Cross-Couplings Go With The Flow

Two MIT research groups have combined their talents to develop an efficient Suzuki-Miyaura cross-coupling reaction in a continuous-flow microreactor system (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201101480). Microreactor expert Klavs F. Jensen’s group and organic chemist Stephen L. Buchwald’s group took on the effort to see how they might develop multistep organic syntheses in a more streamlined manner. Microreactors provide safer operation, better heat and mass transfer, improved control over reactant residence time, more protection from air and moisture, and ease of scale-up than does batch processing, they note. In a test reaction, the MIT researchers first combined a phenol with triflic anhydride in a 100-μL tube reactor to create an aryl triflate intermediate. In the subsequent step, a palladium catalyst in a 400-μL packed-bed reactor mediated coupling of the aryl triflate with an aryl boronate to produce the biaryl product. Key to the success of the synthesis was using a microfluidic liquid-liquid extractor unit to purify the aryl triflates on the fly and using the packed-bed reactor that optimized reagent mixing in the coupling step. The reactions were completed in as little as seven minutes of residence time, the team reports, and produced isolated yields of 95% or better on a millimole-per-hour scale.