Copper-Mediated One-Pot Synthesis of Indoles through Sequential Hydroamination and Cross-Dehydrogenative Coupling Reaction

Article abstract of DOI:10.1055/s-0039-1690240

Starting from simple anilines and ester arylpropiolates, an efficient one-pot synthesis of 2-arylindole-3-carboxylate derivatives has been developed through copper-mediated sequential hydroamination and cross-dehydrogenative coupling (CDC) reaction. The i

Full text of DOI:10.1055/s-0039-1690240

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
de
P. Sun et al.
Paper
Synthesis
Copper-Mediated One-Pot Synthesis of Indoles through Sequential
Hydroamination and Cross-Dehydrogenative Coupling Reaction
Peng Sun §a,b
Jiaojiao Yang §a
Zirui Songa
O
OR
Ar
Cu-promoted
hydroamination
Cu-mediated
CDC reaction
O
OR
Ar
N
Ar
Ar
Ar
+
NH2
H
(1)
(2)
N
O
OR
H
Yichao Caia
Ar
intermediates
Yajie Liua
Chunxia Chen*a,b
Xin Chena,b
32 examples
up to 88% yield
CuCl2/Phenanthroline, KMnO4/KHCO3
benzene, 120 °C for 24 h; then DMSO, 130 °C for 24 h
One-pot sequential synthesis
Jinsong Peng*a
0
0
0
0-0
0
0
2-7
8
2
2-4
5
6
0
a College of Chemistry, Chemical Engineering and Resource Utilization,
Northeast Forestry University, No. 26 Hexing Road, Harbin 150040,
P. R. of China
ccx0109@nefu.edu.cn
jspeng1998@nefu.edu.cn
b Material Science and Engineering College, Northeast Forestry University,
No. 26 Hexing Road, Harbin 150040, P. R. of China
§ These authors contributed equally to this work
Received: 26.07.2019
Cl
O
Accepted after revision: 15.10.2019
Published online: 05.11.2019
DOI: 10.1055/s-0039-1690240; Art ID: ss-2019-h0420-op
O
O
N
O
O
Me
O
N
N
CO2R
R = H
Me
N
H
Ph
Pr
Indometacin
N
Abstract Starting from simple anilines and ester arylpropiolates, an ef-
ficient one-pot synthesis of 2-arylindole-3-carboxylate derivatives has
been developed through copper-mediated sequential hydroamination
and cross-dehydrogenative coupling (CDC) reaction. The initial hy-
droamination of anilines to ester arylpropiolates in benzene can pro-
ceed in a stereoselective manner to give ester (Z)-3-(arylamino)acry-
lates in the presence of CuCl2/phenanthroline, KMnO4, and KHCO3 at
120 °C. Sequentially, these in situ functionalized adducts can undergo
direct intramolecular oxidative alkenylation of aromatic C–H bond in
mixed solvents (benzene/DMSO 1:1) at 130 °C affording multi-
substituted indoles in good to high yields.
NH
O
N
Pr
H
N
R =
O
N
Tropisetron
O
Dolasetron
O
Proglumetacin
OMe
MeO
MeO
MeO
O
OMe
O
O
Me
N
N
OMe
OH
O
Me
N
H
H
N
O
Me
NH
anticancer
N
O
N
Ph
N
OMe
microtublin inhibitor
H
Ondansetron
GPRC6A receptor
Key words copper-mediated, indoles, hydroamination, cross-
dehydrogenative coupling, oxidation
Figure 1 Selected examples of bioactive C3-functionalized indole de-
rivatives
As one of the most abundant structural motifs, the in-
dole unit has been widely found in biologically active natu-
ral products,1 agrochemicals,2 and pharmaceuticals.3 Sub-
stituted indoles have been utilized as ‘privileged scaffolds’
for drug discovery;4 numerous compounds display versatile
biological activities such as anticancer, antifungal, antibac-
terial, anti-inflammatory, antioxidant, antirheumatoidal,
and anti-HIV.5 In particular, indole-3-carboxylic esters and
3-acylindoles are prevalent in a number of marketed drugs,
such as Dolasetron (nausea), Tropisetron (antiemetic), In-
domethacin/Proglumetacin (anti-inflammatory), and On-
dansetron (nausea); and bioactive molecules (Figure 1).
Therefore, C3-functionalized indole derivatives are of great
interest for pharmaceutical and biological research.
