Zinc 1,1,2,2-Tetrafluoroethanesulfinate: A Synthetically Useful Oxidative and Photoredox Source of the 1,1,2,2-Tetrafluoroethyl Radical.

1,1,2,2-Tetrafluoroethyl-containing molecules are of potential importance in drug discovery, but the efficient synthesis of such compounds is still relatively unexplored due to the lack of readily available reagents for the incorporation of the HCF2CF2 group. Herein, we introduce a new reagent, zinc 1,1,2,2-tetrafluoroethanesulfinate, which can be useful for the oxidative tetrafluoroethylation of arylboronic acids and heteroarenes as well as for a novel photoredox, three component hydro-tetrafluoroethylation of two alkenes of complementary reactivity.

Visible-Light-Induced Three-Component Tetrafluoroethyl-heteroarylation of Alkenes with 1,1,2,2-Tetrafluoroethanesulfonyl Chloride and Quinoxalin-2(1H)-ones.

1,1,2,2-Tetrafluoroethyl-containing compounds are valuable structures due to their unique physicochemical properties, which have increasing potential application in drug discovery. However, synthetic methods for preparing such compounds are rare. Herein, we report the first use of 1,1,2,2-tetrafluoroethanesulfonyl chloride to introduce the HCF2 CF2 group into organic molecules via a three-component, radical tetrafluoroethyl-heteroarylation of alkenes with readily available quinoxalin-2(1H)-ones. This method provides a new and facile approach for late-stage functionalization of potential biologically active molecules.

Difluoromethylarylation of α,ß-unsaturated amides via a photocatalytic radical smiles rearrangement.

A photocatalytic Smiles rearrangement, triggered by radical difluoromethylation of conjugated arylsulfonylated amides, was developed to construct both ß-difluoromethyl amide and heterocyclic scaffolds selectively. This transformation features mild conditions and broad substrate scope. More importantly, the chemoselectivity of the intermediate amidyl radical could be altered completely by simply changing the light source, along with addition of water to the reaction mixture.

Photocatalytic difluoromethylarylation of unactivated alkenes via a (hetero)aryl neophyl-like radical migration.

Photoredox-catalyzed addition of the difluoromethylradical to unactivated alkenes has been found to trigger neophyl-like aryl and heteroaryl migrations which allowed the construction of a diverse series of difluoromethyl ketones. The reaction featured mild reaction conditions and broad substrate scope.

Synthesis of 6-SF5-indazoles and an SF5-analog of gamendazole.

This work describes an efficient synthetic approach for a new type of SF5-substituted heterocyclic system, namely 6-SF5-indazoles. During this study, various derivatives of 6-SF5-indazoles such as bromo, iodo, nitro, N-acetyl and N-benzyl substituted compounds were synthesized and characterized. In addition, the utility of the synthetic methodology was demonstrated via the synthesis of 6-SF5-gamendazole - a fully matched analog of the experimental male contraceptive gamendazole, which has a 6-CF3-substituted indazole core.

Ni/Ir-Catalyzed Photoredox Decarboxylative Coupling of S-Substituted Thiolactic Acids with Heteroaryl Bromides: Short Synthesis of Sulfoxaflor and Its SF5 Analog.

Metallaphotoredox cross-coupling reactions have recently emerged as a powerful tool for the construction of C(sp2 )-C(sp3 ) bonds between alkyl chains and aromatic systems, including electron-deficient heteroaryls, which are known to be challenging coupling partners. In this article, we disclose the Ni/Ir-catalyzed photoredox decarboxylative coupling of readily available S-substituted thiolactic acids with electron-deficient heteroaryl bromides, which resulted in the formation of simple but otherwise not easily accessible heteroarenes with alkylsulfide side chains. To demonstrate a practical use of this coupling reaction, we have shown its efficiency in the one-step synthesis of a key intermediate in the synthesis of the recently marketed insecticide Sulfoxaflor, and for the short synthesis of SF5 -Sulfoxaflor.

Photoredox Catalyzed Intramolecular Fluoroalkylarylation of Unactivated Alkenes.

The first example of photoredox catalyzed difluoromethylation of unactivated alkenes coupled with C-C bond formation to an aryl ring is reported. The reactions are conducted under mild conditions and afford tetralin derivatives bearing difluoromethyl as well as other fluoroalkyl groups in good to high yields. In addition, the study indicates that 6-exo radical cyclization of an alkyl radical to a phenyl ring is faster than the respective 5-exo radical cyclization. A computational study provides insights to the experimental results.

