A simple synthesis of benzimidazole N-oxides from 2-nitroaniline derivatives - Scope and limitations

Article abstract of DOI:10.1139/v04-083

Several benzimidazole N-oxide derivatives were synthesized in very good yield by heating at reflux the corresponding N-alkyl-2-nitroaniline derivative with NaOH in 60% 1,4-dioxane-water. The effect of substituents on the aromatic ring and amino group on t

Full text of DOI:10.1139/v04-083

1322
A simple synthesis of benzimidazole N-oxides
from 2-nitroaniline derivatives — Scope and
limitations
Elba I. Buján and María Laura Salum
Abstract: Several benzimidazole N-oxide derivatives were synthesized in very good yield by heating at reflux the
corresponding N-alkyl-2-nitroaniline derivative with NaOH in 60% 1,4-dioxane–water. The effect of substituents on
the aromatic ring and amino group on the reaction is discussed.
Key words: synthesis, benzimidazole N-oxides.
Résumé : On a réalisé la synthèse de plusieurs dérivés de N-oxydes de benzimidazole avec de très bons rendements
en chauffant au reflux le dérivé N-alkyl-2-nitroaniline correspondant avec du NaOH dans un mélange à 60 % de 1,4-
dioxane/eau. On discute de l’effet sur la réaction des substituants présents sur le noyau aromatique ainsi que sur le
groupe amino.
Mots clés : synthèse, N-oxydes de benzimidazole.
[Traduit par la Rédaction] Buján and Salum 1327
Introduction
methanolic hydrochloric acid of 1-amino-2-nitrobenzene and
1-amino-4-chloro-2-nitrobenzene with pyrrolidine, piperi-
dine, or morpholine as the amino group (10), and photolysis
in 0.5% acetic acid of N-(2′,6′-dinitro-4′-trifluoromethyl-
phenyl)-2-aminobutyric acid (11). Recently, examples of
cyclization of N-alkyl-2,4-dinitro-6-trifluoromethylanilines
in 50% EtOH–H2O with KHCO3 resulting in 2-alkyl-
substituted benzimidazole N-oxides have been reported (12).
We have previously reported on the synthesis of
benzimidazole N-oxides by cyclization of two 2-nitroaniline
derivatives having electron-donating groups β to the amino
group; namely, 7-nitro-2-n-propyl-1H-benzimidazole-3-oxide
(1) and 5,7-dinitro-2-n-propyl-1H-benzimidazole-3-oxide (2)
were synthesized by cyclization of N-n-butyl-2,6-dinitro-
aniline (3) and N-n-butyl-2,4,6-trinitroaniline (4), respec-
tively (13). The method that we proposed was superior to all
others because shorter reaction times were required, there
was no need for a substituent in the N-alkyl group, generally
Benzimidazole and benzimidazole N-oxides have biologi-
cal activity. Some benzimidazole derivatives are known as
antivirals, antifungals, and antibacterials (1). Fluorinated
benzimidazoles are insecticides or herbicides (2). N-Oxides
derived from purines have antitumoral, antimicrobial, or an-
tiviral activity (3, 4). Some 1-alkoxy-2-alkylbenzimidazoles
derived from 2-nitroanilines also exhibit activity against
HIV-1 (5).
Although several classes of amines are oxidized to their
corresponding N-oxides (6), we could find no reports on di-
rect oxidation of benzimidazoles to benzimidazole N-oxides.
Synthetic methods known to give benzimidazole N-oxides
include Pt-catalyzed hydrogenation of 2′-nitro-N-phenyl-
acetanilide in EtOH–HCl (7), cyclization of 2-nitroaniline
derivatives having electron-withdrawing substituents β to the
amino group in basic media (3, 8, 9), photolysis in aqueous
Received 2 December 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 2 November 2004.
E.I. Buján1 and M.L. Salum. Instituto de Investigaciones en Fisicoquímica de Córdoba (INFIQC), Dpto. de Química Orgánica,
Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000, Córdoba, Argentina.
