Synthetic Routes to Arylsulfonyl Fluorides

+33-04-72-44-85-28 Abstract: The goal of this mini-review is to shed the light on the existing methodologies to access arylsulfonyl ﬂuorides. Today, a plethora of methods making use of a different pool of starting materials and in the presence of catalyst or under catalyst free conditions are disclosed in the literature. Abstract: The goal of this mini-review is to shed the light on the existing methodologies to access arylsulfonyl fluorides. Today, a plethora of methods making use of a different pool of starting materials and in the presence of catalyst or under catalyst free conditions are disclosed in the literature.


Direct Arylsulfonyl Fluoride Synthesis Reactions
The direct formation of the C-SO 2 F bond constitutes the most elegant approach. Indeed, it allows straightforward access to arylsulfonyl fluorides, which constitutes an attractive option in late-stage functionalization. For this purpose, several research groups recently developed different strategies to address this challenge. Overviews of the most efficient methods are summarized herein.

Sulfonyl Fluorides Synthesis from Aryl Halides
The first example for the synthesis of arylulfonyl fluorides was reported by the groups of Willis and Bagley. The developed methodology is a one-pot two-step procedure in which sulfinates are in-situ formed through cross coupling between aryl bromide derivatives and DABSO (1,4-diazabicyclo [2.2.2] octane bis(sulfur dioxide) adduct) [29]. The commercially available PdCl 2 (AmPhos) 2 (AmPhos: di-tert-butyl(4-dimethylaminophenyl)phosphine) was used as the active catalyst (5 mol%) and the reactions were performed in the presence of Et 3 N as the base in iPrOH at 75 • C for 24 h. Afterwards, treatment of the reaction media with 1.5 equivalent of NFSI (N-Fluorobenzenesulfonimide) led to the desired sulfonyl fluoride (Scheme 2a). It is worth noting that the reaction conditions tolerate the presence of several functional groups, and a wide variety of electron-donating and electronwithdrawing starting aryl bromides were converted to the desired products in good to excellent yields.
Furthermore, the authors turned their attention to the study of the reactions starting with heterocyclic compounds. Unfortunately, only very low yields were observed when the previous conditions were applied. In order to foster the reaction outcome, the authors demonstrated that upon microwave irradiation at 110 • C and by using N,N-Dicyclohexylmethylamine (Cy 2 NMe) as the base, the conversion of several bromopyridine derivatives was achieved in moderate to very good yields. The authors assume that the steric hindrance of the base plays a key role in decreasing the homocoupling process of the starting aryl bromide as well as the rapid generation of the active palladium (0) catalyst (Scheme 2b).
It should be noted that a palladium-free procedure was also disclosed by using Grignard reagents in conjunction with DABSO in THF at room temperature. In that case, sulfinates were also formed as intermediates and the corresponding arylesulfonyl fluorides were obtained in very good to excellent yields upon treatment with NFSI (Scheme 2c).
In order to further demonstrate the versatility of the developed methodology, the authors proved its applicability to N-Boc-L-4-halophenylalanine methyl to generate the sulfonyl fluoride analogue 4 with good yields, starting from both bromide and iodide substrate (Scheme 3a). Next, aryl sulfonyl fluoride 4 reacts with the N-Boc-L-lysine methyl ester to form the sulfonamide 5. Along the same lines, the halogenated tetramer 6 produced its corresponding sulfonyl fluoride 7 with good yield (Scheme 3b).
Shortly after, the group of Ball reported the synthesis of arylsulfonyl fluorides using aryl iodides as starting materials in conjunction with DABSO [30]. The reactions were carried out in the presence of Pd(OAc) 2 (0.05 equiv.)/CataCXium A (di-adamantylalkylphosphine or PAd 2 Bu) (0.08 equiv.) as a precatalyst, Et 3 N, and iPrOH at 75 • C for 16 h. In this method, Selectfluor was used for the formation of the desired product from the sulfinate. Regarding the scope, aryl iodides bearing both electron-withdrawing and donating groups were converted smoothly to their corresponding aryl sulfonyl fluorides, producing products in good to excellent yields (Scheme 4). The authors also demonstrated that aryl sulfonyl fluorides react with several nucleophiles yielding the corresponding sulfones in very good to excellent yields.

