A simple approach to benzothiazoles from 2-chloronitrobenzene, elemental sulfur, and aliphatic amine under solvent-free and catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2014.08.037

A novel solvent-free and catalyst-free synthesis of benzothiazoles from 2-chloronitrobenzene, elemental sulfur, and aliphatic amine has been developed. The reaction tolerated a wide range of functionalities, and various benzothiazoles were synthesized in moderate to good yields in the absence of external oxidant or reductant.

Full text of DOI:10.1016/j.tetlet.2014.08.037

Accepted Manuscript
A simple approach to benzothiazoles from 2-chloronitrobenzene, elemental sul-
fur, and aliphatic amine under solvent-free and catalyst-free conditions
Yao Tong, Qiang Pan, Zengqiang Jiang, Dazhuang Miao, Xuesong Shi, Shiqing
Han
PII:
S0040-4039(14)01358-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.037
TETL 45004
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 June 2014
31 July 2014
9 August 2014
Please cite this article as: Tong, Y., Pan, Q., Jiang, Z., Miao, D., Shi, X., Han, S., A simple approach to benzothiazoles
from 2-chloronitrobenzene, elemental sulfur, and aliphatic amine under solvent-free and catalyst-free conditions,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.037
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Graphical Abstract
A simple approach to benzothiazoles from 2-
chloronitrobenzene, elemental sulfur, and
aliphatic amine under solvent-free and
catalyst-free conditions
Yao Tong, Qiang Pan, Zengqiang Jiang,
Dazhuang Miao, Xuesong Shi, and Shiqing
Han*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A simple approach to benzothiazoles from 2-chloronitrobenzene, elemental
sulfur, and aliphatic amine under solvent-free and catalyst-free conditions
Yao Tong a, Qiang Pan a,Zengqiang Jiang a, Dazhuang Miao a, Xuesong Shi a, and Shiqing Han a,b,
*
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel solvent-free and catalyst-free synthesis of benzothiazoles from 2-chloronitrobenzene,
elemental sulfur and aliphatic amine has been developed. The reaction tolerated a wide range of
functionalities, and various benzothiazoles were synthesized in moderate to good yields in the
absence of external oxidant or reductant.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
Benzothiazoles
2-Chloronitrobenzene
Sulfur
Aliphatic Amine
Catalyst-free
2-Substituted azoles such as benzothiazoles have attracted
much attention because of their wide range of biological
properties, such as their antitumor,1 antimicrobial,2
antiinflammatory,3 and anticonvulsant activities.4 Consequently,
efficient preparation of substituted benzothiazole derivatives
ns without an added oxidant or reductant. Inspired by recent
reports that the methylene of benzylamine is easy to be oxidized
which can construct some important heterocycles,9 we envision
the methylene of benzylamine also can act as a carbon synthon
and a similar transformation can be achieved between 2-
chloronitrobenzene, elemental sulfur and benzylamine (Scheme
1).
represents
a worthwhile goal of heterocyclic synthesis.
Traditional methods for their syntheses typically involve the
condensation of 2-aminothiophenols with aryl aldehydes,
carboxylic acids, or its derivatives (Scheme 1a).5 However, this
method suffers that the starting 2-aminothiophenols are not
conveniently available. Alternative approaches employ direct
arylation via C-H bond functionalization catalyzed by transition-
metal between benzothiazoles and aryl halides or 2-halide-
substituted benzothiazoles with aryl metals (Scheme 1b).6
However, these methods often employ expensive metal catalysts
and drastic reaction conditions which limit their synthetic
applications. To overcome these drawbacks, some novel methods
for the synthesis of benzothiazoles by means of one-pot three-
component reactions have been also developed, in which
elemental sulfur (Scheme 1c), hydrated sodium sulfhydrate
(NaHS·nH2O), disodium disulfide (Na2S2) or sodium sulfide
nonahydrate (Na2S·9H2O) were used as the source of sulfur.7
Nevertheless, these methods are associated with several
limitations such as usage of toxic and unstable aldehydes,
complex ligands and considerable amounts of base. Recently,
Nguyen’s group developed a simple and atom economic
approach to 2-hetarylbenzothiazoles starting from 2-
halonitroarene, methylhetarene, and elemental sulfur (Scheme
1d),8 which is highlighted by the direct redox nitro-methyl
Scheme 1. Different routes for the synthesis of benzothiazoles.
With this idea in mind, we optimized the reaction conditions
using 2-chloronitrobenzene 1a, elemental sulfur, andbenzylamine
2a as model substrates under solvent-free conditions (Table 1).
reaction for carbon-nitrogen bond formation under mild conditio-
____________
* Corresponding author. Tel: +86-25-58139970; Fax: 86-25-58139369.
E-mail address:hanshiqing@njtech.edu.cn (S. Han).

