An efficient procedure for synthesis of 2-formylcyclopent-2-enecarboxylic acid

Article abstract of DOI:10.1007/s11164-014-1719-1

Abstract A synthetic method for 2-formylcyclopent-2-enecarboxylic acid is described. This procedure comprises two steps. The first step is a [2 + 2] cycloaddition reaction, and the second step is a hydrolysis and ring-opening reaction. A plausible mechanism of the hydrolysis and ring-opening reaction was supposed. Then, the effects of different solvents, base mol ratio, concentration of base, and reaction temperature on the yield of the second step were studied. Finally, under the obtained optimized conditions, the product was achieved and isolated in 59.4 % yield, which was more than double the ones reported previously. An improved and efficient procedure for the synthesis of 2-formylcyclopent-2-enecarboxylic acid has been developed.

Full text of DOI:10.1007/s11164-014-1719-1

Res Chem Intermed
DOI 10.1007/s11164-014-1719-1
An efficient procedure for synthesis of
2-formylcyclopent-2-enecarboxylic acid
•
Chaohang Xu Wei Li Xiaodong Jin
•
•
•
Guangke He Hongjun Zhu
Received: 21 March 2014 / Accepted: 17 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A synthetic method for 2-formylcyclopent-2-enecarboxylic acid is
described. This procedure comprises two steps. The first step is a [2 ? 2] cyclo-
addition reaction, and the second step is a hydrolysis and ring-opening reaction. A
plausible mechanism of the hydrolysis and ring-opening reaction was supposed.
Then, the effects of different solvents, base mol ratio, concentration of base, and
reaction temperature on the yield of the second step were studied. Finally, under the
obtained optimized conditions, the product was achieved and isolated in 59.4 %
yield, which was more than double the ones reported previously. An improved and
efficient procedure for the synthesis of 2-formylcyclopent-2-enecarboxylic acid has
been developed.
Keywords 2-Formylcyclopent-2-enecarboxylic acid Á Improved Á Efficient Á
Hydrolysis and ring-opening reaction
Introduction
2-Formylcyclopent-2-enecarboxylic acid and its derivatives have gained much
attention in both organic synthesis and medicinal chemistry due to their wide
versatility as synthetic intermediates of medicines, such as inhibitors, cyclopente-
none antibiotics, carbanucleosides, and prostaglandins [1–8]. As a result, several
approaches for the synthesis of 2-formyl cyclopent-2-enecarboxylic acid and its
derivatives were proposed [9–17], involving the hydrolysis and ring-opening
reaction of 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one. These approaches use trieth-
ylamine and potassium carbonate as a base in a mixed solvent of tert-butyl alcohol
C. Xu Á W. Li Á X. Jin Á G. He Á H. Zhu (&)
Department of Applied Chemistry, College of Sciences, Nanjing Tech University,
Nanjing 211816, China
e-mail: zhuhj@njtech.edu.cn
123

