Buchwald-Hartwig Coupling
Pd-catalyzed C–N (and C–O) coupling for aryl amines
What is the Buchwald-Hartwig Coupling?
The Buchwald-Hartwig coupling replaced classical Ullmann-type amination with a palladium-catalyzed alternative that runs under far milder conditions and tolerates a much wider range of functional groups. It forms the C–N bond between an aryl (or vinyl) halide/pseudohalide and a primary or secondary amine, and the same catalytic manifold extends to phenols and amides, giving diaryl ethers and anilides as well.
The reaction's success hinges on the supporting ligand. Bulky, electron-rich monophosphines and biaryl phosphines (developed largely by the Buchwald group) accelerate the otherwise slow reductive elimination step and suppress unproductive β-hydride elimination pathways, which is what makes the modern versions practical for hindered and electron-poor substrates that defeated earlier catalyst generations.
Reaction schemes
Catalytic cycle
Oxidative addition
Ln Pd(0) inserts into the Ar–X bond of the aryl halide, giving an Ln Pd(II)(Ar)(X) complex.
Ligand exchange
The amine coordinates to Pd(II) and is deprotonated by base, placing the amido nitrogen directly on palladium.
Reductive elimination
The Ar–N bond forms and Pd(0) is released to re-enter the cycle.
Applications
- Installing aryl amine motifs in drug candidates (kinase inhibitors, CNS actives) without harsh nitration/reduction sequences.
- Multikilogram process routes at companies such as Eli Lilly and Pfizer (see the worked examples below).
- C–O coupling variants for diaryl ether synthesis using the same catalyst systems.
Worked examples
Every example below — reagents, conditions, and literature source — is reproduced from Cross-Coupling Reactions: Mechanisms and Examples by Marcos San Segundo, PhD.
Cross-Coupling Reactions: Mechanisms and Examples
This page covers the Buchwald-Hartwig Coupling — one of 21 named reactions in the book, each with its full catalytic cycle and every worked example shown here, drawn straight from the primary literature.