Conjugate Addition of Stabilized Carbon Nucleophiles

As also happened in the iminium activation case, the Michael reaction has been the most studied conjugate addition reaction in this context, also serving as a 

Backbone axiai chiraiity Provides ohirai information for asymmetric induction 

Controi of catalyst-substrate binding geometry steric shielding of stereotopic faces of the acceptor 

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Thus, present technology permits conjugate addition of stabilized carbon nucleophiles under formally basic (enolate), neutral (enamine), or acidic (Lewis acid) conditions. In general, the softer enamine and enol ether additions show a greater preference for 1,4- over 1,2-addition than do isosteric metal enolates. 

The Michael reaction is addition of a carbon nucleophile to the /3 position of an a,/3-unsaturated carbonyl compound or its equivalent. It also may be called a 1,4-addition reaction (the carbonyl oxygen is counted as 1 and the )3-carbon as 4). The conjugation of the v bond with thp carbonyl group imparts positive character to the /3 position, making it susceptible to reaction with a nucleophile. The product of this reaction, an enolate ion, also is stabilized by resonance. 

Highly stabilized phosphorus ylides are prepared from acetylenic esters, a carbon-based nucleophile, and triphenylphosphine in aqueous media.40 In acetone-water (2 1) solvent, the reaction proceeds via the conjugate addition of triphenylphosphine to dialkyl acetylenedicarboxy-lates the resulting vinyl triphenylphosphonium salts undergo Michael addition reaction with a carbon-nucleophile to give the corresponding highly stabilized phosphorus ylides. 

The first step is conjugate addition of the highly stabilized anion. The intermediate enolate then closes the three-membered ring by favourable nucleophilic attack on the allylic carbon. The leaving group is the sulfinate anion and the stereochemistry comes from the most favourable arrangement in the transition state for this ring closure. The product is the methyl ester of the important chrysan-themic acid found in the natural pyrethrum insecticides. 

In a reaction similar to those given in Eqs. (20) and (25), Grigg [40,41] also employed lithium acetate as an oxygen nucleophile in place of the amine and stabilized carbon nucleophile, respectively, shown in these equations. This led to a 1,4-addition of carbon and oxygen to the conjugated diene. 

The addition of a noii-stabilized carbon nucleophile and another nucleophile to a conjugated diene has similarities to the addition of H-Nu (cf. Section 8.2.1). The formation of RPdX from oxidative addition of RX and Pd(0) corresponds to the genei-ation of a palladium hydride species in the H-Nu addition (Scheme 8-3). 

With two activating substituents, as in the ester 4.159, conjugate reduction (and conjugate addition of carbon nucleophiles) is fast and almost always observed with any nucleophile.390 The stability of the conjugated enolate product 4.160, and Coulombic and frontier orbital factors, all readily explain this observation. 

The use of a stabilized carbanion as an external nucleophile in the arylation or vinylation of conjugated dienes leads to a 1,4-addition of two carbon atoms. This was first demonstrated by Dieck et al. [40] in 1983, who showed that 1-bromo-2-methylpropene and sodium dimethyl malonate reacted with isoprene in the presence of a palladium catalyst to give a 1,4-adduct in moderate yield (22%). 

Enantioselective Conjugate Additions of Enolates and other Stabilized Carbon Nucleophiles... 

Protonation of the enolate ion is chiefly at the oxygen, which is more negative than the carbon, but this produces the enol, which tautomerizes. So, although the net result of the reaction is addition to a carbon-carbon double bond, the mechanism is 1,4 nucleophilic addition to the C=C—C=0 (or similar) system and is thus very similar to the mechanism of addition to carbon-oxygen double and similar bonds (see Chapter 16). When Z is CN or a C=0 group, it is also possible for Y to attack at this carbon, and this reaction sometimes competes. When it happens, it is called 1,2 addition. 1,4 Addition to these substrates is also known as conjugate addition. The Y ion almost never attacks at the 3 position, since the resulting carbanion would have no resonance stabilization " ... 

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