Synthesis of 3-methyl-6-amino-5-cyano-4-aryl-1-phenyl-1,4-dihydropyrano [2,3-c]pyrazole catalysed by KF-montmorillonite

Article abstract of DOI:10.3184/030823408X282695

The reaction of substituted arylidenemalononitrilesand3-methyl-1-phenyl-2- pyrazolin-5-one in DMF in the presence of KF-montmorillonite provides a rapid synthesis of 3-methyl-6-amino-5-cyano-4-aryl-1-phenyl-1,4-dihydropyrano[2,3-c] pyrazole derivatives.

Full text of DOI:10.3184/030823408X282695

16 RESEARCH PAPER
JANUARY, 16–17
JOURNAL OF CHEMICAL RESEARCH 2008
Synthesis of 3-methyl-6-amino-5-cyano-4-aryl-1-phenyl-
1,4-dihydropyrano [2,3-c]pyrazole catalysed by KF-montmorillonite
Nan Wu*a, Xinnian Lia, Yumei Wanga and Daqing Shi*b
aDepartment of Aviation Oil and Material, Xuzhou Airforce College, Xuzhou 221000, Jiangsu, China
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou (Soochow)
University, Suzhou, China
The reaction of substituted arylidenemalononitriles and 3-methyl-1-phenyl-2-pyrazolin- 5-one in DMF in the presence
of KF-montmorillonite provides
pyrano[2,3-c]pyrazole derivatives.
a rapid synthesis of 3-methyl-6-amino-5-cyano-4-aryl-1-phenyl-1,4-dihydro-
Keywords: 1,4-dihydropyrano[2,3-c]pyrazole, KF-montmorillonite, synthesis, 4H-pyran
4H-Pyran derivatives are important building blocks for
many natural compounds1-4 with anti-allergic5 and anti-
cancer6,7 activities. Substituted pyrazole and fused pyrazole
derivatives are also important pharmaceutical products and
biodegradable agrochemicals.8 Consequently the synthesis of
1,4-dihydropyrano[2,3-c]pyrazole derivatives has an attractive
research field.
KF-montmorillonite is a catalyst possessing a high proportion
of large interlamellar spacing with some discrete spacings.
Because of its stability, selectivity and ease of separation,
KF-montmorillonite has found widespread acceptance in
a variety of heterogeneous reactions, such as substitution,9
addition,10 oxidation,11 rearrangement12-14 and reductation15,16
reactions. Montmorillonite clays have been used as acidic
catalysts for many reactions. For example, we have reported
its use as an alkaline catalyst in the synthesis of 3-aryl-
3-cyclohexeneyl propanoic ester and biscoumarins.17,18
Here, we describe the first example of the application of the
KF-montmorillonite solid system as the basic system for
the synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives
in DMF.
Table 1 The synthesis of 1,4-dihydropyrano[2,3-c]pyrazole in
aqueous media
Entry
Ar
Yield/%
m.p./°Cref
3a
3b
3c
3d
3e
3f
4-CH3OC6H4
3-NO2C6H4
4-BrC6H4
3,4-(CH3O)2C6H3
4-FC6H4
2-ClC6H4
2,4-Cl2C6H3
4-NO2C6H3
4-CH3C6H4
4-ClC6H4
90
80
88
80
87
80
75
83
80
92
174–17619
199–20019
191–192
193–19420
170–17220
207–208
3g
3h
3i
185–18620
196–19719
179–18120
180–18119
3j
1
characterised by their IR, H NMR and MS. The probable
mechanism for this reaction is also shown in Scheme 2.
In conclusion, we have developed a mild and efficient
method for the synthesis of 3-methyl-6-amino-5-cyano-
4-aryl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole derivatives
from substituted arylidenemalononitriles and 3-methyl-1-
phenyl-2-pyrazolin-5-one in DMF.
