Synthesis of substituted quinolines via B(C6F5)3-catalyzed aniline-aldehyde-pyruvate oxidative annulation

Article abstract of DOI:10.1002/jhet.3730

A metal-free method to construct quinoline derivatives via B(C₆F₅)₃-catalyzed cyclization of anilines with aldehyde derivatives and pyruvates is described. This three-component cascade reaction provides an efficient approa

Full text of DOI:10.1002/jhet.3730

Received: 8 March 2019
DOI: 10.1002/jhet.3730
Revised: 31 July 2019
Accepted: 23 August 2019
A R T I C L E
Synthesis of substituted quinolines via B(C F ) ‐catalyzed
6
5 3
aniline‐aldehyde‐pyruvate oxidative annulation
Fei Ling
| Jiachen Chen | Zhen Xie | Huacui Hou | Zhentao Pan | Cong Feng |
Haiwei Shen | Weihui Zhong
Key Laboratory for Green Pharmaceutical
Abstract
A metal‐free method to construct quinoline derivatives via B(C
Technologies and Related Equipment of
Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou,
People's Republic of China
F ) ‐catalyzed
6 5 3
cyclization of anilines with aldehyde derivatives and pyruvates is described.
This three‐component cascade reaction provides an efficient approach for the
easy access to various substituted quinoline‐4‐carboxylic esters with 71% to
Correspondence
92% yield. The utility of this methodology was further demonstrated by gram‐
Weihui Zhong, Key Laboratory for Green
Pharmaceutical Technologies and Related
Equipment of Ministry of Education,
College of Pharmaceutical Sciences,
Zhejiang University of Technology.
Hangzhou 310014, People's Republic of
China.
scale formal synthesis of the antimalarial drug DDD107498.
Email: weihuizhong@zjut.edu.cn
Funding information
Natural Science Foundation of Zhejiang
Province of China, Grant/Award Number:
LY19B060011; National Natural Science
Foundation of China, Grant/Award
Numbers: 21676253 and 21706234
1
| INTRODUCTION
conditions, and product diversity. In this context, the Hu
group reported a CuBr ‐catalyzed simple one‐pot reaction
2
Quinoline is an important N‐heterocycle, existing in
of aromatic amines, glyoxylic ester, and pyruvate, leading
[1–4]
numerous drugs and natural products (Figure 1).
Par-
to a variety of quinoline‐2,4‐dicarboxyl derivatives
[
23]
ticularly, quinoline‐4‐carboxylic esters represent a class
of versatile scaffolds, widely used in catalyst design and
drug discovery. For example, quinine isolated from
Rubiaceae plant Cinchona, acted as a powerful organo‐
(Scheme 1a).
Moreover, Gao and coworkers achieved
4‐esteryl quinolines in high yields by using an elegant tri-
ple zirconocene/brϕnsted acid/CuO cooperative catalysis
[
24]
system (Scheme 1b).
Recently, Wu's group discovered
[5–12]
catalyst in a plenty of asymmetric reactions.
More-
a highly efficient I ‐catalyzed Povarov‐type reaction of
2
over, DDD107498 showed excellent inhibition against
structure. Methyl ketones, arylamines, and α‐ketoesters
[13–15]
[25]
3
D7 parasites, with the EC50 value of 1.0nM.
Due
to form versatile quinolines (Scheme 1c).
Despite their
[
23,24]
to this great importance, a deal of effort has been devoted
to develop new and efficient synthetic methods for these
unarguable efficiency, the use of metal catalysts
or
[
25]
harsh conditions
limited their further application in
[
16–22]
structures.
Particularly, the aniline‐aldehyde‐
pharmaceuticals. As a consequence, there is an urgent
demand to develop efficient and practical methodologies
to access quinoline‐4‐carboxylic esters.
3
pyruvate reaction (also recognized as the A reaction) rep-
resents one of the most powerful and efficient methods for
the direct synthesis of 4‐esteryl quinolines owing to its
readily available starting materials, mild reaction
[
26]
B(C F ) , reported
in 1964, re‐emerged as a para-
6
5 3
digm for small molecule activation in the past decade,
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
LING ET AL.
previous work, herein, we reported our studies on B
(
C F ) ‐catalyzed aniline‐aldehyde‐pyruvate annulation
6
5 3
reaction for the synthesis of substituted 4‐esteryl quino-
line derivatives (Scheme 1d).
2
| RESULT AND DISCUSSION
Our initial attempt to realize this transformation was con-
ducted with the reaction of aniline (1a), 4‐
chlorobenzaldehyde (2a), and methyl pyruvate (3a),
using 10 mol % of B(C F ) . Delightfully, the desired quin-
6
5 3
oline 4a was obtained in a yield of 47% when stirring the
solution of 1a, 2a, and 3a with a ratio of 1.2:1.1:1 in tolu-
ene at 100°C for 2 hours in the presence of B(C F )
FIGURE 1 Drugs and nature products containing quinoline
structure [Color figure can be viewed at wileyonlinelibrary.com]
6
5 3
(Scheme 2). Interestingly,
a
by‐product N‐(4‐
chlorobenzyl)aniline (5a) was also produced in 42% yield.
A possible explanation for the formation of 5a is that a
transfer hydrogenation process occurred in the oxidation
step to form the quinoline where the imine acts as a
especially as a component in frustrated Lewis pairs
[
27–32]
(
FLPs) chemistry.
Moreover, B(C F ) has been
6 5 3
successfully employed in various other transforma-
[
33–40]
[41]
tions.
