Catalytic Synthesis of 3-Thioindoles Using Bunte Salts as Sulfur Sources under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.6b00636

An efficient catalytic method for the synthesis of 3-thioindoles has been successfully developed, which uses odorless, stable, readily available crystalline Bunte salts as the sulfenylating agents, iodine as nonmetallic catalyst, and DMSO as both the oxid

Full text of DOI:10.1021/acs.joc.6b00636

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Article
Catalytic Synthesis of 3-Thioindoles Using Bunte
Salts as Sulfur Sources under Metal-Free Conditions
Hong Qi, Tongxin Zhang, Kefeng Wan, and Meiming Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00636 • Publication Date (Web): 27 Apr 2016
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Catalytic Synthesis of 3-Thioindoles Using Bunte Salts as Sulfur
Sources under Metal-Free Conditions
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Hong Qi,† Tongxin Zhang,*,‡ Kefeng Wan,† Meiming Luo*,†
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†
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of
China.
‡ School of Pharmacy, Liaocheng University, Liaocheng 252000, Shandong, People’s
Republic of China.
Fax: (+86)ꢀ28ꢀ85462021; Tel: (+86)ꢀ28ꢀ85462021; eꢀmail: luomm@scu.edu.cn
xintongzhang123@163.com
,
TOC Graphic
Abstract
An efficient catalytic method for the synthesis of 3ꢀthioindoles has been successfully
developed, which uses odorless, stable, readily available crystalline Bunte salts as the
sulfenylating agents, iodine as nonmetallic catalyst, DMSO as both the oxidant and
solvent. This method is practical and environmentally benign in terms of sulfur
sources, catalyst and solvent. The catalytic reaction is selective at C3 position of
indoles, and compatible with a wide range of substrates giving the desired products in
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good to excellent yields.
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Introduction
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The substituted indoles are prevalent in numerous natural products and are important
in medicinal chemistry.1 Among numerous indole derivatives known, 3ꢀthioindoles
have attracted considerable attentions due to their therapeutic values. As for the
treatment of HIV,2 cancer,3 obesity,4 heart disease5 and allergies,6 3ꢀthioindoleꢀbased
medicines have exhibited excellent activities. Besides, they also show potent activities
such as inhibitor of tubulin polymerization and cell growth.7
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There has been longꢀstanding interest in the development of efficient methods for the
synthesis of 3ꢀthioindoles and a number of different strategies have been developed.8
To date, despite a few electrophilic cyclization methods were reported which
employed
less
commonly
available
oꢀalkynylanilines
or
2ꢀ(gemꢀdibromo(chloro)vinyl)anilines as starting material,9 the direct sulfenylation of
indole core by using electrophilic sulfenylating agents is the major route to
3ꢀthioindoles. The most widely used sulfenylating reagents are thiols,10 disulfides,11
and sulfenyl halides.12 Nevertheless, in the view of green chemistry, disadvantages
encountered in those methods should be addressed: (1) thiols are repulsiveꢀsmelling
and frequently require large amount of strong bases and/or metal catalysts to promote
the reaction; (2) disulfides are prepared from smelly thiols; (3) most of the sulfenyl
halides (especially sulfenyl iodides) are really unstable compounds, and the formation
of sulfenyl halides requires toxic and hard to handle chlorine (or bromine) and thiols.
Other sulfenylating agents have also been reported, such as quinone
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monoꢀO,Sꢀacetals,13 Nꢀ(arylthio)phthalimides,14 arylsulfonyl chlorides,15 arylsulfonyl
cyanides,16 sodium sulfinates17 and sulfonyl hydrazides.18 However, many of those
sulfenylating agents are complicated, expensive or airꢀ and waterꢀsensitive, and some
of them need excess of reductants. Thus, developing a green and generally efficient
method for the C3 sulfenylation of indole core, which uses odorless, stable and
readily available sulfur sources and nonmetallic catalyst, is challenging and highly
desirable.
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Bunte salts (RSSO3Na) are stable, easy to handle crystalline solidꢀsalts and generally
have little or no odor.19 In addition to traditional synthetic methods starting from
thiols,20 Bunte salts can also be conveniently prepared by the reaction of odorless and
inexpensive sodium thiosulfate with various alkyl halides,21 aryl halides,22 alkenes,23
and aromatic thiocyanates.24 It was reported that Bunte salts reacted with iodine to
generate electrophilic sulfenyl iodide (RSI) species25 which was known to undergo
sulfenylation reaction of indoles with concomitant formation of HI.11b, 11d, 17a On the
other hand, iodide anions are readily oxidized to iodine by dimethyl sulfoxide (DMSO)
in the presence of an acid.26 Thus, we surmised that a catalytic route to 3ꢀthioindoles
might be designed by using Bunte salts as environmental benign sulfur sources,22
iodine as nonmetalic catalyst, and DMSO as both the oxidant and solvent (Scheme 1).
