Copper-catalyzed intramolecular cyclization to N-substituted 1,3-dihydrobenzimidazol-2-ones

Article abstract of DOI:10.1021/ol8011106

(Chemical Equation Presented) An efficient and convenient method was developed for preparing N-substituted 1,3-dihydrobenzimidazol-2-ones from Na?2-substituted N-(2-halophenyl)ureas via a CuI/DBU-catalyzed cyclization in DMSO under microwave heating. High yields were obtained and a variety of functional groups were tolerated under these conditions, including Na?2-aryl, alkyl, heterocyclic, various N-(substituted 2-halophenyl) and N-(2-iodopyridyl)ureas. ? 2008 American Chemical Society.

Full text of DOI:10.1021/ol8011106

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3263-3266
Copper-Catalyzed Intramolecular
Cyclization to N-Substituted
1,3-Dihydrobenzimidazol-2-ones
Zhaoguang Li,†,‡ Hongbin Sun,‡ Hualiang Jiang,†,§ and Hong Liu*,†
Drug DiscoVery and Design Centre, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, Center for
Drug DiscoVery, College of Pharmacy China Pharmaceutical UniVersity, 24 Tongjia
Xiang, Nanjing 210009, China, and School of Pharmacy, East China UniVersity of
Science and Technology, Shanghai 200237, China
hliu@mail.shcnc.ac.cn
Received May 20, 2008
ABSTRACT
An efficient and convenient method was developed for preparing N-substituted 1,3-dihydrobenzimidazol-2-ones from N′-substituted N-(2-
halophenyl)ureas via a CuI/DBU-catalyzed cyclization in DMSO under microwave heating. High yields were obtained and a variety of functional
groups were tolerated under these conditions, including N′-aryl, alkyl, heterocyclic, various N-(substituted 2-halophenyl) and N-(2-iodopyridyl)ureas.
1,3-Dihydrobenzimidazol-2-ones are an important class of
compounds owing to their potency as selective vasopressin
1R receptor antagonists,1 HIV-1 RT non-nucleoside inhibi-
tors,2 CGRP receptor antagonists,3 p38 MAP kinase inhibi-
tors,4 respiratory syncytial virus fusion inhibitors,5 and
progesterone receptor antagonists.6 Therefore, much attention
has been paid to the development of efficient methods for
preparing 1,3-dihydrobenzimidazol-2-ones. Two common
approaches were applied for the construction of the dihy-
drobenzimid-azol-2-one rings. The first approach involves
the selective alkylation or arylation of either nitrogen atom
of 1,3-dihydrobenzimidazol-2-ones, which often requires a
protection strategy.7 The second one involves nucleophilic
displacement of 2-fluoronitrobenzenes with amines and
subsequent reduction and cyclization with carbonyldiimida-
zole,4,7 which is the limitation of the diversity of the products
because of the commercial unavailability of the key reagent
of 2-fluoronitrobenzenes.
† Shanghai Institute of Materia Medica.
‡ China Pharmaceutical University.
§ East China University of Science and Technology.
(1) Guillaume, M. Org. Process Res. DeV. 2006, 10, 1227.
(2) Barreca, M. L.; Rao, A.; De Luca, L.; Zappala`, M.; Monforte, A. M.;
Maga, G.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Chimirri, A.;
Monforte, P. J. Med. Chem. 2005, 48, 3433.
(5) Yu, K.-L.; Sin, N.; Civiello, R. L.; Wang, X. A.; Combrink, K. D.;
Gulgeze, H. B.; Venables, B. L.; Wright, J. J. K.; Dalterio, R. A.; Zadjura,
L.; Marino, A.; Dando, S.; D’Arienzo, C.; Kadow, K. F.; Cianci, C. W.;
Li, Z.; Cianci, C. W.; Clarke, J.; Genovesi, E. V.; Medina, I.; Lamb, L.;
Colonno, R. L.; Yang, Z.; Krystal, M.; Meanwell, N. A. Bioorg. Med. Chem.
Lett. 2007, 17, 895.
(3) Bell, I. M.; Bednar, R. A.; Fay, J. F.; Gallicchio, S. N.; Hochman,
J. H.; McMasters, D. R.; Miller-Stein, C.; Moore, E. L.; Mosser, S. D.;
Pudvah, N. T.; Quigley, A. G.; Salvatore, C. A.; Stump, C. A.; Theberge,
C. R.; Wong, B. K.; Zartman, C. B.; Zhang, X.-F.; Kane, S. A.; Graham,
S. L.; Vacca, J. P.; Williams, T. M. Bioorg. Med. Chem. Lett. 2006, 16,
6165.
(6) Terefenko, E. A.; Kern, J.; Fensome, A.; Wrobel, J.; Zhu, Y.; Cohen,
J.; Winneker, R.; Zhang, Z.; Zhang, P. Bioorg. Med. Chem. Lett. 2005, 15,
3600.
(7) (a) Li, Q.; Li, T.; Woods, K. W.; Gu, W.-Z.; Cohen, J.; Stoll, V. S.;
Galicia, T.; Hutchins, C.; Frost, D.; Rosenberg, S. H.; Sham, H. L. Bioorg.
Med. Chem. Lett. 2005, 15, 2918. (b) Kawamoto, H.; Nakashima, H.; Kato,
T.; Arai, S.; Kamata, K.; Iwasawa, Y. Tetrahedron 2001, 57, 981.
(4) Hammach, A.; Barbosa, A.; Gaenzler, F. C.; Fadra, T.; Goldberg,
D.; Hao, M.-H.; Kroe, R. R.; Liu, P.; Qian, K. C.; Ralph, M.; Sarko, C.;
Soleymanzadeh, F.; Moss, N. Bioorg. Med. Chem. Lett. 2006, 16, 6316.
10.1021/ol8011106 CCC: $40.75
Published on Web 07/02/2008
2008 American Chemical Society

