Visible-Light Induced and Oxygen-Promoted Oxidative Cyclization of Aromatic Enamines for the Synthesis of Quinolines Derivatives

Article abstract of DOI:10.1021/acs.joc.7b01206

The dual transition metal-visible light photoredox catalysis for the synthesis of quinoline derivatives by using dioxygen as an oxygen source is developed. By using visible light, the direct oxidative cyclization of aromatic enamines with alkynes or alkenes can be achieved at mild conditions with an aid of copper or palladium catalysts, and a variety of multisubstituted quinoline derivatives could be obtained in good to moderate yields under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.7b01206

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Article
Visible-Light Induced and Oxygen-Promoted Oxidative Cyclization
of Aromatic Enamines for the Synthesis of Quinolines Derivatives
Xiao-Feng Xia, Guo-Wei Zhang, Dawei Wang, and Su-Li Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01206 • Publication Date (Web): 21 Jul 2017
Downloaded from http://pubs.acs.org on July 21, 2017
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VisibleꢀLight Induced and OxygenꢀPromoted Oxidative
Cyclization of Aromatic Enamines for the Synthesis of
Quinolines Derivatives
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XiaoꢀFeng Xia,* GuoꢀWei Zhang, Dawei Wang, SuꢀLi Zhu
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China. Eꢀmail:
xiaxf@jiangnan.edu.cn
ABSTRACT: The dual transition metalꢀvisible light photoredox catalysis for the synthesis of quinoline
derivatives by using dioxygen as an oxygen source is developed. By using visible light, the direct oxidative
cyclization of aromatic enamines with alkynes or alkenes can be achieved at mild conditions with an aide of
copper or palladium catalysts, and a variety of multiꢀsubstituted quinoline derivatives could be obtained in
good to moderate yields under mild reaction conditions.
INTRODUCTION
The quinoline unit represents an important structural motif among bioactive compounds and natural products
and has therefore been a target of numerous methodology developments.1 The classical route to quinoline
ring system proceeded from the condensation of substituted aryl anilines with βꢀdiketones or βꢀketoesters
under strongly acidic conditions.2 However, this procedure involves harsh reaction conditions, poor
functional group tolerance, and difficulty in controlling regioselectivity, which limited their application in
organic synthesis. To overcome these problems, recently, many different addition/cyclization approaches
using transitionꢀmetal catalysis were investigated to achieve high value quinoline rings from simple, readily
accessible starting materials.3 Although significant progress has been achieved for the construction of
quinoline skeletons, these methodologies are confined for the lack of generality and limited functionalꢀgroup
tolerance, especially for the synthesis of multiꢀsubstituted quinolines. Therefore, there remains big demand
for versatile and effective methodologies to construct multiꢀsubstituted quinoline derivatives via selective
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control of condensation patterns from readily accessible building blocks under mild conditions.
Recently, visible light photoredox catalysis has been demonstrated as an ecoꢀfriendly method for the
synthesis of nitrogenous heterocyclic compounds.4 Aromatic enamine as the active group was widely utilized
for the synthesis of heterocycles under metalꢀcatalyzed 5 or photoredox catalysis conditions.6 In particular,
photoredox catalysis strategy for the synthesis of heterocycles from aromatic enamines has attracted
significant attention. For instance, in 2014, Rueping and coworkers reported a palladiumꢀcatalyzed
photoredox indole synthesis from aryl enamine, in which molecular oxygen plays a role of the terminal
oxidant, and catalytic amount of photocatalyst could regenerate the palladium catalyst (Scheme 1ꢀ1).6b In
2016, Wu group realized an oxidantꢀfree strategy to synthesize indoles using iridium(III) photosensitizer and
cobaloxime catalyst system.6c In Wu’s work, the double bond in enamines can be easily oxidized to generate
a alkyl radical adjacent to carbonyl groups, which can go through an intramolecular radical addition to give
rise to indoles (Scheme 1ꢀ2). Intrigued by this phenomenon and based on our previous work on photoredox
catalysis,7 we envisaged that if alkynyl groups were introduced into the orthoꢀposition of enamine,
quinolines can be produced via an intramolecular oxidative cyclization/oxygen insertion sequence 4i,8 with a
synergistic catalysis approach (Scheme 1ꢀ3).
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Scheme 1. Combination of photoredox and transition metal catalysis for the synthesis of Nꢀcontaining
heterocyclic.
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RESULTS AND DISCUSSION
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To realize the conceptually simple photoredox cyclization, firstly, substrate 1 was synthesized according to
our previous report (Scheme 2).8a On the basis of our previous report,7b acridinium MesꢀAcrꢀMe+ was
selected as the photocatalyst, which was capable of activating molecular oxygen.9 Table 1 presents an
abbreviated summary of the optimization conditions conducted under the copperꢀvisible light photoredox
catalyzed conditions, culminating in 70% isolated yield of 2a. Photocatalysts played a crucial role in this
transformation, other catalysts such as Ru(bpy)3Cl2, Eosin Y, and Rose bengal all gave poor results
compared with acridinium (entries 1ꢀ3). When the loading of acridinium was decreased to 2 mol%, only
20% yield was obtained (entry 4). The loading of copper catalysts and ligand was also essential for this
oxidative cyclization (entries 5ꢀ7). Additional oxidant TBHP was needed for further increasing the yield, 3.0
equivalents were the optimal (entries 11 and 12), and other oxidants such as DTBP and K2S2O8 both gave
poor results (entries 8 and 9). 2 Atm of oxygen was also tried, and a similar result was observed (entry 10).
In addition, in order to improve the yield, other solvents such as CH3CN, acetone, and CHCl3 were also
tested, but no better results were obtained (entries 13ꢀ15). When molecular oxygen was omitted, no product
was observed, which meant that the oxygen atom of carbonyl of ketone (2a) did not come from TBHP (entry
16). Last, experiments without blue light irradiation or without dye under irradiation were carried out. As
expected, only less than 5% of yield was observed (entries 17 and 18).
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Scheme 2. The route for the synthesis of substrate 1.
Table 1. Screening of the reaction conditions a
Entry
Deviation from above
2% Ru(bpy)3Cl2
5% Eosin Y
5% Rose bengal
2% MesꢀAcrꢀMe+
10% CuCl
Yield (%)b
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30
28
20
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30
10% CuCl2
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Without ligand
DTBP (3.0 equiv.)
K2S2O8 (3.0 equiv.)
2 Atm. of oxygen
Without TBHP
TBHP (2.0 equiv.)
CH3CN (2 mL)
Acetone (2 mL)
CHCl3 (2 mL)
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<5
<5
<5
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at 1 atm Ar
Without photocatalyst
Without light
a
Reaction conditions: 1a (0.3 mmol), solvent (3.0 mL), blue LEDs (λ= 450±15 nm, 5 W electrical power),
r.t., for 24h. b Isolated yields. c For 48h.
