Transition-metal-free direct trifluoromethylthiolation of electron-rich aromatics using CF3SO2Na in the presence of PhPCl2

Article abstract of DOI:10.1016/j.tet.2017.11.019

A novel transition metal-free route for the direct trifluoromethylthiolation of electron-rich aromatics using CF₃SO₂Na in the presence of PhPCl₂ was developed. More specifically, PhPCl₂ was used as both a reducing and a chlorinating reagent for the first time in this CF₃SO₂Na-based trifluoromethylthiolation reaction. The absence of transition metals and the use of cheap and readily available reagents render this method an alternative and practical strategy for the trifluoromethylthiolation of electron-rich aromatics.

Full text of DOI:10.1016/j.tet.2017.11.019

Accepted Manuscript
Transition-metal-free direct trifluoromethylthiolation of electron-rich aromatics using
CF SO Na in the presence of PhPCl
2
3
2
Xia Zhao, Xiancai Zheng, Miaomiao Tian, Jianqiao Sheng, Yifan Tong, Kui Lu
PII:
S0040-4020(17)31155-9
10.1016/j.tet.2017.11.019
TET 29099
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 August 2017
Revised Date: 4 November 2017
Accepted Date: 7 November 2017
Please cite this article as: Zhao X, Zheng X, Tian M, Sheng J, Tong Y, Lu K, Transition-metal-free
direct trifluoromethylthiolation of electron-rich aromatics using CF SO Na in the presence of PhPCl ,
3
2
2
Tetrahedron (2017), doi: 10.1016/j.tet.2017.11.019.
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Transition-Metal-Free Direct
Trifluoromethylthiolation of Electron-rich
Aromatics Using CF3SO2Na in the Presence
of PhPCl2
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Xia Zhao,* Xiancai Zheng, Miaomiao Tian, Jianqiao Sheng, Yifan Tong, and Kui Lu*

1
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Tetrahedron
journal homepage: www.elsevier.com
Transition-Metal-Free Direct Trifluoromethylthiolation of Electron-rich Aromatics
Using CF3SO2Na in the Presence of PhPCl2
Xia Zhaoa, , Xiancai Zhenga, Miaomiao Tiana, Jianqiao Shenga, Yifan Tonga and Kui Lu b,
a College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key laboratory of Inorganic-organic Hybrid Functional
Material Chemistry, Ministry of Education, Tianjin Normal University, Tianjin 300387, China
b College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel transition metal-free route for the direct trifluoromethylthiolation of electron-rich
aromatics using CF3SO2Na in the presence of PhPCl2 was developed. More specifically, PhPCl2
was used as both a reducing and a chlorinating reagent for the first time in this CF3SO2Na-based
trifluoromethylthiolation reaction. The absence of transition metals and the use of cheap and
readily available reagents render this method an alternative and practical strategy for the
trifluoromethylthiolation of electron-rich aromatics.
Available online
Keywords:
Trifluoromethylthiolation
CF3SO2Na
PhPCl2
Indole
Electron-rich aromatics
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
CF3SO2Na/(EtO)2P(O)H/chlorotrimethylsilane (TMSCl) system
(Scheme 2, equations 2 and 3).16 In these two protocols, PPh3 and
(EtO)2P(O)H were used as reductants, while N-chlorophthalimide
and TMSCl were employed as the chlorination reagents.
The trifluoromethylthio (SCF3) group is an important
pharmacophore that is present in many pharmaceutical and
agrochemical products, including cefazaflur, tiflorex, toltrazuril,
and vaniliprole.1 Indeed, the incorporation of an SCF3 group into
pharmaceuticals is known to greatly improve their metabolic
stabilities2 and cell membrane permeabilities.3 As such, the
incorporation of SCF3 groups into small molecules is an active
research area in synthetic chemistry. Indeed, great progress has
recently been made in the electrophilic trifluoromethylthiolation
of aromatic compounds, and a series of shelf-stable electrophilic
SCF3 reagents have been developed (compounds 1–9, Scheme
1).4–13
However,
the
above
mentioned
CF3SO2Na-based
trifluoromethylthiolation reaction also required the use of
transition metal catalysis.
