DOI: 10.1002/chem.201303435
Extending the Stetter Reaction with 1,6-Acceptors
Katherine R. Law and Christopher S. P. McErlean*[a]
The advent of readily accessible N-heterocyclic carbenes
mediate 2 onto an a,b-unsaturated carbonyl to give a 1,4-di-
carbonyl containing product.[7a,8] In the 40 years since that
seminal publication, the Stetter reaction has been signifi-
cantly improved upon by the use of more reactive azolium
(pre)catalysts, enabling both intra- and intermolecular var-
iants, and the rendering of the reaction both enantio- and di-
astereoselective.[6b,c,9] The heightened synthetic potential of
the 1,4-dicarbonyl (or equivalent) products significantly in-
creases the value of the transformation over and above that
of the parent benzoin condensation.
(NHCs) has fuelled a reinvigoration of acyl anion chemistry.
The archetypical acyl anion reaction, the benzoin condensa-
tion, was reported as early as 1824 (Scheme 1).[1] Pioneering
We reasoned that the utility of the process could be fur-
ther enhanced by conducting a “vinylogous Stetter reac-
tion”. That is, effecting the inversion of conventional alde-
hyde reactivity using an NHC and treating the generated in-
termediate 2 with an a,b,g,d-unsaturated carbonyl com-
pound (Scheme 1). The product of this transformation
would contain a minimum of three sites for further synthetic
manipulation. Investigations of 1,6-additions have under-
gone a recent renaissance.[10] However, given the decreased
electrophilicity associated with such polyunsaturated sys-
tems and the possibility of a competing hetero-Diels–Alder
process,[11] the success of the vinylogous Stetter reaction was
far from certain. To favour 1,6-addition over 1,4-addition,
we elected to concentrate our initial efforts on the intramo-
lecular variant. The outcomes of those investigations are re-
ported below.
Scheme 1. The proposed vinylogous Stetter reaction.
studies by Liebig and Wçhler in 1832 and then Fischer in
1882,[2] firmly entrenched this reaction in the toolkit of syn-
thetic chemists. Although those early examples required cat-
alytic cyanide, Ukai discovered that this highly toxic species
could be replaced with less hazardous thiazolium-derived
NHCs.[3] The mechanism of the condensation, originally pro-
posed by Lapworth[4] and later adapted by Breslow,[5] is
commonly held to involve nucleophilic addition of an NHC
onto benzaldehyde (1; Scheme 1), followed by proton trans-
fer to give the reactive intermediate 2 in which the carbon
atom of the aldehyde has undergone a formal polarity rever-
sal (umpolung) and become nucleophilic. Treatment of 2
with a second equivalent of aldehyde yields the benzoin
product. Despite recent advances including the invention of
mixed cross-benzoin condensations and enantioselective var-
iants,[6] the benzoin reaction is restricted by the relatively
narrow synthetic utility of the a-hydroxyketone products.
In 1973, Stetter and Schreckenberg reported the first “vi-
nylogous benzoin condensation” (Scheme 1).[7] That epony-
mous reaction involves the conjugate addition of the inter-
Alkylation of salicylaldehyde (3) with methyl bromosor-
bate gave 4, a suitable substrate to test the feasibility of the
vinylogous Stetter reaction (Scheme 2). Our first task was to
Scheme 2. Synthesis of compound 4; [a] see Table S1 in the Supporting
Information.
uncover reaction conditions under which the proposed 1,6-
additions would take place. To that end, the catalytic effec-
tiveness of NHCs generated from various, representative
azolium salts was examined (Figure 1). The NHC generated
from the commercially available and inexpensive thiazolium
salt 6 furnished the desired product 5 in low yield under
a range of reaction conditions (Table 1 in the Supporting In-
[a] K. R. Law, Dr. C. S. P. McErlean
School of Chemistry, The University of Sydney
Sydney NSW 2006 (Australia)
Supporting information for this article is available on the WWW
15852
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Chem. Eur. J. 2013, 19, 15852 – 15855