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.