untitled


European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2015	Atlanta	Publishing	House	LLC	‐	All	rights	reserved	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.6.1.78‐83.1148	

	
	

	

	

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

	 	 	

Synthesis	and	characterization	of	new	3,5‐disubstituted‐4,5‐dihydro‐1H‐
pyrazole	and	their	carbothioamide	derivatives	

Mohammad	Mahmoud	Ibrahim	

Department	of	Chemistry,	Faculty	of	Sciences,	University	of	Al	Al‐Bayt,	Al‐Mafraq,	25113,	Jordan	

*	Corresponding	author	at:	Department	of	Chemistry,	Faculty	of	Sciences,	University	of	Al	Al‐Bayt,	Al‐Mafraq,	25113,	Jordan.		
Tel.:	+962.2.6297000/2174.	Fax:	+962.2.6297021.	E‐mail	address:	mohammadibrahim@aabu.edu.jo	(M.M.	Ibrahim).		

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.6.1.78‐83.1148	

Received:	08	September	2014	
Received	in	revised	form:	07	October	2014	
Accepted:	07	October	2014	
Published	online:	31	March	2015	
Printed:	31	March	2015	

	 A	 new	 series	 of	 substituted	 pyrazolines	 (6‐10)	 were	 synthesized	 in	 moderate	 to	 excellent
yield	 by	 treatment	 of	 chalcones	 (1‐5)	 with	 hydrazine	 monohydrate.	 The	 carbothioamide
compounds	(11‐14)	were	obtained	in	65%	to	quantitative	yield	by	treatment	of	chalcones	(2,
4,	 and	5)	 either	with	 thiosemicarbazide	 or	 with	 phenylisothiocyanate.	 All	 new	 compounds
were	characterized	by	various	spectroscopic	methods	such	as	1H	NMR,	13C	NMR,	DEPT,	COSY,
HSQC	spectroscopy,	elemental	analysis,	and	high	resolution	mass	spectroscopy.	The	obtained
compounds	 are	 currently	 under	 biological	 investigations,	 and	 the	 results	 will	 be	 reported
elsewhere.	

KEYWORDS	
Chalcones		
Pyrazolines	
Isothiocyanate		
Carbothioamide	
Claisen‐Schmidt	
Thiosemicarbazide	 Cite	this:	Eur.	J.	Chem.	2015,	6(1),	78‐83	

	
1.	Introduction	
	

Chalcones	 are	 a	 class	 of	 important	 organic	 compounds.	
They	are	the	main	precursors	for	the	synthesis	of	a	wide	range	
of	 a	 biologically	 active	 heterocyclic	 compounds	 such	 as	
pyrazoles	 [1‐5],	 isoxazoles	 [4,5],	 oxazines	 [6],	 pyrimidines	
[7,8],	 thiazine	 derivatives,	 and	 many	 other	 heterocycles	 [9].	
Chalcone	substructure	is	also	well‐known	for	the	biosynthesis	
of	flavonoids	and	isoflavonoids	that	have	high	therapeutic	and	
preventive	 potential	 of	 many	 diseases	 [10‐13].	 Moreover,	
chalcones	 themselves	 exhibit	 various	 interesting	 biological	
activities	 such	 as;	 antimicrobial	 [14],	 antimalarial	 [15],	
antileishmanial	 [15],	 anti‐diabetic	 [16],	 anti‐inflammatory	
[17],	 anticancer	 [18,19],	 antioxidant	 [20,21],	 and	many	other	
activities	[22,23].		

Pyrazolines	are	important	heterocyclic	compounds	due	to	
their	potential	applications	in	medicinal	chemistry.	They	have	
been	reported	to	posses	activities	such	as;	EGFR‐TK	inhibitors	
[24],	 anticancer	 [24‐27],	 MAO‐B	 inhibitors	 [28,29],	 anti‐
microbial	[30‐32],	anti‐inflammatory	[33],	and	antidepressant	
[34‐37],	along	with	other	biological	activities	[38,39].	

Also,	 carbothioamide	 derivatives	 were	 found	 to	 have	
significant	 pharmacological	 activities	 such	 as	 antitubercular	
[40],	anti‐cancer	[41],	and	anticonvulsant	[42].	Therefore,	this	
work	 reports	 the	 synthesis	 of	 a	 variety	 of	 4,5‐dihydro‐1H‐

pyrazoles	 and	 pyrazolines	 containing	 carbothioamide	moiety	
derived	from	chalcones.	

	
2.	Experimental	

	
2.1.	Instrumentation	

	
1H	and	13C	NMR	spectra	were	recorded	on	a	Bruker	Avance	

(300	or	400	MHz)	spectrometer.	Chemical	shifts	are	expressed	
in	 ppm	 with	 reference	 to	 TMS	 as	 internal	 standard.	 Mass	
spectra	were	 obtained	 from	 a	Micromass	 Zabtec	 or	 Finnigan	
MAT	95	XP	instrument.	Elemental	analysis	was	performed	on	
a	 Euro	 Vector	 Euro	 EA	 3000	 Elemental	 Analyzer.	 Thin	 layer	
chromatography	 (TLC)	 was	 carried	 out	 on	 ALUGRAM®	 SIL	
G/UV254	 (Macherey‐Nagel)	 and	 visualized	 by	 UV.	 Flash	
column	 chromatography	was	 performed	using	 silica	 gel	 60M	
(Macherey‐Nagel).	 Melting	 points	 were	 determined	 on	 an	
Electrothermal‐9002	 apparatus.	 IR	 spectra	were	 recorded	 as	
thin	 films	 on	 a	 Varian	 IR‐660	 spectrometer.	 For	 analyses,	 all	
new	 compounds	 were	 further	 purified	 on	 preparative	 TLC	
silica‐gel	plates	using	chloroform	as	eluent.		

	
2.2.	Material	

	
Aldehydes	were	purchased	from	Aldrich.	2,5‐Dichloro		



Ibrahim	/	European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	 79	
 

	

 
	

Scheme	1
	

 
	

Scheme	2	
	

thiophene	was	purchased	from	Acros.	The	hydrazines,	used	in	
this	 study,	were	 purchased	 from	 Fluka.	 3‐Acetyl‐2,5‐dichloro	
thiophene	 was	 prepared	 according	 to	 literature	 procedure	
[43].	
	
