Electrophilic acetylation and formylation of pyrrolo[1,2-a]pyrazines: substituent effects on regioselectivity

Abstract

Described herein is electrophilic acetylation and formylation of pyrrolo[1,2-a]pyrazines with substituent(s) at C1 and/or C3 position(s) where substituents around the core skeleton allowed regiodivergent access to C6-or C8-acetylpyrrolo[1,2-a]pyrazines. While acetylation of pyrrolo[1,2-a]pyrazines (R(1) = H and R(3) = aryl or methyl) mainly gave rise to C8-acetylated products, acetylation with pyrrolo[1,2-a]pyrazines (R(1) = methyl and R(2) = aryl or methyl) provided C6-acetylated compounds as major products. In contrast, Vilsmeier-Haack formylation of pyrrolo[1,2-a]pyrazines took place at C6 position irrespective of the substituents at C1 and/or C3 site(s).

Tandem [4+1+1] Annulation Approach to 4-Acyl-3,4-dihydropyrrolo[1,2-a]pyrazines: Diastereoselective Construction of Dihydropyrazine Units from Pyrroles

“…As part of our research interest on nitrogen-fused heterocycles, 3 the first principle was applied to some pyrrolo[1,2a]pyrazines: intermolecular Pd-catalyzed direct arylation 4 and regiodivergent electrophilic acetylation/formylation 5 allowed us to get access to pyrrolo[1,2-a]pyrazine-based new chemical scaffolds with unprecedented substitution styles, respectively (Scheme 1a,b). As a means to introduce new functional moieties to a pyrrolo[1,2-a]pyrazine nucleus by way of the second principle, we initially envisioned that three-component assembly of 4 with aldehyde and ammonium acetate in the presence of base would afford 4-acylated pyrrolo[1,2-a]pyrazine (5) (Scheme 1c). Previously, compound 4 has been utilized to make several heterocyclic systems having an acyl group at the C4 position through ring annulation methods.…”