Synthesis and potent antifungal activity against Candida species of some novel 1H-benzimidazoles

Article abstract of DOI:10.1002/jhet.179

(Chemical Equation Presented) A series of 47 novel N¹-alkylated- 2-aryl-5(6)-substituted-1H-benzimidazoles and their three novel indole analogues were synthesized and evaluated for in vitro antifungal activities against Candida species by the tube dilution method. The results showed that compounds 79 and 80, having pyridine at the position C-2, of benzimidazoles exhibited the greatest activity with MIC values of 6.25-3.12 μg/mL. Indole analogues 108-110 have no inhibitory activity.

Full text of DOI:10.1002/jhet.179

936
Synthesis and Potent Antifungal Activity Against Candida
Species of Some Novel 1H-Benzimidazoles
Vol 46
a
Hakan Goker, * Mehmet Alp, Zeynep Ateꢀs-Alagoz, and Sulhiye Yıldız
a
a
b
¨
¨
aFaculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Tandogan,
Ankara 06100, Turkey
bFaculty of Pharmacy, Department of Microbiology, Ankara University, Tandogan,
Ankara 06100, Turkey
*E-mail: hakan.goker@pharmacy.ankara.edu.tr
Received January 30, 2009
DOI 10.1002/jhet.179
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 47 novel N1-alkylated-2-aryl-5(6)-substituted-1H-benzimidazoles and their three novel
indole analogues were synthesized and evaluated for in vitro antifungal activities against Candida spe-
cies by the tube dilution method. The results showed that compounds 79 and 80, having pyridine at the
position C-2, of benzimidazoles exhibited the greatest activity with MIC values of 6.25–3.12 lg/mL.
Indole analogues 108–110 have no inhibitory activity.
J. Heterocyclic Chem., 46, 936 (2009).
INTRODUCTION
several amines in N,N-dimethylformamide gave 16–33
(Table 3). Their reduction with hydrogen gas by using
palladium carbon or tin/hydrochloric acid produced 34–
59 (Table 4). Condensation of these derivatives with the
sodium metabisulfite adduct of appropriate benzalde-
hydes gave the targeted benzimidazoles 60–73, 75, 78–
80, 83, 84, 90–97, 99–102, 104 [1]. Heck and Nolley [23]
reaction of 73 with (trimethylsilyl)acetylene led to 74a,
whose silyl group was cleaved to yield 5-ethynylbenzimi-
dazole 74. 77 was prepared by diazotation of 76, fol-
lowed by treatment with sodium azide. Acylation of
3-amino-4-(butylamino)benzonitrile with 4-pyridazine
and pyrazine carbonyl chlorides gave the corresponding
monoamide derivatives 81a and 82a, following this cycli-
zation of these compounds with glacial acetic acid and
anhydrous sodium acetate afforded 81 and 82. The nitrile
group of I was converted to carboxyaldehyde 85, by
using diisobutylaluminum hydride (DIBAL), in a moder-
ato yield, and aldehyde group was transformed to the
oxime ether 86. The 1,2,4-oxadiazol-3-yl-1H-benzimida-
zole 88 was obtained by reaction of I first with hydroxyl-
amine to amidoxime 87 and subsequently with acetic
anhydride. In addition, another 1H-benzimidazole-5-car-
bonitrile 89a reacted with sodium azide at high tempera-
ture to yield 5-substituted 1H-tetrazole 89. Benzylic
cleavage of 97 afforded 98 by reduction with hydrogen
gas. Alkylation of tautomeric imidazole NH of 99–102
with butyl bromide in N,N-dimethylformamide gave 103,
We have already reported the synthesis and potent anti-
fungal evaluation of a series of 2-substituted-phenyl-1H-
benzimidazole-5-carbonitriles [1]. The study revealed
that among the synthesized benzimidazoles compound I
exhibited greatest antifungal activity with the MIC of
3.12 lg/mL against Candida albicans, Candida krusei,
Candida glabrata, and Candida parapsilosis (Fig. 1).
We planned to modify the structure of compound I in
order to find more potent new antifungal agents.
RESULTS AND DISCUSSION
Noncommercial starting material o-phenylenediamines
were prepared according to the literature methods, which
are given in Scheme 1. The synthetic pathways for prepa-
ration of the targeted benzimidazoles listed in Table 1 are
shown in Schemes 2 and 3. Nucleophilic displacement of
the chloro group of 1–15 (Table 2), by the reaction with
C
V
2009 HeteroCorporation

September 2009
Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
937
Scheme 1. Synthesis of noncommercial o-phenylenediamines.
105–107 in good yield. For the preparation of 110 which
is the indole analogous of 89a, first 108 was prepared by
the well-known Fischer indole synthesis method (Scheme
3) [24]. Alkylation of this compound gave 109, then bro-
mine was converted to the nitrile with copper(I) cyanide.
The benzimidazoles 60–110 were tested in vitro for
antifungal activity against C. albicans (ATCC 10231),
C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019),
and C. glabrata (Clinical isolate) by the tube dilution
method [25] and the MIC values are listed in Table 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 1
In vitro antifungal activities and formulas of 60–110.
MIC100 (lg/mL)
0
No
R1
R7
R6
R5
R4
R4
L
X
Y
Z
W
C a
C k
C p
C g
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
Cl
CN
F
F
F
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
>50
>50
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
6.25
6.25
25
>50
>50
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
>50
6.25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
12.5
3.12
12.5
>50
25
>50
>50
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
CF3
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
pentyl
butyl
butyl
butyl
Cl
Cl
F
F
F
F
F
F
F
Br
CN
Cl
CN
F
Cl
Cl
Br
F
F
F
F
F
F
CH
CH
CH
CH
CH
CH
CH
CH
N
I
HCBCA
NO2
NH2
N3
NC
NC
NC
NC
CH
CH
CH
N
CH
N
12.5
25
25
25
N
NC
NC
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
>50
25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
CH
CH
CH
CH
CH
CH
CH
CH
Cl
NC
CHO
F
F
F
>50
>50
>50
>50
>50
>50
MeOAN¼CHA
87
88
89
butyl
F
F
F
N
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
butyl
propyl
90
91
92
93
94
95
96
97
butyl
butyl
CH3CO
F
F
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
>50
>50
>50
25
>50
>50
>50
25
>50
>50
>50
3.12
6.25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
>50
>50
25
CN
Br
F
F3C
F
N
N
F
F
F
F
F
F
N
N
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
>50
>50
>50
1.56
1.56
25
12.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
>50
>50
>50
12.5
25
F
F
F
F
N
N
OBn
OH
F
98
99
F
Cl
F
Cl
N
N
N
100
101
102
103
104
105
106
107
108
109
110
I
Cl
Cl
Cl
F
Br
NC
Br
NC
F
F
N
N
butyl
butyl
butyl
butyl
butyl
Cl
Cl
F
F
N
N
Cl
Cl
Cl
Br
NC
F
N
Br
NC
Br
F
F
N
N
>50
>50
>50
>50
1.56
3.12
>50
>50
>50
>50
25
F
F
CH
CH
CH
N
propyl
propyl
butyl
Br
NC
NC
F
F
Flu
25
MIC100 ¼ Minimum inhibitory concentrations, C a, Candida albicans; C k, Candida krusei; C p, Candida parapsilosis; C g, Candida glabrata; I,
formula in Figure 1; Flu, Fluconazole.

September 2009
Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
939
Scheme 2. Synthesis of benzimidazoles 60–107. Reagents (a) Na2S2O5 adduct of the corresponding benzaldehydes; (b) (Trimethylsilyl)-acetylen;
(c) KOH/MeOH; (d) SnCl2/HCl; (e) NaNO2-HCl/NaN3; (f) For 81a: 4-Pyridazinecarboxylic acid and HBTU; For 82a: Pyrazinecarbonyl chloride;
(g) Glacial acetic acid/anhydrous Na-acetate; (h) DIBAL; (i) Methoxyl-amine HCl; (j) NH2OH.HCl, i-Pr2NEt; (k) (CH3CO)2O; (l) Pd.C/H2; and
(m) Butyl bromide/NaH.
The synthesized compounds and reference drugs were
dissolved in dimethyl sulfoxide-water (50%) at a concen-
tration of 400 lg/mL. The concentration was adjusted to
100 lg/mL by fourfold dilution with media culture and
fungi solution at the first tube. Data was not taken for the
initial solution because of the high concentration (12.5%).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Goker, M. Alp, Z. Ateꢀs-Alagoz, and S. Yıldız
¨
940
Vol 46
Scheme 3. Synthesis of indole analogues 108–110. Reagents (a) 40-fluoroacetophenone, trimethylamine; (b) PPA; (c) Propyl bromide, NaH; and (d)
CuCN, N-methyl-2-pyrrolidone.
The result demonstrates that some of the benzimida-
zoles in this series showed the good activity profiles ver-
sus some Candida species. Among of them, compounds
79 and 80 exhibited the greatest activity with MIC val-
ues of 6.25–3.12 lg/mL. These compounds are having
pyridine moiety at the position of C-2 instead of phenyl
in compound I (Fig. 1). Replacement of phenyl moiety
to 4-pyridazine (81) or pyrazine (82) caused to reduce
inhibitory activity. Most of the other electron withdraw-
ing group which could be the bioequivalence of cyano
at the position of C-5 were tested, however, as no better
result were found with them, cyano group was accepted
Table 2
Formulas and some properties of 1–15.
Comp
R7
Cl
R6
Cl
R5
R4
X
Formulas
References, physical and spectral data
1
2
3
4
5
6
Cl
Cl
Cl
Cl
Cl
Cl
C6H3Cl2NO2
C6H3Cl2NO2
C6H3ClFNO2
C6H3Cl2NO2
C6H3BrClNO2
C6H3ClINO2
Commercial
Commercial
Commercial
F
Cl
Br
I
Commercial
mp 69ꢀC, ref. 2, 71–72ꢀC
mp 74ꢀC, ref. 3, 74.5ꢀC;
1H NMR: d 7.28
(d, 1H, J ¼ 8.4 Hz),
7.82 (dd, 1H, J ¼ 2, 8.6 Hz),
8.17 (d, 1H, J ¼ 2 Hz)
ref. 4
7
8
9
10
11
12
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
C6H3BrClNO2
C6H2Cl3NO2
C7H3ClN2O2
C7H3ClN2O2
C7H3ClN2O2
C7H3ClN2O2
Cl
ref. 5
ref. 6
ref. 1
Commercial
mp 65ꢀC,a ref. 7 mp 85ꢀC; IR
(potassium bromide): 2240
(CN) cmꢁ1 1H NMR: d 7.57
;
CN
CN
CN
CN
(t, 1H, J ¼ 7.6 Hz), 7.69 (dd,
1H, J ¼ 1.2, 7.6 Hz), 7.75
(dd, 1H, J ¼ 1.2, 8.5 Hz)
ref. 8, mp 83ꢀC, ref. 9, 84–85ꢀC
Commercial
13
14
15
Cl
CN
COCH3
NO2
F
Cl
Cl
C7H2ClFN2O2
C8H6ClNO3
C6H3ClN2O4
Commercial
aMelting point is not in agreement with the data given in ref. 7. However, our elemental analysis result confirms the structure. Anal. Calcd for
C7H3ClN2O2: C, 46.05; H, 1.66; N, 15.34. Found C, 45.62; H, 1.695; N, 15.17.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
941
Table 3
Formulas and some properties of 16–33.
