Copper-catalyzed synthesis of benzazoles via aerobic oxidative condensation of o-amino/mercaptan/hydroxyanilines with benzylamines

Article abstract of DOI:10.1039/c3ra42175a

A simple and efficient method for the synthesis of benzazoles via Cu-catalyzed aerobic oxidative condensation of o-amino/mercaptan/hydroxyanilines with benzylamines was developed.

Full text of DOI:10.1039/c3ra42175a

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Copper-catalyzed synthesis of benzazoles via aerobic
oxidative condensation of o-amino/mercaptan/
hydroxyanilines with benzylamines3
Cite this: DOI: 10.1039/c3ra42175a
Received 2nd May 2013,
Accepted 9th July 2013
a
a
a
a
ab
Tiebo Xiao, Shengwei Xiong, Yang Xie, Xichang Dong and Lei Zhou*
DOI: 10.1039/c3ra42175a
www.rsc.org/advances
1
8
A simple and efficient method for the synthesis of benzazoles via
Cu-catalyzed aerobic oxidative condensation of o-amino/mercap-
tan/hydroxyanilines with benzylamines was developed.
reported by Adimurthy and co-workers. However, the undesired
symmetrical imines were difficult to be avoided in some cases
when two different amines were employed as the substrates for
the reaction. We envisioned that this problem might be solved by
introducing a cyclizable group to the ortho-position of anilines,
which would lead to the formation of some interesting hetero-
Benzazole moieties are common structural units in natural
products and exhibit interesting biological activities and potential
1
19
pharmaceutical applications. For example, benzimidazole deriva-
cyclic compounds. Herein we report an efficient aerobic
tives have shown excellent therapeutic activities as antihypergly-
oxidative approach to synthesize 2-substitued benzimidazoles,
benzoxazoles, and benzothiazoles via Cu-catalyzed condensation
of benzylamines with o-phenylenediamine, 2-aminophenol, and
2-aminothiophenol respectively.
2
3
4
cemic,
antiinflammatory,
antihypertensive,
and
5
antihypercholesterolemic agents. Benzothiazole is the pharmaco-
phore of zopolrestat, which has been used for the treatment of
diabetes. Benzoxazoles are also well known for their biological
activities, e.g. as an inhibitor for the D-alanyl-D-alanine ligase, a
HIV reverse transcriptase inhibitor, COX-2 inhibitor and an
anticonvulsant agent. Given the importance of these hetero-
cycles, many methods have been developed for the preparation of
these benzofused heterocyclic structures in recent decades. The
classical method to synthesize benzazole derivatives is the
condensation of anilines with carboxylic acid derivatives (nitriles,
imidates, or orthoesters) or aldehydes. The transition metal-
catalyzed intramolecular coupling reaction and some other
methods have also been frequently utilized. Although numerous
methods have been disclosed, the efforts to develop new strategies
for benzazole synthesis from readily available materials under
mild reaction conditions have never been stopped.
6
Initially, the reaction conditions were optimized starting from
benzylamine 1a and o-phenylenediamine 2a in toluene at 100 uC
with various copper catalysts, and CuBr2 gave the best result
(Table 1, entries 1–4). The reaction catalyzed by other metal salts
such as FeCl , FeBr and CoBr2 were also effective, albeit
7
8
9
10
3
2
11
generating the product with slightly diminished yields (Table 1,
entries 5–7). Notably, the desired benzimidazole 3a was isolated in
17% yield when 10 mol% of TsOH was employed as the catalyst
(Table 1, entry 8). Increasing the amount of TsOH to 1 equiv, the
yield of benzimidazole 3a was dramatically improved to 68%
(Table 1, entry 9). Although TsOH showed less efficiency for the
12
13
14
15
reaction than CuBr , this result indicates that a metal-free
2
19a,d
approach to benzimidazole is also possible.
Next, we
investigated the effect of solvents. A series of solvents such as
xylene, MeCN, dioxane, MeNO2 and DMF were examined,
however, they are all less efficient compared with toluene
(Table 1, entries 10–14). Two control experiments showed that
no product could be detected in the absence of copper catalyst or
under argon atmosphere (Table 1, entries 15 and 16). Finally, we
found that the yield of 3a decreased sharply when the reaction was
carried out at lower temperature (Table 1, entry 17).
With the optimized reaction conditions in hand, the scope of
this transformation was studied by using o-phenylenediamine and
different benzylamines. As shown in Table 2, not only benzyla-
mine 1a, but para, meta, and ortho- methyl-substituted benzyla-
mines all worked well in the present system to give good yields of
benzimidazoles (Table 2, entries 2–4). Functional groups at the
para-position of benzylamines, including fluoro, chloro, bromo,
Recently, considerable progress has been made in developing
16
catalytic oxidation of primary amines into imines. Moreover, for
the consideration of green chemistry and atom economy aspects,
catalytic systems utilizing molecular oxygen as green oxidant have
17
also been reported. Compared to the classic condensation
reaction of carbonyl compounds with primary amines, the direct
oxidative coupling of amines to imines provides a novel alternative
to imines without using any carbonyl compound. Recently, elegant
work for Cu-catalyzed aerobic oxidation of amines to imines was
a
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135
Xingang west road, Guangzhou 510275, China. E-mail: zhoul39@mail.sysu.edu.cn;
Tel: +8620-84110217
b
Beijing National Laboratory for Molecular Sciences, Beijing, 100871, China
