Fluorinated organic molecules account for >20% of active pharmaceutical ingredients due to their improved metabolic stabilities and membrane permeabilities compared to their non-fluorinated analogues. Despite this interest, common fluorination reagents are unselective, highly reactive, and hazardous. Simple fluorinated building blocks such as vinylidene fluoride (VDF), trifluoropropene (TFP), trifluoromethyl iodide (TFMI), and hexafluoropropene (HFP) represent inexpensive starting materials for the controlled introduction of fluorinated functional groups. However, these reagents remain underexplored because they are gases at room temperature and pressure. As such, a universal strategy for the safe handling of fluorinated gases in the laboratory would greatly facilitate the synthesis of fluorinated molecules relevant to the pharmaceutical industry.

Herein, fluorinated gases are adsorbed within porous solids, which allows for their facile handling as solid reagents. Among porous solids, metal-organic frameworks (MOFs)—crystalline materials constructed from organic linkers and inorganic nodes—are uniquely modular, allowing for the optimization of storage capacity and binding enthalpy for any gas of interest. Using this strategy, fluorinated gases VDF, TFP, HFP, and TFMI can be stored within MOFs with high storage capacities and strong binding enthalpies. The resulting gas–MOF reagents can be handled as solids on the benchtop and stored in air at low temperatures or in wax capsules at room temperature prior to gas release into solution. Employing these gas–MOF reagents, we established two Pd-catalyzed fluorovinylation reactions using VDF to streamline access to α-fluorostyrenes from (hetero)arylboronic acids and β,β-difluorostyrenes from (hetero)aryl halides under mild conditions. Likewise, TFP can be used to prepare β-trifluoromethylstyrenes from (hetero)aryl halides and TFMI can be engaged in the Fe-catalyzed oxidative trifluoromethylation of electron-rich (hetero)arenes. While here we focus on fluorinated gases, in theory, this approach can be generalized to enable the safe handling of any gas in the laboratory, facilitating the development of countless new transformations employing gaseous reagents.

Mary Zick

Appearances