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

Nadeem S. Sheikh, Daniele Leonori, Graeme Barker, James D. Firth, Kevin R. Campos, Anthony J. H. M. Meijer, Peter O'Brien, Iain Coldham

Research output: Contribution to journalArticle

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 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ∼10 h at −78 °C and ∼3.5 min at −50 °C. In contrast, for the piperidine, t1/2 was determined to be ∼4 s at −78 °C.
Original languageEnglish
Pages (from-to)5300-5308
Number of pages9
JournalJournal of the American Chemical Society
Volume134
Issue number11
Early online date7 Mar 2012
DOIs
Publication statusPublished - 21 Mar 2012

Fingerprint

Piperidines
Monitoring
Nuclear magnetic resonance spectroscopy
Density functional theory
Infrared spectroscopy
piperidine
Experiments
Temperature
pyrrolidine
n-butyllithium

Cite this

Sheikh, Nadeem S. ; Leonori, Daniele ; Barker, Graeme ; Firth, James D. ; Campos, Kevin R. ; Meijer, Anthony J. H. M. ; O'Brien, Peter ; Coldham, Iain. / 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. In: Journal of the American Chemical Society. 2012 ; Vol. 134, No. 11. pp. 5300-5308.
@article{94519618629941d39e8303d43e8e03af,
title = "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",
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 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ∼10 h at −78 °C and ∼3.5 min at −50 °C. In contrast, for the piperidine, t1/2 was determined to be ∼4 s at −78 °C.",
author = "Sheikh, {Nadeem S.} and Daniele Leonori and Graeme Barker and Firth, {James D.} and Campos, {Kevin R.} and Meijer, {Anthony J. H. M.} and Peter O'Brien and Iain Coldham",
year = "2012",
month = "3",
day = "21",
doi = "10.1021/ja211398b",
language = "English",
volume = "134",
pages = "5300--5308",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "11",

}

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. / Sheikh, Nadeem S.; Leonori, Daniele; Barker, Graeme; Firth, James D.; Campos, Kevin R.; Meijer, Anthony J. H. M.; O'Brien, Peter; Coldham, Iain.

In: Journal of the American Chemical Society, Vol. 134, No. 11, 21.03.2012, p. 5300-5308.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Sheikh, Nadeem S.

AU - Leonori, Daniele

AU - Barker, Graeme

AU - Firth, James D.

AU - Campos, Kevin R.

AU - Meijer, Anthony J. H. M.

AU - O'Brien, Peter

AU - Coldham, Iain

PY - 2012/3/21

Y1 - 2012/3/21

N2 - 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 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ∼10 h at −78 °C and ∼3.5 min at −50 °C. In contrast, for the piperidine, t1/2 was determined to be ∼4 s at −78 °C.

AB - 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 1H NMR spectroscopy. For the pyrrolidine, the half-life (t1/2) for rotation of the Boc group was found to be ∼10 h at −78 °C and ∼3.5 min at −50 °C. In contrast, for the piperidine, t1/2 was determined to be ∼4 s at −78 °C.

U2 - 10.1021/ja211398b

DO - 10.1021/ja211398b

M3 - Article

VL - 134

SP - 5300

EP - 5308

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 11

ER -