Sulfonyl Fluorides Synthesis from Arynes
The use of sulfuryl fluoride SO 2 F 2 for the synthesis of aryl sulfonyl fluorides was reported by the group of Kim [31]. They performed a multicomponent reaction (MCR) involving the in-situ generation of aryne precursors from (trimethylsilyl) phenyl trifluoromethanesulfonate, secondary amines and SO 2 F 2 . This methodology allows the straightforward synthesis of 2-dialkyl-, 2-alkylaryl-, or 2-diarylamino-substituted arylesulfonyl fluoride derivatives.
Depending on the substituents of the secondary amines, different reaction temperatures were used as shown in (Scheme 5). For instance, high yields were obtained with alkylarylamines with a reaction temperature of −10 • C (Scheme 5a). The o-dialkylamino substituted benzenesulfonyl fluorides were obtained in good yields when reactions involving dialkylamines were conducted at room temperature (25 • C) (Scheme 5b). Finally, reactions involving diarylamines were conducted at −30 • C and reduced yields were obtained due to the decreased activity at low temperatures (Scheme 5c). The authors proposed the following mechanism (Scheme 6): upon the generation of the aryne B with the fluoride anion, a nucleophilic attack of the amine leads to the intermediate C. The latter reacts with SO2F2 via hydrogen bonding with the ammonium intermediate (enhancing the electrophilic character of SO2F2) to finally produce the desired product E after the loss of HF. The authors proposed the following mechanism (Scheme 6): upon the generation of the aryne B with the fluoride anion, a nucleophilic attack of the amine leads to the intermediate C. The latter reacts with SO 2 F 2 via hydrogen bonding with the ammonium intermediate (enhancing the electrophilic character of SO 2 F 2 ) to finally produce the desired product E after the loss of HF.
The authors proposed the following mechanism (Scheme 6): upon the generation the aryne B with the fluoride anion, a nucleophilic attack of the amine leads to the int mediate C. The latter reacts with SO2F2 via hydrogen bonding with the ammonium int mediate (enhancing the electrophilic character of SO2F2) to finally produce the desir product E after the loss of HF. Scheme 6. Proposed mechanism for the multi-component fluorosulfurylation of arynes.

Sulfonyl Fluorides Synthesis from Grignard Reagents
By also using SO2F2, the groups of Sammis and Ball disclosed a new method for direct synthesis of sulfonyl fluorides by making use of alkyl, aryl and heteroaryl Grigna Scheme 6. Proposed mechanism for the multi-component fluorosulfurylation of arynes.

Sulfonyl Fluorides Synthesis from Grignard Reagents
By also using SO 2 F 2 , the groups of Sammis and Ball disclosed a new method for the direct synthesis of sulfonyl fluorides by making use of alkyl, aryl and heteroaryl Grignard reagents [32]. The reactions were performed in THF at room temperature and the desired compounds were obtained in moderate to good yields.
Regarding the scope of the fluorosulfurylation of substituted phenylmagnesium bromide reagents, substrates bearing halogen, including para-F or Cl, were effective in moderate to very good yields. Aryl magnesium bromides substituted with electron-donating groups were smoothly converted to the desired products, 10d and 10f-10h. The arylmagnesium bromide, substituted with two trifluoromethyl substituents 10i, is sluggish toward the transformation.
The authors have also proved that this protocol encompasses heteroaryl sulfonyl fluoride derivatives (Scheme 7b). Indeed, thiophene and thiazole, as well as pyridine derivatives, were converted to their corresponding products with moderate to good reaction outcomes.

Sulfonyl Fluorides Synthesis from Aryldiazonium Salts
Recently, the group of Liu and Chen disclosed a new copper-based method for converting a large series of aryldiazonium salts to arylsulfonyl fluorides in the presence of DABSO and KHF 2 [33].
The reactions were carried out in MeCN in the presence of catalytic amounts of CuCl 2 (20 mol%) and 6,6 -dimethyl-2,2 -dipyridyl (dmbp) (20 mol%) at room temperature. Aryldiazonium salts were converted to the desired arylsulfonyl fluoride analogues in good yields. Both electron rich and electron poor arenes were converted in moderate to good yields. Furthermore, quite a large number of functionalities were tolerated under the reaction conditions. Indeed, aryldiazonium salts bearing amide 12e, ester 12f and ketone 12i, as well as cyano 12j groups, were smoothly converted to their corresponding arylsulfonyl fluoride products. Additionally, the authors demonstrated that various heteroaryldiazonium salts could also be used under the reaction conditions (Scheme 8).
To further demonstrate the versatility of the methodology, product 12b was synthesized on the gram scale with a good reaction outcome.
The authors proposed two plausible mechanisms. On the one hand, aryldiazonium salt A easily generates the aryl radical through reduction by Cu(I) species via a single electron transfer (SET) process. The aryl radical is quickly trapped by SO 2 to produce the resulting relatively stabilized arylsulfonyl radical [ArSO 2 • ]. Afterwards, a Sandmeyer-type reaction occurs by transferring a chloride to the arylsulfonyl radical to form ArSO 2 Cl and regenerates the Cu(I). Finally, a fluorine/chlorine exchange takes place to generate the desired product B (Scheme 9, path A). groups were smoothly converted to the desired products, 10d and 10f-10h. The arylmagnesium bromide, substituted with two trifluoromethyl substituents 10i, is sluggish toward the transformation.
The authors have also proved that this protocol encompasses heteroaryl sulfonyl fluoride derivatives (Scheme 7b). Indeed, thiophene and thiazole, as well as pyridine derivatives, were converted to their corresponding products with moderate to good reaction outcomes. Scheme 7. Fluorosulfurylation using various Grignard reagents.

