSA

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


S. CHASSAING

Centre National de la Recherche Scientifique, Université
de Toulouse, Toulouse, France
Centre Pierre Potier, ITAV, Université de Toulouse,
F-31106 Toulouse, France
INSA, F-31400 Toulouse, France

J. M. COXON

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

M. R. CRAMPTON

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

N. DENNIS

3 Camphor Laurel Court, Stretton, Brisbane, Queensland
4116, Australia

E. GRAS

Laboratoire de Chimie de Coordination, Centre National
de la Recherche Scientifique, Toulouse, France

A. C. KNIPE


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

ˇ
´
P. KOCOVSK
Y

Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University, Stockholm SE 10691, Sweden
Department of Organic Chemistry, Charles University,
12843 Prague 2, Czech Republic

R. A. McCLELLAND

Department of Chemistry, University of Toronto, Toronto,
80 St George Street, Toronto, Ontario M5S 1A1, Canada

K. C. WESTAWAY

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

v

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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.

vii

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Contents
1. Reactions of Aldehydes and Ketones and their Derivatives
by A. C. Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their
Derivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Oxidation and Reduction by K. K. Banerji. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Carbenes and Nitrenes by E. Gras and S. Chassaing . . . . . . . . . . . . . . . . . . . . .
5. Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Carbocations by R. A. McClelland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Nucleophilic Aliphatic Substitution by K. C. Westaway. . . . . . . . . . . . . . . . . .
8. Carbanions and Electrophilic Aliphatic Substitution by M. L. Birsa . . . . .
9. Elimination Reactions by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Addition Reactions: Polar Addition by P. Koˇcovsk´y . . . . . . . . . . . . . . . . . . . . .
11. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . . .
12. Molecular Rearrangements by J. M. Coxon . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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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 . .
Organic Reaction Mechanisms 2012, First Edition. Edited by A. C. Knipe.
© 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd.

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Organic Reaction Mechanisms 2012

Oxidation and Reduction of Carbonyl Compounds . . . . . . . . .
Regio-, Enantio-, and Diastereo-selective Reduction Reactions
Other Reduction Reactions . . . . . . . . . . . . . . . . . . .
Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . .
Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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35
35
36
37

38
39
41

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
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 CH3 CHO (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 13 C 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
The quantitative transacetalization of 2-formylpyrrole found in RONa/ROH may
involve highly reactive azafulvene intermediates.8
Baldwin’s rules can account for the unprecedented ring expansion, whereby polyoxygenated eight- and nine-membered rings are formed regioselectively by rhodiumcatalysed 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
A kinetic study of intermolecular hydroamination of allylic amines by Nalkylhydroxylamines has revealed a first-order dependence on aldehyde catalyst.

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ee
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3

1 Reactions of Aldehydes and Ketones and their Derivatives
R1
N
•

+

R2

+

N

R1


Au+

O−

OMe

O

−MeOH

R2
H
H

OMe

OMe
Scheme 1

R4

O

R1

H
N

+
R2


R3

N
H

OH

R4

R3

R3

N O

H

(Catalyst)

R1

N

H
R2

R1

H

N

N

OH

R2

Scheme 2

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
Coupling of alkenyl ethers (Ene–OR) with ketene silyl acetals R1 R2 C=C(OR3 )
OSiMe3 , catalysed by GaBr3 , forms 𝛼-alkenylated esters Ene–C (R1 R2) CO2 R3 .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 13 C
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
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-1,2diphenylcyclopropene 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

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Organic Reaction Mechanisms 2012

undermined by partial anomerization of the intermediate 𝛽-bromide to the unreactive
𝛼-isomer.23
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
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 1 H 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

de

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
Asymmetric synthesis of trans-𝛽-lactams from disubstituted ketenes and Ntosyl 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

Formation and Reactions of Nitrogen Derivatives
Imines: Synthesis, Tautomerism, and Catalysis
A restricted Hartree–Fock study of formation of Schiff base (N-[(Z)-furan-2ylmethylidene]-4-methoxyaniline) from aromatic amine and furaldehyde has revealed
that an auxiliary water molecule enables proton transfer in the carbinolamine-forming

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1 Reactions of Aldehydes and Ketones and their Derivatives

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 Ph2 CO and
PhNH2 under mild conditions catalysed by a Lewis acid–base pair (AlCl3 –Et3 N).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

ee

OMe
10 mol% (1)

Ar

OH
N

N
H

N
Cl
(1)


Ar

PhMe, 0.1 M

Z

N

Ar = 4-NO2Ph
ee ≤ 94%
CF3

Z

CF3

Z = RCH2 or RC6H4
(2)

(3)

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
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

ee
de

ee

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
Three-component Mannich reactions of cyclohexanone and anilines with aromatic aldehydes, in the presence of H2 O, 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

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Organic Reaction Mechanisms 2012

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

N
R1

O2 S

Boc
+

(7)
0.5–5 mol%

OPri


H

DMF

H
(4)
R1

de

ee

de

de

N

Ar

N

N

R2

ee

P


N
Pri

ee

Pri
N

Ar

ee

Boc O2S
NH N
R1

OPri
(6)

(5)

R2

anti/syn up tp 99 : 1

= aryl, alkyl
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 aminothiourea organocatalysts.54 Mannich reaction of glycinate Schiff bases (Ar2 C=

