Copper-Catalyzed Aerobic Oxidative Carbocyclization Reactions of N -[(E)-Stilben-2-yl]amine Derivatives

Article abstract of DOI:10.1055/s-0034-1378870

A synthetic method for highly functionalized 2-quinolinones and quinolines has been developed. The copper(II)-catalyzed aerobic oxidative carbocyclization reactions of α-substituted N-[(E)-stilben-2-yl]acetamides, via the intramolecular carbocupration onto the alkenyl moiety, produced 3-substituted 2-quinolinones. Several useful functional groups including benzoyl, acetyl, cyano, and ethoxycarbonyl groups are compatible with the reaction conditions. This strategy was further applied to N-[(E)-stilben-2-yl]enamines to prepare 2,3-disubstituted quinolines in good yields.

Full text of DOI:10.1055/s-0034-1378870

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3687–3700
paper
3687
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
Copper-Catalyzed Aerobic Oxidative Carbocyclization Reactions
of N-[(E)-Stilben-2-yl]amine Derivatives
Cheng-Yen Lu
Ph
O
Ph
Che-Ping Chuang*
O
O
O
O
O
O
Department of Chemistry, National Cheng Kung University,
Tainan, Taiwan 70101, Taiwan
cpchuang@mail.ncku.edu.tw
Ph
Ph
CuCl2
Ph
+
DABCO
Phen, O2
N
N
N
TMBn
TMBn 71%
TMBn
8%
12 other examples
Received: 25.05.2015
Accepted after revision: 29.06.2015
Published online: 14.08.2015
as oxidant coupled with catalytic metal system provides an
attractive greener approach owing to its economic, high
abundance, and environmentally friendly features. The cop-
per-catalyzed oxidative reactions through direct C–H func-
tionalization have received considerable attention because
of their efficiencies and low costs, and have become a pow-
erful tool for the construction of synthetically useful het-
erocycles, such as pyrroles,8 indoles,9 oxazoles,10 oxin-
doles,11 pyrazoles,12 and quinolines.13
Although a number of synthetic methods for 2-quinoli-
nones are available, the search for mild and simple methods
is continuously being pursued. As part of our studies on the
development of new methods for the synthesis of heterocy-
clic compounds,14–17 we now report an effective route for
the synthesis of various functionalized 2-quinolinone de-
rivatives via the carbocyclization of copper-enolate onto
the alkenyl moiety in which the molecular oxygen was em-
ployed as the oxidant (Scheme 1).
DOI: 10.1055/s-0034-1378870; Art ID: ss-2015-f0331-op
Abstract A synthetic method for highly functionalized 2-quinolinones
and quinolines has been developed. The copper(II)-catalyzed aerobic
oxidative carbocyclization reactions of α-substituted N-[(E)-stilben-2-
yl]acetamides, via the intramolecular carbocupration onto the alkenyl
moiety, produced 3-substituted 2-quinolinones. Several useful func-
tional groups including benzoyl, acetyl, cyano, and ethoxycarbonyl
groups are compatible with the reaction conditions. This strategy was
further applied to N-[(E)-stilben-2-yl]enamines to prepare 2,3-disubsti-
tuted quinolines in good yields.
Key words copper salts, oxidative, cyclization, N-[(E)-stilben-2-
yl]amines, quinolines
2-Quinolinones have long been targeted in synthetic in-
vestigations for their known biological activities and phar-
macological properties, which include antiviral (HIV) activ-
ities,1a–c inotropic,1d 5HT3 receptor antagonists,1e farnesyl
transferase inhibitors,1f and maxi-K channel opening
agents.1g The development of new and efficient method for
their synthesis represents a challenge in organic and medi-
cal chemistry. Besides classic base-catalyzed Friedländer
reaction and acid-catalyzed Knorr reaction,2 several alter-
native methods have been employed in the synthesis of 2-
quinolinones including free radical cyclization of anilides,3
cyclization of Baylis–Hillman adducts,4 transition-metal-
catalyzed cyclization of anilines,5 and Pd-catalyzed amida-
tion of 3-arylacrylamides.6 Since the substituents on the 2-
quinolinone rings have a great influence on the properties
of these compounds, effective methods for the preparation
of highly functionalized 2-quinolinones are highly desir-
able.
R3
R2
R1
Cu salt
R3
base, O2
O
N
R
1
O
R2
O
R2
O
R1
R1
+
N
R
N
R
2
3
Scheme 1
In the past decades, transition-metal-catalyzed func-
tionalization of the C–H bond has emerged as an attractive
strategy in organic synthesis.7 The use of molecular oxygen
Our studies were initiated with the readily available 2-
benzoyl-N-[(E)-stilben-2-yl]acetamide 1a (R1 = H, R2 = COPh,
R3 = H, R = TMBn), which was prepared by the DCC-mediat-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3688
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
ed condensation reaction between 2-benzoylacetic acid and
(E)-stilben-2-ylamine (see the Supporting Information).
With this acetamide 1a in hand, its reaction was examined
under various conditions (Table 1). The reaction of 1a with
CuCl2 (10 mol%), 1,10-phenanthroline (20 mol%), and DAB-
CO (2 equiv) was carried out in DMF at 100 °C under an ox-
ygen atmosphere until 1a was completely consumed (7 h).
To our surprise, the expected 4-benzoyl-substituted prod-
uct 3a, derived from the elimination18 of [Cu(II)OH] from
peroxy intermediate 7a followed by oxidation (Scheme 1,
path B), was obtained in only 8% yield and the unexpected
fragmentation (path A) product 2a was produced in 71%
yield (Table 1, entry 1). Identical results were achieved at a
loading of 20 mol% of CuCl2 (entry 2). In the absence of
1,10-phenanthroline as a ligand, the reaction became slug-
gish and the yield of 2a dropped (entry 3). Screening of var-
ious solvents, such as DMF, DMAc, and DMSO, showed that
DMF and DMAc were suitable for this reaction (entries 1, 4,
and 5). Experiments suggest that the choice of base also
plays an important role in this reaction: Li2CO3 and NMP
were found to be inferior to DABCO (entries 6 and 7). Other
copper salts were also evaluated with the result that CuCl2
and CuCl displayed a higher catalytic activity than other
copper salts, such as CuBr, CuI, and Cu(OAc)2 (entries 1 and
8–11).
To probe into the possible reaction mechanism, the re-
action of 1a was carried out under the optimized condi-
tions in the presence of TEMPO (1 equiv), an effective radi-
cal scavenger, and products 2a and 3a were obtained in
comparable yields (Table 1, entries 1 and 12). Thus, a radi-
cal intermediate might not be involved in the reaction.
Based on this observation and the previous literature re-
ports,19–21 a plausible reaction mechanism for the forma-
tion of 2-quinolinones 2a and 3a is formulated (Scheme 2).
The reaction of 1a with copper(II) chloride under basic con-
ditions leads to the formation of copper(II) enolate 4a. Sub-
sequently, copper-catalyzed 6-exo-trig cyclization of 4a
onto the alkenyl moiety gives copper(II) intermediate 5a,
which is then oxidized by oxygen to generate the copper
peroxy intermediate 6a. Finally, peroxy intermediate 7a,
formed by the isomerization of 6a, undergoes either frag-
mentation20c,21 to give 2-quinolinone 2a and benzalde-
hyde22a (path A) or elimination18 of [Cu(II)OH] followed by
oxidation to produce 4-benzoyl-2-quinolinone 3a (path B).
Under the optimal CuCl2/DABCO/Phen conditions (Table
1, entry 1, Method A), the scope and limitations of this cop-
per-catalyzed oxidative cyclization reactions were investi-
gated (Table 2, entries 1–6). N-[(E)-Stilben-2-yl]acetamides
1a–e underwent efficient intramolecular ring closure to
provide the expected 2-quinolinones 2a–e in moderate
Table 1 Optimization of Reaction Conditions with 2-Benzoyl-N-[(E)-stilben-2-yl]acetamide 1aa
Ph
Ph
O
O
O
O
O
Ph
Ph
Ph
Cu salt
+
O
N
base, O2
N
O
N
1a
TMBn
2a
3a
TMBn
TMBn
Entry
Cu salt
Baseb
Solventc
Time (h)
2a, Yield (%)d
3a, Yield (%)d
1
2e
3
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
DABCO/Phen
DABCO/Phen
DABCO
DMF
DMF
DMF
DMAc
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
7
7
71
72
58
70
11
58
55
71
58
43
43
70
8
7
7
6
7
6
7
8
6
5
5
8
12
7
4
DABCO/Phen
DABCO/Phen
Li2CO3/Phen
NMP/Phen
5
9
6
12
7
7
8
DABCO/Phen
DABCO/Phen
DABCO/Phen
DABCO/Phen
DABCO/Phen
7
9
CuBr
9
10
11
12f
CuI
12
12
7
Cu(OAc)2
CuCl2
a TMBn: 2,4,6-trimethylbenzyl.
b DABCO: 1,4-diazobicyclo[2,2,2]octane; Phen: 1,10-phenanthroline; NMP: N-methylpiperidine.
c DMAc: N,N-dimethylacetamide.
d Yield of isolated product.
e With 20 mol% of CuCl2.
f TEMPO (1 equiv) was added. TEMPO: 2,2,6,6-Tetramethyl-piperidinyloxy.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3689
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
yields. A variety of electron-withdrawing or -donating
groups (R1) on the aniline moiety, including 4-chloro, 4-flu-
oro, 4-methyl, and 4,5-dimethyl, survived well in this trans-
formation (entries 2–5). However, with 1f (R1 = 4,6-Me2)
bearing a methyl group at the 6-position of aniline frag-
ment, it proceeded much slower (24 h) and a much poor re-
sult was obtained (entry 6). This is presumably due to the
steric effect between 6-Me and N-TMBn groups. Indeed, by
decreasing the size of R group, the reaction yield for 2g
(R = Bn) was improved to 57% and the reaction time was
shortened to 15 hours (entry 7). Other acetamides 1h–m,
bearing different functional groups (R2) such as acetyl, cya-
no, and ethoxycarbonyl groups at the α-position also
worked well, and 3-substituted 2-quinolinones 2h–m were
obtained in reasonable yields (entries 8–13). 4-Benzoyl-2-
quinolinones 3 were also obtained in 0–31% yields. The che-
moselectivities for the formation of 2k–m (R2 = CN and
CO2Et) are much lower than that of 2a–j (R2 = COPh and
COMe). It can be ascribed to the weaker acidity of HA in 7k–
m and the rate of fragmentation (path A) was diminished.
This copper(II) chloride-catalyzed oxidative carbocycliza-
tion of N-[(E)-stilben-2-yl]acetamides 1 provides an effi-
cient and low cost method for the synthesis of 3-substitut-
ed 2-quinolinones 2.
Quinolines also represent an important class of hetero-
cycles and are known to possess a wide range of biological
activities27 and a large number of methods for the synthe-
ses of functionalized quinolines have been developed.28
Nevertheless, most of these methods suffer from harsh re-
action conditions, low yields, and low stability of carbonyl
reagents.
Recently, we reported that the manganese(III) acetate
mediated oxidative free radical cyclizations of N-[(E)-stil-
ben-2-yl]enamines 9a–i (Scheme 3).16c This transformation
provided a synthetically useful method for the synthesis of
2,3-disubstituted quinolines 10a–i, however, a stoichiomet-
ric amount of manganese(III) acetate was required.
Ph
R1
R2
Mn(OAc)3, O2
R3
R3
HN
N
9a–i
R1
10a–i
R2
Scheme 3
In view of the good results shown above, we reasoned
that it might be possible to produce these 2,3-disubstituted
quinolines 10 by the copper(II)-catalyzed oxidative carbo-
cyclization reactions of N-[(E)-stilben-2-yl]enamines 9 via a
similar reaction route shown in Scheme 2.
