A green and one-pot synthesis of a library of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives using thiourea dioxide (TUD) as an efficient and reusable organocatalyst

Article abstract of DOI:10.1007/s11164-015-2308-7

Abstract: The efficacy of thiourea dioxide (TUD) as an efficient, inexpensive, and readily accessible organocatalyst for the synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives via a four-component reaction of ethyl acetoacetate, hyd

Full text of DOI:10.1007/s11164-015-2308-7

Res Chem Intermed
DOI 10.1007/s11164-015-2308-7
A green and one-pot synthesis of a library
of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile
derivatives using thiourea dioxide (TUD)
as an efficient and reusable organocatalyst
1
1
•
Rajesh H. Vekariya
1
Hitesh D. Patel
•
Kinjal D. Patel
Received: 17 July 2015 / Accepted: 28 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The efficacy of thiourea dioxide (TUD) as an efficient, inexpensive, and
readily accessible organocatalyst for the synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-
5
-carbonitrile derivatives via a four-component reaction of ethyl acetoacetate, hydrazine
hydrate, aryl aldehydes, and malononitrile is described. Upon completion of the reaction,
the product was isolated by filtration, and the remaining aqueous TUD solution could be
reused several times with consistent catalytic activity. High yields, simple work-up
process, avoiding the use of organic solvents, short reaction time, and recyclable catalyst
are the superior advantages of the present protocol.
Graphical Abstract
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2308-7)
contains supplementary material, which is available to authorized users.
&
Hitesh D. Patel
drhiteshpatel1@gmail.com
1
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
123

R. H. Vekariya et al.
Keywords 1,4-Dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives Á
Thiourea dioxide (TUD) Á One-pot synthesis Á Aqueous-phase synthesis Á
Organocatalysis
Introduction
Recently, the expansions of green protocols that are environmentally benign and
pollution free have received substantial levels of consideration because of the
increasing tendency of the chemical industry towards greener unit processes.
Nowadays, Multi-component reactions (MCRs) have received much attention in the
field of organic and medicinal chemistry, because the strategies of MCR offer
significant advantages over conventional synthetic methodologies [1]. The average
molecular complexity occurred per operation is completely dependent from the
length of organic synthesis, which depends in turn on the number of chemical bonds
being formed [2]. Therefore, planning reactions that accomplish multi-bond
formation in one operation are becoming one of the foremost challenges in the
field of green organic synthesis. Synthesis of biological active molecules as well as
important organic intermediates through an MCR approach delivers a number of
merits over conventional transformations, such as shorter reaction times, higher
product yields, lower costs, and environmental wellbeing [3–5].
4
H-Pyrans analogue heterocyclic scaffolds signify a fortunate structural motif
well distributed in naturally occurring compounds [6, 7]. Furthermore, 4H-pyrane
derivatives displays a broad spectrum of biological activities such as anticancer [8],
anti-HIV [9], anti-inflammatory [10], antimalarial [11], antimicrobial [12], antiviral
[
13], and anti-proliferative [14]. These potent outlines of biological activities have
encouraged widespread studies for the preparation of 1,4-dihydropyrano[2,3-
c]pyrazole derivatives [15]. Condensed pyrazolo derivatives are also biologically
important compounds and their chemistry has recently received considerable
attention [16]. Several pyrano[2,3-c]pyrazoles are reported to have beneficial
biological activities such as anti-inflammatory and analgesic [17]. In addition, the
biological activity of fused azoles has led to exhaustive research on their synthesis
[
18]. Because of the presence of the 1,4-dihydropyrano[2,3-c]pyrazole scaffold in
several biologically active compounds, new approaches in the direction of the
synthesis of highly functionalized pyrano[2,3-c]pyrazoles are of great attention.
Thus, these derivatives were synthesized using different catalysts like maltose [19],
saccharose [20], urea [21], lipase [22], meglumine [23], diaminocyclohexane-
thiourea [24], isonicotinic acid [25], acetic acid [26], DBU [27], DABCO [28],
piperidine and pyridine [29], pyrrolidine [30], citric acid [31], disulfonic acid
imidazolium chloroaluminate [32], sodium benzoate [17], nano-titania sulfuric acid
(
ported preyssler-type heteropolyacid [36], nano TiO [37], nano-CuFe O [38],
TSA) [33], nano-ZnO [34], CuO–CeO2 nanocomposite [35], nano-titania-sup-
2
2 4
nickel nanoparticles [39], nano-CuI [40], Fe O nanoparticles [41], SnO quantum
3
4
2
dots [42], amberlyst A21 [43], cetyltrimethylammonium chloride (CTACl) [44],
NaOH [45], tetraethylammonium bromide (TEABr) [46], CeCl [47], CSF [48],
3
1
23

