A clean and simple synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1, 4-dihydropyrano[2,3-c]pyrazole in water

Article abstract of DOI:10.1081/SCC-200046527

A simple and clean method for producing 6-amino-4-aryl-5-cyano-3-methyl-1- phenyl-1,4- dihydropyrano[2,3-c]pyrazole from aromatic aldehyde, malononitrile and 3-methyl-1-phenyl- 2-pyrazolin-5-one catalyzed by hexadecyltrimethylammonium bromide (HTMAB) in w

Full text of DOI:10.1081/SCC-200046527

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A Clean and Simple Synthesis of
6‐Amino‐4‐Aryl‐5‐Cyano‐3‐Methyl‐1
in Water
Tong‐Shou Jin a , Ai‐Qing Wang a , Zhao‐Li Cheng a
Jian‐She Zhang a & Tong‐Shuang Li a
,
a Department of Chemistry, College of Chemistry
and Environmental Science, Hebei University,
Baoding, 071002, P. R. China
Version of record first published: 05 Aug 2006.
To cite this article: Tong‐Shou Jin , Ai‐Qing Wang , Zhao‐Li Cheng ,
Jian‐She Zhang & Tong‐Shuang Li (2005): A Clean and Simple Synthesis of
6‐Amino‐4‐Aryl‐5‐Cyano‐3‐Methyl‐1‐Phenyl‐1,4‐Dihydropyrano[2,3‐c]Pyrazole in Water,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:1, 137-143
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Synthetic Communicationsw, 35: 137–143, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200046527
A Clean and Simple Synthesis of 6-Amino-4-
Aryl-5-Cyano-3-Methyl-1-Phenyl-1,4-
Dihydropyrano[2,3-c]Pyrazole in Water
Tong-Shou Jin, Ai-Qing Wang, Zhao-Li Cheng,
Jian-She Zhang, and Tong-Shuang Li
Department of Chemistry, College of Chemistry and Environmental
Science, Hebei University, Baoding, P. R. China
Abstract: A simple and clean method for producing 6-amino-4-aryl-5-cyano-3-
methyl-1-phenyl-1,4- dihydropyrano[2,3-c]pyrazole from aromatic aldehyde, malono-
nitrile and 3-methyl-1-phenyl- 2-pyrazolin-5-one catalyzed by hexadecyltrimethylam-
monium bromide (HTMAB) in water is described. This method provides several
advantages such as mild reaction conditions, simple workup procedure, and being
environmentally friendly.
Keywords: Pyrano[2,3-c]pyrazole, hexadecyltrimethyl ammonium bromide, water
INTRODUCTION
In the past decade, there has been growing recognition that water is an attrac-
tive medium for many organic reactions not only for the advantage accorded
by avoiding extensive drying reactants, catalyst, and solvent, but also for the
unique reactivity and selectivity that some times result.[1–3] On the other hand,
organic reaction in water without using harmful organic solvents is the great
current interest especially in relation to environmental concerns today.
However, water as a solvent was not frequently used until recently for
Received in Poland August 20, 2004
Address correspondence to Tong-Shou Jin, Department of Chemistry, College
of Chemistry and Environmental Science, Hebei University, Baoding 071002,
P. R. China. E-mail: orgsyn@mail.hbu.edu.cn

