Proton Mobility in 2-Substituted 1,3-Dichlorobenzenes: ortho or meta Metalation
FULL PAPER
ium 2,2,6,6-tetramethylpiperidide under otherwise identical condi-
tions, the ratio of acids 2c and 3c exceeded 99:1; yield 5.01 g (81%).
2,6-Dichlorotoluene (1g): 2,6-Dichlorotoluene (3.1 mL, 4.0 g,
25 mmol) was added to a solution of sec-butyllithium (25 mmol) in
cyclohexane (20 mL) and tetrahydrofuran (30 mL) kept in a dry
ice/methanol bath. After 45 min at –75 °C, the mixture was poured
on dry ice before being, at +25 °C, acidified with 2.0 hydrochloric
acid (25 mL) and extracted with ethyl acetate (3×25 mL). One
tenth of the organic solution was treated with ethereal diazometh-
ane. According to gas chromatographic analysis (30 m, DB-Wax,
200 °C; 30 m, DB-1, 200 °C; tridecane as the internal calibrated
standard), the crude product mixture contained (2,6-dichlo-
rophenyl)acetic acid,[43,44] 2,4-dichloro-3-methylbenzoic acid[45]
(2g) and 3,5-dichloro-4-methylbenzoic acid (3g; see Section 2) in a
80:16:4 ratio; yield 4.56 g (89%). C8H6Cl2O2 (205.01): calcd. C
46.87, H 2.95; found C 46.91; H 3.10. When lithium 2,2,6,6-tet-
ramethylpiperidide (25 mmol) was used as the metalating reagent,
(2,6-dichlorophenyl)acetic acid and acid 2g were obtained in a
75:25 ratio and in a yield of 3.49 g (68%), whereas lithium diisopro-
pylamide (25 mmol) gave only (2,6-dichlorophenyl)acetic acid; col-
orless needles (from hexanes); m.p. 154–156 °C (ref.[43,44] m.p. 156–
157 °C). –1H NMR: δ = 7.33 (d, J = 8.0 Hz, 2 H), 7.18 (t, J =
8.3 Hz, 1 H), 4.08 (s, 2 H) ppm.
(2,6-Dichlorophenoxy)triethylsilane (1d): (2,6-Dichlorophenoxy)tri-
ethylsilane (5.0 mL, 6.9 g, 25 mmol) was added to a solution of sec-
butyllithium (25 mmol) in cyclohexane (19 mL) and tetra-
hydrofuran (30 mL) cooled to –75 °C. After 45 min at that tem-
perature, the reaction mixture was poured onto freshly crushed dry
ice. At +25 °C, it was acidified with 2.0 hydrochloric acid (20 mL)
and extracted with ethyl acetate (3×25 mL). One tenth of the or-
ganic solution was treated with diazomethane until the yellow color
persisted. According to gas chromatography (30 m, DB-Wax,
270 °C; 30 m, DB-1, 280 °C, standard: pentadecane), the raw mate-
rial contained 2,4-dichloro-3-hydroxybenzoic acid[33] (2d) and 3,5-
dichloro-4-hydroxybenzoic acid[40–42] (3d) in a ratio of 91:9; yield
4.45 g (86%). Crystallization of the crude material from ethyl ace-
tate afforded pure 2,4-dichloro-3-hydroxybenzoic acid[33] (2d); m.p.
210–212 °C (ref.[33] m.p. 211–212 °C); yield 3.62 g (70%). 1H NMR:
δ = 7.58 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H) ppm. When
the metalation was accomplished with lithium 2,2,6,6-tetrameth-
ylpiperidide (25 mmol), the ratio of acids 2d and 3d exceeded 99:1;
yield 3.83 g (58%).
2,6-Dichloro-N,N-dimethylaniline (1e): 2,6-Dichloro-N,N-dimeth-
ylaniline (4.8 g, 25 mmol) was added to a solution of sec-butyllith-
ium (25 mmol) in cyclohexane (20 mL) and tetrahydrofuran
(30 mL) kept in a dry ice/methanol bath. After 45 min at –75 °C,
the reaction mixture was poured onto an excess of freshly crushed
dry ice was added and, when it had reached +25 °C, acidified with
2.0 hydrochloric acid (25 mL) and extracted with ethyl acetate
(3×25 mL). One tenth of the combined organic layers was treated
with ethereal diazomethane. According to gas chromatography
(30 m, DB-Wax, 250 °C; 30 m, DB-1, 250 °C; pentadecane as the
internal calibrated standard), the raw material was composed of
2,4-dichloro-3-(dimethylamino)benzoic acid (2e) and 3,5-dichloro-
4-(dimethylamino)benzoic acid (see Section 2; 3e) in a 80:20 ratio;
yield 3.63 g (62%). When lithium 2,2,6,6-tetramethylpiperidide
(25 mmol) was used as the metalating reagent, 3,5-dichloro-4-(di-
methylamino)benzoic acid (3e) was obtained exclusively; yield 2.98 g
(51%); m.p. 97–99 °C (dec.). –1H NMR: δ = 7.55 (d, J = 8.3 Hz, 1
H), 7.46 (d, J = 8.3 Hz, 1 H), 2.89 (s, 6 H) ppm. 13C NMR: δ
= 167.7, 157.7, 149.0, 139.7, 134.5, 130.4, 128.8, 43.0 (2 C) ppm.
