Synthesis of furan-2,3,4-tricarboxylate in biphasic water-Et2O solvent system

Article abstract of DOI:10.1007/s10593-015-1778-2

[Figure not available: see fulltext.] The reaction of dialkyl acetylenedicarboxylates with ethyl bromopyruvate or α-chlorocarbonyl compounds in the presence of 1,4-diazabicyclo[ 2.2.2]octane led to furan-2,3,4-tricarboxylates or the related 2-acetylfuran-3,4-dicarboxylates in excellent yield.

Full text of DOI:10.1007/s10593-015-1778-2

DOI 10.1007/s10593-015-1778-2
Chemistry of Heterocyclic Compounds 2015, 51(9), 804–807
Synthesis of furan-2,3,4-tricarboxylate
in biphasic water–Et O solvent system
2
1
1
Maryam Sabbaghan *, Ali Yousefi
1
Chemistry Department, Faculty of Sciences,
Shahid Rajaee Teacher Training University, PO Box 16785-163, Tehran, Iran;
e-mail: sabbaghan@srttu.edu
Submitted July 20, 2015
Accepted August 24, 2015
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2
015, 51(9), 804–807
The reaction of dialkyl acetylenedicarboxylates with ethyl bromopyruvate or α-chlorocarbonyl compounds in the presence of 1,4-diaza-
bicyclo[2.2.2]octane led to furan-2,3,4-tricarboxylates or the related 2-acetylfuran-3,4-dicarboxylates in excellent yield.
Keywords: α-chlorocarbonyl, dialkyl acetylenedicarboxylate, 1,4-diazabicyclo[2.2.2]octane, ethyl bromopyruvate, furan-2,3,4-tri-
carboxylate.
Polysubstituted furan derivatives are fundamentally
important heterocyclic molecules. This class of compounds
methodology for the preparation of furan-2,3,4-tricarboxy-
lates by the reaction of α-halocarbonyl compounds and
dialkyl acetylenedicarboxylates promoted by the catalytic
amount of DABCO at room temperature in one step and
good yield.
1
includes many natural and medicinal molecules. These
2
3
moieties are widely found in antiviral, anti-inflammatory,
4
5
antiallergic and antiasthmatic, antitumor, and anti-
diabetic activity 6 agents. Slight alterations of the substi-
tution patterns in the furan ring cause significant changes in
As a preliminary, we directed our studies toward
examination of the effect of various solvents on the
reaction of dimethyl acetylenedicarboxylate and ethyl
bromopyruvate as the model reaction. Interestingly, it
turned out that mixture H O–Et O, 1:1, and DMF were
7
their biological activities. Furan subunits have also been
used as building blocks for a large number of heterocyclic
compounds and as synthons in natural product synthesis.8
For these reasons, over the past few decades, many
chemists have devoted their efforts to the development of
novel and efficient methods for the synthesis of mono-, di-,
2
2
superior to other solvents (Table 1) and, owing to green
chemistry principles, H O–Et O mixture was selected as
2
2
the optimal solvent. Using the standard reaction conditions
the scope of the methodology was examined. The results
are summarized in Table 2. As shown in Table 2, various
α-halocarbonyl compounds reacted smoothly with dialkyl
acetylenedicarboxylate under the optimized reaction
conditions and gave the corresponding furan-2,3,4-tri-
carboxylates or 2-acetylfuran-3,4-tricarboxylates 1a–f in
good to excellent yields.
9
tri-, and polysubstituted furans.
As a part of our current studies on the development of
1
0
new routes to heterocyclic systems in water, we wish to
report a convenient and facile synthesis of functionalized
furan derivatives in excellent yields. In 2008, we described
the reaction of dialkyl acetylenedicarboxylates with ethyl
bromopyruvate in the presence of enaminones giving rise
to 2-ethyl 3,4-dialkyl 4-bromo-4,5-dihydrofuran-2,3,4-tri-
carboxylates in good yields, but with low atomic economy.
These compounds were converted to the corresponding
The reactions provide regioselectively a furan ring with
acetyl or carboxylate groups at positions C-2, C-3, and C-4.
Both ethyl bromopyruvate and 2-chloroacetoacetate reacted
with diethyl acetylenedicarboxylate leading to function-
nalized furans 1b,f with the same arrangement of ester
groups at positions 2, 3, and 4.
2
,3,4-trisubstituted furans by using 4-dimethylamino-
11
pyridine in the next step. Liang and coworkers have
reported the synthesis of polysubstituted furans and
functionalized 2H-pyrans from the reaction of α-halo-
carbonyl compounds with dimethyl acetylenedicarboxylate
1
Structures of the products were assigned by IR, H and
13
1
C NMR spectra. For example, the H NMR spectrum of
(
DMAD) catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO)
compound 1c in CDCl showed two singlet signals at 3.84
3
1
2
at room temperature. Herein, we report a simple and green
and 3.91 ppm readily assigned to methoxy groups and two
0
009-3122/15/5109-0804©2015 Springer Science+Business Media New York
804

