548 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Xu et al.
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tively (Table 4, Entry 5, 6). However, the yield of 8 de-
creased when the diazotization temperature rose to 75 C,
o
which may result from the fast dissociation of HNO2 at such
a temperature and the formation of yellow brown gas (N2O4)
is the proof of this explanation. Therefore, the optimal reac-
tion conditions are relatively high diazotization temperature,
high hydrolysis temperature and longer reaction time as il-
lustrated in Entry 6 of Table 4.
In summary, we have established a highly efficient, che-
moselective method for the synthesis of important organic
intermediates 2-methoxy-4-substituted pyrimidines from
commercially available 2,4-dichloropyrimidine. Under
nonaqueous
diazotization
conditions,
4-bromo-2-
methoxypyrimidine and 4-chloro-2-methoxypyrimidine can
be selective synthesized by using isoamyl nitrite as the dia-
zotization agent, while in aqueous medium, 4-hydroxy- 2-
methoxypyrimidine was obtained with NaNO2 as the diazoti-
zation agent.
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ACKNOWLEDGEMENT
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synthesis of highly functionalized pyrimidines. Org. Biomol. Chem.
2009, 7, 2841. (b) Xie, F.C.; Li, S.K.; Bai, D.L.; Lou, L.G.; Hu,
Y.H. Three-component, one-pot synthesis of 2,4,5-substituted
pyrimidines library for screening against human hepatocellular car-
cinoma BEL-7402 cells. J. Comb. Chem. 2007, 9, 12. (c) Rong,
L.C.; Han, H.X.; Wang, H.Y.; Jiang, H.; Tu, S.J.; Shi, D.Q. An
efficient and facile synthesis of pyrimidine and quinazoline
derivatives via one-pot three-component reaction under solvent-
free conditions. J. Heterocyclic Chem. 2009, 46, 152. (d) Cosimelli,
B.; Greco, G.; Ehlardo, M.; Novellino, E.; Settimo, F.D.; Taliani,
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hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3
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Karpov, A.S.; Merkul, E.; Rominger, F.; Muller, T.J.J. Concise
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component pyrimidine synthesis. Angew. Chem. Int. Ed. 2005, 44,
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active and reusable heterogeneous catalyst for the one-pot synthesis
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(a) Cherng, Y.J. Synthesis of substituted pyridines by the reactions
of halopyridines with sulfur, oxygen and carbon nucleophiles under
focused microwave irradiation. Tetrahedron 2002, 58, 887. (b)
Fang, W.P.; Cheng, Y.T.; Cheng, Y.R.; Cherng, Y.J. Synthesis of
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This work was financially supported by Bellen Chemistry
Co., Ltd.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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Typical procedure for the synthesis of 6: The mixture of 4-amino-
2-methoxypyrimidine (0.75 g, 6 mmol), CuBr2 (1.46 g, 6.5 mmol)
and isoamyl nitrite (1.05 g, 9 mmol) in MeCN (50 mL) was re-
fluxed for 6 h. After the reaction, the mixture was cooled and then
filtered. The filtrate was concentrated to give a white solid as the
crude product 6 (1.08 g). Purification by column chromatography
on silica gel with petroleum ether/ethyl acetate (10/1, v/v) as the
eluant provided 4-bromo-2-methoxypyrimidine (6) (0.99 g, 87%).
1H NMR (400 MHz, CDCl3) ꢀ 4.03 (d, 3H, OCH3), 7.15 (d, 1H, Br-
Ar-H), 8.28 (d, 1H, N-Ar-H). Anal Calcd for C5H5BrN2O: C,
31.77; H, 2.67; N, 14.82. Found: C, 31.80; H, 2.65; N, 14.79.
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