Electrochemical Hydrogenation of Aza-Arenes Using H2O as H Source

TL;DR

This paper introduces a safe and efficient method to hydrogenate aza-arenes using water and electricity, making drug discovery processes more sustainable.

Contribution

A general electrochemical hydrogenation method using Ni foam and water as H source under ambient conditions.

Findings

The method achieves broad substrate generality and excellent functional group tolerance.

It enables scalable synthesis up to 25 g with stable operation for 22 hours.

Mechanistic studies suggest two plausible hydrogenation pathways based on substrate redox properties.

Abstract

Electrochemical hydrogenation
of aza-arenes is an appealing strategy
to gain access to privileged saturated heterocycles for drug discovery,
overcoming the limitations of classical hydrogenations that often
suffer from energy-intensive conditions and safety hazards. Herein,
we demonstrate an operationally simple, sustainable, and general electrochemical
hydrogenation of aza-arenes with commercialized Ni foam electrodes
and setup. With water as the hydrogen donor under acidic conditions,
the reaction proceeds at ambient temperature and pressure to deliver
broad substrate generality, excellent functional group tolerance,
and excellent selectivity. The method tolerates a wide range of aza-arenesincluding
(iso)­quinolines, quinoxalines, pyridines, and their nium saltshighlighting
its generality and robustness. Synthetic utility was showcased through
the preparation of bioactive molecules, while scalability was achieved
up to 25 g of product, highlighting the method’s technical
applicability with stable 22 h operation without changes in the cell
voltage or significant electrode degradation. Extensive mechanistic
investigations using a combination of cyclic and RDE linear sweep
voltammetry suggest two plausible routes based on the substrate’s
redox properties: hydrogenation by chemisorbed hydrogen (H
ads) or initial substrate reduction followed by H
ads transfer. This work sets a clean, practical,
and versatile platform for aza-arene dearomatization, bridging academic
interest with industrial targets in electrochemical hydrogenation.

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