Michael Addition of Indoles to Enones Catalyzed by a Cationic Iron Salt

Article abstract of DOI:10.1055/s-0040-1705997

Indoles are one of the most valuable nucleophiles in Michael additions catalyzed by a proper Lewis acid. In this paper, we found that a cationic iron salt is effective to carry out the Michael addition of indoles. β-Mono- and disubstituted enones reacted

Full text of DOI:10.1055/s-0040-1705997

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1087–1094
feature
1087
en
T. Inishi et al.
Feature
Synthesis
Michael Addition of Indoles to Enones Catalyzed by a Cationic Iron
Salt
Tsukasa Inishi
O
Goki Hirata
RN
cationic
Fe cat.
"Fe"
Takashi Nishikata*
0
0
0
0
-
0
0
0
2
-
2
6
5
9
-
4
8
2
6
O
+
O
rt
Graduate School of Science and Engineering, Yamaguchi University,
2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
nisikata@yamaguchi-u.ac.jp
N
up to 99% yield
23 examples
R
TGeMarkaaadiCsulhoanirtiresNeikSisscaphhtoiaokn@oadyltianaogmf SAacguieuthncohceri-aun.adc.Ejpngineering, Yamaguchi University, 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
Received: 04.11.2020
Accepted after revision: 16.11.2020
Published online: 07.01.2021
tuted enones,19 but a turnover number (TON) of the iron
catalyst was not high. In this context, we envisaged that a
highly Lewis acidic iron catalyst (tuning cationicity of the
iron salt) could realize an efficient conjugate addition of in-
dole derivatives (Scheme 1). Herein, we would like to report
cationic iron-catalyzed conjugate additions of indoles to -
substituted enones.
DOI: 10.1055/s-0040-1705997; Art ID: ss-2020-f0565-fa
Abstract Indoles are one of the most valuable nucleophiles in Mi-
chael additions catalyzed by a proper Lewis acid. In this paper, we found
that a cationic iron salt is effective to carry out the Michael addition of
indoles. -Mono- and disubstituted enones reacted smoothly with in-
doles under our conditions. The cationic iron catalyst is very active, and
the maximum TON was up to 425. Moreover, cationic iron-catalyzed
conditions enabled a chemoselective Michael addition of a substrate
possessing both enone and ,-unsaturated ester moieties.
O
RN
"Fe"
Fe cat.
O
+
O
Key words iron, enones, Michael addition, Friedel–Crafts reaction,
chemoselectivity
N
R
Scheme 1 This work
The Friedel–Crafts-type conjugate (Michael) addition
reaction of indoles is one of the most important reactions to
synthesize substituted indole derivatives, which can be
seen in important bioactive molecules.1 Although various
organocatalyst or metal catalyst systems for conjugate addi-
tions of indoles have been reported,2–13 the desired reaction
with sterically congested substrates such as -mono- and
disubstituted enones is still difficult.
In our previous studies, increasing the Lewis acidity of
palladium was very effective to carry conjugate addition of
arylboronic acids,14 silanes15 and bismuths,16 and Fujiwara-
type C–H functionalization reactions.17 There are numerous
coupling and addition reactions using palladium salts,
whereas earth-abundant iron-catalyzed related reactions
are still challenging.17 One successful example of indole Mi-
chael additions was reported by Kawatsura’s group who
carried out iron-catalyzed Michael addition reactions of in-
doles and enones possessing a terminal vinyl group in ionic
liquids.18 But, the iron catalyst activity was not so high be-
cause sterically congested enones did not react with indoles
under their conditions. On the other hand, there are a few
reports on iron-catalyzed Michael additions using -substi-
Initially, we screened various iron salts as a catalyst in
the reaction of 1a and 2a in 1,2-dimethoxyethane (DME) at
room temperature (Table 1). Without an iron catalyst, the
reaction did not occur (Run 1). On the other hand, the cor-
responding Michael adduct 3a was obtained in the presence
of FeCl2 (Run 2). More Lewis acidic FeCl3 gave 49% yield of
3a (Run 3). Other iron salts, such as Fe(acac)3, Fe(OAc)2, [Cp-
Fe(CO)3]2, and Fe2(SO4)3 hydrate, were not effective at all
(Runs 4–7). In previous iron-catalyzed indole Michael addi-
tions with simple enones possessing a terminal vinyl group,
[Fe(H2O)6](BF4)2 was effective,18 but it did not show a good
Lewis acidity in our reaction (Run 8). Finally, a cationic iron
salt, [Fe(H2O)6](OTs)3, was found to be the best catalyst, in
which 72% yield of 3a was obtained (Run 9). This catalyst
was very active. For example, when
2
mol%
[Fe(H2O)6](OTs)3 was used, the yield was not decreased
compared with the 10 mol% catalyst conditions. We also
tested various solvents, such as THF, Et2O, CH2Cl2, and EtOH,
but the yield was not dramatically increased (see Support-
ing Information). When the reaction was carried out in the
presence of in situ generated cationic iron salt, 69% yield of
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1088
T. Inishi et al.
Feature
Synthesis
3a was obtained (Run 10). In this case, addition of water did
not improve the chemical yield of 3a. Therefore, water
might not be important for the final protolysis process in
the catalytic cycle (see Scheme 4).
The reactivities of various 1 and 2 were examined under
the optimized reaction conditions (Scheme 2). -Methyl-
substituted enones 1b–1e possessing an -aryl group gave
79–99% yield of 3b–3e. Although aliphatic enone 1h gave
an excellent yield of 3h, benzalacetone derivative 1f pos-
sessing a bromine on the phenyl group and chalcone (1g)
had moderate to low reactivity. According to the literature,
the electrophilicity of 1g is higher than that of 1a,20 but 1g
had low reactivity (1g was recovered after the reaction).
,-Unsaturated carboxamide 1i and ester 1j were not suit-
able for this reaction due to low electrophilicity of each Mi-
chael acceptor. We also tried heating conditions with these
substrates, but they were not effective. The reactivity of in-
dole and substituted indoles 2 was tested. Thus, indoles
possessing a boron moiety (2f, 2g) or sterically hindered
substituents (2c–2e) showed excellent reactivities to give
the corresponding adducts 3k–3p in high yields.
A ligand effect is important to improve yields in transi-
tion-metal-catalyzed reactions. We screened various li-
gands, including phosphine, nitrogen, and amino acid li-
gands, in the presence of [Fe(H2O)6](OTs)3 (Table 2). But, the
yields were not higher than the conditions without ligand.
