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European	Journal	of	Chemistry	5	(2)	(2014)	291‐295	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.2.291‐295.861	

	
	

	

	

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

	 	 	

An	environmentally	benign	and	efficient	synthesis	of	2‐thio‐substituted	
benzothiazoles	

Gaddam	Satish,	Kasireddy	Harsha	Vardhan	Reddy,	Katla	Ramesh,		
Jilla	Shankar,	and	Yadavalli	Venkata	Durga	Nageswar	*	

Council	of	Scientific	and	Industrial	Research,	Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	Uppal	Road,	Hyderabad	
500‐007,	India	

*Corresponding	author	at:	Council	of	Scientific	and	Industrial	Research,	Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	
Uppal	Road,	Hyderabad	500‐007,	India.		
Tel.:	+91.40.2791654.	Fax:	+91.40.27193189.	E‐mail	address:	dryvdnageswar@gmail.com	(Y.V.D.	Nageswar).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.5.2.291‐295.861	

Received:	24	June	2013	
Received	in	revised	form:	27	July	2013	
Accepted:	31	July	2013	
Online:	30	June	2014	

KEYWORDS	

	 An	 environmentally	 benign,	 simple	 and	 highly	 efficient	method	 for	 the	 synthesis	 of	 2‐thio‐
substituted	 benzothiazole	 derivatives	 has	 been	 achieved	 in	 good	 to	 excellent	 yields	 by
reacting	 a	 series	 of	 aryl	 halides	 with	 2‐mercapto	 benzothiazole,	 using	 recyclable	 CuFe2O4

nanoparticles	under	ligand	free	conditions	in	PEG‐400	as	solvent.	In	the	present	protocol,	the
copper	ferrite	nanoparticles	can	be	recovered	and	reused	up	to	four	cycles	without	significant
loss	of	activity.	

CuFe2O4	
PEG‐400	
Benzothiazole	
Iodo	benzenes	
Magnetically	separable	
2‐Mercapto	benzothiazole	

	
1.	Introduction	
	

In	 the	 area	 of	 heterocyclic	 chemistry,	 fused	 five	 member	
systems	are	important	building	blocks,	and	among	these	2‐thio‐
substituted	 benzothiazoles	 have	 been	 designed	 and	
synthesized	 for	 biological	 evaluation.	 2‐Thio‐substituted‐1,3‐
benzothiazoles	are	significant	scaffolds	found	in	a	large	number	
of	 pharmaceutically	 active	 molecules	 [1‐6].	 These	 include	
Cathepsin‐D	 inhibitor,	 potent	 heat	 shock	 protein‐90	 inhibitor,	
avarol‐3′‐thiobenzothiazole,	 2‐(thiocyanatomethylthio)‐1,3‐
benzothiazole,	 and	 dual	 antagonist	 for	 the	 human	 CCR1	 and	
CCR3	 receptors	 [7,8].	 2‐Thio‐substituted‐1,3‐benzothiazoles	
have	also	been	found	 in	advanced	materials	used	as	corrosion	
inhibitors	 and	 vulcanization	 catalysts	 in	 the	 rubber	 industry	
and	 reagents	 for	 metal‐catalyzed	 cross‐coupling	 reactions.	
Some	 of	 the	 biologically	 active	 2‐thio‐substituted	 benzo‐
thiazoles	are	given	in	Figure	1.	Due	to	the	significance	attached	
to	2‐thio‐substituted	benzothiazoles	many	research	groups	are	
attracted	 towards	 exploring	 various	 ecofriendly	 protocols	 [9].	
Recently	 green	 chemistry	 has	 attracted	 the	 attention	 of	 all	
research	groups	to	peruse	organic	synthetic	transformations	in	
sustainable	reaction	mediums	[10].		

	

 
	

Figure	1.	Biologically	active	N‐substituted‐2‐aminobenzothiazole	derivatives.
	
	



292	 Satish	et	al.	/	European	Journal	of	Chemistry	5	(2)	(2014)	291‐295	
	

Polyethylene	 glycol	 (PEG)	 is	 a	 polymerized	 compound	 of	
ethylene	 oxide,	 which	 is	 hydrophilic	 in	 nature.	 It	 has	 benign	
characteristic	 properties	 with	 respect	 to	 environment	 and	
chemical	 industry	 such	 as	 low	 cost,	 low	 flammability,	 low	
toxicity,	 recyclability,	 facile	 degradability,	 and	miscibility	with	
various	 organic	 solvents	 likes	 toluene,	 dichloromethane,	
alcohol,	 and	 acetone	 [11],	 compared	 to	 ionic	 liquids,	
supercritical	 fluids,	 and	 micellar	 systems	 [12].	 Polyethylene	
glycol	 is	 compatible	 with	 several	 organic	 synthetic	
transformations	 like	substitution	reactions	[13],	oxidation	and	
reduction	 reactions	 [14],	 Heck	 reaction	 [15],	 asymmetric	
dihydroxylation	 [16],	 Suzuki	 cross‐coupling	 reaction	 [17],	
Wacker	reaction	[18],	and	partial	reductions	of	alkynes	[19].	