Generation of ortho-SF5-Benzyne and Its Diels-Alder Reactions with Furans: Synthesis of 1-SF5-Naphthalene, Its Derivatives, and 1,6(1,7)-Bis-SF5-naphthalenes.

Generation of ortho-SF5-benzyne was achieved by a lithiation/elimination sequence starting from 2-fluoro-SF5-benzene. The highly reactive ortho-SF5-benzyne intermediate was trapped by furan or 2-methylfuran in situ, and the obtained stable Diels-Alder adducts were subjected to the series of further chemical transformation, which led to the formation of previously unknown 1-SF5-naphthalene and its derivatives with bromo, amino, hydroxy, and methyl substituents, including bis-SF5-substituted naphthalenes. NMR spectroscopy experiments revealed characteristic through-space coupling between the SF5-group's equatorial fluorines and proton/carbon nuclei of -H, -CH3, and -OH substituents in the peri-position to the SF5-group of 1-SF5-naphthalenes.

Through-space (19) F-(15) N couplings for the assignment of stereochemistry in flubenzimine.

Through-space (19) F-(15) N couplings revealed the configuration of flubenzimine, with the CF3 group on N4 pointing towards the lone pair of N5. The (19) F-(15) N coupling constants were measured at natural abundance using a spin-state selective indirect-detection pulse sequence. As (15) N-labelled proteins are routinely synthesized for NMR studies, through-space (19) F-(15) N couplings have the potential to probe the stereochemistry of these proteins by (19) F labelling of some amino acids or can reveal the site of docking of fluorine-containing drugs. Copyright © 2016 John Wiley & Sons, Ltd.

Direct Photoredox-Catalyzed Reductive Difluoromethylation of Electron-Deficient Alkenes.

Photoredox-catalyzed reductive difluoromethylation of electron-deficient alkenes was achieved in one step under tin-free, mild and neutral conditions. This protocol affords a facile method to introduce RCF2 (R=H, Ph, Me, and CH2N3) groups at sites ß to electron-withdrawing groups. It was found that TTMS (tris(trimethylsilyl)silane) served nicely as both the H-atom donor and the electron donor in the catalytic cycle. Experimental and DFT computational results provided evidence that RCF2 (R=H, Ph, Me) radicals are nucleophilic in nature.

Chloro, difluoromethylation and chloro, carbomethoxydifluoromethylation: reaction of radicals derived from RfSO2Cl with unactivated alkenes under metal-free conditions.

Difluoromethyl and carbomethoxydifluoromethyl radicals were generated from their respective sulfonyl chlorides under mild, metal-free conditions leading to efficient atom transfer radical additions (ATRA) to unactivated alkenes to form chloro, difluoromethylated and chloro, carbomethoxydifluoromethylated products.

The Unexpected Formation of 9,9,10,10-Tetrafluoro-1,2,4,12-tetraphenyl[2.2]paracyclophan-1-ene.

An investigation of the palladium-catalyzed Kumada cross-coupling reaction between PhMgBr and (pseudo-ortho) 4,12-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane revealed that in addition to the expected cross-coupled product, an unintended major product was generated. The product was determined to be 9,9,10,10-tetrafluoro-1,2,4,12-tetraphenyl[2.2]paracyclophan-1-ene by X-ray crystallography and is proposed to be formed via the first reported example of reductive defluorination by a Grignard reagent.

Synthesis and characterization of 2-pyridylsulfur pentafluorides.

Current approaches to prepare SF5 -substituted heterocycles during the synthesis of targeted heterocyclic compounds require the use of SF5 -functionalized aryl or alkyne reagents or SF5 Cl as a source of the SF5  functional group. Herein we report that excess oxidative fluorination of 2,2'-dipyridyl disulfide with a KF/Cl2 /MeCN system leads to the formation of thirteen new 2-pyridylsulfur chlorotetrafluorides (2-SF4 Cl-pyridines). These molecules are found to undergo further chlorine-fluorine exchange reactions by treatment with silver(I) fluoride enabling ready access to a series of ten new substituted 2-pyridylsulfur pentafluorides (2-SF5 -pyridines). This is the first preparatively simple and readily scalable example of the transformation of an existing heterocyclic sulfur functionality to prepare SF5 -substituted heterocycles.

Efficient Cu-catalyzed atom transfer radical addition reactions of fluoroalkylsulfonyl chlorides with electron-deficient alkenes induced by visible light.

Fluoroalkylsulfonyl chlorides, R(f)SO2Cl, in which R(f)=CF3, C4F9, CF2H, CH2F, and CH2CF3, are used as a source of fluorinated radicals to add fluoroalkyl groups to electron-deficient, unsaturated carbonyl compounds. Photochemical conditions, using Cu mediation, are used to produce the respective α-chloro-ß-fluoroalkylcarbonyl products in excellent yields through an atom transfer radical addition (ATRA) process. Facile nucleophilic replacement of the α-chloro substituent is shown to lead to further diverse functionalization of the products.