A green and one-pot synthesis of a library of…
poly(4-vinylpyridine) [49], borax [50], silica-supported tetramethylguanidine [51],
iodine [52], cerium ammonium nitrate (CAN) [53], and tungstate sulfuric acid [54].
Among the recently developed expansions of interest, the use of catalysis by
small organic molecules called organocatalysis has become an extensive area of the
research in synthetic organic chemistry, which is one of the most important
possibilities for sustainable chemistry. Ambitious because of environmental
concerns, there is great need to develop an inexpensive, non-metallic readily
accessible, recyclable and reusable, small organic molecule catalyst [55].
Organocatalysis offers numerous advantages including lower activation energy,
high stability, metal free environment, reduced toxicity and mild reaction conditions
[
56–58]. Small molecules such as urea [59–61] and thiourea [62–64] derivatives,
due to their strong hydrogen-bonding activity, have also ascended to be potential
organocatalysts for the preparation of important organic molecules. Owing to the
growing environmental concerns, there is continued pressure on pharmaceutical as
well as on chemical industries to reduce chemical waste. In this regard utilization of
heterogeneous catalysts may offer the advantages of facile recovery and recycling of
the catalyst, which reduces chemical pollution [65–69].
Simply oxidation of thiourea with hydrogen peroxide affords thiourea dioxide
TUD) [70]. TUD is a highly stable material. Moreover, TUD retains the ability to
(
activate organic substrates through hydrogen bonding. Furthermore, TUD can form
strong hydrogen bonding interaction and provide higher levels of activation than the
corresponding thiourea, because it possesses two extra oxygen atoms. In addition,
thiourea dioxide is insoluble in common organic solvents; and, therefore, it can
easily be recovered from the reaction and reused several times without significant
loss of efficiency. Recently, TUD has emerged as a promising novel organocatalyst
in the one-pot synthesis of a library of novel heterocyclic compounds [71],
hydrolysis of imines [72], synthesis of naphthopyrans [73], synthesis of pyrano[4,3-
b]pyrans [74], synthesis of 4-aryl-2-naphthalen-2-yl-5H-indeno [1,2-b]pyridin-5-
ones [75], in oxidation of sulfides to sulfoxides [76], in reduction of aldehydes [77],
and synthesis of dihydropyrido[2,3-d]pyrimidine-2,4-diones [78]. Our literature
survey exposed that there is no report on the use of TUD as a green organocatalyst
in the synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles. Herein, we
wish to report the development of an environmentally friendly process for the
preparation of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives via the
one-pot, four-component synthesis catalyzed by TUD in aqueous media
(
Scheme 1).
Experimental
Apparatus and analysis
All chemicals, unless otherwise specified, were purchased from commercial sources
and were used at analytical grade. The products were characterized by a comparison
of their physical data and melting points with those of known samples or by their
spectral data. Melting points were measured on an Optimelt MPA 100 melting point
123

R. H. Vekariya et al.
Scheme 1 Synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles (1–15)
apparatus and are uncorrected. FT-IR spectra were recorded on a Perkin Elmer FT-
IR 377 spectrometer using KBr. Proton NMR spectra were recorded on a Bruker AV
4
00 MHz spectrometer using DMSO as solvent and TMS as the internal reference.
Mass spectra were recorded at Advion expression CMS, USA. Acetone is used as
the mobile phase, and electron spray ionization (ESI) is used as the ion source.
Elemental analysis was performed on a CHN elemental analyzer. The development
of reactions was monitored by thin layer chromatography (TLC) analysis on Merck
pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.
Synthesis of thiourea dioxide (Catalyst) [33]
Thiourea (25 g) was dissolved in pure water (250 mL) at 40 °C, and the solution
was cooled to 8–10 °C. Hydrogen peroxide solution (aq. 50 wt%, 80 mL) was
added slowly at a rate such that the solution temperature was held below10 °C and
stirred over a period of 90 min. Thereafter, the solution was cooled to 0 °C. After
the crystallization, the resulting solid–liquid mixture was filtered off immediately at
0 °C, and the crystals so obtained were dried at 50 °C, to yield thiourea dioxide
26.0 g (75 %).
General method for the preparation of 1,4-dihydropyrano[2,3-c]-pyrazole-
-carbonitriles (1–15)
5
In a 25-mL round-bottomed flask, ethyl acetoacetate (1 mmol), hydrazine hydrate
1.5 mmol, 80 %), aromatic aldehydes (1 mmol), and malononitrile (1 mmol) were
(
stirred in the presence of 10 mol% of TUD in 5 mL water at 80 °C for 30–50 min.
During the reflux, the progress of the reaction mixture was monitored by TLC
analysis. The mixture was then poured into water (10 mL), and the resulting solid
was removed by filtration, and washed with water. The remaining aqueous
thioureadioxide was collected, water was evaporated under vacuum, and catalyst
was dried. This recovered catalyst could be reused four times without significant
loss of its efficiency. The crude products were purified by recrystallization from
ethanol. The reaction products were identified by comparing their physical and
1
23

