The Basicity Gradient-driven Migration of Iodine
FULL PAPER
anol/dry ice bath. After 2 h at Ϫ75 °C, the mixture was treated with
a precooled solution of iodine (26 g, 0.10 mol) in tetrahydrofuran
9.1 g, 25 mmol) were added consecutively to a solution of butyl-
lithium (25 mmol) in tetrahydrofuran (50 mL) and hexanes (15 mL),
(0.10 L) and, when at ϩ25 °C, some sodium thiosulfate (1.5 g) was cooled in a methanol/dry ice-bath. After 2 h at Ϫ75 °C, the mixture
added. Evaporation of the volatiles, extraction with hot hexanes, was poured onto an excess of freshly crushed pieces of solid carbon
filtration, concentration, and crystallization afforded the product 7
as colorless needles; m.p. 72Ϫ74 °C; yield: 24.1 g (66%). 1H NMR:
δ ϭ 7.10 (t, J ϭ 5.6 Hz, 2 H) ppm. 13C NMR: δ ϭ 158.1 (dd, J ϭ
dioxide. The volatiles were evaporated and the residue was dis-
solved in a 1.0 aqueous solution of sodium hydroxide (50 mL).
After washing with diethyl ether (2 ϫ 25 mL), the alkaline phase
245, 4 Hz, 2 C), 115.6 (symm. m, 2 C), 97.5 (symm. m, 2 C) ppm. was acidified to pH 2 and extracted with diethyl ether (3 ϫ 25 mL).
C6H2F2I2 (365.89): calcd. C 19.70, H 0.55; found C 19.57, H 0.58.
The combined organic layers were washed with brine (25 mL) and
treated with an ethereal solution of diazomethane until the yellow
color of the reagent persisted. According to gas chromatography
(30 , DB-1, 100 °C [15 min] Ǟ 175 °C [10 min]; heating rate: 30
°C/min; 30 m DB-WAX, identical temperature program; internal
standard: tridecane), the ethereal solution contained 31% of the
methyl ester of acid 8 along with 18% of the methyl ester of acid
3. The bulk of the solution was evaporated to dryness and the res-
idue was triturated with ethyl acetate before being crystallized from
methanol: colorless needles; m.p. 153Ϫ155 °C; yield: 10.4 g (19%).
1H NMR: δ ϭ 3.99 (s, 3 H) ppm. 13C NMR: δ ϭ 163.6 (s), 157.5
(dd, J ϭ 242, 3 Hz), 154.0 (dd, J ϭ 251, 3 Hz), 128.7 (d, J ϭ
25 Hz), 98.5 (d, J ϭ 10 Hz), 98.2 (d, J ϭ 14 Hz), 79.2 (dd, J ϭ 35,
3 Hz), 53.5 (s) ppm. C8H3F2I3O2 (549.82): calcd. C 17.48, H 0.55;
found C 17.62, H 0.64.
1-Fluoro-2,3-diiodobenzene (12): This compound was produced
from 1-fluoro-3-iodobenzene (12 mL, 22 g, 0.10 mol) as described
in the preceding paragraph (see the preparation of compound 7);
colorless needles; m.p. 40.5Ϫ42.5 °C (from chloroform); yield:
1
32.0 g (92%). H NMR: δ ϭ 7.68 (dd, J ϭ 7.8, 1.6 Hz, 1 H), 7.07
(td, J ϭ 8.0, 5.6 Hz, 1 H), 7.01 (td, J ϭ 8.0, 1.3 Hz, 1 H) ppm. 13
C
NMR: δ ϭ 161.5 (d, J ϭ 248 Hz), 134.9 (d, J ϭ 3 Hz), 131.0 (d,
J ϭ 8 Hz), 114.5 (d, J ϭ 25 Hz), 109.1 (s), 96.8 (d, J ϭ 27 Hz)
ppm. C6H3FI2 (347.90): calcd. C 20.71, H 0.87; found C 20.60,
H 0.97.
