Novel biocompatible glucose-based deep eutectic solvent as recyclable medium and promoter for expedient multicomponent green synthesis of diverse three and four substituted pyrazole-4-carbonitrile derivatives

Article abstract of DOI:10.1007/s11164-017-2908-5

A novel biocompatible glucose-based deep eutectic solvent (DES) is reported for the first time in the multicomponent synthesis of diverse three and four substituted pyrazole-4-carbonitrile derivatives under catalyst-free condition without using any harmful organic solvent even for purification of the products. The desired products were obtained with high degree of diversity from the reaction of malononitrile, aromatic aldehydes and various hydrazine derivatives as nitrogen source at room temperature within short reaction times and good to excellent product yields. The deep eutectic solvent was also recycled and reused at least four times with only a slight loss of efficiency. A plausible mechanism was also proposed indicating the role of DES hydrogen bonding in the reaction promotion.

Full text of DOI:10.1007/s11164-017-2908-5

Res Chem Intermed
DOI 10.1007/s11164-017-2908-5
Novel biocompatible glucose-based deep eutectic solvent
as recyclable medium and promoter for expedient
multicomponent green synthesis of diverse three
and four substituted pyrazole-4-carbonitrile derivatives
Reza Aryan1 Hamid Beyzaei1 Masoomeh Nojavan1
Meysam Rezaei1
•
•
•
Received: 30 November 2016 / Accepted: 11 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A novel biocompatible glucose-based deep eutectic solvent (DES) is
reported for the first time in the multicomponent synthesis of diverse three and four
substituted pyrazole-4-carbonitrile derivatives under catalyst-free condition without
using any harmful organic solvent even for purification of the products. The desired
products were obtained with high degree of diversity from the reaction of
malononitrile, aromatic aldehydes and various hydrazine derivatives as nitrogen
source at room temperature within short reaction times and good to excellent pro-
duct yields. The deep eutectic solvent was also recycled and reused at least four
times with only a slight loss of efficiency. A plausible mechanism was also proposed
indicating the role of DES hydrogen bonding in the reaction promotion.
Keywords Glucose-based deep eutectic solvents Á Green chemistry Á
Multicomponent reaction Á Pyrazole-4-carbonitrile derivatives Á Catalyst-free
conditions Á Recyclable medium
Introduction
Green chemistry considerations have recommended the application of biocompat-
ible building blocks such as natural products as reactant, medium and/or catalyst in
designing novel synthetic protocols to address the traditional inadequacies of
organic synthesis [1]. These thoughts dramatically influenced organic chemists’
research ideas more recently especially by the development of a novel class of
alternative solvents called deep eutectic solvents [2, 3]. Deep eutectic solvents
began to become very popular at the first years of the present century. These media
&
Reza Aryan
rezaaryanchemist@yahoo.com; rezaaryan@uoz.ac.ir
1
Department of Chemistry, Faculty of Science, University of Zabol,
P. O. Box 9861335856, Zabol, Iran
123