Several studies have reported transition-metal-catalyzed
formation of C-N via nitrogen nucleophilic displacement
of aryl halogen.8 Carolina Bened´ı and co-workers9 carried
out palladium-catalyzed synthesis of 1,3-dihydrobenzimid-
azol-2-ones and obtained low yields (32%). D. Ma et al.10
reported the process of cascade coupling/cyclization to
N-substituted 1,3-dihydrobenzimidol-2-ones; however, these
reactions were only limited to N-alkylated 1,3-dihydrobenz-
imidol-2-ones and could not be applied to N-aryl or
heterocyclic products. As part of our continuing effort to
assemble heterocycles by a copper-catalyzed coupling reac-
tion,11 we aimed to develop a new protocol for synthesizing
N-substituted 1,3-dihydrobenzimidol-2-ones via a copper-
catalyzed intramolecular cyclization process from N′-
substituted-N-(2-halophenyl)ureas in a short time (Scheme
1). In comparison with the existing methods, the present
Table 1. Optimization for Synthesis of N-Substituted
1,3-Dihydrobenzimidazol-2-onesa
entry
catalyst
base
temp (°C) time (min) yield (%)
1
-
-
100
100
100
100
100
120
120
120
120
120
120
5
5
5
5
5
0
0
5
2b
3
Pd(OAc)2
CuI
CuI
CuI
CuI
Cs2CO3
NaOH
TEA
DBU
DBU
DBU
DBU
DBU
DBU
DBU
4
5
6
7
8
9
0
64
73
82
93
46
73
87
5
CuI
10
20
20
20
90
CuI
CuIc
Scheme 1
.
Copper-Catalyzed Synthesis of N-substituted
1,3-Dihydrobenzimidazol-2-ones
d
10
Cu(OAc)2
CuI
11e
a Reaction conditions: 1a (0.5 mmol), catalyst (0.1 mmol), base (1
mmol), DMSO (2 mL). b The solvent was dry DMF. c CuI (0.05 mmol).
d Cu(OAc)2 (0.25 mmol). e The general method without microwave heating
was adopted, CuI (0.1 mmol).
The reaction could not be conducted and no target
compound was generated in the base-free condition without
a catalyst, which indicated that the presence of a catalyst
and base was very crucial to the intramolecular cyclization
(entry 1, Table 1). There is no improvement in yield when
Pd(OAc)2 is adopted as a catalyst (entry 2, Table 1).
Subsequently, we employed the conditions used in our
previously published study11 for copper-catalyzed formation
of C-N from a halide and an amine. Moderate conversion
of 1a to 2a was observed using CuI (0.2 equiv) as the
catalyst, dimethyl sulfoxide (DMSO) as the solvent, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as a base. The nature
of bases was found to have a pronounced impact on the
process. DBU was proven to be better than the inorganic
base NaOH, while triethlyamine (TEA) was ineffective
(entries 3 to 5, Table 1). The yields improved significantly
when the temperature was up to 120 °C and the reaction
approach offers the following advantages: (i) it proceeds
faster and affords good to excellent yields within minutes
under microwave heating, (ii) it is very cost-effective and
uses the inexpensive catalyst CuI or/and the ligand (L-
proline), and (iii) it is applicable to a broader range of
substrates, including N′-aryl, alkyl, heterocyclic, and various
N-(substituted 2-halophenyl)ureas.
The requisite cyclization precursors N′-substituted-N-(2-
halophenyl)ureas (1) are readily synthesized from com-
mercially available o-haloanilines through reactions with
triphosgene and different kinds of amines or isocyanates,
including aryl, alkyl, and heterocyclic amines12 or substituted
isocyanates13 (Scheme 2). The desired ureas were obtained
in high yields and purity without further purification.
Scheme 2
.
Synthesis of N′-Substituted-N-(2-halophenyl)ureas
from o-Haloaniline
(8) (a) Salcedo, A.; Neuville, L.; Rondot, C.; Retailleau, P.; Zhu, J. P.
Org. Lett. 2008, 10, 857. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999,
1, 35. (c) Ghotas, E.; Robert, A. B. Org. Lett. 2003, 5, 133. (d) Klapars,
A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
126, 3529. (e) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (f)
Yang, T.; Lin, C. X.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett. 2005, 7,
4781. (g) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661.
(9) Bened`ı, C.; Bravo, F.; Uriz, P.; Ferna´ndez, E.; Claver, C.; Castillo´n,
S. Tetrahedron Lett. 2003, 44, 6073.
(10) Zou, B. L.; Yuan, Q. L.; Ma, D. W. Org. Lett. 2007, 9, 4291.
(11) (a) Huang, H.; Liu, H.; Jiang, H. L. J. Comb. Chem. 2008,
accepted. (b) Chen, S. Y.; Huang, H.; Liu, X. J.; Shen, J. K.; Jiang, H. L.;
Liu, H. J. Comb. Chem. 2008, 10, 358.
N′-(4-Trifluoromethylphenyl)-N-(2-iodophenyl)urea (1a)
was first used as the model substrate to optimize the reaction
conditions, including different bases, various solvents, reac-
tion temperatures, reaction times, and different amounts of
catalyst (Table 1).
(12) Ye, D. J.; Deng, G. H.; Wenfeng, L.; Zhou, Y.; Feng, E.; Jiang,
H.; Liu, H. Tetrahedron 2008, 64, 6544.
(13) (a) Shahnaz, P.; Hai, S. M. A.; Khan, R. A.; Khan, K. M.; Afza,
N.; Sarfaraz, T. B. Synth. Commun. 2005, 35, 1663. (b) Lee, S. H.;
Matsushita, H.; Koch, G.; Zimmermaunn, J.; Clapham, B.; Janda, K.
J. Comb. Chem. 2004, 6, 822.
3264
Org. Lett., Vol. 10, No. 15, 2008

