A simple and efficient method for the synthesis of novel trifluoromethyl benzimidazoles under microwave irradiation conditions

Article abstract of DOI:10.1081/SCC-120003394

The condensation of trifluoromethyl -o-phenylenediamines and aromatic aldehydes under microwave irradiation on metal halide supported alumina resulted exclusively trifluoromethyl-2-aryl benzimidazoles.

Full text of DOI:10.1081/SCC-120003394

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A SIMPLE AND EFFICIENT METHOD FOR THE SYNTHESIS
OF NOVEL TRIFLUOROMETHYL BENZIMIDAZOLES UNDER
MICROWAVE IRRADIATION CONDITIONS*
G. Venkat Reddy a , V. V. V. N. S. Rama Rao a , B. Narsaiah a & P. Shanthan Rao b
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad, 500007,
India
b Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad, 500007,
India
Published online: 16 Aug 2006.
To cite this article: G. Venkat Reddy , V. V. V. N. S. Rama Rao , B. Narsaiah & P. Shanthan Rao (2002) A SIMPLE AND EFFICIENT
METHOD FOR THE SYNTHESIS OF NOVEL TRIFLUOROMETHYL BENZIMIDAZOLES UNDER MICROWAVE IRRADIATION CONDITIONS*,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:16,
2467-2476, DOI: 10.1081/SCC-120003394
To link to this article: http://dx.doi.org/10.1081/SCC-120003394
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2467–2476, 2002
A SIMPLE AND EFFICIENT METHOD FOR
THE SYNTHESIS OF NOVEL
TRIFLUOROMETHYL BENZIMIDAZOLES
UNDER MICROWAVE IRRADIATION
CONDITIONS*
G. Venkat Reddy, V. V. V. N. S. Rama Rao,
B. Narsaiah, and P. Shanthan Raoy
Organic Chemistry Division-II, Indian Institute of
Chemical Technology, Hyderabad 500007, India
ABSTRACT
The condensation of trifluoromethyl -o-phenylenediamines
and aromatic aldehydes under microwave irradiation on
metal halide supported alumina resulted exclusively trifluoro-
methyl-2-aryl benzimidazoles.
The benzimidazole nucleus is found in a variety of pharmaceuticals
as cardiotonic agents,[1,2] potential antitumor agents[3] and antiulcer
agents.[4] In particular the trifluoromethyl benzimidazoles[5–7] have import-
ance as pesticidal and antibacterial compounds. Conventional methods
on the synthesis of 2-aryl benzimidazoles involve the condensation of o-dia-
mino aromatic compound and benzoic acid derivatives[8,9] in presence of
*y IICT Communication No. 4776.
Corresponding author. E-mail: shanthanRao@iict.ap.nic.in
2467
DOI: 10.1081/SCC-120003394
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2468
REDDY ET AL.
strong acidic medium or in high boiling solvents. In recent years there
has been a considerable growth in interest on the synthesis of 2-aryl benzi-
midazoles by different methods viz., palladium catalysed reactions,[10]
and solid phase reactions[11]. Further studies on the efficient synthesis of
aryl benzimidazoles is of current interest because of their wide range
of applications. As a continued interest on the synthesis of trifluoromethyl
substituted molecules of biological interest,[12,13] we wish to report here for
the first time a simple and convenient method of preparation of 2-aryl
benzimidazoles using metal halide supported, solvent free solid phase
reaction under microwave irradiation conditions.
In a specified experiment, the reaction is mainly the condensation of
3-nitro-5-trifluoromethyl-o-phenylene diamine 1 and 4-methoxybenzalde-
hyde 2c in presence of a catalytic amount of anhydrous zinc chloride.
