Home Cross-CouplingWillis Pyridinates for Palladium-Catalyzed Cross-Coupling Reactions

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.

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Representative Scheme and Examples
Advantages
References

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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.³Both aryl bromides and aryl chlorides can be employed as coupling partners to access challenging and medicinally relevant linked pyridine-heterocycle building blocks.

Six chemical structures, each with a unique product number below them. The structures are variations of benzene rings with different functional groups attached, such as amine (NH2), sulfonate (SO3Na), methyl (CH3), fluorine (F), and ketone (C=O). The product numbers are 900757, 900762, 900760, 900759, 900763, and 900760.

Representative Scheme and Examples

A series of chemical reactions showcasing the use of Willis Pyridinates in Palladium-Catalyzed Cross-Coupling Reactions. At the top, a reaction scheme illustrates the transformation of a pyridine sulfinate compound to various substituted pyridines using Pd(OAc)2 as a catalyst, XPhos as a ligand, and K2CO3 as a base in 1,4-dioxane at 150°C. Below are six examples of this reaction with different substituents on the pyridine ring and their corresponding yields, one notably being 92% with an annotation of ‘6.9 grams’. Each product is depicted with clear molecular structures indicating the position and type of substituents like fluorine atoms or methoxy groups.

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