N-Trihalomethyl derivatives of benzimidazole, benzotriazole and indazole

Article abstract of DOI:10.1016/S0022-1139(00)00321-3

1-Chlorodifluoromethyl- and 1-trifluoromethyl-substituted 2-methylbenzimidazoles and benzotriazoles were obtained by chlorination of the corresponding methyl 1-azoledithiocarboxylates and subsequent fluorination of the resulting 1-trichloromethyl derivatives. The condensation of N-sodium salts of 2-alkylbenzimidazoles and indazole with CF₂Br₂ was shown to afford the corresponding 1-bromodifluoromethylated compounds.

Full text of DOI:10.1016/S0022-1139(00)00321-3

Journal of Fluorine Chemistry 106 (2000) 181±187
N-Trihalomethyl derivatives of benzimidazole,
benzotriazole and indazole
Lev M. Yagupolskii*, Dmitrij V. Fedyuk, Kirill I. Petko,
Valeriya I. Troitskaya, Valentina I. Rudyk, Vitalij V. Rudyuk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya Street,
Kiev 02094, Ukraine
Received 11 April 2000; accepted 24 July 2000
Abstract
1-Chlorodi¯uoromethyl- and 1-tri¯uoromethyl-substituted 2-methylbenzimidazoles and benzotriazoles were obtained by chlorination of
the corresponding methyl 1-azoledithiocarboxylates and subsequent ¯uorination of the resulting 1-trichloromethyl derivatives. The
condensation of N-sodium salts of 2-alkylbenzimidazoles and indazole with CF2Br2 was shown to afford the corresponding 1-
bromodi¯uoromethylated compounds. # 2000 Elsevier Science B.V. All rights reserved.
Keywords: Heterocycles; Dithiocarboxylates; Trihalomethylation; Azoles; Triazoles
1. Introduction
it hydrolyzes to give, after treatment with ammonia, 2-
methylbenzimidazole.
N-Trihalomethyl-substituted derivatives of nitrogen het-
erocyclic compounds are poorly known [1] and for benzi-
midazole, benzotriazole and indazole they have not been
reported at all.
We have synthesized various N-trihalomethyl derivatives
of the indicated heterocyclic bases which turned out to be
useful intermediates for preparation of drug products, pes-
ticides and dyestuffs [2,3].
2-Methyl-1-trichloromethylbenzimidazole 3 was ob-
tained by treatment of the salt 2 with triethylamine in
THF. The compound is unstable in storage and easily
hydrolyzed. On heating at re¯ux with SbF3 in dioxane, 3
is transformed into 1-chlorodi¯uoromethyl-2-methylbenzi-
midazole 4, a liquid stable in air and distillable in vacuo
(Scheme 2).
The attempts at substituting all the chlorine atoms in 3 or 4
with ¯uorine by heating with SbF3 in the absence or in the
presence of catalysts (SbCl5 or Br2) were unsuccessful and
led to tarring.
2. Results and discussion
On treating with anhydrous HF at 208C, the trichloro-
methyl group in 2 remains untouched. The resulting less
stable hydro¯uoride salt loses hydrogen ¯uoride in vacuo to
give the base 3.
We have proposed a suitable method for substitution of
hydrogen at the nitrogen atom of the heterocycles with
trihalomethyl groups by the reaction of their N-sodium salts
with carbon disul®de and methyl iodide followed by chlor-
ination of the (methylthio)thiocarbonyl function and ¯uor-
ination of the resulting trichloromethyl group (Scheme 1).
Compound 1 was previously described [4]. On chlorina-
tion, it affords the hydrochloride salt 2 in quantitative yield.
The salt is storage-stable in the absence of moisture. In water
The N-sodium derivative of benzotriazole is dithiocar-
boxylated with carbon disul®de at 10 to 08C. The reaction
is inhibited by water even in trace amounts. The resulting
methyl dithiocarboxylate 5 is converted into 1-trichloro-
methylbenzotriazole 6 in good yield on treatment with
chlorine in CCl4. Since benzotriazole is a weaker base
compared to benzimidazole, it gives on chlorination the
free base 6 rather than the hydrochloride salt. On heating
with anhydrous hydrogen ¯uoride, compound 6 converts
into 1-tri¯uoromethylbenzotriazole 7, a storage-stable liquid
resistant to hydrolysis (Scheme 3).
