Convenient synthesis of benzothiazoles and benzimidazoles through bronsted acid catalyzed cyclization of 2-amino thiophenols/anilines with β-diketones

Article abstract of DOI:10.1021/ol403475v

Bronsted acid catalyzed cyclization reactions of 2-amino thiophenols/anilines with β-diketones under oxidant-, metal-, and radiation-free conditions are described. Various 2-substituted benzothiazoles/benzimidazoles are obtained in satisfactory to excellent yields. Different groups such as methyl, chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.

Full text of DOI:10.1021/ol403475v

Letter
pubs.acs.org/OrgLett
Convenient Synthesis of Benzothiazoles and Benzimidazoles
through Brønsted Acid Catalyzed Cyclization of 2‑Amino
Thiophenols/Anilines with β‑Diketones
Muhammad Shareef Mayo,† Xiaoqiang Yu,*,† Xiaoyu Zhou,† Xiujuan Feng,† Yoshinori Yamamoto,†,‡
and Ming Bao*,†
†State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
‡WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University, Sendai 980-8577, Japan
S
* Supporting Information
ABSTRACT: Brønsted acid catalyzed cyclization reactions of
2-amino thiophenols/anilines with β-diketones under oxidant-,
metal-, and radiation-free conditions are described. Various 2-
substituted benzothiazoles/benzimidazoles are obtained in
satisfactory to excellent yields. Different groups such as methyl,
chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.
ynthesis of privileged benzothiazoles and benzimidazoles
through an economical and environment friendly method
method involves the condensation reactions of 2-amino
thiophenols/anilines with β-ketonitriles,6 β-ketoesters,7 or β-
diketones8 under microwave radiation and high temperature
conditions (Scheme 1, eq 3).
S
is always desirable because benzothiazole moieties are of
paramount interest in medicinal chemistry due to their
antitumor, anticancer, and antimicrobial activities.1 The
benzimidazole structural motif is also a building block of
pharmaceutics and functional materials.2
Over the past few decades, three main methods have been
developed for the synthesis of benzothiazoles and benzimida-
zoles. One method involves the condensation reactions of 2-
amino thiophenols/anilines with carboxylic acids3 or aldehydes4
under oxidative conditions (Scheme 1, eq 1). Another method
involves the transition-metal-catalyzed intramolecular cycliza-
tion of 2-haloanilides/analogues (Scheme 1, eq 2).5 The last
Recently, metal-free methods for the synthesis of benzothia-
zoles and benzimidazoles through the cyclization reaction of 2-
amino thiophenols/anilines with alkyl amines9 or aryl ketones10
at high temperature under oxidative conditions were also
reported. However these methods have one or more short-
comings such as microwave radiation, metal catalysts, additives,
and/or high temperature conditions which adversly affect the
economics as well as the ecofriendly nature of the reaction.
In the course of our research on the development of efficient
methods for heterocycle synthesis,11 we found that benzothia-
zoles and benzimidazoles can readily be obtained from the
Brønsted acid catalyzed cyclization reactions of 2-amino
thiophenols/anilines with β-diketones (Scheme 1, eq 4). The
results are reported in this paper.
Scheme 1. Pathways for the Synthesis of Benzothiazoles and
Benzimidazoles
In our initial studies, the reaction of 2-amino thiophenol (1a)
with 2,4-pentanedione (2a) was chosen as a model to optimize
the reaction conditions. The results are shown in Table 1. No
reaction was observed when 1a and 2a were treated in
acetonitrile (CH3CN) at room temperature in the absence of
an acid catalyst (entry 1). However, the desired product 2-
methyl benzothiazole (3a) was obtained in more than 99%
yield merely by using p-toluene sulfonic acid (TsOH·H2O) as a
catalyst (entry 2).
Then we tried different acids such as benzoic acid
(PhCOOH), trifluoroacetic acid (CF3COOH), and acetic
acid (CH3COOH). The results show that CF3COOH and
TsOH·H2O are equally effective for this reaction (entries 2−5).
