Regioselective C 2 sulfonylation of indoles mediated by molecular iodine

Article abstract of DOI:10.1021/jo402831k

A facile and general method for regioselective C2 sulfonylation reaction of indoles mediated by iodine is described. The 2-sulfonylated products were obtained up to 96% yield under mild reaction conditions (room temperature, 2 h).

Full text of DOI:10.1021/jo402831k

Article
pubs.acs.org/joc
Regioselective C2 Sulfonylation of Indoles Mediated by Molecular
Iodine
Praewpan Katrun,† Charoensak Mueangkaew,† Manat Pohmakotr,† Vichai Reutrakul,† Thaworn Jaipetch,‡
Darunee Soorukram,† and Chutima Kuhakarn*,†
†Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol
University, Rama VI Road, Bangkok 10400, Thailand
‡Mahidol University, Kanchanaburi Campus, Saiyok, Kanchanaburi 71150, Thailand
S
* Supporting Information
ABSTRACT: A facile and general method for regioselective
C2 sulfonylation reaction of indoles mediated by iodine is
described. The 2-sulfonylated products were obtained up to
96% yield under mild reaction conditions (room temperature,
2 h).
in a highly regioselective manner via a molecular iodine-
mediated reaction.
INTRODUCTION
■
Indole represents an important structural scaffold omnipresent
in naturally occurring compounds and pharmacologically
important agents (Figure 1).1,2 Therefore, new approaches
directing synthesis of indole nucleus have long inspired
synthetic organic chemists.3 In addition to the state of the art
with synthetic strategy toward construction of the indole motif,
development of novel methods for indole functionalization has
also received remarkable attention.4 In this context, it has been
widely proven that the C3 position of indole has priority in
functionalization over the C2 position. Hence, the direct C2
functionalization of indole has been more difficult and less
studied.
The presence of a sulfur moiety either as a sulfanyl, a sulfinyl,
or a sulfonyl in a molecular motif adds variety to its chemical
architecture and also enhances the biological activity of the
compound.5 In particular, the 2-sulfanylindoles possess an
inhibitory effect toward nucleoside triphosphate hydrolase
enzyme, and a sulfonyl group in 2-sulfonylindoles serves as a
temporary functional group that can be later removed by β-
elimination.6 Literature methods available for accessing 2-
sulfanylindoles and 2-sulfonylindoles are not straightforward;
they require multistep synthesis, moisture-sensitive alkyllithium
reagent, or metal-mediated reactions.7 Therefore, an explora-
tion of a facile method for a direct regioselective installation of
the sulfur moiety to the indole scaffold would be highly
desirable. Recently, Liang and co-workers reported an elegant
work on regioselective C2 amination of indole and derivatives.8
During our investigation on mechanistic study and the process
of preparation of this manuscript, a report on the use of the
reagent combination ArSO2Na, I2, TBHP in AcOH for
regioselective 2-sulfonylation of indoles was disclosed by
Deng and co-workers.9 This prompted us to report our
findings. We report herein a direct C2 sulfonylation of indoles
RESULTS AND DISCUSSION
■
In order to achieve optimum reaction conditions, a series of
reaction parameters including reagent stoichiometry and
solvents were screened employing indole as a prototype
(Table 1). To our delight, treatment of indole (1a) and
sodium p-toluenesulfinate (2a, 1 equiv) with iodine (1 equiv)
in methanol at room temperature for 2 h gave 2-(p-
toluenesulfonyl)indole (3a) in 42% yield (Table 1, entry 1).
Higher yields were obtained when 2a was employed in excess
amount (2 equiv) and the reaction time was prolonged from 2
to 8 h (Table 1, entries 2 and 3). When the amount of iodine
was increased to 1.5 equiv, 64% yield of 3a was obtained after 2
h (Table 1, entry 4). Increasing the stoichiometry of 2a from 2
equiv to 3 and 4 equiv led to a significant increase in product
yields (Table 1, entries 5 and 6). Next, the effect of solvent on
the reaction efficiency was examined (Table 1, entries 7−16). It
was found that methanol was the most suitable solvent for the
present transformation, possibly due to an intrinsically better
solubility of the sodium p-toluenesulfinate in methanol. It is
worth mentioning that the order of reagent addition has
significant effect on the reaction profile. If indole was exposed
to iodine prior to the addition of sodium p-toluenesulfinate or
the iodine and sodium p-toluenesulfinate was premixed before
the addition of indole, the yields of 3a slightly dropped (Table
1, entries 17 and 18). Finally, if an indole was stirred with
iodine for 1 h, followed by the addition of sodium p-
toluenesulfinate, and the reaction was further stirred for 2 h,
product 3a was obtained in only 14% yield while the starting
Received: December 20, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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Figure 1. Representative examples of biologically active indolyl aryl sulfones.
As shown in Table 2, the electronic nature of the substituents
on the benzene unit of indoles was found to have considerable
effect on the reaction efficiency. Electron-donating substituents
(5-Me, 7-Me, and 5-MeO) gave better reactivity and provided
the corresponding 2-sulfonylated products in good to excellent
yields (76−96%, Table 2, entries 2−4). In contrast, the 5-
bromo- and 5-fluoroindoles (1e,f) furnished products in low to
moderate yields (22−58%, Table 2, entries 5 and 6). In case of
5-formylindole (1g) and methyl 1H-indole-5-carboxylate (1h),
low yields (10−31%) were obtained with all the sulfinate salts
tested and 1g and 1h were recovered in all cases (Table 2,
entries 7 and 8). The reaction did not proceed when 5-
nitroindole (1i) was employed as a substrate (Table 2, entry 9).
Compound 1i remained untouched and the corresponding
methyl sulfonates were detected as major components. In an
effort to improve the yields of the sulfonylated products derived
from 1e−i, the reactions were carried out at elevated
temperature (refluxing methanol). Unfortunately, no improve-
ment in the yields was observed. N-Methylindole (1j), N-
ethylindole (1k), and N-benzylindole (1l) gave moderate to
high yields (54−93%) of the products (Table 2, entries 10−
12). To our surprise, 3-methylindole (1m) gave poor reactivity,
providing the corresponding products in low to moderate yields
(30−60%), and 1m was recovered in a range of 20−60%,
(Table 2, entry 13). However, 3m was obtained in higher yield
(68% yield vs 50% yield) when the reaction was carried out for
8 h. The reactions of sodium p-toluenesulfinate with N-
protected indoles, including N-Cbz-, N-Bz-, and N-Ms-, did not
proceed under standard reaction conditions or at prolonged
reaction time (from 2 to 8 h). In all cases, the starting materials
were recovered and the methyl p-toluenesulfonate was detected
as a major component. Most importantly, when 2-methylindole
was employed as a substrate to react with sodium p-
toluenesulfinate, our reaction conditions failed to provide any
sulfonylated adduct and methyl p-toluenesulfonate was
detected as a major component. Finally, no reaction was
observed with the less reactive benzothiophene, benzofuran,
and electron-poor quinoline as substrates, under standard
reaction conditions; methyl p-toluenesulfonate was obtained in
all cases.