3-Enaminones are useful synthetic precursors and their
utilization in organic synthesis is a subject of great current
interest. The transition-metal-catalyzed annulations of 3-
enaminones provided efficient methods for the synthesis of
pyrroles,8,23 indoles,9,24 pyridine,25 pyrazoles,12 and quino-
lines.13,26
N-[(E)-Stilben-2-yl]enaminone 9a (R1 = H, R2 = Ph,
R3 = COPh), prepared readily by the condensation of diben-
zoylmethane with (E)-stilben-2-ylamine (see the Support-
Ph
CuII
Ph
CuII
Ph
O
O
O
O
O
O
O2
DABCO
Cu(II)
Ph
Ph
Ph
N
N
N
5a
1a
4a
TMBn
TMBn
TMBn
CuII
O
HB
O
OH
Ph
CuII
Ph
O
Ph
O
O
O
O
O
O
O
path B
DABCO
HA
Ph
Ph
Ph
– CuIIOH
N
N
N
7a
8a
6a
TMBn
TMBn
TMBn
path A
DABCO
– CuIIOH
Ph
O
O
O
Ph
Ph
+
PhCHO
O
N
O
N
3a
2a
TMBn
TMBn
Scheme 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3690
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
Table 2 Oxidative Carbocyclic Reactions of N-[(E)-Stilben-2-yl]acetamides 1a
R3
R3
O
R2
R2
O
R2
R1
R1
+
R1
CuCl2, Phen
DABCO, O2
O
N
R
N
R
O
N
R
1
2
3
Entry
R1
R2
R3
R
Time (h)
2, Yield (%)b
3, Yield (%)b
1
H
COPh
COPh
COPh
COPh
COPh
COPh
COPh
COMe
COMe
COMe
CN
H
TMBn
7
11
9
2a (71)
2b (73)
2c (73)
2d (73)
2e (74)
2f (35)
2g (57)
2h (59)
2i (62)
2j (65)
2k (62)
2l (61)
2m (49)
3a (8)
3b (6)
3c (6)
3d (6)
3e (7)
3f (4)
2
6-Cl
H
TMBn
TMBn
TMBn
TMBn
TMBn
Bn
3
4
6-F
H
6-Me
6,7-Me2
6,8-Me2
6,8-Me2
H
H
11
9
5
H
6
H
24
15
2
7
H
3g (7)
3h (0)
3i (0)
8
H
TMBn
TMBn
TMBn
TMBn
TMBn
TMBn
9
6-Me
6-Cl
H
2
10
1122b
1222b
1322b
H
2
3j (0)
H
4-MeO
4-MeO
4-MeO
1
3k (30)
3l (31)
3m (21)
6-Me
H
CN
1
CO2Et
24
a Method A: 1 (0.21 mmol), CuCl2 (10 mol%), Phen (20 mol%), DABCO (2.0 equiv), O2 (1 atm) in DMF (2.5 mL) at 100 °C. TMBn: 2,4,6-trimethylbenzyl.
b Yield of isolated product.
ing Information), was chosen as the model substrate to
probe the feasibility of the proposed conversion. We were
pleased to find that the reaction of 9a with CuCl2 (10 mol%),
1,10-phenanthroline (20 mol%), and DABCO (2 equiv) in
DMF at 100 °C under an oxygen atmosphere for six hours
(Method A), successfully afforded quinolines 10a and 11a in
84% and 9% yield, respectively (Table 3, entry 1). The gener-
alities of this reaction were examined with other enami-
nones 9b–f (R3 = COPh), and the results are summarized in
Table 3. Substrates 9b and 9c, bearing 4-methyl and 4-
chloro groups (R1) on the aniline moiety, were tolerated in
the developed reaction conditions and 10b,c were obtained
in good yields (Table 3, entries 2 and 3). When R2 was a
methyl substituent, the desired oxidative cyclization prod-
ucts 10d–f were also obtained in acceptable yields (entries
4–6). 2-[(E)-Stilben-2-yl]aminoacrylonitriles 9g–i (R3 = CN)
also showed good reactivity, producing the corresponding
quinolines 10g–i in 79–84% yields (entries 7–9). In most
cases, small amounts of 4-benzoylquinolines 11a–i were
also obtained as the minor products.
cur. These 2-aminofumarates 9j–n were readily available
from the addition of (E)-stilben-2-ylamines to dimethyl
acetylenedicarboxylate (see the Supporting Information).
Indeed, when the reaction of 2-[(E)-stilben-2-yl]aminofu-
marate 9j (R1 = H, R2 = R3 = CO2Me) was carried out under
CuCl2/DABCO/Phen conditions (method A) for one hour, the
target cyclization product 10j was obtained in 67% yield
(Table 3, entry 10). It is noteworthy that the yield can be
improved to 86% using CuCl/NMP conditions (method B)
and the reaction time was shortened to 30 minutes (entry
13, see also Table 2 in the Supporting Information). As
shown in Table 3 (entries 13–17), a variety of 2-aminofu-
marates 9j–n were converted to the corresponding quino-
lines effectively. Regardless of R1 on the aniline moiety,
electron-donating or -withdrawing substituents, the oxida-
tive cyclization products 10j–n were achieved in good to
moderate yields. These copper-catalyzed oxidative carbocy-
clization reactions of N-[(E)-stilben-2-yl]enamines 9 pro-
vide a mild and straightforward method for the synthesis of
2,3-disubstituted quinolines 10 in high yields.
Due to the structural analogy of 2-[(E)-stilben-2-yl]ami-
nofumarates with N-[(E)-stilben-2-yl]enaminones, the cop-
per(II)-catalyzed oxidative carbocyclization of 2-[(E)-stil-
ben-2-yl]aminofumarates 9j–n could be envisioned to oc-
In conclusion, the syntheses of highly functionalized 2-
quinolinones and 2,3-disubstituted quinolines are de-
scribed. Copper(II) enolate 4, produced by the reaction of N-
[(E)-stilben-2-yl]acetamide 1 with copper(II) chloride and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3691
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
Table 3 Oxidative Carbocyclic Reactions of N-[(E)-Stilben-2-yl]enamines 9a–i and 2-[(E)-Stilben-2-yl]aminofumarates 9j–n
Ph
Ph
R3
R2
O
R3
R2
Cu salt
R1
R1
+
R1
base, O2
N
HN
N
R3
9
10
11
R2
Entry
R1
R2
R3
Time (h)
10, Yield (%)a
11, Yield (%)a
1b
2b
H
Ph
COPh
6
10a (84)
10b (82)
10c (81)
10d (43)
10e (50)
10f (51)
10g (80)
10h (79)
10i (84)
10j (67)
10k (61)
10l (61)
10j (86)
10k (79)
10l (87)
10m (76)
10n (73)
11a (9)
11b (7)
11c (10)
11d (19)
11e (17)
11f (18)
11g (0)
11h (7)
11i (6)
6-Me
6-Cl
H
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
COPh
COPh
COPh
COPh
COPh
CN
6
3b
6
4b
6
5b
6-Me
6-Cl
H
6
6b
6
7b
1
8b
6-Me
6-Cl
H
CN
1
9b
CN
1
10b
11b
12b
13c
14c
15c
16c
17c
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
1
11j (9)
6-Me
6-Cl
H
1
11k (8)
11l (10)
11j (8)
1
0.5
0.5
0.5
0.5
0.5
6-Me
6-Cl
11k (13)
11l (11)
11m (11)
11n (10)
6,7-Me2
6,8-Me2
a Yield of isolated product. For abbreviations, see Table 1.
b Method A: 9 (0.25 mmol), CuCl2 (10 mol%), Phen (20 mol%), DABCO (2.0 equiv), O2 (1 atm) in DMF (2.5 mL) at 100 °C.
c Method B: 9 (0.31 mmol), CuCl (10 mol%), NMP (2.0 equiv), O2 (1 atm) in DMAc (2.5 mL) at 100 °C.
DABCO, undergoes an intramolecular carbocupration onto
the alkenyl moiety efficiently. This reaction provides an ef-
ficient and low costs method for the synthesis of 3-substi-
tuted 2-quinolinones. A variety of functional groups includ-
ing benzoyl, acetyl, cyano, and ethoxycarbonyl groups are
compatible with the reaction conditions. This strategy was
further applied to N-[(E)-stilben-2-yl]enamines derivatives
affording 2,3-disubstituted quinolines in good yields.
Copper(II)-Catalyzed Cyclization Reactions of N-[(E)-Stilben-2-
yl]acetamides 1; 3-Benzoyl-1-(2,4,6-trimethylbenzyl)quinolin-
2(1H)-one (2a) and 3,4-Dibenzoyl-1-(2,4,6-trimethylbenzyl)quino-
lin-2(1H)-one (3a); Typical Procedure (Method A)
A mixture of 2-benzoyl-N-[(E)-stilben-2-yl]acetamide 1a (101 mg,
0.21 mmol), CuCl2 (4 mg, 0.02 mmol), 1,10-phenanthroline (7 mg,
0.04 mmol), and DABCO (47 mg, 0.42 mmol) in DMF (2.5 mL) was
stirred at 100 °C for 7 h under an O2 atmosphere (1 atm). The reaction
mixture was then diluted with EtOAc (50 mL), and the organic layer
was washed with H2O (3 × 50 mL), dried (Na2SO4), and concentrated
in vacuo. The crude product was purified by column chromatography
over silica gel (20 g, eluent: 1:8 EtOAc–hexane) followed by crystalli-
zation (EtOAc–hexane) to give 2a (57 mg, 71%) and 3a (8 mg, 8%).
Melting points are uncorrected. IR spectra were taken with a Hitachi
260-30 spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker AMX-400 spectrometer. Chemical shifts are reported in ppm
relative to TMS as internal reference. The multiplicity of the 13C NMR
signals was determined by means of DEPT 135 experiments. Elemen-
tal analyses were performed with Heraeus CHN-Rapid Analyzer. Mass
spectra were recorded on a Jeol JMS-SX 102A mass spectrometer. An-
alytical TLC was performed with precoated silica gel 60 F-254 plates
(0.25 mm thick) from EM Laboratories and visualized by UV. The re-
action mixture was purified by column chromatography over EM Lab-
oratories silica gel (70–230 mesh).
3-Benzoyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one (2a)
Yield: 57 mg (71%); light yellow needles; mp 201–202 °C (EtOAc–
hexane).
IR (KBr): 1660, 1645, 1565, 1455, 1215 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.24 (s, 9 H, 3 × CH3), 5.65 (s, 2 H,
NCH2), 6.81 (s, 2 H, ArH), 7.06 (d, J = 7.9 Hz, 1 H, ArH), 7.19 (t, J = 7.9
Hz, 1 H, ArH), 7.40 (t, J = 7.9 Hz, 1 H, ArH), 7.46 (t, J = 7.7 Hz, 2 H, ArH),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3692
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
7.59 (t, J = 7.7 Hz, 1 H, ArH), 7.62 (d, J = 7.9 Hz, 1 H, ArH), 7.88 (d,
J = 7.7 Hz, 2 H, ArH), 8.01 (s, 1 H, CH).
3-Benzoyl-6,7-dimethyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-
one (2e)
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.7 (q), 42.3 (t), 115.3
(d), 119.8 (s), 122.6 (d), 128.4 (2 d), 129.4 (2 d), 130.0 (d), 130.22 (s),
130.26 (2 d), 131.4 (s), 131.9 (d), 133.3 (d), 135.9 (2 s), 136.7 (s), 137.2
(s), 140.2 (s), 140.6 (d), 160.7 (s), 194.3 (s).
Yield: 63 mg (74%); white needles; mp 249–250 °C (EtOAc–hexane).
IR (KBr): 1640, 1595, 1555, 1455, 1240 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H, CH3), 2.23 (s, 3 H, CH3),
2.25 (s, 3 H, CH3), 2.26 (s, 6 H, 2 × CH3), 5.61 (s, 2 H, NCH2), 6.81 (s, 2 H,
ArH), 6.89 (s, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.44 (t, J = 7.6 Hz, 2 H, ArH),
7.56 (t, J = 7.6 Hz, 1 H, ArH), 7.86 (d, J = 7.6 Hz, 2 H, ArH), 7.95 (s, 1 H,
CH).
Anal. Calcd for C26H23NO2: C, 81.86; H, 6.08; N, 3.67. Found: C, 81.97;
H, 6.08; N, 3.63.
3-Benzoyl-6-chloro-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2b)
13C NMR (100.6 MHz, CDCl3): δ = 18.9 (q), 20.3 (2 q), 20.7 (q), 20.9 (q),
42.1 (t), 116.2 (d), 118.0 (s), 128.3 (2 d), 129.4 (2 d), 130.0 (d), 130.08
(s), 130.13 (2 d), 130.5 (s), 131.6 (s), 133.1 (d), 136.0 (2 s), 136.6 (s),
137.5 (s), 138.7 (s), 140.6 (d), 142.0 (s), 160.6 (s), 194.7 (s).
Yield: 61 mg (73%); white needles; mp 253–254 °C (EtOAc–hexane).
IR (KBr): 1675, 1645, 1485, 1285, 1215 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
5.65 (s, 2 H, NCH2), 6.84 (s, 2 H, ArH), 7.02 (d, J = 9.1 Hz, 1 H, ArH),
7.36 (dd, J = 9.1, 2.3 Hz, 1 H, ArH), 7.49 (t, J = 7.5 Hz, 2 H, ArH), 7.60 (d,
J = 2.3 Hz, 1 H, ArH), 7.62 (t, J = 7.5 Hz, 1 H, ArH), 7.89 (d, J = 7.5 Hz, 2
H, ArH), 7.92 (s, 1 H, CH).
Anal. Calcd for C28H27NO2: C, 82.12; H, 6.65; N, 3.42. Found: C, 82.05;
H, 6.64; N, 3.41.
3-Benzoyl-6,8-dimethyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-
one (2f)
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.7 (q), 42.4 (t), 116.7
(d), 120.8 (s), 128.1 (s), 128.5 (2 d), 128.8 (d), 129.4 (2 d), 129.9 (s),
130.4 (2 d), 131.8 (d), 132.6 (s), 133.5 (d), 135.9 (2 s), 136.8 (s), 137.0
(s), 138.6 (s), 139.1 (d), 160.3 (s), 193.8 (s).
Yield: 43 mg (35%); yellow crystals; mp 208–209 °C (EtOAc–hexane).