The	 fascinating	area	of	cross‐coupling	chemistry	 led	many	
research	 groups	 to	 develop	 new	 catalytic	 systems	 to	 obtain	
several	libraries	of	new	molecules.	Due	to	various	applications	
associated	 with	 2‐thio‐substituted	 benzothiazoles,	 C‐S	 bond	
formation	 through	 coupling	 reaction	 using	 copper	 has	 been	
developed	[20].	Recently,	Wei‐Yi	Wu	and	co‐workers	described	
the	synthesis	of	2‐thiosubstituted	benzothiazole	by	FeCl3.6H2O	
catalyzed	 C‐S	 bond	 formation	 from	 2‐mercapto	 benzothiazole	
with	corresponding	aryl	halide	[21].	Even	though,	the	reported	
methods	 serve	 the	 purpose	 of	 obtaining	 2‐thio‐substituted	
benzothiazoles,	 these	 reported	 catalytic	 systems	 are	 not	
recyclable.		

In	 continuation	 of	 our	work	 in	 the	 field	 of	 cross‐coupling	
reactions	[22‐30]	herein,	we	describe	an	inexpensive,	air‐stable	
and	recyclable	nanocopper	ferrite	as	a	catalyst	for	the	synthesis	
of	 2‐thio‐substituted	 benzothiazoles	 under	 ligand‐free	
conditions.	 Heterogeneous	 catalysts	 are	 useful	 both	 from	
economic	 and	 industrial	 point	 of	 view	 when	 compared	 to	
homogeneous	 catalysts.	 The	 high	 surface	 area	 and	 reactive	
morphologies	 of	 nanomaterials	 allow	 them	 to	 be	 effective	
catalysts	 for	 organic	 synthesis.	 Copper	 ferrite	 nanoparticles	
(CuFe2O4	 nanoparticles)	 have	 the	 advantages	 of	 recyclability,	
easy	workup,	 and	 cleaner	 reaction	profiles	 apart	 from	 lack	 of	
nessesity	 of	 external	 ligands	 minimizing	 the	 organic	 waste	
generation	as	compared	to	 the	conventional	catalytic	systems.	
A	mixture	 of	 2‐iodo	 aniline	 (0.5	mmol),	 carbon	 disulfide	 (0.6	
mmol),	 CuFe2O4	 nanoparticles	 (0.06	 mmol),	 and	 Cs2CO3	 (1.5	
mmol)	 in	 PEG‐400	 (3	 mL)	 was	 stirred	 at	 90	 °C	 for	 8	 h.	 The	
product	2‐mercapto	benzothiazole	was	synthesized	 in	good	 to	
excellent	yield.	The	results	are	included	in	Table	1.	The	identity	
and	purity	of	 the	product	was	confirmed	by	1H	NMR,	and	ESI‐
MS	and	compared	with	authentic	samples	in	literature	[31].	
	
2.	Experimental	
	

All	 materials	 were	 purchased	 from	 Sigma	 Aldrich.	 Dry	
solvents,	 CuFe2O4	 nanopowder	 (<50	 nm)	 were	 used	 for	 the	
reactions.	Column	chromatography	was	carried	out	using	silica	
gel	 (60‐120	mesh	 size).	 Analytical	 thin	 layer	 chromatography	
(TLC)	was	carried	out	using	silica	gel	60	F254	pre‐coated	plates.	
Visualization	 was	 accomplished	 with	 UV	 lamp,	 I2	 stain,	 and	
phosphomolybdic	 acid	 charring.	 All	 the	 products	 were	
characterized	 by	 their	 NMR	 (Varian	 200	 or	 Avance	 300	
spectrometer)	 and	Mass	 spectra	 (VG	 Autospec).	 1H	 NMR	 and	
13C	NMR	were	recorded	on	200	or	300	MHz	 in	CDCl3,	and	 the	
chemical	 shifts	 were	 reported	 in	 parts	 per	 million	 (ppm,	 δ)	
downfield	 from	 the	 tetramethylsilane.	 Scanning	 electron	
microscopy	 (SEM)	 analyses	 were	 performed	 using	 a	 Make:	
Hitachi	S‐	3000N	scanning	electron	microscope.	Powder	X‐ray	
diffraction	 (XRD)	 analyses	 were	 performed	 using	 a	 Make:	
Bruker,	Model:	D8‐	Advance,	Detector:	Lynx‐Eye.		
	