Sulfonyl Fluorides Synthesis from Aryldiazonium Salts
Recently, the group of Liu and Chen disclosed a new copper-based method for converting a large series of aryldiazonium salts to arylsulfonyl fluorides in the presence of DABSO and KHF2 [33].
The reactions were carried out in MeCN in the presence of catalytic amounts of CuCl2 (20 mol%) and 6,6′-dimethyl-2,2′-dipyridyl (dmbp) (20 mol%) at room temperature. Aryldiazonium salts were converted to the desired arylsulfonyl fluoride analogues in good yields. Both electron rich and electron poor arenes were converted in moderate to good yields. Furthermore, quite a large number of functionalities were tolerated under the reaction conditions. Indeed, aryldiazonium salts bearing amide 12e, ester 12f and ketone Scheme 7. Fluorosulfurylation using various Grignard reagents. 12i, as well as cyano 12j groups, were smoothly converted to their corresponding arylsulfonyl fluoride products. Additionally, the authors demonstrated that various heteroaryldiazonium salts could also be used under the reaction conditions (Scheme 8).
To further demonstrate the versatility of the methodology, product 12b was synthesized on the gram scale with a good reaction outcome. The authors proposed two plausible mechanisms. On the one hand, aryldiazonium salt A easily generates the aryl radical through reduction by Cu(I) species via a single electron transfer (SET) process. The aryl radical is quickly trapped by SO2 to produce the  More recently, Weng and co-workers reported a copper-free fluorosulfonylation of aryldiazonium salts using sodium metabisulfite as the source of sulfur dioxide and Selectfluor as the fluorinating agent [34]. The reaction was performed in MeOH at 70 °C. The aryldiazonium tetrafluoroborates bearing either electron-donating or withdrawing groups were obtained with good yields. Interestingly, this protocol was applied to diazonium salts derived from a neratinib (anticancer) intermediate, producing the corresponding sulfonyl fluorides 13k in a synthetically useful yield. Radical scavenger and radical clock experiment suggested the formation of aryl radical in this transformation as a key intermediate (Scheme 10). The latter reacts with sodium metabisulfite to form the sulfonyl radical. The desired compound is formed after reaction with Selectfluor. On the other hand, aryldiazonium salt A easily generates the aryl radical through activation with DABSO and is quickly trapped by SO 2 under the reaction conditions to produce the resulting relatively stabilized arylsulfonyl radical [ArSO2 • ], which can combine with the fluorine anion offered by KHF 2 to give the radical anion [ArSO 2 F −• ]. The radical anion could be responsible for the reduction of the aryldiazonium salt A through SET, generating a new aryl radical and the desired product B (Scheme 9, path B).
More recently, Weng and co-workers reported a copper-free fluorosulfonylation of aryldiazonium salts using sodium metabisulfite as the source of sulfur dioxide and Selectfluor as the fluorinating agent [34]. The reaction was performed in MeOH at 70 • C. The aryldiazonium tetrafluoroborates bearing either electron-donating or withdrawing groups were obtained with good yields. Interestingly, this protocol was applied to diazonium salts derived from a neratinib (anticancer) intermediate, producing the corresponding sulfonyl fluorides 13k in a synthetically useful yield. Radical scavenger and radical clock experiment suggested the formation of aryl radical in this transformation as a key intermediate (Scheme 10). The latter reacts with sodium metabisulfite to form the sulfonyl radical. The desired compound is formed after reaction with Selectfluor. A step further; the direct use of commercially available anilines as starting materials for the synthesis of arylsulfonyl fluorides has also been undertaken. The authors demonstrated that a one-pot two-step procedure could take place for the generation of the diazonium salt followed by the synthesis of the desired product with a moderate reaction outcome (Scheme 11). Very recently, we demonstrated that aryl sulfonyl fluorides could be obtained under visible-light metal-free procedures by using cyanoarenes as organophotocatalysts [35] [36][37][38][39][40]. Indeed, the association of diazonium salts with DABSO in the presence or not of an external fluoride source (KHF2) allows access to a wide variety of arylsulfonyl fluorides with moderate to very good yields (Scheme 12). The reactions were performed in MeCN as a solvent at room temperature under blue LED irradiation. Both electron withdrawing and electron donating groups were tolerated under the reaction conditions (15a-15d and 15i-15l). Interestingly, the reaction in the presence of halogen substituents gave the desired products in synthetically useful yields (15e-15h). To some extent, heterocyclic com-Scheme 10. Fluorosulfonylation of aryldiazonium salts.
A step further; the direct use of commercially available anilines as starting materials for the synthesis of arylsulfonyl fluorides has also been undertaken. The authors demonstrated that a one-pot two-step procedure could take place for the generation of the diazonium salt followed by the synthesis of the desired product with a moderate reaction outcome (Scheme 11).

