Fluoro-containing heterocycles. IV. Synthesis of benzimidazole derivatives

Article abstract of DOI:10.1023/A:1012446305955

2-Mercapto-5,6-difluorobenzimidazole reacts with aliphatic and alicyclic ketones in acetic acid in the presence of catalytic amount of sulfuric acid to afford fluorinated derivatives of 2,3-disubstituted benz[4,5]imidazo[2,1-b][1,3]thiazoles. Reaction with aromatic α-haloketones occurs in another way: to furnish 2-phenylacylthio-5,6-difluorobenzimidazoles that in the system acetic anhydride - pyridine undergo cyclization into the corresponding fluorinated derivatives of benz[4,5]imidazo[2,1-b][1,3]thiazoles.

Full text of DOI:10.1023/A:1012446305955

Russian Journal of Organic Chemistry, Vol. 37, No. 4, 2001, pp. 564 569. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 4, 2001,
pp. 598 603.
Original Russian Text Copyright
2001 by Kotovskaya, Perova, Baskakova, Romanova, Charushin, Chupakhin.
Fluoro-containing Heterocycles. IV.* Synthesis
of Benzimidazole Derivatives**
S. K. Kotovskaya, N. M. Perova, Z. M. Baskakova, S. A. Romanova,
V. N. Charushin, and O. N. Chupakhin
Ural State Technical University, Yekaterinburg, 620002 Russia
Received March 9, 2000
Abstract 2-Mercapto-5,6-difluorobenzimidazole reacts with aliphatic and alicyclic ketones in acetic acid in
the presence of catalytic amount of sulfuric acid to afford fluorinated derivatives of 2,3-disubstituted
benz[4,5]imidazo[2,1-b][1,3]thiazoles. Reaction with aromatic -haloketones occurs in another way: to
furnish 2-phenylacylthio-5,6-difluorobenzimidazoles that in the system acetic anhydride pyridine undergo
cyclization into the corresponding fluorinated derivatives of benz[4,5]imidazo[2,1-b][1,3]thiazoles.
Compounds of the benzimidazole series play
significant role among farmaceuticals: spasmolytic
drug dibazole, neuroleptics pimozide, droperidole,
antihistaminic preparation astemizole etc. [2].
Benzimidazo[2,1-b]thiazoles are commonly prepared
from 2-mercaptobenzimidazole by reaction with
-haloketones [3 7]. Recently an original preparation
method was developed for the benzimidazo[2,1-b]-
thiazoles proceeding from reaction of the mercapto-
benzimidazole with ketones in acetic acid medium
[8].
By the reduction of 2-nitro-4,5-difluoroaniline (I) [14]
with hydrogen on Ni-Ra catalyst was obtained
diamine II, and its condensation with carbon disulfide
in ethanol in the presence of triethylamine afforded
azole III.
Scheme 1.
Aryl(heteroaryl)thioacetophenones are known to
form in reactions of the corresponding thiols with the
derivatives of phenacyl halides [9 11], with ketones
and aldehydes in the presence of iodine [12], and also
with aromatic ketones in acetic acid in the presence
of sulfuric acid as a catalyst [8]. The behavior in
these reactions of fluoro-containing benzimidazoles
was not studied before. The interest to these com-
pounds is due to the high biological activity of a
number among these substances, and therewith the
biological activity thereof is significantly stronger
than that of the nonfluorinated analogs [13]. We
report here on the first synthesis of fluorinated deriv-
atives of benzimidazo[2,1-b]thiazoles that contains
a large promise for the search of biologically active
substances.
By the reaction of 2-mercapto-5,6-difluorobenz-
imidazole (III) with aliphatic ketones, e.g. acetone,
methyl ethyl ketone, acetylacetone, benzoylacetone,
ethyl acetoacetate, in acetic acid in the presence of
catalytic amounts of sulfuric acid we obtained the
corresponding
2-R-3-methyl-6,7-difluorobenzimid-
azo[2,1-b]thiazoles IVa e in 30 40% yield. Alicyclic
ketones, as cyclopentanone, cyclohexanone, cyclo-
heptanone, in reaction with thiol III under similar
conditions (AcOH H2SO4) afforded tetracyclic
compounds Va c in 45 60% yield (Scheme 2).
The synthesis of initial 2-mercapto-5,6-difluoro-
The mechanism of benzimidazo[2,1-b]thiazoles
formation we did not study. It is presumable ana-
logous to published data [8] that the reaction involves
an intermediate disulfide formation which further
undergoes cyclization with enols. The structure of
compounds IVa e and Va c obtained and also the
benzimidazole (III) was carried out along Scheme 1.
*
Communication III see [1].
The study was carried out under financial support from the
**
Ministry of Science of the Russian Federation, grant
no. 9.1.06.
1070-4280/01/3704-0564$25.00 2001 MAIK Nauka/Interperiodica

