Abstract

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic
one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is
previously unreported. Reaction of anthranilamide with DMFDMA at 150 ◦C for short periods gives
mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide
di(primary-alkyl)acetals leads to subsequent alkylation at N3. 3-Substituted anthranilamides give
8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide
dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N3-alkyl
group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded
dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving
4-isopropoxyquinazolines, along with N3-methylquinazolin-4-ones where the methyl is derived from
N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding
dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide
di(neopentyl)acetal forms a mixture of quinazolin-4-one and N3-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.