Scheme 10. Fluorosulfonylation of aryldiazonium salts.
A step further; the direct use of commercially available anilines as starting materials for the synthesis of arylsulfonyl fluorides has also been undertaken. The authors demonstrated that a one-pot two-step procedure could take place for the generation of the diazonium salt followed by the synthesis of the desired product with a moderate reaction outcome (Scheme 11). Very recently, we demonstrated that aryl sulfonyl fluorides could be obtained under visible-light metal-free procedures by using cyanoarenes as organophotocatalysts [35] [36][37][38][39][40]. Indeed, the association of diazonium salts with DABSO in the presence or not of an external fluoride source (KHF2) allows access to a wide variety of arylsulfonyl fluorides with moderate to very good yields (Scheme 12). The reactions were performed in MeCN as a solvent at room temperature under blue LED irradiation. Both electron withdrawing and electron donating groups were tolerated under the reaction conditions (15a-15d and  15i-15l). Interestingly, the reaction in the presence of halogen substituents gave the desired products in synthetically useful yields (15e-15h). To some extent, heterocyclic com- Very recently, we demonstrated that aryl sulfonyl fluorides could be obtained under visible-light metal-free procedures by using cyanoarenes as organophotocatalysts [35][36][37][38][39][40]. Indeed, the association of diazonium salts with DABSO in the presence or not of an external fluoride source (KHF 2 ) allows access to a wide variety of arylsulfonyl fluorides with moderate to very good yields (Scheme 12). The reactions were performed in MeCN as a solvent at room temperature under blue LED irradiation. Both electron withdrawing and electron donating groups were tolerated under the reaction conditions (15a-15d  and 15i-15l). Interestingly, the reaction in the presence of halogen substituents gave the desired products in synthetically useful yields (15e-15h). To some extent, heterocyclic compounds 15m and 15n were also tolerated under this protocol. More interestingly, the complex molecular structure of the estrone derivative 15o was smoothly converted to the corresponding arylsulfonyl fluoride. In order to shed the light on the mechanism, several techniques were combined. Lu minescence quenching allows the confirmation of the reduction of the diazonium salt Quantum yield measurement allows the confirmation of the stepwise nature of the mech anism. Moreover, EPR spectroscopy confirmed the formation of aryl radical formed through single electron transfer from the exited photocatalyst to the diazonium salt, and the corresponding adduct was obtained with N-tert-butyl-α-phenylnitrone (PBN) as radical trapping agent. Performing the same reaction with DABSO also allows the confir mation of the presence of the ArSO2 radical and this adduct was also observed with PBN Finally, density functional theory (DFT) calculations allow us to confirm the presence of sulfonium intermediate formed through radical-radical coupling between ArSO2 radica and DABCO .+ generated through the reduction of PC .+ to regenerate the catalyst at it ground state (Scheme 13). In order to shed the light on the mechanism, several techniques were combined. Luminescence quenching allows the confirmation of the reduction of the diazonium salt. Quantum yield measurement allows the confirmation of the stepwise nature of the mechanism. Moreover, EPR spectroscopy confirmed the formation of aryl radical formed through single electron transfer from the exited photocatalyst to the diazonium salt, and the corresponding adduct was obtained with N-tert-butyl-α-phenylnitrone (PBN) as a radical trapping agent. Performing the same reaction with DABSO also allows the confirmation of the presence of the ArSO 2 radical and this adduct was also observed with PBN. Finally, density functional theory (DFT) calculations allow us to confirm the presence of a sulfonium intermediate formed through radical-radical coupling between ArSO 2 radical and DABCO .+ generated through the reduction of PC .+ to regenerate the catalyst at its ground state (Scheme 13).