One of the research hotspots is the borane‐
hydrogen acceptor.
catalyzed multicomponent reactions (MCRs). Recently, a
remarkable work made by Ingleson and coworkers
Next, the optimization of the reaction conditions was
firstly studied on the ratio of the substrates. As expected,
raising the ratio of both 1a and 2a (Table 1, entries 1‐3)
improved the reaction yield significantly. The best yield
of 78% was accomplished by using 3.6:3.3:1 of 1a:2a:3a,
further, increasing the ratio did not benefit the reaction
outcomes. In addition, the effect of reaction temperature
was investigated (Table 1, entries 3 and 4). The results
indicated that lowering reaction temperature from 100°
C to 80°C did not affect the reaction efficiency, while a
covered
a
B(C F ) ‐initiated aldehyde‐aniline‐alkyne
6
5 3
reaction, which enabled the synthesis of various function-
[
41]
alized quinolines.
However, the high catalyst loading
(
20 mol %) and the utility of expensive alkynes limited
its practicability to some degree. Very recently, our group
have devoted much efforts to B(C F ) ‐catalyzed
6
5 3
MCRs, furnishing versatile 2,4,6‐triarylpyridines and bis
[42–44]
(
indolyl)alkanes in high yields.
Inspired by our
SCHEME 1 Preparation of quinoline‐4‐
3
carboxylic esters via the A reactions
[
Color figure can be viewed at
wileyonlinelibrary.com]

LING ET AL.
3
SCHEME 2 The initial attempt of B
(C F ) ‐catalyzed aniline‐aldehyde‐
6 5 3
pyruvate reaction [Color figure can be
viewed at wileyonlinelibrary.com]
a
TABLE 1 Optimization of reaction conditions
b
Entry
1a/2a/3a
x
T, °C
Solvent
t, h
Yield of 4a, %
1
2
3
4
5
6
7
8
9
2.4/2.2/1.0
3.6/3.3/1.0
4.8/4.4/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
3.6/3.3/1.0
10
10
10
10
10
10
10
10
10
5
100
100
100
80
Toluene
Toluene
Toluene
Toluene
Toluene
2
73
2
78
2
78
4
77
60
8
71
80
CHCl
3
5
69
80
Hexane
THF
12
9
61
80
32
80
EtOH
12
2
48
1
1
1
1
0
1
2
3
80
Toluene
Toluene
Toluene
Toluene
77
2.5
1
80
3
77
80
6
62
0
80
6
Trace
The data in bold and italic represents the optimal reaction conditions.
a
6 5 3
Note. Reaction conditions: 1a, 2a, 3a, and B(C F ) in solvent for 2 to 12 h under air.
b
Isolated yields based on 3a.
drop on yield of 4a from 78% to 71% was observed when
the reaction was conducted at 60°C, even
better yields than those with an electron‐withdrawing
group (–F, –Cl, or –CF ). Moreover, the substitution pat-
3
after 8 hours. Notably, the reaction solvents had great
impact on this transformation, and toluene still turned
out to be the best medium (Table 1, entries 6‐9). Satisfy-
ingly, this process proceeded smoothly without loss of
efficiency in yield even with the reduced catalyst load-
ing from 10 to 2.5 mol % (Table 1, entry 11), while no
product 4a was obtained in the absence of B(C F )
tern had no impact on this transformation, leading to
the meta‐product 4f and ortho‐product 4 g in 80% and
85% yields, respectively. Notably, other aromatic amines
were also compatible with this reaction, affording the
corresponding products 4j and 4k in excellent yields.
Subsequently, the scope of this reaction with respect to
the aldehydes 2 was studied, and the desired products
were achieved in 71% to 92% yield. Aldehyde with an
electron‐donating group (–OMe) produced the expected
product in lower yield (4n, 77%) than that with an
6
5 3
(
Table 1, entry 13). With the optimal reaction conditions
in hand, we set out to expand the generality and scope
of B(C F ) catalyzed three‐component cascade reaction
6
5 3
(
Scheme 3). The substrate scope of this reaction was ini-
tially explored with a range of aromatic amines 1 with
‐chlorobenzaldehyde (2a) and methyl 2‐oxopropanoate
electron‐withdrawing group (–CF , 4m, 92%). Delight-
3
fully, hetero‐aromatic aldehydeslike 3‐pyridylaldehyde
(2p), 2‐thenaldehyde (2q), and furaldehyde (2r) were also
tolerated in this reaction, affording the corresponding
products 4p‐4r in excellent yields. As expected, treating
4
(
1
3a). Variation of R showed that benzene rings with
an electron‐donating group (–Me, –OMe, or –t‐Bu) gave

4
LING ET AL.
SCHEME 3 Substrate scope of B(C
6
F
5
)
3
‐catalyzed aniline‐aldehyde‐pyruvate reaction [Color figure can be viewed at wileyonlinelibrary.
com]
ethyl pyruvate with 4‐methoxyaniline and 4‐
chlorobenzaldehyde under standard conditions furnished
the desired substituted quinoline 4t in 84% yield.
To demonstrate the scalability and utility of this
method, we applied it in the formal synthesis of
78% yield. Then, nucleophilic attack of 4u by morpholine,
followed by hydrolysis of the ester group resulted in the
formation of 4‐carboxyl quinoline 5u in 1.15 g, 85% yield
over two steps. Finally, 5u could be converted into
[
45]
DDD107498 according to the literature.
