Exploration of fluorination reagents starting from FITS reagents

Journal of Fluorine Chemistry 167 (2014) 3–15

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Exploration of fluorination reagents starting from FITS reagents Teruo Umemoto * R&D Center, Zhejiang Jiuzhou Pharmaceutical Co., Ltd., Waisha Road 99, Jiaojiang, Taizhou City, Zhejiang Province 318000, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 June 2014 Received in revised form 23 July 2014 Accepted 28 July 2014 Available online 5 August 2014

There was lack of fluorination reagents around 1978 when the author started his fluorine research. This account presents the author’s ideas and development of many reagents which include (perfluoroalkyl)phenyliodonium triflates (FITS reagent) and sulfates (FIS), (1,1-dihydroperfluoroalkyl)phenyliodonium triflates (FMITS), N-trifluoromethyl-N-nitroso-benzene- and -trifluoromethane-sulfonamide (TNS-B and -Tf), N-fluoropyridinium salt series (F-PlusTM), N-fluoropyridinium-2-sulfonate series, N,N0 -difluoro-2,20 -bipyridinium salt series (MEC-31, SynFluorTM), N,N0 -difluoro-1,4-diazoniabicyclo[2.2.2]octane salts, S-, Se-, and Te-(trifluoromethyl)dibenzo-thio-, -seleno-, and -tellurophenium salts and their 3-sulfonate series, O-(trifluoromethyl)dibenzofuranium salts and their precursors, 4-tertbutyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEADTM), and arylsulfur chlorotetrafluorides. These reagents have made new areas and significant advancement in fluorine chemistry. The incidental fruits are also described, which include discoveries of new cyclic carbene reactions of N-fluoropyridinium salts and the first practical industrial method for production of arylsulfur pentafluorides. Application of Nfluoropyridinium salts to electronic materials is briefly mentioned. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Fluorinating agent Fluorination Trifluoromethylating agent Trifluoromethylation Perfluoroalkylating agent N-Fluoropyridinium salt

1. Introduction Fluorine has the highest electronegativity and makes a much stronger C–F bond (484 kJ/mol) than that (411 kJ/mol) of a C–H bond. Unlike other halogens, a fluorine atom can replace any hydrogen atom of an organic molecule since a fluorine atom has the smallest Van der Waals radius (1.35 A˚) after a hydrogen atom (1.1 A˚). Replacement of hydrogen with fluorine in an organic molecule can bring about a remarkable change in the physical, chemical, and biochemical properties of the original molecule. Till now, a large number of useful fluorinated compounds have been developed in many different fields such as pharmaceuticals, agrochemicals, polymers, dyes, solvents, liquid crystals, and others [1–9]. When the author searched something in a library sometime around 1976, it happened that the author met a paper which described an abnormal molecule CF3OOOCF3. As such a hydrocarbon compound never existed as a stable molecule, the author then kindled his interest in fluorine chemistry as a new and prospective field. When the author started fluorine chemistry in 1978, the number of chemists who had an interest in fluorine chemistry was rather limited. The barrier was great difficulty in preparing

* Tel.: +86 576 88827180. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jfluchem.2014.07.029 0022-1139/ß 2014 Elsevier B.V. All rights reserved.

fluorinated compounds. As organofluoro compounds are rare in nature [10], man-made fluorination processes are necessary. At that time, the reagents for preparation of organofluoro compounds were limited and many of them were hard to handle because of extremely toxic and explosive nature. Thus, there was significant lack of easy-to-handle fluorination reagents that were reactive and selective. Useful bioactive fluorinated compounds could roughly be classified to two groups, monofluoro and difluoro compounds and trifluoromethyl group-containing compounds from a standpoint of synthetic methodology. Mono- and di-fluoro compounds could be placed in the same group because the same fluorination method may be applied. Therefore, the author noticed the importance of fluorinating agents and trifluoromethylating agents and believed that the development of these useful reagents would be a key for the prospective advancement of fluorine chemistry. In this account, the author’s ideas and development of his reagents are described chronologically.

2. Development of electrophilic perfluoroalkylating and dihydroperfluoroalkylating agents As mentioned above, the author noticed the importance of two kinds of reagents, fluorinating agents and trifluoromethylating agents. He thought that the former should be derived from molecular fluorine (F2) because he thought that the organofluorine

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chemistry starting from F2 would be developed as another prospective field in future, whereas fluorine chemistry based on Cl2 industry had been developed as seen in fluoropolymer and Freon industry [11]. Therefore, the author thought to make them by using F2. However, at that time, he had no experience of fluorine chemistry, all the more, of treating dangerous F2. Therefore, the author started on the research for trifluoromethylating agents in 1978. 2.1. (Perfluoroalkyl)phenyliodonium trifluoromethanesulfonates and sulfates (FITS and FIS reagents) There are three basic methods for perfluoroalkylation including trifluoromethylation as shown below. All the three methods are essential for the development of synthetic chemistry. However, at that time, there were no reports on the third, electrophilic perfluoroalkylation. Perfluoroalkylation methodologies (Rf = CnF2n+1) 1. Nucleophilic method: Rf + C+ ! Rf–C 2. Free radical method: Rf + C ! Rf–C 3. Electrophilic method: Rf+ + CS ! Rf–C Electrophilic perfluoroalkylation was extremely difficult compared to electrophilic alkylation in hydrocarbon chemistry, because electronegativity of Rf (CF3, 3.45) is much higher than that of alkyl (R) (CH3, 2.28), and higher than those of iodine (2.5), bromine (2.8), and chlorine atom (3.0). Whereas the electrophilic alkylation easily occurs in the reaction of R–X (X = I, Br, Cl) with a nucleophile, the electrophilic perfluoroalkylation never do in a d d similar manner because the polarization of Rf -I + is opposite to d+ d R -I . Even trifluoromethyl triflate (CF3-OTf), which is a combination with an OTf group (Tf = SO2CF3), one of the strongest leaving group, could not undergo electrophilic perfluoroalkylation [12]. Nucleophiles did not attack its CF3, but the sulfur atom. This meant the Rf–O bond is very strong. From these information, the author realized that a new type of reagents must be needed for electrophilic perfluoroalkylation and thought a Rf-Y-X type of compounds (Y = an eliminable heteroatom, X = a leaving group) to be an eligible candidate for it.

According to literature, Rf-I(p-tolyl)-Cl was synthesized in 1971 by Yagupolskii et al. [13]. However, its reactivity was not examined. The author prepared it and found that it reacted with PhCH2MgCl to give PhCH2Rf, but not with n-C8H17MgCl. It had no reactivity toward substrates such as unsaturated compounds of double and triple bonds. Just after that, a paper by Yagupolskii et al. appeared, which reported perfluoroalkylations of ArSNa, ArSeNa, N,N-dimethylaniline etc. with RfI(p-Tolyl)Cl, but that of N,Ndimethylaniline was of low yield [14]. Thus, the author designed Rf-Y-OTf for the reactive perfluoroalkylation and found that 2 readily reacted with benzene in the presence of triflic acid (TfOH) (1 eq) at room temperature to give stable 3 (R = H) (Rf = CmF2m+1, m  2) in high yields, called FITS-m reagents (Scheme 1). FITS-m having a different carbon chain (m = 2–10) were synthesized, but unfortunately FITS-1 was failed. The use of fluorobenzene gave 3 (R = F), FITS(F)-m reagents, which were more stable crystalline compounds. In contrast, 3 (R = Me, m = 3) was an unstable crystalline material, which decomposed for the large part within a day at ambient temperature. The use of sulfuric acid instead of triflic acid provided a series of (perfluoroalkyl)aryliodonium sulfates 4 [R = H and R = F], FIS-

Scheme 1. Synthesis of FITS and FITS(F) reagents.

