One-Pot Synthesis of Quinolin-4(1 H)-one Derivatives by a Sequential Michael Addition-Elimination/Palladium-Catalyzed Buchwald-Hartwig Amination Reaction

Article abstract of DOI:10.1055/s-0034-1380496

A convenient approach has been developed for the construction of quinolin-4(1H)-one frameworks, starting from (Z)-β-chlorovinyl aromatic ketones and amines. Intermolecular Michael addition of an amine to a (Z)-β-chlorovinyl ketone was followed by eliminat

Full text of DOI:10.1055/s-0034-1380496

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1851–1860
paper
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Paper
Synthesis
One-Pot Synthesis of Quinolin-4(1H)-one Derivatives by a Sequential
Michael Addition–Elimination/Palladium-Catalyzed Buchwald–
Hartwig Amination Reaction
Yinghua Wang
Hanyu Liang
Chunxia Chen*
Deqiang Wang
Jinsong Peng*
Department of Chemistry and Chemical Engineering, College
of Science, Northeast Forestry University, Harbin 150040, P. R.
of China
jspeng1998@nefu.edu.cn
080122@nefu.edu.cn
Received: 06.01.2015
Accepted after revision: 03.03.2015
Published online: 26.03.2015
Camps,9 Conrad–Limpach,10 or Niementowski cyclization.11
Although these methods have been widely used in the
preparation of quinolin-4-ones, they require harsh reaction
conditions (high temperatures and/or strong bases), dra-
matically limiting their scope. To develop milder processes
for assembling the quinolin-4-one ring system, methods
mediated by transition metals, such as palladium,12 cop-
per,13 or gold,14 have been extensively investigated.
As part of our continuing efforts in relation to sequential
one-pot syntheses of nitrogen heterocycles by palladium-
catalyzed reactions,15 we set out to develop a new protocol
for the synthesis of quinolin-4-ones from the correspond-
ing (Z)-β-chlorovinyl aromatic ketones (Scheme 1). These
ketones are readily prepared by regio- and stereoselective
addition of acid chlorides to alkynes in the presence of low-
cost iron catalysts16 and they are valuable intermediates for
the synthesis of various heterocyclic compounds.17 We sur-
mised that β-chloroalkenyl aryl ketones 1, derived from the
appropriate 2-chlorobenzoyl chlorides and terminal
alkynes, might react with amines in the presence of a palla-
dium complex and a base to give the corresponding N-sub-
stituted quinolones. Because of the versatile chemical prop-
erties of the β-chlorovinyl ketone moiety, we initially won-
dered whether enones 1 might serve as both the aryl
chloride and the vinyl chloride electrophilic coupling part-
DOI: 10.1055/s-0034-1380496; Art ID: ss-2015-h0007-op
Abstract A convenient approach has been developed for the construc-
tion of quinolin-4(1H)-one frameworks, starting from (Z)-β-chlorovinyl
aromatic ketones and amines. Intermolecular Michael addition of an
amine to a (Z)-β-chlorovinyl ketone was followed by elimination of a
chloride anion to give enamine intermediates, with full retention of the
initial Z-configuration. The enamine intermediates were transformed
into quinolin-4(1H)-one products by a palladium-catalyzed intramolec-
ular N-arylation in a tandem one-pot manner, with good to excellent
yields.
