Many congratulations to Professors Heck, Negishi, and Suzuki on receiving the Nobel Prize for their pioneering research into metal-catalyzed cross-coupling reactions. Their influential work has led to processes for APIs, intermediates, drug candidates, and more.
Process understanding of cross-couplings is deepening and mild reaction conditions have been developed. After extensive DoE screening GSK workers developed a Pd-catalyzed coupling that proceeds under very mild conditions: KHCO3, iPrOH – H2O (4:1), 60 ºC / 2 hours, 82% isolated yield []. A group from AstraZeneca and the University of Bristol has shown through incisive NMR studies that in a Pd-catalyzed cross-coupling of trifluoroborates water provides sustained release of the corresponding arylboronic acid and leads to improved yields; THF – H2O (10 : 1) was the optimal solvent mixture []. In the case of a Pd-catalyzed amidation of o-bromotoluene 2.5 eq. of H2O was optimal when the reaction was run with Cs2CO3 in toluene; in dioxane or with PhONa or NaOtBu as base the amidation was less sensitive to H2O. The authors posed that H2O increased the solubility of the base in the reaction solvent []. Snieckus and coworkers have shown that 10 mol% H2O is optimal in a study of Ni-catalyzed couplings with boroxines; increased charges of H2O lead to the formation of NiO / Ni(OH)2 []. The Burke group found that in Pd-catalyzed cross-couplings anhydrous conditions are necessary to prevent hydrolysis of arylboronic acids protected with the MIDA group []; MIDA boronates effectively cross-couple in Pd-mediated processes wherein the boronic acid is generated under alkaline conditions []. Lipshutz’s group has extended their work on reactions in aqueous microemulsions, and have shown that Fujiwara – Moritani reactions can be conducted at room temperature in water []. Workers at Syncom and DSM have written an extensive review on cross-couplings of heteroarenes []. Consider the possible benefits and limitations of water in your cross-coupling processes.
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