IR (KBr): 1655, 1565, 1445, 1275, 1235 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.07 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.40 (s, 3 H, CH3), 2.68 (s, 3 H, CH3), 5.36 (s, 2 H, NCH2), 6.77 (s, 2 H,
ArH), 7.21 (t, J = 7.8 Hz, 2 H, ArH), 7.26 (s, 1 H, ArH), 7.28 (s, 1 H, ArH),
7.44 (t, J = 7.8 Hz, 1 H, ArH), 7.49 (d, J = 7.8 Hz, 2 H, ArH), 7.83 (s, 1 H,
CH).
Anal. Calcd for C26H22ClNO2: C, 75.08; H, 5.33; N, 3.37. Found: C,
75.04; H, 5.42; N, 3.37.
3-Benzoyl-6-fluoro-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2c)
13C NMR (100.6 MHz, CDCl3): δ = 20.29 (q), 20.32 (2 q), 20.8 (q), 23.2
(q), 49.9 (t), 121.6 (s), 124.7 (s), 128.0 (2 d), 128.2 (d), 129.4 (2 d),
129.6 (2 d), 131.0 (s), 131.7 (s), 132.3 (s), 132.9 (d), 136.37 (s), 136.43
(s), 136.9 (2 s), 137.9 (d), 141.1 (d), 141.6 (s), 162.1 (s), 194.0 (s).
Yield: 60 mg (73%); white needles; mp 212–213 °C (EtOAc–hexane).
IR (KBr): 1670, 1645, 1575, 1440, 1235 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.23 (s, 6 H, 2 × CH3), 2.24 (s, 3 H, CH3),
5.64 (s, 2 H, NCH2), 6.82 (s, 2 H, ArH), 7.03 (dd, J = 9.4, 4.3 Hz, 1 H,
ArH), 7.13 (ddd, J = 9.4, 8.0, 2.9 Hz, 1 H, ArH), 7.28 (dd, J = 8.0, 2.9 Hz,
1 H, ArH), 7.46 (t, J = 7.6 Hz, 2 H, ArH), 7.59 (t, J = 7.6 Hz, 1 H, ArH),
7.87 (d, J = 7.6 Hz, 2 H, ArH), 7.91 (s, 1 H, CH).
Anal. Calcd for C28H27NO2: C, 82.12; H, 6.65; N, 3.42. Found: C, 82.00;
H, 6.68; N, 3.35.
3-Benzoyl-1-benzyl-6,8-dimethylquinolin-2(1H)-one (2g)
Yield: 49 mg (57%); yellow needles; mp 132–133 °C (EtOAc–hexane).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.7 (q), 42.5 (t), 114.5
(dd, JC,F = 22.1 Hz), 117.0 (dd, JC,F = 8.0 Hz), 119.8 (dd, JC,F = 24.1 Hz),
120.6 (d, JC,F = 8.0 Hz), 128.5 (2 d), 129.4 (2 d), 130.0 (s), 130.3 (2 d),
132.8 (s), 133.5 (d), 135.9 (2 s), 136.7 (s), 136.8 (s), 136.9 (s), 139.2
(dd, JC,F = 3.0 Hz), 157.7 (d, JC,F = 244.5 Hz), 160.3 (s), 193.9 (s).
IR (KBr): 1595, 1455, 1280, 1240, 1020 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.36 (s, 3 H, CH3), 2.57 (s, 3 H, CH3),
5.71 (s, 2 H, CH2), 7.05 (d, J = 7.2 Hz, 2 H, ArH), 7.21 (s, 1 H, ArH), 7.19
(t, J = 7.2 Hz, 1 H, ArH), 7.29 (t, J = 7.2 Hz, 2 H, ArH), 7.31 (s, 1 H, ArH),
7.42 (t, J = 7.5 Hz, 2 H, ArH), 7.54 (t, J = 7.5 Hz, 1 H, ArH), 7.85 (d,
J = 7.5 Hz, 2 H, ArH), 8.00 (s, 1 H, CH).
13C NMR (100.6 MHz, CDCl3): δ = 20.1 (q), 23.9 (q), 49.4 (t), 121.6 (s),
124.6 (s), 125.5 (2 d), 126.8 (d), 128.3 (2 d), 128.7 (2 d), 129.1 (d),
129.4 (2 d), 130.6 (s), 132.6 (s), 133.1 (d), 137.2 (s), 138.0 (s), 138.9
(d), 139.5 (s), 142.1 (d), 161.8 (s), 194.0 (s).
Anal. Calcd for C26H22FNO2: C, 78.18; H, 5.55; N, 3.51. Found: C, 78.06;
H, 5.59; N, 3.48.
3-Benzoyl-6-methyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2d)
Yield: 60 mg (73%); white needles; mp 231–232 °C (EtOAc–hexane).
Anal. Calcd for C25H21NO2: C, 81.72; H, 5.76; N, 3.81. Found: C, 81.73;
H, 5.78; N, 3.78.
IR (KBr): 1675, 1645, 1570, 1445, 1235 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.23 (s, 9 H, 3 × CH3), 2.35 (s, 3 H, CH3),
5.63 (s, 2 H, NCH2), 6.81 (s, 2 H, ArH), 6.96 (d, J = 8.7 Hz, 1 H, ArH),
7.22 (dd, J = 8.7, 1.9 Hz, 1 H, ArH), 7.39 (s, 1 H, ArH), 7.45 (t, J = 7.6 Hz,
2 H, ArH), 7.58 (t, J = 7.6 Hz, 1 H, ArH), 7.87 (d, J = 7.6 Hz, 2 H, ArH),
7.95 (s, 1 H, CH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.4 (q), 20.7 (q), 42.3 (t),
115.1 (d), 119.8 (s), 128.4 (2 d), 129.4 (2 d), 129.6 (d), 130.2 (2 d),
130.4 (s), 131.3 (s), 132.2 (s), 133.2 (d), 133.3 (d), 135.9 (2 s), 136.6 (s),
137.3 (s), 138.3 (s), 140.5 (d), 160.6 (s), 194.5 (s).
3-Acetyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one (2h)
Yield: 47 mg (59%); light yellow needles; mp 196–197 °C (EtOAc–
hexane).
IR (KBr): 1675, 1645, 1560, 1445, 1215 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.18 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.80 (s, 3 H, CH3), 5.67 (s, 2 H, NCH2), 6.80 (s, 2 H, ArH), 7.01 (d, J = 8.6
Hz, 1 H, ArH), 7.17 (t, J = 7.5 Hz, 1 H, ArH), 7.40 (ddd, J = 8.6, 7.5, 1.5
Hz, 1 H, ArH), 7.66 (dd, J = 7.5, 1.5 Hz, 1 H, ArH), 8.40 (s, 1 H, CH).
Anal. Calcd for C27H25NO2: C, 82.00; H, 6.37; N, 3.54. Found: C, 81.87;
H, 6.36; N, 3.50.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3693
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 20.2 (2 q), 20.7 (q), 31.0 (q), 42.3 (t),
115.1 (d), 119.5 (s), 122.6 (d), 128.9 (s), 130.1 (s), 130.3 (2 d), 131.1
(d), 132.8 (d), 135.8 (2 s), 136.6 (s), 140.9 (s), 142.9 (d), 161.4 (s),
198.6 (s).
IR (KBr): 2230, 1655, 1570, 1500, 1230 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.18 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.35 (s, 3 H, CH3), 5.63 (s, 2 H, NCH2), 6.80 (s, 2 H, ArH), 6.96 (d, J = 8.8
Hz, 1 H, ArH), 7.29 (dd, J = 8.8, 1.9 Hz, 1 H, ArH), 7.37 (s, 1 H, ArH),
8.16 (s, 1 H, CH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.4 (q), 20.7 (q), 43.0 (t),
106.7 (s), 115.47 (s), 115.51 (d), 118.9 (s), 129.6 (s), 129.7 (d), 130.3
(2 d), 133.0 (s), 135.3 (d), 135.9 (2 s), 137.0 (s), 138.7 (s), 147.4 (d),
159.4 (s).
Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.91;
H, 6.66; N, 4.35.
3-Acetyl-6-methyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2i)
Yield: 49 mg (62%); yellow crystals; mp 206–207 °C (EtOAc–hexane).
Anal. Calcd for C21H20N2O: C, 79.92; H, 6.37; N, 8.85. Found: C, 79.65;
H, 6.37; N, 8.81.
IR (KBr): 1675, 1645, 1565, 1350, 1225 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.34 (s, 3 H, CH3), 2.79 (s, 3 H, CH3), 5.65 (s, 2 H, NCH2), 6.79 (s, 2 H,
ArH), 6.91 (d, J = 8.7 Hz, 1 H, ArH), 7.22 (dd, J = 8.7, 1.6 Hz, 1 H, ArH),
7.43 (s, 1 H, ArH), 8.34 (s, 1 H, CH).
13C NMR (100.6 MHz, CDCl3): δ = 20.2 (2 q), 20.4 (q), 20.7 (q), 31.1 (q),
42.3 (t), 115.0 (d), 119.5 (s), 128.9 (s), 130.27 (2 d), 130.28 (s), 130.6
(d), 132.2 (s), 134.3 (d), 135.8 (2 s), 136.6 (s), 139.0 (s), 142.7 (d),
161.3 (s), 198.8 (s).
3-Ethoxycarbonyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2m)
Yield: 37 mg (49%); light yellow crystals; mp 127–128 °C (EtOAc–
hexane).
IR (KBr): 1745, 1650, 1565, 1450, 1210 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.1 Hz, 3 H, CH3), 2.18 (s, 6
H, 2 × CH3), 2.22 (s, 3 H, CH3), 4.44 (q, J = 7.1 Hz, 2 H, OCH2), 5.67 (s, 2
H, NCH2), 6.79 (s, 2 H, ArH), 7.00 (d, J = 8.7 Hz, 1 H, ArH), 7.16 (t, J = 7.5
Hz, 1 H, ArH), 7.39 (ddd, J = 8.7, 7.5, 1.4 Hz, 1 H, ArH), 7.61 (dd, J = 7.5,
1.4 Hz, 1 H, ArH), 8.40 (s, 1 H, CH).
Anal. Calcd for C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C, 79.24;
H, 6.96; N, 4.20.
13C NMR (100.6 MHz, CDCl3): δ = 14.3 (q), 20.3 (2 q), 20.7 (q), 42.5 (t),
61.6 (t), 115.1 (d), 119.1 (s), 122.4 (d), 122.5 (s), 130.2 (2 d), 130.3 (d),
132.6 (d), 135.9 (2 s), 136.6 (s), 140.7 (s), 143.8 (d), 159.7 (s), 165.0 (s).
3-Acetyl-6-chloro-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2j)
Yield: 53 mg (65%); light yellow needles; mp 204–205 °C (EtOAc–
hexane).
Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63; N 4.01. Found: C, 75.59;
H, 6.66; N, 4.01.
IR (KBr): 1680, 1655, 1560, 1485, 1210 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.78 (s, 3 H, CH3), 5.65 (s, 2 H, NCH2), 6.81 (s, 2 H, ArH), 6.94 (d, J = 9.1
Hz, 1 H, ArH), 7.33 (dd, J = 9.1, 2.4 Hz, 1 H, ArH), 7.62 (d, J = 2.4 Hz, 1
H, ArH), 8.28 (s, 1 H, CH).
3,4-Dibenzoyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one (3a)
Yield: 8 mg (8%); white crystals; mp 206–207 °C (EtOAc–hexane).
IR (KBr): 1670, 1635, 1610, 1455, 1235 cm–1
.
13C NMR (100.6 MHz, CDCl3): δ = 20.2 (2 q), 20.7 (q), 31.0 (q), 42.4 (t),
116.6 (d), 120.5 (s), 128.1 (s), 129.7 (d), 129.8 (s), 130.0 (s), 130.4
(2 d), 132.7 (d), 135.8 (2 s), 136.9 (s), 139.3 (s), 141.4 (d), 161.0 (s),
198.2 (s).
1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H, CH3), 2.31 (s, 6 H, 2 × CH3),
5.70 (s, 2 H, NCH2), 6.85 (s, 2 H, ArH), 7.06 (t, J = 7.8 Hz, 1 H, ArH), 7.14
(d, J = 7.8 Hz, 1 H, ArH), 7.30 (d, J = 7.8 Hz, 1 H, ArH), 7.39 (t, J = 7.8 Hz,
1 H, ArH), 7.41 (t, J = 7.6 Hz, 2 H, ArH), 7.43 (t, J = 7.7 Hz, 2 H, ArH),
7.54 (t, J = 7.6 Hz, 1 H, ArH), 7.58 (t, J = 7.7 Hz, 1 H, ArH), 7.81 (d,
J = 7.6 Hz, 2 H, ArH), 7.86 (d, J = 7.7 Hz, 2 H, ArH).
Anal. Calcd for C21H20ClNO2: C, 71.28; H, 5.70; N, 3.96. Found: C,
71.21; H, 5.73; N, 3.90.
