Rethinking coupling methods for more sustainable organic synthesis

Coupling reactions are among the most transformative tools in organic chemistry, enabling the formation of crucial chemical bonds in pharmaceuticals, agrochemicals, and advanced materials. Since their introduction, they have been one of the backbones of modern organic synthesis. However, these methods have long relied on environmentally taxing transition metal catalysts, such as palladium, which are often scarce, costly, and generate unwanted byproducts.

The limitations of conventional coupling methods have prompted researchers to seek alternative strategies that better align with the principles of green and sustainable chemistry (GSC). Such alternatives aim to minimize waste, reduce reliance on rare metals, and lower energy consumption, all while maintaining high efficiency and selectivity. Addressing these challenges is essential for the development of more sustainable industrial and pharmaceutical synthesis methods.

Now, a research team, led by Professor Toshifumi Dohi from the College of Pharmaceutical Sciences, Ritsumeikan University, and Professor Yasuyuki Kita, Visiting Senior Researcher at the Research Organization of Science and Technology, Ritsumeikan University, has provided a comprehensive overview of recent advancements in transition metal-free coupling methods. Their comprehensive review article, made available online on March 7, 2025, and published in Volume 125 Issue 6 of Chemical Reviews on March 26, 2025, highlights emerging strategies that enable the activation of aryl-iodide bonds under environmentally benign conditions. The review particularly emphasizes coupling via the hypervalent iodine strategy, a field in which the authors have been leading contributors for decades. Other members of the team included Dr. Elghareeb Elshahat Elboray, Dr. Kotaro Kikushima, and Dr. Koji Morimoto, all from Ritsumeikan University.

The hypervalent iodine approach leverages the unique properties of diaryliodonium salts, which serve as highly reactive intermediates in coupling reactions. By strategically manipulating the oxidation state of iodine atoms, researchers have been able to generate aryl cation-like species, radicals, and aryne precursors that facilitate selective bond formation. This transition metal-free approach reduces reliance on costly catalysts while also enhancing the atom economy of coupling processes. “Our study presents hypervalency strategy, an innovative next-generation approach for coupling which better aligns with GSC requirements, intended for use in the synthesis of pharmaceuticals, related molecules, and functional organic compounds,” remarks Prof. Dohi.

One of the key advantages of hypervalent iodine-mediated coupling is its broad substrate scope, which allows for the efficient synthesis of diverse molecular architectures. The method also exhibits high functional group tolerance, making it particularly attractive for applications in medicinal chemistry. Additionally, researchers have devised various strategies to recycle the aryl iodide byproducts generated in these reactions, addressing previous concerns about waste and enhancing the overall atom efficiency.

Beyond hypervalent iodine strategies, the review also discusses alternative transition metal-free activation methods, including base-promoted aryl–iodide dissociation, photoinduced activation, electrochemical activation, and electrophotochemical activation. Each of these approaches offers unique benefits, such as reducing energy consumption, utilizing mild reaction conditions, or eliminating the need for certain hazardous reagents. By compiling and analyzing recent advances, the authors wish to guide and inspire further research in this area. “We hope that this review will be of interest to researchers aiming to develop new methods of solving the problems associated with this field of chemistry,” says Prof. Kita.

With the growing need for greener and more efficient chemical synthesis methods, the strategies outlined in this review have the potential to reshape the future of organic chemistry. By reducing environmental impact and lowering production costs, these methods may play a critical role in the long-term development of pharmaceuticals and other fine chemicals. As the field continues to evolve, the present contributions will hopefully serve as a foundation for future breakthroughs in sustainable chemistry.

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Reference

Title of original paper: Iodoarene Activation: Take a Leap Forward toward Green and Sustainable Transformations

Journal: Chemical Reviews

DOI: 10.1021/acs.chemrev.4c00808

About Ritsumeikan University, Japan

Ritsumeikan University is one of the most prestigious private universities in Japan. Its main campus is in Kyoto, where inspiring settings await researchers. With an unwavering objective to generate social symbiotic values and emergent talents, it aims to emerge as a next-generation research-intensive university. It will enhance researcher potential by providing support best suited to the needs of young and leading researchers, according to their career stage. Ritsumeikan University also endeavors to build a global research network as a “knowledge node” and disseminate achievements internationally, thereby contributing to the resolution of social/humanistic issues through interdisciplinary research and social implementation.

Website: http://en.ritsumei.ac.jp/

Ritsumeikan University Research Report: https://www.ritsumei.ac.jp/research/radiant/eng/

About Professor Toshifumi Dohi from Ritsumeikan University, Japan

Dr. Toshifumi Dohi is a Professor at the College of Pharmaceutical Sciences, Ritsumeikan University. He received his PhD degree in 2005 from the Graduate School of Pharmaceutical Sciences of Osaka University, Japan. His current research interests focus on reagent/catalyst design and the development of new reactions using hypervalent iodine reagents. He received the IUPAC-ICOS 15 Poster Award for excellence in presentation, the Pharmaceutical Society of Japan Award for Young Scientists (2009), the Banyu Chemist Award (2013), the Thieme Chemistry Journal Award (2014), the GSC Encouragement Award (2015), and the International Congress on Pure & Applied Chemistry Lecture Award (2019).

About Professor Yasuyuki Kita from Ritsumeikan University, Japan

Dr. Yasuyuki Kita is a Visiting Senior Researcher at the Research Organization of Science and Technology, Ritsumeikan University. He received his PhD from Osaka University in 1972. In 2008, he joined Ritsumeikan University as the Dean of the College of Pharmaceutical Sciences. He has served as the Director of the Research Center for Drug Discovery and Development Science since 2011 and Visiting Research Professor at the Research Organization of Science and Technology since 2015. His current research interests focus on hypervalent iodine chemistry. He has published more than 510 original papers. His awards include the Pharmaceutical Society of Japan (PSJ) Award for Young Scientists (1986), the PSJ Award for Divisional Scientific Contribution (1997), and the Japanese Society for Process Chemistry Award for Excellence (2005).

Funding information

The authors acknowledge financial support from the Japan Society for the Promotion of Science (JSPS), the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the New Energy and Industrial Technology Development Organization (NEDO), JSPS KAKENHI grant numbers 19K05466, 23K04827, and 23K06060, JST CREST grant number JPMJCR20R1, and the Ritsumeikan Global Innovation Research Organization (R-GIRO) project.