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Development of Electrophilic Trifluoromethylating Reagents
Development of Electrophilic Trifluoromethylating Reagents
10
T. Umemoto Zhejiang Jiuzhou Pharmaceutical Co., Ltd., Taizhou, Zhejiang, China
Chapter Outline 1. Introduction 265 2. Historical Background 266 3. Electrophilic Trifluoromethylating Reagents 3.1 3.2 3.3
267
Sulfonium, Selenonium, and Telluronium Salts 267 Oxonium Salts 279 Iodine(III) Compounds 280
4. Conclusion 283 References 284
1. Introduction Since the CF3 group has unique properties such as high electronegativity, stability, and lipophilicity, the introduction of the CF3 group into an organic molecule could bring about a remarkable change in the properties of the original molecule. This is the reason why the CF3 group has been drawing much interest of researchers in modifying lead compounds to develop new effective medicines and agrochemicals.1 Some typical examples developed so far are shown in Fig. 10.1. Electrophilic trifluoromethylation is one of the fundamental methods for trifluoromethylation, the others being nucleophilic and free radical. However, since it is very hard to generate CF3 þ in solution due to the strongly electron-withdrawing effect of the CF3 group, electrophilic trifluoromethylation is extremely difficult compared with electrophilic alkylation in hydrocarbon chemistry, which is easily accomplished by treating a methyl halide with a nucleophile (CH3X þ Nu / CH3Nu þ X).2a Accordingly, studies on making useful electrophilic trifluoromethylating agents have long been continued, as described in this chapter. There are several reviews for electrophilic trifluoromethylating reagents and their reactions.2
Modern Synthesis Processes and Reactivity of Fluorinated Compounds. http://dx.doi.org/10.1016/B978-0-12-803740-9.00010-X Copyright © 2017 Elsevier Inc. All rights reserved.
266
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
CF 3 O 2N
N
S CF 3 OH CF 3
CF 3
N
NO 2
CH2(CH2) 2NMe2
Trifluraline (herbicide)
Triflupromazine (antipsychotic)
H
O HN Cl
F3 C
HO
CF 3
N H
Flutamide (anti-prostate cancer)
Efavirenz (anti-HIV)
H2N
OH
O O
Falecalcitriol (analogue of calcitriol; active form of vitamin D)
Figure 10.1 Some examples of trifluoromethyl-containing medicines and agrochemicals. HIV, human immunodeficiency virus.
2.
Historical Background
Electrophilic perfluoroalkylating reagents having two or more carbons (CnF2nþ1, n 2) were developed around 1980. The reagents were (perfluoroalkyl)aryliodonium chlorides 4 by Yagupolskii3 and triflates 5 by Umemoto,4,2a which were prepared from perfluoroalkyl iodides (Rf-I) as shown in Scheme 10.1. The latter (perfluoroalkyl)phenyliodonium trifluoromethanesulfonates 5 (FITS reagents) were stable crystals, but were very reactive because of strong activation by TfO group. FITS reacted with many kinds of nucleophilic organic substrates under mild conditions to give various perfluoroalkylated compounds.2a
Scheme 10.1 Synthesis of electrophilic perfluoroalkylating reagents 4 and 5.
Development of Electrophilic Trifluoromethylating Reagents
267
However, both Yagupolskii and Umemoto failed to synthesize the corresponding (trifluoromethyl)aryliodonium salts from CF3I, probably due to the instability of the intermediates or final products.4b,5 Another approach reported by Umemoto in 19826 and 19867 was an attempt to make trifluoromethyl azo compounds 8 by reaction of CF3NO with NH2OH followed by treatment with an arene- or perfluoroalkane-sulfonyl halide (Scheme 10.2). He expected to generate CF3 þ with evolution of N2 from 8 by heterolytic bond cleavage.8 However, the isolated products were N-CF3-N-nitroso derivatives 9aee.
Scheme 10.2 Synthesis of N-trifluoromethyl-N-nitroso sulfonamides.
It was found that 9a reacted photochemically with activated aromatics, disulfides, and others and 9d did so both photo- and thermo-chemically to produce trifluoromethylated compounds. The mechanism suggested was that CF3 radicals were generated via isomerization to the diazo compound 8 followed by homolytic cleavage (Scheme 10.3). Thus, these trifluoromethylations were considered radical reactions.
Scheme 10.3 Mechanism of trifluoromethylation with 9d.
3. Electrophilic Trifluoromethylating Reagents 3.1
Sulfonium, Selenonium, and Telluronium Salts
In 1984, Yagupolskii et al. synthesized stable (trifluoromethyl)diarylsulfonium salts 12a,b9 (Scheme 10.4). Sulfoxide 10 was deoxofluorinated with SF3 þ SbF6 and then treated with SbF5 to give intermediate 11, which was then reacted with m-xylene and anisole to produce 12a and 12b, respectively. Since 11 was extremely hygroscopic, the procedure was carried out in completely dry atmosphere.
268
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 10.4 Synthesis of S-CF3-diarylsulfonium salts.
12a,b reacted with p-nitrobenzenethiolate 13 in N,N-dimethylformamide (DMF) at room temperature to produce CF3 sulfide 14 in 65% yield (Scheme 10.5). This was the first report that trifluoromethylsulfonium salts acted as electrophilic trifluoromethylating reagents, but only for an arenethiolate. 12a,b did not react with an activated aromatic substrate, N,N-dimethylaniline, even at temperatures up to 70 C.
Scheme 10.5 Reactions of S-CF3-diarylsulfonium salts.
In 199010 and 1993,11 Umemoto et al. published new, reactive, and stable S-, Se-, and Te-(trifluoromethyl)dibenzo-thio-, -seleno-, and -telluro-phenium salts and their alkyl and nitro derivatives 15e17 as power-variable electrophilic trifluoromethylating reagents (Fig. 10.2). R
2
1
9
8
R 7
3 4
5
A+ CF3
6
X-
15: A=S 16: A=Se 17: A=Te R: Me, t Bu, NO2 X: TfO, BF4
Figure 10.2 S-, Se-, and Te-CF3-dibenzoheterocyclic onium salts.
Thiophenium salts 15 were synthesized by oxidation of sulfide 18 with m-chloroperbenzoic acid (MCPBA) followed by easy cyclization of the resulting sulfoxides 19 with triflic anhydride (Tf2O) in high yields (Scheme 10.6). 15 were also prepared from 18 by a one-pot reaction, direct fluorination using F2/N2 (1/9 v/v) in the presence of HX (TfOH, HBF4 or BF3$Et2O), or stepwise treatment of the direct fluorination followed by treatment with HX. S-(Perfluoro-ethyl, -propyl, -butyl, and -octyl)dibenzothiophenium triflates were synthesized in a similar manner.11
Development of Electrophilic Trifluoromethylating Reagents
269
Scheme 10.6 Synthesis of S-CF3-dibenzothiophenium salts.
The mononitration of 15a was carried out by treatment of nitronium triflate, which was in situ prepared from nitric acid and Tf2O in nitromethane solvent (Scheme 10.7). The dinitration of 15a was completed in high yield by using excess of nitronium triflate without nitromethane.
Scheme 10.7 Nitration of S-CF3-dibenzothiophenium salts.
Selenophenium salts 16a (A ¼ Se, R ¼ H, X ¼ TfO), 16b (A ¼ Se, R ¼ 2,8-diMe, X ¼ TfO), and dinitro salt 16c (A ¼ Se, R ¼ 3,7-diNO2, X ¼ TfO) were synthesized in the same manner as thiophenium salts 15. Salt 16a was dinitrated much faster than 15a to give 16c. Tellurophenium salts 17 were synthesized in a different manner (Scheme 10.8). 2-(CF3Te)biphenyl 20 underwent quick intramolecular cyclization by treatment with Tf2O in the presence of dimethyl sulfoxide (DMSO) to give 17a in 84% yield. 17a was also synthesized in 63% yield by treatment of 20 with bromine followed by heating with TfOH. Dinitration of 17a was easily carried out to give 17d in 76% yield. BF4 salt 17c was synthesized in 73% yield by conversion to bromide 17b followed by treatment with AgBF4. Another heterocyclic salt 22 was synthesized by the intramolecular cyclization of 21. However, the reaction was very slow and the yield was very low (Scheme 10.9). An unsubstituted acyclic salt, S-(trifluoromethyl)diphenylsulfonium triflate (24), was synthesized by condensation of sulfoxide 23 with benzene by action of Tf2O (Scheme 10.10).11 The reaction was slow.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 10.8 Synthesis of Te-CF3-dibenzotellurophenium salts.
Scheme 10.9 Synthesis of S-CF3-phenoxathiinium triflate.
Scheme 10.10 Synthesis of S-CF3-diphenylsulfonium triflate.