FLUORO-CONTAINING HETEROCYCLES: IV.
565
Scheme 2.
IV), R = H (a), CH3 (b), COCH3 (c), COC6H5 (d), COOC2H5 (e); V, n = 1 (a), 2 (b), 3 (c).
regio orientation of the fused fragment in benzimid-
stituents in para-position affording cleanly the cor-
responding 2-phenacylthiobenzimidazoles [8]. In reac-
tion with aromatic ketones of 2-mercapto-5,6-difluoro-
benzimidazole (III) the effect of two fluorine atoms
although remote from the reaction site nonetheless
was decisive, and we failed to obtain by this method
fluorinated derivatives of 2-phenacylthiobenzimid-
azoles. Therefore we prepared aryl and heteryl deriv-
atives of fluorinated benzimidazo[2,1-b]thiazoles
via two-step synthesis through -haloacetophenones.
azo[2,1-b]thiazoles IVa e was unambiguously proved
1
by H and 13C NMR spectra and by experiments with
the nuclear Overhauser effect registration. For
instance, the irradiation on the frequency correspond-
ing to the methyl protons resonance in compound IVe
( 3.08) resulted in increase of the intensity of the
signal belonging to the proton H5 at 8.18 ppm by
18%; this fact unambiguously proved the position of
the substituents in the thiazole ring.
We obtained substituted 2-phenacylthio-5,6-di-
fluorobenzimidazoles VIa g by reaction of thiol
The 2-mercaptobenzimidazole is known to react
with aromatic ketones containing electron-donor sub-
1
Table 1. H and 13C NMR spectra of benzimidazothiazoles IVe and Va
Atom
no.
Atom
Number
no.
Compd. no.
IVe
Characteristics
Characteristics
IVe
Va
Va
C2
111.60
139.29
125.02
11.3
1.1
8.18
123.42
133.16
123.79
11.4
C8
105.94a
168.0
20.4
143.56
11.1
1.4
154.88
2.4
105.42a
166.0
20.2
141.62
11.1
C3
1J(C8, H8)
2J(C8, F7)
C4a
3J(C4a, F6)
4J(C4a, F7)
C8a
C9a
3J(C8a, F7)
4J(C8a, F6)
H5
C5
C6
C7
H8
7.85
10.0
1.3
161.74
3J(H5, F6)
4J(H5, F7)
10.5
7.5
7.0
5J(C9a, F7)
5J(C9a, F6)
101.29a
170.0
24.1
98.71a
168.0
23.5
0.9
1J(C5, H5)
2J(C5, F6)
Other
signals
3-CH3
2-CH3
2-CH2
C=O
145.57b
269.9
15.3
145.26b
239.6
15.6
12.72c
13.78c
61.45
1J(C6, F6)
2J(C6, F7)
147.47b
271.6
14.8
146.84b
239.2
15.0
161.12
1J(C7, F7)
2J(C7, F6)
(CH2)3
24.85,
25.52,
27.40
7.77
11.0
7.5
7.65
11.5
7.5
3J(H8, F7)
4J(H8, F6)
a, b
The assignment of signals may be reversed. c The signals are assigned from 13C spectra.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

