Rh(III)-Catalyzed Trifluoromethylthiolation of Indoles via C-H Activation

Article abstract of DOI:10.1021/acs.joc.5b00940

Cp?Rh(III) complexes have been applied as efficient catalysts for the C-H activation and trifluoromethylthiolation of indoles functionalized with a heterocycle. With N-trifluoromethylthiosaccharin being an electrophilic SCF₃ reagent, this C-S coupling occurred selectively at the 2-position with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.5b00940

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Rh(III)ꢀCatalyzed Trifluoromethylthiolation of Indoles via CꢀH
Activation
Qiang Wang, Fang Xie, Xingwei Li*
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Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China
xwli@dicp.ac.cn
Abstract. Cp*Rh(III) complexes have been applied as efficient catalysts for the CꢀH
activation and trifluoromethylthiolation of indoles functionalized with a heterocycle.
3
With Nꢀtrifluomethylthiosaccharin being an electrophilic SCF reagent, this CꢀS
coupling occurred selectively at the 2ꢀposition with good functional group tolerance.
3
It has been well accepted that incorporation of a SCF moiety into organic
molecules greatly contributes to enhancement of transmembrane permeation owing to
the enhancement of the lipophilicity, solubility, metabolic stability, and bioavailability
1
of the molecule. Thus, the introduction of trifluoromethylthio group has been of great
interest to the pharmaceutical and agrochemical industries for its utilization in
2
isosetereꢀbased drug design. Over the decades, much attention has been devoted to
the development of convenient methods for introduction of trifluoromethylthio group
3
into organic molecules.
In early times, halogenꢀfluorine exchange reactions of polyhalogenomethyl
4
thioethers or trifluoromethythiolation of sulphurꢀcontaining compounds such as
5
disulfides, thiocyanates, and thiols via a singleꢀelectron transfer mechanism were
typically employed to introduce a SCF moiety. However, the harsh reaction
3
conditions limited its utilization. In this context, the trifluoromethythiolation of
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compounds such as (hetero)aryl halides have been developed employing nucleophilic
trifluoromethylthiolation reagents such as AgSCF , CuSCF , and NH SCF . These
3
3
4
3
reagents are generally not sufficiently stable; making it inconvenient for storage over
6
extended periods. Therefore, the development of important methodologies for
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CꢀSCF bond formation has received increasing attention. Thus, some shelfꢀstable and
3
easilyꢀtoꢀhandle
reagents
have
been
developed
Among
for
electrophilic
Munavalli’s
trifluoromethylthiolation
of
arenes.
them,
7
Nꢀtrifluoromethylthiophthalimide (A, Scheme 1), Billard’s trifluoromethanesulfanylꢀ
8
9
amides (B), Lu and Shen’s trifluoromethanesulfenate (D) have received significant
attention. In addition, Shibata described an elegant method of trifluomethylthiolation
using a stable hypervalent iodine reagent E, which releases a SCF
3
group upon
reduction and rearrangement. These reagents showed high reactivity toward terminal
10a
10b
alkynes, βꢀketoesters, and arylboronic acid. In addition, Shen
and we
independently reported reagent F for the trifluoromethylthiolation of electronꢀrich
arenes. Shen also reported that terminal alkynes, amines, alcohols, and ketoesters are
10a
also viable substrates besides arenes.
Scheme1. Shelfꢀstable trifluoromethylthiolating reagents.
Chemical transformations through transition metalꢀcatalyzed CꢀH bond activation
11
represent one of the most promising strategies in organic synthesis. In this context,
12
CꢀS coupling has been realized via CꢀH activation of arenes under palladiumꢀ,
13
14
copperꢀ, and rhodiumꢀcatalyzed conditions when functionalized by electrophilic
sulfur reagents. However, trifluoromethylthiolation of arenes through direct CꢀH bond
15
activation is still rare and only a few systems have been reported. Recently, it has
been demonstrated that Cp*Rh(III) complexes are highly active in the CꢀH activation
of a broad scope of arenes with high functional group compatibility under relatively
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mild conditions. While no rhodium(III)ꢀcatalyzed CꢀH trifluoromethylthiolation has
been reported, we reasoned that the rather high activity of rhodium(III) complexes
and the high polarity and nucleophilicity of the Rh(III)ꢀaryl bond may bode well for
1
6
N
trifluoromethylthiolation of arenes via a formal S type transformation.
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We initiated our studies with optimizing the coupling reaction condition of
*
2
ꢀpyridylꢀ5ꢀchloroindole (1i) with reagent F. When [Cp RhCl
2
]
2
/AgSbF
6
was applied
o
as the catalyst in DCE at 50 C, the expected trifluoromethylthiolation reaction
occurred in low efficiency and the product 2i was isolated in only 32% yield (Table 1,
entry 1). The use of an electrophilic Ag(I) additive proved necessary since omission of
it or switching to other silver salts led to lower yields (Table 1, entries 4, 5).
Furthermore, switching to preformed cationic rhodium complex such as
*
[
Cp Rh(MeCN) ](SbF ) and [Cp*Rh(H O) ](OTf) all gave inferior results (entries 7,
3
6 2
2
3
2
8). The reaction efficiency is strongly temperature dependent (entries 9), and an
o
isolated yield of 77% was obtained when the temperature was raised to 100 C (entry
10b
1
0). Our previous work indicated that Lewis acid can effectively activate reagent F.
2
Thus, the product was isolated in 83% yield when Zn(OTf) (50 mol %) was further
introduced as an additive (entry 11). The role of the Zn(II) is likely a suitable Lewis
acid. When we replaced the Zn(OTf) with Cu(OTf) (Table 1, entry 17), the product
2
2
yield decreased sharply, which may indicate that oxidative property is not related in
this reaction system. Screening of solvents revealed that DCE seems optimal (entries
12 to 15).
a
Table 1. Optimization Studies
o
b
entry
silver salt
additive (mol %)
temp ( C)
solvent
DCE
DCE
DCE
DCE
DCE
yield
32%
N.D.
