Facile Construction of Quinoline-2-carboxylate Esters through Aerobic Oxidation of Alkyl 4-Anilinocrotonates Induced by a Radical Cation Salt

Article abstract of DOI:10.1002/asia.201700560

A facile construction of quinoline-2-carboxylate esters through an aerobic oxidation of alkyl 4-anilinocrotonates is described. In the presence of dioxygen, sp³ C?H bonds in 4-anilinocrotonates can easily be oxidized by using a catalytic amount of a radical cation salt, providing a radical intermediate. After further oxidation and domino cyclization, the desired quinoline derivatives were afforded in high yields. This reaction provides a new way to construct the pharmaceutically relevant quinoline skeleton, avoiding harsh reaction conditions and tedious starting material synthesis.

Full text of DOI:10.1002/asia.201700560

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: A Facile Construction of Quinoline-2-carboxylate Esters through
An Aerobic Oxidation of Alkyl 4-Anilinocrotonates Induced by
Radical Cation Salt
Authors: Xiao Dong Jia, Pengfei Li, Yu Shao, Yu Yuan, Wentao Hou,
Xiaofei Liu, Xuewen Zhang, and Honghe Ji
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10.1002/asia.201700560
Chemistry - An Asian Journal
COMMUNICATION
A Facile Construction of Quinoline-2-carboxylate Esters through
An Aerobic Oxidation of Alkyl 4-Anilinocrotonates Induced by
Radical Cation Salt
Xiaodong Jia*[a], Pengfei Li, [b] Yu Shao, [c] Yu Yuan, [a] Wentao Hou, [b] Xiaofei Liu, [b] Xuewen Zhang,
[a] and Honghe Ji [b]
[10]
Abstract: A facile construction of quinoline-2-carboxylate esters
through an aerobic oxidation of alkyl 4-anilinocrotonates was
described. In the presence of dioxygen, sp3 C-H bonds in 4-
anilinocrotonates can easily be oxidized by catalytic radical cation
salt, providing a radical intermediate. After further oxidation and
domino cyclization, the desired quinoline derivatives were afforded in
high yields. This reaction provided a new way to construct the
pharmaceutically relevant quinoline skeleton, avoiding harsh reaction
conditions and tedious starting material synthesis.
remained limited (Figure 2).
In 2016, Chen and Yin reported
an efficient copper-catalyzed aerobic oxidative esterification of 2-
methylquinoline with alcohols, avoiding the use of SeO2 as the
stoichiometric oxidant. [10a] Miller developed a domino reduction--
condensation process to quinoline formation, in which only one
[10c]
example of quinoline-2-carboxylate ester was provided.
Based on
a
copper-promoted N=N bond cleavage of
azobenzenes, Yi and Xi reported an elegant synthesis of quinoline
derivatives, albeit harsh reaction conditions (120 oC in sealed
tube) were necessary to achieve high yields of the desired
[10d]
products.
A copper-catalyzed [5+1] annulation of 2-
The quinoline skeleton, as substructures in a broad range of
bioactive molecules, plays an important role in organic and
pharmaceutical chemistry, exhibiting various biological activities,
ethynylanilines with an N,O-acetal as a C1 unit were also utilized
[10e]
to preparation of quinoline-2-carboxylate esters.
Although
these methods provided different routes to quinoline-2-
carboxylate esters, some shortcomings such as harsh reaction
conditions, tedious starting material synthesis and narrow
substrate scope still restricted their broader applications in
synthesis of quinoline-2-carboxylate esters. Consequently, use of
lower functionalized substrates, which avoided inaccessible
substrate preparation and incompatibility between functional
groups and harsh reaction conditions, is highly desirable to
construct this structure.
[1]
[2]
[3]
such as antimalarial, anti-inflammatory, antibacterial and
[4]
others.
In these huge compound libraries, quinoline-2-
carboxylates possess an indispensable position, and exist in a
number of natural products (Figure 1). [5] For example, Kynurenic
acid derivatives were reported to possess glycine/NMDA
[5b, c]
antagonist activity.
