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

Reference:

Nathubhai, A., Patterson, R., Woodman, T. J., Sharp, H. E. C., Chui, M. T. Y., Chung, H. H. K., Lau, S. W. S., Zheng, J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2011. N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides. Organic and Biomolecular Chemistry, 9 (17), pp. 6089-6099.

Related documents:

	Microsoft PowerPoint (Harriet_ESI_full_OBC_revised_renumber.ppt) Download (8MB)
	Microsoft Word (Harriet_OBC_on_template_B_revised_renumber.doc) Download (579kB)

Official URL:

http://dx.doi.org/10.1039/c1ob05430a

Abstract

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formic acid oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 degrees 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.

Export

Actions (login required)