Studying Regioisomer Formation in the Pd‐Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

• Published in: Angewandte Chemie International Edition 2023-04, Vol.62 (15), p.e202300109-n/a
• Main Authors: Ye, Yuxuan, Kim, Seoung‐Tae, King, Ryan P., Baik, Mu‐Hyun, Buchwald, Stephen L.
• Format: Article
• Language: English
• Subjects: Additives; Chemical reactions; Computer applications; Dearomatization; Density-Functional Calculations; Fluorination; Ligands; Mixtures; Palladium; Reaction Mechanism; Regioselectivity
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202300109

Pd‐catalyzed nucleophilic fluorination reactions are important methods for the synthesis of fluoroarenes and fluoroalkenes. However, these reactions can generate a mixture of regioisomeric products that are often difficult to separate. While investigating the Pd‐catalyzed fluorination of cyclic vinyl triflates, we observed that the addition of a substoichiometric quantity of TESCF3 significantly improved the regioselectivity of the reaction. Herein, we report a combined experimental and computational study on the mechanism of this transformation focusing on the role of TESCF3. The poor regioselectivity of the reaction in the absence of additives results from the formation of LPd‐cyclohexyne complexes (L=biaryl monophosphine ligand). When TESCF3 is added to the reaction mixture, the generation of the Pd‐cyclohexyne complexes is diminished by an unexpected pathway involving the dearomatization of the ligand by nucleophilic attack from a trifluoromethyl anion (CF3−). A combined experimental and computational study was conducted to investigate the regioisomer formation in the Pd‐catalyzed fluorination of cyclic vinyl triflates. Results suggested that the TESCF3 additive unlocked an alternative reaction pathway involving a usual in situ ligand dearomatization. This new mechanism prevented the formation of Pd‐cyclohexyne intermediates and significantly increased the regioselectivity of the reaction.