title: N3-alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides.
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 N(3). 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 N(3)-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 N(3)-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 N(3)-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.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, UK BA2 7AY.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathubhai
authors.forename: Richard
authors.initials: R
authors.lastname: Patterson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Woodman
authors.forename: Harriet E C
authors.initials: HE
authors.lastname: Sharp
authors.forename: Miranda T Y
authors.initials: MT
authors.lastname: Chui
authors.forename: Hugo H K
authors.initials: HH
authors.lastname: Chung
authors.forename: Stephanie W S
authors.initials: SW
authors.lastname: Lau
authors.forename: Jun
authors.initials: J
authors.lastname: Zheng
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000478:Alkylation; D000577:Amides / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D062367:ortho-Aminobenzoates / Q000737:chemistry*
chemical_list: D000577:Amides; D011799:Quinazolines; D062367:ortho-Aminobenzoates; C000219:anthranilamide