An efficient four-component, one-pot synthesis of 6-amino-4-aryl-3-methyl- 2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles under phase-transfer catalyst

Article abstract of DOI:10.2174/157017812803521135

A series of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5- carbonitriles (5a-5j) were synthesized by four-component one-pot reaction of methyl acetoacetate (or ethyl acetoacetate), hydrazine hydrate, arylaldehydes and malononitrile in the pre

Full text of DOI:10.2174/157017812803521135

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Letters in Organic Chemistry, 2012, 9, 639-643
639
An Efficient Four-Component, One-Pot Synthesis of 6-Amino-4-Aryl-3-
Methyl-2,4-Dihydropyrano[2,3-C]Pyrazole-5-Carbonitriles Under Phase-
Transfer Catalyst
Keyume Ablajan*, Wang Liju, Anagu Tuoheti and Yakefujiang Kelimu
Key Laboratory of Oil & Gas Fine Chemical, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of
Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R. China
Received July 31, 2012: Revised August 26, 2012: Accepted August 29, 2012
Abstract: A series of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles (5a–5j) were synthe-
sized by four-component one-pot reaction of methyl acetoacetate (or ethyl acetoacetate), hydrazine hydrate, arylaldehydes
and malononitrile in the presence of phase transfer catalyst. A highest yield of product was obtained while using 30 mol %
of HDBAC as a catalyst.
Keywords: Four-component reaction, one-pot synthesis, phase-transfer catalysis, pyrano[2,3-c]pyrazole.
INTRODUCTION
til now, there has been no report of using HDBAC as a cata-
lyst in the multi-componet one-pot reaction.
Multi component reaction (MCR) is a chemical process
for the formation of a new compound that contains all the
components of main structural fragments by the reaction of
three or more compounds through one pot route [1]. A fast
synthesis of large amounts of structural diversity can be im-
plemented and establishing an appropriate compound library
by using MCR method, thus it is widely used in new drug
development and total synthesis of natural products [2].
In this article, to search a high yield method for the
preparation of 6-amino-4-aryl-3-methyl-2,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitriles (5a–5j) (Scheme 1), four
kinds of phase-transfer catalysts were used in four compo-
nent one pot reaction, respectively. The results revealed that
the highest yields of products were obtained while using
hexadecyl dimethyl benzyl ammonium chloride (HDBAC)
as a catalyst. In addition, when ethyl acetoacetate was re-
placed by methyl acetoacetate, an increasing yield of around
10% was observed. The structures of resulting products were
4
H-Pyran is the structural unit forming bioactive natural
products [3], which received much attention in terms of drug
synthesis due to its wide variety of pharmacological and
physiological activities [4-5]. Pyrano[2,3-c]pyrazoles are
important heterocycles possessing a wide range of biological
activities such as anti-cancer [6], anti-inflammatory [7], and
antibacterial activities [8] besides providing pest control [9].
Recently, many papers reported one-pot synthetic method of
multi-substituted pyrano[2,3-c]pyrazole-5-carbonitriles[10–
1
confirmed and characterized by using of IR, H-NMR and
ESI-MS spectral methods. The current research has to pro-
vide an efficient phase transfer catalyst for the synthesis of
multi-substituted pyrano[2,3-c] pyrazoles.
RESULTS AND DISCUSSION
1
6]. Thus, the synthesis of pyrano[2,3-c]pyrazoles has be-
come one of the hot issues in organic synthesis and medici-
nal chemistry. Green method is one of the optimal ap-
proaches in the synthesis of bioactive heterocylces. Phase-
transfer catalysts have many advantages and important appli-
cation in organic synthesis, such as speeding up of reaction
rate, simplification of operations, lower reaction tempera-
tures, change in the selectivity of reaction, inhibiting the
formation of by-products, resulting in increasing yields of
product [17]. The efficient and clean synthesis of pantopyra-
zole sodium [18] and benzylidenerhodanine [19] using
tetrabutylammonium bromide (TBAB) as a phase-transfer
catalyst in an aqueous medium was reported previously. Un-
In continuation of our interest in the application of multi-
component one pot reaction to the synthesis of bioactive
heterocycles, one-pot synthesis of pyrano-pyrazole derivat-
vies was investigated by using phase transfer catalyst. Until
now, there are no reports on the application of phase transfer
catalyst HDBAC in the synthesis of pyrano[2,3-c]pyrazoles.
