Enantioselective deprotometalation of N,N-dialkyl ferrocenecarboxamides using metal amides

Abstract

et al.. Enantioselective deprotometalation of N,N-dialkyl ferrocenecarboxamides using metal amides.1 TOC Our attempts to deprotometalate N,N-dialkyl ferrocenecarboxamides enantioselectively by using chiral lithium or lithium-zinc dialkylamides are reported. Abstract:N,N-Diisopropylferrocenecarboxamide can be enantioselectively deprotometalated by combining butyllithium with (-)-sparteine in diethyl ether at low temperature. It is of interest to identify conditions that could allow substrates bearing more reactive functional groups (such as esters and ketones) to be similarly converted. We here report our efforts to use different chiral lithium-zinc bases, made from a simple chiral lithium amide, (R,R)-or (S,S)-lithium bis (1-phenylethyl)amide (PEALi), for the enantioselective deprotonation of N,N-diisopropylferrocenecarboxamide. First, different zinc-based in situ traps were employed to intercept the formed ferrocenyllithium; optimization using enantiopure lithium bis[1-(S)-phenylethyl]amide ((S)-PEALi) led to the 2-iodo derivative in 96% yield and 69% ee in favor of the RP enantiomer. The method was extended to N,N-dimethylferrocenecarboxamide, morpholinoferrocenecarboxamide and N,N-diethylferrocenecarboxamide; for the latter, similar yield and enantioselectivity were recorded. DFT calculations on a model reaction showed very small differences between the activation energies leading to (RP)-and (SP)-2-lithioferrocenecarboxamides. Next, the behavior of various mixed amino-alkyl lithium zincates of the types R2[(S)-PEA]ZnLi and R2[(S)-PEA]2ZnLi2 (R = alkyl) was studied, notably by varying the reaction temperature and time, and the amount of base. The best results were obtained with Me2[(S)-PEA]2ZnLi2, affording the 2-iodo derivative in 97% yield and 86% ee in favor of the SP enantiomer.

O‐Isopropylferrocenesulfonate: Synthesis of Polysubstituted Derivatives and Electrochemical Study

“…By following studies on the use of chiral lithium-zinc mixed amides and combinations to reach the same goal, [33] we showed in 2019 that zinc-based in situ traps generally give better results than chlorotrimethylsilane. [34] In particular, we evidenced [Zn {(S)-PEA} 2 ], in situ prepared from ZnCl 2 • TMEDA and (S)-PEALi in a 1 : 2 ratio, as the best one to this purpose. Indeed, upon addition of (S)-PEALi (1 equiv) to a mixture of [Zn{(S)-PEA} 2 ] (1 equiv) and N,N-diisopropylferrocenecarboxamide in THF at À 70°C before slow warming to À 10°C (over 3 h) and iodolysis, the corresponding 2-iodo derivative was obtained in 96 % yield and 69 % ee.…”

Exploring the boundaries of ferrocenesulfonyl fluoride chemistry

“…This was demonstrated by Price and Simpkins who reported the asymmetric deprotolithiation of P,Pdiphenylferrocenephosphine oxide in 54% ee by using lithium bis[(S)-1-phenylethyl]amide [(S)-PEALi] in the presence of trimethylsilyl chloride as an in situ trap. 66 We recently demonstrated that the use of more efficient chiral zinc-based in situ traps could be beneficial for some substrates and managed to reach enantioenriched N,N-dialkylferrocenecarboxamides, 67 O-alkylferrocenecarboxylates 68 and Oisopropylferrocenesulfonate 55 with ee ranging from 64 to 80%. Here, we initially evaluated the use of alkyllithium•chiral diamine chelates to perform the enantioselective deprotolithiation of the substrate 2 before adding a suitable electrophile.…”

Enantioselective deprotometalation of alkyl ferrocenecarboxylates using bimetallic bases

“…Mixed amido/organo lithium zincates are generally less reactive bases than lithium amide-zinc trap combinations. 43,73 Nevertheless, in order to reduce competitive deprotonation by the chiral ferrocenyldiamidozincates formed during these reactions, we tested lower temperatures. However, by using (endo-S)3ZnLi [59][60][61] at -30 °C, 1-I was formed with a yield of 77% and an ee of 39% in favor of the RP enantiomer, a result similar to that obtained at rt.…”

“…85,86 We realized in 19 2019 that, while chlorotrimethylsilane is often used as an in situ trap in deprotolithiation reactions using hindered lithium amides, 44 its ability to intercept lithium species is low compared to other traps such as ZnCl2•TMEDA and Zn(TMP)2. 73 As a consequence, this was no surprise when we tested chlorotrimethylsilane as an in situ trap in the reaction between 1-H and LiTMP in THF at -30 °C: poor results were obtained due to the degradation before trapping of the ferrocenyllithiums formed (not shown).…”