chapter-4 synthesis of 1h-imidazo[1,2-b]pyrazoles chapter...
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 144
Chapter 4
Synthesis of some new 1H-imidazo[1,2-b]pyrazole derivatives and their antimicrobial activities
4.1 Introduction
Biheterocycles have attracted significant attention from the scientific
community because of their relevance in medicinal chemistry. Many bicyclic pyrazole
fused with various heterocycles such as imidazole, pyrimidine and pyridine are well
recognized for their potent and diverse biological activities1-7 and have been used as a
key pharmacophore. Generally imidazopyrazoles are synthesized by annelation of
imidazole to the pyrazole ring. Mainly two different possible isomers 1H-
imidazo[1,2-b]pyrazole (1) and 1,4-dihydroimidazo[4,5-c]pyrazole (2) exist. Among
these two isomers 1H-imidazo[1,2-b]pyrazole is most studied one and show
anticancer, antimicrobial, anti-inflammatory activities, while imidazo[4,5-c]pyrazole
remains largely unexplored and show promise as antineurodegenerative drugs.8,9
Figure-4.1
4.2 Pharmacological profile
Imidazopyrazoles, as unusual fused heterocyclic compounds, are attractive
compounds for drug discovery because many compounds incorporating these
scaffolds exhibit a wide range of biological and pharmaceutical activities, mainly
including antitumor activities,10 herbisidal activities,11 anti-inflammatory activities,12
antiviral activity against herpes simplex virus type 1,13 and antineoplastic activity
against L1210 leukemia cells.14 In addition, some compounds of this class show
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 145
inhibitory effects on deoxyribonucleic acid synthesis,10 MAP kinase,12 L1220 tumor-
derived ribonucleotide reductase,15,16 and ribonucleoside diphosphate reductase,17 as
well as synchronization of human lymphoid cells and HeLa cells.18,19 Recently, other
members of this group of compounds have been shown to be useful as nonsteroidal
agonists and antagonists of the androgen receptor modulators that are useful in the
treatment of a variety of diseases.20-22 Additionally, some imidazopyrazoles have been
used as central nervous system agents.23 Therefore development of simple and rapid
synthetic methods for these derivatives is an important aim in organic synthesis.
Ennis et al.10 were first to describe the inhibitory effect of 2,3-Dihydro-1H-
imidazo[1,2-b]pyrazole (IMPY) on DNA synthesis in mammalian cells. In mouse L
cells, HeLa cells, and Sarcoma 180 mouse tumor cells exposed to IMPY, they
reported complete inhibition of DNA synthesis without any significant inhibitory
effect on RNA and protein synthesis. Awtar Krishan et al.18 was carried out in vitro
study of IMPY in cell cycle synchronization of human lymphoid cells. Larry M. Allen
et al.24 has been made a study of the biochemical, cytokinetic, and pharmacological
effects of imidazopyrazole (IMPY) on P815 mastocytoma ascites cells maintained in
mice and of cells maintained in culture. Ram Ganapathi et al.25 have studied effect of
IMPY on the Proliferation of Mouse Leukemic and Normal Cells in Vivo. The result
shows Administration of IMPY 250 to 500 mg/kg, in Day 5 L 1210 and P388 (ascites)
tumor-bearing mice did not consistently prolong the life span of tumor-bearing
animals. Grant S. et al.26 was examined the effect of IMPY on the metabolism and
cytotoxicity of subsequently administered 1-β-D-arabinofuranosylcytosine (ara-C)
was examined in the human promyelocytic leukemic cell line HL-60.
Figure-4.2
Olga Bruno et al.27,28 have synthesized some new 2-phenyl-2,3-dihydro-1H-
imidazo[1,2-b]pyrazole (1) and N-aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-
1-carboxamide derivatives (2) as possible multi-target anti-inflammatory agents and
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 146
tested them in vitro in order to evaluate their ability to interfere with human
neutrophil functions. All tested compounds showed strong inhibition of N-formyl-
methionyl-leucyl-phenylalanine fMLP-OMe-induced chemotaxis, although they
appeared unable to block degranulation and the fMLP-OMe-induced respiratory burst,
and were inactive in binding experiments.
N NN
HNOAr R
NN
NH
(1) (2)
R = H,COOH, COOEt,CONH2CO-cyclopropylamino, CO-piperidino
Figure-4.3
Ashish T. Baviskar et al.29 was studied on the basis of structures of known
topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-
fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They
were synthesized by multicomponent reactions and evaluated against human
topoisomerase IIR (hTopoIIα) in decatenation, relaxation, cleavage complex, and
DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic
scaffolds, it was found that imidazopyridine, imidazopyrazole (1), and
imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic
activity of hTopoIIα while not showing DNA intercalation.
