Synthesis of fluorine-containing benzimidazole derivatives

Article abstract of DOI:10.1007/s11172-010-0060-0

Various fluorine-containing benzimidazoles were obtained by the reaction of o-phenylenediamine, 3,4-diaminotoluene, and 1,2-diamino-4-chlorobenzene with hexafluoropropene or perfluoro(methyl vinyl ether) in DMF. A new efficient method of synthesis of 2-(1,2,2,2-tetrafluoroethyl)benzimidazole by the reaction of o-phenylenediamine with hexafluoropropene in the presence of diethylamine or dimethylamine in ethyl acetate is developed.

Full text of DOI:10.1007/s11172-010-0060-0

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 186—191, January, 2010
186
Synthesis of fluorineꢀcontaining benzimidazole derivatives*
T. P. Vasilyeva, N. M. Karimova, and Yu. V. Slavich
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: dꢀ20@mail.ru
Various fluorineꢀcontaining benzimidazoles were obtained by the reaction of oꢀphenyleneꢀ
diamine, 3,4ꢀdiaminotoluene, and 1,2ꢀdiaminoꢀ4ꢀchlorobenzene with hexafluoropropene or
perfluoro(methyl vinyl ether) in DMF. A new efficient method of synthesis of 2ꢀ(1,2,2,2ꢀtetꢀ
rafluoroethyl)benzimidazole by the reaction of oꢀphenylenediamine with hexafluoropropene in
the presence of diethylamine or dimethylamine in ethyl acetate is developed.
Key words: 2ꢀ(1,2,2,2ꢀtetrafluoroethyl)ꢀ1Нꢀbenzimidazole, 2ꢀ[(fluoro)trifluoromethoxyꢀ
methyl]ꢀ1Нꢀbenzimidazole, 2ꢀdifluoromethylꢀ1Нꢀbenzimidazole, 6ꢀ or 5ꢀsubstituted
2ꢀ(1,2,2,2ꢀtetrafluoroethyl)ꢀ and 2ꢀ[(fluoro)trifluoromethoxymethyl]ꢀ1Нꢀbenzimidazoles,
oꢀphenylenediamine, 3,4ꢀdiaminotoluene, 1,2ꢀdiaminoꢀ4ꢀchlorobenzene, hexafluoropropene,
perfluoro(methyl vinyl ether), heterocyclization, silylation.
Benzimidazoles belong to a very important class of
DMF)4,5,9 or 2ꢀfluoroꢀ2ꢀtrifluoromethoxyacetic acid7, or
organic compounds and many of them (especially, 2ꢀsubꢀ
stituted) are used as drugs. 2ꢀBenzylbenzimidazole (dibazole)
is among them, it is used as a hypotensive drug and for flu
prevention. Some compounds with high antiꢀHIV activity
were found among fluorineꢀcontaining 2ꢀarylsubstituted
benzimidazoles.1 It is known that modification of bioacꢀ
tive compounds by introducing fluorine or fluoroalkyl
substituents often leads to enhancement of pharmacokiꢀ
netic properties. Therefore, the development of new methꢀ
ods of synthesis of 2ꢀfluoroalkyl benzimidazoles is topical.
The purpose of the present work is the development of
optimal conditions of synthesis of 2ꢀ(αꢀhydropolyfluꢀ
oroalkyl)benzimidazoles starting from oꢀphenylenediꢀ
amines and fluoroolefins, the study of the influence of the
olefin structure, catalysts, and the solvent on the heteroꢀ
cyclization reaction .
Et2NCF2CH(F)CF3 (in THF)10 were mentioned. The drawꢀ
back of the latter procedure is that it requires special prepꢀ
aration of starting N,NꢀdiethylꢀNꢀ(1,1,2,3,3,3ꢀhexafluꢀ
oropropꢀ1ꢀyl)amine. The reactions of 1a with other terminal
perfluoroolefins are documented. The reaction with perfluꢀ
oroisobutylene at room temperature (in an autoclave) reꢀ
sulted in 2ꢀ(CF3)2CHꢀsubstituted benzimidazole11, whereas
heterocyclization of 1a with perfluorinated heptꢀ1ꢀene or
allylbenzene at elevated temperature was complicated by subꢀ
sequent dehydrofluorination with formation of 2ꢀperfluoꢀ
roalkenyl benzimidazoles in moderate yields12 (Scheme 1).