Based on our findings and the related references,
a plausible reaction mechanism for the present B(C F ) ‐
[33–44]
DDD107498 on a gram scale (Scheme 4). Initially, the B
3
(
C F ) ‐catalyzed
A
reaction of 4‐fluoroaniline,
6
5 3
6 5 3
4
‐(bromomethyl)benzaldehyde, and methyl pyruvate was
catalyzed aniline‐aldehyde‐pyruvate annulation reaction
conducted to afford the targeted product 4u in 1.40 g,
is depicted in Scheme 5. Upon heating, B(C F ) is
6
5 3

LING ET AL.
5
SCHEME 4 Gram‐scale synthesis of the
key intermediate 5u of DDD107498 [Color
figure can be viewed at wileyonlinelibrary.
com]
SCHEME 5 Proposed mechanism
[Color figure can be viewed at
wileyonlinelibrary.com]
generated from a Lewis adduct or the hydroxy borate to
activate the imine I derived from aniline 1a and aldehyde
tolerance, and low catalyst loading. The utility of this
method was further demonstrated by the formal synthesis
of the antimalarial drug DDD107498 on a gram scale.
2
a, which then undergoes nucleophilic
addition of pyruvate 3a to form the intermediate III.
Subsequently, the electron‐rich benzene ring attacked
the keto‐carbonyl group to afford the species IV. Then,
the release of B(C F ) and H O from IV resulted the
dihydroquinoline V. Finally, the oxidation of the
dihydroquinoline V by an equivalent of imine I to furnish
the product 4a, accompanied by the formation of by‐
product 5a.
4
4
| EXPERIMENTAL
6
5 3
2
.1 | General information
All starting materials and reagents were purchased from
commercial sources and used as received unless other-
wise noted. Reactions were monitored using thin‐layer
chromatography (TLC) on commercial silica gel plates.
Visualization of the developed plates was performed
under UV light (254 nm). Flash column chromatography
was performed on silica gel. NMR spectra were recorded
on a Bruke Avance III spectrometer, operating at
3
| CONCLUSIONS
In conclusion, we have presented a B(C F ) ‐catalyzed
6
5 3
cyclization of anilines with aldehydes and pyruvates to
afford various substituted quinoline‐4‐carboxylic esters
in high yields (71%‐92%). The three‐component cascade
reaction has a broad substrate scope covering a wide
range of aryl and alkyl aldehydes, functional group
1
13
400 MHz ( H) and 100 MHz ( C) respectively. Chemical
shifts (δ) were reported in parts per million (ppm) down-
field from TMS (=0) or relative to CHCl (7.254 ppm) for
3
1
13
H NMR. For C NMR, chemical shifts were reported in

6
LING ET AL.
the scale relative to CHCl (77.16 ppm) as an internal ref-
4.2.4 | Methyl2‐(4‐chlorophenyl)‐6‐
3
erence. Multiplicities are abbreviated as s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet; and br, broad. The
coupling constants are expressed in Hz. Melting points
were determined with a Büchi B‐540 capillary melting
point apparatus and are uncorrected.
(trifluoromethyl)quinoline‐4‐carboxylate
(4d)
1
White solid; 270 mg, 74% yield; m.p. 135.8°C‐136.9°C; H
NMR (400 MHz, CDCl , ppm) δ 8.53 (d, J = 10.8 Hz, 1H),
3
8
7
.47 (s, 1H), 8.26‐8.20 (m, 1H), 8.17 (d, J = 8.0 Hz, 2H),
.59 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 4.10
1
3
(s, 3H). C NMR (100 MHz, CDCl , ppm) δ 166.0,
3
4
.2 | Preparation method for the synthesis
1
1
1
57.4, 150.1, 136.8, 136.4, 136.2, 131.3 (2C), 129.3 (2C),
28.9 (2C), 125.8 (d, J = 3.1 Hz), 123.8 (d, J = 4.6 Hz),
of compound 4
23.2, 121.0 (2C), 53.1. HRMS‐ESI (m/z) calcd for
4
.2.1 | Methyl‐2‐(4‐chlorophenyl)
+
C H ClF NO [M + H] : 366.0503, found: 366.0521.
1
8
12
3
2
quinoline‐4‐carboxylate (4a)
1
White solid; 229 mg, 77% yield; m.p. 85.1°C‐87.8°C; H
4
.2.5 | Methyl2‐(4‐chlorophenyl)‐6‐
NMR (400 MHz, CDCl , ppm) δ 8.76 (d, J = 8.4 Hz,
3
methylquinoline‐4‐carboxylate (4e)
1
H), 8.37 (s, 1H), 8.21 (t, J = 12.6 Hz, 1H), 8.18 (d,
J = 8.4 Hz, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.71‐7.62 (m,
1
1
3
White solid; 256 mg, 82% yield; m.p. 119.7°C‐121.2°C; H
1
H), 7.53 (d, J = 8.4 Hz, 2H), 4.10 (s, 3H). C NMR
NMR (400 MHz, CDCl , ppm) δ 8.50 (s, 1H), 8.28 (s, 1H),
.15‐8.10 (m, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.59 (dd,
J = 8.4, 1.6 Hz, 1H), 7.50‐7.46 (m, 3H), 4.07 (s, 2H), 2.58
(s, 3H). C NMR (100 MHz, CDCl , ppm) δ 166.8,
3
3
(
100 MHz, CDCl , ppm) δ 166.7, 155.3, 149.2, 137.1,
3
8
1
1
36.0, 135.7, 130.3, 130.1, 129.1 (2C), 128.7 (2C), 128.0,
25.5, 124.0, 119.9, 52.8. HRMS‐ESI (m/z) calcd for
1
3
+
C H ClNO [M + H] : 298.0629 found: 298.0621.
