Copper-catalyzed synthesis of 2-aminobenzothiazoles from carbodiimide and sodium hydrosulfide

Article abstract of DOI:10.1039/c4ra04047c

An efficient copper-catalyzed method for the synthesis of a variety of 2-aminobenzothiazoles has been developed. The reaction proceeded from carbodiimide and sodium hydrosulfide via a tandem reaction in the presence of copper(ii) trifluoromethanesulfonate to afford the corresponding 2-aminobenzothiazole derivatives in good to perfect yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra04047c

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Copper-catalyzed synthesis of 2-
aminobenzothiazoles from carbodiimide and
Cite this: RSC Adv., 2014, 4, 31003
sodium hydrosulfide†
a
a
a
a
b
Received 3rd May 2014
Accepted 14th July 2014
*
*
Weilan Zeng, Pan Dang, Xiaoyun Zhang, Yun Liang and Caiyun Peng
DOI: 10.1039/c4ra04047c
www.rsc.org/advances
An efficient copper-catalyzed method for the synthesis of a variety of aminobenzothiazoles used the carbon disulde as sulfur
2-aminobenzothiazoles has been developed. The reaction proceeded source.11 Nevertheless, the toxicity and unpleasant odor of
from carbodiimide and sodium hydrosulfide via a tandem reaction in carbon disulde impedes its application. Therefore, used
the presence of copper(II) trifluoromethanesulfonate to afford the simple, nontoxic, readily available sulfur sources for the
corresponding 2-aminobenzothiazole derivatives in good to perfect synthesis of 2-aminobenzothiazoles are of great value.
yields.
Recently, the nontoxic, odorless, and readily available sulfur
sources such as metal suldes have received considerable
attention to synthesize the sulfur-containing heterocyclic
compounds via a double thiolation reaction.12 We are also
interested in this synthetic strategy, and have successfully
synthesized benzo[b]thiophene,13 benzo[d]thiazole14 and benzo-
[d]thiazol-2(3H)-one15 used potassium sulde as sulfur source.
In the present research, we found that o-haloarylcarboniimide16
and metal suldes could undergo a cascade process to afford 2-
aminobenzothiazoles. As shown in Scheme 1, the proposed
reaction might proceed through a cross-coupling of o-haloaryl-
carboniimide 1 and NaHS under copper-catalyzed conditions
(step a, the plausible intermediate 3 would be formed, and
copper catalyst was regenerated),12–15,17 followed by the forma-
tion of 2-aminobenzothiazoles 2 or the intermediate of benzo[d]-
thiazol-2(3H)-imine 4 via an intramolecular nucleophile addi-
tion (step b, the process might be analogous to those reported
nucleophile addition to a certain extent).16,18 Rearrangement
and isomerization of the intermediate 4 also give rise to the
product 2 (step c). Here in, we wish to detail our results.
2-Aminobenzothiazoles,1–5 categorized as signicant derivatives
of benzothiazoles, are broadly found in bioorganic and medic-
inal chemistry with applications in drug discovery and devel-
opment for the treatment of various diseases, such as AIDS,2
diabetes,3 epilepsy,4 and tuberculosis.5 Consequently, many
efficient methods were developed for the synthesis of 2-ami-
nobenzothiazoles. Among them, the common method was
based on metal-catalyzed intermolecular cross-coupling reac-
tion between 2-halobenzothiazoles and amines,6 2-amino-
benzothiazoles and aryl halides,7 or simple benzothiazoles and
amines.8 The other two methods of direct construction of 2-
aminobenzothiazole have attracted more attention from the
viewpoints of operational simplicity: (1) intramolecular cycli-
zation of o-haloarylthioureas or arylthioureas;9 and (2) inter-
molecular cyclization of 2-halophenylamines or 2-
aminobenzenethiols with isothiocyanates.10 However, these
methods usually require several steps and harsh reaction
conditions for the preparation of sulfur-containing substrates
such as benzothiazoles, arylthioureas, isothiocyanates, which
limit their application in synthesis. Recently, Ma and co-worker
developed
a simple method for the synthesis of 2-
aNational & Local Joint Engineering Laboratory for New Petro-chemical Materials and
Fine Utilization of Resources, Key Laboratory of Chemical Biology and Traditional
Chinese Medicine Research, Ministry of Education, Hunan Normal University,
Changsha, Hunan 410081, China. E-mail: yliang@hunnu.edu.cn; paudy@126.com;
Fax: +86 0731 88872533
bSchool of Pharmaceutical Science, Hunan University of Chinese Medicine, Changsha,
Hunan, 410208, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra04047c
Scheme 1 Proposed one-pot synthesis of 2-aminobenzothiazoles via
a copper-catalyzed coupling/addition process.
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Table 1 Optimization of reaction conditionsa
were isolated respectively (entries 18–19). Finally, the amount of
catalyst and the reaction temperature were evaluated, and
relatively low yields were found with any reduction in the
reaction temperature or the amount catalyst (entries 20–21).
Thus, the optimized reaction condition were as follow: 1a (0.3
mmol), NaHS (0.9 mmol), Cu(OTf)2 (20 mol%), in DMF (2 mL)
ꢀ
under a N2 atmosphere at 120 C.
Entry Sulfur source Catalyst
Ligand
Solvent Yieldb/2a
Under the optimized conditions, the substituent of the
nitrogen moiety of o-iodobenzylcarboniimide was screened,
and the results were summarized in Table 2. Various N-
substituted 2-aminobenzothiazoles were obtained from good