1Corresponding author (e-mail: elba@dqo.fcq.unc.edu.ar).
Can. J. Chem. 82: 1322–1327 (2004)
doi: 10.1139/V04-083
© 2004 NRC Canada

Buján and Salum
1323
Scheme 1.
Table 1. Synthesis of benzimidazole N-oxides 6.
[NaOH] Time
Substrate (mol/L) (min) Product
Yielda
(%)
pKa1 pKa2
5a
5a
5a
5a
5a
5b
5c
5d
5d
0.20
0.20c
0.11
0.05
0.01
0.20
0.20
0.05
0.01
10
10
10
10
15
40
30
20
35
6ab
6ab
6ab
6ab
6ab
6b
62
72
75
89
94
74
76
69
74
2.02
5.91
1.59
2.46
1.92
5.39
7.02
5.74
6c
6db
6db
aPercentage yield of isolated product.
bPhenol 7 was formed but could not be isolated.
cThe reaction was carried out under N2.
dialkylated anilines, namely, N-n-butyl-N-methyl-2,6-
dinitroaniline (9) (14) and N,N-diethyl-2,4-dinitro-6-tri-
fluoromethylaniline (10) (12), cyclization requires the pres-
ence of the NH proton. This is in agreement with the
mechanism proposed for cyclization that requires ionization
of the amino group as the initial step (14).
better yields were obtained, and the reaction could be carried
out in a solvent with high water content.
To determine the scope of the method in regard to the de-
rivatives that can be prepared, we carried out a study on the
reaction of substrates 5a–5d and the results are reported
here.
In the reactions of compounds 5b and 5c, the only prod-
ucts isolated were benzimidazole N-oxides 6b and 6c, re-
spectively. Although the yield of both reactions was ~75%,
neither the corresponding phenol nor the unreacted substrate
or any other product was observed by TLC so the actual
yield was probably higher, with some product being lost dur-
ing work-up. Benzimidazole N-oxide was also the only
product found in the reaction of 3 in 60% 1,4-dioxane–H2O
at 25 °C (14) or at reflux (13). These results indicate that the
formation of benzimidazole N-oxide is not dependent on the
length of the alkyl chain (3 or 4 carbon atoms).
Another derivative of 2-nitroaniline, namely, N-n-butyl-4-
cyano-2,6-dinitroaniline (5e), was also tested as a precursor
for an N-oxide. In this case, with NaOH concentrations of
both 0.20 and 0.01 mol/L, four products were detected by
TLC, but they could not be isolated. While one of them
seemed to be the N-oxide, the others may have originated
from the reaction of base with the cyano group, as was ob-
served for other cyanobenzenes (15).
The substituents on the aromatic ring have an important
effect on the competition between substitution and cycli-
zation. The absence of a second group ortho to the amino
group prevents cyclization, as was observed with N-n-butyl-
2,4-dinitroaniline, which gave 2,4-dinitrophenol in 100%
yield after 24 h at reflux with 0.01 mol/L NaOH (13). When
both of the substituents ortho to the amino group are NO2,
the yield of the cyclization product increases as the electron-
Results and discussion
When compounds 5a–5d were heated at reflux in 60%
(v/v) 1,4-dioxane–H2O with NaOH, they afforded the corre-
sponding benzimidazole N-oxides 6a–6d in very good yields
(Scheme 1, Table 1). The structures of 6a–6d were con-
firmed by their 1H NMR, 13C NMR, and IR spectra. In some
cases, substitution of the amino group competed with
N-oxide formation. For instance, in the reaction of N-n-
butyl-2,6-dinitro-4-trifluoromethylaniline (5a) and N-n-
propyl-2,6-dinitro-4-trifluoromethylaniline (5d), 2,6-dinitro-
4-trifluoromethylphenol (7) was also formed (Table 1). The
substitution product was also found in the reaction of 3 in
10% 1,4-dioxane–H2O at 25 °C (14) and in the reaction of 4
in 60% 1,4-dioxane–H2O at reflux (13). In all cases, the
yield of the phenol decreased with decreasing NaOH con-
centration.
