1,3-Di-n-butylimidazolium tribromide-mediated chemoselective oxidative cyclization of benzothiazoyl carbaimides: A novel approach toward the synthesis of N-bis-benzothiazole derivatives

Article abstract of DOI:10.1002/jhet.736

4-(N,N-Dimethylamino)pyridine is found to be an efficient catalyst for the synthesis of benzothiazoyl carbaimide derivatives using 2-aminobenzothiazoles and phenylisothiocyanates, which on treatment with ionic liquid [bbim][Br ₃] at 70°C afforded exclusive formation of N-bis-benzothiazole derivatives in good yield. Copyright

Full text of DOI:10.1002/jhet.736

342
1,3-Di-n-butylimidazolium Tribromide-Mediated Chemoselective
Oxidative Cyclization of Benzothiazoyl Carbaimides: A Novel
Approach toward the Synthesis of N-bis-benzothiazole
Derivatives
Vol 49
Ravindra M. Kumbhare,* Tulshiram Dadmal, Umesh Kosurkar,
and K. Vijay Kumar
Division of Flouroorganics, Indian Institute of Chemical Technology, Tarnaka,
Hyderabad 500067, India
*E-mail: rakumbhare@yahoo.com
Received July 28, 2010
DOI 10.1002/jhet.736
Published online 20 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
4-(N,N-Dimethylamino)pyridine is found to be an efficient catalyst for the synthesis of benzothiazoyl
carbaimide derivatives using 2-aminobenzothiazoles and phenylisothiocyanates, which on treatment with
ionic liquid [bbim][Br3] at 70ꢀC afforded exclusive formation of N-bis-benzothiazole derivatives in
good yield.
J. Heterocyclic Chem., 49, 342 (2012).
INTRODUCTION
In view of this, there is still a need to develop a general,
efficient, and catalyst-free method for the synthesis of
more functionalized N-bis-benzothiazole derivatives.
4-Dimethylaminopyridine (DMAP) is a nucleophilic
catalyst, which catalyzes a variety of reactions examples
of which include esterifications with anhydrides [14],
Baylis–Hillman reaction [15], hydrosilylation [16], the
Steglich rearrangement [17], Staudinger synthesis of
b-lactams [18], and phosphorylation of amino and
hydroxylgroups [19]. Recently ionic liquid has gained
more attention in synthetic organic chemistry [20]. The
ionic liquid having low volatility and unique catalytic
activity have received considerable attention as eco-
friendly solvent as well as catalyst and reagent in the
context of green synthesis. Several reactions have been
performed successfully showing their great potential as
reaction media and some cases enhancing chemical
reactivity and selectivity [21].
2-Aminobenzothiazoles have received much attention
due to their unique structures and interesting biological
properties that lead to their use as anticonvulsant [1],
analgesic [2], anti-tumor [3,4], antibacterial [5,6], and
muscle relaxant agents [7]. Especially, interesting are
bis-benzothiazole derivatives, which are known to pos-
sess remarkable amyloid-imaging [8], antifungal [9],
vulcanization accelerators [10], and starting materials
for various pharmaceuticals industry [11].
Generally, thioureas are prepared by direct reaction of
isothiocyanate with amine. Using this approach, some
benzothiazoyl carbaimides [12] have been synthesized.
Although these synthetic methods are limited due to
harsh reaction conditions, longer reaction time, low
yields, and so forth, it is thus evident that there remains
a wide scope for the development of clean and efficient
methodologies for the preparation of benzothiazoyl car-
baimide compounds.
RESULT AND DISCUSSION
Methods for preparation of N-bis-benzothiazole are
scarce in literature. Earlier Garin et al. [13] synthesized
N-bis-benzothiazole from Hugershoff’s synthesis using
NBS and sulphuric acid as an oxidizing agent. But, this
method has limitations such as use of stoichiometric or
excess amount of toxic reagents like bromine. Although
the reported methods provide good isolated yields, these
methods suffer from tedious work-up and longer reac-
tion time and not explored for different functionalities.
As part of our continuing efforts on the development
of new routes for the preparation of biologically active
2-aminobenzothiazole derivatives [22], we report herein
a novel method for the synthesis of benzothiazoyl car-
baimides from 2-aminobenzothiazoles and phenyliso-
thiocyanates using 4-dimethylaminopyridine (DMAP) as
a catalyst, and a new ecofriendly version of Hugersh-
off’s synthesis for chemoselective oxidative cyclization
C
V
2011 HeteroCorporation

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1,3-Di-n-butylimidazolium Tribromide-Mediated Chemoselective Oxidative Cyclization of
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Benzothiazoyl Carbaimides: A Novel Approach toward the Synthesis of N-bis-benzothiazole Derivatives
Scheme 1. 4-DMAP-catalyzed synthesis of benzothiazoyl carbaimide
of benzothiazoyl carbaimides for the synthesis of sym-
metrical and unsymmetrical N-bis-benzothiazole deriva-
tives by using ionic liquid.
act as hydrogen bond donar [23]. Probably, reaction pro-
ceeds via coordination of C2 proton of ionic liquid 5
with nitrogen of benzothiazole ring in 3 which prevents
participation of nitrogen in ring cyclization, leading to
product 6 chemoselectively (Scheme 4).
In conclusion, we have developed an efficient proto-
col for synthesis of benzothiazoyl carbaimides, and sym-
metrical and unsymmetrical N-bis-benzothiazole deriva-
tives. This method can be classified as ‘‘green’’ as it
uses mild reaction conditions, eliminates toxic bromine
vapors, and avoids the use of organic solvents. This
work is the first application of synthesis of these com-
pounds using ionic liquid.
