Acyl anion equivalents, reactions with carbonyls

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. 

The carbanion derived from diethyl l-(trimethylsiloxy)-l-phenylmethanephosphonate 291 served as an acyl anion equivalent. Its reaction with carbonyl compounds afforded the silylated benzoin derivatives 292 (equation 182)443. This reaction was useful for the synthesis of 2-phenylbenzo[h]furans without laborious isolation of the intermediate benzoin. 

Difluoro-l-(tosyloxy)vinyllithium 586 has been employed as an acyl anion equivalent of the type 587. This anion was prepared by treatment of 2,2,2-trifluoroethyl tosylate with two equiv of LDA at —78 °C860 (Scheme 159). The reaction of intermediate 586 with carbonyl compounds, followed by acid hydrolysis, gave compounds 588 which, after basic treatment with sodium hydroxide, afforded ct-keto acids 589. The reaction of the intermediate 586 with boranes provided the corresponding borates, which have been used in the synthesis of fluorinated molecules861. 

In 1,2-alkylative carbonyl transpositions where the carbonyl group moves forward into the newly added fragement, e. g. 63 - 64, the reagent behaves as an acyl anion equivalent. We have seen one example of this in the synthesis of the occidentalol intermediate 8. Phosphine oxides with OR or SR substituents on the a-carbon 65 are ideal reagents for this process as the Horner-Wittig reaction gives vinyl compounds which can be hydrolysed to 64. 

The yields in these reactions are not wonderful and most syntheses planned with acyl anion or d1 synthons are realised with one of the reagents we are about to describe rather than with acyl-lithiums. Things may change as understanding of these rather reactive intermediates develops. There are three main types of acyl anion equivalent reagents which can be considered as modified acetals, that is protected aldehydes, masked carbonyl compounds such a nitroalkanes, and substituted vinyl-lithiums. The rest of this chapter will be devoted to these reagents. 

Lithium salts of r-butylhydrazones of aldehydes have been shown to be useful acyl anion equivalents.73 Treatment of an aldehyde r-butylhydrazone with an alkyllithium reagent or LDA gives the am-bident nucleophile (95), which reacts with both aldehydes and ketones to give carbon-substituted products as shown in equation (35). The condensation works best with nonenolizable carbonyl derivatives. Extension of this chemistry to the reaction of (95) with a,(3-unsaturated carbonyl compounds met with mixed success. While good yields of Michael products were seen in the addition of (95) to methyl crotonate, other a,(3-unsaturated electrophiles such as methyl acrylate, acrylonitrile and methyl P,(3-di-methylacrylate gave negligible yields of carbon-substituted products. 

The six-membered ring must therefore be disconnected first. The a,18-disconnection gives triketone (43) with all 1,4-reIationships, and the best strategy here is to use an acyl anion equivalent for the central carbonyl group and disconnect by two Michael reactions. 

Aliphatic nitro compounds serve as good acyl anion equivalents. After electrophilic alkylation at the a-carbon atom, they can be converted into carbonyl compounds by the Nef reaction or by reductive hydrolysis with titanium(III) chloride. The a-nitro carbanions serve as excellent donors in Michael addition reactions with a, -unsaturated systems and therefore the sequence of Michael addition followed by reductive hydrolysis of the nitro group provides a good route to 1,4-dicarbonyl compounds. ds-Jasmone, for example, was readily obtained by using this strategy (1.111). 

Homologation of aldehydes can be achieved by reaction of the anion (26) with the aldehyde, metallating with BuLi, and hydrolysing the intermediate thus obtained. " The alkenyl-lithiums (27) and (28) provide routes to functionalized carbonyl compounds, both cyclic and acyclic, on reaction with a variety of conventional electrophiles. By employing bulky substituents at the carbonyl group of the enones (29a and b), a -activity is enforced. Lithium amides may be carbonylated to give the corresponding carbamoyl-lithiums (30), which are useful acyl anion equivalents. ... 

An interesting 3-carbon ring-expansion reaction utilizing the allyl silane (87) has been used to convert the cyclic ketone (88) into muscone (89) in high yield. In its reaction with carbonyl compounds, the trimethylsilylallyl anion acts as a j8-acyl anion equivalent, enabling the preparation of y-lactones (90). ... 

Trimethylsilyl)vinylketene (95) is stable and a reactive enophile in [4 + 2]cycloadditions. Trimethylsilylallenes have been used (Scheme 18) in the stereoselective synthesis of rra/t5-a,/3-unsaturated carbonyl compounds they have also been used to prepare the acetylenes (96) and (97) from ethylenic acylcyanides and carbonyl compounds/ respectively. In the presence of KF-18-crown-6, benzoyl trimethylsilanes (PhCOSiMea) behave as acyl anion equivalents in their reaction with organic halides to give ketones, ... 

---