Abstract
3-(4-Oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazin-2-yl)propanoic acid and its ethyl ester 6ab have been prepared via succinoylation of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thlophene-3-carboxylate 1, followed by ester hydrolysis, selective esterification, and acetic anhydride induced cyclization of the thiophenecarboxylic acid derivatives 3, 5. Reaction of 1 with diethyl malonate gave the malonic acid diamide 7, which on ester hydrolysis followed by acetic anhydride induced water elimination furnished the 2-substituted 4H-benzo[4,5]thieno[2,3-d][1,3]oxazine derivative 10 in high yield. A series of new benzo[4,5]thieno[2,3-d]pyrimidines 11-19, which bear a propanoic acid substituent in the 2-position and an amino, aryl, aminosugar, and arylmethylideneamino-substituents in the 3-position have been prepared via the reaction of 6ab with hydrazine hydrate or aromatic amines followed by treatment with aromatic aldehydes, isatin, or aldoses. The aldimines 18a-d underwent unprecedented acid catalyzed tandem cyclization-transannular aldehyde extrusion into octalzydro-1H-benzo[4'.5']thieno[2'.3'.4,5]pyrimido[1,2-b]pyridazines 21. Two other unequivocal approaches for 21 also have been explored, either by treatment of the amino acid derivative 11 with thionyl chloride or by thermal cyclization of the amino ester derivative 12.