On-Water Silver(I)-Catalyzed Cycloisomerization of Acetylenic Free Amines/Amides towards 7-Azaindole/Indole/Isoquinolone Derivatives

Article abstract of DOI:10.1055/s-0036-1589072

Silver-catalyzed on-water intramolecular cyclization of acetylenic free amines is reported, which affords 7-azaindoles in good to excellent yields. Neither strong base/acid catalysts nor N-substituted substrates are required to achieve this cycloisomerization. Hydrogen bonds between water medium and the substrates play an important role in improving chemical reactivity and regioselectivity. Furthermore, the on-water reaction is extendable to acetylenic amides for isoquinolone synthesis.

Full text of DOI:10.1055/s-0036-1589072

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
H. Sun et al.
Paper
Synthesis
On-Water Silver(I)-Catalyzed Cycloisomerization of Acetylenic
Free Amines/Amides towards 7-Azaindole/Indole/Isoquinolone
Derivatives
Hongpeng Suna◊
Li Xiaoa◊
Wei Lia,b
Qiong Xie*a,b
general synthetic approach
high yield up to 98%
simple workup
N
H
H2O
X
Liming Shao*a,b
AgNO3
110–130 °C,16 h
X
Nu
a School of Pharmacy, Fudan University, 826 Zhangheng
Road, Zhangjiang Hi-tech Park, Pudong, Shanghai
201203, P. R. of China
regioselectivity
total yield >70%
+
NH
O
O
X = CH, Nu = amine, amide
X = N, Nu = amine
O
limingshao@fudan.edu.cn
qxie@fudan.edu.cn
b Shanghai Center for Drug Discovery & Development, 826
Zhangheng Road, Zhangjiang Hi-tech Park, Pudong,
Shanghai 201203, P. R. of China
◊ These authors contributed equally to this work
Received: 19.04.2017
Accepted after revision: 14.06.2017
Published online: 25.07.2017
amines (generally obtained via an additional step, e.g.,
Sonogashira coupling) appears an effective strategy for the
direct synthesis of 7-azaindoles or indoles, hence consider-
able efforts have been devoted in this direction.3,4
DOI: 10.1055/s-0036-1589072; Art ID: ss-2017-h0264-op
Abstract Silver-catalyzed on-water intramolecular cyclization of acety-
lenic free amines is reported, which affords 7-azaindoles in good to ex-
cellent yields. Neither strong base/acid catalysts nor N-substituted sub-
strates are required to achieve this cycloisomerization. Hydrogen bonds
between water medium and the substrates play an important role in
improving chemical reactivity and regioselectivity. Furthermore, the
on-water reaction is extendable to acetylenic amides for isoquinolone
synthesis.
Mechanism of the intramolecular cyclization is that the
amino group attacks activated triple bonds to afford N-con-
taining heterocycles. Most reported reactions were focused
on the synthesis of either indoles or 7-azaindoles (Scheme
1, A),3 and only a few could be applied to both (Scheme 1,
B).4 Catalysts employed for this cyclization include strong
bases (KH, t-BuOK, etc.),3a–c expensive transition-metal cat-
alysts (Pd,3d AuCl3,4b etc.), or strong acid (e.g., TFA).3e In ad-
dition, the reaction conditions suffered from other limita-
tions, such as high catalyst loading, complicated operational
procedures, harsh reaction conditions, and uses of toxic sol-
vents (e.g., NMP, DMSO, toluene).3,4 Thus, new synthetic
protocols of wide substrate range, resource-saving condi-
tions, and simple operations are needed to be explored.
Key words on-water, cycloisomerization, 7-azaindoles, indoles, iso-
quinolones
7-Azaindole and indole derivatives have attracted con-
siderable attention in organic synthesis because of their
presence in many natural products and potent biological
activities.1,2 Intramolecular cyclization of 3-alkynylpyridyl-
Previous work:
indoles or 7-azaindoles
R = Me,Ar,Ts,Ms,H
acid, base
A)
on-water
Pd,
X
NH
R
N
X
transition metal
R
H2O
C)
A
B
C
+
0%
solubility
0%
0%
indoles and 7-azaindoles
quant.
1 AuCl3, EtOH
B)
2 t-BuOK, DMSO
N
X
X
NH2
H
3 KH, NMP
X = CH, N
Scheme 1 Previous work (A, B) and ideal green reactions (C)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
H. Sun et al.
Paper
Synthesis
On-water reaction is a class of unique water-mediated
reaction, in which insoluble reactants form aqueous sus-
pension under vigorous stirring.5 Sharpless and co-workers
first reported such reactions in 2005 where water-insoluble
reactants gave high yields of products in pure water.5a As
presented in Scheme 1 (C), on-water reaction comes very
close to the ideal green reaction.5d More importantly, the
solvent effect of water (mainly hydrogen-bond) could play a
key role in improving reactivity and regioselectivity.5 Re-
cently on-water reactions have been used to synthesize di-
verse frameworks.5e–i
Our aim was to develop a general and simple synthetic
protocol employing acetylenic free amines as substrates to
synthesize 7-azaindole and indole derivatives. Herein we
report on the silver(I)-catalyzed on-water ring-closure reac-
tions towards 7-azaindoles, indoles, isoquinolones, and iso-
coumarins (Scheme 2).
