Copper-catalyzed synthesis of substituted benzothiazoles via condensation of 2-aminobenzenethiols with nitriles

Article abstract of DOI:10.1021/ol400379z

An efficient and convenient method was developed for the formation of 2-substituted benzothiazoles via a copper-catalyzed condensation of 2-aminobenzenethiols with nitriles. The developed method is applicable to a wide range of nitriles containing different functional groups furnishing excellent yields of the corresponding products.

Full text of DOI:10.1021/ol400379z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Synthesis of
Substituted Benzothiazoles via
Condensation of 2‑Aminobenzenethiols
with Nitriles
Yadong Sun,†,‡ Huanfeng Jiang,*,† Wanqing Wu,† Wei Zeng,† and Xia Wu†
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China, and College of Chemistry and Chemical Engineering,
Xinjiang University, Urumqi 830046, China
jianghf@scut.edu.cn
Received February 7, 2013
ABSTRACT
An efficient and convenient method was developed for the formation of 2-substituted benzothiazoles via a copper-catalyzed condensation of
2-aminobenzenethiols with nitriles. The developed method is applicable to a wide range of nitriles containing different functional groups
furnishing excellent yields of the corresponding products.
Substituted benzothiazoles are present in many pharma-
ceuticals that exhibit remarkable biological and therapeu-
tic activities. For example, zopolrestat(1) has been usedfor
the treatment of diabetes,1 while 5F203 (2) and PMX 610
(3) show excellent antitumor activity;2 Schiff bases (4) are
used as amyloid inhibitors for treatment of Alzheimer’s
disease3 (Figure 1). Moreover, benzothiazole moieties are
also found in many functional molecules such as ratio-
metric fluorescent pH indicators and ligands for catalytic
reactions.4 Therefore, the fascinating biological profiles of
this group of compounds stimulated researchers to explore
Figure 1. Examples of bioactive substituted benzothiazoles.
† South China University of Technology.
efficient methods for the synthesis of benzothiazoles and
‡ Xinjiang University.
(1) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.;
their structural analogues.5
Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Singleton, D. H. J. Med.
Different synthetic methods have been developed for the
construction of benzothiazoles. Among these approaches,
Chem. 1991, 34, 108.
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Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem.
2006, 49, 179. (b) Aiello, S.; Wells, G.; Stone, E. L.; Kadri, H.; Bazzi, R.;
Bell, D. R.; Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.;
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ꢀ
r
10.1021/ol400379z
XXXX American Chemical Society

