Synthesis of indole and indolenine derivatives starting from indoline-2-thiones

Article abstract of DOI:10.1002/jhet.5570380115

Indoline-2-thiones 1a-b,d,f,h, which have at least one hydrogen at the 3-position reacted with α-halo ester 2a-d, α-halo ketones 2e-f, and α-bromoacetonitrile 2g to give 2-alkylthioindole derivatives 3-11. In a similar manner treatment of 3,3-disubstituted indoline-2-thiones 1c,e with α-halo esters 2a,c,d and α-halo ketone 2e gave 2-alkylthioindolenines 12-16. Treatment of 1,3,3- trisubstituted indoline-2-thiones 1g,i with ethyl bromo-acetate 2a resulted in recovery of starting materials. Desulfurization of indolenine 14 with triphenylphosphine gave 2-alkylideneindoline 19.

Full text of DOI:10.1002/jhet.5570380115

Jan-Feb 2001
Synthesis of Indole and Indolenine Derivatives
Starting from Indoline-2-thiones
105
Takehiko Nishio*, Osamu Saku and Hiroshi Yamamoto [a]
Department of Chemistry, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571 Japan
[a] Faculty of Education, Ibaraki University, Bunkyo, Mito-shi, Ibaraki, 310-0056 Japan
Received May 15, 2000
In Memorial Professor Raymond N. Castle
Indoline-2-thiones 1a-b,d,f,h, which have at least one hydrogen at the 3-position reacted with α-halo ester
2a-d, α-halo ketones 2e-f, and α-bromoacetonitrile 2g to give 2-alkylthioindole derivatives 3-11. In a similar
manner treatment of 3,3-disubstituted indoline-2-thiones 1c,e with α-halo esters 2a,c,d and α-halo ketone 2e
gave 2-alkylthioindolenines 12-16. Treatment of 1,3,3- trisubstituted indoline-2-thiones 1g,i with ethyl
bromo-acetate 2a resulted in recovery of starting materials. Desulfurization of indolenine 14 with
triphenylphosphine gave 2-alkylideneindoline 19.
J. Heterocyclic Chem., 38, 105 (2001).
Indoline-2-thiones, which are easily accessible by direct
3,5,7,10-11. Treatment of indoline-2-thione 1f with ethyl
bromoacetate 2a in the absence of triphenylphosphine under
the same conditions also gave indole derivative 7, but in low
yield. In a similar manner indoline-2-thiones 1b,d,f reacted
smoothly with α-bromoketones 2e-f and bromoacetonitrile
2g to give the corresponding 2-substituted indole derivatives
4,6,8-9. Reductive product, propiophenone was formed by
the reaction of 1b and α-bromopropiophenone 2e. The
structures of 3-11 were elucidated on the basis of
spectroscopic properties and microanalyses, the latter
indicating that they were the dehydrohalogenation products
of 1:1 adduct of indoline-2-thiones 1 and 2. Treatment of
1-methyl-2-(ethoxycarbonyl-methylthio)-3-phenylindoline 7
with equimolar amount of m-chloroperbenzoic acid
(MCPBA) gave the corresponding sulfoxide 17 in 59%
yield, exclusively, while treatment of 7 with 2 molar
equivalent of MCPBA gave the corresponding sulfoxide 17
and sulfone 18 in 16 and 17% yields, respectively, along with
sulfurization of their oxygen analogues with dimer of
p-methoxyphenylthionophosphine (Lawesson's reagent), are
useful synthetic intermediates for the synthesis of indole
derivatives [1]. In addition 2-alkylideneindolines are
regarded as important starting materials for the synthesis of
photochromic compounds, spiropyrans [2]. The
Eschenmoser condensation-extrusion reaction is an efficient
method for the C-C bond formation [3-4]. In this paper, we
describe the results of direct condensation of indoline-2-
thiones 1 with α-activated esters 2a-d and ketones 2e-f
yielding the indole 3-11 and indolenine derivatives 12-16.
Indoline-2-thiones 1a-b,d,f,h, which have at least one
hydrogen at 3-position, were treated with α-activated esters
such as ethyl bromoacetate 2a, ethyl chloroacetate 2b, ethyl
2-bromobutanoate 2c and methyl bromoacetate 2d in the
presence of triphenylphosphine, triethylamine and sodium
iodide to yield 2-(alkoxycarbonylalkylthio)indole derivatives
Table
Yields of Indole 3-11 and Indolenine Derivatives 12-16.