R. Aryan et al.
are usually composed of Lewis or Brønsted acids and bases but some of these
mixtures do not truly display an exact eutectic point or melting point but rather a
glass transition temperature point, and therefore they are also called low-melting
mixtures [4]. Moreover, this class of novel sustainable solvents is taken into account
as a new generation of designer solvents lacking deficiencies of ionic liquids as its
predecessors such as difficult synthesis and storage, high costs and biodegradability
issues [5]. These alternative reaction media have successfully been used for a
variety of scientific and technological applications. The production of biodiesel [6],
extraction of bioactive natural products [7], extraction and desulfurization of fuels
[8], and CO2 capture [9] have been reported most recently as some of the significant
industrial and technological roles of this novel class of solvents. These solvents
have been applied broadly for organic synthetic targets too. The synthesis of some
benzofused seven membered heterocycles [10], some thiophene derivatives [11],
2-aminoimidazoles [12], a-acyloxyamides [13], pyranopyrazole derivatives [14],
fully substituted naphthyridines [15], and cyanohydrin derivatives are among the
most recent reports in this research area. Most recently, deep eutectic solvents based
on natural products such as carbohydrates have gained much interest according to
the new perspectives of green chemistry. Numerous mixtures of this type of novel
sustainable green solvents have been prepared and their physical and structural
aspects were studied [16]. Therefore, deep eutectic solvents (DESs) can be regarded
as key constituent of the current novel synthetic methodologies. Not only can these
solvents play an individual role as the reaction medium but also they offer a
synergistic assistance to the normally used catalysts [4, 5].
Among heterocyclic building blocks, pyrazole derivatives have exhibited a broad
range of applications in medicinal chemistry and pharmacology. In recent years, this
heterocyclic scaffold has been utilized as partial agonists for nicotinic acid receptors
[17], CDK inhibitors [18], p38 kinase inhibitors [19], novel antidepressants [20]
novel antiviral agents [21], novel antimicrobial agents [22], and novel antifungal
agents [23] solely or along with the contribution of various other structural motifs.
The application of pyrazole derivatives in the development of anticancer agents has
been also thoroughly investigated and verified [24, 25]. Furthermore, a number of
natural products possessing pyrazole moiety such as pyrazofurin, pyrazofurin B,
pyrazole-3(5)-carboxylic acid and 4-methylpyrazole-3(5)-carboxylic acid have been
isolated and their medicinal features have been investigated [26] (Fig. 1).
The presence of specific substituents such as aryl, cyano or amino groups on
pyrazole ring appears to play an important role in the observed bioactivity effects of
pyrazole containing building blocks. For instance, a library of novel pyrazole
CONH2
NH
CONH2
NH
HO
HO
H3C
O
N
O
N
NH
NH
N
N
HOOC
HO
HO
HOOC
OH
OH
HO
HO
4-Methylpyrazole-3(5)-carboxylic acid
Pyrazole-3(5)-carboxylic acid
Pyrazofurin B
Pyrazofurin
Fig. 1 Structures of some natural products possessing pyrazole ring with various polar substituents
123

Novel biocompatible glucose-based deep eutectic solvent…
derivatives possessing amino and cyano substituents on positions 3 and 4 of the
pyrazole ring has been synthesized recently as a new class of potent inhibitors of
interleukin 8-induced neutrophile chemotaxis (Fig. 2a) [27]. Most recently, some
other novel pyrazole derivatives containing aryl substituents on C-3 or C-5 have
been exposed to have arginine methyltransferase inhibition effects (Fig. 2b) [28].
Consequently, these facts reveal that pyrazole heterocycles have a great potential
to be considered as the target for diversity-oriented organic synthesis (DOS)
strategies from the medicinal chemistry viewpoints. Access to complex and diverse
small molecules that are disclosing great potential in modifying the activity of many
targets that have largely been outside the horizon of traditional compound libraries
will be achieved as a result of this type of synthetic strategy [29]. Multicomponent
reactions are the most efficient tools in order to simply introducing diversity into the
structure of chemical compounds [30–32]. The reaction of hydrazine derivatives
with in situ prepared dielectrophilic reagents is one of the most popular MCR type
strategies for the synthesis of pyrazoles but the reported methodologies suffer from
drawbacks of using traditional synthetic methods such as using toxic reagents,
strong acidic or basic conditions, expensive reagents and catalysts [33–35].
With a view of these considerations, and as part of our ongoing efforts toward
introducing novel green and straightforward synthetic protocols toward valuable
heterocyclic derivatives [36–38], herein, we wish to disclose the introduction of
novel glucose-based deep eutectic solvent as medium and promoter in the
multicomponent synthesis of three and four substituted pyrazole-4-carbonirile
derivatives as our primary objective. The secondary objective was to provide target
products possessing significant aryl, amino and cyano substituents at various
positions of the pyrazole ring. The products having these structural units would
seriously be as potential candidates for developing drugs with promising
bioactivities.
Experimental
The chemicals applied in this work were obtained from Fluka or Merck companies
and used without further purification. Melting points of the products were recorded
on a Buchi B-540 apparatus and are uncorrected. FT-IR spectra were recorded on an
1
ABB Bomem Model FTLA 200-100 instrument. H and 13C NMR spectra were
(a)
(b)
O
NC
O
O
O
HN
N
N
N
N
H
N
N
OH
N
H
Fig. 2 Chemical structure of a novel interleukin 8-induced neutrophil chemotaxis inhibitors and
b arginine methyltransferase inhibitor is presented. The crucial structural parts are shown inside circles
123

