Copper-Catalyzed Tandem Reaction of Enamino Esters with ortho-Halogenated Aromatic Carbonyls: One-Pot Approach to Functionalized Quinolines

Article abstract of DOI:10.1002/ejoc.201701472

An efficient and practical approach for the synthesis of functionalized quinolines has been developed by using the copper-catalyzed tandem C–C bond formation and C–N coupling reaction of enamino esters and ortho-halogenated aromatic carbonyl compounds. Various functional groups were tolerated under the reaction conditions, and a series of quinolines were easily obtained in moderate to good yields. A gram-scale reaction was also performed to demonstrate a further application of this synthetic method.

Full text of DOI:10.1002/ejoc.201701472

A Journal of
Accepted Article
Title: Copper-catalyzed tandem reaction of enamino esters with ortho-
halogen aromatic carbonyls: one pot approach to functionalized
quinolines
Authors: Zhiwei Chen, Fei Peng, Jin Liu, and Lili Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701472
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10.1002/ejoc.201701472
European Journal of Organic Chemistry
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Copper-catalyzed tandem reaction of enamino esters with ortho-
halogen aromatic carbonyls: one pot approach to functionalized
quinolines
Fei Peng,[a] Jin Liu,[a] Lili Li [a] and Zhiwei Chen*[a]
Abstract: A novel, efficient, and practical approach for the synthesis
of functionalized quinolines has been developed through the copper-
catalyzed C–C bond formation and C–N coupling of enamino esters
with ortho-halogen aromatic carbonyls. By using this methodology, a
series of quinolines can be easily obtained in moderate to good
yields with favorable functional group tolerance. A gram-scale
reaction was also performed to demonstrate the scaled-up
applicability of this methodology.
(Scheme 1c).[9] In addition, syntheses of quinolines via Ru-
catalyzed cyclization process have also been reported by
Kapur,[10] Sun[11] and Hu[12] groups, respectively. However, all
these methods employed precious metals as the catalysts, and
in terms of sustainability and practicability, thus it is highly
desirable to exploit efficient methods to access these structural
motifs using inexpensive and widely abundant metals as
catalyst.[13] In this concern, copper is an extremely diverse and
earth-abundant transition metal that has received increasing
attention for the construction of various bonds in organic
synthesis during the past years.[14] Copper-catalyzed Ullmann C–
N coupling has made great progress towards the construction of
N-heterocycles.[15] Recently, Kaeobamrung group reported the
copper-catalyzed 2-halobenzaldehydes and cyclic enaminones
to accomplish dihydroacridines, and acyclic enaminones to
achieve quinolines,[15g] our work was focused on the chain
enamino esters formation of functionalized quinolines which can
be used to complement Kaeobamrung’s work. On the other
hand, enamino esters are useful synthons showing prevalent
application in organic synthesis and have been discovered with
widespread application in the construction of N-containing
Introduction
The quinoline skeleton is a core structure in various natural
products and pharmaceuticals (Figure 1).[1] Quinoline derivatives
play an important role in medicinal chemistry, which exhibit a
diverse range of biological properties, such as anticancer,[2]
antimicrobial,[3] anti-parasitic,[4] and antipsychotic activities.[5]
Accordingly, the development of new reliable and practical
synthetic approaches to prepare quinolines from readily
available starting materials is of great interest.
heterocyclic compounds such as pyrroles,[16] pyridines[17]
,
pyrazoles[18] and oxazoles.[19] During our continuous research in
constructing nitrogenous heterocyclic compounds using
enamino esters[20], a copper-catalyzed tandem approach is
designed for the synthesis of quinolines via cascade formation of
one C–C and one C–N bonds (Scheme 1d).
Figure 1. Selected examples bearing the quinoline core structure.
Recently, transition-metal-catalyzed C–H functionalization has
emerged as an efficient and versatile method for accessing
various heterocycles and carbocycles.[6] In this context, various
methodologies have been developed to produce versatile
quinolines via transition-metal-catalyzed C–H functionalization.
In 2012, Liu and co-workers described the Au-catalyzed [4 + 2]
cyclization of 2-aminoaryl carbonyls and alkynes to form 3-acyl
quinolines (Scheme 1a).[7] Similarly, an elegant work reported by
Zhou group disclosed an efficient approach for the preparation
of quinolines through PdII-catalyzed syntheses from 2-amino
aromatic ketones and alkynes (Scheme 1b).[8] Recently, Jiang
group developed an efficient method for the synthesis of
functionalized quinolines through C–C double bond cleavage
[a]
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology; College
of Pharmaceutical Sciences, Zhejiang University of Technology.
Chao Wang Road 18th, 310014, Hangzhou (China)
E-mail: chenzhiwei@zjut.edu.cn
Scheme 1. Different protocols for the synthesis of quinolines.
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10.1002/ejoc.201701472
European Journal of Organic Chemistry
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Results and Discussion
dependent on electronic effects of substitutes at the aryl
segments of enamino esters, as the aryl para- and ortho-
position of enamino esters with electron-donating substituents
showed higher yield than those with electron-withdrawing groups
(3ba, 3ca vs. 3da and 3ja, 3ka vs. 3la). In addition, meta-chloro
and methyl substituted substrates reacted smoothly and resulted
in the target quinolines (3ha and 3ia) in 61–66% yields.