Scheme 1
Despite high bioactivity of fluorineꢀcontaining benzꢀ
imidazoles, their synthesis is studied insufficiently yet.
Thus it was reported that 2ꢀdifluoromethylꢀ1Нꢀbenzimiꢀ
dazole (2) was obtained by the reaction of oꢀphenyleneꢀ
diamine (1a) with tetrafluoroethylene in an autoclave
(135 atm, 136 °С, the yield 50%)2 or with oxo ester
F2CHC(O)CBr2COOMe (yield 20—30%).3 But these
methods are not preparative ones. In other papers by
Russian4—8 and Japanese authors9,10 devoted basically
to the study of biological activity4—6 or crystal strucꢀ
tures7,8 of fluorineꢀsubstituted benzimidazoles, no proceꢀ
dures of their synthesis were given, rather only the reacꢀ
tants, oꢀphenylenediamine (1a) and hexafluoropropene (in
* The present paper is dedicated to the memory of Professor
A. F. Kolomiets.
i. 20 °C, DMF;
ii. 80 °C, MeCN or dioxane; RF = C4F9, C6F5
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 182—187, January, 2010.
1066ꢀ5285/10/5901ꢀ0186 © 2010 Springer Science+Business Media, Inc.

Synthesis of fluorineꢀcontaining benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
187
Scheme 3
Results and Discussion
The preparative methods of synthesis of benzimidaꢀ
zoles containing fluoroalkyl substituents in position 2
(CHF2, CH(F)CF3, and CH(F)OCF3) and substituents
(Me or Cl) in the aromatic ring are described in the present
paper. Our first attempts to obtain 2ꢀdifluoromethylbenzꢀ
imidazole (2) by the reaction of 1a with tetrafluoroethylꢀ
ene in an open system in the presence of Et2NH as an HF
acceptor (in AcOEt) were unsuccessful, probably, because
of low reactivity of this olefin. Therefore, 2 was syntheꢀ
sized by a traditional method for benzimidazoles, i.e., by
condensation of 1a with difluoroacetic acid in an organic
solvent in the presence of 5 mol.% of pꢀtoluenesulfonic
acid (Scheme 2).
R = Me, Et
Scheme 2
ture to 25 °С resulted in a decrease in the yield of 3 beꢀ
cause of the increase in the amount of the side product,
N,Nꢀdialkylꢀ2,3,3,3ꢀtetrafluoropropionamide (up to 30%,
entry 9, Table 1). Among the catalysts tested, only tertiary
amines (Et3N, Py) deserve attention, since the presence of
them prevents the formation of a sediment of intermediate
А (see Scheme 3); this is important from the technological
point of view.
We assume that the mechanism of the threeꢀcompoꢀ
nent reaction includes the transient formation of a crysꢀ
talline complex 1 : 1 : 1 (А) insoluble in AcOEt, which
then undergoes cyclization to fluorasol 3 upon eliminaꢀ
tion of dialkylamine dihydrofluoride. Apparently, along
with formation of phenylene intermediate А, competing
reaction of hexafluoropropene with dialkylamines takes
place resulting in α,αꢀdifluoroamines В. Possibly, the reꢀ
action of the latter with 1a also affords fluorasol 3, while
the side products (dialkylamides) form in the reaction with
the atmospheric moisture (Scheme 4).