566
KOTOVSKAYA et al.
Scheme 3.
R= Ph (a), 2-CH3C6H4 (b), 4-BrC6H4 (c), 4-ClC6H4 (d), 2,4-Cl2C6H3 (e), 2,4-(CH3O)2C6H3 (f), 2-tienyl (g); X= Cl, Br.
III with -haloketones at room temperature in ethanol
in the presence of triethylamine (Scheme 3). It should
be noted that in contrast to the procedure with the
use of 2-mercaptobenzimidazole potassium salt
described in the literature in our case it is necessary
to use the organic bases to exclude the alkaline
hydrolysis of fluorine in initial compound III
and also to significantly simplify the isolation of the
target product. Compounds VIa g react with acetic
anhydride at room temperature to furnish the cor-
responding N-acetyl derivatives VIIa g. The heating
of compounds VIa g in a mixture acetic anhydride
pyridine gives rise to their acylation and cyclodehydr-
ation to yield 2-aroyl-3-methyl-6,7-difluorobenzimid-
azo[2,1-b]thiazoles (VIIIa g). Compound VIIIa
was also obtained at heating of N-acetyl derivative
VIIa in acetic anhydride.
gen to 3.2 atmosphere pressure. The stirring and
heating were switched on, and the reduction continu-
ed at 60 70 C for 7 h. On cooling the reaction mix-
ture the catalyst was filtered off. The most part of the
solvent was distilled off in a vacuum, and on cooling
the residue precipitated dark-gray crystals of diamine
II. Yield 199 g (82%).
2-Mercapto-5,6-difluorobenzimidazole (III).
A mixture of 20 g (0.14 mol) of diamine II in 240 ml
of ethanol, 25.3 ml (31.9 g, 0.42 mol) of carbon
disulfide, and 31.9 ml (28.3 g, 0.28 mol) of triethyl-
amine was heated under reflux on a water bath for
4 h. Then the solvent was distilled off, and the
residue was poured into 240 ml of water. The
separated precipitate was filtered off, dried, and re-
crystallized from ethanol. Yield 21 g (81%), mp
1
220 C. H NMR spectrum (DMSO-d6), , ppm: 7.05
Thus fluorinated derivatives of benzimidazo[2,1-
b]thiazoles can be prepared either in one stage by
reaction of 2-mercapto-5,6-difluorobenzimidazole
with aliphatic ketones in AcOH H2SO4 or in two
stages: First in reaction with the aromatic -halo-
ketones form 2-phenacylthio-5,6-difluorobenzimid-
azoles that in the Ac2O pyridine medium undergo
acylation and cyclodehydration into the corresponding
benz[4,5]imidazo[2,1-b][1,3]thiazoles.
m (2H, H4,7), 12.48 br.s (1H, NH).
2,3-Substituted 6,7-difluorobenz[4,5]imidazo-
[2,1-b][1,3]thiazoles IVa e, Va c. A mixture of
10 mmol ot thiol III and 15 mmol of an appropriate
ketone was boiled for 4 h in 40 ml of acetic acid
containing 5 10 drops of H2SO4. The reaction mix-
ture was cooled, diluted with 80 ml of water, and
neutralized with aqueous NH4OH till pH 7. The
precipitate was filtered off, dried, and recrystallized.
EXPERIMENTAL
2-Phenacylthio-5, 6-difluorobenzimidazoles
VIa g. In 20 ml of ethanol was dissolved 10 mmol
of thiol III, was added dropwise at stirring 10 mmol
of triethylamine and then by portions 10 mmol of
aromatic -haloketone. The precipitate started to
form nearly immediately. The reaction mixture was
maintained for 2 12 h at 18 20 C. The precipitate
was filtered off, dried, and recrystallized.
1H and 13C NMR spectra were registered on
spectrometers Bruker WH-250 and DRX-500,
internal reference TMS. Yields, melting points,
1
elemental analyses, and H NMR spectra of com-
pounds synthesized are presented in Table 2.
1,2-diamino-4,5-difluorobenzene (II). Into
a
high-pressure reactor was charged 174.1 g (1 mol) of
2-nitro-3,4-difluoroaniline (I), 200 ml of anhydrous
ethanol, and 14 g of Ni-Ra catalyst, and then hydro-
3-Acetyl-2-phenacylthio-5,6-difluorobenzimid-
azoles VIIa g. A mixture of 10 mmol of compound
VIa g and 10 ml of acetic anhydride was stirred at
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