Initially, we performed the reaction of 2-aminobenzo-
thiazole 1 with phenyl isothiocyanate 2 in the presence
of 4-DMAP (5 mol %) in N,N-dimethyl formamide. The
reaction underwent smoothly at room temperature in 2 h
affording benzothiazoyl carbaimide 3a in 90% yield
(Scheme 1).
These results encouraged us to extend this process for
various substituted 2-aminobenzothiazoles and substi-
tuted phenyl isothiocyanates. Interestingly several 2-ami-
nobenzothiazoles reacted readily with different phenyl
isothiocyanates to produce corresponding benzothiazoyl
carbaimides. The reaction conditions are compatible
with various functionalities such as fluoro, chloro, and
ethyl ether (Table 1).
EXPERIMENTAL
General procedure for the synthesis of 1-(benzo[d]thia-
zol-2-yl)-3-phenylthiourea (3a). A mixture of 2-aminobenzo-
thiazole (1.50 g, 1 mmol), phenyl isothiocynate (1.35 g, 1
mmol), and dimethyl amino pyridine (5 mol %) in DMF (8
mL) was stirrer at room temperature for 2.0 h, and the pro-
gress of the reaction was followed by TLC. After completion
of the reaction, water (10 mL) was added to the reaction mix-
ture and extracted with ethyl acetate (2 ꢁ 15 mL). The organic
layer was separated and dried over anhydrous Na2SO4, and
solvent was removed under reduced pressure. The crude prod-
uct was purified by column chromatography (60–120 mesh)
using (ethyl acetate: n-hexane, 10:90) to obtain 3a (2.45 g,
86%) as a white powder.
Next, we examined the oxidative cyclization of ben-
zothiazoyl carbaimide using new tribromide-based ionic
liquid 1,3-di-n-butylimidazolium tribromide [bbim][Br3]
as a reagent of choice. 1,3-Di-n-butylimidazolium bro-
mide 4 on drop wise addition of molecular bromine
under stirring formed exothermally red liquid 1,3-di-n-
butylimidazolium tribromide 5 (Scheme 2). Excess of
bromine absorbed by 4 was completely removed under a
high vacuum. IL 5 can be stored for several months
without change of structure and loss of activity.
Subsequently, the reaction of benzothiazoyl carbai-
mide 3a was performed in 1,3-di-n-butylimidazolium tri-
bromide[bbim][Br3] (5). The reaction was sluggish at
room temperature. Surprisingly reaction proceeded well
at 70ꢀC giving N-bis-benzothiazole 6a exclusively in
89% yield (Scheme 3).
Preparation
of
1,3-di-n-butylimidazoliumtribromide
[bbim][Br3] (5). In a fume cupboard, molecular bromine (0.97
mL, 0.019 mol) was added drop wise over 10 min to 1,3-di-n-
butylimidazolium bromide (5.0 g, 0.019 mol) under stirring
and cooling in a ice-bath affording a deep red liquid IL (5),
and stirring was continued for 2 h. Under reduced pressure
over 5 h at 60ꢀC, 4.0 g (95.2 %) of the pure IL 5 was obtained
as red oil.
The structure of product 6a was determined on the
1
basis of H NMR spectrum. It shows only two doublets
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼ 1.00 (t, J ¼
7.31 Hz, 6H), 1.35–1.43 (m, 4H), 1.86–1.93 (m, 4H), 4.26 (t, J
¼ 7.31 Hz, 4H), 7.68 (s, 2H), 9.25 (s, 1H). 13C NMR (75
MHz, CDCl3 þ DMSO): d ¼ 12.34, 18.20, 30.87, 48.49,
121.46, 134.90. ESI-MS (m/z): 181 (M-X3); Anal. Calcd. For
C11H21Br3N2: C, 31.16; H, 5.70; N, 6.61. found: C, 31.31; H,
5.25; N, 6.64.
Procedure for the synthesis of N-bis-benzothiazole (6). A
mixture of benzothiazole carbamide (1 mmol) and 1,3-di-n-
butylimidazolium bromide (1 mL) was heated at 70ꢀC for 30
min, and the progress of the reaction was monitor by TLC.
and two triplets with same coupling constant (J ¼ 7.5
Hz), which are consistent with structure of 6a. Other
benzothiazoyl carbaimides also participated well in this
reaction. The scope of above reaction is illustrated with
respect to different functionalities, and the results are
summarized in Table 2.
It is interesting to mention that the oxidative cycliza-
tion of benzothiazoyl carbaimide in ionic liquid 5 is
chemoselective. It is known that the C2 hydrogen atom
of the 1,3-dialkylimidazolium cation ionic liquids (ILs)
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R. M. Kumbhare, T. Dadmal, U. Kosurkar, and K. Vijay Kumar
Vol 49
Table 1
DMAP catalysed synthesis of benzothiazoyl carbaimide.a
Entry
R1
H
R2
H
Productb (3)
Time (h)
3.0
Yieldc(%)
a
b
c
d
90
84
85
91
H
H
p-F
p-Cl
H
3.5
3.5
3.5
6-F
e
6-F
6-F
p-F
p-Cl
H
5.0
4.0
3.5
84
86
90
f
g
4-Cl
h
i
4-Cl
4-Cl
p-F
4.5
5.0
88
83
p-Cl
j
6-Me
6-Me
6-OEt
6-OEt
p-F
p-Cl
H
3.0
3.0
3.5
3.5
89
93
91
83
k
l
m
p-F
a Reaction was performed at 1 mmol scale.
b All the products were characterised by 1H NMR, IR, and mass spectroscopy.
c Yield refers to pure product after column chromatography.
Scheme 2. Preparation of 1,3-di-n-butylimidazolium tribromide [bbim]Br3.
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Benzothiazoyl Carbaimides: A Novel Approach toward the Synthesis of N-bis-benzothiazole Derivatives
Scheme 3. Synthesis of N-bis-benzothiazole.
