Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp2)–C(sp3) Bond-Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists**

L. Reginald Mills, Francesca Di Mare, David Gygi, Heejun Lee, Eric M. Simmons, Junho Kim, Steven R. Wisniewski, Paul J. Chirik

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Evaluation of the relative rates of the cobalt-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(OiPr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first-order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution.

Original languageEnglish (US)
Article numbere202313848
JournalAngewandte Chemie - International Edition
Volume62
Issue number51
DOIs
StatePublished - Dec 18 2023

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry

Keywords

  • Cobalt Catalysis
  • Cross-Coupling Reactions
  • High-Throughput Experimentation
  • N,O Ligands
  • Phenoxythiazoline

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