Reagent-Controlled Divergent Synthesis of 2‑Amino-1,3-Benzoxazines and 2‑Amino-1,3-Benzothiazines

A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-benzoxazines and related biologically important heterocycles in high yields under mild conditions. These scaffolds could be efficiently constructed using two different chemoselective reactions that rely on the choice of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a mild cyclodehydrating agent) and triethylamine as the base. The described protocol represents the first example for the synthesis of 4H-1,3-benzoxazines via the dehydrosulfurization method using molecular iodine as the reagent.本研究开发了一种试剂调控的化学选择性合成方法，可在温和条件下以高收率制备4H-1,3-苯并噁嗪（4H-1,3-benzoxazines）及其他具有重要生物活性的杂环化合物。该类分子骨架可通过两种依赖试剂与反应条件选择的不同化学选择性反应高效构建。将各类2-氨基芳基烷基醇与异硫氰酸酯（isothiocyanates）反应，可得到硫脲（thiourea）中间体；随后该中间体在三乙胺（triethylamine）存在下与分子碘（molecular iodine）原位反应，即可得到2-氨基-4H-1,3-苯并噁嗪。而若将硫脲中间体在T3P（一种温和环脱水试剂）与碱三乙胺的存在下进行反应，则可获得对应的2-氨基-4H-1,3-苯并噻嗪（4H-1,3-benzothiazines）。本报道的合成策略为首例以分子碘为试剂、通过脱硫化方法合成4H-1,3-苯并噁嗪的案例。