【Frontiers in HaiChuan Chemical Technology】USTC invents a method for the direct deamination of aromatic amines; traditional diazotization deamination methods face competition
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This post was last edited by HaiChuanLaoYu on 2025-11-3 09:17. Submitted to Nature in September, and published in October. A recent Nature paper by the team led by Zhang Xiaheng, a researcher at the Hangzhou Advanced Institute of the University of Chinese Academy of Sciences (hereinafter referred to as “Hangzhou Advanced Institute”), was quickly accepted. In their research, they used \"molecular editing\" to solve a century-old problem in this field, bringing about new advances in the processes for using aromatic amines that have been in use since 1884. This approach enables the direct conversion of the C-N bonds in aromatic amines into C-X or C-C bonds, which are necessary for producing drugs, using inexpensive reagents; it also holds promise for avoiding the potential explosion risks and heavy metal contamination associated with traditional methods. It also challenges an industrial tradition that has lasted for 140 years, and may trigger an innovation related to amines. The relevant paper was described by Scott Bagley, the R&D director at American pharmaceutical company Pfizer and one of the reviewers, as a true masterpiece. It is understood that the feeding process in this method is extremely simple, allowing both students conducting experiments and workers in pharmaceutical factories to start adding materials quickly and safely. It acts like a multi-functional interface that can accommodate various molecular structures and amino group positions, enabling \"deamination functionalization\". Although there are companies willing to purchase the patent, the team still chose to share it publicly, not only to share its scientific value but also to ensure the safety and sustainability of this achievement. To date, this method has been successfully validated in the modification of various drug intermediates, and kilogram-scale validation has also been completed. Meanwhile, Zhang Xiaheng’s team is in talks with several pharmaceutical companies, with the aim of using these compounds for the synthesis of intermediates for anticancer drugs; this could help reduce the production costs of certain drug intermediates in the future.
What this achievement by Zhang Xiaheng’s team takes into account is the direct replacement of the amino groups on the \"building blocks\" with functional groups. That is, aromatic amines are allowed to form N-nitroamines in situ under mild conditions, and then the C-N bond is broken by removing dinitrogen monoxide, thereby creating a deamination pathway free from explosion risks. Through hundreds of condition optimizations, they repeatedly verified the universality of the relevant reactions. By testing hundreds of aromatic amine scaffold intermediates, it was found that almost all aromatic amines can be converted efficiently. This “molecular editing” technique is very straightforward; it’s like a one-click replacement, allowing molecules to be modified in a manner similar to rewriting code. As a direct deamination method, it eliminates the need to use hazardous diazonium salts as intermediates; instead, it allows the C-N bond in aromatic amines to be converted into various key bonds required for drug synthesis, much like the replace and find functions used in computer documents. The entire process is not only smooth and controllable but also does not generate dangerous intermediates. At the same time, to further improve operational convenience, they also developed a strategy called \"one-pot deamination cross-coupling\". When using this strategy, it is sufficient to directly add the appropriate coupling reagent to the deamination reaction intermediates, thereby enabling multiple cross-coupling reactions to be carried out in the same reaction system. This opens up new pathways for rapidly constructing complex molecules using readily available materials, thereby advancing research and development in the field of medicinal chemistry. This achievement is made possible by the team’s careful attention to detail. Once, after completing their experiments, the research team discovered some by-products. Under normal procedures, such waste would have been discarded, but after careful analysis, they accidentally stumbled upon a breakthrough that led to their paper being published in Nature. Tu Guangliang, a postdoctoral researcher at the School of Chemistry and Materials Science of Hangzhou Higher People’s Court, Xiao Ke, a graduate student, Chen Xiaoping, an associate researcher, and Xu Haoran, a graduate student at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, are the co-first authors of the paper; Zhang Xiaheng and Xue Xiaosong, researchers at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, serve as corresponding authors. This work was also covered by the American magazine Chemical & Engineering News, and Tobias Ritter, director of the Max Planck Institute for Coal Research in Germany, described this reaction as \"reliable and highly practical\".
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