New Pyrimidylboronic Acids and Functionalized Heteroarylpyrimidines
(4.2 mL, 18.2 mmol) in anhydrous THF (20 mL) and toluene
(5 mL) at –78 °C was added nBuLi (2.5 in hexane, 6.2 mL,
15.6 mmol) dropwise. The reaction mixture was stirred for 4 h at
–78 °C; it was then quenched with water (40 mL) and warmed to
room temperature with stirring overnight. The organic solvent was
evaporated in vacuo, and the remaining aqueous layer was washed
with diethyl ether (3ϫ10 mL) to remove unreacted starting mate-
rial. The aqueous layer was then acidified to pH 5 (with 48% aq.
HBr) to precipitate 6 as a white solid (1.75 g, 85%); m.p. 200 °C
(decomp.). 1H NMR (400 MHz, [D6]DMSO): δ = 8.87 (s, 2 H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.3, 161.8 ppm. MS
(EI): m/z = 157.8 [M]+. C4H4BClN2O2 (158.4): calcd. C 30.34, H
2.55, N 17.69; found C 30.62, H 1.94, N 17.10.
Conditions (c): The boronic acid (1.1 equiv.) the aryl halide
(1.0 equiv.) Pd(OAc)2 (ca. 5 mol-%) and DtBPF (ca. 5 mol-%) were
sequentially added to degassed 1,4-dioxane (10 mL) and the mix-
ture stirred at 20 °C for 30 min. Degassed aqueous Na2CO3 solu-
tion (1 , 3.0 equiv.) was added and the reaction mixture was
heated under argon at reflux (typically for 65 h). 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 col-
umn. On some occasions an additional recrystallization was neces-
sary.
Conditions (d): As for conditions (b), with a second addition of
boronic acid 8 (1.1 equiv.) after 24 h reflux.
X-ray Diffraction Measurement: The experiment (from a pseudo-
merohedrally twinned crystal) was carried out with a SMART 3-
circle diffractometer with a 1 K CCD area detector by using graph-
Conditions (e): The boronic acid (1.1 equiv.) the aryl halide
(1.0 equiv.) [Pd2(dba)3] (ca. 1 mol-%) and PCy3 (ca. 2.4 mol-%)
were sequentially added to degassed 1,4-dioxane (2.7 mL), and the
mixture was stirred at 20 °C for 30 min. Degassed aqueous K3PO4
solution (1.27 , 1.7 equiv.) was added, and the reaction mixture
was heated under argon at reflux (typically between 1–30 h). 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 or by recrystallization.
¯
ite-monochromated Mo-Kα radiation (λ = 0.71073 Å) and a Cryo-
stream (Oxford Cryosystems) open-flow N2 cryostat. The structure
was solved by direct methods and refined by full-matrix least-
squares against F2 of all reflections by using SHELXTL software
(version 6.12, Bruker AXS, Madison WI, USA, 2001). Crystal
data: 6, C4H4BClN2O2, M = 158.35, T = 120 K, monoclinic, space
group P21/n (no. 14), a = 6.644(2) Å, b = 14.578(4) Å, c =
7.155(2) Å, β = 116.60(1)°, V = 619.7(3) Å3, Z = 4, Dc
=
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic details and characterization data for compounds 24–
34. Copies of NMR spectra of compound 34.
1.697 gcm–3, µ = 0.54 mm–1, 6468 reflections with 2θ Յ 55°, Rint
= 0.051, R = 0.051 on 1379 data with I Ն2σ(I), wR(F2) = 0.136
on all 1444 unique data.
CCDC-651541 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Acknowledgments
We thank Vertellus Specialties UK Ltd. for funding this work.
2-Amino-5-pyrimidylboronic Acid (8): To a solution of 2-amino-5-
bromopyrimidine (7) (1.74 g, 10 mmol) and triisopropylborate
(2.9 mL, 12 mmol) in anhydrous THF (50 mL) at –78 °C was added
nBuLi (2.5 in hexane, 10 mL, 25 mmol) dropwise over 1 h. The
reaction mixture was stirred for 3.5 h at –78 °C, then warmed to
–20 °C and quenched with water (50 mL) before being stirred for
30 min. The organic solvent was evaporated in vacuo, and the re-
maining aqueous layer was filtered to remove inorganic salts. The
filtrate was washed with diethyl ether (3ϫ50 mL) to remove unre-
acted starting material, and the aqueous layer was filtered to re-
move inorganic salts. The filtrate was then acidified to pH 6 (with
48% aq. HBr) to precipitate 8 as a white solid. Yields of pure prod-
uct from several reactions varied between 25% and 46%; m.p. Ͼ
[1] Reviews of cross-coupling methodology: a) B. U. W. Maes, Top.
Heterocycl. Chem. 2006, 1, 155–211; b) A. de Meijere, F. Died-
erich (Eds.), Metal-Catalyzed Cross-Coupling Reactions, Wiley-
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7781–7786; b) K. Billingsley, K. W. Anderson, S. L. Buchwald,
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1
300 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.49 (s, 2 H), 7.96
[br. s, 2 H, B(OH)2] ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
164.1, 163.9 ppm. C4H6BN3O2 (138.9): calcd. C 34.58, H 4.35, N
30.25; found C 34.46, H 4.34, N 30.37.
[5] For a review of heterocyclic boronic acids: E. Tyrrell, P.
Brookes, Synthesis 2003, 469–483.
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General Procedure for the Cross-Coupling Reactions
Conditions (a): The boronic acid (1.1 equiv.), the aryl halide
(1.0 equiv.) and [Pd(PPh3)2Cl2] (ca. 5 mol-%) were sequentially
added to degassed 1,4-dioxane[27] (10 mL), and the mixture was
stirred at 20 °C for 30 min. Degassed aqueous Na2CO3 solution
(1 , 3.0 equiv.) was added, and the reaction mixture was heated
under argon at reflux (typically for 24 h). 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 recrystallization was necessary.
[8] Reviews of lithiation of azines: a) F. Mongin, G. Quéguiner,
Tetrahedron 2001, 57, 4059–4090; b) A. Turck, N. Plé, F. Mon-
gin, G. Quéguiner, Tetrahedron 2001, 57, 4489–4505.
Conditions (b): As for conditions (a) with the addition of tBu3P
(ca. 5 mol-%) to the initial mixture.
Eur. J. Org. Chem. 2007, 5712–5716
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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