Stabilized carbanions Michael reaction

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Michael addition of stabilized carbanions to unsaturated ketones or esters is a useful C—C bond forming reaction. As shown in Scheme 103, 5 mol % potassium ferf-butoxide complexed with a chiral crown... 

A variety of cyclopropyl derivatives has been prepared utilizing this methodology from malonic ester anion or related stabilized carbanions and Michael acceptors such as 56,57310 and 58311. The reactions are nonstereospecific in general as expected from the mechanism... 

Many carbanionic nucleophiles that would be considered too hard to react as Michael donors can be made into effective reagents for conjugate addition reactions by appending resonance or inductively stabilizing groups to soften their intrinsic Lewis basicity. Such stabilized anionic Michael donors include enolates, alkylthio-substituted carbanions, ylides and nitro-substituted carbanions. 

The stability of an a-silyl carbanion is responsible for the unproved synthetic utility of the Stork annulation over other annulations195,196. These reactions involve the Michael addition of an enolate ion to an enone, and in the absence of a a-silyl substituent suffer drawbacks due to the reversibility of the Michael reaction. However, the addition of enolate ions to a-trimethylsilylvinyl ketones is not reversible, owing to a-silicon stabilization of the canonical form 152 shown in equation 122. 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

The conjugate addition of nucleophiles to a,/3-unsaturated carbonyl compounds at the /3-position was described in Section 18.10. Enolate and related carbanion nucleophiles also add in a conjugate manner to a./Tunsaturated carbonyl compounds in a process known as the Michael reaction or Michael addition. In many of the examples the enolate ion is one that is stabilized by two carbonyl (or similar) groups. The ,/3-unsatura(cd compound is called the Michael acceptor. 

An interesting sequence based on an intermolecular Michael addition and a subsequent transition metal-catalyzed carbocyclization was recently explored. Much of the development of this strategy relies on recent studies related to the intramolecular carbometalation reaction of stabilized carbanions bearing an unactivated alkynyl group. Several transition metal complexes such as Cu [52], Pd [53], Ti [54], Zn [55], Co [56] and Sn [57] have been reported to catalyze this reaction (Scheme 17). 

Milder reaction conditions have been developed for the HWE reaction of phosphonate-stabilized carbanions to increase yields, accommodate sensitive substrates and to minimize undesired side reactions such as double bond migrations, the Cannizzaro reaction, Knoevenagel condensation and Michael addition. For example, a number of different bases have been employed to generate the carbanion. These include sodium hydroxide under phase-transfer conditions, potassium carbonate, barium hydroxide, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene (see Protocol 10).22... 

In a second part, the reactivity of a-phenylselanyl enolates, derived from ketones, esters, lactones and a,/i-unsatm ated carbonyl compounds, is discussed. Alkylation, aldolisation and Michael reactions are considered as the use of selenium-stabilized carbanions in the natural product synthesis. Others a-fimctionalyzed species are also presented. 

It seems appropriate to inquire whether or not it is possible to carry out other Michael reactions and, generally, other nucleophilic additions to unsaturated compounds as a sequence of kinetically independent steps using one s choice of nucleophiles and electrophiles The answer is definitely yes . A rationale similar to that used to describe the Robinson annulation provides us with the key to how this goal may be attained. First of all, the initial step of the reaction, addition of the nucleophilic component across a double (or triple) bond, needs to be carried out in the absence of the external electrophiles (preferably in aprotic solvents). Secondly, a carbanionic intermediate, incipiently formed at this step, requires sufficient stabilization to survive as a chemical entity under... 

Michael reaction (Section 24.8) A reaction in which a resonance-stabilized carbanion (usually an enolate) adds to the P carbon of an a,p-unsaturated carbonyl compound. 

Immobilization of chiral ligands to effect asymmetric induction in alkylation of aromatic aldehydes by diorganozinc reagents promoted by PEG-im-mobilized ligands 54-57 can also be promoted by soluble polystyrene-bound species. A recent example of this is work where a polystyrene-bound BINOL was prepared [ 105]. This polymer 69 was used to form titanium-BINOLate and AlLibis(binaphthoxide) catalysts for Et2Zn reaction with benzaldehyde and for asymmetric Michael additions of stabilized carbanions to cyclohexenone. While good stereoselectivities were obtained with these catalysts, the synthetic yields were modest. 

We know how stabilized carbanions such as enols and enolated enamines are key intermediates in biological isomerization reactions and in carbon-carbon bond-forming and bond-breaking events. In this chapter, we will look at two more important reaction types, called Michael additions and -eliminations, which involve stabilized carbanion species as intermediates. In a Michael addition, a nucleophile and a proton are added to the two carbons of an alkene that is conjugated to a carbonyl group. The reverse of a Michael addition is called a -elimination. 

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