Electrochemical Trifluoromethylation of Thiophenols with Sodium Trifluoromethanesulfinate

Article abstract of DOI:10.1021/acs.joc.0c02659

We developed an electrochemical trifluoromethylation of thiophenols without the use of metal catalysts and oxidants. This reaction features mild reaction conditions, readily available substrate, as well as moderate to good yields. In addition, this protocol can be easily scaled up with moderate efficiency.

Full text of DOI:10.1021/acs.joc.0c02659

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Electrochemical Trifluoromethylation of Thiophenols with Sodium
Trifluoromethanesulfinate
Xing-Xing Zhu, Huai-Qin Wang, Chen-Guang Li, Xiao-Lan Xu, Jun Xu, Jian-Jun Dai,* and Hua-Jian Xu*
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ABSTRACT: We developed an electrochemical trifluoromethylation of
thiophenols without the use of metal catalysts and oxidants. This reaction
features mild reaction conditions, readily available substrate, as well as
moderate to good yields. In addition, this protocol can be easily scaled up with
moderate efficiency.
ecause of the unique ability of the fluorine atom, the
Bintroduction of fluorine atoms into organic molecules will
significantly change the dipole moment, acidity, lipophilicity,
and chemical and metabolic stability of the molecule.1 Today
fluorinated drugs account for ∼25% of all drug molecules and
even up to 30% of pesticide chemicals.2 In the organofluorine
family, the trifluoromethylthio group (-SCF3) has very high
lipophilicity and hydrophobic parameters.3 Introducing -SCF3
into drug molecules can greatly enhance the lipophilicity and
biological permeability of drugs.4 Therefore, organic molecules
containing -SCF3 groups have great potential application value
in medicine, pesticides, and other fields. Examples of
trifluoromethylthiolated drugs including Toltrazuril,5 Losartan
analogues,6 Adrenergic agent,7 and Tiforex8 are shown in
Figure 1.
In recent decades, significant progress has been made in the
synthesis of trifluoromethyl aryl sulfide; many novel methods
and effective reagents have emerged.9−14 In 2007, Togni and
co-workers disclosed a trifluoromethylation of thiophenols by
using electrophilic hypervalent iodine(III)-CF3 reagent (Togni
reagent) as a CF3 source (Scheme 1a).12a In 2014, Wang and
the supporting electrolyte and CH3CN as the solvent under
argon atmosphere. We chose NaBr as the mediator according
to a previous report,17 which proved that bromide can mediate
the electrochemical trifluoromethylation. To our delight, the
desired product 3a was obtained in 76% yield (Table 1, entry
1). With LiClO4 as the supporting electrolyte, the yield
decreases slightly (Table 1, entry 2). But with other supporting
electrolytes such as nBu4NPF6 and NaBF4, only a trace amount
of 3a was observed (Table 1, entries 3 and 4). Subsequently, a
series of solvents was examined, and replacement of CH3CN
with CH2Cl2 gave a significantly decreased yield (Table 1,
entry 5). When dimethylformamide (DMF) was used as the
reaction solvent, none of the desired product was formed
(Table 1, entry 6). In addition, NaBr was proved to be the best
mediator for the reaction (Table 1, entries 7 and 8). Only 43%
yield of 3a was obtained in the absence of NaBr (Table 1, entry
9). Other current systems can also proceed the reaction, but
the yields were significantly reduced (Table 1, entries 10 and
11). When the reaction was performed under air atmosphere, a
significantly reduced yield of 3a was obtained (Table 1, entry
12). Note that the nature of the electrode material has a great
influence on the reaction;18 with platinum and nickel as the
anode, the yields reduced to 26% and 68%, respectively (Table
1, entries 13 and 14). Finally, control experiments demon-
strated that an electric current was indispensable for the
reaction (Table 1, entry 15).