Table 2. Synthesis of N-Substituted 1,3-Dihydrobenzimidazol-2-ones
a Reaction conditions: X ) I, 1 (0.5 mmol), CuI (0.1 mmol), DBU (1 mmol), MW, 120 °C, 20 min. b X ) Br, L-Proline (0.25 mmol) was added. c X
) Br, without L-proline. d Run at 140 °C.
time was prolonged to 20 min (entries 5 to 8, Table 1). The
conversion of 1a was poor (entry 9, Table 1) when the
concentration of the catalyst was lower (0.1 equiv). The
bivalent copper salt Cu(OAc)2 was not as effective as CuI,
although the intramolecular cyclization could proceed (entry
10, Table 1). Finally, we performed a reaction under general
conditions without microwave heating to compare the
difference between the two different conditions, and an 89%
yield was obtained under general conditions after refluxing
at 120 °C for 90 min. The increase in the yield resulting
from decrease in the reaction time under microwave irradia-
tion was significant (entry 11, Table 1); therefore, microwave
heating was adopted in the next investigation. To our
knowledge, this is the first report of catalytic intramolecular
cyclization of N′-substituted-N-(2-halophenyl)ureas using
copper salts.
After determining the optimized conditions, we examined
the generality of the process. First, we found that the method
was applicable to a broad range of substrates for various
N′-substituted-N-(2-iodophenyl)ureas, including N′-aro-
matic-, N′-aliphatic-, and N′-heterocyclic-substituted ureas
(Table 2). The electron-donating or electron-withdrawing
substituents on the N′-phenyl group of 1 had no perceptible
effect on the yields (entries 1 and 3, Table 2), and the ortho
and para substituents had no significant steric effects (entries
1 to 4, Table 2). Several functional groups were employed
in the copper-catalyzed process. The N′-(4-bromophenyl),
N′-(4-ethoxycarbonyl)phenyl, and N′-(3-nitrile)phenyl groups,
which are sensitive to alkali or acid, were all tolerated (entries
6 to 8, Table 2), and good conversions were observed for
N′-(3-ethynyl)phenyl, N′-(4-ethenyl)phenyl, and N′-vinyl
substituents (entries 9, 10, and 12, Table 2) in the cyclization
process. Except for N′-aryl substituents, several N′-aliphatic
ones were also obtained in moderate to high yields when
temperatures were increased to 140 °C (entries 11 to 14,
Table 2). N′-heterocyclic groups such as thiazol-2-yl and
pyridine-4-yl proceeded well in good yields to afford the
desired products (entries 15 and 16, Table 2).
We next investigated the application of the developed
protocol to N′-substituted-N-(2-bromophenyl)ureas. Unfor-
tunately, the desired product, 2a, was obtained in a low yield
(32%) under the optimized conditions (entry 1, Table 2).
Several groups have reported L-proline-catalyzed formation
of C-N/C-C.14,15 When L-proline was adopted in the
cyclization process, there was a great improvement in the
yields, including those of N′-aryl substituents (entries 1, 5,
9, and 10, Table 2) and N′-alkyl substituents (entries 13,
(14) (a) Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (c) Shafir, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 8742. (d) Taillefer, M.; Xia, N.; Ouali, A.
Angew. Chem., Int. Ed. 2007, 46, 934. (e) Correa, A.; Bolm, C. Angew.
Chem., Int. Ed. 2007, 46, 8862
.
Org. Lett., Vol. 10, No. 15, 2008
3265

