Oxone-mediated oxidative 3-arylthio substitution of indoles

Article abstract of DOI:10.1080/00397910701860174

Oxone-mediated oxidative 3-arylthio substitution of indoles with benzenethiols in methanol has been succeeded, giving 3-arylthioindoles. Indoles bearing a 2-methyl group particularly exhibited higher activities toward 3-arylthio substitutions. 3-(2'-Pyrid

Full text of DOI:10.1080/00397910701860174

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Oxone‐Mediated Oxidative 3‐Arylthio
Substitution of Indoles
Guaili Wu a , Jing Wu a , Jialiang Wu a & Longmin Wu a
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University ,
Lanzhou, Gansu, 730000, China
Published online: 12 Mar 2008.
To cite this article: Guaili Wu , Jing Wu , Jialiang Wu & Longmin Wu (2008) Oxone‐Mediated Oxidative
3‐Arylthio Substitution of Indoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:7, 1036-1043, DOI: 10.1080/00397910701860174
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Synthetic Communicationsw, 38: 1036–1043, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701860174
Oxone-Mediated Oxidative 3-Arylthio
Substitution of Indoles
Guaili Wu, Jing Wu, Jialiang Wu, and Longmin Wu
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, Gansu, China
Abstract: Oxone-mediated oxidative 3-arylthio substitution of indoles with benze-
nethiols in methanol has been succeeded, giving 3-arylthioindoles. Indoles bearing a
2-methyl group particularly exhibited higher activities toward 3-arylthio substitutions.
3-(20-Pyridylthio)indoles used as selective COX-2 inhibitors were prepared in good to
excellent yields.
Keywords: 3-Arylthioindole, benzenethiol, 2-mercaptopyridine, oxone, selective
COX-2 inhibitor
The 3-arylthiolation of indoles and their derivatives is important because the
resulting 3-arylthioindoles could serve as selective cyclooxygenase-2
(COX-2) inhibitors[1] whose determinant structural requirements are (a) an
indole nucleus and (b) a 3-arylthio group. Otherwise, the introduction of
sulfur into aromatic rings would make it accessible to many synthetic trans-
formations.[2] Various approaches for the direct 3-arylthiolation of indoles
have been developed, such as the alkylation of disulfide with the C-3 organo-
zinc[3a] or organosodium[3b] salt of an indole, the trimethylsilyl trifluoro-
methanesulfonate (TMSOTf)-catalyzed sulfenylation of an indole using
mono-O,S-acetals,[3c,3d] the substitution of an indole by a sulfenyl
Received in Japan October 13, 2007
Address correspondence to Longmin Wu, State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China. E-mail: nlaoc@lzu.
edu.cn
1036

Oxidative 3-Arylthio Substitution of Indoles
1037
chloride,[3e,3f] the thiolation of an indole via a sulfenium ion promoted
Pummerer rearrangement,[3g] the application of phenyliodine(III)bis trifluor-
oacetate (PIFA) in (CF3)CHOH,[3h] or vanadium oxyacetylacetonate
[VO(acac)2] serving as a catalyst for the direct synthesis of 3-sulfanylindoles
from indoles and thiols.[3i] In all these cases, indole molecules featured
nucleophiles.[3a–g] These methods, however, limit the preparation of some
3-arylthioindoles, which would be candidates for selective COX-2 inhibitors,
owing to their lesser availability. In particular, starting materials are not
readily available. In addition, the 3-arylthiolation of indoles can be realized
using the Fisher indole synthesis.[4] Yet, it is unfavorable for some
3-arylthioindoles used as selective COX-2 inhibitors. Hence, a mild general
approach for the direct 3-arylthiolation of indoles is in demand.
On reviewing these methods, we are particularly interested in thiolation
approaches via a nucleophilic substitution because the electron-rich pyrrole
moiety of indoles can be readily oxidized to cationic species, on which a
nucleophilic attack of a mercaptide ion will result in the formation of
thioethers. Such a consideration emerged from our recent studies on oxone-
mediated oxidative addition of thiocyanate to aromatic and heteroaromatic
compounds[5a] as well as olefins,[5b] leading to carbon-hetero bond formations.
