Iodine-PPh3-mediated C3-sulfenylation of indoles with sodium sulfinates

Article abstract of DOI:10.1039/c4ra02607a

3-(Alkylsulfanyl)- and 3-(arylsulfanyl)indoles were efficiently prepared by the reaction of indoles with sodium sulfinates mediated by iodine-PPh ₃ in ethanol. The salient features of the present protocol are simplicity, high efficiency, non-anhydrous conditions, environmentally friendly reagents and solvent, and short reaction time.

Full text of DOI:10.1039/c4ra02607a

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Iodine–PPh3-mediated C3-sulfenylation of indoles
with sodium sulfinates†
Cite this: RSC Adv., 2014, 4, 18933
Praewpan Katrun,a Sakchai Hongthong,a Sornsiri Hlekhlai,a Manat Pohmakotr,a
Vichai Reutrakul, Darunee Soorukram, Thaworn Jaipetch and Chutima Kuhakarn
a
a
b
a
*
Received 25th March 2014
Accepted 6th April 2014
3-(Alkylsulfanyl)- and 3-(arylsulfanyl)indoles were efficiently prepared by the reaction of indoles with
sodium sulfinates mediated by iodine–PPh3 in ethanol. The salient features of the present protocol are
simplicity, high efficiency, non-anhydrous conditions, environmentally friendly reagents and solvent, and
short reaction time.
DOI: 10.1039/c4ra02607a
www.rsc.org/advances
Sulfur-containing organic molecules are important structural hydrazide.14 Although a number of synthetic approaches have
motifs in organic synthesis, organic materials, and pharma- been described for sulfenylation of indoles, they are oen found
ceutically important compounds.1 The unique properties derive impractical in view of expensive reagents, harsh reaction
from the enhanced physical and chemical features of the sulfur conditions, high reagent loadings, uncommon solvents,
atom. Therefore, introduction of sulfur moieties into organic unpleasant smell of reagents, requirement of inert atmosphere
molecules is an important process for organic materials and as well as long reaction time. Thus, it is still desirable to develop
drug development and other ne chemicals synthesis. In an alternative method that is improving the efficiency, mini-
particular, 3-sulfanylindoles are signicant class of compounds mizing the energy, cost, and chemical waste.
due to their potential uses as drugs in several disease areas
In continuation of our ongoing research dealing with the
(Fig. 1), for example, HIV,2 obesity,3 allergies,4 cancer5 and heart development of new methods for the synthesis of sulfur-con-
disease.6 Hence, the development of synthetic strategies that taining molecules,15 we have recently described an efficient
achieve an installation of the 3-(alkylsulfanyl)- or 3-(arylsulfanyl) regioselective C2 sulfonylation of indoles mediated by molec-
functionality into an indole substrate has been the subject of ular iodine.16 In our initial studies on the optimization of this
intense research efforts. A number of electrophilic sulfenylating reaction, the C3 sulfenylated indoles were isolated as competing
reagents are available for the preparation of 3-sulfanylindoles as products depending on the reaction conditions. Encouraged by
well as arylsulfanyl-substituted electron-rich arenes, including these results and on the basis of an unprecedented use of
reactions with disuldes,7 sulfonyl chlorides,8 sulfenyl sodium sulnates as sulfenylating agents, we therefore decided
chlorides,9 thiols,10 quinone mono-O,S-acetals,11 N-(arylthio) to examine these results in details. During our investigation and
phthalimide,12 arylsulfonyl cyanide,13 and recently sulfonyl preparation of the manuscript, an elegant publication by Deng
and co-workers on the use of sodium sulnates for C3 sulfe-
nylation of indoles catalyzed by molecular iodine appeared.17
This prompts us to report our own ndings. We report herein
that a range of indole derivatives readily undergo C3 sulfeny-
lation with sodium sulnates mediated by I2–PPh3 in reuxing
ethanol.
