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Oxidative Radical Intermolecular Trifluoromethylthioarylation of Styrenes by Arenediazonium Salts and Copper(I) Trifluoromethylthiolate Zhiwei Xiao, Yongan Liu, Liping Zheng, Chao Liu, Yong Guo, and Qing-Yun Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00650 • Publication Date (Web): 16 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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The Journal of Organic Chemistry

Oxidative Radical Intermolecular Trifluoromethylthioarylation of Styrenes by Arenediazonium Salts and Copper(I) Trifluoromethylthiolate Zhiwei Xiao†, Yongan Liu†, Liping Zheng‡, Chao Liu†,*, Yong Guo†, Qing-Yun Chen†,* † Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ School of Chemical Engineering and Food Science, Zhengzhou Institute of Technology, 18 Yingcai Street, Zhengzhou 450044 E-mail: [email protected]; [email protected]

Table of Content

Abstract An efficient oxidative radical intermolecular trifluoromethylthioarylation of styrenes with arenediazonium salts and copper(I) trifluoromethylthiolate under mild conditions is described for the first time. The reactions provide good yields of the corresponding trifluoromethylthioarylation products with broad substrate scope and excellent functional group compatibility.

It is well-known that incorporation of a trifluoromethylthio (CF3S) group into an organic molecule can drastically alter its chemical, physical and biological properties due to the intrinsic properties of CF3S, including the strong electron-withdrawing power and high lipophilicity,1 which has stimulated increasing interest in the development of new methods for the direct and efficient introduction of the CF3S group into organic compounds.2 Among numerous approaches to prepare various trifluoromethylthiolated compounds, relatively limited methods for the formation of C(sp3)-SCF3 bonds are available, compared with those for the formation of C(sp2)-SCF3 and C(sp)-SCF3 bonds. Recent and representative methods for direct construction of C(sp3)-SCF3 bonds include nucleophilic,3 electrophilic,4 and radical5 trifluoromethylthiolation. On the other hand, radical difunctionalization of simple alkenes has developed into a powerful tool for the generation of highly functionalized organic compounds commonly with the formation of two C(sp3)-X bonds, and has been widely applied in the synthesis of many fluorinated compounds with simultaneous introduction of a fluorine or fluoroalkyl group with another functional group into alkenes.6 Despite the successful development of radical ACS Paragon Plus Environment

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difunctionalization of alkenes for incorporating both CF3S group and another functional group5d-l, radical intermolecular trifluoromethylthioarylation of alkenes has not been reported. Arenediazonium salts, commonly derived from economical arylamines under mild conditions in high yields, are very important organic intermediates and have been extensively utilized in organic synthesis due to their ready availability, rich reactivity and diverse transformations.7 Besides their classical applications in aromatic substituents, they are important sources of aryl radical and extensively used in famous Meerwein arylation.8 Although much progress has been achieved on Meerwein arylation of alkenes with the introduction of an aryl group and another valuable functional group, including F9a, Cl9b, Br9c, SCN9c. To the best of our knowledge, there is no report on Meerwein trifluoromethylthioarylation of alkenes. In 2015, we reported the direct oxdative radical trifluoromethylthiolation of unactivated alkanes using AgSCF3 and K2S2O8 (Scheme 1a).5b Later on, oxidative decarboxylative radical trifluoromethylthiolation of aliphatic carboxylic acids by AgSCF3/selectfluor was developed (Scheme 1b).5c As an extension of our oxidative radical trilfuoromethylthiolation, we wish to present herein the first example of oxidative radical intermolecular trifluoromethylthioarylation of styrenes with arenediazonium salts and copper(I) trifluoromethylthiolate (CuSCF3)10 under mild conditions, efficiently leading to simultaneous formation of both C(sp3)-SCF3 and C(sp3)-aryl bonds (Scheme 1c).

Scheme 1. Oxidative radical trilfuoromethylthiolation Our initial study commenced with the attempted reaction of 4-methoxybenzenediazonium tetrafluoroborate 1a with methyl acrylate using silver(I) trifluoromethylthiolate (AgSCF3) or CuSCF3 as CF3S source under Ar atmosphere in DMSO at room temperature for 1 hour (Scheme 2). It was found that the reaction proceeded fast and mainly led to a mixture of various trifluoromethylthioarylation polymethyl acrylates with a small amount of Sandmeyer product. Careful examination of the influence of the number of equivalents of 1a and methyl acrylate, solvents, additive sequence did not provide better results (See the Supporting Information for details). These results suggest that 1a is very prone to undergo telomerization, although 1a as an electron-deficient olefin is the preferred substrate for Meerwein arylations and comparatively fast addition of aryl radical to the olefin allows effective suppression of corresponding Sandmeyer product.

