N‐Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N‐demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible‐light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.
Dinitrogen trioxide (N 2 O 3 ) is a powerful and efficient nitrosating agent that comes with an unprecedented atom economy. However, the synthetic application of N 2 O 3 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 N 2 O 3 solution (up to 1 M), which can be further used for reactions under batch and flow conditions. The accuracy and stability of N 2 O 3 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 Nnitrosative steps are also explored.
A continuous-flow Pd-catalyzed oxidative carbonylation protocol utilizing CO and O 2 gas for the synthesis of carbonylated heterocycles is described. The optimization of temperature, pressure, CO/O 2 ratio, catalyst loading, and reaction time resulted in process intensified conditions for this transformation. The optimized continuous flow conditions (120 °C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone, 2-benzoxazolidinone, and other biologically and synthetically important fiveand six-membered carbonylated heterocycles in good overall yield and purity (14 examples). The continuous-flow process enables the safe and scalable oxidative carbonylation using CO/O 2 under elevated pressures and temperatures.
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