Ball milling has emerged as a powerful and sustainable technique for the synthesis of heterocyclic compounds, offering significant advantages over conventional methods. This review explores recent advancements in the application of ball milling for environmentally friendly synthesis, highlighting its role in accelerating reaction times, enhancing yields, and minimizing solvent usage. Various studies have demonstrated its efficacy in synthesizing diverse nitrogen, oxygen, and sulfur-containing heterocyclic frameworks, including benzoxazines, quinoxalines, pyrazolothienopyrimidines, chalcones, spiro(indole-pyrrolidine) derivatives, quinolines, pyridazines, triazolochromenes, arylsulfonyl 4H-pyrans, aminothiophenes, methylcoumarins, and benzothiazoles. Notably, high-energy and planetary ball milling have facilitated key transformations such as hydroamination, Knoevenagel condensation, and reductive reactions, often yielding products with excellent enantiomeric purity while eliminating the need for chromatographic purification. Despite its advantages, challenges like scalability, reaction monitoring, and equipment wear persist. Innovations in reactor design, monitoring techniques, and computational modeling can enhance the application of ball mill in green chemistry. By providing a comprehensive analysis of reaction mechanisms and sustainability aspects, this review underscores the potential of mechanochemical synthesis to redefine heterocyclic chemistry and drive advancements in pharmaceuticals, agrochemicals, and materials science.

Graphical abstract

Ball-mill-assisted mechanochemical synthesis of heterocyclic compounds

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用于杂环化合物合成的球磨机辅助机械化学方法（2015-2024）

球磨已成为一种强大且可持续的杂环化合物合成技术，与传统方法相比具有显著优势。本文探讨了球磨在环保合成中的应用的最新进展，重点介绍了其在加快反应时间、提高产量和减少溶剂用量方面的作用。各种研究表明，它在合成各种含氮、氧和硫杂环框架方面的有效性，包括苯并噁嗪、喹喔啉、吡唑并噻吩嘧啶、查耳酮、螺（吲哚-吡咯烷）衍生物、喹啉、哌嗪、三唑并铬烯、芳基磺酰 4H-吡喃、氨基噻吩、甲基香豆素和苯并噻唑。值得注意的是，高能和行星球磨促进了氢胺化、Knoevenagel 缩合和还原反应等关键转化，通常产生具有出色对映体纯度的产品，同时无需色谱纯化。尽管具有优势，但可扩展性、反应监测和设备磨损等挑战仍然存在。反应器设计、监测技术和计算建模方面的创新可以增强球磨机在绿色化学中的应用。通过对反应机理和可持续性方面的全面分析，这篇综述强调了机械化学合成在重新定义杂环化学并推动制药、农用化学品和材料科学进步方面的潜力。

 图形摘要

球磨机辅助机械化学合成杂环化合物