41%
22%
20%
1
2
3
4
5
AgSbF
6
ꢀ
ꢀ
50
50
50
50
50
ꢀ
AgSbF6
AgOAc
AgOTf
Zn(OTf) (30)
2
Zn(OTf) (30)
2
Zn(OTf)
2
(30)
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AgSbF
6
Zn(OTf)
Zn(OTf)
Zn(OTf)
ꢀ
2
2
2
(30)
(30)
(30)
50
dioxane
DCE
N.D.
23%
20%
65%
77%
81%
83%
57%
nd
c
ꢀ
50
d
ꢀ
50
DCE
AgSbF
6
80
DCE
10
AgSbF6
AgSbF
AgSbF6
ꢀ
100
100
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120
100
DCE
11
6
Zn(OTf)
2
(30)
DCE
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Zn(OTf) (50)
DCE
THF
2
1
AgSbF
6
6
Zn(OTf)
2
2
(50)
(50)
14
AgSbF
Zn(OTf)
tꢀAmOH
DCM
DCE
15
16
17
AgSbF6
Zn(OTf) (50)
81%
87%
53%
2
AgSbF
6
6
Zn(OTf)
2
(50)
(50)
AgSbF
Cu(OTf)
2
DCE
a
Conditions: indole 1i (0.2 mmol), reagent F (0.2 mmol), [RhCp*Cl ] (4 mol %), AgSbF
6
2
2
b
(
2
16 mol %), additive, solvent (3 mL), sealed tube under N atmosphere, 12 h. Isolated yield.
c
*
d
*
[
Cp Rh(MeCN)
3
](SbF
6
)
2
(8 mol %) was used as a catalyst. [Cp Rh(H
2
O)
3
](OTf)
2
(8 mol %)
was used as a catalyst.
With the established optimal conditions, we next explored the scope of the indole
substrate (scheme 2). It turned out that indoles bearing various electronꢀdonating and
–
withdrawing groups at different positions all coupled smoothly. In addition, a
bromide substituent was also compatible (2k, 2s), which should offer opportunity for
further functionalization. A slight decrease of the yield was observed when pyrimidine
was used as a direct group (2f). We noted that in the absence of the rhodium and the
silver additive, the reaction of indoles with blocked 3ꢀpositions (2e-g) could also
proceed albeit in lower yields. This observation indicates that this transformation can
10b
be catalyzed by Lewisꢀacids, which is consistent with our latest report. The arene is
not limited to indoles; the coupling of 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)pyridine occurred in high
1
5b
yield (2x-z). In addition, trifluomethylthiolation of 2ꢀphenylpyridine could also be
realized under the standard conditions, albeit with somewhat lower yield (2w).
a,b
Scheme 2. Substrate Scope for Trifluoromethylthiolation
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*
O
O
N
[Cp RhCl2]2 (4 mol %)
AgSbF6 (16 mol %)
S
H
SCF3
N
N
+
SCF3
Zn(OTf)2 (50 mol %)
N
N
DCE, 100 o
C
O
1
F
2
SCF3
SCF3
N
N
SCF3
N
SCF3
N
N
N
N
N
10
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F3C
2a, 88%
2b, 81%
2c, 80%
2d, 79%
Ph
CO2Et
SCF3
SCF3
SCF3
N
N
N
N
SCF3
N
N
N
N
N
2e, 91% (83%c)
2f, 77% (69%c)
2g, 80% (61%c)
2h, 88%
Cl
MeO
Br
F
SCF3
N
SCF3
N
SCF3
N
N
SCF3
N
N
N
N
2i, 83%
2j, 87%
2k, 82%
2l, 82%
BnO
Ar
SCF3
SCF3
SCF3 2o: Ar = Ph, 85%
N
N
N
N
N
2
p: Ar = 3-OMe(C6H4), 87%
2q: Ar = 4-tBu(C6H ), 81%
N
4
2m, 85%
2n, 85%
BnO
MeO2C
SCF3
F
Br
SCF3
SCF3
SCF3
N
N
N
N
N
N
N
N
2r, 86%
2s, 83%
2t, 82%
2u, 86%
SCF3
N
SCF3
SCF3
N
N
N
SCF3
N
N
SCF3
N
N
N
OMe
2v, 86%
2w, 61%
2x, 87%
2y, 81%
2z, 89%
a
2 2
Reaction conditions: arene (0.2 mmol), F (0.2 mmol), [Cp*RhCl ] (4 mol%),
o
AgSbF
6
(16 mol %) and Zn(OTf)
2
(50 mol %) DCE (3 mL), 100 C, sealed tube under
b
c
2
N for 12 h. Isolated yield. Standard conditions except that the Rh(III) catalyst and
AgSbF were omitted.
6
Furthermore, when the reaction performed in 3 mmol scale with a decreased
catalyst loading of 2 mol %, the corresponding product could be isolated in moderate
yield under air (eq 1), which demonstrates the potential industrial utilization of this
transformation.
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In contrast, when 1ꢀphenylꢀ1Hꢀindole was used as a substrate under the standard
conditions, the functionalization occurred exclusively at the 3ꢀposition (eq 2). Thus,
the selectivity is correlated to the Nꢀsubstituent. In the presence of an Nꢀdirecting
group, the reaction occurred via a CꢀH activation pathway, while in the absence of
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10b
such a group the reaction is Lewis acidꢀcatalyzed.
Preliminary mechanistic studies have been performed. When the reaction of
1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole was conducted under conditions with CD CO D in the
3
2
absence of reagent F, H/D exchange at the 2ꢀ, 3ꢀ, and 7ꢀpositions was observed,
indicating that the initial C−H activation at the 2ꢀposition is reversible (eq 3). A
significant primary kinetic isotope effect (k
intermolecular competitive coupling using an equimilar mixture of 2ꢀphenylpyridine
and 2ꢀphenylpyridineꢀd (eq 4). This relatively large value suggests that CꢀH
activation is probably involved in the catalytic cycle.
H D
/k = 4.0) was observed from an
5
17
We further performed an intermolecular competition experiment using an
1
equimolar mixture of two indoles (1l and 1j) that differ in electronic effect (eq 5). H
NMR analysis of the product mixture revealed that products 2l and 2j were generated
in a nearly 1:3 ratio, indicating that an electroꢀrich indole is kinetically favored.