̈
Noel developed a photocatalytic trifluoromethylation of
thiophenols, respectively (Scheme 1a).12b In 2016, Yi et al.
reported the trifluoromethylation of thiophenols with sodium
trifluoromethanesulfinate using iodine pentoxide and as an
oxidant (Scheme 1a).12c,d Since organic electrosynthesis has
the advantages of less pollution, short process flow, and mild
reaction conditions, organic electrosynthesis has emerged as an
eco-friendly synthetic tool in synthetic chemistry.15 Inspired by
these works and as a continuation of our studies on
electrochemical reactions,16 we describe an electrochemical
trifluoromethylation of thiophenols under metal- and oxidant-
free undivided electrosynthetic conditions (Scheme 1b).
Initially, a model reaction of 4-methoxythiophenol (1a) with
CF3SO2Na (2a) was chosen to optimize the reaction
conditions (Table 1). The initial reaction was performed in
an undivided cell with graphite plates as electrodes under 10
With the optimized reaction conditions established, we
began to evaluate the substrate scope. As summarized in
Scheme 2, a variety of thiophenols with ortho, meta, or para
substituents on the benzene ring are well-tolerated, and no
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: November 6, 2020
n
mA constant current at room temperature using Bu4NBF4 as
https://dx.doi.org/10.1021/acs.joc.0c02659
© XXXX American Chemical Society
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A

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Note
Figure 1. Examples of SCF3-containing biologically active compounds.
a
Scheme 1. Approaches for Trifluoromethylation of
Scheme 2. Substrate Scope
Thiophenols
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
none
76
70
n
LiClO4 instead of Bu4NBF4
NaBF4 instead of Bu4NBF4
nBu4NPF6 instead of Bu4NBF4
n
trace
trace
23
n.r.
68
n
5
6
7
CH2Cl2 instead of CH3CN
DMF instead of CH3CN
KBr instead of NaBr
a
Standard conditions: Undivided cell, graphite plate anode: (10 mm
8
9
Et4NBr instead of NaBr
no NaBr
under air
8 mA instead of 10 mA, 12.5 h
14 mA instead of 10 mA, 7 h
platinum instead of graphite as the anode
nickel instead of graphite as the cathode
45
43
21
47
34
26
68
× 15 mm), constant current: 10.0 mA, 1a−1w (0.5 mmol, 1.0 equiv),
n
2a (1.5 mmol, 3.0 equiv), NaBr (0.5 mmol, 1.0 equiv), Bu4NBF4
10
11
12
13
14
(0.63 mmol, 1.25 equiv), CH3CN (10 mL), Ar, r.t., 10 h.
derivatization. Versatile functional groups such as ether (3a,
3f, and 3m), nitro (3g), or amide (3j) groups were well-
tolerated. Furthermore, the disubstituted thiols could undergo
the reaction smoothly to afford the desired product (3q) in
53% yield. Unfortunately, 4-aminothiophenol failed in this
transformation, and 4-mercaptophenol was poorly tolerated;
the desired product 3r was only obtained in 16% yield. The
next step in the research on the scope of substrates was focused
on substrates containing heterocycles (Scheme 2B). The
results showed that pyridine (3t and 3u), pyrimidine (3v), and
benzoxazole (3w) derivatives obtained the target product with
moderate 60−78% yields.
a
Standard conditions: graphite plate anode: (10 mm × 15 mm),
constant current: 10.0 mA, 1a (0.5 mmol, 1.0 equiv), 2a (1.5 mmol,
3.0 equiv), NaBr (0.5 mmol, 1.0 equiv), Bu4NBF4 (0.63 mmol, 1.25
equiv), CH3CN (10 mL) in an undivided cell under Ar atmosphere,
n
b
10 h at room temperature. Isolated yield. n.r. = no reaction.
matter whether the benzene ring had an electron-donating
group or an electron-withdrawing group, it could be
successfully converted to the corresponding trifluoromethylth-
io product (Scheme 2A). Alkyl (isopropyl, tert-butyl, e.g., 3b
and 3c), halide (Cl, Br, e.g., 3d, 3e, and 3k), ester (3i, 3l, 3n,
and 3o), and carboxyl (3h and 3p) functional groups were all
untouched, providing potential reactive sites for further
To illustrate the synthetic practicability of this electro-
chemical trifluoromethylation of thiols, a gram-scale (2.8 g, 20
mmol) reaction was also conducted under the optimum
B
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conditions (Scheme 3). The desired product 3a was obtained
with 67% yield (2.79 g) after 28 h of constant-current
electrolysis.