Table 2
Chemoselective oxidative cyclization of thiourea using ionic liquid [bbim][Br3].a
Entry
a
Thiourea (3)
Productb (6)
Time (min)
30
Yieldc(%)
3a
89
82
86
83
b
c
d
3b
3c
3d
30
35
40
e
f
3e
3f
40
35
35
85
80
86
g
3g
h
i
3h
3i
40
35
84
80
j
3j
3k
3l
35
30
30
30
87
84
90
92
k
l
m
3m
a All reaction were run with 1 mmol of thiourea (3) in 1 mL ionic liquid [bbim][Br3] at 70ꢀC.
b All compounds showed satisfactory 1H NMR, IR, and mass spectral data.
c Isolated yield based on thiourea (3).
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R. M. Kumbhare, T. Dadmal, U. Kosurkar, and K. Vijay Kumar
Vol 49
(d, J ¼ 7.93 Hz, 2H). 13C NMR (75 MHz, CDCl3 þ DMSO):
d ¼ 106.50, 111.97, 113.38, 117.58, 123.32, 124.12, 124.69,
127.62, 137.95, 156.52, 161.90, 179.03. ESI-MS (m/z): 304
(MþH); Anal. Calcd. For C14H10FN3S2: C, 55.43; H, 3.32; N,
13.85. Found: C, 55.44; H, 3.30; N, 13.86.
Scheme 4. Plausible reaction mechanism of chemoselective oxidative
cyclization.
1-(6-Fluorobenzo[d]thiazol-2-yl)-3-(p-fluorophenyl) thiourea
(3e). White solid, mp 204–206ꢀC. IR (KBr) mmax ¼ 3167,
3017, 1567, 1532, 1506, 1459, 1250, 1195, 814, 686, 604
cmꢂ1
.
1H NMR (300MHz, CDCl3 þ DMSO): d ¼ 7.01–7.16
(m, 3H), 7.45 (d, J ¼ 7.93 Hz, 1H), 7.54–7.75 (m, 4H); 13C
NMR (75 MHz, CDCl3 þ DMSO): d ¼ 107.04, 113.21,
113.56, 114.30, 114.61, 125.53, 133.67, 148.81, 159.40,
160.80, 168.91, 179.73. ESI-MS (m/z): 322 (MþH); Anal.
Calcd. For C14H9F2N3S2: C, 52.32; H, 2.82; N, 13.08. Found:
C, 52.34; H, 2.80; N, 13.08.
1-(p-Chlorophenyl)-3-(6-fluorobenzo[d] thiazol-2-yl) thiourea
(3f). White solid, mp 203–205ꢀC. IR (KBr) mmax ¼ 3171, 3018,
1566, 1533, 1489, 1461, 1313, 1252, 1196, 1089, 1012, 823,
726 cmꢂ1
.
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼ 7.10
After completion of the reaction, chloroform was added in to
the reaction mixture and product got separated out. After filtra-
tion, the solid product was purified by recrystallization using
ethanol as a solvent to give the corresponding N-bis-benzothia-
zole derivatives. The chloroform filtrate was evaporated under
reduced pressure to give ionic liquid and recycles repeated for
three times.
(dt, J ¼ 8.68 and 2.45 Hz, 1H), 7.26 (d, J ¼ 8.68 Hz, 2H), 7.42
(dd, J ¼ 7.93 and 2.26 Hz, 1H), 7.45–7.54 (m, 2H), 7.66 (d, J ¼
8.68 Hz, 1H), 9.40 (s, 1H). 13C NMR (75 MHz, CDCl3
þ
DMSO): d ¼ 108.10, 114.15, 123.41, 125.96, 126.60, 126.81,
127.96, 129.35, 136.20, 146.15, 161.96, 174.12. ESI-MS (m/z):
338 (MþH); Anal. Calcd. For C14H9ClFN3S2: C, 49.77; H,
2.69; N, 12.44. Found: C, 49.85; H, 2.67; N, 12.46.
1-(Benzo[d]thiazol-2-yl)-3-phenylthiourea (3a). White solid,
mp 201–203ꢀC. IR (KBr) mmax ¼ 3154, 2986, 1565, 1516,
1-(4-Chlorobenzo[d]thiazol-2-yl)-3-phenylthiourea (3g). White
solid, mp 198–200ꢀC. IR (KBr) mmax ¼ 3163, 3015, 1566,
1
1441, 1369, 1256, 1183, 685, 641 cmꢂ1. H NMR (300 MHz,
1523, 1453, 1412, 1253, 1185, 733, 690, 644 cmꢂ1. H NMR
1
CDCl3 þ DMSO) d ¼ 7.17 (t, J ¼ 6.58 Hz, 1H), 7.24 (t, J ¼
(300 MHz, CDCl3 þ DMSO): d ¼ 7.20 (dt, J ¼ 7.93 and 2.07
Hz, 2H), 7.33–7.43 (m, 3H), 7.68 (t, J ¼ 8.30 Hz, 2H), 7.76
(d, J ¼ 7.93 Hz, 2H); 13C NMR (75 MHz, CDCl3 þ DMSO):
d ¼ 118.09, 118.74, 120.36, 121.01, 122.28, 123.22, 124.46,
125.09, 127.53, 131.20, 148.28, 166.62. ESI-MS (m/z): 320
(MþH); Anal. Calcd. For C14H10ClN3S2: C, 52.57; H, 3.15;
N, 13.14. Found: C, 52.67; H, 3.13; N, 13.17.