No
R1
H
R7
Cl
R6
R5
R4
Cl
Formulas
References, physical and spectral data
16
C6H5ClN2O2
mp 108–109, ref. 10 mp 108–108.5; 1H NMR: d 6.7 (dd, 1H, J ¼
1.2, 8.4 Hz), 6.82 (dd, 1H, J ¼ 1.2, 8.5 Hz), 7.16 (t, 1H, J ¼ 8.3)
Oily; 1H NMR: d 0.93 (t, 3H), 1.39 (m, 2H), 1.58 (m, 2H), 3.41 (q,
2H), 6.67 (br.s, 1H), 6.72 (t, 1H), 7.48 (dd, 1H, J ¼ 1.6, 8.2 Hz),
7.91 (dd, 1H, J ¼ 1.6, 8.4 Hz); ms: m/z 229 (100), 231 (33)
Oily, ref. 11
17
n-butyl
C
10H13ClN2O2
18
19
20
21
n-butyl
n-butyl
n-butyl
n-butyl
Cl
C10H13ClN2O2
F
Cl
Br
C
10H13FN2O2
C10H13ClN2O2
10H13BrN2O2
ref. 12
ref. 1
C
Purification: ethyl acetate:hexane (10:90) cc; Oily; 1H NMR: d 0.98
(t, 3H), 1.48 (m, 2H), 1.71 (m, 2H), 3.28 (q, 2H), 6.75 (d, 1H,
J ¼ 8.8), 7.48 (dd, 1H, J ¼ 2.4, 8.8 Hz), 8.03 (br.t, 1H), 8.31
(d, 1H, J ¼ 2.4 Hz); ms: m/z 273 (100), 275 (100)
22
23
n-butyl
n-butyl
I
C10H13IN2O2
Purification: ethyl acetate:hexane (10:90) cc; Oily; 1H NMR: d 0.985
(t, 3H), 1.48 (m, 2H), 1.70 (m, 2H), 3.28 (q, 2H), 6.64 (d, 1H,
J ¼ 9.2 Hz), 7.61 (dd, 1H, J ¼ 2, 9.2 Hz), 8.04 (br.t, 1H), 8.46
(d, 1H, J ¼ 2Hz); ms: m/z 321
Br
C10H13BrN2O2
Purification: ethyl acetate:hexane (20:80) cc; Oily; 1H NMR: d 0.92
(t, 3H), 1.38 (m, 2H), 1.58 (m, 2H), 3.25 (q, 2H), 6.05 (br.s, 1H),
6.68 (t, 1H), 7.67 (dd, J ¼ 1.6, 7.6 Hz, 1H), 7.87 (dd, J ¼ 1.6,
8.4 Hz, 1H); ms: m/z 273 (100), 275 (100)
24
25
26
27
n-butyl
H
Cl
Cl
C10H12Cl2N2O2
C7H5N3O2
Purification: ethyl acetate:hexane (10:90) cc; Oily; 1H NMR: d 0.93
(t, 3H), 1.37 (m, 2H), 1.58 (m, 2H), 3.4 (q, 2H), 6.72 (br.s, 1H),
7.49 (d, 1H), 7.94 (d, 1H); ms: m/z 263 (100), 265 (61), 267(11)
mp 133–135ꢀC, ref. 13 mp 129–130ꢀC; 1H NMR (Deuteriochloro-
form þ D2O): d 6.79 (t, 1H, J ¼ 8 Hz), 7.7 (dd, 1H, J ¼ 1.2,
7.6 Hz), 8.4 (dd, 1H, J ¼ 1.6, 8 Hz)
CN
CN
n-butyl
n-butyl
C11H13N3O2
C11H13N3O2
Purification: ethyl acetate:hexane (40:60) cc; mp 37ꢀC; 1H NMR:
d 0.96 (t, 3H), 1.46 (m, 2H), 1.72 (m, 2H), 3.83 (q, 2H), 6.68 (t, 1H),
7.17 (dd, 1H), 8.35 (dd, 1H), 8.46 (br.s, 1H); ms: m/z 220 (100)
Purification: Cryst. ethanol; mp 83–85ꢀC; 1H NMR: d 1.02 (t, 3H),
1.48 (m, 2H), 1.72 (m, 2H), 3.30 (q, 2H), 6.85 (dd, 1H), 7.15
(d, 1H, J ¼ 1.5 Hz), 8.03 (br.s, 1H), 8.26 (d, 1H, J ¼ 8.4);
ms: m/z 220 (100)
CN
28
29
n-butyl
n-pentyl
CN
CN
C11H13N3O2
C
ref. 1
1
12H15N3O2
Purification: Cryst. ethanol; H NMR: d 0.95 (t, 3H), 1.47 (m, 4H),
1.73 (m, 2H), 3.35 (q, 2H), 6.92 (d, J ¼ 9.1, 1H), 7.58 (dd, 1H),
8.41 (br.s, 1H), 8.51 (d, 1H, J ¼ 1.3)
30
31
n-butyl
n-butyl
CN
C11H13N3O2
Purification: ethyl acetate:hexane (40:60) cc; mp 82–84ꢀC; 1H NMR:
d 0.98 (t, 3H), 1.46 (m, 2H), 1.71 (m, 2H), 3.32 (q, 2H), 7.08 (d,
1H), 7.12 (d, 1H), 7.46 (t, 1H), 8.13 (br.s, 1H); ms: m/z 220 (100)
Purification: Cryst. ethanol; mp 83ꢀC; 1H NMR: d 1.02 (t, 3H), 1.49
(m, 2H), 1.75 (m, 2H), 3.34 (q, 2H), 6.94 (s, 1H), 8.38 (s, 1H),
8.5 (s, 1H); ms: m/z 254 (100), 256 (33)
Cl
CN
C11H12ClN3O2
32
33
n-butyl
n-butyl
COCH3
NO2
C12H16N2O3
C10H13N3O4
ref. 14
ref. 15
as a best pharmacophore at this position. Moreover,
changing the position of cyano group from C-5, to C-4
(91), C-6 (68), and C-7 (66), did not give better result.
In addition, this cyano group was converted to the alde-
hyde (85), oxime (86), oxadiazole (88), and tetrazole
(89), unfortunately activity was reduced again. Because
we have already reported that, the best group was butyl at
position N-1, no more modifications have been done in
this study, only compound 83 with n-pentyl group was
prepared, which also caused to reduce activity. Among
the halogenated compounds, the best results were
obtained with 93 against C. parapsilosis with the MIC
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Goker, M. Alp, Z. Ateꢀs-Alagoz, and S. Yıldız
¨
942
Vol 46
Table 4
Formulas and some properties of 34–59.
