Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch

Abstract

Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C-H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, we demonstrate the meta-C-H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The preparation of various meta- and para-difluoromethylated pyridines through this approach is presented. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs. Sequential double functionalization of pyridines is presented, which further underlines the value of this work.

Fig. 1. Site-selective C−H difluoromethylation of pyridines.

a Bioactive compounds containing a difluoromethylated pyridine moiety. b Three possible regioisomers for the C−H difluoromethylation of pyridines. c Our design: switchable C−H functionalization of pyridines. Oxazino pyridines that are present under basic conditions show nucleophilic reactivity at the β- and δ-positions, while the pyridinium ions formed under acidic conditions show electrophilic reactivity at the γ-position. d The two difluoromethylated pyridines that can be regioselectively accessed upon switching from oxazino pyridines to pyridinium ions.

Fig. 2. Establishment of meta and para C−H difluoromethylation of pyridines.

a Choice of difluoromethylation reagent. b meta-functionalization. c para-functionalization. Yield of 5 was determined by ¹⁹F NMR using 1-bromo-4-fluorobenzene as the internal standard. E = CO₂Me. EWG electron-withdrawing group, TMP 2,2,6,6-tetramethylpiperidine, CSA camphorsulfonic acid.

Fig. 3. Substrate scope.

^aYields were based on isolated oxazino pyridines. ^bYield was determined by ¹⁹F NMR using 1-bromo-4-fluorobenzene as the internal standard. DMAD: dimethyl acetylenedicarboxylate. MP: methyl pyruvate. m:d: ratio of mono:di at the meta position. r.r. regioselectivity in the oxazino pyridine (δ:β-selectivity).

Fig. 4. Synthetic applications and difunctionalizations.

a Late-stage difluoromethylation of drugs and drug derivatives. b One-pot difluoromethylation of loratadine. c Consecutive meta,meta’- or meta,para-difunctionalization of pyridines. NCS N-chlorosuccinimide.