Synthesis of Aminoindolizidines through the Chemoselective and Diastereoselective Catalytic Hydrogenation of Indolizines

Indolizidines are bioactive heterocyclic compounds of great potential normally prepared following multistep routes. However, to the best of our knowledge, the synthesis of 1-aminoindolizidines has never been reported. Herein, 1-(dialkylamino)-3-substituted indolizidines have been straightforwardly synthesized using an atom-economic protocol that involves a copper-catalyzed three-component synthesis of indolizines followed by heterogeneous catalytic hydrogenation. The latter was found to be chemoselective using platinum(IV) oxide as the catalyst at 3.7 atm, providing the aminoindolizidines in modest-to-high yields (35–95%) and high diastereoselectivity (92:8 to >99:1). It has been experimentally demonstrated that the hydrogenation occurs through the intermediate 5,6,7,8-tetrahydroindolizine, which contains a pyrrole moiety. Moreover, the diastereomerically pure 1-(dibenzylamino)-3-substituted indolizidines could be further transformed into the corresponding monobenzylated or fully debenzylated aminoindolizidines by selective hydrogenolysis catalyzed by Pt/C or Pd/C, respectively, under ambient conditions.This work was generously supported by the Spanish Ministerio de Economía y Competitividad (MINECO, CTQ2011-24151). M.J.A. and M.J.G.-S. acknowledge the Instituto de Síntesis Orgánica (ISO) of the Universidad de Alicante for both grants