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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<A NAME="RS08411ST-14">14 </A>
The activity of commercial TFFH was
found to vary among suppliers. Material from TCI and Oakwood consistently provided
reproducible results.
<A NAME="RS08411ST-15">15 </A> Toluene provided slightly better
results but the formation of a gum was deemed undesirable especially
in potential scale up of this reaction
<A NAME="RS08411ST-16">16 </A>
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).
<A NAME="RS08411ST-17">17 </A>
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 Et3 N×3HF (2 equiv) and Et3 N (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
H2 O to remove the tetramethylurea by-product.