With the optimized conditions on hand, the intramolecular oxidative cyclization scope of the transformation
was investigated. As described in Scheme 3, a variety of 4ꢀcarbonylꢀquinolines were produced in moderate
to good yields (58ꢀ84%). It is obvious that the electronic property of alkyne substitutions did not show great
influences on the reaction efficiency. Electronꢀwithdrawing substituents such as F, Cl, Br, and CF3 can be
well maintained without erosion by the photoredox catalysis. Heterocycleꢀsubstituent such as thiophene also
appeared to be excellent in the reaction, and the product 2l was isolated in 78% yield. Interestingly, when
CF3 was introduced into R1, a deꢀesterification product 2m was produced in 58% yield. In our opinion, CF3
as a strong electron withdrawing group may induce deꢀesterification in the presence of nucleophile. In
addition, when alkyl alkyne substrate was submitted into the standard conditions, an acceptable yield was
obtained (2n, 38%). Unfortunately, enaminones could not participate in this system, and the starting
materials were recovered. These phenomena meant that electron withdrawing group (COOEt) was needed to
stabilize the alkyl radical in the reaction (see Scheme 7). A disubstituted alkene substrate (Z)ꢀmethyl 3ꢀ((2ꢀ
(phenylethynyl)phenyl)amino)acrylate was also synthesized, however, a mixture was observed under the
standard conditions, and the main product in the mixture might be (Z)ꢀmethyl 3ꢀ(2ꢀphenylꢀ1Hꢀindolꢀ1ꢀ
yl)acrylate (see the Supporting Information). To confirm further the structural assignment of products in the
present intramolecular oxidative cyclization, the structure of the product 2e was unambiguously assigned by
Xꢀray crystallography (see the Supporting Information).
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O
OEt
5% Mes-Acr-Me+
20% CuCl2
20% Phen
N
Ph
Ph
R1
NH
COOEt
R2
R1
TBHP (3.0 equiv.)
O2 (1 atm), DMF(3.0 mL)
blue LED, r.t., 24h
6
O
7
R2
8
2
0.3 mmol
1
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N
N
N
N
COOEt
COOEt
COOEt
F
COOEt
Cl
O
O
O
O
2a, 70%
2d, 68%
2c
, 65%
2b
, 68%
N
N
N
N
COOEt
COOEt
COOEt
COOEt
F
O
O
O
O
F
Br
2h
, 72%
2g
, 64%
2e, 65%
2f
, 61%
N
N
N
N
Cl
COOEt
Br
COOEt
COOEt
F
COOEt
S
O
O
O
O
2l
, 78%
2k
, 84%
2j
, 72%
2i, 65%
N
N
Ph
N
Ph
Ph
N
COOEt
F3C
O
O
O
O
trace
trace
2n, 38%
2m
, 58%
Scheme 3. The scope of intramolecular oxidative cyclization.
In view of these results, we turned our attention to investigate the intermolecular addition/oxidative
cyclization. As shown in Scheme 4, a great variety of aminoalkynes were converted to the corresponding 4ꢀ
carbonylꢀquinolines in the presence of catalytic amounts of Ru(bpy)3Cl2 (5 mol%), CuCl (20 mol%), at room
temperature under 1 atm of O2. Several useful functional groups were tolerated, including chloride, nitro,
methyl and ether substituents. An electronꢀdonating substituent in R2 and R1 favored product formation,
whereas an electronꢀwithdrawing group slightly hindered the reaction (4f, 4g, 4j). When a sterically
demanding ortho substituent such as methyl and methoxyl was embedded in R1 or R2, a lower yield was
obtained (4h and 4l). To our disappointment, when methyl propiolate and methyl 3ꢀphenylpropiolate were
introduced into the reaction, no target products were obtained and substrate 3 can be recovered. Under the
standard condition, no Michael Addition intermediate was observed in the reaction using methyl propiolate
or methyl 3ꢀphenylpropiolate as substrate, and the reaction cannot proceed. In addition, dimethyl butꢀ2ꢀ
ynedioate was more electron deficiency than methyl propiolate and methyl 3ꢀphenylpropiolate, which was
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tend to go through Michael Addition under the standard conditions.
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Scheme 4. The scope of intermolecular addition/oxidative cyclization.
Then, we pay our attention on investigating the intermolecular addition/oxidative cyclization of oꢀ
alkenylanilines with dimethyl butꢀ2ꢀynedioate for the synthesis of quinolines in Scheme 5. This
transformation can undergo intermolecular addition of alkyne, insertion of the olefin, and oxidative cleavage
of CꢀC bond sequence. In previous reports,3a dimethyl butꢀ2ꢀynedioate was not suitable for the oxidative
cyclization. Here, we found that oxidative cyclization can be smoothly proceed to achieve quinolines in
moderate yields under the photoredox conditions, and substituents such as F, Cl and Br were tolerated.
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Scheme 5. The scope of intermolecular addition/oxidative cyclization of oꢀalkenylanilines.
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To gain more insights into the mechanism, the control experiments were performed. The photoꢀcatalysis
cyclization reaction was found to be completely suppressed using 2.0 equiv. of TEMPO (2,2,6,6ꢀtetramethylꢀ
1ꢀpiperidinyloxy) as the typical radical scavenger, implying that some radicals are involved in this reaction
system (Scheme 6ꢀ1). In addition, the reaction of substrate 1h with H218O under the standard conditions
afforded the 4ꢀcarbonylꢀquinoline product 2h without any 18O atoms, as determined by MS (Scheme 6ꢀ2).
When the reaction was conducted under 18O2 atmosphere, the 4ꢀcarbonylꢀquinoline product [18O]ꢀ2h
containing a 18O atom in ketone was afforded. These results indicated that the oxygen atom in ketone was
originated from molecular oxygen (O2) (Scheme 6ꢀ3).
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Scheme 6. Control experiments.
According to previous reports5c,6b,7,8 and the control experiments, a tentative mechanism was proposed in
Scheme 7. Photosensitizer MesꢀAcrꢀMe+ is initially irradiated by visible light to reach its excited state, then
the electron transfer from 1a to MesꢀAcrꢀMe* leads to MesꢀAcrꢀMe+. and intermediate A, which is in
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resonance with B. The forming alkyl radical intermediate B can be stabilized by electron withdrawing group
(COOEt).6c The oxidation of the generated MesꢀAcrꢀMe+. by oxygen or TBHP regenerates the photocatalyst.
The resulting B undergoes an intramolecular radical addition to give rise to C, which was further captured by
oxygen and copper to give intermediate D. Then, intermediate D goes through deprotonative OꢀO bond
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cleavage to give 4ꢀcarbonylꢀquinoline 2a along with the generation of Cu(II).10
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Mes-Acr-Me+
O2 or TBHP
hv
Mes-Acr-Me
Mes-Acr-Me*
O
OEt
O
N
OEt
-H+
O
N
OEt
Ph
N
Ph
Ph
Ph
NH
COOEt
radical
cyclization
B
A
C
1a
Cu(II) + O2
Cu(II)
N
Ph
N
Ph
COOEt
COOEt
H
O
O
O
(III)Cu
2a
D
Scheme 7. Proposed mechanism.
■ CONCLUSION
In conclusion, we demonstrated a dual transition metalꢀvisible light photoredox catalyzed oxidative
cyclization of aromatic enamines for the synthesis of multiꢀsubstituted quinoline derivatives. This protocol
allows the formation of CꢀC and CꢀO bonds simultaneously through an intramolecular oxidative
cyclization/oxygen insertion sequence. The method proceeded well using molecular oxygen as the oxygen
source under mild reaction conditions, making this transformation sustainable and practical.