In order to find an efficient phase transfer catalyst for the
synthesis of pyrano-pyrazoles, four kinds of catalyst were
subjected to the above reaction. The same product was ob-
tained in different yields by using different catalysts such as
benzyltriethylammonium chloride (TEBA), hexadecyl
trimethyl ammonium bromide (CTAB), hexadecyl trimethyl
ammonium chloride (CTAC) and HDBAC, respectively
(
Table 1). As the results are shown in Table 1, the yield of 5e
*
Address correspondence to this author at the Key Laboratory of Oil & Gas
Fine Chemical, Ministry of Education & Xinjiang Uyghur Autonomous
Region, College of Chemistry and Chemical Engineering, Xinjiang Univer-
sity, Urumqi 830046, P. R. China; Tel: +86-13999135640; Fax: +86-991-
obtained when using HDBAC was higher than the others.
Then the amount of catalyst was investigated. The result
revealed that the yield of product was higher (90 %) while
8
58-1249; E-mail: ablajan209@hotmail.com
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

6
40 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Ablajan et al.
Ar
O
H3C
HN
CN
HDBAC
reflux
CH3COCH2CO2R
+
NH2NH2.H2O
+
ArCHO
+
CH2(CN)2
3
4
EtOH,
1
2
N
NH2
5a-5j
R=CH3 or CH CH3
2
Ar = C6H5 (a); 4-Me-C6H4 (b); 4-OH-3-MeO-C6H4 (c); 4-F-C6H4 (d); 4-Cl-C6H4 (e); 2-Cl-C6H4 (f); 4-Br-C6H4 (g);
-NO2-C6H4 (h); 3-OH-C6H4 (i), 4-OH-C6H4 (j)
4
Scheme 1. Synthetic route for titled products 5a–5j.
Table 1. The Influence of Catalyst on the Yields of Compounds 5a–5j.
a
Entry
Product
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
7
5e
5e
5e
5e
5e
5e
5e
5e
CTAC (30 mol %)
TEBA (30 mol %)
HDBAC (30 mol %)
CTAB (30 mol %)
HDBAC (10 mol %)
HDBAC (20 mol %)
HDBAC (40 mol %)
HDBAC (50 mol %)
30
30
30
30
30
30
30
30
75
72
90
78
20
65
90
90
8
a
Isolated yield.
Table 2. The Yields of Products 5a–5j Using Different ꢀ-carbonyl Acetate in the Presence of HDBAC (30 mol %) as a Catalyst.
CH
3
COCH
2
CO
2
CH
3
(1A)
CH
3
COCH
2
CO
2
C
2
H
5
(1B )
Entry
Ar
Product
a
a
Time (min)
Yield (%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
5a
5b
5c
5d
5e
5f
30
30
30
30
30
30
30
60
60
60
80
82
79
72
90
86
84
70
70
74
45
45
45
45
45
45
45
60
60
60
73
76
65
64
81
80
80
60
60
65
4-MeC
4-HO-3-MeOC
4-FC
6 4
H
6 3
H
6
H
4
4-ClC
6
H
4
4
2-ClC
6
H
4-BrC
6
H
4
5g
5h
5i
4-NO
2
C
6
H
4
3-HOC
6
6
H
H
4
1
0
4-HOC
4
5j
a
Isolated yield.
using 30 mol % HDBAC. It has been noted that the yield of
product did not change with the increasing amount of cata-
lyst.
acetoacetate, respectively. As a result, a higher yield of
product was obtained when using methyl acetoacetate rather
than using ethyl acetoacetate which produced lower yield of
product around 5–10 % (Table 2). At last, ten products 5a–5j
were prepared under similar conditions as optimized above.
