Conjugate Addition to Carbonyl Compounds

Conjugate addition of organometals and enol ethers to a,fS-unsaturated carbonyl compounds is one of the backbones in organic synthesis. A less common approach is the use of free radicals, which also add to unactivated double bonds. However, the regiocontrol of such additions is best achieved by means of electronically withdrawing groups (such as carbonyls, nitriles, sulfones, and nitro), which direct the radical attack to the fi-position. 

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Since aromatic substitutions, aliphatic substitutions, additions and conjugate additions to carbonyl compounds, cycloadditions, and ring expansion reactions catalyzed by Fe salts have recently been summarized [17], this section will focus on reactions in which iron salts produce a critical activation on unsaturated functional groups provided by the Lewis-acid character of these salts. 

These reactions mainly involve conjugate additions to carbonyl compounds by nucleophiles such as the cyanide ion, CN, and primary or secondary amines, RNH2 or R2NH. Figure 11-31 shows the conjugate addition by the cyanide ion, and Figure 11-32 shows the conjugate addition by a secondary amine. 

The authors of Principles of Asymmetric Synthesis have managed to cover the theme (on ca. 350 pages) in a most condensed and masterly way. In contrast to many a competitor they have chosen well-defined topics (enolate alkylations, direct and conjugate addition to carbonyl compounds with formation of one or... 

Conjugate addition to carbonyl compounds. Complexation to the bulky Lewis acid prevents attack at the carbonyl group, and the addition occurs at the o- or p-positions of aromatic aldehydes and ketones. With relatively bulky nucleophiles, such as s-BuLi and. BuLi, products from addition in the p-position prevail. 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

Conjugate additions to enals and enones.1 In the presence of zinc (or tin) allyl halides undergo 1,2-addition to carbonyl compounds. The reaction is facilitated by sonication and proceeds in highest yield in saturated aqueous ammonium chlo-ride/THF (5.1).1... 

When the donor and the acceptor of the conjugate addition are carbonyl compounds, the amine catalyst may activate both reagents, forming the iminium and enamine intermediates, respectively. The major mechanistic path is dictated by the structure of the substrates and catalyst and, to a lesser extent, by the reaction conditions. 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

Enantioselective Copjugate Additions. The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,p-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine. Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2) ... 

Addition to carbonyl compounds. A useful group transformation is reductive ge/n-dimethylation of a ketone. It can be performed in one step using the MesAl-MesSiOTf combination. In the presence of CuBr, trialkylaiuminums add to conjugated ketones and aldehydes in the 1,4-manner. ... 

An important variant of nucleophilic additions to carbonyl compounds is the conjugate addition of a nucleophile to the / -position of an a,/ -unsaturated carbonyl compound. The enolate so produced is then protonated, producing a / -substituted carbonyl compound as the final product. 

Conjugate addition to a (3 unsat urated carbonyl compounds (Sec tions 18 11 through 18 14) The... 

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... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Ammonia and amines undergo conjugate addition to a 3 unsaturated carbonyl compounds (Section 18 12) On the basis of this information predict the pnncipal organic product of each of the following reactions... 

Conjugate addition (Sections 10.10 and 18.12) Addition reaction in which the reagent adds to the termini of the conjugated system with migration of the double bond synonymous with 1,4 addition. The most common examples include conjugate addition to 1,3-dienes and to a,(3-unsaturated carbonyl compounds. 

H )-Euranones are useful building blocks in the synthesis of a variety of organic compounds. In addition, they often serve as valuable synthetic intermediates in the stereoselective construction of substituted y-butyrolactones via conjugated addition to the Q ,/3-unsaturated carbonyl moiety or catalytic hydrogenation of the double bond (88JOC1560). 

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