The reaction of indole (1a) with sodium p-toluenesulnate
(2a) was investigated to explore the optimal reaction conditions,
and the results are summarized in Table 1. Without the
requirement for moisture-free conditions, indole (1a) was
Fig. 1 Some biologically active 3-(arylsulfanyl)indoles.
treated with sodium p-toluenesulnate (2a, 2 equiv.), iodine (1
equiv.) and triphenylphosphine (2 equiv.) in reuxing
dichloromethane for 3 h. Much to our delight, the corre-
sponding product 3-(p-toluenesulfanyl)indole (3a) was obtained
in 67% yield (Table 1, entry 1). Among several organic solvents
screened (Table 1, entries 2–11), ethanol gave the best efficiency
in terms of product yield (84% yield) and as an environmentally
benign solvent (Table 1, entry 8). While the reaction time can be
aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok
10400, Thailand. E-mail: chutima.kon@mahidol.ac.th; Fax: +66-2-3547151; Tel:
+66-2-2015155
bMahidol University, Kanchanaburi Campus, Saiyok, Kanchanaburi 71150, Thailand
† Electronic supplementary information (ESI) available: Spectroscopic data of all
compounds (copies of 1H and 13C NMR). See DOI: 10.1039/c4ra02607a
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Table 1 Optimization of the reaction conditions for I2–PPh3 mediated Table 2 C3 Sulfenylation of indole derivatives with sodium sulfinates
C3 sulfenylation reaction of indole (1a)a mediated by I2–PPh3 systema
Entry R1
R2
R3
Time (h) Product, yieldb (%)
2a
I2
PPh3
Time Yieldb
Entry (equiv.) (equiv.) (equiv.) Solvent
(h)
(%)
1
2
3
4
5
6
7
8
H
H
H
H
CH3
Boc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
pTol
Ph
2
2
2
8
2
2
2
2
2
2
2
3
3
3
5
8
5
3a, 85
3b, 75
3c, 97
3d, 44
3e, 88
1
2
2
2
2
2
2
2
2
2
2
2
2
1.5
1.2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
1.5
1.2
1
CH2Cl2
ClCH2CH2Cl
Hexanes
Toluene
THF
Acetone
1,4-Dioxane
EtOH
CH3CN
DMF
DMSO
EtOH
EtOH
3
3
3
3
3
3
3
3
3
3
3
2
2
2
5
67
76
42
82
18d
49
49
84
84
79
61
85
79
68
51
pClC6H4
CH3
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
3
4c
5
c
—
2-CH3
5-CH3
6-CH3
7-CH3
5-OCH3
5-F
3f, 89
3g, 92
3h, 81
3i, 83
3j, 88
3k, 85
3l, 69
3m, 72
3n, 73
3o, 32d
6
7
8
9
9
10
11
12
13
14
15
16
17
10c
11c
12
13
14
15e
5-Cl
5-Br
5-CO2CH3 pTol
5-NO2
5-CHO
EtOH
EtOH
pTol
pTol
1.5
1.5
e
—
a
b
Conditions: 1a (0.5 mmol) in 0.25 M of solvent. Isolated yield aer
c
column chromatography (SiO2). Reactions were carried out at 80 ꢀC.
d
e
1a was recovered in 80% yield. Reaction was carried out at room
18
H
3-CH3
pTol
2
temperature.
a
Conditions:
1 (0.5 mmol), 2 (1.5 equiv.), I2 (1 equiv.), and
b
shorten from 3 h to 2 h, reduction in the stoichiometry of
sodium p-toluenesulnate (2a) and triphenylphosphine resul-
ted in slight decrease in yields of 3a (from 85% yield to 68% 68% yield.
triphenylphosphine (1.5 equiv.) in 0.25 M of EtOH. Isolated yield
c
aer column chromatography (SiO2). N-Boc-indole was recovered in
d
e
5-Nitroindole was recovered in 61% yield.
Formylindole was totally consumed.