Table 1. Optimization of the Reaction Conditions for
Iodine-Mediated C2 Sulfonylation Reaction of Indole (1a)
a
b
entry I2 (equiv) 2a (equiv)
solvent
MeOH
time (h) yield (%)
1
1
1
2
2
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
3
2
2
8
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
42
56
2
1
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
3
1
69
4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
64
5
85
6
90
7
74
8
CH3CN
CH2Cl2
ClCH2CH2Cl
EtOAc
acetone
THF
32
9
54
10
11
12
13
14
15
16
17
18
19
45
26
17
18
DMSO
Et2O
trace
32
c
H2O
d
e
f
MeOH
MeOH
MeOH
70
68
14
a
Conditions: 1a (0.5 mmol) in 0.25 M of solvent at room
b
c
d
temperature. Isolated yield. Reaction did not occur. Iodine was
added to a solution of 1a in methanol prior to the addition of sodium
e
p-toluenesulfinate. Iodine and sodium p-toluenesulfinate were
f
premixed prior to the addition of 1a. Compound 1a was stirred
with iodine for 1 h followed by the addition of sodium p-
toluenesulfinate.
indole was totally consumed (Table 1, entry 19). On the basis
of the experimental results shown in Table 1, the optimized
reaction conditions were chosen as follows: 1a (1 equiv), I2
(1.5 equiv), 2a (3 equiv) in methanol at room temperature for
2 h (Table 1, entry 5).
Having accomplished the optimized reaction conditions in
hand, we next explored the substrate scope and limitations of
the procedure. Indoles possessing electronically different
substituents and sodium sulfinates including sodium p-
toluenesulfinate, sodium benzenesulfinate, sodium 4-chloro-
benzenesulfinate, and sodium methanesulfinate were employed.
At this point, the reaction mechanism should be addressed. It
has long been known that sulfonyl iodide prepared from the
reaction of sodium sulfinate and molecular iodine can react
with unsaturated systems through a radical process to yield β-
iodosulfones with an anti-Markovnikov fashion.10 In an effort to
elucidate the reaction mechanism, a series of probing
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The Journal of Organic Chemistry
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a
Table 2. Iodine-Mediated C2 Sulfonylation of Indole Derivatives
b
substrate
product; R3 =; yield (%)
entry
R1 =
R2 =
pTol, 3
3a; 85
Ph, 4
4-Cl-C6H4, 5
Me, 6
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
Me
Et
Bn
H
H
4a; 89
4b; 90
4c; 92
4d; 96
4e; 46
4f; 54
5a; 88
6a; 70
6b; 88
6c; 76
6d; 77
6e; 29
6f; 22
5-Me
7-Me
5-OMe
5-Br
3b; 81
3c; 87
3d; 89
3e; 43
3f; 58
5b; 92
5c; 94
g
5e; 33
5-F
g
c
d
d
d
7
1g
1h
1i
5-CHO
5-CO2Me
5-NO2
H
3g; 21
3h; 13
e
4g; 31
4h; 22
e
g
6g; 20
6h; 10
e
c
d
d
d
8
g
9
g
10
11
12
13
1j
3j; 86
3k; 90
3l; 75
f
3m; 50 (68)
4j; 87
4k; 93
4l; 79
f
4m; 60
5j; 75
6j; 72
6k; 74
6l; 54
f
6m; 30
1k
1l
H
g
g
g
H
h
1m
3-Me
a
d
h
b
c
Unless otherwise noted. Conditions: 1 (0.5 mmol), 2 (3 equiv), I2 (1.5 equiv) in MeOH (0.25 M), rt, 2 h. Isolated yield. Reaction time = 3 h.
e
f
g
About 30−40% of 1g and 1h were recovered. Reactions did not occur. About 20−60% of 1m was recovered. Reaction was not performed.
Reaction time = 8 h.
a
Table 3. Effect of Additives on Iodine-Mediated C2
Table 4. Reaction of 1a with p-Toluenesulfonyl Iodide
Sulfonylation of Indole (1a) with Sodium p-Toluenesulfinate
a
(2a)
b
entry
p-Tol-SO2I (equiv)
solvent
3a, yield (%)
1
2
3
4
1
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
45
54
58
b
entry
additive (equiv)
3a, yield (%)
1.5
3
1
2
3
4
5
6
7
8
9
none (normal reaction)
none (dark, 30−32 °C)
none (dark, 15−20 °C)
85
c
75
3
23
b
a
69
Conditions: 1a (0.5 mmol) in MeOH (0.25 M), rt, 2 h. Isolated
yield. Methyl p-toluenesulfonate was isolated in 29% yield.
c
c
none (light, rt)
79
TEMPO (0.2, dark)
TEMPO (0.2)
TEMPO (1)
74
73
and 8). The reaction ceased when TEMPO (5 equiv) was
employed (Table 3, entry 9). As the presence of TEMPO
drastically reduced the yield of 3a, these observations implied
that the reaction may be proceeding through a radical
intermediate. Additionally, we found that 3a was obtained in
moderate yields (45−58%) when indole (1a) was allowed to
react with a freshly prepared p-toluenesulfonyl iodide (yellow-
ish solid) using dichloromethane as the solvent (Table 4,
entries 1−3).10g It is worth noting that 3a was obtained in 54%
yield when the reaction carried out in CH2Cl2 with the in situ
generation of p-toluenesulfonyl iodide (Table 1, entry 9).
However, when methanol was employed as the solvent, 3a and
methyl p-toluenesulfonate were obtained in 23% and 29%
yields, respectively (Table 4, entry 4).
On the basis of the control experiments in Tables 3 and 4
and relevant reports on the iodosulfonylation−dehydroiodina-
tion of alkenes mediated by sulfonyl iodide, we proposed
possible reaction pathways for regioselective C2 sulfonylation of
indole and derivatives as shown in Scheme 1. The sulfinate
sodium salt reacts with iodine to give sulfonyl iodide
intermediate that could undergo homolytic cleavage to yield a
sulfonyl radical.10 Addition of the sulfonyl radical to the indole
nucleus takes place chemoselectively to form a benzylic radical
45
TEMPO (3)
29
TEMPO (5)
trace
a
Unless otherwise noted. Conditions: 1a (0.5 mmol), 2a (3 equiv), I2
b
c
(1.5 equiv) in MeOH (0.25 M), rt, 2 h. Isolated yield. Irradiated
with light (100 W tungsten filament bulb) during and after addition of
reagents.
experiments employing the reactions of 1a and 2a were carried
out (Tables 3 and 4). Reactions carried out in the dark either at
room temperature (30−32 °C) or at lower temperature (15−
20 °C) were less efficient, leading to 3a in 75% and 69% yields,
respectively (Table 3, entries 2 and 3). The yield of 3a was not
improved when the reaction was carried out under irradiated
light (100 W tungsten filament bulb), and 3a was isolated in
79% yield (Table 3, entry 4). The addition of TEMPO had
considerable effects on the yields. When a catalytic amount of
TEMPO (0.2 equiv) was added to the reactions carried out
either in the dark or under standard reaction conditions, a slight
decrease in the yields of 3a was observed (Table 3, entries 5
and 6). The yield of 3a dropped significantly when TEMPO
was employed in stoichiometric amounts (Table 3, entries 7
C
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The Journal of Organic Chemistry
Article
(2 × CH), 126.8 (C), 125.9 (CH), 122.4 (CH), 121.4 (CH), 112.5
(CH), 109.2 (CH) ppm; IR (KBr) ν 3392 (N−H), 1321 and 1146
(SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C14H11NO2SNa 280.0408, found 280.0409.