2.3.	Synthesis	
	
2.3.1.	General	procedure	for	the	synthesis	of	chalcones	1‐5		

	
A	 solution	 of	 the	 corresponding	 acetylethiophene	 (2.0	

mmol)	in	methanol	(5.0	mL)	was	added	dropwise	to	a	solution	
containing	 of	 the	 corresponding	 aldehyde	 (2.0	 mmol)	 and	
sodium	hydroxide	 (4.0	mmol,	 2	 equiv.)	 in	methanol	 (20	mL).	
The	reaction	mixture	was	stirred	for	6	h	at	room	temperature	
until	 completion	 of	 the	 reaction.	 The	 precipitate	 formed,	
filtered	 off,	washed	with	 cold	methanol,	 and	 dried.	 The	 solid	
product	was	recrystallized	from	methanol.	The	progress	of	all	
reactions	was	monitored	by	thin	layer	chromatography	(TLC)	
(Scheme	1).	

(E)‐1‐(2,	 5‐Dichlorothiophen‐3‐yl)‐3‐phenylprop‐2‐en‐1‐one	
(1):	Color:	Yellow	solid.	Yield:	74%	(Lit.	83%)	[44].	M.p.:	52‐54	
°C	(Lit.	53‐54	°C)	[44].	FT‐IR	(KBr,	,	cm‐1):	3046	(C‐H),	1659	
(C=O).	 1H	 NMR	 (300	 MHz,	 CDCl3,	 δ,	 ppm):	 7.24	 (s,	1H,	
thiophene‐H),	7.32	(d,	1H,	 J	=	15.4	Hz,	 ‐CO‐CH=CH),	7.39‐7.58	
(m,	5H,	Ar‐H),	7.65	 (d,	1H,	 J	 =	15.4	Hz,	 ‐CO‐CH=CH).	 13C	NMR	
(75	 MHz,	 CDCl3,	 δ,	 ppm):	 124.8,	 125.5,	 126.9,	 127,1,	 127.4,	
128.5,	128.7,	132.1,	132.3,	133.5,	136.9,	143.2,	183.8.	MS	 (EI,	
m/z	(%)):	283	(M+,	100).	Anal.	calcd.	for	C13H8Cl2OS:	C,	55.14;	
H,	2.85.	Found:	C,	54.91;	H,	2.65%.		

(E)‐3‐(4‐Bromophenyl)‐1‐(2,	 5‐dichlorothiophen‐3‐yl)prop‐
2‐en‐1‐one	 (2):	Color:	Yellow	solid.	Yield:	87%.	M.p.:	106‐108	
°C.	FT‐IR	 (KBr,	,	 cm‐1):	3048	 (C‐H),	2941	 (C‐H),	1653	 (C=O).	
1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	7.18	(s,	1H,	 thiophene‐H),	
7.35	(d,	1H,	J	=	15.7	Hz,	‐CO‐CH=CH),	7.45	(d,	2H,	J	=	8.4	Hz,	Ar‐
H),	7.60	(d,	2H,	J	=	8.6	Hz,	Ar‐H),	7.66	(d,	1H,	J	=	15.7	Hz,	‐CO‐
CH=CH).	 13C	 NMR	 (100	 MHz,	 CDCl3,	 δ,	 ppm):	 124.1,	 125.3,	
127.1,	 127.2,	 129.9,	 131.4,	 132.3,	 133.4,	 137.7,	 143.9,	 183.6.	
MS	(EI,	m/z	(%)):	361	(M+,	100).	Anal.	calcd.	for	C13H7BrCl2OS:	
C,	43.12;	H,	1.95.	Found:	C,	43.23;	H,	1.93%.		

(E)‐1‐(5‐Chlorothiophen‐2‐yl)‐3‐phenylprop‐2‐en‐1‐one	 (3):	
Color:	Yellow	solid.	Yield:	82%	(Lit.	89%)	[46].	M.p.:	89‐92	°C	
(lit.	 91‐93	 °C)	 [46].	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3115	 (C‐H),	 1648	
(C=O).	 1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	6.92	(d,	1H,	 J	=	4.2	
Hz,	 thiophene‐H),	 7.33	 (d,	1H,	 J	 =	 15.2	Hz,	 ‐CO‐CH=CH),	7.35‐
7.44	(m,	5H,	Ar‐H),	7.63	(d,	1H,	J	=	4.2	Hz,	 thiophene‐H),	7.75	
(d,	 1H,	 J	 =	 15.2	Hz,	 ‐CO‐CH=CH).	 13C	NMR	 (75	MHz,	 CDCl3,	 δ,	
ppm):	 124.4,	 125.8,	 126.2,	 127.3,	 128.4,	 130.9,	 131.4,	 132.1,	
141.2,	 143.4,	 143.9,	 181.2.	 MS	 (EI,	m/z	 (%)):	 248	 (M+,	 100).	
Anal.	calcd.	for	C13H9ClOS:	C,	62.78;	H,	3.65.	Found:	C,	62.27;	H,	
3.49%.		

(E)‐3‐(4‐Bromophenyl)‐1‐(5‐chlorothiophen‐2‐yl)prop‐2‐en‐
1‐one	(4):	Color:	White	solid.	Yield:	77%.	M.p.:	147‐148	°C.	FT‐
IR	(KBr,	,	cm‐1):	3028	(C‐H),	2941	(C‐H),	1668	(C=O).	1H	NMR	
(300	MHz,	CDCl3,	δ,	ppm):	7.15	(d,	1H,	J	=	4.1	Hz,	thiophene‐H),	
7.30	(d,	1H,	J	=	15.5	Hz,	‐CO‐CH=CH),	7.49	(d,	2H,	J	=	8.6	Hz,	Ar‐
H),	 7.56	 (d,	 2H,	 J	 =	 8.6	 Hz,	 Ar‐H),	 7.64	 (d,	 1H,	 J	 =	 4.1	 Hz,	
thiophene‐H),	 7.76	 (d,	 1H,	 J	 =	 15.6	Hz,	 ‐CO‐CH=CH).	 13C	NMR	
(75	 MHz,	 CDCl3,	 δ,	 ppm):	 120.8,	 125.1,	 127.8,	 129.9,	 131.3,	
132.5,	 133.4,	 140.1,	 143.1,	 144.0,	 180.8.	 Anal.	 calcd.	 for	
C13H8BrClOS:	C,	47.66;	H,	2.46.	Found:	C,	47.35;	H,	2.28%.	

