Multifunctionalization of Indoles: Synthesis of 3-Iodo-2-sulfonyl Indoles

Article abstract of DOI:10.1002/bkcs.11882

The selective multifunctionalization of indoles by using thiosulfonates, trimethyl sulfoxonium iodide (Me₃SOI), and H₂O₂ was studied. The reaction of thiosulfonates with Me₃SOI and H₂O₂ produced sulfonyl radicals and an iodination reagent, both of which were incorporated in indoles to form 3-iodo-2-sulfonyl indoles under carefully controlled conditions. The related reaction mechanism and the substrate scope of 3-iodo-2-sulfonyl indoles are presented.

Full text of DOI:10.1002/bkcs.11882

Article
DOI: 10.1002/bkcs.11882
BULLETIN OF THE
H. Park et al.
KOREAN CHEMICAL SOCIETY
Multifunctionalization of Indoles: Synthesis of 3-Iodo-2-sulfonyl
Indoles
*
Hyowon Park, Junryeol Bae, Soobin Son, and Hye-Young Jang
Department of Energy Systems Research, Ajou University, Suwon 16499, South Korea.
*E-mail: hyjang2@ajou.ac.kr
Received August 21, 2019, Accepted September 10, 2019
The selective multifunctionalization of indoles by using thiosulfonates, trimethyl sulfoxonium iodide
(Me3SOI), and H2O2 was studied. The reaction of thiosulfonates with Me3SOI and H2O2 produced sulfo-
nyl radicals and an iodination reagent, both of which were incorporated in indoles to form 3-iodo-
2-sulfonyl indoles under carefully controlled conditions. The related reaction mechanism and the substrate
scope of 3-iodo-2-sulfonyl indoles are presented.
Keywords: Sulfonylation, Indole, Iodination, Thiosulfonate, Multifunctionalization
Introduction
Experimental
Sulfonylated indoles are useful building blocks in therapeu-
tic agents and drugs.1 Apart from the development of a
variety of synthetic methods involving the incorporation of
a sulfonyl group in indole derivatives, the use of efficient
sulfonylating agents for the synthesis of sulfonylated
indoles has been investigated; sulfonyl chloride, sodium
sulfinates, and sulfonyl hydrazides are commonly employed
for 2- or 3-sulfonylation of indoles.2,3 In particular, for the
synthesis of 2-sulfonyl indoles, sodium sulfinates and sulfo-
nyl hydrazides are commonly used under oxidation condi-
tions involving I− or I2. It is known that the reaction of
iodine with sulfonyl precursors produces sulfonyl radicals
that promote the coupling reaction of the sulfonyl group
with indoles in a radical manner. Although iodine is a good
halogenation reagent,4 the incorporation of the iodo group
in sulfonylated indoles is rare.1c Therefore, the develop-
ment of protocols for promoting the site-selective introduc-
tion of both sulfonyl and iodo groups in indoles would be
useful, since iodo- and sulfonyl-functionalized indoles can
be used as useful building blocks in transition metal
catalysis.5
Our research group has been rigorously studying the sul-
fonylation of organic compounds by using thiosulfonates,6
which are synthesized via the copper-catalyzed aerobic oxi-
dation of thiols.7 In the presence of I− or I2, thiosulfonates
are converted to sulfonyl iodides. These sulfonyl iodides
promoted the formation of C-S bonds, leading to the incor-
poration of sulfonyl groups in the organic compounds. In
this study, the combination of thiosulfonates, trimethyl sul-
foxonium iodide (Me3SOI), and H2O2 induced the selective
C2- and C3-multifunctionalization of indoles. The judicious
variation of the reaction conditions helped control the prod-
uct distribution, affording 3-iodo-2-sulfonyl indoles over
2-sulfonyl indoles selectively (Scheme 1).
General Procedure for the Synthesis of 3-Iodo-2-
sulfonyl indole. Trimethylsulfoxonium iodide (55.1 mg,
0.25 mmol) was added to
a mixture of S-phenyl
benzenesulfonothiolate (125.2 mg, 0.50 mmol) and indole
(29.3 mg, 0.25 mmol) with 0.5 mL methanol in a 5 mL
round-bottom flask under N2 atmosphere. The solution was
stirred at 0 ꢀC for 1 min. Then, 0.2 mL hydrogen peroxide
(34.5 wt % in H2O) was slowly added to the reaction mix-
ture at 0 ꢀC for 10 min. The reaction was stirred at room
temperature for 16 h. The reaction mixture was extracted
with aqueous sodium thiosulfate solution and dic-
hloromethane. The organic layer was dried with sodium
sulfate, concentrated, and purified by column chromatogra-
phy on a silica gel column eluting with 5% ethyl acetate in
hexane.
