Convenient method for the preparation of 2-aryl-1H-benzimidazole-4- carboxylic acids

Article abstract of DOI:10.1080/00397910500188942

The oxidative cyclization of 2,3-diaminobenzoic acid and aromatic aldehydes to give 2-aryl-1H-benzimidazole-4-carboxylic acids is reported. Moreover, three methods were compared in different perspectives from experimental manipulation to yield. Copyright

Full text of DOI:10.1080/00397910500188942

This article was downloaded by: [The UC Irvine Libraries]
On: 27 October 2014, At: 00:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Convenient Method
for the Preparation of
2‐Aryl‐1H‐benzimidazole‐4‐carboxy
Acids
Jun Cheng a , Naiyun Xiu b , Xiangbin Li a & Xianjin
Luo a
a School of Chemistry and Chemical Technology ,
Shanghai Jiaotong University , Shanghai, China
b College of Life and Environment Sciences ,
Shanghai Normal University , Shanghai, China
Published online: 18 Aug 2006.
To cite this article: Jun Cheng , Naiyun Xiu , Xiangbin Li & Xianjin Luo (2005)
Convenient Method for the Preparation of 2‐Aryl‐1H‐benzimidazole‐4‐carboxylic Acids,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:18, 2395-2399
To link to this article: http://dx.doi.org/10.1080/00397910500188942
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 2395–2399, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500188942
Convenient Method for the Preparation
of 2-Aryl-1H-benzimidazole-4-
carboxylic Acids
Jun Cheng
School of Chemistry and Chemical Technology, Shanghai Jiaotong
University, Shanghai, China
Naiyun Xiu
College of Life and Environment Sciences, Shanghai Normal University,
Shanghai, China
Xiangbin Li and Xianjin Luo
School of Chemistry and Chemical Technology, Shanghai Jiaotong
University, Shanghai, China
Abstract: The oxidative cyclization of 2,3-diaminobenzoic acid and aromatic alde-
hydes to give 2-aryl-1H-benzimidazole-4-carboxylic acids is reported. Moreover,
three methods were compared in different perspectives from experimental manipulation
to yield.
Keywords: Benzimidazole, pharmaceutical synthesis, potassium ferricyanide
INTRODUCTION
Inhibition of PARP (poly [ADP-ribose] polymerase) may strengthen
radiotherapy and some kinds of cancer chemotherapy.[1–3] 2-Aryl-1H-benzi-
midazole-4-carboxamides (1) are proved to be a class of potent PARP
inhibitors.[4,5]
Received in Japan December 2, 2004
Address correspondence to Xianjin Luo, School of Chemistry and Chemical Tech-
nology, Shanghai Jiaotong University, Shanghai, China. Tel.: (þ86)-021-54745863;
E-mail: luoxianjin@sjtu.edu.cn
2395

2396
J. Cheng et al.
In the synthetic route of 2-aryl-1H-benzimidazole-4-carboxamides (1),
the benzimidazole ring formation is the key step. In Phillips synthesis,[6,7]
2-substituted-1H-benzimidazoles were obtained by heating o-phenylenedi-
amine and carboxylic acids in the presence of hydrochloric or polyphosphoric
acid. Although Phillips synthesis is very suitable for benzimidazole cycli-
zation of o-phenylenediamine and carboxylic acids, the condensation of
2,3-diaminobenzoic acid and benzoic acids is not that efficient.[8] White
et al.[5] designed a multistep synthetic route that was complicated and also
lacked good yields. Another method is the cyclization of 2,3-diaminobenzoic
acid and appropriate aromatic aldehydes in the presence of copper acetate.[9]
DISCUSSION AND RESULTS
In this article, the oxidative cyclization of 2,3-diaminobenzoic acid and
aromatic aldehydes is reported, and potassium ferricyanide acted as an
oxidant. Using the same oxidant, different procedures were employed. To
compare two methods, Denny synthesis[9] was also practiced. Detailed pro-
cedures are shown in the Experimental section. Method I adopted Denny
synthesis. Method II and method III both employed potassium ferricyanide
but different solvents, methanol–water and DMF respectively.
We made the compound according to Denny Methods but found that it
needed too much methanol to dissolve 2,3-diaminobenzoic acid. An acidic
medium was necessary for the existence of copper acetate. In addition, the post-
treatment was very burdensome. Therefore, potassium ferricyanide was chosen
as an oxidant to act in an alkaline medium. In this case, the solvent quantity
decreased deeply and the yields were similar to Denny synthesis. An absolute
water environment was tried and proved to be inefficient because of the occur-
rence of by-products, indicating that the existence of methanol was necessary.
The employment of DMF as a solvent on account of its good solubility was
further considered. As shown in method III, the reaction procedure was simpli-
fied greatly and gave good yield. The reaction temperature should be controlled
at about 608C. When the temperature rose to about 808C, by-products appeared
(Scheme 1).
The cyclizations of 2,3-diaminobenzoic acid, 2-, 3-, and 4-pyridylalde-
hyde, and 4-hydroxylphenylaldehyde were investigated in all three methods.
The yields are respectively shown in Table 1. Method I and method II gave
similar yields, but the posttreatment of method II was far easier than that