A green and one-pot synthesis of a library of…
spectral data (i.e., IR, 1H and 13C NMR, and MS) with those reported in the
literature.
Spectral data of representative compounds
6-amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5)
-
1
Light yellow solid, White solid. IR mmax (KBr) cm : 3411, 3385 (NH ), 3320 (–
2
NH–), 3070, 3022 (Aromatic), 2933 (–CH ), 2590 (–OCH ), 2206 (–CN), 1482 (–
1
3
3
NH–), 812 (Para-NO ). H NMR (400 MHz, DMSO-d ): d (ppm) 1.79 (s, 3H,
2
6
H
CH ), 2.27 (s, 3H, OCH ), 4.55 (s, 1H, 4H), 6.87 (s, 2H, NH ), 7.30–7.32 (d, 2H,
1
3
3
2
3
J = 7.96 Hz, Ar–H), 7.76–7.78 (d, 2H, J = 8.04 Hz, Ar–H), 12.11 (s, 1H, NH).
C
NMR (100 MHz, DMSO-d ): d (ppm) 9.86, 27.98, 55.18, 99.32, 111.68, 112.74,
6
C
1
21.11, 128.55, 127.53, 134.45, 135.18, 163.34. MS (ESI) m/z for (282.11): 282.1
?
?
(
M) , 283.3 (M ? 1) . Elemental Analysis (CHN): calcd. for C H N O : C
14 11 5 3
56.56, H 3.73, N 23.56 %; found: C 56.58, H 3.72, N 23.55 %. The spectroscopic
data is in full agreement with the reported literature data.
6-amino-4-(4-chlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (8)
-
1
Off-white solid, IR mmax (KBr) cm : 3400, 3391 (NH ), 3317 (–NH–), 3066, 3017
2
(
1
Aromatic), 2931 (–CH ), 2211 (–CN), 1488 (–NH–), 1058 (Ar–Cl), 815 (Para-Cl).
3
H NMR (400 MHz, DMSO-d ): d (ppm) 1.79 (s, 3H, CH ), 4.64 (s, 1H, 4H), 6.96
6
H
3
(
s, 2H, NH ), 7.19–7.21 (d, 2H, J = 8.40 Hz, Ar–H), 7.37–7.39 (d, 2H,
2
1
3
J = 8.40 Hz, Ar–H), 12.17 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d
6
C
(
ppm) 9.71, 35.51, 56.68, 97.15, 120.65, 128.43, 129.07, 129.34, 129.70, 130.00,
?
31.20, 135.67, 143.44, 154.65, 160.87. MS (ESI) m/z for (286.06): 286.1 (M) ,
1
2
3
?
88.1 (M ? 2) . Elemental Analysis (CHN): calcd. for C H ClN O: C 58.65, H
.87, N 19.54 %; found: C 58.63, H 3.88, N 19.55 %. The spectroscopic data is in
1
4
11
4
full agreement with the reported literature data.
6-amino-4-(4-hydroxy-3,5-dimethoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (11): (Novel Compound)
-
1
Off-white solid. IR mmax (KBr) cm : 3452 (C–OH), 3393, 3384 (NH ), 3310 (–NH–),
2
3
7
1
059, 3010 (Aromatic), 2925 (–CH ), 2590 (–OCH ), 2205 (–CN), 1481 (–NH–),
3 3
1
42 (Ortho), 772 (Meta), 805 (Para). H NMR (400 MHz, DMSO-d ): d (ppm)
6
H
.86 (s, 3H, CH ), 3.71 (s, 6H, 2 9 OCH ), 4.53 (s, 1H, 4H), 6.43 (s, 2H, NH ), 6.85
3
3
2
1
s, 2H, Ar–H), 8.28 (s, 1H, –OH), 12.08 (s, 1H, NH). C NMR (100 MHz, DMSO-
3
(
d6): dC (ppm) 9.88, 36.24, 55.93, 57.32, 97.63, 104.82, 120.89, 134.25, 134.45,
?
35.66, 147.80, 154.66, 160.73. MS (ESI) m/z for (328.1): 329.1 (M ? 1) , 351.1
1
?
(
M ? Na) . Elemental Analysis (CHN): calcd. for C H N O : C 58.53, H 4.91, N
16 16 4 4
1
7.06 %; found: C 58.54, H 4.90, N 17.06 %.
123

R. H. Vekariya et al.
6-amino-4-(4-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(12)
-
1
White solid. IR mmax (KBr) cm : 3405, 3390 (NH ), 3317 (–NH–), 3062, 3028
2
(
Aromatic), 2930 (–CH ), 2205 (–CN), 1626 (=C=N–), 1487 (–NH–), 1069 (Ar–Br),
3
1
8
10 (Para-Br). H NMR (400 MHz, DMSO-d ): d (ppm) 2.15 (s, 3H, CH ), 4.72 (s,
6
H
3
1
H, 4H), 6.55 (s, 2H, NH ), 7.44–7.46 (d, 2H, J = 8.48 Hz, Ar–H), 7.56–7.58 (d, 2H,
1
2
3
J = 8.48 Hz, Ar–H), 10.93 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d (ppm)
6
C
9
.66, 27.2, 40.57, 98.02, 113.88, 113.94, 120.81, 129.95, 131.53, 138.05, 139.18,
?
58.97. MS (ESI) m/z for (330.0): 330.2 (M) , 332.3 (M ? 2) . Elemental Analysis
?
1
(
CHN): calcd.forC H BrN O:C 50.77,H 3.35, N 16.92 %;found:C50.72, H3.38, N
14 11 4
1
6.89 %. The spectroscopic data is in full agreement with the reported literature data.
6
-amino-4-(4-nitrophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
14)
(
-
1
-1
Yellow solid. IR mmax (KBr) cm : White solid. IR mmax (KBr) cm : 3414, 3389
(
NH ), 3323 (–NH–), 3073, 3025 (Aromatic), 2936 (–CH ), 2209 (–CN), 1485
2 3
1
–NH–), 1354, 1563 (Ar–NO ), 818 (Para-NO ). H NMR (400 MHz, DMSO-d ):
(
2
2
6
d (ppm) 1.82 (s, 3H, CH ), 4.84 (s, 1H, 4H), 7.08 (s, 2H, NH ), 7.46–7.48 (d, 2H,
H
3
2
1
3
J = 8.48 Hz, Ar–H), 8.20–8.22 (d, 2H, J = 8.48 Hz, Ar–H), 12.22 (s, 1H, NH).
C
NMR (100 MHz, DMSO-d ): d (ppm) 9.71, 35.84, 55.84, 96.52, 120.47, 123.87,
6
C
1
28.81, 135.84, 146.34, 152.08, 154.63, 161.11. MS (ESI) m/z for (297.1): 397.2
?
?
(
M) , 398.3 (M ? 1) . Elemental Analysis (CHN): calcd. for C H BrN O: C
14 11 4
50.77, H 3.35, N 16.92 %; found: C 50.72, H 3.38, N 16.89 %. The spectroscopic
data is in full agreement with the reported literature data.
6-amino-4-(3,4,5-trimethoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (19)
-
1
Off-white solid. IR mmax (KBr) cm : 3432 (C–OH), 3391, 3382 (NH ), 3316 (–NH–),
2
3
7
1
069, 3017 (Aromatic), 2922 (–CH ), 2593 (–OCH ), 2207 (–CN), 1487 (–NH–),
3 3
1
42 (Ortho), 772 (Meta), 805 (Para). H NMR (400 MHz, DMSO-d ): d (ppm)
6
H
.89 (s, 3H, CH ), 3.55 (s, 9H, 3 9 OCH ), 4.61 (s, 1H, 4H), 6.49 (s, 2H, NH ), 6.92
3
3
2
1
3
(
s, 2H, Ar–H), 12.13 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d (ppm) 9.91,
6
C
3
6.46, 55.74, 56.84, 59.91, 97.28, 104.49, 105.50, 120.87, 135.73, 136.07, 140.07,
?
52.76, 153.13, 154.67, 160.95. MS (ESI) m/z for (342.13): 343.1 (M ? 1) , 366.2
1
?
M ? Na) . Elemental Analysis (CHN): calcd. for C H N O : C 59.64, H 5.30, N
(
1
7 18 4 4
16.37 %; found: C 59.63, H 5.33, N 16.36 %. The spectroscopic data is in full
agreement with the reported literature data.
6-amino-4-(4-cyanophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(22)
-
1
Off-white solid, IR mmax (KBr) cm : 3402, 3394 (NH ), 3314 (–NH–), 3067, 3020
(
2
1
Aromatic), 2931 (–CH ), 2213 (Ar–CN), 1486 (–NH–), 817 (Para-CN). H NMR
3
1
23