Scheme 5. Proposed Reaction Mechanism
Scheme 3. Gram-Scale Synthesis of 3a
To elucidate the mechanism insight into this electrochemical
transformation, a series of control experiments was conducted
(Scheme 4). First, we performed free-radical trapping experi-
ments. We observed that radical scavengers such as
tetramethylpiperidinoxyl (TEMPO), 2,6-di-tert-butyl-4-meth-
ylphenol (BHT), and 1,1-diphenylethylene inhibited the
electrochemical conversion, and the corresponding free
radicals were captured (see the Supporting Information for
more details); this result indicated that electrocatalysis was
gone through the free radical pathway. Subsequently, with the
replacement of thiophenol 1a with sulfide 4 under standard
conditions, the desired product of 3a was obtained in 73%
yield, which indicated that the sulfide 4 may be the
intermediate involved in this reaction.
On the basis of the preliminary experiments and literature
reports,17,19 a possible mechanism is proposed in Scheme 5.
Initially thiol undergoes hydrogen evolution in the anode to
generate a thiol radical; subsequently, the thiol radical
generates the disulfide 4 in situ. Meanwhile, bromide ions
produced by sodium bromide (NaBr) in the reaction solution
are oxidized to produce molecular Br2, followed by a reaction
with CF3SO2Na to afford sulfonyl hypobromide 5, which is in
equilibrium with intermediate 6. The intermediate 5 or 6 is
reduced or homolytically cleaved at the cathode to release SO2
gas, regenerate bromide ions, and generate free radicals at the
same time. Once the CF3 free radical is formed, it reacts with 4
to generate the desired product 3. Finally, the hydrogen ions at
the cathode are reduced to release hydrogen.
In summary, an electrochemical trifluoromethylation of thiol
has been developed that avoids the use of metal catalysts and
oxidants. Mild reaction conditions, readily available substrate,
as well as moderate to good yields made this reaction,
providing an alternative electrochemical trifluoromethylation
manner for the functionalization of biological molecules.
Experimental Section. General Information. All solvents and
1
reagents were used as received from commercial sources. H
NMR, 13C NMR, and 19F NMR spectra were recorded on a
Bruker Advance 400 or 600 spectrometer at the ambient
temperature in CDCl3 or deuterated dimethyl sulfoxide
(DMSO-d6). Chemical shifts (δ) are reported in parts per
million (ppm) using tetramethylsilane (TMS) as internal
standard (s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, ddd = triplet of doublets, m = multiplet).
Data for the 1H NMR are reported as follows: chemical shift (δ
ppm), multiplicity, coupling constant (Hz), and integration.
Chemical shifts were referenced to internal TMS at δ 0.00 ppm
or to the signal of residual proton solvent peak: CDCl3 at δ
7.26 ppm. Data for the 13C NMR are reported in terms of
chemical shift (δ ppm). Chemical shifts were referenced to the
residual solvent peak: CDCl3 at δ 77.2 ppm. Data for the 19F
NMR are reported in terms of chemical shift (δ ppm).
Chemical shifts were referenced to internal or external CFCl3
Scheme 4. Control Experiments
C
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1
3
at δ 0.00 ppm. In DMSO-d6, the chemical shifts in the H
NMR and 13C NMR spectra were determined based on the
chemical shift of DMSO-d6 (δ = 2.50 ppm and δ = 39.52 ppm,
respectively). Gas chromatography-mass spectrometry (GC-
MS) analyses were performed on a Thermo Scientific AS 3000
Series GC-MS system. Analytical thin-layer chromatography
(TLC) was done on precoated silica gel plates. Organic
solutions were concentrated under reduced pressure on a
308.3 Hz), 123.0 (q, C−F, JC−F = 2.4 Hz). 19F NMR (376
MHz, CDCl3) δ −43.03 (s, 3F).