(E)‐1‐(5‐Chlorothiophen‐2‐yl)‐3‐(furan‐2‐yl)	 prop‐2‐en‐1‐
one	 (5):	Color:	Brown	solid.	Yield:	82%	(Lit.	 94%)	 [47].	M.p.:	
90‐92	°C	(lit.	100.3	°C)	 [47].	FT‐IR	(KBr,	,	cm‐1):	3038	(C‐H),	
2943	 (C‐H),	 1664	 (C=O).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	
6.50	(dd,	1H,	J	=	3.4	Hz,	J	=	1.8	Hz,	furan‐H),	6.71	(d,	1H,	J	=	3.4	
Hz,	furan‐H),	6.97	(d,	1H,	J	=	4.1	Hz,	thiophene‐H),	7.20	(d,	1H,		
J	=	15.2	Hz,	‐CO‐CH=CH),	7.51	(d,	1H,	J	=	1.5	Hz,	furan‐H),	7.56	
(d,	 1H,	 J	 =	 15.3	 Hz,	 ‐CO‐CH=CH),	 7.60	 (d,	 1H,	 J	 =	 4.1	 Hz,	
thiophene‐H).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	112.8,	116.8,	
117.8,	 127.7,	 130.2,	 131.0,	 139.6,	 144.4,	 145.1,	 151.3,	 180.7.	
MS	(EI,	m/z	(%)):	238	(M+,	100).	Anal.	calcd.	for	C11H7ClO2S:	C,	
55.35;	H,	2.96.	Found:	C,	55.18;	H,	2.67%.	
	
2.3.2.	General	procedure	for	the	synthesis	of	pyrazolines	6‐
10	
	

A	mixture	of	chalcone	(0.50	mmol)	and	hydrazine	hydrate	
(1.00	mmol,	 2	 equiv.)	was	 dissolved	 in	 dioxane	 (25	mL)	 and	
refluxed	for	3‐6	hrs.	The	reaction	mixture	was	then	cooled,	the	
precipitate	 formed,	 filtered	 off,	 washed	 with	 cold	 methanol,	
and	dried.	The	solid	product	was	recrystallized	from	methanol.	
The	 progress	 of	 all	 reactions	 was	 monitored	 by	 thin	 layer	
chromatography	(TLC)	(Scheme	2).	

3‐(2,	5‐Dichlorothiophen‐3‐yl)‐5‐phenyl‐4,	5‐dihydro‐1H‐
pyrazole	(6):	Color:	Yellow	solid.	Yield:	74%.	M.p.:	100‐102	°C.	
FT‐IR	(KBr,	,	 cm‐1):	3218	 (N‐H),	3049	(C‐H),	1558	 (C=N).	 1H	
NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.73	(dd,	1H,	JAB	=	16.4	Hz,	
JAX	=	10.6	Hz,	A‐H),	3.38	(dd,	1H,	JAB	=	16.3	Hz,	JBX	=	10.6	Hz,	B‐
H),	 4.85	 (td,	 1H,	 JAX	 =	2.8	Hz,	 JBX	 =	10.6	Hz,	X‐H),	 7.24	 (s,	 1H,	
thiophene‐H),	7.18‐7.37	(m,	5H,	Ar‐H),	7.65	(d,	1H,	 J	=	2.8	Hz,	
NH).	 13C	NMR	 (75	MHz,	 DMSO‐d6,	 δ,	 ppm):	 40.3,	 62.8,	 124.9,	
125.4,	126.2,	127.4,	130.1,	131.2,	136.4,	142.1,	143.4.	MS	 (EI,	
m/z	 (%)):	 298	 ([M+H],	 100).	 Anal.	 calcd.	 for	 C13H10Cl2N2S:	 C,	
52.54;	H,	 3.39;	N,	 9.43;	 S,	 10.79.	 Found:	 C,	 52.19;	H,	 3.22;	N,	
9.31;	S,	10.74%.	

5‐(4‐Bromophenyl)‐3‐(2,	 5‐dichlorothiophen‐3‐yl)‐4,	 5‐
dihydro‐1H‐pyrazole	 (7):	 Color:	 Pale‐yellow	solid.	 Yield:	 88%.	
M.p.:	 74‐76	 °C.	 FT‐IR	 (KBr,	,	 cm‐1):	 3210	 (N‐H),	 3052	 (C‐H),	
1542	(C=N).		

	
	



80	 Ibrahim	/	European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	
	

	

 

Scheme	3	
	
	
1H	NMR	 (300	MHz,	DMSO‐d6,	 δ,	 ppm):	 2.89	 (dd,	 1H,	 JAB	 =	

16.6	Hz,	JAX	=	10.7	Hz,	A‐H),	3.55	(dd,	1H,	JAB	=	16.6	Hz,	JBX	=	10.8	
Hz,	B‐H),	4.85	(td,	1H,	JAX	=	2.9	Hz,	JBX	=	10.8	Hz,	X‐H),	7.30	(s,	
1H,	thiophene‐H),	7.32	(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.54	(d,	2H,	J	=	
8.3	Hz,	Ar‐H),	7.86	 (d,	1H,	 J	=	2.8	Hz,	NH).	 13C	NMR	(75	MHz,	
DMSO‐d6,	δ,	ppm):	41.7,	63.2,	120.3,	120.9,	125.4,	126.5,	128.9,	
131.3,	131.7,	142.1,	142.5.	HRMS	(ESI)	Calc.	for	C13H8BrCl2N2S:	
372.89631	 [M‐H];	 Found:	 372.89673.	 Anal.	 calcd.	 for	
C13H9BrCl2N2S:	 C,	 41.52;	 H,	 2.41;	 N,	 7.45;	 S,	 8.53.	 Found:	 C,	
41.95;	H,	2.43;	N,	7.61;	S,	8.49%.	