Use of fluoroform as a source of difluorocarbene in the synthesis of difluoromethoxy- and difluorothiomethoxyarenes.

Fluoroform, CHF3, a non-ozone-depleting, nontoxic, and inexpensive gas can be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives. The reactions are carried out at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/dioxane or water/acetonitrile) process to provide moderate to good yields of the respective products.

Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, a difluorocarbene reagent with reactivity comparable to that of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA).

Under specific high concentration, high temperature conditions, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA) has been found to act as a very efficient source of difluorocarbene, exhibiting carbene reactivity characteristics comparable to those exhibited by trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA). For example, in reaction with highly unreactive n-butyl acrylate and using only 2 equiv of MDFA, a yield of 76% of difluorocyclopropane product was obtained after 2 days.

Atropisomerism of a monosubstituted perfluoro[2.2]paracyclophane. A combined synthetic, kinetic, spectroscopic and computational study.

The product of S(N)Ar addition of the enolate of ethyl acetoacetate to perfluoro[2.2]para-cyclophane exists entirely as its enol tautomer 5. This enol exhibits two NMR signals for its enolic proton, and these signals were shown to derive from the presence of two, equal energy conformations that were observable as distinct, stable conformations at room temperature, but which when heated, interconverted with an energy barrier of 23.5 kcal mol(-1). These atropisomers were characterized by NMR, with details of this analysis being provided. Computational work corroborated the NMR conclusions, and provided additional insight into all structural, thermodynamic and kinetic results. Enol product 5 was cyclized, under basic conditions, to form a benzofuran product 6. Its structure was confirmed by NMR, with further structural and mechanistic insights being provided by calculations.

Friedel-Crafts reactions of 2,2-difluorocyclopropanecarbonyl chloride: unexpected ring-opening chemistry.

The Friedel-Crafts reactions of 2,2-difluorocyclopropanecarbonyl chloride with various arenes did not lead to the straightforward formation of the expected aryl 2,2-difluorocyclopropyl ketones. Instead the reactions proceeded, to various degrees depending on the reactivity of the arene, via an apparent rearrangement of the initially formed acylium ion to form novel aryl 3-chloro-3,3-difluoropropyl ketones. The ring-opened product was formed exclusively, and therefore the reaction may be synthetically useful when relatively unreactive arene substrates such as benzene, toluene, and p-xylene are used. No conditions were found where ring-intact products could be formed exclusively when using substituted benzenes as substrates, with the very reactive substrate thiophene being most selective in that regard, favoring ring intact product 3 with a selectivity of 98:2. The regioselectivity of ring-opening was examined and compared with other related systems computationally.

19F chemical shifts, coupling constants and conformational preferences in monosubstituted perfluoroparacyclophanes.

In the process of studying the chemistry of perfluoro[2.2]paracyclophanes (PFPCs), a novel class of compounds, it became necessary to identify some disubstituted products. To achieve this goal, we characterize in this work some monosubstituted PFPCs, identifying their (19)F-(19) F coupling patterns, and establishing a methodology for the assignment of their (19)F chemical shifts. The pattern of coupling constants indicates a skewed geometry in which the upper deck moves towards or away from the substituent, depending on the substituent electron-donor character and size. Quantum chemical calculations, performed at the HF/6-311 + G(d,p)//B3LYP/EPR-III level of theory, confirmed the conformations inferred from coupling constants and reproduced well the values of the couplings. Transmission mechanisms for the FC term of four- and five-bond (19)F-(19) F couplings are discussed in detail. Understanding the conformational preferences of PFPCs and how they are reflected by the coupling constants facilitates the assignment of (19)F chemical shifts in monosubstituted PFPCs and the identification of the disubstituted products.

Preparation of pentafluorosulfanyl (SF5) pyrrole carboxylic acid esters.

Pyrrole derivatives bearing a pentafluorosulfanyl group are currently unknown. In this paper, a facile preparation of SF5-substituted pyrrole carboxylic acid esters in good yield is reported. Utilizing the cycloaddition of an azomethine ylide to pentafluorosulfanylalkynes, a series of dihydropyrroles were prepared and oxidized to the respective 1-tert-butyl-4-(pentafluorosulfanyl)pyrrole-2-carboxylic acid esters in good yield. Further treatment of these pyrroles with catalytic triflic acid allowed removal of the tert-butyl group.