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F. Cottet, M. Schlosser / Tetrahedron 60 (2004) 11869–11874
to 50 8C in the course of 45 min, 5-bromo-2-chloro-4-
iodopyridine (32 g, 0.10 mol) were added. After 20 h at
50 8C, the reaction mixture was poured into 12% aqueous
ammonia (0.20 L) and extracted with diethyl ether (3!
0.20 L). The combined organic layers were washed with
12% aqueous ammonia (2!0.20 L), 2.0 M hydrochloric
acid (0.10 L), a saturated solution (0.10 L) of aqueous
sodium hydrogen carbonate and brine (0.10 L). After drying
and upon distillation, a colorless oil was collected; bp 80–
81 8C/16 mm Hg; mp 11–13 8C; n2D0 1.5084; d420 1.813;
yield: 18.3 g (64%). 1H NMR: dZ8.68 (s, 1H), 7.62 (s, 1H).
13C NMR: dZ153.9, 151.2, 140.0 (q, JZ33 Hz), 122.6 (q,
JZ5 Hz), 121.0 (q, JZ275 Hz), 115.8 (q, JZ2 Hz). Anal.
Calcd for C6H2BrClF3N (260.44): C 27.67, H 0.77. Found:
C 27.75, H 0.56.
between diethyl ether (20 mL) and a 2.0 M aqueous solution
of sodium thiosulfate (20 mL). The phases were separated
and the aqueous one extracted with diethyl ether (20 mL).
The combined organic layers were washed with 2.0 M
hydrochloric acid (20 mL), saturated sodium hydrogen
carbonate aqueous solution, dried and evaporated. The
residue crystallized from hexanes as yellow needles; 5.35 g
1
(87%); mp 83–85 8C. H NMR: dZ8.63 (s, 1H), 8.15 (s,
1H). 13C NMR: dZ148.3, 146.0 (q, JZ35 Hz), 140.4,
131.8, 120.2 (q, JZ275 Hz). Anal. Calcd for C6H2ClF3IN
(307.44): C 23.44, H 0.65. Found: C 23.16, H 0.78.
3.2.7. 2-Iodo-3-chloro-6-(trifluoromethyl)pyridine (10).
(1.5 g,
5-Chloro-4-iodo-2-(trifluoromethyl)pyridine
5.0 mmol) was added to the solution prepared from
butyllithium (5.0 mmol) and diisopropylamine (0.71 mL,
0.51 g, 5.0 mmol) in tetrahydrofuran (20 mL) and hexanes
(3 mL) kept in a dry ice/methanol bath. After 2 h at K75 8C,
the mixture was treated with water (2.0 mL) and the
solvents were evaporated. The residue was taken up in
diethyl ether (30 mL) and was washed with 2.0 M
hydrochloric acid (20 mL) and saturated sodium hydrogen
carbonate aqueous solution. After evaporation, the residue
crystallized from hexanes as yellowish prisms; 1.27 g
(83%); mp 62–64 8C. 1H NMR: dZ7.81 (dq, JZ8.0,
0.6 Hz, 1H), 7.60 (d, JZ8.0 Hz, 1H). 13C NMR: dZ146.5
(q, JZ36 Hz), 141.8, 136.9, 121.6, 120.4 (q, JZ3 Hz),
120.3 (q, JZ275 Hz). Anal. Calcd for C6H2ClF3IN
(307.44): C 23.44, H 0.65. Found: C 23.53, H 0.65.
3.2.3. 2-Bromo-6-chloro-4-(trifluoromethyl)pyridine (5).
5-Bromo-2-chloro-4-(trifluoromethyl)pyridine (2.9 mL,
5.2 g, 20 mmol) was added to the solution prepared at
0 8C from 2,2,6,6-tetramethylpiperidine (6.8 mL, 5.7 g,
40 mmol) and butyllithium (40 mmol) in diethyl ether
(0.10 L) and hexanes (25 mL) kept in a dry ice/methanol
bath. After 2 h at K75 8C, the mixture was treated with
1.0 M hydrochloric acid (50 mL). The organic layer was
filtered through a pad of basic alumina (50 mL) which was
rinsed with diethyl ether (0.10 L). Upon distillation, a
colorless oil was obtained; bp 68–70 8C/12 mm Hg; nD20
1.4966; d240 1.770; yield: 3.52 g (68%). H NMR: dZ7.66
1
(s, 1H), 7.53 (s, 1H). 13C NMR: dZ152.4, 142.6 (q, JZ
33 Hz), 141.7, 122.9 (q, JZ4 Hz), 121.2 (q, JZ274 Hz),
119.5 (q, JZ4 Hz). Anal. Calcd for C6H2BrClF3N (260.44):
C 27.67, H 0.77. Found: C 27.75, H 0.75.
