Angewandte
Chemie
DOI: 10.1002/anie.201305861
Asymmetric Organocatalysis
3
À
Functionalization of Benzylic C(sp ) H Bonds of Heteroaryl
Aldehydes through N-Heterocyclic Carbene Organocatalysis**
Xingkuan Chen, Song Yang, Bao-An Song,* and Yonggui Robin Chi*
Aromatic units are common scaffolds in bioactive molecules,
natural products, and polymer materials. The catalytic
functionalization of aromatic sp2 carbon atoms and attached
branched sp3 carbon atoms is therefore an important subject
of research. Success in this area has mainly been achieved
using functional-group-directed transition-metal-catalyzed
[1]
À
C H activation. With the pioneering work on trienamine
organocatalysis[2] by the groups of Jørgensen, Melchiorre, and
Chen, the 2-methyl substituent of an a,b-unsaturated alde-
hyde (enal) with a 2-methylindole substituent in the b posi-
tion could be activated.[3] We were interested in using the
addition of an N-heterocyclic carbene (NHC) organocata-
lyst[4] to a carbonyl functional group as an initial step towards
the development of new reactions. Aldehydes are the most
extensively studied substrates in NHC catalysis.[5] With
saturated alkyl aldehydes or a,b-unsaturated aldehydes as
the substrates, the NHC-catalyzed functionalization of a, b,
and g-carbon atoms has been achieved.[6,7] However, when
aryl aldehydes are used, only the carbonyl carbon could thus
far be functionalized (through an acyl-anion intermediate or
an NHC-bound ester intermediate). The catalytic activation
of the aromatic carbon atoms and the branched carbon atoms
of aryl aldehydes remains challenging (Scheme 1a).
Scheme 1. Catalytic activation and cyclization of 2-methyl indole
aldehyde.
Although the long-term goal of this unusual activation of
simple aryl aldehydes still remains elusive at this moment,
herein we report our initial success with heteroaryl aldehydes
that contain an indole, benzofuran, or benzothiophene moiety
(Scheme 1b). NHC-catalyzed oxidative activation of 2-meth-
ylindole-3-carboxaldehyde (I) generates catalyst-bound het-
erocyclic ortho-quinodimethane (III) as a key intermediate.[8]
This intermediate then undergoes formal [4+2] cycloaddition
with a trifluoromethyl ketone or an isatin to form a polycyclic
lactone, which contains a quaternary or spirocyclic carbon
center. Notably, compounds containing indole, trifluoro-
methyl, and/or isatin moieties, such as Efavirenz (anti-
HIV),[9] CJ-17493 (neurokinin 1 receptor antagonist)[10] and
NITD609 (anti-malarial)[11] are used as pharmaceutical, agro-
chemical, or other bioactive agents.
[*] X. Chen, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Experimentally, we started with the reaction between an
aryl aldehyde (1a or 1b) and trifluoroacetophenone (2a) to
form the proposed lactone product 3a (Table 1). Triazolium
salt A was employed as the NHC precatalyst, and quinone 4
(developed by Studer et al. as an oxidant for NHC cataly-
sis)[12d] was chosen as the oxidant, to transform the acyl anion
intermediate into an NHC-bound ester-equivalent, acyl
azolium ion II. Similar oxidation methods for forming acyl
azolium ions from aldehydes have been studied by several
groups, and by our laboratory.[12] With simple 2-methylben-
zaldehyde (1a) as the substrate, the desired lactone product
was not observed under various conditions. Instead,
2-methylbenzaldehyde was partially oxidized to the corre-
sponding carboxylic acid. Indole moieties, however, exhibit
unique reactivity when compared to phenyl groups; thus we
moved to examine 2-methylindole-3-carboxaldehyde (1b) as
a model substrate, and succeeded in isolating 3b in 67% yield
E-mail: robinchi@ntu.edu.sg
Prof. Dr. S. Yang, Prof. Dr. B.-A. Song
State Key Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering
Key Laboratory of Green Pesticide and Agricultural Bioengineering
Ministry of Education, Guizhou University
Huaxi District, Guiyang 550025 (China)
E-mail: basong@gzu.edu.cn
[**] We thank the Singapore National Research Foundation (NRF),
Singapore Economic Development Board (EDB), GlaxoSmithKline
(GSK) and Nanyang Technological University (NTU) for generous
financial support, and Drs. Y. Li and R. Ganguly (NTU) for
assistance with X-ray crystallography. S.Y. and B.-A.S. acknowledge
financial support from the National Key program for Basic Research
(2010CB 126105) and the National Natural Science Foundation of
China (21132003).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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