Satisfyingly, thienyl- 1m and pyridy- 1n enamino esters
proceeded well to afford desired products 3ma in 51% and 3na
86% yield, respectively. Fused aryl enamino esters were also
compatible with the reaction and gave products 3oa, 3pa and
3qa in moderate yields. This reaction was also applicable to
substrates possessing bulky tert-butyl ester and methyl ester
groups (3ra and 3sa), steric hindrance of tert-butyl might result
in the lower yield of 3ra. However, no reaction occurred when
the aliphatic enamino esters 1t and 1u were used as the
substrates.
The model substrates initially used to evaluate the domino
reaction were ethyl 3-amino-3-phenylacrylate (1a) and 2-
bromobenzaldehyde (2a) (Table 1). After exploring a set of
copper salts, CuI turned out to be the optimal catalyst, leading to
the desired product 3a in 76% yield. Next, various solvents, such
as toluene, dioxane and CH3CN, were examined, while DMF
gave the highest yield (entries 5–8). Subsequently, effect of
bases was investigated (entries 9–12), stronger bases did not
afford higher yields (entries 11 and 12), and K2CO3 provided the
best result (entry 5). Changing the ligand to 2, 2’-bipyridine or 1,
10-phen was also observed to be detrimental leading to a slight
drop in the yields (entries 13 and 14). No reaction occurred in
the absence of copper catalyst (entry 15), whereas a decrease
in yield was observed in the absence of ligand or base (entries
16 and 17). Finally, the screening of reaction temperatures
indicated that the reaction gave the best result at 120 oC (entries
5, 18 and 19). Hence, the most optimal conditions of 10 mol%
CuI, 20 mol% L-proline and 3.0 eq. of K2CO3 in DMF at 120 oC
were simultaneously used for further investigation.
Table 1. Optimization of Reaction Conditions for Synthesis of quinolines. [a]
Yield (%)
Entry
Catalyst
Base
Ligand
Solvent
[b]
1
2
3
CuCl
CuBr
CuI
K2CO3
K2CO3
K2CO3
L-Proline
L-Proline
L-Proline
DMSO
DMSO
DMSO
61
55
76
4
5
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
t-BuONa
K2CO3
K2CO3
K2CO3
K2CO3
-
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
2, 2’-bipyridine
1, 10-Phen
-
DMSO
DMF
60
86
77
59
74
80
48
78
63
81
76
N.R.
67
47
75
84
6
Toluene
dioxane
CH3CN
DMF
7
8
9
10
11
12
13
14
15
16
17
18 [c]
19 [d]
DMF
Scheme 2. The tandem reaction of enamino esters with 2-
DMF
bromobenzaldehyde. [a]
DMF
DMF
DMF
[a] Reaction conditions: enamino esters 1 (0.5 mmol), 2-bromobenzaldehyde
2a (0.6 mmol), CuI (0.05 mmol), K2CO3 (1.5 mmol), L-Proline (0.1 mmol), 2.0
mL DMF, 120 °C, 18 h, nitrogen atmosphere, in sealed Schlenk tube. [b] The
reaction was performed for 24 h.
DMF
CuI
CuI
CuI
CuI
-
DMF
L-Proline
L-Proline
L-Proline
DMF
K2CO3
K2CO3
DMF
DMF
To further evaluate the versatility and compatibility of the
present protocol, attention was next turned toward exploring the
scope of ortho-halogen aromatic carbonyls. As shown in scheme
3, various substituted ortho-bromine aromatic aldehydes 2 were
coupled with ethyl 3-amino-3-phenylacrylate 1a under the
current reaction conditions to deliver the structurally diverse
quinoline motifs in 55–79% yields (3ab–3ae). A number of
electron-donating groups and halogen groups were well
tolerated. Notably, the ortho-bromoacetophenone could also
participate smoothly in the reaction, leading to the corresponding
product 3af in high yield, steric hindrance of tert-butyl ketone
can not participate in the reaction to give the product 3ag. For
ortho-iodobenzaldehyde, similar reactivity was observed (X = I,
3aa, 81%). However, ortho-chlorobenzaldehyde was not
[a] Reaction conditions: ethyl-3-amino-3-phenylacrylate 1a (0.5 mmol), 2-
bromobenzaldehyde 2a (0.6 mmol), copper catalyst (0.05 mmol), base (1.5
mmol), ligand (0.1 mmol), 2.0 mL solvent, 120 oC, 18 h, nitrogen atmosphere,
in sealed Schlenk tube. [b] Isolated yield based on 1a. [c] At 110 oC. [d] At 130
oC. N. R. = no reaction.
Having identified the optimized reaction conditions, we next
investigated the scope of enamino esters 1, as the tandem
reaction partner with 2-bromobenzaldehyde 2a. As shown in
scheme 2, a broad range of electron-withdrawing and electron-
donating substituents at the aryl para- and ortho- position of
enamino esters were well tolerated, and the corresponding
products (3aa–3ga and 3ja–3la) were delivered in moderate to
good yields. It was worth noting that the reaction yield was
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10.1002/ejoc.201701472
European Journal of Organic Chemistry
FULL PAPER
reactive and no desired product was observed (X = Cl, 3aa, 0%).
Furthermore, the method was also tested for the synthesis of
thieno[3,2-b]pyridine derivatives, which are useful bioactive
compounds and possess a diverse range of biological functions
such as urotensin-II receptor antagonists,[21] Src kinase
inhibitor,[22] and RON receptor tyrosine kinase inhibitor.[23] To our
presence of base, II would lead to III. The resulting intermediate
III on reductive elimination would give quinolines 3 via copper-
catalyzed Ullmann C–N coupling.
delight,
desired
ethyl
5-phenylthieno[3,2-b]pyridine-6-
carboxylate 3ah was successfully synthesized in moderate yield.