EXPERIMENTAL SECTION
1
General Remarks: Column chromatography was carried out on silica gel. Unless noted H NMR spectra
were recorded on 400 MHz in CDCl3, 13C NMR spectra were recorded on 100 MHz in CDCl3, 19F NMR
spectra were recorded on 376 MHz in CDCl3. IR spectra were recorded on an FTꢀIR spectrometer and only
major peaks are reported in cmꢀ1. Melting points were determined on a microscopic apparatus and were
uncorrected. All new products were further characterized by HRMS (high resolution mass spectra), high
resolution mass spectrometry (HRMS) spectra was obtained on a micrOTOFꢀQ instrument equipped with an
ESI source; copies of their 1H NMR and 13C NMR spectra are provided.
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The procedure for the synthesis of product 2. An ovenꢀdried Schlenk tube (10 mL) was equipped with a
magnetic stir bar, aromatic enamine (1a, 0.3 mmol), MesꢀAcrꢀMe+ (5 mol%, 0.015 mmol), CuCl2 (20
mmol%, 0.06 mmol), phen (20 mmol%, 0.06 mmol), TBHP (3 equiv.). The flask was evacuated and
backfilled with O2 for 3 times. Then DMF (3.0 mL) was added with syringe. The reaction mixture was then
stirred for 24 h at room temperature under the irradiation of blue LEDs (λ= 450±15 nm, 5 W electrical
power). After the reaction, 6 mL water was added to quench the reaction, and the resulting mixture was
extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and
concentrated. Purification of the crude product by flash column chromatography afforded the product
(petroleum ether/ethyl acetate as eluent (8:1)).
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Ethyl 4ꢀbenzoylꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2a). CAS: 1373169ꢀ66ꢀ4. 80 mg, 70%, m. p. = 125ꢀ
126oC, 1H NMR (400 MHz, CDCl3): 8.25 (d, J = 8.5 Hz, 1H), 7.85 (m, 3H), 7.76ꢀ7.55 (m, 4H), 7.48 (m, 6H),
3.87 (q, J = 7.1 Hz, 2H), 0.81 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 195.4, 166.9, 157.2, 148.0,
146.9, 140.1, 136.5, 134.2, 131.4, 130.0, 129.8, 129.6, 128.9, 128.8, 128.5, 128.3, 127.8, 127.2, 125.7, 123.4,
123.0, 61.7, 13.1. IR (cmꢀ1): 3060, 2985, 1727, 1679, 1549, 1451, 1364, 1297, 1237, 1170, 1108, 1077, 1017,
924, 760, 626. HRMS (ESI) m/z calcd for C25H20NO3+ (M+H)+: 382.1438, found 382.1438.
Ethyl 4ꢀ(4ꢀmethylbenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2b). CAS: 1374309ꢀ36ꢀ0. 81 mg, 68%, m. p. =
o
1
135ꢀ136 C, H NMR (400 MHz, CDCl3): 8.27 (d, J = 8.2 Hz, 1H), 7.76 (ddd, J = 10.5, 7.5, 5.7 Hz, 5H),
7.68 (dd, J = 8.4, 0.7 Hz, 1H), 7.54ꢀ7.44 (m, 4H), 7.28 (d, J = 8.0 Hz, 2H), 3.91 (q, J = 7.1 Hz, 2H), 2.43 (s,
3H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.9, 166.9, 157.2, 147.9, 147.0, 145.3, 140.1,
134.2, 131.3, 129.9, 129.7, 129.5, 128.8, 128.5, 128.3, 127.7, 127.1, 125.7, 123.3, 123.0, 61.7, 21.7, 13.1. IR
(cmꢀ1): 3062, 2984, 1728, 1674, 1603, 1556, 1454, 1352, 1296, 1237, 1171, 1108, 1021, 924, 826, 769, 741,
698, 599. HRMS (ESI) m/z calcd for C26H22NO3+ (M+H)+: 396.1594, found 396.1595.
1
Ethyl 4ꢀ(4ꢀfluorobenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2c). 78 mg, 65%, m. p. = 169ꢀ171oC, H NMR
(400 MHz, CDCl3): 8.28 (d, J = 8.3 Hz, 1H), 8.00ꢀ7.38 (m, 10 H), 7.17 (t, J = 8.7 Hz, 2H), 3.92 (q, J = 7.1
Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 193.9, 166.9 (d, J = 256 Hz), 157.2, 148.0,
146.5, 140.0, 133.1, 133.0, 132.3 (d, J = 10 Hz), 131.5, 130.0, 128.9, 128.5, 128.4 (d, J = 13 Hz), 127.9,
127.1, 125.5, 123.3, 122.8, 116.2, 116.0, 61.8, 13.1. 19F NMR (376 MHz, CDCl3) δ ppm ꢀ102.47. IR (cmꢀ1):
3064, 2980, 2928, 2855, 1727, 1679, 1599, 1552, 1505, 1454, 1411, 1376, 1352, 1295, 1236, 1156, 1108,
1063, 1016, 926, 845, 764, 704, 600. HRMS (ESI) m/z calcd for C25H19FNO3+ (M+H)+: 400.1343, found
400.1344.
Ethyl 4ꢀ(3ꢀchlorobenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2d). CAS: 1373169ꢀ81ꢀ3. 85 mg, 68%, m. p. =
1
165ꢀ167oC, H NMR (400 MHz, CDCl3): 8.28 (d, J = 8.5 Hz, 1H), 7.89ꢀ7.79 (m, 3H), 7.77ꢀ7.69 (m, 2H),
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7.63 (dd, J = 8.3, 0.7 Hz, 1H), 7.55ꢀ7.45 (m, 6H), 3.93 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): 194.3, 166.8, 157.3, 148.0, 146.4, 140.8, 140.0, 134.9, 131.5, 130.8, 130.1, 129.2,
128.9, 128.6, 128.5, 128.3, 127.9, 125.4, 123.3, 122.8, 61.8, 13.1. IR (cmꢀ1): 3063, 2973, 1727, 1682, 1587,
1549, 1489, 1396, 1295, 1235, 1169, 1101, 1016, 969, 924, 837, 762, 702, 655, 611. HRMS (ESI) m/z calcd
for C25H19ClNO3+ (M+H)+: 416.1048, found 416.1049.
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Ethyl 4ꢀ(4ꢀbromobenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2e). CAS: 1374309ꢀ39ꢀ3. 89.5 mg, 65%, m. p.
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= 161ꢀ163oC, H NMR (400 MHz, CDCl3): 8.28 (d, J = 8.4 Hz, 1H), 7.84 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H),
7.81ꢀ7.68 (m, 4H), 7.63 (dd, J = 12.2, 4.8 Hz, 3H), 7.57ꢀ7.47 (m, 4H), 3.93 (q, J = 7.1 Hz, 2H), 0.85 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.5, 166.9, 157.3, 148.0, 146.4, 140.0, 135.3, 132.2, 131.6,
130.9, 130.1, 129.7, 128.9, 128.5, 128.3, 127.9, 125.4, 123.4, 122.8, 61.8, 13.1. IR (cmꢀ1): 3061, 2928, 1714,
1682, 1583, 1549, 1456, 1396, 1346, 1295, 1234, 1170, 1105, 1066, 1011, 837, 765, 698, 649, 608. HRMS
+
(ESI) m/z calcd for C25H19BrNO3 (M+H)+: 460.0543, found 460.0543.