The reactants were adsorbed on alumina and subjected to microwave
irradiation for a specified time to result product. The product is isolated
by extraction with chloroform and purified by passing through a column
of silicagel using n-Hexane : Chloroform (1 : 1) as eluents. Based on spectral
data, it has been characterized as 2-(4-methoxyphenyl) -5-trifluoromethyl-7-
nitrobenzimidazole 3c (Scheme 1). This reaction has been extended to other
substituted aromatic aldehydes and obtained the respective 2-arylbenzimi-
dazoles. The structure of 3c is confirmed after ethylation and comparing
with an authentic sample prepared independently. Thus the 3-amine-5-nitro-
4-ethylamino benzotrifluoride 6 is prepared from p-chloro benzotrifluoride
5 via nitration and amination by a known method[14] followed by controlled
reduction using NaHS. The condensation of compound 6 with 4-metho-
xybenzaldehyde under thermal conditions obtained 1-ethyl-2 (4-metho-
xyphenyl)5-trifluoromethyl 7-nitrobenzimidazole 7. Alternately the direct
Scheme 1.

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TRIFLUOROMETHYL BENZIMIDAZOLES
2469
Scheme 2.
ethylation of 3c using ethyl iodide also gave 7 (Scheme 2). The compound
7 which was prepared independently by both the routes is found to be
1
similar in their m.p. IR, H NMR and Mass spectra.
In general the formation of benzimidazoles involve the initial forma-
tion of a Schiff ’s base 4 and its cyclisation followed by dehydrogenation
to give the desired compound 3. The intermediate Schiff ’s base 3-N0-aryli-
dene-4-amino-5-nitrobenzotrifluoride 4a–j is prepared by the reaction of
diamine and aldehyde in ethanol with constant stirring at reflux tempera-
ture. The possibility of the formation of other isomer for 4 may be ruled
out based on electronic factors. The nucleophilic attack of 3-amino group
of compound 1 on to aldehyde is more possible as the lone pair electrons
of 3-amino group is easily available for Schiff’s base formation, whereas
that of the 4-amine group is in conjugation with the trifluoromethyl group
present at para position. The Schiff ’s base 4a–j is subjected to microwave
irradition in presence of ZnCl2 on alumina to give corresponding benzimi-
dazoles 3a–j.
In order to compare the rate of reaction, yields of the products and
substituent effect, the reactions were conducted under thermal conditions.
However we found that the rate of reaction is fast, yields are high and
substituents have no effect on the formation of products under microwave
conditions (Table 1).
In conclusion the developed methods i.e., cyclisation of Schiffs base
and also o-diamine condensation can be universally applied for the synthesis
of variety of benzimidazoles. These compounds will become as active
synthons for building tricyclic heterocycles.
EXPERIMENTAL
Melting points are determined in open glass capillaries on a Fisher
Johnes melting point apparatus. IR spectra are recorded on FT-IR
Schimadzu Perkin–Elmer 1310 infrared spectrophotometer. 1H NMR spectra

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2470
REDDY ET AL.
Table 1. Synthesis of Substituted-2-aryl Benzimidazoles
Time (min)
Yield (%)
Entry
Ar
M.P. (ꢀC) Microwave Thermal Microwave Thermal
3a
3b
3c
3d
3e
3f
Phenyl
217
215
245
228
207
206
4
4
4
4
4
4
120
120
120
120
120
120
84
83
72
86
90
85
80
77
64
65
60
66
4-Fluorophenyl
4-Methoxyphenyl
4-Methylphenyl
4-Chlorophenyl
4-(N,N-
Dimethyl)phenyl
4-Nitrophenyl
4-Hydroxyphenyl
Furyl
3g
3h
3i
>270
>270
210
4
4
4
4
120
120
120
120
87
85
82
80
62
80
64
62
3j
Naphthyl
>270
are recorded on Varian Gemini (200 MHz) spectrometer and TMS is used as
internal standard. Mass spectra are recorded on a VG-micromass 7070H
instrument at 70 eV. Elemental analysis were carried out on a Elemental
Vario EL (Germany) apparatus.
Synthesis of Substituted 2-Aryl Benzimidazoles 3
General Procedure
Microwave Conditions
A mixture of diamine 1 (0.01 mole), aromatic aldehyde (0.01 mole)
and anhydrous ZnCl2 (0.001 mole) is adsorbed on alumina transferred in
to a tube and subjected to microwave irradiation for 4 min in a domestic
oven (600 watt, BPL BMD 700T) allowed to cool to room temperature.