Figure-4.4
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 147
4.3 Synthetic aspects for the imidazopyrazole
Imidazopyrazole derivatives have rarely been reported. However they exhibit
various biological activities. In spite of enormous literatures reported for the synthesis
of fused pyrazole derivatives, relatively few successful synthesis of imidazo[1,2-b]
pyrazoles has been reported.30-38
Peter Langer et al.39 have been reported regioselective cyclization reactions between
oxaldiimidoyl dichlorides (1) and 3-aminopyrazole (2), which provide convenient
access to biologically relevant 3H-imidazo[1,2-b]pyrazoles in good yields (Figure-
4.5).
Figure-4.5
A new synthetic approach to 4-substituted imidazo[4,5-c]pyrazoles is proposed by
Kostiantyn Liubchak et al.40 on the basis of the N’-(4-halopyrazol-5-yl)amidine
cyclization under the conditions of copper-catalyzed cross-coupling reactions. Using
5-aminopyrazoles and copper catalysts as starting materials, the method is
inexpensive and convenient and allows a wide range of substituents at all positions of
the imidazo[4,5-c]pyrazole nucleus (Figure-4.6).
Figure-4.6
Ahmad M. Farag et al.41 have reported a facile one-pot synthesis of imidazo[1,2-
b]pyrazoles by reacting hydrazonoyl bromides with 5-amino-3-phenyl-1H-pyrazole in
ethanol under reflux condition (Figure-4.7). Abdelhamid A. O. et al.42 have also
reported synthesis of imidazo[1,2-b]pyrazoles using hydrazonoyl halides.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 148
Figure-4.7
Ming Li et al.43,44 have been synthesized a series of new 2-aryl-7-cyano/ethoxy
carbonyl-6-methylthio/phenyl-1H-imidazo[1,2-b]pyrazoles (5) in moderate to good
yields, via a two-step cyclocondensation procedure of 5-amino-4-cyano/ethoxy
carbonyl-3-methylthio/ phenyl-1H-pyrazole (1) and α-bromoacetophenones (3) or α-
tosyloxyacetophenones (2). The intermediates, 5-amino-1-(aroylmethyl)-4- cyano/
ethoxycarbonyl-3-methylthio/phenyl-1H-pyrazoles (4), have been isolated, serving as
evidence for the regioselectivity. By using potassium carbonate to displace sodium
carbonate in the synthesis of (4), in the case of (1) (R= CN), two novel
cyclocondensation products have been isolated and fully characterized (Figure-4.8).
Figure-4.8
An efficient method has been developed by Abbas Rahmati et al.45 for the synthesis
of a novel series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines in good-to-
high yields by the three-component condensation of an aromatic aldehyde, an
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 149
aminopyrazole, and an isocyanide in acetonitrile with 4-toluenesulfonic acid as a
catalyst at room temperature (Figure-4.9).
Figure-4.9
Magda A. Barsy et al.46 have synthesized Pyrazolo[1,5-a]pyrimidine and imidazo[1,2-
b]pyrazole derivatives via intermolecular aza-Wittig reaction of 5-(triphenyl
phosphoranylideneamino)-3-phenylpyrazole (1) derived from 5-amino-3-phenyl
pyrazole with some selected α-chloroketones. The reaction of compound (1) with α-
chloroacetylacetone in dry toluene at reflux temperature gave the corresponding
pyrazolo[1,5-a]pyrimidine (2) in good yield On the other hand, reaction of
iminophosphorane (1) with 2-chloro-2-phenylacetophenone, chloroacetylchloride and
α-chloro-α-phenylazoacetone afforded the imidazo[1,2-b]pyrazole derivatives (3)
(Figure-4.10).
NNH
Ph
N PPh3
chloroketones
N N
NPh
CH3
RR'
N
N
NPh
R'
R(1)
(2)
(3)
Figure-4.10
Kee-Jung Lee et al.47,48 have reported a synthesis of pyrazolo-fused heterocycles by a
tandem Appel’s dehydration/electrocyclization methodology. The hydrazones of
benzophenone was allowed to react with acetoacetanilide to give azinoamides (1), and
the reaction of this azinoamides (1) with Appel’s dehydration conditions
(triphenylphosphine/carbontetrachloride/triethyl amine) led to the corresponding
azinoketimines (2), which underwent electrocyclic ring closure under the reaction
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 150
conditions to give pyrazolo-fused heterocycle 2,3-dihydro-1H-imidazo[1,2-b]pyrazol-
2-one (3) and 1H-imidazo[1,2-b]-pyrazole (4) (Figure-4.11).