R. Aryan et al.
measured on a Bruker DRX-300 spectrometer, at 400 and 100 MHz respectively,
using TMS as an internal standard. Chemical shifts (d) were reported relative to
TMS, and coupling constants (J) were reported in Hertz (Hz). Mass spectra were
recorded on a Shimadzu QP 1100 EX mass spectrometer with 70-eV ionization
potential. Elemental analyses of new compounds were performed with a Vario EL
III 0 serial no. 11024054 instrument. Viscosity of the prepared glucose:urea-(1:5)
was measured by a Brookfield DV-II? Pro EXTRA viscometer according to ASTM
D445 testing method (Table 1).
Preparation of deep eutectic solvents
The chemical components of biocompatible deep eutectic solvents used in the
present study were poured and mixed thoroughly by stirring inside the reaction
vessel with the specified molar ratios under heating at 100–120 °C (Table 2). After
around 30 min, a nearly transparent liquid was formed in each case (for example for
glucose:urea-1:5, Fig. 3). The prepared solvents were then directly applied in the
subsequent synthetic reactions.
General procedure for the deep eutectic solvent promoted synthesis of pyrazole-
4-carbonitrile derivatives:
Benzaldehyde derivative (1 mmol), malononitrile (1 mmol) and hydrazine
derivative (1 mmol) were added consecutively to the reaction vessel containing
1 g of the freshly preformed glucose:urea-(1:5). The reaction mixture was stirred at
ambient temperature for specified times (Table 3) and monitored by thin layer
chromatography analysis using various mixtures of ethyl acetate and n-hexane as
eluent. After completion of the reactions, water (10 ml) was added to the reaction
mixture and the mixture was stirred for around half an hour at ambient temperature
until products completely separated. The precipitates were then filtered off under
reduced pressure by a Bu¨chi funnel and washed by ethanol–water mixtures
whenever necessary to furnish the desired product. No tedious chromatographic
purification was needed.
Spectroscopic and physical data of new 5-amino-3-arylpyrazole-4-carbonitrile
derivatives (Table 3):
Table 1 Exploration of various glucose:urea mixtures for possible novel deep eutectic solvents
Entry
Mixture
Proportion
Physical state at
room temperature
Melting point
(°C)
Viscosity at
25 8C (cPa)
1
2
3
4
5
6
7
8
Glucose/urea
Glucose/urea
Glucose/urea
Glucose/urea
Glucose/urea
Glucose/urea
Glucose/urea
Glucose/urea
1:1
1:2
1:3
1:4
1:5
1:6
2:1
3:1
Solid
120
106
86
–
Solid
–
Solid
–
Solid
72
–
Clear colorless liquid
15
10,550
Solid
Solid
Solid
77
–
–
–
78
72
123

