Cu-Catalyzed oxidative 3-amination of indoles via formation of indolyl(aryl)iodonium Imides Using o-Substituted (Diacetoxyiodo)arene as a High-Performance Hypervalent Iodine Compound

Article abstract of DOI:10.3390/molecules24061147

An oxidative 3-amination of indole derivatives using hypervalent iodine(III) and bissulfonimides, which proceeds via the formation of indolyl(aryl)iodonium imides, was developed. This reaction was followed by an indole-selective copper-catalyzed oxidative C–N coupling reaction to obtain 3-amino indole derivatives as single regioisomers. o-Alkoxy(diacetoxyiodo)arenes showed higher reactivity in the reaction than o-alkyl(diacetoxyiodo)arenes, efficiently promoting the formation of indolyl(aryl)iodonium imides in the first step.

Full text of DOI:10.3390/molecules24061147

molecules
Article
Cu-Catalyzed Oxidative 3-Amination of Indoles via
Formation of Indolyl(aryl)iodonium Imides Using
o-Substituted (Diacetoxyiodo)arene as a
High-Performance Hypervalent Iodine Compound
Kazuhiro Watanabe and Katsuhiko Moriyama *
Department of Chemistry, Graduate School of Science, and Molecular Chirality Research Center,
Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan; cars9s66@chiba-u.jp
*
Correspondence: moriyama@faculty.chiba-u.jp; Tel.: +81-43-290-3693
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Kazunori Miyamoto
Received: 27 February 2019; Accepted: 21 March 2019; Published: 22 March 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: An oxidative 3-amination of indole derivatives using hypervalent iodine(III) and
bissulfonimides, which proceeds via the formation of indolyl(aryl)iodonium imides, was developed.
This reaction was followed by an indole-selective copper-catalyzed oxidative C–N coupling reaction
to obtain 3-amino indole derivatives as single regioisomers. o-Alkoxy(diacetoxyiodo)arenes showed
higher reactivity in the reaction than o-alkyl(diacetoxyiodo)arenes, efficiently promoting the formation
of indolyl(aryl)iodonium imides in the first step.
Keywords: o-substituted iodoarene; indole; Cu catalyst; C–N coupling reaction; hypervalent iodine;
one-pot reaction; regioselectivity
1
. Introduction
The direct installation of an amino group into an indole skeleton is a very important strategy to
generate amino indole derivatives, which are key building blocks for indole-based natural products and
biologically active compounds [ ]. The novel 3-selective amination of indole derivatives has attracted
1–6
considerable attention from synthetic organic chemists. Regarding previous work on the 3-selective
amination of indole derivatives, the nitration of protecting-group-free and N-protected indoles with
metal nitrate or nitric acid is well known (Scheme 1A) [
7–12]. Sudalai and coworkers reported an
azidation of indole derivatives with a stoichiometric amount of I and NaN to give 3-azide indole
2
3
derivatives (Scheme 1B) [13]. Wang and coworkers developed an electrophilic amidation of indoles
with N-[(benzenesulfonyl)oxy]amide as the electrophilic nitrogen agent in the presence of ZnCl2
(Scheme 1C) [14]. As examples of the C–N coupling reaction of indoles with a nucleophilic nitrogen
source, the azidation with NaN via the formation of indolyl(phenyl)iodonium azide (Scheme 1D) [15],
3
and the amination of alkylamines via the formation of indolyl(Mes)iodonium tosylate (Scheme 1E) [16
]
from electron-donating group protected 2-substituted indoles using hypervalent iodine compounds
were developed by Suna and coworkers. Regarding the 3-amination of electron-withdrawing group
protected indoles, the 3-imidation of N-acetyl indoles with (PhSO ) NF under transition-metal-free
2
2
conditions was developed by Yang and coworkers (Scheme 1F) [17].
On the other hand, we were able to prepare indolyl(aryl)iodonium imides, which are related to
I–N bonding hypervalent iodine compounds, from N-electron-withdrawing group protected indoles,
bissulfonimides, and (diacetoxyiodo)arenes [18,19], and to achieve the dual functionalization of indoles
via halo-amination with halogen reagents using the indolyl(aryl)iodonium imides [18,20].
Molecules 2019, 24, 1147; doi:10.3390/molecules24061147
www.mdpi.com/journal/molecules

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Scheme 1. 3-Installation of amino group into indole skeleton.
electron-donating group protected indoles: ( ) Azidation, ( ) Electrophilic amidation, (
via formation of indolyl(phenyl)iodonium azide, ( ) Amidation via formation of indolyl(Mes)iodonium
tosylate. 3-Amination of electron-withdrawing group protected indoles: ( ) Electrophilic amidation,
G) Amidation via formation of indolyl(aryl)iodonium imide.
(
A
) Nitration. 3-Amination of
B
C
D
) Azidation
E
F
(
We report herein a 3-selective C–N coupling reaction of N-electron-withdrawing group protected
indoles with various bissulfonimides using hypervalent iodine compounds (Scheme 1G). In our
previous work, the indole-selective C–N coupling reaction of indolyl(aryl)iodonium imides promoted
by a copper catalyst gave 3-amino indole derivatives [21]. Furthermore, in the copper-catalyzed C–N
coupling reaction, indolyl(2-butoxyphenyl)iodonium bistosylimide showed high indole selectivity
whereas indolyl(phenyl)iodonium bistosylimide showed aryl selectivity (Scheme 2). From the results,
we envisioned that (diacetoxy)iodoarene bearing an o-substituted phenyl group would promote
the copper-catalyzed C–N coupling reaction of indoles with bissulfonimides via the formation of
indolyl(aryl)iodonium imides. To obtain the corresponding 3-amino indole derivatives using this
method, the formation of indolyl(aryl)iodonium imides should proceed effectively other than indole
selectivity in the C–N coupling reaction of indolyl(aryl)iodonium imides. However, it is possible that
2
2
steric hindrance by o-substituted bissulfonimidoiodoarene (ArI(OAc)(N(SO R ) ) or ArI(N(SO R ) ) ),
2
2
2
2 2
which is generated in situ from the reaction of (diacetoxyiodo)arene with bissulfonimides, would

