One-pot copper-catalyzed synthesis of 2-substituted benzothiazoles from 2-iodoanilines, benzyl chlorides and elemental sulfur

Article abstract of DOI:10.1016/j.tetlet.2017.05.004

An efficient one-pot three-component reaction of 2-iodoanilines, benzyl chlorides and elemental sulfur to form 2-substituted benzothiazoles in satisfactory yields (up to 98%) has been described. The reaction tolerated a wide range of functional groups on the aromatic ring. And heterocycle methylene chlorides substrates were also found to be compatible.

Full text of DOI:10.1016/j.tetlet.2017.05.004

Accepted Manuscript
One- pot Copper-catalyzed Synthesis of 2-Substituted Benzothiazolesfrom2-
Iodoanilines, Benzyl Chlorides and Elemental Sulfur
Zhao Yang, Renhe Hu, Xiaotong Li, Xin Wang, Ren Gu, Shiqing Han
PII:
S0040-4039(17)30578-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.004
TETL 48897
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 March 2017
28 April 2017
4 May 2017
Please cite this article as: Yang, Z., Hu, R., Li, X., Wang, X., Gu, R., Han, S., One- pot Copper-catalyzed Synthesis
of 2-Substituted Benzothiazolesfrom2-Iodoanilines, Benzyl Chlorides and Elemental Sulfur, Tetrahedron Letters
(
2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.004
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Graphical Abstract
One-pot Copper-catalyzed Synthesis of 2-
Substituted Benzothiazoles from 2-Iodoanil-
ines, Benzyl Chlorides and Elemental Sulfur
Zhao Yang, Renhe Hu, Xiaotong Li, Xin Wang,
Ren Gu and Shiqing Han*

1
Tetrahedron Letters
journal homepage: www.els evier.com
One-pot Copper-catalyzed Synthesis of 2-Substituted Benzothiazoles from 2-
Iodoanilines, Benzyl Chlorides and Elemental Sulfur
a
a
a
a
Zhao Yang , Renhe Hu , Xiaotong Li , Xin Wang , Ren Gu and Shiqing Han
a
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
An efficient one-pot three-component reaction of 2-iodoanilines, benzyl chlorides and elemental
sulfur to form 2-substituted benzothiazoles in satisfactory yields (up to 98%) has been described.
The reation tolerated a wide range of functional groups on the aromatic ring. And heterocycle
methylene chlorides substrates were also found to be compatible.
Received in revised form
Accepted
Available online
Keywords:
one-pot
copper-catalyzed
benzyl chloride
2
-substituted benzothiazoles
2-Substituted benzothiazoles are one important class of
bicyclic privileged substructures present in a myriad of natural
1
products and synthetic compounds, and have attracted much
attention due to their diverse biological and pharmacological
2
3
properties,
including antitumor,
antimicrobial,
anti-
4
5
inflammatory and anticonvulsant activities. Thus, development
of efficient methods for the synthesis of these compounds is
valuable in drug discovery. Common methods involve the
condensation reactions of 2-aminothiophenol with aldehydes,
carboxylic acids or α-ketone acids under oxidative conditions
6
Scheme 1a), the transition-metal-catalyzed intramolecular
(
7
cyclization of thiobenzanilides analogues (Scheme 1b), Cu-
catalyzed three-component reaction of 2-iodoanilines, aldehydes
or benzylamine, and elemental sulfur to form benzothiazoles in a
8
one-pot procedure (Scheme 1c), the redox condensation of o-
halonitrobenzenes, elemental sulfur and benzylamines, arylacetic
9
acids or methylhetarene (Scheme 1d). However, these methods
have several shortcomings, such as prefunctionalization of the
starting materials, employing expensive ligands or catalysts,
unsatisfactory yields, harsh reaction conditions, etc.
Recently, our group successfully used benzyl chloride as the
new carbon source, for the synthesis of 2-arylbenzothiazole
Scheme 1. Different routes for the synthsis of 2-substituted
benzothiazoles.
1
0
derivatives via a three component reaction. Inspired by this
results, we wish to develop a one-pot synthetic approach for the
synthesis of 2-substituted benzothiazoles from easily available 2-
iodoanilines, benzyl chlorides and elemental sulfur (Scheme 1e).
The reaction was optimized by varying different parameters
using a model reaction of 2-iodoaniline (1a) and benzyl chloride
(2a) in the presence of elemental sulfur (Table 1). The study was
commenced using K
1
2 3
CO in DMSO under nitrogen atmosphere at
00 °C for 24 h, which led to the formation of desired product 2-
arylbenzothiazole (3aa) in 47% yield (Table 1, entry 1).
Increasing the reaction temperature to 130 °C improved the
product yield considerably (92%, entries 2-4). Comparison of
_
___________
*
Corresponding author. Tel: +86-25-58139970; Fax: 86-25-58139369.
E-mail address:hanshiqing@njtech.edu.cn (S. Han).
different Cu(II) salts indicated that Cu(OAc)
to other sources, including Cu(OAc) , CuSO
2
·H
2
O was superior
2
4
and CuO (Table 1,