A green and one-pot synthesis of a library of…
(
NH ), 7.38–7.40 (d, 2H, J = 8.12 Hz, Ar–H), 7.79–7.81 (d, 2H, J = 8.08 Hz, Ar–
400 MHz, DMSO-d ): d (ppm) 1.79 (s, 3H, CH ), 4.76 (s, 1H, 4H), 7.04 (s, 2H,
6
H
3
2
1
3
H), 12.20 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d (ppm) 9.69, 36.10,
6
C
5
5.97, 96.61, 109.60, 118.76, 120.52, 128.56, 132.57, 135.77, 150.02, 154.66,
?
61.10. MS (ESI) m/z for (277.28): 277.2 (M) , 278.1 (M ? 1) . Elemental
?
1
Analysis (CHN): calcd. for C H N O: C 64.97, H 4.00, N 25.26 %; found: C
1
5 11 5
64.93, H 4.02, N 25.23 %. The spectroscopic data is in full agreement with the
reported literature data.
6
5
-amino-4-(2-hydroxy-5-nitrophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
-carbonitrile (23): (Novel Compound)
-
1
Yellow solid, IR mmax (KBr) cm : 3436 (C–OH), 3406, 3397 (NH ), 3317 (–NH–),
2
3
065, 3024 (Aromatic), 2935 (–CH ), 2217 (–CN), 1488 (–NH–), 1355, 1566 (Ar–
3
1
NO ), 744 (Ortho), 774 (Meta), 803 (Para). H NMR (400 MHz, DMSO-d ): d
2
6
H
(ppm) 2.10 (s, 3H, CH ), 4.77 (s, 1H, 4H), 6.99 (s, 2H, NH ), 7.20–7.22 (d, 1H,
3 2
J = 7.44 Hz, Ar–H), 7.88 (s, 1H, Ar–H), 8.05–8.07 (d, 1H, J = 6.28 Hz, Ar–H),
1
3
1
1
1
0.67 (s-broad, 2H, NH and OH). C NMR (100 MHz, DMSO-d ): d (ppm) 9.80,
6
C
8.50, 28.66, 54.91, 56.01, 104.35, 117.05, 120.15, 123.45, 124.71, 124.96, 136.80,
?
43.46, 153.05, 159.20, 160.04. MS (ESI) m/z for (313.27): 313.3 (M) , 314.1
?
M ? 1) . Elemental Analysis (CHN): calcd. for C H N O : C 53.68, H 3.54, N
(
1
4 11 5 4
2
2.36 %; found: C 53.66, H 3.52, N 22.33 %.
6
5
-amino-4-(2-hydroxy-5-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
-carbonitrile (24): (Novel Compound)
-
1
Light yellow solid, IR mmax (KBr) cm : 3440 (C–OH), 3411, 3399 (NH ), 3319 (–NH–),
2
3
7
2
068, 3028 (Aromatic), 2937 (–CH ), 2218 (–CN), 1491 (–NH–), 1062 (Ar–Br),
1
3
40 (Ortho), 773 (Meta), 810 (Para). H NMR (400 MHz, DMSO-d ): d (ppm)
6
H
.06 (s, 3H, CH ), 4.64 (s, 1H, 4H), 6.65 (s, 2H, NH ), 6.95–6.97 (d, 1H,
3
2
J = 6.2 Hz, Ar–H), 7.09 (s, 1H, Ar–H), 7.34–7.36 (d, 1H, J = 8.68 Hz, Ar–H),
1
3
1
1
1
0.58 (s-broad, 2H, NH and OH). C NMR (100 MHz, DMSO-d ): d (ppm) 9.79,
6
C
8.55, 28.63, 54.94, 56.03, 104.39, 117.02, 120.18, 123.44, 124.74, 124.93, 136.81,
?
43.44, 153.07, 159.22, 160.06. MS (ESI) m/z for (347.17): 347.2 (M) , 349.1
?
M ? 2) . Elemental Analysis (CHN): calcd. for C H BrN O : C 48.43, H 3.19,
(
N 16.14 %; found: C 48.46, H 3.18, N 16.13 %.
1
4
11
2 2
6
5
-amino-4-(2-hydroxy-5-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
-carbonitrile (25): (Novel Compound)
-
1
Brown Solid, IR mmax (KBr) cm : 3447 (C–OH), 3416, 3396 (NH ), 3314 (–NH–),
2
3
062, 3025 (Aromatic), 2939 (–CH ), 2214 (–CN), 1492 (–NH–), 1062 (Ar–Cl), 740
3
1
(
Ortho), 773 (Meta), 810 (Para). H NMR (400 MHz, DMSO-d ): d (ppm) 2.06 (s,
6
H
3
H), 7.09 (s, 1H, Ar–H), 7.34–7.36 (d, 1H, J = 8.68 Hz, Ar–H), 10.58 (s-broad, 2H,
H, CH ), 4.64 (s, 1H, 4H), 6.65 (s, 2H, NH ), 6.95–6.97 (d, 1H, J = 6.2 Hz, Ar–
3
2
1
3
NH and OH). C NMR (100 MHz, DMSO-d ): d (ppm) 10.56, 32.99, 34.79,
6
C
123

