Continuous Flow Microwave-Assisted Reaction Optimization and Scale-Up Using Fluorous Spacer Technology

Microwave-assisted organic synthesis in a laboratory-scale monomodal microwave reactor is investigated for continuous flow applications using fluorous spacer technology. The benchtop continuous flow microwave described allows sequential processing of multiple plugs using small amounts of reagents for reaction optimization, scale-up and array synthesis. The system features online monitoring of temperature, pressure and microwave power. Several different reactions have been scaled up, including a Suzuki−Miyaura cross-coupling reaction and nucleophilic substitutions. In all cases it was possible to optimize the reaction conditions on a small scale (∼300 μL processing volume), and achieve similar conversions on an intermediate scale (∼30 mL), offering the potential for further scale-up without modifying the optimized conditions (direct scalability) producing similar isolated yields in the C−C bond formation reaction.