Transition metal-free direct trifluoromethylthiolation of indoles using trifluoromethanesulfonyl chloride in the presence of triphenylphosphine

Article abstract of DOI:10.1039/c6ob02465c

A novel triphenylphosphine-mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl chloride as the SCF₃ source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which was found to accelerate this transformation. The use of a transition metal-free protocol, readily available reagents, and mild reaction conditions allowed this protocol to be easily scaled up.

Full text of DOI:10.1039/c6ob02465c

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DOI: 10.1039/C6OB02465C
Organic & Biomolecular Chemistry
ARTICLE
Transition Metal‐Free Direct Trifluoromethylthiolation of Indoles
using Trifluoromethanesulfonyl Chloride in the Presence of
Triphenylphosphine
Received 00th January 20xx,
Accepted 00th January 20xx
Kui Lu,*a Zhijie Deng,b Ming Li,a Tianjiao Li,b and Xia Zhao*b
DOI: 10.1039/x0xx00000x
A novel triphenylphosphine‐mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl
chloride as the SCF3 source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which
was found to accerelate this transformation. The use of a transition metal‐free protocol, readily available reagents, and mild
reaction conditions allowed this protocol to be easily scaled up.
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highly desirable for both organic and medicinal chemists. To address
the issue of long synthetic routes, Yi and Zhang developed a sodium
Introduction
trifluoromethansulfinate
(CF3SO2Na)‐based
direct
The trifluoromethylthiol (CF3S) group has attracted substantial
attention both in the academic community and in the
pharmaceutical industry because of its electron withdrawing effect,
good lipophilicity, and good bioavailability.1 The incorporation of a
CF3S moiety into a drug candidate therefore has the potential to
substantially improve its metabolic stability2 and cell membrane
permeability.3
trifluoromethylthiolation using diethyl phosphonate as the
reductant in the presence of CuCl.17 In addition, as part of our on‐
going program to develop efficient methods to construct C‐S
bonds,18 we found that aryl sulfonyl chloride and
difluoromethanesulfonyl chloride could be reduced using
triphenylphosphine (PPh3) to give aryl sulfenyl chloride and
difluoromethanesulfenyl chloride respectively, which served as
sulfenylation reagents.19 Hence, we decided to focus on the
development of a trifluoromethanesulfonyl chloride (CF3SO2Cl)‐
based transition metal‐free trifluoromethylthiolation of indole in the
presence of PPh3. However, during the course of our investigation
and manuscript preparation, the direct trifluoromethylthiolation of
indole derivatives using CF3SO2Cl as the trifluoromethylthiolation
reagent and trimethylphosphine (PMe3) or diethyl phosphonate as
the reducing agent was developed.20, 21
To meet the growing demand for CF3S‐containing compounds, a
range of strategies have been developed to introduce the CF3S group
into
molecules.
One
general
strategy
involves
the
trifluoromethylation of thiols to prepare the corresponding
trifluoromethylthiolated compounds.4 An alternate straightforward
strategy is the direct introduction of this CF3S moiety either through
nucleophilic trifluoromethylthiolation using AgSCF3, CuSCF3,5 or
Me4NSCF3,6 or through the more efficient and practical electrophilic
trifluoromethylthiolation using CF3Cl.7 However, the latter reagent is
particularly corrosive and toxic, and so a series of shelf‐stable and
easy‐to‐handle trifluoromethylthiolation reagents have been
developed (see compounds 1–8, Figure 1).8–16
Figure 1. Typical electrophilic trifluoromethylthiolation reagents
Although the above‐mentioned trifluoromethylthiolation reagents
demonstrated high efficiency in the majority of electrophilic
trifluoromethylthiolation reactions, their preparation generally
requires multiple steps and a diverse fluorinate starting material.