It was shown that the power (reactivity) of trifluoromethylating reagent increased in the order 17a (Te) < 24 (S, acyclic) < 15c (S, 2,8-diMe) < 15d (S, 3,7-ditBu) < 16a (Se) 17d (Te, 3,7-diNO2) < 15a (S) < 15f (S, 3-NO2) < 16c (Se, 3,7-diNO2) < 15g (S, 3,7-diNO2). The power order in each of the structures, heteroatoms, and substituents was as follows: acyclic structure < cyclic structure; Te < Se < S; and 2,8dimethyl < 3,7-di-tert-butyl < H < 3-nitro < 3,7-dinitro. Thus, the power depended on the structure and electronegativity of the heteroatom and ring substituent. Importantly, the effect of NO2 group overcame the effect of heteroatoms. The substituent effect was clearly reflected in the 19F chemical shift of CF3 groups. In the S series, the chemical shift appeared in the order 2,8-diMe (53.8 ppm) < 3,7-ditBu (53.1) < unsubstituted (52.6) < 3-nitro (50.5) < 3,7-dinitro (48.4). Thus, the power depended on the electron density of the CF3 group. The higher reactivity of the cyclic structure than the acyclic structure was clearly demonstrated by kinetic studies and explained by its greatly enhanced entropy DS.12 The (trifluoromethyl)dibenzoheterocyclic salts 15e17 first made it possible to trifluoromethylate a wide range of nucleophilic substrates.11 The suitable CF3-dibenzoheterocyclic salt reagent was chosen for the substrate. In general, a less reactive substrate was trifluoromethylated by a powerful reagent, whereas a reactive substrate was satisfactorily done with a less powerful reagent. Actually, trifluoromethylations of
many different substrates were carried out by using three different salts, 15a, 15g, and 16a (power order 16a < 15a < 15g) (Scheme 10.11 and Table 10.1). These trifluoromethylations were accompanied by quantitative formation of dibenzoheterocycle 25.
Scheme 10.11 Trifluoromethylation with 15a, 15g, and 16a.
As seen in Table 10.1, 15a was suitable for salts of active methylene compounds, silyl enol ethers, enamines, heteroaromatics such as pyrrole, and sodium iodide and nitrate.11,13 The most powerful 15g was suitable for trifluoromethylations of aromatics such as aniline, dihydroquinone and naphthol, and phosphines, whereas the least powerful 16a was suitable for thiolates and metal acetylides.11 Although the yields were a little low, dialkyl S-CF3 salt 15c or 15d could be replaced with Se-CF3 salt 16a.11
Trifluoromethylation of various substrates with 15a, 15g, and 16a Table 10.1
272
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Metal enolates of ketones could not be trifluoromethylated in satisfactory yields with any of the salts. For this case, the complexes of potassium enolates with 2phenyl-1,3,2-benzodioxaborole as a Lewis acid were in situ prepared and then treated with 15a to give the desired a-trifluoromethyl ketones in high yields.14 The first enantioselective a-trifluoromethylation of a ketone made by this methodology provided a 45%ee yield (chemical yield 54%).14 In these trifluoromethylations, dibenzoheterocycle 25 was formed as another product, which was soluble in an organic layer. Therefore, the separation of CF3 products from 25 was difficult. To solve it, S-, Se-, and Te- (trifluoromethyl)dibenzo-thio-, -seleno-, and -telluro-phenium-3-sulfonates, 26a-c, 27a, and 28a, were synthesized (Scheme 10.12).15 S-(Perfluoro-ethyl, -butyl, and -octyl)dibenzothiophenium-3-sulfonates were also synthesized.15
Scheme 10.12 Synthesis of S-, Se-, and Te-CF3-dibenzo-thio-, -seleno-, and -telluro-pheniumsulfonates.
Their power was also examined. The order was shown to be 15a z 26a < 26c < 15f. The power of internal salt 26a was almost the same as that of the external salt 15a. Salt 26a reacted with sodium salt 29 of a diketone to produce CF3 product 30 in 86% yield, and sodium dibenzothiophenium-3-sulfonate 31 was easily removed by washing the reaction mixture with water (Scheme 10.13).
Scheme 10.13 Trifluoromethylation with S-CF3-dibenzothiophenium-3-sulfonate (26a).
Effective methods for the preparation of 15a,b and 26a were developed (Scheme 10.14).16 2-Mercaptobiphenyl (32) was prepared from cheap 2-hydroxybiphenyl in high yield and then derived to 2-(trifluoromethylthio)biphenyl (35) by three methods. 35 was treated with H2O2 in acetic acid, and the resulting sulfoxide 36 was reacted
Development of Electrophilic Trifluoromethylating Reagents
273
with fuming sulfuric acid, followed by treatment with NaOTf and NaBF4 to give 15a and 15b, respectively, in high yields. 36 was treated with excess fuming sulfuric acid to directly give the internal salt 26a in high yield. These reactions were carried out at a large scale (a half kg).
Scheme 10.14 Effective methods for preparation of CF3 reagents, 15a,b and 26a.
S-(Trifluoromethyl)dibenzothiophenium salts 15a,b called later as Umemoto’s reagents have been commercialized and distributed worldwide since the early 2000s by chemical reagent companies. Since then, many new reactions of 15a,b have been reported,2e which include iodide anion-catalyzed trifluoromethylation of active methylene compounds and others,17 Pd(II)-catalyzed o-trifluoromethylation of aromatics,18 Cu-catalyzed trifluoromethylation of aryl boronic acids19; CuCl-catalyzed trifluoromethylation of terminal alkynes20; oxy-, amino-, and keto-trifluoromethylation of alkenes catalyzed by photoredox catalyst under visible light21; Ru-photocatalyzed hydrotrifluoromethylation of alkenes22; Cu-promoted Sandmeyer trifluoromethylation of anilines23; direct aromatic trifluoromethylation via an electron donoreacceptor complex24; one-step synthesis of 4-trifluoromethyl-2,3-dihydropyroliums from amino alkynes25; one-step preparation of 3-trifluoromethylindoles from 2-alkynylanilines26; and one-step preparation of 2-trifluoromethyl-dihydronaphthalene derivatives.27 Highly enantioselective trifluoromethylation of b-ketoesters was also reported.28 Newly designed high-valent CF3-Ni(IV) catalysts were prepared through the reaction with Ni(II) precursors.29 Umemoto suggested that the reaction mechanism for the trifluoromethylation with the S- and Se-CF3 reagents could vary from CF3 free radical to CF3 þ cation species, depending on the reactivity of nucleophiles, the trifluoromethylating power of CF3 reagents, and reaction conditions.30 Umemoto also discussed the possible insertion mechanism to the doubly positive Sdþ-Cdþ bond of the S-CF3 group accompanied
274
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
by a one-electron or two-electron exchange, which was completely different from the SN2 mechanism.12 Magnier suggested a single electron-transfer pathway on the basis of the radical trapping experiment of trifluoromethylation of a silyl enol ether with Umemoto reagent 15a and analogous reagents.31 Shibata discussed the reaction mechanism based on the calculations.32 Many metal-mediated trifluoromethylations with Umemoto reagents were explained by the reductive mechanism via a single electron-transfer from metal.2i In 1998, Shreeve et al. published acyclic S-(trifluoromethyl)diarylsulfonium salts 37aee having electron-withdrawing substituent(s) as another set of power-variable reagents (Scheme 10.15).33 37aec were prepared by the reaction of 23 with a large excess amount of each of Tf2O and an aromatic compound. Salts 37d,e were prepared by nitration of 37a,b.
Scheme 10.15 Synthesis of S-CF3-diarylsulfonium triflates 37.
The trifluoromethylation experiments of dihydrobenzoquinone, pyrrole, and aniline showed that the power increased in the order of 37a z 37b < 37c < 37d z 37e. Thus, two fluorine atoms or a nitro group definitely increased the reactivity. The reaction pattern was the same as for the S-CF3-dibenzothiophenium salts. In 2005, Adachi et al. disclosed 1-oxo-1-(trifluoromethyl)-1l6-benzo[d]isothiazol3-one 39 and S-(trifluoromethyl)-N-triflyl- and -benzoyl-S-phenylsulfoximide 41 and 42 as electrophilic trifluoromethylating reagents in their patent application,34 although their structure was assigned by 1H and 19F nuclear magnetic resonance (NMR) data alone (Schemes 10.16 and 10.17). 39 and 42 reacted with lithium arylacetylides and sodium arenethiolates to give the corresponding CF3 products in 47e73% yields. It was also reported that 39 and 41 reacted with phenylmagnesium bromide in tetrahydrofuran (THF)/hexamethylphosphoramide (1/3) at 30 C to room temperature to give benzotrifluoride in 24% and 15% yield, respectively, whereas Umemoto reagent 15a gave benzotrifluoride in only 3% yield under the same reaction conditions.
Scheme 10.16 Synthesis of 1-oxo-1-CF3-1l6-benzo[d]isothiazol-3-one (39).
Development of Electrophilic Trifluoromethylating Reagents
275
Scheme 10.17 Synthesis of S-CF3-phenylsulfoximides 41 and 42.
In 2006, Magnier et al. reported the one-pot preparation of S-(trifluoromethyl) diarylsulfonium triflates 24 and 43aed from the reaction of an arene, a trifluoromethanesulfinate salt, and Tf2O (Scheme 10.18).35 The emergence of the one-pot process aroused usefulness of acyclic 24 among chemists, and new reactions of 24 were developed, which were trifluoromethylations of aryl iodides,36 aryl boronic acids,37 benzyl bromides,38 styrenes,39 and alkynes40 in the presence of copper, cupper iodide, rongalite, or a photocatalyst.
