Structure-reactivity relationship of trifluoromethanesulfenates: Discovery of an electrophilic trifluoromethylthiolating reagent

Article abstract of DOI:10.1021/jo502645m

A family of electrophilic trifluoromethanesulfenates was prepared. Structure-reactivity relationship studies showed that the substituted groups on the aryl ring of the trifluoromethylthiolating reagent did not have an obvious influence on their reactivities. A simplified electrophilic trifluoromethylthiolating reagent 1c was then identified that can react with a wide range of nucleophiles such as Grignard reagents, arylboronic acids, alkynes, indoles, β-ketoesters, oxindoles, and sodium sulfinates under mild reaction conditions. A variety of functional groups were tolerated under these conditions.

Full text of DOI:10.1021/jo502645m

Subscriber access provided by Northern Illinois University
Article
Structure-Reactivity Relationship (SAR) of Trifluoromethanesulfenates:
Discovery of An Electrophilic Trifluoromethylthiolating Reagent
Xinxin Shao, Chunfa Xu, Long Lu, and Qilong Shen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Jan 2015
Downloaded from http://pubs.acs.org on January 28, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Structure-Reactivity Relationship (SAR) of Trifluoromethanesulfenates:
Discovery of An Electrophilic Trifluoromethylthiolating Reagent
Xinxin Shao, Chunfa Xu, Long Lu* and Qilong Shen*
9
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
lulong@mail.sioc.ac.cn, shenql@mail.sioc.ac.cn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract
family
A
of
electrophilic
trifluoromethanesulfenates
was
prepared.
Structureꢀreactivity relationship studies showed that the substituted groups on the aryl
ring of the trifluoromethylthiolating reagent didn’t have obvious influence on their
reactivities. A simplified electrophilic trifluoromethylthiolating reagent 1c was then
identified that can react with a wide range of nucleophiles such as Grignard reagents,
arylboronic acids, alkynes, indoles, βꢀketoesters, oxindoles and sodium sulfinates
under mild reaction conditions. A variety of functional groups were tolerated under
these conditions.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 42
1
2
3
4
Introduction
5
6
In 2013, we reported the preparation of an air and moisture stable
7
8
9
trifluoromethylthiolating reagent 1a, which was isolated as a colorless liquid with a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
boiling point 151ꢀ153 C. Reagent 1a was characterized by H, 13C, and 19F NMR
spectroscopy, as well as elemental analysis. Reagent 1a is a powerful
trifluoromethylthiolating reagent that allows the trifluoromethylthiolation of a variety
of nucleophiles such as aryl, vinyl, alkyl boronic acids, alkynes, indoles, carbonyl
derivatives such as βꢀketoesters, aldehydes, or amides.1 In addition,
a
quinineꢀcatalyzed highly enantioselective trifluoromethylthiolation of ꢀketoesters
β
and oxindoles with reagent 1a was achieved under mild conditions.2 Furthermore,
using reagent 1a as the radical trap, a silverꢀcatalyzed decarboxylative
trifluoromethylthiolation of secondary and tertiary aliphatic carboxylic acids in
aqueous emulsion was also described.3 The structure of reagent 1a was initially
proposed to be a trifluoromethylthioꢀsubstituted hypervalent iodine reagent. Very
recently, Buchwald and coꢀworkers4 revised the structure of the reagent as a
trifluoromethanesulfenate 1b, based on a combination of spectroscopic techniques,
derivatization experiments and the crystal sponge method (Figure 1).
Figure 1. Electrophilic trifluoromethylating reagent: its initial proposed structure 1a and
revised structure 1b.
One question that arose from the structure revision is the role of the iodide atom
ACS Paragon Plus Environment

Page 3 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
for the reactivity of the reagent 1. One possible scenario is that structure 1a and 1b
may exist as a tautomeric equilibria where structure 1b is the major form. If 1a is
much more reactive than 1b when a nucleophile reacts with the electrophilic
trifluoromethylthiolating reagent, the reaction might proceed via nucleophilic
substitution with structure 1a and the equilibrium might then shift toward right
(Figure 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Tautomeric equilibrium between 1a and 1b and one possible reaction
pathway when reagent 1 reacts with nucleophiles.
To probe if this is the case and the role of the iodide for the reactivity of the
trifluoromethylthiolating reagent, we synthesized
a
family of substituted
trifluoromethanesulfenates and studied their structureꢀreactivity relationship (SAR).
We found that substituted trifluoromethanesulfenates with or without iodide atom
showed similar reactivities toward a variety of nucleophiles. Subsequent studies
showed that a simplified trifluoromethanesulfenate 1c, which is shelf stable and easily
handled, can be used as an equally effective electrophilic trifluoromethylthiolating
reagent as 1b. Herein, we disclose these findings and report the scope of the
trifluoromethylthiolating reagent 1c with a variety of different nucleophiles.
Results and Discussion
1. Preparation of substituted electrophilic trifluoromethanesulfenates.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 42
1
2
3
4
5
6
7
8
9
The substituted trifluoromethanesulfenates were readily synthesized from
corresponding tertiary alcohols 2aꢀh with trifluoromethylthiolated saccharin, an
electrophilic trifluoromethylthiolating reagent 3 developed in our own group.5
Typically, the tertiary alcohols were converted to the trifluoromethanesulfenates in
good to excellent yields within 5 min at room temperature using Et3N as the base
(Table 1). Notably, these reactions can be easily scaled up without loss of the yields.
For example, reaction of 2ꢀphenylpropanꢀ2ꢀol (20 mmol) with reagent 3 generated the
trifluoromethanesulfenate 1c in 80% yield on 3.8 g scale. Alternatively,
trifluoromethanesulfenate 1c could be synthesized by reaction of lithium
2ꢀphenylpropanꢀ2ꢀolate and trifluoromethylthiolated phthalimide 4 in 85% yield on
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.0
g
scale under mild conditions (Eq 1).6 These substituted
trifluoromethanesulfenates are bench stable compounds except for compound 1g.
o
They are usually stored at 0ꢀ4 C and no obvious decomposition was observed for at
least 5 months as determined by 19F NMR spectroscopy. Compound 1g is much less
stable since it was found that compound 1g was completely decomposed when we
tried to purify it by flash chromatography.
Table 1. Preparation of Substituted Trifluoromethanesulfenates.a
ACS Paragon Plus Environment