Thione 1
Halide 2
1
2
3
4
5
R
R
R
R
R
X
Yield (%) [a] of 3-16
1a
1b
1c
1c
1d
1d
1e
1e
1e
1f
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
H
H
2a
2e
2a
2d
2d
2f
2a
2c
2e
2a
2a
2b
2f
H
Me
H
H
H
H
H
Et
Me
H
EtO
Ph
EtO
MeO
MeO
Ph
EtO
EtO
Ph
EtO
EtO
EtO
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
3 (46)
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
H
Me
Me
H
4 (45) propiophenone (50)
12 (84)
13 (72)
5 (23)
6 (29)
14 (46)
H
Ph
Ph
Ph
H
H
H
H
H
Me
H
H
15 (44)
16 (66) propiophenone (31)
7 (93)
1f[b]
1f
1f
H
H
H
7 (19)
7 (75)
8 (95)
9 (75)
no reaction
10 (30)
11 (76)
1f
2g
2a
2a
2c
2a
BrCH CN
2
1g
1h
1h
1i
H
H
Et
H
EtO
EtO
EtO
EtO
Br
Br
Br
Br
H
Me
Me
no reaction
[a] Isolated yield; [b] In the absence of Ph P.
3

106
T. Nishio, O. Saku and H. Yamamoto
Vol. 38
esters 2a, c-d and α-bromopropiophenone 2e under similar
conditions yielded indolenine derivatives 12-16.
Treatment of 2-(ethoxycarbonylmethylthio)-3,3-
diphenylindolenine 14 thus obtained with sodium hydride
and triphenylphosphine gave the corresponding 2-alkyl-
ideneindoline 19 in good yield. The mechanism for the for-
mation of 19 can be explained in terms of episulfide inter-
mediate E [3]. When 1,3,3-trisubstituted indoline-2-
thiones 1g,i were treated with ethyl bromoacetate 2a under
the same conditions, the unchanged starting materials were
recovered quantitatively.
EXPERIMENTAL
Melting and boiling points were measured with Yanaco micro
melting point apparatus (MP-3J) and Sibata glass tube oven
distillation apparatus (GOT-350RD) respectively and are
uncorrected. The ir spectra were recorded on JASCO FT/IR-300
-1
1
13
spectrophotometer (in cm ). The H and C nmr spectra were
run on JEOL JMN-EX 270 (270 MHz) and Varian GEMINI 200
(200 MHz) spectrometers in deuteriumchloroform using TMS as
an internal standard (δ in ppm, J in Hz). Chromatogaphic
purifications were carried out on a silica gel column (flash
chromatography: Wakogel C-300).
Reaction of Indoline-2-thiones 1 with α-Halo Esters 2a-d,
α -Bromopropiophenone 2e, α -Bromoacetophenone 2f, or
Bromoacetonitrile 2g.
Typical procedure: To a solution of indoline-2-thione 1
(1 mmol), the corresponding halide 2 (1 mmol), and sodium
iodide (2 mmol) in acetonitrile (50 ml) under argon was added
dropwise a solution of triphenylphosphine (2 mmol) and
triethylamine (2 mmol) in acetonitrile (20 ml) at reflux
temperature. The mixture was refluxed for 4-10 hours, and then
poured into water and extracted with ethyl acetate. The organic
layer was washed with dilute hydrochloric acid (HCl), sodium
bicarbonate (NaHCO ) solution, and H O and dried over
3
2
anhydrous magnesium sulfate (MgSO ). After removal of the
several small amounts of unidentified products. Attempts for
the sulfur extrusion of 2-(ethoxycarbonylmethylthio)indole
7 were unsuccessful. Treatment of 7 with base such as
triethylamine and sodium hydride, and triphenylphosphine
resulted in recovery of unchanged 7. On the other hand,
treatment of 3,3-disubstituted indoline-2-thiones 1c,e
possessing no hydrogen at the 3-position with α-halo
4
solvent, the residue was chromatographed on a silica gel column
with toluene-hexane (4:1-1:1) to give indole or indolenine
derivatives 3-16.
