Four-Component Synthesis of pyrano[2,3-c]pyrazoles Catalyzed by Triphenylphosphine in Aqueous Medium

Article abstract of DOI:10.2174/1570178613666151203213214

Background: The pyrano[2,3-c]pyrazoles have various biological properties such as antiinflammatory, anti-cancer, antifongical, analgesics and have a potential inhibitor for human ChK1 kinase. For these reasons several synthetic methods are reported. For o

Full text of DOI:10.2174/1570178613666151203213214

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Letters in Organic Chemistry, 2016, 13, 85-91 85
Four-Component Synthesis of pyrano[2,3-c]pyrazoles Catalyzed by
Triphenylphosphine in Aqueous Medium
Imène Amine Khodja, Amina Fisli, Oumeima Lebhour, Raouf Boulcina, Boudjemaa Boumoud and
Abdelmadjid Debache*
Laboratoire de Synthèse de Molécules d’Intérêts Biologiques, Université Constantine1, 25000
Constantine, Algérie
Received February 02, 2015: Revised October 26, 2015: Accepted December 01, 2015
Abstract:
Background: The pyrano[2,3-c]pyrazoles have various biological properties such as anti-
inflammatory, anti-cancer, antifongical, analgesics and have a potential inhibitor for human ChK1
kinase. For these reasons several synthetic methods are reported. For our part we want to propose a
method which respects the environment. ꢀ
Method: To achieve our study we used as a model the condensation reaction of hydrazine hydrate, ethyl acetoacetate, ben-
zaldehyde and malononitrile in the respective proportions of 1/1/1/1 and in the presence of Triphenylphosphine in various
concentrations and different solvents.
Results: We found that the optimal conditions for this reaction are 10 mol% of catalyst in refluxed H2O. Given these re-
sults and to show the generality of the procedure, we applied the optimized reaction conditions for the synthesis of various
dihydropyrano[2,3-c]pyrazoles from a range of substituted aromatic and heteroaromatic aldehydes. We have also applied
these conditions by changing hydrazine by phenylhydrazine. The desired products are obtained in good to excellent
yields.
Conclusion: We describe a simple, efficient and benign method for the dihydropyrano[2,3-c]pyrazoles synthesis by a
four-component condensation between hydrazine (or phenylhydrazine), ethyl acetoacetate, malononitrile and a variety of
aromatic and heteroaromatic aldehydes, catalyzed by Triphenylphosphine.
Keywords: Aqueous medium, multicomponent reaction, pyrano[2,3-c]pyrazoles, triphenylphosphine.
INTRODUCTION
triethylbenzylammonium chloride in H2O [10], hexadecyltri-
methylammonium bromide [11], nanoparticles La0.7Sr0.3
MnO3 [12] and Palladium(0) [13], ionic liquids [14, 15], p-
toluenesulfonic acid [16] and Cesium fluoride [17].
The pyrano[2,3-c]pyrazoles have various biological
properties; they are, for example, antibacterial [1], anti-
inflammatory [2], anti-cancer [3], antifongical [4], analgesics
[5] and have a potential inhibitor for human ChK1 kinase
[6]. For these reasons they have attracted the researcher’s
interest and this is reflected in the large number of the syn-
thetic methods of this class of compounds reported in the
literature. The first described pyranopyrazoles syntheses are
the two-component reactions of 3-methyl-1-phenylpyra-
zolon-5-one and tetracyanoethylene in refluxing ethanol [7]
or between 4-arylidene-3-methyl-2-pyrazoline-5-one and
malononitrile in the presence of triethylamine [8] or of
arylidenemalononitriles and 3-methyl-1-phenylpyrazolon-5-
one catalyzed also by triethylamine [9]. Thereafter were pro-
posed the three-component approaches of pyrazol-5-one de-
rivatives, aromatic aldehydes and malononitrile catalyzed by
Another three-component method from methyl acetyldi-
carboxylate, an isonitrile and 3-methyl-1-phenylpyrazolon-5-
one without catalyst in refluxed acetonitrile was also de-
scribed [18].
However the majority of described methods during recent
years are four-component reactions of hydrazine (and its
derivatives), ethyl acetoacetate, malononitrile and diverse
aldehydes catalyzed by piperazine in water at room tempera-
ture [19], triethylamine in ethanol [20], ꢀ-cyclodextrin with-
out solvent [21], imidazole in H2O at 80°C [22], L-proline in
aqueous medium [23], ꢁ-alumina in reflux water [24],
Ba(OH)2 in also reflux water [25], sodium bisulfate under
ultrasonic irradition without solvent [26].
Pyrano[2,3-c]pyrazoles four-component synthesis was
also successfully performed under influence of catalysts such
as iodine [27], sodium benzoate [28], silica [29], ionic liq-
uids [30], nanoparticles [31], heteropolyacids [32], and As-
pergillus Niger lipase [33].
*Address correspondence to this author at the Laboratoire de Synthèse de
Molécules d’Intérêts Biologiques, Université Constantine1, 25000
Constantine, Algérie; Tel/Fax: +213 31 81 11 77;
E-mail: a_debache@yahoo.fr
1875-6255/16 $58.00+.00
© 2016 Bentham Science Publishers

