An efficient heterogeneous gold(I)-catalyzed intermolecular cycloaddition of 2-aminoaryl carbonyls and internal alkynes leading to polyfunctionalized quinolines

Article abstract of DOI:10.1080/00397911.2019.1567788

The first heterogeneous intermolecular cycloaddition of 2-aminoaryl carbonyls and internal alkynes was realized in DMF at 100 °C by using a triphenylphosphine-functionalized MCM-41-supported gold(I) complex [MCM-41-PPh₃-AuCl] and AgOTf as catal

Full text of DOI:10.1080/00397911.2019.1567788

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
An efficient heterogeneous gold(I)-catalyzed
intermolecular cycloaddition of 2-aminoaryl
carbonyls and internal alkynes leading to
polyfunctionalized quinolines
Wenli Hu, Weisen Yang, Tao Yan & Mingzhong Cai
To cite this article: Wenli Hu, Weisen Yang, Tao Yan & Mingzhong Cai (2019): An efficient
heterogeneous gold(I)-catalyzed intermolecular cycloaddition of 2-aminoaryl carbonyls and
internal alkynes leading to polyfunctionalized quinolines, Synthetic Communications, DOI:
10.1080/00397911.2019.1567788
To link to this article: https://doi.org/10.1080/00397911.2019.1567788
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https://doi.org/10.1080/00397911.2019.1567788
An efficient heterogeneous gold(I)-catalyzed intermolecular
cycloaddition of 2-aminoaryl carbonyls and internal alkynes
leading to polyfunctionalized quinolines
Wenli Hua, Weisen Yanga,b, Tao Yana, and Mingzhong Caia
aKey Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Chemistry
b
and Chemical Engineering, Jiangxi Normal University, Nanchang, China; Fujian Key Laboratory of Eco-
Industrial Green Technology, College of Ecology and Resources Engineering, Wuyi University,
Wuyishan, China
ABSTRACT
ARTICLE HISTORY
Received 20 October 2018
The first heterogeneous intermolecular cycloaddition of 2-aminoaryl
carbonyls and internal alkynes was realized in DMF at 100ꢀC by
using a triphenylphosphine-functionalized MCM-41-supported gold(I)
complex [MCM-41-PPh3-AuCl] and AgOTf as catalysts, yielding a var-
iety of polyfunctionalized quinolines in good to excellent yields. This
heterogeneous gold(I) complex could easily be prepared via a simple
two-step procedure from commercially available reagents and recov-
ered by filtration of the reaction mixture. The recovered catalyst
could be reused at least seven times with almost consistent activity
without addition of AgOTf as a cocatalyst.
KEYWORDS
Cycloaddition; gold;
heterogeneous catalysis;
internal alkynes; quinoline
GRAPHICAL ABSTRACT
Introduction
Quinolines, existing in many biologically active compounds and pharmaceuticals,[1] are
a significant class of annulated six-membered nitrogen heterocycles. Quinoline-contain-
ing natural products have many interesting biological activities and are widely used as
antibacterial,[2] antifungal,[3] antimalarial,[4] anti-inflammatory,[5] antiepileptic,[6]
CONTACT Mingzhong Cai
caimzhong@163.com
Key Laboratory of Functional Small Organic Molecule, Ministry of
Education and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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W. HU ET AL.
analgesic,[7] and antitumor drugs.[8] Based on the high importance of quinoline and its
derivatives, the development of various methods for their synthesis has attracted great
interest. Consequently, many named reactions have been developed, including Skraup,[9]
Doebner-von Miller,[10] Conrad-Limpach,[11] Pfitzinger,[12] and Friedlander concentra-
tion syntheses.[13] However, these classical methods suffer from some drawbacks such as
harsh reaction conditions, hazardous reagents in stoichiometric amounts, a limited sub-
strate scope, and poor functional tolerance. Recently, transition metal-catalyzed con-
struction of quinolines was extensively investigated and a variety of transition metals,
including Pd,[14] Rh,[15] Ru,[16] Ag,[17] In,[18] Co,[19] Cu,[20] Fe,[21] and Ni[22] salts have
been used as catalysts for quinoline synthesis. Besides, metal-free coupling/cyclization
strategy has also emerged as one of the most powerful tools for the construction of
quinoline framework.[23] Although significant progress has been achieved for the syn-
thesis of quinoline derivatives, most of these known methods are confined for the lack
of generality, the use of non-readily available starting materials, and limited functional
group tolerance, especially for the construction of multisubstituted quinolines.
Therefore, the development of versatile and efficient methodologies to construct multi-
substituted quinoline derivatives from readily available starting materials still remains a
demanding goal due to their high significance.
During the past two decades, homogeneous gold-catalyzed organic reactions have
become a powerful tool for the preparation of valuable building blocks.[24] Recently,
gold-catalyzed synthesis of heterocyclic compounds, including furans,[25] pyrroles,[26]
indoles,[27] oxazoles,[28] and quinolines[29] has received much attention because of their
high efficiency and mild reaction conditions, which greatly enriched the synthetic meth-
odologies of heterocyclic compounds. However, applications of these homogeneous gold
complexes in large-scale synthesis or multistep syntheses remain a challenge because
expensive gold catalysts are difficult to separate and are difficult to recycle. In homoge-
neous catalysis, this problem in part can be avoided by highly active catalysts, which
need only low catalyst loadings.[30] Recycling of homogeneous metal catalysts, especially
expensive and/or toxic heavy metal complexes, is a task of great economic and environ-
mental significance in the chemical and pharmaceutical industries. This is achieved for
hydroformylation (18 megatonnes yearly volume) for an Rh catalyst on the bulk chem-
ical scale, the same applies to the Karstedt’s catalyst (Platinum) for the homogeneous
hydrosilylation to form different silicones for technical applications on large scale, too.
Both are very efficiently recycled from homogeneous catalysis reactors with minimum
loss of metal. Immobilization of the existing homogeneous gold catalysts on various
supports appears to be an attractive solution to this problem.[31] Very recently, we
reported the synthesis of a triphenylphosphine-functionalized MCM-41-supported
gold(I) complex [MCM-41-PPh3-AuCl] and found that it is a highly efficient and recyc-
lable catalyst for the direct Csp2–Csp bond functionalization of aryl alkynes through a
nitrogenation process to amides with TMSN3 as a nitrogen source.[32] In order to fur-
ther expand the application of this heterogeneous gold(I) catalyst in organic synthesis,
herein we report an efficient, heterogeneous Au(I)-catalyzed intermolecular cycloadd-
ition of 2-aminoaryl carbonyls and internal alkynes by using MCM-41-PPh3-AuCl and
AgOTf as catalysts, providing polyfunctionalized quinolines in good to excellent yields
(Scheme 1).