Moreover, either Lewis acid activation or transition metal catalysis
are required when using these reagents. As such, the development
of cheap and readily accessible trifluoromethylthiolation reagents is
a. China International Science and Technology Cooperation Base of Food
Nutrition/Safety and Medicinal Chemistry, Key Laboratory of Industrial
Microbiology of Ministry of Education, Tianjin Key Laboratory of Industry
Microbiology, College of Biotechnology, Tianjin University of Science & Technology,
Tianjin, China, 300457, E‐mail:lukui@tust.edu.cn
b. 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; E‐mail:hxxyzhx@mail.tjnu.edu.cn
Thus, we herein report the transition metal‐free direct
trifluoromethylthiolation of indoles using CF3SO2Cl in the presence of
c. Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available:.
See
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J. Name., 2013, 00, 1‐3 | 1
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PPh3 (Scheme 1). Our protocol is superior to that reported by Shibata Table 1 Optimization of the trifluoromethylthiolationVoiefw9AarticwleitOhnl1in0e
a
and Cahard as we employ PPh3 instead of PMe3, the former of which in the presence of PPh3
is odourless, more stable, and cheaper. In addition, we avoid the use
of low temperature reactions, and propose the requirement of fewer
equivalents of the trifluoromethylthiolation reagent to obtain
satisfactory yields (i.e., 1.2 eq CF3SO2Cl c.f., 1.8 eq CF3SO2Cl).
Furthermore, the use of sodium iodide (NaI) in our protocol was
expected to improve yields. These properties render the scale up of
DOI: 10.1039/C6OB02465C
CF3SO2Cl PPh3
(equiv) (equiv)
our protocol relatively facile (Scheme 1).
Entry
Solvent
Yield (%)
T (C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.1
1.2
1.2
1.2
1.2
1.2
1.2
3
3
3
3
3
3
3
3
3
2.4
2.2
2.4
2.4
2.4
2.4
2.4
2.4
1,4‐dioxane
Toluene
DMF
50
50
50
50
50
50
40
60
70
60
60
60
60
60
60
60
60
63
76
75
56
trace
77
75
83
81
86
DCE
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
73b
92c
92d
46e
23f
18g
Scheme 1 Trifluoromethylthiolation of indole using sodium
trifluoromethansulfinate and trifluoromethanesulfonyl chloride as
SCF3 sources.
a Reaction conditions: 9a (0.5 mmol), 10 (0.55‐0.75 mmol), PPh3
(1.1‐1.5 mmol), Solvent (2 mL) for 0.5‐4 h. b CH3CN (1 mL) was
used. c CH3CN (3 mL) was used. d CH3CN (4 mL) was used. e triethyl
phosphite was used as reductant. f diethyl phosphonate was used
as reductant. g trimethylphosphine was used as reductant
Results and discussion
Based on our previous studies, the addition of iodide to the
reaction system was expected to facilitate this transformation.17 We
therefore examined a number of classical iodide sources for use as
We initially investigated the treatment of indole 9a with CF3SO2Cl
10 in the presence of PPh3 in 1,4‐dioxane at 50 °C to yield the desired
trifluoromethylthiolation product 11a in 63% yield. Optimisation of
the reaction conditions was then carried out by first examining the
effect of solvent. Toluene, N,N‐dimethylformamide (DMF), 1,2‐
dichloroethane (DCE), ethanol (EtOH), and CH3CN (Table 1, Entries 2–
6) were tested, with CH3CN giving the highest yield (Table 1, Entry 6).
The effect of temperature was then evaluated between 40 and 70 °C.
Upon increasing the reaction temperature to 60 °C, the yield
increased to 83% (Table 1, Entry 8), although a further increase to
70 °C led to a decrease in yield (Table 1, Entry 9). In terms of
substrate loading, upon decreasing the loadings of CF3SO2Cl and PPh3
to 1.2 equiv. and 2.4 equiv., respectively, the yield increased to 86%
(Table 1, Entry 10). However, a further decrease in these loadings led
to a decreased yield (Table 1, Entry 11). Finally, we investigated the
effect of reaction concentration and reducing agents. When the
concentration of 9a was increased from 0.25 M to 0.5 M, the yield
decreased from 86% to 73% (Table 1, Entry 12). However, upon
decreasing the concentration of 9a from 0.25 M to 0.17 M, the yield
increased from 86% to 92% (Table 1, Entry 13). A further decrease in
concentration had little effect on the resulting yield (Table 1, Entry
14). In terms of the reducing agents, various trivalent phosphorus
species were examined (Table 1, Entries 15–17), including triethyl
phosphite [P(OMe)3], diethyl phosphonate [(EtO)2P(O)H] (i.e., the
best reductant in Yi’s report),21 and PMe3 (the best reductant in
Shibata and Cahard’s report),20 all of which yielded poor results
compared to PPh3.
