Preparation of Dinitrogen Trioxide for Organic Synthesis: A Phase Equilibrium Approach.

Dinitrogen trioxide (N2O3) is a potent nitrosating agent featured with high reactivity and appealing atom economy. Because of its instability and the entanglement of chemical and phase equilibria, N2O3 has rarely been utilized in organic synthesis as a stock reagent with well-defined composition. In this review, the preparations of pure N2O3 and its concentrated solution (>0.1 M) are discussed from the aspect of phase equilibrium. Understanding the physical and chemical characteristics of N2O3, along with how reaction parameters (temperature, pressure, molar ratio) interact, plays a crucial role in managing the concentration of N2O3 in the liquid phase. This control holds practical significance in achieving quantitative reactions.

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

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.

Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen.

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.

Visible Light-Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor.

The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or elevated temperatures to proceed. A very attractive alternative is the in situ generation of Vilsmeier-Haack reagents, by means of photoredox catalysis, as promoters for the thermal Beckmann rearrangement. Investigation of the reaction parameters for this light-induced method using a one-pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps. Using a continuous flow reactor, the photochemical and thermal processes have been separated by integrating a flow photoreactor unit at low temperature for the electrophile generation with a second reactor unit, at high temperature, where the rearrangement takes place. This strategy has enabled excellent conversions and yields for a diverse set of oximes, minimizing the formation of side products obtained with the original one-pot method.

Continuous-Flow Electrophilic Amination of Arenes and Schmidt Reaction of Carboxylic Acids Utilizing the Superacidic Trimethylsilyl Azide/Triflic Acid Reagent System.

A continuous flow protocol for the direct stoichiometric electrophilic amination of aromatic hydrocarbons and the Schmidt reaction of aromatic carboxylic acids using the superacidic trimethylsilyl azide/triflic acid system is described. Optimization of reagent stoichiometry, solvent, reaction time, and temperature led to an intensified protocol at elevated temperatures that allows the direct amination of arenes to be completed within 3 min at 90 °C. In order to improve the selectivity and scope of this direct amination protocol, aromatic carboxylic acids were additionally chosen as substrates. Selected carboxylic acids could be converted to their corresponding amine counterparts in good to excellent yields (11 examples, 55-83%) via a Schmidt reaction employing similar flow reaction conditions (<5 min at 90 °C) and a similar reactor setup as for the amination. The safety issues derived from the explosive, toxic, and volatile hydrazoic acid intermediate, the corrosive nature of triflic acid, and the exothermic quenching were addressed by designing a suitable continuous flow reaction setup for both types of transformations.