2
entries 4-7). However, the reaction did not take place with CuI
and a lower yield was obtained when copper powder and
other hand, 2-iodoaniline with electron-withdrawing benzyl
chloride generated the corresponding products in 53-96% yields
(3ai-3ao). It is particularly noteworthy that the use of the meta-
bromo benzyl chloride proved to be more effective compared
with ortho- and para-bromo benzyl chloride, resulting in the
formation of the corresponding 2-substituted benzothiazoles
derivatives in excellent yields (3am-3ao). Heteroaromatic methyl
chlorides also worked well under standard conditions and offered
3ap-3au in satisfactory yields, especially 3ar, a dinitrogen donor,
was obtained in 90% yield.
FeCl
Subsequently, various bases were tested for this reaction, among
them Na CO showed the best efficiency (Table 1, entries 11-14).
3
2
·6H O were chosen as catalysts (Table 1, entries 8-10).
2
3
Furthermore, reducing the amount of elemental sulfur (4 equiv.
changed to 3 equiv.) resulted in a lower yield, and 89% yield was
obtained (Table 1, entry 15). To our delight, the desired product
3
aa could be isolated in moderate yields when we replaced 2-
iodoaniline with 2-bromoaniline, or benzyl chloride with benzyl
bromide (Table 1, entries 16-17). Conducting the reaction under
air atmosphere restrained the result (Table 1, entries 18). Finally,
changing the equivalent of the base or catalyst didn’t improve the
reaction yield (Table 1, entries 19-22).
Table 2. Reaction of 2-iodoaniline, elemental sulfur and
different benzyl chlorides.
a
a
Table 1. Reaction conditions optimization
b
Entry
1
benzyl chlorides
Product
Yield
97%
b
Catalyst
mol %)
Temperature
o
( C)
Yield
(%)
47
Entry
Base
2
90%
(
1
2
3
4
5
6
7
8
9
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
·H
·H
·H
·H
2
2
2
2
O
O
O
O
K
K
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
100
110
120
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
80
86
K
2
3
4
5
6
98%
67%
96%
55%
K
2
92
90
50
68
Cu(OAc)
2
K
2
CuSO
CuO
CuI
4
K
2
K
2
K
2
0
60
Cu
K
2
10
11
12
13
14
FeCl
3
·6H
2
O
K
2
43
38
97
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
·H
·H
2
O
NaOH
Na CO
NaHCO
KHCO
2
O
O
O
O
O
O
O
O
O
O
O
2
3
·H
·H
·H
·H
·H
·H
·H
·H
·H
·H
2
3
trace
trace
89
2
2
2
2
2
2
2
2
2
3
c
1
5
6
7
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
d
e
f
1
1
1
3
67
77
3
8
3
80
83
7
65%
g
1
2
9
0
3
h
i
3
86
52
2
2
1
3
j
2
3
96
8
9
82%
90%
95%
a
Reaction conditions: 2-iodoaniline 1a (0.5 mmol), benzyl chloride 2a (1
mmol), elemental sulfur (2 mmol), catalyst (20 mol%) and base (1 mmol) in
o
DMSO (3 mL) under nitrogen atmosphere at 130 C for 24 h.
b
Isolated yields.
c
8
S 3 equiv.
d
e
f
1
a = 2-bromoaniline.
a = benzyl bromide.
1
0
2
Air atmosphere
Base 1.5 equiv
g
h
i
11
93%
95%
Base 2.5 equiv
Catalyst (15 mol%)
Catalyst (25 mol%)
j
1
2
With the optimized reaction conditions in hand, we then
examined the scope of the reaction. The results of 2-iodoaniline
a with various benzyl chlorides under standard reaction
1
conditions were shown in Table 2. A variety of benzyl chlorides
with both electron-donating and electron-withdrawing groups
afforded the corresponding 2-substituted benzothiazole
derivatives in moderate to excellent yields (53-98%) (3ab-3ao).
For example, benzyl chloride containing electron-donating
groups such as 2-methyl, 3-methyl, 4-methyl, 3-methoxy, 4-
methoxy, 3,4-dimethoxy, and 4-tert-butyl groups provided the
desired products in 55–98% yields (3ab-3ah). It is worthy to note
that meta-methyl or meta-methoxy benzyl chloride could provide
the corresponding products with higher yields than para-methyl
or para-methoxy benzyl chloride (3ac, 3ae vs 3ad, 3af). On the
13
96%
53%
63%
1
1
4
5

