Efficient 2-aryl benzothiazole formation from aryl ketones and 2-aminobenzenethiols under metal-free conditions

Article abstract of DOI:10.1021/ol302902e

2-Aryl benzothiazole formation from aryl ketones and 2-aminobenzenethiols under metal- and I₂-free conditions was described. Various 2-aryl benzothiazoles were selectively obtained in good yields using molecular oxygen as oxidant. DMSO played an important role in this transformation. Functional groups such as methyl, methoxy, fluoro, chloro, bromo and nitro groups were tolerated under the optimized reaction conditions.

Full text of DOI:10.1021/ol302902e

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6004–6007
Efficient 2‑Aryl Benzothiazole Formation from
Aryl Ketones and 2‑Aminobenzenethiols
under Metal-Free Conditions
Yunfeng Liao,† Hongrui Qi,† Shanping Chen,† Pengcheng Jiang,† Wang Zhou,‡ and
Guo-Jun Deng*,†
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China, and
College of Chemical Engineering, Xiangtan University, Xiangtan 411105, China
gjdeng@xtu.edu.cn
Received October 21, 2012
ABSTRACT
2-Aryl benzothiazole formation from aryl ketones and 2-aminobenzenethiols under metal- and I2-free conditions was described. Various 2-aryl
benzothiazoles were selectively obtained in good yields using molecular oxygen as oxidant. DMSO played an important role in this transformation.
Functional groups such as methyl, methoxy, fluoro, chloro, bromo and nitro groups were tolerated under the optimized reaction conditions.
Aryl-substituted benzothiazoles are one of the most
important classes of heterocycles and have shown a wide
range of biological activities, such as antitumor, antiviral,
and antimicrobial activities.1 In addition, benzothiazole
moieties have been found frequently in other molecules
such as industrial dyes, natural products, functional ma-
terials, and agrochemical compounds.2 Consequently, de-
velopment of efficient methods for rapid construction of
aryl-substituted benzothiazoles has stimulated consider-
able interest. The conventional methods for the synthesis
of these important compounds typically involve two
approaches. One is the metal-catalyzed intramolecular
cyclization of o-haloanilides or their analogues (Scheme 1, a).3
The second approach mainly involes the condensation of
2-aminobenzenethiol with either a carboxylic acid derivative
under strong acid/high temperature conditions or an aromatic
aldehyde under strong oxidative conditions (Scheme 1, b).4
Recently, Ma and Jiang developed a novel and practical
synthesis of substituted benzothiazoles from 2- haloanilides
and metal sulfides using CuI as catalyst under mild reaction
conditions.5 Meanwhile, aryl-substituted benzothiazoles have
been successfully synthesized by direct CÀH activation and
subsequent arylation of benzothiazoles with aryl halides,6
arylsilanes,7 aromatic carboxylic acids,8 aryl boronic acids,9
sodium sulfinates and aryl triflates,10 aldehydes,11 and even
with arene CÀH bonds via double CÀH activations.12
† College of Chemistry, Xiangtan University
‡ College of Chemical Engineering, Xiangtan University
(1) (a) Zirngibl, L. Antifungal Azoles: A Comprehensive Survey
of Their Structures and Properties; Wiley-VCH: Weinheim, 1998.
(b) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. Comprehensive Hetero-
cyclic Chemistry III; Pergamon: Oxford, 1999; Vol. 1. (c) Katritzky, A.;
Pozharskii, A. Handbook of Heterocyclic Chemistry, 1st ed.; Pergamon:
Oxford, 2003.
The preparation of substituted benzothiazoles under
transition-metal free conditions is highly desirable espe-
cially for pharmaceutical purposes due to the low threshold
(2) Hartley, D.; Kidd, H. The Agrochemical Handbook; Royal Society
of Chemistry: Nottingham, 1983. (b) Baker, D. R.; Basarab, G. S.; Fenyes,
J. G. Synthesis and Chemistry of Agrochemicals IV; American Chemical
Society: Washington D. C., 1995.
(3) For selected examples, see: (a) Evindar, G.; Batey, R. A. J. Org.
