Sodium ascorbate as an expedient catalyst for green synthesis of polysubstituted 5-aminopyrazole-4-carbonitriles and 6-amino-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles

Article abstract of DOI:10.1007/s11164-018-3260-0

Sodium ascorbate (SA) was used as a safe catalyst for the synthesis of 5-aminopyrazole-4-carbonitriles from the one-pot three-component cyclocondensation (3-CC) of aldehydes, phenylhydrazine, and malononitrile at 50?°C. This 3-CC proceeds in a mixture of

Full text of DOI:10.1007/s11164-018-3260-0

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3260-0
Sodium ascorbate as an expedient catalyst
for green synthesis of polysubstituted
5
‑aminopyrazole‑4‑carbonitriles and 6‑amino‑1,4‑dihyd
ropyrano[2,3‑c]pyrazole‑5‑carbonitriles
Hamzeh Kiyani1 · Maryam Bamdad1
Received: 23 November 2017 / Accepted: 8 January 2018
©
Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Sodium ascorbate (SA) was used as a safe catalyst for the synthesis of
-aminopyrazole-4-carbonitriles from the one-pot three-component cyclocondensa-
5
tion (3-CC) of aldehydes, phenylhydrazine, and malononitrile at 50 °C. This 3-CC
proceeds in a mixture of ethanol–water as a green reaction medium to give the
desired densely functionalized pyrazoles in good to high yields. 6-Amino-1,4-dihy-
dropyrano-[2,3-c]pyrazole-5-carbonitriles were also synthesized in the presence of
SA via an eco-friendly and simple four-component cyclocondensation (4-CC). This
4
-CC performed in reꢀuxing water as a green medium and dihydropyrano-[2,3-c]
pyrazole products were obtained in excellent yields and relatively shorter reaction
times. These environmentally friendly multicomponent cyclocondensations oꢁer
some interesting advantages, including time-saving, easily available starting materi-
als, mild conditions, minimizing the amount of waste, good atom eꢂciency, avoid-
ing hazardous organic solvents or catalysts, and the ease of the work-up.
Keywords 5-Aminopyrazole-4-carbonitrile · 6-Amino-1,4-dihydropyrano-[2,3-c]
pyrazole-5-carbonitrile · Green · Phenylhydrazine · Hydrazine · Sodium ascorbate
Introduction
A pyrazole unit possessing two adjacent nitrogen atoms in a ꢃve-membered het-
eroaromatic ring is a compound which shows a wide range of interesting biologi-
cal activities, such as antimicrobial, anti-inꢀammatory, analgesic, antiviral, anti-
bacterial, anticancer, anticonvulsant, cardiovascular, antihypertensive, antipyretic,
*
Hamzeh Kiyani
hkiyani@du.ac.ir
1
School of Chemistry, Damghan University, Damghan 36716-41167, Iran
1
3

H. Kiyani, M. Bamdad
cytotoxic, and antitubercular activities [1–9]. Pyrazoles are also known as key build-
ing blocks and structural motifs in the synthesis of pesticides, UV stabilizers, cos-
metic colorings, insecticides, fungicides, and ligands in coordination chemistry, as
well as antimalarial and antileishmanial agents [10–12]. Aminopyrazole as a type
of pyrazole has a widespread distribution in organic synthesis for the construction
of compounds with promising biological activity and as drug candidates [13–16].
Given such medicinal signiꢃcance of these heterocycles, the methods developed for
the synthesis of polysubstituted pyrazoles employ diꢁerent catalysts. Some of these
include the use of ionic liquids [17], molecular iodine [18–20], piperidinium acetate
[
21], Cu(OAc) [22], [Cp*RhCl ] and NaOAc [23], graphene oxide-TiO (GO-TiO )
2 2 2 2
[
24], oxone [25], CuO/ZrO [26], piperidine [27], eosin Y under atmospheric oxy-
2
gen [28], 1-methylimidazolium trinitromethanide {[HMIM]C(NO ) } [29], cerium
2
3
(
IV) ammonium nitrate [30], silica chloride [31], alum [32], Yb(PFO) [33], pal-
3
ladium and copper [34], CuBr-bpy [35], and AgOTf [36]. Moreover, PEG-400 and
water using ultrasound waves [37] is another synthetic method for the construction
of these signiꢃcant heterocyclic scaꢁolds.
