WO2022008283A1

WO2022008283A1 - Reagents for the polyfluoroalkylthiolation of organic compounds and method for production thereof

Info

Publication number: WO2022008283A1
Application number: PCT/EP2021/067690
Authority: WO
Inventors: Jordi MESTRE; Omar BOUTUREIRA; Sergio Castillon; Miguel BERNUS
Original assignee: Universitat Rovira I Virgili; Fundació Eurecat
Priority date: 2020-07-07
Filing date: 2021-06-28
Publication date: 2022-01-13
Also published as: EP4178950A1; CN116057048A

Abstract

The present invention to a group of compounds of formula (I) useful for the transfer of polyfluoroalkylthiol groups of at least two carbons atoms into a great variety of organic compounds as well as to the process for their preparation. The invention is also directed to the method for the polyfluoroalkylthiolation of an organic compound with the reagents of the invention.

Description

REAGENTS FOR THE POLYFLUOROALKYLTHIOLATION OF ORGANIC

COMPOUNDS AND METHOD FOR PRODUCTION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a family of reagents for polyfluoroalkylthiolation reactions. More specifically, it refers to a group of compounds useful for the transfer of polyfluoroalkylthiol groups of at least two carbons atoms into a great variety of organic compounds. The invention also relates to the process for their preparation as well as to their use as reagents for polyfluorolakythiolation reactions. The invention is also directed to the method for the polyfluoroalkylthiolation of an organic compound with the reagents of the invention.

BACKGROUND OF THE INVENTION

Introduction of fluoroalkyl motifs has been one of the pillars of synthetic, medicinal and crop chemistry due to the special attributes they confer to organic molecules. Increased lipophilicity, reinforced metabolic stability and improved ability to cross cell membranes and blood-brain barrier are some of the features benefited by these motifs [a) Ojima, I. In Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, 2009; b) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley; Hoboken, 2008; c) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH. Weinheim, 2004]. In this regard, fluoroalkyl-containing thioethers have been on the spotlight since not only show outstanding Hansch lipophilicity (e.g. CF₃, 0.88 VS SCF₃, 1.44) [Bootwicha, T.; Liu, X; Pluta, R.; Atodiresei, I.; Rueping, M. Angew. Chem. Int. Ed. 2013, 52, 12856- 12859], but also serve as pivotal groups to access to other appreciated derivatives as fluorinated sulfoxides, sulfones or sulfonamides.

Among all the possible combinations of fluorinated thioethers, the -SCF₃ motif has largely been the most explored. Conventional methods to construct -SCF₃ moieties include electrophilic or radical fluoroalkylation of thiols with CF₃I [Harsanyi, A.; Dorko, E; Csapo, A.; Bako, T.; Peltz, C.; Rabat. J. J. Fluorine Chem. 2011, 132, 1241- 1246.], Togni [a) Zak, M.; Rormero, F. A.; Cheng, Y.-X; Li, Wei. U.S. Patent 20180334465, 2018; b) Hediger, M. E. WO Patent WO2011097421 , 2011], Langlois [a) Ma, J.-J.; Yi, W.-B.; Lu, G.-P.; Cai, C. Catal. Sci. Technol. 2016, 6, 417-421; b) Ma, J.; Liu, Q.; Lu, G.; Yi, W. J. Fluorine Chem. 2017, 193, 113-117] and Umemoto reagents [a) Mei, B.; Zhang, P.; Li, Y. CN Patent, CN107540655, 2018; b) Kamiyama, H.; Itoh, S. WO Patent, WO2009014267, 2009; c) Verhoog, S.; Kee, C. W.; Wang, Y.; Khotavivattana, T.; Wilson, T. C.; Kersemans, V.; Smart, S.; Tredwell, M.; Davis, B. G.; Gouverneur, V. J. Am. Chem. Soc.2018, 140, 1572–1575.], or via trifluoromethylation of thiocyanates with nucleophilic TMSCF₃ [a) Kong, D.-L.; Du, J.-X.; Chu, W.-M.; Ma, C.-Y.; Tao, J.-Y.; Feng, W.-H. Molecules 2018, 23, 2727; b) Wu, C.- C.; Wang, B.-L.; Liu, J.-B.; Wei, W.; Li, Y.-X.; Liu, Y.; Chen, M.-G.; Xiong, L.-X.; Yang, N.; Li, Z.-M. Chinese Chem. Lett.2017, 28, 1248–1251.] and CuCF₃ reagents [Potash, S.; Rozen, S. J. Fluorine Chem. 2014, 168, 173–176.]. Alternatively, C-SCF₃ disconnection reveals a trifluoromethylthiolation process, typically addressed via direct late-stage modification using predefined SCF3 transfer agents, avoiding pre- functionalization steps and increasing the flexibility of the system [Barata-Vallejo, S.; Bonesi, S.; Postigo, A. Org. Biomol. Chem. 2016, 14, 7150–7182.]. This latter approach, also for the introduction of SCF2H motif [Zhu, D.; Gu, Y.; Lu, L.; Shen, Q. J. Am. Chem. Soc.2015, 137, 10547–10553.], has flourished the field with numerous protocols and reagents mostly based on imide, sulfonamide or sulfimide structures [a) Xu, C.; Ma, B.; Shen, Q. Angew. Chem. Int. Ed.2014, 53, 9316 –932; b) Alazet, S.; Ollivier, K.; Billard, T. Beilstein J. Org. Chem.2013, 9, 2354–2357; c) Xu, C.; Shen, Q. Org. Lett.2014, 16, 2046-2049; d) Billard, T.; Alazet, S. Synlett 2015, 26, 76–78; e) Abubakar, S. S.; Benaglia, M.; Rossi, S.; Annunziata, R. Catal. Today 2018, 308, 94–101; f) Liu, X.; An, R.; Zhang, X.; Luo, J.; Zhao, X. Angew. Chem. Int. Ed.2016, 55, 5846 –5850; g) Zhang, P.; Li, M.; Xue, X.-S.; Xu, C.; Zhao, Q.; Liu, Y.; Wang, H.; Guo, Y.; Lu, L; Shen, Q. J. Org. Chem.2016, 81, 7486–7509, h) Zhu, D.; Gu, Y.; Lu, L.; Shen, Q. J. Am. Chem. Soc.2015, 137, 33, 10547–10553; i) Xiao, Q.; He, Q.; Li, J.; Wang, J.Org. Lett.2015, 17, 6090–6093]. Meaningfully, the state of the art in trifluoromethylthiolation, sustained by a wide reaction development and the presence of commercially available reagents, increases the opportunities to disclose new active ingredients with SCF3 motifs. Despite the advances in the installation of SCF3 and SCF2H modifications, chemical development comprising polyfluorinated ethyl congeners is scarce. Only few examples have been reported by Billard, who described the preparation of SC₂F₅ aniline (first generation) and sulfenamide (second generation) derivatives able to transfer the fluorinated moiety into phenols, alkynes and Grignard reagents [a) Baert, F.; Colomb, J.; Billard, T. Angew. Chem. Int. Ed.2012, 51, 10382–10385; b) Billard, T.; Alazet, S. Synlett 2015, 26, 76–78; Tlili, A.; Alazet, S.; Glenadel, Q.; Billard, T. Chem. Eur. J. 2016, 22, 10230–10234.]. The dearth of reaction development in terms of variability of the fluoroalkyl chain and reaction scope is limiting the research in drug discovery and medicinal chemistry areas. Expanding the range of polyfluorinated thioethers would presumably enable a better tuning of pharmacokinetic properties of target compounds. Moreover, broadening the chemical toolbox with substituents containing terminal difluoromethylenes (e.g. SCF₂CF₂H or SCH₂CF₂H), may introduce new opportunities for enabling hydrogen-bonding interactions, which role has been demonstrated to be critical in the mode of action of CF₂H-derived ingredients [Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov E.; Saphier, S. J. Med. Chem. 2017, 60, 797−804; Chem. Commun.; 2019, 55, 12487–12490; J. Am. Chem. Soc.2017, 139, 27, 9325–9332.]. Therefore, there is a need in the state of the art of new reagents suitable for the electrophilic transference of a variety of polyfluoroalkylthiols and, specially, of polyfluoroalkylthiols with two or more carbon atoms in their structure. The authors of the present invention have developed new saccharine-derived reagents which have proven to be highly efficient in the transfer of polyfluoroalkyl thiols of up to ten carbon atoms, more preferably of up to 5 carbon atoms. In order to develop these reagents, the inventors have been capable of solving the stability problems of the intermediates during the preparation process of the reagents with polyfluoroalkylthiols moieties with two or more carbon atoms. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Reaction of the electrophilic reagent according to the invention (compound 3a) with N-H-indole in various solvents. Figure 2: a) state-of-the-art preparation of electrophilic trifluoromethylthiolation reagents; b) failed attempts to prepare longer polyfluoroalkylthiolation reagents; c) approach for the synthesis of reagents according to the invention. Rf represents polyfluoroalkyl chain from 2 to 10 carbon atoms. Figure 3: Preparation of polyfluoroalkyl thiol electrophilic reagents according to the invention. Figure 4: Polyfluoroalkylthiolation of different chemical species with a compound according to the invention (compound 3a). Figure 5: Reaction of various electrophilic reagents according to the invention with N-H indole. Yields are calculated by ¹⁹F NMR using 1,4-difluorobenzene as internal standard. OBJECT OF THE INVENTION The present invention discloses novel compounds that show a high efficiency in the transfer of polyfluoroalkyl thiols of two or more carbon atoms in a variety of organic molecules. Therefore, they are useful as reagents for polyfluoroalkylthiolation reactions, especially in life sciences and more generally in the field of organic chemistry. Thus, the main aspect of the present invention is related to compounds of general formula (I):