When the reaction of 5a was performed under a N2 atmo-
sphere with 0.2 mol/L NaOH, the yield of 6a increased ap-
proximately 10% (Table 1). This is consistent with the
mechanism previously proposed (14).
An N,N-disubstituted derivative of 5d, namely, N,N-di-n-
propyl-2,6-dinitro-4-trifluoromethylaniline (trifluralin) (8),
yielded the phenol 7 along with unreacted substrate after
18 h at reflux with 0.01 mol/L NaOH in 60% 1,4-dioxane–
H2O. It was previously reported that with other N,N-
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Can. J. Chem. Vol. 82, 2004
Table 2. UV–visible data for 2,4,6-trinitroaniline (11),a N-n-
butyl-2,6-dinitro-4-trifluoromethylaniline (5a), N-n-butyl-2,4-
dinitro-6-trifluoromethylaniline (4b), and N-n-butyl-2,4,6-
trinitroaniline (4).
1
Table 3. Experimental and calculated H NMR chemical shifts
for aliphatic protons in compounds 5a, 5b, and 4.
5a
5b
4
Atom
Exptl.
Calcd.
Exptl.
Calcd.
Exptl.
Calcd.
λ
ε
λ
ε
H(1′)
H(2′)
H(3′)
H(4′)
3.03
1.69
1.42
0.94
3.48
1.59
1.43
0.95
3.37
1.71
1.45
0.97
3.30
1.59
1.43
0.95
3.11
1.73
1.44
0.97
3.48
1.59
1.43
0.95
Compound
(nm)
(L mol–1 cm–1)
(nm)
(L mol–1 cm–1)
11
4
5a
5b
318
338
416
340
12 000
16 588
7 026
408
413
325
7800
6336
1893
Note: Chemical shifts were calculated with ACD/Chem Sketch (20).
16 507
a Data from ref. 16.
Table 4. C(1)–N(7) bond length (Å) and selected torsion angles
(°) for 5a, 5b, and 4.
withdrawing ability of the para substituent decreases. This is
evident from the fact that with an NaOH concentration of
0.20 mol/L, the yield of N-oxide is 95.6%, 61.6%, and 0%
for 3 (13), 5a, and 4 (13), respectively. The replacement of
an o-NO2 group by an o-CF3 completely inhibits the substi-
tution reaction (compare the results for 5a and 5b). Because
of this and the fact that the absence of a second ortho
substituent inhibits cyclization (12–14), we believe that the
substituent on C(6) plays a very important role in the reac-
tion. We propose that the conformation of compounds hav-
ing two ortho substituents may favour the cyclization
reaction.
5a
5b
4
1.356
1.363
– 46.05
131.56
–7.468
153.47
1.352
–40.63
136.95
–16.51
156.53
C(1)–N(7)
C(3)–C(2)–N(8)–O(9)
C(3)–C(2)–N(8)–O(10)
C(6)–C(1)–N(7)–H
C(6)–C(1)–N(7)–C(1′)
C(5)–C(6)–C(1)–N(7)
C(3)–C(2)–C(1)–N(7)
–41.06
136.36
–17.32
152.95
–168.72
172.55
–175.014
166.52
–165.95
163.85
Note: Calculated with MOPAC program (23).
To investigate the conformation of compounds 5a, 5b, and
4 in solution, we analyzed their UV–visible spectra in meth-
anol; the spectral data are summarized in Table 2. The spec-
trum of 2,4,6-trinitroaniline (11) in methanol shows two
absorption bands: one at 318 nm (band 1) and the other at
408 nm (band 2). These bands correspond to electronic tran-
sitions from the amino group to the p-nitro (band 1) and o-
nitro (band 2) groups, respectively (16). In compound 4,
bathochromic displacements of bands 1 and 2 relative to
those of 11 were observed. Similar bathochromic displace-
ments in related 2,4-dinitroaniline and 2,4,6-trinitroaniline
derivatives were interpreted as a consequence of destabi-
lization of the ground state of the molecule due to rotation
around the C(1)–N bond or to steric enhancement of reso-
nance caused by rotation around the C(2)–N and (or) the
C(6)–N bond or by a combination of both factors (16–19).
