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European	Journal	of	Chemistry	7	(4)	(2016)	431‐435	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2016	Atlanta	Publishing	House	LLC	‐	All	rights	reserved	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.7.4.431-435.1485 

	
	

	

	

European	Journal	of	Chemistry	
Journal	webpage:	www.eurjchem.com	 	

	 	 	

Microwave	assisted	multicomponent	reaction:	An	environmentally	benign	
protocol	for	the	synthesis	of	substituted	imidazo[2,1‐b]thiazole‐2‐
carbohydrazide	derivatives	under	solvent	free	condition	

Shuddhodan	Narhari	Kadam	1,	Ajay	Niwruttirao	Ambhore	1,	Milind	Vithalrao	Gaikwad	1,															
Rahul	Datta	Kamble	2,	Shrikant	Vasantappa	Hese	1,	Madhav	Janardan	Hebade	1	and																					
Bhaskar	Sadashiv	Dawane	1,*	

1	School	of	Chemical	Sciences,	Swami	Ramanand	Teerth	Marathwada	University,	Nanded,	431606,	India	
2	Amruteshwar	Arts,	Commerce	and	Science	College,	Vinzar,	Tal.	Velhe	Dist.,	Pune,	412213,	India	

*	Corresponding	author	at:	School	of	Chemical	Sciences,	Swami	Ramanand	Teerth	Marathwada	University,	Nanded,	431606,	India.		
Tel.:	+91.942.3584000.	Fax:	+91.246.2229574.	E‐mail	address:	bhaskardawane@rediffmail.com	(B.S.	Dawane).	

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI: 10.5155/eurjchem.7.4.431-435.1485	

Received:	12	May	2016	
Received	in	revised	form:	21	June	2016	
Accepted:	26	June	2016	
Published	online:	31	December	2016	
Printed:	31	December	2016

 

	 The	present	report	describes	a	microwave	assisted	convenient	and	efficient	protocol	for	the
synthesis	 of	 new	 6‐(4‐substituted‐phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydra‐
zide	derivatives.	The	current	method	holds	a	tag	of	green	synthesis	by	virtue	of	catalyst	and
solvent	free	media.	Moreover,	the	procedure	offers	excellent	yield	and	purity	of	the	products
under	mild	condition	compared	with	conventional	method.	

KEYWORDS	
Thiazole	
Imidazol	
Microwave	
Carbohydrazide	
Multi‐component	
Solvent	free	reaction	

Cite	this:	Eur.	J.	Chem.	2016,	7(4),	431‐435	

	
1.	Introduction	
	

In	 the	 last	 decade,	 synthetic	 chemists	 have	 oriented	
towards	a	sound	interest	in	the	development	of	one‐pot	multi‐
component	 reactions	 (MCRs),	 in	order	 to	develop	 libraries	of	
diver’s	 heterocyclic	 compounds.	 The	 high	 efficiency,	 conve‐
niences	 and	 atom	 economy	 are	 the	 reticular	 properties	 of	
MCRs	 in	 comparison	 with	 multistage	 procedure	 [1‐4].These	
properties	 of	 the	 MCRs	 are	 always	 woven	 to	 the	 green	
chemistry	 protocol,	 which	 fascinated	 the	 researchers	 to	
synthesis	various	bioactive	compounds	using	MCRs	[5‐9].	

Microwave	 assisted	 organic	 synthesis	 had	 become	
compelling	 and	 prominent	 approach	 in	 synthetic	 chemistry	
because,	 it	 meets	 various	 scientific	 challenges	 coming	 from	
traditional	 synthetic	 procedure	 such	 as	 consumption	 of	
conventional	 organic	 solvents	 [10],	 prolonged	 reaction	
time[11],	 high	 cost	 of	 catalyst	 and	 low	 selectivity	 of	 the	
product	 [12].	 MCRs	 incorporated	 with	 microwave	 assisted	
synthesis	 enhances	 reaction	 rate	 [13‐15]	 and	 product	 yield	
[16‐18]	with	high	atom	efficiency	[19,20]	proving	themselves	

in	 accordance	 with	 the	 green	 chemistry	 protocols	 [21‐25].	
Synthesis	of	biologically	important	pharmacophore	by	solvent	
and	 catalyst	 free	 microwave	 assisted	 MCRs	 results	 in	
achievement	to	decreased	cost	and	time	required	for	reaction.	