wherein: the dotted line represents an optional bond; Z is -CO- or -SO₂- ; G₁ represents a group –[CH₂]_n-R₁ ; G₂ represents a group –[CH₂]_m-R₂; or G₁ together with G₂ form a fused or non-fused aromatic or heteroaromatic ring optionally substituted by one or more R₃ substituents; n and m are 0 or 1; x is an integer between 2 and 10; y is an integer between 1 and 21 but always lower than (2x+1) R₁ and R₂ are independently from one another a hydrogen atom, a C_1-6 alkyl, a phenyl ring optionally substituted by one or more R₃ substituents; R3 is a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxy, halogen atom, a -OH, a -CN, a -NO2, a -CF3, -COR, -COOR, -CONRR’ wherein R and R’ represent a hydrogen or a C1-6 alkyl; or a salt, stereoisomer or solvate thereof. It is also an object of the invention different processes for the preparation of compounds of formula (I). Another object of the invention refers to the use of such compounds of general formula (I) as reactive for the polyfluoroalkylthiolation of organic compounds. Finally, it is an object of the invention a method for the polyfluoroalkylthiolation of an organic compound that comprises reacting a compound according to formula (I) with said organic compound. DESCRIPTION OF THE INVENTION A first and main aspect of the invention is a compound of general formula (I):

wherein: the dotted line represents an optional bond; Z is -CO- or -SO₂- ; G₁ represents a group –[CH₂]_n-R₁ ; G₂ represents a group –[CH₂]_m-R₂; or G₁ together with G₂ form a fused or non-fused aromatic or heteroaromatic ring optionally substituted by one or more R₃ substituents; n and m are 0 or 1; x is an integer between 2 and 10; y is an integer between 1 and 21 but always lower than (2x+1) R1 and R2 are independently from one another a hydrogen atom, a C1-6 alkyl, a phenyl ring optionally substituted by one or more R3 substituents; R₃ is a hydrogen atom, a C_1-6 alkyl, a C_1-6 alkoxy, halogen atom, a -OH, a -CN, a -NO₂, a -CF₃, -COR, -COOR, -CONRR’ wherein R and R’ represent a hydrogen or a C_1-6 alkyl; or a salt, stereoisomer or solvate thereof. For the sake of interpretation some definitions are herein provided: “Halogen” or “halo” as referred in the present invention represents fluorine, chlorine, bromine or iodine. When the term “halo” is combined with other substituents, such as for instance “C_1-6 haloalkyl” or “C_1-6 haloalkoxy” it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom. “C1-6 alkyl”, as referred to in the present invention, are saturated aliphatic radicals. They may be linear (unbranched) or branched and may be optionally substituted. C1-6-alkyl as expressed in the present invention means an alkyl radical of 1, 2, 3, 4, 5 or 6 carbon atoms. Preferred alkyl radicals according to the present invention include but are not restricted to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, n-pentyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl or 1-methylpentyl. The most preferred alkyl radical are C1-4 alkyl, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. Alkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a C1-6- alkoxy radical, a C1-6-alkyl radical, a C1-6-haloalcoxy radical, a C1-6-haloalkyl radical, CN, a trihaloalkyl radical and a hydroxyl group. “C1-6 alkoxy” as referred to in the present invention, is understood as meaning an alkyl radical/group as defined above attached via an oxygen linkage to the rest of the molecule. Examples of alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy or tert-butoxy. “Aromatic ring” as referred to in the present invention, is understood as meaning cyclic system formed by a single aromatic ring without heteroatoms. It can also be a fused system with at least one additional ring system that can be either aromatic or not. Aromatic rings may optionally be mono- or polysubstituted by substitutents independently selected from a halogen atom, a C_1-6-alkyl radical, a C_1-6-alkoxy radical, a C_1-6-haloalcoxy radical, a C_1-6-haloalkyl radical and a hydroxyl group. Preferred examples of non-fused and fused aromatic ring include but are not restricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl or anthracenyl radicals, which may optionally be mono- or polysubstituted, if not defined otherwise. More preferably aromatic rings in the context of the present invention are 6-membered ring systems, optionally at least monosubstituted. “Heteroaromatic ring” as referred to in the present invention, is understood as meaning heterocyclic system formed by a single aromatic ring that contains one or more heteroatoms from the group consisting of N, O and S. It can also be a fused system with at least one additional ring system that can be either aromatic or not and contain further heteroatoms selected from the group consisting of N, O and S or not. Heteroaromatic rings may optionally be mono- or polysubstituted by substituents independently selected from a halogen atom, a C1-6-alkyl radical, a C1-6-alkoxy radical, a C1-6-haloalkoxy radical, a C1-6-haloalkyl radical and a hydroxyl group. Preferred examples of non-fused and fused heteroaromatic ring include but are not restricted to furan, benzofuran, thiophene, thiazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, imidazole, imidazo[4,5-b]pyridine, isoxazole, oxadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole or quinazoline. More preferably heteroaromatic ring in the context of the present invention are 5- or 6-membered ring systems, optionally at least monosubstituted. “Salt” is to be understood as meaning any form of the compound of formula (I) according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or it is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes assembled by ionic interactions. “Solvate” is to be understood as meaning any form of the compound of formula (I) according to the invention in which this compound interacts via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate. “Leaving group” is an atom or a molecular entity that in a heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving groups are well known in the art and include Cl, Br, I and -O-SO₂R’, wherein R’ is F, C_1-4-alkyl, C_1-4-haloalkyl, or optionally substituted phenyl. The preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate. In a particular embodiment of the invention n and m are 0. In another particular embodiment, a proviso is applicable to compounds of formula (I) by means of which when n is 0 and/or m is 0 while at the same time that Z is -SO₂-, then R₁ and R₂ are not H. In another particular embodiment of the invention R₁ and R₂ are independently from one another a C_1-6 alkyl, preferably a methyl; or a phenyl ring. In a still more particular and preferred embodiment n and m are 0 and R1 and R2 are independently from one another a C1-6 alkyl, preferably a methyl or a phenyl ring. Yet another particular and preferred embodiment of the invention is represented by compounds of formula (I) where G1 together with G2 form a benzene ring optionally substituted by one or more R3 substituents. Although in the present invention x may represent in the compounds of formula (I) an integer starting from 2 and up to 10, in a particular a preferred embodiment x is 2, 3, 4 or 5. Under this preferred embodiment, y may be represented an integer going from 1 to a maximum of 10 when x is 5. In a particular embodiment of the invention the compounds of formula (I) have one of the following subformulas:

wherein Z, R₁, R₂, R₃, x and y are as defined before for formula (I). In a still more particular and especially preferred embodiment the compounds of the invention show one of the following subformulas:

wherein R₁, R₂, R₃, x and y are as defined before for formula (I). The compounds of the present invention are suitable for the transfer of polyfluoroalkylthiol groups of two or more carbon atoms. The groups transferred in the fluoroalkylthiolation reaction are those represented by the moiety -S[CxFyH(2x+1-y)] of the compounds of formula (I). In a particular and preferred embodiment, the -S[C_xF_yH_(2x+1-y)] moiety in the compounds of formula (I) is represented by one of the followings: -SCH₂CF₃ -SCH₂CF₂H -SCF₂CF₂H -SCF₂CF₃ -SCH₂(CF₂)₃CF₂H -S(CF₂)₃CF₃ -SCF(CF₃)₂ The preferred embodiments of the invention are represented by the following reagents of formula (I): ● 2-((1,1,2,2-Tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 6-Nitro-2-((1,1,2,2-tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzamide; ● N-(methylsulfonyl)-N-((perfluoroethyl)thio)methanesulfonamide; ● N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzenesulfonamide; ● 2-((Perfluoropropan-2-yl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((Perfluorobutyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((2,2,3,3,4,4,5,5-Octafluoropentyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((Perfluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; and ● 2-((2,2,2-Trifluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide. The compounds of the present invention have shown to be very stable in different solvents such as acetonitrile (ACN), Toluene, tetrahydrofuran (THF) and 1,2- dichloroethane (DCE). They have also shown to be very effective in the transfer of polyfluoroalkylthiol groups under varied conditions. For instance, the tolerance and robustness of the reagents has been proved by performance of the polyfluoroalkylthiolation reaction in solvents of very different nature (chlorinated, protic, aprotic polar and aprotic non-polar solvents) as shown in figure 1. In a further aspect, the invention refers to a process for producing a compound of general formula (I) comprising the reaction of a compound of formula (II) or a salt thereof:

with a compound of formula (III):