R. H. Vekariya et al.
9
1
2.98, 112.95, 113.27, 114.99, 125.64, 125.83, 127.19, 127.94, 131.24, 137.40,
?
40.89, 145.62, 156.34, 157.53. MS (ESI) m/z for (337.07): 337.1 (M) , 338.2
?
M ? 1) . Elemental Analysis (CHN): calcd. for C H ClN O: C 60.45, H 3.58, N
(
1
7
12
5
2
0.73 %; found: C 60.46, H 3.55, N 20.77 %.
Results and discussion
The main objective of the current work was to develop an efficient and green
protocol for the synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles in a
non-toxic solvent like water. In the beginning, the reaction of equimolar quantities
of ethyl acetoacetate (1 mmol), hydrazine hydrate (1.5 mmol, 80 %), aromatic
aldehydes (1 mmol), and malononitrile (1 mmol) was used as a model reaction to
identify suitable conditions for the transformation using TUD as a catalyst. To
optimize the reaction conditions and evaluate the catalytic activity of TUD
compared with other catalysts for the formation of compound 1, comparative
experiments were performed, and the data are shown in Table 1. Different catalysts
were tested, including FeCl Á6H O, InCl , ZnCl , Sulfamic acid, p-TSA, Ceric
3
2
3
2
ammonium nitrate (CAN), and TUD. However, TUD was found to be the most
efficient in terms of the reaction time and yield of the product (Table 1, Entries
1
–6).
The model reaction was used to identify suitable conditions, including solvents,
amounts of catalyst, and temperatures. The results are summarized in Table 2. In
this transformation, catalyst loadings in the range of 0–15 % were tested. From the
result table, we concluded that the lower yield of the product was observed in the
absence of the catalyst (Table 2, Entry 1). In addition, it was discovered that the
reaction was rather slow and resulted in poor yield (29 %) in the absence of the
catalyst when the reaction was carried out in refluxing water for 60 min (Table 2,
Entry 2), which demonstrates that the catalyst is essential for formation of the
product in high yield. The yields of product were also increased slightly by adding
5 and 10 mol% of TUD to the reaction mixture at room temperature (Table 2,
Entries 3, 4).
Table 1 Evaluation of catalytic
activity of different catalysts for
the condensation of
a
Entry Catalyst
Catalyst loading
mol%)
Time
(min)
Yield
(%)
(
benzaldehyde, malononitrile,
ethyl acetoacetate and hydrazine
hydrate in water at 80 °C
1
2
3
4
5
6
FeCl
InCl
ZnCl
3
Á6H
2
O
10
10
10
10
10
10
40
40
40
40
40
30
58
66
72
60
68
96
3
2
p-TSA
CAN
TUD
a
Isolated yields
1
23

A green and one-pot synthesis of a library of…
Table 2 Optimization of the reaction conditions
a
Yield (%)
Entry
Solvent
Catalyst loading
mol%)
Temperature (°C)
Time (min)
(
1
2
3
4
5
6
7
8
9
H
H
H
H
H
2
2
2
2
2
O
–
r.t.
30
60
30
60
40
40
40
40
40
40
40
30
30
30
30
30
30
30
30
Trace
29
36
48
74
70
72
55
43
38
36
96
72
79
88
69
78
84
96
O
–
80 °C
r.t.
O
5.0
O
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
2.5
r.t.
O/EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80 °C
50 °C
60 °C
70 °C
80 °C
80 °C
80 °C
80 °C
MeOH
EtOH
MeCN
CH
EtOAc
CHCl
2
Cl
2
10
11
12
13
14
15
16
17
18
19
3
H
2
O
O
O
O
O
O
O
O
H
2
H
2
H
2
H
2
H
2
H
2
H
2
5.0
7.5
12.5
Bold value indicates optimize reaction conditions
a
Isolated yields
To evaluate the effects of different solvents on the reaction, the model reaction
was conducted in a range of different solvents, including methanol, ethanol,
acetonitrile, dichloromethane, ethyl acetate, chloroform, and water under reflux
conditions in the presence of 10 mol% TUD catalyst (Table 2, Entries 6–11).
Aprotic solvents gave the desired product in lower yields, whereas protic solvents
gave the product in good to excellent yields. Water was clearly identified as the
solvent of choice, because it provided the highest yield of the desired product, as
well as being the most cost-effective and environmental acceptable of the solvents
tested (Table 2, Entry 12). On the other hand, a mixture of EtOH:H O (1:1, v/v)
2
afforded a moderate yield of the desired product 5a under similar conditions
(
Table 2, Entry 5). Having optimized the solvent for the reaction, we proceeded to
investigate the use of different temperatures including room temperature and 50, 60,
0, and 80 °C (Table 2, Entries 12–15). Increasing the temperature of the reaction
7
from room temperature to 80 °C led to a reduction in the reaction time. The greatest
yield in the shortest reaction time was obtained in water at 80 °C (Table 2, Entry
1
2). In the next step, the reaction was carried out with various amounts of catalyst in
water at 80 °C. It was found that, by increasing the amount of catalyst from 2.5 to
0 mol% under reflux conditions, the yield of 6-amino-3-methyl-4-phenyl-1,4-
1
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) was improved (Table 2, Entries 8
and 16–18). In addition, higher amounts of catalyst, that is 12.5 mol%, can not
123