Page 5 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
SCF3
O
S
O
R
OH
R'
R
O
CH2Cl2, Et3N
rt, 5 min
N SCF3
+
R'
O
1
2a-h, 6.0 mmol
3 (1.3 equiv)
9
SCF3
SCF3
SCF3
O
SCF3
O
I
Br
Me
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1b, 87%
1c, 85%
80% on 3.8 g scale
SCF3
1d, 85%
1e, 87%
SCF3
O
O
O
Me
F3CS
O
SCF3
Cl
MeO
1f, 86%
1g, 92%
1h, 67%
1i, 82%
aReaction conditions: alcohol (6.0 mmol), reagent 3 (7.8 mmol), Et3N (2.0 mL) in CH2Cl2 (40 mL) at
room temperature for 5 min. Isolated yield.
2.
Structure-reactivity
Relationship
(SAR)
studies
of
the
trifluoromethanesulfenates. With reagents 1bꢀi in hand, we began to study their
structureꢀreactivity relationship (SAR) with a variety of different nucleophiles such as
aryl and alkyl boronic acids,7 βꢀketoester,1 indole,8 alkyne, 2ꢀphenylꢀoxindole9 and
1ꢀadamamtame carboxylic acid3 under the previously optimized conditions, and the
results were summarized in Table 2. Interestingly, the SAR studies showed that in
most cases, trifluoromethanesulfenates with or without iodide displayed similar
reactivities when reacted with the same nucleophile under the same reaction
conditions. These results clearly indicated that the iodide in reagent 1b does not play
an important role for the high reactivity of the reagent and the scenario described in
Figure 2 is likely not going to take place. Interestingly, these studies also showed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 42
1
2
3
4
5
6
7
8
9
reagents 1b, 1c, 1d and 1f showed different reactivities from reagents 1g, 1h and 1i
when reacted with some nucleophiles. For example, in the presence of the copper
catalyst, reactions of 2ꢀphenylethyl boronic acid with trifluoromethanesulfenates 1b,
1c, 1d or 1f generated the corresponding trifluoromethylthiolated products in 80%,
74%, 70% and 70%, respectively, while the same reaction with reagent 1g, 1h and 1i
gave the products in trace, 37% and 52% yields respectively (Table 2, entry 2).
Similar trends were also observed when these reagents were subjected to the
conditions of the silverꢀcatalyzed decarboxylative trifluoromethylthiolation with
1ꢀadamantane carboxylic acid (Table 2, entry 7). Notably, it was discovered that
reagent 1g is less thermally stable than other reagents. Heating of reagent 1g in
1,2ꢀdichloroethane at 120 oC for 12 h led to complete decomposition as determined by
19F NMR spectroscopy. The low yield for the reaction of reagent 1g with indole in the
presence of 10 mol% of camphorsulfonic acid may also due to the low stability of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
reagent in the presence of the BrØnsted acid. Considering the easy availability of the
starting materials, the cost and the atom economy of the reagent, we chose reagent 1c,
which is shelf stable and easily handled, as an equally effective electrophilic
trifluoromethylthiolating reagent as 1b.
Table 2. Structure-reactivity Relationship (SAR) studies of the
trifluoromethanesulfenates with Different Nucleophiles.a
Trifluoromethanesulfenates
1b
1c
1d
1e
1f
1g
1h
1i
1b
2c
99% 57% 57% 54% 81%
80% 74% 70% 21% 70%
70%
81% 52%
37% 52%
trace
ACS Paragon Plus Environment

Page 7 of 42
The Journal of Organic Chemistry
1
2
3
4
5
3d
98% 95% 92% 99% 91%
99%
94% 95%
6
7
8
9
4e
5f
99% 92% 94% 59% 57%
99% 98% 73% 90% 92%
85% 85% 85% 99% 77%
98% 95% 94% 68% 96%
23%
86%
88%
trace
57% 70%
80% 36%
79% 91%
50% 75%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6g
7h
aYields were determined by 19F NMR spectroscopy with benzotrifluoride as an internal standard;
Reaction conditions: b4ꢀBiphenyl boronic acid (0.1 mmol), electrophilic trifluoromethylthiolating
reagent (0.1 mmol), Cu(MeCN)4PF6 (10 mol %), 2,2'ꢀbipyridine (20 mol %) and K2CO3 (2.0 equiv) in
diglyme (0.5 mL) at 35 oC for 15 h; cAlkylboronic acid (0.15 mmol), electrophilic
trifluoromethylthiolating reagent (0.1 mmol), CuCl2•2H2O (20 mol %), 2,2'ꢀbipyridine (40 mol %) and
K2CO3 (2.0 equiv) in 1,2ꢀdichloroethane (0.5 mL) at 120 oC for 12 h; dβꢀKetoester (0.1 mmol),
electrophilic trifluoromethylthiolating reagent (0.2 mmol), DMAP (0.11 mmol) in CH2Cl2 (0.5 mL)
e
room temperature for 12 h; Indole (0.1 mmol), electrophilic trifluoromethylthiolating reagent (0.11
o
f
mmol), camphorsulfonic acid (10 mol %) in 0.5 mL of 1,2ꢀdichloroethane 40 C for 20 h; Alkynes
(0.20 mmol, 2.0 equiv), CuBr(SMe2) (20 mol %), 2,2’ꢀbiyridine (40 mol %), K2CO3 (2.0 equiv) and
o
electrophilic trifluoromethylthiolating reagent (0.1 mmol) in 1,2ꢀdichloroethane (0.5 mL) at 80 C for
g
14 h; Reaction conditions for oxindole (0.1 mmol), electrophilic trifluoromethylthiolating reagent
(0.15 mmol), DMAP (0.11 mmol) in CH2Cl2 (0.5 mL), room temperature for 12 h; h1ꢀAdamantane
carboxylic acid (0.1 mmol), electrophilic trifluoromethylthiolating reagent (0.2 mmol), sodium
1ꢀdodecanesulfate (0.02 mmol), AgNO3(0.03 mmol), K2S2O8 (0.1 mmol) in H2O (0.5 mL), 50 oC for 12
h.
3 Scope of reagent 1c with different nucleophiles.
3.1 Reactions of reagent 1c with Grignard reagents.
Trifluoromethylthiolated arenes are important structural motif found in many drug
molecules and agrochemicals.10 As a result, development of efficient methods for the
preparation of trifluoromethylthiolated arenes is of great interest in the field of
medicinal chemistry and argochemistry.11ꢀ12 One straightforward way for the synthesis
of the trilfluoromethylthiolated arenes is direct trifluoromethylthiolation of Grignard
reagents with electrophilic trifluoromethylthiolating reagent, which has been
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 42
1
2
3
4
5
6
7
8
9
previously reported by Billard and coworkers.13 It was found that reactions of a
variety of Grignard reagents with electrophilic trifluoromethylthiolating reagent 1c
occurred smoothly in THF to give the corresponding trifluoromethylthiolated arenes
in good to excellent yields. The reactions are facile and full conversions were
observed after 3 h at room temperature (Table 3). Grignard reagents with functional
groups such as chloride or methoxy group also gave the corresponding products in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
good yields.
Table 3. Substrate Scope for Reaction of Reagent 1c with Grignard Reagents.a
o
aReaction conditions: RMgBr (0.5 mmol), reagent 1c (0.5 mmol), in THF (2.5 mL), 0 C for 30 min,
then room temperature for 3 h. Isolated yield.
3.2 Reactions of Reagent 1c with Arylboronic Acids.
Even though Grignard reagents react with reagent 1c under mild conditions, there is
one drawback of using Grignard reagents for the preparation of
trifluoromethylthiolated arenes. In general, Grignard reagents are incompatible with
various functional groups. To address this disadvantage of using Grignard reagents,
we previously have developed a copperꢀcatalyzed trifluoromethylthiolation of aryl
boronic acids with reagent 1b under mild conditions.1 Likewise, reactions of a variety
of electronꢀrich and electronꢀdeficient arylboronic acids with reagent 1c gave the
ACS Paragon Plus Environment