Key words quinolines, ketones, Michael additions, aminations, tan-
dem reactions, cyclizations
Quinolin-4-one frameworks are frequently found in a
diverse array of compounds, including natural products,1
synthetic building blocks,2 and therapeutically active mole-
cules (Figure 1), such as antibacterial,3 antitumor,4 antima-
larial,5 or antimitotic agents6 or HIV-1 integrase inhibitors.7
Consequently, the construction of this valuable structural
unit has received considerable attention, and much effort
has been focused on the development of new and efficient
synthetic methods.8 The classical synthetic approaches are
based on various cyclocondensation strategies, such as the
O
O
O
F
CO2H
O
O
N
N
N
R
N
Me
HN
N
MeS
SMe
R = Et
R = c-Pr
norfloxacin
ciprofloxacin
intervenolin
graveolinine
Figure 1 Representative quinolin-4-one moieties in pharmaceuticals and natural products
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Synthesis
Pd, R3NH2, base
Pd-catalyzed sequential
N-vinylation/N-arylation
path A
Cl
R2
Cl
O
O
+
R3NH2, base
R1
Fe
O
R1
anti-E2/addition
R2
Cl
R2
N
R3
path C
O
Cl
R1
1
Cl
path B
R3NH2, base
Pd/ligand
R1
Pd-catalyzed
N-arylation
Michael addition–
elimination
HN
R3
R2
intermediates
Scheme 1 Possible pathways to quinolin-4-ones from β-chlorovinyl ketones and amines
ners18 in a palladium-catalyzed double Buchwald–Hartwig
amination reaction to give the target molecules (Scheme 1;
path A);19 Alternatively, enones 1 might serve Michael ac-
ceptors that would undergo a base-promoted tandem con-
jugate addition–elimination process20 to give the corre-
sponding enamine intermediates. (An alternative pathway
involving an elimination–Michael addition reaction could
not be ruled out.)12e,21 The enamine intermediates could
then be transformed into quinolin-4-ones through a palla-
dium-catalyzed intramolecular N-arylation reaction
(Scheme 1; paths B and C).
results show that a Michael addition–elimination process
(Scheme 1; path B) is more reasonable than a palladium-
catalyzed N-vinylation process (Scheme 1; path A). Howev-
er, at this point, path A could not be completely ruled out.
Finally, by using a Buchwald-type ligand22 {[2′-(dicyclohex-
ylphosphino)biphenyl-2-yl]dimethylamine (DavePhos) or
dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine
(Xphos)} for aromatic C–Cl bond activation, with potassium
tert-butoxide as the base, intermediate i-1 was efficiently
transformed into the quinolin-4-one 3aa in good yield
(Scheme 2; reaction 4). Therefore, a two-step procedure in-
volving reactions 2 and 4 is a practicable method for the
synthesis of quinolin-4-ones in a tandem one-pot fashion.
Next, we conducted extensive experiments on the one-
pot preparation of quinolin-4-one 3aa through a sequential
Michael addition–elimination/palladium-catalyzed intra-
molecular amination reaction (Table 1). We first examined
the model reaction in tetrahydrofuran for 24 hours with
tetrakis(triphenylphosphine)palladium as the catalyst and
potassium tert-butoxide as the base, and we obtained the
desired product 3aa in 40% and 15% yields at 110 and 80 °C,
respectively (Table 1, entry 1). We then examined the ef-
fects of various Buchwald-type or bidentate phosphorus li-
gands in an attempt to increase the yield (entries 2–5). Dav-
ePhos performed best, and the yield was increased to 60%
(entry 4). Screening of various sources of palladium [for ex-
ample, palladium(II) chloride, palladium(II) acetate, or
tris(dibenzylideneacetone)dipalladium] in tetrahydrofuran,
showed that DavePhos with tetrakis(triphenylphos-
phine)palladium was the best catalyst system and potassi-
um tert-butoxide was the best base (entries 4 and 6–8). A
survey of reaction media showed that tetrahydrofuran as a
solvent gave better results than 1,4-dioxane, toluene, or
N,N-dimethylformamide (entries 9–11). Finally, we focused
on the choice of a suitable base for this tandem process (en-
tries 12–16). The nature of the base was found to be very
important in determining the outcome of the reaction. Use
To determine the nature of the synthetic pathways, we
chose
(Z)-3-chloro-1-(2-chlorophenyl)-3-phenylprop-2-
en-1-one (1a) and aniline (2a) as model substrates and we
conducted several control experiments (Scheme 2). First,
treatment of enone 1a with potassium carbonate, a mild
base, in the absence of aniline in toluene, tetrahydrofuran,