Scheme 1. Proposed Reaction Mechanism
2-[(4-Chlorophenyl)sulfonyl]-1H-indole (5a):9 white solid (128.4
mg, 88% yield); mp = 159−160 °C; TLC (20% EtOAc in hexanes) Rf
1
= 0.31; H NMR (400 MHz; CDCl3) δ 9.63 (br s, 1 H), 7.93 (d, J =
8.7 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.43−7.38 (m, 3 H), 7.33−
7.29 (m, 1 H), 7.23 (d, J = 1.3 Hz, 1 H), 7.16 (t, J = 7.9 Hz, 1 H) ppm;
13C NMR (100 MHz; CDCl3) δ 140.1 (C), 139.8 (C), 137.5 (C),
133.2 (C), 129.6 (2 × CH), 128.6 (2 × CH), 126.9 (C), 126.2 (CH),
122.6 (CH), 121.6 (CH), 112.5 (CH), 109.6 (CH) ppm; IR (KBr) ν
3389 (N−H), 1332 and 1155 (SO2) cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C14H10ClNO2SNa 314.0018, found 314.0017.
2-(Methylsulfonyl)-1H-indole (6a):12 white solid (67.0 mg, 70%
yield); mp = 167−168 °C; TLC (40% EtOAc in hexanes) Rf = 0.34;
1H NMR (400 MHz; CDCl3) δ 9.47 (br s, 1 H), 7.71 (d, J = 8.1 Hz, 1
H), 7.49 (d, J = 8.4 Hz, 1 H), 7.40−7.36 (m, 1 H), 7.26−7.20 (m, 2
H), 3.22 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ 137.4 (C),
133.4 (C), 126.4 (C), 125.6 (CH), 122.4 (CH), 121.1 (CH), 112.6
(CH), 108.1 (CH), 45.1 (CH3) ppm; IR (KBr) ν 3378 (N−H), 1308
and 1140 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C9H9NO2SNa 218.0252, found 218.0260.
5-Methyl-2-[(4-methylphenyl)sulfonyl]-1H-indole (3b): pale yel-
low solid (115.1 mg, 81% yield); mp = 150−151 °C; TLC (20%
EtOAc in hexanes) Rf = 0.26; 1H NMR (500 MHz; CDCl3) δ 9.21 (br
s, 1 H), 7.91 (d, J = 8.2 Hz, 2 H), 7.45 (s, 1 H), 7.34−7.29 (m, 3 H),
7.17 (d, J = 8.5 Hz, 1 H), 7.13 (s, 1 H), 2.44 (s, 3 H), 2.40 (s, 3 H)
ppm; 13C NMR (125 MHz; CDCl3) δ 144.4 (C), 138.7 (C), 135.6
(C), 134.3 (C), 130.9 (C), 129.9 (2 × CH), 127.9 (CH), 127.4 (C),
127.3 (2 × CH), 121.8 (CH), 112.0 (CH), 108.4 (CH), 21.5 (CH3),
21.3 (CH3) ppm; IR (KBr) ν 3433 (N−H), 1324 and 1143 (SO2)
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H15NO2SNa
308.0721, found 308.0713.
1A. Subsequently, 1A abstracts the iodine radical either from
the sulfonyl iodide10b or the molecular iodine9 providing 1B,
which readily undergoes HI elimination to provide the
observed products 3−6.
CONCLUSION
■
We have developed a convenient and highly efficient method
for direct C2 sulfonylation reaction of indoles mediated by
iodine using sodium sulfinate as a reagent. The reactions
proceed under mild reaction conditions in a neutral solvent
allowing a broad scope of 2-sulfonylindole derivatives being
prepared. This protocol should be very useful in organic
synthesis because of the ease of operation and its wide scope.
5-Methyl-2-(phenylsulfonyl)-1H-indole (4b): pale yellow solid
(109.5 mg, 90% yield); mp = 116−117 °C; TLC (40% EtOAc in
EXPERIMENTAL SECTION
1
hexanes) Rf = 0.49; H NMR (400 MHz; CDCl3) δ 9.43 (br s, 1 H),
■
General Procedure. All isolated compounds were characterized
on the basis of 1H NMR and 13C NMR spectroscopic data, IR spectra,
and HRMS data. 1H NMR and 13C NMR chemical shifts are reported
in ppm using tetramethylsilane (TMS) as an internal standard or
residual nondeuterated solvent peak as an internal standard.
General Procedure for the Synthesis of 2-Sulfonylindole.
Iodine (190.5 mg, 0.75 mmol) was added to a solution of indole (0.5
mmol) and sodium arenesulfinate or sodium methanesulfinate (1.5
mmol) in MeOH (2 mL; 0.25 M), and the reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was quenched by
the addition of satd aq Na2S2O3 (5 mL). Further stirring was followed
by extraction with EtOAc (2 × 20 mL). The combined organic
extracts were washed with H2O (20 mL) and brine (20 mL), dried
(MgSO4), filtered, and concentrated (aspirator). The residue was
purified by column chromatography using EtOAc/hexanes as eluent to
afford the corresponding product.
8.02−7.99 (m, 2 H), 7.55−7.51 (m, 1 H), 7.47−7.42 (m, 3 H), 7.31
(d, J = 8.5 Hz, 1 H), 7.14−7.12 (m, 2 H), 2.40 (s, 3 H) ppm; 13C
NMR (100 MHz; CDCl3) δ 141.5 (C), 135.8 (C), 133.6 (C), 133.3
(CH), 130.9 (C), 129.3 (2 × CH), 128.0 (CH), 127.2 (C), 127.1 (2 ×
CH), 121.7 (CH), 112.1 (CH), 108.8 (CH), 21.3 (CH3) ppm; IR
(KBr) ν 3387 (N−H), 1316 and 1146 (SO2) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C15H13NO2SNa 294.0565, found
294.0560.
2-[(4-Chlorophenyl)sulfonyl]-5-methyl-1H-indole (5b): pale yellow
solid (140.7 mg, 92% yield); mp = 152−153 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.31; H NMR (400 MHz; CDCl3) δ 9.58 (br s, 1 H),
7.91 (d, J = 8.6 Hz, 2 H), 7.41−7.37 (m, 3 H), 7.30 (d, J = 8.5 Hz, 1
H), 7.14−7.12 (m, 2 H), 2.40 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 139.96 (C), 139.94 (C), 135.9 (C), 133.0 (C), 131.1 (C),
129.6 (2 × CH), 128.5 (2 × CH), 128.2 (CH), 127.1 (C), 121.7
(CH), 112.1 (CH), 109.1 (CH), 21.3 (CH3) ppm; IR (KBr) ν 3344
(N−H), 1321 and 1157 (SO2) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C15H12ClNO2SNa 328.0175, found 328.0172.
