Silver-catalyzed one-step synthesis of multiply substituted quinolines

Article abstract of DOI:10.1016/j.tetlet.2015.12.028

A silver-catalyzed formation of C-C bond for the construction of a series of polysubstituted quinolines from arylamines, aldehydes, and ketones or arylamines and 1,3-diketones has been developed. The transformation is effective for a broad range of substrates, thus enabling the expansion of constituent architectures on the heterocyclic framework. This use of a single catalytic system to mediate chemical transformations in a synthetic operation is important for the development of new atom-economic strategies and this strategy is efficient in building complex structures from simple starting materials in an environmentally benign fashion.

Full text of DOI:10.1016/j.tetlet.2015.12.028

Accepted Manuscript
Silver-catalyzed one-Step Synthesis of Multiply Substituted Quinolines
Xuefeng Xu, Wenmin Liu, Zhiqiang Wang, Yuquan Feng, Yanlei Yan, Xu
Zhang
PII:
S0040-4039(15)30444-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.028
TETL 47075
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 October 2015
5 December 2015
7 December 2015
Please cite this article as: Xu, X., Liu, W., Wang, Z., Feng, Y., Yan, Y., Zhang, X., Silver-catalyzed one-Step
Synthesis of Multiply Substituted Quinolines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.028
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Graphical Abstract
Silver-catalyzed one-Step Synthesis of
Multiply Substituted Quinolines
Xuefeng Xu, Wenmin Liu, Zhiqiang Wang, Yuquan Feng, Yanlei Yan and Xu Zhang*

1
Tetrahedron Letters
Silver-catalyzed one-Step Synthesis of Multiply Substituted Quinolines
Xuefeng Xu, Wenmin Liu, Zhiqiang Wang, Yuquan Feng, Yanlei Yan and Xu Zhang*
School of Chemistry and Pharmacony Engineering, Nanyang Normal University, Nanyang 473061, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A silver-catalyzed formation of C-C bond for the construction of a series of polysubstituted
quinolines from arylamines, aldehydes, and ketones or arylamines and 1,3-diketones have been
developed. The transformation is effective for a broad range of substrates, thus enabling the
expansion of constituent architectures on the heterocyclic framework. This use of a single
catalytic system to mediate chemical transformations in a synthetic operation is important for the
development of new atom-economic strategies and this strategy is efficient in building complex
structures from simple starting materials in an environmentally benign fashion.
Available online
Keywords:
Siver-catalyzed;
Quinoline derivatives;
Amines;
Ketones;
Aldehydes.
1. Introduction
heterocycle forming protocols, we have reported silver-mediated
tandem protocol for the synthesis of quinolines involving the
Silver catalyzed transformations are attractive methodologies
for the synthesis of heterocyclic compounds, and enable the
direct formation of complicated molecules from readily
accessible starting materials under mild conditions, which has
received increased attention in the organic synthesis arena by
virtue of its expanding reactivity patterns that have been
discovered.1 Recently. Indeed, silver-mediated organic
transformations have emerged as an important synthetic tool for
the construction of many architecturally intriguing molecules.2 In
particular, the carbo-, oxo-, and azaphilicity associated with this
precious metal have enabled the generation of functionally
diverse heterocycle compounds, such as quinolines, are
frequently used in medicinal chemistry due to their active roles in
biological systems.3 Quinolines are integral to a large number of
synthetic drug substances with activities including antimalarial,
oxidative coupling/cyclization of N-arylimines and alkynes, and
HOTf catalyzed synthesis quinolines by N-arylimines and
alkenes.15 Although so many methods have been developed with
regard to the modification of quinolines,16 such reactions are
synthetically useful for preparing multifunctionalized quinolines
derivatives and therefore need more studies. Herein, we report a
tandem(domino) reaction course to the synthesis of
multifunctionalized quinolines using arylamines, aldehydes, and
ketones or arylamines and 1,3-diketones (Scheme 1).
Scheme 1. Synthesis of Polysubstituted quinolines.
antiinflammatory,
antineoplastic,
antifungal,
antiseptic/antiinfective, and analgesic properties.4 Due to their
interesting activities, numbers of classical methods, including the
Skraup,5 Doebner-von Miller,6 Doebner,7 Combes,8 Pfitzinger,9
and Friedländer protocols,10 have been used to synthesize the
quinoline core. In recent years, a novel cascade reaction of
nickel-catalyzed Michael addition/deiodination was developed by
the Korivi group.11 Li group have reported for yielding 2,4- and
3,4-substituted quinolines from ortho acylanilines and alkynones,
alkynes or alkenyl iodides catalyzed by Fe, Ag or Cu,
respectively.12 Akio Baba et al. showed that the HCl (cat)-DMSO
system effectively activates carbonyl compounds to give the
quinolines by the sufficient use of an equimolar amount of
imines.13 Uneyama has described synthesis of 3-fluoro-4-
(trifluoromethyl)quinolines from pentafluoropropen-2-ol and
their molecular modification.14 However, the acetophenone did
not give the desired product. During the course of our ongoing
study on the development of transition metal catalyzed
Initially, our initial examination of the reaction among aniline
1 (0.5 mmol), Benzaldehyde 2 (0.5 mmol) and acetophenone 3a
(0.75 mmol) in the presence of AgOTf (0.025 mmol, 5 mol%),
HOTf (0.05 mmol, 10 mol%) in toluene under air afforded 2,6-
diphenylquinoline 4a in 86% yield (entry 1). Several additives
were examined, AgOTf is an indispensable species, and that the
addition of HOTf could greatly improve the yield of the product
(entries 2 - 5). After extensive screening of the reaction
conditions (the silver catalyst, additives, and solvents), it was
concluded that the optimized reaction conditions included the use
of AgOTf as catalyst and HOTf as additive (entries 6 - 11), and
toluene is the solvent of choice for the oxidative
coupling/cyclization tandem sequence and the reaction can be
carried out in air. Other catalysts, such as Pd(OAc)2, FeCl3, and

