Soft Electrophiles reaction with enolate

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

A wasteful side reaction which sometimes occurs in the alkylation of 1,3-dicarbonyl compounds is the formation of the 0-alkylated product. For example, reaction of the sodium salt of cyclohexan-l,3-dione with butyl bromide gives the 0-alkylated product (37%) and only 15 % of the C-alkylated 2-butylcyclohexan-1,3-dione. In general, however, 0-alkylation competes significantly with C-alkylation only with reactive methylene compounds in which the equilibrium concentration of enol is relatively high (as in 1,3-dicarbonyl compounds). The extent of C- versus 0-alkylation for a particular 1,3-dicarbonyl compound depends on the choice of cation, solvent and electrophile. Cations (such as Li+) that are more covalently bound to the enolate oxygen atom or soft electrophiles (such as alkyl halides) favour C-alkylation, whereas cations such as K+ or hard electrophiles (such as alkyl sulfonates) favour 0-alkylation. 

Simultaneous treatment of a carbonyl compound with a Lewis acid and a tertiary amine or another weak base ( soft enolization ) can sometimes be used to generate enolates of sensitive substrates which would have decomposed under strongly basic reaction conditions [434]. Boron enolates, which readily react with aldehydes at low temperatures, can also be prepared in situ from sensitive, base-labile ketones or carboxylic acid derivatives [293, 295, 299]. Unwanted decomposition of a carbanion may also be prevented by generating it in the presence of an electrophile which will not react with the base (e.g. silyl halides or silyl cyanides [435]). 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

In summary, the Pd-catalyzed allylic substitution reaction between allyl acetates (and related electrophiles) with soft enolates has a wide scope and continues to attract considerable interest as a synthetic tool. 

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