The importance of the indole framework in drug discov-
ery has pushed it to the forefront of synthetic develop-
ments. Over the past century, much effort has been focused
on the development of new synthetic methods, and a large
number of different approaches for indole preparation have
been reported.6 While classical procedures based on con-
densation and cyclization are well established,6b transition-
metal-mediated C–C and C–N bond formation has recently
emerged as an attractive alternative methodology for mod-
ular indole syntheses.7 Specifically, reactions of alkynes and
different nitrogen partners (such as aryl hydrazines,8 aryl
isonitriles,9 nitroarenes,10 diaziridinone,11 and aniline de-
rivatives12–21) set the stage for the development of practical
approaches to diversely substituted indoles in the last few
decades (Scheme 1).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
P. Sun et al.
Paper
Synthesis
R3
With this consideration in mind, aniline (1a) and ethyl
3-phenylpropiolate (2a) were selected as the coupling part-
ners to verify the above assumption. In the presence of Cu-
Cl2 or CuI/2-(di-tert-butylphosphino)biphenyl (L1)29n and
KHCO3 as the base, the model reaction was initially con-
ducted in a single solvent (MeCN, toluene, DCE, THF, 1,4-di-
oxane, DMF, DMA, and DMSO) at 120 or 130 ° for 24 hours
with O2 as the oxidant; however, no successful examples
were obtained. Thus, based on these failed results, different
solvent system was used to carry out hydroamination and
CDC reaction, respectively. The optimization of reaction
conditions are summarized in Table 1. First, a screen of cop-
per salts [CuBr, CuCl, Cu(OTf)2, Cu(OAc)2, and CuCl2] showed
that CuCl and CuCl2 gave a similar yield (12% vs 13%, Table 1,
entries 3 and 6), whereas other copper salts led to lower
yields (entries 1–6). It must be noted that the direct use of
mixed solvents (MeCN/DMSO = 1:1) gave no product (en-
tries 1 and 2). To increase the yield of 3aa, the influence of
ligands (phosphorus ligands L1–L3, N-heterocyclic carbene
ligand L4, and nitrogen-based bidentate ligands L5–L7) on
the reaction was then examined (entries 6–12). Bidentate
nitrogen-containing ligand 1,10-phenanthroline (phen, L7)
performed best, and the yield of 3aa can be improved to
33% (entry 12). Next, the effect of bases such as KHCO3,
Li2CO3, NaOt-Bu, NaOMe, NaOAc, NaOH, Na2CO3, and NEt3
on the reaction was investigated (entries 12–19). The na-
ture of base greatly influenced the outcome of the reaction;
KHCO3 gave the best result with O2 as the oxidant (entry
12). To reveal the crucial role of the oxidant, we then
screened different types of oxidants (such as O2, KMnO4,
1,4-benzoquinone, K2S2O8, MnO2, and K2Cr2O7, entries 20–
24), and the yield was improved to 53% in the presence of
KMnO4 (entry 20). Finally, a survey of reaction media
showed that benzene as the solvent for the hydroamination
step provided better results than those obtained in MeCN,
THF, DMF, toluene, DCE, and 1,4-dioxane (entries 20 and
25–30); furthermore, the binary mixed solvent composed
of benzene and DMSO efficiently promoted the intramolec-
ular CDC process at 130 °C to give the final product 3aa in
88% yield (entry 30). A set of experiments were carried out
to assess the crucial role of the amount of CuCl2 (entry 31).
When the amount was reduced to 50, 25 and 15 mmol%,
the desired product was isolated in much lower yields.
Having established the feasibility of indole synthesis via
copper-mediated sequential hydroamination/oxidative CDC
process, we then explored the scope and limitation of ani-
lines using ethyl 3-phenylpropiolate (2a) as the coupling
partner (Table 2). As shown in Table 2, most of substituents
(such as Me, OMe, F, Cl, and Br) on the aromatic moiety of
anilines were applicable, and the corresponding indoles
3ba–la were obtained in good to high yields (71–88%). Pri-
mary aromatic amines containing electron-donating groups
at the ortho- (1g and 1h), meta- (1k and 1l), or para-posi-
tion (1b and 1c) were generally more reactive than those
bearing electron-withdrawing substituents (1d–f, and 1i)
X
NH2
N
Ar
+
R1
R2
R1
R1
N
H
Ar
R2
+
R3
X = Cl, Br, I
Ar
R2
N
H
R2
Ar
R3
R2
NH2
Ar
NC
R3
+
(i) this work
R2
Cu-mediated
Ar
R2
R3NH2
N
R1
hydroamination/CDC
R1
+
DG
R1
+
Pd
N
R2
R3
Ar
X
Pd (g)
13a hydrazones14
acetanilides,
R3
N-arylurea,15 N-nitroso anilines16
nitrones,17 triazene,18 hydrazines19
N-2-pyridyl or pyrimidyl anilines20
pyrazolones21
R3
R2
I
O
+
R2
Ar
+
+
Ar
N
N
NO2
R1
R1
2nd
1st row transition metal
Ni, Co
Rh, Pd, and Ru
Scheme 1 Metal-mediated indole synthesis from alkynes and different
nitrogen sources
Due to improved atom and step economy, recent years
have witnessed an upsurge in indole synthesis based on C–
H activation processes. For example, since Glorius group22a
reported an efficient synthesis of indoles via Pd-catalyzed
oxidative cyclization of N-arylenaminones/esters in 2008,
much effort has been focused on the development of intra-
molecular cross-dehydrogenative coupling (CDC) strategy.23
In addition, various one-pot methods have also been well
established through sequential addition/metal-catalyzed
CDC reaction by Cacchi,24 Fagnou,13a,b Jiao,12a and others.12d,e
Using simple anilines12 or aniline derivatives with diverse
directing groups13–21 (Scheme 1h), instead of o-haloanilines,
o-alkynylanilines, o-alkynylaryl isocyanides, o-alkynyl-
haloarenes25 and o-gem-dihalovinylanilines26 as the sub-
strates (Scheme 1b–e),7 various metal-catalyzed protocols
have been established through oxidative annulation of
alkynes. Compared with Au/PhI(OAc)2,12e Rh, Pd, and Ru cat-
alysts, indole synthesis catalyzed by first-row transition
metals is still very scarce. Despite Co-15c,16c,17d,19b or Ni-cata-
lyzed20d indole synthesis through group-directed oxidative
C–H annulation has been investigated in recent years, find-
ing more available and cheaper first-row metals to synthe-
size indoles is still in great demand. As an alternative non-
precious metal, copper-mediated C-heteroatom and C–C
bond formation27 through either traditional or C–H func-
tionalization processes has aroused great interest in the
synthesis of heterocycles.28,29
With our continuous efforts on metal-catalyzed (Cu29n,30
and Pd31) C–H functionalization, herein we envisioned that
simple anilines and alkynes should be suitable substrates
for atom and step-economic synthesis of indoles through
sequential copper-mediated hydroamination32 and oxida-
tive CDC reaction22–24 (Scheme 1i). To realize this proposed
tandem process, rational reaction conditions should be es-
tablished to accommodate two fundamentally different
copper-mediated reactions in one-pot manner.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

C
P. Sun et al.
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Synthesis
Table 1 Optimization of Reaction Conditions for the Synthesis of Indole 3aaa
O
O
OEt
OEt
Ph
copper salt, ligand, base
+
NH2
solvent, oxidant, temperature
N
1a
2a
3aa
Ph
H
Entry
Copper salt
Ligandb
Base
KHCO3
Oxidant
Solvent
Yield (%)c
1
2d
3
CuBr
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
O2
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
MeCN; DMSO
THF; DMSO
8
CuBr
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
Li2CO3
t-BuONa
NaOMe
NaOAc
NaOH
O2
NR
CuCl
O2
12
4
Cu(OTf)2
Cu(OAc)2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
O2
trace
5
O2
trace
6
O2
13
7
O2
NR
8
O2
NR
9
O2
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31e
O2
18
O2
25
O2
33
O2
NR
O2
28
O2
19
O2
13
O2
NR
Na2CO3
Et3N
O2
NR
O2
NR
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KMnO4
1,4-BQ
K2S2O8
MnO2
K2Cr2O7
KMnO4
KMnO4
KMnO4
KMnO4
KMnO4
KMnO4
KMnO4
53
NR
32
40
38
18
DMF; DMSO
NR
toluene; DMSO
DCE; DMSO
61
NR
1,4-dioxane; DMSO
benzene; DMSO
benzene; DMSO
57
88
trace (11f/32g)
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), copper salt (0.2 mmol), ligand (30 mol%), base (0.2 mmol), solvent (1 mL), O2 (1 atm) or oxidant
(0.2 mmol), 120 °C, 24 h; then DMSO (1 mL), 130 °C, 24 h.