Chemistry of Heterocyclic Compounds 2015, 51(9), 804–807
Table 1. The effect of the solvent on the yield of furan 1a
other singlets (2.36 and 2.62 ppm) corresponding to the
methyl groups. The proton-decoupled 13C NMR spectrum
of compound 1c showed eleven distinct resonances in
13
agreement with the proposed structure. The C signals of
carbonyl groups in 13C NMR spectrum of compound 1c
appear at 160.8, 164.1, and 191.5 ppm.
The mechanism for the formation of compounds 1 has
been proposed as a sequence of following steps: the
formation of quaternary ammonium salt 2 from reaction of
α-halocarbonyl with DABCO, formation of ylide 3 with a
base, its addition to acetylenedicarboxylate to give
intermediate 4, intramolecular transfer of RCO group to
form a rearranged intermediates 5 and 6, finally, formation
of cyclic furan derivative 1 (Scheme 1).12
The development of environmentally friendly solvents
for organic chemistry is an area of considerable impor-
tance.13 However, its application is still limited due to the
low solubility of organic substrates in water, which often
results in low reaction rates. In this two-phase water–diethyl
ether system, some steps of the reaction path like generation
of intermediates 2 and 3 are accelerated in water.
Solvent
Time, h
Yield, %
MeCN
1
72
1
60
0
2
H O
DMF
EtOH
90
0
72
2
Et
MeCN–Et
O–Et O, 1:1
DMF–Et O, 1:1
EtOH–Et O, 1:1
NMIM–Et O, 1:1*
2
O
20
50
85
40
10
30
2
O, 1:1
2
H
2
2
1
2
1
2
2
2
2
*
NMIM – 1-Butyl-3-methylimidazolium bromide (an ionic liquid).
Table 2. Synthesis of furan-2,3,4-tricarbonyl derivatives 1a–f*
Acetylenedicarboxylate
C–C≡C–CO Me
α-Halocarbonyl
Product
MeO2C
Yield, %
85
MeO
2
2
CO2Me
O
1
CO Et
2
a
EtO
2
C–C≡C–CO
2
Et
80
90
84
82
MeO
2
C–C≡C–CO
2
Me
O
O
O
Me
Me
Me
Cl
EtO
2
C–C≡C–CO
2
Et
O
EtO C
2
CO2Et
COMe
Me
Cl
Me
O
1
d
2 2
MeO C–C≡C–CO Me
EtO
2
C–C≡C–CO
2
Et
80
O
O
Me
OEt
Cl
*
Reaction conditions: α-halocarbonyl (1.5 mmol), DABCO (0.1 mmol), H
2 2
O–Et O, 1:1 (5 ml), rt, 30 min, then
acetylenedicarboxylate (0.5 mmol), K CO (1.5 mmol), rt, 1 h.
2
3
8
05