R. H. Vekariya et al.
improve product yields and the reaction times (Table 2, Entry 19). Hence, the best
results were obtained by performing the reaction in the presence of 10 mol% of
TUD in refluxing water.
To evaluate the scope of this catalytic transformation, the optimized reaction
conditions were subsequently applied to the reaction of ethyl acetoacetate,
hydrazine hydrate, and malononitrile with a variety of different aromatic aldehydes
(
Table 3, Entries 1–24). A wide range of aromatic aldehydes bearing either
electron-releasing or electron-withdrawing substituents reacted successfully to give
the corresponding products in high to excellent yields over short reaction times. In
all cases, the reaction was found to be selective and afforded the desired products in
high purity without any evidence of the formation of any side products. In addition,
Table 3 Synthesis of synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles catalyzed by TUD
a
Entry
Ar
Time (min)
Yield (%)
Mp (°C)
Ref.
1
2
3
4
5
6
7
8
9
C
6
H
5
30
38
38
40
45
50
30
34
40
48
45
35
38
32
40
33
30
38
40
40
30
32
40
36
96
92
86
92
95
90
96
94
88
87
94
95
90
94
88
94
92
90
88
88
94
95
92
95
245–246
224–226
167–169
209–211
211–212
193–195
147–148
233–235
207–209
217–219
199–201
179–180
187–189
251–252
259–260
248–249
220–222
251–252
209–210
191–192
244–246
196–197
254–255
227–228
[79]
[79]
[32]
[80]
[79]
[79]
[79]
[79]
[79]
[34]
–
4-OH–C
4-N(Me)
2-OH–C
4-OMe–C
3-NO –C
6 5
H
2 6 5
–C H
6
H
5
6
H
5
2
6 5
H
2-Cl–C
6
6
H
5
5
4-Cl–C
H
4-Me–C
6 5
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2-furayl
b
3,5-diOMe–4-OH–C
4-Br–C
3,4-diOMe–C
6 3
H
6
H
5
[79]
[81]
[79]
[79]
[51]
[51]
[51]
[51]
[51]
[51]
[46]
–
6 4
H
4-NO
3-OH–C
2-Br–C
2-NO –C
2-OMe–C
2
–C
6
H
5
6 5
H
6 5
H
2
6
H
5
6 5
H
3,4,5-triOMe–C
6 3
H
2-Thienyl
4-F–C
4-CN–C
2-OH–5-NO
2-OH–5-Br–C
6 5
H
6 5
H
2 6 5
–C H
6
H
5
–
Reaction conditions: Ethyl acetoacetate (1 mmol), hydrazine hydrate (1.5 mmol, 80 %), aromatic alde-
hydes (1 mmol), and malononitrile (1 mmol) in water at the 80 °C in the presence of TUD (10 mol%)
a
Isolated yield
b
Novel compound
1
23

A green and one-pot synthesis of a library of…
heterocyclic aldehyde like 2-furfuraldehyde and 2-thienyl could also reacted
efficiently, which afforded product in excellent yields (Table 3, Entries 10 and 20).
To broaden the scope of the reaction, we have prepared quinoline hybride
pyrano[2,3-c]pyrazolo derivative efficiently using TUD as a green organocatalyst.
For this synthesis, we used 2-chloroquinoline-3-carbaldehyde, which was synthe-
sized from the acetanilide via a Vilsmeier-Haack reaction [82]. Here, we achieved
9
2 % of product yield within 32 min (Mp = 270–272 °C) (Scheme 2).
Scheme 2 Synthesis of 6-amino-4-(2-chloroquinolin-3-yl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-
-carbonitrile (25)
5
Scheme 3 Probable mechanistic pathway
123

R. H. Vekariya et al.
Fig. 1 Recyclability of TUD for
the synthesis of compound 1
Recyclability of the TUD
100
95
90
85
80
1
2
3
4
5
Run No.
We have also proposed a possible mechanism for the building of final products
1–15) (Scheme 3). The nitrile anion (E) was formed by the removal of acidic
(
hydrogen from malononitrile (D) catalyzed by TUD. Finally, the arylidene nitrile
intermediates (Knoevenagel adducts, F) are formed through the Knoevenagel
condensation reaction of the intermediate nitrile anion (E) with aldehydes (C). On
other hand, the reaction of ethyl acetoacetate and hydrazine hydrate afforded
compound (G), which was enolised in the presence of TUD to formed compound
(
H). Subsequently, the enolizable compound (H) condensed with the Knoevenagel
adducts (F) via Michael addition, which results in the in situ formation of
intermediate (I) (Michael adducts). Then there is subsequent intramolecular
nucleophilic cyclization (Thorpe–Ziegler type reaction) and tautomerization to
afford the desired compounds (1–15).
Next, we checked the recyclability of the catalyst by performing the reaction of
ethyl acetoacetate, hydrazine hydrate, benzaldehyde, and malononitrile in the
presence of a catalytic amount of 10 mol% of TUD in water. After completion of
the reaction, the reaction mixture was diluted with water (10 mL), and the resulting
solid was removed by filtration, and washed with water. The remaining aqueous
thiourea dioxide was collected, water was evaporated under vacuum, and the
obtained catalyst was washed with ethyl acetate and dried. The recycling ability of
the TUD was tested for four runs, which providing 96–90 % of the desired product
yield in a similar reaction time. The results of recycling experiments are given in
Fig. 1.
Conclusion
In summary, we have established a green and highly efficient one-pot four-
component protocol for the preparation of various 6-amino-1,4-dihydropyrano[2,3-
c]-pyrazole-5-carbonitriles catalyzed by TUD. The TUD catalyst was easily
prepared by the oxidation of thiourea with hydrogen peroxide. There are numerous
striking features to this protocol, including high yield of products with high purity, a
simple work-up process, avoidance of the use of hazardous organic solvents,
aqueous conditions, and a simple work-up procedure make the present method a
valuable contribution in agreement with green chemistry principles. The use of
TUD as an inexpensive, reusable, and non-volatile catalyst makes the method
environmentally friendly, green, and economically viable.
1
23

