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

Francos, Javier and Zaragoza-Calero, Silvia and O'Hara, Charles T. (2014) Optimisation of a lithium magnesiate for use in the non-cryogenic asymmetric deprotonation of prochiral ketones. Dalton Transactions, 43 (3). pp. 1408-1412. ISSN 1477-9234

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    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 nBu 2Mg, 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)(CH2SiMe 3)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)(CH2SiMe 3)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.