Palladium zinc enolate addition

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

A procedure has been developed for the palladium-catalysed a-arylation of amides by aryl bromides using the zinc enolates of the amides. The reaction works well with bromoarenes carrying a variety of ring substituents and with bromopyridine. In addition, the reaction has been shown to be effective with morpholine amides to give products which are precursors for aldehydes and ketones.39 A new method has been reported for the allylation of aryl halides using homoallyl alcohols as the allyl source the palladium-catalysed reaction, which may be both stereo- and regio-sepecific, uses a retro-allylation reaction to form a a-allyl(aryl)palladium intermediate.40... 

The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homo-chiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3). 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

For instance, it is reported that a chiral copper catalyst (R,R)-L promotes asymmetric conjugate addition of dialkyl zinc to a,p-unsaturated ketone 19 to form homochiral zinc enolate 20. This intermediate is then trapped in situ with NPP as electrophile, without the need of additional palladium catalysis. Good yield, high trans/cis (95/5) ratio, and excellent enantioselectivity (99%) are obtained. Moreover, the multi-functionalized nature of 21 makes it a versatile intermediate for further elaboration. 

Miscellaneous Applications. The chemoselective oxidation of alcohols and diols using T 0-i- r)Jt-Butyl Hydroperoxide has been reported. The title reagent has also been employed as a catalyst in Diels-Alder reactions and as an additive in the palladium-catalyzed reaction of aryl-substituted allylic alcohols with zinc enolates of p-dicarbonyl compounds (eq 24). The latter... 

The first attempts to use transition metal-catalyzed cross-coupling methodology to couple enolates with aryl halides were far from being broadly applicable, and involved less-attractive preformed zinc- or tin-enolates [210]. In addition, only ketones or acetates could be employed as enolate precursors. At that time, nickel was the predominant transition metal to mediate these couplings [211]. In an early contribution, CiufoHni arylated soft enolates in an intramolecular fashion with aryl halides using Pd(PPh3)4, along with NaH, in DMF at elevated temperatures [212]. This represented one of the first palladium-catalyzed arylations of enolates. 

After the intermolecular palladium-catalyzed arylation of enolates had been discovered by the research groups of Buchwald, Hartwig, and Miura [63], it was an obvious idea to explore a stereoselective variant that was based on the reliable Evans auxiliaries, while catalytic, enantioselective protocols (cf. Section 5.2) were developed at the same time. However, only relatively moderate diastereoselectivity in the formation of arylation products 133 was achieved when the silyl ketenimine (S)-132 derived from Af-propionyl oxazolidinone was coupled with aryl bromides under palladium catalysis, as disclosed by Hartwig and Liu [64]. The additive zinc(ll) f-butoxide permitted to lower the temperature to 25 °C so that the diastereoselectivity could be enhanced (Scheme 4.26). The authors noticed that Ley s chiral dioxanone 134 proves itself as an auxiliary that induced excellent diastereoselectivity and led to the formation of arylated compounds 135 in very high diastereomeric ratios. The chiral auxiliary group was readily removed by treatment with chlorotrimethylsUane and methanol, so... 

Scheme 5.109 Copper-catalyzed enantioselective conjugate addition of dimethyl zinc and enolate trapping by palladium-catalyzed allylic alkylation to ketone 427. Application to a synthesis of pumiliotoxin C.

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