Synthesis of 1-(1-arylsulfanylalkyl)indoles and 2,2-bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes by acid-catalyzed reactions of indoles with aryl vinyl sulfides

Article abstract of DOI:10.3987/COM-09-11867

We report a facile synthesis of 1-(1-arylsulfanylalkyl)indoles and 2,2-bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes under mild conditions. Thus, treatment of 3-substituted indoles with aryl vinyl sulfides in dichloromethane at room temperature in the presence of a catalytic amount of (±)-camphor-10-sulfonic acid yields the former indole derivatives in moderate to fair yields. 3-Nonsubstituted indoles can be transformed into the latter indole derivatives in satisfactory yields on treatment with excess aryl vinyl sulfides in the presence of a catalytic amount of the acid under similar conditions.

Full text of DOI:10.3987/COM-09-11867

HETEROCYCLES, Vol. 81, No. 2, 2010
433
HETEROCYCLES, Vol. 81, No. 2, 2010, pp. 433ꢀ- 439. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd November, 2009 Accepted, 22nd DecemberꢀꢀPublished online, 25th December, 2009
DOI: 10.3987/COM-09-11867
SYNTHESIS
OF
1-(1-ARYLSULFANYLALKYL)INDOLES
AND
BY
2,2-BIS[1-(1-ARYLSULFANYLALKYL)INDOL-3-YL]PROPANES
ACID-CATALYZED REACTIONS OF INDOLES WITH ARYL VINYL
SULFIDES
Kazuhiro Kobayashi,* Yuu Shirai, Shuhei Fukamachi, and Hisatoshi
Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract – We report a facile synthesis of 1-(1-arylsulfanylalkyl)indoles and
2,2-bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes under mild conditions. Thus,
treatment of 3-substituted indoles with aryl vinyl sulfides in dichloromethane at
room temperature in the presence of a catalytic amount of (±)-camphor-
10-sulfonic acid yields the former indole derivatives in moderate to fair yields.
3-Nonsubstituted indoles can be transformed into the latter indole derivatives in
satisfactory yields on treatment with excess aryl vinyl sulfides in the presence of
a catalytic amount of the acid under similar conditions.
Indoles are undoubtedly important heterocycles not only in medicinal chemistry but also in synthetic
organic chemistry. Recently, we described syntheses of 1-(1-alkoxyalkyl)indoles and 2,2-bis[1-(1-
alkoxyalkyl)indol-3-yl]propanes by acid catalyzed reactions of indoles with vinyl ethers.1 On
continuation of this work, we became interested in investigating reactions of indoles with aryl vinyl
sulfides under acidic conditions, which would give 1-(1-arylsulfanylalkyl)indoles and 2,2-bis[1-(1-
arylsulfanylalkyl)indol-3-yl]propanes, because there have been no reports on the synthesis of these types
of indole derivatives and they may be of biological importance. We found that the reactivity of aryl vinyl
sulfides to indoles is analogous to that of vinyl ethers and that the expected above indole derivatives
could be obtained from 3-substituted indoles and 3-nonsubstituted indoles, respectively. Herein, we
report the results of our work, which provide facile synthetic routes to these indole derivatives under
mild conditions.

The preparation of 1-(1-arylsulfanylalkyl)indoles (3) from 3-substituted indoles (1) and aryl isopropenyl
sulfides (2) was accomplished under the conditions shown in Scheme 1. 3-Methylindole (1a) was
commercially available. 3-Ethylindole (1b) and 5-methoxy-3-methylindole (1c) were prepared by
Ito-Saegusa indole synthesis.2 The three aryl isopropenyl sulfides (2) were prepared by reacting the
respective aryl isopropyl sulfoxides with a magnesium amide generated from ethylmagnesium bromide
and diisopropylamine under the conditions developed by us.3 3-Substituted indoles (1) were allowed to
react with two molar amounts of aryl isopropenyl sulfides (2) in dichloromethane containing 0.05 molar
amount of (±)-camphor-10-sulfonic acid (CSA) in the presence of Molecular Sieves 3A at room
temperature. The reactions proceeded smoothly as expected to afford the desired 1-(1-
arylsulfanylalkyl)indoles (3) in the yields ranging from 55 to 69%. In all cases the presence of
Molecular Sieves was essential for satisfactory production of the desired products; the reactions in the
absence of Molecular Sieves resulted in the formation of only traces of the products. This may be
attributable to inhibition of the reaction by contaminated water in the reaction mixtures. Aryl
isopropenyl sulfides (2) seem to be labile to water under the present acidic conditions; they were
transformed into 1-arylsulfanylpropan-2-ones before reaction with indoles. Although we have no
explanation for the mechanism of this transformation at the present stage, the participation of water in it
is evident.
R2
R1
R2
R1
SAr
Me
cat. CSA, CH2Cl2, rt
N
+
N
H
SAr
Me
Me
1
2
3
Scheme 1
Table 1. Preparation of 1-(1-Arylsulfanylalkyl)indoles (3)
Entry
1
1a (R1 = H, R2 = Me)
1a
1a
1b (R1 = H, R2 = Et)
1c (R1 = OMe, R2 = Me)
2
3 (Yield/%)a
3a (56)
1
2
3
4
5
2a (Ar = Ph)
2b (Ar = p-Tol)
2c (Ar = 4-MeOC6H5)
3b (64)
3c (69)
3d (64)
3e (55)
2b
2a
aIsolated yields.
2,2-Bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes (5a) and (5b) were obtained by the reaction of indole
(4; R = H) with four molar amounts of isopropenyl 4-methylphenyl sulfide (2b) or isopropenyl

