Microwave-assisted one-pot synthesis of 2-(substituted phenyl)-1H- benzimidazole derivatives

Article abstract of DOI:10.1080/00397910701473325

A series of 2-(substituted phenyl)-1H-benzimidazole derivatives with various 5-and 6-position substituents (-H, -CH3, -CF3) were synthesized via microwave irradiation using a short synthetic route and Na2S2O5 as oxidant. This simple, fast, and efficient p

Full text of DOI:10.1080/00397910701473325

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Microwave‐Assisted One‐Pot Synthesis of
2‐(Substituted phenyl)‐1H‐benzimidazole
Derivatives
a
a
Gabriel Navarrete‐Vázquez , Hermenegilda Moreno‐Diaz , Samuel
a
a
b
Estrada‐Soto , Mariana Torres‐Piedra , Ismael León‐Rivera , Hugo
b
c
d
Tlahuext , Omar Muñoz‐Muñiz & Hector Torres‐Gómez
a
Faculty of Pharmacy, Autonomous University of Morelos State, Cuernavaca,
México
b
Chemical Research Center, Autonomous University of Morelos State,
Cuernavaca, México
c
Unit for Service and Support in Analytic Resolution, Veracruzana
University, Xalapa, México
d
Faculty of Sciences, Autonomous University of Morelos State, Cuernavaca,
México
Version of record first published: 30 Aug 2007
To cite this article: Gabriel Navarrete‐Vázquez, Hermenegilda Moreno‐Diaz, Samuel Estrada‐Soto, Mariana
Torres‐Piedra, Ismael León‐Rivera, Hugo Tlahuext, Omar Muñoz‐Muñiz & Hector Torres‐Gómez (2007):
Microwave‐Assisted One‐Pot Synthesis of 2‐(Substituted phenyl)‐1H‐benzimidazole Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:17,
2815-2825
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Synthetic Communications , 37: 2815–2825, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701473325
Microwave-Assisted One-Pot Synthesis of
2
-(Substituted phenyl)-1H-benzimidazole
Derivatives
Gabriel Navarrete-V a´ zquez, Hermenegilda Moreno-Diaz,
Samuel Estrada-Soto, and Mariana Torres-Piedra
Faculty of Pharmacy, Autonomous University of Morelos State,
Cuernavaca, M e´ xico
Ismael Le o´ n-Rivera and Hugo Tlahuext
Chemical Research Center, Autonomous University of Morelos State,
Cuernavaca, M e´ xico
Omar Mu n˜ oz-Mu n˜ iz
Unit for Service and Support in Analytic Resolution, Veracruzana
University, Xalapa, M e´ xico
Hector Torres-G o´ mez
Faculty of Sciences, Autonomous University of Morelos State,
Cuernavaca, M e´ xico
Abstract: A series of 2-(substituted phenyl)-1H-benzimidazole derivatives with
various 5-and 6-position substituents (-H, -CH
microwave irradiation using a short synthetic route and Na
3
, -CF
3
) were synthesized via
as oxidant. This
2 2 5
S O
simple, fast, and efficient preparation of benzimidazole derivatives has been
developed using readily available and inexpensive reagents (aldehydes and 1,2-pheny-
lenediamines) under solvent-free conditions.
Keywords: benzimidazole, microwave-assisted synthesis, solvent-free reaction
Received in the USA January 10, 2007
Address correspondence to Gabriel Navarrete-V a´ zquez, Facultad de Farmacia, Uni-
versidad Aut o´ noma del Estado de Morelos, Cuernavaca, Mor. 62210, M e´ xico. E-mail:
gabriel_navarrete@uaem.mx
2
815

