New strategies toward the preparation and use of unstable nitroso species

Abstract

Nitroso species and their wide variety are known for decades and are involved in numerous applications such as hetero Diels-Alder reactions or electrophilic aminations on α-ketones. However, they intrinsic poor stability, toxicity and their relative hazardous profile tuned down their potential use at an industrial-scale. In a conventional batch reactor, these reactions are relatively long (20-45 min) and the conversions associated are uncomplete. In this work, safe and efficient continuous-flow procedures for the preparation of α-chloro-nitroso species from aqueous sodium hypochlorite and oximes were developed. The conditions were first developed in a microfluidic setup, and next transposed to an industrial mesofluidic flow reactor. The lab-scale continuous-flow setup developed in this project affords complete conversion within minutes for different kinds of starting oximes (aliphatic and alicyclic, including chiral substrates). The process is very safe, and in-line IR analysis complements the control over the process conditions. The setup is amenable to the generation of libraries of α-chloro-nitroso and sustains productivities of up to 6 mL min-1, delivering ready-to-use α-chloro-nitroso species. The scope of the method was next assessed with a concrete application of α-chloro-nitroso species toward the synthesis of pharmacological active norephedrine. The optimized strategy toward norephedrine from propiophenone involved four steps with an overall isolated yield of 53%. Besides, several α-chloro-nitroso classes (aliphatic, alicyclic and chiral) were tested. In the last part of this work, we assessed the full development of a continuous-flow process toward norephedrine from a propiophenone derivative. Encouraging preliminary data was obtained.