Moreover, additional advantage can be found by using DMSO as solvent since it has
been claimed as a green solvent suitable for replacing toxic solvents due to its high
boiling point, a very low vapor pressure (0.6 mmHg at 25 °C), and ready
biodegradability.27 DMSO has been also classified as a nontoxic solvent with no risk
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to human health by the U.S. Environmental Protection Agency (EPA).28 In the
designed catalysis, Bunte salts may react with iodine to form sulfenyl iodide (RSI)
species which then undergoes electrophilic substitution with indole core to yield
3ꢀthioindole and HI. HI is then oxidized into iodine by DMSO to complete the
catalytic cycle (Scheme 1). Based on this proposed route, herein we report an efficient
method for the synthesis of 3ꢀthioindoles in DMSO by using Bunte salts as odorless,
stable and readily available sulfur sources and iodine as the nonmetallic catalyst.
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Scheme 1. Proposed Iodine-Catalyzed Synthesis of 3-Thioindoles Using Bunte
Salts as Sulfur Sources.
Results and Discussion
Initially, the reaction of 1Hꢀindole with sodium Sꢀ(3ꢀmethoxyphenyl)thiosulfate was
investigated in the presence of iodine as a model system to identify and optimize the
reaction parameters (Table 1). To our delight, when the reaction was carried out with
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iodine (10 mol%) in DMSO at ambient temperature, the desired product could be
formed in 45% yield (Table 1, entry 1). It was found that the reaction temperature
affected the product yield significantly. The product yield was improved to 82% with
the increasing of the reaction temperature to 80 °C (Table 1, entry 4). Higher
temperature (100 °C) did not improve the reaction yield further (Table 1, entry 5). The
influence of the amount of Bunte salt on the reaction was also examined. The results
showed that more than 1.5 eq. Bunte salt was not necessary for the best yield (Table 1,
entry 6). Then the catalyst loading was evaluated (Table 1, entries 8ꢀ10), the best
result was obtained in the presence of 20 mol% of iodine (Table 1, entry 10). Water
and ethanol were also explored as solvents (Table 10ꢀ12), and DMSO was found to be
the best. Thus, the optimized reaction conditions for the C3 sulfenylation reaction of
indoles involved using Bunte salt (1.5 eq.) as the sulfenylating agent, iodine (20 mol%)
as the catalyst, DMSO as both the oxidant and the solvent, and conducting the
reaction at 80 °C.
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Table 1. Optimization of the Reaction Conditionsa
Entry
I2 (mol%)
Solvent
DMSO
DMSO
DMSO
Temp ( oC)
2a (eq.)
Yield (%)
1
2
3
10
10
10
25
40
60
2
2
2
45
56
73
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10
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DMSO
DMSO
80
2
2
82
79
100
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6
7
10
10
10
5
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
80
80
80
80
80
80
80
80
1.5
1.2
1
83
76
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1.5
1.5
1.5
1.5
1.5
74
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13
20
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20
88
n.r.b
n.r.b
81c
Ethanol
DMSO
a Reaction conditions: 1Hꢀindole (0.4 mmol), sodium Sꢀ3ꢀmethoxyphenyl thiosulfate,
b
iodine, solvent (3 mL), Ar, 12 h.
5 eq DMSO was used as the oxidant in the
reaction, n.r. = no reaction. c The reaction was performed under air.
With the optimized reaction conditions in hand, we then evaluated the scope of the
reactions of sodium Sꢀ(3ꢀmethoxyphenyl)thiosulfate (2a) with various indole
derivatives. As shown in Table 2, indoles with electronꢀdonating methyl, phenyl and
methoxyl groups (Table 2, entries 1−6) gave higher yields compared to those having
electronꢀwithdrawing groups (Table 2, entries 7−16). Methyl group on different
positions of indole did not change the product yield significantly (Table 2, entries
1−4). The reaction is tolerant with fluoro, chloro and bromo substituents on the
aromatic ring of indole, and the corresponding target products were obtained in good
yields (75−82%; Table 2, entries 7−11). Indoles with strong electronꢀwithdrawing
nitryl and cyano groups needed longer time to finish the reaction and gave product
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yields of 70% and 71% respectively (Table 2, entries 12 and 13). Meanwhile,
probably due to additional steric hindrance, 1Hꢀindoleꢀ2ꢀcarboxylate gave a lower
yield of 66% and required longer reaction time (Table 2, entry 14) compared to its
5ꢀcarboxylate and 6ꢀcarboxylate isomers (Table 2, entries 15 and 16). The protocol
was also applied to 1Hꢀpyrrolo[2,3ꢀb]pyridine giving the desired product 3ra in 87%
yield (Table 2, entry 17).
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Table 2. Reaction of Sodium S-(3-Methoxyphenyl)thiosulfate with Various Indole
Derivatives a
Entry
1
Indole derivative
Product
Yield (%)
89
1b
3ba
S
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84
1c
OCH3
3ca
3da
CH3
N
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86
84
1e
1f
3ea
3fa
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90
82
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75
1g
1h
1i
3ga
3ha
3ia
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1j
3ja
3ka
3la
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1k
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70b
71b
1m
1n
3ma
3na
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66b
1o
1p
3oa
3pa
76
16
17
70
87
1q
1r
3qa
3ra
a
Reaction conditions: 1 (0.4 mmol), 2a (0.6 mmol), iodine (0.08 mmol), DMSO (3 mL),
80 °C, Ar, 12 h. b The reaction time was 16 h.
