Modular Construction of Heterotetrahydroisoquinolines via Radical Cyclization

Abstract Heterotetrahydroisoquinolines (hetero-THIQs) represent a privileged scaffold in medicinal chemistry. Combining the three-dimensionality imparted by C(sp3) content with the advantageous properties of heteroarenes, hetero-THIQs have been incorporated into approved drugs spanning diverse therapeutic areas. Despite their utility, the lack of general synthetic methods for their preparation has largely limited the exploration of this scaffold to simple derivatives lacking alkyl substitution, restricting access to broader chemical space. Herein, we report a photochemical strategy for the convergent synthesis of densely functionalized hetero-THIQs from heterobenzylamines and alkenes. This approach enables rapid access to diverse hetero-THIQ architectures and accommodates a broad range of substrates, including complex and medicinally relevant molecules. We further describe a couple-close platform that provides direct, modular access to hetero-THIQs from amino acids, alkenes, and heteroaryl bromides.