Ascidiathiazones A and B, which were
isolated from the New Zealand ascidian Aplidium species, can
inhibit the production of superoxide by PMA stimulated human
neutrophils in a dose-dependent manner. [5d]
O
O
O
OH
Ph
N
O
O
O
O
N
Ph
NO2
oneBr
S
S
N
CO2H
O
e
CO2R
exampl
CuI
eq)
OH
eq)
o
120
(5
N
H
N
CO2R
N
H
(1
N
exampl
(5
CO2R
2
C
eq)
o
C
e
2
one
O
O
O
ZnCl
70
R = H and Me
Ascidiathiazones and
SnCl
N
A
B
Kynurenic acid
[O]
ROH
CO2R
CuBr2
N
CO2R
MeO
Figure 1. Some natural quinoline-2-carboxylate structures
N
Me
reflux
TBPA
(10 mol %)
[Cu]
DCM,
NH2
Due to the great importance of quinoline derivatives,
considerable efforts were devoted to synthesizing them, such as
N
H
CO2R
29 examples;
up to 95% yield.
This work
[6]
the Conrad_Limpach_Knorr synthesis,
the Skraup-Doebner-
[7]
[8]
Von Miller synthesis,
the Friedländer synthesis,
However, the methods to quinoline-2-carboxylates
and other
[9]
methods.
Figure 2. Different approaches to quinoline-2-carboxylates
[a]
Prof. X. Jia, Prof. Y. Yuan and Mr. X. Zhang
School of Chemistry & Chemical Engineering
Yangzhou University
Yangzhou, Jiangsu 225002, China
E-mail: jiaxd1975@163.com
In the past decades, free radical mediated transformations
have become a powerful method to construct complex molecules.
Inspired by these elegant methodologies, our group has
developed several related methodologies to build a series of
[11]
[b]
[c]
Mr. P. Li, Mr. W. Hou, Ms. X. Liu and Mr. H. Ji
College of Chemistry & Chemical Engineering
Northwest Normal University
Lanzhou, Gansu 730070, China
Ms. Y. Shao
School of Information Engineering
Yangzhou University
Yangzhou, Jiangsu 225127, China
heterocyclic structures based on oxidative Povarov reaction and
its variants.
[12]
In these investigations, the sp3 C-H bonds in N-
aryl glycines were found to be reactive and easily oxidized to the
corresponding radicals due to the captodative effect. [13] Since the
captodative effect can be delivered by the C=C double bond
through -conjugation, we questioned whether alkyl 4-
anilinocrotonates could also be employed to achieve the C-H
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bond functionalization (Figure 2). Herein, we reported a facile
construction of quinoline-2-carbloxylate esters through radical
cation salt induced aerobic oxidation of sp3 C-H bonds in alkyl 4-
anilinocrotonates.
amount of aniline (10 mol %) was then examined under similar
conditions to initiate the Michael-type attack to the generated
iminium intermediate (entries 11-15). To our delight, not only the
reaction efficiency was increased to 74% yield, but also the
reaction time was greatly shortened. Further copper catalysts
examination revealed that CuBr gave the best result, and the
corresponding quinoline derivative was observed in a 90% yield
(entry 14).
