Lithium organocuprates 1,4-addition

Lithium organocuprates are reagents for cross-coupling, conjugate addition, epoxide opening, ketone synthesis and addition to acetylenes ... 

In this concluding section, we will recall that a-selanylvinylmetal derivatives can be produced by a-deprotonation of vinylic aryl selenides 11, cleavage of ketene selenoacetals 12 or bromine/lithium exchange of a-bromovinyl selenides 13 (Scheme 49). These strategies involve vinylic selenides whose syntheses are not simple. More recent works have used organocuprate additions, hydrometala-tions (M = Sn, Zr) or hydroborations of readily available acetylenic selenides 14 (Scheme 49). The process can be regio- and stereocontrolled and produce the a-selanylvinylmetal derivatives under mild conditions. The latter can be considered as vinyl dianion equivalents and are very useful intermediates for cross-coupling reactions. 

Solvent effects on chemoselectivity. Use of donor solvents (THF or HMPT) enhances the rate of displacement reactions of lithium organocuprates with alkyl halides, but retards conjugate addition to enones. House and Lee have examined the effect of solvents on the reaction of (CH3)2CuLi with the bromo enone 1. Reaction of 1 with the cuprate in ether-(CH3)2S gives the product of... 

Most of the organocuprate -addition-a-alkylations of cyclopent-l-enones and cyclohex-2-enones have involved introduction of the nucleophilic -substituent and the electrophilic a-substituent preferentially in a trans-configuration. In contrast lithium diphenylcuprate addition to cyclopent-2-enone followed by a-alkylation involves attachment of the two new groups stereoselectively in a cis-relationship, even though such c/s-2-alkyl-3-phenylcyclopentanones are less stable than their trans-epimers [equation (14)]. ... 

The most widely used reagents, however, which have been developed during the past 20 years, are the lithium organocuprates, R CuLi. They are prepared in situ, in ether or THF, by addition of two mol of alkyllithium to copper(I) halide below 0°C under a nitrogen atmosphere. It is convenient to use Me S.CuBr as this is more resistant to oxidation in air than CuBr and can thus be introduced without contamination by copper(II). 

It has also been shown that reduction of the ethylenic bond in enones may occur via copper hydride derivatives formed by thermal decomposition of the lithium organocuprate. This can pose a problem since such decomposition occurs above 243 K in the temperature region where many cuprates are only beginning to react at appreciable rates with the substrate. However, addition of excess n-butyl-lithium appears to eliminate this complication. 

The conjugate addition of Grignard reagents to a-phenyl-a/8-unsaturaled esters has been reported. The first example of a conjugate 1,6-addition of a lithium organocuprate to an unsaturated ester has been observed (Scheme 44) in a synthesis of a volatile constituent of Bartlett pears. 

Our current mechanistic imderstanding of copper(l)-catalysed 1,4-ACA is derived from the cumulative experimental data obtained from the studies carried out with the stoichiometric (uncatalysed) addition of lithium organocuprates [104, 105]. This approach is based on the assumption that each catalytic event in copper(l)-catalysed reactions can be considered as a single addition reactimi of an... 

The Cu-catalyzed conjugate addition of organomanganese reagents to a,/3-ethyle-nic aldehydes gives similar results than those obtained via lithium organocuprates in the presence of trimethylchlorosilane (Scheme 13.41) [36]. However, the reaction is easier to carry out since the aldehyde is obtained in one step instead of the two steps required with an organocuprate. It is important since the partial aldoli-... 

The stereoselective 1,4-addition of lithium diorganocuprates (R2CuLi) to unsaturated carbonyl acceptors is a valuable synthetic tool for creating a new C—C bond.181 As early as in 1972, House and Umen noted that the reactivity of diorganocuprates directly correlates with the reduction potentials of a series of a,/ -unsaturated carbonyl compounds.182 Moreover, the ESR detection of 9-fluorenone anion radical in the reaction with Me2CuLi, coupled with the observation of pinacols as byproducts in equation (40) provides the experimental evidence for an electron-transfer mechanism of the reaction between carbonyl acceptors and organocuprates.183... 

Addition of RJCuLi to bridgehead enones.1 Ordinarily organocuprates do not react with a bridgehead halide. However, they can undergo conjugate addition to bridgehead enones generated in situ from p-bromo ketones with potassium t-butoxide or lithium 2,6-di-r-butyl-4-methylphenoxide (6,95). 

It was already noted that activated enynes bearing an acceptor substituent at the double bond react with organocuprates under 1,6-addition to provide functionalized allenes (see Section III.A)38. Interestingly, the preference of these reagents for triple bonds persists even when the distance between the acceptor group and the triple bond is increased by the introduction of further double bonds. For example, lithium dimethylcuprate attacked ethyl 8,8-dimethyl-2,4-nonadien-6-ynoate at the triple bond exclusively, and regioselective... 

The addition of organocuprates to chiral decalin enone systems has been explored in the context of steroid synthesis. For the addition of lithium dimethylcuprate to enones 28, 31, and 34, the major diastereomer obtained can easily be predicted by employment of a qualitative conformational analysis (Scheme 6.6) [11-13]. Thus,... 

INT2, Scheme 10.7) undergoes further reaction (Li/Cu transmetalation) and generates a new organocuprate compound. (Note however that this difference could become more subtle since the product of conjugate addition (PD) might behave more like an a-cuprio(I) ketone complexed with a lithium cation [52] than a lithium enolate complexed with copper(I)). In neither reaction was any evidence of radical intermediates (i.e., SET) found by theoretical calculations [79]. 

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