Cu Oxamate-Promoted Cross-Coupling of α-Branched Amines and Complex Aryl Halides: Investigating Ligand Function through Data Science
Adrian D. Matthews, Ellyn Peters, John S. Debenham, Qi Gao, Maya D. Nyamiaka, Jianping Pan, Li‐Kang Zhang, Spencer D. Dreher, Shane W. Krska, Matthew S. Sigman, Mycah R. Uehling
Abstract
Synthesis of α-branched aryl amines is a continuing challenge in synthetic and medicinal chemistry. Although transition-metal-promoted C–N cross-coupling is a desirable approach to the synthesis of α-branched aryl amines, there are limited examples of methods that demonstrate broad generality and applicability using structurally complex substrates. Herein, we report a method to cross-couple α-branched amines and aryl halides promoted by Cu using an oxamate ligand system. The method is compatible with many druglike aryl halides and amines and can be executed using miniaturized high-throughput experimentation (HTE) techniques that enable the rapid production of high-quality, consistent data sets. In addition to exploring the substrate scope and executing late-stage library synthesis of an active pharmaceutical, we used miniaturized HTE to interrogate the performance of a library of ligands across multiple substrate combinations in parallel at multiple time points. The data were used to build statistical models that provided insight as to what ligand features are important for function, which further enabled the design of ligands with improved reaction performance.