Iron-catalyzed one-pot synthesis of 2-aminobenzothiazoles from 2-aminobenzethiols and isothiocyanates under ligand-free conditions in water

Article abstract of DOI:10.3987/COM-10-12051

A practical and efficient method for the synthesis of 2-aminobenzothiazoles has been developed via an iron-catalyzed one-pot tandem reaction. Various 2-aminobenzothiazoles were conveniently synthesized in moderate to excellent yields. It is highlighted that the reaction is conducted under ligand-free conditions in water. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12051

HETEROCYCLES, Vol. 81, No. 12, 2010
2841
HETEROCYCLES, Vol. 81, No. 12, 2010, pp. 2841 - 2847. © The Japan Institute of Heterocyclic Chemistry
Received, 21st August, 2010, Accepted, 1st October, 2010, Published online, 4th October, 2010
DOI: 10.3987/COM-10-12051
IRON-CATALYZED
ONE-POT
SYNTHESIS
OF
2-AMINOBENZOTHIAZOLES FROM 2-AMINOBENZETHIOLS AND
ISOTHIOCYANATES UNDER LIGAND-FREE CONDITIONS IN WATER
Wenying Wang,a Wenying Zhong,a Runxia Zhou,a Jinsheng Yu,a Juan Dai,a
Qiuping Ding,*, a, b and Yiyuan Peng*, b
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99
Ziyang Road, Nanchang 330022, China, E-mail:dqpjxnu@gmail.com
b
Key Laboratory of Green Chemistry of Jiangxi Province, 99 Ziyang Road,
Nanchang 330022, China
Abstract – A practical and efficient method for the synthesis of
2-aminobenzothiazoles has been developed via an iron-catalyzed one-pot tandem
reaction. Various 2-aminobenzothiazoles were conveniently synthesized in
moderate to excellent yields. It is highlighted that the reaction is conducted under
ligand-free conditions in water.
2-Aminobenzothiazole derivatives are an important class of common heterocyclic compounds that exhibit
a wide range of biological activities and medicinal properties. Some 2-aminobenzothiazoles are potential
drugs for tuberculosis,1 epilepsy,2 diabetes,3 antitumor (e.g. R116010),4 and glutamate (e.g. Riluzole).5
Due to the importance of 2-aminobenzothiazoles, many synthetic methods have been reported over the
last decade. The transition metal-catalyzed intramolecular cyclization of 2-bromophenylthioureas is one
6
of the most efficient methods. One-pot strategies for the synthesis of various useful heterocyclic
compounds have been received much attention because of their more convenient manipulations and good
efficiencies during the past decade. Recently, 2-aminobenzothiazoles as a significant N- and
S-heterocyclic compounds have been reported via one-pot strategies.7 Among the strategies, we described
a novel and efficient via Cu(I)-catalyzed one-pot tandem intermolecular addition-intramolecular
cyclization reactions to prepare 2-aminobenzothiazole derivatives.7a Subsequently, FeF3 or

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HETEROCYCLES, Vol. 81, No. 12, 2010
CuBr-catalyzed one-pot tandem methods were reported by Li and co-workers.7b and 7c Although powerful
methods to prepare 2-aminobenzothiazoles have been emerged, the transition metal combined with a
ligand and using organic solvent were essential to obtain good result.6,7 From environmental points of
view, the development of a cheap and efficient catalyst under ligand-free conditions in aqueous medium
is still desirable. As a part of our continuing interest in the use of transition metal-catalyzed one-pot
multicomponent tandem cyclization for benz-fused heterocycle synthesis,8 herein we report the successful
realization the synthesis of 2-aminobenzothiazoles using ligand-free iron-catalyzed one-pot tandem
strategy in water. To the best of our knowledge, there is no report about the formation of
2-aminobenzothiazoles via one-pot iron-catalyzed coupling process under ligand-free conditions in water.
Although we recently reported a very efficient method for the synthesis of such compounds via
FeCl3-catalyzed tandem reaction of 2-iodoaniline with isothiocyanate in water, 1,10-phenanthroline as
ligand was essential to obtain a good result. 8a
Preliminary studies were performed by treatment of 2-aminobenzenethiol 1a and phenyl isothiocyanate
2a in water in the presence of a catalytic amount of various Fe or Cu catalysts (Table 1). To our
delight, we found that the desired product 3a could be afforded in 70% yield when Fe2(SO4)3·H2O (10
mol%) was utilized as catalyst under ligand- and base-free conditions (Table 1, entry 1). Blank
experiment showed that Fe2(SO4)3·H2O was essential to obtain good result (Table 1, entry 2), although
Pazdera reported the similar reaction in organic solvent without catalyst in moderate to good yield.9 The
yield (86%) was greatly enhanced in the presence of Na2CO3 (Table 1, entry 3). Several other bases were
examined meanwhile, and Na2CO3 showed as the best one. Subsequently, five other Fe salts
[Fe(NO3)3·9H2O, FeSO4·7H2O, Fe(NH4)2(SO4)2·H2O, FeCl3 and FeS] and four Cu salts (CuI, CuCl, CuBr,
CuO) catalysts were evaluated, and the results showed that Fe(NO3)3·9H2O was the best choice (Table 1,
entry 9). Further investigation showed that sodium dodecylbenzenesulfonate (SDBS) as an additive
(phase-transfer catalysts) can improve the yield (96%) of product to some extent (Table 1, entry 18).
Therefore, the optimized conditions were to use a combination of Fe(NO3)3·9H2O (10 mol%) and SDBS
(20 mol%) in the presence of Na2CO3 as base in water at 80 C.
Table 1. Condition screening for Fe- or Cu-catalyzed tandem reaction of 2-aminobenzenethiol 1a with
phenyl isothiocyanate 2a in watera
Cat. (10 mol %)
NH2
SH
NCS
N
S
PTC (20 mol%)
NHPh
+
base, H2O, 80 C
3a
2a
1a

