Ionic liquid catalyzed one-pot, three component synthesis of dihydropyrano[2,3-c]pyrazole under green conditions

Article abstract of DOI:10.14233/ajchem.2016.20008

A new series of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives were synthesized, where the three-component reaction of ethyl 3-oxobutanoate, hydrazinehydrate, aromatic aldehyde and malononitrile performed under green

Full text of DOI:10.14233/ajchem.2016.20008

Asian Journal of Chemistry; Vol. 28, No. 11 (2016), 2441-2445
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.20008
Ionic Liquid Catalyzed One-Pot, Three Component Synthesis of
Dihydropyrano[2,3-c]pyrazole under Green Conditions
1,*
1
1
1
2
S. YAKAIAH , G. BUCHAPPA , K. DURGAPRASAD , K. RAVIBABU and P. APARNA
1Natco Research Centre, B-13, Industrial Estate, Sanathnagar, Hyderabad-500 018, India
2Jawaharlal Nehru Technological University, Hyderabad-500 085, India
*Corresponding author: Fax: +91 40 23710578; Tel: +91 40 23710575; E-mail: prasannasargam1984@gmail.com
Received: 4 April 2016; Accepted: 30 June 2016; Published online: 10 August 2016;
AJC-18014
A new series of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives were synthesized, where the
three-component reaction of ethyl 3-oxobutanoate, hydrazinehydrate, aromatic aldehyde and malononitrile performed under green conditions
by using ionic liquid [Bmim]BF4 as reaction media. This method has the several advantages such as good yields, shorter reaction time,
operational simplicities and eco-friendliness. The chemical structures of all the synthesized compounds were well characterized by
physical, analytical and spectroscopic techniques.
Keywords: Multi-component reaction, Ionic liquid, Dihydropyrano[2,3-c]pyrazole.
However, after literature survey, we found that their poor
yields, tedious workup procedures, time and resource-wasting
procedures, have occurred along with these multistage proce-
dures dihydropyrano[2,3-c]pyrazole [16-20]. Further research
suggested that the ionic liquid [Bmim]BF4 catalyzed multi-
component condensations of ethyl 3-oxobutanoate, hydrazine
hydrate, with the precursors of various aromatic aldehyde
and malononitrile can be taken up for improving the work up
methodology (Scheme-I).
INTRODUCTION
In the past decade, ionic liquids have gained considerable
attention of academic researchers and chemical industry as
potential “green” substitutes for conventional organic solvents
[1,2]. The “green” aspect of ionic liquids is mainly derived
from their undetectable vapour pressure, flammability and
toxicity thereby reducing air pollution [3]. Because of the
serious pollution problems and minimizing environmental risks
to designing new green technologies [4] attained researchers
attention in recent year. Ionic liquids (ILs) have attracted
increasing interest in heterocyclic synthesis, because they can
provided green and efficient medium for heterocyclic reactions
[5,6]. In parallel with use of ionic liquids in organic reactions,
they have also been used as reaction medium for multicom-
ponent reactions (MCRs) [7]. In this view, eco-environmental
technologies in “green chemistry”, have become more
favoured in organic chemistry [8,9]. Heterocyclic containing
the dihydropyrano[2,3-c]pyrazole derivatives are important
targets in synthetic and medicinal chemistry since this fragment
is a key moiety to exhibit various biological activities, such as
antimicrobial [10], antioxidants [11] and anticancer [12]. Some
of cathepsin S inhibitors [13], protein tyrosine phosphatase
inhibitors [14] and plasmodial serinehydroxymethyltransferase
(SHMT) [15] have dihydropyrano[2,3-c]pyrazole (DHP) moiety
as a part of the core structure. Hence, the synthesis of dihydro-
pyrano[2,3-c]pyrazole is of considerable interest for both organic
chemistry and medicinal chemistry.
EXPERIMENTAL
All reagents were commercially available and used as
without further purification. Reaction progress was observed
by thin layer chromatography (TLC) making use of aluminium
sheets pre-coated with silica gel 60F254, purchased from
Merck. Column chromatography made using silica gel 60, 100-
200 mesh. The IR spectral data of all the compounds were
recorded on Bruker FT-IR spectrometer (Model: TENSOR-
27), KBr from 400 to 4000 cm-1. The 1H NMR and 13C NMR
were recorded on BRUKERAVANCE-III 400 MHz, 100 MHz
by using DMSO-d6 as a solvent and tetramethylsilane as internal
standard. Mass spectra were recorded on Waters Quattro micro
triple quadrapole Mass spectrometer. Elemental analyses
(CHN) were performed on Q-Toff-2010 elemental analyzer.