an
additive,
including
potassium
iodide
(KI),
NaI,
tetrabutylammonium iodide (n‐Bu4NI), and ammonium iodide (NH4I)
with NaI giving the highest yield (see Table 2). To further optimise
the reaction conditions, the additive loading and overall reaction
concentration were examined. The optimised reaction conditions for
the trifluoromethylthiolation of 9a were therefore as follows: 9a
(0.5 mmol), 10 (0.6 mmol), PPh3 (1.2 mmol), NaI (0.05 mmol), and
CH3CN (4 mL), at 60 °C.
Table 2 Screening of additive and reaction concentration
Solvent Volume
Entry Additive Additive (equiv)
Yield (%)
(mL)
1
2
3
4
5
6
7
8
KI
n‐Bu4NI
NH4I
NaI
NaI
NaI
0.2
0.2
0.2
0.2
0.1
0.05
0.1
0.1
3
3
3
3
3
3
2
4
94
79
88
95
94
87
90
98
NaI
NaI
2 | J. Name., 2012, 00, 1‐3
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a
Reaction conditions: 9a (0.5 mmol), 10 (0.6 mmol), PPh3 (1.2
triphenylphosphine oxide, sodium chloride and iodine which reacts
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mmol), additive (0.025‐0.1 mmol), CH3CN (2‐4 mL) at 60 oC for 2 h
with PPh3 to give iodotriphenylphosphoniumDOioI:d1i0d.e101339./CR6eOduB0ci2n4g651C0
by 13 via intermediate 14 forms trifluoromethanesulfinic chloride 15,
triphenylphosphine oxide and regenerates iodine. A second similar
process gives trifluoromethanesulfenyl chloride 17 which undergoes
an electrophilic trifluoromethylthiolation with indole 9 to give the
corresponding indole trifluoromethylthioethers 11.
With the optimised reaction conditions in hand, the substrate
scope was investigated using a series of indole derivatives, and the
results are presented in Table 3. Both electron donating and electron
withdrawing substitutions in the 4‐, 5‐, 6‐, and 7‐position (9b–9n)
were well tolerated in this reaction, and the desired 3‐
trifluoromethylthiolation products were obtained in very good to
excellent yields. Moreover, the N‐substituted N‐methylindoles (9o
and 9q) and N‐phenylindole (9p) were successfully transformed into
their corresponding trifluoromethylthiolation products 11o, 11q, and
11p in 90%, 70%, and 92% yields, respectively. Interestingly, although
3‐methylindole (9t) was previously reported to yield only trace
amounts of the desired 2‐trifluoromethylthiolation product in the
presence of 2.2 equiv. CF3SO2Cl and 4.4 equiv. PMe3,20 in our system,
9t was tolerated, despite a relatively low yield of the desired product
11t being obtained. Notably, the trifluoromethylthiolation of indoles
bearing electron withdrawing groups (e.g., ester (9i) and nitro (9j)
groups) was slower compared with that of indoles bearing electron
donating groups (i.e., methoxy (9b and 9m), hydroxyl (9c), and
methyl (9d, 9e, 9n, 9q, and 9r) groups).
Scheme 2 Proposed reaction mechanism.
Table 3 Scope of trifluoromethylthiolation of indole derilativesa
To support our proposed mechanism, CF3SO2Cl 10 (1.0 eq.) and
iodotriphenylphosphonium iodide 13 (2.0 eq.) was mixed in CH3CN
with stirring at 60 °C for 4 h, iodine was detected by starch.
Moreover, when indole 9a was treated with CF3SO2Cl 10, PPh3 and
NaI in CH3CN at room temperature, the byproduct S‐(trifluoromethyl)
1H‐indole‐3‐sulfinothioate 18a was obtained in 20% yield which
meant that intermediate 15 was formed in this transformation
(Scheme 3).