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Scheme 1. Heterogeneous gold(I)-catalyzed synthesis of polysubstituted quinolines.
Scheme 2. Preparation of MCM-41-PPh3-AuCl complex.
Results and discussion
The MCM-41-PPh3-AuCl complex was prepared by a simple two-step procedure from
readily available reagents as shown in Scheme 2.[32] The condensation of mesoporous
MCM-41 with 1-(4-(diphenylphosphino)phenyl)-3-(3-(triethoxysilyl)propyl)urea in tolu-
ene at 110 ꢀC for 24 h, followed by silylation with Me3SiCl in toluene at room tempera-
ture for 24 h generated a triphenylphosphine-functionalized MCM-41 [MCM-41-PPh3].
The latter was then reacted with Me2SAuCl in dichloromethane (DCM) at room tem-
perature for 8 h to afford the MCM-41-supported phosphine gold(I) complex [MCM-
41-PPh3-AuCl] as a gray powder. The gold content of the complex was determined to
be 0.39 mmol gꢁ1 by ICP-AES analysis.
The MCM-41-supported phosphine gold(I) complex [MCM-41-PPh3-AuCl] was then
used as a catalyst for the intermolecular cycloaddition of 2-aminoaryl carbonyls and
internal alkynes. Initial experiments with 2-aminobenzaldehyde 1a and ethyl 3-phenyl-
propiolate 2a were performed to optimize the reaction conditions, and the results are
summarized in Table 1. At first, various heterogeneous gold(I) complexes as catalysts
were tested at 100 ꢀC in DMF as solvent (entries 1–6). When MCM-41-PPh3-AuCl was
used as a catalyst, the desired product 3a was not detected (entry 1). Silver salts as addi-
tives have been known to complement gold catalysts by increasing the electrophilicity of
the gold center through halide abstraction. When various silver salts such as AgNO3,
AgOTf, AgNTf2, AgBF4, and Ag2CO3 were used as co-catalysts, AgOTf was the best
choice and the desired 3a was obtained in 86% isolated yield (entry 3), while other
silver salts were less effective and Ag2CO3 was not effective (entries 2 and 4–6).