Scheme 2. Synthesis of FIS and FIS(F)-m reagents.

m and FIS(F)-m reagents (Scheme 2), which are economical [15,16]. FITS were easy-to-handle stable crystalline materials, which were highly reactive Rf+ agents toward carbanions [17,18], aromatics [19], alkenes [20], alkadienes [20], alkynes [21], trimethylsilyl enol ethers [22], and thiols [23]. FITS reacted with Grignard reagents to give perfluoroalkyl compounds. With bdiketones and b-keto esters, C-Rf and O-Rf compounds were produced. The C/O ratio varied on the reaction temperature. With bulky phenols, O- and C-perfluoroalkylation occurred [24]. FITS undertook a substitution reaction or an addition reaction of Rf+ with a nucleophile on an alkene and alkadiene to give a substitution or addition product [20]. By means of these, many kinds of functionalized Rf compounds were prepared by a onestep. The economical FIS was also stable, but it had slightly less reactivity than FITS because of low solubility. Thus, FITS and FIS opened a new field of electrophilic perfluoroalkylation in fluorine chemistry. In addition, FITS and FIS undertook oxy-perfluoroalkylation with alkenes, alkadienes, and alkyl enol ethers in the presence of molecular oxygen to give b-Rf carbonyl or g-Rf-a, b-unsaturated carbonyl compounds [25]. Trifluoromethyl compounds were derived from Rf products prepared by FITS-2 and -3i [26]. FITS reagents are commercially available. (Perfluoroalkylene)bis(phenyliodonium triflates) (double-FITS reagents) were developed as the bifunctional reagents (Fig. 1) [27]. Polymer-supported FITS reagents were also developed [28]. NafionTM was used as a supporting polymer. Yagupolskii et al. reported the synthesis of (perfluoroalkyl)phenyliodonium tetrafluoroborates and the reactions with sodium nitrite, potassium thiocyanate, and N,N-dimethylaniline [29,30]. They also reported (perfluoroalkylene)bis(phenyliodonium tetrafluoroborates) and the reaction with sodium p-chlorothiophenoxide [31].

Fig. 1. Chemical structure of double-FITS and polymer-supported FITS reagents.

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Scheme 3. Synthesis of FMITS and FMITS(F) reagents.

2.2. (1,1-Dihydroperfluoroalkyl)phenyliodonium trifluoromethanesulfonates (FMITS reagents) [32] Electrophilic 1,1-dihydroperfluoroalkylation was also difficult to achieve, because RfCH2 group still remains highly electronegative. The reactivity of halides (RfCH2X) was low toward nucleophilies, and that of the analogous derivatives such as tosylates and triflates (RfCH2OTf) was still low. Next, we developed (1,1dihydroperfluoroalkyl)phenyliodonium triflates (FMITS-m, m  1) and p-fluoro derivatives [FMITS(F)-m, m  1] in a similar way as FITS and FITS(F) reagents (Scheme 3). A double-FMITS reagent was also prepared in a similar way as double-FITS reagents [33,34]. FMITS were highly reactive RfCH2+ reagents toward nucleophiles [35–37]. FMITS-1 [CF3CH2-I(Ph)-OTf] reacted with O, N, S, and P-nucleophiles such as amines, alcohols, carboxylic acids, thiols, sulfides, and phosphines to produce the corresponding CF3CH2 compounds in high yields. Aniline was treated with 2 eq or more FMITS-1 (a base, CH2Cl2, rt, 2 h), giving PhN(CH2CF3)2 in high yield. This mild bistrifluoroethylation was a good example to show the high reactivity of FMITS reagents. C-nucleophilies such as Grignard reagents, active methylene compounds, trimethylsilyl enol ethers, and heterocycles such as furan were also 1,1-dihydroperfluoroalkylated with FMITS. There was some difference between FMITS and FITS. For example, FMITS reacted with N,N-dimethylaniline to give N-RfCH2 product, while FITS produced ortho- and para-C-Rf products. Treatment of FMITS-2, 3, and 7 with sodium hydride afforded interesting (1H-perfluoro-1-alkenyl)aryliodonium triflates [34]. Yagupolskii et al. [38] reported the synthesis of (a, a, vtrihydroperfluoroalkyl)phenyliodonium tetrafluoroborates and a, a, v-trihydroperfluoroalkylation of some substrates with them. They failed in synthesizing (2,2,2-trifluoroethyl)phenyliodonium tetrafluoroborate [38]. 3. Development of N-trifluoromethyl-N-nitroso sulfonamides as trifluoromethylating agents 3.1. N-Trifluoromethyl-N-nitrosobenzenesulfonamide (TNS-B) Unfortunately, we failed to synthesize the trifluoromethyl analog (FITS-1) because of the abnormality of CF3 group. However, the author’s idea of Rf-Y-X mentioned above worked well except for CF3 because FITS reagents (Rf  2) were demonstrated to be

very reactive Rf+ reagents. Therefore, we intended to synthesize another new type of CF3 compounds having –N5 5N– as Y, which may be eliminable as N2 gas. Given a hint from a report by Makarov et al. [39], we planned to synthesize 9 (R = Ar) by the reaction of ArSO2Cl with 8, which might be formed from CF3NO and hydroxylamine (Scheme 4). To do this, firstly we improved the preparative method for CF3NO [40] and then we tried the synthesis of 9 (R = Ph). Instead, we isolated N-trifluoromethyl-N-nitrosobenzenesulfonamide 10a (TNS-B) as a stable crystalline compound in 57% yield (Scheme 5) [41]. We then found that TNS-B worked as a new photochemical trifluoromethylating agent for activated aromatics, heteraromatics such as pyrrole, and disulfides [41]. However, TNS-B was too thermally stable to act as a thermal reagent. In order to enhance the reactivity, we synthesized mononitro and dinitro derivatives 10b, 10c and others [42,43]. However, their reactivity was rather low. 3.2. N-Trifluromethyl-N-nitrosotrifluoromethanesulfonamide (TNS-Tf) We then planned to replace an aryl group with a perfluoroalkyl group that is strongly electronegative. We synthesized Ntrifluoromethyl-N-nitroso-n-nonafluorobutanesulfonamide (10d, TNS-Nf) (Scheme 6) and found 10d was photochemically and thermally reactive, but, unexpectedly and surprisingly, the products were both trifluoromethylated and perfluorobutylated compounds. Finally we prepared N-trifluoromethyl-N-nitrosotrifluoromethanesulfonamide (10e, TNS-Tf) using CF3SO2F in 58% yield [44]. TNS-Tf was a very effective trifluoromethylating agent photochemically and thermally because the two CF3 groups in a molecule were usable for trifluoromethylation. TNS-Tf reacted with substrates such as aromatics, thiols, disulfides, and uridines to produce the corresponding trifluoromethyl compounds in good yields. In addition, TNS-Tf reacted with copper powder (2 eq mol) with evolution of a gas in a polar solvent at room temperature, giving an almost homogeneous brown solution of CF3–Cu complex, with which 1-iodonaphthalene was treated at 100 8C to give 1-CF3naphthalene in a high yield. This was the first example that CF3Cu complex was generated at room temperature. This applied to other iodoarenes to give the corresponding CF3-arenes in high yields.

Scheme 4. Possible route for the synthesis of CF3–N5 5N-OSO2R.

Scheme 5. Synthesis of TNS-B reagents 10a.

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Scheme 6. Synthesis of TNS-Nf and -Tf reagents.

Scheme 7. Trifluoromethylation mechanism of TNS-Tf reagent.

We measured a mass spectrum of the gas evolved from the photoreaction of TNS-Tf with p-tert-butylphenol. Surprisingly again, nitrogen (N2) and C2F6 were detected, but not N2O. This strongly suggested the trifluoromethylation occurred through the isomerization to the azo compound 9 (R = CF3) that we expected at the beginning, followed by generation of two CF3 free radicals by homolytic cleavage (Scheme 7) [44]. Regrettably, the author’s idea of 9 did not work for the generation of CF3+ because 9 did not decompose by heterolytic cleavage of the bonds like 9 (R = CF3) ! ‘‘CF3+’’ + N2 " + OTf, but rather underwent homolytic decomposition. Unfortunately TNS-Tf (mp 3.2–4 8C) could not be stored at room temperature because of decomposition. As it was stored in acetonitrile for a long time, it was easily and safely treated as an acetonitrile solution (1–0.5 mol/L). Reaction of arenesulfonamides with CF3NO provided trifluoromethylazosulfonylarenes, ArSO2–N5 5N–CF3, in high yields, which were shown to become trifluoromethylating agents toward arenes and disulfides thermally and photochemically [45]. However, its effectiveness was low. In addition, we found that reaction of CF3NO with arenesulfonohydrazides produced N-trifluoromethyl-N-hydroxyarenesulfonamides in high yields [46]. 4. Development of electrophilic fluorinating agents During the development of perfluoroalkylating and trifluoromethylating agents above, we obtained knowledge and information necessary for using dangerous F2 safely and then made a fluorination reactor using F2 in our lab. 4.1. N-Fluoropyridinium salts Extremely reactive, explosive, and toxic molecular fluorine (F2) was of very limited use for the selective fluorination of organic compounds. Therefore, fluorinating agents such as CF3OF [47], FClO3 [48], CF3COOF [49], CH3COOF [50], XeF2 [51], and CsSO4F [52] were used as fluorinating agents in those days. However, they were still explosive, toxic, unstable or extremely hygroscopic materials which required special equipment and techniques. On the other hand, N-fluorosulfonamides [53] and N-fluoropyridone [54] had been developed as stable fluorinating agents. However, they had narrow application because of their low reactivity. Thus, the reactive fluorinating reagents were difficult to handle, while the stable fluorinating reagents had poor application. We had an interest in an unstable and very hygroscopic pyridine-F2 adduct whose structure was not clear. The adduct decomposes violently at more than 2 8C. It was suggested that the adduct had an ionic structure [py-F2] ! [py-F]+F [55,56]. The author thought that the instability of the adduct might be due to