2-Fluoro-1,3-diiodobenzene (17): This compound was produced
analogously, from 1-fluoro-2-iodobenzene (22 g, 0.10 mol); color-
less needles; m.p. 67- 69 °C (from hexanes); yield: 28.9 g (83%). 1H
NMR: δ ϭ 7.71 (dd, J ϭ 7.8, 5.9 Hz, 2 H), 6.63 (t, J ϭ 8.0 Hz, 1
H) ppm. 13C NMR: δ ϭ 160.1 (d, J ϭ 243 Hz), 139.5 (s, 2 C),
127.3 (d, J ϭ 4 Hz), 80.6 (d, J ϭ 29 Hz, 2 C) ppm. C6H3FI2
(347.90): calcd. C 20.71, H 0.87; found C 20.68, H 0.75.
2,5-Difluoro-3,6-diiodobenzoic Acid (8): Diisopropylamine (3.4 mL,
2.5 g, 25 mmol) and 1,4-difluoro-2,5-diiodobenzene (9; 9.1 g, 25
mol; see Section 4) were added consecutively to a solution of butyl-
lithium (25 mmol) in tetrahydrofuran (50 mL) and hexanes
(15 mL), kept in a methanol/dry ice bath. After 2 h at Ϫ75 °C, the
mixture was poured onto an excess of freshly crushed pieces of
solid carbon dioxide and worked up as described above (see acid
1); tiny, colorless needles; m.p. 151Ϫ153 °C (decomp.; crystallized
from ethyl acetate); yield: 8.2 g (80%). 1H NMR: δ ϭ 7.47 (dd, J ϭ
6.4, 5.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 164.9 (s), 157.8 (dd, J ϭ
247, 3 Hz), 154.1 (dd, J ϭ 248, 3 Hz), 130.2 (d, J ϭ 25 Hz), 125.2
(d, J ϭ 29 Hz), 81.0 (dd, J ϭ 29, 7 Hz), 80.5 (dd, J ϭ 30, 3 Hz)
ppm. C7H2F2I2O2 (409.90): calcd. C 20.51, H 0.49; found C 20.71,
H 0.59.
2,3-Difluoro-1,4-diiodobenzene (19): This compound was produced
analogously, from 1,2-difluoro-3-iodobenzene (24 g, 0.10 mol); col-
orless needles; m.p. 55Ϫ57 °C (from hexanes); yield: 31.8 g (87%).
1H NMR: δ ϭ 7.25 (symm. m, 2 H) ppm. 13C NMR: δ ϭ 150.0
(dd, J ϭ 253, 18 Hz, 2 C), 134.9 (s, 2 C), 82.3 (symm. m, 2 C) ppm.
C6H2F2I2 (365.89): calcd. C 19.70, H 0.55; found C 19.74, H 0.64.
1-Fluoro-2-iodonaphthalene (24): This compound was produced
analogously, from 1-fluoronaphthalene (15 g, 0.10 mol); colorless
liquid; m.p. 11Ϫ13 °C; b.p. 91Ϫ93 °C/2 Torr; n2D0 ϭ 1.6789; yield:
1
25.0 g (92%). H NMR: δ ϭ 8.04 (symm. m, 1 H), 7.8 (m, 1 H),
7.67 (dd, J ϭ 8.9, 6.2 Hz, 1 H), 7.53 (symm. m, 2 H), 7.37 (d, J ϭ
8.6 Hz, 1 H) ppm. 13C NMR: δ ϭ 158.0 (d, J ϭ 250 Hz), 134.3 (d,
J ϭ 4 Hz), 134.1 (s), 127.4 (d, J ϭ 2 Hz), 127.2 (s), 126.8 (s), 124.9
(d, J ϭ 5 Hz), 123.5 (d, J ϭ 18 Hz), 120.1 (d, J ϭ 4 Hz), 75.5 (d,
J ϭ 26 Hz) ppm. C10H6FI (272.06): calcd. C 44.15, H 2.22; found
C 44.27, H 2.21.
2-Fluoro-3,6-diiodobenzoic Acid (13): This compound was produced
from 1-fluoro-2,3-diiodobenzene (12; 8.7 g, 25 mmol) as described
in the preceding paragraph; colorless platelets; m.p. 163Ϫ165 °C
1
(decomp.; cryst. from ethyl acetate); yield: 9.2 g (94%). H NMR:
δ ϭ 7.46 (dd, J ϭ 8.3, 6.2 Hz, 1 H), 7.37 (d, J ϭ 8.3 Hz, 1 H) ppm.