In this context, sodium trifluoromethanesulfinate (CF3SO2Na,
10), otherwise known as the Langlois reagent, is an essentially
odourless, readily accessible solid, which has been employed as a
trifluoromethylation reagent.14 In addition, Yi and Zhang
reported a CuCl-mediated trifluoromethylthiolation of C(sp2)-H
bonds using a CF3SO2Na/ diethyl phosphonate ((EtO)2P(O)H)
system (Scheme 2, equation 1).15 Furthermore, the Cai group
recently reported the trifluoromethylthiolation of indoles using a
CF3SO2Na/triphenylphosphine
system, while the Yi and Zhang group reported a similar
transformation using
(PPh3)/N-chlorophthalimide
Scheme 1 Thiolation of indolizines and N-methylindoles using sulfonyl
chlorides as sulfenylation reagents
a
———
Xia Zhao. E-mail: hxxyzhx@mail.tjnu.edu.cn
Kui Lu. E-mail: lukui@tust.edu.cn

2
Tetrahedron
In addition, both our group and the Liu group recently
Table 1 Optimisation of the trifluoromethylthiolation of 11a
ACCEPTED MANUSCRIPT
a
independently
reported
the
CF3SO2Na-based
with 10 in the presence of PhPCl2
trifluoromethylthiolation of electron-rich aromatics in the
presence of PCl3, which was employed both as a reductant and as
a chlorination reagent (Scheme 2, equation 4).17 In our protocol,
the slow addition of PCl3 was carried out using a syringe pump,
as this reagent reacted rapidly with indole. Thus, as we are
interested in developing efficient methods to construct C-S
bonds,13c, 17b, 18 we herein report the development of a CF3SO2Na-
based transition metal-free trifluoromethylthiolation of electron-
rich aromatics in the presence of dichloro(phenyl)phosphane
(PhPCl2), as the latter is less electrophilic than PCl3, and so is
expected to react less rapidly with indole (Scheme 2, equation 5).
Entry
1
Solvent
Volume (mL) Temperature (°C) Yield (%)
CH3CN
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
0.5
1.0
1.0
1.0
60
60
60
60
50
70
80
70
70
70
70
70
70
70
39
59
65
50
60
70
58
70
75
80
66
84b
89c
90d
2
Toluene
3
1,4-Dioxane
DCE
4
(EtO)2P(O)H, 2.0 eq
5
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
SCF3
DMSO, 3.0 eq.
6
CuCl, 1.0 eq.
(1)
CF3SO2Na
2.0 eq.
+
Toluene, 110 o
C
N
H
N
H
7
Ref. 15
8
PPh3, 3.0 eq
SCF3
9
N-chlorophthalimide
1.5 eq.
(2)
(3)
CF3SO2Na
1.5 eq.
+
10
11
12
13
14
N
H
N
H
CH3CN, r.t.
Ref. 16a
SCF3
(EtO)2P(O)H, 3.0 eq
TMSCl, 2.0 eq.
CF3SO2Na
2.0 eq.
+
Toluene, 85 o
C
N
H
N
H
Ref. 16b
a
Reaction conditions: 11a (0.5 mmol), 10 (0.6 mmol), PhPCl2
(0.6 mmol), 0.5 h. b 10 (0.65 mmol) and PhPCl2 (0.65 mmol) were used.
c 10 (0.7 mmol) and PhPCl2 (0.7 mmol) were used. d 10 (0.75 mmol) and
PhPCl2 (0.75 mmol) were used.
SCF3
PCl3, 1.2 eq
added by syringe pump
CH3CN, 60 o
(4)
(5)
CF3SO2Na
1.2 eq.
+
+
N
H
N
H
C
Ref. 17b
SCF3
PhPCl2, 1.2 eq
added in one portion
With the optimised conditions in hand, the substrate scope of
the trifluoromethylthiolation reaction was examined using a
series of indole derivatives (Table 2).
CF3SO2Na
1.2 eq.
1,4-dioxane, 70 o
C
N
H
N
H
this work
Scheme 2 Trifluoromethylthiolation of indole using CF3SO2Na as an SCF3
Table
2
Scope of trifluoromethylthiolation of indole
derivativesa
source
SCF3
PhPCl2, 1.4 eq.
R3
R3
2. Results and discussion
R1
CF3SO2Na
1.4 eq.
R1
+
N
N
1,4-dioxane
70 oC, 0.5 h
R2
R2
11
12
To probe the trifluoromethylthiolation of electron-rich
aromatics using our CF3SO2Na/PhPCl2 system, we treated indole
11a with CF3SO2Na (10) in the presence of PhPCl2 in acetonitrile
(CH3CN) at 60 °C over 0.5 h to yield the desired product 12a in
39% yield. Optimisation of the reaction conditions was then
carried out to enhance this yield. Initially, the effect of the
reaction solvent was investigated using toluene, 1,4-dioxane, and
1,2-dichloroethane (DCE) (Table 1, entries 2–4), with 1,4-
dioxane giving the optimal yield (i.e., 65%, entry 3). The effect
of the reaction temperature was then examined between 50 and
80 °C. Upon decreasing the reaction temperature to 50 °C, the
yield of 12a decreased to 60% (entry 5), while increasing the
temperature to 70 °C increased the yield to 70% (entry 6).
However, further increasing the reaction temperature to 80 °C led
to a diminished yield (i.e., 58%, entry 7). Finally, the reaction
concentration and stoichiometry were investigated (entries 8–14).
More specifically, upon increasing the concentration of 11a from
0.167 to 0.5 M, the yield of 12a increased from 70 to 80%
(entries 8–10), while a further increase in the concentration of
11a had a detrimental effect (i.e., 66%, entry 11). In addition,
upon increasing the loading of 10 and PhPCl2 from 1.2 to
1.4 equiv., the yield increased from 80 to 89% (entries 10, 12,
and 13), although a further increase to 1.5 equiv. had little effect
on the obtained yield (i.e., 90%, entry 14). The optimised
reaction conditions for this transformation were therefore
confirmed to be as follows: 11a (0.5 mmol), 10 (0.7 mmol),
PhPCl2 (0.7 mmol), and 1,4-dioxane (1 mL) at 70 °C over 0.5 h.