In related nitroanilines, hypsochromic and hypochromic dis-
placement of band 2 was attributed to rotation around the
C(2)–N and (or) the C(6)–N bond, while a decrease in the
intensity of band 1 was attributed to rotation around the
C(1)–N bond (16–19). Compound 5a shows a bathochromic
and hypochromic displacement of band 1 as well as a hypso-
chromic and hypochromic displacement of band 2 when
compared to 11. These observations indicate nonplanarity of
the two o-nitro groups and the amino group with the aro-
matic ring. The bathochromic displacement and increased
intensity (increase in ε due to steric effects) of band 1 and
the complete disappearance of band 2 in 5b point to
nonplanarity of the o-nitro group with the aromatic ring.
and 5a, which could be attributed to the ring current pro-
duced by the electrons of benzene (21). Therefore, the
butylamine moiety must be out-of-plane with respect to the
plane of the aromatic ring in these compounds. The fact that
the chemical shift of the α-methylene protons in 5b is nearly
the same as the calculated value could mean that there is no
rotation around the C(1)–N bond. However, considering that
CF3 is sterically more bulky than the NO2 group as evi-
denced by its steric substituent constant ES or ν (22), it is
reasonable to think that there must be some loss of
coplanarity between the lone pair of electrons on nitrogen
and the π electrons of the benzene ring.
We have also performed geometry optimization of the
structures of compounds 5a, 5b, and 4 using the quantum
chemistry program MOPAC (23); some of the results are
shown in Table 4. The length of the C(1)–N bond varies in
the order 5b > 5a > 4, indicating the greatest double bond
character in 4. The rotation around the C(2)–N bond is
greater in 5b than in the other compounds, in agreement
with the UV–visible spectra. Rotation around the C(1)–N
bond can be inferred by comparing the dihedral angles de-
fined by C(6)–C(1)–N–H (5a > 4 > 5b) or C(6)–C(1)–N–
C(1′) (5a ≈ 5b > 4). In addition, the bending of the amino
nitrogen out of the aromatic plane is evidenced by the dihed-
ral angles C(5)–C(6)–C(1)–N and C(3)–C(2)–C(1)–N; the
deviation from planarity is 6.5°, 12.5°, and 15° for 5b, 5a,
and 4, respectively.
These results indicate that rotation of the ortho substitu-
ents favours cyclization while nonplanarity of the amino
group favours the substitution reaction. We have shown in
previous work that in 2,4,6-trinitro-1-pyrrolidinobenzene
(12a), 2,4,6-trinitro-1-piperidinobenzene (13a), and 1-mor-
pholino-2,4,6-trinitrobenzene (14a) (17), in 2,4-dinitro-1-
piperidinobenzene (13b) (18), and in 2,4-dinitro-1-pyrroli-
dinobenzene (12b) and 1-morpholino-2,4-dinitrobenzene
(14b) (19), nonplanarity of the o-nitro groups and the amino
1
Analysis of the H NMR chemical shifts of the methylene
protons α to the nitrogen was performed to confirm the
nonplanarity of the amino group (Table 3). The chemical
shifts of the methylene protons α to the amino group in 5a,
5b, and 4 were calculated by computational methods (20).
