The Selective N-Monoalkylation of Amides with Alkyl Halides in the Presence of Alumina and KOH

Article abstract of DOI:10.1246/bcsj.58.838

The effects of alumina impregnated with KOH (KOH/Al2O3) and a mixture of alumina and powdered KOH (KOH+Al2O3) have been examined using the alkylation of benzamide under various conditions.In each case, alkylation occurs exclusively in the pores of the alumina, the extent depending upon the alumina-pore size.For both yield and selectivity for N-monoalkylation, KOH+Al2O3 is superior to KOH/Al2O3.Dioxane is the best of the solvents employed.It is proposed that, in dioxane, an enolate-like species, PhC(O-K+)=NR', exists as stable ion pair aggregates, which are true reactants in the pore.This method, using KOH/Al2O3 or KOH+Al2O3, has been applied to N-alkylation of the other amides, giving the N-monoalkylated products in substantial yields with extremely high selectivities. 2-Phenylacetamide is regioselectively N-monoalkylated in high yields.This regioselectivity is explained in terms of steric hindrance.