The Fluorinated asymmetric reformatsky reaction with aromatic ketones and imines

One of the most challenging topics in organofluorine chemistry is the asymmetric introduction of fluorine atoms, difluoromethylene and trifluoromethyl groups. Outstanding progress has been made in recent years, but further developments are necessary for chiral fluorinated molecules to be increasingly used in medicinal, agricultural and material chemistry. The enantioselective addition of the fluorinated Reformatsky reagent to aromatic aldehydes in the presence of chiral aminoalcohols to give α,α-difluoro-β-hydroxy esters in good enantiomeric excess is well established. However, the two step protocol is inconvenient because of the need for zinc activation, as well as the relatively high temperatures required for the generation of the fluorinated Reformatsky reagent. Consequently, a one-pot asymmetric Reformatsky reaction of ethyl bromodifluoroacetate with benzaldehyde promoted by diethylzinc under mild reaction conditions (0 oC) has been developed. A very good yield (66 %) and enantiomeric excess (69 % ee) was obtained in the presence of the chiral ligand, N-methylephedrine. The first example of the asymmetric Reformatsky reaction of ethyl iododifluoroacetate with aromatic ketones performed in the presence of (1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol was developed. The reaction of 2.5 equivalents of the Reformatsky reagent prepared from ethyl iododifluoroacetate and zinc dust gave good isolated yields (63-99 %) and high enantiomeric excesses (75-84 %) with a series of aromatic ketones. However, the more convenient one-step protocol at -40 oC involving activation with diethylzinc gave 62-90 % yields and even better enantiomeric excesses (81-91 %) in a shorter reaction time and with a smaller amount of the expensive ethyl iododifluoroacetate (2.0 equivalents). The protocol of the one-step enantioselective Reformatsky reaction with ketones promoted by diethylzinc was extended to ethyl iodofluoroacetate and excellent yields (84-99 %) and enantiomeric excesses (79-95 %) were obtained. A high level of diastereomeric control was obtained in the chiral reactions with ketones with an extended aliphatic group. The absolute configuration of the new chiral centres for the major enantiomer of the difluorinated esters, and for the major enantiomers of both diastereoisomers of monofluorinated esters obtained in the reactions performed in the presence of (1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol was determined to be (S). A range of aromatic imines were tested in the convenient one-step asymmetric Reformatsky reaction of ethyl iododifluoroacetate and after optimisation, good enantiomeric excesses (63-68 % ee) were obtained with imines containing a methoxy group in the ortho-position in the presence of N-methylephedrine.