 | ||
(Thio)urea organocatalysis describes the utilization of properly designed derivatives of urea and thiourea to accelerate and stereochemically alter organic transformations through predominantly double hydrogen-bonding interactions with the respective substrate(s) (non-covalent organocatalysis). The scope of these small-molecule H-bond donors termed (thio)urea organocatalysts covers both non-stereoselective and stereoselective applications in organic synthesis (asymmetric organocatalysis).
Contents
In nature non-covalent interactions such as hydrogen bonding ("partial protonation") play a crucial role in enzyme catalysis that is characterized by selective substrate recognition (molecular recognition), substrate activation, and enormous acceleration and stereocontrol of organic transformations. Based on the pioneering examinations by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on hydrogen bonding interactions of small, metal-free compounds with electron-rich binding sites Schreiner and co-workers performed series of theoretical and experimental systematic investigations towards the hydrogen-bonding ability of various thiourea derivatives.
These purely organic compounds were found to reveal significant rate enhancements of simple Diels-Alder reaction, act like weak Lewis acid catalysts, but operate through explicit double hydrogen bonding instead of covalent (strong) binding known from traditional metal-ion mediated catalysis and Brønsted acid catalysis.
Overview
Schreiner and co-workers identified and introduced electron-poor thiourea derivatives as hydrogen-bonding organocatalysts. N,N'-bis[[3,5-bis(trifluormethyl)phenyl thiourea is to date the most effective achiral thiourea derivative and combines all typical structural features for double H-bonding mediated organocatalysis:
Advantages of thiourea organocatalysts:
To date various organic transformations are organocatalyzed through double hydrogen-bonding N,N'-bis[3,5-bis(trifluoromethyl)]phenyl thiourea at low catalyst loadings and in good to excellent product yields. This electron-poor thiourea derivative enjoys the status of being a privileged catalyst and represents the benchmark for the design of a broad variety of explicit double hydrogen-bonding (thio)urea organocatalysts - achiral, and chiral as well as monofunctional and bifunctional representatives:
Catalysts
Since 2001 research groups worldwide (e.g., Berkessel, Connon, Jacobsen, Nagaswa, Takemoto) have realized the potential of thiourea derivatives and developed various achiral/chiral mono- and bifunctional derivatives incorporating the electron-poor 3,5-bis(trifluoromethyl)phenyl substrate-"anchor" functionality. A broad variety of monofuctional and bifunctional (concept of bifunctionality) chiral double hydrogen-bonding (thio)urea organocatalysts have been developed to accelerate various synthetically useful organic transformations employing H-bond accepting substrates, e.g., carbonyl compounds, imines, nitroalkenes as the starting materials. The research towards the design and implementations of these catalysts in organic synthesis is still in the focus of interest.