Simple and Scalable Cathodic Synthesis of 1H-1-Hydroxyquninolin-4-ons and 4H-4-Hydroxy-1,2,4-benzothiadiazine-1,1-dioxides
Authors: Prenzel Tobias , Wirtanen Tom , Waldvogel Siegfried R 
Published: July 2022

Cathodic synthesis is a highly attractive technique for N,O bond reduction.[1] Especially, electro-reductions of nitro arenes enable the access to high-valuable products like nitrones and N-heterocycles.[2] These substances are in general unique structural motifs in natural products or in compounds with significant biological properties, such as antibiotic, antiplasmodial, antimycotic, antihypertensive, hyperglycemic and cytotoxic activities.[3] Commonly used synthesis methods require large amounts of metallic reducing agents, expensive transition metal catalysts, or hazardous oxidizers in case the corresponding heterocycles are accessible otherwise.[4] Several examples have been described with constant potential conditions using mercury or sacrificial lead electrodes.[5] Due to cathodic corrosion of heavy metals, this proves to be a critical aspect and mercury is banned in the most countries for technical applications.[6] Therefore, the urge for more sustainable processes is of high focus.

We describe an access to 1H-1-hydroxyquninolin-4-ons by cathodic reaction of nitrobenzoyl acetones synthesized from broad available nitrobenzoic acids. Using metal-free BDD cathodes (boron-doped diamond), sulfuric acid as a simple supporting electrolyte, in addition to an aqueous electrolyte system with an environmentally benign co-solvent agree with sustainable and green aspects. The scalability under constant current conditions in an undivided cell has been shown in a twentyfold scale. The electrochemical synthesis protocol was applied to 18 examples including the antibiotic substance HQNO (1H-2-heptyl-1-hydroxy quinolin-4-ons) and various precursors for enzymatic aurachine synthesis.[7]

Furthermore, we developed a method to a novel substance class of 4H-4-hydroxy-1,2,4-benzothiadiazine-1,1-dioxides. Reduction of the nitro precursors applying BDD cathodes result in hydroxylamines using divided cells with glass frits as separators. The applicability of this electro-reductive cyclisation is demonstrated by the synthesis of a broad product scope with activated, deactivated, labile and sterically demanding substitution patterns for potential further modification towards pharmaceutical applications.[8] Particularly, we described the synthesis of the N-Hydroxy analogues of diazoxide, a medication on the WHO list of essential medicines.[8,9] Studies on the biological activities of these new compounds are currently performed.

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[6] T. Wirtanen, T. Prenzel, J.-P. Tessonnier, S. R. Waldvogel, Chem. Rev.
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[7] a) T. Prenzel, S. R. Waldvogel 2021, in preparation; b) E. Stec, D. Pistorius, R. Müller, S.-M. Li, ChemBioChem
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[8] T. Prenzel, T. Wirtanen, S. R. Waldvogel 2021, in preparation.

[9] World Health Organization, Model List of Essential Medicines – 22nd List, 2021, World Health Organization, Geneva, 2021.

Figure 1