3-Iodo-2-(phenylsulfonyl)-1H-indole (1c). The represen-
tative experimental procedure was applied to S-phenyl
benzenesulfonothioate (125.2 mg, 0.50 mmol) with indole
(29.3 mg, 0.25 mmol) to obtain 1c as yellow solid in 53%
(50.8 mg) yields. 1H NMR (CDCl3, 600 MHz): δ 9.82
(s, 1H), 8.13 (d, J = 7.6 Hz, 2H), 7.59–7.62 (m, 1H), 7.52
(t, J = 7.9 Hz, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.43
(d, J = 8.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24
(q, J = 7.6 Hz, 1H) ppm. 13C NMR (CDCl3, 151 MHz):
140.32, 136.14, 133.99, 133.79, 131.38, 129.35, 128.00,
127.24, 123.21, 122.42, 112.72, 65.25 ppm. HRMS m/z
(EI, [M]+): C14H10NO2SI, calcd: 382.9477, found:
382.9478. FTIR (neat, cm−1): 3325, 2922, 1319, 1144,
724 cm−1. Mp (ꢀC): 148–149 ꢀC.
2-((4-Fluorophenyl)sulfonyl)-3-iodo-1H-indole (2c). The
representative experimental procedure was applied to S-
(4-fluorophenyl) 4-fluorobenzenesulfonothioate (143.1 mg,
0.50 mmol) with indole (29.3 mg, 0.25 mmol) to obtain 2c
1
as yellow solid in 52% (51.5 mg) yields. H NMR (CDCl3,
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(d, J = 24.16 Hz), 64.18 ppm. HRMS m/z (EI, [M]+):
C14H9FNO2SI, calcd: 400.9383, found: 400.9385. FTIR
(neat, cm−1): 3330, 2923, 1498, 1310, 1141, 600 cm−1. Mp
(ꢀC): 175 ꢀC.
3-Iodo-5-methoxy-2-(phenylsulfonyl)-1H-indole (6c). The
representative experimental procedure was applied to S-
phenyl benzenesulfonothioate (125.2 mg, 0.50 mmol) with
5-methoxyindole (35.2 mg, 0.25 mmol) to obtain 6c as yel-
low solid in 50% (50.1 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 9.66 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.59
(t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.9 Hz, 2H), 7.31
(d, J = 9.0 Hz, 1H), 7.03 (dd, J = 9.0, 2.8 Hz, 1H), 6.81
(d, J = 2.1 Hz, 1H), 3.85 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz: δ 156.09, 140.44, 133.88, 133.77, 131.93,
131.22, 129.30, 127.96, 119.26, 113.79, 102.81, 64.36,
55.83 ppm. HRMS m/z (EI, [M]+): C15H12FNO3SI, calcd:
412.9583, found: 412.9580. FTIR (neat, cm−1): 3319,
2924, 1497, 1319, 1143, 724 cm−1. Mp (ꢀC): 138 ꢀC.
3-Iodo-5-methyl-2-tosyl-1H-indole (7c). The representa-
tive experimental procedure was applied to S-(p-tolyl)
4-methylbenzenesulfonothioate (139.2 mg, 0.50 mmol)
with 5-methylindole (32.8 mg, 0.25 mmol) to obtain 7c as
Scheme 1. Chemoselective synthesis of sulfonylated indoles.
600 MHz): δ 9.76 (s, 1H), 8.14 (q, J = 4.1 Hz, 2H), 7.48
(d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.39
(t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19
(t, J = 8.3 Hz, 2H) ppm. 13C NMR (CDCl3, 151 MHz):
δ 166.01 (d, J = 257.3 Hz) 136.37, 136.16, 133.66, 131.41,
131.00 (d, J = 8.758 Hz), 127.42, 123.28, 122.59, 116.74
(d, J = 23.3 Hz), 112.75, 65.38 ppm. HRMS m/z (EI,
[M]+): C14H9FNO2SI, calcd: 400.9383, found: 400.9380.
FTIR (neat, cm−1): 3326, 2923, 1589, 1491, 1323,
1141 cm−1. Mp (ꢀC): 142 ꢀC.
