Communications
DOI: 10.1002/anie.201007144
Organocatalysis
A Highly Regio- and Stereoselective Cascade Annulation of Enals and
Benzodi(enone)s Catalyzed by N-Heterocyclic Carbenes**
Xinqiang Fang, Kun Jiang, Chong Xing, Lin Hao, and Yonggui Robin Chi*
À
À
The rapid catalytic construction of relatively complex mole-
cules in a highly selective manner is an attractive goal in
organic synthesis.[1] In the area of N-heterocyclic carbene
(NHC) catalysis, the unconventional NHC-mediated activa-
tion of enal compounds has led to a diverse set of new
reactions,[2] such as lactone and lactam formations,[3] cyclo-
addition reactions,[4] Michael reactions,[5] and self-redox ester
formations.[6,7] This diversity exists in the catalytic formation
of multifarious intermediates that include activated carbox-
ylates, enolates, and homoenolate equivalents.[8] Of particular
interest to us is the generation of three consecutive reactive
carbon centers [Eq. (1)], which opens an opportunity for the
C C and C O bond formations to generate the cascade
products containing four stereogenic centers. Mechanistically,
the reaction proceeds exclusively through Michael-type
additions of the b- and a-carbon atoms of the enals to the
two enone branches of the di(enone)s, and subsequent
intramolecular enol ester formation to yield the products.
Cyclopropene- or indane-based adducts, as might be postu-
lated based on previous studies,[9–11,12] were not observed as
products in our reactions.
We first studied the reaction between cinnamaldehyde
(1a) and benzodi(enone) 2a using imidazolium precatalysts
(Table 1, entries 1–3). We initially expected a product that
would result from a decarboxylation[9–11] as the last step.
Surprisingly, no such cyclopentene-containing products were
detected. Instead, benzotricyclic acylated enol 3a was formed
Table 1: Annulation of enal 1a and di(enone) 2a mediated by NHCs.[a]
rapid assembly of relatively complex molecules containing
rings and multiple chiral centers. Recently, the research
groups of Nair,[9] Bode,[10] and Scheidt[11] reported enal/enone
condensations to form cyclopentene derivatives using NHC
or NHC/Lewis acid cooperative catalysts. Sanchez-Larios and
Gravel reported a diastereoselective racemic indane synthesis
via NHC-mediated activation of aldehydes for Stetter–
Michael cascade reactions with benzodi(enone)s.[12a] Herein,
we disclose a new annulation of enals and di(enone)s that
generates benzotricyclic products with exceptionally high
regio-, diastereo-, and enantioselectivities [Eq. (1)]. All of the
three reactive carbon centers of the enals are involved in new
Entry
NHC
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
A
B
C
D
E
F
76
40
0
95
0
12:1
20:1
–
20:1
–
–
–
–
–
–
[*] Dr. X. Fang, K. Jiang, C. Xing, L. Hao, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
5
6
51
84
10:1
13:1
99
99
7[e]
F
E-mail: robinchi@ntu.edu.sg
[a] Reaction conditions: 1a (0.225 mmol), 2a (0.15 mmol). [b] Yield of
isolated product. [c] Determined by 1H NMR analysis of unpurified
reaction mixtures. [d] Major diastereoisomer, determined by HPLC
analysis on a chiral stationary phase. The configuration of 3a was
determined by X-ray crystallography of its derivative 3a’ (see [Eq. (2)] and
the Supporting Information). [e] Two equivalents of 1a was used and one
equivalent of MgSO4 was added. DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene, Mes=2,4,6-trimethylphenyl, THF=tetrahydrofuran.
[**] We are grateful for financial support from the Singapore National
Research Foundation (NRF-RF2009-03) and Nanyang Technological
University (start-up funds). We thank Prof. P. H. Leung and his
research group (polarimeter measurements) and Dr. Y. Li (X-ray
structural analysis).
Supporting information for this article is available on the WWW
1910
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1910 –1913