Scheme 3 Trifluoromethylthiolation of indole at room temperature.
Finally, to illustrate the potential practical application of this
trifluoromethylthiolation protocol, the reaction was scaled up using
1 g of the substrate 9a. As shown in Scheme 4, the desired product
11a was obtained in 80% yield.
SCF3
PPh3, 1.2 eq.
NaI, 0.1 eq.
+
CF3SO2Cl
CH3CN
N
N
60 o
C
H
H
9a
10
11a
1.0 g, 8.55 mmol
1.73 g, 10.26 mmol
80%
Scheme 4 Scale up of the trifluoromethylthiolation reaction.
Experimental
1) General methods and material
All solvents were distilled prior to use. The solvents for reaction were
distilled over Na (for toluene, 1,4‐dioxane and THF) or CaH2 (for DCE
and MeCN) under a nitrogen atmosphere. All reactions were carried
out in oven‐dried glassware under an inert atmosphere (nitrogen or
argon). For chromatography, 200−300 mesh silica gel was employed.
1H NMR 13C NMR and 19F NMR spectra were recorded at 400 MHz,
Based on literatures20, 22and our previous work,19 a plausible
mechanism for this reaction was proposed (see Scheme 2). Initially,
CF3SO2Cl 10 reacts with PPh3 and sodium iodide to form
trifluoro((trifluoromethyl)sulfinothioyl)methane
12,
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100 MHz and 376 MHz respectively. Chemical shifts are reported in 5‐chloro‐3‐((trifluoromethyl)thio)‐1H‐indole
(11g):17
After
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ppm using tetramethylsilane as internal standard. HRMS was purification by silica gel column chromatograDpOhIy: ,10co.1m03p9o/Cu6nOdB1012g4w65aCs
1
performed on an FTMS mass instrument. Melting points are reported isolated as a white solid (117 mg, 93%): H NMR (400 MHz, CDCl3): δ
as uncorrected.
General
8.56 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.35 (d, J
Procedure
Sodium
iodide‐promoted = 8.8 Hz, 1H), 7.25 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H); 13C NMR (100 MHz,
trifluoromethylthiolation of Indoles (Table 3). To a flame‐dried CDCl3): δ 134.4, 134.0, 130.7, 129.3 (q, J = 310 Hz, 1C), 127.7, 124.0,
Schlenk tube was added indole (0.5 mmol), PPh3 (315 mg, 1.2 mmol) 119.0, 112.8, 95.5. (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ
and NaI (7.5 mg, 0.05 mmol) and dry CH3CN (4 mL). −44.49 (s).
trifluoromethanesulfonyl chloride (101 mg, 0.6 mmoL) was added to 5‐fluoro‐3‐((trifluoromethyl)thio)‐1H‐indole
(11h):17
After
o
the reaction mixture and the mixture was heated to 60 C by a purification by silica gel column chromatography, compound 11h
preheated oil bath for 0.5‐24 h. The mixture was cooled to room was isolated as a white solid (111 mg, 93%): 1H NMR (400 MHz,
temperature. The solvent was evaporated under reduced pressure CDCl3): δ 8.53 (s, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.44 (dd, J = 9.2 Hz, J =
and the residue was purified by silica gel column chromatography to 2.4 Hz, 1H), 7.35 (dd, J = 8.8 Hz, J = 4.4 Hz, 1H), 7.04 (td, J = 8.8 Hz, J
afford the pure product.
= 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 159.1 (d, J = 236 Hz, 1C),
134.3, 132.4, 130.4 (d, J = 10.4 Hz, 1C), 129.4 (q, J = 310 Hz, 1C), 112.6
3‐((trifluoromethyl)thio)‐1H‐indole (11a):17 After purification by (d, J = 9.6 Hz, 1C), 112.2 (d, J = 26.4 Hz, 1C), 104.6 (d, J = 24.5Hz, 1C),
silica gel column chromatography, compound 11a was isolated as a 95.8 (q, J = 2.6 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −44.60 (s),
white solid (106 mg, 98%): 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), −121.59 (s).