Catalyst	 plays	 a	 vital	 role	 in	 synthesis	 by	 enhancing	 the	
rate	 of	 reaction	without	making	 any	 change	 in	 product	 [26].	
Almost	 all	 the	 time	 the	 catalyst	 was	 thrown	 out	 after	 the	
completion	of	the	reaction.	This	may	be	incorporated	with	the	
use	 of	 eco‐friendly	 solvents,	 as	 they	 are	 safer	 to	 handle	 and	
gives	desired	product,	purity	and	good	yield	[27,28].	Despite	of	
this	use	of	solvent	and	catalyst	may	interrupt	the	environment	
by	consuming	natural	resources.	Thus	MCRs	designed	without	
the	use	of	catalyst	and	solvents	accompanied	with	microwave	
assisted	 synthesis	 are	 most	 welcome	 and	 adapted	 in	 the	
synthetic	field.	

Hydrazides	were	perceived	as	crucial	 starting	material	of	
wide	 range	 of	 derivatives	 applied	 in	 pharmaceutical	 indust‐
ries.	Hydrazides	have	been	 studied	 comprehensively	 because	
of	 their	 diverse	 chemical	 reactivity	 and	 broad	 spectrum	 of	
biological	activity.		



432	 Kadam	et	al.	/	European	Journal	of	Chemistry	7	(4)	(2016)	431‐435	
	

	

	
	

Scheme	1	
	
	

	
	

Scheme	2	
	
	
Numbers	 of	 hydrazide	 derivatives	 are	 known	 to	 possess	

anti‐tubercular	 [29,30],	 antifungal	 [31],	 antibacterial	 [32,33],	
antihelmintic	 [34],	anticonvulsant	 [35]	and	anti	HIV	activities	
[36].		

These	facts	create	vital	interest	of	researcher	to	develop	a	
competent	method	for	their	synthesis.	As	a	part	of	our	efforts	
for	 the	 development	 of	 green	 methodology	 for	 synthesis	 of	
biologically	 important	 scaffolds	 [37‐44],	 herein	 we	 report	
microwave	 assisted	 MCR	 for	 synthesis	 of	 new	 6‐(4‐substi‐
tuted‐phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐
carbohydrazide	derivatives.	
	
2.	Experimental		
	
2.1.	Material	and	methods	
	

All	 reagents	 and	 chemicals	 were	 used	 laboratory	 grade	
and	 purified	 prior	 to	 use.	 Melting	 points	 of	 all	 synthesized	
compounds	 were	 recorded	 in	 open	 capillary	 tubes	 and	 are	
uncorrected.	IR	spectra	were	recorded	in	KBr	pellets	on	a	FT‐
IR	 Shimadzu	 spectrophotometer,	 and	 1H	 NMR	 spectra	 in	
dimethylsulfoxide	 solvent	 were	 scanned	 on	 an	 AVANCE	
300/400	 MHz	 spectrometer	 using	 TMS	 as	 an	 internal	
standard.	 The	 MS	 were	 recorded	 on	 an	 EI‐Shimadzu‐GC‐MS	
spectrometer.	 Elemental	 analysis	was	 carried	 out	 on	 a	 Carlo	
Erba	106	Perkin‐Elmer	model	240analyzer.	
	