In our previous cationic palladium chemistry in Michael ad-
ditions, phosphorus ligands were effective, but no ligand
was effective in the current cationic iron-catalyzed reac-
tion. This could be attributed to decreased cationicity of the
iron salt with ligands, which indicates that the cationic
iron-catalyzed indole Michael addition could include a Frie-
del–Crafts-type reaction.
Biographical Sketches
Tsukasa Inishi received his BS
degree from Yamaguchi Univer-
sity (Japan) in 2020. Since 2020,
he has been a graduate student
at the same university under
the supervision of Prof. Takashi
Nishikata.
Goki Hirata received his Ph.D.
from Nagasaki University (Ja-
pan) in 2017 under the supervi-
sion of Prof. Masanari Kimura.
He spent two years as a post-
doctoral fellow at Ritsumeikan
University (Japan; Prof. Hiromit-
su Maeda). Since 2019, he has
been an assistant professor at
Yamaguchi University (Japan).
Takashi Nishikata received
his Ph.D. from Hokkaido Univer-
sity (Japan) in 2005 under the
supervision of Prof. Norio Mi-
yaura. He spent three years as a
JST postdoctoral fellow in the
same group. From 2008 to
2010, he worked as a postdoc-
toral fellow at the University of
California, Santa Barbara (USA)
under the direction of Prof.
Bruce H. Lipshutz. In 2010, he
joined Prof. Hideo Nagashima’s
group as an assistant professor
at Kyushu University (Japan). In
2012, he was appointed as an
associate professor at Yamagu-
chi University. Since 2020, he
has been a full professor at Ya-
maguchi University.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

1089
T. Inishi et al.
Feature
Synthesis
We next tested a highly congested enone, namely ,-
dimethyl-substituted enone 1k (Scheme 3). A highly con-
gested enone to give a quaternary center is one of the most
challenging substrates for iron-catalyzed Michael addi-
tion.18,19 As we expected, the reactivity of 1k was very low,
and 1k did not react with 2 at room temperature. But, ele-
vated temperature (50 °C) was effective to obtain the corre-
sponding adducts 3. For example, 1k and 2b underwent the
Michael addition reaction to produce 3q in 76% yield. Halo-
gen-substituted indoles 2h and 2i gave good yields of ad-
ducts 3u and 3v, respectively. Compounds 2j–2l possessing
an electron-withdrawing group gave moderate yields of ad-
ducts 3w, and 3y. When the reactions for those compounds
were carried out in MeCN/MeOH, the yields were slightly
improved. Sterically hindered indoles (2c and 2d) were not
suitable for this reaction.
Table 1 Iron Salt Optimizationa
O
Ph
MeN
1a: 1 equiv
10 mol% Fe cat.
O
+
H
DME
rt, 20 h
Ph
3a
N
Me
2a: 2 equiv
The addition of indole to enone could give the corre-
sponding enolate anion. The resulting enolate anion could
be protonated to produce the Michael adduct 3. Therefore,
we next checked whether indole is a proton source (Scheme
4). As a result, when deuterated 2a (2a-D) was used as a
substrate in the presence of in situ generated cationic iron
salt [Fe(OTs)3: FeCl3 + AgOTs], the corresponding deuterated
adduct 3b-D (70% D) was obtained without contact of H2O
or D2O. This result indicated that the proton could come
Run
Iron catalyst
Yield (%) 3a
1
2
none
0 (48 h)
FeCl2
17
3
FeCl3
49
4
Fe(acac)3
0
5
Fe(OAc)2
0
6
[CpFe(CO)3]2
Fe2(SO4)3nH2O
[Fe(H2O)6](BF4)2
[Fe(H2O)6](OTs)3
0
7
0
8
9
O
9
72, 70b
69, 73c
R
R'
1: 1 equiv
FG
R"N
R
10
FeCl3 (5 mol%)/AgOTs (20 mol%)
+
H
2 mol% [Fe(H2O)6](OTs)3
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Fe salt (10 mol%),
DME (1.0 mL), rt, 20 h. Isolated yields are shown.
b 2 mol% Fe catalyst was used.
O
FG
DME
rt, 20 h
R'
N
R"
c In the presence of 1 equivalent of water.
3
2: 2 equiv
Reactions with 2a
Substrate 1/Product 3
Table 2 Ligand Effectsa
O
O
O
O
Ph
1a: 1 equiv
MeN
2 mol%
[Fe(H2O)6](OTs)3
1b/3b: 88%
1c/3c: 99%
1d/3d: 92%
O
O
O
O
+
H
3 mol% ligand
DME, rt, 20 h
Ph
Ph
Ph
CO2Me Br
3a
N
1e/3e: 79%
1f/3f: 62%
(5 mol% Fe, 48 h)
O
1g/3g: 24%
Me
2a: 2 equiv
O
O
Ph
N
Ph
OPh
Run
Ligand
Yield (%) 3a
O
1h/3h: 85%
1i/3i: 0%
1j/3j: 0%
1
2
3
4
5
6
7
8
9
none
dppm
dppe
70
14
13
15
12
19
33
28
20
Reactions with 1a
Substrate 2/Product 3
Ph
N
H
N
H
N
H
DPEphos
2b/3k: 89%
2c/3l: 87%
2d/3m: 88%
Qphos
pinB
Bpy
Bpin
picolic acid
phenylalanine
phenylglycine
N
N
N
Me
Me
Me
2g/3p: 80%
2e/3n: 89%
2f/3o: 88%
Scheme 2 Substrate scope 1. Reagents and conditions: 1 (0.5 mmol),
2 (1.0 mmol), [Fe(H2O)6](OTs)3 (2 mol%), DME (1.0 mL), rt, 20 h.
Isolated yields are shown.
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [Fe(H2O)6](OTs)3 (2
mol%), ligand (3 mol%), DME (1.0 mL), rt, 20 h. Isolated yields are shown.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

1090
T. Inishi et al.
Feature
Synthesis
from indole 2. In this reaction, we also obtained C-2 deuter-
ated product (3b-D: 25% D), but the generation process for
this product is not clear.
2a
N
Me
O
5 mol% [Fe(H2O)6](OTs)3
+
By using the different electrophilicity between enone
and ,-unsaturated ester,20 we carried out a chemoselec-
tive Michael addition (Scheme 5). When substrate 1l pos-
sessing both enone and ,-unsaturated ester moieties re-
acted with 2a, 2a selectively added to the enone to produce
3z as the sole adduct in 65% yield. Our mild addition condi-
tions had realized a chemoselective Michael reaction.
