Functionalization of Piperidine Derivatives for the Site-Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate

• Authors: Wenbin Liu, Emory University; Tobias Babl, Emory University; Alexander Röther, University of Regensburg; Oliver Reiser, University of Regensburg; Huw Davies, Emory University
• Journal Title: CHEMISTRY-A EUROPEAN JOURNAL
• Volume: Volume 26, Number 19
• Publisher: WILEY-V C H VERLAG GMBH | 2020-04-01, Pages 4236-4241
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/chem.201905773
• Subjects: Chemistry, General; Biology, Cell; Chemistry, Organic
• Keywords: Science & Technology; Physical Sciences; Chemistry, Multidisciplinary; Chemistry; C-H functionalization; diastereoselectivity; piperidines; regioselectivity; rhodium; H BOND FUNCTIONALIZATION; ACTIVATION; ARYLDIAZOACETATES; DIVERSIFICATION; HYDROXYLATION; NITROGEN; PROLINE; ENABLES; ALPHA; TOOLS

Abstract

Rhodium-catalyzed C−H insertions and cyclopropanations of donor/acceptor carbenes have been used for the synthesis of positional analogues of methylphenidate. The site selectivity is controlled by the catalyst and the amine protecting group. C−H functionalization of N-Boc-piperidine using Rh2(R-TCPTAD)4, or N-brosyl-piperidine using Rh2(R-TPPTTL)4 generated 2-substitited analogues. In contrast, when N-α-oxoarylacetyl-piperidines were used in combination with Rh2(S-2-Cl-5-BrTPCP)4, the C−H functionalization produced 4-susbstiuted analogues. Finally, the 3-substituted analogues were prepared indirectly by cyclopropanation of N-Boc-tetrahydropyridine followed by reductive regio- and stereoselective ring-opening of the cyclopropanes.