HSAB-driven chemoselective N1-alkylation of pyrimidine bases and their 4-methoxy- or 4-acetylamino-derivatives

Article abstract of DOI:10.1016/j.tet.2006.04.098

The lithium salts of the conjugated bases of 4-methoxy- and 4-acetylamino-2(1H)-pyrimidinones 1-3 undergo highly chemoselective N¹-methylation or ethylation when treated with methyl- or ethylsulfate (hard electrophiles) in dry dioxane, while the use of DMF as solvent results in competitive O²-alkylation. Potassium salts of the same bases in DMF undergo prevalent O²-attack. Under the same conditions, a similar but less chemoselective behaviour is observed in alkylation of thymine and uracil, where some N³-attack occurs. This can be rationalised in terms of the HSAB principle.