Subsequently, a range of Bunte salts was explored by reacting with 1Hꢀindole (1a),
and the results were listed in Table 3. Aromatic and aliphatic Bunte salts with a
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variety of substituents afforded the products in good to excellent yields under the
optimum reaction conditions. Aromatic Bunte salts bearing functional groups
including methoxyl, methyl, chloro, bromo, fluoro, nitryl, and trifluoromethyl
generated the desired products in good to excellent yields (Table 3, entries 1ꢀ8). It is
noteworthy that the method could apply to quinolineꢀbased Bunte salt, giving a good
yield of 70% (Table 3, entry 9). Aliphatic Bunte salts underwent the reaction more
quickly than aromatic Bunte salts, giving the desired product 3aj, 3ak and 3al in 85%,
86% and 74% yield respectively (Table 3, entries 10, 11 and 12).
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Table 3. Reaction of 1H-Indole with Various Bunte Saltsa
Entry
1
Bunte salt
Product
Yield (%)
88
2a
2b
2c
3aa
3ab
3ac
2
3
84
88
CH3
S
N
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90
92
82
77
2d
2e
2f
3ad
3ae
3af
3ag
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2g
8
9
78
70
2h
2i
3ah
3ai
10
11
12
2j
2k
2l
3aj
3ak
3al
85b
86b
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a
Reaction conditions: 1a (0.4 mmol), 2 (0.6 mmol), iodine (0.08 mmol), DMSO (3 mL),
5
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80 °C, Ar, 12 h. b Reaction time: 2 h. c Reaction time: 4 h.
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Methyl 5ꢀmethoxyꢀ3ꢀ((3,4,5ꢀtrimethoxyphenyl)thio)ꢀ1Hꢀindoleꢀ2ꢀcarboxylate, which
is known as a potent inhibitor of tublin polymerization7 and showing excellent
antitumor activities,3a,3b was synthesized previously in literature in a very low yield of
4% using malodorous thiol as the sulfur source.29 Notably, using our method as shown
in Scheme 2, this compound was successfully prepared in a good yield of 67% on a 2
mmol scale.
Scheme 2. Synthesis of Methyl 5-Methoxy-3-((3,4,5-trimethoxyphenyl)thio)-
1H-indole-2-carboxylate.
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Conclusions
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In summary, we have designed and successfully developed an efficient catalytic
method for the synthesis of 3ꢀthioindoles. This protocol displays attractive features
including using odorless, stable, readily available and environmentꢀfriendly Bunte
salts as the sulfenylating agents, using iodine as nonmetallic catalyst, employing
DMSO as the oxidant and the solvent. The reaction is compatible with a wide range of
functional groups. In particular, it is successfully applied to prepare methyl
5ꢀmethoxyꢀ3ꢀ((3,4,5ꢀtrimethoxyphenyl)thio)ꢀ1Hꢀindoleꢀ2ꢀ carboxylate in good yield.
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Experimental Section
General. Unless otherwise noted, all reagents were obtained from commercial
suppliers and used without further purification. Bunte salts were prepared according
to the literature.21,22,24 Column chromatography was performed with silica gel (200–
300 mesh). Thin layer chromatography was carried out using silica gel GF254 plates.
Highꢀresolution mass spectra (HRMS) were obtained with a QꢀTOF Premier (ESI). 1H
13
NMR and C NMR spectra were recorded on a 400 MHz NMR instrument. Spectra
were reported relative to Me4Si (δ 0.0 ppm), CDCl3 (δ 7.26 ppm), and DMSOꢀd6 (δ
13
2.50 ppm). C NMR were reported relative to CDCl3 (δ 77.0 ppm) and DMSOꢀd6 (δ
39.5 ppm). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet;
1
m, multiplet. Products were characterized by comparison of H and 13C NMR
spectroscopic data with those available in the literature. Melting points were
determined with a melting point apparatus and uncorrected.
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General Procedure for the Synthesis of 3-Thioindoles. A tube with a magnetic
stirring bar was charged with indoles (0.4 mmol) and Bunte salts (0.6 mmol) under an
argon atmosphere. Then the DMSO (3 mL) solution containing iodine (0.08 mmol)
was injected into the tube. The mixture was allowed to react in the sealed tube at
80 °C for the required time. The mixture was then cooled to room temperature, diluted
with 30 mL saturated Na2S2O3 (aq.), and extracted with CH2Cl2 (4 × 20 mL). The
organic phase was washed with water (2 × 40 mL), then dried and concentrated in
vacuo. The residue was further purified by a short flash chromatography on a silica
gel column to afford the pure product.
