Enantioselective deprotometalation of alkyl ferrocenecarboxylates using bimetallic bases

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 RP 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 RP 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 RP 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.