Theory and Defination :
The Buchwald–Hartwig amination is a chemical reaction used in organic chemistry for the synthesis of carbon–nitrogen bonds via the palladium-catalyzed cross-coupling of amines with aryl halides. Though publications with similar focus were published as early as 1983, credit for its development is typically assigned to Stephen L. Buchwald and John F. Hartwig, whose publications between 1994 and the late 2000s established the scope of the transformation. The reaction's synthetic utility stems primarily from the shortcomings of typical methods (nucleophilic substitution, reductive amination, etc.) for the synthesis of aromatic C–N bonds, with most methods suffering from limited substrate scope and functional group tolerance. The development of the Buchwald–Hartwig reaction allowed for the facile synthesis of aryl amines, replacing to an extent harsher methods (the Goldberg reaction, nucleophilic aromatic substitution, etc.) while significantly expanding the repertoire of possible C–N bond formation.
General Reaction :
Over the course of its development, several 'generations' of catalyst systems have been developed, with each system allowing greater scope in terms of coupling partners and milder conditions, allowing virtually any amine to be coupled with a wide variety of aryl coupling partners. Because of the ubiquity of aryl C-N bonds in pharmaceuticals and natural products, the reaction has gained wide use in synthetic organic chemistry, finding application in many total syntheses and the industrial preparation of numerous pharmaceuticals. Several reviews have been publish
Mechanism :
The reaction mechanism for this reaction has been demonstrated to proceed through steps similar to those known for palladium catalyzed C-C coupling reactions. Steps include oxidative addition of the aryl halide to a Pd(0) species, addition of the amine to the oxidative addition complex, deprotonation followed by reductive elimination. An unproductive side reaction can compete with reductive elimination wherein the amide undergoes beta hydride elimination to yield the hydrodehalogenated arene and an imine product.
Over the course of the development of this reaction, there has been a great deal of work to determine the exact palladium species responsible for each of these steps, with several mechanistic revisions occurring as more data was garnered. These studies have revealed a divergent reaction pathways depending on whether monodentate or chelating phosphine ligands are employed in the reaction, and a number of nuanced influences have been revealed (especially concerning the dialkylbiarylphosphine ligands developed by Buchwald).The catalytic cycle proceeds as follows:
For monodentate ligand systems, monophosphine palladium (0) species is believed to form before oxidative addition, forming the palladium (II) species which is in equilibrium with the μ-halogen dimer. The stability of this dimer decreases in the order of X = I > Br > Cl, and is thought to be responsible for the slow reaction of aryl iodides with the first-generation catalyst system. Amine ligation followed by deprotonation by base produces the palladium amide. (Chelating systems have been shown to undergo these two steps in reverse order, with base complexation preceding amide formation.) This key intermediate reductively eliminates to produce the product and regenerate the catalyst. However, a side reaction can occur wherein β-hydride elimination followed by reductive elimination produces the hydrodehalogenated arene and the corresponding imine. Not shown are additional equilibria wherein various intermediates coordinate to additional phosphine ligands at various stages in the catalytic cycle.
For chelating ligands, the monophosphine palladium species is not formed; oxidative addition, amide formation and reductive elimination occur from L2Pd complexes. The Hartwig group found that "reductive elimination can occur from either a four-coordinate bisphosphine or three-coordinate monophosphine arylpalladium amido complex. Eliminations from the three-coordinate compounds are faster. Second, β-hydrogen elimination occurs from a three-coordinate intermediate. Therefore, β-hydrogen elimination occurs slowly from arylpalladium complexes containing chelating phosphines while reductive elimination can still occur from these four-coordinate species.
Examples and Application :
1) using relatively unreactive aryl chlorides
2) large scale synthesis of BINAP,Under similar reaction conditions, phosphorus- and sulfur-based groups can be introduced. Strong bases are unnecessary in those cases.
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