Enolate anions conjugate addition

Stable enolates promote conjugate addition by a making the aldol reaction more reversible a making the enolate anion softer... 

In the late nineteenth century, Michael found that the enolate anion (46) derived from diethyl malonate reacts with ethyl acrylate at the P-carbon (as shown in the illustration) to give an enolate anion, 47, as the product. Remember from Chapter 22 (Section 22.7.4) that the a-proton of a 1,3-dicarbonyl compound such as diethyl malonate is rather acidic (pK of about 11), and even a relatively weak base will deprotonate to form the enolate anion. Michael addition of 46 with ethyl acrylate will give enolate anion 47, and aqueous acid workup leads to the isolated product, 48. Attack at the -carbon is possible because that carbon is less hindered than the acyl carbon, so reaction at the C=C unit is somewhat faster than attack at the acyl carbon. Michael addition occurs with relatively stable carbanion nucleophiles, such as malonate derivative 46 and some other common nucleophiles. Other conjugated carbonyl derivatives react similarly. 

Acyl Anion Conjugate Additions. The lithio reagent readily undergoes 1,4-addition to unsaturated substrates (eq 6), in direct contrast to the corresponding 2-lithio-2-trimethylsilyl-l,3-dithiane, which is a poor Michael donor. The initial Michael adducts can also be alkylated to provide highly functionalized products. Very good levels of diastereoselectivity have been observed in the 1,4-addition and enolate alkylations of cyclic enoates (eq 7)2 and acyclic enones (eq 8). ... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

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... 

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. 

Pyridinium p-toluenesulfonylmethylide 91 has been used as a formyl anion equivalent for conjugate addition to N-substituted maleimides to give the enol ethers 92, which were readily deprotected to give the aldehydes 93 (80TL705). 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

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-... 

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 CPop intermediate is the j5-cuprio ketone intermediate widely debated in mechanistic discussions of conjugate addition (cf. Scheme 10.3). On the basis of recent theoretical analysis, two limiting structures for CPop may now be considered these are shown in the bottom box in Scheme 10.5. The reason for the exceptional stability of CPop as a trialkylcopper(III) species can be readily understood in terms of the j5-cuprio(III) enolate structure, with the internal enolate anion acting as a strong stabilizing ligand for the Cu state [82]. 

The racemization process involves removal of the a-hydrogen to form the enolate anion, which is favoured by both the enolate anion resonance plus additional conjugation with the aromatic ring. Since the a-protons in esters are not especially acidic, the additional conjugation is an important contributor to enolate anion formation. The proton may then be restored from either side of the planar system, giving a racemic product. 

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... 

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. 

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

Again, this produces a favourable tertiary carbocation. Loss of a proton gives the required alkene. Note that potentially three different carbons could lose a proton. The reaction shown generates the most stable product this has the maximum number of alkyl substituents and also benefits from extended conjugation. We then get another aldol-type reaction. The enolate anion is produced from the ethyl chloroacetate, and simple addition yields an anion that is subsequently protonated. 

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. 

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

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]. 

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