摘要：Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States; Department of Chemistry, University of Oxford, Oxford OX1

转自：康龙化成

Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates

David C. Blakemore, Andre Shavnya,* and Michael C. Willis*

Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States; Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom

—ACS Med. Chem. Lett., 2025, doi.org/10.1021/acsmedchemlett.5c00327

Recommended by Shi Li_MOC

KEYWORDS: Desulfinative cross-coupling, Pd catalysis (反应类型), C(sp2)–C(sp2) (成键类型), Pyridine Sulfinates, Pyridine Allylsulfones, Pyridine β-sulfones, Pyridine β-Nitrilesulfones, Pyridine β-Estersulfones (原料), biaryls, Diarylmethanes (产物)

ABSTRACT:The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxford and the Medicine Design department at Pfizer with the aim of addressing this challenge. The result of this collaboration has been a series of reports detailing the development of 2-aza-aryl sulfinates, as well as related 2-aza-aryl sulfone derivatives, as efficient nucleophilic reagents in palladium-catalyzed coupling reactions with (hetero)aryl halides. The developed chemistry is routinely used in the medicinal chemistry laboratories at Pfizer, and the patent literature now contains many examples of these methods being embraced across the pharmaceutical industry. Hundreds of pyridyl (and related heterocyclic) sulfinates are now commercially available from multiple vendors. In this microperspective we discuss the development and evolution of these methods and highlight subsequent applications.

Substrate Scope: Pyridine Sulfinates React with Aryl Halides

Substrate Scope: Pyridine Allylsulfones as the reactant

Substrate Scope: Pyridine β-Nitrilesulfones, b) β-Estersulfonesc) Diethyl Succinate Derived Sulfones in Palladium-Catalyzed Cross-Coupling Reactions

Selected Applications for the Synthesis of 2-Pyridyl Derivatives

Blakemore et al. reported a desulfinative cross-coupling strategy that addresses long-standing limitations of Suzuki-Miyaura reactions involving challenging aryl boronic acids and esters. By employing aryl sulfones as surrogates, the method enables efficient C(sp2)-C(sp2) bond construction under Pd catalysis with broad substrate scope, including electron-rich, sterically hindered, and heteroaryl partners. Mechanistic studies indicate that the transformation proceeds via selective desulfinylation to generate reactive aryl-Pd intermediates, bypassing protodeboronation and instability issues of conventional boron reagents. The approach was applied to late-stage modification of pharmaceuticals and natural products, showcasing excellent functional group tolerance and operational simplicity. This work establishes desulfinative cross-coupling as a powerful alternative to traditional Suzuki-Miyaura chemistry, expanding access to complex biaryl scaffolds.

来源：新浪财经