Cu(I)-catalyzed synthesis of 2-substituted benzimidazoles from 2-iodoanilines and amides

Article abstract of DOI:10.1002/cjoc.201300429

A novel and efficient approach to the synthesis of 2-substituted benzimidazoles has been developed via CuI/DMEDA-catalyzed coupling reaction and post-cyclization with glacial acetic acid from readily available 2-iodoanilines and amides. This method is suitable for the construction of a variety of benzimidazoles in moderate to good yields under short reaction times. A novel and efficient approach to the synthesis of 2-substituted benzimidazoles has been developed via CuI/DMEDA-catalyzed coupling reaction and post-cyclization with glacial acetic acid from readily available 2-iodoanilines and amides. This method is suitable for the construction of a variety of benzimidazoles in moderate to good yields under short reaction times. Copyright

Full text of DOI:10.1002/cjoc.201300429

COMMUNICATION
DOI: 10.1002/cjoc.201300429
Cu(I)-Catalyzed Synthesis of 2-Substituted Benzimidazoles
from 2-Iodoanilines and Amides
Hua Yuan,a,b Yongxin Chen,a,b Jinli Song,a,b Chunxia Chen,a,b and Baohua Chen*,a,b
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou,
Gansu 730000, China
A novel and efficient approach to the synthesis of 2-substituted benzimidazoles has been developed via
CuI/DMEDA-catalyzed coupling reaction and post-cyclization with glacial acetic acid from readily available
2-iodoanilines and amides. This method is suitable for the construction of a variety of benzimidazoles in moderate
to good yields under short reaction times.
Keywords 2-substituted benzimidazoles, CuI/DMEDA, 2-iodoanilines, amides, synthesis
Introduction
or long reaction times. Accordingly, a cheap and effi-
cient synthetic method is in high demand to be devel-
oped.
In recent years, some researchers have claimed that
1,2-disubstituted benzimidazoles could be synthesized
starting from 2-halo anilines[32] or 2-halo nitro-
arenes[33,34] with amides. Based on the pervious results,
herein we reported a novel and efficient Cu(I)-catalyzed
route to synthesis of 2-substituted benzimidazoles from
2-iodoanilines and amides under short reaction times.
With a “privileged” structure, benzimidazoles serve
as an increasingly important series of nitrogen-hetero-
cycles which display a wide range of biological and
therapeutic activities,[1-3] meanwhile, their derivatives
are extensively employed as pharmaceutical and agro-
chemical substances.[4-7] Consequently, they have at-
tracted considerable attention of organic and medicinal
chemists. There are two classical methods[8-11] for the
synthesis of benzimidazoles. The first route is the direct
reaction of 1,2-phenylenediamines with carboxylic acids
under strongly acidic conditions. The second route is the
condensation of 1,2-phenylenediamines with aldehydes
by the aid of various oxidative reagents. Although they
are very efficient processes, they all result in regio-
isomers in products that employ 1,2-phenylenediamines
as starting materials.
Recently, some examples have been discovered for
the synthesis of N-heterocycles through transition-
metal-catalyzed cross-coupling reaction.[12-27] For in-
stance, Brain et al.[28-30] developed a palladium-cata-
lyzed N-arylation of (o-bromophenyl)-amidines to get
benzimidazoles. Buchwald et al.[31] found an efficient
approach to the Cu(OAc)2-catalyzed synthesis of ben-
zimidazoles through a C－H functionalization/C－N
bond forming process in the presence of O2 from
amidines. The previous methods to synthesize benzimi-
dazoles were very efficient, however, there are very few
general methods that convert commercially available or
readily accessible materials in one step into benzimida-
zoles, and most of these procedures required expensive
metal catalysts, specific additives, microwave assistance
Experimental
Typical procedure for the synthesis of 2-phenyl-1H-
benzimidazole 3aa
An oven-dried Schlenk tube was charged with ben-
zamide (1a, 30.2 mg, 0.25 mmol), 2-iodoaniline (2a,
87.6 mg 0.4 mmol), CuI (5 mg, 0.025 mmol),
K3PO4•3H2O (133 mg, 0.50 mmol). The tube was sealed
and then evacuated and backfilled with nitrogen (3
times). DMEDA (6 μL, 0.05 mmol) and dioxane (1 mL)
were added via syringe into the reaction system. The
mixture was stirred at 100 ℃ for 3 h, then 1 mL of
AcOH was added and the mixture was stirred for 10－
20 min. After cooling to room temperature, the solvent
was partitioned with ethyl acetate and aqueous NaHCO3.