We next checked the maximum TON for the reaction of
1b with 2a in the presence of 2, 0.2, 0.1, 0.06, or 0.02 mol%
iron catalyst (Figure 1). Although 2 mol% iron catalyst gave
88% yield of 3b with a TON of 44, a better TON was achieved
in the reaction with 0.2 mol% iron catalyst (TON = 425).
When the reaction was carried out using 0.1 or 0.06 mol%
iron catalyst, low yields of 3b were obtained with a TON of
ca. 200. The reaction was stopped when 0.02 mol% iron cat-
alyst was employed.
DME
rt, 48 h
O
1l
O
MeN
O
O
O
3z: 65%
Scheme 5 Chemoselective Michael addition
X mol% [Fe(H2O)6](OTs)3
DME, rt, 20 h
+
1b
2a
3b
1 equiv
2 equiv
TON
500
Yield (%)
100
Yield (%)
TON
88%
85%
80
50
20
O
300
100
FG
1k: 2 equiv
RN
+
5 mol% [Fe(H2O)6](OTs)3
H
21%
0.1
O
DME
50 °C, 20 h
13%
FG
0%
N
R
2
0.2
0.06
0.02
2: 1 equiv
3
Fe cat. (X mol%)
Substrate 2/Product 3
Figure 1 TON in this reaction
N
N
N
H
Me
H
2b/3q: 76%
2a/3r: 55% (64%)a
2c/3s: 19%a
In conclusion, we have discovered that a cationic iron
catalyst, [Fe(H2O)6](OTs)3, is effective to carry out Michael
additions of indoles with -mono- and disubstituted
enones. In this reaction, various indole adducts were ob-
tained with TONs up to 425. These results are useful to car-
ry out indole Michael additions with minimal amounts of
inexpensive iron metals. Further improvements, including
an asymmetric reaction, will be described in due course.
Cl
Br
Ph
N
H
N
H
N
H
2h/3u: 80%
2i/3v: 83%
2d/3t: 0%
NC
O2N
MeO2C
N
H
N
H
N
H
2l/3y: 53%a
2j/3w: 49%
2k/3x: 10%a
Scheme 3 Substrate scope 2. Reagents and conditions: 1k (1 mmol),
2 (0.5 mmol), [Fe(H2O)6](OTs)3 (5 mol%), DME (1 mL), 50 °C, 20 h. Iso-
lated yields are shown. a MeCN/MeOH (1:1) was used instead of DME.
All reactions were carried out under nitrogen (99.95%) atmosphere.
For TLC analyses, precoated Kieselgel 60 F254 plates (Merck, 0.25 mm
thick) were used; for column chromatography, SiliaFlash P60 (SiliCy-
cle, 40–63 m) was used. Visualization was accomplished by UV light
(254 nm). 1H and 13C NMR spectra were obtained using a JEOL 400 or
500 MHz NMR spectrometer. Chemical shifts for 1H NMR are de-
scribed in parts per million (chloroform as an internal standard,  =
7.26) in CDCl3. Chemical shifts for 13C NMR are expressed in parts per
million in CDCl3 as an internal standard ( = 77.16). High-resolution
mass analyses were obtained using an ACQUITY UPLC/TOF-MS for EI.
Anhydrous solvents were purchased from Kanto Chemical Co., Ltd.
Other chemicals were purchased from TCI, Sigma, and Wako, and di-
rectly used from the bottles.
1b
MeN
10 mol% FeCl3
30 mol% AgOTs
D
+
D
O
(25%)
DME
rt, 20 h
Ph
N
Me
D
(70%)
2a-D
3b-D: 59% yield
(95% D)
Scheme 4 Reaction with deuterated indole 2a-D
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

1091
T. Inishi et al.
Feature
Synthesis
Compounds 3a–3z; General Procedure
HRMS (EI): m/z calcd for C20H21NO [M+]: 291.1623; found: 291.1626.
3-(1-Methyl-1H-indol-3-yl)-1-(o-tolyl)butan-1-one (3d)
Fe salt (2–10 mol%), 1 (0.50 mmol or 1.0 mmol), and 2 (1.0 mmol or
0.5 mmol) were sequentially added under air to a dram vial equipped
with a stir bar. Dried DME (1.0 mL) was added by syringe, and the re-
sulting mixture was vigorously stirred under nitrogen atmosphere
[charged by general N2 (99.95%) gas flow] for 20 h, unless noted oth-
erwise (3f, 3z), at room temperature (3a–3p, 3z) or 50 °C (3q–3y). Af-
ter this time, the contents of the flask were filtered through a plug of
silica gel and then concentrated by rotary evaporation. The residue
was purified by silica gel column chromatography [n-hexane/EtOAc,
10:1 (v/v)] to afford the desired product 3.
1-(o-Tolyl)but-2-en-1-one (1d; 80.1 mg, 0.50 mmol), 1-methylindole
(2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3d (pale yellow oil, 134.0 mg, 92%).
IR (neat): 1681, 1270, 735 cm–1
.
1H NMR (396 MHz, CDCl3):  = 1.43 (d, J = 6.9 Hz, 3 H), 2.41 (s, 3 H),
3.16 (dd, J = 8.9, 16.5 Hz, 1 H), 3.39 (dd, J = 5.5, 16.5 Hz, 1 H), 3.72 (s, 3
H), 3.72–3.79 (m, 1 H), 6.85 (s, 1 H), 7.09 (t, J = 6.9 Hz, 1 H), 7.19–7.24
(m, 3 H), 7.28 (d, J = 8.3 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.57 (d, J = 7.6
Hz, 1 H), 7.62 (d, J = 7.5 Hz, 1 H).
13C NMR (99.5 MHz, CDCl3):  = 21.1, 21.5, 27.5, 32.7, 50.0, 109.4,
118.8, 119.4, 120.0, 121.7, 125.2, 125.7, 126.8, 128.4, 131.1, 132.0,
137.3, 137.9, 138.7, 204.4.
4-(1-Methyl-1H-indol-3-yl)-4-phenylbutan-2-one (3a)
4-Phenylbut-3-en-2-one (benzalacetone, 1a; 73.1 mg, 0.50 mmol), 1-
methylindole (2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTs)3 (16.7 mg,
0.025 mmol), and DME (1.0 mL) were used. The crude residue was pu-
rified by column chromatography to afford 3a (pale yellow oil, 97.1
mg, 70%).
HRMS (EI): m/z calcd for C20H21NO [M+]: 291.1623; found: 291.1625.
IR (neat): 1709, 1154, 737, 700 cm–1
.
