康 · 学术 | Reaction of the Day No. 1767

Acidic Suzuki-Miyaura Coupling Enables Pyridylation of Heteroaryl Halides

Libo Xiang, Yu Chen, Tianyuan Ou, Li Zhang*

The Fourth Affiliated Hospital of Soochow University & Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and

Materials Science, Soochow University, Suzhou 215123, P. R. China

—Org. Chem. Front., 2026, 13(20), 6944-6951.

Recommended by Shi Li _ MOC

KEYWORDS: Pd catalysis, Suzuki coupling (反应类型), heteroaryl halides, zwitterionic pyridinium trifluoroborates (原料), heterobiaryl products (产物), C(sp2)-C(sp2) (成键类型), ZnO (其他)

ABSTRACT: Pyridines are among the most prevalent heterocyclic motifs in pharmaceuticals and bioactive molecules. However, their use as nucleophilic coupling partners in cross-coupling reactions remains challenging because of the limited stability and reactivity of pyridyl organometallic reagents. The coupling of pyridyl nucleophiles with heteroaryl halides is more difficult, likely due to catalyst deactivation arising from coordination of heterobiaryl products to the metal center. The development of acidic Suzuki-Miyaura coupling conditions for heteroaryl thianthrenium salts has significantly improved heterocycle compatibility. However, heteroaryl halides, one of the most widely available classes of heteroaryl electrophiles, remain underdeveloped in direct pyridylation reactions, possibly because of the lack of an efficient transmetallation step in the presence of halides. Herein, the authors report an acid-tolerant Suzuki-Miyaura coupling that enables the efficient cross-coupling of heteroaryl halides with zwitterionic pyridinium trifluoroborates, providing a practical and general approach for the synthesis of bipyridine motifs.

Background and This Work

Optimization

Substrate Scope (Selected)

Late-Stage Pyridylation of Heteroaryl Drug Molecules

Summary and Comments

Li Zhang et al. have developed an acid-tolerant Suzuki-Miyaura cross-coupling protocol to suppress catalyst deactivation that enables the direct pyridylation of heteroaryl halides using zwitterionic pyridinium trifluoroborate reagents. In contrast to previous strategies that rely on C6-substituted pyridyl nucleophiles, the present method provides straightforward access to diverse bipyridine scaffolds. The utility of the protocol was further demonstrated by the broad scope of heteroaryl halides and its applicability to the late-stage functionalization of heterocycle-containing pharmaceuticals.

Li Zhang等人开发了一种耐酸性的Suzuki-Miyaura交叉偶联新策略。该方法利用两性离子型吡啶三氟硼酸盐作为偶联试剂，有效克服了传统条件下催化剂易失活的难题，实现了杂芳卤化物的直接吡啶化。与以往主要依赖C6位取代吡啶亲核试剂的合成路径不同，该体系能够直接构建多样化的双吡啶骨架。此外，广泛的底物适用性实验及含杂环药物分子的后期功能化修饰案例，进一步证实了该方法在复杂分子合成中的实用价值。