13C NMR: δ ϭ 165.9 (s), 157.5 (d, J ϭ 252 Hz), 140.6 (s), 136.2
(d, J ϭ 4 Hz), 130.0 (d, J ϭ 23 Hz), 91.8 (s), 81.5 (d, J ϭ 26 Hz)
ppm. C7H3FI2O2 (391.90): calcd. C 21.45, H 0.77; found C 21.56,
H 0.61. Acid 13 was also obtained when 2-fluoro-1,3-diiodoben-
zene (17; 35 g, 0.10 mol) was treated consecutively with lithium
2,2,6,6-tetramethylpiperidide and carbon dioxide (for details, see
the following paragraph); yield: 26.3 g (67%).
3. Isomerization and Carboxylation of Iodination Products
2,6-Difluoro-3-iodobenzoic Acid (3): This compound was produced
from 1,3-difluoro-2-iodobenzene[24] (2; 24 g, 0.10 mol) as described
above (see Section 1, preparation of acid 6). Ϫ Methyl Ester: color-
less prisms; m.p. 53Ϫ55 °C (from ethyl acetate); b.p. 64Ϫ65 °C/
1 Torr; 14.6 g (49%). 1H NMR: δ ϭ 7.82 (ddd, J ϭ 8.9, 7.0, 6.2 Hz,
1 H), 6.81 (td, J ϭ 8.9, 1.3 Hz, 1 H), 3.96 (s, 3 H) ppm. 13C NMR:
δ ϭ 161.1 (s), 160.7 (dd, J ϭ 258, 5 Hz), 159.6 (dd, J ϭ 254, 6 Hz),
141.4 (dd, J ϭ 10, 3 Hz), 113.9 (dd, J ϭ 22, 4 Hz), 111.7 (t, J ϭ
20 Hz), 75.6 (dd, J ϭ 27, 4 Hz) 53.1 (s) ppm. C8H5F2IO2 (298.03):
calcd. C 32.24, H 1.69; found C 32.47, H 1.47. Ϫ Hydrolysis of the
ester to the free acid 3: colorless platelets; m.p. 137Ϫ139 °C (from
ethyl acetate; ref.[25]: m.p. 134Ϫ139 °C); yield: 6.9 g (97%). 1H
NMR: δ ϭ 7.84 (dt, J ϭ 8.9, 6.3 Hz, 1 H), 6.83 (td, J ϭ 8.9, 1.1 Hz,
1 H).
2,3-Difluoro-4,6-diiodobenzoic Acid (20): 2,2,6,6-Tetramethylpiper-
idine (17 mL, 14 g, 0.10 mol) and 2,3-difluoro-1,4-diiodobenzene
(19; 37 g, 0.10 mol) were added consecutively to a solution of butyl-
lithium (0.10 mol) in tetrahydrofuran (0.20 L) and hexanes
(65 mL), cooled in a methanol/dry ice bath. After 2 h at Ϫ75 °C,
the reaction mixture was poured onto an excess of freshly crushed
pieces of solid carbon dioxide and was worked up as described
above (see acid 1); colorless prisms; m.p. 180Ϫ182 °C (from ethyl
acetate); yield: 29.6 g (72%). 1H NMR: δ ϭ 8.01 (dd, J ϭ 5.1,
2.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 165.2 (s), 150.8 (dd, J ϭ 249,
Methyl
2,5-Difluoro-3,4,6-triiodobenzoate:
Diisopropylamine 14 Hz), 146.3 (dd, J ϭ 261, 17 Hz), 142.8 (d, J ϭ 4 Hz), 131.4 (d,
(3.4 mL, 2.5 g, 25 mmol) and 1,4-difluoro-2,3-diiodobenzene (7;
J ϭ 18 Hz), 85.8 (d, J ϭ 5 Hz), 84.6 (d, J ϭ 23 Hz) ppm.
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