Chiral vicinal diamines represent an important class of organic building blocks that play essential roles in various fields in chemical and material sciences. Their syntheses have continued to attract attention to enhance their yield, selectivity, and scope, but all of the procedures reported so far in the literature are solvent-based reactions. We herein report the first example of mechanochemical diaza-Cope rearrangement to convert a wide variety of aldehyde substrates into chiral diimines, which upon hydrolysis lead to the formation of chiral vicinal diamines. This solvent-free protocol is highlighted with high yield, fast reaction, and simple synthetic operation with commercially available precursors and is easily scalable to gram quantity. Mechanistic investigations revealed a distinct reaction profile for mechanochemical-induced reactions compared to solution-based reactions. Reaction time course studies showed that the diaza-Cope rearrangement step, which requires a highly ordered six-membered chair-like TS, is rapid in mechanochemical-induced reactions. This enhanced rate stems from the formation of effective solid-state packing in mechanochemical reaction settings. The powder X-ray diffraction analysis of the milled sample confirmed the formation of a new crystalline phase during the mechanochemical reaction, which leads to continuation of the reaction even after ball milling is stopped. Furthermore, we developed a one-pot two-step procedure to synthesize chiral salen metal complexes, a “privileged” chiral catalyst, directly from arylaldehydes without the need for isolating the rearrangement products. From a practicality perspective, this work demonstrates a mechanochemical synthesis of chiral vicinal diamines that can be readily adapted in academic laboratories and, potentially, in industrial settings.

Chiral vicinal diamines, a unique class of optically-active building blocks, play a crucial role in material design, pharmaceutical, and catalysis. Traditionally, their syntheses are all solvent-based approaches, which make organic solvent an indispensable part of their production. As part of our program aiming to develop chemical processes with reduced carbon footprints, we recently reported a highly practical and environmentally-friendly synthetic route to chiral vicinal diamines by solvent-free mechanochemical diaza-Cope rearrangement. We herein showed that a new protocol by co-milling with common laboratory solid additives, such as silica gel, can significantly enhance the efficiency of the reaction, compared to reactions in the absence of additives. One possible explanation is the Lewis acidic nature of additives that accelerates a key Schiff base formation step. Reaction monitoring experiments tracing all the reaction species, including reactants, intermediates, and product, suggested that the reaction profile is distinctly different from ball-milling reactions without additives. Collectively, this work demonstrated that additive effect is a powerful tool to manipulate a reaction pathway in mechanochemical diazo-Cope rearrangement pathway, and this is expected to find broad interest in organic synthesis using mechanical force as an energy input.