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Final Report Summary - FLACH (C-H activation and carbonylation in continuous-microflow)

Transition metal-catalyzed reactions have impacted the construction of carbon-carbon and carbon-heteroatom bonds in synthetic chemistry. These methods have been widely employed for the development of pharmaceuticals and other biologically active molecules, and functional materials. Inspired by selective biosynthetic pathways, C–H activation has emerged as a new and promising new area for the construction of carbon-carbon and carbon-heteroatom bonds. Moreover, C–H bonds are the fundamental linkage in organic molecules and, consequently, C–H activation strategies would allow for very versatile transformations. This provides an atom-efficient and cost-effective alternative for the traditional cross-coupling strategies. In order to cleave the C–H bond, harsh reaction conditions, long reaction times and high catalyst loadings are required. The research focused primarily on the development of continuous-flow strategies for enabling and accelerating challenging C−H functionalizations, thus providing additional advantages over batch in terms of safety, scalability, reaction time and selectivity. The main research line gravitated around the selective C−H functionalization of heteroarenes.
Firstly, a fast and straightforward continuous-flow protocol for the dehydrogenative C-3 olefination of indoles was developed.[1] Thanks to the enhanced gas-liquid mass transfer provided by micro flow technology, molecular oxygen could be utilized as sole oxidant, boosting reaction kinetics and thus accelerating hour-scale reactions in batch to the minute range in flow.[2]
Next, a mild and versatile protocol for the C−H acylation of indoles, via dual photoredox/palladium catalysis, was established.[3] Various aromatic and aliphatic (primary and secondary) aldehydes were successfully employed as acylating reagents. The room temperature procedure tolerated a wide variety of functional groups resulting in a diverse set of selective C-2 acylated indoles (28 examples). Moreover, the implementation of continuous-flow technology significantly decreased reaction times (2 h vs 20 h in batch), iridium catalyst loading (0.5 mol % vs 2 mol% in batch), and afforded increased yields while allowing easy scale-up of the reaction conditions.
In addition, a third strategy for the mild and selective C-H arylation of heteroarenes was developed through experiment and computation.[4] This open flask arylation method relies on equimolar amounts of aryldiazonium tetrafluoroborates as arylating agents and requires low palladium loadings (0.5 – 2 mol%). Moreover, optimization of the reaction conditions resulted in the use of green solvents (2-MeTHF) and room temperature operation. A broad substrate scope was obtained with perfect selectivity (C-2 for indoles and benzofurans, C-3 for benzothiophenes, total 46 examples). DFT calculation and mechanistic experiments support a Heck-Matsuda-type coupling, with preliminary results indicating a non-innocent behavior of the BF4- counter ions of the diazonium salts.
Furthermore, a parallel research line focused on the development of integrated multi-step flow processes to access valuable intermediates in a streamlined manner.
Therefore, a practical and effective modular flow process was designed for the continuous manufacturing of meta-arylated anilines.[5] Four continuous-flow modules (i.e., diaryliodonium salt synthesis, meta-selective C−H arylation, inline copper extraction and aniline deprotection) were developed and optimized. The four modules can be operated individually or in series, thus providing direct access to meta-arylated anilines with a total residence time of 1 hour. The desired meta-arylated anilines were obtained in excellent yield and purity, without the need for any chromatography method.
The flow synthesis of diaryliodonium triflates was further explored and flow calorimetry revealed the highly exothermic nature of the reaction (ΔH up to -180 kJ/mol).[6] The reaction scope was then expanded to a broad spectrum of both electron-rich and electron-deficient compounds with excellent scalability (45 examples). A productivity of up to 3.8 g/h for a single 100 µL reactor was achieved.

In conclusion, we have developed a number of CH activation methods which greatly benefited from continuous-flow processing. Advantages, such as enhanced mass transfer (gas-liquid reactions), enhanced heat transfer (exothermic reactions), increased safety profile (hazardous reagents, exothermic reactions), dual catalysis (merging CH activation and photoredox catalysis) and process integration (combining reaction and work up) have all been demonstrated during the entire course of the Flach project. We believe that insights gained in this project will be of great interest to those researchers working in academia and industry.

[1] H. P. L. Gemoets, V. Hessel, T. Noël, Org. Lett. 2014, 16, 5800-5803.
[2] H. P. L. Gemoets, Y. Su, M. Shang, V. Hessel, R. Luque, T. Noel, Chem. Soc. Rev. 2016, 45, 83-117.
[3] U. K. Sharma, H. P. L. Gemoets, F. Schröder, T. Noël, E. V. Van der Eycken, ACS Catal. 2017, 7, 3818-3823.
[4] H. P. L. Gemoets, I. Kalvet, A. V. Nyuchev, N. Erdmann, V. Hessel, F. Schoenebeck, T. Noël, Chem. Sci. 2017, 8, 1046-1055.
[5] H. P. L. Gemoets, G. Laudadio, K. Verstraete, V. Hessel, T. Noël, Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201703369.
[6] H. P. L. Gemoets, G. Laudadio, V. Hessel, T. Noël, (submitted).

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