10
O
OH
SCF3
SCF3
SCF3
SCF3
Cl
N
N
N
H
N
H
H
H
12b, 77%
12c, 91%
12d, 36%
12e, 78%
O
SCF3
SCF3
SCF3
SCF3
Br
F
O2N
O
N
N
N
N
H
H
H
H
12f, 78%
12g, 86%
12h, 65%b
12i, 35%c
SCF3
SCF3
SCF3
SCF3
N
N
N
H
N
F
Cl
O
H
H
H
12j, 88%
12k, 70%
12l, 76%
12m, 88%
SCF3
SCF3
Ph
SCF3
SCF3
N
H
N
N
N
H
12n, 76%
12o, 69%
12p, 89%
12q, 82%
SCF3
SCF3
N
H
N
Ph
12r, 48%
12s, 15%
a
Reaction conditions: 11 (0.5 mmol), 10 (0.7 mmol), PhPCl2 (0.7 mmol), 1,4-dioxane
(1.0 mL) at 70 oC. b 10 (1.0 mmol) and PhPCl2 (1.0 mmol) were used. c 10 (0.9 mmol)
and PhPCl2 (0.9 mmol) were used for 12 h.

3
mechanism, the desired product 12a was obtained in 89% and
98% yields, respectively (Scheme 5).
ACCEPTED MANUSCRIPT
As indicated, both electron-donating and electron-withdrawing
substituents were well tolerated in the 2, 4, 5, 6, and 7 positions
(11b, 11c, 11e–11o), as were N-substituted indoles (11p–11r),
with the desired products being obtained in moderate to good
yields. However, when 4-hydroxylindole (11d) and 3-
methylindole (11s) were employed as substrates, relatively low
yields of the desired products were obtained (i.e., 36 and 15%,
respectively). Notably, when indoles bearing electron-
withdrawing substituents (11h and 11i) were employed, it was
necessary to increase the number of equivalents of 10 and PhPCl2
to obtain acceptable yields (i.e., 65 and 35%, respectively).
O
CF3
S
SCF3
PhPCl2, 1.0 eq.
1,4-dioxane, 70 o
C
N
N
H
H
13a
12a, 89%
O
CF3
SCF3
S
PhPCl2, 1.0 eq.
H2O, 1.0 eq.
1,4-dioxane, 70 o
C
N
H
N
H
13a
12a, 98%
Scheme 5 Reduction of 13a to 12a by PhPCl2 or PhP(OH)Cl
Encouraged by these results, the use of other electron-rich
aromatics and alkene, such as pyrrole (13a–13c), indolizine
Finally, to demonstrate the practical application of this method,
the gram-scale trifluoromethylthiolation of indole was carried out
to give the desired product 12a in 84% yield (Scheme 6).
(13d–13g),
5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(13h), 1,3,5-trimethoxybenzene (13i) and methyl (E)-3-
(benzylamino)but-2-enoate (13j) was examined under the
optimised conditions. Indeed, we found that these substrates
could be smoothly transformed into the desired products (14a–
14j) in moderate yields (i.e., 40–68%, Scheme 3).
Scheme 6 Large scale synthesis of 13a
3. Experimental Section
1) General methods and material
All solvents were distilled prior to use. Unless otherwise noted,
chemicals were used as received without further purification. For
chromatography, 200−300 mesh silica gel was employed. 1H and
13C NMR spectra were recorded at 400 MHz and 100 MHz
respectively. Chemical shifts are reported in ppm using
tetramethylsilane as internal standard. HRMS was performed on
an FTMS mass instrument. Melting points are reported as
uncorrected.
2) General procedure for trifluoromethylthiolation of
electron-rich aromatic by CF3SO2Na in the presence of
PhPCl2:
To a flame-dried Schlenk tube was added electron-rich aromatic
(0.5 mmol), CF3SO2Na (118 mg, 0.7 mmol) dry 1,4-dioxane or
CH3CN (1 mL). The mixture was heated to 60 °C by a preheated
oil bath. PhPCl2 (125 mg, 0.7 mmoL) was added. The reaction
mixture was stirred at 70 °C for the indicated time. Then the
reaction mixture was cooled to room temperature. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography to afford the pure
product.
Scheme 3 Trifluoromethylthiolation of other aromatics with 10 in the
presence of PhPCl2
Based on previous literature,17b a plausible reaction mechanism
for this reaction was then proposed (Scheme 4). More
specifically, CF3SO2Na (10) can initially react with PhPCl2 to
form intermediate A, which reacts twice with indole-based
substrates to afford 13 in addition to intermediate (B).