17
13
2
1
1
54.2, 147.8, 138.2, 137.2, 135.7, 134.8, 132.3, 129.9,
29.0 (2C), 128.5 (2C), 124.2, 124.0, 119.7, 52.7, 22.2.
+
HRMS‐ESI (m/z) calcd for C H ClNO [M + H] :
1
8
15
2
4
.2.2 | Methyl2‐(4‐chlorophenyl)‐6‐
312.0786, found: 312.0790.
fluoroquinoline‐4‐carboxylate (4b)
1
White solid; 246 mg, 78% yield; m.p. 112.3°C‐113.9°C; H
4
.2.6 | Methyl2‐(4‐chlorophenyl)‐7‐
NMR (400 MHz, CDCl , ppm) δ 8.53 (d, J = 10.8 Hz, 1H),
3
methylquinoline‐4‐carboxylate (4f)
8
7
.47 (s, 1H), 8.28‐8.20 (m, 1H), 8.17 (d, J = 8.0 Hz, 2H),
1
3
.59 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H).
C
1
White solid; 249 mg, 80% yield; m.p. 116.7°C‐118.6°C; H
NMR (600 MHz, CDCl , ppm) δ 8.63 (d, J = 8.8 Hz, 1H),
NMR (100 MHz, CDCl , ppm) δ 166.3, 162.8 (J
3
C‐
3
=
240 Hz) 154.7, 146.5, 136.8, 136.1, 134.9 (JC‐
F
8
2
.27 (s, 1H), 8.16‐8.09 (m, 2H), 7.97 (s, 1H), 7.52‐7.48 (m,
H), 7.46 (dd, J = 8.8, 1.6 Hz, 1H), 4.07 (s, 3H), 2.58 (d,
=
5.9 Hz), 132.7 (d, J = 9.3 Hz), 129.2 (2C), 128.6,
F
1
25.0 (d, J = 11.3 Hz), 120.8, 120.5 (d, J = 26.0 Hz),
13
J = 1.2 Hz, 3H). C NMR (100 MHz, CDCl , ppm) δ
3
1
09.6 (d, J = 25.1 Hz), 52.9. HRMS‐ESI (m/z) calcd for
1
1
2
3
66.7, 155.1, 149.4, 140.4, 137.2, 135.8, 135.3, 130.3,
29.2, 129.0 (2C), 128.6 (2C), 125.1, 122.1, 118.9, 52.7,
1.7. HRMS‐ESI (m/z) calcd for C H ClNO [M + H] :
+
C H ClFNO [M + H] : 316.0535, found: 316.0528.
17
12
2
+
1
8
15
2
12.0786, found: 312.0780.
4
.2.3 | Methyl6‐chloro‐2‐(4‐chlorophenyl)
quinoline‐4‐carboxylate (4c)
4
.2.7 | Methyl2‐(4‐chlorophenyl)‐8‐
1
White solid; 262 mg, 79% yield; m.p. 121.5°C‐122.9°C; H
methylquinoline‐4‐carboxylate (4g)
NMR (400 MHz, CDCl , ppm) δ 8.84 (d, J = 2.4 Hz, 1H),
3
8
7
.43 (s, 1H), 8.19‐8.16 (m, 2H), 8.14 (d, J = 8.8 Hz, 1H),
.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.56‐7.51 (m, 2H), δ 4.11
White solid; 265 mg, white solid, 85% yield; m.p. 92.1°C‐
1
93.2°C; H NMR (400 MHz, CDCl , ppm) δ 8.56 (d,
3
13
(
s, 3H). C NMR (100 MHz, CDCl , ppm) δ 166.2,
J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J = 8.4 Hz, 2H),
7.62 (d, J = 6.8 Hz, 1H), 7.52 (t, J = 8.4 Hz, 3H), 4.08 (s,
3
1
1
55.5, 147.7, 136.7, 136.3, 134.6, 134.2, 131.7, 131.1,
1
3
29.2 (2C), 128.7 (2C), 124.6 (2C), 120.7, 53.0. HRMS‐
3H), 2.90 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ
3
+
ESI (m/z) calcd for C H Cl NO [M + H] : 332.0240,
found: 332.0243.
167.0, 153.4, 148.0, 138.1, 137.3, 136.0, 135.8, 130.2,
129.0 (2C), 128.5 (2C), 127.7, 124.0, 123.0, 119.0, 52.8,
1
7
12
2
2

LING ET AL.
7
+
1
3
8.5. HRMS‐ESI (m/z) calcd for C H ClNO [M + H] :
12.0786, found: 312.0795.
122.3, 119.2, 52.8. HRMS‐ESI (m/z) calcd for
1
8
15
2
+
C H ClNO [M + H] : 348.0786, found: 348.0781.
