Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides, Bromides and Tosylates

Article abstract of DOI:10.1002/cjoc.201500905

A direct nucleophilic trifluoromethylthiolation of alkyl chlorides, bromides and tosylates with AgSCF₃ was described. It was found that the presence of nBu₄NI or a combination of nBu₄NI/nBu₄NBr significantly enhanced the reaction rates. The reaction conditions were mild, thus allowing the tolerance of a variety of functional groups.

Full text of DOI:10.1002/cjoc.201500905

FULL PAPER
DOI: 10.1002/cjoc.201500905
Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides,
Bromides and Tosylates
Chunfa Xu, Qingyun Chen, and Qilong Shen*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
A direct nucleophilic trifluoromethylthiolation of alkyl chlorides, bromides and tosylates with AgSCF3 was de-
scribed. It was found that the presence of nBu4NI or a combination of nBu4NI/nBu4NBr significantly enhanced the
reaction rates. The reaction conditions were mild, thus allowing the tolerance of a variety of functional groups.
Keywords trifluoromethylthiolation, nucleophilic, fluorine, alkyl halides
Introduction
Experimental
Due to its strong electron-withdrawing and high lipo-
philic nature,[1] the trifluoromethylthio group (CF3S－)
is generally considered by the medicinal chemists as one
of the most prominent groups in their isostere-based
drug design.[2] Consequently, development of efficient
methods for the introduction of trifluoromethylthio
group has been the recent focus of pharmaceutical/ag-
rochemical industries, and academic community as
well.[3] In this context, in the past several years, we have
witnessed an explosive increase in the number of the
methodologies for the incorporation of CF3S group into
small molecules that involved the formation of Csp-SCF3,
Csp2-SCF3 or Csp3-SCF3 bond by employing transition
metal catalyzed trifluoromethylthiolation,[4] radical tri-
fluoromethylthiolation[5] or direct trifluoromethylthiola-
tion with an electrophilic trifluoromethylthiolating re-
agent.[6]
General information
1
All solvents were purified by standard method. H
NMR spectra were recorded on a 500 MHz, 400 MHz
or 300 MHz. 19F NMR were recorded on a 376 MHz or
282 MHz spectrometer. 13C NMR spectra were recorded
on a Bruker AM400 spectrometer and Agilent 400 or
500 MHz spectrometer. H NMR and 13C NMR chemi-
1
cal shifts were determined relative to internal standard
TMS at δ 0.0 and 19F NMR chemical shifts were deter-
mined relative to CFCl3 as inter standard. The following
abbreviations were used to explain the multiplicities:
s＝singlet, d＝doublet, t＝triplet, q＝quartet, m＝
multiplet, br＝broad. Flash column chromatograph was
carried out using 300－400 mesh silica gel at medium
pressure. Detection of melting point was conducted on
the SGW X-4 microscopic melting point meter.
Materials
One of the simplest methods for the formation of
alkyl-trifluoromethylthioether is the nucleophilic triflu-
oromethylthiolation of an appropriate electrophile by a
nucleophilic trifluoromethylthiolating reagent.[7] For
example, direct nucleophilic trifluoromethylthiolation of
alkyl halides with Hg(SCF3)2 was reported by
Muetterties as early as 1959.[7a] Yet, with few excep-
tions,[7e,7g] most of the known nucleophilic trifluoro-
methylthiolation methods involved the reactions of ac-
tivated electrophiles such as allylic halides, benzylic
halides or α-halo carbonyl compounds. Herein, we re-
ported a nucleophilic trifluoromethylthiolation of unac-
tivated alkyl chlorides, bromides and tosylates using
easily available AgSCF3[8] as the nucleophile. The reac-
tions were typically conducted at 80－100 ℃ and a
variety of functional groups were compatible.
All reagents were received from commercial sources.
Solvents were freshly dried and degassed according to
the purification handbook Purification of Laboratory
Chemicals before using.
General procedure A for trifluoromethylthiolation of
alkyl bromides
A 25 mL Schlenk tube charged with a magnetic bar,
alkyl bromides (0.5 mmol), nBu4NI (0.65 mmol, 240.5
mg) and AgSCF3 (0.65 mmol, 135.2 mg) was evacuated
under high vacuum and backfilled with argon three
times. Fresh distilled acetone (2.0 mL) was then added
under argon via syringe. The reaction mixture was
stirred at 80 ℃ for 3－24 h, and then cooled to room
temperature. After removal of the solvent under reduced
pressure, the residue was purified by silica-gel column
*
E-mail: shenql@mail.sioc.ac.cn; Tel.: 0086-021-54925197
Received December 27, 2015; accepted January 14, 2016; published online March 8, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500905 or from the author.
Chin. J. Chem. 2016, 34, 495—504
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Xu, Chen & Shen
FULL PAPER
chromatography to give the corresponding products.
2, 2c) The general procedure A with ethyl 7-bromo-
heptanoate (118 mg, 0.5 mmol), gave 118 mg (92%) of
ethyl 7-[(trifluoromethyl)thio]heptanoate as a pale yel-
General procedure B for trifluoromethylthiolation of
alkyl chlorides
1
low liquid. H NMR (400 MHz, CDCl3) δ: 4.09 (q, J＝
A 25 mL Schlenk tube charged with a magnetic bar,
alkyl chlorides (0.5 mmol), nBu4NI (1.0 mmol, 370.0
mg), nBu4NBr (1.0 mmol, 322.0 mg) and AgSCF3 (1.0
mmol, 208.0 mg) was evacuated under high vacuum and
backfilled with argon three times. Fresh distilled THF
(2.0 mL) was then added under argon via syringe. The
reaction mixture was stirred at 80 ℃ for 15 h, and then
cooled to room temperature. After removal of the sol-
vent under reduced pressure, the residue was purified by
silica-gel column chromatography to give the corre-
sponding products.
7.1 Hz, 2H), 2.84 (t, J＝7.4 Hz, 2H), 2.26 (t, J＝7.4 Hz,
2H), 1.70－1.56 (m, 4H), 1.43－1.28 (m, 4H), 1.22 (t,
J＝7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ: 41.39
(s, 3F); 13C NMR (101 MHz, CDCl3) δ: 173.64, 131.29
(q, J＝305.6 Hz), 60.28, 34.22, 29.82, 29.30, 28.51,
28.19, 24.77, 14.27. MS (EI) m/z: 258.1; HRMS (EI):
calcd for C10H17O2F3S: 258.0901, found 258.0903. IR ν:
2939, 2861, 1735, 1251, 1119 cm1.
1-(4-(3-((Trifluoromethyl)thio)propoxy)phenyl)-
ethanone (Scheme 2, 2d)[9] The general procedure A
with 1-[4-(3-bromopropoxy)phenyl]ethanone (128 mg,
0.5 mmol), gave 138 mg (99%) of 1-(4-(3-((trifluoro-
methyl)thio)propoxy)phenyl)ethanone as a pale yellow
General procedure C for trifluoromethylthiolation of
alkyl tosylates
1
liquid. H NMR (400 MHz, CDCl3) δ: 7.90 (d, J＝8.2
A 25 mL Schlenk tube charged with a magnetic bar,
alkyl tosylates (0.5 mmol), nBu4NI (1.0 mmol, 370.0
mg) and AgSCF3 (1.0 mmol, 208.0 mg) was evacuated
under high vacuum and backfilled with argon three
times. Fresh distilled CH3CN (2.0 mL) was then added
under argon via syringe. The reaction mixture was
stirred at 100 ℃ for 6 h, and then cooled to room tem-
perature. After removal of the solvent under reduced
pressure, the residue was purified by silica-gel column
chromatography to give the corresponding products.
(3-Phenylpropyl)(trifluoromethyl)thioether
(Scheme 2, 2a)[7g] The general procedure A with
(3-bromopropyl) benzene (198 mg, 1.0 mmol), gave 157
mg (72%) of (3-phenylpropyl)(trifluoromethyl) sulfane
Hz, 2H), 6.90 (d, J＝8.3 Hz, 2H), 4.11 (t, J＝5.6 Hz,
2H), 3.08 (t, J＝7.1 Hz, 2H), 2.51 (s, 3H), 2.21－2.16
(m, 2H); 19F NMR (376 MHz, CDCl3) δ: 41.17 (s, 3F);
13C NMR (101 MHz, CDCl3) δ: 196.66, 162.48, 131.07
(q, J＝307.5 Hz), 130.61, 114.40, 114.13, 65.57, 29.22,
26.56 (q, J＝2.1 Hz), 26.30. MS (EI) m/z: 278.1; HRMS
(EI): calcd for C12H13O2F3S: 278.0588, found 278.0591.
