Chan-Evans-Lam Cross-Coupling
Cu-mediated C–N/C–O coupling of boronic acids under mild, base-free conditions
What is the Chan-Evans-Lam Cross-Coupling?
The Chan-Evans-Lam coupling forms C–N and C–O bonds between a boronic acid and an N–H or O–H nucleophile — amines, amides, anilines, phenols, alcohols — using copper instead of palladium. Because it runs near room temperature without a strong base, it is often the first reaction chemists reach for when a substrate is too sensitive for Buchwald-Hartwig conditions or when Pd contamination has to be avoided (e.g., late-stage medicinal chemistry).
Air or another mild oxidant is used to reoxidize copper back to the active Cu(II) state, so the reaction can be run with only a catalytic loading of copper salt rather than the stoichiometric copper originally reported. Boronic acids being bench-stable, non-toxic, and widely commercially available makes this an attractive, operationally simple amination method.
Reaction schemes
Catalytic cycle
Transmetalation
The arylboronic acid transfers its aryl group to Cu(II), forming an Ar–Cu(II) species.
Ligand exchange
The N– or O–nucleophile binds to copper, displacing the boron byproduct.
Oxidation / reductive elimination
Cu(II) is oxidized to Cu(III) (by air or an added oxidant) and reductively eliminates the C–N or C–O bond, regenerating catalytically active copper.
Applications
- Room-temperature N-arylation of amines and amides where Pd catalysis is undesirable.
- O-arylation of phenols to diaryl ethers without the strong bases Ullmann-type conditions require.
- Widely used in medicinal chemistry parallel synthesis for its operational simplicity.
Worked examples
Every example below — reagents, conditions, and literature source — is reproduced from Cross-Coupling Reactions: Mechanisms and Examples by Marcos San Segundo, PhD.
Coupling between a secondary aliphatic amine and an aryl boronic acid catalyzed by Cu(OAc)2.
Synthesis of a retinoic acid 4-hydroxylase (CYP26) inhibitor.
Cross-Coupling Reactions: Mechanisms and Examples
This page covers the Chan-Evans-Lam Cross-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.