Synthetic approaches to 2-substituted pyrimidines have been studied in an effort to facilitate the preparation of the pyrimidine moiety of bleomycin (2). Ethyl 2,5-dimethyl-4-oxopyrimidine-6-carboxylate (4) has been utilized as starting material; its conversion to the respective ethyl 2-(carboalkoxy)-5-methyl-4-oxopyrimidine-6-carboxylates provided electrophilic intermediates for attempted elaboration of the 2-substituent, while treatment of 4 with pyridine promoted the nucleophilic addition of the C-2 methyl group to chloral. Introduction of the requisite β-aminoalaninamide substituent was attempted in several ways, including conjugate addition reactions, the use of imine or enamine intermediates, and via nucleophilic halide displacement. Of particular interest were the use of 4-azidopyrimidines as synthetic intermediates leading to the required 4-aminopyrimidines and the solvent- dependent rearrangement of ethyl 3-azido-3-[4-azido-6-(carboethoxy)-5-methylpyrimidin-2-yl]propionate (46) to ethyl 3-amino-3-[4-azido-6-(carboethoxy)-5-methylpyrimidin-2-yl]acrylate (47) at ambient temperature.
ASJC Scopus subject areas
- Organic Chemistry