IR ν: 2943, 1678, 1602, 1508, 1392, 1359, 1272, 1255,
1116, 835 cm1.
2-(4-((Trifluoromethyl)thio)butyl)isoindoline-1,3-
dione (Scheme 2, 2e)[9] The general procedure A with
2-(4-bromobutyl)isoindoline-1,3-dione (140 mg, 0.5
mmol), gave 144 mg (99%) of 2-(4-((trifluoromethyl)-
thio)butyl)isoindoline-1,3-dione as a pale yellow liquid.
1H NMR (400 MHz, CDCl3) δ: 7.79－7.77 (m, 2H),
7.68－7.65 (m, 2H), 3.67 (t, J＝6.7 Hz, 2H), 2.89 (t,
J＝7.0 Hz, 2 H), 1.80－1.69 (m, 4 H); 19F NMR (376
MHz, CDCl3) δ: 41.20 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 168.31, 134.02, 132.04, 131.08 (q, J＝307.4
Hz), 123.26, 37.06, 29.30 (q, J＝2.0 Hz), 27.42, 26.77.
MS (EI) m/z: 303.1; HRMS (EI): calcd for
C13H12NO2F3S: 303.0541, found 303.0538. IR ν: 2945,
1772, 1712, 1397, 1374, 1119, 1032, 720 cm1.
1
as a colorless liquid. H NMR (400 MHz, CDCl3) δ:
7.40 (m, 2H), 7.34－7.24 (m, 3H), 2.95 (t, J＝7.3 Hz,
2H), 2.82 (t, J＝7.5 Hz, 2H), 2.11 (m, 2H); 19F NMR
(376 MHz, CDCl3) δ: 41.00 (s, 3F); 13C NMR (126
MHz, CDCl3) δ: 140.58, 131.27 (q, J＝306.4 Hz),
128.63, 128.51, 126.30, 34.31, 30.70, 29.24. MS (EI)
m/z: 220.1; HRMS (EI) m/z: calcd for C10H11F3S:
220.0534, found 220.0529. IR ν: 3065, 3029, 2928,
1497, 1455, 1115, 744, 699 cm1.
(4-(Naphthalen-2-yloxy)butyl)(trifluoromethyl)-
thioether (Scheme 2, 2b) The general procedure A
with 2-(4-bromobutoxy)naphthalene (139 mg, 0.5
mmol), gave 154 mg (99%) of (4-(naphthalen-2-
yloxy)butyl) (trifluoromethyl)sulfane as a pale yellow
liquid. 1H NMR (400 MHz, CDCl3) δ: 7.85－7.80 (m, 3
H), 7.54－7.50 (m, 1H), 7.44－7.40 (m, 1H), 7.26－
7.17 (m, 2H), 4.10 (t, J＝5.4 Hz, 2H), 3.02 (t, J＝6.6 Hz,
2H), 2.01－1.94 (m, 4H); 19F NMR (376 MHz, CDCl3)
δ: 40.99 (s, 3F); 13C NMR (126 MHz, CDCl3) δ:
156.82, 134.69, 131.33 (q, J ＝ 305.7 Hz), 129.54,
129.13, 127.78, 126.83, 126.51, 123.76, 118.97, 106.67,
67.05, 29.78, 28.10, 26.50. MS (EI) m/z: 300.1; HRMS
(EI): calcd for C15H15OF3S: 300.0796, found 300.0798.
IR ν: 3059, 2945, 2877, 1629, 1600, 1509, 1465, 1391,
1260, 1218, 1107, 1051, 840, 753 cm1.
4-Methyl-7-(4-((trifluoromethyl)thio)butoxy)-2H-
chromen-2-one (Scheme 2, 2f)[9] The general proce-
dure A with 7-(4-bromobutoxy)-4-methyl-2H-chromen-
2-one (155 mg, 0.5 mmol), gave 123 mg (77%) of
4-methyl-7-(4-((trifluoromethyl)thio)butoxy)-2H-chro-
men-2-one as a pale yellow liquid. 1H NMR (400 MHz,
CDCl3) δ: 7.43 (d, J＝8.8 Hz, 1H), 6.79 (dd, J＝8.8, 2.4
Hz, 1H), 6.71 (d, J＝2.4 Hz, 1H), 6.06 (d, J＝1.0 Hz,
1H), 4.00 (t, J＝5.5 Hz, 2H), 2.94 (t, J＝6.6 Hz, 2H),
2.34 (s, 3H), 1.95－1.84 (m, 4H); 19F NMR (376 MHz,
CDCl3) δ: 41.13 (s, 3 F); 13C NMR (101 MHz, CDCl3)
δ: 161.76, 161.12, 155.13, 152.56 131.06 (q, J＝305.9
Hz), 125.55, 113.54, 112.40, 111.82, 101.24, 67.56,
29.55 (q, J＝2.0 Hz), 27.73, 26.22, 18.54. MS (EI) m/z:
332.2; HRMS (EI): calcd for C15H15O3F3S: 332.0694,
found 332.0690. IR ν: 2950, 1720, 1615, 1388, 1294,
1119, 1071, 849 cm1.
Ethyl 7-((trifluoromethyl)thio)heptanoate (Scheme
496
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Chin. J. Chem. 2016, 34, 495—504

Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides, Bromides and Tosylates
9-(4-((Trifluoromethyl)thio)butyl)-9H-carbazole
(Scheme 2, 2g) The general procedure A with 9-(4-
bromobutyl)-9H-carbazole (155 mg, 0.5 mmol), gave
152 mg (94%) of 9-(4-((trifluoromethyl)thio) butyl)-9H-
carbazole as a white solid. 1H NMR (400 MHz, CDCl3)
δ: 8.19 (d, J＝7.7 Hz, 2H), 7.56 (t, J＝8.4 Hz, 2H), 7.42
(d, J＝8.2 Hz, 2H), 7.34 (t, J＝7.2 Hz, 2H), 4.32 (t, J＝
7.0 Hz, 2H), 2.86 (t, J＝7.2 Hz, 2H), 2.02－1.97 (m,
2H), 1.82－1.76 (m, 2H); 19F NMR (376 MHz, CDCl3)
δ: 40.98 (s, 3F); 13C NMR (101 MHz, CDCl3) δ:
140.32, 131.15 (q, J ＝ 305.9 Hz), 125.84, 122.99,
120.52, 119.10, 108.56, 42.30, 29.59 (q, J＝2.0 Hz),
27.84, 27.22. MS (EI) m/z: 323.2; HRMS (EI): calcd for
C17H16NF3S: 323.0956, found 323.0955. IR ν: 3047,
2943, 2860, 1592, 1484, 1468, 1325, 1122, 752 cm1.
Dimethyl 2-allyl-2-(2-((trifluoromethyl)thio)ethyl)
malonate (Scheme 2, 2h) The general procedure A
with dimethyl 2-allyl-2-(2-bromoethyl)malonate (59 mg,
0.21 mmol), gave 63 mg (99%) of dimethyl 2-allyl-2-(2-
((trifluoromethyl)thio)ethyl)malonate as a pale yellow
4-(4-bromobutoxy)benzoate (150 mg, 0.5 mmol), gave
149 mg (92%) of ethyl 4-(4-((trifluoromethyl)thio)bu-
1
toxy)benzoate as a pale yellow liquid. H NMR (400
MHz, CDCl3) δ: 7.98 (d, J＝8.9 Hz, 2H), 6.87 (d, J＝
8.9 Hz, 2H), 4.33 (q, J＝7.1 Hz, 2H), 4.00 (t, J＝5.4 Hz,
2H), 2.95 (t, J＝6.5 Hz, 2H), 1.90－1.89 (m, 4H), 1.36
(t, J＝7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
41.19 (s, 3F); 13C NMR (126 MHz, CDCl3) δ: 166.35,
162.55, 131.59, 131.19 (q, J ＝ 307.7 Hz), 123.11,
114.02, 67.23, 60.67, 29.68, 27.95, 26.36, 14.39. MS
(EI) m/z: 322.2; HRMS (EI): calcd for C14H17O3F3S:
322.0851, found 322.0848. IR ν: 2952, 1712, 1607,
1510, 1278, 1254, 1115, 771 cm1.
