Active methylene compounds with allylic esters

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

In most cases, treatment of allylic halides containing one ASG with a nucleophile does not result in formation of electrophilic cyclopropanes (MIRC product) instead, other reaction pathways are followed, e.g. addition, substitution, rearrangement and elimination reactions.However, with certain alkenes or nucleophiles or under the appropriate conditions a conjugate addition-nucleophilic substitution pathway is favored, resulting in cyclopropanes substituted with one ASG. Representative examples are compiled in Tables 20 and 21 where organometallic compounds or active methylene compounds are used as the nucleophilic species in combination with allyl bromides containing an ester or a sulfone as ASG. 

In general, allyl ethers are less reactive than esters and therefore rarely used as substrates in the palladium-assisted alkylation with soft nucleophiles. Phenyl a- or )5-D-eor//jro-hex-2-enopyra-nosides react with a variety of soft carbanions under neutral conditions to give the a- or t -C -g]ycopyranosides, respectively in good to excellent yields both stereoselectively and with complete regioselectivity88. Since the liberated phenoxide ion deprotonates the active methylene compounds, no external base has to be added. 

A difficulty sometimes encountered in the alkylation of active methylene compounds is the formation of unwanted dialkylated products. During the alkylation of the sodium salt of diethylmalonate, the monoalkyl derivative formed initially is in equilibrium with its anion. In ethanol solution, dialkylation does not take place to any appreciable extent because ethanol is sufficiently acidic to reduce the concentration of the anion of the alkyl derivative, but not that of the more acidic diethylmalonate itself, to a very low value. However, replacement of ethanol by an inert solvent favours dialkylation. Dialkylation also becomes a more serious problem with the more acidic cyanoacetic esters and in alkylations with very reactive electrophiles such as allyl or benzyl halides or sulfonates. 

Reactions of soft carbon nucleophiles derived from active methylene compounds such as /3-keto esters or malonates proceed by attack of the nucleophiles at the central sp carbon of the allenyl complexes. The attack of the nucleophiles generates cr-allyl anion intermediates, which are regarded as palladium-carbene complexes. These intermediates pick up a proton from the active methylene compound to form 7r-allylpalladium complexes, which undergo further reaction with the nucleophile as expected, and hence the alkenes are formed by introduction of two molecules of the carbon nucleophiles (Scheme 21). 

Since the initial studies of Tsuji and Trost, it has been known that Tr-allylpalladium complexes react irreversibly with active methylene compounds to form new carbon-carbon bonds. Applying this information, Kunz introduced dimedone and A,A-dimethylbarbi-turic acid (NDMBA) as nucleophiles in the Pd-catalyzed deprotection of allyl carbamates and carbonates. The presumed catalytic cycle for this process is shown in Scheme 4. Dimedone and NDMBA have also been employed as nucleophiles in the deprotection of aUyl esters. Dimethyl malonate has also been used occasionally in allyl carbamate deprotection, although it appears to be less reactive than the other carbon nucleophiles.f ... 

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