2.2.	General	procedure	for	synthesis	of	6‐(4‐substituted‐
phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydrazide	
	
2.2.1.	Method	A:	Conventional	synthesis		
	

For	 the	 synthesis	 of	 the	 6‐(4‐substituted‐phenyl)‐3‐
methylimidazo[2,	1‐b]thiazole‐2‐carbohydrazide	derivatives,	
ethyl	 2‐amino‐4‐methylthiazole‐5‐carboxylate	 (1	 mmol)	 and	
substituted	 phenacyl	 bromide	 (1	 mmol)	 was	 taken	 in	 round	
bottom	 flask	 and	 reflux	 for	 3	 hours	 at	 100‐130°C.	 Reaction	
mass	 was	 examined	 by	 thin‐layer	 chromatography	 (TLC)	
clearly	 reflect	 the	 formation	 of	 intermediate	 ethyl	 6‐(4‐
substituted‐phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐car‐
boxylate.	 Thenceforth	 in	 the	 same	 pot	 excess	 of	 hydrazine	
hydrate	was	added	and	the	reaction	mass	was	further	refluxed	
for	2	to	3	hours,	at	the	same	temperature.	Finally,	the	reaction	
mixture	 was	 poured	 on	 crushed	 ice	 to	 form	 the	 final	 6‐(4‐
substituted‐phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐car‐
bohydrazide	derivatives	as	a	solid	(Scheme	1	‐	3).	

2.2.2.	Method	B:	Microwave	assisted	synthesis	
	

For	 the	 synthesis	 of	 target	 compound	 ethyl	 2‐amino‐4‐
methylthiazole‐5‐carboxylate	 (1	 mmol)	 and	 substituted	
phenacyl	bromide	(1	mmol)	was	taken	in	open	vial	and	placed	
under	 microwave	 radiation	 at	 110	 to	 120	 °C.	 At	 regular	
interval	 of	 1	 minute,	 product	 was	 examined	 by	 TLC	 using	
petroleum	 ether	 and	 ethyl	 acetate	 as	 eluent	 (8:2	 ratios).	
Completion	 of	 reaction	 is	 confirmed	 by	 TLC	 after	 2	 to	 3	
minutes.	 After	 this	 subsequently	 few	 drops	 of	 hydrazine	
hydrate	was	added	in	same	vessel	and	again	the	reaction	mass	
was	 radiated	 by	microwave	 radiation	 at	 120	 °C	 after	 2	 to	 3	
minutes	 TLC	 shows	 the	 completion	 of	 reaction.	 The	 formed	
semisolid	 reaction	 mixture	 was	 poured	 on	 crushed	 ice	 and	
formed	 solid	 was	 filtered,	 dried	 and	 recrystallized	 with	
aqueous	 acetic	 acid.	 Product	 is	 observed	 to	 be	 in	 good	 to	
excellent	yield.	The	reaction	is	shown	in	Scheme	1	and	2.	

6‐(4‐Bromophenyl)‐3‐methylimidazo[2,	 1‐b]thiazole‐2‐car	
bohydrazide	 (6a):	 Color:	 Pale	 yellow.	 Yield:	 80%.	 M.p.:	 110‐
112	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3330	 (NH2),	 3247	 (NH),	 1670	
(C=O)(amide).	 1H	NMR	 (400	MHz,	DMSO‐d6,	 δ,	 ppm):	2.78	 (s,	
3H,	CH3),	4.55	(s,	2H,	NH2),	7.50‐7.53	(dd,	2H,	Ar‐H,	J	=	7.6	Hz),	
8.00‐8.12	(dd,	2H,	Ar‐H,	J	=	8	Hz),	8.54	(s,	1H,	CH),	9.69	(s,	1H,	
NH).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	155,	150,	140,	136,	
130,	 128,	 107.	 MS	 (EI,	m/z	 (%)):	 351	 (M+).	 Anal.	 calcd.	 for	
C13H11BrN4OS:	C,	44.46;	H,	3.16;	N,	15.95.	Found:	C,	44.41;	H,	
3.19;	N,	15.91%.		

