Heterogeneous gold(III)-catalyzed tandem cyclization of 2-alkynylbenzamides with ammonium acetate toward 1-aminoisoquinolines

Article abstract of DOI:10.1177/1747519820924736

Heterogeneous tandem cyclization of 2-alkynylbenzamides with ammonium acetate is achieved in acetonitrile at 85 °C using a magnetic nanoparticles-immobilized bipy-gold(III) complex and AgSbF₆ as catalysts to afford a variety of 1-aminoisoquinoline derivatives in moderate to high yields. This heterogeneous gold catalyst can be easily recovered from the reaction mixture by simply applying an external magnetic field and can be recycled at least seven times without any apparent loss of catalytic activity.

Full text of DOI:10.1177/1747519820924736

924736CHL0010.1177/1747519820924736Journal of Chemical ResearchYang et al.
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Journal of Chemical Research
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Heterogeneous gold(III)-catalyzed
tandem cyclization of 2-alkynylbenzamides
with ammonium acetate toward
1-aminoisoquinolines
https://doi.org/10.1177/1747519820924736
DOI: 10.1177/1747519820924736
journals.sagepub.com/home/chl
Weisen Yang1,2, Yingying Du2, Feiyan Yi2
and Mingzhong Cai2
Abstract
Heterogeneous tandem cyclization of 2-alkynylbenzamides with ammonium acetate is achieved in acetonitrile at
85°C using a magnetic nanoparticles-immobilized bipy-gold(III) complex and AgSbF6 as catalysts to afford a variety of
1-aminoisoquinoline derivatives in moderate to high yields. This heterogeneous gold catalyst can be easily recovered
from the reaction mixture by simply applying an external magnetic field and can be recycled at least seven times without
any apparent loss of catalytic activity.
Keywords
1-aminoisoquinolines, gold, heterogeneous catalysis, magnetic nanoparticles, tandem reactions
Date received: 12 January 2020; accepted: 17 April 2020
Fe3O4@SiO2-bipy-AuCl3
(6 mol%)
AgSbF6 (6 mol%)
MeCN, 85oC, Ar, 24 h
O
NH2
NH2
N
R
+
NH4OAc
(3 equiv)
R
R1
R1
2
t
OE
O
O
Cl
C
Si
N
H
N
N
l
e
e
u
F
F
O
4
4
3 O
3
A
Fe3O4@SiO2-bipy-AuCl3
=
O
O
Cl
H
N
SiO2
Si
t
OE
include the domino electrophilic cyclization reactions of
2-alkynylbenzamides9 or 2-alkynylbenzaldoximes10–12 and
transition-metal-catalyzed annulations of benzamidine
derivatives with internal alkynes using rhodium,13,14 ruthe-
nium,15,16 or cobalt17 complexes as catalysts.
Over the past decades, homogeneous gold-catalyzed
organic reactions have become highly efficient and power-
ful tools for the construction of valuable building
blocks.18–22 Recently, gold-catalyzed synthesis of
Introduction
1-AminoisoquinolinesareaclassofimportantN-heterocycles
and exhibit a wide range of biological activities. For
instance, they are inhibitors of thrombin, factor Xa, and rho
kinase-1, and they demonstrate activity toward cancers,
tumors, malaria, and Parkinson’s disease.1–4 There is a high
demand for efficient syntheses of 1-aminoisoquinoline
derivatives for high-throughput drug screening due to
their excellent biological profiles. The most common
method for the preparation of 1-aminoisoquinolines
involves the nucleophilic aromatic substitution reaction of
1-haloisoquinolines with amino compounds.5–8 One main
drawback of this method is that harsh reaction conditions
are required such as the use of strong bases, high reaction
temperatures, or high pressures for the preparation of either
the target products or the starting materials. In recent years,
several alternative approaches have been developed for
the construction of 1-aminoisoquinolines. These methods
1College of Ecology and Resources Engineering, Wuyi University,
Wuyishan, P.R. China
2College of Chemistry & Chemical Engineering, Jiangxi Normal
University, Nanchang, P.R. China
Corresponding author:
Mingzhong Cai, College of Chemistry & Chemical Engineering, Jiangxi
Normal University, Nanchang 330022, P.R. China.
Email: caimzhong@163.com

2
Journal of Chemical Research 00(0)
Et
i
O
(EtO)3Si(CH2)3NH
O
O
N
N
i
S
N
N
H
e
e
F
O
4
3
F
3 O
e
e
F
O
4
F
3 O
4
3
4
(EtO)3Si(CH2)3NH
O
O
H
N
N
i
S O2
i
S O2
S
toluene, 110oC, 24 h
Et
O
Fe3O4@SiO2
Fe3O4@SiO2-bipy
Et
O
O
O
l
C
C
i
S
N
H
N
N
AuCl3
MeOH, reflux
l
e
e
F
O
F
3O4
3
4
Au
O
O
l
C
H
N
SiO2
Si
OEt
Fe3O4@SiO2-bipy-AuCl3
Scheme 1. Preparation of the Fe3O4@SiO2-bipy-AuCl3 complex.
N-heterocycles such as pyrroles,23,24 indoles,25–27 oxa-
zoles,28–30 and quinolines or isoquinolines31,32 has attracted
considerable attention due to its high efficiency and mild
reaction conditions. Long et al. reported the synthesis of
1-aminoisoquinolines by gold(III)-mediated domino reac-
tions from 2-alkynylbenzamides and ammonium acetate.33
However, homogeneous gold catalysts are expensive, not
recyclable, and difficult to recover from reaction mixtures,
which restrict their applications in large-scale or multistep
syntheses. Recycling of homogeneous metal catalysts rep-
resents one of the most important features of green syn-
thetic methods. Immobilization of existing homogeneous
catalysts on various solid supports appears to be a logical
solution to this problem.34 Furthermore, heterogeneous
catalysis can minimize the waste generated from reaction
work-up, thus developing green and sustainable chemical
processes.35 However, to our knowledge, no examples of
the heterogeneous gold-catalyzed synthesis of isoquino-
lines have been reported until now.
