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J.W. Lyga, R.M. Patera/ Journal of Fluorine Chemistry 92 (1998) 141±145
1
NMR spectra were recorded on a General Electric QE300
spectrometer (300 MHz 1H) and a Brucker AMX2-500
(470 MHz 19F). Deuteriochloroform was used as the
NMR solvent unless otherwise speci®ed. Chemical shifts
are expressed in ppm down®eld from internal tetramethy-
silane (1H) and up®eld from internal CFCl3 (19F). Mass
spectra were recorded on a Kratos analytical pro®le instru-
ment. Elemental analyses were determined at FMC Cor-
poration, Analytical Services Department or at Quantitative
Technologies, Whitehouse, NJ. Chromatography was per-
formed using EM Silica Gel 60 (0.040±0.063 mm). Solvents
and reagents were used as purchased.
9, H-NMR ꢀ: 6.96 (t, 1H, JH±F 61 Hz), 7.11 (s, 1H)
7.37±7.47 (m, 5H), 8.00 (s, 1H); 19F-NMR ꢀ: 91.3 (JF±H
61 Hz) Anal. Calc. for C10H8F2N2: C, 61.85; H, 4.15; N,
14.43. Found: C, 61.39; H, 4.09; N, 14.11.
4.3. Difluoromethylation of 3-phenyl-1,2,4-triazole.
Difluoromethylation of 3-phenyl-1,2,4-triazole 1-
difluoromethyl-3-phenyl-1,2,4-triazole (11), 2-
difluoromethyl-3-phenyl-1,2,4-triazole (12), and 4-
difluoromethyl-3-phenyl-1,2,4-triazole (13)
Prepared using method A from 3-phenyl-1,2,4-triazole
[14], 3.0 g, (21 mmol), DMF (25 ml), NaH (1.0 g,
25 mmol), and CHClF2 to yield 3.9 g of a mixture of three
compounds which were chromatographed using CH2Cl2
followed by CH2Cl2±CH3OH (95 : 5) to afford 11, clear
oil, 2.0 g (66%), Rf 0.1 (CH2Cl2), 12. Clear oil, 0.42 g
(14%), Rf 0.3 (CH2Cl2), and 13. White solid, m.p. 57±
588, 0.61 g (20%), Rf 0.6 (CH2Cl2).
4.1. Difluoromethylation of 2-phenylimidazole and 1-N-
difluoromethyl-2-phenylimidazole (6)
Method A: Sodium hydride (60% dispersion in mineral
oil, 0.49 g, 12.2 mmol) was washed with petroleum ether
and then suspended in anhydrous THF (10 ml). The mixture
was stirred at ambient temperature as 2-phenylimidazole (5)
(1.75 g, 12.2 mmol) dissolved in THF (10 ml) was added
dropwise. After the addition, the mixture was stirred at
ambient temperature for 30 min and CHClF2 was bubbled
into the reaction mixture until saturated (excess CHClF2
was contained using a dry ice condenser). The mixture was
stirred for 1 h and then poured into 100 ml of water. After
extraction with CH2Cl2 (2 Â 100 ml) and drying (MgSO4)
the solvent was evaporated in vacuo and the crude product
distilled to yield 1.8 g (75%) of an oil, with b.p. 1028 at
1.4 mm Hg.
11, 1H-NMR ꢀ: 7.10 (t, 1H, JH±F 59 Hz), 7.52±7.65 (m,
5H), 8.59 (s, 1H). 19F-NMR ꢀ: 91.9 (JF±H 59 Hz). m/z
195, 194, 104, 89, 77, 63, and 51; Anal. Calc: for C9H7F2N3:
C, 55.39; H, 3.62; N, 21.53. Found: C, 55.66; H, 3.81; N,
21.40.
