TBAI-assisted direct C-H activation of indoles with β-E -styrene sulfonyl hydrazides: A stereoselective access to 3-styryl thioindoles

Article abstract of DOI:10.1039/d1ra02444b

The current work describes the challenging introduction of a vinyl sulfide group by simple C-H activation on a variety of substrates. The direct C-H activation of indoles with β-(E)-styrene sulfonyl hydrazides under the sulfenylation conditions, assisted by the iodic catalyst tert-butyl ammonium iodide (TBAI), afforded a series of (E)-styrylthioindoles. Accordingly, β-(E)-styrene sulfonyl hydrazides undergo radical cross-coupling reactions with a variety of substituted indoles to afford structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity. This method is metal-catalyst-free and is valuable not only because of its novelty, but also for providing a convenient synthetic pathway to a variety of (E)-styrylthioindoles with retention of the configuration. The current study paves the way for the use of β-(E)-styrene sulfonyl hydrazides as a unique styryl mercaptan source in chemical synthesis.

Full text of DOI:10.1039/d1ra02444b

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TBAI-assisted direct C–H activation of indoles with
b-E-styrene sulfonyl hydrazides: a stereoselective
access to 3-styryl thioindoles†
a
Cite this: RSC Adv., 2021, 11, 15608
and Aamer Saeed *b
Saira Hafeez
The current work describes the challenging introduction of a vinyl sulfide group by simple C–H activation
on a variety of substrates. The direct C–H activation of indoles with b-(E)-styrene sulfonyl hydrazides under
the sulfenylation conditions, assisted by the iodic catalyst tert-butyl ammonium iodide (TBAI), afforded
a series of (E)-styrylthioindoles. Accordingly, b-(E)-styrene sulfonyl hydrazides undergo radical cross-
coupling reactions with a variety of substituted indoles to afford structurally diverse indole vinyl
thioethers in moderate to high yields with E-stereoselectivity. This method is metal-catalyst-free and is
valuable not only because of its novelty, but also for providing a convenient synthetic pathway to
a variety of (E)-styrylthioindoles with retention of the configuration. The current study paves the way for
the use of b-(E)-styrene sulfonyl hydrazides as a unique styryl mercaptan source in chemical synthesis.
Received 28th March 2021
Accepted 13th April 2021
DOI: 10.1039/d1ra02444b
rsc.li/rsc-advances
suldes was reported by the Venkataraman group, but employs
1
. Introduction
a moisture-sensitive Cu(I) catalyst, and requires a high reaction
22
One of the essential goals of modern organic synthesis is to temperature. Later, Cook and co-workers reported a milder
23
develop efficient and environmentally friendly approaches protocol for the synthesis of vinyl suldes. The iron-catalyzed
towards the construction of valuable molecular frameworks. cross-coupling reaction of alkyl vinyl halides with thiols has also
24
Vinyl suldes constitute a ubiquitous molecular framework in been reported. The triethyl-bromide-catalyzed radical addition
natural products, pharmaceuticals, and important synthetic of thiols to acetylenes results in alkenyl suldes with good
1
25
intermediates in chemical transformations. These compounds stereocontrol. However, all these methods require the use of
nd extensive applications in chemical and materials science, either metal catalysts, base, or additives to afford the corre-
and can be used as versatile building blocks for carbonyl sponding vinyl suldes. Furthermore, all these reports describe

2
3
compounds and as Michael acceptors. The most popular the nucleophilic addition of thiols to an unsaturated system,
synthetic procedures to construct such molecules involve the and none describes direct C–H activation via the addition of
addition of thiols to alkynes either using transition metal a vinyl sulde moiety from a single source. Fig. 1 depicts
4
–12
13–15
16–18
catalysts,
free radicals,
Wittig olenation
or nucleo- a comparison of the various synthetic methods towards E-vinyl
Nevertheless, harsh thioethers with the current work.
19,20
philic substitution of vinyl halides.
reaction conditions, expensive starting substrates and a lack of
The indole ring is the key structural unit of many bioactive
26,27
stereo-control are limitations of these methods. Consequently, molecules
and the development of efficient synthetic
a milder, more convenient, and more stereoselective protocol to methods to access differently substituted indoles is a topic of
28,29
obtain these signicant scaffolds would be highly desirable.
the utmost interest in organic synthesis.
