Cross-coupling reactions reductive elimination

Direct palladation of C-H bonds can be achieved by treatment of, for example, electron-rich arenes with Pd(II) salts (see also Section8.11). After cross-coupling via reductive elimination the resulting Pd(0) must be reoxidized to Pd(II) if Pd-catalysis is the aim [85], Reoxidation of Pd(0) with Cu or Ag salts (as in the Wacker process) is not always well suited for C-C bond-forming reactions [86], but other oxidants, for example peroxides, have been used with success (Scheme8.9). The required presence of oxidants in the reaction mixture limits the scope of these reactions to oxidation-resistant starting materials. 

These are called cross-coupling reactions and usually involve three basic steps oxidative addition, transmetallation, and reductive elimination. In the transmetallation step an organic group is transferred from the organometallic reagent to palladium. 

It proceeds by the standard mechanism for cross-coupling reactions oxidative addition of Pd(0) to the C-I bond, transmetallation to give the C-Pd(II)-C compound, and reductive elimination. 

These reductive eliminations occur for instance also in cross-coupling reactions where they are particularly effective when one of the partners of the reductive elimination has an sp2-hybridised carbon atom bonded to the metal. A theoretical analysis of the reductive elimination of propene from cis-(PH3)2Pd(CH3)(CH=CH2) shows that the best description for this reaction is a migration of the methyl group to the sp2-carbon of the vinyl unit [48],... 

The formation of the C-X bond in hetero-cross coupling reactions is thought to proceed via a migration of the hetero atom to the aryl group, which develops a negative charge, which is Jt-stabilised by mesomeric interaction with acceptor substituents. Both for this reductive elimination and its reverse (oxidative addition) resonance-stabilised Meisenheimer complexes have been proposed [42,49,50,51], This stabilised structure is depicted in Figure 12.18. 

Knochel and co-workers developed the Ni(acac)3-catalyzed cross-coupling reaction between polyfunctional primary iodoalkanes and a variety of primary diorganozinc compounds in the presence of w-trifluoromethylstyrene as a promoter. " The addition of this unsaturated promoter is required in order to coordinate to the nickel center and remove electron density from the metal atom, to facilitate the reductive elimination step. " " The scope of the reaction is extended, when Ni(acac)2 is used in the presence of BU4NI and fluorostyrene (Scheme With these... 

An acyl-palladium complex might undergo a series of follow up reactions. Subsequent transmetalation and reductive elimination lead to the formation of a carbonyl compound. This process is also coined carbonylative coupling, referring to the cross-coupling reaction, which would take place in the absence of carbon monoxide under similar conditions (for more details see Chapter 2.4.). 

The first step in the cycle, analogous to the cross-coupling reactions, is the oxidative addition of an aryl (vinyl) halide or sulfonate onto the low oxidation state metal, usually palladium(O). The second step is the coordination of the olefin followed by its insertion into the palladium-carbon bond (carbopalladation). In most cases palladium is preferentially attached to the sterically less hindered end of the carbon-carbon double bond. The product is released from the palladium in a / -hydrogen elimination and the active form of the catalyst is regenerated by the loss of HX in a reductive elimination step. To facilitate the process an equivalent amount of base is usually added to the reaction mixture. 

The final step of the process is the detachment of the product from the metal in reductive elimination. Unlike in most cross-coupling reactions, this step was the limiting factor in the early reports on the Buchwald-Hartwig reaction. The use of sterically demanding mono and bidentate ligands, however helped to overcome this difficulty by facilitating the closing step. 

The palladium-catalyzed cross-coupling of an aryl, alkenyl, or benzylzinc bromide 11 with aryl iodide 12 succeeds with 0.15 mol-% [Pd P(C6H4C6Fi3)3 4] in toluene/1-bromoperfluorooctane, taking advantage of variable miscibility through thermoregulation [20], In this case the electron-deficiency of the phosphanes, due to the perfluorinated side chains, appears to influence the reductive elimination step in the cross-coupling reactions. 

The mechanism of the Sonogashira reaction has not yet been established clearly. This statement, made in a 2004 publication by Amatore, Jutand and co-workers, certainly holds much truth [10], Nonetheless, the general outline of the mechanism is known, and involves a sequence of oxidative addition, transmetalation, and reductive elimination, which are common to palladium-catalyzed cross-coupling reactions [6b]. In-depth knowledge of the mechanism, however, is not yet available and, in particular, the precise role of the copper co-catalyst and the structure of the catalytically active species remain uncertain [11, 12], The mechanism displayed in Scheme 2 includes the catalytic cycle itself, the preactivation step and the copper mediated transfer of acetylide to the Pd complex and is based on proposals already made in the early publications of Sonogashira [6b]. 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

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