On the other hand, 1,4-dihydropyrano[2,3-c]pyrazole and its derivatives are
another important fused heterocyclic frameworks that have many applications in
pharmaceutical chemistry. In many reports, 1,4-dihydropyrano[2,3-c]pyrazoles are
introduced as compounds that have attractive biological properties, such as antimi-
crobial, anti-inꢀammatory, analgesic, anticancer, vasodilator, human Chk1 kinase
inhibitor, and molluscicidal activities. In addition to using them in pharmaceutical
chemistry, 1,4-dihydropyrano[2,3-c]pyrazoles are recognized as antifungal agents
[
38–40].
The most well-known method for the synthesis of the pyrano[2,3-c]pyrazole
scaꢁold is the four-component cyclocondensation (4-CC) of aldehydes, hydrazine
derivatives, ethyl acetoacetate, and malononitrile. Up to now, the above-mentioned
4
-CC has been catalyzed by various catalysts, including β-cyclodextrin (β-CD)
[
41], cocamidopropyl betaine (CAPB) [42], lipase [43], urea [44], ZrO nanopar-
2
ticles [45], cetyltrimethylammonium chloride (CTACl) [46], NaOH [47], poly(4-
vinylpyridine) [48], meglumine [49], tetraethylammonium bromide (TEABr) [50],
silica-bonded N-propylpiperazine sodium n-propionate (SBPPSP) [51], nickel
nanoparticles [52], β-cyclodextrin-SO H [53], silica sodium carbonate (SSC) [54],
3
NaOAc [55], methyltriphenylpho-sphonium bromide [56], iodine [57], tungstate sul-
furic acid [58], molecular sieves [59], isonicotinic acid [60], 1,4-diazabicyclo[2.2.2]
octane (DABCO) [61], phase transfer catalyst [62], thiourea dioxide (TUD) [63],
p-toluenesulfonic acid (p-TsOH) [64], phenylboronic acid [65], starch-sulfuric acid
(
SSA) [66], sodium benzoate [67], and the juice of Citrus limon [68].
Multistep one-pot processes in organic synthetic chemistry that generate a single
product from more than two substrates are called multicomponent reactions (MCRs)
[
69, 70]. MCRs have a special place in modern organic chemistry due to high eꢂ-
cacy, the rapid achievement of high levels of complexity and diversity of molecules,
time-saving operation, mild conditions, simplicity, environmental friendliness,
elimination of waste production, atom economy, energy eꢂciency, fewer side reac-
tions, costly puriꢃcation processes, the avoidance of changing the conditions dur-
ing the implementation of the reaction, and excellent functional group compatibility.
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
Scheme 1 Reaction of aldehydes (1a–s) with phenylhydrazine (2) and malononitrile (3) for the synthe-
sis of highly functionalized 5-aminopyrazole-4-carbonitriles (4a–r) in the presence of sodium ascorbate
(
SA)
Scheme 2 Four-component synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles (7a–p) catalyzed by SA
Also, carrying out of a MCR with a fuscous to avoid hazardous solvents and cata-
lysts has also received considerable attention [71–80]. Thus, according to the points
mentioned above, the development of eꢂcient and facile methods for the synthe-
sis of aminopyrazoles and 1,4-dihydropyrano[2,3-c]pyrazoles is still a challenge in
organic synthesis. Due to a variety of applications of the described heterocycles,
and in continuation of our previous work to develop green chemistry [71–75], in
this contribution, the catalytic performance of sodium ascorbate (SA) as the basic
organocatalyst has been explored in the rapid and eꢂcient synthesis of highly func-
tionalized 5-aminopyrazole-4-carbonitriles (Scheme 1) and 1,4-dihydropyrano[2,3-
c]pyrazole heterocyclic compounds (Scheme 2) in green solvents through MCRs.
To our knowledge, SA has not been used as the catalyst in the synthesis of 5-ami-
nopyrazole-4-carbonitriles and 1,4-dihydropyrano[2,3-c]pyrazoles under aqueous
conditions.