Page 9 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
corresponding products in good to excellent yields, although the yields for reactions
of some aryl boronic acids with reagent 1c were less than those with reagent 1b.
Various functional groups, including ethers, alkenes, ketones, esters, chloride and
iodine were tolerated under the standard reaction conditions. In addition, reaction of
2ꢀmethoxyꢀ3ꢀpyridylboronic acid with reagent 1c gave the trifluoromethylthiolated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pyridine derivative in 58% yield (Table 4, 6h).
Table 4. Substrate Scope for Reaction of Reagent 1c with Arylboronic Acids.a
aReaction conditions: arylboronic acid (0.65 mmol), reagent 1c (0.5 mmol), Cu(MeCN)4PF6 (10
o
mmol %), bpy (20 mmol %), K2CO3 (1.0 mmol) in diglyme (2.5 mL) at 35 C for 15–24 h. Isolated
yields.
3.3 Reactions of Reagent 1c with Alkynes.
Trifluoromethylthiolated alkynes, which could be converted to other functionalized
trifluoromethylthioethers, are also important structural motif found in many drug
molecules and agrochemicals. In 2012, Qing reported a transitionꢀmetal free oxidative
trifluoromethylthiolation of alkynes with moderate yields at room temperature.14
Billard reported that trifluoromethylthiolated alkynes could be easily accessed from
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 42
1
2
3
4
5
6
7
8
9
reaction of alkynyl lithium with trifluoromethanesulfanamide, an electrophilic
trifluoromethylthiolating reagent developed in Billard’s laboratory.15 We have
previously reported that in the presence of a copper catalyst, reactions of a variety of
alkynes with reagent 1b occurred in good to excellent yields.1 Under the same
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
conditions, reaction of various alkynes with reagent 1c at 80 C after 14 h generated
the corresponding trifluoromethylthiolated alkynes in good to excellent yields. A wide
range of functional groups, including nitro, chloride, ester, fluoride and bromide were
compatible with the reaction conditions (Table 5, 7a-7h). Aliphatic and hetero alkynes
also
reacted
under
these
conditions
to
give
the
corresponding
alkynylꢀtrifluoromethylthioethers in satisfactory yields (Table 5, 7iꢀj).
Table 5. Substrate Scope for Reaction of of Reagent 1c with Terminal Alkynes.a
aReaction conditions: alkyne (0.60 mmol), reagent 1c (0.3 mmol), CuBr·SMe2 (20 mol %), bpy (40
mol %), K2CO3 (0.60 mmol) in 1,2ꢀdichloroethane (1.5 mL) at 80 oC for 14 h. Isolated yields.
3.4 Reaction of Reagent 1c with Indoles.
Indole is among one of the privileged structural motif in biologically active natural
products such as amino acids and alkaloids.16 Development of efficient methods for
ACS Paragon Plus Environment

Page 11 of 42
The Journal of Organic Chemistry
1
2
3
4
functionalization including trifluoromethylthiolation of indole is, therefore, of great
5
6
7
current interests. Notably, Billard and Langlois reported the first BrØsted
8
9
acidꢀmediated electrophilic trifluoromethylthiolation of indoles under mild
conditions.13b In 2013, Shibata described a copperꢀcatalyzed trifluoromethylthiolation
of indoles with an electrophilic trifluoromethanesulfonyl hypervalent iodonium ylide
via an in situ reduction of the CF3SO2 group to form a trifluoromethylthiolated
ammonia salt that was responsible for the trifluoromethylthiolation.17 It was found
that in the presence of 10 mol% of camphorsulfonic acid, reactions of indoles with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
electronꢀdonating
or
withdrawing
groups
with
the
electrophilic
trifluoromethylthiolating reagent 1c gave the corresponding trifluoromethylthiolated
indoles in moderate to good yields (Table 6). Reaction of 3ꢀmethylꢀindole formed the
corresponding 2ꢀtrifluoromethylthiolated indole in 43% yield (Table 6, 8f). NꢀMethyl
indole also reacted under standard conditions to give the corresponding product in
94% yield (Table 6, 8g).
Table 6. Substrate Scope for Reaction of Reagent 1c with Indoles.a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 42
1
2
3
4
SCF3
O
SCF3
CSA (10 mol%)
5
6
7
8
R1
R1
+
N
R2
ClCH2CH2Cl
40 oC, 48 h
N
R2
1c (1.2 equiv)
8
9
SCF3
SCF3
SCF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
MeO2C
Me
N
N
N
H
H
H
R = Br, 40%, 8a
CN, 23%, 8b
8c, 69%
8d, 35%
SCF3
Me
SCF3
Me
SCF3
Me
N
Me
N
H
N
H
8e, 95%
8f, 43%
8g, 94%
aReaction conditions: indole (0.3 mmol), reagent 1c (0.33 mmol), catalyst(10 mol %) in 1.5 mL of
1,2ꢀdichloroethane for 20ꢀ48 h. Isolated yields.
3.5 Reaction of Reagent 1c with β-ketoesters and Oxindoles
We have previously showed that reactions of βꢀketoesters and oxindoles with the
electrophilic trifluoromethylthiolating reagent 1b occurred in good to excellent yields
in presence of 4ꢀdimethylaminopyridine (DMAP) as the base.1,9 The same reaction
conditions were applied for the reactions of βꢀketoesters and oxindoles with reagent
1c. It was found that reactions of various βꢀketoesters derived from indanone,
tetralone, or 1ꢀbenzosuberone gave the corresponding products in good to excellent
yields (Table 7, 9aꢀe). Likewise, reactions of oxindoles generated the corresponding
trifluoromethylthiolated products also in good to excellent yields (Table 7, 9fꢀl).
Table 7. Substrate Scope for Reaction of of Reagent 1c with β-ketoesters and
Oxindoles.a
ACS Paragon Plus Environment