wherein Z, G1, G2, x and y are as defined in claim 1 and X is a suitable leaving group, preferably a halogen group, more preferably a chlorine. The process for producing the compounds of formula (I) can be carried out in a suitable aprotic solvent, preferably in a solvent such as CH2Cl2 (DCM), chloroform, DCE or diethyl ether. The reaction is preferably carried out at a temperature between -30ºC and 50ºC more preferably between 0ºC and 30 ºC. The process for the preparation of the reagents of formula (I) of the present invention was developed after some reported failed approaches for the preparation of polyfluoroalkyl reagents of 2 or more carbon atoms (see figure 2b). The present invention was able to solve the problem of providing reagents for the transfer of polyfluoroalkyl thiol groups with long alkyl chains (from 2 to 10 carbons) by means of a new and effective approach (see figure 2c). Contrary to the reported methods for the preparation of CF3S- or HCF2S- reagents (see figure 2a), the synthesis of polyfluorinated alkyl compounds was tackled by pre- synthetizing the sulfenyl chloride chains, i.e the intermediate of general formula (III), which can be accessed following two strategies depending on the presence of ^-fluorines to the sulfur (see figure 3). Thus, for instance, RfCH2SCl compounds are prepared via tosylation/thioacetylation sequence from the corresponding alcohols followed by cleavage of the acyl group and further halogenation, preferably chlorination. On the other hand, RfSCl compounds bearing fluorines on the ^-carbon, can be synthetized by preparation of benzyl thioether and further halogenation, preferably chlorination. A variety of fluoroalkyl chains, with different fluorination grade and number of carbons to show the generality and validity of this approach have been prepared. The detailed synthesis of each sulfenyl chloride is described later in the experimental section. In turn, intermediates of formula (II) can either be commercially purchased or produced by methods commonly known to a skilled person. In a preferred embodiment of the invention the intermediate of formula (II) is reacted in the form of a suitable salt, preferably as a potassium, sodium or silver salt. Another aspect of the invention is related to the use of compound of formula (I) according to the invention as reagent for the polyfluoroalkylthiolation of organic compounds. The reagents of the present invention are useful in the transfer of polyfluoroalkylthiol groups into a great variety of chemical species (see figure 4) proving the versatility of the compounds of the invention. In particular, the compounds of formula (I) are especially suited for polyfluoroalkylthiolation of organic compounds selected from alcohols, amines, thiols, phosphines, 1,3-dicarbonylic compounds, ketones, phenols, enol ethers, aromatic heterocycles, alkenes, alkynes or organometallic compounds. In addition, the compounds of the invention have proven to be highly efficient in the transfer of various fluoroalkyl chains. Figure 5 represents the high yield obtained in the transfer reaction of different polyfluoroalkyl thiol groups into N-H-indole and the reaction conditions in each case. A final aspect of the inventions somehow connected to the previous one is a method for the polyfluoroalkylthiolation of an organic compound that comprises reacting a reagent of formula (I) according to the invention with said organic compound. In a particular embodiment of the invention, the polyfluoroalkylthiolation method is carried out over an organic compound selected from alcohols, amines, thiols, phosphines, 1,3- dicarbonylic compounds, ketones, phenols, enol ethers, aromatic heterocycles, alkenes, alkynes or organometallic compounds. Although the method can be performed under very variable conditions of temperature and in solvent of very different nature, in a particular embodiment the reaction is carried out in the presence of a catalyst or additive, preferably in the presence of trimethylsilyl chloride (TMSCl). The invention will be described in more detail by means of the following examples. The description below discloses some embodiments and examples of the invention in such detail that a person skilled in the art is able to utilize the invention based on the disclosure. Not all the steps of the embodiments are disclosed in detail, as many of them will be obvious for a person skilled in the art. EXAMPLES Materials and methods Proton (¹H NMR), carbon (¹³C NMR) and fluorine (¹⁹F NMR) nuclear magnetic resonance spectra were recorded on a Varian Mercury spectrometer or a Bruker Avance Ultrashield (400 MHz for ¹H), (100.6 MHz for ¹³C) and (376.5 MHz for ¹⁹F). All chemical shifts are quoted on the δ scale in parts per million (ppm) using the residual solvent as internal standard (¹H NMR: CDCl₃ = 7.26, CD₃OD = 3.31 and ¹³C NMR: CDCl₃ = 77.16, CD₃OD = 49.0). Coupling constants (J) are reported in Hz with the following splitting abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, app = apparent and hept = heptuplet. High–resolution mass spectra (HRMS) were recorded on an Agilent 1100 Series LC/MSD mass spectrometer with electrospray ionization (ESI). Nominal and exact m/z values are reported in Daltons. Thin layer chromatography (TLC) was carried out using commercial backed sheets coated with 60 Å F₂₅₄ silica gel. Visualization of the silica plates was achieved using a UV lamp (λmax = 254 nm), 6% H2SO4 in EtOH, cerium molybdate and/or potassium permanganate staining solutions. Flash column chromatography was carried out using silica gel 60 Å CC (230–400 mesh). Mobile phases are reported in relative composition (e.g.1:1 Ethyl acetate/hexane v/v). All reactions using anhydrous conditions were performed using oven-dried apparatus under an atmosphere of argon. Brine refers to a saturated solution of sodium chloride. Anhydrous sodium sulfate (Na₂SO₄) was used as drying agent after reaction work-up, as indicated. All reagents were purchased from Sigma Aldrich, Cymit, Carbosynth, Apollo Scientific, Fluorochem and Manchester Organics chemical companies. EXAMPLE 1: PREPARATION OF INTERMEDIATE COMPOUNDS Example 1a: synthesis of ^-fluorinated intermediates The synthesis of polyfluoroalkylsulfenyl chlorides with fluorinated ^-methylene groups (RCF2SCl) was performed following the protocols depicted in scheme 1. Some fluoroalkyl benzyl thioethers have been previously described [Scott, P. J. H., Campbell, I. B., Steel, P. G. J. Fluorine Chem.2005, 126, 1196–1201; b) Nguyen, T., Rubinstein, M., Wakselman, C. J. Org. Chem.1981, 46, 1938–1940].

Scheme 1. Synthetic strategy for the preparation of sulfenyl chlorides with fluorinated α- carbons. Bn: benzyl. Benzyl(perfluoroethyl)sulfane (18b):

A flask containing KF (3.31 g, 56.97 mmol, 1.2 eq.) and KSCN (6.92 g, 71.2 mmol, 1.5 eq.) was evacuated and backfilled with argon three times followed by sequential addition of dry ACN (23 mL), benzyl bromide (5.64 mL, 47.47 mmol, 1 eq.) and TMSCF2CF3 (10 mL, 56.97 mmol, 1.2 eq.). The mixture was stirred under argon at 100 ºC for 2 hours. Next, the reaction mixture was cooled down and diluted with diethyl ether (Et2O). The organic phase was extracted with brine and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and the residue was purified by distillation under reduced pressure to afford benzyl(perfluoroethyl)sulfane 18b (5.84 g, 50%) as a colorless liquid. ¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.37–7.28 (m, 5H), 4.16 (s, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 135.5, 129.2, 129.0, 128.1, 123.8 (tt, J = 283.4, 30.1 Hz), 109.9 (tt, J = 252.8, 38.2 Hz), 32.4 (t, J = 4.0 Hz); ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -83.4 (t, J = 3.7 Hz, 3F), -92.4 (q, J = 3.7 Hz, 2F). Benzyl(perfluorobutyl)sulfane (18d):

A Schlenk flask charged with benzyl thiocyanate (4.97 g, 33.3 mmol, 1 eq.) was evacuated and backfilled with argon three times. Dry pyridine (30 mL) and 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (11.46 mL, 66.6 mmol, 2 eq.) were sequentially added under argon atmosphere and the mixture was cooled to 0 ºC using an ice/water bath. Zinc dust (3.26 g, 49.95 mmol, 1.5 eq.) was added and the mixture stirred 30 minutes at 0 ºC and 17 h at room temperature. Another portion of Zn dust (5.0 g, 76.47 mmol, 2.3 eq.) was added at 0 ºC under vigorous stirring and after 30 minutes, the temperature was increased to room temperature and stirred for 5 h. The mixture was then diluted with Et₂O (100 mL) and acidified with 10% aqueous HCl (50 mL) and transferred to an extraction funnel. The aqueous layer was separated, and the organic phase was further washed with 10% aqueous HCl (3 x 10 mL), saturated aqueous NaHCO3 (3 x 10 mL) and brine (10 mL). The organic fraction was dried with Na2SO4, filtrated and the solvent concentrated under reduced pressure. The residue was distilled under reduced pressure affording benzyl(perfluorobutyl)sulfane (18d) (6.46 g, 57% yield) as a yellowish liquid.¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.46–7.29 (m, 5H), 4.20 (s, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 134.7, 129.3, 129.1, 128.3, 124.4 (tt, J = 291, 34.6 Hz), 119.0 (tt, J = 288.6, 33.5 Hz), 114.1-105.2 (m), 33.2 (t, J = 4.3 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –81.0 (tt, J = 9.8, 2.4 Hz, 3F), –87.8 (m, 2F), –120.7 (m, 2F), –125.6 (m, 2F). Benzyl(perfluoropropan-2-yl)sulfane (18c):

A Schlenk flask charged with benzyl thiocyanate (750 mg, 5.0 mmol, 1 eq.) was evacuated and backfilled with argon three times. Dry pyridine (5 mL) and 1,1,1,2,3,3,3- heptafluoro-2-iodopropane (1.40 mL, 10 mmol, 2.0 eq.) were sequentially added under argon atmosphere and the mixture was cooled to 0 ºC using an ice/water bath. Zinc dust (500 mg, 7.5 mmol, 1.5 eq.) was added and the mixture stirred for 30 minutes at 0 ºC and 20 h at room temperature. The mixture was then diluted with Et₂O (30 mL) and acidified with 10% aqueous HCl (20 mL) and transferred to an extraction funnel. The aqueous layer was separated, and the organic phase was further washed with 10% aqueous HCl (3 x 5 mL), saturated aqueous NaHCO₃ (3 x 10 mL) and brine (10 mL). The organic fraction was dried with Na₂SO₄, filtrated and the solvent concentrated under reduced pressure. The residue was dissolved using the minimum amount of pentane (2 mL), filtrated through a short path of silica and eluted with more pentane (30 mL). The solvent was evaporated under reduced pressure to give benzyl(perfluoropropan-2- yl)sulfane 18c (734 mg, 50% yield) as a yellowish liquid.¹H NMR (CDCl₃, 400 MHz) δ in ppm: 7.42–7.30 (m, 5H), 4.18 (s, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 134.0, 129.6, 129.2, 128.5, 120.8 (qd, J = 288.8, 29.9 Hz), 98.2 (m), 33.6; ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –74.7 (d, J = 10.8 Hz, 6F), –162.1 (m, 1F). Benzyl(1,1,2,2-tetrafluoroethyl)sulfane (18a):

A 250 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium hydroxide (90%, 1.68 g, 30 mmol, 0.33 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 60 mL of anhydrous ACN were added using a syringe followed by benzyl mercaptan (11.7 mL, 100 mmol, 1 eq.). Then, a current of tetrafluoroethylene was passed through the solution for 15 minutes. The mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated in a rotary evaporator and the product distilled under reduced pressure to afford benzyl(1,1,2,2-tetrafluoroethyl)sulfane 18a (15.1 g, 67% yield) as a colorless oil. ¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.48–7.31 (m, 5H), 5.80 (tt, J = 53.9, 3.3 Hz, 1H), 4.19 (s, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 135.5, 129.2, 129.0, 128.1, 123.8 (tt, J = 283.4, 30.1 Hz), 109.9 (tt, J = 252.8, 38.2 Hz), 32.4 (t, J = 4.0 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -92.03 (td, J = 9.0, 3.2 Hz, 2F), -132.00 (dt, J = 54.0, 9.0 Hz, 2F). Chlorination of benzyl thioethers: General procedure: To a solution of benzyl thioether in the indicated solvent was bubbled an excess of chlorine gas (Cl2) at 0 ºC. The reaction mixture was stirred at room temperature and the conversion monitored by ¹⁹F NMR. After completion of the reaction, the mixture was distilled to collect the desired sulfenyl chloride as a solution in the reaction solvent. An aliquot (0.5 mL) of the distilled fraction was transferred to an NMR tube followed by addition of 1,4-difluorobenzene (20 ^L, internal standard) to determine the concentration by quantitative ¹⁹F NMR. Details are specified in the table 1 below:

Example 1b: synthesis of non- ^-fluorinated intermediates (RfCH2SCl chains) 1 Kunshenko, B. V.; Omarov, V. O.; Muratov, N. N.; Yagupol'skii, L. M. Zh. Org. Khim.1992, 28, 892– 900. 2 Abe, T., Shreeve, J. M. J. Fluorine Chem.1973, 3, 187-196. 3 Harris, J. F. J. Org. Chem.1979, 444, 563-569. 4 Sizov, A. Y., Kovregin, A. N., Serdyuk, R. N., Vorob’ev, M. V., Porosyatnikov, V. A., Tsvetkov, A. A., Korneev, D. O. Ermolov, A. F. Russ.Chem. Bull. Int. Ed.2006, 55, 1200-1208. The synthesis of polyfluoroalkanesulfenyl chlorides in the absence of fluorinated ^- methylene groups (RCH2SCl) was performed following modified reported protocols [a) Menczinger, B., Nemes, A., Szíjjártó, C., Rábai, J. J. Fluorine Chem.2018, 210, 70– 77; b) Sizov, A. Y., Kovregin, A. N., Serdyuk, R. N., Vorob’ev, M. V., Porosyatnikov, V. A., Tsvetkov, A. A., Korneev, D. O. Ermolov, A. F. Russ.Chem. Bull. Int. Ed.2006, 55, 1200-1208].

Scheme 2. Synthetic strategy for the preparation of sulfenyl chlorides with non- fluorinated α-carbons.

2,2,2-Trifluoroethyl 4-methylbenzenesulfonate (19e):

To a 2 L reaction flask equipped with a magnetic stir bar, Et3N (279 mL, 2 mol, 2 eq.) was added to a solution of trifluoroethanol (72.86 mL, 1 mol, 1 eq.) in DCM (1 L) at room temperature. The mixture was cooled to 0 ºC using an ice/water bath and tosyl chloride (190 g, 1 mol, 1 eq.) was added portionwise over a period of 30 minutes. The mixture was stirred for 30 minutes at 0 ºC and then 16 h at room temperature. The reaction mixture was cooled to 0 ºC and acidified using 10% aqueous HCl (500 mL) under vigorous stirring. After 15 minutes, the mixture was transferred to an extraction funnel, additional water (500 mL) was added and the organic layer was separated. The aqueous phase was extracted with three portions of DCM (3 x 200 mL) and the combined organic fractions were dried with Na2SO4, filtrated and the solvent evaporated under reduced pressure. The obtained crude product (240 g, 94% yield) was used in the next step without further purification. 2,2-Difluoroethyl 4-methylbenzenesulfonate (19g):

Et3N (92 mL, 660 mmol, 2 eq.) was added to a solution of 2,2-difluoroethanol (19.4 mL, 183 mmol, 2 eq.) in DCM (180 mL) at room temperature. The mixture was cooled to 0 ºC using an ice/water bath and TsCl (35 g, 183 mmol, 1 eq.) was added portionwise over a period of 30 minutes. The mixture was stirred for 30 minutes at 0 ºC and then 16 h more at room temperature. The reaction mixture was cooled to 0 ºC and acidified using 10% aqueous HCl (100 mL) under vigorous stirring. After 15 minutes, the mixture was transferred to an extraction funnel, additional water (100 mL) was added and the organic layer was separated. The aqueous phase was extracted with three portions of DCM (3 x 100 mL) and the combined organic fractions were dried with Na2SO4, filtrated and the solvent evaporated under reduced pressure. The obtained crude product (39.8 g, 92% yield) was used in the next step without further purification. 2,2,3,3,4,4,5,5-Octafluoropentyl 4-methylbenzenesulfonate (19f):

Et₃N (70 mL, 500 mmol, 2.0 eq.) was added to a solution of 2,2,3,3,4,4,5,5- octafluoropentan-1-ol (34.8 mL, 250 mmol, 1.0 eq.) in DCM (200 mL) at room temperature. The mixture was cooled to 0 ºC using an ice/water bath and TsCl (47.7 g, 250 mmol, 1.0 eq.) was added portionwise over a period of 30 minutes. The mixture was stirred for 30 minutes at 0 ºC and then 16 h at room temperature. The reaction mixture was cooled to 0 ºC and acidified using 10% aqueous HCl (100 mL) under vigorous stirring. After 15 minutes, the mixture was transferred to an extraction funnel, additional water (100 mL) was added and the organic layer was separated. The aqueous phase was extracted with three portions of DCM (3 x 100 mL) and the combined organic fractions were dried with Na₂SO₄, filtrated and the solvent evaporated under reduced pressure. The obtained crude product (112.5 g, 93% yield) was used in the next step without further purification. S-(2,2,2-trifluoroethyl) ethanethioate (20e):

To a flask containing K₂CO₃ (40.7 g, 295 mmol) and dimethylsulfoxide (DMSO, 100 mL) thioacetic acid (42 mL, 588 mmol) was added under argon at 0 ºC during a period of 20 minutes and stirred at rt for 1 h. After addition of 2,2,2-trifluoroethyl 4- methylbenzenesulfonate 19e (50 g, 196 mmol) at rt, the mixture was stirred at 40 ºC for 24 h. The mixture was then diluted with DCM (400 mL) and water (1 L) transferred to an extraction funnel, the organic layer was separated, and the aqueous phase further extracted with 3 portions of DCM (3 x 100 mL). The combined organic fractions were dried with Na₂SO₄, filtered and the product distilled under reduced pressure to obtain a 61% (w/w) solution in DCM of S-(2,2,2-trifluoroethyl) ethanethioate (20e) (49.6 g, 192 mmol, 98% yield). S-(2,2-difluoroethyl) ethanethioate (20g):

To a flask containing K₂CO₃ (15.5 g, 112.5 mmol) and DMSO (50 mL) thioacetic acid (16 mL, 225 mmol) was added under argon at 0 ºC during a period of 20 minutes and stirred at rt for 1 h. After addition of 2,2-Difluoroethyl 4-methylbenzenesulfonate 19g (17.72 g, 75 mmol) at rt, the mixture was stirred at 40 ºC for 24 h. The mixture was then diluted with DCM (200 mL) and water (500 mL) transferred to an extraction funnel, the organic layer was separated, and the aqueous phase further extracted with 3 portions of DCM (3 x 50 mL). The combined organic fractions were dried with Na₂SO₄, filtered and the product distilled under reduced pressure to obtain S-(2,2-difluoroethyl) ethanethioate (20g) (8.8 g, 63 mmol, 84% yield) as a yellowish liquid. S-(2,2,3,3,4,4,5,5-octafluoropentyl) ethanethioate (20f):

A 250 mL round-bottom flask, equipped with a magnetic stir bar, was charged with thioacetic acid (5.4 mL, 76.2 mmol, 3.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 130 mL of degassed DMF (argon-sparged) were added using a syringe. Then, K₂CO₃ (5.26 g, 38.1 mmol, 1.5 eq.) was added portionwise, controlling the rate of CO₂ formation, to the flask and the mixture was stirred for 30 minutes at room temperature. Next, 2,2,3,3,4,4,5,5-octafluoropentyl 4- methylbenzenesulfonate (19f) (9.4 g, 25.4 mmol, 1.0 eq.) was added and the mixture was heated at 80 ºC for 16 hours. The reaction mixture was washed with H₂O, extracted with Et₂O and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by reduced-pressure distillation (14 mbar, 60 ºC) to afford the desired product S-(2,2,3,3,4,4,5,5-octafluoropentyl) ethanethioate (20f) as a yellow oil (6.4 g, 87% yield). 2,2,2-Trifluoroethane-1-thiol (21e):

