R.D. Chambers et al. / Journal of Fluorine Chemistry 126 (2005) 1002–1008
1007
(s, Ar), 125.8 (s, Ar), 129.7 (s, Ar), 129.9 (s, Ar), 152.5 (s,
4. Synthesis of bridged oxygen derivatives 14
Ar), 155.6 (s, Ar), 155.9 (d, 1JCF 241.1, C-6), 156.2 (d, 3JCF
15.3, C-2), 158.9 (d, 3JCF 4.6, C-4); m/z (EI+) 349 (M+, 19%),
351 (M++2, 12%), 353 (M++4, 2%).
4.1. General procedure
A mixture consisting of 6a, bis-silyl derivative 13 and
CsF in monoglyme (50 ml) was heated at reflux temperature
and stirred for 3 days. The resulting mixture was poured into
cold water and extracted with dichloromethane. The organic
layer was separated, dried (MgSO4) and the solvent removed
under reduced pressure to give a crude product which was
purified by either distillation, recrystallisation or column
chromatography on silica gel.
3.2. Reactions of 3,5-dichloro-2,4,6-trimethoxypyridine 9
3.2.1. 3,5-Dichloro-2,4,6-triisopropoxypyridine 10
A mixture consisting of 9 (6 g, 0.025 mol) and sodium
(4.6 g, 0.2 mole) in isopropanol (50 ml) was heated under
reflux with continual stirring. After 6 days, the resulting
material was poured into cold water and extracted into
methylene dichloride. The organic layer was separated, dried
(MgSO4), and evaporated to give crude material (5.7 g)
which was shown by gc/ms to consist of three components in
the ratio 0.5:1.5:17.5. Column chromatography on silica gel
using light petroleum:CH2Cl2 (8:2) as eluent, gave 3,5-
dichloro-2,4,6-tri-isopropoxypyridine 10 (5.1 g, 89%) as a
colourless liquid; b.p. 259–260 8C, Rf 0.52. (Found C, 52.5;
H, 6.7; N, 4.5 C14H21Cl2NO3 requires: C, 52.2; H, 6.5; N,
4.3%); dH 1.3 (6H, d, 3JHH 6.0, CH3), 1.3 (12H, d, 3JHH 6.4,
CH3, C-8), 4.7 (1H, sept, 3JHH 6.0, CH at C-4), 5.1 (2H, sept,
3JHH 6.0, CH at C-7); dC 22.0 (s, CH3), 22.5 (s, CH3), 69.9
(s, CH), 77.5 (s, CH), 103.6 (s, C-3), 155.9 (s, C-2), 160.3 (s,
C-4); m/z (EI+) 323 (10%, M++2) 321 (15%, M+), 239 (10),
237 (16), 197 (59), 195 (100), 43 (51).
4.2. 6-[2-(3,5-Dichloro-6-fluoro-4-methoxy(2-
pyridyloxy))ethoxy]-3,5-dichloro-2-fluoro-4-
methoxypyridine 14a
6a (6.5 g, 30 mmol), 13a (3 g, 12 mmol) and CsF (3.5 g,
23 mmol) in monoglyme (50 ml), after recrystallisation
from n-hexane, gave 6-[2-(3,5-dichloro-6-fluoro-4-meth-
oxy(2-pyridyloxy))ethoxy]-3,5-dichloro-2-fluoro-4-methox-
ypyridine 14a (6.0 g, 90%) as a white solid; m.p. 146–
148 8C. (Found: C, 37.4; H, 2.2; N, 6.2. C14H10Cl4F2N2O4
requires C, 37.3; H, 2.2; N, 6.2%); dH 4.0 (3H, s, OCH3),
4.7 (2H, s, CH2); dF ꢀ74.0 (s); dC 61.2 (s, CH3), 65.5 (s,
2
4
CH2), 103.3 (d, JCF 34.2, C-3), 108.7 (d, JCF 7.6, C-5),
156.1 (d, 3JCF 15.9, C-4), 155.7 (d, 1JCF 237, C-2), 163.3 (d,
3JCF 4.6, C-6); m/z (EI+) 454 (M+, 1%), 452 (M+, 3%),
450 (M+, 5%), 448 (M+, 4%), 242 (11), 240 (65), 239(10),
238 (100).
3.2.2. 3-chloro-2,4,6-trimethoxypyridine 11 and 2,4,6-
trimethoxypyridine 12
To cold (0 8C), stirred solution of 9 (5 g, 24 mmol) in
ether was added 0.32 N LiAlH4 in ether (32 gm in 40 ml).
