A modified and green methodology for preparation of polysubstituted furans

Article abstract of DOI:10.1002/hc.20086

In this study, we introduced a very simple, one-pot and green methodology for preparation of polysubstituted furans by reaction of aromatic aldehydes, DMAD, and alkylisocyanides in water and at room temperature.

Full text of DOI:10.1002/hc.20086

Heteroatom Chemistry
Volume 16, Number 4, 2005
A
Modified and Green Methodology
for Preparation of Polysubstituted Furans
Javad Azizian, Mohammad R. Mohammadizadeh,
Ali A. Mohammadi, and Ali R. Karimi
Department of Chemistry, Faculty of Sciences, Shahid Beheshty University, PO Box 19395-1775,
Tehran, Iran
Received 15 July 2004; revised 29 November 2004
Recently some new methods have been reported
ABSTRACT: In this study, we introduced a very
for synthesis of densely polysubstituted furans [7–
simple, one-pot and green methodology for prepa-
1
0]. Of the simplest and the most interesting report
ration of polysubstituted furans by reaction of aro-
matic aldehydes, DMAD, and alkylisocyanides in wa-
ter and at room temperature. ꢀC 2005 Wiley Periodicals,
Inc. Heteroatom Chem 16:259–262, 2005; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
is the procedure which is based on three-component
reaction of alkyl isocyanides, dialkyl acetylendicar-
boxylates, and aromatic aldehydes [7]. The addi-
tion of nucleophilic carbenes such as isocyanides to
dimethyl acetylenedicarboxylate (DMAD) has been
investigated in detail [11]. Furans with different sub-
stituents have been formed from the reaction of ini-
tially formed 1:1 zwitter ionic species I (Fig. 1) and
aromatic aldehydes [7].
10.1002/hc.20086
INTRODUCTION
However, in spite of very good improvements in
synthesis of furans, development of alternative mod-
ifications is essential. In the context of our general
interest in the synthesis of heterocyclic compounds
by the reaction of dipolar species with carbonyl com-
pounds [12], here we report a new green one-pot
three-component methodology for preparation of
polysubstituted furans by trapping of zwitterionic
intermediate I (Fig. 1) with aromatic aldehydes in
water as eco-compatible solvent.
Polysubstituted furans play an important role in or-
ganic chemistry not only due to their presence as
key structural units in many natural products and
in important pharmaceuticals, but they can also be
employed in synthetic chemistry as building blocks
[1,2]. Furans can be, in principle, synthesized from
either cyclization of acyclic precursors or derivati-
zation of the furan ring [3,4]. In the latter case, usu-
ally the introduction of substituents at the 2- or 5-
position is relatively easy, while a similar operation
at the 3- or 4-position is difficult. Thus, one of the
most pursued entries to polysubstituted furans is the
cyclization reaction of acyclic precursors since dif-
ferent substituents can be preloaded at the desired
locations in the starting materials [5,6]. Thus, the
substituent-incorporation capability of the starting
materials will be a key point for the efficiency of the
related methodology.
RESULTS AND DISCUSSION
Water has all factors of an ideal solvent and so syn-
thetic organic chemistry in water has been widely
used in recent years [13]. Moreover, because of high-
heat capacity, water provides the best surroundings
for product scale-up. As was mentioned, in Introduc-
tion, recently Nair and Vinod [7] reported a novel
one-pot three-component procedure for preparation
Correspondence to: Javad Azizian; e-mail: J-azizian@sbu.ac.ir.
ꢀ
c 2005 Wiley Periodicals, Inc.
2
59