Chem. 2006, 71, 1802. (b) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71,
8261. (c) Itoh., T.; Mase, T. Org. Lett. 2007, 9, 3687. (d) Saha, P.;
Ramana, T.; Purkait, N.; Ali, M.; Paul, R.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 8719. (e) Wang, H.; Wang, L.; Shang, J.; Li, X.; Wang,
H.; Gui, J.; Lei, A. W. Chem. Commun. 2012, 48, 76. (f) Bernardi, D.; Ba,
L. A.; Kirsch, G. Synlett 2007, 2121. (g) Benedi, C.; Bravo, F.; Uriz, P.;
Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073.
(4) (a) Riadi, Y.; Azzalou, R.; Lazar, S.; Mamouni, R.; Haddad, M.;
Routier, S.; Guillaumet, G. 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.
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Chem., Int. Ed. 2009, 48, 4222.
r
10.1021/ol302902e
Published on Web 11/14/2012
2012 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Pathways for 2-Arylbenzothiazole Formation
yield (%)b
3a 4a
entry
solvent
additive
1
toluene
DMF
PhCl
0
0
0
2
0
3
0
0
4
DMSO
PhCl
54
53
60
82
50
50
20
28
59
65
trace
30
5
DMSO (1 mL)
13
6
PhCl
DMSO (1.5 mmol)
DMSO (1.0 mmol)
DMSO (0.5 mmol)
DMSO (1.0 mmol)
DMSO (1.0 mmol)
DMSO (1.0 mmol)
DMSO (1.0 mmol)
DMSO (1.0 mmol)
DMSO (1.0 mmol)
trace
7
PhCl
PhCl
trace
8
0
0
1
2
0
0
0
9
toluene
NMP
H2O
10
11
12c
13d
14e
residual tolerance of metals. Aromatic ketones are cheap,
commercially available and relatively stable. The sp3 CÀH
bond of aromatic ketones can be activated by transition
metals under oxidative reaction conditions.13 Very recently,
the research groups of Wu and Prabhu developed various
PhCl
PhCl
PhCl
a Conditions: 1a (0.9 mmol), 2a (0.5 mmol), solvent (2.0 mL), 16 h,
140 °C under oxygen unless otherwise noted. b GC yield based on 2a
using dodecane as internal standard. c Under air. d At 120 °C. e Under
argon.
(6) For selected reviews on CÀH functionalization, see: (a) Dyker, G.
Handbook of C-H Transformations: Applications in Organic Synthesis;
Wiley-VCH: Weinheim, 2005. (b) Yu, J.; Shi, Z. CÀH Activation; Springer:
Berlin, 2010. (c) Goldberg, K. I.; Goldman, A. S. Activation and Functio-
nalization of CÀH Bond, ACS Symposium Series 885; American Chemical
Society: Washington D. C., 2004. For recent selected examples, see: (d)
Turner, G.; Morris, J.; Greaney, M. Angew. Chem., Int. Ed. 2007, 46, 7996.
(e) Do, H.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (f) Canivet,
J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (g) Zhao,
D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew.
Chem., Int. Ed. 2009, 48, 3296. (h) Huang, J.; Chan, J.; Chen, Y.; Borths,
C.; Kyle, K.; Larsen, R.; Margaret, M. J. Am. Chem. Soc. 2010, 132,
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46, 2471. (j) Shibahara, F.; Yamaguchi, E.; Murai, T. J. Org. Chem.
2011, 76, 2680. (k) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet,
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6, 169. (c) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12,
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Chem. 2011, 9, 7675. (e) Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. S.
Chem.;Eur. J. 2011, 17, 13415. (f) So, C.; Lau, C.; Kwong, F. Chem.;
Eur. J. 2011, 17, 761.
efficient approaches for aryl ketone sp3 CÀH bond functio-
nalization under transition-metal-free conditions. However,
in most cases, I2 or N-iodosuccinamide (NIS) is used to
activate the less reactive sp3 CÀH bond adjacent to the
carbonyl group in aromatic ketones.14 The preparation of
2-aryl benzothiazoles from aryl ketones under metal and I2
free conditions is a challenge. Herein, we report an efficient
approach for 2-aryl substituted benzothiazoles from 2-ami-
nobenzenethiols and aryl ketones under metal- and I2-free
conditions using molecular oxygen as oxidant (Scheme 1, c).