2
816
G. Navarrete-V a´ zquez et al.
It is well-known that the benzimidazole pharmacophore is an important
structural core in medicinal chemistry that shows a broad spectrum of pharma-
cological activities. Several compounds containing the benzimidazole scaffold
[
1]
[2]
[3]
have been used as antiparasitic, antimicrobial, antitumor, and antihista-
[
4]
minic agents.
Recently, the microwave as heating source has been used for the rapid
synthesis of a variety of heterocyclic compounds both in solution phase as
[5]
well as under solvent-free conditions. Usually, 2-arylbenzimidazoles have
been prepared by classical cyclocondensation of 1,2-phenylenediamines
with the corresponding carboxylic acids under harsh dehydrating reaction con-
[
6]
[7]
ditions or aldehydes under oxidative conditions. The condensation of 1,2-
phenylenediamines and aldehydes requires an oxidative reagent to generate
[8]
the benzimidazole core. Various reagents such as nitrobenzene, benzoqui-
[11]
[
9]
none, sodium metabisulfite,
[2,7,10]
and air
have been employed for this
purpose. Because of the availability of commercial aldehydes, this method
has been chosen as the most general procedure. However, in most of the
cases, the reaction requires at least 4 to 48 h, giving yields between 30 to
75%. Using microwave irradiation as heating source, the rates of reactions
involving polar components are usually very fast. Reactions that require
hours or even days by conventional heating may often be accomplished in
seconds by microwave heating, and that is the reason why this technology
is widely applied to drug discovery.
Taking this into consideration, we planned to apply microwave method-
ology to our research project aimed at the discovery of new vasorelaxant and
[12–14]
spasmolytic drugs based on the benzimidazole scaffold.
The design of
these new benzimidazole derivatives explore the change in the electronic
density of the pharmacophoric group by introducing nonclassical bioisosteric
groups (-CH , -CF , -H) with different electronic properties in the C-5(6)
3
3
position of the benzimidazole ring. In addition, substitution of the
phenyl ring at positions 2–5 with -OH, -OR, -NO , and -NMe radicals is
explored.
2
2
In this study, 36 benzimidazole derivatives (1–36) have been synthesized
by the reaction of 1,2-phenylenediamines 37–39 with aromatic substituted
aldehydes (Scheme 1) and sodium metabisulfite under microwave irradiation
(
Table 1). Solid compounds were purified by recrystallization, and the
Scheme 1.

Table 1. Comparison of yields and reaction times of synthesized 2-(substituted phenyl)benzimidazole derivatives obtained under microwave and
thermal conditions
Reaction time
Yield (%)
Microwave
irradiation
Thermal
conditions
Microwave
irradiation
Thermal
conditions
Entry
R1
R2
R3
R4
R5
Mp (8C)
1
2
3
4
5
6
7
8
9
H
H
H
OH
H
H
H
H
H
H
293.0–296.1
242.1–243.5
171.7–173.9
149.4–150.3
168.0–170
46 s
36 s
48 s
50 s
48 s
48 s
60 s
60 s
60 s
60 s
40 s
50 s
40 s
40 s
40 s
50 s
24 s
48 s
48 s
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
88
95
89
89
88
92
96
88
90
85
87
94
85
94
86
88
75
85
95
83
80
75
78
55
75
82
70
76
70
72
80
72
78
75
80
58
73
80
H
OCH3
OCH CH
NO
H
H
H
H
2
3
H
H
H
H
2
H
H
H
H
H
H
H
H
H
H
OH
OCH3
H
254.1–256.6
229.9–231.4
294.2–296.3
224.7–225.4
235.5–236.7
258.7 –259.7
259.9 –262.1
216.9–219.7
240.2–242.1
200.5–203.7
179.2–181.2
212.1–215.0
300.1–302.6
H
H
H
H
H
OCH
N(CH
OH
OCH3
3
)
2
H
H
3
H
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
H
OCH3
H
H
H
OCH
H
3
3
OCH
OCH
H
3
3
OCH
OCH
H
3
3
H
CH3
OCH
H
3
H
CH
CH
3
3
OH
OCH
H
H
H
H
H
H
CH3
OCH CH
2
H
H
H
3
CH
CH
CH
3
3
3
NO
H
2
H
H
H
H
OH
OCH
H
a
ND
H
H
3
H
(
continued)