2
60 Azizian et al.
In summery, we have described a very simple,
efficient, and green methodology for preparation of
polysubstituted furans in water as eco-compatible
solvent. The carried out study allows us to obtain
furans in good to high yields, using ordinary temper-
atures, and for relatively low-reaction time.
FIGURE 1
EXPERIMENTAL
of polysubstituted furans using DMAD, alkyl iso-
cyanides, and aromatic aldehydes (Scheme 1, condi-
tions i). Reactions were accomplished in refluxing
benzene and completed after 2–8 h, and the products
were formed in moderate yields. These authors ap-
parently believed that water prevented the reaction
progress, and thus they used dry and deoxygenated
benzene as the reaction medium.
We found that water not only has a preventive ef-
fect on reaction improvement but also it effectively
accelerated the reaction rate. In a typical procedure,
to a 1:1 mixture of aromatic aldehyde 1 and dialkyl
acetylenedicarboxylate 2 in water, 1 equivalent of
alkyl isocyanide 3 was added, and the reaction mix-
ture was allowed to rotate at room temperature for
an appropriate time (see Table 1). The pure products
Melting points were measured on the Electrother-
mal 9100 apparatus and are uncorrected. IR spec-
tra were measured on a Bomen FT-IR-MB 100 spec-
1
13
trometer. H and C NMR spectra were measured
with a Bruker DRX-300 Avance spectrometer at 300
and 75 MHz using TMS as internal standard. Chem-
ical shifts are reported (δ) relative to TMS and cou-
pling constants (J) are reported in hertz (Hz). Mass
spectra were recorded on a Shimadzu QP 1100 EX
mass spectrometer. Elemental analysis for C, H, and
N were performed using a Heraus CHN rapid an-
alyzer. DMAD and isocyanides derivatives were ob-
tained from Merck and Fluka and were used without
further purification.
4
were afforded in good to excellent yields with re-
Synthesis of 2-(Cyclohexylmethyl)-5-(4-
nitrophenyl)furan-3,4-dicarboxylic Acid
Dimethyl Ester (4a) as a General Procedure
crystallization from ethanol (for entries a–f) or by
column chromatography using hexane–ethyl acetate
mixture as the eluent (entries g–j). The results ob-
tained are summarized in Table 1.
To
a
magnetically stirred suspension of 4-
All products 4a–e are new compounds, and they
were characterized unambiguously by their elemen-
tal analysis and spectroscopic data (see Experimen-
tal section). Their IR spectra showed signals at 3310–
nitrobenzaldehyde 1a (0.200 g, 1.32 mmol) and
DMAD 2a (0.207 g, 1.45 mmol) in water (40 mL),
cyclohexyl isocyanide 3a (0.159 g, 1.45 mmol) was
added and the reaction mixture was stirred at room
temperature for 1.5 h. After filtration, the crude
product was recrystallized from ethanol to give pure
−
1
3
433 cm assignable to the NH groups and two
−
1
strong absorptions at about 1730 and 1660 cm
1
◦
assignable to the two ester carbonyls. In the H NMR
spectra, the amine protons resonated in the range of
δ 6.5–7 and are water exchangeable.
4a as light-yellow solid. Yield 95%, mp 169–171 C.
IR (KBr) υ: 3433 (NH), 1726 and 1674 (2C O), 1325,
−
1
1
1223, 1104 cm . H NMR (CDCl
11H, cyclohexyl), 3.80–3.98 (broad s, 7H, CH-N and
2CO CH
), 6.74 (s, 1H, NH), 7.62 (d, J = 8.90, 2H),
) δ: 24.48,
3
) δ: 1.28–2.10 (m,
1
3
In the C NMR spectra the two ester carbonyls
resonated at δ 163 and 164. In addition, aliphatic
protons and carbons could be carefully assigned at
the ranges of δ 1.2–4.0 and 14–81 ppm, respectively.
Compounds 4f–j are known [7] and characterized by
comparison of their physical properties and spectro-
scopic data with those of previously reported.
2
3
1
3
8.22 (d, J = 8.92, 2H). C NMR (CDCl
3
25.33, 33.35, 51.38, 51.72, 52.96, 88.80, 117.84,
123.93, 124.26, 134.94, 137.89, 145.90, 161.54,
164.36, 165.35. MS m/z (%): 402 (100), 371 (20),
320 (45), 288 (99), 256 (30), 151 (80), 55 (90). Anal.
SCHEME 1