Substituted
The stereoselective synthesis of (E)-vinyl suldes has been indoles, particularly thiolated indoles, constitute a signicant
achieved by several methods. Banerjee and co-workers reported class of heterocyclic compounds because of their wide range of
30–32
an indium-iodide-promoted one-pot synthesis of (E)-vinyl applications in medicines and biologically active molecules.
suldes via the palladium-catalyzed condensation of vinyl Consequently, considerable effort has been made to develop
21
33
bromides using disuldes as a sulfur source. One of the most new synthetic routes to indole-based heterocycles. 3-Thiolated
signicant catalytic processes for the synthesis of (E)-vinyl indoles represent one of the most important classes of bioactive
34
molecules used in the treatment of cancer and allergies. The
various synthetic strategies that have been reported for the 3-
arylthiolation of indoles include the use of sulfonyl chlorides,
a
35
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui
2
30026, China
36
37
38
sodium sulnates, Bunte salts, sulfonyl hydrazides and N-
b
Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad, Pakistan.
E-mail: aamersaeed@yahoo.com; asaeed@aiou.edu.pk
39
hydroxy sulfonamides as thiolating agents. The only method
to synthesize radio-protective vinyl thioindoles was reported by
Skvortsova and co-workers and involves the nucleophilic
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/d1ra02444b
1
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Fig. 1 Comparison of synthetic studies of E-vinyl thioethers with the current work.
4
0
ꢀ
addition of thioindoles to acetylenes. The present work temperature of 90 C resulted in a slight decrease in the yield of
describes the challenging introduction of a vinyl sulde moiety the product (entry 14), and was thus found to be optimum
by simple C–H activation on a variety of substituted indoles temperature for this conversion. In contrast, further increasing
ꢀ
using b-(E)-styrene sulfonyl hydrazides (Fig. 2). Sulfonyl hydra- the temperature to 120 C dropped the yield to 69% (entry 15). A
zides are readily available, inexpensive, and stable solids that decrease or increase in catalyst loading (5 mol% & 20 mol%)
41–43
can act as sulfenylation agents.
Consequently, herein, we also resulted in a decrease in the yield of the product (entries 16
wish to report the use of b-(E)-styrene sulfonyl hydrazides as and 17).
unique and direct sulfenylation agents for the synthesis of vinyl
Attempts to decrease in reaction time from 8 to 10 h resulted
thioindoles with excellent stereocontrol under simple reaction in lower consumption of the starting materials and thus low
conditions.
yields of the product.
2. Results and discussion
2.1 Optimization of the reaction conditions
2.2 Scope and limitations of substrates
Scheme 1 outlines the synthetic pathway and conditions
Scope with respect to substituted indoles. With the opti-
adopted for the preparation of the target molecules. We started mized conditions in hand, we next studied the scope of
with the reaction of b-(E)-styrene sulfonyl hydrazide (1a) with substituted indoles for this catalytic transformation. In the
ꢀ
indole (2a) in the presence of 10 mol% of iodine at 70 C in presence of 10 mol% of TBAI, a range of substituted indoles
a sealed tube for 12 hours, but the desired product was formed having both electron-donating and electron-withdrawing
in only 25% yield (Table 1, entry 1). To our delight, the yield was groups on the indole ring underwent sulfenylation with b-(E)-
ꢀ
increased to 46% by increasing the temperature to 100 C (entry styrene sulfonyl hydrazides to give structurally diverse 3-styryl
2). Further screening of various solvents afforded the product in thioindoles in good to high yields (66–88%) with excellent
moderate yields (entries 3–5) and an improved yield of 65% was stereoselectivity (Scheme 2).
obtained using 1,4-dioxane (entry 6). Conducting the reaction
Effect of the nature of the substituents (electron donating/
under an inert atmosphere to avoid the formation of by- withdrawing) on the indole ring. Under the optimized condi-
products enhanced the yield to 71% (entry 7). Next, the cata- tions, the reaction was repeated with an electron-donating (2h)
lytic effect of various iodic reagents in this transformation was or an electron-withdrawing group (2k) on the indole ring, and
studied (entries 8–13), and the best result was obtained by using the results summarized in the scheme below clearly depict the
ꢀ
TBAI in 1,4-dioxane at 100 C for 12 hours under an N
2
atmo- enhanced yield due to the presence of the electron-donating
sphere (entry 10). Repeating the reaction with a decreased group.
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It might be possible to expand this protocol to other acti- corresponding hydrazide with indole under the optimized
vated rings including heteroaromatics by adding some additives conditions.
1
and varying the reaction conditions.
Examining the H-NMR spectra, the broad signal at
Scope with regard to b-(E)-styrene sulfonyl hydrazides. Aer 8.40 ppm corresponds to the N–H of indole, whilst the sharp
investigating the scope of the indoles, we next studied the scope singlet at 7.20 ppm is assignable to the C–H of the indole
of substituted b-(E)-styrene sulfonyl hydrazides for this coupling ring; additionally, the two doublets at 6.75 and 6.25 ppm with
reaction (Scheme 3). The reactions of 4-Me, 4-Br, and 4-Cl large coupling constants of 16.0 Hz indicate the presence of
derivatives of b-(E)-styrene sulfonyl hydrazides with the indole mutually coupled protons of the trans double bond, thus
gave the corresponding coupling products 4a, 4b and 4c in 68%, conrming the connection of the two partner molecules. The
1
3
72% and 73% yield, respectively. (E)-3-((2-(Naphthalen-2-yl)
C-NMR showed the doubly bonded carbons of the vinyl
vinyl)thio)-1H-indole 4d was obtained in 63% via the reaction of moiety at 126 and 119 ppm and the C–H of indole at 130 ppm,
respectively, whereas the ]C–N peak at 138 ppm indicated
Fig. 2 Previous reported work on thioindole synthesis and the current strategy.