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5 6 3
Oxidation of 2e using H IO catalyzed by CrO afforded the corresponding sulfone
5 in 73% yield (eq 6), which is another class of useful fluorineꢀcontaining products.
In conclusion, we have developed the first example of a Rh(III)ꢀcatalyzed
electrophilic trifluoromethylthiolation of arenes via a CꢀH activaton pathway. The
reaction occurred selectively at the 2ꢀposition. Moreover, this coupling system gives
high efficiency and tolerates a broad range of substrates bearing different functional
groups. This coupling system expanded the scope of Rh(III)ꢀcatalyzed CꢀH activation.
Future work will be directed to other electrophilic functionalization of arenes via CꢀH
activation.
EXPERIMENTAL SECTION
All manipulations were carried out under an inert atmosphere using a
nitrogenꢀfilled glove box. All reagents were obtained from commercial sources and
were used without further purification. NMR spectra were recorded on a spectrometer
1
13
19
at 400 MHz ( H NMR), 100 MHz ( C NMR), and 376 MHz ( F NMR). All coupling
constants
were
reported
in
Hz.
HRMS data were obtained via ESI mode with a TOF mass analyzer.
1
0b
Preparation of N-(Trifluoromethylthio)saccharin (F)
To a solution of Nꢀbromosaccharin (5 mmol, 1.31 g) in CH
3
added solution of AgSCF (5 mmol, 1.05 g) with CH CN (10 mL). After the reaction
3
CN (10 mL) was
3
was stirred at room temperature for 3 hours, the solvent was removed under reduced
pressure, then the crude product was purified by flash column chromatography
1
(CH
2
Cl
2
) to yield Nꢀ(trifluoromethylthio)saccharin (F, 1.07 g, 76%). H NMR (400
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MHz, CDCl
3
): δ 8.19 (d, J = 7.6 Hz, 1H), 8.03 (t, J = 6.8 Hz, 2H), 7.94 (t, J = 6.5 Hz,
1
3
1
1
H). C NMR (100 MHz, CDCl ) δ 158.3, 137.9, 136.3, 134.9, 127.2 (q, J = 315 Hz),
3
1
9
26.5, 126.1, 120.0. F NMR (376 MHz, CDCl
3
): δ ꢀ47.33. HRMS (M+H) calcd for
C
8
H
4
F
3
NO : m/z 283.9663, found: 283.9660.
3 2
S
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Procedures for the Trifluoromethylthiolation of Indoles.
Nꢀ(trifluoromethylthio)saccharin (F, 0.2 mmol, 59.5 mg) and a substituted indole
(0.2 mmol) were added to a pressure tube equipped with a magnetic stir bar, to which
*
were added (Cp RhCl
2
)
2
(0.008 mmol, 2.5 mg, 4 mol %)，AgSbF
6
(0.032 mmol, 5.5
mg), and DCE (3 mL). The reaction tube was placed into a preheated oil bath at
00 °C and was heated for 12 h. The solvent was then removed under reduced
1
pressure and the residue was purified by silica gel (300−400 mesh) column
chromatography to provide the final product 2.
1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2a). Following the general
procedure, 2a was isolated by column chromatography on silica gel (petroleum
1
ether/CH Cl : 50/1) as a solid (52 mg, 88%). H NMR (400 MHz, CDCl ) δ 8.69 (dd,
2
2
3
J = 4.8, 1.4 Hz, 1H), 7.94 (td, J = 7.8, 1.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.48 (d, J
=
8.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 7.4, 4.9 Hz, 1H), 7.34 – 7.28 (m,
13
1
1
H), 7.26 – 7.20 (m, 2H). C NMR (100 MHz, CDCl
3
) δ 150.0, 149.5, 139.2, 138.2,
28.3 (q, J = 309 Hz ), 127.4, 125.0, 122.8, 122.1, 121.6, 121.3, 118.9, 117.6, 111.3.
1
9
F NMR (376 MHz, CDCl
3
9 3 2
) δ ꢀ43.70. HRMS m/z (M+H) calcd for C14H F N S:
o
295.0517, found: 295.0524. mp 61ꢀ62 C.
1ꢀ(6ꢀmethylpyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2b). Following the
general procedure, 2b was isolated by column chromatography on silica gel
1
(petroleum ether/CH
2
Cl
2
: 60/1) as a solid (50 mg, 81%). H NMR (400 MHz, CDCl
3
)
δ 7.78 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.24 (ddt,
13
J = 19.1, 12.7, 3.3 Hz, 5H), 2.61 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 158.9, 149.2,
1
39.0, 138.4, 128.3 (q, J = 309 Hz ), 127.4, 124.8, 122.38, 121.5, 121.3, 119.1, 118.8,
19
117.0, 111.4, 24.2. F NMR (376 MHz, CDCl
3
) δ ꢀ43.60. HRMS m/z (M+H) calcd
o
for C15
H
11
F
3
N
2
S: 309.0673, found: 309.0686. mp 60ꢀ61 C.
1ꢀ(4ꢀmethylpyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2c). Following the
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general procedure, 2c was isolated by column chromatography on silica gel
1
(
petroleum ether/CH Cl /diethyl ether: 50/2/1) as an oil (50 mg, 80%). H NMR (400
2
2
3
MHz, CDCl ) δ 8.51 (s, 1H), 7.79 – 7.63 (m, 2H), 7.37 (t, J = 9.0 Hz, 2H), 7.30 (t, J =
13
7.7 Hz, 1H), 7.25 – 7.18 (m, 2H), 2.46 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 149.8,
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
147.7, 139.3, 138.7, 132.8, 128.2 (q, J = 309 Hz ), 127.3, 124.8, 121.6, 121.4, 121.3,
1
9
1
18.9, 117.2, 111.3, 18.1. F NMR (376 MHz, CDCl
calcd for C15 S: 309.0673, found: 309.0675.
ꢀ(4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole
3
) δ ꢀ43.69. HRMS m/z (M+H)
11 3 2
H F N
1
(2d).