To address the problems of catalyst recovery and recy-
cling, magnetic nanoparticles-supported catalysts have
proven to be advantageous because their magnetic separa-
tion is an attractive alternative to conventional filtration as it
avoids loss of the catalyst and improves the reusability.36–38
Recently, we described the preparation of a magnetic nano-
particle-supported bipy-gold(III) complex (Fe3O4@SiO2-
bipy-AuCl3) and its application to the oxidative α-cyanation
of tertiary amines.39 To further expand the application range
of this heterogeneous gold catalyst, herein we report a het-
erogeneous gold(III)-catalyzed tandem cyclization reaction
of 2-alkynylbenzamides with ammonium acetate by using
Fe3O4@SiO2-bipy-AuCl3 and AgSbF6 as the catalysts lead-
ing to 1-aminoisoquinolines in moderate to good yields. The
heterogeneous gold(III) catalyst could be easily recovered
from the reaction mixture by simply applying an external
magnet, and its catalytic activity remains almost unchanged
even after recycling seven times.
Results and discussion
The magnetic nanoparticles-immobilized bipy-gold(III)
complex (Fe3O4@SiO2-bipy-AuCl3) was synthesized by a
simple two-step procedure, as presented in Scheme 1.39 First,
the condensation reaction of silica-coated Fe3O4 (Fe3O4
@SiO2) with 4,4′-bis[3-(triethoxysilyl)propylaminomethyl]-
2,2′-bipyridine (BTESBPY) in toluene at 110°C for 24h pro-
vided the bipyridine-modified magnetic nanoparticles
(Fe3O4@SiO2-bipy). The Fe3O4@SiO2-bipy was then reacted
with AuCl3 in methanol at reflux for 24h to afford the mag-
netic nanoparticles-immobilized bipy-gold(III) complex
(Fe3O4@SiO2-bipy-AuCl3) as brown nanoparticles; the gold
content was found to be 0.62mmolg−1 based on inductively
coupled plasma atomic emission spectroscopy (ICP-AES)
analysis.
The magnetic nanoparticles-immobilized bipy-gold(III)
complex (Fe3O4@SiO2-bipy-AuCl3) was then used as the
catalyst for the tandem cyclization reactions of 2-alkynylb-
enzamides with ammonium acetate. In our initial screens,
the cyclization of 2-(phenylethynyl)benzamide (1a) with
ammonium acetate was chosen as a model reaction to opti-
mize the reaction conditions and the results are summarized
in Table 1. When AuCl3 or AgSbF6 alone was used as the
catalyst, the reaction in MeCN at 85°C gave the desired
product 2a in 53%–62% yields (entries 1 and 2). The reac-
tion did not occur at all in the absence of any catalyst (entry
3). The Fe3O4@SiO2-bipy-AuCl3 complex exhibited simi-
lar activity to AuCl3 and afforded the desired product 2a in
61% yield (entry 4). However, a combination of Fe3O4@
SiO2-bipy-AuCl3 (6mol%) and AgSbF6 (6mol%) proved to
be more efficient than Fe3O4@SiO2-bipy-AuCl3 or AgSbF6
alone and afforded a 88% yield of product 2a (entry 5).
Reducing the reaction temperature to 60°C resulted in a sig-
nificant decrease in the yield (entry 6). We next examined
the effect of solvents on the model reaction. Replacement of
MeCN with other solvents such as 1,2-dichloroethane

Yang et al.
3
Table 1. Optimization of the reaction conditions.a
NH2
O
Catalyst
NH2
N
+
NH4OAc
Solvent, Temp
Ph
a
2
a
1
Ph
Entry
Catalyst (mol%)
Solvent
Temperature (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
AuCl3 (6)
AgSbF6 (6)
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
DME
THF
MeCN
MeCN
85
85
85
85
85
60
85
85
85
85
85
62
53
0
Fe3O4@SiO2-bipy-AuCl3 (6)
61
88
37
13
36
29
81
42
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (6)/AgSbF6 (6)
Fe3O4@SiO2-bipy-AuCl3 (3)/AgSbF6 (3)
10c
11
DCE: 1,2-dichloroethane; DME: 1,2-dimethoxyethane; THF: tetrahydrofuran.
aAll reactions were performed using 1a (0.3mmol), NH4OAc (0.9mmol), and solvent (3mL) under Ar for 24h.
bIsolated yield.
cTwo equivalents of NH4OAc were used.
(DCE), 1,2-dimethoxyethane (DME), and tetrahydrofuran bond and the desired products 2l and 2m were produced in
(THF) furnished 2a in low yields of 13%–36% (entries good yields. Subsequently, a range of 4- or 5-substituted
7–9). Lowering the amount of NH4OAc to 2 equiv. gave a 2-alkynylbenzamides having methyl, methoxy, and fluoro
lower yield of 2a (entry 10). When the amount of the gold groups were then subjected to these reaction conditions and
catalyst was decreased to 3mol%, a moderate yield of 42% all were found to be compatible. For example, 5-methyl-
was obtained (entry 11). Thus, the optimized reaction con- substituted 2-alkynylbenzamides 1n–p and 4-methyl-
ditions for this transformation are the use of Fe3O4@SiO2- substituted 2-alkynylbenzamides 1q–s underwent the
bipy-AuCl3 (6mol%) and AgSbF6 (6mol%) as catalysts in intermolecular cyclization effectively to furnish the corre-
MeCN as the solvent at 85°C under Ar for 24h (entry 5).