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W. HU ET AL.
Table 1. Cycloaddition of 2-aminobenzaldehyde and ethyl 3-phenylpropiolate in different condi-
tions.a
Entry
Silver salt (mol%)
Solvent
Temp. (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
–
AgNO3 (10)
AgOTf (10)
AgNTf2 (10)
AgBF4 (10)
Ag2CO3 (10)
AgOTf (10)
–
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (5)
AgOTf (20)
AgOTf (10)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
THF
CH2Cl2
DMAc
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
80
67
45
100
80
60
12
12
4
6
8
12
12
4
12
12
24
12
8
12
3
12
2
0
8
86
75
47
0
5
6
7c
8d
9
0
87
56
45
11
64
77
63
84
81
85
87
10
11
12
13
14
15
16
17
18e
110
100
100
100
3
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), MCM-41-PPh3-AuCl (10 mol%), silver salt (10 mol%), solvent (5 mL),
under Ar.
bIsolated yield.
cWithout MCM-41-PPh3-AuCl.
d10 mol% of MCM-41-PPh3-AuOTf was used as a catalyst.
ePh3PAuCl (10 mol%) was used instead of 10 mol% of MCM-41-PPh3-AuCl.
When AgOTf alone was used as the catalyst, no reaction was observed (entry 7). These
results indicated that the real catalyst for this transformation was MCM-41-PPh3-
AuOTf, generated in situ from MCM-41-PPh3-AuCl and AgOTf. In order to further
confirm that the supported AuOTf is the real catalyst, we prepared MCM-41-PPh3-
AuOTf by the reaction of MCM-41-PPh3-AuCl with AgOTf in DCM at 25 ꢀC for 0.5 h
and employed it as the catalyst, the desired product 3a was isolated in 87% yield after
4 h (entry 8). Our next studies focused on the effect of solvent on the model reaction
and a significant solvent effect was observed (entries 9-12). Replacement of DMF with
other solvents such as MeCN, THF, and DMAc resulted in decreased yields, and
CH2Cl2 was less effective, so DMF as a solvent was the most efficient (entry 3). When
reaction temperature was reduced to 80 or 60 ꢀC, lower yields were obtained and longer
reaction times were required (entries 13 and 14). Raising the temperature to 110 ꢀC also
resulted in a slightly decreased yield (entry 15), thus, the reaction temperature was fixed
at 100 ꢀC. Finally, the gold catalyst and silver additive loadings were screened. When
the loadings were decreased to 5 mol%, a slightly decreased yield of 81% was observed
and the reaction time was prolonged to 12 h (entry 16). The increase of the loadings to
20 mol% could shorten the reaction time but did not improve the yield (entry 17).
When a homogeneous Ph3PAuCl (10 mol%)/AgOTf (10 mol%) catalytic system was
used, the desired 3a was also isolated in 87% yield (entry 18), indicating that the