2.1.	Recovering	of	CuFe2O4	nanoparticles	
	

The	 reusability	 of	 the	 nano	 copper	 ferrite	 catalyst	 was	
examined,	 after	 completion	 of	 the	 reaction,	 CuFe2O4	 nano	
particles	were	 allowed	 to	 be	 on	 the	 bottom	 of	 the	 flask	 by	 a	
neodymium	 magnet,	 and	 the	 supernatant	 solution	 was	

removed.	The	separated	nano	catalyst	was	washed	successively	
with	10	mL	of	water,	 ethanol,	 ethyl	 acetate,	 dichloromethane,	
and	 hexane	 and	 then	 dried.	 No	 significant	 loss	 of	 catalyst	
activity	was	observed	up	 to	 four	 cycles.	 It	was	observed	 from	
the	SEM	studies	(Figure	2)	that	the	used	CuFe2O4	nanoparticles	
were	 similar	 in	morphology,	 to	 the	 native	 catalyst	 even	 after	
four	cycles.	

	

(a)	 (b)	
	

Figure	 2. SEM	 images	 of	 CuFe2O4 nanoparticles	 (a)	 native	 CuFe2O3
nanoparticles,	(b)	CuFe2O4	nanoparticles	after	four	cycles.	
	
	
2.2.	General	procedure	for	the	synthesis	of	2‐thio‐substituted	
benzothiazole	derivatives	
	

A	 mixture	 of	 2‐mercapto	 benzothiazole	 (0.5	 mmol),	 iodo	
benzene	 (0.6	mmol),	 CuFe2O4	 nanoparticles	 (0.06	mmol),	 and	
Cs2CO3	(1.3	mmol)	in	PEG‐400	(3	mL)	was	stirred	at	90	°C	for	8	
h.	 After	 completion	 of	 the	 reaction,	 CuFe2O4	 nano	 particles	
were	allowed	to	be	at	the	bottom	of	the	flask	by	a	neodymium	
magnet,	 and	 the	 supernatant	 solution	 was	 removed.	 The	
supernatant	solution	was	extracted	with	ethyl	acetate	and	the	
organic	layer	was	washed	with	water	and	brine,	and	then	dried	
over	 Na2SO4.	 After	 removal	 of	 the	 solvent	 in	 vacuum,	 the	
residue	was	purified	 by	 silica‐gel	 chromatography	 to	 give	 the	
desired	 2‐thio‐substituted	 benzothiazoles.	 The	 identity	 and	
purity	of	the	product	was	confirmed	by	1H	NMR,	13C	NMR	and	
ESI‐MS.	
	
2.3.	General	procedure	for	the	synthesis	of	2‐mercapto	
benzothiazole	derivatives	
	

A	 mixture	 of	 2‐iodo	 aniline	 (0.5	 mmol),	 carbon	 disulfide	
(0.6	 mmol),	 CuFe2O4	 nanoparticles	 (0.06	 mmol),	 and	 Cs2CO3	
(1.5	mmol)	in	PEG‐400	(3	mL)	was	stirred	at	90	°C	for	5	h.	After	
the	 reaction,	 after	 completion	 of	 the	 reaction,	 CuFe2O4	 nano	
particles	 were	 allowed	 to	 be	 at	 the	 bottom	 of	 the	 flask	 by	 a	
neodymium	 magnet,	 and	 the	 supernatant	 solution	 was	
removed.	 The	 supernatant	 solution	 was	 extracted	 with	 ethyl	
acetate	and	the	organic	layer	was	washed	with	water	and	brine,	
and	 then	 dried	 over	 Na2SO4.	 After	 removal	 of	 the	 solvent	 in	
vacuum,	the	residue	was	purified	by	silica‐gel	chromatography	
to	 give	 the	 desired	 substituted	 2‐mercapto	 benzothiazoles	 in	
good	to	excellent	yields	(Scheme	1).	

