Buchwald-Hartwig Coupling
The Buchwald-Hartwig coupling is the direct Pd-catalyzed C–N or C–O bond formation between aryl halides and amines or alcohols in the presence of a stoichiometric amount of base.
General features:
1. The coupling can be both inter- and intramolecular. 2. The typical substrates for this transformation are aryl bromides or iodides, but aryl chlorides can also be coupled with the desired amines or alcohols. 3. The Pd(0)-catalyst is usually complexed with chelating phosphine type ligands such as BINAP, DPPF, XANTPHOS, and DBA. 4. The base has to be present in stoichiometric amounts and the temperature for the reaction can be sometimes as low as 25 °C.
Buchwald-Hartwig Coupling
Reaction Mechanism
1. Oxidative addition of Pd(0) to the aryl halide. 2. The Pd(II)-aryl amide is either formed by direct displacement of the halide by the amine or via a Pd(II)-alkoxide intermediate. 3. Reductive elimination results in the formation of the C–N bond and the regeneration of the Pd(0) catalyst.
Example
Experimental Procedure
A screwcap vial provided with a magnetic stir bar was charged with the aryl halide (0.13 mmol, 1.0 eq), Pd(PPh3)4 (5 mol%), and Cs2CO3 (2.0 eq). A solution of freshly distilled aniline (2.0 eq) in anhydrous PhMe (1.30 mL) was added, and the cap was fitted and the contents of the vial were stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to rt, the vial was carefully opened, and the contents were partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to afford the desired organic product (48% yield).
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