Chiral tertiary amine-thiourea catalyst

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

In addition, various chiral amine-thioureas have been successfully applied to promote asymmetric Mannich reactions. As an example, Takemoto and Miyabe have employed a chiral bifunctional organocatalyst possessing a thiourea moiety and a tertiary amino group as catalyst of the Mannich reaction between ethyl malonate and A-Boc arylimines, which provided the corresponding products in excellent yields and enantioselectivities (93-98% ee), as shown in Scheme S.lb. The degree of enantioselectivity was shown to be dependent on the reaction temperature, with the best results obtained at low temperature. 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

MichaeU-Henry Reaction Liu et al. and Xie et al. independently found that tertiary amine-thioureas could stereoselectively promote the addition of diethyl a-aminomalonate-derived azomethine ylides to nitroolefms, affording Michael adducts other than dipolar cycloaddition adducts as the major products. Using monofunctional chiral thioureas 140d instead of tertiary amine-thiourea catalysts, Liu et al. successfully developed a three-component [3-1-2] dipolar cycloaddition of benzaldehydes 3, diethyl a-aminomalonates 45a, and nitrostyrenes 165, resulting directly in the enantioenriched pyrrolidines 208 as the only products (Scheme 2.56) [81a] while Xie et al. efficiently converted the Michael adducts 210 to pyrrolidines 208 in high yield and maintained ee by the use of 30 equiv of 2,2,2-trifluoroethanol as the additive (Scheme 2.56) [81b]. 

Takemoto and coworkers [32] elaborated bifunctional catalyst 27, which was found, after this initial report, to be highly versatile in promoting a large variety of transformations. The combination of a thiourea and a tertiary amine separated by a chiral scaffold, (R,l )-l,2-cyclohexyldiamine, was studied to build a new type of organocatalyst. Aminothiourea 27 was first examined as catalyst for the enantioselective addition of malonate to nitroaUcenes (Scheme 34.5). The thiourea moiety of catalyst 27 guides and activates the nitroolefin while the tertiary amine part deprotonates the malonate. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

On the other hand, Kim el al. have obtained excellent enantioselectivities (97-99% ee) for the aminated products generated by the amination of ot-cyanoketones with azodicarboxylates performed in the presence of a chiral thiourea-tertiary amine catalyst." As shown in Scheme 4.2, good to excellent yields were achieved for all the substrates examined in this study at a low catalyst loading of 1 mol %. 

The asymmetric conjugate addition with thiol nucleophiles was demonstrated using 2-mercaptobenzaldehydes. The utiUty of the same chiral cyclohexane-diamine catalysts 35 mediated the domino Michael-aldolof 2-sulfanylbenzaldehydes with maleimides (Scheme 13.10) [28]. The products of the reaction consist of fused heterocycles in high yield and high enantiomeric ratios. The stereochemical outcome sheds insight into the proposed mechanism whereby the catalyst simultaneously activates the thiol group via the cyclohexyl tertiary amine while the maleimide is stabilized by the thiourea component... 

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