Table 2). The rate of intramolecular cyclization of N′-
substituted-N-(2-halophenyl)ureas follows the order I > Br,
which was consistent with the order reported previously.10,16
To explore the variation possible in the aryl substitutents
of N′-substituted-N-(2-halophenyl)ureas, various substitutions
of 2-iodophenylureas (4a-f) were carried out (Scheme 3).
incorporated, and good yields of the desired products 5a-f
were obtained. Azabenzimidazol-2-ones were identified as
potent respiratory syncytial virus inhibitors.5 Their analogues,
namely, imidazopyridin-2(3H)-ones, were synthesized in this
study (Scheme 4). The yield of product 7 was moderate
Scheme 4. Synthesis of 6-Chloro-3-
(4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-one
Scheme 3
. Synthesis of Various N-Substituted
1,3-Dihydrobenzimidazol-2-ones
(54%) when 6 intramolecularly coupled under the catalysis
of CuI, with the reaction time prolonged to 40 min.
In conclusion, we have demonstrated an efficient method
to generate N-substituted 1,3-dihydrobenzimidazol-2-ones
using N′-substituted-N-(2-halophenyl)ureas, which can be
easily prepared from commercial o-haloanilines on reaction
with triphosgene and different kinds of amines or isocyanates.
Heterocycle formation involves copper-catalyzed formation
of C-N by intramolecular cyclization.
A variety of functional groups can be employed, rendering
this method particularly attractive for the efficient preparation
of biologically and medicinally interesting molecules.
Acknowledgment. We gratefully acknowledge the finan-
cial support from the State Key Program of Basic Research
of China (Grant 2006BAI01B02), the National Natural
Science Foundation of China (Grants 20721003, and
20472094), the Basic Research Project for Talent Research
Group from the Shanghai Science and Technology Com-
mission, and the 863 Hi-Tech Program of China (Grant
2006AA020602).
aYield.
We found that both an electron-donating methoxy substituent
and an electron-withdrawing fluorin or ester could be readily
(15) (a) Kunaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (b) Ma, D. W.; Cai,
Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (c) Lu, B.; Ma, D. W. Org. Lett.
2006, 8, 6115. (d) Xie, X. A.; Chen, Y.; Ma, D. W. J. Am. Chem. Soc.
Supporting Information Available: Reaction procedures
and characterization of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
2006, 128, 16050
.
(16) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802
.
OL8011106
3266
Org. Lett., Vol. 10, No. 15, 2008