Molecules 2019, 24, 1147
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suppress the formation of indolyl(aryl)iodonium imides. The necessity of appropriate steric hindrance
and the electronic effect of o-alkoxy group substituted iodoarene moiety on hypervalent iodine(III)
compounds in the 3-amination of N-electron-withdrawing group protected indoles were evaluated on
the basis of comparisons with other o-substituted (diacetoxyiodo)arenes.
Scheme 2. Effect of substituent on iodoarene in copper-catalyzed C–N coupling reaction of
indolyl(aryl)iodonium imides.
2
. Results and Discussion
First, we conducted screening for (acetoxy)iodoarene, copper catalyst, and solvent for the
-amination of indoles on the basis of previously reported reaction conditions (Table 1). It is
3
important to use MeCN as a solvent in the formation of indolyl(aryl)iodonium imides (in the
first step) and toluene-related solvent (i.e., toluene and xylene) in the copper-catalyzed C–N
coupling reaction (in the second step) to progress each reaction efficiently [18
,20,21]. Treatment
of N-pivaloyl indole (1a) with Ts NH (1.6 equiv.) and PhI(OAc) (1.2 equiv.) in MeCN at
2
2
◦
0 C for 7 h, followed by the addition of Cu(MeCN) BF (5 mol%) in toluene under reflux
4 4
4
conditions for 1 h provided N-pivaloyl-3-bistosylimido indole (2a) in 26% yield together with
N,N-bistosylaniline in 58% yield as a byproduct (Entry 1). When (diacetoxyiodo)2-butoxybenzene
(A), (diacetoxyiodo)2,4,6-trimethylbenzene (B), and (diacetoxyiodo)2,6-dimethoxybenzene (D) were
used instead of PhI(OAc) , the C–N coupling reaction showed high indole selectivity to obtain
2
the desired product (2a) in high yields (76–82% yield) (Entries 2, 3, and 5). The use of
(
diacetoxyiodo)2,4,6-triisopropylbenzene (C) and 1-acetoxy-1,2-benziodoxol-3-(1H)-one (
E) gave 2a
in moderate to low yields (Entries 4 and 6). (Diacetoxyiodo)arenes (
hypervalent iodine compounds were adopted for use in xylene at 130 C for the 3-amination of indoles,
and similar reactivity to that in toluene under reflux conditions was realized (Entries 7–9). By contrast,
A
,
B
, and
D
) as o-substituted
◦
the reaction with (diacetoxyiodo)arenes
yields (16–42% yield) (Entries 10–12).
A,
B, and
D in the absence of copper catalyst gave 2a in low
Then, (diacetoxyiodo)arenes
A
,
B, and D were utilized in the reaction with N-pivaloyl
5
-chloroindole (1b) under two conditions (in toluene under reflux conditions and in xylene at 130
◦
C) to clarify substrate generality for the 3-amination of indoles (Scheme 3). Treatment of 1b with
◦
(diacetoxyiodo)2-butoxybenzene (
A
) in xylene at 130 C in the second step provided the desired
product (2b) in 75% yield. However, when (diacetoxyiodo)2,4,6-trimethylbenzene (
similar conditions to those in the reaction with , the reactivity of with 1b declined to give 2b in
8% yield. (Diacetoxyiodo)2,6-dimethoxybenzene ( ) showed similar reactivity to (68% yield). It is
noteworthy that the reaction of 1b in toluene under reflux conditions in the second step using the three
B) was used under
A
B
4
D
A
(
diacetoxyiodo)arenes (
A
,
B
, and
D
) generated small quantities of 2-aminated indole derivative as
◦
byproduct (5–9% yield). Therefore, we determined that the reaction in xylene at 130 C in the presence
of Cu(MeCN) BF catalyst was the best option for the second step in the 3-amination of indoles using
4
4
(diacetoxyiodo)arenes.

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Table 1. Screening for ArI(OAc) and solvent for 3-amination of indole (1a).
2
Temp. 1 ( C)
◦
Solvent
Temp. 2 ( C)
◦
Yield (%)
Entry
ArI(OAc)2
1
2
3
4
5
6
7
8
PhI(OAc)2
40
40
60
60
60
60
40
60
60
40
60
60
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
130
130
130
130
130
26 (58) a
76
A
B
C
D
E
A
B
D
A
B
82
55 (19) b
81
2 (76) b
78
76
9
78
16 (67)
c
d
1
1
1
0
1
2
c
c
d
42 (9)
32 (64) d
D
130
a
Number in parentheses indicates yield of N,N-bistosylaniline. b Numbers in parentheses indicate recovery of
c
d
1
a.
The reaction was carried out in the absence of Cu(MeCN)
4
BF
4
.
Numbers in parentheses indicate yield of
indolyl(aryl)iodonium imide (4).
Scheme 3. Copper-catalyzed 3-amination of 1b with o-substituted (diacetoxyiodo)arenes. a Numbers
in parentheses indicate yield of N-pivaloyl-2-bistosylimdo-5-chloroindole (3b).
To compare the reactivities of (diacetoxyiodo)arenes (
-amination of indoles, N-protected indoles ( ) were examined under optimum conditions
Scheme 4). Treatment of N-pivaloyl indole (1a) with various bissulfonimides, containing an
aromatic group, an aliphatic group, or a dissymmetric functional group provided corresponding
-amino indole derivatives (2c ) in 51–81% yields, respectively. Unfortunately, the reaction with
A, B, and D) in the copper-catalyzed
3
1
(
3
–f
Ms NH gave N-pivaloyl-2-dimesylimido-indole derivative (3f) in 10–14% yields as the by-product.
2
The reaction of 5- and 6-substituted indoles bearing an alkyl group (1g and 1o), a halogen
(
1h
produced corresponding products (2g
indole (1u) and 2-substituted indole (1w) derivatives in the present reaction also furnished the
,
1i, and 1p
–
r
), an ether (1j and 1s), an ester (1k and 1l), and a phthalimide (1n) also
–
l,
2n ) in 39–84% yields, respectively. Use of 7-substituted
–s

