Fluorinated organic molecules account for 20–30% of active pharmaceutical ingredients (APIs) due to their improved metabolic stabilities and membrane permeabilities compared to their non-fluorinated analogues. Despite this interest, the selective introduction of fluorine and fluoroalkyl groups into APIs remains a frontier in organic synthesis. Indeed, common fluorination reagents are expensive, highly reactive, and, in some cases, explosive. 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 standard temperature and pressure (STP), which makes them challenging to safely employ for high-throughput reaction discovery and late-stage functionalization without specialized equipment. 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. We demonstrate that the optimal MOF for reversibly storing fluorinated gases is one that possesses coordinatively unsaturated Mg(II) centers, due to the hard-hard match of F and Mg. The resulting gas–MOF reagents can be handled on the benchtop and stored in air at low temperatures prior to gas release into solution. The gas can be released from the gas-MOF reagent simply by submerging the reagent in a coordinating solvent. 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-fluorostyrenes 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. In theory, this approach can be generalized to enable the safe handling of any gas in the laboratory, enabling the development of countless new transformations employing gaseous reagents.

Mary Zick

Appearances