1-Bromo-4-[(trifluoromethyl)thio]benzene (3e). Purified by
flash column chromatography (petroleum ether) as a colorless
oil (76.8 mg, 60% yield).12b 1H NMR (600 MHz, CDCl3) δ
7.57−7.56 (m, 2H), 7.52−7.51 (m, 2H). 13C{1H} NMR (151
1
MHz, CDCl3) δ 137.9, 133.0, 129.4 (q, C−F, JC−F = 308.2
3
Hz), 126.2, 123.6 (d, C−F, JC−F = 2.3 Hz). 19F NMR (565
Bu
̈
chi rotary evaporator. Flash column chromatographic
MHz, CDCl3) δ −42.64 (s, 3F).
purification of products was accomplished using forced-flow
chromatography on silica gel (200−300 mesh).
1-Methylthio-4-[(trifluoromethyl)thio]benzene (3f). Puri-
fied by flash column chromatography (petroleum ether) as a
colorless oil (81.8 mg, 73% yield).12b 1H NMR (600 MHz,
CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H).
2.50 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 143.4,
136.8, 129.7 (q, C−F, 1JC−F = 308.3 Hz), 126.5, 119.9 (d, C−
General Procedure. To a 25 mL tube were sequentially added
the substrate 1 (0.5 mmol, 1.0 equiv), CF3SO2Na (1.5 mmol,
3.0 equiv, 234 mg), NaBr (0.5 mmol, 1.0 equiv, 51.5 mg),
nBu4NBF4(0.63 mmol, 1.25 equiv, 208 mg), and CH3CN (10
mL). The tube was equipped with two graphite plate
electrodes (10 mm × 15 mm). The electrolysis was performed
at r.t. under Ar atmosphere with a constant current of 10.0 mA
for 10 h. After the completion of the reaction, the mixture was
concentrated and subjected to flash chromatography on silica
gel eluting with petroleum ether/ethyl acetate to afford the
desired product.
3
F, JC−F = 2.5 Hz), 15.1. 19F NMR (565 MHz, CDCl3) δ
−43.15 (s, 3F).
1-Nitro-4-[(trifluoromethyl)thio]benzene (3g). Purified by
flash column chromatography (petroleum ether) as a colorless
oil (42.4 mg, 38% yield).12b 1H NMR (400 MHz, CDCl3) δ
8.28 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 149.3, 136.3, 132.8 (d, C−F, 3JC−F
= 2.1 Hz), 129.1 (q, C−F, 1JC−F = 308.8 Hz), 124.5. 19F NMR
(376 MHz, CDCl3) δ −41.32 (s, 3F).
Gram-Scale Reaction. In a 500 mL container equipped with a
stir bar, 1a (2.80 g, 20 mmol), 2a (9.36 g, 60 mmol), NaBr
n
4-[(Trifluoromethyl)thio]benzoic acid (3h). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 2:1) as a light yellow solid (79.9 mg, 72% yield).12b 1H NMR
(600 MHz, DMSO-d6) δ 8.02 (d, J = 8.0 Hz, 2H), 7.74 (d, J =
7.8 Hz, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 172.3,
(2.04 g, 20 mmol), and Bu4NBF4 (8.22 g, 25 mmol) were
dissolved in CH3CN (200 mL), followed by graphite plates as
anode and cathode (5 cm × 4 cm × 2 mm each, ∼2 cm
immersed in the solution) under an argon atmosphere
(operated in glovebox). Then the electrolysis system was
stirred at a constant current of 160 mA at r.t. for 28 h. Then
the solvent was removed with a rotary evaporator, and the
desired product was purified by column chromatography (silica
gel) using petroleum ether as eluent. The desired product was
obtained as a colorless oil with 67% yield (2.79 g).
1
135.5, 130.4, 129.6, 129.5 (q, C−F, JC−F = 307.8 Hz), 125.6.
19F NMR (564 MHz, DMSO-d6) δ −46.00 (s, 3F).
