One-pot synthesis of 2,4-disubstituted quinolines via silver-catalyzed three-component cascade annulation of amines, alkyne esters and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2019.03.003

Described herein is a new and general method for one-pot synthesis of 2,4-disubstituted quinolines via silver-catalyzed [3 + 1 + 2] annulation of simple amines, alkyne esters and terminal alkynes. The versatile transformation might initiate with the facil

Full text of DOI:10.1016/j.tetlet.2019.03.003

Accepted Manuscript
One-pot synthesis of 2,4-disubstituted quinolines via silver-catalyzed three-
component cascade annulation of amines, alkyne esters and terminal alkynes
Yunlan Li, Qiurui Zhang, Xuefeng Xu, Xu Zhang, Yurong Yang, Wei Yi
PII:
S0040-4039(19)30203-5
https://doi.org/10.1016/j.tetlet.2019.03.003
TETL 50644
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 November 2018
26 February 2019
1 March 2019
Please cite this article as: Li, Y., Zhang, Q., Xu, X., Zhang, X., Yang, Y., Yi, W., One-pot synthesis of 2,4-
disubstituted quinolines via silver-catalyzed three-component cascade annulation of amines, alkyne esters and
terminal alkynes, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.003
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Graphical Abstract
One-pot synthesis of 2,4-disubstituted
quinolines via silver-catalyzed three-
component cascade annulation of amines,
alkyne esters, and terminal alkynes
Yunlan Li,a Qiurui Zhang,a Xuefeng Xu,a Xu Zhang,a,** Yurong Yangb and Wei Yib*
CO2Me
NH2
N
R2
R1
R1
HN
R2
[Ag]
+
R3
R3
H
identified
R2
CO2Me
40 examples
R1
(up to 99% yield)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot synthesis of 2,4-disubstituted quinolines via silver-catalyzed three-
component cascade annulation of amines, alkyne esters and terminal alkynes
Yunlan Li,a Qiurui Zhang,a Xuefeng Xu,a Xu Zhang,a,  Yurong Yangb and Wei Yib,
aSchool of Chemistry and Pharmacony Engineering, Nanyang Normal University, Nanyang 473061, China.
bKey Laboratory of Molecular Target and Clinical Pharmacology & State Key Laboratory of Respiratory Disease,, School of Pharmaceutical
Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +086-020-37104196; fax: +086-020-37104196; e-mail: yiwei@gzhmu.edu.cn
 Corresponding author. Tel.: +086-0377-63513540; fax: +086-0377-63513540; e-mail: zhangxuedu@126.com
Article history:
Received
Described herein is a new and general method for one-pot synthesis of 2,4-disubstituted
quinolines via silver-catalyzed [3+1+2] annulation of simple amines, alkyne esters and terminal
Received in revised form
Accepted
Available online
alkynes. The versatile transformation might initiate with the facile formation of the enamine
species with the feature of good to excellent yields, exclusive regioselectivity, and excellent
substrate/functional group tolerance.
Keywords:
AgOTf catalyst;
Amines;
Alkyne esters;
Terminal alkynes;
2,4-disubstituted quinolines.
1. Introduction
pot and with excellent regioselectivity. In general, the mandatory
introduction of both a proximal directing group and an external
Quinoline, structurally belonging to the N-heterocycle family,
is one of commonly occurring structural motif found in numerous
natural and unnatural products, which displayed highly attractive
biological and medicinal properties including antimalarial,
antibacterial, antifungal, anthelmintic, cardiotonic, anti-
inflammatory and anticancer.1 Besides, the quinoline nucleus is
also existed in a variety of synthetically and functionally valuable
molecular skeletons such as chiral ligands,2 phosphorescent
materials3 and fluorosensors.4 Therefore, the development of
efficient methods towards its construction has become a hot topic
in modern organic synthesis. As a consequence, a plethora of
classical procedures including many well-known name reactions
have been established for the synthesis of quinoline framework.5-
oxidant is indispensable for achieving the desired ortho C−H
bond functionalization, which to some extent limited their
synthetic utility. Moreover, terminal alkynes are commonly
incompatible in most of transition-metal-catalyzed cases because
the undesired homocoupling of terminal alkynes often occurs
under transition-metal-catalyzed oxidative conditions.9 Clearly,
more efforts are needed to explore and develop new and suitable
transition-metal-catalyzed direct strategies for building the
privileged quinoline unit without the assistance of the directing
group by taking advantage of ubiquitous terminal alkynes as the
efficient coupling partners with the reaction of other basic
chemical starting material.
6
In 2013, Su group reported a beautiful Pd-catalyzed cross-
coupling example for direct alkynylation of heterocycles with
terminal alkynes, in which they found that the introduction of a
proper bronsted acid could efficiently diminish the undesired
homocoupling of the terminal alkyne substrate by inhibiting the
dissociation of relatively acidic terminal proton.10 A similar
finding has also been observed in our recent study.11 More
recently, we have revealed a Pd-catalyzed three-component
cascade reactions of simple amines, alkyne esters with terminal
alkenes for one-pot synthesis of pyrroles (Eq. 1),12 which
employed the enamine species as the key intermediate.
However, by reviewing these developed strategies, most of
them need pre-functionalized substrates, harsh conditions and/or
many steps, thereby giving relatively simple quinoline products
in low efficiency with limited substitution patterns, which
extremely hindered their applications. Obviously, developing
new, easy and general synthetic strategies for direct construction
of the privileged quinoline core with specific and highly valuable
substitution patterns is still highly desirable.
In recent years, transition-metal-catalyzed C−H bond
activation/annulation has played an increasingly popular role in
synthetic organic chemistry.7 Indeed, such strategy could
complement the traditional methods in terms of reactivity,
selectivity, reaction conditions, substrate scope and functional
group tolerance. On the basis of the versatile strategy, and up to
now, a tremendously large number of privileged N-heterocycles,
such as quinolines,8 have been conveniently synthesized in one-