1-(1H-Pyrrol-1-yl)-2-((trifluoromethyl)thio)pro-
pan-1-one (Scheme 2, 2l) The general procedure A
with 2-bromo-1-(1H-pyrrol-1-yl)propan-1-one (80 mg,
0.4 mmol), nBu4NI (222 mg, 0.6 mmol), AgSCF3 (125
mg, 0.6 mmol), gave 81 mg (90%) of 1-(1H-pyrrol-1-
yl)-2-((trifluoromethyl)thio)propan-1-one as a pale yel-
low liquid. 1H NMR (400 MHz, CDCl3) δ: 10.11 (s, 1H),
7.18－7.16 (m, 1H), 7.04－7.03 (m, 1H), 6.36－6.33
(m, 1H), 4.68 (q, J＝7.1 Hz, 1H), 1.70 (d, J＝7.1 Hz,
3H); 19F NMR (376 MHz, CDCl3) δ: 40.60 (s, 3F); 13C
NMR (101 MHz, CDCl3) δ: 186.41, 130.70 (q, J＝
307.0 Hz), 128.84, 127.27, 117.98, 111.40, 44.09 19.94.
MS (EI) m/z: 222.9; HRMS (EI): calcd for C8H8NOF3S:
223.0279, found 223.0277. IR ν: 3299, 2984, 2936,
1636, 1544, 1451, 1403, 1115, 1049, 1009, 910, 756
cm1.
1
liquid. H NMR (400 MHz, CDCl3) δ: 5.67－5.58 (m,
1H), 5.14 (d, J＝12.4, 2H), 3.73 (s, 6H), 2.85－2.81 (m,
2H), 2.66 (d, J＝7.4 Hz, 2H), 2.26－2.22 (m, 2H); 19F
NMR (376 MHz, CDCl3) δ: 41.35 (s, 3F); 13C NMR
(101 MHz, CDCl3) δ: 170.71, 131.56, 130.89 (q, J＝
306.3 Hz), 119.82, 57.20, 52.66, 37.84, 33.44, 24.97 (q,
J＝2.1 Hz). MS (EI) m/z: 300.1; HRMS (EI): calcd for
C11H15O4F3S: 300.0643, found 300.0644. IR ν: 3457,
2956, 1735, 1115, 927, 756 cm1.
(4-Nitrophenethyl)(trifluoromethyl)thioether
(Scheme 2, 2i) The general procedure A with 1-(2-
bromoethyl)-4-nitrobenzene (119 mg, 0.5 mmol), gave
120 mg (96%) of (4-nitrophenethyl) (trifluoromethyl)-
Phenyl
2-((trifluoromethyl)thio)propanoate
(Scheme 2, 2m) The general procedure A with phenyl
2-bromopropanoate (91.2 mg, 0.4 mmol), nBu4NI (222
mg, 0.6 mmol), AgSCF3 (125 mg, 0.6 mmol), gave 75
mg (75%) of phenyl 2-((trifluoromethyl)thio) pro-
1
sulfane as a pale yellow liquid. H NMR (400 MHz,
1
CDCl3) δ: 8.17 (d, J＝8.6 Hz, 2H), 7.38 (d, J＝8.6 Hz,
2H), 3.18－3.12 (m, 4H); 19F NMR (376 MHz, CDCl3)
δ: 41.01 (s, 3F); 13C NMR (101 MHz, CDCl3) δ:
147.16, 146.38, 131.03 (q, J ＝ 308.7 Hz), 129.64,
124.01, 35.77, 30.58 (q, J＝1.9 Hz). MS (EI) m/z: 251.1;
HRMS (EI): calcd for C9H8NO2F3S: 251.0228, found
251.0223. IR ν: 3081, 2945, 2856, 1606, 1521, 1348,
1115, 855, 757 cm1.
(4-(4-Methoxyphenoxy)butyl)(trifluoromethyl)
thioether (Scheme 2, 2j)[9] The general procedure A
with 1-(4-bromobutoxy)-4-methoxybenzene (129 mg,
0.5 mmol), gave 105 mg (74%) of (4-(4-methoxyphe-
noxy) butyl)(trifluoromethyl)sulfane as a pale yellow
liquid. 1H NMR (400 MHz, CDCl3) δ: 6.85 (s, 4H), 3.95
(t, J＝5.4 Hz, 2H), 3.78 (s, 3H), 2.98 (t, J＝6.7 Hz, 2H),
1.93－1.87 (m, 4H); 19F NMR (376 MHz, CDCl3) δ:
41.15 (s, 3F); 13C NMR (126 MHz, CDCl3) δ: 154.02,
153.08, 131.27 (q, J＝281.6 Hz), 115.51, 114.76, 67.73,
55.74, 29.77 (q, J＝2.0 Hz), 28.26, 26.49. MS (EI) m/z:
280.1; HRMS (EI): calcd for C12H15O2F3S: 280.0745,
found 280.0743. IR ν: 2950, 2871, 1508, 1469, 1232,
1118, 1040, 825, 734 cm1.
panoate as a pale yellow liquid. H NMR (400 MHz,
CDCl3) δ: 7.41 (t, J＝7.8 Hz, 2H), 7.27 (t, J＝7.4 Hz,
1H), 7.12 (d, J＝7.7 Hz, 2H), 4.16 (q, J＝7.3 Hz, 1H),
1.74 (d, J＝7.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
40.35 (s, 3F); 13C NMR (101 MHz, CDCl3) δ: 169.89,
150.55, 130.24 (q, J ＝ 308.6 Hz), 129.71, 126.48,
121.19, 41.57 (q, J＝1.7 Hz), 18.14. MS (EI) m/z: 250.1;
HRMS (EI): calcd for C10H9O2F3S: 250.0275, found
250.0274. IR ν: 1766, 1593, 1493, 1454, 1322, 1232,
1195, 1164, 1115, 1076, 757, 688 cm1.
N,N-Diethyl-2-((trifluoromethyl)thio)propanamide
(Scheme 2, 2n)
2-bromo-N,N-diethylpropanamide (104 mg, 0.5 mmol),
gave 101 mg (88%) of N,N-diethyl-2-((trifluoromethyl)-
thio)propanamide as a colorless liquid. H NMR (400
MHz, CDCl3) δ: 4.19 (q, J＝6.8 Hz, 1H), 3.42－3.30 (m,
4H), 1.63 (d, J＝6.8 Hz, 3H), 1.23 (t, J＝7.1 Hz, 3H),
1.11 (t, J＝7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
40.90 (s, 3F); 13C NMR (101 MHz, CDCl3) δ: 169.50,
131.01 (q, J＝306.8 Hz), 42.51, 40.93, 40.54, 20.48,
14.63, 12.64. MS (EI) m/z: 229.1; HRMS (EI): calcd for
C8H14NOF3S: 229.0784, found 229.0743. IR ν: 2976,
2933, 1651, 1513, 1461, 1432, 1263, 1135, 1120, 1062,
792 cm1.
The general procedure A with
1
Ethyl 4-(4-((trifluoromethyl)thio)butoxy)benzoate
(Scheme 2, 2k)[9] The general procedure A with ethyl
Chin. J. Chem. 2016, 34, 495—504
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Xu, Chen & Shen
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1-(4-Fluorophenyl)-2-((trifluoromethyl)thio)pro-
pan-1-one (Scheme 2, 2o) The general procedure A
with 2-bromo-1-(4-fluorophenyl)propan-1-one (115 mg,
0.5 mmol), gave 105 mg (83%) of 1-(4-fluorophenyl)-
2-((trifluoromethyl)thio)propan-1-one as a pale yellow
(EI) m/z: 245.9; HRMS (EI): calcd for C11H9OF3S:
246.0326, found 246.0330. IR ν: 2937, 1687, 1599,
1486, 1456, 1434, 1354, 1312, 1276, 1224, 1116, 1025,
1006, 949, 895, 816, 795, 757, 741, 619, 471 cm1.
