Chemical generator of acylnitroso species for the preparation of versatile oxazine synthons

Abstract

This work is devoted to the development of a novel strategy for the synthesis of 3,6-dihydro-1,2-oxazines through the traceless photooxidation of hydroxamic acids/N-hydroxycarbamates with ROS to produce acylnitroso species followed by their subsequent trapping with various dienes via a n-HDA reaction. The free oxazine scaffold can be efficiently retrieved after orthogonal (photo)deprotection. Among the oxidation procedures studied, the NaIO4 route provided a quantitative conversion within 1 h and a 12-90% selectivity. H2O2 in the presence of CuCl offered a quantitative conversion within 2-3 hours and a 44-97% selectivity. Our newly developed route was proved to be robust and versatile, providing a 39-70% conversion, a 25-89% selectivity and a 7-64% crude yield within 1 h for a large scope of cycloadducts. A quantitative conversion was reached for several compounds within 3-6 h. The photooxidation process was implemented under flow conditions and the space/time-controlled generation of singlet oxygen successfully suppressed the side reactions between the diene and 1O2 while maintaining the superoxide anion contribution to the oxidation. Therefore, we succeeded in keeping nitrosoformate species, generated in a first fluidic module under irradiation, alive long enough to ensure their n-HDA reaction with 1,3-cyclohexadiene in the next fluidic module. Furthermore, we observed the appearance of a vibration band of N2O, a well-known dimerization side product, by in-line IR monitoring, therefore supporting the formation of acylnitroso species during the process. Finally, the photodeprotection step was fully achieved within 4 min of 365 nm LEDs irradiation under continuous flow conditions, yielding the coveted oxazine bearing a free amine.