However TsOH·H2O was chosen as a catalyst for solvent
Received: December 1, 2013
© XXXX American Chemical Society
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Letter
a
a
Table 1. Reaction Condition Screening
Table 2. Synthesis of Benzothiazoles
b
entry
acid catalyst/mol %
solvent
yield (%)
c
1
none
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
NR
2
TsOH·H2O/10
PhCOOH/10
CF3COOH/10
CH3COOH/10
TsOH·H2O/10
TsOH·H2O/10
TsOH·H2O/10
TsOH·H2O/10
TsOH·H2O/5
TsOH·H2O/2
TsOH·H2O/1
>99
67
3
4
>99
65
5
6
93
7
DCE
>99
91
8
EtOH
none
d
9
>99
d
10
11
12
none
>99
d
none
88
d
none
71
a
Reaction conditions: 2-amino thiophenol (1a, 0.5 mmol), 2,4-
pentanedione (2a, 0.75 mmol), acid catalyst, and solvent (4 mL) at
b
room temperature for 16 h. GC yield; 5-methoxy indole was used as
c
d
an internal standard. No reaction. 1.0 mmol of 1a and 1.5 mmol of
2a were used.
screening due to its low cost and ease in handling. The product
3a was obtained in almost the same excellent yield when the
solvents CH3CN, tetrahydrofuran (THF), 1,2-dichloroethane
(DCE), and ethanol (EtOH) were examined (entries 2 and 6−
8). These results indicate that the solvent has negligible
influence on the reaction. Therefore, the reaction of 1a with 2a
under solvent-free conditions was performed. As expected, the
product 3a was obtained in the same yield, as was obtained by
using the solvent (entry 9). The product 3a was also obtained
in more than 99% yield when the acid catalyst loading was
decreased from 10 to 5 mol % (entry 10). However, a further
decrease in acid catalyst loading resulted in relatively low yields
of 3a (entries 11 and 12). Therefore, we decided to perform the
subsequent reactions of the 2-amino thiophenols with various
β-diketones in the presence of TsOH·H2O as a catalyst at room
temperature under solvent-free conditions for 16 h.
a
Reaction conditions: 2-amino thiophenol (1, 1.0 mmol), β-diketone
(2, 1.5 mmol), and TsOH·H2O (5 mol %, 9.51 mg) at room
b
temperature under solvent-free conditions for 16 h. Isolated yield.
c
d
No reaction. The reaction of 0.5 mmol of 2-amino thiophenol with
0.75 mmol of β-diketone was carried out in acetonitrile (4 mL) at 80
°C for 16 h. Toluene was used as the solvent instead of acetonitrile;
e
Table 2 shows the results of Brønsted acid (TsOH·H2O)
catalyzed cyclization reactions of 2-amino thiophenols with
various β-diketones. An excellent yield similar to that of 3a was
observed when the reaction of 2a with 3,5-heptanedione (2b)
was carried out under optimized reaction conditions (entry 1 vs
2; 3a, 92%; 3b, 90%). The reaction of 1a with a sterically
hindered β-diketone 2,6-dimethylheptane-3,5-dione (2c) pro-
vided the desired product 3c in moderate yield (entry 3, 65%).
Reactions of 4-chloro-2-amino thiophenol (1b), a solid
substrate, with 2a or 2b also proceeded smoothly under the
solvent-free conditions to provide the desired products 3d and
3e in satisfactory yields (entries 4 and 5; 75% and 71%,
respectively). No reaction was observed when a mixture of the
solid 1b and the sterically hindered 2c was treated under the
solvent-free conditions (entry 6). Delightfully, the benzothia-
zole product 3f was finally obtained in 63% yield when the
reaction of 1b with 2c was performed in CH3CN at 80 °C
(entry 7). As expected, the yields of 3d and 3e were improved
by using CH3CN as a solvent at 80 °C (entries 8 and 9; 86%
and 89%, respectively). The 2-aryl-substituted product, 2-
phenyl benzothiazole (3g), could also be obtained from the
reaction of 1a with 1,3-diphenylpropane-1,3-dione (2d) in
the reaction was carried out in a sealed reactor at 130 °C.
CH3CN at 80 °C though the yield was relatively low (entry 10,
51%). The yield of 3g was increased to 85% when the reaction
was performed at high temperature (entry 11, 130 °C). No
reaction was observed when a mixture of 1a and a more
sterically hindered β-diketone, 1,3-di(tert-butyl)propane-1,3-
dione (2e), was treated even at high temperature (entry 12).
