Regioselectivity Houben-Hoesch reaction

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

The metal-template effect is also exploited as a powerful tool to achieve highly selective phenol ort/io-acylation with trichloroacetonitrile according to a typical Houben-Hoesch reaction [111]. The best catalyst is boron chloride, which, by reacting with phenols in 1,2-dichloroethane, produces dichlorophenoxyboron derivatives, the reactive species responsible for the activation of trichloroacetonitrile as well as for the ort/jo-regioselective attack. By using zinc chloride and acetic anhydride without any solvent, an equimolecular mixture of 2- and 4-hydroxyacetophenone (36 and 40% yield, respectively) is produced, excluding any remarkable metal-template effect in the ZnClj-based system. 

The Houben-Hoesch has also been used in reactions with indoles. " As a representative example, dimethoxyindole 20 is reacted with benzylcyanide under acidic conditions to produce the indole 21 which has been acylated at the 7-position. The SnCU-mediated Houben-Hoesch acylation of indole at the 3-position has also been reported to proceed in high yield and with exclusive regioselectivity. ... 

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