Carbon nucleophiles conjugate addition

In 1986, we found that alkynyl-A3-iodanes serve as good Michael acceptors toward soft nucleophiles, because of the highly electron-deficient nature of the /3-acetylenic carbon atom. This conjugate addition of nucleophiles constitutes a key step of a highly versatile cyclopentene annulation of alkynyl-A3-iodanes via the tandem Michael-carbene insertion (MCI) reaction [Eq. (103)] [185]. 

The normal addition process is identical to the other reactions that have been encountered so far in this chapter The nucleophile bonds to the carbonyl carbon and the electrophile bonds to the oxygen of the carbonyl group. In a conjugate addition the nucleophile bonds to the /3-carbon. The electrophile, a proton, can bond to either the a-carbon or the oxygen of the resonance stabilized anion. It actually reacts faster at the oxygen, producing an enol in an overall 1,4-addition. However, as discussed in Section 11.6, ends are less stable than the carbonyl tautomers, so the product that is isolated contains the carbonyl group. 

The compounds that we are now calling dienophiles were the stars of Chapters 10, 23, and 29 where we called them Michael acceptors as they were the electrophilic partners in conjugate addition reactions. Nucleophiles always add to the (3 carbon atoms of these alkenes because the product is then a stable enolate. Ordinary alkenes do not react with nucleophiles. 

Nucleophilic addition to the carbonyl carbon of an a,f3-unsaturated Class II carbonyl compound is called direct addition addition to the j8-carbon is called conjugate addition. Whether direct or conjugate addition occurs depends on the nature of the nucleophile, the structure of the carbonyl compound, and the reaction conditions. Nucleophiles that form unstable direct addition products— halide ions, cyanide ion, thiols, alcohols, and amines— form conjugate addition products. Nucleophiles that form stable addition products—hydride ion and carbaiuons—form direct... 

The actual umpolung reaction that allows a ketene dithioacetal to function as if it had an electrophilic carbon a to a carbonyl is achieved by conjugate addition of nucleophiles to the ketene dithioacetal, followed by hydrolysis. Both sulfide and sulfoxide ketene derivatives can be used. Conjugate addition of an ester enol-ate derived from ferf-butyl acetate (secs. 9.2, 9.4.B, 9.7.A) to the ketene dithioacetal [CH2=C(SOMe)2] gave the stable dithioacetal anion (382). Conversion of the dithioacetal to the bis(sulfoxide) enhanced the ability of that species to function as a Michael acceptor. Subsequent transformation of 382 gave the aldehyde-ester (383).370... 

The p carbon of an a,p-unsaturated carbonyl compound is electrophilic nucleophiles, especially weakly basic ones, react with a,p-unsaturated aldehydes and ketones by conjugate addition. The nucleophile bonds to the p carbon. 

Catalytic Asymmetric Addition Reactions of Cu(I)-Conjugated Soft Carbon Nucleophiles... 

Section 10 10 Protonation at the terminal carbon of a conjugated diene system gives an allylic carbocation that can be captured by the halide nucleophile at either of the two sites that share the positive charge Nucleophilic attack at the carbon adjacent to the one that is protonated gives the product of direct addition (1 2 addition) Capture at the other site gives the product of conjugate addition (1 4 addition)... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

FIGURE 18 7 Nucleophilic addition to a p unsaturated aldehydes and ketones may take place either in a 1 2 or 1 4 manner Direct addition (1 2) occurs faster than conjugate addition (1 4) but gives a less stable product The product of 1 4 addition retains the carbon-oxygen double bond which is in general stronger than a carbon-carbon double bond... 

P carbon atom of an a 3 unsatu rated carbonyl compound is elec trophilic nucleophiles especially weakly basic ones yield the prod ucts of conjugate addition to a 3 unsaturated aldehydes and ketones... 

The conjugated stmcture of 1,3-butadiene gives it the abiUty to accept nucleophiles at both ends and distribute charge at both carbon 2 and 4. The initial addition of nucleophiles leads to transition states of TT-ahyl complexes in both anionic and transition-metal polymerizations. 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

The conjugate addition of a nucleophile to an a,fi-unsaturated aldehyde or ketone is caused by the same electronic factors that are responsible for direct addition. The electronegative oxygen atom of the a,/3-unsaturated carbonyl compound withdraws electrons from the /3 carbon, thereby making it electron-poor and more electrophilic than a typical alkene carbon. 

As noted previously, conjugate addition of a nucleophile to the j3 carbon of an cr,/3-unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the a carbon to give the saturated product (Figure 19.16). The net effect is addition of the nucleophile to the C=C bond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no reaction would occur, without the carbonyl group. 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

Step 2 of Figure 29.3 Conjugate Addition of Water The a,(3-unsaturated acyl CoA produced in step 1 reacts with water by a conjugate addition pathway (Section 19.13) to yield a jG-hydroxyacyl CoA in a process catalyzed by enoyl CoA hydratase. Water as nucleophile adds to the 3 carbon of the double bond, yielding an enolate ion intermediate that is protonated on the a position. 

Conjugate addition (Section 19.13) Addition of a nucleophile to the (3 carbon atom of an a./3-unsaturated carbonyl compound. 

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