A solvent free tandem lactamization-decarboxylation route to (S)-Pregabalin lactam

[Display omitted] Herein we describe a novel lactamization-decarboxylation tandem reaction to form (S)-N-benzyl-pregabalin lactam in solvent-free condensation of benzyl amine with (S)-4-isobutyl α-ethylaceto γ–butyrolactone, obtained in two steps from commercially available starting material. Triflic acid-mediated debenzylation in the same pot gave (S)-pregabalin lactam, which constitutes a formal synthesis of the anticonvulsant and anxiolytic drug pregabalin. Isolation of the lactamization intermediates indicates that the initially formed kinetic hydroxyamide is in equilibrium with lactone and the formation of amino acid precedes lactamization.