Scheme 13.
Proposed mechanism for the visible-light synthesis of arysulfonyl fluorides.

Indirect Arylesulfonyl Fluoride Synthesis Reactions
In addition to direct synthetic strategies, indirect methodologies are an alternative for the synthesis of arylsulfonyl fluorides and are well described in the literature. They actually complete the toolbox, offering a variety of retrosynthetic options to access the desired compounds. Herein, indirect methodologies are outlined.

Sulfonyl Fluorides Synthesis from Arylsulfonyl Chlorides
The best known methodology makes use of arylsulfonyl chlorides as the starting materials [17,41,42]. In 1977, Bianchi and co-workers reported an easy and simple method for the synthesis of sulfonyl fluorides using 18-crown-6 ether and potassium fluoride. The reaction takes place at room temperature in the presence of the 18-crown-6 ether catalyst, sulfonyl chlorides and an excess of potassium fluoride in acetonitrile. Sulfonyl chlorides undergo fluorine substitution with excellent reaction outcomes (Scheme 14).

Indirect Arylesulfonyl Fluoride Synthesis Reactions
In addition to direct synthetic strategies, indirect methodologies are an alternative for the synthesis of arylsulfonyl fluorides and are well described in the literature. They actually complete the toolbox, offering a variety of retrosynthetic options to access the desired compounds. Herein, indirect methodologies are outlined.

Sulfonyl Fluorides Synthesis from Arylsulfonyl Chlorides
The best known methodology makes use of arylsulfonyl chlorides as the starting materials [17,41,42]. In 1977, Bianchi and co-workers reported an easy and simple method for the synthesis of sulfonyl fluorides using 18-crown-6 ether and potassium fluoride. The reaction takes place at room temperature in the presence of the 18-crown-6 ether catalyst, sulfonyl chlorides and an excess of potassium fluoride in acetonitrile. Sulfonyl chlorides undergo fluorine substitution with excellent reaction outcomes (Scheme 14).

Indirect Arylesulfonyl Fluoride Synthesis Reactions
In addition to direct synthetic strategies, indirect methodologies are an alternative for the synthesis of arylsulfonyl fluorides and are well described in the literature. They actually complete the toolbox, offering a variety of retrosynthetic options to access the desired compounds. Herein, indirect methodologies are outlined.

Sulfonyl Fluorides Synthesis from Arylsulfonyl Chlorides
The best known methodology makes use of arylsulfonyl chlorides as the starting materials [17,41,42]. In 1977, Bianchi and co-workers reported an easy and simple method for the synthesis of sulfonyl fluorides using 18-crown-6 ether and potassium fluoride. The reaction takes place at room temperature in the presence of the 18-crown-6 ether catalyst, sulfonyl chlorides and an excess of potassium fluoride in acetonitrile. Sulfonyl chlorides undergo fluorine substitution with excellent reaction outcomes (Scheme 14). Sharpless and co-workers also used sulfonyl chlorides as starting materials for the formation of sulfonyl fluorides derivatives [17]. The reactions were carried out in the presence of saturated aqueous solution of KFHF in acetonitrile, which produces a biphasic mixture (THF or CH 2 Cl 2 ) at room temperature.
A wide variety of electron-donating and electron-withdrawing functional groups gave the desired products in excellent yields. A large functional group tolerance was also observed, including carboxylic acid 17e, nitro 17b and cyano 17c groups. The presence of an unsaturated alkene is also tolerated 17f (Scheme 15). Sharpless and co-workers also used sulfonyl chlorides as starting materials for the formation of sulfonyl fluorides derivatives [17]. The reactions were carried out in the presence of saturated aqueous solution of KFHF in acetonitrile, which produces a biphasic mixture (THF or CH2Cl2) at room temperature.
A wide variety of electron-donating and electron-withdrawing functional groups gave the desired products in excellent yields. A large functional group tolerance was also observed, including carboxylic acid 17e, nitro 17b and cyano 17c groups. The presence of an unsaturated alkene is also tolerated 17f (Scheme 15). Scheme 15. Sulfonyl fluorides synthesis from sulfonyl chlorides.