2
1
15
2
4
.2.8 | Methyl2‐(4‐chlorophenyl)‐6‐
4.2.12 | Methyl 2‐phenylquinoline‐4‐
carboxylate (4l)
methoxyquinoline‐4‐carboxylate (4h)
1
White solid; 298 mg, white solid, 91% yield; m.p. 102.1°C‐
White solid; 187 mg, 71% yield; m.p. 50.5°C‐51.6°C; H
1
1
8
2
3
03.5°C; H NMR (400 MHz, CDCl , ppm) δ 8.37 (s, 1H),
.21 (s, 1H), 8.11 (t, J = 10.4 Hz, 3H), 7.50 (d, J = 8.0 Hz,
NMR (400 MHz, CDCl , ppm) δ 8.78 (dd, J = 8.4,
3
3
1.2 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.26‐
8.22 (m, 2H), 7.80 (dd, J = 8.4, 6.8 Hz, 1H), 7.65 (dd,
J = 8.4, 6.8 Hz, 1H), 7.57 (dd, J = 8.0, 6.8 Hz, 2H), 7.54‐
H), 7.43 (d, J = 9.2 Hz, 1H), 4.65‐4.49 (m, 2H), 3.99 (s,
1
3
H), 1.53 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3,
1
3
ppm) δ 166.4, 159.1, 152.7, 145.6, 137.3, 135.4, 133.9,
7.50 (m, 1H), 4.09 (s, 3H). C NMR (100 MHz, CDCl3,
ppm) δ 166.8, 156.7, 149.2, 149.2, 135.6, 130.3, 130.3,
129.9, 129.8, 129.0 (2C), 127.8, 127.5, 125.4, 124.0, 120.4,
1
5
31.6, 129.0 (2C), 128.4, 125.6, 123.0, 120.2, 103.3, 61.8,
5.6, 14.4. HRMS‐ESI (m/z) calcd for C H ClNO
1
8
15
3
+
+
[M + H] : 328.0735, found: 328.0741.
52.8. HRMS‐ESI (m/z) calcd for C H NO [M + H] :
1
7
14
2
264.1019, found: 264.1010.
4
.2.9 | Methyl6‐(tert‐butyl)‐2‐(4‐
chlorophenyl)quinoline‐4‐carboxylate (4i)
4.2.13 | Methyl2‐(4‐(trifluoromethyl)phe-
nyl)benzo[h]quinoline‐4‐carboxylate (4 m)
1
White solid; 293 mg, 83% yield; m.p. 133.5°C‐135.1°C; H
NMR (400 MHz, CDCl , ppm) δ 8.43 (s, 1H), 8.24 (s, 1H),
1
White solid; 351 mg, 92% yield; m.p. 141.0°C‐142.3°C; H
3
8
.18‐8.08 (m, 3H), 7.58 (d, J = 7.8 Hz, 2H), 7.44 (d,
NMR (400 MHz, CDCl , ppm) δ 9.46‐9.39 (m, 1H), 8.61
3
J = 9.1 Hz, 1H), 4.08 (s, 3H), 4.00 (s, 3H), 1.41 (s, 9H).
(d, J = 9.2 Hz, 1H), 8.42 (d, J = 9.2 Hz, 3H), 7.90 (t,
13
13
C NMR (100 MHz, CDCl , ppm) δ 167.0, 158.9, 154.2,
J = 8.8 Hz, 2H), 7.85‐7.72 (m, 4H), 4.11 (s, 3H).
C
3
1
1
52.5, 145.7, 136.2, 133.2, 131.7, 126.9 (2C), 125.9 (2C),
NMR (100 MHz, CDCl , ppm) δ 166.8, 152.9, 147.4,
3
25.4, 122.7, 120.7 (2C), 103.3, 55.6, 52.6, 34.8, 31.3.
142.0, 135.6, 133.4, 131.4, 129.6, 128.8, 127.7 (2C), 127.5
(2C), 127.3 (2C), 125.87‐125.67 (m), 125.0, 123.0, 122.1
(2C), 119.5, 52.8. HRMS‐ESI (m/z) calcd for C H F NO
+
HRMS‐ESI (m/z) calcd for C H ClNO [M + H] :
2
1
21
2
3
54.1255, found: 354.1265.
2
2
15
3
2
+
[
M + H] : 383.1049, found: 383.1053.
4
.2.10 | Methyl6‐(4‐chlorophenyl)‐[1,3]
dioxolo[4,5‐g]quinoline‐8‐carboxylate (4j)
4.2.14 | Methyl2‐(2‐methoxyphenyl)benzo
h]quinoline‐4‐carboxylate (4n)
[
1
White solid; 311 mg, 91% yield; m.p. 190.2°C‐191.8°C; H
NMR (400 MHz, CDCl , ppm) δ 8.24 (s, 1H), 8.16 (s, 1H),
1
White solid; 265 mg, 77% yield; m.p. 134.9°C‐135.8°C; H
3
8
3
1
.14‐8.09 (m, 2H), 7.53‐7.46 (m, 3H), 6.17 (s, 2H), 4.06 (s,
NMR (400 MHz, CDCl , ppm) δ 9.51 (dd, J = 7.8, 1.6 Hz,
1H), 8.75‐8.62 (m, 2H), 8.25 (dt, J = 7.8, 1.6 Hz, 1H), 7.98‐
7.89 (m, 2H), 7.76 (pd, J = 7.2, 1.6 Hz, 2H), 7.55‐7.45 (m,
3
13
H). C NMR (100 MHz, CDCl , ppm) δ 166.9, 153.2,
3
50.9, 149.5, 148.1, 137.2, 135.5, 134.1, 129.0 (2C), 128.4
(
(
2C), 121.7, 118.0, 106.4, 102.1, 101.2, 52.7. HRMS‐ESI
1H), 7.25 (q, J = 7.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 4.11
+
13
m/z) calcd for C H ClNO [M + H] : 342.0528, found:
(s, 3H), 3.96 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ
18
13
4
3
3
42.0522.
