(Trifluoromethyl)imidazoles
J . Org. Chem., Vol. 63, No. 25, 1998 9453
1
4-F lu or o-2-m eth ylim id a zole (15). The following proce-
dure is patterned after the syntheses of other fluoroimida-
zoles12a,16d with some modifications. A solution of 2-methyl-4-
nitroimidazole (5.08 g, 40 mmol) in tetrafluoroboric acid (42%,
200 mL) was cooled to -10 °C, and zinc dust (5.08 g, 130 mmol)
was added in portions of ca. 0.1 g with rapid stirring. Each
addition was made only after the prior portion had dissolved
and the temperature had fallen to at least -5 °C. The addition
required ca. 1 h. Small aliquots were removed, diluted with
water, and examined by UV. Total loss of the chromophore at
310 nm was taken to indicate complete reduction. A solution
of sodium nitrite (2.04 g, 44 mmol) in 10 mL of water was then
added dropwise. The resulting solution of the diazonium
compound was diluted to 380 mL with cold 42% tetrafluoro-
boric acid and was irradiated under argon in a Pyrex immer-
sion-well photoreactor using a 400 W high-pressure mercury
lamp (Riko 400-HA).23 After 90 min, the diazonium chro-
mophore at 280 nm had disappeared. The solution was cooled
to -10 °C with dry ice, neutralized slowly with 25% aqueous
sodium hydroxide to pH 5-6, and extracted with 5 × 200 mL
of ethyl acetate. The combined extracts were dried (Na2SO4)
and evaporated. The residual material was purified on 100 mL
of silica gel with ethyl acetate as eluent to give 1.06 g (27%)
of 15 as a colorless powder: mp 142-144 °C (lit.12a mp 142-
143 °C); MS m/e 100 (M+), 99, 86, 72, 58.
and 170 (M+), 152 and 150 (M+ - HF), 125, 123; H NMR δ
7.37 (s, 5-H); 19F NMR δ 13.6 (s, 2-CF3). Anal. Calcd for C4H2-
ClF3N2: C, 28.17; H, 1.18; N, 16.43. Found: C, 28.29; H, 1.17;
N, 16.39. Continued elution gave 19 (0.66 g, 39%) as colorless
needles from ether: mp 158-159 °C; MS m/e 172 and 170 (M+),
153 and 151 (M+ - F), 152 and 150 (M+ - HF), 145, 143, 115;
1H NMR δ 7.82 (s, 2-H); 19F NMR δ 17.3 (s, 5-CF3). Anal. Calcd
for C5H4F4N2: C, 28.17; H, 1.18; N, 16.43. Found: C, 28.25;
H, 1.20; N, 16.49.
4,5-Dich lor o-2-(tr iflu or om eth yl)im id a zole (21). Similar
photochemical trifluoromethylation of 4,5-dichloroimidazole
(20, 1.10 g, 8 mmol) gave 0.26 g (32%) of 21 as colorless plates
from benzene: mp 188-189 °C (lit.9 mp 186-188 °C); MS m/e
208, 206, and 204 (M+), 186, 184, 176, 123; 19F NMR δ 13.2 (s,
2-CF3).
4,5-Dich lor o-2-(tr iflu or om eth yl)im idazole (21) by Ch lo-
r in a tion . To a suspension of 1 (0.544 g, 4 mmol) in 200 mL of
tetrachloromethane was added N-chlorosuccinimide (5.34 g,
40 mmol), and the mixture was heated at reflux with stirring
for 10 h. The solution was cooled to ambient temperature and
was aerated with argon for 1 h. A white solid (consisting of
succinimide and N-chlorosuccinimide) was removed by filtra-
tion. The filtrate was evaporated to dryness, and the residual
material was dissolved in acetonitrile (200 mL). Passage of
hydrogen sulfide through the solution for 2 h resulted in the
separation of a pale yellow solid (sulfur), which was removed
by filtration. The filtrate was evaporated, and the residual
material was purified on 100 mL of silica gel, with dichlo-
romethane-hexane (1:1) as eluent. Pale yellow crystals were
obtained, which were recrystallized from benzene to give 0.62
g (76%) of 21 as colorless plates, mp 188-189 °C.
2,5-Dich lor o-4-(tr iflu or om eth yl)im id a zole (25). Chlo-
rination of 6 (1.36 g, 10 mmol) with 13.4 g (100 mmol) of
N-chlorosuccinimide and subsequent reduction with H2S,
following the procedure described for 21, gave 0.78 g (38%) of
25 as pale yellow needles from chloroform-cyclohexane: mp
135-139 °C: MS m/e 208, 206 and 204 (M+), 189, 187, and
185 (M+ - F), 188, 186, and 184 (M+ - HF), 151 and 149 (M+
- HF - Cl); 19F NMR δ 16.7 (s, 4-CF3). Anal. Calcd for C4-
HCl2F4N2: C, 23.44; H, 0.49; N, 13.67. Found: C, 23.55; H,
0.45; N, 13.74.
4-F lu or o-2-m eth yl-5-(tr iflu or om eth yl)im id a zole (16).
Photochemical trifluoromethylation of 4-fluoro-2-methylimi-
dazole (15, 1.00 g, 10 mmol) was performed as described above
for 10 and gave 0.22 g (26%) of 16 as colorless plates from
ethyl acetate-benzene: mp 179-181 °C; MS m/e 168 (M+),
149 (M+ - F), 148 (M+ - HF), 147, 121, 86, 72; 1H NMR δ
2.33 (q, J ) 0.8 Hz, 2-CH3); 19F NMR σ 19.4 (dq, 3, J ) 11 and
0.8 Hz, 5-CF3) and -63.6 (q, 1, J ) 11 Hz, 4-F). Anal. Calcd
for C5H4F4N2: C, 35.73; H, 2.40; N, 16.67. Found: C, 35.82;
H, 2.41; N, 16.73.
