Acyl anion synthon

Again we need a reagent for an acyl anion synthon (A). We find this in the acetyhde ion since substituted acetylenes can be hydrated to ketones ... 

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

The acyl anion (R-C=0) is not stable as such, but when an aldehyde is converted into a 1,3-dithiane by reaction with propane-1,3-dithiol and then treated with base, it forms an acyl anion equivalent, and hence is susceptible to attack by electrophilic reagents (see Section 5.9). Two extensive compilations of formyl and acyl anion synthons together with references to their reactions... 

The retrosynthetic disconnection for the y-keto acid shown below generates an acyl anion synthon and a three-carbon carbocation. 

A sequence in which a carbonyl group has been masked as a sulfur derivative, alkylated with an electrophile, and then revealed again is a nucleophilic acylation. These nucleophilic equivalents of carbonyl compounds are known as acyl anion equivalents. In the retrosynthetic terms of Chapter 50 they are d1 reagents corresponding to the acyl anion synthon. 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

Acyl anion synthons derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction " However, further reaction with electrophiles is confined to carbonyl compounds and Michael acceptors. 

Jurgens, A.R., Green, K., Ruso, E.R., Jennings, M.N., Blum, D.M., and Feigelson, G.B., Process improved preparation of a versatile a-ketoester acyl anion synthon, Synth. Commun., 24, 1171, 1994. 

T. A. Hase and J. K. Koshimies, A Compilation of References of Formyl and Acyl Anion Synthons , Aldrichimica Acta, 1981,14, 73. 

We have already seen the anion of an alkyne as an acyl anion synthon (Figure 20.6). The a-hydroxyketone is disconnected to a ketone and an acyl anion, for which [HC=C] is the synthon. The final step in the forward reaction is Markovnikov addition of water to the alkyne followed by tautomerization. 

---