N,N-Dimethylamino-Functionalized Basic Ionic Liquid Catalyzed One-Pot Multicomponent Reaction for the Synthesis of 4H-Benzo[b]pyran Derivatives under Solvent-Free Condition

Article abstract of DOI:10.1002/hc.20516

A simple, clean, and environmentally benign three-component process for the synthesis of 4H-benzo[b]pyran derivatives using basic ionic liquid N,N-dimethylaminoethylbenzyldimethylammonium chloride ([PhCH₂Me ₂N⁺CH₂

Full text of DOI:10.1002/hc.20516

Heteroatom Chemistry
Volume 20, Number 2, 2009
N,N-Dimethylamino-Functionalized Basic
Ionic Liquid Catalyzed One-Pot
Multicomponent Reaction for the Synthesis
of 4H-Benzo[b]pyran Derivatives under
Solvent-Free Condition
Lu Chen, Yi-Qun Li, Xu-Jiang Huang, and Wen-Jie Zheng
Department of Chemistry, Jinan University, Guangzhou 510632, People’s Republic of China
Received 13 November 2008; revised 30 January 2009
INTRODUCTION
ABSTRACT: A simple, clean, and environmentally
benign three-component process for the synthesis of
4H-benzo[b]pyran derivatives using basic ionic liquid
N,N-dimethylaminoethylbenzyldimethylammonium
chloride ([PhCH2Me2N+CH2CH2NMe2]Cl−) as an
efficient catalyst under solvent-free condition is
described. A wide range of aromatic aldehydes easily
undergoes condensation with malononitrile and
5,5-dimethylcyclohexane-1,3-dione (dimedone) under
solvent-free condition to afford the desired products
of good purity in excellent yields. Taking into ac-
count environmental and economical considerations,
the protocol presented here has the merits of envi-
ronmentally benign, simple operation, convenient
In recent years, 4H-benzo[b]pyran compounds have
attracted much attention due to their wide range
of biological and pharmacological activities [1]. It
has been reported that benzo[b]pyran derivatives
have diverse pharmacological activities such as
anticoagulant, anticancer, spasmolytic, antianca-
phylactia, etc. [2]. In addition, 4H-benzo[b]pyrans
also constitute the structural unit of a series of
natural products [3].
Considering the importance of these com-
pounds, many methods for the synthesis of 4H-
benzo[b]pyran derivatives have been reported suc-
cessively. The conventional synthesis involves the
condensation of 5,5-dimethylcyclohexane-1,3-dione
(dimedone) with aromatic aldehyde and malonon-
itrile under refluxing DMF [4] or acetic acid [5].
However, these solvents make the workup pro-
cedure complicated, lead to poor yields of prod-
ucts, and pollute the environment. The use of mi-
crowave [6] and ultrasound irradiations [7] is also
reported for the synthesis of pyrans. Recently, many
methods have been reported for the preparation
of 4H-benzo-[b]pyrans through two-component [8]
or three-component condensation including the use
of 4-dodecylbenzenesulfonic acid [9], rare earth
perfluorooctanoate (RE(PFO)3) [10], (NH4)2HPO4
[11], NaBr [12], tetramethyl ammonium hydrox-
ide [13], basic ionic liquid ([bmim]+OH−) [14],
ꢀ
C
workup, and good yields.
2009 Wiley Periodicals,
Inc. Heteroatom Chem 20:91–94, 2009; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20516
Correspondence to: Yi-Qun Li; e-mail: tlyq@jnu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20672046.
Contract grant sponsor: Guangdong Natural Science
Foundation.
Contract grant number: 8151063201000016.