some nucleophilicity of F in the polar structure and might be improved by exchanging F for a non-nucleophilic anion such as CF3SO3 (OTf). We prepared the pyridine-F2 adduct by the reaction of pyridine with F2/N2 (1:9) in CFCl3 at 75 8C and then treated it with NaOTf in acetonitrile at 40 8C (Scheme 8, Method I). Surprisingly, we obtained very stable and non-hygroscopic crystalline solid (mp 185–187 8C), which was completely identified to be N-fluoropyridinium triflate 16 (R1–5 = H, X = OTf) by spectral and elemental analysis [57,58]. This was also featured as the first 1:1 salt of pyridine nucleus and halonium ion [57]. The other halogens (Z = Cl, Br, and I) form a stable 2:1 halonium salt [py-Z-py]+. This success opened a new chemistry, N-fluoropyridinium salt. We found many ways for the synthesis of N-fluoropyridinium salts (Scheme 8, Methods I–VIII). By means of these, we synthesized many kinds of stable N-fluoropyridinium salts possessing different counteranions and different electron-donating and -withdrawing substituents at a, b, and g positions on the pyridine ring. The counteranions (X) were X = OTf, FSO3, MeSO3, CCl3SO3, n-C4F9SO3, CamphSO3, BF4, PF6, AsF6, SbF6, and ClO4. The substituents were F, Cl, Me, CF3, tert-Bu, CH2OMe, CH2OAc, CH2OCOPh, CH2F, –(CH2)4, OAc, OMenth, Ph, COOMe, COOEt, COMe, CN, and NO2 [57–59]. N–F 19F chemical shifts of N-fluoropyridinium salts were independent of the counteranions, supporting the completely ionic structure. The 19F shifts of b- and g-substituted Nfluoropyridinium salts were correlated to pKa values of the corresponding pyridines, respectively. However, the 19F shifts of a-substituted N-fluoro salts except for alkyl-substituted ones showed abnormal up-field shifts, regardless of the pKa [60]. Extensive studies on the fluorination reactivity of various Nfluoropyridinium salts showed that the electrophilic fluorinating power of N-fluoropyridinium salts changed greatly with the electron density of the N+-F site, which correlated to the electronic nature of the ring substituents. Electron-withdrawing substituents increased the fluorinating power, while electron-donating substituents decreased the power. It clearly correlated the pKa of the corresponding original pyridines. The variation in power made possible the fluorination of a wide range of nucleophilic substrates differing in reactivity by using N-fluoropyridinium salt of suitable power. A powerful N-fluoropyridinium salt fluorinated a less reactive nucleophile well, while a less powerful salt satisfactorily did a reactive nucleophile. We called N-fluoropyridinium salts as power-variable electrophilic fluorinating agents. By means of this methodology, the N-fluropyridinium salts fluorinated aromatics, carbanions, active methylene compounds, enol alkyl and silyl enol ethers, vinyl acetates, ketene silyl acetals, olefins, and sulfides [61– 64]. It was a revolutionary thing that all these fluorinations were carried out in a glassware reactor without any special equipment and techniques.

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Scheme 8. Synthetic methods for N-fluoropyridinum salts.

We actually selected a series of N-fluoropyridinium salts 16a, b, c, d, and e (Fig. 2) whose fluorinating power increased in the order of 16a < 16b < 16c < 16d < 16e. In this series, 16a was the least powerful, while 16e was the most powerful. It was remarkable that 16e was more powerful than N,N0 -difluoro-1,4diazoniabicyclo[2.2.2]octane bis(BF4) in the fluorination of styrene (see Section 4.5 below). It was understandable from the fact that the pKa of pentachloropyridine is much lower than pK a1 (3.0) of triethylenediamine, considering pKa of 2-chloropyridine is 0.5. N-Fluoropyridinium salt reagents are commercially available, which are produced as F-PlusTM T and B series reagents. The author proposed a single electron transfer mechanism as the fluorination mechanism [63]. The power of fluorination may be very important factor in the electrophilic fluorination, where the two reactions, fluorination and oxidation, are competing with each other. There should be a suitable match for the fluorination between the power of N-fluoropyridinum salt and substrate’s nucleophilicity. This could suggest a reaction concept beyond the conventional organic electronic theory (two electron-transfer mechanism) because F+ could not exist as an actual reactive species in the standard organic solvent conditions because of extremely high ionization energy, being quite different from other

halogens. By other research groups, the N–F fluorination power was discussed with oxidation potential measurement [65–67]. 4.2. Base-initiated carbene reactions of N-fluoropyridinium salts and other applications During the studies on the reactivity of N-fluoropyridinium salts, we unexpectedly found very unusual reactions, base-initiated reactions of N-fluoropyridinium salts, which was a discovery of a new type of reaction in pyridine chemistry. We proposed a novel cyclic carbene 18 as a reactive species, which provided unique products [68–70]. Ab initio MO calculations revealed the structure and properties of the labile deprotonated N-fluoropyridinium cation and supported the carbene mechanism rather than a pyridynium or pyridyl cation mechanism [69]. It was suggested that some known reactions might be explained by the new carbene mechanism. As shown in Scheme 9, it was successfully applied for the preparation of 2-fluoropyridines 19 from N-fluoropyridinium tetrafluoroborates 17 [71]. The carbene reaction was further developed for the preparation of condensed heterocycles by Kiselyov [72]. Our experience obtained in the fluorination of pyridines with F2 made us try to do direct fluorination of some organic compounds.

Fig. 2. Power-variable electrophilic fluorinating agents; power order 16a < I6b < I6c < 16d < 16e.

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Some of N-fluoropyridinium-2-sulfonates are commercially available. 4.4. N,N0 -Difluoro-bipyridinium salts

Scheme 9. Preparation of 2-fluoropyridines by base-initiated carbene reaction of Nfluoropyridinium tetrafluorobrates.

Thus, we developed a direct fluorination technology in solvent, useful to fluorinate active methylene compounds with F2 [73]. The author thought that the power-variable N-fluoropyridinum salts should have useful application in electronic material field such as battery. The author et al. showed that N-fluoropyridinium salts worked as a positive material of lithium battery [74,75]. This revealed unique electron-conducting property of solid and liquid N-fluoropyridinium salts. A new photo-etching of silicon with liquid N-fluoropyridinium salts reported later by Morita et al. is particularly interesting, which can markedly reduce the number of processes in lithography [76]. Its technology was further applied to make Si surface textures for solar cells by the same group [77]. There have been reported many synthetic applications with the N-fluoropyridinium salts by other groups. Among them, some significant applications were reported in the organometal chemistry. Sanford and Yu reported the first palladium-metal-catalyzed aromatic fluorinations with N-fluoropyridinium salts [78,79]. Sanford treated a trifluoromethyl-Pd-complex with N-fluoro-2,4,6trimethylpyridinium salt to give a trifluoromethyl-coupling compound through reduction elimination from palladium(IV) [80]. 4.3. N-Fluoropyridinium-2-sulfonates We found that structural variation by ring substituents and counteranion parts greatly reflected selectivity in fluorination [63,81]. Based on this, we developed another series of powervariable N-fluoropyridinium salts, counteranion-bound N-fluoropyridinium salts 20a–e (Fig. 3) as highly selective, electrophilic fluorinating agents [81]. The fluorinating power increased in the order of 20a < 20b < 20c < 20d < 20e. We showed many examples for selective fluorination with 20a–e. As a typical example, reaction of 20e with phenol at room temperature almost exclusively produced o-fluorophenol in high yield (selectivity, o/p = 84/1). It was explained by the intermediate p-complex 21 in which there is a hydrogen-bonding interaction between the SO3 and the OH group (Scheme 10).