1
Ethyl 4ꢀ(3ꢀfluorobenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2f). 73 mg, 61%, m. p. = 94ꢀ96oC, H NMR
(400 MHz, CDCl3): 8.26 (d, J = 8.5 Hz, 1H), 7.82 (m, 1H), 7.75ꢀ7.67 (m, 2H), 7.67ꢀ7.59 (m, 2H), 7.59ꢀ7.37
(m, 6H), 7.32 (m, 1H), 3.90 (q, J = 7.1 Hz, 2H), 0.82 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.4,
194.3, 166.8, 162.9 (d, J = 248 Hz), 157.3, 148.0, 146.4, 140.0, 138.6, 131.6, 130.6, 130.1, 128.9, 128.4 (d, J
= 19 Hz), 128.0, 125.6, 125.4, 123.3, 122.8, 121.3, 121.1, 115.6 (d, J = 28 Hz), 61.8, 13.1. 19F NMR (376
MHz, CDCl3) δ ppm ꢀ110.98. IR (cmꢀ1): 3066, 2979, 1725, 1680, 1591, 1553, 1485, 1451, 1291, 1245, 1172,
1109, 1018, 888, 773, 698, 651, 616. HRMS (ESI) m/z calcd for C25H19FNO3+ (M+H)+: 400.1343, found
400.1344.
Ethyl 4ꢀ(2ꢀfluorobenzoyl)ꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2g). 77 mg, 64%, oil, 1H NMR (400 MHz,
CDCl3): 8.23ꢀ8.25 (m, 1 H), 7.97ꢀ8.01 (m, 1 H), 7.78ꢀ7.82 (m, 1 H), 7.67ꢀ7.70 (m, 3 H), 7.57ꢀ7.60 (m, 1 H),
7.51ꢀ7.53 (m, 1 H), 7.45ꢀ7.48 (m, 3 H), 7.28ꢀ7.31 (m, 1 H), 7.06ꢀ7.10 (m, 1 H), 3.87ꢀ3.93 (q, J = 8.0 Hz, 2
H), 0.82 (t, J = 8.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3): 192.1, 167.0, 163.4 (d, J = 259 Hz), 160.8, 157.5,
148.6, 148.1, 140.3, 136.1, 131.4, 131.2, 130.1, 128.5, 128.4, 128.3, 127.8, 127.2, 124.9, 122.3, 117.1, 116.9,
61.7, 13.1; 19F NMR (376 MHz, CDCl3) δ ppm ꢀ108.54. IR (cmꢀ1): 3063, 2982, 1723, 1677, 1555, 1454,
1372, 1349, 1297, 1233, 1105, 1067, 1016, 768, 702; HRMS (ESI) m/z calcd for C25H19FNO3+ (M+H)+:
400.1343, found 400.1343.
Ethyl 4ꢀbenzoylꢀ6ꢀmethylꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2h). CAS: 1373169ꢀ79ꢀ9. 85 mg, 72%, m. p. =
o
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106ꢀ107 C, H NMR (400 MHz, CDCl3): 8.17 (d, J = 8.7 Hz, 1H), 7.92ꢀ7.87 (m, 2H), 7.81ꢀ7.70 (m, 2H),
7.69ꢀ7.60 (m, 2H), 7.53ꢀ7.43 (m, 6H), 3.86 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 0.82 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): 195.6, 167.0, 156.2, 146.7, 146.1, 140.2, 138.1, 136.5, 134.1, 133.8, 129.8, 129.6,
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129.5, 128.8, 128.7, 128.5, 128.2, 127.0, 124.3, 123.2, 123.0, 61.6, 21.7, 13.0. IR (cmꢀ1): 3070, 2983, 1729,
1682, 1595, 1553, 1494, 1447, 1405, 1436, 1294, 1236, 1177, 1110, 1058, 1019, 952, 830, 777, 727, 698,
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+
626. HRMS (ESI) m/z calcd for C26H22NO3 (M+H)+: 396.1594, found 396.1595.
Ethyl 4ꢀbenzoylꢀ6ꢀfluoroꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2i). 78 mg, 65%, m. p. = 101ꢀ103oC, H NMR
(400 MHz, CDCl3): 8.29 (dd, J = 9.3, 5.4 Hz, 1H), 7.94ꢀ7.84 (m, 2H), 7.83ꢀ7.55 (m, 4H), 7.54ꢀ7.34 (m, 5H),
7.33ꢀ7.25 (m, 1H), 3.89 (q, J = 7.1 Hz, 2H), 0.84 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.9,
166.7, 161.1 (d, J = 250 Hz), 156.6, 146.2, 146.1, 145.2, 139.8, 136.2, 134.5, 132.6 (d, J = 9 Hz), 129.6,
129.0, 128.9, 128.4 (d, J = 8 Hz), 127.2, 124.2, 123.7, 123.6, 122.0, 121.8, 109.2 (d, J = 20 Hz), 61.9, 29.7,
13.2. 19F NMR (376 MHz, CDCl3) δ ppm ꢀ109.69. IR (cmꢀ1): 3062, 2929, 2859, 1732, 1681, 1626, 1552,
1493, 1454, 1376, 1290, 1235, 1185, 1108, 1059, 1020, 960, 839, 804, 773, 730, 624. HRMS (ESI) m/z
calcd for C25H19FNO3+ (M+H)+: 400.1343, found 400.1344.
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Ethyl 4ꢀbenzoylꢀ6ꢀchloroꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2j). CAS: 1373169ꢀ77ꢀ7. 90 mg, 72%, m. p. =
136ꢀ137oC, H NMR (400 MHz, CDCl3): 8.21 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.72 (m, 5H),
1
7.57ꢀ7.42 (m, 5H), 3.87 (q, J = 7.1 Hz, 2H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.6,
166.6, 157.3, 146.4, 145.8, 139.6, 136.1, 134.5, 133.8, 132.5, 131.5, 129.8, 129.6, 129.1, 128.9, 128.6, 128.5,
128.4, 127.2, 124.3, 124.2, 123.6, 76.6, 61.9, 13.0. IR (cmꢀ1): 3066, 2980, 2933, 1732, 1673, 1595, 1548,
1477, 1450, 1344, 1293, 1235, 1180, 1110, 1059, 1020, 941, 831, 769, 694, 647, 620. HRMS (ESI) m/z
calcd for C25H19ClNO3+ (M+H)+: 416.1048, found 416.1049.
Ethyl 4ꢀbenzoylꢀ6ꢀbromoꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2k). CAS: 1373169ꢀ78ꢀ8. 116 mg, 84%, m. p. =
124ꢀ126oC, H NMR (400 MHz, CDCl3): 8.14 (d, J = 9.0 Hz, 1H), 8.00ꢀ7.83 (m, 4H), 7.75ꢀ7.71 (m, 2H),
1
7.68ꢀ7.63 (m, 1H), 7.53ꢀ7.47 (m, 5H), 3.86 (q, J = 7.1 Hz, 2H), 0.82 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 194.6, 166.5, 157.4, 146.6, 145.6, 139.6, 136.1, 135.0, 134.4, 131.6, 129.8, 129.6, 129.1, 128.9,
128.8, 128.6, 128.5, 128.4, 127.6, 127.2, 124.1, 124.0, 122.0, 61.9, 13.0. IR (cmꢀ1): 3059, 2975, 1731, 1683,
1540, 1468, 1289, 1234, 1109, 1020, 926, 831, 774, 706, 655, 613. HRMS (ESI) m/z calcd for
C25H19BrNO3+ (M+H)+: 460.0543, found 460.0544.
