Copper-catalyzed cascade addition/cyclization: An efficient and versatile synthesis of N-substituted 2-heterobenzimidazoles

Article abstract of DOI:10.1021/jo900743y

(Chemical Equation Presented) A novel and efficient one-pot synthesis of various N-substituted 2-heterobenzimidazoles has been developed. Through a Cu(I)-catalyzed cascade intermolecular addition/intramolecular C-N coupling process, a wide variety of 2-he

Full text of DOI:10.1021/jo900743y

pubs.acs.org/joc
possess fungicidal activity,5b,5c and might be employed as
Copper-Catalyzed Cascade Addition/Cyclization: An
Efficient and Versatile Synthesis of N-Substituted
2-Heterobenzimidazoles
anti-ischemic agents;5a and some 2-phenoxylbenzimidazoles
(D) are claimed to be antiviral active compounds6 (Figure 1).
Although these N-substituted 2-heterobenzimidazoles
play an important role in biological and pharmaceutical
areas, efficient methods for the assembly of these molecules
are limited. The classical approaches to 2-aminobenzimida-
zoles employ o-phenylenediamine as precursors. For
example, Carpenter and co-workers recently synthesized
2-dimethylaminobenzimidazole from 2-amino-1-anilino-
4-nitrobenzene and phosgene iminium chloride;2d Sun et al.
reported o-phenylenediamines could react with isothiocyna-
nates to give 2-aminobenzimidazoles.7 Other approaches
include the SNAr reaction between 2-chlorobenzimidazoles
and N-nucleophiles,2b,2c,3a,8 Pd-catalyzed coupling of 2-ha-
lobenzimidazoles with amines,9 etc. However, these methods
might suffer from the limited availability of the starting
materials, harsh conditions, poor yields, narrow scopes,
and/or expensive catalysts. Recently, Batey and co-workers
reported Cu- or Pd-catalyzed intramolecular aryl guanidi-
nylation.10 Although it provided an efficient approach to
2-aminobenzimidazoles, the precursors o-haloguanidines
needed to be previously synthesized, and the diversity of
the substituents on the 2-position was limited (only for
certain aliphatic amino groups). The available methods that
lead to 2-imidazylbenzimidazoles5c,11 or 2-phenoxylbenzi-
midazoles6,12 are much rarer. Therefore, more efficient and
facile routes to these useful molecules under mild conditions
are needed.
Xin Lv and Weiliang Bao*
Department of Chemistry, Xixi Campus, Zhejiang University,
Hangzhou 310028, People’s Republic of China
wlbao@css.zju.edu.cn
Received April 8, 2009
A novel and efficient one-pot synthesis of various
N-substituted 2-heterobenzimidazoles has been devel-
oped. Through a Cu(I)-catalyzed cascade intermolecular
addition/intramolecular C-N coupling process, a wide
variety of 2-heterobenzimidazoles could be synthesized
from o-haloarylcarbodiimides and N- or O-nucleophiles.
1,2-Disubstituted benzimidazole derivatives have shown
their wide range of biological activities.1 Among them,
2-heterobenzimidazoles such as 2-aminobenzimidazoles,
2-imidazylbenzimidazoles, and 2-phenoxylbenzimidazoles are
important classes of heteroaromatics in biological chemistry
and pharmaceutical areas.2 For example, a number of
2-piperazinylbenzimidazoles (A) exhibit anti-inflammatory3b
and antihistaminic activities;3a certain N-aryl 2-amino-
benzimidazoles (B) were studied for their potential antista-
phylococcal activity;4 several 2-imidazylbenzimidazoles (C)
In the past decade, copper-mediated sp2 C-X (X = N, O,
S, etc.) bond formation reactions have drawn considerable
attention for their efficiency and low cost.13 And recently,
these copper-catalyzed strategies have been successfully
applied to the assembly of various heterocyclic compounds
(6) Fujishita, T.; Abe, K.; Naito, A.; Makino, I.; Matsumoto, H.;
Onodera, N.; Endoh, T.; Iwata, M. Wordwide Patent 2005,121,132, 2005;
Chem. Abstr. 2005, 144, 69,828.
(1) (a) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M.
D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283. (b) Morphy, R.; Rankovic, Z.
