Metalation and Derivatization of Dichlorobenzotrifluorides
FULL PAPER
2,6-Dichloro-3-(trifluoromethyl)benzoic Acid (2): A solution of 2,4-
dichloro-1-(trifluoromethyl)benzene (3.6 mL, 5.4 g, 25 mmol) and
butyllithium (25 mmol) in tetrahydrofuran (25 mL) and hexanes
(15 mL) was kept at –75 °C for 45 min. The dark violet mixture
was poured onto an excess of freshly crushed dry ice covered with
tetrahydrofuran (25 mL). After evaporation of the solvents, the res-
idue was partitioned between water (10 mL) and hexanes (10 mL).
The aqueous layer was acidified with concentrated hydrochloric
acid (10 mL) and extracted with diethyl ether (3×25 mL).
Crystallization from hexanes afforded colorless needles; m.p. 95–
97 °C; yield: 4.87 g (75%). 1H NMR: δ = 7.72 (d, J = 8.6 Hz, 1 H),
7.50 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR: δ = 169.5 (s), 135.4 (s),
135.0 (s), 130.4 (q, J = 2 Hz), 129.1 (q, J = 5 Hz), 128.1 (s), 127.9
(q, J = 32 Hz), 122.1 (q, J = 274 Hz) ppm. C8H3Cl2F3O2 (259.01):
calcd. C 37.10, H 1.17; found C 37.17, H 1.18.
reflux for 5 min. After evaporation of the solvent, crystallization
from hexanes afforded colorless needles; m.p. 140–141 °C; yield:
1
0.676 g (87%). H NMR: δ = 8.39 (s, 1 H), 7.70 (s, 1 H) ppm. 13C
NMR: δ = 168.6 (s), 139.6 (s), 137.6 (s), 134.3 (s), 131.6 (q, J =
5 Hz), 127.5 (q, J = 32 Hz), 126.7 (s), 122.0 (q, J = 273 Hz) ppm.
C8H3Cl2F3O2 (259.01): calcd. C 37.10, H 1.17; found C 37.20, H
1.50.
2-Bromo-1,3-dichloro-4-(trifluoromethyl)benzene
(6):
Bromine
(7.0 mL, 22 g, 0.14 mol, 2.5 equiv.) and [2,6-dichloro-3-(trifluoro-
methyl)phenyl]trimethylsilane (3; 12 mL, 16 g, 55 mmol) in tetra-
chloromethane (55 mL) were heated to reflux for 20 h. The solution
was poured into a saturated solution of sodium sulfite (50 mL), the
organic layer was separated, the solvents evaporated, and the resi-
due distilled as a colorless liquid; b.p. 47–48 °C/0.7 Torr; n2D0
=
1.5261; yield: 12.1 g (75%). 1H NMR: δ = 7.61 (d, J = 8.3 Hz, 1
H), 7.50 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR: δ = 140.4 (s), 134.8
(s), 128.5 (q, J = 32 Hz), 128.0 (s), 126.8 (s), 126.4 (q, J = 5 Hz),
122.0 (q, J = 273 Hz) ppm. C7H2BrCl2F3 (293.90): calcd. C 28.60,
H 0.68; found C 28.85, H 0.80.
[2,6-Dichloro-3-(trifluoromethyl)phenyl]trimethylsilane (3): A solu-
tion of 2,4-dichloro-1-(trifluoromethyl)benzene (7.2 mL, 11 g,
50 mmol) and butyllithium (50 mmol) in tetrahydrofuran (50 mL)
and hexanes (30 mL) was kept at –75 °C for 45 min. Chlorotrimeth-
ylsilane (6.3 mL, 5.4 g, 50 mmol) was poured into the violet solu-
tion. Water (5.0 mL) was added and the resulting suspension fil-
tered. After evaporation of the solvents, distillation afforded a col-
orless liquid; b.p. 65–66 °C/0.6 Torr; n2D0 = 1.4975; yield: 11.8 g
(82%). 1H NMR: δ = 7.57 (d, J = 8.4 Hz, 1 H), 7.34 (d, J = 8.5 Hz,
1 H), 0.54 (s, 9 H) ppm. 13C NMR: δ = 145.4 (s), 140.3 (s), 139.8
(q, J = 2 Hz), 128.8 (q, J = 6 Hz), 128.6 (s), 127.6 (q, J = 31 Hz),
122.9 (q, J = 273 Hz), 3.1 (s, 3 C) ppm. C10H11Cl2F3Si (287.18):
calcd. C 41.82, H 3.86; found C 42.01, H 3.80.
[3-Bromo-2,6-dichloro-5-(trifluoromethyl)phenyl]trimethylsilane (7):
2,2,6,6-Tetramethylpiperidine (8.5 mL, 10 g, 50 mmol) and 2-
bromo-1,3-dichloro-4-(trifluoromethyl)benzene (6; 7.9 mL, 15 g,
50 mmol) were added consecutively to a solution of butyllithium
(50 mmol) in tetrahydrofuran (50 mL) and hexanes (30 mL) cooled
in a dry ice/toluene bath. After 45 min at –75 °C, chlorotrimethyl-
silane (6.3 mL, 5.4 g, 50 mmol) was poured into the yellow mixture.
The suspension was partitioned between 2.0 m hydrochloric acid
(50 mL) and hexanes (50 mL), the organic layer was dried with
sodium sulfate, concentrated, and the residue was distilled to afford
a colorless oil that solidified in the course of 3 d; b.p. 78–79 °C/
0.8 Torr; m.p. 43–45 °C; yield: 10.5 g (57%). 1H NMR: δ = 7.94 (s,
1 H), 0.55 (s, 9 H) ppm. 13C NMR: δ = 144.7 (s), 142.9 (s), 138.2
(q, J = 2 Hz), 132.9 (q, J = 6 Hz), 128.5 (q, J = 31 Hz), 122.7 (s),
122.0 (q, J = 274 Hz), 3.4 (s, 3 C) ppm. C10H10BrCl2F3Si (366.08):
calcd. C 32.81, H 2.75; found C 32.76, H 2.69.
