Substrate-promoted ligand-free CuI catalyzed S-arylation of 2-mercaptobenzothiazoles with aryl iodides in water

Article abstract of DOI:10.1016/j.tetlet.2013.07.096

A green and efficient method has been developed for the cross-coupling of 2-mercaptobenzothiazoles with aryl iodides in water. The reactions proceeded smoothly under ligand-free conditions in the presence of TBAB to give the corresponding products in good yields. The protocol showed good tolerance toward a variety of functional groups. A substrate-promoted mechanism for this catalytic reaction has been proposed.

Full text of DOI:10.1016/j.tetlet.2013.07.096

Accepted Manuscript
Substrate-Promoted Ligand-Free CuI Catalyzed S-Arylation of 2-Mercapto‐
benzothiazoles with Aryl Iodides in Water
Guozhen He, Yuan Huang, Yao Tong, Jie Zhang, Dan Zhao, Shuangli Zhou,
Shiqing Han
PII:
S0040-4039(13)01255-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.096
TETL 43294
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 June 2013
11 July 2013
18 July 2013
Please cite this article as: He, G., Huang, Y., Tong, Y., Zhang, J., Zhao, D., Zhou, S., Han, S., Substrate-Promoted
Ligand-Free CuI Catalyzed S-Arylation of 2-Mercaptobenzothiazoles with Aryl Iodides in Water, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.096
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Graphical Abstract
Substrate-Promoted Ligand-Free CuI Catalyzed
S-Arylation of 2-Mercaptobenzothiazoles with Aryl
Iodides in Water
Guozhen He, Yuan Huang, Yao Tong, Jie Zhang, Dan Zhao, Shuangli Zhou, Shiqing Han*
1

Tetrahedron Letters
journal homepage: www.elsevier.com
Substrate-Promoted Ligand-Free CuI Catalyzed S-Arylation of 2-
Mercaptobenzothiazoles with Aryl Iodides in Water
Guozhen He, a Yuan Huang, a Yao Tong, a Jie Zhang, a Dan Zhao, a Shuangli Zhou, a Shiqing Han a,b,
*
a College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, 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 green and efficient method has been developed for the cross-coupling of 2-
mercaptobenzothiazoles with aryl iodides in water. The reactions proceeded smoothly under
ligand-free conditions in the presence of TBAB to give the corresponding products in good
yields. The protocol showed good tolerance towards a variety of functional groups. A substrate-
promoted mechanism for this catalytic reaction has been proposed.
Available online
2013 Elsevier Ltd. All rights reserved
Keywords:
C-S Cross coupling
2-Mercaptobenzothiazole
Copper(I) iodide
Aqueous medium
Ligand-free
2-(Arylthio)benzothiazoles are an important class of bioactive
and industrially organic compounds.1 In recent years, increasing
numbers of 2-thio-substituted benzothiazoles, especially 2-
(arylthio)benzothiazoles, have been designed and synthesized for
biological evaluation, including cathepsin-D inhibitor (A),
avarol-3′-thiobenzothizole (B), PPAR receptor activator (C),
and heat shock protein-90 inhibitor (D) (Figure 1).
C-S bond formation of dithiocarbamate salts and the subsequent
coupling of these salts with aryl halides.6 The same group also
reported that 2-thio-substituted benzothiazoles could be
elaborated from 2-haloaryl isothiocyanates and thiols via a
cascade condensation.7 In a separate report, Ma8 described the
development of a facile and diverse method for the construction
of 2-thio-substituted benzothiazoles via the condensation of
carbon disulfide with thiols in the presence of K2CO3 to generate
carbonotrithioate salts in situ. These salts then underwent
coupling reactions with 2-iodoanilines followed by sequential
intramolecular condensation and elimination reactions to give
the desired 2-thio-substituted benzothiazole products.8 Liu9a and
several other research groups9b,c recently presented a general and
highly efficient C−S cross-coupling method involving the direct
functionalization of a heterocyclic C−H bond with aryl thiols in
the presence of a copper reagent. Although significant progress
has been achieved towards the synthesis of these compounds, it
is still highly desirable to develop mild and efficient methods for
the preparation of 2-(arylthio)benzothiazoles because of the
importance of this substance class.
In recent years, the development of environmentally friendly
reaction systems using water as a reaction medium has been the
subject of considerable levels of attention because water is non-
toxic, low price and widely available, and can provide higher
levels of chemo-selectivity than can organic solvents.10 In recent
years, significant progress has been made towards the
development of copper-catalyzed cross coupling reactions in
water,11 and our group have also developed different copper
catalyst systems that can be used in coupling reactions under
green conditions.12 Based on the idea of substrate-promoted
catalysis, we envisaged that the reaction of 2-
mercaptobenzothiazoles with aryl halides in the presence of a
Figure 1 Some biologically active 2-(arylthio)benzothiazoles
Classically, 2-(arylthio)benzothiazoles have been synthesized
via the cross-coupling reactions of 2-mercaptobenzothiazoles
with aryl halides2 or aryl boronic acids,3 or the nucleophilic
attack of arylthiols on preformed 2-halobenzothiazoles.4 Several
other methods are available for the synthesis of 2-
(arylthio)benzothiazoles, including the S-arylation of diaryl
disulfides with triarylbismuthanes, and the cross-coupling
reactions of thiols with Grignard reagents.5 Patel et al.6 recently
reported the development of method providing direct access to 2-
arylthiobenzothiazoles via the copper-catalyzed intramolecular
2

