Trifluoromethyl-Substituted Pyridines
FULL PAPER
2-Bromo-5-iodopyridine: As described in the preceding paragraph,
1.4147 (ref.[34]: n2D0 1.415); yield: 3.6 g (25%). 1H NMR: δ ϭ 8.82
2,5-dibromopyridine (36 g, 0.15 mol) was consecutively treated (d, J ϭ 5.1 Hz, 1 H), 7.53 (d, J ϭ 5.2 Hz, 1 H). 13C NMR: δ ϭ
with butyllithium and iodine. After the same workup of the mix-
ture, the product was crystallized from ethanol as colorless needles;
m.p. 125Ϫ126 °C (ref.[25] m.p. 124Ϫ126 °C); yield: 35.8 g (84%).
150.5, 138.3 (q, J ϭ 34.0 Hz), 122.3 (q, J ϭ 273 Hz), 119.2.
2-Chloro-6-(trifluoromethyl)pyridine (4): From 2-chloro-6-iodopyri-
dine (24 g, 0.10 mol); white needles (from hexanes); m.p. 28Ϫ29
3-Bromo-5-iodopyridine: A solution of 3,5-dibromopyridine (24 g,
0.10 mol) and isopropylmagnesium chloride (0.10 mol) in tetrahy-
drofuran was kept for 2 h at 25 °C. At Ϫ75 °C, a precooled solution
of iodine (24 g, 0.10 mol) in tetrahydrofuran (0.10 L) was added all
at once. At 25 °C, the mixture was diluted with diethyl ether
(0.20 L) and washed with a saturated aqueous solution (0.20 L) of
ammonium chloride, a 2.0 aqueous solution (0.10 L) of sodium
thiosulfate and brine (0.20 L). Upon evaporation of the volatiles
and recrystallization of the residue from ethanol, thin colorless
needles were obtained; m.p. 117Ϫ118 °C; yield: 17.3 g (61%). 1H
NMR: δ ϭ 8.76 (d, J ϭ 1.8 Hz, 1 H), 8.64 (d, J ϭ 2.0 Hz, 1 H),
8.20 (t, J ϭ 2.0 Hz, 1 H). 13C NMR: δ ϭ 153.9, 149.4, 146.2, 121.1,
93.2. C5H3BrIN (283.89): calcd. C 21.15, H 1.07; found C 21.16,
H 1.12.
1
°C; b.p. 77Ϫ78 °C/23 Torr; yield: 10.7 g (59%). H NMR: δ ϭ 7.9
(m, 1 H), 7.64 (d, J ϭ 7.5 Hz, 1 H), 7.55 (d, J ϭ 8.1 Hz, 1 H). 13C
NMR: δ ϭ 152.0, 148.3 (q, J ϭ 36.0 Hz), 140.0, 127.6, 120.6 (q,
J ϭ 274 Hz), 119.0. 19F NMR: δ ϭ Ϫ68.6 (s). C6H3ClF3N (181.54):
calcd. C 39.70, H 1.67, N 7.72; found C 39.21, H 1.55, N 7.59.
2-Bromo-6-(trifluoromethyl)pyridine (5): From 2-bromo-6-iodopyri-
dine (28 g, 0.10 mol); white needles; m.p. 45Ϫ46 °C (from hexanes);
1
b.p. 95Ϫ96 °C/30 Torr; yield: 17.9 g (79%). H NMR: δ ϭ 7.76 (t,
J ϭ 7.9 Hz, 1 H), 7.70 (d, J ϭ 7.7 Hz, 1 H), 7.66 (dd, J ϭ 7.7,
1.0 Hz, 1 H). 13C NMR: δ ϭ 148.7 (q, J ϭ 36.0 Hz), 142.4, 139.6,
131.4, 120.5 (q, J ϭ 274 Hz), 119.4. 19F NMR: δ ϭ Ϫ68.6 (s).
C6H3BrF3N (225.99): calcd. C 31.89, H 1.34, N 6.20; found C
31.61, H 1.34, N 6.27.
