Continuous-flow Suzuki-Miyaura reaction in supercritical carbon dioxide

The Suzuki-Miyaura cross-coupling of p-tolylboronic acid 1 and iodobenzene 2 to form 4-phenyltoluene 3 in the presence of tetrabutylammonium methoxide 4 and the immobilized catalyst PdEnCat as stationary phase has been carried out in continuous-flow mode using conventional organic and supercritical carbon dioxide solvent systems between temperatures of 55 to 120 degrees C and pressures up to of 250 bar. Laboratory-scale reaction studies have been undertaken on a 5 cm x 4.5 mm i.d. column packed with Pd(II)EnCat 40 catalyst [Lee et al., Chem Commun. 2005, 2175] using conventional organic solvents in continuous flow. We now report exploratory commercial-scale continuous flow using a 14.5 cm x 25.4 mm i.d. ModCol column with toluene/methanol solvent and, most significantly, continuous flow using a 48.5 cm x 25.4 mm i.d. high-pressure column using supercritical CO2 solvent + MeOH cosolvent. Conversion to 4-phenyltoluene 3 was found to be 81% in the supercritical CO2 system and 74% in the organic solvent system after a single pass through the continuous-flow reactor. The conversion in the organic solvent system was increased to quantitative after adopting pH control and further recycling. Experimental design included variation in temperature, supercritical pressure, the residence time, and the number of passes, and for each experiment the product conversion is reported. System hydrodynamics are interpreted in terms of Reynolds, Schmidt, Sherwood, and Peclet numbers. The work demonstrates the application of continuous-flow mode reactions in supercritical carbon dioxide as a potentially benign manufacturing process.