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

• Type of Material: Article
• Authors: Wenbin Liu, Emory University; Tobias Babl, Emory University; Alexander Röther, University of Regensburg; Oliver Reiser, University of Regensburg; Huw Davies, Emory University
• Language: English
• Date: 2020-04-01
• Publisher: WILEY-V C H VERLAG GMBH
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/chem.201905773
• Title of Journal or Parent Work: CHEMISTRY-A EUROPEAN JOURNAL
• Volume: 26
• Issue: 19
• Start Page: 4236
• End Page: 4241
• Grant/Funding Information: Financial support (HMLD) was provided by NSF under the CCI Center for Selective C−H Functionalization (CHE‐1700982) and AbbVie. Financial support (OR) was provided by Elitenetzwerk Bayern (SYNCAT).; Funds to purchase the NMR and X‐ray spectrometers used in these studies were supported by NSF (CHE 1531620 and CHE 1626172).; Financial support for the development of the catalyst, Rh2(R‐TPPTTL)4 was provided by NIH (GM099142‐05).
• Keywords: PROLINE; C-H functionalization; DIVERSIFICATION; H BOND FUNCTIONALIZATION; NITROGEN; diastereoselectivity; HYDROXYLATION; rhodium; ENABLES; Chemistry, Multidisciplinary; piperidines; Chemistry; Science & Technology; regioselectivity; ACTIVATION; TOOLS; ARYLDIAZOACETATES; ALPHA; Physical Sciences
• Research Categories: Biology, Cell; Chemistry, Organic; Chemistry, General

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.