138
T.-S. Jin et al.
several reasons, such as the fact that many organic materials do not dissolve in
water and many reactive intermediates and catalysts are decomposed in water.
So it is necessary to use some phase-transfer catalysis (PTC) or surfactant such
as hexadecyltrimethylammonium bromide (HTMAB), tetrabutylammonium
bromide (TBAB), 4-dodecylbenesulfonic acid (DBSA), because they benefit
the organic materials to form a uniform dispersion in water in the course of
synthesis. Based on our recent research, we have developed novel routes for
the synthesis of some hetreocyclics compounds catalyzed by these PTC or sur-
factant in water.[4–6] Our important aim of this research is to synthesize
additional hetreocyclic compounds in an aqueous media as well.
It is known that polyfunctionalized benzopyrans and its derivatives are a
kind of very useful compound. They have been widely used as medicine inter-
mediates due to their useful biological and pharmacological properties, such
as antibacterial, molluscacides, have anthelmintic, hypnotic and insecticidal
properties. such as anticoagulant, spasmolytic, diuretic, anticancer, antiana-
phylactin.[7–9] Some 2-amino-4H-pyrans can be employed as photoactive
meterials.[10] Furthermore, multisubstitutional 4H-pyrans also constitute a
structural unit of a series of natural products.[11] Besides, substituted
pyrazole and derivatives can be used as important pharmaceuticals and agri-
cultural chemicals. Usually these compounds are synthesized in organic
solvent.[12–14] Our interest in organic reaction carried out exclusively in
water led us to investigate this compound through a simple route. Herein
we reported a highly efficient method for synthesis 6-amino-4-aryl-5-cyano-
3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole catalyzed by HTMAB
in water (Scheme 1).
RESULT AND DISCUSSION
When the reaction of aldehyde, malononitrile, and 3-methyl-1-phenyl-2-
pyrazolin-5-one was performed in water in the presence of HTMAB at
60–808C, high yields of products 4 were found. The results are summarized
in Table 1.
Scheme 1.

Synthesis of Pyrano[2,3-c]Pyrazole in Water
139
Table 1. Synthesis of pyrano[2,3-c]pyrazoles in water
Mp (8C)
Entry
Ar
Yielda (%)
Found
Reported11
168–170
a
b
c
d
e
f
C6H5
2-ClC6H4
89
91
87
92
91
89
91
85
88
79
90
169–171
144–146
158–159
175–177
185–187
190–191
196–198
211–212
174–176
175–177
177–179
3-ClC6H4
4-ClC6H4
174–175
2,4-Cl2C6H4
3-NO2C6H4
4-NO2C6H4
4-HOC6H4
4-CH3OC6H4
3,4-OCH2OC6H3
4-CH3C6H4
188–190
194–196
g
h
i
170–172
j
k
aIsolated yield.
As shown in Table 1, we can find a series of aromatic aldehyde 1 were
reacted with 2 and 3 in the presence of HTMAB in water at 85–908C, the
reaction proceed smoothly to afford the corresponding products 4 in good
yields. All aromatic aldehydes containing electron-withdrawing groups (such
as nitro group, halide) or electron-donating groups (such as hydroxyl group,
alkoxyl group) were employed and reacted well to give the corresponding
product 4 in good to excellent yields under these reaction conditions, so we
conclude that no obvious effect of electron and nature of substituents on the
aromatic ring were observed. We also found that the reaction did not proceed
in the case in which aliphatic aldehyde was used. The reason we think this is
the activity of aliphatic aldehydes is less than that of aromatic aldehyde.
Taking the reaction of 4-chlorobenzaldehyde as an example, we investi-
gated the effect of the catalysts on the reaction. It was found that the HTMAB
plays a crucial role in the success of the reaction in terms of the rate and the
yields. For example, the reaction could be carried out in the absence of
HTMAB when the mixture (1d, 2, and 3) in water at temperature for 8 h,
but it obtained very poor yield (46%). We have also studied the kind of
catalyst for this reaction. Some other often-used PTC or surfactant such as
TBAB, DBSA, sodium dodecyl sulfate (SDS) were tested and the yields
were 86%, 89%, 68%, respectively. These data indicated that the HTMAB
is the most suitable for this reaction.
We propose the possible following mechanism to account for the reaction.
One molecule of aromatic aldehyde 1 was first condensed with malononitrile 2
to afford a-cyanocinnamonitrile derivative 5. The step (1 þ 2 ! 5) can be
regarded as a fast knoevenagel addition. The active methylene of 3 by