2
Tetrahedron letters
sharply (entry 13). Finally, changing AgOTf to other well-known
CO2Me
"Our previous work"
MeO2C
NH2
catalysts, such as Pd(OAc)2 and Cu(OTf)2, all gave the inferior
results (Table 1, entries 14-18). In summary, the optimal
conditions for the three-component cascade reaction were
identified as the following: 5 mol % AgOTf, 10 mol % HOTf in
MeOH at 120 oC for 24 h under an atmosphere of air.
[Pd]
(1)
Ph
N
Ph
Pyrrole
+
HN
CO2Me
CO2Me
"This work"
[Ag]
N
CO2Me
MeO2C
CO2Me
Ph
H
(2)
Quinoline
Ph
Scheme 1. Scope of amines.a
AgOTf (5 mol%)
HOTf (10 mol%)
CO2Me
NH2
N
R2
Motivated by these and with our continuing interest in
R1
R1
+
+
CH3OH
120 oC, 24 h
Ph
R2
developing the transition-metal-catalyzed methodologies for the
direct construction of privileged N-heterocycles,13 in this paper,
we would like to reveal an efficient, general and straightforward
method for the one-pot cascade synthesis of diverse 2,4-
disubstituted quinolines through a three-component assembly
from simple and readily available amines, alkyne esters, and
terminal alkynes (Eq. 2). The regioselective [3+1+2] cascade
annulation is catalyzed by AgOTf and uses the enamines as the
key intermediates. Notably, this versatile transformation
represents the first example of silver-catalyzed sequential
reactions with terminal alkynes for direct construction of
quinoline framework.
3a
2
1
Ph
4
R1
R1
N
CO2Me
N
CO2Me
N
CO2Me
R1
Ph
Ph
Ph
4h, R1 = F, 72%
4i, R1 = Cl, 74%
4j, R1 = CH3, 84%
4l, R1 = F, 64%
4m, R1 = Cl, 68%
4n, R1 = CH3, 76%
4a, R1 = H, 89%
4b, R1 = F, 78%
4c, R1 = Cl, 81%
4d, R1 = Br, 79%
4e, R1 = CH3, 94%
4f, R1 = OCH3, 82%
4g, R1 = SCH3, 84%
4k, R1 = OCH3, 79%
N
CO2Me
4o, 87%
Ph
Table 1. Optimization of reaction conditions.a
Cl
N
CO2Me
R1
N
Ph
N
CO2Me
H
COOCH3
N
COOCH3
NH2
Catalyst
O
+
+
Additive
Solvent, T
Ph
Ph
Ph
4r, 82%
Ph
3a
COOCH3
2a
4p, R1 = OCH3, 96%
4q, R1 = CF3, 82%
Ph
4a
4s, 80%
1a
N
Ph
N
Ph
N
Entry
Catalyst
Additive
-------
TsOH
HOAC
TFA
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
Tol
T (oC)
120
120
120
120
120
120
120
120
120
120
120
120
100
120
120
120
120
120
Yieldb (%)
N
N
R1
1
2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
Ag2CO3
Ag2SO4
AgNO3
18
12
21
34
89
<5
58
0
O
Ph
Ph
Ph
4t, R1 = OCH3, 73%
4u, R1 = F, 64%
4w, 94%
N
4v, 89%
N
3
F
4
Ph
CO2Et
N
Ph
5
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
Cl
6
Ph
Ph
4z, 95%
Ph
7
EtOH
DMF
4x, 62%
4y, 66%
8
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol) and 3a (1.2 mmol) in
MeOH (2 mL) at 120 oC for 24 h under air, isolated yield was given.
9
DMSO
THF
0
10
11
12
13
14
15
16
17
18
32
12
35
62
0
Diox
With this efficient catalytic system in hand, we first examined
the scope of this reaction with respect to the amine substrates
(Scheme 1). To our delight, we found that the established
Ag/HOTf catalysis proved to be broadly applicable, thus, a wide
range of amines reacted smoothly with 2a and 3a to deliver the
desired products in good to excellent yields (64-95%). Both
electron-donating and electron-withdrawing substituents either at
the para- (4a-g), meta- (4h-k), or ortho- (4l-n) position were all
well tolerated. Importantly, the reaction also showed good
compatibility with many valuable functional groups such as
fluoro (4b, 4h, 4l and 4u), chloro (4c, 4i and 4m), methyl (4e, 4j
and 4n), methoxy (4f, 4k, 4p and 4t), trifluoromethyl (4q), and
methylthio (4g) substituents, some of which were very useful
precursors for next synthetic transformations. Notably, ring-fused
anilines, such as 2,3-dihydro-1H-inden-4-amine (1o) and
naphthalen-1-amine (1r), were also viable substrates, giving the
corresponding quinoline products with impressive yields (for 4o,
87%; for 4r, 82%). Moreover, the scope with respect to the
alkyne ester substrates was studied. Gratifyingly, replacement of
the CO2Me substituent of alkyne ester 2a with phenyl, methyl or
CO2Et group, were perfectly compatible with the catalytic
system, providing the corresponding quinolines in generally good
yields. For instance, methyl 3-phenylpropiolate (2b, R2 = Ph)
worked well with heterocyclic amines (for the morpholinyl
DCE
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0
0
Cu(OTf)2
Pd(OAc)2
53
0
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.2 mmol), catalyst
(5 mol %), additive (10 mol %), solvent (2.0 mL), 24 h, under air.
bIsolated yields.
At the outset of this study, we employed simple and
commercially available aniline 1a, dimethyl but-2-ynedioate 2a
and phenylacetylene 3a as the model substrates and used AgOTf
as the active catalyst for the reaction development (Table 1). To
our delight, the desired 2,4-substituted quinoline 4a was obtained
in 18% isolated yield under initial conditions (entry 1).
Encouraged by this finding, we next investigated the effects of
additive and solvent for the optimization of the reaction. The
results revealed that the introduction of both HOTf and MeOH
was the best choice for the reaction outcome (entries 2-12). An
attempt to lower the reaction temperature cut down the yield

