Organophotoredox-Catalyzed Decarboxylative Carbon-Heteroatom Bond Formation: Access to Ampakine APIs and Quinazolinone Alkaloids

The study describes a novel and general protocol for metal-free intramolecular decarboxylative construction of carbon-heteroatom (oxygen, nitrogen, and sulfur) bond, enabling direct access to the bioactive ampakine and quinazolinone class of molecules. The cross-coupling of natural or unnatural amino acid based electrophiles with phenols, amides, and thiophenols via organophotoredox catalysis represents an innovative approach towards the synthesis of bioactive heterocycles. The present approach utilizes photochemical decarboxylative single electron oxidation to generate carbon-centered radical intermediate directly from amino acids under mild conditions, eliminating the need for preactivation. The designated protocol offers a convenient method to synthesize ampakine drug molecules CX-614 and CX-554, which have promising potential for treating Alzheimer’s and Parkinson’s diseases. Interestingly, with nitrogen nucleophile, quinazolinone class of natural products deoxyvasicinone and mackinazolinone could be synthesized, whereas sulfur nucleophile furnished dihydro-thiazenone scaffolds. The reported protocol exhibits high functional group tolerance and scalability. A plausible mechanism has been proposed based on fluorescence quenching experiments and cyclic voltammetry analysis.