2-Ethoxycarbonylmethylthioindole (3).
This compound had mp 42-43°; ir: ν (KBr) 3388, 1726, 1296,
1
1181; H nmr: δ 1.26 (t, 3H, J=7.2), 3.51 (s, 2H), 4.21 (q, 2H, J =
13
7.2), 6.67 (s, 1H), 7.05-7.57 (m, 4H), 9.12 (br s, 1H); C nmr: δ
13.6, 38.0, 61.7, 108.5, 110.5, 119.7, 120.0, 122.5, 126.9, 127.7,
137.1, 171.3.
Anal. Calcd. for C H NO S (233.2): C, 61.27; H, 5.57; N,
12 13
2
5.96. Found: C, 61.07; H, 5.51; N, 5.75.
2-(1-Benzoylethylthio)-3-methylindole (4).
1
This compound had mp 44-45°; ir: ν (KBr) 3374, 1680; H
nmr: δ 1.47 (d, 3H, J = 7.0), 2.27 (s, 3H), 4.55 (q, 1H, J = 7.0),
13
7.04-7.59 (m, 8H), 7.89-7.95 (m, 1H), 8.14 (br s, 1H); C nmr: δ
9.1, 16.4, 45.7, 110.4, 119.0, 120.4, 123.0, 128.3, 133.0, 135.7,
197.5.
Anal. Calcd. for C H NOS (295.3): C, 73.20; H, 5.80; N,
18 17
4.74. Found: C, 73.30; H, 5.85; N, 4,61.

Jan-Feb 2001
Synthesis of Indole and Indolenine Derivatives Starting from Indoline-2-thiones
107
2-Methoxycarbonylmethylthio-3-phenylindole (5).
2-Ethoxycarbonylmethylthio-3,3-dimethylindolenine (12).
This compound had mp 167-169°; ir: ν (KBr) 1725, 1306,
This compound had bp 185° at 2 Torr; ir: ν (film) 1737, 1619,
1
1
1257, 1159, 1140; H nmr: δ 2.16 (s, 3H), 4.25 (s, 2H), 7.23-7.77
1298, 1209, 1090; H nmr: δ 1.30 (t, 3H, J = 8.3), 1.38 (s, 6H),
13
13
(m, 8H), 8.14-8.19 (m, 1H); C nmr: δ 30.3, 37.6, 112.9, 118.3,
4.13 (s, 2H), 4.21 (q, 2H, J = 8.3), 7.02-7.48 (m, 4H); C nmr: δ
123.0, 124.6, 126.6, 126.9, 128.0, 128.2, 128.7, 131.2, 132.0,
172.7
13.5, 24.5, 32.3, 54.6, 61.3, 118.2, 120.4, 123.3, 127.2, 145.2,
+
152.8, 168.3, 186.1; Ms: m/z 263 (M ), 176.
Anal. Calcd. for C H NO S (297.3): C, 68.67; H, 5.06; N,
17 15
2
Anal. Calcd. for C H NO S (263.3): C, 63.86; H, 6.51; N,
14 17
2
4.71. Found: C, 68.77; H, 5.31; N, 5.02.
5.32. Found: C, 63.81; H, 6.60; N, 5.65.
2-Benzoylmethylthio-3-phenylindole (6).
2-Methoxycarbonylmethylthio-3,3-dimethylindolenine (13).
This compound had mp 116-117°; ir: ν (KBr) 3369, 1673, 749,
699; H nmr: δ 4.07 (s, 2H), 7.07-7.96 (m, 14H), 9.15 (br s, 1H);
C nmr: δ 41.8, 110.6, 119.3, 120.0, 122.0, 123.0, 125.6, 126.3,
127.1, 128.0, 128.2, 128.4, 129.6, 133.6, 134.9, 135.8, 196.1.
This compound had mp 136-137°; ir: ν (KBr) 1713, 1675,
1
1
1338, 1225, 1212; H nmr: δ 1.38 (s, 6H), 3.78 (s, 3H), 4.18
13
13
(s, 2H), 7.10-7.50 (m, 4H); C nmr: δ 24.5, 32.0, 52.3, 54.4,
118.5, 120.6, 124.0, 124.4, 145.6, 152.7, 169.0, 186.0.
