Fluorohalomethylsulfonium Salts as a Fluorohalocarbene Source.

Synthesis of fluoroorganic compounds is of great importance due to their extensive application in medicinal chemistry, agrochemicals, and materials. Herein, we report efficient synthesis of novel diaryl fluorohalomethyl sulfonium salts. The application showcased proficient reagents for Freon-free fluorochloro-, fluorobromo-, and fluoroiodocarbene transfer to alkenes.

Recent Advances in Monofluorinated Carbenes, Carbenoids, Ylides, and Related Species.

The synthesis of monofluorinated compounds is of great interest because of the vast applications of organofluorine compounds. Recently, the introduction of monofluorocarbene synthons has emerged as an important strategy for the synthesis of fluorine-containing products. In contrast to direct fluorination, in which C-F bonds are formed, the use of monofluorinated carbenes and related reactive species involves C-C or C-X bond formation while delivering valuable fluorine atoms into the target structure.

Synthetic Access to Fluorocyclopropylidenes.

Herein we report an approach for the straightforward preparation of fluorocyclopropylidene group from aldehydes and ketones via Julia-Kocienski olefination using the newly developed reagent 5-((2-fluorocyclopropyl)sulfonyl)-1-phenyl-1-tetrazole. Derivatization of monofluorocyclopropylidene compounds includes hydrogenation to deliver fluorocyclopropylmethyl compounds and fluorinated cyclobutanones. The utility of the described method is demonstrated by the synthesis of a fluorocyclopropyl-containing analogue of ibuprofen.

Merging Copper(I) Photoredox Catalysis and Iodine(III) Chemistry for the Oxy-monofluoromethylation of Alkenes.

A simple process for the oxy-monofluoromethylation of alkenes is described. In combination with visible-light copper(I) photoredox catalysis, an easily accessible iodine(III) reagent containing monofluoroacetoxy ligands serves as a powerful source of a monofluoromethyl (CH F) radical, enabling the step economical synthesis of γ-fluoro-acetates from a broad range of olefinic substrates under mild conditions. Applications to late-stage diversification of alkenes derived from complex molecules, amino acids and the synthesis of fluoromethylated heterocycles are also demonstrated.

Iron-Catalyzed Fluoromethylene Transfer from a Sulfonium Reagent.

Herein, we report the first example of an iron porphyrin catalyzed fluoromethylene transfer from (2,4-dimethylphenyl)(fluoromethyl)(phenyl)sulfonium tetrafluoroborate to unactivated alkenes. The fluorocarbene or fluoromethylene synthon is the smallest "organic" in a molecular graph of the organofluorine compounds. In this work, we present alternative solution to unavailable fluorodiazomethane (CHFN), a missing one-carbon C1 piece in fluorine chemistry, by using a fluoromethylsulfonium reagent.

Monofluorinated 5-membered rings via fluoromethylene transfer: synthesis of monofluorinated isoxazoline N-oxides.

The synthesis of five-membered rings using fluoromethylene transfer chemistry is an attractive method for building fluorinated products of high value. This work demonstrates for the first time that one-fluorine-one-carbon modification of a substrate could be a viable strategy to access monofluorinated five-membered rings. The synthetic methodology was developed to access monofluorinated isoxazoline-N-oxides in one step starting from substituted 2-nitroacrylates using fluoromethylsulfonium reagents.

Residual Solvent Signal of CDCl as a qNMR Internal Standard for Application in Organic Chemistry Laboratory.

A nuclear magnetic resonance (NMR) spectrometer is a key instrument in the organic synthesis laboratory for structure determination, reaction control, and compound purity analysis. In addition to qualitative analysis, the application of NMR for quantitative analysis (qNMR) is gaining popularity. qNMR allows for simple quantification of crude product mixtures, determination of reaction yields, and purity of organic compounds.

Optimized Monofluoromethylsulfonium Reagents for Fluoromethylene-Transfer Chemistry.

An investigation of the properties and reactivity of fluoromethylsulfonium salts resulted in the redesign of the reagents for fluoromethylene transfer chemistry. The model reaction, fluorocyclopropanation of nitrostyrene, turned out to be a suitable platform for the discovery of more streamlined fluoromethylene transfer reagents. The incorporation of halides on one aryl ring increased the reactivity, and 2,4-dimethyl substitution on the other aryl ring provided a balance between the reactivity/crystallinity of the reagent as well as the atom economy.

-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs.

Investigation of the -fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved profile compared to the parent nonfluorinated structure.

Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes: scope and limitations.

Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain a range of monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts have displayed the broadest scope for direct fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives, diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene group to alkenes giving access to the challenging products - fluorocyclopropane derivatives.

Diastereoselective Monofluorocyclopropanation Using Fluoromethylsulfonium Salts.

Diarylfluoromethylsulfonium salts, alternatives to freons or advanced fluorinated building blocks, are bench stable and easy-to-use sources of direct fluoromethylene (:CHF) transfer to alkenes. These salts enabled development of a -selective monofluorinated Johnson-Corey-Chaykovsky reaction with vinyl sulfones or vinyl sulfonamides to access synthetically challenging monofluorocyclopropane scaffolds. The described method offers rapid access to monofluorinated cyclopropane building blocks with further functionalization opportunities to deliver more complex synthetic targets diastereoselectively.

Fluoromethylene Transfer from Diarylfluoromethylsulfonium Salts: Synthesis of Fluorinated Epoxides.

Diarylfluoromethyl sulfonium salts are efficient fluoromethylene transfer reagents equivalent to fluorocarbene, which is difficult to access. This was demonstrated by the development of a monofluorinated Johnson-Corey-Chaykovsky reaction with ketones and aldehydes, delivering uncommon 2-unsubstituted fluoroepoxides. This is the first evidence for the feasibility of sulfur fluoromethylylide and its action as a reaction intermediate.

Copper-Catalyzed Insertion into Heteroatom-Hydrogen Bonds with Trifluorodiazoalkanes.

Copper-catalyzed Si-H, B-H, P-H, S-H, and N-H insertion reactions of 2,2,2-trifluoro-1-diazoethane and 1-aryl 2,2,2-trifluorodiazoethanes generated a large number of new fluorine-containing chemical entities for medicinal chemists. With selected Si-H and B-H insertion reactions, we demonstrate successful extension to asymmetric catalysis.

Three steps in one pot: synthesis of linear bilateral extended 2,2':6',2″-terpyridineruthenium(II) complexes.

Metal complexes of linear bilateral extended 2,2':6',2″-terpyridine [2,6-bis(2-substituted furo[2,3-c]pyridin-5-yl)pyridine] are topological tridentate analogues of 5,5'-functionalized 2,2'-bipyridine. The present methodology provides access to linear bilateral extended 2,2':6',2″-terpyridineruthenium(II) complexes starting from 5,5″-bis(methoxymethoxy)-4,4″-bis(substituted ethynyl)-2,2':6',2″-terpyridines via one-pot cleavage of the methoxymethyl (MOM) protecting group, cycloisomerization, and metal complexation in the presence of Ru(DMSO)4Cl2. In this reaction, ruthenium(II) likely plays a triple role, acting as a Lewis acid to cleave the MOM ether, a catalyst facilitating 5-endo-dig cyclization, and a coordination metal center, being an integral part of the final product.