6-((Trifluoromethyl)thio)hexyl cyclohexane car-
boxylate (Scheme 4, 3b) The general procedure B
with 6-chlorohexyl cyclohexanecarboxylate (98.4 mg,
0.4 mmol), gave 119 mg (95%) of 6-((trifluoromethyl)-
thio)hexyl cyclohexanecarboxylate as a pale yellow liq-
1
liquid. H NMR (400 MHz, CDCl3) δ: 8.08－8.04 (m,
2H), 7.18－7.14 (m, 2H), 5.24 (q, J＝6.6 Hz, 1H), 1.90
(d, J＝6.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
39.85 (s, 3F), 103.09 (m, 1F); 13C NMR (101 MHz,
CDCl3) δ: 194.82, 166.43 (d, J＝256.9 Hz), 131.64 (d,
J＝9.5 Hz), 130.82 (q, J＝308.4 Hz), 130.58 (d, J＝3.0
Hz), 116.38 (d, J＝22.1 Hz), 44.33, 19.76. MS (EI) m/z:
251.9; HMRS (EI): calcd for C10H8OF4S: 252.0232,
found 252.0230. IR ν: 3353, 3075, 2936, 2876, 1686,
1599, 1508, 1452, 1410, 1315, 1205, 1239, 1115, 975,
849, 819, 756, 591 cm1.
1
uid. H NMR (400 MHz, CDCl3) δ: 4.02 (t, J＝6.3 Hz,
2H), 2.84 (t, J＝7.2 Hz, 2H), 2.28－2.21 (m, 1H), 1.86
(d, J＝12.7 Hz, 2H), 1.70－1.58 (m, 7H), 1.45－1.31
(m, 6H), 1.26－1.16 (m, 3H); 19F NMR (376 MHz,
13
CDCl3) δ: 41.60 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 176.13, 131.16 (q, J＝305.7 Hz), 63.85, 43.24, 29.71
(q, J＝2.0 Hz), 29.27, 29.03, 28.44, 28.06, 25.75, 25.43,
25.34. MS (EI) m/z: 312.1; HRMS (EI): calcd for
C14H23O2F3S: 312.1371, found 312.1374. IR ν: 2935,
2858, 1731, 1452, 1117, 756 cm1.
1-(4-Bromophenyl)-2-((trifluoromethyl)thio)pro-
pan-1-one (Scheme 2, 2p)[7i] The general procedure A
with 2-bromo-1-(4-bromophenyl)propan-1-one (145 mg,
0.5 mmol), gave 109 mg (70%) of 1-(4-bromophenyl)-
2-((trifluoromethyl)thio)propan-1-one as a pale yellow
6-((Trifluoromethyl)thio)hexyl benzoate (Scheme
4, 3c) The general procedure B with 6-chlorohexyl
benzoate (96 mg, 0.4 mmol), gave 146 mg (95%) of
6-((trifluoromethyl)thio)hexyl benzoate as a pale yellow
1
liquid. H NMR (400 MHz, CDCl3) δ: 7.83 (d, J＝8.8
Hz, 2H), 7.65 (J＝8.8 Hz, 2H), 4.89 (q, J＝7.1 Hz, 1H),
1.71 (d, J＝7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
39.75 (s, 3F); 13C NMR (101 MHz, CDCl3) δ: 195.23,
132.79, 132.35, 130.61 (q, J ＝ 308.5 Hz), 130.16,
129.45, 44.14, 19.47. MS (EI) m/z: 312, 314; HRMS
(EI): calcd for C10H8OF3SBr: 311.9431, found 311.9429.
IR ν: 2936, 1687, 1585, 1566, 1485, 1452, 1398, 1380,
1317, 1296, 1241, 1203, 1118, 1072, 1011, 972, 952,
840, 769, 756, 471 cm1.
1
liquid. H NMR (400 MHz, CDCl3) δ: 8.04－8.01 (m,
2H), 7.56－7.51 (m, 1H), 7.44－7.39 (m, 2H), 4.30 (t,
J＝6.5 Hz, 2H), 2.86 (t, J＝7.4 Hz, 2H), 1.79－1.68 (m,
4H), 1.51－1.42 (m, 4H); 19F NMR (376 MHz, CDCl3)
δ: 41.34 (s, 3F); 13C NMR (101 MHz, CDCl3) δ:
166.60, 132.85, 130.88 (q, J ＝ 306.8 Hz), 130.44,
129.52, 128.33, 64.75, 29.75, 29.30, 28.54, 28.12, 25.48.
MS (EI) m/z: 306.1; HRMS (EI): calcd for C14H17O2F3S:
306.0901, found 306.0899. IR ν: 2940, 2816, 1720,
1602, 1585, 1491, 1452, 1275, 1116 cm1.
1-(4-Chlorophenyl)-2-((trifluoromethyl)thio)pro-
pan-1-one (Scheme 2, 2q) The general procedure A
with 2-bromo-1-(4-chlorophenyl)propan-1-one (123 mg,
0.5 mmol), gave 98 mg (73%) of 1-(4-chlorophenyl)-2-
((trifluoromethyl)thio)propan-1-one as a pale yellow
6-((Trifluoromethyl)thio)hexyl
2-phenylacetate
(Scheme 4, 3d) The general procedure B with
6-chlorohexyl 2-phenylacetate (101 mg, 0.4 mmol),
gave 118 mg (92%) of 6-((trifluoromethyl)thio)hexyl
2-phenylacetate as a pale yellow liquid. 1H NMR (400
MHz, CDCl3) δ: 7.35－7.25 (m, 5H), 4.09 (t, J＝6.6 Hz,
2H), 3.62 (s, 2H), 2.84 (t, J＝7.4 Hz, 2H), 1.66－1.59
(m, 4H), 1.43－1.30 (m, 4H); 19F NMR (376 MHz,
1
liquid. H NMR (400 MHz, CDCl3) δ: 7.89 (d, J＝8.6
Hz, 2H), 7.63 (d, J＝8.6 Hz, 2H), 5.22 (q, J＝6.6 Hz,
1H), 1.90 (d, J＝6.6 Hz, 3H); 19F NMR (376 MHz,
13
CDCl3) δ: 39.79 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 195.17, 140.38, 132.51, 130.77 (q, J＝308.4 Hz),
130.25, 129.49, 44.31, 19.64. MS (EI) m/z: 268.0;
HRMS (EI): calcd for C10H8OF3SCl: 267.9936, found
267.9940. IR ν: 2934, 1686, 1590, 1319, 1119, 842
cm1.
13
CDCl3) δ: 42.36 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 171.55, 134.18, 131.21 (q, J＝306.8 Hz), 129.24,
128.55, 127.07, 64.99, 41.82, 29.71, 29.29, 28.35, 28.00,
25.45. MS (EI) m/z: 320.2, HRMS (EI): calcd for
C15H19O2F3S: 320.1058, found 320.1063. IR ν: 2940,
2861, 1735, 1497, 1455, 1115, 723 cm1.