A 250 mL round-bottom flask, equipped with a magnetic stir bar, was charged with sodium metal (0.22 g, 0.94 mmol, 0.05 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 94 mL of ethylene glycol were added. Next, S- (2,2,2-trifluoroethyl) ethanethioate (20e) (2.96 g, 18.7 mmol, 1.0 eq.) was added to the mixture. Then, the reaction mixture stirred overnight at room temperature. The mixture was purified by distillation to render the desired product 2,2,2-trifluoroethane-1-thiol (21e) as a yellow oil (1.78 g, 82% yield). 2,2,2-Trifluoroethanesulfenyl chloride (22e):

A 50 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 2,2,2- trifluoroethane-1-thiol (21e) (581 mg, 5.0 mmol, 1.0 eq.). Subsequently, 28 mL of anhydrous CHCl₃ were added using a syringe. Then, a current of chlorine gas was passed through the solution for 15 minutes. The crude reaction was distilled under atmospheric pressure to afford a solution of 2,2,2-trifluoroethanesulfenyl chloride (22e) in CHCl₃. An aliquot was transferred to an NMR tube and quantitative NMR analysis indicated a concentration of 0.17 M of 22e in CHCl₃. 2,2,3,3,4,4,5,5-Octafluoropentanesulfenyl chloride (22f):

A 25 mL round-bottom flask, equipped with a magnetic stir bar was charged with S- (2,2,3,3,4,4,5,5-octafluoropentyl) ethanethioate (20f) (1.0 g, 3.45 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 11.5 mL of anhydrous DCM were added using a syringe. Then, a current of chlorine gas was passed through the solution for 15 minutes. Then, the reaction mixture was concentrated under reduced pressure and redissolved in 5 mL of anhydrous DCM. An aliquot was transferred to an NMR tube and quantitative NMR analysis that indicated a concentration of 0.69 M of 2,2,3,3,4,4,5,5-octafluoropentanesulfenyl chloride (20f) in DCM. 2,2-Difluoroethylsulfenyl chloride (22g):

A 100 mL round-bottom flask, equipped with a magnetic stir bar was charged with S- (2,2-difluoroethyl) ethanethioate (20g) (8.8 g, 63 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 60 mL of anhydrous DCE were added using a syringe. Then, a current of chlorine gas was passed through the solution for 15 minutes. The crude reaction was distilled under reduced pressure and moderate heating (20 mbar, 35 ºC) to afford a solution of 2,2-difluoroethanesulfenyl chloride (22g) in DCE. An aliquot was transferred to an NMR tube and quantitative NMR analysis indicated a concentration of 0.97 M of 22g in DCE. EXAMPLE 2: PREPARATION OF THE REAGENTS OF FORMULA (I) 2-((1,1,2,2-Tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3a):

A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium saccharin salt (221 mg, 1.5 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.6 mL of anhydrous CHCl₃ were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 1.23 M solution of 1,1,2,2-tetrafluoroethanesulfenyl chloride in CHCl₃ was added (0.81 mL, 1 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (287 mg, 91% yield).¹H NMR (CDCl₃, 400 MHz) δ in ppm: 8.17 (d, J = 7.7 Hz, 1H), 8.05–7.96 (m, 2H), 7.96–7.89 (m, 1H), 6.12 (tt, J = 52.8, 4.3 Hz, 1H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 158.9, 137.8, 136.5, 135.1, 126.5, 126.2, 120.3 (tt, J = 294.3, 30.1), 120.0, 109.2 (tt, J = 253.9, 34.6 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -96.9 (bd, J = 225.0 Hz, 1F), -99.8 (bd, J = 225.0 Hz, 1F), -133.9 (ddd, J = 52.9, 16.6, 8.7 Hz, 2F).; HRMS (TOF ES⁺) for (M+H)⁺ C9H5F4NO3S2⁺ (m/z): calc. 315.9720; found 315.9727. 6-Nitro-2-((1,1,2,2-tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (4a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium 6-nitrobenzo[d]isothiazol-3(2H)-one 1,1-dioxide salt (703 mg, 2.64 mmol, 1.32 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 5 mL of anhydrous CHCl3 were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 2.0 M solution of 1,1,2,2-tetrafluoroethanesulfenyl chloride in CHCl3 was added (1.0 mL, 2 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a yellowish solid (186 mg, 22% yield). ¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.87 (d, J = 1.9 Hz, 1H), 8.76 (dd, J = 8.4, 1.9 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 6.10 (tt, J = 53.0, 3.8 Hz, 1H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 157.2, 152.4, 139.2, 130.6, 130.0, 128.3, 120.5 (m), 118.2, 109.2 (tt, J = 254.1, 35.1 Hz); ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -96.60 (m, 2F), -133.18 (d, J = 53.0 Hz, 2F). N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzamide (5a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium N-(phenylsulfonyl)benzamide salt (790 mg, 2.64 mmol, 1.3 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 5 mL of anhydrous CHCl3 were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 2.0 M solution of 1,1,2,2-tetrafluoroethanesulfenyl chloride in CHCl3 (1.0 mL, 2 mmol, 1.0 eq.) was added. The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a colourless oil (804 mg, 77% yield). ¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.13-8.08 (m, 2H), 7.70–7.60 (m, 3H), 7.60–7.52 (m, 3H), 7.46–7.40 (m, 2H), 5.89 (tt, J = 53.1, 3.6 Hz, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 171.7, 137.1, 134.9, 133.3, 132.0, 129.6, 129.5, 129.2, 128.7, 121.3 (tt, J = 293.7, 30.4 Hz), 109.1 (tt, J = 253.6, 36.0 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -94.81 (d, J = 234.3 Hz, 1F), -98.94 (d, J = 234.3 Hz, 1F), -133.31 (m, 2F); HRMS (TOF ES⁺) for (M+H)⁺ C15H12F4NO3S2⁺ (m/z): calc.394.0189; found 394.0192. N-(methylsulfonyl)-N-((perfluoroethyl)thio)methanesulfonamide (6a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium N-(methylsulfonyl)methanesulfonamide salt (558 mg, 2.64 mmol, 1.3 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 5 mL of anhydrous CHCl₃ were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 2.0 M solution of 1,1,2,2-tetrafluoroethanesulfenyl chloride in CHCl₃ was added (1.0 mL, 2 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (360 mg, 45% yield). ¹H NMR (CDCl₃, 400 MHz) δ in ppm: 6.12 (tt, J = 52.9, 4.1 Hz, 1H), 3.39 (s, 6H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 120.6 (tt, J = 293.6, 29.8 Hz), 109.1 (tt, J = 253.3, 34.9 Hz), 43.2; ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -98.7 (td, J = 9.2, 4.1 Hz, 2F), -134.0 (dt, J = 52.9, 9.2 Hz, 2F). N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzenesulfonamide (7a):

A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with silver N-(phenylsulfonyl)benzenesulfonamide salt (446 mg, 1.5 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.6 mL of anhydrous CHCl3 were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 1.23 M solution of 1,1,2,2-tetrafluoroethanesulfenyl chloride in CHCl3 was added (0.81 mL, 1 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (386 mg, 90% yield).¹H NMR (CDCl₃, 400 MHz) δ in ppm: 8.02-7.96 (m, 4H), 7.70-7.62 (m, 2H), 7.57-7.48 (m, 4H), 6.18 (tt, J = 53.0, 4.7 Hz, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 137.5, 135.0, 129.2, 129.0, 120.0 (tt, J = 296.4, 29.0 Hz), 109.0 (tt, J = 253.1, 34.2 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -99.29 (td, J = 10.1, 4.7 Hz, 2F), -135.08 (dt, J = 53.0, 10.1 Hz, 2F). 2-((Perfluoropropan-2-yl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3c):

An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with potassium saccharin salt (655 mg, 2.96 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1 ml of anhydrous CHCl₃ were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 0.28 M solution of 1,1,1,2,3,3,3-heptafluoro-propane-2-sulfenyl chloride in CHCl₃ was added (7 mL, 1.97 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (740 mg, 98% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.20-8.16 (m, 1H), 8.05–7.97 (m, 2H), 7.95-7.90 (m, 1H); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –73.7 (quin, J = 10.5 Hz, 3F), –74.0 (quin, J = 9.1 Hz, 3F), –156.1 (hept, J = 10.5 Hz, 1F); HRMS (TOF ES⁺) for (M+H)⁺ C10H5F7NO3S2⁺ (m/z): calc. 383.9594; found 383.9602. 2-((Perfluorobutyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3d):

A 25 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium saccharin salt (1.15 g, 5.2 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 3 mL of anhydrous DCE were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 0.57 M solution of perfluorobutanesulfenyl chloride in DCE was added (6.0 mL, 3.42 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (1.40 g, 95% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.22-8.17 (m, 1H), 8.08–7.97 (m, 2H), 7.97-7.90 (m, 1H); ¹⁹F NMR (376 MHz, CDCl3) δ -80.9 (tt, J = 9.6, 2.2 Hz, 3F), -90.1 (m, 2F), -120.9 (m, 2F), -125.7 (m, 2F); HRMS (TOF ES⁺) for (M+H)⁺ C11H5F9NO3S2⁺ (m/z): calc.433.9562; found 433.9577. 2-((2,2,3,3,4,4,5,5-Octafluoropentyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3f):

A 25 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium saccharin salt (764 mg, 3.45 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 5 mL of anhydrous DCM were added using a syringe. Then, the mixture was cooled down to 0 ºC and a 0.69 M solution of 2,2,3,3,4,4,5,5-octafluoropentanesulfenyl chloride in DCM was added (5.0 mL, 3.45 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (1.33 g, 90% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.13 (d, J = 7.6 Hz, 1H), 8.05–7.84 (m, 3H), 6.04 (tt, J = 51.8, 5.4 Hz, 1H), 3.68 (t, J = 17.1 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ -114.2 (bs, 2F), -124.9 (bs, 2F), -129.7 (m, 2F), -137.4 (m, 2F); HRMS (TOF ES⁺) for (M+H)⁺ C₁₂H₈F₈NO₃S₂ ⁺ (m/z): calc. 429.9812; found 429.9823. 2-((Perfluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3b):