2
Initially, the reaction was carried out with 2-chloronitrobenzene
1a (1 mmol), sulfur (1 equiv), benzylamine 2a (3 equiv) at 120
oC and we were pleased to observe that these conditions afforded
desired product benzothiazole 3a in 55% (Table 1, entry 1). The
desired product was obtained in 67% when 1.5 equiv sulfur was
used (Table 1, entry 2). A slightly higher yield was obtained
when increased the amount of sulfur to 2 equiv (Table 1, entry 3)
while further increase the sulfur to 3 equiv resulted in a lower
yield (Table 1, entry 4). To increase the efficiency of the
reaction, the temperature was increased to 130 oC, as a result, the
reaction yield could be improved to 78% (Table 1, entry 5).
However, the reaction yield remarkably decreased to 63% when
the temperature was increased to 140 oC (Table 1, entry 6).
2b, R2 = R3 =
H, R4 = Me
1a
1a
1a
3a
3a
3a
67
65
63
2
3
2c, R2 = H,
R3 = R4 = Me
2d, R2 =R3 =
H, R4 = Bn
4c
2e, R2 = H, R3
= R4 = Bn
5d
6
1a
1a
3a
55
75
1a
1a
55
61
7
8
Table 1. Reaction conditions optimizationa
1a
1a
52
80
72
70
52
62
9
Entry
S (equiv)
2a (equiv)
Temp (oC)
120
Yieldb (%)
1
2
3
4
5
6
1
1.5
2
3
2
3
3
3
3
3
3
55
67
70
66
78
63
10
11
12
13
14
120
120
120
130
1b, R1 = 5-
2a
2f
Me
2
140
a Reaction conditions: 2-chloronitrobenzene 1a (1 mmol), benzylamine 2a (3
mmol), 24 h under nitrogen.
1b
1b
1b
b Isolated yield.
2g
2j
With the optimal conditions established, we explored the
scopeof the three-component reactions of 2-chloronitrobenzenes,
elemental sulfur, and various amines under optimized conditions
(Table 2). We found that in most examined cases the three-
component reactions occurred smoothly and furnished the
corresponding products in moderate to good yields. It turned out
thatbenzylamine 2a, 4-methyl-benzylamine 2f, 4-chloro-
benzylamine 2g, 3-fluoro-benzylamine 2h, and 2,3-dichloro-
benzylamine 2i were all good substrates for the formation of
benzothiazoles (Table 2, entries 1, 6-9, 12-13, 16-17, 20-21, 24-
25). A series of functional groups including methyl, methoxy,
chloro, and bromo on the phenyl moiety of 2-chloronitrobenzene
were well tolerated under the optimal reaction conditions, and the
desired products were obtained in moderate to good yields (Table
2, entries 11, 15, 19, 23, 27-28). In addition, Benzylamines N-
mono- and di-substituted by methyl or benzyl groups also
underwent this transformation smoothly, although the products
were formed in slightly lower yields and the higher temperatures
were required (Table 2, entries 2-5). To further investigate the
substrate scope, the aromatic heterocyclic amine was also tested.
Interestingly, the 4-picolinamine 2j proved to be a suitable
substrate (Table 2, entries 10, 14, 18, 22, 26) and the yield could
be up to 80% (Table 2, entry 10).
1c, R1 = 5-
OMe
2a
2f
80
76
58
15
16
17
1c
1c
2g
1c
1d, R1 = 5-Cl
1d
2j
2a
2f
75
78
76
18
19
20
Table 2. Synthesis of benzothiazoles from 2-
1d
1d
2g
2j
60
70
21
22
chloronitrobenzenes, elemental sulfur and aliphatic aminesa
1e, R1 = 5-Br
2a
2f
60
58
62
23
24
25
1e
1e
Nitrobenzene
Yieldb
(%)
Entry
1
Amine 2
Product 3
1
2g
2a, R2 = R3 =
R4 = H
1a, R1 = H
78