The N-fluoropyridinium salt reagents of wide fluorinating power were developed by our two significant findings, (1) replacement of a counteranion F with a non-nucleophilic anion provides remarkably stable and non-hygroscopic salts and (2) fluorination power is greatly variable depending on electron density of N-F site. Thereafter, based on these findings, some other reactive and easy-to-handle N-fluoro fluorinating agents such as Nchloromethyl-N0 -fluoro-1,4-diazoniabicylco[2,2,2]octane bis(BF4) (SelectFluorTM) (MW 354) [82] and N-fluoro-N0 -hydroxy-1,4diazoniabicyclo[2,2,2]octane bis(BF4) (AccuFluorTM) (MW 322) [83] were developed by other groups. However, these reactive fluorinating agents have low effective fluorine content (54–59 g/kg). We designed and synthesized a series of N-fluoropyridinium salt dimers 22 for reactive reagents of high fluorine content [84] [Fig. 4]. These N,N0 -difluoro-bipyridinium salts 22 were stable, non-hygroscopic salts. These dimeric salts were more powerful than the monomeric N-fluoropyridinium salt and their power increased in the order of 4,40 (22a)  3,30 (22b) < 2,40 (22c)  2,20 isomer (22d). This clearly correlated to the pKa of the original bipyridines. The two fluorine atoms in 22 were effective for the fluorination. The fluorination occurred in a step-by-step manner and the reactivity difference between the first and second fluorination was very small. N,N0 -Difluoro-2,20 -bipyridinium bis(tetrafluoroborate) 22d (X = BF4) was thus shown to be the most powerful and easy-tohandle electrophilic fluorinating agent with high fluorine content (103.3 g/kg). It was demonstrated that 22d was useful for fluorination of many kinds of substrates [84]. 22d called as MEC-31 or SynFluorTM has been commercially available. 4.5. N,N0 -Difluoro-1,4-diazoniabicyclo[2,2,2]octane salts Banks et al. [82] reported that attempt to synthesize N,N0 difluoro-1,4-diazoniabicylco[2.2.2]octane salts failed. Later they synthesized them, but they failed to synthesize the pure compounds [85]. Independently, we succeeded in the synthesis of the pure salts that were stable [86]. Our studies revealed that direct fluorination reaction of 1,4-diazabicyclo[2.2.2]octane (23) was sensitive to the nature and amount of the acid used. Finally we found a one-pot method for the preparation of the pure bis(BF4) salt 25, using cheap sulfuric acid and BF3 etherate (Scheme 11). The isolation was a very

Fig. 3. N-Fluoropyridinium-2-sulfonates series; power-order 20a < 20b < 20c < 20d < 20e.

Scheme 10. Selective fluorination with N-fluoro-4,6-bis(trifluoromethyl)pyridinium-2-sulfonate 20e.

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Fig. 4. N,N0 -difluorobipyridinium salt series and their fluorinating power 22a  22b < 22c << 22d

Scheme 11. One-pot preparation method for pure N,N0 -difluoro-1,4-diazoniabicyclo[2.2.2]octane bis(BF4) 25.

simple filtration process since the pure product appeared as precipitates from the reaction mixture. This was the only method to prepare the pure 25, which was non-hygroscopic, stable and thus, easy-to-handle salt. We demonstrated that 25 was a useful fluorinating agent for various nucleophilic substrates. 25 was more reactive than N-chloromethyl-N0 -fluorodiazoniabicylco[2.2.2]octane bis(BF4) (SelectFluorTM) [86]. One of 2N-F in 25 was effective for the fluorination and the other played a role to activate its fluorination power. The reaction of bis(triflate) salt of 25 with styrene in acetic acid took 5 h at room temperature to give 1-AcO-2-fluoro-1-phenylethane in 30% yield, while that of N-fluoro-2,3,4,5,6-pentafluoropyridinium triflate 16e (X = OTf) was fast (<1 h at room temperature) and the same product was obtained in 72% yield [86]. This meant that 25 was less powerful than 16e. Unfortunately, 25 has not been commercially available yet. It is more powerful than SelectFluorTM and it may be prepared at less cost because of its simple one batch process in contrast to the three step process of SelectFluorTM. 5. Development of O-, S-, Se-, and Te-trifluoromethylated dibenzoheterocyclic onium salts as electrophilic trifluoromethylating agents 5.1. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and tellurophenium salts 5N-OTf (9, R = CF3) As described above, unfortunately, CF3–N5 did not work as a CF3+ reagent. However, it worked as a very novel free radical trifluoromethylating agent which has two effective CF3 radicals in a molecule. In 1984, Yagupolskii et al. [87] reported synthesis of S(trifluoromethyl)(p-chlorophenyl)(p-methoxyphenyl)sulfonium hexafluoroantimonate and showed that it reacted with sodium pnitrobenzenethiolate, giving p-nitrophenyl trifluoromethyl sulfide in 65% yield. However, it did not react with N,N-dimethylaniline, an activated aromatic compound, even at elevated temperature. Based on our experience obtained from the development of power-variable electrophilic N-fluoropyridinium salts, we assumed that the reactivity of CF3 sulfonium salts could be increased by reduction of the electron density of the heteroatom connecting to CF3 group. Thus, we designed and synthesized a series of S-, Seand Te-CF3 dibenzoheterocyclic onium salts 28 and 29 including electron-donating or -withdrawing substituents as shown in Scheme 12 [88,89]. The intramolecular cyclization was fast and the products were easily isolated as crystalline products. The electrophilic nitration onto the heterocyclic rings was easy because of the conjugation of the two benzene rings.

Thus, the advantage of the dibenzo heterocyclic system was easy condensation reaction, easy isolation of the products, and easy further activation such as nitration. In contrast, although a non-heterocyclic salt, S-(trifluoromethyl)diphenylsulfonium triflate (30), was prepared by the condensation of PhS(O)CF3 with benzene in the presence of Tf2O, the reaction was slow and isolation of the product was not easy because of its low crystallinity. It required column-chromatography. S-CF3-phenoxathiinium triflate was synthesized, but its yield was very low [89]. The heterocyclic onium salts 28 and 29 were demonstrated to be useful electrophilic trifluoromethylating agents with different trifluoromethylating power. We called these as powervariable electrophilic trifluoromethylating agents. The power increased in the order of Te < Se < S and alkyl < H < NO2. This order was in good agreement with the electronegativity order of Te < Se < S and the electron-withdrawal order of alkyl < H < NO2. This reflected the electron deficiency of the CF3 group, which was clearly supported by the 19F NMR chemical shifts of CF3 groups. A good linear correlation was observed with the Hammett constants sp or sm of the substituents [89]. Significantly, the heterocyclic salt was more powerful than the non-heterocyclic salt. The kinetic study revealed that the lower reactivity of non-heterocyclic triflate 30 than heterocyclic 28 (Y = S, R1,2 = H) was due to the entropy factor (DS) (steric factor) rather than the enthalpy factor (DH). The higher reactivity of diNO2 salt 29 (Y = S) than 28 (Y = S, R1,2 = H) was due to the enthalpy factor that resulted from the strong electronegativity of the two nitro groups [90]. By means of a wide range of trifluoromethylating power, these reagents made it possible to trifluoromethylate a wide range of nucleophilic substrates differing in reactivity. The substrates included carbanions, activated aromatics, heteroaromatics, trimethylsilyl enol ethers, enamines, phosphines, and thiolates. In the same way as N-fluoropyridinium fluorinating agents, the less reactive substrates were trifluoromethylated well with the powerful trifluoromethylating agents, while the reactive substrates were done so well with less powerful agents. Intermediately reactive substrates were satisfactorily trifluoromethylated by moderately powerful reagents. The trifluoromethylation might compete with an oxidation reaction. This was reflected clearly in the reaction with an alkanethiolate, in which a less powerful CF3 reagent increased a CF3–S product, while a powerful CF3 reagent increased a byproduct that was a disulfide, an oxidation product. These might suggest that a quantifiable correlation existed between the power of trifluoromethylating agent and the nucleophilicity of substrate for the best trifluoromethylation in a similar way as the fluorination with N-fluoropyridinium salts.

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Scheme 12. Synthesis of S-, Se-, and Te-CF3-dibenzo-thio-, -seleno-, and -tellurophenium salts.

