A simple preparation of ethyl 2,5-dimethylfuran-3-carboxylate and 2,5-dimethylfuran-3,4-dicarboxylic acid from diethyl 2,3-diacetylsuccinate

Article abstract of DOI:10.1002/jhet.92

(Chemical Equation Presented) A simple preparation of ethyl 2,5-dimethylfuran-3-carboxylate (3), 2,5-dimethylfuran-3,4-dicarboxylic acid (4), and diethyl 2,5-dimethylfuran-3,4-dicarboxylate (5) by treatment of diethyl 2,3-diacetylsuccinate (2) with aqueous HCl is reported. The reaction is performed under organic solvent free conditions from a readily available cheap starting material.

Full text of DOI:10.1002/jhet.92

540
A Simple Preparation of Ethyl 2,5-Dimethylfuran-3-Carboxylate
and 2,5-Dimethylfuran-3,4-Dicarboxylic Acid from
Diethyl 2,3-Diacetylsuccinate
Vol 46
Gang-Qiang Wang,a Zhi Guan,a Rong-Chang Tang,a Zeljko Ostojic,b
T. Nicholas Jones,b Ting-Ting Wu,a and Yan-Hong Hea*
aSchool of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
bDepartment of Chemistry, College of Saint Benedict/Saint John’s University, St. Joseph,
Minnesota 56374
*E-mail: heyh@swu.edu.cn
Received July 19, 2008
DOI 10.1002/jhet.92
Published online 5 May 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple preparation of ethyl 2,5-dimethylfuran-3-carboxylate (3), 2,5-dimethylfuran-3,4-dicarboxylic
acid (4), and diethyl 2,5-dimethylfuran-3,4-dicarboxylate (5) by treatment of diethyl 2,3-diacetylsucci-
nate (2) with aqueous HCl is reported. The reaction is performed under organic solvent free conditions
from a readily available cheap starting material.
J. Heterocyclic Chem., 46, 540 (2009).
INTRODUCTION
21] in aqueous HCl. Using this procedure, trisubstituted
furan (3) and tetrasubstituted furan (4) or (5) can be eas-
ily prepared at will by adjusting the concentrations of
aqueous HCl. The reaction is simple to perform, and the
starting material is cheap and readily available.
Highly substituted furans play an important role as
structural elements of many pharmaceutical and natural
substances [1]. Moreover, they are useful building
blocks in synthetic organic chemistry [2]. Especially,
ethyl 2,5-dimethylfuran-3-carboxylate (3) (Scheme 1) is
an important trisubstituted furan. Its derivatives have
been used as wood preservatives [3], microbicides,
insecticides [4], and fungicides [5]. 2,5-Dimethylfuran-
3,4-dicarboxylic acid (4) and diethyl 2,5-dimethylfuran-
3,4-dicarboxylate (5) are also useful intermediates in
medicinal chemistry and organic synthesis [6–8].
Among the different approaches to multiply substituted
furans [9–15], there are some methods for the prepara-
tion of 3, such as gold(I) catalyzed cascade reaction of
propargyl Claisen rearrangement and heterocyclization
of propargyl vinyl ethers [1], polymer-supported sele-
nium-induced electrophilic cyclization [16], I2-induced
cyclization of 2-alkenyl substituted 1,3-dicarbonyl com-
pounds [17], treatment of a,b-unsaturated ketones with
N-bromosuccinimide followed by cyclization [18], and
treatment of ethyl 2-acetyl-4-oxopentanoate with mont-
morillonite clay in toluene at reflux with water removal
[5]. Some methods require expensive reagents and some
use unreadily accessed starting materials or hazardous
organic solvents. Thus, the development of convenient
strategies is still of considerable interest. We now wish
to report a simple preparation of trisubstituted furan (3)
starting from diethyl 2,3-diacetylsuccinate (2) by decar-
boxylation and subsequent Paal–Knorr cyclization [19–
RESULTS AND DISCUSSION
Diethyl 2,3-diacetylsuccinate (2) (Scheme 1) was pre-
pared according to literature from ethyl acetoacetate (1)
using sodium in diethyl ether followed by treatment
with iodine at room temperature [22]. In our initial ex-
ploration, treatment of 2 with 0.4N aqueous HCl at
reflux for 14–15 h in oil bath afforded trisubstituted
furan monoester (3) and tetrasubstituted furan diacid (4),
in 30–50% and 40–60% yields, respectively. Different
aqueous HCl concentrations were further compared for
the reaction under both oil bath heating and microwave
irradiation (Table 1). When 2 was treated with 6N aque-
ous HCl or 3N aqueous HCl, tetrasubstituted furan
diacid (4) was obtained as the only product in excellent
to quantitative yields. Whereas using dilute aqueous
HCl, trisubstituted furan monoester (3) was obtained.
The highest yield of 3 was observed in 57% under oil
bath heating in 0.3N aqueous HCl, and 50% under
microwave irradiation in 0.2N aqueous HCl. Interest-
ingly, tetrasubstituted furan ester (5) was obtained only
under microwave irradiation possibly because of the
shorter reaction time.
C
V
2009 HeteroCorporation