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1-Methyl-3-((3-methoxyphenyl)thio)-1H-indole (3ba). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
white solid (96 mg, 89%). Mp: 117ꢀ118 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 7.62
(d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H),
7.17 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.66ꢀ6.70 (m, 2H), 6.58ꢀ6.61
(m,1H), 3.85 (s, 3H), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 159.9, 141.4,
137.7, 134.8, 130.0, 129.6, 122.7, 120.6, 119.8, 118.2, 110.6, 110.3, 109.8, 100.4, 55.3,
33.3. HRMS (ESI): m/z calcd for C16H16NOS [M + H]+, 270.0953; found, 270.0956.
2-Methyl-3-((3-Methoxyphenyl)thio)-1H-indole30 (3ca). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
0
1
white solid (93 mg, 86%). Mp: 73ꢀ75 C. H NMR (CDCl3, 400 MHz, ppm): δ 8.25
(br s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 6.8 Hz, 1H),
7.13 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.58ꢀ6.64 (m, 3H). 3.66 (s, 3H),
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2.51 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 159.5, 141.4, 141.1, 135.5, 130.3,
129.7, 122.2, 120.8, 119.0, 118.0, 111.3, 110.8, 110.0, 55.1, 12.0. HRMS (ESI): m/z
calcd for C16H16NOS [M + H]+, 270.0953; found, 270.0955.
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5-Methyl-3-((3-methoxyphenyl)thio)-1H-indole (3da). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
white solid (91 mg, 84%). Mp: 106ꢀ107 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.34
(br s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.08 (t, J =
7.6 Hz, 2H), 6.67ꢀ6.69 (m, 2H), 6.59 (m, 1H), 3.70 (s, 3H), 2.42 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm): δ 160.0, 141.1, 134.8, 131.1, 130.5, 129.7, 129.5, 124.8,
119.2, 117.8, 111.4, 111.4, 110.3, 101.6, 51.2, 21.3. HRMS (ESI): m/z calcd for
C16H16NOS [M + H]+, 270.0953.; found, 270.0956.
7-Methyl-3-((3-methoxyphenyl)thio)-1H-indole (3ea). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded
colorless oil (93 mg, 86%). 1H NMR (CDCl3, 400 MHz, ppm): δ 8.36 (br s, 1H), 7.48
(d, J = 2.8 Hz, 2H), 7.06ꢀ7.12 (m, 3H), 6.68ꢀ6.70 (m, 2H), 6.59ꢀ6.62 (m, 1H), 3.69 (s,
3H), 2.53 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0, 141.0, 136.1, 130.6,
129.6, 128.8, 123.7, 121.2, 120.9, 118.3, 117.4, 111.6, 110.3, 102.9, 55.3, 16.5.
HRMS (ESI): m/z calcd for C16H16NOS [M + H]+, 270.0953.; found, 270.0956.
2-Phenyl-3-((3-methoxyphenyl)thio)-1H-indole30 (3fa). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
1
white solid (111 mg, 84%). Mp: 112ꢀ114 0C. H NMR (CDCl3, 400 MHz, ppm): δ
8.55 (br s, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.37ꢀ7.45 (m, 4H),
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7.28ꢀ7.30 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H),
6.68ꢀ6.71 (m, 2H), 6.61 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 3.68 (s, 3H). 13C NMR (CDCl3,
100 MHz, ppm): δ 160.0, 142.2, 140.9, 135.8, 131.5, 131.3, 129.8, 128.9, 128.8,
128.2, 123.5, 121.3, 120.0, 118.1, 111.3, 110.3, 99.2, 55.1. HRMS (ESI): m/z calcd
for C21H18NOS [M + H]+, 332.1109; found, 332.1106.
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5-Methoxy-3-((3-methoxyphenyl)thio)-1H-indole (3ga). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded
yellow oil (103 mg, 90%). 1H NMR (CDCl3, 400 MHz, ppm): δ 8.41 (s, 1H), 7.42 (d,
J = 2.8 Hz, 1H), 7.29 (t, J = 8.8 Hz, 1H), 7.07ꢀ7.13 (m, 2H), 6.92 (dd, J = 2.4 Hz, 8.8
Hz, 1H), 6.68 ꢀ6.72 (m, 2H), 6.63 (dd, J = 2.4 Hz, 8.8 Hz, 1H). 3.80 (s, 3H), 3.70 (s,
3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0, 155.2, 141.1, 131.6, 131.5, 130.1,
129.7, 118.1, 113.7, 111.4, 110.3, 101.9, 1008.8, 55.9, 55.3. HRMS (ESI): m/z calcd
for C16H16NO2S [M + H]+, 286.0902; found, 286.0904.
5-Fluoro-3-((3-methoxyphenyl)thio)-1H-indole (3ha). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded
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colorless oil (90 mg, 82%). H NMR (CDCl3, 400MHz, ppm): δ 8.44 (br s, 1H), 7.49
(d, J = 2.4 Hz, 1H), 7.32 (dd, J = 4.4 Hz, 8.8 Hz, 1H), 7.25ꢀ7.28 (m, 1H), 7.08ꢀ7.12
(m, 1H), 7.02 (dt, J = 2.4 Hz, 8.8 Hz, 1H), 6.66ꢀ6.68 (m ,1H), 6.60ꢀ6.62 (m, 2H), 3.70
(s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0, 158.7 (d, J = 235.4 Hz), 140.5,
133.0, 132.6, 130.0 (d, J = 10.0 Hz), 129.8, 118.4, 112.6 (d, J = 9.5 Hz), 111.8, 111.7
(d, J = 26.4 Hz), 110.5, 104.7 (d, J = 24.1 Hz), 102.8 (d, J = 4.7 Hz), 55.3. HRMS
(ESI): m/z calcd for C15H13FNOS [M + H]+, 274.0702; found, 274..0706.
