An efficient one-pot synthesis of aminobenzimidazoles

Article abstract of DOI:10.1055/s-2004-834925

An efficient one-pot procedure for the preparation of aminobenzimidazoles from dinitroaniline derivatives is described. The process helps to avoid the troublesome acetonitrile-mediated reductive ethylation reaction.

Full text of DOI:10.1055/s-2004-834925

SHORT PAPER
17
An Efficient One-Pot Synthesis of Aminobenzimidazoles
O
ne-Pot Synthesis
a
of
A
minob
v
enzimidazole
i
s
d M. D. Fouchard,1,a L. M. Viranga Tillekeratne,a,b Richard A. Hudson*a,b
a
Department of Chemistry, College of Arts & Sciences, University of Toledo, Toledo, OH 43606, USA
Department of Medicinal & Biological Chemistry, College of Pharmacy, University of Toledo, Toledo, OH 43606, USA
Fax +1(419)5307946; E-mail: richard.hudson@utoledo.edu
b
Received 28 June 2004; revised 13 September 2004
ter the inefficient synthesis of 2,3,5-trinitroanisole from
commercially available 3,5-dinitroanisole.4 No yield was
given for the nitration reaction, which had also been re-
ported earlier by Blanksma.5
Abstract: An efficient one-pot procedure for the preparation of
aminobenzimidazoles from dinitroaniline derivatives is described.
The process helps to avoid the troublesome acetonitrile-mediated
reductive ethylation reaction.
Key words: benzimidazoles, pyrroloquinoline quinines, reductive To improve the synthesis of benzimidazole 5, we devel-
ethylation, bicyclic compounds, fused ring systems
oped an alternative strategy (Scheme 2) avoiding selec-
tive reduction of the ortho-nitro group in the dinitro
intermediate 2 (Scheme 1) by carrying out the complete
reduction of 2 to yield the triamino intermediate under
conditions facilitating simultaneous formation of the imi-
dazole ring. Refluxing compound 2 in the presence of tri-
ethylammonium formate and palladium on carbon in
acetonitrile gave the desired benzimidazole in one step.
However, large amounts of the ethylaminobenzimidazole
6 were also formed. The ratio of 6 to 5 was about 3:1.
Recently we reported the synthesis of several imidazole
ester analogs of the important vitamin cofactor pyrrolo-
quinoline quinone (PQQ).2 These syntheses proceeded
from commercially available benzene derivatives through
4,6-disubstituted benzimidazole intermediates, which
were also potentially important physiologically active
compounds.3
Compound 6 resulted from the apparent initial acetoni-
trile-mediated reductive ethylation of the nitro group dur-
The synthesis of the benzimidazole 5 (Scheme 1) pro-
ceeded from the known 2-amino-3-methoxy-5-nitro-
aniline (3) in two steps by ring-forming condensation with
acetic acid and hydrogenation of the nitro group. While
these two steps were accomplished in excellent overall
yield (85%), the earlier steps which involved selective ni-
tration of commercially available 2-methoxy-4-nitro-
aniline (1) followed by subsequent selective reduction of
the ortho-nitro group in the dinitro intermediate 2 oc-
curred in modest yield (28% overall). Nevertheless, the
yield of benzimidazole 5 from the commercially available
compound 1 was sufficient to carry out the earlier report-
ed syntheses of PQQ analogs.2 An earlier synthesis of
compound 3 proceeded in three steps from 2,3,5-trini-
troanisole with an overall reported yield of about 40%, af-
NO2
NH2
+
NH2
HNO3
H2SO4
Et3NH formate
Pd/C, aq CH3CN
O2N
OCH3
O2N
OCH3
1
2
CH3
CH3
HN
N
HN
N
+
C2H5HN
OCH3
H2N
OCH3
5
6
Scheme 2
NH2
NO2
+
NH2
NH2
NH2
Et3NH formate
HNO3
Pd/C, aq CH3CN
55%
H2SO4
O2N
OCH3
O2N
OCH3
O2N
HN
OCH3
51%
3
1
2
CH3
N
CH3
HN
N
CH3CO2H
86%
H2/Pd/C
EtOH, 100%
O2N
OCH3
H2N
OCH3
4
5
Scheme 1
SYNTHESIS 2005, No. 1, pp 0017–0018
x
x
.
x
x
.2
0
0
4
Advanced online publication: 17.11.2004
DOI: 10.1055/s-2004-834925; Art ID: M04604SS
© Georg Thieme Verlag Stuttgart · New York