3
moiety, see 1v; for the piperazinyl moiety, see 1w) and 3a to
deliver the desired products in excellent yields. Interestingly,
methyl but-2-ynoate (2c, R2 = Me) was also well performed
under established standard conditions leading to desired 4t and
4u in 64% and 73% yield, respectively.
Scheme 3. Mechanistic experiments.
CO2Me
N
CO2Me
MeO2C
Standard
conditions
H
H
N
MeOH
RT
+
a)
H
Ph
MeO2C
3a
N
CO2Me
2a
Ph
4a, 89%
Ph
1a
6
N
CO2Me
MeO2C
MeO2C
Scheme 2. Scope of terminal alkynes.a
b)
HOTf (10 mol%)
H
+
Ph
Ag
N
AgOTf (5 mol%)
HOTf (10 mol%)
CH3OH
120 oC, 24 h
CO2Me
+
NH2
+
N
R2
Ph
4a, 91%
7
Ph
6
R1
R1
CH3OH
120 oC, 24 h
R3
R1
R2
H/D
D
H
3
2a+3a
2
1
R3
5
N
CO2Me
NH2
D
NH2
H
"standard conditions"
c)
+
N
CO2Me
kH : kD = 1.16 : 1
N
CO2Me
N
CO2Me
Ph
R1
R1
Inspired by the aforementioned results and in combination
with literature precedents,14 we reasoned that the enamine species
might be used as an active intermediate for the AgOTf-catalyzed
[3+1+2] cascade annulation. Thus, the enamine 6 was prepared
from the easy concentration of 1a and 2a and designated as a
substrate to probe the reaction mechanism (Scheme 3a). As
predicted, the reaction of 6 and 3a occurred successfully under
standard conditions to produce the product 4a in 89% yield,
which confirmed our speculation. Moreover, treatment of the
synthesized (phenylethynyl)silver 715 with enamine 6 in the
presence of HOTf delivered the product 4a in 91% isolated yield
(Scheme 3b), suggesting that Ag(I) catalyzed the [3+1+2]
annulation might be via the formation of the active alkynyl Ag(I)
species. Finally, the kinetic isotope effect has also been evaluated
to further understand the reaction mechanism (Scheme 3c). The
results showed that an almost equivalent kH/kD ratio was observed
(kH/kD = 1.16), revealing that the C−H bond cleavage process was
unlikely involved in the rate-determining step.
O
O
5e, R1 = H, 92%
5f, R1 = CH3, 99%
5a, R1 = F, 81%
5b, R1 = CH3, 97%
5c, R1 = F, 76%
5d, R1 = CH3, 89%
N
CO2Me
N
Ph
N
CO2Me
R1
R1
n-Bu
F
5i, R1 = H, 74%
5j, R1 = CH3, 78%
5k, 91%
5g, R1 = H, 78%
5h, R1 = F, 69%
N
CO2Me
N
CO2CH3
N
CO2Me
S
5l, 54%
5n, 79%
5m, 67%
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol) and 3 (1.2 mmol) in MeOH
(2 mL) at 120 oC for 24 h under air, isolated yield was reported.
Taking these experimental observations into consideration, a
plausible reaction mechanism is proposed in Scheme 4. Initially,
enamine 6 is generated handily from in situ nucleophilic addition
of amine 1a to alkyne ester 2a. Moreover, the reaction of 3a with
AgOTf gives the alkynyl Ag(I) species. Subsequently,
regioselectively intermolecular nucleophilic addition of silver
acetylide to imine A from the isomerization of enamine 6 in the
presence of HOTf to alkynyl Ag(I) species produces the
intermediate B, followed by C−C bond cleavage to provide the