Table 2. Characteristics of synthesized compounds
Compd. Yield,
no.
mp,
(solvent for
crystallization)
C
Found, %
H
Calculated, %
%
1H NMR spectrum, ppm
Formula
C
N
C
H
N
IVaa
38
175 177
2.69 s (3H, CH3), 6.38 s (1H, H22), 7.56 m 53.31 2.54 12.34 C10H2F2N2S
53.58 2.70 12.49
55.47 3.39 11.76
54.15 3.04 10.52
62.20 3.07 8.53
52.71 3.41 9.45
57.61 3.23 11.19
59.09 3.82 10.60
60.43 4.36 10.07
59.20 3.31 9.21
58.95 3.61 8.02
62.18 3.07 8.53
60.36 3.80 8.80
59.99 3.92 7.78
(EtOH H2O) (2H, H5 *)
IVba
IVbb
IVda
IVea
Vaa
40
38
34
32
45
57
59
64
91
66
83
56
265 267
(EtOH)
202 203
(EtOH)
200 202
(EtOH)
175 177
2.36 s (3H, CH3), 2.58 s (3H, CH3), 7.51 m 55.69 3.54 11.82 C11H8F2N2S
(2H, H5 *)
2.56 s (3H, COCH3), 3.08 s (3H, CH3), 7.64 m 54.32 3.17 10.74 C12H8F2N2OS
(2H, H5 *)
2.86 s (3H, CH3), 7.59 m (5H, COC6H5), 7.83 m 61.94 2.90 8.60 C17H10F2N2OS
(2H, H5 *)
1.41 t (3H, OCH2CH3), 3.08 s (3H, CH3), 52.60 3.52 9.60 C13H10F2N202
S
(EtOH H2O) 4.40 q (2H, OCH2CH3), 7.60 m (2H, H5 *)
230 232
(EtOH)
203 20
(EtOH)
173 175
(EtOH)
170 172
(EtOH)
158
(CH3CN)
192 193
(EtOH)
176 177
(CH3CN)
115 116
(EtOH)
2.37, 3.01, 3.12 m [6H, (CH2)3], 7.44 m 57.30 3.41 11.09 C12H8F2N2S
5 *
(2H,
)
Vba
5 2.00, 2.72, 2.96 m [8H, (CH2)4], 7.47 m 59.34 3.96 10.74 C13H10F2N2S
5 *
(2H,
)
Vca
2.05, 2.76, 3.16 m [10H, (CH2)5], 7.52 m 60.24 4.18 9.94 C14H12F2N2S
5 *
(2H,
)
VIab
VIIab
VIIIab
VIbb
VIIbb
4.75 s (2H, CH2), 7.47 m (5H, C6H5), 8.03 m 58.85 3.57 9.02 C15H10F2N2OS
(2H, B4 7), 10.00 br.s (1H, NH)
2.84 s (3H, COCH3), 4.88 s (2H, CH2), 7.62 m 58.68 3.61 8.02 C17H12F2N2OS
7
(5H,
C6H5), 8.05
m
(2H,
B4 )
2.74 s (3H, CH3), 7.59 m (5H, C6H5), 7.81 m 62.00 2.97 8.40 C17H10F2N2OS
(2H, H)
2.41 s, 3H, CH3), 4.80 s (2H, CH2), 7.29 m 60.14 3.92 8.62 C16H12F2N2OS
7
(4H, C6H4CH3), 7.65 m (2H, B4 )
2.40 s (3H, CH3), 2.83 s (3H, COCH3), 4.68 s 60.13 4.00 7.90 C18H14F2N202
S
(2H, CH2), 7.34 m (4H, C6H4CH3), 7.88 m
7
(2H, B.4
)
VIIIbb
Vlcb
86
74
223 225
(CH2CN)
198 199
(EtOH)
2.36 s (3H, CH3), 2.57 s (3H, CH3), 7.41 m 62.94 3.42 8.24 C18H12F2N2OS
63.14 3.53 8.18
47.01 2.37 7.31
(4H, C6H4CH3), 7.82 m (2H, H5 )
4.92 s (2H, CH2), 7.50 m (4H, C6H4Br), 7.98 m 46.94 2.49 7.37 C15H9BrF2N2OS
7
(2H, B4 ), 12.62 br.s (1H, NH)

