Stetter Reaction - Applications

Applications

The Stetter reaction is an effective tool in organic synthesis. The products of the Stetter reaction, 1,4-dicarbonyls, are valuable moieties for the synthesis of complex molecules. For example, Trost and coworkers employed a Stetter reaction as one step in their synthesis of rac-hirsutic acid C. The intramolecular coupling of an aliphatic aldehyde with a tethered α,β-unsaturated ester led to the desired tricyclic 1,4-dicarbonyl in 67% yield. This intermediate was converted into rac-hirsutic acid C in seven more steps.

The Stetter reaction is commonly used in sequence with the Paal-Knorr synthesis of furans and pyrroles, which a 1,4-dicarbonyl undergoes condensation with itself or in the presence of an amine under high temperature, acidic conditions. In 2001, Tius and coworkers reported the asymmetric total synthesis of roseophilin utilizing an intermolecular Stetter reaction to couple an aliphatic aldehyde with a cyclic enone. After ring-closing metathesis and alkene reduction, the 1,4-dicarbonyl product was converted to a pyrrole via the Paal-Knorr synthesis and further elaborated to the natural product.

In 2004, a one-pot coupling-isomerization-Stetter-Paal Knorr sequence was reported. This procedure first utilizes palladium cross-coupling chemistry to couple aryl halides with propargylic alcohols to give α,β-unsaturated ketones, which can then undergo a Stetter reaction with an aldehyde. Once the 1,4-dicarbonyl compound is formed, heating in the presence of acid will give the furan, while heating in the presence of ammonium chloride and acid will give the pyrrole. The entire sequence is performed in one-pot with no work-up or purification between steps.

Ma and coworkers developed an alternative method for accessing furans utilizing the Stetter reaction. In their report, 3-aminofurans are synthesized under Stetter conditions for coupling aromatic aldehydes with dimethyl acetylenedicarboxylate (DMAD), whereby the thiazolium ylide is hydrolyzed by the aromatization of the furan product. As the thiazolium is destroyed under these conditions, it is not catalytic and must be used in stoichiometric quantities.

They further elaborated on this work by developing a method in which 2-aminofurans are synthesized by cyclization onto a nitrile. In this method, the thiazolium ylide is employed catalytically and the free amine product is generated.