HETEROCYCLES, Vol. 81, No. 12, 2010
2843
Entry Catalyst
Base
-
-
Na2CO3
K2CO3
NaHCO3
DBU
PTC
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Yieldb (%)
70
1
Fe2(SO4)3·H2O
2
-
55c
86
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19e
20
21
22
23
24
Fe2(SO4)3·H2O
Fe2(SO4)3·H2O
Fe2(SO4)3·H2O
Fe2(SO4)3·H2O
Fe2(SO4)3·H2O
Fe2(SO4)3·H2O
Fe(NO3)3·9H2O
FeSO4·7H2O
Fe(NH4)2(SO4)2·H2O Na2CO3
FeCl3
FeS
CuCl
CuBr
CuI
Cu2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
70
78
52
83
78
89
88
78
63
68
70
83
87
86
96
76
Et3N
DABCO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
-
-
PTC1d
PTC1d
PTC2d
PTC3d
PTC4d
PTC5d
90
80
93
92
PEG-400 trace
a) Reaction conditions: 2-aminobenzenethiol 1a (0.3 mmol), phenyl isothiocyanate 2a (1.2 equiv), Cat.
(10 mol%), base (2.0 equiv), PTC (phase-transfer catalysis, 20 mol %), H2O (3 mL), 80 C, overnight. b)
Isolated yield based on 2-aminobenzenethiol 1a. c) 72 h. d) PTC1: sodium dodecylbenzenesulfonate
(SDBS), PTC2: hexadecyldimethylbenzylammonium chloride, PTC3: tetrabutylammonium bromide
(TBAB), PTC4: octadecyltrimethylammonium chloride, PTC5: sodium dodecylsulfonate. e) rt, 48 h.
The scope of the process was studied under the optimized reaction conditions. From Table 2, for most
cases, the transformation proceeded smoothly with a wide range of isothiocyanates and
2-aminobenzenethiols leading to the corresponding products 3 in moderate to good yields. As expected,
the reaction of 2-aminobenzenethiol 1a and 4-nitrophenyl isothiocyanate 2b gave rise to the desired
product 3b in 84% yield (Table 2, entry 2). Similar or better yield was generated when 4-fluorophenyl
isothiocyanate 2c or 4-chlorophenyl isothiocyanate 2d was used as a partner in the reaction (Table 2,
entries 3 and 4). 4-Methylphenyl isothiocyanate 2e also furnished the corresponding product in good
yield using 2-aminobenzethiol 1a (Table 2, entry 5). To our delight, alkyl isothiocyanate was also good
substrate for this one-pot tandem reaction in moderate yield (Table 2, entry 6). Methoxy-, bromo- or
iodo-substituted 2-aminobenzenethiols 1b, 1c and 1d were examined meanwhile, and the desired products
were obtained in moderate to excellent yields (Table 2, entries 7-12).