or N,N-dimethylformamide did not give the conjugated
alkynyl ketone through anti-elimination of hydrogen chlo-
ride (Scheme 2; reaction 1), and enone 1a was completely
recovered from the reaction mixture. This result appears to
preclude the possibility of a reaction pathway involving a
tandem anti-E2/Michael addition process to enamine inter-
mediates (Scheme 1; path C). When we examined the reac-
tion of enone 1a with aniline (2a) in tetrahydrofuran or tol-
uene containing potassium carbonate as a base, the enam-
ine intermediate i-1 was obtained in 67% and 92% yield,
respectively (Scheme 2; reaction 2). When 1a and 2a were
treated in the presence of a palladium catalyst, the reaction
gave the same product, i-1 (Scheme 2; reaction 3). Com-
pared with the palladium-free reaction in toluene, the use
of palladium catalyst gave a lower yield of the enamine
product i-1 (78% versus 92%). Furthermore, the oxidative
addition of an aryl chloride (a similar electrophilic coupling
reagent to a vinyl chloride) to palladium did not proceed to
give the product 3aa through a N-arylation reaction under
the same reaction conditions (Scheme 2; reaction 3). These
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Synthesis
Table 1 Optimization of the Conditions for the One-Pot Reactiona
Cl
O
Cl
Cl
O
K2CO3
Ph
O
(1)
Cl
O
H
Ph
toluene, THF, DMF
Pd, ligand, base
+
PhNH2
1a
alkynyl ketone
anti-E2
solvent, 110 °C, 24 h
N
Ph
2a
Cl
1a
Entry Catalyst
Ph
Ph
3aa
Cl
O
Cl
Cl
O
NHPh
Ph
PhNH2 (2a)
Yieldb (%)
Ph
(2)
Ligand
Base
t-BuOK
Solvent
K2CO3, solvent, 110 °C
H
H
1
Pd(PPh3)4
Pd(PPh3)4
-
THF
THF
THF
THF
THF
THF
THF
THF
40 (15)c
56
THF: 67%
toluene: 92%
1a
i-1
2
t-BuMephosd
MePhose
DavePhosf
dppfg
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2
36
Cl
O
NHPh
Ph
4
60
Cl
O
Cl
PhNH2 (2a)
5
44
(3)
(4)
30 (24)h
48 (39)i
36
Ph
H
6
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
Pd(OAc)2, Ph3P
H
i-1
7
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3, toluene, 110 °C
78%
1a
8
O
9
1,4-dioxane 44
Cl
O
NHPh
Ph
10
11
12
13
14
15
16j
toluene
DMF
36
Pd(PPh3)4, DavePhos
trace
46
N
Ph
KOt-Bu, solvent, 110 °C
t-BuONa THF
H
Ph
THF: 93%
toluene: 38%
K2CO3
Na2CO3
K3PO4
THF
THF
THF
42
i-1
3aa
DMF: 96% [Pd(OAc)2, Xphos]
25
22
Scheme 2 Investigations of possible synthetic pathways
K2CO3/t- THF
82 (73)k
BuOK
of milder bases, such as potassium carbonate, sodium car-
bonate, or tripotassium phosphate (entries 13–15) gave in-
ferior results to those achieved with strong bases such as
potassium or sodium tert-butoxide (entries 4 and 12). For
the Michael addition–elimination process, a mild base pro-
vides the enamine intermediate i-1 in good yields [Scheme
2; Reaction 2]; however, a strong base is more suitable for
the palladium-catalyzed C–N cross-coupling process
(Scheme 2; Reaction 4 and Table 1, entry 4). On the other
hand, the moderate yields of the target 3aa (40–60%; Table
1) made us wonder whether a strong base, such as potassi-
um or sodium tert-butoxide, would be more suitable for the
nucleophilic addition–elimination process. In fact, when
(Z)-β-chlorovinyl ketone 1a was treated with potassium
tert-butoxide in tetrahydrofuran, partial decomposition of
(Z)-1a occurred to give an unidentifiable mixture.21b We
therefore conducted the synthesis of 3aa as a one-pot two-
step process using potassium carbonate as the base for the
formation of enamine intermediate and potassium tert-bu-
toxide as the base for the intramolecular C–N bond forma-
tion; this tandem reaction gave a high yield [82% for
Pd(PPh3)4–DavePhos, 73% for Pd(OAc)2–Xphos; Table 1, en-
try 16].
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv), PhNH2 (2a; 0.3 mmol, 1.5
equiv), base (3.0 equiv), Pd catalyst (5 mol%), ligand (10 mol%), solvent (2
mL), 110 °C, 24 h.
b Isolated yield after chromatography.
c At 80 °C.
d Dicyclohexyl(2′-methylbiphenyl-2-yl)phosphine.
e Di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine.
f [2′-(Dicyclohexylphosphino)biphenyl-2-yl]dimethylamine.
g 1,1′-Bis(diphenylphosphinyl)ferrocene
h Ligand = PPh3.
i 5 mol% of ligand was used.
j The reaction was carried out in a one-pot, two-step manner. 1a and 2a
were treated with K2CO3 (1.5 equiv) in THF for 12 h; Pd(PPh3)4, DavePhos,
and t-BuOK (1.5 equiv) were added; and the mixture was kept for another
12 h.
k Pd(OAc)2 and Xphos were used in the second step.