Methyl-4-[(trifluoromethyl)thio]benzoate (3i). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 50:1) as a colorless oil (94.4 mg, 80% yield).21 1H NMR
(400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.3
Hz, 2H), 3.94 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
Characterization data for all products. (4-
Methoxyphenyl)(trifluoromethyl)sulfane (3a). Purified by
flash column chromatography (petroleum ether) as a colorless
oil (78.9 mg, 76% yield).12b 1H NMR (400 MHz, CDCl3) δ
7.58 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.84 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.1, 138.5, 129.8
(q, C−F, 1JC−F = 308.1 Hz), 115.2, 115.1 (d, C−F, 3JC−F = 2.1
Hz), 55.6. 19F NMR (376 MHz, CDCl3) δ −43.95 (s, 3F).
(4-Isopropylphenyl)(trifluoromethyl)sulfane (3b). Purified
by flash column chromatography (petroleum ether) as a
colorless oil (82.5 mg, 75% yield).13j 1H NMR (600 MHz,
CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H),
3
166.2, 135.7, 132.3, 130.6, 130.0 (d, C−F, JC−F = 2.0 Hz),
129.4 (q, C−F, 1JC−F = 308.4 Hz), 52.6. 19F NMR (564 MHz,
CDCl3) δ −41.89 (s, 3F).
N-[4-[(Trifluoromethyl)thio]phenyl]acetamide (3j). Puri-
fied by flash column chromatography (petroleum ether/ethyl
acetate = 5:1) as a white solid (77.6 mg, 66% yield).12b 1H
NMR (600 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.74−7.72 (m,
2H), 7.65−7.62 (m, 2H), 2.07 (s, 3H). 13C{1H} NMR (151
MHz, DMSO-d6) δ 168.9, 142.3, 137.3, 129.6 (q, C−F, 1JC−F
=
3
308.1 Hz), 119.8, 115.5 (d, C−F, JC−F = 2.3 Hz), 24.1. 19F
2.98−2.93 (m, 1H), 1.28 (s, 1H), 1.27 (s, 1H). 13C{1H} NMR
NMR (565 MHz, DMSO-d6) δ −42.79 (s, 3F).
1
(151 MHz, CDCl3) δ 152.3, 136.6, 129.9 (q, C−F, JC−F
=
1-Bromo-2-[(trifluoromethyl)thio]benzene (3k). Purified by
flash column chromatography (petroleum ether) as a colorless
oil (57.6 mg, 45% yield).20 1H NMR (600 MHz, CDCl3) δ
3
307.9 Hz), 127.8, 121.3 (d, C−F, JC−F = 2.3 Hz), 34.2, 23.9.
19F NMR (565 MHz, CDCl3) δ −43.01 (s, 3F).
7.78−7.72 (m, 2H), 7.39−7.31 (m, 2H). 13C{1H} NMR (101
(4-(tert-Butyl)phenyl)(trifluoromethyl)sulfane (3c). Purified
by flash column chromatography (petroleum ether) as a
colorless oil (85.4 mg, 73% yield).12b 1H NMR (600 MHz,
CDCl3) δ 7.59 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H),
1.35 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.6,
136.3, 129.9 (q, C−F, 1JC−F = 309.3 Hz), 126.8, 121.1 (d, C−
F, 3JC−F = 2.3 Hz), 35.1, 31.3. 19F NMR (376 MHz, CDCl3) δ
−42.89 (s, 3F).
1
MHz, CDCl3) δ 138.2, 134.2, 132.3, 129.4 (q, C−F, JC−F
=
3
309.9 Hz), 130.8, 128.4, 126.5 (d, C−F, JC−F = 2.3 Hz). 19F
NMR (376 MHz, CDCl3) δ −41.91 (s, 3F).
Methyl-2-[(trifluoromethyl)thio]benzoate (3l). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 50:1) as a colorless oil (70.8 mg, 60% yield).20 1H NMR
(400 MHz, CDCl3) δ 7.93 (dd, J = 7.8, 1.1 Hz, 1H), 7.74 (d, J
= 8.0 Hz, 1H), 7.54 (td, J = 7.9, 1.3 Hz, 1H), 7.44 (t, J = 7.7
Hz, 1H), 3.94 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
166.8, 132.8, 132.7, 132.6, 131.1, 129.7 (q, C−F, 1JC−F = 309.1
(4-Chlorophenyl)(trifluoromethyl)sulfane (3d). Purified by
flash column chromatography (petroleum ether) as a colorless
oil (66.8 mg, 63% yield).12b 1H NMR (400 MHz, CDCl3) δ
3
7.60−7.58 (m, 2H), 7.42−7.39 (m, 2H). 13C{1H} NMR (101
Hz), 128.8, 128.5 (d, C−F, JC−F = 1.6 Hz), 52.8. 19F NMR
1
MHz, CDCl3) δ 137.8, 132.9, 130.0, 129.5 (q, C−F, JC−F
=
(564 MHz, CDCl3) δ −41.39 (s, 3F).
