Enolates allylic alkylation

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

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]. 

It is noteworthy that ZnEt2 has been used as a base in enantioselective allylic substitutions. A remarkable increase in ee was observed when ZnEt2 was used instead of KH, NaH, LiH, LDA, or BuLi in the Pd-catalyzed alkylations of allylic acetates by enolates of malonic esters and related compounds.403 In contrast, application of ZnEt2 was not as very effective as in similar iridium-catalyzed allylic alkylations.404... 

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. 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Tab. 10.3 The scope of the regioselective rhodium-catalyzed allylic alkylation with copper(l) enolates.

Extension of the rhodium-catalyzed allylic alkylation to a-subshtuted enolates was found to facilitate the introduction of an additional stereogenic center (Eq. 5). 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

The preparation of a-lithio aldehydes, o -lithio ketones, and related compounds and their applications to organic synthesis has been reviewed.10 The Tsuji-Trost allylic alkylation with ketone enolates has been highlighted.11... 

The regio- and stereo-selective rhodium-catalysed allylic alkylations of chelated enolates have been investigated.25 It has been found that the Rh-catalysed allylic alkylation is as efficient and versatile as the Pd-catalysed version. In reactions of chelated enolates with suitable protecting groups, high yields and selectivities were obtained, and the regioselectivity can be directed by the reaction parameters. 

Palladium-catalysed asymmetric a-allyl alkylation of acyclic ketones has been reported allyl enol carbonates of a wide range of ketones undergo allyl transfer in high yields and ees at room temperature.197... 

A regio- and enantio-selective palladium-catalysed allylic alkylation of ketones has been reported, using allyl enol carbonate chemistry in which a CO2 unit tethers the allylating agent to the nucleophile.198... 

The ruthenium complex Cp Ru(bipyridyl)Cl has been developed as a catalyst for the first regioselective tandem Michael addition-allylic alkylation of activated Michael acceptors. The net outcome is the decarboxylative insertion of Michael acceptors into allyl /3-keto esters to produce (215). The reaction combines the generation of Ru-tt-allyl and enolate from (213) the enolate is first added to the Michael acceptor (214) and the resulting species is captured by the Ru-tt-allyl.254... 

Other known methods for preparing O-alkyl enol ethers include, most notably, alcohol elimination from acetals, double bond isomeri2ation in allylic ethers, reduction of alkoxy enol phosphates, and phosphorane-based condensation approaches.5 These methods, however, suffer from poor stereoselectivity, low yields, or lack of generality, if not a combination of these drawbacks. 

In the case of alkyl enol ethers the normal oie process competes with solvent incorporated and 1,2-di-oxetane products. Here however the ene process seems to be less inevitaUe when allylic protons are available and the product distribution may be effectively contndled by manipulation of solvent and temperature combinations. Best results are nonetheless achieved where the competitive processes are restricted. Thus enol ether (79) produces hydroxylated dimethoxy acetal (W) via direct incorporation of methanol or through reduction of the 1,2-dioxetane (81). 

More reactive anions, such as the very well studied enolate anions from ketones and esters, do not imdergo allylic alkylation except in special cases. Tin enolate derivatives are generally effective (equation 52). 

Unsubstituted malonate esters and ethyl acetonate give highest yields, while methyl substituted analogs are less effective. Esters and ketones enolates are do not undergo allylic alkylation, and instead induce proton abstraction, generating acyldienes. There seems to be competition between nucleophilic attack and proton abstraction when utilizing unstable carbanions. ... 

Allylic alkylation reactions with amino acid enolates. 397... 

E. Ketone Enolates as Nucleophiles in Transition-metal Catalyzed Allylic Alkylations... 

In 1980 Trost and Keinan reported on allylic alkylations of tin enolates such as 33 catalyzed by tetrakis(triphenylphosphine)palladium (equation 12). The stannyl ethers led to a rapid and clean monoaUcylation with high regioselectivity. Thereby, alkylation generally occurred at the less substituted end of the allyl moiety with formation... 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

An intramolecnlar palladium-mediated allylic alkylation via a ketone enolate of piperidinone 54 was reported by Williams and coworkers for the synthesis of R)-l-hydroxyquinine 57 (eqnations 17 and 18) °. The key step involves a palladium-mediated Sjv2 -type cyclization reaction of enol ether 55 in the presence of BnsSnF, giving rise to a quinuclidine ketone, which was immediately rednced to 56 to avoid equilibration and /3-elimination. Interestingly, none of the undesired C3-vinyl stereoisomer was observed. 

Evans and Leahy reported on a method for the rhodium-catalyzed allylic alkylation using copper enolates, generated by transmetalation of the corresponding lithium enolates (equation 19). These enolates are softer and less basic nucleophiles than lithium enolates and therefore problems typically associated with enolate nncleophiles in metal-allyl chemistry can be avoided. A copper(I) enolate, derived from acetophenone derivative 63, was used as nucleophile in a regio- and stereoselective rhodinm-catalyzed alkylation of the in situ activated allylic alcohol 62. Thereby, the synthesized ketone 64, a key intermediate in the total synthesis of (—)-sugiresinol dimethyl ether (65), was produced as the only detectable regioisomer with complete conservation of enantiomeric excess. 

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. 

Besides allylic alkylation reactions chelated zinc ester enolates 231 also give good results in various types of standard enolate reactions, including alkylations, aldol reactions" and Michael additions" . 

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). 

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