Dominik Polterauer, Simon Wagschal*, Michael Bersier, Clara Bovino, Dominique M. Roberge, Christopher A. Hone* and C. Oliver Kappe*,
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Deoxyfluorination of Ketones with Sulfur Tetrafluoride (SF4) and Dialkylamines in Continuous Flow Mode
Fluorinated molecules are prevalent in biologically active substances, in particular, the gem-difluoro motif. However, the selective incorporation of a gem-difluoro motif into organic molecules is a laborious task. Deoxyfluorination is a promising and widely used methodology to achieve this transformation, which is usually costly or highly hazardous. Herein, we report a deoxyfluorination protocol using sulfur tetrafluoride (SF4) and diethylamine (Et2NH) to prepare gem-difluorides in continuous flow mode. The process does not require the addition of exogenous HF, and in situ generated reagents were quenched in-line, which improved safety. The methodology was successfully applied to convert a broad range of 4-, 5-, and 6-membered ketone derivatives to their corresponding difluorinated compounds while minimizing the undesired vinyl fluoride formation. In summary, these findings improve safety and selectivity toward the synthesis of gem-difluoro compounds drastically, enabling a more efficient production of fluorinated active pharmaceutical ingredients.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.