We also tried to synthesize 1,8-naphthyridine 3ai and
pyridoindole structures 3aj, but unfortunately we did not get the
product.
Scheme 5. Possible mechanism
Conclusions
In conclusion, we have developed a novel, efficient, and
practical copper-catalyzed tandem method for construction of
functionalized quinolines. The protocol uses cheap and readily
available CuI as the catalyst, substituted enamino esters and
ortho-halogen aromatic carbonyls as the starting materials, and
the corresponding quinolines were obtained in moderate to good
yields. The thienopyridine skeleton also has been constructed,
this method would provide a new and useful strategy for
constructing of fused aza-heterocyclic compound.
Scheme 3. The tandem reaction of ortho-halogen aromatic carbonyls with
ethyl-3-amino-3-phenylacrylate. [a]
[a] Reaction conditions: ethyl-3-amino-3-phenylacrylate 1a (0.5 mmol), ortho-
halogen aromatic carbonyls 2 (0.6 mmol), CuI (0.05 mmol), K2CO3 (1.5 mmol),
L-Proline (0.1 mmol), 2.0 mL DMF, 120 °C, 18 h, nitrogen atmosphere, in
sealed Schlenk tube. [b] The reaction was performed for 24 h.
Experimental Section
To examine the practicality of the reaction system, the
copper-catalyzed tandem annulation reaction was conducted on
a gram scale, and the desired product 3aa was obtained in a
good yield of 75%, thus highlighting the synthetic utility of this
methodology (Scheme 4).
Materials and general experimental details
All reagents were obtained from commercial sources (purity > 99%)
and used without further purification, unless otherwise indicated. Silica
gel for column chromatography was purchased from Qingdao Haiyang
Chemical Co., Ltd. Reactions were stirred using Teflon-coated magnetic
stir bars. Thin-layer chromatography (TLC)
Melting points were determined using a Büchi B-540 capillary melting
point apparatus. 1H NMR and 13C NMR were recorded with Bruker
Avance III instruments at 600 and 150 MHz in CDCl3 using
tetramethylsilane (TMS, δ = 0 ppm) as internal standard. Data were
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet), respectively. Mass spectra were
measured with Thermo Finnigan LCQ-Advantage. High resolution mass
spectral (HRMS) analyze was measured on an Agilent 1290-6540
UHPLC Q-Tof HR-MS System ESI spectrometer.
Scheme 4. Gram-scale experiment
On the basis of the above experimental results and
previously published results,[16–20] a plausible mechanism for the
tandem reaction is depicted in Scheme 5. Initially, the reaction of
enamino esters 1 and ortho-halogen aromatic carbonyls 2 gives
intermediate I via C–C bond formation. The intermediate I would
then undergo oxidative addition to give intermediate II. In the
General procedure for the synthesis of quinolines 3. A 25 mL sealed
Schlenk tube was charged with enamine 1 (0.5 mmol), ortho-halogen
aromatic carbonyls 2 (0.6 mmol), CuI (0.05 mmol), L-proline (0.1 mmol),
K2CO3 (1.5 mmol) and DMF (2 mL) under nitrogen atmosphere. The
reaction was performed at 120 oC for 18-24 h. The resulting mixture was
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10.1002/ejoc.201701472
European Journal of Organic Chemistry
FULL PAPER
cooled to room temperature and queous NH4Cl (30 mL) was added. The
aqueous phase was extracted with ethyl acetate (3 x 25 mL). The
combineid organc extracts were dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to afford the corresponding products 3.
7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.6,
157.0, 148.4, 139.7, 139.5, 131.8, 131.3, 130.3, 129.5, 128.3, 127.5,
125.9, 125.0, 123.1, 61.7, 13.8. HRMS (ESI): m/z: calcd for C18H15BrNO2
[M + H]+ 356.0281, found: 356.0282.
Ethyl 2-(3-chlorophenyl)quinoline-3-carboxylate (3ha). Yellow oil (95
mg, 61% yield). 1H NMR (600 MHz, CDCl3) δ 8.72 (s, 1H), 8.21 (d, J =
8.4 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.86 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H),
7.69 – 7.64 (m, 2H), 7.51 (dt, J = 7.2, 1.2 Hz, 1H), 7.47 – 7.40 (m, 2H),
4.26 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 167.5, 156.7, 148.3, 142.5, 139.6, 134.1, 131.9, 129.6, 129.4,
128.8, 128.62, 128.3, 127.6, 126.9, 126.0, 125.1, 61.7, 13.8. HRMS (ESI):
m/z: calcd for C18H15ClNO2 [M + H]+ 312.0786, found: 312.0783.
Ethyl 2-phenylquinoline-3-carboxylate (3aa). Yellow oil (119 mg, 86%
yield). 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H),
7.93 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.64 – 7.60 (m, 3H),
7.49 – 7.44 (m, 3H), 4.20 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). 13
C
NMR (150 MHz, CDCl3) δ 168.0, 158.2, 148.4, 140.8, 139.1, 131.6,
129.6, 128.6 (2), 128.2 (2), 127.3, 125. 9, 125.6, 61.6, 13.7. HRMS (ESI):
m/z: calcd for C18H16NO2 [M + H]+ 278.1176, found: 278.1178.
