Synthesis of 1,2-disubstituted benzimidazoles by a Cu-catalyzed cascade aryl amination/condensation process

Article abstract of DOI:10.1002/anie.200700071

(Chemical Equation Presented) Helpful neighbors: A wide range of 1,2-disubstituted benzimidazoles can be assembled from 2-haloanilides and primary amines by using a copper-catalyzed amination reaction promoted by an orthosubstituent effect of an NHCOR gro

Full text of DOI:10.1002/anie.200700071

Communications
DOI: 10.1002/anie.200700071
Nitrogen Heterocycles
Synthesis of 1,2-Disubstituted Benzimidazoles by a Cu-Catalyzed
Cascade Aryl Amination/Condensation Process**
Benli Zou, Qiliang Yuan, and Dawei Ma*
1
,2-Disubstituted benzimidazoles are an important class of
available starting materials. In an attempt to circumvent this
restriction, metal-catalyzed intramolecular amination
heterocyclic compounds that exhibit a wide range of biolog-
ical properties. Previous syntheses of 1,2-disubstituted
benzimidazole structures not only led to drug leads such as
the hepatitis C virus (HCV) NS5B polymerase inhibitor 1
and the agonist 2 against the g-aminobutyric acid A receptor
a
[
1]
[7]
approach was recently reported. However, the products
are limited to the 2-aminobenzimidazoles. Herein, we report a
new cascade process for the formation of 1,2-disubstituted
benzimidazoles from 2-haloanilides and primary amines.
In recent years, we have witnessed great progress in the
[
2]
[
3]
(
GABA ), but also resulted in commercial pharmaceutical
A
products such as the antihypertensive telmisartan (3,
Scheme 1).
development of mild Cu-catalyzed Ullmann-type reactions
[
4]
[8,9]
using N,N-, N,O-, and O,O-bidentate ligands.
Several
useful domino processes have been developed based on
[
10]
these investigations. During studies on the CuI-catalyzed
assembly of diaryl ethers using amino acids as ligands we
discovered that there is an ortho-substituent effect directed by
[
11]
NHCOR groups in Ullmann-type CÀO bond formations.
Further explorations revealed that the same effect exists in
the coupling of aryl halides with activated methylene
[
12]
compounds.
We were interested in whether this effect
could promote aryl amination to afford ortho-aminoanilides
at low reaction temperatures, which in turn would provide 1,2-
disubstituted benzimidazoles through an intramolecular con-
densation. It is noteworthy that low reaction temperatures are
essential for obtaining ortho-aminoanilides because ortho-
haloanilides can undergo the Cu-catalyzed cyclization at 808C
Scheme 1. Structures of pharmacologically important 1,2-disubstituted
benzimidazoles. Bn=benzyl.
[13]
to afford benzoxazoles.
With this idea in mind, we carried out the reaction of 2-
iodotrifluoroacetanilide (4a) with benzylamine catalyzed by
CuI /l -proline (Scheme 2). We were pleased to find that after
12 h at room temperature, 4a was consumed to give a mixture
of aniline 5a (46% yield) and benzimidazole 6a (30% yield).
Although 1,2-disubstituted benzimidazoles play an impor-
tant role in pharmaceutical science, the available synthetic
strategies that lead to these compounds are limited compared
with those that lead to the structurally related indoles. The
classical methods for the assembly of these molecules include
Since iodobenzene does not couple with benzylamine under
[
2]
[9f,h]
acylation/cyclization processes from ortho-aminoanilines,
reduction/cyclization processes from ortho-nitroanilines,
the same conditions,
the formation of 5a and 6a clearly
[
5]
demonstrate that the ortho-NHCOCF group promotes the
3
[
3,6]
and alkylation of 2-substituted benzimidazoles.
The draw-
amination. We then tried to transform 5a into 6a in a one-pot
reaction, and found that 6a was formed exclusively when the
back of these procedures is the limited diversity of the
[*] Prof. Dr. D. Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
B. Zou, Q. Yuan
Department of Chemistry
Fudan University
Shanghai 200433 (P.R. China)
[**] The authors are grateful to the Chinese Academy of Sciences and the
National Natural Science Foundation of China (grant 20321202 and
20572119) for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Coupling of 4a with benzylamine catalyzed by CuI/l-proline.