Scheme 10.18 One-pot preparation of S-CF3-diarylsulfonium triflates.
In 2009, they extended it to the preparation of S-(trifluoromethyl)dibenzothiophenium triflate 15a and its methyl and nitro derivatives 44aed (Scheme 10.19).41 However, the yields were very low. Their examination showed that methylated salts 44aed trifluoromethylated aniline in better yields than unsubstituted Umemoto reagent 15a.
Scheme 10.19 One-pot preparation of Umemoto reagent 15a and its multi-methylated analogs.
276
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
In 2014, Laali et al. synthesized S-(trifluoromethyl)dibenzothiophenium triflate 45 possessing an electron-withdrawing pentafluorosulfanyl group in 55% yield by the same one-pot synthesis (Scheme 10.20).42 They surveyed the reactivity of 45 toward reactive aromatics. However, the distinguished effect of SF5 group was not observed.
Scheme 10.20 One-pot preparation of SF5-substituted S-CF3-dibenzothiophenium triflate.
The one-pot method could not apply for direct synthesis of (trifluoromethyl)diarylsulfonium salts possessing strong electron-withdrawing group(s) such as NO2. In 2008, Yagupolskii et al. published another method from diaryldifluorosulfurane 47 by the action of (trifluoromethyl)trimethylsilane (TMSCF3)/F followed by treatment with BF3$Et2O to produce 48aee43 (Scheme 10.21). S-(4-Nitrophenyl)-Sphenyl-S-(trifluoromethyl)sulfonium triflate (49) could be prepared in 42.5% yield by the reaction of 4-nitrophenyl trifluoromethyl sulfoxide with a large excess of benzene (51 eq) and Tf2O (5 eq).43
Scheme 10.21 Synthesis of S-CF3-diarylsulfoinium salts 48aee.
The power order was 48a (H) < 48d (NO2) < 48e (diNO2) from the comparison in the reaction with NaI, giving CF3I. N-Methylpyrrole, N,N-dimethyaniline, tetraethylthiourea, and Michler’s thioketone were trifluoromethylated with 48d or triflate 49 in 72e90% yields. The thiourea and thioketone produced S-trifluoromethylated salts. In 2008, Shibata et al. reported N,N-dimethyl-S-phenyl-S-(trifluoromethyl)sulfoximinium tetrafluoroborate (52) (Scheme 10.22).44 As triflate 51 was viscously oil, it was transformed to 52, which was a crystalline compound. 52 trifluoromethylated b-ketoesters and dicyanoalkylidenes in the presence of 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU) or a phosphazene base to give the C-CF3 products in fair to high yields. Later, Magnier et al. reported that triflate 51 reacted with lithium arylacetylides to give CF3 alkynes (ArChCCF3) in 12e53% yields.45
Development of Electrophilic Trifluoromethylating Reagents
277 N
O 23
NaN3 SO3-H2SO4
S
MeI/K2CO3
40
in THF refl. 7 h
81%
H3C
O
S
CF3
97%
MeOTf r.t. 6 h
H3C
N+ CH3 CF3
TfO51
50
CH3
O S
NaBF4 aq. MeOH r.t. 13 h
N+ CH3 CF3
BF4-
93%
52
92%
Scheme 10.22 Synthesis S-CF3-phenylsulfoximinium salt 52.
In 2009, Magnier et al. reported a safe process for the preparation of sulfoximine 40, which avoided the use of NaN3 in hot oleum (Scheme 10.23).46 Sulfoxide 23 was treated with acetonitrile in the presence of Tf2O, followed by oxidation with KMnO4 to produce 40 in high yield.
23
1. CH3CN, Tf 2O 2. KMnO4, NaOH/H2O
40
overall yield 88%
Scheme 10.23 Safe preparation of S-CF3-phenylsulfoximine 40.
In 2010, Shibata et al. reported another type of cyclic salts, S-(trifluoromethyl) benzothiophenium triflates 54aej, which were synthesized by intramolecular cyclization of 53 with TfOH (Scheme 10.24).47 They were useful reagents for trifluoromethylation of b-ketoesters and dicyanoalkylidenes. It was later shown that 54 undertook reverse reaction in DMF at room temperature to get back to the starting materials 53.48
Scheme 10.24 Synthesis of S-CF3-benzothiophenium triflates.
278
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
They also synthesized optically active salt 57 having (þ)-camphor substituent (Scheme 10.25). However, no asymmetric trifluoromethylation occurred in the reaction with a b-ketoester.47
Scheme 10.25 Synthesis of optically active S-CF3-benzothiophenium triflate 57.
Most lately, Lu and Shen synthesized trifluoromethyl sulfonium ylide 59 as an electrophilic trifluoromethylating reagent (Scheme 10.26).49 59 was not air and moisture sensitive and did not decompose for 3 months. 59 reacted with various cyclic b-ketoesters in DMF at 100 C in the presence of K2CO3 to give the corresponding a-CF3-b-ketoesters in 48e75% yields. Treatment with aryl iodides in the presence of Cu afforded the CF3 arenes in high yields.
Scheme 10.26 Synthesis of S-CF3 sulfonium ylide 59 and its reactions.
Shibata et al. reported another trifluoromethylating agent 61 as a similar strategy, which was prepared by diazotization of 60 with TsN3 in the presence of DBU.50 61 reacted with nucleophiles such as ketoesters, dicyanoalkylidenes, and trimethylsilyl enol ethers in the presence of Rh2(OAc)4 catalyst in acetonitrile under reflux, giving the corresponding trifluoromethyl compounds in 23e80% yield (Scheme 10.27). Sulfonium ylide 62 was suggested as a reactive intermediate.
Development of Electrophilic Trifluoromethylating Reagents
279
Scheme 10.27 Synthesis of CF3S diazoketoester 61 and its reactions.
3.2
Oxonium Salts
In 1996 and 2007, Umemoto et al. published the synthesis and reactivity of the first trifluoromethyl oxonium salts, O-(trifluoromethyl)dibenzofuranium salts 64, which were thermally unstable at >70 C (Scheme 10.28).2a,30 They were in situ prepared from diazonium salts 63 by photoreaction at very low temperature (90 w 100 C) and identified by 19F and 1H NMR analysis at 70 C.
Scheme 10.28 In situ synthesis of O-CF3-dibenzofuranium salts.
It was revealed that the stability depended on the nucleophilicity of the counteranion X. It increased in the order of BF4 < PF6 < SbF6 < Sb2 F11 . The most nonnucleophilic Sb2 F11 gave the highest yield and stability. The stability also depended on the electronic nature of the ring substituent R: F < H < tBu. Electrondonating tert-butyl group gave the highest stability of the substituents examined. Salt 64d (X ¼ Sb2F11, R ¼ tBu) had the longest half-life of 415 min at 60 C. Salt 64g (X ¼ BF4, R ¼ F) had the shortest half-life of 13 min at 60 C. These salts were extremely reactive. They decomposed to give CF4 and a dibenzofuran. Surprisingly, CF4 was formed even when X was Sb2 F11 , which has been known to be a really nonnucleophilic anion. It was thus suggested that real CF3 þ was generated as a transit species in these reactions. It was a sharp contrast to the fact that O-methyldibenzofuranium salt was stable up to 80 C. This meant that CF3 þ was generated much easier than CH3 þ , which had been suggested by the calculations.51 O-Trifluoromethyl oxonium salt 64c acted as a source of real CF3 þ . 64c was in situ generated by photo reaction of 63c at the low temperature and then treated with N- and
280
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
O-nucleophilies such as amines, alcohols, and phenols to give the corresponding N- and O-CF3 products in fair to high yields (Scheme 10.29). Tertiary amines and pyridines were trifluoromethylated to give N-CF3 quaternary ammonium and pyridinium salts in fair to high yields.
Scheme 10.29 O- and N-trifluoromethylations with O-CF3-dibenzofuranium salt 64c.
Some of the O- and N-trifluoromethylations were carried out by the thermal decomposition method of diazonium salt 63a, in which a mixture of 63a and an O- or N-nucleophile was heated in dichloromethane under reflux for 3 h.2a,30 Recently, the synthesis of N-(trifluoromethoxy)pyridinium hexafluoroantimonates containing an electron-withdrawing substituent(s) on the pyridine ring from pyridine N-oxides by this thermal method was disclosed.52
3.3
Iodine(III) Compounds
Long after the attempt by Yagupolskii and Umemoto, Togni et al. succeeded in synthesizing cyclic type of CF3-iodine(III) compounds, 1-(trifluoromethyl)-1,2benziodoxol-3(1H)-one (69) and 1-(trifluoromethyl)-1,3-dihydro-3,3-dimethyl-1,2benziodoxole (74), by the Umpolung methodology using TMSCF3 in 2006 (Schemes 10.30 and 10.31).53 TMSCF3 was found to be useful for nucleophilic trifluoromethylation in 1989 by Prakash et al.54
Scheme 10.30 Synthesis of 1-CF3-1,2-benziodoxol-3(H)-one (69).