D
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1-Methoxy-3-[(trifluoromethyl)thio]benzene (3m). Purified
by flash column chromatography (petroleum ether) as a
colorless oil (60.3 mg, 58% yield).21 1H NMR (600 MHz,
CDCl3) δ 7.34−7.32 (m, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.19−
(ESI): Calcd for C9H9F3NO2S ([M + H]+): 252.0301, found:
252.0311.
2-[(Trifluoromethyl)thio]-5-(chloro)pyridine (3u). Purified
by flash column chromatography (petroleum ether/ethyl
1
7.18(m, 1H), 7.04−7.02 (m, 1H), 3.83 (s, 3H). 13C{1H} NMR
acetate = 20:1) as a colorless oil (63.9 mg, 60% yield). H
1
NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz, 1H), 7.71 (dd,
(151 MHz, CDCl3) δ 160.1, 130.3, 129.8 (q, C−F, JC−F
=
J = 8.4, 2.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H). 13C{1H} NMR
3
308.0 Hz), 128.5, 125.4 (d, C−F, JC−F = 1.8 Hz), 121.3,
117.0, 55.6. 19F NMR (564 MHz, CDCl3) δ −42.59 (s, 3F).
Methyl-3-[(trifluoromethyl)thio]benzoate (3n). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 30:1) as a light yellow solid (72.2 mg, 65% yield). 1H NMR
(400 MHz, CDCl3) δ 8.33 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H),
7.85 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 3.95 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 165.9, 140.5, 137.4,
3
(101 MHz, CDCl3) δ 149.8, 147.3 (d, C−F, JC−F = 2.7 Hz),
137.5, 133.2, 129.2 (q, C−F, 1JC−F = 308.7 Hz), 129.1 (d, C−
F, 4JC−F = 1.7 Hz). 19F NMR (376 MHz, CDCl3) δ −40.29 (s,
3F). HRMS (ESI): Calcd for C6H4ClF3NS ([M + H]+):
213.9700, found: 213.9709.
[(Trifluoromethyl)thio]pyrimidine (3v). Purified by flash
column chromatography (petroleum ether/ethyl acetate =
10:1) as a colorless oil (70.2 mg, 78% yield).12b 1H NMR (400
MHz, CDCl3) δ 8.63 (d, J = 4.9 Hz, 2H), 7.18 (t, J = 4.9 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 158.1, 128.4
1
132.1, 131.8, 129.7, 129.6 (q, C−F, JC−F = 308.2 Hz),125.3
(d, C−F, 3JC−F = 2.2 Hz), 52.6. 19F NMR (564 MHz, CDCl3)
δ −42.48 (s, 3F). High-resolution mass spectrometry (electro-
spray ionization) (HRMS (ESI)): Calcd for C9H8F3O2S ([M +
H]+): 237.0192, found: 237.0201.
1
(q, C−F, JC−F = 307.8 Hz), 119.1. 19F NMR (376 MHz,
CDCl3) δ −41.07 (s, 3F).
