G3 and G4 Buchwald Precatalysts

Introduction

Over the last decade the Buchwald group has developed a series of highly active and versatile palladium precatalysts from the corresponding family of biarylphosphine ligands. These compounds are commonly referred to as Buchwald precatalysts and ligands, and have become a valuable set of tools for use in cross-coupling reactions for the formation of C-C, C–N, C–O, C–F, C–CF3, and C–S bonds. The ligands are electron-rich, and highly tunable to provide catalyst systems with a diverse scope, high stability and reactivity.

While highly successful, the first (G1) and second (G2) generations of the Buchwald precatalysts suffered from significant limitations either in their synthesis or in the scope of their applications. Advances in precatalyst development over the past few years by the Buchwald group have led to the third generation (G3) family of precatalysts which quickly and quantitatively generate active LPd(0) catalyst in reactions. These precatalysts exhibit greater stability in solution and accommodate a wider variety of ligands than the previous generations.1

In some rare cases, the carbazole leaving group can inhibit the active catalyst or consume starting materials in a reaction. Additionally, trace amounts of residual primary aminobiphenyls can pose potential health risks in pharmaceutical applications. To circumvent these issues, the Buchwald group has modified the G3 catalyst by methylating the amino group of the biphenyl backbone. These G4 precatalysts exhibit higher solubilities in cross-coupling reactions while maintaining excellent catalytic activity.3

 

Advantages

  • Quantitative generation of the active Pd(0) catalyst
  • Accommodates a broader ligand scope
  • G3 catalysts are compatible with the BrettPhos family, and extremely bulky t-Bu phosphines
  • Increased stability in solution, compared to G1 and G2 precatalysts
  • G4 catalysts generate less intrusive N-methylcarbazole byproduct

Representative Applications

The G3 and G4 precatalysts are both effective when employed in the Suzuki–Miyaura coupling of unstable boronic acids that are commonly prone to protodeboronation. The success of this coupling process is dependent on very rapid activation of the precatalyst in conjunction with a high level of catalytic activity. The XPhos Pd G3 precatalyst (763381) couples unstable boronic acids with electron-rich, sterically hindered, and heteroaryl chlorides under mild conditions (rt to 40 °C) with short reaction times (30 minutes) and in high yields. Similarly, the XPhos Pd G4 precatalyst (804274) successfully provides the biaryls in very high yields.1,2


 



Additionally, the BrettPhos family of precatalysts (G3 : 761605; G4 : 804355) have demonstrated excellent facility in N-arylation of primary and secondary amines. In the case of arylation of 4-haloanisoles, the catalyst loading can be reduced down to 0.01 mol % while maintaining excellent yields.1,2



The even-bulkier tBuBrettPhos Pd G3 precatalyst (745979) is very efficient in the arylation of primary amides, and tolerant of some functional diversity. The catalyst readily arylates the amide, but resists the competitive arylation of the indole and unprotected alcohol group in the explored substrates.3



The RockPhos Pd G3 precatalyst (773905) has demonstrated utility in C–O bond formation, coupling primary aliphatic alcohols with aryl halides in good to excellent yields.3

Materials

     
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