Following the general procedure, 2d was isolated by column chromatography on
1
silica gel (petroleum ether/CH
CDCl
.58 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.30 – 7.21 (m,
2
2
Cl : 50/1) as a solid (57 mg, 79%). H NMR (400 MHz,
3
) δ 8.95 – 8.90 (m, 1H), 8.13 (dd, J = 8.4, 2.3 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H),
7
13
2H). C NMR (100 MHz, CDCl
3
) δ 152.8, 146.6 (q, J = 4 Hz), 138.8, 135.6 (q, J = 4
Hz), 128.1 (q, J = 309 Hz) 127.7, 125.6, 125.3 (q, J = 34 Hz), 122.3, 121.6, 121.2,
19
1
19.1, 118.8 (q, J = 2 Hz), 113.8, 111.4. F NMR (376 MHz, CDCl ) δ ꢀ43.72, ꢀ62.11.
3
o
HRMS m/z (M+H) calcd for C15
8 6 2
H F N S: 363.0391, found: 363.0403. mp 70ꢀ71 C.
3
ꢀmethylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2e). Following the
general procedure, 2e was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 50/1) as a solid (55 mg, 91%). H NMR (400 MHz, CDCl
3
)
δ 8.60 – 8.54 (m, 1H), 7.79 (td, J = 7.7, 1.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.35 –
13
7.28 (m, 2H), 7.27 – 7.17 (m, 2H), 7.17 – 7.09 (m, 1H), 2.47 (s, 3H). C NMR (100
MHz, CDCl ) δ 150.5, 149.5, 139.0, 138.09, 128.6 (q, J = 310 Hz ), 127.7, 127.1,
3
19
125.5, 122.6, 122.5, 121.0, 120.0, 115.8 (q, J = 2 Hz ), 111.4, 10.1. F NMR (376
1
9
MHz, CDCl
3
) δ ꢀ43.25. F NMR (376 MHz, CDCl
3
) δ ꢀ43.25. HRMS m/z (M+H)
o
calcd for C H F N S: 309.0673, found: 309.0682. mp 65ꢀ66 C.
15
11
3
2
3
ꢀmethylꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2f). Following the
general procedure, 2f was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 50/1) as a solid (49 mg, 77%). H NMR (400 MHz, CDCl
3
)
δ 8.71 (dd, J = 4.8, 1.2 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H),
7.29 (t, J = 7.7 Hz, 1H), 7.16 (dd, J = 14.7, 7.4 Hz, 1H), 7.08 (dd, J = 8.7, 4.0 Hz, 1H),
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
2
.46 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 158.2, 157.1, 138.4, 130.1, 128.9 (q, J =
1
9
3
10 Hz ), 128.5, 126.2, 122.0, 119.9, 117.9, 116.2, 116.1, 113.2, 10.3. F NMR (376
MHz, CDCl
3
10 3 3
) δ ꢀ43.05. HRMS m/z (M+H) calcd for C14H F N S: 309.0673, found:
o
309.0679. mp 58ꢀ59 C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethylꢀ2ꢀ(1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindolꢀ3ꢀyl)acetate
(2g).
Following the general procedure, 2g was isolated by column chromatography on silica
1
gel (petroleum ether/CH
CDCl
Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39 (dt, J = 6.2, 3.1 Hz, 2H), 7.35 – 7.28 (m, 1H),
.23 (dd, J = 11.4, 4.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.06 (s, 2H), 1.25 (t, J = 7.1
2
Cl
2
: 30/1) as a solid (61 mg, 80%). H NMR (400 MHz,
3
) δ 8.68 (dd, J = 4.8, 1.2 Hz, 1H), 7.92 (td, J = 7.8, 1.9 Hz, 1H), 7.72 (d, J = 8.0
7
1
3
Hz, 3H). C NMR (100 MHz, CDCl
3
) δ 170.5, 150.2, 149.6, 139.1, 138.2, 128.1 (q, J
=
311 Hz), 126.9, 125.7, 123.3, 122.9, 122.7, 121.5, 120.5, 117.3, 111.5, 61.0, 31.6,
19
14.1. F NMR (376 MHz, CDCl
3
) δ ꢀ43.01. HRMS m/z (M+H) calcd for
o
C
18
H
15
F
3
N
2
O
2
S: 381.0885, found: 381.0885. mp 89ꢀ90 C.
4
ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2h). Following the
general procedure, 2h was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 50/1) as a solid (70 mg, 88%). H NMR (400 MHz, CDCl
3
)
δ 8.73 (dd, J = 4.9, 1.2 Hz, 1H), 7.96 (td, J = 7.7, 1.9 Hz, 1H), 7.72 (d, J = 7.4 Hz,
2
H), 7.54 (dd, J = 16.1, 8.0 Hz, 3H), 7.48 – 7.36 (m, 5H), 7.31 (dd, J = 6.2, 1.8 Hz,
1
3
1
3
H). C NMR (100 MHz, CDCl ) δ 150.1, 149.6, 140.2, 139.8, 138.3, 135.4, 128.8,
128.7, 128.2 (q, J = 309 Hz ), 127.5, 125.8, 125.3, 123.0, 122.3, 121.4, 119.2 (q, J = 2
19
Hz), 117.2, 110.4. F NMR (376 MHz, CDCl ) δ ꢀ43.57. HRMS m/z (M+H) calcd for
3
o
C
20
H
13
F
3
N
2
S: 371.0830, found: 371.0837. mp 135ꢀ136 C.
5
ꢀchloroꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2i). Following the
general procedure, 2i was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
CDCl
.36 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.3, 5.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.16
2
2
Cl : 50/1) as a solid (54 mg, 83%). H NMR (400 MHz,
3
) δ 8.66 – 8.54 (m, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H),
7
1
3
(
3
dd, J = 8.9, 1.9 Hz, 1H), 7.08 (s, 1H). C NMR (100 MHz, CDCl ) δ 149.6, 149.6,
138.4, 137.4, 128.2, 128.1 (q, J = 309 Hz), 127.3, 123.4, 123.1, 121.9, 120.6, 120.5 (q,
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J = 2 Hz), 116.6, 112.6. F NMR (376 MHz, CDCl
3
) δ ꢀ43.44. HRMS m/z (M+H)
o
calcd for C H ClF N S: 329.0127, found: 329.0130. mp 75ꢀ77 C.
