Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N-3 can be more easily alkylated than N-1 under basic conditions. In this study, we explored methods for direct N-1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide ((BuOK)-Bu-t) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N-1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

Automated summary

This study explored methods for direct N-1-selective methylation of phenytoin using potassium bases in THF, yielding N-1-monomethylated phenytoin and found applicability for various hydantoins and alkyl halides. Despite examining the effects of methylated phenytoins on P-glycoprotein, none showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.