Development of Electrophilic Trifluoromethylating Reagents
281
At first, 69 was synthesized by ligand exchange of 68 with TMSCF3 in the presence of tetra-n-butylammonium difluorotriphenylsilicate (TBAT) or CsF (route I, Scheme 10.30). Reassessment of the synthetic route showed that chloride 70 was a suitable intermediate (route II) and finally provided a one-pot, three-step process (route III) for the preparation of 69.55
Scheme 10.31 Synthesis of 1-CF3-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (74).
74 was synthesized from 71 by oxidation with tBuOCl followed by treatment with KOAc and then TMSCF356 (Scheme 10.31). For large-scale application, trichlorocyanuric acid (TCICA) was used in place of tBuOCl and the chlorine atom of 72 was replaced with a fluorine atom. A one-pot, two-step process of 72 to 74 was finally developed.55 Many CF3I(III) compounds 75e78 with different side chains were synthesized and evaluated. Even though a certain trend was indicated in their reactivity, no strong correlation could be established among them.57 Nitro derivative 79 was also synthesized.58 79 showed high reactivity to p-toluenesulfonic acid. However, the desired CF3 product, p-TsOCF3, was not formed. Another limitation of 79 was its poor solubility in common organic solvents 57,2h (Fig. 10.3).
Figure 10.3 1-CF3-1,2-benziodoxol analogs.
Since 69 and 74, known as Togni’s reagents, could be prepared by short steps and they have been sold commercially, many new reactions with them have been developed by many research groups.2h As seen in Scheme 10.32, Togni reagents were reactive and versatile reagents for trifluoromethylations of various substrates such as carbonyl compounds,59,60 aromatics,61 heteroaromatics,61 silyl enol
282
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
ethers,62 enamides,63 aryl and vinyl boronic acids,64e66 alkynes,67 alkenes,68e70 as well as O-, S-, and P-nucleophiles such as alcohols,71 sulfonates,72,73 and phosphines74 and N-nucleophiles.75 The starting material 65 or 71 was restored from the trifluoromethylations. O
N N
Ph2PCF3
87%
78%
COOH N
SCF3
95%
N CF3
R2N
Ph2PH CH2Cl2 r.t. 69 74 thiol
SiMe3 CH2Cl2 r.t. 74
COOR keto ester K2CO3 Bu4NI CH3CN r.t. 74
aromatics TMSSCl CH3CN 80 oC 74
93%
PhC CH CuI, K2CO3 ligand, r.t. CH2Cl2 Ph
PhC
69 or 74
Zn(NTf 2)2 69
69
75%
Ph
CF3 88%
CF3
98%
O
CF3
OSiMe3 CH3CN, 80 oC
69 BF3K
N H
74
74
FeCl2 MeOH r.t.
CCF3
58%
CH3CN 80 oC heterocycle 74 Zn(NTf 2)2
-78oC
n-C5H11OH (solv) r.t.
OMe CF3
66%
CH2Cl2
CF3OC5H11n
CF3
41%
NHAc
74 ArB(OH)2 CuI, K2CO3, ligand, 35 oC diglyme
Ph
Ph
NHAc
CF3 CuCl THF r.t.
81%
Ph CF3 CF3 90%
Scheme 10.32 Trifluoromethylation of various substrates with 69 and 74.
In addition, alkoxy-,76 azido-,77 cyano-,78 oxy-,79 and amino-trifluoromethylations80 including concomitant cyclization and trifluoromethylations with other C-C bond formation and rearrangement reactions2h were developed. Highly enantioselective trifluoromethylations of aldehydes81 and b-ketoesters28b were successful. Lewis acids, Brɸnsted acids, copper catalysts, organocatalysts, and photocatalysts were successfully used for many trifluoromethylations with 69 and 742h. However, it was cautioned that 74 caused a rapid exothermic decomposition above its melting point (78 C)56,82 and 69 was dangerously explosive.82 Electrochemical data for the first reduced reaction of different CF3 reagents were reported48: 15a (or 15b), 0.63 V; 54i, 0.72 V; 54a, 0.49 V; 54e, 0.49 V; 54l, 0.47 V; 69, 1.10 V; 74, 1.82 V (V vs. Ag/Agþ in CH3CN) (54l, R ¼ 2,4dinitrophenyl in 54). Thus the oxidation potential of the trifluoromethylating reagents
Development of Electrophilic Trifluoromethylating Reagents
283
increased in the order 74 << 69 << 54i < 15a (15b) < 54e ¼ 54a < 54l. The oxidation potentials of CF3I(III) compounds were considerably lower than those of the CF3 sulfonium salts. In the series 54, the electronic nature of substituent at 2-position was reflected in the potentials: 54i (cyclopropyl) << 54e (4-methoxyphenyl) ¼ 54a (phenyl) < 54l (2,4-dinitrophenyl). Another group’s data21a,40 were as follows (V vs. Cp2Fe in CH3CN): 74 (1.49 V) < 69 (1.34 V) < 24 (1.11 V) << 15b (0.75 V). Acyclic sulfonium salt 24 had higher potential than Togni reagents 69 and 74, but lower than Umemoto reagent 15b. In 2013, Wang and Liu reported the trifluoromethylation of nucleophilic substrates with PhI(OAc)2 and TMSCF3 in the presence of KF (Scheme 10.33).83 In their studies, they detected a peak corresponding to [PhICF3]þ species 82 by mass spectrometric analysis of the reaction mixture in CH3CN. It was thus proposed that acyclic (trifluoromethyl)phenyliodonium acetate (81) was formed as an intermediate, which was the target compound attempted by Yagupolskii and Umemoto around 35 years ago. Some other trifluoromethylation reactions with PhI(OAc)2/TMSCF3/base were explained by a similar mechanism.84
Scheme 10.33 Trifluoromethylation with PhI(OAc)2/TMSCF3/KF.
4. Conclusion85 Many electrophilic trifluoromethylating reagents have been developed so far. Many new trifluoromethylations with them have been reported by many newcomers to the fluorine chemistry during the past decade. Accordingly, the field of electrophilic trifluoromethylation, which had been considered to be left undeveloped, has markedly been advanced. The electrophilic trifluoromethylating reagents have a deep and complex chemistry because their reactions may include electron transfer or reduction/oxidation processes. There is still a lot of room to be investigated. Since this chapter could not satisfactorily cover the reactions by the trifluoromethylating reagents because of limited space, readers are advised to read original papers and reviews cited.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
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48. Mizuta, S.; Verhoog, S.; Wang, X.; Shibata, N.; Gouverneur, V.; Médebielle, M. J. Fluor. Chem. 2013, 155, 124e131. 49. Liu, Y.; Shao, X.; Zhang, P.; Lu, L.; Shen, Q. Org. Lett. 2015, 17, 2752e2755. 50. Saidalimu, I.; Tokunaga, E.; Shibata, N. ACS Catal. 2015, 5, 4668e4672. 51. Raynolds, C. H. J. Chem. Soc. Chem. Commun. 1991, 975e976. 52. Umemoto, T.; Zhu, M.; Hu, J. Chinese Patent Application. CN 105017143A, 2015. 53. Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579e2586. 54. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757e786. 55. Matousek, V.; Pietrasiak, E.; Schwenk, R.; Togni, A. J. Org. Chem. 2013, 78, 6763e6768. 56. Eisenberger, P.; Kieltsch, I.; Koller, R.; Stanek, K.; Togni, A. Org. Synth. 2011, 88, 168e180. 57. Niedermann, K.; Welch, J. M.; Koller, R.; Cvengros, J.; Santschi, N.; Battaglia, P.; Togni, A. Tetrahedron 2010, 66, 5753e5761. 58. Santschi, N.; Sarott, R. C.; Otth, E.; Kissner, R.; Togni, A. Beilstein J. Org. Chem. 2014, 10, 1e6. 59. Keiltsch, I.; Eisenbeger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754e757. 60. Matousek, V.; Togni, A.; Bizet, V.; Cahard, D. Org. Lett. 2011, 13, 5762e5765. 61. Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluor. Chem. 2010, 131, 951e957. 62. Kieltsch, I.; Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008, 62, 260e263. 63. Feng, C.; Loh, T. -P. Chem. Sci. 2012, 3, 3458e3462. 64. Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342e2345. 65. Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem. Int. Ed. 2012, 51, 2947e2950. 66. Yasu, Y.; Koike, T.; Akita, M. Chem. Commun. 2013, 49, 2037e2039. 67. Weng, Z.; Li, H.; He, W.; Yao, L. -F.; Tan, J.; Chen, J.; Yuan, Y.; Huang, K. -W. Tetrahedron 2012, 68, 2527e2531. 68. Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9120e9123. 69. Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410e16413. 70. Wang, X. -P.; Lin, J. -H.; Zhang, C. -P.; Xiao, J. -C.; Zheng, X. Beilstein J. Org. Chem. 2013, 9, 2635e2640. 71. Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew. Chem. Int. Ed. 2009, 48, 4332e4336. 72. Koller, R.; Huchet, Q.; Battaglia, P.; Welch, J. M.; Togni, A. Chem. Commun. 2009, 5993e5995. 73. Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Ind. Ed. 2007, 46, 754e757. 74. Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem. Commun. 2008, 1575e1577. 75. Niedermann, K.; Fruh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A. Angew. Chem. Int. Ed. 2012, 51, 6511e6515. 76. Egami, H.; Shimizu, R.; Sodeoka, M. Tetrahedron Lett. 2012, 53, 5503e5506. 77. Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem. Int. Ed. 2014, 53, 1881e1886. 78. He, Y. -T.; Li, L. -H.; Yang, Y. -F.; Zhou, Z. -Z.; Hua, H. -L.; Liu, X. -Y.; Liang, Y. -M. Org. Lett. 2014, 16, 270e273. 79. a. Li, Y.; Studer, A. Angew. Chem. Int. Ed. 2012, 51, 8221e8224. b. Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462e12465. c. Zhu, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 12655e12658. d. Yu, Q.; Ma, S. Chem. Eur. J. 2013, 19, 13304e13308. e. He, Y. -T.; Li, L. -H.; Yang, Y. -F.; Wang, Y. -Q.; Luo, J. -Y.; Liu, X. -Y.; Liang, Y. -M. Chem. Commun. 2013, 49, 5687e5689.