3-Iodo-2-tosyl-1H-indole (3c). The representative experi-
mental procedure was applied to S-(p-tolyl) 4-methyl-
benzenesulfonothioate (139.2 mg, 0.50 mmol) with indole
(29.3 mg, 0.25 mmol) to obtain 3c as brown solid in 10%
(9.9 mg) yields. 1H NMR (CDCl3, 600 MHz): δ 9.64
(s, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 1H),
7.42 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.31
(d, J = 8.3 Hz, 2H), 7.24 (q, J = 8.0 Hz, 1H), 2.40 (s, 3H)
ppm. 13C NMR (CDCl3, 151 MHz): δ 145.12, 137.39,
135.95, 134.29, 131.41, 129.95, 128.08, 127.09, 123.19,
122.36, 112.59, 64.76, 21.75 ppm. HRMS m/z (EI, [M]+):
C15H12NO2SI, calcd: 396.9634, found: 396.9634. FTIR
(neat, cm−1): 3318, 2923, 1492, 1320, 1144, 678 cm−1. Mp
(ꢀC): 155 ꢀC.
3-Iodo-5-methyl-2-(phenylsulfonyl)-1H-indole (4c). The
representative experimental procedure was applied to S-
phenyl benzenesulfonothioate (125.2 mg, 0.50 mmol) with
5-methylindole (32.8 mg, 0.25 mmol) to obtain 4c as yel-
low solid in 52% (51.6 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 9.67 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.59
(t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.31
(d, J = 8.3 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 7.20
(d, J = 8.3 Hz, 1H), 2.44 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz): 140.45, 134.50, 133.88, 133.56, 132.15,
131.54, 129.29, 129.24, 127.94, 122.34, 112.38, 64.63,
21.50 ppm. HRMS m/z (EI, [M]+): C15H12NO2SI, calcd:
396.9634, found: 396.9631. FTIR (neat, cm−1): 3324,
2920, 1309, 1143, 753 cm−1. Mp (ꢀC): 189 ꢀC.
5-Fluoro-3-iodo-2-(phenylsulfonyl)-1H-indole (5c). The
representative experimental procedure was applied to S-
phenyl benzenesulfonothioate (125.2 mg, 0.50 mmol) with
5-fluoroindole (33.8 mg, 0.25 mmol) to obtain 5c as brown
solid in 32% (31.6 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 10.12 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H),
7.60–7.62 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.39 (q,
J = 4.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 2H) ppm. 13C NMR
(CDCl3, 151 MHz): δ 159.11 (d, J = 240.09 Hz), 140.02,
135.25, 134.20, 132.80, 131.99 (d, J = 10.57 Hz), 129.45,
1
yellow solid in 19% (19.5 mg) yields. H NMR (CDCl3,
600 MHz): δ 9.32 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.30 (t,
J = 7.6 Hz, 3H), 7.23 (s, 1H), 7.20 (d, J = 9.0 Hz, 1H),
2.44 (s, 3H), 2.39 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz): δ 144.98, 137.51, 134.23, 134.11, 132.10,
131.60, 129.89, 129.10, 128.05, 122.39, 112.18, 64.19,
21.74, 21.49 ppm. HRMS m/z (EI, [M]+): C16H14NO2SI,
calcd: 410.9790, found: 410.9793. FTIR (neat, cm−1):
3319, 2920, 1497, 1319, 1143, 680 cm−1. Mp (ꢀC): 160 ꢀC.
5-Fluoro-3-iodo-2-tosyl-1H-indole (8c). The representa-
tive experimental procedure was applied to S-(p-tolyl)
4-methylbenzenesulfonothioate (139.2 mg, 0.50 mmol)
with 5-fluoroindole (33.8 mg, 0.25 mmol) to obtain 8c as
brown solid in 4% (3.6 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 9.36 (s, 1H), 7.98 (d, J = 9.0 Hz, 2H), 7.37
(q, J = 4.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.13–7.16
(m, 2H), 2.41 (s, 3H) ppm. 13C NMR (CDCl3, 151 MHz):
δ 159.07 (d, J = 241.6 Hz) 145.35, 137.06, 135.97, 132.35,
132.14, 132.11 (d, J = 9.1 Hz), 128.19, 116.46 (d,
J = 27.2 Hz), 113.85 (d, J = 7.6 Hz), 107.90 (d,
J = 25.7 Hz), 63.75, 21.78 ppm. HRMS m/z (EI, [M]+):
C15H11FNO2SI, calcd: 414.9539, found: 414.9539. FTIR
(neat, cm−1): 3310, 2918, 1497, 1142, 1320, 679 cm−1. Mp
(ꢀC): 155 ꢀC.
