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Direct, enantioselective, and nickel(II) catalyzed reactions of N-azidoacetyl thioimides with trimethyl orthoformate: a new combined methodology for the rapid synthesis of lacosamide and derivatives
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A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C−C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.
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TELOXA, Saul F., et al. Direct, enantioselective, and nickel(II) catalyzed reactions of N-azidoacetyl thioimides with trimethyl orthoformate: a new combined methodology for the rapid synthesis of lacosamide and derivatives. Chemistry-A European Journal. 2020. Vol. 26, num. 49, pags. 11540-11548. ISSN 0947-6539. [consulted: 13 of August of 2026]. Available at: https://hdl.handle.net/2445/170414