Tautomerism, protonation, and methylation in methylthiopurines; factors determining electrophilic attack on purines

Abstract

The predominant tautomeric forms, the position of protonation in aqueous solution, and the course of methylation in aprotic solvents have been determined for all possible mono- and bis-methylthiopurines and for 2,6,8-trismethyl-thiopurine. As a rule, protonation creates resonating cations in which the charge is distributed over both rings. The site of methylation varies. Like purine itself, the 8-methylthio- and the 2,8-bismethylthio-derivatives are attacked by methyl iodide at N-1. In 6-methylthio-, 6,8-bismethylthio- and 2,6,8-trismethylthiopurine, N-3 undergoes alkylation. In 2-methylthio- and in 2,6-bismethylthio-purine, methylation takes place at both positions 7 and 9. These results are explained in terms of the combined influence of electronic and steric factors.