CONSPECTUS: The previous decade has witnessed the expeditious uptake of flow chemistry techniques in modern synthesis laboratories, and flow-based chemistry is poised to significantly impact our approach to chemical preparation. The advantages of moving from classical batch synthesis to flow mode, in order to address the limitations of traditional approaches, particularly within the context of organic synthesis are now well established. Flow chemistry methodology has led to measurable improvements in safety and reduced energy consumption and has enabled the expansion of available reaction conditions. Contributions from our own laboratories have focused on the establishment of flow chemistry methods to address challenges associated with the assembly of complex targets through the development of multistep methods employing supported reagents and in-line monitoring of reaction intermediates to ensure the delivery of high quality target compounds. Recently, flow chemistry approaches have addressed the challenges associated with reactions utilizing reactive gases in classical batch synthesis. The small volumes of microreactors ameliorate the hazards of high-pressure gas reactions and enable improved mixing with the liquid phase. Established strategies for gas-liquid reactions in flow have relied on plug-flow (or segmented flow) regimes in which the gas plugs are introduced to a liquid stream and dissolution of gas relies on interfacial contact of the gas bubble with the liquid phase. This approach confers limited control over gas concentration within the liquid phase and is unsuitable for multistep methods requiring heterogeneous catalysis or solid supported reagents. We have identified the use of a gas-permeable fluoropolymer, Teflon AF-2400, as a simple method of achieving efficient gas-liquid contact to afford homogeneous solutions of reactive gases in flow. The membrane permits the transport of a wide range of gases with significant control of the stoichiometry of reactive gas in a given reaction mixture. We have developed a tube-in-tube reactor device consisting of a pair of concentric capillaries in which pressurized gas permeates through an inner Teflon AF-2400 tube and reacts with dissolved substrate within a liquid phase that flows within a second gas impermeable tube. This Account examines our efforts toward the development of a simple, unified methodology for the processing of gaseous reagents in flow by way of development of a tube-in-tube reactor device and applications to key C-C, C-N, and C-O bond forming and hydrogenation reactions. We further describe the application to multistep reactions using solid-supported reagents and extend the technology to processes utilizing multiple gas reagents. A key feature of our work is the development of computer-aided imaging techniques to allow automated in-line monitoring of gas concentration and stoichiometry in real time. We anticipate that this Account will illustrate the convenience and benefits of membrane tube-in-tube reactor technology to improve and concomi...

A visible-light photocalytic method for the chemoselective transfer hydrogenation of imines in batch and continuous flow is described. The reaction utilizes EtN as both hydrogen source and single-electron donor, enabling the selective reduction of imines derived from diarylketimines containing other reducible functional groups including nitriles, halides, esters, and ketones. The dual role of EtN was confirmed by fluorescence quenching measurements, transient absorption spectroscopy, and deuterium-labeling studies. Continuous-flow processing facilitates straightforward scale-up of the reaction.

The general catalytic synthesis of aryl and vinyl thioethers from readily available halides remains a challenge. Herein we report a unified method for the thiolation of aryl and vinyl iodides with dialkyl disulfides using visible light photoredox catalysis. A range of thioether products bearing diverse functional groups can be accessed in high yield and with excellent chemoselectivity. We demonstrate the versatility of this method through the expedient synthesis of a family of thioether-rich natural products. A detailed investigation of the photocatalytic mechanism is presented from both steady-state and time-resolved luminescent quenching as well as transient absorption spectroscopy experiments.