BuchwaldHartwigreaksjoner

Buchwald–Hartwig amination is a palladium-catalyzed cross-coupling reaction that forms C–N bonds by coupling aryl halides or related electrophiles with amines to produce aryl amines and related heterocyclic amines. Developed in the late 1990s by researchers including Samuel J. Buchwald and Jon F. Hartwig, it provided a high-yielding, broadly applicable alternative to traditional Ullmann-type couplings, often under milder conditions and with a wide range of substrates.

The reaction generally proceeds through oxidative addition of the aryl electrophile to a Pd(0) catalyst, followed by coordination and deprotonation of the amine to form a Pd–amido intermediate. Reductive elimination then furnishes the C–N bond and regenerates the Pd(0) species. The choice of ligand is crucial, as bulky biaryl phosphines or N-heterocyclic carbenes stabilize reactive intermediates and enable coupling with hindered or deactivated amines and aryl chlorides. Bases such as sodium tert-butoxide or carbonate bases facilitate amine deprotonation, and solvents like toluene, dioxane, or dimethylformamide are commonly used.

Scope and limitations: the method accommodates a wide variety of aryl iodides and bromides, and increasingly aryl chlorides with appropriate ligands. Both primary and secondary amines, including bulky ones, can be employed, as well as heteroaryl substrates. Limitations include sensitivity to functional groups that poison palladium or coordinate strongly to the metal, and the need for careful catalyst and condition selection for challenging substrates. Variants with different ligands and precatalysts have expanded its applicability, including enantioselective versions and late-stage functionalization in complex molecules.