2009 Wiley Periodicals, Inc.
c
ꢀ
91

92 Chen et al.
N-methylimidazole [15], (S)-proline [16], etc., as cat-
alysts have been introduced for the synthesis of 4H-
benzo[b]pyrans. In spite of the merits of these pro-
cedures, each of them suffers at least from one of
the following limitations: low yields, unavailabil-
ity of the reagents, long reaction times, effluent
pollution, harsh reaction conditions, and tedious
workup procedures. As part of our program aimed
at developing new, synthetic, and useful methodolo-
gies based on the use of functionalized ionic liq-
uid as catalyst for the preparation of various bi-
ologically active heterocyclic compounds, we now
report a highly efficient procedure for the prepa-
ration of 4H-benzo[b]pyrans via a one-pot, three-
component tandem Knoevenagel cyclocondensation
reaction using basic ionic liquid catalyst, N,N-di-
methylaminoethylbenzyldimethylammonium chlo-
ride as catalyst under solvent-free conditions.
SCHEME 1
lectivity were obtained. All of the results are shown
in Table 1.
As can be seen from Table 1, in all cases,
aromatic aldehydes substituted with either electron-
donating or electron-withdrawing groups un-
derwent the reaction smoothly and gave the
products in good yields. The aromatic aldehydes
bearing electron-donating groups (such as N,N-
dimethylamino group, hydroxyl group, methoxyl
group, and methyl group) required a longer reaction
time and gave lower yields than those bearing
electron-withdrawing groups (such as the nitro
group, halide; Table 1, entries 7–10). It is worthy
of note that the reaction proceeded without the
protection of acidic hydroxyl substituents (Table 1,
entry 9).
One of the main aims of our study was to in-
vestigate the reuse and recycling of the ionic liquid
catalyst. The catalyst was easily recovered by the re-
moval of the methanol filtrate after filtering off the
products. Reusabilities of the catalyst were exam-
ined with the reaction of 4-nitrobenzaldehyde (1a),
malononitrile (2), and dimedone (3) for the model
reaction. It can be seen from Fig. 1 that the catalyst
could be run for five times without the loss of the
activities.
RESULTS AND DISCUSSION
Initially, we investigated the condensation re-
action of 4-nitrobenzaldehyde (1a), malononi-
trile (2), and 5,5-dimethylcyclohexane-1,3-dione
(3) in the presence of 5 mol% of N,N-dimethyl-
aminoethylbenzyldimethylammonium chloride un-
der solvent-free condition at 60◦C for 30 min.
It was found that N,N-dimethylaminoethylbenzyl-
dimethylammonium chloride showed excellent cat-
alytic activity; the reaction proceeded very smoothly
and gave the product 4a in 94% yield (Table 1,
entry 1). No product was detected in the absence
of the catalyst, and it showed that the catalyst was
essential in the reaction. Encouraged by this result,
we further demonstrated the scope and generality of
the present method by the reaction of various alde-
hydes (1) with malononitrile (2) and dimedone (3)
under the above-mentioned unoptimum conditions
(Scheme 1). In all cases, good yields with good se-
CONCLUSION
In conclusion, we have described a practical
and efficient procedure for the preparation of
4H-benzo[b]pyrans through the three-component
TABLE 1 Synthesis of 4H-Benzo[b]pyrans Catalyzed by N,N-dimethylaminoethylbenzyldimethylammonium Chloride under
Solvent-Free Conditiona
Entry
Ar
Time (min)
Product
Yield (%)b
1
2
3
4
5
6
7
8
4-NO2-C6H4
3-NO2-C6H4
2,4-2Cl-C6H3
4-Cl-C6H4
4-Br-C6H4
C6H5
4-Me2N-C6H4
4-MeO-C6H4
4-HO-C6H4
4-Me-C6H4
30
30
30
30
50
30
80
50
35
30
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
92
89
91
83
76
73
85
86
75
9
10
4j
aReaction conditions: aromatic aldehyde (1 equiv.), malononitrile (1 equiv.), dimedone (1 equiv.), catalyst (5 mol%), solvent free, 60◦C.
bYields refer to those of pure isolated products characterized by IR, 1H NMR, and 13C NMR spectroscopic data.
