Enones conjugate addition-enolate alkylation

Use of TMSCl in combination with HMPA, DMAP, or TMEDA all favored 1,2-addition over 1,4-addition. Sequential a-alkoxyalkylcuprate conjugate addition, enolate trapping with TMSCl, and silyl enol ether alkylation provides a one-pot synthesis of tetrahydrofurans (Scheme 3.35) [129]. Cyclic enones afford as-fused tetrahydrofurans, while acyclic systems give complex mixtures of diastereomers. a-Alkoxyalkylcopper reagents also participate in allylic substitution reactions with ammonium salts [127]. 

Alcoholysis of epoxides. FeCl.i is an effective catalyst for the transformation. Oxidative cleavage of trimethylsiloxycyclopropanes. This method of enone generation, in combination with conjugate addition, enolate trapping, and Simmons-Smith reaction, complete the sequence of ring expansion that also incorporates a substituent at the y-position of a lower homolog. Thus 4-alkyl-2-cyclohexenones are readily prepared from cyclopentenone. 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

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... 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

Where possible, it may be most economical to effect a chiral transformation on a pre-formed, pro-chiral ring. Ben Feringa of the University of Groningen prepared (Chem Commun. 2005, 1711) the enone 2 from 4-methoxypyridine 1. Cu -catalyzed conjugate addition of dialkyl zincs to 2 proceeded in up 96% . Pd-mediated allylation of the intermediate zinc enolate led to 3, with the two alkyl subsituents exclusively trans to each other. 

The addition of lithium alkoxydienolates to a,P-enones occurs exclusively in the l,4(a)-mode. For example, alkoxydienolate (202), obtained from ethyl senecioate, adds efficiently, in a tandem conjugate addition-allylation protocol, to cyclopentenone to afford the a,(3-functionalized cyclopentanone (203),153 In contrast, the lithium dienolate (204), from 5-methylbutenolide, affords exclusive y-alkylation,154 b while the analogous phthalide enolates (206) can be exploited to accomplish regiospecific polynuclear aromatic syntheses (Scheme 76).l54c ... 

Conjugate addition of organocuprates to enones followed by selenenylation of the resultant enolates and oxidation provides a valuable method for P-alkylation with enone restoration, although with double bond rearrangement in the example below. 

A useful technique to accomplish overall vicinal dialkylation of enones is to trap the enolate initially formed in the conjugate addition with TMS-Cl, and then regenerate the enolate under suitable conditions for its alkylation. Lithium 1-enolates of 3,5-dialkylcyclohexanones generated from the reaction of the corresponding TMS enol ethers with lithium amide in liquid ammonia-THF can be alkylated efficiently in liquid ammonia-THF, even with an unreactive alkylating agent such as n-butyl iodide (Scheme 10). ... 

An interesting observation from organocuprate chemistry is that the initial step in 1,4-addition to enones may be electron transfer. Thus the relative reactivity of enones toward conjugate addition parallels their ease of reduction. One problem with any reaction between a ketone or aldehyde and a metal alkyl is deprotonation, when a hydrogens are present, to yield an enolate. Given the considerable basicity of metal alkyls, this side reaction should be anticipated. 

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