Sulfonyl Fluorides Synthesis from Sulfonyl Hydrazides and Sodium Arylsulfinates
Tang and Wang have developed a simple and effective fluorination method using sulfonyl hydrazide in water without additives or catalysts to obtain sulfonyl fluorides in good to excellent yields [43]. Selecfluor was used as a fluorinating agent and the reactions were performed in water at 60 °C.
The reaction scope encompasses a large panel of starting materials including electron-donating and electron-withdrawing substituents with moderate to excellent reaction outcomes. Aliphatic substrates were also effective under the reaction conditions. The reaction was also scaled-up, 1.86 g of compound 18a was obtained in 88% yield (Scheme 16). Furthermore, the authors have shown that the use of sodium arylsulfinates as starting materials under the same reaction conditions is also effective for the formation of arylesulfonyl fluorides with similar yields to those obtained with sulfonyl hydrazides (Scheme 16).

Sulfonyl Fluorides Synthesis from Sulfonyl Hydrazides and Sodium Arylsulfinates
Tang and Wang have developed a simple and effective fluorination method using sulfonyl hydrazide in water without additives or catalysts to obtain sulfonyl fluorides in good to excellent yields [43]. Selecfluor was used as a fluorinating agent and the reactions were performed in water at 60 • C.
The reaction scope encompasses a large panel of starting materials including electrondonating and electron-withdrawing substituents with moderate to excellent reaction outcomes. Aliphatic substrates were also effective under the reaction conditions. The reaction was also scaled-up, 1.86 g of compound 18a was obtained in 88% yield (Scheme 16). Furthermore, the authors have shown that the use of sodium arylsulfinates as starting materials under the same reaction conditions is also effective for the formation of arylesulfonyl fluorides with similar yields to those obtained with sulfonyl hydrazides (Scheme 16).

Sulfonyl Fluorides Synthesis from Thiols and Disulfides
Hallstrom and Wright reported a new method using heteroaromatic thiols as a starting material for the synthesis of heteroaromatic sulfonyl fluorides [44]. Heteroaromatic thiols are oxidized with aqueous sodium hypochlorite to obtain the corresponding sulfonyl chlorides, then KHF 2 is added to perform a Cl-F exchange, forming the sulfonyl fluoride products.
The authors have shown that a wide variety of heteroaromatic thiols, even in the presence of electron-donating groups, are tolerated under these conditions, including pyrimidine 19a and 19c, pyridine 19b and pyridazine 19d (Scheme 17).

Sulfonyl Fluorides Synthesis from Thiols and Disulfides
Hallstrom and Wright reported a new method using heteroaromatic thiols as a starting material for the synthesis of heteroaromatic sulfonyl fluorides [44]. Heteroaromatic thiols are oxidized with aqueous sodium hypochlorite to obtain the corresponding sulfonyl chlorides, then KHF2 is added to perform a Cl-F exchange, forming the sulfonyl fluoride products.
The authors have shown that a wide variety of heteroaromatic thiols, even in the presence of electron-donating groups, are tolerated under these conditions, including pyrimidine 19a and 19c, pyridine 19b and pyridazine 19d (Scheme 17). Later, the group of Kirihara used disulfides as starting materials for the synthesis of arylsulfonyl fluorides. Selectfluor was used in high amounts (6.5 equiv.) as both the oxidant and the electrophilic source of fluorine [45].

