Lithium amides conjugate addition reactions

Conjugate Addition Reactions. - Two protocols for achieving the enantioselective conjugate addition of an alkyl group to an enone using a cuprate containing a chiral ligand have been reported. In one case the lithium amide (28) was used to prepare an amidocuprate... 

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). 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

Methylbenzoic acid 513 can be laterally lithiated with two equivalents of lithium amide base (LDA" or L1TMP °) or alkyllithium provided the temperature is kept low to avoid addition to the carbonyl group (Scheme 201). It is usually preferable to carry out the lithiation using aUcyllithiums", since with lithium amides the subsequent reaction of 514 with electrophiles is disrupted by the presence of the amine by-product (diisopropylamine, for example) . The dilithio species 514 is stable in THF even at room temperature, and (as with the amide 483) since LDA will also dilithiate 515 stabilization presumably comes principally from conjugation with the carboxylate. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on ,/i-unsaluralcd esters. Michael adducts were obtained in up to 76% ee by combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent in which the reaction was conducted.224... 

The ability of lithium amides to add on enoates to provide lithium enolates has been known for some while161. This reaction has found many useful synthetic applications, one of the most spectacular being the tandem, stereocontrolled, conjugate additions (Scheme 38)162. 

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). ... 

This more dramatic reaction starts with the simple conjugate addition of the Davies chiral version of LDA 89 to unsaturated esters first given in chapter 24. The lithium amide gives the Z-enolate of the product 90 and hence the adduct 91. The transition state 92 gives the correct stereochemistry.15... 

Another auxiliary that became well known in enolate chemistry is chiral acyl iron complexes for alkylation, aldol reactions, and conjugate additions indeed, so-called Davies-Liebeskind enolates [60] can be generated either by deprotonation of alkanoyl complexes 124a or conjugate addition of strong nucleophiles like alkyllithium compounds or lithium amides to alkenoyl complexes 127. 

Neurokinin-1 receptor antagonists such as 120 (Scheme 2.19) have been identified as potential antiinflammatory agents by researchers at Merck Research Laboratories. To access the tra 5-3,4-disubstituted 8-lactone 119, a key intermediate in the synthesis of 120, an asymmetric conjugate addition strategy was developed. As depicted in Scheme 2.19, reaction of the lithium enolate derived from the amide 115 with enoate 116 afforded... 

The reaction of a silylacetate derivative with an aldehyde or ketone was initially studied by Rathke and Yamamoto. Rathke and coworicers studied the addition of the lithium anion of r-butyl (trimethylsi-lyl)acetate (340) with a variety of aldehydes and ketones (equation 78). The anion can be formed directly from the silyl compound on treatment with LDA. The reaction proceeded to give the conjugated alkenes in excellent yields. Unsaturated compounds reacted via 1,2-addition. No discussion of alkene geometry was present. In the Yamamoto work, the ethyl (trimethylsilyl)acetate derivative (342) was used in a variety of reactions with aldehydes and ketones (equation 79). The anion was formed wiA dicyclohexyl-amide in THF. It was stated in the experimental section that the ( ) (Z) ratios of alkenes were dependent on the reaction conditions. In all the examples presented in this work, the ( )-isomer was predominantly formed. 

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