Optimisation of a lithium magnesiate for use in the non-cryogenic asymmetric deprotonation of prochiral ketones?

Dalton Transactions Pub Date: 2013-11-01 DOI: 10.1039/C3DT52577E

Abstract

A study has been conducted to determine whether lithium magnesiates are feasible candidates for the enantioselective deprotonation of 4-alkylcyclohexanones. The commercially available chiral amine (+)-bis[(R)-1-phenylethyl]amine (2-H) was utilised to induce enantioselection. When transformed to its lithium salt and combined with nBu2Mg, improved enantioselective deprotonation of 4-tert-butylcyclohexanone (with respect to the monometallic lithium amide) at 20 °C was observed. In an attempt to optimise the reaction further, different additives were added to the lithium amide. The best performing deprotonations at 0 °C were those in which (Me3SiCH2)2Mg (er pro-S 74?:?26) and (Me3SiCH2)2Mn (er pro-S 72?:?28) were added, hence the lithium magnesiate “LiMg(2)(CH2SiMe3)2” was used in the remainder of the study. The optimum solvent for the reaction was found to be THF. NMR spectroscopic studies of a D8-THF solution of “LiMg(2)(CH2SiMe3)2” appear to show that this mono-amide bis-alkyl species is in equilibrium with a bis-amide mono-alkyl compound (and a tris-alkyl lithium magnesiate). When a genuine bis-amide lithium magnesiate solution is used, the deprotonation results were essentially identical to those obtained for “LiMg(2)(CH2SiMe3)2”. By adding LiCl to “LiMg(2)(CH2SiMe3)2” the er at 0 °C improved to 81?:?19. At ?78 °C good yields and an er of 93?:?7 were obtained. This LiCl-containing base was used to successfully deprotonate other 4-alkylcyclohexanones.

Graphical abstract: Optimisation of a lithium magnesiate for use in the non-cryogenic asymmetric deprotonation of prochiral ketones
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