2-Aryl-1H-benzimidazole-4-carboxylic Acids
2397
Scheme 1. Synthesis of 2-aryl-1H-benzimidazole-4-carboxylic acid.
of method I, and solvent quantity in method II was much less than that
in method I. Compared with method II, method III not only simplified the
experimental process but also gave better yields.
EXPERIMENTAL
General Procedure of Method I
2,3-Diaminobenzoic acid (5 g) in methanol (200 ml) was made acidic with
acetic acid, and a solution of corresponding aldehyde (1.05 eq) in methanol
(100 ml) was added, followed by
a
solution of cupric acetate
.
[Cu(Ac)2 H2O, 1.2 eq] in water (150 ml). The mixture was stirred vigorously
and heated to boiling and then filtered hot. The precipitate was washed with
water and dissolved in methanol (250 ml) containing concentrated hydrochlo-
ride acid (13 ml). A slight excessive water solution of sodium sulfide
was added, and the mixture was filtered hot to get rid of the copper sulfide.
The filtrate was adjusted to pH 5–6 with sodium hydroxide solution, diluted
with water (100 ml), and concentrated to give crude product. The crude
Table 1. Yields using different methods
Yield of
method I
(%)
Yield of
method II
(%)
Yield of
method III
(%)
Compounds
Aromatic aldehydes
2
3
4
5
2-Pyridylaldehyde
3-Pyridylaldehyde
62
60
56
52
56
58
63
60
78
80
81
78
4-Pyridylaldehyde
4-Hydroxylphenylaldehyde

2398
J. Cheng et al.
product was purified by column chromatography (acetone and slight
ammonia) to give 2-aryl-1H-benzimidazole-4-carboxylic acid.
General Procedure of Method II
2,3-Diaminobenzoic acid (2 g) was added in methanol (30 ml), followed by
sodium hydroxide (1 eq) dissolved in water (10 ml). The solution was stirred
during the addition of appropriate aldehyde (1.05 eq), dissolved in methanol
(10 ml), and followed by potassium ferricyanide (2 eq) and sodium
hydroxide (2 eq) dissolved in water (50 ml). The resulting mixture was
heated to boiling. After the reaction finished (monitored by TLC), sediment
was filtrated out and filtrate was adjusted to pH 5–6. The precipitate was
collected and purified to get pure product by column chromatography
(acetone and slight ammonia).
General Procedure of Method III
2,3-Diaminobenzoic acid (2 g) was dissolved in DMF (30 ml), followed by a
solution of appropriate aldehyde (1.05 eq) in DMF (10 ml) dropwise.
Potassium ferricyanide (2 eq) was added directly into the solution. The
suspension was stirred vigorously and heated to 608C. The reaction lasted
about 10 h. The sediment was filtrated out and DMF was removed by
vacuum distillation to give crude product. The pure product was obtained
by column chromatography (acetone and slight ammonia).
2-(2-Pyridyl)-1H-benzimidazole-4-carboxylic acid (2): 1H MNR
(DMSO, 400 MHz) d: 7.34–7.38 (t, 1H, J ¼ 8.0 Hz, H-6), 7.56–7.59
(m, 1H), 7.69–7.71 (d, 1H, J ¼ 8.0 Hz, H-7), 7.87–7.89 (d, 1H, J ¼ 8.0 Hz,
H-5), 8.02–8.06 (m, 1H), 8.45–8.47 (d, 1H), 8.76–8.77 (m, 1H). MS:
Mþ ¼ 239. Anal. calcd. for C13H9N3O2: C, 65.27; H, 3.77; N, 17.57.
Found: C, 65.54; H, 3.68; N, 17.40.
2-(3-Pyridyl)-1H-benzimidazole-4-carboxylic acid (3): 1H MNR (DMSO,
400 MHz) d: 7.34–7.38 (t, 1H, J ¼ 8.0 Hz, H-6), 7.60–7.63 (m, 1H), 7.74–
7.76 (d, 1H, J ¼ 8.0 Hz, H-7), 7.88–7.80 (d, 1H, J ¼ 8.0 Hz, H-5), 8.56–8.59
(m, 1H), 8.71–8.73 (m, 1H), 9.45 (s, 1H, H-20). MS: Mþ ¼ 239. Anal. calcd.
for C13H9N3O2: C, 65.27; H, 3.77; N, 17.57. Found: C, 65.01; H, 3.80; N, 17.62.
2-(4-Pyridyl)-1H-benzimidazole-4-carboxylic acid (4): 1H MNR (DMSO,
400 MHz) d: 7.34–7.38 (t, 1H, J ¼ 8.0 Hz, H-6), 7.86–7.87 (d, 1H,
J ¼ 8.0 Hz, H-7), 7.94–7.96 (d, 1H, J ¼ 8.0 Hz, H-5), 8.26–8.27þ(d, 2H,
J ¼ 4.0 Hz, H-30, 50), 8.75–8.76 (d, 2H, J ¼ 4.0 Hz, H-20, 60). MS: M ¼ 239.
Anal. calcd. for C13H9N3O2: C, 65.27; H, 3.77; N, 17.57. Found: C, 65.15; H,
3.82; N, 17.72.
2-(4-Hydroxylphenyl)-1H-benzimidazole-4-carboxylic acid (5): 1H
MNR (DMSO, 400 MHz) d: 6.92–6.94 (d, 2H, J ¼ 8.0 Hz, H-30, 50),

