An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: controlling the formation of quaternary stereocenters

Journal of the American Chemical Society
Nadeem S SheikhIain Coldham

Abstract

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, ...Continue Reading

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Citations

Aug 14, 2012·Journal of the American Chemical Society·Timothy K BengRobert E Gawley
Oct 13, 2015·The Journal of Organic Chemistry·Yuri KotomoriKei Takeda
Jul 15, 2016·Journal of the American Chemical Society·Jin-Shun LinXin-Yuan Liu
Sep 28, 2016·Chemical Reviews·Renata Marcia de FigueiredoJean-Marc Campagne
Jun 3, 2017·The Journal of Organic Chemistry·James D FirthLeigh Ferris
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May 14, 2016·Organic & Biomolecular Chemistry·Ruaa A TalkIain Coldham
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May 15, 2015·The Journal of Organic Chemistry·Edward J CochraneIain Coldham

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