14
8
3
2
5
ꢀmethoxyꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2j). Following the
general procedure, 2j was isolated by column 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
1
(petroleum ether/CH Cl : 20/1) as a solid (56 mg, 87%). H NMR (400 MHz, CDCl )
2
2
3
δ 8.66 (dd, J = 4.8, 1.2 Hz, 1H), 7.91 (td, J = 7.7, 1.7 Hz, 1H), 7.44 (d, J = 8.0 Hz,
1
2
1
H), 7.36 (t, J = 6.8 Hz, 2H), 7.15 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 9.1,
1
3
3
.5 Hz, 1H), 3.85 (s, 3H). C NMR (101 MHz, CDCl ) δ 155.27, 150.12, 149.47,
38.28, 134.50, 128.2 ( q, J = 309 Hz), 127.83, 122.72, 121.88, 118.77, 117.22,
19
1
15.92, 112.47, 102.00, 55.75. F NMR (376 MHz, CDCl
3
) δ ꢀ43.79. HRMS m/z
o
(M+H) calcd for C15
H
11
F
3
N
2
OS: 325.0622, found: 325.0627. mp 66ꢀ67 C.
5
ꢀbromoꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifleoromethylthio)ꢀ1Hꢀindole (2k). Following the
general procedure, 2k was isolated by column chromatography on silica gel
1
(petroleum ether/CH
2
Cl
2
: 50/1) as a solid (61 mg, 82%). H NMR (400 MHz, CDCl
3
)
δ 8.68 (dd, J = 4.8, 1.0 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.82 (d, J = 1.5 Hz,
13
1
H), 7.47 – 7.36 (m, 3H), 7.30 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H). C NMR (100 MHz,
CDCl
3
) δ 149.64, 149.61, 138.5, 137.7, 128.8, 128.1 (q, J = 309 Hz), 127.9, 123.7,
19
1
23.2, 122.0, 120.3, 116.5, 114.8, 113.0. F NMR (376 MHz, CDCl
3
) δ ꢀ43.43.
8 3 2
HRMS m/z (M+H) calcd for C14H BrF N S: 372.9622, found: 372.9627. mp 76ꢀ77
o
C.
5ꢀfluoroꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2l). Following the
general procedure, 2l was isolated by column chromatography on silica gel
1
(petroleum ether/CH
2
Cl
2
: 60/1) as a solid (51 mg, 82%). H NMR (400 MHz, CDCl
3
)
δ 8.68 (dd, J = 4.8, 1.2 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (d, J = 8.0 Hz,
1
7
1
1
H), 7.39 (ddd, J = 13.6, 8.2, 4.6 Hz, 2H), 7.33 (dd, J = 8.9, 2.4 Hz, 1H), 7.19 (s, 1H),
13
.05 (td, J = 9.1, 2.5 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 158.6 (d, J = 237 Hz),
49.8, 149.6, 138.4, 135.7, 128.1 (q, J = 309 Hz), 127.6 (d, J = 10 Hz), 123.1, 122.0,
20.5, 117.1, 117.0, 113.7 (d, J = 26 Hz), 112.6 (d, J = 10 Hz), 105,9 (d, J = 24 Hz).
1
9
F NMR (376 MHz, CDCl
3
) δ ꢀ43.50, ꢀ121.81. HRMS m/z (M+H) calcd for
o
C
14
H
8
F
4
N
2
S: 313.0423, found: 313.0437. mp 59ꢀ60 C.
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ꢀ(benzyloxy)ꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoroꢀmethylthio)ꢀ1Hꢀindole (2m). Following
the general procedure, 2m was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 20/1) as a solid (67 mg, 85%). H NMR (400 MHz, CDCl
3
)
δ 8.71 – 8.64 (m, 1H), 7.91 (td, J = 7.7, 1.1 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.40
(ddd, J = 12.5, 10.7, 6.6 Hz, 6H), 7.19 (td, J = 8.2, 2.5 Hz, 1H), 7.01 (dd, J = 8.3, 3.1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Hz, 1H), 6.65 (dd, J = 7.8, 2.1 Hz, 1H), 5.24 (s, 2H). C NMR (100 MHz, CDCl
3
) δ
1
1
52.5, 150.1, 149.5, 140.7, 138.2, 137.0, 128.2 (q, J = 310 Hz), 128.6, 128.0, 127.4,
19
26.1, 122.9, 122.2, 118.9, 117.1, 115.5, 104.7, 102.4, 70.1. F NMR (376 MHz,
CDCl
3
15 3 2
) δ ꢀ43.85. HRMS m/z (M+H) calcd for C21H F N OS: 401.0935, found:
o
4
01.0943. mp 120ꢀ121 C.
5
ꢀmethylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2n). Following the
general procedure, 2n was isolated by column chromatography on silica gel
1
(petroleum ether/CH
2
Cl
2
: 50/1) as a solid (52 mg, 85%). H NMR (400 MHz, CDCl
3
)
δ 8.66 (dd, J = 4.8, 1.1 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.48 – 7.40 (m, 2H),
13
7
1
1
.38 – 7.28 (m, 2H), 7.18 – 7.03 (m, 2H), 2.44 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
50.1, 149.4, 138.2, 137.6, 131.0, 128.3 (q, J = 309 Hz), 127.6, 126.7, 122.6, 121.8,
19
20.7, 118.6, 117.2, 111.1, 21.3. F NMR (376 MHz, CDCl
3
) δ ꢀ43.79. HRMS m/z
o
(
M+H) calcd for C15
H
11
F
3
N
2
S: 309.0673, found: 309.0675. mp 57ꢀ58 C.
