Tetramethylfluoroformamidinium Hexafluorophosphate (TFFH) as a Mild Deoxofluorination Reagent

Abstract

The solid, air-stable peptide coupling reagent TFFH (tetramethylfluoroformamidinium hexafluorophosphate) was found to activate a variety of alcohols towards deoxofluorination. These conditions are compatible with carbonyl functional groups thus offering interesting possibilities for the application to sensitive molecules.

Key words

deoxofluorination - fluoroformamidinium - fluoride - TFFH - fluorination

References and Notes

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• 15 Toluene provided slightly better results but the formation of a gum was deemed undesirable especially in potential scale up of this reaction

7

Differential scanning calorimetry (DSC) analysis of TFFH revealed a generation of 146 J/g at T _max of 370 ˚C. See reference 6a for comparative data with other reagents.

11

This conclusion can only be applied to a subset of the reactions studied as this behavior could be substrate dependent.

13

^¹9F NMR experiments were collected using a Bruker-Biospin 5 mm BBFO probe on Bruker AVANCE III NMR spectrometer operating at 400 MHz. Limit of detection evaluated at 0.1%.

14

The activity of commercial TFFH was found to vary among suppliers. Material from TCI and Oakwood consistently provided reproducible results.

16

The mildest of the sulfur fluoride based reagents, XtalFluor, was found to transform carbonyls into gem-difluoro moieties at ambient temperatures. This reaction in bifunctional substrates could be mitigated by using cryogenic temperatures (-78 ˚C).

17

Typical Procedure: The alcohol (1 equiv) was dissolved in EtOAc (concentration of 0.5 M) at ambient temperature. The solution was cooled to 5 ˚C and Et₃N×3HF (2 equiv) and Et₃N (2 equiv) were successfully added in a dropwise manner. After stirring for 5 min, TFFH was added in one portion (1.5 equiv). The solution was then allowed to stir at the necessary temperature. Upon completion, the reaction was quenched with sat. NaHCO₃ to pH 7 and diluted with additional EtOAc. Layers were separated and the organic layer was concentrated to a crude residue. The crude residue could be purified by flash chromatography or partitioned between MTBE and H₂O to remove the tetramethylurea by-product.