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5-Chloro-3-((3-methoxyphenyl)thio)-1H-indole (3ia). Purification by column
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chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
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white solid (92 mg, 79%). MP: 87ꢀ88 C. H NMR (CDCl3, 400MHz, ppm): δ 8.48
(br s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H),
7.20 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.09ꢀ7.14 (m, 1H), 6.69ꢀ6.71 (m, 1H), 6.63ꢀ6.65 (m,
2H). 3.71 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0, 140.4, 134.9, 132.3,
130.4, 129.8, 127.0, 123.6, 119.1, 118.4, 112.8, 111.8, 110.4, 102.4, 55.3. HRMS
(ESI): m/z calcd for C15H12ClNOS [M + H]+, 290.0406; found, 290.0409.
6-Chloro-3-((3-methoxyphenyl)thio)-1H-indole (3ja). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded
colorless oil (90 mg, 78%). 1H NMR (CDCl3, 400 MHz, ppm): δ 8.43 (br s, 1H), 7.51
(d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.08ꢀ7.14 (m,
2H), 6.62ꢀ6.71 (m, 3H), 3.7 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0,
140.4, 136.9, 131.4, 129.8, 129.1, 127.8, 121.8, 120.7, 118.4, 111.8, 111.7, 110.5,
103.1, 55.3. HRMS (ESI): m/z calcd for C15H13ClNOS [M + H]+, 290.0406; found,
290.0404.
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4-Bromo-3-((3-methoxyphenyl)thio)-1H-indole (3ka). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
0
1
white solid (102 mg, 76%). Mp: 144ꢀ146 C. H NMR (CDCl3, 400 MHz, ppm): δ
8.52 (br s, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz,
1H), 7.12 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.61ꢀ6.69 (m, 3H). 3.70 (s,
3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 159.9, 142.7, 142.6, 137.8, 133.4, 126.5,
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126.3, 126.1, 124.1, 118.4, 114.7, 111.7, 111.2, 110.2, 103.5, 55.3. HRMS (ESI): m/z
calcd for C15H13BrNOS [M + H]+, 333.9901; found, 333.9905.
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5-Bromo-3-((3-methoxyphenyl)thio)-1H-indole (3la). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
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white solid (100 mg, 75%). Mp: 101ꢀ102 C. H NMR (CDCl3, 400 MHz, ppm): δ
8.48 (s, 1H), 7.76 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.29ꢀ7.36 (m, 2H), 7.10 (t, J = 8.4
Hz, 1H), 6.62ꢀ6.68 (m, 3H), 3.70 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.0,
142.0, 135.2, 132.1, 131.0, 129.8, 126.1, 122.2, 118.3, 114.6, 113.2, 111.8, 110.5,
102.4, 55.3. HRMS (ESI): m/z calcd for C15H13BrNOS [M + H]+, 333.9901; found,
333.9904.
5-Nitro-3-((3-methoxyphenyl)thio)-1H-indole (3ma). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v) afforded a
0
1
yellow solid (84 mg, 70%). Mp: 140ꢀ141 C. H NMR (CDCl3, 400 MHz, ppm): δ
8.89 (br s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.65ꢀ7.66
(d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.09ꢀ7.14 (m, 1H), 6.69ꢀ6.71 (m, 1H),
6.64ꢀ6.66 (m, 2H), 3.71 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.1, 142.8,
139.5, 139.3, 134.0, 129.9, 129.0, 118.9, 118.8, 117.0, 112.4, 112.1, 110.9, 106.3, 55.2.
HRMS (ESI): m/z calcd for C15H13N2O3S [M + H]+, 301.0647; found, 301.0645.
3-((3-Methoxyphenyl)thio)-1H-indole-5-carbonitrile (3na). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v) afforded a
white solid (80 mg, 71%). Mp: 137ꢀ138 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 9.0
(br s, 1H), 7.96 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.46ꢀ7.52 (m, 2H), 7.12 (t, J = 8.0
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Hz, 1H), 6.61ꢀ6.69 (m, 3H), 3.71 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 159.9,
139.5, 138.4, 133.0, 129.9, 129.1, 126.1, 125.4, 120.4, 118.7, 112.7, 112.1, 110.6,
104.5, 55.2. HRMS (ESI): m/z calcd for C16H13N2OS [M + H]+, 281.0749; found,
281.0746.
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Methyl 3-((3-methoxyphenyl)thio)-1H-indole-2-carboxylate 31 (3oa). Purification by
column chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v)
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afforded a white solid (83 mg, 66%). Mp: 154ꢀ155 C. H NMR (CDCl3, 400 MHz,
ppm): δ 9.30 (br s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (t, J =
8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.73ꢀ6.76 (m, 2H),
6.64 (dd, J = 2.4 Hz, 8.0 Hz, 1H), 3.94 (s, 3H), 3.69 (s, 3H). 13C NMR (CDCl3, 100
MHz, ppm): δ 161.9, 159.9, 139.1, 135.9, 130.0, 129.7, 128.7, 126.4, 121.9, 121.7,
119.8, 113.0, 112.2, 111.1, 110.5, 55.3, 52.4. HRMS (ESI): m/z calcd for C17H16NO3S
[M + H]+, 314.0851; found, 314.0855.