The products are extracted with chloroform and concentrated to get crude
product. Then the products were purified by passing through a silicagel
column using n-Hexane : Chloroform (1 : 1) as eluent.
Thermal Conditions
A mixture of diamine 1 (0.01 mole), aromatic aldehyde (0.01 mole)
were dissolved in nitrobenzene (6 mL) and heated at 160ꢀC for 2 h.

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TRIFLUOROMETHYL BENZIMIDAZOLES
2471
The reaction mixture is cooled and diluted with pentane. The separated
solid is filtered, washed with pentane, dried and recrystallised from chloro-
form to give substituted 2-aryl benzimidazoles 3.
The spectral data of compounds 3a–j are shown in below.
2-Phenyl-5-trifluoromethyl-7-nitrobenzimidazole(3a):
1H NMR
(CDCl3) ꢀ 10.9 (s, 1H, NH), 8.5 (s, 1H, Ar), 8. 4 (s, 1H, Ar), 8.2 (m, 2H,
Ar), 7.6 (m, 3H, Ar), IR (KBr, cmÀ1) 3384 (NH), 1645, 1524, 1338, 1290,
MS (EI, m/z) Mþ 307, Analysis calcd. for C14H8F3N3O2; C, 54.73; H, 2.62;
N, 13.67. Found: C, 54.71; H, 2.60; N, 13.59.
2-(4–Fluorophenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3b): 1H NMR
(CDCl3) ꢀ 13.2 (s, 1H, –NH), 8.6 (s, 1H, Ar–H), 8.5 (s, 1H, Ar–H), 8.2
(d, 2H, Ar–H), 7.2 (d, 2H, Ar–H), IR (KBr, cm-1) 3394 (NH), 1645, 1524,
1339, 1291, MS (EI, m/z) Mþ 325 Analysis calcd. for C14H8F4N3O2; C,
51.70; H, 2.16; N, 12.92. Found. C, 51.62; H, 2.20; N, 13.01.
2-(4–Methoxyphenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3c): 1H NMR
(CDCl3) ꢀ 10.7 (s, 1H, -NH), 8.4 (s, 1H, Ar–H), 8.3 (s, 1H, Ar–H), 8.1 (d,
2H, Ar–H), 7.1 (d, 2H, Ar–H), 3.9 (s, 3H, -OCH3) IR (KBr, cmÀ1) 3390
(NH), 1645, 1524, 1339, 1291 MS (EI, m/z) Mþ 337 Analysis calcd. for
C15H10F3N3O3; C, 53.42; H, 2.98; N, 12.45. Found: C, 53.29; H, 2.99;
N, 12.41.
2-(4-Methylphenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3d): 1H NMR
(CDCl3) ꢀ 10.8 (s, 1H, -NH), 8.5 (s, 1H, Ar–H), 8.4 (s, 1H, Ar–H), 8.1 (d,
2H, Ar–H), 7.4 (d, 2H, Ar–H), 2.3 (s, 3H, -CH3) IR (KBr, cmÀ1) 3357 (NH),
1608, 1520, 1332, 1292, MS (EI, m/z) Mþ 321 Analysis calcd. for
C15H10F3N3O2; C, 56.08; H, 3.13; N, 13.08. Found: C, 55.98; H, 3.11; N,
13.10.
2-(4–Chlorophenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3e): 1H NMR
(CDCl3) ꢀ 10.8 (s, 1H, -NH), 8.5 (s, 1H, Ar–H), 8.4 (s, 1H, Ar–H), 8.2 (d,
2H, Ar–H), 7.2 (d, 2H, Ar–H), IR (KBr, cm-1) 3392 (NH), 1644, 1523, 1338,
1290, MS (EI, m/z) Mþ 341 Analysis calcd. for C14H7ClF3N3O2; C, 49.21;
H, 2.06; N, 12.30. Found: C, 49.41; H, 2.10; N, 12.28.