3
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra42175a
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a
Table 1 Optimization of reaction conditions
Table 2 Cu-catalyzed oxidative condensation of benzylamines 1 with 2a
b
Entry
Catalyst (mol%)
Solvent
Yield (%)
b
Entry Benzylamine
1
Product
Yield (%)
1
2
3
4
5
6
7
8
9
CuBr
CuCl
2
(1)
(1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
94
76
66
89
80
86
64
17
68
73
55
62
47
61 c
ND
ND
43
91
2
CuCl (1)
Cu(OAc)
2
(1)
FeCl
FeBr
CoBr
3
(1)
(1)
(1)
2
3
88
87
2
2
TsOH (10)
TsOH (100)
10
11
12
13
14
15
16
17
CuBr
CuBr
CuBr
CuBr
CuBr
none
CuBr
CuBr
2
2
2
2
2
(1)
(1)
(1)
(1)
(1)
MeCN
dioxane
MeNO
DMF
2
toluene
toluene
toluene
d
e
4
89
2
2
(1)
(1)
a
Reactions were carried out using 1a (0.24 mmol), 2a (0.2 mmol),
catalyst (1 mol%), solvent (2.0 mL) at 100 uC under air for 24 h.
b
c
d
Isolated yield. ND: not detected. The reaction was carried out
5
6
92
84
e
under argon atmosphere. The reaction was performed at 80 uC.
methoxy groups are all tolerated under the reaction conditions
(Table 2, entries 5–8). We were pleased to find that the heterocyclic
methylamines 1i and 1j reacted with o-phenylenediamine
smoothly, affording the corresponding benzimidazoles 3i and 3j
in the yields of 79% and 85% respectively (Table 2, entries 9 and
7
8
83
94
10). 2-Aminomethyl pyridine 1k was also suitable for the reactions,
generating the product 3k in 82% yield (Table 1, entry 13).
To further expand the scope of the reaction, various substituted
o-phenylenediamines were employed as the substrates to react
with benzylamine 1a. The reaction was found not significantly
affected by the substituents on the aromatic ring of o-phenylene-
diamines; both electron-rich (Table 3, entries 1–3) and electron-
deficient aryl substituted benzylamines (Table 3, entries 4 and 5)
were effective. In another case, oxidative condensation of
benzylamine with 2,3-diaminonaphthalene (2g) led to the product
9
79
85
82
10
3q in 80% yield (Table 3, entry 6). In addition, we checked the
1
1
possibility of assembling benzothiazole by this process and the
reaction of 2-aminobenzenethiol 2h with benzylamine delivered
the benzothiazole 3r in the yield of 93% (Table 3, entry 7).
Similarly, treatment of 2-aminophenol 2i and 2j with benzylamine
furnished the corresponding benzoxazoles 3s and 3t in the yields
of 85% and 81% respectively (Table 3, entries 8 and 9).
a
Conditions: 1 (0.24 mmol), 2a (0.2 mmol), CuBr (1 mol%),
2
b
toluene, air, 100 uC for 24 h. Isolated yield.
Very recently, Jiang and co-workers reported a method for the
synthesis of benzothiazoles from 2-aminobenzenethiols and
standard condition, no desired benzimidazole was detected from
the reaction of o-phenylenediamine and benzonitrile, both starting
materials remained unreacted. However, the imine 4 could
convert to the benzimidazole smoothly in the yield of 96% after
stirring at 100 uC in toluene for 24 h.
20
nitriles catalyzed by Cu(OAc)
2
.
The direct oxidation of primary
amines to nitriles in the presence of oxygen was also a known
21
process. To understand the mechanism of the reaction, we
performed two ‘‘control experiments’’ (Scheme 1). Under the
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Table 3 Cu-catalyzed oxidative condensation of benzylamine 1a with various
a
anilines 2
b
Entry Aniline
1
Product
Yield (%)
Scheme 1 Control experiments.
92
18
tion of complex A gives benzylimine intermediate B and Cu(I).
2
87
Cu(I) is oxidized by air to regenerate the Cu(II) catalyst. Reaction of
benzylimine B with anilines 2 leads to the formation of imine C
with liberation of ammonia. Finally, the intramolecular addition
by the amine group (or OH, SH) affords cyclic aminal D which is
further oxidized to benzazole 3 under air.
In conclusion, the use of primary amines as suitable substrates
for the copper-catalyzed synthesis of 2-substitued benzimidazoles,
benzoxazoles, and benzothiazoles was developed. The reaction
was carried out under mild conditions by using low catalyst
3
4
5
6
83
93
95
2
loading of CuBr and air, which is the most environment friendly
oxidant. A series of pharmaceutically important benzofused
heterocycles were obtained in high yields. Further investigation
of the reaction mechanism and the synthetic applications is
ongoing in our group.
We thank the National Natural Science Foundation of China
80
93
85
81
(Grant No. 21202207), Research Fund for Guangzhou Peal River
New Star of Science and Technology, and Beijing National
Laboratory of Molecular Sciences (BNLMS) for the financial
support. We thank our colleague Prof. Hsiu-Yi Chao for proof-
reading of the manuscript.
c
7
c
8
c
9
a
All the reactions were carried out using 1a (0.24 mmol), 2 (0.2
2
mmol) and 1 mol% of CuBr under air in toluene at 100 uC for 24 h.
b
c
Isolated yield. 0.1 mL of AcOH was used as the additive.
These results suggest that the first step of the reaction
described in this paper is via imine intermediate rather than the
oxidation of primary amines to nitriles followed by the condensa-
tion of anilines with resulted nitriles.
According to the above observations and previous reports in
literature, a possible pathway for the overall process was proposed
as shown in Scheme 2. Initially, the coordination of Cu(II) to the
benzylamine generates intermediate A. Subsequently, the oxida-
Scheme 2 Possible pathways for the copper-catalyzed aerobic oxidative synthesis
of benzazoles from benzyl amines.
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