sponding 1-aminoisoquinolines 2n–s in good yields. The
Having optimized the reaction conditions, we next reaction of 5-methoxy-substituted 2-alkynylbenzamides
examined the scope of this heterogeneous gold(III)-cata- 1t–v (bearing a strong electron-donating group) gave the
lyzed cyclization reaction using a variety of 2-alkynylben- desired products 2t–v in 63%–70% yields. It is noteworthy
zamides as the substrates and the results are summarized in that 5- or 4-fluoro-substituted 2-alkynylbenzamides 1w–y
Table 2. The cyclization reactions of 2-alkynylbenzamides were also good substrates and afforded the expected prod-
1a–e, bearing various aryl groups at the distal position of ucts 2w–y in 69%–72% yields.
the alkyne triple bond, with ammonium acetate proceeded
To confirm the heterogeneous nature of this reaction,
smoothly under the optimized conditions to afford the cor- we focused on the reaction of 2-(phenylethynyl)benza-
responding 1-aminoisoquinolines 2a–e in 70%–89% yields. mide (1a) with ammonium acetate. After the reaction had
2-Alkynylbenzamide 1e bearing an electron-deficient aryl been conducted for 10h, the catalyst was separated mag-
group showed a comparatively lower reactivity than 2-alky- netically from the reaction mixture at 85°C and the cata-
nylbenzamides 1a–d bearing electron-neutral or electron- lyst-free solution was transferred into another reaction
rich aryl groups. When a bulky naphthyl group was tube and allowed to react further under identical conditions
introduced at the same position of the alkyne triple bond, a for 14h. It was found that no increase in the conversion of
slower reaction was observed and the expected product 2f 2-(phenylethynyl)benzamide (1a) was observed and no
was obtained in only 50% yield. Notably, 2-alkynylbenza- gold species could be detected in the solution based on ICP-
mides 1g, h bearing heteroaryl 3-pyridyl and 3-thienyl AES analysis, which rules out the contribution to observed
groups at the distal position of the alkyne triple bond also catalysis from a soluble gold species and confirms the het-
proved to be suitable substrates and afforded the desired erogeneous nature of this cyclization reaction.
products 2g, h in good yields. Besides, 2-alkynylbenza-
A possible mechanism for this heterogeneous gold(III)-
mides 1i–k bearing an alkyl group at the distal position of catalyzed synthesis of 1-aminoisoquinolines 2 from 2-alky-
the alkyne triple bond were compatible with the standard nylbenzamides 1 and NH4OAc is illustrated in Scheme 2.33
conditions and delivered the corresponding 1-aminoisoqui- First, coordination of the Fe3O4@SiO2-bipy-AuCl3 com-
nolines 2i–k in 72%–80% yields. Interestingly, a sterically plex to alkyne moiety in 2-alkynylbenzamide 1 produces an
hindered tert-butyl group and an alkenyl moiety were well Fe3O4@SiO2-bound gold(III)–alkyne–π complex interme-
accommodated at the distal position of the alkyne triple diate A. The latter undergoes an intramolecular 6-endo-dig

4
Journal of Chemical Research 00(0)
Table 2. Heterogeneous Au(III)-catalyzed synthesis of 1-aminoisoquinolines.a,b
O
NH2
N
Fe3O4@SiO2-bipy-AuCl3 (6 mol%)
NH2
AgSbF6 (6 mol%)
R
+ NH4OAc
(3 equiv)
R
MeCN, 85oC, Ar, 24 h
R1
R1
1
2
NH2
NH2
N
NH2
N
NH2
NH2
N
N
N
2a
2b
, 83%
2c
2d
2e
NH2
, 88%
NH2
N
, 89%
NH2
, 85%
, 70%
O
l
C
NH2
NH2
N
N
N
N
N
S
2f
2g
, 67%
2h
, 85%
2i
2j
, 50%
, 80%
, 78%
NH2
NH2
NH2
NH2
NH2
N
N
N
N
N
N
C
2k
2l
2m
2n
, 75%
2o
, 86%
, 72%
NH2
, 78%
, 74%
NH2
e
M
O
NH2
NH2
NH2
O
N
N
N
N
N
2p
, 74%
2q
, 78%
2r
2s
2t
, 67%
NH2
, 74%
, 70%
F
NH2
NH2
NH2
NH2
F
O
O
F
N
N
N
N
N
F
2x
,72%
2u
, 65%
2v
2w
, 71%
, 63%
2y
, 69%
O
l
C
aReaction conditions: 1 (0.3mmol), NH4OAc (0.9mmol), Fe3O4@SiO2-bipy-AuCl3 (6mol%), AgSbF6 (6mol%), MeCN (3mL), 85 ºC, Ar, 24h.
bIsolated yield.
cyclization to generate an Fe3O4@SiO2-bound vinylgold temperature and diluted with EtOAc. More than 99% of the
cation intermediate B, which is converted to the isobenzo- gold catalyst could be conveniently recovered by simply
pyrylium salt intermediate C after protodeauration. The fixing a magnet to the outside of the reaction tube. The
nucleophilic addition of ammonia to intermediate C pro- recovered gold catalyst was washed with MeCN, air-dried,
vides the isochromene intermediate D. After deprotonation and used directly in the next cycle. The recovered gold cat-
of the ammonium nitrogen atom and protonation of the alyst was employed for seven consecutive cycles under
oxygen atom in intermediate D, isochromenylium interme- identical conditions and the results are summarized in
diate E forms. The C‒O bond in intermediate E dissociates Table 3. As shown in Table 3, the isolated yield of the prod-
to produce enol intermediate F, which subsequently con- uct 2a in eight consecutive cycles was found to be over
verts to intermediate G after deprotonation and tautomer- 83%, which indicated that this heterogeneous gold(III)
izes to ketone intermediate H. Intramolecular nucleophilic catalyst can be recycled up to seven times with only a
addition of the amino group to the ketone carbonyl group slight decrease in the catalytic activity. It is noteworthy that
delivers intermediate I. Finally, intermediate I undergoes the cyclization reaction catalyzed by the recovered gold
dehydration and subsequent aromatization to afford the catalyst did not require the addition of AgSbF6 because the
desired target product 2.
