1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylates/carboxylic acids: Synthesis, structural modifications, and ADMET prediction of bioactivity

A preparatively convenient methodology for the synthesis of new 1-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylates is presented, which includes a sequence of consecutive transformations: N-alkylation of available pyrrole-3-carboxylates with 2-azidoethyl methanesulfonate, subsequent selective reduction of the obtained 1-(2-azidoethyl)pyrrole-3-carboxylates to 1-(2-aminoethyl)pyrrole-3-carboxylates, and further intramolecular aza-Friedel–Crafts reaction under the action of aldehydes. Corresponding partially hydrogenated pyrrolo[1,2-a]pyrazine-7-carboxylic acids were synthesized by alkaline hydrolysis of 1-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylates and 3,4-dihydropyrrolo[1,2-a]pyrazine-7-carboxylates obtained from them by oxidation with PIDA. It was shown that hydrolysis of 1-trifluoro(difluoro)methyl-3,4-dihydropyrrolo[1,2-a]pyrazine-7-carboxylates is accompanied by dehydrofluorination and aromatization of the pyrazine ring. An in silico evaluation of the potential bioactivity of the synthesized esters and acids was carried out.