3
Though the exact mechanism of the transformation is still not
1e
2j
65
26
27
28
clear at present, on the basis of the above observations and
previous literature a plausible mechanism is proposed and shown
in Scheme 3. Firstly, benzylamine 2a can be oxidized by
elemental sulfur to generate imine A,10 imine A reacted with 2a
to form N-benzylbenzaldimine B via transimination reaction.11
Subsequently, in the presence of a protonic acid medium, B
underwent a hydrogenolysis process and benzyl radical C may be
formed during the transformation.12 This highly active radical C
could be trapped by the nitro group of 1a to generate D. Finally,
sulfuration the methylene of D afforded intermediate E, which
followed by a cascade reaction of cyclization and reduction13 to
furnish 2-phenylbenzothiazole 3a.
1f, R1 = 3-Cl
1g, R1 = 4-Me
2a
2a
54
79
a
Reaction conditions: 2-chloronitrobenzenes (1 mmol), sulfur (2 equiv),
amines (3 equiv), 24 h, 130 oC.
b Isolated yield.
c At 140 oC.
d At 150 oC.
To further clarify the mechanism, some control experiments
were carried out, as shown in Scheme 2. Sulfur with 1a was
heated together, and 1a was recovered unchanged (Scheme 2, eq
1). When 1a was heated with 2a, the expected product N-benzyl-
2-nitroaniline 1a1was obtained in 90% yield (Scheme 2, eq 2).
Treatment of 1a1 with sulfur did not work and all starting
materials wererecovered unchanged (Scheme 2, eq 3). N-
benzylthiobenzamide 2a1 is a byproduct during the reaction,
which we speculated it may be the intermediate of the reaction.
However, reaction of 1a with 2a1 did not give the desired product
(Scheme 2, eq 4). When 2-chloroaniline 1a2 was heated with
sulfur and 2a under optimized reaction conditions, the starting
1a2 was recovered unchanged (Scheme 2, eq 5). On the basis of
these results, sulfur could not reduce 1a to 1a2 and some possible
intermediates such as N-benzyl-2-nitroaniline 1a1 and N-
benzylthiobenzamide 2a1 did not play a significant role in the
formation of benzothiazoles. It should be noted that when 1 equiv
radical scavenger 2,2,6,6-tetramethylpiperidinooxy (TEMPO)
was added under the standard reaction conditions, the desired
product 3a was obtained in 56% yield. Futher increased TEMPO
to 2 equiv, the yield of 3a was only 32%, indicating that a free
radical perhaps was involved in the present reaction process
(Scheme 2, eq 6).
Scheme 3. Proposed mechanism.
In conclusion, we have developed a green and simple method
for the synthesis of 2-substituted benzothiazoles by using
inexpensive, readily available 2-chloronitrobenzenes, elemental
sulfur and aliphatic amines as starting materials. In most cases, the
corresponding 2-substituted benzothiazoles were obtained in
moderate to good yields in the absence of external oxidant or
reductant. The high efficiency and easy manipulation make it
superior in both academic and industrial application. Further
investigation of the reaction mechanism and the synthetic
applications of this method is on going in our group.
Acknowledgments
This work was supported by grants from Natural Science
Foundation of China (Grant No: 21072095), National High
Technology Research and Development Program of China (863
Program 2014AA022100) and Graduate Student Innovation
Project in Jiangsu Province (Grant No. CXLX13_433).
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Scheme 2. Control experiments.

4
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14. General procedure for the synthesis of benzothiazoles : A mixture
of 2-chloronitrobenzene (1 mmol), amine
(3 mmol) and
elemental sulfur (2 mmol) was stirred in a sealed tube under
nitrogen atmosphere at indicated temperature for 24 h ( See
Table 2). After being cooled to room temperature, the crude
reaction mixture was triturated and dissolved in ethyl acetate,
then filtered and the filtrate was concentrated, and the residue was
purified by column chromatography on silica gel to afford the
desired product. Selected spectral data for 2-Phenylbenzothiazole
1
(Table 2, entry 1): H NMR (300 MHz, CDCl3): δ 7.39 (t, 1 H),
7.48−7.51 (m, 4 H), 7.91 (d, J = 9.0 Hz, 1 H), 8.07−8.12 (m, 3 H);
13C NMR (75 MHz, CDCl3): δ 121.6, 123.2, 125.1, 126.3, 127.5,
129.0, 130.9, 133.7, 135.0, 154.1, 171.8.