Palladium‐Catalysed CH Bond Electrophilic Fluorination of Highly Substituted Arylpyrazoles: Experimental and DFT Mechanistic Insights

Abstract A general protocol for palladium‐catalysed CH mono‐ and di‐fluorination of highly substituted arylpyrazoles is reported. Coupling pathways and substrate limitations are discussed in the light of complementary mechanistic experimental and density functional theory (DFT) studies. The mono‐ and di‐ ortho ‐fluorination of arylpyrazoles having substituted pyrazole groups and ortho ‐, meta ‐, or para ‐substituted arene moieties is achieved. Various pyrazole groups can efficiently promote the direct CH activation/fluorination of substrates bearing valuable reactive ester, cyano, halide and nitro functions. The presence of methoxy, methyl and trifluoromethyl is tolerated on the pyrazole directing groups. However, steric substituent effects have a marked influence which is evidenced by calculations. DFT modelling suggested also a previously unseen outer‐sphere oxidative addition of N ‐fluorobenzenesulfonimide (NFSI) to Pd(II) as an alternative mechanism to the commonly assumed Pd(II)/Pd(IV) process. This unprecedented proposal, which is supported by the mass spectrometry identification of a key Pd(II) monomer under the stoichiometric conditions deserves more attention. The influence of elaborate highly substituted directing groups on the course of Pd‐catalysed fluorination has generally received limited attention although this question has a crucial synthetic utility; herein, appropriate conditions for isolating pure products are reported. magnified image