LETTER
General Regioselective Synthesis of 2,4-Diarylpyrimidines from 2-Thiouracil
1307
cross-couplings of dihaloheterocycles with problematic
regioselectivities.16
Acknowledgment
This work was supported by the Academy of Sciences of the Czech
Republic (RVO: 61388963), by the institutional support of the
Charles University, by the Czech Science Foundation
(P207/12/0205), and by Gilead Sciences, Inc.
General Procedure for the Pd-Catalyzed Direct Arylation of 2-
(Methylsulfanyl)pyrimidin-4(3H)-one (2) with Aryl Boronic
Acids 3a,3c–f via C–OH Bond Activation Using PyBroP
1,4-Dioxane (4 mL) and Et3N (0.21 mL, 1.5 mmol) were added
through a septum to an argon purged vial containing 2-(methylsul-
fanyl)pyrimidin-4(3H)-one (2, 71.1 mg, 0.5 mmol), PyBroP (280
mg, 0.6 mmol), and the mixture was stirred in a sealed tube at r.t.
for 2 h. Then, the aryl boronic acid 3a,c–f, 1 mmol), PdCl2(PPh3)2
(17.5 mg, 0.025 mmol, 5 mol%), Na2CO3 (265 mg, 2.5 mmol), and
H2O (1 mL) were added, and the mixture was stirred at 100 °C in
the sealed tube for 4 h. After cooling to r.t., the mixture was diluted
with EtOAc, washed with H2O and brine, and the combined organic
layer was dried over MgSO4, filtered, and concentrated. Com-
pounds 4a,c–e were purified by column chromatography on 70 g of
silica gel in eluent 3% EtOAc in hexane and the compound 4f in
gradient 3% EtOAc to 10% EtOAc in hexane.
Supporting Information for this article is available online at
a complete experimental section, and copies of NMR spectra and
crystal structures.onmornfiItangionmuoitpnrfoSnrItagiStupor
References
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data can be obtained free of charge from The Cambridge
2-(Methylsulfanyl)-4-phenylpyrimidine (4a)
Compound 4a was prepared from 2 according to general procedure,
in 99% yield, as a white powder, mp 76–78 °C (lit.17 mp 76–77 °C).
1H NMR (499.8 MHz, CDCl3): δ = 2.61 (s, 3 H, CH3S), 7.35 (d, 1
H, J5,6 = 5.1 Hz, H-5), 7.42–7.49 (m, 3 H, H-3,4-Ph), 8.04 (m, 2 H,
H-2-Ph), 8.495 (d, 1 H, J6,5 = 5.1 Hz, H-6). 13C NMR (125.7 MHz,
CDCl3): δ = 14.21 (CH3S), 111.80 (CH-5), 127.35 (CH-2-Ph),
128.98 (CH-3-Ph), 131.53 (CH-4-Ph), 136.00 (C-i-Ph), 156.64
(CH-6), 164.47 (C-4), 172.23 (C-2). IR: 3064, 2923, 1603, 1556,
1541, 1494, 1413, 1349, 1309, 1200, 1180, 1075 cm–1. MS (EI+):
m/z (% relative intensity) = 77 (6), 102 (11), 129 (22), 156 (43), 202
(100) [M+]. HRMS: m/z calcd for C11H10N2S [M+]: 202.0565;
found: 202.0570.
General Procedure for Carbon–Carbon Cross-Coupling of 2-
(Methylsulfanyl)-4-arylpyrimidines 4a,c–f with Aryl Boronic
Acids 3b–f
A microwave vial sealed with septum was charged with the corre-
sponding 2-(methylsulfanyl)-4-arylpyrimidines (4a,c–f, 0.5 mmol),
the corresponding aryl boronic acid (3b–f, 0.75 mmol), CuTC (286
mg, 1.5 mmol), and Pd(PPh3)4 (57.8 mg, 0.05 mmol, 10 mol%). The
reaction vessel was sealed and flushed with argon. Through the sep-
tum anhyd THF (4 mL) was added. The mixture was heated in a mi-
crowave reactor at 100 °C for 1 h. After cooling to r.t., the solvent
was evaporated. The crude reaction mixture was purified by column
chromatography on silica gel to provide the desired 2,4-diaryl-
pyrimidines 5.
4-Phenyl-2-p-tolylpyrimidine (5ab)
Compound 5ab was prepared from 4a (101 mg, 0.5 mmol) accord-
ing to the general procedure, in 99% yield, as white crystals from
hexane–EtOAc, mp 86–87 °C (lit.18 mp 86–87 °C). 1H NMR (500.0
MHz, CDCl3): δ = 2.45 (s, 3 H, CH3); 7.34 (m, 2 H, H-3-Tol), 7.55
(m, 3 H, H-3,4-Ph), 7.62 (d, 1 H, J5,6 = 5.4 Hz, H-5), 8.24 (m, 2 H,
H-2-Ph), 8.50 (m, 2 H, H-2-Tol), 8.84 (d, 1 H, J6,5 = 5.4 Hz, H-6).
13C NMR (125.7 MHz, CDCl3): δ = 21.54 (CH3), 114.20 (CH-5),
127.36 (CH-2-Ph), 128.40 (CH-2-Tol), 128.99 (CH-3-Ph), 129.41
(CH-3-Tol), 131.25 (CH-4-Ph), 134.30 (C-i-Tol), 136.73 (C-i-Ph),
141.49 (C-4-Tol), 156.84 (CH-6), 163.07 (C-2), 164.51 (C-4). IR:
3058, 2921, 1582, 1545, 1492, 1424, 1405, 1381, 1322, 1276, 1175,
1104, 1020 cm–1. MS (EI+): m/z (%) = 77 (4), 102 (17), 117 (10),
129 (6), 169 (4), 232 (8), 246 (100) [M+]. HRMS: m/z calcd for
C17H14N2 [M+]: 246.1157; found: 246.1155. Anal. Calcd for
C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C, 82.60; H, 5.56; N,
11.17.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1305–1308