Influence of Halogen Bonding in Catalytic Enantioselective α - Halogenation Reaction

Enantioselective carbon-halogen(F, Cl, Br)bond formations are particularly important due to their potential as synthetic intermediates as well as marine natural products and pharmaceuticals. Among the various methods available to build carbon-halogen bonds, the enantioselective electrophilic alpha-halogenation of carbonyl compounds is one of the most common. Over the past few decades, alpha-halogenation reactions using 1,3- dicarbonyl compounds, aldehydes, and ketones have been well established. However, few reports are available on catalytic enantioselective alpha-chlorination for carboxylic acid derivatives with pK(a) that are relatively high, and hence it has been considered to be challenging to generate enolate species catalytically. Here, chiral pi-copper(II) complex-catalyzed enantioselective alpha-fluorination and pi-copper(II)-pi complex-catalyzed enanti-oselective alpha-chlorination and alpha-bromination reactions of N-acyl-3,5-dimethylpyrazoles are described. The pi-coppe(II)complex of Cu(OTf)(2) with 3(-2-naphthyl)- L-alanine-derived amides greatly accelerate the alpha-fluorination in the presence of an external base such as 2,6-lutidine. In sharp contrast, the pi-coppe(II)-pi complexation of Cu(OTf)(2) with 3(-2-naphthyl)-L-alanine-derived amides further increases the Lewis acidity, and triggers the in situ generation of enolate species without an external base, which has a suppressing effect for alpha-chlorination and alpha-bromination due to undesired halogen bonding. This strategy provides facile access to alpha-halogenated compounds in high yield with excellent enantioselectivity. X-ray crystallographic and ESR analyses of the catalyst complexes suggest that the release of two counter anions(2TfO(-))from the copper(II)center might be crucial for the efficient activation of N-acyl-3,5-dimethylpyrazoles.