Table 1. Optimization of Reaction Conditions a
TBPA
(10 mol %)
MeO
MeO
additive
N
CO2Me
solvent, T oC, O2
N
CO2Me
H
1aa
2aa
Scheme 1. Scope of Anilines a
entry
additive
none
solvent
time (h)
yield (%) b
38
1
MeCN
72
48
72
120
120
160
48
160
8
TBPA
(10 mol %)
R1
R1
2
none
THF
29
CuBr (10 mol %)
ArNH2 (10 mol %)
N
CO2Me
CO2Me
N
CO2Me
H
1,4-dioxane, 60 oC, O2
1
2
3
none
PhOMe
30
R1
4
none
DCE
43
N
CO2Me
N
N
CO2Me
5
none
CCl4
48
OMe
Me
R1 = OMe,
, 90% (3h)
, 71% (1h)
, 87% (2h)
2aa
2ha
, 64% (3.5h)
2ia
, 47% (4.5h)
2ba
= OEt,
= Me,
6
none
CHCl3
41
Me
Br
Me
Me
2ca
2da
, 62% (12h)
= F,
7
none
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
51
N
CO2Me
N
CO2Me
2ea
= Cl,
= Br,
= H,
, 59% (13h)
, 70% (12h)
, 62% (8.5h)
Cl
F
2fa
8
TfOH
TFA
55
2ja
, 85% (1.5h)
2ka
, 66% (8.5h)
2ga
F
9
56
N
CO2Me
N
CO2Me
10
11 c
12 c
13 c
14 c
15 c
CuOAc
CuOAc
CuCl2
CuBr2
CuBr
CuCl
4
60
N
CO2Me
Me
Me
Me
2ma
2na
, 83% (7h)
, 91% (4h)
4
74
2la, 53% (4h)
Me
OMe
3
83
MeO
N
CO2Me
3
78
N
CO2Me
N
CO2Me
Me
OMe
2pa
3
90
2oa
2qa
, 45% (8h)
, 51% (8h)
, 40% (7h)
R
3
84
N
CO2Me
a Unless otherwise specified, the reaction was carried out with 1aa (0.1 mmol)
in the presence of TBPA+., and anhydrous solvent (1.0 mL) at 60 oC. b Yield of
crude product 1HNMR using 1,3,5-trimethoxylbenzene as internal standard. c 4-
Anisidine (10 mol %) was added.
R = NO2, CF3
no reaction
N
CO2Me
2ra
, 41% (4h)
Reaction conditions: 1 (1 mmol), TBPA+. (10 mol %), CuBr (10 mol %), the
a
corresponding anilines (10 mol %), 1,4-dioxane (5 mL), 60 °C under O2, isolated
yield.
To find the best conditions to achieve the efficient synthesis
of quinoline-2-carboxylate esters, we started our study on alkyl 4-
anilinocrotonate 1aa in the presence of 10 mol % TBPA+. (tris(4-
bromophenyl)aminium hexachloroantimonate) in MeCN (Table
1). To our delight, the reaction occurred smoothly, and the desired
quinoline 2aa was detected in 38% yield (entry 1). Then the
solvent screen was performed to increase the reaction efficiency
(entries 1-7), and the results show that halogenated solvents gave
higher yields with elongated reaction time (entries 4-6), and when
1,4-dioxane used, the best result was obtained, providing the
expected product in 51% yield (entry 7). We found that these
aerobic oxidative conditions are sufficient to promote the full
conversion of the starting material, however, the yields of the
desired product remain unsatisfied. The reasons were attributed
to decomposition of the generated iminium intermediate, which
implied that the cyclization process to quinoline ring should be
accelerated. Then some additives were added to increase the
reaction efficiency (entries 8-15). In the presence of 10 mol %
CuOAc, the yield of the quinoline was improved to 60%. Taking
the mechanism into account (vide infra), addition of a catalytic
With optimized reaction conditions in hand, the scope and
limitations of the title procedure were explored. Firstly, the scope
of anilines was investigated, and the results were compiled in
Scheme 1. Aniline derivatives bearing electron-donating groups
such as MeO, EtO and Me at the para-position of the aromatic
ring underwent this transformation smoothly to produce the
desired quinoline products in good yields (2aa-2ca). Slightly lower
yields were obtained for the halogenated and unsubstituted
systems with elongated reaction time (2da-2ga), for the
conjugated effect between the lone pair on nitrogen and the
generated radical center was weakened. Ortho-substituted
analogues provided similar results (2ha and 2ia). Various 2,4-
disubstituted anilines were then tested, and the substrates with
electron-donating groups still gave higher yields (2ja-2na). The
reaction efficiency was reduced by 2,5-disubstituted substrates
(2oa-2pa), probably due to the higher steric hindrance. When
meta-group existed, the cyclization occurred selectively on para-
position probably due to steric reasons, and the corresponding
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product 2qa was isolated in a moderate yield. Naphthylamine was
shown to be compatible under the current oxidative conditions,
affording the desired product 2ra in 41% yield. The oxidation of
sp3 C-H bonds was totally inhibited in the presence of strong
electron-withdrawing groups such as NO2, CF3, and the
corresponding starting materials were fully recovered.