SA is a well-known anti-oxidant, which is often added to meat products and is
capable of reducing a variety of oxidative compounds, especially free radicals
[
81–84]. Furthermore, SA as a safe, green, and eꢁective organocatalyst has been
used for the Knoevenagel condensation of aldehydes with 2,2-dimethyl-1,3-dioxane-
,6-dione (Meldrum′s acid) [85], the synthesis of triazole ring by “click reaction”
4
1
3

H. Kiyani, M. Bamdad
strategy [86–88], and the synthesis of isoxazoles [89, 90]. It has also been applied as
a reducing agent in the synthesis of copper nanoparticles [91–93].
Experimental
General
All chemicals, unless otherwise speciꢃed, were purchased from commercial sources
and were used without further puriꢃcation, except liquid aldehydes, which were dis-
tilled before use. All the solvents were freshly dried and distilled before use. The
products were characterized by comparison of their physical data with those of
known samples or by their spectral data. Melting points of the products were meas-
1
13
ured on a Buchi 510 melting point apparatus and are uncorrected. H NMR and
C
NMR spectra were acquired with a Bruker Avance DRX-400 at 400 MHz in the
appropriate solvent (CDCl or DMSO-d ) at room temperature (rt). FT-IR spectra
3
6
were recorded on a Perkin Elmer RXI spectrometer. The development of the reac-
tions and purity of the products were monitored by thin layer chromatography (TLC)
analysis on Merck pre-coated silica gel 60 F aluminum sheets, visualized by UV
2
54
light.
General procedure for the 3‑C synthesis of polysubstituted
‑aminopyrazole‑4‑carbonitriles (4a–r)
5
A mixture of equimolar quantities of aryl/heteroaryl aldehyde (1, 1 mmol), phenyl-
hydrazine (2, 1 mmol), malononitrile (3, 1 mmol), and 15 mol% SA in a mixture
of ethanol:water (2:1, 5 mL) was stirred at 50 °C. After completion of the reac-
tion (monitored by TLC analysis), the reaction mixture was cooled to rt and poured
into water. The ꢃltered and the residue was taken in hot EtOH and ꢃltered again to
separate the product as ꢃltrate from the catalyst. The product was formed by cooling
the ꢃltrate or evaporation of the solvent. If necessary, further puriꢃcation was per-
formed by recrystallization from hot ethanol to give desired compounds in good to
high yields. NMR data for some target compounds are as follows:
5
‑Amino‑1,3‑diphenyl‑1H‑pyrazole‑4‑carbonitrile (4a)
1
H NMR (400 MHz, CDCl ): δ = 6.89 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.9 Hz, 2H),
3
7
.14 (d, J = 7.8 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.68
1
3
(
d, J = 8.5 Hz, 2H), 7.81 (s, 2H); C NMR (100 MHz, CDCl ): δ = 112.8, 113.4,
3
1
20.4, 126.5, 127.9, 128.1, 129.7, 135.8, 137.9, 146.2, 150.4, 156.4.
4
‑Amino‑3‑(4‑(dimethylamino)phenyl)‑1‑phenyl‑1H‑pyrazole‑5‑carbonitrile (4e)
1
H NMR (400 MHz, CDCl ): δ = 3.13 (s, 6H), 7.16 (s, 2H), 7.24–7.28 (m, 2H),
3
1
3
7
.63 (s, 1H), 7.66–7.81 (m, 2H), 7.79–7.82 (m, 4H); C NMR (100 MHz, CDCl ):
3
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
δ = 41.2, 108.4, 113.5, 115.4, 123.2, 125.5, 127.9, 128.2, 128.6, 129.5, 137.3, 144.1,
1
51.2.
5
‑Amino‑3‑(4‑nitrophenyl)‑1‑phenyl‑1H‑pyrazole‑4‑carbonitrile (4f)
1
H NMR (400 MHz, CDCl ): δ = 6.96 (s, 1H), 7.21–7.32 (m, 2H), 7.75–7.78 (m,
3
1
3
3
H), 7.81 (d, J = 7.6 Hz, 2H), 8.02 (s, 1H), 8.25 (d, J = 7.6 Hz, 2H); C NMR
(
100 MHz, CDCl ): δ = 112.4, 113.5, 123.4, 122.8, 129.9, 130.8, 131.6, 135.3,
3
1
38.8, 146.4, 149.7, 156.5.