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HETEROCYCLES, Vol. 81, No. 12, 2010
Table 2. Fe(NO3)3·9H2O-catalyzed one-pot tandem reaction of 2-aminobenzenethiol 1 with
isothiocyanate 2a
Fe(NO3)3 9H2O (10 mol %)
NH2
N
SDBS (20 mol%)
NHR2
+ R2 NCS
Na2CO3, H2O, 80 C
R1
SH
R1
S
1
2
3
Entry
1/R1
2/R2
Yield of
Entry
1/R1
2/R2
Yield
3 (%)b
3a, 96
3b, 84
3c, 70
3d, 91
3e, 75
3f, 65
of 3 (%)b
1
2
3
4
5
6
1a/H
1a/H
1a/H
1a/H
1a/H
1a/H
2a/C6H5
7
1b/OMe
1b/OMe
1b/OMe
1c/Br
2a/C6H5
3g, 94
2b/4-NO2C6H4
2c/4-FC6H4
8
2e/4-MeC6H4 3h, 77
2d/4-ClC6H4 3i, 72
2e/4-MeC6H4 3j, 57
9
2d/4-ClC6H4
2e /4-MeC6H4
2f/Cyclohex.
10
11
12
1d/I
2a/C6H5
3k, 65
3l, 80
1d/I
2d/4-ClC6H4
a) Reaction conditions: 2-aminobenzenethiol 1 (0.3 mmol), isothiocyanate 2 (1.2 equiv), Fe(NO3)3·9H2O
(10 mol %), Na2CO3 (2.0 equiv.), SDBS (20 mol %), H2O (3 mL), 80 C. b) Isolated yield based on
2-aminobenzenethiol 1
In conclusion, we have described a practical and efficient route for generation of diverse
2-aminobenzothiazoles via Fe(NO3)3·9H2O-catalyzed one-pot tandem addition/cyclization reaction of
2-aminobenzenethiol and isothiocyanate. It is noteworthy that the reaction is conducted under ligand-free
conditions in water. We believe that this methodology may become a very useful tool in organic
synthesis.
EXPERIMENTAL
General procedure for Fe(NO3)3·9H2O-catalyzed one-pot tandem reaction of 2-aminobenzenethiol 1 with
isothiocyanate 2: A mixture of 2-aminobenzenethiol 1 (0.30 mmol), isothiocyanate 2 (0.36 mmol, 1.2
equiv.), Na2CO3 (0.6 mmol, 2.0 equiv.), Fe(NO3)3·9H2O (0.03 mmol, 10 mol%), SDBS (0.06 mmol, 20
mol%) was stirred in water (3.0 mL) at 80 C under air. After completion of the reaction as indicated by
TLC, the reaction mixture was cooled in ice bath. The solid was filtered off and washed with saturated
brine, then washed with water, and dried under vacuum. Then the solid was washed with petroleum ether,
and the product 3 was obtained in almost pure form (except for 3b needing to pass through a small plug
of silica).

HETEROCYCLES, Vol. 81, No. 12, 2010
2845
o
1
N-Phenylbenzo[d]thiazol-2-amine (3a),7a white solid, mp 158-160 C; H NMR (400 MHz, CDCl3) δ
7.13-7.19 (m, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 HZ, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.56 (d, J =
8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1Hz), 9.0 (br, 1H); 13 C NMR (100 MHz, CDCl3) δ 118.7, 119.9, 120.3,
121.9, 123.9, 125.6, 129.1, 129.3, 129.5, 150.7, 164.5.
o
1
N-(4-Nitrophenyl)benzo[d]thiazol-2-amine (3b),7a yellow solid, mp 230-231 C; H NMR (400 MHz,
DMSO-d6) δ 7.24 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6
13
Hz, 1H), 8.10 (d, J = 9.2 Hz, 2H), 8.27 (d, J = 9.2 Hz, 2H), 11.2 (br, 1H); C NMR (100 MHz,
DMSO-d6) δ 117.6, 120.5, 121.9, 123.7, 125.9, 126.7, 130.8, 141.4, 146.9, 152.0, 161.2.
o
1
N-(4-Fluorophenyl)benzo[d]thiazol-2-amine (3c),8a white solid, mp 216-217 C; H NMR (400 MHz,
DMSO-d6) δ 7.14 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 8.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0
13
2
Hz, 1H), 7.77-7.82 (m, 3H), 10.52 (br, 1H); C NMR (100 MHz, DMSO-d6) δ 116.0 (d, J CF = 22 Hz),
119.7 (d, 2J CF = 18 Hz), 119.8, 121.5, 122.8, 126.3, 130.3, 137.4, 152.4, 157.9 (d, 1J CF = 237 Hz), 162.0.
o
1
N-(4-Chlorophenyl)benzo[d]thiazol-2-amine (3d),8a white solid, mp 208-209 C; H NMR (400 MHz,
DMSO-d6) δ 7.19 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.0
13
Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, DMSO-d6) δ 119.1, 119.3, 121.0, 122.4, 125.4,
125.9, 128.8, 129.9, 139.5, 151.9, 162.2.
o
1
N-p-Tolylbenzo[d]thiazol-2-amine (3e),8a white solid, mp 178-179 C; H NMR (400 MHz, CDCl3) δ
2.37 (s, 3H), 7.13 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4
13
Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 20.9, 119.1,
120.8, 121.2, 122.1, 126.0, 129.8, 130.1, 134.6, 137.4, 151.5, 165.9.
N-Cyclohexylbenzo[d]thiazol-2-amine (3f) 1H NMR (400 MHz, CDCl3) δ 1.18-1.45 (m, 5H), 1.61-1.77
(m, 3H), 2.11-2.13 (m, 3H), 3.5 (br, 1H), 5.79 (br, 1H), 7.05 (t, J = 7.2 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H),
7.52 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.8, 25.4, 33.2, 54.6,
118.6, 120.7, 121.2, 125.8, 130.3, 152.4, 166.9; HRMS Calcd for C13H17N2S [M+H]+: 233.1112. Found:
233.19.
o
1
6-Methoxy-N-phenylbenzo[d]thiazol-2-amine (3g) white solid, mp 131-132 C; H NMR (400 MHz,
CDCl3) δ 3.80 (s, 3H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H),
13
7.35 ( t, J = 8.0 Hz, 2H), 7.44 (s, 1H), 7.47 (t, J = 8.8 Hz, 2H), 8.40 (br, 1H); C NMR (100 MHz,
CDCl3) δ 55.9, 105.3, 114.0, 119.9,120.0, 123.9, 129.4, 131.1, 140.2, 145.8, 155.9, 162.6; HRMS Calcd
for C14H13N2OS [M+H]+: 257.0749. Found: 257.0739.
o
1
6-Methoxy-N-p-tolylbenzo[d]thiazol-2-amine (3h) white solid, mp 164-165 C; H NMR (400 MHz,
CDCl3) δ 2.34 (s, 3H), 3.80 (s, 3H), 6.90 (dd, J = 2.4, 8.8 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 7.17 (d, J =
13
8.4 Hz, 2H), 7.33 ( d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 8.35 (br, 1H); C NMR (100 MHz,