Heteroatom Chemistry DOI 10.1002/hc

N,N-Dimethylamino-Functionalized Basic Ionic Liquid Catalyzed One-Pot Multicomponent Reaction 93
All of the products are known, and the data are
found to be identical with those that are reported in
the literature elsewhere. The spectral data of selected
products are given below.
2-Amino-3-cyano-4-(4ꢁ-nitrophenyl)-7,7-dimethyl-
5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (4a): mp
176–177◦C (lit. [12] 177–178◦C); FT-IR (KBr): ν:
3408, 3321, 3181, 2187, 1673, 1632, 1597, 1520,
1
1351, 1216 cm−1; H NMR (d6-DMSO, 300 MHz) δ:
0.91 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.07 (d, J = 16.1
Hz, 1H, H-6), 2.23 (d, J = 16.1 Hz, 1H, Hꢁ-6), 3.58 (s,
2H, CH2), 4.32 (s, H, CH), 7.41 (d, J = 8.6 Hz, 2H,
ArH), 8.14 (d, J = 8.6 Hz, 2H, ArH) ppm; 13C NMR
(d6-DMSO, 75 MHz), δ: 27.83 (CH3), 29.18 (CH3),
32.74 (C-7), 36.56 (C-4), 40.38 (C-8), 50.75 (C-6),
57.85 (C-3), 112.62 (C-4a), 120.28 (CN), 124.60
(2C ), 129.54 (2C ), 147.15 (C ), 153.22 (C ),
159.49 (C-2), 164.03 (C-8a), 196.63 (C O) ppm.
2-Amino-3-cyano-4-(4ꢁ-chlorophenyl)-7,7-dimeth-
FIGURE 1 Recycling of ionic liquid catalyst.
reaction of aromatic aldehydes, malononitrile, and
dimedone by using a catalytic amount of N,N-di-
methylaminoethylbenzyldimethylammonium chlo-
ride as catalyst under solvent-free condition. This
procedure offers several advantages including mild
reaction conditions, cleaner reaction, satisfactory
yields of products, as well as a simple experimen-
tal and isolated procedure that makes it a useful
and attractive protocol for the synthesis of these
compounds.
yl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran
(4d):
mp 212–214◦C (lit. [12] 215–217◦C); FT-IR (KBr)
ν: 3382, 3185, 2190, 1676, 1637, 1606, 1366, 1216
1
cm−1; H NMR (d6-DMSO, 300 MHz) δ: 0.90 (s, 3H,
CH3), 0.99 (s, 3H, CH3), 2.06 (d, J = 16.1 Hz, 1H,
H-6), 2.21 (d, J = 16.1 Hz, 1H, Hꢁ-6), 3.58 (s, 2H,
CH2), 4.15 (s, 1H, CH), 7.13 (d, J = 8.4 Hz, 2H,
ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH) ppm; 13C NMR
(d6-DMSO, 75 MHz), δ: 27.76 (CH3), 29.24 (CH3),
32.72 (C-7), 36.02 (C-4), 40.11 (C-8), 50.83 (C-6),
58.63 (C-3), 113.22 (C-4a), 120.52 (CN), 129.22
(2C ), 130.04 (2C ), 132.03 (C ), 144.68 (C ),
159.40 (C-2), 163.54 (C-8a), 196.61 (C O) ppm.
2-Amino-3-cyano-4-phenyl-7,7-dimethyl-5-oxo-
EXPERIMENTAL
Melting points were measured on an Electrother-
mal X6 microscopy digital melting point apparatus
and are uncorrected. IR spectra were recorded on
a Bruker Equinox 55 spectrometer using KBr pel-
lets. 1H NMR and 13C NMR spectra were recorded in
d6-DMSO on a Bruker AVANCE 300 (300 MHz) in-
strument with the TMS at δ 0.00 ppm as an internal
standard.
