Enolates palladium-catalyzed alkylation

Palladium-catalyzed alkylation of enolate requires the presence of a base, and rubidium and cesium carbonates have been used for this purpose (Scheme 2.33)... 

Chiral phosphinous amides have been found to act as catalysts in enantio-selective allylic alkylation. Horoi has reported that the palladium-catalyzed reaction of ( )-l,3-diphenyl-2-propenyl acetate with the sodium enolate of dimethyl malonate in the presence of [PdCl(7i-allyl)]2 and the chiral ligands 45 gave 46 in 51-94% yields and up to 97% ee (Scheme 38). It is notorious that when the reaction is carried out with the chiral phosphinous amide (S)-45a, the product is also of (S) configuration, whereas by using (R)-45b the enantiomeric (R) product is obtained [165]. 

Ceric ammonium nitrate promoted oxidative addition of silyl enol ethers to 1,3-butadiene affords 1 1 mixtures of 4-(/J-oxoalkyl)-substituted 3-nitroxy-l-butene and l-nitroxy-2-butene27. Palladium(0)-catalyzed alkylation of the nitroxy isomeric mixture takes place through a common ij3 palladium complex which undergoes nucleophilic attack almost exclusively at the less substituted allylic carbon. Thus, oxidative addition of the silyl enol ether of 1-indanone to 1,3-butadiene followed by palladium-catalyzed substitution with sodium dimethyl malonate afforded 42% of a 19 1 mixture of methyl ( )-2-(methoxycarbonyl)-6-(l-oxo-2-indanyl)-4-hexenoate (5) and methyl 2-(methoxycarbonyl)-4-(l-oxo-2-indanyl)-3-vinylbutanoate (6), respectively (equation 12). 

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

Andersson, C.-M., and Hallberg, A. 1989. Palladium-catalyzed vinylation of alkyl vinyl ethers with enol triflates. A convenient synthesis of 2-alkoxy 1,3-dienes. J Org Chem 54, 1502-1505. 

The efficiency of the palladium-catalyzed asymmetric alkylation of ketone enolates was shown by Trost and coworkers in their synthesis of hamigeran B (50), a potent antiviral agent with low cytotoxicity to host cells (equation 15). The quaternary center... 

The great importance of nonproteinogenic amino acids including a-substituted derivatives led to numerous investigations of modified amino acid enolates as nucleophiles in both classical alkylation or Mannich reactions and palladium-catalyzed allylic alkylations. 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

These peptide enolates could also be used as excellent nucleophiles in palladium-catalyzed allylic alkylations. Reactions of numerous dipeptides (e.g. 263) with different allylic substrates (e.g. 264) and [AllPdClja as catalyst delivered (S,/f)-configured peptides with y,5-unsaturated side chains (265), usually in high yields and diastereoselectivities (equation 69). 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

On the other hand, unsaturated aldehydes and ketones were obtained using allylic alcohols as alkene components [68]. Similarly, allyl f-butyldimethylsilyl ether and N-allylamides gave silyl enol ethers [69] and enamides [70], respectively. The ruthenium-catalyzed alkene-alkyne coupling was successfully combined with the palladium-catalyzed intramolecular asymmetric allylic alkylation [71] to provide a novel one-pot heterocyclization method [72]. 

Braum M, Meier T. New developments in stereoselective palladium-catalyzed allylic alkylations of preformed enolates. 

Ceric ammonium nitrate promoted oxidative addition of silyl enol ethers to 1,3-1 mixtures of 4-(/l-oxoalkyl)-substituted 3-nitroxy-l-butene and Palladium(O)-catalyzed alkylation of the nitroxy isomeric mixture... 

Transition Metal-catalyzed Allylic Alkylation. Simple ketone enolates were found to be suitable nucleophiles for palladium-catalyzed allylic alkylations. The palladium-catalyzed asymmetric allylic alkylation of a-aryl ketones will take place in the presence of NaHMDS and allyl acetate to produce the desired a,a-disubstituted ketone derivative in high yields andee (eq 16). ... 

Mori and Shibasaki s group described the use of a special titanium-isocyanate complex for a novel one-step synthesis of isoindolinones and quinazolinones starting from o-halophenyl alkyl ketones [260]. As shown in Scheme 2.35, this reaction proceeds through the oxidative addition of the enol lactone, generated by palladium-catalyzed carbonylation of o-halophenyl alkyl ketones, to the titanium-isocyanate complex A. 

As the palladium-catalyzed aUyUc substitution with chelated enolates already proceeds at — 78°C, they provide a good chance to circumvent a nearly unsolved problem in palladium-catalyzed aUylic alkylations the it-a-it-isomerization. The reaction with the (Z)-carbonate 96 (97% ee) almost exclusively yields the desired (Z)-substitution product 98 (Z/ >99/l). The outstanding selectivities (ds 98%, 97% ee) observed even surpassed the very good results of the reaction with the ( )-carbonate 97 (Scheme 12.51). In contrast, the reaction with the corresponding acetate furnished an ( /Z)-mixture in a lower yield. While the carbonates already react at —78°C, where it-o-7t-isomerization obviously does not occur, the reaction of the acetates takes place at a higher temperature during the warm-up. 

---