167.5, 157.6, 154.4, 147.3, 134.4, 133.3, 132.0, 132.7, 130.7,
1
1
28.9, 128.8, 128.4, 127.6, 127.1, 125.2, 124.5, 122.4, 122.2,
21.3, 111.6, 55.8, 52.7. HRMS‐ESI (m/z) calcd for
4
.2.11 | Methyl2‐(4‐chlorophenyl)benzo[h]
+
C H NO [M + H] : 344.1281, found: 344.1270.
2
2
18
3
quinoline‐4‐carboxylate (4k)
1
White solid; 309 mg, 89% yield; m.p. 133.1°C‐135.9°C; H
4.2.15 | Methyl2‐(naphthalen‐1‐yl)benzo
[h]quinoline‐4‐carboxylate (4o)
NMR (400 MHz, CDCl , ppm) δ 9.43 (s, 1H), 8.66‐8.55 (m,
3
1
H), 8.41 (d, J = 6.0 Hz, 1H), 8.29 (s, 2H), 7.89 (d,
1
J = 12.4 Hz, 2H), 7.76 (s, 2H), 7.54 (d, J = 7.2 Hz, 2H),
White solid; 258 mg, 71% yield; m.p. 169.1°C‐170.4°C; H
13
4
1
1
.10 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ 167.0,
NMR (400 MHz, CDCl , ppm) δ 9.50‐9.41 (m, 1H), 8.76
(d, J = 9.2 Hz, 1H), 8.54‐8.45 (m, 1H), 8.39 (s, 1H), 8.07‐
7.95 (m, 4H), 7.89 (d, J = 6.8 Hz, 1H), 7.80‐7.73 (m,
3
3
53.4, 147.4, 137.2, 135.8, 135.6, 133.5, 131.5, 129.3,
29.1 (2C), 128.7 (2C), 128.5, 127.7, 127.2, 125.1, 122.7,

8
LING ET AL.
2
4
1
1
1
H), 7.68 (t, J = 7.6 Hz, 1H), 7.59 (dd, J = 7.2, 4.0 Hz, 2H),
4.2.19 | Methyl2‐cyclohexyl‐6‐
13
.11 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ 167.1,
methoxyquinoline‐4‐carboxylate (4s)
3
57.4, 147.4, 138.1, 135.3, 134.2, 133.5, 131.7, 131.3,
29.5, 129.4, 128.7, 128.5, 128.5, 127.7, 127.3, 126.8,
1
White solid; 231 mg, 77% yield; m.p. 122.3°C‐123.5°C; H
26.1, 125.9, 125.4, 125.4, 124.2, 122.4, 122.3, 52.8.
NMR (400 MHz, CDCl , ppm) δ 8.18 (d, J = 2.8 Hz, 1H),
3
+
HRMS‐ESI (m/z) calcd for C H NO [M + H] :
8.00 (d, J = 9.2 Hz, 1H), 7.87 (s, 1H), 7.39 (dd, J = 9.2,
2
5
18
2
3
64.1332, found: 364.1326.
2.8 Hz, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.00‐2.85 (m, 1H),
2.09‐2.01 (m, 2H), 1.95‐1.88 (m, 2H), 1.81 (d,
J = 12.4 Hz, 1H), 1.65 (dd, J = 12.4, 3.2 Hz, 2H), 1.49
13
(dt, J = 12.8, 2.8 Hz, 2H), 1.36 (d, J = 4.8 Hz, 1H).
C
NMR (100 MHz, CDCl , ppm) δ 167.1, 163.5, 158.5,
4
.2.16 | Methyl6‐methoxy‐2‐(pyridin‐3‐yl)
3
1
5
45.1, 133.0, 130.9 (2C), 125.2, 122.3, 121.5, 103.3, 55.5,
quinoline‐4‐carboxylate (4p)
2.5, 47.1, 32.8, 29.7, 26.5, 26.0. HRMS‐ESI (m/z) calcd
1
+
White solid; 239 mg, 81% yield; m.p. 121.3°C‐122.5°C; H
for C18
H
22NO
3
[M + H] : 300.1594, found: 300.1591.
NMR (400 MHz, CDCl , ppm) δ 9.12 (s, 1H), 8.78 (d,
3
J = 4.4 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.31 (d,
J = 2.4 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.91 (t,
J = 7.6 Hz, 1H), 7.46 (dd, J = 9.2, 2.4 Hz, 1H), 7.44‐7.37
4
.2.20 | Ethyl2‐(4‐chlorophenyl)‐6‐
methoxyquinoline‐4‐carboxylate (4t)
1
3
(
m, 1H), 4.08 (s, 3H), 4.02 (s, 3H). C NMR (100 MHz,
1
White solid; 287 mg, 84% yield; m.p. 129.1°C‐130.9°C; H
NMR (400 MHz, CDCl , ppm) δ 8.37 (s, 1H), 8.21 (s, 1H),
CDCl , ppm) δ 167.0, 159.6, 155.7, 153.0, 149.1, 145.3,
3
3
1
1
37.1, 133.3, 131.8, 126.8, 124.0, 122.9, 121.4, 120.8,
8.11 (t, J = 10.4 Hz, 3H), 7.50 (d, J = 8.0 Hz, 2H), 7.43 (d,
03.3, 55.7, 52.5. HRMS‐ESI (m/z) calcd for C H N O
1
7
15 2 3
J = 9.2 Hz, 1H), 4.64‐4.49 (m, 2H), 3.99 (s, 3H), 1.53 (t,
J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl , ppm) δ
+
[M + H] : 295.1077, found: 295.1068.