Having determined the optimal conditions for the one-
pot reaction, we next explored its scope and generality. As
shown in Scheme 3, a variety of simple primary amines can
be used as starting materials, giving good yields of the cor-
responding products 3aa–ap. The reaction conditions were
compatible with various functional groups on the benzene
ring of aromatic amines, including methyl, methoxy, fluoro,
trifluoromethyl, chloro, and cyano (Scheme 3; 3ab–ap). Ste-
ric hindrance by ortho-substituents on the aryl ring did not
appear to hamper the reaction and the corresponding quin-
olin-4-ones 3ab and 3ac were obtained in 66% and 76%
yield, respectively. Alicyclic primary amines such as cyclo-
hexylamine (2k) or cyclopropylamine (2l) were also toler-
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Synthesis
O
N
Cl
O
(1) K2CO3, THF, 110 °C, 12 h
+
RNH2
Ph
(2) Pd(PPh3)4, DavePhos, KOt-Bu, 12 h
2
Cl
1a
Ph
in one-pot fashion
R
3
Ph
N
Ph
N
Ph
Ph
N
CF3
O
O
O
N
O
OMe
3ac
76%
3aa
82%
3ab
66%
3ad
63%
Ph
N
Ph
N
Ph
N
Ph
N
O
O
O
O
Cl
O
F
O
O
CN
3ag
69%
3ae
82%
3af
58%
3aha
87%
Ph
N
Ph
N
Ph
N
Ph
N
OMe O
3ak
61%
3ai
64%
3aj
67%
3al
62%
Ph
N
Ph
N
Ph
N
Ph
N
O
Me
O
O
O
3aoa
3ama,b
3an
3apa
47%
82%
56%
59%
Scheme 3 Scope of amine reactants. Reagents and conditions (one-pot, two-step operation): 1a (0.2 mmol), amine 2 (0.3 mmol), K2CO3 (0.3 mmol),
THF (2 mL), 110 °C, 12 h; then Pd(PPh3)4 (0.01 mmol), DavePhos (0.02 mmol), t-BuOK (0.3 mmol), 12 h. The yields are those of the isolated product
after chromatography. a The reaction was carried out in a one-pot, one-step manner. b MeNH2·H2O was used.
ated in the process, giving good yields of the corresponding
products 3ak and 3al. Furthermore, various aliphatic
amines (methylamine monohydrate, isopropylamine, bu-
tylamine, or hexylamine) were smoothly converted into the
desired products in moderate to good yields.
In an attempt to simplify the operational procedure, we
examined the reaction of various (Z)-β-haloalkenyl aromat-
ic ketones 1 with butylamine (2o) in the presence of the
palladium catalyst and base in a one-pot, one-step fashion.
As shown in Table 2, various functional groups R1 and R2 on
enone 1 were well tolerated. In the case of substituent R2,
substrates with aryl groups showed higher reactivities than
did those with alkyl groups, and good yields were obtained
with either electron-donating or electron-withdrawing
substituents on the aromatic ring (Table 2, entries 1–4). 2-
Chloro aromatic ketones (Table 2, entries 5 and 6) or 2-bro-
mo aromatic ketones (Table 2, entries 8–10) bearing ortho-,
meta-, or para-substituents R1 were also smoothly trans-
formed into the corresponding products 3fo–ko in good
yields. Note that the compatibility of the chloro functional
group in substrates 1 is particularly appealing because this
substituent offers a considerable range of opportunities for
further synthetic manipulations (Table 2, entries 1 and 9).
Our proposed reaction mechanism is shown in Scheme
4. Nucleophilic Michael addition of amine 2 to (Z)-β-chloro-
vinyl aromatic ketone 1 gives intermediate 4, which under-
goes elimination of a halide anion in the presence of a base
to give the Z-configured enamine intermediate 5. Oxidative
addition of the C–X bond of intermediate 5 to palladium(0)
followed by intramolecular reaction of the enamine and
base give intermediate 6. Complex 6 undergoes a C−N bond-
forming reductive elimination to give the desired product 3
with regeneration of the active catalytic species.