When substituted arylidenemalononitriles (1) and 3-methyl-
1-phenyl-2-pyrazolin- 5-one (2) were stirred at 80°C for 4–6 h
in DMF catalysed by KF-montmorillonite, 3-methyl-6-amino-
5-cyano-4-aryl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole
derivatives (3) were obtained in good to excellent yields.
The results are shown in Table 1. All the products were fully
Experimental
Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on a FT IR-8101 spectrometer
in KBr with absorptions in cm-1. 1H NMR was measured on a Bruker
400 MHz spectrometer in DMSO-d6 with TMS as internal standard.
Elemental analysis were determined using Perkin Elmer 2400
Ar
H3C
H3C
CN
CN
KF-Montmarillonite
+
HC
C
N
Ar
N
80°C
N
Ph
O
NH2
O
N
Ph
CN
1
2
3
Scheme 1
Ar
Ar
CN
CN
H3C
H3C
H3C
CN
ArHC
C
CN
N
CN
N
N
N
C
N
N
Ph
O
N
Ph
O
N
Ph
O
Ar
Ar
O
H3C
H3C
CN
NH
CN
NH2
N
N
O
N
Ph
Ph
Scheme 2
* Correspondent. E-mail: wunan_china@163.com
PAPER: 08/5019

JOURNAL OF CHEMICAL RESEARCH 2008 17
elemental analyser. KF-montmorillonite was prepared according to
the literature.21
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.
Typical procedure for the synthesis of compound 3
3-Methyl-6-amino-5-cyano-4-(4-nitrophenyl)-1-phenyl-1,
4-dihydropyrano[2,3-c]pyrazole (3h): M.p. 196–197°C (Lit.19 194–
196°C); 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 = 8.8 Hz, ArH), 7.79 (2H, d, J = 7.2 Hz,
ArH), 8.23 (2H, d, J = 8.4 Hz, ArH); IR (KBr, n, cm-1): 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.
A dry 50-ml flask was charged with KF-montmorillonite clay
(250 mg), arylidenemalononitrile (1) (2 mmol), 3-methyl-1-phenyl-
2- pyrazolin-5-one (2) (2 mmol) and DMF (15 ml). The mixture
was stirred at 80oC for 4–6 h. The solid material was filtered off.
The filtrate was poured into 200 ml water. The white solid was
filtered off, then washed with water. The crude solid was purified by
recrystallisation from 95% EtOH to give pure compound (3).
Spectroscopic data
3-Methyl-6-amino-5-cyano-4-(4-methyphenyl)-1-phenyl-1,
4-dihydropyrano[2,3-c]pyrazole (3i): M.p. 179–181°C (Lit.20: 176–
3-Methyl-6-amino-5-cyano-4-(4-methoxyphenyl)-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole (3a): M.p. 174–176°C (Lit.19: 173–
1
178°C); H NMR (DMSO-d6, d, ppm): 1.78 (3H, s, CH3), 2.28 (3H,
1
s, CH3), 4.62 (1H, s, C4-H), 7.14–7.16 (6H, m, NH2 + ArH), 7.31–
7.33 (1H, m, ArH), 7.46–7.50 (2H, m, ArH), 7.78 (2H, d, J = 8.0 Hz,
ArH); IR (KBr, n, cm-1): 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.
175°C); H 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 = 8.4 Hz, ArH), 7.16–
7.17 (4H, m, NH2 + ArH), 7.30–7.34 (1H, m, ArH), 7.47–7.51 (2H,
m, ArH), 7.78 (2H, d, J = 8.8 Hz, ArH); IR (KBr, n, cm-1): 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 70.46, H 4.90, N 15.43.
