Conjugate addition with tandem alkylation

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

Tandem conjugate addition-alkylation has proven to be an efficient means of introducing groups at both a- and (3-positions at enones.307 As with simple conjugate addition, organocopper reagents are particularly important in this application, and they are discussed further in Section 8.1.2.3. 

When the conjugate addition is carried out under kinetic conditions with stoichiometric formation of the enolate, the adduct is also an enolate until the reaction mixture is quenched with a proton source. It should therefore be possible to effect a second reaction of the enolate if an electrophile is added prior to protonation of the enolate. This can be done by adding an alkyl halide to the solution of the adduct enolate, which results in an alkylation. Two or more successive reactions conducted in this way are referred to as tandem reactions. 

Prior to protonolysis, the products of conjugate addition to unsaturated carbonyl compounds are enolates and, therefore, potential nucleophiles. A useful extension of the conjugate addition method is to combine it with an alkylation step that adds a substituent at the a position.52 Several examples of this tandem conjugate addition/alkylation procedure are given in Scheme 8.2. 

Further transformations of the intermediate alkenyloxydialkylboranes (46), as shown in Scheme 10, include aqueous hydrolysis to the homologated aldehydes or ketones 30 electrophilic additions to afford the corresponding a-dialkylaminomethyl aldehydes and ketones (47),31 and a-halogenated (48)32 or a-arylselenylated aldehydes or ketones (49) 33 transmetallation-alkylation to afford a-substituted aldehydes or ketones (50) 34 and aldol condensations with aldehydes (51).35 These reagents offer the equivalent of the tandem 1,4-conjugate addition-electrophile-trapping protocol. A prototypical prosta-... 

Enoate 3-substitution and 3-disubstitution cause a decrease in the rate of the initial conjugate addition step of the reaction sequence that is directly related to the steric bulk of the substituent.103,105 Equation (24) provides a representative case in the a-alkylation of enoates by means of conjugate amination-enol-ate alkylation followed by dehydroamination.106 When 3-substitution results in stereoisomeric ( )- and (Z)-alkenoate substrates, tandem difunctionalization typically proceeds with greater facility for ( )-isomers.64103 Obviously, when the double bond of the ester is part of a medium-sized ring, an ( )-alke-noate geometry is mandated in such cases, tandem vicinal difunctionalization proceeds with uniformly excellent results (equation 25).25... 

Among the most important of these tandem conjugate addition-alkylation reactions are those of cyclopentenones. With cyclopentenone itself, the trans diastereoisomer usually results because the alkylating agent approaches from the less hindered face of the enolate. 

It is not even necessary to have a stereogenic centre in an unsaturated ring if we want to create stereochemistry. A tandem conjugate addition and alkylation creates two new stereogenic centres in one operation. The conjugate addition of a lithium cuprate makes a lithium enolate, which will react 11] [ u with an alkyl halide. The product is usually h tins. 

Conjugate addition of the cuprate to the a,(3-unsaturated ketone leads to an eno-late ion, 143. It is possible to have this enolate anion reacts with an electrophilic species tandem vicinal difunctionalization), in some cases at the O and in other cases at the For example, if an alkyl halide R X is present (R = primary... 

Initiated by conjugate addition of iodide ion, which is under stereocontrol by the chiral auxiliary of an iV-alkenyl-2-oxazolidinone, a tandem intramolecular alkylation is also enan-tioselective. Based on this reasoning it is possible to prepare cyclic compounds with new stereocenters of defined absolute configuration. ... 

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