Palladium-Catalyzed Aminocarbonylation of Isoquinolines Utilizing Chloroform-COware Chemistry

Abstract

The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for in or ex situ generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this "Chloroform-COware" technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.