Solvent effects on the mixed aggregates of chiral 3-aminopyrrolidine lithium amides and alkyllithiums

The condensation of n-butyllithium on o-tolualdehyde in the presence of a chiral 3-aminopyrrolidine lithium amide led to the expected alcohol with ee strongly dependent on the solvent (THF, diethylether and toluene). A NMR and theoretical study of this effect was undertaken to rationalize these results. The addition of two equivalents of methyllithium to a 3-aminopyrrolidine [benzhydryl-(1-benzylpyrrolidin-3-yl)-amine] led, in THF- d 8 and at −90 °C, to an exo aza-norbornyl-type mixed aggregate, similar to that characterized previously between the lithium amide and n-butyllithium in the same solvent. In diethyl ether, a non-covalent complex presenting a comparable exo topology was obtained despite a ∼1 ppm high-field drift of the chemical shift of one of its two 6Li nuclei (Li 2). The progressive addition of THF to the medium brought the Li 2 signal back to its original value, suggesting that this atom could also be the target of the incoming aldehyde. When reacting the same aminopyrrolidine with MeLi and BuLi in toluene, the expected lithium amide was recovered, apparently under two forms, which did not aggregate with the excess MeLi or BuLi until THF was added to the medium. Reacting the aminopyrrolidine with n-butyllithium, which is more soluble in toluene, led to a comparable complex. Finally, a discussion on the interaction between a mixed aggregate and the aldehyde, based on a theoretical analysis of the solvation energies of the two lithium atoms by three different ethers, is proposed. Graphical Abstract