2-[(4-Methylphenyl)sulfonyl]-1H-indole (3a):7c white solid (114.3
mg, 85% yield); mp = 194−195 °C (lit.7c mp 196 °C) ; TLC (20%
EtOAc in hexanes) Rf = 0.26; 1H NMR (400 MHz; CDCl3) δ 9.37 (br
s, 1 H), 7.90 (d, J = 8.3 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.41 (d, J =
8.4 Hz, 1 H), 7.33−7.25 (m, 3 H), 7.18−7.14 (m, 2 H), 2.37 (s, 3 H)
ppm. 13C NMR (100 MHz; CDCl3) δ 144.5 (C), 138.5 (C), 137.2
(C), 134.4 (C), 130.0 (2 × CH), 127.3 (2 × CH), 127.0 (C), 125.9
(CH), 122.5 (CH), 121.4 (CH), 112.4 (CH), 108.8 (CH), 21.5
(CH3) ppm; IR (KBr) ν 3398 (N−H), 1320 and 1146 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H13NO2SNa
294.0565, found 294.0566.
5-Methyl-2-(methylsulfonyl)-1H-indole (6b): white solid (91.6 mg,
88% yield); mp = 159−160 °C; TLC (40% EtOAc in hexanes) Rf =
1
0.34; H NMR (400 MHz; CDCl3) δ 9.02 (br s, 1 H), 7.46 (s, 1 H),
7.35 (d, J = 8.5 Hz, 1 H), 7.20 (dd, J = 8.5, 1.2 Hz, 1 H), 7.10 (d, J =
1.5 Hz, 1 H), 3.17 (s, 3 H), 2.43 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 135.3 (C), 133.1 (C), 131.2 (C), 128.2 (CH), 127.2 (C),
121.9 (CH), 112.0 (CH), 108.2 (CH), 45.5 (CH3), 21.4 (CH3) ppm;
IR (KBr) ν 3318 (N−H), 1303 and 1157 (SO2) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C10H11NO2SNa 232.0408, found
232.0416.
2-(Phenylsulfonyl)-1H-indole (4a):11 white solid (119.3 mg, 92%
yield); mp = 137−138 °C; TLC (20% EtOAc in hexanes) Rf = 0.23;
1H NMR (400 MHz; CDCl3) δ 9.92 (br s, 1 H), 8.02 (d, J = 8.0 Hz, 2
H), 7.63 (d, J = 8.1 Hz, 1 H), 7.49−7.38 (m, 4 H), 7.27−7.24 (m, 2
H), 7.12 (t, J = 7.5 Hz, 1 H) ppm; 13C NMR (100 MHz; CDCl3) δ
141.3 (C), 137.4 (C), 133.7 (C), 133.4 (CH), 129.3 (2 × CH), 127.1
7-Methyl-2-[(4-methylphenyl)sulfonyl]-1H-indole (3c): white solid
(125.9 mg, 87% yield); mp =177−178 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.25; H NMR (500 MHz; CDCl3) δ 9.57 (br s, 1 H),
7.97 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.2 Hz,
2 H), 7.22 (d, J = 2.2 Hz, 1 H), 7.12−7.06 (m, 2 H), 2.48 (s, 3 H),
D
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2.38 (s, 3 H) ppm; 13C NMR (125 MHz; CDCl3) δ 144.4 (C), 138.7
(C), 137.2 (C), 134.1 (C), 129.9 (2 × CH), 127.3 (2 × CH), 126.7
(C), 126.1 (CH), 122.0 (C), 121.7 (CH), 120.1 (CH), 109.5 (CH),
21.5 (CH3), 16.7 (CH3) ppm; IR (KBr) ν 3375 (N−H), 1314 and
1149 (SO2) cm−1; IR (KBr) ν 3375 (N−H), 1314 and 1149 (SO2)
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H15NO2SNa
308.0721, found 308.0716.
(SO2), 1295 and 1096 (C−O) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C10H11NO3SNa 248.0357, found 248.0352.
5-Bromo-2-[(4-methylphenyl)sulfonyl]-1H-indole (3e): pale yellow
solid (74.6 mg, 43% yield); mp = 193−194 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.50; H NMR (400 MHz; acetone-d6) δ 11.44 (br s, 1
H), 7.91 (d, J = 8.4 Hz, 2 H), 7.88 (d, J = 1.8 Hz, 1 H), 7.46 (d, J = 8.8
Hz, 1 H), 7.41−7.38 (m, 3 H), 7.20 (dd, J = 2.2, 0.8 Hz, 1 H), 2.35 (s,
3 H) ppm; 13C NMR (100 MHz; acetone-d6) δ 145.7 (C), 139.7 (C),
137.9 (C), 137.3 (C), 130.9 (2 × CH), 129.3 (C), 129.1 (CH), 128.3
(2 × CH), 125.6 (CH), 115.4 (CH), 114.6 (C), 108.1 (CH), 21.5
(CH3) ppm; IR (KBr) ν 3348 (N−H), 1328 and 1153 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H12BrNO2SNa
371.9670, found 371.9679.
7-Methyl-2-(phenylsulfonyl)-1H-indole (4c):9 pale yellow solid
(120.0 mg, 92% yield); mp = 139−140 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.51; H NMR (400 MHz; CDCl3) δ 9.95 (br s, 1 H),
8.10−8.08 (m, 2 H), 7.52−7.42 (m, 4 H), 7.25 (d, J = 2.1 Hz, 1 H),
7.08−7.02 (m, 2 H), 2.45 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 141.5 (C), 137.4 (C), 133.5 (C), 133.3 (CH), 129.3 (2 ×
CH), 127.1 (2 × CH), 126.5 (C), 126.2 (CH), 122.2 (C), 121.6
(CH), 120.0 (CH), 109.9 (CH), 16.7 (CH3) ppm; IR (KBr) ν 3372
(N−H), 1309 and 1148 (SO2) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C15H13NO2SNa 294.0565, found 294.0567.
5-Bromo-2-(phenylsulfonyl)-1H-indole (4e):9 pale yellow solid
(76.8 mg, 46% yield); mp = 158−159 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.45; H NMR (400 MHz; CDCl3) δ 9.77 (br s, 1 H),
8.03−8.00 (m, 2 H), 7.77 (d, J = 1.8 Hz, 1 H), 7.59−7.55 (m, 1 H),
7.51−7.47 (m, 2 H), 7.37 (dd, J = 8.8, 1.8 Hz, 1 H), 7.30 (d, J = 8.8
Hz, 1 H), 7.13 (dd, J = 2.1, 0.7 Hz, 1 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 141.0 (C), 135.8 (C), 135.1 (C), 133.7 (CH), 129.5 (2 ×
CH), 129.1 (CH), 128.5 (C), 127.3 (2 × CH), 124.9 (CH), 114.7
(C), 114.0 (CH), 108.3 (CH) ppm; IR (KBr) ν 3363 (N−H), 1322
and 1157 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C14H10BrNO2SNa 357.9513, found 357.9510.
7-Methyl-2-(methylsulfonyl)-1H-indole (6c): pale yellow solid
(78.4 mg, 76% yield); mp = 141−142 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.33; H NMR (400 MHz; CDCl3) δ 9.44 (br s, 1 H),
7.53 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 7.17−7.09 (m, 2
H), 3.23 (s, 3 H), 2.51 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ
137.1 (C), 132.8 (C), 126.4 (CH), 126.3 (C), 122.1 (C), 121.9 (CH),
120.2 (CH), 109.4 (CH), 45.4 (CH3), 16.8 (CH3) ppm; IR (KBr) ν
3309 (N−H), 1323 and 1135 (SO2) cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C10H11NO2SNa 232.0408, found 232.0413.
