Palladium-catalyzed amination reactions of aryl halides (Buchwald-Hartwig aminations) involve the formation of a bond between an sp2-hybridized carbon atom and nitrogen mediated by a palladium complex and stoichiometric base. These reactions are an important alternative to nucleophilic aromatic substitutions that afford anilines, which generally require extremely electron-poor arenes, high temperatures, and strongly basic amide anions. The scope of the electrophile includes aryl bromides, chlorides, and sulfonates. A wide variety of nitrogen nucleophiles can be employed, including amines of any substitution pattern, azoles, sulfonamides, amides, carbamates, and hydrazines. Buchwald-Hartwig aminations employing palladium catalysts use milder conditions than related copper-catalyzed transformations and have largely supplanted the latter.
The general mechanism of Buchwald-Hartwig amination begins with oxidative addition of the aryl halide to a palladium(0) species at a rate that is generally independent of the structure of the amine. The resulting arylpalladium(II) complex reacts with the amine and base, which results in the formation of a metal–nitrogen bond. This process may proceed through a few different mechanisms. When a very strong base that can deprotonate the amine is employed, the conjugate base of the amine may displace halide at the metal center; however, use of bases this strong is not common in Buchwald-Hartwig reactions. When the arylpalladium(II) halide species contains an open coordination site, the amine may coordinate to palladium prior to transferring a proton to the base. Finally, when the arylpalladium(II) halide species lacks an open coordination site, the base may displace halide at the metal center and deprotonate the amine through an inner-sphere mechanism.
Reductive elimination forges the C–N bond and regenerates a palladium(0) species. This step is commonly turnover limiting and strongly influences the scope of the reaction. In general, the greater the electron density at nitrogen, the faster the rate of reductive elimination. In addition, three-coordinate complexes (generated using sterically bulky phosphines) undergo reductive elimination at a faster rate than four-coordinate complexes. As a result, palladium complexes of sterically bulky tert-butyl or adamantyl phosphines are commonly paired with relatively weak nitrogen nucleophiles such as sulfonamides.