Ethyl 2-(p-tolyl)quinoline-3-carboxylate (3ba). Yellow oil (129 mg, 89%
yield). 1H NMR (600 MHz, CDCl3) δ 8.62 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H),
7.91 (d, J = 7.8 Hz, 1H), 7.80 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.61 (ddd, J
= 7.8, 7.2, 1.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H),
4.22 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ 168.2, 158.1, 148.4, 138.9, 138.5, 137.8, 131.5,
129.5, 128.9, 128.6, 128.2, 127.1, 125.8, 125.5, 61. 6, 21.4, 13.8. HRMS
(ESI): m/z: calcd for C19H18NO2 [M + H]+ 292.1332, found: 292.1334.
Ethyl 2-(m-tolyl)quinoline-3-carboxylate (3ia). Yellow oil (96 mg, 66%
yield). 1H NMR (600 MHz, CDCl3) δ 8.63 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H),
7.91 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 7. 8Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H),
7.49 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.26 (s,
1H), 4.20 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). 13
C
NMR (150 MHz, CDCl3) δ 168.1, 158.3, 148.4, 140.7, 138.9, 137.9,
131.5, 129.6, 129.4, 129.2, 128.2, 128.1, 127.2, 125.9, 125.8, 125.7,
61.5, 21.5, 13.7. HRMS (ESI): m/z: calcd for C19H18NO2 [M + H]+
292.1332, found: 292.1333.
Ethyl 2-(4-methoxyphenyl)quinoline-3-carboxylate (3ca). Yellow oil
(110 mg, 72% yield). 1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.16 (d, J
= 8.4 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.80 (ddd, J = 8.4, 7.8, 1.2 Hz,
1H), 7.61 (d, J = 8.4 Hz, 2H), 7.58 (ddd, J = 8.4, 7.8, 1.2 Hz, 1H), 7.00 (d,
J = 6.0 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.16 (t, J = 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 168.3, 160.2, 157.5, 148.4, 139.0,
133.1, 131.5, 130.1, 129.4, 128.2, 127.0, 125.7, 125.5, 113.7, 61.6, 55.4,
13.9. HRMS (ESI): m/z: calcd for C19H18NO3 [M + H]+ 308.1281, found:
308.1282.
Ethyl 2-(2-fluorophenyl)quinoline-3-carboxylate (3ja). Yellow oil (96
mg, 65% yield). 1H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H), 8.19 (dd, J =
8.4, 0.6 Hz, 1H), 7.98 – 7.94 (m, 1H), 7.83 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H),
7.72 (td, J = 7.2, 1.8 Hz, 1H), 7.63 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.43 (m,
1H), 7.32 (td, J = 7.2, 1.2 Hz, 1H), 7.11 (ddd, J = 10.2, 8.4, 1.2 Hz, 1H),
4.26 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 166.6, 160.9, 159.3, 153.4, 148.8, 139.5, 131.8, 130.9 (JC-F
=
3.0 Hz), 130.5 (JC-F = 7.5 Hz), 129.6, 129.1 (JC-F = 15.0 Hz), 128.5, 127.6,
125.9 (JC-F = 106.5 Hz), 124.5 (JC-F = 3.0 Hz), 115.0 (JC-F = 21.0 Hz),
61.5, 13.8. HRMS (ESI): m/z: calcd for C18H15FNO2 [M + H]+ 296.1081,
found: 296.1076.
Ethyl 2-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylate (3da).
White solid (97 mg, 56% yield). mp 114-116 oC. 1H NMR (600 MHz,
CDCl3) δ 8.75 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H),
7.85 (t, J = 7.8 Hz, 1H), 7.74 (s, 4H), 7.65 (t, J = 7.2 Hz, 1H), 4.22 (q, J =
7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.2,
156.9, 148.4, 144.5, 139.8, 132.0, 130.6(JC-F = 132.0 Hz), 129.6, 129.1,
128.4, 127.7, 126.1, 125.1 (JC-F = 24.0, 18.0 Hz), 124.9, 123.3, 61.7, 13.7.
HRMS (ESI): m/z: calcd for C19H15F3NO2 [M + H]+ 346.1048, found:
346.1041.
Ethyl 2-(2-chlorophenyl)quinoline-3-carboxylate (3ka). Yellow oil (78
mg, 50% yield). 1H NMR (600 MHz, CDCl3) δ 8.90 (s, 1H), 8.22 (d, J =
8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 – 7.83 (m, 1H), 7.70 – 7.65 (m,
1H), 7.55 (dd, J = 7.2, 1.8 Hz, 1H), 7.47 – 7.39 (m, 3H), 4.23 (q, J = 7.2
Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.1,
156.7, 148.6, 140.5, 139.8, 132.6, 131.9, 130.3, 129.6, 129.5, 129.0,
128.6, 127.7, 126.9, 126.4, 125.1, 61.5, 13.7. HRMS (ESI): m/z: calcd for
C18H15ClNO2 [M + H]+ 312.0786, found: 312.0789.
Ethyl 2-(4-fluorophenyl)quinoline-3-carboxylate (3ea). White solid
(100 mg, 68% yield). mp 76-77 oC. 1H NMR (600 MHz, CDCl3) δ 8.66 (s,
1H), 8.17 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz,
1H), 7.68 – 7.58 (m, 3H), 7.22 – 7.13 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H),
1.15 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.8, 164.0,
162.4, 157.1, 148.4, 139.3, 136.8 (JC-F = 3.0 Hz), 131.7, 130.5 (JC-F = 9.0
Hz), 129.5, 128.3, 127.4, 125.9, 125.2, 115.3(JC-F = 22.5 Hz), 61.6, 13.8.
HRMS (ESI): m/z: calcd for C18H15FNO2 [M + H]+ 296.1081, found:
296.1082.
