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The Grieco three-component condensation is an
The Grieco three-component condensation is an organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, ...
reaction that produces nitrogen-containing six-member heterocycles via a multi-component reaction In chemistry, a multi-component reaction (or MCR), sometimes referred to as a "Multi-component Assembly Process" (or MCAP), is a chemical reaction where three or more compounds
react to form a single product. By definition, multicomponent reaction ...
of an aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
, a nitrogen component, such as aniline
Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starti ...
, and an electron-rich alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
. The reaction is catalyzed by trifluoroacetic acid
Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with ...
or Lewis acids
A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any spe ...
such as ytterbium
Ytterbium is a chemical element with the symbol Yb and atomic number 70. It is a metal, the fourteenth and penultimate element in the lanthanide series, which is the basis of the relative stability of its +2 oxidation state. However, like the othe ...
trifluoromethanesulfonate (Yb(OTf)3). The reaction is named for Paul Grieco
Paul Grieco is an organic chemist at Montana State University. His research focuses on the total synthesis of natural products and the study of solvent effects in various organic reactions. He has received several awards for his work, including t ...
, who first reported it in 1985. 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 The Povarov reaction is an organic reaction described as a formal cycloaddition between an aromatic imine and an alkene. The imine in this organic reaction is a condensation reaction product from an aniline type compound and a benzaldehyde type comp ...
.
The reaction process involves the formation of an aryl immonium ion intermediate followed by an aza Diels-Alder reaction with an alkene. Imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
s 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
The inverse electron demand Diels–Alder reaction, or DAINV or IEDDA is an organic chemical reaction, in which two new chemical bonds and a six-membered ring are formed. It is related to the Diels–Alder reaction, but unlike the Diels–Alder ( ...
.
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 Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
settings. Kielyov and Armstrong 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 show that a polymer-supported scandium
Scandium is a chemical element with the symbol Sc and atomic number 21. It is a silvery-white metallic d-block element. Historically, it has been classified as a rare-earth element, together with yttrium and the Lanthanides. It was discovered in ...
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
Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only sli ...
libraries for drug discovery.
See also
*Povarov reaction The Povarov reaction is an organic reaction described as a formal cycloaddition between an aromatic imine and an alkene. The imine in this organic reaction is a condensation reaction product from an aniline type compound and a benzaldehyde type comp ...
References
{{reflist Organic reactions Multiple component reactions Name reactions