We began our study by examining the reaction of 2-ami-
nobenzenethiol (1a) with acetophenone (2a) in organic
solvents by using molecular oxygen (1 atm) as oxidant at
140 °C. When acetophenone reacted with 1.8 equiv of
2-aminobenzenethiol in the absence of any catalyst, no
desired product 3a was obtained in common organic sol-
vents such as toluene, DMF and chlorobenzene as deter-
mined by GC and 1H NMR methods (Table 1, entries 1À3).
DMSO was proved to be an efficient reaction media for this
kind of transformation, and the use of DMSO resulted the
desired product 3a in 54% yield together with 30% yield of
acylated adduct 4a (entry 4). A mixture of DMSO with
chlorobenzene was also proved to be good solvent for the
condensation reaction. Good yield was obtained when the
amount of DMSO decreased to 2 equiv, and the desired
product was obtained in 82% yield, and only trace amount
of byproduct 4a was observed (entry 7). DMSO played an
important role for this kind of transformation. Decreasing
the amount of DMSO decreased the reaction yield signifi-
cantly (entry 8). The replacement of chlorobenzene with
other solvents decreased the reaction yield (entries 9À11).
(11) Liu, S.; Chen, R.; Guo, X.; Yang, H.; Deng, G. J.; Li, C.-J. Green
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Chem. Commun. 2011, 47, 12876. (e) Nishino, M.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2012, 51, 6993.
(13) Du, F.; Ji, J. X. Chem. Sci. 2012, 3, 460.
(14) (a) Zhu, Y.; Jia, F.; Liu, M.; Wu, A. X. Org. Lett. 2012, 14, 4414.
(b) Zhu, Y.; Jia, F.; Liu, M.; Wu, L.; Cai, Q.; Gao, Y.; Wu, A. X. Org.
Lett. 2012, 14, 5378. (c) Zhu, Y.; Lian, M.; Jia, F.; Liu, M.; Yuan, J.;
Gao, Q.; Wu, A. X. Chem. Commun. 2012, 48, 9086. (d) Lamani, M.;
Prabhu, K. R. Chem.;Eur. J. 2012, 18, 14638. (e) Zhu, Y.; Jia, F.; Yuan,
J.; Gao, Q.; Lian, M.; Wu, A. X. Org. Lett. 2012, 14, 3392. (f) Zhu, Y.;
Gao, Q.; Lian, M.; Yuan, J.; Liu, M.; Zhao, Q.; Yang, Y.; Wu, A. X.
Chem. Commun. 2011, 47, 12700.
Org. Lett., Vol. 14, No. 23, 2012
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Table 2. Reaction of 2-Aminobenzenethiol (1a) with Various
Ketonesa
Table 3. Reaction of Various 2-Aminobenzenethiols with Aryl
Ketonesa
a Conditions: 1 (0.9 mmol), 2 (0.5 mmol), DMSO (1.0 mmol), PhCl
(2.0 mL), 140 °C, 16 h, under oxygen. b Isolated yield based on 2. c 1 equiv
of DMSO was used.
coupling of heteroaromatic ketones such as 4-acetylpyr-
idine (2m) and 2-acetylthiophene (2n) with 1a afforded 3j
and 3k in 55 and 60% yields, respectively (entries 13 and 14).
Unfortunately, aliphatic ketones are not suitable substrates
for this kind of transformation under the optimal conditions.