Ethyl 2-(o-tolyl)quinoline-3-carboxylate (3la). Yellow oil (132 mg, 91%
yield). 1H NMR (600 MHz, CDCl3) δ 8.82 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H),
7.99 (d, J = 8.4 Hz, 1H), 7.85 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.68 – 7.62
(m, 1H), 7.38 – 7.32 (m, 1H), 7.30 – 7.21 (m, 3H), 4.15 (q, J = 7.2 Hz,
2H), 2.19 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
166.8, 159.3, 148.5, 141.0, 139.4, 135.5, 131.7, 129.9, 129.5, 128.5,
128.2, 128.2, 127.9, 127.3, 126.0, 125.5, 61.4, 19.7, 13.6. HRMS (ESI):
m/z: calcd for C19H18NO2 [M + H]+ 292.1332, found: 292.1339.
Ethyl 2-(4-chlorophenyl)quinoline-3-carboxylate (3fa). White solid (78
mg, 50% yield). mp 88-89 oC. 1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H),
8.16 (dd, J = 8.4, 0.6 Hz, 1H), 7.92 (dd, J = 8.4, 1.2 Hz, 1H), 7.82 (ddd, J
= 8.4, 7.2, 1.2 Hz, 1H), 7.61 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.59 – 7.56
(m, 2H), 7.47 – 7.43 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 167.6, 157.0, 148.4, 139.4, 139.2,
134.8, 131.8, 130.1, 129.5, 128.4, 128.3, 127.5, 125.9, 125.1, 61.7, 13.8.
HRMS (ESI): m/z: calcd for C18H15ClNO2 [M + H]+ 312.0786, found:
312.0791.
Ethyl 2-(thiophen-2-yl)quinoline-3-carboxylate (3ma). Yellow oil (72
mg, 51% yield). 1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 8.12 (d, J =
8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.80 – 7.76 (m, 1H), 7.56 (t, J = 7.2
Hz, 1H), 7.48 (dd, J = 5.4, 0.6 Hz, 1H), 7.41 (dd, J = 3.6, 0.6 Hz, 1H),
7.11 (dd, J = 4.8, 3.6 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 168.4, 150.1, 148.2, 143.1, 138.2,
131.5, 129.3, 128.5, 128.1, 128.0, 127.6, 127.2, 125.6, 125.1, 61.9, 14.0.
HRMS (ESI): m/z: calcd for C16H14NO2S [M + H]+ 284.0740, found:
284.0745.
Ethyl 2-(4-bromophenyl)quinoline-3-carboxylate (3ga). White solid
(119 mg, 67% yield). mp 81-82 oC. 1H NMR (600 MHz, CDCl3) δ 8.68 (s,
1H), 8.16 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.83 (ddd, J = 8.4,
7.2, 1.2 Hz, 1H), 7.64 – 7.58 (m, 3H), 7.53 – 7.49 (m, 2H), 4.23 (q, J =
Ethyl 2-(pyridin-4-yl)quinoline-3-carboxylate (3na). Yellow solid (119
mg, 86% yield), mp 111-113 oC. 1H NMR (600 MHz, CDCl3) δ 8.77 (s,
1H), 8.73 (d, J = 5.4 Hz, 2H), 8.19 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 8.4 Hz,
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European Journal of Organic Chemistry
FULL PAPER
1H), 7.86 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz,
1H), 7.54 (dd, J = 4.2, 1.8 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.13 (t, J =
7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.9, 155.8, 149.5, 148.7,
148.4, 139.9, 132.1, 129.6, 128.4, 128.0, 126.3, 124.6, 123.3, 61.8, 13.7.
HRMS (ESI): m/z: calcd for C17H15N2O2 [M + H]+ 279.1128, found:
279.1130.
123.5, 123.0, 106.0, 102.9, 102.1, 61.4, 13.7. HRMS (ESI): m/z: calcd for
C19H16NO4 [M + H]+ 322.1074, found: 322.1075.
Ethyl 6-fluoro-2-phenylquinoline-3-carboxylate (3ad). Yellow solid (84
mg, 57 % yield). mp 73-74 oC. 1H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H),
8.18 (dd, J = 9.0, 5.4 Hz, 1H), 7.64 – 7.60 (m, 2H), 7.58 (ddd, J = 9.0, 8.4,
2.4 Hz, 1H), 7.53 (dd, J = 8.4, 2.4 Hz, 1H), 7. 49 – 7.45 (m, 3H), 4.20 (q,
J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
Ethyl 2-(naphthalen-2-yl)quinoline-3-carboxylate (3oa). Yellow oil
(119 mg, 73% yield). 1H NMR (600 MHz, CDCl3) δ 8.69 (s, 1H), 8.22 (d, J
= 8.4 Hz, 1H), 8.14 (s, 1H), 7.94 – 7.88 (m, 4H), 7.85 – 7.79 (m, 1H),
7.76 (dd, J = 8.4, 1.8 Hz, 1H), 7.60 (dd, J = 7.8, 7.2 Hz, 1H), 7.54 – 7.48
(m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (150
MHz, CDCl3) δ 168.0, 158.0, 148.5, 139.2, 138.2, 133.3, 133.2, 131.6,
129.6, 128.6, 128.3, 128.2, 127.8, 127.7, 127.3, 126.5, 126.4, 126.3,
125.9, 125.7, 61.6, 13.8. HRMS (ESI): m/z: calcd for C22H18NO2 [M + H]+
328.1332, found: 328.1337.