b L1: 2-(Di-tert-butylphosphino)biphenyl; L2: 2-(Dicyclohexylphosphino)-2′-methylbiphenyl; L3: 2-Dicyclohexylphosphino-2,6-diisopropoxybiphenyl; L4:
1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride; L5: 2, 2-Bipyridine; L6: Glyoxime; L7: 1,10-Phenanthroline.
c Isolated yield after chromatography.
d A mixed solvent (MeCN/DMSO = 1:1) was directly used.
e CuCl2: 15 mmol%.
f CuCl2: 25 mmol%.
g CuCl2: 50 mmol%.
and provided higher yields. However, the incorporation of
strong electron-withdrawing group (NO2 and CF3) in the
para-position of arylamine seriously hampered copper-
mediated hydroamination of alkynes, and the correspond-
ing indoles 3ma and 3na cannot be obtained. For meta-
substituted arylamines 1k and 1l, regioselectivity issues
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

D
P. Sun et al.
Paper
Synthesis
surfaced in the CDC process, and a mixture of two regioiso-
mers was obtained. Intramolecular CDC reaction occurred
at two different sites to give products 3ka/3k′a (1.6:1) and
3la/3l′a (1.5:1), respectively. In addition, disubstituted aro-
matic amine 1j underwent the reaction smoothly and af-
forded the corresponding indole 3ja in 83% yield. It is worth
noting that when the reaction was carried out on a 1.0
mmol scale, the product 3aa can be obtained in 73% yield.
spectively. However, when the scope of substrates was ex-
tended to aliphatic propiolate ester [ethyl oct-2-ynoate
(2j)], ynones [4-phenylbut-3-yn-2-one (2r) and diphenyl-
propynone (2s)], and arylpropiolamides 2t and 2u, the re-
actions cannot proceed to provide the corresponding prod-
ucts 3aj and 3ar–au. Other alkyl aylpropiolates, such as
methyl, n-propyl, n-butyl, isopropyl, and benzyl esters 2k–o
were also examined under the standard conditions, the re-
action can smoothly proceed to give the corresponding
products 3ak–ao in high yields (68–81%).
Table 2 Variation of Arylamine Substratesa,b
Table 3 Variation of Ester Arylpropiolatesa,b
O
O
OEt
OEt
Ph
NH2
R
CuCl2, phen, KHCO3, KMnO4
+
R
O
N
H
benzene, 120 °C, 24 h; then DMSO, 130 °C, 24 h
O
OR
OR
Ar
1a–n
2a
Ph
NH2
CuCl2, phen, KHCO3, KMnO4
3aa–na
+
N
H
benzene, 120 °C, 24 h; then DMSO, 130 °C, 24 h
1a
O
O
O
O
Ar
2a–q
OEt
OEt
OEt
OEt
3aa–aq
Me
MeO
F
O
O
O
O
N
N
N
N
OEt
OEt
OEt
OEt
H
H
H
H
3aa
3ba
85%
3ca
84%
3da
77%
Me
OMe
F
88% (73%)c
N
H
N
N
N
H
H
H
O
O
O
O
OEt
OEt
3aa
88%
3ab
77%
3ac
75%
3ad
82%
OEt
OEt
Cl
Br
O
O
O
O
N
H
N
H
OEt
OEt
OEt
OEt
N
H
N
H
Me
OMe
Cl
3ea
75%
3fa
75%
3ga
80%
3ha
79%
N
H
N
H
N
H
N
H
Me
OMe
F
O
O
O
O
3ae
81%
3af
78%
3ag
75%
3ah
80%
OEt
Me
Me
OEt
OEt
OEt
O
+
O
O
O
OnPr
OEt
N
OEt
OMe
N
H
N
H
N
H
Me
Me
H
Cl
3ia
71%
3ja
83%
3ka
3k'a
N
H
N
N
H
3ak
N
H
3al
81%
H
78% (1.6:1)d
OEt
Me
3ai
67%
3aj
0%
79%
O
O
O
O
OMe
OEt
OEt
OEt
O
O
O
O
O2N
F3C
OnBu
OiPr
OBn
OEt
+
N
N
H
N
H
N
H
MeO
H
N
H
S
N
H
N
N
H
3la
3l'a
3ma
0%
3na
0%
H
3am
76%
3an
75%
3ao
68%
3ap
79%
73% (1.5:1)e
O
R1
a Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), CuCl2 (0.2 mmol),
O
O
O
OEt
N
Me
Ph
Me
phen (30 mol%), KHCO3 (0.2 mmol), benzene (1 mL), KMnO4 (0.2 mmol),
120 °C, 24 h; then DMSO (1 mL), 130 °C, 24 h.
b Isolated yield after chromatography.
Ph
N
H
N
H
N
H
N
H
c One millimole scale.
R1 = H, Ph
3au
d m-Toluidine was used, and the ratio of the regioisomers was determined
by NMR analysis.
3aq
55%
3ar
0%
3as
0%
0%
e 3-Methoxyaniline was used, and the ratio of the regioisomers was deter-
mined by NMR analysis.
a Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), CuCl2 (0.2 mmol),
phen (30 mol%), KHCO3 (0.2 mmol), benzene (1 mL), KMnO4 (0.2 mmol),
120 °C, 24 h; then DMSO (1 mL), 130 °C, 24 h.
b Isolated yield after chromatography.