* Corresponding author. Tel.: ‡38-044-559-03-49;
fax: ‡38-044-573-26-43.
E-mail address: lev@fluor-ukr.kiev.ua (L.M. Yagupolskii).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 2 1 - 3

182
L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 106 (2000) 181±187
Scheme 1.
On chlorination, methyl 1-carbazoledithiocarboxylate 10
gives a mixture of products from which 3,3-dichloro-1-
trichloromethyl-2,3-dihydrocarbazole 11 was isolated as
crystals in 17% yield. After heating with 10% H2SO4, 11
was converted to the previously described 3-hydroxycarba-
zole [5] (Scheme 5).
Scheme 2.
The structure of Compound 11 was con®rmed by chemi-
1
cal analysis and H NMR spectrum which, in addition to
The interaction of the N-sodium derivative of indazole
with carbon disul®de and methyl iodide under the same
conditions leads to a 1:3 mixture of methyl 1- and 2-
indazoledithiocarboxylates 8 and 9 in good yield. The
isomers were separated by chromatography on silica gel
(Scheme 4).
signals of the aromatic protons, displayed the signals of two
protons in the 2-position (AB-system) and two doublets of
the protons at the C4=C5 double bond.
One further approach to N-trihalomethyl derivatives of
the indicated heterocyclic compounds was employed, that is,
the condensation of their sodium salts with CF2Br2. Only
one example of this reaction with 4-ethoxycarbonylpyrazole
has been reported to date [1].
The chlorination of these compounds in CCl4 at 08C gives
a complex mixture of unidenti®ed products.
We used the same approach to prepare N-trichloromethy-
lated carbazole. The reaction of its N-sodium derivative with
carbon disul®de is less sensitive to moisture and temperature
compared to the systems considered above. Sodium hydride
can be replaced with sodium hydroxide, but the yield
decreases from 90 to 30%. With other heterocycles sodium
hydroxide is totally ineffective in the dithiocarboxylation
reaction.
It was found that 2-methyl-, 2-propyl-, 2-benzylbenzimi-
dazole and 2-methylnaphtho[2,3-d]imidazole give in this
reaction the corresponding 1-bromodi¯uoromethylated ben-
zimidazoles and naphthimidazole. The reaction of benzimi-
dazoles having two electron-donor methoxy groups in
positions 5 and 6 or two ethoxy substituents in positions
4 and 7 is accompanied by tarring and no individual product
can be isolated from the reaction mixture (Scheme 6).
Scheme 3.
Scheme 4.

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 106 (2000) 181±187
183
Scheme 5.
Scheme 7.
which was separated by fractional distillation in vacuo
(Scheme 8).
In contrast to 12a, the substitution of the bromine for
¯uorine in 1-bromodi¯uoromethyl-4-dimethylaminopyridi-
nium bromide with tetramethylammonium ¯uoride proceeds
at room temperature in a dichloromethane solution [6].
Compound 12a can be converted into 14 also by heating
with SbF3, but the end product is dif®cult to isolate from the
reaction mixture.
Compounds 12a and 14 were transformed into tertiary
salts 15 by treatment with methyl iodide and AgBF4
(Scheme 9).
The sodium salt of benzotriazole does not react with
dibromodi¯uoromethane under the indicated conditions.
The reaction of more nucleophilic sodium derivatives of
carbazole or alkoxybenzimidazoles with CF2Br2 is accom-
panied by heavy tarring.
Scheme 6.
The halogen substituents in the benzene ring of benzi-
midazole do not interfere with the reaction. Thus, 1-bromo-
di¯uoromethyl-5,6-dichloro-2-methylbenzimidazole12e and
1-bromodi¯uoromethyl-4,5,6,7-tetra¯uoro-2-methylbenzi-
midazole 12f were obtained in high yields. The reaction is
accelerated in the presence of zinc dust.