Com
R1
R7
Cl
R6
R5
R4
Formulas
References, physical and spectral data
34
35
C6H7ClN2
Oily; 1H NMR: d 3.45 (br.s, 2H), 3.75 (br.s, 2H), 6.62 (m, 2H),
6.814 (m, 1H); ms: m/z 143 (100), 145 (31)
n-butyl
Cl
C
10H15ClN2
Purification: ethyl acetate:hexane (20:80) cc; Oily; 1H NMR: d 0.94
(t, 3H), 1.43 (m, 2H), 1.56 (m, 2H), 2.92 (t, 2H), 3.95 (br.s, 1H),
6.59 (dd, 1H, J ¼ 1.6, 7.2 Hz), 6.76 (m, 2H); ms: m/z 199 (100),
201 (36)
36
n-butyl
Cl
C10H15ClN2
1H NMR: d 0.98 (t, 3H), 1.47 (m, 2H), 1.64 (m, 2H), 3.1 (t, 2H), 3.2
(br.s), 6.61 (m, 3H); ms: m/z 199 (100), 201 (32)
ref. 12
37
38
39
n-butyl
n-butyl
n-butyl
F
Cl
Br
C10H15FN2
C
10H15ClN2
10H15BrN2
ref. 1
C
Oily; 1H NMR: d 0.97 (t, 3H), 1.47 (m, 2H), 1.64 (m, 2H), 3.06
(t, 2H), 3.32 (br.s, 3H), 6.50 (d, 1H, J ¼ 8.8), 6.83 (d, 1H, J ¼
2Hz), 6.89 (dd, 1H, J ¼ 2.4, 8.4 Hz); ms: m/z 243 (100), 245 (100)
Oily; 1H NMR: d 0.96 (t, 3H), 1.46 (m, 2H), 1.63 (m, 2H), 3.06
(t, 2H), 3.32 (br.s, 3H), 6.39 (d, 1H, J ¼ 8.8), 6.98 (d, 1H, J ¼ 2
Hz), 7.09 (dd, 1H, J ¼ 2.1, 8.4 Hz); ms: m/z 291 (100)
Oily; 1H NMR: d 0.91 (t, 3H), 1.45 (m, 2H), 1.58 (m, 2H), 2.91
(t, 2H), 3.28 (br.s, 1H), 3.98 (br.s, 2H), 6.64 (dd, 1H, J ¼ 1.2,
7.6 Hz), 6.74 (t, 1H, J ¼ 7.9 Hz), 6.91 (dd, 1H, J ¼ 1.6, 8 Hz);
ms: m/z 243 (100), 245 (100)
40
41
n-butyl
n-butyl
I
C10H15IN2
Br
C10H15BrN2
42
43
44
n-butyl
n-butyl
Cl
Cl
C10H14Cl2N2
C7H7N3
Waxy; 1H NMR: d 0.92 (t, 3H), 1.38 (m, 2H), 1.92 (m, 2H), 3.43
(t, 2H), 6.72 (d, 1H, J ¼ 1.2), 6.82 (d, 1H, J ¼ 1.2); ms: m/z
233 (100), 235 (63), 237 (11)
1H NMR: d 3.43 (br.s, 2H), 4.11 (br.s, 2H), 6.67 (t, J ¼ 8 Hz, 1H),
6.84 (d, J ¼ 8 Hz, 1H), 6.96 (d, J ¼ 8.4 Hz, 1H); ms: m/z 134
(100)
Oily; 1H NMR (Deuteriochloroform þ D2O): d 0.94 (t, 3H), 1.43
(m, 2H), 1.58 (m, 2H), 3.19 (t, 2H), 3.28 (br.s, 1H), 3.66 (br.s,
2H), 6.85 (m, 2H), 6.95 (dd, 1H, J ¼ 1.6, 7.6 Hz); ms: m/z
190 (100)
CN
CN
C11H15N3
45
46
47
48
n-butyl
n-butyl
n-pentyl
n-butyl
CN
C11H15N3
ms: m/z 190 (100)
ref. 1
CN
CN
C
C
11H15N3
12H17N3
Not isolated, because it was immediately getting black colored
mp 76–78ꢀC; 1H NMR: d 0.97 (t, 3H), 1.44 (m, 2H), 1.65 (m, 2H),
3.09 (t, 2H), 4.28 (br.s), 6.78 (m, 2H), 6.91 (m, 1H); ms: m/z
190 (100)
1H NMR: d 0.98 (t, 3H), 1.44 (m, 2H), 1.7 (m, 2H), 3.2 (t, 2H), 6.6
(s, 1H), 6.9 (s, 1H); ms: m/z 224 (100), 226 (33)
ref. 14
CN
C11H15N3
49
n-butyl
Cl
CN
C11H14ClN3
50
51
52
53
54
55
56
57
58
59
n-butyl
n-butyl
COCH3
NO2
CF3
C12H18N2O
C10H15N3O2
C7H7F3N2
C7H6BrF3N2
C6H6Cl2N2
C6H6F2N2
C6H5F3N2
C6H6Cl2N2
C6H6Br2N2
C8H6N4
ref. 15
Commercial
Br
Cl
CF3
Commercial
refs. 16, and 17
Cl
F
F
F
F
refs. 18, and 19
refs. 19, and 20
F
Cl
Br
CN
Cl
Br
CN
Commercial
ref. 21
ref. 22
values of 3.12 lg/mL. Dramatically reduced antifungal
activity was also seen by changing the benzimidazole ring
to indoles with similar substitutions (108–110). Further
studies are needed to confirm these preliminary results
and in vivo and mode of action studies are required to
optimize the effectiveness of this series of compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
943
EXPERIMENTAL
metabisulfite (0.8 g) in 5 mL H2O was added in portions. The
reaction mixture was stirred vigorously and more ethanol was
added. The mixture was kept in a refrigerator for a several
hours. The precipitate was filtered and dried (yield over 93%).
The mixture of these salts (0.5 mmol) and 34–59 (0.5 mmol)
in N,N-dimethylformamide (1 mL) were heated at 120ꢀC for 4
h. The reaction mixture was cooled, poured into water, and the
solid was filtered.
7-Chloro-2-(4-fluorophenyl)-1H-benzimidazole (60). Purifi-
cation, cc, ethyl acetate-hexane (1:3), mp 208ꢀC, yield 56%.
1H NMR d (DMSO-d6): 7.18 (t, 1H), 7.26 (dd, 1H, J ¼ 0.8,
6.4 Hz), 7.4 (t, 2H), 7.52 (d, 1H, J ¼ 6 Hz), 8.25 (br.s, 2H);
ms: m/z 247 (M þ1, 100), 249 (M þ3, 34). Anal. Calcd for
C13H8ClFN2 HOH: C, 59.00; H, 3.81; N, 10.58. Found C,
58.96; H, 3.80; N, 10.54.
2-(4-Fluorophenyl)-1H-benzimidazole-7-carbonitrile
(61). Purification, cc, ethyl acetate-hexane (1:1), mp 224–
225ꢀC, yield 47.4%. 1H NMR d (DMSO-d6): 7.35 (t, 1H),
7.43 (t, 2H), 7.67 (d, 1H, J ¼ 7.2 Hz), 7.86 (d, 1H, J ¼ 7.2
Hz), 8.26 (br.s, 2H), 13.5 (br.s, 1H); ms: m/z 238 (M þ1,
100). Anal. Calcd for C14H8FN3 0.1 HOH: C, 70.35; H, 3.46;
N, 17.57. Found C, 70.44; H, 3.48; N, 17.15.
2-(4-Fluorophenyl)-5-(trifluoromethyl)-1H-benzimidazole
(62). Purification, cc, ethyl acetate-hexane (1:1), mp 178–
180ꢀC, yield 46.4%. 1H NMR d (DMSO-d6): 7.45 (m, 2H),
7.54 (dd, 1H, J ¼ 1.2, 8.8 Hz), 7.79 (d, 1H, J ¼ 8 Hz), 7.96
(s, 1H), 8.26 (m, 2H), 13.35 (br.s, 1H); ms: m/z 281 (M þ1,
100). Anal. Calcd for C14H8F4N2: C, 60.00; H, 2.88; N, 10.00.
Found C, 59.63; H, 2.89; N 9.93.
Mp were measured with a capillary melting point apparatus
Electrothermal 9100 and are uncorrected. The 1H and 13C NMR
spectra were recorded with VARIAN Mercury 400 FT-NMR
spectrophotometer, d scale (ppm) in deuteriochloroform, if not
stated otherwise. LC/MS analyses were performed with Waters
Alliance (equipped with a diode array UV detection monitoring
at 254 nm) and Micromass ZQ by using ESI(þ) method, if not
stated otherwise. Elemental analyses were taken on a Leco 932
CHNS analyser; cc, column chromatography. Compound 89a
was synthesized as described in our previous study [1].
3-Chloro-2-nitrobenzonitrile (12). The mixture of 0.5 g
(2.48 mmol) of 3-chloro-2-nitrobenzoic acid toluene (3 mL) and
thionyl chloride (2 mL) were heated at 80ꢀC for 4 h. Excess of
thionyl chloride and solvent were evaporated, then the residue
was stirred in ammonium hydroxide (5 mL) at room tempera-
ture for 1 h. The formed precipitate 3-chloro-2-nitrobenzamide
was collected. The solid (0.46 g, 2.3 mmol) was added to a solu-
tion of PPSA (20 mL), and the mixture was refluxed for 48 h.
The reaction mixture was directly carried out to a long silica gel
column and eluted with hexanes (200 mL), then dichlorome-
thane. Concentration of the dichloromethane gave the desired
nitrile, as a white solid, 0.14 g (33.4%). Then eluting with 5%
methanol in dichloromethane recovered 0.16 g of starting mate-
rial. See Table 2 for spectral data.
2-Amino-3-nitrobenzonitrile (25). The mixture of 9 (0.3 g,
1.65 mmol) and saturated ethanolic ammonia solution (30 mL)
were heated in a sealed tube at 120ꢀC for 5 h, ethanol was
removed, and washing with water of the residue gave pure
compound, 0.2 g (74 %). See Table 3 for spectral data.
General procedure for synthesis of (17–24, 26–33). To a
solution of 1–15 (5 mmol) in ethanol (5 mL), butyl or pentyl
amine (15 mmol) was added and heated under reflux until the
starting material was consumed (determined by TLC, 8–48 h).
The mixture was cooled, water was added. The resultant yel-
low residue was crystallized from ethanol or purified by cc by
using the mixture of ethyl acetate-hexane (30–40:70–60) as
eluent (Table 3).
General procedure for synthesis of (34, 37, 38, 43–51, 55,
56). Appropriate nitro derivatives (3 mmol) in ethanol
(30 mL) were reduced by hydrogenation using 40 psi of H2
and 10% Pd-C until cessation of H2 uptake. The catalyst was
filtered off on a bed of Celite, washed with ethanol, and the
filtrate was concentrated. This procedure was carried out at the
atmospheric pressure for compound 33 (Table 4).
1-Butyl-7-chloro-2-phenyl-1H-benzimidazole (63). Purification,
cc, ethyl acetate-hexane (1:4), oily, yield 51.5%. 1H NMR d:
0.8 (t, 3H), 1.18 (m, 2H), 1.76 (m, 2H), 4.49 (t, 2H), 7.2 (t,
1H), 7.26 (dd, 1H, J ¼ 1.2, 7.4 Hz), 7.53 (m, 3H), 7.67 (m,
2H), 7.71 (dd, 1H, J ¼ 1.2, 8 Hz); ms: m/z 285(M þ1, 100),
287 (M þ3, 36). Anal. Calcd for C17H17ClN2: C, 71.69; H,
6.02; N, 9.84. Found C, 71.24; H, 6.15; N, 9.77.
1-Butyl-7-chloro-2-(4-fluorophenyl)-1H-benzimidazole
(64). Purification, cc, ethyl acetate-hexane (1:3), mp 60ꢀC,
yield 32%. 1H NMR d: 0.8 (t, 3H), 1.18 (m, 2H), 1.75 (m,
2H), 4.46 (t, 2H), 7.25 (m, 4H), 7.66 (m, 3H); ms: m/z 303 (M
þ1, 100), 305 (M þ3, 35). Anal. Calcd for C17H16ClFN2: C,
67.44; H, 5.33; N, 9.25. Found C, 67.29; H, 5.27; N, 9.23.
