Issue 17, 2011

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 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.

Graphical abstract: N 3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

Supplementary files

Article information

Article type
Paper
Submitted
18 Mar 2011
Accepted
25 May 2011
First published
26 May 2011

Org. Biomol. Chem., 2011,9, 6089-6099

N 3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

A. Nathubhai, R. Patterson, T. J. Woodman, H. E. C. Sharp, M. T. Y. Chui, H. H. K. Chung, S. W. S. Lau, J. Zheng, M. D. Lloyd, A. S. Thompson and M. D. Threadgill, Org. Biomol. Chem., 2011, 9, 6089 DOI: 10.1039/C1OB05430A

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