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desired products (2u and 2w) in good yields (60–76%). Other indole protecting groups, such as
benzoyl (1x) and tosyl (1y) groups, instead of a pivaloyl group also enhanced the reactivities of
(
diacetoxyiodo)arenes in the present reaction to give 3-amino indole derivatives (2x and 2y) in high
yields (72–91%). In the reaction of 5-cyano (1m), 4-fluoro (1t), and 5,6-dichloro indole (1v) derivatives,
diacetoxyiodo)2-butoxybenzene ( ) or (diacetoxyiodo)2,6-dimethoxybenzene ( ) improved the yields
of 3-amino indole derivatives (2m 2t, and 2v) to 50–59% yield, whereas other (diacetoxyiodo)arenes
showed low reactivity (20–36% yield). It is noteworthy that (diacetoxyiodo)arenes and are superior
to (diacetoxyiodo)2,4,6-trimethylbenzene (B) in the one-pot 3-amination of indoles.
(
A
,
D
A
D
Scheme 4. Copper-catalyzed 3-amination of N-protected indoles (
yield of N-pivaloyl-2-bismesylimdo-chloroindole (3f). For 24 h (in the first step). At 100 C (in the
1
). a Numbers in parentheses indicate
b
c
◦
second step).
Furthermore, we examined the reaction of N-pivaloyl-5-chloroindole (1b) with Ts NH and
2
◦
(
(
diacetoxyiodo)arene (
A
,
B
, and
D
) in MeCN at 40 C, which forms indolyl(aryl)iodonium imide
4b) (in the first step), to elucidate the reason why the reactivities of (diacetoxyiodo)arenes differ in
) and
the 3-amination of indole derivatives (Scheme 5). When (diacetoxyiodo)2-butoxybenzene (
A

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(
diacetoxyiodo)2,6-dimethoxybenzene (D) were used in this reaction, indolyl(aryl)iodonium imide (4b)
was obtained in good yields (54% and 65%) together with 3-amino indole derivative (2b) (14% and 19%)
and 2-amino indole derivative (3b) (12% and 13%). In contrast, (diacetoxyiodo)2,4,6-trimethylbenzene
(
B
) showed lower reactivity than ArI(OAc)2
From the results, we suggest that the difference in reactivity among the (diacetoxyiodo)arenes in the
-amination of indoles is strongly dependent on the reactivity in the formation of indolyl(aryl)iodonium
imide in the first step.
A and D (25% yield of 4b and 15% recovery of 1b).
3
Scheme 5. Comparison of (diacetoxyiodo)arenes in the formation of indolyl(aryl)iodonium imide.
In addition, it is possible that 3b is converted into 2b via rearrangement by a copper catalyst,
◦
based on the results that 3b was not generated in xylene at 130 C, but was obtained in toluene under
reflux conditions (Scheme 3). The reaction of N-pivaloyl 2-bistosylimido-5-chloroindole (3b) in the
◦
presence of Cu(MeCN) BF catalyst in xylene at 130 C provided a complex mixture without the
4
4
formation of 2b (Scheme 6).
Scheme 6. Reaction of 2-amino indole derivatives (3b) in the presence of copper-catalyst.
Based on the results of mechanistic studies, we propose a reaction mechanism for the
3
-amination of indole derivatives, as shown in Scheme 7. The reaction of indole derivatives (
1
)
2
with (diacetoxyiodo)arenes (ArI(OAc) ) and bissulfonimides ((R SO ) NH) in MeCN, which generates
2
2 2
2
2
(
sulfonimidoiodo) arene intermediates (ArI(OAc)(N(SO R ) ) or ArI (N(SO R ) ) ) in situ, provides
2 2 2 2 2
indolyl(aryl)iodonium imides (
4
) together with 3-amino indole derivatives (2) and 2-amino indole
derivatives (
than the alkyl groups to induce the formation of amino group-containing products. Subsequently,
indolyl(aryl)iodonium imides ( ) are converted into 3-amino indole derivatives ( ) through an
oxidative C–N coupling reaction using Cu(MeCN) BF catalyst [21]. It is noteworthy that the
3) in the first step. The alkoxy groups at o-positions of iodoarenes result in higher reactivity
4
2
4
4
o-substituent on iodoarene is essential to prompt the indole selectivity for the C–N coupling reaction

Molecules 2019, 24, 1147
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of
4. In contrast, 2-amino indole derivatives (3) are decomposed in the presence of a copper catalyst
under heating conditions.
Scheme 7. Plausible reaction mechanism for 3-amination of indole derivatives.
. Materials and Methods
3
3
.1. General Procedure
1H NMR spectra were measured on a JEOL ECS-500 (500 MHz) spectrometer at ambient
temperature. Data were recorded as follows: chemical shift in ppm from internal tetramethylsilane on
the scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; sep = septet; m = multiplet; br
broad), coupling constant (Hz), integration, and assignment. C NMR spectra were measured on a
δ
13
=
JEOL ECS-500 (125 MHz) spectrometer (see Supplementary Materials). Chemical shifts were recorded
in ppm from the solvent resonance employed as the internal standard (deuterochloroform at 77.0
ppm). High-resolution mass spectra were recorded by Thermo Fisher Scientific Exactive Orbitrap mass
spectrometers. Infrared (IR) spectra were recorded on a JASCO FT/IR 4100 spectrometer. Single crystal
X-ray diffraction data were collected at 173K on a Bruker SMART APEX II ultra CCD diffractometer
with Cu Kα (λ = 1.54178) radiation and graphite monochromator. For thin-layer chromatography (TLC)
analysis throughout this work, Merck precoated TLC plates (silica gel 60GF254 0.25 mm) were used.
The products were purified by neutral column chromatography on silica gel (Kanto Chemical Co., Inc.
silica gel 60N, Prod. No. 37560-84; Merck silica gel 60, Prod. No. 1.09385.9929). Visualization was
accomplished by UV light (254 nm), anisaldehyde, KMnO , and phosphomolybdic acid. In experiments
4
that required dry solvents such as MeCN, toluene, and xylene (mixed isomers), these were distilled in
prior to use.
3
.2. General Procedure for 3-Amination of Indoles 1
A mixture of 1-(diacetoxyiodo)-2-butoxybenzene (94.6 mg, 0.24 mmol) and Ts NH (104.1 mg,
2
0
.32 mmol) in MeCN (2.0 mL) was stirred at room temperature for 30 min under argon atmosphere.
◦
Then, N-pivaloylindole (1a) (40.3 mg, 0.20 mmol) was added, and the solution was stirred at 40 C for
7
h under argon atmosphere. The reaction mixture was concentrated under reduced pressure and the