Anal. Calcd. for C H NOS (343.4): C, 76.93; H, 4.99; N,
22 17
Anal. Calcd. for C H NO S (249.3): C, 62.64; H, 6.07; N,
13 15
2
4.08. Found: C, 76.69; H, 5.07; N, 4.07.
5.62. Found: C, 62.83; H, 5.85; N, 5.31.
2-Ethoxycarbonylmethylthio-N-methyl-3-phenylindole (7).
This compound had bp 250° at 2 Torr; ir: ν (film) 1731, 1370,
2-Ethoxycarbonylmethylthio-3,3-diphenylindolenine (14).
1
This compound had mp 132-133°; ir: ν (KBr) 1744, 1301,
1323, 1268, 1126; H nmr: δ 1.14 (t, 3H, J = 7.2), 3.34 (s, 2H),
1
13
1167, 1121; H nmr: δ 1.28 (t, 3H, J = 7.3), 4.03 (s, 2H), 4.23
4.00 (s, 3H), 4.01 (q, 2H, J = 7.2), 7.19-7.83 (m, 9H); C nmr: δ
13
(q, 2H, J = 7.3), 7.07-7.52 (m, 14H); C nmr: δ 14.1, 33.7, 61.7,
13.3, 29.7, 38.0, 60.9, 109.3, 119.5, 119.7, 123.6, 124.8, 126.1,
127.8, 128.7, 129.6, 133.5, 137.4, 168.5.
73.0, 119.4, 124.1, 125.0, 127.5, 128.2, 128.3, 128.6, 128.7,
131.9, 141.2, 144.9, 153.8, 168.6, 183.7.
Anal. Calcd. for C H NO S (325.3): C, 70.10; H, 5.89; N,
19 19
2
Anal. Calcd. for C H NO S (387.4): C, 74.39; H, 5.46; N,
4.31. Found: C, 69.95; H, 5.98; N, 4.01.
24 21
2
3.62. Found: C, 74.58; H, 5.60; N, 3.33.
2-Benzoylmethylthio-N-methyl-3-phenylindole (8).
This compound had mp 112-113°; ir: ν (KBr) 1684, 751, 701;
2-(1-Ethoxycarbonylpropylthio)-3,3-diphenylindolenine (15).
1
13
H nmr: δ 3.93 (s, 3H), 3.92 (s, 2H), 7.18-7.80 (m, 14H);
C
This compound had bp 240° at 2 Torr; ir: ν (film) 1731, 1302,
1
nmr: δ 29.7, 42.0, 109.5, 119.6, 119.9, 123.2, 123.3, 126.3, 128.0,
128.1, 128.2, 129.8, 133.0, 134.4, 134.8, 137.3, 193.8.
1258, 1158, 1119; H nmr: δ 0.99 (t, 3H, J = 7.4), 1.24 (t, 3H, J =
7.2), 1.85-2.05 (m, 2H), 4.23 (q, 2H, J = 7.4), 4.61 (t, 1H, J = 7.2),
Anal. Calcd. for C H NOS (357.4): C, 77.28; H, 5.36; N,
13
23 19
7.03-7.52 (m, 14H); C nmr: δ 11.1, 13.7, 24.7, 49.4, 61.0, 72.8,
3.92. Found: C, 76.91; H, 5.50; N, 3.74.
119.0, 123.8, 124.6, 125.0, 127.1, 127.3, 128.2, 128.7, 137.5,
140.7, 141.1, 144.6, 158.3, 171.4, 183.5.
2-Cyanomethylthio-N-methyl-3-phenylindole (9).
Anal. Calcd. for C H NO S (415.5): C, 75.16; H, 6.07; N,
26 25
2
This compound had bp 235° at 2 Torr; ir: ν (film) 2230, 1600,
3.37. Found: C, 75.01; H, 6.07; N, 3.44.
1
1460, 744, 699; H nmr: 2.91 δ (s, 2H), 3.78 (s, 3H), 6.95-7.56
13
2-(1-Benzoylethylthio)-3,3-diphenylindolenine (16).
(m, 9H); C nmr: δ 21.7, 30.2, 109.9, 120.0, 120.3, 124.0, 125.8,
126.8, 128.2, 128.5, 129.9, 132.9, 137.4.