167.8, 161.61, 159.95, 157.5 (JC-F = 3.0 Hz), 145.5, 140.4, 138.2 (JC-F
=
4.5 Hz), 132.1 (JC-F = 9.0 Hz), 128.69, 128.55, 128.25, 126.5 (JC-F = 10.5
Hz), 126.39, 121.8 (JC-F = 25.5 Hz), 111.1 (JC-F = 22.5 Hz), 61.71, 13.68.
HRMS (ESI): m/z: calcd for C18H15FNO2 [M + H]+ 296.1081, found:
296.1084.
Ethyl 6,7-dimethoxy-2-phenylquinoline-3-carboxylate (3ae). Yellow
solid (133 mg, 79 % yield). mp 154-156 oC. 1H NMR (600 MHz, CDCl3) δ
8.52 (s, 1H), 7.61 – 7.56 (m, 2H), 7.51 (s, 1H), 7.47 – 7.40 (m, 3H), 7.14
(s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 1.07 (t, J = 7.2
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 168.1, 156.6, 154.3, 150.4, 145.9,
141.2, 137.3, 128.6, 128.2, 128.1, 123.4, 121.6, 108.1, 105.2, 61.3, 56.4,
56.2, 13.7. HRMS (ESI): m/z: calcd for C20H20NO4 [M + H]+ 338.1387,
found: 338.1390.
6H-chromeno[4,3-b]quinolin-6-one (3pa). Yellow solid (95 mg, 77 %
yield). mp 222-224 oC. 1H NMR (600 MHz, CDCl3) δ 9.22 (s, 1H), 8.79
(dd, J = 7.8, 1.8 Hz, 1H), 8.24 (dd, J = 8.4, 0.6 Hz, 1H), 8.02 (d, J = 8.4
Hz, 1H), 7.92 (ddd, J = 8.4, 6.6, 1.2 Hz, 1H), 7.64 (ddd, J = 8.4, 6.6, 1.2
Hz, 1H), 7.61 – 7.58 (m, 1H), 7.46 – 7.41 (m, 1H), 7.39 (dd, J = 8.4, 0.6
Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 161.5, 152.7, 151.1, 149.6, 141.1,
133.4, 132.4, 129.6, 129.4, 127.4, 127.3, 125.3, 125.0, 119.7, 117.4,
115.8. HRMS (ESI): m/z: calcd for C16H10NO2 [M + H]+ 248.0706, found:
248.0709.
Ethyl 4-methyl-2-phenylquinoline-3-carboxylate (3af). Yellow oil (121
mg, 83% yield). 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H),
8.11 (d, J = 8.4 Hz, 1H), 7.81 – 7.77 (m, 1H), 7.73 – 7.69 (m, 2H), 7.64 (t,
J = 7.8 Hz, 1H), 7.50 – 7.45 (m, 3H), 4.17 (q, J = 7.2 Hz, 2H), 2.79 (s,
3H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.1, 156.3,
147.2, 142.8, 140.6, 130.4, 130.3, 128.8, 128.7, 128.4, 127.5, 127.0,
126.1, 124.1, 61.6, 15.7, 13.6. HRMS (ESI): m/z: calcd for C19H18NO2 [M
+ H]+ 292.1332, found: 292.1333.
Ethyl
2-(benzo[d][1,3]dioxol-5-yl)quinoline-3-carboxylate
(3qa).
Yellow solid (109 mg, 68 % yield). mp 94-96 oC. H NMR (600 MHz,
CDCl3) δ 8.59 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H),
7.80 (dd, J = 8.4, 7.2 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.10
(d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.02 (s, 2H), 4.26 (q, J = 7.2
Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 168.1,
157.3, 148.2, 147.7, 139.0, 134.7, 131.5, 129.4, 128.2, 127.2, 125.8,
125.5, 122.9, 109.3, 108.2, 101.3, 61.6, 29.7, 13.9. HRMS (ESI): m/z:
calcd for C19H16NO4 [M + H]+ 322.1074, found: 322.1076.
1
Ethyl 5-phenylthieno[3,2-b]pyridine-6-carboxylate (3ah). Yellow oil
(63 mg, 45% yield). 1H NMR (600 MHz, CDCl3) δ 8.69 (s, 1H), 7.94 (d, J
= 5.4 Hz, 1H), 7.66 (d, J = 5.4 Hz, 1H), 7.58 – 7.55 (m, 2H), 7.47 – 7.43
(m, 3H), 4.17 (q, J = 7.2 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H). 13C NMR (150
MHz, CDCl3) δ 168.0, 157.1, 157.0, 140.7, 134.4, 133.0, 130.9, 128.6,
128.4, 128.1, 125.3, 122.8, 61.5, 13.7. HRMS (ESI): m/z: calcd for
C16H14NO2S [M + H]+ 284.0740, found: 284.0741.
Tert-butyl 2-phenylquinoline-3-carboxylate (3ra). Yellow oil (96 mg,
63% yield). 1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.17 (d, J = 8.4 Hz,
1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.64 –
7.58 (m, 3H), 7.48 – 7.44 (m, 3H), 1.32 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ 167.2, 158.2, 148.2, 141.2, 138.8, 131.3, 129.5, 128.8, 128.4,
128.2, 127.2, 127.1, 126.02, 82.3, 27.6. HRMS (ESI): m/z: calcd for
C20H20NO2 [M + H]+ 306.1489, found: 306.1496.
Acknowledgements
We thank the National Natural Science Foundation of China (No.
21676253 and 21276238) for financial support.