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Scheme 2. Reaction of 4-methoxybenzenediazonium tetrafluoroborate 1a with methyl acrylate and AgSCF3 or CuSCF3 under various conditions In order to achieve the desired trifluoromethylthioarylation product, it is very important to maintain the specific reaction order among the aryl radical source, the olefin and the trapping reagent.8a Considering that arenediazonium salt 1a and CF3S source in the above reaction system are not easily changed, we reasoned that the intermolecular trifluoromethylthioarylation may be improved by switching the activated olefin methyl acrylate to styrene, which has comparatively fast addition with aryl radical and are not prone to telomerization compared with methyl acrylate. We then focused on optimization of reaction conditions of the trifluoromethylthioarylation of styrene 2a with arenediazonium salt

and AgSCF3 or CuSCF3 (Table 1). To our delight, the reaction of 1a with 2a and

CuSCF3 or AgSCF3+CuI in DMSO at room temperature for 1 hour successfully resulted in the desired trifluoromethylthioarylation product 3a and almost no formation of various trifluoromethylthioarylation polystyrenes and Sandmeyer product was observed, while no desired product was formed with the use of AgSCF3 under similar conditions (Table 1, entries 1-3). These results exhibited the importance of copper cation for the reaction. Moreover, it was found that ligand played a key role in the reaction and 1,10-phenanthroline (phen) stood out to be the best one among the ligands examined (Table 1, entries 4-8). However, a stoichiometric amount of the ligand phen was required for the desired reaction, while less amount of phen led to lower yields of the desired product (See the Supporting Information for details). In addition, A careful survey of solvents revealed that DMSO was the best solvent and water was harmful for the desired reaction (Table 1, entries 8-12). Table 1. Optimization of Reaction Conditionsa

entry 1 2 3 4 5 6

MSCF3 AgSCF3+CuIb CuSCF3 AgSCF3 CuSCF3 CuSCF3 AgSCF3+CuIb

ligand -c -c -c 2,2'-bpy f L1g 1,10-pheni


solvent DMSO DMSO DMSO DMSO DMSO DMSO

yield (%)d 25 32 0 30 22 46


7 8 9 10 11 12 a

CuSCF3 CuSCF3 CuSCF3 CuSCF3 CuSCF3 CuSCF3

L2h 1,10-pheni 1,10-pheni 1,10-pheni 1,10-pheni 1,10-pheni

Page 4 of 18 DMSO DMSO DMF CH3CN acetone DMSOe

23 80 38 38 16 0

Reaction conditions: MSCF3 (0.2 mmol, 1.0 equiv), ligand (0.2 mmol, 1.0 equiv), 1a (0.6 mmol, 3.0 equiv), 2a (1.2 mmol, 6.0 equiv), solvent (2 mL), Ar atmosphere, RT, 1 h. bAgSCF3 (0.2 mmol) and CuI (0.2 mmol) were used. cNo ligand was used. dYields were determined by 19F NMR spectroscopy using trifluoromethylbenzene as an internal standard. eDMSO:H2O = 95:5 vol/vol was used. f2,2'-bpy = 2,2'-bipyridine. gL1 = 4,4'-di-tert-butyl-2,2'-bipyridine. hL2 = N,N,N',N'-tetramethylethylenediamine. i1,10-phen = 1,10-phenanthroline.

With the optimized reaction conditions in hand (Table 1, entry 8), the substrate scope of various styrenes was examined. As can be seen in Scheme 3, a series of substrates bearing electron-rich (3b-c) and electron-deficient (3i,j) groups were all applied to the intermolecular trifluoromethylthioarylation reactions. The structure of the product was unambiguously characterized by X-ray diffraction studies of 3k (See the Supporting Information for details). Interestingly, the position of substituents on the benzene ring of styrene had slight effect on the reaction, since o-, m- and p-substituted styrenes gave similar yields of the desired products (3f-h).

a

Reaction conditions: CuSCF3 (0.5 mmol, 1.0 equiv), 1,10-phenanthroline (0.5 mmol, 1.0 equiv), 1a (1.5 mmol, 3.0 equiv), 2 (3.0 mmol, 6.0 equiv), DMSO (5 mL), Ar atmosphere, RT, 1 hour. Yields of isolated products were reported.

Scheme 3. Substrate scope of styrenes for the intermolecular trifluoromethylthioarylation reactions.a Next, the scope of the intermolecular trifluoromethylthioarylation reaction was evaluated on various arenediazonium salts and the results are summarized in Scheme 4. A wide range of arenediazonium salts underwent the intermolecular trifluoromethylthioarylation with styrenes to produce the desired products in good yields. A variety of functional groups in Scheme 3, including halogens (4a-d, 4k, 4l), nitro (4h), acetyl (4o), cyano (4p), ether (4g, 4s), were all well tolerated under the standard conditions. Noticeably, pyridinyl (4n), amino (4t), amido (4r) and carboxyl (4v) groups were also compatible with the reaction conditions, resulting in the corresponding products in good ACS Paragon Plus Environment

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yields. But ortho-substituted arenediazonium salt 4i only resulted in trace amount of the desired product. Finally, gram-scale synthesis of 4h was conducted and good yield of the desired product was obtained, demonstrating good scalability of the reaction.



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a

Reaction conditions: CuSCF3 (0.5 mmol, 1.0 equiv), 1,10-phenanthroline (0.5 mmol, 1.0 equiv), 2 (3.0 mmol, 6.0 equiv), 1a (1.5 mmol, 3.0 equiv), DMSO (5 mL), Ar atmosphere, RT, 1 h. Yields of isolated products were reported. b CuSCF3 (6.0 mmol, 1.0 equiv), 1,10-phen (6 mmol, 1.0 equiv), 2 (18 mmol, 6.0 equiv),1a (36 mmol, 3.0 equiv) and DMSO (50 mL) were used. cYields were determined by 19F NMR spectroscopy with trifluoromethylbenzene as an internal standard.