C9H9Cl2NO2 (234.11): calcd. C 46.17, H 3.88; found C 46.06, H
3.89.
1,3-Dichloro-2-ethylbenzene (1h): At –75 °C, 1,3-dichloro-2-ethyl-
benzene (3.5 mL, 4.4 g, 25 mmol) was added to a solution of sec-
butyllithium (25 mmol) in cyclohexane (20 mL) and tetra-
hydrofuran (30 mL) After 45 min at –75 °C, the mixture was
poured onto an excess of freshly crushed dry ice. At +25 °C, it
was acidified with 2.0 hydrochloric acid and extracted with ethyl
acetate (3×25 mL). One tenth of the organic phase was treated
with ethereal diazomethane. According to gas chromatography
(30 m, DB-Wax, 200 °C; 30 m, DB-1, 200 °C, tridecane as the in-
ternal calibrated standard), the raw material contained 2,4-
dichloro-3-ethylbenzoic acid (2h) and 3,5-dichloro-4-ethylbenzoic
acid (see Section 2; 3h) in a 74:26 ratio; yield 4.51 g (77%). Lithium
2,2,6,6-tetramethylpiperidide (25 mmol) as the base produced ex-
clusively 2,4-dichloro-3-ethylbenzoic acid (2h); yield 1.70 g (31%);
m.p. 98–100 °C (from hexanes). 1H NMR: δ = 7.72 (d, J = 8.3 Hz,
1 H), 7.37 (d, J = 8.3 Hz, 1 H), 3.06 (q, J = 7.4 Hz, 2 H), 1.20 (t,
J = 7.5 Hz, 3 H) ppm. 13C NMR: δ = 167.4, 142.5, 138.9, 134.7,
133.9, 130.5, 129.7, 26.3, 13.5 ppm. C9H8Cl2O2 (219.04): calcd. C
49.35, H 3.68; found C 49.27, H 3.60.
2,6-Dichlorobenzotrifluoride (1i): 2,6-Dichloro-4-(trifluoromethyl)-
benzene (5.4 g, 25 mmol) in tetrahydrofuran (30 mL) and cyclohex-
ane (20 mL) was treated consecutively with sec-butyllithium
(25 mmol; 2 h at –75 °C) and dry ice. A small portion of the crude
reaction mixture (equivalent to roughly 1.0 mmol) was acidified to
pH 1, esterified with ethereal diazomethane and hydrogenolytically
dechlorinated.[46,47] Gas chromatographic analysis (30 m, DB-Wax,
150 °C; 30 m, DB-30, 130 °C; tridecane as the internal standardЈЈ)
revealed the presence of methyl 2-, 3- and 4-(trifluoromethyl)benzo-
ate in an 8:3:1 ratio corresponding to yields of 49%, 19% and 6%
(in total 74%). When the bulk of the mixture was worked up by
neutralization and extraction, the main product 3-chloro-2-(trifluo-
romethyl)benzoic acid was obtained after crystallization from an
ethanol/hexanes mixture as colorless needles; m.p. 119–121 °C;
yield 1.74 g (31%). The second abundant component, the 2,4-
dichloro-3-(trifluoromethyl)benzoic acid (2i), was identified in the
mother liquors by 1H NMR spectroscopy. It was independently
prepared from 2,6-dichloro-4-(trifluoromethyl)benzene (25 mmol)
by consecutive treatment with LITMP and dry ice; colorless plate-
lets; m.p. 136–138 °C; yield 4.60 g (71%). All further details can be
found in a previous report.[48]
tert-Butyl (2,6-dichlorophenyl)carbamate (1f): Potassium tert-butox-
ide (5.6 g, 50 mmol) and tert-butyl (2,6-dichlorophenyl)carbamate
(6.5 g, 25 mmol) were consecutively added to a solution of butyl-
lithium (50 mmol) in hexanes (30 mL) and tetrahydrofuran (70 mL)
kept in a dry ice/methanol bath. After 12 h at –75 °C, the reaction
mixture was poured onto freshly crushed dry ice. At +25 °C, the
reaction mixture was acidified with a 2.0 aqueous solution
(25 mL) of citric acid and extracted with ethyl acetate (3×25 mL)
before being dried and the solvents evaporated. According to 1H
NMR (using dioxane as an internal standard for quantification),
the white residue contained 2,4-dichloro-3-(tert-butoxycarboxam-
ido)benzoic acid (2f) and 3,5-dichloro-4-(tert-butoxycarboxamido)-
benzoic acid (3f) in a 95:5 ratio; yield 4.28 g (56%). Pure 3-(tert-
butoxycarboxamido)-2,4-dichlorobenzoic acid (2f) was obtained by
crystallization from ethyl acetate; colorless needles; m.p. 147–
149 °C; yield 3.52 g (46%). 1H NMR: δ = 7.94 (d, J = 8.6 Hz, 1
H), 7.46 (d, J = 8.6 Hz, 1 H), 1.40 (s, 9 H) ppm. 13C NMR: δ =
166.2, 149.0, 137.2, 136.3, 134.1, 131.0, 129.9, 126.9, 83.0, 30.0 (3
C) ppm. C12H13Cl2NO4 (306.15): calcd. C 47.07, H 4.28; found C
46.77, H 4.06.
Eur. J. Org. Chem. 2006, 4398–4404
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4403