May 2009
A Simple Preparation of Ethyl 2,5-Dimethylfuran-3-Carboxylate and
2,5-Dimethylfuran-3,4-Dicarboxylic Acid from Diethyl 2,3-Diacetylsuccinate
541
Scheme 1. Reaction conditions: (a) (i) Na, Et2O, r.t., 12 h, (ii) I2, Et2O, r.t., 4 h, 66%; (b) HCl-H2O, reflux under oil bath heating or under micro-
wave irradiation; (c) 5% NaOH, reflux, 5 h, 96%; (d) H2, 5% Pd/C, EtOH-H2O, 4d, 90%.
A previous report by Fales et al. described the forma-
tion of diethyl 2,5-dimethylfuran-3,4-dicarboxylate (5)
from diethyl 2,3-diacetylsuccinate (2) by using concen-
trated H2SO4 in CCl4 [23]. In our procedure, tetra- or
trisubstituted furans can be easily prepared by using dif-
ferent aqueous HCl concentrations. The product selectiv-
ity appears to be controlled by acid concentrations.
More dilute aqueous HCl can provide trisubstituted
furan monoester (3) probably through decarboxylation
and subsequent Paal–Knorr dehydrative cyclization.
Meanwhile, higher concentrations of aqueous HCl gave
tetrasubstituted furan diacid (4) as main or even only
product possibly through Paal–Knorr cyclization and
subsequent hydrolysis. It is notable that no decarboxyl-
ation was observed under more acidic conditions. We
think that it is possibly because the higher concentra-
tions of aqueous HCl can accelerate dehydrative cycliza-
tion step to form furan ring before decarboxylation, and
the resulting conjugated system between the furan ring
and dicarbonyl groups is strong enough to prevent it
from decarboxylation under employed reaction condi-
tions. Actually, no decarboxylation of 4 was observed in
our investigation. Therefore, compound 4 would be the
major product if cyclization is faster than decarboxyl-
ation, otherwise 3 would be the major one.
To confirm the structure of 3, the hydrolysis of 3 with
5% aqueous NaOH was performed to afford 2,5-dime-
thylfuran-3-carboxylic acid (6) as crystals (Scheme 1).
The X-ray crystallographic analysis of 6 was shown in
Figure 1 [24].
Moreover, we investigated the selective hydrogenation
of 3. Treatment of 3 with 5% Pd/C in EtOH-H2O at H2
atmosphere for 4 days yielded dihydrofuran 7 as the
only product in excellent yield (Scheme 1). This selec-
tive hydrogenation is a useful approach for dihydrofur-
ans which are also important structural elements of
many pharmaceutical and natural products [16,25–27].
The procedure described earlier is a practical method
for the preparation of trisubstituted furan 3. Although 3
was obtained in medium yield, it is still a valuable
approach because the starting material is a readily
accessed symmetrically substituted 1,4-dicarbonyl com-
pound. Moreover, using this procedure trisubstituted
furan (3) and tetrasubstituted furan (4 or 5) can be easily
prepared at will by adjusting the concentrations of
Table 1
Comparison of different HCl concentrations as reagents for diethyl
2,3-diacetylsuccinate (2) cyclization.
Yield (%)a
Concentration
of HCl (N)
Reaction
condition
Reaction
time (h)
Entry
3
4
5
1
2
3
6
Oil bath
Oil bath
Oil bath
Oil bath
Oil bath
Oil bath
Oil bath
Oil bath
Oil bath
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
14
14
14
14
15
15
15
15
15
1
89
91
82
86
40
38
58
52
3
1
3
4
5
0.5
0.4
0.3
0.2
0.1
H2O
3
8
50
57
41
44
6
7
8
9
10
11
12
13
14
15
16
100
1
1
2
20
21
39
50
38
24 52
61
52
0.4
0.3
0.2
0.1
H2O
2
2.5
2.5
3
46
56
a Refers to yield of isolated product.
Figure 1. X-ray crystallographic analysis of 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

