An efficient multicomponent synthesis of highly functionalized cyclopentenes

Article abstract of DOI:10.1055/s-0030-1258994

An efficient, one-pot and multicomponent synthesis of dialkyl 5,5-dicyano-3-aryl-2-cyclopentene-1,2-dicarboxylates is described. A mixture of a phenacyl bromide, malononitrile, and a dialkyl acetylenedicarboxylate in the presence of triphenylphosphine and triethylamine undergo a smooth addition reaction in absolute ethanol at ambient temperature to afford the highly functionalized cyclopentenes in good to excellent yields.

Full text of DOI:10.1055/s-0030-1258994

LETTER
2775
An Efficient Multicomponent Synthesis of Highly Functionalized
Cyclopentenes
Multicomponent Synth
e
esis of
H
ig
h
hly Function
d
a
lized Cyclo
i
pentenes Adib,*a Ehsan Sheikhi,a Pouyan Haghshenas,a Hamid Reza Bijanzadehb
a
School of Chemistry, University College of Science, University of Tehran, PO Box 14155–6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modarres University, PO Box 14115–175, Tehran, Iran
Received 14 June 2010
ring-closing metathesis reaction,12 and intramolecular
Wittig reaction.13
Abstract: An efficient, one-pot and multicomponent synthesis of
dialkyl 5,5-dicyano-3-aryl-2-cyclopentene-1,2-dicarboxylates is
described. A mixture of a phenacyl bromide, malononitrile, and a
dialkyl acetylenedicarboxylate in the presence of triphenylphos-
phine and triethylamine undergo a smooth addition reaction in ab-
solute ethanol at ambient temperature to afford the highly
functionalized cyclopentenes in good to excellent yields.
In 2002, synthesis of a spirocyclopentene derivative was
reported in which reaction between a dimedone derivative
and dimethyl acetylenedicarboxylate in the presence of
triphenylphosphine resulted to dimethyl 8,8-dimethyl-
6,10-dioxo-3-phyenylspiro[4.5]deca-2-ene-1,2-dicarbox-
ylate in fairly good yield.14
Key words: phenacyl bromides, alkynes, cyclopentenes, multi-
component reactions, cyclizations, intramolecular Wittig reactions
The intramolecular Wittig reaction, in which a C=C bond
is formed by condensation of a carbonyl function with an
alkylidenephosphorane group incorporated in the same
molecule, has been applied to the preparation of common
five-, six-, and also seven-membered carbo- and heterocy-
cles and has been used as a key step in several routes to
the synthesis of natural products.13,15
Recently multicomponent reactions (MCRs) in which
three or more reactants are combined in a one-pot proce-
dure have emerged as an efficient and powerful tool in
modern synthetic organic chemistry due to their valued
features such as atom economy, straightforward reaction
design, and the opportunity to construct target compounds
by the introduction of several diversity elements in a sin-
gle chemical event. Typically, purification of products re-
sulting from MCRs is also simple since all the organic
reagents employed are consumed and are incorporated
into the target compound.1 Thus, they are perfectly ame-
nable to automation for combinatorial synthesis.2 The im-
mense possibilities of synthetic variations make it likely
to find starting materials and conditions suitable for the
discovery of new MCRs.3
As part of our current studies on the development of effi-
cient methods for the preparation of important carbo- and
heterocyclic compounds,16 herein we describe a one-pot
multicomponent synthesis of highly functionalized cyclo-
pentenes. Thus a mixture of a phenacyl bromide (1),
malononitrile (2), triphenylphosphine, and a dialkyl acet-
ylenedicarboxylate 3 in the presence of Et3N undergo a
new MCR at ambient temperature in absolute ethanol to
afford dialkyl 5,5-dicyano-3-aryl-2-cyclopentene-1,2-di-
carboxylates 4a–k in 85–96% yields (Scheme 1, Table 1).
All the reactions went to completion within a few hours.
1H NMR spectroscopic analysis of the reaction mixtures
clearly indicated formation of the corresponding 5,5-dicy-
ano-3-aryl-2-cyclopentene-1,2-dicarboxylate 4 in good to
excellent yields.17
Five-membered carbocycles have received considerable
attention because of their chemical and biological impor-
tance.4 Among this family of compounds, cyclopentenes
are particularly important intermediates in organic syn-
thesis. Cyclopentenes are common substructures in a wide
array of natural products and biologically active com-
pounds.4–6
CO2R
CN
O
Ar
CN
+ Ph3P
Et3N
CN
HBr
Ph PO
+
3
+
+
+
There have been many reports in the literature for the
preparation of cyclopentene derivatives in the past few
years. The most common synthetic approaches to cyclo-
pentene derivatives involve: (i) classical intramolecular
Michael-type conjugate addition to activated alkenes,
alkynes,7 and allenyl sulfones,8 (ii) Ramberg–Bäcklund
rearrangement of thiosugar-derived sulfones,9 (iii) rear-
rangement of vinylcyclopropanes,10 (iv) intramolecular
Morita–Baylis–Hillman reaction,11 (v) intramolecular
Ar
EtOH, r.t.
CN
RO2C
CO2R
Br
CO2R
1
2
3
4
Scheme 1
The structures of the isolated products 4 were deduced on
the basis of IR, 1H and 13C NMR spectroscopy, mass spec-
trometry, and elemental analysis. The IR spectrum of 4a
showed absorptions at 2251, 1752 and 1724 cm–1 indicat-
ing the presence of nitrile and ester functionalities. The
mass spectrum of 4a displayed the molecular ion [M+]
peak at m/z = 310, which was consistent with the 1:1:1 ad-
SYNLETT 2010, No. 18, pp 2775–2777
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258994; Art ID: D15010ST
© Georg Thieme Verlag Stuttgart · New York