2ꢀ(1,2,2,2ꢀTetrafluoroethyl)benzimidazole (3) (drug
"fluorasol") can find application in medicine and veteriꢀ
nary due to its high physiological activity,4—6 therefore we
have studied its synthesis in detail. A method for preparaꢀ
tion of fluorasol 3, similar to that shown in scheme 2, is
noneconomic because the starting 2,3,3,3ꢀtetrafluoroproꢀ
pionic acid is hardly accessible. The reaction of 1a with
hexafluoropropene in DMF4,5,9 should be carried out in
sealed tubes, which is also unacceptable in case of considꢀ
erable loads. Therefore, we developed a new method of
manufacture of fluorasol 3 in an open system suitable for
scaling. It consists of a threeꢀcomponent reaction of 1a,
hexafluoropropene, and a secondary amine in AcOEt as
a solvent (Scheme 3). Various amines (dimethylamine or
diethylamine), catalysts, and temperature conditions were
tested for procedure optimization. Thus entries 1—4 refer
to the absence of a catalyst; a crown ether (entry 5) and
a phaseꢀtransfer catalyst (entry 6) were added to the reacꢀ
tion mixtures (0.15—0.24 mol.%), as well as pyridine (enꢀ
try 7) and triethylamine (entries 8, 9) (10 mol.% with
respect to 1a) (Table 1). It was shown that the presence of
a catalyst (as well as its nature) is not of considerable
influence on the yield and the purity of product 3. The
temperature regime is more important, because the reacꢀ
tion with hexafluoropropene, unlike that with tetrafluoroꢀ
ethylene, is exothermic (Scheme 3).
Scheme 4
R = Me, Et
Further, we compared the aboveꢀdescribed method
with the known methods4,5,9 by examples of reactions of
compound 1a and its monosubstituted analogs (1b,c) with
both hexafluoropropene and perfluoro(methyl vinyl ether).
The best results were obtained in the temperature range
from 7 to 12 °С with Et2NH (entry 4) or at 0 °С with
Me2NH (entry 2). The increase in the reaction temperaꢀ

188
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Vasilyeva et al.
Table 1. The influence of the reaction conditions on the yield and purity of fluorasol 3 prepared by coupling of oꢀphenyleneꢀ
diamine (1a) with hexafluoropropene
Entry
1a/g
(mol)
R2NH
/g (mol)
AcOEt
/mL
Catalyst
/mg (mmol)
Ta/°С
Yield of 3
/g (%)
M.p. of 3
/°С
1
2
3
4
5
5.4
(0.05)
Me2NH
2.7 (0.06)
40
40
40
40
26
—
—
—
—
–10
0
8.05 (74)
9.5 (87)
186—195
195—197
195—197
188—192
190—192
5.4
(0.05)
Me2NH
2.7 (0.06)
5.4
(0.05)
Me2NH
2.7 (0.06)
10
7.87—7.93
(72—73)b
5.4
(0.05)
Et2NH
4.38 (0.06)
7—12
10
9.3 (85)
3.51
(0.032)
Et2NH
2.85 (0.039)
Dicyclohexanoꢀ
18ꢀcrownꢀ6
5.59 (79)b
17.6 (0.047)
6
7
8
9
3.51
(0.032)
Et2NH
2.85 (0.039)
25
40
[PhCH2NEt3]+Cl–
17.6 (0.077)
10
5.25 (74)
8.3 (76)
190—191
195—199
185—193
188—190
5.4
(0.05)
Et2NH
4.38 (0.06)
Py
400 (5.06)
15—20
15—20
≥25
5.4
(0.05)
Et2NH
4.38 (0.06)
40
Et3N
510 (5)
8.88 (81.5)
22.89 (70)c
16.2
Et2NH
130
Et3N
(0.15)
11.5 (0.16)
1515 (15)
a Temperature of the reaction.
b Two runs.
c
CF3CH(F)CONEt2 (9 g, 30%) with b.p. 76 °С (10 Torr) was isolated from the filtrate by distillation.
Scheme 5
It is found that, indeed, replacement of the solvent (DMF
instead of AcOEt) brings about spontaneous cycloconꢀ
densation of different phenylenediamine derivatives with
fluoroolefins in the absence of dialkylamines. In this way,
both the previously known and novel 2ꢀfluoroalkylbenzꢀ
imidazoles 3—8 were obtained (Scheme 5).
