E. Marzi, C. Bobbio, F. Cottet, M. Schlosser
FULL PAPER
2. Functionalization of 3-Fluorophenol
1
3.48 g (73%). H NMR*: δ = 7.81 (dd, J = 8.8, 8.4 Hz, 1 H), 6.96
(dd, J = 8.9, 1.6 Hz, 1 H) ppm. 13C NMR*: δ = 164.6 (d, J =
4 Hz), 160.9 (d, J = 260 Hz), 159.7 (d, J = 3 Hz), 131.9 (d, J =
4 Hz), 112.1 (d, J = 10 Hz), 110.1 (d, J = 20 Hz) ppm. MS (c.i.):
m/z (%) = 209 (1) [M+ + 18], 192 (8) [M+ + 1], 191 (3) [M+], 190
(22) [M+ – 1], 173 (100). C7H4ClO3 (190.56): calcd. C 44.12, H
2.12; found C 44.40, H 2.02.
2-Fluoro-6-hydroxybenzoic Acid (1): A mixture of 1-fluoro-3-(meth-
oxymethoxy)benzene[2] (3.2 mL, 3.9 g, 25 mmol) and sec-butyllith-
ium (25 mmol) in tetrahydrofuran (35 mL) and cyclohexane
(15 mL) was kept at –75 °C for 2 h before being poured onto an
excess of freshly crushed dry ice. After evaporation of the volatiles,
the residue was treated with 2.0 m hydrochloric acid (25 mL) and
extracted with diethyl ether (3×25 mL). Evaporation of the solvent
and crystallization from toluene afforded 3.63 g (93%) of colorless
platelets; m.p. 159–161 °C (ref.[2]: 159–161 °C). 1H NMR ([D6]-
DMSO): δ = 7.36 (td, J = 8.5, 6.5 Hz, 1 H), 6.76 (d, J = 7.4 Hz, 1
H), 6.70 (dd, J = 10.3, 8.4 Hz, 1 H) ppm.
4-Fluoro-2-hydroxybenzoic Acid (2): Palladium (10% on charcoal,
0.53 g) was added to a solution of 3-chloro-4-fluoro-2-hydroxyben-
zoic acid (6; 1.9 g, 10 mmol) and ammonium formate (3.8 g,
60 mmol) in methanol (10 mL). The slurry was stirred for 20 h at
25 °C. After filtration and evaporation, the residue was dissolved
in 1.0 m hydrochloric acid (20 mL) and extracted with diethyl ether
(3×20 mL). Evaporation of the combined organic layers and
crystallization from a 1:4 (v/v) mixture of ethyl acetate and hexanes
mixture gave colorless platelets; m.p. 188–189 °C; (ref.[31]: m.p.
186 °C); yield: 1.48 g (95%). 1H NMR*: δ = 7.96 (dd, J = 8.6,
6.6 Hz, 1 H), 6.7 (m, 2 H) ppm. 13C NMR*: δ = 171.6, 167.6 (d, J
= 252 Hz), 164.7 (d, J = 14 Hz), 133.3 (d, J = 12 Hz), 109.7 (d, J
= 3 Hz), 107.4 (d, J = 13 Hz), 104.2 (d, J = 24 Hz) ppm. MS (c.i.):
m/z (%) = 174 (1) [M+ + 18], 157 (11) [M+ + 1], 156 (65) [M+], 155
(9) [M+ – 1], 138 (100).
2-Chloro-1-fluoro-3-(methoxymethoxy)benzene (5): As described
above, but running the reaction on a 0.10 mol scale and using 1,1,2-
trichloro-1,2,2-trifluoroethane (12 mL, 19 g, 0.10 mol) as the rea-
gent. Immediate distillation afforded a colorless liquid; b.p. 75–
76 °C/2 Torr; n2D0 = 1.5042; d420 = 1.31; yield: 15.8 g (83%). 1H
NMR: δ = 7.1 (m, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.80 (t, J =
8.2 Hz, 1 H), 5.24 (s, 2 H), 3.49 (s, 3 H) ppm. 13C NMR: δ = 159.1
(d, J = 248 Hz), 154.4 (d, J = 3 Hz), 127.4 (d, J = 10 Hz), 111.4
(d, J = 19 Hz), 111.3 (d, J = 3 Hz), 109.7 (d, J = 21 Hz), 95.3,
56.5 ppm. MS (c.i.): m/z (%) = 205 (35) [M+ + 18], 192 (27) [M+
+
1], 191 (24) [M+], 190 (100) [M+ – 1], 159 (78), 117 (76).