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Scheme 1 Synthetic pathway and optimization of the reaction conditions.
Table 1 Optimization study with respect to the catalyst, solvent, and to purple black, indicating the formation of iodine during this
temperature
reaction. On the basis of experiment and observations, the
b
following reaction mechanism can be suggested for this radical
cross-coupling reaction. Initially, disulde compound 3s is
generated from b-E-styrene sulfonyl hydrazide 1 in the presence
of TBAI, and then reacts with iodine to produce PhCH]CHSI
Catalyst
(mol%)
Solvent
(mL)
Temperature
( C)
Time
(h)
Yield
(%)
ꢀ
Entry
a
1
I
2
I
2
I
2
I
2
I
2
I
2
I
2
EtOH
EtOH
DMSO
DCE
70
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
25
46
29
51
11
65
71
41
59
84
72
68
57
86
68
49
63
a
2
100
100
100
100
100
100
100
100
100
100
100
100
90
(II). Nucleophilic attack of the indole on III produces radical
a
3
a
intermediate IV and an iodine radical. Extrusion of HI leads to
the formation of the nal product, thioether 3. The produced HI
reacts with TBAOH to remove a water molecule, and the
regenerated TBAI can react with sulfonyl hydrazide to produce
disulde again (Scheme 5).
The proposed mechanism is based on reports in the litera-
ture; the free-radical pathway was conrmed by the control
experiment (A) and the formation of the major intermediate 3s
was conrmed by EI-MS analysis (ESI S-48†).
4
a
5
3
CH CN
a
6
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
e
7
e
8
CuI
KI
TBAI
NIS
e
9
e
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
e
e
e
e
e
c
3 3
(CH ) SOI
NaI
TBAI
TBAI
TBAI
TBAI
120
100
100
3. Experimental section
d
3
.1 Materials and instruments
Indole and its derivatives were purchased from Sinopharm
in a sealed tube. Isolated yields. 5 mol% of TBAI was used. Chemical Reagent Co., Meryer, Acros, Alfa Aesar, and TCI, and
a
Reaction conditions: 1a (0.48 mmol), 2a (0.4 mmol), catalyst
10 mol%), and solvent (1.5 mL) at the indicated temperature under
(
b
c
N
2
2
d
e
0 mol% of TBAI was used. Reaction conducted under an N
2
were used without further purication. b-(E)-Styrene sulfonyl
atmosphere.
chlorides and their derivatives were prepared according to
9
literature procedures. Melting points were determined in open
glass capillaries using a Stuart SMP3 (UK) melting point appa-
ratus and are uncorrected.
that the desired transformation had successfully been
carried out.
1
13
H and C NMR spectra were recorded using a Bruker AC-
00 FT spectrometer (400 MHz and 100 MHz, respectively)
4
using TMS as an internal standard. NMR multiplicities are
abbreviated as follows: s ¼ singlet, d ¼ doublet, dd ¼ double
doublet, t ¼ triplet, m ¼ multiplet, q ¼ quartet, br ¼ broad
signal. Chemical shis (d) were recorded using an LC-TOF
spectrometer (Micromass). Electron spray ionization (ESI)
mass spectrometry data are expressed in ppm, while coupling
constants (J) are expressed in Hz. High resolution mass spectra
2
.3 Proposed mechanistic pathway
To elucidate the mechanism of this reaction, we turned our
attention to some control experiments. The reaction of indole
with b-(E)-styrene sulfonyl hydrazide (1) under the optimal
conditions in the presence of the radical inhibitor 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 1.2 equiv.) completely
inhibited the formation of the desired product, suggesting the
involvement of a sulfonyl radical during the reaction (Scheme 4A).
The reaction of (1) with indole in the absence of TBAI also results
in product formation, but in a very low yield (Scheme 4B). In the
absence of indole, a mixture of the products 3s (major) and 3t
(HRMS) were obtained using a Thermo LTQ Orbitrap XL
instrument equipped with an ESI source and controlled by the
soware Xcalibur. Elemental analyses were conducted using
a LECO-183 CHNS analyzer.