Table 2. (Contd.)
Compd. Yield,
mp,
(solvent for
crystallization)
C
Found, %
H
Calculated, %
no.
%
1H NMR spectrum, ppm
Formula
C
N
C
H
N
VIlbb
84
169 170
(EtOH)
230 232
(CH2CN)
214 215
2.83 s (3H, COCH3), 4.83 s (2H, CH2), 7.62 m 47.76 2.79 6.87 Cl7H11BrF2N2O2S
(4H, C6H4Br), 7.98 m (2H, H4 7)
48.01 2.61 6.59
50.14 2.33 6.88
53.18 2.68 8.27
53.62 2.91 7.36
56.27 2.50 7.72
48.27 2.16 7.51
49.17 2.43 6.75
51.40 2.03 7.05
56.03 3.87 7.69
VIIIcb
VIdb
66
77
78
69
64
69
81
63
2.76 s (3H, CH3), 7.76 m (4H, C6H4Br), 7.88 m 50.36 2.23 7.00 Cl7H9BrF2N2OS
(2H, H5 8)
4.93 s (2H, CH2), 7.46 m (4H, C6H4Cl), 8.05 m 53.14 2.82 8.34 Cl5H9ClF2N2OS
(EtOH DMF) (2H, H4’7), 12.62 br.s (1H, NH)
VIIdb
VIIdb
VIab
177 178
(EtOH)
221 222
(CH2CN)
153 154
(EtOH)
2.83 s (3H, COCH3), 4.83 s (2H, CH2), 7.62 m 53.47 2.80 7.40 Cl7H11ClF2N2O2S
(4H, C6H4Cl), 8.06 m (2H, H4 7)
2.76 s (3H, CH3), 7.85 m (4H, C6H4Cl), 7.84 m 56.05 2.47 7.85 Cl7H9ClF2N2OS
(2H, H5
)
4.72 s (2H, CH2), 7.38 m (3H, C6H3Cl2), 7.70 m 48.50 2.34 7.68 Cl5H8Cl2F2N2OS
(2H, H4 7), 12.50 br.s (1H, NH)
VIIcb
VIIIcb
VIeb
158 159
(CH2CN)
264 266
2.81 s (3H, COCH3), 4.59 s (2H, CH2), 7.46 m 48.98 2.36 6.75 Cl7H10Cl2F2N202
(3H, C6H3Cl2), 7.83 m (2H, H4 7)
S
2.67 s (3H, CH3), 7.65 m (3H, C6H3Cl2), 7.89 m 51.12 1.93 7.22 Cl7H8Cl2F2N2OS
(EtOH DMF) (2H, H5 *)
154 155
(EtOH)
3.87 s (3H, OCH3), 3.98 s (3H, OCH3), 55.94 3.99 7.65 Cl7H14F2N203
S
S
S
4.76 s (2H, CH2), 6.60 m (2H), 7.72 m (1H)
[C6H3(OCH3)2] 7.32 m (2H, H4 7)
VIIfb
79
84
178 179
(EtOH)
2.81 s (3H, COCH3), 3.87 s (3H, OCH3), 56.35 4.07 6.62 Cl9H16F2N204
3.99 s (3H, OCH3), 6.59 m (2H), 7.69 m (1H)
[C6H3(OCH3)2], 7.61 m (2H, H4 7)
56.15 3.97 6.89
58.75 3.63 7.28
VIIIfb
190 191
(EtOH)
2.68 s (3H, CH3), 3.87 s (3H, OCH3), 58.57 3.47 7.28 Cl9H14F2N203
3.88 s (3H, OCH3), 6.63 m (2H), 7.35 m (1H)
[C6H3(OCH3)2] , 7.82 m (2H, H5 *)
VIgb
64
48
55
170 171
(EtOH)
147 148
(EtOH)
201 203
(EtOH)
4.86 s (2H, CH2), 7.26 m (3H, Tienyl), 8.00 m 50.17 2.37 8.76 Cl3H8F2N2OS2
(2H, H4’7), 12.64 br.s (1H, NH)
50.31 2.60 9.03
51.27 2.58 7.97
53.88 2.41 8.38
VIIgb
VIIIgb
2.83 s (3H, COCH3), 4.80 s (2H, CH2), 7.55 m 51.50 2.64 7.97 C15H9F2N2OS2
(3H, Tienyl), 8.02 m (2H, H4 7)
2.98 s (3H, CH3), 7.56 m (3H, Tienyl), 8.03 m 54.01 2.37 8.38 Cl5H8F2N2OS2
*
(2H, H5
)
a
b
Solvents for recording NMR spectra: CDCl3, DMSO-d41) .
6

FLUORO-CONTAINING HETEROCYCLES: IV.
569
18 20 C for 2 20 h, the precipitate was filtered off,
dried, and recrystallized.
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2-Aroyl-3-methyl-6,7-difluorobenz[4,5]imidazo-
[2,1- ][1,3]thiazoles (VIIIa g). In 15 30 ml of a
b
mixture Ac2O pyridine 10 mmol of compound VIa g
was stirred for 3 h at 100 120 C. On cooling the
reaction mixture was poured into 90 ml of ice water.
Gradually precipitated crystals that were filtered off,
dried, and recrystallized.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001