Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles Chapter ...shodhganga.inflibnet.ac.in/bitstream/10603/15979/9/09_chapter 4.pdf · chloroacetylacetone in dry toluene at reflux temperature

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



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



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



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.



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



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



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



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.



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).



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



= 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



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



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



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.



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.



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 %).



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.



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.



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


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,


C19H21BrN4OS: C, 52.66; H, 4.88; N, 12.93; Found: C, 52.78; H, 4.81; N, 12.99.



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



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.



1H NMR spectrum of Int-6a

D2O exchange spectrum of Int-6a



1H NMR spectrum of comp-5a

D2O exchange spectrum of comp-5a



1H NMR spectrum of SPG-4a

Expanded 1H NMR spectrum of SPG-4a



1H NMR spectrum of SPG-4c

Expanded 1H NMR spectrum of SPG-4c



1H NMR spectrum of SPG-4d

D2O exchange spectrum of SPG-4a



13C NMR spectrum of SPG-4a

13C NMR spectrum of SPG-4c



13C NMR spectrum of SPG-4d

Mass spectrum of Int-6a



Mass spectrum of comp-5a

Mass spectrum of SPG-4a



Mass spectrum of SPG-4c

Mass spectrum of SPG-4d



IR spectrum of Int-6a

IR spectrum of comp-5a



IR spectrum of SPG4c

IR spectrum of SPG4d



4.8 References

1. Vanotti, E.; Fiorentini, F.; Villa, M. J.; Heterocyclic Chem. 1994, 31, 737.

2. Kinnamon, K. E.; Poon, B. T.; Hanson, W. L.; Wait, V. B.; Am. J. Trop. Med. Hyg.

1998, 56, 804.

3. Kinnamon, K. E.; Engle, R. R.; Poon, B. T.; Ellis, W. Y.; McCall, J. W.; Pzimianski, M. T.;

Proc. Soc. Exp. Biol. Med. 2000, 224, 45.

4. Keshi, O.; Bahar, I.; Jernigan, R. L.; Beutler, J. A.; Shoemaker, R. H.; Sausville, E. A.;

Covell, D. G.; Anti-Cancer Drug Des. 2000, 15, 79.

5. Fong, K.-L. L.; Ho, D. H.; Yap, B. S.; Stewart, D.; Brown, Nita S.; Benjamin, Robort, S.;

Freireich, E. J.; Bodery, G. P.; Cancer Treat. Rep. 1980, 64, 1253.

6. Terada, A.; Wachi, K.; Miyazawa, H.; Iizuka, Y.; Tabata, K.; Hasegawa, K.; EP 353,047,

July 26, 1988.

7. Terada, A.; Wachi, K.; Myazawa, H.; Iizuka, Y.; Hasegawa, K.; Tabata, K.; JP 07,278,148,

November 18, 1994.

8. Vicentini, C. B.; Veronese, A.; Guarneri, M.; Patent EP 190457A1. Aug. 13, 1986;

Chem. Abstr., 1986, 105, 226578t;

9. Beck, J. P.; Gilligan, P. J.; Patent US 6714912B1. Jan. 16, 2001; Chem. Abstr., 1999, 130,

223271.

10. Ennis, H. L.; Möller, L.; Wang, J. J.; Selawry, O. S.; Biochem. Pharmacol. 1971, 20, 2639.

11. Vicentinia, C. B.; Manfrinia, M.; Mazzantia, M.; Scatturina, A.; Romagnolib, C.;

Maresc, D.; Arch. Pharm. Pharm Med. Chem., 1999, 332, 337.

12. Dombroski, M. A.; Letavic, M. A.; McClure, K. F.; WO 02072576, 2002.

13. Pelling, J. C.; Shipman, C.; Jr. Biochem. Pharmacol. 1976, 25, 2377.

14. Matsumoto, M.; Weckbecker, G.; Cory, J. G.; Cancer Commun. 1990, 2, 1.

15. Goddard, A. J.; Orr, R. M.; Stock, J. A.; Wilman, D. E.; Anti-Cancer Drug Des. 1987, 2, 235.

16. Ahmet, M. T.; Douglas, K. T.; Silver, J.; Goddard, A. J.; Wilman, D. E.; Anti-Cancer Drug

Des. 1986, 1, 189.

17. Moore, E. C.; Hurlbert, R. B.; Pharmacol. Ther. 1985, 27, 167.

18. Krishan, A.; Paika, D.; Frei, E.; Cancer Res. 1976, 36, 138.

19. Beer, C. T.; Kajiwara, K.; Mueller, G. C.; Biochem. Pharmacol. 1974, 23, 1115.

20. Zhang, X.; Sui, Z.; US 7655683, 2010.

21. Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z;. J. Med.

