Site-Selective Metalation Reactions
FULL PAPER
δ ϭ 7.19 (td, J ϭ 7.5, 1.5 Hz, 1 H), 7.1 (m, 2 H), 6.94 (symm. m, to pH 5 with citric acid (about 10 g) and extracted with dichloro-
1 H), 5.20 (s, 2 H), 3.61 (s, 3 H). Ϫ 13C NMR: δ ϭ 153.3 (d, J ϭ methane (3 ϫ 15 mL). One tenth of the combined organic layers
245.7 Hz), 145.1 (d, J ϭ 10.4 Hz), 124.4 (d, J ϭ 3.2 Hz), 122.7 (d, was withdrawn and a known amount of benzoic acid (approx.
J ϭ 7.2 Hz), 118.2 (s), 116.4 (d, J ϭ 18.5 Hz), 95.7 (s), 56.3 (s). Ϫ 2 mg, 1 mmol) was added as an internal reference compound. After
MS (CI): m/z (%) ϭ 174 (97) [Mϩ ϩ NH4], 156 (19) [Mϩ], 126
(100).
the solution had been treated with ethereal diazomethane until per-
sistence of the yellow color, it was analyzed by gas chromatography
(2 m, 5% SE-30, 140 °C; 2 m, 5% C-20M, 200 °C). The amount
of methyl 3-fluoro-2-methoxymethoxy)benzoate (1b) formed was
determined by comparison of its peak area with that of the ‘‘in-
ternal standard’’ (methyl benzoate) after response correction using
calibration factors obtained by the evaluation of controls made
with authentic mixtures. The yield thus found was 81%. The re-
mainder (90%) of the dichloromethane solution was evaporated to
dryness and the residue crystallized from a 1:9 (v/v) mixture of
ethyl acetate and hexanes in the form of colorless needles; m.p.
71Ϫ73 °C; 3.6 g (79%). Ϫ 1H NMR: δ ϭ 7.50 (d, J ϭ 8.1 Hz, 1
H), 7.33 (ddd, J ϭ 8.1, 6.5, 1.8 Hz, 1 H), 7.22 (td, J ϭ 5.2, 3.0 Hz,
1 H), 5.36 (s, 2 H), 3.61 (s, 3 H). Ϫ C9H9FO4 (200.17): calcd. C
54.00, H 4.53; found C 54.02, H 4.55.
1-Fluoro-3-(methoxymethoxy)benzene: Prepared as above from 3-
fluorophenol (4.5 mL, 5.6 g, 50 mmol); b.p. 25Ϫ26 °C/0.6 Torr);
n2D0 ϭ 1.4790; d420 ϭ 1.117; 5.0 g (64%). Ϫ 1H NMR: δ ϭ 7.20 (ddd,
J ϭ 8.2, 6.7, 1.3 Hz, 1 H), 6.8 (m, 2 H), 6.68 (tdd, J ϭ 8.7, 3.2,
0.8 Hz, 1 H), 5.13 (s, 2 H), 3.44 (s, 3 H). Ϫ 13C NMR: δ ϭ 163.6
(d, J ϭ 244.9 Hz), 158.6 (d, J ϭ 10.5 Hz), 130.3 (d, J ϭ 9.7 Hz),
111.9 (s), 108.7 (d, J ϭ 20.8 Hz), 104.0 (d, J ϭ 24.1), 94.5 (s), 56.0
(s). Ϫ MS: m/z (%) ϭ 156 (6) [Mϩ], 114 (100), 97 (52). Ϫ C8H9FO2
(156.16): calcd. C 61.53, H 5.81; found C 61.95, H 6.07.
1-Fluoro-4-(methoxymethoxy)benzene: Prepared as above from 4-
fluorophenol (5.6 g, 50 mmol); b.p. 26Ϫ27 °C/0.4 Torr); n2D0
ϭ
1
1.4776; d420 ϭ 1.114; 4.3 g (55%). Ϫ H NMR: δ ϭ 7.0 (m, 4 H),
5.08 (s, 2 H), 3.43 (s, 3 H). Ϫ 13C NMR: δ ϭ 158.0 (d, J ϭ
239.3 Hz), 153.4 (s), 117.6 (d, J ϭ 7.2 Hz, 2 C), 115.8 (d, J ϭ
22.4 Hz, 2 C), 95.0 (s), 55.8 (s). Ϫ MS: m/z (%) ϭ 156 (11) [Mϩ],
115 (39), 114 (100). Ϫ C8H9FO2 (156.16): calcd. C 61.53, H 5.81;
found C 61.84, H 6.14.