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Table 2. Heterogeneous gold(I)-catalyzed cycloaddition of ethyl 3-phenylpropiolate and various
2-aminoaryl carbonyls.a,b
aReaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), MCM-41-PPh3-AuCl (10 mol%), AgOTf (10 mol%) in DMF (5 mL) at
100 ꢀC under Ar for 4 h.
bIsolated yield.
catalytic activity of MCM-41-PPh3-AuOTf was comparable to that of Ph3PAuOTf.
Therefore, the optimized reaction conditions for this transformation are the use of
10 mol% of MCM-41-PPh3-AuCl/AgOTf in DMF as solvent at 100 ꢀC for 4 h (Table 1,
entry 3).
With the optimal reaction conditions (10 mol% of MCM-41-PPh3-AuCl/AgOTf in
DMF at 100 ꢀC for 4 h) in hand, we started to investigate the scope of this heteroge-
neous gold(I)-catalyzed cycloaddition reaction by using a variety of 2-aminoaryl carbon-
yls and internal alkynes as substrates. First, the scope of 2-aminoaryl carbonyls was
examined with ethyl 3-phenyl propiolate 2a as a substrate. As shown in Table 2, the
reaction of 20-aminoacetophenone 1 b with 2a proceeded smoothly under the standard
conditions to give the desired product 3 b in 91% yield. 2-Aminobenzophenone 1c dis-
played a similar reactivity with 20-aminoacetophenone 1 b and afforded the target prod-
uct 3c in 90% yield. 40-Methyl- or 40-chloro-substituted 2-amino benzophenones 1d and
1e were also suitable substrates and produced the corresponding products 3d and 3e in
81–87% yields. Notably, bulky (2-aminophenyl)(naphthalene-2-yl)methanone 1f also
reacted well in this transformation, thus providing the expected product 3f in good
yield. In addition, 5-halo-substituted 2-amino benzophenones 1 g and 1 h were compat-
ible with the standard conditions and furnished the corresponding products 3 g and 3 h
in slightly lower yields than 2-amino benzophenone 1c, presumably due to the presence
of electron-withdrawing halo groups, which decreasing the nucleophilicity of
amino group.

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W. HU ET AL.
Table 3. Heterogeneous gold(I)-catalyzed cycloaddition of 2-aminobenzaldehyde or 2’-aminoaceto-
phenone with various internal alkynes.a,b
.
aReaction conditions: 1a or 1b (0.5 mmol), 2 (0.75 mmol), MCM-41-PPh3-AuCl (10 mol%), AgOTf (10 mol%) in DMF (5 mL)
at 100 ꢀC under Ar for 4 h.
bIsolated yield.
Under the optimized reaction conditions, we next examined the scope of internal
alkynes by using 2-amino benzaldehyde 1a and 20-aminoacetophenone 1 b as substrates
and the results are summarized in Table 3. The reactions of 2-amino benzaldehyde 1a
with various substituted ethyl 3-phenylpropionates bearing either electron-donating or
electron-withdrawing groups 2b–2e proceeded smoothly under the optimized reaction
conditions to give the corresponding quinolines 3i–3l in 79–92% yields. The reactivity
of ethyl 3-phenylpropiolates bearing electron-donating substituents was higher than that
of ones bearing electron-withdrawing substituents, but the difference is less significant
and good yield was acquired even for ethyl 3-(4-nitrophenyl)propiolate 2e.
Furthermore, bulky ethyl 3-(naphthalen-1-yl)propiolate 2f also reacted well in this
transformation, thus giving the desired product 3 m in 83% yield. In addition, alkyl
alkynes displayed a similar reactivity with aryl alkynes. For example, the reaction of
ethyl but-2-ynoate 2 g with 1a gave the expected product 3n in a high yield of 87%.
Besides ethyl propiolates, 4-phenylbut-3-yn-2-one 2 h was also compatible with the