2-((4-Fluorophenyl)sulfonyl)-3-iodo-5-methyl-1H-indole
(9c).
The representative experimental procedure was
applied to S-(4-fluorophenyl) 4-fluorobenzenesulfonothioate
(143.1 mg, 0.50 mmol) with 5-methylindole (32.8 mg,
0.25 mmol) to obtain 9c as yellow solid in 56% (57.6 mg)
yields. 1H NMR (CDCl3, 600 MHz): δ 9.64 (s, 1H),
8.11–8.13 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H),
7.16–7.21 (m, 3H), 2.44 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz):
δ
165.90 (d,
J
=
257.5 Hz), 136.48
128.05, 116.64 (d,
J = 27.18 Hz), 114.24, 107.75
(d, J = 2.8 Hz), 134.50, 133.36, 132.29, 131.53, 130.90
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Multifunctionalization of Indoles
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(d, J = 10.1 Hz), 129.38, 122.35, 116.63 (d, J = 23.1 Hz),
112.39, 64.72, 21.51 ppm. HRMS m/z (EI, [M]+):
C15H11FNO2SI, calcd: 414.9539, found: 414.9541. FTIR
(neat, cm−1): 3325, 1588, 1491, 1320, 1139, 833 cm−1. Mp
(ꢀC): 80 ꢀC.
(0.5 mL) produced the 3-iodo-2-sulfonyl indole 1c in 33%
yield and the 2-sulfonyl indole 1d in 26% yield (entry 1).
Increasing the amount of H2O2 (0.2 mL) dramatically chan-
ged the selectivity of the reaction toward 1c (entry 2). On
the other hand, increasing the amount of Me3SOI (2 equiv)
completely changed the reaction route to form 1d in 57%
yield and 1c in 4% yield (entry 3). The reaction tempera-
ture was increased to 65 ꢀC for determining the key factors
controlling the formation of 1c and 1d, but the major prod-
uct remained the same (entries 4 and 5). Replacing the
iodide source Me3SOI with KI provided a mixture of 1c
(23% yield) and 1d (18% yield) (entry 6). The use of NaI
and tetrabutylammonium iodide (TBAI) as iodide sources
produced 1c with 25% and 29% yield, respectively (entries
7 and 8). Next, the effect of oxidants was examined. Tert-
Butyl hydrogen peroxide (TBHP) was employed to form 1c
with 15% yield (entry 9). di-tert-Butyl peroxide (DTBP)
and oxygen did not promote the desired reaction (entries
10–11). In the absence of oxidants, the reaction did not pro-
ceed at room temperature, but product 1d was isolated with
10% yield along with 3-sulfenylated indole 1e 60% yield at
65 ꢀC (entry 12).8 In the absence of an iodide source, no
desired product was observed (entry 13). In addition to
MeOH, toluene, dichloromethane, DMF, DMSO, CH3CN,
and THF were examined for the formation of 1c using con-
ditions of entry 2; the reactions in CH3CN and in THF
afforded 1c with 20% and 11% yields, respectively, but
other solvents did not promote the formation of either
1c or 1d.
After the optimization results were obtained, the sub-
strate scope of the reaction was investigated (Table 2). The
reaction conditions of entries 2 and 3 of Table 1 were
employed for synthesizing 3-iodo-2-sulfonyl indoles
(Method A) and 2-sulfonyl indoles (Method B), respec-
tively. In the case of the formation of 3-iodo-2-sulfonyl
indoles (Method A), the electronic effect of thiosulfonates
and indoles was observed. The electron-donating group of
thiosulfonates induced the formation of product 3c in lower
yield than 1c or 2c (entries 1–3). 5-Substituted indoles con-
taining an electron donor and an electron acceptor were
examined. Electron-rich indoles were converted to the
desired products 4c and 6c with yields higher than the
fluoro-substituted product 5c (entries 4–6). The electronic
effect of the indole was not as critical as the effect of sub-
stituents of thiosulfonates (entries 7–10). The reactions of
4-methyl substituted thiosulfonates with 5-methyl
substituted indole and 5-fluoro substituted indole showed
diminished yields, which was due to the low reactivity of
4-methyl substituted thiosulfonates (entries 7 and 8). The
reactions of 4-fluoro substituted thiosulfonates with
5-methyl indole and 5-fluoro indole showed higher yields
than results of entries 7 and 8 (entries 9 and 10). The reac-
tion of 3-methyl indole with thiosulfonates afforded
2-sulfonyl indoles 11d with Methods A and B, because the
iodination position is blocked by the methyl group (entry
11). Although N-methyl indole was exposed to conditions
5-Fluoro-2-((4-fluorophenyl)sulfonyl)-3-iodo-1H-indole (10c).