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80. a. Lin, J. -S.; Xiong, Y. -P.; Ma, C. -L.; Zhao, L. -J.; Tan, B.; Liu, X. -Y. Chem. Eur. J. 2014, 20, 1332e1340. b. Egami, H.; Kawamura, S.; Miyazaki, A.; Sodeoka, M. Angew. Chem. Int. Ed. 2013, 52, 7841e7844. c. Ji, G.; Wang, X.; Zhang, S.; Xu, Y.; Ye, Y.; Li, M.; Zhang, Y.; Wang, J. Chem. Commun. 2014, 50, 4361e4363. 81. Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986e4987. 82. Fiederling, N.; Haller, J.; Schramm, H. Org. Process Res. Dev. 2013, 17, 318e319. 83. Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.; Wang, M.; Liu, Q. Chem. Eur. J. 2013, 19, 9104e9109. 84. a. Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846e4849. b. Li, L.; Deng, M.; Zheng, S. -C.; Xiong, Y. -P.; Tan, B.; Liu, X. -Y. Org. Lett. 2014, 16, 504e507. c. Fu, W.; Xu, F.; Fu, Y.; Xu, C.; Li, S.; Zou, D. Eur. J. Org. Chem. 2014, 709e712. 85. After this chapter was completed, a significant paper appeared; Li, M.; Xue, X. -S.; Guo, J.; Wang, Y.; Cheng, J. -P.. J. Org. Chem. 2016, 81, 3119e3126. The paper provided an þ energetic guide for estimating the trifluoromethyl cation (CFþ 3 )-donating abilities (TC DA) of the electrophilic trifluoromethylating reagents. The TCþDA values clearly revealed the relative reactivity of various types of electrophilic trifluoromethylating agents developed so far.
10
T. Umemoto Zhejiang Jiuzhou Pharmaceutical Co., Ltd., Taizhou, Zhejiang, China
Chapter Outline 1. Introduction 265 2. Historical Background 266 3. Electrophilic Trifluoromethylating Reagents 3.1 3.2 3.3
267
Sulfonium, Selenonium, and Telluronium Salts 267 Oxonium Salts 279 Iodine(III) Compounds 280
4. Conclusion 283 References 284
1. Introduction Since the CF3 group has unique properties such as high electronegativity, stability, and lipophilicity, the introduction of the CF3 group into an organic molecule could bring about a remarkable change in the properties of the original molecule. This is the reason why the CF3 group has been drawing much interest of researchers in modifying lead compounds to develop new effective medicines and agrochemicals.1 Some typical examples developed so far are shown in Fig. 10.1. Electrophilic trifluoromethylation is one of the fundamental methods for trifluoromethylation, the others being nucleophilic and free radical. However, since it is very hard to generate CF3 þ in solution due to the strongly electron-withdrawing effect of the CF3 group, electrophilic trifluoromethylation is extremely difficult compared with electrophilic alkylation in hydrocarbon chemistry, which is easily accomplished by treating a methyl halide with a nucleophile (CH3X þ Nu / CH3Nu þ X).2a Accordingly, studies on making useful electrophilic trifluoromethylating agents have long been continued, as described in this chapter. There are several reviews for electrophilic trifluoromethylating reagents and their reactions.2
Modern Synthesis Processes and Reactivity of Fluorinated Compounds. http://dx.doi.org/10.1016/B978-0-12-803740-9.00010-X Copyright © 2017 Elsevier Inc. All rights reserved.
266
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
CF 3 O 2N
N
S CF 3 OH CF 3
CF 3
N
NO 2
CH2(CH2) 2NMe2
Trifluraline (herbicide)
Triflupromazine (antipsychotic)
H
O HN Cl
F3 C
HO
CF 3
N H
Flutamide (anti-prostate cancer)
Efavirenz (anti-HIV)
H2N
OH
O O
Falecalcitriol (analogue of calcitriol; active form of vitamin D)
Figure 10.1 Some examples of trifluoromethyl-containing medicines and agrochemicals. HIV, human immunodeficiency virus.
2.
Historical Background
Electrophilic perfluoroalkylating reagents having two or more carbons (CnF2nþ1, n 2) were developed around 1980. The reagents were (perfluoroalkyl)aryliodonium chlorides 4 by Yagupolskii3 and triflates 5 by Umemoto,4,2a which were prepared from perfluoroalkyl iodides (Rf-I) as shown in Scheme 10.1. The latter (perfluoroalkyl)phenyliodonium trifluoromethanesulfonates 5 (FITS reagents) were stable crystals, but were very reactive because of strong activation by TfO group. FITS reacted with many kinds of nucleophilic organic substrates under mild conditions to give various perfluoroalkylated compounds.2a
Scheme 10.1 Synthesis of electrophilic perfluoroalkylating reagents 4 and 5.
Development of Electrophilic Trifluoromethylating Reagents
267
However, both Yagupolskii and Umemoto failed to synthesize the corresponding (trifluoromethyl)aryliodonium salts from CF3I, probably due to the instability of the intermediates or final products.4b,5 Another approach reported by Umemoto in 19826 and 19867 was an attempt to make trifluoromethyl azo compounds 8 by reaction of CF3NO with NH2OH followed by treatment with an arene- or perfluoroalkane-sulfonyl halide (Scheme 10.2). He expected to generate CF3 þ with evolution of N2 from 8 by heterolytic bond cleavage.8 However, the isolated products were N-CF3-N-nitroso derivatives 9aee.
Scheme 10.2 Synthesis of N-trifluoromethyl-N-nitroso sulfonamides.
It was found that 9a reacted photochemically with activated aromatics, disulfides, and others and 9d did so both photo- and thermo-chemically to produce trifluoromethylated compounds. The mechanism suggested was that CF3 radicals were generated via isomerization to the diazo compound 8 followed by homolytic cleavage (Scheme 10.3). Thus, these trifluoromethylations were considered radical reactions.
Scheme 10.3 Mechanism of trifluoromethylation with 9d.
3. Electrophilic Trifluoromethylating Reagents 3.1
Sulfonium, Selenonium, and Telluronium Salts
In 1984, Yagupolskii et al. synthesized stable (trifluoromethyl)diarylsulfonium salts 12a,b9 (Scheme 10.4). Sulfoxide 10 was deoxofluorinated with SF3 þ SbF6 and then treated with SbF5 to give intermediate 11, which was then reacted with m-xylene and anisole to produce 12a and 12b, respectively. Since 11 was extremely hygroscopic, the procedure was carried out in completely dry atmosphere.
268
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 10.4 Synthesis of S-CF3-diarylsulfonium salts.
12a,b reacted with p-nitrobenzenethiolate 13 in N,N-dimethylformamide (DMF) at room temperature to produce CF3 sulfide 14 in 65% yield (Scheme 10.5). This was the first report that trifluoromethylsulfonium salts acted as electrophilic trifluoromethylating reagents, but only for an arenethiolate. 12a,b did not react with an activated aromatic substrate, N,N-dimethylaniline, even at temperatures up to 70 C.
Scheme 10.5 Reactions of S-CF3-diarylsulfonium salts.
In 199010 and 1993,11 Umemoto et al. published new, reactive, and stable S-, Se-, and Te-(trifluoromethyl)dibenzo-thio-, -seleno-, and -telluro-phenium salts and their alkyl and nitro derivatives 15e17 as power-variable electrophilic trifluoromethylating reagents (Fig. 10.2). R
2
1
9
8
R 7
3 4
5
A+ CF3
6
X-
15: A=S 16: A=Se 17: A=Te R: Me, t Bu, NO2 X: TfO, BF4
Figure 10.2 S-, Se-, and Te-CF3-dibenzoheterocyclic onium salts.
