Triazole-gold (TAAu) catalyzed three-component coupling (A3 reaction) towards the synthesis of 2, 4-disubstituted quinoline derivatives

Article abstract of DOI:10.1016/j.cclet.2018.05.036

A gold-catalyzed three-component coupling reaction (A3 reaction) was developed as an efficient approach for the synthesis of challenging 2, 4-disubstituted quinoline derivatives. Compared to previously reported Cu/Au bi-catalyst system, this protocol enables achieving A3 reaction only in the presence of triazole-gold catalyst. Notably, 4-alkyl substituted or 2-alkyl substituted quinoline derivatives were obtained with good yields, which highlighted the unique advantage of this new strategy.

Full text of DOI:10.1016/j.cclet.2018.05.036

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CCLET 4568 No. of Pages 3
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Triazole-gold (TAAu) catalyzed three-component coupling
(A3 reaction) towards the synthesis of 2, 4-disubstituted
quinoline derivatives
a,
Fusong Zhanga, Qi Laia, Xiaodong Shib, , Zhiguang Song
*
*
a
Department of Chemistry, Jilin University, Changchun, Jilin 130021, China
Department of Chemistry, University of South Florida, Tampa, FL33620, United States
b
A R T I C L E I N F O
A B S T R A C T
Article history:
A gold-catalyzed three-component coupling reaction (A3 reaction) was developed as an efficient
approach for the synthesis of challenging 2, 4-disubstituted quinoline derivatives. Compared to
previously reported Cu/Au bi-catalyst system, this protocol enables achieving A3 reaction only in the
presence of triazole-gold catalyst. Notably, 4-alkyl substituted or 2-alkyl substituted quinoline
derivatives were obtained with good yields, which highlighted the unique advantage of this new strategy.
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 22 March 2018
Received in revised form 9 May 2018
Accepted 22 May 2018
Available online xxx
Keywords:
Quinoline
Gold catalysis
A3 reaction
Triazole-gold
Multicomponent reactions have been raised tremendous
attention in the past, as it provided efficient ways to construct
complex molecules through a one-pot reaction [1,2]. Among them,
three components coupling reaction of aldehyde, alkyne and
amine, known as A3 coupling reaction, is particularly interesting
[3]. Generally, this protocol contains two sequential steps. The first
step involved the addition of alkyne to imine, which was generated
by aldehyde and amine in situ, to afford propargylic aryl amine
derivatives. Various of metals with Lewis acid properties have been
reported to promote this step, such as Ag, Cu, Fe, etc. [4,5]. The
second step involved the activation of internal alkyne. In the
presence of aryl amine, an intramolecular electrophilic aromatic
substitution to alkyne will take place to furnish the 2, 4-
disubstituted quinoline derivatives under the oxidative conditions
(Scheme 1A) [6]. Quinoline is one category of heterocyclic
structures with interesting biologic activities [7,8]. Therefore, A3
reaction is one of the valuable protocols to quick assemble
quinoline motif. However, the difficulty of internal alkyne
activation makes the cyclization step become challenging.
Gold catalysis has been flourished over the past decade [9,10].
In particular, as an efficient carbophilic Lewis acid, gold(I)
catalysis has facilitated numerous interesting transformations
through the activation of alkynes, allenes, and alkenes [11,12].
Therefore, gold catalyst will be
a good candidate for this
transformation. As shown in Scheme 1A, Wang reported the
first successful example to synthesis 2, 4-disubstituted quinoline
from propargyl amine under gold catalysis conditions [6]. AuCl3
was found to be the optimal catalyst for cyclization of propargyl
amine. However, the overall reaction efficiency was largely
restricted by the stability of gold catalyst. At room temperature, it
took days (4 days) to finish the cyclization. When increasing the
temperature, AuCl3 will decompose quickly into gold mirror or
nano-particles. Microwave assistant was demanded for a fast
reaction kinetic (15 min), however, sacrificing the yield. Another
drawback of AuCl3 is that it could not promote the addition of
alkyne to imine. To achieve the one pot reaction, CuBr was
employed for the alkyne addition. Moreover, the substrate scope
is limited to 2, 4-diaryl-quinoline, due to the problematic internal
alkyl alkyne activation. Recently, Lin and coworkers reported the
synthesis of 4-alkyl-quinoline with the combination of CuCl and
AuCl [13]. Notably, Cu salt is still required to form copper
acetylene addition to imine. Since gold acetylene has already
been widely reported, and the addition of gold acetylene to
various electrophiles, such as oxonium cation, has been well
investigated [14]. It is reasonable to be expected that A3 coupling
reaction could be achieved with gold catalyst alone. One plausible
reason is that Au(I) cation is required for effective gold acetylene
Few metal catalysts have the capability to serve as both Lewis
acid for the first step and p-acid for the internal alkyne activation.
Therefore, a new metal catalyst to promote one-pot reaction is
highly desired.
* Corresponding authors.
E-mail addresses: xmshi@usf.edu (X. Shi), szg@jlu.edu.cn (Z. Song).
https://doi.org/10.1016/j.cclet.2018.05.036
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Zhang, et al., Triazole-gold (TAAu) catalyzed three-component coupling (A3 reaction) towards the synthesis
of 2, 4-disubstituted quinoline derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.05.036

