Takemotos Tertiary Amine Thiourea

In an effort to expand the scope of the electrophiles, Takemoto showed three years later that henzimides were ahle to perform a Michael 

NMR and IR analysis revealed an intramolecular hydrogen-bonding interaction between the NH of the imide and the methojgr group of the aromatic ring. This interaction is believed to enhance the electrophilicity of the N-alkenoyl moiety of the imide since the electron density of the nitrogen atom is decreased. Furthermore, thiourea 15 was able to catalyse the subsequent 1,2-addition of hard nucleophiles to the resulting dicyano benzamides. 

During the same year, Takemoto and coworkers reported the asymmetric aza-Henry reaction of nitroalkanes with N-Boc imines utilising thiourea 15. 5yn-p-Nitroamines were isolated in good diastereoselectivities and high enantioselectivities, while the thiourea group was revealed to play a dual role, both activating the substrates and inducing chirality. Various types 

2 Other Bifunctional Tertiaiy Amine Thio(ureas) 

In the same year, Rieei and eoworkers reported the use of a Cinchona-derived thiourea for the asymmetrie aza-Michael addition of O-ben l-hydro Q lamine to traizs-ehaleones. Although 20 mol% catalyst loading, temperatures of 4-20 °C and 1.2 equiv. of 0-benzylhydro q lamine were employed, the observed enantioseleetivities were relatively low (30-60%). 

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In addition, an asymmetric Petasis-type transformation of quinolines with vinylboronic acid was developed by Miyabe and Takemoto by using a chiral bifunctional tertiary amine-thiourea, providing the corresponding 1,2-adducts in the presence of phenyl chloroformate as an activator. As shown in Scheme 2.60, the products were obtained in good yields and excellent... 

The Takemoto group synthesized a series ofdiaminocyclohexane-based thiourea derivatives (e.g., 12, 40, 57, and 58) for catalysis of the Michael addition [149-152] ofmalonates to trons-j3-nitrostyrenes (Figure 6.18) [129, 207]. In the model, Michael addition of diethyl malonate to trons-]3-nitrostyrene at room temperature and in toluene as the solvent tertiary amine-functionalized thiourea 12 (10mol% loading) was identified to be the most efficient catalyst in terms of catalytic activity (86%... 

Chen et al. identified (R,R)-l,2-diphenylethylenediamine-derived tertiary amine-functionalized thiourea 79 (20mol% loading), an analog of Takemoto s bifunc-... 

In 2003, Takemoto and coworkers published the enantioselective Michael addition of malonates to nitro-olefins catalysed by the first bifunctional thiourea 15, providing the corresponding products in high yields and enantioselectivities. The proposed mechanism involved a bifunctional transition state, where activation of the nitro-olefin is promoted by the thiourea group, while the activation of the malonate occurred by the tertiary amine (Scheme 19.18). ... 

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... 

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. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

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