5
ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2o). Following the
general procedure, 2o was isolated by column chromatography on silica gel
1
(petroleum ether/CH
2
Cl
2
: 50/1) as a solid (63 mg, 85%). H NMR (400 MHz, CDCl
3
)
δ 8.68 (dd, J = 4.9, 1.2 Hz, 1H), 7.91 (td, J = 7.8, 1.9 Hz, 1H), 7.87 (d, J = 1.2 Hz,
1H), 7.64 – 7.60 (m, 2H), 7.55 (dd, J = 8.7, 1.7 Hz, 1H), 7.50 – 7.40 (m, 4H), 7.39 –
13
7
3
.32 (m, 2H), 7.27 (s, 1H). C NMR (100 MHz, CDCl ) δ 150.0, 149.5, 141.7, 138.6,
1
38.3, 135.2, 128.8, 128.3 (q, J = 309 Hz), 127.9, 127.3, 126.8, 124.9, 122.9, 121.9,
19
1
19.7, 119.5 (q, J = 2 Hz), 117.8, 111.7. F NMR (376 MHz, CDCl
3
) δ ꢀ43.58.
o
HRMS m/z (M+H) calcd for C20
H
13
F
3
N
2
S: 371.0830, found: 371.0836. mp 91ꢀ92 C.
5
ꢀ(3ꢀmethoxyphenyl)ꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole
(2p).
Following the general procedure, 2p was isolated by column chromatography on
1
silica gel (petroleum ether/CH
2
Cl
2
: 60/1) as a solid (69 mg, 87%). H NMR (400 MHz,
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CDCl
3
) δ 8.69 (dd, J = 4.8, 1.0 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.89 (s, 1H), 7.55
(dd, J = 8.7, 1.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.38 (dd, J = 14.8, 7.5 Hz, 2H),
7
.29 (s, 1H), 7.26 – 7.20 (m, 1H), 7.17 (s, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H).
1
3
C NMR (100 MHz, CDCl
3
) δ 160.0, 150.0, 149.6, 143.2, 138.6, 138.3, 135.0, 129.7,
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
128.3 (q, J = 309 Hz), 127.8, 126.6, 124.9, 122.9, 121.9, 119.8, 119.7, 119.5, 117.8,
1
9
1
13.1, 112.2, 111.7, 55.3. F NMR (376 MHz, CDCl
3
) δ ꢀ43.59. HRMS m/z (M+H)
o
calcd for C21
H
15
F
3
N
2
OS: 401.0935, found: 401.0936. mp 127ꢀ128 C.
5
ꢀ(4ꢀtertꢀbutylphenyl)ꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole
(2q).
Following the general procedure, 2q was isolated by column chromatography on
1
silica gel (petroleum ether/CH
CDCl
Hz, 1H), 7.56 (dd, J = 13.8, 5.0 Hz, 3H), 7.51 – 7.46 (m, 4H), 7.39 (dd, J = 7.4, 4.9
2
2
Cl : 50/1) as a solid (73 mg, 81%). H NMR (400 MHz,
3
) δ 8.69 (dd, J = 4.8, 1.2 Hz, 1H), 7.93 (td, J = 7.8, 1.9 Hz, 1H), 7.88 (d, J = 1.0
1
3
Hz, 1H), 7.28 (s, 1H), 1.37 (s, 9H). C NMR (100 MHz, CDCl
3
) δ 150.0, 149.8,
149.5, 138.7, 138.52 138.3, 135.1, 128.3 (q, J = 310 Hz), 127.8, 127.0, 125.7, 124.9,
19
1
19.5, 119.3, 117.9, 111.6, 34.5, 31.4. F NMR (376 MHz, CDCl ) δ ꢀ43.63. HRMS
3
o
m/z (M+H) calcd for C24
21 3 2
H F N S: 427.1456, found: 427.1453. mp 90ꢀ91 C.
5
ꢀ(benzyloxy)ꢀ1ꢀ(6ꢀmethylpyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole
(2r).
Following the general procedure, 2r was isolated by column chromatography on silica
1
gel (petroleum ether/CH
CDCl
7.32 (t, J = 7.2 Hz, 1H), 7.24 – 7.12 (m, 3H), 7.00 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.8
2
Cl
2
: 30/1) as a solid (69 mg, 86%). H NMR (400 MHz,
3
) δ 7.76 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 3H),
1
3
Hz, 1H), 5.22 (s, 2H), 2.61 (s, 3H). C NMR (100 MHz, CDCl ) δ 158.9, 152.4,
3
149.3, 140.6, 138.3, 137.1, 128.5, 128.3 (q, J = 309 Hz),127.9, 127.3, 126.7, 125.8,
19
1
22.4, 118.9, 117.2, 115.0, 104.7, 102.3, 70.0, 24.2. F NMR (376 MHz, CDCl
3
) δ
ꢀ
43.73. HRMS m/z (M+H) calcd for C H F N OS: 415.1092, found: 415.1092. mp
22
17
3
2
o
9
9ꢀ100 C.
6
ꢀbromoꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2s). Following the
general procedure, 2s was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 50/1) as a solid (62 mg, 83%). H NMR (400 MHz, CDCl
3
)
δ 8.68 (d, J = 3.8 Hz, 1H), 7.94 (td, J = 7.8, 1.7 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.5
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2
2
2
2
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3
3
3
3
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4
4
4
4
4
4
4
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5
5
5
5
5
5
6
13
Hz, 1H), 7.46 – 7.37 (m, 2H), 7.32 (dd, J = 8.5, 1.3 Hz, 1H), 7.19 (s, 1H). C NMR
(
100 MHz, CDCl ) δ 149.7, 149.5, 139.7, 138.4, 128.0 (q, J = 309 Hz), 126.1, 125.1,
3
19
1
23.2, 122.5, 122.0, 119.7, 119.7 (q, J = 2 Hz), 117.5, 114.5. F NMR (376 MHz,
CDCl
3
8 3 2
) δ ꢀ43.54. HRMS m/z (M+H) calcd for C14H BrF N S: 372.9622, found:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
372.9625. mp 80ꢀ81 C.
Methylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindoleꢀ6ꢀcarboxylate
(2t).