3-Methyl-6-amino-5-cyano-4-(4-chlorophenyl)-1-phenyl-
3-Methyl-6-amino-5-cyano-4-(3-nitrophenyl)-1-phenyl-1,4-
1,4-dihydropyrano[2,3-c]pyrazole (3j): M.p. 180–181°C (Lit.19
dihydropyrano[2,3-c]pyrazole (3b): M.p. 199–200°C (Lit.19:198–
1
177–178°C); H NMR (DMSO-d6, d, ppm): 1.79 (3H, s, CH3), 4.73
1
201°C); H NMR (DMSO-d6, d, ppm): 1.81 (3H, s, CH3), 4.98 (1H,
(1H, s, C4-H), 7.25 (2H, s, NH2), 7.29–7.34 (3H, m, ArH), 7.41 (2H,
d, J = 8.0 Hz, ArH), 7.47–7.51(2H, m, ArH), 7.78(2H, d, J = 8.0 Hz,
ArH); IR (KBr, n, cm-1): 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.
s, C4-H), 7.32–7.52 (5H, m, NH2 + ArH), 7.66–7.70 (1H, m, ArH),
7.77–7.81 (3H, m, ArH), 8.15 (2H, d, J = 4.0 Hz, ArH); IR (KBr, n,
cm-1): 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 64.50, H 3.89, N 18.68.
3-Methyl-6-amino-5-cyano-4-(4-bromophenyl)-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole (3c): M.p. 191–192°C; 1H NMR
(DMSO-d6, d, ppm): 1.79 (3H, s, CH3), 4.73 (1H, s, C4-H), 7.15–7.20
(2H, m, ArH), 7.22 (2H, s, NH2), 7.29–7.35 (3H, m, ArH), 7.48–
7.52(2H, m, ArH), 7.77–7.80(2H, m, ArH); IR (KBr, n, cm-1): 3454,
3329, 2203, 1665, 1596, 1518, 1494, 1444, 1390, 1264, 1226, 1126,
1068, 1027, 812, 753, 685; Anal. Calcd for C20H15BrN4O: C 58.98, H
3.71, N 13.76; found C 58.63, H 3.86, N 13.80.
Received 1 January 2008; accepted 14 January 2008
Paper 08/5015
doi: 10.3184/030823408X282695
References
1
S. Hatokeyama, N. Ochi, H. Numata and S. Takano, J. Chem. Soc., Chem.
Commun., 1988, 17, 1202.
3-Methyl-6-amino-5-cyano-4-(3,4-dimethoxyphenyl)-1-phenyl-
2
3
J. Bloxham, C.P. Dell and C.W. Smith, Heterocycles, 1994, 38, 399.
G.A.M. Nawwar, F.M. Abdelrazek and R.H. Swcllam, Arch. Pharm.,
1991, 342, 875.
1,4-dihydropyrano[2,3-c]pyrazole (3d): M.p. 193–194°C(Lit.20:
1
193–195°C); 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), 7.80
(2H, d, J = 8.0 Hz, ArH); IR (KBr, n, cm-1): 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.
4
5
J. Zamocka, E. Misikova and J. Durinda, Pharmazie, 1991, 46, 610.
E.C. Witte, P. Neubert and A. Roesoh, Ger Offen DE3427985, 1986.
[Chem. Abstr. 1986, 104:224915f].
6
T. Hyama and H. Saimoto, Jpn. KoKai Tokkyo Koho, JP 62181276, 1987.
[Chem. Abstr. 1988, 108:37645p].
7
J.L. Wang, D. Liu, Z.J. Zhang, S. Shan, X. Han, S.M. Srinivasula,
C.M. Croce, E.S. Alnemri and Z. Huang, Proc. Natl. Acad. Sci. USA,
2000, 97, 7124.
3-Methyl-6-amino-5-cyano-4-(4-fluorophenyl)-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazole (3e): M.p. 170–172°C (Lit.20: 167–
168°C); 1H NMR(DMSO-d6) d: 1.78(s, 3H, CH3), 4.72(s, 1H, C4-H),
7.15–7.19(m, 2H, ArH), 7.22(s, 2H, NH2), 7.29–7.34(m, 3H, ArH),
7.47–7.51(m, 2H, ArH), 7.78(d, J = 8 Hz, 2H, ArH); IR(KBr) n: 3454,
3329, 2203, 1666, 1597, 1519, 1445, 1390, 1264, 1226, 1158, 1126,
1096, 1068, 1027, 812, 753, 685 cm-1; Anal. Calcd for C20H15FN4O:
C 69.35, H 4.37, N 16.18; found C 69.49, H 4.13, N 16.05.