Novel biocompatible glucose-based deep eutectic solvent…
Table 2 The results of the stepwise synthesis of pyrazole-4-carbonitrile derivatives in the presence of
various DES
Run Solventa
No.
Temperatureb Time for
Yield for
stepwise
Time for
Yield for
(°C)
stepwise
multicomponent multicomponent
approach (min.) approachd (%)
processc (h) processd
(%)
1
2
3
Glucose/
urea 1:5
30
70
30
4
3
6
66
75
52
30
30
90
91
92
73
Glucose/
urea 1:5
Citric
acid/
urea/
CaCl2
5:4:1
4
Citric
acid/
urea/
CaCl2
5:4:1
70
5
63
75
74
5
6
Ribose/
urea/
30
70
7.5
6.5
49
64
120
100
68
71
CaCl2
5:4:1
Ribose/
urea/
CaCl2
5:4:1
7
8
9
Urea/ChCl 30
2:1
6
65
72
–
50
84
Urea/ChCl 70
2:1
4.5
24
50
86
Tartaric
acid/
ChCl 1:2
30
24 h
Trace
10
Tartaric
acid/
ChCl 1:2
70
24
–
24 h
Trace
a
The amount of solvent mixtures used for 1 mmol of the reactants was 1 g
The temperature was kept constant since the addition of first reactants
b
c
d
The reported times are due to the times required for the reactions after addition of hydrazine hydrate
The isolated products yield
5-Amino-3-(2-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (entry 2)
M. p. 213–216 °C. IR (KBr): 3456, 3081, 3069, 2280, 1620 cm-1
.
1HNMR
(400 MHz, DMSO-d6): 7.38–7.46 (m, 5H), 8.24 (d, J = 7.2 Hz), 9.1 (s, 1H) ppm.
13CNMR (100 MHz, DMSO-d6): 84.6, 127.1, 128.3, 130.1, 131.4, 132.2, 135.8,
123

R. Aryan et al.
Fig. 3 The prepared glucose:urea-1:5 natural deep eutectic solvent
154.3, 156.9, 159.1 ppm. MS (m/z): 200 (M?), Elemental Analysis: C10H8N4O
calculated: C, 59.99; H, 4.03; N, 27.99; O, 7.99; Found: C, 59.62; H, 4.32; N, 27.71;
O, 7.76.
5-Amino-3-(2-chloroxyphenyl)-1H-pyrazole-4-carbonitrile (entry 3)
1
M. p. 172 °C. IR (KBr): 3456, 3081, 3069, 2280, 1620 cm-1. HNMR (400 MHz,
DMSO-d6): 7.00 (t, 1H, J = 7.2 Hz), 7.06 (d, 1H, J = 7.6 Hz), 7.38–7.42 (m, 2H),
8.75 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6): 81.2, 116.8, 128.9, 129.3, 130.4,
131.2, 132.7, 133.8, 149.9, 153.6 ppm. MS (m/z): 218 (M?) 220 (M?), Elemental
Analysis: C10H7ClN4 calculated: C, 54.93; H, 3.23; N, 25.62; Found: C, 54.62; H,
3.52; N, 25.88.
5-Amino-3-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile (entry 4)
1
M. p. 194 °C. IR (KBr): 3456, 3081, 3069, 2280, 1620 cm-1. HNMR (400 MHz,
DMSO-d6): 7.84 (t, 1H, J = 8.0 Hz), 8.33 (d, 1H, J = 7.6 Hz), 8.38 (d, 1H,
J = 8.0 Hz), 8.73 (s, 1H), 8.94 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6): 81.2,
116.8, 128.9, 129.3, 130.4, 131.2, 132.7, 133.8, 149.9, 153.6 ppm. MS (m/z): 229
(M?), Elemental Analysis: C10H7N5O2 calculated: C, 52.40; H, 3.08; N, 30.56;
Found: C, 52.12; H, 3.52; N, 30.88.
5-Amino-3-(4-benzyloxyphenyl)-1H-pyrazole-4-carbonitrile (entry 6)
1
M. p. 194 °C. IR (KBr): 3456, 3081, 3069, 2280, 1620 cm-1. HNMR (400 MHz,
DMSO-d6): 7.06 (d, 2H, J = 8.8 Hz), 7.43–7.46 (m, 5H), 7.82 (d, 2H, J = 8.8 Hz),
8.66 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6): 67.3, 78.2, 116.9, 117.7, 127.1,
127.8, 128.3, 128.8, 130.6, 138.4, 145.7, 154.3, 158.9 ppm. MS (m/z): 290 (M?),
Elemental Analysis: C17H14N4O calculated: C, 70.33; H, 4.86; N, 19.30; Found: C,
70.02; H, 5.02; N, 19.61.
123