Following the general procedure, 2t was isolated by column chromatography on silica
1
gel (petroleum ether/CH
2
Cl
2
: 20/1) as a solid (57 mg, 82%). H NMR (400 MHz,
CDCl
3
) δ 8.72 – 8.69 (m, 1H), 8.13 (s, 1H), 7.99 (td, J = 7.8, 1.4 Hz, 1H), 7.90 (d, J =
8
7
1
.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.49 – 7.41 (m, 1H),
13
.25 (s, 1H), 3.91 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 167.5, 149.7, 149.4, 138.7,
38.3, 130.7, 128.2 ( q, J = 309 Hz), 126.5, 123.3, 122.8, 122.4, 122.0, 121.1, 116.5,
19
113.5, 52.2. F NMR (376 MHz, CDCl
3
) δ ꢀ43.11. HRMS m/z (M+H) calcd for
o
C
16
H
11
F
3
N
2
O
2
S: 353.0572, found: 353.0568. mp 88ꢀ89 C.
6
ꢀfluoroꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (2u). Following the
general procedure, 2u was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 50/1) as a solid (53 mg, 86%). H NMR (400 MHz, CDCl
3
)
δ 8.73 – 8.60 (m, 1H), 7.94 (td, J = 7.8, 1.9 Hz, 1H), 7.62 (dd, J = 8.7, 5.4 Hz, 1H),
7
1
.44 (d, J = 8.0 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.23 (s, 1H), 7.15 (dd, J = 9.8, 2.2 Hz,
13
3
H), 7.00 (td, J = 9.1, 2.3 Hz, 1H). C NMR (100 MHz, CDCl ) δ 161.5 (d, J = 241
Hz) , 149.7, 149.6, 139.4 (d, J = 12 Hz), 138.4, 128.1 (q, J = 309 Hz), 123.8, 123.1,
19
122.5 (d, J = 10 Hz), 121.9, 119.0, 117.9, 110.1 (d, J = 24 Hz), 98.1(d, J = 27 Hz). F
NMR (376 MHz, CDCl
3
8 4 2
) δ ꢀ43.85, ꢀ115.72. HRMS m/z (M+H) calcd for C14H F N S:
o
3
13.0423, found: 313.0429. mp 60ꢀ61 C.
6
ꢀ(3ꢀmethoxyphenyl)ꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀindole
(2v).
Following the general procedure, 2v was isolated by column chromatography on silica
1
gel (petroleum ether/CH
CDCl
.49 (s, 1H), 7.37 (dd, J = 11.2, 4.4 Hz, 2H), 7.28 (dd, J = 7.3, 5.0 Hz, 1H), 7.23 (t, J
2
Cl
2
: 50/1) as a solid (69 mg, 86%). H NMR (400 MHz,
3
) δ 8.62 – 8.54 (m, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H),
7
= 7.9 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.77
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(
dd, J = 8.1, 2.3 Hz, 1H), 3.73 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 159.9, 150.0,
1
1
49.6, 143.3, 139.6, 138.5, 138.4, 129.7, 128.3 (q, J = 310 Hz), 126.8, 123.0, 122.2,
19
21.7, 121.6, 120.1, 119.4 (q, J = 2 Hz), 117.5, 113.5, 112.3, 109.9, 55.3. F NMR
(376 MHz, CDCl
3
15 3 2
) δ ꢀ43.63. HRMS m/z (M+H) calcd for C21H F N OS: 401.0935,
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11
12
13
14
15
16
17
18
19
20
21
22
23
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29
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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
found: 401.0937. mp 110ꢀ112 C.
1
0a
2
ꢀ(2ꢀ(trifluoromethylthio)phenyl)pyridine (2w). Following the general procedure,
2
6
7
2 2
w was isolated by column chromatography on silica gel (petroleum ether/CH Cl :
1
0/1) as an oil (31 mg, 61%). H NMR (400 MHz, CDCl
3
) δ 8.70 (d, J = 4.8 Hz, 1H),
.80 (dd, J = 8.5, 4.3 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.46
13
(
t, J = 7.6 Hz, 1H), 7.35 – 7.28 (m, 1H). C NMR (100 MHz, CDCl
3
) δ 157.7, 148.9,
1
45.2, 136.2, 135.8, 130.7, 130.1, 129.6 ( q, J = 307 Hz ), 129.1, 124.2, 124.1, 122.4.
1
9
F NMR (376 MHz, CDCl ) δ ꢀ41.76. HRMS m/z (M+H) calcd for C H F NS:
3
12
8 3
256.0408, found: 256.0405.
2ꢀ(2ꢀ(trifluoromethylthio)ꢀ1Hꢀpyrrolꢀ1ꢀyl)pyridine (2x). Following the general
procedure, 2x was isolated by column chromatography on silica gel (Petroleum
1
ether/CH
2
Cl
2
: 50/1) as a solid (43 mg, 87%). H NMR (400 MHz, CDCl
3
) δ 8.56 (dd,
J = 4.8, 1.1 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.35 – 7.28
13
(
m, 1H), 6.87 (dd, J = 3.6, 1.8 Hz, 1H), 6.41 (t, J = 3.4 Hz, 1H). C NMR (100 MHz,
CDCl
3
) δ 151.4, 150.9, 149.0, 138.0, 128.2 (q, J = 311 Hz), 127.8, 125.5, 122.5, 119.4,
S: 245.0360, found: 245.0365. mp
1
10.6. HRMS m/z (M+H) calcd for C10H F N
7 3 2
o
55ꢀ56 C.
4ꢀmethylꢀ2ꢀ(2ꢀ(trifluoromethylthio)ꢀ1Hꢀpyrrolꢀ1ꢀyl)pyridine (2y). Following the
general procedure, 2y was isolated by column chromatography on silica gel
1
(
petroleum ether/CH
2
Cl
2
: 60/1) as a oil (41 mg, 81%). H NMR (400 MHz, CDCl
3
) δ
8
.41 (d, J = 5.0 Hz, 1H), 7.42 (s, 1H), 7.27 (s, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.86 (d, J
13
=
3
1.8 Hz, 1H), 6.39 (t, J = 3.3 Hz, 1H), 2.45 (s, 3H). C NMR (100 MHz, CDCl ) δ
1
2
2
51.0, 149.6, 148.6, 128.2 (q, J = 310 Hz), 127.8, 125.2, 123.7, 120.3, 110.5, 109.5,
19
1.2. F NMR (376 MHz, CDCl
3 9 3 2
) δ ꢀ45.26. HRMS m/z (M+H) calcd for C11H F N S:
59.0517, found: 259.0511.
