Conjugate addition reactions carbon nucleophiles

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 previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

The fluoride ion is an effective catalyst for conjugate additions involving relatively acidic carbon nucleophiles.292 The reactions can be done in the presence of excess... 

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. The pK of HCN is 9.3, so addition in hydroxylic solvents is feasible. An alcoholic solution of potassium or sodium cyanide is suitable for simple compounds. 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

Fig. 6.7 Carbon nucleophiles for Deng s asymmetric conjugate addition reactions.

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. 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

Sections 1.1.1 and 1.1.2 described the formation of enolates, silyl enol ethers and enamines and their alkylation or conjugate addition reactions. Reaction of these carbon nucleophiles with aldehydes is known generally as the aldol reaction and... 

In 2012, Alexakis and co orkers disclosed the first stereoselective annulation reaction between ynals and a-cyano-l,4-diketones which is mediated by a catalytic amount of a triazolium salt precatalyst and a weak carboxylate base. This transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon, and affords privileged bicyclic scaffolds in 61-90% yields with up to 20 1 diastereomeric preference. A mechanistic rationalization for the NHC-catalyzed annulation of a-cyano-l,4-diketones with ynals is proposed as the following. Initially, the free carbene condenses with a molecule of ynal to form the key d,p-unsaturated acylazolium intermediate followed by a direct nucleophilic conjugate addition of 1,4-diketone. Subsequent intramolecular H-migration and an irreversible lactonization furnish the observed bicyclic product and liberate free carbene for the next catalytic cycle (Scheme 7.98). 

The first report of asymmetric heteroatom conjugate addition to a,P-unsaturated sulfoxides was made in 1971 [11,12], and has been followed by few studies in this area relative to the analogous asymmetric reactions with carbon nucleophiles. The addition of piperidine in methanol to (-)-(S)-cis-propenyl p-tolyl sulfoxide (133)... 

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