5-
yield) (Table 1, entries 12–14). The best yield of 3a was obtained
when the amounts of sodium p-toluenesulnate (2a) and tri-
phenylphosphine employed were as low as 1.5 equiv. each
(Table 1, entry 13). Finally, when the reaction was carried out at untouched (Table 2, entry 6). Methyl-substituted indoles at C2,
room temperature with prolonged reaction time, the yield of 3a C5, C6, and C7 worked equally well, leading to the corre-
was signicantly lower (Table 1, entry 15). Based on the exper- sponding products in 81–92% yields (Table 2, entries 7–10). 5-
imental results shown in Table 1, the optimized reaction Methoxyindole gave good results, yielding the product in 88%
conditions were chosen as follows: indole substrate (1 equiv.), yield (Table 2, entry 11). Reactions of electron-decient
sodium sulnate (1.5 equiv.), I2 (1 equiv.), and triphenylphos- substituted indoles, including 5-F, 5-Cl, 5-Br, 5-CO2CH3 and 5-
phine (1.5 equiv.) in ethanol at reuxing temperature for 2 h NO2 substituted indoles were found less efficient and required
(Table 1, entry 12).
longer reaction time; the corresponding products were obtained
Having established efficient access to 3-(p-toluenesulfanyl) in moderate to high yields (Table 2, entries 12–16). It was found
indole (3a), we further demonstrated that our method could be that a formyl group was incompatible under the reaction
used as a general route for C3 sulfenylation of structurally conditions; the crude reaction mixture revealed indenite
different indoles and sodium sulnates. The results are spots. (Table 2, entry 17). Finally, 3-methylindole gave 3-methyl-
summarized in Table 2. Sodium arenesulnates, including 2-(p-toluenesulfanyl)indole (4) in 75% yield (Table 2, entry 18).18
sodium p-toluenesulnate, sodium benzenesulnate, and
To address a plausible reaction pathway, some control
sodium p-chlorobenzenesulnate reacted with indole to provide experiments were carried out (Table 3). Product 3a was not
the corresponding products in high yields (Table 2, entries 1–3). observed when iodine was excluded from the reaction; indole
The reaction of 1a with sodium methanesulnate required (1a) and triphenylphosphine were recovered in 88% and 95%
longer reaction time (8 h) and gave low yield of the corre- yields, respectively (Table 3, entry 1). On the other hand, the
sponding product 3d (Table 2, entry 4). The reaction of N- reaction carried out in the absence of triphenylphosphine led to
methylindoles smoothly proceeded, yielding the corresponding 2-(p-toluenesulfonyl)indole (5) as a major product in 46% yield
product in good yield (Table 2, entry 5) while N-Boc-indole was while the desired product 3a was obtained in 21% yield (Table 3,
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Table 3 Control experimentsa
Product, yieldb (%)
Entry
1a or 10 (equiv.)
S source (equiv.)
I2 (equiv.)
PPh3 (equiv.)
3a
5
6
7
8
9
1c
2
3
4
5
1a (1.0)
1a (1.0)
—
2a (1.5)
2a (1.5)
2a (1.0)
7 (1.0)
6 (1.0)
7 (1.0)
—
—
1
1
1
1
1.5
—
—
21
—
—
Trace
18
—
—
46
—
—
—
—
—
—
—
34
60
—
19
—
—
—
38
35
—
—
—
—
—
—
—
79
—
—
—
—
—
—
—
56
—
1.5
1.5
1.5
1.5
1.5
—
1a (1.0)
1a (1.0)
10 (1.0)
6
1
1
7c
a
b
All reactions were carried out in reuxing EtOH (0.25 M) for 2 h. Isolated yield aer column chromatography (SiO2). c No reaction took place.
entry 2). This means that in the absence of triphenylphosphine,
sodium p-toluenesulnate (2a) readily reacted with iodine,
generating p-toluenesulfonyl iodide which can react with indole
(1a) to yield 2-(p-toluenesulfonyl)indole (5) as
a major
pathway.16 Under the reaction conditions, p-toluenesulfonyl
iodide can be reduced to generate a sulfenylating species which
can react with indole (1a) to yield 3-(p-toluenesulfanyl)indole
(3a) as a minor pathway.19 In the absence of indole (1a), treat-
ment of sodium p-toluenesulnate (2a) with I2 (1.0 equiv.) and
triphenylphosphine (1.5 equiv.) under standard reaction
conditions yielded 1,2-di-p-tolyldisulfane (6, 34% yield) and S-p-
tolyl 4-methylbenzenesulfonothioate (7, 38% yield) (Table 3,
entry 3). It is worth to note that S-p-tolyl 4-methyl-
benzenesulfonothioate (7) can be converted to 1,2-di-p-tolyldi-
sulfane (6) under the reaction conditions (Table 3, entry 4).
