Synthesis of Trialkylhydroxylamines by Stepwise Reduction of O‑Acyl N,N‑Disubstituted Hydroxylamines: Substituent Effects on the Reduction of O‑(1-Acyloxyalkyl)hydroxylamines and on the Conformational Dynamics of N‑Alkoxypiperidines

The influence of the electron-withdrawing azide group on the reduction of O-(1-acyloxy-ω-azido)­hydroxylamines by triethylsilane in the presence of boron trifluoride etherate is studied and found to increase with increasing proximity to the reaction site, suggesting that the reaction proceeds by way of aminoxocarbenium ion intermediates. The ability to carry azides through the reaction sequence affords O-(ω-azidoalkyl-N,N-dialkylhydroxylamines thereby making such functionality available for use in click chemistry. A series of 4-substituted N-alkoxypiperidines were prepared and studied by variable temperature NMR spectroscopy leading to the conclusion that the rate-determining step in the stereomutation of such piperidines is the piperidine ring flip and not nitrogen inversion or rotation about the N–O bond. The process of N–O bond rotation only becomes rate determining when in the presence of pervasive steric hindrance as is the case with the N-alkoxy-2,2,6,6-tetramethylpiperidines.