The organic layer was dried over anhydrous Na2SO4 and
evaporated in vacuo, the crude product was purified by
column chromatography on silica gel (ethyl acetate/
petroleum ether, 1∶2, V/V) to give 3aa (34.5 mg, 70%)
1
as white solid (Table 2, Entry 1). H NMR (300 MHz,
DMSO-d6) δ: 7.22－7.26 (m, 2H), 7.44－7.48 (m, 1H),
7.49－7.60 (m, 2H), 7.66－7.70 (m, 2H), 8.28－8.31
*
E-mail: chbh@lzu.edu.cn
Received May 31, 2013; accepted July 8, 2013; published online July 26, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300429 or from the author.
Chin. J. Chem. 2013, 31, 1247—1249
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1247

Yuan et al.
COMMUNICATION
(m, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 151.465,
139.522, 130.323, 129.899, 129.014, 126.610, 122.257,
115.217. Melting point: 297－299 ℃.
per-catalyzed approach to the construction of 1H-benzi-
Table 1 Optimization of reaction conditionsa
O
H
N
NH2
I
Results and Discussion
[Cu], base
NH2
+
solvent, temp.
In an initial attempt, we selected benzamide 1a and
2-iodoaniline 2a as the model substrates to probe the
reaction conditions. First, the desired product 3aa was
obtained in 20% yield after 3 h, when 1a (0.3 mmol)
and 2a (0.25 mmol) were treated with 10 mol% of CuI,
20 mol% of DMEDA and 2 equiv. of K3PO4•3H2O in
dioxane at 100 ℃ (Entry 1, Table 1). Gratifyingly,
when the amount of 2a was increased to 0.4 mmol, the
yield was enhanced to 70% (Entry 2, Table 1). Reaction
at a lower temperature (80 ℃) resulted in poorer con-
version while no obvious improvement was achieved
when the temperature was increased to 120 ℃ (Entries
3－4, Table 1). Next, various copper-catalysts were in-
vestigated, and CuI showed the highest activity (Entries
5－8, Table 1). With CuI as a catalyst, a variety of bases
such as Cs2CO3, K2CO3, KOBu-t were also evaluated,
but they were less efficient than K3PO4•3H2O (Entries 9
－11, Table 1). Furthermore, different solvents such as
DMF, toluene, and THF were failed to improve the
yield (Entries 12－14, Table 1). In addition, it was not
found significant change when reaction time was ex-
tended to 6 h (Entry 15, Table 1).
Having the optimized condition, we then attempted
to extend the scope of this reaction, and the results are
illustrated in Table 2. Generally, the reaction of various
amides with 2-iodoanilines proceeded smoothly and led
to the desired product 3 in moderate to good yields,
showing good functional groups tolerance of both elec-
tron-donating substituents (Me, OMe) and electron-
withdrawing substituents (F, Cl, CF3). The benzamides
1 containing electron-donating groups (Entries 2－4, 7,
Table 2) resulted in slightly lower yields than electron-
withdrawing ones (Entries 5－6, 8, 10, Table 2). The
benzamide 1 with fluoro on the 3-position was also
examined, and resulted in the corresponding product
3ha in 75% yield. It was also found that under the opti-
mized conditions, the 2-phenylacetamide was also well
tolerated (Entry 9, Table 2), producing 3ia in 61% yield
respectively. For 2-iodoanilines, the electron-rich sub-
stituents showed better reactivities and gave higher
yields than electron-deficient ones (Entries 11－17, Ta-
ble 2).
