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

by Selleckchem | Jul 08 2023

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.

Comments:

The passage you provided describes a research study on the selective electrochemical synthesis of 1H-indazoles and their N-oxides, as well as the subsequent C-H functionalization of the 1H-indazole N-oxides. The authors investigated the effects of different cathode materials on the electrochemical outcomes.

When a reticulated vitreous carbon cathode was used, a wide range of 1H-indazole N-oxides were selectively synthesized. Additionally, when a Zn cathode was employed, the electrosynthesis products were deoxygenated to N-heteroaromatics through the cathodic cleavage of the N-O bond via paired electrolysis. This method allowed for the synthesis of diverse 1H-indazole N-oxides, accommodating both electron-rich and electron-poor substrates.

The versatility of this electrochemical protocol was demonstrated through the late-stage functionalization of various bioactive molecules, making it an attractive reaction for the synthesis of 1H-indazole derivatives in pharmaceutical research and development. The authors also performed detailed mechanistic investigations using techniques such as electron paramagnetic resonance spectroscopy and cyclic voltammetry. These investigations suggested a radical pathway involving iminoxyl radicals.

Moreover, owing to the rich reactivity of 1H-indazole N-oxides, the authors successfully conducted diverse C-H functionalization reactions. They showcased the synthetic utility of 1H-indazole N-oxides by synthesizing several pharmaceutical molecules such as lificiguat and YD (3), which are key intermediates for bendazac, benzydamine, norepinephrine/serotonin reuptake inhibitors, SAM-531, gamendazole analogues, and a precursor for organic light-emitting diodes.

Overall, this research study presents a comprehensive electrochemical strategy for the selective synthesis of 1H-indazoles and their N-oxides, followed by C-H functionalization. The broad scope and synthetic utility demonstrated by this strategy make it valuable for the development of 1H-indazole derivatives in pharmaceutical research and related fields.