HETEROCYCLES, Vol. 81, No. 2, 2010
435
4-methoxyphenyl sulfide (2c) in the presence of 0.15 molar amount of (±)-camphor-10-sulfonic acid
under conditions similar to those described above for the preparation of 3 in moderate yields, as shown
in Scheme 2. Similar treatment of 5-bromoindole (4; R = Br) with 2c also led to the facile formation of
the corresponding desired bis(indolyl)propane derivative (5c) in moderate yield. However, it was
surprising to find that the reaction of indole (4; R = H) with isopropenyl phenyl sulfide (2a) under the
same reaction conditions resulted in an almost quantitative recovery of the starting materials. Probably,
indole is not reactive enough toward this sulfide in the present reaction. Elevating the reaction
temperature to reflux resulted in the formation of an intractable mixture of products. The
bis(indolyl)propane structure of these products was confirmed by FAB-mass spectroscopic analyses as
well as 1H and 13C NMR spectra. The use of 0.1 molar amount of the acid gave rather lower yields of the
desired products. In each case the absence of Molecular Sieves gave a disappointing result as mentioned
above for the preparation of 3.
R
R
Me
Me
R
cat. CSA, CH2Cl2, rt
+
2 (excess)
N
H
N
N
SAr
Me
ArS
4
Me
Me
Me
5a R = H, Ar = p-Tol 41%
5b R = H, Ar = 4-MeOC6H5 53%
5c R = Br, Ar = 4-MeOC6H5 48%
Scheme 2
In conclusion, we have discovered that acid catalyzed reactions of indoles with aryl isopropenyl sulfides,
which provide efficient synthetic routes to 1-(1-arylsulfanylalkyl)indoles and 2,2-bis[1-(1-
arylsulfanylalkyl)indol-3-yl]propanes. These methods may find value in preparing these indole
derivatives, because the starting materials are readily available and operations are very simples.
EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are
uncorrected. IR spectra were determined with a Shimadzu FTIR-8300 spectrophotometer. The 1H NMR
spectra were determined in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR
spectrometer operating at 500 MHz or a JEOL LA400 FT NMR spectrometer operating at 400 MHz.
13
The C NMR spectra were determined in CDCl3 using TMS as an internal reference with a JEOL
ECP500 FT NMR spectrometer operating at 125 MHz or a JEOL LA400 FT NMR spectrometer
operating at 100 MHz. Low-resolution MS spectra (EI, 70 eV or FAB) and a high-resolution MS

