Ketones, conjugated => alkyl halides

Thiolates, generated in situ by the action of ammonium tetra-thiomolybdate on alkyl halides, thiocyanates, and disulfides, undergo conjugate addition to a, (1-unsaturatcd esters, nitriles, and ketones in water under neutral conditions (Eq. 10. II).29 Conjugate addition of thiols was also carried out in a hydrophobic ionic liquid [bmim]PF6/water-solvent system (2 1) in the absence of any acid catalyst to afford the corresponding Michael adducts in high to quantitative yields with excellent 1,4-selectivity under mild and neutral conditions (Eq. 10.12). The use of ionic liquids helps to avoid the use of either acid or base catalysts... 

Nitro compounds can be alkylated and are good at conjugate addition (chapter 21) so the products of these reactions can be used to make aldehydes, ketones and amines. A simple synthesis of octanal5 shows that these methods can work very well indeed. Alkylation of nitromethane with bromoheptane gives the nitro-compound 11. Formation of the anion 12 and oxidation with KMnC>4 gives octanal in 89% yield. This chemistry gives us the disconnection to an alkyl halide and a carbonyl anion. The anion 12 is an acyl anion equivalent and we shall need these in the next chapter. 

In general, the zinc promoted condensation of alkyl halides with aliphatic aldehydes and ketones gives only poor results.2 In contrast good results are obtained when one of the reactants is unsaturated. Thus the addition of an allylic group to a carbonyl compound, or the conjugate addition of an alkyl moiety to an activated olefin, occur in excellent yields. Some corrections to this schematic view will be given in the following discussion. 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

This reaction illustrates a stereoselective preparation of (Z)-vinylic cuprates, 5 which are very useful synthetic Intermediates. They react with a variety of electrophiles such as carbon dioxide,5,6 epoxides,5,6 aldehydes,6 allylic halides,7 alkyl halides,7 and acetylenic halides 7 they undergo conjugate addition to a,6-unsaturated esters,5 6 ketones,6 aldehydes,6 and sulfones.8 Finally they add smoothly to activated triple bonds6 such as HCSC-OEt, HC3C-SEt, HC=C-CH(0Et)2. In most cases these cuprates transfer both alkenyl groups. The uses and applications of the carbocupration reaction have been reviewed recently.9 The configurational purity in the final product 1s at least 99.951 Z in the above transformations. 

Lateral metallation at C-2(a) of l-/ftt-butoxycarbonyl-2-methylimidazoline 709 (Scheme 173) with r f-BuLi results in the formation of a bright yellow lithiated intermediate that reacts with alkyl halides, diphenyldiselenide, and phosphoryl chlorides to give 710. In the case of reaction with esters, the conjugated ketones 711 are formed <2000T2061>. In the case of acylation with esters, conjugated enamino-ketones were the tautomer isolated. Further alkylation is also possible under similar conditions, to give 712. 

Conjugate addition of the cuprate to the a,(3-unsaturated ketone leads to an eno-late ion, 143. It is possible to have this enolate anion reacts with an electrophilic species tandem vicinal difunctionalization), in some cases at the O and in other cases at the For example, if an alkyl halide R X is present (R = primary... 

Conjugate reduction of enones with K-Selectride (K[5ec-Bu3BH]) is a valuable method for regiospecifically generating enolate anions. As illustrated below, the enolate species reacts with an alkyl halide to give the corresponding a-alkylated ketone in good yield. 

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