2-Fluoro-6-(methoxymethoxy)benzoic Acid (2a): Prepared as above
from 1-fluoro-3-(methoxymethoxy)benzene (1.4 mL,
1.6 g,
10 mmol), although the metalation was accomplished in 2 h at Ϫ75
°C with sec-butyllithium (10 mmol) in the presence of
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (2.1 mL, 1.7 g,
10 mmol); colorless needles; m.p. 42Ϫ44 °C; 1.68 g (93%). Ϫ 1H
NMR: δ ϭ 7.38 (td, J ϭ 8.2, 6.0 Hz, 1 H), 7.02 (d, J ϭ 8.2 Hz, 1
H), 6.83 (t, J ϭ 8.2 Hz, 1 H), 5.27 (s, 2 H), 3.52 (s, 3 H). Ϫ
C9H9FO4 (200.17): calcd. 54.00, H 4.53; found C 54.01, H 4.58. Ϫ
Ester 2b: 93% (by gas chromatography).
1-Methoxymethoxy-2-(trifluoromethyl)benzene: Prepared as above
from 2-(trifluoromethyl)phenol (4.1 g, 25 mmol); b.p. 73Ϫ74 °C/
1
8 Torr; n2D0 ϭ 1.4459; 3.8 g (74%). Ϫ H NMR: δ ϭ 7.72 (dd, J ϭ
8.0, 1.2 Hz, 1 H), 7.61 (t, J ϭ 8.0 Hz, 1 H), 7.36 (d, J ϭ 8.6 Hz, 1
H), 7.19 (t, J ϭ 7.8 Hz, 1 H), 5.37 (s, 2 H), 3.57 (s, 3 H). Ϫ 13C
NMR: δ ϭ 155.0 (s), 133.2 (s), 127.1 (q, J ϭ 4.8 Hz), 123.7 (q, J ϭ
273.1 Hz), 121.1 (s), 119.6 (q, J ϭ 30.5 Hz), 115.2 (s), 94.2 (s), 56.3
(s). Ϫ MS: m/z (%) ϭ 206 (22) [Mϩ], 72 (90), 57 (100). Ϫ C9H9F3O2
(206.17): calcd. C 52.43, H 4.40; found C 52.76, H 4.38.
5-Fluoro-2-(methoxymethoxy)benzoic Acid (3a): Prepared as above
from 1-fluoro-4-(methoxymethoxy)benzene (1.4 mL,
1.6 g,
10 mmol), the metalation conditions being the same as for the pre-
paration of acid 1a (butyllithium, 6 h at Ϫ75 °C); colorless needles;
1
m.p. 56Ϫ58 °C; 1.28 g (71%). Ϫ H NMR: δ ϭ 7.87 (dd, J ϭ 8.5,
1-Methoxymethoxy-3-(trifluoromethyl)benzene: Prepared as above
from 3-(trifluoromethyl)phenol (3.1 mL, 4.1 g, 25 mmol); b.p.
71Ϫ72 °C/8 Torr; n2D0 ϭ 1.4394; 3.9 g (76%). Ϫ 1H NMR: δ ϭ 7.52
(t, J ϭ 8.0 Hz, 1 H), 7.42 (d, J ϭ 1.4 Hz, 1 H), 7.39 (dd, J ϭ 7.5,
0.9 Hz, 1 H), 7.34 (dd, J ϭ 8.4, 2.3 Hz, 1 H), 5.29 (s, 2 H), 3.54 (s,
3 H). Ϫ 13C NMR: δ ϭ 157.5 (s), 132.0 (q, J ϭ 32.2 Hz), 130.1 (s),
124.0 (q, J ϭ 273.0 Hz), 119.6 (s), 118.6 (q, J ϭ 4.0 Hz), 113.3 (q,
J ϭ 3.2 Hz), 94.5 (s), 56.2. Ϫ MS: m/z (%) ϭ 206 (12) [Mϩ], 169
(12), 97 (34), 83 (59), 57 (100). Ϫ C9H9F3O2 (206.17): calcd. C
54.43, H 4.40; found C 52.78, H 4.10.
3.0 Hz, 1 H), 7.3 (m, 2 H), 5.40 (s, 2 H, 3.57 (s, 3 H). Ϫ C9H9FO4
(200.17): calcd. 54.00, H 4.53; found C 53.78, H 4.62. Ϫ Ester 3b:
69% (by gas chromatography).