Actual trifluoromethylations were carried out by using three reagents, the most powerful dinitro 29 (Y = S), the intermediately powerful 28 (Y = S, R1,2 = H), and the less powerful 28 (Y = Se, R1,2 = H). However, any of the power-variable trifluoromethylating agents could not satisfactorily trifluoromethylate metal enolates, as the reactivity of the enolates was too high. We found a suitable match between the nucleophilicity of metal enolates and the power of trifluoromethylating agents by complexing the enolates with a boron Lewis acid such as 2-phenyl-1,3,2-benzodioxaborole 32 (Scheme 13). This methodology was successfully applied to the trifluoromethylation of many kinds of carbonyl compounds, giving a and g-trifluoromethyl carbonyl compounds in high yields [91]. The first enantioselective trifluoromethylation was achieved by using an optically active and bulky boron compound derived from 2,20 -dihydroxynaphthalene, though its e.e. yield was not high (42– 45%) [91]. We also developed a Zwitter-ion type of power-variable trifluoromethylating agents, S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium-3-sulfonates 35 and nitro derivative 36 (Scheme 14) [92]. The sulfonation and nitration occurred smoothly. The Zwitter-ionic reagents were practically useful because the byproduct resulting from trifluoromethylation reaction, dibenzothiophenesulfonic acid or salt, was easily

separated from the trifluoromethylated products by washing with water. The reaction mechanism of trifluoromethylation by the CF3 reagent was discussed [89,90]. The reagents were electrophilic in nature and acted as sources of trifluoromethyl cation (CF3+). We proposed a bimolecular ionic substitution mechanism consisting of a side-on attack to the CF3–S bond, which ruled out the conventional SN2 attack mechanism [90]. We later called these CF3 reagents as pseudo-CF3+ reagents [93]. Magnier et al. [94] proposed that the reaction proceeds by a single-electron transfer mechanism. S-(Perfluoro-ethyl-, -propyl-, -butyl-, and -octyl)dibenzothiophenium triflates and the corresponding 3-sulfonates were also synthesized in a similar manner to the CF3 analogs [89,92]. These perfluoroalkyl (C4,8) reagents reacted similarly to the corresponding CF3 reagents. Their reactivity was different from the FITS reagents. For example, they reacted with sodium salt of b-diketone to produce only C-Rf products, while FITS afforded both C- and O-Rf products. We developed the economical processes for a large scale of production of the trifluoromethylating agents, 28 (Y = S, R1,2 = H, X = OTf and BF4) and 35 (Y = S, R1 = H), starting from cheap 2hydroxybiphenyl. They were scaled up to a 500 g scale production a batch for each of the trifluoromethylating agents [95].

Scheme 13. Trifluoromethylation of enolate anions with trifluoromethylating agent 28 using boron Lewis acid 32.

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Scheme 14. Synthesis of S-, Se-, and Te-CF3-dibenzo-thio-, -seleno-, and -telluro-phenium-3-sulfonates.

Afterwards, some other groups developed new electrophilic trifluoromethylating agents such as S-(trifluoromethyl)diarylsulfonium salts having electron-withdrawing groups by Shreeve’s group [96], and a-substituted S-(trifluoromethyl)benzothiophenium salts by Shibata’s group [97]. Some of the trifluoromethylating agents are commercially available. 28 (Y = S, R1,2 = H, X = OTf and BF4) have often been referred as Umemoto’s reagent, with which many applications have been reported [98,99]. 5.2. O-(Trifluoromethyl)dibenzofuranium salts and their precursors Even the most powerful S-CF3-dinitrodibenzothiophenium triflate 29 (Y = S) could not produce O- and N-CF3 products except for the following cases; (1) its decomposition at 140 8C produced an O-CF3 product, trifluoromethyl triflate (CF3OTf), in high yield, (2) its decomposition in a polar solvent such as THF or CH3CN took place at room temperature to give CF3OTf, and (3) heating of 29 (Y = S) in phenol as a solvent produced CF3OPh in 13% yield. It suggested us that the electron-withdrawing effect of the sulfonium atom was not enough to generate a real CF3+ species. It really attracted us to the yet unknown O-CF3 oxonium salts because the oxygen atom has the highest electronegativity in the heteroatom series (Te < Se < S < O). As precursors for O-CF3-dibenzofuranium salts, we synthesized many 2-CF3O-biphenylyl-20 -diazonium salts 37 possessing different counteranions and ring substituents, which were stable at room temperature. We succeeded in in situ synthesis of thermally unstable CF3-oxonium salts 38 by photochemical decomposition of 37 at 90 to 100 8C (Scheme 15) [93,100,101]. The nature of the counteranion was very important. Thus, the yields of the CF3-O salts remarkably depended on the nucleophilicity of the counteranions. The least nucleophilic Sb2F11 anion provided the highest yield of 93%, SbF6 gave 87%, PF6 64%, and the more nucleophilic BF4 anion gave the lower yield of 32%, as the nucleophilicity order is Sb2F11 < SbF6 < PF6 < BF4. These CF3-O salts started decomposition at 60 8C and completely decomposed at 30 8C. The decomposition product was CF4. The stability depended on both the nucleophilicity of the

Scheme 15. In situ synthesis of O-(trifluoromethyl)dibenzofuranium salts from the precursors.

counteranions and the electronic nature of the substituents on the rings. Increment of the nucleophilicity decreased the stability, while electron-donating ring substituents increased it. The half-life times of the salts 38 (R = tert-Bu) at 60 8C were 29 min (X = BF4), 36 min (PF6), 270 min (SbF6), and 415 min (Sb2F11), and those of salts 38 (X = Sb2F11) at 60 8C were 13 min (R1 = F), 63 min (H), and 415 min (tert-Bu). Thus, the stability order was BF4 < PF6 < SbF6 < Sb2F11 for counteranions and F < H < tert-Bu for substituents. The CF3-O salt 38 (X = SbF6, R1 = tert-Bu) in situ prepared photochemically from 37 (X = SbF6, R1 = tert-Bu, R2 = H) was successfully applied as a real CF3+ species reagent. It directly and effectively O- and N-trifluoromethylated many kinds of O- and N-nucleophiles such as alcohols, phenols, amines, and pyridines in high yields [93,101]. Unfortunately, the CF3-oxonium salts were unstable at room temperature. However, O- and N-trifluoromethylations of nucleophiles such as alcohols, sulfonic acids, and pyridines were achieved by thermal decomposition method of precursor 37 (X = SbF6, R1 = R2 = H), which was stable at room temperature, in the presence of a nucleophile in refluxing dichloromethane solvent [93,101]. As shown in Scheme 16, we discussed the reaction mechanism and proposed SN2 mechanism which might contain the transient formation of free CF3+ ion [93]. The formation of CF4 from 38 (X = Sb2F11) was a surprising thing because it showed that CF3+ reacted with Sb2F11 that is known as the extremely nonnucleophilic anion. Our results showed that the exceedingly reactive CF3+ species was generated much easier than the CH3+ species, contrary to the common sense that CF3+ was extremely difficult to generate in solution [93]. The oxygen atom of the CF3-O salts has a strong electron-withdrawing effect enough to generate the real CF3+ species. Thus, the long-standing synthetic challenge to generate the real CF3+ species in solution was solved by these studies of us. 6. Development of nucleophilic fluorinating agents 6.1. 4-tert-Butyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEADTM) Among nucleophilic fluorinating agents, deoxofluorinating agents that replace an oxygen atom for a fluorine atom(s) are very useful because an endless number of oxygen-containing compounds are available. Among deoxofluorinating agents, sulfur fluoride compounds are particularly useful. In 1960, gaseous and toxic SF4 was used for first deoxofluorination of aldehydes, ketones, and carboxylic acids [102]. In the 1970s, reactive and liquid dialkylaminosulfur trifluorides, represented by diethylaminosulfur trifluoride (DAST), were developed as an alternative to SF4 [103,104]. Since then, DAST had been used widely, although it had a serious defect that was a thermally unstable, explosive nature in addition to strong fuming in air, explosive reaction on contact with

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Scheme 16. Reaction mechanism of trifluoromethylation by O-CF3-dibenzofuranium salts.

water, and no capability of converting a carboxylic group to a CF3 group. The explosive nature precluded a large scale reaction necessary for industrial production in addition to requiring necessary shipping restrictions. In 1999, an analog, bis(methoxyethyl)aminosulfur trifluoride (Deoxo-FluorTM) with enhanced thermal stability was developed [105]. It fumed in air and its reactivity was similar to DAST. In 1960, liquid phenylsulfur trifluoride (PhSF3) was synthesized and its reactivity was evaluated [106,107]. It was just after the report [102] of fluorination with SF4. The evaluation showed that PhSF3 was useful for benzaldehyde but not for alkylaldehydes, ketones, carboxylic acids due to low reactivity and yields. Since the discovery of reactive DAST, PhSF3 had been mostly ignored except for a report in 1981 that it fluorinated a specific cholesterol in good yield under certain limited reaction conditions [108]. The report also revealed that p-nitrophenysulfur trifluoride did not afford any fluorinated product, but rather an ether compound. The developing needs by non-fluorine organic chemists for a safe, easy-to-handle, and reactive fluorinating agents stimulated us to develop a new deoxofluorinating agent that has both high reactivity and high stability. This was not easy because the two properties of reactivity and stability were basically in conflict. The thermal analysis studies of DAST indicated that the first stage of the thermal decomposition was the disproportionation of DAST to (Et2N)2SF2 and SF4 and the second step was detonation of (Et2N)2SF2 [109]. This meant that the cleavage of weak S–N bond accounted for the thermally explosive properties of DAST. In our attempt to develop a new deoxofluorinating agent, we chose a PhSF3 structure which has prominent advantages that the