A green and one-pot synthesis of a library of…
Acknowledgments The authors are thankful to the Department of Chemistry, Gujarat University
Ahmedabad, for providing the necessary facilities. UGC-Info net and INFLIBNET Gujarat University are
acknowledged for providing the e-resource facilities, NFDD Centre for proton NMR and carbon NMR
and Synzeal laboratory for mass spectroscopy. R.H.V. is thankful to UGC-BSR [F.7-74/2007 (BSR)] for
financial assistance.
References
1. A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
2. J. Zhu, H. Bienayme, Multicomponent Reactions (Wiley, Weinheim, 2006)
3. N.P. Prajapati, R.H. Vekariya, H.D. Patel, Synth. Commun. (2015). doi:10.1080/00397911.
00392015.01045986
4. D.M. D’Souza, T.J. Mueller, Chem. Soc. Rev. 36, 1095 (2007)
5. M.S. Singh, S. Chowdhury, RSC Adv. 2, 4547 (2012)
6. G. Feuer, G. Ellis, G. West, Ed. Ellis, GP and West, GB, North Holland Publishing Co., New York,
10, 85 (1974)
7. A. Goel, V.J. Ram, Tetrahedron 65, 7865 (2009)
8. J.Y.C. Wu, W.F. Fong, J.X. Zhang, C.H. Leung, H.L. Kwong, M.S. Yang, D. Li, H.Y. Cheung, Eur.
J. Pharmacol. 473, 9 (2003)
9. M. Rueping, E. Sugiono, E. Merino, Chem. Eur. J. 14, 6329 (2008)
1
1
1
0. D.O. Moon, K.C. Kim, C.Y. Jin, M.H. Han, C. Park, K.J. Lee, Y.M. Park, Y.H. Choi, G.Y. Kim, Int.
Immunopharmacol. 7, 222 (2007)
1. V.F. de Andrade-Neto, M.L.O. Goulart, J.F. da Silva Filho, M.J. da Silva, F. Maria do Carmo, A.V.
Pinto, M.G. Zalis, L.H. Carvalho, A.U. Krettli, Bioorg. Med. Chem. Lett. 14, 1145 (2004)
2. L.R. Morgan, B.S. Jursic, C.L. Hooper, D.M. Neumann, K. Thangaraj, B. LeBlanc, Bioorg. Med.
Chem. Lett. 12, 3407 (2002)
1
1
3. A. Mart ´ı nez-Grau, J. Marco, Bioorg. Med. Chem. Lett. 7, 3165 (1997)
4. A. Venkatesham, R.S. Rao, K. Nagaiah, J. Yadav, G. RoopaJones, S. Basha, B. Sridhar, A. Add-
lagatta, Med. Chem. Comm. 3, 652 (2012)
1
1
1
1
1
5. S. Hatakeyama, N. Ochi, H. Numata, S. Takano, Chem. Commun. 17, 1202 (1988)
6. F. Karcı, F. Karcı, Dyes Pigments 76, 97 (2008)
7. H. Kiyani, H. Samimi, F. Ghorbani, S. Esmaieli, Curr. Chem. Lett. 2, 197 (2013)
8. D. Shi, J. Mou, Q. Zhuang, L. Niu, N. Wu, X. Wang, Synth. Commun. 34, 4557 (2004)
9. M. Kangani, N. Hazeri, M.T. Mghsoodlou, S.M. Habibi-khorasani, S. Salahi, Res. Chem. Intermed.
41, 2513 (2015)
20. M. Kangani, N. Hazeri, M.T. Maghsoodlou, K. Khandan-Barani, M. Kheyrollahi, F. Nezhad-
shahrokhabadi, J. Iran. Chem. Soc. 12, 47 (2015)
2
2
2
1. G. Brahmachari, B. Banerjee, A.C.S. Sustain, Chem. Eng. 2, 411 (2013)
2. P.P. Bora, M. Bihani, G. Bez, J. Mol. Catal. B Enzym. 92, 24 (2013)
3. R.Y. Guo, Z.M. An, L.P. Mo, S.T. Yang, H.X. Liu, S.X. Wang, Z.H. Zhang, Tetrahedron 69, 9931
(2013)
2
2
4. H.F. Zhang, Z.Q. Ye, G. Zhao, Chin. Chem. Lett. 25, 535 (2014)
5. M.A. Zolfigol, M. Tavasoli, A.R. Moosavi-Zare, P. Moosavi, H.G. Kruger, M. Shiri, V. Khakyzadeh,
RSC Adv. 3, 25681 (2013)
2
6. V.L. Gein, T.M. Zamaraeva, I.V. Kozulina, Russ. J. Org. Chem. 50, 691 (2014)
7. S. Bhavanarushi, V. Kanakaiah, E. Yakaiah, V. Saddanapu, A. Addlagatta, J. VatsalaRani, Med.
Chem. Res. 22, 2446 (2013)
2
2
2
3
3
3
8. A. Keyume, Z. Esmayil, L. Wang, F. Jun, Tetrahedron 70, 3976 (2014)
9. L.K. Katariya, G.J. Kharadi, Int. J. Pharm. Res. Sch. 3, 627 (2014)
0. W. Liju, K. Ablajan, Curr. Org. Synth. 11, 310 (2014)
1. P.B. Pawar, S.D. Jadhav, B.M. Patil, R.V. Shejwal, S. Patil, Arch. Appl. Sci. Res. 6, 150 (2014)
2. A.R. Moosavi-Zare, M.A. Zolfigol, E. Noroozizadeh, M. Tavasoli, V. Khakyzadeh, A. Zare, New J.
Chem. 37, 4089 (2013)
3
3. D. Azarifar, S.M. Khatami, M.A. Zolfigol, R. Nejat-Yami, J. Iran. Chem. Soc. 11, 1223 (2013)
4. S.U. Tekale, S.S. Kauthale, K.M. Jadhav, R.P. Pawar, J. Chem. 2013, 1 (2013). doi:10.1155/2013/
3
840954
123