1-(4-Chlorobenzo[d]thiazol-2-yl)-3-(p-fluorophenyl) thiourea
(3h). White solid, mp 202–204ꢀC. IR (KBr) mmax ¼ 3273,
3048, 1639, 1537, 1452, 1413, 1303, 1270, 1105, 880, 724,
683, 605 cmꢂ1
7.40 Hz, 1H), 7.36 (t, J ¼ 7.40 Hz, 3H), 7.61 (s, 1H), 7.66–
7.76 (m, 4H), 11.97 (s, 1H). 13C NMR (75 MHz, CDCl3
þ
DMSO): d 118.74, 120.17, 122.45, 124.02, 125.04, 127.26,
130.15, 137.57, 145.66, 151.64, 157.82. ESI-MS (m/z): 286
(MþH); Anal. Calcd. For C14H11N3S2: C, 58.92; H, 3.89; N,
14.72. Found: C, 58.93; H, 3.85; N, 14.73.
1-(Benzo[d]thiazol-2-yl)-3-(p-fluorophenyl) thiourea (3b). White
solid, mp 194–196ꢀC. IR (KBr) mmax ¼ 3140, 2959, 1576, 1552,
1524, 1446, 1369, 1265, 1190, 828, 750, 696, 606 cmꢂ1 1H
.
NMR (300 MHz, CDCl3 þ DMSO): d ¼ 7.07 (t, J ¼ 8.05 Hz,
2H), 7.24 (t, J ¼ 7.16 Hz, 1H), 7.36 (t, J ¼ 7.16 Hz, 1H), 7.60
(s, 1H), 7.63–7.76 (m, 4H), 12.07 (s, 1H). 13C NMR (75 MHz,
CDCl3 þ DMSO): d ¼ 113.74, 114.03, 120.22, 122.47, 123.18,
124.67, 125.07, 133.77, 156.89, 160.19, 172.12, 178.45. ESI-
MS (m/z): 304 (MþH); Anal. Calcd. For C14H10FN3S2: C,
55.43; H, 3.32; N, 13.85. Found: C, 55.44; H, 3.30; N, 13.86.
1-(Benzo[d]thiazol-2-yl)-3-(p-chlorophenyl) thiourea (3c). White
solid, mp 193–194ꢀC. IR (KBr) mmax ¼ 3170, 3027, 1568,
1522, 1488, 1441, 1365, 1262, 1189, 1088, 1014, 755, 653
.
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼
6.92 (t, J ¼ 7.92 Hz, 1H), 7.19 (dd, J ¼ 7.93 and 0.94 Hz,
2H), 7.37–7.58 (m, 5H). 13C NMR (75 MHz, CDCl3
þ
DMSO): d 114.15, 114.45, 118.30, 120.65, 121.27, 124.71,
125.69, 125.81, 131.36, 148.41, 167.00. ESI-MS (m/z): 338
(MþH); Anal. Calcd. For C14H9ClFN3S2: C, 49.77; H, 2.69;
N, 12.44. Found: C, 49.85; H, 2.67; N, 12.46.
1-(4-Chlorobenzo[d]thiazol-2-yl)-3-(p-chlorophenyl) thiourea
(3i). White solid, mp 207–209ꢀC. IR (KBr) mmax ¼ 3166,
3016, 1565, 1524, 1491, 1455, 1411, 1258, 1188, 1091, 1017,
825, 684 cmꢂ1
7.21 (t, J ¼ 7.80 Hz, 1H), 7.34 (d, J ¼ 8.78 Hz, 2H), 7.40
(dd, J ¼ 7.80 and 0.97 Hz, 1H), 7.67 (d, J ¼ 7.80 Hz, 2H),
7.77 (dd, J ¼ 7.80 and 0.97 Hz, 2H), 12.17 (s, 1H). 13C NMR
(75 MHz, CDCl3 þ DMSO): d ¼ 118.87, 123.39, 123.69,
125.27, 126.78, 127.63, 136.12, 139.02, 144.94, 146.65,
158.07, 173.10. ESI-MS (m/z): 355 (MþH); Anal. Calcd. For
C14H9Cl2N3S2: C, 47.46; H, 2.56; N, 11.86. Found: C, 47.60;
H, 2.54; N, 11.90.
1
cmꢂ1. H NMR (300 MHz, CDCl3 þ DMSO): d ¼ 7.24 (t, J
¼ 7.74 Hz, 1H), 7.29–7.41 (m, 3H), 7.59 (d, J ¼ 7.55 Hz,
.
1H NMR (300MHz, CDCl3 þ DMSO): d ¼
1H), 7.65–7.77 (m, 4H). 13C NMR (75 MHz, CDCl3
þ
DMSO): d ¼ 118.90, 120.95, 121.15, 124.70, 125.30, 126.96,
127.84, 129.98, 136.10, 152.15, 172.84, 178.30. ESI-MS (m/z):
320 (MþH); Anal. Calcd. For C14H10ClN3S2: C, 52.57; H,
3.15; N, 13.14.found: C, 52.53; H, 3.12; N, 13.16.
1-(6-Fluorobenzo[d]thiazol-2-yl)-3-phenylthiourea (3d). White
solid, mp 196–198ꢀC. IR (KBr) mmax ¼ 3155, 3000, 1569,
1
1527, 1457, 1381, 1251, 1190, 854, 692, 637 cmꢂ1. H NMR
(300 MHz, CDCl3 þ DMSO): d ¼ 7.10 (dt, J ¼ 8.87 and 2.45
Hz, 1H), 7.20 (t, J ¼ 8.12 Hz, 1H), 7.37 (t, J ¼ 7.74 Hz, 2H),
7.43 (dd, J ¼ 8.12 and 2.07 Hz, 1H), 7.54–7.61 (m, 2H), 7.67
1-(p-Fluorophenyl)-3-(6-methylbenzo[d] thiazol-2-yl) thiourea
(3j). White solid, mp 186–188ꢀC. IR (KBr) mmax ¼ 3172,
3022, 1576, 1524, 1464, 1362, 1264, 1192, 810, 690, 605
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Benzothiazoyl Carbaimides: A Novel Approach toward the Synthesis of N-bis-benzothiazole Derivatives
cmꢂ1
.
