Catalytic Asymmetric Fluorination of α-Chloro-β-ketoesters in the Presence of Chiral Palladium Complexes

Abstract

The chemistry of organic fluorine compounds is a rapidly developing area of research because of their importance in biochemical and medicinal applications and material science. Introduction of fluorine atom into biologically active compounds often leads to improvement of chemical and physical properties of the parent compounds due to unique properties of the fluorine atom. 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 stereoselectively fluorinated compounds having a fluorine atom at a stereogenic carbon center is critical in order to further advances of fluorine chemistry. Until now, a number of enantioselective fluorinations have been achieved by reagent-controlled and catalytic enantioseletive fluorination. Recently, several groups have been reported the catalytic enantioselective fluorination of active methine derivatives using chiral Lewis acids such as Binap-Pd(II) and transition metal-bis(oxazoline) complexes and organocatalysts such as cinchonine-derived quaternary ammonium salt, imidazolidinone, and proline derivatives. A few synthetic methods for the preparation of α-chloroα-fluoro-β-ketoesters have been reported. In general, αchloro-α-fluoro-β-ketoesters were prepared by the electrophilic fluorination of α-chloro-β-ketoesters using NFSI or F2 in the presence of formic acid. Togni has recently reported the first catalytic enantioselective synthesis of α-chloro-αfluoro-β-ketoesters using chiral titanium complexes with up to 65% selectivity. As part of research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we reported the catalytic enantioselective α-fluorination and α-amination of β-ketoesters with excellent enantioselectivity which promoted by chiral ammonium salts and chiral palladium complexes. In this letter, we wish to report the catalytic enantioseletive electrophilic α-fluorination of α-chloro-β-ketoesters using chiral palladium complexes 3 which are airand moisturestable. To determine suitable reaction condition for the catalytic enantioselcetive fluorination of α-chloro-β-ketoesters 1, we first examined electrophilic fluorination of 1-chloro benzoylacetate 1a with N-fluorobenzenesulfonimide (NFSI) in the presence of 5 mol% of 3a in MeOH at room temperature (Table 1). As can be seen from Table 1, the fluorinated