1
copper catalyst would afford the corresponding S-arylation
products under ligand-free conditions in water.
mercaptobenzothiazoles under the optimized conditions (Table
2, entries 1-2 in parentheses). Pleasingly, the amine substituent
did not have a marked effect on the yield of the reaction (Table
2, entry 11). Furthermore, the optimized reaction conditions
To test our hypothesis, 2-mercaptobenzothiazole and aryl
iodide were chosen as the model substrates to optimize the
reaction conditions, and a variety of bases and catalysts were
screened at 100 C for 24 h, as show in Table 1. First, bases were
screened by using 10 mol% of CuI as the catalyst, 10 mol% of
tetrabutyl ammonium bromide (TBAB) as the phase transfer
catalyst (PTC), and H2O as the solvent (Table 1, entries 1–8).
Na2CO3 as the base provided the highest yield of the product at
93% (Table 1, entry 3). Several copper catalysts were then
investigated (Table 1, entries 3, 9–15), and CuI was determined
to be the most effective catalyst for the current reaction (Table 1,
entry 3). Interestingly, the reaction only afforded a 6% yield of
the desired product when it was conducted in the absence of the
copper catalyst (Table 1, entry 16). Control experiments revealed
that no product was isolated in the absence of TBAB (Table 1,
entry 17). In addition, a 63% yield of the desired product was
achieved when the temperature was reduced to 80 C (Table 1,
entry 18). When 5 mol% of CuI was used as the catalyst, the
yield of the product was reduced to 57% (Table 1, entry 19). It is
noteworthy that an increase in the amount of catalyst to 15 mol%
did not have any impact on the outcome of the reaction (Table 1,
entry 20). Thus, the combination of 10 mol% CuI, 10 mol% n-
Bu4NBr, and 2 equiv. of Na2CO3 in water was chosen as the
optimal conditions for further exploration.
provided smooth access to
a variety of substituted 2-
mercaptobenzothiazoles (Table 2, entries 12-16). To further
illustrate the utility of our method, we completed a formal
synthesis of the Cathepsin-D inhibitor (A) (Scheme 1).9a The
amine-substituted
successfully with 3,5-dichloro-2-hydroxybenzoic acid in the
presence of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-
2-(arylthio)benzothiazoles
reacted
tetramethyluronium hexafluorophosphate (HATU) at room
temperature to give the Cathepsin-D inhibitor (A) in good yield.
Table 2. Copper-catalyzed cross-coupling reaction of aryl
halides with 2-mercaptobenzothiazoles in watera
Entry
1
Yieldb (%)
93 (33c, 0d)
Product
Table 1. Screening of the reaction conditions for the
copper-catalyzed S-arylation of 2-mercaptobenzothiazoles
in watera
85 (31c)
2
3
4
5
Entry
1
2
3
4
5
6
7
8
Catalyst (mol%)
Base
K2CO3
K3PO4
Na2CO3
KOH
Cs2CO3
NaOH
CH3ONa
KOtBu
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Yieldb (%)
85
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuBr (10)
CuCl (10)
Cu2O (10)
CuO (10)
87
77
93
84
28
79
13
84
78
86
75
80
86
76
81
6
83
9
10
11
12
13
14
15
16
17c
18d
19
20
81
.
CuCl2 2H2O (10)
.
CuSO4 5H2O (10)
Cu (10)
-
CuI (10)
CuI (10)
CuI (5)
CuI (15)
0
63
57
93
80
6
a Reaction conditions: 2-Mercaptobenzothiazole (0.5 mmol), aryl
iodide (0.6 mmol), catalyst (10 mol%), n-Bu4NBr (10 mol%), base (2
equiv.), and H2O (2 mL) in a sealed tube at 100 C for 24 h.
b Isolated yields.
83
87
7
8
c No n-Bu4NBr was added.
d Performed at 80 C.
With the optimized reaction conditions in hand, we proceeded
to explore the scope of the reaction with a range of aryl halides
and 2-mercaptobenzothiazoles, as summarized in Table 2.13
Notably, both electron-rich and electron-deficient aryl iodides
were successfully transformed under the optimized conditions
into the desired products (Table 2, entries 1-10). Aryl bromides
and chlorides, however, did not react successful with 2-
3