2‐(Phenylthio)benzo[d]thiazole	 (Table	 1,	 Entry	 1,	 3a):	 1H	
NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm)	 7.89	 (d,	 1H,	 J	=	8.3	Hz,	 Ar‐H),	
7.79‐7.72	(m,	2H,	Ar‐H),	7.66	(d,	1H,	J	=	8.3	Hz,	Ar‐H),	7.54‐7.46	
(m,	3H,	Ar‐H),	7.45‐7.38	(m,	1H,	Ar‐H)	7.32‐7.27	(m,	1H,	Ar‐H).	
13C	 NMR	 (75	MHz,	 CDCl3,	 δ,	 ppm):	 135.3,	 130.4,	 129.9,	 126.1,	
124.31,	121.9,	120.7	(Ar‐C).	ESI‐MS	(m/z	):	244	(M	+	H)+..	

2‐(Phenylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	(Table	1,	
Entry	2,	3b):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.66	(s,	1H,	Ar‐
H),	7.57‐7.43	(d,	1H,	Ar‐H),	7.30‐7.23	(m,	2H,	Ar‐H),	7.20‐7.07	
(m,	3H,	Ar‐H),	6.81	(d,	1H,	J	=	9.0	Hz,	Ar‐H).	13C	NMR	(75	MHz,	
CDCl3,	δ,	ppm):	114.5	(Ar‐C),	120.6	(Ar‐C),	123.5	(CF3‐C),	124.3	
(Ar‐C),	 125.9	 (Ar‐C),	 126.7	 (Ar‐C),	 129.1	 (Ar‐C),	 134.5	 (Ar‐C),	
140.4	(Ar‐C),	153.9	(Ar‐C).	ESI‐MS	(m/z):	312	(M	+	H)+..	

	
	



Satish	et	al.	/	European	Journal	of	Chemistry	5	(2)	(2014)	291‐295	 293	
 

	
Table	1.	Synthesis	of	2‐phenyl‐2,3‐dihydroquinazolin‐4(1H)‐one	derivatives	a.	
Entry	 R	 R’	 Product	 Time	(h)	 Yield	(%)	b	

1	

	

	 	

8	 91

2	

	
	

	

8	 90	

	

	

	

3	

	

	 S

N
S

F3C

CF3

	

8	 88	

	

	

	

	

4	

	

	 S

N
S

F3C

F

	

8	 80

	

	

	

5	

	

	

	

8	 60	

	

	

6	

	 	

	

8	 52

7	

	
	

	

8	 45	

8	

	 	

	

8	 82

9	

	 	

	

8	 80

10	

	 	

	

8	 84

11	

	
	

	

8	 78

12	

	
	

	

8	 70

a	Reaction	conditions:	A	mixture	of	2‐mercapto	benzothiazole	(0.5	mmol),	iodo	benzene	(0.6	mmol),	CuFe2O4	nanoparticles	(0.06	mmol),	and	Cs2CO3	(1.3	mmol)	
in	PEG‐400	(3	mL)	was	stirred	at	90	oC	for	8h.	
b	Isolated	yield.	



294	 Satish	et	al.	/	European	Journal	of	Chemistry	5	(2)	(2014)	291‐295	
	

	

 
	

Scheme	1
	

	
Table	2.	Screening	of	nanoparticles	for	the	synthesis	of	2‐thio‐substituted	benzothiazoles	a.	

 

 
	

Entry	 Catalyst	 Base	 Solvent Temperature	(°C)	 Yield	(%)	b
1	 Nano	CuFe2O4	 Cs2CO3	 PEG 90 91	
2	 Nano	CuFe2O4	 K2CO3	 PEG 90 40	
3	 Nano	CuFe2O4	 Na2CO3	 PEG 90 20	
4	 Nano	CuFe2O4	 K3PO4	 PEG 90 40	
5	 Nano	CuFe2O4	 Cs2CO3	 PEG Room	temperature Trace	
6	 Nano	CuFe2O4	 Cs2CO3	 CH3CN 90 25	
7	 Nano	CuFe2O4	 Cs2CO3	 Toluene	 90	 30	
8	 Nano	CuFe2O4	 Cs2CO3	 THF	 90	 15	
9	 Nano	CuFe2O4	 Cs2CO3	 PEG	 50	 20	
10	 Nano	CuFe2O4	 	‐	 PEG 90 0	c	
11	 Nano	CuFe2O4	 Cs2CO3	 H2O 90 0	
12	 	‐	 Cs2CO3	 PEG 90 0	d	
13	 Nano	Y2O3	 Cs2CO3	 PEG 50 15	
14	 Nano	NiO	 Cs2CO3	 PEG 50 10	
15	 Nano	Co3O4	 Cs2CO3	 PEG 50 Trace	
16	 Nano	NiFe2O4	 Cs2CO3	 PEG 50 13	
a	Reaction	conditions:	A	mixture	of	2‐mercapto	benzothiazole	(0.5	mmol),	iodo	benzene	(0.6	mmol),	CuFe2O4	nanoparticles	(0.06	mmol),	and	Cs2CO3	(1.3	mmol)	
in	PEG‐400	(3	mL)	was	stirred	at	90	°C	for	8	h.	
b	Isolated	yield.	
c	In	absence	of	the	catalyst.	
d	In	absence	of	the	base.	