Methyl 4-(3-(1-Methyl-1H-indol-3-yl)butanoyl)benzoate (3e)
1H NMR (396 MHz, CDCl3):  = 2.09 (s, 3 H), 3.17 (dd, J = 7.7, 15.4 Hz, 1
H), 3.26 (dd, J = 6.7, 15.4 Hz, 1 H), 3.74 (s, 3 H), 4.84 (t, J = 7.7 Hz, 1 H),
6.85 (s, 1 H), 7.03 (t, J = 7.7 Hz, 1 H), 7.27–7.34 (m, 5 H), 7.33 (d, J = 7.7
Hz, 2 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.45 (d, J = 8.7 Hz, 1 H).
13C NMR (99.5 MHz, CDCl3):  = 30.4, 32.7, 38.5, 50.6, 109.4, 117.4,
117.5, 119.1, 119.7, 121.9, 126.3, 126.5, 127.1, 127.8, 127.8, 127.8,
127.8, 128.6, 128.6, 137.5, 144.3, 207.9.
Methyl 4-(but-2-enoyl)benzoate (1e; 102.1 mg, 0.50 mmol), 1-me-
thylindole (2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg,
0.025 mmol), and DME (1.0 mL) were used. The crude residue was pu-
rified by column chromatography to afford 3e (pale yellow oil, 132.5
mg, 79%).
IR (neat): 2768, 1450, 1360, 1022, 968 cm–1
.
1H NMR (396 MHz, CDCl3):  = 1.47 (d, J = 6.9 Hz, 3 H), 3.25 (dd, J = 8.3,
15.8 Hz, 1 H), 3.49 (dd, J = 4.8, 15.8 Hz, 1 H), 3.74 (s, 3 H), 3.81 (sext,
J = 7.5 Hz, 1 H), 3.95 (s, 3 H), 6.89 (s, 1 H), 7.11 (t, J = 8.2 Hz, 1 H), 7.23
(d, J = 7.7 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1 H), 7.98
(d, J = 8.2 Hz, 2 H), 8.09 (d, J = 8.2 Hz, 2 H).
13C NMR (99.5 MHz, CDCl3):  = 21.3, 27.2, 32.7, 47.2, 52.6, 109.5,
118.9, 119.4, 119.8, 121.8, 125.2, 126.7, 128.1, 129.9, 133.8, 137.3,
140.7, 166.4, 199.4.
HRMS (EI): m/z calcd for C19H19NO [M+]: 277.1467; found: 277.1469.
3-(1-Methyl-1H-indol-3-yl)-1-phenylbutan-1-one (3b)
Phenyl 1-propenyl ketone (1b; 73.1 mg, 0.50 mmol), 1-methylindole
(2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3b (pale yellow oil, 122.0 mg, 88%).
IR (neat): 1680, 1277, 736, 689 cm–1
.
HRMS (EI): m/z calcd for C21H21NO3 [M+]: 335.1521; found: 335.1522.
1H NMR (396 MHz, CDCl3):  = 1.48 (d, J = 6.8 Hz, 3 H), 3.25 (dd, J = 9.7,
15.9 Hz, 1 H), 3.49 (dd, J = 4.8, 15.9 Hz, 1 H), 3.75 (s, 3 H), 3.81–3.90
(m, 1 H), 6.91 (s, 1 H), 7.14 (t, J = 6.8 Hz, 1 H), 7.26 (t, J = 8.7 Hz, 1 H),
7.32 (d, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.56 (t, J = 7.8 Hz, 1 H),
7.70 (d, J = 8.7 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 2 H).
13C NMR (99.5 MHz, CDCl3):  = 21.2, 27.1, 32.6, 46.7, 109.5, 118.8,
119.4, 120.2, 121.7, 125.2, 126.8, 128.3, 128.7, 133.1, 137.4, 137.5,
199.9.
4-(4-Bromophenyl)-4-(1-methyl-1H-indol-3-yl)butan-2-one (3f)
4-(4-Bromophenyl)but-3-en-2-one (1f; 112.5 mg, 0.5 mmol), 1-me-
thylindole (2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (33.4 mg, 0.05
mmol), and DME (1.0 mL) were used, with a reaction time of 48 h. The
crude residue was purified by column chromatography to afford 3f
(pale yellow oil, 110.4 mg, 62%).
IR (neat): 1711, 1484, 1072, 1008, 737 cm–1
.
HRMS (EI): m/z calcd for C19H19NO [M+]: 277.1467; found: 277.1464.
1H NMR (396 MHz, CDCl3):  = 2.14 (s, 3 H), 3.17 (dd, J = 7.6, 16.5 Hz, 1
H), 3.28 (dd, J = 6.8, 16.5 Hz, 1 H), 3.78 (s, 3 H), 4.85 (t, J = 7.5 Hz, 1 H),
6.87 (s, 1 H), 7.08 (t, J = 6.9 Hz, 1 H), 7.23–7.25 (m, 3 H), 7.31 (d, J = 8.2
Hz, 1 H), 7.42–7.43 (m, 3 H).
13C NMR (99.5 MHz, CDCl3):  = 30.5, 32.9, 37.8, 50.2, 109.4, 116.9,
119.2, 119.5, 120.2, 122.0, 126.2, 126.8, 129.6, 131.7, 137.5, 143.4,
207.2.
3-(1-Methyl-1H-indol-3-yl)-1-(4-tolyl)butan-1-one (3c)
1-(p-Tolyl)but-2-en-1-one (1c; 80.1 mg, 0.50 mmol), 1-methylindole
(2a; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3c (pale yellow oil, 144.2 mg, 99%).
IR (neat): 1676, 1278, 1179, 806, 735 cm–1
.
HRMS (EI): m/z calcd for C19H18BrNO [M+]: 355.0572; found:
355.0575.
1H NMR (396 MHz, CDCl3):  = 1.45 (d, J = 6.9 Hz, 3 H), 2.41 (s, 3 H),
3.22 (dd, J = 8.9, 15.8 Hz, 1 H), 3.46 (dd, J = 4.8, 15.8 Hz, 1 H), 3.74 (s, 3
H), 3.81–3.86 (m, 1 H), 6.90 (s, 1 H), 7.12 (t, J = 6.9 Hz, 1 H), 7.24–7.25
(m, 3 H), 7.30 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.88 (d, J = 8.1
Hz, 2 H).
13C NMR (99.5 MHz, CDCl3):  = 21.3, 21.7, 27.3, 32.7, 46.7, 109.4,
118.8, 119.4, 120.3, 121.7, 125.1, 126.8, 128.4, 129.3, 135.0, 137.3,
143.7, 199.4.
