An environmentally friendlier approach - Ionic liquid catalysed, water promoted and grinding induced synthesis of highly functionalised pyrazole derivatives

Article abstract of DOI:10.1039/c3ra42493f

Grinding induced synthesis of highly functionalised pyrazoles derivatives by use of malanonitrile, phenyl hydrazine and diversified aldehyde. Ionic liquid is used as a catalyst with water, and no by-products form. A high yield is obtained and simple handl

Full text of DOI:10.1039/c3ra42493f

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An environmentally friendlier approach—ionic liquid
catalysed, water promoted and grinding induced
synthesis of highly functionalised pyrazole derivatives
Cite this: DOI: 10.1039/c3ra42493f
Received 21st May 2013,
Accepted 22nd July 2013
Madhulika Srivastava,a Pratibha Rai,a Jaya Singhb and Jagdamba Singh*a
DOI: 10.1039/c3ra42493f
www.rsc.org/advances
Grinding induced synthesis of highly functionalised pyrazoles
derivatives by use of malanonitrile, phenyl hydrazine and
diversified aldehyde. Ionic liquid is used as a catalyst with water,
and no by-products form. A high yield is obtained and simple
handling are the benefits of the adopted route, and this route
fulfils all shades of green chemistry.
can dissolve a wide range of polar and non polar organic and
inorganic molecules. Many types of reactions reported in literature
are promoted by different types of ionic liquids including
alkylation,5b condensation,5c esterification,5d hydrogenation,5e
hydroformylation,5f oxidation,5g with excellent yield. They have
also other properties like non-inflammably and extremely low
vapour pressure which maintains their fluidity and volume.13
Thus an ionic liquid serves as a better solvent and catalyst as
compared to most organic solvents.
With the above mentioned aspects in our mind we performed
and studied the reaction which is grinding induced and employs
an ionic solvent which plays a great role in catalysis. We have
chosen pyrazole moiety due to its importance in the field of
pharmaceutical chemistry and agriculture.
Pyrazole framework occurs in many natural products and
shows a large range of pharmacological activities like antitumor,6a
antimicrobial,6b anti-inflammatory,6c antiviral,6d and analgesic6e
activities. pyrazoleoxime ethers have also proven to be very
important, for example compound (A) of this class shows
antitumor activity and compound (B) shows cytotoxic activity
(Fig. 1).7
Pyrazole moiety Celebrex8 is a drug used for arthritis. Similarly,
Viagra9 is used to treat pulmonary arterial hypertension (PAH),
and Rimonabant9b is an anarectic anti-obesity drug.
5-Methylpyrazole–3-carboxylic acid10a shows anti-diabetic activity,
deracoxib10b is a nonsteroidal veterinary medicine to treat
osteoarthritis in dogs.
The current interest of the organic chemist is to synthesise
biodynamic heterocyclic molecules with the maintenance of green
chemistry protocols.1 This involves all factors like easy handling,
atom economy, energy saving, cost effectiveness and the use of
non-renewable resources.
In addition, Mechanochemistry2a involving mechanical action
and mechanical energy is a good alternative synthesis approach
for chemists. Out of several methods which fall in this type of
chemistry, one of the fascinating methods is ‘grinding induced
reaction’.2b This method carries a pool of advantages,2c one of
them being that the reactant particles break down2d to smaller
particles and thus provide a larger surface area for the reactions to
occur. In literature many examples of reaction in which the
reaction was mostly carried out at room temperature2e using pestle
and mortar are available such as Reformatsky reaction,3a Grignard
reaction,3b Dickmann condensation,3c Reduction,3d Aldol conden-
sation3e etc.
Multicomponent reaction is now being paid extraordinary4a
attention since it involves a liquid which also behaves as a catalyst.
Moreover, it involves the formation of more than one bond4b in a
single step which encourages atom economy and easy handling.
In contrast, a multi step reaction involves a catalyst which may be
highly toxic and may at times be difficult to be removed from the
reaction mixture.4c A multi step reaction may require purification
at each individual step.4d It also saves the environment from the
hazardous effects of organic solvents.
Ionic liquids are considered to be good solvents5a for organic
synthesis because (1), they are liquid at room temperature and (2),
aDepartment Of Chemistry, University Of Allahabad, Allahabad, uttarpradesh, India.
