Base‐Free Cross‐Couplings of Aryl Diazonium Salts in Methanol: Pd^II–Alkoxy as Reactivity‐Controlling Intermediate

Abstract

Pd‐catalyzed cross‐coupling reactions of aryl diazonium salts are generally assumed to proceed via cationic PdII intermediates which in turn would be highly reactive in the subsequent transmetalation step. Contrary to this belief, we herein report our observation and rationalization of opposing reactivities of ArN2+ in Suzuki (=effective) and Stille (=ineffective) cross‐couplings in MeOH. Our systematic experimental and computational studies on the roles of transmetalating agent, solvent, base and the likely involvement of in situ formed diazoether derivatives challenge the currently accepted mechanism. Our data suggest that the observed solvent dichotomy is primarily due to PdII‐methoxy intermediates being formed, which are unreactive with arylstannanes, but highly reactive with arylboronic acids, complementing the Suzuki “Pd‐oxy” mechanism with the direct demonstration of transmetalation of a PdII‐alkoxy complex. Lewis acids were found to circumvent this reactivity divergence, promoting efficient couplings regardless of the employed conditions or coupling partners.

Development of copper-catalyzed deaminative esterification using high-throughput experimentation

“…5). The reaction was successful regardless of whether the carboxylic acid was reagent grade or obtained from the crushed pill, with no additional treatment to remove fillers or excipients, giving esters derived from aspirin (42), naproxen (43), ibuprofen (44), and fexofenadine (45) in comparable yield and demonstrating that even substrates contaminated with pill excipients are viable. Remarkably, the basic amine and free alcohols of 45 were tolerated, albeit in somewhat reduced yield.…”

“…3A). Recent studies employ diazonium salts as substrates in palladium [42][43][44][45][46][47] , copper [48][49][50] , and gold 51 catalyzed Meerwein-type, Suzuki-type, and Sonogashira-type coupling reactions. There has also been a resurgence of Sandmeyer-type reactions forging C-heteroatom bonds from diazonium salts to leverage the low cost of aryl amines 33,52,53 .…”

Lewis acid-mediated Suzuki–Miyaura Cross-Coupling Reaction

“…1B). [12][13][14][15] These pioneering studies have solved the base problem by substrate design. Herein, we report a strategy to avoid the addition of base to the SMC reaction of readily available organohalides with organoborons enabled by design of catalytic intermediates.…”

Base-Free Suzuki–Miyaura Cross-Coupling Reaction Mediated by Lewis Acids

“…1B). [12][13][14][15] These pioneering works have solved the base problem by designing the substrates. Herein, we report a base-free SMC reaction of readily available organohalides with organoborons enabled by designing catalytic intermediates.…”