PhPh
O
NN
Me NH
NH
OPh
PhPh
O
NN
Me N Ph
Ph3P, CCl4, Et3N
CH2Cl2
N N N
N N N
MePh
Ph OPh
PhPh
MePh(1)
(2)
(3)
(4)
Figure-4.11
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 151
4.4 Current research work
The fused pyrazole nucleus is present in wide variety of biologically
interesting compounds, which exhibited anti-inflammatory, antipyretic, antibacterial,
anticancer activities. As we described, very tremendous biological activity mainly
anticancer activity of imidazo[1,2-b]pyrazole scaffolds have attracted many chemist
to synthesize this class of compounds. Thus the practical synthesis of structurally
divers imidazopyrazole based molecules is of great significance.
In present work the reaction of various α-haloacetophenone with 5-amino pyrazole
was carried out under reflux using potassium carbonate as a base and dioxane as
solvent. Thus, obtained intermediate was purified and further refluxed in dioxane in
presence of catalytic amount of HCl to afforded imidazo[1,2-b]pyrazole in excellent
yield and purity. The newly synthesized compounds are characterized by IR, Mass, 1H
NMR, 13C NMR spectroscopy and elemental analysis. All synthesized compounds are
evaluated for their antimicrobial activity.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 152
4.5 Result and discussion
Imidazo[1,2-b]pyrazoles was synthesized from 5-amino pyrazole and α-
chloroacetophenone. Initially the reaction of ethylcynoacetate with cyclohexylamine
in toluene at refluxed was carried out to afford the cyanoacetamides (Int-1) in 90%
yields. Which was further reacted with carbon disulfide in the presence of base in
DMF followed by methylation to afford corresponding 2-cyano-3,3-bis(methylthio)-
N-phenylacrylamide (Int-2). Which on reaction with hydrazine hydrate undergoes
cyclization to form 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-
carboxamide (Int-3) (Scheme-4.1).
Scheme-4.1 Synthesis of 5-amino pyrazole derivative
The α-chloroacetophenones are a kind of useful and versatile reagent in
organic synthesis; they are, however, difficult to obtain and highly lachrymatory,
toxic, and not readily available. The reaction of 5-amino-pyrazole (Int-3) and α-
chloroacetophenones or α-bromoacetophenones was carried out at reflux in dioxane
using potassium carbonate as base for 4-8 hrs to afford intermediate (Int-6), which
was purified by column chromatography and further refluxed in ethanol using
catalytic amount of hydrochloric acid to obtained analytically pure imidazo[1,2-
b]pyrazoles (SPG-4a-j) (Scheme-4.2).
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 153
Scheme-4.2 Synthesis of Imidazo[1,2-b]pyrazoles
When reaction of Int-3 and int-4 was carried out using potassium carbonate in
dioxane, the reaction generated two compounds com-5 and Int-6 in around (40:60 %)
which was isolated and purified by column chromatography (Scheme-4.2). The
isolated compound Int-6 was desire intermediate and identified by 1H NMR followed
by cyclocondensation under an acidic condition to obtained final imidazo[1,2-
b]pyrazoles (SPG-4a-n).
The other one novel compound (comp-5a) was isolated unexpectedly and structure
was identify by 1H NMR which shows one singlet at 5.786 δppm for two proton
indicates –CH2 of imidazole ring. There is indentify absence of any –NH or –NH2
proton other than amide by D2O exchange, which shows formation of azomethine at
NH2 of pyrazole. The formation of comp-5 is different phenomenon than previously
reported in literature (Figure-4.8).43,44 A plausible mechanism for the formation of
compounds (comp-5) and (Int-6) is proposed in (Figure-4.12).
The 1H NMR spectrum of (comp-5a) shows a four multiplet δ = 1.250 to 1.865 ppm
assign to (5 x –CH2) of cyclohexane, a multiplet at δ = 3.829 ppm assign (–CH) of
cyclohexane, a singlet at δ = 5.786 ppm assign (-CH2) of imidazole ring, a triplet at δ
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 154
= 7.422-7.464 ppm (2 x Ar-H) assign aromatic proton, a doublet at δ = 8.167-8.181
ppm (2 x Ar-H) assign aromatic protons, and one doublet at δ = 7.593-7.612 ppm
assign to -CONH group (D2O exchange).
