Progress in Wolff-Kishner reduction: developments toward milder and more efficient conditions

For over a century, the Wolff-Kishner reduction has been a cornerstone of organic synthesis, serving as a primary strategy for the selective deoxygenation of carbonyl groups into their corresponding methylene analogues. While classical protocols and their subsequent modifications are simple and broadly applicable, they are frequently limited by harsh reaction conditions, poor functional group tolerance, and substrate sensitivity, thus giving rise to alternative approaches of higher efficiency. This review provides a survey of the evolution of the Wolff-Kishner reduction from early modifications up to the most recent trends, which include metal catalysis, continuous flow techniques, microwave-induced methods, and solar-driven activation. In addition, mechanistic considerations regarding the decomposition of hydrazones and carbanion formation are also presented. Although significant steps towards the improvement of deoxygenation processes have been accomplished, further research is required due to the existing deficiencies in substrate compatibility, reagent demand, and pharmaceutical applications, outlining a distinct path forward for upcoming scientific investigations.