Molecules 2019, 24, 1147
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crude product was dissolved xylene (mixed isomers) (2.0 mL). Cu(MeCN) BF (3.1 mg, 0.01 mmol)
4
4
◦
was added to the reaction mixture at room temperature, and further stirred at 130 C for 1 h under
argon atmosphere. Saturated NaHCO aqueous solution (10 mL) was added to the reaction mixture,
3
and the product was extracted with AcOEt (15 mL
×
3). The combined extracts were washed with
brine (10 mL) and dried over Na SO . The organic phase was concentrated under reduced pressure
2
4
and the crude product was purified by silica gel column chromatography (eluent: hexane/AcOEt =
5
/1), to give the desired product 2a (82.3 mg, 78% yield).
◦
4
-Methyl-N-(1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2a). White solid, mp 214.0–214.5 C,
1
H NMR (500 MHz, CDCl3)
δ
1.40 (s, 9H), 2.46 (s, 6H), 7.07 (d, J = 7.8 Hz, 1H), 7.14–7.19 (m, 1H),
7
.30–7.37 (m, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.46 (s, 1H), 7.87 (d, J = 8.2 Hz, 4H), 8.46 (d, J = 8.3 Hz, 1H).
13
C NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.5 (3C), 41.3, 115.8, 117.3, 118.6, 124.1, 126.0, 126.8, 127.7,
–
1
128.6 (4C), 129.6 (4C), 135.7, 136.2 (2C), 145.2 (2C), 176.7. IR (neat) 1702, 1374, 1357, 1316, 1165 cm .
+
MS (ESI) calcd for C H N O S [M + H] 525.1512, found 525.1501. Crystal data for 2a: Formula
C H N O S , colorless, crystal dimensions 0.30
a = 9.475(2) Å, b = 10.144(2) Å, c = 13.660(3) Å,
=
27
29
2
5 2
3
×
0.20
= 98.118(3) ,
= 1.367 g cm , F(000) = 552, (MoK
×
0.20 mm , Triclinic, space group P
−
1,
2
7
28
2
5 2
◦
◦
◦
α
β
= 91.348(3) ,
) = 0.250 mm , T = 173 K. 7413
(I) (2θmax = 27.572 ), and 330 parameters
γ
−1
= 100.871(3) , V
3
−3
1274.7(5) Å , Z = 2,
ρ
calc
µ
α
◦
reflections collected, 5602 independent reflections with I > 2
σ
were used for the solution of the structure. The non-hydrogen atoms were refined anisotropically.
R = 0.0508 and wR = 0.1031. GOF = 1.015. Crystallographic data (excluding structure factors) for the
1
2
structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-1860598. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: int. code + 44(1223)336-033;
E-mail: deposit@ccdc.cam.ac.uk].
N-(5-Chloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2b): White solid, mp 205.5–
◦
1
2
2
06.0 C, H NMR (500 MHz, CDCl )
δ
1.41 (s, 9H), 2.48 (s, 6H), 6.81 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.9,
.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 4H), 7.52 (s, 1H), 7.85 (d, J = 8.5 Hz, 4H), 8.38 (d, J = 8.9 Hz, 1H). 13
21.7 (2C), 28.4 (3C), 41.3, 115.2, 118.2, 118.4, 126.2, 128.0, 128.6 (4C), 128.7,
3
C
NMR (125 MHz, CDCl3)
δ
–
1
1
29.7 (4C), 130.0, 133.9, 136.0 (2C), 145.6 (2C), 176.6. IR (neat) 1708, 1379, 1351, 1307, 1163, 1085 cm .
MS (ESI) calcd for C H ClN O S [M + H] 559.1123, found 559.1119.
+
27
28
2
5 2
◦
N-(Phenylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)benzenesulfonamide (2c). White solid, mp 182.0–183.0 C,
H NMR (500 MHz, CDCl3)
1
δ 1.39 (s, 9H), 7.01 (d, J = 8.0 Hz, 1H), 7.12–7.18 (m, 1H), 7.31–7.37 (m, 1H),
13
7.48 (s, 1H), 7.50–7.56 (m, 4H), 7.67 (t, J = 7.5 Hz, 2H), 7.97–8.02 (m, 4H), 8.47 (d, J = 8.5 Hz, 1H).
C
NMR (125 MHz, CDCl3)
δ 28.5 (3C), 41.3, 115.5, 117.3, 118.5, 124.2, 126.1, 126.6, 127.7, 128.5 (4C), 129.0
–1
(
4C), 134.1 (2C), 135.6, 139.0 (2C), 176.7. IR (neat) 1704, 1381, 1344, 1315, 1159 cm . MS (ESI) calcd for
+
C H N O S [M + H] 497.1199, found 497.1205.
25
25
2
5 2
4
2
-Methyl-N-(methylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)benzenesulfonamide (2d). White solid, mp 221.5–
◦
2.0 C, H NMR (500 MHz, CDCl ) δ 1.44 (s, 9H), 2.43 (s, 3H), 3.56 (s, 3H), 7.23–7.30 (m, 3H), 7.30–7.34
3
1
13
(
(
1
m, 1H), 7.34–7.40 (m, 1H), 7.62 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 8.48 (d, J = 8.3 Hz, 1H). C NMR
125 MHz, CDCl3) 21.7, 28.5 (3C), 41.4, 44.0, 115.2, 117.4, 118.2, 124.4, 126.2, 126.7, 127.2, 128.8 (2C),
29.6 (2C), 135.1, 135.7, 145.6, 176.7. IR (neat) 1704, 1366, 1349, 1317, 1157 cm . MS (ESI) calcd for
δ
–1
+
C H N O S [M + H] 449.1199, found 449.1198.
21
25
2
5 2
N-(1-Pivaloyl-1H-indol-3-yl)-N-(propylsulfonyl)propane-1-sulfonamide (2e). White solid, mp 190.0–191.0
◦
1
◦
C, H NMR (500 MHz, CDCl , 60 C)
δ
1.07 (t, J = 7.3 Hz, 6H), 1.52 (s, 9H), 1.88–2.01 (m, 4H), 3.37–3.55
3
(
1
1
m, 2H), 3.55–3.75 (m, 2H), 7.31–7.41 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.88 (s, 1H), 8.50 (d, J = 8.0 Hz,
1
3
◦
H). C NMR (125 MHz, CDCl , 60 C) δ 12.8 (2C), 17.1 (2C), 28.7 (3C), 41.5, 57.7 (2C), 115.5, 117.6,
3
–1
18.5, 124.5, 126.2, 126.9, 127.2, 135.9, 176.7. IR (neat) 1703, 1370, 1347, 1316, 1151 cm . MS (ESI) calcd
+
for C H N O S [M + H] 429.1512, found 429.1512.
19
29
2
5 2

