Development of a Practical Copper-Catalyzed C-N Cross-Coupling for Heteroaryl Chlorides and Base Sensitive Substrates

We report a new ligand for Cu-catalyzed C-N cross-coupling of (hetero)aryl chlorides with a broad range of nitrogen nucleophiles. Nucleophiles include primary, secondary and α-branched amines, amides, hydrazines, ammonia surrogates, NH-heterocycles, and base-sensitive substrates such as aminomethyl-functionalized azoles. Aryl and heteroaryl halides, including pyridyl and pyrimidyl chlorides, are competent reaction partners. Key reactivity trends of azole methanamines as a function of its azole identity and isomer were elucidated in a head-to-head comparison of heterogenous and homogenous C-N cross-coupling conditions using 42 different nucleophiles in a parallel library synthesis. The modular nature of the investigated ligands enabled a systematic structure-activity relationship study to elucidate key design principles, as well as steric and electronic effects on catalysis.