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼ 2.45 (s,
120.92, 121.01, 123.80, 124.10, 125.10, 125.92, 128.74,
130.05, 141.30, 151.30, 173.80. ESI-MS (m/z): 318 (MþH);
Anal. Calcd. For C14H8ClN3S2: C, 52.91; H, 2.54; N, 13.22.
Found: C, 52.99; H, 2.52; N, 13.25.
N-(Benzo[d]thiazol-2-yl)-6-fluorobenzo[d] thiazol-2-amine
(6d), White solid, mp 269–271ꢀC. IR (KBr) mmax ¼ 3169,
3033, 1605, 1545, 1498, 1454, 1306, 1278, 1251, 1097, 846,
3H), 7.07 (t, J ¼ 8.49 Hz, 2H), 7.17 (d, J ¼ 8.68 Hz, 1H),
7.49 (s, 2H), 7.60–7.74 (m, 3H), 11.98 (s, 1H). 13C NMR (75
MHz, CDCl3 þ DMSO): d ¼ 19.82, 106.98, 112.09, 114.01,
115.38, 118.89, 119.73, 125.80, 130.68, 155.60, 157.92,
164.72, 170.23; ESI-MS (m/z): 318 (MþH); Anal. Calcd. For
C15H12FN3S2: C, 56.76; H, 3.81; N, 13.24. Found: C, 55.77;
H, 3.80; N, 13.25.
751, 614 cmꢂ1
.
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼
1-(p-Chlorophenyl)-3-(6-methylbenzo[d] thiazol-2-yl) thiourea
(3k). White solid, mp 180–182ꢀC. IR (KBr) mmax ¼ 3168,
3020, 1569, 1525, 1489, 1462, 1365, 1261, 1192, 1088, 1015,
7.08 (dt, J ¼ 8.87 and 2.45 Hz, 1H), 7.18 (t, J ¼ 7.36 Hz,
1H), 7.34 (t, J ¼ 7.17 Hz, 1H), 7.43 (dd, J ¼ 8.12 and 2.64
Hz, 1H), 7.54–7.71 (m, 3H). 13C NMR (75 MHz, CDCl3
þ
809, 711, 668 cmꢂ1; H NMR (300 MHz, CDCl3 þ DMSO):
DMSO): d ¼ 106.15, 112.98, 119.95, 122.84, 123.38, 124.10,
124.53, 125.10, 126.89, 135.10, 146.15, 155.76, 173.80. ESI-
MS (m/z): 302 (MþH); Anal. Calcd. For C14H8FN3S2: C,
55.80; H, 2.68; N, 13.94. Found: C, 55.81; H, 2.67; N, 13.95.
Bis(6-fluorobenzo[d]thiazol-2-yl)amine (6e), White solid,
mp 291–293ꢀC. IR (KBr) mmax ¼ 3166, 3067, 2943, 1610,
1
d ¼ 2.45 (s, 3H), 7.17 (d, J ¼ 8.30 Hz, 1H), 7.31 (d, J ¼ 8.49
Hz, 2H), 7.48 (s, 2H), 7.70 (d, J ¼ 8.49 Hz, 3H), 12.07 (s,
1H); 13C NMR (75 MHz, CDCl3 þ DMSO): d ¼ 19.80,
105.74, 113.96, 114.92, 118.68, 119.52, 124.97, 130.01,
156.48, 156.79, 163.90, 169.84. ESI-MS (m/z): 334 (MþH);
Anal. Calcd. For C15H12ClN3S2: C, 53.96; H, 3.62; N, 12.59.
Found: C, 54.05; H, 3.61; N, 12.61.
1549, 1456, 1305, 1252, 1195, 849, 650 cmꢂ1. H NMR (300
1
MHz, CDCl3 þ DMSO): d ¼ 7.08 (dt, J ¼ 8.95 and 2.68 Hz,
2H), 7.43 (dd, J ¼ 8.05 and 1.79 Hz, 2H), 7.58 (dd, J ¼ 8.95
and 4.47 Hz, 2H), 12.41 (s, 1H). 13C NMR (75 MHz, CDCl3
þ DMSO): d ¼ 108.10, 113.05, 124.68, 130.10, 148.74,
158.93, 172.78. ESI-MS (m/z): 320 (MþH); Anal. Calcd. For
C14H7F2N3S2: C, 52.65; H, 2.21; N, 13.16. Found: C, 52.66;
H, 2.19; N, 13.17.
1-(6-Ethoxybenzo[d]thiazol-2-yl)-3-phenylthiourea (3l). White
solid, mp 168–170ꢀC. IR (KBr) mmax ¼ 3191, 3029, 1556,
1527, 1493, 1461, 1384, 1343, 1257, 1194, 1061, 696, 640
cmꢂ1. H NMR (300 MHz, CDCl3 þ DMSO): d ¼ 1.44 (t, J
1
¼ 6.98 Hz, 3H), 4.06 (q, J ¼ 6.98 Hz, 2H), 6.93 (dd, J ¼ 8.87
and 2.45 Hz, 1H), 7.15 (s, 1H), 7.31 (t, J ¼ 7.93 Hz, 2H),
7.38 (d, J ¼ 7.74 Hz, 1H), 7.45–7.57 (m, 3H), 7.68 (d, J ¼
N-(6-Chlorobenzo[d]thiazol-2-yl)-6-fluorobenzo[d]thiazol-2-
¼
7.93 Hz, 1H), 9.08 (s, 1H). 13C NMR (75 MHz, CDCl3
þ
amine (6f), White solid, mp 295–297ꢀC. IR (KBr) mmax
3210, 3072, 2926, 1606, 1541, 1489, 1450, 1309, 1250, 1197,
DMSO): d ¼ 13.70, 62.86, 104.29, 113.98, 123.10, 123.90,
127.46, 137.62, 137.97, 149.48, 154.79, 168.48, 170.67,
178.90. ESI-MS (m/z): 330 (MþH); Anal. Calcd. For
C16H15N3OS2: C, 58.33; H, 4.59; N, 12.76. Found: C, 58.35;
H, 4.57; N, 12.76.
