Synthesis of 2-mercaptobenzothiazoles via DBU-promoted tandem reaction of o-haloanilines and carbon disulfide

Article abstract of DOI:10.1021/ol2011105

An efficient strategy for the synthesis of a variety of 2-mercaptobenzothiazole derivatives has been developed. The reaction proceeded from o-haloaniline derivatives and carbon disulfide via a tandem reaction in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the corresponding 2-mercaptobenzothiazole derivatives in good to excellent yields.

Full text of DOI:10.1021/ol2011105

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3202–3205
Synthesis of 2-Mercaptobenzothiazoles
via DBU-Promoted Tandem Reaction of
o-Haloanilines and Carbon Disulfide
Fei Wang, Shangjun Cai, Zhipeng Wang, and Chanjuan Xi*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, China, and State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
cjxi@tsinghua.edu.cn
Received April 27, 2011
ABSTRACT
An efficient strategy for the synthesis of a variety of 2-mercaptobenzothiazole derivatives has been developed. The reaction proceeded from
o-haloaniline derivatives and carbon disulfide via a tandem reaction in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the
corresponding 2-mercaptobenzothiazole derivatives in good to excellent yields.
2-Mercaptobenzothiazoles (MBTs), categorized as sig-
nificant derivatives of benzothiazoles, have frequently
been used as core structures for development of pharma-
ceutical agents.1 Recently, successful examples (Figure 1)
include heat shock protein-90 (HSP) inhibitors,2 cathep-
sin-D inhibitors3 and protoporphyrinogen IX oxidase
(PPO) inhibitors.4 Very recently 6-methyl-2-mercaptoben-
zothiazole was demonstrated as a radioprotective chemical,
which has been applied in the treatment of cancer patients
during radiotherapy in order to protect the normal tissues
adjacent to the treated tumor.5 6-Trifluoromethyl-2-mer-
captobenzothiazole was evaluated asa potent antibacterial
against Staphylococcus aureus, Escherichia coli, and other
clinical isolates with different antimicrobial resistance
profiles.6 Furthermore, profited by special electronizc
properties, MBTs spontaneously acted as a significant
ligand to metallic complexes, which were regarded as the
promising luminescent materials.7 Conventionally, proto-
cols for preparation of 2-mercaptobenzothiazoles included
the reaction of thiocarbanilide with sulfur or interaction of
o-aminothiophenol with carbon disulfide under high
pressure.8 Another way to prepare 2-mercaptobenzothia-
zoles was by nucleophilic aromatic substitution (SNAr)
(1) (a) Wilde, R. G.; Billheimer, J. T.; Germain, S. J.; Gillies, P. J.;
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r
10.1021/ol2011105
Published on Web 05/17/2011
2011 American Chemical Society

of various useful heterocyclic compounds via CꢀX (X =
N, O, and S) bond formation.10ꢀ12 For example, ben-
zothiazole could be efficiently formed via S-arylation/
condensative cyclization processes.12aꢀd More recently,
our group performed copper-catalyzed reactions for
the synthesis of heterocycles by using heterocumu-
lenes such as isothiocyanates and carbodiimides, which
provided a straightforward method to heterocyclic
compounds.13 Encouraged by these results, we first
screened copper-catalyzed reaction conditions by using
o-iodoaniline and carbon disulfide as a model reaction
(Table 1). Surprisingly, a more highly efficient tandem
reaction for the synthesis of 2-mercaptobenzothiazole
derivatives was observed in the absence of a copper
salt (entry 12, Table 1). Herein, we report the unex-
pected transition-metal-free intramolecular tandem
condensation/S-arylation reaction of o-haloanilines
and carbon disulfide leading to 2-mercaptobenzothia-
zole derivatives.
Initially, we used the o-iodoaniline 1a and carbon dis-
ulfide as the starting materials and CuI as catalyst, Cs2CO3
as base in toluene at 80 °C. However, the product 2a was
not observed, and only the starting material 1a was
remained (Table 1, entry 1). Then different bases such as
K2CO3, K3PO4, tBuONa, Et3N, 1,4-diazobicyclo[2.2.2]oc-
tane (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) were screened (entries 2ꢀ7). The results demon-
strated that the organic bases were efficient than inorganic
bases. DBU showed an excellent performance as base
in the reaction condition (entry 7). No reaction was
observed in the absence of a base (entry 8). Next, the
ligands were examined in the reaction. N,N0-dimethyl-
ethane-1,2-diamine (DMEDA), N,N,N0,N0-tetramethyl-
ethane-1,2-diamine (TMEDA), and 1,10-phenanthroline
gave the similar yield compared with ligand free condition
(entries 9ꢀ11). Surprisingly, the reaction also worked well
in the absence of a copper catalyst at 80 °C (entry 12). The
solvents were also evaluated in the reaction. Toluene was
superior to 1,4-dioxane, CH3CN, DMF, and DMSO
(entries 13ꢀ16). The reaction showed a dependence on
the temperature. When the reaction was treated at 70 °C,
the yield was moderate and a considerable amount of
stating material 1a remained (entry 17).
Figure 1. Examples of some biologically active compounds.
reaction of a potassium/sodium o-ethyl dithiocarbonate
with o-haloaniline followed by a subsequent cycli-
zation.6,9 Although some approaches to the 2-mercap-
tobenzothiazole derivatives have been developed, the
methods often suffer from harsh reaction conditions,
limited substrates, poor substituent tolerance, and
low yields. Accordingly, development of a facile and
scalable route to construct the MBT scaffold is still
desirable.
Recently, a transition-metal-mediated cascade reaction
provided a straightforward method for the synthesis
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see: (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
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On the basis of these results, the optimal condition
involved the following parameters: DBU as a base,
toluene as a solvent, and reaction temperature at
80 °C. Under these optimized conditions, a study on
the substrate scope was carried out, and the results are
summarized in Table 2. First, we used o-iodoaniline
derivatives 1 to react with carbon disulfide. Both
methyl group and fluorine atom on phenyl showed
good performance (entries 2 and 3). Then o-bromoan-
iline and its derivatives were applied under the reaction
conditions at 100 °C. In general, electron-donating and
electron-withdrawing substituents on the o-bromoan-
iline ring have generated 2-mercaptobenzothiazoles in
(12) For recent reactions based on CꢀS bond formation, see: (a)
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Org. Lett., Vol. 13, No. 12, 2011
3203