E-mail: dr.jdsau@gmail.com
bDepartment Of Chemistry, L R PG College, Sahibabad, Uttar Pradesh, India
Fig. 1 Some examples of pyrazoleoxime ethers.
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Table 1 Optimization studies for solvent effect
Entry
Solvent
Yield (%)
1
2
3
4
5
H2O
52
54
60
16
22
CH3OH
CH3CH2OH
C6H5CH3
THF
Scheme 1 Ionic liquid induced synthesis of highly functionalised pyrazole
derivatives.
Well known wide spectrum qualities of pyrazoles motivated us
to devise a new protocol for pyrazole derivatives. Recently many
research groups reported the synthesis of pyrazole derivatives
implementing various strategies. For example Glorius et al.
synthesised pyrazoles using 2-methyl-3-(phenylamino)but-2-enoate
and benzonitrile, catalysed by Cu(OAC)2.11a Dembinski et al. used
diketone and hydrazine.11b Yaziciet and co-workers have reported
formation of hydrazone by a,b-unsaturated carbonyl compounds
with hydrazine followed by intermolecular cyclization in the
presence of I2/NaHCO3.11c Odam et al. reported Ti(NMe2)2(PyPyr)2
catalysed pyrazoles synthesis using cyclohexylisonitrile, hydrazine
and alkynes.11d Wang and co-workers synthesised pyrazoles from
aldehyde, hydrazine and alkynes using PTSA as a catalyst.11e We
synthesised the pyrazoles starting from easily available and simple
starting materials aldehyde (1), malanonitrile (2) and phenylhy-
drazine (3), affording densely functionalized pyrazoles.12
We mixed reagents 1, 2 and 3 in stoichiometric amounts in
mortar and ground the mixture with the help of a pestle. After the
completion of the experiment, more than one pot is present on
TLC plate. To overcome this problem we ground the mixture in a
sequential manner.13 We took 1 and 2 in mortar and ground the
reactants until the completion of the reaction. This was followed
by the addition of phenyl hydrazine and continuous grinding led
to the formation of a single product. Next we performed the
experiment twice—once by taking 1 ml water so as to make a paste
of the reactants we were grinding and the second time by using
ethanol instead of water. It was found that the reaction proceeded
more smoothly14 in the presence of ethanol than in water. We
hence concluded that an increase in the polarity of the organic
solvent reduces the reaction time and also increases the overall
yield of the product (Table 1).
Table 3 Optimization of catalyst (Bim)OH
Entry
Amount (mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
10
15
20
30
40
50
15
15
15
15
15
15
15
65
70
76
76
76
76
90
Catalyst system
being that an ionic solvent of basic nature facilitates Knoevengal
reaction, and also the second step which is Micheal addition. Only
20 mol% of (Bim)OH is sufficient for maximum yield. When the
amount of catalyst was decreased from 20 mol% to 10 mol% and
15 mol% relative to substrate 1, the yield of the product 4a is
reduced, but the use of 30 mol%, 40 mol%, and 50 mol% of
catalyst did not affect the yield (Table 3).
Moreover, cyclisation occurs with greater ease in a polar
solvent.14 Thus, using 1 ml water with ionic liquid gives dramatic
improvement of the reaction in terms of yield and reaction rate.15
We performed the experiment with different solvents with ionic
liquid and the best result was obtained with basic ionic liquid with
water16 the yield of the product remarkably increases from 76% to
90% (Table 3, entry 3 and 7). Hence we prepared the ionic liquid
and water system by taking 20 mol% of (Bim)OH and 1 ml water
and performed the batch of reactions to achieve an insight into
the role of electronic effect on the reaction. It was found that
Table 4 Synthesis of pyrazole derivativesa
Our next approach was to study the scope of taking various
types of ionic liquids as catalyst (20 mol%) during the time of
grinding (Table 2, Scheme 1). This enhanced the yield to a great
extent. The best result was obtained with (Bim)OH, the reason
Entry
R1
R2
R3
2
3
Time
Yieldb (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
H
H
H
H
H
H
Cl
H
H
H
H
OH
H
H
H
H
OCH3
H
NO2
H
H
H
OCH3
H
H
H
OCH3
H
NO2
H
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
15
20
22
12
12
14
15
10
30
24
25
30
16
25
90
89
88
96
96
95
95
97
85
82
80
75
88
86
Table 2 Effect of different types of ionic liquid as a catalyst
Entry
Solvent
Time (min)
Yielda (%)
H
F
1
2
3
4
5
6
(Bmim)OH
(Hmim)H2PO4
(Hmim)HSO4
(Bmim)Cl
(Bmim)PF6
(Bmim)BF4
20
40
35
50
45
47
76
60
65
62
56
58
OCH3
N(CH3)2
CH3
H
CN
H
H
H
H
3
3(4 Cl)
a
b
a
Is isolated yield
Time in min. Yield of isolated of purified product.