The products 12 are crystallized from hexane as low
melting solids. Some of them (12a, b and f) are distilled
in vacuo.
We were able to prepare 1-bromodi¯uoromethylimida-
zole (13), but in small yield (9%), by conducting the
condensation reaction in acetonitrile at a low concentration
of the reagents. The sodium salt of imidazole is only
dif®cultly soluble in this solvent (Scheme 7).
The sodium salt of indazole interacts with CF2Br2 to
afford a 1:0.75 mixture of 1- and 2-bromodi¯uoromethy-
lindazole 16 and 17 in about 60% overall yield. The isomers
were not separated (Scheme 10).
1-Bromodi¯uoromethylbenzimidazoles react with aro-
matic aldehydes in the presence of tetrakis(dimethylami-
no)ethylene (TDAE) to form compounds 18 of potential
interest for medicinal chemistry [7,8] (Scheme 11).
The di¯uoromethylene group in 18 is stable and is not
hydrolyzed with dilute acids and bases at room temperature.
1-Bromodi¯uoromethyl-2-methylbenzimidazole
was
converted into the 1-tri¯uoromethyl derivatives 14 by re¯ux-
ing with tetramethylammonium ¯uoride in anhydrous
monoglyme. The reaction is accompanied by the formation
of the 1-di¯uoromethylated product in signi®cant amount
Scheme 8.

184
L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 106 (2000) 181±187
calculated for C9H8Cl4N2:Cl 49.65%, Compound 2 was
used without puri®cation.
3.3. 2-Methyl-1-trichloromethylbenzimidazole (3)
A mixture of 2 (5 g, 18 mmol) and Et3N (2.6 ml,
19.8 mmol) in dry THF (50 ml) was re¯uxed for 5 h. The
solvent was evaporated under reduced pressure and the
residue was extracted with hot hexane. The extract was
evaporated to leave a crude product which was puri®ed by
crystallization from hexane to give 3.6 g (80%) of 3 as light
yellow crystals, mp 83 848C, 1H NMR (acetone-D6):
d ˆ 2:58 (s, 3H); 6.83±8.00 (m, 4H). Found: Cl 42.60,
calculated for C9H7Cl3N2: Cl 42.62%.
Scheme 9.
3.4. 1-Chlorodifluoromethyl-2-methylbenzimidazole (4)
Scheme 10.
To a solution of 3 (1 g, 4 mmol) in dry dioxane (50 ml)
was added SbF3 (1.08 g, 6 mmol). The mixture was heated
under re¯ux for 6 h and evaporated under reduced pressure.
The residue was extracted with hexane. The extract was
concentrated in vacuo and distilled to give 0.5 g (58%) of 4
as a colorless liquid, bp 68±708C (0.1 Torr), n1D8 ˆ 1:5372,
1H NMR (CDCl3): d ˆ 2:77 (s, 3H); 7.3±7.8 (m, 4H). 19F
NMR (CDCl3): d ˆ 33:96 (s, CF2Cl). Found: Cl 16.15,
calculated for C9H7ClF2N2: Cl 16.37%.
3. Experimental
3.1. General
1
Boiling and melting points are uncorrected. H NMR:
Varian VXR-300 (300 MHz) (TMS as internal standards).
19F NMR: Varian VXR±300 (288 MHz) (CFCl3 as internal
standard). Mass spectra were obtained on a MX-1321 mass
spectrometer at 70 eV.
3.5. General procedure for synthesis of methyl
azoledithiocarboxylates
3.2. 2-Methyl-1-trichloromethylbenzimidazole
hydrochloride (2)
To a suspension of sodium hydride (60%, 1 g, 25 mmol)
in anhydrous DMF (10 ml) was added under the inert atmo-
sphere at 108C a solution of the appropriate N±H azole
(20 mmol) in dry DMF (10 ml). The mixture was stirred for
40 min at 08C and cooled to 108C in an argon stream. CS2
(2 ml, 2.5 g, 35 mmol) was added dropwise and the resulting
red solution was stirred for 20 min at 08C and cooled again
to 108C. Methyl iodide (2 ml, 4.1 g, 27 mmol) was added
in one portion with vigorous stirring. The color changed
from red to yellow. The temperature was allowed to rise to
‡208C and after 5 min the mixture was poured into water
(150 ml).