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Table 2 Scope of β-Chlorovinyl Aromatic Ketonesa
Cl
O
O
N
Pd(PPh3)4, DavePhos
KOt-Bu, THF, 110 °C, 24 h
R1
+
BuNH2
R1
Cl
R2
R2
2o
1
Bu
3
Entry Substrate 1
Product 3
Yieldb Entry Substrate 1
(%)
Product 3
Yieldb
(%)
O
O
N
Cl
Cl
Cl
O
O
Cl
Cl
Cl
Cl
1
2
43
56
6
7
80
67
Cl
N
F
F
Bu
Bu
1g
1b
3go
3bo
O
O
O
O
Cl
Cl
N
N
Br
Bu
Bu
1h
1c
3co
3ho
O
O
O
O
Cl
MeO
MeO
3
4
5
62
49
68
8
58
81
87
Cl
N
N
Br
Bu
Bu
1i
F
F
3io
1d
1e
3do
O
N
O
Cl
O
O
Cl
Cl
Cl
9
N
Cl
Br
Bu
Bu
1j
3eo
3jo
O
F
O
O
F
Cl
O
Cl
Cl
10
N
N
Br
Bu
Bu
1k
1f
3fo
3ko
a Reaction conditions (one-pot, one-step operation): 1 (0.2 mmol), BuNH2 (2o; 0.3 mmol), t-BuOK (0.6 mmol), Pd(PPh3)4 (0.01 mmol), DavePhos (0.02 mmol),
THF (2 mL), 110 °C, 24 h.
b Yield of isolated product after chromatography.
In conclusion, we have developed an efficient protocol
for the sequential one-pot synthesis of quinolin-4-one de-
rivatives. The process is based on the intermolecular
Michael addition of an amine to a (Z)-β-chlorovinyl aromat-
ic ketone, subsequent elimination of a chloride anion to give
a Z-enamine, and, finally, a palladium-catalyzed intramo-
lecular N-arylation. The result presented here, together
with previous research, have potential applications in the
synthesis of valuable molecules in medicinal science.
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R2
R3
R2
X
O
Cl
H
O
NHR3
R2
X
N
elimination
step 2
O
N
R3
H
(Z)-5
4
base
Pd(0)
3
reductive
elimination
oxidative
addition
R3NH2
R3
R2
step 3
step 1
X
Michael
addition
N
Pd
R2
H
KOt-Bu
R3
Pd
N
O
Cl
O
X
R2
6
O
KX
1
Scheme 4 Proposed mechanism for the sequential Michael addition–elimination/palladium-catalyzed N-arylation process
Chemicals were all purchased from commercial suppliers and were
used without further purification unless otherwise stated. Before use,
solvents were dried and purified by the standard procedures. (Z)-β-
Chlorovinyl aromatic ketones were prepared from the corresponding
acid chlorides and alkynes by the reported methods.16 All reactions
were carried out in dried glassware, and monitored by TLC. Yields re-
fer to isolated yields of compounds. Melting points were determined
on a melting-point apparatus in open capillaries and are uncorrected.
1H and 13C NMR spectra were recorded on a Bruker 400 MHz spec-
trometer with CDCl3 as solvent. The reported chemical shifts are rela-
tive to CDCl3 (1H NMR: CDCl3, δ = 7.26 ppm; 13C NMR: CDCl3, δ = 77.2
ppm). High-resolution mass spectra were recorded on a Bruker Bio
TOF-Q mass spectrometer.
(2Z)-3-Anilino-1-(2-chlorophenyl)-3-phenylprop-2-en-1-one (i-1)
White solid; yield: 122.5 mg (92%); mp 122–124 °C.
IR (KBr): 3450, 1609, 1588, 1567, 1481, 1325, 756, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 12.65 (s, 1 H), 7.59–7.56 (m, 1 H),
7.43–7.29 (m, 8 H), 7.14 (t, J = 8.0 Hz, 2 H), 7.01 (t, J = 7.2 Hz, 1 H), 6.82
(d, J = 7.6 Hz, 2 H), 5.79 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 190.7, 161.4, 140.9, 139.2, 135.3,
131.0, 130.5, 130.3, 129.9, 129.5, 128.8, 128.6, 128.5, 126.8, 124.5,
123.5, 100.9.
ESI-MS: m/z = 333 [M+], 334 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C21H16ClNNaO: 356.0818; found:
356.0821.
