N3-alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

Amit Nathubhai, Richard Patterson, Timothy J Woodman, Harriet E C Sharp, Miranda T Y Chui, Hugo H K Chung, Stephanie W S Lau, Jun Zheng, Matthew D Lloyd, Andrew S Thompson, Michael D Threadgill*

*Corresponding author for this work

Research output: Contribution to JournalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)6089-6099
Number of pages11
JournalOrganic and Biomolecular Chemistry
Issue number17
Early online date26 May 2011
Publication statusPublished - 7 Sept 2011


  • Alkylation
  • Amides/chemistry
  • Quinazolines/chemical synthesis
  • ortho-Aminobenzoates/chemistry


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