Through a stirred and cooled ( 58C) solution of methyl 2-
methylbenzimidazole-1-dithiocarboxylate(11.6 g,5.2 mmol)
in CCl4 (800 ml) was bubbled dry Cl2 for 2 h at a tempera-
ture below 08C. Then the mixture was warmed up to room
temperature over 2 h. The precipitate was ®ltered under an
atmosphere of dry argon, washed with anhydrous CCl4
(3 Â 100 ml), and dried in vacuo to afford 15 g (100%) of
2 as colorless crystals, mp 185±1898C. Found: Cl 48.90,
3.6. Methyl 1-benzotriazoledithiocarboxylate (5)
The yellow crystals obtained, were ®ltered off, washed
with water, dried at 308C, and recrystallized from CCl4.
1
Yield 60%, mp 98±1008C, H NMR (CDCl3): d ˆ 2:57 (s,
3H); 7.5±7.7 (m, 2H); 8.1±8.2 (m, 1H); 8.7±8.8 (m, 1H).
Found: S 30.54, calculated for C8H7N3S2: S 30.64%.
3.7. Methyl 1- and 2-indazoledithiocarboxylates (8, 9)
The crystals were ®ltered off, washed with water, dried at
308C and chromatographed on SiO2 (MN-Kieselgel 60,
eluent CCl4/hexane 1:1).
Scheme 11.

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 106 (2000) 181±187
185
8: Yellow crystals, Rf ˆ 0:25, yield 17%, mp 88±898C
(from hexane), 1H NMR (CDCl3): d ˆ 2:67 (s, 3H); 7.4±7.7
(m, 2H); 7.9±8.0 (m, 1H); 8.42 (s, 1H); 9.1±9.2 (m, 1H).
Found S 30.42, calculated for C9H8N2S2:S 30.79%.
9: Yellow crystals, Rf ˆ 0:15, yield 52%, mp 113±1148C
(from hexane), 1H NMR (CDCl3): d ˆ 2:80 (s, 3H); 7.1±7.2
(m, 1H); 7.4±7.5 (m, 1H); 7.6±7.7 (m, 1H); 7.9±8.0 (m, 1H);
9.25 (s, 1H). Found: S 30.37, calculated for C9H8N2S2: S
30.79%.
mixture was allowed to stand for 12 h at 208C, the solvent
was evaporated in vacuo and the residue was evacuated
(0.01 Torr, 308C, 2 h). The oily mixture of the chlorination
products was dissolved in hexane (5 ml) and held at 08C for
24 h. The white precipitate was ®ltered off and washed with
hexane to give 0.3 g (17%) of 11, mp 167±1708C, 1H NMR
(CDCl3): d ˆ 4:95 (double, AB-system, 2H); 5.97 (d,
J ˆ 5 Hz, 1H); 6.37 (d, J ˆ 5 Hz, 1H); 7.35±7.55 (m,
2H); 7.61±7.68 (m, 1H); 8.19±8.26 (m, 1H). Found: Cl
50.24, calculated for C13H8Cl5N: Cl 49.87%.
