Copper-catalyzed one-pot synthesis of substituted benzimidazoles

Article abstract of DOI:10.1002/adsc.200900706

A copper-catalyzed one-pot synthesis of functionalized benzimidazoles has been developed. The procedure combines the copper-catalyzed three-component cascade reaction of sulfonyl azides, alkynes and 2-bromoaniline and the copper-catalyzed intramolecular N-arylation of sulfon-amides in one sequence, which afforded the products in moderate to good yields.

Full text of DOI:10.1002/adsc.200900706

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DOI: 10.1002/adsc.200900706
Copper-Catalyzed One-Pot Synthesis of Substituted
Benzimidazoles
Hongwei Jin,a,b Xiaoliang Xu,b Jianrong Gao,b Jianhua Zhong,a
and Yanguang Wanga,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of China
Fax : (+86)-571-8795-1512; e-mail: orgwyg@zju.edu.cn
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, Peopleꢀs
b
Republic of China
Received: October 11, 2009; Revised: December 16, 2009; Published online: February 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900706.
Abstract: A copper-catalyzed one-pot synthesis of
functionalized benzimidazoles has been developed.
The procedure combines the copper-catalyzed
three-component cascade reaction of sulfonyl
azides, alkynes and 2-bromoaniline and the copper-
catalyzed intramolecular N-arylation of sulfon-
a rapidly evolving research area and have attracted
the attention of both academic and industrial scien-
tists in the past few years. Recently, Chang et al. re-
ported several CuI-catalyzed MCRs of sulfonyl azides
and terminal alkynes with amines, water, alcohol,
imines, or ammonium salts, which resulted in the syn-
thesis of different types of nitrogen-containing com-
pounds.[8] Previously, we reported MCRs starting
from terminal alkynes, sulfonyl azides, and nucleo-
philes, leading to a number of important heterocycles,
such as 2-iminocoumarins, 2-iminothiochromenes, 2-
ACHTUNGTRENNUNGamides in one sequence, which afforded the prod-
ucts in moderate to good yields.
Keywords: arylation; benzimidazoles; cascade reac-
tions; copper catalysts; multicomponent reactions
imino-1,2-dihydroquinolines,
2-imino-5-arylidene-3-
pyrrolines, benzimidazoles, and 2-alkylidene-1,2,3,4-
tetrahydropyrimidines.[9] As a part of our research
program aiming at new approaches to diverse hetero-
The 2-substituted benzimidazole moiety can be found cyclic systems by MCRs, we combined the copper-cat-
in a variety of bioactive compounds and drugs.[1] Clas- alyzed three-component reaction of alkynes, sulfonyl
sical methods for the synthesis of 2-substituted 1-sul- azides, and 2-bromoanilines with the copper-catalyzed
fonylbenzimidazoles involve treatment of 1,2-pheny- intramolecular arylation of sulfonamides in one se-
ACHTUNGTRENNUNG
which is followed by sulfonylation with the corre- phenylacetylene (2a), and 2-bromoaniline (3a) was
sponding alkyl or aryl sulfonyl chloride.[3] However, chosen to screen for suitable reaction conditions
these methods suffered from major shortcomings such (Table 1). Using CuI as the catalyst, several solvents,
as limited substituents, and troublesome management ligands, and bases were examined to set up standard
of the chemical processes. Although 1,2-substituted reaction conditions. Accordingly, the tandem process
benzimidazoles can be generated by some other was conducted using 0.1 equivalent of CuI, 1 equiva-
methods,[4] more efficient strategies for constructing lent of triethylamine (TEA) in THF at room tempera-
this class of important heterocycles are always de- ture for 2 h, and then 0.1 equivalent of CuI, 0.4 equiv-
sired.
alent of N,N-dimethylglycine and 4.0 equivalents of
Multicomponent reactions (MCRs) involving cas- cesium carbonate in THF at room temperature for
cade processes with at least three different simple 4 h, the desired product 4a was obtained in 36% yield
substrates reacting in a defined manner to form a (Table 1, entry 1). Several other solvents such as
single compound have emerged as a powerful synthet- CH2Cl2, CH3CN, 1,4-dioxane, DMF (Table 1, en-
ic strategy.[5] Owing to their synthetic efficiency,[6] var- tries 2–5), and DMSO (Table 1, entries 6–11) were
iability and convergency,[7] novel MCRs have become further surveyed, and DMSO afforded the higher
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347