1
3
3
1
1
5
66.4, 159.1, 152.7, 145.6, 137.3, 135.4, 133.9, 131.6,
29.0 (2C), 128.4 (2C), 125.6, 123.0, 120.2, 103.3, 61.8,
5.6, 14.4. HRMS‐ESI (m/z) calcd for C H ClNO
1
9
17
3
4
.2.17 | Methyl6‐methoxy‐2‐(thiophen‐2‐
+
[
M + H] : 342.0925, found: 342.0917.
yl)quinoline‐4‐carboxylate (4q)
1
White solid; 240 mg, 80% yield; m.p. 123.2°C‐124.9°C; H
NMR (400 MHz, CDCl , ppm) δ 8.33 (s, 1H), 8.19 (s, 1H),
4
.3 | Gram‐scale synthesis of the
3
intermediate 5u
8
1
3
1
1
.05 (d, J = 9.2 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J = 4.8 Hz,
H), 7.41 (d, J = 9.2 Hz, 1H), 7.22‐7.14 (m, 1H), 4.07 (s,
4
.3.1 | The procedure for the preparation
13
H), 3.99 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ
3
of 4u
66.7, 158.9, 149.4, 145.4, 144.7, 133.1, 131.2, 128.3,
28.1, 125.5, 125.5, 122.9, 119.6, 103.5, 55.6, 52.7. HRMS‐
4‐(Bromomethyl)benzaldehyde (3.3 g, 16.5 mmol), 4‐
fluoroaniline (2.0 g, 18 mmol), methyl pyruvate
(510 mg, 5.0 mmol), and B(C F ) (64 mg, 0.125 mmol)
+
ESI (m/z) calcd for C H NO S [M + H] : 300.0689,
found: 300.0693.
1
6
14
3
6
5 3
were dissolved in toluene (25 mL) under ambient atmo-
sphere. The mixture was stirred at 80°C for 4 hours mon-
itored by TLC. Subsequently, the mixture was
concentrated in vacuo, and the crude residue was purified
by column chromatography to afford 4u in 78% yield.
4
.2.18 | Methyl2‐(furan‐2‐yl)‐6‐
methoxyquinoline‐4‐carboxylate (4r)
1
White solid; 256 mg, 86% yield; m.p. 87.8°C‐89.9°C; H
Methyl2‐(4‐(bromomethyl)phenyl)‐6‐fluoroquinoline‐
4‐carboxylate (4u)
White solid; 1.4 g, 78% yield; m.p. 124.4°C‐126.1°C; H
NMR (400 MHz, CDCl , ppm) δ 8.37 (s, 1H), 8.22 (d,
3
1
J = 2.7 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H),
7
.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H),
.61 (dd, J = 2.8, 1.6 Hz, 1H), 4.07 (s, 3H), 3.99 (s, 3H).
NMR (400 MHz, CDCl , ppm) δ 8.53 (dd, J = 10.8,
3
6
2.4 Hz, 1H), 8.48 (s, 1H), 8.26‐8.21 (m, 1H), 8.19 (d,
J = 8.4 Hz, 2H), 7.57 (dd, J = 15.6, 5.2 Hz, 3H), 4.60 (s,
13
C NMR (100 MHz, CDCl , ppm) δ 166.7, 159.0, 153.2,
3
1
3
1
1
46.2, 145.4, 143.9, 133.2, 131.3 (2C), 125.5, 123.0, 119.4,
2H), 4.10 (s, 3H). C NMR (100 MHz, CDCl , ppm) δ
3
12.3, 109.6, 103.5, 55.6, 52.6. HRMS‐ESI (m/z) calcd for
166.3, 162.8, 160.3, 155.2 (d, J = 2.9 Hz), 146.5, 139.4,
138.4, 134.7 (d, J = 5.9 Hz), 132.7 (d, J = 9.4 Hz), 129.6,
+
C H NO [M + H] : 284.0917, found: 284.0915.
16
14
4

LING ET AL.
9
1
1
29.2, 127.7 (d, J = 6.6 Hz), 125.0 (d, J = 11.1 Hz), 121.0,
[4] J. P. Michael, Nat Prod Rep 2008, 25, 166.
20.3 (d, J = 26.0 Hz), 109.5 (d, J = 25.1 Hz), 52.8, 32.9.
[5] T. Su, J. C. Zhu, R. Sun, H. Zhang, Q. Huang, X. Zhang, R. Du,
+
L. Qiu, R. Cao, Eur J Med Chem 2019, 178, 154.
HRMS‐ESI (m/z) calcd for C H BrFNO [M + H] :
3
1
8
14
2
74.0186, found 374.0172.
[6] N. V. Kailasam, P. Kolandhaivel, S. Deval, M. Subbiah, P. E.
Kuppannagounder, Med Chem Res 2019, 28, 1298.
[
[
7] H. Saito, S. Miyairi, Curr Top Med Chem 2014, 14, 224.
4
.3.2 | The procedure for the preparation
8] S. Zheng, C. M. Schienebeck, W. Zhang, H.‐Y. Wang, W. Tang,
Asian J Org Chem 2014, 3, 366.
of 5u
[
9] G. Singh, E. M. O. Yeboah, Rep. Org Chem 2016, 6, 47.