18
D. M. D. Fouchard et al.
SHORT PAPER
C (370 mg). This suspension was cooled to 15 °C in a cold water
bath. A solution of 96% formic acid (6.4 mL) in MeCN (20 mL) was
then added over a period of 15 min while maintaining the tempera-
ture at 15 °C during the addition. The resulting mixture was then re-
fluxed for 3 h. Completion of the reaction was monitored by TLC
analysis (hexane-EtOAc, 1:1). The catalyst was removed by filtra-
tion through a silica gel plug and rinsed with acetone. The solvent
was removed in vacuo, and the resulting solid mixture chromato-
graphed on silica gel (hexane-EtOAc, 1:1) to yield 2-amino-3-
methoxy-5-nitroaniline (3) as a red powder; yield: 3.80 g (55%).
Recrystallization from absolute EtOH yielded dark orange crystals;
Rf 0.50 (5% MeOH in CH2Cl2); mp 167 °C (Lit.4 mp 165-167 °C).
ing or after reduction to the amine. By reducing the
quantity of acetonitrile used to avoid the aminoethylation
reaction, and completing the imidazole ring formation
with acetic acid and hydrolyzing the acetanilide formed
with aqueous sodium hydroxide, the synthesis of com-
pound 5 could be completed in 55% yield in a one-pot pro-
cedure (Scheme 3). The acetanilide-benzimidazole
intermediate was independently analyzed and character-
ized.
CH3
+
1H NMR (CD3OD): d = 3.89 (s, 3 H), 4.89 (s, 3 H), 7.29 (d, 1 H,
J = 2.4 Hz), 7.38 (d, 1 H, J = 2.4 Hz).
13C NMR (CD3OD): d = 56.52, 99.25, 106.81, 133.59, 134.31,
139.15, 146.90.
1. Et3NH formate
HN
NO2
Pd/C, aq CH3CN
2. CH3CO2H
N
NH2
H2N
OCH3
3. NaOH
55%
O2N
OCH3
5
Anal. Calcd for C7H9N3O3: C, 45.89; H, 4.96; N, 22.94. Found: C,
45.95; H, 4.89; N, 22.82.
2
Scheme 3
One-Pot Conversion of 2-Methoxy-4,6-dinitroaniline (2) to 6-
Amino-4-methoxy-2-methyl-1H-benzimidazole (5)
2-Methoxy-4,6-dinitroaniline (2; 1.00 g, 4.69 mmol) and 10% Pd/C
(250 mg) were suspended in a mixture of Et3N (4.5 mL) and MeCN
(3.75 mL) under argon. The flask was placed in a water bath at r.t.,
and a solution of 96% formic acid (1.8 mL) in MeCN (3.75 mL) was
added dropwise. The mixture was then refluxed for 24 h, and cooled
to r.t. The catalyst was removed by filtration and rinsed with MeOH
In summary, the reduction of both nitro groups could be
completed with simultaneous formation of the imidazole
ring in an efficient one-pot process subsequent to selective
nitration of the commercially available 2-methoxy-4-ni-
troaniline. This process should have general applicability
to the synthesis of other amino-substituted benzimida- and the solvent was removed in vacuo. Glacial AcOH (15 mL) was
added to the residue and the resulting mixture was refluxed under
zoles.
argon for 12 h. The AcOH was then removed in vacuo and the res-
idue was dissolved in aq 1 M NaOH solution (75 mL) and refluxed
NMR spectra were recorded on a Varian 400 MHz spectrometer.
Chemical shifts were expressed in ppm relative to TMS or the resid-
ual signal of deuterated solvent. For mixtures of tautomers, the 1H
NMR chemical shifts reported are for the major tautomer, whereas
all 13C chemical shifts are reported. Some 13C NMR spectra present-
ed fewer signals than expected and was attributed to scalar relax-
