A. E. Smith, K. M. Clapham, A. S. Batsanov, M. R. Bryce, B. Tarbit
FULL PAPER
precipitate 4 as white solid, and the aqueous phase was extracted
with ethyl acetate (2ϫ50 mL). The organic extracts were com-
bined, and the solvent was evaporated in vacuo to yield a yellowish
solid which was dissolved in the minimal amount of ethyl acetate,
and then the boronic acid 4 was precipitated as a white solid on
addition of tBu3P (5–10 mol-%) to the initial mixture. Conditions c:
As for conditions b, but using Cs2CO3 instead of Na2CO3. Condi-
tions d: Pd(OAc)2, tBu3P, 1,4-dioxane, Na2CO3 (1 ), reflux. Condi-
tions e: As for conditions d, but using Cs2CO3 instead of Na2CO3.
Conditions f: As for conditions a, but at 150 °C, 5 min in a micro-
addition of water (0.57 g, 60%);m.p. 125.8–126.5 °C. 1H NMR wave oven at 150 W. Conditions g: As for conditions f, but with
3
(400 MHz, [D6]DMSO): δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.54 (s, 2
heating for 20 min instead of 5 min.
H), 6.35 (d, 3J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 3.85 (s, 3 H) ppm. 13
C
Supporting Information (see footnote on the first page of this arti-
cle): Detailed procedures and characterization data for compounds
8, 16–29, 31 and 32; X-ray molecular structure of 19; NMR spectra
of compound 32; X-ray crystallographic data for structures
8·0.5H2O and 10.
NMR (100 MHz, [D6]DMSO): δ = 166.5, 164.3, 148.2, 101.3, 53.2,
53.1 ppm. C7H10BNO4 (183.0): calcd. C 45.95, H 5.51, N 7.66;
found C 45.91, H 5.27, N 7.40.
(2,6-Difluoro-3-pyridyl)boronic Acid (6): To a solution of diisopro-
pylamine (6.5 mL, 47.7 mmol) in anhydrous diethyl ether (50 mL)
at 0 °C, nBuLi (2.5 in hexane, 20 mL, 52.1 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 0.5 h and
then cooled to –78 °C, before 2,6-difluoropyridine (5, 5.0 g,
43.4 mmol) was added dropwise. The reaction mixture was stirred
at –78 °C for 3 h, then triisopropyl borate (15 mL, 65.0 mmol) was
added slowly. The reaction mixture was stirred at –78 °C for an-
other 0.5 h, then quenched with water (50 mL) and warmed to
room temperature with stirring overnight. The organic solvent was
evaporated in vacuo and the residue washed with diethyl ether
(3ϫ50 mL) to remove unreacted starting material. The aqueous
layer was then acidified to pH = 6 (with 48% HBr) and then ex-
tracted with ethyl acetate (3ϫ50 mL). The organic layer was con-
centrated in vacuo and the crude product recrystallized from tolu-
ene to give 6 as a white solid (5.6 g, 82%); m.p. 136.7–137.2 °C. 1H
Acknowledgments
We thank Vertellus Specialities UK Ltd. for funding this work.
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3
NMR (400 MHz, [D6]DMSO): δ = 8.28 (q, J = 8.4 Hz, 1 H), 7.47
(s, 2 H), 7.03 (d, 3J = 8.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]-
1
3
1
DMSO): δ = 164.6 (dd, J = 178.4, J = 13.6 Hz), 162.1 (dd, J =
178.4, 3J = 13.6 Hz), 153.0, 106.6 (dd, 2J = 32.4, 4J = 5.4 Hz) ppm.
C5H4BF2NO2 (159.0): calcd. C 37.79, H 2.54, N 8.81; found C
37.92, H 2.34, N 8.67.
(2,3-Dichloro-4-pyridyl)boronic Acid (10): To a solution of diisopro-
pylamine (9.5 mL, 67.6 mmol) in anhydrous THF (50 mL) at 0 °C,
nBuLi (2.5 in hexane, 27.0 mL, 67.6 mmol) was added dropwise.
The reaction mixture was stirred at 0 °C for 0.5 h and then cooled
to –78 °C, before 2,3-dichloropyridine (9, 5.0 g, 33.8 mmol) in an-
hydrous THF (25 mL) was added dropwise. The reaction mixture
was stirred at –78 °C for 3 h, then triisopropyl borate (9.3 mL,
40.5 mmol) was added slowly. The reaction mixture was stirred at
–78 °C for another 1 h, then quenched with water (50 mL) and
warmed to room temperature with stirring overnight. The organic
solvent was evaporated in vacuo and the residue then filtered. The
filtrate was washed with diethyl ether (3ϫ25 mL) to remove unre-
acted starting material. The aqueous layer was then acidified to pH
= 6 (with 48% HBr) to precipitate 10 as white solid (3.6 g, 56%);
m.p. 140.2–141.0 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.30
(d, J = 4.4 Hz, 1 H), 7.41 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 147.4, 146.9, 130.9, 126.8 ppm. MS
(EI): m/z = 190.8 [M+]. C5H4BCl2NO2 (191.8): calcd. C 31.31, H
2.10, N 7.30; found C 30.71, H 1.94, N 6.90.
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General Procedures for the Cross-Coupling Reactions. Conditions a:
The boronic acid, the aryl halide and Pd(PPh3)2Cl2 (ca. 5 mol-%)
were sequentially added to degassed 1,4-dioxane and the mixture
stirred at 20 °C for 30 min. Degassed aqueous Na2CO3 solution
(1 ) was added, and the reaction mixture heated under argon at
reflux. The solvent was removed in vacuo, then ethyl acetate was
added, and the organic layer was washed with brine, separated, and
dried with MgSO4. The mixture was purified by chromatography
on a silica gel column. On some occasions an additional recrystalli-
zation was necessary. Conditions b: As for conditions a, but with the
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