Page 13 of 42
The Journal of Organic Chemistry
1
2
3
O
O
4
5
6
7
8
9
CO2R
SCF3
CO2R
SCF3
O
n
n
DMAP (1.1 equiv)
or
+
or
CH2Cl2
rt, Overnight
Ar
Ar
SCF3
O
R
R
1c
1.5-2.0 equiv
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
Boc
Boc
9
O
O
O
MeO
MeO
Me
CO2Ad
SCF3
CO2Me
SCF3
CO2Me
SCF3
F
9a, 95 %
9b, 91 %
9c, 90 %
O
Me
SCF3
CO2Ad
OMe O
SCF3
SCF3
CO2Ad
O
N
Boc
OMe
9d, 82 %
9e, 85 %
9f, 75%
Ph
Ph
Ph
SCF3
O
N
Boc
SCF3
O
SCF3
O
Cl
Br
N
N
Boc
Boc
9g, 83%
9h, 81%
9i, 85%
MeO
F
SCF3
O
F
SCF3
O
SCF3
O
N
N
Boc
N
Boc
9j, 90%
Boc
9k, 91%
9l, 89%
aReaction conditions for βꢀketoester (0.3 mmol), reagent 1c (0.6 mmol), DMAP (0.33 mmol) in CH2Cl2
(1.5 mL), room temperature for 12 h; Reaction conditions for oxindole (0.3 mmol), reagent 1c (0.45
mmol), DMAP (0.33 mmol) in CH2Cl2 (1.5 mL), room temperature for 12 h. Isolated yields.
3.6 Reaction of Reagent 1c with Sodium Sulfinates.
Thiosulfonates are a family of valuable compounds that have shown insecticidal
activity in azuki bean weevils and rice stem borer larvae.18 In addition, thiosulfonates
can act as a thioꢀtransfer reagent for the preparation of a variety of thiolated
compounds.19 Interestingly, no methods for the preparation of trifluoromethylthiolated
sulfonates have been reported previously. It was found that treatment of sodium
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 42
1
2
3
4
5
6
7
8
9
sulfinates with reagent 1c in acetic acid after 12 h at room temperature generated the
corresponding trifluoromethylthiolated sulfonates in good to excellent yields. The
reaction was compatible with a variety of functional groups such as chloride, bromide,
fluoride, nitrile, nitro and ester group (Table 8, 10aꢀh). Sodium heteroarylsulfinates
also reacted with reagent 1c under the standard conditions to give the corresponding
products in excellent yields (Table 8, 10iꢀj). The structure of compound 10j was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
further confirmed by xꢀray diffraction of its single crystals.
Table 8. Substrate Scope for Reactions of Reagent 1c with Sodium Sulfinates.a
aReaction conditions: sodium sulfinates (0.75 mmol), reagent 1c (0.5 mmol), in AcOH (2.5 mL), room
temperature for 12 h. Isolated yields.
4. Comparasion of the Reactivity of Reagent 1c and 3.
ACS Paragon Plus Environment

Page 15 of 42
The Journal of Organic Chemistry
1
2
3
4
Both reagents 1c and
3
can act as highly reactive electrophilic
5
6
7
8
9
trifluoromethylthiolating reagent for a wide range of the substrates. Nevertheless, the
substrate scope of two reagents is complementary. Reagent 1c shows better reactivity
than reagent 3 in copperꢀcatalyzed trifluoromethylthiolation of aryl/alkyl boronic
acids and silverꢀcatalyzed decarboxylative trifluoromethylthiolation of aliphatic
carboxylic acids. For example, reaction of 2ꢀphenylethylboronic acid with reagent 1c
in the presence of 20 mol% of CuCl2 •2H2O and 40 mol% 2,2’ꢀbipyridine as the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
catalyst occurred to 74% yield after 12 h at 120 C, while the same reaction using
reagent 3 as the electrophilic trifluoromethylthiolating reagent gave trace amount of
the coupled product (Eqs. 2ꢀ3). Likewise, silverꢀcatalyzed Hunsdieckerꢀtype
decarboxylative trifluoromethylthiolating reaction of adamantine carboxylic acid
using reagent 1c afford the corresponding trifluoromethylthiolated product in 95%
yield, while the same reaction using reagent
3 did not generate the
trifluoromethylthiolated product (Eqs. 4ꢀ5). On the other hand, reagent 3 displays
much higher reactivity than reagent 1c in direct nucleophilic trifluoromethylthiolating
reactions such as reactions with alcohols, amines, thiols and βꢀketoesters.5 For these
nucleophiles, no products were observed when reagent 1c was used as the
electrophilic trifluoromethylthiolating reagents. One obvious example of the higher
reactivity of reagent 3 in direct nucleophilic substitution reaction is that reagent 1c
itself was prepared from reagent 3. Similarly, reaction of βꢀketoester 11 with reagent 3
formed the monoꢀtrifluoromethylthiolated product in 75% yield, while the same
reaction with reagent 1 was messy and the monotrifluoromethylthiolated product was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 42
1
2
3
4
observed in less than 5% yield as determined by 19F NMR spectroscopy (Eqs. 6ꢀ7).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Summary
In this work, we described the preparation of a family of substituted
trifluoromethanesulfenates. Structureꢀreactivity relationship (SAR) studies showed
that substituted trifluoromethanesulfenates with or without iodide atom display
similar reactivities toward a variety of nucleophiles. As a result, a simplified
trifluoromethanesulfenate 1c, which is shelf stable and easily handled, was identified
as an equally effective electrophilic trifluoromethylthiolating reagent as 1b. Reaction
of reagent 1c with various nucleophiles such as aryl Grignard reagents, aryl boronic
ACS Paragon Plus Environment