2-(4-N,N-Dimethylphenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3f):
1H NMR (CDCl3) ꢀ 10.6 (s, 1H, -NH), 8.4 (s, 1H, Ar–H), 8.2 (s, 1H, Ar–H),
8.0 (d, 2H, Ar–H), 6.8 (d, 2H, Ar–H), 3.1 (s, 6H, -CH3) IR (KBr, cmÀ1) 3350
(NH), 1606, 1520, 1330, 1291, MS (EI, m/z) Mþ 350 Analysis calcd. for
C16H13F3N4O2; C, 54.85; H, 3.74; N, 15.99. Found: C, 54.65; H, 3.42;
N, 16.01.
2-(4–Nitrophenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3g): 1H NMR
(CDCl3) ꢀ 12.4 (s, 1H, -NH), 8.5 (s, 1H, Ar–H), 8.4 (s, 1H, Ar–H), 8.1 (d,
2H, Ar–H), 7.4 (d, 2H, Ar–H), IR (KBR, cmÀ1) 3390 (NH), 1645, 1520,
1339, 1290 MS (EI, m/z) Mþ 352 Analysis calcd. for C14H7F3N4O4; C,
47.73; H, 2.00; N, 15.90. Found: C, 47.63; H, 2.02; N, 15.95.

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2472
REDDY ET AL.
2-(4–Hydroxyphenyl)-5-trifluoromethyl-7-nitrobenzimidazole(3h):
1HNMR (CDCl3) ꢀ 13.0 (s, 1H, –NH), 9.9 (s, 1H, -OH), 8.4 (m, 4H, Ar–H),
6.9 (d, 2H, Ar–H), IR (KBr, cmÀ1) 3390 (NH), 3310 (OH), 1645, 1523, 1340,
1292, MS (EI, m/z) Mþ 323 Analysis calcd. for C14H8F3N3O3; C, 52.02; H,
2.49; N, 13.00. Found: C, 52.20; H, 2.51; N, 13.02.
1
2-Furyl-5-trifluoromethyl-7-nitrobenzimidazole (3i): H NMR (CDCl3)
ꢀ 13.1 (s, 1H, -NH), 8-.2 (d, 2H, Ar–H), 7.9 (s, 1H, Ar–H), 6.9 (s, 1H, Ar–
H), IR (KBr, cmÀ1) 3384 (NH), 1640, 1520, 1337, 1288. MS (EI, m/z) Mþ
297 Analysis calcd. for C12H6F3N3O3; C, 48.49; H, 2.03; N, 14.13. Found:
C, 49.51; H, 2.21; N, 14.41.
1
2-Napthyl-5-trifluoromethyl-7-nitrobenzimidazole (3j): H NMR (CDCl3)
ꢀ 10.9 (s, 1H, -NH), 8-.9 (d, 1H, Ar–H), 8.5 (d, 1H, Ar–H), 8.2 (d, 1H, Ar–
H), 8.0 (m, 2H, Ar–H), 7.7 (m, 4H, Ar–H) IR (KBr, cmÀ1) 3390 (NH), 1640,
1520, 1500, 1340, 1290, MS (EI, m/z) Mþ 357 Analysis calcd. for
C18H10F3N3O2; C, 60.50; H, 2.82; N, 11.76. Found: C, 60.41; H, 2.71; N,
11.80.
Synthesis of 3-N-Arylidene-4-amino-5-nitrobenzotrifluoride (4)
General Procedure
The diamine 1 (0.01 mole) and aromatic aldehyde (0.01 mole) were
dissolved in ethanol (10 mL) and refluxed for 1.5 h. The reaction mixture
is cooled to room temperature and the solvent is removed from the reaction
mixture. The residual solid is purified by recrystallisation with dichloro-
methane and dried.
3-N-Benzilidene-4-amino-5-nitro benzotrifluoride (4a): Yield 80% m.p.