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (2 q), 20.7 (q), 42.4 (t), 115.7
(d), 118.0 (s), 122.9 (d), 127.9 (d), 128.4 (2 d), 128.8 (2 d), 129.26 (2 d),
129.28 (s), 129.9 (2 d), 130.0 (s), 130.4 (2 d), 131.9 (d), 133.5 (d), 134.5
(d), 135.9 (2 s), 136.1 (s), 136.89 (s), 136.94 (s), 139.6 (s), 148.5 (s),
160.3 (s), 193.7 (s), 194.7 (s).
3-Cyano-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one (2k)
Yield: 47 mg (62%); light yellow crystals; mp 232–233 °C (EtOAc–
hexane).
IR (KBr): 2230, 1645, 1590, 1565, 1455 cm–1
.
Anal. Calcd for C33H27NO3: C, 81.63; H, 5.60; N, 2.88. Found: C, 81.38;
H, 5.63; N, 2.81.
1H NMR (400 MHz, CDCl3): δ = 2.19 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
5.65 (s, 2 H, NCH2), 6.81 (s, 2 H, ArH), 7.07 (d, J = 8.6 Hz, 1 H, ArH),
7.23 (t, J = 7.5 Hz, 1 H, ArH), 7.47 (ddd, J = 8.6, 7.5, 1.4 Hz, 1 H, ArH),
7.60 (dd, J = 7.5, 1.4 Hz, 1 H, ArH), 8.23 (s, 1 H, CH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.7 (q), 43.1 (t), 106.9 (s),
115.3 (s), 115.6 (d), 118.9 (s), 123.2 (d), 129.4 (s), 130.2 (d), 130.4
(2 d), 133.9 (d), 135.9 (2 s), 137.0 (s), 140.6 (s), 147.6 (d), 159.4 (s).
3,4-Dibenzoyl-6-chloro-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-
one (3b)
Yield: 6 mg (6%); white needles; mp 217–218 °C (EtOAc–hexane).
IR (KBr): 1665, 1640, 1560, 1420, 1315, 1230 cm–1
.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C, 79.33;
H, 6.01; N, 9.29.
1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H, CH3), 2.29 (s, 6 H, 2 × CH3),
5.67 (s, 2 H, NCH2), 6.85 (s, 2 H, ArH), 7.08 (d, J = 9.2 Hz, 1 H, ArH),
7.25 (d, J = 2.4 Hz, 1 H, ArH), 7.34 (dd, J = 9.2, 2.4 Hz, 1 H, ArH), 7.41 (t,
J = 7.5 Hz, 2 H, ArH), 7.44 (t, J = 7.5 Hz, 2 H, ArH), 7.55 (t, J = 7.5 Hz, 1
H, ArH), 7.61 (t, J = 7.5 Hz, 1 H, ArH), 7.78 (d, J = 7.5 Hz, 2 H, ArH), 7.84
(d, J = 7.5 Hz, 2 H, ArH).
3-Cyano-6-methyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-one
(2l)
Yield: 44mg (61%); light yellow needles; mp 215–216 °C (EtOAc–
hexane).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3694
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (2 q), 20.8 (q), 42.5 (t), 117.1
(d), 119.0 (s), 126.8 (d), 128.5 (2 d), 128.6 (s), 129.0 (2 d), 129.3 (2 d),
129.6 (s), 129.9 (2 d), 130.2 (s), 130.5 (2 d), 132.0 (d), 133.8 (d), 134.9
(d), 135.7 (s), 135.9 (2 s), 136.6 (s), 137.2 (s), 138.1 (s), 147.1 (s), 159.9
(s), 193.1 (s), 194.0 (s).
13C NMR (100.6 MHz, CDCl3): δ = 19.0 (q), 20.4 (2 q), 20.7 (q), 20.9 (q),
42.2 (t), 116.1 (s), 116.6 (d), 127.6 (d), 127.8 (s), 128.3 (2 d), 128.8
(2 d), 129.2 (2 d), 129.8 (2 d), 130.2 (2 d), 130.3 (s), 132.0 (s), 133.3 (d),
134.4 (d), 136.0 (2 s), 136.2 (s), 136.8 (s), 137.2 (s), 138.1 (s), 142.2 (s),
148.5 (s), 160.2 (s), 194.0 (s), 195.1 (s).
Anal. Calcd for C33H26ClNO3: C, 76.22; H, 5.04; N, 2.69. Found: C,
76.06; H, 5.06; N, 2.63.
Anal. Calcd for C35H31NO3: C, 81.84; H, 6.08; N, 2.73. Found: C, 81.69;
H, 6.10; N, 2.71.
3,4-Dibenzoyl-6-fluoro-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-
3,4-Dibenzoyl-6,8-dimethyl-1-(2,4,6-trimethylbenzyl)quinolin-
one (3c)
2(1H)-one (3f)
Yield: 6 mg (6%); yellow needles; mp 220–220 °C (EtOAc–hexane).
Yield: 6 mg (4%), yellow crystals; mp 246–247 °C (EtOAc–hexane).
IR (KBr): 1670, 1645, 1600, 1440, 1235 cm–1
.
IR (KBr): 1650, 1555, 1450, 1260 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H, CH3), 2.29 (s, 6 H, CH3),
5.69 (s, 2 H, NCH2), 6.85 (s, 1 H, ArH), 6.96 (d, J = 9.1 Hz, 1 H, ArH),
7.09–7.14 (m, 2 H, ArH), 7.40 (t, J = 7.7 Hz, 2 H, ArH), 7.44 (t, J = 7.7 Hz,
2 H, ArH), 7.54 (t, J = 7.7 Hz, 1 H, ArH), 7.60 (t, J = 7.7 Hz, 1 H, ArH),
7.79 (dd, J = 7.7, 1.0 Hz, 2 H, ArH), 7.84 (dd, J = 7.7, 1.1 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (2 q), 20.8 (q), 42.6 (t), 112.9
(dd, JC,F = 24.1 Hz), 117.4 (dd, JC,F = 8.0 Hz), 118.8 (d, JC,F = 9.1 Hz),
119.9 (dd, JC,F = 24.1 Hz), 128.5 (2 d), 129.0 (2 d), 129.3 (2 d), 129.8 (s),
129.9 (2 d), 130.5 (2 d), 133.7 (d), 134.8 (d), 135.7 (s), 135.9 (2 s),
136.2 (s), 136.7 (s), 137.2 (s), 147.3 (s), 157.7 (d, JC,F = 244.5 Hz), 158.9
(s), 160.0 (s), 193.3 (s), 194.1 (s).
1H NMR (400 MHz, CDCl3): δ = 2.14 (s, 6 H, 2 × CH3), 2.24 (s, 3 H, CH3),
2.26 (s, 3 H, CH3), 2.71 (s, 3 H, CH3), 5.37 (s, 2 H, NCH2), 6.79 (s, 2 H,
ArH), 6.95 (s, 1 H, ArH), 7.12 (t, J = 7.7 Hz, 2 H, ArH), 7.28 (s, 1 H, ArH),
7.39 (t, J = 7.7 Hz, 1 H, ArH), 7.39 (t, J = 7.4 Hz, 2 H, ArH), 7.40 (d,
J = 7.7 Hz, 2 H, ArH), 7.55 (t, J = 7.4 Hz, 1 H, ArH), 7.81 (d, J = 7.4 Hz, 2
H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.40 (2 q), 20.43 (q), 20.8 (q), 23.2
(q), 50.5 (t), 119.8 (s), 125.2 (s), 125.7 (d), 128.0 (2 d), 128.7 (2 d),
129.37 (2 d), 129.44 (2 d), 129.7 (2 d), 130.5 (s), 132.6 (s), 133.1 (d),
134.3 (d), 136.24 (s), 136.26 (s), 136.7 (s), 136.9 (2 s), 137.7 (d), 141.3
(s), 148.4 (s), 161.6 (s), 193.3 (s), 195.2 (s).
Anal. Calcd for C33H26FNO3: C, 78.71; H, 5.20; N, 2.78. Found: C, 78.28;
H, 5.22; N, 2.76.
Anal. Calcd for C35H31NO3: C, 81.84; H, 6.08; N, 2.73. Found: C, 81.54;
H, 6.13; N, 2.67.
3,4-Dibenzoyl-6-methyl-1-(2,4,6-trimethylbenzyl)quinolin-2(1H)-
3,4-Dibenzoyl-1-benzyl-6,8-dimethylquinolin-2(1H)-one (3g)
one (3d)
Yield: 8 mg (7%); yellow crystals; mp 187–188 °C (EtOAc–hexane).
Yield: 6 mg (6%); white crystals; mp 243–244 °C (EtOAc–hexane).
IR (KBr): 1650, 1555, 1450, 1255, 1215 cm–1
.
IR (KBr): 1645, 1445, 1240, 1210 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H, CH3), 2.60 (s, 3 H, CH3),
5.71 (s, 2 H, NCH2), 7.01 (s, 1 H, ArH), 7.12 (d, J = 7.2 Hz, 2 H, ArH),
7.20 (s, 1 H, ArH), 7.23 (t, J = 7.2 Hz, 1 H, ArH), 7.31 (t, J = 7.2 Hz, 2 H,
ArH), 7.35 (t, J = 7.4 Hz, 2 H, ArH), 7.43 (t, J = 7.5 Hz, 2 H, ArH), 7.48 (t,
J = 7.4 Hz, 1 H, ArH), 7.58 (t, J = 7.5 Hz, 1 H, ArH), 7.76 (d, J = 7.4 Hz, 2
H, ArH), 7.90 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (q), 23.9 (q), 50.2 (t), 119.9 (s),
125.3 (s), 125.6 (2 d), 126.3 (d), 126.9 (d), 128.3 (2 d), 128.4 (s), 128.7
(2 d), 128.8 (2 d), 129.1 (2 d), 129.8 (2 d), 132.9 (s), 133.3 (d), 134.4
(d), 136.1 (s), 136.9 (s), 137.6 (s), 138.8 (d), 139.3 (s), 149.3 (s), 161.5
(s), 193.3 (s), 195.2 (s).
1H NMR (400 MHz, CDCl3): δ = 2.19 (s, 3 H, CH3), 2.25 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 5.68 (s, 2 H, NCH2), 6.84 (s, 2 H, ArH), 7.04 (d,
J = 8.8 Hz, 1 H, ArH), 7.07 (s, 1 H, ArH), 7.21 (dd, J = 8.8, 1.8 Hz, 1 H,
ArH), 7.39 (t, J = 7.4 Hz, 2 H, ArH), 7.43 (t, J = 7.5 Hz, 2 H, ArH), 7.53 (t,
J = 7.4 Hz, 1 H, ArH), 7.58 (t, J = 7.5 Hz, 1 H, ArH), 7.80 (d, J = 7.4 Hz, 2
H, ArH), 7.86 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (2 q), 20.6 (q), 20.8 (q), 42.4 (t),
115.6 (d), 118.0 (s), 127.4 (d), 128.4 (2 d), 128.8 (2 d), 129.0 (s), 129.3
(2 d), 129.9 (2 d), 130.2 (s), 130.3 (2 d), 132.6 (s), 133.4 (d), 133.5 (d),
134.5 (d), 135.9 (2 s), 136.1 (s), 136.8 (s), 137.0 (s), 137.7 (s), 148.2 (s),
160.1 (s), 193.8 (s), 194.9 (s).
Anal. Calcd for C32H25NO3: C, 81.51; H, 5.34; N, 2.97. Found: C, 81.44;
H, 5.38; N, 2.95.
Anal. Calcd for C34H29NO3: C, 81.74; H, 5.85; N, 2.80. Found: C, 81.39;
H, 5.89; N, 2.74.
3-Cyano-4-(4-methoxybenzoyl)-1-(2,4,6-trimethylbenzyl)quino-
3,4-Dibenzoyl-6,7-dimethyl-1-(2,4,6-trimethylbenzyl)quinolin-
lin-2(1H)-one (3k)
2(1H)-one (3e)
Yield: 33 mg (30%); yellow needles; mp 206–207 °C (EtOAc–hexane).
Yield: 7 mg (7%); yellow crystals; mp 219–220 °C (EtOAc–hexane).
IR (KBr): 2230, 1650, 1600, 1555, 1455, 1255 cm–1
.
IR (KBr): 1685, 1635, 1450, 1230, 1020 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H, CH3), 2.26 (s, 6 H, 2 × CH3),
3.90 (s, 3 H, CH3), 5.71 (s, 2 H, NCH2), 6.84 (s, 2 H, ArH), 6.99 (d, J = 8.5
Hz, 2 H, ArH), 7.13 (t, J = 7.9 Hz, 1 H, ArH), 7.14 (d, J = 7.9 Hz, 1 H,
ArH), 7.38 (d, J = 7.9 Hz, 1 H, ArH), 7.47 (t, J = 7.9 Hz, 1 H, ArH), 7.86 (d,
J = 8.5 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (2 q), 20.7 (q), 43.3 (t), 55.7 (q),
103.5 (s), 113.4 (s), 114.7 (2 d), 116.0 (d), 117.1 (s), 123.5 (d), 127.6
(s), 128.5 (d), 129.3 (s), 130.5 (2 d), 132.5 (2 d), 134.2 (d), 135.9 (2 s),
137.2 (s), 140.5 (s), 157.2 (s), 158.9 (s), 165.5 (s), 189.9 (s).