Fe3O4@SiO2-bipy-AuCl3 complex had been transformed
For the practical application of a supported metal cata- into the [Fe3O4@SiO2-bipy-AuCl2]SbF6 complex after the
lyst, its ease of separation from the product and the ability first cycle. The good reusability of the Fe3O4@SiO2-bipy-
to recycle it are important factors that have to be examined. AuCl3 catalyst might arise from the chelating action of the
We next studied the recycling of the Fe3O4@SiO2-bipy- bidentate bipyridine ligand on the gold center.
AuCl3 catalyst in the reaction of 2-(phenylethynyl)benza-
In conclusion, we have developed a novel, efficient, and
mide (1a) with ammonium acetate. Upon completion of practical method for the construction of 1-aminoisoquino-
the reaction, the reaction mixture was cooled to room lines through the gold(III)-catalyzed cyclization reaction of

Yang et al.
5
NH2
NH2
NH2
O
O
LAuCl3
O
R
R
R
L = Fe3O4@SiO2-bipy
R1
R1
R1
1
LAu(III)
LAu(III)
B
A
NH4OAc
NH3
NH2
NH2
NH2
H2N
H3N
1) - H
2) H
H
O
O
HOAc
- LAu(III)
O
R
R
R
R1
R1
R1
H
H
H
E
D
C
NH
NH2
NH
H2N
H2N
H2N
O
H
H
O
O
- H
R
R
R
R
R1
R1
R1
H
H
H
F
G
NH2
NH
NH
- H2O
N
N
NH
R
R
H
O
R1
R1
R1
2
I
J
H
Scheme 2. Proposed catalytic cycle.
Table 3. Recycling of the Fe3O4@SiO2-bipy-AuCl3 complex.a
NH2
O
Fe3O4@SiO3-bipy-AuCl3 (6 mol%)
NH2
N
+
NH4OAc
(3.0 equiv)
oC, Ar, 24 h
MeCN, 85
Ph
a
2
a
1
Ph
Entry
Catalyst
Time (h)
Yield (%)b
Entry
Catalyst
Time (h)
Yield (%)b
1
2
3
4
Fresh
24
24
24
24
88
87
86
87
5
6
7
8
Recycle 4
Recycle 5
Recycle 6
Recycle 7
24
26
28
30
85
84
84
83
Recycle 1
Recycle 2
Recycle 3
aReaction conditions: 1a (0.3mmol), NH4OAc (0.9mmol), Fe3O4@SiO2-bipy-AuCl3 (6mol%), AgSbF6 (6mol%), MeCN (3mL), 85°C, Ar, 24h.
bIsolated yield.
2-alkynylbenzamides with ammonium acetate using a mag-
Experimental
netic nanoparticles-supported gold(III)-bipy complex
All reagents were used as received without further purifica-
[Fe3O4@SiO2-bipy-AuCl3] and AgSbF6 as catalysts. The
tion unless otherwise indicated. 2-Alkynylbenzamides
1a–y were prepared according to a literature method.33 The
reactions produced a variety of 1-aminoisoquinoline deriv-
atives in moderate to high yields under mild conditions.
Fe3O4@SiO2-bipy-AuCl3 complex was prepared according
Importantly, this supported gold catalyst can be easily
to our previous procedure;39 the gold content was found to
recovered by simply fixing an external magnet near to the
be 0.62mmolg−1. All reactions were carried out under Ar in
oven-dried glassware with magnetic stirring. H NMR
spectra were recorded on a Bruker Avance 400 (400 MHz)
spectrometer with TMS as an internal standard using CDCl3
reaction tube and can be recycled up to eight times without
1
any apparent loss of activity. The Fe3O4@SiO2-bipy-AuCl3
catalyst not only solves the basic problems of catalyst sepa-
ration and recovery but also avoids the use of AgSbF6 in the
recycling process. This makes our protocol facile, econom- as the solvent. 13C NMR spectra were recorded on a Bruker
ical, and environmentally benign.
Avance 400 (100MHz) spectrometer using CDCl3 as the

6
Journal of Chemical Research 00(0)
solvent. Microanalyses were measured using a Yanaco
3-(4-Chlorophenyl)isoquinolin-1-amine (2e):40 Light
1
MT-3 CHN microelemental analyzer. The gold content was yellow solid. m.p. 128°C–130°C. H NMR (400MHz,
determined with an inductively coupled plasma atom emis- CDCl3): δ=8.01 (dd, J=6.4, 2.0 Hz, 2H), 7.80 (d, J=8.4Hz,
sion Atomscan16 (ICP-AES, TJA Corporation). HRMS 1H), 7.76 (d, J=8.0Hz, 1H), 7.65–7.60 (m, 1H), 7.51–7.48
spectra were recorded on an AGILENT 6520 Accurate- (m, 1H), 7.47 (s, 1H), 7.43 (dd, J=6.8, 2.0Hz, 2H), 5.23 (br
Mass QTOF LC/MS spectrometer with the electrospray s, 2H). 13C NMR (100MHz, CDCl3): δ=155.9, 148.3,
mode (ES).
