Chemoselective reactions of electrophiles with quinazoline amides; 3-alkylquinazoline-2,4-(1H,3H)-diones, and 2-arylquinazoline-4(3H)ones and their thioamide regioisomers

The study draws a solid theoretical basis governing the reaction of amides and thioamides with electrophiles to give either N, O or S- substitutions. This study was carried out on the model compounds quinazoline amides; 3-alkylquinazoline-2,4-(1H,3H)-diones and 2-arylquinazoline-4(3H)ones and their thioamide regioisomers. The normal behavior of amides represented by 3-alkylquinazoline-2,4-(1H,3H)-diones; amides react with soft electrophiles and gave N-substitution, while expected to give O-subsitution with hard electrophiles. For a special case structure feature represented by 2-arylquinazoline-4(3H)ones, the amide group specially O-atom of the lactim form contributes in a continuous conjugated system, extended by an almost planar aryl group at position 2. Amides react with both soft electrophiles and hard electrophiles to give O-substitution. Similarly, for thioamides the normal behavior represented by 3-alkyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-ones; thioamides react with soft electrohiles and gave S-substitution while expected to give N-subsitution with hard electrophiles. For a special case structure feature represented by 2-phenylquinazoline-4(3H)thione, the thioamide group specially S-atom of the thiol form contributes in a continuous conjugated system, extended by an almost planar aryl group at position 2. Thioamides react with both soft electrohiles and hard electrophiles to give S-substitution. This behavior was ruled by Hard-Soft Acid-Base Principle (HSAB Principle) and supported computational analysis and reported literature.