2-((Trifluoromethyl)thio)benzo[d]oxazole (3w). Purified
by flash column chromatography (petroleum ether/ethyl
acetate = 10:1) as a colorless oil (67.9 mg, 62% yield).12a 1H
NMR (600 MHz, CDCl3) δ 7.79−7.78 (m, 1H), 7.60−7.58
(m, 1H), 7.45−7.39 (m, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ 152.9 (d, C−F, 3JC−F = 3.6 Hz), 152.5, 141.5, 127.8
Ethyl-3-[(trifluoromethyl)thio]benzoate (3o). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 20:1) as a colorless oil (82.6 mg, 70% yield). 1H NMR (400
MHz, CDCl3) δ 8.32 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.84
(d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.40 (q, J = 7.2
Hz, 2H), 1.43−1.39 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 165.4, 140.4, 137.4, 132.2, 132.0, 129.7, 129.6 (q,
C−F, 1JC−F = 308.2 Hz), 125.2 (d, C−F, 3JC−F = 2.1 Hz), 61.7,
14.4. 19F NMR (376 MHz, CDCl3) δ −42.50 (s, 3F). HRMS
(ESI): Calcd for C10H10F3O2S ([M + H]+): 250.0348, found:
251.0355.
1
(q, C−F, JC−F = 311.2 Hz), 126.6, 125.4, 120.6, 111.0. 19F
NMR (565 MHz, CDCl3) δ −38.54 (s, 3F).
ASSOCIATED CONTENT
■
sı
* Supporting Information
3-[(Trifluoromethyl)thio]benzoic acid (3p). Purified by
flash column chromatography (petroleum ether/ethyl acetate
= 2:1) as a colorless oil (80.1 mg, 64% yield).9b 1HNMR (600
MHz, DMSO-d6) δ 8.18 (s, 1H), 8.15−8.13 (m, 1H), 7.97 (d,
J = 7.8 Hz, 1H), 7.72−7.65 (m, 1H). 13C{1H} NMR (151
MHz, DMSO-d6) δ 166.0, 140.2, 136.4, 132.5, 132.1, 130.5,
129.5 (q, C−F, 1JC−F = 308.2 Hz), 123.8 (d, C−F, 3JC−F = 2.4
Hz). 19F NMR (376 MHz, DMSO-d6) δ −41.92 (s, 3F).
1,2-Dimethoxy-4-[(trifluoromethyl)thio]benzene (3q). Pu-
rified by flash column chromatography (petroleum ether/ethyl
acetate = 50:1) as a colorless oil (63.1 mg, 53% yield).13j 1H
NMR (400 MHz, CDCl3) δ 7.23 (d, J = 11.5 Hz, 1H), 7.09 (d,
J = 22.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.91 (d, J = 3.1 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.7, 149.4, 130.3,
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02659.
Mechanism study, gram-scale reaction and NMR spectra
of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Jian-Jun Dai − School of Food and Biological Engineering,
School of Chemistry and Chemical Engineering, Anhui
Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, Hefei University of Technology, Hefei
230009, China; orcid.org/0000-0001-7918-0080;
Email: daijj@hfut.edu.cn
Hua-Jian Xu − School of Food and Biological Engineering,
School of Chemistry and Chemical Engineering, Anhui
Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, Hefei University of Technology, Hefei
230009, China; orcid.org/0000-0002-0789-3484;
Email: hjxu@hfut.edu.cn
1
125.9 (d, C−F, JC−F = 309.1 Hz), 119.1, 116.2, 111.6, 56.4,
56.3. 19F NMR (565 MHz, CDCl3) δ −43.61 (s, 3F).
4-((Trifluoromethyl)thio)phenol (3r). Purified by flash
column chromatography (petroleum ether/ethyl acetate =
5:1) as a brown solid (15.5 mg, 16% yield).12b 1H NMR (600
MHz, CDCl3) δ 7.54 (d, J = 8.6 Hz, 2H), 6.88−6.86 (m, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ 158.1, 138.7, 129.7 (q,
1
3
C−F, JC−F = 308.1 Hz), 116.7, 115.5 (d, C−F, JC−F = 2.4
Authors
Hz). 19F NMR (565 MHz, CDCl3) δ −43.21 (s, 3F).
Xing-Xing Zhu − School of Food and Biological Engineering,
School of Chemistry and Chemical Engineering, Anhui
Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, Hefei University of Technology, Hefei
230009, China
Huai-Qin Wang − School of Food and Biological Engineering,
School of Chemistry and Chemical Engineering, Anhui
Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, Hefei University of Technology, Hefei
230009, China
2-[(Trifluoromethyl)thio]nicotinic acid ethyl ester (3t).