7-Bromo-1-butyl-2-(4-fluorophenyl)-1H-benzimidazole
(65). Purification, cc, ethyl acetate-hexane (1:1), mp 62ꢀC,
yield 53%. 1H NMR d: 0.79 (t, 3H), 1,18 (m, 2H), 1.73 (m, 2H),
4.48 (t, 2H), 7.15 (t, 1H), 7.24 (m, 2H), 7.46 (d, 1H, J ¼ 8 Hz),
7.66 (m, 2H), 7.74 (d, 1H, J ¼ 8.4 Hz); ms: m/z 347 (M þ1,
100), 349 (M þ3, 100). Anal. Calcd for C17H16BrFN2 0.2 HOH:
C, 58.20 H; 4.71; N, 7.98. Found C, 58.11; H, 4.47; N, 8.08.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazole-7-carbonitrile
(66). Purification, cc, ethyl acetate-hexane (2:8), mp 53–54ꢀC,
yield 40.5%. 1H NMR d: 0.86 (t, 3H), 1.3 (m, 2H), 1.85 (m,
2H), 4.54 (t, 2H), 7.29 (m, 2H), 7.44 (t, 1H), 7.71 (d, 1H, J ¼
7.2 Hz), 7.77 (m, 2H), 8.15 (d, 1H, J ¼ 8.4 Hz); 13C NMR d:
164.2 (d, J ¼ 250 Hz), 155.1, 143.8, 134.6, 131.75 (d, J ¼ 8.3
Hz), 129.4, 125.7 (d, J ¼ 2.5 Hz), 125.5, 123.0, 117.1, 116.4
(d, J ¼ 22.1 Hz), 95.1, 45.4, 33.3, 19.5, 13.67; ms: m/z 294
(M þ1, 100). Anal. Calcd for C18H16FN3: C, 73.70; H, 5.50;
N, 14.32. Found C, 73.84; H, 5.61; N, 14.09.
General procedure for synthesis of (35, 36, 39–42,
54). Compound 17, 20–23 (1 mmol), tin(II) chloride dihydrate
(0.75 g, 3.33 mmol), a granule tin in the mixture of ethanol (3
mL), hydrochloric acid (3 mL), (for 20 HBr and for 21 sulfuric
acid were used without tin(II) chloride), and 1.5 mL water
were stirred at room temperature for 6–7 h. For compound 40,
the reaction mixture was heated under reflux for 3 h. Then,
water and ethyl acetate were added. The pH was rendered ba-
sic by addition of an ammonium solution. The slurry was fil-
tered on a Buchner, the resulting solid was washed with ethyl
acetate. The combined organic phases were concentrated
(Table 4).
General procedure for synthesis of 60–73, 75, 78–80, 83,
84, 90–97, 99–102, 104. The corresponding benzaldehydes
(7.5 mmol) were dissolved in 25 mL ethanol and sodium
1-Butyl-6-chloro-2-(4-fluorophenyl)-1H-benzimidazole
(67). Purification, cc, ethyl acetate-hexane (1:2), mp 100–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Goker, M. Alp, Z. Ateꢀs-Alagoz, and S. Yıldız
¨
944
Vol 46
101ꢀC, yield 39.7%. 1H NMR d: 0.88 (t, 3H), 1.27 (m, 2H),
1.75 (m, 2H), 4.16 (t, 2H), 7.19–7.28 (m, 3H), 7.39 (d, 1H, J
¼ 1.6 Hz), 7.65–7.73 (m, 3H); 13C NMR d: 165.2 (d, J ¼ 249
Hz), 153.8, 141.9, 136.5, 131.5 (d, J ¼ 8.4 Hz), 128.7, 126.6,
123.3, 121, 116.2 (d, J ¼ 22 Hz), 110.4, 44.9, 31.9, 20.1,
13.7; ms: m/z 303 (M þ1, 100) 305 (M þ3, 40). Anal. Calcd
for C17H16ClFN2: C, 67.44; H, 5.33; N, 9.25. Found C, 67.47;
H, 5.31; N, 9.17.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazole-6-carbonitrile
(68). Purification, cc, ethyl acetate-hexane (1:3), mp 128ꢀC,
yield 72% [26]. 1H NMR d: 0.88 (t, 3H), 1.28 (m, 2H), 1.79
(m, 2H), 4.23 (t, 2H), 7.25 (m, 2H), 7.55 (d, 1H, J ¼ 8.4 Hz),
7.71 (m, 2H), 7.74 (s, 1H), 7.84 (d, 1H, J ¼ 8 Hz); 13C NMR
d: 164.2 (d, J ¼ 250 Hz), 156.2, 146.2, 135.5, 131.5 (d, J ¼
8.4 Hz), 126.2, 125.9, 121.1, 120.1, 116.4 (d, J ¼ 18 Hz),
115.3, 105.8, 45.2, 32.1, 20.2, 13.7; ms: m/z 294(M þ1,100).
Anal. Calcd for C18H16FN3: C, 73.70; H, 5.50; N, 14.32.
Found C, 73.48; H, 5.56; N, 14.15.
162ꢀC, yield 62%. 1H NMR d: 0.86 (t, 3H), 1.27 (m, 2H),
1.77 (m, 2H), 4.26 (t, 2H), 7.25 (m, 2H), 7.45 (d, 1H, J ¼ 9.2
Hz), 7.71 (m, 2H), 8.21 (dd, 1H, J ¼ 2.4, 9 Hz), 8.64 (d, 1H,
J ¼ 2.4 Hz); ms: m/z 314 (M þ1, 100). Anal. Calcd for
C17H16FN3O2: C, 65.17; H, 5.15; N, 13.41. Found C, 65.37;
H, 5.20; N, 13.35.
1-Butyl-2-(pyridin-2-yl)-1H-benzimidazole-5-carbonitrile
(78). Purification, cc, ethyl acetate-hexane (1:1), mp 117–
119ꢀC, yield 38%. 1H NMR d: 0.93 (t, 3H), 1.37 (m, 2H),
1.85 (m, 2H), 4.85 (t, 2H), 7.41 (m, 1H), 7.51 (d, 1H, J ¼ 8.8
Hz), 7.57 (dd, 1H, J ¼ 1.6, 8.2 Hz), 7.88 (td, 1H, J ¼ 1.6, 8
Hz), 8.14 (d, 1H, J ¼ 0.8 Hz), 8.39 (d, 1H, J ¼ 7.6 Hz), 8.72
(dd, 1H, J ¼ 1, 4 Hz); 13C NMR d: 152.5, 150.0, 149.0,
142.3, 139.5, 137.2,126.5, 125.3, 125.2, 124.6, 120.1, 111.4,
105.8, 45.9, 32.3, 20.2, 13.8; ms: m/z 277 (M þ1, 100). Anal.
Calcd for C17H16N4 0.15 C4H8O2: C, 73.01; H, 5.98; N, 19.35.
Found C, 73.42; H, 5.88; N, 19.12.
1-Butyl-2-(pyridin-3-yl)-1H-benzimidazole-5-carbonitrile
(79). Purification, cc, ethyl acetate-hexane (2:1), mp 130–
131ꢀC, yield 52%. 1H NMR d: 0.85 (t, 3H), 1.26 (m, 2H),
1.77 (m, 2H), 4.25 (t, 2H), 7.44–7.59 (m, 3H), 8.06 (d, 1H, J
¼ 7.6 Hz), 8.10 (s, 1H), 8.77 (d, 1H, J ¼ 4.8 Hz), 8.94 (d,
1H, J ¼ 1.2 Hz); 13C NMR d: 153.4, 151.5, 149.8, 142.9,
138.6, 137.1, 126.6, 126.3, 125.4, 123.9, 119.9, 111.6, 106.2,
45.2, 32.2, 20.1, 13.7; ms: m/z 277(M þ1, 100). Anal. Calcd
for C17H16N4: C, 73.87; H, 5.84; N, 20.27. Found C, 73.76; H,
5.82; N, 20.01.
1-Butyl-5-fluoro-2-(4-fluorophenyl)-1H-benzimidazole
(69). Purification, cc, ethyl acetate-hexane (1:3), mp 82–83ꢀC,
yield 29%. 1H NMR d: 0.86 (t, 3H), 1.26 (m, 2H), 1.77 (m,
2H), 4.19 (t, 2H), 7.06 (m, 1H), 7.25 (m, 2H), 7.32 (m, 1H),
7.46 (dd, 1H, J ¼ 2, 9.4 Hz), 7.67 (m, 2H); ms: m/z 287(M
þ1, 100). Anal. Calcd for C17H16F2N2: C, 71.31; H, 5.63; N,
9.78. Found C, 71.26; H, 5.49; N, 9.84.
1-Butyl-5-chloro-2-(4-fluorophenyl)-1H-benzimidazole
(70). Purification, cryst., ethyl acetate-hexane, mp 81–82ꢀC,
1
yield 31.5%. H NMR d: 0.87 (t, 3H), 1.25 (m, 2H), 1.76 (m,
1-Butyl-2-(pyridin-4-yl)-1H-benzimidazole-5-carbonitrile
(80). Purification, cc, chloroform-isopropanol (10:2), mp 135–
2H), 4.18 (t, 2H), 7.18–7.37 (m, 4H), 7.68 (m, 2H), 7.77 (d,
1H, J ¼ 2 Hz); 13C NMR d: 163.9 (d, J ¼ 250 Hz), 154.1,
144.1, 134.4, 131 (d, J ¼ 8.3 Hz), 128.2, 126.6, 123.4, 119.9,
116.2 (d, J ¼ 21 Hz), 111.1, 44.9, 32, 20.1, 13.7; ms: m/z 303
(M þ1, 100) 305 (M þ3, 40). Anal. Calcd for C17H16ClFN2:
C, 67.44; H, 5.33; N, 9.25. Found C, 67.33; H, 5.25; N, 9.24.
1-Butyl-5-chloro-2-(pyridin-4-yl)-1H-benzimidazole (71). Puri-
fication, cryst., ethyl acetate-hexane, mp 96–98ꢀC, yield 34%.
1H NMR d: 0.82 (t, 3H), 1.22 (m, 2H), 1.74 (m, 2H), 4.18
(t, 2H), 7.25 (dd, 1H, J ¼ 2, 8.6 Hz), 7.29 (dd, 1H, J ¼ 0.8,
8.8 Hz), 7.6 (dd, 2H, J ¼ 1.6, 4.6 Hz), 7.75 (t, 1H), 8.75 (dd,
2H, J ¼ 1.6, 4.4 Hz); ms: m/z 286 (M þ1, 100), 288 (M þ3,
35). Anal. Calcd for C16H16ClN3 0.25 HOH: C, 66.2; H, 5.73;
N, 14.48. Found C, 66.4; H, 5.56; N, 14.29.