of the chelator 1 with an aryl iodide would lead to the formation
of Cu(III)(Ar)I intermediate 2, and nucleophilic substitution of
2-mercaptobenzothiazole with 2 with the help of a base would
provide an ArSCu(III)(Ar) intermediate 3, and then eventually
an elimination reaction occurs on it to result the product and
restore the Cu(I) chelator 1.
88
85
85
9
10
11
12
77
81
80
79
13
14
Scheme 1. Formal Synthesis of the Cathepsin-D inhibitor (A)
In summary, we have developed a simple and effective
method for the synthesis of a series of 2-(arylthio)benzothiazole
derivatives using CuI as a catalyst. The reaction was conducted
under ligand-free conditions in the presence of TBAB in an
aqueous medium. This synthetic method may find a number of
applications in the pharmaceutical, agrochemical, and industrial
science sectors.
15
16
17
18
81
0
0
a Reaction conditions: 2-Mercaptobenzothiazoles (0.5 mmol), aryl
iodides (0.6 mmol), CuI (10 mol%), TBAB (10 mol%), Na2CO3 (2
equiv), and H2O (2 mL) in a sealed tube at 100 C for 24 h.
b Isolated yields.
Figure 2. Proposed substrate-promoted mechanism
c Performed with an aryl bromide.
Acknowledgment
d Performed with an aryl chloride.
We are grateful for the financial support received from the
Natural Science Foundation of China (Grant nos. 20942006 and
21072095) and the Program for ChangJiang Scholars and
Innovative Research Team in University (Grant no. IRT1066).
Unfortunately,
2-mercaptobenzoxazole
and
2-
mercaptobenzimidazole did not give the desired S-arylation
products under the optimized reaction conditions (Table 2,
entries 17-18). On the basis of the results presented above, we
have proposed a substrate-promoted mechanism for the current
transformation (Figure 2). Given that sulfur is a stronger
nucleophile than nitrogen or oxygen, 2-mercaptobenzothiazole
was considered to be more nucleophilic and more capable of
forming the Cu(I) chelator 1 with CuI via deprotonation of thiol
group in the presence of base. The subsequent oxidative addition
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13. General procedure for the copper-catalyzed S-Arylation of 2-
Mercaptobenzothiazoles with Aryl Iodides in Water: To a 10 mL
sealed tube with a stir bar was added CuI (0.05mmol), Aryl iodides
(0.6 mmol), 2-mercaptobenzothiazoles (0.5 mmol), Na2CO3 (1.0
mmol), H2O (2 mL) and the mixture was stirred for 24 h at 100 C.
The mixture was then cooled to r.t. and extracted with EtOAc (3 × 10
mL). The organic layers were combined, washed with sat. brine (2 ×
10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography.
Selected spectral data for 4-(benzo[d]thiazol-2-ylthio)aniline (Table 2,
1
entry 11): H NMR (300 MHz, CDCl3): = 6.74-6.77 (d, J = 8.0 Hz,
2H), 7.21-7.24 (t, 1H), 7.36-7.39 (t, 1H), 7.49-7.52 (d, J = 8.0 Hz,
2H, ), 7.62-7.63(d, J = 8.0 Hz, 1H), 7.83-7.85 (d, J = 8.0 Hz, 1H). 13
C
NMR (75 MHz, CDCl3): = 115.9, 116.8, 120.7, 121.6, 123.9, 126,
135.4, 137.6, 148.8, 154.3, 173.3.
5