Grieco three-component condensation

The Grieco three-component condensation is an organic chemistry reaction that produces nitrogen-containing six-member heterocycles via a multi-component reaction of an aldehyde, a nitrogen component, such as aniline, and an electron-rich alkene. The reaction is catalyzed by trifluoroacetic acid or Lewis acids such as ytterbium trifluoromethanesulfonate (Yb(OTf)₃). The reaction is named for Paul Grieco, who first reported it in 1985.^[1][2] In the original paper the nitrogen component were benzylamine, methyl amine or ammonium chloride, the reaction now also include anilines, similar to the earlier Povarov reaction.

Grieco three-component coupling

Mechanism of the Grieco three-component coupling

The reaction process involves the formation of an aryl immonium ion intermediate followed by an aza Diels-Alder reaction with an alkene. Imines are electron-poor, and thus usually function as the dienophile. Here, however, the alkene is electron-rich, so it reacts well with the immonium diene in an Inverse electron-demand Diels–Alder reaction.

Researchers have extended the Grieco three-component reaction to reactants or catalysts immobilized on solid support, which greatly expands the application of this reaction to various combinatorial chemistry settings. Kielyov and Armstrong^[3] were the first to report a solid-supported version of this reaction, they found that this reaction works well for each reactants immobilized on solid support. Kobayashi and co-workers^[4] show that a polymer-supported scandium catalyst catalyze the Grieco reaction with high efficiency.

Given the effectiveness of the reaction and the commercial availability of various Grieco partners, the Grieco three-component coupling is very useful for preparing quinoline libraries for drug discovery.

See also

• Povarov reaction