spectrum (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. TLC was carried out on
a Merck Kieselgel 60 PF254. Column chromatography was performed using Merck Kieselgel 60
(0.063–0.200 mm). All of the organic solvents used in this study were dried over appropriate drying
agents and distilled prior to use.
Starting Materials. Vinyl sulfides 2a and 2b were prepared according to the procedure reported
previously by us.3 All other chemicals used in this study were commercially available.
1-Ethyl-2-isocyano-5-methoxybenzene. This compound was prepared by treating 1-isocyano-2-
lithiomethyl-4-methoxybenzene with iodomethane according to the procedure reported by Ito et al.2 in
1
63% yield; a pale-yellow liquid; bp 88 ˚C (bath temp)/1.1 mmHg; IR (neat) 2120, 1607 cm–1; H NMR
(500 MHz) ꢀ 1.27 (3H, t, J = 7.3 Hz), 2.76 (2H, q, J = 7.3 Hz), 3.82 (3H, s), 6.71 (1H, dd, J = 8.7, 2.8
Hz), 6.77 (1H, d, J = 2.8 Hz), 7.28 (1H, d, J = 8.7 Hz). HR-MS Calcd for C10H11NO: M, 161.0841.
Found: m/z 161.0857.
5-Methoxy-3-methylindole. This compound was prepared by treating the above isocyanide with lithium
2,2,6,6-tetramethylpiperidide according to the procedure reported by Ito et al.2 in 54% yield; mp 64–66
1
˚C (hexane) (lit.,4 mp 66 ˚C). The spectral (IR and H NMR) data for this compound were identical to
those reported previously.5
Isopropenyl 4-Methoxyphenyl Sulfide (2c).6 This compound was prepared by treating isopropyl
4-methoxyphenyl sulfoxide,7 prepared by a successive treatment of 4-methoxybenzenethiol with sodium
hydride and 2-iodopropane and the subsequent NaIO4 oxidation of the resulting isopropyl
4-methoxyphenyl sulfide,8 with a magnesium amide, generated from i-Pr2NH and EtMgBr, under
conditions reported previously by us1 in 66% yield; a pale-yellow oil; Rf 0.37 (1:5 CH2Cl2–hexane); IR
(neat) 1615 cm–1; 1H NMR (400 MHz, CDCl3) ꢀ 1.95 (3H, d, J = 1.5 Hz), 3.82 (3H, s), 4.63 (1H, s), 4.98
(1H, q, J = 1.5 Hz), 6.89 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.7 Hz).
Typical Procedure for the Preparation of 1-(Arylsulfanylalkyl)indoles (3). 3-Methyl-1-[1-methyl-1-
(phenylsulfanyl)ethyl]indole (3a). To a stirred solution of 3-methylindole (1) (0.13 g, 1.0 mmol) and
isopropenyl phenyl sulfide (2a) (0.30 g, 2.0 mmol) in CH2Cl2 (3 mL) containing MS 3A (1.3 g) at rt was
added (±)-camphor-10-sulfonic acid (11 mg, 0.050 mmol); the mixture was stirred for 2 h. After removal
of molecular sieves by filtration, saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (7 mL) were added.
The layers were separated, and the aqueous layer was extracted with CH2Cl2 twice (5 mL each). The
combined extracts were washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent
gave a residue, which was purified by preparative TLC on silica gel to afford 3a (0.16 g, 56%); a
pale-yellow oil; Rf 0.67 (1:5 THF–hexane); IR (neat) 3051, 1611 cm–1; 1H NMR (500 MHz) ꢀ 1.98 (6H,
s), 2.22 (3H, s), 6.66 (1H, s), 6.77 (2H, d, J = 7.8 Hz), 7.07 (2H, dd, J = 7.8, 7.3 Hz), 7.18 (1H, dd, J =
7.8, 6.9 Hz), 7.21 (1H, t, J = 7.3 Hz), 7.27 (1H, dd, J = 7.8, 6.9 Hz), 7.58 (1H, d, J = 7.8 Hz), 8.07 (1H,
13
d, J = 7.8 Hz); C NMR (125 MHz) ꢀ 9.46, 30.15, 67.80, 109.68, 115.23, 118.90, 119.07, 121.00,