140
T.-S. Jin et al.
reaction with the electrophilic C55C double bond giving the intermediate 6.
Then the intermediate 6 was cyclized by the nucleophilic attack of OH group
on the cyano (CN) moiety and gave the intermediate 7. Finally the expected
products 4 were afforded by isomerization of water (7 ! 8 ! 4). In this
process, HTMAB could promote these reactions as an emulsifier (Scheme 2).
1
The products have been identified by H NMR, and IR analyses.
In conclusion, a procedure for the preparation of 6-amino-4-aryl-5-cyano-
3-methyl-1-phenyl-1,4-dihydropyrano[2, 3-c]pyrazole catalyzed by HTMAB
in aqueous media has been developed. This is a one–pot three-component
condensation in water. It is noteworthy that the experimental procedure is
very simple, and anhydrous conditions are not required. Water solution is a
clean and environmentally desirable system. No harmful organic solvents
are used. This report has proposed and demonstrated a new useful and attrac-
tive process for the synthesis of these compounds.
EXPERIMENTAL
Liquid aldehydes were distilled before use. IR spectra were recorded on a
1
Bio-Rad FTS-40 spectrometer (KBr). H NMR spectra were measured on a
Scheme 2.

Synthesis of Pyrano[2,3-c]Pyrazole in Water
141
Bruker AVANCE 400 (400 MHz) spectrometer using TMS as internal
reference and CDCl3 as solvent.
GENERAL PROCEDURE
A mixture of an aromatic aldehyde (1, 1 mmol), malononitrile (2, 1 mmol),
3-methyl-1-phenyl- 2-pyrazolin-5-one (3, 1 mmol), and HTMAB (10 mol%)
in water (20 mL) was stirred at 85–908C for 3 h. Then the mixture was
cooled to room temperature; solid was filtered off and washed with H2O
(40 ml). The crude products were purified by recrystallization by ethanol
(95%).
Data of some compounds are shown below:
6-amino-5-cyano-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]
pyrazole (4a): IR (KBr) nmax: 3472, 3320, 2195, 1660, 1590, 1264, 1125,
;
1027, 753 cm21 1H NMR d: 1.94 (s, 3H, CH3), 4.68(s, 1H, 4-H),
4.74(s, 2H, NH2), 7.15-7.31(m, 10H, ArH).
6-amino-4-(2-Chlorophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]-pyrazole (4b): IR (KBr) nmax: 3472, 3324, 2194, 1655, 1591,
1389, 1264, 1125, 1029, 752 cm21; 1H NMR d: 1.91 (s, 3H, CH3), 4.73(s, 2H,
NH2), 5.32(s, 1H, 4-H), 7.21–7.43(m, 5H, ArH), 7.48(d, 2H, J ¼ 8.0 Hz,
ArH), 7.67(d, 2H, J ¼ 8.0 Hz, ArH).
6-amino-4-(3-Chlorophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]-pyrazole 4c: IR (KBr) nmax: 3463, 3319, 2193, 1655, 1594,
1
1391, 1070, 756 cm21; H NMR d: 1.93 (s, 3H, CH3), 4.67(s, 1H, 4-H),
4.74(s, 2H, NH2), 7.19–7.37(m, 5H, ArH), 7.48(d, 2H, J ¼ 8.0 Hz, ArH),
7.67(d, 2H, J ¼ 8.0 Hz, ArH).
6-Amino-4-(4-chlorophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4d): IR (KBr) nmax: 3469, 3325, 2200, 1661, 1595,
1389, 1262, 1122, 1015, 751cm21 1H NMR d: 1.89 (s, 3H, CH3),
;
4.73(s, 2H, NH2), 6.32(s, 1H, 4-H), 7.29–7.38(m, 3H, ArH) 7.41(d, 2H,
J ¼ 8.0 Hz, ArH), 7.47–7.51(m, 2H, ArH), 7.78(d, 2H, J ¼ 8.0 Hz, ArH).
6-Amino-4-(2,4-dichlorophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4e): IR (KBr) nmax: 3456, 3321, 2198, 1660, 1591,
1392, 1269, 1126, 1049, 758 cm21 1H NMR d: 1.78 (s, 3H, CH3),
;
5.12(s, 1H, 4-H), 6.73(s, 2H, NH2), 7.31–7.78(m, 8H, ArH),
6-Amino-4-(3-nitrophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole 4f: IR (KBr) nmax: 3420, 3330, 2194, 1675, 1597,
;
1389, 1264, 1125, 1029, 752 cm21 1H NMR d: 1.93 (s, 3H, CH3),
4.76(s, 1H, 4-H), 4.98(s, 2H, NH2), 8.12–8.94(m, 9H, ArH).
6-Amino-4-(4-nitrophenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4g): IR (KBr): nmax ¼ 3430, 3340, 2192, 1665, 1595,
1354, 1124, 831, 753 cm21; 1H NMR d ¼ 1.79(s, 3H, CH3), 4.95(s, 1H, 4-H),
6.98(s, 2H, NH2),7.32–7.35(m, 1H, ArH), 7.48–7.52(m, 2H, ArH),

