Continuous flow chemistry platforms enable palladium-catalyzed C-C and C-N coupling reactions (two of the most widely utilized cross-coupling reactions across pharmaceutical industry) to be performed at high temperatures and/or pressures while removing the need for handling dangerous intermediates [1,2]. Although continuous flow strategies have proven to be a powerful technique for high-throughput characterization of cross-coupling reactions, however salt and byproduct formation during the coupling reactions could potentially clog the reactor, hindering the adaptation of flow chemistry platforms from pharmaceutical industry. Bi-phasic cross-coupling reactions utilizing an aqueous base can solubilize the formed salts or byproducts, thereby reducing the chance of clogging and enabling the reactions to be efficiently performed . However, the presence of two immiscible phases involved in bi-phasic systems would require a high degree of small scale mixing and mass transfer to achieve conversions and yields similar to batch reaction.
In this study, a three-phase oscillatory flow strategy is designed and developed to address mixing and mass transfer limitations associated with continuous slug flow chemistry platforms for studies of bi-phasic C-C and C-N cross-coupling reactions. Capitalizing on the difference between surface energies of aqueous and organic phases, the oscillatory motion of a bi-phasic slug (10-20 μL) within a Teflon tubular reactor (fluorinated ethylene propylene, FEP), under inert atmosphere (argon), enables complete engulfment of the aqueous phase within the organic phase over the course of the coupling reaction. The enhanced available interfacial area in the oscillatory flow strategy compared to continuous slug flow approaches facilitates reproduction of reaction yields similar to batch systems for bi-phasic Pd catalyzed C-C and C-N cross-coupling reactions. The developed oscillatory three-phase flow strategy provides similar mixing characteristics for different processing times and removes the residence time limitation associated with continuous flow chemistry approaches while using reagent volumes 200 times lower than batch systems. The oscillatory flow approach could potentially be adopted as a universal technique for fully-automated screening, optimization and library development of single/multi-phase reactions.
1. T. Noel and S. L. Buchwald, Chem. Soc. Rev. 40(10), 5010-5029 (2011).
2. R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem. Int. Ed. 50(33), 7502-7519 (2011).
3. M. Carril, R. SanMartin and E. Dominguez, Chem. Soc. Rev. 37 (4), 639-647 (2008).