Fortunately, this kind of reaction has been successfully broadened for
3-arylthio substitution of indoles in methanol with benzenethiols, which are
capable of generating a mercaptide ion, and applied for the preparation of
3-arylthioindoles used as selective COX-2 inhibitors in the present work.
Our initial experiment involved the reaction of 2-methyl-indole 1e and
2-mercaptopyridine in the presence of oxone in methanol, which led to
3-(20-pyridylthio)-2-methylindole 2e as colorless crystallines (Scheme 1). Its
structure was identified by 1H and 13C NMR, electron impact mass
spectrum (EIMS), high-resolution electrospray ionization mass spectrum
(HR-ESI-MS), infrared (IR), and X-ray crystallography diffraction (Fig. 1).
The X-ray crystallographic structure of 2e (deposition number CCDC-
612645) shown in Fig. 1 clearly shows that the monosulfenylation highly
regioselectively occurred at position 3 of the indole. Various thiols and
indoles afforded the corresponding sulfenylated products in various yields
under similar reaction conditions. The results are gathered in Table 1.
Table 1 suggests that an aliphatic group such as a methyl group at C2 dra-
matically enhanced the reactivity of indoles toward the sulfenylation and
Scheme 1.

1038
G. Wu et al.
Figure 1. Molecular structure of 2e.
afforded good yields, indicated by the cases of 1a, 1c, 1d, and 1e. This obser-
vation is in agreement with those obtained by Matsugi et al.[3d] It implies that
the sulfenylation most likely proceeds via an intermediate that requires stabi-
lizing by the substituent, such as a methyl group, at position 2 of the indole.
Furthermore, the electronic nature of the benzene moiety appears dramatically
to affect the reactivity of indoles and the product yield. An electron-donating
group such as the methoxy group at position 5 of 1g facilitated the reaction and
gave a high yield (98.0%), whereas an electron-withdrawing group such as
Table 1. Sulfenylation of indoles with oxone in methanol at room temperature
pKA of ArSH Time Conv Yield of
Entry R1
R2
R3
Ar
in watera
(h)b (%)
2(%)c
1a
1b
1c
1d
1e
1f
H
H
CH3
H
H
H
Ph
Ph
6.50 (25 8C)
6.50 (25 8C)
6
24
6
.99
48.7
.99
.99
.99
94
71.3
34.7
81.6
70.5
85.4
93.4
98.0
92.9
42.5
NR
H
CH3
CH3
CH3
H
H
p-OCH3-Ph 6.52 (25 8C)
H
H
p-Cl-Ph
20-Py
20-Py
20-Py
20-Py
20-Py
20-Py
20-Py
PhCH2
5.90 (25 8C)
21.07 (20 8C)
21.07 (20 8C)
21.07 (20 8C)
21.07 (20 8C)
21.07 (20 8C)
21.07 (20 8C)
21.07 (20 8C)
ꢀ 11 (25 8C)
6
H
H
6
H
H
6
1g
1h
1i
H
H
OCH3
H
6
97
CH3
H
H
6
.99
68
H
Br
NO2
—
H
24
48
12
24
1j
H
H
—
—
94
1k
1md
H
68
H
CH3
89.9
6.8
aFrom Ref. [6].
bThe reaction time.
cIsolated yields of the products after column chromatography.
dThe yield was determined by GC-MS. Substrate 1m was overoxidized to products
that were not detected by GC-MS.

Oxidative 3-Arylthio Substitution of Indoles
1039
NO2 in 1j froze the reaction and no sulfenylation product was obtained.
Table 1 indicates that benzenethiols with higher acidity are favorable for
the thiolation. 2-Pyridylthiol is the strongest acid among the benzenethiols
used in this work. It afforded good to excellent yields of 3-arylthioindoles.