These results imply that both sulfonothiolate 7 and disulde 6
would probably be formed under the reaction conditions and 6
should be generated from 7. Since both of them were previously
described being used as sulfenylating agents,7a,b,14 our next
attempts were to use 6 and 7 as reagents in place of sodium
sulnate (Table 3, entries 5 and 6). Both 6 and 7 exhibited
poorer reactivity as sulfenylating agents under our reaction
conditions; 6 led to the corresponding thiol 8 while 7 gave 2,3-
disulfenylated product 9 as a major product. Finally, when 3-(p-
toluenesulfonyl)indole (10) was treated with I2 (1.0 equiv.) and
triphenylphosphine (1.5 equiv.) in uxing ethanol for 2 h, no
reaction took place; 10 was recovered in 97% yield (Table 3,
entry 7). This suggested that a combination of I2–PPh3 was
unable to cause reduction of sulfone to sulde. Thus, a reduc-
tion of sodium sulnate mediated by a combination of I2–PPh3,
leading to a sulfenylating species should primarily and feasibly
occur prior to other processes.
Scheme 1 Plausible reaction pathway.
PPh3 system,19 a plausible reaction pathway was proposed
(Scheme 1). First, iodine reacts with triphenylphosphine to
form iodotriphenylphosphonium iodide which then reacts with
sodium sulnate, nally leading to an electrophilic sulfenylat-
ing species, most probably, sulfenyl iodide. Depending on
whether or not C3 carbon is substituted, indole substrate
readily reacts with the sulfenyl iodide, yielding either 3-sulfe-
nylation or 2-sulfenylation product.
Conclusions
We have described a convenient and simple protocol to access
3-(alkylsulfanyl)- and 3-(arylsulfanyl)indoles using sodium sul-
nates as the reagents mediated by I2–PPh3 system. The reac-
tion readily proceeded in reuxing ethanol within a few hours.
In view of simplicity, high efficiency, non-anhydrous condi-
tions, environmentally benign solvent and short reaction time,
it is believed that this protocol should offer an alternative and
rapid approach to 3-sulfanylindoles.
On the basis of the experimental results described above and
a report by Togo et. al. on the reduction of sulfonic acid by I2–
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(CH), 102.4 (C); HRMS (ESI-TOF) calcd for C14H10ClNS [M]+:
259.0222, found 259.0225.
Experimental
General information
3-(Methylsulfanyl)-1H-indole (3d).7a White oil (35.9 mg,
44%); 1H NMR (400 MHz, CDCl3): d 8.08 (br s, 1H), 7.70–7.68 (m,
1H), 7.26–7.23 (m, 1H), 7.17–7.10 (m, 3H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 136.2 (C), 128.6 (C), 127.8 (CH), 122.6 (CH),
120.2 (CH), 119.1 (CH), 111.5 (CH), 107.9 (C), 20.1 (CH3).
1-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3e).8b White
solid (111.5 mg, 88%); m.p. ¼ 115.5–117 ꢀC (from CH2Cl2/
hexanes); 1H NMR (400 MHz, CDCl3): d 7.53 (d, J ¼ 7.9 Hz, 1H),
7.28 (d, J ¼ 8.2 Hz, 1H), 7.22–7.18 (m, 2H), 7.09–7.05 (m, 1H), 6.94
(d, J ¼ 8.3 Hz, 2H), 6.88 (d, J ¼ 8.1 Hz, 2H), 3.73 (s, 3H), 2.16 (s,
3H); 13C NMR (100 MHz, CDCl3): d 137.5 (C), 135.9 (C), 134.8
(CH), 134.5 (C), 129.8 (C), 129.4 (2 ꢁ CH), 126.1 (2 ꢁ CH), 122.4
(CH), 120.4 (CH), 119.7 (CH), 109.6 (CH), 101.1 (C), 33.1 (CH3),
20.8 (CH3); HRMS (ESI-TOF) calcd for C16H15NSNa [M + Na]+:
276.0823, found 276.0837.