3-(1-Methyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one (3g)21
Chalcone (1g; 104.1 mg, 0.50 mmol), 1-methylindole (2a; 131.2 mg,
1.00 mmol), Fe[(H2O)6](OTf)3 (16.8 mg, 0.025 mmol), and DME (1.0
mL) were used. The crude residue was purified by column chromato-
graphy to afford 3g (pale yellow oil, 40.7 mg, 24%).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

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Feature
Synthesis
IR (neat): 1711, 1484, 1072, 1008, 737 cm–1
.
1-Phenyl-3-(2-phenyl-1H-indol-3-yl)butan-1-one (3m)
1H NMR (500 MHz, CDCl3):  = 3.72–3.83 (m, 5 H), 5.06 (t, J = 7.2 Hz, 1
H), 6.84 (s, 1 H), 7.00–7.03 (m, 1 H), 7.14–7.20 (m, 2 H), 7.25 (m, 2 H),
7.27 (d, J = 4.3 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 2 H), 7.42–7.45 (m, 3 H),
7.54 (t, J = 7.4 Hz, 1 H), 7.93–7.94 (m, 2 H).
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), 2-phenylindole
(2d; 193.3 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3m (pale yellow oil, 149.4 mg, 88%).
IR (neat): 1681, 1470, 1280, 735, 690 cm–1
.
13C NMR (125 MHz, CDCl3):  = 32.8, 38.2, 45.5, 109.3, 117.9, 119.0,
119.7, 121.8, 126.4, 127.1, 127.9, 128.2, 128.6, 128.7, 133.1, 137.2,
137.5, 144.5, 198.7.
1H NMR (396 MHz, CDCl3):  = 1.57 (d, J = 6.8 Hz, 3 H), 3.50 (dd, J = 5.8,
16.4 Hz, 1 H), 3.57 (dd, J = 8.7, 16.4 Hz, 1 H), 4.00 (sext, J = 6.8 Hz, 1 H),
7.16–7.25 (m, 2 H), 7.35–7.41 (m, 4 H), 7.44–7.53 (m, 4 H), 7.85–7.87
(m, 3 H), 8.04 (s, 1 H).
4-(1-Methyl-1H-indol-3-yl)heptan-2-one (3h)
13C NMR (99.5 MHz, CDCl3):  = 21.3, 27.6, 45.8, 111.4, 117.3, 119.6,
120.5, 122.1, 127.5, 128.1, 128.3, 128.6, 128.9, 129.0, 133.0, 133.4,
134.3, 136.5, 137.3, 200.0.
3-Hepten-2-one (1h; 56 mg, 0.50 mmol), 1-methylindole (2a; 131.2
mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol), and DME
(1.0 mL) were used. The crude residue was purified by column chro-
matography to afford 3h (pale yellow oil, 103.4 mg, 85%).
HRMS (EI): m/z calcd for C24H21NO [M+]: 339.1623; found: 339.1625.
IR (neat): 1710, 1467, 735 cm–1
.
1H NMR (396 MHz, CDCl3):  = 0.89 (t, J = 6.5 Hz, 3 H), 1.26–1.32 (m, 2
H), 1.66–1.80 (m, 2 H), 2.04 (s, 3 H), 2.81 (dd, J = 6.9, 15.9 Hz, 1 H),
2.89 (dd, J = 7.5, 15.9 Hz, 1 H), 3.49 (quint, J = 6.2 Hz, 1 H), 3.74 (s, 3 H),
6.85 (s, 1 H), 7.12 (t, J = 6.9 Hz, 1 H), 7.23 (t, J = 6.9 Hz, 1 H), 7.30 (d, J =
8.2 Hz, 1 H), 7.66 (d, J = 8.2 Hz, 1 H).
3-(1,2-Dimethyl-1H-indol-3-yl)-1-phenylbutan-1-one (3n)
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), 1,2-dimethylin-
dole (2e; 145.2 mg, 1.0 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025
mmol), and DME (1.0 mL) were used. The crude residue was purified
by column chromatography to afford 3n (pale yellow oil, 129.7 mg,
89%).
13C NMR (99.5 MHz, CDCl3):  = 14.2, 20.2, 30.5, 32.6, 32.7, 38.4, 50.5,
IR (neat): 1681, 1470, 1280, 735, 690 cm–1
.
109.4, 117.6, 118.7, 119.5, 121.5, 126.1, 127.1, 137.3, 209.0.
HRMS (EI): m/z calcd for C16H21NO [M+]: 243.1623; found: 243.1622.
1H NMR (396 MHz, CDCl3):  = 1.44 (d, J = 6.7 Hz, 3 H), 2.31 (s, 3 H),
3.33 (dd, J = 7.7 and 16.4 Hz, 1 H), 3.47 (dd, J = 6.8 and 16.4 Hz, 1 H),
3.50 (s, 3 H), 3.70 (sext, J = 7.7 Hz, 1 H), 7.00 (t, J = 6.8 Hz, 1 H), 7.07 (t,
J = 6.8 Hz, 1 H), 7.16 (d, J = 7.7 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.41 (t,
J = 7.7 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 1 H), 7.81 (d, J = 7.7 Hz, 2 H).
13C NMR (99.5 MHz, CDCl3):  = 10.3, 21.2, 27.5, 29.3, 45.8, 108.8,
114.8, 118.4, 119.0, 120.1, 126.0, 127.9, 128.3, 132.2, 132.7, 136.9,
137.3, 200.0.
3-(1H-Indol-3-yl)-1-phenylbutan-1-one (3k)
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), indole (2b; 117.15
mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol), and DME
(1.0 mL) were used. The crude residue was purified by column chro-
matography to afford 3k (pale yellow oil, 117.2 mg, 89%).
IR (neat): 1674, 1278, 738, 688 cm–1
.
HRMS (EI): m/z calcd for C20H21NO [M+]: 291.1623; found: 291.1618.
1H NMR (396 MHz, CDCl3):  = 1.49 (d, J = 6.9 Hz, 3 H), 3.27 (dd, J = 9.0,
16.5 Hz, 1 H), 3.51 (dd, J = 4.8, 16.5 Hz, 1 H), 3.87 (sext, J = 6.8 Hz, 1 H),
7.02 (s, 1 H), 7.15 (t, J = 6.9 Hz, 1 H), 7.22 (t, J = 8.2 Hz, 1 H), 7.36 (d, J =
7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.71 (d, J =
7.5 Hz, 1 H), 7.98 (d, J = 7.5 Hz, 2 H), 8.07 (s, 1 H).
13C NMR (99.5 MHz, CDCl3):  = 21.1, 27.3, 46.6, 111.4, 119.30, 119.33,
120.4, 121.5, 122.1, 126.4, 128.2, 128.7, 133.1, 136.7, 137.4, 200.0.
