Innovative strategy towards (bicyclo)-3,6-dihydro-1,2-oxazines from a novel class of photocleavable acylnitroso

Abstract

The present research project is devoted to the preparation of polyfunctional (bicyclo)-3,6-dihydro-1,2-oxazine scaffold (OS) bearing a free amine through a nitroso hetero Diels Alder (nHDA) reaction using a novel class of photocleavable acylnitroso compound followed by the orthogonal removal of the photolabile moiety. We successfully developed a 3-step strategy to reach the coveted OS. In the first step, we obtained the key hydroxycarbamate precursor in 81% yield and >99% purity, which is composed of two parts: a nitropiperonyl based photolabile copula and the N-hydroxycarbamate. This precursor was subsequently oxidized to yield a highly reactive nitroso dienophile species to perform various nHDA reactions using a small diene library. Among the oxidation procedures employed, H2O2 in the presence of CuCl afforded the best results with yields and purities ranging from 78-86% and 84-97%, respectively. We have also designed a new promising procedure for the precursor photooxidation under continuous flow conditions. Finally, the targeted OS bearing a free amine was obtained after irradiating the cycloadduct at 365 nm for 30 s under continuous flow conditions. The results obtained demonstrated the feasibility as well as the potency and robustness of our novel strategy for the preparation of a multitude of OS bearing a free amine.