1H NMR spectra were recorded with a Bruker Ascend™ 400 (400
MHz) and Bruker Avance-500 (500 MHz) spectrometer in CDCl3
by using tetramethylsilane (d ¼ 0 ppm) as an internal standard.
13C NMR spectra were recorded with a Bruker Ascend™ 400
(400 MHz) and Bruker Avance-500 (500 MHz) spectrometer.
Infrared spectra were recorded with a Perkin-Elmer 683 GX FTIR
System spectrometer. High-resolution mass spectra (HRMS)
were recorded with a Bruker micro TOF spectrometer in the ESI
mode. Melting points were recorded with a digital Electro-
thermal Melting 9100 apparatus and were uncorrected. All
reagents and solvents were obtained from commercial sources
and used without further purication. Column chromatography
was performed by using Merck silica gel 60 PF254 (Art 7734).
2-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3f). Brown
solid (112.7 mg, 89%); m.p. ¼ 96.5–98 ꢀC (from CH2Cl2/
General procedure
Iodine (127.0 mg, 0.50 mmol) was added to a solution of indole hexanes) (lit.,7a 98.2–100 ꢀC); 1H NMR (400 MHz, CDCl3): d 8.16
(0.5 mmol), sodium sulnate (0.75 mmol) and triphenylphos- (br s, 1H), 7.58 (d, J ¼ 7.8 Hz, 1H), 7.32 (d, J ¼ 7.9 Hz, 1H), 7.22–
phine (0.75 mmol) in EtOH (2 mL; 0.25 M), and the reaction 7.12 (m, 2H), 6.98 (s, 4H), 2.49 (s, 3H), 2.26 (s, 3H); 13C NMR (100
mixture was stirred at reuxing temperature for 2–8 h. The MHz, CDCl3): d 140.9 (C), 135.6 (C), 135.3 (C), 134.3 (C), 130.2
reaction mixture was quenched by the addition of sat. aq. (C), 129.4 (2 ꢁ CH), 125.7 (2 ꢁ CH), 122.0 (CH), 120.6 (CH),
Na2S2O3 (5 mL). Further stirring was followed by extraction with 118.9 (CH), 110.6 (CH), 99.7 (C), 20.8 (CH3), 12.0 (CH3); HRMS
EtOAc (2 ꢁ 20 mL). The combined organic extracts were washed (ESI-TOF) calcd for C16H15NSNa [M + Na]+: 276.0823, found
with H2O (20 mL) and brine (20 mL), dried (MgSO4), ltered, 276.0827.
and concentrated (aspirator). The residue was puried by
5-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3g). White
column chromatography using acetone/hexanes as eluent to solid (116.5 mg, 92%); m.p. ¼ 135.5–137 ꢀC (from CH2Cl2/
1
afford the corresponding product.
hexanes) (lit.,7g 137–138 ꢀC); H NMR (400 MHz, CDCl3): d 8.18
3-[(4-Methylphenyl)sulfanyl]-1H-indole (3a). White solid (br s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.29 (d, J ¼ 8.3 Hz, 1H), 7.14–
(101.7 mg, 85%); m.p. ¼ 122–124 ꢀC (from CH2Cl2/hexanes) 7.01 (m, 5H), 2.45 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz,
(lit.,10c 125–126 ꢀC); 1H NMR (400 MHz, CDCl3): d 8.25 (br s, 1H), CDCl3): d 135.7 (C), 134.6 (C), 134.5 (C), 130.7 (CH), 130.2 (C),
7.53 (d, J ¼ 7.7 Hz, 1H), 7.34 (d, J ¼ 2.6 Hz, 1H), 7.32 (d, J ¼ 8.1 129.4 (2 ꢁ CH), 129.3 (C), 125.9 (2 ꢁ CH), 124.5 (CH), 119.0
Hz, 1H), 7.19–7.15 (m, 1H), 7.09–7.05 (m, 1H), 6.95 (d, J ¼ 8.3 (CH), 111.2 (CH), 102.2 (C), 21.4 (CH3), 20.8 (CH3); HRMS (ESI-
Hz, 2H), 6.89 (d, J ¼ 8.1 Hz, 2H), 2.16 (s, 3H); 13C NMR (100 TOF) calcd for C16H15NSNa [M + Na]+: 276.0823, found
MHz, CDCl3): d 136.4 (C), 135.4 (C), 134.6 (C), 130.4 (CH), 129.4 276.0825.
