Addition, conjugate of enolate anions

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

The conjugate addition of enolate anions onto a,P-unsaturated systems is an important synthetic reaction, and is termed the Michael reaction, though this terminology may often be used in the broader... 

Michael reaction conjugate addition of enolate anion onto unsaturated carbonyl... 

Conjugate addition of enolate anion to a, b-unsaturated carbonyl compounds is known as Michael addition. 

Michael Reaction—Conjugate Addition of Enolate Anions... 

The conjugate addition of enolate anions to activated 3-trimethylsilyl-3-buten-2-one helped solve another long-standing problem in organic synthesis by permitting the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration is avoided. The annulation of thermodynamically unstable lithium enolates with MVK, where equilibration to the more stable enolate occurs prior to Michael addition, often yields a mixture of stractmal isomers. For exan le, Boeckman successfully employed 3-trimethylsilyl-3-buten-2-one in a Robinson annulation sequence (eq 2). Thus treatment of cyclohexenone with lithium dimethylcuprate in diethyl ether and then with 3-trimethylsilyl-3-buten-2-one gives the desired Michael adduct, which is converted into the functionalized octalone in 52% overall yield. ... 

In contrast to the reaction of an enolate anion with an alkyl halide, which requires one equivalent of base, conjugate addition of enolates can be carried out with a catalytic amount of base. All the steps are reversible. 

The succinct synthesis of warfarin starts with condensation of ort/zo-hydroxy-acetophenone (1-2) with ethyl carbonate to give the (3-ketoester (1-3) as the presumed intermediate shown in the enol form. Attack of the phenoxide on the ester grouping will lead to cyclization and the formation of the coumarin (1-4). Conjugate addition of the anion from that product to methyl styryl ketone (1-5) gives the corresponding Michael adduct and thus warfarin (1-6) [1]. 

In Magnus studies of jff-azidonation of triisopropylsilyl (TIPS) enol ethers, it was found that addition of TEMPO had a profound effect on the reaction pathway [82]. When TIPS protected enol ether 49 was allowed to react with PhIO and TMSN3 in the absence of TEMPO, compound 51 was obtained as the major product however, in the presence of catalytic TEMPO, compound 53 was obtained (Scheme 27). The formation of product 51 is postulated to occur via conjugate addition of azide anion to an enonium cation intermediate 50, whereas compound 53 is proposed to form via the formation of azide radical, which adds to the silyl enol ether double bond to form intermediate 52. 

This epoxidation proceeds by conjugate addition of hydroperoxide anion followed by cyclisation of the resulting enolate in similar fashion to the Wietz-Scheffer process. It is proposed that the polyamino acid, present as an a—helix, forms a simple active site near the N-terminus within which the epoxidation occurs, and that catalysis arises from stabilisation of the intermediate enolate by interaction with an oxy-anion hole formed within this active site. 

A conjugated addition of this anion to die unsatm-ated ester leads to an ester enolate. 

A conjugate addition of this anion on the unsaturated ester gives an ester enolate. 

Jones and colleagues have prepared 1,4-dicarbonyl compounds by conjugate additions of enolate and related anions to a,P-unsaturated sulfoxides [80,81]. For example, the lithium enolate of acetone dimethylhydrazone (83), in the presence of dimethyl sulfide-copper(I) bromide complex, underwent conjugate addition to 2-phenylsulfinyloct-l-ene (82). Quenching the reaction mixture with dimethyl disulfide gave the doubly protected 1,4-diketone derivative (84), which, on sequential hydrolysis with copper(II) acetate and trifluoroacetic acid gave the dodecane-2,5-dione (85) as the product in 54% yield from (82) (Scheme 5.27). Other examples of the addition of enolate-type species to a,p-unsaturated sulfoxides have also been reported [82.83]. 

Nucleophilic addition of enolate anions to o , 8-unsaturated carbonyl compounds was first reported in 1887 by the American chemist Arthur Michael. Following are two examples of Michael reactions. In the first example, the nucleophile adding to the conjugated system is the enolate anion of diethyl malonate. In the second example, the nucleophile is the enolate anion of ethyl acetoacetate. 

Cinchona alkaloids or their derivatives. Mechanistically, Cinchona alkaloids deprotonate an acidic proton affording a contact ion pair hetween the anion and protonated amine, resulting in a chiral environment around the anion. A typical example which could potentially he applied to drug discovery is the asymmetric conjugate addition of enolate 325 to nitroalkene 326, catalysed hy Cinchona alkaloid 328, as descrihed hy Li et al. (Scheme 14.99). ... 

Robinson annulation (Section 18.13) A combination of conjugate addition of an enolate anion to an a,p-unsaturated ketone with subsequent intramolecular aldol condensation. 

Posner recently reported a very simple and fast way to activate epoxides towards nucleophilic opening by ketone lithium enolate anions by use of BF3 Et20 (1 equiv.) [73]. The application of this procedure to the nucleophilic opening of propene oxide with the lithium enolate of 2-cycloheptanone, obtained by the conjugate addition of trimethylstannyllithium to 2-cycloheptenone, afforded the stan-... 

The reaction is considered as a combination of a Michael reaction, the conjugate addition of an enolate anion on to an unsaturated carbonyl compound, plus an aldol reaction followed by elimination of water. 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

The reaction is conjugate addition of the thiolate anion 2 to the enone 7 making an enolate intermediate that captures a proton from PhSH 8 to give the target molecule 4 and regenerate the nucleophile 2. 

After conjugate addition of the hydroperoxide anion to the chelated a,p-unsaturated lactone, the resulting enolate counterattacks the proximal [3-hydroperoxide group to form an epoxide. The latter then ring-expands to create another enolate, which captures a proton from water. The product hemiacetal finally undergoes ring-opening and saponification to produce 9 (Scheme 6.5). 

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