The 1H NMR spectrum of Int-6a shows a four multiplet δ = 1.285 to 1.844 ppm
assign to (5 x –CH2) of cyclohexane, a multiplet at δ = 3.795 ppm assign (–CH) of
cyclohexane, a singlet at δ = 5.588 ppm assign (-CH2), a singlet at δ = 6.424 ppm
assign (-NH2) (D2O exchange), one doublet at δ = 6.847-6.866 ppm assign to -CONH
group (D2O exchange), a triplet at δ = 7.410-7.453 ppm (2 x Ar-H) assign aromatic
proton and a triplet at δ = 8.097-8.131 ppm (2 x Ar-H) assign aromatic proton.
The structure of SPG-4a supported by its mass (m/z 372), which agrees with its
molecular formula C19H21FN4OS. a four multiplet δ = 1.336 to 1.853 ppm assign to (5
x –CH2) of cyclohexane, a multiplet at δ = 3.573-3.809 ppm assign (–CH) of
cyclohexane, δ=7.071-7.089 (d, 1H, j=1.2, -CONH), δ= 7.322-7.367 ppm (m, 2H, Ar-
H), δ=7.875-7.906 ppm (m, 2H, Ar-H), δ=8.190-8.193 ppm (d, 2H, j=1.2, -CH,
imidazole ring), δ=12.414 ppm (s, 1H, -NH imidazole).
Table 4.1: Synthesis of Imidazo[1,2-b]pyrazoles
Entry R Time h Yield % mp oC
SPG-4a 4-F 1.0 92 114-116 SPG-4b 4-Cl 1.2 95 132-134 SPG-4c 4-Br 1.2 88 128-130 SPG-4d 4-CH3 1.0 85 150-152 SPG-4e 4-OCH3 1.5 92 144-146 SPG-4f 3-NO2 2.0 80 158-160 SPG-4g 3,4-di-CH3 1.5 85 152-154 SPG-4h 2-Br, 5-Cl 1.2 86 140-142 SPG-4i 2-OCH3, 5-Br 1.5 90 144-146 SPG-4j 4-NO2 2.2 78 154-156 SPG-4k 2-Br, 4-Cl 1.2 88 138-140 SPG-4l 3-Br 1.5 86 124-126
SPG-4m 3,4-di-OCH3 1.5 91 136-138 SPG-4n 2,4-di-Cl 1.5 87 152-154
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 155
The proposed mechanism for the formation of 1H-imidazo[1,2-b]pyrazole is
depicted in (Figure-4.12).
NH
N
S
H2N
R
OCl
NN
S
H2N
R
O
NN
S
H2N
R
ON
N
S
H
NH
HHO
NN
S
HN
HH
NN
S
HN
R R
R
+ K2CO3 H+
H2O
H3O+
NH
N
S
H2NNH
N
S
HNK2CO3
R
O
Cl
NH
N
S
N
ClR
NN
S
N
R
-HCl
Figure-4.12 Proposed mechanism for the formation of imidazo[1,2-b]pyrazole
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 156
Antimicrobial Sensitivity Assay
Sr.
No. Code no.
