2023 Volume 81 Issue 5 Pages 474-482
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 α-halogenation of carbonyl compounds is one of the most common. Over the past few decades, α-halogenation reactions using 1,3-dicarbonyl compounds, aldehydes, and ketones have been well established. However, few reports are available on catalytic enantioselective α-chlorination for carboxylic acid derivatives with pKa that are relatively high, and hence it has been considered to be challenging to generate enolate species catalytically. Here, chiral π-copper(II) complex-catalyzed enantioselective α-fluorination and π-copper(II)-π complex-catalyzed enantioselective α-chlorination and α-bromination reactions of N-acyl-3,5-dimethylpyrazoles are described. The π-copper(II) complex of Cu(OTf)2 with 3-(2-naphthyl)-L-alanine-derived amides greatly accelerate the α-fluorination in the presence of an external base such as 2,6-lutidine. In sharp contrast, the π-copper(II)-π 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 α-chlorination and α-bromination due to undesired halogen bonding. This strategy provides facile access to α-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.
