Oxidative Mizoroki-Heck process

As mentioned in the discussion of the reaction mechanism for this transformation, the active species is a dicoordinate Pd(0) complex, and it is unclear whether an associative or a dissociative process is operative for oxidative addition. In this context, different NHC complexes containing only one carbene ligand have been tested in the Mizoroki-Heck reaction. The most successful are those prepared by Beller, which were able to perform the Mizoroki-Heck reaction of non-activated aryl chlorides with moderate to good yields in ionic liquids (Scheme 6.13). The same compounds have also been applied to the Mizoroki-Heck reaction of aryldiazonium... 

Combination of the oxidative addition of aryl halide with olefin insertion followed by -hydrogen elimination provides a useful olefin arylation process catalyzed by a palladium complex (Mizoroki-Heck reaction) [63-65]. The essential part of the catalytic cycle is shown in Scheme 1.23. 

C-0 bond cleavage of aryl triflates or tosylates is also studied in relation to Mizoroki-Heck type reactions [101], Oxidative addition of PhOTf to Pd(PPh3)4 is 10 times slower than that of Phi. Since similar trend is observed for the catalytic Mizoroki-Heck reaction, the oxidative addition of aryl compound is considered to be the rate-determining step in the overall catalytic process. This feature suggests that the C-0 bond cleavage of aryl triflate proceeds by the concerted SNAr mechanism. However, since the triflate normally acts as a non-coordinating anion, thermally unstable cationic arylpalladium(II) complexes are formed in this reaction (Scheme 3.54). 

In their enantioselective total synthesis of the alkaloid cephalotaxine (246), Tietze and Schirok [127] used a combination of a Tsuji-Trost and a Mizoroki-Heck reaction (Scheme 8.62). It was necessary to adjust the reactivity of the two palladium-catalysed transformations to allow a controlled process. Reaction of 243a using Pd(PPh3)4 as catalyst led to 244, which furnished 245 in a second palladium-catalysed reaction. In this process, the nucleophilic substitution of the allylic acetate is faster than the oxidative addition of the arylbromide moiety in 243a however, if one uses the iodide 243b, then the yield drops dramatically due to an increased rate of the oxidative addition. 

The Wacker oxidation [146], amongst other nucleophilic additions to alkenes, is the most important reaction based on a palladium(II) catalysis. It is also used industrially for the synthesis of acetaldehyde from ethene and water. This oxidative process has been combined with a Mizoroki-Heck reaction by Tietze and coworkers [13] for an enantioselective total synthesis of vitamin E (293) [147] using BOXAX ligand 291 [148]. In this way the chromane ring and parts of the side chain of vitamin E (293) can be introduced in one... 

Tri- and tetra-substituted dihydropyranones and furanones have also been synthesized by a Wacker/Mizoroki-Heck domino process (Scheme 8.72). Gouvemeur and cowoikers [151] very recently prepared these kinds of compounds using different palladium sources, copper acetate as redox mediator, oxygen as oxidant and lithium bromide as additive. The coupling of two electron-poor substrates, ethyl acrylate and -hydroxy alkynones 294, led to the desired compounds 295a-e in moderate yields. 

The catalytic system proved not only applicable to alkyl hahdes, but also allowed for the intramolecular conversion of aryl halides. Interestingly, the corresponding Mizoroki-Heck-type cyclization products were formed selectively, without traces of reduced side-products (Scheme 10.27) [55]. Therefore, a radical reaction via a single electron-transfer process was generally disregarded for cobalt-catalysed Mizoroki-Heck-type reactions of aromatic hahdes. Instead, a mechanism based on oxidative addition to yield an aryl-cobalt complex was suggested [51]. 

This fundamental experiment has strong implications on related catalyst-controlled Mizoroki-Heck cyclizations of precursors of this type. As axial chirality in 113 sets the stereochemistry in 114, enantioinduction was rationalized to arise from a dynamic kinetic resolution of (at elevated temperature) rapidly interconverting enanhomers of 113 in the oxidative addition step, rather than in the alkene coordination-migratory insertion event. Such a dynamic kinetic resolution process has been previously proposed by Stephenson et al. within their mechanistic study regarding the conformations of helically chiral 2-iodoanilides in intramolecular asymmetric Mizoroki-Heck reactions [72],... 

In the Mizoroki-Heck reaction, the catalysis begins with the oxidative addihon of a C(sp )—X bond to a palladium(O) complex to give a C(sp )—Pd(II) complex common to almost all palladium(O)-catalyzed cross-coupling reachons (cf. Section 7.2.1). There are, however, alternative ways to generate the central o-aryl palladium(II) intermediate and to effect a Mizoroki-Heck-type process (Scheme 7.42). 

First, the interaction of a Lewis acidic palladium 11) complex with a C(sp —H bond of an electron-neutral or electron-rich (het)arene might result in its electro-phiUc palladation (173 175 Scheme 7.42), a fundamental process later referred to as electrophilic C—H bond activation. In contrast, the oxidative addition of a C(sp )—X bond to palladium(O) is favored for electron-poor (het)arenes, thus providing an orthogonal entry into Mizoroki-Heck chemistry. After C—H activation, convenhonal alkene insertion (175 176) and P-hydride elimination (176 177) eventually lead to the formation of catalytically inactive palladium(O). In order to achieve catalytic turnover, however, paUadium(O) must be reoxidized to palladium(II). 

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