Page 17 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acids, alkynes, indoles, βꢀketoesters, 2ꢀsubstituted oxindoles and sodium sulfinates
under mild conditions have thus been developed. The ease in preparation, thermal and
moisture stability and broad range of reactivity toward different nucleophiles under
mild reaction conditions make reagent 1c attractive as a general electrophilic
trifluoromethylthiolating reagent for the incorporation of the trifluoromethylthio
group into small molecules. The investigation of reactions of reagent 1c with other
nucleophiles are undergoing currently in our laboratory.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
1
General information. All solvents were purified by standard method. H, 19F NMR
and 13C NMR spectra were recorded on 300 MHz, 282 MHz and 100 MHz
1
spectrometer, respectively. H NMR and 13C NMR chemical shifts were determined
relative to internal standard TMS at δ 0.0 ppm and 19F NMR chemical shifts were
determined relatived to CFCl3 as inter standard. Chemical shifts (δ) are reported in
ppm, and coupling constants (J) are in hertz (Hz). The following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. All reactions were monitored by TLC or 19F NMR. Flash
column chromatograph was carried out using 300ꢀ400 mesh silica gel at medium
pressure.
Materials. All reagents were received from commercial sources. Pure CuI was freshly
prepared under the condition of the reference (Dieter, R. K. J. Am. Chem. Soc. 1985,
107, 4679). Solvents were freshly dried and degassed according to the purification
handbook Purification of Laboratory Chemicals before using.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 42
1
2
3
4
Synthesis of tertiary alcohols
5
6
7
8
9
A dry and nitrogenꢀflushed 25 mL flask equipped with a magnetic stirrer and a septum
was charged with 56.25 mL of 2.0 M MeMgBr in Et2O. 40 mL of methyl benzoates
(50 mmol) in Et2O was added dropwise in 30 min and the reaction was allowed to
warm slowly to room temperature. The reaction was stirred for overnight and was
quenched with an NH4Cl solution (70 mL contain 10 mL ice water). 80 mL of Et2O
was added and the organic phase was separated. The aqueous phase was extracted
with Et2O (3 × 40 mL) and the combined organic extracts were dried over anhydrous
Na2SO4, and concentrated in vacuo. The product was purified by flash
chromatography on silica gel to give the tertiary alcohol as a colorless liquid.
2-(2-Bromophenyl)propan-2-ol.20 Colorless liquid (6.74 g, 63%). Eluent: ethyl
acetate/petroleum ether = 1 /10, Rf = 0.6. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.59 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.21 (t, J = 8.0 Hz, 1 H), 7.01 (t, J
= 8.0 Hz, 1 H), 2.77 (s, 1 H), 1.69 (s, 6 H) ppm
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(O-tolyl)propan-2-ol.21 White solid (4.58 g, 61%). Eluent: ethyl acetate/petroleum
ether = 1/10, Rf = 0.6. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.48ꢀ7.45 (m, 1 H),
7.18ꢀ7.16 (m, 3 H), 2.62 (s, 3 H), 1.85 (s, 1 H), 1.67 (s, 6 H) ppm
2-(4-Chlorophenyl)propan-2-ol.22 Colorless liquid (6.55 g, 77%). Eluent: ethyl
acetate/petroleum ether = 1/10, Rf = 0.6. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.42 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H), 1.82 (s, 1 H), 1.57 (s, 6 H) ppm
2-(4-Methoxyphenyl)propan-2-ol.22 Colorless liquid (5.90 g, 71%). Eluent: ethyl
acetate/petroleum ether = 1/10, Rf = 0.4. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
ACS Paragon Plus Environment

Page 19 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7.41 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 3.81(s, 3 H), 1.87 (s, 1 H), 1.57 (s,
6 H) ppm.
7
8
9
General procedure for the preparation of trifluoromethanesulfenates.
General method 1. A 50 mL roundꢀbottomed flask with a magnetic stirrer was
charged with alcohols (6.0 mmol), Nꢀtrifluoromethylthiosaccharin (2.2 g, 7.8 mmol) ,
Et3N (2.0 mL, 14.4 mmol) and CH2Cl2 (40 mL). The mixture was stirred at room
temperature for 5 min. The resulting mixture was purified by flash column
chromatography (Eluent: petroleum ether) to give trifluoromethanesulfenate as a light
yellow liquid. The light yellow liquid was further purified by flash column
chromatography (Eluent: petroleum ether) to give a colorless liquid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General method 2. A 50 mL roundꢀbottomed flask with a magnetic stirrer was
charged with lithium 2ꢀphenylpropanꢀ2ꢀolate (10 mmol), trifluoromethylthiolated
o
phthalimide (10 mmol) in 40 mL of CH2Cl2. The reaction was stirred at 50 C and
monitored by 19F NMR spectroscopy until the disappearance of the
trifluoromethylthiolating reagent. The mixture was filtered through a pad of Celite
and the solvent was removed in vacuo. The product was purified by flash
chromatography on silica gel to give reagent 1c as a colorless liquid (2.0 g, 85%
yield).
((2-Phenylpropan-2-yl)oxy)(trifluoromethyl)sulfane 1c.5 Colorless liquid (3.8 g,
80%). Eluent: petroleum ether, Rf = 0.8. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.42ꢀ7.32 (m, 5 H), 1.70 (s, 6 H); 19F NMR (376 MHz, CDCl3) δ ꢀ52.1 (s, 3 F) ppm.
((2-(2-Bromophenyl)propan-2-yl)oxy)(trifluoromethyl)sulfane 1d. Colorless liquid
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 42
1
2
3
4
1
(1.6 g, 85%). Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K,
5
6
7
8
9
TMS) δ 7.66 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H),
7.17 (t, J = 7.9 Hz, 1 H), 1.86 (s, 6 H); 19F NMR (376 MHz, CDCl3) δ ꢀ51.5 (s, 3 F);
13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ 141.8, 136.2, 130.7 (q, J = 312.9 Hz),
129.8, 128.6, 126.0, 121.4, 87.6, 26.6 ppm. IR (KBr): ν = 2990, 2935, 1590, 1566,
1470, 1386, 1368, 1278, 1251, 1124, 1048, 1023, 933, 585, 756, 724 cmꢀ1. Elemental
Analysis for C10H10F3OBrS: Calculated: C, 38.11; H, 3.20, Found: C, 37.72; H, 3.12.
((2-(O-tolyl)propan-2-yl)oxy)(trifluoromethyl)sulfane 1e. Colorless liquid (1.3 g,
87%). Eluent: petroleum ether, Rf = 0.8. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.34ꢀ7.32 (m, 1 H), 7.25ꢀ7.18 (m, 3 H), 2.58 (s, 3 H), 1.79 (s, 6 H); 19F NMR (376
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
MHz, CDCl3) δ ꢀ51.6 (s, 3 F); C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ 141.1,
136.9, 133.3, 130.8 (q, J = 312.1 Hz), 128.5, 127.0, 125.9, 87.9, 27.4 (q, J = 1.4 Hz),
21.7 ppm. IR (KBr): ν = 2990, 1490, 1458, 1383, 1367, 1293, 1259, 1128, 1108, 1057,
849, 805, 761, 726, 582 cmꢀ1. Elemental Analysis for C11H13F3OS: Calculated: C,
52.79; H, 5.24, Found: C, 52.69; H, 5.21.
((2-(4-Chlorophenyl)propan-2-yl)oxy)(trifluoromethyl)sulfane 1f. Colorless liquid
1
(1.4 g, 86%). Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K,
TMS) δ 7.37 (s, 4 H), 1.71 (s, 6 H); 19F NMR (376 MHz, CDCl3) δ ꢀ51.6 (s, 3 F); 13C
NMR (100.7 MHz, CDCl3, 293 K, TMS) δ 142.9, 135.3, 130.6 (q, J = 312.9 Hz),
128.9, 128.7, 87.2, 27.6 ppm. IR (KBr): ν = 2990, 2935, 1590, 1566, 1470, 1386,
1368, 1278, 1251, 1124, 1048, 1023, 933, 585, 756, 724 cmꢀ1. Elemental Analysis for
C10H10F3OClS: Calculated: C, 44.37; H, 3.72, Found: C, 44.19; H, 3.68.
ACS Paragon Plus Environment

