Joerg Sedelmeier

KMnO4-Mediated Oxidation as a Continuous Flow Process

An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO(2) slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system.

Multi-Step Synthesis by Using Modular Flow Reactors: The Preparation of Yne―Ones and Their Use in Heterocycle Synthesis

The development of new and improved chemical processing techniques that conduct both complex and routine chemical transformations in a safe, reproducible and scalable fashion without recourse to costly route modification or redevelopment is very desirable. The introduction of continuous-flow reactor technologies offers the ability to test, optimise and create scalable syntheses rapidly by using a simple bench-top device. In combination with the concept of immobilised reagents, scavengers and catch-and-release protocols, a powerful tool arises that can perform chemical transformations without the need for traditional workup procedures. Moreover, these devices enable the rapid progression of a clean product flow stream from one synthetic transformation to the next in a multi-step sequence. Furthermore, the intrinsic design of the flow equipment allows realtime, in-line monitoring and accommodates high temperatures and pressures, which permit reactions to be performed that were previously difficult to carry out in conventional batch synthesis. The reaction setup also facilitates containment of hazardous reagents or intermediates and is readily scalable to provide bulk samples. Herein, we report the palladium-catalysed acylation of terminal alkynes for the synthesis of yne ones and their further transformation into various heterocycles. The reactions are performed as a continuous-flow procedure by using a commercially available pumping system and heated flow coils in combination with a suite of packed Omnifit glass tubes containing appropriate scavenger materials to ensure the quality of the final product. We also present an extension of the simple flow configuration that allows for easy batch splitting through a four-way splitter device and the generation of a heterocyclic library. For this work we used a commercially available synthesis platform, the Vapourtec R2+ /R4 unit (Figure 1). The Vapourtec integrates a twin pumping unit with an independent-

C1-symmetric oxazolinyl sulfoximines as ligands in copper-catalyzed asymmetric mukaiyama aldol reactions.

Aryl-bridged C1-symmetric oxazolinyl sulfoximines are applicable in copper-catalyzed asymmetric Mukaiyama aldol reactions with methyl pyruvate. The resulting alpha-hydroxy esters have been obtained with up to 94% ee in good yields. They contain a quaternary stereogenic center and represent valuable precursors for biologically active molecules.

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross-Couplings in Flow

Abstract We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

An efficient and transition metal free protocol for the transfer hydrogenation of ketones as a continuous flow process

We report the efficient reduction of a selection of ketones to the corresponding secondary alcohols using only catalytic amounts of LiOtBu in iPrOH facilitated by using a continuous flow reactor.

A multistep flow process for the synthesis of highly functionalized benzoxazoles.

An efficient and scalable transformation of 3-halo-N-acyl anilines to the corresponding benzoxazoles within a continuous flow reactor is reported. This transformation proceeds via base-mediated deprotonation, ortho-lithiation, and intramolecular cyclization to provide unstable lithiated benzoxazole moieties. The subsequent in-line electrophilic quench results in the formation of substituted benzoxazoles in high yield and quality. Continuous flow technology allowed for accurate temperature control and immediate in-line quench while minimizing the hold-up time for the unstable lithiated intermediates thereby minimizing associated byproduct formation.

Flow Chemistry on Multigram Scale: Continuous Synthesis of Boronic Acids within 1 s

The benefits and limitations of a simple continuous flow setup for handling and performing of organolithium chemistry on the multigram scale is described. The developed metalation platform embodies a valuable complement to existing methodologies, as it combines the benefits of Flash Chemistry (chemical synthesis on a time scale of <1 s) with remarkable throughput (g/min) while mitigating the risk of blockages.

Toolbox study for application of hydrogen peroxide as a versatile, safe and industrially-relevant green oxidant in continuous flow mode

Hydrogen peroxide embodies an ideal oxidant in terms of atom-economy, availability and green metrics. However, its use has been limited because of risks associated with disproportionation and the exothermic potential of oxidizing reaction mixtures. This study aims to showcase the versatility of hydrogen peroxide in a range of oxidations, while ensuring that such processes operate practically and with a defined and minimized risk. To offset the hazards of using peroxides, continuous-flow equipment was utilized to limit the volume of unquenched peroxides and to maintain process control. A methodological approach was established relying on kinetic and calorimetric understanding. Finally, scalability was highlighted in an organocatalysed heterocyclic N-oxidation using a cascade of stirred tank reactors with nitrogen flushing.

Dichloromethyllithium: Synthesis and Application in Continuous Flow Mode

A simple and robust procedure for the synthesis and use of thermally unstable dichloromethyllithium in continuous flow mode is described. By utilizing residence times in the range of milliseconds for the generation and electrophilic quench of dichloromethyllithium, the straightforward synthesis of dichlorocarbinols and benzylic pinacol esters was realized at reaction temperatures of -30 °C, whereas typical temperatures in traditional batch mode are below -78 °C. The excellent purity profile obtained from the flow process allows us to directly telescope the exiting flow stream into semibatch quenches for further modifications. All transformations gave the desired products in remarkable purity and yield on gram scale with no need for chromatography.

A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters

Abstract We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin‐3‐ol or 4‐dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron‐deficient olefins via radical addition to efficiently form C−C coupled products in a redox‐neutral fashion. The Lewis base catalyst was shown to form a redox‐active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.