C–S bond is much stronger than the N–S bond and the reactivity of the PhSF3 could be varied by altering the substituents on the phenyl ring in a similar way to the power-variable fluorinating and trifluoromethylating agents as mentioned above. We thought that electron-donating substituents could increase the reactivity of PhSF3. It was lucky for us that an economical process for the preparation of PhSF3 from PhSSPh with Cl2/KF was reported in 2003 [110]. From a viewpoint of industrial application, we focused on alkyl-substituted PhSF3 that may be cheap. We actually synthesized many kinds of substituted PhSF3 by both AgF2 method [107] and Cl2/KF [110] or Cl2/CsF method (Scheme 17) and evaluated their reactivity [111,112]. Fluorination of benzyl alcohol was examined as a model reaction. As a result, we selected 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (41a) as a highly effective reagent. Thus, 41a afforded a high yield (88%) of benzyl fluoride, whereas PhSF3 and any of methyl-, dimethyl-, trimethyl-, and tert-butyl-PhSF3 gave the low yields (19–52%). The reaction of PhSF3 with benzyl alcohol was accompanied with the formation of a large amount of polymer as a side-reaction. Thus, the bulky tert-butyl group at the 4position of 41a played an important role to inhibit the polymerization side-reaction in addition to the activation of fluorination reaction together with other 2,6-dimethyl groups by their electron-donating effect. 2,4,6-Tri(isopropyl)phenylsulfur trifluoride gave a low yield (46%) of benzyl fluoride, probably due to the slow reaction caused by the bulkiness around the SF3. We also found that 2,6-bis(CH3OCH2) groups have the effect to inhibit the side-reaction.

Scheme 17. Synthesis of arylsulfur trifluorides 41.

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Scheme 18. Stereoselective fluorination of cis-diol with FLUOLEADTM.

Crystalline 41a was an excellent deoxofluorinating agent which had very high thermal stability compared to DAST and DeoxoFluorTM. The decomposition temperature of 41a was 232 8C, while DAST and Deoxo-FluorTM each was ca. 140 8C. Surprisingly, crystalline 41a had unusual resistance to water, because the decomposition was slow on contact with water, whereas DAST and Deoxo-FluorTM reacted explosively when contacted on water. 41a fluorinated many kinds of hydroxyl- and carbonylcompounds. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 41a fluorinated non-enolizable carbonyl groups to CF2 groups, and carboxylic groups to CF3 groups, in high yields. Neither DAST nor Deoxo-Fluor converted a carboxylic group to a CF3 group. 41a also converted C( = S) and OC(=S)SMe to CF2 and OCF3 groups, respectively, in high yields. In addition, 41a undertook highly stereoselective deoxofluoroarylsulfinylation of diols to give fluoroalkyl (4-tert-butyl-2,6dimethylphenyl)sulfinates such as 44 in high yields, as exemplified by Scheme 18. These reactions proceeded with inversion of configuration at fluorine and the simultaneous, selective formation of one configurational isomer at the sulfoxide atom. With amino alcohols, a two-step method, treatment with 41a and Et3N(HF)3 or pyridine(HF)9 (Olah’s reagent) followed by treatment with Et3N, afforded fluoroalkyl (4-tert-butyl-2,6-dimethylphenyl)sulfinamides in good to excellent yields. The arylsulfinyl group was a good protecting group for OH and NH groups. 41a made it possible to prepare 4-fluoropyrrolidine-2-carbonyl fluorides, useful synthetic intermediates, by the double deoxofluorination of 4-hydroxypyrrolidines [113]. The use of DAST and Deoxo-FluorTM provided a considerable amount of alkylamide byproducts, because the alkylamine was formed due to easy cleavage of the weak N–S bond during the reaction. The alkylamine reacted with the product, carbonyl fluorides, to form the byproducts. 41a has been commercialized as FLUOLEADTM. After our presentation of FLUOLEADTM at Winter Fluorine Conference in January 2009, crystalline dialkylamidodifluorosulfinium tetrafluoroborates ([R2N+=SF2]BF4) were reported to be

useful deoxofluorinating agents when combined with Et3N(HF)3 [114]. 6.2. Arylsulfur chlorotetrafluorides 6.2.1. Background: the first practical industrial method for production of arylsulfur pentafluorides During the search for a useful deoxofluorinating agent (FLUOLEADTM), we unexpectedly detected an arylsulfur chlorotetrafluoride (ArSF4Cl) from the reaction of a diaryl disulfide (ArSSAr) with chlorine and potassium fluoride, then we found that a diaryl disulfide was treated with a large excess of chlorine and potassium fluoride to produce ArSF4Cl in a high yield. We further found that ArSF4Cl was treated with a fluoride source such as zinc fluoride to produce an arylsulfur pentafluoride (ArSF5) in good yield. ArSF5 are very thermally and chemically stable compounds and the pentafluorosulfanyl group (SF5) is more lipophilic and electronegative than CF3 and hence, a more attractive group in medicinal and agrochemical chemistry than CF3. Therefore, ArSF5 have long been expected to be very useful compounds for the development of new medicines and agrochemicals and other new materials. However, there had been no practically useful preparative methods. Our extensive studies accomplished the first practical industrial method for the production of ArSF5 46, which consisted of two-step processes; (1) treatment of a diaryl disulfide 40 or an aryl thiol with chlorine in the presence of an alkali metal fluoride and (2) treatment of the resulting ArSF4Cl 45 with a fluoride source such as ZnF2, HF, and Sb(III/V) fluorides [115] (Scheme 19). By means of this method, a wide range of ArSF5 containing electron-donating or withdrawing substituents were prepared. This method was also successfully applied to the preparation of bis and tris(SF5) aromatic compounds [115]. 6.2.2. Application to deoxo- and dethioxo-fluorinations The industrial application for the large scale production of ArSF5 46 will produce a large amount of ArSF4Cl 45 as intermediates. The availability of inexpensive ArSF4Cl could give birth to another

Scheme 19. The first practical production method for arylsulfur pentafluorides 46.

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Scheme 20. In situ preparation of PhSF3 from PhSF4Cl by a reducing agent.

Scheme 21. In situ preparation of neat phenylsulfur trifluoride by disproportionation.

industrial application of ArSF4Cl. The author thought that one of other applications of ArSF4Cl could be an industrial fluorinating agent. A typical compound of ArSF4Cl is phenylsulfur chlorotetrafluoride (PhSF4Cl). However, PhSF4Cl did not react with an alcohol, an aldehyde, and a carboxylic acid. Our studies on FLUOLEADTM made us notice the potential fluorination capability of phenylsulfur trifluoride (PhSF3), although it was reported that PhSF3 was not a useful fluorinating agent [107]. We found a method for in situ preparation of PhSF3 from PhSF4Cl with a reducing agent (Scheme 20). Among reducing agents, pyridine was most suitable [116]. The in situ prepared PhSF3 satisfactorily fluorinated alcohols, aldehydes, ketones, and diketones to give the corresponding fluoro compounds in high yields under the reaction conditions by using pyridine(HF)9 as an additive. It also reacted with a trimethylsilyl ether of diol to directly give a fluoroalkyl arylsulfinate in a high yield. However, the method using a reducing agent gave PhSF3 and another product resulting from the reducing agent, which hurt some fluorinations. We found that neat PhSF3 was in situ prepared by disproportionation of PhSF4Cl with 1/6PhSSPh, since Cl2 was easily removed from liquid PhSF3 because of its gaseous nature (Scheme 21) [116]. The neat PhSF3 was highly reactive. Thus, it fluorinated not only alcohols, ketones, and thiocarbonyl compounds, but also aryl and alkyl carboxyl acids to give the corresponding CF3 compounds in high yields. It reacted with diols and their bistrimethylsilyl derivatives to give fluoroalkyl arylsulfinates in high yields. It readily and cleanly reacted with bistrimethylsilyl derivatives of amino alcohols by a one-step method to give fluoroalkyl arylsulfinamides in high yields. FLUOLEADTM required the twostep method to obtain good yields of the fluoroalkyl arylsulfinamides [112]. The in situ generation method for neat PhSF3 from PhSF4Cl was highly useful because PhSF3 was extremely moisturesensitive. PhSF3 was very hard to isolate and store, while PhSF4Cl was not sensitive to moisture and easily isolated and stored. We also found that PhSF4Cl itself was an excellent dethioxofluorinating agent [116]. ROC(S)SMe reacted with one equimolar amount of PhSF4Cl to give ROCF3 in a high yield, while PhSF3 required its 3 equimolar amount to get a high yield of the product. FLUOLEADTM required a SbCl3 catalyst. PhSF4Cl converted a C– C(S)SMe to a C–CF3 compound at room temperature in an excellent yield, while PhSF3 required 70 8C without solvent for the conversion. The high reactivity of PhSF4Cl compared to PhSF3 toward the thio compounds is due to higher sulfur valence (VI) of PhSVIF4Cl than PhSIVF3. We also showed that substituted PhSF4Cl and PhSF3 having methyl, halogen atom, or nitro substituent were useful for the fluorination reaction in the same way as PhSF4Cl and PhSF3 themselves [116]. As the ArSF5 industry develops, ArSF4Cl will be produced as intermediates at a large scale. As ArSF4Cl, in particular, PhSF4Cl, will be available as an inexpensive chemical, ArSF4Cl and ArSF3 will be used for the practical production of many organofluorine compounds in industry.

