Three-component one-pot synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives in aqueous media

Article abstract of DOI:10.1081/SCC-200043224

6-Amino-5-cyano-4-aryl-1,4-dihydropyrano[2,3-c]pyrazoles were synthesized by three-component reaction of aromatic aldehydes, malononitrile, and 3-methyl-1-phenyl-2-pyrazolin-5-one using triethylbenzylammonium chloride (TEBA) as catalyst in aqueous media.

Full text of DOI:10.1081/SCC-200043224

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Three‐Component
One‐Pot Synthesis of
1,4‐Dihydropyrano[2,3‐c]pyrazole
Derivatives in Aqueous Media
Daqing Shi a b , Jie Mou a , Qiya Zhuang a b , Lihui
Niu a , Nan Wu a & Xiangshan Wang a b
a Department of Chemistry, Xuzhou Normal
University, Xuzhou, 221116, P.R. China
b The Key Laboratory of Biotechnology on Medical
Plant of Jiangsu Province, Xuzhou, P.R. China
Version of record first published: 10 Jan 2011
To cite this article: Daqing Shi, Jie Mou, Qiya Zhuang, Lihui Niu, Nan
Wu & Xiangshan Wang (2004): Three‐Component One‐Pot Synthesis of
1,4‐Dihydropyrano[2,3‐c]pyrazole Derivatives in Aqueous Media, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:24, 4557-4563
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4557–4563, 2004
Three-Component One-Pot Synthesis of 1,4-
Dihydropyrano[2,3-c]pyrazole Derivatives
in Aqueous Media
1
Daqing Shi,1,2, Jie Mou, Qiya Zhuang,1,2 Lihui Niu,1
*
Nan Wu,1 and Xiangshan Wang1,2
1Department of Chemistry, Xuzhou Normal University,
Xuzhou, P.R. China
2The Key Laboratory of Biotechnology on Medical Plant
of Jiangsu Province, Xuzhou, P.R. China
ABSTRACT
6-Amino-5-cyano-4-aryl-1,4-dihydropyrano[2,3-c]pyrazoles were synthe-
sized by three-component reaction of aromatic aldehydes, malononitrile,
and 3-methyl-1-phenyl-2-pyrazolin-5-one using triethylbenzylammonium
chloride (TEBA) as catalyst in aqueous media. The reaction has the
advantages of good yield, less pollution, ease of separation, and of being
environment friendly.
Key Words: Aqueous media; 1,4-dihydropyrano[2,3-c]pyrazoles; One-
pot synthesis; Three component.
*
Correspondence: Daqing Shi, Department of Chemistry, Xuzhou Normal University,
Xuzhou 221116, P.R. China; E-mail: dqshi@263.net.
4557
DOI: 10.1081/SCC-200043224
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4558
Shi et al.
In recent years, the synthesis of 4H-pyran has attracted considerable inter-
est as an important intermediate of many heterocycles.[1–3] This type of
compound exhibits attractive pharmacological and biological properties as
antiallergic[4] and antitumor agents.[5,6] 2-Amino-3-cyano-4H-pyrans pos-
sesses photochemical activity.[1] Polyfunctionalized 4H-pyrans are a
common structural unit in a number of natural products.[7] The 4H-pyran
ring can be transformed to pyridine systems, which relate to pharmacologi-
cally important calcium antagonists of the DHP type.[2,8,9] 4H-pyran deriva-
tives are generally prepared by reaction of substituted cinnamicnitrile and
3-methyl-1-phenyl-2-pyrazolin-5-one in organic solvent (i.e., ethanol or
DMF) using piperidine or triethylamine as catalyst,[10] but most of them are
toxic.
The need to reduce the amount of toxic waste and by-products arising
from chemical processes requires increasing emphasis on the use of less
toxic and environmentally compatible materials in the design of new synthetic
methods. One of the most promising approaches is using water as reaction
media. Breslow, Bovy, and Hersch,[11] who showed that hydrophobic effects
could strongly enhance the rate of several organic reactions, rediscovered
the use of water as a solvent in organic chemistry in the 1980’s. Previously,
the scant solubility of the reactants was the main reason that ruled out this
solvent from studies. Further reasons that make water unique among solvents
are that it is cheap, not inflammable, and more importantly, it is not toxic.
Recently, there has been increasing recognition that water is an attractive
medium for many organic reactions.[12] Based on our previous studies on
the use of water as a solvent for carrying out carbon-carbon forming reactions
under phase transmitting catalyst,[13] here we would like to report one-pot syn-
thesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives by three-component
reaction in aqueous media.
When aromatic aldehydes (1), malononitrile (2), 3-methyl-1-phenyl-2-
pyrazolin-5-one (3), and triethylbenzylammonium chloride (TEBA) were
stirred at 908C for 6–10 h in water, the products (4) were obtained in good
yields (Sch. 1) and the results are shown in Table 1.
Scheme 1.