6‐(4‐Chlorophenyl)‐3‐methylimidazo[2,	 1‐b]thiazole‐2‐car	
bohydrazide	(6b):	Color:	Yellow.	Yield:	75%.	M.p.:	105‐107	°C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3225	 (NH2),	 3200	 (NH),	 1669	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 2.69	 (s,	 3H,	
CH3),	 4.55	 (s,	 2H,	 NH2),	 7.41‐7.43	 (dd,	 2H,	 Ar‐H,	 J	 =	 7.5	 Hz),	
7.85‐7.87	(dd,	2H,	Ar‐H,	J	=	7.5	Hz),	8.33	(s,	1H,	C5CH),	9.61	(s,	
1H,	 NH).	 13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 161.02,	
146.59,	 145.71,	 132.55,	 131.81,	 130.96,	 128.41,	 126.39,	
108.26,	 12.91.	 MS	 (EI,	m/z	 (%)):	 307	 (M+).	 Anal.	 calcd.	 for	
C13H11ClN4OS:	 C,	 50.90;	H,	 3.61;	N,	 18.26.	 Found:	 C,	 50.88;	H,	
3.63;	N,	18.23%.		

6‐(4‐Fluorophenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbo	
hydrazide	(6c):	Color:	Pale	white.	Yield:	75%.	M.p.:	111‐113	°C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3333	 (NH2),	 3300	 (NH),	 1678	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 3.00	 (s,	 3H,	
CH3),	 5.33	 (s,	 2H,	 NH2),	 7.44‐7.46	 (dd,	 2H,	 Ar‐H,	 J	 =	 7.0	 Hz),	
8.55‐8.57	(dd,	2H,	Ar‐H,	J	=	8.0	Hz),	8.01	(s,	1H,	C5	CH),	9.66	(s,	
1H,	NH).		

	



Kadam	et	al.	/	European	Journal	of	Chemistry	7	(4)	(2016)	431‐435	 433	
 

	

S

N
NH2

O

O
R1

Br

O

R2
S

N

O
O

N

O

R1

R2

H

H
S

N

O
O

N
OH

R1

R2

H

H

-HOH

S

N

O
O

N

R1

R2

H
S

N

O
O

N

R1

R2

H2N NH2

S

N

H
N

O

N

R1

R2

H2N

-EtOH

1
2

3
4

-Br -H

	
	

Scheme	3
	
	
13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 166.01,	 149.59,	

143.71,	130.54,	131.81,	129.95,	125.40,	126.30,	100.25,	12.90.	
MS	 (EI,	m/z	 (%)):	 290	 (M+).	 Anal.	 calcd.	 for	 C13H11FN4OS:	 C,	
53.78;	H,	3.82;	N,	19.30.	Found:	C,	53.74;	H,	3.83;	N,	19.34%.		

3‐Methyl‐6‐(p‐tolyl)imidazo[2,	 1‐b]thiazole‐2‐carbohydra	
zide	(6d):	Color:	Pale	yellow.	Yield:	77%.	M.p.:	100‐102	°C.	FT‐
IR	(KBr,	,	cm‐1):	3200	(NH2),	3000	(NH),	1660	(C=O)	(amide).	
1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.11	(s,	3H,	CH3),	3.21	(s,	
3H	Ar‐CH3),	4.55	(s,	2H,	NH2),	7.23‐7.25	(dd,	2H,	Ar‐H,	 J	=	7.5	
Hz),	 8.00‐8.14	 (dd,	 2H,	 Ar‐H,	 J	 =	 8.0	Hz),	 8.00	 (s,	 1H,	 C5	 CH),	
9.11	 (s,	 1H,	 NH).	 13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	
165.12,	 150.40,	 145.11,	 140.44,	 125.40,	 120.99,	 119.40,	
115.00,	100.20,	21.33,	12.30.	MS	(EI,	m/z	(%)):	286	(M+).	Anal.	
calcd.	 for	 C14H14N4OS:	 C,	 58.72;	 H	 4.93;	 N,	 19.57.	 Found:	 C,	
58.70;	H,	4.95;	N,	19.55%.		