5-Methoxy-2-[(4-methylphenyl)sulfonyl]-1H-indole (3d):13 white
solid (132.9 mg, 89% yield); mp = 159−160 °C; TLC (40% EtOAc in
5-Bromo-2-[(4-chlorophenyl)sulfonyl]-1H-indole (5e): brown solid
(61.2 mg, 33% yield); mp = 184−185 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.28; H NMR (400 MHz; acetone-d6) δ 11.57 (br s, 1
H), 8.04 (d, J = 8.7 Hz, 2 H), 7.90 (d, J = 1.2 Hz, 1 H), 7.65 (d, J = 8.8
Hz, 2 H), 7.48 (d, J = 8.8 Hz, 1 H), 7.42 (dd, J = 8.8, 1.8 Hz, 1 H),
7.26 (s, 1 H) ppm; 13C NMR (100 MHz; acetone-d6) δ 141.3 (C),
140.4 (C), 137.3 (C), 136.6 (C), 130.6 (2 × CH), 130.0 (2 × CH),
129.4 (CH), 129.2 (C), 125.6 (CH), 115.4 (CH), 114.7 (C), 108.8
(CH) ppm; IR (KBr) ν 3344 (N−H), 1323 and 1142 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H9BrClNO2SNa
393.9103, found 393.9101.
1
hexanes) Rf = 0.45; H NMR (400 MHz; CDCl3δ 9.04 (br s, 1 H),
7.87 (d, J = 8.3 Hz, 2 H), 7.31−7.26 (m, 3 H), 7.09 (dd, J = 2.0, 0.7
Hz, 1 H), 7.03 (d, J = 2.3 Hz, 1 H), 6.99 (dd, J = 9.0, 2.4 Hz, 1 H),
3.82 (s, 3 H), 2.38 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ
155.1 (C), 144.4 (C), 138.6 (C), 134.5 (C), 132.4 (C), 129.9 (2 ×
CH), 127.5 (C), 127.2 (2 × CH), 117.6 (CH), 113.3 (CH), 108.4
(CH), 102.5 (CH), 55.7 (CH3), 21.5 (CH3) ppm; IR (KBr) ν 3369
(N−H), 1327 and 1148 (SO2), 1292 and 1100 (C−O) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C16H15NO3SNa 324.0670, found
324.0671.
5-Bromo-2-(methylsulfonyl)-1H-indole (6e): pale yellow solid
(38.3 mg, 29% yield); mp = 188−189 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.29; H NMR (400 MHz; acetone-d6) δ 11.37 (br s, 1
5-Methoxy-2-(phenylsulfonyl)-1H-indole (4d):9 white solid (142.4
mg, 96% yield); mp = 121−122 °C; TLC (40% EtOAc in hexanes) Rf
H), 7.94 (d, J = 1.9 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.46 (dd, J =
8.8, 1.9 Hz, 1 H), 7.16 (dd, J = 2.2, 0.7 Hz, 1 H), 3.27 (s, 3 H) ppm;
13C NMR (100 MHz; acetone-d6) δ 137.4 (C), 137.0 (C), 129.3 (C),
129.1 (CH), 125.7 (CH), 115.6 (CH), 114.6 (C), 107.6 (CH), 45.2
(CH3) ppm; IR (KBr) ν 3293 (N−H), 1303 and 1126 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C9H8BrNO2SNa
295.9357, found 295.9341.
1
= 0.41; H NMR (400 MHz; CDCl3) δ 9.86 (br s, 1 H), 8.00 (d, J =
7.3 Hz, 2 H), 7.50−7.46 (m, 1 H), 7.42−7.38 (m, 2 H), 7.30 (d, J =
9.0 Hz, 1 H), 7.16 (d, J = 1.4 Hz, 1 H), 7.02 (d, J = 2.3 Hz, 1 H), 6.95
(dd, J = 9.0, 2.4 Hz, 1 H), 3.79 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 155.2 (C), 141.6 (C), 134.1 (C), 133.4 (CH), 132.5 (C),
129.3 (2 × CH), 127.5 (C), 127.2 (2 × CH), 117.8 (CH), 113.3
(CH), 108.8 (CH), 102.5 (CH), 55.7 (CH3) ppm; IR (KBr) ν 3359
(N−H), 1326 and 1151 (SO2), 1293 and 1099 (C−O) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C15H13NO3SNa 310.0514, found
310.0519.
2-[(4-Chlorophenyl)sulfonyl]-5-methoxy-1H-indole (5d): white
solid (151.2 mg, 94% yield); mp = 124−125 °C; TLC (20% EtOAc
in hexanes) Rf = 0.24; 1H NMR (400 MHz; CDCl3) δ 9.66 (br s, 1 H),
7.90 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.29 (d, J = 9.0 Hz,
1 H), 7.13 (d, J = 1.2 Hz, 1 H), 7.02 (d, J = 1.9 Hz, 1 H), 6.97 (dd, J =
9.0, 2.4 Hz, 1 H), 3.80 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ
155.1 (C), 139.94 (C), 139.88 (C), 133.3 (C), 132.8 (C), 129.5 (2 ×
CH), 128.5 (2 × CH), 127.3 (C), 118.0 (CH), 113.4 (CH), 109.0
(CH), 102.3 (CH), 55.6 (CH3) ppm; IR (KBr) ν 3380 (N−H), 1332
and 1151 (SO2), 1293 and 1091 (C−O) cm−1; HRMS (ESI-TOF) m/
z [M + Na]+ calcd for C15H12ClNO3SNa 344.0124, found 344.0125.
5-Methoxy-2-(methylsulfonyl)-1H-indole (6d): white solid (86.4
mg, 77% yield); mp = 177−178 °C; TLC (40% EtOAc in hexanes) Rf
= 0.26; 1H NMR (400 MHz; acetone-d6) δ 11.02 (br s, 1 H), 7.47 (d, J
= 9.0 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 7.07 (dd, J = 2.2, 0.8 Hz, 1
H), 7.01 (dd, J = 9.0, 2.4 Hz, 1 H), 3.81 (s, 3 H), 3.22 (s, 3 H) ppm;
13C NMR (100 MHz; acetone-d6) δ 156.0 (C), 135.9 (C), 133.6 (C),
128.1 (C), 117.9 (CH), 114.5 (CH), 107.9 (CH), 103.2 (CH), 55.8
(CH3), 45.3 (CH3) ppm; IR (KBr) ν 3286 (N−H), 1325 and 1165
5-Fluoro-2-[(4-methylphenyl)sulfonyl]-1H-indole (3f): white solid
(78.5 mg, 58% yield); mp = 142−143 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.48; H NMR (400 MHz; acetone-d6) δ 11.41 (br s, 1
H), 7.92 (d, J = 8.4 Hz, 2 H), 7.52 (dd, J = 9.1, 4.5 Hz, 1 H), 7.42 (d, J
= 7.9 Hz, 3 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (td, J = 9.2, 2.6 Hz, 1
H), 2.38 (s, 3 H) ppm; 13C NMR (100 MHz; acetone-d6) δ 159.1 (d, J
= 234 Hz, C), 145.6 (C), 139.9 (C), 138.2 (C), 135.5 (C), 131.0 (2 ×
CH), 128.3 (2 × CH), 128.0 (d, J = 11 Hz, C), 115.3 (d, J = 27 Hz,
CH), 115.0 (d, J = 9 Hz, CH), 108.7 (d, J = 5 Hz, CH), 107.4 (d, J =
24 Hz, CH), 21.5 (CH3) ppm; IR (KBr) ν 3273 (N−H), 1308 and
1157 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H12FNO2SNa 312.0470, found 312.0477.