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(Hz). 13C NMR spectra were recorded on the same instrument at
100 MHz in CDCl3 and TMS was used as the internal reference.
Mass (EI) spectra were recorded on a JEOL D-300 mass spectro-
meter.
B. General procedure for the synthesis of pyrazoles (4a to 4n)
Aldehyde (1 mmol), malanonitrile (1 mmol), (Bim)OH (20 mol%)
and 1 ml water, were thoroughly ground with pestle and mortar.
After the formation of Knoevengel adduct added phenyl hydrazine
(1 mmol) and again thoroughly ground for an appropriate time
(Table 4). When the reaction was complete (check by TLC) we
added 5 ml water and the mixture was extracted with DCM (3 6 5
ml). The combined organic phase was dried over MgSO4. Filtered
and evaporated under reduced pressure. The resulting product
was recrystallised by hot ethanol. Only 4g semisolid and 4h was
liquid. After isolation of the product, the remaining mother liquid
containing the ionic liquid was washed with DCM (3 6 5 ml) to
remove any organic impurity. Dried under vacuum at 90 uC to
afford (Bim)OH, which was used in subsequent runs without
purification.
5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (4a). White
solid, Melting point, 159–160 uC. IR (KBr) nmax, 3483, 3344, 3081,
2357, 1589, 1422, 1251, 1124, 1110, 1065 cm21 1H NMR (400
;
Scheme 2 A plausible pathway for the synthesis of pyrazole derivatives.
MHz, CDCl3) d 7.74 (d, J = 7.2 Hz, 2H), 7.71 (s, 1H). 7.63 (s, 1H),
7.40 (t, J = 7.6 Hz, 2H), 7.36 (m, 3H), 7.16–7.29 (d, J = 7.6 Hz, 2H),
6.92 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 156.52,
150.42, 146.09, 137.85, 135.77, 129.74, 128.05, 127.9, 126.64,
120.56, 113.25, 112.82, EIMS (m/z): 260 (M).+
aldehyde with an electron withdrawing substituent provided better
results in comparison to those having an electron donating
substituent. A withdrawing group (Table 4, entry 4h) present on
aldehydes facilitates the first step of the reaction, i.e., Knoevengeal
reaction and basic nature of catalyst system also promotes this
step (Scheme 2).
5-amino-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbo-
nitrile (4b). Light brown white solid, Melting point, 106–108 uC.
IR (KBr) nmax, 3350, 3270, 3030, 2820, 2630, 2215, 1540, 860 cm21
;
1H NMR (400 MHz, CDCl3) d 7.83–7.85 (m, 1H), 7.67 (s, 1H), 7.58–
7.61 (m, 2H), 7.24–7.28 (m, 1H), 7.09 (d, J = 7.6, 2H), 7.00 (m, 1H),
6.89–6.93 (m, 2H), 6.83 (t, 1H) 3.83 (s, 3H); 13C NMR (100 MHz,
CDCl3), d 160.03, 144.93, 143.44, 137.43, 128.10, 127.58, 127.10,
119, 114.11, 112.66, 99.98, 59.33, 55.35; EIMS (m/z) 290(M).+
5-amino-3-(2-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbo-
Conclusion
In summary, we have disclosed a mild and green procedure for the
synthesis of novel pyrazole derivatives with the aim of causing no
harmful effects to the environment and introducing the use of the
ionic liquid with water in grinding fashion. The adopted route has
many significant features like short time, simple handling and is
an eco-friendly approach.