138.3, 138.2, 134.2, 130.4, 128.7, 128.1, 127.6, 126.2,
122.6, 117.1, 108.8.
3-(Naphthalen-1-yl)isoquinolin-1-amine (2f):33 Light
yellow solid. m.p. 168°C–170°C. H NMR (400MHz,
CDCl3): δ=8.17 (d, J=8.4Hz, 1H), 7.92–7.85 (m, 2H),
7.80 (d, J=8.0Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.68–7.62
General procedure for the heterogeneous
gold-catalyzed synthesis of 1-aminoiso-
quinolines
1
A 20-mL Schlenk tube was charged with Fe3O4@SiO2- (m, 2H), 7.57–7.42 (m, 4H), 7.29 (s, 1H), 5.34 (br s, 2H).
bipy-AuCl3 (29mg, 0.018mmol), AgSbF6 (6.2mg, 13C NMR (100MHz, CDCl3): δ=155.8, 151.2, 139.1,
0.018mmol), NH4OAc (69mg, 0.9mmol), 2-alkynylbenza- 138.0, 134.0, 131.6, 130.3, 128.4, 128.2, 127.4, 127.2,
mide 1 (0.3mmol), and aceonitrile (3mL) under Ar. The 126.3, 126.1, 126.0, 125.7, 125.4, 122.6, 116.7, 113.3.
reaction mixture was stirred at 85°C for 24h. After being
3-(Pyridin-3-yl)isoquinolin-1-amine (2g):40 Light
1
cooled to room temperature, the resulting mixture was brown solid. m.p. 123 °C–125 °C. H NMR (400 MHz,
diluted with ethyl acetate (10mL) and the supported cata- CDCl3): δ = 9.27 (d, J = 1.6 Hz, 1H), 8.60 (dd, J = 4.8,
lyst was magnetically separated. The reaction solution was 1.6 Hz, 1H), 8.38–8.34 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H),
washed with brine (10mL) and the aqueous phase was 7.78 (d, J = 8.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.53–97.4
extracted with ethyl acetate (2×10mL). The combined (m, 2H), 7.40–7.36 (m, 1H), 5.28 (br s, 2H). 13C NMR
organic layers were dried over anhydrous MgSO4, evapo- (100 MHz, CDCl3): δ = 156.2, 149.1, 148.3, 146.8, 138.0,
rated under reduced pressure, and the residue purified by 135.4, 134.2, 130.6, 127.7, 126.5, 123.5, 122.7, 117.2,
column chromatography on silica gel (eluting with hexane/ 109.3.
ethyl acetate=5:1) to give the desired product 2. The recov-
ered catalyst was washed with MeOH (2×2mL), air-dried, low solid. m.p. 109°C–111°C. 1H NMR (400MHz, CDCl3):
and used directly for the next run.
3-(Thiophen-3-yl)isoquinolin-1-amine (2h):33 Light yel-
δ=7.94 (d, J=2.0Hz, 1H), 7.78 (d, J=8.4Hz, 1H), 7.73 (d,
3-Phenylisoquinolin-1-amine (2a):33 Light yellow solid. J=8.0Hz, 1H), 7.66 (d, J=4.8Hz, 1H), 7.60 (t, J=7.6Hz,
m.p. 91°C–93°C. 1H NMR (400MHz, CDCl3): δ=8.05 (d, 1H), 7.44 (t, J=7.6Hz, 1H), 7.41–7.36 (m, 2H), 5.24 (br s,
J=8.0Hz, 2H), 7.79 (d, J=8.4Hz, 1H), 7.75 (d, J=8.4Hz, 2H). 13C NMR (100MHz, CDCl3): δ=155.9, 145.7, 142.6,
1H), 7.64–7.58 (m, 1H), 7.50–7.41 (m, 4H), 7.39–7.36 (m, 138.3, 130.3, 127.4, 126.1, 126.0, 125.7, 122.8, 122.7,
1H), 5.36 (br s, 2H). 13C NMR (100MHz, CDCl3): δ=155.9, 117.0, 108.4.
148.5, 139.0, 138.1, 130.7, 128.6, 128.4, 127.5, 126.9,
3-Butylisoquinolin-1-amine (2i): Light yellow solid.
1
126.2, 122.9, 117.0, 108.9.
m.p. 104°C–106°C. IR (KBr, cm−1): ν=3380, 3215. H
3-(p-Tolyl)isoquinolin-1-amine (2b):40 White solid. m.p. NMR (400MHz, CDCl3): δ=7.75 (d, J=8.4Hz, 1H), 7.63
1
105°C–107°C. H NMR (400MHz, CDCl3): δ=7.95 (d, (d, J=8.4Hz, 1H), 7.59–7.53 (m, 1H), 7.43–7.37 (m, 1H),
J=8.0Hz, 2H), 7.78 (d, J=8.4Hz, 1H), 7.74 (d, J=8.4Hz, 6.88 (s, 1H), 5.20 (br s, 2H), 2.72 (t, J=7.8Hz, 2H), 1.78–
1H), 7.62–7.57 (m, 1H), 7.46 (s, 1H), 7.45–17.4 (m, 1H), 1.69 (m, 2H), 1.46–71.3 (m, 2H), 0.95 (t, J=7.2Hz, 3H).
7.27 (d, J=8.0Hz, 2H), 5.26 (br s, 2H), 2.40 (s, 3H). 13C 13C NMR (100MHz, CDCl3): δ=155.7, 154.1, 138.2,
NMR (100MHz, CDCl3): δ=155.9, 149.6, 138.3, 138.1, 130.0, 126.7, 125.1, 122.5, 116.2, 109.9, 37.8, 31.9, 22.6,
+
137.1, 130.2, 129.3, 127.5, 126.7, 125.8, 122.6, 116.9, 14.1. HRMS (ESI): m/z [M]+ calcd for C13H16N2 :
108.5, 21.3.
