Exploring Synthetic Strategies for 1H-Indazoles and Their N-Oxides: Electrochemical Synthesis of 1H-Indazole N-Oxides and Their Divergent C-H Functionalizations.

The selective electrochemical synthesis of 1H-indazoles and their N-oxides and the subsequent C-H functionalization of the 1H-indazole N-oxides are described. The electrochemical outcomes were determined by the nature of the cathode material. When a reticulated vitreous carbon cathode was used, a wide range of 1H-indazole N-oxides were selectively synthesized, and the electrosynthesis products were deoxygenated to N-heteroaromatics, owing to cathodic cleavage of the N-O bond via paired electrolysis, when a Zn cathode was used. The scope of this electrochemical protocol is broad, as both electron-rich and electron-poor substrates were tolerated. The potency of this electrochemical strategy was demonstrated through the late-stage functionalization of various bioactive molecules, making this reaction attractive for the synthesis of 1H-indazole derivatives for pharmaceutical research and development. Detailed mechanistic investigations involving electron paramagnetic resonance spectroscopy and cyclic voltammetry suggested a radical pathway featuring iminoxyl radicals. Owing to the rich reactivity of 1H-indazole N-oxides, diverse C-H functionalization reactions were performed. We demonstrated the synthetic utility of 1H-indazole N-oxides by synthesizing the pharmaceutical molecules lificiguat and YD (3); key intermediates for bendazac, benzydamine, norepinephrine/serotonin reuptake inhibitors, SAM-531, and gamendazole analogues; and a precursor for organic light-emitting diodes.