Search

Chlorinated 4-aminophenol derivatives are widespread in pharmaceutical ingredients. An electrochemical procedure for the synthesis of these compounds via mono- and dichlorination of the corresponding electron-rich precursors using dichloromethane (DCM) both as the solvent and the chlorine source has been developed. The method is based on the degradation of DCM at the cathode, which releases chloride ions that can be used to generate active chlorine at the anode. Key to the success of this protocol is the utilization of a "quasi-divided" cell with a cathode surface area much smaller than the anode, ensuring that only the solvent and not the molecules in solution are degraded by cathodic reduction. The electrochemical protocol has been demonstrated for a wide range of substrates (25 examples) in moderate to excellent isolated yield (up to 94%). Importantly, the procedure has been translated to a parallel plate flow electrolysis cell. To achieve this goal, a bespoke cell design featuring a PTFE mesh that partially covers the cathode surface has been developed, which provides adequate anode to cathode surface area ratio for quasi-divided cell operation. This is the first example of quasi-divided cell operation in a parallel plate flow electrochemical reactor. [ABSTRACT FROM AUTHOR]

A continuous flow metal‐free protocol for the synthesis of sulfonyl chlorides from thiols and disulfides in the presence of nitric acid, hydrochloric acid and oxygen was developed. The influence of the reaction parameters was investigated under batch and flow conditions. Online 19F NMR was successfully implemented to investigate different reaction conditions within a single experiment. The sulfonyl chlorides were isolated (mostly in 70–81 % yield) after performing a simple aqueous washing procedure. In particular, the protocol was successfully operated for >6 hours to convert diphenyl disulfide to its corresponding sulfonyl chloride, achieving a throughput of 3.7 g h−1. The environmental impact of the protocol was assessed and compared to an existing continuous flow protocol using 1,3‐dichloro‐5,5‐dimethylhydantoin (DCH) as reagent. The process mass intensity (PMI) for the newly‐developed flow protocol (15) compared favorably to the DCH flow process (20). [ABSTRACT FROM AUTHOR]

Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low‐volume optimization experiments are reported. A Buchwald–Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self‐optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor. [ABSTRACT FROM AUTHOR]

An asymmetric enantioselective flow process is reported for the formal synthesis of a 1,2,3,4‐tetrahydroquinoline selective estrogen receptor modulator. Starting from an easily available 2‐nitrochalcone, the first part of the process comprised a telescoped nitro reduction/intramolecular cyclocondensation sequence using diboronic acid as a simple reductant. Subsequent enantioselective transfer hydrogenation in the presence of an immobilized phosphoric acid organocatalyst followed by telescoped N‐alkylation furnished the targeted chiral intermediate. The approach ensures flexibility regarding the scale of the synthesis, whilst minimizing the need for intermediate purifications and ensuring environmentally benign metal‐free conditions. [ABSTRACT FROM AUTHOR]

The utilization of water as a sustainable reaction medium has important advantages over traditional organic solvents. Hydroxypropyl methylcellulose has emerged as a biomass‐based polymeric additive that enables organic reactions in water through hydrophobic effects. However, such conditions imply slurries as reaction mixtures, where the efficacy of mass transfer and mixing decreases with increasing vessel size. In order to circumvent this limitation and establish an effectively scalable platform for performing hydroxypropyl methylcellulose‐mediated aqueous transformations, we utilized oscillatory plug flow reactors that feature a smart dimensioning design principle across different scales. Using nucleophilic aromatic substitutions as valuable model reactions, rapid parameter optimization was performed first in a small‐scale instrument having an internal channel volume of 5 mL. The optimal conditions were then directly transferred to a 15 mL reactor, achieving a three‐fold scale‐up without re‐optimizing any reaction parameters. By precisely fine‐tuning the oscillation parameters, the system achieved optimal homogeneous suspension of solids, preventing settling of particles and clogging of process channels. Ultimately, this resulted in a robust and scalable platform for performing multiphasic reactions under aqueous conditions. [ABSTRACT FROM AUTHOR]

An explorative study on the continuous flow generation of the N-F reagent 2,6-dichloro-1-fluoro-pyridinium tetrafluoroborate from 2-6-dichloropyridine and 10% F2/N2 and its telescoped downstream electrophilic fluorination reaction with an enamine is reported. The 2-step procedure was performed in a modular lab-scale silicon carbide flow reactor, which safely allowed processing corrosive F2 and precise temperature control. Both reaction sequences turned out to be very fast when carried out in flow at − 10 °C: the N-F generation step could be done within 7.9 s and only 6.6 s were necessary for the fluorination of the enamine. [ABSTRACT FROM AUTHOR]