Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies.
Keywords: 1,3-dipolar cycloaddition; Schmidt reaction; Ullmann reaction; indanone; isoquinolinone; isoxazole; isoxazolidine; nitrile oxide; nitrone.