3,5-Dibromo-2-iodopyridine: At Ϫ75 °C and under high-speed stir-
ring (Ultraturrax, approx. 10000 rpm), butyllithium (0.15 mol) in
5-Bromo-2-(trifluoromethyl)pyridine (6): From 5-bromo-2-iodopyri-
dine (28 g, 0.10 mol); colorless needles; m.p. 40Ϫ41 °C (from hex-
anes); b.p. 76Ϫ78 °C/25 Torr; yield: 15.6 g (69%). 1H NMR: δ ϭ
8.79 (d, J ϭ 1.9 Hz, 1 H), 8.02 (dd, J ϭ 8.3, 1.9 Hz, 1 H), 7.59 (d,
J ϭ 8.3 Hz, 1 H). 13C NMR: δ ϭ 151.3, 146.6 (q, J ϭ 35.0 Hz),
140.0, 124.0, 121.7, 121.3 (q, J ϭ 274 Hz). 19F NMR: δ ϭ Ϫ68.4
(s). C6H3BrF3N (225.99): calcd. C 31.89, H 1.34, N 6.20; found C
31.75, H 1.40, N 6.24.
hexanes (90 mL) and, 45 min later, pulverized iodine (38 g, 0.15
[30]
mol) were added to 2,3,5-tribromopyridine
(47 g, 0.15 mol) in
toluene (0.30 L). After a further 2 h at Ϫ75 °C, the mixture was
filtered through a pad of basic alumina (0.3 L) which was rinsed
with more toluene. Recrystallization from ethanol of the residue
left after evaporation of the solvents gave colorless platelets; m.p.
72Ϫ73 °C (ref.[33] m.p. 70.5 °C); yield: 43.0 g (75%). 1H NMR: δ ϭ
8.38 (d, J ϭ 2.2 Hz, 1 H), 7.96 (d, J ϭ 2.2 Hz, 1 H). 13C NMR:
δ ϭ 149.3, 141.6, 130.4, 121.5, 120.0. C5H2Br2IN (362.79): calcd.
C 16.55, H 0.56; found C 16.66, H 0.59.
2-Bromo-5-(trifluoromethyl)pyridine (7): From 2-bromo-5-iodopyri-
dine (28 g, 0.10 mol); colorless needles; m.p. 43Ϫ44 °C (from hex-
anes); b.p. 98Ϫ99 °C/50 Torr; yield: 6.7 g (29%). 1H NMR: δ ϭ
8.66 (s, 1 H), 7.80 (dd, J ϭ 8.5, 2.5 Hz, 1 H), 7.66 (d, J ϭ 8.4 Hz,
1 H). 13C NMR: δ ϭ 147.1 (q, J ϭ 4.0 Hz), 145.9, 135.3 (q, J ϭ
3.0 Hz), 128.3, 126.0 (q, J ϭ 33.0 Hz), 123.1 (q, J ϭ 273 Hz). 19F
NMR: δ ϭ Ϫ63.0 (s). C6H3BrF3N (225.99): calcd. C 31.89, H 1.34,
N 6.20; found C 32.12, H 1.33, N 6.30.
2-(Trifluoromethyl)pyridine (1): Potassium fluoride (6.4 g, 0.11 mol)
and cuprous iodide (21 g, 0.11 mol) were thoroughly mixed and
flame-heated under gentle shaking and at reduced pressure (1 Torr)
during some 30 min until a greenish color appeared. 2-Iodopyri-
[25]
dine
(21 g, 0.10 mol), (trifluoromethyl)trimethylsilane (15 mL,
14 g, 0.10 mol), anhydrous N,N-dimethylformamide (0.10 L) and
anhydrous N-methylpyrrolidone (0.10 L) were added and the slurry,
which eventually became a brown solution, was vigorously stirred
for 6 h at 25 °C before being poured into 6.4 aqueous ammonia
(0.20 L). The product was then extracted with diethyl ether (3 ϫ
0.10 L). The combined organic layers were washed with 6.4 aque-
ous ammonia (3 ϫ 50 mL), 1.0 hydrochloric acid, a saturated
aqueous solution (0.10 L) of sodium hydrogen carbonate and brine
(0.10 L), dried and the solvents evaporated. Upon distillation, a
colorless oil was collected; b.p. 138Ϫ140 °C (ref.[34] b.p. 139Ϫ140
°C); nD20 1.4183 (ref.[34]: n2D0 1.418); yield: 10.0 g (68%). 1H NMR:
δ ϭ 8.74 (d, J ϭ 4.7 Hz, 1 H), 7.89 (tm, J ϭ 7.8 Hz, 1 H), 7.70 (d,
J ϭ 7.9 Hz, 1 H), 7.50 (ddm, J ϭ 7.4, 4.8 Hz, 1 H). 13C NMR:
δ ϭ 150.1, 148.4 (q, J ϭ 35.0 Hz), 137.5, 126.5, 121.6 (q, J ϭ
274 Hz), 120.2.
3-Bromo-5-(trifluoromethyl)pyridine (8): From 3-bromo-5-iodopyri-
dine (28 g, 0.10 mol); colorless needles; m.p. 35Ϫ36 °C (from hex-
anes); b.p. 65Ϫ66 °C/25 Torr; yield: 10.8 g (48%). 1H NMR: δ ϭ
8.89 (s, 1 H), 8.82 (s, 1 H), 8.08 (s, 1 H). 13C NMR: δ ϭ 154.4,
144.8 (q, J ϭ 4.0 Hz), 135.8 (q, J ϭ 3.0 Hz), 128.0 (q, J ϭ 34.0 Hz),
122.6 (q, J ϭ 273 Hz), 120.7. 19F NMR: δ ϭ Ϫ63.0 (s). C6H3BrF3N
(225.99): calcd. C 31.89, H 1.34, N 6.20; found C 31.79, H 1.46,
N 6.15.
2-Chloro-3-(trifluoromethyl)pyridine (9): From 2-chloro-3-iodopyri-
[27]
dine
(24 g, 0.10 mol); colorless needles; m.p. 38Ϫ39 °C (from
hexanes); b.p. 75Ϫ76 °C/30 Torr; yield: 12.3 g (67%). 1H NMR: δ ϭ
8.59 (dd, J ϭ 4.8, 1.3 Hz, 1 H), 8.04 (dd, J ϭ 7.8, 1.9 Hz, 1 H),
7.41 (dd, J ϭ 7.4, 4.8 Hz, 1 H). 13C NMR: δ ϭ 152.4, 149.1, 136.7
(q, J ϭ 5.0 Hz), 125.5 (q, J ϭ 33.0 Hz), 122.2 (q, J ϭ 273 Hz),
122.1. 19F NMR: δ ϭ Ϫ64.3 (s). C6H3ClF3N (181.54): calcd. C
39.70, H 1.67, N 7.72; found C 39.38, H 1.80, N 7.72.
The same reaction conditions and workup protocol were applied
to the preparation of the (trifluoromethyl)pyridines 2؊11.
3-(Trifluoromethyl)pyridine (2): From 3-iodopyridine[25] (21 g, 0.10
mol); colorless oil; b.p. 110Ϫ114 °C (ref.[34] b.p. 113Ϫ115 °C); n2D0
1.4145 (ref.[34]: n2D0 1.415); yield: 3.4 g (23%). 1H NMR: δ ϭ 8.91
(s, 1 H), 8.81 (d, J ϭ 4.8 Hz), 7.94 (d, J ϭ 8.0 Hz), 7.88 (dd, J ϭ
7.9, 4.9 Hz). 13C NMR: δ ϭ 153.3, 146.9 (q, J ϭ 4.0 Hz), 133.1 (q,
J ϭ 3.0 Hz), 127.8 (q, J ϭ 33.0 Hz), 123.5 (q, J ϭ 273 Hz), 123.5.
2-Chloro-4-(trifluoromethyl)pyridine (10): From 2-chloro-4-iodo-
pyridine[28] (24 g, 0.10 mol); colorless oil; m.p. Ϫ19 to Ϫ18 °C; b.p.
1
146Ϫ147 °C; n2D0 1.4493; d240 1.411; yield: 12.2 g (67%). H NMR:
δ ϭ 8.61 (d, J ϭ 5.1 Hz, 1 H), 7.58 (dq, J ϭ 1.5, 0.8 Hz, 1 H), 7.47
(dm, J ϭ 5.1 Hz, 1 H). 13C NMR: δ ϭ 152.7, 151.0, 141.1 (q, J ϭ
35.0 Hz), 122.1 (q, J ϭ 273 Hz), 120.7 (q, J ϭ 4.0 Hz), 118.2 (q,
J ϭ 3.0 Hz). 19F NMR: δ ϭ Ϫ65.3 (s). C6H3ClF3N (181.54): calcd.
4-(Trifluoromethyl)pyridine (3): From 4-iodopyridine [26] (21 g, 0.10
mol); colorless oil; b.p. 105Ϫ106 °C (ref.[34] b.p. 110Ϫ113 °C); n2D0 C 39.70, H 1.67; found C 39.82, H 1.87.
Eur. J. Org. Chem. 2002, 327Ϫ330
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