3‐(5‐Chlorothiophen‐2‐yl)‐5‐phenyl‐4,	5‐dihydro‐1H‐pyra	
zole	(8):	Color:	Yellow	solid.	Yield:	61%.	M.p.:	97‐99	°C.	FT‐IR	
(KBr,	,	 cm‐1):	 3198	 (N‐H),	 3041	 (C‐H),	 1557	 (C=N).	 1H	NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	2.81	(dd,	1H,	JAB	=	16.2	Hz,	JAX	=	
10.7	Hz,	A‐H),	3.41	 (dd,	1H,	 JAB	 =	16.3	Hz,	 JBX	 =	10.8	Hz,	B‐H),	
4.84	(td,	1H,	JAX	=	3.0	Hz,	JBX	=	10.7	Hz,	X‐H),	6.98	(d,	1H,	J	=	3.9	
Hz,	 thiophene‐H),	 7.07	 (d,	 1H,	 J	 =	 3.9	Hz,	 thiophene‐H),	 7.25‐
7.35	 (m,	5H,	Ar‐H),	7.65	 (d,	1H,	 J	 =	2.8	Hz,	NH).	 13C	NMR	(75	
MHz,	DMSO‐d6,	δ,	ppm):	40.7,	63.9,	125.6,	126.6,	127.3,	127.4,	
127.9,	 128.5,	 136.2,	 142.5,	 144.2.	 MS	 (EI,	 m/z	 (%)):	 263	
([M+H],	100).	Anal.	calcd.	for	C13H11ClN2S:	C,	59.43;	H,	4.22;	N,	
10.66;	S,	12.20.	Found:	C,	59.84;	H,	4.12;	N,	10.07;	S,	12.28%.	

5‐(4‐Bromophenyl)‐3‐(5‐chlorothiophen‐2‐yl)‐4,	 5‐dihydro‐
1H‐pyrazole	(9):	Color:	Yellow	solid.	Yield:	79%.	M.p.:	75‐77	°C.	
FT‐IR	 (KBr,	,	 cm‐1):	3215	(N‐H),	3044	 (C‐H),	1563	(C=N).	 1H	
NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.79	(dd,	1H,	JAB	=	16.3	Hz,	
JAX	=	10.6	Hz,	A‐H),	3.42	(dd,	1H,	JAB	=	16.3	Hz,	JBX	=	10.8	Hz,	B‐
H),	 4.83	 (t,	 1H,	 J	 =	 10.7	 Hz,	 X‐H),	 6.98	 (d,	 1H,	 J	 =	 3.8	 Hz,	
thiophene‐H),	7.07	(d,	1H,	J	=	3.9	Hz,	thiophene‐H),	7.31	(d,	2H,	
J	 =	 8.4	Hz,	Ar‐H),	 7.53	 (d,	 2H,	 J	=	8.3	Hz,	Ar‐H),	 7.69	 (sb,	 1H,	
NH).	 13C	NMR	 (75	MHz,	 DMSO‐d6,	 δ,	 ppm):	 40.6,	 63.2,	 120.2,	
125.8,	 127.4,	 128.0,	 128.9,	 131.3,	 136.0,	 142.0,	 144.3.	 HRMS	
(ESI)	 Calc.	 for	 C13H11BrClN2S:	 342.94881	 [M+H];	 Found:	
342.94705.	Anal.	calcd.	for	C13H10ClBrN2S:	C,	45.70;	H,	2.95;	N,	
8.20;	S,	9.38.	Found:	C,	45.30;	H,	2.75;	N,	8.13;	S,	9.24%.	

3‐(5‐Chlorothiophen‐2‐yl)‐5‐(furan‐2‐yl)‐4,	 5‐dihydro‐
1H‐pyrazole	(10):	Color:	Brown	solid.	Yield:	72%.	M.p.:	80‐82	
°C.	FT‐IR	(KBr,	,	cm‐1):	3208	(N‐H),	3053	(C‐H),	1544	(C=N).	
1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.86	(dd,	1H,	JAB	=	16.4	
Hz,	JAX	=	10.5	Hz,	A‐H),	3.13	(dd,	1H,	JAB	=	16.4	Hz,	JBX	=	10.5	Hz,	
B‐H),	4.96	(t,	1H,	J	=	10.7	Hz,	X‐H),	6.22	(d,	1H,	J	=	2.9	Hz,	furan‐
H),	 6.26	 (dd,	 1H,	 J	=	3.0	Hz,	 furan‐H),	 6.83	 (d,	1H,	 J	 =	 3.9	Hz,	
thiophene‐H),	6.96	(d,	1H,	J	=	3.9	Hz,	thiophene‐H),	7.48	(d,	1H,	
J	 =	 3.0	 Hz,	 furan‐H),	 7.78	 (sb,	 1H,	 NH).	 13C	 NMR	 (75	 MHz,	
DMSO‐d6,	δ,	ppm):	41.4,	56.8,	108.1,	110.2,	128.1,	128.9,	131.0,	
133.4,	141.3,	150.9,	154.3.	MS	(EI,	m/z	(%)):	253	([M+H],	100).	
Anal.	 calcd.	 for	 C11H9ClN2OS:	 C,	 52.28;	 H,	 3.59;	 N,	 11.08;	 S,	
12.69.	Found:	C,	52.04;	H,	3.78;	N,	10.94;	S,	12.78%.	
	
2.3.3.	Procedure	for	the	synthesis	of	carbothioamide	
derivative	11	
	

Phenylisothiocyanate	 (27	 mg,	 0.02	 mmol,	 2	 equiv.)	 was	
added	to	a	solution	of	pyrazole	7	(38	mg,	0.01	mmol)	in	ether	
(5	mL).	The	reaction	mixture	was	then	stirred	for	24	h	at	room	
temperature	until	 completion	of	 the	 reaction.	The	precipitate	
formed,	 filtered	 off,	 washed	 with	 ether,	 and	 dried	 to	 give	
carbothioamide	11	as	 spectroscopically	 and	analytically	pure	

brown	 solid.	 The	 progress	 of	 the	 reaction	was	monitored	 by	
thin	layer	chromatography	(TLC)	(Scheme	3).	