This compound had mp 136-138°; ir: ν (KBr) 1679, 1592,
Anal. Calcd. for C H N S (278.3): C, 73.36; H, 5.07; N,
17 14
2
1
1503, 765, 748, 698; H nmr: δ 1.61 (d, 3H, J = 7.2), 5.77 (q, 1H,
10.07. Found: C, 73.47; H, 5.23; N, 10.37.
13
J = 7.2), 7.08-8.08 (m, 19H); C nmr: δ 17.2, 44.7, 73.9, 119.3,
2-Ethoxycarbonylmethylthio-N-phenylindole (10).
124.5, 125.4, 127.7, 127.8, 128.1, 128.2, 128.4, 128.5, 131.9,
133.0, 133.6, 135.6, 137.0, 141.0, 141.6, 154.2, 197.8.
This compound had mp 34°; ir: ν (KBr) 1739, 1286, 1183,
Anal. Calcd. for C H NOS (433.5): C, 80.35; H, 5.35; N,
29 23
1
1149, 1105; H nmr: δ 1.12 (t, 3H, J = 7.2), 3.25 (s, 2H), 4.04
3.23. Found: C, 80.04; H, 5.45; N, 3.07.
13
(q, 2H, J = 7.2), 6.84 (s, 1H), 7.10-7.78 (m, 9H); C nmr: δ 13.5,
37.2, 61.1, 109.5, 110.1, 119.9, 120.2 122.6, 127.8, 128.1, 128.3,
129.0, 131.8, 132.0, 138.7, 169.0.
Oxidation of 2-Ethoxycarbonylmethylthio-N-methyl-3-phenyl-
indole 7 with m-Chloroperbenzoic Acid (MCPBA).
Anal. Calcd. for C H NO S (311.3): C, 69.44; H, 5.50; N,
4.50. Found: C, 69.50; H, 5.31; N, 4.45.
18 17
2
To a solution of 2-ethoxycarbonylmethylthio-N-methyl-3-
phenylindole 7 (1 mmol) in dichloromethane (30 ml) was
added dropwise a solution of MCPBA (1-2 mmol) in
dichloromethane (20 ml) at 0° (ice-bath) under argon and then
the mixture was stirred for 2-4 hours at room temperature. The
reaction mixture was poured into water and extracted with
dichloromethane. Organic layer was washed with dilute HCl,
2-(1-Ethoxycarbonylpropylthio)-N-phenylindole (11).
This compound had bp 215° at 2 Torr; ir: ν (film) 1731, 1312,
1
1296, 1213, 1156; H nmr: δ 0.77 (t, 3H, J = 7.4), 1.03 (t, 3H, J =
7.1), 1.45-1.80 (m, 2H), 3.14 (t, 1H, J = 7.4), 3.96 (q, 2H, J = 7.1),
13
6.88 (s, 1H), 7.06-7.61 (m, 9H); C nmr: δ 11.1, 13.5, 24.1, 52.6,
NaHCO solution, water, and then dried over anhydrous
60.6, 110.3, 111.8, 120.1, 120.2, 122.9, 126.8, 127.1 128.4,
128.8, 136.8, 138.8, 171.2.
3
MgSO . After removal of the solvent, the residue was
4
chromatographed with toluene-hexane (4:1) to give the
Anal. Calcd. for C H NO S (339.4): C, 70.71; H, 6.24; N,
20 21
2
corresponding sulfinyl 17 and sulfonyl compounds 18.
4.13. Found: C, 70.89; H, 6.33; N, 4.14.

108
T. Nishio, O. Saku and H. Yamamoto
Vol. 38
2-Ethoxycarbonylmethylsulfinyl-N-methyl-3-phenylindole (17).