542
G.-Q. Wang, Z. Guan, R.-C. Tang, Z. Ostojic, T. N. Jones, T.-T. Wu, and Y.-H. He
Vol 46
The solvents were removed to obtain compound 6 (61 mg,
96%) as white crystals, mp 131–132ꢀ; 1H NMR (CDCl3) d
2.26 (s, 3H), 2.55 (s, 3H), 6.25 (s, 1H); 13C NMR (CDCl3) d
13.3, 14.0, 106.4, 113.5, 150.4, 159.5, 169.9. Identical to that
previously reported [29].
aqueous HCl under organic solvent free conditions.
Both conventional and microwave heating were investi-
gated for this method.
Ethyl 2,5-dimethyl-4,5-dihydrofuran-3-carboxylate (7). A
mixture of 3 (230 mg, 1.25 mmol) and 5% Pd/C (146 mg) in
EtOH-H2O (6:1, 3 mL) was vigorously stirred at r.t. at H2
atmosphere under ordinary pressure for 4 days. The reaction
mixture was extracted with diethyl ether. The combined
extracts were washed with water, brine, dried (Na2SO4), and
filtered. The solvents were removed and the residue was puri-
fied by flash chromatography (petroleum ether/diethyl ether
20:1) to get compound 7 (206 mg, 90%) as colorless oil. 1H
NMR (CDCl3) d 1.26 (t, 3H, J ¼ 7.1 Hz), 1.34 (d, 3H, J ¼
6.2 Hz), 2.16 (s, 3H), 2.47 (1H, dd, J ¼ 7.6, 14.0 Hz), 2.98
(dd, 1H, J ¼ 11.0, 14.0 Hz), 4.14 (q, 2H, J ¼ 7.1 Hz), 4.76
(m, 1H); 13C NMR (CDCl3) d 14.3, 14.6, 22.0, 37.0, 59.5,
78.8, 101.6, 166.5, 167.7. Identical to that previously reported
[30].
EXPERIMENTAL
1
General methods. H NMR (300 MHz) and 13C NMR (75
MHz) spectra were recorded on a Bruker AV-300 spectrometer
with TMS as an internal standard. The chemical shifts (d) are
given in ppm, and the coupling constants (J) in hertz (Hz). X-
ray diffraction analysis was performed on a Bruker P4 X-ray
diffraction meter. Melting points were determined on an X-4
digital display micro melting point apparatus and were uncor-
rected. Unless otherwise noted, all reagents were obtained
from commercial suppliers and were used without further puri-
fication. Organic solvents used were dried by standard methods
when necessary. All reactions were monitored by TLC with
Haiyang GF254 silica gel plates. Flash column chromatogra-
phy was carried out using 200–300 mesh silica gel at increased
pressure.
Ethyl 2,5-dimethylfuran-3-carboxylate (3) and 2,5-dime-
thylfuran-3,4-dicarboxylic acid (4). A solution of diethyl 2,3-
diacetylsuccinate (2) (145 mg, 0.56 mmol) in aqueous HCl
(0.4N, 1.8 mL) was refluxed for 15 h in oil bath. After cooling
to r.t., the reaction mixture was extracted with diethyl ether
thoroughly. The combined extracts were washed with water,
brine, dried (Na2SO4), and filtered. The solvents were removed
and the residue was purified by flash chromatography (petro-
leum ether/diethyl ether 5:1, then pure diethyl ether) to give
compound 3 (47 mg, 50%) as colorless oil, and compound 4
(41 mg, 40%) as white crystals.
Acknowledgment. This work was supported by Scientific
Research Foundation for the Returned Overseas Chinese Scholars
of the State Education Ministry, the Natural Science Foundation
Project of CQ CSTC (CSTC, 2006BB5377), High-Tech Training
Fund of Southwest University (XSGX0601), and Doctoral Fund
of Southwest University (SWNUB2005012).
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Journal of Heterocyclic Chemistry
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A Simple Preparation of Ethyl 2,5-Dimethylfuran-3-Carboxylate and
2,5-Dimethylfuran-3,4-Dicarboxylic Acid from Diethyl 2,3-Diacetylsuccinate
543
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