3-Methyl-6-amino-5-cyano-4-(2-chlorophenyl)-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (3f): M.p. 207–208°C; 1H NMR (DMSO-
d6, d, ppm): 1.80 (3H, s, CH3), 4.72 (1H, s, C4-H), 7.23–7.25 (4H,
m, NH2 + ArH), 7.31–7.35 (1H, m, ArH), 7.48–7.56 (4H, m, ArH),
7.78–7.80 (2H, m, ArH); IR (KBr, n, cm-1): 3450, 3324, 2199, 1660,
1594, 1518, 1488, 1391, 1127, 1126, 1070, 1010, 752, Anal. Calcd
for C20H14Cl2N4O: C 66.21, H 4.17, N 15.44; found C 66.30, H 4.23,
N 15.51.
8
9
Y.A. Monamed, M.A. Zahran, M.M.Ali,A.M. El-AgrodyandU.H. El-Said,
J. Chem. Res.(s), 1995, 32.
A. Cornelis, C. Dony, P. Laszlo and K.M. Nsunda, Tetrahedron Lett.,
1991, 32, 1423.
10 M.E.F. Braibante, H.S. Braibante, L. Missio and A. Andricopulo,
Synthesis, 1994, 898.
11 A. Cornelis and P. Laszlo, Synthesis, 1980, 849.
12 V. Hauke, J.M. Trendel and P. Albrecht, Tetrahedron Lett., 1994, 35,
2227.
13 S. Chalais, P. Laszlo and A. Mathy, Tetrahedron Lett., 1986, 27, 2627.
14 W.G. Dauben, J.M. Cogen and V. Behar, Tetrahedron Lett., 1990, 31,
3241.
15 K. Mukkanti, Y.V.S. Rao and B.M. Choudary, Tetrahedron Lett., 1989,
30, 251.
16 B.M. Choudary and K.K. Rao, Tetrahedron Lett., 1992, 33, 121.
17 D.Q. Shi, Q.Y. Zhuang, L.C. Rong, J.X. Wang and X.S. Wang, J. Xuzhou
Normal University (Natural Science Edition), 2003, 21, 37.
18 N. Wu, X.N. Li, X. Xu and D.Q. Shi, J. Chem. Res.(S), 2007, 561.
19 J.F. Zhou, S.J. Tu, Y. Gao and M. Ji, Chin. J. Org. Chem., 2001, 21, 742.
20 D.-Q. Shi, J. Mou, Q.-Y. Zhuang, L.H. Niu, N. Wu and X.S. Wang, Syn.
Comm., 2004, 34, 1.
3-Methyl-6-amino-5-cyano-4-(2,4-dichlorophenyl)-1-phenyl-1,
4-dihydropyrano[2,3-c]pyrazole (3g): M.p. 185–186°C (Lit.20: 182–
1
184°C); H NMR (DMSO-d6, d, ppm): 1.78 (3H, s, CH3), 5.16 (1H,
s, C4-H), 7.31–7.44 (5H, m, NH2 + ArH), 7.48–7.52 (2H, m, ArH),
7.62 (1H, s, ArH), 7.78 (2H, d, J = 8.0 Hz, ArH); IR (KBr, n, cm-1):
3458, 3325, 2198, 1660, 1583, 1560, 1520, 1493, 1470, 1457, 1392,
21 D.Q. Shi, X.S. Wang, C.S. Yao and L.C. Rong, J. Chem. Res.(S), 2002,
344.
PAPER: 08/5019