The Optional Functionalization of 2,3,5-Trihalopyridines at the 4- or 6-Position
146.0 (s), 145.9 (d, J ϭ 15 Hz), 125.8 (d, J ϭ 5 Hz), 114.8 (d, J ϭ ded at Ϫ100 °C to a vigorously stirred solution of hexane-free bu-
FULL PAPER
39 Hz); C6H2Cl2FNO2 (209.99): calcd. C 34.32, H 0.96; found C
34.40, H 1.02.
tyllithium (30 mmol) in tetrahydrofuran (30 mL). The temperature
was raised during 45 min to Ϫ75 °C where it was kept constant for
15 min before the mixture was poured onto an excess of freshly
crushed dry ice. Extraction (as described above, see the preparation
of acids 1) and trituration with chloroform of the red oil obtained
gave colorless prisms; m.p. 179Ϫ181 °C (from chloroform); yield
2.5 g (50%); 13C NMR (D3CCOCD3): δ ϭ 162.6 (s), 155.8 (d, J ϭ
242 Hz), 145.6 (s), 132.2 (s), 115.6 (d, J ϭ 14 Hz), 114.5 (d, J ϭ
38 Hz); C6HCl2FINO2 (335.89): calcd. C 21.45, H 0.30; found C
21.50, H 0.40.
5-Chloro-2,3-difluoro-4-pyridinecarboxylic Acid (1c): Prepared as
described above from 5-chloro-2,3-difluoropyridine (3.7 g,
25 mmol); colorless needles; m.p. 115Ϫ117 °C (from chloroform);
yield 3.3 g (69%); 1H NMR (D3CCOCD3): δ ϭ 8.23 (d, J ϭ 1.8,
0.8 Hz); 13C NMR (D3CCOCD3): δ ϭ 161.4 (d, J ϭ 3 Hz), 151.6
(dd, J ϭ 238, 15 Hz), 142.8 (dd, J ϭ 267, 32 Hz), 142.3 (dd, J ϭ
14, 7 Hz), 133.9 (d, J ϭ 17 Hz), 126.1 (d, J ϭ 5 Hz); C6H2ClF2NO2
(193.54): calcd. C 37.24, H 1.04; found C 37.30, H 1.12.
5-Chloro-2,3-difluoro-6-iodo-4-pyridinecarboxylic Acid (3c): Prior to
carboxylation, 5-chloro-2,3-difluoro-4-iodopyridine (2c; 4.1 g,
15 mmol) was treated with lithium 2,2,6,6-tetramethylpiperidide es-
sentially as described in the two preceding paragraphs, but for only
45 min at Ϫ100 °C. Trituration with chloroform of the red oil ob-
tained after extraction afforded colorless prisms; m.p. 166Ϫ168 °C
(from chloroform; dec.); yield 1.4 g (29%); 13C NMR
(D3CCOCD3): δ ϭ 161.0 (s), 149.2 (dd, J ϭ 244, 15 Hz), 142.5 (dd,
J ϭ 267, 31 Hz), 134.2 (d, J ϭ 16 Hz), 132.2 (d, J ϭ 5 Hz), 110.1
(dd, J ϭ 12, 5 Hz); C6HClF2INO2 (319.43): calcd. C 22.56, H 0.31;
found C 22.77, H 0.53.
5-Chloro-2,3-dihalo-4-iodopyridines 2
2,3,5-Trichloro-4-iodopyridine (2a): Diisopropylamine (3.5 mL,
2.5 g, 25 mmol) and 2,3,5-trichloropyridine (4.6 g, 25 mmol) were
consecutively added at Ϫ75 °C to butyllithium (25 mmol) in tetra-
hydrofuran (35 mL) and hexanes (15 mL). After 2 h at Ϫ75 °C, the
reaction mixture was siphoned through a Teflon capillary into a
vigorously stirred solution of iodine (7.7 g, 30 mmol) in tetrahy-
drofuran (15 mL) kept at Ϫ75 °C. The mixture was diluted with
diethyl ether (100 mL), washed with a saturated aqueous solution
(3 ϫ 50 mL) of sodium thiosulfate, water (25 mL) and brine
(25 mL), dried and concentrated. The residue was crystallized from
methanol affording colorless needles; m.p. 116Ϫ118 °C; yield 6.9 g
5-Chloro-2,3-dihalo-6-iodopyridines 4
1
(89%); H NMR: δ ϭ 8.24 (s); 13C NMR: δ ϭ 146.0 (s), 144.3 (s),
2,3,5-Trichloro-6-iodopyridine (4a): 2,2,6,6-Tetramethylpiperidine
(8.4 mL, 7.1 g, 50 mmol) and 2,3,5-trichloro-6-iodopyridine (2a;
7.7 g, 25 mmol) were consecutively added at Ϫ100 °C to a vigor-
ously stirred solution of butyllithium (50 mmol) in tetrahydrofuran
(60 mL) and hexanes (30 mL). After 2 h at Ϫ100 °C, the mixture
137.3 (s), 136.7 (s), 116.8 (s); C5HCl3IN (308.33): calcd. C 19.48,
H 0.33; found C 19.69, H 0.48.
