Synthesis of Quinazolinone-Fused Tetrahydroisoquinolines and Related Polycyclic Scaffolds by Iodine-Mediated sp3 C-H Amination

An iodine-mediated intramolecular sp3 C-H amination reaction producing quinazolinone-fused polycyclic skeletons from 2-aminobenzamide precursors is reported. This reaction does not use transition metals, has a broad substrate scope, and can be used on a gram scale. Under the optimal reaction conditions, a variety of quinazolinone-fused tetrahydroisoquinolines and derivatives of Rutaecarpine were synthesized from readily accessible compounds. The reaction proceeds well with crude 2aminobenzamide derivatives, allowing for the synthesis of the products from simple 2-aminobenzoic acids and tetrahydroisoquinolines without purification of the 2-aminobenzamide intermediates. Preliminary biological experiments have identified Cereblon (CRBN) inhibitory activity and relevant anti-myeloma medicinal properties in some of these polycyclic products.

Automated summary

An iodine-mediated intramolecular sp3 C-H amination reaction that produces quinazolinone-fused polycyclic skeletons from 2-aminobenzamide precursors is described. The reaction is transition metal-free, has a wide substrate scope, and can be performed on a large scale. By using crude 2-aminobenzamide derivatives, the synthesis of quinazolinone-fused tetrahydroisoquinolines and Rutaecarpine derivatives from easily accessible compounds is possible without purification of the intermediates. Some of the synthesized polycyclic products exhibit inhibitory activity against Cereblon (CRBN) and show potential as anti-myeloma drugs in preliminary biological experiments.