Table 1. Continued
Reaction time
Yield (%)
Microwave
Thermal
Microwave
Thermal
Entry
R
1
R
2
R
3
R
4
R
5
Mp (8C)
irradiation
conditions
irradiation
conditions
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
CH3
H
H
H
OCH
OCH
H
N(CH3)2
OH
OCH
H
H
209.5–211.0
225.3–227.1
202.9–204.1
224.1–226.3
249.0–251.2
ND
50 s
60 s
60 s
60 s
60 s
50 s
50 s
50 s
50 s
30 s
50 s
50 s
50 s
60 s
60 s
60 s
60 s
3 h
3 h
85
82
80
85
80
85
80
82
80
65
80
75
78
75
80
83
89
75
70
70
75
72
80
64
70
78
60
65
60
75
56
68
70
70
CH
CH
3
3
3
3
H
3
H
3 h
3 h
CH3
CH3
OCH3
H
OCH3
OCH3
H
OCH3
OCH3
H
OCH3
3 h
CF
CF
3
3
H
H
H
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
4.5 h
OH
OCH3
OCH CH
H
H
263.6–265.4
204.3–205.5
121.5–122.9
155.8–157.1
300.2–303.3
250.3–253.1
222.1–224.4
214.4–216.6
192.5–194.2
214.8–217.0
238.4–240.2
CF3
H
H
H
CF
CF
3
3
2
3
H
H
H
NO
2
H
H
OH
H
CF3
H
H
H
H
H
H
H
CF
CF
3
3
H
OCH
3
H
H
OCH3
N(CH
OH
3
)
2
H
CF3
H
CF
CF
CF
3
3
3
OCH
H
3
OCH
OCH
OCH
3
3
3
H
OCH
H
3
OCH
OCH
3
3
OCH
3
a
ND: Not determined.

Microwave Synthesis of Benzimidazoles
2819
structure of the pure compounds was established by spectroscopic and
spectrometric data. All prepared compounds showed blue emissions under UV
irradiation in methanol solutions. The reaction between 1,2-phenylenedia-
mines 37–39 and the corresponding aromatic aldehyde was carried out in
2
4–60 s under microwave irradiation and afforded the corresponding products
–36 in good yield (Table 1). After irradiation for 10 s, the reaction mixture
1
was taken out, mixed again, and then heated at the same power level for an
additional 10 s. This step was repeated until the starting materials were
consumed (TLC). All reactions were performed without solvent in only 60 s
as a maximum time, confirming that the focused microwave irradiation is a
very effective technique for accelerating thermal organic reactions in solvent-
free conditions. Table 2 reports microanalysis data and molecular ions
obtained in mass spectra from all compounds.
With extended heating times, a decrease of the yield due to formation of
several by-products was observed. For comparison, Benzimidazoles 1–36
were also prepared by the classical thermal method (i.e., refluxing the 1,2-phe-
nylendiamine, the aldehyde, and sodium metabisulfite in DMF for 3–4.5 h).
Classical heating afforded lower yields for almost all compounds and other
by-products, for which separation was difficult. The reaction proceeded
smoothly under microwave irradiation within 24–60 s whereas under reflux
conditions it needed 3–4.5 h. The most important result of our approach is
the optimization of yields and reaction times using microwave irradiation.
In conclusion, we have developed a simple, rapid, and efficient method for
the preparation of 2-(substituted phenyl)-1H-benzimidazole compounds
under solvent-free conditions using readily available and inexpensive
reagents and a household microwave oven.
EXPERIMENTAL
Melting points were determined on a B u¨ chi B-540 melting-point apparatus
and are uncorrected. Reactions were monitored by thin-layer chromatography
1
TLC) on 0.2-mm precoated silica-gel 60 F plates (E. Merck). H NMR and
(
1
2
54
3
C NMR spectra were measured with a Varian EM-390 (300 MHz and
5.5 MHz) spectrometer. Chemical shifts are given in parts per million
7
(
ppm) relative to tetramethylsilane (Me Si, d ¼ 0) in CDCl ; J values are
4
3
given in Hertz. The following abbreviations are used: s, singlet; d, doublet;
q, quartet; dd, doublet of doublet; t, triplet; m, multiplet; bs, broad signal.
MS were recorded on a Jeol JMS-SX102A spectrometer by electron impact
(EI). Elemental analyses were performed by Elementar Vario ELIII
Analyzer, and results for C,H,N were within +0.4% of calculated values.
All the chemicals and solvents used in this study were of analytical grade.
Reactions under microwave irradiation were performed in a domestic
microwave oven, Samsung MW1446WC, 1000 W.