The representative experimental procedure was applied
S-(4-fluorophenyl)-4-fluorobenzenesulfonothioate (143.1 mg,
0.50 mmol) with 5-fluoroindole (33.8 mg, 0.25 mmol) to
1
obtain 10c as red solid in 40% (40.8 mg) yields. H NMR
(CDCl3, 600 MHz): δ 9.65 (s, 1H), 8.12–8.14 (m, 2H), 7.39
(q, J = 4.1 Hz, 1H), 7.21 (t, J = 8.6 Hz, 2H), 7.15 (t,
J = 8.6 Hz, 2H) ppm. 13C NMR (CDCl3, 151 MHz): δ
166.07 (d, J = 258.8 Hz), 159.14 (d, J = 239.9 Hz), 136.00,
135.26, 132.54, 132.07 (d,
J
=
10.1 Hz), 131.07
(d, J = 10.1 Hz), 116.87 (d, J = 5.74 Hz), 116.71, 114.02
(d, J = 10.1 Hz), 107.92 (d, J = 24.6 Hz), 64.28 (d,
J = 6.04 Hz) ppm. HRMS m/z (EI, [M]+): C14H8F2NO2SI,
calcd: 418.9289, found: 418.9291. FTIR (neat, cm−1): 3319,
1589, 1492, 1142, 1083, 834, 683 cm−1. Mp (ꢀC): 165 ꢀC.
3-Methyl-2-(phenylsulfonyl)-1H-indole (11d). The repre-
sentative experimental procedure was applied to S-phenyl
benzenesulfonothioate (125.2 mg, 0.50 mmol) with
3-methylindole (32.8 mg, 0.25 mmol) to obtained 11d as
white solid in 53% (36.1 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 9.08 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.60
(d, J = 7.6 Hz, 1H), 7.55 (t, J = 6.9 Hz, 1H), 7.49
(t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.33
(t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 2.54 (t,
J = 14.8 Hz, 3H) ppm. 13C NMR (CDCl3, 151 MHz): δ
142.03, 136.09, 133.40, 129.43, 129.23, 128.40, 127.02,
126.34, 120.88, 120.86, 119.00, 112.35, 9.05 ppm. HRMS
m/z (EI, [M]+): C15H13NO2S, calcd: 271.0667, found:
271.0669. FTIR (neat, cm−1): 3343, 1307, 1150, 628 cm−1
Mp (ꢀC): 140 ꢀC.
.
1-Methyl-2-(phenylsulfonyl)-1H-indole (12d). The repre-
sentative experimental procedure was applied to S-phenyl
benzenesulfonothioate (125.2 mg, 0.50 mmol) with N-
methylindole (32.8 mg, 0.25 mmol) to obtained 12d as red
solid in 54% (53.6 mg) yields. 1H NMR (CDCl3,
600 MHz): δ 7.95–7.96 (m, 2H), 7.70 (d, J = 8.3 Hz, 1H),
7.58 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H),
7.35–7.38 (m, 2H), 7.30 (d, J = 9.0 Hz, 1H), 7.18 (t,
J = 7.9 Hz, 1H), 3.84 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz): δ 141.36, 139.60, 134.84, 133.48, 129.40,
127.72, 125.83, 125.29, 122.95, 121.27, 110.91, 110.33,
31.08 ppm. HRMS m/z (EI, [M]+): C15H13NO2S, calcd:
271.0667, found: 271.0668. FTIR (neat, cm−1): 1317,
1153 cm−1. Mp (ꢀC): 125 ꢀC.
Results and Discussion
The coupling reaction of S-phenyl benzenesulfonothiolate
1a with an indole 1b was examined under the conditions
listed in Table 1. The reaction of 1a and 1b in the presence
of Me3SOI (1 equiv) and H2O2 (0.1 mL) in MeOH
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Multifunctionalization of Indoles
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Table 1. Optimization for the formation of 3-iodo-2-sulfonyl indole 1c.