124–127ꢀC, 1H-NMR (CDCl3) ꢀ 8.6 (s, 1H, Ar–H), 8.4 (s, 1H, –CH¼N), 8.0
(d, 2H, Ar–H), 7.5 (m, 3H, Ar–H), 7.3 (s, 1H, Ar–H), 7.0 (s, 2H, –NH2), IR
(KBr, cmÀ1) 3479, 3360 (NH2), 1628, 1456, 1341, 1252. MS (EI, m/z) Mþ
309 Analysis calcd. for C14H10F3N3O2; C, 54.37; H, 3.25; N, 13.58. Found:
C, 54.39; H, 3.29; N, 13.64.
3-N-(4–Fluorobenzilidene)-4-amino-5-nitrobenzotrifluoride (4b): Yield 82%
m.p. 134ꢀC, H NMR (CDCl3) ꢀ 8.6 (s, 1H, Ar–H), 8.35 (s, 1H, -CH¼N),
1
8.0 (d, 2H, Ar–H), 7.4 (s, 1H, Ar–H),7.2 (d, 2H, Ar–H), 7.0 (s, 2H, –NH2),
IR (KBr, cmÀ1) 3479, 3360 (NH2), 1628, 1456, 1310, 1256, MS (EI, m/z) Mþ
327 Analysis calcd. for C14H9F4N3O2; C, 51.38; H, 2.77; N, 12.84. Found:
C, 51.42; H, 2.79; N, 12.71.
3-N-(4–Methoxybenzilidene)-4-amino-5-nitrobenzotrifluoride (4c): Yield
80% m.p. 85–87ꢀC, H NMR (CDCl3) ꢀ 8.5 (s, 1H, Ar–H), 8.3 (s, 1H,
1
–CH¼N), 7.9 (d, 2H, Ar–H), 7.4 (s, 1H, Ar–H) 7.0 (d, 2H, Ar–H), 7.1

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TRIFLUOROMETHYL BENZIMIDAZOLES
2473
(s, 2H, –NH2), 3.9 (s, 3H, -OCH3), IR (KBr, cmÀ1) 3478, 3359 (NH2), 1629,
1456, 1341, 1252 MS (EI, m/z) Mþ 339 Analysis calcd. for C15H12F3N3O3;
C, 53.10; H, 3.56; N, 12.38. Found: C, 53.21; H, 3.61; N, 12.42.
3-N-(4–Methylbenzilidene)-4-amino-5-nitrobenzotrifluoride (4d): Yield
70% m.p. 125–127ꢀC, H NMR (CDCl3) ꢀ 8.6 (s, 1H, Ar–H), 8.3 (s, 1H,
1
-CH¼N), 7.8 (d, 2H, Ar–H), 7.3 (d, 2H, Ar–H) 7.25 (s, 1H, Ar–H), 7.2 (s,
2H, -NH2), 2.3 (s, 3H, -CH3) IR (KBr, cmÀ1) 3473, 3335 (NH2), 1628, 1456,
1301, 1256 MS (EI, m/z) Mþ 323 Analysis calcd. for C15H12F3N3O2; C,
55.73; H, 3.74; N, 12.99. Found C, 55.71; H, 3.76; N, 13.01.
