N-vinyl azoles are prevalent moieties in pharmaceuticals, and fluorovinyl groups are widely recognized as carbonyl bi-oisosteres in drug design. Thus, N-fluorovinylated heteroarenes represent highly desirable functional groups in medicinal chemistry. To streamline the development of novel N-fluorovinylation and N-pentafluoropropenylation reactions, herein we safely handle fluorinated gases, such as vinylidene fluoride (VDF) and hexafluoropropene (HFP), as solid reagents using a metal–organic framework (MOF), Mg2(dobdc) (dobdc4− = 2,5-dioxidobenzene-1,4-dicarboxylate). Free (NH)-heteroarenes react directly with VDF via a defluorinative pathway under mild conditions, yielding terminal N-fluorovinylated products. Various complex, biologically active molecules smoothly undergo N-fluorovinylation under these conditions in much higher yields than with the gas alone. Mechanistic investigations, including deuterium incorpo-ration experiments and density functional theory calculations, suggest that this transformation represents a rare example of a concerted nucleophilic vinylic substitution (SNV) process. This protocol can be performed on gram scale, and the resulting N-fluorovinyl moieties can be further diversified to yield valuable motifs, such as N-fluorocyclopropyl groups. Finally, this defluorinative coupling can be generalized to other fluorinated alkene gases, such as HFP. Overall, this robust defluorinative coupling offers a straightforward strategy for synthesizing diverse fluorinated heteroarenes from readily available starting materials, providing broad access to these valuable motifs for the first time.
Fluorine is an increasingly common substituent in pharmaceuticals and agrochemicals because it improves the bioavailability and metabolic stability of organic molecules. Fluorinated gases represent intuitive building blocks for the late-stage installation of fluorinated groups, but they are generally overlooked because they require the use of specialized equipment. We report a general strategy for handling fluorinated gases as benchtop-stable solid reagents using metal-organic frameworks (MOFs). Gas-MOF reagents are prepared on gram-scale and used to facilitate fluorovinylation and fluoroalkylation reactions. Encapsulation of gas-MOF reagents within wax enables stable storage on the benchtop and controlled release into solution upon sonication, which represents a safer alternative to handling the gas directly. Furthermore, our approach enables high-throughput reaction development with these gases.
Fluorine is ubiquitous in the pharmaceutical and agrochemical industries because it improves the bioavailability and metabolic stability of molecules. However, most modern fluoroalkylation and fluorovinylation protocols rely on reagents that are expensive, explosive, or otherwise challenging to use. Fluorinated gaseous reagents are promising alternatives that are overlooked for late-stage functionalization because they require specialized equipment. Herein, we report a general strategy for safely handling inexpensive fluorinated gaseous building blocks as benchtop-stable solid reagents using porous metal–organic frameworks (MOFs). Gas–MOF reagents are employed to facilitate novel fluorovinylation and fluoroalkylation reactions, which represent safe, efficient, and atom-economical alternatives to current methods. Our approach enables high-throughput reaction development with any gaseous reagent, opening the door for the development of myriad new synthetic transformations.
Abstract Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal‐organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H 2 S for therapeutic applications, 129 Xe for magnetic resonance imaging, O 2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next‐generation porous materials for the storage and delivery of medicinally relevant gases.
Metal-organic frameworks (MOFs) are porous, crystalline solids constructed from organic linkers and inorganic nodes that have been widely studied for applications in gas storage, chemical separations, and drug delivery. Owing to their highly modular structures and tunable pore environments, we propose that MOFs have significant untapped potential as catalysts and reagents relevant to the synthesis of next-generation therapeutics. Herein, we outline the properties of MOFs that make them promising for applications in synthetic and organic chemistry, including new reactivity and selectivity, enhanced robustness, and user-friendly preparation. In addition, we outline the challenges facing the field and propose new directions to maximize the utility of MOFs for drug synthesis. This perspective aims to bring together the organic and MOF communities to develop new heterogeneous platforms capable of achieving synthetic transformations that can-not be replicated by homogeneous systems.
Metal–organic frameworks (MOFs) are porous crystalline solids constructed from organic linkers and inorganic nodes that have been widely studied for applications in gas storage, chemical separations, and drug delivery. Owing to their highly modular structures and tunable pore environments, we propose that MOFs have significant untapped potential as catalysts and reagents relevant to the synthesis of next-generation therapeutics. Herein, we outline the properties of MOFs that make them promising for applications in synthetic organic chemistry, including new reactivity and selectivity, enhanced robustness, and user-friendly preparation. In addition, we outline the challenges facing the field and propose new directions to maximize the utility of MOFs in drug synthesis. This Perspective aims to bring together the organic and MOF communities to develop new heterogeneous platforms capable of achieving synthetic transformations that cannot be replicated by homogeneous systems.
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