7.82‐7.80 (m, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.44‐7.40 (m, 1H), 7.32‐ methyl 3‐((trifluoromethyl)thio)‐1H‐indole‐5‐carboxylate (11i):17
7.26 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 136.0, 132.8, 130.0 (q, J = After purification by silica gel column chromatography, compound
310 Hz, 1C), 129.5, 123.5, 121.7, 119.4, 111.7, 95.6 (q, J = 2.4 Hz, 1C); 11i was isolated as a white solid (124 mg, 90%): 1H NMR (400 MHz,
19F NMR (376 MHz, CDCl3): δ −44.55 (s).
4‐methoxy‐3‐((trifluoromethyl)thio)‐1H‐indole
CDCl3): δ 8.87 (s, 1H), 8.55 (s, 1H), 8.01 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H),
(11b):17
After 7.63 (d, J = 2.8 Hz, 1H), 7.47 (d, , J = 8.8 Hz, 1H), 3.97 (s, 3H); 13C NMR
purification by silica gel column chromatography, compound 11b (100 MHz, DMSO‐d6): δ 167.3, 139.5, 137.6, 129.8 (q, J = 310 Hz, 1C),
was isolated as a white solid (121 mg, 98%): 1H NMR (400 MHz, CDCl3): 129.2, 123.9, 123.0, 120.7, 113.3, 93.4 (q, J = 2.4 Hz, 1C), 52.4; 19F
δ 8.45 (s, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.01 (dd, NMR (376 MHz, DMSO‐d6): δ −44.18 (s).
J = 8.4 Hz, J = 0.4 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H); 13C NMR 5‐nitro‐3‐((trifluoromethyl)thio)‐1H‐indole (11j):17 After purification
(100 MHz, CDCl3): δ 154.6, 137.9, 132.3, 129.5 (q, J = 310 Hz, 1C), by silica gel column chromatography, compound 11j was isolated as
124.4, 118.6, 104.8, 102.1, 94.6 (q, J = 2.5 Hz, 1C), 55.5; 19F NMR (376 a white solid (128 mg, 95%): 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H),
MHz, CDCl3): δ −45.48 (s).
8.76 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.75 (d, J
= 2.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H); 13C NMR (100 MHz, DMSO‐d6)：
δ 142.4, 139.8, 139.2, 129.4 (q, J = 310 Hz, 1C), 128.7, 118.1, 114.7,
113.7, 94.4 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, DMSO‐d6)：δ
−44.18 (s).
3‐((trifluoromethyl)thio)‐1H‐indol‐4‐ol (11c):17 After purification by
silica gel column chromatography, compound 11c was isolated as a
1
white solid (100 mg, 86%): H 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, 128.4 (q, J = 310 Hz, 1C), 125.1, 116.5, 107.1,
104.4, 91.5 (q, J = 2.3Hz, 1C); 19F NMR (376 MHz, CDCl3): δ −45.74 (s).
6‐fluoro‐3‐((trifluoromethyl)thio)‐1H‐indole
(11k):17
After
purification by silica gel column chromatography, compound 11k was
isolated as a white solid (106 mg, 90%): 1H NMR (400 MHz, CDCl3): δ
8.49 (s, 1H), 7.71 (dd, J = 8.4 Hz, J = 5.6 Hz, 1H), 7.52 (d, J = 2.4 Hz,
1H), 7.11 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 7.04 (td, J = 9.2 Hz, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 160.6 (d, J = 239 Hz, 1C), 136.0 (d,
J =12.6 Hz, 1C), 133.1, 129.4 (q, J = 310 Hz, 1C), 125.9, 120.4 (d, J = 10
Hz, 1C), 110.6 (d, J = 25 Hz, 1C), 98.1 (d, J = 26 Hz, 1C), 96.0 (q, J = 2.7
Hz, 1C); 19F NMR(376 MHz, CDCl3): δ −44.50 (s), −119.05 (s).