2,4-Dichloro-5-(trifluoromethyl)-3-(trimethylsilyl)benzoic Acid (4):
N,NЈ,NЈ,NЈЈ,NЈЈ-Pentamethyldiethylenetriamine (2.1 mL, 1.7 g,
10 mmol) and [2,6-dichloro-3-(trifluoromethyl)phenyl]trimethyl-
silane (3; 2.2 mL, 2.9 g, 10 mmol) were added consecutively to a
solution of sec-butyllithium (10 mmol) in tetrahydrofuran (20 mL)
and hexanes (10 mL) cooled to –100 °C. After 15 min at –100 °C,
the dark violet mixture was poured onto an excess of freshly
crushed dry ice covered with tetrahydrofuran (25 mL). After evapo-
ration of the solvents, the residue was partitioned between water
(10 mL) and hexanes (10 mL). The aqueous layer was acidified with
concentrated hydrochloric acid (10 mL) and extracted with diethyl
ether (3×25 mL). A 76:24 ratio of isomers was determined by gas
chromatography after treatment of an aliquot of the mixture with
diazomethane to obtain the corresponding esters. Crystallization
from hexanes afforded colorless needles; m.p. 125–126 °C; yield:
2-Bromo-3,5-dichloro-6-(trifluoromethyl)-4-(trimethylsilyl)benzoic
Acid (8): 2,2,6,6-Tetramethylpiperidine (4.0 mL, 3.3 g, 20 mmol)
and [3-bromo-2,6-dichloro-5-(trifluoromethyl)phenyl]trimethyl-
silane (7; 7.3 g, 20 mmol) were added consecutively to a solution
of butyllithium (20 mmol) in tetrahydrofuran (20 mL) and hexanes
(15 mL) cooled in a dry ice/toluene bath. After 45 min at –75 °C,
the solution was poured onto an excess of freshly crushed dry ice
covered with tetrahydrofuran (20 mL). After evaporation of the sol-
vents, the residue was partitioned between brine (20 mL) and hex-
anes (20 mL). The aqueous layer was acidified with concentrated
hydrochloric acid (10 mL) and extracted with diethyl ether
(3×20 mL). Precipitation in hexanes afforded a white powder; m.p.
1
1.40 g (42%). H NMR: δ = 8.15 (s, 1 H), 0.58 (s, 9 H) ppm. 13C
NMR: δ = 171.6 (s), 145.1 (s), 144.3 (s), 144.1 (s), 131.6 (q, J =
6 Hz), 129.7 (s), 128.6 (q, J = 32 Hz), 123.1 (q, J = 274 Hz), 4.3 (s)
ppm. C11H11Cl2F3O2Si (331.19): calcd. C 39.89, H 3.35; found C
40.22, H 3.42. The pure acid 4 was obtained directly from a solu-
tion of [3-bromo-2,6-dichloro-5-(trifluoromethyl)phenyl]trimethyl-
silane (7; 9.2 g, 25 mmol) and butyllithium (25 mmol) in tetra-
hydrofuran (25 mL) and hexanes (15 mL) at –100 °C for 45 min.
The mixture was poured onto an excess of freshly crushed dry ice
covered with tetrahydrofuran (25 mL). After evaporation of the sol-
vents, the residue was partitioned between water (10 mL) and hex-
anes (10 mL). The aqueous layer was acidified with concentrated
hydrochloric acid (10 mL) and extracted with diethyl ether
(3×25 mL). Crystallization from hexanes afforded colorless need-
les; yield: 6.03 g (73%).
1
195–198 °C; yield: 6.08 g (74%). H NMR: δ = 0.57 (s) ppm. 13C
NMR: δ = 170.3 (s), 145.9 (s), 144.3 (s), 139.6 (s), 136.9 (q, J =
3 Hz), 124.9 (q, J = 31 Hz), 121.6 (q, J = 275 Hz), 120.6 (s), 3.4 (s,
3 C) ppm. C11H10BrCl2F3O2Si (410.09): calcd. C 32.22, H 2.46;
found C 32.16, H 2.36.
3,5-Dichloro-2-(trifluoromethyl)benzoic Acid (9): At 0 °C, butylmag-
nesium chloride (8.0 mmol) in tetrahydrofuran (6.0 mL) was added
to a solution of butyllithium (16 mmol) in hexanes (10 mL). The
suspension was diluted with tetrahydrofuran (25 mL) and cooled
to –75 °C. 2-Bromo-3,5-dichloro-6-(trifluoromethyl)-4-(trimethyl-
silyl)benzoic acid (8; 5.0 g, 12 mmol) was added all at once. The
solution was allowed to reach 0 °C in the course of 45 min, poured
into 5.0 m hydrochloric acid (10 mL), and extracted with diethyl
ether (3×10 mL). A solution of tetrabutylammonium fluoride trih-
ydrate (3.8 g, 12 mmol) in tetrahydrofuran (25 mL) was added to
2,4-Dichloro-5-(trifluoromethyl)benzoic Acid (5): A solution con-
taining 2,4-dichloro-5-(trifluoromethyl)-3-(trimethylsilyl)benzoic
acid (4; 1.0 g, 3.0 mmol) and tetrabutylammonium fluoride trihy-
drate (0.95 g, 3.0 mmol) in tetrahydrofuran (10 mL) was heated to
Eur. J. Org. Chem. 2005, 4393–4400
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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