3.2.8. 2,3-Dibromo-5-chloropyridine. At 60 8C, 2-amino-
3-bromo-5-chloropyridine20 (73 g, 0.35 mol) was dissolved
in 48% hydrobromic acid (0.20 L, 0.30 kg, 1.8 mol). After
cooling to K5 8C, bromine (36 mL, 0.11 kg, 0.70 mol) was
added dropwise over 20 min. A solution of sodium nitrite
(60 g, 0.90 mol) in water (80 mL) was then added at a rate to
keep the temperature of the reaction mixture between K5
and 0 8C. When finished, the temperature was allowed to
reach 25 8C. The bromine was reduced with an excess of
solid sodium sulfite, and the reaction mixture was extracted
with diethyl ether (3!0.20 L). The combined organic layers
were filtered through a pad of basic alumina (0.25 L) which
was rinsed with diethyl ether (0.40 L). Evaporation of the
volatiles afforded pure 2,3-dibromo-5-chloropyridine; mp
38–41 8C (lit.24 mp 39.5–43.0 8C); yield: 64.9 g (68%).
3.2.4. 5-Chloro-2-iodopyridine. 2-Bromo-5-chloropyri-
dine23 (9.6 g, 50 mmol) was heated to reflux in the presence
of sodium iodide (22 g, 0.15 mol) and chlorotrimethylsilane
(6.4 mL, 5.4 g, 50 mmol) in propionitrile for 6 h. The
reaction mixture was poured into 2.0 M aqueous solution of
sodium hydroxide and extracted with diethyl ether (2!
50 mL). The combined organic layers were washed with
brine (50 mL), dried and evaporated. The residue crystal-
lized from hexanes as colorless platelets; mp 85–87 8C
(lit.23 mp 85–87 8C); yield: 10.4 g (87%; lit.23 52% from the
2,5-dichloropyridine).
3.2.5. 5-Chloro-2-(trifluoromethyl)pyridine. Analogously
from 5-chloro-2-iodopyridine (24 g, 0.10 mol), a colorless
solid was obtained after sublimation of the reaction product;
mp 37–39 8C; 13.1 g (72%). 1H NMR: dZ8.69 (d, JZ
2.3 Hz, 1H), 7.87 (dd, JZ8.3, 2.3 Hz, 1H), 7.66 (d, JZ
8.3 Hz, 1H). 13C NMR: dZ149.0, 146.2 (q, JZ35 Hz),
137.0, 135.2, 121.3 (q, JZ2 Hz), 121.2 (q, JZ274 Hz).
Anal. Calcd for C6H3ClF3N (181.54): C 39.70, H 1.67.
Found: C 39.66, H 1.60.
3.2.9. 3-Bromo-5-chloro-2-iodopyridine. A mixture of
2,3-dibromo-5-chloropyridine (20 g, 75 mmol), sodium
iodide (33 g, 0.22 mol) and chlorotrimethylsilane (9.5 mL,
8.1 g, 75 mmol) in propionitrile (75 mL) was heated under
reflux for 45 min. The reaction mixture was then poured into
a 2.0 M aqueous solution of sodium hydroxide (0.20 L) and
extracted with diethyl ether (3!0.20 L). The combined
organic layers were washed with brine and evaporated to
yield some 20 g of a brownish oil containing 2-iodo-3-
bromo-5-chloropyridine (79%) and 3-bromo-5-chloropyri-
dine (21%) as determined by gas chromatography (DB-1,
20 m, 150 8C, pentadecane as an internal standard). Twofold
crystallization from methanol afforded pure 3-bromo-5-
chloro-2-iodopyridine as tiny colorless needles; mp 58–
60 8C; yield: 9.7 g (42%). 1H NMR: dZ8.30 (d, JZ2.2 Hz,
1H), 7.83 (d, JZ2.2 Hz, 1H). 13C NMR: dZ147.2, 139.1,
131.9, 130.0, 120.7. Anal. Calcd for C5H2BrClIN (318.34):
3.2.6. 5-Chloro-4-iodo-2-(trifluoromethyl)pyridine (9).
5-Chloro-2-(trifluoromethyl)pyridine (3.6 g, 50 mmol) was
added to the solution prepared from butyllithium (20 mmol)
and diisopropylamine (2.8 mL, 2.0 g, 20 mmol) in tetra-
hydrofuran (30 mL) and hexanes (13 mL) kept in a dry ice/
methanol bath. After 2 h at K75 8C, the mixture was treated
with iodine (5.1 g, 20 mmol) in tetrahydrofuran (20 mL).
The solvents were evaporated and the residue partitioned