Ethyl 2ꢀphenylꢀ4ꢀ(thiopheneꢀ2ꢀcarbonyl)quinolineꢀ3ꢀcarboxylate (2l). 90.5 mg, 78%, m. p. = 78ꢀ80oC, H
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NMR (400 MHz, CDCl3): 8.33ꢀ8.21 (m, 1H), 7.89ꢀ7.80 (m, 3H), 7.76ꢀ7.69 (m, 2H), 7.57 (dd, J = 7.9, 7.3 Hz,
1H), 7.49 (dd, J = 5.9, 1.3 Hz, 3H), 7.34 (dd, J = 3.8, 0.7 Hz, 1H), 7.14ꢀ7.05 (m, 1H), 3.97 (q, J = 5.7 Hz,
2H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 187.0, 166.8, 157.1, 148.0, 145.8, 143.8, 140.0,
136.0, 135.9, 131.5, 129.9, 128.9, 128.5, 128.4, 128.3, 127.9, 125.6, 123.3, 122.7, 61.9, 13.1. IR (cmꢀ1): 3072,
2981, 1727, 1653, 1559, 1457, 1403, 1350, 1295, 1240, 1168, 1104, 1041, 914, 858, 770, 737, 692, 624.
HRMS (ESI) m/z calcd for C23H18NO3S+ (M+H)+: 388.1002, found 388.1003.
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Phenyl(2ꢀphenylꢀ6ꢀ(trifluoromethyl)quinolinꢀ4ꢀyl)methanone (2m). 66 mg, 58%, m. p. = 138ꢀ140oC, 1H
NMR (400 MHz, CDCl3): 9.08 (s, 1H), 8.81 (d, J = 8.8 Hz, 1H), 8.03ꢀ7.94 (m, 2H), 7.83 (s, 1H), 7.68ꢀ7.50
(m, 6H), 7.44 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): 165.1, 141.6, 134.3, 132.4, 131.4, 129.4,
129.0, 128.7, 128.6, 128.5 (q, J = 4.0 Hz), 127.0, 126.7, 126.6 (q, J = 3.0 Hz), 125.7, 125.3, 125.0, 123.7 (q,
J = 270 Hz), 121.5, 118.9, 112.5, 98.2, 83.0. 19F NMR (376 MHz, CDCl3) δ ppm ꢀ62.30. IR (cmꢀ1): 3039,
1653, 1587, 1532, 1493, 1473, 1419, 1340, 1317, 1270, 1164, 1113, 1098, 1070, 1023, 894, 835, 790, 753,
710, 687, 636, 593. HRMS (ESI) m/z calcd for C23H15F3NO+ (M+H)+: 378.1100, found 378.1107.
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Ethyl 4ꢀbutyrylꢀ2ꢀphenylquinolineꢀ3ꢀcarboxylate (2n). 40 mg, 38%, Liquid, H NMR (400 MHz, CDCl3):
8.23 (d, J = 8.5 Hz, 1H), 7.89ꢀ7.82 (m, 1H), 7.74 (dd, J = 8.4, 0.8 Hz, 1H), 7.69ꢀ7.60 (m, 3H), 7.53ꢀ7.44 (m,
3H), 4.12 (q, J = 7.1 Hz, 2H), 2.99 (t, J = 7.4 Hz, 2H), 1.90 (m, 2 H), 1.09 (t, J = 7.4 Hz, 3H), 0.99 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3): 205.5, 167.4, 157.4, 149.2, 148.0, 140.4, 131.4, 130.2, 128.8, 128.4,
128.3, 127.9, 124.7, 121.7, 121.5, 61.9, 46.8, 16.7, 13.7, 13.3. IR (cmꢀ1): 3066, 2964, 2937, 2878, 1716, 1614,
1571, 1552, 1489, 1458, 1446, 1403, 1376, 1352, 1297, 1236, 1169, 1148, 1107, 1079, 1030, 867, 838, 766,
+
700, 618. HRMS (ESI) m/z calcd for C22H22NO3 (M+H)+: 348.1594, found 348.1593.
The procedure for the synthesis of product 4. An ovenꢀdried Schlenk tube (10 mL) was equipped
with a magnetic stir bar, 2ꢀ(phenylethynyl)aniline (3a, 0.3 mmol), dimethyl butꢀ2ꢀynedioate (2
equiv., 0.6 mmol), Ru(bpy)3Cl2 (5 mol%, 0.015 mmol), CuCl (20 mmol%, 0.06 mmol). The flask
was evacuated and backfilled with O2 for 3 times. Then DMF (3.0 mL) was added with syringe. The
reaction mixture was then stirred for 24 h at room temperature under the irradiation of blue LEDs
(λ= 450±15 nm, 5 W electrical power). After the reaction, 6 mL water was added to quench the
reaction, and the resulting mixture was extracted twice with EtOAc. The combined organic extracts
were washed with brine, dried over Na2SO4 and concentrated. Purification of the crude product by
flash column chromatography afforded the product (petroleum ether/ethyl acetate as eluent (8:1)).
Dimethyl 4ꢀbenzoylquinolineꢀ2,3ꢀdicarboxylate (4a). CAS: 1373169ꢀ75ꢀ5. 65 mg, 60%, m. p. = 105ꢀ106oC,
1H NMR (400 MHz, CDCl3): 8.28 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H),
7.68ꢀ7.56 (m, 3H), 7.44 (t, J = 7.6 Hz, 2H), 4.04 (s, 3H), 3.64 (s, 3H). 13C NMR (100 MHz, CDCl3): 194.3,
166.1, 165.0, 149.1, 148.0, 147.5, 136.2, 134.2, 132.3, 130.3, 129.5, 129.2, 128.8, 125.9, 124.4, 121.6, 53.2,
52.7. IR (cmꢀ1): 3652, 3452, 3335, 3065, 3011, 2964, 2854, 2600, 2322, 1986, 1739, 1677, 1595, 1579, 1559,
1497, 1446, 1399, 1376, 1313, 1240, 1168, 1129, 1067, 1028, 988, 941, 863, 832, 804, 765, 726, 695, 640,
597. HRMS (ESI) m/z calcd for C20H16NO5+ (M+H)+ 350.1023, found 350.1015.
Dimethyl 4ꢀ(4ꢀmethylbenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4b). CAS: 1374309ꢀ22ꢀ4. 54 mg, 50%, m. p. =
107ꢀ109oC, 1H NMR (400 MHz, CDCl3): 8.31 (d, J = 8.5 Hz, 1H), 7.88 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.68
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(d, J = 7.7 Hz, 3H), 7.63ꢀ7.57 (m, 1H), 7.27 (d, J = 8.2 Hz, 2H), 4.07 (s, 3H), 3.69 (s, 3H), 2.43 (s, 3H). 13
C
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NMR (100 MHz, CDCl3): 194.0, 166.3, 165.2, 149.1, 148.3, 147.5, 145.6, 133.9, 132.2, 130.4, 129.7, 129.6,
129.5, 126.1, 124.6, 121.2, 53.3, 52.8, 21.8. IR (cmꢀ1): 3066, 3039, 2957, 2925, 2851, 1740, 1669, 1603,
1560, 1497, 1442, 1395, 1364, 1309, 1250, 1202, 1179, 1154, 1127, 1079, 985, 937, 830, 772, 742, 710, 612.
HRMS (ESI) m/z calcd for C21H18NO5+ (M+H)+: 364.1179, found 364.1179.