condensation of 2-aminobenzenethiols with carboxylic
acids or aldehydes is the most common. However, most
of these transformations involve the use of harsh reaction
conditions, such as high reaction temperature or strong
acidic or oxidative conditions (Figure 2a).6 An alternative
method is the cyclization of thioformanilides, which is
performed with the aid of transition-metal catalysts, radi-
cal condition, or Jacobson’s method.7 However, these
methods usually suffer from low functional group toler-
ance since in most cases the preparation of thioformani-
lides requires the use of P4S10 or Lawesson’s reagent.
Meanwhile, Ma and co-workers developed a copper-
catalyzed synthesis of benzothiazoles via coupling reac-
On the basis of the known ability of transition metals to
activate nitriles9 and recently developed copper-catalyzed
method for the construction of heterocycles or γ-lactones,10
we envisioned a direct synthesis of the substituted
benzothiazole by the reaction of 2-aminobenzenethiol
and nitriles involving transition-metal-catalyzed CÀS
and CdN bond formation. To explore this approach,
we selected 2-aminobenzenethiol (1a) and benzonitrile
(2a) for reaction development and screened several transi-
tion-metal catalysts in common solvents for their catalytic
activity. When 1a and 2a were reacted in the presence of 10
mol % of CuI at 80 °C for 6 h, 2-phenylbenzo[d]thiazole
(3a) was obtained in 38% yield (Table 1, entry 1). After
metal catalyst evaluation, we found that Cu(OAc)2 was
the best and afforded 3a with 81% GC yield (entry 6),
while other metals just led to low yields (entries 2À5). In
the absence of a metal source, no product formation was
observed (entry 7). Further investigation revealed that the
base played a critical role in this transformation (entries
8À12). Except for Et3N, almost all kinds of bases, includ-
ing NaOAc, NaHCO3, Na2CO3, NaOH, and t-BuONa,
were ineffective. The effects of different solvents were also
studied (entries 13 and 14). Ethanol was found to be the
best solvent, and the yield reached 86% (entry 14). Thus,
the optimal catalytic conditions consist of Cu(OAc)2
(10 mol %) and Et3N (1.0 equiv) in ethanol at 70 °C for 6 h.
tions of 2-haloanilides and Na2S 9H2O to solve this
3
problem.8 More recently, Lewis-acid-catalyzed cyclization
of orthoesters with 2-aminobenzenethiols has been re-
ported,5d but this reaction also needs the preparation steps
for the starting materials (Figure 2b). Therefore, a new
strategy for the synthesis of substituted benzothiazoles
from readily available materials under mild reaction con-
ditions needs to be explored (Figure 2c).
Table 1. Optimization of the Reaction Conditionsa
Figure 2. Strategies for the synthesis of benzothiazoles.
entry catalyst
base
Et3N
solvent
temp (°C) yieldb (%)
1
2
CuI
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
80
80
80
80
80
80
80
80
80
80
80
100
70
50
90
38
27
29
3
CuCl
ZnCl2
FeCl3
CuCl2
Et3N
Et3N
Et3N
Et3N
(6) (a) Riadi, Y.; Mamouni, R.; Azzalou, R.; Haddad, M.; Routier,
S.; Guillaumet, G.; Lazar, S. Tetrahedron Lett. 2011, 52, 3492. (b) Bose,
D. S.; Idrees, M. Synthesis 2010, 398. (c) Chen, F.; Shen, C.; Yang, D.
Tetrahedron Lett. 2011, 52, 2128. (d) Kangani, C.; Kelley, D.; Day, B.
Tetrahedron Lett. 2006, 47, 6497. (e) Wang, Y.; Sarris, K.; Sauer, D.;
Djuric, S. Tetrahedron Lett. 2006, 47, 4823. (f) Seijas, J.; Vazquez-Tato,
M.; Carballido-Reboredo, M.; Crecente-Campo, J.; Romar-Lopez, L.
Synlett 2007, 313.
(7) (a) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004,
446. (b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (c)
Wang, J.; Peng, F.; Jiang, J.; Lu, Z.; Wang, L.; Bai, J.; Pan, Y.
Tetrahedron Lett. 2008, 49, 467. (d) Inamoto, K.; Hasegawa, C.; Hiroya,
K.; Doi, T. Org. Lett. 2008, 10, 5147. (e) Saha, P.; Ramana, T.; Purkati,
N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74,
8719. (f) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991,
47, 10119. (g) Downer, N. K.; Jackson, Y. A. Org. Biomol. Chem. 2004,
2, 3039.
3
4
5
41
81
np
np
np
np
np
np
72
86
42
86
6
Cu(OAc)2 Et3N
Et3N
7
8
Cu(OAc)2 NaOAc
9
Cu(OAc)2 NaHCO3 1,4-dioxane
Cu(OAc)2 Na2CO3 1,4-dioxane
10
11
12
13
14
15
16
Cu(OAc)2 NaOH
1,4-dioxane
Cu(OAc)2 t-BuONa 1,4-dioxane
Cu(OAc)2 Et3N
Cu(OAc)2 Et3N
Cu(OAc)2 Et3N
Cu(OAc)2 Et3N
toluene
ethanol
ethanol
ethanol
(8) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew.
Chem., Int. Ed. 2009, 48, 4222.
(9) (a) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
(b) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
7790. (c) Suri, M.; Jousseaume, T.; Neumann, J. J.; Glorius, F. Green
Chem. 2012, 14, 2193.
a Conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10 mol %), base
(0.3 mmol), solvent (2.5 mL), 6 h. b GC yield based on 2a using dodecane
as internal standard.
(10) (a) Huang, L.; Jiang, H.; Qi, C.; Liu, X. J. Am. Chem. Soc. 2010,
132, 17652. (b) Qi, C.; Jiang, H.; Huang, L.; Yuan, G.; Ren, Y. Org. Lett.
2011, 13, 5520. (c) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.;
Jiang, H. Chem. Sci. 2012, 3, 3463. (d) Jiang, H.; Zeng, W.; Li, Y.; Wu,
W.; Huang, L.; Fu, W. J. Org. Chem. 2012, 77, 5179. (e) Guru, M. M.;
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M. M.; Punniyamurthy, T. J. Org. Chem. 2012, 77, 5063.
With the optimum reaction conditions in hand, a wide
range of aromatic nitriles and substituted 2-amino-
benzenethiols were examined to explore the scope of the
subsrrates, and the representative results are sum-
marized in Table 2. Generally, benzonitriles containing
B
Org. Lett., Vol. XX, No. XX, XXXX