Yet, benzyl sulfhydrate, as in the case of 1m, is the weakest acid among the
benzenethiols used. Its lower reactivity led to a large portion of it oxidized
by oxone to disulfide.[7]
Several solvents have been employed in the reaction to optimize the
reaction conditions. Solvents examined were carbon tetrachloride, dichloro-
methane, methanol, ethanol, and acetonitrile. Among them, methanol was
highly favorable for the sulfenylation under consideration.
In summary, a direct one-pot 3-arylthiolation of indoles using oxone in
methanol with various benzenethiols has been accomplished. A 2-methyl sub-
stituent on the pyrrole moiety and an electron-donating substituent on the
benzo moiety of indoles were especially favorable for the 3-arylthiolation of
indoles. 2-Mercaptopyridyl substitution of indoles afforded the corresponding
3-arylthioindoles as selective COX-2 inhibitors[8] in good to excellent yields.
EXPERIMENTAL
Melting points were measured on a Yanagimoto melting-point apparatus and
were are uncorrected. IR spectra (KBr) were conducted on a Nicolet Nexus
1
670 FT-IR spectrophotometer. H and 13C NMR spectra were recorded on a
Varian Mercury Plus 300/400 NMR spectrometer. Chemical shifts (d) are
reported relative to TMS (1H) or CDCl3 (13C) as an internal standard. EI-MS
(70 eV) determinations were carried out on an HP 5985A spectrometer. TR-
ESI-MS detections were run on a Bruker Daltonics Apex II 47e spectrometer
with an ESI. Reactions were monitored by silica-gel-coated thin-layer
chromatography (TLC). Silica gel (200–300 mesh) was used for column
chromatography. The X-ray crystallographic analysis was performed on a
Bruket AXS Smart Apex CCD single-crystal diffractometer.
General Procedure for the Sulfenylation of Indoles
In a typical experiment, 0.7 mmol of oxone was added portion wise into a
solution of 2-methyl-indole 1e (1 mmol) and 2-mercaptopyridine (1.5 mmol)
in 10 mL of methanol, which was allowed to stir at room temperature until com-
pletion of the reaction as monitored by TLC and then diluted with water and
extracted with 4 ꢀ 15 mL of dichloromethane (DCM). DCM was then evapor-
ated and the residue purified by column chromatography on silica gel (200–300
mesh, ethyl acetate/hexane) to afford 3-(20-pyridylthio)-2-methylindole 2e as
colorless crystal. The single-crystal growth was carried out in ethyl acetate–
hexane at room temperature. Products were identified by 1H/13C NMR,
EIMS, HR-ESI-MS, and IR.

1040
G. Wu et al.
Characterization Data for Products
3-(Phenylthio)-2-methylindole (2a): Colorless prisms, mp 109–110 8C. IR
(KBr): vmax cm21 3398.8, 3055.8, 1580.9, 1476.4, 1454.2, 1403.6, 1290.6,
741.9, 692.0. 1H NMR (300 MHz, CDCl3): d 8.17 (s, 1H, NH), 7.53
(d, J ¼ 7.5 Hz, 1H, arom), 7.31 (d, J ¼ 7.5 Hz, 1H, arom), 7.15 (m, 4H,
arom), 7.01 (m, 3H, arom), 2.47 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 141.1, 139.3, 135.4, 130.2, 128.7, 125.4, 124.5, 122.1, 120.6, 118.9,
110.6, 99.1, 12.1. MS (EI): m/z 239 (Mþ), 223, 162, 130, 118, 77. HR-ESI-
MS: m/z found M þ H ¼ 240.0843, C15H13NS requires M þ H ¼ 240.0841.