On completion of addition the reaction mixture was heated
under reflux with continually stirring. After 6 h, cooled
(0 8C) and 2N H2SO4 acid (10 ml) was added slowly. The
resulting material was poured into cold water and extracted
into methylene dichloride. The organic layer was separated,
dried (MgSO4) and evaporated to give a crude product (2 g)
which was shown by gc/ms to consist of two compounds
(ratio 1:1). Column chromatography on silica gel using
hexane:dichloromethane ratio (8:2) as eluent, gave 3-chloro-
2,4,6-trimethoxypyridine 11 (0.5 g, 27%) as a colourless
liquid; b.p. 65–66 8C, Rf 0.28. (Found: C, 47.1; H, 4.9; N,
6.8. C8H10ClNO3 requires C 47.2; H, 4.9; N, 6.9%); dH 3.9
4.3. 6-{2-[2-(3,5-Dichloro-6-fluoro-4-methoxy(2-
pyridyloxy)) ethoxy]ethoxy}-3,5-dichloro-
2-fluoro-4-methoxypyridine 14b
6a (6.5 g, 30 mmol), 13b (3 g, 12 mmol) and CsF
(3.5 g, 23 mmol) in monoglyme (50 ml), after recrystallisa-
tion from petroleum ether 40–60, gave 6-{2-[2-(3,5-
dichloro-6-fluoro-4-methoxy(2-pyridyloxy))ethoxy]ethoxy}-
3,5-dichloro-2-fluoro-4-methoxy pyridine 14b (6.6 g, 90%)
as white solid; m.p. 98–100 8C. (Found: C, 38.9; H, 2.8; N,
5.7. C16H14Cl4F2N2O5 requires C, 38.9; H, 2.8; N, 5.7%); dH
3.9 (2H, m, CH2OCH2), 4.0 (3H, s, OCH3), 4.4 (2H, m, Ar-
OCH2); dF ꢀ74.1(s); dC 61.2 (s, CH3), 67.4 (s, CH2OCH2),
69.2 (s, Ar-OCH2), 103.0 (d, 2JCF 34.2, C-3), 108.5 (d, 4JCF
8.0, C-5), 155.8 (d, 1JCF 237, C-2), 156.4 (d, 3JCF 15.6, C-4),
163.2 (d, 3JCF 5.0, C-6); m/z (EI+) 496 (3%, M+), 494 (6%,
M+), 492 (4%, M+), 242 (11), 240(65), 239(11), 238 (100),
213 (18), 212 (13), 211(28).
5
5
(3H, d, JHH 2, C-8), 3.9 (3H, d, JHH 2, C-9), 4.0 (3H, d,
5
5JHH 2, C-7), 5.9 (1H, d, JHH 2.8, C-5); dC 53.5 (s, C-9),
54.1 (s, C-7), 56.3 (s, C-8), 86.3 (s, C-5), 96.4 (s, C-3), 158.4
(s, C-6), 161.5 (s, C-2), 164.3 (s, C-4); m/z (EI+) 205 (28%,
M++3), 204 (36%, M++2), 203 (89%, M++1), 202 (100%,
M+), 174 (33), 173 (27), 160 (14), 110 (11), 69 (18), 53 (20);
and, 2,4,6-trimethoxypyridine 12 (0.4 g, 25%) as colourless
liquid; b.p. 45–47 (lit., [10] 47–48 8C), Rf 0.18. (Found: C,
53.6; H, 6.1; N, 7.8. C8H11NO3 requires C, 56.8; H, 6.5; N,
8.2%); dH 3.8 (3H, m, C-8), 3.9 (6H, m, C-7), 5.9 (2H, m, C-
3); dC 53.6 (s, 2-OMe), 55.3 (s, 4-OMe), 87.3 (s, C-3), 164.3
(s, C-2), 170.1 (s, C-4); m/z (EI+) 170 (7%, M++1), 168
(65%, M+), 169 (100%, M+-1), 140 (16), 139 (29), 69 (21).
4.4. 6-[3-(3,5-Dichloro-6-fluoro-4-methoxy(2-pyridyloxy))
5-methylphenoxy]-3,5-dichloro-2-fluoro-4-
methoxypyridine 14c
6a (5.35 g, 25 mmol), 1-methyl-3,5-bis-trimethylsilany-
loxy-benzene 13c (2.68 g, 10 mmol) and CsF (2.28 g,