Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD®/Olah's reagent under solvent-free conditions.

A new protocol enabling the formation of trifluoromethyl compounds from acyl fluorides has been developed. The combination of FLUOLEAD® and Olah's reagent in solvent-free conditions at 70 °C initiated the significant deoxyfluorination of the acyl fluorides and resulted in the corresponding trifluoromethyl products with high yields (up to 99%). This strategy showed a great tolerance for various acyl fluorides containing aryloyl, (heteroaryl)oyl, or aliphatic acyl moieties, providing good to excellent yields of the trifluoromethyl products. Synthetic drug-like molecules were also transformed into the corresponding trifluoromethyl compounds under the same reaction conditions. A reaction mechanism is proposed.

An eccentric rod-like linear connection of two heterocycles: synthesis of pyridine trans-tetrafluoro-λ6-sulfanyl triazoles.

The trans-tetrafluoro-λ6-sulfane (SF4) group has been utilized as a unique three-dimensional building block for the linear connection of two independent N-heterocycles, pyridines and triazoles. The linearly connected heterocyclic compounds were synthesized by thermal Huisgen 1,3-dipolar cycloaddition between previously unknown pyridine SF4-alkynes and readily available azides, providing a series of rod-like SF4-connected N-heterocycles in good to excellent yields. X-ray crystallographic analysis of the target products revealed the trans-geometry of the SF4 group, which linearly connects two independent N-heterocycles. This research will open the field of chemistry of SF4-connected heterocyclic compounds.

Synthesis of fluoro-functionalized diaryl-λ3-iodonium salts and their cytotoxicity against human lymphoma U937 cells.

Conscious of the potential bioactivity of fluorine, an investigation was conducted using various fluorine-containing diaryliodonium salts in order to study and compare their biological activity against human lymphoma U937 cells. Most of the compounds tested are well-known reagents for fluoro-functionalized arylation reactions in synthetic organic chemistry, but their biological properties are not fully understood. Herein, after initially investigating 18 fluoro-functionalized reagents, we discovered that the ortho-fluoro-functionalized diaryliodonium salt reagents showed remarkable cytotoxicity in vitro. These results led us to synthesize more compounds, previously unknown sterically demanding diaryliodonium salts having a pentafluorosulfanyl (SF5) functional group at the ortho-position, that is, unsymmetrical ortho-SF5 phenylaryl-λ3-iodonium salts. Newly synthesized mesityl(2-(pentafluoro-λ6-sulfanyl)phenyl)iodonium exhibited the greatest potency in vitro against U937 cells. Evaluation of the cytotoxicity of selected phenylaryl-λ3-iodonium salts against AGLCL (a normal human B cell line) was also examined.

Silver-induced self-immolative Cl-F exchange fluorination of arylsulfur chlorotetrafluorides: synthesis of arylsulfur pentafluorides.

A novel strategy for the synthesis of arylsulfur pentafluorides by silver carbonate-induced Cl-F exchange fluorination of arylsulfur chlorotetrafluorides is reported. This fluorination does not require any exogenous fluoride sources. Rather, the reaction proceeds via the self-immolation of the substrate Ar-SF4Cl.

SF5-Pyridylaryl-λ3-iodonium salts and their utility as electrophilic reagents to access SF5-pyridine derivatives in the late-stage of synthesis.

Electrophilic pentafluorosulfanyl (SF5) heteroarylation of target molecules using novel reagents is described. Unsymmetrical diaryliodonium reagents 1 having 2-SF5-pyridine have been synthesized in good yields. They are efficient electrophilic reagents for carbon and heterocentered nucleophiles, producing the corresponding SF5-pyridine derivatives in good to excellent yields.

Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ(6) -sulfanyl-Substituted Pyridines.

Although there are ways to synthesize ortho-pentafluoro-λ(6) -sulfanyl (SF5 ) pyridines, meta- and para-SF5 -substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5 -substituted pyridines and SF5 -substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4 Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5 -pyridines. After enabling the synthesis of an SF5 -substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SN Ar pathway. This methodology provides access to a variety of previously unavailable SF5 -substituted pyridine building blocks.

Synthesis of Diaryliodonium Salts Having Pentafluorosulfanylarenes and Their Application to Electrophilic Pentafluorosulfanylarylation of C-, O-, N-, and S-Nucleophiles.