DMSO=dimethyl sulfoxide.
2
598
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coupling-reaction mixture was heated at 1008C for five hours
procedure A), or when acetic acid was added and the
reaction mixture heated at 508C for two hours (procedure B).
sterically hindered amines couple with both electron-rich and
(
electron-deficient 2-iodotrifluoroacetanilides at room tem-
perature, thus providing benzimidazoles 6b–6h in good yield
(Table 1, entries 1–7). These results differ to those observed
when using benzylamine, which indicates that subtle changes
in the size of the amines will alter the reaction process.
Cyclohexylamine was found to be
In response to this encouraging result, we used a range of
2
-iodoacetanilides and primary amines to investigate the
scope and limits of this reaction. As shown in Table 1, less-
[
a]
Table 1: Synthesis of 1,2-disubstituted benzimidazoles from 2-iodoacetanilides.
similar to benzylamine and further
heating in HOAc was required for
the completion of the condensation/
cyclization reaction (procedure B,
entry 8).
The coupling reaction of 2-
iodoacetanilide with 2-hydroxy-
ethylamine had to be carried out
at 408C to ensure complete conver-
sion, and condensation product 6j
was formed after the reaction mix-
ture had been heated at 1208C for
Entry
Step 1
T [8C]/t [h]
Step 2
procedure/T [8C]/t [h]
Product
Yield
[%]
[b]
1
2
3
25/24
25/24
25/10
–
–
–
6b, R’=CH CH OH
6c, R’=n-C H
6d, R’=allyl
92
90
94
2
2
6
13
1
2 h or after treatment of the reac-
tion mixture with HOAc at 408C for
h (Table 1, entries 9 and 10). It is
4
noteworthy that during the coupling
reaction, no 6j was observed, which
indicates that for both coupling and
condensation steps, substrates bear-
ing a trifluoroacetyl group instead
of an acetyl group are generally
more reactive. However, the rela-
4
5
6
7
25/17
25/15
25/24
25/24
–
–
–
–
6e, X=4,6-dimethyl
6 f, X=6-OMe
94
89
72
90
6g, X=6-CO Me
2
6h, X=6-COCH3
[
9f,h]
tively low reaction temperature
required for the coupling with 2-
iodoacetanilide indicates that an
ortho-substituent effect from the
8
25/24
B/50/5
94
HNCOCH group remained influ-
3
ential during the course of the
reaction. Similar results were
obtained when other iodides that
contain aliphatic and aromatic
amido groups were used (Table 1,
entries 11–17), which indicates that
the ortho-substituent effect is not
9
A/120/12
B/40/4
64
75
79
1
1
0
1
40/2
A/120/12
1
1
1
2
3
4
40/4
40/6
B/40/8
81
70
97
limited to the HNCOCF group and
3
that variation at the 2-position of
the benzimidazoles is possible by
using this method. For the conden-
sation/cyclization reaction, treat-
ment of the coupling-reaction mix-
ture with HOAc generally gave
better results than direct heating
(Table 1, entries 9–16). Further-
more, entry 18 illustrates that a
benzimidazole 6o with an amino
ester group can also be obtained.
Similar compounds have shown
potential for the treatment of
A/120/20
B/40/10
1
5
A/140/30
73
1
1
6
7
40/10
40/8
B/60/12
B/60/10
6m, X=H
6n, X=CO
88
83
2
Me
1
8
40/36
B/70/12
61
[
14]
[15]
hypertension, diabetes, hyper-
[
a] Reaction conditions: step 1. Aryl iodide 4 (0.5 mmol), amine (0.75 mmol), CuI (0.05 mmol), l-
proline (0.1 mmol), K CO (1 mmol), DMSO (1 mL); step 2. Procedure A: the reaction mixture was
heated at the indicated temperature; procedure B: 5 mL of AcOH was added, and then the reaction
mixture was heated at the indicated temperature. [b] Yield of isolated product.