(2 ꢁ CH), 129.0 (C), 126.2 (2 ꢁ CH), 122.9 (CH), 120.8 (CH),
6-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3h). White
119.6 (CH), 111.5 (CH), 103.4 (C), 20.8 (CH3); HRMS (ESI-TOF) solid (102.6 mg, 81%); m.p. ¼ 124.5–126 ꢀC (from CH2Cl2/
calcd for C15H13NSNa [M + Na]+: 262.0666, found 262.0664.
hexanes); 1H NMR (400 MHz, CDCl3): d 8.15 (br s, 1H), 7.40 (d,
3-(Phenylsulfanyl)-1H-indole (3b). White solid (84.5 mg, J ¼ 8.1 Hz, 1H), 7.30 (d, J ¼ 2.5 Hz, 1H), 7.13 (s, 1H), 6.95–6.88
75%); m.p. ¼ 147–148 ꢀC (from CH2Cl2/hexanes) (lit.,10e 149–151 (m, 5H), 2.39 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d
ꢀC); 1H NMR (400 MHz, CDCl3): d 8.34 (br s, 1H), 7.61 (d, J ¼ 7.9 136.9 (C), 135.6 (C), 134.5 (C), 132.9 (C), 129.8 (CH), 129.4 (2 ꢁ
Hz, 1H) 7.44 (d, J ¼ 2.6 Hz, 1H), 7.41 (d, J ¼ 8.2 Hz, 1H), 7.28– CH), 126.9 (C), 126.1 (2 ꢁ CH), 122.6 (CH), 119.3 (CH), 111.4
7.23 (m, 1H), 7.18–7.02 (m, 6H); 13C NMR (100 MHz, CDCl3): d (CH), 103.1 (C), 21.7 (CH3), 20.8 (CH3); HRMS (ESI-TOF) calcd
139.2 (C), 136.4 (C), 130.7 (CH), 129.0 (C), 128.7 (2 ꢁ CH), 125.8 for C16H15NS [M]+: 253.0925, found 253.0927.
(2 ꢁ CH), 124.8 (CH), 123.0 (CH), 120.9 (CH), 119.6 (CH), 111.6
7-Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole (3i). White
(CH), 102.7 (C); HRMS (ESI-TOF) calcd for C14H11NSNa [M + solid (105.1 mg, 83%); m.p. ¼ 115–117 ꢀC (from CH2Cl2/
Na]+: 248.0510, found 248.0508.
hexanes); 1H NMR (500 MHz, CDCl3): d 8.31 (br s, 1H), 7.49 (d,
3-[(4-Chlorophenyl)sulfanyl]-1H-indole (3c). White solid J ¼ 7.3 Hz, 1H), 7.46 (d, J ¼ 2.6 Hz, 1H), 7.12–7.05 (m, 4H), 6.99
(126.0 mg, 97%); m.p. ¼ 126–128 ꢀC (from CH2Cl2/hexanes) (d, J ¼ 8.3 Hz, 2H), 2.53 (s, 3H), 2.26 (s, 3H); 13C NMR (125 MHz,
(lit.,10c 127.5–128.3 ꢀC); 1H NMR (500 MHz, CDCl3): d 8.42 (br s, CDCl3): d 136.0 (C), 135.6 (C), 134.6 (C), 130.1 (CH), 129.4 (2 ꢁ
1H), 7.61 (d, J ¼ 8.0 Hz, 1H), 7.47 (d, J ¼ 2.6 Hz, 1H), 7.45 (d, J ¼ CH), 128.7 (C), 126.3 (2 ꢁ CH), 123.5 (CH), 121.0 (CH), 120.6 (C),
8.2 Hz, 1H), 7.32–7.29 (m, 1H), 7.22–7.19 (m, 1H), 7.14 (d, J ¼ 8.6 117.4 (CH), 104.0 (C), 20.8 (CH3), 16.3 (CH3); HRMS (ESI-TOF)
Hz, 2H), 7.04 (d, J ¼ 8.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): d calcd for C16H15NSNa [M + Na]+: 276.0823, found 276.0828.