Hongwei Jin et al.
COMMUNICATIONS
Table 1. CuI-catalyzed reaction of p-tolylsulfonyl azide with
phenylacetylene and 2-bromoaniline under various condi-
tions.[a]
a two-carbon source for the formation of 4g, 4j, and
4m with concomitant desilylation under the reaction
conditions (Table 2, entries 7, 10 and 13). It was found
that the electron-rich bromoaniline 3b (Table 2,
entry 18) gave a higher yield than the electron-defi-
cient bromoaniline 3c (Table 2, entry 19). 2-Iodoani-
line (3d) (Table 2, entry 20) gave 4a in comparable
yield as with 2-bromoaniline (3a) (Table 2, entry 1),
whereas 2-chloroaniline (3e) did not afford the de-
sired product even at 808C for 24 h (Table 2,
entry 21).
Encouraged by these results, we extended our reac-
tion to heteroaryl bromides as the substrates
(Table 3). It was found that 2-bromopyridin-3-amine
(5a) and 5-methyl-3-bromopyridin-2-amine (5b) fol-
lowed the same paths as 2-bromoaniline (3a), giving
the corresponding imidazopyidine derivatives 6a and
6b in 61% and 45% yields, respectively.
Entry
Solvent
Ligand[b]
Base
Yield [%][c]
1
2
3
4
5
6
7
8
THF
A
A
A
A
A
A
A
A
B
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
36
10
20
45
50
53
55
60
62
20
75
65
CH2Cl2
CH3CN
dioxane
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
A plausible mechanism was proposed for this cas-
cade process as shown in Scheme 1. In the presence
of TEA and CuI, sulfonyl azide 1 reacts with terminal
alkyne 2 to form the ketenimine species A.[8,9] A is
quickly attacked by nucleophile 3 to generate N-sulfo-
nylamidine B. The amidine B tautomerizes to sulfona-
mide C. The subsequent CuI/l-proline-catalyzed in-
10
11
12[d]
C
D
D
[a]
Reaction conditions: p-toluenesulfonyl azide (0.5 mmol),
phenylacetylene (0.5 mmol), 2-bromoaniline (0.55 mmol),
TEA (0.5 mmol), CuI (0.05 mmol), solvent (2 mL), room
temperature, 2 h, then CuI (0.05 mmol), ligand
(0.2 mmol), base (2 mmol), room temperature, 4 h.
Ligands: A, N,N-dimethylglycine; B, N-methylglycine; C,
1,10-phenanthroline; D, l-proline.
À
tramolecular C N coupling of sulfonamide C breaks
[b]
the interconvertible tautomerization and affords the
desired product 4.
[c]
[d]
Isolated yields for 4a referred to phenylacetylene.
Intramolecular coupling reaction time: 12 h.
In conclusion, we have developed a novel protocol
for the synthesis of substituted benzimidazole deriva-
tives via a CuI-catalyzed sequential three-component
À
yields. On switching the base to K3PO4 (Table 1, cascade reaction/intramolecular C N coupling strat-
entry 7) or K2CO3 (Table 1, entries 8–11) for the intra- egy. This one-pot method is efficient, mild, and gener-
À
molecular C N bond formation, a better result was al, and the substrates of sulfonyl azides, alkynes, and
observed when compared to that with K2CO3. Further 2-bromoanilines are readily available. Further syn-
improvement was achieved when l-proline was used thetic applications for this method are under investi-
as the ligand (Table 1, entry 11), while a similar result gation in our laboratory, and will be reported in due
was obtained with using N-methylglycine as the time.
ligand (Table 1, entry 9) and a poor yield with 1,10-
phenanthroline (Table 1, entry 10). Prolonging the re-
action time could not improve the result (Table 1,
entry 12). Since both steps of this two-step approach
Experimental Section
shared the same copper catalyst, we have tried to per-
form the second step reaction without addition of an-
other portion of CuI. However, it was found that the
General Procedure for Synthesis of 2-Substituted 1-
sulfonylbenzimidazoles (4)
intramolecular amidination step did not work.
As a next step, we investigated the scope of the re- (0.5 mmol), 2-bromoanlines
To a solution of sulfonyl azides 1 (0.5 mmol), alkynes 2
(0.55 mmol), and CuI
3
(0.05 mmol) in DMSO (2 mL) in a Schlenk tube was added
TEA (0.5 mmol) slowly via a syringe. The reaction solution
was stirred at room temperature under N2 for 2 h. To the so-
lution were then added CuI (0.05 mmol), K2CO3 (2 mmol)
and l-proline (0.2 mmol), and the mixture was stirred at
room temperature under N2 for 4 h. The reaction mixture
was partitioned between ethyl acetate and saturated NH4Cl
solution, the organic layer was washed with brine, dried
over Na2SO4 and concentrated under vacuum. The residue
was purified by column chromatography on silica gel with
action with various sulfonyl azides, terminal alkynes,
and 2-haloanilines under the optimized reaction con-
ditions (Table 2). It was found that all aromatic sulfo-
nyl azides gave the corresponding 2-substituted 1-are-
nesulfonylbenzimidazoles in moderate to good yields,
while aliphatic sulfonyl azides gave slightly lower
yields (Table 2, entries 16 and 17). As far as the al-
kynes were concerned, both aromatic and aliphatic al-
kynes afforded good yields (Table 2, entries 1–6). It is
noteworthy that trimethylsilylacetylene could serve as petroleum ether and ethyl acetate (4:1 to 7:1).
348
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Adv. Synth. Catal. 2010, 352, 347 – 350