3-(Phenylthio)-indole (2b): Colorless prisms, mp 149–151 8C. IR (KBr): vmax
cm21 3402.6, 3050.7, 2198.5, 1574.2, 1472.9, 1068.1, 1015.6, 739.5, 575.4. 1H
NMR (300 MHz, CDCl3): d 8.37 (s, 1H, NH), 7.63 (d, 1H, J ¼ 5.7 Hz, arom),
7.48 (d, 1H, J ¼ 1.8 Hz, arom), 7.44 (d, 1H, J ¼ 6 Hz, arom), 7.29 (d, 1H,
J ¼ 5.4 Hz, arom), 7.26 (d, 1H, J ¼ 2.1 Hz, arom), 7.18 (m, 3H, arom), 7.16
(d, 1H, J ¼ 5.1 Hz, arom), 7.06 (t, 1H, J ¼ 5.1 Hz, J ¼ 6 Hz, arom). 13C
NMR (75 MHz, CDCl3): d 130.6, 129.0, 128.7, 125.8, 124.7, 123.0, 120.9,
119.6, 111.6. MS (EI): m/z 225 (Mþ), 193, 165, 148, 121, 77. HR-ESI-MS:
m/z calcd. for C14H11NS þ H: 226.0685; found: 226.0691.
3-(4-Methoxyl-phenylthio)-2-methylindole (2c): Colorless prisms, mp 119–
120 8C. IR (KBr): nmax cm21 3394.9, 1592.8, 1490.9, 1455.7, 1287.2, 1241.5,
1176.3, 1029.7, 823.7, 746.6. H NMR (300 MHz, CDCl3): d 8.14 (s, 1H,
1
NH), 7.60 (d, 1H, J ¼ 7.5 Hz, arom), 7.32 (d, 1H, J ¼ 1.2 Hz, arom), 7.21
(m, 2H, arom), 7.07 (m, 2H, arom), 6.74 (dd, 2H, J ¼ 2.4 Hz, J ¼ 3.0 Hz,
J ¼ 9.0 Hz, arom), 3.74 (s, 3H, OCH3), 2.51 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d 157.5, 140.6, 135.3, 129.8, 127.8, 122.0, 120.6, 118.9,
114.4, 110.6, 100.8, 55.3, 12.1. MS (EI): m/z 269 (Mþ), 254, 238, 223,
162, 77. Anal. calcd. for C16H15N1S1O1: C, 71.35; H, 5.61; N, 5.20; O,
5.94; S, 11.90. Found: C, 70.97; H, 5.97; N, 5.13; O, 6.06; S, 11.87.
3-(4-Chloro-phenylthio)-2-methylindole (2d): Colorless prisms, mp 106–
107 8C. IR (KBr): nmax cm21 3394.1, 3056.9, 2915.6, 1473.1, 1453.8,
1089.8, 1009.4, 814.8, 745.6. H NMR (300 MHz, CDCl3): d 8.20 (s, 1H,
1
NH), 7.54 (d, 1H, J ¼ 6.9 Hz, arom), 7.35 (d, 1H, J ¼ 7.5 Hz, arom), 7.18
(m, 4H, arom), 6.97 (dd, 2H, J ¼ 1.8 Hz, J ¼ 2.4 Hz, J ¼ 8.7 Hz, arom),
2.51 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 141.2, 137.9, 135.4,
130.2, 129.9, 128.7, 126.7, 122.3, 120.8, 118.8, 110.7, 98.9, 12.1. MS (EI):
m/z 273 (Mþ), 238, 161, 146, 117, 77. Anal. calcd. for C15H12N1S1Cl1: C,
65.81; H, 4.42; N, 5.12; Cl, 12.95; S, 11.71. Found: C, 65.92; H, 4.46; N,
4.69; Cl, 12.85; S, 12.08.
3-(20-Pyridylthio)-2-methylindole (2e): Colorless prisms, mp 159–160 8C.