J. Med. Chem. 2005, 48, 6523. (c) Hauel, N. H.; Nar, H.; Priepke, H.; Ries, U.;
Stassen, J.-M.; Wienen, W. J. Med. Chem. 2002, 45, 1757. (d) Saluja, S.; Zou,
R.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1996, 39, 881. (e) Gupta, R.
P.; Larroquette, C. A.; Agrawal, K. C. J. Med. Chem. 1982, 25, 1342.
(2) (a) Murru, S.; Patel, B. K.; Bras, J. L.; Muzart, J. J. Org. Chem. 2009,
74, 2217. (b) Martin, R. E.; Green, L. G.; Guba, W.; Kratochwil, N.; Christ,
A. J. Med. Chem. 2007, 50, 6291. (c) Bonfanti, J.-F.; Doublet, F.; Fortin, J.;
Lacrampe, J.; Guillemont, J.; Muller, P.; Queguiner, L.; Arnoult, E.; Gevers,
T.; Janssens, P.; Szel, H.; Willebrords, R.; Timmerman, P.; Wuyts, K.;
Janssens, F.; Sommen, C.; Wigerinck, P.; Andries, K. J. Med. Chem. 2007,
50, 4572. (d) Carpenter, A. J.; Al-Barazanji, K. A.; Barvian, K. K.; Bishop,
M. J.; Britt, C. S.; Cooper, J. P.; Goetz, A. S.; Grizzle, M. K.; Hertzog, D. L.;
Ignar, D. M.; Morgan, R. O.; Peckham, G. E.; Speake, J. D.; Swain, W. R.
Bioorg. Med. Chem. Lett. 2006, 16, 4994.
(7) Bendale, P. M.; Sun, C.-M. J. Comb. Chem. 2002, 4, 359.
(8) (a) Zhang, G. B.; Ren, P. D.; Gray, N. S.; Sim, T.; Liu, Y.; Wang, X.;
Che, J. W.; Tian, S.-S.; Sandberg, M. L.; Spalding, T. A.; Romeo, R.;
Iskandar, M.; Chow, D.; Seidel, H. M.; Karanewsky, D. S.; He, Y. Bioorg.
Med. Chem. Lett. 2008, 18, 5618. (b) Ellingboe, J. W.; Spinelli, W.; Winkley,
M. W.; Nguyen, T. T.; Parsons, R. W.; Moubarak, I. F.; Kitzen, J. M.;
Engen, D. V.; Bagli, J. F. J. Med. Chem. 1992, 35, 705.
(9) (a) Zheng, N.; Anderson, K. W.; Huang, X. H.; Nguyen, H. N.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7509. (b) Wang, X. Q.;
Bhatia, P. A.; Daanen, J. F.; Latsaw, S. P.; Rohde, J.; Kolasa, T.; Hakeem, A.
A.; Matulenko, M. A.; Nakane, M.; Uchic, M. E.; Miller, L. N.; Chang, R. J.;
Moreland, R. B.; Brioni, J. D.; Stewart, A. O. Bioorg. Med. Chem. 2005, 13,
4667. (c) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2003, 68, 2861. (d) Hong, Y. P.; Senanayake, C. H.; Xiang, T. J.; Vanden-
bossche, C. P.; Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett.
1998, 39, 3121.
(3) (a) Iemura, R.; Kawashima, T.; Fukuda, T.; Ito, K.; Tsukamoto, G. J.
Med. Chem. 1986, 29, 1178. (b) Kodama, T.; Takai, A.; Nakabayashi, M.;
Watanabe, L.; Sadaki, H.; Abe, N.; Kurokawa, A. Japanese Patent
50,126,682, 1975; Chem. Abstr. 1976, 84, 44,060.
(4) Ozden, S.; Atabey, D.; Yꢀıldꢀız, S.; Goker, H. Eur. J. Med. Chem. 2008,
43, 1390.