1H NMR (400 MHz, CDCl3): δ = 2.08 (s, 3 H, CH3), 2.17 (s, 3 H, CH3),
2.25 (s, 3 H, CH3), 2.32 (s, 6 H, 2 × CH3), 5.66 (s, 2 H, NCH2), 6.85 (s, 2 H,
ArH), 6.98 (s, 1 H, ArH), 7.01 (s, 1 H, ArH), 7.39 (t, J = 7.6 Hz, 2 H, ArH),
7.42 (t, J = 7.6 Hz, 2 H, ArH), 7.52 (t, J = 7.6 Hz, 1 H, ArH), 7.57 (t, J = 7.6
Hz, 1 H, ArH), 7.79 (d, J = 7.6 Hz, 2 H, ArH), 7.85 (d, J = 7.6 Hz, 2 H,
ArH).
Anal. Calcd for C28H24N2O3: C, 77.04; H, 5.54; N, 6.42. Found: C, 77.07;
H, 5.55; N, 6.43.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3695
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
3-Cyano-4-(4-methoxybenzoyl)-6-methyl-1-(2,4,6-trimethylben-
zyl)quinolin-2(1H)-one (3l)
3-Benzoyl-6-methyl-2-phenylquinoline (10b)16c
Yield: 96 mg (82%); white needles; mp 148–149 °C (EtOAc–hexane).
IR (KBr): 1660, 1445, 1270, 890, 735 cm–1
1H NMR (400 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3), 7.22–7.30 (m, 3 H,
ArH), 7.32 (t, J = 7.6 Hz, 2 H, ArH), 7.47 (t, J = 7.6 Hz, 1 H, ArH), 7.58–
7.63 (m, 2 H, ArH), 7.65–7.69 (m, 2 H, ArH), 7.71 (d, J = 8.2 Hz, 2 H,
ArH), 8.14 (d, J = 9.2 Hz, 1 H, ArH), 8.25 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.6 (q), 125.8 (s), 126.8 (d), 128.3
(4 d), 128.6 (d), 129.2 (2 d), 129.3 (d), 129.9 (2 d), 132.7 (s), 133.2 (d),
133.5 (d), 136.9 (d), 137.1 (s), 137.3 (s), 139.8 (s), 147.0 (s), 156.5 (s),
197.1 (s).
Yield: 32 mg (31%); yellow crystals; mp 212–213 °C (EtOAc–hexane).
.
IR (KBr): 2230, 1645, 1595, 1560, 1510, 1250, 1165 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.22 (s, 3 H, CH3), 2.25 (s, 9 H, 3 × CH3),
3.90 (s, 3 H, CH3), 5.69 (s, 2 H, NCH2), 6.83 (s, 2 H, ArH), 6.99 (d, J = 8.5
Hz, 2 H, ArH), 7.03 (d, J = 8.6 Hz, 1 H, ArH), 7.13 (s, 1 H, ArH), 7.29 (dd,
J = 8.6, 1.8 Hz, 1 H, ArH), 7.87 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.39 (2 q), 20.44 (q), 20.7 (q), 43.2
(t), 55.7 (q), 103.3 (s), 113.5 (s), 114.7 (2 d), 115.9 (d), 117.1 (s), 127.6
(s), 127.8 (d), 129.5 (s), 130.4 (2 d), 132.5 (2 d), 133.4 (s), 135.7 (d),
135.9 (2 s), 137.1 (s), 138.6 (s), 156.9 (s), 158.8 (s), 165.5 (s), 190.1 (s).
Anal. Calcd for C23H17NO: C, 85.42; H, 5.30; N, 4.33. Found: C, 85.27;
H, 5.33; N, 4.29.
Anal. Calcd for C29H26N2O3: C, 77.31; H, 5.82; N, 6.22. Found: C, 77.38;
H, 5.86; N, 6.17.
3-Benzoyl-6-chloro-2-phenylquinoline (10c)16c
3-Ethoxycarbonyl-4-(4-methoxybenzoyl)-1-(2,4,6-trimethylben-
zyl)quinolin-2(1H)-one (3m)
Yield: 96 mg (81%); white needles; mp 161–162 °C (EtOAc–hexane).
IR (KBr): 1665, 1475, 1270, 885, 720 cm–1
.
Yield: 21 mg (21%); white crystals; mp 181–182 °C (EtOAc–hexane).
1H NMR (400 MHz, CDCl3): δ = 7.25–7.31 (m, 3 H, ArH), 7.34 (t, J = 7.5
Hz, 2 H, ArH), 7.49 (t, J = 7.5 Hz, 1 H, ArH), 7.58–7.64 (m, 2 H, ArH),
7.70 (d, J = 7.5 Hz, 2 H, ArH), 7.76 (dd, J = 9.0, 2.3 Hz, 1 H, ArH), 7.89 (d,
J = 2.3 Hz, 1 H, ArH), 8.18 (d, J = 9.0 Hz, 1 H, ArH), 8.24 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 126.4 (s), 126.6 (d), 128.4 (4 d),
129.0 (d), 129.2 (2 d), 129.9 (2 d), 131.2 (d), 132.1 (d), 133.0 (s), 133.5
(d), 133.6 (s), 136.5 (d), 136.7 (s), 139.3 (s), 146.7 (s), 157.6 (s), 196.5
(s).
IR (KBr): 1745, 1645, 1600, 1560, 1455, 1260, 1165 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.07 (t, J = 6.8 Hz, 3 H, CH3), 2.24 (s, 3
H, CH3), 2.26 (s, 6 H, 2 × CH3), 3.87 (s, 3 H, CH3), 4.12 (q, J = 6.8 Hz, 2 H,
OCH2), 5.71 (s, 2 H, NCH2), 6.83 (s, 2 H, ArH), 6.94 (d, J = 8.3 Hz, 2 H,
ArH), 7.04 (t, J = 7.9 Hz, 1 H, ArH), 7.08 (d, J = 7.9 Hz, 1 H, ArH), 7.34 (d,
J = 7.9 Hz, 1 H, ArH), 7.37 (t, J = 7.9 Hz, 1 H, ArH), 7.85 (d, J = 8.3 Hz, 2
H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 13.6 (q), 20.4 (2 q), 20.7 (q), 42.7 (t),
55.6 (q), 61.8 (t), 114.2 (2 d), 115.5 (d), 117.4 (s), 121.8 (s), 122.8 (d),
128.2 (d), 129.0 (s), 130.0 (s), 130.3 (3 d), 131.9 (d), 132.3 (d), 135.9
(2 s), 136.8 (s), 139.9 (s), 149.2 (s), 159.2 (s), 164.1 (s), 164.6 (s), 192.1
(s).
Anal. Calcd for C22H14ClNO: C, 76.86; H, 4.10; N, 4.07. Found: C, 76.77;
H, 4.15; N, 4.03.
3-Benzoyl-2-methylquinoline (10d)16c
Yield: 32 mg (43%); pale yellow oil.
Anal. Calcd for C30H29NO5: C, 74.52; H, 6.04; N, 2.90. Found: C, 74.63;
H, 6.07; N, 2.88.
IR (film): 1660, 1595, 1240, 880, 690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.75 (s, 3 H, CH3), 7.51 (t, J = 7.6 Hz, 2
H, ArH), 7.56 (t, J = 7.8 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH),
7.76–7.83 (m, 1 H, ArH), 7.80 (d, J = 7.8 Hz, 1 H, ArH), 7.85 (d, J = 7.6
Hz, 2 H, ArH), 8.09 (d, J = 7.8 Hz, 1 H, ArH), 8.13 (s, 1 H, ArH).
Copper(II)-Catalyzed Cyclization Reactions of N-[(E)-Stilben-2-
yl]enamines 9a–i; 3-Benzoyl-2-phenylquinoline (10a) and 3,4-
Benzoyl-2-phenylquinoline (11a); Typical Procedure (Method A)
13C NMR (100.6 MHz, CDCl3): δ = 24.2 (q), 125.3 (s), 126.6 (d), 128.1
(d), 128.7 (3 d), 130.1 (2 d), 131.0 (d), 132.2 (s), 133.7 (d), 136.7 (d),
137.3 (s), 148.0 (s), 156.6 (s), 196.7 (s).
A mixture of N-[(E)-stilben-2-yl]enaminone 9a (101 mg, 0.25 mmol),
CuCl2 (3 mg, 0.03 mmol), 1,10-phenanthroline (9 mg, 0.05 mmol),
and DABCO (59 mg, 0.53 mmol) in DMF (2.5 mL) was stirred at 100 °C
for 6 h under an O2 atmosphere (1 atm). The reaction mixture was
then diluted with EtOAc (50 mL), washed with H2O (3 × 50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was purified
by column chromatography over silica gel (20 g, eluent: 1:8 EtOAc–
hexane) followed by crystallization (EtOAc–hexane) to give 10a (65
mg, 84%) and 11a (9 mg, 9%).
HMRS (EI): m/z [M]+ calcd for C17H13NO: 247.0997; found: 247.0992.
3-Benzoyl-2,6-Dimethylquinoline (10e)16c
Yield: 37 mg (50%); colorless needles; mp 68–69 °C (EtOAc–hexane).
IR (KBr): 1660, 1595, 1245, 830, 730 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.54 (s, 3 H, CH3), 2.72 (s, 3 H, CH3),
7.50 (t, J = 7.7 Hz, 2 H, ArH), 7.56 (s, 1 H, ArH), 7.62 (dd, J = 8.7, 1.9 Hz,
1 H, ArH), 7.64 (t, J = 7.7 Hz, 1 H, ArH), 7.84 (d, J = 7.7 Hz, 2 H, ArH),
7.98 (d, J = 8.7 Hz, 1 H, ArH), 8.04 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.5 (q), 24.1 (q), 125.3 (s), 126.9 (d),
128.3 (d), 128.7 (2 d), 130.1 (2 d), 132.1 (s), 133.3 (d), 133.6 (d), 136.2
(d), 136.6 (s), 137.4 (s), 146.7 (s), 155.6 (s), 196.9 (s).
3-Benzoyl-2-phenylquinoline (10a)16c
Yield: 65 mg (84%); white needles; mp 133–134 °C (EtOAc–hexane).
IR (KBr): 1655, 1595, 1270, 775, 690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.31 (m, 3 H, ArH), 7.33 (t, J = 7.6
Hz, 2 H, ArH), 7.48 (t, J = 7.8 Hz, 1 H, ArH), 7.60–7.66 (m, 3 H, ArH),
7.72 (d, J = 7.6 Hz, 2 H, ArH), 7.84 (t, J = 7.8 Hz, 1 H, ArH), 7.92 (d,
J = 7.8 Hz, 1 H, ArH), 8.25 (d, J = 7.8 Hz, 1 H, ArH), 8.35 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 125.8 (s), 127.3 (d), 128.1 (d), 128.4
(4 d), 128.8 (d), 129.3 (2 d), 129.7 (d), 130.0 (2 d), 131.2 (d), 132.8 (s),
133.3 (d), 137.0 (s), 137.6 (d), 139.7 (s), 148.3 (s), 157.5 (s), 196.9 (s).
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 82.59;
H, 5.79; N, 5.32.
3-Benzoyl-6-chloro-2-methylquinoline (10f)16c
Yield: 39 mg (51%); colorless needles; mp 121–122 °C (EtOAc–
hexane).
Anal. Calcd for C22H15NO: C, 85.41; H, 4.89; N, 4.53. Found: C, 85.21;
H, 5.01; N, 4.60.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3696
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
IR (KBr): 1660, 1595, 1275, 835, 725 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.16 (t, J = 7.4 Hz, 2 H, ArH), 7.19–7.28
(m, 3 H, ArH), 7.33 (t, J = 7.4 Hz, 1 H, ArH), 7.41 (t, J = 7.4 Hz, 2 H, ArH),
7.47 (d, J = 7.4 Hz, 2 H, ArH), 7.52 (t, J = 7.8 Hz, 1 H, ArH), 7.58 (t,
J = 7.9 Hz, 1 H, ArH), 7.59–7.67 (m, 3 H, ArH), 7.81 (d, J = 7.4 Hz, 2 H,
ArH), 7.84 (t, J = 7.8 Hz, 1 H, ArH), 8.32 (d, J = 7.8 Hz, 1 H, ArH).
1H NMR (400 MHz, CDCl3): δ = 2.72 (s, 3 H, CH3), 7.51 (t, J = 7.7 Hz, 2
H, ArH), 7.65 (t, J = 7.7 Hz, 1 H, ArH), 7.71 (dd, J = 8.9, 2.3 Hz, 1 H, ArH),
7.78 (d, J = 2.3 Hz, 1 H, ArH), 7.83 (d, J = 7.7 Hz, 2 H, ArH), 8.02 (d,
J = 8.9 Hz, 1 H, ArH), 8.02 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 123.3 (s), 125.8 (d), 127.8 (d), 128.0
(2 d), 128.4 (2 d), 128.7 (2 d), 129.0 (d), 129.3 (2 d), 129.6 (2 d), 130.0
(2 d), 130.1 (d), 130.4 (s), 131.2 (d), 133.2 (d), 134.3 (d), 136.9 (s),
137.2 (s), 139.5 (s), 147.0 (s), 148.0 (s), 156.9 (s), 196.4 (s), 196.7 (s).