To further explore the scope of the reaction, various
2-aminobenzenethiols were employed to react with 2a
under the optimized conditions (Table 3). A series of
functional groups including methyl, methoxy, chloro and
bromo were well tolerated under the optimal conditions,
and the desired products were obtained in moderate to
good yields (Table 3, entries 1À4). The position of the
substituents on the phenyl ring of 2-aminobenzenethiols
affected the reaction yield significantly, and the use of
2-amino-3-chlorothiophenol (1g) only gave a trace amount
of product (entry 6). An electron-donating group in the
phenyl ring of 2-aminobenzenethiol could improve the
reaction yield slightly, and the reaction of 2-amino-5-meth-
oxythiophenol (1c) with various aromatic ketones all re-
sulted the desired products in good yields (entries 8À11).
To get more information about the reaction mechanism,
several control experiments were set up under the standard
conditions. The reaction of 2-aminobenzenethiol with
acetophenone in 1 h mainly gave an imine intermediate
a Conditions: 1a (0.9 mmol), 2 (0.5 mmol), DMSO (1.0 mmol), PhCl
(2.0 mL), 140 °C, 16 h, under oxygen. b Isolated yield based on 2.
Moderate yield was obtained when the reaction was carried
out under an atmosphere of air (entry 12). The reaction
temperature was another important factor for the yield of
the product. The reaction yield decreased to 65% when the
reaction temperature was decreased to 120 °C (entry 13).
Under the optimized reaction conditions, the scope and
generality of the oxidative condensation was explored
(Table 2). Besides acetophenone, other aromatic carbonyl
compounds such as propiophenone (2b), ethyl benzoyla-
cetate (2c) and benzaldehyde (2d) were also successfully
reacted with 1a and gave the desired products in good
yields (entries 2À4). The reactions with aromatic ketones
bearing electron-donating groups at the aromatic ring
proceeded smoothly to give the desired products in good
yields (entries 5 and 6). The position of substituents on
phenyl ring of aryl ketones affected the reaction yield
slightly (entries 8 and 9). Functional groups such as fluoro,
chloro, trifluoromethyl and nitro were well tolerated under
the optimized conditions (entries 7À11). Notably, the
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Org. Lett., Vol. 14, No. 23, 2012

and 4a (Scheme 2, c). Further treatment of 4a under the
standard reaction conditions did not yield 3a. This means
the reaction did not take a decarbonylative pathway. In
addition, we performed a 13C labeling experiment under
the optimized conditions with acetophenone-R-13C, and
the desired product 5a was obtained in 80% yield together
with 20% of 6a (Scheme 2, d). On the basis of these
observations, a plausible mechanism to rationalize this
transformation is illustrated in Scheme 3, although the role
of DMSO is not clear at this stage. Condensation of 1a
with 2a generates the corresponding imine intermediate A,
which can becyclizedtoformanintermediateB. Oxidation
of the methyl group generates an aldehyde compound C.
The elimination of a proton and CHO group generates the
final product 3a.
Scheme 2. Control Experiments
In summary, we have developed an efficient 2-aryl
benzothiazole formation from 2-aminobenzenethiols and
aryl ketones using molecular oxygen as oxidant under
metal- and I2-free conditions. Solvent played an important
role in this transformation, and the best yield was obtained
in a mixture of DMSO/chlorobenzene. Functional groups
such as methyl, methoxy, fluoro, chloro, bromo and nitro
groups were all well tolerated under the optimized reaction
conditions. This method affords a cheap and efficient
alternative route for the rapid synthesis of heteroaromatic
biaryls. The scope, mechanism, and synthetic applications
of this reaction are under investigation.
Scheme 3. Proposed Mechanism
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20902076,
21172185), the Hunan Provincial Natural Science Foun-
dation of China (11JJ1003), the New Century Excellent
Talents in University from Ministry of Education of China
(NCET-11-0974) and the Scientific Research Foundation
for Returned Scholars, Ministry of Education of China
(2011-1568).
and the desired product 3a was formed in only 6.8% yield
as determined by GC (Scheme 2, a). However, the desired
product could be improved to 50.7% when the reaction
time was prolonged to 3 h (Scheme 2, b). The reaction of
2-aminobenzenethiol with phenylglyoxal, which is a key
intermediate in the ketone functionalization under I2
promoted oxidative conditions,14 gave a mixture of 3a
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.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
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