Methyl 3-((3-methoxyphenyl)thio)-1H-indole-5-carboxylate (3pa). Purification by
column chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v)
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afforded a yellow solid (95 mg, 76%). Mp: 124ꢀ126 C. H NMR (CDCl3, 400 MHz,
ppm): δ 8.67 (br s, 1H), 8.39 (s, 1H), 7.98 (dd, J = 1.4 Hz, 8.4 Hz, 1H), 7.56 (d, J =
2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.09 (t, J = 8.8 Hz, 1H), 6.68 (d, J = 7.6 Hz,
1H), 6.60ꢀ6.64 (m, 2H). 3.81 (s, 3H), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm):
δ 168.0, 159.9, 140.4, 139.1, 132.3, 129.6, 128.9, 124.5, 123.1, 122.4, 118.3, 111.7,
111.4, 104.4, 55.2, 52.0. HRMS (ESI): m/z calcd for C17H16NO3S [M + H]+, 314.0851;
found, 314.0854.
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Methyl 3-((3-methoxyphenyl)thio)-1H-indole-6-carboxylate (3qa). Purification by
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column chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v)
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afforded a white solid (88 mg, 70%). Mp: 130ꢀ131 C. H NMR (CDCl3, 400 MHz,
ppm): δ 8.74 (br s, 1H), 8.21 (s, 1H), 7.85 (dd, J = 1.2 Hz, 8.4 Hz, 1H), 7.63ꢀ7.65 (m,
2H), 7.07ꢀ7.11 (m, 1H), 6.60ꢀ6.68 (m, 3H), 3.94 (s, 3H), 3.68 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm): δ 168.0, 160.0, 140.3, 136.0, 134.0, 133.0, 129.8, 125.0,
122.1, 119.5, 118.4, 114.2, 111.8, 110.6, 103.5, 54.8, 52.0. HRMS (ESI): m/z calcd for
C17H16NO3S [M + H]+, 314.0851; found, 314.0850.
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3-((3-Methoxyphenyl)thio)-1H-pyrrolo[2,3-b]pyridine (3ra). Purification by
column chromatography on silica gel (petroleum ether/diethyl ether = 10:1, v/v)
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afforded a white solid (89 mg, 87%). Mp: 165ꢀ166 C. H NMR (CDCl3, 400 MHz,
ppm): δ 11.68 ( br s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 7.97 (dd, J = 1.6 Hz, 7.6 Hz, 1H),
7.71 (d, J = 4.4 Hz, 1H), 7.17 (dd, J = 4.8 Hz, 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H),
6.68ꢀ6.71 (m, 1H), 6.61ꢀ6.66 (m, 2H), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz,
ppm): δ 160.1, 149.4, 143.3, 140.5, 132.3, 129.7, 128.7, 122.4, 118.4, 116.9, 111.7,
110.7, 101.1, 55.3. HRMS (ESI): m/z calcd for C14H13N2OS [M + H]+, 257.0749;
found, 257.0746.
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3-((3-Methoxyphenyl)thio)-1H-indole
(3aa). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
0
1
white solid (90 mg, 88%). Mp: 88ꢀ90 C. H NMR (CDCl3, 400 MHz, ppm): δ 8.42
(br s,1H), 7.63 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 2.8. Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H),
7.27ꢀ7.29 (m, 1H), 7.16ꢀ7.20 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.68ꢀ6.72 (m, 2H),
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6.61ꢀ6.63 (m, 1H), 3.69 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 159.9, 140.9,
136.5, 129.7, 129.2, 123.2, 121.1, 119.7, 118.3, 110.7, 110.6, 110.4, 102.6, 55.3.
HRMS (ESI): m/z calcd for C15H14NOS [M + H]+, 256.0796; found, 256.0798
3-(Phenylthio)-1H-indole33(3ab). Purification by column chromatography on silica
gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a white solid (76 mg, 84%). Mp:
152ꢀ153 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.37 (br s , 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.48 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.27ꢀ7.31 (m,1H), 7.05ꢀ7.20
(m, 6H). 13C NMR(CDCl3, 100 MHz, ppm): δ 139.3, 136.6, 130.8, 129.8, 128.8,
126.0, 124.7, 123.2, 121.0, 119.8, 111.7, 102.9. HRMS (ESI): m/z calcd for C14H12NS
[M + H]+, 226.0690; found, 226.0693.
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3-(p-Tolylthio)-1H-indole33 (3ac). Purification by column chromatography on silica
gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a white solid (95 mg, 88%). Mp:
124ꢀ126 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.35 (br s 1H), 7.63 (d, J = 8.0 Hz,
1H), 7.47 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.25ꢀ7.29 (m, 1H), 7.17 (t, J = 7.6 Hz,1H),
7.04 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H). 2.26 (s, 3H) 13C NMR (CDCl3, 100
MHz, ppm): δ 136.5, 135.6, 134.8, 130.6, 129.6, 129.2, 126.4, 123.1, 120.9, 119.8,
111.7, 21.0. HRMS (ESI): m/z calcd for C15H14NS [M + H]+, 240.0847; found,
240.0845.
3-((4-Chlorophenyl)thio)-1H-indole33
(3ad).
Purification
by
column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
0
white solid (103 mg, 90%). Mp: 130ꢀ131 C.1H NMR (CDCl3, 400 MHz, ppm): δ
8.44 (br s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 2.8 Hz, 1H), 7.45 (d, J = 8.0 Hz,
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1H), 7.29 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.11ꢀ7.14 (m, 2H), 7.01ꢀ7.04
(m, 2H). 13C NMR (CDCl3, 100 MHz, ppm): δ 137.9, 136.6, 130.8, 130.7, 128.9,
127.2, 123.3, 121.2, 119.6, 111.8, 102.6. HRMS (ESI): m/z calcd for C14H11ClNS [M
+ H]+, 260.0301; found, 260.0304.
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3-((4-Bromophenyl)thio)-1H-indole33
(3ae).
Purification
by
column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a
0
1
white solid (123 mg, 92%). Mp: 142ꢀ144 C. H NMR (CDCl3, 400 MHz, ppm): δ
8.36 (br s 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 7.40 (d, J = 8.0
Hz,1H), 7.20ꢀ7.24 (m, 3H), 7.14 (t, J = 8.0 Hz,1H), 6.90ꢀ6.93 (m,2H). 13C NMR
(CDCl3, 100 MHz, ppm): δ 138.7, 136.6, 131.8, 130.9, 129.0, 127.5, 123.4, 121.2,
119.6, 118.4, 111.8, 102.4. HRMS (ESI): m/z calcd for C14H11BrNS [M + H]+,
303.9796; found, 303.9799.
3-((3-Nitrophenyl)thio)-1H-indole33 (3af). Purification by column chromatography
on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded a white solid (98 mg,
82%). Mp: 136ꢀ137 0C. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.5 (br s, 1H), 7.88ꢀ7.92
(m, 2H), 7.54ꢀ7.57 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz,1H), 7.30 (t,
J = 8.0 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz,ppm): δ 148.7,
142,7, 136.7, 131.5, 131.4, 129.4, 128.6, 123.6, 121.4, 120.3, 119.8, 119.3, 112.0,
100.9. HRMS (ESI): m/z calcd for C14H11N2O2S [M + H]+, 271.0541; found,
271.0543.
3-((4-(Trifluoromethyl)phenyl)thio)-1H-indole34 (3ag). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 2:1, v/v) afforded a
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white solid (90 mg, 77%). Mp: 130ꢀ132 0C. 1H NMR(CDCl3, 400 MHz, ppm): δ 8.51
(br s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H),
7.38 (d, J = 8.0 Hz, 2H), 7.28ꢀ7.33 (m, 1H), 7.18ꢀ7.21 (m, 1H), 7.14 (d, J = 8.0 Hz,
2H). 13CNMR (CDCl3, 100 MHz,ppm): δ 144.8, 136.7, 131.2, 128.9, 127.0, 126.8 (q,
32.4 Hz), 125.8 (q, J = 3.7 Hz), 124.4 (q, J = 269.9 Hz), 123.5, 121.4, 119.5, 111.9,
101.3. HRMS (ESI): m/z calcd for C15H11F3NS [M + H]+, 294.0564; found, 294.0566.
3-((2-Methyl-4-fluoro-pheny)thio)-1H-indole (3ah). Purification by column
chromatography on silica gel (petroleum ether/diethyl ether = 4:1, v/v) afforded
yellow oil (80 mg, 78%). 1H NMR (CDCl3, 400 MHz, ppm): δ 8.51（br s, 1H), 7.57 (d,
J = 8.0 Hz, 1H), 7.46ꢀ7.50 (m, 2H), 7.29 (m, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H),
7.05ꢀ7.08 (m,1H), 6.65 (dt, J = 2.8 Hz, 8.4 Hz,1H), 6.37 (dd, J = 2.8 Hz, 10.0 Hz, 1H),
2.44 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 161.8 (d, J = 242.5 Hz), 140.9 (d,
J = 7.6 Hz), 136.7, 131.2, 130.9 (d, J = 8 Hz), 129.6 (d, J = 3 Hz), 129.0, 123.4, 121.3,
119.6, 112.0, 111.8, 111.7, 111.1 (d, J = 21.3 Hz), 101.5, 19.2. HRMS (ESI): m/z
calcd for C15H13FNS [M + H]+, 258.0753; found, 258.0756.
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3-(3-Quinolinylthio)-1H-indole (3ai). Purification by column chromatography on
silica gel (petroleum ether/diethyl ether = 2:1, v/v) afforded a yellow solid (77 mg,
0
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70%). Mp: 196ꢀ198 C. H NMR (DMSOꢀd6, 400 MHz, ppm): δ 11.84 (s, 1H), 8.67
(br s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64 (t, J =
7.2 Hz, 1H), 7.48ꢀ7.54 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H),
7.06 (t, J = 7.2 Hz, 1H). 13C NMR (DMSOꢀd6, 100 MHz, ppm): δ 148.6, 145.4, 136.8,
133.1, 132.8, 130.9, 128.8, 128.7, 128.3, 127.8, 127.3, 127.1, 122.4, 120.4, 118.1,
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112.6, 97.8. HRMS (ESI): m/z calcd for C17H13N2S [M + H]+, 277.0799; found,
277.0795.