C. Xu et al.
(TBA) and water, or use sodium bicarbonate as a base in a single solvent of water.
However, all these approaches suffer from drawbacks such as poor yield (only
20–25 %) and operational difficulties (for example, the reaction temperature needs
to be adjusted accurately). To overcome these disadvantages, it is essential to
develop reaction conditions that are eco-friendly, efficient, and give better yields.
Herein, several key parameters such as solvent, reaction temperature, and base
(including kind, molar ratio, and molar concentration) were selected and studied
according to a plausible mechanism for the hydrolysis and ring-opening reaction.
Additionally, in view of the low cost, relative abundance, eco-friendliness, and
inherent safety of water, chemists have begun investigating the possibility of
organic reactions in water, and many hydrolysis reactions have been carried out in
water efficiently [18–21]. Thus, it would be meaningful if efficient synthesis of
2-formylcyclopent-2-enecarboxylic acid were developed in water.
Results and discussion
The synthetic procedure is illustrated in Scheme 1. In this procedure, 7,7-dichloro-
bicyclo[3.2.0]hept-2- en-6-one (2) is carried out as reported previously [22–24], which
is a [2 ? 2] cycloaddition of cyclopentadiene and dichloroacetyl chloride. Subse-
quently, 2-formylcyclopent-2-enecarboxylic acid (1) is obtained via a hydrolysis and
ring-opening reaction of 2 in the presence of a base, which is reported in poor yields.
To overcome this drawback, we have made many efforts on the hydrolysis and ring-
opening reaction. In the initial stage of our research, we obtained an intermediate of
this reaction using 1.0 equiv of NaOH as a base in water, which was confirmed as
3-chloro-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-1-one, and a plausible mecha-
nism of the hydrolysis and ring-opening reaction was outlined in Scheme 2 based on
our experimental results and the work of Stevens et al. [25]. Nucleophilic attack of
hydroxide on the carbonyl center of 2 may take place and result in the formation of
intermediate A. Then, intermediate A is transformed to intermediate lactone B via an
intramolecular nucleophilic substitution. The subsequent step is a hydrolysis of
lactone B under base condition to give intermediate C. Finally, the shifting of the
double bond into conjugation with the formyl substituent gives rise to the target
compound 1. The mechanism indicates that sufficient equivalent of base (3.0 equiv or
more) could be favorable to the reaction, however, when a larger excess of base is used,
a side reaction could be accelerated resulting in more co-product (the enal group is
unstable in the presence of strong base). In addition, the screening of solvent and
temperature is also important. Therefore, we studied the effects of some key
parameters such as solvents, different bases, base mol ratio, and reaction temperature
of the reaction.
Effects of solvents on the hydrolysis and ring-opening reaction
Solvent as a reaction medium plays a major role in the reaction. Several kinds of
mixed solvents and single solvent were screened with 3.5 equiv of NaOH (Table 1).
It was found that reactions in water resulted in better performance compared with
123

Synthesis of 2-formylcyclopent-2-enecarboxylic acid
COOH
O
(i)
(ii)
O
Cl
Cl
H
3
2
1
Scheme 1 Synthesis of 2-formylcyclopent-2-enecarboxylic acid. Reagents and conditions: (i) n-hexane,
Cl2CHCOCl, Et3N. (ii) base (NaOH, KOH, Na2CO3, K2CO3, t-BuONa or t-BuOK), solvent (water or
aqueous solution of t-BuOH, THF, C2H5OH), 40–70 °C, 2 M HCl
O
OH
O
O
O
O
O
O
OH
CCl2
OH
Cl
Cl
-Cl
Cl
Cl
Cl
Cl
CHCl2
A
2
O
OH
O
OH
O
COOH
O
COO
COOH
O
CH
OH
H3O
-Cl
OH
O
O
O
H
O
Cl
Cl
H
H
Cl
B
C
1
Scheme 2 Plausible mechanism of the hydrolysis and ring-opening reaction
those in mixed solvents. Reaction in water resulted in stable yields and could be
controlled easily, whereas reactions in TBA ? H2O took place violently and only
little or even no target compound was obtained. That is, in only 5 min the reaction
in TBA ? H2O finished and must be cooled immediately, otherwise the yield would
be decreased. Similarly, reactions in THF ? H2O or C2H5OH (95 %) took place but
no product was obtained. This may be attributed to the effects of different base
strength in different solvent systems. That is to say, equal amounts of NaOH show
stronger alkalinity in mixed organic solvents, which could make the reaction violent
and lead to more side reactions than those in water.
Effects of mol ratios and different bases on the hydrolysis and ring-opening
reaction
According to the plausible mechanism above, mol ratios play a major role in the
reaction. Too little base cannot keep the reaction environment sufficiently basic to
favor the reaction, whereas too much base would accelerate the side reaction. In
addition, this reaction involved a hydrolysis and ring-opening in the presence of
base, and different bases play a major role in the reaction. Thus, the effects of mol
ratios and different bases have been investigated (Table 2). Initially, the reactions
were conducted by using 1.0, 2.0, 3.0, 3.5, and 4.0 mol ratio of NaOH in water at
50 °C, and the results showed that reactions were found to be not completely
finished with the fewer equiv of 3, which was in agreement with the plausible
mechanism. Improved results were observed with 3.5 equiv of NaOH in water, in
which the product was obtained in a better yield (entry 4). Then, reactions were
conducted by using different bases (3.5 equiv) in water at 50 °C. The results showed
123