General procedure for the synthesis of dihydropyrano-
[2,3-c]pyrazole derivatives: (5a-l): A mixture of ethyl 3-
oxobutanoate (1 mmol), hydrazine hydrate (1 mmol), 4-chloro-
benzaldehyde (1 mmol), malononitrile (1 mmol) and [Bmim]BF4

2442 Yakaiah et al.
Asian J. Chem.
were refluxed at 70 °C for 1 h.After the reaction was completed
as indicated by TLC, the reaction mixture was allowed to the
room temperature. Water was added to the reaction mixture
and the resulting solid was collected by filtration, washed with
water and followed by drying under vacuum. Further purifi-
cation, of the solid product was carried out by using silica gel
column chromatography (1:1, ethyl acetate: hexane) to afford
the title compound 5a-l. All the synthesized compounds were
Hz), 160.90, 154.70, 143.47, 135.68, 129.36 (d, JC-F, 20.0 Hz),
117.35(d, JC-F, 16.0 Hz), 120.64, 97.20, 56.77, 35.55, 9.72;
MS (ES m/z): 271.03[M + H]+; Anal. calcd. for C14H11N4OF;
C, 62.16; H, 4.07; N, 20.72; Found: C, 62.22; H, 4.10; N,
20.73.
6-Amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5e): White solid; m.p.:
190- 194 °C; IR (KBr, νmax, cm-1): 3414, 3373, 3314 (N-H),
3170 (Ar C-C), 2972 (aliphatic C-C), 2186 (C≡N), 1653
(C=N), 1609 (C=C), 1595, 1349 (N-O) 1491(N-H), 1411 (C-
N), 1048 (C-O); 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.77
(s, 3H, CH3), 5.09 (s, 1H, CH), 7.04 (br s, 2H, NH2), 7.32 (dd,
J = 8.0 0.8 Hz, 1H, Ar-CH), 7.47-7.51 (m, 1H, Ar-CH), 7.64-
7.68 (m, 1H, Ar-CH), 7.85 (dd, J = 8.0 0.4 Hz, 1H, Ar-CH),
12.21 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ ppm):
161.20, 154.98, 149.16, 137.61, 135.77, 133.38, 131.30,
128.34, 123.61, 120.27, 96.40, 56.06, 31.44, 9.51MS (ES m/z):
298.09 [M + H]+; Anal. calcd. for C14H11N5O3; C, 56.56; H,
3.73; N, 23.56; Found: C, 56.20; H, 3.65; N, 23.36.
6-Amino-3-methyl-4-(3-nitrophenyl)-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5f): Off white solid;
m.p.: 228- 230 °C; IR (KBr, νmax, cm-1): 3473, 3224 (N-H),
3115 (Ar C-C), 2932 (aliphatic C-C), 2194 (C≡N), 1652
(C=N), 1609 (C=C), 1596, 1348 (N-O) 1492 (N-H), 1401 (C-
N), 1043 (C-O); 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.81
(s, 3H, CH3), 4.88 (s, 1H, CH), 7.06 (br s, 2H, NH2), 7.63-
7.69 (m, 2H, Ar-CH), 8.02-8.03 (m, 1H, Ar-CH), 8.11-8.14
(m, 1H, Ar-CH), 12.22 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6, δ ppm): 161.15, 154.70, 147.89, 146.83, 135.92,
134.39, 130.25, 121.99, 121.85, 120.52, 96.67, 56.16, 35.65,
9.76MS (ES m/z): 298.23 [M + H]+; Anal. calcd. for
C14H11N5O3; C, 56.56; H, 3.73; N, 23.56; Found: C, 56.92; H,
3.78; N, 23.23.
1
characterized by their melting point, IR, H NMR, 13C NMR
and mass spectra and elemental analysis.
6-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (5a): Off white solid; m.p.: 238-
240 °C; IR (KBr, νmax, cm-1): 3372, 3169 (N-H), 3021 (Ar C-
C), 2875 (aliphatic C-C), 2192 (C≡N), 1648 (C=N), 1610
(C=C), 1489 (N-H), 1401, (C-N), 1160 (C-O); 1H NMR (400
MHz, DMSO-d6, δ ppm): 1.78 (s, 3H, CH3), 4.59 (s, 1H, CH),
6.87 (br s, 2H, NH2), 7.15-7.17 (d, J = 7.2 Hz, 2H, Ar-CH),
7.20-7.24 (t, J = 7.2 Hz, 1H, Ar-CH), 7.29-7.33 (t, J = 7.2 Hz,
2H, Ar-CH) 12.09 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6, δ ppm): 160.83, 154.73, 144.40, 135.52, 128.38, 127.42,
126.68, 120.72, 97.59, 57.19, 36.22, 9.69; MS (ES m/z): 251.10
[M + H]+; Anal. calcd. for C14H12N4O; C, 66.59; H, 4.75; N,
22.19; Found: C, 66.65; H, 4.79; N, 22.21.