Scheme

Substrate

4.

scope

of

arenediazonium

salts

for

the

intermolecular

a

trifluoromethylthioarylation reactions

Based on the above experimental results and the literature,8 a plausible reaction mechanism was proposed as shown in Scheme 5. Dimeric complex [(phen)Cu(I)SCF3]211 was in situ oxidized by arenediazonium salts to produce the corresponding [(phen)Cu(II)SCF3]2 species and aryl radical, respectively. Fast addition of the aryl radical with styrenes results in the formation of intermediate A. Its following reaction with (phen)Cu(II)SCF3 could proceed in two different ways. The alkyl radical intermediate A could be trapped by (phen)Cu(II)SCF3 to generate intermediate B, followed by reductive elimination to afford the desired trifluoromethylthioarylation product.12 Alternatively, it might be readily oxidized by Cu(II) cation to generate intermediate C and the subsequent attack by CF3S ion finished the final desired product.

Scheme 5. Proposed mechanism for the intermolecular trifluoromethylthioarylation of styrenes with arenediazonium salts and CuSCF3 In summary, we have developed the oxidative radical intermolecular trifluoromethylthioarylation of styrenes with arenediazonium salts and CuSCF3 under mild conditions to simultaneously construct both C(sp3)-SCF3 and C(sp3)-aryl bonds. The reaction exhibits broad substrate scope and excellent functional group compatibility. Copper cation and 1,10-phenanthroline play a key role in the reaction. Further investigation on other difunctionalization of alkenes to introduce both CF3S and another functional group is on the way.

EXPERIMENTAL SECTION General Infromation. NMR spectra were obtained on a 400 MHz spectrometer using CDCl3 as deuterated solvents, with proton, carbon and fluorine resonances at 400 MHz, 100 MHz and 376 MHz, respectively. 1H NMR and 13C NMR chemical shifts were determined relative to internal standard TMS at δ 0.0 ppm and

19

F NMR chemical shifts were determined relatived to CFCl3 as inter standard.

Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in hertz (Hz). The following ACS Paragon Plus Environment

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abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. The NMR yield was determined by 19F NMR using benzotrifluoride (19F NMR: δ -63.0 ppm) as an internal standard before working up the reaction. GC-MS (EI) data were determined on an Agilent 5975C. LRMS (EI) and HRMS (EI) data were tested on a Water Micromass GCT Premier. Element analysis data were determined on Elementar VARIO EL apparatus. IR spectra were recorded on a Thermo Scientific Nicolet 380 FT-IR spectrometer. Unless otherwise noted, solvents were freshly dried and degassed according to the purification handbook Purification of Laboratory Chemicals before using. Flash column chromatography was carried out using 300-400 mesh silica gel. General Procedure for Arenediazonium salts. To a solution of arylamine (8.0 mmol, 1.0 equiv) in THF (10.0 mL), BF3.Et2O (12.0 mmol, 1.5 equiv) was added slowly under cooling with an ice-water bath. tBuONO (9.6 mmol, 1.2 equiv) was then added dropwise. The reaction mixture was stirred for 20 min, then diethyl ether (50 mL) was added. The precipitate formed was filtered, washed with diethyl ether, and dried under reduced pressure at room temperature to give the desired arenediazonium salt. General Procedure for intermolecular trifluoromethylthioarylation of various styrenes with arenediazonium salts and CuSCF3. An oven-dried Schlenck-tube equipped was added CuSCF3 (98.5 mg, 0.5 mmol), 1,10-phenanthroline (36.0 mg, 0.5 mmol) and freshly-distilled DMSO (5.0 mL) under Ar atmosphere at room temperature. After stirring for 10 minutes styrene (3.0 mmol), arenediazonium salts (1.5 mmol) were added in turn. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure after extraction. The crude product was purified by column chromatography on silica gel or HPLC to give the desired product. (2-(4-methoxyphenyl)-1-phenylethyl)(trifluoromethyl)sulfane (3a): Obtained as a colorless liquid in 81% yield (127 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.19 (m, 5H), 6.89 (d, J = 8.5, 2H), 6.73 (d, J = 8.5, 2H), 4.53-4.44 (m, 1H), 3.74 (s, 3H), 3.27-3.08 (m, 2H).

19

F NMR (376 MHz, CDCl3) δ: -39.72 (s, 3F).

13

C NMR (100 MHz,

CDCl3) δ: 158.6, 134.0, 130.6 (q, J = 306 Hz), 131.0, 129.5, 128.8, 128.4, 127.9, 113.9, 55.3, 51.5(d, J = 1 Hz), 42.6. HRMS (EI): calcd for C16H15F3OS (M+) 312.0796, found 312.0789. (2-(4-methoxyphenyl)-1-(p-tolyl)ethyl)(trifluoromethyl)sulfane (3b): Obtained as a colorless liquid in 76% yield (128 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.09 (s, 3H), 6.91 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.6 Hz, 1H), 4.49-4.40 (m, 1H), 3.74 (s, 3H), 3.28-3.08 (m, 2H), 2.31 (s, 3H). 19F NMR (376 MHz, CDCl3) δ: -39.72 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.4, 137.6, 136.7, 130.5 (q, J = 306 Hz), 130.2, 129.5, 129.3, 127.6, 113.7, 55.2, 51.2 (d, J = 2 Hz), 42.4, 21.1. HRMS (EI): calcd for C17H17F3OS (M+) 326.0952, found 326.0944.