Intermediate (B) then reacts with PhPCl2 to generate PhP(OH)Cl
(C), and subsequent reduction of 13 by PhPCl2 and (C) affords
the corresponding indole trifluoromethylthioethers 12.
3-((trifluoromethyl)thio)-1H-indole (12a):13c After purification
by silica gel column chromatography (PE : EA = 10 : 1),
compound 12a was isolated as a pale yellow solid (97 mg, 89%);
Rf (PE : EA = 10 : 1) = 0.21; mp (melting point) = 52–53 °C; 1H
NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.82-7.79 (m, 1H), 7.52
(d, J = 2.7 Hz, 1H), 7.40-7.44 (m, 1H), 7.32-7.26 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 136.0, 132.8, 129.5 (q, J = 308.2 Hz,
1C), 129.4, 123.4, 121.6, 119.3, 111.7, 95.5 (q, J = 2.4 Hz, 1C);
19F NMR (376 MHz, CDCl3): δ -44.59 (s, 3F).
4-methoxy-3-((trifluoromethyl)thio)-1H-indole (12b):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12b was isolated as a yellow solid (95 mg, 77%);
Rf (PE : EA = 10 : 1) = 0.20; mp (melting point) = 61-63 °C; 1H
NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.40 (d, J = 2.4 Hz,
1H), 7.19 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.0 Hz, 0.6 Hz, 1H),
6.64 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 154.5, 137.9, 132.3, 129.4 (q, J = 307.5 Hz, 1C),
124.3, 118.6, 104.8, 102.1, 94.5 (q, J = 2.6 Hz, 1C), 55.5 (q, J =
2.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -45.48 (s, 3F).
4-methyl-3-((trifluoromethyl)thio)-1H-indole (12c):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12c was isolated as a pink solid (105 mg, 91%); Rf
(PE : EA = 10 : 1) = 0.24; mp (melting point) = 63–65 °C; 1H
NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.51 (d, J = 2.8 Hz,
1H), 7.26 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.99 (d, J
Scheme 4 Proposed reaction mechanism
To confirm this mechanism, 3-((trifluoromethyl)sulfinyl)-1H-
indole (13a) was treated with either PhPCl2 (1.0 equiv.) or
chloro(hydroxy)(phenyl)phosphane (PhP(OH)Cl) (1.0 equiv.),
generated in situ from PhPCl2 (1.0 equiv.) and H2O (1.0 equiv.),
in 1,4-dioxane at 70 °C. As expected based on our proposed

4
Tetrahedron
ACCEPTED MANUSCRIPT
= 6.8 Hz, 1H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.71 (dd, J = 8.8 Hz,
136.4, 134.0, 131.6, 129.2 (q, J = 307.5 Hz, 1C), 126.7, 123.4,
123.4, 109.7, 95.1 (q, J = 2.6 Hz, 1C), 19.31; 19F NMR (376
MHz, CDCl3): δ -45.88 (s, 3F).
5.2 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.10 (dd, J = 9.2 Hz, 2.4
Hz, 1H), 7.04 (td, J = 9.2 Hz, 2.2 Hz, 0.6 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 160.6 (d, J = 238.8 Hz, 1C), 136.0 (d, J = 12.5
Hz, 1C), 133.1, 129.4 (q, J = 308.1 Hz, 1C), 127.8, 120.4 (d, J =
10.1 Hz, 1C), 110.6 (d, J = 24.4 Hz, 1C), 98.1 (d, J = 27.0 Hz,
1C), 96.1 (q, J = 3.0 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -
44.54 (s, 3F), -119.06 (s, 1F).
3-((trifluoromethyl)thio)-1H-indol-4-ol
(12d):13c
After
purification by silica gel column chromatography (PE : EA =5 :
1), compound 12d was isolated as a white solid (42 mg, 36%); Rf
(PE : EA = 5 : 1) = 0.30; mp (melting point) = 120–122 °C; 1H
NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 7.45 (d, J = 2.8 Hz,
1H), 7.17 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.72 (s,
1H), 6.71 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
150.5, 137.7, 132.7, 128.3 (q, J = 310 Hz, 1C), 125.1, 116.5,
107.1, 104.4, 91.6 (q, J = 2.3Hz, 1C); 19F NMR (376 MHz,
CDCl3): δ −45.75 (s, 3F).
6-chloro-3-((trifluoromethyl)thio)-1H-indole (12k):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12k was isolated as a brown solid (88 mg, 70%);
1
Rf (PE : EA = 10 : 1) = 0.21; mp (melting point) = 55–58 °C; H
NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H),
7.53 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.24 (dd, J =
8.5 Hz, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 136.4,
133.3, 129.6, 129.3 (q, J = 308.0 Hz, 1C), 128.0, 122.5, 120.4,
111.6, 96.2 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -
44.46 (s, 3F).