C. Xu et al.
Yield (%)
Table 1 Screening of solvents of hydrolysis and ring-opening reaction
Entry
Solvent
Temperature (°C)
1
TBA ? H2O
TBA ? H2O
THF ? H2O
THF ? H2O
C2H5OH (95 %)
C2H5OH (95 %)
H2O
10
70
10
70
10
70
10
70
Trace
2b
3c
4c
5
Uncertain
0
0
0
6
0
7
Trace
37.9
8
H2O
a
Reaction condition: 3.5 equiv of NaOH as base, and reactions were monitored by TLC and HPLC
Vt-BuOH: VH2O = 1:2, the yield varies with the reaction time
b
c
VTHF: VH2O = 1:1, and water was added dropwise into THF
Table 2 Screening of bases and mol ratios of hydrolysis and ring-opening reactiona
Entry
Temperature (°C)
Base
n2:nbase
Yield (%)c
1b
2b
3
50
50
50
50
50
50
50
50
50
50
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
1:1.0
1:2.0
1:3.0
1:3.5
1:4.0
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
–
–
35.3
41.9
34.8
21.3
31.2
24.3
26.5
17.6
4
5
6
7
Na2CO3
K2CO3
t-BuONa
t-BuOK
8
9
10
a
Reaction conditions: water as solvent, 1 h
b
c
The reaction was not finished completely from the TLC, and we did not get the isolated yield
Isolated yield
Table 3 Screening of reaction temperature of hydrolysis and ring-opening reactiona
Entry
Temperature (°C)
Base
n2:nbase
Yield (%)b
1
2
3
4
a
40
50
60
70
NaOH
NaOH
NaOH
NaOH
1:3.5
1:3.5
1:3.5
1:3.5
27.7
41.9
49.3
37.9
Reaction conditions: water as solvent, 1 h
Isolated yield
b
123

Synthesis of 2-formylcyclopent-2-enecarboxylic acid
Table 4 Screening of
b
Entry Concentration of Temperature n2: nbase Yield (%)
NaOH (mol l-1
concentration of NaOH of the
hydrolysis and ring-opening
reactiona
)
(8C)
1
2
3
4
5
2.0
60
60
60
60
60
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
poor
poor
41.7
59.4
42.7
1.0
0.50
0.25
0.20
a
Reaction conditions: water as
solvent, 1 h
b
Isolated yield
that the use of NaOH resulted in much better performance than other bases such as
KOH, Na2CO3, K2CO3, t-BuONa, and t-BuOK (entries 4, 6–10).
Effects of reaction temperature on the hydrolysis and ring-opening reaction
Temperature always plays a significant role in the reaction process, therefore, as a
part of optimization strategy, reactions were performed at different temperatures
(40–70 °C) with 3.5 mol ratio of NaOH in water (Table 3). Experimental results
indicated that higher temperature can promote the reaction, such as the result of
60 °C was better than those of 40 °C and 50 °C (entries 1–3), whereas the yield was
decreased if the temperature was too high, for example, where 70 °C is worse than
that of 60 °C (entries 3, 4). The optimum results were obtained when the reaction
was carried out using 3.5 equiv of NaOH at 60 °C (entry 3).
Effects of concentration of base on the hydrolysis and ring-opening reaction
According to the experiments, concentration of base has an obvious effect on the
hydrolysis and ring-opening reaction. Reactions were conducted by using different
concentration of NaOH (2.0 M, 1.0 M, 0.50 M, 0.25 M, 0.20 M), and the best
improvement was observed (Table 4). There is a tendency that the yield of the
transformation is increased with the decrease of concentration (entries 1–4).
However, when the concentration of base is lower than 0.25 M, the yield is
decreased (entry 5). Therefore it is preferred that the concentration of NaOH is
0.25 M in water.
Conclusions
In conclusion, an improved and efficient procedure for preparation of 2-for-
mylcyclopent-2-enecarboxylic acid has been developed via a [2 ? 2] cycloaddition
reaction and a hydrolysis and ring-opening reaction. Several key parameters of the
later reaction such as solvents, different bases, base mol ratio, and reaction
temperature of the reaction were screened. More product (59.4 % yield) than double
the ones reported could be obtained under the optimized condition, that is using 3.5
equiv of sodium hydroxide (0.25 M), reacting 1 h in water at 60 °C.
123

