2 research outputs found
An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of <i>N</i>-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters
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 <i>N</i>-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: <i>n</i>-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 <i>tert</i>-butoxycarbonyl (Boc)
group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine;
low yields for the lithiation–substitution of <i>N</i>-Boc-2-phenylpyrrolidine at −78 °C can be ascribed to
this slow rotation. For <i>N</i>-Boc-2-phenylpyrrolidine
and -piperidine, the barriers to rotation of the Boc group were determined
using density functional theory calculations and variable-temperature <sup>1</sup>H NMR spectroscopy. For the pyrrolidine, the half-life (<i>t</i><sub>1/2</sub>) 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, <i>t</i><sub>1/2</sub> was determined to be ∼4 s at −78 °C
An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of <i>N</i>-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters
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 <i>N</i>-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: <i>n</i>-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 <i>tert</i>-butoxycarbonyl (Boc)
group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine;
low yields for the lithiation–substitution of <i>N</i>-Boc-2-phenylpyrrolidine at −78 °C can be ascribed to
this slow rotation. For <i>N</i>-Boc-2-phenylpyrrolidine
and -piperidine, the barriers to rotation of the Boc group were determined
using density functional theory calculations and variable-temperature <sup>1</sup>H NMR spectroscopy. For the pyrrolidine, the half-life (<i>t</i><sub>1/2</sub>) 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, <i>t</i><sub>1/2</sub> was determined to be ∼4 s at −78 °C