A 50 mL round-bottom flask, equipped with a magnetic stir bar, was charged with potassium saccharin salt (1.52 g, 6.88 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, the flask was cooled down to 0 ºC and a 0.17 M solution of perfluoroethanesulfenyl chloride in DCM was added (27 mL, 4.59 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (1.48 g, 99% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.18 (d, J = 7.7 Hz, 1H), 8.05–7.98 (m, 2H), 7.96–7.89 (m, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 158.5, 138.0, 136.5, 135.1, 126.6, 126.1, 122.1, 118.2 (tq, J = 41.8, 299.5 Hz), 118.1 (qt, J = 286.7, 35.3 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -82.4 (t, J = 3.0 Hz, 3F), -95.36 (m, 2F). 2-((2,2-difluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3g):

To a 50 mL round-bottom flask equipped with a magnetic stir bar was charged with potassium saccharin salt (5.42 g, 24.51 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, the flask was cooled down to 0 ºC and a 0.97 M solution of 2,2-difluorooethanelsulfenyl chloride in DCE was added (16.8 mL, 16.34 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product contaminated with saccharine. The solid was washed with 5 mL of Et2O/pentane (1:4) 5 times to afford the desired product (3.0 g, 66% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.15–8.10 (m, 1H), 8.00–7.92 (m, 2H), 7.91–7.85 (m, 1H), 3.62 (q, J = 9.4 Hz, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 159.7, 138.0, 135.9, 134.8, 126.9, 126.1, 121.8, 121.8 (t, J = 243.4 Hz), 42.0 (q, J = 25.4 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -114.2 (dt, J = 55.8, 14.2 Hz, 2F). 2-((2,2,2-Trifluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3e):

To a 25 mL round-bottom flask equipped with a magnetic stir bar was charged with potassium saccharin salt (136 mg, 0.62 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, the flask was cooled down to 0 ºC and a 0.055 M solution of 2,2,2-trifluoroethanelsulfenyl chloride in DCM was added (7.5 mL, 0.41 mmol, 1.0 eq.). The mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford the desired product as a white solid (110 mg, 90% yield).¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.17–8.14 (m, 1H), 8.00–7.93 (m, 2H), 7.92–7.86 (m, 1H), 3.62 (q, J = 9.4 Hz, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 158.8, 137.9, 135.9, 134.9, 126.8, 126.3, 124.3 (q, J = 275.7 Hz), 121.7, 40.9 (q, J = 33.9 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -66.30 (t, J = 9.5 Hz, 3F). EXAMPLE 3: POLYFLUOROALKYLTHIOLATION REACTIONS 3-((1,1,2,2-tetrafluoroethyl)thio)-1H-indole (8a): Protocol A: using reagent 3a

An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with 1H-indole (35 mg, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.5 mL of anhydrous DCM were added using a syringe. Then, reagent 3a (104 mg, 0.33 mmol, 1.1 eq.) was added to the flask and the mixture was stirred for 1 hour at 40 ºC. The reaction mixture was diluted with DCM, washed with NaHCO₃ (saturated) and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2:8 Ethyl acetate/hexane) to afford the desired product as a white solid (71 mg, 95% yield). Protocol B: using reagent 6a An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with 1H-indole (35 mg, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.5 mL of anhydrous DCM were added using a syringe. Then, reagent 6a (101 mg, 0.33 mmol, 1.1 eq.) was added to the flask and the mixture was stirred for 5 minutes at room temperature. The reaction mixture was diluted with DCM, washed with aqueous NaHCO₃ and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2:8 Ethyl acetate/hexane) to afford the desired product as a white solid (72 mg, 97% yield). R_f (2:8 Ethyl acetate/hexane): 0.39; ¹H NMR (CDCl₃, 400 MHz) δ in ppm: 8.44 (bs, 1H), 7.88-7.81 (m, 1H), 7.50 (d, J = 2.7 Hz, 1H), 7.47-7.39 (m, 1H), 7.36-7.28 (m, 2H), 5.75 (tt, J = 53.7, 4.0 Hz, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 136.1, 133.3, 129.9, 123.6, 122.2 (tt, J = 284.4, 28.5 Hz), 121.8, 119.4, 111.9, 109.4 (tt, J = 252.8, 36.8 Hz), 94.4 (t, J = 3.9 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –94.4 (td, J = 9.8, 4.0 Hz, 2F), –133.7 (dt, J = 53.7, 9.8 Hz, 2F). (Adamantan-1-yloxy)(1,1,2,2-tetrafluoroethyl)sulfane (9a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 1- adamantol (46 mg, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 6 mL of anhydrous DCM were added using a syringe followed by triethylamine (104 µl, 0.75 mmol, 2.5 eq.). Then, reagent 3a (123 mg, 0.39 mmol, 1.3 eq.) was quickly added to the flask. The mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 100% pentane) to afford the desired product as a white solid (78 mg, 91% yield). R_f (Pentane): 0.26; ¹H NMR (CDCl₃, 400 MHz) δ in ppm: 5.99 (tt, J = 53.5, 4.3 Hz, 1H), 2.23 (bs, 3H), 1.80 (m, 6H), 1.61 (m, 6H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 123.3 (tt, J = 286.6, 28.2 Hz), 109.17 (tt, J = 252.9, 35.6 Hz), 82.6, 41.6, 35.9, 31.4; ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -103.9 (td, J = 9.9, 4.3 Hz, 2F), -135.1 (dt, J = 53.5, 9.9 Hz, 2F). N-benzyl-S-(1,1,2,2-tetrafluoroethyl)thiohydroxylamine (10a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with benzylamine (33 µl, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 6 mL of anhydrous DCM were added using a syringe. Then, reagent 3a (99 mg, 0.32 mmol, 1.05 eq.) was quickly added to the flask. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 8:2 hexane/ethyl acetate) to afford the desired product as a yellowish oil (48 mg, 67% yield). R_f (Pentane): 0.15; ¹H NMR (CDCl₃, 400 MHz) δ in ppm: 7.40-7.28 (m, 4H), 5.92 (tt, J = 53.8, 3.8 Hz, 1H), 4.20 (d, J = 5.6 Hz, 2H), 2.98 (bs, 1H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 138.6, 128.8, 128.3, 128.1, 123.3 (tt, J = 287.0, 29.8 Hz), 109.7 (tt, J = 252.0, 37.8 Hz), 58.3; ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: –102.0 (td, J = 8.4, 3.8 Hz, 2F), –134.3 (dt, J = 53.7, 8.4 Hz, 2F). 2-((1,1,2,2-Tetrafluoroethyl)disulfaneyl)benzo[d]oxazole (11a):

A 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 2- mercaptobenzoxazole (48 mg, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 2 mL of anhydrous DCM and 2 mL of anhydrous ACN were added using a syringe. Then, the mixture was cooled down to 0 ºC and reagent 3a (104 mg, 0.33 mmol, 1.1 eq.) was quickly added to the flask. The mixture was stirred for 5 minutes at temperature. The reaction mixture was diluted with ethyl acetate (Ethyl acetate), washed with NaHCO3 (saturated) and dried over MgSO4. Upon filtration, the organic layer was concentrated under reduced pressure and the organic residue was dissolved in pentane and concentrated again under reduced pressure to give the desired product as a yellow oil (85 mg, 99% yield). Rf (1:9 Ethyl acetate/hexane): 0.33; ¹H NMR (CDCl3, 400 MHz) δ in ppm 7.74–7.68 (m, 1H), 7.56– 7.50 (m, 1H), 7.39–7.33 (m, 2H), 6.11 (tt, J = 53.2, 3.5 Hz, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 159.6, 152.6, 141.8, 125.9, 125.2, 121.3 (t, J = 290.5, 30.0 Hz), 120.1, 110.7, 109.2 (t, J = 253.7, 36.1 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -95.02 (td, J = 8.6, 3.6 Hz, 2F), -132.96 (dt, J = 53.3, 8.6 Hz, 2F). 1-(4-Fluorophenyl)-2-((1,1,2,2-tetrafluoroethyl)thio)ethan-1-one (12a):

An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with 4- fluoroacetophenone (12 µl, 0.1 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 0.6 mL of anhydrous ACN were added using a syringe. Then, reagent 3a (41 mg, 0.13 mmol, 1.3 eq.) and trimethylsilyl chloride (25 µl, 0.2 mmol, 2.0 eq.) were quickly added to the flask. The mixture was stirred for 16 hours at 80 ºC. An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with 4-fluoroacetophenone (12 µl, 0.1 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 0.6 mL of anhydrous ACN were added using a syringe. The mixture was stirred for 16 hours at 80 ºC. An aliquot (0.5 mL) was transferred to an NMR tube and 1,4-difluorobenzene (0.1 mmol) was added. Quantitative ¹⁹F NMR indicated 12a was produced in 85% yield.¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.03–7.96 (m, 2H), 7.22–7.13 (m, 2H), 5.90 (tt, J = 53.8, 3.3 Hz, 1H), 4.45 (s, 2H).; ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –91.6 (m, 2F), –104.4 (m, 1F), –132.7 (dt, J = 53.2, 9.1 Hz, 2F). Diethyl 2-benzyl-2-((1,1,2,2-tetrafluoroethyl)thio)malonate (13a):

