Enantioselective deprotometalation of alkyl ferrocenecarboxylates using bimetallic bases

Abstract

The enantioselective deprotometalation of alkyl ferrocenecarboxylates (FcCO₂R) using mixed lithium-zinc or lithium-cadmium bases is described. By using FcCO₂Me as the substrate, chiral lithium alkyl-amidozincates prepared from exo-(αR)- or endo-(αS)-N-(α-phenylethyl)bornylamine (H-exo-born-R or H-endo-born-S) were tested; the best results (27% yield and 62% ee in favor of the R_P enantiomer) were obtained by using Bu₂(endo-born-S)ZnLi in tetrahydrofuran (THF) at −30 °C before iodolysis. Due to the low compatibility of FcCO₂Me with alkyl-containing lithium zincates, 1 : 1 mixtures of lithium and zinc amides were tested. Chiral (H-exo-born-R or H-endo-born-S) or/and achiral (lithium 2,2,6,6-tetramethylpiperidide or lithium diisopropylamide) secondary amines gave good results, the best (81% yield and 44% ee in favor of the R_P enantiomer) being obtained by using (endo-born-S)₃ZnLi in THF at room temperature. Among other secondary amines also prepared and/or tested, commercial (S,S)-bis(α-phenylethyl)amine (H-PEA-S) proved promising. After optimization of the reaction conditions, the best enantioselectivity (26% yield and 80% ee in favor of the R_P enantiomer) was observed by treating a THF solution of FcCO₂Me and Zn(PEA-S)₂ with Li-PEA-S at −80 °C before iodolysis. That no reaction took place with cadmium instead of zinc suggests the formation of ‘ate complexes upon treatment of Cd(PEA-S)₂ by Li-PEA-S while Zn(PEA-S)₂ and Li-PEA-S would rather work in tandem (Li-PEA-S as the base and Zn(PEA-S)₂ as the in situ trap for the formed ferrocenyllithium). While FcCO₂Me, FcCO₂tBu and FcCO₂iPr could be converted into their racemic 2-iodinated derivatives with a yield of 84 to 87% by employing LiTMP (2 equiv.) in the presence of ZnCl₂·TMEDA (1 equiv.) as an in situ trap, their enantioselective deprotometalation rather required Li-PEA-S together with Zn(PEA-S)₂ to produce the enantio-enriched derivatives with yields of 45–82% and 71% ee.