5
‑Amino‑3‑(4‑hydroxy‑3‑methoxyphenyl)‑1‑phenyl‑1H‑pyrazole‑4‑carbonitrile (4j)
1
H NMR (400 MHz, DMSO-d ): δ = 3.92 (s, 3H), 6.85–6.93 (m, 2H), 7.07 (d,
6
J = 7.1 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.4 Hz, 2H), 7.41 (s, 1H),
1
3
7
1
1
.62 (s, 1H), 9.91 (s, 1H), 10.81 (s, 1H); C NMR (100 MHz, DMSO-d ): δ = 56.1,
6
13.5, 114.6, 118.9, 119.0, 119.4, 120.5, 131.8, 131.9, 133.0, 133.3, 138.7, 140.3,
50.5, 157.6.
5
‑Amino‑3‑(3‑nitrophenyl)‑1‑phenyl‑1H‑pyrazole‑4‑carbonitrile (4l)
1
H NMR (400 MHz, CDCl ): δ = 6.98 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H),
3
7
.36 (t, J = 7.5 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.89 (s, 1H), 8.02
1
3
(
d, J = 7.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H); C NMR (100 MHz,
CDCl ): δ = 112.2, 113.5, 121.2, 121.5, 123.1, 129.8, 130.0, 131.9, 134.1, 137.8,
3
1
44.5,149.3, 156.3.
5
‑Amino‑1‑phenyl‑3‑(thiophen‑2‑yl)‑1H‑pyrazole‑4‑carbonitrile (4q)
1
H NMR (400 MHz, CDCl ): δ = 6.92 (t, J = 7.3 Hz, 1H), 7.05 (dd, J = 3.6, 4.9 Hz,
3
1
H), 7.12 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 5.0 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H),
1
3
7
.51 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 7.84 (s, 1H); C NMR (100 MHz, CDCl ):
3
δ = 113.2, 114.2, 122.4, 120.6, 126.9,127.8, 128.7, 129.8, 132.7, 140.9, 142.9,
55.1.
1
General procedure for the 4‑C synthesis of 6‑amino‑1,4‑dihydropyrano‑[2,3‑c]
pyrazole‑5‑carbonitriles (7a‑p)
A mixture of aryl/heteroaryl aldehyde (1, 1 mmol), malononitrile (3, 1 mmol),
hydrazine hydrate (5, 1 mmol), ethyl acetoacetate (6, 1 mmol), and 15 mol% SA in
water (5 mL) was stirred under the reꢀuxing condition. After completion of the reac-
tion as indicated by TLC analysis, the reaction mixture was cooled to rt and the pre-
cipitated products were formed. The precipitated products were ꢃltered oꢁ and then
were taken in hot EtOH or chloroform and ꢃltered again to separate the products as
ꢃltrate from the catalyst (SA insoluble in chloroform and very slightly soluble in
water). The product was formed by cooling the ꢃltrate or evaporation of solvent. The
1
3

H. Kiyani, M. Bamdad
solid products were further puriꢃed through recrystallization in ethanol. NMR data
for some 6-amino-1,4-dihydropyrano-[2,3-c]pyrazole-5-carbonitriles are as follows:
6
‑Amino‑3‑methyl‑4‑phenyl‑2,4‑dihydropyrano[2,3‑c]pyrazole‑5‑carbonitrile(7a)
1
H NMR (400 MHz, DMSO-d ): δ = 1.78 (s, 3H), 4.57 (s, 1H), 6.87 (s, 2H),
6
1
3
7
.17–7.24 (m, 3H), 7.27–7.31 (m, 2H), 12.06 (s, 1H); C NMR (100 MHz, DMSO-
d ): δ = 9.7, 36.2, 57.2, 97.7, 126.7, 127.6, 127.8, 128.8, 135.7, 144.6, 154.8, 160.8.
6
6
‑Amino‑4‑(4‑methylphenyl)‑3‑methyl‑2,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7b)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 2.34 (s, 3H), 4.63 (s, 1H), 6.84
6
1
3
(
(
s, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 12.18 (s, 1H); C NMR
100 MHz, DMSO-d ): δ = 10.1, 22.5, 35.5, 56.5, 113.2, 118.0, 125.3, 128.2, 132.4,
6
1
35.8, 139.2, 155.6, 161.9.
