Direct Synthesis of 1_2_Benzisoxazoles Via Palladium Catalysis

The 1,2-benzisoxazole heterocycle represents an important chemical motif in modern medicine. Several FDA approved drugs featuring this component, such as Zonisamide and Paliperidone, are widely administered to treat epilepsy and schizophrenia. Other small molecules that contain a 1,2-benzisoxazole are under study for the treatment of Alzheimer's disease, obesity and certain types of cancer. Because these molecules are not found in nature, chemical synthesis is the only route to accessing 1,2-benzisoxazole derivatives. Current methodologies for their laboratory synthesis are chemically and economically inefficient. In order to access new 1,2-benzisoxazole medicines and to optimize derivatives currently under study, a new synthetic method is highly desired. To address this need, a palladium-catalyzed cascade merger of aryl halides and linear nitrones is proposed. This method provides a direct and selective route to 1,2-benzisoxazoles from readily available chemicals. Catalysis allows chemists to prepare complex chemicals under mild reaction conditions; thus, the proposed method will enable the synthesis of 1,2-benzisoxazole derivatives currently inaccessible. This proposal provides strategies inspired by modern technology aided by the rich history of nitrones and palladium catalysis to open new doors for medicinal chemists and ultimately modern medicine.