Novel biocompatible glucose-based deep eutectic solvent…
Table 3 Glucose/urea 1:5 mixture promoted synthesis of highly substituted pyrazole-4-carbonitrile
derivatives
Entry Ra
Benzaldehyde
substituent
Product
Time
(min)
Yield
(%)a
CN
1
2
H
H
H
30
93
H2N
HN
N
CN
2-OH
20
89
H2N
HN
N
HO
Cl
CN
3
H
2-Cl
20
88
H2N
HN
N
CN
4
5
6
7
8
9
H
H
H
H
H
Ph
3-NO2
4-Cl
20
30
30
30
15
10
90
91
96
85
89
85
H2N
HN
NO2
Cl
N
CN
H2N
HN
N
CN
4-BnO
4-Acetamido
4-Cyano
H
O
Ph
H2N
HN
N
H
CN
N
H2N
HN
O
N
CN
CN
H2N
HN
N
H2N
CN
N
N
H2N
CN
10
11
12
Ph
Ph
Ph
2-OH
2-Cl
20
20
15
90
83
88
HO
Cl
N
N
H2N
CN
N
N
N
CN
H2N
3-NO2
N
NO2
123

R. Aryan et al.
Table 3 continued
Entry Ra
Benzaldehyde
substituent
Product
Time
(min)
Yield
(%)a
CN
13
14
Ph
4-Cl
H2N
15
96
N
N
Cl
CN
H2N
Ph
4-Cyano
20
91
N
N
CN
H2N
NO2
CN
15
16
2,4-(NO2)2Ph
H
50
45
89
92
N
N
O2N
O2N
H2N
CN
2,4-(NO2)2Ph 4-Cl
NO2
N
N
Cl
a
Isolated yields
5-Amino-3-(4-acetamidophenyl)-1H-pyrazole-4-carbonitrile (entry 7)
M. p. 320–322 °C. IR (KBr): 3466, 3320, 3098, 3043, 2260, 1665, 1620 cm-1
.
1HNMR (400 MHz, DMSO-d6): 2.08, (s, 3H), 7.71 (d, 2H, J = 8.8 Hz), 7.80 (d,
2H, J = 8.8 Hz), 8.61 (s, 1H), 10.2 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6):
24.1, 82.4, 116.9, 118.7, 118.8, 128.3, 128.4, 129.1, 141.8, 147.2, 160.7, 168.6 MS
(m/z): 241 (M?), Elemental Analysis: C12H11N5O calculated: C, 59.74; H, 4.60; N,
29.03; Found: C, 59.48; H, 4.81; N, 29.31.
5-Amino-3-(4-cyanophenyl)-1H-pyrazole-4-carbonitrile (entry 8)
M. p. 304–306 °C. IR (KBr): 3421, 3073, 3052, 2227, 1624 cm-1
.
1HNMR
(400 MHz, DMSO-d6): 7.61 (d, 2H, J = 8.4 Hz), 7.69 (s, 2H), 7.74 (d, 2H,
J = 8.4 Hz), 8.56 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6): 78.5, 121.1,
125.3, 129.0, 132.4, 132.8, 135.1, 141.8, 152.1 ppm. MS (m/z): 209 (M?),
Elemental Analysis: C11H7N5 calculated: C, 63.15; H, 3.37; N, 33.48; Found: C,
62.91; H, 3.61; N, 33.11.
5-Amino-1-(2,4-dinitrophenyl)-3-phenyl-1H-pyrazole-4-carbonitrile (entry 15)
1
M. p. 225–227 °C. IR (KBr): 3315, 3285, 3096, 3039, 2223, 1621 cm-1. HNMR
(400 MHz, DMSO-d6): 7.48–7.50 (m, 1H), 7.56 (t, 3H, J = 7.6 Hz), 7.65 (d, 2H,
J = 7.2 Hz), 7.93 (d, 3H, J = 7.6 Hz), 8.41 (s, 1H) ppm. 13CNMR (100 MHz,
DMSO-d6): 82.9, 112.6, 113.7, 116.8, 121.1, 123.5, 127.3, 129.0, 129.6, 130.8,
123

