Direct Synthesis of 1_2_Benzisoxazoles Via Palladium Catalysis

描述(申请人提供)：1，2-苯并异恶唑杂环代表了现代医学中一个重要的化学基元。FDA批准的几种含有这种成分的药物，如唑尼沙胺和帕利培酮，被广泛用于治疗癫痫和精神分裂症。其他含有1，2-苯并恶唑的小分子正在研究中，用于治疗阿尔茨海默病、肥胖症和某些类型的癌症。由于这些分子在自然界中不存在，化学合成是获得1，2-苯并恶唑衍生物的唯一途径。目前实验室合成它们的方法在化学和经济上都是低效的。为了获得新的1，2-苯并恶唑类药物和优化目前正在研究的衍生物，迫切需要一种新的合成方法。为了满足这一需求，提出了一种钯催化的芳基卤化物和线性硝酮的级联合并。该方法提供了从易得的化学品中直接和选择性地合成1，2-苯并异恶唑的路线。催化使化学家能够在温和的反应条件下制备复杂的化学品；因此，所提出的方法将使目前无法合成的1，2-苯并恶唑衍生物成为可能。这一建议提供了受现代技术启发的战略，并辅之以硝酮和钯催化的丰富历史，为药物化学家和最终的现代医学打开了新的大门。

DESCRIPTION (provided by applicant): 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.