In situ generation of formyl fluoride for Pd-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides

Acyl fluorides have gained much attention as robust and versatile synthetic tools in synthetic chemistry. While several synthetic routes to acyl fluorides have been reported, a procedure involving the direct insertion of the "fluoro-carbonyl" moiety using a single reagent has not yet been realized.

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Before this, the synthetic routes to R-COFs are categorized into two groups. The first group, which involves the fluorination of carboxylic acids or their derivatives, including aldehydes via deoxyfluorinations, halogen-exchange reactions, or C–H activation reactions, is the central area of the traditional research (type I, cleavage 1 in Fig. 1) The other group includes step-wise fluoro-carbonylation reactions of organic halides using a combination of toxic gaseous carbon monoxide (CO) or more stable alternative sources of CO, and fluorinating reagents (type II, cleavages 1 and in Fig.1).

                                                                 Fig.1

For common aromatic halides, the ideal synthesis method is to use fluorine atoms and carbon monoxide moieties directly into the site of the acid chloride instead of using highly toxic carbon monoxide for simultaneous fluorination. Formyl fluoride, as the most straightforward kind of acyl fluoride, grabbed our attention. From our experience in fluorine chemistry research, we thought difluoromethoxy anion (–OCF2H) should decompose into formyl fluoride by releasing a fluoride anion (F). Thus, we designed a type III (in Fig.1) strategy based on the fluoride-catalyzed in-situ generation of formyl fluoride, followed by a cross-coupling reaction with aryl halides in the presence of a Pd-catalyst.

We reported the preparation of acyl fluorides by palladium-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine under CO-free conditions. A wide variety of acyl fluorides are efficiently and safely obtained in high yield (up to 99%).

Further investigations into the extension of this fluoro-carbonylation strategy to generate more complex substrates. Furthermore, we plan to search for a large-scale supply method that can be widely used by the general public.

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You can read more about our research here: Communications Chemistry, Volume 3, Article number 59 (2020), https://www.nature.com/articles/s42004-020-0304-3 by Yumeng Liang, Zhengyu Zhao & Norio Shibata.

Yumeng Liang

Post-Doctoral Fellow, Nagoya Institute of Technology

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