Thiophenium salts 15 were synthesized by oxidation of sulfide 18 with m-chloroperbenzoic acid (MCPBA) followed by easy cyclization of the resulting sulfoxides 19 with triflic anhydride (Tf2O) in high yields (Scheme 10.6). 15 were also prepared from 18 by a one-pot reaction, direct fluorination using F2/N2 (1/9 v/v) in the presence of HX (TfOH, HBF4 or BF3$Et2O), or stepwise treatment of the direct fluorination followed by treatment with HX. S-(Perfluoro-ethyl, -propyl, -butyl, and -octyl)dibenzothiophenium triflates were synthesized in a similar manner.11
Development of Electrophilic Trifluoromethylating Reagents
269
Scheme 10.6 Synthesis of S-CF3-dibenzothiophenium salts.
The mononitration of 15a was carried out by treatment of nitronium triflate, which was in situ prepared from nitric acid and Tf2O in nitromethane solvent (Scheme 10.7). The dinitration of 15a was completed in high yield by using excess of nitronium triflate without nitromethane.
Scheme 10.7 Nitration of S-CF3-dibenzothiophenium salts.
Selenophenium salts 16a (A ¼ Se, R ¼ H, X ¼ TfO), 16b (A ¼ Se, R ¼ 2,8-diMe, X ¼ TfO), and dinitro salt 16c (A ¼ Se, R ¼ 3,7-diNO2, X ¼ TfO) were synthesized in the same manner as thiophenium salts 15. Salt 16a was dinitrated much faster than 15a to give 16c. Tellurophenium salts 17 were synthesized in a different manner (Scheme 10.8). 2-(CF3Te)biphenyl 20 underwent quick intramolecular cyclization by treatment with Tf2O in the presence of dimethyl sulfoxide (DMSO) to give 17a in 84% yield. 17a was also synthesized in 63% yield by treatment of 20 with bromine followed by heating with TfOH. Dinitration of 17a was easily carried out to give 17d in 76% yield. BF4 salt 17c was synthesized in 73% yield by conversion to bromide 17b followed by treatment with AgBF4. Another heterocyclic salt 22 was synthesized by the intramolecular cyclization of 21. However, the reaction was very slow and the yield was very low (Scheme 10.9). An unsubstituted acyclic salt, S-(trifluoromethyl)diphenylsulfonium triflate (24), was synthesized by condensation of sulfoxide 23 with benzene by action of Tf2O (Scheme 10.10).11 The reaction was slow.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 10.8 Synthesis of Te-CF3-dibenzotellurophenium salts.
Scheme 10.9 Synthesis of S-CF3-phenoxathiinium triflate.
Scheme 10.10 Synthesis of S-CF3-diphenylsulfonium triflate.
It was shown that the power (reactivity) of trifluoromethylating reagent increased in the order 17a (Te) < 24 (S, acyclic) < 15c (S, 2,8-diMe) < 15d (S, 3,7-ditBu) < 16a (Se) 17d (Te, 3,7-diNO2) < 15a (S) < 15f (S, 3-NO2) < 16c (Se, 3,7-diNO2) < 15g (S, 3,7-diNO2). The power order in each of the structures, heteroatoms, and substituents was as follows: acyclic structure < cyclic structure; Te < Se < S; and 2,8dimethyl < 3,7-di-tert-butyl < H < 3-nitro < 3,7-dinitro. Thus, the power depended on the structure and electronegativity of the heteroatom and ring substituent. Importantly, the effect of NO2 group overcame the effect of heteroatoms. The substituent effect was clearly reflected in the 19F chemical shift of CF3 groups. In the S series, the chemical shift appeared in the order 2,8-diMe (53.8 ppm) < 3,7-ditBu (53.1) < unsubstituted (52.6) < 3-nitro (50.5) < 3,7-dinitro (48.4). Thus, the power depended on the electron density of the CF3 group. The higher reactivity of the cyclic structure than the acyclic structure was clearly demonstrated by kinetic studies and explained by its greatly enhanced entropy DS.12 The (trifluoromethyl)dibenzoheterocyclic salts 15e17 first made it possible to trifluoromethylate a wide range of nucleophilic substrates.11 The suitable CF3-dibenzoheterocyclic salt reagent was chosen for the substrate. In general, a less reactive substrate was trifluoromethylated by a powerful reagent, whereas a reactive substrate was satisfactorily done with a less powerful reagent. Actually, trifluoromethylations of
many different substrates were carried out by using three different salts, 15a, 15g, and 16a (power order 16a < 15a < 15g) (Scheme 10.11 and Table 10.1). These trifluoromethylations were accompanied by quantitative formation of dibenzoheterocycle 25.
Scheme 10.11 Trifluoromethylation with 15a, 15g, and 16a.
As seen in Table 10.1, 15a was suitable for salts of active methylene compounds, silyl enol ethers, enamines, heteroaromatics such as pyrrole, and sodium iodide and nitrate.11,13 The most powerful 15g was suitable for trifluoromethylations of aromatics such as aniline, dihydroquinone and naphthol, and phosphines, whereas the least powerful 16a was suitable for thiolates and metal acetylides.11 Although the yields were a little low, dialkyl S-CF3 salt 15c or 15d could be replaced with Se-CF3 salt 16a.11
Trifluoromethylation of various substrates with 15a, 15g, and 16a Table 10.1
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Metal enolates of ketones could not be trifluoromethylated in satisfactory yields with any of the salts. For this case, the complexes of potassium enolates with 2phenyl-1,3,2-benzodioxaborole as a Lewis acid were in situ prepared and then treated with 15a to give the desired a-trifluoromethyl ketones in high yields.14 The first enantioselective a-trifluoromethylation of a ketone made by this methodology provided a 45%ee yield (chemical yield 54%).14 In these trifluoromethylations, dibenzoheterocycle 25 was formed as another product, which was soluble in an organic layer. Therefore, the separation of CF3 products from 25 was difficult. To solve it, S-, Se-, and Te- (trifluoromethyl)dibenzo-thio-, -seleno-, and -telluro-phenium-3-sulfonates, 26a-c, 27a, and 28a, were synthesized (Scheme 10.12).15 S-(Perfluoro-ethyl, -butyl, and -octyl)dibenzothiophenium-3-sulfonates were also synthesized.15
Scheme 10.12 Synthesis of S-, Se-, and Te-CF3-dibenzo-thio-, -seleno-, and -telluro-pheniumsulfonates.
Their power was also examined. The order was shown to be 15a z 26a < 26c < 15f. The power of internal salt 26a was almost the same as that of the external salt 15a. Salt 26a reacted with sodium salt 29 of a diketone to produce CF3 product 30 in 86% yield, and sodium dibenzothiophenium-3-sulfonate 31 was easily removed by washing the reaction mixture with water (Scheme 10.13).
Scheme 10.13 Trifluoromethylation with S-CF3-dibenzothiophenium-3-sulfonate (26a).
Effective methods for the preparation of 15a,b and 26a were developed (Scheme 10.14).16 2-Mercaptobiphenyl (32) was prepared from cheap 2-hydroxybiphenyl in high yield and then derived to 2-(trifluoromethylthio)biphenyl (35) by three methods. 35 was treated with H2O2 in acetic acid, and the resulting sulfoxide 36 was reacted
Development of Electrophilic Trifluoromethylating Reagents
273
with fuming sulfuric acid, followed by treatment with NaOTf and NaBF4 to give 15a and 15b, respectively, in high yields. 36 was treated with excess fuming sulfuric acid to directly give the internal salt 26a in high yield. These reactions were carried out at a large scale (a half kg).
Scheme 10.14 Effective methods for preparation of CF3 reagents, 15a,b and 26a.
S-(Trifluoromethyl)dibenzothiophenium salts 15a,b called later as Umemoto’s reagents have been commercialized and distributed worldwide since the early 2000s by chemical reagent companies. Since then, many new reactions of 15a,b have been reported,2e which include iodide anion-catalyzed trifluoromethylation of active methylene compounds and others,17 Pd(II)-catalyzed o-trifluoromethylation of aromatics,18 Cu-catalyzed trifluoromethylation of aryl boronic acids19; CuCl-catalyzed trifluoromethylation of terminal alkynes20; oxy-, amino-, and keto-trifluoromethylation of alkenes catalyzed by photoredox catalyst under visible light21; Ru-photocatalyzed hydrotrifluoromethylation of alkenes22; Cu-promoted Sandmeyer trifluoromethylation of anilines23; direct aromatic trifluoromethylation via an electron donoreacceptor complex24; one-step synthesis of 4-trifluoromethyl-2,3-dihydropyroliums from amino alkynes25; one-step preparation of 3-trifluoromethylindoles from 2-alkynylanilines26; and one-step preparation of 2-trifluoromethyl-dihydronaphthalene derivatives.27 Highly enantioselective trifluoromethylation of b-ketoesters was also reported.28 Newly designed high-valent CF3-Ni(IV) catalysts were prepared through the reaction with Ni(II) precursors.29 Umemoto suggested that the reaction mechanism for the trifluoromethylation with the S- and Se-CF3 reagents could vary from CF3 free radical to CF3 þ cation species, depending on the reactivity of nucleophiles, the trifluoromethylating power of CF3 reagents, and reaction conditions.30 Umemoto also discussed the possible insertion mechanism to the doubly positive Sdþ-Cdþ bond of the S-CF3 group accompanied
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
by a one-electron or two-electron exchange, which was completely different from the SN2 mechanism.12 Magnier suggested a single electron-transfer pathway on the basis of the radical trapping experiment of trifluoromethylation of a silyl enol ether with Umemoto reagent 15a and analogous reagents.31 Shibata discussed the reaction mechanism based on the calculations.32 Many metal-mediated trifluoromethylations with Umemoto reagents were explained by the reductive mechanism via a single electron-transfer from metal.2i In 1998, Shreeve et al. published acyclic S-(trifluoromethyl)diarylsulfonium salts 37aee having electron-withdrawing substituent(s) as another set of power-variable reagents (Scheme 10.15).33 37aec were prepared by the reaction of 23 with a large excess amount of each of Tf2O and an aromatic compound. Salts 37d,e were prepared by nitration of 37a,b.