137.8 (C), 136.5 (C), 130.7 (CH), 130.5 (C), 128.77 (C), 128.72 (2 ꢁ
5-Methoxy-3-[(4-methylphenyl)sulfanyl]-1H-indole (3j).7k Pale
CH), 127.1 (2 ꢁ CH), 123.2 (CH), 121.0 (CH), 119.5 (CH), 111.7 yellow liquid (118.5 mg, 88%); 1H NMR (400 MHz, CDCl3): d 8.24
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(br s, 1H), 7.23 (d, J ¼ 2.7 Hz, 1H), 7.12 (d, J ¼ 8.8 Hz, 1H), 6.95 20.9 (CH3); HRMS (ESI-TOF) calcd for C15H12N2O2SNa [M + Na]+:
(s, 1H), 6.92 (d, J ¼ 8.0 Hz, 2H), 6.86 (d, J ¼ 8.4 Hz, 2H), 6.79 (dd, 307.0517, found 307.0512.
J ¼ 8.8, 2.3 Hz, 1H), 3.65 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz,
3-Methyl-2-[(4-methylphenyl)sulfanyl]-1H-indole (4). White
CDCl3): d 154.9 (C), 135.5 (C), 134.5 (C), 131.3 (C), 131.2 (CH), solid (95.0 mg, 75%); m.p. ¼ 96.5–97.5 ꢀC (from CH2Cl2/
129.8 (C), 129.4 (2 ꢁ CH), 125.9 (2 ꢁ CH), 113.3 (CH), 112.4 hexanes); 1H NMR (500 MHz, CDCl3): d 7.88 (br s, 1H), 7.54 (d, J
(CH), 102.3 (C), 100.7 (CH), 55.7 (CH3), 20.7 (CH3); HRMS (ESI- ¼ 8.0 Hz, 1H), 7.23–7.17 (m, 2H), 7.11–7.08 (m, 1H), 6.98–6.93
TOF) calcd for C16H15NOSNa [M + Na]+: 292.0772, found (m, 4H), 2.35 (s, 3H), 2.22 (s, 3H); 13C NMR (125 MHz, CDCl3): d
292.0767.
136.8 (C), 135.8 (C), 133.2 (C), 129.8 (2 ꢁ CH), 128.5 (C), 127.2 (2
5-Fluoro-3-[(4-methylphenyl)sulfanyl]-1H-indole (3k). White ꢁ CH), 123.3 (CH), 122.3 (C), 119.5 (CH), 119.32 (CH), 119.26
solid (109.4 mg, 85%); m.p. ¼ 137.5–139.5 ꢀC (from CH2Cl2/ (C), 110.8 (CH), 20.9 (CH3), 9.4 (CH3); HRMS (ESI-TOF) calcd for
hexanes); 1H NMR (400 MHz, CDCl3): d 8.30 (br s, 1H), 7.41 (d, J
¼ 2.6 Hz, 1H), 7.24 (dd, J ¼ 8.8, 4.2 Hz, 1H), 7.17 (dd, J ¼ 8.6, 2.4
Hz, 1H), 6.95–6.88 (m, 5H), 2.17 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 158.5 (d, J ¼ 235.3 Hz, C), 134.93 (C), 134.89 (C), 132.8
C
16H15NS [M]+: 253.0925, found 253.0924.