Page 21 of 42
The Journal of Organic Chemistry
1
2
3
4
((2-(4-Methoxyphenyl)propan-2-yl)oxy)(trifluoromethyl)sulfane 1g. Colorless
5
6
7
1
liquid (1.5 g, 92%). Eluent: petroleum ether, Rf = 0.6. H NMR (500 MHz, CDCl3,
8
9
293 K, TMS) δ 7.36 (d, J = 8.0 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 3.84 (s, 3 H), 1.71
(s, 6 H); 19F NMR (376 MHz, CDCl3) δ ꢀ52.1 (s, 3 F); 13C NMR (125.0 MHz, CDCl3,
293 K, TMS) δ 136.3, 130.8 (q, J = 313.0 Hz), 127.2, 126.8, 113.9, 86.4, 55.4, 27.6
ppm. IR (KBr): ν = 2692, 2837, 1608, 1582, 1513, 1465, 1442, 1413, 1366, 1291,
1252, 1155, 1113, 1038, 829 cmꢀ1. Elemental Analysis for C11H13F3O2S: Calculated: C,
49.62; H, 4.92, Found: C, 49.75; H, 5.19.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1,1-Diphenylethoxy)(trifluoromethyl)sulfane 1h. Colorless liquid (1.2 g, 67%).
1
Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K, TMS) δ
19
7.36ꢀ7.33 (m, 10 H), 2.07 (s, 3 H); F NMR (376 MHz, CDCl3) δ ꢀ51.7 (s, 3 F); 13C
NMR (100.7 MHz, CDCl3, 293 K, TMS) δ 144.6, 130.8 (q, J = 312.7 Hz), 128.5,
128.2, 127.1, 89.8, 25.9 (q, J = 1.5 Hz) ppm. IR (KBr): ν = 3062, 3030, 2992, 1599,
14894, 1447, 1316, 1252, 1221, 1124, 1069, 1043, 1029, 589, 792, 698, 627, 582 cmꢀ1.
Elemental Analysis for C15H13F3OS: Calculated: C, 60.39; H, 4.39, Found: C, 59.94;
H, 4.30.
((2-Methyl-1-phenylpropan-2-yl)oxy)(trifluoromethyl)sulfane 1i.5 Colorless liquid
1
(1.2 g, 80%). Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K,
TMS) δ 7.36ꢀ7.29 (m, 3 H), 7.23ꢀ7.21 (m, 2 H), 2.91 (s, 2 H), 1.32 (s, 6 H); 19F NMR
(376 MHz, CDCl3) δ ꢀ52.9 (s, 3 F) ppm.
General Procedure for electrophilic trifluoromethylthiolation of Grignard
reagents with reagent 1c.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 42
1
2
3
4
5
6
7
8
9
A dry and nitrogenꢀflushed 25 mL flask equipped with a magnetic stirrer and a septum
was charged with RMgBr (0.5 mL, 2.0 M in THF, 1.0 mmol). The reaction mixture
was cooled to 0 °C, and reagent 1c (118.2 mg, 0.5 mmol) in 1.0 mL was added
dropwise. After 30 min of stirring, the reaction temperature was increased to room
temperature. The reaction was stirred for further 3 h and monitored by 19F NMR
spectroscopy until the disappearance of the electrophilic trifluoromethylthiolating
reagent 1c (typically 24 h). 15 mL of brine and 10 mL of CH2Cl2 was added and the
organic phase was separated. The aqueous phase was extracted with CH2Cl2 (3 × 10
mL) and the combined organic extracts were dried over anhydrous Na2SO4, and
concentrated in vacuo. The product was purified by flash chromatography on silica
gel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4-Chlorophenyl)(trifluoromethyl)sulfane 5a.23 Colorless liquid (90.1 mg, 85%).
Eluent: petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.60 (d,
J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H) ppm; 19F NMR (375 MHz, CDCl3) δ ꢀ42.9
(s, 3 F) ppm.
1-(Methoxy)-4-[(trifluoromethyl)thio]benzene 5b.12f Colorless liquid (72.8 mg,
70%). Eluent: petroleum ether, Rf = 0.6. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.58 (d, J = 8.8 Hz , 2 H), 6.93 (d, J = 8.8 Hz , 2 H), 3.84 (s, 3 H); 19F NMR (375
MHz, CDCl3) δ ꢀ44.0 (s, 3 F) ppm.
(4-(tert-Butyl)phenyl)(trifluoromethyl)sulfane 5c.12e Colorless liquid (87.8 mg,
75%). Eluent: petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.59 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 1.35 (s, 9 H); 19F NMR (375 MHz,
ACS Paragon Plus Environment

Page 23 of 42
The Journal of Organic Chemistry
1
2
3
4
CDCl3) δ ꢀ43.0 (s, 3 F) ppm.
5
6
7
8
Phenyl(trifluoromethyl)sulfane 5d.13c Colorless liquid (74.8 mg, 84%). Eluent:
petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.66 (d, J = 7.2
Hz , 2 H), 7.50ꢀ7.41 (m, 3 H) ppm; 19F NMR (375 MHz, CDCl3) δ ꢀ42.8 (s, 3 F) ppm.
P-tolyl(trifluoromethyl)sulfane 5e.12h Colorless liquid (81.6 mg, 85%). Eluent:
petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.53 (d, J = 8.0
Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 2.37 (s, 3 H); 19F NMR (375 MHz, CDCl3) δ ꢀ42.3
(s, 3 F) ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for copper-catalyzed trifluoromeththiolation of aryl boronic
acids with 1c.
Cu(MeCN)4PF6 (18.6 mg, 0.05 mmol, 10 mol%), 2,2’ꢀbiyridine (16.0 mg, 0.20 mmol,
20 mol%), aryl boronic acid (0.65 mmol, 1.3 equiv), K2CO3 (138.2 mg, 1.0 mmol, 2.0
equiv), and reagent 1c (118.1 mg, 0.50 mmol, 1.0 equiv) were placed into an
ovenꢀdried Schlenk tube that is equipped with a stirring bar under Ar. The tube was
quickly sealed with a rubber stopper and 2.5 mL of freshly distilled diglyme was
o
added. The reaction was stirred at 35 C and monitored by 19F NMR spectroscopy
until the disappearance of reagent 1c (typically 15 h). 25 mL of distilled water and 10
mL of Et2O was added and the organic phase was separated. The aqueous phase was
extracted with Et2O (5 x 10 mL) and the combined organic extracts were dried over
anhydrous Na2SO4, and concentrated in vacuo. The product was purified by flash
chromatography on silica gel, and further purified by Kugelrohr distillation.
(4-(tert-Butyl)phenyl)(trifluoromethyl)sulfane 6a.12e Colorless liquid (105.3 mg,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 42
1
2
3
4
5
6
7
8
9
90%). Eluent: petroleum ether (Rf = 0.9). 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.59 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 1.35 (s, 9 H); 19F NMR (375 MHz,
CDCl3) δ ꢀ43.0 (s, 3 F) ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Ethenyl -4-[(trifluoromethyl)thio]benzene 6b.12e Colorless liquid (48.9 mg, 48%).
Eluent: petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.61 (d,
J = 8.0 Hz, 2 H), 7.50 (d, J = 8.0 Hz , 2 H), 6.73 (dd, J = 17.6 Hz, J = 11.2 Hz, 1 H),
5.84 (d, J = 17.6 Hz, 1 H), 5.39 (d, J = 10.8 Hz, 1 H); 19F NMR (375 MHz, CDCl3) δ
ꢀ42.9 (s, 3 F) ppm.
(4-Chlorophenyl)(trifluoromethyl)sulfane 6c.23 Colorless liquid (86.9 mg, 82%).
Eluent: petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.60 (d,
J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H); 19F NMR (375 MHz, CDCl3) δ ꢀ42.9 (s, 3
F) ppm.
(4-Iodophenyl)(trifluoromethyl)sulfane 6d.24 Light brown liquid (94.2 mg, 62%).
Eluent: petroleum ether, Rf = 0.9. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ 7.74 (d,
J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H); 19F NMR (375 MHz, CDCl3) δ ꢀ42.7 (s, 3
F) ppm.
Methyl 4-[(trifluoromethyl)thio]benzoate 6e.12e Colorless liquid (59.5 mg, 55%).
1
Eluent: ethyl acetate/petroleum ether = 1/10 (Rf = 0.8). H NMR (400 MHz, CDCl3,
19
293 K, TMS) δ 8.07 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 7.8 Hz, 2 H), 3.94 (s, 3 H); F
NMR (375 MHz, CDCl3) δ ꢀ41.8 (s, 3 F) ppm.
4-((Trifluoromethyl)thio)benzaldehyde 6f.25 Colorless liquid (30.9 mg, 30%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
ACS Paragon Plus Environment