Novel biocompatible glucose-based deep eutectic solvent…
134.7, 147.9, 152.7, 160.0 ppm. MS (m/z): 350 (M?). Elemental analysis:
C16H10N6O4 Calculated: C, 54.86; H, 2.88; N, 23.99; Found: C, 54.57; H, 3.10;
N, 23.68.
5-Amino-1-(2,4-dinitrophenyl)-3-(4-chlorophenyl)-1H-pyrazole-4-carbonitrile
(entry 16)
1
M. p. 234–236 °C. IR (KBr): 3415, 3343, 3109, 3065, 2228, 1613 cm-1. HNMR
(400 MHz, DMSO-d6): 7.56 (d, 1H, J = 8.8 Hz), 7.67 (d, 1H, J = 9.6 Hz), 7.72 (d,
2H, J = 8.8 Hz), 7.82 (d, 1H, J = 8.8 Hz), 7.95 (d, 2H, J = 8.8 Hz), 8.6 (s, 1H),
8.70 (s, 1H) ppm. 13CNMR (100 MHz, DMSO-d6): 82.2, 115.5, 121.0, 122.9, 123.4,
128.0, 129.1, 129.7, 132.1, 133.1, 139.0, 148.0, 152.6, 160.1 ppm. MS (m/z): 384
(M?) Elemental analysis: C16H9ClN6O4 Calculated: C, 49.95; H, 2.36; Cl, 9.21; N,
21.84; Found: C, 49.72; H, 2.62; Cl, 9.21; N, 21.62.
Results and discussion
Mixtures of various glucose:urea ratios were prepared and all were heated at
100–120 °C in order to checking the possibility for novel deep eutectic solvents.
Only the glucose/urea-(1:5) mixture ratio was remained liquid after cooling to room
temperature (Fig. 3) (Table 1). Therefore, this mixture was employed in the
exploration of novel green and effective conditions for the synthesis of novel
pyrazole-4-carbonitrile derivatives. The efficiency of this mixture for our synthetic
purpose was also compared to some previously introduced DESs. The reaction of
4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol) and hydrazine hydrate
(1 mmol) was studied under two different reaction protocols in the presence of
various deep eutectic solvents including the novel glucose-based mixture prepared
in this work.
The reaction of 4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol) and
hydrazine hydrate (1 mmol) was studied under two different reaction protocols in
the presence of various deep eutectic solvents including the novel glucose-based
mixture prepared in this work. Primarily under one-pot stepwise pattern, the
aldehyde and the malononitrile were allowed to react in the presence of several deep
eutectic solvents without using any extra catalyst (Scheme 1a). Hydrazine hydrate
was subsequently added to the reaction mixture to react with the in situ formed
benzylidene malononitrile. Then, in order to examine multicomponent approach, the
reactants were added simultaneously to the reaction vessel containing preformed
deep eutectic solvent mixtures under various reaction temperatures without using
any extra catalyst and reactant (Scheme 1b). In both approaches, the DESs were first
allowed to be cooled down near room temperature after formation under heating and
before addition of reactants. Two different temperatures were applied to the reaction
for fixed amount of any DES. Both protocols resulted in the formation of the desired
product 5-(4-chlorophenyl)-3-aminopyrazole-4-carbonitrile with remarkable dis-
similarities in reactivities and reaction progresses. The results are shown in Table 2.
123

