N-heterocyclic carbene-catalyzed reaction of chalcones and enals via homoenolate: An efficient synthesis of 1,3,4-trisubstituted cyclopentenes

Article abstract of DOI:10.1021/ja0625677

Nucleophilic heterocyclic carbene-catalyzed cyclopentannulation of enals and chalcones via homoenolate has been observed for the first time. Serendipitously, the reaction lead to a very efficient synthesis of 3,4-trans-disubstituted-1-aryl cyclopentenes i

Full text of DOI:10.1021/ja0625677

Published on Web 06/20/2006
N-Heterocyclic Carbene-Catalyzed Reaction of Chalcones and Enals via
Homoenolate: an Efficient Synthesis of 1,3,4-Trisubstituted Cyclopentenes
Vijay Nair,*,† Sreekumar Vellalath,† Manojkumar Poonoth,† and Eringathodi Suresh‡
Organic Chemistry Section, Regional Research Laboratory (CSIR), TriVandrum 695 019, India, and Central Salt
and Marine Chemicals Research Institute (CSIR), BhaVnagar 364 002, India
Received April 13, 2006; E-mail: vijaynair_2001@yahoo.com
Scheme 1. Reaction of 4-Methoxycinnamaldehyde with Chalcone
The concept of homoenolate anions was introduced by Nickon
and Lambert1 in their seminal paper in 1962. Their application in
organic synthesis during the last four decades, however, was limited,
presumably due to the difficulty in generating homoenolates
directly. Helquist et al. were the first to circumvent this problem
by using â-propionaldehyde anion equivalent as a homoenolate
equivalent.2 Subsequent efforts to generate homoenolate equivalents3
include the use of â-propionate anion equivalent,4 cyclopropanone
silyl hemiketal,5 and R-heteroatom-substituted allyl anion by a
number of investigators.3,6 The elegant work on the generation and
synthetic uses of chiral homoenolate equivalents, such as 1-hetero-
substituted 2-alkenyl-metal derivatives for stereocontrolled homoal-
dol reactions by Hoppe et al.7 and Beak and Whisler8 is especially
noteworthy in this context. Very recently, a conceptually new
approach to the generation of homoenolate9 was introduced
independently by Bode et al.9a and Glorius and Burstein.9b This
work involves the nucleophilic heterocyclic carbene (NHC)-
catalyzed10-12 annulation of enals with aldehydes, leading to the
efficient synthesis of γ-butyrolactones; imines afford the corre-
sponding γ-lactams.9d In the course of our work on the reactions
of NHCs,13 we have found that 1,2-diones undergo efficient
annulation with enals to afford spiro γ-butyrolactones.14 Subse-
quently, we were intrigued by the possibility that the homoenolate
annulation, if successful with an activated carbon-carbon double
bond such as that of a chalcone, would constitute a cyclopentanone
synthesis (eq 1). The results of our work serendipitously leading
to a very efficient synthesis of 3,4-trans-disubstituted-1-aryl cy-
clopentenes15 instead of the expected cyclopentanones are presented
in this communication.
Table 1. Scope of NHC-Catalyzed Cyclopentannulation
entry
R1
R2
R3
product
yield (%)
1
2
3
4
5
6
7
8
9
2-MPb
phenyl
4-MPb
4-MPb
4-MPb
phenyl
4-MPb
4-MPb
4-MPb
4-MPb
4-MPb
2-thienyl
1-naphthyl
2-thienyl
4-cyanophenyl
phenyl
phenyl
4-fluorophenyl
4-chlorophenyl 4-chlorophenyl
2-thienyl
2-furyl
methyl
4-chlorophenyl
4-chlorophenyl
4-methylphenyl
4-chlorophenyl
phenyl
4b
4c
4d
4e
4f
4g
4h
4i
88
76
85
76
88
78
78
76
86
70
55
73
phenyl
4-chlorophenyl
phenyl
4j
4k
4l
10
11
12
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
methyl 2-thienyl
4m
a Isolated yield. b MP ) methoxy phenyl.
Scheme 2. Reaction of 4-Methoxycinnamaldehyde with
Thienylidene Tetralone
determination. It is noteworthy that only one diastereomer was
formed in this reaction.
The generality of this promising cyclopentannulation was
investigated using a number of chalcones and a variety of enals;
the results are summarized in Table 1.
In the first instance, the reaction of 4-methoxy cinnamaldehyde
1 with chalcone 2 in the presence of catalytic amount of 1,3-
dimesityl imidazol-2-ylidene (IMes) 3 formed in situ by the
deprotonation of IMes chloride (6 mol %) using DBU (12 mol %)
afforded a product in 90% yield, and this was characterized as the
1,3,4-trisubstituted cyclopentene 4a (Scheme 1).
The structure of the product was established by spectroscopic
analysis, and final confirmation of the structure and stereochemistry
of the compound 4a was obtained from single-crystal X-ray
Interestingly, the reaction is not limited to â-(hetero)aryl-
substituted enones; it occurs efficiently with â-alkyl-substituted
enones also (entry 11). Even more interesting is the reaction
involving thienylidene tetralone 5 and 4-methoxycinnamaldehyde,
leading to tricyclic cyclopentene 6 in moderate yield (Scheme 2).
1
Relative stereochemistry of the product was obtained by H NOE
† Organic Chemistry Section, Regional Research Laboratory (CSIR).
‡ Central Salt and Marine Chemicals Research Institute (CSIR).
difference spectroscopic studies.16
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J. AM. CHEM. SOC. 2006, 128, 8736-8737
10.1021/ja0625677 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Postulated Catalytic Cycle Involving NHC
Acknowledgment. This paper is dedicated with best regards
to Professor Gilbert Stork. The authors thank the Council of
Scientific and Industrial Research (CSIR) and Department of
Science and Technology (DST), New Delhi, for financial assistance.
We thank Dr. Luxmi Varma and Mr. Thirumalai Kumaran for
assistance with NMR spectroscopy.
Supporting Information Available: General experimental proce-
dure, spectroscopic characterization of all new compounds, and single-
crystal X-ray data of compound 4a. This material is available free of
charge via the Internet at http://www.pubs.acs.org.
References
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A mechanistic rationale for the reaction may be advanced along
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IIa, which participates in intramolecular aldol reaction to deliver
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ring, thus rendering it relatively planar. The trans disposition of R1
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efficient formation of 1,3,4-trisubstituted cyclopentenes. The simple
and mild reaction conditions and the high yields of products are
likely to make the reaction attractive for its application in the
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