MIC (μg/mL)
antibacterial activity antifungal activity
E.coli P.aeruginosa S.aureus S.pyogenus C.albicans A.niger A.clavatus
1 SPG-4a 500 500 62.5 500 1000 >1000 >1000
2 SPG-4b 500 250 250 500 1000 500 500
3 SPG-4c 1000 1000 500 500 500 500 500
4 SPG-4d 250 500 200 500 1000 1000 1000
5 SPG-4e 1000 500 250 250 500 >1000 >1000
6 SPG-4f 250 1000 500 500 200 500 500
7 SPG-4g 200 500 250 500 500 200 500
8 SPG-4h 1000 500 1000 500 >1000 >1000 500
9 SPG-4i 250 500 500 250 1000 500 1000
10 SPG-4j 500 500 1000 500 1000 >1000 1000
11 SPG-4k 500 250 500 500 500 1000 >1000
12 SPG-4l 200 500 250 500 500 250 1000
13 SPG-4m 500 500 250 250 1000 500 1000
14 SPG-4n 200 250 500 250 500 500 1000
Gentamycin 0.05 1 0.25 0.5 - - -
Ampicilin 100 100 250 100 - - -
Chloramphenicol
50 50 50 50 - - -
Ciprofloxacin 25 25 50 50 - - -
Norfloxacin 10 10 10 10 - - -
Nystatin - - - - 100 100 100
Greseofulvin - - - - 500 100 100
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 157
4.6 Conclusion
In summary, we have synthesized a library of imidazo[1,2-b]pyrazole
derivatives functionalized with carboxamide moieties with excellent yield. During
synthesis one novel compound was isolated and structure was identified. This
phenomenon for the formation of undesired compound is differing from the
previously reported synthesis. All the synthesized compounds were evaluated for their
antimicrobial activity. The investigation of antibacterial and antifungal screening data
revealed that all the tested compounds showed moderate to potent activity.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 158
4.7 Experimental section Thin-layer chromatography was accomplished on 0.2-mm precoated plates of
silica gel G60 F254 (Merck). Visualization was made with UV light (254 and 365nm)
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer
using DRS prob. 1H (400 MHz), 13C (100 MHz) NMR spectra were recorded on a
Bruker AVANCE II spectrometer in CDCl3 and DMSO. Chemical shifts are
expressed in δ ppm downfield from TMS as an internal standard. Mass spectra were
determined using direct inlet probe on a GCMS-QP 2010 mass spectrometer
(Shimadzu). Solvents were evaporated with a BUCHI rotary evaporator. Melting
points were measured in open capillaries and are uncorrected.
Synthesis of 2-cyano-N-cyclohexylacetamide (Int-1).
In a 250mL round bottom flask equipped with magnetic stirrer and
thermometer was placed ethyl 2-cyanoacetate (0.25mol), cyclohexaylamine (0.25mol)
and toluene (100mL). The reaction mixture was heated up to 110-115 oC for 8 h. The
progress of reaction was monitored by thin layer chromatography. The reaction
mixture was cooled to room temperature and the solid product was filtered, washed
with toluene to afford 90% yield.
Synthesis of 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (Int-2).
A 100mL conical flask equipped with magnetic stirrer and septum was
charged with a solution of 2-cyano-N-cyclohexylacetamide (1), (10 mmol) in DMF
(10 mL). Dry K2CO3 (10 mmol) was added and the mixture was stirred at room
temperature for 2 h. CS2 (30 mmol) was added and the mixture was stirred for an
additional 2 h at room temperature. Then, methyl iodide (20 mmol) was added at 0-5 oC and the mixture was stirred for 4 h at room temperature. The progress of the
reaction was monitored by thin layer chromatography. After completion of the
reaction, it was poured into 50ml cold water. The precipitated crude product was
purified by filtration followed by crystallization from EtOH.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 159
Synthesis of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-
carboxamide (Int-3).
A 100mL conical flask equipped with magnetic stirrer and septum was
charged 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (2) (0.1mol) in
isopropyl alcohol (100mL) and hydrazine hydrate (0.1mol). The Reaction mixture
was heated to reflux for 2 h. After completion of the reaction, it was poured into
50mL cold water. The precipitated crude product was purified by filtration followed
by crystallization from EtOH.
General Synthesis of 5-amino-N-cyclohexyl-1-(2-(4-fluorophenyl)-2-
oxoethyl)-3-(methylthio)-1H-pyrazole-4-carboxamide (Int-6a-n).
To a solution of Int-3 (5 mmol) in 20 mL of dioxane was added K2CO3 (10
mmol) and α-chloroacetophenone or α-bromoacetophenone (5 mmol), the reaction
mixture than refluxed for 4-6 hours. After completion of the reaction, it was poured
into 100 mL cold water. The precipitated crude product was filtered and dried. The
obtained mixture of two compounds then isolated by column chromatography
(hexane: ethylacetate). Yield int-6a-n (60 %), comp-5a-n (40 %).
General synthesis of N-cyclohexyl-2-(4-fluorophenyl)-6-(methylthio)-1H-
imidazo[1,2-b]pyrazole-7-carboxamide (SPG-4a-n).
The solution of Int-6a-n (5 mmol) in dioxane was refluxed for 1-3 hours in
the presence of catalytic amount of HCl. After the completion of reaction solid
material was obtained, which was filtered and dried to afford analytically pure
compounds (yield 80-90 %).
