Guanidinium thiourea catalysts

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. 

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 brfimctional 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 K1 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 xyn-nitroalcohols preferentially. 

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