2776
M. Adib et al.
LETTER
d = 113.21, 115.27 (for the two CN groups), 162.85 and
167.64 ppm(due to the two carbonyl groups) along with
other three CH and three quaternary carbons in the down-
field region of the spectrum in agreement with the pro-
posed structure.17
Table 1 Synthesis of Substituted Cyclopentenes 4a–k
4
Ar
R
Yield (%)a
4a
Ph
Me
Me
Me
Me
Me
Et
95
92
88
90
96
85
93
86
90
93
89
4b
4-MeOC6H4
4-ClC6H4
4-PhC6H4
4-MeC6H4
Ph
A mechanistic rationalization for this reaction is provided
in Scheme 2. Initially, treatment of phenacyl bromide
with malononitrile in the presence of Et3N produces 2-(2-
aryl-2-oxoethyl)malononitrile 5. Next, the reactive 1:1
zwitterionic intermediate 6, formed from the initial addi-
tion of triphenylphosphine to the electron-deficient acety-
lenic compound 3 , s protonated by the in situ prepared
CH-acid 5. Then, the positively charged vinyl phosphoni-
um ion 8 may be attacked by the conjugate base of the acid
7 to form phosphorane 9. This adduct may undergo in-
tramolecular Wittig reaction of the ylide moiety with the
adjacent ketone carbonyl to afford the isolated 5,5-dicy-
ano-3-aryl-2-cyclopentene-1,2-dicarboxylate 4 by remov-
al of triphenylphosphine oxide.
4c
4d
4e
4f
4g
4-MeOC6H4
4-ClC6H4
4-MeC6H4
Ph
Et
4h
Et
4i
Et
4j
tBu
tBu
4k
4-ClC6H4
In conclusion, we have succeeded in synthesizing dialkyl
5,5-dicyano-3-aryl-2-cyclopentene-1,2-dicarboxylates of
potential synthetic interest via a one-pot and multicompo-
nent reaction between phenacyl bromides, malononitrile,
and dialkyl acetylendicarboxylates in the presence of
triphenylphosphine. Use of simple and readily available
starting materials, mild reaction conditions, relatively
short reaction times, and high yields of the products are
the main advantages of this reaction. The simplicity of the
present procedure makes it an interesting alternative to
other approaches. In view of extensive use of cyclo-
pentenes as synthetic intermediates and target com-
pounds, the dialkyl 5,5-dicyano-3-aryl-2-cyclopentene-
1,2-dicarboxylates prepared in the present study may find
useful applications in synthetic organic chemistry.
a Isolated yield.
duct of 2-bromo-1-phenylethanone, malononitrile, and
dimethyl acetylenedicarboxylate losing a hydrogen bro-
mide molecule and an oxygen atom. The H NMR spec-
1
trum of 4a showed two single sharp lines readily
recognized as arising from the two methoxy (d = 3.68 and
3.90 ppm) groups. One of the two diastereotopic H atoms
of the cyclopentene methylene group was observed as a
doublet (dA = 3.61 ppm, 2J = 17.3 Hz) and the other one as
a doublet of doublet (d = 3.85 ppm, 2J = 17.3, 4J = 1.6 Hz)
as a result of a further long range coupling with the ring
methine proton. The ring methine proton was seen as a
fairly broad singlet (d = 4.61 ppm). The 1H decoupled 13C
NMR spectrum of 4a showed characteristic signals at
d = 34.50 [due to the C(CN)2], 49.50 (arising from the
CH2), 52.16, 53.59 (for the two OCH3), and 60.92 ppm
(due to the CHCO2CH3) in the aliphatic region of the
spectrum. Four characteristic resonances were evident at