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 160
Spectral data of the synthesized compounds
5-amino-N-cyclohexyl-1-(2-(4-fluorophenyl)-2-oxoethyl)-3-(methylthio)-1H-
pyrazole-4-carboxamide (Int-6a): White solid; mp 84-86°C; Rf 0.35 (3:7 hexane-
EtOAc); IR (KBr): 3597, 3429, 3392, 3327, 2926, 2850, 1693, 1635, 1602, 1539,
1508, 1413, 1309, 1230, 1157, 1039, 972, 835, 781, 713, 594 cm-1; 1H NMR: δ 1.156-
1.844 (4xm, 10H, cyclohexane), 2.333 (s, 3H, s-CH3), 3.795 (m, 1H, -CH), 5.588 (s,
2H, -CH2), 6.424 (s, 2H, -NH2), 6.847 (s, 1H, -CONH), 7.410-7.453 (t, 2H, Ar-H),
8.097-8.131 (t, 2H, Ar-H); MS (m/z): 390 (M+); Anal. Calcd for C19H23FN4O2S: C,
58.44, H, 5.94, N, 14.35; Found: C, 58.67; H, 5.23; N, 14.64.
N-cyclohexyl-2-(4-fluorophenyl)-6-(methylthio)-3H-imidazo[1,2-b]pyrazole-7-
carboxamide (comp-5a): Off White solid; mp 174-176°C; Rf 0.23 (3:7 hexane-
EtOAc); IR (KBr): 3333, 3059, 3020, 2928, 2854, 1616, 1531, 1450, 1417, 1240,
1190, 891, 840, 731, 688, 592, 509 cm-1; 1H NMR: δ 1.258-1.873 (4xm, 10H,
cyclohexane), 2.328 (s, 3H, s-CH3), 3.838 (m, 1H, -CH), 5.788 (s, 2H, -CH2), 7.427-
7.470 (t, 2H, Ar-H), 7.593 (s, 1H, -CONH), 8.152-8.186 (t, 2H, Ar-H); MS (m/z): 390
(M+); Anal. Calcd for C19H21FN4OS: C, 61.27, H, 5.68, N, 15.04; Found: C, 61.39; H,
5.49; N, 15.86.
N-cyclohexyl-2-(4-fluorophenyl)-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4a): White solid; mp 114-116°C; Rf 0.52 (3:7 hexane-EtOAc);
IR (KBr): 3344, 3316, 2940, 2860, 1632, 1540, 1480, 1435, 1324, 1187, 1092, 830,
765, 744 cm-1; 1H NMR: δ 1.336-1.853 (5xm, 10H, cyclohexane), 2.444 (s, 3H, s-
CH3), 3.573-3.809 (m, 1H, -CH), 7.071 (s, 1H, -CONH), 7.322-7.367 (m, 2H, Ar-H),
7.875-7.911 (m, 2H, Ar-H), 8.193 (s, 1H, -CH imidazole), 12.414 (s, 1H, NH-
imidazole); 13C NMR (100 MHz, DMSO): 14.21, 25.05, 32.67, 34.09, 47.54, 66.31,
91.37, 105.05, 115.70, 115.91, 125.92, 127.00, 127.07, 130.14, 139.27, 160.41; MS
(m/z): 372 (M+); Anal. Calcd for C19H21FN4OS: C, 61.27; H, 5.68; N, 15.04; Found:
C, 61.34; H, 5.72; N, 15.11.
2-(4-chlorophenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4b): White solid; mp 132-134°C; Rf 0.48 (3:7 hexane-EtOAc);
IR (KBr): 3354, 3324, 3082, 2943, 2865, 1636, 1544, 1366, 12123 1164, 1023, 849,
763, 682, 588 cm-1; MS (m/z): 388.91 (M+); Anal. Calcd for C19H21ClN4OS: C, 58.68,
H, 5.44, N,14.41; Found: C, 58.74; H, 5.37; 14.36.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 161
2-(4-bromophenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4c): Yellow solid; mp 128-130°C; Rf 0.42 (3:7 hexane-EtOAc);
IR (KBr): 3350, 3302, 2928, 2852, 1624, 1543, 1487, 1448, 1323, 1199, 1072, 1006,
825, 767, 727 cm-1; 1H NMR: δ 1.315-1.820 (5xm, 10H, cyclohexane), 2.344 (s, 3H,
s-CH3), 3.796 (m, 1H, -CH), 7.298 (s, 1H, -CONH), 7.658-7.679 (d, 2H, Ar-H, j=8.4
Hz), 7.845-7.866 (d, 2H, Ar-H, j=8.4 Hz), 8.278 (s, 1H, -CH imidazole), 12.740 (s,
1H, NH-imidazole); 13C NMR (100 MHz, DMSO): 14.16, 24.95, 25.18, 32.61, 47.46,
66.24, 91.33, 105.59, 120.63, 126.69, 128.53, 129.86, 131.65, 139.40, 152.49, 160.30;
MS (m/z): 433.37 (M+); Anal. Calcd for C19H21BrN4OS: C, 52.66; H, 4.88; N, 12.93;
Found: C, 52.71; H, 4.93; N, 12.87.
