Efficient Lewis Acid Systems for the A3 Coupling reaction

Efficient Lewis Acid Systems for the A3 Coupling reaction Cimarelli C., a Navazio F.,a Rossi F. V.a, Del Bello F., Marcantoni E.a aSchool of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino; e-mail: cristina.cimarelli@unicam.it Propargylamines are an attractive class of molecules because of their particular molecular skeleton, that contains an amine group located in β-position to an alkyne moiety suitable for many chemical transformations. In recent years they received a growing interest as key intermediates for several biologically active compound, natural products and also different heterocycles.[1,2] Our goal was the development of green and simple methodologies for the synthesis of secondary propargylamines by Lewis acid catalyzed or promoted A3 reaction among aldehydes, alkynes and primary amines, that are in general less applied in such reactions because of their lower reactivity. In particular, we studied two different pathway: the CuSO4/NaI system in one pot fashion and the CeCl3/CuI system in one pot/two steps way (Scheme 1). Scheme 1. CeCl3·7H2O/CuI and CuSO4/NaI catalyzed A3 reaction. Heptahydrated CeCl3 is reported to be an excellent catalyst for many useful organic transformation as the synthesis of imines. Its efficacy as Lewis acid is enhanced in the presence of inorganic iodides/iodide salt and being cooper the transition metal of choice for A3 reactions, CuI was used.[3] Also the CuSO4/NaI couple has revealed to be an interesting Lewis acid system as an alternative to CeCl3/CuI system which allow the formation of CuI in situ by quantitative spontaneous reaction that takes place in few seconds.[4] Typically CuSO4/NaI catalysed reactions are faster than CeCl3·7H2O/CuI reactions, but suffer of some disadvantages, such as lower yields, and a narrower applicability. Both reaction conditions have been applied to different aldehydes (aromatic and aliphatic) and to chiral starting materials, the amine in general has no effect on the reaction outcome. The relevant Glaser coupling drawback observed in the CuSO4/NaI system conditions has been suppressed by adding some benzoic acid, and has not been observed with the CeCl3/CuI system. References: 1) Lauder, K.; Toscani, A.; Scalacci, N.; Castagnolo, D. Chem. Rev. 2017, 117, 14091. 2) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790. 3) G. Bartoli, E. Marcantoni, M. Marcolini, L. Sambri, Chem. Rev. 2010, 110, 6104. 4) Bailey, A. D.; Cherney, S. M.; Anzalone, P. W.; Anderson, E. D.; Ernat, J. J.; Mohan, R. S. Synlett 2006, 215.