We assume that in this case initial addition of the amiꢀ
no group to the double bond of the olefin takes place;
dehydrofluorination of 1 : 1 adducts formed affords the
reactive imidoyl fluorides С, which undergo cyclization in
compounds 3—8. As a result of prototropic tautomerizaꢀ
tion of benzimidazoles,13 the cyclization of 4ꢀmethylꢀ or
4ꢀchloroꢀsubstituted phenylenediamines with fluorooleꢀ
fins results in 5ꢀ or 6ꢀХꢀsubstituted benzimidazoles 5—8
in which the positions 5 and 6 are equivalent (see Scheme 5).
The process is lengthy, which is a drawback of this methꢀ
od. The reaction is exothermic in the presence of secondꢀ
ary amines (see Scheme 3) and completes in 1—2 h, whereꢀ
as in DMF (see Scheme 5) reaction with CF2=CF—RF
takes from 2—3 (RF = CF3) to 4—7 days (RF = OCF3);
therefore, the latter reaction was carried out in sealed tubes.
In addition, the reactions in DMF were complicated by
polymerization (which probably involved the double bond
—N=C< of intermediate С), which made difficult the isoꢀ
lation and purification of the products. After multiple treatꢀ
ments with activated charcoal and sublimations, the yields
X = H (1a), Me (1b), Cl (1c)
Compound
X
RF
3
H
4
H
5
Me
CF3
6
Me
OCF3
7
Cl
CF3
8
Cl
OCF3
CF3
OCF3

Synthesis of fluorineꢀcontaining benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
189
of the cyclization products were lower (49—60%) than in
the former method (see Scheme 3, 72—87%).
stable and can be stored without changes at room temperꢀ
ature for no less than 5 years. The stability of compounds
3, 4, and 6 in DMF solution with heating was estimated
by spectroscopy. No changes in the 19F NMR spectra of
trifluoromethoxybenzimidazoles 4 and 6 occured upon
heating (100 1 °С) for 10 h in DMF (at a concentration
of 20%). Under the same conditions, the concentration
of fluorasol 3 reduced nearly twofold; at the same time,
a new signal at δ > 100 appeared. The increased stability of
4 and 6 toward heating in DMF (as compared with fluoroꢀ
azol 3) can be related to the presence of Нꢀbonds in their
molecules.
In addition, we began studying the reactivities of comꢀ
pounds obtained. It is known that benzimidazoles are easꢀ
ily alkylated, acylated,13 and silylated with hexamethylꢀ
disilazane.14,15 However, fluorineꢀsubstituted analogs were
found to be very stable and inert toward alkyl halides,
sulfenyl chlorides, chlorotrimethylsilane, and hexamethꢀ
yldisilazane because of dramatic decrease in the imine
nitrogen basicity. Silylation of fluorasol 3 was succesful
only with N,NꢀdiethylꢀNꢀtrimethylsilylamine in the presꢀ
ence of catalytic amounts of ammonium sulfate; Nꢀtrimeꢀ
thylsilylfluoroazol 9 was obtained in high yield (Scheme 6),
which will allow modification of fluorineꢀcontaining benꢀ
zimidazoles at the nitrogen atom in the future.
The yields and physicochemical properties of comꢀ
pounds obtained are listed in Table 2, and their spectral
characteristics are given in Table 3. Unsubstituted benzꢀ
imidazoles are waterꢀsoluble13; in contrast, fluorineꢀsubꢀ
stituted benzimidazoles 2—8 are insoluble in water, diꢀ
ethyl ether, and petroleum ether. They are soluble in alcoꢀ
hols, AcOEt, MeCN, DMF, and DMSO and are moderꢀ
ately soluble in CHCl3 and benzene. They are easily subꢀ
limed in vacuum at elevated temperatures, which is tyꢀ
pical of them. In the IR spectra of fluorineꢀcontainꢀ
ing benzimidazole derivatives, ν(C=N) are observed at
1590—1630 cm–1 and ν(N—Н) at 2600—3200 cm–1. The
1Н NMR spectra of benzimidazoles with RF = CF3 (3, 5,
7) contain a doublet of quartets of the methine proton
(CHF) at δ ≈ 6; for compounds with RF = OCF3 (4, 6, 8),
it is a doublet at δ~7 (in CDCl3). In DMSOꢀd6, the sigꢀ
nals for CHF are shifted to the lower field by ~1 ppm (for 3)
and 0.45 ppm (for 4). On the basis of the NMR spectra of
benzimidazoles with substituents in the aromatic ring,
RF = OCF3, Х = Me (6) and Cl (8), it can be assumed that for
solutions in CDCl3 these compounds exist in both the free
form and the form of a stereoisomer with intraꢀ or interꢀ
molecular Нꢀbond >CHF...H—N<, which was revealed
by doubling of signals for the CHF groups in the 19F NMR
spectra and by complication of the signals for aromatic
protons in the 1Н NMR spectra (see Table 3).
