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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. Although Pd-catalyzed C-N couplings were reported 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. 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 published. ==History== The first example of a palladium catalyzed C–N cross-coupling reaction was published in 1983 by Migita and coworkers and described a reaction between several aryl bromides and N,N-diethylamino-tributyltin using 1 mol% PdCl2()2. Though several aryl bromides were tested, only electronically neutral, sterically unencumbered substrates gave good to excellent yields. Then, in 1984, Dale L. Boger and James S. Panek reported an example of Pd(0)-mediated C–N bond formation in the context of their work on the synthesis of lavendamycin which utilized stoichiometric Pd(PPh3)4. Attempts to render the reaction catalytic were unsuccessful. These reports were virtually uncited for a decade, until the reports from Buchwald and Hartwig. In February 1994, Hartwig reported a systematic study of the palladium compounds involved in the original Migita paper, concluding that the d10 complex Pd()2 was the active catalyst. Proposed was a catalytic cycle involving oxidative addition of the aryl bromide. In May of the same year, Buchwald published an extension of the Migita paper offering two major improvements over the original paper. First, transamination of Bu3SnNEt2 followed by argon purge to remove the volatile diethylamine allowed extension of the methodology to a variety of secondary amines (both cyclic and acyclic) and primary anilines. Secondly, the yield for electron rich and electron poor arenes was improved via minor modifications to the reaction procedure (higher catalyst loading, higher temperature, longer reaction time), although no ortho-substituted aryl groups were included in this publication. The following year, back to back studies from each lab showed that the couplings could be conducted with free amines in the presence of a bulky base (KOtBu in the Buchwald publication, LiHMDS in the Hartwig publication), allowing for organotin-free coupling. Though these improved conditions proceeded at a faster rate, the substrate scope was limited almost entirely to secondary amines due to competitive hydrodehalogenation of the bromoarenes. (See Mechanism below) These results established the so-called "first generation" of Buchwald–Hartwig catalyst systems. The following years saw development of more sophisticated phosphine ligands that allowed extension to a larger variety of amines and aryl groups. Aryl iodides, chlorides, and triflates eventually became suitable substrates, and reactions run with weaker bases at room temperature were developed. These advances are detailed in the Scope section below, and the extension to more complex systems remains an active area of research. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Buchwald–Hartwig amination」の詳細全文を読む スポンサード リンク
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