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Efficient C−N Bond Formation to lower the cost of medicine

The AshPhos ligand is a newly developed phosphine ligand that significantly enhances Buchwald−Hartwig aminations, a key reaction in pharmaceutical synthesis. This ligand is designed to improve catalytic efficiency, especially for challenging heteroaryl halides and sterically hindered amines that often show poor reactivity with existing catalysts.

How It Works

  1. Ligand Structure & Chelation

    • AshPhos is derived from an electron-rich aryl system, designed to enhance chelation with palladium catalysts.
    • This structure stabilizes the catalyst and prevents deactivation, which is a common issue with five- and six-membered heteroaryl halides.

  2. Catalytic Mechanism

    • Oxidative Addition: The Pd(0)-AshPhos complex undergoes oxidative addition with the heteroaryl bromide/chloride.
    • Transmetalation: The amine reacts with the palladium complex.
    • Reductive Elimination: The final C−N bond is formed, regenerating the catalyst for another cycle.
    • Avoiding Dormant Species: At elevated temperatures (70-90°C), AshPhos prevents the formation of catalytically inactive species.

  3. Key Benefits

    • Lower Cost: Made from affordable materials with a simpler synthesis (1–2 steps).
    • High Yield: Works with over 55 challenging substrates, including sterically hindered and heteroatom-rich amines.
    • Broad Scope: Effective for both heteroaryl bromides and chlorides.
    • Sustainability: Uses low palladium loadings and avoids expensive bases or solvents.

Implementation Guide

1. Materials Required

  • AshPhos ligand
  • Palladium precatalyst ([Pd(crotyl)Cl]₂ recommended)
  • Heteroaryl bromide or chloride
  • Cyclic secondary or bulky amine
  • Base (NaOtBu preferred)
  • Solvent (THF or toluene)

2. Reaction Conditions

  • Standard Conditions:

    • [Pd] loading: 1–3 mol%
    • AshPhos loading: 2–6 mol%
    • Base: 2.0 equivalents of NaOtBu
    • Solvent: THF or toluene
    • Temperature: 70–90°C
    • Reaction Time: 12–16 hours

  • Optimized Protocol (Example for thiophenyl bromide + tert-butylamine):

    • 0.5 mmol heteroaryl bromide
    • 0.6 mmol amine
    • 1 mol% [Pd(crotyl)Cl]₂
    • 2 mol% AshPhos
    • 2.0 equiv NaOtBu
    • 1 mL THF
    • 70°C for 16 h

  • Alternative Conditions for Heteroaryl Chlorides:

    • Higher Pd and AshPhos loading (3 mol% Pd, 6 mol% AshPhos)
    • Higher temperature (90°C)

3. Workup & Purification

  • Reaction is monitored by TLC or GC-MS.
  • The crude product is purified by column chromatography using EtOAc/hexanes as eluent.

It can be found here

Ashish Dusunge, David K. Leahy, and Sachin Handa JACS Au 2025 5 (1), 91-98 DOI: 10.1021/jacsau.4c00772

Sources & citation

Ashish Dusunge, David K. Leahy, and Sachin Handa JACS Au 2025 5 (1), 91-98 DOI: 10.1021/jacsau.4c00772