5-chloro-3-((trifluoromethyl)thio)-1H-indole (12e):13c After
purification by silica gel column chromatography (PE : EA = 7 :
1), compound 12e was isolated as a brown solid (98 mg, 78%);
1
Rf (PE : EA = 5 : 1) = 0.27; mp (melting point) = 57–59 °C; H
NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H),
7.55 (d, J = 2.8 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 0.3 Hz, 1H), 7.24
(dd, J = 8.4 Hz, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
134.4, 133.9, 130.7, 129.3 (q, J = 308.1 Hz, 1C), 127.7, 124.0,
118.9, 112.8, 95.5 (q, J = 2.6 Hz, 1C); 19F NMR (376 MHz,
CDCl3): δ -44.53 (s, 3F).
6-methoxy-3-((trifluoromethyl)thio)-1H-indole (12l):13c After
purification by silica gel column chromatography (PE : EA = 5 :
1), compound 12l was isolated as a pale yellow solid (94 mg,
76%); Rf (PE : EA = 5 : 1) = 0.20; mp (melting point) = 161–
163 °C; 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.65 (d, J =
8.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 6.95 (dd, J = 8.7 Hz, 2.2
Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 3.85 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 157.5, 136.9, 131.6, 129.4 (q, J = 308.1 Hz, 1C),
123.7, 120.0, 111.7, 95.7 (q, J = 2.3 Hz, 1C), 95.0, 55.7 (q, J =
1.8 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -44.63 (s, 3F).
7-methyl-3-((trifluoromethyl)thio)-1H-indole (12m):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12m was isolated as a pale yellow solid (102 mg,
88%); Rf (PE : EA = 10 : 1) = 0.24; mp (melting point) = 176-
5-bromo-3-((trifluoromethyl)thio)-1H-indole (12f):13c After
purification by silica gel column chromatography (PE : EA = 5 :
1), compound 12f was isolated as a pink solid (115 mg, 78%); Rf
1
(PE : EA = 5 : 1) = 0.21; mp (melting point) = 53–55 °C; H
NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.93 (d, J = 1.3 Hz, 1H),
7.54 (d, J = 2.8 Hz, 1H), 7.38 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.31
(d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 134.7, 133.8
(d, J = 10 Hz, 1C), 131.2, 129.2 (q, J = 308.3 Hz, 1C), 126.6,
122.0, 115.2, 113.1, 95.5 (q, J = 2.4 Hz, 1C); 19F NMR (376
MHz, CDCl3): δ -44.50 (s, 3F).
1
77 °C; H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.65 (d, J =
8.0 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H),
7.10 (d, J = 7.1 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 135.6, 132.4, 129.4 (q, J = 308.2 Hz, 1C), 129.1, 124.0,
121.8, 120.8, 117.0, 96.2 (q, J = 2.5 Hz, 1C), 16.3; 19F NMR (376
MHz, CDCl3): δ -44.57 (s, 3F).
5-fluoro-3-((trifluoromethyl)thio)-1H-indole (12g):13c After
purification by silica gel column chromatography (PE : EA = 7 :
1), compound 12g was isolated as a brown solid (101 mg, 86%);
Rf (PE : EA = 5 : 1) = 0.30; mp (melting point) = 52–54 °C; 1H
NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.57 (d, J = 2.8 Hz, 1H),
7.44 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.36 (dd, J = 8.8 Hz, 4.0 Hz,
1H), 7.04 (td, J = 9.2 Hz, 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 159.1 (d, J = 236.4 Hz, 1C), 134.3, 132.5, 130.4 (d, J =
9.0 Hz, 1C), 129.3 (q, J = 308.0 Hz, 1C), 112.6 (d, J = 9.0 Hz,
1C), 112.2 (d, J = 26.4 Hz, 1C), 104.6 (d, J = 24.5 Hz, 1C), 95.8
(q, J = 2.2 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -44.62 (s, 3F),
-121.59(s, 1F).
2-methyl-3-((trifluoromethyl)thio)-1H-indole (12n):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12n was isolated as a pink solid (88 mg, 76%); Rf
1
(PE : EA = 10 : 1) = 0.24; mp (melting point) = 58-60 °C; H
NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.71-7.69 (m, 1H),
7.31-7.28 (m, 1H), 7.24-7.19 (m, 2H), 2.56 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 143.6, 135.0, 130.6, 129.8 (q, J = 309.0 Hz,
1C), 122.6, 121.3, 118.6, 110.8, 92.4 (q, J = 2.2 Hz, 1C), 11.8;
19F NMR (376 MHz, CDCl3): δ -44.46 (s, 3F).
methyl
3-((trifluoromethyl)thio)-1H-indole-5-carboxylate
(12h):13c After purification by silica gel column chromatography
(PE : EA = 3 : 1), compound 12h was isolated as a white solid
(89 mg, 65%); mp (melting point) = 177–179 °C; Rf (PE : EA =
2-phenyl-3-((trifluoromethyl)thio)-1H-indole (12o):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12o was isolated as a brown solid (101 mg, 69%);
Rf (PE : EA = 10 : 1) = 0.27; mp (melting point) = 83–85 °C; 1H
NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 7.86-7.84 (m, 1H),
7.78-7.76 (m, 2H), 7.54-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.33-
7.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 144.4, 135.3,
131.4, 130.6, 129.7 (q, J = 309.4 Hz, 1C), 129.2, 128.8, 128.7,
123.7, 121.8, 119.8, 111.2, 92.6 (q, J = 2.3 Hz, 1C); 19F NMR
(376 MHz, CDCl3): δ -43.43 (s, 3F).