1-Butyl-5-bromo-2-(4-fluorophenyl)-1H-benzimidazole
(72). Purification, ethyl acetate-hexane (2:8), mp 77–79ꢀC,
yield 84% [27]. 1H NMR d: 0.86 (t, 3H), 1.25 (m, 2H), 1.75
(m, 2H), 4.18 (t, 2H), 7.19–7.31 (m, 3H), 7.4 (dd, 1H, J ¼
1.6, 8.8 Hz), 7.68 (m, 2H), 7.92 (d, 1H, J ¼ 1.2 Hz); 13C
NMR d: 164.2 (d, J ¼ 249 Hz), 153.9, 144.6, 134.8, 131.5 (d,
J ¼ 8.4 Hz), 126.6, 126, 123, 116.4 (d, J ¼ 22 Hz), 115.6,
111.55, 44.9, 32, 20.1, 13.7; ms: m/z 347 (M þ1, 100) 349 (M
þ3, 100). Anal. Calcd for C17H16BrFN2: C, 58.80; H, 4.64; N,
8.07. Found C, 58.51; H, 4.68; N, 8.13.
1
137ꢀC, yield 47%. H NMR d (DMSO-d6): 0.74 (t, 3H), 1.12
(m, 2H), 1.62 (m, 2H), 4.41 (t, 2H), 7.74 (dd, 1H, J ¼ 1,6, 8.4
Hz), 7.83 (dd, 2H, J ¼ 1.6, 4.4 Hz), 7.95 (d, 1H, J ¼ 8.8 Hz),
8.3 (d, 1H, J ¼ 1.4 Hz), 8.82 (dd, 2H, J ¼ 1.6, 4.4 Hz); 13C
NMR d (DMSO-d6): 153.5, 151.1, 142.6, 139.4, 137.8, 127,
125.4, 124.1, 120.4, 113.6, 105.4, 44.9, 31.9, 19.8, 13.9; ms:
m/z 277(M þ1, 100). Anal. Calcd for C17H16N4. 0.5 HOH: C,
71.55; H, 6.00; N, 19.63. Found C, 71.28; H, 5.73; N, 19.33.
1-Pentyl-2-phenyl-1H-benzimidazole-5-carbonitrile
(83). Purification, cc, ethyl acetate-hexane (1:3), mp 124–
125ꢀC, yield 17.5%. 1H NMR d: 0.83 (t, 3H), 1.24 (m, 4H),
1.8 (m, 2H), 4.25 (t, 2H), 7.47 (d, 1H, J ¼ 7.6 Hz), 7.56 (m,
4H), 7.7 (m, 2H), 8.13 (d, 1H, J ¼ 0.8 Hz); 13C NMR d:
156.4, 142.9, 138.5, 130.6, 129.8, 129.4, 129.1, 126.2, 125.2,
120.1, 111.3, 105.7, 45.2, 29.6, 28.9, 22.2, 14.0; ms: m/z 290
(M þ1, 100). Anal. Calcd for C19H19N3: C, 78.86; H, 6.62; N,
14.52. Found C, 78.66; H, 6.72; N, 14.39.
1-Butyl-6-chloro-2-(4-fluorophenyl)-1H-benzimidazole-5-
carbonitrile (84). Purification, cc, ethyl acetate-hexane (1:4),
1
mp 138ꢀC, yield 34%. H NMR d: 0.89 (t, 3H), 1.28 (m, 2H),
1.77 (m, 2H), 4.21 (t, 2H), 7.27 (t, 2H), 7.53 (s, 1H), 7.7 (m,
2H), 8.1 (s, 1H); 13C NMR d: 164.1 (d, J ¼ 251 Hz), 156.0,
141.3, 138.9, 131.3 (d, J ¼ 8.4 Hz), 130.2, 126.1, 125.4 (d, J
¼ 3.1 Hz), 116.9, 116.3 (d, J ¼ 22 Hz), 111.7, 107.0, 45.0,
31.7, 19.8, 13.4; ms: m/z 328 (M þ1, 100) 330 (M þ3, 35).
Anal. Calcd for C18H15ClFN3: C, 65.96; H, 4.61; N, 12.82.
Found C, 65.75; H, 4.59; N, 12.87.
1-[1-Butyl-2-(4-fluorophenyl)-1H-benzimidazol-5-yl]etha-
none (90). Purification, cc, ethyl acetate-hexane (1:3), mp 75–
77ꢀC, yield 21.5%. 1H NMR d: 0.88 (t, 3H), 1.27 (m, 2H),
1.83 (m, 2H), 2.68 (s, 3H), 4.35 (t, 2H), 7.28 (m, 2H), 7.56 (d,
1H, J ¼ 8.4 Hz), 7.85 (m, 2H), 8.11 (d, 1H, J ¼ 8.8 Hz), 8.46
1-Butyl-5-iodo-2-(4-fluorophenyl)-1H-benzimidazole
(73). Purification, ethyl acetate-hexane (2:8), mp 125–126ꢀC,
yield 88%. 1H NMR d: 0.86 (t, 3H), 1.25 (m, 2H), 1.75 (m,
2H), 4.18 (t, 2H), 7.15–7.29 (m, 3H), 7.58 (d, 1H, J ¼ 8.8
Hz), 7.69 (m, 2H), 8.14 (s, 1H); ms: m/z 395 (M þ1, 100).
Anal. Calcd for C17H16FIN2: C, 51.79; H, 4.09; N, 7.11. Found
C, 51.72; H, 4.24; N,7.20.
1-Butyl-5-nitro-2-(4-fluorophenyl)-1H-benzimidazole
(75). Purification, cc, ethyl acetate-hexane (3:7), mp 160–
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Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
945
(s, 1H); 13C NMR d: 198.1, 163.9 (d, J ¼ 250 Hz), 154.8, 142.8,
139.1, 132.5, 131.4 (d, J ¼ 8.5 Hz), 126.4 8 (d, J ¼ 3.4 Hz),
123.2, 121.8, 116.3 (d, J ¼ 22 Hz), 110.3, 44.9, 32.1, 26.9, 20.1,
13.7; ms: m/z 311 (M þ1,100). Anal. Calcd for C19H19FN2O: C,
73.53; H, 6.17; N, 9.03. Found C, 73.82; H, 6.53; N, 8.58.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazole-4-carbonitrile
(91). Purification, cc, ethyl acetate-hexane (2:8), mp 83–84ꢀC,
71.4%. 1H NMR d (DMSO-d6): 7.31 (s, 2H), 7.43 (t, 2H),
8.38 (m, 2H), 13.48 (br.s, 1H); ms: m/z 281 (M þ1, 100) 283
(M þ3, 72) 285 (M þ5, 15). Anal. Calcd for C13H7Cl2FN2.
0.25 C4H8O2. 0.4 HOH: C, 54.18; H, 3.18; N, 9.03. Found C,
54.03; H, 3.07; N, 9.07.
5,6-Dibromo-2-(4-fluorophenyl)-1H-benzimidazole
(101). Purification, cryst., ethanol, mp 273–275ꢀC, yield
1
1
yield 44.5%. H NMR d: 0.87 (t, 3H), 1.26 (m, 2H), 1.76 (m,
68.4%. H NMR d (DMSO-d6): 7.4 (m, 2H), 7.96 (s, 2H), 8.2
2H), 4.24 (t, 2H), 7.25 (m, 2H), 7.35 (t, 1H), 7.63 (dd, 2H, J
¼ 1.6, 7.6 Hz), 7.74 (m, 2H); 13C NMR d: 164.1 (d, J ¼ 250
Hz), 155.2, 144.1, 136.1, 131.8 (d, J ¼ 8.4 Hz), 127.5, 126 (d,
J ¼ 3.1 Hz), 122.6, 117.0, 116.4 (d, J ¼ 21.3 Hz), 115.0,
103.3, 45.1, 32.0, 20.0, 13.6; ms: m/z 294 (M þ1,100). Anal.
Calcd for C18H16FN3: C, 73.70; H, 5.50; N, 14.33. Found C,
74.19; H, 5.74; N, 13.94.
(m, 2H); ms: m/z 369 (M þ1, 50), 371 (M þ3, 100), 373 (M
þ5, 48). Anal. Calcd for C13H7Br2FN2 0.25 HOH: C, 41.69;
H, 2.02; N, 7.48. Found C, 41.50; H, 1.99; N, 7.61.
2-(4-Fluorophenyl)-1H-benzimidazole-5,6-dicarbonitrile
(102). Purification, cc, (1) ethyl acetate-hexane (1:1), (2) ethyl
acetate, (3) ethyl acetate-ethanol (95:5), mp > 300ꢀC, yield
59.8%. 1H NMR d (DMSO-d6): 7.48 (t, 2H), 8.31 (m, 2H),
8.44 (s, 2H); ms: m/z 263 (M þ1,100). Anal. Calcd for
C15H7FN4. 0.75 HOH: C, 65.33; H, 3.11; N, 20.32. Found C,
64.94; H, 3.76; N, 20.53.
7-Bromo-5-(trifluoromethyl)-2-phenyl-1H-benzimidazole
(92). Purification, cc, ethyl acetate-hexane (1:1), mp 179–
1
181ꢀC, yield 59%. H NMR d (DMSO-d6): 7.57 (m, 3H), 7.72
(s, 1H), 7.88 (s, 1H), 8.2 (d, 2H, J ¼ 5.2 Hz), 13.98 (br.s,
1H); ms: m/z 341 (M þ1,100) 343 (M þ3,100). Anal. Calcd
for C14H8BrF3N2: C, 49.29; H, 2.36; N, 8.21. Found C, 49.1;
H, 2.41; N, 8.17.
5,6-Difluoro-2-phenyl-1H-benzimidazole (93). Purification,
cc, ethyl acetate-hexane (1:1), mp 213–215ꢀC, yield 77%. 1H
NMR d (DMSO-d6): 7.43 (m, 5H), 7.99 (d, 2H, J ¼ 6.8 Hz),
13.03 (br.s, 1H); ms: m/z 231 (M þ1,100). Anal. Calcd for
C13H8F2N2: C, 67.82; H, 3.50; N, 12.17. Found C, 68.00; H,
3.57; N, 11.98.
1-Butyl-5,7-dichloro-2-(4-fluorophenyl)-1H-benzimidazole
(104). Purification, cc, (1) dichloro-methane-hexane (2:8) (2)
1
ethyl acetate-ethanol (1:9), mp 58ꢀC, yield 27.3%. H NMR d:
0.81 (t, 3H), 1.17 (m, 2H), 1.74 (m, 2H), 4.44 (t, 2H), 7.25
(m, 3H), 7.65 (m, 3H); 13C NMR d: 163.8 (d, J ¼ 250 Hz),
155.8, 145.6, 131.6 (d, J ¼ 8.4 Hz), 130.1, 128.0, 126.0 (d, J
¼ 3.8 Hz), 124.5, 118.6, 116,8, 116.1 (d, J ¼ 22 Hz), 45.7,
34.0, 19.4, 13.4; ms: m/z 337 (M þ1, 100) 339 (M þ3, 60)
341 (M þ5, 11). Anal. Calcd for C17H15Cl2FN2: C, 60.55; H,
4.48; N, 8.31. Found C, 60.14; H, 4.44; N, 8.32.