N-cyclohexyl-6-(methylthio)-2-(p-tolyl)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4d): Off white solid; mp 150-152°C; Rf 0.53 (3:7 hexane-
EtOAc); IR (KBr): 3342, 3061, 3020, 2929, 2856, 1637, 1572, 1529, 1446, 1415,
1313, 1234, 1192, 1074, 972, 891, 813, 723, 688, 644 cm-1; 1H NMR: δ 1.282-1.812
(5xm, 10H, cyclohexane), 2.341 (s, 3H, s-CH3), 2.420 (s, 3H, -CH3) 3.771-3.825 (m,
1H, -CH), 7.347 (s, 1H, -CONH), 7.262-7.282 (d, 2H, Ar-H, j=8.0 Hz), 7.770-7.790
(d, 2H, Ar-H, j=8.0 Hz), 8.136 (s, 1H, -CH imidazole), 12.634 (s, 1H, NH-imidazole); 13C NMR (100 MHz, DMSO): 14.12, 20.79, 25.10, 25.26, 32.70, 47.55, 66.31, 91.25,
104.59, 124.79, 126.48, 129.34, 131.08, 137.27, 139.00, 152.39, 160.42; MS (m/z):
368.50 (M+); Anal. Calcd for C20H24N4OS: C, 65.19; H, 6.56; N, 15.20; Found: C,
65.24; H, 6.62; N, 15.14.
N-cyclohexyl-2-(3-methoxyphenyl)-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4e): White solid; mp 144-146°C; Rf 0.50 (3:7 hexane-EtOAc);
IR (KBr): 3408, 3321, 3281, 2929, 2852, 1681, 1622, 1593, 1543, 1500, 1444, 1410,
1263, 1213, 1055, 1014, 893, 813, 659, 617, 590 cm-1; MS (m/z): 384.50 (M+); Anal.
Calcd for C20H24N4O2S: C, 62.48; H, 6.29; N, 14.57; Found: C, 62.52; H, 6.16; N,
14.68.
N-cyclohexyl-6-(methylthio)-2-(3-nitrophenyl)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4f): Yellow solid; mp 158-160°C; Rf 0.41 (3:7 hexane-EtOAc);
IR (KBr): 3326, 3086, 2933, 2846, 1637, 1556, 1545, 1467, 1354, 1235, 1143, 1047,
956, 898, 812, 753, 682, 654 cm-1; MS (m/z): 399.47 (M+); Anal. Calcd for
C19H21N5O3S: C, 57.13; H, 5.30; N, 17.53; Found: C, 57.22; H, 5.24; N, 17.54.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 162
N-cyclohexyl-2-(3,4-dimethylphenyl)-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-
7-carboxamide (SPG-4g): White solid; mp 152-154°C; Rf 0.52 (3:7 hexane-EtOAc);
IR (KBr): 3325, 3035, 2954, 2850, 1654, 1584, 1468, 1324, 1264, 1142, 1037, 925,
845, 760, 685 cm-1; MS (m/z): 382.52 (M+); Anal. Calcd for C20H24N4O2S: C, 62.48;
H, 6.29; N, 14.57; Found: C, 62.34; H, 6.32; N, 14.62.
2-(2-bromo-5-chlorophenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-
b]pyrazole-7-carboxamide (SPG-4h): Pale yellow solid; mp 140-142°C; Rf 0.42
(3:7 hexane-EtOAc); IR (KBr): 3346, 3304, 3015, 2947, 2846, 1634, 1532, 1423,
1305, 1298, 1148, 1005, 988, 865, 802, 703, 665 cm-1; MS (m/z): 467.81 (M+); Anal.
Calcd for C19H20BrClN4OS: C, 48.78; H, 4.31; N, 11.98; Found: C, 48.87; H, 4.24; N,
12.06.