Table 1. Optimization between o-Iodoaniline and Carbon
Disulfidea
Table 2. Synthesis of 2-Mercaptobenzothiazole Derivativesa
yield of
temp (°C) 2a (%)b
entry
base
ligand
solvent
toluene
1
Cs2CO3
K2CO3
K3PO4
tBuONa
Et3N
80
80
80
80
80
80
80
80
80
80
80
NR
NR
NR
33
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3
4
5
57
6
DABCO
DBU
65
7
86
8
NR
83
9
DBU
DBU
DBU
DMEDA
TMEDA
10
11
80
1,10-phenan- toluene
throline
82
12c DBU
toluene
80
80
80
80
80
70
84
79
54
44
41
68
13
14
15
16
17
DBU
DBU
DBU
DBU
DBU
1,4-dioxane
CH3CN
DMF
DMSO
toluene
a Unless otherwise noted the reactions were performed in a sealed
tube with 1a (0.5 mmol), carbon disulfide (1.0 mmol), CuI (10 mol %),
and ligand (20 mol %) in solvent (1 mL) for 24 h. b The yields were
evaluated by NMR with Cl2CdCHCl as internal standard. c CuI was not
added in the reaction.
good to excellent yields. para-Substituents ranging
from a weak electron-withdrawing group, such as
Br, to a strong electron-withdrawing group, such as
CO2Me, CF3O, and CN, along with an electron-donating
Me group, all generated the corresponding substi-
tuted 2-mercaptobenzothiazole derivatives in satisfying
yields (entries 5ꢀ11). A substrate with two substituents
situated para and ortho to amino group also afforded a
high yield of the corresponding 2-mercaptobenzothia-
zole derivatives (entries 12ꢀ15). It is noteworthy that
when o-chloroaniline was used, the reaction did not
proceed even when the reaction was treated at 120 °C
for 36 h.
On the basis of the above results, the mechanism of
this reaction is proposed as shown in Scheme 1. In the
presence of organic base, such as DBU,14 the nucleo-
philic nitrogen of o-haloaniline 1 would attack the
carbon atom of carbon disulfide, which might be acti-
vated by DBUHþ to form intermediate 3 (step a). The
a Unless otherwise noted the reactions were performed in a sealed
tube with 1 (0.5 mmol), carbon disulfide (1.0 mmol), and DBU
(1.0 mmol) in toluene (1 mL). b Isolated yields.
intermediate 3 could convert into the product 2 via an
intramolecular SNAr reaction (step b).
In summary, we have developed a simple, practical,
and highly efficient base-promoted method for the synthesis
of 2-mercaptobenzothiazole derivatives. The protocol uses
readily available anilines and carbon disulfide as the
(14) (a) Wang, F.; Wang, Y.; Cai, L.; Miao, Z.; Chen, R. Adv. Synth.
Catal. 2008, 350, 2733. (b) Uchiyama, M.; Ozawa, H.; Takuma, K.;
Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett.
2006, 8, 5517.
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Org. Lett., Vol. 13, No. 12, 2011

utilization of any metals, and therefore compounds are
of potential interest in both academic and pharmaceu-
tical research. Further application of the system to
pharmaceutical and biochemical areas is in progress.
Scheme 1. Proposed Reaction Pathway
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20872076,
20972085, and 21032004) and by Specialized Research
Fund for the Doctoral Program of Higher Education
(200800030072).
Supporting Information Available. Experimental pro-
cedures and full characterization including 1H NMR
and 13C NMR data for compounds 2aꢀ2l. This material
is available free of charge via the Internet at http://pubs.
acs.org.
starting materials under the mild condition to afford
the corresponding 2-mercaptobenzothiazoles in good
to excellent yields. Furthermore, the reaction avoids
Org. Lett., Vol. 13, No. 12, 2011
3205