2-((Trifluoromethyl)thio)-3,4-dihydronaphthalen-
1(2H)-one (Scheme 2, 2r) The general procedure A
with 2-bromo-3,4-dihydronaphthalen-1(2H)-one (112
mg, 0.5 mmol), gave 80 mg (65%) of 2-((trifluorometh-
yl)thio)-3,4-dihydronaphthalen-1(2H)-one as a pale yel-
low liquid. 1H NMR (400 MHz, CDCl3) δ: 8.03 (dd, J＝
7.9, 1.0 Hz, 1H), 7.53 (td, J＝7.5, 1.4 Hz, 1H), 7.38－
7.30 (m, 1H), 7.27 (d, J＝7.9 Hz, 1H), 4.36 (dd, J＝
10.9, 4.4 Hz, 1H), 3.17－3.06 (m, 2H), 2.75－2.63 (m,
1H), 2.47－2.31 (m, 1H); 19F NMR (376 MHz, CDCl3)
δ: 38.73 (s, 3F); 13C NMR (101 MHz, CDCl3) δ:
192.17, 142.97, 134.31, 131.10, 130.77 (q, J＝308.2
Hz), 128.77, 128.17, 127.18, 51.76, 31.23, 28.18. MS
2-((6-((Trifluoromethyl)thio)hexyl)oxy)tetrahydro-
2H-pyran (Scheme 4, 3e) The general procedure B
with 2-(6-chlorohexyloxy)tetrahydro-2H-pyran (88 mg,
0.4 mmol), gave 130 mg (91%) of 2-((6-((trifluoro-
methyl)thio)hexyl)oxy)tetrahydro-2H-pyran as a pale
1
yellow liquid. H NMR (400 MHz, CDCl3) δ: 4.57 (m,
1H), 3.87－3.81 (m, 1H), 3.74－3.69 (m, 1H), 3.50－
3.45 (m, 1H), 3.39－3.33 (m, 1H), 2.85 (t, J＝7.4 Hz,
2H), 1.79－1.77 (m, 1H), 1.70－1.64 (m, 3H), 1.58－
1.48 (m, 6H), 1.41－1.36 (m, 4H); 19F NMR (376 MHz,
13
CDCl3) δ: 41.38 (s, 3F); C NMR (101 MHz, CDCl3)
498
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 495—504

Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides, Bromides and Tosylates
δ: 131.17 (q, J＝305.6 Hz), 98.80, 67.23, 62.21, 30.70,
29.69, 29.44, 29.29, 28.23, 25.60, 25.44, 19.59. MS (EI)
m/z: 285.1 (MH); HRMS (EI): calcd for C12H20O2F3S
(M-H): 285.1136, found 285.1135. IR ν: 2940, 2862,
1455, 1352, 1119, 1078, 1034, 869 cm1.
118.17, 64.32, 29.72, 29.31, 28.53, 28.12, 25.42. MS
(EI) m/z: 332.2; HRMS (EI): calcd for C16H19O2F3S:
332.1058, found 332.1056. IR ν: 2940, 2860, 1713,
1638, 1327, 1311, 1202, 1119, 768 cm1.
6-((Trifluoromethyl)thio)hexyl furan-2-carboxy-
late (Scheme 4, 3j) The general procedure B with
6-chlorohexyl furan-2-carboxylate (115 mg, 0.5 mmol),
gave 137 mg (92%) of 6-((trifluoromethyl)thio)hexyl
(2-(4-Fluorophenoxy)ethyl)(trifluoromethyl)thio-
ether (Scheme 4, 3f) The general procedure B with
1-(2-chloroethoxy)-4-fluorobenzene (87 mg, 0.5 mmol),
gave 100 mg (83%) of (2-(4-fluorophenoxy)ethyl) (tri-
1
furan-2-carboxylate as a pale yellow liquid. H NMR
1
fluoromethyl)sulfane as a pale yellow liquid. H NMR
(400 MHz, CDCl3) δ: 7.67－7.50 (m, 1H), 7.15 (d, J＝
3.5 Hz, 1H), 6.58－6.15 (m, 1H), 4.28 (t, J＝6.4 Hz,
2H), 2.86 (t, J＝7.3 Hz, 2H), 1.76－1.67 (m, 4H),
1.54－1.43 (m, 4 H); 19F NMR (376 MHz, CDCl3) δ:
41.97 (s, 3F); 13C NMR (101 MHz, CDCl3) δ: 158.76,
146.21, 144.80, 131.16 (q, J＝305.7 Hz), 117.75, 111.77,
64.69, 29.70, 29.26, 28.47, 28.06, 25.33. MS (EI) m/z:
296.1; HRMS (EI): calcd for C12H15O3F3S: 296.0694,
found 296.0692. IR ν: 3445, 2942, 2862, 1728, 1581,
1298, 1118, 764 cm1.
6-((Trifluoromethyl)thio)hexyl thiophene-2-car-
boxylate (Scheme 4, 3k) The general procedure B
with 6-chlorohexyl thiophene-2-carboxylate (112 mg,
0.5 mmol), gave 158 mg (91%) of 6-((trifluoromethyl)-
thio)hexyl thiophene-2-carboxylate as a pale yellow
liquid. 1H NMR (400 MHz, CDCl3) δ: 7.78 (dd, J＝3.7,
0.8 Hz, 1H), 7.53 (dd, J＝5.0, 0.8 Hz, 1H), 7.08 (dd,
J＝4.7, 3.9 Hz, 1H), 4.27 (t, J＝6.6 Hz, 2H), 2.86 (t,
J＝7.4 Hz, 2H), 1.89－1.61 (m, 4H), 1.52－1.38 (m,
4H); 19F NMR (376 MHz, CDCl3) δ: 41.34 (s, 3F); 13C
NMR (101 MHz, CDCl3) δ: 162.54, 133.97, 133.30,
132.24, 131.17 (q, J＝306.9 Hz), 127.72, 64.92, 29.75,
29.30, 28.49, 28.10, 25.41. MS (EI) m/z: 312.1; HRMS
(EI): calcd for C12H15O2F3S2: 312.0466, found 312.0464.
IR ν: 2940, 2861, 1710, 1526, 1420, 1281, 1262, 1116,
752 cm1.
(400 MHz, CDCl3) δ: 7.10－6.93 (m, 2H), 6.94－6.80
(m, 2H), 4.18 (t, J＝6.4 Hz, 2H), 3.25 (t, J＝6.4 Hz,
2H); 19F NMR (376 MHz, CDCl3) δ: 40.98 (s, 3F),
122.99 (s, 1F); 13C NMR (101 MHz, CDCl3) δ: 157.84
(q, J＝239.3 Hz), 154.36 (d, J＝2.1 Hz), 131.08 (q, J＝
306.2 Hz), 116.14 (d, J＝23.2 Hz), 115.96 (d, J＝8.1
Hz), 67.48, 29.13. MS (EI) m/z: 240.1; HRMS (EI):
calcd for C9H8OF4S: 240.0232, found 240.0229. IR ν:
2945, 1507, 1496, 1248, 1222, 1116, 1030, 829 cm1.
(2-(4-Bromophenoxy)ethyl)(trifluoromethyl)thio-
ether (Scheme 4, 3g) The general procedure B with
1-bromo-4-(2-chloroethoxy)benzene (117 mg, 0.5
mmol), gave 102 mg (68%) of (2-(4-bromophenoxy)-
ethyl)(trifluoromethyl)sulfane as a pale yellow liquid.
1H NMR (400 MHz, CDCl3) δ: 7.40 (d, J＝9.0 Hz, 2H),
6.79 (d, J＝9.0 Hz, 2H), 4.19 (t, J＝6.4 Hz, 2H), 3.26 (t,
J＝6.4 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 40.98
(s, 3F); 13C NMR (101 MHz, CDCl3) δ: 157.33, 132.55,
131.03 (q, J＝307.4 Hz), 116.55, 113.84, 66.85, 29.02
(q, J＝2.1 Hz). MS (EI) m/z: 300.0; HRMS (EI): calcd
for C9H8OF3SBr: 299.9431, found 299.9435. IR ν: 2939,
2881, 1592, 1580, 1489, 1466, 1299, 1243, 1115, 1072,
1029, 822 cm1.