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(1-(4-(tert-butyl)phenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane

(3c):

Obtained

as

a

colorless liquid in 82% yield (145 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.30 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 4.49-4.43 (m, 1H), 3.74 (s, 3H), 3.26-3.12 (m, 2H), 1.29 (s, 9H). 19

F NMR (376 MHz, CDCl3) δ: -39.72 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 158.4, 150.9, 136.7,

130.6 (q, J = 306 Hz), 130.2, 129.6, 127.3, 125.5, 113.7, 55.2, 51.1 (d, J = 1 Hz), 42.4, 34.5, 31.3. HRMS (EI): calcd for C20H23F3OS (M+) 368.1422, found 368.1425. (1-(4-fluorophenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3d): Obtained as a colorless liquid in 81% yield (134 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.19-7.14 (m, 2H), 6.96 (t, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H),

6.74 (d, J = 8.7 Hz, 2H), 4.51-4.46 (m, 1H), 3.75 (s, 3H), 3.26-3.01 (m, 2H). CDCl3) δ: -39.73 (s, 3F), -114.04-114.11 (m, 1F).

13

19

F NMR (376 MHz,

C NMR (100 MHz, CDCl3) δ: 162.2 (d, J = 246.9

Hz), 158.6, 135.6 (d, J = 3.3 Hz), 130.4 (q, J = 305 Hz), 130.2, 129.4 (d, J = 8.2 Hz), 129.0, 115.5 (d, J = 21.7 Hz), 113.8, 55.2, 50.6 (d, J = 1.1 Hz), 42.4. HRMS (EI): calcd for C16H14F4OS (M+) 330.0702, found 330.0704. (1-(4-chlorophenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3e): Obtained as a colorless liquid in 80% yield (139 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.25 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.6 Hz,

2H), 6.74 (d, J = 8.7 Hz, 2H), 4.49-4.38 (m, 1H), 3.74 (s, 3H), 3.26-3.03 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.68 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 158.6, 138.5, 133.7, 130.3 (q, J = 306 Hz),

130.2, 129.1, 128.8, 125.7, 113.8, 55.2, 50.6 (d, J = 1 Hz), 42.2. HRMS (EI): calcd for C16H14ClF3OS (M+) 346.0406, found 346.0402. (1-(4-bromophenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3f): Obtained as a colorless liquid in 75% yield (146 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 8.4, 2H), 7.08 (d, J = 8.5, 2H), 6.88 (d, J= 8.5, 2H), 6.74 (d,

J= 8.6, 2H), 4.49-4.38 (m, 1H), 3.75 (s, 4H), 3.27-3.01 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.69 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.6, 139.0, 131.7, 130.3 (q, J = 306 Hz), 130.2, 129.4, 128.8, 121.8, 113.9, 55.2, 50.7 (d, J = 1 Hz), 42.2. HRMS (EI): calcd for C16H14BrF3OS (M+) 389.9901, found 389.9903. (1-(3-bromophenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3g): Obtained as a colorless liquid in 75% yield (147 mg)by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.40-7.36 (m, 2H), 7.17-7.09 (m, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.75 (d,

J = 8.7 Hz, 2H), 4.46-4.39 (m, 1H), 3.75 (s, 3H), 3.23-3.05 (m, 2H).

19

F NMR (376 MHz, CDCl3) δ:

-39.71 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.6, 142.4, 131.1, 130.7, 130.2 (q, J = 306 Hz), 130.2, ACS Paragon Plus Environment

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130.1, 128.7, 126.5, 122.6, 113.9, 55.2, 50.7 (d, J = 1 Hz), 42.2. HRMS (EI): calcd for C16H14BrF3OS (M+) 389.9901, found 389.9897. (1-(2-bromophenyl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3h): Obtained as a colorless liquid in 80% yield (156 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.50 (d, J = 7.4 Hz, 1H), 7.47-7.40 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H),

7.11 (td, J = 8.0, 1.6 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.15 (brs, 1H), 3.77 (s, 3H), 3.26-3.09 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.86 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.6, 139.2, 133.0, 130.4 (q, J = 306 Hz), 130.3, 129.5, 129.2, 128.7, 127.7, 123.6, 113.7, 55.2, 49.6, 41.6. HRMS (EI): calcd for C16H14BrF3OS (M+) 389.9901, found 389.9894. (2-(4-methoxyphenyl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfane (3i): Obtained as a colorless liquid in 76% yield (135 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 4.60-4.54 (m, 1H), 3.76 (s, 3H), 3.29-3.05 (m, 2H).

19

F NMR (376 MHz,

CDCl3) δ: -39.69 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.8, 147.6, 147.4, 130.1, 130.0 (q, J = 306 Hz), 128.7, 128.0, 123.8, 114.0, 55.2, 50.4 (d, J = 1 Hz), 41.9. HRMS (EI): calcd for C16H14F3NO3S (M+) 357.0647, found 357.0643. (2-(4-methoxyphenyl)-1-(3-nitrophenyl)ethyl)(trifluoromethyl)sulfane (3j): Obtained as a colorless liquid in 70% yield (125 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.30 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.7 Hz,

2H), 6.74 (d, J = 8.7 Hz, 2H), 4.63-4.57 (m, 1H), 3.74 (s, 3H), 3.26-3.12 (m, 2H), 1.29 (s, 9H).

