Rationally Designed Malonate-Derived Ligands Enable Copper-Catalyzed C–N Coupling via a Cu(I)/Cu(III) Mechanism
Sridhar Regati, Praveen Gajula, Pei-Pei Xie, Anji Chen, Badrinath Kakde, Sailu Munnuri, Lalitha Gummidi, Arun D. R. Shada, Rahul Dilip Shingare, Shanika M. P. Gamage, Nageswara Rao Kalikinidi, Venkatarathnam Nasipireddy, Virendra Tiwari, Srinivasarao Tenneti, Santhosh Reddy Naini, Omkar Revu, Srinivasrao Ganipisetti, Annada Maity, Venumadhav Janganati, Giridhar Basawani, Gopal Sirasani, Rajender Reddy Leleti, Bo Qu, Peng Liu, Chris H. SenanayakeAbstract
A class of sterically decorated, malonamide ligands has been developed to enable copper-catalyzed C–N coupling for the synthesis of pharmaceutically relevant heterocycles. This methodology facilitates the efficient coupling of aryl and heteroaryl bromides with a broad range of nitrogen nucleophiles, including aryl, heteroaryl, and alkyl amines, delivering the corresponding products in high yields. The practical utility of this approach is highlighted by the streamlined synthesis of several active pharmaceutical ingredients, demonstrating both the generality and scalability of the catalyst system. Density functional theory calculations support a Cu(I)/Cu(III) catalytic cycle as the operative mechanism and reveal that the ligand backbone substituents affect the conformation and steric properties of the catalyst system and the C–N coupling reactivity.