At hiourea-catalyzed addition reactionw ith indoles to aliphatic b,g-unsaturated a-ketoesters has been developed. The easily accessible thiourea aminoindanol derivative makest his approacha ni nteresting alternative for the use of these aliphatic substrates, very scarcely employed in previously reported procedures,h ighlighting the complementarity of the strategy presented here. The final adducts, whicha re valuable intermediates for synthesizing the corresponding a-amino acid or a-hydroxy acid derivatives, are obtained in good yields and enantiomeric excess under mild reaction conditions.
The reaction of nitrones with enals through iminium activation can be modulated by using cooperative hydrogen‐bonding catalysis to induce the participation of a nitrone ylide (C‐N‐C) instead of the classical C‐N‐O dipole. As a consequence, N‐hydroxypyrrolidines are obtained, rather than the expected isoxazolidines. The reaction proceeds smoothly and high enantioselectivities are observed in all cases. By using the appropriate substrate, polysubstituted pyrrolidines incorporating quaternary stereocenters can be efficiently prepared.
The experimental and computational study of the mechanism of the iminium-organocatalyzed formation of Nhydroxypyrrolidines from nitrones, as a case study, revealed a hitherto unknown mode of action for the Schreiner's thiourea used as co-catalyst. The experimental data suggest that thiourea promotes the formation of the iminium ion through hydroxyl anion recognition forming a stable ion pair. Such an ion pair facilitates enolization of the nitrone through a H-bond network thus promoting the reaction with iminium ion. The computational model supports the mechanism and the catalytic cycle. This mechanistic rationale is supported by the lack of reactivity of preformed iminium ion with the nitrone in the absence of thioureahydroxyl complex and the observed reactivity when a complex thiourea-tetrabutylammonium hydroxide is added.
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