hand, when the reaction of 1fa was conducted in the presence of
more nucleophilic anisidine (1 equivalent), the quinoline product
2aa and 2fa were detected in 51% and 12% yields, respectively
14
(eq 4). These results suggested that the cyclization step is a
Friedel-Crafts-type reaction, and the more electron-rich aniline is
preferred. Since hydrolysis of the generated iminium intermediate
could release an aniline to initiate the Michael addition, we added
1 equivalent of water to the reaction mixture, and the yield was
decreased to 25% (eq 5), which means that the C-N bond
cleavage does not mainly occur at the iminium intermediate
formation step, and the extra aniline is necessary to promote the
initial Michael addition. These results are also supported by the
reaction condition optimization (see Table 1, entries 11-15).
We next examined various ester groups to test the reaction
scope and functional group tolerance. Ethyl and phenyl esters
performed well with good yields, giving the desired products 2ab
and 2ac in 70% and 95% respectively. Then, esters with another
relatively active benzyl C-H bond were employed to test the
selectivity of the C-H bond oxidation (2ad-2ag), and the results
showed that the reaction process was not disturbed, providing the
expected quinolines in high yields. Other sensitive groups such
as cyclopropyl ring (2ah), C-C double bond (2ai) and triple bonds
(2aj) were completely tolerated in these mild oxidative conditions.
It is worth noting that the congener of diethyl phosphate was also
suitable for construction of quinolin-2-yl phosphonates 2ak, which
furnished desired quinolin-2-yl phosphonates in satisfactory yield.
However, the reaction efficiency of methyl substituted crotonate
was decreased (2al) probably due to steric reasons.
Scheme 3. Control Experiments
standard conditions
1aa
1aa
1aa
2aa
2aa
1)
2)
TEMPO (1 eq)
trace
standard conditions
argon
no reaction
Scheme 2. Scope of Esters a
standard conditions
2aa
60%
2fa
trace
3)
4)
+
+
4-BrC6H4NH2
(1 eq)
TBPA
(10 mol %)
MeO
standard conditions
1fa
2aa
51%
2fa
12%
Het
O
CO2R2
4-MeOC6H4NH2
(1 eq)
CuBr (10 mol %)
ArNH2 (10 mol %)
N
CO2R2
H
1,4-dioxane, 60 o
C
2
1
TBPA
(10 mol %)
2aa
5)
1aa
CuBr (10 mol %)
MeO
Het
O
Ph
Het
Naph-2
25%
1,4-dioxane, 60 oC
O
Ph
H2O (1 eq)
O
N
CO2R2
2af
2ag
, 62% (2h)
, 76% (2h)
R2 = Et,
= Ph,
, 70% (2h)
Scheme 4. Proposed Mechanism
2ab
2ac
Het
O
Ph
Het
O
O
, 95% (2h)
, 70% (2h)
, 85% (3h)
O
2ad
2ae
= Bn,
2ah
2ai
, 63% (3h)
= Cy,
, 84% (3h)
Ar
2
N
CO2Me
Cu(II)
ArNH2
Cu
H
MeO
B
Het
Het
O
O2
Cu(I)
CO2Me
P(OEt)2
O
O
N
CO2Et
2al
, 34% (2h)
NHAr
2aj
2ak
, 88% (2h)
MeO
, 53% (1.5h)
Ar
N
NH
Het =
H
R
A
Ar
N
N
E
CO2Me
CO2Me
Cu
H
C
O2
N
TBPA
NHAr
1
a
Reaction conditions: 1 (1 mmol), TBPA+. (10 mol %), CuBr (10 mol %), the
[O]
corresponding anilines (10 mol %), 1,4-dioxane (5 mL), 60 °C under O2, isolated
yield.