4‐methyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11d):17
After
purification by silica gel column chromatography, compound 11d
was isolated as a white solid (102 mg, 88%): 1H NMR (400 MHz,
CDCl3): δ 8.50 (s, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H),
7.17 (t, J = 8.0 Hz, 1H), 6.99 (dd, J = 7.2 Hz, J = 0.4 Hz, 1H), 2.83 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 136.4, 134.0, 131.7, 129.2 (q, J = 310 Hz,
1C), 126.8, 123.5, 123.4, 109.7, 95.1 (q, J = 2.4 Hz, 1C), 19.4; 19F NMR
(376 MHz, CDCl3): δ −45.88 (s).
6‐chloro‐3‐((trifluoromethyl)thio)‐1H‐indole
(11l):17
After
purification by silica gel column chromatography, compound 11l was
isolated as a white solid (115 mg, 91%): 1H NMR (400 MHz, CDCl3): δ
8.51 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.42 (d, J
= 1.6 Hz, 1H), 7.25 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 136.4, 133.4, 129.5, 129.4 (q, J = 310 Hz, 1C), 128.1, 122.5,
120.4, 111.7, 96.0 (q, J = 2.4 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ
−44.45 (s).
5‐methyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11e):17
After
purification by silica gel column chromatography, compound 11e
was isolated as a white solid (102 mg, 88%): 1H NMR (400 MHz,
CDCl3): δ 8.40 (s, 1H), 7.58 (s, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.30 (d, J =
8.4 Hz, 1H), 7.12 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 2.49 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 134.3, 132.8, 131.2, 129.7, 129.5 (q, J = 310 Hz,
1C), 125.1, 118.9, 111.4, 94.9 (q, J = 2.4 Hz, 1C), 21.5; 19F NMR (376
MHz, CDCl3): δ −44.61 (s).
5‐bromo‐3‐((trifluoromethyl)thio)‐1H‐indole
purification by silica gel column chromatography, compound 11f was
isolated as a white solid (138 mg, 93%): H NMR (400 MHz, CDCl3): δ
8.56 (s, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.39 (dd,
J = 8.4 Hz, J = 2.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 134.7, 133.8, 131.2, 129.2 (q, J = 308 Hz, 1C), 126.5, 122.0,
115.2, 113.1, 95.4 (q, J = 2.3 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ
−44.46 (s).
6‐methoxy‐3‐((trifluoromethyl)thio)‐1H‐indole
(11m):
After
purification by silica gel column chromatography, compound 11m
was isolated as a white solid (114 mg, 92%): 1H NMR (400 MHz, CDCl3):
δ 8.37 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 6.94 (dd,
J = 8.4 Hz, J = 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 157.4, 136.9, 131.6, 129.5 (q, J = 310 Hz, 1C),
123.6, 120.0, 111.7, 95.6 (q, J = 2.5 Hz, 1C), 95.0, 55.7; 19F NMR (376
MHz, CDCl3): δ −44.63 (s); HRMS (ESI) m/e calcd for C10H7NOF3S (M‐
H)‐ 246.0206, found 246.0194.
(11f):17
After
1
7‐methyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11n):17
After
purification by silica gel column chromatography, compound 11n
4 | J. Name., 2012, 00, 1‐3
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Organic & Biomolecular Chemistry
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was isolated as a white solid (105 mg, 91%): 1H NMR (400 MHz, CDCl3):
δ 8.45 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.18‐
7.22 (m, 1H), 7.10 (d, J = 7.2 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 135.6, 132.4, 129.4 (q, J = 310 Hz, 1C), 129.1, 123.9, 121.8,
120.8, 117.0, 96.0 (q, J = 2.4 Hz, 1C), 16.3; 19F NMR (376 MHz, CDCl3):
δ −45.56 (s).
In summary, we have developed
trifluoromethylthiolation protocol for the synthesis of indole
a
VnieewwArticledOirnelincet
DOI: 10.1039/C6OB02465C
trifluoromethylthioethers using trifluoromethanesulfonyl chloride in
the presence of triphenylphosphine. Sodium iodide was found to
facilitate this reaction by generating iodine in situ which could
accerelate this transformation. Moreover, the use of a transition
metal‐free protocol, readily available reagents, and mild reaction
conditions allowed this protocol to be scaled up, and so it may be
applicable for use on larger industrial scales.