1-(4-(2-((Trifluoromethyl)thio)ethoxy)phenyl)eth-
anone (Scheme 4, 3h) The general procedure B with
1-(4-(2-chloroethoxy)phenyl)ethanone (99 mg, 0.5
mmol), gave 123 mg (93%) of 1-(4-(2-((trifluoromethyl)
thio)ethoxy)phenyl)ethanone as a pale yellow liquid. 1H
NMR (400 MHz, CDCl3) δ: 7.92 (d, J＝8.9 Hz, 2H),
6.91 (d, J＝8.8 Hz, 2H), 4.26 (t, J＝6.3 Hz, 2H), 3.27 (t,
J＝6.4 Hz, 2H), 2.54 (s, 3H); 19F NMR (376 MHz,
6-((Trifluoromethyl)thio)hexyl picolinate (Scheme
4, 3l) The general procedure B with 6-chlorohexyl
picolinate (97 mg, 0.4 mmol), gave 104 mg (85%) of
6-((trifluoromethyl)thio)hexyl picolinate as a pale yel-
1
low liquid. H NMR (400 MHz, CDCl3) δ: 8.74－8.73
(m, 1H), 8.11－8.08 (m, 1H), 7.81 (td, J＝7.7, 1.7 Hz,
1H), 7.45 (ddd, J＝7.6, 4.7, 1.2 Hz, 1H), 4.39 (t, J＝6.8
Hz, 2H), 2.85 (t, J＝7.4 Hz, 2H), 1.83－1.77 (m, 2H),
1.70－1.69 (m, 2H), 1.46－1.43 (m, 4H); 19F NMR
(376 MHz, CDCl3) δ: 42.00 (s, 3F); 13C NMR (101
MHz, CDCl3) δ: 165.23, 149.88, 148.20, 136.95, 131.14
(q, J＝305.7 Hz), 126.81, 125.07, 65.68, 29.70, 29.25,
28.45, 28.08, 25.33. MS (EI) m/z: 307; HRMS (EI):
calcd for C13H16NO2F3S: 307.0854; found 307.0857. IR
ν: 2940, 2861, 1740, 1720, 1306, 1292, 1119, 747 cm1.
Dodecyl(trifluoromethyl)thioether (Scheme 5,
4a)[10] The general procedure C with dodecyl 4-methyl-
benzene sulfonate (170 mg, 0.5 mmol), gave 104 mg
(77%) of dodecyl(trifluoromethyl)sulfane as a pale yel-
13
CDCl3) δ: 40.99 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 196.70, 161.86, 130.95, 130.86 (q, J＝307.5 Hz),
130.66, 114.19, 66.56, 28.79, 26.37. MS (EI) m/z: 264.1;
HRMS (EI): calcd for C11H11O2F3S: 264.0432, found
264.0433. IR ν: 3003, 1678, 1600, 1508, 1150, 1111,
1017, 829 cm1.
6-((Trifluoromethyl)thio)hexyl cinnamate (Scheme
4, 3i). The general procedure B with 6-chlorohexyl cin-
namate (106 mg, 0.4 mmol), gave 115 mg (86%) of
6-((trifluoromethyl)thio)hexyl cinnamate as a pale yel-
1
low liquid. H NMR (400 MHz, CDCl3) δ: 7.69 (d, J＝
16.0 Hz, 1 H), 7.53－7.51 (m, 2H), 7.38－7.37 (m, 3H),
6.44 (d, J＝16.0 Hz, 1H), 4.20 (t, J＝6.6 Hz, 2H), 2.88
(t, J＝7.4 Hz, 2H), 1.79－1.63 (m, 4H), 1.51－1.38 (m,
4H); 19F NMR (376 MHz, CDCl3) δ: 41.22 (s, 3F); 13C
NMR (101 MHz, CDCl3) δ: 166.97, 144.68, 134.45,
131.22 (q, J ＝ 303.8 Hz), 130.25, 128.88, 128.05,
1
low liquid. H NMR (400 MHz, CDCl3) δ: 2.88 (t, J＝
7.5 Hz, 2H), 1.72－1.64 (m, 2H), 1.40－1.27 (m, 18H),
0.89 (t, J＝6.8 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ:
41.41 (s, 3F); 13C NMR (126 MHz, CDCl3) δ: 131.41
Chin. J. Chem. 2016, 34, 495—504
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499

Xu, Chen & Shen
FULL PAPER
(q, J＝305.6 Hz), 32.11, 30.06 (q, J＝1.9 Hz), 29.81,
29.73, 29.60, 29.54, 29.15, 28.71, 22.87, 14.25. MS (EI)
m/z: 269.3; HRMS (EI): calcd for C13H24F3S (MH):
269.1553, found 269.1555. IR ν: 2926, 2855, 1467,
1153, 1118 cm1.
220.1; HRMS (EI): calcd for C10H11F3S: 220.0534,
found 220.0529. IR ν: 3023, 2926, 1516, 1451, 1115,
806, 756 cm1.
4-(2-((Trifluoromethyl)thio)ethyl)benzonitrile
(Scheme 5, 4f)
The general procedure C with
Dec-9-en-1-yl(trifluoromethyl)thioether (Scheme
5, 4b) The general procedure C with dodec-11-enyl
4-methylbenzenesulfonate (169 mg, 0.5 mmol), gave
111 mg (93%) of dec-9-en-1-yl(trifluoromethyl)sulfane
4-cyanophenethyl 4-methylbenzenesulfonate (151 mg,
0.5 mmol), gave 83 mg (71%) of 4-(2-((trifluoromethyl)
thio)ethyl)benzonitrile as a pale yellow liquid. H NMR
1
(400 MHz, CDCl3) δ: 7.61 (d, J＝7.9 Hz, 2H), 7.32 (d,
J＝8.0 Hz, 2H), 3.14 (t, J＝7.2 Hz, 2H), 3.06 (t, J＝7.2
Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 41.00 (s, 3F);
13C NMR (101 MHz, CDCl3) δ: 144.27, 132.61, 131.08
(q, J＝307.2 Hz), 129.55, 118.77, 111.10, 36.05, 30.61
(q, J＝1.9 Hz). MS (EI) m/z: 231.1; HRMS (EI): calcd
for C10H8NF3S: 231.0330, found 231.0329. IR ν: 2940,
2229, 1609, 1506, 1417, 1115, 822 cm1.
1
as a pale yellow liquid. H NMR (400 MHz, CDCl3) δ:
5.81 (ddt, J＝16.9, 10.2, 6.7 Hz, 1H), 5.03－4.92 (m,
2H), 2.88 (t, J＝7.5 Hz, 2H), 2.08－2.02 (m, 2H), 1.73
－1.66 (m, 2H), 1.44－1.28 (m, 10H); 19F NMR (376
MHz, CDCl3) δ: 41.36 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 139.04, 131.22 (q, J＝305.6 Hz), 114.16,
33.77, 29.84 (q, J＝1.9 Hz), 29.39, 29.24, 28.99, 28.91,
28.86, 28.49. MS (DART POS) m/z: 241.1 (M＋H);
HRMS (DART POS): calcd for C11H20F3S (M＋H):
241.1238, found 241.1232. IR ν: 3078, 2977, 2928,
2856, 1641, 1465, 1153, 1117, 910 cm1.
(4-Methoxyphenethyl)(trifluoromethyl)thioether
(Scheme 5, 4g) The general procedure C with 4-meth-
oxyphenethyl 4-methylbenzenesulfonate (153 mg, 0.5
mmol), gave 110 mg (93%) of (4-methoxyphenethyl)-
1
(2-(4-Fluorophenoxy)ethyl)(trifluoromethyl)thio-
ether (Scheme 5, 4c) The general procedure C with
4-fluorophenethyl 4-methylbenzenesulfonate (147 mg,
0.5 mmol), gave 106 mg (95%) of (2-(4-fluorophenoxy)
(trifluoromethyl)sulfane as a pale yellow liquid. H
NMR (400 MHz, CDCl3) δ: 7.14 (d, J＝8.3 Hz, 2H),
6.88 (d, J＝8.4 Hz, 2H), 3.81 (s, 3H), 3.11 (t, J＝7.7 Hz,
2H), 2.95 (t, J＝7.5 Hz, 2H); 19F NMR (376 MHz,
1
13
ethyl) (trifluoromethyl)sulfane as a colorless liquid. H
CDCl3) δ: 41.38 (s, 3F); C NMR (101 MHz, CDCl3)
NMR (400 MHz, CDCl3) δ: 7.19－7.16 (m, 2H), 7.02
(m, 2H), 3.11 (t, J＝7.5 Hz, 2H), 2.98 (t, J＝7.5 Hz,
2H); 19F NMR (376 MHz, CDCl3) δ: 41.05 (s, 3F),
115.95 (m, 1F); 13C NMR (101 MHz, CDCl3) δ:
162.02 (d , J＝245.1 Hz), 134.71 (d, J＝3.3 Hz), 131.27
(q, J＝307.2 Hz), 130.19 (d, J＝8.0 Hz), 115.68 (d, J＝
21.4 Hz), 35.32, 31.44. MS (EI) m/z: 224.1; HRMS (EI):
calcd for C9H8F4S: 224.0283, found 224.0280. IR ν:
2931, 1602, 1510, 1227, 1159, 1112, 824, 757 cm1.