A Modified and Green Methodology for Preparation of Polysubstituted Furans 261
TABLE 1 Reaction Time and Yields of Furans 4
4
Ar
R1
R2
Time (h)
Yield a
a
b
c
d
e
f
g
h
i
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
3-Nitrophenyl
Phenyl
3-Chlorophenyl
4-Chlorophenyl
4-Tolyl
Me
Me
t-Bu
t-Bu
Et
Me
Me
Me
Me
Me
Cyclohexyl
t-Bu
Cyclohexyl
t-Bu
1.5
1.5
1.5
2
1.5
2
4
3
4
5
95
92
88
90
73
93
84
88
87
91
t-Bu
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
j
aRelated to isolated yields.
◦
Calcd for C20
H
22
N
2
O
7
(402): C, 59.70; H, 5.51; N,
solid; yield 90%, mp 159–162 C, IR (KBr) υ: 3380
6
.96. Found: C, 59.64; H, 5.23; N, 7.05.
(NH), 3075 (CH), 1708 and 1680 (2 CO
2
Bu-t), 1609,
) δ: 1.49 (s, 9H, CO Bu-t),
Bu-t), 1.62 (s, 9H, CO Bu-t), 7.28 (s,
1H, NH), 7.64 (d, J = 9.00, 2H), 8.22 (d, J = 9.00,
2H). C NMR (CDCl ) δ: 28.15, 28.63, 29.81, 52.76,
−
1 1
For viscous liquid products 4g–j, after comple-
1420 cm . H NMR (CDCl
1.56 (s, 9H, CO
3
2
tion of the reaction, crude products were extracted
with dichloromethane (3 × 15 mL). The organic sol-
vent was evaporated, and the final purification was
carried out by column chromatography using a
2
2
1
3
3
81.13, 83.04, 91.11, 119.78, 123.98, 124.15, 135.50,
137.79, 145.61, 161.55, 163.57, 163.62. Anal. Calcd
8
.5:1.5 hexane–ethyl acetate mixture.
for C24
H
32
N
2
7
O (460.21): C, 62.59; H, 7.00; N, 6.08.
Found: C, 62.41; H, 7.09; N, 6.15.
2
-tert-Butylamino-5-(4-nitro-phenyl)-furan-3,4-
dicarboxylic Acid Dimethyl Ester (4b). Light-orange
solid; yield 92%, mp 168–170 C, IR (KBr) υ: 3330
◦
2-tert-Butylamino-5-(4-nitro-phenyl)-furan-3,4-
(
NH), 1730 and 1672 (2 CO
2
CH
) δ: 1.53 (s, 9H, (CH
), 3.97 (s, 3H, CH C), 6.98 (s, 1H,
NH), 7.62 (d, J = 8.79, 2H), 8.23 (d, J = 8.72, 2H).
C NMR (CDCl ) δ: 29.69, 51.31, 52.95, 53.05, 89.62,
3
), 1609, 1324, 1210
dicarboxylic Acid Diethyl Ester (4e). Yellow-orange
−
1
1
◦
cm . H NMR (CDCl
s, 3H, CO CH
3
3
)
3
N), 3.8
solid; yield 73%, mp 117–119 C, IR (KBr) υ: 3335
−
1
(
2
3
3
O
2
(NH), 1720, and 1668 (2 CO
2
Et), 1590, 1325 cm .
) δ: 1.33 (t, J = 6.00, 3H, CH ),
1.41 (t, J = 6.00, 2H, CH ), 1.53 (s, 9H, t-But), 4.26
(q, J = 6.00, 2H, OCH Me), 4.43 (q, J = 6.00, 2H,
OCH
Me), 7.02 (s, 1H, NH), 7.61 (d, J = 9.00, 2H),
) δ: 14.03,
1
H NMR (CDCl
3
3
1
3
3
3
117.48, 123.82, 124.29, 134.86, 138.24, 145.85,
2
161.81, 164.42, 165.38. MS m/z (%): 376 (100), 320
2
1
3
(
90), 288 (82), 151 (78), 57 (98). Anal. Calcd for
(376.13): C, 57.44; H, 5.36; N, 7.44.
Found: C, 57.53; H, 5.20; N, 7.37.
8.22 (d, J = 9.00, 2H). C NMR (CDCl
3
C
18
H
20
N
2
O
7
14.33, 29.75, 53.01, 60.18, 62.13, 89.78, 117.98,
123.71, 124.34, 135.07, 137.96, 145.80, 161.89,
1
64.21, 165.01. Anal. Calcd for C20
H
24
N
2
7
O (404.16):
C, 59.40; H, 5.98; N, 6.93. Found: C, 59.33; H, 5.79;
N, 6.86.
2
-Cyclohexylamino-5-(4-nitro-phenyl)-furan-3,4-
dicarboxylic Acid Di-tert-butyl Ester (4c). Orange
solid; yield 88%, mp 178–180 C. IR (KBr) υ: 3410
NH), 1731, and 1703 (2 CO
H NMR (CDCl
◦
−
1
(
2
Bu-t), 1614, 1476 cm .
1
REFERENCES
3
) δ: 1.56 (s, 9H, t-Bu), 1.6 (s, 9H,
t-Bu), 1.33–2.32 (m, 10H, cyclohexyl), 3.72 (d, 1H,
CH N), 6.73 (s, 1H, NH), 7.63 (d, J = 8.82, 2H),
[
1] Lipshutz, B. H. Chem Rev 1986, 86, 795.
[2] Nkanishi, K. Natural Products Chemistry; Kondasha:
Tokyo, 1974.
1
3
8
2
1
1
.21 (d, J = 8.80, 2H). C NMR (CDCl
3
) δ: 24.52,
[3] (a) Katrizky, A. R.; Rees, C. W. Comprehensive Hete-
rocyclic Chemistry; Pergamon: New York, 1984; Vol.
5.40, 28.15, 28.66, 33.47, 51.54, 81.05, 82.99, 90.33,
20.09, 124.4, 124.1, 135.52, 137.39, 145.63, 161.34,
63.48, 163.61. 486 (98), 430 (25), 374 (100), 357
4
, pp. 531–712; (b) Katrizky, A. R.; Rees, C. W.;
Scriven, E. F. V. Comprehensive Heterocyclic Chem-
istry II; Pergamon: New York, 1996; Vol. 2, pp. 259–
(
30), 292 (42), 274 (75), 57 (99). Anal. Calcd for
(486.24), C, 64.18; H, 7.04; N, 5.76.
Found: C, 64.12; H, 7.134; N, 5.66.
4
1
36; (c) Shipman, M. Contemp Org Synth 1995, 2,
–17.
C
26
H
34
N
2
O
7
[
4] (a) For the most recent reviews, see: Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong,
S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955; (b)
Keay, B. A. Chem Soc Rev 1999, 28, 209.
2
-tert-Butylamino-5-(4-nitro-phenyl)-furan-3,4-
dicarboxylic Acid Di-tert-butyl Ester (4d). Orange

