NHC-catalyzed annulation of enals to 2,4-dien-1-ones: Efficient diastereoselective synthesis of 1,3-diaryl-4-styrenyl cyclopentenes

Article abstract of DOI:10.1055/s-0033-1339308

Nucleophilic heterocyclic carbene (NHC)-catalyzed annulation strategy has been utilized for the efficient synthesis of styrenyl-substituted cyclopentenes from 2,4-dienones. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339308

LETTER
▌1671
lNettHer C-Catalyzed Annulation of Enals to 2,4-Dien-1-ones: Efficient Diastereo-
selective Synthesis of 1,3-Diaryl-4-styrenyl Cyclopentenes
NHC-Catalyzed Annulation of Enals to 2,4-Dien-1-ones
C. R. Sinu, D. V. M. Padmaja, P. Jini, K. C. Seetha Lakshmi, V. Nair*
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695019, India
Fax +91(471)2491712; E-mail: Vijaynair_2001@yahoo.com
Received: 10.05.2013; Accepted after revision: 01.06.2013
groups, including our own, has uncovered the application
Abstract: Nucleophilic heterocyclic carbene (NHC)-catalyzed
of homoenolates in the synthesis of a variety of com-
annulation strategy has been utilized for the efficient synthesis of
pounds such as γ-spirolactones,7 lactams,8 cyclopen-
styrenyl-substituted cyclopentenes from 2,4-dienones.
tenes,9 pyrazolidinones10 and cyclopentanols.11 Efficient
Key words: NHC, catalysis, homoenolate, annulation, cyclopen-
tene
homoenolate
additions
to
nitrostyrenes,12
sulfonimines8a,13 and assorted electrophiles14 have also
been reported. Other homoenolate reactions of note in-
clude co-operative Lewis acid/N-heterocyclic carbene
catalysis15 and intramolecular reactions.16
In the context of organocatalysis,1 defined as catalysis of
organic reactions by small organic molecules, nucleophil-
ic heterocyclic carbenes (NHCs) have emerged as power-
ful tools with uniquely inherent ability to impose polarity
reversal (umpolung) on aldehydes. Historically, definitive
experiments by Breslow2 in 1958 revealing the catalysis
of benzoin condensation by the ylide (currently called
NHC) liberated from a thiazolium salt laid the foundation
of NHC catalysis. However, just as it happens with many
original discoveries, the Breslow protocol remained dor-
mant for more than four decades except for its application
in Stetter reaction.3 With the renaissance of organocataly-
sis, the situation changed dramatically, and in recent years
a number of synthetic procedures availing NHC catalysis
have been reported.4 The signal change in this area may be
attributed to the NHC-catalyzed formation of homoeno-
late and the addition of the latter to aldehydes culminating
in the synthesis of γ-lactones reported by Glorius and
Bode.5,6 In short order, work in this area by different
The happenstance of an NHC-catalyzed annulation of ho-
moenolate to chalcones, constituting an unprecedented
synthesis of trisubstituted cyclopentenes may be singled
out for its mechanistic intrigue and potential applications
in synthesis. In the course of our exploration of this reac-
tion, we were impressed by the versatility of homoenolate
in delivering a range of products by engaging a variety of
carbonyl compounds (Scheme 1).
In view of the results outlined in the above scheme, it was
of great interest to examine the reactivity of homoenolate
towards 2,4-dien-1-ones. Our studies commenced by ex-
posing homoenolate derived from 4-methoxycinnamalde-
hyde (1a) to 1,5-diphenylpenta-2,4-dien-1-one (2a) in
dichloromethane. The reaction afforded a product in 87%
yield, and it was characterized as the styryl-substituted
cyclopentene 3a (Scheme 2).
R
Ar
O
R
O
refs. 9a,f
O
R
R
R
O
Ar
O
O
R
OH
R
Mes
R
R
O
R
N
Ar
ref. 14f
O
ref. 9g
O
Ar
N
R
R
Mes
R
R
ref. 14g
MeOH
ref. 11
R
O
R
O
O
HO
R
R
MeO
Ar
Ar
Scheme 1 Homoenolate reaction towards enone
SYNLETT 2013, 24, 1671–1674
Advanced online publication: 17.07.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339308; Art ID: ST-2013-R0437-L
© Georg Thieme Verlag Stuttgart · New York