(4-Bromophenethyl)(trifluoromethyl)thioether
δ: 158.62, 131.25 (q, J＝306.9 Hz), 131.00, 129.54,
114.12, 55.23, 35.10, 31.51 (q, J＝1.7 Hz). MS (EI) m/z:
236.1; HRMS (EI): calcd for C10H11OF3S: 236.0483,
found 236.0488. IR ν: 3005, 2938, 2837, 1612, 1514,
1466, 1250, 1178, 1108, 1037, 822 cm1.
(2-Iodobenzyl)(trifluoromethyl)thioether (Scheme
5, 4h) The general procedure C with 2-iodobenzyl
4-methylbenzenesulfonate (116 mg, 0.3 mmol), gave 87
mg (95%) of (2-iodobenzyl)(trifluoromethyl)sulfane as
1
a colorless liquid. H NMR (400 MHz, CDCl3) δ: 7.87
(Scheme 5, 4d)
4-bromophenethyl 4-methylbenzenesulfonate (177 mg,
0.5 mmol), gave 136 mg (96%) of (4-bromophenethyl)-
The general procedure C with
(d, J＝7.9 Hz, 1H), 7.41 (d, J＝7.5 Hz, 1H), 7.34 (t, J＝
7.5 Hz, 1H), 7.00 (t, J＝7.6 Hz, 1H), 4.22 (s, 2 H); 19F
NMR (376 MHz, CDCl3) δ: 41.30 (s, 3F); 13C NMR
(101 MHz, CDCl3) δ: 140.07, 138.33, 130.76 (q, J＝
308.5 Hz), 130.42, 129.86, 128.85, 100.40, 39.74 (q,
J＝2.4 Hz). MS (EI) m/z: 318.0, HRMS (EI): calcd for
C8H6F3SI: 317.9187, found 317.9184. IR ν: 3061, 1585,
1566, 1465, 1438, 1150, 1115, 1014, 756, 727 cm1.
(2-(Naphthalen-2-yl)ethyl)(trifluoromethyl)thio-
ether (Scheme 5, 4i) The general procedure C with
1
(trifluoromethyl)sulfane as a colorless liquid. H NMR
(400 MHz, CDCl3) δ: 7.45 (d, J＝8.1 Hz, 2H), 7.09 (d,
J＝8.1 Hz, 2H), 3.11 (t, J＝7.5 Hz, 2H), 2.96 (t, J＝7.6
Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 40.99 (s, 3F);
13C NMR (101 MHz, CDCl3) δ: 137.92, 131.94, 131.20
(q, J＝307.3 Hz), 130.42, 120.97, 35.50, 31.09 (q, J＝
1.9 Hz). MS (EI) m/z: 284.0; HRMS (EI): calcd for
C9H8F3SBr: 283.9482, found 283.9481. IR ν: 2927,
1488, 1114, 1073, 1012, 802, 756 cm1.
2-(naphthalen-2-yl)ethyl
4-methylbenzenesulfonate
(130 mg, 0.4 mmol), gave 80 mg (78%) of (2-(naphtha-
len-2-yl)ethyl)(trifluoromethyl)sulfane as a colorless
(4-Methylphenethyl)(trifluoromethyl)thioether
(Scheme 5, 4e)
1
The general procedure C with
liquid. H NMR (400 MHz, CDCl3) δ: 7.99 (d, J＝8.2
4-methylphenethyl 4-methylbenzenesulfonate (145 mg,
0.5 mmol), gave 86 mg (78%) of (4-methylphenethyl)-
(trifluoromethyl)sulfane as a pale yellow liquid. H
Hz, 1H), 7.91 (d, J＝7.5 Hz, 1H), 7.80 (d, J＝8.1 Hz,
1H), 7.60－7.50 (m, 2H), 7.45 (t, J＝7.5 Hz, 1H), 7.38
(d, J＝6.7 Hz, 1H), 3.49 (t, J＝8.0 Hz, 2H), 3.26 (t, J＝
7.8 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 40.82 (s,
3F); 13C NMR (126 MHz, CDCl3) δ: 135.08, 134.10,
131.55, 131.37 (q, J ＝ 306.8 Hz), 129.16, 127.94,
126.87, 126.57, 125.94, 125.68, 123.09, 33.65, 30.59 (q,
J＝1.8 Hz). MS (EI) m/z: 256.1; HRMS (EI): calcd for
C13H11F3S: 256.0534, found 256.0538. IR ν: 061, 2947,
1
NMR (400 MHz, CDCl3) δ: 7.17 (d, J＝7.8 Hz, 2H),
7.12 (d, J＝7.5 Hz, 2H), 3.14 (t, J＝7.6 Hz, 2H), 2.98 (t,
J＝7.6 Hz, 2H), 2.37 (s, 3H); 19F NMR (376 MHz,
13
CDCl3) δ: 41.40 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 136.66, 136.01, 131.36 (q, J＝305.9 Hz), 129.53,
128.54, 35.68, 31.48 (q, J＝1.7 Hz), 21.15. MS (EI) m/z:
500
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Chin. J. Chem. 2016, 34, 495—504

Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides, Bromides and Tosylates
1598, 1511, 1117, 779 cm1.
ther improved to 97% when 1.3 equivalents of AgSCF3
2-(2-((Trifluoromethyl)thio)ethyl)isoindoline-1,3-
dione (Scheme 5, 4j) The general procedure C with
2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methylbenzene sul-
fonate (103 mg, 0.3 mmol), gave 34 mg (41%) of
2-(2-((trifluoromethyl)thio) ethyl)isoindoline-1,3-dione
and nBu4NI were used (Scheme 1, Entry 16).
Scheme 1 Trifluoromethylthiolation of alkyl bromide in the
presence of different additivesa
conditions
+
Br
AgSCF3
Ph
1
Ph
SCF3
as a pale yellow liquid. H NMR (400 MHz, CDCl3) δ:
1a
2a
7.87－7.84 (m, 2H), 7.75－7.72 (m, 2H), 3.99 (t, J＝7.0
Entry
1
Additive Solvent Temp/℃ Time/h Yieldb/%
Hz, 2H), 3.20 (t, J＝7.0 Hz, 2H); 19F NMR (376 MHz,
13
none
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
80
80
80
80
80
80
60
40
r.t.
80
80
80
80
80
80
80
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
－
－
－
－
84
－
58
26
14
46
67
79
63
74
58
97
CDCl3) δ: 41.05 (s, 3F); C NMR (101 MHz, CDCl3)
δ: 167.94, 134.37, 131.93, 130.78 (q, J＝307.8 Hz),
123.63, 37.48, 27.97 (q, J＝1.9 Hz). MS (EI) m/z: 275.1;
HRMS (EI): calcd for C11H8NO2F3S: 275.0228, found
275.0231. IR ν: 3476, 3063, 2947, 1775, 1719, 1615,
1468, 1439, 1333, 1115, 1007, 865, 715 cm1.
2
3
CuCl
CuBr
Bu4NI
NaI
4
5
6
7
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Results and Discussion
8
In 1972, Yagupolskii reported that AgSCF3 can react
with activated electrophile 2-bromo-1-phenylethanone
to give α-trifluoromethylthiolated ketone in good
yield.[7c] Yet, low conversion was observed when other
non-activated electrophiles were subjected. AgSCF3
which could be easily prepared from AgF and CS2 is
air,[8] moisture and light insensitive, representing an
ideal nucleophilic trifluoromethylthiolating reagent. We
reason that the low reactivity of AgSCF3 is likely due to
the covalent bond nature of the Ag－S bond in AgSCF3.
