Exploration of C-H Transformations of Aldehyde Hydrazones: Radical Strategies and Beyond

The chemistry of hydrazones has gained great momentum due to their involvement throughout the evolution of organic synthesis. Herein, we discuss the tremendous developments in both the methodology and application of hydrazones. Hydrazones can be recognized not only as synthetic equivalents to aldehydes and ketones but also as versatile synthetic building blocks. Consequently, they can participate in a range of practical synthetic transformations. Furthermore, hydrazone derivatives display a broad array of biological activities and have been widely applied as pharmaceuticals. Owing to the weak directing group effect of simple aldehydes and ketones in C-H bond functionalizations, the C-H bond functionalizations of hydrazones that have been developed in the past five years represent a significant step forward. These novel transformations open a new door to a broader library of functionalized and complex small molecules. Moreover, a wide range of biologically important N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) can be efficiently synthesized in an atom- and step-economical manner through single, double, or triple C-H bond functionalizations of hydrazones. Both radical C-H functionalizations and transition metal-catalyzed directing-group strategies have enhanced the synthetic utility of hydrazones in the chemical community because these strategies solve the long-standing challenge of C-H functionalizations adjacent to aldehydes and ketones. We began this study based on our ongoing interest in visible-light photoredox catalysis. Visible-light photoredox catalysis has become a powerful tool in contemporary synthetic chemistry due to its remarkable advantages in sustainability and use of radical chemistry. By exploiting a photoredox-catalyzed aminyl radical polar crossover (ARPC) strategy, we successfully achieved visible light -induced C(sp(2))-H difluoroalkylation, trifluoromethylation, and perfluoroalkylation of aldehyde-derived hydrazones. This intriguing result was later applied in the C(sp(2))-H amination of hydrazones and a cascade cyclization reaction for the synthesis of polycyclic compounds. Encouraged by this redox-neutral C-H functionalization of aldehyde hydrazones, we extended the oxidative C-H/P-H cross-coupling method, which represents a novel and efficient method for the synthesis of alpha-iminophosphine oxides. Furthermore, an elegant [3 + 2] cycloaddition of azides and aldehyde hydrazones for the synthesis of functionalized tetrazoles was advantageously developed during our investigation of the oxidative C(sp(2))-H azidation of aldehyde hydrazones with TMSN3. The sequential C(sp(2))-H/C(sp(3))-H bond functionalization of aldehyde-derived hydrazones with simple 2,2-dibromo-1,3-dicarbonyls was achieved by employing relay photoredox catalysis, and it provides a novel method of accessing bioactive fused dihydropyrazole derivatives. The notable feature of this approach was further reflected in the formal [4 + 1] annulation of aldehyde-derived N-tetrahydroisoquinoline hydrazones with 2-bromo-1,3-dicarbonyls. To complement these radical C-H functionalization strategies, we recently applied a directing-group strategy in the Rh-catalyzed C(aldehyde)-H functionalization of aldehyde-derived hydrazones for the synthesis of distinctive and bioactive 1H-indazole scaffolds. In summary, this Account presents recent contributions to the exploration, development, mechanistic insights, and synthetic applications of C-H bond functionalizations of aldehyde hydrazones.