Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines by Lithiation and Substitution, with in Situ IR Spectroscopy and Configurational Stability Studies

Lithiation of <i>N</i>-Boc-1-phenyltetrahydroisoquinolines was optimized by in situ IR spectroscopy. The kinetics for rotation of the carbamate group and for the enantiomerization of the organolithium were determined. The organolithium is configurationally stable at low temperature, and the asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines can be achieved with high yields and high enantiomer ratios. The chemistry was applied to the preparation of FR115427 and provides a way to recycle the undesired enantiomer in the synthesis of solifenacin

Preparation of 1‑Substituted Tetrahydro-β-carbolines by Lithiation–Substitution

A method to prepare 1-substituted <i>N</i>-Boc-tetrahydro-β-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (<i>N</i>-methyltetrahydroharman) and 11-methylharmicine

Arylthio-Metal Exchange of α‑Arylthioalkanenitriles

The addition of BuLi, Bu₃MgLi, Et₂ZnBuLi, or Me₂CuLi to α-arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three-coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations

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 ¹H NMR spectroscopy. For the pyrrolidine, the half-life (<i>t</i>_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, for the piperidine, <i>t</i>_1/2 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 ¹H NMR spectroscopy. For the pyrrolidine, the half-life (<i>t</i>_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, for the piperidine, <i>t</i>_1/2 was determined to be ∼4 s at −78 °C