Thus, the following order of reactivity of fluoroolefins
with respect to oꢀphenylenediamine was found in the
present study:
We studied the stability of the fluorineꢀcontaining benꢀ
zimidazole derivatives obtained. In solid state, they all are
F2C=CF2 < F2C=CF—OCF3 < F2C=CF—CF3.
Table 2. Physicochemical characteristics of fluorineꢀcontaining benzimidazole derivatives
a
Comꢀ
pound
Yield
(%)
M.p./°С
(solvent)
Found
Calculated
Molecular
formula
RF
(%)
C
H
N
2
3
65
72—87с
60d
153b (Pri—H2O)
191—193; 195—197c
(AcOEt—hexane)
189—190d (PhH)
140—141
—
49.44
49.54
—
2.70
2.75
—
12.77
12.84
С8H6F2N2
С9H6F4N2
0.26
0.40
4
5
6
7
8
52
49
57
59
50
46.14
46.15
—
2.51
2.56
—
11.97
11.97
—
C9H6F4N2O
C10H8F4N2
0.44
0.41
0.47
0.48
0.55
(PhH—petrol. ether)
176—177e
(PriOH—H2O)
123—124 f
48.21
48.39
—
3.24
3.23
—
11.28
11.29
—
C10H8F4N2O
C9H5ClF4N2
C9H5ClF4N2Oi
144—146g,h
(CHCl3—hexane)
124—126h
40.12
40.22
1.87
1.86
10.19
10.43
a Crimson spot in UV light; system AcOEt—petroleum ether, 1 : 3. b M.p. 155—156 °С (see Ref. 2); 146—148 °С (see Ref. 3).
с Obtained in accordance with Scheme 3 (entries 1—8, see Table 1); m.p. 184 °С (see Refs 4, 5). d Obtained in accordance
with Scheme 5. e M.p. 176 °С (see Ref. 9); 174—175 °С (see Ref. 10). f Purified by sublimation in vacuo (1 Torr) at 80 °С.
g M.p. 143—144 °С (see Ref. 9); 142—143 °С (see Ref. 10). h Purified by sublimation in vacuo (3 Torr) at 120—154 °С.
i Found: F, 28.32%, calculated: F, 28.31%.

190
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Vasilyeva et al.
