Domino Strategies in Heterocycle Synthesis: Advancing from Organocatalysis to Photo-/Organo-Autocatalysis

Abstract The increasing structural complexity of heterocycles in pharmaceuticals, agrochemicals, and functional materials continues to challenge synthetic design, particularly when step economy, scalability, and sustainability are considered simultaneously. Domino reactions, in which multiple bond-forming events proceed sequentially in a single operation, offer an inherently concise strategy to transform simple building blocks into densely functionalized architectures while minimizing purification steps and waste. In this Outlook, we examine the evolution of domino heterocycle synthesis from classical organocatalysis to photo- and organo-autocatalytic systems, highlighting how metal-free activation, visible-light processes, and in situ-generated catalytic species expand reactivity while improving catalyst, energy, and atom economy. We discuss key advances in domino reactions toward chiral heterocycles, heteroaromatic construction, total synthesis, and self-catalyzed photochemical processes, emphasizing challenges such as catalyst loading, robustness, photon efficiency, and reaction scalability. The future development of domino synthesis will rely on combining new mechanistic ideas with sustainability and rational reaction design. By focusing on the deliberate development of efficient, low-input organo- and photo/organo-autocatalyzed domino reactions, we aim to spur progress toward streamlined and industrially practical methods for heterocycle synthesis.