200.1313; found: 200.1309.
3-(4-Methoxyphenyl)isoquinolin-1-amine (2c):33 White
3-(3-Phenylpropyl)isoquinolin-1-amine (2j): Light
1
solid. m.p. 137°C–139°C. H NMR (400MHz, CDCl3): brown solid. m.p. 89°C–91°C. IR (KBr, cm−1): ν=3367,
δ=8.01 (d, J=8.8Hz, 2H), 7.78 (d, J=8.4Hz, 1H), 7.74 (d, 3198. H NMR (400MHz, CDCl3): δ=7.75 (d, J=7.2Hz,
1
J=8.0Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.48–7.41 (m, 2H), 1H), 7.64–7.53 (m, 2H), 7.39 (t, J=7.4Hz, 1H), 7.29–7.15
7.00 (d, J=8.8Hz, 2H), 5.22 (br s, 2H), 3.87 (s, 3H). 13C NMR (m, 5H), 6.85 (s, 1H), 5.45 (br s, 2H), 2.79–2.65 (m, 4H),
(100MHz, CDCl3): δ=159.9, 155.8, 149.3, 138.4, 132.5, 2.13–2.05 (m, 2H). 13C NMR (100MHz, CDCl3): δ=155.8,
130.2, 128.0, 127.4, 125.6, 122.6, 116.7, 114.0, 107.9, 55.4.
153.0, 142.4, 138.1, 130.2, 128.5, 128.3, 126.7, 125.7,
3-(m-Tolyl)isoquinolin-1-amine (2d): Light yellow 125.3, 122.6, 116.3, 109.9, 37.3, 35.6, 31.2. HRMS (ESI):
solid. m.p. 84°C–86°C. IR (KBr, cm−1): ν=3345, 3207. 1H m/z [M]+calcd for C18H18N2 : 262.1470; found: 262.1471.
+
NMR (400MHz, CDCl3): δ=7.88 (s, 1H), 7.83 (d,
4-(1-Aminoisoquinolin-3-yl)butanenitrile (2k):33 Light
1
J=7.6Hz, 1H), 7.80–7.71 (m, 2H), 7.60 (t, J=7.4Hz, 1H), yellow solid. m.p. 106°C–108°C. H NMR (400MHz,
7.47 (s, 1H), 7.44 (t, J=7.6Hz, 1H), 7.35 (t, J=7.6Hz, 1H), CDCl3): δ=7.78 (d, J=8.4Hz, 1H), 7.67–7.57 (m, 2H),
7.19 (d, J=7.2Hz, 1H), 5.29 (br s, 2H), 2.44 (s, 3H). 13C 7.46 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 5.30 (br s, 2H), 2.85
NMR (100MHz, CDCl3): δ=155.9, 149.8, 139.9, 138.3, (t, J = 7.0 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.18–2.10
138.2, 130.3, 129.0, 128.5, 127.6, 127.5, 125.9, 124.0, (m, 2H). 13C NMR (100MHz, CDCl3): δ=156.0, 150.8,
122.6, 117.0, 109.0, 21.6. HRMS (ESI): m/z [M]+ calcd for 138.0, 130.4, 126.8, 125.7, 122.6, 119.7, 116.5, 110.7,
+
C16H14N2 : 234.1157; found: 234.1164.
36.1, 25.0, 16.5.

Yang et al.
7
3-(tert-Butyl)isoquinolin-1-amine (2l):33 Light yellow 5.11 (br s, 2H), 2.48 (s, 3H), 1.37 (s, 9H). 13C NMR
1
oil. H NMR (400MHz, CDCl3): δ=7.73 (d, J=8.4Hz, (100MHz, CDCl3): δ=154.9, 152.6, 138.4, 137.2, 127.4,
1H), 7.65 (d, J=8.4Hz, 1H), 7.57–27.5 (m, 1H), 7.41–7.36 126.4, 122.3, 114.4, 106.0, 36.6, 30.0, 21.8. HRMS (ESI):
+
(m, 1H), 7.01 (s, 1H), 5.15 (br s, 2H), 1.38 (s, 9H). 13C m/z [M]+ calcd for C14H18N2 : 214.1470; found: 214.1468.
NMR (100MHz, CDCl3): δ=161.3, 155.1, 138.2, 129.8,
7-Methoxy-3-phenylisoquinolin-1-amine (2t):33 Light
brown solid. m.p. 126°C–128°C. H NMR (400MHz,
1
127.2, 125.3, 122.4, 116.2, 106.3, 36.7, 30.0.
3-(Cyclohex-1-en-1-yl)isoquinolin-1-amine
(2m):33 CDCl3): δ=8.05–8.02 (m, 2H), 7.70 (d, J=9.2Hz, 1H),
Light yellow oil. 1H NMR (400MHz, CDCl3): δ=7.74 (d, 7.49–7.42 (m, 3H), 7.39–7.33 (m, 1H), 7.30 (dd, J=8.8,
J=8.4Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.59–7.53 (m, 1H), 2.4Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 5.14 (br s, 2H), 3.92
7.43–7.37 (m, 1H), 7.04 (s, 1H), 6.96–6.90 (m, 1H), 5.09 (s, 3H). 13C NMR (100MHz, CDCl3): δ=157.9, 155.0,
(br s, 2H), 2.54–2.49 (m, 2H), 2.34–2.22 (m, 2H), 1.85–1.78 147.5, 139.9, 133.4, 129.2, 128.6, 127.9, 126.6, 122.3,
(m, 2H), 1.73–1.64 (m, 2H). 13C NMR (100MHz, CDCl3): 117.8, 109.0, 101.7, 55.5.