One-Pot Synthesis of 1,4-Dihydropyrano[2,3-c]pyrazole
4559
Table 1. The synthesis of 1,4-dihydropyrano[2,3-c]pyrazole in aqueous media.
Entry
Ar
Time (h)
Yield (%)
4a
4b
4c
4d
4e
4f
C6H5
6
6
99
99
99
98
96
89
98
99
87
90
4-CH3C6H4
4-ClC6H4
4-FC6H4
6
6
4-CH3OC6H4
4-NO2C6H4
3,4-OCH2OC6H3
2,4-Cl2C6H3
3,4-(CH3O)2C6H3
3-NO2C6H4
6
10
6
4g
4h
4i
6
8
10
4j
According to our results, we can propose the reaction mechanism shown
in Sch. 2.
In summary, the three-component reaction of aromatic aldehydes, malo-
nonitrile, and 3-methyl-1-phenyl-2-pyrazolin-5-one to 6-amino-5-cyano-
4-aryl-1,4-dihydropyrano[2,3-c]pyrazoles has been efficiently performed in
aqueous media. The easy purification of products by simple crystallization,
and the use of water as solvent combined with the exploitation of the
multicomponent strategy open to this process suggest good prospects for its
industrial applicability.
Scheme 2.

4560
Shi et al.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
IR spectra were recorded on an FTIR-8101 spectrometer in KBr with absorp-
1
tions in cm21. H NMR was measured on a Bruker 400 MHz spectrometer
in DMSO-d6 with TMS as internal standard. Elemental analyses were deter-
mined using Perkin-Elmer 2400 II elemental analyzer.
General Procedure
A mixture of the aromatic aldehydes 1 (2 mmol), malononitrile 2
(2 mmol), 3-methyl-1-phenyl-2-pyrazolin-5-one 3 (2 mmol), and TEBA
(0.15 g) in H2O (10 mL) was refluxed for 6–10 h at 908C, then cooled to
room temperature. The crystalline powder formed was collected by filtration,
washed with water, and recrystallized from ethanol to give pure (4).
4a: M.p. 168–1708C (Lit.[14] 168–1708C); 1H NMR (DMSO-d6, d, ppm):
1.78 (3H, s, CH3), 4.68 (1H, s, C4-H), 7.20 (2H, s, NH2), 7.25–7.37 (6H, m,
ArH), 7.48–7.51 (2H, m, ArH), 7.79 (2H, d, J ¼ 8.8 Hz, ArH); IR (KBr, n,
cm21): 3471, 3324, 2198, 1658, 1592, 1516, 1491, 1457, 1444, 1386, 1264,
1125, 1065, 1027, 753, 702, 685; Anal. Calcd. for C20H16N4O: C 73.15, H
4.91, N 17.06; found C 73.27, H 5.03, N 17.31.
1
4b: M.p. 176–1788C; H NMR (DMSO-d6, d, ppm): 1.78 (3H, s, CH3),
2.28 (3H, s, CH3), 4.62 (1H, s, C4-H), 7.14–7.16 (6H, m, NH2 þ ArH),
7.31–7.33 (1H, m, ArH), 7.46–7.50 (2H, m, ArH), 7.78 (2H, d, J ¼ 8.0 Hz,
ArH); IR (KBr, n, cm21): 3467, 3345, 2185, 1649, 1589, 1516, 1488,
1444, 1388, 1263, 1181, 1126, 1072, 1024, 839, 796, 759, 692, 666; Anal.
Calcd. for C21H18N4O: C 73.67, H 5.30, N 16.36; found C 73.81, H 5.07,
N 16.54.
4c: M.p. 177–1788C (Lit.[14] 174–1758C); 1H NMR (DMSO-d6, d, ppm):
1.79 (3H, s, CH3), 4.73 (1H, s, C4-H), 7.25 (2H, s, NH2), 7.29–7.34 (3H, m,
ArH), 7.41 (2H, d, J ¼ 8.0 Hz, ArH), 7.47–7.51 (2H, m, ArH), 7.78 (2H, d,
J ¼ 8.0 Hz, ArH); IR (KBr, n, cm21): 3459, 3325, 2202, 1661, 1594, 1518,
1491, 1444, 1391, 1262, 1127, 1089, 1066, 1015, 831, 804, 751, 686; Anal.
Calcd. for C20H15ClN4O: C 66.21, H 4.17, N 15.44; found C 66.29, H 3.96,
N 15.62.
1
4d: M.p. 167–1688C; H NMR (DMSO-d6, d, ppm): 1.78 (3H, s, CH3),
4.72 (1H, s, C4-H), 7.15–7.19 (2H, m, ArH), 7.22 (2H, s, NH2), 7.29–7.34
(3H, m, ArH), 7.47–7.51 (2H, m, ArH), 7.78 (2H, d, J ¼ 8.0 Hz, ArH); IR
(KBr, n, cm21): 3454, 3329, 2203, 1666, 1597, 1519, 1445, 1390, 1264,
1226, 1158, 1126, 1096, 1068, 1027, 812, 753, 685; Anal. Calcd. for
C20H15FN4O: C 69.35, H 4.37, N 16.18; found C 69.49, H 4.13, N 16.05.