The scope and generality of ester propiolates were next
explored in this one-pot sequential process (Table 3). For
ethyl arylpropiolates, the electronic nature of the aromatic
motifs did not seem to affect the efficiency: both electron-
donating (Me and MeO) and electron-withdrawing substit-
uents (F and Cl) can be incorporated at the ortho- (2i), me-
ta- (2f–h), and para-position (2b–e), providing indole de-
rivatives 3ab–ai in good to high yields (67–82%). In addi-
tion, heteroaryl (thiophene) and -naphthylpropiolates 2p
and 2q can also be efficiently transformed into the corre-
sponding products 3ap and 3aq in 79% and 55% yield, re-
To gain insight into the mechanism of this sequential
annulation process, some designed control experiments
were conducted (Scheme 2). At first, the reaction of aniline
(1a) and ethyl phenylpropiolate (2a) was examined in ben-
zene at 120 °C for 24 hours in the presence of KHCO3; how-
ever, the starting materials were completely recovered
(Scheme 2, eq 1), which indicated that ethyl (Z)-3-phenyl-
3-(phenylamino)acrylate (4aa) cannot be obtained through
aza-Michael addition reaction.12d With CuCl2 as the catalyst,
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

E
P. Sun et al.
Paper
Synthesis
the reaction can give ethyl (Z)-3-phenyl-3-(phenylamino)-
acrylate (4aa) specifically (Scheme 2, eq 2) even in the pres-
ence of stronger bases such as NaOH, NaOMe, and t-BuONa
when using benzene as the sole solvent. Intermediate 4aa
was most probably derived from copper-mediated hy-
droamination of alkyne.33 More interesting, the adduct 4aa
of 1a and 2a was isolated in higher yield (98%) in the pres-
ence of KMnO4 as the oxidant (Scheme 2, eq 3); however,
copper-mediated intramolecular CDC reaction of 4aa can-
not proceed further to give indole 3aa only using benzene
as the solvent. To demonstrate CDC process, 4aa was isolat-
ed and tested in two different reaction conditions (Scheme
2, eqs 4 and 5). In the absence of CuCl2/phen, KMnO4 cannot
promote this oxidative CDC reaction (Scheme 2, eq 4) in bi-
nary mixed solvents (benzene/DMSO, 1:1) at 130 °C. On the
other hand, the target product 3aa was obtained in 75%
yield under the standard conditions (Scheme 2, eq 5), fur-
ther confirming that the reaction pathway was comprised
of intermolecular hydroamination of alkyne followed by an
intramolecular copper-mediated oxidative CDC sequence.
moted the dissociation of chloride anion from Cu(II) center,
leading to the formation of cationic Cu(II)-alkyne complex
4. Aniline 1 reacted with 4 possibly through two distinct
pathways. The first pathway involved direct intermolecular
nucleophilic attack of aniline 1 on the alkyne ligated to cat-
ionic copper center. However, this route was less likely
since aromatic amines with electron-withdrawing groups
should react faster. In fact, strong electron-withdrawing
groups (NO2 and CF3) hampered copper-mediated hydro-
amination process. The other route, involving the coordina-
tion of aniline 1, syn migratory insertion of alkyne into N–
Cu, and protonation of C–Cu bond to give E-enamine 7, ap-
peared more probable. In the presence of base, 7 was then
gradually isomerized into a more stable Z-isomer 8. The co-
ordination of Z-isomer 8 to Cu(II) gave a six-membered
chelate ring complex 9, which was then transformed into a
new C–Cu(II) complex 11 through base-promoted depro-
tonation of NH, dissociation of chloride anion, and com-
plexation of the resulting cationic Cu(II) species at -carbon
of 10. Imine-containing Cu(II)-alkyl complex 11 was then
transformed into alkenylcopper 12 through a deprotona-
tion/re-protonation process under basic conditions. Ortho-
metalation of aniline-tethered alkenyl Cu(II) complex 12 led
to the formation of six-membered copper-cycle intermedi-
ate 13, which was then transformed into indole 3. Finally,
Cu(0) resulting from reductive elimination process was oxi-
dized to Cu(II) by KMnO4.
KHCO3, benzene,120 °C, 24 h
(1)
0%
O
OEt
Ph
O
CuCl2, phen, KHCO3
benzene,120 °C, 24 h
N
H
NH2
+
(2)
(3)
(4)
78%
OEt
Ph
1a
4aa
CuCl2, phen, KHCO3
2a
KMnO4, benzene,120 °C, 24 h
98%
In conclusion, we have developed a novel approach for
the synthesis of C3-functionalized indoles, which are prom-
inent structural motifs in many biologically active mole-
cules. Using simple anilines as the starting materials, this
tandem reaction sequence is comprised of copper-mediat-
ed intermolecular hydroamination of alkynes and intramo-
lecular oxidative cross-dehydrogenative coupling in a one-
pot manner.
KMnO4, 130 °C, 24 h
benzene/DMSO (1:1)
0%
O
OEt
Ph
Ph
N
H
N
H
3aa
O
OR
4aa
CuCl2, phen, KHCO3, KMnO4
benzene/DMSO (1:1),130 °C, 24 h
(5)
75%
Scheme 2 Investigation of the reaction mechanism
On the basis of the above results, a plausible mechanism
was outlined for this tandem reaction. Scheme 3 shows a
simplified sequence of events beginning with the active
Cu(II) species. The coordination of alkyne 2 to CuCl2 pro-
Chemicals were purchased from commercial supplies and used with-
out further purification, unless otherwise stated. Solvents were dried
and purified according to the standard procedures before use. Reac-
tions were monitored by analytical TLC. All reactions were conducted
in dried glassware. Purification of reaction products was done by
CO2
R
CO2R
Cu CO2R
H
Ar
PhNH2
1
KHCO3
Ar
N
H
3
Cu
N
H
Cl
O
KCl
N
H
Ar
Cl Ph
Cu
Ar
Cl
CO2R
5
OR
OR
13
O
Cu
4
Ph
12
N
H
Ar
Ar
Cl
Cu(0)
Ar
Cu
Cl
BH
hydroamination
CDC
B
H
base
N
CO2R
2
H
6
KMnO4
Cl
O
Cl
Ph
O
OR
H
Cu2+
Cu
N
CuCl2
Cu
N
OR
Cl
Ar
H
O
Ar
O
Ph
OR
Ph
Cl
10
11
H
N
Ar
Ph
H
Ar
O
N
H
Cl Cu
OR
Ar
O
Ph
OR
Cu Cl
N
8
H
Ph
N
H
OR
Ph
base
Cl
H
Ar
9
7
Scheme 3 Proposed mechanism
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

F
P. Sun et al.
Paper
Synthesis
flash chromatography with 230–400 mesh silica gel. Ester arylpropio-
late substrates were prepared according to the literature methods.34
Melting points were determined on a melting point apparatus in open
1H NMR (500 MHz, CDCl3):  = 8.88 (s, 1 H), 7.75 (d, J = 8.8 Hz, 1 H),
7.47 (d, J = 4.9 Hz, 2 H), 7.25 (br, 3 H), 7.09 (dd, J = 8.6, 4.3 Hz, 1 H),
6.88–6.85 (m, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 1.19 (t, J = 7.1 Hz, 3 H).