1-(6-Ethoxybenzo[d]thiazol-2-yl)-3-(p-fluorophenyl) thiourea
(3m). White solid, mp 173–175ꢀC. IR (KBr) mmax ¼ 3174,
3023, 2970, 2926, 1566, 1533, 1505, 1459, 1260, 1206, 1060,
815, 680, 607 cmꢂ1. H NMR (300 MHz, CDCl3 þ DMSO): d
1097, 854, 807, 730, 618 cmꢂ1 1H NMR (300 MHz, CDCl3
.
þ DMSO): d ¼ 7.10 (dt, J ¼ 9.25 and 1.88 Hz, 1H), 7.31 (dd,
J ¼ 8.68 and 1.70 Hz, 1H), 7.45 (d, J ¼ 7.55 Hz, 1H), 7.56
(dd, J ¼ 8.68 and 1.70 Hz, 2H), 7.67–7.81 (m, 1H), 12.53 (s,
1H). 13C NMR (75 MHz, CDCl3 þ DMSO): d ¼ 107.73,
112.98, 123.58, 124.96, 125.12, 125.83, 126.43, 128.14,
130.30, 143.10, 144.70, 157.15, 172.25. ESI-MS (m/z): 336
(MþH); Anal. Calcd. For C14H7ClFN3S2: C, 50.07; H, 2.10;
N, 12.51. Found: C, 50.15; H, 2.09; N, 12.54.
1
¼ 1.40 (t, J ¼ 7.16 Hz, 3H), 4.03 (q, J ¼ 7.16 Hz, 2H), 6.90
(dd, J ¼ 8.95 and 2.68 Hz, 1H), 7.04 (t, J ¼ 8.05 Hz, 2H),
7.19 (s, 1H), 7.47 (s, 1H), 7.60–7.66 (m, 2H), 7.80–7.85 (m,
1H), 11.85 (s, 1H). 13C NMR (75 MHz, CDCl3 þ DMSO): d
¼ 14.54, 63.85, 105.13, 114.91, 122.45, 125.43, 125.56,
128.47, 128.56, 129.90, 135.28, 155.61, 162.86, 171.73. ESI-
MS (m/z): 348 (MþH); Anal. Calcd. For C16H14FN3OS2: C,
55.31; H, 4.06; N, 12.09. Found: C, 55.32; H, 4.05; N, 12.10.
Di(benzo[d]thiazol-2-yl)amine (6a). White solid, mp 246–
248ꢀC. IR (KBr) mmax ¼ 3030, 2925, 1601, 1541, 1489, 1438,
N-(Benzo[d]thiazol-2-yl)-4-chlorobenzo[d] thiazol-2-amine
(6g), White solid, mp 172–174ꢀC. IR (KBr) mmax ¼ 3159,
2929, 1678, 1610, 1575, 1520, 1491, 1436, 1265, 1191, 896,
1
840, 748, 654 cmꢂ1. H NMR (300 MHz, CDCl3 þ DMSO): d
¼ 7.08–7.26 (m, 2H), 7.32–7.42 (m, 2H), 7.44–7.55 (m, 1H),
7.63–7.76 (m, 2H), 12.74 (s, 1H); 13C NMR (75 MHz, CDCl3
þ DMSO): d ¼ 117.94, 119.10, 120.48, 122.03, 122.26,
123.10, 124.27, 127.43, 128.10, 130.30, 144.80, 147.10, 171.98.
ESI-MS (m/z): 318 (MþH); Anal. Calcd. For C14H8ClN3S2 C,
52.91; H, 2.54; N, 13.22. Found: C, 52.99; H, 2.52; N, 13.25.
4-Chloro-N-(6-fluorobenzo[d]thiazol-2-yl)benzo[d]thiazol-2-
1280, 1170, 930, 886, 805, 749, 684 cmꢂ1 1H NMR (300
.
MHz, CDCl3 þ DMSO): d ¼ 7.18 (t, J ¼ 7.55 Hz, 2H), 7.34
(t, J ¼ 7.55 Hz, 2H), 7.60 (d, J ¼ 7.55 Hz, 2H), 7.70 (d, J ¼
amine (6h), White solid, mp 184–186ꢀC. IR (KBr) mmax
3215, 3084, 2932, 1609, 1545, 1492, 1454, 1402, 1318, 1252,
1201, 1099, 1015, 861, 809, 738, 623 cmꢂ1 1H NMR
¼
7.55 Hz, 2H), 12.54 (s, 1H). 13C NMR (75 MHz, CDCl3
þ
DMSO): d ¼ 117.32, 120.42, 121.96, 125.17, 128.16, 146.98,
172.69. ESI-MS (m/z): 284 (MþH); Anal. Calcd. For
C14H9N3S2: C, 59.34; H, 3.20; N, 14.83. Found: C, 59.36; H,
3.18; N, 14.84.
