LETTER
Synthesis of 2-Substituted 6-Nitrobenzimidazoles
341
As shown in Table 1, the preferential reduction of the C-2 (Scheme 1) is an alkyl group, the reaction proceeded with
nitro group of the acylanilines was completed within good yields, while reduction where R is an alkyl group
several hours and lead to the formation of 2-aminoacyl- bearing halogen substituents or hydrogen, proceeded very
anilines as the major isolated products.
sluggishly and with modest yields. The reaction with
baker’s yeast is simple and highly selective, attributes that
make this methodology an attractive tool for the synthesis
of precursors of highly functionalized bioactive benzimi-
dazoles.
Table 1 Regioselective Reduction of 1a–j by Baker’s Yeast and
Cyclization of 2a–j into 3a–j
Entry Starting
materiala,b
R
Time
(h)
Yield of 2 Yield of 3
(%)a
40
82
84
85
90
83
79
36
47
86
(%)a
80
92
94
91
90
93
86
94
80
90
Acknowledgment
1
2
1a
1b
1c
1d
1e
1f
H
12
4
We are grateful to CONACYT-MEXICO (Grant Num. 34328-N)
for financial support.
CH3
3
CH2CH3
(CH2)2CH3
(CH2)3CH3
(CH2)4CH3
(CH2)6CH3
CF3
4
References
4
4
(1) (a) D’Arrigo, P.; Pedrocchi-Fantoni, G.; Servi, S. Adv. Appl.
Microbiol. 1997, 44, 81. (b) Csuk, R.; Glänzer, B. I. Yeast-
Mediated Stereoselective Biocatalysis, In Stereoselective
Biocatalysis; Patel, R. N., Ed.; Marcel-Dekker: New York,
2000, Chap. 19, 527. (c) Davey, C. L.; Powell, L. W.;
Turner, N. J.; Wells, A. In Preparative Biotransformations;
Roberts, S. M., Ed.; John Wiley and Sons: Chichester, 1994,
Chap. 2, 8.
5
4
6
4
7
1g
1h
1i
4
8
12
12
4
9
CH2Cl
(2) Hudlicky, M. In Reductions in Organic Chemistry;
American Chemical Society: Washington DC, 1999, Chap.
8, 91.
10
1j
(CH2)2COOH
a All the starting materials, intermediates and products were identified
by spectroscopic means (1H NMR, 13C NMR, IR, and MS).
b The starting materials (compounds 1a–j) were prepared by the reac-
tion of 2,4-dinitroaniline with acid anhydride and few drops of con-
centrated H2SO4 as the catalyst at reflux temperature, according to a
reported procedure.17
(3) (a) Navarro-Ocaña, A.; Jiménez-Estrada, M.; González-
Paredes, M.; Bárzana, E. Synlett 1996, 695. (b) Navarro-
Ocaña, A.; Olguín, L. F.; Luna, H.; Jiménez-Estrada, M.;
Bárzana, E. J. Chem. Soc., Perkin Trans. 1 2001, 2754.
(4) Kapinos, L.; Sigel, H. Eur. J. Inorg. Chem. 1999, 1781.
(5) Sarlauskas, J.; Dickancaite, E.; Nemeikaite, A.;
Anusevicius, Z.; Nivinskas Segura-Aguilar, H. J.; Cenas, N.
Arch. Biochim. Biophys. 1997, 346, 219.
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Chem. 1996, 39, 3477.
(7) Purygin, P. P.; Sergeeva, L. I.; Kuz´mina, V. E.; Labazova,
O. N. Pharm. Chem. J. 2002, 36 (8), 415..
It is noteworthy to mention that reduction of the C-2 nitro
group of 2,4-dinitro-N-acylanilines occurred without
affecting the chemical integrity of other functionalities
present in the molecule, and that the reaction time for the
regioselective reduction was influenced by the nature of
the acyl group in 1 (entries 1, 8, 9 and 2–7).
(8) Njoya, Y.; Boufatah, N.; Gellis, A.; Rathelot, P.; Crozet, P.
M.; Vanelle, P. Heterocycles 2002, 57 (8), 1423.
(9) Dincer, S. Dyes Pigm. 2002, 53, 263.
In most cases, 2,4-dinitro-N-acylanilines 1b–g and 1j
(entries 2–7 and 10) were easily reduced by baker’s yeast
in basic media to provide 2b–g and 2j in good yields. Only
in few cases, 1a and 2h,i (entries 1 and 8, 9) the yields for
the reduction were low, due to the formation of 2,4-di-
nitroanilines, caused from the hydrolysis of the starting
materials promoted by yeast.
(10) Rodembusch, F. S.; Buckup, T.; Segala, M.; Tavares, L.;
Bordalo-Correia, R. R.; Stefani, V. Chem. Phys. 2004, 305,
115.
(11) (a) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
(b) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43,
1893.
(12) Esser, F.; Ehrengart, P.; Ignatow, H. P. J. Chem. Soc., Perkin
Trans. 1 1999, 1153.
(13) (a) Kihel, A. E.; Benchidmi, M.; Essassi, E. M.; Danion-
Bougot, R. Synth. Commun. 1999, 29, 387. (b) Chauhan, P.
M. S.; Bhakuni, D. S. Indian. J. Chem., Sect. B 1986, 25,
1146.
(14) (a) Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Burgess, J. P.;
Carroll, F. I. Tetrahedron Lett. 1997, 29, 5099. (b) Patel, K.
M.; Patel, V. H.; Patel, M. P.; Patel, R. G. Dyes Pigm. 2002,
55, 53. (c) See ref.5 and ref.10
(15) (a) Porter, H. K. Org. React. 1973, 20, 455. (b) Terpko, M.
O.; Heck, R. F. J. Org. Chem. 1980, 45, 4992.
(16) Phillips, M. A. J. Chem. Soc. 1928, 2393.
(17) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell,
A. R., Eds.; Longman: London, 1989.
Once the regioselective reduction was achieved, the next
step was the acid-catalyzed cyclization of amines 2; thus
when 2-amino-N-acyl-4-nitroanilines 2a–j were treated
with glacial acetic acid at 60 °C, cyclization took place re-
sulting in the formation of benzimidazoles 3 as yellow
solids in good isolated yields (80–94%).
In summary, we have been able to show for the first time,
that baker’s yeast may be efficiently used for the regiose-
lective reduction of 2,4-dinitro-N-acylanilines, and that
the reduced products can be conveniently transformed
afterwards into the corresponding 2-substituted 6-ni-
trobenzimidazoles.18 The regioselective reduction is influ-
enced by the nature of the substrate’s acyl group: when R
Synlett 2005, No. 2, 340–342 © Thieme Stuttgart · New York