13C NMR (100.6 MHz, CDCl3): δ = 24.2 (q), 125.9 (s), 126.6 (d), 128.8
(2 d), 130.1 (2 d), 130.3 (d), 131.8 (d), 132.3 (s), 133.1 (s), 133.9 (d),
135.4 (d), 136.9 (s), 146.4 (s), 156.9 (s), 196.3 (s).
Anal. Calcd for C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C, 72.34;
H, 4.35; N, 4.95.
HRMS (EI): m/z [M]+ calcd for C29H19NO2: 413.1416; found: 413.1414.
3,4-Benzoyl-6-methyl-2-phenylquinoline (11b)
3-Cyano-2-phenylquinoline (10g)16c
Yield: 11 mg (7%), white crystals; mp 182–183 °C (EtOAc–hexane).
Yield: 58 mg (80%); white needles; mp 195–196 °C (EtOAc–hexane).
IR (KBr): 1660, 1550, 1450, 1345, 1230 cm–1
.
IR (KBr): 2220, 1555, 1375, 755, 690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 7.14 (t, J = 7.5 Hz, 2
H, ArH), 7.17–7.27 (m, 3 H, ArH), 7.31 (t, J = 7.5 Hz, 1 H, ArH), 7.40 (t,
J = 7.6 Hz, 2 H, ArH), 7.40 (s, 1 H, ArH), 7.45 (d, J = 7.5 Hz, 2 H, ArH),
7.56 (t, J = 7.6 Hz, 1 H, ArH), 7.58–7.63 (m, 2 H, ArH), 7.67 (dd, J = 8.7,
1.7 Hz, 1 H, ArH), 7.80 (d, J = 7.6 Hz, 2 H, ArH), 8.20 (d, J = 8.7 Hz, 1 H,
ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.8 (q), 123.3 (s), 124.4 (d), 128.0
(2 d), 128.3 (2 d), 128.7 (2 d), 128.8 (d), 129.3 (2 d), 129.5 (2 d), 129.7
(d), 130.0 (2 d), 130.1 (s), 133.2 (d), 133.6 (d), 134.2 (d), 136.9 (s),
137.2 (s), 138.1 (s), 139.6 (s), 146.1 (s), 146.8 (s), 155.9 (s), 196.6 (s),
196.8 (s).
1H NMR (400 MHz, CDCl3): δ = 7.52–7.61 (m, 3 H, ArH), 7.67 (t, J = 7.9
Hz, 1 H, ArH), 7.90 (t, J = 7.9 Hz, 1 H, ArH), 7.91 (d, J = 7.9 Hz, 1 H,
ArH), 7.97–8.04 (m, 2 H, ArH), 8.21 (d, J = 7.9 Hz, 1 H, ArH), 8.67 (s, 1
H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 105.6 (s), 117.9 (s), 125.0 (s), 127.7
(d), 128.1 (d), 128.7 (2 d), 129.1 (2 d), 129.9 (d), 130.1 (d), 133.0 (d),
137.6 (s), 144.2 (d), 148.7 (s), 158.0 (s).
Anal. Calcd for C16H10N2: C, 83.46; H, 4.38; N, 12.17. Found: C, 83.38;
H, 4.38; N, 12.16.
3-Cyano-6-methyl-2-phenylquinoline (10h)16c
HRMS (EI): m/z [M]+ calcd for C30H21NO2: 427.1572; found: 427.1577.
Yield: 88 mg (79%); colorless needles; mp 172–173 °C (EtOAc–
hexane).
3,4-Benzoyl-6-chloro-2-phenylquinoline (11c)
IR (KBr): 2220, 1590, 1380, 830, 695 cm–1
.
Yield: 16 mg (10%); white crystals; mp 172–173 °C (EtOAc–hexane).
1H NMR (400 MHz, CDCl3): δ = 2.59 (s, 3 H, CH3), 7.50–7.62 (m, 3 H,
ArH), 7.66 (s, 1 H, ArH), 7.72 (dd, J = 8.6, 1.9 Hz, 1 H, ArH), 7.96–8.03
(m, 2 H, ArH), 8.10 (d, J = 8.6 Hz, 1 H, ArH), 8.57 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.6 (q), 105.4 (s), 118.1 (s), 125.0
(s), 126.4 (d), 128.6 (2 d), 129.0 (2 d), 129.5 (d), 129.9 (d), 135.3 (d),
137.7 (s), 138.3 (s), 143.4 (d), 147.3 (s), 157.1 (s).
IR (KBr): 1660, 1595, 1450, 1310, 1225 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.17 (t, J = 7.4 Hz, 2 H, ArH), 7.20–7.29
(m, 3 H, ArH), 7.34 (t, J = 7.4 Hz, 1 H, ArH), 7.41 (t, J = 7.8 Hz, 2 H, ArH),
7.45 (d, J = 7.4 Hz, 2 H, ArH), 7.55–7.64 (m, 4 H, ArH), 7.77 (d, J = 9.0,
2.1 Hz, 1 H, ArH), 7.78 (d, J = 7.8 Hz, 2 H, ArH), 8.25 (d, J = 9.0 Hz, 1 H,
ArH).
Anal. Calcd for C17H12N2: C, 83.58; H, 4.95; N, 11.47. Found: C, 83.58;
H, 4.97; N, 11.47.
13C NMR (100.6 MHz, CDCl3): δ = 123.9 (s), 124.4 (d), 128.1 (2 d),
128.4 (2 d), 128.8 (2 d), 129.23 (d), 129.27 (2 d), 129.6 (2 d), 130.0
(2 d), 131.1 (s), 131.6 (d), 132.3 (d), 133.5 (d), 133.9 (s), 134.6 (d),
136.5 (s), 136.9 (s), 139.2 (s), 145.9 (s), 146.4 (s), 157.1 (s), 195.6 (s),
196.3 (s).
6-Chloro-3-cyano-2-phenylquinoline (10i)16c
Yield: 96 mg (84%); white needles; mp 197–198 °C (EtOAc–hexane).
IR (KBr): 2220, 1550, 1475, 925, 695 cm–1
.
HRMS (EI): m/z [M]+ calcd for C29H18ClNO2 447.1026; found:
447.1017.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.61 (m, 3 H, ArH), 7.82 (dd,
J = 9.0, 2.2 Hz, 1 H, ArH), 7.90 (d, J = 2.2 Hz, 1 H, ArH), 7.96–8.03 (m, 2
H, ArH), 8.15 (d, J = 9.0 Hz, 1 H, ArH), 8.58 (s, 1 H, ArH).
3,4-Benzoyl-2-methylquinoline (11d)
13C NMR (100.6 MHz, CDCl3): δ = 106.6 (s), 117.5 (s), 125.5 (s), 126.2
(d), 128.8 (2 d), 129.1 (2 d), 130.3 (d), 131.5 (d), 133.9 (d), 134.1 (s),
137.3 (s), 143.1 (d), 147.1 (s), 158.2 (s).
Yield: 20 mg (19%); yellow crystals; mp 175–176 °C (EtOAc–hexane).
IR (KBr): 1660, 1595, 1320, 1290 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3 H, CH3), 7.38 (t, J = 7.4 Hz, 2
H, ArH), 7.40 (t, J = 7.4 Hz, 2 H, ArH), 7.45 (t, J = 7.3 Hz, 1 H, ArH),
7.53–7.59 (m, 3 H, ArH), 7.69 (d, J = 7.4 Hz, 2 H, ArH), 7.71 (d, J = 7.4
Hz, 2 H, ArH), 7.78 (t, J = 7.3 Hz, 1 H, ArH), 8.16 (d, J = 7.3 Hz, 1 H,
ArH).
Anal. Calcd for C16H9ClN2: C, 72.60; H, 3.43; N, 10.58. Found: C, 72.36;
H, 3.46; N, 10.53.
3,4-Benzoyl-2-phenylquinoline (11a)
Yield: 9 mg (9%), white crystals; mp 192–193 °C (EtOAc–hexane).
13C NMR (100.6 MHz, CDCl3): δ = 24.4 (q), 122.9 (s), 125.7 (d), 127.2
(d), 128.66 (2 d), 128.69 (2 d), 129.2 (d), 129.8 (2 d), 130.0 (2 d), 130.8
(d), 130.9 (s), 134.1 (d), 134.4 (d), 136.7 (s), 136.9 (s), 144.4 (s), 147.7
(s), 155.1 (s), 196.0 (s), 196.7 (s).
IR (KBr): 1655, 1595, 1550, 1450, 1235 cm–1
.
HRMS (EI): m/z [M]+ calcd for C24H17NO2: 351.1259; found: 351.1250.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3697
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
3,4-Benzoyl-2,6-dimethylquinoline (11e)
Copper(I)-Catalyzed Cyclization Reactions of 2-[(E)-Stilben-2-
yl]aminofumarates 9j–n; Dimethyl Quinoline-2,3-dicarboxylate
(10j) and Dimethyl 4-Benzoylquinoline-2,3-dicarboxylate (11j);
Typical Procedure (Method B)
Yield: 18 mg (17%); yellow solid; mp 177–178 °C (EtOAc–hexane).
IR (KBr): 1670, 1595, 1450, 1380, 1290 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3), 2.58 (s, 3 H, CH3),
7.31 (s, 1 H, ArH), 7.38 (t, J = 7.6 Hz, 4 H, ArH), 7.56 (t, J = 7.6 Hz, 2 H,
ArH), 7.61 (d, J = 8.5 Hz, 1 H, ArH), 7.68 (d, J = 7.6 Hz, 2 H, ArH), 7.69
(d, J = 7.6 Hz, 2 H, ArH), 8.04 (d, J = 8.5 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.7 (q), 24.2 (q), 122.9 (s), 124.3 (d),
128.65 (2 d), 128.67 (2 d), 128.8 (d), 129.9 (2 d), 130.1 (2 d), 130.6 (s),
133.2 (d), 134.1 (d), 134.4 (d), 136.7 (s), 136.9 (s), 137.5 (s), 143.7 (s),
146.5 (s), 154.0 (s), 196.3 (s), 196.8 (s).
A mixture of 2-[(E)-stilben-2-yl]aminofumarate (9j; 104 mg, 0.31
mmol), CuCl (3 mg, 0.03 mmol), and NMP (66 mg, 0.67 mmol) in
DMAc (2.5 mL) was stirred at 100 °C for 30 min under an O2 atmo-
sphere (1 atm). The reaction mixture was then diluted with EtOAc (50
mL), and the organic layer was washed with H2O (3 × 50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was purified
by column chromatography over silica gel (20 g, eluent: 1:8 EtOAc–
hexane) followed by crystallization (EtOAc–hexane) to give 10j (65
mg, 86%) and 11j (9 mg, 8%).
HRMS (EI): m/z [M]+ calcd for C25H19NO2: 365.1416; found: 365.1417.
Dimethyl Quinoline-2,3-dicarboxylate (10j)
3,4-Benzoyl-6-chloro-2-methylquinoline (11f)
Yield: 65 mg (86%); white crystals; mp 106–107 °C (EtOAc–hexane).
Yield: 19 (18%); light yellow crystals; mp 213–214 °C (EtOAc–
hexane).
IR (KBr): 1730, 1445, 1270, 1200, 1135 cm–1
.
IR (KBr): 1670, 1595, 1450, 1380, 1240 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.99 (s, 3 H, OCH3), 4.07 (s, 3 H, OCH3),
7.69 (t, J = 7.9 Hz, 1 H, ArH), 7.88 (t, J = 7.9 Hz, 1 H, ArH), 7.95 (d,
J = 7.9 Hz, 1 H, ArH), 8.22 (d, J = 7.9 Hz, 1 H, ArH), 8.78 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 52.9 (q), 53.2 (q), 122.3 (s), 127.0 (s),
128.6 (d), 128.7 (d), 129.9 (d), 132.5 (d), 139.6 (d), 148.1 (s), 150.5 (s),
165.6 (s), 167.1 (s).
1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 7.40 (t, J = 7.7 Hz, 4
H, ArH), 7.54 (d, J = 2.0 Hz, 1 H, ArH), 7.55–7.62 (m, 2 H, ArH), 7.66 (d,
J = 7.7 Hz, 4 H, ArH), 7.72 (dd, J = 9.0, 2.0 Hz, 1 H, ArH), 8.09 (d, J = 9.0
Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.3 (q), 123.5 (s), 124.4 (d), 128.75
(2 d), 128.77 (2 d), 129.8 (2 d), 130.1 (2 d), 130.8 (d), 131.5 (s), 131.8
(d), 133.3 (s), 134.3 (d), 134.7 (d), 136.3 (s), 136.6 (s), 143.3 (s), 146.2
(s), 155.5 (s), 195.3 (s), 196.2 (s).
Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.63;
H, 4.55; N, 5.73.
