We converted diverse commercial meta-substituted phenols to the allyl-substituted precursors via nucleophilic substitution using batch technology to allow processing these in microflow by means of the photo-Claisen rearrangement. The latter process is researched on its own, as detailed below, and also prepares the ground for a fully continuous two-step microflow synthesis, as outlined above. It is known that batch processing of electronically deactivated phenols (e.g., bearing a cyano or nitro group) has several orders of magnitude lower reactivity than their parental counterparts . Thus, we here explore if the high quantum yield of microflow, yet at very short residence time, is sufficient to activate the deactivated molecules. In addition, the realization of a true orthogonal two-step flow synthesis can open the door to a large synthetic scope of our approach and possibly overcome limitations due to missing orthogonality of our previously reported thermal approach of combined nucleophilic substitution-Claisen rearrangement in microflow. Consequently, we make for our photo microflow approach an orthogonality check, as previously reported for the thermal approach, and compare both.
To get a broader picture, we have investigated some major parametric sensitivities such as the irradiation intensity, the choice of solvent, the reactant concentration, and, most notably, the influence of the substitution pattern. The irradiation intensity was varied by increasing distance between a lamp and the microflow capillary. In addition, the normal photo-Claisen microflow process (at room temperature) is compared to a high-temperature photo-Claisen microflow process, to check the potential of such novel process window . This is difficult to realize in batch, as the combination of strong ultraviolet (UV) irradiation and high temperature causes a high hazard potential. Yet, under microflow, this can be safely handled.
Pincock, A. L.; Pincock, J. A.; Stefanova, R. J.Am. Chem. Soc.2002, 124, 9768–9778.
Pincock, A. L.; Pincock, J. A.; Stefanova, R. J.Am. Chem. Soc.2002, 124, 9768–9778.)| false