Table 1 Optimization of the Cyclization Conditionsa
catalyst
solvent
N
N
H
N
NH2
1a
2a
Entry Catalyst
Solvent
Temp Time Yield
(°C)
(20 mol%)
(h)
(%)b
1
2
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
85
48
33
42
51
63
87
96
NR
82
100
110
100
110
130
130
130c
130
130
130
130
130
130
130
130
130
130
130
36
36
24
24
16
16
8
3
4
5
AgNO3
6
AgNO3
7
–
Our work:
8
AgNO3
9
AgOTf
16
16
16
16
16
16
16
16
16
16
16
trace
Ag+
N
H
X
10
11
12
13
14
15
16
17
18
19
AgOAc
trace
trace
92
H2O
Ag2CO3
X
Nu
AgF
+
NH
O
X = CH, Nu = amine, amide
X = N, Nu = amine
AgClO4
93
O
O
ScOTf
NR
Scheme 2 Silver-catalyzed synthesis of 7-azaindoles, indoles, isoquino-
lones, and isocoumarins
Cu(OAc)2
FeCl3
NR
NR
In initial reaction exploration, 3-(phenylethynyl)pyri-
dine-2-amine (1a) was chosen as the substrate, which can
be readily prepared from the corresponding alkynes and 2-
amino-3-bromopyridine by Sonogashira coupling in satis-
factory yield according to the literature protocol.6 3-
(Phenylethynyl)pyridine-2-amine (1a) was stirred in water
with AgNO3 (10 mol%) at 85 °C (Scheme 3). The reaction
was stopped at 48 hours with the starting material still re-
maining. Pure product 2-phenyl-7-azaindole (2a) was ob-
tained in 33% yield after flash column chromatography,
which encouraged us to further investigate the reaction
conditions.
concd HCl (1 equiv)
concd HNO3 (1 equiv)
NR
NR
Cu(OCOCF3)2·×H2O
NR
1-ethylpiperidine (2 equiv)
20
21
22
23
24
AuCl3
H2O
130
130
130
100
130
16
16
16
16
16
95
81
NR
30
AuCl3 (10 mol%)
AgNO3
H2O
toluene
EtOH
DMF
AgNO3
AgNO3
trace and
complex
25
AgNO3
neat
130
16
11
a Reaction conditions: 1a (50 mg), solvent (2 mL), sealed tube in oil bath. Tf
= triflate.
b Isolated yields. NR: No reaction.
c Microwave heating, detected by HPLC every 2 h.
AgNO3
N
N
85 °C
H2O
H
Increasing the catalyst loading from 10 mol% to 20 mol%
shortened the reaction time (Table 1, entries 2–5). Reaction
temperature was also an important factor because the sub-
strate was almost completely converted to 2-phenyl-7-
azaindole (2a) after increasing the temperature from 100 to
130 °C (entries 4–6). No reaction occurred in the absence of
catalyst at 130 °C (entry 7). We also tried to apply micro-
wave irradiation to shorten the reaction time, but the result
was unsatisfactory (entry 8). Some other silver(I) salts were
screened (entries 9–13), among which AgNO3 displayed the
N
NH2
1a
2a
Scheme 3 Initial example of silver-catalyzed 7-azaindole synthesis
Subsequently, 3-(phenylethynyl)pyridine-2-amine (1a)
was used as the model substrate to optimize reaction con-
ditions including different catalysts and temperatures, and
results are summarized in Table 1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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H. Sun et al.
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highest catalytic activity with a yield of 96% (entry 6).
Meanwhile, the other two water soluble silver salts (entries
12, 13) provided much better yields than the insoluble ones,
the latter just gave a trace amount of cyclized product 2a
(entries 9–11). No reaction occurred when ScOTf, FeCl3,
Cu(OAc)2, HCl,3p HNO3, and Cu(OCOCF3)2·×H2O3q were used
as the catalysts (entries 14–19). Among them HCl and
Cu(OCOCF3)2·xH2O had been used to synthesize indoles,3p,q
but they could not be applied to synthesize 7-azaindoles
under our reaction conditions. One possible reason is that
the pyridine N atom weakens the NH2 moiety’s nucleophilic
reactivity. AuCl3 also provided a yield of 95% under the
same condition (entry 20), but a poorer yield was obtained
at lower catalyst loading (entry 21). Thus, AgNO3 was cho-
sen as the catalyst for its relatively lower cost.
drogen bond network at the oil-water interface could stabi-
lize the transition state as proposed by Marcus.5c More im-
portantly, the hydrogen bond between water and N atom
on pyridine ring strengthens the aromaticity of pyridine
and then enhances NH2 moiety’s nucleophilic reactivity,
which may explain why aprotic solvents like DMF and tolu-
ene cannot effectively mediate the synthesis of desired
product 2a (Scheme 4). It is certain that AgNO3 as the cata-
lyst also plays an important role in promoting the cycliza-
tion.