Acknowledgements
(C), 132.0 (CH), 129.9 (d, J ¼ 10.1 Hz, C), 129.5 (2 ꢁ CH), 126.3 (2 We thank the Thailand Research Fund (TRF-DBG5480017), the
ꢁ CH), 112.3 (d, J ¼ 9.4 Hz, CH), 111.5 (d, J ¼ 26.4 Hz, CH), 104.7 Center of Excellence for Innovation in Chemistry (PERCH-CIC),
(d, J ¼ 24.0 Hz, CH), 103.7 (d, J ¼ 4.5 Hz, C), 20.8 (CH3); HRMS the Office of the Higher Education Commission, Mahidol
(ESI-TOF) calcd for C15H12FNSNa [M + Na]+: 280.0572, found University under the National Research Universities Initiative
280.0578.
and the Development and Promotion of Science and Tech-
5-Chloro-3-[(4-methylphenyl)sulfanyl]-1H-indole (3l). White nology Talent Project (DPST), the Institute for the Promotion of
solid (94.5 mg, 69%); m.p. ¼ 124.5–125.5 ꢀC (from CH2Cl2/ Teaching Science and Technology for nancial support.
1
hexanes); H NMR (400 MHz, CDCl3): d 8.44 (br s, 1H), 7.63 (s,
1H), 7.49 (d, J ¼ 2.5 Hz, 1H), 7.35 (d, J ¼ 8.7 Hz, 1H), 7.23 (dd, J ¼
Notes and references
8.6, 2.0 Hz, 1H), 7.07–7.02 (m, 4H), 2.30 (s, 3H); 13C NMR (100
MHz, CDCl3): d 134.94 (C), 134.88 (C), 134.7 (C), 131.7 (CH),
130.3 (C), 129.6 (2 ꢁ CH), 126.8 (C), 126.3 (2 ꢁ CH), 123.4 (CH),
119.1 (CH), 112.6 (CH), 103.4 (C), 20.8 (CH3); HRMS (ESI-TOF)
calcd for C15H12ClNS [M]+: 273.0379, found 273.0380.
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5-Bromo-3-[(4-methylphenyl)thio]-1H-indole (3m). White
solid (114.6 mg, 72%); m.p. ¼ 120–122 ꢀC (from CH2Cl2/
hexanes) (lit.,7k 123–125 ꢀC); 1H NMR (400 MHz, CDCl3): d 8.29
(br s, 1H), 7.65 (d, J ¼ 1.8 Hz, 1H), 7.28 (d, J ¼ 2.6 Hz, 1H), 7.20
(dd, J ¼ 8.6, 1.8 Hz, 1H), 7.12 (d, J ¼ 8.6 Hz, 1H), 6.92–6.87 (m,
4H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3): d 135.0 (C), 134.93
(C), 134.85 (C), 131.6 (CH), 130.9 (C), 129.6 (2 ꢁ CH), 126.2 (2 ꢁ
CH), 125.9 (CH), 122.1 (CH), 114.3 (C), 113.0 (CH), 103.1 (C),
20.8 (CH3); HRMS (ESI-TOF) calcd for C15H12BrNS [M]+:
316.9874, found 316.9877.
Methyl-3-[(4-methylphenyl)sulfanyl]-1H-indole-5-carboxylate
ꢀ
(3n). Pale yellow solid (108.5 mg, 73%); m.p. ¼ 181–183.5 C
(from CH2Cl2/hexanes); 1H NMR (400 MHz, acetone-d6): d
11.13 (br s, 1H), 8.28 (s, 1H), 7.90 (dd, J ¼ 8.6, 1.6 Hz, 1H), 7.82
(d, J ¼ 2.6 Hz, 1H), 7.62 (d, J ¼ 8.6 Hz, 1H), 7.01 (s, 4H), 3.84
(s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, acetone-d6): d 168.0
(C]O), 140.7 (C), 136.4 (C), 135.6 (C), 134.6 (CH), 130.4 (2 ꢁ
CH), 129.7 (C), 126.9 (2 ꢁ CH), 124.5 (CH), 123.4 (C), 122.3
(CH), 113.0 (CH), 104.2 (C), 52.1 (CH3), 20.8 (CH3); HRMS (ESI-
TOF) calcd for C17H15NO2SNa [M + Na]+: 320.0721, found
320.0727.
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