ation of the second kind due to the high number of nitrogen atoms
present in the molecule. Crude yields are reported for products,
which are, in general, greater than 90% pure based on NMR spec-
troscopy. Melting points are uncorrected. Elemental analyses were
performed by Atlantic Microlab Inc., Norcross, Georgia, U.S.A.
for 2 h. The mixture was then cooled to r.t., and the solution was
brought to pH 10 with conc. HCl and evaporated to dryness. The
residue was taken up in 10% MeOH in CH2Cl2 and passed through
a silica gel plug to afford the product, after removal of solvent in
vacuo; yield: 578 mg (68%). Full details on the characterization of
this compound are given elsewhere.2 The intermediate N-acetyl
compound was recrystallized from EtOH in separate experiments.
N-(4-Methoxy-2-methyl-1H-benzimidazol-6-yl)acetamide
Rf 0.14 (10% MeOH in CH2Cl2). Mp >300 °C.
1H NMR (CD3OD): d = 2.12 (s, 3 H), 2.49 (s, 3 H), 3.92 (s, 3 H),
6.86 (br, 1 H), 7.42 (s, 1 H).
13C NMR (CD3OD): d = 14.18, 23.97, 56.24, 98.83, 99.77, 126.79,
135.80, 140.09, 149.44, 152.28, 171.67.
2-Methoxy-4,6-dinitroaniline (2)
A mixture of 2-methoxy-4-nitroaniline (1; 60 g, 0.357 mol), glacial
AcOH (180 mL), and conc. H2SO4 (300 mL) was stirred mechani-
cally until the solid had completely dissolved. The resulting solu-
tion was then cooled to 0 °C. A mixture of 70% HNO3 (23.3 mL,
0.368 mol) and conc. H2SO4 (13.6 mL, 0.245 mol) was added slow-
ly with constant stirring while maintaining the temperature below
10 °C. The reaction mixture was allowed to warm to r.t., stirred for
1 h, and poured onto crushed ice (1.5 kg). A solid precipitate was
formed within 15–20 min, which was filtered and rinsed with cold
water to yield a brown powder; yield: 39 g (51%). Recrystallization
from CH2Cl2-hexane gave yellow crystals; Rf 0.73 (CH2Cl2); mp
173-176 °C (Lit.6 mp 174 °C; Lit.7 mp 181 °C).
Anal. Calcd for C11H13N3O2: C, 60.26; H, 5.98; N 19.17. Found: C,
60.29; H, 6.00; N, 19.16.
References
(1) Current address: Department of Chemistry and
Biochemistry, Montana State University (Gaines Hall,
#328), Bozeman, MT 59715, USA.
(2) Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A. J.
Org. Chem. 2004, 69, 2626.
(3) (a) Novelli, F.; Tasso, B.; Sparatore, A. Farmaco 1997, 52,
499. (b) Sondhi, S. M.; Singhal, N.; Johar, M.; Reddy, B. S.
N.; Lown, J. W. Curr. Med. Chem. 2002, 9, 1045.
(4) Gillespie, H. B.; Engelman, M.; Graff, S. J. Am. Chem. Soc.
1954, 76, 3531.
1H NMR (CDCl3): d = 4.06 (s, 3 H), 7.73 (d, 1 H, J = 2.7 Hz), 8.83
(d, 1 H, J = 2.7 Hz).
13C NMR (CDCl3): d = 56.99, 106.95, 115.61, 129.35, 135.91,
141.16, 147.77.
Anal. Calcd for C7H7N3O5: C, 39.73; H, 3.32; N, 19.72. Found: C,
40.05; H, 3.28; N, 19.38.
(5) Blanksma, J. J. Recl. Trav. Chim. Pays-Bas Belg. 1901, 23,
113.
(6) Medola, R.; Hay, J. G. J. Chem. Soc. 1907, 91, 1474.
(7) Blanksma, J. J. Proc. K. Akad. Wetensch: Amsterdam 1903,
5, 650; J. Chem. Soc. Abstr. 1903, 84, 623.
2-Amino-3-methoxy-5-nitroaniline (3)
To a solution of 2-methoxy-4,6-dinitroaniline (2; 8 g, 37.5 mmol) in
a mixture of Et3N (24 mL) and MeCN (20 mL) was added 10% Pd/
Synthesis 2005, No. 1, 17–18 © Thieme Stuttgart · New York