N
NH
AgNO3
2a: R = Ph
R
proto-
demetallation
Additionally, we performed the model reaction in or-
ganic solvents, such as DMF, toluene, EtOH, and without
solvent under the same conditions (Table 1, entries 22–25),
none of them could effectively mediate the synthesis of de-
sired product 2a. We also observed the solubility of organic
molecule in the progress of reaction (Figure 1). At the initial
and final state, the organic phase was solid (Figure 1, P1,
P3). During the progress of reaction, the organic phase was
oily liquid under 130 °C, and this kind of oil-water state was
beneficial to form aqueous suspension under vigorous stir-
ring (Figure 1, P2). These results confirmed that the model
reaction belonged to on-water reaction class.
Ag
H
N
N
Ag
O
– H
R
N
H
H
NH
H
R
O
H
O
H
O
H
H
H
H
Scheme 4 Proposed mechanism of the on-water reaction
With the optimal conditions established, the substrate
scopes including 2-(phenylethynyl)anilines were subse-
quently explored, and the results are shown in Table 2.
Most products were obtained in good to excellent yields
(80–98%) after simple filtration and drying process (2a–p).
These cases were close to the ideal green reaction shown in
Scheme 1 (C). Furthermore, this reaction condition was ap-
plied successfully to synthesize both 7-azaindoles 2a–h and
indoles 2i–p. This reaction system also could be applied to
the synthesis of 2-propyl-7-azaindole (2r) and provides
62% yield, while the product need to be isolated by column
chromatography.
The excellent reactivity of amine as a nucleophile for
this transformation prompted us to investigate amide group
for the synthesis of isoquinolones (Table 3, 4a–d). 2-(Phenyl-
ethynyl)benzamides were successfully cyclized to form iso-
quinolones, but the products were impure and the isolated
yields (35–54%) were not as satisfactory as indoles or 7-
azaindoles. Interestingly, another series of isocoumarin
products were isolated (Table 3, 5a–d) in comparable yields
(24–42%). For each reaction, the yield of the isoquinolone
and isocoumarin derivatives in total was higher than 70%
(73–86%). Ketonic oxygen addition products were avoided
because of the key hydrogen bond between the O atom and
water, which reduces the nucleophilicity of the amide oxy-
gen (Scheme 5). Additionally, aqueous AgNO3 solution is
acidic, and 6-endo cyclization product is the major product
instead of 5-exo under acidic conditions.7 To the best of our
Figure 1 Appearance of solubility in the reaction progress. P1: Initial
state. P2: Up to 130 °C. P3: Final state.
The on-water phenomenon is a unique chemistry that
occurs at the water–oil phase boundary. Under vigorous ag-
itation or high temperature, at large hydrophobic surfaces
about 1 in 4 of the water molecules in the final layer has an
OH-free group directed at the boundary. These bare protons
act as both hydrogen-bond donors and acceptors, and
therefore are involved in trans-phase hydrogen bonding
with the transition state, which lowers the activation ener-
gy of the reaction.5c
On the basis of the results obtained above and previous-
ly reported literature,5c a plausible mechanism of this on-
water reaction is illustrated in Scheme 4. A cooperative hy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
H. Sun et al.
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Synthesis
Table 2 Synthesis of 2a–p under Optimized Conditionsa
R2
R2
AgNO3
R1
R1
H2O
N
H
X
X
NH2
130 °C
1a–p
X = CH, N
2a–p
O
Cl
N
H
N
H
N
H
N
N
N
2a, 96%
2b, 90%
2c, 94%
Cl
Cl
N
N
H
N
N
N
H
H
N
2e, 92%
2f, 86%
2i, 98%
2d, 96%
Cl
Cl
N
N
H
N
H
N
H
N
2g, 86%
2h, 80%
Cl
Cl
O
N
H
N
H
N
H
2j, 91%
2k, 90%
2l, 92%
N
H
N
H
N
H
Cl
Cl
2m, 98%
2p, 96%
2n, 94%
2o, 91%
O
N
H
N
H
N
2r, 62%
a Reaction conditions: 1a–p (50 mg), AgNO3 (20 mol%), H2O (2 mL); 8–24 h, sealed tube in oil bath; isolated yields.
knowledge, the on-water synthetic method of isoquinolo-
nes has not been reported.8
Recycling of the retained aqueous AgNO3 medium was
also investigated. Results from the recycling study on the
reaction of 5-chloro-2-(p-tolylethynyl)aniline (1o) are
shown in Table 4. After the third recycle, isolated yield still
achieved 93% without AgNO3 addition, but the reaction
time was prolonged from 10 to 36 hours. The product of ev-
ery recycle was simply obtained by filtration and the result-
ing colorless aqueous filtrate (containing AgNO3) was used
in the next recycle immediately.
