Migrating 1H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Abstract

The alkylation of adenine using alkyl halides under basic conditions in dimethyl sulfoxide (DMSO), a common reaction to achieve N9-alkylated adenine derivatives, is often low yielding with unreacted adenine and complicated reaction mixtures. Herein, we report the reaction monitoring of the alkylation of adenine in DMSO in the presence of NaH using benzylic halides via realtime 1H NMR spectroscopy. NMR analysis revealed that under these generally used reaction conditions, the adeninate anion starting material is protonated as the anionic nucleophile abstracts a labile proton from an alkoxy sulfonium ion intermediate formed via the Kornblum oxidation reaction. To prevent the protonation of the adeninate anion, the reaction was performed in the presence of a mop-up base DBU. Simultaneously increasing the concentration of the alkyl halide and the mop-up base in a 1:1 ratio resulted in a complete reaction; however, increasing the temperature of the reaction promoted depletion of the starting material by protonation and hence reduced conversion to products. This result implies that heating of such electrophiles in DMSO should be avoided. The addition of a mop-up base can help resolve the complication of protonation arising from the Kornblum oxidation reaction in alkylation reactions under similar conditions.