Table 3. Spectral characteristics of fluorineꢀcontaining benzimidazole derivativesa
Comꢀ
pound
Solvent
1Н NMR, δ (J/Hz)
19F NMR,
δ (J/Hz)b
2
3
CDCl3
DMSOꢀd6
CDCl3
6.99 (t, 1 Н, СHF2, J = 53.9); 7.43 (m, 2 Н, Н(5)+Н(6));
7.76 (br.s, 2 Н, Н(4)+Н(7)); 10.59 (br.s, 1 Н, NH)
6.81 (dq, 1 Н, СHF, J = 42.3, J = 6.4); 7.35 (m, 2 Н, Н(5)+Н(6));
7.70 (br.s, 2 Н, Н(4)+Н(7)); 13.26 (br.s, 1 Н, NH)
5.84 (dq, 1 Н, СHF, J = 46.8, J = 8.5); 7.03 (m, 2 Н, Н(5)+Н(6));
7.58 (m, 2 Н, Н(4)+Н(7)); 9.58 (br.s, 1 Н, NH)
37.45 (s, CF2)
–2.03 (d, CF3, J = 13.9);
119.68 (q, CHF, J = 13.9)
—
4
CDCl3
7.05 (d, 1 Н, СHF, J = 56.2); 7.44 (m, 2 Н, Н(5)+Н(6)); 7.60,
7.88 (both br.s, 1 Н each, Н(4)+Н(7)); 10.44 (br.s, 1 Н, NH)
7.50 (d, 1 Н, СHF, J = 53.9); 7.33 (m, 2 Н, Н(5)+Н(6));
7.67 (br.s, 2 Н, Н(4)+Н(7)); 13.15 (br.s, 1 Н, NH)
2.56 (s, 3 Н, Mе); 6.07 (dq, 1 Н, СHF, J = 43.5, J = 5.9);
7.25 (d, 1 Н, Н(5), J = 8.4); 7.50,
7.63 (both br.s, 1 Н each, Н(4)+Н(7)); 10.08 (br.s, 1 Н, NH)
2.56 (s, 3 Н, Mе); 7.01 (d, 1 Н, СHF, J = 56.3);
7.25 (m, 1 Н, Н(5)c,d; 7.38 (br.s, 1 Н, Н(7), 43%)c;
7.47 (br.d, 1 Н, Н(7), J = 8.1, 57%)d; 7.68 (br.s, 1 Н, Н(4), 43%)с;
7.77 (br.d, 1 Н, Н(4), J = 8.1, 57%)d; 10.09 (br.s, 1 Н, NH)
6.07 (dq, 1 Н, СHF, J = 43.7, J = 5.8); 7.41 (s, 1 Н, Н(7));
7.55 (m, 1 Н, Н(5)); 7.80 (m, 1 Н, Н(4)); 10.52 (s, 1 Н, NH)
7.02 (d, 1 Н, СHF, J = 56.2); 7.38 (m, 1 Н, Н(7));
–18.39 (d, ОCF3, J = 5.05);
45.81 (q, CHF, J = 5.05)
—
DMSOꢀd6
CDCl3
5
6
–0.06 (d, CF3, J = 14.0);
120.02 (q, CHF, J = 14.0)
CDCl3
–18.43 (d, ОCF3, J = 5.0);
45.62 (q, CHF, J = 4.1, 43%)c;
45.44 (q, CHF, J = 4.6, 57%)d
7
8
CDCl3
CDCl3
–0.10 (d, CF3, J = 13.6);
121.25 (m, CHF)
–18.38 (d, ОCF3, J = 5.0);
46.27 (q, CHF, J = 4.5, 44%)c;
46.14 (q, CHF, J = 5.2, 56%)d
7.56 (m, 1 Н, Н(5)); 7.82 (m, 1 Н, Н(4)); 10.44 (s, 1 Н, NH)
a IR spectra (ν/cm–1) for 3: 1600—1630 (C=N), 2600—3200 (NH); for 4: 1590 (C=N), 2600—3200 (NH); for 6: 1600 (C=N),
2600—3200 (NH).
b Relative TFA, with proton suppression (19F{H}).
c Free form.
d Stereoisomer with the Нꢀbond >CHF...H—N<.
Scheme 6
Experimental
NMR spectra were recorded on a Bruker AVꢀ300 spectrometer
at frequencies 300 MHz for 1Н, and 282 MHz for 19F (CF3CO2H).
All the solvents employed in the reactions were dried with the
appropriate drying agents. The reactions were monitored by TLC
on silica gel plates (Merck 60 F254). Characteristics of the comꢀ
pounds synthesized are given in Tables 2 and 3.