1
2 : 1) = 0.40; H NMR (400 MHz, d6-DMSO): δ 12.4 (s, 1H),
8.30 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.87 (dd, J = 8.6 Hz, 1.6
Hz, 1H), 7.62 (dd, J = 8.6 Hz, 0.4 Hz, 1H), 3.88 (s, 3H); 13C
NMR (100 MHz, DMSO): δ 166.7, 139.0, 137.0, 129.3 (q, J =
308.2 Hz, 1C), 128.6, 123.4, 122.6, 120.2, 112.8, 92.8 (q, J = 2.2
Hz, 1C), 51.9; 19F NMR (376 MHz, CDCl3): δ -44.11 (s, 3F)
5-nitro-3-((trifluoromethyl)thio)-1H-indole
(12i):13c
After
purification by silica gel column chromatography (PE : EA = 3 :
1), compound 12i was isolated as a yellow solid (46 mg, 35%);
Rf (PE : EA = 2 : 1) = 0.35; mp (melting point) = 170–172 °C; 1H
NMR (400 MHz, d6-DMSO): δ 12.7 (s, 1H), 8.48 (d, J = 2.0 Hz,
1H), 8.25 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 9.2 Hz, 2.4 Hz, 1H),
7.71 (d, J = 9.6 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ
142.3, 139.6, 139.0, 129.2 (q, J = 308.1 Hz, 1C), 128.5, 117.9,
114.6, 113.6, 94.3 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz,
CDCl3): δ -43.97 (s, 3F).
1-methyl-3-((trifluoromethyl)thio)-1H-indole (12p):13c After
purification by silica gel column chromatography (PE : EA = 20 :
1), compound 12p was isolated as a pale yellow solid (103 mg,
89%); Rf (PE : EA = 10 : 1) = 0.50; mp (melting point) = 58–
1
59 °C; H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.6 Hz, 1H),
7.38-7.35 (m, 2H), 7.31 (td, J = 6.8 Hz, 1.2 Hz, 1H), 7.27 (td, J =
7.3 Hz, 1.6 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 137.2, 136.9, 130.2, 129.4 (q, J = 308.2 Hz, 1C), 122.9, 121.3,
119.4, 109.8, 93.1 (q, J = 2.3 Hz, 1C), 33.3; 19F NMR (376 MHz,
CDCl3): δ -44.95 (s, 3F).
6-fluoro-3-((trifluoromethyl)thio)-1H-indole (12j):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12j was isolated as a brown solid (103 mg, 88%);
Rf (PE : EA = 10 : 1) = 0.21; mp (melting point) = 60–61 °C; 1H
1,2-dimethyl-3-((trifluoromethyl)thio)-1H-indole (12q):13c After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 12q was isolated as a pale yellow solid (100 mg,

5
82%); Rf (PE : EA = 10 : 1) = 0.50; mp (melting point) = 114–
116 °C; 1H NMR (400 MHz, CDCl3): δ 7.73-7.71 (m, 1H), 7.33-
7.31 (m, 1H), 7.28-7.21 (m, 2H), 3.74 (s, 3H), 2.57 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 145.1, 136.9, 130.1, 129.8 (q, J =
309.1 Hz, 1C), 122.2, 121.1, 118.7, 109.2, 91.2 (q, J = 2.2 Hz,
1C), 30.3, 10.8; 19F NMR (376 MHz, CDCl3): δ -44.92 (s, 3F).
1-phenyl-3-((trifluoromethyl)thio)-1H-indole (12r):13c After
purification by silica gel column chromatography (PE),
compound 12r was isolated as a white solid (70 mg, 48%); Rf
(PE) = 0.67; mp (melting point) = 53–55 °C; 1H NMR (400 MHz,
CDCl3): δ 7.87-7.85 (m, 1H), 7.65 (s, 1H), 7.56-7.48 (m, 5H),
7.45-7.41 (m, 1H), 7.34-7.28 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 138.5, 136.7, 135.9, 130.6, 129.8, 129.4 (q, J = 308.3
Hz, 1C), 127.7, 124.7, 123.7, 122.1, 119.7, 111.1, 96.3 (q, J = 2.3
Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -44.31 (s, 3F).
NMR (400 MHz, CDCl3): δ 8.55 (d, J = 7.2 Hz, 1H), 7.49 (d, J
ACCEPTED MANUSCRIPT
= 7.2 Hz, 1H), 7.08 (s, 1H), 6.97-7.01 (m, 1H), 6.83-6.86 (m, 1H),
3.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.1, 136.4, 128.3
(q, J = 311 Hz), 127.4, 124.1, 121.7, 120.3, 113.9, 104.7, 102.1,
51.9; 19F NMR (376 MHz, CDCl3): δ -43.56 (s, 3F); HRMS (ESI)
m/e calcd for C11H8F3NO2S+ (M+H)+ 276.0301, found 276.0300.