In summary, we have developed a general and simple
method to synthesize N-containing benzoheterocycles (in-
cluding 7-azaindoles, indoles, and isoquinolones) via Ag(I)-
catalyzed on-water reaction. The products of 7-azaindoles
and indoles displayed high yields and most of them were
isolated by simple filtration. Isoquinolone derivatives could
be successfully synthesized from amides by this on-water
reaction, while the isolated yields were unsatisfactory due
to amide hydrolysis. In addition, this reaction provided an-
other way to synthesize isocoumarins.
Ag
X
NH2
hydrolysis
OH
X = NH, O
O
O
H
water
OH
Scheme 5 Proposed mechanism for on-water amide cyclization reac-
tion
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Table 3 Synthesis of 4a–d under Optimized Conditionsa
at 130 °C for about 16 h. The reaction product was filtered, washed
with H2O, and dried to give a brown solid; yield: 48 mg (96%); mp
209–210 °C; HPLC purity 98%.
1H NMR (400 MHz, DMSO-d6): δ = 12.13 (s, 1 H), 8.30–8.20 (m, 1 H),
8.00 (d, J = 7.8 Hz, 1 H), 7.95–7.89 (m, 2 H), 7.47 (t, J = 7.7 Hz, 2 H),
7.39–7.32 (m, 1 H), 7.12 (dd, J = 7.9, 4.6 Hz, 1 H), 6.96 (d, J = 1.9 Hz, 1
H).
R
AgNO3
R
R
+
NH
H2O
NH2
O
110 °C
O
4a–d
O
O
13C NMR (151 MHz, DMSO-d6): δ = 149.1, 143.1, 138.2, 131.2, 128.8 (2
C), 128.5, 128.0, 125.2 (2 C), 121.3, 116.0, 97.2.
3a–d
5a–d
HRMS (ESI): m/z calcd for C13H11N2+: 195.0922; found: 195.0928.
R
4 Yield (%)b
5 Yield (%)b
Total yield (%)
H
4a (35)
4b (50)
4c (48)
4d (54)
5a (42)
5b (24)
5c (25)
5d (32)
77
74
73
86
2-(4-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (2b)
4-Me
4-OMe
4-CO2Me
Brown solid; yield: 45 mg (90%); mp 200–202 °C; HPLC purity 93%.
1H NMR (400 MHz, DMSO-d6): δ = 12.01 (s, 1 H), 8.15 (d, J = 4.7 Hz, 1
H), 7.89–7.85 (m, 3 H), 7.04–7.01 (m, 3 H), 6.78 (d, J = 2.0 Hz, 1 H),
3.79 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 148.7, 143.2, 134.8, 131.2, 130.9,
130.6, 130.3, 129.4, 128.2, 127.3, 120.0, 115.8, 101.4, 69.6.
a Reaction conditions: 3a–e (50 mg), AgNO3 (20 mol%), H2O (2 mL), 10–16
h, in sealed tube.
b Isolated yields.
HRMS (ESI): m/z calcd for C14H13N2O+: 225.1028; found: 225.1032.
Table 4 Recycling of the Aqueous AgNO3 Mediuma
2-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridine (2c)
Brown solid; yield: 47 mg (94%); mp 235–236 °C; HPLC purity 94%.
1H NMR (400 MHz, DMSO-d6): δ = 12.19 (s, 1 H), 8.22 (s, 1 H), 7.94
(dd, J = 8.2, 5.9 Hz, 3 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.06 (dd, J = 7.8, 4.5
Hz, 1 H), 6.96 (s, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 149.5, 143.0, 136.8, 132.3, 130.3,
128.8 (2 C), 127.9, 126.8 (2 C), 120.7, 116.0, 97.6.
AgNO3
N
H
H2O, 130 °C
Cl
Cl
NH2
1o
2o
HRMS (ESI): m/z calcd for C13H10ClN2+: 229.0533; found: 229.0541.
Entry
Recycle
Time (h)
Yield (%)b
1
2
3
1
2
3
10
16
36
96
94
93
2-(2-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridine (2d)
Brown solid; yield: 48 mg (96%); mp 238–239 °C; HPLC purity 94%.
