Direct Electrochemical Synthesis of 2,3‐Disubstituted Quinoline N‐oxides by Cathodic Reduction of Nitro Arenes

Abstract

The use of electric current in synthetic organic chemistry offers a sustainable tool for the selective reductive synthesis of quinoline N‐oxides starting from easily accessible nitro compounds. The reported method employs mild and reagent‐free conditions, a simple undivided cell, and constant current electrolysis set‐up which provides conversion with a high atom economy. The synthesis of 30 differently substituted quinoline N‐oxides was successfully performed in up to 90 % yield. Using CV studies, the mechanism of the selective formation of the quinoline N‐oxides was elucidated. The technical relevance of the described reaction could be shown in a 50‐fold scale‐up reaction.

Simple and scalable electrosynthesis of 1H-1-hydroxy-quinazolin-4-ones

“…29 Based on previous work by the Waldvogel lab, a foundation for the electrochemical conditions for nitro reduction were initially tested (Table 1, entry 1). 30–32…”

“…29 Based on previous work by the Waldvogel lab, a foundation for the electrochemical conditions for nitro reduction were initially tested (Table 1, entry 1). [30][31][32] The starting conditions used a water-methanol mixture (1 : 1 (v/v)) as a green solvent capable of dissolving the nitro compound 5a. A moderate concentration of sulphuric acid (0.5 M) was used as the supporting electrolyte based on previous investigations into the concentration effect of the acidic component on the electrochemical reduction.…”

“…A plausible mechanism for the electrochemical cyclisation sequence is proposed based on earlier nitro reduction studies and cyclic voltammetry (CV) measurements of benzamide 5a (Scheme 2; for detailed information see ESI †). 16,[31][32][33] Accordingly, the reactions starts with the reduction of the nitro group on the BDD cathode which is evidenced by a single broad, irreversible wave (−0.94 V vs. FcH/FcH + ) corresponding to the 4e − /4H + reduction to the hydroxylamine. It has been previously suggested that the reaction proceeds with two 2e − steps via intermediates Int-I and Int-II.…”

Scalable Electrochemical Reduction of Nitrobenzotrifluorides to 3-Trifluoromethylanilines

“…Recently, more effort has been focused on the nitro-reductive approaches, such as electrochemical reduction. ,− Electrochemical reduction has received significant attention because it is cleaner and more efficient and the costs are comparable with other cutting-edge techniques. , In electrosynthesis it is not necessary to use excess of reducing agents, rare and expensive catalyst (e.g., Pd), high pressures, or elevated temperatures since the activation by electrons occurs under mild and usually ambient conditions . In contrast to reduction by dissolving metals, compatibility with strong acids is given. , The high tolerance to acids stems from the fact that common cathode materials (e.g., leaded bronze) have low exchange current densities for proton reduction.…”

Synthesis of Aromatic N-Oxides Using Electrochemically Generated Peroxodicarbonate

“…Quinoline and pyridine N -oxides are important structural motifs encountered in organic chemistry and metabolites in organisms. − Furthermore, the ortho position in these molecules is activated for substitution reactions and they also serve as valuable precursors to several rearrangements (see the Supporting Information). ,− However, direct electrochemical oxidation of quinolines and pyridines to their N -oxides is impossible, relying instead on reductive cyclization of laboriously constructed nitro-compounds (Scheme , right side). − While undoubtedly elegant, direct modification of a heterocyclic scaffold is more desirable, e.g., in library synthesis of pharmaceuticals . Thus, the use of electrochemically generated oxidizers would be more advantageous as it obviates the use of hazardous peracids, thereby improving scalability and safety of the process (Scheme , left side).…”