6-bromo-3-((trifluoromethyl)thio)indolizine-1-carboxylate (14f)
After purification by silica gel column chromatography (PE : EA
= 30 : 1), compound 13f was isolated as a white solid (112 mg,
63%); Rf (PE : EA = 30 : 1) = 0.26; mp (melting point) = 129–
131 °C; 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.20 (d, J =
9.6 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J = 9.6 Hz, 1H), 3.91 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 164.0, 137.6, 129.4, 128.5, 128.3
(q, J = 312 Hz), 124.8, 120.7, 109.3, 106.8, 103.4, 51.5 (q, J =
2.3 Hz); 19F NMR (376 MHz, CDCl3): δ -44.10 (s, 3F); HRMS
(ESI) m/e calcd for C11H7BrF3NO2S+ (M+H)+ 352.9328, found
352.9329.
3-methyl-2-((trifluoromethyl)thio)-1H-indole (12s):13c After
purification by silica gel column chromatography (PE : EA = 20 :
1), compound 12s was isolated as a pale yellow solid (17 mg,
15%); Rf (PE : EA = 10 : 1) = 0.33; mp (melting point) = 92–
94 °C; 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.54 (dd, J =
8.0 Hz, 0.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.25-7.21 (m, 1H),
7.11-7.07 (m, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
137.4, 128.7 (q, J = 309.8 Hz, 1C), 127.9, 124.8, 123.7, 120.1,
120.0, 113.0 (q, J = 2.2 Hz, 1C), 111.1, 9.4; 19F NMR (376 MHz,
CDCl3): δ -43.08 (s, 3F).
dimethyl
7-methyl-3-((trifluoromethyl)thio)indolizine-1,2-
dicarboxylate (14g) After purification by silica gel column
chromatography (PE : EA = 10 : 1), compound 13g was isolated
as a white solid (128 mg, 68%); Rf (PE : EA = 10 : 1) = 0.27; mp
1
(melting point) = 66–68 °C; H NMR (400 MHz, CDCl3): δ 8.41
(d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 6.86 (dd, J = 7.2Hz, 1.6 Hz, 1H),
4.47 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H),
1.42 (t, J = 7.2 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 164.7, 162.8, 139.9, 137.6, 134.7, 128.2 (q, J =
313 Hz), 123.8, 118.8, 117.4, 102.5, 100.6, 61.9, 60.2, 21.4, 14.3,
14.1; 19F NMR (376 MHz, CDCl3): δ -43.30 (s, 3F); HRMS (ESI)
m/e calcd for C16H16F3NO4S+ (M+H)+, 376.0825, found 376.0828.
ethyl
2,4-dimethyl-5-((trifluoromethyl)thio)-1H-pyrrole-3-
carboxylate (14a):13c After purification by silica gel column
chromatography (PE : EA = 10 : 1), compound 13a was isolated
as a brown solid (87 mg, 65%); Rf (PE : EA = 10 : 1) = 0.37; mp
1
(melting point) = 142–145 °C; H NMR (400 MHz, CDCl3): δ
1,3-dimethyl-4-((trifluoromethyl)thio)-1H-pyrazol-5-ol
(14h)
12.04 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.26 (s, 3H),
1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.2,
140.2, 132.1, 128.5 (q, J = 310.3 Hz, 1C), 112.0, 102.9 (q, J = 2.3
Hz, 1C), 58.8, 14.2, 13.5 (q, J = 1.2 Hz, 1C), 11.7; 19F NMR (376
MHz, CDCl3): δ -44.48 (s, 3F).
After purification by silica gel column chromatography (DCM :
MeOH = 10 : 1), compound 13h was isolated as a white solid (42
mg, 40%); Rf (DCM : MeOH = 10 : 1) = 0.48; mp (melting point)
1
= 190–192 °C; H NMR (400 MHz, d6-DMSO): δ 12.0 (s, 1H),
3.46 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ
157.2, 150.7, 129.5 (q, J = 309 Hz, 1C), 77.8, 33.1, 11.9; 19F
NMR (376 MHz, d6-DMSO): δ -45.50 (s, 3F); HRMS (ESI) m/e
calcd for C6H8F3N2OS+ (M+H)+ 213.0304, found 213.0304.
(trifluoromethyl)(2,4,6-trimethoxyphenyl)sulfane (14i)13c After
purification by silica gel column chromatography (PE : EA = 30 :
1), compound 13i was isolated as a white solid (87 mg, 65%); Rf
2,5-dimethyl-1-phenyl-3-((trifluoromethyl)thio)-1H-pyrrole
(14b)13c After purification by silica gel column chromatography
(PE), compound 13b was isolated as a brown solid (79 mg, 58%);
1
Rf (PE) = 0.47; mp (melting point) = 62–64 °C; H NMR (400
MHz, CDCl3): δ 7.51-7.42 (m, 3H), 7.21-7.18 (m, 2H), 6.12 (s,
1H), 2.10 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
138.31, 136.57, 129.78 (q, J = 307.5 Hz, 1C), 129.47, 129.36,
128.46, 128.04, 112.62, 97.61 (q, J = 2.2 Hz, 1C), 12.70, 11.10;
19F NMR (376 MHz, CDCl3): δ -45.31 (s, 3F).
