Mr. Nicholas Wade (University of Illinois Urbana-Champaign) Seminar

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Title: Boronic Ester Design Enables Rapid, Stereospecific B-Alkyl Suzuki-Miyaura Cross-Coupling

Abstract: In the past decades, the Suzuki-Miyaura cross-coupling (SMCC) has been well renowned as the premier method for the facile and selective construction of C(sp2)–C(sp2) bonds. In recent years, B-alkyl SMCC has gained considerable intrigue as a method for creation of C(sp2)–C(sp3) linkages for drug discovery and development. Despite advances made in both ligand and boronate design, these challenging cross-coupling reactions typically suffer from poor yields and long reaction times, stemming from slow transmetalation of alkylboronates and rapid -hydride elimination of alkylpalladium(II) complexes. Previous work using neopentyl glycol boronic esters and potassium trimethyl silanolate (TMSOK) enabled primary alkyl SMCC to numerous aryl halides. Unfortunately, these conditions were unsuccessful with secondary alkylboronic esters due to deleterious protodehalogenation arising from the boronic ester backbone. Investigation of many sec-butylboronic esters indicated that substitution proximal to the oxygens on the ester skeleton was crucial for circumventing protodehalogenation and enabling productive cross-coupling. Thus, there was a need for a highly reactive boronic ester scaffold without the capability to undergo -hydride elimination. Further experimentation led to the identification of a boronate generated in situ from tetramethyl-N-methyliminodiacetic acid (TIDA) alkylboronates and TMSOK, tentatively identified as R-B(OTMS)3, that could undergo secondary B-alkyl SMCC. After high-throughput optimization screening solvents and phosphine ligands, coupling was achieved with both cyclic and acyclic secondary alkylBTIDAs. Under optimized conditions, a variety of aryl, heteroaryl and alkenyl halides were operative in cross-coupling with good to great yields, high branched/linear selectivity, and fast reaction times. Furthermore, preliminary studies suggest that this transformation is highly stereospecific with retention of configuration. Overall, this method not only improves upon known precedent but also facilitates new reactivity with previously unreported coupling partners and novel stereochemical outcomes, positioning this method as a state-of-the-art approach for direct secondary C(sp3)–C(sp2) bond formation.