The difference between the calculated and observed values
shows shielding of the protons of the butylamine moiety in 4
© 2004 NRC Canada

Buján and Salum
1325
Fig. 1. (A) Spectrum of 5a in 10% 1,4-dioxane–H2O at pH 7.22
(Na2HPO4/KH2PO4 buffer); [5a]0 = 3.91 × 10–5 mol/L. (B, C)
Spectra of 6a in 10% 1,4-dioxane–H2O at different pHs; [6a]0 =
1.00 × 10–4 mol/L: (B) pH 7.22 (Na2HPO4/KH2PO4 buffer);
(C) pH 1.11 (HCl 0.1 mol/L).
group relative to the aromatic ring occurs both in the solid
state and in solution. The decrease of the interaction of the
lone pair of electrons of the amino nitrogen with the π sys-
tem due to nonplanarity and the formation of σ complexes
by addition of a nucleophile to an unsubstituted position on
the aromatic ring favours substitution of the amino group
(24).
The UV–visible spectra of 6a–6d change with the pH of
the solution (in the range 1.00 < pH < 8.00) as shown for 6a
in Fig. 1. These spectra are attributed to acid–base equilibria
as shown in Scheme 2 (25). Spectrophotometric titration
gave two inflection points corresponding to two pKas; the
values are summarized in Table 1 and are similar to those re-
ported for 1 (13) and 6-nitro-3H-benzimidazole-1-oxide (8).
We conclude that benzimidazole N-oxides can be obtained
in a very simple way and with good yields starting with N-
alkylanilines that have two ortho substituents, one of them
being a nitro group. Several new derivatives have been pre-
pared and isolated. The method offers advantages over previ-
ously reported procedures since easily available materials
can be used, shorter reaction times are required, and com-
pounds with a nitro group at the C(7) position of benzi-
midazole can be obtained.
Scheme 2.
Experimental
1,4-Dioxane was purified as described previously (26).
Water purified in a Millipore Milli-Q apparatus was used
throughout. All of the inorganic reagents were of analytical-
reagent grade and were used without further purification.
NaOH concentrations are expressed in terms of total solvent
volume (1,4-dixane–H2O). Melting points were determined
on an electrothermal apparatus. Proton (200 MHz) and 13C
(50 MHz) NMR spectra were recorded on a Bruker ACE
200 spectrometer. Chemical shifts in CDCl3 are reported as δ
values downfield from Me4Si, and those in (CD3)2SO are
referenced to the solvent signal. The mass spectra (EI) and
HRMS (EI) were done at Unidad de Espectrometría de
Masas, Universidad de Santiago de Compostela, Spain. IR
spectra in KBr were obtained on a Nicolet 5SXC FT-IR
spectrometer. UV–visible spectra in 10% (v/v) 1,4-dioxane–
H2O or methanol were obtained on a Shimadzu UV 2101
spectrophotometer. TLC was carried out using silica gel 60
F254 (Merck), and spots were visualized by UV or I2. Silica
gel, 60 mesh size (0.063–0.200 nm) (Merck), was used for
column chromatography.
TLC comparison with an authentic sample. It was contami-
nated with solvent, and no further attempts to purify it were
made. The phenol 7 was synthesized in DMSO–H2O by fol-
lowing a reported method (27); the reaction mixture was
subjected to liquid–liquid extraction with Et2O, the solvent
was evaporated, and the solid obtained was recrystallized in
CHCl3 (mp 49–51 °C (lit. (27) 46–48 °C)). 1H NMR
((CD3)2SO, 200 MHz): δ = 8.10.
The pKas of compounds 6a–6d were determined by spec-
trophotometric titration in 10% 1,4-dioxane–H2O at 25 °C.
Solutions for the various pH ranges were prepared using
HCl (0.7–3.0 mol/L), acetic acid/sodium hydroxide (3.5–5.5
mol/L), and Na2HPO4/KH2PO4 (5.8–8.0 mol/L).
The second product formed in the reaction of 5a and 5d
was identified as 2,6-dinitro-4-trifluoromethylphenol (7) by
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
evaporator. The salts were separated from the products by
column chromatography on silica gel by eluting with vari-
able amounts of hexane–EtOAc. The products were treated
with acetone, in which the phenol is completely soluble
while the N-oxide precipitates. The N-oxide was isolated by
vacuum filtration as a yellow powder that decomposed at
196 °C.
