Cascade coupling/cyclization process to N-substituted 1,3- dihydrobenzimidazol-2-ones

Article abstract of DOI:10.1021/ol701792j

Assembly of N-substituted 1,3-dihydrobenzimidazol-2-ones is achieved starting from methyl o-haloarylcarbamates via a Cul/amino acid catalyzed coupling with amines and subsequent condensative cyclization. A number of functional groups are tolerated by thes

Full text of DOI:10.1021/ol701792j

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4291-4294
Cascade Coupling/Cyclization Process
to N-Substituted
1,3-Dihydrobenzimidazol-2-ones
Benli Zou,† Qiliang Yuan,† and Dawei Ma*,‡
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received July 29, 2007
ABSTRACT
Assembly of N-substituted 1,3-dihydrobenzimidazol-2-ones is achieved starting from methyl o-haloarylcarbamates via a CuI/amino acid catalyzed
coupling with amines and subsequent condensative cyclization. A number of functional groups are tolerated by these reaction conditions,
including vinyl, nitro, carboxylate, amide, ester, ketone, and silyl ether groups.
The 1,3-dihydrobenzimidazol-2-one moiety can be found in
many pharmaceutically important molecules that possess a
wide range of biological activities. Recent examples include
RWJ-333966 (1), a selective vasopressin 1a receptor an-
tagonist that is a promising candidate for the treatment of
anxiety disorders,1 HIV-1 RT non-nucleoside inhibitor 2,2
orally bioavailable sirohydantoin CGRP receptor antagonist
3,3 p38 MAP kinase inhibitor 4,4 respiratory syncytial virus
fusion inhibitor 5,5 as well as the progesterone receptor
antagonist 66 (Figure 1).
Two typical methods have generally been applied for the
elaboration of N-substituted 1,3-dihydrobenzimidazol-2-ones.
One is the selective alkylation or arylation of either nitrogen
atoms of 1,3-dihydrobenzimidazol-2-ones, which often re-
quires a protection strategy.3,5,6 Another one involves nu-
cleophilic displacement of 2-fluoronitrobenzenes with amines
and subsequent reduction and cyclization with carbonyl-
diimidazole.4,7 This route is problematic for the synthesis of
diverse products because of the limited source of 2-fluoro-
nitrobenzenes. These drawbacks have prompted Kuethe and
co-workers to develop a Pd-catalyzed aryl amination strategy
† Fudan University.
‡ Chinese Academy of Sciences.
(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.
(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.
(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.
(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.
(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/ol701792j CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/15/2007