5-Fluoro-2-(phenylsulfonyl)-1H-indole (4f): pale yellow solid (74.7
mg, 54% yield); mp = 144−145 °C; TLC (40% EtOAc in hexanes) Rf
1
= 0.44; H NMR (400 MHz; CDCl3) δ 9.80 (br s, 1 H), 8.01 (d, J =
8.7 Hz, 2 H), 7.57−7.53 (m, 1 H), 7.48−7.45 (m, 2 H), 7.36 (dd, J =
9.1, 4.4 Hz, 1 H), 7.26 (dd, J = 9.1, 2.4 Hz, 1 H), 7.15 (d, J = 1.4 Hz, 1
H), 7.05 (td, J = 9.0, 2.5 Hz, 1 H) ppm; 13C NMR (100 MHz; CDCl3)
δ 158.3 (d, J = 237 Hz, C), 141.0 (C), 135.3 (C), 133.9 (C), 133.6
(CH), 129.4 (2 × CH), 127.2 (2 × CH), 127.1 (C), 115.3 (d, J = 27
Hz, CH), 113.6 (d, J = 10 Hz, CH), 108.9 (d, J = 5 Hz, CH), 106.8 (d,
J = 24 Hz, CH) ppm; IR (KBr) ν 3326 (N−H), 1327 and 1146 (SO2)
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H10FNO2SNa
298.0314, found 298.0332.
E
dx.doi.org/10.1021/jo402831k | J. Org. Chem. XXXX, XXX, XXX−XXX

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5-Fluoro-2-(methylsulfonyl)-1H-indole (6f): pale yellow solid (23.5
mg, 22% yield); mp = 157−158 °C; TLC (40% EtOAc in hexanes) Rf
= 0.30; 1H NMR (400 MHz; acetone-d6) δ 11.32 (br s, 1 H), 7.60 (dd,
J = 9.0, 4.5 Hz, 1 H), 7.46 (dd, J = 9.4, 2.5 Hz, 1 H), 7.21−7.16 (m, 2
H), 3.27 (s, 3 H) ppm; 13C NMR (100 MHz; acetone-d6) δ 159.2 (d, J
= 234 Hz, C), 137.7 (C), 135.1 (C), 127.9 (d, J = 11 Hz, C), 115.2 (d,
J = 25 Hz, CH), 115.1 (d, J = 7 Hz, CH), 108.1 (d, J = 6 Hz, CH),
107.4 (d, J = 24 Hz, CH), 45.2 (CH3) ppm; IR (KBr) ν 3311 (N−H),
1326 and 1159 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C9H8FNO2SNa 236.0157, found 236.0146.
2-[(4-Methylphenyl)sulfonyl]-1H-indole-5-carbaldehyde (3g):
pale yellow solid (31.9 mg, 21% yield); mp = 174−174 °C; TLC
(40% EtOAc in hexanes) Rf = 0.55; 1H NMR (300 MHz; DMSO-d6) δ
12.88 (br s, 1 H), 9.96 (s, 1 H), 8.31, (d, J = 0.8 Hz, 1 H), 7.89 (d, J =
8.3 Hz, 2 H), 7.78 (dd, J = 8.7, 1.5 Hz, 1 H), 7.56 (dd, J = 8.7, 0.5 Hz,
1 H), 7.44−7.41 (m, 3 H), 2.33 (s, 3 H) ppm; 13C NMR (75 MHz;
DMSO-d6) δ 192.5 (CO of aldehyde), 144.9 (C), 140.8 (C), 137.9
(C), 137.0 (C), 130.4 (C), 130.3 (2 × CH), 128.6 (CH), 127.3 (2 ×
CH), 125.8 (C), 124.2 (CH), 113.7 (CH), 109.6 (CH), 21.2 (CH3)
ppm; IR (KBr) ν 3293 (N−H), 2855 (C−H of aldehyde), 1671 (C
O), 1324 and 1144 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C16H13NO3SNa 322.0514, found 322.0515.
2-(Phenylsulfonyl)-1H-indole-5-carbaldehyde (4g): pale yellow
solid (43.7 mg, 31% yield); mp = 159−160 °C; TLC (40% EtOAc
in hexanes) Rf = 0.50; 1H NMR (300 MHz; DMSO-d6) δ 12.92 (br s,
1 H), 9.96 (s, 1 H), 8.31 (s, 1 H), 8.02 (d, J = 8.2 Hz, 2 H), 7.78 (dd, J
= 8.7, 1.3 Hz, 1 H), 7.70−7.55 (m, 4 H), 7.44 (d, J = 1.2 Hz, 1 H)
ppm; 13C NMR (75 MHz; DMSO-d6) δ 192.4 (CO of aldehyde),
140.9 (C), 140.8 (C), 136.6 (C), 134.1 (CH), 130.4 (C), 129.8 (2 ×
CH), 128.6 (CH), 127.2 (2 × CH), 125.8 (C), 124.2 (CH), 113.7
(CH), 109.9 (CH) ppm; IR (KBr) ν 3306 (N−H), 2834 and 2740
(C−H of aldehyde), 1678 (CO), 1331 and 1147 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H11NO3SNa
308.0357, found 308.0354.
2-(Methylsulfonyl)-1H-indole-5-carbaldehyde (6g): pale yellow
solid (22.7 mg, 20% yield); mp = 167−168 °C; TLC (40% EtOAc
in hexanes) Rf = 0.39; 1H NMR (300 MHz; acetone-d6) δ 11.66 (br s,
1 H), 10.05 (s, 1 H), 8.37 (t, J = 0.7 Hz, 1 H), 7.89 (dd, J = 8.7, 1.5
Hz, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.38 (dd, J = 2.1, 0.7 Hz, 1 H),
3.30 (s, 3 H) ppm; 13C NMR (75 MHz; acetone-d6) δ 192.3 (CO
of aldehyde), 141.2 (C), 138.0 (C), 132.0 (C), 129.0 (CH), 127.2 (C),
124.9 (CH), 114.3 (CH), 109.8 (CH), 45.0 (CH3) ppm; IR (KBr) ν
3298 (N−H), 2818 and 2769 (C−H of aldehyde), 1686 (CO),
1310 and 1124 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C10H9NO3SNa 246.0201, found 246.0202.
Methyl 2-(methylsulfonyl)-1H-indole-5-carboxylate (6h): pale
yellow solid (12.8 mg, 10% yield); mp = 167−168 °C; TLC (40%
1
EtOAc in hexanes) Rf = 0.21; H NMR (400 MHz; acetone-d6) δ
11.53 (br s, 1 H), 8.49 (d, J = 0.5 Hz, 1 H), 7.99 (dd, J = 8.8, 1.6 Hz, 1
H), 7.65 (d, J = 8.8 Hz, 1 H), 7.34 (d, J = 1.8 Hz, 1 H), 3.89 (s, 3 H),
3.30 (s, 3 H) ppm; 13C NMR (100 MHz; acetone-d6) δ 167.7 (CO
of ester), 140.6 (C), 137.8 (C), 127.2 (C), 126.8 (CH), 126.3 (CH),
124.3 (C), 113.6 (CH), 109.6 (CH), 52.3 (CH3), 45.1 (CH3) ppm; IR
(KBr) ν 3323 (N−H), 1702 (CO), 1262 and 1099 (C−O), 1314
and 1138 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C11H11NO4SNa 276.0306, found 276.0318.