3
To further clarify the mechanism, some control experiments
1
6
60%
were carried out as shown in Scheme 2. According to the results
of this transformation, first of all, the reaction was carried out
2 3
using benzyl chloride and Na CO in DMSO for 5h to provide
1
1
1
7
8
9
65%
90%
76%
benzaldehyde in 94% yield (Scheme 2A). Subsequently, the
reaction was carried out using 2-iodoaniline, benzyl chloride and
2 3
Na CO in DMSO to provide N-benzyl-2-iodoaniline 4 in 78%
yield and a small amount of benzaldehyde (Scheme 2B). It
showed that benzyl chloride first reacted with 2-iodoaniline to
generated 4, then excessive benzyl chloride was oxidized to
benzaldehyde. Subseqently, the reaction of 4 with elemental
sulfur afforded 2-substituted benzothiazoles and N-(2-
iodophenyl)benzothioamide in a trace amount (Scheme 2C).
2
2
0
1
75%
89%
Whereas, in the presence of Cu(OAc)
2
2
·H O, a significant increase
Cl
in yield of target product was observed, which demomstrated that
a copper catalytic cycle was involved in this reaction (Scheme
2
D). In addition, the reaction was carried out using 2-iodoaniline,
2
u
benzaldehyde and elemental sulfur under the standard reaction
a
Reaction conditions: 2-iodoaniline 1a (0.5 mmol), different benzyl chloride
conditions to provide 3aa in 96% yield (Scheme 2E).
2
(1 mmol), elemental sulfur (2 mmol), catalyst (20 mol%) and base (1
o
mmol) in DMSO (3 mL) under nitrogen atmosphere at 130 C for 24 h.
b
Isolated yields.
To expand the scope of this methodology, we also examined a
series of substituted 2-haloanilines. As summarized in Table 3,
several functional groups, such as trifluoromethyl, fluoro, chloro,
and methyl groups, were well-tolerated under the standard
reaction conditions and gave the corresponding benzothiazoles in
moderate to excellent yields ranging from 59% to 98% (3ba-3ha).
When the substituted 2-haloanilines were substituted 2-
iodoaniline (3ba-3fa), the yield of target products were above
9
0%. In addition, substituted 2-bromoaniline (3ga, 3ha) could
also be converted into the corresponding products in spite of
lower efficiency.
Table 3. Reaction of benzyl chloride, elemental sulfur and
a
different 2-haloanilines.
b
Entry
1
2-haloanilines
Product
Yield
Scheme 2. Control experiments.
F3C
S
95%
N
3ba
On the basis of the above observations and previous
literature, an outline mechanism is proposed and shown in
Scheme 3. Firstly, 2-iodoaniline 1a reacts with benzyl chloride
2
3
4
5
6
97%
98%
91%
93%
67%
1
1
2
a to form N-benzyl-2-iodoaniline 4. Then the copper-catalyzed
coupling of N-benzyl-2-iodoaniline 4 with sulfur powder
1
2
provides a disulfide product 5. The disulfide product 5 is
unstable and will fracture to produce intermediate 6 in alkaline
1
3
conditions.
Subsequently, intermediate
6 undergoes an
intramolecular nucleophilic attack as well as addition to produce
1
4
intermediate 7. Finally, an oxidative dehydrogenation sequence
1
affords the desired product benzothiazole 3aa. Considering the
5
fact in control experiments Scheme 2A ,Scheme 2B and Scheme
2
E, an alternative approach to the product 3aa is also possible:
First of all, benzyl chloride was generated benzaldehyde under
the action of base and DMSO, then reacted with 2-iodoaniline 1a
and elemental sulfur to generated the target product under the
Cl
Br
8
copper salt catalyst.
7
59%
NH2
1
h
a
Reaction conditions: different 2-iodoaniline 1 (0.5 mmol), benzyl chloride
2
a (1 mmol), elemental sulfur (2 mmol), catalyst (20 mol%) and base (1
o
mmol) in DMSO (3 mL) under nitrogen atmosphere at 130 C for 24 h.
b
Isolated yields.