R. Aryan et al.
Some important points can be deduced from data in Table 2. First of all, the
reactions well proceeded under the three component reaction protocol compared to
stepwise methodology resulting in shorter reaction times and relatively higher
product yields except for entries 9 and 10 related to tartaric acid/choline chloride
solvent mixture. The reaction did not advance remarkably in this DES mixture even
at more elevated temperatures and longer reaction times. The second important
point was that the reactions were performed within similar times and with
comparable yields at two different temperatures when the stepwise and multicom-
ponent reaction approaches were studied separately. This clarified that elevated
temperature condition could not affect the reaction progress independently. Among
the DES mixtures used in this reaction, the glucose/urea-(1:5) mixture was found as
the optimum solvent for both stepwise one-pot and multicomponent reaction
patterns.
Then, the effect of glucose/urea-(1:5) solvent mixture amount was studied. The
higher amounts of solvent led to comparable results of reaction times and yields for
the three-component model reaction. Although, the lower amounts of DES resulted
in forming a considerably more viscose reaction medium in which the reaction did
not perform simply. Thus, the amount of 1 g per 1 mmol of the reactants and the
reaction temperature of 30 °C were used as the optimum conditions.
The scope and generality of the present protocol was then examined using
various aldehydes and hydrazine derivatives as shown in Scheme 2. Literature
survey showed that phenylhydrazine and other more complex hydrazine derivatives
have been used as the nitrogen source in most cases and the products accessible
using hydrazine hydrate itself have been reported less abundantly [32–34]. Products
of hydrazine hydrate as nitrogen source were all prepared with the present protocol
efficiently (Table 2, entries 1–8). The structures of products along with the specific
reaction times and yields are presented in Table 2. Various hydrazine and
benzaldehyde derivatives were employed successfully and the products were
obtained within short reaction times in good to excellent yields. All reactions were
performed smoothly and the products were simply obtained by aqueous separation
O
(a)
N
N
1)
, DES
H2N
HN
CN
Cl
2) NH2NH2
N
N
Cl
N
N
Cl
(b)
O
CN
H2N
HN
DES
NH2NH2
+
+
N
Cl
N
Cl
Scheme 1 Deep eutectic solvent mediated model reactions for the synthesis of 3-amino-5-(4-
chlorophenyl)pyrazole-4-carbonitrile: a stepwise one-pot protocol, b multicomponent protocol
123

Novel biocompatible glucose-based deep eutectic solvent…
of the DES. So, the present protocol offered a broad scope for reactant diversity
from steric and electronic points of view. The electron donation or withdrawing and/
or steric hindrance of the reactants did not substantially affect the course of the
process. In comparison to two very recently reports [32–34], most of the products
were synthesized with considerably shorter reaction times and no need to use any
organic solvents even for purification and separation of the products.
Reusability has been always an option for consideration in the case of alternative
green solvents. Therefore, the possibility of recycling and reusing the glucose/urea
mixture solvent was studied in the model reaction. Water was poured to the reaction
mixture and the mixture was stirred for at least 1 h to assure complete dissolution of
solvent. After filtration of the product residues, water was removed under reduced
pressure and the residues of DES were then heated at 100–130 °C until the deep
eutectic solvent reformed. Then, the recycled solvent was again applied in the
model reaction so as to evaluating reusability of glucose/urea mixture. The results
presented in Fig. 3 showed a good reusability with a slight loss of efficiency after
four runs. The physical properties of this medium are an important factor in order to
explaining the role of DES in the fast and convenient synthesis of pyrazole-4-
carbonitrile derivatives. The pH value of glucose:urea-(1:5) mixture was measured
according to the method described in a previous report and a value of 6.80 was
found. [39] So, this mixture is not noticeably acidic or basic and the presence of
many hydrogen bonds between the solvent components should be the significant
criterion for explaining the observed reactivity in the present study [4, 5]. The
model reaction was led solely to the formation of 2-(4-chlorobenzylidene)
malononitrile even when performed under N2 as inert atmosphere at room
temperature for 12 h (Scheme 3). According to these findings, a plausible
mechanism is proposed in Scheme 4.
The glucose/urea-(1:5) mixture provides a wide array of hydrogen bonding for
activation of reactants dipoles. Thus, nucleophilic attack on benzaldehyde by
malononitrile results in forming 2-arylidenemalononitrile intermediate (1) which is
subjected to conjugate addition with hydrazine derivative. The adduct (2) undergoes
cyclization by intramolecular nucleophilic attack and the cyclized intermediate (3)
forms. This intermediate will be transformed to the desired product through
tautomerization and oxidation under reaction conditions in the presence of
atmospheric oxygen. It appears when the reaction performs under inert atmosphere;
CN
N
O
R2
Glu:Urea
1:5
H2N
R3
R4
R4
+
H2N NH
R1
+
N
30°C
N
R1
R3
R2
16 examples
N
R1 = H, Ph, 2,4-(NO2)2Ph
R2, R3, R4 = H, Cl, NO2, OH, BnO, AcNH, CN
Scheme 2 Efficient natural deep eutectic solvent mediated synthesis of highly substituted pyrazole-4-
carbonitrile derivatives
123