Scheme 10.15 Synthesis of S-CF3-diarylsulfonium triflates 37.
The trifluoromethylation experiments of dihydrobenzoquinone, pyrrole, and aniline showed that the power increased in the order of 37a z 37b < 37c < 37d z 37e. Thus, two fluorine atoms or a nitro group definitely increased the reactivity. The reaction pattern was the same as for the S-CF3-dibenzothiophenium salts. In 2005, Adachi et al. disclosed 1-oxo-1-(trifluoromethyl)-1l6-benzo[d]isothiazol3-one 39 and S-(trifluoromethyl)-N-triflyl- and -benzoyl-S-phenylsulfoximide 41 and 42 as electrophilic trifluoromethylating reagents in their patent application,34 although their structure was assigned by 1H and 19F nuclear magnetic resonance (NMR) data alone (Schemes 10.16 and 10.17). 39 and 42 reacted with lithium arylacetylides and sodium arenethiolates to give the corresponding CF3 products in 47e73% yields. It was also reported that 39 and 41 reacted with phenylmagnesium bromide in tetrahydrofuran (THF)/hexamethylphosphoramide (1/3) at 30 C to room temperature to give benzotrifluoride in 24% and 15% yield, respectively, whereas Umemoto reagent 15a gave benzotrifluoride in only 3% yield under the same reaction conditions.
Scheme 10.16 Synthesis of 1-oxo-1-CF3-1l6-benzo[d]isothiazol-3-one (39).
Development of Electrophilic Trifluoromethylating Reagents
275
Scheme 10.17 Synthesis of S-CF3-phenylsulfoximides 41 and 42.
In 2006, Magnier et al. reported the one-pot preparation of S-(trifluoromethyl) diarylsulfonium triflates 24 and 43aed from the reaction of an arene, a trifluoromethanesulfinate salt, and Tf2O (Scheme 10.18).35 The emergence of the one-pot process aroused usefulness of acyclic 24 among chemists, and new reactions of 24 were developed, which were trifluoromethylations of aryl iodides,36 aryl boronic acids,37 benzyl bromides,38 styrenes,39 and alkynes40 in the presence of copper, cupper iodide, rongalite, or a photocatalyst.
Scheme 10.18 One-pot preparation of S-CF3-diarylsulfonium triflates.
In 2009, they extended it to the preparation of S-(trifluoromethyl)dibenzothiophenium triflate 15a and its methyl and nitro derivatives 44aed (Scheme 10.19).41 However, the yields were very low. Their examination showed that methylated salts 44aed trifluoromethylated aniline in better yields than unsubstituted Umemoto reagent 15a.
Scheme 10.19 One-pot preparation of Umemoto reagent 15a and its multi-methylated analogs.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
In 2014, Laali et al. synthesized S-(trifluoromethyl)dibenzothiophenium triflate 45 possessing an electron-withdrawing pentafluorosulfanyl group in 55% yield by the same one-pot synthesis (Scheme 10.20).42 They surveyed the reactivity of 45 toward reactive aromatics. However, the distinguished effect of SF5 group was not observed.
Scheme 10.20 One-pot preparation of SF5-substituted S-CF3-dibenzothiophenium triflate.
The one-pot method could not apply for direct synthesis of (trifluoromethyl)diarylsulfonium salts possessing strong electron-withdrawing group(s) such as NO2. In 2008, Yagupolskii et al. published another method from diaryldifluorosulfurane 47 by the action of (trifluoromethyl)trimethylsilane (TMSCF3)/F followed by treatment with BF3$Et2O to produce 48aee43 (Scheme 10.21). S-(4-Nitrophenyl)-Sphenyl-S-(trifluoromethyl)sulfonium triflate (49) could be prepared in 42.5% yield by the reaction of 4-nitrophenyl trifluoromethyl sulfoxide with a large excess of benzene (51 eq) and Tf2O (5 eq).43
Scheme 10.21 Synthesis of S-CF3-diarylsulfoinium salts 48aee.
The power order was 48a (H) < 48d (NO2) < 48e (diNO2) from the comparison in the reaction with NaI, giving CF3I. N-Methylpyrrole, N,N-dimethyaniline, tetraethylthiourea, and Michler’s thioketone were trifluoromethylated with 48d or triflate 49 in 72e90% yields. The thiourea and thioketone produced S-trifluoromethylated salts. In 2008, Shibata et al. reported N,N-dimethyl-S-phenyl-S-(trifluoromethyl)sulfoximinium tetrafluoroborate (52) (Scheme 10.22).44 As triflate 51 was viscously oil, it was transformed to 52, which was a crystalline compound. 52 trifluoromethylated b-ketoesters and dicyanoalkylidenes in the presence of 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU) or a phosphazene base to give the C-CF3 products in fair to high yields. Later, Magnier et al. reported that triflate 51 reacted with lithium arylacetylides to give CF3 alkynes (ArChCCF3) in 12e53% yields.45
Development of Electrophilic Trifluoromethylating Reagents
277 N
O 23
NaN3 SO3-H2SO4
S
MeI/K2CO3
40
in THF refl. 7 h
81%
H3C
O
S
CF3
97%
MeOTf r.t. 6 h
H3C
N+ CH3 CF3
TfO51
50
CH3
O S
NaBF4 aq. MeOH r.t. 13 h
N+ CH3 CF3
BF4-
93%
52
92%
Scheme 10.22 Synthesis S-CF3-phenylsulfoximinium salt 52.
In 2009, Magnier et al. reported a safe process for the preparation of sulfoximine 40, which avoided the use of NaN3 in hot oleum (Scheme 10.23).46 Sulfoxide 23 was treated with acetonitrile in the presence of Tf2O, followed by oxidation with KMnO4 to produce 40 in high yield.
23
1. CH3CN, Tf 2O 2. KMnO4, NaOH/H2O
40
overall yield 88%
Scheme 10.23 Safe preparation of S-CF3-phenylsulfoximine 40.
In 2010, Shibata et al. reported another type of cyclic salts, S-(trifluoromethyl) benzothiophenium triflates 54aej, which were synthesized by intramolecular cyclization of 53 with TfOH (Scheme 10.24).47 They were useful reagents for trifluoromethylation of b-ketoesters and dicyanoalkylidenes. It was later shown that 54 undertook reverse reaction in DMF at room temperature to get back to the starting materials 53.48
Scheme 10.24 Synthesis of S-CF3-benzothiophenium triflates.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
They also synthesized optically active salt 57 having (þ)-camphor substituent (Scheme 10.25). However, no asymmetric trifluoromethylation occurred in the reaction with a b-ketoester.47
Scheme 10.25 Synthesis of optically active S-CF3-benzothiophenium triflate 57.
Most lately, Lu and Shen synthesized trifluoromethyl sulfonium ylide 59 as an electrophilic trifluoromethylating reagent (Scheme 10.26).49 59 was not air and moisture sensitive and did not decompose for 3 months. 59 reacted with various cyclic b-ketoesters in DMF at 100 C in the presence of K2CO3 to give the corresponding a-CF3-b-ketoesters in 48e75% yields. Treatment with aryl iodides in the presence of Cu afforded the CF3 arenes in high yields.
Scheme 10.26 Synthesis of S-CF3 sulfonium ylide 59 and its reactions.
Shibata et al. reported another trifluoromethylating agent 61 as a similar strategy, which was prepared by diazotization of 60 with TsN3 in the presence of DBU.50 61 reacted with nucleophiles such as ketoesters, dicyanoalkylidenes, and trimethylsilyl enol ethers in the presence of Rh2(OAc)4 catalyst in acetonitrile under reflux, giving the corresponding trifluoromethyl compounds in 23e80% yield (Scheme 10.27). Sulfonium ylide 62 was suggested as a reactive intermediate.
Development of Electrophilic Trifluoromethylating Reagents
279
Scheme 10.27 Synthesis of CF3S diazoketoester 61 and its reactions.
3.2
Oxonium Salts
In 1996 and 2007, Umemoto et al. published the synthesis and reactivity of the first trifluoromethyl oxonium salts, O-(trifluoromethyl)dibenzofuranium salts 64, which were thermally unstable at >70 C (Scheme 10.28).2a,30 They were in situ prepared from diazonium salts 63 by photoreaction at very low temperature (90 w 100 C) and identified by 19F and 1H NMR analysis at 70 C.
Scheme 10.28 In situ synthesis of O-CF3-dibenzofuranium salts.