IR (KBr): vmax cm21 3387.8, 3179.8, 3155.6, 1577.3, 1556.3, 1450.9,

Oxidative 3-Arylthio Substitution of Indoles
1041
1415.5, 1127.6, 742.7. 1H NMR (400 MHz, CDCl3): d 8.52 (s, 1H, NH), 8.40
(dd, 1H, J ¼ 2.4 Hz, J ¼ 5.6 Hz, arom), 7.54 (d, 1H, J ¼ 7.6 Hz, arom), 7.36
(dd, 1H, J ¼ 0.8 Hz, J ¼ 8.4 Hz, arom), 7.31 (m, 1H, arom), 7.20 (m, 1H,
arom), 7.13 (m, 1H, arom), 6.93 (m, 1H, arom), 6.63 (d, 1H, J ¼ 8.4 Hz,
arom), 2.48 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 162.8, 149.0,
141.7, 136.7, 135.7, 129.8, 122.1, 120.6, 119.5, 119.2, 118.6, 110.9, 97.6,
12.1. MS (EI): m/z 240 (Mþ), 207, 162, 130, 115. HR-ESI-MS: m/z calcd
for C14H12N2S þ H: 241.0794. Found: 241.0793. X-ray diffraction:
C14H12N2S1, Mr ¼ 240.32, monoclinic, space group P2(1)/n with unit
˚
˚
cell parameters: a ¼ 12.3718(5) A, b ¼ 7.5220(3) A, c ¼ 13.7106(7)
3
˚
˚
A, a ¼ 90.008, b ¼ 103.943(2)8, g ¼ 90.008, V ¼ 1238.32(9) A , Z ¼ 4,
rcalcd ¼ 1.289 g/cm3, m ¼ 0.239 mm21, F(000) ¼ 504.0, 2 15 ꢁ h ꢁ 15,
2 8 ꢁ k ꢁ 9, 2 12 ꢁ l ꢁ 16, 5.098 ꢁ 2u ꢁ 53.828, 2795 data collected, 1801
unique data (R(int) ¼ 0.0191), 1643 data with I . 2s(I) 203 refined
parameters. GOF(F2) ¼ 1.092, R1 ¼ 0.0403, wR2 ¼ 0.0978. The crystallo-
graphic data for the structure of 2e have been deposited with the Cambridge
Crystallographic Data Center as Supplementary Publication No. CCDC-
612645.
3-(20-Pyridylthio)-indole (2f): Colorless prisms, mp 136–137 8C. IR (KBr):
vmax cm21 3395.3, 3153.7, 3080.2, 1577.3, 1558.2, 1451.3, 1416.9, 1125.2,
744.7. 1H NMR (300 MHz, CDCl3): d 9.38 (s, 1H, NH), 8.39 (d, 1H,
J ¼ 4.5 Hz, arom), 7.62 (d, 1H, J ¼7.8 Hz, arom), 7.54 (t, 1H, J ¼ 1.2 Hz,
J ¼ 2.4 Hz, arom), 7.41 (t, 1H, J ¼ 1.2 Hz, J ¼ 5.1 Hz, arom), 7.35 (m, 1H,
arom), 7.26(m, 1H, arom), 7.17 (m, 1H, arom), 6.95 (m, 1H, arom), 6.80
(d, 1H, J ¼ 8.4 Hz, arom). 13C NMR (75 MHz, CDCl3): d 162.8, 148.9,
126.7, 131.5, 128.8, 122.9, 120.8, 119.9, 119.3, 119.2, 111.9, 100.5. MS
(EI): m/z 226 (Mþ), 225, 148, 121, 78. HR-ESI-MS: m/z calcd for
C13H10N2S þ H: 227.0637. Found: 227.0634.
3-(20-Pyridylthio)-5-methoxylindole (2g): Colorless prisms, mp 165–167 8C.
IR (KBr): vmax cm21 3392.6, 3152.6, 2921.8, 1577.5, 1557.8, 1485.3, 1452.1,
1416.2, 1205.8, 758.9. 1H NMR (300 MHz, CDCl3): d 9.29 (s, 1H, NH), 8.40
(dd, 1H, J ¼ 1.2 Hz, J ¼ 5.1 Hz, arom), 7.43 (d, 1H, J ¼3 Hz, arom), 7.36
(m, 1H, arom), 7.30 (d, 1H, J ¼ 8.7 Hz, arom), 7.03 (d, 1H, J¼2.1 Hz,
arom), 6.95 (dd, 1H, J ¼ 4.8 Hz, J ¼ 5.4 Hz, J ¼ 7.2 Hz, arom), 6.90 (dd,
1H, J ¼ 2.1 Hz, J ¼ 2.4 Hz, J ¼ 8.6 Hz, arom), 6.79 (d, 1H, J ¼ 2.1 Hz,
arom), 3.77 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): d 162.8, 155.1,
148.9, 136.7, 131.9, 131.6, 129.6, 119.8, 119.3, 113.5, 112.7, 100.4, 100.0,
55.8. MS (EI): m/z 256 (Mþ), 241, 213, 178, 135. HR-ESI-MS: m/z calcd
for C14H12N2SO þ H: 257.0743. Found: 257.0738.