6-Amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-5- carbonitrile (5b): Yellow solid;
m.p.: 208-211 °C; IR (KBr, νmax, cm-1): 3482, 3225 (N-H), 3103
(Ar C-C), 2960 (aliphatic C-C), 2191 (C≡N), 1642 (C=N),
1598 (C=C), 1493 (N-H), 1392 (C-N), 1259, 1052 (C-O); 1H
NMR (400 MHz, DMSO-d6, δ ppm): 1.78 (s, 3H, CH3), 3.72
(s, 3H, O-CH3), 4.53 (s, 1H, CH), 6.82 (br s, 2H, NH2), 6.87
(d, J = 8.8 Hz, 2H, Ar-CH), 7.07 (d, J = 8.4 Hz, 2H, Ar-CH),
12.07 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ ppm):
160.67, 157.96, 154.75, 136.48, 135.55, 128.48, 120.82,
113.75, 97.88, 57.62, 54.99, 35.43, 9.74. MS (ES m/z): 283.12
[M + H]+; Anal. calcd. for C16H17N5O; C, 63.82; H, 5.00; N,
19.85; Found: C, 63.40; H, 5.05; N, 19.36.
6-Amino-4-(4-chlorophenyl)-3-methyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5c): Off white solid;
m.p.: 229- 231 °C; IR (KBr, νmax, cm-1): 3479, 3235 (N-H),
3107 (Ar C-C), 2934 (aliphatic C-C), 2193 (C≡N), 1645
(C=N), 1611 (C=C), 1492 (N-H), 1395 (C-N), 1071 (C-O),
799 (C-Cl); 1H NMR (400 MHz, DMSO-d6, δ ppm): 1.79 (s,
3H, CH3), 4.63 (s, 1H, CH), 6.93 (br s, 2H, NH2), 7.19 (d, J =
8.42H,Ar-CH), 7.38 (d, J = 8.42H, Ar-CH) 12.14 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6, δ ppm): 160.90, 154.70,
143.47, 135.68, 131.23, 129.36, 128.45, 120.64, 97.19, 56.78,
35.56, 9.73; MS (ES m/z): 287.16 [M + H]+ and 289.13 [M+2]+;
Anal. calcd. for C14H11N4OCl; C, 58.65; H, 3.87; N, 19.54;
Found: C, 58.87; H, 3.95; N, 19.18.
6-Amino-4-(4-fluorophenyl)-3-methyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5d): Yellow solid;
m.p.: 227- 229 °C; IR (KBr, νmax, cm-1): 3470, 3230 (N-H),
3110 (Ar C-C), 2960 (aliphatic C-C), 2191 (C≡N), 1632 (C=N),
1615 (C=C), 1485 (N-H), 1381 (C-N), 1109 (C-F), 1045 (C-O);
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.78 (s, 3H, CH3),
4.62 (s, 1H, CH), 6.91 (br s, 2H, NH2), 7.33 (dd, J = 8.4, 5.42
H, Ar-CH), 7.38 (t, J = 9.42H, Ar-CH) 12.12 (s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6, δ ppm): 162.35 (d, JC-F, 240.0
6-Amino-3-methyl-4-(4-nitrophenyl)-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5g): Yellow solid;
m.p.: 245- 247 °CIR (KBr, νmax, cm-1): 3477, 3228 (N-H), 3117
(Ar C-C), 2971 (aliphatic C-C), 2196 (C≡N), 1650 (C=N),
1608 (C=C), 1594, 1353 (N-O) 1492 (N-H), 1401 (C-N), 1048
1
(C-O); H NMR (400 MHz, DMSO-d6, δ ppm): 2.21 (s, 3H,
CH3), 3.76 (s, 3H, CH3)4.83 (s, 1H, CH), 7.06 (br s, 2H, NH2),
7.47 (d, J = 8.8 Hz, 2H, Ar-CH), 8.21 (d, J = 8.8 Hz, 2H, Ar-
CH), 12.21 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ
ppm): 161.17, 154.70, 152.09, 146.41, 135.92, 128.85, 123.89,
120.49, 96.58, 55.98, 35.92, 9.74; MS (ES m/z): 296.06 [M -
H]-; Anal. calcd. for C14H11N5O3; C, 56.56; H, 3.73; N, 23.56;
Found: C, 56.98; H, 3.80; N, 23.17.