3.8. Methyl 1-carbazoledithiocarboxylate (10)
3.12. General procedure for synthesis 1-
bromodifluoromethyl-2-alkylbenz- and naphthimidazoles
(12a±f)
The mixture of crystals and oil was extracted with ether
(3 Â 30 ml), washed with water (2 Â 30 ml), and dried
(CaCl2, 12 h). The solvent was evaporated, the product
was crystallized from hexane, yield 87%, mp 55±578C,
1H NMR (CDCl3): d ˆ 2:85 (s, 3H); 7.3±7.5 (m, 4H);
8.0±8.1 (m, 2H); 8,5±8.6 (m, 2H). Found: S 25.14, calcu-
lated for C14H11NS2: S 24.92%
To a stirred solution of 2-alkylbenzimidazole (20 mmol)
in 50 ml of anhydrous acetonitrile cooled to 158C, was
added zinc dust (0.1 g, 1.5 mmol) under an argon atmo-
sphere, followed by sodium hydride (0.53 g, 22 mmol)
added in portions. After the addition, the mixture was stirred
at 10 to 58C for 3 h, cooled to 158C and to a stirred
solution dibromodi¯uoromethane (2.74 ml, 30 mmol) was
added dropwise. The mixture was warmed to room tem-
perature over 2 h and stirred for 14 h. The solvent was
evaporated under reduced pressure and the residue was
extracted with hot hexane (3 Â 50 ml). The exstract was
®ltered and evaporated to leave a brown oil, which was
puri®ed by vacuum distillation or by crystallization from
hexane.
3.9. 1-Trichloromethylbenzotriazole (6)
Chlorine-gas was bubbled through a suspension of 5
(6.3 g, 30 mmol) in CCl4 (50 ml) at 08C, with stirring, until
a clear solution was formed. After stirring for 12 h at 208C,
the solvent was evaporated in vacuo, the residue was evac-
uated (2 h, 0.01 Torr), and crystallized from hexane to give
1
5.72 g (81%) of 6, as colorless crystals, mp 55±578C, H
NMR (CDCl3): d ˆ 7:55 7:60 (m, 1H); 7.65±7.70 (m, 1H);
8.05±8.10 (m, 1H); 8.10±8.15 (m, 1H). Found: Cl 44.20,
calculated for C7H4Cl3N3: Cl 44.97%.
3.13. 1-Bromodifluoromethyl-2-methylbenzimidazole
(12a)
3.10. 1-Trifluoromethylbenzotriazole (7)
Yield 76%, mp 29±308C, bp 80±828C (0.01 Torr), 1H
NMR (CDCl3): d ˆ 2:77 (s, 3H); 7.3±7.9 (m, 4H). 19F NMR
(CDCl3): d ˆ 27:76 (s, ±CF2Br). Found: C 41.88; H 2.56;
N 10.41, calculated for C9H7BrF2N2: C 41.41; H 2.70; N
10.73%.
Compound 6 (2 g, 8.5 mmol) was placed in a platinum
cylinder in anhydrous HF (3 ml). The cylinder was held in a
stainless steel bomb at 508C for 5 h. The volative products
were evaporated and the residue was extracted with hexane
(20 ml). The extract was washed with 1 M aq K2CO3
(2 Â 20 ml) and water (2 Â 20 ml). The organic layer was
dried over CaCl2 for 10 h, evaporated under reduced pres-
sure and the residue was distilled in vacuo. A drop of
pyridine was added to the distillate (1.07 g, 77%) and within
2 h, the product was distilled once again to give 0.82 g
(52%) of pure 7 as a colorless stable liquid, bp 77±788C
(15 Torr), 1H NMR (CDCl3): d ˆ 7:71 7:78 (m, 1H); 7.89±
7.95 (m, 1H); 7.98±8.02 (m, 1H); 8.28±8.34 (m, 1H). 19F
NMR (CDCl3): d ˆ 57:68 (s, CF3). Found: C 44.76; H
2.76; N 22.31, calculated for C7H4F3N3: C 44.93; H 2.15; N
22.46%.
3.14. 1-Bromodifluoromethyl-2-propylbenzimidazole
(12b)
1
Yield 80%, mp 44±458C, bp 102±1038C (0.01 Torr), H
NMR (acetone-D6): d ˆ 0:98 (t, 3H); 1.79 (spt, 2H); 2.28 (t,
2H); 7.2±7.9 (m, 4H). 19F NMR (acetone-D6): d ˆ 27:51
‡
‡
(s, ±CF2Br). m/z 290 (M ‡ 1, 9.7); 288 (M 1, 9.9); 260
‡
‡
‡
(M ±C2H5, 15.2); 209 (M ±Br, 100.0); 159 (M ±CF2Br,
7.7); 43 (C3H7 , 2.5).