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Dimethyl 4ꢀ(3,4ꢀdimethylbenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4c). CAS: 1374309ꢀ25ꢀ7. 57 mg, 50%, m. p.
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= 124ꢀ125oC, H NMR (400 MHz, CDCl3): 8.32 (d, J = 8.5 Hz, 1H), 7.88 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H),
7.69 (dd, J = 8.4, 0.7 Hz, 1H), 7.65ꢀ7.56 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 4.08 (s,
3H), 3.70 (s, 3H), 2.34 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3): 194.3, 166.3, 165.2, 149.1, 148.5,
147.5, 144.4, 137.5, 134.3, 132.2, 130.4, 130.1, 129.4, 127.4, 126.2, 124.7, 121.1, 53.3, 52.9, 20.2, 19.6. IR
(cmꢀ1): 3070, 3039, 2957, 2921, 2851, 1732, 1669, 1603, 1563, 1501, 1442, 1399, 1368, 1305, 1250, 1200,
1172, 1129, 1074, 1043, 998, 953, 867, 791, 769, 733, 706, 628, 595, 586. HRMS (ESI) m/z calcd for
+
C22H20NO5 (M+H)+: 378.1336, found 378.1335.
Dimethyl 4ꢀ(4ꢀmethoxybenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4d). CAS: 1374309ꢀ23ꢀ5. 48 mg, 42%, m. p. =
1
130ꢀ132oC, H NMR (400 MHz, CDCl3): 8.31 (d, J = 8.5 Hz, 1H), 7.94ꢀ7.84 (m, 1H), 7.76 (d, J = 7.4 Hz,
2H), 7.70 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.3, 7.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.07 (s, 3H), 3.87 (s,
3H), 3.70 (s, 3H). 13C NMR (100 MHz, CDCl3): 192.8, 166.2, 165.3, 164.5, 148.9, 148.2, 147.5, 132.2,
131.8, 130.4, 129.5, 126.1, 124.6, 121.3, 114.2, 55.5, 53.3, 52.8. IR (cmꢀ1): 3072, 3029, 2957, 2843, 1736,
1665, 1599, 1575, 1509, 1442, 1399, 1376, 1309, 1250, 1200, 1168, 1129, 1078, 1027, 980, 937, 839, 773,
+
636, 608. HRMS (ESI) m/z calcd for C21H18NO6 (M+H)+: 380.1129, found 380.1128.
Dimethyl 4ꢀ(4ꢀ(benzyloxy)benzoyl)quinolineꢀ2,3ꢀdicarboxylate (4e). CAS: 1374309ꢀ24ꢀ6. 48 mg, 35%, m. p.
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= 130ꢀ132oC, H NMR (400 MHz, CDCl3): 8.32 (d, J = 8.5 Hz, 1H), 7.88 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H),
7.77ꢀ7.70 (m, 2H), 7.65ꢀ7.60 (m, 1H), 7.46ꢀ7.34 (m, 6H), 7.02 (d, J = 9.1 Hz, 2H), 5.14 (s, 2H), 4.08 (s, 3H),
3.70 (s, 3H). 13C NMR (100 MHz, CDCl3): 192.8, 166.2, 165.3, 163.7, 148.9, 148.2, 147.5, 135.7, 132.2,
131.8, 130.4, 129.7, 129.5, 128.6, 128.3, 127.4, 126.2, 124.6, 121.4, 115.0, 70.3, 65.8, 53.5, 53.3, 52.9, 52.8,
15.2. IR (cmꢀ1): 3070, 3039, 2957, 2362, 2319, 1740, 1669, 1599, 1575, 1509, 1458, 1438, 1313, 1250, 1200,
+
1168, 1129, 1074, 996, 839, 773, 741, 702, 643, 587. HRMS (ESI) m/z calcd for C27H22NO6 (M+H)+:
456.1442, found 456.1441.
Dimethyl 4ꢀ(4ꢀchlorobenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4f). CAS: 1374309ꢀ26ꢀ8. 39 mg, 34%, m. p. =
92ꢀ94oC, 1H NMR (400 MHz, CDCl3): 8.32 (d, J = 8.5 Hz, 1H), 7.90 (ddd, J = 8.5, 4.6, 3.7 Hz, 1H), 7.74 (d,
J = 8.4 Hz, 2H), 7.67ꢀ7.60 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 4.07 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz,
CDCl3): 193.3, 166.2, 165.0, 149.2, 147.6, 141.0, 134.7, 132.4, 130.6, 130.5, 129.7, 129.3, 125.8, 124.3,
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121.0, 53.3, 52.9, 29.6. IR (cmꢀ1): 3064, 3007, 2954, 2852, 2326, 1735, 1679, 1587, 1563, 1492, 1438, 1399,
1365, 1307, 1247, 1197, 1172, 1129, 1094, 1074, 1012, 978, 840, 796, 770, 730, 699, 644, 587, 541. HRMS
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(ESI) m/z calcd for C20H15ClNO5 (M+H)+: 384.0633, found 384.0633.
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Dimethyl 4ꢀ(4ꢀnitrobenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4g). CAS: 1374309ꢀ29ꢀ1. 35.5 mg, 30%, m. p. =
135ꢀ137oC, 1H NMR (400 MHz, CDCl3): 8.34 (t, J = 8.8 Hz, 3H), 7.95 (ddd, J = 9.1, 8.4, 5.1 Hz, 3H), 7.69ꢀ
7.63 (m, 1H), 7.61ꢀ7.56 (m, 1H), 4.09 (s, 3H), 3.74 (s, 3H). 13C NMR (100 MHz, DMSO): 193.3, 165.7,
164.4, 150.6, 149.2, 147.3, 147.2, 139.8, 133.4, 130.5, 129.9, 125.7, 124.3, 123.5, 119.8, 53.2, 53.1. IR (cmꢀ
1): 3067, 3030, 2957, 2855, 1736, 1685, 1603, 1532, 1442, 1348, 1313, 1250, 1200, 1168, 1129, 1074, 855,
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765, 706, 643, 589. HRMS (ESI) m/z calcd for C20H15N2O7 (M+H)+: 395.0874, found 395.0875.
Dimethyl 4ꢀ(2ꢀmethoxybenzoyl)quinolineꢀ2,3ꢀdicarboxylate (4h). CAS: 1374309ꢀ30ꢀ4. 45.5 mg, 40%, oil,
1H NMR (400 MHz, CDCl3): 8.26ꢀ8.28 (m, 1 H), 8.04ꢀ8.07 (m, 1 H), 7.82ꢀ7.84 (m, 1 H), 7.74ꢀ7.76 (m, 1 H),
7.55ꢀ7.61 (m, 2 H), 7.10ꢀ7.14 (m, 1 H), 6.87ꢀ6.89 (m, 1 H), 4.04 (s, 3 H), 3.63 (s, 3 H), 3.31 (s, 3 H); 13C
NMR (100 MHz, CDCl3): 192.6, 166.4, 165.6, 159.8, 151.3, 148.9, 147.5, 135.9, 130.3, 125.8, 124.1, 121.1,
119.8, 112.5, 55.5, 53.2, 52.5; IR (cmꢀ1): 2952, 2842, 1735, 1681, 1594, 1485, 1438, 1285, 1250, 1172, 1129,
+
765; HRMS (ESI) m/z calcd for C21H18NO6 (M+H)+: 380.1129, found 380.1130.