19

F

NMR (376 MHz, CDCl3) δ: -39.63 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.8, 148.3, 142.5, 133.9, 130.2, 130.1 (q, J = 306 Hz), 129.6, 128.0, 123.0, 122.7, 114.0, 55.2, 50.4 (d, J = 1.0 Hz), 41.9. HRMS (EI): calcd for C16H14F3NO3S (M+) 357.0647, found 357.0638. (1-([1,1'-biphenyl]-4-yl)-2-(4-methoxyphenyl)ethyl)(trifluoromethyl)sulfane (3k): Obtained as a white solid in 84% yield (164 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 7.60-7.56 (m, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H),

7.37-7.31 (m, 1H), 7.28 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 4.68-4.37 (m, 1H), 3.74 (s, 3H), 3.29-3.16 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.63 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 158.6, 139.0, 131.7, 130.3 (q, J = 306 Hz), 130.2, 129.4, 128.8 (d, J = 2.8 Hz), 121.8, 113.9, 55.2, 50.7 (d, J = 1.0 Hz), 42.2. HRMS (EI): calcd for C22H19F3OS (M+) 388.1109, found 388.1103. m.p.: 91-92 oC. (2-(4-fluorophenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4a): Obtained as a yellow liquid in 73% yield (110 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.33-7.25 (m, 3H), 7.21-7.16 (m, 2H), 6.95-6.85 (m, 4H), 4.50-4.43 (m, 1H), ACS Paragon Plus Environment


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3.32-3.14 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.72 (s, 3F), -115.80 (ddd, J = 14.0, 8.5, 5.6 Hz). 13

C NMR (100 MHz, CDCl3) δ: 161.8 (d, J = 245.2 Hz), 139.4, 132.9 (d, J = 3.3 Hz), 130.7 (d, J = 8.0

Hz), 130.4 (q, J = 305 Hz), 128.7, 128.1, 127.6, 115.2 (d, J = 21.3 Hz), 51.1, 42.5. HRMS (EI): calcd for C15H12F4S (M+) 300.0596, found 300.0593. (2-(4-bromophenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4b):

Obtained as a colourless liquid in 75%

yield (135 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NM6-34R- (400 MHz, CDCl3) δ: 7.34-7.22 (m, 5H), 7.22-7.15 (m, 2H), 6.84 (d, J = 8.2 Hz, 2H), 4.50-4.42 (m, 1H), 3.29-3.13 (m, 2H).

19

F NMR (376 MHz, CDCl3) δ: -39.78 (s, 3F).

13

C NMR (100

MHz, CDCl3) δ: 139.2, 136.2, 131.5, 130.9, 130.4 (q, J = 306 Hz), 128.8, 128.2, 127.6, 120.9, 50.8 (d, J = 2 Hz), 42.7. HRMS (EI): calcd for C15H12BrF3S (M+) 359.9795, found 359.9789. (2-(3-bromophenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4c): Obtained as a yellow liquid in 76% yield (138 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.28 (q, J = 8.2 Hz, 4H), 7.20 (d, J = 7.6 Hz, 2H), 7.14 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.54-4.43 (m, 1H), 3.31-3.13 (m, 2H).

19

F NMR (376 MHz, CDCl3) δ:

13

-39.76 (s, 3F). C NMR (100 MHz, CDCl3) δ: 139.5, 139.2, 132.2, 130.3 (q, J = 305 Hz), 130.1, 129.9, 128.8, 128.2, 127.9, 127.6, 122.4, 50.8, 42.9. HRMS (EI): calcd for C15H12BrF3S (M+) 359.9795, found 359.9802. (2-(4-iodophenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4d): Obtained as a yellow liquid in 77% yield (158 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.2 Hz, 2H), 7.26-7.18 (m, 3H), 7.15-7.10 (m, 2H), 6.65 (d, J = 8.1 Hz, 2H), 4.42-4.36 (m, 1H), 3.23-3.04 (m, 2H). 19F NMR (376 MHz, CDCl3): δ -39.82 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 139.2, 137.4, 136.8, 131.8 (q, J = 306 Hz ), 131.2, 128.7, 128.1, 127.6, 92.4, 50.7 (d, J = 1 Hz), 42.8 . HRMS (EI): calcd for C15H12F3IS (M+) 407.9657, found 407.9652. (1-phenyl-2-(4-(trifluoromethyl)phenyl)ethyl)(trifluoromethyl)sulfane (4e): Obtained as a yellow liquid in 91% yield (160 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m, 3H), 7.22-7.17 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 4.63-4.39 (m, 1H), 3.42-3.22 (m, 2H).

19

F NMR (376 MHz, CDCl3): δ -39.86 (s, 3F),

-62.55 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 141.2 (d, J = 1 Hz), 139.0, 130.3 (q, J = 306 Hz ), 129.5, 129.2 (q, J = 32 Hz ), 128.8, 128.3, 127.6, 125.3 (q, J = 3.7 Hz), 124.1 (q, J = 270 Hz ),50.6, 43.0. HRMS (EI): calcd for C16H12F6S (M+) 350.0564, found 350.0563. (2-(4-(tert-butyl)phenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4f): Obtained as a yellow liquid in 72% yield (122 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.19 (m, 7H), 6.93 (d, J = 7.9 Hz, 2H), 4.56-4.49 (m, 1H), 3.29-3.15 (m, 2H), 1.27 (s, 9H).