Entry
I− source (equiv)
Oxidant (mL)
Temp. (ꢀC)
Yield (1c)
Yield (1d)
1
2
3
4
5
6
7
8
Me3SOI (1)
Me3SOI (1)
Me3SOI (2)
Me3SOI (1)
Me3SOI (2)
KI (1)
H2O2 (0.1)a
H2O2 (0.2)a
H2O2 (0.1)a
H2O2 (0.2)a
H2O2 (0.1)a
H2O2 (0.1)a
H2O2 (0.1)a
H2O2 (0.1)a
TBHP (0.16)b
DTBP (0.21)c
O2
25
25
25
65
65
25
25
25
25
25
25
25
25
33%
53%
4%
40%
—
26%
—
57%
—
36%
18%
—
23%
25%
29%
15%
—
NaI (1)
TBAI (1)
Me3SOI (1)
Me3SOI (1)
Me3SOI (1)
Me3SOI (1)
—
—
9
—
10
11
12
13
—
—
—
—(10%)d
—
—
H2O2 (0.1)ass
—
—
a H2O2 in water (34.5 wt %).
b TBHP in water (70 wt %).
c DTBP 98%.
d 65 ꢀC. Reaction conditions: 1a (0.5 mmol) and 1b (0.25 mmol) in MeOH (0.5 mL) were subjected to the indicated reaction conditions.
Table 2. Examples of 3-iodo-2-sulfonyl indoles and 2-sulfonyl indoles.
Method Aa
Method Bb
Entry
R1
R2
R3
Yield (c)
Yield (d)
Yield (c)
Yield (d)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
5-Me
5-F
5-MeO
5-Me
5-F
5-Me
5-F
3-Me
H
Ph
4-FPh
4-MePh
Ph
Ph
Ph
4-MePh
4-MePh
4-FPh
4-FPh
Ph
53% (1c)
52% (2c)
10% (3c)
52% (4c)
32% (5c)
50% (6c)
19% (7c)
4% (8c)
56% (9c)
40% (10c)
—
—
4% (1c)
5% (2c)
2% (3c)
6% (4c)
—
57% (1d)
30% (2d)
29% (3d)
54% (4d)
45% (5d)
41% (6d)
40% (7d)
11% (8d)
44% (9d)
36% (10d)
55% (11d)
68% (12d)
—
—
—
—
—
11% (6c)
3% (7c)
2% (8c)
9% (9c)
6% (10c)
—
—
—
9
—
10
11
12
H
H
Me
—
53% (11d)
54% (12d)
Ph
—
—
a Method A: Indole (1 equiv, 0.25 mmol), thiosulphonate (2 equiv), Me3SOI (1 equiv), and H2O2 (0.2 mL) in MeOH (0.5 mL) at r.t.
b Method B: Indole (1 equiv, 0.25 mmol), thiosulphonate (2 equiv), Me3SOI (2 equiv), and H2O2 (0.1 mL) in MeOH (0.5 mL) at r.t.
Bull. Korean Chem. Soc. 2019, Vol. 40, 1128–1133
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BULLETIN OF THE
Article
Multifunctionalization of Indoles
KOREAN CHEMICAL SOCIETY
favorable for the formation of 3-iodo-2-sulfonyl indoles,
only the 2-sulfonylation product 12d was obtained in the
absence of iodination (entry 12). N-sulfonyl indole was
examined, but the desired sulfonylation product was not
observed.
When reaction conditions favorable for the formation of
2-sulfonyl indoles (Method B) were employed, 2-sulfonyl
indoles were isolated as the major product. 4-Fluoro and
4-methyl-substituted thiosulfonates participated in the reac-
tions to form 2d and 3d with yields lower than 1d (entries
2 and 3). The electronic properties of indoles for the forma-
tion of 2-sulfonyl indoles were not as important as the for-
mation of 3-iodo-2-sulfonyl indoles (entries 4–10). The
reaction of N-methyl indole afforded 2-sulfonyl indoles with
a yield higher than obtained with Method A (entry 12).
Although the reaction optimization results showed the
selective reaction conditions for the formation of 1c or 1d,
the mechanism for the formation of 1c or 1d as the major
product was not apparent. Control experiments were per-
formed to investigate the mechanism, and they are described
here (Scheme 2). Because past studies have reported the for-
mation of sulfonyl iodide (PhSO2I) from thiosulfonates and
iodides, PhSO2I was reacted with the indole 1b, and 1d was
obtained formation with 21% and 22% yield without H2O2
and with H2O2, respectively (Eq. (1)). In entry 12 of
Table 1, thiosulfonate 1a and Me3SOI were employed in the
absence of H2O2, and 1d was not formed at r.t., but at an
elevated temperature albeit with a low yield. On the basis of
the results of Eq. (1) of Scheme 2 and entry 12 of Table 1, it
was observed that in the absence of H2O2, a high PhSO2I
concentration and a high temperature favored the formation
of 1d rather than 1c.