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standard conditions and gave the target product 3o in good yield. Subsequently, the
reactions of 2’-aminoacetophenone 1 b with various internal alkynes were carried out
and the results are also listed in Table 3. As expected, the reactions of 2’-aminoaceto-
phenone 1 b with various ethyl propiolates 2 b and 2d-2g proceeded smoothly to pro-
vide the corresponding polysubstituted quinolines 3p-3t in good to excellent yields.
Notably, the reaction also worked well with alkyl- or cyclopropyl-substituted methyl
propiolates 2i and 2j, producing the desired quinolines 3 u and 3v in 88 and 80% yield,
respectively. Although 4-phenylbut-3-yn-2-one 2h and bulky ethyl 3-(naphthalen-1-yl)pro-
piolate 2f showed a slightly lower reactivity than ethyl 3-phenylpropiolate 2a, the
reactions with 2-amino benzophenone 1c could proceeded effectively to give the desired
products 3w and 3x in good yields. The present method provides a facile, general and
practical procedure for the construction of polysubstituted quinoline derivatives.
It would be a concern if the leaching of active gold species into the solution is sub-
stantial. A hot-filtration experiment[33] was performed to examine the leaching of gold
species from MCM-41-PPh3-AuOTf. For this, the intermolecular cycloaddition reaction
of 2-amino benzaldehyde 1a and ethyl 3-phenylpropiolate 2a was carried out until a
conversion of approximately 40%. Then the catalyst was removed from the reaction
mixture by filtration at the reaction temperature (100 ꢀC) and the catalyst-free solution
was again stirred at 100 ꢀC for 4 h. In this case, no significant increase in conversion of
1a was observed, indicating that leached gold species from the catalyst (if any) are not
responsible for the observed activity. It was further confirmed by ICP-AES analysis that
no gold species could be detected in the clear solution. These results exclude any contri-
bution to the observed activity from the leached gold species, indicating that MCM-41-
PPh3-AuOTf was stable during the cycloaddition reaction, and the observed catalysis
was intrinsically heterogeneous.
A plausible reaction mechanism for this heterogeneous gold(I)-catalyzed intermolecu-
lar cycloaddition is shown in Scheme 3. Firstly, coordination of the MCM-41- PPh3-
AuOTf catalyst to internal alkyne 2 and subsequent hydroamination reaction with
2-aminoaryl carbonyl 1 generates an MCM-41-immobilized vinyl gold cation intermedi-
ate A. Then, intermediate A undergoes protonolysis of the Au–C bond via a 1,3-proton
shift, followed by recoordination of the gold(I) catalyst to oxygen atom of the carbonyl
to provide intermediate B. Subsequently, the intramolecular enamine addition of inter-
mediate B occurs to produce intermediate C, which undergoes 1,5-proton shift to form
intermediate D and regenerate the gold(I) catalyst. Finally, dehydration of intermediate
D readily happens to afford the desired quinoline 3.
From the green and sustainable chemistry point of view, the recyclability of MCM-
41-PPh3-AuOTf was evaluated in the reaction between 2-amino benzaldehyde 1a and
ethyl 3-(4-methoxyphenyl)propiolate 2c under the optimized conditions. After the first
reaction cycle, filtration of the reaction mixture followed by washing of the resulting
solid with NH3ꢂH2O, distilled water and acetone allowed the easy recovery of the
gold(I) catalyst. The recovered catalyst could be recycled up to seven times, and
almost the same yield of 3j was observed (Fig. 1). It is noteworthy that the reaction
catalyzed by the recovered catalyst didn’t need the addition of AgOTf because the
MCM-41-PPh3-AuCl had been converted into the MCM-41-PPh3-AuOTf after the
first cycle.

8
W. HU ET AL.
Scheme 3. Proposed catalytic cycle.
100
80
60
40
20
0
1
2
3
4
5
6
7
8
Reaction cycles
Figure 1. Recycle of the MCM-41-PPh3-AuOTf catalyst.
Conclusions
In summary, we have developed a highly efficient heterogeneous gold(I)-catalyzed inter-
molecular cycloaddition of 2-aminoaryl carbonyls and internal alkynes leading to poly-
functionalized quinolines, which are commonly found in many bioactive molecules.
This heterogeneous intermolecular cycloaddition has many attractive features, such as:
(1) the substrate scope is broad, and a wide range of 2-aminoaryl carbonyls and internal