NCH2 CO2 Bu-t) with aliphatic imines (RCH=NTs) generated in situ from 𝛼amidosulfones(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 Ph2 C=NCH2 CO2 R′ 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=NSO2 Bu-t.58
Imidazoline-anchored phosphine ligand–Zn(II) complexes promote asymmetric
Mannich-type reaction of F2 C=C(R3 )OTMS with hydrazones (R1 CH=NNHCOR2 )
under mild conditions.59

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1 Reactions of Aldehydes and Ketones and their Derivatives

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

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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
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
Enantioselective synthesis of homopropargyl amines can be effected through coppercatalysed 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 R1 CH=CR2 BF3 K have also been reported.72


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Me
Ph

O
X

O
S

Ph Me

+

N

R2

BF3K
3

R1


R

O

Rh (cat.)
MeOH (5 equiv)
THF, 55 °C

X

O
S

NH
R1 2
R

R3

99 % ee
19 : 1 dr
Scheme 4

A metal complex has also been used to promote enantioselective arylation of 𝛼-imino
esters by Ar2 B(OH)2 and provide direct access to chiral arylglycine derivatives
(Scheme 5).73
Allylation of imines R1 CH=NR2 by CH2 =CHCH2 SnBu3 in tetrahydrofuran
(THF) has been achieved enantioselectively (ee ≤ 98%) using a newly developed

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Organic Reaction Mechanisms 2012
Ar1

OEt

N

+ Ar2B(OH)2

O
CH3NO2, 50 °C, 15–48 h catalyst (10 mol%)

O

Ar2
Ar1

N

OEt

NH

O

N
Pd

O

AcO

up to 95% yield
up to 99% ee

OAc

(S, S)-catalyst

Scheme 5

𝜋-allylpalladium catalyst that incorporates (−)-𝛽-pinene bearing an isobutyl sidechain;74 a menthane-based complex was less effective.75
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
R′′
H

+

R

R′


R

R′′
H

N

ee

H

H

R′′

N

H

cat. Re(I)

R′

R′′

R
Re+
Re

R


•·

H
R′′
R′′

R′
N−

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

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

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1 Reactions of Aldehydes and Ketones and their Derivatives

ammonium betaines; high 𝛼-selectivity with 95–99% ee has been reported for the
nitroallyl addition.79
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 Nprotected 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

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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
Hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines has been promoted by an Ir–diphosphine complex with up to 96% ee.88
Bifunctional rhenium complexes [Re(H)(NO)(PR3 )(C5 H4 OH)] (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


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ee

ee

H
−B(C F )
6 5 2
+

N
R1

R2

But3PH

HN
PhMe2SiH

R1

R2

*

ee ≤ 87%

Scheme 7

A selectivity determining hydride transfer identical to that for a related B(C6 H5 )3 catalysed carbonyl reaction has been proposed for hydrosilylation of imines by a silane
reactant catalysed by an axially chiral borane (Scheme 8).91

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Organic Reaction Mechanisms 2012
R

Si
+

N

Ph
H
C6F5

Ar
Me

−

B


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

ee

ee
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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
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

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
R′

+

N

−

O

Cl
+

R
R′′

Y
N

Z

−H+

R′

N

O


Y

R′
[3,3]

N

R

Z

R′′
Scheme 9

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1 Reactions of Aldehydes and Ketones and their Derivatives
O

O

Ph

Ph

NHPh
N2

N

N2

N

N

(S)-VBC

(S) or (R)-VBC

R


Ph

OEt

R

CONHPh

R

CO2Et

R = Ar, 1er, 2er, 3er, alkyl
Scheme 10

(S)-VANOL boroxinate catalysts (VBCs); the high diastereoselectivity achieved is
summarized in Scheme 10.99
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
A DFT study of 1,3-dipolar cycloadditions of azomethine imines with electrondeficient dipolarophiles CH2 =CH–CN, CH2 =CHCO2 Me, 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,Nbicyclic 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
Ar
O


PAr2

P

PAr2

N

O

( )n

Ar
Pri
(9a): n = 1, Ar = 2-Naph
(9b): n = 0, Ar = Ph

(8): Ar =
Pri
AcO

N
R1

R3

R4

R3


R3
N

TMS

or

Pd,

R2

PhCH3

R1 R2

R4

Scheme 11

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Organic Reaction Mechanisms 2012

Dinitrogen-fused heterocycles have been formed in high yield by thermal
3 + 2-cycloadditions of two types of azomethine imines with allenoates.104 Rhodiumcatalysed 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

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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-C5 H9 MgCl in Et2 O, 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
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 (Ar1 CH=
NCO2 CH2 Ar2 ) 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
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
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

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1 Reactions of Aldehydes and Ketones and their Derivatives
O
R

O

O

1

N
H

R2

+ R

3

1

R

Sc(III)-inda-pybox


H

N

CH2Cl2

R2

H
R3
N
H
80–98% ee

NH2

Scheme 12

EtO2C

R*
N

H

R*

NsONHCO2Et

−


CO2Et

ONs
H

N

CaO

H

N

N
−

R*
*

R
H N
NsO CO Et
2

N
R*

N


−NsO−
very fast

(10)

H

N
N
N R*
EtO2C
(11)
H

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
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.
Ph

Ph

O
Ph


O
NH HN

NH
S
O
p-Tol

Ph
HN

O

O
S
O
p-Tol

(12)

Oximes, Hydrazones, and Related Species
A statistical study for prediction of pKa values of substituted benzaldoximes has been
based on quantum chemical methods.125

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