(
minor) was obtained (detected via GC-MS and EI-MS), indicating
3
.2 General procedure for the preparation of b-(E)-styrene
that (1a) is converted into these species before reacting with
indole to give the styryl thioether (Scheme 4C).
sulfonyl hydrazides
In addition, during the course of the reaction, we noticed Hydrazine monohydrate (50 mg, 1 mmol, 2.5 equiv.) was added
a change in the color of the reaction mixtures from light brown dropwise to a solution of b-(E)-styrene sulfonyl chloride
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a
ꢀ
Scheme 2 Substrate scope for indoles. 1a (0.48 mmol), 2a (0.4 mmol), TBAI (10 mol%), and 1,4-dioxane (1.5 mL) at 90 C under an N
atmosphere for 10 h.
2
ꢀ ꢀ
2
0.4 mmol, 1 equiv.) in THF (2 mL) at 0 C under an N atmo- addition of hydrazine. The reaction mixture was stirred at 0 C
(
sphere. The mixture became brown due to the formation of for 30 to 45 minutes, diluted with ethyl acetate (10 mL), washed
a white precipitate of hydrazine hydrochloride during the with brine (2 ꢁ 10 mL), dried over sodium sulfate, and ltered.
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a
Scheme 3 Substrate scope for b-(E)-styrene sulfonyl hydrazides. Reaction conditions: 1a (0.48 mmol), 1b (0.4 mmol), TBAI (10 mol%), and 1,4-
ꢀ
dioxane (1.5 mL) at 90 C under an N
2
atmosphere in a sealed tube for 12–14 h.
Scheme 4 Control experiments.
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(
6
dd, J ¼ 8 Hz, 1H) 7.22–7.16 (m, 5H), {6.80 (d, J ¼ 16 Hz, 1H),
1
3
.23 (d, J ¼ 16 Hz, 1H) olenic}. C NMR (100 MHz, CDCl )
3
d (141.2, C ), 137, 135.7, 131.3, 130.9, 128.8, 128.7, (128.5,
8
aromatic), 128.3, (128.1, aromatic), (126.6, C ), 126.2, (125.7,
1
olenic), 125.5, 123.3, 121.1, (119.9, olenic), 111.2, (98.9, C–S).
+
HRMS (ESI) m/z [M + H] calculated for C22
H18NS (328.1082),
found 328.1086.
(
E)-3-Methyl-2-(styrylthio)-1H-indole (3d). Light yellow solid,
ꢀ
1
(
71.4 mg, 71%), mp 132–133 C; H NMR (400 MHz, CDCl )
3
d 7.98 (s, br, 1H, N–H), 7.58 (d, J ¼ 8 Hz, 1H), 7.31–7.23 (m, 5H,
aromatic), 7.21–7.12 (m, 3H, aromatic), {6.64 (d, J ¼ 16 Hz, 1H),
1
3
6
.35 (d, J ¼ 16 Hz, 1H), olenic}, 2.40 (s, 3H, –Me). C NMR (100
MHz, CDCl
3
) d (136.8, C
8
), 136.4, (128.8, aromatic), 128.6, 128.5,
Scheme 5 Proposed mechanistic pathway.
128.4, (127.4, olenic), (125.9, aromatic), 123.9, 123.4, (121.2,
C
1
), (119.7, olenic), 119.4, 118.8, (110.9, C–Me), (9.5, –Me).
The ltrate was slowly added to stirred hexane (10 mL) over
+
HRMS (ESI) m/z [M + H] calculated for C17H16NS (265.0925),
found 266.1001.
5
min. Aer being stirred for 10 min, the mixture was ltered
and then dried under vacuum to obtain the b-(E)-styrene
sulfonyl hydrazides as a brown solid.
(
E)-5-Bromo-3-(styrylthio)-1H-indole (3e). White solid, mp
ꢀ
68.4 mg, 68%), 117–118 C; H NMR (400 MHz, CDCl ) d 8.45 (s,
3
1
(
br, 1H, N–H), 7.85 (s, 1H), 7.45 (d, J ¼ 4 Hz, 1H), 7.38–7.30 (m,
3
H, aromatic and C –H), 7.23–7.15 (m, 4H, aromatic), {6.72 (d, J
1
3
.3 General procedure for the TBAI-assisted direct C–H
13
¼
16 Hz, 1H), 6.27 (d, J ¼ 16 Hz, 1H), olenic}. C NMR (100
activation of indoles with b-(E)-styrene sulfonyl hydrazides
MHz, CDCl
3
) d 138.5, 136.8, (133.9, C
1
), 130.5, (128.5, aromatic),
To a mixture of b-(E)-styrene sulfonyl hydrazide 1a (0.48 mmol, 126.4, (126.6, olenic), 126.2, (125.7, aromatic), 122.2, (118.8,
+
1
0
N
.2 equiv.), indole 2a (0.4 mmol, 1 equiv.) and TBAI (18.5 mg, olenic), 113.3, 110.8, (100.9, C–S). HRMS (ESI) m/z [M + H]
.05 mmol, 10 mol%) was added 1,4-dioxane (1.5 mL) under an calculated for C16 13NSBr (329.9952), found 329.9944.
(E)-2,5-Dimethyl-3-(styrylthio)-1H-indole (3f). Yellow solid,
H
2
atmosphere in a sealed tube. The resulting mixture was
ꢀ
ꢀ
1
stirred at 100 C for 12 h and cooled to room temperature, and (82.4 mg, 82%), mp 131–133 C; H NMR (400 MHz, CDCl
)
3
ethyl acetate (10 mL) was added. The mixture was washed with d 8.15 (s, br, 1H, N–H), 7.40 (s, 1H), 7.24–7.16 (m, 5H, aromatic),
brine (2 ꢁ 10 mL), dried over Na SO , and puried using silica 7.15–7.09 (m, 1H), 7.01 (dd, J ¼ 8 Hz, 1H), {6.70 (d, J ¼ 16 Hz,
2
4
gel chromatography eluted with petroleum ether/ethyl acetate 1H), 6.15 (d, J ¼ 16 Hz, 1H), olenic}, 2.51 (s, 3H, C
5
–Me), 2.43
) d 140.2, (137.1, C ),
E)-3-(Styrylthio)-1H-indole (3a). Brown solid, (84.5 mg, 133.6, 130.3, 130.1, (128.5, aromatic), 128.3, 126.8, (126.5,
1
3
(10 : 1 to 1 : 1) to give the indole styryl thioether 3a.
(s, 3H, C
1
–Me). C NMR (100 MHz, CDCl
3
1
(
ꢀ
1
8
1
4%), mp 128–129 C; H NMR (400 MHz, CDCl
3
) d 8.38 (s, br, olenic), (125.5, aromatic), 125.2, 123.6, (118.6, olenic), 110.3,
–Me), (12.2, C –Me). HRMS (ESI) m/z [M +
–H), H] calculated for C18 18NS (280.1160), found 280.1152.
.20–7.16 (m, 2H, aromatic), 7.15–7.11 (m, 1H, aromatic), {6.77
(E)-5-Chloro-3-(styrylthio)-1H-indole (3g). Yellow solid,
H, N–H), 7.72 (d, J ¼ 8 Hz, 1H), 7.45 (q, 2H, aromatic), 7.29 (dd, (98.3, C–S), (21.5, C
5
1
+
J ¼ 8 Hz, 1H), 7.25–7.21 (m, 2H, aromatic), 7.20 (s, 1H, C
1
H
7
(
1
3
ꢀ
1
d, J ¼ 16 Hz, 1H), 6.29 (d, J ¼ 16 Hz, 1H) olenic}. C NMR (100 (78.4 mg, 78%), mp 121–122 C; H NMR (400 MHz, CDCl
3
)
MHz, CDCl ) d (137, C ), 136.4, (129.5, C ), 128.9, 128.7, (128.6, d 8.43 (s, br, 1H, N–H), 7.37 (s, 1H), 7.26 (t, J ¼ 4 Hz, 2H,
3
8
1
1
aromatic), 128.4, 126.72, 126.71, (126.2, olenic), (125.6, aromatic), 7.17 (s, 1H, C –H), 7.16–7.13 (m, 3H, aromatic), 7.10–
aromatic), 123.1, (120.9, olenic), 119.6, 111.6, (102.8, C–S). 7.08 (m, 2H), {6.78 (d, J ¼ 16 Hz, 1H), 6.22 (d, J ¼ 16 Hz, 1H),
+
13
HRMS (ESI) m/z [M + H] calculated for C16
H
13NS (251.0769), olenic}. C NMR (100 MHz, CDCl
) d (136.8, C ), 136.1, (130.1,
3 8
found 251.0763.
C
1
), 127.6, 127.5, 127.3, 127.2, 125.8, (125.7, olenic), (125.4, C–
(
E)-2-Methyl-3-(styrylthio)-1H-indole (3b). Yellow solid, Cl), 124.6, 124, 122.6, (121.2, olenic), 109.4, (102.3, C–S).
ꢀ
1
+
(
66.3 mg, 66%), mp 133–135 C; H NMR (400 MHz, CDCl
d 8.38 (s, br, 1H, N–H), 7.72 (d, J ¼ 8 Hz, 1H), 7.46–7.42 (m, 2H), found 286.0450.