Molecules 2019, 24, 1147
9 of 13
◦
N-(Methylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)methanesulfonamide (2f). White solid, mp 205.0–207.0 C,
1
H NMR (500 MHz, CDCl ) δ 1.54 (s, 9H), 3.44 (s, 6H), 7.35–7.40 (m, 1H), 7.40–7.45 (m, 1H), 7.58–7.63
δ 28.6 (3C), 41.5, 42.9 (2C),
14.6, 117.7, 118.0, 124.7, 126.3, 126.4, 127.1, 135.8, 176.8. IR (neat) 1703, 1349, 1317, 1159 cm . MS (ESI)
3
13
(
1
m, 1H), 7.94 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H). C NMR (125 MHz, CDCl3)
–1
−
calcd for C H ClN O S [M + Cl] 407.0508, found 407.0515.
15
20
2
5 2
4
2
-Methyl-N-(5-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2g). White solid, mp 217.0–
◦
17.5 C, H NMR (500 MHz, CDCl ) δ 1.39 (s, 9H), 2.28 (s, 3H), 2.47 (s, 6H), 6.71–6.73 (m, 1H), 7.12–7.16
3
1
13
(
(
1
m, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.42 (s, 1H), 8.87 (d, J = 8.2 Hz, 4H), 8.31 (d, J = 8.6 Hz, 1H). C NMR
125 MHz, CDCl3) 21.2, 21.7 (2C), 28.5 (3C), 41.2, 115.6, 116.9, 118.4, 126.9, 127.4, 127.6, 128.7 (4C),
29.5 (4C), 133.8, 133.9, 136.3 (2C), 145.2 (2C), 176.6. IR (neat) 1701, 1379, 1353, 1308, 1156 cm . MS
δ
–1
+
(ESI) calcd for C H N O S [M + H] 539.1669, found 539.1672.
28 31 2 5 2
N-(5-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2h). White solid, mp 214.5–
◦
1
2
15.2 C, H NMR (500 MHz, CDCl )
δ
1.40 (s, 9H), 2.47 (s, 6H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 7.05 (td, J
3
=
9.0, 2.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 4H), 7.51 (s, 1H), 7.86 (d, J = 8.5 Hz, 4H), 8.43 (dd, J = 9.0, 4.5 Hz,
13
1H). C NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.5 (3C), 41.3, 104.3 (d, JC–F = 25.0 Hz), 113.9 (d, JC–F
= 9.5 Hz), 128.5 (4C), 129.0,
=
25.0 Hz), 115.5 (d, JC–F = 3.5 Hz), 118.6 (d, JC–F = 9.5 Hz), 128.1 (d, J
C–F
1
9
1
29.7 (4C), 131.9, 136.1 (2C), 145.5 (2C), 159.9 (d, JC–F = 240.8 Hz), 176.5. F NMR (471 MHz, CDCl3)
δ
–1
+
−
117.9. IR (neat) 1708, 1376, 1359, 1311, 1237, 1169 cm . MS (ESI) calcd for C H FN O S [M + H]
27 28 2 5 2
5
43.1418, found 543.1422.
N-(5-Bromo-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2i). White solid, mp 215.0–
◦
1
2
4
(
1
16.0 C, H NMR (500 MHz, CDCl )
δ
1.41 (s, 9H), 2.48 (s, 6H), 6.09 (d, J = 1.8 Hz, 1H), 7.31–7.35 (m,
H), 7.40 (dd, J = 9.0, 1.8 Hz, 1H), 7.51 (s, 1H), 7.82–7.86 (m, 4H), 8.32 (d, J = 9.0 Hz, 1H). 13C NMR
21.7 (2C), 28.4 (3C), 41.3, 115.0, 117.7, 118.7, 121.3, 128.4, 128.50, 128.55 (4C), 128.8,
3
125 MHz, CDCl3)
δ
–1
29.7 (4C), 134.3, 136.0 (2C), 145.6 (2C), 176.6. IR (neat) 1703, 1382, 1348, 1306, 1164, 659 cm . MS (ESI)
calcd for C H BrN O S [M + H] 603.0618, found 603.0620.
+
27
28
2
5 2
N-(5-Methoxy-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2j). White solid, mp 220.0–
◦
1
2
21.0 C, H NMR (500 MHz, CDCl )
δ
1.39 (s, 9H), 2.46 (s, 6H), 3.62 (s, 3H), 6.37 (d, J = 2.6 Hz, 1H),
3
6
.92 (dd, J = 9.1, 2.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.43 (s, 1H), 7.88 (d, J = 8.2 Hz, 4H), 8.34 (d, J = 9.1
13
Hz, 1H). C NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.6 (3C), 41.2, 55.2, 100.1, 115.4, 115.6, 118.3, 127.8,
1
1
28.0, 128.6 (4C), 129.6 (4C), 130.2, 136.4 (2C), 145.2 (2C), 156.7, 176.4. IR (neat) 1701, 1380, 1358, 1312,
–1
+
162, 1086 cm . MS (ESI) calcd for C H N O S [M + H] 555.1618, found 555.1621.
28
31
2
6 2
◦
3
-((4-Methyl-N-tosylphenyl)sulfonamido)-1-pivaloyl-1H-indol-5-yl pivalate (2k): White solid, mp 225.0 C
1
(
dec.), H NMR (500 MHz, CDCl )
δ
1.35 (s, 9H), 1.40 (s, 9H), 2.45 (s, 6H), 6.64 (d, J = 2.5 Hz, 1H), 7.02
3
(
dd, J = 9.0, 2.5 Hz, 1H), 7.33 (d, J = 8.3 Hz, 4H), 7.48 (s, 1H), 7.88 (d, J = 8.3 Hz, 4H), 8.46 (d, J = 9.0 Hz,
13
1
1
1
6
H). C NMR (125 MHz, CDCl3)
δ 21.7 (2C), 27.1 (3C), 28.5 (3C), 38.9, 41.3, 113.3, 115.7, 118.1, 120.0,
27.6, 128.58 (4C), 128.63, 129.7 (4C), 133.2, 136.2 (2C), 145.3 (2C), 147.7, 176.5, 176.8. IR (neat) 1750,
–1
+
708, 1377, 1358, 1311, 1167, 1119 cm . MS (ESI) calcd for C H N O S [M + H] 625.2037, found
32
37
2
7 2
25.2937.
Methyl 3-((4-methyl-N-tosylphenyl)sulfonamido)-1-pivaloyl-1H-indole-5-carboxylate (2l). White solid, mp
◦
1
2
21.0–221.5 C, H NMR (500 MHz, CDCl ) δ 1.41 (s, 9H), 2.46 (s, 6H), 3.89 (s, 3H), 7.33 (d, J = 8.3 Hz,
3
4
=
H), 7.54 (s, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 4H), 8.02 (d, J = 8.9, 1.5 Hz, 1H), 8.50 (d, J
8.9 Hz, 1H). 13C NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.4 (3C), 41.4, 52.0, 116.2, 117.1, 120.7, 126.1,
1
1
26.6, 127.2, 128.6 (4C), 128.8, 129.7 (4C), 136.0 (2C), 138.1, 145.5 (2C), 166.7, 176.7. IR (neat) 1717, 1379,
–1
+
360, 1313, 1165 cm . MS (ESI) calcd for C H N O S [M + H] 583.1567, found 583.1571.
29
31
2
7 2
N-(5-Cyano-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2m). White solid, mp 214.0–
◦
15.0 C, H NMR (500 MHz, CDCl ) δ 1.42 (s, 9H), 2.49 (s, 6H), 7.17 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 8.0
3
1
2
13
Hz, 4H), 7.55 (dd, J = 9.0, 1.5 Hz, 1H), 7.64 (s, 1H), 7.83 (d, J = 8.0 Hz, 4H), 8.55 (d, J = 8.5 Hz, 1H).
C