2846
HETEROCYCLES, Vol. 81, No. 12, 2010
CDCl3) δ 20.2, 55.4, 104.8, 113.3, 119.2, 120.1, 129.5, 130.6, 133.5, 137.1, 145.4, 155.2, 162.9; HRMS
Calcd for C15H15N2OS [M+H]+: 271.0905. Found: 271.0909.
o
1
N-(4-Chlorophenyl)-6-methoxybenzo[d]thiazol-2-amine (3i) white solid, mp 179-181 C; H NMR
(400 MHz, CDCl3) δ 3.83 (s, 3H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4
Hz, 2H), 7.45 ( d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 56.0, 105.3,
114.2, 120.5, 120.6, 128.7, 129.5, 131.4, 138.7, 146.0, 156.3, 161.9; HRMS Calcd for C14H12ClN2OS
[M+H]+: 291.0359. Found: 291.0375.
o
1
6-Bromo-N-p-tolylbenzo[d]thiazol-2-amine (3j) yellow solid, mp 202-203 C; H NMR (400 MHz,
CDCl3) δ 2.36 (s, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.40 ( s, 2H), 7.70 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.9, 114.6, 120.3, 121.0, 123.3, 129.3, 130.2, 131.7, 134.9, 136.8, 150.6,
165.5; HRMS Calcd for C14H12BrN2S [M+H]+: m/z 318.9905. Found: 318.9917.
o
1
6-Iodo-N-phenylbenzo[d]thiazol-2-amine (3k) white solid, mp 184-186 C; H NMR (400 MHz,
CDCl3) δ 7.17 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.60 (d, J = 8.4 Hz,
13
2H), 7.59 (dd, J = 1.6, 8.4 Hz, 1H), 7.89 ( s, 1H), 8.50 (br, 1H); C NMR (100 MHz, CDCl3) δ 120.3,
121.1, 124.7, 129.1, 129.5, 129.6, 135.1, 139.4, 151.8; HRMS Calcd for C13H10IN2S [M+H]+: 352.9609.
Found: 352.9615.
o
1
N-(4-Chlorophenyl)-6-iodobenzo[d]thiazol-2-amine (3l) white solid, mp 214-215 C; H NMR (400
MHz, DMSO-d6) δ 7.35-7.38 (m, 3H), 7.59 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H),
13
10.67 (br, 1H); C NMR (100 MHz, DMSO-d6) δ 85.2, 119.3, 121.2, 125.7, 128.8, 129.0, 132.5, 134.5,
139.0, 151.4, 161.6; HRMS Calcd for C13H9ClIN2S [M+H]+: 386.9220. Found: m/z 386.9230.
ACKNOWLEDGEMENTS
Financial supported from National Natural Science Foundation of China (21002042), Natural Science
Foundation of Jiangxi Educational Committee (GJJ10387), Jiangxi Province of China (2009GQH0054),
and Startup Foundation for Doctors of Jiangxi Normal University (200900266) is gratefully
acknowledged.
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