Scalable Synthesis of 4-Substituted 5-Bromo-6-methylpyrimidines

Abstract

Small halogenated heteroaromatic ring systems are valuable monomers, which can enable rapid access to novel and desirable chemical space, in part because of their ability to participate in established cross coupling chemistry such as the Heck, Stille, and Suzuki reactions. Described is a practical, scalable synthetic route towards the construction of a diverse array of 4-substituted 5-bromo-6-methylpyrimidine monomers.

Key words

heterocycle - heteroaromatic ring - pyrimidine - library monomer

References

• 1 Foster HM. Snyder HR. Org. Synth.  1955,  35:  80 
• 2 Brown DJ. J. Soc. Chem. Ind.  1950,  69:  353 
• 3 Katritzky AR. Yousaf TI. Can. J. Chem.  1986,  64:  2087 
• 5 Yamanaka H. Sakamoto T. Nishimura S. Sagi M. Chem. Pharm. Bull.  1987,  35:  3119 
• 6 Zapol’skii VA. Namyslo JC. Altug C. Gjikaj M. Kaufmann DE. Synthesis  2008,  304 
• 7 Gillespie RJ. Bamford SJ. Clay A. Gaur S. Haymes T. Jackson PS. Jordan AM. Klenke B. Leonardi S. Liu J. Mansell HL. Ng S. Saadi M. Simmonite H. Stratton GC. Todd RS. Williamson DS. Yule IA. Bioorg. Med. Chem. Lett.  2009,  17:  6590 
• 8 Koryakova AG. Ivanenkov YA. Ryzhova EA. Bulanova EA. Karapetian RN. Mikitas OV. Katrukha EA. Kazey VI. Okun I. Kravchenko DV. Lavrovsky YV. Korzinov OM. Ivachtchenko AV. Bioorg. Med. Chem. Lett.  2008,  18:  3661 
• 9 Dolakova P. Masojidkova M. Holy A. Heterocycles  2007,  71:  1107 
• 12 Kress TJ. Heterocycles  1994,  38:  1375 

4

Yields as high as 95% are consistently obtained on a five-gram scale.

10

Significant quantities of highly soluble 5-bromo-4-(bromo-methyl)-6-methylpyrimidine and an unidentified tribro-minated product were detected in the mother liquor by NMR and LCMS analyses.

11

Three steps from 5-bromo-4,6-dimethylpyrimidin-2-ol.