Expedient Synthesis of 1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylates

As a part of the ongoing COVID Moonshot project, an expedient approach to 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylates is described. The method is based on a one-pot tandem Michael amination – lactamization sequence starting from of 2-(3-alkoxymethoxy-3-oxoprop-1-en-2-yl)benzoic acids and primary amines. The scope of the N-nucleophiles included various aliphatic, and aromatic, and heteroaromatic primary amines; the reaction tolerates and was compatible with ether, ester, amide, alcohol, carbamate, and free alcoholazole, or azine moieties. The developed protocol; allowed for the preparation of target tetrahydroisoqunoline derivatives in 40–75% yield on up to 109 g scale. A mechanistic scheme involving a ring-chain tautomerism for the electrophilic component of the reaction is proposed. The method was used in the synthesis of DNDI-6510, SARS-CoV-2 main protease inhibitor that showed promising results obtained in preclinical studies.