Fluorinating reagents and fluoroalkylation
The introduction of fluorine atoms or fluoroalkyl groups into active agents leads to greater effectiveness in many cases. This step frequently occurs in a late stage of synthesis. This process is reflected in the term “late-stage-fluorination”.
Gaseous fluorine, hydrogen fluoride, hydrogen fluoride pyridine mixtures, halogen fluorides (e.g. iodine pentafluoride), xenon difluoride, sulfonylfluorides, sulfur tetrafluoride (SF4) and derivates such as DAST or quaternary ammonium fluorides are available to the chemist as reagents for fluorination, amongst others. Recent developments represent bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), 4-tert-Butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead®) as well as (diethylamino)difluorosulfonium tetrafluoroborate (XtalFluor-E®) and difluoro(morpholino)sulfonium tetrafluoroborate (XtalFluor-M®).
Metal fluorides such as aluminium, antimony, silver, molybdenum or cobalt(III)-fluoride are used, depending on the substrate. You can also find gaseous fluorides such as arsenic pentafluoride (AsF5) or rhenium hexafluoride (ReF6) in the abcr catalogue.
You can also choose between the following for the fluoroalkylation of diverse reagents:
Fluoroiodomethane (FIM) represents an easy to handle reagent for the introduction of fluoromethyl groups. Trifluoromethyl or difluoromethyl groups can typically be transferred via so-called Togni reagents. These hypervalent iodine compounds act as electrophilic CF3 sources, having been continuously refined over the years.
Besides electrophilic CH2F, CHF2 and CF3 sources, nucleophilic, radical or carbenoid sources are also used. Many of these reagents are based on sulfonium or sulfonyl compounds, thus for instance the Umemoto reagents.
Other examples of trifluoromethylation reagents are represented by trifluoromethyltrimethylsilane (TMSCF3), trifluoromethane (CHF3), trifluoromethyliodide (CF3I) and sodium trifluoromethanesulfinate (CF3SO2Na). On account of its instability, trifluoromethyllithium (CF3Li) is not available to synthesis chemists. Complexed trifluorumethyl copper reagents provide alternatives here.
You can also find a series of trifluorumethoxy- or trifluoromethylthio-substituted building blocks in the abcr catalogue.
Although trifluoromethyl-substituted building blocks are long known, the corresponding pentafluoroethyl compounds have only become accessible recently. For the introduction of pentafluoroethyl groups, abcr recommends the new reagent tetraphenylphosphonium pentakis(pentafluoroethyl)stannate. This is available as a solid with long-term stability and does not require any gaseous educts.