2-Aryl-1H-benzimidazole-4-carboxylic Acids
2399
7.28–7.32 (t, 1H, J ¼ 8.0 Hz, H-6), 7.77–7.79 (d, 1H, J ¼ 8.0 Hz, H-7),
7.84–7.86 (d, 1H, J ¼ 8.0 Hz, H-5), 8.14–8.16 (d, 2H, J ¼ 8.0 Hz, H-20,
60), 10.09 (s, 1H, OH-40). MS: M þ ¼ 254. Anal. calcd. for C14H10N2O3:
C, 66.14; H, 3.94; N, 11.02. Found: C, 65.95; H, 4.08; N, 11.20.
REFERENCES
1. Griffin, R. J.; Curtin, N. J.; Newell, D. R.; Golding, B. T.; Durkacz, B. W.;
Calvert, A. H. The role of inhibitors of poly(ADP-ribose) polymerase as resist-
ance-modifying agents in cancer chemotherapy. Biochemie 1995, 77, 408–422.
2. Dantzer, F.; Schreiber, V.; Niedergang, C.; Trucco, C.; Flatter, E.; De La Rubia, G.;
Oliver, J.; Rolli, V.; Menissier de Murcia, J.; de Murrcia, G. Involvement of
poly(ADP-ribose) polymerase in base excision repair. Biochemie 1999, 81, 69–75.
3. Kameshita, I.; Matsuda, Z.; Taniguchi, T.; Shizuta, Y. Poly(ADP-ribose) synthase:
Separation and identification of three proteolytic fragments as the substrate binding
domain, the DNA binding domain, and the automodification domain. J. Biol. Chem
1984, 259, 4770–4776.
4. Griffin, R. J.; Srinivasan, S.; White, A. W.; Bowman, K.; Calvert, A. H.;
Curtin, N. J.; Newell, D. R.; Golding, B. T. Novel benzimidazole and quinazolinone
inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase. Pharm. Sci.
1996, 2, 43–47.
5. White, A. W.; Almassy, T.; Calvert, A. H.; Crutin, N. J.; Griffin, R. J.; Hostomsky, Z.;
Maegley, K.; Newell, D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying
agents. 9. Synthesis and biological properties of benzimidazole inhibitors of DNA
repair enzyme poly(ADP-ribose) polymerase. J. Med. Chem. 2000, 43, 4084–4097.
6. Phillips, M. A. The formation of 2-methyl benzimidazoles. J. Chem. Soc. 1928,
172–177.
7. Phillips, M. A. The formation of 2-substituted benzimidazoles. J. Chem. Soc. 1928,
2393–2399.
8. Griffin, R. J.; Calvert, A. H.; Curtin, N. J.; Newell, D. R.; Golding, B. T. Benzimi-
dazole Compounds. US Patent 6,100,283, Aug. 8, 2000.
9. Denny, W. A.; Rewcastle, G. W.; Baguley, B. C. Potential antitumor agents. 59.
Structure–activity relationships for 2-phenylbenzimidazole-4-carboxamides, a
new class of “minimal” DNA-intercalating agents which may not act via topoiso-
merase II. J. Med. Chem. 1990, 33, 814.