[
16]
glycemia-related disorders,
well as bone diseases.
as
2
3
[
17]
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Communications
During the course of our research we investigated the
reaction temperatures were required to complete the cou-
pling reaction. Aryl bromides with electron-withdrawing and
electron-donating groups were compatible, although the use
of the latter gave relatively low yields (entries 7 and 8).
When 3-amido-2-bromopyridines were employed, the
process afforded polysubstituted imidazo[4,5-b]pyridines
(entries 9–12), which are found in the core skeletons of a
coupling reaction of 2-bromoacetanilides with primary
amines. To our delight, the reaction of 2-bromotrifluoroace-
tanilides 7a and 7b with several primary amines took place at
room temperature to provide the benzimidazoles 6b, 6c, 6i,
and 6h after treatment with HOAc (Table 2, entries 1–4). The
smooth coupling reaction displayed by these bromides most
likely results from the ortho-substituent effect, and represents
the first example of a room-temperature amination of aryl
[
18,19]
number of pharmaceutically important compounds.
In
the case of the dibromopyridine 7h, no coupling at the 6-
position was observed, which indicates that good regioselec-
tivity can be obtained (Table 2, entry 10), and the remaining
bromide functionality in 6t can undergo further coupling
reactions. For the formation of imidazo[4,5-b]pyridines 6u
and 6v, treatment with HOAc at 1008C was found to give
poor yields as a result of decomposition. However, satisfac-
[
9i]
bromides.
As with the aryl iodides, aryl bromides with different
amide groups in the ortho position were compatible under the
reaction conditions, and delivered the corresponding benz-
imidazoles in satisfactory yields (Table 2, entries 5–8). How-
ever, in comparison with the aryl iodides, slightly higher
[
a]
Table 2: Synthesis of 1,2-disubstituted benzimidazoles from 2-bromoacetanilides.
Entry
Bromide
Amine
Step 1
T [8C]/t [h]
Step 2
procedure/T [8C]/t [h]
Product
Yield
[%]
[
b]
1
25/24
B/50/1
6b
90
2
3
n-hexylamine
cyclohexylamine
25/10
25/10
B/50/2
B/50/5
6c
6i
80
90
25/24
B/50/1
6h
85
4
5
6
7
cyclohexylamine
allylamine
45/10
50/10
50/12
B/50/6
B/50/6
B/80/10
70
80
70
6k
cyclohexylamine
8
9
cyclohexylamine
50/10
B/90/10
62
cyclohexylamine
benzylamine
40/12
40/7
B/90/4
B/90/4
72
78
1
1
1
0
1
2
45/6
45/7
A/150/12
A/150/12
76
78
benzylamine
[a] Reaction conditions: step 1. Aryl bromide 7 (0.5 mmol), amine (0.75 mmol), CuI (0.1 mmol for entries 1–4, 0.05 mmol for entries 5–12), l-proline
(
0.2 mmol for entries 1–4, 0.1 mmol for entries 5–12), K CO (1 mmol), DMSO (1 mL); step 2. Procedure A: the reaction mixture was heated at the
2
3
indicated temperature; procedure B: 5 mL of AcOH was added, and then the reaction mixture was heated at the indicated temperature. [b] Yield of
isolated product.
2
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was heated at 1508C (Table 2, entries 11 and 12).
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In conclusion, we have demonstrated that NHCOR
groups provide an ortho-substituent effect in the amination
of 2-haloacetanilides catalyzed by CuI /l -proline. Based on
this observation, a novel and highly practical method for
elaborating benzimidazoles has been developed. Variation at
the 1- and 2-positions of the benzimidazole is possible when
different primary amines are employed and with variation in
the amido groups of the 2-haloacetanilides. Moreover, in
contrast to the existing methods, our strategy allows the
introduction of substituents in different positions of the
benzimidazole phenyl ring. Thus, the present cascade process
allows the assembly of a wide range of polysubstituted
benzimidazoles.
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Keywords: benzimidazoles · copper · cross-coupling ·
domino reactions · nitrogen heterocycles
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www.angewandte.org 2601