2
Tetrahedron
Cu(OAc)2, were not effect for this reaction (entries 12 - 14). It
synthesize a variety of substituents quinolines. The broad scope
of quinoline formation was demonstrated by using anilines with a
variety of substituents, such as meta-substituents (-CH3, -F, -CF3),
and para-substituents (-CH3, -OCH3, -Piperidino, -CF3), which
could afford good yields, as shown in Scheme 3. But the
electronic properties of the substituents on the amine exert
certain influence on the yields. Lower yields were generally
observed for substrates with electron-withdrawing substituents as
compared with those with electron-donating substituents. Then,
we elucidated the scope of aldehydes that are applicable for this
reaction. In general, the reactions of aldehyde such as
formaldehyde, acetaldehyde, cyclohexanecarbaldehyde, and
heteroaryl aldehydes (furan-2-carbaldehyde, ferrocene-2-
carbaldehyde) all proceeded smoothly under standard conditions
and gave the expected quinolines in moderate to excellent yields
upon isolation, regardless of the electron-donating or electron-
withdrawing nature of the substituents on the aldehyde ring.
was concluded that the optimized reaction conditions included
the use of AgOTf as catalyst and HOTf as additive, and toluene
is the solvent of choice for the oxidative coupling/cyclization
tandem sequence and the reaction can be carried out in air.
Table 1. Optimization of reaction conditions.a
Temp.
(oC)
Isolated
Yield
Entry
Catalyst
Solvent
1
2
AgOTf/HOTf
AgOTf
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
DMF
120
120
120
80
86%
34%
NR
3
HOTf
4
AgOTf/HOTf
AgOTf/HOTf
AgOTf/HOTf
AgOTf/HOTf
AgOTf/HOTf
AgOTf/HOTf
AgOTf/HOTf
AgNO3/HOTf
Pd(OAc)2/HOTf
FeCl3/HOTf
Cu(OAc)2/HOTf
43%
64%
54%
67%
NR
Scheme 3. Examples of quinoline derivatives synthesis.a
5
100
120
120
80
6
7
8
CH3CN
CCl4
9
80
NR
10
11
12
13
14
Dioxane
Toluene
Toluene
Toluene
Toluene
80
26%
14%
NR
80
120
120
120
NR
NR
a Reaction conditions: aniline 1 (0.5 mmol), benzaldehyde 2 (0.5 mmol),
acetophenone 3a (0.75 mmol), AgOTf (0.025 mol, 5 mol%), HOTf (0.05
mmol, 10 mol%), in toluene (2 mL) at 120 oC in air for 12 h. Yields of
isolated products are reported.
Scheme 2. Proposed mechanism.
a Reaction conditions: arylamine 1 (0.5 mmol), aldehyde 2 (0.5 mmol),
acetophenone 3a (0.75 mmol), AgOTf (0.025 mol, 5 mol%), HOTf (0.05
mmol, 10 mol%), in toluene (2 mL) at 120 oC in air for 12 h. Yields of
isolated products are reported.
The scope of the ketone substrates were next examined in the
coupling with arylamine and aromatic aldehydes. Surprisingly,
acetone as the substrate also worked well, though the product of
4-methyl-2-phenylquinoline 5a in relatively low yield. To our
delight, reactions of arylamines, aromatic aldehydes, and 1-
phenylpropanone proceeded smoothly to give 3,4-disubstituted
quinolines in good to excellent yields. This synthetic method
gives quinolines with high regioselectivity, for the 1-
phenylpropanone, the phenyl group is located in the 4-position
and methyl group to 3-position in the products (5b - 5d). But the
electronic properties of the substituents on the amine influence of
the yields are very obvious. The withdrawing character of the
amine substituents was employed, the yield decrease is relatively
low. Notably, the reaction is not sensitive to steric hindrance, as
the transformation can be effected for an ketone with two phenyl
substituents (5e). For acetylcyclohexan, the cyclohexane group is
located in the 4-position in the product (5f). Cyclic ketone
These results suggest that the plausible mechanism described
in Scheme 2. The acetophenone is in equilibrium with the enol
form, the equilibrium is highly inclined toward the enol form
under the catalyst of silver, the generated enol immediately reacts
with imine (which was easily obtained by condensed the amine
and the aldehyde) to form intermediate D via intramolecular
cyclization. Oxygen in the air apparently acts as an effective
oxidant for aromatization of D to the quinoline product.15
The silver-catalyzed tandem reaction of benzaldehyde, aniline,
and carbonyl compounds give the corresponding quinoline was
successfully extended to various substrates, and the results are
listed in Scheme 3. As indicated, reactions worked well for
various substrates, the scope and limitation of our reaction for the
synthesis of substituted quinolines under the optimized
conditions were examined (Scheme 3). Initially, a range of
anilines were treated with aldyhyde, and acetophenone to