5‐(4‐Bromophenyl)‐3‐(2,5‐dichlorothiophen‐3‐yl)‐N‐phenyl‐
4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide	 (11):	 Color:	 Brown	
solid.	Yield:	Quant.	M.p.:	182‐184	°C.	FT‐IR	(KBr,	,	cm‐1):	3405	
(N‐H),	3058	(C‐H),	1584	(C=N),	1345	(C=S).	1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	3.21	(dd,	1H,	JAB	=	18.3	Hz,	JAX	=	3.9	Hz,	A‐H),	
4.05	(dd,	1H,	JAB	=	18.3	Hz,	JBX	=	11.7	Hz,	B‐H),	5.97	(dd,	1H,	JAX	=	
3.8	Hz,	JBX	=	11.6	Hz,	X‐H),	7.13‐7.20	(m,	3H,	Ar‐H),	7.34	(t,	2H,	J	
=	7.7	Hz,	Ar‐H),	7.48	(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.50	(d,	2H,	J	=	8.3	
Hz,	 Ar‐H),	 8.01	 (s,	 1H,	 thiophene‐H),	 10.19	 (s,	 1H,	 NH).	 13C	
NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 43.1,	 63.2,	 120.1,	 125.3,	
125.8,	 126.0,	 127.0,	 127.4,	 127.8,	 128.1,	 129.9,	 131.5,	 139.2,	
141.9,	 148.9,	 174.0.	 HRMS	 (ESI)	 Calc.	 for	 C20H15BrCl2N3S2:	
509.92623	 [M+H];	 Found:	 509.92695.	 Anal.	 calcd.	 for	
C20H14BrCl2N3S2:	C,	46.98;	H,	2.76;	N,	8.22;	S,	12.54.	Found:	C,	
46.52;	H,	2.11;	N,	7.13;	S,	12.13%.	
	
2.3.4.	General	procedure	for	the	synthesis	of	carbothio	
amide	derivatives	12‐14	
	

The	 appropriate	 chalcone	 (2,	 4	 and	 5)	 (0.5	 mmol)	 was	
added	 to	 a	 solution	 of	 KOH	 (56	 mg,	 1.0	 mmol,	 2	 equiv.)	 in	
ethanol	(5.0	mL).	Then	thiosemicarbazide	(91	mg,	1.0	mmol,	2	
equiv.)	 was	 added	 at	 room	 temp.	 The	 resulting	mixture	was	
left	 to	 stirred	 and	 reflux	 for	 5	 h.	 Upon	 cooling,	 the	 solid	
product	precipitated,	filtered	off	then	crystallized	from	ethanol	
(Scheme	4).	

5‐(4‐Bromophenyl)‐3‐(2,	 5‐dichlorothiophen‐3‐yl)‐4,	 5‐
dihydro‐1H‐pyrazole‐1‐carbothioamide	 (12):	 Color:	 Brown	
solid.	Yield:	71%.	M.p.:	135‐137	°C.	FT‐IR	(KBr,	,	cm‐1):	3473	
(N‐H),	3054	(C‐H),	1573	(C=N),	1324	(C=S).	1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	3.11	(dd,	1H,	JAB	=	18.3	Hz,	JAX	=	3.8	Hz,	A‐H),	
3.99	(dd,	1H,	JAB	=	18.3	Hz,	JBX	=	11.7	Hz,	B‐H),	5.85	(dd,	1H,	JAX	=	
3.0	Hz,	JBX	=	11.6	Hz,	X‐H),	7.07	(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.50	(d,	
2H,	 J	 =	 8.3	 Hz,	 Ar‐H),	 7.79	 (s,	 1H,	 thiophene‐H),	 8.00	 (s,	 1H,	
NH),	 8.19	 (s,	 1H,	 NH).	 13C	 NMR	 (75	MHz,	 DMSO‐d6,	 δ,	 ppm):	
42.6,	 62.5,	 120.0,	 126.0,	 126.5,	 127.2,	 127.7,	 129.9,	 131.5,	
142.2,	 145.3,	 176.3.	 HRMS	 (ESI)	 Calc.	 for	 C14H11BrCl2N3S2:	
433.89493	 [M+H];	 Found:	 433.89426.	 Anal.	 calcd.	 for	
C14H10BrCl2N3S2:	C,	38.64;	H,	2.32;	N,	9.66;	S,	14.74.	Found:	C,	
38.92;	H,	2.50;	N,	9.14;	S,	14.47%.	

5‐(4‐Bromophenyl)‐3‐(5‐chlorothiophen‐2‐yl)‐4,	 5‐dihydro‐
1H‐pyrazole‐1‐carbothioamide	 (13):	Color:	Brown	solid.	Yield:	
65%.	M.p.:	204‐205	°C.	FT‐IR	(KBr,	,	cm‐1):	3478	(N‐H),	3056	
(C‐H),	1571	(C=N),	1328	(C=S).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	
ppm):	3.13	(dd,	1H,	 JAB	=	19.6	Hz,	 JAX	=	4.3	Hz,	A‐H),	3.86	(dd,	
1H,	JAB	=	17.9	Hz,	JBX	=	11.5	Hz,	B‐H),	5.92	(dd,	1H,	JAX	=	3.3	Hz,	
JBX	=	11.4	Hz,	X‐H),	7.07	(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.19	(d,	1H,	J	=	
4.0	Hz,	thiophene‐H),	7.34	(d,	1H,	J	=	4.0	Hz,	thiophene‐H),	7.51	
(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.68	(s,	1H,	NH),	8.10	(s,	1H,	NH).	13C	
NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 42.8,	 63.0,	 121.6,	 127.1,	
127.2,	 129.5,	 132.0,	 132.3,	 135.0,	 140.4,	 150.3,	 176.3.	 HRMS	
(ESI)	 Calc.	 for	 C14H12BrClN3S2:	 399.93391	 [M+H];	 Found:	
399.93350.	Anal.	calcd.	for	C14H11BrClN3S2:	C,	41.96;	H,	2.77;	N,	
10.49;	S,	16.00.	Found:	C,	41.74;	H,	2.72;	N,	10.14;	S,	15.78%.	

3‐(5‐Chlorothiophen‐2‐yl)‐5‐(furan‐2‐yl)‐4,	 5‐dihydro‐
1H‐pyrazole‐1‐carbothioamide	(14):	Color:	Brown	solid.		



Ibrahim	/	European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	 81	
 

	
Table	1.	Scope	of	chalcones	and	their	yields.	
Entry	 R	 R’	 Product	 Yield	(%)a	
a	

	 	

74	

b	

	 	

87	

c	

	 S

Cl 	

82	

d	

	
	

77	

e	

	
	

82	

a	Yield	after	crystallization.	
	