2ꢀDifluoromethylꢀ1Нꢀbenzimidazole (2). A mixture of oꢀpheꢀ
nylenediamine (1a) (10.8 g, 0.1 mol), difluoroacetic acid (10 g,
0.104 mol), and TsOH•H2O (0.95 g, 0.005 mol) in xylene
(60 mL) and benzene (10 mL) was refluxed with a Dean—Stark
trap until liberation of water ceased (~6 h) and cooled. The
precipitate that formed was filtered off, dissolved in AcOEt
(100 mL), and stirred with activated charcoal (2 g) for 5 h. The
residue after removal of charcoal and the solvent was purified by
precipitation with water from a solution in PriOH to yield 11 g of
compound 2.
When attempted to carry out the reaction of 1a with tetrafluꢀ
oroethylene in the presence of Et2NH in AcOEt (by analogy
with the synthesis of 3), no product 2 was formed (TLC control).
2ꢀ(1,2,2,2ꢀTetrafluoroethyl)ꢀ1Нꢀbenzimidazole (fluorasol)
(3). To a fourꢀneck flask with a stirrer, thermometer, bubbler,
and a reflux condenser connected to the trap cooled to –40 °С,
1a and a solution of a secondary amine (Me2NH or Et2NH) in
ethyl acetate were placed. Entries 1—4 (see Table 1) refer to the
The preparative methods of synthesis were proposed
for the known and novel fluorineꢀsubstituted benzꢀ
imidazoles 2—8. Their stabilities were determined. A new
method for manufacture of the promising bioactive
compound ftorazol (3) was developed; this consists of
heterocyclization of 1a with hexafluoropropene in the
presence of secondary amines in ethyl acetate. This
method has good reproducibility and is suitable for
the synthesis of other benzimidazoles containing fluꢀ
oroalkyl substituents HFC—RF, where RF = OCF3 or
CnF2n+1 (n = 2—6), in position 2. Silylated fluorasol (9)
with high synthetic potential was synthesized for the
first time.

Synthesis of fluorineꢀcontaining benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
191
absence of a catalyst. The following catalysts were tested: crown
ether (entry 5), a phaseꢀtransfer catalyst (entry 6) (0.5% mass
in respect of 1a), and tertiary amines (entries 7—9) (10 mol.%
in respect of 1a). The reaction temperatures are shown in Table 1.
Hexafluoropropene was passed at this temperature with vigorous
stirring (the reaction is exothermic) until the excess of hexafluoꢀ
ropropene began to condense in the trap (1 h 15 min — 2 h
20 min). During the reaction, a lightꢀcolored precipitate of inꢀ
termediate А formed at the beginning, and then dissapeared.
In the presence of tertiary amines (entries 7—9), no formation of
a precipitate was observed.
After completion of the reaction (dissapearance of the startꢀ
ing 1a as judged by TLC in the solvent system acetone—CCl4,
1 : 3), the excess of hexafluoropropene (from the trap) was addꢀ
ed to the reaction flask and the mixture was stirred and gradually
warmed to 20 °С. The reaction mixture was washed with water
(×3), the organic layer was separated, and aqueous layers were
extracted with ethyl acetate (×3). The organic layers were comꢀ
bined and discolored by stirring with activated charcoal (10% in
respect of the starting 1a) for 1—1.5 h. After removal of charcoal
by filtration, the fitrate was concentrated in vacuo, the solid
precipitate was washed on a filter with hexane and dried in air.
The loads in the experiments, their conditions, and the reꢀ
sults (yields and m.p. of 3) are presented in Table 1, the physicoꢀ
chemical characteristics and NMR (1H and 19F) spectra of ftorꢀ
azol 3 are given in Tables 2 and 3.
column, supplied with bubbler and a tube filled with КОН (at
the outlet). The mixture was heated in a flow of argon at
120—140 °С (bath) until the distillation of diethylamine ceased
(1.5 h). The excess of Me3SiNЕt2 was removed in vacuo, the
residue was distilled to give compound 9 (7.08 g, 81%) as a viscous
lightꢀbrown sirup, b.p. 95 °С (0.05 Torr), which is soluble
in CH2Cl2, CHCl3, and MeOH. 1H NMR (CDCl3, δ): 0.67
(s, 9 H, SiMe3); 6.08 (dq, 1 Н, CHF, J = 44.4 Hz, J = 5.1 Hz);
7.37 (m, 2 Н, Н(5)+Н(6)); 7.65, 7.92 (two m, both 1 Н, Н(4),
Н(7)). 19F NMR (CDCl3, δ): –3.14 (dd, CF3, J = 14.4 Hz,
J = 5.1 Hz); 112.35 (dq, CHF, J = 44.4 Hz, J = 14.4 Hz).
