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

被引:19
作者
Nathubhai, Amit [1 ]
Patterson, Richard [1 ]
Woodman, Timothy J. [1 ]
Sharp, Harriet E. C. [1 ,2 ]
Chui, Miranda T. Y. [1 ]
Chung, Hugo H. K. [1 ]
Lau, Stephanie W. S. [1 ]
Zheng, Jun [1 ]
Lloyd, Matthew D. [1 ]
Thompson, Andrew S. [1 ]
Threadgill, Michael D. [1 ]
机构
[1] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[2] Bruton Sch Girls, Bruton BA10 0NT, Somerset, England
关键词
ENZYME POLY(ADP-RIBOSE) POLYMERASE; RESISTANCE-MODIFYING AGENTS; BIOLOGICAL-PROPERTIES; DIMETHYL ACETAL; PRIMARY AMINES; INHIBITORS; ESTERS; QUINAZOLIN-4(3H)-ONES; REARRANGEMENT; DERIVATIVES;
D O I
10.1039/c1ob05430a
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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 degrees C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl) acetals leads to subsequent alkylation at N-3. 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 N-3-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 N-3-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 N-3-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.
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页码:6089 / 6099
页数:11
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