.30–7.26 (m, 1H), 7.22–7.17 (m, 1H), 7.10–7.01 (m, 4H, (E)-6-Methyl-3-(styrylthio)-1H-indole (3h). Brown solid, mp
aromatic), {6.70 (d, J ¼ 16 Hz, 1H), 6.30 (d, J ¼ 16 Hz, 1H), (73.4 mg, 73%), 134–135 C; H NMR (400 MHz, CDCl
3
)
HRMS (ESI) m/z [M + H] calculated for C16H13NClS (286.0457),
7
ꢀ
1
3
) d 8.28 (s,
) d (134.1, br, 1H, N–H), 7.61 (d, J ¼ 8 Hz, 1H), 7.38 (d, J ¼ 4 Hz, 1H), 7.27–
), (129.2, aromatic) 128.8, 127.6, 126.3, (125.5, 7.24 (m, 2H, aromatic), 7.23 (s, 1H, C –H), 7.21–7.13 (m, 3H,
aromatic), (125.3, olenic), 124.1, 123, (120.8, olenic), 119.6, aromatic), 7.05 (d, J ¼ 8 Hz, 1H), {6.79 (d, J ¼ 16 Hz, 1H), 6.31 (d,
1
3
olenic}, 2.28 (s, 3H, –Me). C NMR (100 MHz, CDCl
), (129.3, C
3
C
8
1
1
+
13
1
11.5, 102.11, (21.2, –Me). HRMS (ESI) m/z [M + H] calculated J ¼ 16 Hz, 1H), olenic}, 2.5 (s, 3H, –Me). C NMR (100 MHz,
for C17 16NS (266.1003), found 266.1001.
CDCl ) d (137, C ), 136.8, (133.3, C ), (133, C–Cl), 128.8, (128.5,
E)-2-Phenyl-3-(styrylthio)-1H-indole (3c). Yellow solid, aromatic), 126.8, 126.6, (126, olenic), (125.6, aromatic), 122.7,
H
3
8
1
(
ꢀ
77.4 mg, 77%), mp 138–139 C; H NMR (400 MHz, CDCl ) (119.2, olenic), 111.5, (102.7, C–S), (21.7, Me). HRMS (ESI) m/z
3
1
(
+
d 8.55 (s, br, 1H, N–H), 7.81–7.78 (m, 2H, C
Hz, 1H), 7.50–7.44 (m, 4H), 7.43–7.40 (m, 1H, aromatic), 7.29
2
–Ph), 7.75 (d, J ¼ [M + H] calculated for C17
H16NS (266.0998), found 266.0997.
8
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(
E)-5-Fluoro-2-methyl-3-(styrylthio)-1H-indole (3i). Light {6.75 (d, J ¼ 16 Hz, 1H), 6.26 (d, J ¼ 16 Hz, 1H), olenic}, 3.83 (s,
1
13
ꢀ
brown solid, (88.5 mg, 88%), mp 132–133 C; H NMR (400 3H, –Me). C NMR (100 MHz, CDCl
MHz, CDCl
) d 8.23 (s, br, 1H, N–H), 7.27 (d, J ¼ 4 Hz, 1H), 7.25–
), 131.2, 130.3, 129.6, 128.7, 128.6, 128.4, 126.7, (125.9,
.19 (m, 3H, aromatic), 7.19–7.10 (m, 3H, aromatic), 6.95–6.90 olenic) 125.6, (113.6, olenic), 112.5, 102.9, (100.6, C–S), (55.9,
) d (155.1, C–OMe), (137,
3
C
1
3
7
(
2
1
1
+
m, 1H), {6.67 (d, J ¼ 16 Hz, 1H), 6.14 (d, J ¼ 16 Hz, 1H) olenic}, OCH
3
). HRMS (ESI) m/z [M + H] calculated for C17
.52 (s, 3H, Me). C NMR (100 MHz, CDCl ) d (156.4, C–F), 141, (281.0874), found 281.0870.
H16NOS
1
3
3
35.8, (130.6, C ), 127.6, (125.6, olenic), 124.9, (124.6, olenic),
(E)-3-((4-Methylstyryl)thio)-1H-indole (4a). Brown solid
1
1
24.5, 110.3, 110.2, 109.4, 109.2, 103.2, 103, 98.27, (11.3, –Me). (72.2 mg, 68%), H NMR (400 MHz, CDCl
3
) d 8.39 (s, br, 1H, N–
15NFS (284.0903), H), 7.72 (d, J ¼ 4 Hz, 1H), 7.47–7.42 (m, 2H, aromatic), 7.28 (d, J
¼ 8 Hz, 1H), 7.23–7.17 (m, 2H, aromatic including C –H), 7.11–
+
HRMS (ESI) m/z [M + H] calculated for C17
H
found 284.0902.
1
(
E)-5,6-Diuoro-3-(styrylthio)-1H-indole (3j). Light yellow 7.07 (m, 2H, aromatic), 7.05–7.02 (m, 2H, aromatic), {6.70 (d, J ¼
ꢀ
1
solid, (79.4 mg, 79%), mp 138–139 C; H NMR (400 MHz, 16 Hz, 1H), 6.29 (d, J ¼ 16 Hz, 1H), olenic}, 2.28 (s, 3H, –Me).