Sulfonyl Fluorides Synthesis from Thiols and Disulfides
Hallstrom and Wright reported a new method using heteroaromatic thiols as a starting material for the synthesis of heteroaromatic sulfonyl fluorides [44]. Heteroaromatic thiols are oxidized with aqueous sodium hypochlorite to obtain the corresponding sulfonyl chlorides, then KHF2 is added to perform a Cl-F exchange, forming the sulfonyl fluoride products.
The authors have shown that a wide variety of heteroaromatic thiols, even in the presence of electron-donating groups, are tolerated under these conditions, including pyrimidine 19a and 19c, pyridine 19b and pyridazine 19d (Scheme 17). Later, the group of Kirihara used disulfides as starting materials for the synthesis of arylsulfonyl fluorides. Selectfluor was used in high amounts (6.5 equiv.) as both the oxidant and the electrophilic source of fluorine [45]. Later, the group of Kirihara used disulfides as starting materials for the synthesis of arylsulfonyl fluorides. Selectfluor was used in high amounts (6.5 equiv.) as both the oxidant and the electrophilic source of fluorine [45].
The reaction was performed in a refluxed mixture of MeCN-water (10:1). This reaction tolerates the presence of electron-donating groups and the desired products were formed in good to excellent yields (20a-20d). In contrast, electron-withdrawing disulfides were not tolerated (Scheme 18).
Recently, the group of Noël disclosed an electrochemical approach for the synthesis of sulfonyl fluorides [46]. This method makes use of thiols or disulfides as starting materials, with KF (5.0 equiv.) as the source of fluorine and supports electrolyte and pyridine (1.0 equiv.) at room temperature in a mixture of MeCN/HCl aq (1:1). The reagents were introduced into an undivided cell with a graphite anode and a stainless-steel cathode. The current was set at 20 mA, or constant voltage (3.2 V). The reaction was performed in a refluxed mixture of MeCN-water (10:1). This reaction tolerates the presence of electron-donating groups and the desired products were formed in good to excellent yields (20a-20d). In contrast, electron-withdrawing disulfides were not tolerated (Scheme 18). Recently, the group of Noël disclosed an electrochemical approach for the synthesis of sulfonyl fluorides [46]. This method makes use of thiols or disulfides as starting materials, with KF (5.0 equiv.) as the source of fluorine and supports electrolyte and pyridine (1.0 equiv.) at room temperature in a mixture of MeCN/HCl aq (1:1). The reagents were introduced into an undivided cell with a graphite anode and a stainless-steel cathode. The current was set at 20 mA, or constant voltage (3.2 V).
This electrochemical method tolerates substrates with electron-donating and withdrawing groups 21a-21g and halogen 21h-21i, as well as protected amines 21j. The desired compounds were obtained with moderate to excellent reaction outcomes. Furthermore, heterocyclic thiols were also successfully applied 21k-21l (Scheme 19). This electrochemical method tolerates substrates with electron-donating and withdrawing groups 21a-21g and halogen 21h-21i, as well as protected amines 21j. The desired compounds were obtained with moderate to excellent reaction outcomes. Furthermore, heterocyclic thiols were also successfully applied 21k-21l (Scheme 19).
were not tolerated (Scheme 18). Recently, the group of Noël disclosed an electrochemical approach for the synthesis of sulfonyl fluorides [46]. This method makes use of thiols or disulfides as starting materials, with KF (5.0 equiv.) as the source of fluorine and supports electrolyte and pyridine (1.0 equiv.) at room temperature in a mixture of MeCN/HCl aq (1:1). The reagents were introduced into an undivided cell with a graphite anode and a stainless-steel cathode. The current was set at 20 mA, or constant voltage (3.2 V).
This electrochemical method tolerates substrates with electron-donating and withdrawing groups 21a-21g and halogen 21h-21i, as well as protected amines 21j. The desired compounds were obtained with moderate to excellent reaction outcomes. Furthermore, heterocyclic thiols were also successfully applied 21k-21l (Scheme 19). Several versatile organic reactions were performed thanks to electrochemical transformations, which are known for their powerful mode of activation [47][48][49]. This electrochemical method allows the oxidization of thiols and disulfides without the addition of external oxidants, which makes this chemistry more in line with the current environmental concerns. Compared to conventional thermal methods, the parameters of the electrochemical approach can be easily adjusted [47,50,51]. This methodology is able to overcome certain challenges, allowing this transformation to take place. These challenges include the low solubility of potassium fluoride in organic solvents and the difficulty of forming the S-F bond by combining a nucleophilic fluorinated reagent with thiols [52][53][54]. Pyridine plays the role of both electron mediator and of a phase-transfer catalyst to transfer fluorine to the organic phase.
Various experiments have been carried out to obtain information about the reaction mechanism. In particular, kinetic experiments have revealed a rapid conversion of thiols into disulfides, and the addition of radical scavengers confirms the presence of radical intermediates.
In the presence of hydrochloric acid and pyridine, the KF is transferred into the organic phase to react with the disulfides obtained from the oxidation of thiols through the single electron transfer (SET) process. Then, after two consecutive oxidation steps, the desired sulfonyl fluorides are formed (Scheme 20). tal concerns. Compared to conventional thermal methods, the parameters of the electrochemical approach can be easily adjusted [47,50,51]. This methodology is able to overcome certain challenges, allowing this transformation to take place. These challenges include the low solubility of potassium fluoride in organic solvents and the difficulty of forming the S-F bond by combining a nucleophilic fluorinated reagent with thiols [52][53][54]. Pyridine plays the role of both electron mediator and of a phase-transfer catalyst to transfer fluorine to the organic phase.
Various experiments have been carried out to obtain information about the reaction mechanism. In particular, kinetic experiments have revealed a rapid conversion of thiols into disulfides, and the addition of radical scavengers confirms the presence of radical intermediates.
In the presence of hydrochloric acid and pyridine, the KF is transferred into the organic phase to react with the disulfides obtained from the oxidation of thiols through the single electron transfer (SET) process. Then, after two consecutive oxidation steps, the desired sulfonyl fluorides are formed (Scheme 20). Scheme 20. Proposed mechanism for the electrochemical formation of sulfonyl fluorides from thiols or disulfides.