6
‑Amino‑4‑(4‑methoxyphenyl)‑3‑methyl‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7c)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 3.74 (s, 3H), 4.50 (s, 1H), 6.86
6
1
3
(
(
s, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 12.09 (s, 1H); C NMR
100 MHz, DMSO-d ): δ = 9.6, 37.6, 55.4, 58.4, 98.2, 114.3, 121.3, 129.7, 145.5,
6
1
47.9, 155.4, 159.7, 162.6.
6
‑Amino‑4‑(4‑hydroxyphenyl)‑3‑methyl‑2,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7d)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 4.47 (s, 1H), 6.68 (d, J = 8.4 Hz,
6
1
3
2
H), 6.74 (s, 2H), 7.94 (d, J = 8.4 Hz, 2H), 9.26 (s, 1H), 12.03 (s, 1H); C NMR
(
100 MHz, DMSO-d ): δ = 9.7, 35.5, 57.8, 98.0, 115.1, 120.8, 128.4, 134.7, 135.5,
6
1
54.7, 156.0, 160.6.
6
‑Amino‑4‑(4‑(dimethylamino)phenyl)‑3‑methyl‑2,4‑dihydropyrano[2,3‑c]
pyrazole5‑carbonitrile (7e)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 2.85 (s, 6H), 4.45 (s, 1H), 6.66
6
1
3
(
(
d, J = 8.6 Hz, 2H), 6.74 (s, 2H), 6.96 (d, J = 8.6 Hz, 2H), 12.02 (s, 1H); C NMR
100 MHz, DMSO-d ): δ = 9.7, 35.3, 58.0, 98.2, 112.3, 120.9, 127.9, 129.5, 132.0,
6
1
35.4, 149.2, 154.8, 160.5.
6
‑Amino‑3‑methyl‑4‑(4‑nitrophenyl)‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7f)
1
H NMR (400 MHz, DMSO-d ): δ = 1.81 (s, 3H), 4.83 (s, 1H), 7.05 (s, br, 2H), 7.46
6
1
3
(
d, 2H, J = 8.4 Hz), 8.23 (d, 2H, J = 8.4 Hz), 12.14 (s, 1H); C NMR (100 MHz,
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
DMSO-d ): δ = 10.3, 34.2, 60.5, 98.4, 120.8, 124.0, 129.3, 136.0, 146.5, 149.3,
6
1
51.8, 161.5.
6
‑Amino‑4‑(4‑chlorophenyl)‑3‑methyl‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7g)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 4.62 (s, 1H), 6.93 (s, 2H), 7.19
6
1
3
(
d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 12.11 (s, 1H); C NMR (100 MHz,
DMSO-d ): δ = 9.7, 35.7, 56.8, 97.0, 120.5, 128.2, 129.2, 131.3, 135.6, 143.2,
6
1
54.7, 160.8.
6
‑Amino‑4‑(4‑hydroxy‑3‑methoxyphenyl)‑3‑methyl‑2,4‑dihydropyrano[2,3‑c]
pyrazole5‑carbonitrile (7h)
1
H NMR (400 MHz, DMSO-d ): δ = 1.82 (s, 3H), 3.71 (s, 3H), 4.48 (s, 1H), 6.54
6
(
dd, J = 1.8, 8.1 Hz, 1H), 6.73 (t, J = 8.8 Hz, 2H), 6.77 (s, 2H), 8.82 (s, 1H), 12.03
1
3
(
s, 1H, NH); C NMR (100 MHz, DMSO-d ): δ 9.8, 35.8, 55.6, 57.6, 97.9, 111.6,
6
1
15.4, 119.7, 135.4, 135.6, 145.2, 147.3, 160.7
6
‑Amino‑4‑(3,4‑dimethoxyphenyl)‑3‑methyl‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7i)
1
H NMR (400 MHz, DMSO-d ): δ = 1.83 (s, 3H), 3.70 (s, 3H), 3.84 (s, 3H), 4.55 (s,
6
1
H), 6.70 (dd, J = 2.0, 7.5 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.81 (s, 2H), 6.88 (d,
1
3
J = 8.3 Hz, 1H), 12.07 (s, 1H); C NMR (100 MHz, DMSO-d ): δ = 9.8, 35.8, 55.4,
6
5
7.3, 97.7, 111.2, 111.6, 119.6, 120.8, 135.6, 136.9, 147.5, 148.5, 154.8, 160.7.
