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J. Comb. Chem. 2010, 12, 222–224
Scheme 1. Copper-Mediated Approach to
Benzimidazo[1,2-a]quinoxalin-6(5H)-ones
Synthesis of Novel Substituted
Benzimidazo[1,2-a]quinoxalin-6(5H)-ones via
an Intramolecular Goldberg Reaction
Tao Meng, Yongliang Zhang, Min Li, Xin Wang, and
Jingkang Shen*
State Key Laboratory of Drug Research, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, 555 Zu
Chong Zhi Road, Shanghai 201203, China
Initially, the substituted 1-(2-bromophenyl)-1H-ben-
zo[d]imidazole-2-carboxamides, required as the key pre-
cursors for the copper-catalyzed intramolecular cycliza-
tion, were synthesized in a three-step sequence as depicted
in Scheme 2. Commercially available 1-fluoro-2-nitroben-
zene was treated with substituted 2-bromoanilines in
DMSO in the presence of KOH at 150 °C to give
diphenylamines 2{1-3} in good yields, which were used
in the next step without purification. The nitro intermedi-
ates were then successfully converted to the corresponding
amines by reaction with iron in conc. HCl solution under
reflux. Notably, debromination was observerd under Pd/C
hydrogenation condition in this case. Subsequently, the
carboxylate intermediates 3{1-3} were synthesized in
moderate yields by the condensation of diphenylamines
with ethyl triethoxyacetate at 150 °C. However, while the
ethyl carboxylate 3{1} was treated with NaOH/H2O/EtOH
or LiOH/H2O/MeOH, we obtained the decarboxylated
compound 6 instead of acid 5. We thus attempted direct
aminolysis by reacting the carboxylates with various
primary amines. Following heating under microwave
conditions, nine intermediates were obtained in moderate
to high yields, with no decarboxylation observed.
ReceiVed December 21, 2009
The benzimidazole structural subunit is regarded as a
privileged structure in medicinal chemistry and has been
extensively employed in drug design.1,2 Novel fused het-
erocyclic frameworks often have the most diverse physical,
chemical and surprisingly complex biological properties, and
almost unlimited combinations of fused heterocyclic struc-
tures can be designed. As for the benzimidazoles fused with
aza-aromatic ring systems, mostly benzimidazo[2,1-a]iso-
quinolines (I) as anticancer agents3,4 and pyrido[1,2-a]ben-
zimidazole (II) derivatives as anxiolytic,5,6 antiviral,7 and
antimicrobial8 agents have been reported.
To test the feasibility of the proposed cyclization reaction,
compound 4{1,1} was first used as the model substrate.
Several known copper-catalyzed coupling conditions were
tested and are shown in Table 1. However, it was found that
under Ullmann reaction conditions, which Ma et al.12
reported (CuI/L-Proline catalyst, entry 2) or Liu et al.13 used
(bivalent copper salt Cu(OAc)2/DBU-catalyzed conditions,
entry 3), only the debenzylated product 8 was obtained.
Meanwhile, no reaction was observed in the absence of
ligand (entry 1), which indicates that the presence of ligand
is essential for the reaction to occur. Further investigation
revealed that N,N-dimethylglycine as a crucial promoter is
essential for this type of Goldberg reaction.14 When com-
bination of CuI/N,N-dimethylglycine, K2CO3 as base, was
used and the mixture was refluxed in DMF for 12 h (entry
5), cyclized compound 7{1,1} could be isolated in 35% yield.
Probing of the temperature and base effects, we observed a
sharp decrease in yield under lower reaction temperature (100
°C, entry 4), and K3PO4 turned out to be better than K2CO3
with 60% yield (entry 6).
We recently reported a series of 6H-pyrido[2′,1′:2,3]im-
idazo[4,5-c]isoquinolin-5(6H)-ones(III) that showed potent
cytotoxicity.9,10 As part of our ongoing research, we created
a series of novel fused benzimidazole containing structures
IV, which also possesses a structural similarity with III. This
new series of substituted benzimidazo[1,2-a]quinoxalin-
6(5H)-ones (IV) may be used for identification of novel
scaffolds with some interesting biological activities.
Our synthetic strategy for the synthesis of the benzimid-
azo[1,2-a]quinoxalin-6(5H)-one ring is shown in Scheme 1.
We envisioned that the quinoxalinone ring could be synthe-
sized by a Goldberg-type11 intramolecular amide arylation
from 1-(2-bromophenyl)-1H-benzo[d]imidazole-2-carboxa-
mides. Herein, we report our results on a facile synthesis of
nine novel benzimidazo-fused tetracyclic compounds.
Using the optimized conditions, we next investigated
the scope of the reaction with five primary amines for R1
and two 2-bromoanilines for R2 because of their com-
mercial availability. The 1-(2-bromophenyl)-1H-ben-
* To whom correspondence should be addressed. Phone: +86 21
50806600 5407. Fax: +86 21 50807088. E-mail: jkshen@mail.shcnc.ac.cn.
10.1021/cc9001923 2010 American Chemical Society
Published on Web 01/26/2010
Meng, Tao