	

 
	

Scheme	4	
	
	
Yield:	80%.	M.p.:	156‐157	°C.	FT‐IR	(KBr,	,	cm‐1):	3481	(N‐

H),	 3049	 (C‐H),	 1583	 (C=N),	 1321	 (C=S).	 1H	NMR	 (300	MHz,	
DMSO‐d6,	δ,	ppm):	3.30	(dd,	1H,	JAB	=	17.8	Hz,	JAX	=	3.0	Hz,	A‐H),	
3.74	(dd,	1H,	JAB	=	17.8	Hz,	JBX	=	11.5	Hz,	B‐H),	6.00	(dd,	1H,	JAX	=	
2.8	Hz,	JBX	=	11.2	Hz,	X‐H),	6.28	(d,	1H,	J	=	2.8	Hz,	furan‐H),	6.37	
(d,	1H,	 J	=	3.0,	 furan‐H),	7.18	(d,	1H,	 J	=	3.9	Hz,	 thiophene‐H),	
7.39	 (d,	 1H,	 J	 =	 3.9	 Hz,	 thiophene‐H),	 7.51	 (sb,	 1H,	 furan‐H),	
7.58	(s,	1H,	NH),	8.02	(s,	1H,	NH).	13C	NMR	(75	MHz,	DMSO‐d6,	
δ,	 ppm):	 43.8,	 56.9,	 107.7,	 110.6,	 128.2,	 131.1,	 132.4,	 132.9,	
142.3,	150.6,	152.8,	175.8.	HRMS	(ESI)	Calc.	for	C12H11ClN3OS2:	
312.00165	 [M+H];	 Found:	 312.00266.	 Anal.	 calcd.	 for	
C12H10ClN3OS2:	C,	46.22;	H,	3.23;	N,	13.48;	S,	20.57.	Found:	C,	
46.09;	H,	3.22;	N,	13.57;	S,	20.92%.	
	
3.	Results	and	discussion		
	
3.1.	Preparation	of	chalcones	
	

Chalcones	 1‐5	 (Scheme	 1,	 Table	 1)	 were	 prepared	 by	
Claisen‐Schmidt	condensation	of	appropriate	acetylethiophene	
with	 the	 corresponding	 aldehydes	 in	 presence	 of	 potassium	
hydroxide	 in	 methanol	 at	 room	 temperature.	 Although	
chalcones	1,	3‐5	have	been	reported	previously	[44‐47],	their	
pyrazoles	 6‐10	 and	 their	 carbothioamide	 derivatives	 11‐14	
have	not	been	reported	in	the	literature.		
	
3.2.	Preparation	of	pyrazoline	derivatives	
	

Pyrazoline	6‐10	derivatives	were	obtained	in	moderate	to	
good	 yield	 by	 refluxing	 the	 appropriate	 chalcones	 with	 two	
equivalents	 of	 hydrazine	 monohydrate	 for	 3	 to	 6	 hours	 in	
dioxane,	(Scheme	2,	Table	2).	

The	 treatment	 of	 the	 pyrazoline	 7	 with	 phenyliso	
thiocyanate	 (2	equiv.)	 in	ether	at	 room	temperature	afforded	
the	 corresponding	 carbothioamide	 derivative	11	 in	 quantita‐
tive	yield,	Scheme	3.	

A	 series	 of	 3,5‐disubstituted	 pyrazole‐1‐carbothioamides	
12‐14	were	prepared	 in	good	yields	by	cyclocondensation	of	
chalcones	 2,	 4	 and	 5	 with	 thiosemicarbazide	 in	 ethanolic	
solution	of	potassium	hydroxide	 for	6	 to	12	h.	The	 results	of	
these	reactions	are	shown	in	Scheme	4.	

All	 compounds	 1‐14	 were	 characterized	 by	 different	
spectroscopic	 techniques	 including	 IR,	 1H	 NMR,	 13C	 NMR,	
DEPT,	COSY,	HSQC	spectroscopy,	and	Mass	spectrometry	along	
with	elemental	analysis.		

The	MS	spectra	display	the	correct	molecular	ion	peaks	as	
suggested	by	their	molecular	formulas	as	M+	or	M++1.	In	the	IR	
spectra	 of	 chalcones	 1‐5,	 a	 characteristic	 strong	 absorption	
bands	 was	 observed	 in	 the	 region	 1648‐1659	 cm‐1	 which	
might	be	attributed	to	the	carbonyl	group.		

The	 IR	 spectra	 of	 compounds	 6‐10	 showed	 the	
characteristic	bands	for	NH	at	3198‐3218	cm‐1.	The	IR	spectra	
of	 the	 thiocarboamides	 derivatives,	 11‐14,	 showed	 the	
characteristic	C=S	and	NH	bands	in	the	ranges	1321‐1345	cm‐1	
and	3405‐3481	cm‐1,	respectively.	

The	1H	NMR	spectra	of	compounds	1‐5	showed	the	olfenic	
protons	α‐	and	β‐H	as	 two	doublets	 in	 the	region	δ	7.20‐7.76	
ppm,	 with	 a	 coupling	 constant	 value	 of	 3J	 =	 15.2‐15.7	 Hz	 in	
agreement	with	the	formation	of	the	E	isomers.		

In	chalcones	1	and	2,	the	4′‐H	of	thienyl	moiety	appeared	
as	 a	 singlet	 at	 7.24	 and	 7.18	 ppm,	 respectively,	 while	 it	 is	
appeared	 in	 the	region	7.24‐8.01	ppm	for	pyrazoles	6,	7,	and	
carbothioamides	11	and	12.		

	



82	 Ibrahim	/	European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	
	

	
Table	2.	Scope	of	4,5‐dihydro‐1H‐pyrazoles	and	their	yields.		
Entry	 R	 R’	 Product	 Yield	(%)a	
a	

	 	

74	

b	

	 	

88	

c	

	
	

61	

d	

	
	

79	

e	

	
	

72	

a	Yield	after	crystallization.	
	
	

The	two	dd	peaks	at	the	region	2.73‐3.55	ppm	are	assigned	
to	 the	 4‐H	 protons	 of	 the	 pyrazoles	 6‐10	 with	 a	 germinal	
coupling	constant	value	of	3J	=	16.2‐16.6	Hz	and	the	other	low	
field	peaks	which	appeared	in	the	region	4.83‐4.96	assigned	to	
the	5‐H	protons	for	the	same	compounds.	For	carbothioamide	
derivatives	11‐14,	the	4‐H	and	5‐H	protons	shifted	to	a	lower	
field	and	appeared	in	the	regions	3.11‐4.05	ppm	and	5.85‐6.00	
ppm,	respectively.		