N
1a
2a
3aa
Entry Catalyst
Base
K3PO4•3H2O dioxane 100
CuI K3PO4•3H2O dioxane 100
Solvent T/℃ Time/h Yieldb/%
1c
CuI
3
3
3
3
3
3
3
3
3
3
3
3
3
3
6
20
70
trace
71
50
68
18
13
69
28
10
16
62
10
70
2
3
CuI
CuI
K3PO4•3H2O dioxane 80
K3PO4•3H2O dioxane 120
4
5
CuBr K3PO4•3H2O dioxane 100
CuCl K3PO4•3H2O dioxane 100
CuCl2 K3PO4•3H2O dioxane 100
6
7
8
Cu
K3PO4•3H2O dioxane 100
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3
K2CO3
dioxane 100
dioxane 100
dioxane 100
10
11
12
13
14
15
KOBu-t
K3PO4•3H2O DMF 100
K3PO4•3H2O toluene 100
K3PO4•3H2O
THF 100
K3PO4•3H2O dioxane 100
a
Reaction conditions: 1a (0.25 mmol), 2a (0.4 mmol), base (0.5
mmol), catalysts (10 mmol%), DMEDA (20 mmol%) in 1 mL of
solvent under nitrogen; then AcOH (1 mL) for 20－30 min.
Isolated yield. Reaction was carried out with 0.25 mmol 1a
b
c
and 0.3 mmol 2a.
Table 2 Synthesis of 2-substituted benzimidazoles from amides
and 2-iodoanilinesa
.
(1) CuI, DMEDA, K3PO4
3H2O, dioxane
H
N
O
I
2
+
R2
R1
R
R1
NH2
(2) AcOH, 20 - 30 min
NH2
N
3
2
1
Entry
R1
Ph
R2
Yieldb/%
1
2
3
1
2
3c
H
H
H
H
H
H
70
65
62
72
73
79
1a
2a
2a
2a
2a
2a
2a
3aa
3ba
3ca
3da
3ea
3fa
4-CH3Ph
3,4-2-CH3Ph
4-OMePh
4-ClPh
1b
1c
1d
1e
1f
A plausible mechanism for this reaction was pro-
posed in Scheme 1. It may involve Ullmann-type cou-
pling reaction[35] and post-cyclization. Coordination of
2-iodoanilines 2a with CuI first forms I, elimination of Ι
with amides 1a in the presence of base (K3PO4•H2O)
gives П and post-cyclization under AcOH leads to
product 3 with leaving H2O.
4
5
6
4-CF3Ph
O
7
8
9
H
H
H
74
75
61
1g
1h
1i
2a
2a
2a
3ga
3ha
3ia
O
3-FPh
Conclusions
In conclusion, we have developed an efficient cop-
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1247—1249

Cu(I)-Catalyzed Synthesis of 2-Substituted Benzimidazoles from 2-Iodoanilines and Amides
[2] Hu, L.; Kully, M. L.; Boykin, D. W.; Abood, N. Bioorg. Med. Chem.
Continued
Lett. 2009, 19, 3374.
[3] Schiffmann, R.; Neugebauer, A.; Klein, C. D. J. Med. Chem. 2006,
49, 511.
[4] Mckellar, Q. A.; Scott, E. W. J. Vet. Pharmacol. Ther. 1990, 13,
223.
[5] Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893.
[6] Mortimer, C. G.; Wells, G.; Crochard, J. P.; Stone, E. L.; Bradshaw,
T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem. 2006, 49,
179.
[7] Sabat, M.; Vanrens, J. C.; Laufersweiler, M. J.; Brugel, T. A.; Maier,
J.; Golebiowski, A.; De, B.; Easwaran, V.; Hsieh, L. C.; Walter, R.
L.; Mekel, M. J.; Evdokimov, A.; Janusz, M. J. Bioorg. Med. Chem.
Lett. 2006, 16, 5973.