1-Methyl-2-[(4-methylphenyl)sulfonyl]-1H-indole (3j): white solid
(122.4 mg, 86% yield); mp = 152−153 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.35; H NMR (400 MHz; CDCl3) δ 7.83 (d, J = 8.4
Hz, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.35−7.26 (m, 5 H), 7.17−7.13
(m, 1 H), 3.81 (s, 3 H), 2.36 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 144.4 (C), 139.3 (C), 138.0 (C), 135.0 (C), 129.8 (2 ×
CH), 127.5 (2 × CH), 125.5 (CH), 125.0 (C), 122.6 (CH), 121.0
(CH), 110.2 (CH), 110.1 (CH), 30.8 (CH3), 21.4 (CH3) ppm; IR
(KBr) ν 1320 and 1150 (SO2) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C16H15NO2SNa 308.0721, found 308.0703.
1-Methyl-2-(phenylsulfonyl)-1H-indole (4j):11b pale yellow solid
(121.9 mg, 87% yield); mp = 118−119 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.31; H NMR (400 MHz; CDCl3) δ 7.96 (d, J = 8.1
Hz, 2 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.60−7.49 (m, 3 H), 7.38−7.29
(m, 3 H), 7.18 (t, J = 7.1 Hz, 1 H), 3.84 (s, 3 H) ppm; 13C NMR (100
MHz; CDCl3) δ 141.2 (C), 139.5 (C), 134.7 (C), 133.4 (CH), 129.3
(2 × CH), 127.6 (2 × CH), 125.7 (CH), 125.1 (C), 122.8 (CH),
121.1 (CH), 110.8 (CH), 110.2 (CH), 31.0 (CH3) ppm; IR (KBr) ν
1323 and 1157 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C15H13NO2SNa 294.0565, found 294.0572.
2-[(4-Chlorophenyl)sulfonyl]-1-methyl-1H-indole (5j): pale yellow
solid (114.7 mg, 75% yield); mp = 135−136 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.40; H NMR (400 MHz; CDCl3) δ 7.88 (d, J = 8.6
Hz, 2 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.39−
7.35 (m, 2 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 3.83
(s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ 139.9 (C), 139.6 (C),
139.5 (C), 134.1 (C), 129.5 (2 × CH), 129.0 (2 × CH), 125.9 (CH),
125.0 (C), 122.8 (CH), 121.2 (CH), 111.0 (CH), 110.2 (CH), 30.9
(CH3) ppm; IR (KBr) ν 1327 and 1156 (SO2) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C15H12ClNO2SNa 328.0175, found
328.0170.
1-Methyl-2-(methylsulfonyl)-1H-indole (6j): pale yellow solid (78.2
mg, 72% yield); mp = 104−105 °C; TLC (40% EtOAc in hexanes) Rf
1
= 0.39; H NMR (400 MHz; CDCl3) δ 7.68 (d, J = 8.1 Hz, 1 H),
7.43−7.36 (m, 2 H), 7.25 (s, 1 H), 7.24−7.18 (m, 1 H), 4.00 (s, 3 H),
3.16 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ 139.4 (C), 134.5
(C), 125.9 (CH), 125.0 (C), 122.9 (CH), 121.3 (CH), 110.32 (CH),
110.30 (CH), 45.3 (CH3), 31.0 (CH3) ppm; IR (KBr) ν 1311 and
1143 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C10H11NO2SNa 232.0408, found 232.0421.
Methyl 2-[(4-methylphenyl)sulfonyl]-1H-indole-5-carboxylate
(3h): white solid (21.1 mg, 13% yield); mp = 219−220 °C; TLC
(40% EtOAc in hexanes) Rf = 0.41; 1H NMR (400 MHz; acetone-d6)
δ 11.68 (br s, 1 H), 8.44 (t, J = 0.7 Hz, 1 H), 7.95−7.92 (m, 3 H), 7.57
(d, J = 8.8 Hz, 1 H), 7.43−7.37 (m, 3 H), 3.87 (s, 3 H), 2.38 (s, 3 H)
ppm; 13C NMR (100 MHz; acetone-d6) δ 167.6 (CO of ester),
145.8 (C), 141.1 (C), 139.7 (C), 138.4 (C), 131.0 (2 × CH), 128.4 (2
× CH), 127.3 (C), 126.9 (CH), 126.3 (CH), 124.3 (C), 113.5 (CH),
110.1 (CH), 52.3 (CH3), 21.5 (CH3) ppm; IR (KBr) ν 3302 (N−H),
1699 (CO), 1261 and 1102 (C−O), 1328 and 1149 (SO2) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H15NO4SNa
352.0619, found 352.0625.
1-Ethyl-2-[(4-methylphenyl)sulfonyl]-1H-indole (3k): yellow vis-
cous oil (134.6 mg, 90% yield); TLC (20% EtOAc in hexanes) Rf =
1
0.40; H NMR (500 MHz; CDCl3) δ 7.85 (d, J = 8.3 Hz, 2 H), 7.71
(d, J = 8.0 Hz, 1 H), 7.38−7.31 (m, 5 H), 7.20−7.17 (m, 1 H), 4.38
(q, J = 7.2 Hz, 2 H), 2.41 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H) ppm; 13C
NMR (125 MHz; CDCl3) δ 144.4 (C), 138.39 (C), 138.35 (C), 134.6
(C), 129.8 (2 × CH), 127.7 (2 × CH), 125.5 (CH), 125.4 (C), 122.9
(CH), 121.0 (CH), 110.6 (CH), 110.5 (CH), 39.6 (CH2), 21.5
(CH3), 14.9 (CH3) ppm; IR (neat) ν 2981 (C−H), 1317 and 1155
(SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H17NO2SNa 322.0878, found 322.0870.
1-Ethyl-2-(phenylsulfonyl)-1H-indole (4k): yellow viscous oil
(127.4 mg, 93% yield); TLC (20% EtOAc in hexanes) Rf = 0.36;
1H NMR (400 MHz; CDCl3) δ 7.98−7.95 (m, 2 H), 7.71 (d, J = 8.0
Hz, 1 H), 7.60−7.56 (m, 1 H), 7.53−7.49 (m, 2 H), 7.38−7.31 (m, 3
H), 7.20−7.16 (m, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.15 (t, J = 7.2 Hz,
3 H) ppm; 13C NMR (100 MHz; CDCl3) δ 141.3 (C), 138.4 (C),
134.1 (C), 133.4 (CH), 129.3 (2 × CH), 127.6 (2 × CH), 125.7
(CH), 125.4 (C), 123.0 (CH), 121.1 (CH), 111.0 (CH), 110.5 (CH),
Methyl 2-(phenylsulfonyl)-1H-indole-5-carboxylate (4h): white
solid (33.9 mg, 22% yield); mp = 237−238 °C; TLC (40% EtOAc in
1
hexanes) Rf = 0.38; H NMR (400 MHz; DMSO-d6) δ 12.83 (br s, 1
H), 8.41 (d, J = 1.0 Hz, 1 H), 8.04−8.02 (m, 2 H), 7.88 (dd, J = 8.8,
1.6 Hz, 1 H), 7.71−7.61 (m, 3 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.43 (s, 1
H), 3.82 (s, 3 H) ppm; 13C NMR (100 MHz; DMSO-d6) δ 166.6
(CO of ester), 140.8 (C), 140.1 (C), 136.2 (C), 134.0 (CH), 129.8
(2 × CH), 127.1 (2 × CH), 125.7 (CH), 125.6 (C), 125.4 (CH),
122.5 (C), 112.9 (CH), 109.6 (CH), 51.9 (CH3) ppm; IR (KBr) ν
3256 (N−H), 1693 (CO), 1264 and 1110 (C−O), 1329 and 1155
(SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C16H13NO4SNa 338.0463, found 338.0464.