R. H. Vekariya et al.
3
3
3
3
3
4
4
4
4
4
4
5. J. Albadi, A. Mansournezhad, Z. Derakhshandeh, Chin. Chem. Lett. 24, 821 (2013)
6. D. Azarifar, S.M. Khatami, R. Nejat-Yami, J. Chem. Sci. 126, 95 (2014)
7. H.R. Shaterian, K. Azizi, Mild Res. Chem. Intermed. 40, 661 (2014)
8. K. Pradhan, S. Paul, A.R. Das, Catal. Sci. Technol. 4, 822 (2014)
9. J.M. Khurana, K. Vij, Synth. Commun. 43, 2294 (2013)
0. J. Safaei-Ghomi, A. Ziarati, M. Tamimi, Acta Chim. Slov. 60, 403 (2013)
1. M.A. ElAleem, A.A. El-Remaily, Tetrahedron 70, 2971 (2014)
2. S. Paul, K. Pradhan, S. Ghosh, S.K. De, A.R. Das, Tetrahedron 70, 6088 (2014)
3. M. Bihani, P.P. Bora, G. Bez, H. Askari, A.C.S. Sustain, Chem. Eng. 1, 440 (2013)
4. M. Wu, Q. Feng, D. Wan, J. Ma, Synth. Commun. 43, 1721 (2013)
5. A.I. Ilovaisky, M.G. Medvedev, V.M. Merkulova, M.N. Elinson, G.I. Nikishin, J. Heterocycl. Chem.
51, 523 (2014)
46. G.S. Kumar, C. Kurumurthy, B. Veeraswamy, P.S. Rao, P.S. Rao, B. Narsaiah, Org. Prep. Proced.
Int. 45, 429 (2013)
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
7
7
7
7
7
7
7
7
7
7
8
8
8
7. K. Ablajan, L.J. Wang, Z. Maimaiti, Y.T. Lu, Monatsh. Chem. 145, 491 (2014)
8. V.N. Bhosale, J.A. Angulwar, G.S. Khansole, G.S. Waghmare, J. Chem. Pharm. Res. 6, 733 (2014)
9. J. Albadi, A. Mansournezhad, F. Akbari Blout-Bangan, Acta Chim. Slov. 61, 185 (2014)
0. H. Adibi, L. Hosseinzadeh, S. Farhadi, F. Ahmadi, J. Repor. Pharm. Sci. 2, 116 (2013)
1. A.B. Atar, J.T. Kim, K.T. Lim, Y.T. Jeong, Synth. Commun. 44, 2679 (2014)
2. M. Parshad, V. Verma, D. Kumar, Monatsh. Chem. 145, 1857 (2014)
3. K. Ablajan, W. Liju, Y. Kelimu, F. Jun, Mol. Divers. 17, 693 (2013)
4. M. Farahi, B. Karami, I. Sedighimehr, H.M. Tanuraghaj, Chin. Chem. Lett. 25, 1580 (2014)
5. R. Heydari, F. Shahrekipour, Res. Chem. Intermed. 7, 4581 (2015)
6. C.F. Barbas, Angew. Chem. Int. Ed. 120, 44 (2008)
7. C.F. Barbas, Angew. Chem. Int. Ed. 47, 42 (2008)
8. S. Bertelsen, K.A. Jorgensen, Chem. Soc. Rev. 38, 2178 (2009)
9. K.L. Kimmel, M.T. Robak, J.A. Ellman, J. Am. Chem. Soc. 131, 8754 (2009)
0. S. Tanaka, K. Nagasawa, Synlett, 667 (2009). doi:10.1055/s-0028-1087811
1. E.M. Fleming, C. Quigley, I. Rozas, S.J. Connon, J. Org. Chem. 73, 948 (2008)
2. F. Wang, X. Liu, X. Cui, Y. Xiong, X. Zhou, X. Feng, Chem. Eur. J. 15, 589 (2009)
3. A. Peschiulli, Y. Gun’k, S.J. Connon, J. Org. Chem. 73, 2454 (2008)
4. Q.H. Wu, Y.J. Gao, Z. Li, Chin. J. Org. Chem. 27, 1491 (2007)
5. M. Nandi, J. Mondal, K. Sarkar, Y. Yamauchi, A. Bhaumik, Chem. Commun. 47, 6677 (2011)
6. R.H. Vekariya, H.D. Patel, Synth. Commun. 45, 1031 (2014)
7. R.H. Vekariya, H.D. Patel, ARKIVOC 1, 70 (2015)
8. R.H. Vekariya, H.D. Patel, ARKIVOC 1, 136 (2015)
9. R.H. Vekariya, H.D. Patel, RSC Adv. 5, 49006 (2015)
0. O. Ohura, O. Fujimoto, in Process for preparing thiourea dioxide. U.S. Patents, 11 Nov., (1980)
1. S. Verma, S. Kumar, S.L. Jain, B. Sain, Org. Biomol. Chem. 9, 6943 (2011)
2. S. Kumar, S.L. Jain, B. Sain, RSC Adv. 2, 789 (2012)
3. S. Verma, S.L. Jain, Tetrahedron Lett. 53, 6055 (2012)
4. M. Ghashang, S.S. Mansoor, K. Aswin, Chin. J. Catal. 35, 127 (2014)
5. M. Ghashang, S.S. Mansoor, K. Logaiya, K. Aswin, Res. Chem. Intermed. 40, 1135 (2014)
6. S. Kumar, S. Verma, S.L. Jain, B. Sain, Tetrahedron Lett. 52, 3393 (2011)
7. S. Sambher, C. Baskar, R.S. Dhillon, Synth. Commun. 38, 2150 (2008)
8. S. Verma, S.L. Jain, Tetrahedron Lett. 53, 2595 (2012)
9. H. Mecadon, M.R. Rohman, M. Rajbangshi, B. Myrboh, Tetrahedron Lett. 52, 2523 (2011)
0. K. Kanagaraj, K. Pitchumani, Tetrahedron Lett. 51, 3312 (2010)
1. M.B.N. Amin, A.R. Parikh, H. Parikh, M.V. Gudaparthi, Sch. Acad. J. Pharm. 3, 208 (2014)
2. B.F. Abdel-Wahab, R.E. Khidre, A.A. Farahat, ARKIVOC 1, 196 (2011)
1
23