Conjugate Addition of Carbon Nucleophiles

Among the olefination reactions, those of phosphonium ylides, phosphonate anions, silylmethyl anions, and sulfone anions are discussed. This chapter also includes a section on conjugate addition of carbon nucleophiles to a, (J-unsaturated carbonyl compounds. The reactions in this chapter are among the most important and general of the carbon-carbon bond-forming reactions. 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

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... 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

Since early investigations about the asymmetric addition of diethyl sodiomalonate to optically active vinylic sulfoxides,100-101 Posner and his coworkers102-117 have developed a highly useful methodology based on the conjugate addition of carbon nucleophiles to homochiral a-arylsulfinyl-a,(J-unsaturated carbonyl compounds. While acyclic derivatives still lead only to moderate results,103 the strength of this method is for cyclic systems. For example, the 2-sulfinyl-2-cycloalkenones (94) and (95), the 2-sulfinyl-2-alkenolides (96) and (97), as well as their respective enantiomers are excellent substrates. All these compounds are quite readily accessible in enantiomeric purities of >98% and are configurationally stable, at least for several months at 0 C. 

F. F. Fleming, Q. Wang, Unsaturated Nitriles Conjugate Additions of Carbon Nucleophiles to a Recalcitrant Class of Acceptors, Chem. Rev. 2003, 103, 2035-2077. 

A. Conjugate Addition of Carbon Nucleophiles Intermolecular Additions... 

These results are analogous to the pioneering work of Posner, who initially developed highly stereoselective conjugate additions of carbon nucleophiles to chiral 2-(arylsulfinyl)-2-cycloalkenones.25 This methodology has been extended to include novel diastereomer differentiating radical (3-additions in which the two... 

Conjugate addition of carbon nucleophiles to unsaturated esters, ketones, nitriles, sulfones and other activated double bonds is known as the Michael reaction. It is a very useful synthetic method for the formation of the carbon-carbon bond. 

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. 

Michael Reaction. It is mainly a base-promoted conjugate addition of carbon nucleophiles (donors) to activated unsaturated systems (acceptors) as given below ... 

A number of highly enantioselective conjugate additions of carbon nucleophiles to a,P-unsaturated substrates mediated by copper Lewis acids have been reported in the past decade. Chiral copper Lewis acids have proven particularly... 

The Michael reaction is the 1,4-conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl or P-electron-poor vinyl compounds and, as such, represents a useful method for the mild formation of C-C bonds. Similarly to aldol reactions. 

The importance of an -OH group at the C6 position for an organocatalytic reaction was noted by Deng and coworkers in a series of studies of C9 ether derivatives of cupreine and cupreidine [34]. Based on the observation that the C9 0-benzyl and O-phenanthryl ether derivatives (10 and 11, respectively. Figure 6.5) gave similar results for the conjugate addition of carbon nucleophiles to nitroalkenes as obtained with 3 (Scheme 6.18) [34], a transition state model was proposed for this reaction. 

The palladium-catalyzed conjugate addition of carbon nucleophiles generated by suitable precursors such as boronic acids can be conducted in an asymmetric fashion as demonstrated by the Stoltz group. In the presence of the oxazoline ligand shown, high enantiomeric excesses were obtained even for the generation of quaternary stereogenic centers (Scheme 5-44). 

Conjugate addition of carbon nucleophiles to electron-poor alkenes is of paramount importance among the enormous community of synthetic processes devoted to carbon-carbon bond formation. In particular, asymmetric Michael additions between a,(S-unsaturated ketone (enone) and 1,3-dicarbonyl compounds allow for access to a variety of optically active adducts affording synthetically useful motifs for the preparation of biologically active natural products and pharmaceutically attractive intermediates (Scheme 9.1). 

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