1672
C. R. Sinu et al.
LETTER
Mes
N
Cl
OMe
N
Mes
O
(15 mol%)
1a
MeO
DBU (20 mol%)
+
CH2Cl2, r.t., Ar, 6 h
O
3a 87%
2a
Scheme 2 Homoenolate reaction of enal and dienone
The structure of product was established by spectroscopic displayed a peak at δ = 57.8 ppm corresponding to the me-
analysis. In 1H NMR spectrum, the methoxy protons res- thoxy carbon and one at δ = 39.7 ppm due to the methine
onated as singlet at δ = 3.79 ppm, and a peak correspond- carbon. All other signals were in good agreement with the
ing to the olefinic proton was assigned the singlet at δ = assigned structure.
6.19 ppm. The presence of styryl moiety was confirmed
With a view to examine the scope of the reaction, a series
of experiments were performed by varying the enals and
the dienones. The results are summarized in Table 1.
by a doublet of doublet at δ = 6.40 (J1 = 15.8 Hz and J2 =
8.2 Hz) and a doublet at δ = 6.28 (J = 15.8 Hz). The 13C
NMR spectrum, showed a peak at δ = 158.3 ppm attribut-
able to the aromatic carbon bearing OMe group. It also
Table 1 Scope of the Reaction
Mes
N
Cl
N
Mes
(15 mol%)
Ar1
Ar1
O
1
DBU (20 mol%)
Ar3
+
Ar2
CH2Cl2, r.t., Ar, 6 h
O
3
Ar2
Ar3
2
Entry
Ar1
Ar2
Ph
Ar3
Product
Yield (%)
1
2
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
2-methoxyphenyl
2-methoxyphenyl
Ph
Ph
3a
3b
3c
3d
3e
3f
87
86
86
71
74
80
43
61
66
91
90
66
61
4-methoxyphenyl
4-methylphenyl
pyridinyl
Ph
3
4-methoxyphenyl
4
4-methoxyphenyl
5
Ph
Ph
6
4-methoxyphenyl
pyridinyl
Ph
7
Ph
3g
3h
3i
8
Ph
4-methoxyphenyl
pyridinyl
4-bromophenyl
4-bromophenyl
4-bromophenyl
furyl
9
2-methoxyphenyl
4-methoxyphenyl
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
3j
3k
3l
4-methoxyphenyl
4-methoxyphenyl
thienyl
3m
Synlett 2013, 24, 1671–1674
© Georg Thieme Verlag Stuttgart · New York

LETTER
NHC-Catalyzed Annulation of Enals to 2,4-Dien-1-ones
1673
In view of the promising results obtained, we extended the late reaction condition with 5-(4-methoxyphenyl)-1-(4-
reaction to an aliphatic enal, namely crotonaldehyde, and tolyl)penta-2,4-dien-1-one (2b). The reaction proceeded
the results are shown in Table 2.
via the same pathway of enals and afforded the product 7
(Scheme 3).
Table 2 Reaction of Crotonaldehyde with Dienones
A mechanistic rationale for the reaction, analogous to the
one established9a,17 for the original cyclopentene synthe-
sis, may be advanced (Scheme 4). The homoenolate I
formed by the reaction of IMes with enal undergoes con-
jugate addition to the dienone and the subsequent proton
transfer generates the enolate II which endures intramo-
lecular aldol reaction to deliver the cyclopentane carbino-
late III. The latter undergoes β-lactonization to eject
IMes, allowing the catalytic cycle to continue. The β-lac-
tone V thus formed is unstable and undergoes retro [2+2]-
process to yield the cyclopentene A with the loss of car-
bon dioxide.
O
IMesCl (15 mol%)
DBU (20 mol%)
4
Ar2
+
CH2Cl2, r.t., Ar, 6 h
O
Ar1
5
Ar1
Ar2
2
Entry Ar1
Ar2
Product Yield (%)
1
2
3
4
5
6
7
4-methoxyphenyl
pyridinyl
Ph
5a
5b
5c
5d
5e
5f
81
75
78
69
67
87
61
4-methoxyphenyl
In conclusion, a homoenolate annulation strategy has been
utilized for the synthesis of styryl-substituted cyclopen-
tenes.18
4-methoxyphenyl
4-methylphenyl
Ph
Ph
Ph
Ph
Ph
4-bromophenyl
furyl
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for Raja Ramanna Fellowship. The authors also thank the
Council of Scientific and Industrial Research (CSIR) and the Uni-
versity Grants Commission (UGC) New Delhi, for financial assi-
stance.
thienyl
5g
In order to probe the reactivity of dienal towards dienone,
hexa-2,4-dienal (6) was subjected to the above homoeno-
O
IMesCl (15 mol%)
DBU (20 mol%)
6
+
CH2Cl2, r.t., Ar, 6 h
O
OMe
7
45%
MeO
2b
Scheme 3 Homoenolate reaction of dienal to dienone
OH
R
O
R2
N
R1
R
N
R3
N
R2
O
R1
R1
O
R
I
O
R3
N
R
II
••
R
R
N
N
R3
R2
R3
O
R2
O
R
R1
R
N
R1
N
O
R3
R2
N
O
R2
R
R3
N
O
IV
R
III
R1
R1
O
CO2
A
V
Scheme 4 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1671–1674

1674
C. R. Sinu et al.
LETTER
Wang, S.; Vedachalam, S.; Ganguly, R.; Liu, X.-W. Angew.
Chem. Int. Ed. 2012, 51, 8276.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2013, 24, 1671–1674
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