Multistep organic synthesis using flow chemistry

Abstract

The technology enabling synthetic chemistry within flow systems has been advanced through remarkable synthetic designs using multistep sequences to conduct synthetic schemes leading to products of high complexity. Continuous flow reactors provide a synthetic platform for the combination of several chemical transformations as a single process. This synthetic strategy enables the chemist to organize multiple flow reactors in sequence where the reaction intermediates are not isolated but passed onto the next reactor component of the sequence. Each stream requires flow rate optimization to sustain required residence times and temperature effects for each reactor. Single reactors can be optimized for the reaction conditions conducted within the reactor but the situation becomes more complex when one reactor precedes another in sequence. Conditions are required to support each synthetic stage and a single reactor cannot be optimized by itself. The fine balance of conditions can lead to success or failure of such a flow system. By-products can be removed in-line through the use of phase-bound scavenging reagents. These small flow reactors have been shown to enable the use of unstable intermediates such as acyl azides formed as part of the Curtius rearrangement. The simplicity of the reactor sequence permits consideration of splitting synthetic sequences to permit the desired reaction control. An example of multistep synthesis is shown for the neolignin natural product grossamide. A system of three independent pumps delivering reactants through a series of valves using in-line monitoring and feedback control was operated under computer control.