HRMS (EI): m/z [M]+ calcd for C24H16ClNO2: 385.0870; found:
Dimethyl 6-Methylquinoline-2,3-dicarboxylate (10k)
385.0862.
Yield: 59 mg (79%); white crystals; mp 109–110 °C (EtOAc–hexane).
IR (KBr): 1735, 1565, 1230, 1200, 1130 cm–1
.
4-Benzoyl-3-cyano-6-methyl-2-phenylquinoline (11h)
1H NMR (400 MHz, CDCl3): δ = 2.57 (s, 3 H, CH3), 3.97 (s, 3 H, OCH3),
4.05 (s, 3 H, OCH3), 7.68 (s, 1 H, ArH), 7.69 (d, J = 9.0 Hz, 1 H, ArH),
8.10 (d, J = 9.0 Hz, 1 H, ArH), 8.65 (s, 1 H, ArH).
Yield: 11 mg (7%); white crystals; mp 145–146 °C (EtOAc–hexane).
IR (KBr): 1670, 1545, 1450, 1345, 1230 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 7.41 (s, 1 H, ArH),
7.49–7.59 (m, 5 H, ArH), 7.70 (t, J = 7.8 Hz, 1 H, ArH), 7.74 (d, J = 8.5
Hz, 1 H, ArH), 7.88 (d, J = 7.8 Hz, 2 H, ArH), 8.00 (m, 2 H, ArH), 8.17 (d,
J = 8.5 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 21.8 (q), 102.2 (s), 115.8 (s), 122.4
(s), 124.1 (s), 128.7 (2 d), 129.20 (2 d), 129.26 (2 d), 130.0 (d), 130.1
(3 d), 135.26 (s), 135.27 (d), 135.7 (d), 137.4 (s), 139.3 (s), 147.3 (s),
152.9 (s), 157.1 (s), 193.9 (s).
13C NMR (100.6 MHz, CDCl3): δ = 21.7 (q), 52.9 (q), 53.2 (q), 122.5 (s),
127.2 (s), 127.3 (d), 129.5 (d), 134.8 (d), 138.7 (d), 139.1 (s), 146.7 (s),
149.5 (s), 165.8 (s), 167.2 (s).
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.88;
H, 5.07; N, 5.36.
Dimethyl 6-Chloroquinoline-2,3-dicarboxylate (10l)
Yield: 67 mg (87%); white crystals; mp 157–158 °C (EtOAc–hexane).
HRMS (EI): m/z [M]+ calcd for C24H16N2O: 348.1263; found: 348.1269.
IR (KBr): 1730, 1450, 1275, 1140 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3),
7.79 (dd, J = 9.0, 2.3 Hz, 1 H, ArH), 7.91 (d, J = 2.3 Hz, 1 H, ArH), 8.14 (d,
J = 9.0 Hz, 1 H, ArH), 8.66 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 53.0 (q), 53.3 (q), 123.4 (s), 127.1 (d),
127.7 (s), 131.4 (d), 133.4 (d), 134.8 (s), 138.4 (d), 146.4 (s), 150.6 (s),
165.2 (s), 166.8 (s).
4-Benzoyl-6-chloro-3-cyano-2-phenylquinoline (11i)
Yield: 9 mg (6%); white needles; mp 211–212 °C (EtOAc–hexane).
IR (KBr): 1665, 1595, 1550, 1450, 1365, 1225 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55 (t, J = 7.4 Hz, 2 H, ArH), 7.51–7.61
(m, 3 H, ArH), 7.64 (d, J = 2.3 Hz, 1 H, ArH), 7.72 (t, J = 7.4 Hz, 1 H,
ArH), 7.83 (dd, J = 9.1, 2.3 Hz, 1 H, ArH), 7.87 (d, J = 7.4 Hz, 2 H, ArH),
7.97–8.04 (m, 2 H, ArH), 8.22 (d, J = 9.1 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 103.3 (s), 115.4 (s), 122.9 (s), 124.2
(d), 128.8 (2 d), 129.2 (2 d), 129.4 (2 d), 130.2 (2 d), 130.5 (d), 131.9
(d), 134.3 (d), 134.9 (s), 135.0 (s), 135.6 (d), 136.9 (s), 147.0 (s), 152.7
(s), 158.1 (s), 192.9 (s).
Anal. Calcd for C13H10ClNO4: C, 55.83; H, 3.60; N, 5.01. Found: C,
55.80; H, 3.63; N, 5.00.
Dimethyl 6,7-Dimethylquinoline-2,3-dicarboxylate (10m)
Yield: 85 mg (76%), white crystals; mp 121–122 °C (EtOAc–hexane).
IR (KBr): 1755, 1720, 1560, 1280, 1215, 1065 cm–1
.
HRMS (EI): m/z [M]+ calcd for C23H3ClN2O: 368.0716; found:
368.0725.
1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 2.49 (s, 3 H, CH3),
3.96 (s, 3 H, OCH3), 4.04 (s, 3 H, OCH3), 7.65 (s, 1 H, ArH), 7.96 (s, 1 H,
ArH), 8.63 (s, 1 H, ArH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3698
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 20.1 (q), 20.7 (q), 52.8 (q), 53.1 (q),
121.5 (s), 125.7 (s), 127.7 (d), 129.1 (d), 138.3 (d), 139.2 (s), 143.5 (s),
147.2 (s), 149.6 (s), 165.9 (s), 167.4 (s).
13C NMR (100.6 MHz, CDCl3): δ = 53.0 (q), 53.5 (q), 122.3 (s), 124.8 (d),
125.3 (s), 129.1 (2 d), 129.4 (2 d), 132.0 (d), 133.5 (d), 134.7 (d), 136.0
(s), 136.1 (s), 146.0 (s), 147.0 (s), 149.2 (s), 164.9 (s), 166.0 (s), 193.8
(s).
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.89;
H, 5.53; N, 5.08.
Anal. Calcd for C20H14ClNO5: C, 62.59; H, 3.68; N, 3.65. Found: C,
62.56; H, 3.74; N, 3.68.
Dimethyl 6,8-Dimethylquinoline-2,3-dicarboxylate (10n)
Dimethyl 4-Benzoyl-6,7-dimethylquinoline-2,3-dicarboxylate
(11m)
Yield: 55 mg (73%), white crystals; mp 128–129 °C (EtOAc–hexane).
IR (KBr): 1725, 1570, 1360, 1095, 970 cm–1
.
Yield: 17 mg (11%); white needles; mp 146–147 °C (EtOAc–hexane).
1H NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H, CH3), 2.78 (s, 3 H, CH3),
3.97 (s, 3 H, OCH3), 4.04 (s, 3 H, OCH3), 7.51 (s, 1 H, ArH), 7.54 (s, 1 H,
ArH), 8.64 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 17.7 (q), 21.6 (q), 52.7 (q), 52.9 (q),
121.5 (s), 125.3 (d), 127.2 (s), 134.9 (d), 137.7 (s), 138.5 (s), 138.9 (d),
145.9 (s), 148.7 (s), 165.8 (s), 167.8 (s).
IR (KBr): 1670, 1590, 1435, 1210 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 2.49 (s, 3 H, CH3),
3.62 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 7.38 (s, 1 H, ArH), 7.46 (t,
J = 7.6 Hz, 2 H, ArH), 7.62 (t, J = 7.6 Hz, 1 H, ArH), 7.77 (d, J = 7.6 Hz, 2
H, ArH), 8.06 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.4 (q), 20.6 (q), 52.7 (q), 53.3 (q),
120.3 (s), 123.2 (s), 125.0 (d), 128.9 (2 d), 129.3 (2 d), 129.7 (d), 134.3
(d), 136.4 (s), 140.4 (s), 143.6 (s), 146.88 (s), 146.94 (s), 148.3 (s),
165.4 (s), 166.6 (s), 194.9 (s).
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.92;
H, 5.56; N, 5.09.
Dimethyl 4-Benzoylquinoline-2,3-dicarboxylate (11j)
Anal. Calcd for C22H19NO5: C, 70.02; H, 5.07; N, 3.71. Found: C, 69.97;
H, 5.08; N, 3.69.
Yield: 9 mg (8%); white needles; mp 115–116 °C (EtOAc–hexane).
IR (KBr): 1725, 1670, 1435, 1235, 1125 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 3 H, OCH3), 4.07 (s, 3 H, OCH3),
7.47 (t, J = 7.6 Hz, 2 H, ArH), 7.61 (t, J = 7.9 Hz, 1 H, ArH), 7.63 (t, J = 7.6
Hz, 1 H, ArH), 7.67 (d, J = 7.9 Hz, 1 H, ArH), 7.78 (d, J = 7.6 Hz, 2 H,
ArH), 7.88 (t, J = 7.9 Hz, 1 H, ArH), 8.31 (d, J = 7.9 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 52.9 (q), 53.4 (q), 121.2 (s), 124.6 (s),
126.1 (d), 129.0 (2 d), 129.4 (2 d), 129.6 (d), 130.5 (d), 132.4 (d), 134.4
(d), 136.3 (s), 147.6 (s), 148.2 (s), 149.3 (s), 165.2 (s), 166.3 (s), 194.6
(s).
Dimethyl 4-Benzoyl-6,8-dimethylquinoline-2,3-dicarboxylate
(11n)
Yield: 15 mg (10%); white crystals; mp 121–122 °C (EtOAc–hexane).
IR (KBr): 1725, 1670, 1445, 1235, 1165 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, CH3), 2.83 (s, 3 H, CH3),
3.63 (s, 3 H, OCH3), 4.03 (s, 3 H, OCH3), 7.24 (s, 1 H, ArH), 7.46 (t,
J = 7.5 Hz, 2 H, ArH), 7.55 (s, 1 H, ArH), 7.61 (t, J = 7.5 Hz, 1 H, ArH),
7.76 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 17.9 (q), 21.9 (q), 52.7 (q), 53.1 (q),
120.2 (s), 122.6 (d), 124.7 (s), 128.9 (2 d), 129.3 (2 d), 134.2 (d), 135.0
(d), 136.5 (s), 138.4 (s), 139.8 (s), 145.6 (s), 147.42 (s), 147.46 (s),
165.3 (s), 167.0 (s), 195.2 (s).
Anal. Calcd for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C, 68.70;
H, 4.31; N, 4.02.
Dimethyl 4-Benzoyl-6-methylquinoline-2,3-dicarboxylate (11k)
Yield: 14 mg (13%); white solid; mp 148–149 °C (EtOAc–hexane).
Anal. Calcd for C22H19NO5: C, 70.02; H, 5.07; N, 3.71. Found: C, 70.02;
H, 5.08; N, 3.67.
IR (KBr): 1730, 1565, 1440, 1310, 1260 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 3.64 (s, 3 H, OCH3),
4.05 (s, 3 H, OCH3), 7.42 (s, 1 H, ArH), 7.48 (t, J = 7.5 Hz, 2 H, ArH), 7.63
(t, J = 7.5 Hz, 1 H, ArH), 7.71 (dd, J = 8.7, 1.8 Hz, 1 H, ArH), 7.78 (d,
J = 7.5 Hz, 2 H, ArH), 8.20 (d, J = 8.7 Hz, 1 H, ArH).
Acknowledgment
13C NMR (100.6 MHz, CDCl3): δ = 21.9 (q), 52.8 (q), 53.4 (q), 121.3 (s),
124.7 (d), 129.0 (2 d), 129.4 (2 d), 130.2 (d), 134.4 (d), 134.8 (d), 136.3
(s), 140.4 (2 s), 146.3 (s), 147.1 (s), 148.1 (s), 165.3 (s), 166.4 (s), 194.8
(s).
We are grateful to the National Science Council of ROC for financial
support (Grant No. NSC-100-2113-M-006-009-MY2).
Supporting Information
Anal. Calcd for C21H17NO5: C, 69.41; H, 4.72; N, 3.85. Found: C, 69.29;
H, 4.74; N, 3.80.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378870.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Dimethyl 4-Benzoyl-6-chloroquinoline-2,3-dicarboxylate (11l)
Yield: 11 mg (11%); white solid; mp 143–144 °C (EtOAc–hexane).
References
IR (KBr): 1730, 1670, 1580, 1305, 1255, 1130 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 3 H, OCH3), 4.06 (s, 3 H, OCH3),
7.49 (t, J = 7.6 Hz, 2 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H, ArH), 7.65 (d,
J = 2.2 Hz, 1 H, ArH), 7.77 (d, J = 7.6 Hz, 2 H, ArH), 7.82 (dd, J = 9.1, 2.2
Hz, 1 H, ArH), 8.25 (d, J = 9.1 Hz, 1 H, ArH).
(1) (a) Patel, M.; McHugh, R. J. Jr.; Cordova, B. C.; Klabe, R. M.;
Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Bioorg. Med.
Chem. Lett. 2001, 11, 1943. (b) Yong, S. R.; Ung, A. T.; Pyne, S. G.;
Skelton, B. W.; White, A. H. Tetrahedron 2007, 63, 1191. (c) Ellis,
D.; Kuhen, K. L.; Anaclerio, B.; Wu, B.; Wolff, K.; Yin, H.;
Bursulaya, B.; Caldwell, J.; Karanewsky, D.; He, Y. Bioorg. Med.