Molecules 2019, 24, 1147
10 of 13
NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.2 (3C), 41.5, 107.6, 115.5, 118.2, 118.8, 123.4, 126.9, 128.5 (4C),
1
1
28.7, 129.5, 129.8 (4C), 135.7 (2C), 137.2, 145.8 (2C), 176.6. IR (neat) 2221, 1715, 1363, 1348, 1308, 1169,
–1
+
086 cm . MS (ESI) calcd for C H N O S [M + H] 550.1465, found 550.1470.
28
28
3
5 2
N-(5-(1,3-Dioxoisoindolin-2-yl)-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2n). White
◦
1
solid, mp 227.5–228.0 C, H NMR (500 MHz, CDCl )
1
(
2
δ
1.39 (s, 9H), 2.44 (s, 6H), 7.23 (d, J = 2.0 Hz,
H), 7.38 (d, J = 8.3 Hz, 4H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.47 (s, 1H), 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.92
d, J = 8.3 Hz, 4H), 7.96 (dd, J = 5.5, 3.0 Hz, 2H), 8.61 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz, CDCl3)
1.7 (2C), 28.4 (3C), 41.3, 115.6, 117.5, 118.0, 123.6 (2C), 124.7, 127.3, 127.9, 128.6 (4C), 128.9, 129.8 (4C),
31.8 (2C), 134.3 (2C), 134.9, 136.0 (2C), 145.3 (2C), 167.1 (2C), 176.6. IR (neat) 1727, 1705, 1375, 1355,
3
δ
1
1
–1
+
308, 1167, 1080 cm . MS (ESI) calcd for C H N O S [M + H] 670.1676, found 670.1678.
35
32
3
7 2
4
2
7
-Methyl-N-(6-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2o). White solid, mp 203.5–
◦
1
04.2 C, H NMR (500 MHz, CDCl ) δ 1.38 (s, 9H), 2.45 (s, 3H), 2.46 (s, 6H), 6.95 (d, J = 8.0 Hz, 1H),
3
13
.01 (d, J = 8.0 Hz, 1H), 7.29–7.35 (m, 4H), 7.37 (s, 1H), 7.84–7.89 (m, 4H), 8.32 (s, 1H). C NMR (125
21.7 (2C), 21.9, 28.4 (3C), 41.3, 115.8, 117.4, 118.2, 124.6, 125.6, 127.0, 128.6 (4C), 129.6
MHz, CDCl3)
δ
–1
(4C), 136.1, 136.26, 136.28 (2C), 145.2 (2C), 176.9. IR (neat) 1704, 1371, 1339, 1313, 1163 cm . MS (ESI)
–
calcd for C H ClN O S [M + Cl] 573.1290, found 573.1303.
28
30
2
5 2
N-(6-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2p). White solid, mp 215.0–
◦
15.5 C, H NMR (500 MHz, CDCl ) δ 1.40 (s, 9H), 2.46 (s, 6H), 6.89–7.02 (m, 2H), 7.32 (d, J = 8.0 Hz,
3
1
2
4
2
13
H), 7.46 (s, 1H), 7.85 (d, J = 8.0 Hz, 4H), 8.22 (dd, J = 10.3, 2.0 Hz, 1H). C NMR (125 MHz, CDCl3)
1.7 (2C), 28.4 (3C), 41.3, 104.7 (d, JC–F = 29.8 Hz), 112.6 (d, JC–F = 23.9 Hz), 115.7, 119.4 (d, JC–F = 9.5
= 13.1 Hz), 136.1 (2C), 145.4
δ
Hz), 123.1, 127.8 (d, JC–F = 3.5 Hz), 128.5 (4C), 129.7 (4C), 135.7 (d, J
C–F
19
(
1
2C), 161.7 (d, JC–F = 240.9 Hz), 176.6. F NMR (471 MHz, CDCl3)
δ
–115.1. IR (neat) 1707, 1382, 1345,
–1
–
315, 1230, 1162 cm . MS (ESI) calcd for C H ClFN O S [M + Cl] 577.1039, found 577.1055.