Novel reagents for the electrophilic introduction of pentafluorosulfanyl (SF5) arenes into target molecules are disclosed. Unsymmetrical diaryliodonium salts 1 having SF5-arenes were synthesized by a one-pot process from iodo-SF5-benzenes 2 in good yields. The SF5-aryliodonium salts 1 were found to be efficient for the electrophilic SF5-arylation of carbon and heterocentered nucleophiles to furnish the corresponding substituted SF5-arenes in good to high yields.

Synthesis of Phthalocyanines with a Pentafluorosulfanyl Substituent at Peripheral Positions.

The pentafluorosulfanyl (SF5) group is more electronegative, lipophilic and sterically bulky relative to the well-explored trifluoromethyl (CF3) group. As such, the SF5 group could offer access to pharmaceuticals, agrochemicals and optoelectronic materials with novel properties. Here, the first synthesis of phthalocyanines (Pcs), a class of compounds used as dyes and with potential as photodynamic therapeutics, with a SF5 group directly attached on their peripheral positions is disclosed. The key for this work is the preparation of a series of SF5-containing phthalonitriles, which was beautifully regio-controlled by a stepwise cyanation via ortho-lithiation/iodination from commercially available pentafluorosulfanyl arenes. The macrocyclization of the SF5-containing phthalonitriles to SF5-substituted Pcs required harsh conditions with the exception of the synthesis of ß-SF5-substituted Pc. The regiospecificity of the newly developed SF5-substituted Pcs observed by UV/Vis spectra and fluorescence quantum yields depend on the peripheral positon of the SF5 group.

Bis(pentafluorosulfanyl)phenyl azide as an expeditious tool for click chemistry toward antitumor pharmaceuticals.

The inclusion of fluorine in pharmaceutical agents is a well- established means of improving their druglike properties. Different substituents have been used to introduce fluorine, including trifluoromethyl and trifluoromethylthio groups; however, the pentafluorosulfanyl remains relatively underutilized although it is considered to be a "super" trifluoromethyl group. Here, a series of pentafluorosulfanyl-containing 1,4-disubstituted-1,2,3-triazoles were synthesized by click reaction from alkynes and 3,5-bis(pentafluorosulfanyl)phenyl azide in excellent yields. Their biological activities were evaluated against human leukemic monocyte lymphoma U937 cells. In particular, 1-(3,5-bis(pentafluorosulfanyl)phenyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole exhibited potent efficacy in cell viability assays at a concentration of 60 µM and was shown to activate caspase-3 activity, indicating induction of apoptosis. An analogous fluorenol-substituted triazole also exhibited promising cytotoxic effects against U937 cells, with an IC50 value of 6.29 µM. Given these preliminary results, these pentafluorosulfanyl-containing triazoles represent useful building blocks for the further development of novel antitumor agents.

Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of "super-trifluoromethyl" arene chemistry and its industry.

Various arylsulfur pentafluorides, ArSF(5), have long been desired in both academic and industrial areas, and ArSF(5) compounds have attracted considerable interest in many areas such as medicines, agrochemicals, and other new materials, since the highly stable SF(5) group is considered a "super-trifluoromethyl group" due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for the production of various arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (Step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of an alkali metal fluoride, and (step 2) treatment of the resulting arylsulfur chlorotetrafluoride with a fluoride source, such as ZnF(2), HF, and Sb(III/V) fluorides. The intermediate arylsulfur chlorotetrafluorides were isolated by distillation or recrystallization and characterized. The aspects of these new reactions are revealed and reaction mechanisms are discussed. As the method offers considerable improvement over previous methods in cost, yield, practicality, applicability, and large-scale production, the new processes described here can be employed as the first practical methods for the economical production of various arylsulfur pentafluorides and their higher homologues, which could then open up a new era of "super-trifluoromethyl" arene chemistry and its applications in many areas.

Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity.

Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compounds have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into molecules. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, 1k), as a crystalline solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogues. The roles of substituents on 1k in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 1k smoothly converts non-enolizable carbonyls to CF(2) groups, and carboxylic groups to CF(3) groups, in high yields. 1k also converts C(=S) and CH(3)SC(=S)O groups to CF(2) and CF(3)O groups, respectively, in high yields. In addition, 1k effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcohols to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of 1k in addition to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.