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Letters in Organic Chemistry, 2016, Vol. 13, No. 2
Khodja et al.
Ar
4
O
3
1
CN
O
NH2
PPh3 (10 mol%)
H2O, reflux
HN
R
5
N
2
+
+
NC
CN
+
O
Ar
H
EtO
N
R
6
O
NH2
1
2
4
3
5a-i, R=H
6a-d, R=C6H5
1a, R=H
1b, R=C6H5
Scheme 1. Dihydropyrano[2,3-c]pyrazoles synthesis.
Table 1. Synthesis of dihydropyrano[2,3-c]pyrazoles (5a) catalyzed by PPh3 : Effect of the solvent and the temperature.
a
Entry
Solvent
Catalyst (mol %)
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
H2O
H2O
10
10
10
10
10
10
10
10
5
2
1
1
1
1
1
1
Ambient
50
48
61
82
76
67
8
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
8O°C
EtOH
EtOH/H2O
CH2Cl2
CH3CN
-
27
79
a Reactions conditions: benzaldehyde (2 mmol), hydrazine (2 mmol), ethyl acetoacetate (2 mmol), malononitrile (2 mmol), PPh3 (0.1 mmol), solvent (5 ml). b Isolated yields of pure
products.
Particular reaction of aromatic aldehydes, hydrazine,
malononitrile and methyl acetylenedicarboxylate in water
and without catalyst for the preparation of a series of 3-
methylcarboxylate pyrano[2,3-c]pyrazoles was reported [34].
tained with yields ranging between 8 and 79%. However, the
reaction in H2O at reflux gave a better result with a yield of
82% (Table 1, entry 3).
In a second step, we conducted several manipulations in
order to determine the effect of the catalyst and its optimum
amount by carrying out the above condensation in refluxed
water with various amounts of catalyst increasing from 5, 20,
30 to 50 mol%. The results summarized in Table 2 show that
condensations with 5, 20 and 30 mol% of triphenyl-
phosphine provide yields of 51, 72 and 64% respectively.
However, an amount of 10 mol% previously gave signifi-
cantly higher yield (82%) (Table 1, entry 3).
The literature review shows also some enantioselective
syntheses in the presence of L-proline [35] or more com-
plexes organic catalysts [36].
Triphenylphosphine (PPh3) was used as catalyst in a
number of chemical transformations [37]. For our part, we
successfully applied this catalyst in Biginelli [38] and
Hantzsch [39] multicomponent reactions and also in the tet-
rahydrobenzo[b]pyrans synthesis [40].
Therefore the optimal conditions for this reaction are 10
mol% of catalyst in refluxed H2O.
In continuation of our research of new, efficient, inex-
pensive and environmentally friendly procedures [41-43], we
report here the use of triphenylphosphine as an effective
catalyst in the preparation of dihydropyrano[2,3-c]pyrazoles
in aqueous medium (Scheme 1).
Given these results and to show the generality of the pro-
cedure, we applied the optimized reaction conditions for the
synthesis of various dihydropyrano[2,3-c]pyrazoles from a
range of substituted aromatic and heteroaromatic aldehydes.
We have also applied these conditions by changing hydra-
zine by phenylhydrazine. The obtained results are summa-
rized in Table 3.
RESULTS AND DISCUSSION
To achieve our study we used as a model the condensa-
tion reaction of hydrazine hydrate (1a), ethyl acetoacetate
(2), benzaldehyde (3a) and malononitrile (4) in the respec-
tive proportions of 1/1/1/1 and in the presence of 10 mol% of
our catalyst.
Table 3 shows that aldehydes bearing electron donating
or electron-withdrawing groups gave the desired products in
good yields (entries 1-9). Moreover, wherever the position of
substituents (o, m, p), yields are also comparables (entries 2,
3, 4). In addition, the reactions with phenylhydrazine give
excellent yields but with longer reaction times (entries 10-
13). Good yield is observed with heteroaromatic aldehyde
(entry 8).
First, we examined the reaction in various solvents such
as H2O, EtOH, EtOH/H2O (1/1), CH3CN and CH2Cl2 at dif-
ferent temperatures: ambient, 50°C and at reflux. The reac-
tion without solvent at 80°C was also performed. The results
reported in Table 1 show that the desired product (5a) is ob-

