Development of green methods for synthesis of 2-aminobenzoxazoles from organosulfurs

Abstract

2-aminobenzoxazoles are an important motif in pharmaceutical and chemical industries, however, their preparations involve the use of toxic reagents and organic solvents. Therefore, greener methods for preparation of 2-aminobenzoxazoles are highly desired. In this work, we demonstrate two novel methodologies for synthesis of 2-aminobenzoxazoles in aqueous media. The first method involves the use of "on water" microwave reaction to perform the amination of 2-mercaptobenzoxazoles into 2-aminobenzoxazoles. Various 2-aminobenzoxazoles are synthesized under additive-free condition accelerating by microwave irradiation at 100 oC for 1 hour in moderate to good yields. This synthesis can be applied to prepare 2-aminobenzoxazole in gram scale quantity. Importantly, the formal synthesis of Suvorexant, a medication for the treatment of insomnia, is accomplished using our developed on-water amination process. The mechanistic study suggests that the amination process occur via ring-opening/closing process followed by the loss of hydrogen sulfide. Alternatively, we successfully develop an electrochemical one-pot synthesis of 2-aminobenzoxazoles from 2-aminophenols and isothiocyanates using sodium iodide as an electrolyte. The process is carried out in a simple undivided electro-cell equipped with platinum for both electrodes under constant voltage (5 V) at ambient temperature in the mixture of water and ethanol (1:1). With the optimal condition, 21 examples of 2-aminobenzoxazoles are successfully prepared in moderate to good yields. Moreover, potent bioactive compounds (1aa and 1dc) for asthma treatment, are prepared under optimal condition in a gram scale quantity. The cyclic voltammetry and control experiments reveal that the mechanism of this electrocyclization proceed via iodide mediated electrolysis.