3-(20-Pyridylthio)-1-methylindole (2h): Colorless liquid. IR (KBr): vmax
cm21 3046.9, 2945.5, 1572.4, 1560.5, 1511.0, 1449.8, 1416.7, 1125.8,
1
743.8. H NMR (300 MHz, CDCl3): d 8.39 (m, 1H, arom), 7.61 (dd, 1H,

1042
G. Wu et al.
J ¼ 1.2 Hz, J ¼ 9 Hz, arom), 7.39 (d, 1H, J ¼8.1 Hz, arom), 7.28 (m, 3H,
arom), 7.18 (m, 1H, arom), 6.89 (m, 1H, arom), 6.72 (dd, 1H, J ¼ 1.2 Hz,
J ¼ 8.4 Hz, arom), 3.81 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 163.0,
149.1, 137.6, 136.5, 135.3, 129.5, 122.7, 120.6, 119.6, 119.4, 119.1, 109.9,
98.9, 33.2. MS (EI): m/z 240 (Mþ), 225, 162, 120, 78. HR-ESI-MS: m/z
calcd for C14H12N2S þ H: 241.0794. Found: 241.0790.
3-(20-Pyridylthio)-5-Bromoindole (2i): Colorless prisms, mp 261–262 8C.
IR (KBr): nmax cm21 3141.7, 3103.9, 2913.2, 2873.4, 1575.8, 1556.5,
1448.7, 1415.7, 1127.4, 758.4. 1H NMR (300 MHz, d6-DMSO): d 11.96
(s, 1H, NH), 8.35 (d, 1H, J ¼ 3.9 Hz, arom), 7.85 (d, 1H, J ¼3 Hz, arom),
7.50 (m, 3H, arom), 7.30 (t, 1H, J ¼ 1.8 Hz, J ¼ 6.9 Hz, arom), 7.04
(m, 1H, arom), 6.64 (d, 1H, J ¼ 7.8 Hz, arom). 13C NMR (75 MHz, d6-
DMSO): d 162.3, 149.9, 137.8, 136.3, 135.1, 131.3, 125.6, 120.9, 120.4,
119.7, 115.3, 113.7, 98.6. MS (EI): m/z 304 (Mþ), 225, 197, 112, 78. HR-
ESI-MS: m/z calcd for C13H9N2SBr þ H: 304.9743. Found: 304.9749.
2-(20-Pyridylthio)-pyrrole (2k): Colorless liquid. IR (KBr): vmax cm21
3373.9, 3172.9, 3056.5, 2940.9, 1576.3, 1450.6, 1417.3, 1125.6, 1026.8,
758.2, 733.8. 1H NMR (300 MHz, CDCl3): d 9.19 (s, 1H, NH), 8.38
(m, 1H, arom), 7.49 (m, 1H, arom), 7.02 (m, 1H, arom), 6.93 (m, 1H,
arom), 6.70 (m, 1H, arom), 6.57 (d, 1H, J ¼ 0.9 Hz, arom), 6.34 (t, 1H, J
¼3 Hz, arom). 13C NMR (75 MHz, CDCl3): d 162.6, 148.9, 136.9, 122.4,
120.0, 119.7, 118.5, 113.8, 110.4. MS (EI): m/z 176 (Mþ), 148, 132, 98.
HR-ESI-MS: m/z calcd for C9H8N2S þ H: 177.0481. Found: 177.0483.
ACKNOWLEDGMENT
We acknowledge the financial Support of the National Natural Science Foun-
dation of China (Project 20572040).
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