It was revealed that the stability depended on the nucleophilicity of the counteranion X. It increased in the order of BF4 < PF6 < SbF6 < Sb2 F11 . The most nonnucleophilic Sb2 F11 gave the highest yield and stability. The stability also depended on the electronic nature of the ring substituent R: F < H < tBu. Electrondonating tert-butyl group gave the highest stability of the substituents examined. Salt 64d (X ¼ Sb2F11, R ¼ tBu) had the longest half-life of 415 min at 60 C. Salt 64g (X ¼ BF4, R ¼ F) had the shortest half-life of 13 min at 60 C. These salts were extremely reactive. They decomposed to give CF4 and a dibenzofuran. Surprisingly, CF4 was formed even when X was Sb2 F11 , which has been known to be a really nonnucleophilic anion. It was thus suggested that real CF3 þ was generated as a transit species in these reactions. It was a sharp contrast to the fact that O-methyldibenzofuranium salt was stable up to 80 C. This meant that CF3 þ was generated much easier than CH3 þ , which had been suggested by the calculations.51 O-Trifluoromethyl oxonium salt 64c acted as a source of real CF3 þ . 64c was in situ generated by photo reaction of 63c at the low temperature and then treated with N- and
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
O-nucleophilies such as amines, alcohols, and phenols to give the corresponding N- and O-CF3 products in fair to high yields (Scheme 10.29). Tertiary amines and pyridines were trifluoromethylated to give N-CF3 quaternary ammonium and pyridinium salts in fair to high yields.
Scheme 10.29 O- and N-trifluoromethylations with O-CF3-dibenzofuranium salt 64c.
Some of the O- and N-trifluoromethylations were carried out by the thermal decomposition method of diazonium salt 63a, in which a mixture of 63a and an O- or N-nucleophile was heated in dichloromethane under reflux for 3 h.2a,30 Recently, the synthesis of N-(trifluoromethoxy)pyridinium hexafluoroantimonates containing an electron-withdrawing substituent(s) on the pyridine ring from pyridine N-oxides by this thermal method was disclosed.52
3.3
Iodine(III) Compounds
Long after the attempt by Yagupolskii and Umemoto, Togni et al. succeeded in synthesizing cyclic type of CF3-iodine(III) compounds, 1-(trifluoromethyl)-1,2benziodoxol-3(1H)-one (69) and 1-(trifluoromethyl)-1,3-dihydro-3,3-dimethyl-1,2benziodoxole (74), by the Umpolung methodology using TMSCF3 in 2006 (Schemes 10.30 and 10.31).53 TMSCF3 was found to be useful for nucleophilic trifluoromethylation in 1989 by Prakash et al.54
Scheme 10.30 Synthesis of 1-CF3-1,2-benziodoxol-3(H)-one (69).
Development of Electrophilic Trifluoromethylating Reagents
281
At first, 69 was synthesized by ligand exchange of 68 with TMSCF3 in the presence of tetra-n-butylammonium difluorotriphenylsilicate (TBAT) or CsF (route I, Scheme 10.30). Reassessment of the synthetic route showed that chloride 70 was a suitable intermediate (route II) and finally provided a one-pot, three-step process (route III) for the preparation of 69.55
Scheme 10.31 Synthesis of 1-CF3-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (74).
74 was synthesized from 71 by oxidation with tBuOCl followed by treatment with KOAc and then TMSCF356 (Scheme 10.31). For large-scale application, trichlorocyanuric acid (TCICA) was used in place of tBuOCl and the chlorine atom of 72 was replaced with a fluorine atom. A one-pot, two-step process of 72 to 74 was finally developed.55 Many CF3I(III) compounds 75e78 with different side chains were synthesized and evaluated. Even though a certain trend was indicated in their reactivity, no strong correlation could be established among them.57 Nitro derivative 79 was also synthesized.58 79 showed high reactivity to p-toluenesulfonic acid. However, the desired CF3 product, p-TsOCF3, was not formed. Another limitation of 79 was its poor solubility in common organic solvents 57,2h (Fig. 10.3).
Figure 10.3 1-CF3-1,2-benziodoxol analogs.
Since 69 and 74, known as Togni’s reagents, could be prepared by short steps and they have been sold commercially, many new reactions with them have been developed by many research groups.2h As seen in Scheme 10.32, Togni reagents were reactive and versatile reagents for trifluoromethylations of various substrates such as carbonyl compounds,59,60 aromatics,61 heteroaromatics,61 silyl enol
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
ethers,62 enamides,63 aryl and vinyl boronic acids,64e66 alkynes,67 alkenes,68e70 as well as O-, S-, and P-nucleophiles such as alcohols,71 sulfonates,72,73 and phosphines74 and N-nucleophiles.75 The starting material 65 or 71 was restored from the trifluoromethylations. O
N N
Ph2PCF3
87%
78%
COOH N
SCF3
95%
N CF3
R2N
Ph2PH CH2Cl2 r.t. 69 74 thiol
SiMe3 CH2Cl2 r.t. 74
COOR keto ester K2CO3 Bu4NI CH3CN r.t. 74
aromatics TMSSCl CH3CN 80 oC 74
93%
PhC CH CuI, K2CO3 ligand, r.t. CH2Cl2 Ph
PhC
69 or 74
Zn(NTf 2)2 69
69
75%
Ph
CF3 88%
CF3
98%
O
CF3
OSiMe3 CH3CN, 80 oC
69 BF3K
N H
74
74
FeCl2 MeOH r.t.
CCF3
58%
CH3CN 80 oC heterocycle 74 Zn(NTf 2)2
-78oC
n-C5H11OH (solv) r.t.
OMe CF3
66%
CH2Cl2
CF3OC5H11n
CF3
41%
NHAc
74 ArB(OH)2 CuI, K2CO3, ligand, 35 oC diglyme
Ph
Ph
NHAc
CF3 CuCl THF r.t.
81%
Ph CF3 CF3 90%
Scheme 10.32 Trifluoromethylation of various substrates with 69 and 74.
In addition, alkoxy-,76 azido-,77 cyano-,78 oxy-,79 and amino-trifluoromethylations80 including concomitant cyclization and trifluoromethylations with other C-C bond formation and rearrangement reactions2h were developed. Highly enantioselective trifluoromethylations of aldehydes81 and b-ketoesters28b were successful. Lewis acids, Brɸnsted acids, copper catalysts, organocatalysts, and photocatalysts were successfully used for many trifluoromethylations with 69 and 742h. However, it was cautioned that 74 caused a rapid exothermic decomposition above its melting point (78 C)56,82 and 69 was dangerously explosive.82 Electrochemical data for the first reduced reaction of different CF3 reagents were reported48: 15a (or 15b), 0.63 V; 54i, 0.72 V; 54a, 0.49 V; 54e, 0.49 V; 54l, 0.47 V; 69, 1.10 V; 74, 1.82 V (V vs. Ag/Agþ in CH3CN) (54l, R ¼ 2,4dinitrophenyl in 54). Thus the oxidation potential of the trifluoromethylating reagents
Development of Electrophilic Trifluoromethylating Reagents
283
increased in the order 74 << 69 << 54i < 15a (15b) < 54e ¼ 54a < 54l. The oxidation potentials of CF3I(III) compounds were considerably lower than those of the CF3 sulfonium salts. In the series 54, the electronic nature of substituent at 2-position was reflected in the potentials: 54i (cyclopropyl) << 54e (4-methoxyphenyl) ¼ 54a (phenyl) < 54l (2,4-dinitrophenyl). Another group’s data21a,40 were as follows (V vs. Cp2Fe in CH3CN): 74 (1.49 V) < 69 (1.34 V) < 24 (1.11 V) << 15b (0.75 V). Acyclic sulfonium salt 24 had higher potential than Togni reagents 69 and 74, but lower than Umemoto reagent 15b. In 2013, Wang and Liu reported the trifluoromethylation of nucleophilic substrates with PhI(OAc)2 and TMSCF3 in the presence of KF (Scheme 10.33).83 In their studies, they detected a peak corresponding to [PhICF3]þ species 82 by mass spectrometric analysis of the reaction mixture in CH3CN. It was thus proposed that acyclic (trifluoromethyl)phenyliodonium acetate (81) was formed as an intermediate, which was the target compound attempted by Yagupolskii and Umemoto around 35 years ago. Some other trifluoromethylation reactions with PhI(OAc)2/TMSCF3/base were explained by a similar mechanism.84
Scheme 10.33 Trifluoromethylation with PhI(OAc)2/TMSCF3/KF.
4. Conclusion85 Many electrophilic trifluoromethylating reagents have been developed so far. Many new trifluoromethylations with them have been reported by many newcomers to the fluorine chemistry during the past decade. Accordingly, the field of electrophilic trifluoromethylation, which had been considered to be left undeveloped, has markedly been advanced. The electrophilic trifluoromethylating reagents have a deep and complex chemistry because their reactions may include electron transfer or reduction/oxidation processes. There is still a lot of room to be investigated. Since this chapter could not satisfactorily cover the reactions by the trifluoromethylating reagents because of limited space, readers are advised to read original papers and reviews cited.
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