	
	
2‐((4‐(Trifluoromethyl)phenyl)thio)benzo[d]thiazole	 (Table	

1,	Entry	3,	3c):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.91	(d,	1H,	J	
=	7.9	Hz,	Ar‐H),	7.90‐7.79	(d,	2H,	Ar‐H),	7.78‐7.66	(m,	2H,	Ar‐H),	
7.55‐7.42	(m,	2H,	Ar‐H)	7.41‐7.32	(m,	1H,	Ar‐H).	ESI‐MS	(m/z):	
312	(M	+	H)+..	

2‐((4‐Fluorophenyl)thio)benzo[d]thiazole	 (Table	 1,	 Entry	 4,	
3d):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	9.03	(s,	1H,	Ar‐H),	8.15	
(d,	2H,	J	=	8.3	Hz,	Ar‐H),	7.98	(d,	2H,	J	=	7.5	Hz,	Ar‐H),	7.64‐7.43	
(m,	3H,	Ar‐H).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	163.8	(Ar‐C),	
151.3,	F‐C,	135.6	(Ar‐C),	126.1	(Ar‐C),	125.5	(Ar‐C),	123.5	(Ar‐
C),	121.8	(Ar‐C).	ESI‐MS	(m/z):	262	(M	+	H)+..	

2‐(Ethylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	 (Table	 1,	
Entry	5,	3e):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	8.03	(s,	1H,	Ar‐
H),	7.92	(d,	1H,	J	=	8.3	Hz,	Ar‐H),	7.64	(d,	1H,	J	=	9.0	Hz,	Ar‐H),	
3.58‐3.22	 (m,	 2H,	 CH2),	 1.60‐1.39	 (t,	 3H,	 CH3).	 13C	 NMR	 (75	
MHz,	CDCl3,	 δ,	 ppm):	 170.8	 (Ar‐C),	 155.2	 (Ar‐C),	 135.1	 (Ar‐C),	
125.8	(Ar‐C),	122.9	(Ar‐C),	121.3	(Ar‐C),	118.4	(Ar‐C),	27.8,	Ali‐
C,	14.3,	Ali‐C.	
ESI‐MS	(m/z):	264	(M	+	H)+..	

2‐(Pentylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	 (Table	 1,	
Entry	 6,	3f):	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 8.09‐8.01	 (s,	
1H,	Ar‐H),	8.95‐8.90	(d,	1H,	Ar‐H),	7.69‐7.55	(d,	1H,	Ar‐H),	3.45‐
3.28	(t,	2H,	CH2),	1.87‐1.70	(m,	6H,	CH2),	0.93‐0.83	(s,	3H,	CH3).	
ESI‐MS	(m/z):	306	(M	+	H)+..	

2‐(Heptylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	 (Table	1,	
Entry	7,	3g):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	8.03	(s,	1H,	Ar‐
H),	7.92	(d,	1H,	J	=	8.4	Hz,	Ar‐H),	7.77‐7.69	(d,	1H,	Ar‐H),	3.48‐
3.28	(t,	2H,	CH2),	1.99‐1.75	(m,	2H,	CH2),	1.40‐1.20	(m,	8H,	CH2),	
0.97‐0.78	(m,	3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	171.2	
(Ar‐C),	 155.3	 (Ar‐C),	 135.2	 (Ar‐C),	 123.1	 (Ar‐C),	 121.4	 (Ar‐C),	
118.4	(Ar‐C),	33.6,	Ali‐C,	31.6,	Ali‐C,	29.0,	Ali‐C,	28.7,	Ali‐C,	22.5,	
Ali‐C,	14.0,	Ali‐C.	ESI‐MS	(m/z):	334	(M	+	H)+..	

