.
Angewandte
Communications
DOI: 10.1002/anie.201302152
Organocatalysis
Direct b-Activation of Saturated Aldehydes to Michael Acceptors
through Oxidative NHC Catalysis**
Junming Mo, Liang Shen, and Yonggui Robin Chi*
Saturated carbonyl compounds, such as aldehydes and esters,
are basic building blocks for the synthesis of organic
molecules and materials. Reactions with carbonyl compounds
as substrates primarily occur at the carbonyl carbon atom (as
an electrophilic center) or the a-carbon atom (as a prenucleo-
phile). In organocatalysis, several powerful approaches have
been developed for the asymmetric functionalization of a-CH
of aldehydes and esters. For example, many elegant trans-
formations at the a-carbon atom of aldehydes have been
realized by employing enamine[1] or SOMO[2] catalysis. Very
recently, Rovis and co-workers[3] and our laboratory[4] inde-
pendently reported a-carbon functionalization of saturated
aldehydes through oxidative catalysis mediated by N-hetero-
cyclic carbenes (NHCs).[5] We have also realized NHC-
mediated a-functionalization of saturated esters.[6] To func-
tionalize the b-carbon atoms of carbonyl compounds, the
corresponding a,b-unsaturated compounds are typically used.
For example, several groups have developed NHC cataly-
sis[7–9] for the activation of a,b-unsaturated aldehydes (enals
and a-bromoenals)[7,8] and ynals,[9] to form unsaturated
esters[7,9a] or Michael acceptors.[8,9b–e] In particular, Studer
pioneered the addition of 1,3-dicarbonyl compounds to a,b-
unsaturated acyl triazoliums generated from a,b-unsaturated
aldehydes.[8a] Lupton and co-workers have recently pioneered
the NHC-mediated activation of a,b-unsaturated enol ester
and acyl fluorides for eventual functionalizations of the b-sp2
carbon atoms.[10] The enal b-sp2 carbon atom can also be
activated through iminium organocatalysis, as pioneered by
MacMillan and co-workers.[11]
metal catalysis.[12] In organocatalysis, the groups of Wang,
Hayashi, and Enders have successfully oxidized the catalyti-
cally generated enamine intermediates to the corresponding
a,b-unsaturated iminium species as Michael acceptors.[13]
Despite the impressive progress, catalytic direct b-activation
of saturated carbonyl compounds has largely remained
underdeveloped, and new strategies that contribute to this
subject should be of broad interests.[14]
Here, we disclose the first direct activation of the b-C(sp3)
of saturated aldehydes through oxidative NHC catalysis
(Scheme 1). The oxidation of Breslow intermediates to
NHC-bound ester intermediates (I!II, Scheme 1) had been
Scheme 1. Direct b-functionalization of saturated aldehydes: a working
hypothesis.
studied in early 1980s and was recently further advanced by
several groups.[15] The deprotonation of a-CH of the NHC-
bound ester intermediate can form an enolate equivalent
(II!III). This transformation (II!III) was reported in our
earlier work on ester activation[6] and in the recent studies by
Rovis and co-workers[3] and our group[4] on oxidative NHC-
catalyzed a-functionalization of aldehydes. In the present
study, we realized one additional oxidative process, which
transformed the ester enolate intermediate (III) to an NHC-
bound a,b-unsaturated ester intermediate (IV). This inter-
mediate (IV) can behave as an effective Michael acceptor for
enantioselective reactions with 1,3-dicarbonyl compounds.[7-
Several catalytic approaches are available for the direct
activation of a-carbon atoms of carbonyl compounds (and b-
sp2 carbon atoms of unsaturated carbonyl compounds), but
the direct activation of the typically inert b-C(sp3) of
ꢀ
saturated carbonyl compounds is challenging. Notably, C H
activation involving the b-carbon atom of saturated esters and
amides is pursued by several groups employing transition-
[*] J. Mo, L. Shen, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
g,8a,b,d]
The overall reaction involves two oxidative processes
and constitutes a direct functionalization of the b-C(sp3) of
saturated aldehydes.
Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
Experimentally, we treated 3-phenylpropionaldehyde
(1a, 1.0 equiv) with acetyl acetone (2a, 1.0 equiv) in the
presence of 10 mol% triazolium NHC A as precatalyst, and
50 mol% Cs2CO3 as base (Table 1, entry 1). When we used
quinone B (an oxidant pioneered by Studer[7d] for NHC
catalysis), we observed the formation of product 3a, resulting
from the activation of b-CH of the aldehyde functionality,
[**] We thank the Singapore National Research Foundation (NRF), the
Singapore Economic Development Board (EDB), and GlaxoSmith-
Kline (GSK) for generous financial support, and Dr. Y. Li and Dr. R.
Ganguly at the Nanyang Technological University (NTU) for X-ray
structures. NHC=N-heterocyclic carbene.
Supporting information for this article is available on the WWW
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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