Chem. 2007, 50, 3857.

22. Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z.; Bioorg.

Med. Chem. Lett. 2007, 17, 439.

23. Vanotti, E.; Florentini, F.; Villa, M.; J. Heterocycl. Chem. 1994, 31, 737.

24. Allen, L. M.; Thornthwaite, J. T.; Cancer Res 1980, 40, 4059.

25. Ganapathi R.; Krishan A.; Cancer Res., 1980, 40, 1103.

26. Grant S.; Bhalla K.; Rauscher F.; Cancer Res., 1983, 43, 5093.



27. Brullo, C.; Spisani, S.; Selvatici, R.; Bruno, O.; European Journal of Medicinal Chemistry,

2012, 47, 573.

28. Bruno, O.; Brullo, C.; Bondavalli, F.; Ranise, A.; Schenone, S.; Falzarano, M. S.; Varanic, K.;

Spisani, S.; Bioorganic & Medicinal Chemistry Letters, 2007, 17, 3696.

29. Baviskar, A. T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S. K.;

Kundu, C. N.; Banerjee, U. C.; Bharatam, P. V.; J. Med. Chem., 2011, 54, 5013.

30. Ochi, H.; Miyasaka, T.; Kanada, K.; Arakowa, K.; Bull. Chem. Soc. Japan, 1976, 49, 1980.

31. Hecht, S.; Werner, D.; Traficant, D.; Sundanalingam, M.; Prusinger, P.; Eto, T.; Sakurai, T.; J.

Org. Chem., 1975, 40, 1815.

32. Elguero, J.; Knutsson, L.; Mignonac-Monden, S.; Bull. Chem. Soc. France 1975, 255.

33. Elnagdi, M. H.; Hafez, E. A.; El-Fahham, H. A.; Kandeel, E. M.; J. Heterocyclic Chem., 1980,

17, 73.

34. Terada, A.; Wachi, K.; Miyazawa, H.; Iizuka, Y.; Tabata, K.; Hasegawa, K.; European

Patent 353,047 (1988); Chem. Abstr., 1991, 114, 55777.

35. Koga, H.; Hirobe, M.; Okamoto, T.; Chem. Pharm. Bull.,1974, 22, 482.

36. Knutsson, L.; Elguero, J.; An. Quim., 1978, 795.

37. Hammouda, H. A.; El-Barbary, A. A.; Sharaf, M. A. F.; J. Heterocyclic Chem., 1984, 21, 945.

38. Elgemeie, G. E. H.; Elfahham, H. A.; Ghozlan, S. A. S.; Elnagldi, M. H.; Bull. Chem. Soc.

Jpn., 1984, 57, 1650.

39. Langer, P.; Wuckelt, J.; Döring, M.; Schreiner, P. R.; Görls, H.; Eur. J. Org. Chem., 2001,

2257.

40. Liubchak, K.; Tolmachev, A.; Nazarenko, K.; J. Org. Chem., 2012, 77, 3365.

41. Farag, A. M.; Dawood, K. M.; Heteroatom Chemistry, 1997, 8, 129.

42. Abdelhamid, A. O.; Abdelall, E. K. A.; Zak, Y. H.; J. Heterocyclic Chem., 2010, 47, 477.

43. Ming, L.; Guilong, Z.; Lirong, W.; Huazheng, Y.; J. Heterocyclic Chem., 2005, 42, 209.

44. Ming, L.; Guilong, Z.; Lirong, W.; Huazheng, Y.; Synthetic Communications, 2005, 35, 493.

45. Rahmati, A.; Kouzehrash, M. A.; Synthesis, 2011, 18, 2913.

46. Barsy, M. A.; El-Rady, E. A.; J. Heterocyclic Chem., 2006, 43, 523.

47. Lee, K. J.; Kwon, H. T.; Kim, B. G.; J. Heterocyclic Chem., 1997, 34, 1797.

48. Lee, K. J.; Kim, D. W.; Kim, B. G.; J. Heterocyclic Chem., 2003, 40, 363.

gami5. chapter-4

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Chapter-4 Synthesis of 1H-imidazo[1,2-b]pyrazoles Chapter ...shodhganga.inflibnet.ac.in/bitstream/10603/15979/9/09_chapter 4.pdf · chloroacetylacetone in dry toluene at reflux temperature