6‐(4‐Methoxyphenyl)‐3‐methylimidazo[2,	 1‐b]thiazole‐2‐car	
bohydrazide	 (6e):	Color:	 Pale	 yellow.	 Yield:	 70%.	M.p.:	 90‐92	
°C.	 FT‐IR	 (KBr,	,	 cm‐1):	 3250	 (NH2),	 3300	 (NH),	 1669	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 2.41	 (s,	 3H,	
CH3),	3.22	(s,	3H,	OCH3),	4.44	(s,	2H,	NH2),	7.55‐7.57	 (dd,	2H,	
Ar‐H,	 J	=	7.0	Hz),	8.22‐8.25	(dd,	2H,	Ar‐H,	 J	=	7.5	Hz),	8.60	(s,	
1H,	C5	CH),	9.01	 (s,	1H,	NH).	 13C	NMR	(100	MHz,	DMSO‐d6,	 δ,	
ppm):	170.10,	160.44,	150.12,	145.40,	135.42,	130.99,	120.40,	
115.00,	102.20,	30.50,	20.30.	MS	(EI,	m/z	(%)):	302	(M+).	Anal.	
calcd.	 for	 C14H14N4O2S:	 C,	 55.62;	 H,	 4.67;	 N,	 18.53.	 Found:	 C,	
55.60;	H,	4.64;	N,	18.50%.		

3‐Methyl‐6‐(4‐nitrophenyl)imidazo[2,	 1‐b]thiazole‐2‐carbo	
hydrazide	(6f):	Color:	Yellow.	Yield:	90%.	M.p.:	130‐132	°C.	FT‐
IR	(KBr,	,	cm‐1):	3340	(NH2),	3325	(NH),	1669	(C=O)	(amide).	
1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	3.10	(s,	3H,	CH3),	4.50	(s,	
2H,	NH2),	 7.99‐8.00	 (dd,	 2H,	 Ar‐H,	 J	 =	 7.5	Hz),	 8.22‐8.25	 (dd,	
2H,	Ar‐H,	J	=	8.0	Hz),	8.62	(s,	1H,	C5	CH),	11.00	(s,	1H,	NH).	13C	
NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 160.10,	 155.44,	 145.12,	
140.41,	130.40,	125.90,	120.33,	110.22,	100.20,	12.33.	MS	(EI,	
m/z	 (%)):	317	 (M+).	Anal.	 calcd.	 for	C13H11N5O3S:	C,	49.21;	H,	
3.49;	N,	22.07.	Found:	C,	49.20;	H,	3.50;	N,	22.00%.	

3‐Methyl‐6‐(3‐nitrophenyl)imidazo[2,	 1‐b]thiazole‐2‐carbo	
hydrazide	 (6g):	 	 Color:	 Yellow.	 Yield:	 85%.M.p.:	 125‐127	 °C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3324	 (NH2),	 3239	 (NH),	 1670	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 3.10	 (s,	 3H,	
CH3),	4.43	(s,	2H,	NH2),	7.55‐7.57	(m,	4H,	Ar‐H,	J	=	7.0	Hz),	8.01	
(s,	1H,	C5	CH),	10.90	(s,	1H,	NH).	13C	NMR	(100	MHz,	DMSO‐d6,	

δ,	 ppm):	 160.11,	 155.30,	 145.10,	 140.40,	 130.39,	 125.80,	
120.10,	 110.23,	 100.19,	 12.22.	 MS	 (EI,	m/z	 (%)):	 317	 (M+).	
Anal.	calcd.	for	C13H11N5O3S:	C,	49.21;	H	3.49;	N,	22.07.	Found:	
C,49.20;	H,	3.47;	N,	22.11%.		