(10) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(11) (a) Alcalde, E.; Dinares, I. J. Org. Chem. 1991, 56, 4233. (b) Alcalde,
E.; Dinares, I.; Frigola, J.; Jaime, C.; Fayet, J. P.; Vertut, M. C.; Miravitlles,
C.; Pius, J. J. Org. Chem. 1991, 56, 4223. (c) Alcalde, E.; Dinares, I.; Frigola,
J. Tetrahedron Lett. 1988, 29, 491.
(5) (a) Takase, Y.; Watanabe, N.; Matsui, M.; Ikuta, H.; Kimura, T.;
Saeki, T.; Adachi, H.; Tokumura, T.; Mochida, H.; Akita, Y. Worldwide
Patent 93,07,124, 1993; Chem. Abstr. 1993, 119, 203,427. (b) Takahashi, T.;
Kaneko, M.; Kido, Y.; Shibata, T. Japanese Patent 01,063,580, 1989; Chem.
Abstr. 1989, 111, 189,568. (c) Parsons, J. H.; Hunt, R. G.; Leach, S. E.;
Percival, A.; Buss, A. D.; Green, D. E.; Mellor, M. European Patent 247,760,
1987; Chem. Abstr. 1987, 108, 131,827.
(12) (a) Axe, F. U.; Bembenek, S. D.; Butler, C. R.; Edwards, J. P.;
Fourie, A. M.; Grice, C. A.; Savall, B. M.; Tays, K. L.; Wei, J. M. Worldwide
Patent 2005,012,297, 2005; Chem. Abstr. 2005, 142, 219,286. (b) Kulkarni,
M. V.; Patil, V. D. Arch. Pharm. 1981, 314, 440.
(13) For recent reviews, see: (a) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41,
1450. (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096.
5618 J. Org. Chem. 2009, 74, 5618–5621
Published on Web 06/16/2009
DOI: 10.1021/jo900743y
r
2009 American Chemical Society

Lv and Bao
JOCNote
SCHEME 1. Proposed One-Pot Synthesis of 1,2-Disubstituted
Benzimidazoles via a Copper-Catalyzed Addition/Coupling
Process
FIGURE 1. Structures of several biologically active and pharma-
ceutically useful 2-heterobenzimidazoles.
the formation of benzimidazole ring via an intramolecular
C-N coupling (step b). The latter process might be
analogous to those reported Cu-catalyzed intramolecular
aminations to a certain extent.10,18 With this idea in mind,
we originally investigated the reaction of o-iodoarylcar-
bodiimide 1a (X = I, R1 = Me, R2 = Ph) with piperidine
2a. The first attempt was performed in toluene with CuI
(10 mol %) as the catalyst and 1,10-phenanthroline (1,10-
Phen, 20 mol %) as the ligand in the presence of Cs2CO3 (2
equiv) at 80 °C for 20 h.19 Both the desired product 3a and
the additive product 4a were obtained (53% and 31%
yield, respectively), indicating the reaction occurred in
the desired manner. Considering that the unsatisfying
yield of 3a might result from the incomplete conversion
in the intramolecular coupling process, we then tried to
optimize the conditions. It is found that solvent had a
significant influence. The result was improved when DME
or dioxane was used instead of other solvents (toluene,
DMF, and CH3CN), and dioxane was the best. After
screening several ligands including 1,10-Phen, 2,20-bipyr-
idyl, DMEDA, N,N-dimethylglycine, L-proline, and ethyl
2-oxocyclohexanecarboxylate, both 1,10-Phen and L-pro-
line emerged as suitable candidates, and L-proline was
selected as the preferred ligand (1,10-Phen might be a
second candidate). Other bases such as K2CO3 or K3PO4
provided lower yields. Among the Cu-catalysts examined
(CuI, CuBr, CuCl, and Cu2O), CuI acted as the optimal
catalyst. When the reaction was performed in the absence
of either catalyst or ligand, only 4a was recovered and no
desired product 3a was detected, indicating that both Cu-
catalyst and ligand were necessary for the cyclization
process. Increasing the temperature to 90 °C did not give
obvious improvement. Interestingly, the result remained
almost the same upon lowering the temperature to 70 °C,
while further lowering the temperature might lead to a
poor yield. A two-step procedure was tried but the former
one-step procedure is superior for its concise single-step
manipulation and a bit better yield.19
via one-pot strategies.14 For example, Ma et al. reported Cu-
catalyzed coupling/condensation reactions for the synthesis
of substituted indole or benzimidazole derivatives;14k,14n,14q
Buchwald and co-workers developed a useful Cu-catalyzed
cascade coupling/condensation process to assemble 1,2-di-
substituted benzimidazoles;14m other groups also reported
that benzimidazole derivatives could be efficiently
syntheized via Cu-catalyzed one-pot14a,14h or stepwise reac-
tions.2a However, to the best of our knowledge, there is no
report about the versatile synthesis of 2-heterosubstituted
benzimidazoles via a Cu-catalyzed one-pot process. Our
group is interested in one-pot synthesis of heterocycles via
Cu-catalyzed addition/cyclization reactions, which provide
convenient and efficient approaches to potentially useful
heterocyclic compounds.15 Herein, as a part of our continu-
ing effort, we report a novel Cu-catalyzed one-pot protocol
to synthesize various N-substituted 2-heterobenzimidazoles
from o-haloarylcarbodiimides and N-/O-nucleophiles.