Table 2. Microanalysis data and molecular ion in mass spectra of 2-(substituted phenyl)benzimidazole derivatives
Experimental (%)
H
Calculated (%)
H
Molecular
ion (m/z)
Entry
Formula
C
N
C
N
1
2
3
4
5
6
7
8
9
C
C
13
H
H
10
10
N
N
2
2
80.27
73.99
74.90
75.73
65.01
74.19
74.91
75.86
70.06
70.78
67.50
67.43
80.42
5.22
4.66
5.36
5.99
3.82
4.79
5.39
6.43
5.08
5.55
5.62
5.60
6.15
ND
14.51
13.38
12.37
11.81
17.66
13.09
12.36
17.71
11.70
11.10
9.91
80.39
74.27
74.98
75.61
65.27
74.27
74.98
75.92
69.99
70.85
67.59
67.59
80.74
74.98
75.61
76.16
5.19
4.79
5.39
5.92
3.79
4.79
5.39
6.37
5.03
5.55
5.67
5.67
5.81
5.39
5.92
6.39
14.42
13.33
12.49
11.76
17.56
13.33
12.49
17.71
11.66
11.02
9.85
194
210
224
238
239
210
224
237
240
254
284
284
208
224
238
252
13
O
C H N O
1
4
12
2
C
C
15
H
H
14
N
2
O
13
9
N
3
O
2
C H N O
1
3
10
12
15
2
2
3
C
C
14
H
H
N
N
O
15
C H N O
1
4
12
14
16
2
2
2
2
2
3
3
1
1
1
1
1
1
1
0
1
2
3
4
5
6
C
C
15
H
H
N
N
O
O
16
C H N O
9.77
13.43
ND
9.85
1
6
16
2
2
2
2
C H N
13.45
12.49
11.75
11.10
1
4
12
12
14
a
C
C
14
H
H
N
N
O
O
ND
74.31
ND
15
5.92
ND
11.63
ND
C H N O
16 16 2

17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
C
14
H
11
N
C H N O
3
O
2
66.03
ND
ND
4.36
ND
16.39
ND
ND
66.39
74.98
75.61
76.46
70.85
71.62
68.34
68.34
64.12
60.44
61.64
62.74
54.73
60.44
61.64
62.95
58.45
59.63
57.96
57.96
4.37
5.39
5.92
6.82
5.54
6.01
6.08
6.08
3.46
3.26
3.79
4.28
2.62
3.26
3.79
4.62
3.60
4.07
4.29
4.29
16.59
12.49
11.76
16.72
11.01
10.44
9.39
253
224
238
251
254
268
298
298
262
278
292
306
307
278
292
305
308
322
352
352
1
4
12
2
C
C
15
H
H
14
N
2
O
ND
16
7
N
3
76.58
70.72
71.02
67.53
68.29
63.87
60.37
61.12
62.60
54.71
60.62
61.39
63.01
58.36
59.59
57.79
57.89
6.81
5.52
6.01
5.99
6.09
3.35
3.22
3.70
4.21
2.59
3.29
3.68
4.65
3.49
4.05
4.19
4.20
16.61
11.23
10.39
9.38
C H N O
2
1
5
14
2
2
3
3
C H N O
1
6
16
18
18
2
2
2
C
C
17
H
H
N
N
O
O
17
9.36
9.39
C H N F
2
21.66
20.39
19.43
18.52
18.62
20.53
19.42
18.80
18.40
17.66
5.99
21.73
20.48
19.50
18.61
18.55
20.48
19.50
18.67
18.49
17.68
6.18
1
4
9
3
C
C
14
H
H
9
N
2
OF
OF
3
15
11
N
2
3
3
3
C H N OF
13
1
6
2
C
C
14
H
H
8
9
N
3
O
2
F
14
N
2
OF
3
C H N OF
1
5
11
14
11
13
2
3
2
2
3
C
C
C
16
H
15
H
16
H
N
N
N
F
3
O
O
2
F
F
3
3
3
3
2
C H N O F
3
1
7
15
2
C
17
H
15
N
2
O
3
F
6.21
6.18
a
ND: not determined.