Page 25 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
293 K, TMS) δ 10.07 (s, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.0 Hz , 2 H); 19F
NMR (375 MHz, CDCl3) δ ꢀ41.6 (s, 3 F) ppm;
7
8
9
1-(4-Trifluoromethylsulfanyl-phenyl)-ethanone 6g.1 Colorless liquid (55.0 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
55%). Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz,
CDCl3, 293 K, TMS) δ 7.98 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 2.62 (s, 3
H); 19F NMR (375 MHz, CDCl3) δ ꢀ41.8 (s, 3 F) ppm;
2-Methoxy-3-[(trifluoromethyl)thio]pyridine 6h.1 Colorless liquid (60.6 mg, 58%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
293 K, TMS) δ 8.4. (d, J = 2.4 Hz, 1 H), 7.80 (dd, J = 7.6, 2.0 Hz, 1 H), 7.79 (d, J =
8.8 Hz, 1 H), 3.97 (s, 3 H); 19F NMR (375 MHz, CDCl3) δ ꢀ43.9 (s, 3 F) ppm.
General procedure for copper-catalyzed trifluoromethylthiolation of terminal
alkynes with 1c.
CuBr(SMe2) (12.0 mg, 0.06 mmol, 20 mol%), 2,2’ꢀbiyridine (19.2 mg, 0.12 mmol, 40
mol%), alkynes (0.60 mmol, 2.0 equiv), K2CO3 (82.9 mg, 0.60 mmol, 2.0 equiv), and
reagent 1c (70.9 mg, 0.30 mmol, 1.0 equiv) were placed into an ovenꢀdried Schlenk
tube that is equipped with a stirring bar under Ar. The tube was quickly sealed with a
rubber stopper and 1.5 mL of freshly distilled solvent was added. The reaction was
stirred at 80 oC and monitored by 19F NMR spectroscopy until the disappearance of 3
(typically 14 h). 25 mL of distilled water and 10 mL of CH2Cl2 was added and the
organic phase was separated. The aqueous phase was extracted with CH2Cl2 (5 x 10
mL) and the combined organic extracts were dried over anhydrous Na2SO4, and
concentrated in vacuo. The product was purified by flash chromatography on silica
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 42
1
2
3
4
gel.
5
6
7
((4-Chlorophenyl)ethynyl)(trifluoromethyl)sulfane 7a.26 Light yellow liquid (48.1
8
9
1
mg, 68%). Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMS) δ 7.43 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H); 19F NMR (375 MHz,
CDCl3) δ ꢀ43.5 (s, 3 F) ppm.
((4-Bromophenyl)ethynyl)(trifluoromethyl)sulfane 7b.14 Light yellow liquid (55.4
1
mg, 66%). Eluent: petroleum ether, Rf = 0.8. H NMR (300 MHz, CDCl3, 293 K,
TMS) δ 7.49 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ40.6 (s, 3 F) ppm;
4-(((Trifluoromethyl)thio)ethynyl)benzonitrile 7c.5 Light yellow liquid (32.0 mg,
1
47%). Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz,
CDCl3, 293 K, TMS) δ 7.65 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H); 19F NMR
(375 MHz, CDCl3) δ ꢀ42.9 (s, 3 F) ppm. MS (EI): m/z (%) 227，158 (100), 114, 93,
69.
((4-Methoxyphenyl)ethynyl)(trifluoromethyl)sulfane 7d.14 Colorless liquid (48.7
1
mg, 70%). Eluent: ethyl acetate/petroleum ether = 1/100, Rf = 0.8. H NMR (400
MHz, CDCl3, 293 K, TMS) δ 7.46 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 3.83
(s, 3 H); 19F NMR (375 MHz, CDCl3) δ ꢀ44.1 (s, 3 F) ppm.
((4-tert-Butylphenyl)ethynyl)(trifluoromethyl)sulfane 7e.14 Light yellow liquid
(66.6 mg, 86%). Eluent: petroleum ether, Rf = 0.8. 1H NMR (300 MHz, CDCl3, 293 K,
TMS) δ 7.48 (d, J = 7.5 Hz, 2 H), 7.40 (d, J = 8.7 Hz, 2 H), 1.34 (s, 9 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ44.3 (s, 3 F) ppm.
ACS Paragon Plus Environment