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F. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Table 1
Triazole-gold catalyzed A3 reaction.
a
b
Entry
Varieties from standard condition
Yield
1a convn.
4
5
1
2
3
4
5
6
7
8
None
100%
39%
60%
100%
100%
<10%
<10%
<10%
0%
37%
36%
<5%
<5%
–
90%
0%
22%
79%
67%
–
room temperature
60 o
C
5% PPh3AuNTf2
5% PPh3AuCl/AgOTf
5% AuCl
5% AuCl3
5% PyAuCl2
–
–
–
–
a
Standard condition: 5 mol% catalyst, 1a (1.1 mmol), 2a (1.0 mmol), and 3a
(1.0 mmol) in toluene (1 mL). The reaction mixture was stirred at 110 ꢀC for 24 h.
Scheme 1. A3 Reaction.
b
Yield and conversion was determined by 1H NMR using 1, 3, 5-trimethox-
ybenzene as internal standard.
formation, which more tend to decompose at high temperature.
Our group has a long interest in gold catalysis and demonstrated
the application of triazole-Au complexes as thermally stable
catalysts in challenging alkyne activation under harsh conditions,
such as intermolecular alkyne hydroamination and Hashmi
phenol synthesis [15,16]. Triazole can form a dynamic coordina-
tion with Ph3PAu+ cation, which allows the effective activation of
internal alkyne with improved gold cation stability. Inspired by
previous results, we are wondering if triazole-gold (TAAu) could
be applied in this transformation (Scheme 1B).
With this in mind, our initial attempt was carried out using 1a,
2a, and 3a together with triazole-gold catalyst at room tempera-
ture (Table 1, entry 2). To our delight, the propargyl amine product
was observed with 37% yield with incomplete conversion,
indicating the feasible of gold catalyzed propargyl amine
formation. When raising the temperature to 60 ꢀC, cyclization
product 5a was started to form along with 36% of 4. This result
suggested a higher temperature was required for internal alkyne
activation. The reaction was completed with 90% yield of quinoline
product 5a at 110 ꢀC after 24 h. PPh3AuNTf2 and PPh3AuOTf was
also applied but obtained decreased yield of 5a, mainly due to the
decomposition of Au(I) cation at a high temperature. Some gold(III)
catalysts were also tested and no desired products (either 4 or 5a)
were detected, which suggested that gold acetylene was unable to
be formed from Au(III) cation. Notably, the decomposition of
triazole-gold (by formation of gold mirror) was not observed
during the reaction, which highlighted the thermal stability of
triazole-gold catalyst.
Fig. 1. Substrate scopes. Standard condition: 5 mol% TAAu, 1 (1.1 mmol), 2 (1.0 mmol), and 3 (1.0 mmol) in toluene (1 mL). The reaction mixture was stirred at 110 ꢀC for 24–
36 h. Isolated yield.
Please cite this article in press as: F. Zhang, et al., Triazole-gold (TAAu) catalyzed three-component coupling (A3 reaction) towards the synthesis
of 2, 4-disubstituted quinoline derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.05.036

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CCLET 4568 No. of Pages 3
F. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
With this optimal condition in hand, we further explored the
substrate scope as summarized in Fig. 1. Aryl aldehydes with
different substituents (para, ortho, meta) were tested. Generally,
electron deficient aryl aldehydes afforded better yields due to more
feasible imine formation (5a, 5c). The position of substituents has
no obvious effect (5c, 5f, 5i). Although benzaldehyde provided
modest yield, switching to electro-rich aniline, p-toluidine (5 l) and
p-anisidine (5 m), the yield was increased, indicating the second
cyclization of internal alkyne is the rate limiting step. Besides aryl
aldehydes, aliphatic aldehyde (5 m) were also proved to be
tolerable under this condition. Furthermore, more challenging
alkyne substrates were also evaluated, such as 3-thienylacetlyene
(5n), 1-hexyne (5o), and 1-ethynylcyclohexene (5q), revealing the
excellent capability of TAAu towards internal alkyne activation.
Both propargyl alcohol and homo propargyl alcohol failed to
provide the desired products and only imine was observed. It
might due to the inter/intra molecular cyclization of propargyl
alcohol under TAAu catalysis condition, which diminished gold
acetylene formation. Overall, the success of these substrates
indicated the first example of one-pot A3 reaction under gold
catalysis.
Acknowledgments
We are grateful to the National Science Foundation (No. CHE-
1619590), NIH (No. 1R01GM120240-01) and the National Nature
Science Foundation of China (No. 21629201) for financial support.
We also thank the Development Project of the Pharmaceutical
Industry of Jilin Province (Nos. 20150311070YY, 20170307024YY).
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2018.05.036.
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In conclusion, we disclosed the triazole gold catalyzed A3
coupling reaction to synthesize 2, 4-disubstituted quinoline
derivatives. With this protocol, simple and stable TAAu was used
as catalyst alone for the overall sequential reaction, providing a
broad substrate scope. Notably, 4-alkyl substituted, or 2-alkyl
substituted quinoline derivatives were obtained with good yield,
which highlighted the superior of our triazole-gold catalyst in the
combination of both stability and reactivity.
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Please cite this article in press as: F. Zhang, et al., Triazole-gold (TAAu) catalyzed three-component coupling (A3 reaction) towards the synthesis
of 2, 4-disubstituted quinoline derivatives, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.05.036