Thioureas amine catalysts

The best reactivity and selectivity was illustrated with the binaphthol derived thiourea amine catalyst 277. The substrate scope was explored primarily with P-aryl-nitro-olefms of both electron-donating and electron-withdrawing natures. Yields and selectivities were high for the majority of substrates (Scheme 78). 

The best enantioselectivity in the addition of C-nudeophiles to nitroolefins is that achieved by Takemoto et al. using the bifunctional thiourea-amine catalyst 55 (Scheme 4.26) [45]. 

Scheme 2.42 The thiourea/amine catalyst-mediated addition of acyclic ketones to nitrostyrenes.

Fig. 23.12 Homogeneous top) and PEG-immobilized bottom) versions of Miyabe s thiourea/ amine catalyst [32]...

In 2003, Takanoto et al. reported the first highly enantioselective organocatalytic conjugate addition of 1,3-dicarbonyl compounds to nitroolefins catalyzed by bifunctional thiourea-amine catalyst 142 (Fig. 2.15)[238]. After Takemoto s report a wide... 

Scheme 4.6 Mechanism involved in the polymerisation of trimethylene carbonate using bifunctional thiourea—amine catalyst in presence of an alcohol.

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

The proposed polymerization pathway differs fundamentally from the coordination-insertion mechanism involving metal complexes, see Fig. 3.7 [5, 38]. Indeed, the nucleophilic catalyst only activates the monomer toward ring opening, whereas the metal complex activates the monomer, initiates the polymerization, and remains bound to the growing chain. The polymerization mechanism of a superbase or thiourea-amine catalyzed ROP will be discussed in more detail below. 

Fig. 3.10 Thiourea-based organocatalysts. a-c Chemical structure of the bifunctional thiourea-tertiary amine catalyst, bis(3,5-trifluoromethyl)phenyl cyclohexylthiourea (thiourea), and N,N-dimethylcyclohexylamine (Moditied from Dove et til. [42]). d Proposed dual activation pathway of lactide ROP [41] (Adapted with permission from Pratt et al. [41]. Copyright 2013 American Chemictil Society)...

There is an interesting variant of this reaction which involves the use of tert-butyldimethylsilyloxyacetaldehyde as Michael donors and chiral primary amine thiourea bifunctional catalyst 37b (Scheme 2.13). In this case, the diastereoselectivity of the reaction changed from the usually observed syn relative stereochemistry at the final Michael adduct to the formation of the anti diastereoisomer as the major product. This change in diastereoselectivity was explained in terms of the generation of a Z-enamine intermediate assisted by the formation of an intramolecular hydrogen bond between the secondary... 

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... 

Despite this, bifunctional thiourea-tertiary amine catalysts have also emerged as useful and very convenient compounds for the activation of enones in Michael reactions. The mentioned problems associated to the single position available for H-bonding interactions and to the lower Bronsted basicity of the carbonyl moiety are circumvented by the formation of a double H-bonding network in which both lone pairs at the oxygen atom participate with two... 

On the other hand, primary amine catalysts showed improved catalytic activity and stereoselectivity for a,a-disubstituted aldehydes in asymmetric Michael reactions (Scheme 5.7). As described by Jacobsen and co-workers, outstanding activity and selectivity were observed for the primary amine thiourea catalyst 20, applicable for a broad range of a,a-disubstituted aldehydes and nitroalkenes (up to... 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

Yuan and co-workers used a similar strategy to synthesize spirooxindoles by a domino aldol/cyclization of 3-isothiocyanato oxindoles with simple ketones catalyzed by a bifunctional thiourea-tertiary amine catalyst [55]. An interesting feature of this methodology is the creation of two adjacent quaternary carbon atoms with high stereocontrol. 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

The detailed mechanistic explanation pictures the initial weak interaction among the bifunctional thiourea catalyst 158, the malonic ester 157 as nucleophile, and the nitroalkane 140 as electrophile that should promote the first chemo- and stereoselective Michael addition. The resulting adduct A would be poised to participate directly in the second catalytic cycle by acting as donor in a regioselective ititro-Michael reaction with the a,p-unsaturated aldehyde 95, here activated as iminium ion by the secondary amine catalyst (5)-76. The new inteimediate B, with its aldehyde and malonate moiety suitably spatial disposed, would undergo a base-promoted aldol cychzation to efficiently generate the planned cyclohexanol 159 in moderate yield (up to 87%) and marvelous enantioselectivity (up to >99% ee). 

In 2012, Yuan and coworkers [66] reported an enantioselective Petasis reaction among salicylalde-hydes, amines, and organoboronic acids catalyzed by a new thiourea-binol catalyst (Scheme 6.47). 

In addition, Chen et al. developed the aldolisation of cyclohexanone with benzaldehydes in water by using a chiral bifunctional thiourea-secondary amine catalyst bearing a hydrophobic camphor scaffold. In the presence of DBSA as an additive, these reactions afforded the anti- do products in moderate to high yields, and high to excellent diastereo- and enantioselectivities, as shown in Scheme 2.42. 

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 %. 

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