to perfect yields. Initially, the substituents of aryl were screened.
The results showed that increasing the electron density on the
nonhalogenated ring might favor the intramolecular addition
process. For instance, the presence of a weak electron-donating
group (m-Me) and a weak electron-withdrawing group (p-Cl) on
the aromatic ring of 1 provided 93% and 81% yield of corre-
sponding products. Similarly, N-benzyl substituted 2-amino-
benzothiazoles could be obtained in good to high isolated
yields. For example, N-benzylbenzo[d]thiazol-2-amine was
obtained in 95% yield under the optimized condition. For the N-
alkyl substituted benzo[d]thiazol-2-amine, they with linear-
chain, branched-chain, and cycloalkyl groups could all be
afforded in perfect yields. This result showed that the alkyl
1
2
3
K2S
NaHS
Na2S
Na2S2O3
S
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuI
—
—
—
—
—
—
—
—
—
—
—
—
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
48
66
53
58
36
46
53
41
45
48
60
74
11
71
62
68
73
60
67
70
64
4
5c
6
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
7
8
9
CuBr
CuCl
CuCN
CuOTf
Cu(OAc)2
Cu(OTf)2
—
Cu(OTf)2 1,10-Phen
Cu(OTf)2 2,2-Py
Cu(OTf)2 TMEDA
10
11
12
13
14
15
16
17
18
19
20d
21e
Cu(OTf)2 L(ꢁ)-Proline DMF
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
—
—
—
DMSO
NMP
DMF
DMF
a
Conditions: 1a (0.30 mmol), sufur source (0.90 mmol), Cu catalyst (20
Table 2 Synthesis of N-substituted 2-aminobenzothiazoles
b
mol%), ligand (20 mol%), solvent (2 mL), N2, 120 ꢀC, 15 h. Isolated
yield. c Cs2CO3 (0.90 mmol). d 100 ꢀC. e Cu(OTf)2 (10 mol%).
In this work, N-phenylbenzo[d]thiazol-2-amine was obtained
in good yields from N-(2-iodophenyl)-N-phenylmethanediimine
1a and NaHS in one pot, via a copper-catalyzed double thio-
lation. The results of the screening for optimal reaction condi-
tions are shown in Table 1. Our investigation started by an
attempted thiolation of substrate 1a with K2S in DMF at 120 ꢀC
in the presence of CuBr2 as the catalyst, and the desired product
2a was isolated in 48% yield (entry 1). This result encouraged us
to develop an efficient system to synthesize 2-amino-
benzothiazole using N-(2-iodophenyl)-carbodiimine as a start-
ing substrate. A variety of sulfur sources, such as K2S, Na2S,
NaHS, S, NaS2O3, were screened (entries 1–5). The results
indicated that NaHS was the best one for this reaction. Subse-
quently, the effects of copper catalysts (including CuBr, CuI,
CuCl, CuCN, CuOTf, Cu(OAc)2, Cu(OTf)2) are examined (entries
6–12). Cu(OTf)2 achieved the best result, and the product 2a was
obtained in 74% yield. It is noteworthy that copper II has much
better catalysis activity than copper I. The possible reason
attributes copper II could promote the nucleophile addition of
carboniimide.18 Without the copper catalyst, the desired
product decreased to 11% yield (entry 13). Then, the effects of
ligands (include 2,20-bipyridine, 1,10-phen, L(ꢁ)-proline,
TMEDA) were checked also (entries 14–17). However, the
ligands did not show better results. Solvents such as DMSO and
NMP were evaluated, and 60% and 67% yield of the product 2a
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Table
3 Synthesis of 2-aminobenzothiazolones from substituted
o-iodobenzylcarboniimidea
Scheme 2 One-pot synthesis of 2-aminobenzothiazoles.
Entry Substrate
Product
Yieldb (%)
85
2-aminobenzothiazole could offer an opportunity for further
cross-coupling, and facilitating the expedient synthesis of
complex compounds.
1
To our delight, this synthetic method to synthesize 2-ami-
nobenzithiazoles could be further extend from the initial
starting material in one step. For example, N-(2-iodophenyl)-
triphenyliminophosphrane reacted with isocyanate in DMF for
12 h, then NaHS and Cu(OTf)2 were added, and the reaction was
further stirred for 15 h at 120 ꢀC, and the corresponding 2-
aminobenzithiazoles were obtained in good yields (Scheme 2).
In summary, we have developed an efficient coupling/
addition tandem reaction from o-haloarylcarboniimide and
NaHS for the synthesis of 2-aminobenzothiazoles. In this
copper-catalyzed system, the tolerance of diverse functional
groups in o-haloarylcarboniimide makes this present system
attractive in the synthesis of various 2-aminobenzothiazoles. To
our best knowledge, this is the rst example of the use of NaHS
as the sulfur source in the synthesis of 2-aminobenzothiazole
derivatives.
2c
96
87
3
4
89
5
6
90
92
Acknowledgements
7c
66
This work was supported by the Natural Science Foundation of
China (21072054), the Research Project of Chinese Ministry of
Education (213027A, 20094306120003), Hunan Provincial
Natural Science Foundation (12JJ2009), Scientic Research
Fund of Hunan Provincial Education Department (12A095) and
Aid Program for Science and Technology Innovative Research
Team in Higher Educational Institutions of Hunan Province for
nancial support.
a
Conditions: 1 (0.30 mmol), NaHS (0.90 mmol), Cu(OTf)2 (20 mol%),
DMF (2 mL), N2, 120 ꢀC, 15 h. Isolated yield. c R2 ¼ 4-Cl-Ph.
b
substituent did not remarkably affect the reaction. Finally, we
investigated the reactivity of o-bromobenzylcarboniimides.
Importantly, the o-bromobenzylcarboniimides could efficiently
reacted with NaHS and good yields of the products were given.
To expand the scope of this methodology, we also examined
Notes and references
a
series of substituted N-benzyl-N-(2-iodophenyl)meth-
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