We envisaged that o-haloarylcarbodiimide 116 and
proper nucleophile 2 would undergo a cascade process to
afford 1,2-disubstituted benzimidazole derivative 3. As
shown in Scheme 1, the proposed reaction might proceed
through an intermolecular addition of nucleophile 2 to
o-halocarbodiimide 1 under proper conditions (step a, the
plausible intermediate 4 would be formed),17 followed by
(14) Selected examples for the synthesis of heterocycles via a copper-
catalyzed one-pot process: (a) Zhu, J.; Xie, H.; Chen, Z.; Li, S.; Wu, Y.
Chem. Commun. 2009, 2338. (b) Li, L.; Wang, M.; Zhang, X.; Jiang, Y.; Ma,
D. Org. Lett. 2009, 11, 1309. (c) Verma, A. K.; Kesharwani, T.; Singh, J.;
Tandon, V.; Larock, R. C. Angew. Chem., Int. Ed. 2009, 48, 1138. (d) Yao, P.-
Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10, 4275. (e) Ohta, Y.;
Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 3535. (f) Wang,
B.; Lu, B.; Jiang, Y.; Zhang, Z.; Ma, D. Org. Lett. 2008, 10, 2761. (g) Chen,
Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625. (h) Yang, D.; Fu, H.;
Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 7841. (i) Yuan, Q.; Ma, D.
J. Org. Chem. 2008, 73, 5159. (j) Viirre, R. D.; Evindar, G.; Batey, R. A. J.
Org. Chem. 2008, 73, 3452. (k) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int.
Ed. 2007, 46, 2598. (l) Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett.
2007, 9, 5521. (m) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749. (n)
Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291. (o) Rivero, M. R.;
Buchwald, S. L. Org. Lett. 2007, 9, 973. (p) Vina, D.; del Olmo, E.; Lopez-
Perez, J.; Feliciano, A. S. Org. Lett. 2007, 9, 525. (q) Chen, Y.; Xie, X.; Ma, D.
J. Org. Chem. 2007, 72, 9329. (r) Martin, R.; Rivero, M. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 7079.
Encouraged by these results, the scope of this Cu(I)-
catalyzed cascade process was examined by employing dif-
ferent o-iodoarylcarbodiimides and amines (Table 1, entries
1-16). We were pleased to find that a variety of aliphatic
amines were all viable N-nucleophiles. Both cyclic and n-alkyl
secondary amines provided satisfying results at 70 °C (entries
1-3), while the reactions with β-amino alcohols required a
higher temperature and gave relatively lower yields (entries
4 and 5). The electronic effect of the substituents on the
aromatic rings of o-iododiarylcarbodiimides was investigated.
(15) (a) Lv, X.; Liu, Y.; Qian, W.; Bao, W. Adv. Synth. Catal. 2008, 350,
2507. (b) Bao, W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett. 2008, 10, 3899.
(16) Prepared via the aza-Wittig reactions between the corresponding
o-haloaryl aza-Wittig reagents and isocyanates. See the Supporting Infor-
mation.
