Abstract
Palladium-catalyzed cross-coupling reactions are one of the most powerful and versatile methods to synthesize a wide range of complex functionalized molecules. However, the development of solid-state cross-coupling reactions remains extremely limited. Here, we report a rational strategy that provides a general entry to palladium-catalyzed Buchwald-Hartwig cross-coupling reactions in the solid state. 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. Beyond the immediate utility of this protocol, our strategy could inspire the development of industrially attractive solvent-free palladium-catalyzed cross-coupling processes for other valuable synthetic targets.
Highlights
Palladium-catalyzed cross-coupling reactions are one of the most powerful and versatile methods to synthesize a wide range of complex functionalized molecules
The pharmaceutical industry and the fine chemicals industry strongly depend on solvent-based organic synthesis, which has led to serious problems with regard to solvent waste, as organic solvents usually account for ~80–90% of the total mass used in any organic reaction[1,2,3]
Based on a transmission electron microscopy (TEM) analysis, we discovered that some such olefin additives can act as efficient molecular dispersants for palladium catalysts in solid-state media to inhibit undesired aggregation of the catalyst that may lead to catalyst deactivation (Fig. 1c)
Summary
Palladium-catalyzed cross-coupling reactions are one of the most powerful and versatile methods to synthesize a wide range of complex functionalized molecules. Mechanochemical solvent-free 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[33,34,35,36,37,38,39,40], and mechanochemical palladium-catalyzed crosscoupling reactions have already been reported[41,42,43,44,45,46,47,48,49,50,51,52,53] These methods focus mostly on neat liquids[41,42,43,44,45,46,48,49,50,51,52,53]. We anticipate that the present solvent-free solidstate palladium-catalyzed cross-coupling reactions may potentially find broad applications in industrially relevant syntheses
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