electron-donating and electron-withdrawing groups were
well tolerated under the reaction conditions and gave the
corresponding benzothiazoles in moderate to excellent
yields. Additionally, this copper-catalyzed process exhib-
ited compatibility with several functional groups, such as
ether (3c), trifluoromethyl(3f), and nitrile(3g). Itshouldbe
noted that halides (3hÀk) were tolerated on the benzene
ring, enabling further derivatizations through metal-catalyzed
cross-coupling reactions. Furthermore, other aromatic or
heterocyclic nitriles such as 2-naphthonitrile and furan-
2-carbonitrile were also investigated and found to form
the desired products in good yields ranging from 80 to
90% (Table 2, entries 13 and 14). The presence of halide
on the 2-aminobenzenethiol did not interfere with the
formation of the benzothiazole ring. For instance,
when 2-amino-4-chlorobenzenethiol was used instead of
2-aminobenzenethiol, the yield remained quite stable at around
91% (Table 2, entry 15). A larger scale reaction (10 mmol
rather than the typical 0.5 mmol) was also conducted for
the synthesis of 3a. A substantial change in yield was not
observed for this larger scale reaction (that is, the yield for
the 10 mmol reaction was only 2% less than that of the
0.5 mmol reaction). Unfortunately, substitutions on the
ortho-position of benzonitriles had impact on the reaction;
for example, 2-methylbenzonitrile and 2-bromobenzonitrile
were ineffective in the reaction conditions.
To expand the scope of this methodology, a series of
aliphatic nitriles were employed to react with 2-aminoben-
zenethiol under the optimized conditions (Table 3). Var-
ious functional groups including cyclopropyl (3q) and
methoxyl (3v) were well tolerated under the standard
conditions, and the desired products were obtained in
excellent yields. In addition, aromatics containing substi-
tuted phenyl (3r, 3s, 3w), pyridyl (3t), and thienyl (3u) were
also good partners for this transformation. Interestingly, a
long chain nitrile such as dodecanenitrile could also be
employed to afford the desired product in 80% yield (3x).
However, instead of the desired benzothiazole product, the
attempt to use aliphatic nitrile with halide substituent such
as 4-chlorobutanenitrile just led to the formation of
thioether, which was formed by a nucleophilic substitution
reaction of 2-aminobenzenethiol with 4-chlorobutanenitrile.
Table 3. Reaction of 2-Aminobenzenethiol (1a) with Various
Aliphatic Nitrilesa
Table 2. Reaction of Substituted 2-Aminobenzenethiol (1a)
with Various Aromatic Nitrilesa
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), Cu(OAc)2
(10 mol%), Et3N (0.5 mmol), ethanol (2.5 mL), 70 °C, 6 h. b Isolated yields.
To further clarify the mechanism, several control experi-
ments were carried out, as shown in Figure 3. In experi-
ments 1 and 2, 2-aminobenzenethiol could transform to
diaryl disulfide (4) in the absence of nitrile. Treatment of 4
with 2a under optimized reaction conditions did not give
the desired product. On the basis of this result, 4 did not
play a significant role in the formation of benzothiazoles.
In experiments 4 and 5, no addition products could be
detected when aniline or 4-methylbenzenethiol was reacted
with 2a under the optimized reaction conditions.
a Reaction conditions: 1(0.5mmol),2(0.5mmol),Cu(OAc)2 (10mol%),
Et3N (0.5 mmol), ethanol (2.5 mL), 70 °C, 6 h. b Isolated yields.
According to the above observations and previous
reports in literature,9a a tentative proposal is outlined in
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 4. The present reaction should consist of sulfilimine
formation and intramolecular cyclization. Thus, copper
catalyst first promotes the nucleophilic attack of 1a to the
nitrile, probably through the coordination with intermedi-
ate A, to provide sulfilimine B. Then, a copper-induced
intramolecular nucleophilic addition of sulfilimine with
amine affords intermediate C, which releases copper and
NH3 to furnish benzothiazoles 3.
Figure 4. Proposed mechanism.
2-aminobenzenethiols and nitriles in the presence of Cu-
(OAc)2 catalyst. Both the 2-aminobenzenethiols and ni-
triles are cheap and commercially available. Considering
the diverse substrates, ethanol as the environmentally
friendly solvent, the inexpensive catalytic system, mild
conditions combined with an operationally simple proce-
dure render it a powerful component to traditional ap-
proaches for the synthesis of biologically important
compounds containing
a benzothiazole framework.
Further investigation of the reaction mechanism and the
synthetic applications is ongoing in our group.
Acknowledgment. We thank the National Natural
Science Foundation of China (20932002), National Basic
Research Program of China (973 Program) (2011CB808600),
Guangdong Natural Science Foundation (1035106410-
1000000), China Postdoctoral Science Foundation
(2011M501318), and the Fundamental Research Funds
for the Central Universities (2012ZB0011) for financial
support.
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Control experiments.
In conclusion, we have developed an efficient method
for the synthesis of 2-substituted benzothiazoles from
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX