Thiourea organocatalysis

(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).

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:

• electron-poor
• rigid structure
• non-coordinating, electron withdrawing substituents in 3,4, and/or 5 position of a phenyl ring
• the 3,5-bis(trifluoromethyl)phenyl-group is the preferred substituent

Advantages of thiourea organocatalysts:

• no product inhibition due to weak enthalpic binding, but specific binding-“recognition“
• low catalyst-loading (down to 0.001 mol%)
• high TOF (Turn-Over-Frequency) values (up to 5,700 h⁻¹)
• simple and inexpensive synthesis from primary amine functionalized (chiral-pool) starting materials and isothiocyanates
• easy to modulate and to handle (bench-stable), no inert gas atmosphere required
• immobilization on a solid phase (polymer-bound organocatalysts), catalyst recovery and reusability
• catalysis under almost neutral conditions (pk_a thiourea 21.0) and mild conditions, acid-sensitive substrates are tolerated
• metal-free, not toxic (compare traditional metal-containing Lewis-acid catalysts)
• water-tolerant, even catalytically effective in water or aqueous media
• environmentally benign ("Green Chemistry"), sustainable catalysts

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 implemenations of these catalysts in organic synthesis is still in the focus of interest.

1998: Jacobsen's chiral (polymer-bound) Schiff base thiourea derivative for asymmetric Strecker reactions. 1998: Jacobsen's chiral (polymer-bound) Schiff base thiourea derivative for asymmetric Strecker reactions.  2001: Schreiner's N,N'-bis[3,5-bis(trifluoromethyl)phenyl thiourea: complexation of substrate through explicit double hydrogen-bonding, clamplike binding motif. 2001: Schreiner's N,N'-bis[3,5-bis(trifluoromethyl)phenyl thiourea: complexation of substrate through explicit double hydrogen-bonding, clamplike binding motif.  2003: Takemoto's bifunctional chiral thiourea derivative, catalysis of asymmetric Michael- and Aza-Henry reactions. 2003: Takemoto's bifunctional chiral thiourea derivative, catalysis of asymmetric Michael- and Aza-Henry reactions.  2004: Nagasawa's chiral bis-thiourea organocatalyst, catalysis of asymmetric Baylis-Hillman reactions. 2004: Nagasawa's chiral bis-thiourea organocatalyst, catalysis of asymmetric Baylis-Hillman reactions.  2005: Nagasawa's bifunctional thiourea functionalized guanidine, asymmetric catalysis of Henry(Nitroaldol)reactions. 2005: Nagasawa's bifunctional thiourea functionalized guanidine, asymmetric catalysis of Henry(Nitroaldol)reactions.  2005: Ricci's chiral thiourea derivative with additional hydroxy-group, enantioselective Friedel-Crafts alkylation of indols with nitroalkenes. 2005: Ricci's chiral thiourea derivative with additional hydroxy-group, enantioselective Friedel-Crafts alkylation of indols with nitroalkenes.  2005: Wei Wang's bifunctional binaphthyl-thiourea derivative, asymmetric catalysis of Morita-Baylis-Hillman reactions. 2005: Wei Wang's bifunctional binaphthyl-thiourea derivative, asymmetric catalysis of Morita-Baylis-Hillman reactions.  2005: Soos's, Connon and Dobson's bifunctional thiourea functionalized Cinchona alkaloid, asymmetric additions of nitroalkanes to chalcones as well as malonates to nitroalkenes 2005: Soos's, Connon and Dobson's bifunctional thiourea functionalized Cinchona alkaloid, asymmetric additions of nitroalkanes to chalcones as well as malonates to nitroalkenes   2006: Yong Tang's chiral bifunctional pyrrolidine-thiourea, enantioselective Michael additions of cyclohexanone to nitroolefins. 2006: Yong Tang's chiral bifunctional pyrrolidine-thiourea, enantioselective Michael additions of cyclohexanone to nitroolefins.  2006': Berkessel's chiral isophoronediamine-derived bisthiourea derivative, catalysis of asymmetric Morita-Baylis-Hillman reactions. 2006: Berkessel's chiral isophoronediamine-derived bisthiourea derivative, catalysis of asymmetric Morita-Baylis-Hillman reactions.  2006: Takemoto's PEG-bound chiral thiourea, asymmetric catalysis of (tandem-) Michael reactions of trans-β-nitrostyrene, aza-Henry reactions. 2006: Takemoto's PEG-bound chiral thiourea, asymmetric catalysis of (tandem-) Michael reactions of trans-β-nitrostyrene, aza-Henry reactions.  2007: Kotke/Schreiner, polystyrene-bound, recoverable and reusable thiourea derivative for organocatalytic tetrahydropyranylation of alcohols. 2007: Kotke/Schreiner, polystyrene-bound, recoverable and reusable thiourea derivative for organocatalytic tetrahydropyranylation of alcohols.  2007: Wanka/Schreiner, chiral peptidic adamantane-based thiourea, catalysis of Morita-Baylis-Hillman reactions. 2007: Wanka/Schreiner, chiral peptidic adamantane-based thiourea, catalysis of Morita-Baylis-Hillman reactions.  2007: Takemoto's chelating bifunctional hydroxy-thiourea for enantioselective Petasis-type reaction of quinolines. 2007: Takemoto's chelating bifunctional hydroxy-thiourea for enantioselective Petasis-type reaction of quinolines.  2007: Ma Jun-An's Chiral Bifunctional Primary and tertiary Amine-thiourea Catalysts Based on Saccharides. 2007: Ma Jun-An's Chiral Bifunctional Primary and tertiary Amine-thiourea Catalysts Based on Saccharides.