6-Amino-3-methyl-4-(naphthalen-1-yl)-1,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (5h): White solid;
m.p.: 218- 220 °C; IR (KBr, νmax, cm-1): 3402, 3344, 3313 (N-
H), 3162 (Ar C-C), 2924 (aliphatic C-C), 2192 (C≡N), 1654
(C=N), 1611 (C=C), 1486 (N-H), 1406 (C-N), 1050 (C-O);
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.53 (s, 3H, CH3),
5.42 (s, 1H, CH), 6.91 (br s, 2H, NH2), 7.36 (br, s1H, Ar-CH),
7.46-7.50 (m, 3H, Ar-CH), 7.83 (d, J = 8.4 Hz, 1H, Ar-CH)
7.95 (d, J = 9.6 Hz, 1H, Ar-CH), 8.16-8.20 (m, 1H, Ar-CH)
12.07 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ ppm):
160.82, 154.79, 135.50, 133.69, 130.72, 128.82, 127.54,
126.91, 125.79, 125.51, 123.25, 120.59, 98.07, 57.46, 9.72;

Vol. 28, No. 11 (2016)
Ionic Liquid Catalyzed One-Pot, Three Component Synthesis of Dihydropyrano[2,3-c]pyrazole 2443
MS (ES m/z): 303.25[M + H]+; Anal. calcd. for C18H14N4O; C,
71.51; H, 4.67; N, 18.53; Found: C, 71.97; H, 4.72; N, 18.12.
6-Amino-4-(3-chloroisoquinolin-4-yl)-3-methyl-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5i): Yellow
solid; m.p.: 198- 201 °C; IR (KBr, νmax, cm-1): 3448, 3254, (N-
H), 3124 (Ar C-C), 2924 (aliphatic C-C), 2183 (C≡N), 1692,
1638 (C=N), 1489 (N-H), 1399 (C-N), 1044 (C-O); 1H NMR
(400 MHz, DMSO-d6, δ ppm): 1.78 (s, 3H, CH3), 5.20 (s, 1H,
CH), 7.15 (br s, 2H, NH2), 7.54-7.58 (m, 1H, Ar-CH), 7.65-
7.79 (m, 2H, Ar-CH) 7.97-8.08 (m, 1H, Ar-CH), 8.62 (s1H,
Ar-CH)12.09 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ
ppm): 161.51, 156.76, 140.22, 139.52, 137.18, 136.71, 135.59,
130.82, 130.66, 127.94, 127.71, 125.92, 125.50, 120.43,
116.79, 93.82, 48.70, 9.69; MS (ES m/z): 338.01[M + H]+;
Anal. calcd. for C17H12N5OCl; C, 60.39; H, 3.56; N, 20.72;
Found: C, 60.45; H, 3.58; N, 20.73.
6-Amino-4-(7-methoxy-2-naphthyl)-3-methyl-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5j): Yellow
solid; m.p.: 238- 240 °C; IR (KBr, νmax, cm-1): 3472, 3205, (N-
H), 3109 (Ar C-C), 2956 (aliphatic C-C), 2185 (C≡N), 1623
(C=N), 1465 (N-H), 1381 (C-N), 1152, 1045 (C-O); 1H NMR
(400 MHz, DMSO-d6, δ ppm): 1.75 (s, 3H, CH3), 3.76(s, 3H,
O-CH3), 4.71 (s, 1H, CH), 6.92 (br s, 2H, NH2), 7.20-7.25 (m,
2H, Ar-CH), 7.30 (d, J = 2.2 Hz, 1H, Ar-CH) 7.61 (s, 1H, Ar-
CH), 7.73 (d, J = 8.0 Hz, 1H, Ar-CH), 7.80 (d, J = 9.2 Hz, 1H,
Ar-CH), 12.09 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 160.88, 157.51, 154.77, 141.22, 135.58, 131.93,
130.78, 129.35, 126.68, 126.63, 126.20, 120.20, 118.72,
106.71, 97.65, 57.16, 55.46, 36.24, 9.75; MS (ES m/z): 333.16
[M + H]+; Anal. calcd. for C19H16N4O2; C, 68.60; H, 4.81; N,
16.84; Found: C, 68.66; H, 4.85; N, 16.86.