δ=155.1, 150.5, 138.2, 135.6, 130.0, 127.6, 127.4, 125.4,
122.6, 117.1, 107.0, 26.0, 25.9, 23.0, 22.3.
3-(4-Chlorophenyl)-7-methoxyisoquinolin-1-amine
(2u): Light brown solid. m.p. 137°C–139°C. IR (KBr,
7-Methyl-3-phenylisoquinolin-1-amine (2n):33 Light yel- cm−1): ν=3375, 3206. 1H NMR (400MHz, CDCl3): δ=7.96
low oil. 1H NMR (400MHz, CDCl3): δ=7.99 (d, J=7.2Hz, (d, J=8.8Hz, 2H), 7.69 (d, J=9.2Hz, 1H), 7.43–7.39 (m,
2H), 7.67–7.61 (m, 2H), 7.49–7.41 (m, 3H), 7.40–7.35 (m, 3H), 7.31 (dd, J=8.8, 2.4Hz, 1H), 7.06 (d, J=2.0Hz, 1H),
2H), 5.82 (br s, 2H), 2.51 (s, 3H). 13C NMR (100MHz, 5.27 (br s, 2H), 3.94 (s, 3H). 13C NMR (100MHz, CDCl3):
CDCl3): δ=155.7, 147.1, 138.8, 136.3, 136.2, 133.0, 128.6, δ=157.0, 154.0, 145.0, 137.2, 132.8, 132.2, 128.2, 127.6,
128.3, 127.4, 126.9, 122.2, 117.2, 108.8, 21.8.
126.8, 121.4, 116.9, 107.9, 100.7, 54.5. HRMS (ESI): m/z
3-(4-Methoxyphenyl)-7-methylisoquinolin-1-amine [M]+ calcd for C16H13ClN2O+: 284.0716; found: 284.0710.
(2o):33 Light green solid. m.p. 168°C–170°C. H NMR
3-Butyl-7-methoxyisoquinolin-1-amine (2v): Reddish
1
(400MHz, CDCl3): δ=7.98 (d, J=8.8Hz, 2H), 7.63 (d, brown oil. IR (film, cm−1): ν=3371, 3202. H NMR
J=8.0Hz, 1H), 7.56 (s, 1H), 7.43 (d, J=8.0Hz, 1H), 7.37 (400MHz, CDCl3): δ=7.57 (d, J=9.2Hz, 1H), 7.27–7.23
(s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.26 (br s, 2H), 3.85 (s, (m, 1H), 7.01 (d, J=2.0Hz, 1H), 6.86 (s, 1H), 5.02 (br s,
3H), 2.50 (s, 3H). 13C NMR (100MHz, CDCl3): δ=159.5, 2H), 3.91 (s, 3H), 2.70 (t, J=7.8Hz, 2H), 1.75–1.69 (m,
155.3, 148.2, 136.5, 135.4, 132.4, 132.3, 127.9, 127.3, 2H), 1.44–1.38 (m, 2H), 0.95 (t, J=7.4Hz, 3H). 13C NMR
1
121.8, 116.8, 114.0, 107.7, 55.3, 21.8.
(100MHz, CDCl3): δ=157.2, 154.7, 151.8, 133.3, 128.3,
3-Butyl-7-methylisoquinolin-1-amine (2p): Light yel- 122.1, 116.8, 110.0, 101.5, 55.5, 37.6, 32.0, 22.6, 14.1.
low solid. m.p. 76°C–78°C. IR (KBr, cm−1): ν=3325, HRMS (ESI): m/z [M]+ calcd for C14H18N2O+: 230.1419;
3184. 1H NMR (400MHz, CDCl3): δ=7.55–7.49 (m, 2H), found: 230.1417.
7.39 (d, J=8.4Hz, 1H), 6.83 (s, 1H), 5.18 (br s, 2H), 2.70
7-Fluoro-3-phenylisoquinolin-1-amine (2w):33 Light
1
(t, J=7.8Hz, 2H), 2.47 (s, 3H), 1.75–1.68 (m, 2H), 1.44– yellow solid. m.p. 113°C–115°C. H NMR (400MHz,
1.35 (m, 2H), 0.94 (t, J=7.4Hz, 3H). 13C NMR (100MHz, CDCl3): δ=8.06–8.01 (m, 2H), 7.77 (dd, J=8.4, 5.6Hz,
CDCl3): δ=155.2, 153.0, 136.3, 134.8, 132.1, 126.5, 121.7, 1H), 7.50–7.44 (m, 3H), 7.43–7.40 (m, 2H), 7.39–7.36 (m,
116.3, 109.7, 37.6, 31.8, 22.6, 21.7, 14.0. HRMS (ESI): m/z 1H), 5.16 (s, 2H). 13C NMR (100MHz, CDCl3): δ=160.4
[M]+ calcd for C14H18N2 : 214.1470; found: 214.1476.
(d, 1JC-F =245.8Hz), 155.4 (d, 4JC-F =4.9Hz), 149.1 (d, 4JC-
+
3
6-Methyl-3-phenylisoquinolin-1-amine (2q): Reddish F =2.7Hz), 139.6, 135.2, 130.0 (d, JC-F =8.2Hz), 128.7,
2
3
brown solid. m.p. 58°C–60°C. IR (KBr, cm−1): ν=3318, 128.3, 126.8, 120.4 (d, JC-F =24.4Hz), 117.4 (d, JC-
3176. H NMR (400MHz, CDCl3): δ=7.94 (d, J=7.6Hz, F =7.4Hz), 108.6, 106.9 (d, 2JC-F =21.4Hz).
1
2H), 7.53 (d, J=8.4Hz, 1H), 7.40–7.31 (m, 3H), 7.30–7.23
3-Butyl-7-fluoroisoquinolin-1-amine (2x): Brown oil.