2
62 Azizian et al.
[
5] For some of typical examples, see: (a) MaGee, D. I.;
Leach, J. D.; Setiadji, S. Tetrahedron 1999, 55, 2847;
[8] Nair, N.; Menon, R. S.; Vinod, A. U.; Viji, S. Tetrahe-
dron Lett 2002, 43, 2293.
(
b) Lou, F.- T.; Bajji, A. C.; Jeevanandam, A. J Org
[9] (a) Yavari, I.; Alizadeh, A.; Anary-Abbasinejad, M.;
Bijanzadeh, H. R. Tetrahedron, 2003, 59, 6083; (b)
Aurrecoechea, J. M.; Perez, E. Tetrahedron Lett 2003,
44, 3263.
[10] (a) Ma, S.; Li, L. Org Lett 2000, 2, 941; (b) Stauffer,
F.; Neier, R. Org Lett 2000, 2, 3535.
[11] (a) Winterfeldt, E.; Schumann, D.; Dillinger, H. J.
Chem Ber 1969, 102, 1656; (b) Oakes, T. R.; Davide,
H. G.; Nagel, F. G. J Am Chem Soc 1969, 91, 4761;
(c) Takizawa, T.; Obata, N.; Suzuki, Y.; Yanagida, T.
Tetrahedron Lett 1969, 3407.
Chem 1999, 64, 1738; (c) Lou, F.-T.; Jeevanandam,
A.; Bajji, A. C. Tetrahedron Lett 1999, 40, 121; (d)
Forgione, P.; Wilson, P. D.; Fallis, A. G. Tetrahe-
dron Lett 2000, 41, 17; (e) Gabriele, B.; Salerno, G.;
Lauria, E. J Org Chem 1999, 64, 7687; (f) Gabriele, B.;
Salerno, G.; Pascali, F. D.; Costa, M.; Chiusoli, G. P.
J Org Chem 1999, 64, 7693.
[
[
6] (a) Brown, C. D.; Chong, J. M.; Shen, L. Tetrahedron
1
4
999, 55, 14233; (b) Hanna, I. Tetrahedron Lett 1999,
0, 2521; (c) Marshall, J. A.; Robinson, E. D. J Org
Chem 1990, 55, 3450–3451; (d) Marshall, J. A.; Wang,
X. J Org Chem 1991, 56, 960; (e) Marshall, J. A.;
Wallace, E. M. J Org Chem 1995, 60, 796; (f) Marshall,
J. A.; Bartley, G. S. J Org Chem 1994, 59, 7169.
7] (a) Nair, N.; Vinod, A. U.; Abhilash, N.; Menon, R. S.;
Santhi, V.; Varma, R. L.; Viji, S.; Mathew, S.; Srinivas,
R. Tetrahedron 2003, 59, 10279; (b) Nair, N.; Vinod,
A. U. Chem Commun 2000, 1019.
[12] Azizian, J.; Karimi, A.; Mohammadi, A. A.;
Mohammadizadeh, M. R.; Arefrad, H. Monash
Chem (in press).
[13] (a) Mulzer, J.; Altenbach, H-J.; Braun, M.; Krohn,
K.; Reissig, H-U. Organic Synthesis Highlights; VCH:
Weinheim, 1991; pp. 71–76; (b) Li, C.-J.; Tak-Hang,
C. Organic Reactions in Aqueous Media; Wiley:
New York, 1997.