6
‑Amino‑3‑methyl‑4‑(3‑nitrophenyl)‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7j)
1
H NMR (400 MHz, DMSO-d ): δ = 1.82 (s, 3H), 4.88 (s, 1H), 7.06 (s, 2H),
6
1
3
7
.63–7.69 (m, 2H), 8.03 (s, 1H), 8.14 (m, 1H), 12.22 (s, 1H); C NMR (100 MHz,
DMSO-d ): δ = 10.2, 36.0, 56.6, 97.2, 120.9, 122.3, 122.5, 130.8, 134.8, 136.2,
6
1
47.3, 148.4, 155.1, 161.6.
6
‑Amino‑4‑(2‑chlorophenyl)‑3‑methyl‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7k)
1
H NMR (400 MHz, DMSO-d ): δ = 1.80 (s, 3H), 5.17 (s, 1H), 7.06 (s, 2H), 7.26 (d,
6
J = 7.3 Hz, 1H), 7.32–7.44 (m, 2H), 7.49 (dd, J = 1.3, 7.8 Hz, 1H), 12.23 (s, 1H);
1
3
C NMR (100 MHz, DMSO-d ): δ = 9.5, 33.2, 55.6, 96.8, 120.4, 127.8, 128.6,
6
1
29.5, 130.7, 131.9, 135.4, 141.1, 154.8, 161.3.
1
3

H. Kiyani, M. Bamdad
6
‑Amino‑3‑methyl‑4‑(2‑nitrophenyl)‑1,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7l)
1
H NMR (400 MHz, DMSO-d ): δ = 1.79 (s, 3H), 5.21 (s, 1H), 7.06 (s, 2H), 7.35
6
(
d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.84 (d,
1
3
J = 8.0 Hz, 1H), 12.02 (s, 1H); C NMR (100 MHz, DMSO-d ): δ = 10.2, 29.2,
6
5
7.2, 118.1, 120.3, 126.8, 129.5, 132.5, 134.5, 136.7, 138.6, 150.3, 155.6, 165.2.
6
‑Amino‑3‑methyl‑4‑(thiophen‑2‑yl)‑2,4‑dihydropyrano[2,3‑c]
pyrazole‑5‑carbonitrile (7m)
1
H NMR (400 MHz, DMSO-d ): δ = 1.88 (s, 3H), 4.94 (s, 1H), 6.84–6.91 (m, 4H),
6
1
3
7
.29–7.32 (m, 1H), 12.06 (s, 1H); C NMR (100 MHz, DMSO-d ): δ = 9.9, 30.5,
6
5
7.5, 97.8, 121.0, 124.6, 125.0, 126.8, 136.4, 149.6, 153.8, 161.1.
Results and discussion
Our initial test reaction was run by the treatment of benzaldehyde (1a) with phe-
nylhydrazine (2) and malononitrile (3) without any catalyst in a mixture of etha-
nol–water (2:1, v:v) at rt and 50 °C for 30 min. The reaction did not occur in these
tests (Table 1, entries 1 and 2). When catalytic amounts of SA was added to the
same reaction mixture at 50 °C, the desired product (4a) was isolated with moderate
yield (70%) after 30 min (Table 1, entry 3). After achieving this encouraging result,
the reaction conditions were then screened with the aim of optimizing the yield of
4
a. It was observed that 4a could be obtained in 98% yield when SA (15 mol%) was
subjected to the reaction in reꢀuxing ethanol–water for 10 min (Table 1, entry 5).
Further increase of the amount of SA had no signiꢃcant beneꢃcial eꢁect on the reac-
tion (Table 1, entry 6). There were no satisfactory results from the reactions at other
temperatures (Table 1, entries 7–11). The same reaction had no signiꢃcant develop-
ment in other solvents such as water, ethanol, dichloromethane (DCM), dimethylfor-
mamide (DMF) and ethyl acetate (Table 1, entries 12–16). Also, running the reac-
tion in solvent-free conditions did not improve in yield (Table 1, entry 17).