1
(PE : EA = 10 : 1) = 0.38; mp (melting point) = 76–77 °C; H
NMR (400 MHz, CDCl3): δ 6.16 (s, 2H), 3.88 (s, 6H), 3.86 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 164.5, 163.5, 129.5 (q, J =
308.7 Hz, 1C), 91.9 (q, J = 1.4 Hz, 1C), 91.1, 56.2 (q, J = 2.2 Hz,
1C), 55.4 (q, J = 1.9 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ -
43.50 (s, 3F).
ethyl (E)-3-(benzylamino)-2-((trifluoromethyl)thio)but-2-enoate
(14j) After purification by silica gel column chromatography
(PE : EA = 20 : 1), compound 13j was isolated as a yellow oil
(99 mg, 62%); Rf (PE : EA = 20 : 1) = 0.34; 1H NMR (400 MHz,
CDCl3): δ 10.78 (s, 1H), 7.38-7.24 (m, 5H), 4.51 (d, J = 5.6 Hz,
2H), 4.18 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.29 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 171.3, 170.8, 136.8, 130.0
(q, J = 310 Hz, 1C), 129.0, 127.8, 126.8, 76.6 (q, J = 2.1 Hz),
60.1, 48.3, 17.7, 14.3; 19F NMR (376 MHz, CDCl3): δ -47.31 (s,
3F). HRMS (ESI) m/e calcd for C14H17F3NO2S+ (M+H)+
320.0927, found 320.0926.
2-(4-(trifluoromethyl)phenyl)-5-((trifluoromethyl)thio)-1H-
pyrrole (14c)4f After purification by silica gel column
chromatography (PE : EA = 20 : 1), compound 13c was isolated
as a white solid (82 mg, 53%); Rf (PE : EA = 20 : 1) = 0.47; mp
1
(melting point) = 40–45 °C; H NMR (400 MHz, CDCl3): δ 8.69
(s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 6.74 (t,
J = 3.2 Hz, 1H), 6.66 (t, J = 3.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 136.2, 134.5, 129.4 (q, J = 32 Hz, 1C), 128.3 (q, J =
309 Hz, 1C), 126.1 (q, J = 4 Hz, 1C), 124.4, 124.0 (q, J = 271 Hz,
1C), 123.2, 110.0 (q, J = 2 Hz, 1C), 109.6; 19F NMR (376 MHz,
CDCl3): δ -44.77 (s, 3F), - 62.57 (s, 3F).
3-((trifluoromethyl)thio)indolizine-1-carbonitrile (14d): After
purification by silica gel column chromatography (PE : EA = 10 :
1), compound 13d was isolated as a yellow solid (75 mg, 62%);
Rf (PE : EA = 10 : 1) = 0.36; mp (melting point) = 109–110 °C;
1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.0 Hz, 1H), 7.75 (d,
J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.33 (ddd, J = 8.8 Hz, 6.8 Hz, 0.8
Hz, 1H), 7.03 (td, J = 7.0 Hz, 1.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 141.1, 129.5, 128.1 (q, J = 311.9 Hz, 1C), 125.3, 124.9,
118.1, 115.0, 114.5, 103.5 (q, J = 2.9 Hz, 1C), 84.5; 19F NMR
(376 MHz, CDCl3): δ -44.06 (s); HRMS (ESI) m/e calcd for
C10H6F3N2S+ (M+H)+ 243.0198, found 243.0198.
4. Conclusion
In conclusion, we successfully developed a novel transition
metal-free method for the direct trifluoromethylthiolation of
electron-rich aromatics using CF3SO2Na in the presence of
PhPCl2. In this protocol, PhPCl2 was employed as both a
reducing and a chlorinating reagent of CF3SO2Na. Thus, the
absence of transition metal-containing reagents from this
procedure, in addition to the use of cheap and readily available
3-((trifluoromethyl)thio)indolizine-1-carbonitrile (14e) After
purification by silica gel column chromatography (PE : EA = 15 :
1), compound 13e was isolated as a white solid (77 mg, 56%); Rf
1
(PE : EA = 10 : 1) = 0.41; mp (melting point) = 85–87 °C; H

6
Tetrahedron
ACCEPTED MANUSCRIPT
2017, 4, 232-235. (g) Zhao, X.; Li, T.; Yang, B.; Qiu, D.; Lu, K.
Tetrahedron. 2017, 73, 3112-3117.
reagents, render it an alternative strategy for the
trifluoromethylthiolation of electron-rich aromatics.
Acknowledgments
The authors sincerely thank the financial support from
National Science Foundation of China (Grants 21572158).
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