Furthermore, the yields of product were investigated us-
ing two kinds of reactants as methyl acetoacetate and ethyl

An Efficient Four-Component, One-Pot Synthesis of 6-Amino-4-
H N
Letters in Organic Chemistry, 2012, Vol. 9, No. 9 641
2
NH2
H C
CH3
N
3
H C
3
H O
O
H
CH OH
3
2
N
HN
H C
OCH3
3
N
N
N
O
H
OCH3
H
A
HO
O
O
H
CN
Ar
CN
CN
H
CN
H O
2
Ar
H
H C
CH
OH
C
2
O
O
+
Ar
C
N
H
B
O
CN
H C
OCH3
CN
3
Ar
Ar
Ar
H C
Ar
H
3
C
H
3
H C
3
H C
3
CN
CN
CN
H
N
HN
HN
HN
C
N
N
N
C
O
O
N
NH2
OH
O
NH
H
NH
C
5
NH
D
Scheme 2. Proposed mechanism for the formation of the titled products.
The reaction times and yields of the prodcuts obtained using
methyl acetoacetate and ethyl acetoacetate, respectively, are
listed in Table 2.
rected. Infrared (IR) spectra were recorded on a BRUKER-
EQUINOX55 spectrophotometer as KBr pellets. H NMR
spectra were obtained on Bruker INOVA-400 instrument
1
6
DMSO-d as a solvent. Chemical shifts are given in ppm
A condensation of hydrazine with a methyl acetoacetate
is more liable to form than an ethyl acetoacetate, due to easy
loss of methanol in the former condensation. Therefore, it is
possible to assume that the weight and volume of compound
relative to TMS as an internal standard. MS spectra were
determined on MSD1–MS (LC-MS, ESI source). All chemi-
cal reagents were in analytical grade and used without fur-
ther purification.
1
may have certain effect on the efficiency and rate of first
step condensation. The formation of compound 5 was as-
sumed as follows (Scheme 2). At first, reaction of hydrazine
was conducted with methy acetoaetate (1), and aryl alde-
hydes (3) with malononitrile (4) via Knoevnagel condensa-
tion, to afford the intermediates A and B. Then the subse-
quent Michael addition reaction between the two intermedi-
ates A and B by attack of active methylene to C=C resulted
in the intermediate C, which was subsequently converted to
D via an intramolecular reaction as a nucleophilic attack of
the OH group on the CN moiety. Finally, the expected prod-
uct 5 was formed by the isomerization of the intermediate D.
General Procedure for the Synthesis of 6-Amino-4-aryl-
3
-methyl-2,4-dihydropyrano[2,3-c] pyrazole-5-
carbonitriles (5a–5j)
A mixture solution of 2.0 mmol methyl acetoacetate or
2.0 mmol ethyl acetoacetate and 2.5 mmol hydrazine hydrate
in 15 mL abs. EtOH was refluxed for 5 min. Then, 2.0 mmol
aryl aldehydes, 2.0 mmol malononitrile and 30 mol %
HDBAC were added to the mixture, and the reaction system
was further refluxed for 30–60 min. After the reaction was
completed (monitored by TLC), the mixture was cooled, and
large amounts of solids were precipitated in a reaction sys-
tem. The precipitate was filtered off and washed thoroughly
The structures of products were confirmed on the basis of
H NMR, IR and ESI-MS spectral methods. The correspond-
1
2
with H O. The crude product was recrystallized from EtOH
to give the desired products (5a–5j).