F
dx.doi.org/10.1021/jo402831k | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
1
39.6 (CH2), 14.9 (CH3) ppm; IR (neat) ν 2981 (C−H), 1338 and
1155 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C16H15NO2SNa 308.0721, found 308.0728.
= 0.40; H NMR (400 MHz; CDCl3) δ 9.14 (br s, 1 H), 7.66 (d, J =
8.1 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.40−7.36 (m, 1 H), 7.23−
7.19 (m, 1 H), 3.17 (s, 3 H), 2.60 (s, 3 H) ppm; 13C NMR (100 MHz;
CDCl3) δ 135.7 (C), 128.4 (C), 128.0 (C), 126.3 (CH), 120.83 (CH),
120.76 (CH), 118.5 (C), 112.3 (CH), 45.1 (CH3), 8.8 (CH3) ppm; IR
(KBr) ν 3364 (N−H), 1299 and 1145 (SO2) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C10H11NO2SNa 232.0408, found
232.0404.
1-Ethyl-2-(methylsulfonyl)-1H-indole (6k): yellow viscous oil (76.9
mg, 74% yield); TLC (40% EtOAc in hexanes) Rf = 0.46; H NMR
1
(300 MHz; CDCl3) δ 7.60 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 3.8 Hz, 2
H), 7.14−7.08 (m, 2 H), 4.43 (q, J = 7.1 Hz, 2 H), 3.09 (s, 3 H), 1.36
(t, J = 7.1 Hz, 3 H) ppm; 13C NMR (75 MHz; CDCl3) δ 138.2 (C),
133.9 (C), 125.8 (CH), 125.3 (C), 123.0 (CH), 121.2 (CH), 110.6
(CH), 110.4 (CH), 45.5 (CH3), 39.8 (CH2), 15.4 (CH3) ppm; IR
(neat) ν 2983 (C−H), 1317 and 1144 (SO2) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C11H13NO2SNa 246.0565, found
246.0567.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all 2-sulfonylindole
derivatives presented in Table 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
1-Benzyl-2-[(4-methylphenyl)sulfonyl]-1H-indole (3l): white solid
(136.2 mg, 75% yield); mp =133−134 °C; TLC (20% EtOAc in
1
hexanes) Rf = 0.45; H NMR (300 MHz; CDCl3) δ 7.78 (d, J = 7.9
AUTHOR INFORMATION
Corresponding Author
*E-mail: chutima.kon@mahidol.ac.th.
Hz, 1 H), 7.67 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 0.7 Hz, 1 H), 7.33−
7.06 (m, 8 H), 6.72 (d, J = 6.9 Hz, 2 H), 5.69 (s, 2 H), 2.32 (s, 3 H)
ppm; 13C NMR (75 MHz; CDCl3) δ 144.0 (C), 139.2 (C), 137.6 (C),
136.4 (C), 135.5 (C), 129.5 (2 × CH), 128.3 (2 × CH), 127.6 (2 ×
CH), 126.8 (CH), 125.8 (CH), 125.7 (2 × CH), 125.3 (C), 122.7
(CH), 121.3 (CH), 111.1 (CH), 111.0 (CH), 47.6 (CH2), 21.4 (CH3)
ppm; IR (KBr) ν 2976 (C−H), 1316 and 1159 (SO2) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C22H19NO2SNa 384.1034, found
384.1036.
1-Benzyl-2-(phenylsulfonyl)-1H-indole (4l): white solid (121.7 mg,
79% yield); mp = 116−117 °C; TLC EtOAc in hexanes) Rf (20% =
0.39; 1H NMR (400 MHz; CDCl3) δ 7.76−7.73 (m, 3 H), 7.51 (d, J =
0.8 Hz, 1 H), 7.40−7.36 (m, 1 H), 7.28−7.24 (m, 3 H), 7.20−7.03 (m,
5 H), 6.69 (d, J = 6.8 Hz, 2 H), 5.65 (s, 2 H) ppm; 13C NMR (100
MHz; CDCl3) δ 140.7 (C), 139.4 (C), 136.4 (C), 135.1 (C), 133.0
(CH), 128.9 (2 × CH), 128.4 (2 × CH), 127.5 (2 × CH), 127.1
(CH), 126.0 (CH), 125.7 (2 × CH), 125.3 (C), 122.8 (CH), 121.4
(CH), 111.6 (CH), 111.2 (CH), 47.7 (CH2) ppm; IR (KBr) ν 2921
(C−H), 1321 and 1157 (SO2) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C21H17NO2SNa 370.0878, found 370.0863.
1-Benzyl-2-(methylsulfonyl)-1H-indole (6l): white solid (77.6 mg,
54% yield); mp = 126−127 °C; TLC (40% EtOAc in hexanes) Rf =
0.54; 1H NMR (400 MHz; CDCl3) δ 7.67 (d, J = 8.0 Hz, 1 H), 7.34−
7.28 (m, 3 H), 7.23−7.14 (m, 4 H), 6.98 (d, J = 6.9 Hz, 2 H), 5.68 (s,
2 H), 2.65 (s, 3 H) ppm; 13C NMR (100 MHz; CDCl3) δ 139.4 (C),
136.9 (C), 134.4 (C), 128.9 (2 × CH), 127.9 (CH), 126.4 (2 × CH),
126.3 (CH), 125.1 (C), 123.0 (CH), 121.5 (CH), 111.7 (CH), 110.9
(CH), 47.3 (CH2), 45.2 (CH3) ppm; IR (KBr) ν 2996 (C−H), 1314
and 1150 (SO2) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C16H15NO2SNa 308.0721, found 308.0725.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Thailand Research Fund (TRF-DBG5480017),
the Center for Innovation in Chemistry (PERCH-CIC), the
Office of the Higher Education Commission, Mahidol
University under the National Research Universities Initiative
and the Development and Promotion of Science and
Technology Talent Project (DPST), and the Institute for the
Promotion of Teaching Science and Technology for financial
support. We also thank Professor Chi Wi Ong, National Sun
Yat-sen University, and Professor Gunter Grampp, Technical
̈
University of Graz, and Dr. Soraya Pornsuwan and Asst. Prof.
Noppawan Phumala Morales, Mahidol University, for dis-
cussions on the mechanistic study.
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= 0.28; H NMR (400 MHz; CDCl3) δ 9.57 (br s, 1 H), 8.01−7.98
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