C8H8ClFO2Si (190.60): calcd. C 50.41, H 4.23; found C 50.31, H
4.20.
2-Fluoro-4-hydroxybenzoic Acid (3): [2-Fluoro-6-(methoxymethoxy)-
phenyl]trimethylsilane (8; 5.7 g, 25 mmol) was added to a solution
of butyllithium (25 mmol) and potassium tert-butoxide (2.8 g,
25 mmol) in tetrahydrofuran (35 mL) and hexanes (15 mL) cooled
in a dry ice/methanol bath. After 2 h at –75 °C, the reaction mix-
ture was poured onto an excess of freshly crushed dry ice. The
volatiles were allowed to evaporate and the solid left behind was
partitioned between diethyl ether (25 mL) and water (25 mL). The
aqueous phase was acidified to pH 1 with concentrated hydrochlo-
ric acid, extracted with dichloromethane (3×25 mL), dried and
evaporated under reduced pressure. The residue was recrystallised
from methanol; colorless stars; m.p. 202–204 °C (ref.[32]: m.p. 204–
[2-Fluoro-6-(methoxymethoxy)phenyl]trimethylsilane (8): Prepared
and isolated analogously using chlorotrimethylsilane (13 mL, 11 g,
0.10 mol) as the reagent; colorless liquid; b.p. 63–64 °C/2 Torr
(ref.[30]: no physical constants or analysis reported); n2D0 = 1.4854;
d420 = 1.160; yield: 19.6 g (86%). H NMR: δ = 7.23 (dt, J = 8.2,
1
6.4 Hz, 1 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.63 (t, J = 8.3 Hz, 1 H),
5.14 (s, 2 H), 3.45 (s, 3 H) ppm. 13C NMR: δ = 167.9 (d, J =
241 Hz), 163.3 (d, J = 15 Hz), 132.1 (d, J = 11 Hz), 114.7 (d, J =
32 Hz), 109.2 (d, J = 28 Hz), 109.0 (d, J = 3 Hz), 94.5, 56.5, 1.1
(d, J = 4 Hz) ppm. MS (c.i.): m/z (%) = 246 (1) [M+ + 18], 229 (5)
[M+ + 1], 228 (16) [M+], 183 (100), 168 (35), 153 (62). C11H17FO2Si
(228.28): calcd. C 57.86, H 7.50; found C 57.86, H 7.20.
1
205.5 °C); yield: 3.24 g (83%). H NMR*: δ = 7.85 (t, J = 8.6 Hz,
1 H), 6.78 (dd, J = 8.5, 2.2 Hz, 1 H), 6.64 (dd, J = 12.3, 2.2 Hz, 1
H) ppm. 13C NMR*: δ = 165.5 (d, J = 4 Hz), 164.5 (d, J = 258 Hz),
164.2 (d, J = 12 Hz), 134.8 (d, J = 2 Hz), 112.5 (d, J = 2 Hz), 110.7
(d, J = 10 Hz), 104.4 (d, J = 25 Hz) ppm. MS (c.i.): m/z (%) = 174
(0) [M+ + 18], 157 (10) [M+ + 1], 156 (45) [M+], 139 (100). Com-
pound 3 was also prepared starting from 3-chloro-2-fluoro-4-hy-
droxybenzoic acid (7) and using the same reaction conditions de-
scribed for chlorine-free acid 2; yield: 1.39 g (89%).