4H-5,6,7,8-tetrahydrobenzo[b]pyran (4f): mp 222–
223◦C (lit. [15] 224–225◦C); FT-IR (KBr) ν: 3396,
3325, 3211, 2963, 2199, 1664, 1602, 1371, 1214,
1
1036 cm−1; H NMR (d6-DMSO, 300 MHz) δ: 0.91
Chemicals used were of commercial grade,
and they were used without further purification.
The ionic liquid N,N-dimethylaminoethylbenzyl-
dimethylammonium chloride was prepared accord-
ing to the method reported in the literature [17].
(s, 3H, CH3), 1.00 (s, 3H, CH3), 2.06 (d, J = 16.1 Hz,
1H, H-6), 2.22 (d, J = 16.1 Hz, 1H, Hꢁ-6), 3.58 (s,
2H, CH2), 4.13 (s, 1H, CH), 7.09–7.18 (m, 3H, Ar),
7.23–7.28 (m, 2H, ArH) ppm; 13C NMR (d6-DMSO,
75 MHz), δ: 27.70 (CH3), 29.34 (CH3), 32.73 (C-7),
36.5 (C-4), 40.11 (C-8), 50.88 (C-6), 59.18 (C-3),
113.64 (C-4a), 120.69 (CN), 127.50 (C ), 128.08
(2C ), 129.26 (2C ), 145.68 (C ), 159.40 (C-2),
163.42 (C-8a), 196.59 (C O) ppm.
General Procedure for the Synthesis
of 4H-Benzo[b]pyran
An equimolar (3 mmol) mixture of an aromatic alde-
hyde 1, malononitrile 2, dimedone 3 and N,N-di-
methylaminoethylbenzyldimethylammonium chlo-
ride (5 mol%) was vigorously stirred at 60◦C for the
specific time indicated in Table 1. The end of the re-
action was monitored by TLC. Then, the crude prod-
uct obtained was washed with cold methanol. The
resulting solid was purified by recrystallization from
hot methanol to afford the pure products 4.
2-Amino-3-cyano-4-(4ꢁ-methoxyphenyl)-7,7-dime-
thyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (4h):
mp 195–196◦C (lit. [14] 195–197◦C); FT-IR (KBr)
ν: 3376, 3327, 3188, 2920, 2194, 1681, 1657, 1607,
1510, 1370, 1254 cm−1. 1H NMR (d6-DMSO, 300
MHz) δ: 0.90 (s, 3H, CH3), 0.99 (s, 3H, CH3), 2.05
(d, J = 16.1 Hz, 1H, H-6), 2.21 (d, J = 16.1 Hz, 1H,
Hꢁ-6), 3.58 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 4.08
(s, 1H, CH), 6.81 (d, J = 8.6 Hz, 2H, ArH), 7.01 (d,
Heteroatom Chemistry DOI 10.1002/hc

94 Chen et al.
J = 8.6 Hz, 2H, ArH) ppm. 13C NMR (d6-DMSO,
75 MHz), δ: 27.70 (CH3), 29.34 (CH3), 32.73 (C-7),
36.50 (C-4), 40.11 (C-8), 51.07 (C-6), 59.18 (OCH3),
113.64 (C-4a), 120.69 (CN), 127.50 (C ), 128.08
(2C ), 129.26 (2C ), 145.68 (C ), 159.40 (C-2),
163.42 (C-8a), 196.59 (C O) ppm.
C. W. Rees, E. F. V. Scriven (Eds.); Pergamon Press:
Oxford, UK, 1995; Vol. 5, pp. 469–490.
[2] (a) Andreani, L. L.; Lapi, E. Bull Chim Farm 1960, 99,
583–586; (b) Zhang, Y. L.; Chen, B. Z.; Zheng, K. Q.;
Xu, M. L.; Lei, X. H. Yao Xue Xue Bao 1982, 17, 17–
22; (c) Bonsignore, L.; Loy, G.; Secci, D.; Calignano,
A. Eur J Med Chem 1993, 28, 517–520.
[3] (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano,
S. J Chem Soc, Chem Commun 1988,1202–1204; (b)
Cingolani, G. M.; Gualtieri, F.; Pigini, M. J Med Chem
1969, 12, 531–532.