The	 13C	 NMR	 spectra	 of	 chalcones	 1‐5	 showed	 the	
carbonyl	carbon	at	the	region	δ	180.7‐193.6	ppm.	The	13C	NMR	
spectra	 of	 pyrazoles	 6‐10	 showed	 absorption	 in	 the	 range	
141.3‐142.5	 ppm	 corresponding	 to	 the	 C=N	 carbon.	 The	
absorption	 appeared	 in	 the	 range	 174.0‐176.3	 ppm	 in	 the	
spectra	 of	 carbothioamides	 11‐14	 attributed	 to	 the	 C=S	
carbon.	
	
4.	Conclusion	

	
In	this	study,	a	series	of	3,5‐disubstituted‐4,5‐dihydro‐1H‐

pyrazole	 and	 their	 pyrazolines	 containing	 carbothioamide	
moiety	 were	 successfully	 synthesized.	 All	 compounds	 were	
characterized	 by	 standard	 spectroscopic	 techniques.	 The	
obtained	 compounds	 are	 currently	 under	 biological	
investigations,	and	the	results	will	be	reported	elsewhere.	
	
Acknowledgements	
		 	

We	are	grateful	to	Al	Al‐Bayt	University	(Mafraq,	 Jordan),	
the	German	Academic	Exchange	 Service	 (DAAD)	 for	 financial	
support	 (Postdoctoral	 fellowship	 to	Dr.	Mohammad	 Ibrahim)	
and	to	Professor	Dr.	Svetlana	Tsogoeva	(Friedrich‐Alexander‐
Universität	 Erlangen‐Nürnberg/Germany)	 for	 her	 continuous	
support	and	valuable	discussions.		
	
References	
	
[1]. Katritzky,	 A.	 R.;	Wang,	 M.;	 Zhang,	 S.;	 Voronkov,	 M.	 V.	 J.	Org.	 Chem.	

2001,	66,	6787‐6791.		
[2]. Wen,	J.;	Fu,	Y.;	Zhang,	R.	Y.;	Zhang,	J.;	Chen,	S.	Y.;	Yu,	X.	Q.	Tetrahedron	

2011,	67,	9618‐9621.		
[3]. Sid,	A.;	Ziani,	N.;	Demmen‐Debbih,	O.;	Mokhtari,	M.;	Lamara,	K.	Eur.	J.	

Chem.	2013,	4,	268‐271.		
[4]. Voskiene,	 A.;	 Mickevicius,	 V.	 Chem.	 Heterocyc.	 Compd.	 2009,	 45,	

1485‐1488.		
[5]. Hamada,	N.	M.	M.;	Sharshira,	E.	M.	Molecules	2011,	16,	2304‐2312.		
[6]. Sawant,	R.;	Bhangale,	L.;	Wadekar,	J.;	Gaikwad,	P.	Farmacia	2012,	60,	

32‐39.		
[7]. Rahaman,	 S.	 A.;	 Pasad,	 Y.	 R.;	 Kumar,	 P.;	 Kumar,	 B.	 Saudi	 Pharm.	 J.	

2009,	17,	255‐258.		

[8]. Hassan,	S.	Y.	J.	Brazil.	Chem.	Soc.	2011,	22,	1286‐1298.		
[9]. El‐Shehry,	M.	F.;	Swellem,	R.	H.;	Abu‐Bakr,	S.	M.;	El‐Telbani,	E.	M.	Eur.	

J.	Med.	Chem.	2010,	45,	4783‐4787.		
[10]. Wong,	E.	Phytochemistry	1968,	7,	1751‐1758.		
[11]. Lin,	 Y.	 M.;	 Zhou,	 Y.;	 Flavin,	 M.	 T.;	 Zhou,	 L.	 M.;	 Nie,	 W.;	 Chen,	 F.	 C.	

Bioorg.	Med.	Chem.	2002,	10,	2795‐2802.		
[12]. Iwashina,	T.;	Kitajima,	J.;	Shiuchi,	T.;	Itou,	Y.	Biochem.	Sys.	Ecol.	2005,	

33,	571‐584.		
[13]. Mojzis,	 J.;	 Varinska,	 L.;	 Mojzisova,	 G.;	 Kostova,	 I.;	 Mirossay,	 L.	

Pharmacol.	Res.	2008,	57,	259‐265.		
[14]. Konduru,	N.	 K.;	 Dey,	 S.;	 Sajid,	M.;	 Owais,	M.;	 Ahmed,	N.	Eur.	 J.	Med.	

Chem.	2013,	59,	23‐30.		
[15]. Liu,	M.;	Wilairat,	P.;	Croft,	S.	L.;	Tand,	A.	L.	C.;	Go,	M.	L.	Bioorg.	Med.	

Chem.	2003,	11,	2729‐2738.		
[16]. Hsieh,	C.	T.;	Hsieh,	T.	J.;	El‐Shazly,	M.;	Chuang,	D.	W.;	Tsai,	Y.	H.;	Yen,	

C.	T.;	Wu,	S.	F.;	Wu,	Y.	C.;	Chang,	F.	R.	Bioorg.	Med.		
Chem.	Lett.	2012,	22,	3912‐3915.		

[17]. Jeon,	J.	H.;	Kim,	S.	J.;	Kim,	C.	G.;	Kim,	J.	K.;	Jun,	J.	G.	B.	Korean	Chem.	Soc.	
2012,	33,	953‐957.		

[18]. Solomon,	V.	R.;	Lee,	H.	Biomed.	Pharmacother.	2012,	66,	213‐220.		
[19]. Jin,	C.;	Liang,	Y.	J.;	He,	H.;	Fu,	L.	Biomed.	Pharmacother.	2013,	67,	215‐

217.		
[20]. Gacche,	R.;	Khsirsagar,	M.;	Kamble,	S.;	Bandgar,	B.;	Dhole,	N.;	Shisode,	

K.;	Chaudhari,	A.	Chem.	Pharm.	Bull.	2008,	56,	897‐901.		
[21]. Sivakumar,	P.	M.;	Prabhakar,	P.	K.;	Doble,	M.	Med.	Chem.	Res.	2011,	

20,	482‐492.		
[22]. Renate,	 H.	 H.;	 Eric,	 M.	 G.;	 Carmen,	 L.;	 Peter,	 J.	 S.;	 Baojie,	 W.	 S.;	

Franzblau,	 J.	G.;	Philip,	 J.	R.;	Kelly,	C.	Bioorg.	Med.	Chem.	Lett.	2010,	
20,	942‐944.		