nitrile (4c). Red solid, Melting point 130–132 uC. IR (KBr) nmax
,
3480, 3410, 3120, 2830, 2545, 2238, 1650, 1580, 780, 720 cm21; 1H
NMR (400 MHz, CDCl3) d 7.82–7.84 (m, 1H), 7.66 (s, 1H), 7.57–7.60
(m, 2H), 7.23–7.26 (m, 1H), 7.10 (d, J = 7.6, 2H), 7.01 (m, 1H), 6.89–
6.93 (m, 2H), 6.85 (t, 1H) 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) d
161.01, 143.92, 143.37, 137.54, 137.40, 129.01, 127.30, 128.44,
125.84, 118.92, 112.89, 114.02, 56.01; EIMS (m/z) 290(M).+
5-amino-3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4d). Red solid, Melting point 164–166 uC. IR (KBr) nmax, 3465,
3355, 3105, 2354, 1610, 1417, 1456, 1345, 1256, 1133,1108, 1094
cm21; 1H NMR (400 MHz, CDCl3), d 8.25 (d, J = 7.6 Hz, 2H) 8.03 (s,
1H), 7.74–7.77 (m, 3H), 7.20–7.34 (m, 2H), 7.18 (d, J = 7.6 Hz, 2H),
6.96 (s, 1H); 13C NMR (100 MHz, CDCl3) d 156.53, 149.56, 145.26,
137.73, 135.32, 131.72, 130.93, 129.90, 122.78, 122.15, 123.47,
113.43, 112.36, EIMS (m/z) 305(M).+
General methods
A. General information
Reagents were obtained from commercial suppliers (aldehydes by
Sigma Aldrich, hydrazines by Loba Chemie and malanonitrile by
Alfa Aesar) and used without further purification unless otherwise
specified by a reference. All reactions were Performed using oven-
dried glassware. Organic solutions were concentrated using a
Buchi rotary evaporator. TLC was performed using silica gel GF254
(Merck) plates. Melting points were determined by open glass
capillary method and are uncorrected. IR spectra in KBr were
5-amino-3-(3-nitrophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4e). Saffron colour solid, Melting point 128–130 uC, IR (KBr)
nmax, 3455, 3321, 3111, 2355, 1592, 1477, 1445, 1343, 1328,1266,
1149, 1120, 1092 cm21; 1H NMR (400 MHz, CDCl3) d 8.47 (s, 1H)
8.13 (d, J = 8.0 Hz,1H), 8.02 (d, J = 7.6 Hz, 1H), 7.88 (s, 1H), 7.75 (s,
1H) 7.57 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 2H), 7.17 (d, J = 8.4
1
recorded on a Perkin-Elmer 993 IR spectrophotometer, H NMR
spectra were recorded on a Bruker AVII 400 spectrometer in CDCl3
using TMS as internal reference with chemical shift value being
reported in ppm. All coupling constants (J) are reported in Hertz
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Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 13C NMR (100 MHz, CDCl3) d
156.43, 149.26, 144.26, 137.73, 134.32, 131.82, 129.93, 129.87,
122.68, 122.10, 121.37, 113.43, 112.46; EIMS (m/z) 305 (M).+
5-amino-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4f). Cream colour solid, Melting point, 128–130 uC. IR (KBr)
nmax, 3460, 3380, 3130, 2520, 2253, 1660, 1570 cm21; 1H NMR; (400
MHz, CDCl3) d 7.66 (s, 2H) 7.64 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4
Hz, 2H), 7.29–7.33 (m, 2H), 7.16 (d, J = 7.6 Hz, 2H), d 6.95 (t, J = 7.4
Hz, 1H), 13C NMR (100 MHz, CDCl3) d 154.23, 143.41, 142, 133,
130, 129, 127, 126, 119.41, 115.65; EIMS (m/z) 294(M+), 296 (M +
2).+
156.48, 152.20, 150.52, 145.52, 138.03, 130.13, 130.01, 128.16,
125.40, 121.33, 120.23, 119.73, 116.82, 112.61, EIMS (m/z) 276(M).+
5-amino-3-(4-cynophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4m). Yellow solid, Melting Powder, 158–160 uC. IR (KBr)
nmax, 3434,3316, 3275, 2353, 2229, 1583, 1472, 1265, 1155, 1127,
1096 cm21; 1H NMR (400 MHz, CDCl3) d 10.72 (s, 1H), 7.85 (s, 1H),
7.77–7.81 (m, 4H),7.24 (t, J = 7.2 Hz, 2H) 7.13 (d, J = 7.6 Hz, 2H),
6.82 (t, J = 7.2 Hz, 1H), 13C NMR (100 MHz, CDCl3) d = 152.34,
146.19, 137.83, 135.75, 129.70, 128.15, 127.09, 126.74, 120.56,
117.92,115.61, 113.25, 112.82, EIMS (m/z) 285(M)+.
