Ketone Buchwald-Hartwig reaction

Complex 7 was tested for a-ketone arylation reactions (Table 14.9) and Buchwald-Hartwig ami-nation reactions with activated and unactivated aryl chlorides (Table 14.10). In both cases, very good results were obtained using mild temperatures in short reaction times. 

More recently, however, Pd-catalyzed a-arylation of ketones has been reinvestigated mostly by Buchwald, Hartwig,t t ° and Miura. " f It now appears that the reaction is of considerable synthetic value, which is satisfactorily applicable to a-substitution of ketones other than methyl ketones as well as to that of phenols,even though the critical issue of regiochemical control in nonobvious cases stiU remains largely uninvesti-gated. These more recent studies are discussed in Sect. B.ii. 

The Buchwald-Hartwig amination reaction can facilitate the synthesis of nitrogen-containing heterocycles. For instance, Buchwald demonstrated that the amination reaction could be used to prepare N-arylhydrazones from hydrazones and aryl halides. Acid-catalyzed condensation of the hydrazone with a ketone then yielded the desired indoles.Hartwig described a similar arylhydrazone formation with DPPF as a ligand and CS2CO3 as a base."... 

The direct intermolecular a-arylation of relatively less acidic ketones with aryl halides, which proceeds by mechanism B, was reported concurrently in 1997 by the groups of Miura, Buchwald, and Hartwig [35-37]. The intramolecular version was also described by Muratake and coworkers in the same year [38,39], while some intermolecular vinylation reaction had been reported [40, 41]. Taking advantage of this, the reaction of carbonyl compounds and related substrates has been studied extensively. Now a variety of ketones are known to be arylated by using appropriate ligands and bases [42-46]. The reaction usually takes place at a less hindered a position (Eqs. 5-7) [19,20]. 

Scheme 8.4 Buchwald and Hartwig palladium-catalyzed carbonyl arylation reactions via ketone enolates...

Once more, the work developed by the groups of Hartwig and Buchwald has inspired these palladium-a-arylation reactions. Following the finding that bulky electron-rich o-biphenylphosphanes (Scheme 8.55) significantly improved the a-arylation reaction of ketones. 

Asymmetric a-arylations of ketones to form products containing quartemary benzyhc stereogenic centers with high enantioselectivities were also reported by Hartwig et al. and Buchwald et al. Initial studies employed the traditional Pd/BINAP or Tol-BINAP complexes, which in many cases resulted in modest enantioselectivity. Later, other combinations of Pd or Ni precatalysts with ligands such as electron-rich monodentate or bidentate phosphines, l,l -bis-substi-tuted ferrocenyl phosphines, or A(-heterocyclic carbenes/-phosphines expanded the scope of this reaction. 

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