Angewandte
Chemie
DOI: 10.1002/anie.200907167
Synthetic Methods
Tunable Bromomagnesium Thiolate Tishchenko Reaction Catalysts:
Intermolecular Aldehyde–Trifluoromethylketone Coupling**
Linda Cronin, Francesco Manoni, Cornelius J. Oꢀ Connor, and Stephen J. Connon*
The Tishchenko reaction[1] (discovered by Claisen[2] in 1887)
is the disproportionation of two aldehyde molecules to furnish
an ester product (Scheme 1).[3] Aluminum alkoxides[1,4] and
boric acid,[5] were the first classes of synthetically relevant
homogeneous catalysts[6] for this reaction, these were then
followed by a range of transition-metal complexes of low to
high catalytic activity but often limited practical utility.[7,8]
More recently, lanthanide,[9] actinide,[10] and calcium[11] com-
plexes capable of promoting aldehyde dimerization with
excellent activity have been reported. A generalized mech-
anistic outline of the process is given in Scheme 1: reaction of
the transition-metal complex 1 with the aldehyde generates
the metal alkoxide 2, which acts as the hydride-transfer agent
in a metal-mediated redox process (i.e. 3) leading to ester 4.[12]
meaning that the intermolecular reaction cannot currently be
utilized to generate new stereogenic centers.
We were therefore encouraged to attempt the develop-
ment of an alternative catalyst system for the intermolecular
Tishchenko process. Our objective was to devise a simple,
inexpensive, and easy to use small-molecule promoter, the
steric and electronic characteristics of which could be readily
tuned, with the eventual goal of broadening the scope of the
Tishchenko reaction to include ketone substrates. We were
inspired by the mode of action of the glycolytic enzyme
glyceraldehyde-3-phosphate dehydrogenase (G3PDHase),
which promotes aldehyde oxidation through base-catalyzed
addition of a cysteine residue to the aldehyde substrate to give
the corresponding hemithioacetal conjugate base
5
(Scheme 2, A), which participates in an intermolecular
hydride-transfer reaction with enzyme-bound NAD+. The
resulting electrophilic thioester 6 then undergoes either
hydrolysis or substitution by inorganic phosphate (depending
on the enzyme variant).[15–17]
Scheme 1. The Tishchenko reaction.
The Tishchenko reaction is an unusual process from a
mechanistic standpoint with the potential to allow chemists to
plan the synthesis of ester products through an unconven-
tional disconnection. While recent advances in catalyst
development have resulted in increased promise as a general
synthetic methodology, the utility of the Tishchenko reaction
is somewhat limited by two factors: a) Often the reported
catalyst systems result in lower yields of isolated products
from substituted benzaldehydes, and b) intermolecular
crossed-Tishchenko reactions between equimolar amounts
of two different carbonyl moieties are generally not possible.
In particular no examples of intermolecular cross-cou-
pling[13,14] between an aldehyde and a ketone are known,
Scheme 2. Proposed thiolate-catalyzed Tishchenko reaction.
We postulated the viability of an artificial process in which
an analogous hemithioacetal anion 9 generated from benzal-
dehyde (8) and a bromomagnesium thiolate[18] could transfer
hydride[19,20] to another carbonyl moiety to give magnesium
alkoxide 10 and thioester 11,[21] which would subsequently
couple to form the ester product 12 with regeneration of the
thiolate catalyst (Scheme 2, B).
The results of our preliminary experiments to test this
hypothesis are outlined in Table 1. We were pleased to
observe the disproportionation of aldehyde 8 to ester 12
(together with trace amounts of benzyl alcohol 13) in the
presence of the bromomagnesium salts (readily prepared
in situ from the addition of phenylmagnesium bromide to the
thiol in THF)[22] of either thiophenol (15a), cyclohexane thiol
(15b), or benzyl mercaptan (15c) at 5 mol% levels (Table 1,
[*] Dr. L. Cronin, F. Manoni, Dr. C. J. O’ Connor, Dr. S. J. Connon
Centre for Synthesis and Chemical Biology, School of Chemistry
The University of Dublin, Trinity College
Dublin 2 (Ireland)
Fax: (00353)1-671-2826
E-mail: connons@tcd.ie
[**] Financial support from the European Research Council (ERC) and
Science Foundation Ireland (SFI) is gratefully acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 3045 –3048
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3045