AdBippyPhos Promotes Pd-Catalyzed C–N Coupling Between Weakly Nucleophilic Sulfonamides and Heteroaryl Halides

Abstract

Sulfonamides are poor nucleophiles in Pd C-N coupling catalysis, hindering synthesis of densely-functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct this difficult to access moiety. In particular, AdBippyPhos is critical for the installation of heteroaromatic groups. Computational steric parameterization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.<br>

Organopalladium Catalysis as a Proving Ground for Data-Rich Approaches to Reaction Development and Quantitative Predictions

“…In 2019 we, along with collaborators at GSK and Temple University, conducted a similar study of a challenging C-N coupling involving sulfonamide arylation. 89 Multi-substrate HTE revealed the BippyPhos class of ligands as superior, with AdBippyPhos as the optimal candidate.…”

“…License: CC BY-NC-ND 4.0 undergraduate teaching lab experiments on microscale HTE employ Pd-catalyzed reactions as the exemplars. 88 Our research group focuses not only using HTE and data-rich techniques to develop new reactions, [89][90][91][92][93] but also to better understand how reactivity and mechanism change as a function of the reaction system. 41,94,95 To enable these efforts in the realm of organopalladium chemistry, we identified a need for Pd precursor compounds that are specifically suited to HTE studies.…”

BippyPhos: A Highly Versatile Ligand for Pd‐Catalyzed C−N, C−O and C−C Couplings

“…More recently, Stradiotto and co‐workers reported use of BippyPhos/[Pd(cinnamyl)Cl] 2 for arylation of amides and sulfonamides with K 2 CO 3 as base . A related study by GSK showed that AdBippyPhos ( 16 ) was optimal for the coupling of sulfonamides with heteroaryl halides …”

High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides

“…We propose that the success of L6 is related to specific steric properties, as evidenced by the large ECA and G­(Pd) determined through the steric modeling of Pd–phosphine complexes. This interplay of ligand cone angle and G­(Pd) provide a set of criteria for evaluating new potential ligand scaffolds for sulfonamide arylations; work to test this hypothesis is currently underway …”