[23]. Sharma,	 A.;	 Chakravarti,	 B.;	 Gupt,	 M.	 B.;	 Siddiqui,	 J.	 A.;	 Konwar,	 R.;	
Tripathi,	R.	P.	Bioorg.	Med.	Chem.	2010,	18,	4711‐4720.		

[24]. Lv,	P.	C.;	Li	 ,	D.	D.;	Li,	Q.	S.;	Lu,	X.;	Xiao,	Z.	P.;	Zhu,	H.	L.	Bioorg.	Med.	
Chem.	Lett.	2011,	21,	5374‐5377.		

[25]. Havrylyuk,	D.;	Kovach,	N.;	Zimenkovsky,	B.;	Vasylenko,	O.;	Lesyk,	R.	
Arch.	Pharm.	Chem.	Life	Sci.	2011,	344,	514–522.		

[26]. Bhat,	B.	A.;	Dhar,	K.	L.;	Puri,	S.	C.;	Saxena,	A.	K.;	Shanmugavel,	M.;	Qazi,	
G.	N.	Bioorg.	Med.	Chem.	Lett.	2005,	15,	3177‐3180.		

[27]. Amin,	K.	M.;	Eissa,	A.	A.	M.;	Abou‐Seri,	S.	M.;	Awadallah,	F.	M.;	Hassan,	
G.	S.	Eur.	J.	Med.	Chem.	2013,	60,	187‐198.		

[28]. Mishra,	N.;	Sasmal	D.	Bioorg.	Med.	Chem.	Lett.	2011,	21,	1969‐1973	
[29]. Chimenti,	F.;	Carradori,	S.;	Secci,	D.;	Bolasco,	A.;	Bizzarri,	B.;	Chimenti,	

P.;	Granese,	A.;	Yanez,	M.;	Orallo,	F.	Eur.	J.	Med.	Chem.	2010,	45,	800‐
804.		

[30]. Khan,	S.	A.;	Asiri,	A.	M.;	Kumar,	S.;	Sharma,	K.	Eur.	 J.	Chem.	2014,	5,	
85‐90.		

[31]. Liu,	X.	H.;	Lv,	P.	C.;	Li,	B.;	Zhu,	H.	L.;	Song,	B.	A.	Aust.	J.	Chem.	2008,	61,	
223‐230.		

[32]. Goodell,	J.	R.;	Puig‐Basagoiti,	F.;	Forshey,	B.	M.;	Shi,	P.	Y.;	Ferguson,	D.	
M.	J.	Med.	Chem.	2006,	49,	2127‐2137.		

[33]. Amir,	M.;	 Kumar,	 H.;	 Khan,	 S.	 A.	Bioorg	Med.	 Chem.	 Lett.	2008,	 18,	
918‐922.		

[34]. Ozdemir,	Z.;	Kandilci,	H.	B.;	Gumusel,	B.;	Calis,	U.;	Bilgin,	A.	A	Eur.	 J.	
Med.	Chem.	2007,	42,	373‐379.		

[35]. Palaskaa,	 E.;	 Aytemira,	 M.;	 Uzbay,	 I.	 T.;	 Erola,	 D.	Eur.	 J.	Med.	Chem.	
2001,	36,	539‐543.		

[36]. Prasad,	Y.	R.;	Rao,	A.	L.;	Prasoona,	L.;	Murali,	K.;	Kumar,	P.	R.	Bioorg.	
Med.	Chem.	Lett.	2005,	15,	5030‐5034.		



Ibrahim	/	European	Journal	of	Chemistry	6	(1)	(2015)	78‐83	 83	
 

[37]. Siddiqui,	 N.;	 Alam,	 P.;	 Ahsan,	W.	Arch.	Pharm.	Chem.	Life	Sci.	2009,	
342,	173‐181.		

[38]. Christodoulou,	 M.	 S.;	 Liekens,	 S.;	 Kasiotis,	 M.;	 Haroutounian,	 S.	 A.	
Bioorg.	Med.	Chem.	2010,	18,	4338‐4350.		

[39]. Vennerstrom,	 L.	 J.;	 Makler,	 M.	 T.	 Antimicrob.	 Agents	 Ch.	 1995,	 39,	
2671‐2677.		

[40]. Ahsan,	M.	 J.;	 Samy,	 J.	 G.;	 Soni,	 S.;	 Jain,	 N.;	 Kumar,	 L.;	 Sharma,	 L.	 K.;	
Yadav,	H.;	Saini,	L.;	Kalyansing,	R.	G.;	Devenda,	N.	S.;	Prasad,	R.;	Jain,	
C.	B.	Bioorg.	Med.	Chem.	Lett.	2011,	21,	5259‐5261.		

[41]. Lv,	 P.	 C.;	 Li,	H.	 Q.;	 Sun,	 J.;	 Zhou,	H.	 L.	Bioorg.	Med.	Chem.	2010,	18,	
4606‐4614.		

[42]. Bhandari,	 S.;	 Tripathi,	 A.	 C.;	 Saraf,	 S.	 K.	Med.	 Chem.	 Res.	 2013,	 22,	
5290‐5296.		

[43]. Bachjman,	G.	B.;	Heise,	L.	V.	J.	Am.	Chem.	Soc.	1948,	70,	2368‐2387.		
[44]. Tomar,	V.;	Bhattacharjee,	G.;	Kamaluddina,	K.	A.	Bioorg.	Med.	Chem.	

Lett.	2007,	17,	5321‐5324.		
[45]. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7946

920		
[46]. Dannhardt,	G.;	Kiefer,	W.;	Kramer,	G.;	Maehrlein,	S.;	Nowe,	U.;	Fiebich,	

B.	Eur.	J.	Med.	Chem.	2000,	35,	499‐510.		
[47]. Thapa,	P.;	Karki,	R.;	Thapa,	U.;	Jahng,	Y.;	Jung,	M.	J.;	Nam,	J.	M.;	Na,	Y.;	

Kwon,	Y.;	Lee,	E.	S.	Bioorg.	Med.	Chem.	2010,	18,	377‐386.