propargyl imine C.16 Finally, intermediate C undergoes an
intramolecular Friedel-Crafts-type addition to deliver the desired
product 4a.
Further investigation with respect to explore the substrate
scope of terminal alkynes was conducted (Scheme 2). We were
pleased to note that (hetero)aryl and (cyclo)alkyl substituents on
the terminal alkyne all give the desired products in good to
excellent yields (up to 99%). For example, aryl-substituted
terminal alkynes bearing various functional groups at the 4-
position of the benzene ring, such as methoxy (5a-d), methyl (5e-
f), and fluoro (5g-h) substituents, were compatible with the
catalytic system. Both the chain alkyl (5i and 5j)- and cycloalkyl
(5m)-substituted terminal alkynes also worked well to deliver the
desired quinoline products in high yields. As expected, when the
heteroaromatic terminal alkyne (3n) was subjected to the
reaction, the quinoline product (5n) was smoothly obtained in
decent isolated yield. Of note, ethynyltrimethylsilane could also
be accommodated in the catalytic system, giving the 2-ester
substituted product (5l) in a synthetically yield along with the
removal of trimethylsilyl group in one-pot fashion. Taken
together, these listed results further demonstrated the versatility
of our developed silver-catalyzed system.
Scheme 4. Postulated mechanism.
3a
N
CO2Me
Ph
Ag(I)
Ag(I)
Ph
4a
CO2Me
CO2Me
CO2Me
H
N
H
N
CO2Me
A
B
Ph
2a
N
CO2Me
-CH3COOMe
CO2Me
CO2Me
H
C
N
1a
+
Ph
6
In summary, we have developed, for the first time, an
efficient and general AgOTf-catalyzed three-component [3+1+2]
cascade annulation of simple and readily available amines,
alkyne esters, and terminal alkynes for one-pot synthesis of
privileged
2,4-disubstituted
quinolines
with
excellent
substrate/functional group tolerance. Experimental investigations

4
Tetrahedron letters
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formation of the enamine species and subsequently proceeded by
following an intermolecular nucleophilic addition/C−C bond
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scope, mechanism, and application of this versatile
transformation are currently underway.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21877020 and 21502100), Guangdong
Natural Science Funds for Distinguished Young Scholar
(2017A030306031), and Henan province Training Program of
Innovation and Entrepreneurship for Undergraduates
(201710481011).
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Supplementary Material
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 A novel AgOTf-catalyzed three-component
Highlights:
[3+1+2] annulation has been developed

5
 Simple amines, alkyne esters and terminal
alkynes was used as the substrates
 2,4-Disubstituted quinolines were synthesized
in good to excellent yields
 The enamine and alkynyl Ag(I) species might
be involved as the active intermediates