Having established the optimal conditions for the synthesis of 4a, to extend the
catalyst performance, a range of available aldehydes (1a–r) were reacted with phe-
nylhydrazine (2), and malononitrile (3) under optimized reaction condition. The
results are summarized in Table 2. Both electron-deꢃcient, electron-rich, and heter-
oaromatic aldehydes were similarly viable, aꢁording the products (4a–r) in good to
high yields.
After the success of SA in the synthesis of functionalized pyrazoles
(
4a–r), we decided to explore the catalytic activity of SA in the preparation of
1
,4-dihydropyrano[2,3-c]pyrazoles. In this regard, we tried to achieve the best reac-
tion conditions. For this purpose, 4-CC of vanillin (2j), malononitrile (3), hydrazine
monohydrate (5), and ethyl acetoacetate (6) was selected as a model reaction (Table 3).
Excellent conversions of the starting compoundswere achieved and 98% yield
of
6-amino-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
Table 1 Optimization of the reaction conditions for the three-component synthesis of 5-amino-1,3-di-
phenyl-1H-pyrazole-4-carbonitrile (4a)
Entry
Catalyst load-
ing/mol%
Solvent
Temp./°C
Isolated yields/%
Time/min.
1
2
3
4
5
6
7
8
9
–
–
5
EtOH:H O (2:1)
rt
Trace
Trace
70
75
98
99
96
95
90
92
93
86
90
50
30
30
30
16
10
9
10
19
120
120
80
10
10
10
10
10
10
2
EtOH:H O (2:1)
50
50
50
50
50
60
70
25
30
40
50
50
50
50
50
50
2
EtOH:H O (2:1)
2
10
15
20
15
15
15
15
15
15
15
15
15
15
15
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
10
11
12
13
14
15
16
17
EtOH:H O (2:1)
2
EtOH:H O (2:1)
2
H O
2
EtOH
DCM
DMF
EtOAc
–
57
32
25
Optimized conditions are shown in bold
pyrazole-5-carbonitrile (7h) was obtained when the reaction was carried out in
reꢀuxing water in the presence of 15 mol% SA in 4 min (entry 5).
Under the optimal conditions, namely SA (15 mol%) as the catalyst, water as a
solvent, and reꢀux, various substituted aromatic aldehydes carrying either electron-
donating or electron-withdrawing substituents and aliphatic aldehydes (1u–v) were
converted into the expected 1,4-dihydropyrano[2,3-c]pyrazoles (7a–p) in good
to excellent yields. The results are summarized in Table 4. Benzaldehydes with
electron-donating and electron-withdrawing substitutions, heteroaryl aldehydes,
and aliphatic aldehydes worked well in this 4-CC. All the products synthesized in
this 4-CC are precipitated in the reaction vessel after cooling. The targeted com-
pounds were then obtained in high yield without any chromatographic puriꢃcation
methods.
The possible formation mechanism of densely functionalized pyrazoles is sug-
gested in Scheme 3. During the reaction, the aldehydes are activated, and the Kno-
evenagel products (10) are formed via reaction of anion 8 with activated aldehydes
1
3

H. Kiyani, M. Bamdad
Table 2 Sodium ascorbate (SA) promoted three-component synthesis of highly functionalized pyrazole
derivatives (4a–r) via Scheme 1
Comp. no
Structure of pyrazole derivatives Time/min. Isolated
m.p. /°C
yields/% Found
Lit. [17, 18, 29,
4]
7
4
a
10
13
98
95
157–159 159–160
4
b
117–118 118–120
4
c
8
97
95
107–108 106–108
208–210 209–211
4
d
12
4
e
11
10
88
90
104
105–107
4
f
156
164–166
4
4
4
4
g
h
i
14
15
15
10
98
96
92
98
128
128–130
164–165 163–165
Oil
Oil
j
120–121 120–121
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
Table 2 (continued)
Comp. no
Structure of pyrazole derivatives Time/min. Isolated
m.p. /°C
yields/% Found
Lit. [17, 18, 29,
4]
7
4
k
13
95
120–122 120–123
4
l
20
15
86
92
127–129 128–130
4
m
Semi-
solid
Semi-solid
4
4
4
n
0
p
18
18
20
92
93
88
161–162 160–161
130–131 129–130
159–161 160–162
4
4
q
r
10
14
93
91
137–139 138–140
224–225 223–225
(
6). In the next step, the Michael addition occurred between 10 and 11 in the pres-
ence of SA, which gave intermediate 12. After intramolecular cyclization and oxida-
tion, ꢃnal products (4a–r) were formed.