R. Aryan et al.
N
N
NC
CN
O
Glu:Urea
1:5
+
+
H2N NH2
N2 inert
atmosphere
r.t. 12hrs
Cl
Cl
Scheme 3 Model reaction under inert N2 atmosphere
N
H
H
H
H
H
N
H
N
H
H
N
H
N
H
N
H
N
N
H
N
H
H
H
N
O
N
O
H
H
H
H
O
H
O
H
H
O
N
O
O
H
O
H
H
N
O
O
O
O
N
Ar
H
H
H
O
H
N
O
Ar
O
O
O
H
H
O
H
H
H
O
O
O
N
O
H
H
(1)
H
N
H
H2N
H
N
O
H
N
H
NHR
N
H
H
N
H
H
N
H
N
H
N
N
H
H
Ar
H
NH2
N
H
H
N
H
R
H
N
N
H
H
H
N
H
H
T
N
a
a
H
H
o
n
n
u
b
N
x
N
d
t
H
H
N
i
H
o
H
O
d
a
O
a
m
N
e
H
t
H
e
r
i
r
N
i
o
o
H
H
H
O
H
z
O
i
a
c
t
O
H
O
O
i
N
o
n
H
H
H
N
O
O
N
O
O
H
H
O
H
N
O
O
O
O
Ar
H
H
O
N
H
H
H
O
O
O
N
O
H
HN
H
H
H
Ar
N
H
NHR
(2)
H
H
N
O
H
H
N
N
N
H
N
H
H
HN
N
R
H
H
N
H
N
H
N
H
H
(3)
Scheme 4 Proposed mechanism for the formation of pyrazole-4-carbonitrile promoted by glucose/urea-
(1:5) mixture as medium
100
90
80
70
60
50
40
30
Fig. 4 Reusability of glucose/
urea-(1:5) mixture in model
reaction of pyrazole-4-
carbonitrile (Scheme 1b)
1
2
3
4
Reaction run No.
123

Novel biocompatible glucose-based deep eutectic solvent…
the lack of molecular oxygen causes the process to proceed in the reverse manner
and only the 2-arylidenemalononitrile intermediate forms. So, tautomerization
followed by aerobic oxidation is required to achieve the desired products (Fig. 4).
Conclusion
In the present work, a novel deep eutectic solvent based on glucose as medium and
promoter was used under uncatalyzed multicomponent reaction protocol and a
broad array of three and four substituted pyrazole-4-carbonitrile derivatives were
prepared efficiently within short reaction times with high to excellent yields. The
introduction of a novel biocompatible glucose based deep eutectic solvent as the
medium and promoter, not using extra catalyst or harmful organic solvent for any
part of the protocol, simple aqueous purification and separation of products and
synthesis of products using hydrazine hydrate and 2, 4-dinitrophenylhydrazine as
binucleophilic nitrogen sources are the other significant features of this protocol.
The introduced deep eutectic solvent was recycled and reused four times with only a
little loss of reactivity. A plausible mechanism was also proposed according to
findings. The study of bioactivity of the novel pyrazole-4-carbonitrile derivatives is
in progress in our laboratory.
Acknowledgements The authors gratefully acknowledge Prof. Rostamizadeh from K.N. Toosi
University of Technology and Dr. Jadidi from Shahid Beheshti University G. C. for their helpful
consultations. The partial financial support of the present study by Research Council of University of
Zabol is also gratefully appreciated.
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