2
822
G. Navarrete-V a´ zquez et al.
General Method of Synthesis of 2-(Substituted Phenyl)-1H-
benzimidazoles 1–36
Microwave Irradiation Conditions
An appropriate 1,2-phenylenediamine (0.0313 mol), 1.01 equivalents of appro-
priate aldehyde, and 1.01 equivalents of sodium metabisulfite were mixed and
introduced in an open Erlenmeyer flask. The mixture was irradiated in a
household microwave oven for 24–60 s. After irradiation, the mixture was
poured onto cold water. The precipitate was collected by filtration, washed
with water, dried, and recrystallized.
Thermal Conditions
A mixture of an appropriate 1,2-phenylenediamine (0.0313 mol), 1.01 equiva-
lents of appropriate aldehyde, and 1.01 equivalents of sodium metabisulfite in
10 mL of DMF was heated to reflux for 3–4.5 h. After cooling, water (20 mL)
was added, and the mixture was extracted with AcOEt (3 ꢀ 15 mL). The
organic layer was dried over magnesium sulfate and removed under
vacuum. Purification was done by chromatography on silica gel eluting with
chloroform and recrystallization from adequate solvent. The spectral data of
some representative benzimidazoles are given here.
Data
2
-(1H-Benzimidazol-2-yl)phenol (2): White solid, mp 243.5–245.38C
1
0
(
methanol). H NMR (300 MHz, DMSO-d ) d 6.73 (dd, 1H, H-3 , J ¼ 7.91,
6
0
J ¼ 1.3 Hz), 7.11 (td, 1H, H-5 , J ¼ 7.7, J ¼ 7.7, J ¼ 1.3 Hz), 7.18 (td, 1H,
0
H-4 , J ¼ 7.7, J ¼ 7.9, J ¼ 1.7 Hz), 7.21–7.26 (m, 2H, H-5, H-6, J ¼ 8.5,
J ¼ 1.3 Hz), 7.59–7.63 (m, 2H, H-4, H-7, J ¼ 8.5, J ¼ 6.8, J ¼ 1.4 Hz),
0
7
1
.76 (dd, 1H, H-6 , J ¼ 7.7, J ¼ 1.7 Hz), 11.76 (bs, 2H, N-H, O-H) ppm;
3
C NMR (75.5 MHz, DMSO-d ) d 113.93 (C-1), 116.05 (C-4, C-7), 117.56
6
0
0
0
0
(
C-3 ), 120.65 (C-5 ), 123.48 (C-5, C-6), 128.77 (C-6 ), 132.72 (C-4 ),
0
1
41.11 (C-3a, C-7a), 156.39 (C-2), 157.60 (C-2 ) ppm; EIMS: m/z (% rel.
þ
int.) 210 (M , 100), 192 (2), 181 (25); HRMS: calcd. for C H N O:
1
3 10 2
210.0793, found: 210.0795.
2
(
-(2-Ethoxyphenyl)-1H-benzimidazole (4): White solid, mp 149.4–150.38C
1
ethanol). H NMR (300 MHz, DMSO-d ) d 1.53 (t, 3H, CH ), 4.37 (q, 2H,
6
3
0
0
CH -O-), 7.08–7.14 (m, 2H, H-3 , H-5 , J ¼ 8.2, J ¼ 1.1 Hz), 7.18–7.22
2
0
0
(
dd, 1H, H-4 , J ¼ 7.1, J ¼ 2.74 Hz), 7.41 (dd, 1H, H-2 , J ¼ 7.1,
J ¼ 1.6 Hz), 7.59–7.64 (m, 2H, H-5, H-6, J ¼ 6.6, J ¼ 3.3, J ¼ 1.4 Hz),
.52–8.55 (dd, 2H, H-4, H-7, J ¼ 7.96, J ¼ 1.9 Hz), 11.7 (bs, 1H, N-H)
8
ppm; C NMR (75.5 MHz, DMSO-d ) d 14.42 (CH ), 64.64 (CH -O-),
1
3
6
3
2