2-Fluoro-3-(methoxymethoxy)benzoic Acid (4a): At Ϫ75 °C, potas-
sium tert-butoxide (1.1 g, 10 mmol) and 1-fluoro-2-(methoxyme-
thoxy)benzene (1.3 mL, 1.6 g, 10 mmol) were added to a solution
of butyllithium (10 mmol) in tetrahydrofuran (14 mL) and hexanes
(6 mL). The mixture was stirred until homogeneous and then kept
for 2 h at Ϫ75 °C. It was worked up as described for the acid 1a
and the ester 1b. The acid 4a was isolated in the form of white
colorless needles; m.p. 104Ϫ105 °C; 1.51 g (84%). Ϫ 1H NMR: δ ϭ
7.65 (ddd, J ϭ 8.0, 6.2, 1.9 Hz), 7.44 (td, J ϭ 8.0, 1.9 Hz, 1 H),
7.15 (td, J ϭ 8.0, 1.9 Hz), 5.25 (s, 2 H), 3.54 (s, 3 H). Ϫ C9H9FO4
(200.17): calcd. 54.00, H 4.53; found C 54.09, H 4.61. Ϫ Ester 4b:
83% (by gas chromatography).
1-Methoxymethoxy-4-(trifluoromethyl)benzene: Prepared as above
from 4-(trifluoromethyl)phenol (4.1 g, 25 mmol); m.p. Ϫ12 to Ϫ8
1
°C; b.p. 75Ϫ76 °C/8 Torr; n2D0 ϭ 1.4416; 3.3 g (65%). Ϫ H NMR:
δ ϭ 7.68 (d, J ϭ 8.8 Hz, 2 H), 7.24 (d, J ϭ 8.7 Hz, 2 H), 5.31 (s,
2 H), 3.54 (s, 3 H). Ϫ 13C NMR: δ ϭ 159.7 (s), 126.9, (q, J ϭ
4.0 Hz, 2 C), 124.4 (q, J ϭ 271.5 Hz), 124.0 (q, J ϭ 33.0 Hz), 116.1
(s, 2 C), 94.2 (s), 56.2 (s). Ϫ MS: m/z (%) ϭ 207 (23) [Mϩ ϩ 1],
206 (94), [Mϩ], 145 (100). Ϫ C9H9F3O2 (206.17): calcd. C 52.43, H
4.40; found C 52.82, H 4.05.
2-Fluoro-5-(methoxymethoxy)benzoic Acid (5a): Prepared as above
from 1-fluoro-4-(methoxymethoxy)benzene (1.4 mL,
1.6 g,
10 mmol; colorless prisms; m.p. 87Ϫ89 °C; 2.16 g (80%). Ϫ 1H
NMR: δ ϭ 7.66 (dd, J ϭ 6.0, 3.0 Hz, 1 H), 7.2 (m, 1 H), 7.10 (t,
J ϭ 10.0 Hz, 1 H), 5.17 (s, 2 H), 3.49 (s, 3 H). Ϫ C9H9FO4 (200.17):
calcd. 54.00, H 4.53; found C 53.93, H 4.49. Ϫ Ester 5b: 82% (by
gas chromatography).
Reactions with Fluoro(methoxymethoxy)benzenes
3-Fluoro-2-(methoxymethoxy)benzoic Acid (1a): A solution con-
taining 1-fluoro-2-(methoxymethoxy)benzene[7] (3.2 mL, 3.9 g,
25 mmol) and butyllithium (25 mmol) in tetrahydrofuran (35 mL)
and hexanes (15 mL) was kept for 6 h at Ϫ75 °C before being
poured onto an excess of freshly crushed dry ice. After evaporation
of most of the solvent, the residue was partitioned between diethyl
3-Fluoro-2-hydroxybenzoic Acid (1c): The acetal acid 1a (4.5 g,
25 mmol) was dissolved in anhydrous methanol (25 mL) to which
a few drops of boron trifluorideϪdiethyl ether were added. After
ether (15 mL) and 1.0 aqueous sodium hydroxide (25 mL). The having stood overnight (15 h) at ϩ25 °C, the solution was evapor-
aqueous phase was washed with diethyl ether (2 ϫ 5 mL), acidified
ated to dryness and the residue recrystallized from toluene; color-
Eur. J. Org. Chem. 2001, 2911Ϫ2915
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