5-amino-1-(4-chlorophenyl)-3-phenyl-1H-pyrazole-4-carboni-
5-amino-3-(2-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4g). Semi solid, IR(KBr) nmax, 3475, 3425, 3150, 2520, 2335,
trile (4n). Pink solid, Melting point, 133–135 uC. IR (KBr) nmax
,
1
3420, 3322, 3095, 2365, 1598, 1487, 1267, 1134, 1096, cm21; H
1
1660, 1575,765, 720, cm21; H NMR (400 MHz, CDCl3) d 7.61 (s,
NMR (400 MHz, CDCl3) d 7.70 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.56
(s, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.33–7.36 (m, 1H), 7.25 (d, J = 8.4
Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3), d
155.92, 143.67, 138.37, 135.41, 132.28, 129.52, 129.09, 129.02,
126.60, 125.08, 114.22, 112.05, EIMS (m/z) 294 (M)+, 296 (M + 2)+.
2H) 7.58 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.28–7.32 (m,
2H), 7.15 (d, J = 7.6 Hz, 2H), d 6.94 (t, J = 7.6 Hz, 1H), 13C NMR (100
MHz, CDCl3) d 154.82, 144.87, 144.43, 139.44, 138.52, 137.90,
129.41, 128.54, 127.04, 119.34, 117.25, 112.84, 114.04, 99.48; EIMS
(m/z) 294(m+), 296(M + 2).+
5-amino-3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (4h). Yellow oil, IR (KBr) nmax, 3465, 3410, 3143, 2545, 2220,
Acknowledgements
1
1650,1650, 1320, 840 cm21; H NMR (400 MHz, CDCl3) d 7.89–
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing micro-analyses and spectra. The authors also thank
UGC, New Delhi, for the award of Junior Research Fellowship.
7.96(m, 2H), 7.63 (s, 1H), 7.57–7.62 (m, 2H), 7.25–7.27 (m, 2
H),7.11 (d, J = 7.6, 1H), 6.90–6.93 (m, 3H), 13C NMR (100 MHz,
CDCl3) d 157.56, 144.93, 144.51, 136.32, 138.47, 130.56, 129.01,
128.31, 127.41, 119.32, 116.56, 115.67, 113.34; EIMS (m/z) 278(M)+.
5-amino-3-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazole-4-
carbonitrile (4i). White solid, Melting point 120–123 uC. IR (KBr)
nmax, 3310, 3190, 3050, 2840, 2650, 2200, 1535, 1630, 874, 725
cm21; 1H NMR (400 MHz, CDCl3) d 9.75 (s, 1H), 7.68–7.69 (d, 1H, J
= 2 Hz), 7.64 (s, 1H), 7.37–7.39 (m, 1H), 7.25–7.29 (m, 3H arom),
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Pink powder, Melting point, 118–120 uC. IR (KBr) nmax, 3484,
1
3318, 3098, 2927, 2358, 1598, 1418, 1255, 1125, 1123, 1094. H
NMR (400 MHz, CDCl3) d 7.71 (s, 2H).7.58 (d, J = 7.6 Hz, 2H), 7.30–
7.34 (m, 2H), 7.22 (d, J = 7.6 Hz, 2H),7.15 (d, J = 7.76 Hz, 2H), 6.91
(dd, J = 3.4 Hz and J = 7.6 Hz, 1H), d 2.42 (s, 3H), 13C NMR (100
MHz, CDCl3) d 154.22, 150.95, 145.13, 129.26, 128.15, 123.11,
127.84, 115.11, 113.40, 104.65, 21.92; EIMS (m/z) 274 (M).+
5-amino-3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbo-
nitrile (4l). Yellow solid, Melting Point, 160–162 uC, IR (KBr) nmax
,
;
3580, 3487, 3343, 3122, 2354, 2195, 1602, 1413, 1182, 1055 cm21
1H NMR (400 MHz, DMSO) d 10.51 (s, 1H), 10.37 (s, 1H), 8.15 (s,
1H), 7.54 (dd, J = 1.6 Hz and J = 7.6 Hz, 1H), 7.24 (dd, J = 7.6 Hz
and J = 8.4 Hz, 2H), 6.94 (d, J = 7.6 Hz, 2H), 7.14–7.18 (m,1H), 6.84–
6.89 (m, 2H), 6.74 (t, J = 7.2 Hz, 1H), 13C NMR (100 MHz, DMSO): d
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