HETEROCYCLES, Vol. 81, No. 2, 2010
437
123.68, 128.34, 128.70, 130.67, 131.66, 135.40, 135.90; MS m/z 281 (M+, 2.8), 172 (100). Anal. Calcd
for C18H19NS: C, 76.82; H, 6.81; N, 4.98. Found: C, 76.71; H, 6.93; N, 4.93.
3-Methyl-1-[1-methyl-1-(4-methylphenylsulfanyl)ethyl]indole (3b): pale-yellow crystals; mp 81–84
˚C (hexane); IR (KBr) 3051, 1611 cm–1; 1H NMR (400 MHz, CDCl3) ꢀ 1.97 (6H, s), 2.22 (3H, d, J = 1.1
Hz), 2.25 (3H, s), 6.66 (1H, s), 6.67 (2H, d, J = 8.4 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 8.1,
7.0 Hz), 7.25 (1H, dd, J = 8.1, 7.0 Hz), 7.57 (1H, d, J = 8.1 Hz), 8.07 (1H, d, J = 8.1 Hz); 13C NMR (125
MHz, CDCl3) ꢀ 9.47, 21.15, 30.06, 67.65, 109.55, 115.28, 118.86, 119.00, 120.93, 123.72, 128.12,
129.16, 130.65, 135.40, 135.90, 138.83; MS m/z 295 (M+, 2.8), 172 (100). C19H21NS: C, 77.24; H, 7.16;
N, 4.74. Found: C, 76.94; H, 7.40; N, 4.58.
1-[1-(4-Methoxylphenylsulfanyl)-1-methylethyl]-3-methylindole (3c): colorless crystals; mp 80–83
˚C (hexane–CH2Cl2); IR (KBr) 3050, 1611 cm–1; 1H NMR (400 MHz) ꢀ 1.96 (6H, s), 2.21 (3H, s), 3.72
(3H, s), 6.59 (2H, d, J = 9.3 Hz), 6.64 (1H, s), 6.69 (2H, d, J = 9.3 Hz), 7.17 (1H, ddd, J = 7.8, 7.3, 1.0
13
Hz), 7.26 (1H, ddd, J = 7.8, 7.3, 1.0 Hz), 7.57 (1H, d, J = 7.8 Hz), 8.06 (1H, d, J = 7.8 Hz); C NMR
(100 MHz) ꢀ 9.46, 29.91, 55.13, 67.67, 109.50, 113.86, 115.29, 118.84, 118.98, 120.92, 122.43, 123.75,
130.62, 135.40, 137.57, 160.23; MS m/z 311 (M+, 3.0), 172 (100). C19H21NOS: C, 73.27; H, 6.80; N,
4.50. Found: C, 73.13; H, 6.87; N, 4.41.
3-Ethyl-1-[1-methyl-1-(4-methylphenylsulfanyl)ethyl]indole (3d): a yellow oil; Rf 0.46 (1:19
Et2O–hexane); IR (neat) 3050, 1609 cm–1; 1H NMR (500 MHz) ꢀ 1.21 (3H, t, J = 7.3 Hz), 1.98 (6H, s),
2.25 (3H, s), 2.67 (2H, q, J = 7.3 Hz), 6.62 (2H, d, J = 8.2 Hz), 6.63 (1H, s), 6.86 (2H, d, J = 8.2 Hz),
7.16 (1H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.26 (1H, ddd, J = 7.8, 7.3, 0.9 Hz), 7.61 (1H, d, J = 7.8 Hz), 8.06
(1H, d, J = 7.8 Hz);13C NMR (125 MHz) ꢀ 14.78, 18.13, 21.16, 30.07, 67.74, 115.41, 116.60, 118.95,
118.97, 120.92, 122.75, 128.14, 129.12, 129.82, 135.54, 135.91, 138.82; MS m/z 309 (M+, 3.3), 186
(100). C20H23NS: C, 77.62; H, 7.49; N, 4.53. Found: C, 77.71; H, 7.51; N, 4.30.
5-Methoxy-3-methyl-1-[1-methyl-1-(phenylsulfanyl)ethyl]indole (3e): colorless needles; mp 98–100
1
˚C (hexane); IR (KBr) 3050, 1616 cm–1; H NMR (500 MHz) ꢀ 1.96 (6H, s), 2.18 (3H, d, J = 0.9 Hz),
3.91 (3H, s), 6.63 (1H, s), 6.77 (2H, dd, J = 7.8, 1.4 Hz), 6.92 (1H, dd, J = 9.2, 1.8 Hz), 7.00 (1H, d, J =
1.8 Hz), 7.07 (2H, dd, J = 7.8, 7.3 Hz), 7.22 (1H, tt, J = 7.3, 1.4 Hz), 7.96 (1H, d, J = 9.2 Hz);13C NMR
(125 MHz) ꢀ 9.62, 30.23, 55.85, 67.86, 100.88, 109.31, 110.91, 116.01, 124.50, 128.43, 128.78, 130.71,
131.23, 131.79, 136.00, 153.78; MS m/z 311 (M+, 2.9), 202 (100). C19H21NOS: C, 73.27; H, 6.80; N,
4.50. Found: C, 73.26; H, 6.76; N, 4.25.
Typical Procedure for the Preparation of 2,2-Bis[1-(1-arylsulfanylalkyl)indol-3-yl]propanes (5).
1-[1-Methyl-1-(4-methylphenylsulfanyl)ethyl]-3-(1-methyl-1-{[1-methyl-1-(4-methylphenyl-
sulfanyl)ethyl]indol-3-yl}ethyl)indole (5a). To a stirred solution of indole (4; R = H) (0.12 g, 1.0
mmol) and isopropenyl p-tolyl sulfide (2b) (0.66 g, 4.0 mmol) in CH2Cl2 (3 mL) containing MS 3A (1.3
g) at rt was added (±)-camphor-10-sulfonic acid (33 mg, 0.15 mmol). After the mixture was stirred for 2

