Aryl hahdes, reductive coupling

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

The homo-coupling Ullmann reaction can be performed at room temperature or bellow by metallation of suitable substrates such as relatively acidic arenes or aryl hahdes with the -BuLi (or other strong bases) followed by addition of Cu(II) salts [28], Aryllithium reagent undergoes transmetallation with the Cu(II) salts to form diarylcopper(II) which is prone to rapid reductive elimination of the biaryl with extrusion of a copper nrirror. Benincori and coworkers [28] described an efficient procedure for the homo-coupling reaction of bromide 21 via diarylcopperfll) 22 under very mild reaction conditions, where the 3,3 -bibenzo[b]thiophene (23) was obtained in 56% yield. Scheme 4. 

During the silylation with hexamethyldisilane, the reductive dehalogenation and the formation of a biaryl are common side-reactions. However, these can be minimized by using potassium carbonate as the base in the case of electron-rich substrates, or with potassium fluoride in the reactions with electron-poor substrates. The arylsilanes produced by any of above mentioned reactions can be cross-coupled with aryl hahdes by employing the following methods. Table 9. 

The arylation of carbon-hydrogen bonds in polycyclic aromatic hydrocarbons, using aryl boron compoimds or aryl silanes, may be achieved with a palladium acetate/o-chloranil catalyst. The Suzuki-Miyaura reaction involves palladium-catalysed coupling of an arylboronic acid with an aryl hahde in the presence of base. After oxidative addition of palladium to the hahde, reaction with base may form intermediates such as (105). Transmetalation with the boronic acid followed by reductive elimination yields... 

Catalytic processes based on the use of electrogenerated nickel(O) bipyridine complexes have been a prominent theme in the laboratories of Nedelec, Perichon, and Troupel some of the more recent work has involved the following (1) cross-coupling of aryl halides with ethyl chloroacetate [143], with activated olefins [144], and with activated alkyl hahdes [145], (2) coupling of organic halides with carbon monoxide to form ketones [146], (3) coupling of a-chloroketones with aryl halides to give a-arylated ketones [147], and (4) formation of ketones via reduction of a mixture of a benzyl or alkyl halide with a metal carbonyl [148]. 

As the overall cross-coupling reaction proceeds with inversion of stereochemistry and reductive ehmination is well known to undergo retention of stereochemistry, the result imphes that transmetaUation in this reaction proceeds predominantly with retention of stereochemistry. In addition to this study, in 1998, Woerpel and Soderquist [102] independently studied the stereochemistry of transmetaUation for the Suzuki-Miyaura cross-coupling reactions of alkyl boranes with aryl or alkenyl hahdes. Their deuterium labehng study revealed that the transmetaUation of alkyl boranes 163 or 166 proceeds with retention of stereochemistry to give products 165 or 167. Soderquist proposed a closed four-membered cyclic transition state 168 to account for the retention of stereochemistry observed during the reaction. 

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