2‐(Thiophen‐2‐ylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	
(Table	1,	Entry	8,	3h):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	8.15‐
8.00	(m,	1H,	Ar‐H),	7.97‐7.90	(m,	1H,	Ar‐H),	7.73‐7.69	 (m,	1H,	
Ar‐H),	7.65	(d,	1H,	 J	 =	8.3	Hz,	 	Ar‐H),	7.35‐7.30	 (m,	1H,	Ar‐H),	
7.23‐7.18	(m,	1H,	Ar‐H).	ESI‐MS	(m/z):	317	(M	+	H)+..	

2‐(Pyridin‐2‐ylthio)‐6‐(trifluoromethyl)benzo[d]thiazole	
(Table	1,	Entry	9,	3i):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	8.42‐
8.35	 (m,	 2H,	 Ar‐H),	 7.77‐7.70	 (d,	 2H,	 Ar‐H),	 7.37‐7.32	 (m,	 1H,	
Ar‐H),	7.31‐7.28	(m,	2H,	Ar‐H).	ESI‐MS	(m/z):	313	(M	+	H)+..	

2‐((4‐Methoxyphenyl)thio)‐6‐(trifluoromethyl)benzo[d]	
thiazole	 (Table	 1,	 Entry	 10,	3j):	 1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	
ppm):	 7.17‐7.05	 (m,	 2H,	 Ar‐H),	 6.88‐6.70	 (m,	 4H,	 Ar‐H),	 6.66‐
6.55	(m,	1H,	Ar‐H),	3.66	(s,	3H,	OCH3).	ESI‐MS	(m/z):	342	(M	+	
H)+..	

6‐(Trifluoromethyl)benzo[d]thiazole‐2‐thiol	 (Intermediate,	
A1):	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	11.08‐10.88	(m,	1H,	S‐
H),	7.77‐7.72	(s,	1H,	Ar‐H),	7.67‐7.59	(d,	1H,	Ar‐H),	7.39‐7.32	(d,	
1H,	Ar‐H).	ESI‐MS	(m/z):	235	(M	+	H)+..	
	
3.	Results	and	discussion		

	
Initially,	 2‐mercapto	 benzothiazole	 and	 iodobenzene	were	

used	 as	 model	 reactants	 to	 optimize	 the	 reaction	 conditions	
such	 as	 bases,	 solvents,	 and	 reaction	 temperature	 (Table	 2).	
Among,	 several	 bases	 screened,	 Cs2CO3	 was	 found	 to	 be	 an	
excellent	base	(Table	2,	Entry	1).	In	the	presence	of	bases	such	
as	 K2CO3,	 Na2CO3,	 and	 K3PO4,	 lesser	 amount	 of	 the	 desired	
product	was	obtained	(Table	2,	Entry	2,	3,	4).		

The	effect	of	solvents	was	also	investigated	and	the	highest	
yield	 was	 observed	 in	 PEG‐400	 (polyethylene	 glycol),	 while	
reaction	in	solvents	such	as	THF,	CH3CN	and	toluene	resulted	in	
moderate	 yields.	 The	 experiment	 confirmed	 that	 the	 reaction	



Satish	et	al.	/	European	Journal	of	Chemistry	5	(2)	(2014)	291‐295	 295	
 

did	 not	 occur	 in	 the	 absence	 the	 base	 (Table	 2,	 Entry	 10).	
Different	nano	catalysts	were	screened	 in	 this	protocol	 (Table	
2,	 Entries	 13‐16).	When	 the	 reaction	was	 conducted	 at	 room	
temperature	 trace	 amount	 of	 desired	 product	 were	 obtained	
(Table	2,	Entry	5).	Ideal	temperature	for	the	reaction	was	found	
to	be	90	°C.	The	influence	of	the	amount	of	catalyst	on	the	yield	
of	 the	 product	was	 also	 evaluated.	 It	 was	 observed	 that	 0.06	
mmol	 of	 nano	 CuFe2O4	 was	 ideal	 for	 synthesis	 of	 2‐thio‐
substituted	benzothiazoles	under	ligand‐free	conditions.	

The	 reusability	 of	 the	 nano	 copper	 ferrite	 catalyst	 was	
examined	and	the	results	are	summarized	in	Figure	3.		

	

	
	
Figure	3.	Recycling	of	CuFe2O4	nanoparticles	(Reaction	conditions:	A	mixture	
of	2‐mercapto	benzothiazole	(0.5	mmol),	iodo	benzene	(0.6	mmol),	CuFe2O4	
nanoparticles	 (0.06	mmol),	 and	Cs2CO3	 (1.3	mmol)	 in	 PEG‐400	 (3	mL)	was	
stirred	at	90	oC	for	8	h).	