1
capillaries and are uncorrected. H NMR spectra were recorded on a
1
13C NMR (125 MHz, CDCl3):  = 165.4, 159.2 (d, JC,F = 235 Hz), 146.2,
500 MHz spectrometer, and 13C NMR spectra were recorded at 125
MHz. Unless otherwise stated, CDCl3 was used as a solvent. Chemical
shifts () are given in parts per million downfield relative to TMS.
Chemical shifts for carbon resonances are reported in parts per mil-
lion and are referenced to the carbon resonance of the solvent CHCl3
( = 77.16). Coupling constants are given in hertz (Hz). High-resolu-
tion mass spectra were recorded on a BIO TOF Q mass spectrometer
equipped with an electrospray ion source (ESI), operated in the posi-
tive mode.
131.7 (d, 3JC,F = 7 Hz), 129.5, 129.3, 128.3 (d, 3JC,F = 11 Hz), 128.1, 112.1,
2
2
112.0, 111.5 (d, JC,F = 26.5 Hz), 107.3 (d, JC,F = 25.3 Hz), 104.6 (d,
4JC,F = 4.3 Hz), 59.9, 14.3.
Ethyl 5-Chloro-2-phenyl-1H-indole-3-carboxylate (3ea)
Grayish white solid; yield: 44.9 mg (75%); mp 149–151 °C (Lit.36 mp
151–153 °C).
1H NMR (500 MHz, CDCl3):  = 8.80 (s, 1 H), 8.17 (d, J = 1.3 Hz, 1 H),
7.59–7.57 (m, 2 H), 7.41–7.35 (m, 3 H), 7.23–7.17 (m, 2 H), 4.25 (q,
J = 7.1 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.0, 145.7, 133.5, 131.5, 129.5,
129.4, 128.7, 128.1, 127.8, 123.5, 121.7, 112.1, 104.4, 59.9, 14.3.
2-Arylindole-3-carboxylate Derivatives 3; General Procedure
A 10 mL Schlenk tube equipped with a magnetic stirring bar was
charged with CuCl2 (0.2 mmol, 26.9 mg), phenanthroline (0.07 mmol,
13 mg), KHCO3 (20 mg, 0.2 mmol) and KMnO4 (0.2 mmol, 31.6 mg),
and then the respective arylamine 1 (0.4 mmol) and the appropriate
ester arylpropiolate 2 (0.2 mmol) were added. Benzene (1.0 mL) was
then added to the mixture via syringe at rt under air. The tube was
sealed and kept in a preheated oil bath at 120 °C for 24 h. DMSO (1.0
mL) was finally added and the mixture was heated at 130 °C for a fur-
ther 24 h. The mixture was cooled to rt, quenched with H2O (5 mL),
and diluted with CH2Cl2 (10 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic extracts were dried (anhyd Na2SO4), filtered, and concentrated
in vacuo. The crude product was then purified by flash chromatogra-
phy on silica gel (H), eluting with 10–20% EtOAc/PE.
Ethyl 5-Bromo-2-phenyl-1H-indole-3-carboxylate (3fa)
White solid; yield: 51.4 mg (75%); mp 102–104 °C (Lit.35 mp 102–104
°C).
1H NMR (500 MHz, CDCl3):  = 8.73 (s, 1 H), 8.35 (s, 1 H), 7.60 (br, 2 H),
7.41 (br, 3 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 4.27 (q,
J = 7.0 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.0, 145.5, 133.8, 131.5, 129.6,
129.5, 129.3, 128.2, 126.2, 124.8, 115.6, 112.5, 104.4, 60.0, 14.3.
Ethyl 7-Methyl-2-phenyl-1H-indole-3-carboxylate (3ga)
White solid; yield: 44.6 mg (80%); mp 154–156 °C (Lit.35 mp 155–157
°C).
1H NMR (500 MHz, CDCl3):  = 8.56 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H),
7.68–7.55 (m, 2 H), 7.40–7.38 (m, 3 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.05 (d,
J = 7.1 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 2.48 (s, 3 H), 1.28 (t, J = 7.1 Hz,
3 H).
Ethyl 2-Phenyl-1H-indole-3-carboxylate (3aa)
White solid; yield: 46.6 mg (88%); mp 157–159 °C (Lit.35 mp 157–159
°C).
1H NMR (500 MHz, CDCl3):  = 8.79 (s, 1 H), 8.21 (d, J = 7.5 Hz, 1 H),
7.61–7.57 (m, 2 H), 7.39–7.34 (m, 3 H), 7.32–7.29 (m, 1 H), 7.28–7.20
(m, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.5, 144.3, 134.7, 132.2, 129.7,
129.0, 128.0, 127.2, 123.8, 122.2, 120.2, 119.8, 105.2, 59.6, 16.5, 14.3.
13C NMR (125 MHz, CDCl3):  = 164.5, 143.6, 134.2, 131.0, 128.6,
128.0, 127.0, 126.6, 122.1, 121.0, 120.9, 110.1, 103.5, 58.7, 13.3.
Ethyl 7-Methoxy-2-phenyl-1H-indole-3-carboxylate (3ha)37
Ethyl 5-Methyl-2-phenyl-1H-indole-3-carboxylate (3ba)
White solid; yield: 47.4 mg (85%); mp 137–139 °C (Lit.35 mp 136–
139 °C).
1H NMR (500 MHz, CDCl3):  = 8.77–8.66 (br, 1 H), 8.01 (s, 1 H), 7.57
(br, 2 H), 7.35 (br, 3 H), 7.19–7.17 (m, 1 H), 7.05 (d, J = 8.0 Hz, 1 H),
4.23 (q, J = 7.0 Hz, 2 H), 2.48 (s, 3 H), 1.25 (t, J = 7.0 Hz, 3 H).