Thus, if we can make a more ionic trifluoromethylthio
intermediate by the addition of an additive, the reac-
tivity of AgSCF3 could be significantly increased. With
these in mind, we first examined the nucleophilic tri-
fluoromethylthiolation of (3-bromopropyl)benzene 1a
with AgSCF3 in the presence of different additive. A
quick screening revealed that nBu4NI[4a] was superior to
copper salts. The formation of alkyl-trifluoromethylthio-
ether 2a was observed in 84% yield when 1.0 equivalent
of nBu4NI was used, while less than 2% of the corre-
sponding products were detected when CuCl, CuBr or
CuI was added (Scheme 1, Entries 1－5). To probe if
the cation is important for the increased reactivity, we
studied the reaction using NaI as the additive, yet, the
reaction occurred in less than 2% conversion. These
results indicated that upon addition of nBu4NI, it is
likely a more reactive nBu4NSCF3 was formed and re-
acted immediately with electrophile to give the desired
trifluoromethylthiolated compound. After identifying
the effective additive, we then further studied the effects
of the temperature and the solvents on the conversion of
the reactions. These studies suggest that the reaction
conducted at 80 ℃ proceeded to full conversion after 3
h, while the reactions were much slower if the reactions
were conducted below 60 ℃ (Scheme 1, Entries 7－9).
Likewise, these studies also disclosed that reactions in
polar non-protic solvents gave higher yields (Scheme 1,
Entries 10－15). Since acetone is much easy for workup,
we chose acetone for further substrate scope investiga-
tion. Interestingly, the yield of the product could be fur-
9
10
11
12
13
14
15
16c
Bu4NI Acetone
Bu4NI
Bu4NI
Bu4NI
CH3CN
NMP
DMAc
Bu4NI Acetone
a Reaction conditions: alkylbromide (0.05 mmol), AgSCF3 (0.05
mmol), solvent (1.0 mL), additive (0.05 mmol). b Yields were de-
termined by 19F NMR analysis using PhCF3 as internal standard.
c nBu4NI (0.065 mmol), AgSCF3 (0.065 mmol).
The optimized conditions were applied to a variety
of readily available alkyl bromides, the results were
summarized in Scheme 2. In general, the reactions of a
variety of primary alkyl bromides gave rise to the cor-
responding trifluoromethylthiolated products in high
yields (Scheme 2, 2a－2k). Reactions of secondary al-
kyl bromides were much more difficult. Nevertheless,
activated secondary alkyl bromides successfully reacted
to give the trifluoromethylthiolated products in 65%－
90% yields (Scheme 2, 2l－2r). A variety of functional
groups such as ester, enolizable ketone, amide, and hal-
ogens were compatible with the mild reaction condi-
tions.
Alkyl chlorides are generally less reactive than alkyl
bromides. Not surprisingly, reaction of 1-chlorodode-
cane with 1.0 equivalent of AgSCF3 in the presence of
1.0 equivalent of nBu4NI in acetone at 100 ℃ gener-
ated the corresponding trifluoromethylthiolated product
in less than 5% yield (Scheme 3, Entry 1). When THF
was used as the solvent, the yield was improved to 28%,
while reactions in other polar solvents such as DMF,
DMSO, DMA, CH3CN were much less effective
(Scheme 3, Entries 2－6). To our delight, the yield was
improved to 43% when a combination of 1.3 equiv-
alents of nBu4NI and 1.3 equivalents of PhEt3NI was
Chin. J. Chem. 2016, 34, 495—504
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501

Xu, Chen & Shen
FULL PAPER
Scheme 2 Scope for trifluoromethylthiolation of alkyl bromides
in the presence of nBu4NIa
Interestingly, by replacing PhEt3NI with a cheaper ter-
tiary amine salt nBu4NBr, the halogenated side product
was not observed any more (Scheme 3, Entry 9).
Scheme 3 Trifluoromethylthiolation of alkyl chloride in the
presence of different additivea
conditions
Cl
SCF3
AgSCF3
+
9
9
3a
O
Entry
Additive
Bu4NI
Solvent Temp/℃ Time/h Yieldb/%
EtO
SCF3
5
1
2
3
4
5
6
Acetone
DMF
100
100
100
100
100
100
100
80
4
4
4
＜1
28
7
2c 92%
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
O
SCF3
THF
4
N
4
CH3CN
DMAc
DMSO
4
O
4
3
2e 99%
4
＜1
43
90
95
O
O
7 c Bu4NI/PhEt3NI THF
8d Bu4NI/PhEt3NI THF
9e Bu4NI/nBu4NBr THF
4
MeO
OMe
SCF3
10
15
N
4
80
SCF3
2h 99%
a
Reaction conditions: alkyl-Cl (0.05 mmol), AgSCF3 (0.065
2g 94%
mmol), solvent (1.0 mL), nBu4NI (0.065 mmol). b The yield was
determined by 19F NMR analysis using PhCF3 as internal stan-
c
dard. PhEt3NI (0.065 mmol) as another additive. d nBu4NI (0.10
mmol), PhEt3NI (0.10 mmol), AgSCF3 (0.10 mmol). e nBu4NI
(0.10 mmol), nBu4NBr (0.10 mmol), AgSCF3 (0.10 mmol).
O
Under the optimized reaction conditions, a variety of
primary alkyl chlorides were allowed to react with Ag-
SCF3 to give the corresponding trifluoromethylthiolated
products in good to excellent yields. Again, many func-
tional groups were compatible with the reaction condi-
tions.
Me
SCF3
R
R = PhO, 2m 75%
NEt2, 2n 88%
Alkyl alcohols are abundant, cheap commodities that
are easily available. Very recently, Rueping and Qing
independently reported two trifluoromethylthiolating
methods that direct conversion of alkyl alcohols to tri-
fluoromethylthioalkyl ethers.[11,12] The reaction was
proposed to proceed through nucleophilic trifluoro-
methylthiolation of an in situ formed sulfonyl ester. In
light of these findings, we wondered whether isolable
alkyl tosylates can be directly converted to trifluoro-
methylthioalkyl ethers. A quick screening of the reaction
conditions indicated that reaction of alkyl tosylates with
AgSCF3 occurred smoothly after 6 h at 100 ℃ to give
the corresponding trifluoromethylthiolated compounds
in good yields when the reactions were conducted in the
presence of 2.0 equivalents of nBu4NI in CH3CN. Under
these conditions, a variety of alkyl tosylates could be
converted to alkyl trifluoromethylthioethers in good to
excellent yields (Scheme 5). Likewise, secondary alkyl
tosylates were unable to be trifluoromethylthiolated un-
der these reaction conditions.
a Reaction conditions: alkylbromides (0.5 mmol), AgSCF3 (0.65
mmol), nBu4NI (0.65 mmol), acetone (2.0 mL), 80 ℃, 3－24 h,
isolated yields.
used (Scheme 3, Entry 7). The yields could be further
increased to 90% when the reaction was conducted
when a combination of 2.0 equivalents of AgSCF3, 2.0
equivalents of nBu4NI and 2.0 equivalents of PhEt3NI
was used at 80 ℃ for 10 h, as determined by 19F NMR
spectroscopy with PhCF3 as an internal standard
(Scheme 3, Entry 8). However, GC/MS analysis of the
product after column chromatography purification indi-
cated that an inseparable mixture of trifluoromethylthio-
dodecane and iodododecane was formed in the reaction.
502
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Chin. J. Chem. 2016, 34, 495—504

Nucleophilic Trifluoromethylthiolation of Alkyl Chlorides, Bromides and Tosylates
Scheme 4 Scope for trifluoromethylthiolation of alkyl chlorides
in the presence of nBu4NI/nBu4NBra
nBu4NI could significantly promote the trifluorometh-
ylthiolation reaction. It is likely that the in situ formed
nBu4NSCF3 is more ionic than AgSCF3, thus giving rise
to fast nucleophilic substitution reactions. Attempts to
convert unactivated secondary alcohols to the corre-
sponding trifluoromethylthioethers are undergoing cur-
rently in our laboratory and will be reported in the near
future.
O
SCF3
5
R
O
R = Cy, 3b, 95%
Ph, 3c, 95%
Acknowledgement
Bn, 3d, 92%
The authors thank the financial support from the Na-
tional Basic Research Program of China (No.
2012CB821600), the National Natural Science Founda-
tion of China (No. 21372247/21421002) and SIOC.
O
SCF3
R
R = F, 3f, 83%
Br, 3g, 68%
Ac, 3h, 93%
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I
SCF3
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Chin. J. Chem. 2016, 34, 495—504
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Xu, Chen & Shen
FULL PAPER
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(Pan, B.; Fan, Y.)
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Chin. J. Chem. 2016, 34, 495—504