	
After	 completion	 of	 the	 reaction,	 CuFe2O4	 nano	 particles	

were	allowed	to	be	at	the	bottom	of	the	flask	by	a	neodymium	
magnet,	 and	 the	 supernatant	 solution	 was	 removed.	 The	
separated	nano	catalyst	was	washed	successively	with	10	mL	of	
water,	ethanol,	ethyl	acetate,	dichloromethane,	and	hexane	and	
then	dried.	No	significant	loss	of	catalyst	activity	was	observed	
up	 to	 four	 cycles.	 The	 native	 and	 used	 CuFe2O4	 nanoparticles	
were	 analyzed	 by	 powder	 XRD	 and	 SEM	 analysis.	 The	 SEM	
studies	 showed	 that	 the	 morphology	 of	 CuFe2O4	 was	 almost	
similar	 in	 both	 before	 and	 after	 the	 reaction	 conditions.	 The	
powder	 XRD	 spectra	 (Figure	 4	 and	 5)	 also	 confirmed	 the	
intactness	 of	 the	 particles	 after	 four	 cycles	 (supporting.	
information).	
	

	
	

Figure	4.	Powder	XRD	‐	images	of	Native	CuFe2O4	nanoparticles.
	

	
	

Figure	5.	Powder	XRD	‐	images	of	CuFe2O4	nanoparticles	after	four	cycles.	

5.	Conclusion	
 

A	 simple	 and	 green	 protocol	 was	 developed	 for	 the	
synthesis	of	2‐thio‐substituted	benzothiazoles	using	recyclable	
CuFe2O4	nanoparticles	 under	 ligand	 free	 conditions	 in	 an	 eco‐
friendly	PEG‐400	solvent.	
	
Acknowledgement	
	

We	thank	Council	of	Scientific	and	Industrial	Research,	New	
Delhi,	India,	for	fellowship	to,	Gaddam	Satish,	Kasireddy	Harsha	
Vardhan	 Reddy,	 Jilla	 Shankar	 and	 University	 Grants	
Commission	for	fellowship	to	Katla	Ramesh.	
	
References	
	
[1]. Koci,	 J.;	 Klimesova,	 V.;	 Waisser,	 K.;	 Kaustova,	 J.;	 Dahse,	 H.	 M.;	

Moellmann,	U.	Bioorg.	Med.	Chem.	Lett.	2002,	12,	3275‐3278.		
[2]. Zhang,	L.;	Fan,	J.;	Vu,	K.;	Hong,	K.;	Le	Brazidec,	 J.	Y.;	Shi,	 J.;	Biamonte,	

M.;	 Busch,	 D.	 J.;	 Lough,	 R.	 E.;	 Grecko,	 R.;	 Ran,	 Y.;	 Sensintaffar,	 J.	 L.;	
Kamal,	 A.;	 Lundgren,	 K.;	 Burrows,	 F.	 J.;	 Mansfield,	 R.;	 Timony,	 G.	 A.;	
Ulm,	E.	H.;	Kasibhatla,	S.	R.;	Boehm,	M.	F.	J.	Med.	Chem.	2006,	49,	5352‐
5355.		

[3]. Dumas,	J.;	Brittelli,	D.;	Chen,	J.;	Dixon,	B.;	Hatoum‐Mokdad,	H.;	Konig,	
G.;	Sibley,	R.;	Witowsky,	J.;	Wong,	S.	Bioorg.	Med.	Chem.	Lett.	1999,	9,	
2531‐2535.		

[4]. Paramashivappa,	 P.;	 Kumar,	 P.;	 Rao,	 S.	 P.	 V.;	 Rao,	 A.	 S.	Bioorg.	Med.	
Chem.	Lett.	2003,	13,	657‐659.		

[5]. Naya,	K.;	Kobayashi,	K.;	Ishikawa,	M.;	Ohwaki,	K.;	Saeki,	T.;	Noguchi,	K.;	
Ohtake,	N.	Chem.	Pharm.	Bull.	2003,	51(6),	697‐701.		

[6]. Pejin,	 C.;	 Iodice,	 G.;	 Tommonaro,	 S.;	 Rosa,	 D.	 J.	Nat.	 Prod.	2008,	 71,	
1850‐1854.		