solid; m.p.: 204- 207 °C IR (KBr, νmax, cm-1): 3384, 3304 (N-
H), 3007 (Ar C-C), 2917 (aliphatic C-C), 2189 (C≡N), 1644
(C=N), 1612 (C=C), 1488(N-H), 1396 (C-N), 1139 (C-O)1H
NMR (400 MHz, DMSO-d6, δ ppm): 1.78 (s, 3H, CH3), 2.86
(s, 6H, N-CH3), 4.45 (s, 1H, CH), 6.65 (d, J = 8.4 Hz, 2H, Ar-
CH), 6.76 (br s, 2H, NH2), 6.96 (d, J = 8.8 Hz, 2H, Ar-CH),
12.03 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6, δ ppm):
160.55, 154.79, 149.22, 135.48, 132.03, 127.96, 120.93,
112.32, 98.18, 58.03, 40.18, 35.36, 9.76; MS (ES m/z): 296.15
[M + H]+; Anal. calcd. for C16H17N5O; C, 65.07; H, 5.80; N,
23.71; O, 5.42; Found: C, 65.40; H, 5.86; N, 23.36.
6-Amino-3-methyl-4-(7-methylnaphthalen-2-yl)-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5l): Off white
solid; m.p.: 240- 242 °C; IR (KBr, νmax, cm-1): 3482, 3256, (N-
H), 3102 (Ar C-C), 2961 (aliphatic C-C), 2190 (C≡N), 1640
(C=N), 1595 (C=C), 1492(N-H), 1390 (C-N), 1056 (C-O); 1H
NMR (400 MHz, DMSO-d6, δ ppm): 1.74 (s, 3H, CH3), 3.86(s,
3H, Ar-CH3), 4.72 (s, 1H, CH), 6.91 (br s, 2H, NH2), 7.13-
7.20 (m, 2H, Ar-CH), 7.29 (d, J = 2.4 Hz, 1H, Ar-CH)7.67 (s,
1H, Ar-CH), 7.75 (d, J = 8.4 Hz, 1H, Ar-CH), 7.81 (d, J = 9.2
Hz, 1H, Ar-CH), 12.11 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6, δ ppm): 160.84, 157.19, 154.81, 139.33, 135.77,
133.35, 129.15, 128.17, 127.27, 126.28, 125.55, 120.81,
118.65, 105.94, 97.57, 57.33, 55.18, 36.34, 9.70; MS (ES m/z):
333.11 [M + H]+; Anal. calcd. for C19H16N4O; C, 72.13; H,
5.10; N, 17.71; Found: C, 72.83; H, 5.17; N, 17.26.
RESULTS AND DISCUSSION
To show the merit of [Bmim]BF4 ionic liquid as a solvent-
catalyst system in synthesis of dihydropyrano[2,3-c]pyrazole
is shown in Scheme-I. At the onset of our work, ionic liquids
shown in Table-1. We applied this solvent-catalyst system for
6-Amino-4-(4-(dimethyl amino) phenyl)-3-methyl-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5k): Yellow
R
CHO
CN
CN
[Bmim]BF4
70 °C, 2 h
O
CN
N
+
NH2NH2.H2O
+
N
O
O
N
O
R
1
2
3a-l
4
5a-l
Scheme-I
TABLE-1
OPTIMIZATION CONDITIONS FOR THE SYNTHESIS OF DIHYDROPYRANO[2,3-c]PYRAZOLE DERIVATIVES (5a-l)
Entry
1
2
3
4
5
6
7
Catalyst (mol %)
No catalyst
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
–
Temperature (°C)
Time (h)
Yield (%)a
Trace
46
70
70
70
70
70
70
70
70
90
50
12
6
8
5
3
1
1
1
5
5
AcOH
FeCl3 (15)
ZnCl3 (15)
AlCl3 (15)
68
72
56
80
92
92
92
82
[Bmim]BF4 (10)
[Bmim]BF4 (15)
[Bmim]BF4 (20)
[Bmim]BF4 (15)
[Bmim]BF4 (15)
–
–
–
–
8
9
10
aIsolated yields.

2444 Yakaiah et al.
Asian J. Chem.