Protocol A: using reagent 3a A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with NaH (60% in mineral oil, 9 mg, 0.23 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.5 mL of anhydrous THF were added using a syringe followed by diethyl 2-benzylmalonate (35.5 µl, 0.15 mmol, 1.0 eq.) and the mixture is stirred at room temperature for 15 minutes. Then, reagent 3a (118 mg, 0.38 mmol, 1.7 eq.) was quickly added to the flask and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was diluted with Et2O, washed with NH4Cl (saturated) and dried over MgSO4. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a colorless oil (51 mg, 88% yield). Protocol B: using reagent 6a An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with NaH (60% in mineral oil, 3 mg, 0.075 mmol, 1.5 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 0.5 mL of anhydrous THF were added using a syringe followed by diethyl 2-benzylmalonate (11.8 µl, 0.05 mmol, 1.0 eq.) and the mixture is stirred at room temperature for 15 minutes. Then, reagent 6a (26 mg, 0.085 mmol, 1.7 eq.) was quickly added to the flask and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was diluted with Et₂O, washed with NH₄Cl (saturated) and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a colorless oil (47 mg, 81% yield). ¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.30–7.18 (m, 5H), 5.80 (tt, J = 53.7, 3.5 Hz, 1H), 4.29–4.15 (m, 4H), 3.64 (s, 2H), 1.23 (t, J = 7.1 Hz, 6H).; ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: - 88.79 (td, J = 8.9, 3.5 Hz, 2F), -132.48 (dt, J = 53.7, 8.9 Hz, 2F). 4-((1,1,2,2-Tetrafluoroethyl)thio)phenol (14a):

A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with phenol (28 mg, 0.3 mmol, 1.0 eq.). The flask was then evacuated and backfilled with argon three times. Subsequently, 3 mL of anhydrous DCM were added using a syringe followed by trifluoromethanesulfonic acid (32 µl, 0.36 mmol, 1.2 eq.). Then, reagent 3a (114 mg, 0.36 mmol, 1.2 eq.) was quickly added to the flask. The mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with Et2O, washed with NaHCO3 (saturated) and dried over MgSO4. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a yellow oil (66 mg, 97% yield). R_f (1:9 Ethyl acetate/hexane): 0.14; ¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.51 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.75 (tt, J = 53.8, 3.5 Hz, 1H), 5.23 (s, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 158.0, 139.2, 122.4 (tt, J = 283.9, 29.2 Hz), 116.6, 109.6 (tt, J = 252.9, 37.6 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –92.74 (td, J = 9.2, 3.4 Hz, 2F), –132.58 (dt, J = 53.8, 9.5 Hz, 2F). (2R,3R,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-((1,1,2,2- tetrafluoroethyl)thio)-3,4-dihydro-2H-pyran (15a):

A 5 mL round-bottom flask, equipped with a magnetic stir bar, was charged with tri-O- benzyl-D-glucal (42 mg, 0.1 mmol, 1.0 eq.) and 3 Å molecular sieves (20 mg, 3 g/mmol glucal). The flask was then evacuated and backfilled with argon three times. Subsequently, 1.5 mL of anhydrous ACN and reagent 3a (38 mg, 0.12 mmol, 1.2 eq.) were added. The mixture was stirred for 2 hours at room temperature. Then, trimethylsilyl chloride (38 µl, 0.3 mmol, 3 eq.) was added and the mixture was stirred until complete consumption of the starting material monitored by TLC (approximately 3.5 hours). Next, 1,8-Diazabicyclo(5.4.0)undec-7-ene (45 µl, 0.6 mmol, 6 eq.) was added and the reaction mixture was left stirring overnight at room temperature (16 hours). The reaction mixture was diluted with DCM, filtered through Celite® washed with H₂O, brine and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 9:1 hexane/ethyl acetate) to afford the desired product as a colorless oil (44 mg, 80% yield). R_f (1:9 Ethyl acetate/hexane): 0.19; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.23 (m, 15H), 6.98 (s, 1H), 5.87 (tdd, J = 53.7, 4.9, 2.9 Hz, 1H), 4.74 (d, J = 11.1 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.61 (d, J = 11.1 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.53 (s, 2H), 4.47–4.40 (m, 1H), 4.08 (d, J = 4.0 Hz, 1H), 3.91 (dd, J = 5.0, 4.3 Hz, 1H), 3.77 (dd, J = 10.7, 6.3 Hz, 1H), 3.68 (dd, J = 10.7, 4.2 Hz, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 156.1, 137.8, 137.7, 137.5, 128.7, 128.6, 128.24, 128.2, 128.1, 128.0, 127.9, 127.9, 125.9-119.3 (m), 108.2 (tdd, J = 252.7, 38.6, 35.3 Hz), 97.0 (t, J = 2.9 Hz), 77.0, 76.3, 73.6, 73.4, 72.9, 67.9; ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -92.6 (m, 1F), -95.1 (m, 1F), -133.74 (m, 2F). (Phenylethynyl)(1,1,2,2-tetrafluoroethyl)sulfane (16a):

A 0.42 M stock solution of lithium phenylacetylide was prepared using the following procedure: a 5 μL round-bottom flask, equipped with a magnetic stir bar, was charged with phenylacetlylene (102 mg, 1.0 mmol). The flask was then evacuated and backfilled with argon three times. Subsequently, 2 mL of anhydrous THF were added using a syringe and the mixture was cooled down to -78 ºC. Next, a titrated solution of 2.88 M n- BuLi in hexanes (0.38 mL, 1.1 mmol, 1.1 eq.) was added dropwise. The mixture was stirred at -78 ºC for 30 minutes. To a 5 mL round-bottom flask, equipped with a magnetic stir bar, reagent 3a (114 mg, 0.36 mmol, 1.2 eq.) was charged. The flask was then evacuated and backfilled with argon three times. Subsequently, 2.2 mL of anhydrous THF were added using a syringe and the mixture was cooled down to -78 ºC. Then, 0.72 mL of the previously prepared solution of phenyl acetylene (0.3 mmol, 1.0 eq.) were added dropwise to the reaction flask. The reaction mixture is stirred for 15 minutes at -78 ºC and then left to warm up at room temperature. Finally, the crude was cooled down to 0 ºC and first quenched with 5 mL of H₂O and secondly with 5ml of NH₄Cl (saturated). The mixture is transferred to an extraction funnel and the organic layer is separated and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, pentane 100%) to afford the desired product as a colorless oil (59 mg, 84% yield). Rf (Pentane): 0.48; ¹H NMR (CDCl3, 400 MHz) δ in ppm: 7.50-7.45 (m, 2H), 7.40-7.30 (m, 3H), 6.05 (tt, J = 53.4, 3.8 Hz, 1H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 132.2, 129.7, 128.5, 121.6, 121.4 (tt, J = 290.1, 29.5 Hz), 108.9 (tt, J = 254.0, 35.8 Hz), 99.8, 66.9 (s, J = 6.6 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –95.12 (td, J = 8.9, 3.8 Hz, 2F), –133.50 (dt, J = 53.4, 9.0 Hz, 2F). [1,1'-Biphenyl]-4-yl(1,1,2,2-tetrafluoroethyl)sulfane (17a):

A 0.18 M stock solution of [1,1’-biphenyl]-4-yllithium was prepared using the following procedure: a 10 mL round-bottom flask, equipped with a magnetic stir bar, was charged with 4-bromo-1,1’-biphenyl (233 mg, 1.0 mmol). The flask was then evacuated and backfilled with argon three times. Subsequently, 5.5 mL of anhydrous THF were added using a syringe and the mixture was cooled down to -78 ºC. Next, a titrated solution of 2.88 M n-BuLi in hexanes (0.36 mL, 1.0 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at -78 ºC for 1.5 hours. To a 25 mL round-bottom flask, equipped with a magnetic stir bar, reagent 3a (114 mg, 0.36 mmol, 1.2 eq.) was charged. The flask was then evacuated and backfilled with argon three times. Subsequently, 8.4 mL of anhydrous THF were added using a syringe and the mixture was cooled down to -78 ºC. Then, 1.8 mL of the previously prepared solution of [1,1’-biphenyl]-4-yllithium (0.3 mmol, 1.0 eq.) were added dropwise to the reaction flask. The reaction mixture is stirred for 30 minutes at -78 ºC and then left to warm up at room temperature. Finally, the crude was cooled down to 0 ºC and first quenched with 5 mL of H₂O and secondly with 5ml of NH₄Cl (saturated). The mixture is transferred to an extraction funnel and the organic layer is separated and dried over MgSO₄. Upon filtration, the organic layer was concentrated under reduced pressure and purified by flash column chromatography (silica gel, pentane) to afford the desired product as a white solid (60 mg, 70% yield). R_f (pentane): 0.75; ¹H NMR (CDCl₃, 400 MHz) δ in ppm: 7.75-7.69 (m, 2H), 7.67-7.58 (m, 4H), 7.53- 7.45 (m, 2H), 7.44- 7.35 (m, 1H), 5.82 (tt, J = 53.8, 3.4 Hz, 1H); ¹³C NMR (CDCl₃, 100.6 MHz) δ in ppm: 143.68, 139.66, 137.38, 128.96, 128.12, 128.05, 127.20, 122.45 (tt, J = 284.9, 29.3 Hz), 122.05, 109.43 (tt, J = 253.2, 37.5 Hz); ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: –91.8 (td, J = 9.5, 2.8 Hz, 2F), –133.7 (dt, J = 53.8, 9.6 Hz, 2F). 3-((Perfluoroethyl)thio)-1H-indole (8b):

