Asymmetric Electrophilic Fluorination of β-Keto Phosphonates in Ionic Liquid Media Catalyzed by Chiral Palladium Complexes

Abstract

The chemistry of bioactive organofluorine compounds is a rapidly developing area of research because of their importance in biochemical and medicinal application. Chiral organofluorine compounds containing a fluorine atom bonded directly to a stereogenic center have been utilized in studies of enzyme mechanisms and as intermediates in asymmetric syntheses. The development of effective methodologies for the preparation of new selectively fluorinated, stereochemically defined compounds is critical to further advances of fluorine chemistry. The catalytic enantioselective construction of fluorinated stereogenic centers is still important challenge in modern organic chemistry. α-Fluoroalkylphosphonates are better mimics of natural phosphates with matched 2nd pKa vaules (~6.5). The enantioselective construction of α-fluoroalkylphosphonates is extremely important because the stereochemistry of αcarbon does affect enzyme binding. Although there have been several reports for the asymmetric synthesis of αfluoroalkylphosphonates, synthetic methods of chiral αfluoro β-keto phosphonates are limited. The employment of ionic liquids as solvents for chemical reactions has been received increased attention because they have essentially no vapor pressure and provide high solubility for a wide range for organic and organometallic compounds. These solvents are reusable, enhance the reactivity of chemical transformations, simplify product isolation and allow for catalysts recycling. As part of research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we report the catalytic enantioselective fluorination of β-keto phosphonate excellent enantioselectivity (87-97% ee) promoted by a chiral palladium complexes. In this letter, we wish to report the catalytic enantioseletive electrophilic fluorination of β-keto phosphonates using chiral palladium complexes 1 in ionic liquid media. We first examined electrophilic fluorination of β-keto phosphonate 2a with NFSI in the presence of 5 mol% of 1 using [bmim]BF4 at room temperature (Table 1, entry 2). After stirring for 10 h at room temperature, the reaction was quenched by extraction with ether (5 × 5 mL). The combined organic layers concentrated and the crude product purified by silica-gel chromatography to afford α-fluoro βketo phosphonate 3a in 95% yield and 93% ee. Concerning the ionic liquids, the use of [bmim]BF4 and [bmim]OTf gave the best results, whereas the fluorination in [bmim]PF6, [bmim]SbF6 and [emim]BF4 led to lower yields and enantioselectivities or no reaction. The chemical yield and enantioselectivity were almost similar as those obtained in MeOH (8 h, 93% yield, 97% ee), a longer reaction time was necessary for the completion of the reaction. The reaction of phosphonates 2b-2d afforded the corresponding fluorinated phosphonates 3b-3d in 88-91% yield and 90-93% ee. We also tested recycling of the catalyst (Table 2). The reaction was performed seven times without affecting the yield and selectivity. The pale pink color [bmim]BF4 layer and colorless ether layer indicated that chiral palladium catalyst was retained in ionic liquid layer. In the 2nd Table 1. Catalytic enantioselective fluorination of β-keto phosphonates in ionic liquid