New Mechanistic Developments

Much of the recent hteiature on the mechanism of the enantioselective intramolecular Mizoroki-Heck reaction has focused on the anionic mechanism, o-iodoanilide substrates, pathways involving neutral pentacoordinate palladium intermediates and the influence of additives. The new examples and mechanistic findings indicate that the potential may exist to control the stereoselectivity of the intramolecular Mizoroki-Heck reaction through pathways other than the cationic mechanism. However, further research is needed to obtain the level of effectiveness of the traditional cationic pathway. 

A catalytic cycle arising from the common precatalyst mixture of Pd(OAc)2 and PPhs, termed the anionic pathway, has recently been proposed [ 14]. This pathway involves anionic palladinm(O) and palladium(II) intermediates in which the acetate anion is coordinated with palladinm in the catalytically active species persisting after oxidative addition. The anionic pathway has not been invoked or thoroughly explored for enantioselective intramolecular Mizoroki-Heck reactions. However, it may become more significant based on recent studies with Pd(OAc)2 and bidentate phosphine ligands for which the palladium(n) species is only formed in the presence of added acetate ion [15]. 

For bis-ort/ o-snbstituted anilides with a high rotational barrier, such as amide 42, pure enantiomers (M)-(-)-42 and (P)-(+)-42 can be prepared (Table 12.1). If the intramolecular Mizoroki-Heck reaction of 42 is faster than the rate of racemization by rotation about the N—Ar bond, then reaction of a single enantiomer with an achiral palladium catalyst would produce an enantioenriched product. By employing room-temperature Mizoroki-Heck 

The suggestion is then made that the stereoconlrolling step in asymmetric Mizoroki-Heck reactions is oxidative addition (via dynamic kinetic resolution) rather than alkene association or migratory insertion. The implication is that only substrates capable of a dynamic kinetic resolution may cyclize with high enantioselectivity. This would limit the substrate scope of the asymmetric intramolecular Mizoroki-Heck reaction. While the dynamic kinetic resolution during the oxidative addition may be a component of the overall stereoselectivity, it does not rule out contributions from later events in the mechanistic pathway and does not explain the effect of additives on selectivity. What has been shown is that the axial chirality of the o-iodoanilides (as with any enantioenriched isomer of a chiral precursor) influences the stereochemical outcome of their reactions. 

A rationale for the variation in product enantiopurity with the extent of reaction may be gleaned from the reaction of amide 39, in which the purity of Ag3P04 influenced the stereochemical outcome of the reaction (Table 12.3) [20]. When high-purity Ag3P04 from Strem was used, the product (A )-(- -)-40 was obtained. However, when Ag3P04 from Aldrich was employed, the opposite enantiomer was obtained. Upon exposing the 

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