19

F NMR (376 MHz, CDCl3) δ: -39.72 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 149.8,


Page 11 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


140.1, 134.2, 130.5 (q, J = 305 Hz), 128.8, 128.6, 127.9, 127.7, 125.3, 51.1, 42.7, 34.4, 31.3. HRMS (EI): calcd for C19H21F3S (M+) 338.1316, found 338.1311. (2-(2-methoxyphenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4g): Obtained as a yellow liquid in 70% yield (110 mg) by silica gel flash column chromatography eluted with PE:EA = 30 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 7.29-7.20 (m, 5H), 7.19-7.13 (m, 1H), 6.88-6.72 (m, 3H), 4.72-4.65 (m, 1H) 3.79 (s, 3H), 3.40-3.04 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.86 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 157.6, 140.7, 131.1, 130.6 (q, J = 305 Hz),128.4, 128.3, 127.7, 127.6, 125.8, 120.3, 110.3, 55.2, 49.5 (d, J = 1 Hz), 38.3 (d, J = 1 Hz). HRMS (EI): calcd for C16H15F3OS (M+) 312.0796, found 312.0793. (2-(3-nitrophenyl)-1-phenylethyl)(trifluoromethyl)sulfane (4h): Obtained as a yellow liquid in 61% yield (100 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 8.08-8.03 (m, 1H), 7.86 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.33-7.27 (m, 3H), 7.23-7.18 (m, 2H), 4.55-4.50 (m, 1H), 3.47-3.28 (m, 2H). 19F NMR (376 MHz, CDCl3): δ -39.79 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 148.2, 139.1, 138.6, 135.4, 130.2 (q, J = 306 Hz ), 129.3, 128.9, 128.5, 127.5, 124.1, 122.1, 50.4 (d, J = 1

Hz), 42.8. HRMS (EI): calcd for C15H12F3NO2S (M+) 327.0541, found

327.0538. (1-(4-nitrophenyl)-2-(p-tolyl)ethyl)(trifluoromethyl)sulfane (4j): Obtained as a yellow liquid in 70% yield (120 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.14 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 7.9 Hz, 2H), 4.63-4.57 (m, 1H), 3.31-3.07 (m, 2H), 2.28 (s, 3H). 19F NMR (376 MHz, CDCl3) δ: -39.69 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 147.6, 147.4, 137.0, 132.9, 130.0 (q, J = 306 Hz), 129.3, 128.9, 128.7, 123.8, 50.3 (d, J = 1 Hz), 42.2, 21.1. HRMS (EI): calcd for C16H14F3NO2S (M+) 341.0697, found 341.0691. (2-(3-bromophenyl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfane (4k): Obtained as a yellow liquid in 77% yield (157 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.17 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.63-4.56 (m, 1H), 3.34-3.09 (m, 2H). 19

F NMR (376 MHz, CDCl3) δ: -39.67 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 147.6, 146.9, 138.3,

132.1, 130.6, 130.2, 129.9 (q, J = 306 Hz), 128.6, 127.7, 124.0, 122.7, 49.9 (d, J = 1 Hz), 42.1. HRMS (EI): calcd for C15H11BrF3NO2S (M+) 404.9646, found 404.9643. (2-(4-chlorophenyl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfane (4l): Obtained as a yellow solid in 74% yield (133 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.16 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 4.61-4.54 (m, 1H), 3.34-3.09 (m, 2H).19F NMR (376 MHz, CDCl3) δ: -39.71 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 147.6, 147.0, 134.5, 133.4, 130.4, 129.9 (q, J = 306 Hz), 128.9, ACS Paragon Plus Environment


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128.6, 124.0, 45.0 (d, J = 2 Hz), 42.0. HRMS (EI): calcd for C15H11ClF3NO2S (M+) 361.0151, found 361.0150. m.p.: 73-74 oC. (2-(naphthalen-1-yl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfan (4m): Obtained as a red liquid in 75% yield (142 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 15.2, 1.4 Hz, 1H), 7.54-7.49 (m, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H), 4.85-4.78 (m, 1H), 3.92-3.43 (m, 2H).19F NMR (376 MHz, CDCl3) δ: -39.60 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 147.7, 147.5, 134.0, 131.9, 131.4, 130.0 (q, J = 306 Hz), 129.3, 128.5, 128.3, 128.0, 126.7, 125.9, 125.1, 123.8, 122.6, 49.1 (d, J = 2 Hz), 40.1. HRMS (EI): calcd for C19H14F3NO2S (M+) 377.0697, found 377.0699. 3-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)quinoline (4n): Obtained as a yellow liquid in 80% yield (151 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.5 Hz, 1H), 7.80 (d, 1H), 7.75-7.67 (m, 2H), 7.58-7.52 (m, 1H), 7.44 (d, J = 8.7 Hz, 2H), 4.75-4.69 (m, 1H), 3.56-3.35 (m, 2H). 19F NMR (376 MHz, CDCl3): δ -39.61 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 151.1, 147.7, 147.3, 146.6, 135.9, 129.8 (q, J = 308 Hz ), 129.7, 129.3, 128.9, 128.6, 127.6, 127.5, 127.2, 124.2, 49.8 (d, J = 2 Hz), 39.9 . HRMS (EI): calcd for C18H13F3N2O2S (M+) 378.0650, found 378.0647. 1-(3-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)phenyl)ethanone (4o): Obtained as a yellow liquid in 57% yield (105 mg)by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.16 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 4.67-4.61 (m, 1H), 3.41-3.19 (m, 2H), 2.56 (s, 3H).

