Development of a Continuous Flow N-Hydroxycarbamate Generator from Alcohol Derivatives

Abstract

N-Hydroxycarbamates play a key role as intermediates for a variety of compounds either in the pharmaceutical or pesticide industry. The most common synthetic pathway relies on the use of chloroformates intermediates yielded from the use of hazardous phosgene or derivatives such as CDI and hydroxylamine. In this master thesis, the production of N-hydroxycarbamates is disclosed as a two-step procedure relying on a key non-symmetrical carbonate intermediate. Continuous flow technology will be used as a means to intensify the reaction and its parameters. The non-symmetrical carbonate will act as a surrogate to phosgene-derived chloroformates and will be produced using commercially available and innocuous dimethyl carbonate. The robustness of the carbonation reaction under flow conditions was assessed by testing 17 benzyl alcohol derivatives. Conversions ranging from 66% to 96% were observed while testing derivatives with either electron withdrawing or donating groups on the aromatic ring. The reaction was performed in the presence of 3 mol% of TBD as the organocatalyst, 66 equivalents of dimethyl carbonate as both reagent and solvent as well as 1 equivalent of the tested benzyl alcohol derivative. A 10 min residence time was required alongside a 100 psi pressure and 80 °C for the reaction to proceed. The hydroxylamination reaction of non-symmetrical carbonate intermediate was then envisioned resulting in its implementation under both microwave irradiation and later continuous flow conditions with mixed yet encouraging results (66% conversion and 48% selectivity). The optimized continuous flow reaction relied on the use of 1 equivalent of the carbonate substrate, 5 equivalents of hydroxylamine and 0.5 equivalents of gadolinium triflate in 30 min at 80 °C under a 130 psi of counter-pressure. A small scope of previously synthesized carbonates was used to evaluate the efficiency of the reaction offering conversions ranging from 17% to 70% and selectivities from 34% to 49%. Finally, the reaction was tested as a “one-pot” process leading to promising results (22% conversion and 66% selectivity).