Entry
10
R1
4-NO2Ph
Ph
R2
H
Yieldb/%
1
2
3
55
75
76
80
65
73
72
1j
2a
2b
2b
2b
2c
2d
2d
3ja
3ab
3eb
3fb
3ac
3ad
3bd
11
4-CH3
4-CH3
4-CH3
4-Cl
4-Br
4-Br
1a
1e
1f
12
4-ClPh
4-CF3Ph
Ph
13
14
1a
1a
1b
15
Ph
16
4-CH3Ph
O
17
4-Br
65
1g
2d
3gd
O
[8] Grimmett, M. R. Imidazole and Benzimidazole Synthesis Best Syn-
thetic Methods, Ed.: Meth-Cohn, O., Academic Press, London,
1997.
[9] Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1998,
39, 4481.
[10] Beaulieu, P. L.; Hache, B.; von Moos, E. Synthesis 2003, 1683.
[11] Yang, D.; Fokas, D.; Yu, J.; Li, L.; Baldino, C. M. Synthesis 2005,
47.
a Reaction conditions: 1 (0.25 mmol), 2 (0.4 mmol), K3PO4•3H2O
(0.5 mmol), CuI (0.025 mmol), DMEDA (0.05 mmol) at 100 ℃
in dioxane (1 mL) for 3 h under nitrogen; then AcOH (1 mL) for
20－30 min. Isolated yield. Reaction was carried out at 120
℃ for 6 h.
b
c
Scheme 1 A plausible reaction mechanism
[12] Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed.
2005, 44, 403.
[13] Gupta, S.; Agarwal, P. K.; Kundu, B. Tetrahedron Lett. 2010, 51,
1887.
[14] Murru, S.; Patel, B. K.; Bras, J. L.; Muzart, J. J. Org. Chem. 2009,
74, 2217.
[15] Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
[16] Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73,
3452.
O
NH2
1a
NH
I
NH2
2 CuI, DMEDA
N
base
Cu
-HI
N
I
Ι
2a
[17] Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 7509.
NH2
[18] Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
[19] Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 680.
[20] Lygin, A. V.; Meijere, A. Eur. J. Org. Chem. 2009, 5138.
[21] Boeini, H. Z.; Najafabadi, K. H. Eur. J. Org. Chem. 2009, 4926.
[22] Creencia, E. C.; Kosaka, M.; Muramatsu, T.; Kobayashi, M.; Iizuka,
T.; Horaguchi, T. J. Heterocyclic Chem. 2009, 46, 1039.
[23] Aliyan, H.; Fazaeli, R.; Fazaeli, N.; Mssah, A. R.; Naghash, H. J.;
Alizadeh, M.; Emami, G. J. Heteroatom. Chem. 2009, 20, 202.
[24] Zhou, X.; Qu, Y.; Pan, L.; Wu, Z. Tetrahedron 2013, 69, 1717.
[25] Fu, H.; Hu, L.; Yang, D.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73,
7841.
O
N
AcOH
H2O
NH
N
H
П
3aa
midazole skeleton in moderate to good yields. The
method tolerated a range of functional groups using CuI
as catalyst and readily available 2-iodoanilines and am-
ides as starting materials. Further researches of N-2 sub-
stituted triazoles are currently under investigation in our
laboratory.
[26] Deng, X.; Mcalliister, H.; Main, N. S. J. Org. Chem. 2009, 74, 5742.
[27] Chen, B. H.; Liu, X.; Chen, Y.; Li, K.; Wang, D. Chin. J. Org. Chem.
2012, 30, 2285 (in Chinese).
Acknowledgement
[28] Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
[29] Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
[30] Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932.
[31] Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, Q.;
Williams, J. M. J. Org. Lett. 2009, 11, 2039.
We are grateful for support of this project by the Na-
tional Natural Science Foundation of China (No.
J1103307) and the project of Science Foundation of
Gansu Province (No. 1208RJZA266).
[32] Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749.
[33] Alonso, J.; Halland, N.; Nazare, M.; Rkyek, O.; Urmann, M.; Lin-
denschmidt, A. Eur. J. Org. Chem. 2011, 76, 234.
[34] Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654.
[35] Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
References
[1] Gravatt, G. L.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1994,
37, 4338.
(Zhao, X.)
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