19

F NMR (376 MHz, CDCl3) δ: -39.64 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 197.6,

147.6, 147.1, 137.5, 136.7, 133.7, 129.8 (q, J = 306 Hz), 128.9, 128.6, 128.6, 127.7, 124.0, 49.9 (d, J = 1.6 Hz), 42.3, 26.6. HRMS (EI): calcd for C17H14F3NO3S(M+) 369.0647, found 369.0640. 4-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)benzonitrile (4p): Obtained as a yellow solid in 70% yield (124 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.63-4.57 (m, 1H), 3.44-3.20 (m, 2H).19F NMR (376 MHz, CDCl3): δ -39.72 (s, 3F). 13

C NMR (100 MHz, CDCl3): δ 147.7, 146.5, 141.4, 132.5, 129.9, 129.7 (q, J = 306 Hz ), 128.5, 124.1,

118.3, 111.6, 49.5 (d, J = 1.6 Hz), 42.5. HRMS (EI): calcd for C16H11F3N2O2S (M+) 352.0493, found 352.0498. m.p.: 165-166 oC. (2-(4-(methylsulfonyl)phenyl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfane (4q): Obtained

as a

yellow solid in 69% yield (140 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.7 ACS Paragon Plus Environment

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Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.68-4.61 (m, 1H), 3.48-3.24 (m, 2H), 3.04 (s, 3H). 19F NMR (376 MHz, CDCl3): δ -39.68 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 147.7, 146.6, 142.4, 139.7, 130.1, 129.8 (q, J = 306 Hz ), 128.6, 127.8, 124.2, 49.6 (d, J = 1 Hz), 44.4, 42.2. HRMS (EI): calcd for C16H14F3NO4S2 (M+) 405.0316, found 405.0318. m.p.: 74-75 oC. N-(4-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)phenyl)acetamide (4r): Obtained as a yellow liquid in 77% yield (148 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 8.14 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.6 Hz, 4H), 7.33-7.28 (m, 1H),

6.95-6.87 (m, 2H), 4.61-4.55 (m, 1H), 3.32-3.07 (m, 2H), 2.15 (s, 3H). 19F NMR (376 MHz, CDCl3) δ: -39.69 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 168.4, 147.4, 137.2, 131.8, 130.0 (q, J = 306 Hz), 129.7, 128.7, 123.9, 119.9, 50.2, 42.0, 24.6. HRMS (ESI/DART): calcd for C17H16F3N2O3S (M+H+) 385.0828, found 385.0825. (2-(4-(benzyloxy)phenyl)-1-(4-nitrophenyl)ethyl)(trifluoromethyl)sulfane (4s): Obtained as a yellow solid in 70% yield (152 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1

H NMR (400 MHz, CDCl3) δ: 8.14 (d, J = 8.7 Hz, 2H), 7.42-7.31 (m, 6H), 7.26 (s, 1H), 6.89-6.80 (m,

4H), 5.00 (s, 2H), 4.60-4.54 (m, 1H), 3.30-3.03 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.68 (s, 3F). 13

C NMR (100 MHz, CDCl3) δ: 158.0, 147.6, 147.4, 136.8, 130.2, 130.0 (q, J = 306 Hz), 128.7, 128.6,

128.3, 128.0, 127.5, 123.8, 115.0, 70.0, 50.4 (d, J = 1 Hz), 41.9. HRMS (EI): calcd for C22H18F3NO3S (M+) 433.0960, found 433.0955. m.p.: 63-64 oC. 4-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)-N-phenylaniline (4t): Obtained as red liquid in 61% yield (129 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.28-7.22 (m, 2H), 7.02 (d, J = 7.7 Hz, 2H), 6.93 (dd, J = 14.3, 7.9 Hz, 3H), 6.84 (d, J = 8.4 Hz, 2H), 5.66 (s, 1H), 4.62-4.55 (m, 1H), 3.30-3.03 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: -39.63 (s, 3F). 13C NMR (100 MHz, CDCl3) δ: 147.7, 147.4, 142.6, 142.5, 130.1 (q, J = 306 Hz), 130.0, 129.4, 128.8, 128.1, 123.8, 121.4, 118.1, 117.4, 50.4 (d, J = 1 Hz), 42.0. HRMS (EI): calcd for C21H17F3N2O2S (M+)418.0963, found 418.0965. (1-(4-nitrophenyl)-2-(4-tritylphenyl)ethyl)(trifluoromethyl)sulfane (4u): Obtained as yellow solid in 80% yield (229 mg) by silica gel flash column chromatography eluted with PE:EA = 10 : 1 v/v. 1H NMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.27-7.16 (m, 10H), 7.12 (d, J = 7.1 Hz, 5H), 7.05 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 4.61-4.55 (m, 1H), 3.36-3.02 (m, 2H). 19

F NMR (376 MHz, CDCl3) δ: -39.74 (s, 3F).