C. Xu et al.
Experimental
All solvents and reagents for synthesis were purchased from commercial sources
and used without further purification except that hexane was distilled by sodium.
Cyclopentadiene as the starting material was derived through pyrolysis and
distillation of an industrial product with content of 98 % tested by HPLC. Reactions
were monitored by reverse-phase HPLC on a Varian 1200 chromatograph. Content
by HPLC refers to chromatographic area percentage. 1H NMR and 13C NMR
spectra were recorded on a Bruker 400-MHz spectrometer using tetramethylsilane
(TMS) as an internal standard and CDCl3 as solvent.
General procedure for synthesis of 7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one
(2)
7,7-Dichlorobicyclo[3.2.0]hept-2-en-6-one(2) was synthesized according to the
reported procedure [4], and compound 2 was isolated as colorless oil in 84.0 %
1
yield. H NMR(400 MHz, CDCl3, d ppm): 6.04–6.06 (m, 1H,), 5.79–5.82 (m, 1H),
4.25–4.29 (m, 1H), 4.05–4.09 (m, 1H), 2.79–2.85 (m, 1H), 2.55–2.62 (m, 1H); 13C
NMR (100 MHz, CDCl3, d ppm): 197.79, 136.88, 128.41, 88.18, 59.53, 58.60,
35.21.
General procedure for synthesis of 2-formylcyclopent-2-enecarboxylic acid (1)
A three-necked flask equipped with a magnetic stirrer, an addition funnel, and a
thermometer was charged with 7,7-dichlorobicyclo[3.2.0]-hept-2-en-6-one and
water. The mixture was heated to a certain temperature (40–70 °C) and then a certain
equivalent base was added. We monitored the reaction with thin-layer chromatog-
raphy (TLC) and high-performance liquid chromatography (HPLC). After completing
the reaction, the resulting mixture was cooled to about 10 °C and acidified with
concentrated hydrochloric acid to pH = 2, and extracted with ethyl acetate. The
combined organic layer was dried over anhydrous magnesium sulfate, concentrated,
and then purified via column chromatography to get 2-formylcyclopent-2-enecar-
boxylic acid as white solid (m.p. 90–91 °C). 1H NMR (400 MHz, CDCl3, d ppm): 9.77
(s, 1H), 7.10 (dd, J1 = 2.6 Hz, J2 = 4.2 Hz 1H), 3.81–3.83 (m, 1H), 2.76–2.86 (m,
1H), 2.61–2.71 (m, 1H), 2.37 (dd, J1 = 7.2 Hz, J2 = 14.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3, d ppm): 189.21, 177.85, 155.69, 144.55, 47.11, 33.10, 12.08.
3-chloro-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-1-one (B)
1H NMR (400 MHz, CDCl3, d ppm): 5.78–5.80 (m, 1H), 5.61–5.64 (m, 2H), 3.38–3.40
(m, 1H), 3.26–3.31 (m, 1H), 2.67–2.70 (m, 2H).
Acknowledgments We are grateful to the National Key Technology R&D Program of the Ministry of
Science and Technology (2011BAE06A07-04), the Technology R&D Program of Jiangsu province
(BE2012363), the Postgraduate Innovation Fund of Jiangsu province (2012, CXZZ12_0445) and the
Graduate Innovation Fund of Jiangsu province (2013,CXLX13_399), P.R. China.
123

Synthesis of 2-formylcyclopent-2-enecarboxylic acid
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