ing spectral data were in agreement with the proposed struc-
1
ture of all target compounds. In the H NMR spectra of 5a–
5
j, protons at NH and NH
2
groups were evident as a singlet
6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (5a)
at ꢀ 12.05–12.21 and ꢀ 7.13–7.13 respectively. A proton at
C-4 position of pyrano-ring appeared as a singlet at ꢀ 4.56–
White solid, mp 242–244 °C (ref. [20], 245–246 °C). IR
4
.79. In IR spectra, several characteristic absorption peaks
corresponding to CN, NH and NH group were observed at
194 cm and 3118–3419 cm , respectively. In addition,
-1
(
KBr cm ) ꢁmax: 3310, 3170, 2191, 1647, 1598, 1517, 1488;
2
1
-
1
-1
H-NMR (DMSO-d
6
, 400 MHz) ꢀ (ppm): 1.78 (s, 3H, CH
3
),
2
4
.59 (s, 1H, CH), 6.87 (s, 2H, NH
2
), 7.16–7.34 (m, 5H, Ar-
correct molecular mass of target compound was confirmed
according to the adduct molecular ions as (M+H) and
+
+
H), 12.10 (s, 1H, NH); ESI–MS m/z: 253 (M+H) , 275
+
+
(M+Na) .
(
M+Na) appeared in ESI-MS spectra.
6
-Amino-3-methyl-4-p-tolyl-2,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (5b)
EXPERIMENTAL GENERAL
General
Milk white solid, mp 206–208 °C (ref. [16], 206–208 °C).
-1
IR (KBr cm ) ꢁmax: 3441, 3316, 3189, 2191, 1645, 1600,
1
1
511, 1486; H-NMR (DMSO-d
6
, 400 MHz) ꢀ (ppm): 1.79
), 4.36 (s, 1H, CH), 6.84 (s,
Melting points were in an open end capillary tubes on
BUCHIB 2540 digital melting point apparatus and are uncor-
(
s, 3H, CH
3
), 2.27 (s, 3H, CH
3

6
42 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Ablajan et al.
2
2
H, NH
H, J = 8.0 Hz, p-H
2
), 7.12 (d, 2H, J = 8.0 Hz, p-H
3
C-C
6
H
4
), 7.50 (d,
6-Amino-4-(3-hydroxyphenyl)-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5i)
3
C-C ),+12.08 (s, 1H, NH); ESI–MS
6 4
H
+
m/z: 267 (M+H) , 289 (M+Na) .
-1
Milk white solid, mp 233–235 °C. IR (KBr cm ) ꢀmax
:
1
6
-Amino-4-(3-hydroxy-4-methoxylphenyl)-3-methyl-2,4-
3392, 3315, 3132, 2177, 1648, 1587, 1514, 1495; H-NMR
(DMSO-d , 400 MHz) ꢀ (ppm): 1.82 (s, 3H, CH ), 4.89 (s,
H, CH), 6.54–6.64 (m, 3H, 3-HO-C ), 6.85 (s, 2H, NH ),
7.08–7.12 (t, 1H, J = 8.0 Hz, J = 7.6 Hz, 3-HO-C ), 9.31
(s, 1H, OH), 12.09 (s, 1H, NH); ESI–MS m/z: 269 (M+H) ,
dihydropyrano[2,3-c]pyrazol-5-carbonitrile (5c)
6
3
1
6
H
4
2
Light yellow solid, mp 236–237 °C (ref. [20], 233–234
-
1
6 4
H
°C). IR (KBr cm ) ꢀmax: 3489, 3411, 3326, 2194, 1657,
+
1
1
1
6
1
6
607, 1511, 1485; H-NMR (DMSO-d
.82 (s, 3H, CH ), 3.71 (s, 3H, OCH
.53–6.56 (dd, 1H, J = 8.0 Hz, C , 6'-H), 6.69–6.72 (d,
H, J = 8.0 Hz, C , 5'-H), 6.72 (d, J = 2.0 Hz, C , 2'-H),
.80 (s, 2H, NH ), 8.84 (s, 1H, OH), 12.05 (s, 1H, NH); ESI–
6
, 400 MHz) ꢀ (ppm):
+
2
91 (M+Na) .
