Catalysts cinchona derived bifunctional

Figure 12.6 Cinchona-derived bifunctional quaternary ammonium salt phase-transfer catalysts.

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

More recently, Pihko introduced bifunctional tertiary amine-thioureas 26 and 27 for the Mannich reaction of Boc-imines with malonates. ° Dimethylamino-tertiary amine thiourea 26 proved ideal for aliphatic imines, while the Cinchona derivative 27 provided the best results for aromatic substrates. Catalyst loadings as low as 1 mol% could be employed providing the products in high yields and excellent enantioselec-tivities (Scheme 19.34). Notably, both catalysts presented cooperative assistance via intermolecular hydrogen bonding, as first shown by Smith in 2009. ... 

The group of Dixon has reported the use of Cinchona alkaloid-derived bifunctional H-bonding catalysts for the syntheses of drugs like rolipram or paroxetine 420) as well as for the naturally occurring marine alkaloid (-)-nakadomarin (506) 417) (Scheme 111). Nakadomarin (506) was isolated from the sponge... 

Scheme 111 Cinchona alkaloid-derived bifunctional urea catalyst 507 in the total synthesis of (-)-nakadomarin (506)...

This gives chapter an overview of natural cinchona alkaloids and synthetic derivatives together with examples of their use in asymmetric organocatalysis. In recent years, the emphasis has been on the development of cinchona-based bifunctional catalysts, in particular species with a thiourea moiety. The search for new cinchona-based organocatalysts continues and new derivatives are relentlessly being prepared and applied for specific enantioselective reactions. The design of these new... 

Ye, Liang, and coworkers reported the addition of diphenylphosphine oxide to enones catalyzed by a bifunctional primary amine thiourea catalyst (127) derived from cinchona alkaloid (Scheme 33.38) [119], Cyclic and acyclic enones react with phosphine oxides under the optimized conditions to furnish the phosphine derivatives 128 in excellent yields and enantioselectivities. The primary amine of the catalyst activates the enone via an iminium, while the thiourea moiety activates and directs the phosphine group. 

A stereoselective [3+2] dipolar cycloaddition of azomethine imines 141 with ot,P-unsaturated aldehydes catalyzed by ot,a-diarylprolinol salts was also reported by Chen et al. [88]. More important, they extended the strategy to cyclic enones by employing a Cinchona alkaloid-derived bifunctional primary amine catalyst 142 (Scheme 1.52) [89]. The synergistic hydrogen-bonding interaction of the catalyst and 1,3-dipoles 141 plays a critical role in high enantiocontrol (dr >99 1, up to 95% ee). 

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Using the addition of dimethyl malonate to nitro-olefms as the model reaction, Connon et al. [72] in 2(X)5 reported a highly functionahzed Cinchona alkaloid-derived chiral thiourea. Key functional groups were identified to enhance the catalyst s stereodirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid... 

The role of some chiral bifunctional amines and optically active cinchona alkaloid derivatives (Figure 3) as catalysts has been explored in catalytic asymmetric Staudinger reactions. Bicarbonate salts have been used as viable alternatives to... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

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