Dimethyl 4ꢀbenzoylꢀ6ꢀmethylquinolineꢀ2,3ꢀdicarboxylate (4i). CAS: 1373169ꢀ76ꢀ6. 67.5 mg, 62%, m. p. =
137ꢀ139oC, 1H NMR (400 MHz, CDCl3): 8.20 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.7
Hz, 1H), 7.63 (td, J = 7.4, 1.1 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.42 (s, 1H), 4.06 (s, 3H), 3.64 (s, 3H), 2.45
(s, 3H). 13C NMR (100 MHz, CDCl3): 194.6, 166.3, 165.2, 148.0, 147.0, 146.2, 140.3, 136.2, 134.7, 134.3,
130.0, 129.2, 128.9, 124.6, 124.6, 121.2, 53.2, 52.7, 21.8. IR (cmꢀ1): 3065, 3011, 2956, 2326, 1735, 1681,
1587, 1563, 1505, 1438, 1407, 1372, 1313, 1250, 1200, 1168, 1129, 1074, 1035, 988, 957, 871, 832, 807,
773, 721, 701, 642, 578. HRMS (ESI) m/z calcd for C21H18NO5+ (M+H)+: 364.1179, found 364.1180.
Dimethyl 4ꢀbenzoylꢀ6ꢀchloroquinolineꢀ2,3ꢀdicarboxylate (4j). CAS: 1374309ꢀ32ꢀ6. 37 mg, 32%, m. p. =
133ꢀ134oC, 1H NMR (400 MHz, CDCl3): 8.26 (d, J = 9.0 Hz, 1H), 7.83 (dd, J = 9.1, 2.2 Hz, 1H), 7.78 (d, J
= 7.4 Hz, 2H), 7.69ꢀ7.63 (m, 2H), 7.50 (t, J = 7.8 Hz, 2H), 4.07 (s, 3H), 3.65 (s, 3H). 13C NMR (100 MHz,
CDCl3): 193.7, 165.9, 164.8, 149.1, 146.9, 146.0, 133.4, 131.9, 129.6, 129.0, 125.2, 124.7, 122.2, 84.5, 53.4,
52.9, 52.8, 50.7, 39.7, 29.6. IR (cmꢀ1): 3063, 3005, 2953, 2852, 1737, 1679, 1584, 1558, 1481, 1443, 1397,
1363, 1301, 1241, 1194, 1165, 1129, 1092, 1070, 1029, 936, 929, 868, 834, 803, 738, 712, 685, 636, 571.
HRMS (ESI) m/z calcd for C20H15ClNO5 (M+H)+: 384.0633, found 384.0634.
+
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Diethyl 4ꢀbenzoylꢀ6ꢀmethylquinolineꢀ2,3ꢀdicarboxylate (4k). 70 mg, 60%, m. p. = 101ꢀ102oC, H NMR
(400 MHz, CDCl3): 8.20 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.70 (dd, J = 8.7, 1.1 Hz, 1H), 7.63 (t,
J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.41 (s, 1H), 4.53 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H),
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2.45 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 194.7, 166.1,
164.7, 148.9, 147.0, 146.2, 140.0, 136.4, 134.6, 134.2, 130.0, 129.3, 128.8, 124.6, 124.5, 121.0, 62.4, 62.2,
21.8, 14.0, 13.3. IR (cmꢀ1): 3070, 2984, 2945, 2914, 1728, 1677, 1599, 1560, 1497, 1454, 1411, 1380, 1344,
1309, 1243, 1184, 1137, 1070, 1023, 867, 827, 773, 722, 702, 643. HRMS (ESI) m/z calcd for
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C23H22NO5 (M+H)+: 392.1492, found 392.1497.
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Dimethyl 4ꢀbenzoylꢀ6,8ꢀdimethylquinolineꢀ2,3ꢀdicarboxylate (4l). CAS: 1374309ꢀ31ꢀ5. 35 mg, 31%, m. p. =
121ꢀ122oC, 1H NMR (400 MHz, CDCl3): 7.78 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.57 (s, 1H), 7.47
(t, J = 7.8 Hz, 2H), 7.26 (s, 1H), 4.05 (s, 3H), 3.65 (s, 3H), 2.85 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz,
CDCl3): 195.1, 166.9, 165.3, 147.4, 147.3, 145.5, 139.7, 138.3, 136.5, 134.9, 134.1, 129.2, 128.8, 124.6,
122.5, 120.2, 53.0, 52.6, 21.8, 17.8. IR (cmꢀ1): 3011, 2957, 2929, 2847, 1736, 1681, 1622, 1595, 1563, 1493,
1446, 1376, 1297, 1239, 1164, 1129, 1051, 1012, 972, 859, 804, 765, 718, 687, 647, 589. HRMS (ESI) m/z
calcd for C22H20NO5+ (M+H)+: 378.1336, found 378.1338.
The procedure for the synthesis of product 6. An ovenꢀdried Schlenk tube (10 mL) was equipped with a
magnetic stir bar, oꢀalkenylanilines (5a, 0.3 mmol), dimethyl butꢀ2ꢀynedioate (2 equiv., 0.6 mmol),
Ru(bpy)3Cl2 (2 mmol%, 0.006 mmol), PdCl2 (10 mmol%, 0.03 mmol), PPh3 (20 mmol%, 0.06 mmol),
Cu(OAc)2 (20 mmol%, 0.06 mmol), PivOH (1 equiv. 0.3 mmol). The flask was evacuated and backfilled
with O2 for 3 times. Then DMF (3.0 mL) was added with syringe. The reaction mixture was then stirred for
24 h at room temperature under the irradiation of blue LEDs (λ= 450±15 nm, 5 W electrical power). After
the reaction, 6 mL water was added to quench the reaction, and the resulting mixture was extracted twice
with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated.
Purification of the crude product by flash column chromatography afforded the product (petroleum
ether/ethyl acetate as eluent (10:1)).
1
Dimethyl quinolineꢀ2,3ꢀdicarboxylate (6a). CAS: 17507ꢀ03ꢀ8. 34 mg, 46%, m. p. = 100ꢀ101oC, H NMR
(400 MHz, CDCl3): 8.80 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.93ꢀ7.86 (m, 1H), 7.71
(t, J = 7.5 Hz, 1H), 4.08 (s, 3H), 4.00 (s, 3H). 13C NMR (100 MHz, CDCl3): 167.1, 165.5, 150.5, 148.0,
139.5, 132.4, 129.7, 128.6, 128.6, 126.9, 122.2, 53.1, 52.8. IR (cmꢀ1): 3069, 3011, 2956, 2842, 1735, 1622,
1567, 1497, 1446, 1419, 1376, 1347, 1324, 1277, 1234, 1202, 1141, 1124, 1055, 968, 937, 850, 801, 764.
HRMS (ESI) m/z calcd for C13H12NO4+ (M+H)+: 246.0761, found 246.0760.
1
Diethyl quinolineꢀ2,3ꢀdicarboxylate (6b). CAS: 32413ꢀ08ꢀ4. 37 mg, 45%, m. p. = 54ꢀ55oC, H NMR (400
MHz, CDCl3): 8.79 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.86 (ddd, J = 7.0, 4.7, 1.4 Hz,
1H), 7.72ꢀ7.62 (m, 1H), 4.54 (q, J = 7.2 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 5.7 Hz, 3H), 1.43 (t, J
= 4.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): 166.8, 165.0, 150.9, 148.0, 139.5, 132.2, 129.7, 128.6, 128.5,
126.9, 122.4, 62.2, 61.9, 14.1, 14.0. IR (cmꢀ1): 3069, 2987, 2940, 2905, 2870, 1732, 1614, 1599, 1563, 1493,
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1462, 1434, 1372, 1340, 1278, 1235, 1196, 1137, 1051, 1020, 965, 933, 910, 859, 808, 765, 702, 648, 594.