142
T.-S. Jin et al.
7.58(d, 2H, J ¼ 8.4 Hz, ArH), 7.79 (d, 2H, J ¼ 8.4 Hz, ArH), 8.23(d, 2H,
ArH).
6-Amino-4-(4-hydroxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4h): IR (KBr) nmax: 3414, 3314, 2179, 1657, 1593,
;
1399, 1257, 1127, 1026, 753 cm21 1H NMR d: 1.79 (s, 3H, CH3),
4.56(s, 1H, 4-H), 6.72 (d, 2H, J ¼ 8.4 Hz, ArH), 7.04 (d, 2H, J ¼ 8.4 Hz,
ArH) 7.12(s, 2H, NH2), 7.29–7.33(m, 1H, ArH), 7.49((d, 2H, J ¼ 8.0 Hz,
ArH), 7.78 (d, 2H, J ¼ 8.0 Hz, ArH).
6-Amino-4-(4-methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4i): IR (KBr): nmax: 3395, 3322, 2192, 1660, 1595,
1
1394, 1250, 1128, 813 cm21; H NMR d: 1.78 (s, 3H, CH3), 3.72(s, 3H,
OCH3), 4.89(s, 1H, 4-H), 6.82 (d, 2H, J ¼ 8.0 Hz, ArH), 6.95(s, 2H, NH2),
7.05 (d, 2H, J ¼ 8.0 Hz, ArH), 7.19–7.23(m, 1H, ArH), 7.39((d, 2H,
J ¼ 8.0 Hz, ArH), 7.58 (d, 2H, J ¼ 8.0 Hz, ArH).
6-Amino-4-((3,4-dioxymethylenephenyl)-5-cyano-3-methyl-1-phenyl-
1,4-dihydropyrano[2,3-c]pyrazole (4j): IR (KBr): nmax: 3400, 3320, 2198,
1
1661, 1595, 1393, 1254, 1129, 1037, 789 cm21; H NMR d: 2.12 (s, 3H,
CH3), 5.09(s, 1H, 4-H), 5.95(2H, s, OCH2O), 6.92(s, 2H, NH2), 7.02–
7.12(m, 2H, ArH), 7.15(m, 1H, ArH), 7.17(d, 2H, J ¼ 8.0 Hz, ArH),
7.21(m, 1H, ArH) 7.26(d, 2H, J ¼ 8.0 Hz, ArH).
6-Amino-4-(4-methylphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole (4k): IR (KBr) nmax: 3414, 3314, 2179, 1657, 1593,
1
1399, 1257, 1127, 1026, 753 cm21; H NMR d: 1.78 (s, 3H, CH3), 2.28
(s, 3H, CH3), 4.62(s, 1H, 4-H), 6.96(s, 2H, NH2), 7.02 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.08 (d, 2H, J ¼ 8.4 Hz, ArH), 7.29–7.33(m, 1H, ArH), 7.46((d, 2H,
J ¼ 8.0 Hz, ArH), 7.78 (d, 2H, J ¼ 8.0 Hz, ArH).
ACKNOWLEDGMENTS
This project was supported by the National Natural Science Foundation of
China (29872011 and 29572039), Educational Ministry of China, Educational
Department of Hebei Province 990104, Science and Technology Commission
of Hebei Province.
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