Next, the reaction route for the formation of 1c was inves-
tigated. There are two possible routes: (1) 2-sulfonylation
followed by 3-iodination and (2) 3-iodination followed by
2-sulfonylation. As shown in Eqs. (2)–(5), the 2-sulfonyl
indoles 1d underwent iodination to form 1c under various
conditions. The mixture of iodides and peroxides formed
I2, promoting the iodination of 1d. This is supported by
the result of Eq. (4). Interestingly, additional 1a promoted
the iodination of 1d with considerably higher yield
(Eq. (3)). Presumably, the presence of 1a led to the forma-
tion of an efficient iodinating reagent under the indicated
reaction conditions. Sulfonyl iodide did not participate in
the iodination of 1d (Eq. (5)), excluding the possibility of
PhSO2I acting an iodinating reagent. Next, iodination and
subsequent sulfonylation can be ruled out from the result
of Eq. (6). The 3-iodo-2-sulfonyl indole 1c did not
undergo deiodination (Eq. (7)), which excluded the path-
way converting 1c to 1d. The addition of radical inhibitors
(TEMPO and BHT) retard the formation of 1c. With
TEMPO (2 equiv), only 1d was isolated with 15% yield,
and no sulfonylated indole was formed in the presence of
BHT (2 equiv) (Eq. (8)).
Scheme 2. Control experiments.
thiosulfonate 1a reacts with Me3SOI to afford PhSO2I,
which is instrumental in the formation of the 2-sulfonylated
indole 1d at an elevated temperature. At ambient tempera-
ture, sulfinate anion I is oxidized by H2O2 to form sulfonyl
radical II, while sulfenyl iodide (PhSI) reacts with H2O2 to
On the basis of the control experiment results, a plausible
reaction mechanism is proposed (Scheme 3). The
Bull. Korean Chem. Soc. 2019, Vol. 40, 1128–1133
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
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Multifunctionalization of Indoles
KOREAN CHEMICAL SOCIETY
Supporting Information. The supporting information is
available free of charge on the Bulletin of the Korean Chemical
Society website: NMR spectra of 3-iodo-2-sulfonyl indoles.
The NMR spectra of 1c-10c, 11d, and 12d are found in Fig-
ures S1–S24.
References
1. (a) O. Cazorla, A. Lacampagne, J. Fauconnier, G. Vassort, Br.
J. Pharmacol. 2003, 139, 99. (b) H.-Y. Lee, S.-L. Pan, M.-
C. Su, Y.-M. Liu, C.-C. Kuo, Y.-T. Chang, J.-S. Wu, C.-
Y. Nien, S. Mehndiratta, C.-Y. Chang, S.-Y. Wu, M.-J. Lai, J.-
Y. Chang, J.-P. Liou, J. Med. Chem. 2013, 56, 8008.
(c) Q. Xia, X. Bao, C. Sun, D. Wu, X. Rong, Z. Liu, Y. Gu,
J. Zhou, G. Liang, Eur. J. Med. Chem. 2018, 160, 120.
(d) K. Liu, L. Zheng, Adv. Synth. Catal. 2019, 361, 1710.
2. (a) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang, G.-J. Deng,
Org. Lett. 2014, 16, 50. (b) P. Katrun, C. Mueangkaew,
M. Pohmakotr, V. Reutrakul, T. Jaipetch, D. Soorukram,
C. Kuhakarn, J. Org. Chem. 2014, 79, 1778. (c) Y. Yang,
W. Li, C. Xia, B. Ying, C. Shen, P. Zhang, ChemCatChem
2016, 8, 304. (d) R. Rahaman, P. Barman, Synlett 2017, 28,
684. (e) H. Li, X. Wang, J. Yan, New J. Chem. 2017, 41,
4277. (f) M.-L. Feng, L.-Y. Xi, S.-Y. Chen, X.-Q. Yu, Eur.
