Thiourea-based catalyst

Jprgensen s group has very recaitly d onstrated the usefulness of o,P-unsaturated acyl phosphonates as hydrogen-bond acceptors in the enantioselective Hiedel-Crafts reaction with indoles [341]. Since the acyl phosphonate moiety is a powerful ester and amide surrogate, this reaction is an interesting approach towards the synthesis of optically active p-(3-indolyl)esters and amides as represented in Scheme 2.119 for selected examples. The reaction is catalyzed by chiral thiourea-based catalyst ent-191 that activates the nucleophile and the electrophile through hydrogen-bond interactions. 

A very similar approach was followed by the Jacobsen group using the slightly different thiourea-based catalyst 58 [40]. It was shown that using nitroethane highly 5yn-selective nitro-Mannich products 59a-g could be obtained in high yield and impressive ee (Scheme 5.29). 

Initial mechanistic analysis of the Strecker reaction catalyzed by a urea-based organocatalyst (Scheme 3.18) revealed that the catalytic activity is provided by the urea functionality of structurally complex catalyst 1. However, further studies revealed a bifunchonal character of urea and thiourea-based catalysts " as well as the possibility of multiple mechanistic pathways in catalysis of nucleophile-electrophile addition reactions. " Simplified but sufficiently effective (thio)urea catalysts 4a and 4b were used in the hydrocyanation reaction (Scheme 3.19) that was subjected to a combined experimental and computational study. °... 

The enantioselective addition of ketones to nitrostyrenes was developed by using the bifunctional sulfonamide primary amine catalyst 93 (Figure 24.32). No reaction took place when water was used as reaction medium. The best solvent was CHCI3. However, addition of water increased the yield and enantioselectivity, probably because it increased catalyst turnover due to facilitating the release of the primary amine catalyst from the imine. Moreover, the authors reported an explanation of the role of water in the enhancement of enantioselectivity [114], Three different primary thiourea-based catalysts (94—96) were also used with very good results (Figure 24.32) [115-117]. 

Chiral phosphoric acid analogs as catalysts in the F-C alkylation reaction of indoles with a,(l-unsaturated aromatic enones were also devised [53]. p,y-Unsaturated a-ketoesters were also used as electrophiles in organocatalyzed F-C alkylations of indoles and 2-naphthols. With indoles, chiral acidic N-triflylphos-phoramide was successfully employed (Scheme 35.4) [28], whereas in the presence of 2-naphthols a thiourea-based catalyst showed better capacity to mediate a sequential F-C/cycUzation process, giving naphthopyran scaffolds in moderate yields and selectivities (up to 90% ee) [54]. Recently, a,P-unsaturated acyl phos-phonates were effectively used as hydrogen bond acceptors for F-C alkylations of indole derivatives in the presence of thiourea catalyst ent-19 [55]. 

After the optimization of these conditions, by adding an azide to the input stream it was possible to synthesize a range of substituted triazoles in a heterogeneously catalysed three-component reaction (Scheme 18). After the CFC, the stream was passed through a column containing a resin-immobilized copper-based catalyst, which was used in a previous work by the same authors to successfully catalyze the formation of triazoles from alkynes and azides [44]. An immobilized thiourea-containing cartridge was subsequently used to remove any leached Cu catalyst. In a similar way as for the alkynes production, the series of resins was used to purify the product. 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

The simply obtainable thiourea compounds 142-145 were the first organo-catalysts for the catalytic conjugate addition of indoles with nitroalkenes to yield optically active 2-indolyl-l-nitro derivative as 2.R-50 in fairly good yields and enantioselectivity. The simple thiourea-based organo catalyst 145 could be easily accessed in both enantiomeric forms from the commercially available materials. At the same time, the extremely simple methodology has proved the new approach useful for the synthesis of optically active target... 

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>. 

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