[4] Singh, K.; Singh, J.; Singh, H. Tetrahedron 1996, 52,
14273–14280.
[5] Wang, X. S.; Shi, D. Q.; Tu, S. J.; Yao, C. S. Synth
Commun 2003, 33, 119–126.
[6] Tu, S. J.; Gao, Y.; Guo, C.; Shi, D.; Lu, Z. Synth Com-
mun 2002, 32, 2137–2141.
[7] Li, J. T.; Xu, W. Z.; Yang, L. C.; Li, T. S. Synth Com-
mun 2004, 34, 4565–4571.
[8] Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetra-
hedron 2003, 59, 3753–3760.
2-Amino-3-cyano-4-(4ꢁ-methylphenyl)-7,7-dime-
thyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (4j):
mp 211–213◦C (lit. [13] 210–213◦C); FT-IR (KBr)
ν: 3426, 3333, 3224, 2924, 2193, 1677, 1599, 1369,
1
1035 cm−1. H NMR (d6-DMSO, 300 MHz) δ: 0.91
(s, 3H, CH3), 0.99 (s, 3H, CH3), 2.05 (d, J = 16.1 Hz,
1H, H-6), 2.21 (d, J = 16.1 Hz, 1H, Hꢁ-6), 3.57 (s,
2H, CH2), 4.08 (s, 1H, CH), 6.98 (d, J = 8.1 Hz, 2H,
ArH), 7.05 (d, J = 8.4 Hz, 2H, ArH) ppm; 13C NMR
(d6-DMSO, 75 MHz), δ: 21.52 (CH3), 27.66 (CH3),
29.36 (CH3), 32.72 (C-7), 36.09 (C-4), 40.12 (C-8),
50.89 (C-6), 59.30 (C-3), 113.77 (C-4a), 120.71 (CN),
128.00 (2C ), 129.80 (2C ), 236.53 (C ), 142.75
(C ), 159.33 (C-2), 163.21 (C-8a), 196.55 (C O)
ppm.
[9] Jin, T.-S.; Wang, A.-Q.; Zhang, J.-S.; Zhang, F.-S.; Li,
T.-S. Chin J Org Chem 2004, 24, 1598–1600.
[10] Wang, L.-M.; Shao, J.-H.; Tian, H.; Wang, Y.-H.; Liu,
B. J Fluorine Chem 2006, 127, 97–100.
[11] Balalaie, S.; Bararjanian, M.; Sheikh-Ahmadi, M.;
Hekmat, S.; Salehi, P. Synth Commun 2007, 37,
1097–1108.
[12] Devi, I. Bhuyan, P. J. Tetrahedron Lett 2004, 45,
8625–8627.
[13] Balalaie, S.; Sheikh-Ahmadi, M.; Bararjanian, M.
Catal Commun 2007, 8, 1724–1728.
[14] Ranu, B. C.; Banerjee, S.; Roy, S. Indian J Chem B
2008, 47, 1108–1112.
SUPPLEMENTARY INFORMATION
Spectral data of different compounds are available
from the corresponding author (e-mail: tlyq@jnu.
edu.cn) on request.
[15] Lian, X.-Z.; Huang, Y.; Li, Y.-Q.; Zheng, W.-J.
Monatsh Chem 2008, 139, 129–131.
[16] Balalaie, S.; Bararjanian, M.; Amani A. M.;
Movassagh, B. Synlett 2006, 263–266.
[17] Gokel, G. W.; Garcia, B. J. Tetrahedron Lett 1978, 19,
1743–1746.
REFERENCES
[1] Green, G. R.; Evans, J. M.; Vong, A. K. In Compre-
hensive Heterocyclic Chemistry II; A. R. Katritzky,
Heteroatom Chemistry DOI 10.1002/hc