12, 1H-NMR d: 7.30 (t, 1H, JH±F 59 Hz), 7.46 (m, 3H),
8.13 (m, 2H), 8.53 (s, 1H). 19F-NMR ꢀ: 96.3 (JF±H
59 Hz). m/z 195, 168, 149, 89, 77, 63, and 51; Anal. Calc. for
C9H7F2N3: C, 55.39; H, 3.62; N, 21.53. Found: C, 55.74; H,
3.92; N, 21.83. 13, 1H-NMR ꢀ: 7.29 (t, 1H, JH±F 59 Hz),
7.48±7.75 (m, 5H), 8.08 (s, 1H). 19F-NMR ꢀ: 94.6 (JF±H
59 Hz). m/z 195, 167, 149, 104, 89, 77, 63, and 51; Anal.
Calc. for C9H7F2N3: C, 55.39; H, 3.62; N, 21.53. Found: C,
55.74; H, 3.92; N, 21.83.
1H-NMR ꢀ: 7.03 (t, 1H, JH±F 60 Hz), 7.20 (d, 1H,
JH±F 1.5 Hz), 7.37 (d, 1H, JH-F 1.5 Hz), 7.48 (m,
3H), 7.57 (m, 2H) ppm. 19F-NMR ꢀ: 90.9 (JF±H
60 Hz). Anal. Calc. for C10H8F2N2: C, 61.85; H, 4.15; N,
14.43. Found: C, 62.10; H, 3.99; N, 14.62.
4.4. Difluoromethylation of 5-phenyltetrazole using one
equivalent of NaH
Method B: A mixture of 18-crown-6 (1 g), KF (0.42 g,
7.6 mmol), 2-phenylimidazole (1.1 g, 7.6 mmol), methyl
chlorodi¯uoroacetate (0.8 ml, 7.6 mmol), and 2-methoxy-
ethyl ether (10 ml) was heated at 858 for 16 h. Work-up
as in method A afforded 0.75 g (50%) of a clear oil identical
to 6.
The reaction was run using method A from 5-phenyl-
tetrazole (2.92 g, 20 mmol), DMF (40 ml), NaH (60% dis-
persion in mineral oil, 0.8 g, 20 mmol) and excess CHClF2
to yield a quantitative recovery of the starting material.
4.5. Difluoromethylation of 5-phenyltetrazole using two
equivalents of NaH, 1-N-difluoromethyl-5-
phenyltetrazole (15), and 2-N-difluoromethyl-5-
phenyltetrazole (16)
4.2. Difluromethylation of 4-phenylimidazole, 1-N-
difluoromethyl-4-phenylimidazole (8) and 3-N-
difluoromethyl-4-phenylimidazole (9)
Prepared using method A from 4-phenylimidazole (1 g,
6.9 mmol), THF (30 ml), NaH (60% dispersion in mineral
oil, 6.9 mmol), and CHClF2 to yield after chromatography;
0.58 g (43%) of 8, white solid, m.p. 90±928 and 0.41 g
(30%), clear oil.
8, 1H-NMR ꢀ: 7.08 (t, 1H, JH±F 61 Hz), 7.29±7.42 (m,
3H), 7.47 (s, 1H), 7.79 (d, 2H), 7.86 (s, 1H); 19F-NMR ꢀ:
91.8 (JF±H 61 Hz) Anal. Calc. for C10H8F2N2: C, 61.85;
H, 4.15; N, 14.43. Found: C, 61.70; H, 4.05; N, 14.30.
The reaction was run using method A from 5-phenyl-
tetrazole (2.92 g, 20 mmol), DMF (40 ml), NaH (60% dis-
persion in mineral oil, 1.6 g, 40 mmol) and excess CHClF2
to yield 3.8 g of a crude mixture which was chromato-
graphed using ethyl acetate and heptane (1 : 4) to afford 15,
oil, 1.0 g, (26%), lower Rf and 16; higher Rf, 1.9 g (48%) of
a solid, m.p. 29±308.
15, 1H-NMR ꢀ: 7.48 (t, 1H, JH±F 56 Hz), 7.60 (m, 3H),
7.84 (m, 2H); 19F-NMR ꢀ: 95.3 (JF±H 56 Hz), m/z 196,