The use of dialkyl acetals in the N-alkylation of 8-oxoadenosine and guanosine. Mechanistic studies and rate determination

Abstract

The use of seven N,N-dimethylformamide dialkyl acetals (methyl-, ethyl-, benzyl-, n-propyl-, n-butyl-, t-butyl, and neopentyl-) was explored for the exocyclic amine protection and subsequent N-alkylation of 8-oxoadenosine and guanosine. Reactions occurred in good to modest yields (50–95%) upon addition of heat (60°C) using DMF as solvent. We determined relative rates of reaction and kinetic experiments resulted in the following order: Me≫Bn≈t-Bu≫Et≈n-Pr≈n-Bu>Me (Np, neopentyl). We found that groups that stabilize a pseudo-carbocation intermediate facilitate the completion of the reaction and lead to different reaction pathways, including elimination of isobutylene and ethylene in some cases.