(Trifluoromethoxy)pyridines
to reach 25 °C before being treated with an aqueous solution of
sodium hydroxide (5%, 30 mL). The resulting aqueous layer was
collected, washed with diethyl ether (10 mL), and acidified to pH 4
by dropwise addition of hydrochloric acid (6 , 10 mL) before be-
ing extracted with ethyl acetate (3ϫ15 mL). The combined organic
layers were dried with sodium sulfate and the solvents were evapo-
rated. Crystallization of the residue from chloroform afforded col-
orless needles of pure 6-chloro-3-(trifluoromethoxy)picolinic acid
(38, 2.72 g, 11.3 mmol, 61%); m.p. 93–96 °C. 1H NMR (CDCl3,
300 MHz, 25 °C): δ = 7.72 (dq, J = 8.7, 1.3 Hz, 1 H, 4-H), 7.58 (d,
J = 8.7 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ
= 161.4 (COOH), 148.1 (C), 145.1 (C), 139.7 (C), 134.7 (CH), 130.0
75 MHz, 25 °C): δ = 165.1 (COOH), 154.4 (C), 151.5 (CH), 149.6
2
(C), 122.1 (C), 119.9 (q, JC,F = 261 Hz, OCF3), 112.2 (CH) ppm.
19F NMR (CDCl3, 282 MHz, 25 °C):
δ
=
–57.7 ppm.
C7H3ClF3NO3 (241.55): calcd. C 34.81, H 1.25, N 5.80; found C
34.68, H 1.56, N 5.90.
Supporting Information (see footnote on the first page of this arti-
cle): Details concerning the X-ray structures.
Acknowledgments
We thank the Ministère de la Recherche of France and are very
grateful to the Centre National de la Recherche Scientifique
(CNRS) and Bayer CropScience for a PhD grant to B. M.
2
(CH), 120.1 (q, JC,F = 261 Hz, OCF3) ppm. 19F NMR (CDCl3,
282 MHz, 25 °C): δ = –58.1 ppm. HRMS (ESI negative) for
C7H3ClF3NO3: calcd. 239.966 [M – H]; found 239.967.
2-Chloro-6-iodo-5-(trifluoromethoxy)pyridine (39): A solution of
LDA [diisopropylamine (0.6 g, 0.9 mL, 6.2 mmol, 2 equiv.) and
butyllithium (1.56 in hexanes, 4.0 mL, 6.2 mmol, 1.1 equiv.) in
THF (6 mL)] was added dropwise at –78 °C to a solution of 2-
chloro-4-iodo-5-(trifluoromethoxy)pyridine (36b, 1.0 g, 3.1 mmol)
in THF (6 mL) over a period of 20 min and the reaction mixture
was further stirred for 1 h at this temperature. It was then hy-
drolyzed with an aqueous solution of hydrochloric acid (5%, 5 mL)
and extracted with ethyl acetate (3ϫ5 mL). The combined organic
layers were dried with sodium sulfate and the solvents were evapo-
rated. The crude oil was purified by distillation under vacuum (b.p.
96–100 °C/16 mbar) to afford a 1:4 mixture (0.50 g, 1.55 mmol,
50%) of 2-chloro-4-iodo-5-(trifluoromethoxy)pyridine (36b) and 2-
chloro-6-iodo-5-(trifluoromethoxy)pyridine (39). The mixture was
dissolved in THF (4 mL), and BuLi (1.56 in hexanes, 0.2 mL,
0.31 mmol, 0.2 equiv.) was added dropwise at –78 °C. After 10 min
at this temperature, the mixture was neutralized with an aqueous
solution of hydrochloric acid (5%, 5 mL) before being extracted
with diethyl ether (3ϫ5 mL). The combined organic layers were
dried with sodium sulfate and the solvents were evaporated. The
crude oil was purified by distillation under vacuum (b.p. 98–102 °C/
16 mbar) to afford pure 2-chloro-6-iodo-5-(trifluoromethoxy)pyr-
idine (39, 0.30 g, 0.93 mmol, 60% in relation to the previous mix-
ture, 30% overall yield) as a pale yellow oil. 1H NMR (CDCl3,
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2
147.2 (C), 145.7 (C), 128.9 (CH), 123.2 (CH), 119.8 (q, JC,F
=
260 Hz, OCF3), 111.4 (C) ppm. 19F NMR (CDCl3, 282 MHz,
25 °C): δ = –57.8 ppm.
2-Chloro-4-(trifluoromethoxy)nicotinic Acid (40): Butyllithium
(1.42 in hexanes, 6.8 mL, 9.7 mmol, 1.1 equiv.) was added drop-
wise at 0 °C to a solution of diisopropylamine (1.0 g, 1.4 mL,
9.7 mmol, 1.1 equiv.) in THF (25 mL). A solution of 2-chloro-4-
(trifluoromethoxy)pyridine (16, 1.7 g, 8.8 mmol, 1 equiv.) in THF
(5 mL) was added dropwise at –78 °C, and the reaction mixture
was stirred for 2 h at this temperature. The mixture was then
poured onto an excess of freshly crushed dry ice before being
treated with an aqueous solution of sodium hydroxide (5%,
25 mL). The resulting aqueous layer was collected, washed with
diethyl ether (15 mL), and acidified to pH 4 by dropwise addition
of hydrochloric acid (6 , 8 mL). After extraction with ethyl acetate
(3ϫ20 mL), the combined organic layers were dried with sodium
sulfate and the solvents were evaporated. Crystallization from a
mixture of hexanes and ethyl acetate (3:1) afforded pure 2-chloro-
4-(trifluoromethoxy)nicotinic acid (40, 1.70 g, 7.04 mmol, 80%) as
colorless needles; m.p. 111–114 °C. 1H NMR (CDCl3, 300 MHz,
25 °C): δ = 8.51 (d, J = 5.9 Hz, 1 H, 6-H), 8.34 (br. s, 1 H, COOH),
7.21 (dq, J = 5.9, 2.0 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3,
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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