The Hoesch reaction

The Hoesch Reaction is employed for the introduction of the - COR group into the aromatic ring of phenol or a phenolic ether, and usually proceeds particularly readily with polyhydric phenols. If an ethereal solution of resorcinol (I)... 

By the condensation of a nitrile with a phenol or phenol ether in the presence of zinc chloride and hydrogen chloride a hydroxyaryl- or alkoxyaryl-ketone is produced. The procedure is termed the Hoesch reaction and is clearly an extension of the Gattermann aldehyde reaction (Section IV,121). The reaction gives the best results with polyhydric phenols and their ethers with simple monohydric phenols the imino ester hydrochloride is frequently the sole product for example ... 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles ... 

Acylation with Nitriles. The Hoesch Reaction Acylation or Acyl-de-hydrogenation... 

Crystalline derivatives of aliphatic nitriles may be prepared by an application of the Hoesch reaction. Equimolecular proportions of phloroglucinol and the nitrile react in dry ethereal solution in the presence of anhydrous zinc chloride and hydrogen chloride to give an imine hydrochloride, which is converted into a solid alkyl trihydroxyphenyl ketone by hydrolysis. The alkyl 2,4,6-trihydroxy-phenyl ketones are usually highly crystalline solids of sharp melting point and are purified by recrystallisation from hot water. Many contain water of crystallisation which can be removed by drying in vacuo at about 100 °C the melting points of both the hydrated and anhydrous compound should be determined. 

The Hoesch reaction is the most satisfactory method for preparing phloroacetophenone.3 The procedure described above is that of Robinson and Venkataraman.4 Phloroacetophenone has been obtained also by the action of acetyl chloride on phloroglucinol in the presence of aluminum chloride.2... 

The benzoylation of resorcinol to produce 2,4-dihydroxybenzo-phenone has been previously performed with benzotrichloride, which implies the coproduction of 3 mol of hydrochloric acid and consequently a large amounts of acid waste. " Alternative routes to 2,4-dihydroxyben-zophenone involve direct acylation of resorcinol with benzoyl chloride (BC) or the Hoesch reaction with benzonitrile, which also suffer from acid waste production. In a more ecoefficient approach, the reaction was performed with benzoic acid (BAC) in the presence of some solid catalysts, with a special focus on BEA zeolite (Scheme 5.9). The progress of the reaction in para-chlorotoluene is examined, and after 18 h, 2,4-dihy-droxybenzophenone (2,4-DHB) is isolated in 70% yield, together with 20% of resorcinol monobenzoate (RMB), 3% of resorcinol dibenzoate, 5% of BAC, and 2% of resorcinol. The fact that the concentration of resorcinol in the final mixture is somewhat lower than that of BAC is probably due to the preferred adsorption of the former. The process is then studied by using different substituted BACs the different conversions of 2-methyl-,... 

The method was applied to the synthesis of evodionol (Table 12.1) by the reaction of the methyl ether of phloroacetophenone shown, to give the chromene in 65% yield (95% on the intermediate used). In the much longer synthesis of evodionol (ref. 39), at the initial step by the Hoesch reaction on 2,2-dimethyl-5,7-dihydroxychroman, the desired 6-acetyl product was the minor one and following benzylation to give the 7-benzyloxy compound, methylation, hydrogenolysis and DDQ oxidation were the required remaining steps. 

Why is it required to carry out the Hoesch Reaction in an absolute anhydrous condition ... 

The correspondingly substituted benzophenones are obtained in a yield not exceeding 35%, using substituted benzonitriles [20]. E. N. Zil -berman and N. A. Rybakova [21-23] modified the procedure for conducting the Hoesch reaction and S3mthesized a number of aromatic hy-droxyketones in 60-89% yield. According to the procedure they developed, hydrogen chloride is passed into an ether solution of the nitrile and zinc chloride for 2-3 hr at a temperature of 2-5°C, and then resorcinol is added. 

Tri-chloro- and -fluoro-acetyl groups are easily introduced into aromatic systems by means of the Hoesch reaction with the appropriate trihalomethyl cyanide. These groups are stable under the conditions for further electrophilic substitution, but are transformed by treatment with alkali into the corresponding carboxylic acid, whence they may be decarboxylated. Selected positions in phenols [33a], coumarones [33b], and the 3-position in indole [33c] may be protected in this way... 

Resorcinoland5-methylresorcinolreactwith3-oxo-2-aryl-4,4,4-trifluorobutyronitrile using ZnCh in dibutyl ether under the Hoesch reaction conditions to give a low yield of conmarins 312. However, the related reaction with m-methoxyphenol was found to prodnce poor yields of 312 and 313 [173] (Scheme 99). 

Aromatic Substitution. Several important classes of aromatic substitutions are mediated by ZnCU, including the Hoesch reaction (eq 56) and the Fischer indole synthesis (eq 57). Haloalky-lation of aromatic rings using Formaldehyde or Chloromethyl Methyl Ether is readily accomplished through the agency ofZnCb and wanning (eq 58). ... 

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