3-N-(4–Chlorobenzilidene)-4-amino-5-nitrobenzotrifluoride (4e): Yield
78% m.p. 151–152ꢀC, H NMR (CDCl3) ꢀ 8.6 (s, 1H, Ar–H), 8.35 (s, 1H,
1
-CH¼N), 7.8 (d, 2H, Ar–H), 7.3 (d, 2H, Ar–H) 7.25 (s, 1H, Ar–H), 7.2 (s,
2H, -NH2), IR (KBr, cmÀ1) 3479, 3359 (NH2), 1628, 1457, 1312, 1254 MS
(EI, m/z) Mþ343 Analysis calcd. for C14H9ClF3N3O2; C, 48.92; H, 2.63; N,
12.22. Found C, 48.99; H, 2.67; N, 12.23.
3-N-(4–N, N-Dimethylbenzilidene)-4-amino-5-nitrobenzotrifluoride (4f):
Yield 80% m.p. 114–115ꢀC H NMR (CDCl3) ꢀ 8.4 (s, 1H, Ar–H), 8.2 (s,
1
1H, -CH¼N), 7.8 (d, 2H, Ar–H), 7.3 (s, 1H, Ar–H), 7.0 (s, 2H, NH2), 6.8 (d,
2H, Ar–H), 3.0 (s, 6H, -CH3) IR (KBr, cmÀ1) 3470, 3331 (NH2), 1628, 1457,
1300, 1250 MS (EI, m/z) Mþ 352 Analysis calcd. for C16H15F3N4O2; C,
54.54; H, 4.29; N, 15.90. Found C, 54.61; H, 4.31; N, 16.10.
3-N-(4–Nitrobenzilidene)-4-amino-5-nitrobenzotrifluoride (4g): Yield
70% m.p. 180–181ꢀC, H NMR (CDCl3) ꢀ 8.9 (s, 1H, Ar–H), 8.4 (s, 1H,
1
-CH¼N), 8.3 (m, 2H, Ar–H), 8.2 (d, 2H, Ar–H) 7.6 (s, 1H, Ar–H), 7.4 (s,
2H, -NH2), IR (KBr, cmÀ1) 3479, 3360 (NH2), 1628, 1456, 1310, 1252 MS
(EI, m/z) Mþ 354 Analysis calcd. for C14H9F3N4O4; C, 47.46; H, 2.56; N,
15.81. Found C, 47.42; H, 2.52; N, 15.72.
3-N-(4–Hydroxybenzilidene)-4-amino-5-nitrobenzotrifluoride (4h): Yield
78% m.p. 175–177ꢀC, H NMR (CDCl3) ꢀ 9.9 (s, 1H, -OH) 8.7 (s, 1H,
1
Ar–H), 8.2 (s, 1H, -CH¼N), 7.7 (d, 2H, Ar–H), 7 (s, 2H, -NH2), 6.9 (d,
2H, Ar–H) IR (KBr, cmÀ1) 478, 3359 (NH2), 3330, 1629, 1450, 1302, 1257,
MS (EI, m/z) Mþ 325 Analysis calcd. for C14H10F3N3O3; C, 51.69; H, 3.09;
N, 12.91. Found C, 51.67; H, 3.12; N, 12.93.
3-N-Furylidene-4-amino-5-nitrobenzotrifluoride (4i): Yield 68% m.p.
162–164ꢀC, H NMR (CDCl3) ꢀ 8.5 (s, 1H, Ar–H), 8.4 (s, 1H, -CH¼N),
1
7.7 (d, 1H, Ar–H), 7.3 (s, 1H, Ar–H)7.1 (m, 2H, Ar–H), 6.7 (s, 2H, -NH2),
IR (KBr, cmÀ1) 3475, 3360 (NH2), 1630, 1450, 1336, 1250 MS (EI, m/z)
Mþ 299 Analysis calcd. for C12H8F3N3O3; C, 48.17; H, 2.69; N, 14.04.
Found C, 48.23; H, 2.71; N, 14.05.
3-N–Napthylidene-4-amino-5-nitrobenzotrifluoride (4j): Yield 60% m.p.
162–164ꢀC, H NMR (CDCl3) ꢀ 9.2 (s, 1H, Ar–H), 9 (d, 1H, Ar–H), 8.4
(s, 1H, Ar–H), 8.2 (d, 1H, Ar–H) 8.1 (d, 1H, Ar), 7.9 (d, 1H, Ar–H), 7.7
1

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REDDY ET AL.
(m, 3H, Ar–H), (s, 2H, -NH2), IR (KBr, cmÀ1) 3476, 3335 (NH2), 1628,
1456, 1310, 1250 MS (EI, m/z) Mþ359 Analysis calcd. for C18H12F3N3O2; C,
60.17; H, 3.36; N, 11.69. Found C, 60.07; H, 3.32; N, 11.70.