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Four-Component Synthesis
Letters in Organic Chemistry, 2016, Vol. 13, No. 2
87
a
Table 2. Synthesis of dihydropyrano[2,3-c]pyrazoles (5a) catalyzed by PPh3 : Amount of catalyst.
Entry
Solvent
Catalyst (mol%)
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
H2O
H2O
H2O
H2O
H2O
H2O
0
1
1
1
1
1
1
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
59
69
82
76
71
67
5
10
20
30
50
a Reactions conditions: benzaldehyde (2 mmol), hydrazine (2 mmol), ethyl acetoacetate (2 mmol), malononitrile (2 mmol), PPh3 (different amounts) in H2O (5 ml) at reflux. b Isolated
yields of pure products.
a
Table 3. Synthesis of dihydropyrano[2,3-c]pyrazoles (5a-i; 6a-d) catalyzed by PPh3 .
Entry
Product
Ar
R
Time (h)
Yield (%)b
Mp (°C)Ref
1
2
5a
5b
5c
5d
5e
5f
C6H5
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
4-(CH3)2NC6H4
4-H5C2C6H4
2-SC4H3
H
H
1
0.5
0.5
0.5
0.5
2
82
87
84
82
67
63
79
73
88
87
86
92
89
242-24428
244-24628
188-19033
244-24628
168-17024
220-222
3
H
4
H
5
H
6
H
7
5g
5h
5i
H
0.5
1
236-23826
222-22428
206-21033
168-17028
198-20012
210-21228
182-184
8
4-HOC6H4
4-CH3C6H4
C6H5
H
9
H
1
10
11
12
13
6a
6b
6c
6d
C6H5
C6H5
C6H5
C6H5
2
4-O2NC6H4
4-HOC6H4
4-H5C2C6H4
2
2
2
aReaction conditions: Aldehyde (2 mmol), hydrazine or phenylhydrazine (2 mmol), ethyl acetoacetate (2 mmol), malononitrile (2 mmol), PPh3 (0.1 mmol) in water (5 ml) at reflux. b
Isolated yields of pure products.
In Scheme 2 we propose a plausible mechanism [44, 45]
for the formation of dihydropyrano[2,3-c]pyrazoles based on
the nucleophilic character of PPh3 which is able to attack
electrophilic carbons and thus facilitate the reaction in its
different stages. This mechanism is characterized by the
formation of two key intermediates 1 and 2. The first one is
the result of the Knoevenagel reaction of aromatic aldehyde
and malononitrile. The formation of benzylidene 1 is facili-
tated by the nucleophilic character of PPh3 which allows the
formation of entities capable to extract protons and thus cre-
ate the ideal conditions for the Knoevenagel reaction. In the
other hand, intermediate 2 provides from the classic reaction
of hydrazine (or its derivatives) with carbonyls. After enoli-
sation favoured by the medium, 2 reacts with 1 in a Michael-
type condensation. The resulting intermediate 3, after in-
tramolecular cyclization and tautomerization, yields the ex-
pected products 5 or 6.
CONCLUSION
In this work, we have proposed a new procedure for the
synthesis of dihydropyrano[2,3-c]pyrazoles, an important
class of compounds for their various applications in medi-
cine, pharmacy and agriculture. This new method is based on
a four-component condensation of aldehydes, ethyl acetoace-
tate, hydrazine or phenylhydrazine and malononitrile using,
for the first time, triphenylphosphine, a provided molecule,
cheap and somewhat dangerous, as catalyst.
EXPERIMENTAL
General Procedure for the pyrano[2,3-c]pyrazoles 5 Syn-
thesis
A 50 ml flask equipped with magnetic stirrer was
charged with hydrazine hydrate 1a (2 mmol, 0.1 g) or phen-