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3-(n-Butylthio)-1H-indole35 (3aj). Purification by column chromatography on silica
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gel (petroleum ether/diethyl ether = 10:1, v/v) afforded yellow oil (70 mg, 85%). H
NMR (DMSOꢀd6, 400 MHz, ppm): δ 11.35 (br s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49
(d, J = 2.4 Hz,1H), 7.42 (d, J = 8.0 Hz, 1H), 7.07ꢀ7.15 (m, 2H), 2.63 (t, J = 6.8 Hz,
2H), 1.32ꢀ1.48 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H). 13C NMR (DMSOꢀd6, 100 MHz,
ppm): δ 136.3, 129.6, 129.4, 122.7, 120.5, 119.5, 111.6, 106.2, 36.2, 32.1, 21.8, 13.8.
HRMS (ESI): m/z calcd for C12H16NS [M + H]+, 206.1003; found, 206.1007.
3-(n-Octanylthio)-1H-indole33 (3ak). Purification by column chromatography on
silica gel (petroleum ether/diethyl ether = 10:1, v/v) afforded yellow oil (90 mg, 86%).
1H NMR(CDCl3, 400 MHz, ppm): δ 8.22 (br s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.39 (d,
J = 8.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.19ꢀ7.25 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H),
1.24ꢀ1.40 (m,12H), 0.87 (t, J = 6.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ
136.4, 129.5, 129.3, 122.7, 120.5, 119.5, 106.3, 36.5, 31.9, 30.0, 29.3, 28.7, 20.6, 14.2.
HRMS (ESI): m/z calcd for C16H24NS [M + H]+, 262.1629; found, 262.1627.
Ethyl 2-((1H-indol-3-yl)thio)acetate (3al). Purification by column chromatography
on silica gel (petroleum ether/diethyl ether = 10:1, v/v) afforded yellow oil (70 mg,
1
74%). H NMR(CDCl3, 400 MHz, ppm): δ 8.41 (br s, 1H), 7.76 (d, J = 7.2 Hz, 1H),
7.37ꢀ7.39 (m, 2H), 7.20ꢀ7.25 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.41(s, 2H), 1.16 (t, J
= 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz, ppm): δ 170.7, 136.2, 130.5, 129.1,
123.0, 120.8, 119.2, 111.7, 104.6, 61.38, 39.0, 14.2. HRMS (ESI): m/z calcd for
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C12H14NO2S [M + H]+, 236.0745; found, 236.0743.
Synthesis of Methyl 5-Methoxy-3-((3,4,5-trimethoxyphenyl)thio)-
7
8
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1H-indole-2-carboxylate. A tube with a magnetic stirring bar was charged with
methyl 5ꢀmethoxyꢀ1Hꢀindoleꢀ2ꢀcarboxylate (2 mmol, 410 mg) and sodium
Sꢀ(3,4,5ꢀtrimethoxyphenyl)thiosulfate (3 mmol, 907 mg) under an argon atmosphere.
Then the DMSO (15 mL) solution containing iodine (0.4 mmol, 101.6 mg) was
injected into the tube. The mixture was allowed to react in the sealed tube at 80 °C for
16 h. The mixture was then cooled to room temperature, diluted with 150 mL
saturated Na2S2O3 (aq.), and extracted with CH2Cl2 (4 × 100 mL). The organic phase
was washed with water (2 × 100 mL), then dried and concentrated in vacuo. The
residue was further purified by column chromatography on silica gel (petroleum
ether/ether = 2:1, v/v) to afford methyl 5ꢀmethoxyꢀ3ꢀ((3,4,5ꢀtrimethoxyphenyl)thio)ꢀ
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1Hꢀindoleꢀ2ꢀcarboxylate29 as a white solid in 67% yield (541 mg). Mp: 150ꢀ152 C.
1H NMR (CDCl3, 400 MHz, ppm): δ 9.46 (br s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.00
(dd, J = 8.8 Hz, 2.4 Hz, 1H ), 6.92 (d, J = 2.4 Hz, 1H ), 6.47 (s, 2H), 3.94 (s, 3H), 3.78
(s, 3H), 3.73 (s, 3H), 3.67 (s, 6H). 13C NMR (CDCl3, 100 MHz, ppm): δ 160.8, 154.3,
152.5, 135.4, 131.3, 130.2, 129.4, 127.4, 117.2, 112.4, 109.3, 104.4, 100.3, 60.0, 55.2,
54.7, 51.3. HRMS (ESI): m/z calcd for C20H22NO6S [M + H]+, 404.1168; found,
404.1164.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation of China
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(21321061, 21072134 and J1103315/J0104) and the Shandong Provincial Natural
Science Foundation, China (ZR2015PB004) for financial support, and the
Comprehensive Training Platform of Specialized Laboratory, College of Chemistry,
Sichuan University for NMR and MS measurements.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at http://pubs.acs.org. 1H NMR and 13C NMR spectra of all products.
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