Page 27 of 42
The Journal of Organic Chemistry
1
2
3
4
((4-Pentylphenyl)ethynyl)(trifluoromethyl)sulfane 7f.14 Light yellow liquid (75.1
5
6
7
1
mg, 92%). Eluent: petroleum ether, Rf = 0.8. H NMR (300 MHz, CDCl3, 293 K,
8
9
TMS) δ 7.44 (d, J = 7.8 Hz, 2 H), 7.18 (d, J = 8.1 Hz, 2 H), 2.64 (t, J = 7.5 Hz, 2 H),
1.66ꢀ1.61 (m, 2 H), 1.35ꢀ1.31 (m, 4 H), 0.92 (t, J = 6.6 Hz, 3 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ44.3 (s, 3 F) ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
((4-Nitrophenyl)ethynyl)(trifluoromethyl)sulfane 7g.1 Light yellow liquid (53.4
mg, 72%). Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.7. 1H NMR (400 MHz,
CDCl3, 293 K, TMS) δ 8.23 (d, J = 9.2 Hz, 2 H), 7.63 (d, J = 9.2 Hz, 2 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ42.8 (s, 3 F) ppm.
((3-Fluorophenyl)ethynyl)(trifluoromethyl)sulfane 7h.1 Light yellow liquid (42.2
1
mg, 64%). Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K,
TMS) δ 7.35ꢀ7.25 (m, 2 H), 7.18 (d, J = 9.2 Hz, 1 H), 7.12ꢀ7.07 (m, 1 H); 19F NMR
(375 MHz, CDCl3) δ ꢀ43.4 (s, 3 F), ꢀ112.3 (m, 1 F) ppm.
3-((Trifluoromethylthio)ethynyl)thiophene 7i.14 Colorless liquid (34.2 mg, 55%).
1
Eluent: petroleum ether, Rf = 0.8. H NMR (400 MHz, CDCl3, 293 K, TMS) δ
7.64ꢀ7.63 (m, 1 H), 7.31ꢀ7.30 (m, 1 H), 7.19ꢀ7.17 (m, 1 H); 19F NMR (375 MHz,
CDCl3) δ ꢀ43.5 (s, 3 F) ppm.
(6-Iodohex-1-yn-1-yl)(trifluoromethyl)sulfane 7j. Light yellow liquid (33.2 mg,
36%). Eluent: petroleum ether, Rf = 0.8. 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ
3.21 (t, J = 6.8 Hz, 2 H), 2.44 (t, J = 7.2 Hz, 2 H), 1.95ꢀ1.90 (m, 2 H), 1.73ꢀ7.67 (m, 2
H); 19F NMR (375 MHz, CDCl3) δ ꢀ44.2 (s, 3 F); 13C NMR (100.7 MHz, CDCl3, 293
K, TMS) δ 128.6 (q, J = 312.1 Hz), 103.0, 58.1 (q, J = 4.3 Hz), 32.4, 28.9, 19.3, 5.8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 42
1
2
3
4
5
6
7
8
9
ppm. IR (KBr): ν = 2945, 2865, 2204, 1429, 1327, 1288, 1260, 1212, 1158, 1107, 758,
735 cmꢀ1. MS (EI): m/z (%) 308, 261, 159, 139, 79 (100), 70. HRMS: Calcd for
C7H8F3SI: 307.9344; Found: 307.9340.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for electrophilic trifluoromethylthiolation of indoles with
reagent 1c.
Camphorsulfonic acid (CSA) (6.9 mg, 0.03 mmol), indole (0.30 mmol) and reagent 1c
(77.9 mg, 0.33 mmol) were placed into an ovenꢀdried sealed bomb equipped with a
stirring bar under Ar. Under a positive flow of argon, 1.5 mL of freshly distilled
1,2ꢀdichloroethane was added. The reaction was stirred at 40 oC and monitored by 19F
NMR
spectroscopy
until
the
disappearance
of
the
electrophilic
trifluoromethylthiolating reagent 1c (typically 48 h). 15 mL of brine and 10 mL of
CH2Cl2 was added and the organic phase was separated. The aqueous phase was
extracted with CH2Cl2 (3 × 10 mL) and the combined organic extracts were dried over
anhydrous Na2SO4, and concentrated in vacuo. The product was purified by flash
chromatography on silica gel.
5-Bromo-3-((trifluoromethyl)thio)-1H-indole 8a.8 Yellow liquid (30.1 mg, 40%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
293 K, TMS) δ 8.62 (s, 1 H), 7.93 (s, 1 H), 7.54 (s, 1 H), 7.38 (d, J = 8.8 Hz, 1 H),
7.29 (d, J = 8.8 Hz, 1 H); 19F NMR (376 MHz, CDCl3) δ ꢀ44.5 (s, 3 F) ppm.
3-((Trifluoromethyl)thio)-1H-indole-5-carbonitrile 8b.8 Yellow solid (16.6 mg,
1
23%). Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz,
DMSOꢀd6, 293 K, TMS) δ 12.54 (s, 1 H), 8.19 (d, J = 6.4 Hz, 1 H), 8.09 (s, 1 H), 7.69
ACS Paragon Plus Environment

Page 29 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
(d, J = 8.8 Hz, 1 H), 7.60 (dd, J = 8.8, 1.2 Hz, 1 H); 19F NMR (376 MHz, DMSOꢀd6)
δ ꢀ44.1 (s, 3 F) ppm.
7
8
9
2-Methyl-3-((trifluoromethyl)thio)-1H-indole 8c.8 White solid (47.9 mg, 69%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
293 K, TMS) δ 8.35 (s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.34ꢀ7.29 (m, 1 H), 7.24ꢀ7.19
(m, 2 H), 2.58 (s, 3 H); 19F NMR (376 MHz, CDCl3) δ ꢀ44.9 (s, 3 F) ppm.
Methyl 3-((trifluoromethyl)thio)-1H-indole-5-carboxylate 8d.8 White solid (28.9
mg, 35%). Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. 1H NMR (400 MHz,
DMSOꢀd6, 293 K, TMS) δ 12.36 (s, 1 H), 8.28 (s, 1 H), 8.09 (s, 1 H), 7.84 (dd, J = 8.4,
1.6 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 3.85 (s, 3 H) ppm; 19F NMR (376 MHz,
DMSOꢀd6) δ ꢀ44.2 (s, 3 F) ppm.
2,5-Dimethyl-3-((trifluoromethyl)thio)-1H-indole 8e.8 White solid (69.8 mg, 95%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
293 K, TMS) δ 8.22 (s, 1 H), 7.50 (s, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.05 (d, J = 8.0
Hz, 1 H), 2.56 (s, 3 H), 2.49 (s, 3 H); 19F NMR (376 MHz, CDCl3) δ ꢀ44.5 (s, 3 F)
ppm.
3-Methyl-2-((trifluoromethyl)thio)-1H-indole 8f.8 White solid (29.8 mg, 43%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
293 K, TMS) δ 8.13 (s, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.38ꢀ7.31 (m, 2 H), 7.17 (t, J =
7.2 Hz, 1 H), 2.47 (s, 3 H); 19F NMR (376 MHz, CDCl3) δ ꢀ43.0 (s, 3 F) ppm.
1-Methyl-3-((trifluoromethyl)thio)-1H-indole 8g.8 White solid (65.2 mg, 94%).
1
Eluent: ethyl acetate/petroleum ether = 1/10, Rf = 0.8. H NMR (400 MHz, CDCl3,
ACS Paragon Plus Environment