Finally, the reaction of 1a with an unsymmetric β-diketone, 1-
methyl-3-phenyl-1,3-dione (2f), was examined, and product 3a
was obtained in 75% yield (entry 13). This result indicates that
the reactivity of the acetyl group is higher than that of the
benzoyl group.
Then, we examined the reactions of 2-amino anilines with
various β-diketones in the presence of TsOH·H2O as a catalyst
at room temperature with or without solvent. No reaction was
observed under those conditions as mentioned above.
However, we found that the desired reaction could occur in
the presence of TsOH·H2O as a catalyst in CH3CN at 80 °C to
furnish benzimidazoles in satisfactory to excellent yields. The
results are shown in Table 3. Benzimidazole products 5a−5c
B
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Letter
a
2a and 2b, respectively, proceeded smoothly to give
benzimidazole products 5e, 5f, and 5h−5n in 60%−95% yields
(entries 5, 6, and 9−15). These results indicate that substituent
property (electron-donating or -withdrawing) has almost no
influence on the reactivity of 2-amino aniline substrates. The
low reactivity of 2d was demonstrated again in its reaction with
4b. 2-Phenyl-substituted benzimidazole 5g was isolated in 54%
yield (entry 7). Benzimidazole 5e was obtained in 72% yield as
a major product along with 23% of benzimidazole 5g when the
unsymmetric β-diketone 2f was treated with 4b (entry 8).
To explore the mechanism of this type of cyclization
reaction, a mixture of 1a and 2a was treated under solvent-free
conditions at room temperature for a short time (30 min). The
result is shown in Scheme 2. As expected, an intermediate 4-
Table 3. Synthesis of Benzimidazoles
Scheme 2. Controlled Experiment
[(2-mercaptophenyl)imino]pentan-2-one (6) was isolated in
35% yield along with the final product 3a (61% yield). It was
found that the intermediate 6 could easily be transformed to
the final product 3a in the presence of TsOH·H2O as the
catalyst in CH3CN at room temperature.
A plausible mechanism for the Brønsted acid catalyzed
cyclization reactions of 2-amino thiophenols/anilines with β-
diketones is shown in Scheme 3. The Brønsted acid catalyzed
Scheme 3. A Proposed Mechanism
a
Reaction conditions: 2-amino aniline (4, 0.5 mmol), β-diketone (2,
0.75 mmol), and TsOH·H2O (5 mol %, 4.755 mg) in CH3CN (4 mL)
condensation reaction of 1a with 2a would take place to
generate a ketimine intermediate 6. Ketiminium intermediate 7
would generate in the presence of TsOH·H2O. The intra-
molecular nucleophilic addition of 7 would produce adduct 8.
The C−C bond cleavage reaction would finally occur to
generate product 3a.
In summary, we have developed a convenient and efficient
method for the synthesis of benzothiazoles and benzimidazoles.
The mild reaction conditions (no oxidant, no metal catalyst, no
radiation, and low temperature), experimental simplicity, simple
and readily available starting materials, and broad substrate
scope are the features of the novel and general method
proposed in this paper. Further study focusing on the extension
of the reaction scope using 2-hydroxy anilines is underway.
b
c
at 80 °C for 16 h. Isolated yield. Benzimidazole 5g was also isolated
d
as a minor product in 23% yield. The reaction was carried out in the
presence of 10 mol % TsOH·H2O for 24 h.
were isolated in 55%−95% yields from the reactions of 2-amino
aniline (4a) with β-diketones 2a, 2b, and 2c bearing aliphatic
i
groups (Me, Et, and Pr) on their 1,3-positions, respectively
(entries 1−3). The product 2-phenyl benzimidazole (5d) was
also obtained in relatively low yield (49%) due to the low
reactivity of β-diketone 2d bearing aromatic groups on its 1,3-
position (entry 4). The reactions of 2-amino-4-chloro aniline
(4b), 2-amino-4-methyl aniline (4c), 2-amino-4-methoxy
aniline (4d), and 2-amino-4-nitro aniline (4e) with β-diketones
C
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yuxiaoqiang@dlut.edu.cn.
*E-mail: mingbao@dlut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21273026 and 21073025) for their financial
support. This work was also supported by the Fundamental
Research Funds for the Central Universities [DUT12LK44,
DUT13LK03, and DUT11ZD106].
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