1H NMR (400 MHz, DMSO-d6): δ = 12.04 (s, 1 H), 8.25 (dd, J = 4.7, 1.5
Hz, 1 H), 8.02–7.97 (m, 1 H), 7.74 (dd, J = 7.6, 1.8 Hz, 1 H), 7.62–7.58
(m, 1 H), 7.49–7.39 (m, 2 H), 7.09 (dd, J = 7.9, 4.7 Hz, 1 H), 6.85 (s, 1 H).
a Reaction condition: 1o (50 mg), AgNO3 (20 mol%), H2O (2 mL), in sealed
tube.
b Isolated yields.
13C NMR (151 MHz, DMSO-d6): δ = 159.1, 149.4, 142.1, 138.2, 127.2,
126.6 (2 C), 124.0, 121.1, 115.7, 114.2 (2 C), 95.5.
HRMS (ESI): m/z calcd for C13H10ClN2+: 229.0533; found: 229.0538.
5-Methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (2e)
The 1H NMR (400 MHz) spectra were recorded using Varian 400 MHz
with TMS as internal standard, and the 13C NMR (600 MHz) spectra
were recorded using Bruker 600 MHz. MS data were recorded on
Agilent Technologies 6120 quadrupole mass spectrometer. Purity was
recorded on high-performance liquid chromatography (HPLC) using a
Poroshell 120 column (50 mm × 4.6 mm). Conditions were as follows:
MeOH/H2O eluent at 1.2 mL/min flow (containing 0.1% TFA) at 30 °C, 8
min, gradient 40% MeOH to 60% MeOH, monitored by UV absorption
at 254 nm. TLC was carried out with silica gel precoated glass plates.
TLC spots were visualized under UV light. Melting point was recorded
using WRS-1B digital instrument. All the solvents and reagents were
used directly as obtained commercially, unless otherwise noted.
Compounds 1a–p and 3a–d were prepared according to literature
procedures.4b,6,8i
Brown solid; yield: 46 mg (92%); mp 248–250 °C; HPLC purity 99%.
1H NMR (400 MHz, DMSO-d6): δ = 12.00 (s, 1 H), 8.07 (s, 1 H), 7.92 (d,
J = 7.8 Hz, 2 H), 7.74 (s, 1 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.34 (t, J = 7.5 Hz,
1 H), 6.85 (d, J = 2.0 Hz, 1 H), 2.37 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 147.9, 143.7, 138.3, 131.4, 128.7 (2
C), 128.1, 127.8, 125.1 (2 C), 124.4, 121.0, 96.6, 17.9.
HRMS (ESI): m/z calcd for C14H13N2+: 229.0533; found: 229.0538.
5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridine (2f)
Brown solid; yield: 43 mg (86%); mp 240–241 °C; HPLC purity 99%.
1H NMR (400 MHz, DMSO-d6): δ = 12.38 (s, 1 H), 8.30–7.84 (m, 4 H),
7.60–7.29 (m, 3 H), 6.93 (s, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 147.8, 140.6, 140.2, 130.9, 128.8 (2
C), 128.3, 126.7, 125.4 (2 C), 122.6, 121.8, 96.7.
2-Phenyl-1H-pyrrolo[2,3-b]pyridine (2a); Typical Procedure
HRMS (ESI): m/z calcd for C14H13N2+: 229.0533; found: 229.0548.
To a sealed tube (10 mL) was added 3-(phenylethynyl)pyridin-2-
amine (1a; 50 mg, 0.26 mmol), H2O (2 mL), and AgNO3 (8.7 mg, 0.052
mmol). After ultrasonic oscillation for 5 min, the mixture was stirred
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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5-Methyl-2-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (2g)
HRMS (ESI): m/z calcd for C14H11ClN+: 228.0580; found: 228.0577.
Brown solid; yield: 43 mg (86%); mp 260–261 °C; HPLC purity 96%.
6-Methyl-2-phenyl-1H-indole (2m)
1H NMR (400 MHz, DMSO-d6): δ = 11.92 (s, 1 H), 8.03 (s, 1 H), 7.81 (d,
J = 7.9 Hz, 2 H), 7.69 (d, J = 1.9 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 6.77 (d,
J = 2.0 Hz, 1 H), 2.35 (d, J = 8.8 Hz, 6 H).
13C NMR (151 MHz, DMSO-d6): δ = 148.1, 143.1, 138.3, 137.1, 129.2 (2
C), 128.8, 127.2, 125.0 (2 C), 124.1, 120.7, 95.7, 20.7, 18.0.
Brown solid; yield: 49 mg (98%); mp 190–192 °C; HPLC purity 91%.
1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1 H), 7.65–7.59 (m, 2 H), 7.50
(d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.16
(s, 1 H), 6.95 (dd, J = 8.1, 1.4 Hz, 1 H), 6.77 (s, 1 H), 2.46 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 136.7, 136.6, 131.9, 131.6, 128.4 (2 C),
HRMS (ESI): m/z calcd for C15H15N2+: 223.1235; found: 223.1234.
126.8, 126.5 (2 C), 124.4, 121.4, 119.7, 110.3, 99.2, 21.2.
5-Chloro-2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine (2h)
HRMS (ESI): m/z calcd for C15H14N+: 208.1126; found: 208.1135.
Brown solid; yield: 40 mg (80%); mp 255–256 °C; HPLC purity 100%.
6-Chloro-2-phenyl-1H-indole (2n)
1H NMR (400 MHz, DMSO-d6): δ = 12.28 (s, 1 H), 8.24 (d, J = 2.3 Hz, 1
H), 8.11 (d, J = 2.3 Hz, 1 H), 7.73 (dd, J = 7.4, 2.0 Hz, 1 H), 7.62 (dd, J =
7.7, 1.6 Hz, 1 H), 7.50–7.40 (m, 2 H), 6.84 (d, J = 2.0 Hz, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 146.9, 141.2, 136.9, 131.3, 131.0,
130.4, 130.2, 129.8, 127.4, 127.2, 122.5, 120.9, 101.0.
Brown solid; yield: 47 mg (94%); mp 175–177 °C; HPLC purity 94%.
1H NMR (400 MHz, CDCl3): δ = 8.39 (s, 1 H), 7.69–7.62 (m, 2 H), 7.53
(d, J = 8.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.41–7.31 (m, 2 H), 7.09 (dd,
J = 8.4, 1.8 Hz, 1 H), 6.80 (dd, J = 2.1, 1.0 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 138.0, 136.5, 131.3, 128.5 (2 C), 127.4,
HRMS (ESI): m/z calcd for C13H9Cl2N2+: 263.0143; found: 263.0134.
127.2, 124.5 (2 C), 120.8, 120.4, 110.2, 99.3.
2-Phenyl-1H-indole (2i)
HRMS (ESI): m/z calcd for C14H11ClN+: 228.0580; found: 228.0578.
Brown solid; yield: 49 mg (98%); mp 185–187 °C; HPLC purity 93%.
6-Chloro-2-(p-tolyl)-1H-indole (2o)
1H NMR (400 MHz, DMSO-d6): δ = 11.53 (s, 1 H), 7.86 (dt, J = 8.4, 1.7
Hz, 2 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.40 (d, J = 8.1
Hz, 1 H), 7.34–7.28 (m, 1 H), 7.10 (ddd, J = 8.2, 7.0, 1.3 Hz, 1 H), 7.00
(td, J = 7.5, 6.9, 1.1 Hz, 1 H), 6.90 (d, J = 2.2 Hz, 1 H).
Brown solid; yield: 45.6 mg (91%); mp 145–146 °C; HPLC purity 91%.
1H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 H), 7.57–7.48 (m, 3 H), 7.37
(d, J = 1.8 Hz, 1 H), 7.26–7.23 (m, 1 H), 7.08 (dd, J = 8.4, 1.8 Hz, 1 H),
6.74 (s, 1 H), 2.40 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 137.4, 136.9, 132.0, 128.7 (2 C),
13C NMR (151 MHz, CDCl3): δ = 138.8, 138.0, 137.0, 129.8 (2 C), 129.1,
127.9, 127.7, 125.0 (2 C), 121.3, 120.9, 110.7, 99.3, 21.3.
128.4, 127.2, 124.8 (2 C), 121.4, 119.8, 119.2, 111.1, 98.5.
HRMS (ESI): m/z calcd for C14H12N+: 194.0970; found: 194.0972.
HRMS (ESI): m/z calcd for C15H13ClN+: 242.0737; found: 242.0736.
2-(4-Methoxyphenyl)-1H-indole (2j)
Brown solid; yield: 45.5 mg (91%); mp 225–226 °C; HPLC purity 96%.
2-(4-Methoxyphenyl)-6-methyl-1H-indole (2p)
1H NMR (400 MHz, DMSO-d6): δ = 11.41 (s, 1 H), 7.79 (d, J = 8.4 Hz, 2
H), 7.49 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.08–6.93 (m, 4 H),
6.76 (d, J = 2.1 Hz, 1 H), 3.80 (s, 3 H).
Brown solid; yield: 48 mg (96%); mp 220–221 °C; HPLC purity 94%.
1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.60–7.54 (m, 2 H), 7.48
(d, J = 8.0 Hz, 1 H), 7.17 (td, J = 1.7, 0.9 Hz, 1 H), 6.95 (dd, J = 10.0, 8.3
Hz, 3 H), 6.66 (dd, J = 2.1, 1.0 Hz, 1 H), 3.85 (s, 3 H), 2.46 (s, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 158.6, 137.6, 136.7, 128.6, 126.2 (2
13C NMR (151 MHz, CDCl3): δ = 158.5, 136.7, 136.5, 131.1, 126.6,
125.7 (2 C), 124.8, 121.3, 119.3, 113.8 (2 C), 110.1, 98.0, 54.8, 21.2.
C), 124.7, 120.8, 119.5, 119.0, 114.2 (2 C), 110.9, 97.1, 55.0.
HRMS (ESI): m/z calcd for C15H14NO+: 224.1075; found: 224.1077.
HRMS (ESI): m/z calcd for C16H16NO+: 252.1263; found: 252.1258.
2-(4-Chlorophenyl)-1H-indole (2k)
Brown solid; yield: 45 mg (90%); mp 203–205 °C; HPLC purity 97%.
2-Propyl-7-azaindole (2r)
1H NMR (400 MHz, CDCl3): δ = 8.37–8.20 (m, 1 H), 7.59 (dd, J = 20.4,
8.1 Hz, 3 H), 7.39 (dd, J = 8.2, 4.9 Hz, 3 H), 7.23–7.08 (m, 2 H), 6.80 (d,
J = 2.1 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 136.3, 136.0, 132.8, 130.3, 128.6 (2 C),
128.5, 125.7 (2 C), 122.0, 120.1, 119.8, 110.3, 99.8.
To a sealed tube (10 mL) was added 3-(pent-1-yn-1-yl)pyridin-2-
amine (1r; 50 mg, 0.31 mmol), H2O (2 mL), and AgNO3 (10.5 mg, 0.062
mmol). After ultrasonic oscillation for 5 min, the mixture was stirred
at 130 °C for about 16 h. The solid was filtered and purified by column
chromatography to give a white solid; yield: 31 mg (62%); mp 66–
67 °C; HPLC purity 98%.
1H NMR (400 MHz, CDCl3): δ = 11.82 (s, 1 H), 8.27–8.13 (m, 1 H), 7.86
(d, J = 7.8 Hz, 1 H), 7.05 (dd, J = 7.7, 4.8 Hz, 1 H), 6.21 (s, 1 H), 2.85 (t,
J = 7.6 Hz, 2 H), 1.85 (sext, J = 7.5 Hz, 2 H), 1.04 (t, J = 7.4 Hz, 3 H).
LC-MS (ESI): m/z = 228 (M + H).
HRMS (ESI): m/z calcd for C14H11ClN+: 228.0580; found: 228.0580.
2-(2-Chlorophenyl)-1H-indole (2l)
13C NMR (151 MHz, CDCl3): δ = 148.7, 141.7, 140.1, 128.1, 122.2,
115.5, 97.4, 30.7, 22.3, 13.9.
Brown solid; yield: 46 mg (92%); mp 205–206 °C; HPLC purity 96%.
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.66 (dd, J = 7.7, 1.7 Hz, 2
H), 7.44 (ddd, J = 23.0, 8.0, 1.2 Hz, 2 H), 7.33 (td, J = 7.5, 1.4 Hz, 1 H),
7.29–7.24 (m, 1 H), 7.23–7.19 (m, 1 H), 7.14 (m, 1 H), 6.86 (dd, J = 2.3,
1.1 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 136.3, 135.1, 131.3, 131.1, 130.8,
130.7, 128.8, 128.1, 127.2, 122.6, 120.7, 120.2, 111.0, 103.5.
HRMS (ESI): m/z calcd for C10H13N2+: 161.1079; found: 161.1083.
3-Phenylisoquinolin-1(2H)-one (4a)
Slight yellow solid; yield: 17.6 mg (35%); mp 203–204 °C; HPLC purity
96%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
H. Sun et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 9.95 (s, 1 H), 8.41 (d, J = 8.0 Hz, 1 H),
7.75–7.71 (m, 2 H), 7.68 (dd, J = 7.0, 1.2 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1
H), 7.56–7.45 (m, 4 H), 6.81 (s, 1 H).
13C NMR (151 MHz, CDCl3): δ = 163.2, 138.7, 137.7, 133.6, 132.3,
128.9, 128.7, 126.9 (2 C), 126.1, 125.9, 125.4 (2 C), 124.2, 103.9.
3-(4-Methoxyphenyl)-1H-isochromen-1-one (5c)
Pale yellow solid; yield: 13 mg (25%); mp 111–113 °C; HPLC purity
98%.
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8.1 Hz, 1 H), 7.87–7.79 (m, 2
H), 7.70 (td, J = 7.6, 1.4 Hz, 1 H), 7.46 (ddd, J = 8.1, 4.6, 3.2 Hz, 2 H),
7.00–6.94 (m, 2 H), 6.84 (s, 1 H), 3.87 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12NO+: 222.0919; found: 222.0919.
13C NMR (151 MHz, CDCl3): δ = 161.8, 160.5, 153.1, 137.3, 134.2,
3-(p-Tolyl)isoquinolin-1(2H)-one (4b)
129.0, 127.0, 126.2 (2 C), 125.0, 123.9, 119.5, 113.6 (2 C), 99.6, 54.8.
HRMS (ESI): m/z calcd for C16H12O3+: 252.0786; found: 252.0784.
Slight yellow solid; yield: 25 mg (50%); mp 220–221 °C; HPLC purity
96%.
1H NMR (400 MHz, CDCl3): δ = 10.41 (s, 1 H), 8.40 (d, J = 8.1 Hz, 1 H),
7.69–7.62 (m, 3 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.47 (ddd, J = 8.1, 7.0, 1.2
Hz, 1 H), 7.31 (d, J = 7.9 Hz, 2 H), 6.77 (s, 1 H), 2.43 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 164.1, 139.7, 139.6, 138.5, 132.8,
131.4, 129.9 (2 C), 127.5, 126.5 (2×C), 126.0 (2 C), 124.8, 103.9, 21.3.
Methyl 4-(1-Oxo-1H-isochromen-3-yl)benzoate (5d)
Pale yellow solid; yield: 16 mg (32%); mp 136–138 °C; HPLC purity
99%.
1H NMR (400 MHz, CDCl3): δ = 8.33 (ddd, J = 8.5, 1.3, 0.7 Hz, 1 H),
8.16–8.10 (m, 2 H), 7.99–7.94 (m, 2 H), 7.76 (td, J = 7.7, 1.3 Hz, 1 H),
7.55 (td, J = 7.4, 1.1 Hz, 2 H), 7.07 (s, 1 H), 3.95 (s, 3 H).
HRMS (ESI): m/z calcd for C16H14NO+: 236.1075; found: 236.1089.
13C NMR (151 MHz, CDCl3): δ = 166.4, 152.4, 137.0, 136.0, 135.0,
3-(4-Methoxyphenyl)isoquinolin-1(2H)-one (4c)
131.2, 130.1 (2 C), 129.8, 128.8, 126.3, 125.1 (2 C), 120.9, 103.5, 52.3.
HRMS (ESI): m/z calcd for C17H12O4+: 280.0736; found: 280.0731.
Slight yellow solid; yield: 24 mg (48%); mp 241–242 °C; HPLC purity
94%.
1H NMR (400 MHz, CDCl3): δ = 10.14 (s, 1 H), 8.32 (d, J = 8.1 Hz, 1 H),
7.63–7.57 (m, 3 H), 7.51 (d, J = 8.1 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H),
6.98–6.90 (m, 2 H), 6.67 (s, 1 H), 3.80 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 163.5, 160.1, 138.6, 137.9, 132.3,
126.8, 126.7 (2 C), 126.0, 125.7 (2 C), 123.8, 114.1, 102.9, 54.8.
Funding Information
This work was financially supported by the National Basic Research
Program of China (973 Program, 2015CB931804) and Science and
Technology
Commission
of
Shanghai
Municipality
(No.
HRMS (ESI): m/z calcd for C16H14NO2+: 252.1025; found: 252.1042.
15431900100).
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Supporting Information
Slight yellow solid; yield: 27 mg (54%); mp 261–262 °C; HPLC purity
96%.
1H NMR (400 MHz, DMSO-d6): δ = 11.66 (s, 1 H), 8.22 (dd, J = 8.0, 1.1
Hz, 1 H), 8.09–8.02 (m, 2 H), 7.99–7.93 (m, 2 H), 7.78–7.72 (m, 2 H),
7.53 (ddd, J = 8.2, 4.9, 3.4 Hz, 1 H), 7.07 (s, 1 H), 3.89 (s, 3 H).
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589072.
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13C NMR (151 MHz, DMSO-d6): δ = 165.6, 162.5, 138.6, 137.9, 137.4,
132.6, 129.7, 129.3 (2×C), 126.8 (2×C), 126.8, 126.5, 125.1, 104.4, 52.1.
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Pale yellow solid; yield: 12 mg (24%); mp 110–112 °C; HPLC purity
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7.69 (td, J = 7.6, 1.4 Hz, 1 H), 7.50–7.43 (m, 2 H), 7.24 (s, 2 H), 6.90 (s, 1
H), 2.39 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 161.8, 153.3, 139.6, 137.1, 134.2,
129.0, 128.9 (2 C), 128.6, 127.3, 125.2, 124.6 (2 C), 119.8, 100.4, 20.8.
HRMS (ESI): m/z calcd for C16H12O2+: 236.0837; found: 236.0832.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
H. Sun et al.
Paper
Synthesis
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