consumed, and only the cross-coupling product was identi-
fied, indicating that the condensative cyclization required
higher reaction temperatures. After some trials, we found
that the desired cyclization product 8a could be obtained in
moderate yield by heating the reaction mixture at 130 °C
for 6 h after the initial cross-coupling step (entry 1). It is
noteworthy that the cross-coupling reaction was not complete
after heating at 60 °C for 24 h. The lower reactivity displayed
by bromide 7a, compared to the 2-bromoacetanilides reported
earlier by our group,9a demonstrates that the carbamate does
not provide ortho-assistance during the coupling reaction.
Increasing the temperature of the coupling reaction to 70
°C resulted in an improved yield (entry 2). Switching the
base to Cs2CO3 provided a similar result (entry 3), while a
better yield was observed when K3PO4 was employed (entry
4). Further improvement was achieved when trans-4-
hydroxy-L-proline was used as the ligand12 (entry 5). The
change in solubility of either the ligand or metal complex
was tentatively accepted to account for this difference.
We then explored the scope and limits of our newly
developed cascade process by varying the bromides and
amines. We were pleased to find that functionalized amines
such as amino acid 9b, amino amide 9c, and allyl amine 9d
delivered the corresponding 1,3-dihydrobenzimidazol-2-ones
under our reaction conditions (Table 2). Compound 8b is
obviously a promising intermediate for the assembly of the
CGRP receptor antagonist 3. The electronic nature of the
aryl bromides seems to have little influence on the reaction,
which is evident from the fact that both electron-rich and
electron-deficient aryl bromides gave satisfactory results. For
the coupling step, sterically hindered amines generally
required longer reaction times (entries 2 and 6), which is
Figure 1. Structures of some biologically important N-substituted
1,3-dihydrobenzimidazol-2-ones.
leading to substituted imidazo[4,5-b]pyridin-2-ones.8 As a
part of our continuing effort to assemble heterocycles by Cu-
catalyzed cross-coupling reactions,9,10 we became interested
in developing a new protocol for the assembly of N-
substituted 1,3-dihydrobenzimidazol-2-ones via CuI/ligand-
catalyzed aryl amination11 of methyl o-haloarylcarbamates.
The studies thus undertaken are disclosed herein.
The reaction of methyl 2-bromophenylcarbamate 7a and
benzylamine was chosen to screen for suitable reaction
conditions (Table 1). Initially, our standard conditions for
consistent with the observations in our previous work.11l
A
wide range of functional groups on the aryl bromides, such
as ester, ketone, amide, nitro, and silyl ether groups, survived
under these reaction conditions. Heteroaryl bromide 7j
Table 1. Synthesis of N-Benzyl 1,3-Dihydrobenzimidazol-
2-one 8a via Coupling of Bromide 7a and Benzyl Amine 9aa
(10) For recent studies on the synthesis of N-heterocycles through
Ullmann-type couplings from other groups, see: (a) Evindar, G.; Batey, R.
A. Org. Lett. 2003, 5, 133. (b) Altenhoff, G.; Glorius, F. AdV. Synth. Catal.
2004, 346, 1661. (c) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald,
S. L. J. Am. Chem. Soc. 2004, 126, 3529. (d) Yang, T.; Lin, C.; Fu, H.;
Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781. (e) Evindar, G.; Batey, R. A.
J. Org. Chem. 2006, 71, 1802. (f) Martin, R.; Rodr´ıguez, R.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2006, 45, 7079. (g) Rivero, M. R.; Buchwald, S.
L. Org. Lett. 2007, 9, 973. (h) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai,
L.; Li, Y. J. Org. Chem. 2007, 72, 1510.
(11) For selected references, see: (a) Ma, D.; Zhang, Y.; Yao, J.; Wu,
S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459. (b) Goodbrand, H. B.;
Hu, N.-X. J. Org. Chem. 1999, 64, 670. (c) Ma, D.; Xia, C. Org. Lett.
2001, 3, 2583. (d) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727. (e) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (f) Antilla, J. C.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (g) Kwong, F. Y.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (h) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793. (i) Ma, D.; Cai, Q.; Zhang, H.
Org. Lett. 2003, 5, 2453. (j) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.;
Taillefer, M. Chem.-Eur. J. 2004, 10, 5607. (k) Cai, Q.; Zhu, W.; Zhang,
H.; Zhang, Y.; Ma, D. Synthesis 2005, 496. (l) Zhang, H.; Cai, Q.; Ma, D.
J. Org. Chem. 2005, 70, 5164. (m) Shafir, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2006, 128, 8742. (n) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.;
Wan, B. Tetrahedron 2006, 62, 4435. (o) Rao, H.; Jin, Y.; Fu, H.; Jiang,
Y.; Zhao, Y. Chem.-Eur. J. 2006, 12, 3636. (p) Lange, B.; Lambers-
Verstappen, M. H.; Vondervoort, L. S.; Sereinig, N.; Rijk, R.; Vries, A. H.
M.; Vries, J. G. Synlett 2006, 3105.
entry
ligand
base
temp (°C) yield (%)b
1
2
3
4
5
L-proline
L-proline
L-proline
L-proline
K2CO3
K2CO3
Cs2CO3 70-130
60-130
70-130
52
58
55
65
77
K3PO4
70-130
70-130
trans-4-hydroxy-L-proline K3PO4
a
Reaction conditions: 7a (0.5 mmol), 9a (0.5 mmol), CuI (0.1 mmol),
ligand (0.2 mmol), base (1.0 mmol), DMSO (1 mL), 60 °C, 24 h (for entry
b
1), or 70 °C, 4 h (for entries 2-5), then 130 °C, 6 h. Isolated yield.
the amination of aryl bromides were attempted.11i,l Accord-
ingly, the reaction was conducted under the action of 20 mol
% of CuI, 40 mol % of L-proline, and K2CO3 in DMSO at
60 °C. It was found that after 24 h most of the bromide was
(8) Kuethe, J. T.; Wong, A.; Davies, I. W. J. Org. Chem. 2004, 69, 7752.
(9) (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598. (b) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115.
(12) This ligand was found to be more effective than L-proline in our
previous work on CuI-catalyzed C-C bond formation. See: Xie, X.; Chen,
Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
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Org. Lett., Vol. 9, No. 21, 2007

