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.