Microwave Synthesis of Benzimidazoles
2823
0
0
0
0
1
12.97 (C-5 ), 121.11 (C-4, C-7), 122.05 (C-1 ), 123.06 (C-3 , C-5 ), 130.38
0 0
(
C-5, C-6), 131.19 (C-2 ), 131.21 (C-4 ), 150.12 (C-3a, C-7a), 156.39 (C-2),
þ
0
1
67.76 (C-6 ) ppm; EIMS: m/z (% rel. int.) 238 (M , 48), 223 (100), 209
15); 194 (85). HRMS: calcd. for C H N O: 238.1106, found: 238.1119.
(
15 14 2
2
2
7
-(4-Methoxyphenyl)-1H-benzimidazole (7): White solid, mp 228.6–
1
30.58C (ethanol). H NMR (300 MHz, DMSO-d ) d 3.82 (s, 3H, CH -O-),
6
3
0
0
.05–7.09 (m, 2H, H-3 , H-5 , J ¼ 8.5, J ¼ 2.2 Hz), 7.21–7.25 (m, 2H,
H-5, H-6, J ¼ 8.5, J ¼ 7.0, J ¼ 1.4 Hz), 7.57–7.61 (m, 2H, H-4, H-7,
0
0
J ¼ 8.5, J ¼ 1.4 Hz), 8.03–8.06 (m, 2H, H-2 , H-6 , J ¼ 8.5, J ¼ 1.4 Hz),
1
3
1
O-), 114.59 (C-3 , C-5 ), 116.08 (C-4, C-7), 123.48 (C-5, C-6), 125.28
0.88 (bs, 1H, N-H) ppm; C NMR (75.5 MHz, DMSO-d ) d 55.43 (CH -
6 3
0
0
0
0
0
0
(C-2 , C-6 ), 125.22 (C-1 ), 139.85 (C-3a, C-7a), 152.12 (C-2), 161.06 (C-4 )
ppm; EIMS: m/z (% rel. int.) 224 (M , 100), 209 (35), 181 (25); HRMS:
þ
calcd. for C H N O: 224.0949, found: 224.0952.
14 12 2
2
-(3-Hydroxy-4-methoxyphenyl)-1H-benzimidazole (9): Pale yellow solid,
1
mp 224.7–225.48C (methanol). H NMR (300 MHz, DMSO-d6) d 3.97
0
(
s, 3H, -OCH ), 6.91(d, 1H, H-5 , J ¼ 8.4 Hz), 7.11–7.16 (m, 2H, H-5, H-6,
3
0
J ¼ 9.6, J ¼ 3 Hz), 7.53 (sa, 1H, H-6 , J ¼ 0.9 Hz), 7.61 (dd, 2H, H-4, H-7,
J ¼ 8.1, J ¼ 1.8 Hz), 7.74 (d, 1H, H-2, J ¼ 1.5 Hz), 9.57 (bs, 2H, N-H,
1
3
O-H). C NMR (75.5 MHz, DMSO-d ) d55.67 (CH ), 110.24 (C-2 ),
0
6
3
0
0
1
16.07 (C-4, C-7), 117.28 (C-5 ), 123.08 (C-1 ), 123.48 (C-5, C-6), 124.72
0
0
0
(C-6 ), 139.73 (C-3a, C-7a), 146.81 (C-4 ), 150.22 (C-3 ), 151.67 (C-2) ppm.
2
2
6
-(5-Methyl-1H-benzimidazol-2-yl)phenol (14): White solid, mp 240–
1
428C (methanol). H NMR (300 MHz, DMSO-d ) d 2.43 (s, 3H, CH ),
6
3
0
.62 (dd, 1H, H-3 , J ¼ 7.8, J ¼ 1.2 Hz), 7.08–7.11 (m, 1H, H-6, J ¼ 8.6,
0
J ¼ 1.8 Hz), 7.09–7.13 (m, 1H, H-5 , J ¼ 7.7, J ¼ 1.3 Hz), 7.18 (td, 1H,
0
H-4 , J ¼ 7.8, J ¼ 7.7, J ¼ 1.8 Hz), 7.24–7.25 (m, 1H, H-4, J ¼ 1.8 Hz),
0
7
.26–7.28 (m, 1H, H-7, J ¼ 8.6 Hz), 7.78 (dd, 1H, H-6 , J ¼ 7.8 Hz), 7.78
0
13
(dd, 1H, H-6 , J ¼ 7.8, J ¼ 1.8 Hz), 10.95 (bs, 2H, N-H, O-H) ppm;
C
0
NMR (75.5 MHz, DMSO-d ) d 21.86 (CH ), 112.34 (C-7), 113.94 (C-1 ),
6
3
0
0
1
1
1
17.56 (C-3 ), 119.58 (C-4), 119.56 (C-4), 120.65 (C-5 ), 124.42 (C-6),
28.77 (C-6 ), 132.86 (C-4 ), 136.68 (C-3a), 137.43 (C-7a), 140.75 (C-5),
0
0
0
þ
56.39 (C-2), 159.60 (C-2 ) ppm; MS: m/z (% rel. int.) 224 (M , 100), 209
(2), 195 (25); HRMS: calcd. for C H N O: 224.0949, found: 224.0953.
14 12 2
2-(4-Methoxyphenyl)-5-methyl-1H-benzimidazole (19): Workup by extrac-
tion with EtOAc and concentration under vacuum left an oil, which was
purified by column chromatography (4 ꢀ 60 cm, 60 g of silica gel,
1
petroleum ether), colorless oil. H NMR (300 MHz, DMSO-d ) d 2.43
(
6
0 0
s, 3H, CH -C-5), 3.86 (s, 3H, CH -O-), 7.06–7.09 (m, 2H, H-3 , H-5 ,
3 3
J ¼ 8.4, J ¼ 2.4 Hz), 7.08–7.11 (m, 1H, H-6, J ¼ 8.6, J ¼ 1.7 Hz), 7.22–
7
.23 (m, 1H, H-4, J ¼ 1.7 Hz), 7.22–7.26 (m, 1H, H-7, J ¼ 8.6,