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9
alkynes are allowed; (2) a variety of quinoline derivatives were obtained in good to
excellent yields; (3) this intermolecular cyclization of internal alkynes allowed the effi-
cient integration of more functional groups into quinolines; (4) the heterogeneous
gold(I) catalyst can easily be prepared via a simple procedure from commercially avail-
able reagents and recovered by filtration of the reaction solution. The recovered catalyst
[MCM-41-PPh3-AuOTf] can be reused at least seven times with almost consistent activ-
ity. Our catalytic system not only solves the basic problems of catalyst recovery and
recycle but also avoids the use of AgOTf as a co-catalyst in recycling process.
Experimental
All reagents were obtained from commercial sources without further purification, and
commercially available solvents were purified by distillation. All reactions were con-
ducted under an atmosphere of argon. The products were purified by flash chromatog-
raphy on silica gel. Mixture of EtOAc and light petroleum ether was generally used as
1
eluent. H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 MHz
spectrometer with TMS as an internal standard in CDCl3 as a solvent. HRMS spectra
were recorded on a Q-Tof spectrometer with micromass MS software using electrospray
ionization (ESI). Gold content was determined with inductively coupled plasma atom
emission Atomscan16 (ICP-AES, TJA Corporation).
Preparation of MCM-41-PPh3-AuCl
To a suspension of the mesoporous MCM-41 (2.1 g) in dry toluene (120 mL) was added
1-(4-(diphenylphosphino)phenyl)-3-(3-(triethoxysilyl)propyl)urea (0.788 g, 1.5 mmol).[32]
The mixture was then stirred at 110 ꢀC for 24 h under Ar. The resulting solid material
was filtered, washed with CHCl3 (20 mL), and dried in vacuum at 140 ꢀC for 3 h. The
dried solid powder was then soaked in a solution of Me3SiCl (3.0 g) in dry toluene
(90 mL) with stirring at room temperature for 24 h. The resulting product was filtered,
washed with acetone (3 ꢃ 20 mL), and dried in vacuum at 100 ꢀC for 6 h to afford
2.621 g of hybrid material MCM-41-PPh3. The phosphine content was found to be
0.47 mmol gꢁ1 by elemental analysis.
In a small Schlenk tube, MCM-41-PPh3 (1.12 g) was mixed with Me2SAuCl (125 mg,
0.42 mmol) in dry CH2Cl2 (40 mL). The reaction mixture was stirred at room temperature
for 8 h under Ar. The resulting solid product was filtered, washed with CH2Cl2 (2 ꢃ 10 mL),
and dried at 80 ꢀC in vacuum for 5 h to afford 1.153 g of a gray gold(I) complex [MCM-41-
PPh3-AuCl]. The gold content was determined to be 0.39 mmol gꢁ1 by ICP-AES.
General procedure for the heterogeneous Au(I)-catalyzed synthesis
of quinolines
To a solution of 2-aminoaryl carbonyl 1 (0.5 mmol), MCM-41-PPh3-AuCl (128 mg,
0.05 mmol), AgOTf (12.9 mg, 0.05 mmol) in DMF (5 mL) was added internal alkyne 2
(0.75 mmol) under Ar. The reaction mixture was stirred at 100 ꢀC for 4 h (TLC moni-
tored). The resulting mixture was then diluted with ethyl acetate (20 mL) and filtered.
The gold catalyst was washed with NH3ꢂH2O (2 ꢃ 5 mL), distilled water (5 mL), and

10
W. HU ET AL.
acetone (2 ꢃ 5 mL) and reused in the next run. The filtrate was washed with water
(2 ꢃ 10 mL) and brine (2 ꢃ 10 mL), and the organic layers were dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was purified by chroma-
tography on silica gel (eluent: petroleum ether/ethyl acetate ¼ 15/1) to afford the
desired product 3.
1
The characterization data and copies of H and 13C NMR spectra of products 3a-x
have been provided in supplementary material.
Funding
We thank the National Natural Science Foundation of China [No. 21462021], the Natural
Science Foundation of Jiangxi Province of China [No. 20161BAB203086] and Key Laboratory of
Functional Small Organic Molecule, Ministry of Education [No. KLFS-KF-201704] for finan-
cial support.
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