(17) Several references have described that N,N0-disubstituted carbodii-
mides could smoothly react with certain N- or O-nucleophiles to give the
corresponding adducts under suitable conditions. For the addition with
amine see: (a) Park, S. J.; Lee, M. J.; Rhim, H.; Kim, Y.; Lee, J.-H.; Chung,
B. Y.; Lee, J. Y. Bioorg. Med. Chem. 2006, 14, 3502. (b) Heras, M.; Ventura,
M.; Linden, A.; Villalgordo, J. M. Tetrahedron 2001, 57, 4371. (c) Thomas, E.
W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J. J. Med. Chem.
1989, 32, 228. For the addition with imidazole see: (d) Ding, M.-W.; Tu, H.-
Y.; Liu, Z.-J. Synth. Commun. 1997, 27, 3657.(e) Zinner, G.; Perner, M.;
Gruenefeld, J.; Schecker, H. G. Arch. Pharm. 1986, 319, 1073. For the addition
with phenol see: (f) Larksarp, C.; Alper, H. J. Org. Chem. 1999, 64, 9194.
(18) (a) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7,
4781. (b) Szczepankiewicz, B. G.; Rohde, J. J.; Kurukulasuriya, R. Org. Lett.
2005, 7, 1833.
(19) For details, see the Supporting Information.
J. Org. Chem. Vol. 74, No. 15, 2009 5619

Lv and Bao
JOCNote
TABLE 1. One-Pot Synthesis of 2-Aminobenzimidazoles from o-Haloarylcarbodiimides and Aminesa
a Reaction conditions: o-haloarylcarbodiimide 1 (0.5 mmol), amine 2 (0.55 mmol), CuI (0.05 mmol), L-proline (0.1 mmol), and Cs2CO3 (1.0 mmol) in
dioxane (3 mL) under N2 at 70 °C for 20 h. b Isolated yield. c At 80 °C. d For 30 h. e 1,10-Phen (0.1 mmol) as the ligand, at 80 °C. f At 100 °C.
The presence of either a weak electron-donating group (p-Me)
or a weak electron-withdrawing group (m-Cl, p-Cl) on
the aromatic ring of 1 provided good yield (entries 6, 8, and
11). Increasing the electron density on the nonhalogenated
ring might favor the intramolecular C-N coupling process.
The reaction of the o-iododiarylcarbodiimide bearing a
methoxy group afforded the desired product in excellent yield
(entry 10). However, the carbodiimides bearing strong elec-
tron-withdrawing groups (m-CF3, p-NO2) were unfavorable
for the reaction (entries 9 and 12). An ortho-substituted
diarylcarbodiimide was tested and only gave moderate yields,
which might result from the ortho-steric hindrance (entry 7).
N-Aryl-N0-benzylcarbodiimide 1i could smoothly react with
piperidine (entry 13), too. Primary amines were also utilized as
the nucleophiles (entries 14-16), and 1,10-Phen was a super-
ior ligand for these cases. Interestingly, the reactions might
have good regioselectivities. The NH-aryl group would take
priority over the NH-alkyl group in the intramolecular
couping process (entries 14 and 15). When R-phenylethana-
mine was used, its NH-group would be inferior to the NH-
benzyl group in the cyclization process (entry 16). Bromides
are more accessible and economical than iodides. There-
fore, further investigation of the one-pot reaction between
o-bromoarylcarbodiimide and amine was pursued (entries
17-22). Although L-proline could also successfully promote
these reactions, it required a much higher temperature
(entry 17). Switching the ligand to 1,10-Phen led to a milder
condition. Therefore, 1,10-Phen was chosen as the ligand for
these reactions. The results were similar to those obtained
with o-iodoarylcarbodiimides, and the desired products were
delivered in good to excellent yields.
We then attempted to extend this method to the synthesis
of 2-imidazylbenzimidazoles. And we were pleased to find
that our protocol was also efficient when imidazoles were
employed as the N-nucleophiles (Table 2). And 1,10-Phen
seemed to be a suitable ligand for these reactions. Generally,
good to execellent yields could be obtained. Both electron-
donating groups (p-Me, p-MeO) and electron-withdrawing
groups (m-Cl, p-Cl) on the aromatic rings of carbodiimides
were tolerated (entries 1-8). The reaction with 2-methylimi-
dazole required a higher temperature and longer reaction
time, indicating that the ortho-steric hindrance on the nucleo-
phile was unfavorable for the reaction (entries 9 and 10).