Ch lor in a tion of Im id a zole. To a solution of imidazole (34
g, 0.5 mol) in 300 mL of chloroform was added slowly a solution
of chlorine (7.1 g, 0.1 mol) in 100 mL of chloroform. An
exothermic reaction occurred, and a white precipitate was
generated. The reaction mixture was stirred for 1 h, stored
overnight at ambient temperature, and then poured into
aqueous sodium bisulfite. The organic layer was separated,
and the water layer was extracted with ethyl acetate (3 × 150
mL). The combined organic layers were dried (Na2SO4) and
evaporated. The residual material was fractionated on 180 mL
of silica gel with ether as eluent. Initial fractions gave 1.33 g
(19%) of 4,5-dichloroimidazole (20) as colorless plates from
benzene, mp 181-182 °C (lit.24 mp 179-180 °C, lit.25 mp 180-
181 °C).26 Further elution gave 2.58 g (25%) of 4-chloroimida-
zole (17) as colorless plates from ethyl acetate-ether, mp 119-
119.5 °C (lit.24 mp 117-118 °C, lit.25 mp 115-117 °C).
4-Ch lor o-2-(tr iflu or om eth yl)im id a zole (18) a n d 4-Ch lo-
r o-5-(tr iflu or om eth yl)im id a zole (19). Into a solution of 17
(2.05 g, 20 mmol) and triethylamine (1.01 g, 10 mmol) in
methanol (20 mL) was bubbled trifluoromethyl iodide until
1.96 g (10 mmol) had been absorbed. The solution, in a quartz
tube, was irradiated for 3 days by a low-pressure, 60 W
mercury lamp. The reaction mixture was analyzed directly by
19F NMR; integration of peak areas gave the ratio of com-
pounds 18 and 19 as 1:3, respectively. The reaction mixture
was evaporated to dryness, and the residual material was
fractionated on 180 mL of silica gel with ether-ethyl acetate
(1:1) as eluent. The first fractions gave 0.24 g (14%) of 18 as
colorless plates from benzene: mp 142-144 °C; MS m/e 172
Isola t ion a n d Met h a n olysis/H yd r olysis of 2,4,5-Tr i-
ch lor o-2-(tr iflu or om eth yl)[2H]im id a zole (22). To a sus-
pension of 1 (1.36 g, 10 mmol) in 150 mL of ethanol-free
chloroform27 was added N-chlorosuccinimide (4.01 g, 30 mmol),
and the mixture was heated at reflux for 4 h. The reaction
mixture was evaporated to dryness, and the residual material
was purified on 180 mL of silica gel with ether as eluent. There
was obtained 1.98 g (containing solvent) of 22 as a colorless
oil with a penetrating chlorine-like odor: IR (neat) 1568 and
1595 cm-1 (CdN); MS m/e 244, 242, 240, and 238 (M+), 207,
205, and 203 (M+ - Cl), 186, 184, 179, 177, 123, 85, 83, 69;
19F NMR δ 1.3 (s, 2-CF3). Continued elution of the column gave
0.40 g (20%) of 21, which was followed by recovery of 0.26 g
(19%) of 1.
The crude 22 was added to 20 mL of methanol; the solution
was stirred, and an exothermic reaction occurred. After the
solution had reacted for 10 min, an effort was made to isolate
a
characterizable reaction product, without success. The
solution was then evaporated and the residual material was
dissolved in 10 mL of water. The solution was neutralized with
sodium hydroxide and evaporated to dryness. The residual
material was fractionated on 120 mL of silica gel with ether
as eluent to give 1.24 g (63% based on 1) of 2-methyl-2-
(trifluoromethyl)tetrahydroimidazole-4,5-dione (23) as colorless
plates from chloroform: mp 193-195 °C; IR (KBr) 1775 cm-1
(CdO); MS m/e 198 (M+), 167 (M+ - OCH3), 155, 139, 129 (M+
(23) The earlier synthesis made use of a medium-pressure mercury
lamp and a quartz photoreactor. If a high-pressure mercury lamp is
used, a more readily available Pyrex reaction vessel is acceptable
because sufficient energy is transmitted in the absorption range of the
diazonium salt beyond 300 nm.
(24) Lutz, A. W.; DeLorenzo, S. J . Heterocycl. Chem. 1967, 4, 399.
(25) Imbach, J . L.; J acquier, R.; Romane, A. J . Heterocycl. Chem.
1967, 4, 451.
- CF3), 127, 107, 98, 96, 69; H NMR δ 3.36 (s, 2-OCH3); 19F
1
NMR δ -7.1 (s, 2-CF3); 13C NMR (CD3OD) δ 125.0 (q, J ) 3.6
Hz, CF3), 163.7 (s, OCH3), 94.0 (s, CdO’s). Anal. Calcd for
C5H5F3N2O3: C, 30.32; H, 2.54; N, 14.14. Found: C, 30.36; H,
2.56; N, 14.06.
(26) Although chlorination of imidazole with N-chlorosuccinimide
in chloroform was also achieved, separation of the product from
succinimide proved extremely tedious, even on a small scale.
(27) Commercial chloroform was washed three times with water,
dried over MgSO4, distilled, and stored over molecular sieves (4A).