Table 2. Synthesis of Substituted 1,3-Dihydrobenzimidazol-2-ones via a Cascade Coupling/Cyclization Process from Aryl Bromidesa
a
Reaction conditions: bromide 7 (0.5 mmol), amine 9 (0.5 mmol), CuI (0.1 mmol), trans-4-hydroxy-L-proline (0.2 mmol), K3PO4 (1.0 mmol), DMSO
b
c
(1 mL), 70 °C, then 130 °C. Isolated yield. 2.0 mmol of base was added.
reacted with 2-phenylethylamine 9i to afford imidazo[4,5-
b]pyridin-2-one 8k in 62% yield (entry 10). It is noteworthy
that some of its analogues have exhibited potent inhibition
activity against respiratory syncytial virus fusion.5 Our results
demonstrate that the present protocol allows diverse synthesis
of functionalized 1,3-dihydrobenzimidazol-2-ones.
We next focused our attention on employing methyl
o-iodoarylcarbamates as the substrates. After screening a
number of parameters in the reaction of methyl 2-iodo-
phenylcarbamate 10a and benzylamine, the use of K2CO3
as a base and L-proline as a ligand was found to promote
the highest yields (81%, entry 1, Table 3). In these cases,
the coupling reaction proceeded at 50 °C even when using
10 mol % of copper catalyst. Under these reaction conditions,
a number of aryl iodides and amines were applied, and they
all gave the corresponding 1,3-dihydrobenzimidazol-2-ones
in good yields, thereby providing an alternative route for
the synthesis of these heterocyclic compounds. Some of the
products are potential building blocks for the synthesis of
known bioactive compounds. For example, 8n could be used
to assemble vasopressin 1a receptor antagonist RWJ-3339661
and 11b-hydroxysteroid dehydrogenase type I inhibitors.13
When methyl 2-iodo-4-bromophenylcarbamate 10d was
used, 8q was isolated exclusively, indicating that selectivity
between aryl iodides and aryl bromides can be achieved
under the present coupling conditions.
In conclusion, we have developed a novel protocol for
the elaboration of N-substituted 1,3-dihydrobenzimidazol-
2-ones via a CuI/amino acid catalyzed cascade coupling/
(13) Flyre´n, K.; Bergquist, L. O.; Castro, V. M.; Fotsch, C.; Johansson,
L.; St. Jean, D. J., Jr.; Sutin, L.; Williams, M. Bioorg. Med. Chem. Lett.
2007, 17, 3421.
Org. Lett., Vol. 9, No. 21, 2007
4293

Table 3. Synthesis of Substituted 1,3-Dihydrobenzimidazol-2-ones via a Cascade Coupling/Cyclization Process from Aryl Iodidesa
a
Reaction conditions: iodide 10 (0.5 mmol), amine 9 (0.5 mmol), CuI (0.05 mol), L-proline (0.1 mmol), K2CO3 (1.0 mmol), DMSO (1 mL), 50 °C, then
b
130 °C. Isolated yield.
condensative cyclization strategy. This method allows the
use of various primary amines and methyl o-haloarylcar-
bamates to assemble versatile heterocycles in a one-pot
manner. Thus, it should find extensive applications in the
synthesis of biologically active molecules.
of China (grant 20621062 & 20572119), for their financial
support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
OL701792J
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Org. Lett., Vol. 9, No. 21, 2007