27
27
2
5 2
N-(6-Chloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2q). White solid, mp 212.5–
◦
1
2
8
(
(
(
13.0 C, H NMR (500 MHz, CDCl )
δ
1.40 (s, 9H), 2.47 (s, 6H), 6.94 (d, J = 8.6 Hz, 1H), 7.14 (dd, J =
.6, 1.7 Hz, 1H), 7.30–7.35 (m, 4H), 7.46 (s, 1H), 7.82–7.87 (m, 4H), 8.54 (d, J = 1.7 Hz, 1H). 13C NMR
21.7 (2C), 28.4 (3C), 41.3, 115.7, 117.6, 119.4, 124.8, 125.4, 128.1, 128.5 (4C), 129.7
3
125 MHz, CDCl3)
δ
–1
4C), 132.1, 135.8, 136.1 (2C), 145.4 (2C), 176.6. IR (neat) 1706, 1381, 1360, 1337, 1160, 1083 cm . MS
ESI) calcd for C H ClN O S [M + H] 559.1123, found 559.1123.
+
27
28
2
5 2
N-(6-Bromo-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2r). White solid, mp 214.0–
◦
14.8 C, H NMR (500 MHz, CDCl ) δ 1.39 (s, 9H), 2.47 (s, 6H), 6.90 (d, J = 8.5 Hz, 1H), 7.29 (dd, J =
3
1
2
8
13
.5, 1.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 4H), 7.44 (s, 1H), 7.85 (d, J = 8.5 Hz, 4H), 8.71 (d, J = 1.5 Hz, 1H).
C
NMR (125 MHz, CDCl3)
δ
21.7 (2C), 28.3 (3C), 41.3, 115.7, 119.7, 119.9, 120.4, 125.7, 127.5, 128.0, 128.5
–
1
(
4C), 129.7 (4C), 136.06 (2C), 136.11, 145.4 (2C), 176.6. IR (neat) 1705, 1380, 1336, 1308, 1159, 658 cm .
–
MS (ESI) calcd for C H BrClN O S [M + Cl] 637.0239, found 637.0256.
27
27
2
5 2
N-(6-Methoxy-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2s). White solid, mp 201.0–
◦
1
2
01.8 C, H NMR (500 MHz, CDCl )
δ
1.40 (s, 9H), 2.46 (s, 6H), 3.86 (s, 3H), 6.80 (dd, J = 8.5, 2.3 Hz,
3
1
H), 6.90 (d, J = 8.5 Hz, 1H), 7.29–7.34 (m, 4H), 7.36 (s, 1H), 7.84–7.89 (m, 4H), 8.07 (d, J = 2.3 Hz, 1H).
1
3
C NMR (125 MHz, CDCl3)
δ 21.7 (2C), 28.4 (3C), 41.3, 55.6, 100.8, 114.1, 115.9, 119.1, 120.5, 126.2,
1
1
28.5 (4C), 129.6 (4C), 136.3 (2C), 136.7, 145.2 (2C), 159.0, 177.1. IR (neat) 1703, 1378, 1346, 1312, 1286,
–1
–
162 cm . MS (ESI) calcd for C H ClN O S [M + Cl] 589.1239, found 589.1257.
28
30
2
5 2
N-(4-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2t). White solid, mp 220.0–
◦
22.6 C, H NMR (500 MHz, CDCl ) δ 1.42 (s, 9H), 2.46 (s, 6H), 6.85 (dd, J = 10.0, 8.0 Hz, 1H), 7.24–7.30
3
1
2
(
13
m, 1H), 7.30–7.34 (m, 4H), 7.50 (s, 1H), 7.84–7.88 (m, 4H), 8.28 (d, J = 8.5 Hz, 1H). C NMR (125 MHz,
CDCl3) 21.7 (2C), 28.4 (3C), 41.4, 110.2 (d, JC–F = 19.0 Hz), 112.9, 113.3 (d, JC–F = 3.6 Hz), 115.7 (d, JC–F
17.9 Hz), 126.7 (d, JC–F = 7.3 Hz), 128.0, 128.6 (4C), 129.5 (4C), 136.1(2C), 137.7 (d, JC–F = 7.1 Hz), 145.1
δ
=