3-(1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indol-3-yl)-1-phenylbutan-1-one (3o)
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), 1-methyl-2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2f; 257.1
mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol), and DME
(1.0 mL) were used. The crude residue was purified by column chro-
matography to afford 3o (pale yellow oil, 177.5 mg, 88%).
HRMS (EI): m/z calcd for C18H17NO [M+]: 263.1310; found: 263.1310.
IR (neat): 2925, 1115, 1005, 866 cm–1
.
3-(2-Methyl-1H-indol-3-yl)-1-phenylbutan-1-one (3l)
1H NMR (396 MHz, CDCl3):  = 1.37 (d, J = 8.2 Hz, 12 H), 1.53 (d, J = 7.1
Hz, 3 H), 3.49–3.56 (m, 2 H), 3.93 (s, 3 H), 4.37–4.43 (m, 1 H), 7.10 (q,
J = 7.5 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 7.43 (t,
J = 7.5 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 8.00 (d,
J = 7.1 Hz, 2 H).
13C NMR (99.5 MHz, CDCl3):  = 21.5, 24.9, 25.0, 28.6, 32.3, 46.8, 83.6,
110.1, 118.7, 121.3, 123.2, 128.2, 128.5, 128.7, 132.7, 133.1, 137.5,
140.4, 200.3.
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), 2-methylindole
(2c; 131.2 mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3l (pale yellow oil, 120.7 mg, 87%).
IR (neat): 1673, 1458, 1281, 739, 688 cm–1
.
1H NMR (396 MHz, CDCl3):  = 1.54 (d, J = 6.8 Hz, 3 H), 2.38 (s, 3 H),
3.41 (dd, J = 7.8 and 15.4 Hz, 1 H), 3.57 (dd, J = 5.8 and 15.4 Hz, 1 H),
3.78 (quint, J = 6.8 Hz, 1 H), 7.09–7.15 (m, 2 H), 7.25 (d, J = 8.7 Hz, 1 H),
7.41 (t, J = 6.7 Hz, 2 H), 7.52 (t, J = 6.7 Hz, 1 H), 7.71–7.77 (m, 2 H), 7.91
(d, J = 7.7 Hz, 2 H).
HRMS (EI): m/z calcd for C25H30NO3B [M+]: 403.2319; found:
403.2322.
13C NMR (99.5 MHz, CDCl3):  = 11.8, 20.9, 27.3, 45.6, 110.5, 115.3,
118.8, 118.9, 120.5, 127.0, 127.9, 128.3, 130.3, 132.8, 135.5, 137.3,
200.1.
3-(1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indol-3-yl)-1-phenylbutan-1-one (3p)
4-Phenylbut-3-en-2-one (1a; 73.1 mg, 0.50 mmol), 1-methyl-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2g; 257.1
mg, 1.00 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol), and DME
(1.0 mL) were used. The crude residue was purified by column chro-
matography to afford 3p (pale yellow oil, 161.3 mg, 80%).
HRMS (EI): m/z calcd for C19H19NO [M+]: 277.1467; found: 277.1468.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

1093
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Feature
Synthesis
IR (neat): 1682, 1444, 1347, 1140, 689 cm–1
.
4-(5-Chloro-1H-indol-3-yl)-4-methylpentan-2-one (3u)
1H NMR (396 MHz, CDCl3):  = 1.39 (s, 12 H), 1.45 (d, J = 6.9 Hz, 3 H),
3.24 (dd, J = 8.9, 15.8 Hz, 1 H), 3.48 (dd, J = 4.8, 15.8 Hz, 1 H), 3.73 (s, 3
H), 3.82–3.86 (m, 1 H), 6.88 (s, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.45 (t, J =
7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.69 (d, J = 8.2 Hz, 1 H), 7.98 (d, J =
8.2 Hz, 2 H), 8.20 (s, 1 H).
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 5-chloroindole
(2h; 76.0 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol),
and DME (1.0 mL) were used. The crude residue was purified by col-
umn chromatography to afford 3u (pale yellow oil, 100.4 mg, 80%).
IR (neat): 3351, 2963, 1691, 1462, 797 cm–1
.
13C NMR (99.5 MHz, CDCl3):  = 21.5, 25.00, 25.02, 27.1, 32.7, 46.8,
83.5, 108.9, 121.1, 125.2, 126.6, 127.1, 128.0, 128.3, 128.6, 133.0,
137.4, 139.3, 199.8.
HRMS (EI): m/z calcd for C25H30NO3B [M+]: 403.2319; found:
403.2325.
1H NMR (500 MHz, CDCl3):  = 1.52 (s, 6 H), 1.76 (s, 3 H), 2.91 (s, 2 H),
6.98 (d, J = 2.5 Hz, 1 H), 7.15 (dd, J = 2.0, 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz,
1 H), 7.76 (d, J = 2.0 Hz, 1 H), 8.01 (br s, 1 H).
13C NMR (125 MHz, CDCl3):  = 28.9, 32.0, 34.4, 55.0, 112.7, 120.1,
122.1, 122.2, 123.5, 124.9, 126.6, 135.6, 209.2.
HRMS (EI): m/z calcd for C14H17NOCl [M + H+]: 250.0999; found:
250.1001.
4-(1H-Indol-3-yl)-4-methylpentan-2-one (3q)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), indole (2b; 58.4
mg, 0.5 mmol), [Fe(H2O)6](OTf)3 (17.0 mg, 0.025 mmol), and DME (1.0
mL) were used. The crude residue was purified by column chromatog-
raphy to afford 3q (pale yellow oil, 81.6 mg, 76%).
4-(5-Bromo-1H-indol-3-yl)-4-methylpentan-2-one (3v)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 5-bromoindole
(2i; 98.2 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (17.0 mg, 0.025 mmol),
DME (1.0 mL) were used. The crude residue was purified by column
chromatography to afford 3v (pale yellow oil, 121.4 mg, 83%).
IR (neat): 3402, 2961, 1693, 1243, 740 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.57 (s, 6 H), 1.75 (s, 3 H), 2.98 (s, 2 H),
6.91 (m, 1 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.37 (d,
J = 8.0 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 8.13 (br s, 1 H).