Chem. Lett. 2006, 16, 4246. (d) Fujioka, T.; Teramoto, S.; Mori, T.;
Hosokawa, T.; Sumida, T.; Tominaga, M.; Yabuuchi, Y. J. Med.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3699
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
Chem. 1992, 35, 3607. (e) Hayashi, H.; Miwa, Y.; Miki, I.;
Ichikawa, S.; Yoda, N.; Ishii, A.; Kono, M.; Suzuki, F. J. Med. Chem.
1992, 35, 4893. (f) Angibaud, P. R.; Venet, M. G.; Filliers, W.;
Broeckx, R.; Ligny, Y. A.; Muller, P.; Poncelet, V. S.; End, D. W.
Eur. J. Org. Chem. 2004, 479. (g) Boy, K. M.; Guernon, J. M.; Sit, S.-
Y.; Xie, K.; Hewawasam, P.; Boissard, C. G.; Dworetzky, S. I.;
Natale, J.; Gribkoff, V. K.; Lodge, N.; Starret, J. E. Bioorg. Med.
Chem. Lett. 2004, 14, 5089.
Pan, C.; Zhou, X.; Li, X.; Kang, X.; Huang, G. Org. Lett. 2013, 15,
4876. (d) Meyet, C. E.; Larsen, C. H. J. Org. Chem. 2014, 79, 9835.
(14) (a) Jiang, M.-C.; Chuang, C.-P. J. Org. Chem. 2000, 65, 5409.
(b) Wu, Y.-L.; Chuang, C.-P.; Lin, P.-Y. Tetrahedron 2001, 57,
5543. (c) Tseng, C.-C.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron 2002,
58, 7625.
(15) (a) Chuang, C.-P.; Wu, Y.-L. Tetrahedron 2004, 60, 1841. (b) Tsai,
A.-I.; Chuang, C.-P. Tetrahedron 2006, 62, 2235.
(2) For reviews on 2-quinolinone synthesis, see: (a) Jones, G. In
Comprehensive Heterocyclic Chemistry; Vol. 2; Boulton, A. J.;
Mckillop, A., Eds.; Pergamon: Oxford, 1984, 395–510.
(b) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Chem. Commun.
2004, 1754. (c) Li, K.; Forsee, L. N.; Tunge, J. A. J. Org. Chem. 2005,
70, 2881. (d) Sai, K. K. S.; Gilbert, T. M.; Klumpp, D. A. J. Org.
Chem. 2007, 72, 9761. (e) Domínguez-Fernández, F.; López-
Sanz, J.; Pérez-Mayoral, E.; Bek, D.; Martín-Aranda, R. M.; López-
Peinado, A. J.; Čejka, J. ChemCatChem 2009, 1, 241.
(3) (a) Clark, A. J.; Jones, K.; McCarthy, C.; Storey, J. M. D. Tetrahe-
dron Lett. 1991, 32, 2829. (b) Binot, G.; Zard, S. Z. Tetrahedron
Lett. 2005, 46, 7503. (c) Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron
2009, 65, 1982. (d) Tsubusaki, T.; Nishino, H. Tetrahedron 2009,
55, 9448. (e) Mai, W.-P.; Sun, G.-C.; Wang, J.-T.; Song, G.; Mao,
P.; Yang, L.-R.; Yuan, J.-W.; Xiao, Y.-M.; Qu, L.-B. J. Org. Chem.
2014, 79, 8094.
(4) (a) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron Lett. 2005,
46, 1493. (b) Familonni, O. B.; Klaas, P. J.; Lobb, K. A.; Pakade, V.
E.; Kaye, P. T. Org. Biomol. Chem. 2006, 4, 3960. (c) Pathak, R.;
Madapa, S.; Batra, S. Tetrahedron 2007, 63, 451.
(5) (a) Okuro, K.; Kai, H.; Alper, H. Tetrahedron: Asymmetry 1997, 8,
2307. (b) Fujita, K.-i.; Takahashi, Y.; Owaki, M.; Yamamoto, K.;
Yamaguchi, R. Org. Lett. 2004, 6, 2785. (c) Horn, J.; Li, H. Y.;
Marsden, S. P.; Nelson, A.; Shearer, R. J.; Campbell, A. J.; House,
D.; Weingarten, G. G. Tetrahedron 2009, 65, 9002.
(16) (a) Wu, Y.-L.; Chuang, C.-P.; Lin, P.-Y. Tetrahedron 2000, 56,
6209. (b) Chuang, C.-P.; Tsai, A.-I.; Tsai, M.-Y. Tetrahedron 2013,
69, 3293. (c) Tsai, P.-J.; Kao, C.-B.; Chiow, W.-R.; Chuang, C.-P.
Synthesis 2014, 46, 175.
(17) (a) Lin, Z.-Y.; Chen, Y.-L.; Lee, C.-S.; Chuang, C.-P. Eur. J. Org.
Chem. 2010, 3876. (b) Chen, K-P.; Chen, Y.-J.; Chuang, C.-P. Eur. J.
Org. Chem. 2010, 5292.
(18) For similar elimination reactions, see: (a) Lucas, H. R.; Li, L.;
Narducci Sarjeant, A. A.; Vance, M. A.; Solomon, E. I.; Karlin, K. D.
J. Am. Chem. Soc. 2009, 131, 3230. (b) Chiba, S.; Zhang, L.; Lee, J.-
Y. J. Am. Chem. Soc. 2010, 132, 7266. (c) Wang, H.; Wang, Y.;
Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem. Int. Ed. 2011,
50, 5678. (d) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2011, 13,
1622. (e) Toh, K. K.; Wang, Y.-F.; Ng, E. P. J.; Chiba, S. J. Am. Chem.
Soc. 2011, 133, 13942.
(19) For a review on the addition of metal enolates to C–C unsatu-
rated bonds, see: Dénès, F.; Pérez-Luna, A.; Chemla, F. Chem.
Rev. 2010, 110, 2366.
(20) (a) Bouyssi, D.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999,
40, 1297. (b) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.;
Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140. (c) Xie, P.; Wang,
Z.-Q.; Deng, G.-B.; Song, R.-J.; Xia, J.-D.; Hu, M.; Li, J.-H. Adv.
Synth. Catal. 2013, 355, 2257.
(21) For related fragmentation reactions, see: (a) Wang, Z.-Q.; Zhang,
W.-W.; Gong, L.-B.; Tang, R.-Y.; Yang, X.-H.; Liu, Y.; Li, J.-H.
Angew. Chem. Int. Ed. 2011, 50, 8968. (b) Han, J.; Shen, Y.; Sun,
X.; Yao, Q.; Chen, J.; Deng, H.; Shao, M.; Fan, B.; Zhang, H.; Cao,
W. Eur. J. Org. Chem. 2015, 2061.
(6) (a) Berrino, R.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Org.
Chem. 2012, 77, 2881. (b) Inamoto, K.; Kawasaki, J.; Hiroya, K.;
Kondo, Y.; Doi, T. Chem. Commun. 2012, 48, 4332.
(7) For reviews on transition-metal-catalyzed C–H functionaliza-
tions, see: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Chen, X.;
Engle, K.; Wang, D.; Yu, J. Angew. Chem. Int. Ed. 2009, 48, 5094.
(c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (e) Scheuermann, C. J. Chem. Asian J. 2010, 5, 436.
(f) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (g) Sun,
C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(8) (a) Yan, R.-L.; Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.; Liang,
Y.-M. J. Org. Chem. 2010, 75, 5395. (b) Zhao, M.-N.; Ren, Z.-H.;
Wang, Y.-Y.; Guan, Z.-H. Chem. Eur. J. 2014, 20, 1839. (c) Liu, P.;
Liu, J.-l.; Wang, H.-s.; Pan, Y.-m.; Liang, H.; Chen, Z.-F. Chem.
Commun. 2014, 50, 4795.
(22) (a) Benzaldehyde cannot be obtained in pure form. (b) 4-
Methoxybenzaldehyde was also obtained in 59%, 57%, and 51%
yield, respectively.
(23) (a) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Tetrahe-
dron: Asymmetry 2001, 12, 2715. (b) Robinson, R. S.; Dovey, M.
C.; Gravestock, D. Tetrahedron Lett. 2004, 45, 6787. (c) Rakshit,
S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585.
(d) Abdukader, A.; Xue, Q.; Lin, A.; Zhang, M.; Cheng, Y.; Zhu, C.
Tetrahedron Lett. 2013, 54, 5898.
(24) (a) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius, F.
Angew. Chem. Int. Ed. 2008, 47, 7230. (b) Kramer, S.;
Dooleweerdt, K.; Lindhardt, A. T.; Rottländer, M.; Skrydstrup, T.
Org. Lett. 2009, 11, 4208. (c) Shi, Z.; Zhang, C.; Li, S.; Pan, D.;
Ding, S.; Cui, Y.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572.
(d) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.; Liu, X.-Y.; Liang, Y.-M.
Chem. Commun. 2010, 46, 2823. (e) Gao, D.; Back, T. G. Chem.
Eur. J. 2012, 18, 14828. (f) Nguyen, H. H.; Kurth, M. J. Org. Lett.
2013, 15, 362.
(9) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem. Int.
Ed. 2009, 48, 8078.
(10) (a) Cheung, C. W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526.
(b) Xu, Z.; Zhang, C.; Jiao, N. Angew. Chem. Int. Ed. 2012, 51,
11367.
(11) (a) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249. (b) Jia,
Y.-X.; Kündig, E. P. Angew. Chem. Int. Ed. 2009, 48, 1636.
(12) (a) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem. Int. Ed.
2010, 49, 7790. (b) Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H.
J. Org. Chem. 2013, 78, 3636.
(13) (a) Toh, K. K.; Sanjaya, S.; Sahnoun, S.; Chong, S. Y.; Chiba, S. Org.
Lett. 2012, 14, 2290. (b) Xia, X.-F.; Zhang, L.-L.; Song, X.-R.; Liu,
X.-Y.; Liang, Y.-M. Org. Lett. 2012, 14, 2480. (c) Yan, R.; Liu, X.;
(25) (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
(b) Li, L.; Zhao, M.-N.; Ren, Z.-H.; Li, J.-L.; Guan, Z.-H. Org. Lett.
2012, 14, 3506.
(26) (a) Chen, Z.; Zhu, J.; Xie, H.; Li, S.; Wu, Y.; Gong, Y. Chem.
Commun. 2010, 46, 2145. (b) Han, J.; Cao, L.; Bian, L.; Chen, J.;
Deng, H.; Shao, M.; Jin, Z.; Zhang, H.; Cao, W. Adv. Synth. Catal.
2013, 355, 1345.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700

3700
C.-Y. Lu, C.-P. Chuang
Paper
Synthesis
(27) (a) Joshi, A. A.; Viswanathan, C. L. Bioorg. Med. Chem. Lett. 2006,
16, 2613. (b) Billker, O.; Lindo, V.; Panico, M.; Etiene, A.; Rogger,
S. M.; Sinden, R. E. Nature 1998, 389, 289. (c) Chen, Y. L.; Fang, K.
C.; Sheu, J. Y.; Hsu, S. L.; Tzeng, C. C. J. Med. Chem. 2001, 44,
2374. (d) Kym, P. R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.;
Tang, R.; Ratajczyk, J. D.; Larson, D. P.; Elmore, S. W.; Pratt, J. K.;
Stashko, M. A.; Falls, H. D.; Lin, C. W.; Nakane, M.; Miller, L.;
Tyree, C. M.; Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.; Nguyen,
P.; Lane, B. C. J. Med. Chem. 2003, 46, 1016. (e) Chou, L. C.; Tsai,
M. T.; Hsu, M. H.; Wang, S. H.; Way, T. D.; Huang, C. H.; Lin, H. Y.;
Qian, K.; Dong, Y.; Lee, K. H.; Huang, L. J.; Kuo, S. C. J. Med. Chem.
2010, 53, 8047. (f) Dubé, D.; Blouin, M.; Brideau, C.; Chan, C.-C.;
Desmarais, S.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Girard,
M.; Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N.
Bioorg. Med. Chem. Lett. 1998, 8, 1255. (g) Camps, P.; Gómez, E.;
Muñoz-Torrero, D.; Badia, A.; Vivas, N. M.; Barril, X.; Orozco, M.;
Luque, F. J. J. Med. Chem. 2001, 44, 4733. (h) Franck, X.; Fournet,
A.; Prina, E.; Mahieux, R.; Hocquemiller, R.; Figadere, B. Bioorg.
Med. Chem. Lett. 2004, 14, 3635.
(28) For reviews on quinoline synthesis, see: (a) Cheng, C.-C.; Yan, S.-
J. Org. React. 1982, 28, 38. (b) Kouznetsov, V. V.; Vargas Méndez,
L. Y.; Meléndez Gómez, C. M. Curr. Org. Chem. 2005, 9, 141.
(c) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2009, 12, 1116.
(d) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.; do Carmo
Carreiras, M.; Soriano, E. Chem. Rev. 2009, 109, 2652.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3687–3700