[7]. Sorg,	A.;	Bruckner,	R.	Synlett.	2005,	2,	289‐293.		
[8]. Liebeskind,	L.	S.	Org.	Lett.	2002,	4,	979‐982.			
[9]. Dunn,	P.	J.	Chem.	Soc.	Rev.	2012,	41,	1452‐1456.		
[10]. Toda,	F.;	Tanaka,	K.	Chem.	Rev.	2000,	100,	1025‐1029.		
[11]. Zhang,	Z.	H.;	Yin,	L.;	Wang,	Y.	M.;	Liu,	J.	Y.;	Li,	Y.	Green	Chem.	2004,	6,	

563‐565.			
[12]. Chen,	J.;	Spear,	S.	K.;	Huddleston,	J.	G.;	Rogers,	R.	D.	Green	Chem.	2005,	

7,	64‐67.		
[13]. Ferravoschi,	P.;	Fiecchi,	A.;	Grisenti,	P.;	Santaniello,	E.;	Trave,	S.	Synth.	

Commun.	1987,	17,	1569‐1573.		
[14]. Blanton,	J.	R.	Synth.	Commun.	1997,	27,	2093‐2095.		
[15]. Chandrasekhar,	S.;	Narsihmulu,	Ch.;	Sultana,	S.	S.;	Reddy,	N.	R.	K.	Org.	

Lett.	2002,	4,	4399‐4383.		
[16]. Chandrasekhar,	S.;	Narsihmulu,	C.;	Sultana,	S.	S.;	Reddy,	N.	R.	K.	Chem.	

Commun.	2003,	1716‐1717.		
[17]. Namboodiri,	V.	V.;	Varama,	R.	S.	Green	Chem.	2001,	3,	146‐149.		
[18]. Haimov,	A.;	Neumann,	R.	Chem.	Commun.	2002,	876‐879.		
[19]. Chandrasekhar,	 S.;	Narsihmulu,	 C.;	 Chandrasekhar,	 G.;	 Shyamsundar,	

T.	Tetrahedron	Lett.	2004,	45,	2421‐3425.		
[20]. Liu,	Shi.;	Liu,	X.;	Zhang,	H.;	Jiang,	Y.;	Ma,	D.	J.	Org.	Chem.	2011,	76,	420‐

424.		
[21]. Wei‐Yi,	W.;	Jui‐Chan,	W.;	Fu‐Yu,	T.	Green	Chem.	2009,	11,	326‐329.		
[22]. Swapna,	 K.;	 Murthy,	 S.	 N.;	 Jyothi,	 M.	 T.;	 Nageswar,	 Y.	 V.	 D.	Org.	Bio.	

Chem.	2011,	9,	5978‐5982.		
[23]. Swapna,	 K.;	 Murthy,	 S.	 N.;	 Jyothi,	 M.	 T.;	 Nageswar,	Y.	 V.	 D.	Org.	Bio.	

Chem.	2011,	9,	5989‐5993.		
[24]. Reddy,	K.	H.	V.;	Reddy,	V.	P.;	Shanka,	J.;	Madhav,	B.;	Kumar,	B.	S.	P.	A.;	

Nageswar,	Y.	V.	D.	Tetrahedron	Lett.	2011,	52,	2679‐2682.		
[25]. Reddy,	 K.	 H.	 V.;	 Reddy,	 V.	 P.;	 Shanka,	 J.;	 Nageswar,	 Y.	 V.	 D.	 Synlett.	

2011,	9,	1268‐1271.		
[26]. Reddy,	K.	H.	V.;	Satish,	G.;	Ramesh,	K.;	Karnakar	K.;	Nageswar,	Y.	V.	D.	

Chem.	Lett.	2012,	41,	585‐587.		
[27]. Kumar,	B.	S.	P.	A.;	Reddy,	K.	H.	V.;	Madhav,	B.;	Ramesh	K.;	Nageswar,	Y.	

V.	D.	Tetrahedron	Lett.	2012,	53,	4595‐4598.		
[28]. Reddy,	K.	H.	V.;	Satish,	G.;	Ramesh,	K.;	Karnakar	K.;	Nageswar,	Y.	V.	D.	

Tetrahedron	Lett.	2012,	53,	3061‐3065.		
[29]. Reddy,	K.	H.	V.;	Satish,	G.;	Prakash	Reddy,	V.;	Anil,	B.	S.	P.;	Nageswar,	Y.	

V.	D.	RSC	Advance	2012,	2,	11084		
[30]. Satish,	G.;	Reddy,	K.	H.	V.;	Karnakar,	K.;	Ramesh,	K.;	Nageswar,	Y.	V.	D.	

Tetrahedron	Lett.	2012,	53,	2518‐2521.		
[31]. Wang,	F.;	Cai,	S.;	Wang,	Z.;	Xi,	C.	Org.	Lett.	2011,	13,	3203‐3206.