4
1
1
1
0. Gan, H.; Miao, D.; Pan, Q; Hu, R.; Li, X.; Han, S. Chem. Asian
J. 2016, 11, 1770.
1. Hikawa, H.; Izumi, K.; Ino, Y.; Kikkawa, S.; okoyama, Y.;
Azumaya, I. Adv. Synth. Catal. 2015, 357, 103.
2. (a) Chen, H.; Peng, W.; Lee, Y.; Chang, Y.; Chen,Y. ; Lai, Y.;
Jheng, N.; Chen, H. Organometallics. 2013, 32, 5514; (b) Wang,
R.; Ding, Y.; Liu, H.; Peng, S.; Ren, J.; Li, L. Tetrahedron Lett.
2
014, 55, 945.
1
1
3. Tarbell, D. S.; Harnish, D. P. Chemical Reviews. 1951, 49, 1.
4. Zhang, X.; Zeng, W.; Yang, Y.; Huang, H.; Liang, Y. Org. Lett.
2
014, 16, 876.
5. Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem. 2008, 73,
835.
1
1
6
6. General procedure for the synthesis of benzimidazoles: 2-
Iodoaniline 1a (0.5 mmol), benzyl chloride 2a (1 mmol, 126 mg),
2 2
sulfur powder (2 mmol, 64 mg), Cu(OAc) ·H O (20 mg) and
Na CO (1 mmol, 106 mg) in DMSO (3 mL) were put into a
2
3
o
Schlenk tube. The reaction mixture was stirred at 130 C for 24 h
and cooled to room temperature, filtered and extracted with ethyl
2 4
acetate, washed with brine, dried over Na SO , filtered and
Scheme 3. Proposed mechanism.
concentrated. The residue was purified by chromatography on
silica gel (300-400 mesh) to afford desired product 3aa as a light
In summary, we have developed a copper-catalyzed and one-
pot three-component approach providing 2-substituted
benzothiazoles from readily available 2-iodoanilines, benzyl
chlorides and elemental sulfur. Various 2-substituted
benzothiazoles are synthesized in moderate to excellent yields
with good functional group tolerance. Application of the method is
under way in our laboratory and will be reported in due course.
1
yellow solid; yield : 102 mg (97%); H NMR (300 MHz, CDCl
3
):
δ 8.07−8.12 (m, 3 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.48−7.51 (m, 4
1
3
H), 7.39 (t, J = 12.0 Hz, 1 H); C NMR (75 MHz, CDCl
3
): δ
68.0, 154.1, 135.1, 133.6, 130.9, 128.9, 127.5, 126.2, 125.1,
23.2, 121.6.
1
1
Acknowledgments
We thank to the National Natural Science Foundation of China
(
Grant No. 21072095), National High Technology Research and
Development Program of China (863 Program
014AA022100)，Six Talent Peaks Project in Jiangsu Province
No. 2015-SWYY-016) and Graduate Student Innovation Project
2
(
in Jiangsu Province (Grant No. SJLX16_0304) for supporting
this research.
References and notes
1
.