1
3
CDCl
3
) d 8.40 (s, br, 1H, N–H), 7.47–7.41 (m, 2H, aromatic),
C NMR (100 MHz, CDCl
), (129.2, aromatic), (126.3, olenic), (125.5, aromatic), 125.3,
123, 120.8, (119.6, olenic), 116.8, 116.6, 111.5, (98.6, C–S),
3 8
) d (136.5, C ), (134.2, C–Me), (129.3,
7
{
.25–7.21 (m, 3H, aromatic), 7.20–7.13 (m, 3H, aromatic, C –H),
C
1
1
1
3
6.70 (d, J ¼ 16 Hz, 1H), 6.25 (d, J ¼ 16 Hz, 1H) olenic}.
C
+
NMR (100 MHz, CDCl ) d (137, C –F), (136.7, C –F), 130.8, (21.1, –Me). HRMS (ESI) m/z [M + H] calculated for C16
H
16NS
3
4
5
(
130.7, C
1
), 129.6, (128.6, aromatic), 126.9, 126.7, (126.1, (265.0925), found 265.0928.
(E)-3-((4-Bromostyryl)thio)-1H-indole (4b). Brown solid
olenic), 125.7, 125.6, (120.9, olenic), 106.5, 106.3, 99.8, 99.6.
+
1
HRMS (ESI) m/z [M + H] calculated for C16
H
12NF
2
S (288.0653), (95.1 mg, 72%), H NMR (400 MHz, CDCl
H), 7.62 (d, J ¼ 8 Hz, 1H), 7.38–7.35 (m, 2H, aromatic), 7.25 (d, J
), 7.13 (t, J ¼ 8 Hz, 2H,
75.4 mg, 75%), mp 120–121 C; H NMR (400 MHz, CDCl ) aromatic), 6.94 (d, J ¼ 8 Hz, 2H, aromatic), {6.69 (d, J ¼ 16 Hz,
3
) d 8.39 (s, br, 1H, N–
found 288.0651.
(
E)-6-Chloro-3-(styrylthio)-1H-indole (3k). Yellow solid, ¼ 4 Hz, 2H, aromatic including C
1
ꢀ
1
(
3
1
3
d 8.38 (s, br, 1H, N–H), 7.62 (d, J ¼ 4 Hz, 1H), 7.38 (d, J ¼ 4 Hz, 1H), 6.09 (d, J ¼ 16 Hz, 1H), olenic}. C NMR (100 MHz,
1
7
1
1
1
H), 7.28 (d, J ¼ 8 Hz, 1H), 7.17–7.14 (m, 3H), 7.13–7.10 (m, 2H), CDCl
3 1
) d 135.3, 134.8, (130.5, aromatic), 128.6, (127.7, C ),
.10–7.05 (m, 1H), {6.65 (d, J ¼ 16 Hz, 1H), 6.20 (d, J ¼ 16 Hz, (126.8, olenic), (126, aromatic), 123.5, 122.1, (119.9, olenic),
1
3
+
H) olenic}. C NMR (100 MHz, CDCl
29.8, 129.1, (127.5, aromatic), 125.8, 125.5, (125.1, olenic), calculated for C16
24.6, (122.5, C–Cl), (118.1, olenic), 111.6, (101.7, C–S). HRMS
(E)-3-((4-Chlorostyryl)thio)-1H-indole (4c). Brown solid
3
) d 135.7, (133.6, C
1
), 119.1, 118.4, 110.6, (101.2, C–S). HRMS (ESI) m/z [M + H]
13NSBr (329.9874), found 329.9877.
H
+
1
(
2
ESI) m/z [M + H] calculated for C16
H
13NClS (285.0379), found (86.9 mg, 76%), H NMR (400 MHz, CDCl
H), 7.72 (d, J ¼ 8 Hz, 1H), 7.45–7.42 (m, 2H, aromatic), 7.28 (dd, J
E)-1-Methyl-3-(styrylthio)-1H-indole (3l). Light yellow solid, ¼ 8 Hz, 1H), 7.22–7.20 (m, 2H, including C –H), 7.19–7.16 (m,
70.4 mg, 70%), mp 124–125 C; H NMR (400 MHz, CDCl ) 2H, aromatic), 7.15–7.11 (m, 1H), {6.77 (d, J ¼ 16 Hz, 1H), 6.29
3
) d 8.45 (s, br, 1H, N–
85.0371.
