Double electrophilic activation

Maruoka reported the use of the didentate catalyst 8 for double electrophilic activation of carbonyl compounds [70], but since no comparison with monofunctional phenolates was given it is not clear whether having two aluminium centres in the same catalyst offers any special advantages. They used this catalyst to effect transfer hydrogenation between remote aldehyde and alcohol groups in the same molecule [71], but again it is not clear whether the transfer is truly intramolecular or in any way different from that of reduction by an external alcohol using 8 or a monuclear aluminium catalyst. 

Maruoka and co-workers reported a conceptually new MPV reduction system based on bidentate Lewis-acid chemistry [29]. The initial formation of bidentate aluminum catalyst 9 derived from (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylalu-minum) (8 prepared from 2,7-dimethyl-l,8-biphenylenediol and 2 equiv. MesAl) and i-PrOH (4 equiv.), followed by treatment of benzaldehyde with the in situ generated (2,7-dimethyl-l,8-biphenylenedioxy)bis(diisopropoxyaluminum) (9) at room temperature instantaneously produced the reduced benzyl alcohol almost quantitatively (Table 2, entry 2). Even with 5 mol% catalyst 9 the reduction proceeds quite smoothly at room temperature to furnish benzyl alcohol in 81 % yield after 1 h (Table 2, entry 3). This remarkable efficiency can be ascribed to the double electrophilic activation of carbonyls by the bidentate aluminum catalyst (Sch. 7). 

Scheme 1-16. Double electrophilic activation by bidentate aluminum Lewis acid 49 in the reduction of ketones.

Maruoka et al. have developed the aluminum-based bidentate Lewis acid 14 for double electrophilic activation of carbonyl compounds (Scheme 10.9) [37]. The aldol addition of cyclohexanone TMS enolate to benzaldehyde is effected by the bidentate 14, whereas its monodentate counterpart 15 shows no evidence of reaction under similar conditions. In competitive reactions of aldehydes and acetals, 14 effects aldehyde-selective addition [38]. 

The tailored dinuclear aluminium Lewis acid displayed a high Lewis-acid catalytic activity due to a double electrophilic activation of a substrate s carbonyl group. This skilful ligand design turned a standard alkoxide into a real multitool for carbonyl chemistry. This type of catalyst was employed for instance in Mukaiyama aldol reactions, in MPV reductions and Oppenauer oxidations and related Tischchenko coupling reactions. 

In most palladium-catalyzed oxidations of unsaturated hydrocarbons the reaction begins with a coordination of the double bond to palladium(II). In such palladium(II) olefin complexes (1), which are square planar d8 complexes, the double bond is activated towards further reactions, in particular towards nucleophilic attack. A fairly strong interaction between a vacant orbital on palladium and the filled --orbital on the alkene, together with only a weak interaction between a filled metal d-orbital and the olefin ji -orbital (back donation), leads to an electrophilic activation of the alkene9. 

The oxidative addition of palladium(O) to aryl bromide generates the arylpalladium(n) intermediate 126 (Scheme 37). The electrophilic activation of the double bond by palladium facilitates the nucleophilic attack, resulting in cyclization. 

Radical cations resulting from oxidation of olefins, aromatic compounds, amino groups, and so on, can react by electrophilic addition to a nucleophilic center as shown, for example, in Scheme 1 [2, 3]. The double bond activated by an electron-donating substituent is first oxidized leading to a radical cation that attacks the nucleophilic center. The global reaction is a two-electron process corresponding to an ECEC mechanism. 

For the reaction of 1,3-dioxin -ones with electrophiles, activation by deprotonation of the side-chain alkyl group is required. Typically lithium diisopropylamide (LDA) is used as a base. The resulting lithium dienolates react with aldehydes <2002EJ0718> or with allyl bromides in the presence of Ar,Ar -dimethylpropyleneurea (DMPU) <2005AGE820, 2006CEJ2488> exclusively at the side-chain double bond, albeit in modest yields (Equation 25). 

On the other hand, however, these two areas of cationic polymerization are not completely separated fields. In spite of the differences, both processes proceed on electron-deficient active species cations or species with a partial positive charge. Thus, propagation in both cases involves attack of the nucleophile (double bond or heteroatom) on electrophilic active centers. Several basic principles will therefore hold for both vinyl and ring-opening cationic polymerization. 

FJectrophile-promoted cyclization of unsaturated amides results in the formation of substituted lactones. The key step of the reaction is attack on the electrophile-activated double bond by the more nucleophilic oxygen of the bidentate function group, followed by hydrolysis of the imido derivative. 

The presence of an a, -conjugated double bond noticeably reduces the electrophilic activity of a carbonyl carbon. This effect allows one to protect, selectively, an isolated keto group as a ketal in the presence of a conjugated enone moiety. Thus, the selective transformations of conjugated enones, a situation frequently encountered in steroid chemistry, are achieved in this manner. 

In contrast to the allyl halides with one EWG, nucleophilic attack on double bond activated allyl halides (291) normally gives rise to substituted electrophilic cyclopropanes (293) or compounds derived therefrom (equation 87). The formation of these cyclopropanes is strongly dependent on the reaction conditions, the nature of the nucleophiles, the... 

Additions to nonactivated olefins and dienes are important reactions in organic synthesis [1]. Although cycloadditions may be used for additions to double bonds, the most common way to achieve such reactions is to activate the olefins with an electrophilic reagent. Electrophilic activation of the olefin or diene followed by a nucleophilic attack at one of the sp carbon atoms leads to a 1,2- or 1,4-addition. More recently, transition metals have been employed for the electrophilic activation of the double bond [2]. In particular, palladium(II) salts are known to activate carbon-carbon double bonds toward nucleophilic attack [3] and this is the basis for the Wacker process for industrial oxidation of ethylene to acetaldehyde [41. In this process, the key step is the nucleophilic attack by water on a (jt-ethylene)palladium complex. 

The electrophilicity index also accounts for the electrophilic activation/deactivation effects promoted by EW and electron-releasing substituents even beyond the case of cycloaddition processes. These effects are assessed as responses at the active site of the molecules. The empirical Hammett-like relationships found between the global and local electrophilicity indexes and the reaction rate coefficients correctly account for the substrate selectivity in Friedel-Crafts reactions, the reactivity of carbenium ions, the hydrolysis of esters, the reactivity at the carbon-carbon double bonds in conjugated Michael additions, the philicity pattern of carbenes and the superelectrophilicity of nitronium, oxonium and carboxonium ions. This last application is a very promising area of application. The enhanced electrophilicity pattern in these series results from... 

The Meerwein-Eschenmoser-Claisen rearrangement, in particular the Eschen-moser amide acetal version, has been extensively applied toward the synthesis of natural products and other complex target molecules. The literature is replete with cases where the reaction provided the only way to place a substituent in a sterically hindered environment. The following paragraphs provide selected examples of its use and also serve to highlight the further synthetic transformation of the unsaturated N,N-dimethylamides normally obtained. Perhaps the only drawback of the Eschenmoser-Claisen rearrangement is the stabiUty of these amides, whose hydrolysis and reduction requires relatively harsh conditions. However, electrophilic activation via the y,(5-double bond can be used to manipulate this functionality. 

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