J. Org. Chem. 2017, 2746. (g) J. Zhang, Z. Wang, L. Chen,
Y. Liu, P. Liu, B. Dai, RSC Adv. 2018, 8, 41651.
Scheme 3. A plausible reaction mechanism.
form hypoiodous acid (HOI).9 When 1b is introduced, sul-
fonyl radical II reacts with 1b to afford 1d. Subsequently,
1d is iodinated to form 1c. For the iodination of 1d, another
route is possible. Under our reaction conditions, I2 gener-
ated from I− and H2O2 induced the iodination of 1d. How-
ever, additional thiosulfonates increased the yield of 1c
(52%) to a value greater than the yield obtained with I2
generated in situ (12%), indicating the presence of an effi-
cient iodination reagent such as HOI. Overall, two factors
determined the formation of 1c: (1) the presence of excess
thiosulfonate 1a compared with I− and (2) a large excess of
oxidants (H2O2) promoted the 3-iodo-2-sulfonylation of
indoles over the 2-sulfonylation of indoles.
3. (a) J. S. Yadav, B. V. S. Reddy, A. D. Krishna, T. Swamy, Tet-
rahedron Lett. 2003, 44, 6055. (b) M. Rahman, M. Ghosh,
A. Hajra, A. Majee, J. Sulfur Chem. 2013, 34, 342. (c) Y. Du,
Y. Liu, J. Chem. Res. 2016, 40, 579.
4. (a) M. A. Brown, M. A. Kerr, Tetrahedron Lett. 2001, 42, 983.
(b) J. Barluenga, M. Trincado, E. Rubio, J. M. González,
Angew. Chem. Int. Ed. 2003, 42, 2406. (c) D. Tu, J. Luo,
C. Jiang, Chem. Commun. 2018, 54, 2514. (d) L. Sun,
X. Zhang, Z. Li, J. Ma, Z. Zeng, H. Jiang, Eur. J. Org. Chem.
2018, 2018, 4949. (e) L. Sun, X. Zhang, C. Wang, H. Teng,
J. Ma, Z. Li, H. Chen, H. Jiang, Green Chem. 2019, 21, 2732.
5. (a) Y. Liu, G. W. Gribble, Tetrahedron Lett. 2000, 41, 8717.
(b) Y. Liu, G. W. Gribble, Tetrahedron Lett. 2001, 42, 2949.
(c) E. M. Beccalli, G. Broggini, A. Marchesini, E. Rossi, Tet-
rahedron 2002, 58, 6673. (d) H. Zhang, R. C. Larock, J. Org.
Chem. 2002, 67, 7048. (e) H. Zhang, R. C. Larock, J. Org.
Chem. 2002, 67, 9318.
6. (a) P. K. Shyam, H.-Y. Jang, J. Org. Chem. 2017, 82, 1761.
(b) P. K. Shyam, S. Son, H.-Y. Jang, Eur. J. Org. Chem. 2017,
2017, 5025. (c) S. J. Hwang, P. K. Shyam, H.-Y. Jang, Bull.
Kor. Chem. Soc. 2018, 39, 535. (d) S. Son, P. K. Shyam,
H. Park, I. Jeong, H.-Y. Jang, Eur. J. Org. Chem. 2018,
2018, 3365.
Conclusion
We investigated the reaction conditions and efficient
reagent combinations for the multifunctionalization of
indoles. In the presence of H2O2, the combination of
thiosulfonates (sulfonyl precursor) and Me3SOI (iodo pre-
cursor) promoted the formation of 3-iodo-2-sulfonyl
indoles. It was found that the complete conversion of
2-sulfonyl indoles to 3-iodo-2-sulfonyl indoles was pro-
moted by the presence of excess thiosulfonates and H2O2.
Control experiments supported the reaction mechanism
proposed here.
Acknowledgments. This study was supported by the
National
Research Foundation
of Korea
(No.
7. P. K. Shyam, Y. K. Kim, C. Lee, H.-Y. Jang, Adv. Synth.
Catal. 2016, 358, 56.
8. W. Ge, Y. Wei, Green Chem. 2012, 14, 2066.
9. (a) K. Sun, Y. Lv, J. Wang, J. Sun, L. Liu, M. Jia, X. Liu,
Z. Li, X. Wang, Org. Lett. 2015, 17, 4408. (b) W.-K. Luo,
X. Shi, W. Zhou, L. Yang, Org. Lett. 2016, 18, 2036.
2016R1D1A1A09917100) and the Human Resources Pro-
gram in Energy Technology (No. 20154010200820) of the
Korea Institute of Energy Technology Evaluation and Plan-
ning (KETEP), which is funded by the Ministry of Trade,
Industry and Energy, Republic of Korea.
Bull. Korean Chem. Soc. 2019, Vol. 40, 1128–1133
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1133