Sulfonyl Fluorides Synthesis from Sulfonates and Sulfonic Acids
Recently, the group of Qin and Sun used sulfonic acids and sulfonates as starting substrates to synthesize sulfonyl fluorides in a one-pot two-step procedure [55]. This method makes use of cyanuric chloride, as a source of chlorine, and KHF 2, as a source of fluorine. This method is based on the formation of sulfonyl chlorides using cyanuric chloride in the presence of 5 mol% of a catalyst (Tetrabutylammonium bromide TBAB or tetramethylammonium chloride TMAC) at 60 • C in acetonitrile. Then, KHF 2 is added to exchange chlorine with fluorine and form the sulfonyl fluoride products.

Sulfonyl Fluorides Synthesis from Sulfonamides
Very recently, the group of Cornella reported a direct method for the synthesis of sulfonyl fluorides from sulfonamides [56]. The method consists of forming sulfonyl chlorides from sulfonamides through activation with a pyrylium tetrafluoroborate (Pyry-BF4) and MgCl2, and the subsequent in-situ conversion to sulfonyl fluorides by the addition of KF. The reactions were performed in MeCN at 60 °C and the desired compounds were obtained with moderate to very good yields. The high chemoselectivity of Pyry-BF4 towards amino groups allows the formation of sulfonyl fluorides in complex structures. To test the effectiveness of this protocol, the authors examined a series of sulfonates containing several cations (Scheme 21b). The monovalent sulfonate salts Y3a-Y3d were easily converted to the corresponding sulfonyl fluorides with moderate to good yields. However, the sulfonate salts of the divalent metals Y3e-Y3g reacted only slightly, resulting in poor yields. To widen the range of the substrates, they started from sulfonic acids as starting reagents using TMAC as catalyst instead of TBAB. A series of aryl sulfonic acids carrying electron-donating groups (23b and 23c) were obtained with moderate to good yields. Naphthalene-2-sulfonyl fluoride was also obtained with a good yield 23d (Scheme 21c).

Sulfonyl Fluorides Synthesis from Sulfonamides
Very recently, the group of Cornella reported a direct method for the synthesis of sulfonyl fluorides from sulfonamides [56]. The method consists of forming sulfonyl chlorides from sulfonamides through activation with a pyrylium tetrafluoroborate (Pyry-BF 4 ) and MgCl 2 , and the subsequent in-situ conversion to sulfonyl fluorides by the addition of KF. The reactions were performed in MeCN at 60 • C and the desired compounds were obtained with moderate to very good yields. The high chemoselectivity of Pyry-BF 4 towards amino groups allows the formation of sulfonyl fluorides in complex structures. This was proven by examining a wide variety of complex sulfonamides containing various functionalities (Scheme 22).

Conclusions
Arylsulfonyl fluorides are attracting considerable attention in modern organic chemistry due to their wide range of applications. Thus, developing new synthetic strategies

Conclusions
Arylsulfonyl fluorides are attracting considerable attention in modern organic chemistry due to their wide range of applications. Thus, developing new synthetic strategies towards the incorporation of the sulfonyl fluoride moiety is of high interest. We have described herein the existing methods to access fluorosulfonylated compounds using either direct or indirect methodologies. These various works offer different and versatile approaches to form such compounds, tolerating a large variety of functional groups. The easy access to the starting material/catalysts of the developed methodology will definitely foster the emergence of new applications.