N
H
D
CO2Me
Some control experiments were then performed to probe the
mechanism (Scheme 3). In the presence of 1 equivalent of radical
inhibitor TEMPO, the reaction was totally inhibited, and only trace
amount of the desired product was detected by crude product 1H
NMR (eq 1), implying that a radical intermediate might be involved
in this reaction. When the reaction was conducted under argon
atmosphere, no reaction occurred, and the starting material was
fully recovered (eq 2). So dioxygen is crucial to facilitate the C-H
bond oxidation. To reveal the role of the additive, anilines, we
performed this reaction in the presence of 1 equivalent of another
aniline (4-bromoaniline), and the corresponding product 2aa was
isolated in 60% yield with trace amount of 2fa (eq 3). On the other
Based on these results, a radical mediated mechanism was
proposed to rationalize this radical cation-initiated sp3 C-H
oxidation (Scheme 4). In the presence of dioxygen and TBPA+.,
the sp3 C-H bond adjacent to nitrogen was oxidized to a radical
intermediate A. [15] The radical intermediated was further oxidized
by the generated Cu(II) species, providing
a an iminium
intermediate B. The Cu(II) catalyst was reduced to Cu (I), which
was further oxidized by dioxygen to participate next catalytic
cycle. Then the corresponding aniline added to the iminium
[16]
intermediate via a copper accelerated Michael-type addition,
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Chem. 1991, 34,1243; c) S. Manfredini, B. Pavan, S. Vertuani, M.
Scaglianti, D. Compagnone, C. Biondi, A. Scatturin, S. Tanganelli, L.
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affording the adduct C. After an intramolecular Friedel-Crafts-type
cyclization, an aniline substituted tetrahydroquinoline D was
generated. The C-H bond adjacent to nitrogen is more active and
was further oxidized, affording a dihydroquinoline intermediate E.
Enabled by aromatization, the desired quinoline-2-carboxylate
ester 2 was formed, together with aniline extrusion to initiate the
second Michael-type addition.
In summary, a facile construction of quinoline-2-carboxylate
esters was achieved under a radical cation promoted aerobic
oxidation of sp3 C-H bonds. Compared with other methods to this
pharmaceutically relevant skeleton, this approach is superior in
high reaction efficiency, accessible starting materials and mild
reaction conditions. Further studies and applications in quinoline
derivative preparation are still in progress in our laboratory.
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Experimental Section
A solution of 1 (1 mmol), CuBr (10 mol %) and the corresponding aniline
(10 mol %) in 1,4-dioxane(5 mL) was mixed fully and flushed with O2, then
TBPA+. (10 mol %) was added dropwise under oxygen atmosphere. The
reaction solution was stirred under 60oC. After completion monitored by
TLC (by UV visualization), the reaction was quenched by addition of
saturated Na2CO3 in MeOH (10 mL) solution. The mixture was poured into
a separator funnel with the addition of excess DCM (10 mL), and then the
crude organic solution was extracted three times with water to remove
inorganic salts. The organic phase was then dried over anhydrous
magnesium sulfate, filtered, and the solvent was removed under reduced
pressure. The products were separated by silica gel column
chromatography eluted with petroleum ether/acetone (v/v 20:1) to afford
the products.
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Acknowledgements ((optional))
The authors thank Natural Science Foundation of China (NSFC,
No. 21362030 and 21562038) for supporting our research.
Keywords: C-H functionalization • Quinoline-2-carboxylate
esters • Radical cation salt • Radical • Aerobic oxidation
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10.1002/asia.201700560
Chemistry - An Asian Journal
COMMUNICATION
COMMUNICATION
Xiaodong Jia*[a], Pengfei Li, [b] Yu Shao,
[c] Yu Yuan, [a] Wentao Hou, [b] Xiaofei
TBPA
Liu, [b] Xuewen Zhang, [a] and Honghe Ji
H
H
(10 mol %)
R1
R1
N
CO2R2
CuBr (10 mol %)
ArNH2 (10 mol %)
N
CO2R2
[b]
H
1,4-dioxane, 60 oC, O2
29 examples
up to 95% yield
Page No. – Page No.
A Facile Construction of Quinoline-2-
carboxylate Esters through An
Aerobic Oxidation of Alkyl 4-
Anilinocrotonates Induced by Radical
Cation Salt
A facile construction of quinoline-2-carboxylate esters through an aerobic oxidation
of alkyl 4-anilinocrotonates was described. This reaction provided a new way to
construct the pharmaceutically relevant quinoline skeleton, avoiding harsh reaction
conditions and tedious starting material synthesis.
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