5,6-Difluoro-2-(4-fluorophenyl)-1H-benzimidazole (94). Puri-
fication, cc, ethyl acetate-hexane (1:2), mp 207–209ꢀC, yield
81%. H NMR d (DMSO-d6): 7.4 (m, 2H), 7.64 (t, 2H), 8.17
1-Butyl-5-trimethylsilanylethylnyl-2-(4-fluorophenyl)-1H-
benzimidazole (74a). To the mixture of 73 (0.69 mmol, 0.272
g) and (trimethylsilyl)acetylene (0.081g) in N,N-dimethyl
formamide (1 mL) and triethylamine (1 mL) 10 mg of bis(tri-
phenyl-phosphine)palladium (II) chloride and 2 mg of cop-
per(I) iodide were added, and the mixture was stirred for 4.5 h
at 45ꢀC. The solvent was then removed in vacuo and the
resulting residue was dissolved in acetonitrile and ether and
washed with water. The solvent was removed in vacuo. The
crude product was used without purification, yield 0.100 g.
ms: m/z 365 (M þ1, 100).
1
(m, 2H); ms: m/z 249 (M þ1,100). Anal. Calcd for
C13H7F3N2: C, 62.91; H, 2.84; N, 11.29. Found C, 63.04; H,
2.84; N, 11.28.
5,6,7-Trifluoro-2-phenyl-1H-benzimidazole (95). Purification,
cryst., ethyl acetate-hexane, mp 215–216ꢀC, yield 77%. 1H
NMR d (DMSO-d6): 7.4–7.66 (m, 4H), 8.17 (dd, 2H, J ¼ 1.2,
8 Hz); ms: m/z 249 (M þ1,100). Anal. Calcd for C13H7F3N2.
0.5 HOH: C, 60.70; H, 3.13; N, 10.89. Found C, 60.75; H,
3.06; N, 10.96.
1-Butyl-5-ethynyl-2-(4-fluorophenyl)-1H-benzimidazole
(74). 0.1 g (0.27 mmol) of 74a and 1N potassium hydroxide
(0.5 mL) was added 2.5 mL methanol. The mixture was stirred
for 1.5 h at 25ꢀC. The solvent was then removed in vacuo.
The residue was purified by cc chloroform-ethyl acetate
5,6-Difluoro-2-(pyridin-4-yl)-1H-benzimidazole (96). Purifi-
cation, cc, ethyl acetate-ethanol (95:5) mp > 300ꢀC, yield
1
61.5%. H NMR d (DMSO-d6): 7.71 (br.s, 2H), 8.04 (m, 2H),
8.74 (m, 2H), 13.5 (br.s, 1H); ms: m/z 232 (M þ1,100). Anal.
Calcd for C12H7F2N3: C, 62.34; H, 3.05; N, 18.17. Found C,
62.77; H, 3.29; N, 17.65.
1
(20:0.5), mp 114–115ꢀC, yield 31%. H NMR d: 0.86 (t, 3H),
1.26 (m, 2H), 1.76 (m, 2H), 3.06 (s, 1H), 4.19 (t, 2H), 7.24
(m, 2H), 7.34 (d, 1H, J ¼ 8.8 Hz), 7.45 (dd, 1H, J ¼ 1.6, 8.2
Hz), 7.69 (m, 2H), 7.96 (s, 1H); 13C NMR d: 163.7 (d, J ¼
249 Hz), 153.9, 142.8, 135.9, 131.24 (d, J ¼ 8.4Hz), 126.9,
126.5 (d, J ¼ 2.8 Hz), 124.1, 116.0, 116.02 (d, J ¼ 22.1 Hz),
110.2, 84.4, 75.7, 44.6, 31.9, 19.9, 13.5; ms: m/z 293 (M þ1,
100). Anal. Calcd for C19H17FN2: C, 78.05; H, 5.86; N, 9.58.
Found C, 77.69; H, 5.88; N, 9.46.
2-[4-(Benzyloxy)phenyl]-5,6-difluoro-1H-benzimidazole
(97). Purification, cc, ethyl acetate-hexane (1:2), mp 215–
1
217ꢀC, yield 33.7%. H NMR d (DMSO-d6): 5.17 (s, 2H), 7.16
(d, 2H, J ¼ 9.2 Hz), 7.32–7.52 (m, 6H), 7.64 (m, 1H), 8.05 (d,
2H, J ¼ 8.8 Hz), 12.98 (s, 1H); ms: m/z 337 (M þ1,100). Anal.
Calcd for C20H14F2N2O. 0.1 C4H8O2. 0.25 HOH: C, 70.07;
H, 4.41; N, 8.01. Found C, 70.04; H, 4.13; N, 8.14.
5,6-Dichloro-2-(4-fluorophenyl)-1H-benzimidazole (99). Puri-
fication, cryst., ethyl acetate-hexane, mp 278–280ꢀC, yield
69.5%. 1H NMR d: 7.19 (m, 2H), 7.58 (s, 1H), 7.82 (s, 1H),
8.17 (m, 2H); ms: m/z 281 (M þ1,100) 283 (M þ3, 63) 285
(M þ5, 13). Anal. Calcd for C13H7Cl2FN2: C, 55.54; H, 2.51;
N, 9.97. Found C, 55.52; H, 2.46; N, 9.92.
5-Amino-1-butyl-2-(4-fluorophenyl)-1H-benzimidazole HCl
(76). Compound 75 (0.24 g, 0.767 mmol), tin(II) chloride
dihydrate (0.375 g, 1.66 mmol), a granule tin in the mixture of
ethanol (2 mL), hydrochloric acid (2 mL), and 1 mL water
were stirred at 50ꢀC for 2 h. Then water was added, pH was
rendered basic by addition of dilute sodium hydroxide solu-
tion, extracted with ethyl acetate. The slurry was filtered on a
Buchner, the resulting solid was washed with ethyl acetate.
4,7-Dichloro-2-(4-fluorophenyl)-1H-benzimidazole (100). Puri-
fication, cc, ethyl acetate-hexane (2:8), mp 242ꢀC, yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Goker, M. Alp, Z. Ateꢀs-Alagoz, and S. Yıldız
¨
946
Vol 46
The combined organic phases was concentrated, crystallization
of crude product from ethanolic hydrogen chloride gave 76,
whole was stirred and reflux overnight. The reaction mixture
was evaporated, washed with sodium carbonate solution (5%),
extracted with ethyl acetate, and washed with water. The or-
ganic layer was dried over sodium sulfate, and evaporated.
The residue was purified by silicagel cc (ethyl acetate-hexane,
50%), mp 130–133ꢀC, yield 0.11 g, 37.28%. 1H NMR
(DMSO-d6): d 0.87 (t, 3H), 1.33 (m, 2H), 1.49 (m, 2H), 3.12
(q, 2H), 6.16 (t, 1H, J ¼ 5.6 Hz, deuterium oxide-exchange-
able), 6.74 (m, 1H), 7.48 (m, 2H), 8.84 (m, 1H), 8.91 (d, 1H,
J ¼ 2.8 Hz), 9.23 (d, 1H, J ¼ 1.6 Hz), 10.16 (s, 1H, deuterium
oxide-exchangeable); 13C NMR (DMSO-d6): d 163.4, 148.5,
148.2, 145.7, 144.6, 143.9, 132.7, 131.6, 122.86, 120.7,
111.25, 95.8, 42.69, 31.1, 20.3, 14.4; ms: m/z 296 (M þ1,
100).
1-Butyl-2-(pyrazin-2-yl)-1H-benzimidazole-5-carbonitrile
(82). 0.1 g (0.33 mmol) of 82a and 0.1 g of sodium acetate
was dissolved in 1 mL glacial acetic acid. The mixture was
stirred for 4.5 h at 100ꢀC. Then poured into ice-water and fil-
tered. The precipitate was purified by silicagel cc (ethyl ace-
tate-hexane 1:1), mp 174–175ꢀC, yield 33%. 1H NMR d
(DMSO-d6): 0.87 (t, 3H), 1.3 (m, 2H), 1.77 (m, 2H), 4.82 (t,
2H), 7.77 (d, 1H, J ¼ 8 Hz), 7.98 (d, 1H, J ¼ 8.4 Hz), 8.37
(s, 1H), 8.84 (dd, 2H, J ¼ 2.4, 10.2 Hz), 9.51 (s, 1H); 13C
NMR d (DMSO-d6): 150.3, 146.1, 145.9, 145.5, 144.3, 142.1,
139.9, 127.3, 125.6, 120.3, 113.5, 105.6, 45.7, 32.4, 20.0, 14.1;
ms: m/z 278 (M þ1, 100). Anal. Calcd for C16H15N5: C,
69.30; H, 5.45; N, 25.25. Found C, 69.00; H, 5.44; N, 24.84.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazol-5-carboxalde-
hyde (85). To a solution of I (0.293 g, 1 mmol) in dry
dichloromethane (20 mL), 3 mL of DIBAL (1.0M solution in
dichloromethane) was added and the mixture was heated at
reflux for 3h under nitrogen atmosphere. Cool dilute sulfuric
acid (15 mL) was added and stirred overnight, dichlorome-
thane was removed and the residue was neutralized with dilute
sodium carbonate solution, then extracted with ethyl acetate
and evaporated. The residue was purified by silicagel cc (ethyl
acetate-hexane 2:3), mp 85–86ꢀC, yield 31.5%. 1H NMR d:
0.885 (t, 3H), 1.29 (m, 2H), 1.79 (m, 2H), 4.26 (t, 2H), 7.26
(m, 2H), 7.52 (d, 1H, J ¼ 8.4 Hz), 7.72 (m, 2H), 7.9 (dd, 1H,
J ¼ 1.2, 8.8 Hz), 8.27 (s, 1H), 10.1 (s, 1H); 13C NMR d:
192.3, 164.05 (d, J ¼ 250 Hz), 155.2, 143.1, 140.1, 132.2,
131.5 (d, J ¼ 9.1 Hz), 126.3 (d, J ¼ 1.1Hz), 124.3, 123.45,
116.3 (d, J ¼ 22 Hz), 110.9, 45.1, 32.1, 20.1, 13.7; ms: m/z
297 (M þ1, 100). Anal. Calcd for C18H17FN2O: C, 72.96; H,
5.78; N, 9.45. Found C, 73.05; H, 6.01; N, 9.10.
