On Demand Flow Platform for the Generation of Anhydrous Dinitrogen Trioxide and Its Further Use in N-Nitrosative Reactions

Abstract

Dinitrogen trioxide (N₂ O₃ ) is a powerful and efficient nitrosating agent that comes with an unprecedented atom economy. However, the synthetic application of N₂ O₃ is still underdeveloped mostly due to its inherent instability and the lack of reliable protocols for its preparation. This paper presents an open-source setup and procedure for the on-demand generation of anhydrous N₂ O₃ solution (up to 1 M), which can be further used for reactions under batch and flow conditions. The accuracy and stability of N₂ O₃ concentration are guaranteed with the absence of head-space in the setup and with the synchronization of the gas flows. The reliability of this protocol is demonstrated by >30 worked examples in the nitrosative synthesis of heterocycles-a library of structurally diverse benzotriazoles and sydnones. Kinetic and mechanistic aspects of the N-nitrosative steps are also explored.

Keywords: Benzotriazole; Continuous Flow; Dinitrogen Trioxide; Nitrosation; Sydnone.