13C NMR (125 MHz, CDCl3):  = 29.1, 32.0, 32.8, 34.6, 55.3, 109.8,
118.7, 120.9, 121.4, 122.3, 125.5, 126.0, 137.9, 209.4.
IR (neat): 3350, 2963, 1691, 1458, 795 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.52 (s, 6 H), 1.78 (s, 3 H), 2.92 (s, 2 H),
6.93 (t, J = 2.5 Hz, 1 H), 7.22–7.27 (m, 2 H), 7.91 (s, 1 H), 8.17 (br s, 1 H).
13C NMR (125 MHz, CDCl3):  = 28.9, 32.0, 34.4, 55.0, 112.5, 113.2,
122.1, 123.1, 123.3, 124.6, 127.2, 135.9, 209.3.
HRMS (EI): m/z calcd for C14H17NOBr [M + H+]: 294.0494; found:
HRMS (EI): m/z calcd for C14H18NO [M + H+]: 216.1388; found:
216.1389.
294.0494.
4-Methyl-4-(1-methyl-1H-indol-3-yl)pentan-2-one (3r)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 1-methylindole
(2a; 62.3 L, 0.50 mmol), [Fe(H2O)6](OTf)3 (16.8 mg, 0.025 mmol),
MeOH (0.5 mL), and MeCN (0.5 mL) were used. The crude residue was
purified by column chromatography to afford 3r (pale yellow oil, 73.2
mg, 64%).
3-(2-Methyl-4-oxopentan-2-yl)-1H-indole-5-carbonitrile (3w)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 5-cyanoindole
(2j; 71.5 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (17.1 mg, 0.025 mmol),
MeOH (0.5 mL), and MeCN (0.5 mL) were used. The crude residue was
purified by column chromatography to afford 3w (pale yellow oil,
59.3 mg, 49%).
IR (neat): 2960, 1699, 1355, 1239, 737 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.54 (s, 6 H), 1.74 (s, 3 H), 2.95 (s, 2 H),
3.74 (s, 3 H), 6.80 (s, 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.23 (t, J = 7.4 Hz, 1
H), 7.31 (d, J = 8.2 Hz, 1 H), 7.80 (t, J = 8.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 15.7, 30.4, 31.6, 36.2, 55.7, 110.6,
116.4, 119.0, 120.8, 120.8, 127.9, 130.1, 135.2, 209.8.
IR (neat): 3324, 2217, 1697, 1349, 807 cm–1
1H NMR (500 MHz, CDCl3):  = 1.54 (s, 6 H), 1.83 (s, 3 H), 2.94 (s, 2 H),
7.06–7.07 (m, 1 H), 7.40–7.41 (m, 2 H), 8.14 (s, 1 H), 8.56 (br s, 1 H).
13C NMR (125 MHz, CDCl3):  = 29.0, 32.1, 34.3, 54.9, 102.0, 112.7,
121.1, 123.1, 124.4, 124.5, 125.3, 126.2, 139.0, 208.7.
HRMS (EI): m/z calcd for C15H17N2O [M + H+]: 241.1341; found:
.
HRMS (EI): m/z calcd for C15H19NO [M+]: 229.1467; found: 229.1467.
241.1345.
4-Methyl-4-(2-methyl-1H-indol-3-yl)pentan-2-one (3s)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 2-methylindole
(2c; 65.4 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (17.3 mg, 0.025 mmol),
MeOH (0.5 mL), and MeCN (0.5 mL) were used. The crude residue was
purified by column chromatography to afford 3s (pale yellow oil, 21.3
mg, 19%).
4-Methyl-4-(5-nitro-1H-indol-3-yl)pentan-2-one (3x)
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), 5-nitroindole
(2k; 81.4 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (16.9 mg, 0.025 mmol),
MeOH (0.5 mL), and MeCN (0.5 mL) were used. The crude residue was
purified by column chromatography to afford 3x (pale yellow solid,
12.5 mg, 10%); mp 143–145 °C.
IR (neat): 3352, 2961, 1691, 1458, 740 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.62 (s, 6 H), 1.70 (s, 3 H), 2.51 (s, 3 H),
2.98 (s, 2 H), 7.04–7.11 (m, 2 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.70 (br s, 1
H), 7.76 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 15.7, 30.5, 31.6, 36.2, 55.7, 110.6,
116.5, 119.0, 120.8, 120.9, 127.9, 130.0, 135.4, 209.7.
IR (neat): 3280, 1520, 1330, 1082, 737 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.59 (s, 6 H), 1.85 (s, 3 H), 2.99 (s, 2 H),
7.12 (d, J = 2.5 Hz, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 8.11 (dd, J = 2.0, 9.0 Hz,
1 H), 8.43 (br s, 1 H), 8.76 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 29.1, 32.1, 34.4, 54.9, 111.7, 117.6,
117.8, 124.0, 124.9, 126.3, 140.3, 141.3, 208.4.
HRMS (EI): m/z calcd for C15H20NO [M + H+]: 230.1545; found:
230.1545.
HRMS (EI): m/z calcd for C14H17N2O3 [M + H+]: 261.1239; found:
261.1240.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094

1094
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Feature
Synthesis
Methyl 3-(2-Methyl-4-oxopentan-2-yl)-1H-indole-5-carboxylate
(3y)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705997.
4-Methylpent-3-en-2-one (1k; 115 L, 1.00 mmol), methyl indole-5-
carboxylate (2l; 87.6 mg, 0.50 mmol), [Fe(H2O)6](OTf)3 (16.7 mg,
0.025 mmol), MeOH (0.5 mL), and MeCN (0.5 mL) were used. The
crude residue was purified by column chromatography to afford 3y
(pale yellow oil, 71.8 mg, 53%).
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References
IR (neat): 3339, 2955, 1690, 1237, 752 cm–1
.
(1) (a) Moore, R. E.; Cheuk, C.; Patterson, G. M. L. J. Am. Chem. Soc.
1984, 106, 6456. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045.
(2) Manabe, K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001,
343, 174.
(3) (a) Liu, L.; Ma, H.; Xiao, Y.; Du, F.; Qin, Z.; Li, N.; Fu, B. Chem.
Commun. 2012, 48, 9281. (b) Yadav, J. S.; Reddy, B. V. S.; Baishya,
G.; Reddy, K. V.; Narsaiah, A. V. Tetrahedron 2005, 61, 9541.
(4) Huang, Z.-H.; Zou, J.-P.; Jiang, W.-Q. Tetrahedron Lett. 2006, 47,
7965.