1
mp 265–267ꢀC, yield 57.1%. H NMR d (DMSO-d6): 0.75 (t,
3H), 1.16 (m, 2H), 1.68 (m, 2H), 4.36 (t, 2H), 7.29 (d, 1H, J
¼ 8.4 Hz), 7.55 (m, 3H), 7.95 (m, 3H); ms: m/z 284 (M þ1,
100). Anal. Calcd for C17H18FN3. HCl: C, 63.85; H, 5.99; N,
13.14. Found C, 63.59; H, 5.96; N, 12.98.
5-Azido-1-butyl-2-(4-fluorophenyl)-1H-benzimidazole
(77). A cooled solution of 76 (0.16 g, 0.5 mmol) was dis-
solved in 2 mL of aqueous 9M HCl and slowly a sodium
nitrite aqueous solution (0.76 mL, 1.2 mmol) was added. The
reaction temperature was not allowed to rise above 5ꢀC. The
mixture was stirred in an ice bath for 1 h. A solution of 0.6
mL of sodium azide (1.7 mmol) and sodium acetate (0.25g)
was added at 0ꢀC and stirred for 1 h. Then, the mixture was
allowed to warm to room temperature and stirred for 1 h. Po-
tassium carbonate is added to neutralize the mixture and
extracted with ethyl acetate. The solvent was then removed in
vacuo, the residue was chromatographed by using ethyl ace-
1
tate-hexane (2:8), mp 85–87ꢀC, yield 25.2%. H NMR d: 0.87
(t, 3H), 1.27 (m, 2H), 1.77 (m, 2H), 4.19 (t, 2H), 6.99 (dd, 1H,
J ¼ 2, 8.6 Hz), 7.23 (m, 2H), 7.36 (d, 1H, J ¼ 8.8 Hz), 7.46
(d, 1H, J ¼ 2 Hz), 7.69 (m, 2H); 13C NMR d: 163.9 (d, J ¼
249 Hz), 154.2, 144.2, 135.2, 133.6, 131 (d, J ¼ 8.2 Hz),
126.8, 116.3 (d, J ¼ 21.4 Hz), 115, 111.3, 109.9, 44.9, 32.1,
20.1, 13.7; ms: m/z 310 (M þ1, 100). Anal. Calcd for
C17H16FN5: C, 66.00; H, 5.21; N, 22.64. Found C, 66.09; H,
5.28; N, 22.32.
N-[2-(butylamino)-5-cyanophenyl]pyridazine-4-carbox-
amide (81a). A mixture of 4-pyridazinecarboxylic acid (0.11
g, 0.89 mmol), triethylamine (0.41 mL), 3-amino-4-butylami-
nobenzonitrile (0.18 g, 0.95 mmol), and O-(Benzotriazol-1-yl)-
N,N,N0,N0-tetramethyl-uronium hexafluorophosphate (HBTU)
(0.366 g, 0.96 mmol) in N,N-dimethylformamide (1 mL) was
stirred at room temperature for 20 h, water was added to the
reaction mixture, then extracted with ethyl acetate and evapo-
rated. The residue was purified by cc (4:1 toluene/methanol),
1
to give 81a as a white solid (6.75 g, 71%); mp 214–215ꢀC; H
NMR (DMSO-d6) d: 0.89 (t, 3H), 1.35 (m, 2H), 1.51 (m, 2H),
3.15 (q, 2H), 6.38 (t, 1H, J ¼ 6 Hz, deuterium oxide-
exchangeable), 6.76 (d, 1H), 7.52 (m, 2H), 8.14 (m, 1H), 9.51
(d, 1H, J ¼ 5.2 Hz), 9.68 (s, 1H), 10.1 (s, 1H, deuterium ox-
ide-exchangeable), ms: m/z 296 (M þ1, 100).
1-Butyl-2-(pyridazin-4-yl)-1H-benzimidazole-5-carbonitrile
(81). 0.1 g (0.33 mmol) of 81a and 0.1 g of sodium acetate
was dissolved in 1 mL glacial acetic acid. The mixture was
stirred for 4.5 h at 100ꢀC. Then poured into ice-water and fil-
tered. The precipitate was purified by silicagel cc (ethyl ace-
tate-ethanol, 10:0.1), mp 148ꢀC, yield 38%. 1H NMR d: 0.94
(t, 3H), 1.36 (m, 2H), 1.87 (m, 2H), 4.35 (t, 2H), 7.57 (d, 1H,
J ¼ 8 Hz), 7.66 (dd, 1H, J ¼ 1.6, 8.6 Hz), 7.91 (dd, 1H, J ¼
2.4, 5.6 Hz), 8.20 (s, 1H), 9.47 (dd, 1H, J ¼ 0.8, 5.8 Hz), 9.63
(m, 1H); ms: m/z 278 (M þ1, 100). Anal. Calcd for C16H15N5:
C, 69.30; H, 5.45; N, 25.25. Found C, 69.81; H, 5.80; N, not
available.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazole-5-carbalde-
hyde O-methyloxime (86). A solution of 85 (0.1 g, 0.33
mmol) and of methoxylamine hydrochloride (0.028 g, 0.33
mmol) in 1 mL of pyridine and 3 mL of absolute ethanol was
refluxed for 3 h. Solvent was removed in vacuo, water was
added and extracted with ethyl acetate and evaporated. The
residue was crystallized from ethanol, mp 104–105ꢀC, yield
38.3%. 1H NMR d (DMSO-d6): 0.78 (t, 3H), 1.17 (m, 2H),
1.67 (m, 2H), 3.93 (s, 3H), 4.32 (t, 2H), 7.45 (t, 2H), 7.65 (dd,
1H, J ¼ 1.4, 8.5 Hz), 7.71 (d, 1H, J ¼ 8.5 Hz), 7.86 (m, 2H),
7.91 (s, 1H), 8.36 (s, 1H); ms: m/z 326 (M þ1, 100). Anal.
Calcd for C19H20FN3O: C, 70.12; H, 6.20; N, 12.92. Found C,
70.34; H, 6.30; N, 12.61.
N-[2-(butylamino)-5-cyanophenyl]pyrazine-2-carboxamide
(82a). 0.124 g (1 mmol) of pyrazinecarboxylic acid, thionyl
chloride (2 mL), and toluene (5 mL) were heated at reflux for
4 h. After removal of the solvent, a mixture of 3-amino-4-
butylaminobenzonitrile 0.189 g (1 mmol), dichloromethane
(5 mL), and pyridine (0.5 mL) were added, the residue and the
1-Butyl-2-(4-fluorophenyl)-N0-hydroxy-1H-benzimidazole-5-
carboximidamide (87). To a stirring solution of compound I
(1 mmol, 0.293 g) in ethanol (50 mL) was added hydroxyl-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Synthesis and Potent Antifungal Activity against Candida Species
of Some Novel 1H-Benzimidazoles
947
amine hydrochloride (1.43 mmol, 0.1 g) followed by N,N,-dii-
sopropylethylamine (1.43 mmol, 0.184 g). The solution was
heated to reflux and after 6 h, it was concentrated. Residue
was washed with water and crystallized from ethanol, mp
230–233ꢀC, yield 66%. 1H NMR d (DMSO-d6): 0.72 (t, 3H),
1.1 (m, 2H), 1.6 (m, 2H), 4.26 (t, 2H), 5.84 (s, 2H), 7.40 (t,
2H), 7.62 (m, 2H), 7.81 (m, 2H), 7.95 (s, 1H), 9.54 (s, 1H);
ms: m/z 327 (M þ1, 100). Anal. Calcd for C18H19FN4O..0.4
HOH..0.25 C2H6O: C, 64.38; H, 6.22; N, 16.23. Found C,
64.46; H, 5.79; N, 15.93.
1-Butyl-2-(4-fluorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-
1H-benzimidazole (88). To a stirring solution of 87 (0.070 g,
0.214 mmol) in 1,2-dichloroethane was added acetic anhydride
(1 g, 0.97 mL, 10.2 mmol) and then the mixture was heated to
75ꢀC. After 10 h, the reaction was cooled to room temperature
and concentrated under reduced pressure. Water was added and
the mixture was made alkaline with dilute sodium carbonate so-
lution, then extracted with ethyl acetate. The organic layer was
washed with water and evaporated, the residue was purified by
cc eluting with first ethyl acetate-hexane 50%, later ethyl ace-
tate-ethanol (99:1) to give 88 (0.025 g, 33.3%), mp 120–122ꢀC,
1H NMR d: 0.86 (t, 3H), 1.27 (m, 2H), 1.78 (m, 2H), 2.66 (s,
3H), 4.22 (t, 2H), 7.23 (t, 2H), 7.47 (d, 1H, J ¼ 8 Hz), 7.71 (m,
2H), 8.03 (d, 1H, J ¼ 8.8 Hz), 8.51 (s, 1H); ms: m/z 351 (M þ1,
100). Anal. Calcd for C20H19FN4O..0.1 C4H8O2: C, 68.21; H,
5.56; N, 15.59. Found C, 68.35; H, 5.54; N, 15.36.
1-Butyl-4,7-dichloro-2-(4-fluorophenyl)-1H-benzimidazole
(103). Purification, cc, ethyl acetate-hexane (2:8), mp 93–
94ꢀC, yield 52.5%. 1H NMR d: 0.81 (t, 3H), 1.18 (m, 2H),
1.74 (m, 2H), 4.46 (t, 2H), 7.22 (m, 4H), 7.67 (m, 2H); ms: m/
z 337 (M þ1, 100) 339 (M þ3, 63), 341 (M þ5, 13). Anal.
Calcd for C17H15Cl2FN2: C, 60.54; H, 4.48; N, 8.31. Found C,
60.73; H, 4.58; N, 8.29.
1-Butyl-5,6-dichloro-2-(4-fluorophenyl)-1H-benzimidazole
(105). Purification, cc, ethyl acetate-hexane (1:3), mp 85–
86ꢀC, yield 70.5%. 1H NMR d: 0.88 (t, 3H), 1.26 (m, 2H),
1.76 (m, 2H), 4.17 (t, 2H), 7.24 (m, 2H), 7.51 (s, 1H), 7.68
(m, 2H), 7.87 (s, 1H); ms: m/z 337 (M þ1, 100) 339 (M þ3,
57). 341 (M þ5, 13). Anal. Calcd for C17H15Cl2FN2: C, 60.55;
H, 4.48; N, 8.31. Found C, 60.5; H, 4.39; N, 8.31.