2-(5-bromo-2-methoxyphenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-
b]pyrazole-7-carboxamide (SPG-4i): Pale yellow solid; mp 144-146°C; Rf 0.41 (3:7
hexane-EtOAc); IR (KBr): 3312, 3056, 2948, 2864, 1623, 1547, 1413, 1325, 1217,
1106, 1056, 958, 889, 845, 756, 665 cm-1; MS (m/z): 463.39 (M+); Anal. Calcd for
C20H23BrN4O2S: C, 51.84; H, 5.00; N, 12.09; Found: C, 51.77; H, 4.95; N, 12.17.
N-cyclohexyl-6-(methylthio)-2-(4-nitrophenyl)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4j): Yellow solid; mp 154-156°C; Rf 0.38 (3:7 hexane-EtOAc);
IR (KBr): 3321, 3056, 2945, 2814, 1643, 1545, 1438, 1387, 1205, 1159, 1046, 954,
875, 812, 756, 654 cm-1; MS (m/z): 399.47 (M+); Anal. Calcd for C19H21N5O3S: C,
57.13; H, 5.30; N, 17.53; Found: C, 57.22; H, 5.41; N, 17.43.
2-(2-bromo-4-chlorophenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-
b]pyrazole-7-carboxamide (SPG-4k): White solid; mp 138-140°C; Rf 0.41 (3:7
hexane-EtOAc); IR (KBr): 3354, 3045, 2965, 2845, 1621, 1547, 1468, 1347, 1209,
1068, 956, 874, 798, 668 cm-1; MS (m/z): 467.81 (M+); Anal. Calcd for
C19H20BrClN4OS: C, 48.78; H, 4.31; N, 11.98; Found: C, 48.71; H, 4.38; N, 11.89.
2-(3-bromophenyl)-N-cyclohexyl-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-7-
carboxamide (SPG-4l): Pale yellow solid; mp 124-126°C; Rf 0.43 (3:7 hexane-
EtOAc); IR (KBr): 3302, 3045, 2987, 2854, 1634, 1568, 1423, 1374, 1248, 1108,
1006, 986, 887, 854, 756, 663 cm-1; MS (m/z): 433.37 (M+); Anal. Calcd for
C19H21BrN4OS: C, 52.66; H, 4.88; N, 12.93; Found: C, 52.78; H, 4.81; N, 12.99.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 163
N-cyclohexyl-2-(3,4-dimethoxyphenyl)-6-(methylthio)-1H-imidazo[1,2-
b]pyrazole-7-carboxamide (SPG-4m): White solid; mp 136-138°C; Rf 0.46 (3:7
hexane-EtOAc); IR (KBr): 3354, 3058, 2947, 2863, 1687, 1548, 1257, 1168, 1047,
965, 879, 834, 768, 702, 634 cm-1; MS (m/z): 414.52 (M+); Anal. Calcd for
C21H26N4O3S: C, 60.85; H, 6.32; N, 13.52; Found: C, 60.94; H, 6.23; N, 13.47.
N-cyclohexyl-2-(2,4-dichlorophenyl)-6-(methylthio)-1H-imidazo[1,2-b]pyrazole-
7-carboxamide (SPG-4n): White solid; mp 152-154°C; Rf 0.45 (3:7 hexane-EtOAc);
IR (KBr): 3325, 3068, 2954, 2863, 1647, 1538, 1486, 1302, 1156, 1047, 889, 853,
789, 702, 648 cm-1; MS (m/z): 423.36 (M+); Anal. Calcd for C19H20Cl2N4OS: C,
53.90; H, 4.76; N, 13.23; Found: C, 53.82; H, 4.81; N, 13.15.
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 164
1H NMR spectrum of Int-6a
D2O exchange spectrum of Int-6a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 165
1H NMR spectrum of comp-5a
D2O exchange spectrum of comp-5a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 166
1H NMR spectrum of SPG-4a
Expanded 1H NMR spectrum of SPG-4a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 167
1H NMR spectrum of SPG-4c
Expanded 1H NMR spectrum of SPG-4c
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 168
1H NMR spectrum of SPG-4d
D2O exchange spectrum of SPG-4a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 169
13C NMR spectrum of SPG-4a
13C NMR spectrum of SPG-4c
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 170
13C NMR spectrum of SPG-4d
Mass spectrum of Int-6a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 171
Mass spectrum of comp-5a
Mass spectrum of SPG-4a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 172
Mass spectrum of SPG-4c
Mass spectrum of SPG-4d
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 173
IR spectrum of Int-6a
IR spectrum of comp-5a
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 174
IR spectrum of SPG4c
IR spectrum of SPG4d
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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles
Studies on heterocyclic analogues 175
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