Chemistry of Heterocyclic Compounds 2015, 51(9), 804–807
Scheme 1
1
3
In conclusion, we report a transformation involving
C NMR spectrum, δ, ppm: 13.7; 51.5; 53.0; 62.9; 112.5;
acetylenedicarboxylates and α-halocarbonyl compounds in
the presence of 1,4-diazabicyclo[2.2.2]octane as catalyst,
which affords furan-2,3,4-tricarboxylates. The advantage of
the present procedure is that the reaction is performed
under green conditions by simply mixing the starting
materials. The procedure, described here, provides furan
tricarboxylates with a choice of specific ester group in
postitions 2, 3, and 4 of the furan ring.
1
17.9; 154.6; 158.5; 161.9; 168.6; 168.7. Mass spectrum,
+
m/z (Irel, %): 256 [M] (10), 225 (64), 211 (82), 194 (64),
4
5 (86), 31 (100).
Triethyl furan-2,3,4-tricarboxylate (1b). Yield 0.43 g
11
−
1
(
80%). Yellow oil. IR spectrum (neat), ν, cm : 1730,
1
1
725, 1720. H NMR spectrum, δ, ppm (J, Hz): 0.97 (3H, t,
3
3
J = 7.5, CH
3
); 1.09 (3H, t, J = 7.3, CH
3
); 1.14 (3H, t,
); 3.90 (2H, q,
); 7.32 (1H, s,
3
3
3
J = 7.2, CH
3
); 3.82 (2H, q, J = 7.2, OCH
2
3
J = 7.5, OCH
2
); 4.12 (2H, q, J = 7.3, OCH
2
13
Experimental
CH). C NMR spectrum, δ, ppm: 13.4; 13.6; 13.8; 61.1;
6
1.7; 62.3; 111.5; 113.1; 153.2; 159.1; 161.6; 168.1; 169.4.
+
IR spectra were recorded on a Shimadzu IR-460
Mass spectrum, m/z (Irel, %): 284 [M] (15), 239 (76), 194
1
13
spectrometer. H and C NMR spectra were recorded on a
Bruker DRX-250 Avance instrument (250 and 63 MHz,
(85), 149 (54), 135 (62), 90 (62), 45 (100).
Dimethyl
2-acetyl-5-methylfuran-3,4-dicarboxylate
9
k
respectively) in CDCl
3
using TMS as internal standard.
(1c). Yield 0.32 g (90%). White powder. Mp 80–83°C (mp
14 −1
Electron ionization mass spectra were recorded on a
Finnigan Mat TSQ-70 spectrometer operating at an
ionization potential 70 eV. Elemental analyses were carried
out with a Perkin-Elmer model 240-C apparatus. Melting
points were determined on an Electrothermal-9100
apparatus. All reagents were purchased from commercial
sources and used without further treatment.
79–81°C) . IR spectrum (KBr), ν, cm : 1730, 1673, 1596.
1
H NMR spectrum, δ, ppm: 2.36 (3H, s, CH
CH ); 3.84 (3H, s, OCH
3
); 2.62 (3H, s,
3
13
3
3
); 3.91 (3H, s, OCH ). C NMR
spectrum, δ, ppm: 14.9; 29.3; 52.5; 53.1; 122.4; 125.4; 139.1;
157.6; 160.8; 164.1; 191.5. Mass spectrum, m/z (Irel, %): 240
+
[M] (15), 198 (45), 168 (52), 58 (100), 31 (85). Found, %:
C 54.84; H 5.01. C11
H
12
O . Calculated, %: C 55.05; H 5.04.
6
Synthesis of compounds 1a–f (General method).
DABCO (11.2 mg, 0.1 mmol) was added to a stirred
solution of an appropriate α-halocarbonyl compound
Diethyl 2-acetyl-5-methylfuran-3,4-dicarboxylate (1d).
Yield 0.33 g (84%). Pale-yellow powder. Mp 74–76°C.
−
1
1
IR spectrum (KBr), ν, cm : 1745, 1673, 1596. H NMR
3
(
1.5 mmol) in H
was stirred at room temperature for 30 min. Anhydrous
CO (207 mg, 1.5 mmol) and acetylenedicarboxylate
2 2
O–Et O, 1:1, (5 ml). The reaction mixture
spectrum, δ, ppm (J, Hz): 1.33 (3H, t, J = 6.9, CH
3
); 1.38
3
(3H, t, J = 6.8, CH
3
); 2.39 (3H, s, CH
3
); 2.65 (3H, s,
3
3
K
(
2
3
CH
OCH
3
); 4.34 (2H, q, J = 6.9, OCH
2
); 4.41 (2H, q, J = 6.9,
13
0.5 mmol) were then added, and the reaction mixture was
2
). C NMR spectrum, δ, ppm: 14.4; 14.5; 15.4; 29.8;
stirred for 1 h. After completion of the reaction (monitored
62.1; 62.7; 122.7; 125.9; 140.1; 157.7; 161.3; 164.3; 192.1.
+
by TLC, eluent n-hexane–EtOAc, 8:1), the mixture was
Mass spectrum, m/z (Irel, %): 268 [M] (10), 254 (44), 182
2
extracted with 10 ml of Et O. The solvent was removed
(56), 110 (55), 58 (80), 44 (100). Found, %: C 58.01;
under reduced pressure, and the residue was purified by
column chromatography (SiO , n-hexane–AcOEt, 8:1).
-Ethyl 3,4-dimethyl furan-2,3,4-tricarboxylate (1a).
Yield 0.38 g (85%). Yellow oil. IR spectrum (neat), ν,
H 6.00. C13
H
16
O . Calculated, %: C 58.21; H 6.01.
6
2-Ethyl 3,4-dimethyl 5-methylfuran-2,3,4-tri-carb-
2
11
9l
2
oxylate (1e). Yield 0.36 g (82%). Yellow oil. IR spectrum
−
1
1
(neat), ν, cm : 1714, 1606, 1555. H NMR spectrum, δ,
−
1
1
3
cm : 1732, 1730, 1727. H NMR spectrum, δ, ppm (J, Hz):
ppm (J, Hz): 1.25 (3H, t, J = 7.1, CH
3
); 2.58 (3H, s, CH
); 4.21 (2H, q,
). C NMR spectrum, δ, ppm: 13.8; 13.9;
3
);
3
1
.16 (3H, t, J = 7.2, CH
OCH
3
); 3.60 (3H, s, OCH
3
); 3.75 (3H, s,
3.81 (3H, s, OCH ); 3.86 (3H, s, OCH
3
3
3
3
13
3
); 4.19 (2H, q, J = 7.2, OCH
2
); 7.53 (1H, s, CH).
J = 7.1, OCH
2
8
06

