Telescoped Nickel-Catalyzed Borylation-(Phenoxyimine)Nickel-Catalyzed C(sp2)–C(sp3) Suzuki–Miyaura Coupling for Afimetoran Core Synthesis

Gregory L. Beutner; Paul J. Chirik; William P. Gallagher; L. Reginald Mills; Marina Pérez-Jiménez; Eric M. Simmons

doi:10.1021/acs.oprd.5c00410

Telescoped Nickel-Catalyzed Borylation-(Phenoxyimine)Nickel-Catalyzed C(sp²)–C(sp³) Suzuki–Miyaura Coupling for Afimetoran Core Synthesis

Gregory L. Beutner
, Paul J. Chirik
, William P. Gallagher
, L. Reginald Mills
, Marina Pérez-Jiménez
, Eric M. Simmons

Chemistry

Princeton University

Research output: Contribution to journal › Article › peer-review

Abstract

The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp²)–C(sp³) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.

Original language	English (US)
Pages (from-to)	419-430
Number of pages	12
Journal	Organic Process Research and Development
Volume	30
Issue number	2
DOIs	https://doi.org/10.1021/acs.oprd.5c00410
State	Published - Feb 20 2026

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Organic Chemistry

Keywords

base metal catalysis
borylation/Suzuki–Miyaura telescope
nickel catalysis
phenoxyimine
process development

Access to Document

10.1021/acs.oprd.5c00410

Cite this

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title = "Telescoped Nickel-Catalyzed Borylation-(Phenoxyimine)Nickel-Catalyzed C(sp2)–C(sp3) Suzuki–Miyaura Coupling for Afimetoran Core Synthesis",

abstract = "The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.",

keywords = "base metal catalysis, borylation/Suzuki–Miyaura telescope, nickel catalysis, phenoxyimine, process development",

author = "Beutner, \{Gregory L.\} and Chirik, \{Paul J.\} and Gallagher, \{William P.\} and Mills, \{L. Reginald\} and Marina P{\'e}rez-Jim{\'e}nez and Simmons, \{Eric M.\}",

note = "Publisher Copyright: {\textcopyright} 2026 American Chemical Society",

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doi = "10.1021/acs.oprd.5c00410",

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AU - Beutner, Gregory L.

AU - Chirik, Paul J.

AU - Gallagher, William P.

AU - Mills, L. Reginald

AU - Pérez-Jiménez, Marina

AU - Simmons, Eric M.

PY - 2026/2/20

Y1 - 2026/2/20

N2 - The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.

AB - The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.

KW - base metal catalysis

KW - borylation/Suzuki–Miyaura telescope

KW - nickel catalysis

KW - phenoxyimine

KW - process development

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