13

C NMR (100 MHz, CDCl3) δ: 147.4, 147.4, 146.5,

146.1, 133.6, 131.4, 131.02, 129.99 (q, J = 305 Hz), 128.7, 128.2, 127.5, 126.0, 123.7, 64.7, 50.1, 42.2. HRMS (EI): calcd for C34H26F3NO2S (M+) 569.1636, found 569.1639. m.p.: 130-131 oC. 4-(2-(4-nitrophenyl)-2-((trifluoromethyl)thio)ethyl)benzoic acid (4v): Obtained as white solid in 73% yield (136 mg) by silica gel flash column chromatography eluted with MeOH:CH2Cl2 = 1 : 1 v/v. 1H ACS Paragon Plus Environment


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NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 4.68-4.60 (m, 1H), 3.45-3.20 (m, 2H). 19F NMR (376 MHz, CDCl3): δ -39.72 (s, 3F). 13C NMR (100 MHz, CDCl3): δ 171.1, 147.6, 146.8, 142.2, 130.6, 129.3, 128.6, 128.4, 128.3 (q, J = 306 Hz ), 124.0, 49.7 (d, J = 1 Hz), 42.6. HRMS (EI): calcd for C16H12F3NO4S (M+) 371.0439, found 371.0431. m.p.: 149-150 oC.

ASSOCIATED CONTENT SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Optimization of reaction conditions, copies of 1H, 19F and 13C NMR spectra, X-Ray crystallography data of 3k and CuSCF3.0.8H2O. (PDF) Accession Codes CCDC 1829535 and 1814890 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected] ORCID Chao Liu: 0000-0003-1968-031X Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 21421002, 21672239, 21737004) and Science and Technology Commission of Shanghai Municipality (No. 17ZR1437000). REFERENCES (1) (a) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons: New Jersey, 2008. (b) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Hong Kong, 2009. (c) Hagmann, W. K. The Many Roles for Fluorine in Medicinal ACS Paragon Plus Environment

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Chemistry J. Med. Chem. 2008, 51, 4359-4369. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry Chem. Soc. Rev. 2008, 37, 320-330. (e) Müller, K.; Faeh, F.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition Science, 2007, 317, 1881-1886. (f) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; Pozo, C. D.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011) Chem. Rev. 2014, 114, 2432-2506. (g) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry J. Med. Chem. 2015, 58, 8315-8359. (2) For leading reviews on various trifluoromethylthiolation reactions, see: (a) Toulgoat, F.; Alazet, S.; Billard, T. Direct Trifluoromethylthiolation Reactions: The “Renaissance” of an Old Concept Eur. J. Org. Chem.

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with 3-Chloro-2-methylpropene in the Presence of Potassium Chloride, Bromide, and Thiocyanate Russ. J. Gen. Chem., 2008, 78, 133-135. (10) Copper(I) trifluoromethylthiolate was prepared by the reaction of AgSCF35b and CuBr. Its exact molecular formula is CuSCF3.0.8CH3CN, and it was unambiguously characterized by X-ray crystal analysis, which is consistent with the literature (Rheingold, A. L.; Munavalli, S.; Rossman, D. I.; Ferguson, C. P. X-ray Crystallographic Structure of the Acetonitrile Solvate of Copper(I) Trifluoromethanethiolate: (CF3SCu)10.8CH3CN Inorg. Chem. 1994, 33, 1723-1724.). For simplicity, we used CuSCF3 instead of CuSCF3.0.8CH3CN in the text. For details, see the Supporting Information. (11) Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.; Kong, D.; Yuan, Y.; Huang, K. W. An Air-Stable Copper Reagent for Nucleophilic Trifluoromethylthiolation of Aryl Halides Angew. Chem. Int. Ed. 2013, 52, 1548-1552. (12) For representative examples of high-valent copper mediated coupling reactions via radical pathway for the formation of C(sp3)-X bonds, see: (a) Zhu, R.; Buchwald, S. L. Versatile Enantioselective Synthesis of Functionalized Lactones via Copper-Catalyzed Radical Oxyfunctionalization of Alkenes J. Am. Chem. Soc. 2015, 137, 8069-8077. (b) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. Copper-Catalyzed Intermolecular Amidation and Imidation of Unactivated Alkanes J. Am. Chem. Soc. 2014, 136, 2555-2563. (c) Zhang, W.; Wang, F.; Mccann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay Science, 2016, 353, 1014-1018. For a computational study, see: (d) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.; Liu, X.-Y. A Dual-Catalytic Strategy To Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes J. Am. Chem. Soc. 2016, 138, 9357-9360. (e) Cheng, Y.-F.; Dong, X.-Y.; Gu, Q.-S.; Yu, Z.-L.; Liu, X.-Y. Achiral Pyridine Ligand-Enabled Enantioselective Radical Oxytrifluoromethylation of Alkenes with Alcohols Angew. Chem., Int. Ed. 2017, 56, 8883-8886. For reading examples of high-valent copper mediated coupling reactions via radical pathway for the formation of C(sp2)-X bonds, see: (f) Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J. C. Photoinduced Ullmann C-N Coupling: Demonstrating the Viability of a Radical Pathway Science 2012, 338, 647-651. (g) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Asymmetric copper-catalyzed C-N cross-couplings induced by visible light Science 2016, 351, 681-684. (h) Hickman, A. J.; Sanford, M. S. High-valent organometallic copper and palladium in catalysis Nature 2012, 484, 177-185.


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