Quinoline as a Photochemical Toolbox: From Substrate to Catalyst and Beyond.

ConspectusMolecular photochemistry, by harnessing the excited states of organic molecules, provides a platform fundamentally distinct from thermochemistry for generating reactive open-shell or spin-active species under mild conditions. Among its diverse applications, the resurgence of the Minisci-type reaction, a transformation historically reliant on thermally initiated radical conditions, has been fueled by modern photochemical strategies with improved efficiency and selectivity. Consequently, the photochemical Minisci-type reaction ranks among the most enabling methods for C(sp2)-H functionalizations of heteroarenes, which are of particular significance in medicinal chemistry for the rapid diversification of bioactive scaffolds. A persistent challenge, however, lies in the efficient generation of radicals and controllable addition to the electron-deficient heteroaromatic systems. In our pursuit of protocols to overcome these limitations, we unexpectedly uncovered the photochemical potential of quinoline, which is a naturally abundant, synthetically accessible, and structurally versatile heteroaromatic scaffold that has long served as a prototypical substrate in Minisci-type chemistry. Guided by this serendipitous insight and our scientific curiosity, we successfully repurposed quinoline and its derivatives not merely as substrates but also as a versatile and systematic photochemical toolbox capable of participating in, mediating, and ultimately catalyzing a broad spectrum of radical transformations beyond Minisci-type reactions.This Account weaves together our decade-long research program with several interrelated directions that demonstrate quinoline's photosynthetic versatility and adaptability. Our exploration began with the photochemical Minisci-type alkylation of quinolines using alkyl radicals generated via various approaches, highlighting this heterocycle's capacity as a robust radical acceptor for direct C(sp2)-H functionalization of drug-like compounds. This foundational success prompted a deeper inquiry into quinoline's redox behaviors under direct excitation, wherein we discovered its dual ability to engage its own scaffold to form radical intermediates from otherwise challenging precursors while simultaneously partaking in the Minisci-type alkylation as a classic reaction partner. Armed with this insight, we further developed quinoline derivatives that undergo direct photolysis to release alkyl radicals from their structures. Such a design shifts the role of quinolines from passive substrates to photoactive reagents, thereby enabling greater flexibility in the substrate and reaction scope beyond Minisci-type chemistry and expanding the mechanistic space available for radical-based transformations. Progressing toward catalysis, the extended conjugation and redox tunability of diarylquinoline scaffolds guided our design of organophotocatalysts featuring the unique proton- and photon-activation mode, offering efficient alkylative coupling pathways with diverse combinations of radical donors and acceptors. In parallel, we designed a photoactive diarylquinoline-based ligand capable of chelating a range of base metals, thus streamlining the dual metallaphotoredox catalysis into a single metal-ligand framework for diverse C-C and C-X bond-forming cross couplings without external photocatalysts.Together, we presented quinoline's evolution from a common organic substrate to a multifaceted linchpin in modern photochemical synthesis. Through these diverse yet interconnected efforts, we illustrate that simple light irradiation, coupled with rational molecular design, can reimagine a familiar molecular scaffold to unlock unforeseen opportunities across multiple domains, which could inspire more reactivity paradigms for other untapped chemical entities.