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

Nathubhai, Amit, Patterson, R., Woodman, T.J., Sharp, H.E.C., Chui, M.T.Y., Chung, H.H.K., Lau, 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 & Biomolecular Chemistry, 9. pp. 6089-6099. ISSN 1477-0520

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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.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Depositing User: Amit Nathubhai
Date Deposited: 10 Aug 2018 10:50
Last Modified: 18 Dec 2019 16:07
URI: http://sure.sunderland.ac.uk/id/eprint/9793

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