White solid; yield: 46.6 mg (79%); mp 157–159 °C.
1H NMR (500 MHz, CDCl3):  = 8.74 (s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H),
7.72–7.57 (m, 2 H), 7.45–7.42 (m, 3 H), 7.18 (t, J = 8.0 Hz, 1 H), 6.71 (d,
J = 7.8 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 3.94 (s, 3 H), 1.31 (t, J = 7.1 Hz,
3 H).
13C NMR (125 MHz, CDCl3):  = 165.4, 145.8, 143.9, 132.1, 129.7,
129.1, 129.0, 128.1, 125.8, 122.5, 114.7, 105.3, 103.1, 59.7, 55.4, 14.4.
13C NMR (125 MHz, CDCl3):  = 165.7, 144.6, 133.6, 132.2, 131.4,
129.6, 129.0, 128.0, 127.9, 124.7, 121.7, 110.8, 104.1, 59.6, 21.8, 14.3.
Ethyl 7-Chloro-2-phenyl-1H-indole-3-carboxylate (3ia)
White solid; yield: 42.5 mg (71%); mp 145–147 °C (Lit.29m mp 145–
Ethyl 5-Methoxy-2-phenyl-1H-indole-3-carboxylate (3ca)36
147 °C).
White solid; yield: 49.6 mg (84%); mp 148–150 °C.
1H NMR (500 MHz, CDCl3):  = 8.66 (s, 1 H), 8.12 (d, J = 7.9 Hz, 1 H),
7.72–7.59 (m, 2 H), 7.51–7.37 (m, 3 H), 7.33–7.23 (m, 1 H), 7.20 (t,
J = 7.8 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).
1H NMR (500 MHz, CDCl3):  = 8.78 (br, 1 H), 7.63 (d, J = 1.9 Hz, 1 H),
7.52–7.43 (m, 2 H), 7.27 (br, 3 H), 7.10 (d, J = 8.7 Hz, 1 H), 6.83–6.70
(m, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.77 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.8, 144.9, 132.5, 131.5, 129.7,
13C NMR (125 MHz, CDCl3):  = 164.6, 154.7, 143.9, 131.2, 129.3,
129.5, 129.0, 128.2, 122.8, 122.5, 120.9, 116.4, 105.9, 59.9, 14.3.
129.2, 128.5, 127.9, 127.5, 126.9, 112.3, 111.0, 102.6, 58.6, 54.7, 13.2.
Ethyl 4,6-Dimethyl-2-phenyl-1H-indole-3-carboxylate (3ja)
White solid; yield: 48.7 mg (83%); mp 120–122 °C (Lit.29n mp 120–
Ethyl 5-Fluoro-2-phenyl-1H-indole-3-carboxylate (3da)
Grayish white solid; yield: 43.6 mg (77%); mp 151–153 °C (Lit.36 mp
122 °C).
152–154 °C).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

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P. Sun et al.
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Synthesis
1H NMR (500 MHz, CDCl3);  = 8.50 (s, 1 H), 7.56–7.39 (m, 2 H), 7.39–
7.25 (m, 3 H), 6.88 (s, 1 H), 6.81 (s, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 2.61
(s, 3 H), 2.36 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.7, 160.2, 144.8, 135.1, 130.9,
127.6, 124.1, 122.9, 122.0, 121.9, 113.5, 111.1, 103.9, 59.7, 55.3, 14.4.
13C NMR (125 MHz, CDCl3):  = 167.1, 140.4, 136.1, 133.1, 132.5,
130.9, 128.7, 128.5, 128.2, 125.3, 123.6, 108.8, 106.9, 60.4, 21.4, 21.1,
13.9.
Ethyl 2-(4-Fluorophenyl)-1H-indole-3-carboxylate (3ad)
White solid; yield: 46.4 mg (82%); mp 166–168 °C (Lit.35 mp 166–168
°C).
1H NMR (500 MHz, CDCl3):  = 8.73 (s, 1 H), 8.20 (dd, J = 6.2, 2.3 Hz, 1
H), 7.62–7.56 (m, 2 H), 7.35 (dd, J = 6.0, 2.2 Hz, 1 H), 7.28–7.25 (m, 2
H), 7.08 (t, J = 8.6 Hz, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3
H).
Mixture of Ethyl 6-Methyl-2-phenyl-1H-indole-3-carboxylate
(3ka) and Ethyl 4-Methyl-2-phenyl-1H-indole-3-carboxylate
(3k′a)36,38
Yellow oil; the ratio (3ka:3k′a = 1.6:1) was determined by 1H NMR
13C NMR (125 MHz, CDCl3):  = 164.4, 162.2 (d, 1JC,F = 249.4 Hz), 142.5,
analysis; yield: 43.5 mg (78%).
3
134.1, 130.5 (d, JC,F = 8.4 Hz), 127.0, 126.9, 126.4, 122.3, 121.1 (d,
1H NMR (500 MHz, CDCl3):  = 8.92–8.61 (m, 2.4 Hoverlap), 8.07 (d,
J = 8.1 Hz, 1 H3k′a), 7.58–7.56 (m, 1.6 H3ka), 7.48–7.47 (m, 3.5 Hoverlap),
7.34 (br, 8 Hoverlap), 7.22–7.18 (m, 1.5 H3ka), 7.17–7.06 (m, 6.3 Hoverlap),
6.97 (d, J = 6.9 Hz, 2 H3k′a), 4.27–4.20 (m, 2 H3k′a), 4.21–4.16 (m, 3 H3ka),
2.65 (s, 4.7 H3ka), 2.42 (s, 3 H3k′a), 1.26 (t, J = 7.0 Hz, 3 H3k′a), 1.13 (t,
J = 7.1 Hz, 4.9 H3ka).
13C NMR (151 MHz, CDCl3):  = 165.0, 164.9, 143.3, 137.7, 134.7,
133.6, 131.7, 131.1, 131.0, 130.6, 129.8, 128.5, 127.7, 127.6, 127.5,
127.4, 127.1, 126.7, 126.0, 124.6, 124.4, 124.3, 122.5, 122.1, 121.9,
120.4, 110.3, 108.2, 105.6, 102.8, 59.5, 58.6, 20.5, 20.1, 13.2, 12.8.
