Willis Pyridinates for Palladium-Catalyzed Cross-Coupling Reactions

Introduction

The Suzuki-Miyaura cross-coupling reaction is one of the most used transformations in the pharmaceutical industry to form carbon-carbon bonds.^1,2 However, limitations to the application of this reaction in discovery chemistry persist, including the notorious low reaction efficiency, poor stability, and difficulty in preparing pyridine-2-boronates and boronic acids for cross-coupling.

Professor Willis and industrial partners at Pfizer have shown that by replacing boronates with pyridine-2-sulfinates as nucleophilic coupling partners, a palladium-catalyzed desulfinylative cross-coupling process of exceptional scope can be realized.³ Both aryl bromides and aryl chlorides can be employed as coupling partners to access challenging and medicinally relevant linked pyridine-heterocycle building blocks.

Representative Scheme and Examples

Advantages

• Bench-stable, solid reagents
• Efficient nucleophilic cross-coupling partners
• Convenient removal during aqueous work-up

Special thanks to Tim Markovic and Prof. Michael Willis for contributing this Technology Spotlight!

References

1. Miyaura N, Yamada K, Suzuki A. 1979. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Letters. 20(36):3437-3440. https://doi.org/10.1016/s0040-4039(01)95429-2

2. 2016. https://doi.org/10.1039/9781782622086

3. Markovic T, Rocke BN, Blakemore DC, Mascitti V, Willis MC. Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides. Chem. Sci.. 8(6):4437-4442. https://doi.org/10.1039/c7sc00675f