2ꢀ(3,5ꢀdimethylꢀ2ꢀ(trifluoromethylthio)ꢀ1Hꢀpyrrolꢀ1ꢀyl)ꢀ4ꢀmethylpyridine
(2z).
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2
2
2
2
2
2
3
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3
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3
3
3
3
4
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4
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5
5
5
5
5
5
6
Following the general procedure, 2z was isolated by column chromatography on silica
1
gel (petroleum ether/CH Cl : 70/1) as a oil (51 mg, 89%). H NMR (400 MHz, CDCl )
2
2
3
δ 8.46 (d, J = 5.0 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.07 (s, 1H), 6.02 (s, 1H), 2.45 (s,
1
3
3H), 2.24 (s, 3H), 2.12 (s, 3H). C NMR (100 MHz, CDCl
136.0, 132.9, 128.5 (q, J = 312 Hz), 124.3, 124.2, 110.8, 106.7, 21.0, 13.4, 12.0. F
NMR (376 MHz, CDCl ) δ ꢀ45.29. HRMS m/z (M+H) calcd for C13 S:
87.0830, found: 287.0819.
ꢀphenylꢀ3ꢀ(trifluoromethylthio)ꢀ1Hꢀindole (4).
3
) δ 150.9, 149.4, 148.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
3
13 3 2
H F N
2
1
0b
1
Following the general
procedure, 4 was isolated by column chromatography on silica gel (petroleum
1
ether/CH
2
Cl
2
: 50/1) as an oil (31 mg, 61%). H NMR (400 MHz, CDCl
3
) δ 7.86 (m,
13
1
H), 7.64 (s, 1H), 7.56ꢀ7.47 (m, 5H), 7.43 (m, 1H), 7.35 – 7.27 (m, 2H). C NMR
(
100 MHz, CDCl ) δ 138.7, 136.9, 136.2, 130.8, 130.1, 129.5(q, J = 268Hz), 127.9,
3
19
3
124.9, 123.9, 122.3, 119.9, 111.3, 96.5 (d, J = 2 Hz). F NMR (376 MHz, CDCl ) δ
10 3
ꢀ44.30. HRMS m/z (M+H) calcd for C15H F NS : 294.0564, found: 294.0567.
The KIE Experiment
Following the standard procedure for trifluoromethylthiolation reaction, to a mixture
of 2ꢀphenylpyridine (0.1 mmol) and 2ꢀphenylpyridineꢀd
Nꢀ(trifluoromethylthio)saccharin (F, 0.2 mmol), (Cp*RhCl
5
(0.1 mmol) were added
(0.008 mmol, 2.5 mg, 4
2
)
2
mol %)，AgSbF (0.032 mmol, 5.5 mg ) and DCE (3 mL). The reaction mixture was
6
placed into a preheated oil bath at 100 °C and was heated for 12 h. The product was
purified by silica gel column chromatography and the KIE value was determined by
NMR spectroscopy.
The Oxidation of a Sulfide to a Sulfone.
1
8
Following a reported procedure, H
acetonitrile (10 mL) by vigorous stirring at room temperature for 30 min, and then
CrO (0.3 mg, 0.003 mmol, 2 mol %) was added to the solution. To this solution was
then added a solution of 2e (46.2 mg, 0.15 mmol) in CH CN (10 mL) at room
5 6
IO (136.7 mg, 0.6 mmol) was dissolved in
3
3
temperature. The reaction mixture was stirred at room temperature until the oxidation
was completed (monitored by TLC). The mixture was then filtered, and the filter cake
was washed with CH
3
CN (10 mL). The filtrate was concentrated under reduced
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pressure and the residue was extracted with ethyl acetate. The combined extracts were
washed with a saturated aqueous Na SO solution and brine, and were then dried over
2
3
2 4
Na SO . The solvent was removed under reduced pressure and the crude product was
purified by flash silica gel column chromatography (petroleum ether/EtOAc: 10/1) to
10
11
12
13
14
15
16
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
provide the 1ꢀmethylꢀ4ꢀnitroꢀ3ꢀ(trifluoromethylsulfonyl)ꢀ1Hꢀindole (5, 36.8 mg, 96%)
1
as a white solid. NMR spectra, H NMR (400 MHz, CDCl
3
) δ 8.60 (dd, J = 4.9, 1.2
Hz, 1H), 7.92 – 7.84 (m, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.47
(dd, J = 7.5, 0.9 Hz, 1H), 7.34 (td, J = 7.9, 1.3 Hz, 1H), 7.29 (ddd, J = 7.4, 4.9, 0.9 Hz,
13
13
1
3
H), 7.20 (td, J = 7.6, 0.9 Hz, 1H), 1.80 (s, 3H). C NMR (100 MHz, CDCl ) C
NMR (100 MHz, CDCl3) δ 163.3, 160.7, 152.5, 149.3, 134.0, 133.9, 132.8 (q, J = 8
Hz), 132.6, 130.4 (q, J = 312 Hz), 125.8, 124.4, 123.1(d, J = 6 Hz), 119.5, 118.9 (q, J
19
=
22 Hz), 103.3, 20.3. F NMR (376 MHz, CDCl ) δ ꢀ38.48. HRMS m/z (M+H)
3
o
calcd for C15
H
11
F
3
N
2
O
2
S : 341.0572, found: 341.0575. mp 151ꢀ152 C.
ASSOCIATED CONTENT
Supporting Information
1
13
H NMR and C NMR spectra for products 2a−z, 4, and 5. This material is available
free of charge via the Internet at http:// pubs.acs.org.
ACKNOWLEDGEMENTS
Financial support from the Chinese Academy of Science and from the NSFC is
gratefully acknowledged.
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D.; Lu, L.; Shen, Q. Angew. Chem., Int. Ed. 2014, 53, 6105.
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