3‐Methyl‐6‐phenylimidazo[2,	1‐b]thiazole‐2‐carbohydrazide	
(6h):	Color:	Brown.	Yield:	70%.	M.p.:	109‐112	°C.	FT‐IR	(KBr,	
,	cm‐1):	3100	(NH2),	3010	(NH),	1670	(C=O)	(amide).	1H	NMR	
(400	MHz,	 DMSO‐d6,	 δ,	 ppm):	 3.90	 (s,	 3H,	 CH3),	 4.45	 (s,	 2H,	
NH2),	7.94‐7.96	(m,	5H,	Ar‐H,	 J	=	7.5	Hz),	8.52	 (s,	1H,	C5	CH),	
8.90	 (s,	 1H,	 NH).	 13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	
160.02,	 145.50,	 144.70,	 130.50,	 131.80,	 125.90,	 123.41,	
120.39,	107.26,	11.91.	MS	(EI,	m/z	(%)):	273	(M+).	Anal.	calcd.	
for	C13H12N4OS:	C,	57.34;	H,	4.44;	N,	20.57.	Found:	C,	57.30;	H,	
4.43;	N,	20.59%.		

6‐(3‐Bromophenyl)‐3‐methylimidazo[2,	 1‐b]thiazole‐2‐car	
bohydrazide	(6i):	Color:	Pale	yellow.	Yield:	80%.	M.p.:	122‐124	
°C.	 FT‐IR	 (KBr,	,	 cm‐1):	 3100	 (NH2),	 3010	 (NH),	 1675	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 3.90	 (s,	 3H,	
CH3),	4.48	(s,	2H,	NH2),	7.00‐7.12	(m,	4H,	Ar‐H,	J	=	7.2	Hz),	7.55	
(s	1H,	C5	CH),	8.90	(s,	1H,	NH).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	
ppm):	160.11	145.55,	143.70,	133.50,	131.88,	130.96,	126.40,	
123.30,	107.26,	12.90.	MS	(EI,	m/z	(%)):	351	(M+).	Anal.	calcd.	
forC13H11BrN4OS:	C,	44.46;	H,	3.16;	N,	15.95.	Found:	C,	44.49;	
H,	3.19;	N,	15.91%.		

6‐(3‐Chlorophenyl)‐3‐methylimidazo[2,	 1‐b]thiazole‐2‐car	
bohydrazide	(6j):	Color:	Pale	yellow.Yield:	85%.	M.p.:	116‐118	
°C.	 FT‐IR	 (KBr,	,	 cm‐1):	 3110	 (NH2),	 3100	 (NH),	 1670	 (C=O)	
(amide).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 3.01	 (s,	 3H,	
CH3),	4.44	(s,	2H,	NH2),	7.00‐7.13	(m,	4H,	Ar‐H,	J	=	7.5	Hz),	8.00	
(s	1H,	C5	CH),	8.9	(s,	1H,	NH).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	
ppm):	160.00,	145.50,	140.71,	132.50,	131.80,	130.90,	128.42,	
126.33,	108.28,	12.95.	MS	(EI,	m/z	(%)):306	(M+).	Anal.	calcd.	
forC13H11ClN4OS:	C,	50.90;	H,	3.61;	N,	18.26.	Found:	C,	50.93;	H,	
3.60;	N,	18.29%.		
	
3.	Result	and	discussion		
	

Considering	 the	 shortcomings	 of	 the	 conventional	 ref‐
luxing	 method	 like	 prolonged	 reaction	 time,	 resulting	
sometime	 in	 poor	 yield,	 moreover	 the	 formed	 product	 is	
associated	with	unreacted	starting	material.		