We also explored whether our protocol was viable for
the reaction between o-iodoarylcarbodiimides and phenols.
By using 1a and phenol as the model substrates under the
5620 J. Org. Chem. Vol. 74, No. 15, 2009

Lv and Bao
JOCNote
TABLE 2. One-Pot Synthesis of 2-Imidazylbenzimidazolesa
TABLE 3. One-Pot Synthesis of 2-Phenoxylbenzimidazolesa
a Reaction conditions: o-iodoarylcarbodiimide 1 (0.5 mmol), phenol
7 (0.6 mmol), CuI (0.05 mmol), N,N-dimethylglycine (0.10 mmol), and
K3PO4 (1.5 mmol) in DMSO (2 mL) under N2 at 90 °C for 24 h. b Isolated
yield.
SCHEME 2. Synthesis of 2-Aminopyridoimidazole Derivatives
might possess biological and pharmaceutical activities,
were smoothly synthesized via the Cu-catalyzed one-pot
addition/C-N coupling process. Our protocol allows
the introduction of different kinds of hetero-substituents
in the 2-position of the benzimidazole ring. The efficient
and versatile one-pot transformation of the readily
available starting materials into 2-heterobenzimida-
zoles would make this protocol valuable to synthetic
chemists.
a Reaction conditions: o-haloarylcarbodiimide
1 (0.5 mmol),
imidazole 5 (0.6 mmol), CuI (0.05 mmol), 1,10-Phen (0.10 mmol),
and Cs2CO3 (1.0 mmol) in dioxane (3 mL) under N2 at 80 °C for
24 h. b Isolated yield. c At 100 °C. d For 36 h.
Experimental Section
General Experimental Procedures for the Cu(I)-Catalyzed
One-Pot Synthesis of 2-Aminobenzimidazoles. An oven-dried
Schlenk tube was charged with a magnetic stir bar, CuI
(0.05 mmol), ligand (0.1 mmol), and Cs2CO3 (1.0 mmol). The
Schlenk tube was capped, and then evacuated and backfilled
with N2 (3 times). Under a positive pressure of N2, a solution of
amine 2 (0.55 mmol) in dioxane (1.5 mL) was added via syringe
and the mixture was prestirred at 60 °C in a preheated oil
bath for 10 min. Then a solution of o-haloarylcarbodiimide
1 (0.5 mmol) in dioxane (1.5 mL) was added dropwise via syringe
(for about 0.5 h). The tube was sealed and allowed to stir at the
indicated temperature for 20-30 h. The reaction was stopped
and cooled to room temperature. The reaction mixture was
directly passed through Celite and rinsed with an additional
30 mL of AcOEt. The combined filtrate was concentrated and
purified by column chromatography to give the corresponding
product 3.
above optimized conditions, the desired product 2-phenox-
ylbenzimidazole 8a was obtained only in poor yield (<40%).
Shifting the ligand to N,N-dimethylglycine afforded 8a
in moderate yield (57%). Further investigation revealed
DMSO was the best solvent and K3PO4 was the optimal
base, and good yield (76%) could be obtained under these
improved conditions. The scope was explored by varying
different substrates. Moderate to good yields were obtained
(Table 3).
Our one-pot method was also successfully applied to the
assembly of N-aryl-2-aminopyridoimidazoles (Scheme 2).19
Simplified procedures were also tried (for the synthesis
of 3a and 6a), and the results remained almost the same
(94% and 89% yield, respectively).20
In summary, a novel, efficient, and versatile strategy
for the synthesis of various 2-heterobenzimidazoles has
been developed. A number of N-substituted 2-aminoben-
zimidazoles (or 2-aminopyridoimidazoles), 2-imidazyl-
benzimidazoles, and 2-phenoxylbenzimidazoles, which
Acknowledgment. This work was financially supported
by the Specialized Research Fund for the Doctoral Program
of Higher Education of China (20060335036).
Supporting Information Available: Optimization pro-
cedure, experimental procedures, experimental data, and copies
of 1H and 13C NMR spectra for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) The reactions were carried out in a simple oven-dried round-
bottomed flask with a septum and under positive N2 pressure. See the
Supporting Information.
J. Org. Chem. Vol. 74, No. 15, 2009 5621