(m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.17 (br s, 2H), 2.37 IR (film, cm−1): ν=3377, 3195. 1H NMR (400MHz,
(s, 3H). 13C NMR (100MHz, CDCl3): δ=155.9, 149.8, CDCl3): δ=7.64 (dd, J=8.8, 5.6Hz, 1H), 7.45–7.41 (m,
140.4, 140.2, 138.6, 128.5, 128.1, 127.9, 126.9, 126.7, 1H), 7.39–7.35 (m, 1H), 6.88 (s, 1H), 5.12 (br s, 2H), 2.71
122.5, 115.3, 108.6, 21.7. HRMS (ESI): m/z [M]+ calcd for (t, J=7.8Hz, 2H), 1.76–1.66 (m, 2H), 1.45–1.36 (m, 2H),
C16H14N2 : 234.1157; found: 234.1148.
0.95 (t, J=7.4Hz, 3H). 13C NMR (100MHz, CDCl3):
+
3-(4-Fluorophenyl)-6-methylisoquinolin-1-amine (2r): δ=159.9(d, 1JC-F =244.5Hz), 155.2, 153.2(d, 4JC-F =2.6Hz),
1
3
2
Reddish brown oil. IR (film, cm−1): ν=3376, 3197. H 134.1, 129.1 (d, JC-F =8.1Hz), 120.2 (d, JC-F =24.6Hz),
3
2
NMR (400MHz, CDCl3): δ=8.01 (dd, J=7.6, 5.6Hz, 2H), 116.5 (d, JC-F =7.4Hz), 109.6, 106.7 (d, JC-F =21.4Hz),
7.70 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.29 37.5, 31.8, 22.6, 14.1. HRMS (ESI): m/z [M]+ calcd for
+
(d, J=8.0Hz, 1H), 7.13 (t, J=8.8Hz, 2H), 5.29 (br s, 2H), C13H15FN2 : 218.1219; found: 218.1230.
2.51 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 163.1 (d,
6-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-amine
1JC-F = 245.7 Hz), 155.8, 148.4, 140.7, 138.6, 135.9 (d, (2y): Reddish brown oil. IR (film, cm−1): ν=3245, 3116.
4JC-F =2.8Hz), 130.8, 128.5 (d, 3JC-F =8.0Hz), 128.1, 126.7, 1H NMR (400MHz, CDCl3): δ=7.98 (d, J=8.0Hz, 2H),
122.5, 115.3 (d, 2JC-F =21.4Hz), 108.2, 21.7. HRMS (ESI): 7.79–7.74 (m, 1H), 7.33–7.25 (m, 2H), 7.13 (t, J=8.6Hz,
m/z [M]+ calcd for C16H13FN2 : 252.1063; found:252.1058. 1H), 6.98 (d, J=7.6Hz, 2H), 5.29 (br, 2H), 3.85 (s, 3H). 13C
+
1
3-(tert-Butyl)-6-methylisoquinolin-1-amine (2s): Light NMR (100MHz, CDCl3): δ=163.7 (d, JC-F =249.6Hz),
yellow solid. m.p. 93°C–95°C. IR (KBr, cm−1): ν=3381, 160.3, 155.8, 149.9, 140.3 (d, 3JC-F =10.2Hz), 131.5, 128.9,
1
3
2
3219. H NMR (400MHz, CDCl3): δ=7.65 (d, J=8.4Hz, 128.2, 125.8 (d, JC-F =9.8Hz), 115.4 (d, JC-F =25.0Hz),
2
4
1H), 7.44 (s, 1H), 7.24 (dd, J=8.4, 1.2Hz, 1H), 6.93 (s, 1H), 114.1, 110.8 (d, JC-F =20.7Hz), 107.4 (d, JC-F =4.4Hz),

8
Journal of Chemical Research 00(0)
13. Wei X, Zhao M, Du Z, et al. Org Lett 2011; 13: 4636.
14. Jayakumar J, Parthasarathy K, Chen Y-H, et al. Angew Chem
Int Ed 2014; 53: 9889.
55.4. HRMS (ESI): m/z [M]+ calcd for C16H13FN2O+:
268.1012; found: 268.1015.
15. Li J, John M and Ackermann L. Chem Eur J 2014; 20: 5403.
16. Kaishap PP, Duarah G, Chetia D, et al. Org Biomol Chem
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17. Muralirajan K, Kuppusamy R, Prakash S, et al. Adv Synth
Catal 2016; 358: 774.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
18. Hashmi ASK and Toste FD (eds). Modern gold catalyzed
synthesis. Weinheim: Wiley, 2012.
19. Corma A, Leyva-Perez A and Sabater MJ. Chem Rev 2011;
111: 1657.
20. Dorel R and Echavarren AM. Chem Rev 2015; 115: 9028.
21. Huple DB, Ghorpade S and Liu R-S. Adv Synth Catal 2016;
358: 1348.
22. Pflasterer D and Hashmi ASK. Chem Soc Rev 2016; 45:
1331.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: We
thank the National Natural Science Foundation of China (No.
21462021) and the Natural Science Foundation of Jiangxi Province
of China (No. 20161BAB203086) for financial support.
ORCID iD
23. Ueda H, Yamaguchi M, Kameya H, et al. Org Lett 2014; 16:
4948.
Mingzhong Cai
https://orcid.org/0000-0002-1056-2846
24. Li X, Chen M, Xie X, et al. Org Lett 2015; 17: 2984.
25. Shen CH, Li L, Zhang W, et al. J Org Chem 2014; 79: 9313.
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Supplemental material
Supplemental material for this article is available online.
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