Chemistry of Heterocyclic Compounds 2015, 51(9), 804–807
5
1
1
2.4; 53.7; 60.8; 114.1; 126.1; 138.7; 157.5; 161.4; 163.4;
6. Lakshminarayana, N.; Prasad, Y. R.; Gharat, L.; Thomas, A.;
+
Narayanan, S.; Raghuram, A.; Srinivasan, C. V.; Gopalan, B.
Eur. J. Med. Chem. 2010, 45, 3709.
64.4. Mass spectrum, m/z (Irel, %): 270 [M] (5), 226 (85),
98 (42), 58 (80), 44 (100). Found, %: C 53.28; H 5.18.
7.
(a) Wang, T.; Liu, J.; Lv, Z.; Zhong, H.; Chen, H.; Niu, C.;
Li, K. Tetrahedron 2011, 67, 3476. (b) Bock, I.; Bornowski, H.;
Ranft, A.; Theis, H. Tetrahedron 1990, 46, 1199.
12
C H
14
7
O . Calculated, %: C 53.34; H 5.22.
Triethyl 5-methylfuran-2,3,4-tricarboxylate (1f).9g
Yield 0.32 g (80%). Yellow oil. IR spectrum (neat),
ν, cm :1735, 1606, 1560. H NMR spectrum, δ, ppm
(
c) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.;
−
1
1
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 3838.
3
3
(
J, Hz): 1.22 (3H, t, J = 7.0, CH
3
); 1.28 (3H, t, J = 7.0,
3
CH
3
); 1.33 (3H, t, J = 7.0, CH
3
); 2.59 (3H, s, CH
); 4.28 (2H, q, J = 7.0, OCH
3
); 4.23
); 4.33
8. Wright, D. L. In Progress in Heterocyclic Chemistry,
Gribble, G. W.; Joule, J. A., Eds.; Elsevier: New York, 2005,
vol. 17, p. 1.
3
3
(
2H, q, J = 7.0, OCH
2
2
3
13
(
2H, q, J = 7.0, OCH ). C NMR spectrum, δ, ppm: 14.3;
2
9
.
(a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076.
(b) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850.
1
4.4 (2C); 14.5; 61.3; 61.9; 62.4; 114.4; 126.6; 139.4; 157.6;
62.0; 162.5; 163.5. Mass spectrum, m/z (Irel, %): 298 [M]
+
1
(
c) Cao, H.; Zhan, H.; Cen, J.; Lin, J.; Lin, Y.; Zhu, Q.; Fu, M.;
(
8), 261 (82), 240 (58), 58 (52), 44 (100). Found, %:
Jiang, H. Org. Lett. 2013, 15, 1080. (d) Li, E.; Cheng, X.;
Wang, C.; Shao, Y.; Li, Y. J. Org. Chem. 2012, 77, 7744.
C 56.28; H 6.02. C14
H
18
O . Calculated, %: C 56.37; H 6.08.
7
(e) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A.
This work was supported by Shahid Rajaee Teacher
Training University under contract number 17783.
J. Am. Chem. Soc. 2012, 134, 5766. (f) Kim, H. Y.; Li, J. Y.;
Oh, K. J. Org. Chem. 2012, 77, 11132. (g) Liu, W.; Jiang, H.;
Zhang, M.; Qi, C. J. Org. Chem. 2010, 75, 966. (h) Wang, Y.;
Luo, Y. C.; Hu, X. Q.; Xu, P. F. Org. Lett. 2011, 13, 5346.
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Chinn, R. H. Tetrahedron Lett. 1989, 30, 4077. (l) Fan, M.;
Guo, L.; Liu, X.; Liu, W.; Liang, Y. Synthesis 2005, 391.
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