3
3
), 4.50 (s, 1H, CH),
6
H
3
6-Amino-4-(4-hydroxyphenyl)-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5j)
6
H
3
6 3
H
2
+
+
Milk white solid, mp 224–226 °C (ref. [20], 223–224 °C).
MS m/z: 299 (M+H) , 321 (M+Na) .
-1
IR (KBr cm ) ꢀmax: 3386, 3307, 3137, 2176, 1646, 1600,
1
6
-Amino-4-(4-fluorophenyl)-3-methyl-2,4-
1512, 1491; H-NMR (DMSO-d
(s, 3H, CH
6
, 400 MHz) ꢀ (ppm): 1.79
), 6.86 (d,
), 6.95 (d, 2H, J = 8.0 Hz, p-HO-
), 9.27 (s, 1H, OH), 12.05 (s, 1H, NH); ESI–MS m/z:
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5d)
3 2
), 4.47 (s, 1H, CH), 6.68 (s, 2H, NH
H, J = 8.0 Hz, p-HO-C H
2
6 4
Milk white solid, mp 170–172 °C (ref. [12], 170–171 °C).
-
1
C
6
H
4
IR (KBr cm ) ꢀmax: 3479, 3231, 3118, 2194, 1647, 1596,
+
+
1
269 (M+H) , 291 (M+Na) .
1
507, 1492; H-NMR (DMSO-d
s, 3H, CH ), 4.64 (s, 1H, CH), 6.90 (s, 2H, NH
dd, 4H, p-F-C ), 12.12 (s, 1H, NH ); ESI–MS m/z: 271
6
, 400 MHz) ꢀ (ppm): 1.79
(
(
(
3
2
), 7.12–7.23
6
H
4
CONFLICT OF INTEREST
+
+
M+H) , 293 (M+Na) .
The author(s) confirm that this article content has no
conflicts of interest.
6
-Amino-4-(4-chlorophenyl)-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5e)
Light yellow solid, mp 234–236 °C (ref. [20], 234–235
-
1
ACKNOWLEDGEMENTS
°
C). IR (KBr cm ) ꢀmax: 3409, 3368, 3175, 2187, 1644,
1
1
1
7
9
601, 1518, 1490; H-NMR (DMSO-d
.80 (s, 3H, CH ), 4.64 (s, 1H, CH), 6.93 (s, 2H, NH
.22 (d, 2H, J = 9.2 Hz, p-Cl-C ), 7.36–7.39 (d, 2H, J =
.2 Hz, p-Cl-C ), 12.14 (s, 1H, NH); ESI–MS m/z: 287
6
, 400 MHz) ꢀ (ppm):
We acknowledge the financial support from the
Foundation of Natural Science Foundation of Xinjiang
Science Technology Agency (No. 2009 211A02) and Natural
Science Foundation of Education Department of Xinjiang
Uyghur Autonomous Region (No.XJEDU2009S18).
3
2
), 7.19–
6
H
4
6
H
4
+
+
(
M+H) , 309 (M+Na) .
6
-Amino-4-(2-chlorophenyl)-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5f)
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2
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1
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1
591, 1518, 1488;. H-NMR (DMSO-d
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(
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H
4
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3
53 (M+Na) .
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6
-Amino-3-methyl-4-(4-nitrophenyl)-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5h)
7
129.
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J = 8.8 Hz, p-O N-C ), 8.20–8.23 (d, 2H, J = 8.8 Hz, p-
N-C ), 12.21 (s, 1H, NH); ESI–MS m/z: 298 (M+H) ,
20 (M+Na) .
6
, 400 MHz) ꢀ (ppm): 1.80 (s, 3H,
3
2
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2
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