One-Pot Synthesis of 1,4-Dihydropyrano[2,3-c]pyrazole
4561
4e: M.p. 173–1758C (Lit.[14] 170–1728C); 1H NMR (DMSO-d6, d, ppm):
1.78 (3H, s, CH3), 3.74 (3H, s, CH3O), 4.63 (1H, s, C4-H), 6.90 (2H, d,
J ¼ 8.4 Hz, ArH), 7.16–7.17 (4H, m, NH2 þ ArH), 7.30–7.34 (1H, m,
ArH), 7.47–7.51 (2H, m, ArH), 7.78 (2H, d, J ¼ 8.8 Hz, ArH); IR (KBr, n,
cm21): 3391, 3322, 2192, 1660, 1596, 1514, 1456, 1394, 1250, 1173, 1128,
1073, 1027, 813, 759, 692; Anal. Calcd. for C21H18N4O2: C 70.38, H 5.06,
N 15.63; found C 70.54, H 4.89, N 15.40.
4f: M.p. 192–1948C (Lit.[14] 194–1968C); 1H NMR (DMSO-d6, d, ppm):
1.79 (3H, s, CH3), 4.93 (1H, s, C4-H), 7.32–7.35 (1H, m, ArH), 7.38 (2H, s,
NH2), 7.48–7.52 (2H, m, ArH), 7.58 (2H, d, J ¼ 8.8 Hz, ArH), 7.79 (2H, d,
J ¼ 7.2 Hz, ArH), 8.23 (2H, d, J ¼ 8.4 Hz, ArH); IR (KBr, n, cm21): 3431,
3348, 2189, 1665, 1595, 1517, 1394, 1352, 1126, 1054, 831, 753; Anal.
Calcd. for C20H15N5O3: C 64.34, H 4.05, N 18.76; found C 64.25, H 4.09,
N 18.92.
1
4g: M.p. 174–1768C; H NMR (DMSO-d6, d, ppm): 1.79 (3H, s, CH3),
5.11 (1H, s, C4-H), 6.50 (2H, s, OCH2O), 7.25–7.29 (2H, m, ArH), 7.37
(1H, d, J ¼ 8.0 Hz, ArH), 7.66 (2H, s, NH2), 7.80–7.83 (1H, m, ArH),
7.97–8.00 (2H, m, ArH), 8.28 (2H, d, J ¼ 8.0 Hz, ArH); IR (KBr, n,
cm21): 3404, 3323, 2196, 1661, 1595, 1521, 1486, 1445, 1393, 1254,
1235, 1129, 1072, 1037, 926, 841, 802, 789, 759, 691; Anal. Calcd.
for C21H18N4O3: C 67.73, H 4.33, N 15.05; found C 67.94, H 4.05,
N 14.93.
1
4h: M.p. 182–1848C; H NMR (DMSO-d6, d, ppm): 1.78 (3H, s, CH3),
5.16 (1H, s, C4-H), 7.31–7.44 (5H, m, NH2 þ ArH), 7.48–7.52 (2H, m,
ArH), 7.62 (1H, s, ArH), 7.78 (2H, d, J ¼ 8.0 Hz, ArH); IR (KBr, n,
cm21): 3458, 3325, 2198, 1660, 1583, 1560, 1520, 1493, 1470, 1457,
1392, 1269, 1182, 1126, 1102, 1072, 906, 836, 815, 758, 691; Anal. Calcd.
for C20H14Cl2N4O: C 60.47, H 3.55, N 14.10; found C 60.62, H 3.43, N
14.28.
1
4i: M.p. 193–1958C; H NMR (DMSO-d6, d, ppm): 1.83 (3H, s, CH3),
3.73 (6H, s, 2 ꢀ CH3), 4.64 (1H, s, C4-H), 6.75–6.93 (3H, m, ArH), 7.15
(2H, s, NH2), 7.31–7.33 (1H, m, ArH), 7.47–7.51 (2H, m, ArH), 7.78–7.81
(2H, m, ArH); IR (KBr, n, cm21): 3450, 3320, 3200, 2965, 2200, 1660,
1598, 1510, 1450, 1390, 1261, 1150, 1135, 1035, 810, 795, 760; Anal.
Calcd. for C22H20N4O3: C 68.03, H 5.19, N 14.62; found C 68.25, H 5.03,
N 14.74.
4j: M.p. 188–1908C (Lit.[14] 188–1908C); 1H NMR (DMSO-d6, d, ppm):
1.81 (3H, s, CH3), 4.98 (1H, s, C4-H), 7.32–7.52 (5H, m, NH2 þ ArH), 7.66–
7.70 (1H, m, ArH), 7.77–7.81 (3H, m, ArH), 8.15 (2H, d, J ¼ 4.0 Hz, ArH);
IR (KBr, n, cm21): 3460, 3350, 2194, 1665, 1640, 1591, 1580, 1495, 1452,
1387, 1354, 839, 820, 776, 746; Anal. Calcd. for C20H15N5O3: C 64.34, H
4.05, N 18.76; found C 64.52, H 3.87, N 18.63.

4562
Shi et al.
ACKNOWLEDGMENTS
We are grateful to the “Surpassing Project” Foundation of Jiangsu Pro-
vince for financial support.
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Received in Japan June 18, 2004