Roles of Water in Metal-Catalyzed Cross-Couplings

November 10th, 2010 Leave a reply »

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 [[1]].  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 [[2]].  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 [[3]].  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 [[4]].  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 [[5]]; MIDA boronates effectively cross-couple in Pd-mediated processes wherein the boronic acid is generated under alkaline conditions [[6]].  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 [[7]].  Workers at Syncom and DSM have written an extensive review on cross-couplings of heteroarenes [[8]].  Consider the possible benefits and limitations of water in your cross-coupling processes.


[1]. Bullock, K. M.; Mitchell, M. B.; Toczko, J. F. Org. Process Res. Dev. 2008, 12, 896.

[2]. Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones, G. C.; Murray, P. M. “Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride.” Angew. Chem. Int. Ed. 2010, 49, 5156.

[3]. Dallas, A. S.; Gothelf, K. V., “Effect of Water on the Palladium-Catalyzed Amidation of Aryl Bromides.” J. Org. Chem. 2005, 70, 3321.

[4]. Antoft-Finch, A.; Blackburn, T.; Snieckus, V. “N,N-Diethyl O-Carbamate: Directed Metalation Group and Orthogonal Suzuki−Miyaura Cross-Coupling Partner.” J. Am. Chem. Soc. 2009, 131, 17750.

[5]. Ballmer, S. G..; Gillis, E. P.; Burke, M. D. Org. Synth. 2009, 86, 344.

[6]. Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.

[7]. Nishikata, T.; Lipshutz, B. H. Cationic Pd(II)-Catalyzed Fujiwara-Moritani Reactions at Room Temperature in Water” Org. Lett. 2010, 12, 1972.

[8]. Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. “Practical Aspects of Carbon-Carbon Cross-Coupling Reactions Using Heteroarenes” Org. Process Res. Dev. 2010, 14, 30.

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