TABLE-2
SYNTHESIS OF DIHYDROPYRANO[2,3-c]PYRAZOLE DERIVATIVES (5a-l)
Entry
1
2
3
4
5
6
7
8
Product
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
R
H
R1
H
H
H
H
H
3-NO2
H
R2
H
H
H
H
2-NO2
H
H
Time (h)
Yield (%)
92
1
1
1
1
1
1
1
1
1
1
1
1
4-OCH3
4-Cl
4-F
90
90
88
89
86
90
92
88
H
H
4-NO2
C6H5
Quinoline
C6H5-OCH3
N(CH3)2
C6H5-CH3
C6H5
C6H5
9
Quinoline
C6H5-OCH3
H
Quinoline
C6H5-OCH3
H
10
11
12
85
88
90
C6H5-CH3
C6H5-CH3
multicomponent reaction. The reaction of ethyl 3-oxobutanoate
(1 mmol), hydrazinehydrate (1 mmol), aromatic aldehyde (1
mmol) and malononitrile (1 mmol), was examined in the
presence of the optimization conditions that are summarized
in Table-2. It was observed that almost all of the investigated
ionic liquid was capable of solvent-catalyst system of the
synthesis of desired dihydropyrano[2,3-c]pyrazole derivatives
under convenient method at 70 °C for 2 h. Further optimization
studies revealed that when the reaction was carried out acidic
ionic liquid such as [Bmim]Br, [Bmim]Cl and [Bmim]PCl5 as
a solvent-catalysts, under refluxing conditions resulted 5a in
isolated yield of 68, 72 and 56 %, respectively (Table-1, entries
3, 4 and 5). In this work, [Bmim]BF4 was found to effective
solvent-catalyst system for the synthesis of dihydropyrano[2,3-
c]pyrazole as evidenced from the obtained superior results.
[Bmim]BF4 has a dual role to act as catalyst and solvent at 70
°C the reaction time was reduced from 2 h to 1 h with improved
isolated yield (92 %) (Table-1, entry 7). No further improve-
ment in isolated yield was observed by increasing the reaction
time and temperature (Table-1, entry 9 and 10).
A series of dihydropyrano[2,3-c]pyrazole derivatives were
synthesized with excellent yield under conventional method
as shown in Table-2. The reaction was conducted with aromatic
aldehydes contain both electron donating and withdrawing
substituents were found to show no significant effect on the
formation of the final product (Table-2). The 1H NMR of the
compounds (5a) exhibited characteristic peaks of benzylic
proton as singlet at 4.59 ppm, amino group (NH2) attached
tertiary carbon protons at 6.87 ppm and aromatic protons at
7.31 (t), 7.22 (t) and 7.17 (d) indicating the presence of phenyl
group.Additionally, the 13C NMR of the final products showed
characteristic peaks at δ 97.59 ppm which is due to benzylic
carbon and peaks at δ 120.72 ppm due to nitrile carbon group.
The IR spectra of the final compounds displayed absorption
bands at 3372, 3169 and 2192 cm-1, respectively. Absence
of the absorption stretching frequencies of corresponding
NH2, NH and C≡N of the starting materials clearly indicates
the formation of the final product, The formation of desired
product can be achieved via condensation ethyl 3-oxobuta-
noate (1) hydrazine hydrate (2) to form pyrazolone with the
possible intermediate A. Treatment of the intermediate A with
pyrazolone under green condition to form intermediate B
followed by intermolecular proton transfer affords compound
5a.
H3C
H
N
+
BF4
N
Bu
O
CN
H
CN
CN
CN
N
NH2
N
H
O
CN
N
H
N
H
CN
O
CN
C N
N
NH
CH3
N
N
H
O
H
H
O
B
N
N
N
H
Bu
BF4
IL
A
Scheme-II
Conclusion
The combination of ionic liquids with ethyl 3-oxobuta-
noate, hydrazine hydrate, aromatic aldehyde and malononitrile
under green condition was effective for effective for the one-
pot and eco-friendly synthesis of biologically interesting
dihydropyrano[2,3-c]pyrazole derivatives. [Bmim]BF4 was
found to the effective ionic liquid for the synthesis of these
multicomponent reactions. Therefore, we strongly believe that
these eco-efficient and green protocols be of great value for both
synthetic and medicinal chemistry for practical applications.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the support of Natco
Pharma Limited & Natco Research Centre, Hyderabad, India
for providing the research facilities and also for analytical data
like NMR and mass spectral data.

Vol. 28, No. 11 (2016)
Ionic Liquid Catalyzed One-Pot, Three Component Synthesis of Dihydropyrano[2,3-c]pyrazole 2445
12. H. Kumar, D. Saini, S. Jain and N. Jain, Eur. J. Med. Chem., 70, 248 (2013).
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