7. Conclusion The author’s ideas and the history of development of his easyto-handle fluorination reagents were described. It covered from FITS reagents started in 1978 to the recent developed ArSF4Cl. In the meantime, many kinds of other reagents were developed, which includes FIS, Double-FITS, polymer-supported FITS, FMITS, TNS-B and -Tf, various N-fluoropyridinim salt series (F-PlusTM, MEC-31, SynFluorTM etc.), N,N0 -difluoro-1,4-diazoniabicyclo[2.2.2]octane salts, S-, Se-, and Te-(trifluoromethyl)dibenzoheterocylic onium salt series, O-(trifluoromethyl)dibenzofuranium salts and precursors, and FLUOLEADTM. These reagents made significant advancement in fluorine chemistry. In particular, FITS opened a new field of electrophilic perfluoroalkylation, the success of the synthesis of stable N-fluoropyridinium salts led to the epoch-making easy-to-handle electrophilic fluorinating agents of wide application, and the trifluoromethylating agents opened a new field of electrophilic trifluoromethylation and the CF3oxonium version solved the long-standing synthetic challenge to generate a real CF3+ species in solution. FLUOLEADTM is another epoch-making deoxofluorinating agent of high thermal stability, ease of handling, and wide application. These reagents have contributed to the recently revolutionary advancement of synthetic fluorine chemistry, especially in the preparation of pharmaceuticals and agrochemicals. In addition, the unexpected cyclic carbene reactions of N-fluoropyridinium salts opened a new field in the pyridine reactions. The unexpected formation of ArSF4Cl from ArSF3 led to the discovery of the first practical industrial method for the production of ArSF5. As the SF5 group has been considered as a super-CF3 group, it should have opened the industry of ArSF5, which will grow up in a similar way to the case of benzotrifluorides (ArCF3) in which ArCF3 have grown up into a big industry since 1940s when the industrial method was developed. The electron-conducting property of N-fluoropyridinium salts revealed by the author’s application to Li battery materials has linked to a new etching method of silicon in lithography and a new method for making Si surface textures for solar cells with Nfluoropyridinium salts recently invented by another group. Acknowledgements The author deeply thanks all his coworkers shown in the papers for their contribution. The author also thanks all the organizations shown in the papers and patents for fund and support.

References [1] W.A. Sheppard, C.M. Sharts, Organic Fluorine Chemistry, W.A. Benjamin, Inc., New York, 1969. [2] R. Filler, Y. Kobayashi (Eds.), Biomedical Aspects of Fluorine Chemistry, Kodansha Ltd./Elsevier Biomedical Press, Tokyo/Amsterdam/New York/Oxford, 1982. [3] R.E. Banks, D.W. Sharp, J.C. Tatlow (Eds.), Fluorine, The First Hundred Years (1886–1986), Elsevier Sequoia, Lausanne, Switzerland, 1986. [4] T. Hiyama (Ed.), Organofluorine Compounds, Chemistry and Applications, Springer, New York, 2000.

T. Umemoto / Journal of Fluorine Chemistry 167 (2014) 3–15 [5] P. Kirsch, Modern Fluorine Chemistry, Synthesis, Reactivity, Applications, WileyVCH Verlag GmbH & Co. KGaA, Weinheim, 2004. [6] K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, Oxford, 2006. [7] J.-P. Be´gue´, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons, Inc., New York, 2008. [8] A. Tressaud, G. Haufe, Fluorine and Health – Molecular Imaging, Biomedical Materials and Pharmaceuticals, Elsevier, Amsterdam, 2008. [9] I. Ojima (Ed.), Fluorine in Medicinal Chemistry and Chemical Biology, WileyBlackwell, New York, 2009. [10] D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton, C.D. Murphy, Nature 416 (2002) 279. [11] T. Umemoto, in: Y. Kobayashi, I. Kumadaki, T. Taguchi (Eds.), Fussoyakugaku– kiso to jikken (Fluorine Medicinal Chemistry – Basis and Experiment, Hirokawa Publishing Co., Tokyo, 1993, pp. 263–268. [12] Y. Kobayashi, T. Yoshida, I. Kumadaki, Tetrahedron Lett. 20 (1979) 3865–3866. [13] V.V. Lyalia, V.V. Orda, L.A. Alekseeva, L.M. Yagupolskii, J. Org. Chem. U. S. S. R. 7 (1971) 1524–1527. [14] L.M. Yagupolskii, I.I. Maletina, N.V. Kondratenko, V.V. Orda, Synthesis (1978) 835–837. [15] T. Umemoto, Y. Kuriu, H. Shuyama, O. Miyano, S. Nakayama, J. Fluorine Chem. 20 (1982) 695–698. [16] T. Umemoto, Y. Kuriu, H. Shuyama, O. Miyano, S. Nakayama, J. Fluorine Chem. 31 (1986) 37–56. [17] T. Umemoto, Y. Kuriu, Tetrahedron Lett. 22 (1981) 5197–5200. [18] T. Umemoto, Y. Gotoh, Bull. Chem. Soc. Jpn. 59 (1986) 439–445. [19] T. Umemoto, Y. Kuriu, H. Shuyama, Chem. Lett. (1981) 1663–1666. [20] T. Umemoto, Y. Kuriu, S. Nakayama, Tetrahedron Lett. 23 (1982) 1169–1172. [21] T. Umemoto, Y. Kuriu, O. Miyano, Tetrahedron Lett. 23 (1982) 3579–3582. [22] T. Umemoto, Y. Kuriu, S. Nakayama, O. Miyano, Tetrahedron Lett. 23 (1982) 1471–1474. [23] T. Umemoto, Y. Kuriu, Chem. Lett. (1982) 65–66. [24] T. Umemoto, O. Miyano, Bull. Chem. Soc. Jpn. 57 (1984) 3361–3362. [25] T. Umemoto, Y. Kuriu, S. Nakayama, Tetrahedron Lett. 23 (1982) 4101–4102. [26] T. Umemoto, S. Furukawa, O. Miyano, S. Nakayama, Nippon Kagaku Kaishi (1985) 2146–2154. [27] T. Umemoto, T. Nakamura, Chem. Lett. (1984) 983–984. [28] T. Umemoto, Tetrahedron Lett. 25 (1984) 81–82. [29] L.M. Yagupolskii, A.A. Mironova, I.I. Maletina, V.V. Orda, Zh. Org. Khim. 16 (1980) 232–233. [30] L.M. Yagupolskii, J. Fluorine Chem. 36 (1987) 1–28. [31] A.A. Mironova, I.I. Maletina, V.V. Orda, L.M. Yagupolskii, J. Org. Chem. U. S. S. R. 19 (1983) 1082–1085. [32] FMITS=[(perfluoroalkyl)methyl]phenyliodonium trifluoromethanesulfonate [33] T. Umemoto, Y. Gotoh, J. Fluorine Chem. 28 (1985) 235–239. [34] T. Umemoto, Y. Gotoh, Bull. Chem. Soc. Jpn. 60 (1987) 3307–3313. [35] T. Umemoto, Y. Gotoh, J. Fluorine Chem. 31 (1986) 231–236. [36] T. Umemoto, Y. Gotoh, Bull. Chem. Soc. Jpn. 60 (1987) 3823–3825. [37] T. Umemoto, Y. Gotoh, Bull. Chem. Soc. Jpn. 64 (1991) 2008–2010. [38] A.A. Mironova, I.V. Soloshonok, I.I. Maletina, V.V. Orda, L.M. Yagupol’skii, J. Org. Chem. U. S. S. R. 24 (1988) 530. [39] S.P. Makarov, A.Y. Yakubovich, A.S. Filatov, M.A. Englin, Y.Y. Nikiforova, Zh. Obshch. Khim. 38 (1968) 709. [40] T. Umemoto, H. Tsutsumi, Bull. Chem. Soc. Jpn. 56 (1983) 631–632. [41] T. Umemoto, O. Miyano, Tetrahedron Lett. 23 (1982) 3929–3930. [42] T. Umemoto, O. Miyano, J. Fluorine Chem. 22 (1983) 91–94. [43] T. Umemoto, O. Miyano, Nippon Kagaku Kaishi (1985) 2205–2207. [44] T. Umemoto, A. Ando, Bull. Chem. Soc. Jpn. 59 (1986) 447–452. [45] A. Sekiya, T. Umemoto, Chem. Lett. (1982) 1519–1520. [46] A. Sekiya, T. Umemoto, Bull. Chem. Soc. Jpn. 57 (1984) 2962–2964. [47] D. Alker, D.H.R. Barton, R.H. Hesse, J.L. -James, R.E. Markwell, M.M. Pechet, S. Rozen, T. Takeshita, H.T. Toh, Noueveau J. Chem. 4 (1980) 239. [48] M. Schlosser, G. Heinz, Chem. Ber. 102 (1969) 1944–1953. [49] S. Rozen, O. Lerman, J. Org. Chem. 45 (1980) 672–678. [50] S. Rozen, O. Lerman, M. Kol, D. Hebel, J. Org. Chem. 50 (1985) 4753–4758. [51] R. Filler, Isr. J. Chem. 17 (1978) 71–79. [52] E.H. Appelman, L.J. Basile, R.C. Thompson, J. Am. Chem. Soc. 101 (1979) 3384– 3385. [53] W.E. Barnette, J. Am. Chem. Soc. 106 (1984) 452–454. [54] S.T. Purrington, W.A. Jones, J. Org. Chem. 48 (1983) 761–762. [55] H. Meinert, Z. Chim. 5 (1965) 64. [56] A.A. Gakh, V.M. Khutoretskii, Izv. Akad. Nauk SSSR Ser. Khim. 11 (1983) 2655– 2656. [57] T. Umemoto, K. Tomita, Tetrahedron Lett. 27 (1986) 3271–3274. [58] T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada, K. Tomita, Bull. Chem. Soc. Jpn. 64 (1991) 1081–1092.