3-Chloro-4-fluoro-2-hydroxybenzoic Acid (6): 1-Chloro-2-fluoro-6-
(methoxymethoxy)benzene (5; 4.8 g, 25 mmol) and butyllithium
(25 mmol) in tetrahydrofuran (34 mL) and hexanes (16 mL) were
kept in a dry ice/methanol bath for 6 h before the mixture was
poured on an excess of freshly crushed dry ice. The volatiles were
allowed to evaporate and the residue was partitioned between di-
ethyl ether (25 mL) and water (25 mL). The aqueous phase was
acidified with concentrated hydrochloric acid to pH 1 and extracted
with diethyl ether (3×25 mL). The combined organic layers were
dried, filtered and the solvents evaporated. The residue, a white
powder, was recrystallized from a 1:9 (v/v) mixture of ethyl acetate
and hexanes; colorless needles; m.p. 190–192 °C; yield: 3.29 g
[3-Chloro-2-fluoro-6-(methoxymethoxy)phenyl]trimethylsilane (10):
[2-Fluoro-6-(methoxymethoxy)phenyl]trimethylsilane (8; 17 g,
75 mmol) was added to a solution of butyllithium (75 mmol) and
potassium tert-butoxide (8.4 g, 75 mmol) in hexanes (50 mL) and
tetrahydrofuran (90 mL) cooled in a dry ice/methanol bath. After
2 h at –75 °C, the mixture was treated with 1,1,2-trifluoro-1,2,2-
trichloroethane (8.9 mL, 14 g, 75 mmol). After further 45 min, the
slurry was poured into brine (0.10 L) and extracted with diethyl
ether (3×75 mL). The combined organic layers were dried, filtered
and the solvents evaporated. Upon distillation under reduced pres-
1
(69%). H NMR*: δ = 7.94 (dd, J = 9.0, 6.4 Hz, 1 H), 6.93 (t, J =
8.9 Hz, 1 H) ppm. 13C NMR*: δ = 171.5, 162.8 (d, J = 254 Hz),
160.3 (d, J = 5 Hz), 130.5 (d, J = 11 Hz), 110.5, 107.7 (d, J =
22 Hz), 107.6 (d, J = 23 Hz) ppm. MS (c.i.): m/z (%) = 209 (0) [M+
+ 18], 192 (9) [M+ + 1], 190 (26) [M+ – 1], 172 (100). C7H4ClFO3
(190.56): calcd. C 44.12, H 2.12; found C 44.16, H 2.11.
sure, a colorless liquid was collected; b.p. 110–112 °C/3 Torr; n2D0
=
1.5061; yield: 8.67 g (44%). 1H NMR: δ = 7.29 (t, J = 8.7 Hz, 1
H), 6.84 (d, J = 8.7 Hz, 1 H), 5.16 (s, 2 H), 3.48 (s, 3 H), 0.36 (d,
J = 1.9 Hz, 9 H) ppm. 13C NMR: δ = 161.5 (d, J = 241 Hz), 161.0
(d, J = 14 Hz), 131.6 (d, J = 1 Hz), 116.1 (d, J = 32 Hz), 113.7 (d,
J = 23 Hz), 109.6 (d, J = 4 Hz), 94.2, 56.0, 0.5 (d, J = 4 Hz) ppm.
MS (c.i.): m/z (%) = 281 (0) [M+ + 18], 264 (3) [M+ + 1], 263 (4)
[M+], 262 (42) [M+ – 1], 217 (100), 158 (78). C11H16ClFO2Si
(262.78): calcd. C 50.28, H 6.14; found C 50.58, H 6.01.
3-Chloro-2-fluoro-4-hydroxybenzoic Acid (7): 2,2,6,6-Tetramethylpi-
peridide (4.2 mL, 3.5 g, 25 mmol) and 1-chloro-2-fluoro-6-(meth-
oxymethoxy)benzene (5; 4.8 g, 25 mmol) were added consecutively
to butyllithium (25 mmol) in tetrahydrofuran (34 mL) and hexanes
(16 mL) cooled in dry ice/methanol bath. After 2 h at –75 °C, the
reaction mixture was treated and worked up as described in the
preceding paragraph; colorless needles; m.p. 192–194 °C; yield:
2120
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 2116–2123