N-(6-Chlorobenzo[d]thiazol-2-yl)benzo[d] thiazol-2-amine
(6c), White solid, mp 205–207ꢀC. IR (KBr) mmax ¼ 3162,
2927, 1681, 1590, 1570, 1522, 1488, 1439, 1261, 1189, 1014,
893, 835, 753, 652 cmꢂ1
DMSO): d ¼ 7.24 (t, J ¼ 7.93 Hz, 1H), 7.29–7.41 (m, 3H),
7.58 (s, 1H), 7.69 (d, J ¼ 8.68 Hz, 2H), 12.01 (s, 1H). 13C
NMR (75 MHz, CDCl3 þ DMSO): d ¼ 118.30, 119.98,
.
(300MHz, CDCl3 þ DMSO): d ¼ 6.92 (t, J ¼ 7.93 Hz, 1H),
7.19 (dd, J ¼ 7.93 and 0.75 Hz, 1H), 7.35–7.51 (m, 4H), 7.61
(s, 1H). 13C NMR (75 MHz, CDCl3 þ DMSO): d ¼ 109.10,
112.96, 119.53, 121.15, 121.68, 122.29, 123.73, 124.93,
125.30, 130.93, 143.97, 147.81, 174.30. ESI-MS (m/z): 336
(MþH); Anal. Calcd. for C14H7ClFN3S2: C, 50.07; H, 2.10; N,
12.51. Found: C, 50.15; H, 2.09; N, 12.54.
.
1H NMR (300 MHz, CDCl3
þ
N-(6-Fluorobenzo[d]thiazol-2-yl)-6-methylbenzo[d]thiazol-2-
¼
amine (6j). White solid, mp 209–211ꢀC. IR (KBr) mmax
3133, 1609, 1562, 1500, 1454, 1401, 1303, 1276, 1251, 1194,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

348
R. M. Kumbhare, T. Dadmal, U. Kosurkar, and K. Vijay Kumar
Vol 49
1
1115, 867, 839, 808, 617 cmꢂ1. H NMR (300 MHz, CDCl3 þ
DMSO): d ¼ 2.44 (s, 3H), 7.08 (dt, J ¼ 8.87 and 2.45 Hz, 1H),
7.15 (dd, J ¼ 8.30 and 1.13 Hz, 1H), 7.39–7.51 (m, 2H), 7.60 (dd, J
¼ 8.68 and 4.72 Hz, 1H), 7.75–7.83 (m, 1H). 13C NMR (75 MHz,
CDCl3 þ DMSO): d ¼ 19.47, 106.2, 106.46, 111.95, 112.18,
113.92, 115.33, 119.76, 125.76, 130.79, 155.56, 157.94, 164.70.
ESI-MS (m/z): 316 (MþH); Anal. Calcd. for C15H10FN3S2: C,
57.12; H, 3.20; N, 13.32. Found: C, 57.14; H, 3.17; N, 13.33.
N-(6-Chlorobenzo[d]thiazol-2-yl)-6-methylbenzo[d]thiazol-2-
[2] Duggan, P. J.; Lewis, R. J.; Lok, Y. P.; Lumsden, N. G.;
Tuck, K. L.; Yang, A. Biomed Chem Lett 2009, 19, 2763.
[3] Kashiyama, E.; Hutchinson, L.; Chua, M.; Stinson, S. F.;
Phillips, L. R.; Kaur, G.; Sau sville, E. A.; Bradshaw, T. D.; Westwell,
A. D.; Stevens, M. F. G. J Med Chem 1999, 42, 4172.
[4] Hutchinson, B. I.; Jenning, S. A.; Vishnuvajala, B. R.;
Westwell, A. W.; Stevens, M. F. G. J Med Chem 2002, 45, 744–748.
[5] Chavan, A. A.; Pai, N. R. Arkivoc 2007, xvi, 148.
[6] Monasterious, C. J.; Dominguez, M. J.; Castro, N. D. Hetro-
cycl Comm 2002, 8, 275.
amine (6k). White solid, mp 207–209ꢀC. IR (KBr) mmax
3164, 2923, 2848, 1687, 1601, 1548, 1497, 1441, 1309, 1274,
1165, 1011, 898, 841, 746, 683 cmꢂ1 1H NMR (300 MHz,
¼
[7] Gurupadayya, B. M.; Manohara, Y. N.; Gopal, M. Indian J
Hetrocycl Chem 2005, 15, 1136.
.
[8] Chunying, W.; Jingjun, W.; Kuanqiang, G.; Yanming, W.
Bioorg Med Chem 2007, 15, 2789.
CDCl3 þ DMSO): d ¼ 2.45 (s, 3H), 7.14 (d, J ¼ 9.25 Hz,
1H), 7.29 (dd, J ¼ 8.49 and 2.07 Hz, 1H), 7.43–7.51 (m, 2H),
7.57 ( d, J ¼ 8.49 Hz 1H), 7.67 (s, 1H). 13C NMR (75 MHz,
CDCl3 þ DMSO): d ¼ 19.46, 106.10, 115.38, 117.93, 120.25,
121.93, 123.63, 124.73, 125.84, 130.15, 143.24, 144.15, 170.94.
ESI-MS (m/z): 332 (MþH); Anal. Calcd. for C15H10ClN3S2: C,
54.29; H, 3.04; N, 12.66. Found: C, 54.38; H, 3.02; N, 12.69.
N-(Benzo[d]thiazol-2-yl)-6-ethoxybenzo[d] thiazol-2-amine
(6l). White solid, mp 191–193ꢀC. IR (KBr) mmax ¼ 3448,
2967, 2920, 2852, 1601, 1562, 1502, 1457, 1260, 1219, 1060,
¨
[9] Cakir, B.; Uc¸ucu, U.; Buyukbingol, E.; Abbasoglu, U.;
Noyanalpan, N. Gazi Universitesi Eczacilik Fakultesi Dergisi 1987, 4,
143.
[10] Monsanto Co. Brit. Pat. 1,106,577, 1968; Chem.Abstr.
1968, 68, 96660t.