Preparation of Substituted 2-Arylbenzimidazoles 3 from
Schiff’s Base 4
General Procedure
Schiff’s base 4 (10 mmole) and anhydrous zinc chloride (1 mmole) are
adsorbed on alumina and heated for 1 min in microwave oven. The solid is
allowed to cool to 30ꢀC and extracted with ethanol. The solvent is removed
and the solid residue was passed through column of silica gel using
chloroform as eluant to give the corresponding 2-aryl benzimidazoles 3.
Preparation of 3-Amino-4-ethylamino-5-nitrobenzotrifluoride (6)
General Procedure
To a mixture of sodium sulphide nonahydrate (2.6 g, 10 mmole) and
sodiumbicarbonate(0.85 g 10 mmole) is dissolved in distilled water (20 mL)
and methanol (30 mL) is added to it. The separated sodium carbonate is
separated by filtration and filtrate is preserved. To the filtrate a solution of
3,5-dinitro-4-ethylaminobenzotrifluoride (1.4 g, 5 mmole) in methanol
(10 mL) is added and heated at 70ꢀC for 10 min. The methanol is removed
and the residue is poured on to ice. The separated solid is filtered, dried and
recrystallised in aq. methanol to give the compound 6.
M.p. 111ꢀC 1H NMR (CDCl3) ꢀ 7.7 (s, 1H Ar–H), 7 (s, 1H, Ar–H), 6.1
(1H, -NH), 4 (s, 2H, -NH2), 3.2 (q, 2H, -CH2), 1.2 (t, 3H, -CH3) MS (EI,
m/z) Mþ 249 Analysis calcd. for C9H10F3N3O2; C, 43.37; H, 4.04; N, 16.86.
Found C, 43.29; H, 4.01; N, 16.53.
1-Ethyl-2-(4-methoxyphenyl)-5-trifluoromethyl-7-nitrobenzimidozole 7
Method 1: The compound 6 (60 mg, 0.25 mmoles) and 4-methoxyben-
zaldehyde (80 mg 0.58 mmole) were dissolved in nitrobenzene (6 mL) and
heated at 170ꢀC for 2 h. The reaction mixture is cooled and diluted with
pentane. The separated solid is filtered, washed with pentane dried and

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TRIFLUOROMETHYL BENZIMIDAZOLES
2475
purified by passing through a column of silica gel using dichloromethane
as eluant to give the compound 7.
Method 2: To a solution of 2-(4-methoxyphenyl) -5-trifluoromethyl -7-
nitro benzimidazole (100 mg 0.3 mmole) in dry dimethylformamide (5 g)
potassium carbonate (500 mg 3.6 mmole) and ethyliodide (80 mg 0.5 mmole)
is added and the mixture is heated at 110ꢀC for 20 h. The progress of the
reaction is monitored by TLC. The reaction mixture is poured on to crushed
ice. The separated solid is filtered, dried to give 7.
M.p. 181ꢀC 1H NMR (CDCl3) ꢀ 8.4 (s, 1H, Ar–H), 7.9 (s, 1H, Ar–H),
7.8 (d, 2H, Ar–H), 7 (d, 2H, Ar–H), 4.2 (Q, 2H, -CH2), 3.9 (s, 3H, -OCH3),
1.6 (t, 3H, CH3) IR (KBr, cmÀ1) 1643, 1520, 1335, 1290 MS (EI, m/z) Mþ
365 Analysis calcd. for C17H14F3N3O3; C, 55.89; H, 3.86; N, 11.50. Found
C, 55.70; H, 3.81; N, 11.55.
ACKNOWLEDGMENT
The authors are thankful to Dr. K.V. Raghavan, Director, IICT, for
constant encouragement. One of the authors (GVR) is thankful to CSIR,
NewDelhi, for the award of Junior research fellowship and (VVVNSRR) is
thankful to IICT, Hyderabad for the award of IICT research fellowship.
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Received in the UK June 25, 2001