15

[59] T. Umemoto, K. Tomita, K. Kawada, Org. Syn. 69 (1990) 129–143. [60] T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada, K. Tomita, J. Fluorine Chem. 53 (1991) 369–377. [61] T. Umemoto, K. Kawada, K. Tomita, Tetrahedron Lett. 27 (1986) 4465–4468. [62] T. Umemoto, G. Tomizawa, Bull. Chem. Soc. Jpn. 59 (1986) 3625–3629. [63] T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita, J. Am. Chem. Soc. 112 (1990) 8563–8575. [64] T. Umemoto, in: K. Laali (Ed.), Advances in Organic Synthesis, vol. 2, Bentham Science Publishers, 2006, pp. 159–181. [65] A.G. Gilicinski, G.P. Pez, R.G. Syvret, G.S. Lal, J. Fluorine Chem. 59 (1992) 157–162. [66] E. Differing, P.M. Bersier, Tetrahedron 48 (1992) 1595–1604. [67] E.W. Oliver, D.H. Evans, J. Electroanal. Chem. 474 (1) (1999) 1–8. [68] T. Umemoto, G. Tomizawa, Tetrahedron Lett. 28 (1987) 2705–2708. [69] T. Umemoto, G. Tomizawa, H. Hachisuka, M. Kitano, J. Fluorine Chem. 77 (1996) 161–168. [70] T. Umemoto, Preparation, reactivity, and applications of N-fluoropyridinium salts, in: A.A. Gakh, K.L. Kirk (Eds.), Fluorinated Heterocycles, ACS Symposium Series, vol. 1003, American Chemical Society, Washington, DC, 2009, pp. 37–58. [71] T. Umemoto, G. Tomizawa, J. Org. Chem. 54 (1989) 1726–1731. [72] A.S. Kiselytov, Tetrahedron Lett. 46 (2005) 4487–4490. [73] T. Umemoto, G. Tomizawa, US Patent 5,569,778 (filed on 1993). [74] T. Umemoto, N. Izutani, I. Takahashi, US Patent 5,573,868 (filed on 1994). [75] T. Umemoto, K. Adachi, I. Takahashi, 72nd Spring National Meeting of Japanese Chemical Society, Abstract (II), 1997, p. 1299, 3K242. [76] K. Tsukamoto, J. Uchikoshi, S. Goto, T. Kawase, N. Ajari, T. Nagai, K. Adachi, M. Morita, Elecrochem. Solid-State Lett. 13 (11) (2010) D80–D82. [77] M. Otani, J. Uchikoshi, K. Tsukamoto, T. Hirano, T. Nagai, K. Adachi, K. Kawai, K. Arima, M. Morita, ECS Trans. 50 (51) (2013) 109–114. [78] K.L. Hull, W.Q. Anani, M.S. Sanford, J. Am. Chem. Soc. 128 (2006) 7134–7135. [79] X. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 131 (2009) 7520–7521. [80] N.D. Ball, J.W. Kampf, M.S. Sanford, J. Am. Chem. Soc. 132 (2010) 2878–2879. [81] T. Umemoto, G. Tomizawa, J. Org. Chem. 60 (1995) 6563–6570. [82] R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret, J. Chem. Soc. Chem. Commun. (1992) 595–596. [83] S. Stavber, M. Zupan, A. Poss, G.A. Shia, Tetrahedron Lett. 36 (1995) 6769–6772. [84] T. Umemoto, M. Nagayoshi, K. Adachi, G. Tomizawa, J. Org. Chem. 63 (1998) 3379–3385. [85] R.E. Banks, M.K. Besheesh, J. Fluorine Chem. 74 (1995) 165–166. [86] T. Umemoto, M. Nagayoshi, Bull. Chem. Soc. Jpn. 69 (1996) 2287–2295. [87] L.M. Yagupol’skii, N.V. Kondratenko, G.N. Timofeeva, J. Org. Chem. U. S. S. R. (Engl. Transl.) 20 (1984) 103–105. [88] T. Umemoto, S. Ishihara, Tetrahedron Lett. 31 (1990) 3579–3582. [89] T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 115 (1993) 2156–2164. [90] T. Ono, T. Umemoto, J. Fluorine Chem. 80 (1996) 163–166. [91] T. Umemoto, K. Adachi, J. Org. Chem. 59 (1994) 5692–5699. [92] T. Umemoto, S. Ishihara, K. Adachi, J. Fluorine Chem. 74 (1995) 77–82. [93] T. Umemoto, K. Adachi, S. Ishihara, J. Org. Chem. 72 (2007) 6905–6917. [94] Y. Mace´, C. Pradet, M. Popkin, J.-C. Blazejewski, E. Magnier, Tetrahedron Lett. 51 (2010) 5388–5391. [95] T. Umemoto, S. Ishihara, J. Fluorine Chem. 98 (1999) 75–81. [96] J.-J. Yang, R.I. Kirchmeier, J.M. Shreeve, J. Org. Chem. 63 (1998) 2656–2660. [97] A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga, S. Nakamura, N. Shibata, Angew. Chem. Int. Ed. 49 (2010) 572–576. [98] H. Li, Synthesis 23 (15) (2012) 2289–2290. [99] C. Zhang, Org. Biomol. Chem. 12 (2014) 6580–6589. [100] T. Umemoto, Chem. Rev. 96 (1996) 1757–1777. [101] T. Umemoto, K. Adachi, S. Ishihara, US Patent 6,239,289 B1 (2001). [102] W.R. Hasek, W.C. Smith, V.A. Engelhardt, J. Am. Chem. Soc. 83 (1960) 543–551. [103] W.J. Middleton, J. Org. Chem. 40 (1975) 574–578. [104] L.N. Markovskij, V.E. Pashinnik, A.V. Kirsanov, Synthesis (1973) 787–789. [105] G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic, Chem. Commun. (1999) 215–216. [106] W.A. Sheppard, J. Am. Chem. Soc. 82 (1960) 4751–4752. [107] W.A. Sheppard, J. Am. Chem. Soc. 84 (1962) 3058–3063. [108] H. Wei-Yuan, G. Cai-Yun, Acta Chim. Sin. 39 (1981) 63–68. [109] P.A. Messina, K.C. Mange, W.J. Middleton, J. Fluorine Chem. 42 (1989) 137–143. [110] V.E. Pashinnik, E.G. Martyniuk, M.R. Tabachuk, Y.G. Shermolovich, L.M. Yagupolskii, Synth. Commun. 33 (2003) 2505–2509. [111] T. Umemoto, Y. Xu, US Patent 7,265,247 B1 (2007). [112] T. Umemoto, R.P. Singh, Y. Xu, N. Saito, J. Am. Chem. Soc. 132 (2010) 18199– 18205. [113] R.P. Singh, T. Umemoto, J. Org. Chem. 76 (2011) 3113–3121. [114] F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, A. L’Heureux, Org. Lett. 11 (2009) 5050–5053. [115] T. Umemoto, L.M. Garrick, N. Saito, Beilstein J. Org. Chem. 8 (2012) 461–471. [116] T. Umemoto, R.P. Singh, J. Fluorine Chem. 140 (2012) 17–27.