1-Butyl-5,6-dibromo-2-(4-fluorophenyl)-1H-benzimidazole
(106). Purification, cryst., ethanol, mp 100–101ꢀC, yield
1
72.8%. H NMR d: 0.87 (t, 3H), 1.26 (m, 2H), 1.75 (m, 2H),
4.15 (t, 2H), 7.23 (m, 2H), 7.68 (m, 3H), 8.05 (s, 1H); 13C
NMR d: 165.0, 162.6, 154.5, 143.4, 135.8, 131.3, 131.2,
126.0, 125.9, 124.3, 117.9, 117.6, 116.2, 116.0, 114.6, 44.8,
31.7, 19.8, 13.4. ms: m/z 425 (M þ1, 51), 427 (M þ3, 100),
429 (M þ5, 50). Anal. Calcd for C17H15Br2FN2: C, 47.92; H,
3.55; N, 6.57. Found C, 47.52; H, 3.45; N, 6.73.
1-Butyl-2-(4-fluorophenyl)-1H-benzimidazole-5,6-dicarboni-
trile (107). Purification, cc, ethyl acetate-hexane (3:7), mp
1
158–160ꢀC, yield 36.6%. H NMR d (DMSO-d6): 0.76 (t, 3H),
2-(4-Fluorophenyl)-1-propyl-5-(1H-tetrazol-5-yl)-1H-benzi-
midazole (89). A mixture of 89a (0.1 g, 0.358 mmol), sodium
azide (0.11 g, 1.7 mmol), and ammonium chloride (0.11 g,
2.056 mmol) in N,N-dimethylformamide (1 mL) was stirred at
145ꢀC for 24 h. After cooling, the mixture was diluted with
water, acidified to pH 3 with dilute HCl and extracted with
ethyl acetate. The organic layer was washed with water and
evaporated. The residue was purified by c.c. eluting with first
ethyl acetate, later ethyl acetate-ethanol (9:1) to give 89, mp
126–128ꢀC, yield 19.1%. 1H NMR d: 0.68 (t, 3H), 1.64 (m,
2H), 4.26 (t, 2H), 7.39 (t, 2H), 7.83 (m, 3H), 7.97 (d, 1H, J ¼
7.6 Hz), 8.32 (s, 1H); 13C NMR d (DMSO-d6): 163.7 (d, J ¼
250 Hz), 163.15, 156.7, 154.5, 143.1, 138.0, 132.3 (d, J ¼ 9.2
Hz), 127.1, 122.2, 119.2, 118.5, 116.7 (d, J ¼ 22 Hz), 112.7,
46.4, 23.1, 11.4; ms: m/z 323 (M þ1,100). Anal. Calcd for
C17H15FN6. HOH: C, 59.99; H, 5.03; N, 24.69. Found C,
60.03; H, 5.07; N, 24.41.
5,6-Difluoro-2-(4-hydroxyphenyl)-1H-benzimidazole
(98). Compound 97 (0.12 g, 0.357 mmol) in ethanol (10 mL)
were reduced by hydrogenation using 40 psi of H2 and 10%
Pd-C until cessation of hydrogen uptake. The catalyst was fil-
tered off on a bed of Celite, washed with ethanol, and the fil-
trate was concentrated. The residue was crystallized from etha-
nol, mp 286–287ꢀC, yield 43.2%. 1H NMR d (DMSO-d6):
6.88 (d, 2H, J ¼ 8.4 Hz), 7.47 and 7.6 (br.s, 2H), 7.94 (d, 2H,
J ¼ 8.8 Hz), 10.0 (s, 1H), 12.87 (s, 1H); ms: m/z 247 (M
þ1,100). Anal. Calcd for C13H8F2N2O..0.5C4H8O2: C, 62.07;
H, 4.17; N, 9.65. Found C, 62.55; H, 4.29; N, 9.37.
1.14 (m, 2H), 1.64 (m, 2H), 4.4 (t, 2H), 7.49 (t, 2H), 7.91 (m,
2H), 8.57 (s, 1H), 8.75 (s, 1H); ms: m/z 319 (M þ1, 100).
Anal. Calcd for C19H15FN4. 0.15 C4H8O2: C, 71.0; H, 4.92; N,
16.89. Found C, 71.16; H, 4.95; N, 16.78.
1-(4-Fluorophenyl)ethanone (4-bromophenyl) hydrazone
(108a). A mixture of 4-bromo-phenylhidrazine HCl (1.12 g, 5
mmol), 40-fluoroacetophenone (0.69 g, 5 mmol), and triethyl-
amine (1 mL) in ethanol (10 mL) was heated to 80ꢀC for 3 h.
The mixture was allowed to cool and water was added. The re-
sultant precipitate was filtered and dried under vacuum, yield
1.34 g, 87.3%.
5-Bromo-2-(4-fluorophenyl)-1H-indole
(108). Compound
108a (0.92 g, 3 mmol) in polyphosphoric acid (25 g) was
heated to 120ꢀC for 4 h. After cooling to room temperature,
the resultant reaction solution was poured into a mixture of ice
and water, and the solution was basified with 10% sodium hy-
droxide solution. The resultant precipitate was filtered, washed
with water, crystallized from ethanol, mp 178–179ꢀC, ref. 28;
1
180ꢀC, yield 85%. H NMR d (DMSO-d6): 6.87 (s, 1H), 7.21
(dd, 1H, J ¼ 2, 8.8 Hz), 7.33 (m, 3H), 7.71 (s, 1H), 7.91 (m,
2H), 11.77 (s, 1H); 13C NMR d (DMSO-d6): 162.9, 160.4,
138.1, 135.6, 130.4, 128.2, 127.2, 127.1, 123.8, 121.9, 115.9,
115.7, 113.1, 111.7, 98.1; ms [ESI(ꢁ)]: m/z 288 (M ꢁ1, 100)
290 (M þ2, ꢁ1, 100). Anal. Calcd for C14H9BrFN: C, 57.95;
H, 3.13; N, 4.83. Found C, 57.73; H, 3.04s; N, 4.98.
5-Bromo-2-(4-fluorophenyl)-1-propyl-1H-indole
(109). A
solution of 108 (0.58 g, 2 mmol) and sodium hydride (0.072 g, 3
mmol) was stirred in dry N,N-dimethylformamide (3 mL) at 0ꢀC
for 30 min, and then propyl bromide (0.30 g, 2.5 mmol) was
added dropwise and the resulting mixture was stirred at room
temperature for 16 h and then poured into ice-water and
extracted with ethyl acetate (3 ꢂ 10). The organic phase was
washed with brine, dried over sodium sulfate, and concentrated
under reduced pressure. The residue was crystallized from ethyl
General procedure for synthesis of 103, 105–107. A mix-
ture of 99–102 (1 mmol), n-butylbromide (1 mmol), and so-
dium hydride (95%, 1.25 mmol) in N,N-dimethylformamide
(1mL) was stirred at 60ꢀC for 5 h. The reaction mixture was
poured into water and extracted with ethyl acetate. The extract
was washed with water, dried over sodium sulfate, and con-
centrated in vacuo.
1
acetate-hexane, yield 63.3%, mp 55–56ꢀC; H NMR d (DMSO-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Goker, M. Alp, Z. Ateꢀs-Alagoz, and S. Yıldız
¨
948
Vol 46
[7] Grivsky, E. M. U.S. Pat. 3,742,014 (1973).
d6): 0.63 (t, 3H), 1.53 (m, 2H), 4.14 (t, 2H), 6.51 (s, 1H), 7.28
(dd, 1H, J ¼ 2, 8.4 Hz), 7.36 (m, 2H), 7.55 (d, 1H, J ¼ 8.8 Hz),
7.59 (m, 2H), 7.75 (d, 1H, J ¼ 2 Hz); ms: m/z 332 (M þ1, 100)
334 (M þ3, 100). Anal. Calcd for C17H15BrFN: C, 61.46; H,
4.55; N, 4.22. Found C, 61.43; H, 4.56; N, 4.38.
[8] Mackman, R. L.; Hui, H. C.; Bretenbucher, J. G.; Katz, B.
A.; Luong, C.; Martelli, A.; McGee, D.; Radika, K.; Sendzik, M.;
Spencer, J. R.; Sprengeler, P. A.; Tario, J.; Verner, E.; Wang, J. Bio-
org Med Chem Lett 2002, 12, 2019.
[9] Kudo, N.; Furuta, S.; Sato, K. Chem Pharm Bull 1996, 44,
1663.
5-Cyano-2-(4-fluorophenyl)-1-propyl-1H-indole
(110). A
mixture of 109 (0.332 g, 1 mmol) and cuprous cyanide (0.270
g, 3 mmol) in 5 mL of 1-methyl-2-pyrrolidinone was heated at
120ꢀC for 6 h in a Parr Digestion Bomb. The mixture was
cooled to room temperature and washed with 10 mL water, by
stirring with water for 15 min and decanting the water layer.
The washed reaction mixture was mixture with 8 mL of ethyl-
enediamine and 5 mL of water. The resultant precipitate was fil-
tered, washed with 15 mL of 10% sodium cyanide solution then
water and dried. Crude product was purified by using cc (ethyl
acetate-hexane 1:3), mp 141-143ꢀC, yield 23.7%. 1H NMR d
(DMSO-d6): 0.63 (t, 3H), 1.52 (m, 2H), 4.20 (t, 2H), 6.67 (s,
1H), 7.37 (t, 2H), 7.52 (dd, 1H, J ¼ 1.4, 8.6 Hz), 7.61 (m, 2H),
7.77 (d, 1H, J ¼ 8.6 Hz), 8.09 (d, 1H, J ¼ 1 Hz); ms: m/z 279
(M þ1,100). Anal. Calcd for C18H15FN2. 0.15 HOH: C, 76.93;
H, 5.49; N, 9.96. Found C, 77.04; H, 5.76; N, 9.47.
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Acknowledgments. This work was supported by TUBITAK
Project no: 106S202 (SBAG-3450). Central Laboratory of Phar-
macy, Faculty of Ankara University provided support for acquisi-
tion of the NMR, mass spectrometer, and elemental analyzer used
in this work.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet