untitled


European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	

	

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.6.4.482‐487.1325	

	
	

	

	

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

	 	 	

One	pot	synthesis	of	1‐((1‐aryl‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐1H‐benzo[d]	
imidazoles	in	ionic	liquids:	Evaluation	of	antioxidant	and	antimicrobial	
activities	

Suresh	Seeka	1,	Sirassu	Narsimha	1,	Kumaraswamy	Battula	1,	Althaf	Hussain	Shaikh	2,		
Savitha	Jyostna	Tangeda	1	and	Vasudeva	Reddy	Nagavelli	1,*	

1	Department	of	Chemistry,	KakatiyaUniversity,	Warangal,	TS,	506009,	India	
2	Department	of	Biotechnology,	Kakatiya	University,	Warangal,	TS,	506009,	India	

*	Corresponding	author	at:	Department	of	Chemistry,	KakatiyaUniversity,	Warangal,	TS,	506009,	India.		
Tel.:	+91.0870.2461419.	Fax:	+91.0870.2455592.	E‐mail	address:	vasujac3@gmail.com	(V.R.	Nagavelli)	

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.6.4.482‐487.1325	

Received:	18	September	2015	
Received	in	revised	form:	09	October	2015	
Accepted:	18	October	2015	
Published	online:	31	December	2015	
Printed:	31	December	2015	

	 In	view	of	pharmacological	importance	of	benzimidazole	and	1,2,3‐triazole	nuclei,	we	made	an
effort	to	synthesize	the	bi‐functional	mimic	1,2,3‐triazolyl‐benzimidazoles	through	the	copper
catalyzed	 azide‐alkyne	 1,3‐dipolar	 cycloaddition	 reaction	 in	 ionic	 liquids.	 The	 synthesized
compounds	 were	 characterized	 by	 NMR,	 IR	 and	 Mass	 spectral	 analysis.	 The	 synthesized
compounds	were	screened	for	antimicrobial	and	antioxidant	activities.	A	good	number	of	the
compounds	found	to	possess	potent	antioxidant	and	antimicrobial	activities.	

KEYWORDS	
Ionic	liquid	
Benzimidazole	
1,2,3‐Triazoles	
One	pot	synthesis	
Antioxidant	activity	
Antimicrobial	activity	

Cite	this: Eur.	J.	Chem.	2015,	6(4),	482‐487

	
1.	Introduction	
	

Benzimidazole	 and	 1,2,3‐triazole	 nuclei	 are	 valuable	
functionalities	 in	the	field	of	medicinal	chemistry	due	to	their	
important	pharmacological	properties.	The	benzimidazole	has	
been	 an	 important	 pharmacophore	 and	 privileged	 structure,	
encompassing	 a	 diverse	 range	 of	 their	 biological	 properties	
[1,2].	Benzimidazoles	have	been	reported	as	antimicrobial	[3‐
10],	 antiviral	 [11‐14],	 antioxidant	 [15],	 anti‐inflammatory	
[16,17],	 antitumor	 [18]	 and	 anticancer	 agents	 [19‐21].	 1,2,3‐
Triazoles	 due	 to	 their	 exclusive	 chemical	 and	 structural	
properties,	 have	 acknowledged	 a	 lot	 of	 awareness	 over	 the	
past	 decades	 and	 found	 extensive	 applications	 in	 medicinal	
chemistry	 [22‐25],	 biological	 activities	 such	 as	 anti‐HIV	 [27]	
and	antimicrobial	[27,28].	Several	methods	for	the	synthesis	of	
1,2,3‐triazoles	 have	 been	 reported	 in	 the	 literature	 [29,30].	
Among	 them,	 the	 most	 common	 method	 is	 the	 “click	
chemistry”	copper‐catalyzed	cycloaddition	of	azides	to	alkyne	
[31].	During	 the	 investigation	of	highly	efficient	and	environ‐
mentally	benign	processes	ionic	liquids	have	been	emerged	as	
sustainable	 solvents.	 They	were	 employed	 in	many	 reactions	

including,	in	the	synthesis	of	azides	[32],	in	the	N‐alkylation	of	
amines	 [33‐35],	 and	 in	 copper	 catalyzed	 cycloaddition	 of	
azides	to	alkyne	[36,37].	Further,	one	pot	synthetic	procedure	
[38,39]	 has	 been	 become	 an	 attractive	 option	 in	 click	
chemistry	in	which	azides	generated	in	situ,	followed	by	azide‐
alkyne	 cycloaddition	 to	 avoid	 the	 isolation	 of	 the	 azide	
intermediates	 since	 the	 organic	 azides	 tend	 to	 be	 explosive	
and	are	difficult	to	handle.	

In	view	of	the	above	considerations	and	in	continuation	of	
our	 effort	 to	 design	 the	 new	 bifunctional	mimic	 heterocyclic	
compounds	 consisting	 the	1,2,3‐triazole,	 here	 in,	we	 report	 a	
highly	 efficient	 multi	 component	 one	 pot	 method	 for	 the	
synthesis	of	1‐((1‐aryl‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐1H‐benzo	
[d]imidazoles	 using	 N‐propargylbenzimidazole,	 aniline	 and	
sodium	 azide	 in	 ionic	 liquid	 1‐butyl‐3‐methylimidazolium	
hexafluorophosphate	 [BMIM][PF6]	 and	 their	 antioxidant	 and	
antimicrobial	activities.	
	
2.	Experimental	
	
2.1.	Materials	and	methods	



Seeka	et	al.	/	European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	 483	
 

	 	
Table	1.	Synthesized	1,4‐di‐substituted	1,2,3‐triazole	derivatives	of	benzimidazole	(A‐N).	
Ar‐NH2	 Product	

	
Time	(hr)	
	

Yield	(%)	 	 Ar‐NH2	 Product	 Time	(hr)	
	

Yield	(%)	

	

A	 8.0	 95

	

H 8.5	 88

	

B	 9.0	 90	 	 I	 9.5	 75	

	

C	 10.0	 88 J 9	 80

	

D	 8.5	 91 K 8	 92

	

E	 8.5	 90 L 8	 90

NH2Br

	

F	 8.5	 92	 	 M	 9	 86	

	

G	 9.0	 85 N 9.5	 85

	
	

All	 reactions	 were	 carried	 out	 in	 a	 round	 bottom	 flask	
under	 room	 temperature.	 Copper	 (I)	 iodide,	 benzimidazole,	
propargyl	 bromide,	 [BMIM][PF6]	 and	 aromatic	 amines	 were	
purchased	 from	 Aldrich	 chemical	 company.	 All	 the	 reagents	
and	solvents	were	purchased	from	S.D.	Fine	chemicals	limited	
and	 used	 without	 further	 purification.	 Thin‐layer	 chromato‐
graphy	 (TLC)	 was	 performed	 using	 Merck	 silica	 gel	 60F254	
precoated	plates	(0.25	mm)	and	silica	gel	(particle	size	60‐120	
mesh)	was	used	for	column	chromatography.	1H	and	13C	NMR	
spectra	 were	 recorded	 on	 a	 400	 MHz	 instrument.	 1H	 NMR	
spectra	 were	 reported	 relative	 to	 Me4Si	 (δ,	 0.00	 ppm)	 and	
residual	CDCl3	(δ,	7.26	ppm).	13C	NMR	was	reported	relative	to	
CDCl3	 (δ,	 77.16	 ppm).	 FT‐IR	 spectra	 were	 recorded	 on	 a	
Bruker	 spectrometer	 and	 are	 reported	 on	 the	 frequency	 of	
absorption	(cm‐1).	Mass	spectra	were	recorded	on	ESI‐MS.	
	
2.2.	Synthesis	
	
2.2.1.	Synthesis	of	N‐propargylbenzimidazole	
	

N‐Propargylation	 was	 carried	 out	 by	 the	 addition	 of	
propargyl	bromide	(1.2	mmol)	 to	a	mixture	of	benzimidazole	
(1	mmol),	Cs2CO3	(1	mmol)	in	1	mL	of	[BMIM][PF6]	and	3	mL	
of	 H2O	 and	 stirred	 at	 room	 temperature	 for	 12	 hours.	 The	
reaction	was	stopped	by	addition	of	H2O	and	the	product	was	
extracted	 with	 ethylacetate.	 The	 organic	 layer	 was	 washed	
with	 brine,	 dried	 over	 anhydrous	 Na2SO4	 and	 evaporated	
under	 reduced	 pressure	 to	 afford	N‐propargylbenzimidazole.	
The	residue	ionic	liquid	was	washed	with	water	and	reused	for	
the	cycloaddition	reaction.	Color:	Pale	yellow	solid.	Yield:	90%.	
M.p.:	112‐114	°C.	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	7.978	(s,	
1H,	N‐CH=N),	7.820	(d,	1H,	 J	=	8.4	Hz,	Ar),	7.515	 (m,	2H,	Ar),	

7.310	(m,	1H,	J	=	4	Hz,	Ar),	4.762	(s,	2H,	N‐CH2),	2.489	(s,	1H,	
CH‐alkyne).	MS	(EI,	m/z	(%)):	157	(M+H,	100).	

	
2.2.2.	General	procedure	for	1‐{[1‐(aryl)‐1H‐1,	2,	3‐triazol‐
4‐yl]	methyl}‐1H‐benzimidazoles	(A‐N)	
	

Aryl	amines	(0.8	mmol)	were	homogenized	by	mixing	solid	
p‐TsOH	hydrate	(2.4mmol)	and	0.2	mL	of	water	into	a	round‐
bottom	flask	and	cooled	 to	0	 °C	 in	an	 icebath.	To	 this	stirred	
mixture	 NaNO2	 (1.6	 mmol)	 was	 added,	 followed	 by	 the	
solution	 of	 NaN3	 (2.2	mmol)	 in	 [BMIM][PF6]	 (14	mmol,	 2.64	
mL)	 and	 5	 mL	 of	 H2O	 drop	 wise	 and	 thoroughly	 stirred	 at	
room	 temperature	 for	 3	 h.	 N‐Propargylbenzimidazole	 (0.9	
mmol)	and	CuI	(15	mol	%)	were	then	added	and	the	reaction	
was	 stirred	 for	 8	 hours	 at	 room	 temperature.	 The	 reaction	
proceeds	 smoothly	 and	 rapidly	 to	 afford	 1,2,3‐triazoles	 in	
excellent	 yields	 (Figure	 1).	 The	 product	 was	 extracted	 with	
ethyl	 acetate	 (65‐85%	 extraction	 yields)	 and	 the	 results	 are	
presented	in	Table	1.	

	

	

Figure	 1.	Numbering	 of	 carbon	 atoms	 in	 1,4‐disubstituted	 1,2,3‐triazoles	
(A‐N).	

	
1‐{[1‐(4‐Methoxyphenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐1H‐

benzimidazole	 (A):	 Color:	White	 solid.	 Yield:	 95%.	M.p.:	 152‐



484	 Seeka	et	al.	/	European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	
	
154	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3135	 (triazole‐H),	 1593	 (C=C,	
triazole),	 1516	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm)	 :	 8.070	 (s,	 1H,	 N‐CH=N),	 7.820	 (d,	 1H,	 J	 =	 8.4	 Hz,	 Ar),	
7.641	(s,	1H,	triazole‐H),	7.515	(m,	3H,	Ar),	7.310	(t,	2H,	J	=	4	
Hz,	Ar),	6.977	(d,	2H,	J	=	8.8	Hz,	Ar),	5.582	(s,	2H,	N‐CH2),	3.843	
(s,	3H,	O‐CH3).	13C	NMR	(100	MHz,	CDCl3,	δ,	ppm)	:	159.8	(1C,	
C‐41),	145.8	(1C,	C‐4),	143.0	(1C,	C‐22),	138.7	(1C,	C‐92),	135.6	
(1C,	C‐11),	134.1	(1C,	C‐82),	130.2	(2C,	C‐21	&	C‐61),	125.3	(1C,	
C‐52),	124.9	(1C,	C‐62),	122.3	(2C,	C‐31	&	C‐51),	119.1	(1C,	C‐42),	
115.5	(1C,C‐72),	114.7	(1C,	C‐5),	57.3	(1C,	N‐CH2),	55.6	(1C,	O‐
CH3).	MS	(EI,	m/z	(%)):	306	(M+,	100).	

1‐{[1‐(Naphthalen‐1‐yl)‐1H‐1,	 2,	 3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	(B):	Color:	Pale	red	solid.	Yield:	90%.	M.p.:	169‐
171	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3144	 (triazole‐H),	 1594	 (C=C,	
triazole),	 1518	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	 7.933	 (s,	 1H,	 N‐CH=N),	 7.847	 (d,	 2H,	 J	 =	 5.2	 Hz,	 Ar),	
7.710	 (s,	 1H,	 triazole),	 7.540	 (m,	 5H,	 Ar),	 7.324	 (m,	 4H,	 Ar),	
5.676	(s,	2H,	N‐CH2).	13C	NMR	(100	MHz,	CDCl3,	δ,	ppm)	:	145.0	
(1C,	C‐4,	triazole),	142.9	(1C,	C‐22),	139.5	(1C,	C‐92),	138.7	(1C,	
C‐91),	 135.6	 (1C,	 C‐11),	 134.4	 (1C,	 C‐82),	 133.4	 (1C,	 C‐101),	
132.1	(1C,	C‐21),	130.5	(1C,	C‐41),	128.3	(1C,	C‐51),	128.2	(1C,	
C‐81),	127.0	(1C,	C‐31),	126.4	(1C,	C‐61),	124.4	(1C,	C‐52),	124.1	
(1C,	C‐62),	123.5	(1C,	C‐71),	120.1	(1C,	C‐42),	116.5	(1C,	C‐72),	
115.5	 (1C,	C‐5),	57.6	 (1C,	N‐CH2).	MS	 (EI,	m/z	 (%)):	326	 (M+,	
100).	

{2‐[4‐(1H‐Benzimidazol‐1‐ylmethyl)‐1H‐1,	2,	3‐triazol‐1‐yl]‐
4‐fluorophenyl}	methanol	 (C):	Color:	White	 solid.	Yield:	88	%.	
M.p.:	 142‐144	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3390	 (‐OH),	 3131	
(triazole‐H),	 1594	 (C=C,	 triazole),	 1516	 (N=N,	 triazole).	 1H	
NMR	(400	MHz,	CDCl3,	δ,	ppm):	8.191	(s,	1H,	N‐CH=N),	7.641	
(s,	1H,	triazole‐H),	7.498	(m,	2H,	Ar),	7.424	(d,	1H,	J	=	8	Hz,	Ar),	
7.216	(m,	2H,	Ar),	7.130	(m,	1H,	Ar),	6.985	(d,	Ar,	J	=	8	Hz,	1H),	
5.517	(s,	2H,	N‐CH2),	3.910	(s,	2H,	Ar‐CH2‐OH),	3.501	(br	s,	1H,	
‐OH).	 13C	 NMR	 (100	 MHz,CDCl3,	 δ,	 ppm):	 160.9	 (1C,	 C‐41),	
145.0	 (1C,	 C‐4,	 triazole),	 143.1	 (1C,	 C‐22),	 138.2	 (1C,	 C‐92),	
137.7	(1C,	C‐91),	134.6	(1C,	C‐21),	128.2	(1C,	C‐11),	127.0	(1C,	
C‐31),	123.2	(1C,	C‐51),	123.2	(1C,	C‐52),	122.5	(1C,	C‐62),	119.9	
(1C,	C‐42),	116.5	(1C,	C‐72),	115.9	(1C,	C‐5)	 ,	60.7	(1C,	Ar‐CH2‐
OH),	57.5	(1C,	N‐CH2).	MS	(EI,	m/z	(%)):	346	(M+Na,	100).	

1‐{[1‐(4‐Chlorophenyl)‐1H‐1,	 2,	 3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	(D):	Color:	Yellow	solid.	Yield:	91%.	M.p.:	149‐
151	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3132	 (triazole‐H),	 1595	 (C=C,	
triazole),	 1521	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	 8.070	 (s,	 1H,	 N‐CH=N),	 7.935	 (d,	 1H,	 J	 =	 4.4	 Hz,	 Ar),	
7.641	(s,	1H,	triazole‐H),	7.515	(m,	3H,	Ar),	7.314	(m,	2H,	Ar),	
7.050	(d,	2H,	J	=	4	Hz,	Ar),	5.562	(s,	2H,	N‐CH2).	13C	NMR	(100	
MHz,	CDCl3,	δ,	ppm):	148.1	(1C,	C‐41),	144.8	(1C,	C‐4,	triazole),	
143.8	(1C,	C‐22),	138.3	(1C,	C‐92),	137.7	(1C,	C‐82),	134.8	(1C,	
C‐11),	134.1	(1C,	C‐41),	128.8	(2C,	C‐31	&	C‐51),	124.5	(2C,	C‐21	
&	C‐61),	120.0	(1C,	C‐62),	116.5	(1C,	C‐42),	115.5	(1C,	C‐5),	57.5	
(1C,	N‐CH2).	MS	(EI,	m/z	(%)):	310	(M+,	100).	

1‐{[1‐(4‐Fluorophenyl)‐1H‐1,	 2,	 3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (E):	 Color:	 Paleyellow	 solid.	 Yield:	 90%.	
M.p.:136‐138	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3140	 (triazole‐H),	 1593	
(C=C,	triazole),	1515	(N=N,	triazole).	1H	NMR	(400	MHz,	CDCl3,	
δ,	 ppm):	8.110	 (s,	1H,	N‐CH=N),	7.830	 (d,	 J	=	8.4	Hz,	1H,	Ar),	
7.650	(s,	1H,	triazole‐H),	7.516	(m,	3H,	Ar),	7.311	(m,	2H,	Ar),	
7.088	(d,	2H,	J	=	8	Hz,	Ar),	5.518	(s,	2H,	N‐CH2).	13C	NMR	(100	
MHz,	CDCl3,	δ,	ppm):	155.1	(1C,	C‐41),	144.2	(1C,	C‐4,	triazole),	
143.7	(1C,	C‐22),	138.3	(1C,	C‐92),	137.7	(1C,	C‐82),	135.1	(1C,	
C‐11),	134.1	(2C,	C‐31	&	C‐51),	127.5	(2C,	C‐21&C‐61),	123.3	(1C,	
C‐62),	 119.9	 (1C,	 C‐42),	 115.5	 (1C,	 C‐5),	 57.3	 (1C,	N‐CH2).	MS	
(EI,	m/z	(%)):	294	(M+,	100).	

1‐{[1‐(4‐Bromophenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (F):	 Color:	White	 solid.	 Yield:	 90%.	 M.p.:	 141‐
143	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3135	 (triazole‐H),	 1594	 (C=C,	
triazole),	 1516	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	 8.120	 (s,	 1H,	 N‐CH=N),	 7.832	 (d,	 1H,	 J	 =	 9.2	 Hz,	 Ar),	
7.621	(s,	1H,	triazole‐H),	7.511	(m,	2H,	Ar),	7.452	(m,	1H,	Ar),	
7.321	(m,	2H,	Ar),	6.940	(d,	2H,	J	=	9.2	Hz,	Ar),	5.528	(s,	2H,	N‐
CH2).	 13C	 NMR	 (100	 MHz,	 CDCl3,	 δ,	 ppm):	 145.7	 (1C,	 C‐4,	

triazole),	 143.7	 (1C,	 C‐22),	 138.2	 (1C,	 C‐92),	 137.5	 (1C,	 C‐82),	
134.5	(1C,	C‐11),	132.1	(1C,	C‐41),	128.7	(2C,	C‐31	&	C‐51),	127.2	
(2C,	C‐21&C‐61),	123.2	(1C,	C‐62),	119.9	(1C,	C‐42),	115.8	(1C,	C‐
5),	57.5	(1C,	N‐CH2).	MS	(EI,	m/z	(%)):	355	(M+,	100).	

1‐{[1‐(2‐Fluorophenyl)‐1H‐1,	 2,	 3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (G):	 Color:	 Pale	 yellow	 solid.	 Yield:	 85%.	M.p.:	
137‐139	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3140	 (triazole‐H),	 1594	 (C=C,	
triazole),	 1515	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	8.154	(s,	1H,	N‐CH=N),	7.948	(m,	1H,	Ar),	7.927	(s,	1H,	
triazole‐H),	7.452	(m,	2H,	Ar),	7.290	(m,	5H,	Ar),	5.393	(s,	2H,	
N‐CH2).	 13C	NMR	 (100	MHz,	 CDCl3,	 δ,	 ppm):	 160.6	 (1C,	 C‐21),	
145.5	 (1C,	 C‐4,	 triazole),	 143.1	 (1C,	 C‐22),	 138.6	 (1C,	 C‐11),	
137.5	(1C,	C‐92),	136.7	(1C,	C‐82),	134.6	(1C,	C‐31),	133.6	(1C,	
C‐51),	128.2	(1C,	C‐41),	127.0	(1C,	C‐61),	123.2	(1C,	C‐62),	121.6	
(1C,	C‐42),	116.5	(1C,	C‐5),	57.5	(1C,	N‐CH2).	MS	(EI,	m/z	(%)):	
294	(M+,	100).	

1‐{[1‐(4‐Nitrophenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (H):	 Color:	White	 solid.	 Yield:	 88%.	M.p.:	 161‐
163	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3135	 (triazole‐H),	 1593	 (C=C,	
triazole),	 1502	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	8.140	(s,	1H,	N‐CH=N),	7.830	(d,	1H,	J	=	8	Hz,	Ar),	7.645	
(s,	1H,	triazole‐H),	7.520	(m,	3H,	Ar),	7.310	(m,	2H,	Ar),	6.971	
(d,	2H,	J	=	8.8	Hz,	Ar),	5.582	(s,	2H,	N‐CH2).	13C	NMR	(100	MHz,	
CDCl3,	δ,	ppm):	147.3	(1C,	C‐41),	145.5	(1C,	C‐4,	triazole),	143.7	
(1C,	C‐22),	138.5	(1C,	C‐11),	137.7	(1C,	C‐92),	135.5	(1C,	C‐82),	
134.1	(2C	,	C‐31	&	C‐51),	128.2	(2C,	C‐21	&	C‐61),	123.0	(1C,	C‐
62),	120.2	(1C,	C‐42),	116.9	(1C,	C‐5),	56.2	(1C,	N‐CH2).	MS	(EI,	
m/z	(%)):	321	(M+,	100).	

1‐{[1‐(3,5‐dichlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐1H‐	
benzimidazole	 (I):	 Color:	 White	 solid.	 Yield:	 75%.	 M.p.:	 169‐
171	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3133	 (triazole‐H),	 1594	 (C=C,	
triazole),	 1516	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	 8.210	 (s,	 1H,	 N‐CH=N),	 7.830	 (d,	 1H,	 J	 =	 8.4	 Hz,	 Ar),	
7.651	(s,	1H,	 triazole‐H),	7.530	(s,	1H,	Ar),	7.421	(m,	3H,	Ar),	
7.056	(d,	2H,	J	=	4.8	Hz,	Ar),	5.503	(s,	2H,	N‐CH2).	13C	NMR	(100	
MHz,	CDCl3,	δ,	ppm):	145.1	(1C,	C‐4,	triazole),	143.5	(1C,	C‐22),	
137.7	(1C,	C‐92),	135.8	(2C,	C‐31	&	C‐51),	135.5	(1C,	C‐82),	131.8	
(1C,	C‐11),	128.8	(1C,	C‐41),	123.4	(2C,	C‐21	&	C‐61),	123.7	(1C,	
C‐62),	 120.1	 (1C,	 C‐42),	 115.6	 (1C,	 C‐5),	 57.5	 (1C,	 N‐CH2).	MS	
(EI,	m/z	(%)):	345	(M+,	100).	

1‐{[1‐(3‐Chlorophenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]	methyl}‐1H‐
benzimidazole	 (J):	 Color:	 Yellow	 solid.	 Yield:	 80%.	 M.p.:150‐
152	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3139	 (triazole‐H),	 1596	 (C=C,	
triazole),	 1515	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	8.116	 (s,	 1H,	N‐CH=N),	7.840	 (s,	 1H,	 triazole‐H),	7.630	
(d,	 2H,	 J	=	 8.4	 Hz,	 Ar),	 7.517	 (m,	 2H,	 Ar),	 7.291	 (m,	 2H,	 Ar),	
6.994	(d,	2H,	J	=	5.3	Hz,	Ar),	5.512	(s,	2H,	N‐CH2).	13C	NMR	(100	
MHz,	CDCl3,	δ,	ppm):	145.5	(1C,	C‐4,	triazole),	143.1	(1C,	C‐22),	
138.6	(1C,	C‐92),	137.6	(1C,	C‐82),	134.6	(1C,	C‐31),	133.6	(1C,	
C‐21),	131.6	(1C,	C‐11),	128.2	(1C,	C‐41),	127.0	(1C,	C‐51),	126.2	
(1C,	 C‐61),	 122.2	 (1C,	 C‐62),	 121.6	 (1C,	 C‐42),	 116.5	 (1C,	 C‐5),	
57.5	(1C,	N‐CH2).	MS	(EI,	m/z	(%)):	332	(M+Na,	100).	

1‐{[1‐(3‐Methylphenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (K):	 Color:	White	 solid.	 Yield:	 92%.	M.p.:	 134‐
136	 °C.	 	 FT‐IR	 (KBr,	 cm‐1):	 3135	 (triazole‐H),	 1593	 (C=C,	
triazole),	 1516	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	8.120	(s,	1H,	N‐CH=N),	7.830	(d,	1H,	J	=	8	Hz,	Ar),	7.643	
(s,	1H,	triazole‐H),	7.515	(m,	3H,	Ar),	7.310	(m,	2H,	Ar),	6.977	
(d,	2H,	J	=	8.8	Hz,	Ar),	5.582	(s,	2H,	N‐CH2),	2.41	(s,	3H,	Ar‐CH3).	
13C	NMR	(100	MHz,	CDCl3,	δ,	ppm)	 :	144.1	 (1C,	C‐4,	 triazole),	
143.1	(1C,	C‐22),	138.6	(1C,	C‐92),	138.0	(1C,	C‐82),	134.3	(1C,	
C‐11),	128.2	(1C,	C‐31),	127.1	(1C,	C‐21),	126.2	(1C,	C‐61)	123.3	
(1C,	 C‐51),	 122.8	 (1C,	 C‐62),	 119.3	 (1C,	 C‐42),	 115.6	 (1C,	 C‐5),	
57.1	(1C,	N‐CH2),	21.1	(1C,	Ar‐CH3).	MS	(EI,	m/z	(%)):	290	(M+,	
100).	

1‐{[1‐(2,3‐Dimethylphenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐
1H‐benzimidazole	 (L):	 Color:	 White	 solid.	 Yield:	 90%.	 M.p.:	
139‐141	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3141	 (triazole‐H),	 1594	 (C=C,	
triazole),	 1515	 (N=N,	 triazole).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	8.100	(s,	1H,	N‐CH=N),	7.654	(s,	1H,	triazole‐H),	7.531	

	



Seeka	et	al.	/	European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	 485	
 

	
Table	2.	Antibacterial	activity	of	1,4‐di‐substituted	1,2,3‐triazole	derivatives	of	benzimidazole	(A‐N).	
Compound	 MIC,	µg/mL	

E.	coli	 S.	aureus B.	subtilis P.	vulgaris	
A	 46	 48	 50	 66	
B	 80	 46	 58	 78	
C	 NA	 64 62 48	
D	 NA	 62 46 NA	
E	 NA	 78 64 80	
F	 74	 48 NA 68	
G	 58	 45 NA 78	
H	 45	 60 44 NA	
I	 54	 54	 40	 64	
J	 58	 52	 NA	 70	
K	 62	 36	 NA	 NA	
L	 58	 40 42 72	
M	 40	 44	 42	 54	
N	 40	 40 40 44	
Streptomycin	sulphate	 10	 12	 16	 14	
	
	
Table	3.	Antifungal	activity	of	1,4‐di‐substituted	1,2,3‐triazole	derivatives	of	benzimidazole	(A‐N).	
Compound	 MIC,	µg/mL	 	

Aspergillus	sp	 Penicillium	sp	
A	 25	 34
C	 32	 ‐
E	 38	 ‐
F	 50	 28
G	 52	 48
I	 26	 26	
K	 42	 42	
N	 44	 ‐
Ampothericin‐B	 25	 25	
	
	
(m,	 3H,	 Ar),	 7.311	 (m,	 2H,	 Ar),	 6.971	 (d,	 2H,	 J	=	 8.8	 Hz,	 Ar),	
5.553	 (s,	 2H,	 N‐CH2),	 2.781	 (s,	 3H,	 Ar‐CH3),	 2.401	 (s,	 3H,	 Ar‐
CH3).	 13C	 NMR	 (100	 MHz,	 CDCl3,	 δ,	 ppm):	 144.5	 (1C,	 C‐4,	
triazole),	 143.4	 (1C,	 C‐22),	 138.0	 (1C,	 C‐92),	 137.4	 (1C,	 C‐82),	
136.3	(1C,	C‐11),	134.6	(1C,	C‐21),	133.5	(1C,	C‐31),	128.2	(1C,	
C‐61),	127.1	(1C,	C‐51),	123.3	(1C,	C‐41),	122.2	(1C,	C‐62),	119.3	
(1C,	C‐42),	115.5	(1C,	C‐5),	56.6	(1C,	N‐CH2),	24.5	(1C,	Ar‐CH3),	
22.1	(1C,	Ar‐CH3).	MS	(EI,	m/z	(%)):	304	(M+,	100).	

1‐({1‐[3‐(Trifluoromethyl)phenyl]‐1H‐1,	2,	3‐triazol‐4‐yl}	
methyl)‐1H‐benzimidazole	 (M):	 Color:	 Orange	 solid.	 Yield:	
86%.	 M.p.:	 165‐167	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3135	 (triazole‐H),	
1593	(C=C,	triazole),	1516	(N=N,	triazole).	1H	NMR	(400	MHz,	
CDCl3,	δ,	ppm):	8.110	(s,	1H,	N‐CH=N),	7.844	(s,	1H,	triazole‐H),	
7.631	(d,	2H,	 J	=	8.4	Hz,	Ar),	7.514	(m,	2H,	Ar),	7.295	(m,	2H,	
Ar),	6.992	(d,	2H,	J	=	5.3	Hz,	Ar),	5.515	(s,	2H,	N‐CH2).	13C	NMR	
(100	MHz,	CDCl3,	δ,	ppm):	144.5	(1C,	C‐4,	 triazole),	143.2	(1C,	
C‐22),	138.1	(1C,	C‐92),	137.2	(1C,	C‐82),	134.8	(1C,	C‐31),	133.3	
(1C,	C‐21),	131.4	(1C,	C‐11),	128.1	(1C,	C‐41),	127.2	(1C,	C‐51),	
126.8	(1C,	C‐61),	123.3	(1C,	CF3)	122.4	(1C,	C‐62),	121.2	(1C,	C‐
42),	 116.8	 (1C,	 C‐5),	 57.7	 (1C,	N‐CH2).	MS	 (EI,	m/z	 (%)):	 344	
(M+,	100).	

1‐{[1‐(2‐Methylphenyl)‐1H‐1,	2,	3‐triazol‐4‐yl]methyl}‐1H‐
benzimidazole	 (N):	 Color:	White	 solid.	 Yield:	 85%.	M.p.:	 133‐
135	 °C.	 1H	 NMR	 (400	MHz,	 CDCl3,	 δ,	 ppm):	 8.115	 (s,	 1H,	 N‐
CH=N),	 7.834	 (d,	 1H,	 J	=	 8	 Hz,	 Ar),	 7.642	 (s,	 1H,	 triazole‐H),	
7.516	(m,	3H,	Ar),	7.320	(m,	2H,	Ar),	6.978	(d,	2H,	 J	=	8.8	Hz,	
Ar),	5.552	(s,	2H,	N‐CH2),	2.441	(s,	3H,	Ar‐CH3).	13C	NMR	(100	
MHz,	CDCl3,	δ,	ppm):	144.2	(1C,	C‐4,	triazole),	143.3	(1C,	C‐22),	
138.4	(1C,	C‐92),	138.2	(1C,	C‐82),	134.3	(1C,	C‐11),	130.1	(1C,	
C‐21),	128.4	(1C,	C‐31),	127.6	(1C,	C‐41),	126.8	(1C,	C‐61),	123.4	
(1C,	 C‐51),	 122.9	 (1C,	 C‐62),	 119.3	 (1C,	 C‐42),	 115.6(1C,	 C‐5),	
57.1(1C,	 N‐CH2),	 22.4(1C,	 Ar‐CH3).	 IR	 (KBr,	 cm‐1):	 3141	
(triazole‐H),	1595	(C=C,	triazole),	1504	(N=N,	triazole).	MS	(EI,	
m/z	(%)):	290	(M+,	100).	
	
2.4.	Biological	activity	
	
2.4.1.	Antimicrobial	activity	
	

A	broad	panel	of	bacterial	and	fungal	strains	was	used	for	
testing	 the	 antimicrobial	 properties	 of	 the	 synthesized	

molecules.	 The	 molecules	 were	 screened	 against	 both	 Gram	
positive	 (S.	aureus	and	B.	Subtilis)	 and	Gram	negative	 (E.	coli	
and	 P.	 vulgaris)	 organisms.	 The	 samples	 were	 tested	 by	
standard	 protocols,	 Agar	 well	 diffusion	 method	 [40,41]	 for	
antibacterial	 activity	 (Table	 2)	 and	 Agar	 plug	 method	 for	
antifungal	activity	(Table	3).	For	all	the	derivatives,	minimum	
inhibitory	 concentration	was	 determined	 by	 using	microtiter	
plate	 technique	 and	 resazurin	 as	 bio‐indicator.	 Streptomycin	
sulphate	was	used	as	a	standard	drug	for	antibacterial	activity	
and	 ampothericin‐B	 was	 used	 as	 a	 standard	 for	 antifungal	
activity	 and	 they	 were	 also	 screened	 under	 identical	
conditions	for	comparison.	All	the	culture	used	in	this	present	
study	 was	 obtained	 by	 Agricultural	 Research	 Service‐United	
States	Department	of	Agriculture	(ARS‐USDA)	on	request	and	
their	help	in	this	regard	is	duly	acknowledged.	
	
2.4.2.	Antioxidant	activity	
	

The	synthesized	compounds	(A‐N)	were	investigated	for	in	
vitro	 antioxidant	 activity	 in	 terms	 of	 hydrogen	 donating	 or	
radical	 scavenging	ability	by	rapid	and	convenient	 technique,	
i.e.	1,1‐diphenyl‐2‐picryl‐hydrazyl	(DPPH)	assay	[42,43]	using	
trolax	 and	 ascorbic	 acid	 as	 standard	 drugs.	Methanol	 (95%),	
DPPH	solution	and	standard	drugs	were	used	as	blank,	control,	
and	reference,	respectively.	Absorbance	was	calculated	at	517	
nm	 (at	 an	 absorption	 maximum	 of	 DPPH)	 after	 keeping	 the	
mixture	of	100	µL	of	synthesized	compounds	of	concentration	
10	 µg/mL	 (dissolved	 in	 DMSO)	 and	 900	 µL	 of	 DPPH	 radical	
solution	(0.004%	w:v	of	DPPH	in	methanol)	in	a	dark	place	for	
30	min	 incubation	period.	Antioxidant	 activity	was	evaluated	
in	IC50	in	µM	(the	effective	concentration	at	which	50%	of	the	
radicals	were	scavenged)	and	depicted	in	Table	4.	
	
3.	Results	and	discussion	
	
3.1.	Chemistry	
	

In	 the	 present	 work,	 we	 report	 an	 efficient	 N‐pro‐
pargylation	 of	 benzimidazole	 in	 the	 presence	 of	 Cs2CO3	 and	
one	pot	multi‐component	synthesis	of	1,2,3‐triazoles	using		

	



486	 Seeka	et	al.	/	European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	
	

	
Table	4.	Antioxidant	activity	of	1,4‐di‐substituted	1,2,3‐triazole	derivatives	of	benzimidazole	(A‐N)	by	DPPH	method	.	
Compound	 IC50	
A	 50.37±1.35
B	 15.64±1.32
C	 25.93±1.19	
D	 22.49±1.42	
E	 87.02±1.23	
F	 58.05±1.25	
G	 26.34±1.26
H	 51.85±1.10
I	 6.308±1.35
J	 38.31±1.40
K	 94.20±1.52
L	 101.62±1.35
M	 8.51±1.18
N	 134.20±1.32	
Trolox	 14.80±1.43
Ascorbic	acid	 3.0±1.34
	

	
N‐propargylbenzimidazole,	 anilines,	 sodium	 nitrite	 and	
sodium	 azide	 in	 ionic	 liquid	 [BMIM][PF6]·H2O	 at	 room	
temperature.		

N‐Propargylation	 was	 carried	 out	 by	 the	 addition	 of	
propargyl	bromide,	under	stirring,	to	the	[BMIM][PF6]	and	H2O	
mixture	 containing	 benzimidazole	 and	 Cs2CO3	 at	 room	
temperature	 for	 12	 hours	 (Scheme	 1).	 The	 ionic	 liquid	 was	
recycled	and	used	for	the	cycloaddition	reaction.	

	

 
	

Scheme	1	
	

In	 a	 typical	 reaction	 (Scheme	 2),	 aryl	 amines	 were	
homogenized	by	mixing	a	wet	solid	p‐TsOH	hydrate	 followed	
by	addition	of	NaNO2	and	NaN3	in	[BMIM][PF6]·H2O	stirred	at	
room	temperature	for	3	h.	N‐Propargylbenzimidazole	and	CuI	
were	then	added	and	the	reaction	was	stirred	for	8‐10	hrs	at	
room	 temperature.	 The	 reaction	 proceeds	 smoothly	 and	
rapidly	to	afford	1,2,3‐triazoles	in	excellent	yields.	The	results	
are	presented	in	Table	1.	The	residue	ionic	liquid	was	washed	
with	water	and	reused.	
	

 
	

Scheme	2	
	
3.2.	Antimicrobial	activity	
	

All	 the	 new	 compounds	 were	 screened	 for	 their	
antibacterial	and	antifungal	activities	using	standard	protocols	
and	the	minimum	inhibitory	concentration	(MIC)	values	were	
recorded	 (Table	 2	 and	 3).	 Among	 the	 compounds	 tested,	
compound‐B	and	D	exhibited	excellent	antibacterial	activities	
against	gram	negative	bacteria	E.coli	 and	P.vulgaris	while	 the	
compound	 F	 exhibited	 appreciable	 activity	 against	 S.	 aureus	
and	 B.	 Subtilis.	 The	 compounds	 A	 and	 C	 are	 more	 potent	
against	Aspergillus	and	compounds	F	and	I	exhibited	moderate	
activity.	
	
3.3.	Antioxidant	activity	
	

Evaluation	of	antioxidant	activity	revealed	that	the	most	of	
the	 tested	 compounds	 exhibited	 moderate	 to	 strong	 DPPH	
radical	scavenging	ability	compared	with	the	positive	controls	
trolox	 and	 ascorbic	 acid.	 Among	 them,	 the	 compounds	 3,5‐

dichloro	phenyl	and	3‐(trifluoromethyl)	phenyl	on	the	triazole	
ring	that	is	I	and	M	were	found	to	be	more	effective	and	potent	
DPPH	radical	scavenging	ability	when	compared	with	positive	
control	drug	Trolax.	Remaining	all	the	compounds	have	shown	
good	 to	moderate	radical	scavenging	activity	with	 IC50	values	
in	the	range	of	15.64±1.32	and	134.20±1.32	µM.	It	was	noticed	
that,	 the	 compounds	with	 electrons	 attracting	 groups	 on	 the	
phenyl	 ring	were	 found	 to	be	good	 radical	 scavenging	 ability	
(Table	4).	
	
4.	Conclusion		
	

In	 conclusion,	 the	 present	 work	 demonstrated	 an	
environmentally	 benign	 and	 a	 convenient	 method	 for	 the	
synthesis	of	biodynamic	1,2,3‐triazole	hybrid	compounds.	The	
antioxidant	and	antimicrobial	activities	indicate	that	the	newly	
synthesized	 compounds	 are	 worthy	 for	 further	 pharmaco‐
logical	studies.	
	
Acknowledgements	
	

Financial	 assistance	 from	 the	 University	 Grants	
Commission‐Major	 Research	 Project,	 New	 Delhi,	 India,	 is	
greatly	 acknowledged.	 The	 authors	 are	 thankful	 to	 Indian	
institute	 of	 Chemical	 Technology,	 Hyderabad	 for	 providing	
spectral	 data	 and	 Narsimha	 thanks	 Council	 of	 Scientific	 and	
Industrial	 Research	 New	 Delhi,	 for	 the	 award	 of	 senior	
research	fellowship.	
	
References	
	
[1]. Kamal,	S.;	Sumit,	C.;	Sushant	K.	S.;	Pradeep,	M.	Med.	Chem.	Res.	2013,	

22,	5077‐5104.		
[2]. Balasubramanian,	N.;	Deepika,	S.;	Pradeep,	K.	Med.	Chem.	Res.	2012,	

21,	269‐283.		
[3]. Shivakumar,	R.;	Pradeepchandran,	R.	V.;	Narasimha,	J.	K.	Eur.	J.	Chem.	

2011,	2,	558‐560.		
[4]. Love	Kumar,	S.;	Narsinghani,	T.;	Anand,	S.	Med.	Chem.	Res.	2012,	21,	

4330‐4334.		
[5]. Tuncbilek,	 M.;	 Kiper,	 T.;	 Altanlar,	 N.	 Eur.	 J.	 Med.	 Chem.	 2009,	 44,	

1024‐1033.		
[6]. Desai,	N.	C.;	Pandya,	D.	D.;	Joshi,	V.	V.;	Rajpara,	K.	M.;	Vaghani,	H.	V.;	

Satodiya,	H.	M.	Med.	Chem.	Res.	2012,	21,	4463‐4472.		
[7]. Deepkumar,	J.;	Kalpesh,	P.	Med.	Chem.	Res.	2014,	23,	1290‐1299.		
[8]. Afaf,	H.	E.	M.;	Fahmy,	H.	H.;	Ali	Abdelwahed,	S.	H.	Molecules	2000,	5,	

1429‐1438.		
[9]. Ravishankara,	D.	K.;	Chandrashekara,	P.	G.	Eur.	J.	Chem.	2012,	3,	363‐

366.		
[10]. Guruswamy,	B.;	Arul,	R.	K.;	Chaitanya,	M.	V.	S.	R.	K.;	Darsi,	S.	S.	P.	K.	

Eur.	J.	Chem.	2013,	4,	329‐335.		
[11]. Tonelli,	M.;	Matteo,	S.;	Bruno,	T.;	Federica,	N.;	Giuseppina,	S.;	Fabio,	

S.;	Giuseppe,	P.;	Sabrina,	P.;	Vito,	B.;	Gabriele,	G.;	Sylvain,	B.;	Cristina,	
I.;	Roberta,	L.;	Paolo,	L.	C.	Bioorg.	Med.	Chem.	2010,	18,	2937‐2953.		

[12]. Angela,	R.;	Alba,	C.;	Erik,	D.	C.;	Anna,	M.	M.;	Pietro,	M.;	Christophe,	P.;	
Maria,	Z.	Il	Farmaco	2002,	57,	819‐823.		

[13]. Ruiming,	 Z.;	 Kevin,	 R.;	 Ayres,	 J.	 C.;	 Drach,	 L.	 B.;	 Townsend.	 J.	Med.	
Chem.	1996,	39,	3477‐3482.		

[14]. Garuti,	L.;	Roberti,	M.;	G.	Gentilomi,	G.	II	Farmaco	2000,	55,	35‐39.		



Seeka	et	al.	/	European	Journal	of	Chemistry	6	(4)	(2015)	482‐487	 487	
 

[15]. Ravishankara,	D.	K.;	Chandrashekara,	P.	G.	Eur.	J.	Chem.	2012,	3,	359‐
362.		

[16]. Kavitha,	C.	S.	A.;	Kallappa	M.	H.;	Harisha	R.	S.	E.	 J.	Med.	Chem.	2010,	
45,	2048‐2054.		

[17]. Kaushik,	D.;	Ahmed	Khan,	S.;	Gita	C.	Med.	Chem.	Res.	2012,	21,	459‐
467.		

[18]. Galal,	 S.	 A.;	 Abdelsamie,	 A.	 S.;	 Rodriguez,	 M.	 L.;	 Kerwin,	 S.	 M.	 El	
Diwani,	H.	I.	Eur.	J.	Chem.	2010,	1,	67‐72.		

[19]. Nofal.	Z.	M.;	Soliman,	E.	A.;	Abd	El‐Karim,	S.	S.;	Elzahar,	M.	I.;	Srour,	A.	
M.;	Dhavan,	S.	S.;	Maher,	T.	J.	Acta	P.	Pharm.	Drug	Res.	2011,	68,	519‐
534.		

[20]. Ahmed	A.	E.	R.;	Hassan,	Y.	A.	E.	Mini‐Rev.	Med.	Chem.	2013,	13,	399‐	
407.		

[21]. Ali,	E.	S.;	Omer,	O.	A.;	Sama,	A.	A.	Eur.	J.	Chem.	2012,	3,	356‐358.		
[22]. Meldal,	 M.;	 Christian,	W.	 T.;	 Christensen,	 C.	 J.	Org.	 Chem.	2002,	 67,	

3057‐3064.		
[23]. Kamijo,	S.;	Jin,	T.;	Huo,	Z.;	Yamamoto,	Y.	J.	Org.	Chem.	2004,	69,	2386‐

2393.		
[24]. Cristina,	G.	O.;	Jagerovic,	N.;	Goya,	P.;	Alkorta,	I.;	Elguero,	J.;	Cuberes,	

R.;	Dordal,	A.	Arkivoc	2010,	2,	127‐147.		
[25]. Akhtar,	 T.;	 Hameed,	 S.;	 Khan,	 K.	 M.;	 Khan,	 A.;	 Choudhary,	 M.	 I.	 J.	

Enzym	Inhib.	Med.	Ch.	2010,	25,	572‐576.		
[26]. Alvarez,	 S.;	 San,	 F.;	 Aquaro,	 S.	 D.	 C.;	 Perno,	 C,	 F.;	 Karlsson,	 A.;	

Balzarini,	J.;	Camarasa,	M.	J.	J.	Med.	Chem.	1994,	37,	4185‐	4194.		
[27]. Genin,	M.	J.;	Allwine,	D.	A.;	Anderson,	D.	J.;	Barbachyn,	M.	R.;	Emmert,	

D.	 E.;	 Garmon,	 S.	 A.;	 Graber,	 D.	 R.;	 Grega,	 K.	 C.;	 Hester,	 J.	 B.;	
Hutchinson,	 D.	 K.	 M.	 J.;	 Reischer,	 R.	 J.;	 Ford,	 C.	 W.;	 Zurenko,	 G.	 E.;	
Hamel,	J.	C.;	Schaadt,	R.	D.;	Stapert,	D.;	Yagi,	B.	H.	J.	Med.	Chem.	2000,	
43,	953‐970.		

[28]. Narsimha,	S.;	Ranjith,	K.	T.;	Satheesh,	K.	N.;	Yakoob,	S.;	Vasudeva,	R.	
N.	Med.	Chem.	Res.	2014,	23,	5321‐5327.		

[29]. Huisgen.	R.		Angew.	Chem.	1963,	75,	604‐637.		
[30]. David,	A.;	Francesco,	F.;	Oriana,	P.;	Ferdinando,	P.;	Ennio,	Z.;	Luigi,	V.	

J.	Org.	Chem.	2005,	70,	6526‐6529.		
[31]. Sharpless,	 K.	 B.;	 Vsevolod,	 V.	 R.;	 Luke,	 G.	 G.;	 Valery,	 V.	 F.	 Angew.	

Chem.,	Int.	Ed.	2002,	41,	2596‐2599.		
[32]. Firouzeh,	N.;	Ali,	E.	J.	Appl.	Chem.	2012,	7,	29‐33.		
[33]. Jorapur,	 Y.	 R.;	 Jeong,	 J.	 M.;	 C.	 hi,	 D.	 Y.	 Tetrahedron	 Lett.	 2006,	 47,	

2435‐2438.		
[34]. Cinzia,	C.;	,	Daniela,	P.	Green	Chem.	2003,	5,	193‐197	
[35]. Cinzia,	C.;	Paolo,	P.;	Daniela,	P.	Green	Chem.	2006,	8,	277‐281.		
[36]. Alberto,	M.;	Alessandra,	V.;	Cinzia,	C.;	Bernardo,	M.;	Alessandro,	D.	J.	

Org.	Chem.	2008,	73,	2458‐2461.		
[37]. Ya‐Bin,	 Z.;	 Ze‐Yi,	 Y.;	 Yong‐Min,	 Liang.	 Tetrahedron	 Lett.	 2006,	 47,	

1545‐1549.		
[38]. Barral,	 K.;	 Moorhouse,	 A.	 D.;	 Moses,	 J.	 E.	 Org.	 Lett.	 2007,	 9,	 1809‐

1811.		
[39]. Moorhouse,	A.	D.;	Moses,	J.	E.	Synlett.	2008,	14,	2089‐2092.		
[40]. Parekh,	J.;	Chanda,	S.	V.	Turk.	J.	Biol.	2007,	31,	53‐58.		
[41]. Cosentino,	 S.;	 Tuberoso,	 C.	 I.	 G.;	 Pisano,	 B.;	 Satta,	 M.;	 Mascia,	 V.;	

Arzedi,	E.;	Palmas,	F.	Lett.	Appl.	Microbiol.	1999,	29,	130‐135.		
[42]. Gul,	 M.	 Z.;	 Farhan,	 A.;	 Anand,	 K.	 K.;	 Insaf,	 A.	 Q.;	 Irfan,	 A.	 G.	 BMC	

Complem.	Altern.	Med.	2013,	13,	53,	1‐12.		
[43]. Ramesh,	 G.;	 Janardhan,	 B.;	 Ranjith	 Kumar,	 T.;	 Althaf	 Hussain,	 S.	 K.;	

Rajitha,	B.	RSC	Adv.	2015,	5,	33562‐33569.