Historically, most organic transformations are carried out in solution. Accordingly, the pharmaceutical and the fine chemicals industry strongly depend on solvent-based organic synthesis, which often leads to substantial amounts of solvent waste, as organic solvents usually account for approximately 80–90% of the total mass used in organic reactions. In this context, solid-state organic transformations have attracted considerable attention as cleaner and more sustainable synthetic alternatives.

Mechanochemical solvent-free solid-state reactions using ball milling or milling with a catalytic amount of liquid, the so-called liquid-assisted grinding (LAG), have emerged as powerful alternatives to synthesis in solution. Especially Friščić, Bolm, and Browne have made significant contributions to the field of transition-metal-catalyzed reactions using mechanochemistry. However, examples of palladium-catalyzed cross-coupling reactions in the solid state have remained extremely limited.

Herein, we report the development of a potentially general and scalable solvent-free method for solid-state palladium-catalyzed C–N cross-coupling reactions using mechanochemistry. The key finding of this study is that olefin additives can act as efficient molecular dispersants for the palladium-based catalyst in solid-state media to facilitate the challenging solid-state cross-coupling. Considering the broad significance of cross-coupling reactions and the industrial demand for sustainable synthetic methods, the present study constitutes an important milestone toward the development of industrially attractive solid-state syntheses of valuable synthetic targets in various scientific areas.

Furthermore, we expect the results of this study to provide access to an unexplored reaction environment for palladium-catalyzed reactions, where reactivity and selectivity different to those of conventional solution-based reactions may be realized. We are currently working on a new catalyst design that permits solid-state coupling reactions with unique site-selectivity.

We would like to express our sincerest gratitude to the referees, whose instructive and critical comments on the mechanistic studies have helped to significantly improve this manuscript.

You can read more about our research here: Nature Communications, Volume 10, Article number 111 (2019), DOI: 10.1038/s41467-018-08017-9 by: Koji Kubota, Tamae Seo, Katsumasa Koide, Yasuchika Hasegawa & Hajime Ito.