Cinchona thiourea derivatives

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. 

Novel asymmetric conjugate-type reactions have been accomplished with Cinchona alkaloid-derived chiral thioureas, including less traditional reactions such as asymmetric decarboxylation [71]. In the following discussion, asymmetric reactions involving nitro-olefms, aldehydes and enones, and imines will be highlighted (Fig. 5). 

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... 

Cinchona alkaloid-derived chiral thiourea catalyst xo... 

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

The Cinchona alkaloid-derived thiourea (112), has been developed as an organocat-alyst for conjugate addition of a wide range of nucleophilic enol species to enones. The reaction is characterized by high enantioselectivities and mild reaction condition.160... 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

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]. 

Disubstituted flavanones and chromanones are produced with good enantioselectivity from chalcones activated by an a-fert-butyl ester function through an intramolecular Michael addition catalysed by a chiral thiourea derivative. In situ decarboxylation enhances the ee and yields remain high <07JA3830>. A comprehensive study of the asymmetric cyclisation of 2 -hydroxychalcones to flavanones has refuted the ability of camphorsulfonic acid to achieve enantioselectivity but has shown that cinchona-based catalysts can be effective <07EJO5886>. 

Anthracenones are another class of C-H acidic compounds suitable to be employed in this reaction (Scheme 4.16) and, in fact, Takemoto s catalyst has been identified as the most efficient catalyst among a series of different thioureas tested, which also included a family of different cinchona alkaloid-derived candidates." The reaction proceeded satisfactorily for a wide variety of aromatic nitroalkenes tested but poorer results were obtained in the case of the p-alkyl substituted Michael acceptors. 

Asymmetric cyanohydrin synthesis remains an important reaction for organocatalysis and many of the catalyst classes discussed in subsequent chapters give highly effective catalysts for this reaction. These include Cinchona alkaloid derivatives, thioureas, guanidines, amine-oxides, diols and diamines. 

The AFC reaction of indoles with less reaetive aryl aldimines catalyzed by organocatalystwas reported by the group of Deng in 2006. Bifunctional cinchona alkaloid-derived thioureas were utilized to promote the AFC reaetion of indoles with N-Ts- or AT-Bs-protected imines. With 10 mol% of eatalyst 29, 3-indolyl methanamine derivatives 30 were obtained in high yields with up to 97% ee for both aryl and alkyl imines (Scheme 6.12). 

Later Schaus and co-workers used the cinchona alkaloid-derived thiourea catalyst 60 to catalyze the nucleophilic addition of both nitroalkanes (not shown) and dimethyl malonate to the Al-carbamoyl protected imines 46b, 61a-d to produce the corresponding Mannich adducts 62 in excellent yields and high enantioselectivities (Scheme 5.30) [41], The level of selectivity observed in these reactions is indicative of a catalyst-associated complex with a high degree of coordination. Modelling... 

Cinchona alkaloids are amongst the most well-known natural products with exceptional medical history and widely recognised catalytic properties that are elaborated in several reviews and recently a book. For more information see also Chapter 14 of this volume. This chapter summarises their use in carbon-heteroatom bond-forming reactions the most used natural and modified Cinchona alkaloids are shown below, for modified alkaloids, only one pseudoenatiomer is shown. Quaternised, and urea and thiourea derivatives are included in Chapters 16 and 19 of this volume respectively. 

The possibilities of enantioselective sulfa-Michael additions using amino derivatives of Cinchona alkaloids are also demonstrated through tandem (cascade, domino) reactions, thus allowing the formation of multiple stereocentres with up to 99% ee. In comparison to Cfnc/zona-thiourea derivatives, natural Cinchona alkaloids or their ethers gave lower... 

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