Thioureas, as hydrogen-bonding additives

The cycHc urea moiety provides structural rigidity as well as hydrogen-bonding possibihties similar to those of the imidazoles described above. The corresponding 2-imidazolones have been prepared on a soHd phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate followed by intramolecular Michael addition [73]. However, due to the paucity of data presented on the characterized compounds and the brief experimental procedure, this synthesis is not discussed in detail. Access to cyclic ureas or thioureas has also been obtained by reaction with carbonyl- or thiocarbonyldiimidazole through a cyclo-release mechanism [74—76]. 1,3-Dihydroimidazolones have been obtained by treatment of ureido acetals with TFA and subsequent conversion in an intramolecular cyclization via an N-acyliminium ion [77]. 

The first report on the development and use of chiral squaramide derivatives as hydrogen-bond donor catalysts appeared in 2008 by Rawal and coworkers [78]. The authors showcased the usefulness of this new scaffold by evaluating the Michael addihon of 1,3-dicarbonyl compounds to nitroalkenes, the same reaction that was used to illustrate the capabilily of a thiourea catalyst by Takemoto [45]. Of the catalysts examined, the cinchonine-derived squaramide 13 functioned well as a bifunctional catalyst and provided the conjugate addition product in high yield and excellent enanhoselectivity (Scheme 10.12). Less reactive substrates such as a-substituted 1,3-dicarbonyl compounds also participate in the desired reaction. 

Hydrogen-bond donors have the ability to enhance the selectivities and rates of organic reactions. Examples of catalytic active hydrogen-bond donor additives are urea derivatives, thiourea derivatives (Scheme 10, Tables 12 and 13) as well as diols (Table 14). The urea derivative 7 (Scheme 9) increases the stereoselectivity in radical allylation reactions of several sulphoxides (Scheme 10)171. The modest increase in selectivity was comparable to the effects exerted by protic solvents (such as CF3CH2OH) or traditional Lewis acids like ZnBr2172. It was mentioned that the major component of the catalytic effect may be the steric shielding of one face of the intermediate radical by the complex-bound urea derivative. 

As expected, the reaction is fastest in water due to its hydrogen-bonding ability and high dielectric constant. Addition of 1 mol% of the thiourea catalyst 10 increases the yields after 1 h in cyclohexane and chloroform by about 60% a 40 mol% catalyst doubles the yield. A sizeable catalytic effect of the m-trifluoromethyl-substi luted thiourea was also found in water. Explanations for the surprising fact that this hydrogen-bond donor is catalytically active even in a highly competitive solvent such as water will be given in Section III.D.3. 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Dixon et al. screened cinchonine-derived thioureas 117-120 for their performance in the dimethyl malonate Michael addition to tra s-(5-nitrostyrene in dichlo-romethane at room temperature and at -20°C [274]. As shown in Figure 6.38, all candidates revealed comparable activity, but monodentate hydrogen-bond donor 118 exhibited very low asymmetric induction producing the desired Michael... 

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