Houben-Hoesch Synthesis

During the early 1900s, the Friedel-Crafts acylation and the Gattermann formylation were widely used to prepare both aromatic aldehydes and ketones. Preparing monoacylated derivatives of highly activated substrates was not possible, since usually more than one acyl group was introduced using the standard Friedel-Crafts acylation conditions.

In 1915, K. Hoesch reported the extension of the Gattermann reaction for the synthesis of aromatic ketones using nitriles instead of hydrogen cyanide, and by replacing the aluminum chloride with the milder zinc chloride. Over ten years later, J. Houben demonstrated that this reaction principally worked for polyphenols or polyphenolic ethers. Thus forward, the condensation of nitriles with either polyhydroxy- or polyalkoxyphenols to synthesize the corresponding polyhydroxy or polyalkoxyacyloxyphenones became known as the Houben-Hoesch synthesis.

Synthetic applications of the Houben-Hoesch reaction include the total synthesis of the natural product bostrycoidin and Genistein which is an important nutraceutical molecule found in soybean seeds.