A mixture of 4u (1.4 g, 3.9 mmol), morpholine (508 mg,
[
[
[
[
10] S. Liu, Y. Kumatabara, S. Shirakawa, Green Chem 2016, 18, 331.
11] Z.‐Y. Cao, F. Zhou, J. Zhou, Acc Chem Res 2018, 51, 1443.
12] T. Chanda, J. C.‐G. Zhao, Adv Synth Catal 2018, 360, 72.
5
.9 mmol), and dry CH Cl (10 mL) was added K CO
2 2 2 3
(
1.1 g, 7.8 mmol) under ambient atmosphere. The reac-
tion mixture was stirred at room temperature for addi-
tional 1 hour monitored by TLC. Subsequently, the
mixture was concentrated in vacuo, and the crude prod-
uct was used for the next step without further purifica-
tion. The crude product obtained from the above was
dissolved in 10 mL of sodium hydroxide (2M) and
13] B. Baragaña, I. Hallyburton, M. C. S. Lee, N. R. Norcross, R.
Grimaldi, T. D. Otto, W. R. Proto, A. M. Blagborough, S.
Meister, G. Wirjanata, A. Ruecker, L. M. Upton, T. S. Abra-
ham, M. J. Almeida, A. Pradhan, A. Porzelle, M. S.
Martínez, J. M. Bolscher, A. Woodland, T. Luksch, S. Norval,
F. Zuccotto, J. Thomas, F. Simeons, L. Stojanovski, M. Osuna‐
Cabello, P. M. Brock, T. S. Churcher, K. A. Sala, S. E.
Zakutansky, M. B. Jiménez‐Díaz, L. M. Sanz, J. Riley, R.
Basak, M. Campbell, V. M. Avery, R. W. Sauerwein, K. J.
Dechering, R. Noviyanti, B. Campo, J. A. Frearson, I.
Angulo‐Barturen, S. Ferrer‐Bazaga, F. Javier Gamo, P. G.
Wyatt, D. Leroy, P. Siegl, M. J. Delves, D. E. Kyle, S. Wittlin,
J. Marfurt, R. N. Price, R. E. Sinden, E. A. Winzeler, S. A.
Charman, L. Bebrevska, D. W. Gray, S. Campbell, A. H.
Fairlamb, P. A. Willis, J. C. Rayner, D. A. Fidock, K. D. Read,
I. H. Gilbert, Nature 2015, 522, 315.
1
0 mL THF. The reaction mixture was stirred at room
temperature for additional 2 hours monitored by TLC.
Subsequently, the THF was removed in vacuo, and the
residue solution was adjusted to pH 7 to 8 with 10%
HCl. The resulting precipitate was filtered and washed
with water (10 mL) and ethyl acetate (10 mL) to obtain
the desired product 5u as white solid in 85% yield.
6
‐Fluoro‐2‐(4‐(morpholinomethyl)phenyl))quinoline‐4‐
[
14] B. Baragaña, N. R. Norcross, C. Wilson, A. Porzelle, I.
Hallyburton, R. Grimaldi, M. Osuna‐Cabello, S. Norval, J.
Riley, L. Stojanovski, F. R. C. Simeons, P. G. Wyatt, M. J.
Delves, S. Meister, S. Duffy, V. M. Avery, E. A. Winzeler, R.
E. Sinden, S. Wittlin, J. A. Frearson, D. W. Gray, A. H.
Fairlamb, D. Waterson, S. F. Campbell, P. Willis, K. D. Read,
I. H. Gilbert, J Med Chem 2016, 59, 9672.
carboxylic acid (5u)
White solid; 468 mg, 85% yield; m.p. 132.1°C‐133.4°C; H
1
NMR (400 MHz, DMSO‐d ) δ 8.54‐8.44 (m, 2H), 8.28‐8.16
6
(
m, 3H), 7.77 (td, J = 8.8, 2.9 Hz, 1H), 7.53 (d, J = 8.2 Hz,
2
H), 3.65‐3.58 (t, J = 4.4 Hz, 4H), 2.53‐2.50 (m, 6H). MS
+
(
ESI): m/z = 367.1 [M + H] .
[
15] P. Hochegger, J. Faist, W. Seebacher, R. Saf, P. Maeser, M. Kai-
ser, R. Weis, Bioorg Med Chem 2017, 25, 2251.
ACKNOWLEDGMENTS
[
16] J.‐H. Choi, C.‐M. Park, Adv Synth Catal 2018, 360, 3553.
We thank the National Natural Science Foundation of
China (nos. 21676253 and 21706234) and the Natural Sci-
ence Foundation of Zhejiang Province of China (no.
LY19B060011) for financial support.
[17] P. Zhou, B. Hu, Y. Wang, Q. Zhang, X. Li, S. Yan, F. Yu, Eur J
Org Chem 2018, 4527.
[18] W. Wu, Y. Guo, X. Xu, Z. Zhou, X. Zhang, B. Wu, W. Yi, Org
Chem Front 2018, 5, 1713.
[
19] P. Zhou, B. Hua, S. Zhao, Q. Zhang, Y. Wang, X. Li, F. Yu, Tet-
rahedron Lett 2018, 59, 3116.
ORCID
[
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[
20] R. Isshiki, K. Muto, J. Yamaguchi, Org Lett 2018, 20, 1150.
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22] K.‐M. Jiang, J.‐A. Kang, Y. Jin, J. Lin, Org Chem Front 2018, 5,
Fei Ling https://orcid.org/0000-0002-4274-912X
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