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

Abstract

Ag eneral protocolf or palladium-catalysed C À Hm ono-and di-fluorination of highly substituted arylpyrazoles is reported. Coupling pathways and substrate limitations are discussedi nt he light of complementary mechanistic experimental and density functional theory (DFT) studies.T he mono-a nd di-ortho-fluorination of arylpyrazoles having substituted pyrazole groups and ortho-, meta-, or para-substituteda rene moieties is achieved.V arious pyrazole groups can efficiently promote the direct C À Ha ctivation/fluorination of substrates bearing valuable reactive ester, cyano,h alide and nitro functions.T he presence of methoxy,m ethyl and trifluoromethyl is tolerated on the pyrazole directing groups.H owever, steric substituent effects have am arked influence which is evidencedb yc alculations.D FT modelling suggested also ap reviously unseen outer-sphereo xidative addition of N-fluorobenzenesulfonimide (NFSI) to Pd(II) as an alternative mechanism to the commonly assumed Pd(II)/Pd(IV)p rocess.T his unprecedented proposal, which is supported by the mass spectrometry identification of ak ey Pd(II) monomer under the stoichiometric conditions deserves more attention. Thei nfluence of elaborateh ighly substituted directing groups on the course of Pd-catalysed fluorination has generally received limited attentiona lthough this questionh as ac rucial synthetic utility;h erein, appropriate conditions for isolating pure productsare reported.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Wang used Na halides and Rh catalysis for iodination, bromination and chlorination of a few 1-phenyl-1 H -pyrazoles ( Scheme 153K ), 772 while fluorination could be achieved using NFSI with Pd catalysis, as reported by Hierso ( Scheme 153L ). 939 Notably, this functionalisation proved to be fairly substrate-dependent, requiring varying equivalents of NFSI or leading to mono or difluorinated products depending on the substitution pattern.…”

(2‐Pyridyl)sulfonyl Groups for ortho‐Directing Palladium‐ Catalyzed Carbon–Halogen Bond Formation at Functionalized Arenes

“…Unlike the case for bromination reactions, the purification of difluorinated products from starting material was found to be troublesome and a limited yield of 25% only could be isolated to reach satisfactory high purity (99%+). We have already reported on purification limitations with chromatography when a mixture of mono‐ and difluorinated compounds is obtained . Nevertheless, fluorination of tert ‐butyl‐functionalized (2‐pyridyl)sulfonyl 3 gave a 94/6 ratio for 29a and ortho ‐difluorinated derivative 29b with a satisfactory 55% isolated yield (Scheme ).…”

Palladium‐Catalyzed Electrophilic C–H‐Bond Fluorination: Mechanistic Overview and Supporting Evidence

“…In 2015, Roger, Fleurat‐Lessard and Hierso reported a general protocol for palladium‐catalyzed C–H mono‐ and difluorination of highly substituted arylpyrazoles (Scheme , top) …”