Integrated Multistep Photochemical and Thermal Continuous Flow Reactions: Production of Bicyclic Lactones with Kilogram Productivity

Abstract

Combining continuous photochemistry and flow reactions in high-temperature/high-pressure water has enabled us to integrate a multistep sequence into a single process with a reduction in reaction time to <10 min compared to >24 h in batch. At the same time, applying this approach to different substrates has allowed us to increase previously low yields to levels high enough to make these reactions potentially useful for multistage synthesis. In this paper, we describe the [2 + 2] cycloaddition/fragmentation of 3,4,5,6-tetrahydrophthalic anhydride and propargyl alcohol and analogous compounds leading to bicyclic lactones to demonstrate how photochemistry and thermal chemistry can be combined using continuous flow techniques to create complex structures on a relatively large scale. We show how photochemical and high-temperature water flow reactors can be used to carry out a three-step reaction sequence as a single integrated and continuous process. The reaction time has been reduced by exploiting the enhanced acidity of high-temperature water/acetonitrile mixtures. The overall process is demonstrated on an equivalent productivity of a >1 kg/day productivity using lab-scale equipment. Our approach should be simple to scale up in an appropriate facility, for larger scale production of chemicals. Process analytical technology and modeling were used to support the reaction development, while UV and IR time-resolved spectroscopies have been used to provide a deeper understanding of the reaction mechanism.

Ultra‐Fast Continuous‐Flow Photo‐Thiol‐Ene Functionalization of Conformation‐Controlled Cinchona Alkaloids

“…We are now adapting this chemistry to graft quinine derivatives on a thio-cellulose platform [28][29][30][31] with the aim of developing a photochemical process in flow compatible with the requirements of industrial setting. [32][33][34][35] Experimental Section General procedure for the flow photo-thiol-ene functionalization of cinchona alkaloids derivatives. The experimental setup consisted of a single stream equipped with a PEEK injection loop (2 mL, 0.76 mm id) as depicted in Figure 5A.…”

“…The results described in this manuscript provide important insights that go far beyond the scope of this study, particularly for the development of more reactive chiral catalysts from cinchona alkaloids. We are now adapting this chemistry to graft quinine derivatives on a thio‐cellulose platform [28–31] with the aim of developing a photochemical process in flow compatible with the requirements of industrial setting [32–35] …”

Process Intensification of the Continuous Synthesis of Bio-Derived Monomers for Sustainable Coatings Using a Taylor Vortex Flow Reactor

“…27−32 Superheated flow chemistry has also enabled the removal of harsh acid catalysts needed to overcome the activation energy of some processes. 33 There is increased activity in developing linked flow reactions into telescoped sequences since such operation has a number of advantages, including increasing the efficiency of the process and potentially minimizing/avoiding handling of hazardous intermediates. 34 In this work, we investigated the PhotoVortex reactor for the intensification and scale-up of the photo-oxidation of 1 with 1 O 2 and undertook the first flow synthesis of 3−5 using superheated reaction solvents to accelerate the reaction.…”

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

“…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. A self-optimizing flow photochemical reactor was deployed to expedite the optimization stage and the reaction scope was established on four cinchona alkaloids with a variety of organic thiols.…”

“…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…”