[11] (a) Theodor, P. U. S. Pat. 4,369,323; 1983; (b) Bondock,
W.; Fadaly, W.; Metwally, M. A. J Sulfur Chem 2009, 30, 74.
[12] (a) Neville, R. G.; McGee, J. J. Can J Chem 1963, 41,
2123; (b) Sridevi, G.; Rao, J.; Reddy, K. K. Synth Commun 1989, 19,
965; (c) McKay, A. F.; Garmaise, D. L.; Gaudry, R.; Baker, H. A.;
Paris, G. Y.; Kay, R. W.; Just, G. E.; Schwartz, R. J Am Chem Soc
1955, 81, 4328.
924, 742, 620 cmꢂ1. H NMR (300 MHz, CDCl3 þ DMSO):
1
d ¼ 1.44 (t, J ¼ 6.98 Hz, 3H), 4.06 (q, J ¼ 6.98 Hz, 2H),
6.91 (dd, J ¼ 8.87 and 2.45 Hz, 1H), 7.13–7.23 (m, 2H), 7.33
(t, J ¼ 7.17 Hz 1H), 7.48–7.60 (m, 2H), 7.67 (d, J ¼ 7.55 Hz,
1H). 13C NMR (75 MHz, CDCl3 þ DMSO): d ¼ 14.03, 63.17,
104.93, 113.79, 116.90, 118.49, 120.47, 121.86, 125.22,
128.76, 131.26, 147.48, 154.44, 170.16, 174.56. ESI-MS (m/z):
328 (MþH); Anal. Calcd. for C16H13N3OS2: C, 58.69; H,
4.00; N, 12.83. Found: C, 58.71; H, 3.98; N, 12.84.
[13] Garin, J.; Melendez, E.; Merchan, F. L.; Merino, P.;
Orduna, J.; Tejero, T. Synth Commun 1990, 20, 2327.
[14] Kink, S.; Kin, Y. C.; Lee, J. I. Tetrahedron Lett 1983, 24,
3365.
[15] (a) Aggarwal, V. K.; Mereu, A. Chem Commun 1999,
2311; (b) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett 1998, 39,
5965.
6-Ethoxy-N-(6-fluorobenzo[d]thiazol-2-yl)benzo[d]thiazol-2-
¼
[16] (a) Paquette, L. A.; Earle, M. J.; Smith, G. F. Org Synth
1996, 73, 36; (b) Paquette, L. A.; Heidelbaugh, T. M. Org Synth 1996,
73, 44.
amine (6m). White solid, mp 192–194ꢀC. IR (KBr) mmax
3173, 2926, 1705, 1605, 1550, 1453, 1393, 1260, 1216, 1055,
808, 652 cmꢂ1
.
1H NMR (300 MHz, CDCl3 þ DMSO): d ¼
[17] (a) Steglich, W.; Hofle, G. Tetrahedron Lett 1970, 4727; (b)
Hofle, G.; Steglich, W.; Vorbruggen, H. Angew Chem Int Ed Engl
1978, 17, 569; (c) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahe-
dron 1978, 34, 2069; (d) Scriven, E. F. V. Chem Soc Rev 1983, 12,
129.
1.44 (t, J ¼ 7.16 Hz, 3H), 4.05 (q, J ¼ 7.16 Hz, 2H), 6.90
(dd, J ¼ 8.95 and 2.68 Hz, 1H), 7.02–7.10 (m, 2H), 7.16 (s,
1H), 7.39 (dd, J ¼ 8.05 and 2.68 Hz, 1H), 7.47–7.52 (m, 1H),
12.05 (s, 1H). 13C NMR (75 MHz, CDCl3 þ DMSO): d ¼
14.63, 63.58, 106.34, 108.25, 116.93, 121.95, 122.38, 123.27,
123.83, 124.15, 124.67, 145.30, 146.15, 158.70, 173.63. ESI-
MS (m/z): 346 (MþH); Anal. Calcd. for C16H12FN3OS2: C,
55.63; H, 3.50; N, 12.17. Found: C, 55.65; H, 3.48; N, 12.17.
[18] (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Curr Med Chem 2004, 11, 1837; (b) Palomo, C.; Aizpurua, J. M.;
Ganboa, I.; Oiarbide, M. Eur J Org Chem 1999, 3223; (c) Georg, G.
ˆ
I.; Ravikumar, V. T. In The Organic Chemistry of a-Lactams; Georg,
G. I., Ed.; VCH: New York, 1993; p 295.
[19] (a) Berry, D. J.; DiGiovanna, C. V.; Metrick, S. S.; Muru-
gan, R. Arkivoc 2001, i, 201; (b) Wurz, R. P. Chem Rev 2007, 107,
5570.
Acknowledgments. The authors are thankful to Dr. J. S. Yadav,
Director, IICT for providing facilities. T.D. thanks UGC, U.K.
thanks CSIR, New Dellhi, for the award of a fellowship, and
R.M.K thanks S.E.R.C., Department of Science & Technology,
Government of India, for financial assistance under the Fast
Track Scheme for young scientists (SR/FTP/CS-93/2006).
[20] Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta,
N.; Bonacorso, H. G. Chem Rev 2008, 108, 2015.
[21] Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2003.
[22] (a) Kumbhare, R. M.; Ingle, V. N. Asian J Chem 2000, 12,
1317; (b) Kumbhare, R. M.; Ingle, V. N. Indian J Chem B 2009, 48,
996.
REFERENCES AND NOTES
[1] Amnerkar, N. D.; Bhusari, K. P. Eur J Med Chem 2010,
45, 149.
[23] (a) Headley, A. D.; Jackson, N. M. J Phys Org Chem 2002,
15, 52; (b) Dupont, J. J. Braz Chem Soc 2004, 15, 341.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet