Benchmarking Pd(II)-NHC (NHC = N-heterocyclic carbene) catalysts for C-N cross-coupling of aryl halides informers via high throughput experimentation

The Buchwald-Hartwig C−N cross-coupling reaction is a commonly deployed method to access many important classes of aryl amines, including natural products, pharmaceuticals, and biologically active compounds. For the past 30 years, diverse classes of new catalytic systems have been discovered for this transformation, yet the C-N cross-coupling reaction remains highly challenging. N-heterocyclic carbene catalysts (NHCs) complexes are versatile, highly reactive classes of catalysts that are extremely stable, user-friendly systems that have been broadly used in C-C, C-N, C-O and C-S cross-coupling reactions. The Szostak group has developed powerful classes of NHCs catalysts for cross-coupling reactions and recently designed new well defined Pd(II) NHC complexes that could possess better reactivity than existing catalysts for the Buchwald-Hartwig cross-coupling reaction. High throughput experimentation is a powerful tool for reaction optimization and benchmarking of existing methodologies against emerging ones. In my research project with Rutgers, we benchmarked the Szostak group’s new NHC catalysts using high throughput experimentation (HTE) against commercial NHCs in the C-N cross-coupling reaction against aryl halide informers reported by Merck. The aryl halide informers are challenging drug like molecules that were designed by the Merck HTE group to determine how new catalysts stack up against traditional ones. The first part of this thesis will include: (1) validation and prescreening of high throughput experimentation workflows for the C-N coupling reaction of chlorpromazine HCl salt with primary, secondary and aromatic amines with two (2) commercially available NHC catalysts (Ipr)Pd(cin)Cl and Peppsi-IPent. The second part of this thesis will include (2) the development of a new automated HTE screening platform design to minimize solvent evaporation and (3) the head-to-head comparison of Szostak group’s NHCs against two commercial NHC catalysts ((IPr)Pd(cin)Cl, PEPPSI-IPent) in the C-N cross-coupling with 16 aryl halide informers using HTE meso-scale screening. Three of the Szostak’s groups catalysts emerged as extremely reactive, stable and user friendly catalysts that outperformed the commercial NHCs in the C-N cross-coupling reaction.