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

References
  1. Larsen, S. D.; Grieco, P. A., J. Am. Chem. Soc. 1985, 107, 1768.
  2. Greico, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855.
  3. Kiselyov, A. S.; Armstrong, R. W. (1997). "Solid Support Synthesis of Tetrahydroquinolines via the Grieco Three Component Condensation". Tetrahedron Lett. 38 (35): 6163–6166. doi:10.1016/S0040-4039(97)01425-1.
  4. Kobayashi, S.; Nagayama, S. (1996). "A New Methodology for Combinatorial Synthesis. Preparation of Diverse Quinoline Derivatives Using a Novel Polymer-Supported Scandium Catalyst". J. Am. Chem. Soc. 118 (37): 8977–8978. doi:10.1021/ja961062l.
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