‡
3.15. 1-Bromodifluoromethyl-2-benzylbenzimidazole
(12c)
3.11. 3,3-Dichloro-1-trichloromethyl-2,3-dihydrocarbazole
(11)
Yield 72%, mp 44±458C, 1H NMR (CDCl3): d ˆ 4:35 (s,
2H); 7.1±7.9 (m, 9H). 19F NMR (CDCl3): d ˆ 27:24 (s, ±
‡
‡
Chlorine-gas was bubbled through a solution of 10 (1.3 g,
5 mmol) in dry CCl4 (10 ml) at 08C for 2 h. The reaction
CF2Br). m/z 338 (M ‡ 1; 16:0); 336 (M
1, 15.9); 257
(M ±Br, 73.1); 207 (M ±CF2Br, 3.2); 91 (PhCH2 , 100.0).
‡
‡
‡

186
L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 106 (2000) 181±187
3.16. 1-Bromodifluoromethyl-2-methylnaphth[2,3-
d]imidazole (12d)
14: bp 80±828C (12 Torr), 1H NMR (CDCl3): d ˆ 2:74 (s,
3H); 7.3±7.8 (m, 4H). 19F NMR (CDCl3): d ˆ 57:97 (s,
CF3). Found: C 53.88; H 3.46; N 13.44, calculated for
C9H7F3N2: C 54.01; H 3.52; N 14.00%.
1
Yield 81%, mp 93±958C, H NMR (CDCl3): dˆ2:80 (t,
JH ˆ 3 Hz, 3H); 7.4±8.2 (m, 6H). 19F NMR (CDCl3):
F
‡
d ˆ 26:81 (s, ±CF2Br). m/z 312 (M ‡ 1; 26:7); 310
3.21. 2,3-Dimethyl-1-trihalomethylbenzimidazolium
tetrafluoroborates (15a±b)
‡
‡
‡
(M 1, 26.3); 232 (M ±Br, 47.0); 231 (M 1±Br,
100.0); 181 (M ±CF2Br, 5.4).
‡
To a stirred solution of AgBF4 (1 g, 5 mmol) in dichlor-
oethane (2 ml) was added 2-methyl-1-trihalomethylbenzi-
midazole 12a or 14 (1 mmol) in dichloroethane (1 ml) and
CH3I (0.6 ml, 1 mmol). The mixture was stirred at room
temperature for 6 h, then AgI was ®ltered off and washed
with dichloroethane (1 ml). The combined ®ltrate was con-
centrated in vacuo and triturated with diethyl ether to afford
15a or 15b, respectively, as white powders.
3.17. 1-Bromodifluoromethyl-5,6-dichloro-2-
methylbenzimidazole (12e)
Yield 70%, mp 76 788C, 1H NMR (CDCl3): d ˆ 2:66 (t,
JH ˆ 3 Hz, 3H); 7.61 (s, 1H); 7.71 (s, 1H). 19F NMR
F
‡
(CDCl3): d ˆ 28:04 (s, CF2Br). m/z 330 (M , 17.1); 295
‡
‡
‡
(M ±Cl, 1.4); 261 (M ‡ 1±Cl±Cl, 100.0); 251 (M ‡ 1±
‡
‡
Br, 47.7); 250 (M ±Br, 14.0); 200 (M ±CF2Br, 36.5).
3.22. 1-Bromodifluoromethyl-2,3-
dimethylbenzimidazolium tetrafluoroborate (15a)
3.18. 1-Bromodifluoromethyl-4,5,6,7-tetrafluoro-2-
methylbenzimidazole (12f)
Yield 0.160 g (44%), mp 225±2278C. 19F NMR (acetone-
D6): d ˆ 149:96 (s, BF4 ); 34.07 (s, CF2Br). Found C:
33.87; H 2.44; N 7.34, calculated for C10H10BBrF6N2: C
33.09; H 2.76; N 7.72%.