1
3

H. Kiyani, M. Bamdad
Table 3 Optimization of the reaction conditions for the four-component synthesis of 6-amino-4-(4-
hydroxy-3-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (7h)
Entry
Catalyst load-
ing/mol%
Solvent
EtOH
Temp./°C
Isolated yields/%
Time/min.
1
2
3
4
5
6
7
8
9
–
–
5
rta
Trace
Trace
50
55
98
91
88
40
72
30
53
50
67
70
60
60
3
3
4
3
H O
Reꢀux
Reꢀux
Reꢀux
Reꢀux
Reꢀux
Reꢀux
Reꢀux
Reꢀux
Reꢀux
100 °C
25 °C
50 °C
75 °C
2
H O
2
10
15
20
15
15
15
15
15
15
15
15
H O
2
H O
2
H O
2
EtOH
EtOH:H O (2:1)
DCM
DMF
–
6
9
2
12
10
50
40
15
10
10
11
12
13
14
H O
2
H O
2
H O
2
Optimized conditions shown in bold
a
The reaction was checked at r.t., 50, 80, 100, and 120 °C and the product did not form
Conclusions
In summary, SA has been found to be an eꢂcient and environmentally benign cat-
alyst for the synthesis of highly functionalized pyrazoles from aldehydes, phenyl-
hydrazine, and malononitrile as well as 6-amino-1,4-dihydropyrano-[2,3-c]pyra-
zole-5-carbonitrile derivatives from aldehydes, hydrazine, malononitrile, and ethyl
acetoacetate in good to excellent product yields. The reactions proceed eꢂciently
for the synthesis of highly substituted pyrazoles in an ethanol–water solvent sys-
tem at 50 °C. Pyrano-[2,3-c]pyrazoles have also been synthesized in reꢀuxing water
as a friendly reaction medium. These protocols are a promising methodology from
ecological and practical chemistry points of view. The simplicity of experimental
procedures, the ready availability of reactants and catalyst, green reaction media,
and safety of the catalyst makes this approach potentially useful for the synthesis of
four-substituted pyrazoles and dihydropyrano-[2,3-c]pyrazoles.
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
Table 4 The SA catalyzed synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles (7a–p) via Scheme 2
Comp. no
Structure of 1,4-dihydropyrano[2,3-
c]pyrazole derivatives
Time/min Isolated m.p. /°C
yields/%
Found
Lit. [42, 59, 60, 62, 75]
7
a
9
88
242–244 244–246
7
b
2
95
208–209 205–208
211–213 208–211
226–225 225–226
217–219 217–219
7
7
7
c
d
e
3
8
3
90
97
86
7
f
5
88
249–250 248–250
1
3

H. Kiyani, M. Bamdad
Table 4 (continued)
Comp. no
Structure of 1,4-dihydropyrano[2,3-
c]pyrazole derivatives
Time/min Isolated m.p. /°C
yields/%
Found
Lit. [42, 59, 60, 62, 75]
7
7
7
7
g
h
i
8
4
8
3
85
98
92
84
230–232 234–236
238–239 235–238
189–191 188–191
234–236 235–236
j
7
7
k
8
6
80
80
247–248 246–248
224–225 221–225
l
1
3

Sodium ascorbate as an expedient catalyst for green synthesis…
Table 4 (continued)
Comp. no
Structure of 1,4-dihydropyrano[2,3-
c]pyrazole derivatives
Time/min Isolated m.p. /°C
yields/%
Found
Lit. [42, 59, 60, 62, 75]
7
7
m
n
12
15
88
82
192–194 192–194
237–238 237–238
7
7
o
25
25
81
82
144–145 143–144
181–183 182–183
p
Scheme 3 A proposed reaction mechanism for SA-catalyzed synthesis of functionalized 5-aminopyra-
zole-4-carbonitriles (4a–r)
1
3

H. Kiyani, M. Bamdad
Acknowledgements The Damghan University is acknowledged for the provision of facilities.
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