Research

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:

[img] Microsoft PowerPoint (Harriet_ESI_full_OBC_revised_renumber.ppt)
Download (8MB)
    [img] 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.

      Details

      Item Type Articles
      CreatorsNathubhai, 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.
      DOI10.1039/c1ob05430a
      DepartmentsFaculty of Science > Pharmacy & Pharmacology
      RefereedYes
      StatusPublished
      ID Code25145

      Export

      Actions (login required)

      View Item

      Document Downloads

      More statistics for this item...