Synthesis of N-alkyl-2-nitroanilines
Compounds 5a–5c were synthesized and isolated by the
methods previously described (28) from the corresponding
1-chloro derivative and n-butylamine or n-propylamine in
DMF. Compound 5d was synthesized as described elsewhere
(11) and recrystallized from MeOH.
1H NMR ((CD3)2SO, 200 MHz) δ: 1.02 (t, 3H, J = 7.3 Hz,
CH3), 1.86 (m, 2H, J = 7.5 Hz, CH2CH3), 2.98 (t, 2H, J =
7.3 Hz, CH2CH2CH3), 8.25 (s, 1H, Ar), 8.26 (s, 1H, Ar), and
12.52 (s, 1H, NH). 13C NMR ((CD3)2SO, 50 MHz) δ: 13.40,
19.68, 27.26, 111.99 (q, JCF = 4.0 Hz, CHAr), 114.58 (q,
JCF = 4.0 Hz, CHAr), 121.41 (q, JCF = 33.5 Hz, C-CF3),
123.43 (q, JCF = 270 Hz, CF3), 133.12, 134.77, 137.36, and
158.08. IR (KBr, νmax cm–1): 1539.4 (s), 1337.4 (s, 1288.9
(s), and 1258.2 (s). MS m/z: 291.2 ([M+1]+, 20.4%), 289.8
(M+, 82.2), 272.1, 260.8, 244.5, 226.1, 199.3, 142.8, 70.9
(100), 68.8, 42.9, and 41.0. HRMS (EI): m/z calcd. for
C11H10N3O3F3: 289.0674; found: 289.0676.
N-n-Butyl-2,6-dinitro-4-trifluoromethylaniline (5a)
Yellow solid; mp 35.5–37.5 °C. Yield 81%. 1H NMR
(CDCl3, 200 MHz) δ: 0.94 (t, 3H, J = 7.2 Hz, CH3), 1.42 (m,
2H, J = 7.2 Hz, CH2CH3), 1.69 (m, 2H, J = 7.1 Hz,
CH2CH2CH3), 3.03 (td, 2H,
J = 6.9 Hz, 4.7 Hz,
CH2CH2CH2CH3), 8.38 (s, 2H, Ar), and 8.62 (s, 1H, NH).
13C NMR (CDCl3, 50 MHz) δ: 13.47, 19.83, 31.94, 46.38,
115.98 (q, JCF = 36 Hz, C-CF3), 122.45 (q, JCF = 270 Hz,
CF3), 128.99, 137.16, and 141.44. MS m/z: 308.1 ([M+1]+,
10.3), 307.0 (M+, 17.6), 264.0 (100), 218.2, 201.4, 248.2,
218.2, 202.1, 70.9, 68.9, 43.0, 41.0, and 30.2. HRMS (EI):
m/z calcd. for C11H12N3O4F3: 307.0780; found: 307.0784.
N-n-Butyl-2,4-dinitro-6-trifluoromethylaniline (5b)
Yellow oil. H NMR (CDCl3, 200 MHz) δ: 0.97 (t, 3H,
5-Nitro-2-n-propyl-7-trifluoromethyl-1H-benzimidazole 3-
oxide (6b)
1
J = 7.2 Hz, CH3), 1.45 (m, 2H, J = 7.3 Hz, CH2CH3), 1.71
(m, 2H, J = 7.1 Hz, CH2CH2CH3), 3.37 (q, 2H, J = 5.8 Hz,
CH2CH2CH2CH3), 7.74 (s, 1H, NH), 8.63 (d, 1H, J =
2.5 Hz, Ar), and 9.05 (d, 1H, J = 2.9 Hz, Ar). MS m/z: 309.1
([M+1]+, 12.1), 307.8 (M+, 88.8), 264.1 (100), 218.4, 201.4,
247.9, 218.4, 202.2, 70.9, 68.8, 42.9, 40.9, and 30.2. HRMS
(EI): m/z calcd. for C11H12N3O4F3: 307.0780; found:
307.0773.
