1,4-addition of Gilman cuprate

In addition, Figures 10.27,10.32 and 10.46 present the current view on (1) the mechanisms of the addition of Grignard reagents to carbonyl compounds, (2) the mechanism of the additions of organolithium compounds to ,/i-unsaturated ketones and (3) the mechanism of the 1,4-addition of Gilman cuprates to ce,/J-unsaturated ketones, respectively. 

So far only little is known about the mechanisms of such 1,4-additions. To start with, it is uncertain whether they only depend on the metal used or on both metal and substrate. At the beginning of the new millennium, however, the prototype of this reaction, i.e., the 1,4-addition of Gilman cuprates to a,fi-unsaturated ketones, could finally be assigned a mechanism after many years of studies and with a proper finish of crystallographic, NMR-spectroscopic, kinetic and quantum-chemical studies (Figure 10.46, see farther below). 

Figure 10.46 shows the current views on the mechanism of the 1,4-addition of Gilman cuprates to cyclohexenone. The numerous details, which have been elucidated or made plausible over the past years, force us to break down the general view of this mechanism into two halves. 

There is a serious limitation with respect to the structure of ketones that are accessible by 1,4-addition of Gilman or Normant cuprates to a,/l-unsaturated ketones. As a... 

Fig. 10.46. Mechanistic possibilities for the 1,4-addition of a Gilman cuprate to an a,/f-unsaturated ketone. Part 1 shows the reaction up to the rate-determining step (F -> G). For the sake of greater clarity the solvation of the lithium atoms is left unconsidered here.

Figure 13.30 shows that even sterically hindered ketone enolates can he alkylated. The carbon atom in the /3-position relative to the carhonyl carhon of an ,/i-dialkylated a,/3-unsatu-rated ketone can be converted into a quaternary C atom via 1,4-addition of an Gilman cuprate (for conceivable mechanisms, see Figure 10.46). As can he seen, a subsequent alkylation allows for the construction of another quaternary C atom in the a-position even though it is immediately adjacent to the quaternary center generated initially in the /1-position.

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. 

Fig. 8.35. Mechanistic possibilities for the 1,4-addition of a Gilman cuprate to an

The copper-catalyzed 1,4-addition of Grignard reagents to enones has been described by Kharasch in 1941, that is, one decade before the discovery of Gilman cuprates (1952) and more than two decades before the first use of organocuprates in conjugate addition reactions. Consequently, numerous variations and applications of the method have been reported over the years.3 5,7 7a 23 Not surprisingly, several of the advances made in the last decade with... 

Preferential 1,2-addition of Gilman s cuprate to a ketone over the usually much more facile 1,4-mode occurs in the case of keto enone (,67) When Goldsmith and Sakano treated (67) with 2 equiv. of Me2CuLi at —78 C and quenched the reaction with acetic anhydride, enone (66) was formed. At higher temperatures Michael addition begins to take place, although the cuprate also generates products of ketone enolization (68) rather than carbon-carbon bond formation (Scheme 10). 

The enoates 17 were obtained in good yield and diastereoselectivity by subjecting the crude hydroformylation products 6 to Horner-Wadsworth-Emmons olefination conditions (HWE). Reaction of enoates 17 with dialkyl Gilman cuprates gave the anti 1,4-addition... 

Many copper-containing organometallic compounds add to a,/3-unsaturated ketones in smooth 1,4-additions (for the term 1,4-addition see Figure 10.31). The most important ones are Gilman cuprates (Figure 10.43, left). For sterically hindered substrates, their rate of addition can be increased by adding Me3SiCI to the reactants. 

Kharasch and Tawney (1941) reported that copper salts catalyze 1,4-addi-tion of Grignard reagents to a,jS-unsaturated ketones. Gilman et al. (1952) first discovered that phenylcopper reacts with benzalacetophenone in a 1,4-addition. Subsequently House and associates (1966) have revealed the scope of the conjugate addition of cuprate complexes. Now alkyl, vinyl, and aryl groups can be introduced specifically at the p position of a,jS-unsaturated carbonyl compounds. Transfer of an allyl group from lithium diallylcuprate to 2-cyclohexenone is also known (House and Fischer, 1969). However, ethynyl, cyano, and hetero groups attached to the copper atom are difficult to transfer to electron-poor olefins. 

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