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88
Letters in Organic Chemistry, 2016, Vol. 13, No. 2
Khodja et al.
H
H
CN
CN
Ar
Ar
Ph3P
Ar
Ph3P
CN
CN
O
Ph3P
O
+
O
+
H
H
H
H
H
Ar
O
Ph3P
H
+
H
H
-H2O
CN
-H2O
O
Ar
RHN NH2
N
CN
+
Ar
H
-EtOH
O
N
O
R
1
EtO
CN
H
NH2
2
HN
O
N
5a-i
Ar
H
CN
C
N
O
Ar
H
CN
C
N
Ar
R
CN
NH
H
N
R=H
H
H
H
H
N
H
N
O
N
R
N
O
N
O
N
N
H
3
4
3'
R=Ph
Ar
Ar
H
CN
C
Ar
CN
NH2
CN
H
N
H
NH
N
O
N
O
N
O
N
N
N
Ph
Ph
Ph
6a-d
3''
4'
Scheme 2. Plausible mechanism for the formation of pyrano[2,3-c]pyrazoles 5 and 6.
ylhydrazine 1b (2 mmol, 0.236 g), ethyl acetoacetate 2 (2
mmol, 0.260 g), aldehyde 3 (2 mmol, 3a=3j=0.212 g,
3b=3c=3d=3k=0.302 g, 3e=0.298 g, 3f=3m=0.268 g,
3g=0.224 g, 3h=3l=0.244 g, 3i=0.240 g, 3j=0.212 g),
malononitrile 4 (2 mmol, 0.132 g), triphenylphosphine (10
mol%, 0.052 g) in 5 ml of H2O. The mixture is brought to
reflux with continuous stirring until the reaction is finished
(the progress of reaction is monitoring by TLC). After cool-
ing, the mixture is poured onto ice water and the obtained
solid is filtered. The products were purified by crystallization
from ethanol.
6-amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (5b): IR (KBr): nmax = 3413;
1
3313; 2187; 1651; 1600; 1527; 1407; 1218 cm-1. H NMR
(DMSO-d6, ꢀppm, J Hz): 1.8 (s, 3H, CH3); 4.6 (s, 1H, C4-
H); 7.08 (s, 2H, NH2); 7.32 (d, 1H, J = 7.7, Ar-H); 7.47 (t,
1H, J = 7.5, Ar-H); 7.54 (t, 1H, J = 7.5, Ar-H); 7.83 (d, 1H, J
= 7.4, Ar-H); 12.25 (s, 1H, NH). 13C NMR (DMSO-d6,
ꢀppm): 9.63 (CH3); 31.57 (C4); 56.16 (C-CN); 96.50 (C-
pyran); 120.46 (CN); 123.37 (C5’); 124.91 (C4’); 127.99
(C2’); 132.25 (C1’); 134.07 (C3’); 135.93 (C3); 148.24
(C6’); 155.09 (C-O); 161.33 (C-NH2).
6-amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano
Spectral Data for Selected pyrano[2,3-c]pyrazoles
[2,3-c]pyrazole-5-carbonitrile (5c): (KBr): nmax = 3472;
6-amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]
pyrazole-5-carbonitrile (5a): IR (KBr): nmax = 3367; 3170;
2191; 1647; 1600; 1400; 1041 cm-1. 1H NMR (DMSO,
ꢀppm, J Hz): 1.8 (s, 3H, CH3); 4.6 (s, 1H, C4-H); 6.90 (s,
2H, NH2); 7.14-7.42 (m, 5H, ArH); 12.13 (s, 1H, NH). 13C
NMR (DMSO-d6, ꢀppm): 9.87 (CH3); 36.37 (C4); 57.31 (C-
CN); 97.77 (C-pyran); 120.98 (CN); 126.88 (C4’); 127.60
(C3’, C5’); 128.57 (C2’, C6’); 135.78 (C1’); 144.51 (C3);
154.89 (C-O); 161.01 (C-NH2).
1
3117; 2970; 2885; 2195; 1651; 1601; 1528; 1404; 1350. H
NMR (DMSO-d6, ꢀppm, J Hz): 1.8 (s, 3H, CH3); 4.7 (s,
1H); 6.6 (s, 2H, NH2); 7.49 (m, 2H, Ar-H); 8.0 (m, 2H, Ar-
H); 12.10 (s, 1H, NH). 13C NMR (DMSO-d6, ꢀppm): 9.82
(CH3); 36.19 (C4); 56.81 (C-CN); 96.18 (C-pyran); 120.4
(CN); 121.71 (C4’); 121.95 (C3’); 129.47 (C6’); 133.94
(C2’); 135.83 (C1’); 146.16 (C3); 147.98 (C5’); 154.75 (C-
O); 160.97 (C-NH2).