(a) Aiello,S.; Wells, G.; Sone, E. L., Kadri, H.; Bazzi, R.; Bell, D.
R.; Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.; estwell,
A. D. J. Med. Chem. 2008, 51, 5135; (b) Banerjee, A.; Santra, S.
K.; Guin, S.; Rout, S. K.; Patel, B. K. Eur. J. Org. Chem. 2012,
1367; (c) Banerjee, A.; Bera, A., Guin, S.; Rout, S. K.; Patel, B. K.
Tetrahedron. 2013, 69, 2175.
2
.
(a) Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.;
Bradshaw, T. D.; Stevens, M. F.; Westwell, A. D. J. Med. Chem.
2006, 49, 179; (b) Chakraborty, M.; Jin, K. J.; Brewer, S. C.; Peng,
L.; Platz, M. S.; Novak, M.; Org. Lett. 2009, 11, 4862.
3
4
.
.
(a) Bondock, S.; Fadaly, W.; Metwally, M. A. Eur. J. Med. Chem.
2
Wyatt, P. G.; airlamb, A. H. FJ. Biol. Chem. 2011, 286, 8523.
Wang, X.; Sarris, K.; Kage, K.; Zhang, D.; Brown, S. P.; Kolasa,
T.; Surowy, C.; Kouhen, O. F. E.; Muchmore, S. W.; Brioni, J. D.;
Stewart, A. O. J. Med. Chem. 2009, 52, 170.
010, 45, 3692; (b) Konig, J.; Wyllie, S.; Wells, G., Stevens, M. F.;
5
6
.
.
Rana, A.; Siddiqui, N.; Khan, S. A.; Haque, S. E.; Bhat, M. A.
Eur. J. Med. Chem. 2008, 43, 1114.
(a) Sharma, H.; Singh, N.; Jang, D. O.; Green Chem. 2014, 16,
4
922; (b) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.; Qi, X.; Lan, Y.;
Lei, A. Angew.Chem., Int. Ed. 2014, 53, 502; (c) Hu, R.; Li, X.;
Tong, Y.; Miao, D.; Pan, Q.; Jiang, Z.; Gan, H.; Shi,
S. Synlett, 2016,27, 1387.
7
.
(a) Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron
Lett. 1982, 23, 5093; (b) Ma, H.; Xuan, Z. Synlett. 2008, 9, 1335;
(
c) Inamoto, K.; Hasegawa, C.; Kou, H.; Doi, T. Org. Lett. 2008,
1
4
5, 5147; (d) Cheng, Y.; Yang, J.; Qu, Y.; Li, P. Org. Lett. 2012,
0, 98.
8
9
.
.
(a) Deng, H.; Li, Z.; Ke, F.; Zhou, X. Chem. Eur. J. 2012, 18,
840; (b) Wang, R.; Ding, Y.; Liu, H.; Peng, S.; Ren, J.; Li, L.
Tetrahedron Lett, 2014, 55, 945.
4
(a) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org. Lett,
2
013, 15, 4218; (b) Tong, Y.; Pan, Q.; Jiang, Z.; Miao, D.; Shi, X.;
Han, S. Tetrahedron Lett, 2014, 55, 5499; (c) Nguyen, T. B.;
Ermolenko, L.; Retailleau, P.; Al-Mourabit, A. Angew. Chem. Int.
Ed., 2014, 53, 13808; (d) Guntreddi, T.; Vanjari, R.; Singh, K. N.
Org. Lett. 2015, 17, 976.

5
1
2
3
4
. An efficient one-pot three-component reaction.
The yield was up to 98%.
.
. Good functional group tolerance.
. Heterocycle methylene chlorides substrates
were compatible for the reaction.