(
1
ꢀ
1
(
3
1
3
d 7.70 (d, J ¼ 8 Hz, 1H), 7.40–7.37 (m, 1H, aromatic), 7.31 (dd, J (d, J ¼ 16 Hz, 1H), olenic}. C NMR (100 MHz, CDCl
8 Hz, 1H, aromatic), 7.29 (s, 1H, C –H), 7.23–7.16 (m, 5H,
), 134.8, 130.5, 128.6, (127.7, C ), (126.8, olenic), 126, 123.6,
aromatic), 7.15–7.10 (m, 1H, aromatic), {6.76 (d, J ¼ 16 Hz, 1H), 122.1, 121.5, (119.9, olenic), 119.2, 118.8, 118.5, 110.6, (101.2,
3
) d (135.2,
¼
1
C
8
1
1
3
+
6
(
1
.28 (d, J ¼ 16 Hz, 1H) olenic}, 3.85 (s, 3H, N–Me). C NMR C–S). HRMS (ESI) m/z [M + H] calculated for C16
100 MHz, CDCl ) d 137.3, 137, (133.9, C
), 129.5, 128.7, 128.5, (286.0379), found 286.0371.
27.1, (126.6, olenic), 125.9, 125.5, 122.5, 120.4, (119.7,
(E)-3-((2-(Naphthalen-2-yl)vinyl)thio)-1H-indole (4d). Brown
H13NSCl
3
1
+
1
olenic), 109.7, 100.5, (33.1, N–Me). HRMS (ESI) m/z [M + H]
sticky solid (75.8 mg, 63%), H NMR (400 MHz, CDCl
br, 1H, N–H), 7.70 (d, J ¼ 8 Hz, 1H), 7.45–7.42 (m, 2H), 7.28 (t, J
–H), 7.09–
solid, (74.4 mg, 74%), mp 161–162 C; H NMR (400 MHz, 7.06 (m, 2H), {6.75 (d, J ¼ 16 Hz, 1H), 6.19 (d, J ¼ 16 Hz, 1H),
3
) d 8.41 (s,
calculated for C H NS (266.1003), found 266.0994.
1
7
16
(
E)-5-(Benzyloxy)-3-(styrylthio)-1H-indole (3m). Light yellow ¼ 8 Hz, 2H), 7.23–7.16 (m, 5H, aromatic including C
1
ꢀ
1
1
3
CDCl
3
) d 8.33 (s, br, 1H, N–H), 7.47–7.41 (m, 4H, aromatic), olenic}. Proposed C NMR (100 MHz, CDCl
) d 136.9, 134.5,
3
7
7
.35–7.30 (m, 4H, aromatic), 7.24–7.16 (m, 5H, aromatic, C
1
–H), 130.8, 128.7, 127.4, 127.3, 127.2, 127.1, 127.08, 127, 126.9, 126.6,
+
.0 (dd, J ¼ 8 Hz, 1H, aromatic), {6.75 (d, J ¼ 16 Hz, 1H), 6.26 (d, 126.5, 119.7, 114.8, 113.2, 102.5. HRMS (ESI) m/z [M + H]
1
3
J ¼ 16 Hz, 1H) olenic}, 5.10 (s, 2H, –OCH ). C NMR (100 MHz, calculated for C20
H16NS (302.0925), found 302.0922.
2
CDCl ) d (154.2, C–OCH Ph), (137.3, C ), 136.9, 131.4, 130.2,
3
2
1
1
29.6, 128.7, 128.5, 128.47, 128.3, 127.8, 127.7, 126.7, 126.6,
4
. Conclusion
(126, olenic), 125.6, (114.2, olenic), 112.4, 102.2, 70.7. HRMS
+
(
3
ESI) m/z [M + H] calculated for C23
58.1259.
H
20NOS (358.1260), found In conclusion, we have demonstrated an easy and efficient
method for the synthesis of various substituted (E)-styryl thio-
(
E)-5-Methoxy-3-(styrylthio)-1H-indole (3n). Yellow solid, indoles by a TBAI-catalyzed sulfenylation reaction with b-(E)-
ꢀ
1
(
81.4 mg, 81%), mp 138–139 C; H NMR (400 MHz, CDCl
3
)
styrene sulfonyl hydrazides via a radical cross-coupling reaction
d 8.35 (s, br, N–H), 7.44–7.35 (m, 2H, aromatic), 7.31 (d, J ¼ 8 Hz, in moderate to high yields with excellent stereoselectivity. The
1
7
H, aromatic), 7.22 (s, 1H, aromatic), 7.20 (s, 1H, indole C–H), substituted b-(E)-styrene sulfonyl hydrazide precursors are
.19–7.12 (m, 3H, aromatic), 6.92 (dd, J ¼ 8 Hz, 1H, aromatic), easily accessible from simple and inexpensive starting mate-
rials. The current study paves the way for the use of b-(E)-styrene
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15616 | RSC Adv., 2021, 11, 15608–15616
© 2021 The Author(s). Published by the Royal Society of Chemistry