Purified by flash column chromatography (petroleum ether/
ethyl acetate = 20:1) as a light yellow solid (81.6 mg, 65%
1
yield). H NMR (600 MHz, CDCl3) δ 8.66 (dd, J = 4.7, 1.9
Hz), 8.29 (dd, J = 7.9, 1.9 Hz), 7.25 (dd, J = 7.9, 4.7 Hz), 4.42
(q, J = 7.1 Hz), 1.41 (t, J = 7.2 Hz). 13C{1H} NMR (151 MHz,
3
CDCl3) δ 164.87, 156.06 (d, C−F, JC−F = 2.6 Hz), 152.60,
1
138.99, 128.85 (q, C−F, JC−F = 309.3 Hz), 120.94, 62.35,
14.30. 19F NMR (565 MHz, CDCl3) δ. −41.18 (s, 3F). HRMS
E
https://dx.doi.org/10.1021/acs.joc.0c02659
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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Chem. 2001, 109, 87−94. (c) Jouvin, K.; Matheis, C.; Goossen, L. J.
Synthesis of Aryl Tri- and Difluoromethyl Thioethers via a C−H-
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14324−14327.
Chen-Guang Li − School of Food and Biological Engineering,
School of Chemistry and Chemical Engineering, Anhui
Province Key Laboratory of Advance Catalytic Materials and
Reaction Engineering, Hefei University of Technology, Hefei
230009, China
Xiao-Lan Xu − School of Medical Science, Anhui Medical
University, Hefei 230032, China
Jun Xu − School of Food and Biological Engineering, School of
Chemistry and Chemical Engineering, Anhui Province Key
Laboratory of Advance Catalytic Materials and Reaction
Engineering, Hefei University of Technology, Hefei 230009,
China; orcid.org/0000-0002-2985-6609
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02659
(8) Silverstone, T.; Fincham, J.; Plumley, J. B. An evaluation of the
anorectic activity in man of a sustained release formulation of tiflorex.
J. Clin. Pharmacol. 1979, 7, 353−356.
Notes
The authors declare no competing financial interest.
(9) For selected trifluoromethylthiolation of aryldiazonium salts, see:
Adams, D. J.; Goddard, A.; Clark, J. H.; Macquarrie, D. J.
Trifluoromethylthiodediazoniation: a simple, efficient route to
trifluoromethyl aryl sulfides. Chem. Commun. 2000, 987−988.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21871074 and 21971051), the
National Key R&D Program of China (2018YFB1501604), the
Key Research and Development Program Projects in Anhui
Province (201904a07020069), Grants for Scientific Research
of BSKY (XJ201804) from Anhui Medical University, and the
Fundamental Research Funds for the Central Universities.
(b) Danoun, G.; Bayarmagnai, B.; Grunberg, M. F.; Goossen, L. J.
̈
Sandmeyer trifluoromethylthiolation of arenediazonium salts with
sodium thiocyanate and Ruppert-Prakash reagent. Chem. Sci. 2014, 5,
1312−1316. (c) Zhao, X.; Zheng, X.; Tian, M.; Tong, Y.; Yang, B.;
Wei, X.; Qiu, D.; Lu, K. Visible-light photocatalytic trifluoromethylth-
iolation of aryldiazonium salts: conversion of amino group into
trifluoromethylthiol group. Org. Chem. Front. 2018, 5, 2636−2640.
(10) For selected trifluoromethylthiolation of halogenated aromatics,
see: Adams, D. J.; Clark, J. H. Preparation of Trifluoromethyl Aryl
Sulfides Using Silver(I) Trifluoromethanethiolate and an Inorganic
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Surry, D. S.; Buchwald, S. L. Pd-Catalyzed Synthesis of Ar-SCF3
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of Aryl Trifluoromethyl Sulfides at Room Temperature. J. Am. Chem.
Soc. 2012, 134, 183−185. (d) Weng, Z.; He, W.; Chen, C.; Lee, R.;
Tan, D.; Lai, Z.; Kong, D.; Yuan, Y.; Huang, K.-W. An Air-Stable
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