Copper-Catalyzed One-Pot Synthesis of Substituted Benzimidazoles
Table 2. Three-component synthesis of benzimidazoles 4.[a]
Entry
R1
R2
R3/X
Yield [%][b]
1
2
3
4
5
6
7
8
4-MeC6H4 (1a)
1a
1a
1a
1a
1a
1a
C6H5 (1b)
1b
1b
4-ClC6H4 (1c)
1c
1c
4-i-PrC6H4 (1d)
4-MeOC6H4 (1e)
n-Bu (1f)
Me (1g)
1a
1a
1a
1a
Ph (2a)
4-MeC6H4 (2b)
3-MeC6H4 (2c)
3-FC6H4 (2d)
n-Bu (2e)
n-Pentyl (2f)
TMS (2g)
2a
2e
2g
2a
2e
2g
2a
2a
2a
2a
2a
2a
2a
2a
H/Br (3a)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
75 (4a)
70 (4b)
73 (4c)
60 (4d)
70 (4e)
74 (4f)
56 (4g)[d]
46 (4h)
50 (4i)
9
10
11
12
13
14
15
16
17
18
19
20
21[c]
45 (4j)[d]
65 (4k)
78 (4l)
52 (4m)[d]
62 (4n)
56 (4o)
54 (4p)
43 (4q)
78 (4r)
50 (4s)
70 (4a)
0 (4a)
3a
4-Me/Br (3b)
4-Cl/Br (3c)
H/I (3d)
H/Cl (3e)
[a]
Sulfonyl azide (0.5 mmol), alkyne (0.5 mmol), 2-haloaniline (0.55 mmol), TEA (0.5 mmol), CuI (0.05 mmol), DMSO
(2 mL), room temperature, 2 h, then CuI (0.05 mmol), l-proline (0.2 mmol), K2CO3 (2 mmol), room temperature, 4 h.
Isolated yields referred to alkyne.
[b]
[c]
[d]
Intramolecular coupling reaction, 808C, 24 h.
For products 4g, 4j and 4m, R2 =H.
2-Benzyl-1-tosyl-1H-benzo[d]imidazole (4a): White solid;
120.2, 113.7, 35.7, 21.6; ESI-MS: m/z=363 (M+ +1); HR-
MS (ESI): m/z=363.1150, calcd. for C21H18N2O2S ([M+
H]+): 363.1162.
mp 135–1368C; 1H NMR (500 MHz, CDCl3): d=7.96–7.94
(m, 1H), 7.72–7.70 (m, 1H), 7.36–7.32 (m, 4H), 7.31–7.25
(m, 5H), 7.05 (d, J=8.0 Hz, 2H), 4.64 (s, 2H), 2.23 (s, 3H);
13C NMR (125 MHz, CDCl3): d=153.0, 145.6, 141.9, 136.0,
135.0, 133.0, 129.9, 129.2, 128.6, 127.0, 126.9, 124.9, 124.6,
Table 3. Three-component synthesis of imidazopyidines 6.[a]
Entry
X
Y
Z
Product
Yield [%][b]
1
2
CH
N
N
CH
H
Me
6a
6b
61
45
[a]
p-Toluenesulfonyl azide (0.5 mmol), phenylacetylene
(0.5 mmol), heteroaryl bromide (0.55 mmol), TEA
(0.5 mmol), CuI (0.05 mmol), DMSO (2 mL), room tem-
perature, 2 h, then CuI (0.05 mmol), l-proline
(0.2 mmol), K2CO3 (2 mmol), room temperature, 4 h.
Isolated yields referred to alkyne.
Scheme 1. Postulated mechanism for the formation of benz-
AHCTUNGTREGUNiNN midazoles 4.
[b]
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asc.wiley-vch.de
349

Hongwei Jin et al.
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2-Benzyl-3-tosyl-3H-imidazo
G
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1
ACHTUNGTRENNUNG
7.26 (m, 6H), 7.07 (d, J=8.0 Hz, 2H), 4.71 (s, 2H), 2.31 (s,
3H); 13C NMR (125 MHz, CDCl3): d=153.9, 147.1, 145.8,
145.2, 136.0, 134.7, 133.9, 129.5, 129.3, 128.7, 128.5, 127.7,
127.0, 120.3, 36.6, 21.6; ESI-MS: m/z=364 [(M+H)+]; HR-
MS (ESI): m/z=364.1125, calcd. for C20H17N3O2S ([M+
H]+): 364.1120.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20872128) as well as the Scientific Research Fund of Ed-
ucational Bureau of Zhejiang Province (20070304).
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