To a round bottom flask containing 1H-indole (18 mg, 0.15 mmol, 1.0 eq.) was sequentially added dry DCM (0.6 mL) and reagent 3b (55 mg, 0.17 mmol, 1.1 eq.) under argon. The mixture was stirred 24 h at 40 ºC. The solvent was then removed under reduced pressure and the residue was purified by column chromatography (silica gel, 2:8 Ethyl acetate/hexane) to afford 8b (34 mg, 85% yield) as a yellowish solid. Rf (2:8 Ethyl acetate/hexane): 0.22; ¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.51 (bs, 1H), 7.86- 7.78 (m, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.47-7.39 (m, 1H), 7.35-7.27 (m, 2H); ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -82.5 (t, J = 3.4 Hz, 3F), -93.1 (q, J =3.4 Hz, 2F). 3-((2,2,2-Trifluoroethyl)thio)-1H-indole (8e):

To a vial charged with 1H-indole (23 mg, 0.2 mmol, 1.0 eq.) was sequentially added CDCl3 (2 mL) and reagent 3e (71 mg, 0.24 mmol, 1.2 eq.). The mixture was then transferred to an NMR tube and the reaction monitored by ¹H and ¹⁹F NMR. After 19 h at 70 ºC, the estimated conversion of reagent 3e was 76% (20% in excess) and the conversion and yield of 8e was 85%.¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.34 (bs, 1H), 7.81-7.74 (m, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.43-7.38 (m, 1H), 7.32-7.22 (m, 2H), 3.24 (q, J = 9.9 Hz, 2H); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -66.5 (t, J = 9.9 Hz, 3F). 3-((2,2,3,3,4,4,5,5-Octafluoropentyl)thio)-1H-indole (8d):

To a vial charged with 1H-indole (23 mg, 0.2 mmol, 1.0 eq.) was sequentially added CHCl3 (0.6 mL) and reagent 3d (95 mg, 0.22 mmol, 1.1 eq.). The mixture was then transferred to an NMR tube and the reaction monitored by ¹H and ¹⁹F NMR. After 1 h at 70 ºC, quantitative NMR analysis indicated that 8d was produced in >95% yield.¹⁹F NMR (CHCl3, 376.5 MHz) δ in ppm: -114.08 (bs, 2F), -124.92 (bs, 2F), -129.91 (bs, 2F), - 137.25 (bs, 2F); HRMS (TOF ES⁺) for (M+H)⁺ C13H10F8NS⁺ (m/z): calc.364.0401; found 364.0409. 3-((Perfluoropropan-2-yl)thio)-1H-indole (8c):

To a vial charged with 1H-indole (12 mg, 0.1 mmol, 1 eq.) was sequentially added CDCl3 (0.6 mL), 3c (42 mg, 0.11 mmol) and TMSCl (19 ^L, 0.15 mmol, 1.1 eq.). The mixture was then transferred to an NMR tube and the reaction monitored by ¹H and ¹⁹F NMR. After 5 h at 70 ºC, quantitative NMR analysis indicated that 8c was produced in >95% yield.¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.57 (bs, 1H), 7.86-7.76 (m, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.47-7.38 (m, 1H), 7.34-7.26 (m, 2H); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: -74.2 (d, J = 11.4 Hz, 6F), -158.1 (hept, J = 11.1 Hz, 1F). 3-((Perfluorobutyl)thio)-1H-indole (8f):

To a vial charged with 1H-indole (12 mg, 0.1 mmol, 1.0 eq.) was sequentially added dry DCM (0.6 mL) and 3f (43 mg, 0.11 mmol, 10 eq.). The mixture was then transferred to an NMR tube and the reaction monitored by ¹⁹F NMR. After 16 h at room temperature, quantitative NMR analysis indicated that 8f was produced in >95% yield. ¹⁹F NMR (CDCl₃, 376.5 MHz) δ in ppm: -80.87 (tt, J = 9.7, 2.4 Hz, 3F), -90.08 (m, 2F), -120.84 (m, 2F), -125.66 (m, 2F); HRMS (TOF ES⁺) for (M+H)⁺ C₁₂H₇F₉NS⁺ (m/z): calc.368.0150; found 368.0149. 3-((2,2-Difluoroethyl)thio)-1H-indole (8g):

An 8 mL reaction vial, equipped with a magnetic stir bar, was charged with 1H-indole (35 mg, 0.3 mmol, 1.0 eq.). The vial was then evacuated and backfilled with argon three times. Subsequently, 3.0 mL of anhydrous DCM were added using a syringe. Then, reagent 3g (84 mg, 0.3 mmol, 1.0 eq.) and TMSCl (57 μL, 0.45 mmol, 1.5 eq.) were sequentially added and the reaction mixture stirred at room temperature overnight. The crude reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 1:4 Ethyl acetate/hexane) to afford the desired product as a yellowish solid (58 mg, 91% yield). Rf: (1:4 Ethyl acetate/hexane): 0.28; ¹H NMR (CDCl3, 400 MHz) δ in ppm: 8.17 (s, 1H), 7.68 (ddd, J = 6.6, 2.5, 0.9 Hz, 1H), 7.39 – 7.21 (m, 2H), 7.21 – 7.10 (m, 2H), 5.70 (tt, J = 56.6, 4.6 Hz, 1H), 2.90 (td, J = 15.1, 4.7 Hz, 2H); ¹³C NMR (CDCl3, 100.6 MHz) δ in ppm: 136.3, 130.4, 129.0, 123.1, 121.0, 119.0, 115.9 (t, J = 242.5 Hz), 111.8, 103.9, 39.1 (t, J = 23.2 Hz); ¹⁹F NMR (CDCl3, 376.5 MHz) δ in ppm: –115.62 (dt, J = 56.3, 15.0 Hz, 2F).

Claims

CLAIMS 1. A compound of general formula (I):

wherein: the dotted line represents an optional bond; Z is -CO- or -SO₂- ; G₁ represents a group –[CH₂]_n-R₁ ; G2 represents a group –[CH2]m-R2; or G1 together with G2 form a fused or non-fused aromatic or heteroaromatic ring optionally substituted by one or more R3 substituents; n and m are 0 or 1; x is an integer between 2 and 10; y is an integer between 1 and 21 but always lower than (2x+1) R1 and R2 are independently from one another a hydrogen atom, a C1-6 alkyl, a phenyl ring optionally substituted by one or more R3 substituents; R3 is a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxy, halogen atom, a -OH, a -CN, a -NO2, a -CF3, -COR, -COOR, -CONRR’ wherein R and R’ represent a hydrogen or a C1-6 alkyl; or a salt, stereoisomer or solvate thereof.

2. A compound according to claim 1 with the proviso that when n is 0 and/or m is 0 while at the same time that Z is -SO2-, then R1 and R2 are not H.

3. A compound according to claim 1 wherein n and m are 0 and R1 and R2 are independently from one another a C1-6 alkyl, preferably a methyl or a phenyl ring.

4. A compound according to claim 1 wherein G1 together with G2 form a benzene ring optionally substituted by one or more R3 substituents.

5. A compound according to claim 1 or 2 wherein x is 2, 3, 4 or 5.

6. A compound according to claim 1 or 2 having one of the following formulas:

wherein Z, R1, R2, R3, x and y are as defined in claim 1.

7. A compound according to any one of claims 1 or 6 having one of the following formulas:

wherein Z, R1, R2, R3, x and y are as defined in claim 1.

8. A compound according to any one of the previous claims wherein the -S[CxFyH(2x+1-y)] moiety is represented by any of the following: -SCH₂CF₃ -SCH₂CF₂H -SCF₂CF₂H -SCF₂CF₃ -SCH₂(CF₂)₃CF₂H -S(CF₂)₃CF₃ -SCF(CF₃)₂

9. A compound according to any one of previous claims selected from: ● 2-((1,1,2,2-Tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 6-Nitro-2-((1,1,2,2-tetrafluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzamide; ● N-(methylsulfonyl)-N-((perfluoroethyl)thio)methanesulfonamide; ● N-(phenylsulfonyl)-N-((1,1,2,2-tetrafluoroethyl)thio)benzenesulfonamide; ● 2-((Perfluoropropan-2-yl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((Perfluorobutyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((2,2,3,3,4,4,5,5-Octafluoropentyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; ● 2-((Perfluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide; and ● 2-((2,2,2-Trifluoroethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide.

10. A process for producing a compound of general formula (I) comprising the reaction of a compound of formula (II) or a salt thereof:

with a compound of formula (III):

wherein Z, G1, G2, x and y are as defined in claim 1 and X is a suitable leaving group, preferably a halogen group, more preferably a chlorine.

11. A process according to claim 10 wherein the reaction is carried out in an aprotic solvent, preferably DCM, chloroform, DCE or diethyl ether.

12. A process according to claim 10 wherein the compound of formula II is in the form of a salt.

13. Use of a compound according to any one of claims 1-9 as reagent for the polyfluoroalkylthiolation of organic compounds.

14. Use according to claim 13 where the organic compounds are alcohols, amines, thiols, phosphines, 1,3-dicarbonylic compounds, ketones, phenols, enol ethers, aromatic heterocycles, alkenes, alkynes or organometallic compounds.

15. Method for the polyfluoroalkylthiolation of an organic compound that comprises reacting a compound according to any one of claims 1-9 with said organic compound.

16. Method according to claim 15 where the organic compound are alcohols, amines, thiols, phosphines, 1,3-dicarbonylic compounds, ketones, phenols, enol ethers, aromatic heterocycles, alkenes, alkynes or organometallic compounds.

17. The method of claim 15 or 16 where the reaction is carried out in the presence of a catalyst or additive, preferably trimethylsilyl chloride (TMSCl).