1‐methyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11o):17
After
purification by silica gel column chromatography, compound 11o
was isolated as a white solid (104 mg, 90%): 1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.36‐7.25 (m, 3H), 3.82 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 137.2, 136.9, 130.3, 129.5 (q, J = 310 Hz,
1C), 123.0, 121.3, 119.4, 109.9, 93.1 (q, J = 2.4 Hz, 1C), 33.3; 19F NMR
(376 MHz, CDCl3): δ −44.92 (s).
Acknowledgements
1‐phenyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11p):17
After
The authors sincerely thank the financial support from National
Science Foundation of China (Grants 21572158, 21202119,
21202118), Tianjin City High School Science & Technology Fund
Planning Project (20110504) and Youth Innovation Fund of
Tianjin University of Science and Technology (20140X1S07)
purification by silica gel column chromatography, compound 11p
was isolated as a white solid (135 mg, 92%): 1H NMR (400 MHz, CDCl3):
δ 7.85‐7.87 (m, 1H), 7.66 (s, 1H), 7.49‐7.57 (m, 5H), 7.42‐7.46 (m, 1H),
7.29‐7.34 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 138.5, 136.6, 135.9,
129.4 (q, J = 310 Hz, 1C), 130.5, 129.8, 127.7, 124.7,123.7, 122.0,
119.7, 111.0, 96.2 (q, J = 2.5 Hz, 1C); 19F NMR (376 MHz, CDCl3): δ
−44.33 (s).
1,2‐dimethyl‐3‐((trifluoromethyl)thio)‐1H‐indole (11q):17 After
purification by silica gel column chromatography, compound 11q
was isolated as a white solid (86 mg, 70%): 1H NMR (400 MHz, CDCl3):
δ 7.73‐7.71 (m, 1H), 7.31‐7.28 (m, 1H), 7.27‐7.20 (m, 2H), 3.71 (s, 3H),
2.56 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 145.2, 136.9, 130.1, 129.9
(q, J = 310 Hz, 1C), 122.2, 121.2, 118.7, 109.2, 91.1 (q, J = 2.4 Hz, 1C),
30.4, 10.8; 19F NMR (376 MHz, CDCl3): δ −44.88 (s).
Notes and references
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2‐methyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11r):17
After
purification by silica gel column chromatography, compound 11r was
isolated as a white solid (98 mg, 85%): 1H NMR (400 MHz, CDCl3): δ
8.27 (s, 1H), 7.71‐7.69 (m, 1H), 7.32‐7.29 (m, 1H), 7.23‐7.20 (m, 2H),
2.56 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.6, 135.1, 130.6, 129.9
(q, J = 310 Hz, 1C), 122.6, 121.4, 118.7, 110.8, 92.6 (q, J = 2.4 Hz, 1C),
12.1; 19F NMR (376 MHz, CDCl3): δ −44.42 (s).
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,
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2‐phenyl‐3‐((trifluoromethyl)thio)‐1H‐indole
(11s):17
After
purification by silica gel column chromatography, compound 11s was
isolated as a white solid (114 mg, 78%): 1H NMR (400 MHz, CDCl3): δ
8.57 (s, 1H), 7.86‐7.84 (m, 1H), 7.78‐7.76 (m, 2H), 7.54‐7.41 (m, 4H),
7.33‐7.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 144.4, 135.4, 131.5,
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9
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3‐methyl‐2‐((trifluoromethyl)thio)‐1H‐indole
(11t):17
After
purification by silica gel column chromatography, compound 11t was
isolated as a white solid (44 mg, 38%): 1H NMR (400 MHz, CDCl3): δ
8.12 (br,1H), 7.62 (dd, J = 7.2 Hz, J = 0.8 Hz, 1H), 7.35‐7.38 (m, 1H),
7.29‐7.33 (m, 1H), 7.15‐7.19 (m, 1H), 1.56 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 137.4, 128.8 (q, J = 310 Hz, 1C), 128.0, 124.8, 123.7, 120.1,
120.0, 113.0 (q, J = 2.3 Hz, 1C), 111.1, 9.4; 19F NMR (376 MHz, CDCl3):
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Conclusions
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