	



434	 Kadam	et	al.	/	European	Journal	of	Chemistry	7	(4)	(2016)	431‐435	
	

	
Table	1.	Optimization	of	the	reaction	condition	for	synthesis	of	compound	6i.	
Entry	 Catalyst	 Time	(min)	 Temp.	(°C)	 Yield	(%)	
1	 Et3N	 4 110 40	
2	 NaOCH3	 6 120 20	
3	 KOH	 6	 110	 30	
4	 NaOH	 7	 122	 22	
5	 ‐	 4	 100	 80	
	

	

Table	2.	Synthesis	of	6‐(4‐substituted‐phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydrazide.	
Entry	 Products	 Time	(min)	 Yield	(%)	a Melting	point	(°C)

Microwave	heating	 Conventional	heating	 Microwave	heating	 Conventional	heating	
1	 6a	 5	 360	 80 85 110‐112	
2	 6b	 4	 400	 83 75 105‐107	
3	 6c		 5	 370	 75 70 111‐113	
4	 6d	 7	 480	 77	 70	 100‐102	
5	 6e	 4	 500	 70	 65	 90‐92	
6	 6f	 4	 371	 90	 89	 130‐132	
7	 6g	 5	 360	 85 85 125‐127	
8	 6h	 4	 400	 70	 69	 109‐112	
9	 6i	 4	 350	 80 80 122‐124	
10	 6j	 5	 360	 85 83 116‐118	
a	Isolated	yields.	
	
	

The	 newly	 adapted	 microwave	 approach	 is	 observes	 to	
shorten	 the	 reaction	 time	 significantly,	 with	 efficient	
utilization	 of	 starting	 material.	 The	 studied	 method	 for	
synthesis	is	incorporated	with	good	yield	without	use	of	costly	
catalyst,	 or	 solvent.	 Synthesis	 of	 starting	 material	 ethyl	 2‐
amino‐4‐methylthiazole‐5‐carboxylate	is	carried	out	by	known	
method	[45]	as	shown	in	Scheme	1.	

Equimolar	 quantity	 of	 ethyl	 2‐amino‐4‐methylthiazole‐5‐
carboxylate	(3),	substituted	phenacyl	bromide	(4)	and	hydra‐
zinehydrate	 (5)	 were	 added	 sequentially	 in	 same	 pot,	 irra‐
diated	 with	 microwave	 irradiation	 to	 give	 desired	 product	
substituted‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydrazide	
(6a‐j).	The	formed	product	was	characterized	with	the	help	of	
spectral	data	 IR,	 1H	NMR,	 13C	NMR	and	Mass.	 The	 reaction	 is	
shown	in	Scheme	2.	

FT‐IR	 spectra	 of	 the	 compound	 clearly	 reveals	 the	
presence	of	sharp	amidic	carbonyl	stretching	vibration	frequ‐
ency	observed	at	1670	cm‐1,	with	NH	and	NH2	broad	stretching	
vibration	 and	 at	 3330	 and	 3247	 cm‐1,	 respectively.	 1H	 NMR	
clearly	showing	the	presence	of	one	sharp	singlet	for	CH3	at	δ	
2.69	ppm,	singlet	at	 δ	4.55	ppm	for	NH2	protons,	 singlet	at	δ	
8.33	ppm	for	CH	protons,	and	singlet	at	δ	9.61	ppm	for	NH,	and	
all	 remaining	 protons	 are	 in	 their	 corresponding	 aromatic	
region	at	δ	7.41	to	7.87	ppm.	In	mass	spectrum	compound	6b	
shows	peak	at	307	due	to	[M+1].	The	plausible	mechanism	is	
shown	in	Scheme	3.	

Mechanism	 of	 the	 reaction	 indicates	 the	 propagation	 of	
reaction	 takes	 place	 through	 nucleophilic	 attack	 of	 cyclic	
nitrogen	 on	 substituted	 phenacyl	 bromide,	 followed	 by	
cyclization	 to	 form	 five	 membered	 imidazothiazole	 carboxy‐
late	rings.	Lastly	hydrazine	hydrates	reacts	with	ester	to	form	
the	final	product.		