4JC,F = 3.5 Hz), 114.1 (d, 2JC,F = 21.8 Hz), 110.0, 103.7, 58.8, 13.3.
Ethyl 2-(4-Chlorophenyl)-1H-indole-3-carboxylate (3ae)
White solid; yield: 48.1 mg (81%); mp 151–153 °C (Lit.35 mp 152–155
°C).
1H NMR (500 MHz, CDCl3):  = 8.68 (s, 1 H), 8.23–8.16 (m, 1 H), 7.56
(d, J = 8.4 Hz, 2 H), 7.39–7.33 (m, 3 H), 7.31–7.23 (m, 2 H), 4.30 (q,
J = 7.1 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.3, 143.1, 135.3, 135.2, 130.9,
130.4, 128.3, 127.4, 123.5, 122.2, 122.2, 111.1, 105.0, 59.9, 14.3.
Mixture of Ethyl 6-Methoxy-2-phenyl-1H-indole-3-carboxylate
(3la) and Ethyl 4-Methoxy-2-phenyl-1H-indole-3-carboxylate
(3l′a)36
Yellow oil; the ratio (3la:3l′a = 1.5:1) was determined by 1H NMR
Ethyl 2-(m-Tolyl)-1H-indole-3-carboxylate (3af)
White solid; yield: 43.5 mg (78%); mp 143–145 °C (Lit.29m mp 144–
146 °C).
analysis; yield: 43.1 mg (73%).
1H NMR (400 MHz, CDCl3):  = 8.58 (s, 1 H), 8.14 (d, J = 7.5 Hz, 1 H),
7.35–7.33 (d, J = 6.5 Hz, 2 H), 7.24 (t, J = 6.3 Hz, 1 H), 7.22–7.14 (m, 3
H), 7.12 (d, J = 7.7 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 2.28 (s, 3 H), 1.22
(t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 164.5, 143.7, 136.6, 134.1, 130.9,
129.1, 128.8, 126.9, 126.6, 125.8, 122.0, 121.0, 120.9, 110.0, 103.4,
58.6, 20.3, 13.3.
1H NMR (500 MHz, CDCl3):  = 9.12 (s, 0.9 H3la), 8.97 (s, 0.8 H3l′a), 8.05
(d, J = 8.8 Hz, 1 H3l′a), 7.57–7.55 (m, 1.8 Hoverlap), 7.50–7.47 (m, 2.2 Hov-
erlap), 7.35–7.26 (m, 5.5 Hoverlap), 7.09 (t, J = 8.0 Hz, 1 H3l′a), 7.03 (t,
J = 8.0 Hz, 1 H3l′a), 6.92–6.84 (m, 1.8 Hoverlap), 6.73 (d, J = 1.8 Hz, 1 H3l′a),
6.54 (d, J = 7.9 Hz, 1 H3l′a), 6.31 (dd, J = 8.2, 2.1 Hz, 1 H3l′a), 6.26 (dd,
J = 7.9, 1.6 Hz, 1 H3l′a), 6.21 (t, J = 2.2 Hz, 1 H3l′a), 4.42–4.02 (m, 4.5 Hoverlap),
3.83 (s, 3 H3l′a), 3.71 (s, 4.6 H3la), 1.27 (t, J = 7.1 Hz, 4.3 H3la), 1.19 (t,
J = 7.1 Hz, 3 H3l′a).
Ethyl 2-(3-Methoxyphenyl)-1H-indole-3-carboxylate (3ag)
13C NMR (151 MHz, CDCl3):  = 166.4, 164.7, 155.7, 152.4, 142.8,
137.8, 136.0, 135.2, 131.0, 130.7, 128.4, 127.6, 127.3, 127.3, 127.2,
126.8, 122.8, 121.5, 120.7, 115.8, 110.7, 104.8, 103.5, 102.9, 100.6,
93.5, 59.7, 58.6, 54.4, 54.3, 13.2, 13.0.
White solid; yield: 44.3 mg (75%); mp 136–138 °C (Lit.29n mp 136–
138 °C).
1H NMR (400 MHz, CDCl3):  = 8.81 (s, 1 H), 8.23–8.16 (m, 1 H), 7.35–
7.21 (m, 4 H), 7.20–7.11 (m, 2 H), 6.90 (d, J = 8.2 Hz, 1 H), 4.27 (q,
J = 7.1 Hz, 2 H), 3.77 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 165.5, 159.1, 144.3, 135.1, 133.2,
129.1, 127.6, 123.1, 122.0, 121.9, 115.3, 114.6, 111.2, 111.1, 104.5,
59.7, 55.3, 14.3.
Ethyl 2-(p-Tolyl)-1H-indole-3-carboxylate (3ab)
White solid; yield: 42.9 mg (77%); mp 145–147 °C (Lit.29n mp 144–
146 °C).
1H NMR (500 MHz, CDCl3):  = 8.64 (s, 1 H), 8.20 (d, J = 7.2 Hz, 1 H),
7.51 (d, J = 8.0 Hz, 2 H), 7.35–7.31 (m, 1 H), 7.26–7.23 (m, 2 H), 7.19
(d, J = 7.9 Hz, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 2.36 (s, 3 H), 1.32 (t, J = 7.1
Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 165.5, 144.9, 139.3, 135.1, 129.5,
129.0, 128.8, 127.7, 123.0, 122.1, 122.0, 111.0, 104.4, 59.7, 21.4, 14.4.
Ethyl 2-(3-Fluorophenyl)-1H-indole-3-carboxylate (3ah)
White solid; yield: 45.2 mg (80%); mp 160–162 °C (Lit.29m mp 162–
164 °C).
1H NMR (500 MHz, CDCl3):  = 8.72 (s, 1 H), 8.25–8.17 (m, 1 H), 7.41–
7.34 (m, 4 H), 7.31–7.22 (m, 2 H), 7.14–7.02 (m, 1 H), 4.30 (q, J = 7.1
Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
Ethyl 2-(4-Methoxyphenyl)-1H-indole-3-carboxylate (3ac)
White solid; yield: 44.2 mg (75%); mp 164–165 °C (Lit.36 mp 165–
167 °C).