3,5-Dichloro-2-fluoro-4-iodopyridine (2b): Prepared as described
above from 3,5-dichloro-2-fluoropyridine (4.1 g, 25 mmol); color-
less needles; m.p. 121Ϫ124 °C (from methanol); yield 5.3 g (73%); was treated with methanol (5.0 mL) before being poured into water
1H NMR: δ ϭ 8.10 (s); 13C NMR: δ ϭ 156.0 (d, J ϭ 242 Hz), (0.10 L) and extracted with diethyl ether (3 ϫ 50 mL). The com-
142.1 (d, J ϭ 14 Hz), 135.2 (d, J ϭ 5 Hz), 124.3 (d, J ϭ 36 Hz), bined organic layers were washed with brine (2 ϫ 25 mL), dried
118.5 (s); C5HCl2FIN (291.87): calcd. C 20.58, H 0.35; found C and the solvents evaporated. Upon distillation of the residue, a col-
20.66, H 0.31.
orless liquid was collected which crystallized in the form of needles;
m.p. 60Ϫ62 °C (from ethanol); b.p. 125Ϫ127 °C/4 Torr; yield 4.5 g
(59%); H NMR: δ ϭ 7.76 (s); 13C NMR: δ ϭ 146.0 (s), 137.6 (s),
5-Chloro-2,3-difluoro-4-iodopyridine (2c): Prepared as described
above from 5-chloro-2,3-difluoropyridine (3.7 g, 25 mmol); color-
less prisms; m.p. 105Ϫ107 °C (from methanol); yield 5.2 g (75%);
1H NMR: δ ϭ 8.0 (t, J ϭ 1.3 Hz); 13C NMR: δ ϭ 149.2 (dd, J ϭ
226, 17 Hz), 146.8 (dd, J ϭ 262, 30 Hz), 139.2 (dd, J ϭ 14, 6 Hz),
101.1 (d, J ϭ 20 Hz); C5HClF2IN (275.42): calcd. C 21.80, H 0.37;
found C 22.03, H 0.57.
1
137.6 (s), 130.6 (s), 115.8 (s); C5HClF2IN (308.33): calcd. C 19.48,
H 0.33; found C 19.52, H 0.44.
3,5-Dichloro-2-fluoro-6-iodopyridine (4b): 2,2,6,6-Tetramethylpiper-
idine (5.0 mL, 4.2 g, 30 mmol) and 3,5-dichloro-2-fluoro-4-iodopy-
ridine (2b; 7.3 g, 25 mmol) were consecutively added at Ϫ100 °C to
a vigorously stirred solution of hexane-free butyllithium (30 mmol)
in tetrahydrofuran (30 mL). The temperature was slowly raised to
Ϫ75 °C where it was kept constant for 15 min. The mixture was
treated with methanol (5.0 mL) before being poured into water
(0.10 L) and extracted with diethyl ether (3 ϫ 50 mL). The com-
bined organic layers were washed with brine (2 ϫ 25 mL), dried
and the solvents evaporated. Upon distillation of the residue, a col-
orless liquid was collected which solidified to give needles; m.p.
34Ϫ35 °C (from methanol); b.p. 102Ϫ105 °C/4 Torr; yield 4.1 g
5-Chloro-2,3-dihalo-6-iodo-4-pyridinecarboxylic Acids 3
2,3,5-Trichloro-6-iodo-4-pyridinecarboxylic Acid (3a): 2,2,6,6-Tetra-
methylpiperidine (5.0 mL, 4.2 g, 30 mmol) and 2,3,5-trichloro-4-
iodopyridine (2a; 4.6 g, 15 mmol) were consecutively added at
Ϫ100 °C to a vigorously stirred solution of hexane-free butylli-
thium (30 mmol) in tetrahydrofuran (30 mL). After 2 h at Ϫ100 °C,
the mixture was poured onto an excess of freshly crushed dry ice.
Extraction as described above (see the preparation of acids 1) and
trituration with chloroform of the red oil obtained afforded color-
less prisms; m.p. 252 °C (from ethyl acetate; dec.); yield 2.7 g (52%);
13C NMR (D3CCOCD3): δ ϭ 162.7 (s), 145.6 (s), 143.5 (s), 132.4
(s), 125.1 (s), 120.1 (s); C6HCl3INO2 (352.34): calcd. C 20.45, H
0.29; found C 20.64, H 0.35. Virtually the same result was obtained
after pyridine 2a had been treated with lithium diisopropylamide
for 45 min at Ϫ75 °C.
1
(56%); H NMR: δ ϭ 7.78 (d, J ϭ 7.5 Hz); 13C NMR: δ ϭ 155.0
(d, J ϭ 245 Hz), 139.6, 135.9 (d, J ϭ 6 Hz), 117.4 (d, J ϭ 35 Hz),
113.1 (d, J ϭ 13 Hz); C5HCl2FIN (291.87): calcd. C 20.57, H 0.34;
found C 20.70, H 0.54.
5-Chloro-2,3-difluoro-6-iodopyridine (4c): Prepared as described
above for 2b, but starting from 5-chloro-2,3-difluoro-4-iodopyri-
dine (2c; 6.9 g, 25 mmol) and with a reaction time of 45 min; color-
1
3,5-Dichloro-2-fluoro-6-iodo-4-pyridinecarboxylic Acid (3b): 2,2,6,6-
Tetramethylpiperidine (5.0 mL, 4.2 g, 30 mmol) and 3,5-dichloro-
less liquid; b.p. 85Ϫ87 °C/4 Torr; n2D0 1.5824; yield 3.2 g (46%); H
NMR: δ ϭ 7.63 (t, J ϭ 8.0); 13C NMR: δ ϭ 148.3 (dd, J ϭ 246,
2-fluoro-4-iodopyridine (2b; 4.4 g, 15 mmol) were consecutively ad- 15 Hz), 144.7 (dd, J ϭ 268, 29 Hz), 135.5 (d, J ϭ 5 Hz), 127.0 (dd,
Eur. J. Org. Chem. 2001, 4533Ϫ4536 4535