Angewandte
Chemie
DOI: 10.1002/anie.201209291
Organocatalysis
NHC-Catalyzed Hydroacylation of Styrenes**
Michael Schedler, Duo-Sheng Wang, and Frank Glorius*
The hydroacylation of multiple bonds is a highly versatile
reaction that uses abundant starting materials such as alkenes
and aldehydes for the formation of valuable ketone struc-
tures.[1] However, the catalytic hydroacylation is an underex-
plored reaction and has only recently gained considerable
interest. Until now, rhodium complexes have been the most
common catalysts for olefin hydroacylation. A major problem
for these catalyst systems is an undesired decarbonylation
step, which often limits suitable substrates to aldehydes
bearing additional coordinating groups, such as ortho-
hydroxybenzaldehydes,[2] although certain substrate combi-
nations[3] or the use of ruthenium catalysts[4] avoid this
problem. An alternative approach is the intermediate trans-
formation of aldehydes to imines that bind more strongly to
the catalyst preventing decarbonylation.[5]
A promising alternative to metal-catalyzed hydroacyla-
tions is the use of N-heterocyclic carbenes (NHCs) as
organocatalysts.[6] NHCs are versatile catalysts for several
umpolung reactions, including the benzoin condensation and
the Stetter reaction.[7] While the classical Stetter reaction is
Herein we report the NHC-catalyzed hydroacylation of
styrenes [Eq. (3)], the first intermolecular NHC-catalyzed
hydroacylation of unstrained, rather electron-neutral alkenes.
This transformation is remarkable as the organocatalyzed
transformation of electron-neutral alkenes such as styrenes is
a long-standing challenge in organocatalysis; only some rare
examples of organocatalyzed epoxidations[11] and organo-
catalyzed brominations,[12] and a few examples relying on
radical mechanisms have been reported.[13]
À
limited to the addition of an aldehyde to a polarized C C
Recently, we designed a family of novel NHCs bearing
a 2,6-dimethoxyphenyl moiety.[14] We hypothesized that these
electron-rich NHCs would result in increased nucleophilicity
of the Breslow intermediate[15,16] and would thus be suitable
for the challenging hydroacylation of styrenes. Starting with
the slightly activated p-cyanostyrene (2a) under the condi-
tions employed for the hydroacylation of cyclopropenes,[9b] we
were pleased to obtain the linear and branched hydroacyla-
tion regioisomers l-3a and b-3a, respectively. In addition to
the four dimethoxy-NHCs 4a, 5a, 6a, and 7a, we also tested
the commonly used NHCs 4b and 5b (Table 1, entries 1–6).
As seen previously for intermolecular hydroacylations, the
triazolium-derived NHCs were superior to other NHC
scaffolds. We were especially happy to see our hypothesis of
the higher reactivity of the 2,6-dimethoxy moiety confirmed
as 4a was the best of the NHCs tested (Table 1, entry 1, 50%
yield). While a screening of bases and reaction temper-
atures[17] did not improve the yield, the solvent had a marked
influence on the reaction. Changing the solvent to THF
improved the yield to 72% (Table 1, entry 7). All attempts to
further improve the yield in this solvent proved to be futile.[17]
We realized that several different side reactions prevented
us from optimizing the reaction to full conversion. Two side
reactions were of particular importance: Firstly, the 2,6-
dimethoxy NHCs are not only highly reactive catalysts for the
desired hydroacylation, but they also catalyze redox reactions
of benzoin, an ubiquitous reaction intermediate in NHC-
catalyzed umpolung reactions of aldehydes. This side reaction
yields deoxybenzoin 8a and consumes the aldehyde irrever-
sibly (Scheme 1A).
double bond such as in nitroolefins, chalcones, and alkylidene
malonates, the hydroacylation of less activated multiple
bonds would broaden the scope of NHC organocatalysis
significantly. To date, the latter type of NHC-catalyzed
hydroacylation is limited to intramolecular reactions
[Eq. (1)][8] and to compounds with strained multiple bonds
[Eq. (2)].[9,10]
[*] M. Schedler, Dr. D.-S. Wang, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
[**] Generous financial support from the Deutsche Forschungsge-
meinschaft (SFB 858) and the Fonds der Chemischen Industrie
(M.S.) is gratefully acknowledged. The research of F.G. is supported
by the Alfried Krupp Prize for Young University Teachers of the
Alfried Krupp von Bohlen and Halbach Foundation. We thank
Nathalie E. Wurz for helpful discussions and Mirco Fleige and Karin
Gottschalk for skillful technical support. NHC=N-heterocyclic
carbene.
Secondly, the products 3a contain an acidic methylene
group in a-position to the carbonyl group. Under basic
Supporting information for this article is available on the WWW
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