A solution prepared by dissolving 50 mg (0.16 mmol) of
6b in 25 mL of solvent was heated at reflux with NaOH
(0.20 mol/L) for 40 min. Only the N-oxide was formed; it
precipitated upon acidification of the solution with HCl and
was separated by vacuum filtration. It decomposed at 183 °C
(lit. (12) 213 °C).
1H NMR ((CD3)2SO, 200 MHz) δ: 1.01 (t, 3H, J = 7.4 Hz,
CH3), 1.85 (m, 2H, J = 7.4 Hz, CH2CH3), 2.98 (t, 2H, J =
7.6 Hz, CH2CH2CH3), 8.31 (d, 1H, J = 2.0 Hz, Ar), and 8.57
(d, 1H, J = 2.0 Hz, Ar). 13C NMR ((CD3)2SO, 50 MHz) δ:
13.67, 19.95, 27.63, 109.33, 114.31 (q, JCF = 4.9 Hz,
N-n-Propyl-2,6-dinitroaniline (5c)
Yellow solid; mp 79–80 °C. Yield: 83%. 1H NMR
(CDCl3, 200 MHz) δ: 0.99 (t, 3H, J = 7.2 Hz, CH3), 1.71 (m,
2H, J = 7.2 Hz, CH2CH3), 2.96 (td, 2H, J = 6.9 Hz, 4.7 Hz,
CH2CH2CH3), 6.74 (t, 1H, J = 8.2 Hz, Ar), 8.17 (d, 2H, J =
8.0 Hz, Ar), and 8.35 (s, 1H, NH). MS m/z: 226.2 ([M+1]+,
16.3), 225.0 (M+, 54.4), 196.0 (100), 179.8, 150.1, 134.1,
132.9, 56.9, 40.9, 29.1, and 28.1. HRMS (EI): m/z calcd. for
C9H11N3O4: 225.0749; found: 225.0748.
CHAr), 118.29 (q, JCF = 33.0 Hz, C-CF3), 122.93 (q, JCF
=
271 Hz, CF3), 132.69, 138.60, 141.34, and 158.65. IR (KBr,
ν
max cm–1): 1540.8 (s), 1362.4 (s), 1287.2 (s), and 1254.9 (s).
MS m/z: 291.1 ([M+1]+, 18.4%), 289.7 (M+, 64.7), 272.1,
260.8, 244.3 (100), 226.1, 199.1, 143.0, 68.6, 71.1, 43.1, and
40.9. HRMS (EI): m/z calcd. for C11H10N3O3F3: 289.0674;
found: 289.0681.
N-n-Propyl-2,6-dinitro-4-trifluoromethylaniline (5d)
Yellow solid; mp 61–62 °C (lit. (11) 62.5–63.0 °C). Yield:
85%. 1H NMR (CDCl3, 200 MHz) δ: 1.02 (t, 3H, J = 7.3 Hz,
CH3), 1.74 (m, 2H, J = 7.2 Hz, CH2CH3), 3.01 (td, 2H, J =
6.9 Hz, 4.8 Hz, CH2CH2CH3), 8.40 (s, 1H, Ar), and 8.65 (s,
1H, NH).
2-Ethyl-7-nitro-1H-benzimidazole 3-oxide (6c)
A solution prepared by dissolving 50 mg (0.22 mmol) of
5c in 25 mL of solvent was heated at reflux with NaOH
(0.20 mol/L) for 30 min. The only product formed was iso-
lated by column chromatography over silica gel by eluting
with variable amounts of hexane–EtOAc. The solid decom-
posed at 163 °C.
Synthesis of benzimidazole N-oxides; general procedure
The corresponding N-alkyl-2-nitroaniline derivative was
heated at reflux in 60% (v/v) 1,4-dioxane–H2O with NaOH.
The reaction was followed by TLC; when no remaining re-
actant was observed, the heating was stopped; the solution
was cooled to room temperature and acidified to pH ≤ 4 with
3.2 mol/L HCl.
1H NMR ((CD ) SO, 200 MHz) : 1.36 (t, 3H, J = 7.4 Hz,
δ
3 2
CH3), 2.96 (q, 2H, J = 7.6 Hz, CH2CH3), 7.41 (t, 1H, J =
8.04 Hz, Ar), 7.88 (d, 1H, J = 7.66 Hz, Ar), 8.02 (d, 1H, J =
8.02 Hz, Ar), and 12.23 (s, 1H, NH). 13C NMR ((CD3)2SO,
50 MHz) δ: 10.98, 18.93, 115.09, 117.87, 120.94, 130.86,
134.82, 137.54, and 155.95. IR (KBr, νmax cm–1): 1526.1 (s),
1338.7 (s), 1321.2 (s), and 1251.5 (s). MS m/z: 208.1
([M+1]+, 5.1%), 207.3 (M+, 85.1), 193.2, 189.9 (100), 178.1,
143.8, 132.1, 74.9, 56.9, 41.1, and 29.1. HRMS (EI): m/z
calcd. for C9H9N3O3: 207.0644; found: 207.0645.
7-Nitro-2-n-propyl-5-trifluoromethyl-1H-benzimidazole 3-
oxide (6a)
A solution prepared by dissolving 200 mg (0.65 mmol) of
5a in 100 mL of solvent was heated at reflux with NaOH
(0.20–0.01mol/L) for 10–15 min. The reaction mixture was
acidified to pH 4 and the solvent was evaporated in a rotary
2-Ethyl-7-nitro-5-trifluoromethyl-1H-benzimidazole 3-
oxide (6d)
A solution prepared by dissolving 100 mg (0.34 mmol) of
© 2004 NRC Canada

Buján and Salum
1327
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1d in 50 mL of solvent was heated at reflux with NaOH
(0.05 or 0.01 mol/L) for 20–35 min. The reaction mixture
was acidified to pH 2 and the products were extracted with
CH2Cl2. The combined extracts were dried over anhydrous
Na2SO4, filtered, and the solvent evaporated in a rotary
evaporator. The solid obtained was a mixture of 6d and 7;
the N-oxide 6d was isolated as described for 6a. The solid
decomposed at 196 °C (lit. (11) 215–216 °C).
1H NMR ((CD3)2SO, 200 MHz) δ: 1.38 (t, 3H, J = 7.5 Hz,
CH3), 3.02 (q, 2H, J = 7.5 Hz, CH2CH3), 8.24 (s, 1H, Ar),
8.25 (s, 1H, Ar), and 12.48 (s, 1H, NH). 13C NMR
((CD3)2SO, 50 MHz) δ: 10.65, 19.06, 111.81 (q, JCF
=
4.0 Hz, CHAr), 114.47 (q, JCF = 4.0 Hz, CHAr), 121.43 (q,
JCF = 33.5 Hz, C-CF3), 123.41 (q, JCF = 270 Hz, CF3),
133.04, 134.85, 137.36, and 159.11
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Acknowledgements
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Chem. Crystallogr. 27, 499 (1997).
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and R.H. de Rossi. J. Chem. Crystallogr. 25, 801 (1995).
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Phys. Org. Chem. 11, 895 (1998).
This research was supported in part by Consejo Nacional
de Investigaciones Científicas y Técnicas (CONICET), Ar-
gentina; Agencia Córdoba Ciencia; Agencia Nacional de
Promoción Científica y Tecnológica (FONCYT); Fundación
Antorchas, Argentina; and Secretaría de Ciencia
y
Tecnología, Universidad Nacional de Córdoba, Argentina.
M.L.S. is a FONCYT doctoral fellow. We thank Dr.
Alejandro Granados for helpful suggestions.
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ACD/Labs, Toronto, Ont., Canada. 2001.
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© 2004 NRC Canada