1H NMR (500 MHz, CDCl3):  = 1.55 (s, 6 H), 1.75 (s, 3 H), 2.98 (s, 2 H),
3.95 (s, 3 H), 6.99 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.89 (dd,
J = 1.6, 8.7 Hz, 1 H), 8.46 (br s, 1 H), 8.57 (s, 1 H).
13C NMR (125 MHz, CDCl3):  = 29.1, 31.9, 34.5, 52.1, 55.1, 111.5,
121.1, 122.2, 123.1, 123.5, 124.9, 125.2, 140.0, 168.5, 209.3.
HRMS (EI): m/z calcd for C16H20NO3 [M + H+]: 274.1443; found:
274.1443.
(5) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. Adv. Synth. Catal.
2003, 345, 1247.
tert-Butyl 3-(4-(1-(1-Methyl-1H-indol-3-yl)-3-oxobutyl)phe-
nyl)acrylate (3z)
(6) Huang, G.; Sun, H.; Qiu, X.; Shen, Y.; Jiang, J.; Wang, L.
J. Organomet. Chem. 2011, 696, 2949.
(7) Bandini, M.; Fagioli, M.; Garavelli, M.; Melloni, A.; Trigari, V.;
Umani-Ronchi, A. J. Org. Chem. 2004, 69, 7511.
(8) Shi, M.; Cui, S.-C.; Li, Q.-J. Tetrahedron 2004, 60, 6679.
(9) (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva,
S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700. (b) Ranu, B. C.;
Dey, S. S.; Samanta, S. ARKIVOC 2005, (iii), 44.
(10) Swetha, A.; Raghavender, M.; Reddy, B.; Babu, M.; Meshram, H.
M. Tetrahedron Lett. 2017, 58, 4427.
(11) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
(12) An, L.-T.; Zou, J.-P.; Zhang, L.-L.; Zhang, Y. Tetrahedron Lett.
2007, 48, 4297.
(13) Zolfigol, M. A.; Veisi, H.; Mohanazadeh, F.; Sedrpoushan, A.
J. Heterocycl. Chem. 2011, 48, 977.
tert-Butyl 3-(4-(3-oxobut-1-en-1-yl)phenyl)acrylate (1l; 274.3 mg,
1.00 mmol), 1-methylindole (2a; 65.6 mg, 0.50 mmol),
[Fe(H2O)6](OTf)3 (16.7 mg, 0.025 mmol), and DME (1.0 mL) were used,
with a reaction time of 48 h. The crude residue was purified by col-
umn chromatography to afford 3z (pale yellow oil, 131.1 mg, 65%).
IR (neat): 1701, 1633, 1322, 1144, 737 cm–1
.
1H NMR (396 MHz, CDCl3):  = 1.51 (s, 9 H), 2.08 (s, 3 H), 3.15 (dd, J =
8.3, 16.5 Hz, 1 H), 3.24 (dd, J = 7.6, 16.5 Hz, 1 H), 3.72 (s, 3 H), 4.83 (t,
J = 7.6 Hz, 1 H), 6.27 (d, J = 15.8 Hz, 1 H), 6.83 (s, 1 H), 7.01 (t, J = 8.3
Hz, 1 H), 7.18 (t, J = 8.2 Hz, 1 H), 7.25 (t, J = 8.2 Hz, 1 H), 7.31 (d, J = 8.2
Hz, 2 H), 7.38–7.40 (m, 3 H), 7.52 (d, J = 15.8 Hz, 1 H).
13C NMR (99.5 MHz, CDCl3):  = 28.3, 30.5, 32.8, 38.2, 50.2, 80.5, 109.4,
116.9, 119.1, 119.5, 119.7, 122.0, 126.3, 126.9, 128.3, 132.9, 137.4,
143.4, 146.6, 166.6, 207.3.
(14) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem. Int.
Ed. 2003, 42, 2768. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317.
(15) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2003, 32,
752.
(16) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Commun. 2004,
1822.
(17) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115, 3170.
(18) Itoh, T.; Uehara, H.; Ogiso, K.; Nomura, S.; Hayase, S.; Kawatsura,
M. Chem. Lett. 2007, 36, 50.
(19) (a) Wang, X.; Zhang, Y.; Xiao, X.; Li, X. Chem. Lett. 2008, 37,
1284. (b) Gao, Y.-H.; Yang, L.; Zhou, W.; Xu, L.-W.; Xia, C.-G.
Appl. Organomet. Chem. 2009, 23, 114. (c) Veisi, H.; Maleki, B.;
Eshbala, F. H.; Veisi, H.; Masti, R.; Ashrafi, S. S.; Baghayeri, M.
RSC Adv. 2014, 4, 30683.
HRMS (EI): m/z calcd for C26H29NO3 [M+]: 403.2147; found: 403.2147.
3-(1-Methyl-1H-indol-3-yl-2-d)-1-phenylbutan-1-one-2-d (3b-D)
The general procedure was followed using phenyl 1-propenyl ketone
(1b; 73.1 mg, 0.50 mmol), 1-methylindole-3-d (2a-D; 131.2 mg, 1.00
mmol), FeCl3 (8.1 mg, 0.05 mmol), AgOTs (48.8 mg, 0.17 mmol), and
DME (1.0 mL) for 20 h. The crude residue was purified by column
chromatography to afford 3b-D (81.7 mg, 59%).
1H NMR (500 MHz, CDCl3):  = 1.45 (d, J = 6.8 Hz, 3 H), 3.20–3.27 (m,
0.3 H), 3.44–3.49 (m, 0.8 H), 3.75 (s, 3 H), 3.80–3.83 (m, 1 H), 6.89 (s,
0.75 H), 7.11 (t, J = 6.8 Hz, 1 H), 7.23 (t, J = 8.7 Hz, 1 H), 7.30 (d, J = 7.8
Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.67 (d, J = 8.7
Hz, 1 H), 7.96 (d, J = 7.7 Hz, 2 H).
(20) Allgauer, D. S.; Jangra, H.; Asahara, H.; Li, Z.; Chen, Q.; Zipse, H.;
Ofial, A. R.; Mayr, H. J. Am. Chem. Soc. 2017, 139, 13318.
(21) Liang, D.; Li, X.; Zhang, W.; Li, Y.; Zhang, M.; Cheng, P. Tetrahe-
dron Lett. 2016, 57, 1027.
Funding Information
Financial support provided by Yamaguchi University and Japan Soci-
ety for the Promotion of Science [JSPS, KAKENHI Grant Number
JP18H04262(TN), Precisely Designed Catalysts with Customized Scaf-
folding] is gratefully acknowledged.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1087–1094