Compound 9 is unstable: it is quickly hydrolyzed in air to the
initial fluorasol 3 (TLC control).
References
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Nauk USSR, Ser. Khim., 1987, 2527 [Bull. Acad. Sci. SSSR,
Div.Chem. Sci. (Engl. Transl.), 1987].
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Synthesis of 5ꢀ or 6ꢀsubstituted 2ꢀfluoroalkylꢀ and 2ꢀfluoroꢀ
alkoxyꢀ1Нꢀbenzimidazoles (3—8) (general procedure). A soluꢀ
tion of the corresponding оꢀphenylenediamine (0.073 mol) in
DMF (40 mL) was placed in a 250ꢀmL tube, then an excess of
hexafluoropropene or perfluoro(methyl vinyl ether) (0.1—0.2 mol)
–
–
was condensed in the tube at 60— 80 °С. The tube was sealed
and gradually warmed to 20 °С. The heterogeneous reaction
mixture (consisting of two layers) was kept with periodic shaking
until the layer of the fluoroolefin disappeared. The synthesis of
compounds with RF = CF3 (3, 5, 7) was completed in 2—3 days,
but for the preparation of compounds with RF = OCF3 (4, 6, 8)
longer period (from 4 to 7 days) was needed. After the homogeꢀ
nization was attained, the tube was cooled, opened and the conꢀ
tent was poured into ice water (400 ml). If no solidification ocꢀ
curred after mixing with water, water was removed by decantaꢀ
tion, and the residue was mixed with fresh portions of water. The
precipitate was filtered off, thoroughly washed with water (×3),
then with hexane or petroleum ether (×2). The product was
discolored by dissolution in ethyl acetate and stirring with actiꢀ
vated charcoal for 2—3 h (for 10 g of the raw product, 50 mL of
ethyl acetate and 1.5 g of activated charcoal were used). When
necessary, the procedure was repeated. After removal of charꢀ
coal by filtration, the filtrate was concentrated in vacuo, the
residue was purified by recrystallization, reprecipitation, or subꢀ
limation. The characteristics of compounds 3—8 are given in
Tables 2 and 3.
6. E. I. Astashkin, A. S. Gukovskaya, A. M. Surin, I. S. Niꢀ
kolaeva, Yu. V. Slavich, A. F. Kolomiets, A. V. Fokin, Dokl.
Akad. Nauk SSSR, 1988, 300, 249 [Dokl. Biochem. Phys.
Chem. (Engl. Transl.), 1988].
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1999, 365, 72 [Dokl. Chem. (Engl. Transl.), 1999].
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10. H. Iwakiri, N. Fujiwara, N. Ishikawa, Nippon Kagaku Kaiꢀ
shi, 1985, 2161.
11. H. Harada, S. Mizutaki, S. Hayashi, N. Ishikawa, J. Fluorine
Chem., 1978, 12, 211.
12. W. Burger, K. Lunkwitz, J. Fluorine Chem., 1993, 60, 125.
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(in Russian)
14. I. Southon, W. Pfleiderer, Chem. Ber., 1978, 111, 996.
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J. Heterocycl. Chem., 1978, 15, 657.
2ꢀ(1,2,2,2ꢀTetrafluoroethyl)ꢀ1ꢀtrimethylsilylꢀ1Нꢀbenzimidꢀ
azole (9). Fluorasol 3 (6.54 g, 0.03 mol) , N,NꢀdiethylꢀNꢀtrimeꢀ
thylsilylamine (13.05 g, 0.09 mol), and catalytic amount (78 mg)
of (NH4)2SO4 were placed in a Claisen flask with a distillation
Received September 15, 2009