2
824
G. Navarrete-V a´ zquez et al.
0
0
J ¼ 0.9 Hz), 8.03–8.06 (m, 2H, H-2 , H-6 , J ¼ 8.5, J ¼ 1.8 Hz), 11.01 (bs,
1
3
1
H, N-H) ppm; C NMR (75.5 MHz, DMSO-d ) d 20.68 (CH -C-5), 55.47
0 0
CH -O-), 111.36 (C-7), 114.59 (C-3 , C-5 ), 119.60 (C-4), 124.42 (C-6),
3
6 3
(
0 0 0
1
1
25.31 (C-2 , C-6 ), 125.20 (C-1 ), 136.17 (C-3a), 136.68 (C-5), 139.85 (C-7a),
þ
0
52.21 (C-2), 161.12 (C-4 ) ppm; MS: m/z (% rel. int.) 238 (M , 100), 223
(
30), 195 (20); HRMS: calcd. for C H N O: 238.1106; found: 238.1110.
15 14 2
2
-[(5-Trifluoromethyl)-1H-benzimidazol-2-yl]phenol (26): White solid, mp
1
263.6–265.48C (ethanol). H NMR (300 MHz, DMSO-d ) d 7.42 (dd, 1H,
6
0
0
0
H-6 , J ¼ 8.8, J ¼ 1.6 Hz), 7.02 (m, 2H, H-4 , H-5 , J ¼ 7.69, J ¼ 1.09 Hz),
0
7
.59 (d, 1H, H-3 , J ¼ 7.7, J ¼ 1.1 Hz), 7.81 (d, 1H, H-7, J ¼ 8.2 Hz), 8.0
(
1
dd, 1H, H-6, J ¼ 7.7, J ¼ 1.6 Hz), 8.0 (dd, 1H, H-4, J ¼ 1.64 Hz), ppm;
3
C NMR (75.5 MHz, DMSO-d ) d 113.91 (C-7), 114.13 (C-4), 115.94
6
0
0
(
(
(
C-1 ), 119.66 (C-6), 120.65 (C-5 ), 123.85 (q, CF , J ¼ 285.2 Hz), 125.97
3
0
0
q, C-5, J ¼ 285.2 Hz), 128.77 (C-6 ), 132.77 (C-4 ), 139.18 (C-3a), 144.30
0
þ
C-7a), 156.39 (C-2), 157.66 (C-2 ) ppm; MS: m/z (% rel. int.) 278 (M ,
1
2
00), 209 (2), 249 (33); HRMS: calcd. for C H F N O: 278.0667, found:
14 9 3 2
78.0656.
ACKNOWLEDGMENTS
This work was supported in part by a grant from Programa de Mejoramiento de
Profesorado, Secretaria de Educaci o¯ n P u¯ blica (PROMEP–SEP), UAEMOR-
PTC-131 (Gabriel Navarrete-Vazquez (GNV)). We are grateful to Victoria
Labastida and Maria Medina from the Chemical Research Centre (CIQ),
Autonomous University of Morelos State (UAEM), for the determination of
all mass spectra.
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