1H NMR (500 MHz, CDCl3):  = 8.82 (s, 1 H), 8.18 (d, J = 7.7 Hz, 1 H),
7.52 (d, J = 8.7 Hz, 2 H), 7.29–7.19 (m, 3 H), 6.84 (d, J = 8.7 Hz, 2 H),
4.27 (q, J = 7.1 Hz, 2 H), 3.75 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H).
1
13C NMR (125 MHz, CDCl3):  = 165.3, 162.3 (d, JC,F = 246 Hz), 142.7,
3
135.2, 134.0 (d, 3JC,F = 8 Hz), 129.7 (d, JC,F = 8 Hz), 129.2, 127.5, 125.3
(d, 4JC,F = 3 Hz), 123.5, 122.3, 116.9 (d, 2JC,F = 23 Hz), 116.1 (d, 2JC,F = 21
Hz), 111.1, 105.2, 59.9, 14.3.
Ethyl 2-(o-Tolyl)-1H-indole-3-carboxylate (3ai)
White solid; yield: 37.4 mg (67%); mp 76–79 °C (Lit.35 mp 76–79 °C).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

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P. Sun et al.
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Synthesis
1H NMR (500 MHz, CDCl3):  = 8.74 (s, 1 H), 8.23–8.04 (m, 1 H), 7.59–
7.45 (m, 1 H), 7.35–7.29 (m, 2 H), 7.19–7.17 (m, 2 H), 7.05–6.84 (m, 2
H), 4.20 (q, J = 7.1 Hz, 2 H), 3.74 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.3, 155.9, 140.0, 134.0, 131.7,
129.6, 126.1, 121.9, 120.9, 120.6, 119.5, 119.3, 110.0, 109.9, 104.6,
58.5, 54.6, 13.3.
1H NMR (500 MHz, CDCl3):  = 9.02 (br, 1 H), 8.09–8.07 (m, 1 H), 7.52
(d, J = 3.5 Hz, 1 H), 7.26 (d, J = 5.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H),
7.16–7.10 (m, 2 H), 6.91 (t, J = 4.2 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H),
1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.6, 136.4, 134.2, 131.4, 128.3,
126.8, 126.5, 126.1, 122.4, 121.1, 121.0, 110.0, 103.6, 59.0, 13.4.
Methyl 2-Phenyl-1H-indole-3-carboxylate (3ak)
Ethyl 2-(Naphthalen-1-yl)-1H-indole-3-carboxylate (3aq)35
White solid; yield: 39.7 mg (79%); mp 135–137 °C (Lit.29n mp 135–
White solid; yield: 34.6 mg (55%); mp 166–168 °C.
137 °C).
1H NMR (500 MHz, CDCl3):  = 8.57 (br, 1 H), 8.23 (d, J = 7.8 Hz, 1 H),
7.86 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 1
H), 7.48–7.39 (m, 3 H), 7.33–7.28 (m, 2 H), 7.27–7.19 (m, 2 H), 3.92 (d,
J = 7.1 Hz, 2 H), 0.75 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.72 (s, 1 H), 8.24–8.13 (m, 1 H), 7.63–
7.60 (m, 2 H), 7.44–7.39 (m, 3 H), 7.34 (dd, J = 6.1, 2.3 Hz, 1 H), 7.30–
7.21 (m, 2 H), 3.80 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 165.9, 144.7, 135.2, 131.9, 129.6,
129.2, 128.8, 128.2, 127.5, 123.2, 122.1, 111.2, 104.4, 50.9.
13C NMR (125 MHz, CDCl3):  = 163.9, 141.5, 134.2, 132.2, 131.2,
129.5, 128.4, 127.2, 126.9, 126.2, 125.5, 125.1, 124.7, 123.8, 122.2,
121.1, 120.9, 110.0, 106.2, 58.3, 12.7.
Propyl 2-Phenyl-1H-indole-3-carboxylate (3al)
White solid; yield: 45.2 mg (81%); mp 116–118 °C.
Funding Information
1H NMR (500 MHz, CDCl3):  = 8.87 (s, 1 H), 8.12 (d, J = 7.8 Hz, 1 H),
7.47–7.45 (m, 2 H), 7.24–7.23 (m, 3 H), 7.20–7.08 (m, 3 H), 4.03 (t,
J = 6.6 Hz, 2 H), 1.59–1.52 (m, 2 H), 0.79 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.7, 143.7, 134.2, 131.0, 128.6,
128.0, 126.9, 126.6, 122.0, 120.9, 110.2, 103.4, 64.5, 21.0, 9.6.
We are grateful for financial support from the Fundamental Research
Funds for the Central Universities (2572018AB11), National Innova-
tion Experiment Program for University Students (201810225098),
and Natural Science Foundation of Heilongjiang Province (B2017002).
ESI-MS: m/z = 279 [M+], 280 [M + 1]+.
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HRMS-ESI: m/z [M + H]+ calcd for C18H18NO2: 280.1338; found:
280.1334.
Supporting Information
Butyl 2-Phenyl-1H-indole-3-carboxylate (3am)38
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690240.
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White solid; yield: 44.5 mg (76%); mp 154–156 °C.
1H NMR (500 MHz, CDCl3):  = 8.55 (s, 1 H), 8.22–8.06 (m, 1 H), 7.55–
7.53 (m, 2 H), 7.36–7.30 (m, 3 H), 7.30–7.24 (m, 1 H), 7.23–7.12 (m, 2
H), 4.14 (t, J = 6.6 Hz, 2 H), 1.58–1.53 (m, 2 H), 1.29–1.21 (m, 2 H), 0.82
(t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 164.5, 143.5, 134.1, 131.1, 128.6,
128.1, 127.0, 126.6, 122.1, 121.1, 121.0, 110.0, 103.7, 62.6, 29.8, 18.3,
12.7.
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Isopropyl 2-Phenyl-1H-indole-3-carboxylate (3an)39
White solid; yield: 41.9 mg (75%); mp 124–126 °C.
1H NMR (500 MHz, CDCl3):  = 8.73 (s, 1 H), 8.14 (d, J = 7.6 Hz, 1 H),
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Benzyl 2-Phenyl-1H-indole-3-carboxylate (3ao)29m
White solid; yield: 44.5 mg (68%); mp 164–165 °C.
1H NMR (500 MHz, CDCl3):  = 8.68 (s, 1 H), 8.17–8.06 (m, 1 H), 7.46
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White solid; yield: 42.8 mg (79%); mp 155–157 °C.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

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