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DOI: 10.1055/s-0031-1290336
Tetramethylfluoroformamidinium Hexafluorophosphate (TFFH) as a Mild Deoxofluorination Reagent
Publication History
Publication Date:
08 February 2012 (online)
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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
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in potential scale up of this reaction
References and Notes
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.
11This conclusion can only be applied to a subset of the reactions studied as this behavior could be substrate dependent.
13¹9F 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%.
14The activity of commercial TFFH was found to vary among suppliers. Material from TCI and Oakwood consistently provided reproducible results.
16The 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).
17Typical 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.