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HRMS (ESI) m/z calcd for C15H16NO4 (M+H)+: 274.1074, found 274.1073.
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Dimethyl 6ꢀmethylquinolineꢀ2,3ꢀdicarboxylate (6c). CAS: 1238846ꢀ48ꢀ4. 34 mg, 44%, m. p. = 99ꢀ100oC, 1H
NMR (400 MHz, CDCl3): 8.67 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 7.3 Hz, 2H), 4.07 (s, 3H), 3.99
(s, 3H), 2.59 (s, 3H). 13C NMR (100 MHz, CDCl3): 167.1, 165.7, 149.5, 146.6, 139.0, 138.6, 134.7, 129.4,
127.3, 127.1, 122.5, 53.0, 52.7, 21.6. IR (cmꢀ1): 3008, 2957, 2925, 2855, 1728, 1599, 1563, 1497, 1446, 1403,
1360, 1278, 1235, 1200, 1149, 1129, 1063, 972, 933, 827, 808, 792, 730, 698, 643, 604, 561. HRMS (ESI)
m/z calcd for C14H14NO4+ (M+H)+: 260.0917, found 260.0918.
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Dimethyl 6ꢀbromoquinolineꢀ2,3ꢀdicarboxylate (6d). CAS: 107504ꢀ38ꢀ1. 33 mg, 34%, m. p. = 156ꢀ157oC, 1H
NMR (400 MHz, CDCl3): 8.68 (s, 1H), 8.10 (dd, J = 9.6, 5.3 Hz, 2H), 7.94 (dd, J = 9.0, 1.9 Hz, 1H), 4.08 (s,
3H), 4.00 (s, 3H). 13C NMR (100 MHz, CDCl3): 166.7, 165.1, 150.6, 146.5, 138.3, 135.9, 131.4, 130.5,
128.0, 123.2, 122.9, 53.2, 53.0. IR (cmꢀ1): 3000, 2961, 2855, 1736, 1595, 1560, 1481, 1450, 1438, 1399,
1344, 1299, 1277, 1251, 1228, 1196, 1148, 1128, 1054, 967, 919, 832, 803, 754, 696. HRMS (ESI) m/z
calcd for C13H11BrNO4+ (M+H)+: 323.9866, found 323.9869.
Dimethyl 6ꢀfluoroquinolineꢀ2,3ꢀdicarboxylate (6e). CAS: 202808ꢀ05ꢀ7. 34 mg, 43%, m. p. = 127ꢀ129oC, 1H
NMR (400 MHz, CDCl3): 8.70 (s, 1H), 8.22 (dd, J = 9.2, 5.2 Hz, 1H), 7.63 (ddd, J = 11.0, 6.2, 2.8 Hz, 1H),
7.55 (dd, J = 8.2, 2.7 Hz, 1H), 4.06 (s, 3H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3): 166.7, 164.5, 161.5
(d, J = 251 Hz), 149.6, 145.0, 138.5, 132.5, 132.4, 127.8 (d, J = 11 Hz), 122.8, 122.5, 111.5 (d, J = 22 Hz),
53.1, 52.9. 19F NMR (376 MHz, CDCl3) δ ppm ꢀ109.12. IR (cmꢀ1): 3078, 3011, 2957, 2851, 1732, 1630,
1603, 1567, 1494, 1460, 1438, 1409, 1378, 1361, 1279, 1220, 1149, 1115, 1058, 965, 931, 854, 833, 812,
+
789. HRMS (ESI) m/z calcd for C13H11FNO4 (M+H)+: 264.0667, found 264.0666.
Dimethyl 6ꢀchloroquinolineꢀ2,3ꢀdicarboxylate (6f). CAS: 110139ꢀ44ꢀ1. 33.5 mg, 40%, m. p. = 153ꢀ154oC,
1H NMR (400 MHz, CDCl3): 8.68 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.80 (dd, J = 9.0, 2.2 Hz,
1H), 4.07 (s, 3H), 4.00 (s, 3H). 13C NMR (100 MHz, CDCl3): 166.7, 165.1, 150.5, 146.3, 138.3, 134.7, 133.3,
131.3, 127.6, 127.0, 123.3, 53.2, 52.9. IR (cmꢀ1): 3000, 2953, 2925, 2859, 1732, 1595, 1560, 1485, 1450,
1403, 1348, 1270, 1252, 1227, 1196, 1149, 1125, 1055, 1002, 968, 925, 831, 804, 753, 691, 643, 604, 573,
+
542. HRMS (ESI) m/z calcd for C13H11ClNO4 (M+H)+: 280.0371, found 280.0367.
Labeling experiment. An ovenꢀdried Schlenk tube (10 mL) was equipped with a magnetic stir bar, aromatic
enamine (1h, 0.3 mmol), MesꢀAcrꢀMe+ (5 mmol%, 0.015 mmol), CuCl2 (20 mmol%, 0.06 mmol), phen (20
mmol%, 0.06 mmol), TBHP (3 equiv.). The flask was evacuated and backfilled with O2 for 3 times. Then
DMF (3.0 mL) and H218O (10 equiv., 60 uL) was added with syringe. The reaction mixture was then stirred
for 24 h at room temperature under the irradiation of blue LEDs (λ= 450±15 nm, 5 W electrical power).
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After the reaction, 6 mL water was added to quench the reaction, and the resulting mixture was extracted
twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and
concentrated. Purification of the crude product by flash column chromatography afforded the product 2h
(petroleum ether/ethyl acetate as eluent (8:1)).
9
An ovenꢀdried Schlenk tube (10 mL) was equipped with a magnetic stir bar, aromatic enamine (1h, 0.3
mmol), MesꢀAcrꢀMe+ (5 mmol%, 0.015 mmol), CuCl2 (20 mmol%, 0.06 mmol), phen (20 mmol%, 0.06
mmol), TBHP (3 equiv.). The flask was evacuated and backfilled with 18O2 for 3 times. Then DMF (3.0 mL)
was added with syringe. The reaction mixture was then stirred for 24 h at room temperature under the
irradiation of blue LEDs (λ= 450±15 nm, 5 W electrical power). After the reaction, 6 mL water was added to
quench the reaction, and the resulting mixture was extracted twice with EtOAc. The combined organic
extracts were washed with brine, dried over Na2SO4 and concentrated. Purification of the crude product by
flash column chromatography afforded the product [18O]ꢀ2h (petroleum ether/ethyl acetate as eluent (8:1)).
ACKNOWLEDGMENTS
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We thank the National Science Foundation of China NSF 21402066 and the Natural Science Foundation of
Jiangsu Province (BK20140139) for financial support. Financial support from MOE&SAFEA for the 111
project (B13025) is also gratefully acknowledged.
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra of compounds 2aꢀ2n, 4aꢀ4l and 6a−6f, Xꢀray crystallographic data of 2e.
This material is available free of charge via the Internet at http://pubs.acs.org.
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