Bifunctional thiourea

Figure 4.4 Structure of guanidine-thiourea bifunctional organocatalyst 15...

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... 

Figure 2.6 Some amino-thiourea bifunctional catalysts for the MBH reaction.

For a recent NMR study on the active conformation and the aggregation state of an amine-thiourea bifunctional organocatalyst, see G. Tarkanyi, P. Kiraly, T. Soos, S. Varga, Chem. Eur. J. 2012, 18, 1918. 

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]. 

Sohtome, Y Hashimoto, Y Nagasawa, K. Guanidine-Thiourea Bifunctional Organocatalyst for the Asymmetric Henry (Nitroaldol) Reaction. Adv. Synth. Catal. 2005,347,1643-1648. 

Li and coworkers have studied the reaction between cyclic ketones 133 and nitroolefins 134 in the presence of the chiral pyrrolidine-thiourea bifunctional catalyst 135 (Scheme 3.41), finding that it allows an enantioselective synthesis of 3-oxa- and 3-azabicyclo[3.3.1]nonan-9-one derivatives 136, probably via a domino process comprising allylic displacement and Michael reactions as the key steps [90],... 

Aldol reactions of unachvated ketones (164) with isahns (165) are catalyzed by the quinidine-thiourea bifunctional catalyst 166 through an ammonium enolate... 

Interfacially active guanidinium-thiourea bifunctional catalyst 190 catalyzes highly enantioselective nitroaldol reactions in the presence of an external base such as KOH in toluene/water biphasic conditions. Although the retro-nitroaldol reactions generally proceed under basic conditions, addition of KI inhibits the retro-process. A cooperative reaction mode between guanidinium and thiourea moieties is supported by experiments using structural variants of 190. A positive nonlinear effect is observed between the enantiomeric excess of 190 and the product 191. These results support the hypothesis that self-a egation of 190 is necessary for catalysis (Scheme 28.22) (96, 97). Catalyst 190 has been used in the synthesis of chiral tertiary alcohol products obtained in nitroaldol reactions of nitroalkanes and a-ketoesters [98],... 

Like the reactions discussed in Section 28.5.1.2, a highly enantioselective aza-nitroaldol reaction of imines (173) with nitroalkanes (157) is achieved by use of guanidinium-thiourea bifunctional organocatalyst 204 in the presence of external base such as CSCO3 under phase-transfer conditions. Both catalytic activity and enantioselectivity depend upon the substituents on the guanidinium group. The mono-substituted catalyst 190 gives poor results (yield 89%, 9% ee), whereas cyclic amine-substituted catalyst 204 provides excellent enantiomeric excess (Scheme 28.25) [104]. 

Review of guanidinium-thiourea bifunctional catalyst Sohtome, Y. and Nagasawa, K. (2010) Synlett, 1-22. 

Wang et al. s synthesis In 2011, a simple chiral primary amine thiourea bifunctional catalyst was introduced to the asymmetric Michael addition of 4-hydroxycoumarin to enones (Table 9.15). With Wang et al. s catalyst, l-[(15, 25)-2-amino-l,2-diphe-nylethyl]-3-benzylthiourea, all Michael additions could be smoothly performed to afford Michael... 

Mei RQ, Xu XY, Li YC, Fu JY, Huang (JC, Wang LX. Highly effective and enantioselective Michael addition of 4-hydroxy-coumarin to a, p-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011 52(14) 1566-1568. 

Sohtome Y, Hashimoto Y, Nagasawa K. Diastereoselective and enantioselective Henry (nitroaldol) reaction utilizing a guanidine-thiourea bifunctional organocatalyst. Eur. J. Org. Chem. 2006 2894-2897. 

Wang L, Cai C, Curran DP, Zhang W. Enantioselective a-chlorination of aldehydes with recyclable fluorous (S)-pyr-rolidine-thiourea bifunctional organocatalyst. Synlett 2010 3 433 36. 

Reviews of amine-thiourea bifunctional catalysts (a) Siau, W.-Y. and Wang, J. 

Organocatalytic Henry reactions with synthetically useful levels of yields and enantioselectivities came a decade later with the independent work of Nagasawa and Hiemstra. Nagasawa used guanidinium salt/thiourea bifunctional catalyst 2 for the reaction of nitromethane or nitroethane with aliphatic aldehydes (no reaction was observed when aromatic aldehydes were used) [7]. The reaction works under PTC with the assistance of KOH, and to overcome the retro-nitroaldol reaction KI as an additive was required (Scheme 29.2). Two years later, the same group extended this reaction to nitroalkanes other than nitromethane, a process that yields the corresponding syn-nitroalcohols preferentially. 

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