Discrete	 reaction	 conditions	 are	 explored	 for	 the	 optimi‐
zation	 of	 reaction	 including	 temperature,	 catalyst	 and	 time.	
Reaction	 carried	 out	 at	 room	 temperature	 without	 use	 of	
solvent	and	catalyst	doesn’t	get	completed	even	after	3	hours	
of	irradiation	of	microwave	radiation.	Uses	of	various	catalysts	
are	shown	to	alter	the	yield	of	the	product	as	well	as	time	for	
completion	of	reaction.	When	there	was	use	of	strong	base	or	
strong	acid	as	catalyst	the	yield	of	product	appeared	was	poor,	
time	required	 for	 completion	of	 reaction	was	also	more	 [46].	
Use	 of	 mild	 base	 or	 mild	 acid	 as	 a	 catalyst	 shows	 further	
increase	 in	 the	 product	 yield	 with	 lesser	 time,	 up	 to	 some	
extent.	 The	 best	 yield	 in	 less	 time	 is	 observed	 when	 the	
reaction	 is	 carried	 out	 without	 catalyst	 under	 microwave	
condition	[47].	The	temperature	for	the	reaction	is	observed	to	
be	 100	 to	 120	 °C	 without	 solvent.	 All	 the	 three	 observed	
optimized	 reaction	 condition	 shows	 that,	 the	 reaction	 is	
completed	with	excellent	yield	 in	 less	 time	when	 it	 is	carried	

out	 under	 solvent	 and	 catalyst	 free	 condition	 with	
temperature	 100	 to	 120	 °C	 in	microwave.	 The	 results	 of	 the	
optimization	are	described	in	Table	1.	

With	these	results	of	optimization	of	the	reaction,	we	tried	
various	substituted	phenacyl	bromide	for	inspecting	the	scope	
and	capability	of	reaction.	Method	of	the	reaction	is	observed	
to	 applicable	 for	 various	 derivatives,	 with	 good	 to	 excellent	
yield.	 It	 was	 observed	 that	 position	 and	 nature	 of	 the	
substituent	 on	 the	 phenyl	 ring	 of	 substituted	 phenacyl	
bromide	dose	not	 strongly	 affect	 the	 reaction,	however	 there	
was	mild	effect	observed	that	electron	withdrawing	groups	on	
substituted	phenacyl	bromide	were	responsible	for	increase	in	
the	 yield	 of	 the	 reaction,	 up	 to	 some	 extent	 while	 electron	
donate	 groups	were	 decreasing	 the	 yield	 up	 to	 some	 extent.	
These	results	are	described	in	Table	2.	

In	conclusion	herein	we	have	successfully	report	an	easy,	
practical	 and	 efficient	 access	 for	 synthesis	 of	 new	 6‐(4‐sub	
phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydrazide	 by	
solvent	 and	 catalyst	 free	 one	 pot	 microwave	 assisted	
procedure.	 The	 protocol	 reveals	 significant	 advantages	 as	
avoiding	 use	 toxic	 solvents	 and	 catalyst,	 easy	 isolation	 of	
product,	 high	 yield,	 and	 atom	 economy,	 mild	 and	 simple	
condition	 with	 shorter	 reaction	 time.	 This	 process	 provides	
cheap	and	eco‐friendly	method	for	synthesis	of	new	6‐(4‐sub	
phenyl)‐3‐methylimidazo[2,1‐b]thiazole‐2‐carbohydrazide	
derivatives.		
	
Acknowledgments	
	

Author	 Shuddhodan	 Narhari	 Kadam	 (F.	 No.	 38‐07/14	
WRO),	Ajay	Niwruttirao	Ambhore	(F.	No.	36‐33/14	WRO)	and	
Madhav	Janardan	Hebade	(F.	No.	31‐21/14	WRO)	are	grateful	
to	 The	 University	 Grants	 Commission	 for	 the	 teacher	
fellowship	 under	 their	 Faculty	 Development	 Programme	
scheme.	 The	 authors	 gratefully	 acknowledge	 Sophisticated	
Analytical	 Instrumentation	 Facility	 Chandigarh	 and	 Vishnu	
chemicals,	Hyderabad	for	spectral	analysis.	
	
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