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
O
CN
O
1
CN
Et3N
+
– HBr
Ar
Ar
CN
CN
O
CN
_
H
CO2R
Br
2
5
+
Ar
CN
RO2C
PPh3
CO2R
RO2C
_
7
8
Ph3P
+
+
Ph3P
CO2R
CO2R
6
3
Ar
CN
CN
CN
CN
Ar
Ph3PO
+
O
CO2R
CO2R
RO2C
CO2R
Ph3P
4
9
Scheme 2
Synlett 2010, No. 18, 2775–2777 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of Highly Functionalized Cyclopentenes
2777
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(17) General Procedure for the Preparation of Compounds
4a–k
A solution of the appropriate phenacyl bromide (1 mmol),
malononitrile (1 mmol), and Et3N (1 mmol) in EtOH (3 mL)
was stirred at ambient temperature for 1 h. After addition of
Ph3P (1 mmol), a solution of the appropriate dialkyl
acetylenedicarboxylate (1 mmol) in EtOH (2 mL) was
dropwise added to the reaction mixture over 25 min, which
then was stirred at ambient temperature for 5 h. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography (Merck silica gel 230–
240 mesh) using n-hexane–EtOAc (3:1) as eluent. The
solvent was removed and the product was obtained.
Dimethyl 5,5-Dicyano-3-phenyl-2-cyclopentene-1,2-
dicarboxylate (4a)
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Colorless crystals; mp 130–131 °C. IR (KBr): 2251 (CN),
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[M+]. Anal. Calcd (%) for C17H14N2O4 (310.31): C, 65.80; H,
4.55; N, 9.03. Found: C, 65.7; H, 4.6; N, 8.9. 1H NMR (500.1
MHz, CDCl3): d = 3.61 (d, 2J = 17.3 Hz, 1 H, CH), 3.68 (s,
3 H, OCH3), 3.85 (dd, 2J = 17.3 Hz, 4J = 1.6 Hz, 1 H, CH),
3.90 (s, 3 H, OCH3), 4.61 (br s, 1 H, CHCO2CH3), 7.37–7.45
(m, 5 H, 5 × CH). 13C NMR (125.8 MHz, CDCl3): d = 34.50
[C(CN)2], 49.50 (CH2), 52.16 and 53.59 (2 × OCH3), 60.92
(CHCO2CH3), 113.21 and 115.27 (2 × CN), 124.41 (C),
128.09, 128.38 and 130.17 (3 × CH), 132.39 and 151.84 (2
× C), 162.85 and 167.64 (2 × C=O).
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Diethyl 3-(4-Chlorophenyl)-5,5-dicyano-2-cyclopentene-
1,2-dicarboxylate (4h)
Colorless crystals; mp 97–99 °C. IR (KBr): 2255 (CN), 1735
and 1715 (shoulder; C=O) cm–1. MS (EI): m/z (%) = 374 (30)
[M+ 37Cl], 372 (100) [M+ 35Cl]. Anal. Calcd (%) for
C19H17ClN2O4 (372.81): C, 61.21; H, 4.60; N, 7.51. Found:
C, 61.2; H, 4.6; N, 7.4. 1H NMR (500.1 MHz, CDCl3):
d = 1.17 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.37 (t, J = 7.1 Hz, 3
H, CH2CH3), 3.57 (d, 2J = 17.3 Hz, 1 H, CH), 3.80 (dd,
2J = 17.3 Hz, 4J = 1.5 Hz, 1 H, CH), 4.12 and 4.17 [2 × dq,
ABX3 system, 2J = 11.0 Hz, 3J = 7.1 Hz, 2 H, OCHAHBCH3],
4.31 and 4.36 [2 × dq, ABX3 system, 2J = 10.7 Hz, 3J = 7.2
Hz, 2 H, OCHAHBCH3], 4.56 (s, 1 H, CHCO2C2H5), 7.35 (d,
J = 8.7 Hz, 2 H, 2 × CH), 7.38 (d, J = 8.7 Hz, 2 H, 2 × CH).
13C NMR (125.8 MHz, CDCl3): d = 13.83 and 14.07 (2 ×
OCH2CH3), 34.44 [C(CN)2], 49.32 (CH2), 60.74
(CHCO2C2H5), 61.50 and 63.5 (2 × OCH2CH3), 113.06 and
115.27 (2 × CN), 125.61 (C), 128.59 and 129.61 (2 × CH),
130.85, 136.16 and 150.14 (3 × C), 162.15 and 167.11 (2 ×
C=O).
Synlett 2010, No. 18, 2775–2777 © Thieme Stuttgart · New York

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