h, it was worked up and purified in a manner similar to that described for the preparation 3a to afford 5a
(0.13 g, 41%); a white solid; mp 75–78 ˚C (pentane); IR (KBr) 3046, 1611 cm–1; 1H NMR (500 MHz) ꢀ
1.69 (6H, s), 1.99 (12H, s), 2.31 (6H, s), 6.70 (4H, d, J = 8.2 Hz), 6.74 (2H, s), 6.89 (2H, dd, J = 7.8, 7.3
Hz), 6.94 (4H, d, J = 8.2 Hz), 7.16 (2H, dd, J = 8.2, 7.3 Hz), 7.24 (2H, d, J = 7.8 Hz), 8.09 (2H, d, J =
13
8.2 Hz); C NMR (125 MHz) ꢀ 21.27, 30.14, 30.18, 34.65, 67.79, 115.39, 118.49, 120.37, 121.27,
122.58, 122.88, 128.24, 128.74, 129.27, 135.93, 136.20, 138.87; FAB-MS m/z 603.3 [(M+1)+, 100].
Anal. C39H42N2S2: C, 77.69; H, 7.02; N, 4.65. Found: C, 77.61; H, 7.02; N, 4.69.
1-[1-(4-Methoxyphenylsulfanyl)-1-methylethyl]-3-(1-{[1-(4-methoxyphenylsulfanyl)-1-methyl-
ethyl]indol-3-yl}-1-methylethyl)indole (5b): a white solid; mp 84–87 ˚C (MeOH–Et2O); IR (KBr)
1
3046, 1591 cm–1; H NMR (400 MHz) ꢀ 1.54 (6H, s), 1.98 (12H, s), 3.76 (6H, s), 6.65 (4H, d, J = 8.8
Hz), 6.70 (2H, s), 6.73 (4H, d, J = 8.8 Hz), 6.89 (2H, ddd, J = 8.2, 7.3, 1.1 Hz), 7.15 (2H, ddd, J = 8.2,
13
7.3, 1.4 Hz), 7.23 (2H, d, J = 8.2 Hz), 8.07 (2H, d, J = 8.2 Hz); C NMR (125 MHz) ꢀ 30.02, 30.16,
34.65, 55.23, 67.78, 113.98, 115.39, 118.47, 120.37, 121.27, 122.51, 122.55, 122.80, 128.69, 136.18,
137.60, 160.31; FAB-MS m/z 635.3 [(M+1)+, 100]. Anal. C39H42N2O2S2: C, 73.78; H, 6.67; N, 4.41.
Found: C, 73.50; H, 6.64; N, 4.32.
5-Bromo-1-[1-(4-methoxyphenylsulfanyl)-1-methylethyl]-3-(1-{5-bromo-1-[1-(4-methoxyphenyl-
sulfanyl)-1-methylethyl]indol-3-yl}-1-methylethyl)indole (5c): a white solid; mp 149–151 ˚C
(MeOH–Et2O); IR (KBr) 3072, 1591 cm–1; 1H NMR (400 MHz) ꢀ 1.62 (6H, s), 1.98 (12H, s), 3.73 (6H,
s), 6.64 (4H, d, J = 8.8 Hz), 6.73 (4H, d, J = 8.8 Hz), 6.74 (2H, s), 7.20 (2H, dd, J = 8.8, 1.9 Hz), 7.31
(2H, d, J = 1.9 Hz), 7.94 (2H, d, J = 8.8 Hz);13C NMR (125 MHz) ꢀ 30.07, 30.23, 34.40, 55.25, 67.89,
112.38, 114.08, 116.77, 122.17, 122.21, 123.29, 123.40, 123.67, 120.17, 134.92, 137.50, 160.42;
FAB-MS m/z 791.1 [(M+1)+, 100]. Anal. C39H40Br2N2O2S2: C, 59.09; H, 5.09; N, 3.53. Found: C, 58.87;
H, 5.16; N, 3.37.
ACKNOWLEDGEMENTS
Determination of the mass spectra and performance of combustion analyses by Mrs. Miyuki Tanmatsu
of this University are gratefully acknowledged.
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