Molecules 2019, 24, 1147
11 of 13
1
(
1
2C), 154.7 (d, JC–F = 249.1 Hz), 176.7. 9F NMR (471 MHz, CDCl3)
δ
–122.8. IR (neat) 1707, 1375, 1359,
–1
–
309, 1251, 1176 cm . MS (ESI) calcd for C H ClFN O S [M + Cl] 577.1039, found 577.1053.
27
27
2
5 2
4
-Methyl-N-(7-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2u). White solid, mp 190.0–
◦
91.0 C, H NMR (500 MHz, CDCl ) δ 1.41 (s, 9H), 2.30 (s, 3H), 2.45 (s, 6H), 6.94 (dd, J = 7.5, 1.5 Hz,
3
1
1
1
13
H), 7.06–7.12 (m, 2H), 7.20 (s, 1H), 7.29–7.33 (m, 4H), 7.84–7.89 (m, 4H). C NMR (125 MHz, CDCl3)
21.2, 21.7 (2C), 28.9 (3C), 42.1, 114.8, 116.6, 123.8, 125.4, 127.5, 128.00, 128.03, 128.6 (4C), 129.5 (4C),
δ
–1
134.9, 136.3 (2C), 145.1 (2C), 178.2. IR (neat) 1715, 1377, 1361, 1303, 1171 cm . MS (APCI) calcd for
+
C H N O S [M + H] 539.1669, found 539.1670.
28
31
2
5 2
N-(5,6-Dichloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2v). White solid, mp 223.5–
◦
1
2
24.2 C, H NMR (500 MHz, CDCl )
δ
1.41 (s, 9H), 2.48 (s, 6H), 6.87 (s, 1H), 7.32–7.36 (m, 4H), 7.52 (s,
H), 7.82–7.86 (m, 4H), 8.65 (s, 1H). C NMR (125 MHz, CDCl3) 21.7 (2C), 28.3 (3C), 41.3, 115.0, 119.1,
19.5, 126.4, 128.5 (5C), 129.0, 129.8 (4C), 130.1, 134.0, 135.9 (2C), 145.7 (2C), 176.4. IR (neat) 1710, 1382,
3
1
3
1
1
1
δ
–1
+
361, 1330, 1158, 1084 cm . MS (ESI) calcd for C H Cl N O S [M + H] 593.0733, found 593.0732.
27
27
2
2
5 2
4
1
-Methyl-N-(2-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2w). White solid, mp 158.0–
◦
59.0 C, H NMR (500 MHz, CDCl ) δ 1.34 (s, 9H), 1.79 (s, 3H), 2.45 (s, 6H), 6.99–7.06 (m, 2H), 7.12–7.18
3
1
13
(
m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 4H), 7.85 (d, J = 8.5 Hz, 4H). C NMR (125 MHz,
CDCl3) 10.8, 21.6 (2C), 28.0 (3C), 44.4, 110.5, 111.7, 118.7, 121.7, 122.8, 125.8, 128.6 (4C), 129.5 (4C),
33.8, 136.7 (2C), 137.9, 145.0 (2C), 185.8. IR (neat) 1710, 1384, 1360, 1313, 1165, 1084 cm . MS (APCI)
δ
–1
1
+
calcd for C H N O S [M + H] 539.1669, found 539.1671.
28
31
2
5 2
◦
1
N-(1-Benzoyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2x). White solid, mp 214.0–215.0 C, H
NMR (500 MHz, CDCl3) 2.47 (s, 6H), 7.10 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.19–7.24 (m, 1H), 7.32 (d, J
8.5 Hz, 4H), 7.36–7.41 (m, 1H), 7.45–7.51 (m, 2H), 7.59–7.65 (m, 3H), 7.87 (d, J = 8.5 Hz, 4H), 8.37 (d, J
8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3)
21.7 (2C), 116.2, 116.3, 119.0, 1124.5, 125.8, 128.0, 128.59
δ
=
=
δ
(
1
4C), 128.64 (2C), 129.3, 129.4 (2C), 129.6 (4C), 132.5, 133.4, 135.0, 136.2 (2C), 145.2 (2C), 168.1. IR (neat)
694, 1376, 1359, 1325, 1166 cm . MS (ESI) calcd for C H N O S [M + H] 545.1199, found 545.1205.
29 25 2 5 2
–1
+
◦
1
4
-Methyl-N-tosyl-N-(1-tosyl-1H-indol-3-yl)benzenesulfonamide (2y). White solid, mp 182.0–183.0 C, H
2.35 (s, 3H), 2.44 (s, 6H), 7.04 (d, J = 8.0 Hz, 1H), 7.08–7.13 (m, 1H), 7.23–7.30
m, 7H), 7.43 (s, 1H), 7.70–7.77 (m, 6H), 7.92 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3)
21.5, 21.7
2C), 113.5, 116.8, 119.4, 123.9, 125.4, 126.9 (2C), 128.2, 128.3, 128.5 (4C), 129.5 (4C), 130.0 (2C), 133.7,
NMR (500 MHz, CDCl3)
(
(
1
δ
δ
–1
34.5, 136.0 (2C), 145.3 (2C), 145.5. IR (neat) 1595, 1372, 1355, 1283, 1168, 1086 cm . MS (ESI) calcd for
+
C H N O S [M + H] 595.1026, found 595.1027.
29
27
2
6 3
4
. Conclusions
In conclusion, we developed a 3-amination of indole derivatives using a hypervalent iodine(III)
compound that promotes the formation of indolyl(aryl)iodonium imides. This reaction was followed
by a copper-catalyzed oxidative C–N coupling reaction to obtain the 3-amino indole derivatives
regioselectively. The o-alkoxy groups on (diacetoxy)iodoarenes resulted in higher reactivity than
the o-alkyl groups in the formation of indolyl(aryl)iodonium imides (first step). In addition, the
3-amino indole derivatives were given as a single isomer product by a decomposition of 2-amino
indole derivatives under copper-catalyzed reaction conditions (second step). The design of substituted
iodoarene as a high-performance hypervalent iodine compounds and the combined use of hypervalent
iodine compound and a transition-metal catalyst for the unique transformation are underway in
our laboratory.

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Supplementary Materials: The following are available online. The H and 13C NMR spectra of compounds in
1
3
-amination of indole derivatives, and crystal data of 2a can be found in the Supporting Information.
Author Contributions: Conceptualization, K.M.; Methodology, K.M.; Validation, K.M; Investigation and Analyses,
K.W. and K.M.; Writing—original draft preparation, K.M.; Writing—review and editing, K.M.; Visualization, K.M.;
Supervision, K.M.; Project Administration, K.M.; Funding Acquisition, K.M.
Funding: Financial support in the form of a Grant-in-Aid for Scientific Research (No. G15K17819) from the
Ministry of Education, Culture, Sports, Science and Technology in Japan is gratefully acknowledged.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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