1
Yield 86%, bp 94±958C (0.05 Torr), H NMR (CDCl3):
d ˆ 2:73 (t, JH ˆ 4 Hz, 3H). 19F NMR (CDCl3): d ˆ
F
161:8 161:5 (m, 1F); 160.0±159.7 (m, 1F); 151.6±
151.0 (m, 1F); 153.66 (t, J ˆ 1:4 Hz, 1F); 28.21 (d,
‡
‡
JH ˆ 4 Hz, CF Br). m/z 333 (M , 16.2); 252 (M 1±Br,
3.23. 1-Trifluoromethyl-2,3-dimethylbenzimidazolium
tetrafluoroborate (15b)
F
2
‡
‡
100.0); 253 (M ±Br, 11.6); 203 (M ±CF2Br, 12.0); 79 (Br,
1.6).
Yield 0.241 g (80%), mp 167±1698C. 19F NMR (acetone-
D6): d ˆ 149:54 (s, BF4 ), 54.60 (s, CF3). Found: C
40.66; H 3.58; N 9.13, calculated for C10H10BF7N2: C
40.06; H 3.31; N 9.27%.
3.19. 1-Bromodifluoromethylimidazole (13)
To a solution of imidazol (1 g, 15 mmol) in dry acetoni-
trile (100 ml), was added sodium hydride (60%, 0.6 g,
15 mmol). The reaction mixture was stirred for 1 h at room
temperature. After cooling to 158C, zinc powder (0.1 g,
1.5 mmol) was added and, over 10 min CF2Br2 (4.2 g,
20 mmol) was added dropwise. The mixture was stirred
for 4 h at room temperature and evaporated in vacuo at 08C.
The residue was extracted with hot hexane. The residue after
evaporation of the extractant at atmospheric pressure, was
distilled in vacuo to give 0.23 g (9%) of 13. 19F NMR
(CDCl3): d ˆ 28:80 (s, CF2Br). Found: N 14.70, calcu-
lated for C4H3BrF2N2: N 14.22%.
3.24. 1- and 2-Bromodifluoromethylindazoles (16, 17)
To a solution of indazole (1.18 g, 10 mmol) in dry acet-
onitrile (15 ml) was added sodium hydride (60%, 0.6 g,
15 mmol) at 08C. After stirring for 1 h the reaction mixture
was cooled to 158C, and Zn powder (0.1 g, 1.5 mmol) was
added. After 10 min CF2Br2 (3.1 g, 15 mmol) was added
dropwise and the mixture was stirred for 1 h at 08C and 2 h at
20±308C. The solvent was evaporated in vacuo and the
residue was extracted with hot hexane. The extract was
®ltered, evaporated under reduced pressure and the residue
was distilled in vacuo to give 1.48 g (61%) of the mixture of
isomers 16 and 17, bp 69±778C (0.1 Torr); 125±1358C
3.20. 2-Methyl-1-trifluoromethylbenzimidazole (14)
1
A mixture of 12a (5 g, 19 mmol) and tetramethylammo-
nium ¯uoride (3.6 g, 38 mmol) in monoglyme (30 ml) was
re¯uxed for 5 h and evaporated under reduced pressure. The
residue was extracted with hexane. Hexane was removed in
vacuo. The mixture of 1-tri¯uoromethyl- and 1-di¯uoro-
methyl-2-methylbenzimidazoles, obtained after evaporation
of the extract was separated by fractional distillation to give
1.5 g (40%) of 14 and 1.2 g (35%) of 1-di¯uoromethyl-2-
methylbenzimidazole; b.p. 135±1378C/12 Torr, ([9] 120±
1228C/4 Torr).
(20 Torr), H NMR (CDCl3): d ˆ 7:2 7:9 (m, 4H); 8.27
and 8.37 (s, 1-isomer and s, 2-isomer in the ratio 1:0.75, 1H).
19F NMR (CDCl3): d ˆ 33:37 and 31.38 (s, 1-isomer
and s, 2-isomer in the ratio 1:0.75, CF2Br). Found: C 39.21;
H 2.45, calculated for C8H5BrF2N2: C 38.90; H 2.04%.
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