Photo-Claisen Rearrangement of Allyl Phenyl Ether in Microflow: Influence of Phenyl Core Substituents and Vision on Orthogonality

Abstract

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 [1]. 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 photoClaisen microflow process (at room temperature) is compared to a high-temperature photo-Claisen microflow process, to check the potential of such novel process window [2]. 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.

An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone

“…The second step consisted in a [3,3]-Claisen rearrangement of allyl sesamol 6 . Traditionally, sigmatropic rearrangements of allyl phenols are carried out under photochemical, , catalyst or thermal activation . For the latter, high boiling point solvents such as toluene, xylenes and diphenyl ether are required, but we reasoned that the possibility to pressurize the line with an automated BPR could be an appealing opportunity to reach high temperatures with a low boiling point and more sustainable solvent.…”

Developing flow photo-thiol–ene functionalizations of cinchona alkaloids with an autonomous self-optimizing flow reactor

“…[33][34][35] In addition the heat generated by the light source can be more efficiently controlled by a precise control of the flow rate and quickly dissipated thanks to the high surface area to volume ratio of capillary flow reactors. Therefore, it is now widely accepted that photochemical transformations are, in general, much more reproducible, cleaner and faster when carried out in a continuous flow reactor [36][37][38][39][40][41][42][43] even on large scales. [44][45][46][47] In this contribution we describe our effort toward the development of a general strategy for the functionalization of cinchona alkaloids through photochemical thiol-ene reactions conducted in a custom built flow photochemical reactor.…”

“…33–35 In addition the heat generated by the light source can be more efficiently controlled by a precise control of the flow rate and quickly dissipated thanks to the high surface area to volume ratio of capillary flow reactors. Therefore, it is now widely accepted that photochemical transformations are, in general, much more reproducible, cleaner and faster when carried out in a continuous flow reactor 36–43 even on large scales. 44–47…”

Photo isomerization of cis‐cyclooctene to trans‐cyclooctene: Integration of a micro‐flow reactor and separation by specific adsorption

“…Recently, we reported on the combination of a nucleophilic substitution to the thermal-Claisen rearrangement and also to photo-Claisen rearrangement in micro-flow. 30,31 The motivation was to integrate two processes and to address the resulted challenging issues toward orthogonality. Also, here, we would like to design and integrate two processes, photoreaction and adsorption, yet with more in depth theoretical study for each process.…”