Methyl 2-phenylquinoline-3-carboxylate (3sa). Yellow oil (108 mg,
82% yield). 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 8.20 (d, J = 8.4 Hz,
1H), 7.92 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.2 Hz,
2H), 7.61 (t, J = 7.8 Hz, 1H), 7.50 – 7.43 (m, 3H), 3.74 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 168.4, 158.0, 148.4, 140.5, 139.3, 131.7, 129.5,
128.7, 128.6, 128.3, 127.3, 125.8, 125.1, 52.5. HRMS (ESI): m/z: calcd
for C17H14NO2 [M + H]+ 264.1019, found: 264.1022.
Keywords: functionalized quinolines • copper-catalyzed •
enamino esters • ortho-halogen aromatic carbonyls
[1]
a) J. P. Michael, Nat. Prod. Rep. 2004, 21, 650-668; b) J. P. Michael,
Nat. Prod. Rep. 2008, 25, 166-187; c) S. Andrews, S. J. Burgess, D.
Skaalrud, J. X. Kelly, D. H. Peyton, J. Med. Chem. 2010, 53, 916-919;
d) K. Andries, P. Verhasselt, J. Guillemont, H. W. H. hlmann, J.-M.
Neefs, H. Winkler, J. Van Gestel, P. Timmerman, M. Zhu, E. Lee, P.
Williams, D. de Chaffoy, E. Huitric, S. Hoffner, E. Cambau, C. Truffot-
Pernot, N. Lounis, V. Jarlier, Science 2005, 307, 223-227; e) J.-J. Chen,
Y.-L. Chang, C.-M. Teng, C.-C. Su, I.-S. Chen, Planta Med. 2002, 68,
790-793. f) J. Matsui, Y. Funahashi, T. Uenaka, T. Watanabe, A.
Tsuruoka, M. Asada, Clin. Cancer Res. 2008, 14, 5459−5465.
Ethyl 2-phenylbenzo[h]quinoline-3-carboxylate (3ab). Yellow solid (90
mg, 55 % yield). mp 107-108 oC. 1H NMR (600 MHz, CDCl3) δ 9.38 (dd, J
= 6.0, 3.6 Hz, 1H), 8.63 (s, 1H), 7.94 – 7.91 (m, 1H), 7.86 (d, J = 8.4 Hz,
1H), 7.80 – 7.72 (m, 5H), 7.53 – 7.45 (m, 3H), 4.24 (q, J = 7.2 Hz, 2H),
1.12 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 168.5, 156.7,
147.0, 140.9, 138.3, 134.5, 131.2, 129.2, 129.0, 128.6, 128.5, 128.1,
127.9, 127.3, 125.6, 125.3, 124.9, 124.0, 61.6, 13.8. HRMS (ESI): m/z:
calcd for C22H18NO2 [M + H]+ 328.1332, found: 328.1339.
[2]
a) B. Li, A. Wang, J. Liu, Z. Qi, X. Liu, K. Yu, H. Wu, C. Chen, C. Hu, W.
Wang, J. Wu, Z. Hu, L. Ye, F. Zou, F. Liu, B. Wang, L. Wang, T. Ren, S.
Zhang, M. Bai, S. Zhang, J. Liu, Q. Liu, J. Med. Chem. 2016, 59, 8456-
8472; b ) T. P. Heffron, J. Med. Chem. 2016, 59, 10030-10066; c) L. G.
J. Hammarstr m, R. K. Harmel, M. Granath, R. Ringom, Y. Gravenfors,
K. Färnegårdh, P. H. Svensson, D. Wennman, G. Lundin, Y. Roddis, S.
Ethyl
6-phenyl-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate
(3ac).
Yellow oil (122 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H),
7.59 – 7.56 (m, 2H), 7.46 – 7.41 (m, 4H), 7.13 (s, 1H), 6.15 (s, 2H), 4.17
(q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
168.2, 156.5, 152.5, 148.5, 147.2, 140.9, 137.7, 128.6, 128.3, 128.10,
This article is protected by copyright. All rights reserved.

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European Journal of Organic Chemistry
FULL PAPER
S. Kitambi, A. Bernlind, F. Lehmann, P. Ernfors, J. Med. Chem. 2016,
59, 8577-8592.
[22] D. H. Boschelli, B. Wu, A. C. Barrios Sosa, H. Durutlic, J. J. Chen, Y.
Wang, J. M. Golas, J. Lucas, F. Boschelli, J. Med. Chem. 2005, 48,
3891-3902.
[3]
a) B. D. Bax, P. F. Chan, D. S. Eggleston, A. Fosberry, D. R. Gentry, F.
Gorrec, I. Giordano, M. M. Hann, A. Hennessy, M. Hibbs, J. Huang, E.
Jones, J. Jones, K. K. Brown, C. J. Lewis, E. W. May, M. R. Saunders,
O. Singh, C. E. Spitzfaden, C. Shen, A. Shillings, A. J. Theobald, A.
Wohlkonig, N. D. Pearson, M. N. Gwynn, Nature 2010, 466, 935-943;
b) E. Pitta, M. K. Rogacki, O. Balabon, S. Huss, F. Cunningham, E. M.
Lopez-Roman, J. Joossens, K. Augustyns, L. Ballell, R. H. Bates, P. V.
der Veken, J. Med. Chem. 2016, 59, 6709-6728.
[23] F. Raeppel, S. L. Raeppel, E. Therrien, Bioorg. Med. Chem. Lett. 2015,
25, 3810-3815.
[4]
a) T. r hlich, S. B. Tsogoeva, J. Med. Chem. 2016, 59, 9668−9671; b)
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, 9672-9685.
