Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond Formation Using Pentafluoropyridine (PFP)

Abstract

This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via in situ generation of acyl fluorides. This one-pot deoxyfluorination amide bond-forming reaction gives ready access to amides in yields of ≤94%.

Recent Advances in C–F Bond Activation of Acyl Fluorides Directed toward Catalytic Transformation by Transition Metals, N-Heterocyclic Carbenes, or Phosphines

“…Very recently, Cobb et al utilized pentafluoropyridine (PFP) as a deoxyfluorinating agent to form acyl fluorides in situ from carboxylic acids, and then constructed a series of amides and esters in good to excellent yields via intermolecular nucleophilic substitution with amines or alcohols as nucleophiles (Scheme 52b). 100…”

Perfluoropyridine: Discovery, Chemistry, and Applications in Polymers and Material Science

“…Perfluoropyridine has been employed as a nucleophilic fluorination reagent for both alkyl halides ( Scheme 6 , right-to-left ) [ 46 ] as well as deoxyfluorination of carboxylic acids ( Scheme 6 , left-to-right ) [ 47 ] for the preparation of a versatile pool of substrates. Fluorination of organo-halides (R–X) is achieved after generation of the air-stable fluoride salt from the addition of PFPy and dimethylaminopyridine [ 46 ].…”

“…Fluorination of organo-halides (R–X) is achieved after generation of the air-stable fluoride salt from the addition of PFPy and dimethylaminopyridine [ 46 ]. Furthermore, the in situ generation of acyl fluorides is readily accomplished by the nucleophilic addition of carboxylic acids with PFPy [ 47 ]. The ester intermediate then undergoes cleavage from unsequestered fluoride, producing phenol as a by-product and the desired acyl fluoride.…”

“…The halex reverse-substitution was achieved in the 4-para-position of PFPy with LiCl, and additional exchanges on the ring with chlorine were achieved from a combination of kinetic and thermodynamic control [49]. Perfluoropyridine has been employed as a nucleophilic fluorination reagent for both alkyl halides (Scheme 6, right-to-left) [46] as well as deoxyfluorination of carboxylic acids (Scheme 6, left-to-right) [47] for the preparation of a versatile pool of substrates. Fluorination of organo-halides (R-X) is achieved after generation of the air-stable fluoride salt from the addition of PFPy and dimethylaminopyridine [46].…”

Perfluoroaryl and Perfluoroheteroaryl Reagents as Emerging New Tools for Peptide Synthesis, Modification and Bioconjugation

“…In 2021, it was reported that pentafluoropyridine can also be employed to synthesise amide bonds. [21] By mixing a carboxylic acid with pentafluoropyridine it was shown that the corresponding acyl fluoride could be readily generated. By subsequent addition of an amine, the amide could be generated in good to excellent yield across a wide range of examples.…”