This compound had bp 250° at 2 Torr (dec.); ir: ν (film) 1730,
solution, water, and then dried over anhydrous MgSO . After
4
removal of the solvent, the residue was chromatographed with
toluene-hexane (4:1) to give 2-ethoxycarbonylmethylene-3,3-
diphenylindoline 19 (78 %), mp 109-110°; ir: ν (KBr) 3340,
1
1333, 1265, 1099, 1049; H nmr: δ 1.01 (t, 3H, J = 7.2), 3.99
(q, 2H, J = 7.2), 4.02 (d, 1H, J = 13.2), 4.21 (s, 3H), 4.32 (d, 1H,
J = 13.2), 7.11-7.27 (m, 1H), 7.34-7.51 (m, 7H), 7.67 (d, 1H, J =
1
1666, 1613, 1283, 1219; H nmr: δ 1.23 (t, 3H, J = 7.1), 4.13
(q, 2H, J = 7.1), 4.89 (s, 1H), 6.84-6.91 (m, 2H), 7.11-7.30
13
8.3); C nmr: δ 13.6, 31.3, 58.0, 62.1, 109.5, 121.0, 121.3,
13
(m, 12H), 10.0 (br s, 1H); C nmr: δ 14.0, 58.8, 85.5, 109.0,
125.3, 125.6, 127.5, 128.4, 129.3, 130.5, 131.7, 139.3, 163.4: Ms:
121.2, 125.1, 126.7, 128.1, 135.1, 142.6, 143.9, 168.0.
+
m/z 341 (M ), 325, 254. The result of elemental analysis of this
Anal. Calcd. for C H NO (355.4): C, 81.10; H, 5.96; N,
24 21
2
compound was not in accord with the calculated values since 17
decomposed on distillation.
3.94. Found: C, 80.82; H, 6.24; N, 3.66.
2-Ethoxycarbonylmethylsulfonyl-N-methyl-3-phenylindole (18).
Compound 18 as obtained as a viscous oil; ir: ν (film) 1729,
REFERENCES AND NOTES
1
[1a] T. Nishio N. Okuda and C. Kashima, Helv. Chim. Acta, 73,
1719 (1990); [b] T. Nishio and M. Sakamoto, in Review on Heteroatom
Chemistry, Vol 12, S. Oae, ed. MYU, Tokyo, 1995, p. 23; [c] T. Nishio
and M. Oka, Helv. Chim. Acta, 80, 388 (1997).
[2] C. F. Koelsch and W. R. Workman, J. Am. Chem. Soc., 74,
6288 (1952).
1367, 1339, 1262, 1207, 1146; H nmr: δ 1.02 (t, 3H, J = 7.1),
3.92 (s, 3H), 4.02 (q, 2H, J = 7.1), 4.13 (s, 2H), 7.13-7.52
13
(m, 9H), 7.89-8.04 (m, 2H); C nmr: δ 13.2, 31.6, 52.0, 61.5,
109.9, 121.1, 126.3, 127.3, 127.6, 127.7, 129.3, 130.7, 132.6,
+
137.5, 139.0, 161.9; Ms: m/z 357 (M ), 325, 238.
Reaction of 2-Ethoxycarbonylmethylthio-3,3-diphenylindole-
nine 14 with Sodium Hydride and Triphenylphosphine.
[3] M. Roth, P. Dubs, E. Gotschi and A. Eschenmoser, Helv.
Chim. Acta, 54, 710 (1971).
[4a] H. W. Pinnick and Y-H. Chang, J. Org. Chem., 43, 4662
(1978); [b] K. Shiosaki, G. Fels and H. Rapoport, J. Org. Chem., 46, 3230
(1981); [c] J. S. Petersen, G. Fels and H. Rapoport, J. Am. Chem. Soc.,
106, 4539 (1984); [d] G. Saure, N. Le Berre and B. Zacharie, Tetrahedron
Lett., 29, 2299 (1988); [e] P. Marchand, M-C. Fargeau-Bellassoued, C.
Bellec and G. Lhommet, Synthesis, 1118 (1994); [f] P. Marchand, C.
Bellec, M-C. Fargeau-Bellassoued, C. Nerzy and C. Lhommet,
Heterocycles, 43, 63 (1996).
To a solution of 2-ethoxycarbonylmethylthio-3,3-diphenyl-
indolenine 14 (1 mmol) and triphenylphosphine (2 mmol) in
benzene (30 ml) was added dropwise a solution of sodium
hydride (5 mmol) in benzene (20 ml) under argon at room
temperature and then the mixture was refluxed for 10 hours. The
reaction mixture was poured into water and extracted with ethyl
acetate. Organic layer was washed with dilute HCl, NaHCO
3