[5]
[6]
J. Galambos, A. Bielik, M. Krasavin, Z. Orgován, G. Domány, K.
Nógrádi, G. Wágner, G. T. Balogh, Z. Béni, J. Kóti, Z. Szakács, A.
Bobok, S. Kolok, M. L. Mikó-Bakk, M. Vastag, K. Sághy, J. Laszy, A. S.
Halász, O. Balázs, K. Gál, I. Greiner, Z. Szombathelyi, G. M. Keser , J.
Med. Chem. 2017, 60, 2470-2484.
a) H. Huang, X. Ji, W. Wu, H. Jiang, Chem. Soc. Rev. 2015, 44, 1155-
1171; b) K. Shin, H. Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040-
1052; c) H. Kim, S. Chang; Acc. Chem. Res. 2017, 50, 482-486; d) K.
Zhao, L. Shen, Z.-L. Shen, T.-P. Loh, Chem. Soc. Rev. 2017, 46, 586-
602; e) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215-1292.
S. Cai, J. Zeng, Y. Bai, X.-W. Liu, J. Org. Chem. 2011, 77, 801-807.
W. Zhou, J. Lei, Chem. Commum. 2014, 50, 5583-5585.
[7]
[8]
[9]
J. Zheng, Z. Li, L. Huang, W. Wu, J. Li, H. Jiang, Org. Lett. 2016, 18,
3514-3517.
[10] G. S. Kumar, P. Kumar, M. Kapur, Org. Lett. 2017, 19, 2494-2497.
[11] B. Pan, B. Liu, E. Yue, Q. Liu, X. Yang, Z. Wang, W.-H. Sun, ACS Catal.
2016, 6, 1247-1253.
[12] X. Wang, C. Liu, X. Zeng, X. Wang, X. Wang, Y. Hu, Org. Lett. 2017, 19,
3378–3381.
[13] R. M. Bullock, Science 2013, 342, 1054-1055.
[14] a) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed. 2008, 47, 3096-3099;
b) E. A. Lewis, W. B. Tolman, Chem. Rev. 2004, 104, 1047-1076; c) S.
E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem.
Rev. 2013, 113, 6234-6458; d) F. Monnier, M. Taillefer, Angew. Chem.
Int. Ed. 2009, 48, 6954-6971; e) A. E. Wendlandt, A. M. Suess, S. S.
Stahl, Angew. Chem. Int. Ed. 2011, 50, 11062-11087; f) H. Dai, C.-X.
Li, C. Yu, Z. Wang, H. Yan, C. Lu, Org. Chem. Front. 2017, 4, 2008-
2011.
[15] a) S. Biswas, S. Batra, Adv. Synth. Catal. 2011, 353, 2861-2867; b) D.
Lu, C. Ma, S. Yuan, L. Zhou, Q. Zeng, Adv. Synth. Catal. 2015, 357,
3491-3494; c) V. Murugesh, B. Harish, M. Adiseshu, J. B. Nanubolu, S.
Suresh, Adv. Synth. Catal. 2016, 358, 1309-1321; d) B. Zou, Q. Yuan,
D. Ma, Angew. Chem. Int. Ed. 2007, 46, 2598-2601; e) W. Xu, Y. Jin, H.
Liu, Y. Jiang, H. Fu, Org. Lett. 2011, 13, 1274-1277; f) W. Xu, H. Fu, J.
Org. Chem. 2011, 76, 3846-3852; g) B. Kaewmee, V. Rukachaisirikul, J.
Kaeobamrung, Org. Biomol. Chem. 2017, 15, 7387-7395.
[16] a) J. H. Kim, S. Y. Choi, J. Bouffard, S. Lee, J. Org. Chem. 2014, 79,
9253-9261; b) J. Ke, C. He, H. Liu, M. Lia, A. Lei, Chem. Commum.
2013, 49, 7549-7551.
[17] a) S. Hirai, Y. Horikawa, H. Asahara, N. Nishiwaki, Chem. Commum.
2017, 53, 2390-2393; b) N. R. Gade, V. Devendram, M. Pal, J. Iqbal,
Chem. Commum. 2013, 49, 7926-7928.
[18] Y. S. Chun, K. K. Lee, Y. O. Ko, H. Shin, S. Lee, Chem. Commum.
2008, 5098-5100.
[19] P. Gao, J. Wang, Z. Bai, D. Yang, M.-J. Fan, Z.-H. Guan, Chem. Asian
J. 2017, 12, 1865-1868.
[20]
a) Z. Chen, Z. Dai, Z. Zhu, X. Yang, Tetrahedron Lett. 2017, 58, 1258-
1261; b) Z. Chen, H. Chen, X. Yang, X. Chang, Synlett, 2017, 28, 1463-
1466.
[21] C. J. Lim, S. A. Oh, B. H. Lee, K.-S. Oh, K. Y. Yi, Bioorg. Med. Chem.
Lett. 2014, 24, 5832-5835.
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FULL PAPER
Key Topic*
Fei Peng, Jin Liu, Lili Li and Zhiwei
Chen*
Page No. – Page No.
Copper-catalyzed tandem reaction of
enamino esters with ortho-halogen
aromatic carbonyls: one pot
Copper-catalyzed tandem reaction for efficient synthesis of functionalized
quinolines via C–C bond formation and C–N coupling of enamino esters with ortho-
halogen aromatic carbonyls has been demonstrated. The success of gram-scale
reaction and thieno[3,2-b]pyridine derivatives synthesis have been used to extend
the application.
approach to functionalized quinolines
* Functionalized quinolines, Copper-catalyzed
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