Knochel cuprate

Electrophiles, which lead to high yields, are methyl iodide, trialkyltin- and trialkylsUyl chlorides, diphenylphosphinyl chloride, acid chlorides, aldehydes and carbon dioxide. Remarkably, though highly acidic ketones are formed on acylation, no deprotonation or racemization by excess of carbanionic species occurs. Other alkyl halides than methyl iodide react very sluggishly with low yields. Benzylic and aUylic halides lead to partial racemization, presumably due to single-electron transfer (SET) in the alkylation step. As very recently found by Papillon and Taylor, racemization of 42 can be suppressed by copper-zinc-lithium exchange before alkylation to 43 via the Knochel cuprates (equation 7) °. 

The Knochel cuprates are able to tolerate a large variety of other functional groups imbedded in R . 

Alkyl zinc iodides RFG—Zn—I are poor nucleophiles. However, they are turned into good nucleophiles when they are converted into the so-called Knochel cuprates RFG— Cu(CN)ZnHal with solubilized CuCN—that is, CuCN containing LiHal. In the presence of a Lewis acid Knochel cuprates add to aldehydes, provided these are a,/f-unsaturated. With substituted oc,/3-unsaturated aldehydes a 1,2-addition can be observed, as shown in Figure 10.38. With acrolein (an unsubstituted f/./l-u nsaturated aldehyde) or a,/J-unsaturated ketones (Fig. 10.43), however, Knochel cuprates undergo 1,4-additions. 

Zinc-containing C nucleophiles, which tolerate the presence of diverse functional groups, are not limited to the cited Knochel cuprates obtained from alkyl iodides. The other zinc-based C nucleophiles, which can contain a comparably broad spectrum of functional groups, are dialkylzinc compounds. They are best prepared from terminal alkenes. Figure 10.39 shows in the first two reactions how this is done. 

Knochel cuprates likewise add to tt,/i-unsaturated ketones with 1,4 selectivity, but only in the presence of Me3SiCl or BF3-OEt2 (Figure 10.43, right). Under the same conditions, how-... 

Alkyl zinc iodides RFG—Zn—I are poor nucleophiles. However, they are turned into good nucleophiles when they are converted into the so-called Knochel cuprates Rfg—Cu(CN)ZnHal with solubilized CuCN—that is, CuCN containing LiHal. Knochel cuprates add to aldehydes in the presence of Lewis acid, as shown in Figure 8.29. 

The further transformations of the enolate C start with a reductive elimination (additional examples of this type of reaction can be found in Chapter 13), which gives the enolate D. This compound is not a normal lithium enolate because it is associated with one equivalent of CuR. The CuR-containing enolate D remains inert until the aqueous workup. As you can see from Figure 8.35, 50% of the groups R contained in the Gilman cuprate are lost through formation of the stoichiometric by-product CuR. This disadvantage does not occur in the 1,4-additions of Normant and Knochel cuprates. 

Although infrequently encountered in an industrial setting, cuprates and acid chlorides react to afford ketones. Scheme 11.68 depicts the late-stage diversification of a cephalosporin template via euprate acylation. Overall yields were low, but acylation was achieved in the presence of a p-lactam, acetate ester, a-chloro carbonyl, alkylsulfone, and an activated olefin. Modern methods such as the Knochel cuprate might afford the products in higher yields. 

Technically L.O., the Knochel cuprate is economical and conveniently prepared. It is, however, less reactive than a comparable Gilman-type cuprate. 

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