3
compounds all proceeded smoothly to give 3,4-disubstituted
quinolines in good to excellent yields (5h-5l). Interestingly, four-
membered and eight-membered rings were also applicable to this
reaction and stably present in the corresponding quinolines.
the substituents had a significant impact on the yield of the
reaction, regardless of the electron-donating or -withdrawing
ability of the substituents on the arylamine, the reactions were
generated the desired quinolines in high yields.
Scheme 4. Examples of quinoline derivatives synthesis.a
In summary, an efficient and regioselective synthesis of
multiply substituted quinolines from aldehyde, aniline, and
carbonyl compounds, or aniline and 1,3-diketones have been
presented. The yields are practically independent either of the
nature of the ketones used or of its substitution and the electronic
properties of the substituents on the arylamines, aldehydes, and
ketones. The efficiency and functional group tolerance of this
procedure have been fully demonstrated by synthesizing a
number of substituted quinolines. Considering the relatively
inexpensive catalytic system and the commercial availability of
the starting materials, this method should find numerous
applications, including in the industrial field. Further
investigations toward the scope of the reaction, a detailed
mechanism, and applications in organic synthesis are ongoing in
our laboratory.
Acknowledgements
X.Z. gratefully acknowledges support from the National
Natural Science Foundation of China (21502100, 21302105) and
Research fund for the key scientific research program
of Henan Educational Committee (15A150021).
a Reaction conditions: arylamine 1 (0.5 mmol), aromatic aldehydes 2 (0.5
mmol), ketone 3 (0.75 mmol), AgOTf (0.025 mol, 5 mol%), HOTf (0.05
mmol, 10 mol%), in toluene (2 mL) at 120 oC in air for 12 h. Yields of
isolated products are reported.
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4
Tetrahedron
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