Quinolin-4(1H)-ones 3; General Procedures
1,2-Diphenylquinolin-4(1H)-one (3aa)13b
White solid; yield: 48.7 mg (82%); mp 279–281 °C.
Method A: One-Pot Two-Step Procedure
1H NMR (400 MHz, CDCl3): δ = 8.53–8.51 (m, 1 H), 7.50–7.47 (m, 1 H),
7.46–7.33 (m, 4 H), 7.20–7.15 (m, 7 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.44 (s,
1 H).
13C NMR (100 MHz, CDCl3): δ = 177.9, 153.9, 142.6, 139.2, 135.7,
131.9, 130.0, 129.6, 129.2, 128.9, 128.6, 127.9, 126.3, 126.1, 123.8,
118.1, 112.6.
A 25 mL Schlenk tube equipped with a magnetic stirrer bar was
charged with β-chlorovinyl aromatic ketone 1 (0.2 mmol, 1.0 equiv),
amine 2 (0.3 mmol, 1.5 equiv), and K2CO3 (42 mg, 0.3 mmol, 1.5
equiv). THF (2.0 mL) was added from a syringe at r.t., and the tube was
sealed and placed in a preheated oil bath at 110 °C for 12 h. Pd(PPh3)4
(0.01 mmol, 11.5 mg), DavePhos (0.02 mmol, 6.9 mg), t-BuOK (34 mg,
0.3 mmol, 1.5 equiv) were then added and the mixture was heated at
110 °C for a further 12 h.
2-Phenyl-1-(2-tolyl)quinolin-4(1H)-one (3ab)12h
Yellow solid; yield: 41.1 mg (66%); mp 253–255 °C.
Method B: One-Pot One-Step Procedure
1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 6.4
Hz, 1 H), 7.39 (t, J = 6.4 Hz, 1 H), 7.24–7.17 (m, 9 H), 6.76 (d, J = 8.0 Hz,
1 H), 6.46 (s, 1 H), 1.93 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 178.0, 153.9, 141.8, 137.9, 136.6,
135.3, 132.1, 131.5, 130.5, 129.4, 128.8, 128.7, 127.8, 127.0, 126.4,
126.1, 123.8, 117.5, 112.7, 17.5.
A 25 mL Schlenk tube equipped with a magnetic stirrer bar was
charged with β-chlorovinyl aromatic ketone 1 (0.2 mmol, 1.0 equiv),
amine 2 (0.3 mmol, 1.5 equiv), Pd(PPh3)4 (0.01 mmol, 11.5 mg), Dave-
Phos (0.02 mmol, 6.9 mg), and t-BuOK (68 mg, 0.6 mmol, 3.0 equiv).
THF (2.0 mL) was added from a syringe at r.t., and the tube was sealed
and placed in a preheated oil bath at 110 °C for 24 h. The mixture was
then cooled to r.t. and the reaction was quenched with H2O (5 mL).
The mixture was diluted with EtOAc (10 mL), the layers were separat-
ed, and the aqueous layer was extracted with EtOAc (2 × 5 mL). The
organic extracts were combined, dried (Na2SO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash chromatog-
raphy (silica gel, 20–40% EtOAc–PE).
1-(2-Methoxyphenyl)-2-phenylquinolin-4(1H)-one (3ac)12e
Yellow solid; yield: 49.7 mg (76%); mp 222–224 °C.
1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 8.0
Hz, 1 H), 7.37–7.28 (m, 2 H), 7.19–7.11 (m, 6 H), 6.94–6.83 (m, 3 H),
6.42 (s, 1 H), 3.64 (s, 3 H).
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13C NMR (100 MHz, CDCl3): δ = 178.4, 155.6, 154.9, 142.5, 136.0,
132.1, 131.3, 131.0, 128.9, 128.7, 127.9, 127.7, 126.4, 123.8, 121.0,
117.8, 112.5, 112.2, 55.6.
1H NMR (400 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.6 Hz, 1 H), 7.48–7.44
(m, 1 H), 7.39–7.35 (m, 1 H), 7.23–7.13 (m, 7 H), 7.02 (d, J = 8.4 Hz, 2
H), 6.92 (d, J = 8.4 Hz, 1 H), 6.43 (s, 1 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 178.0, 154.2, 142.8, 139.0, 136.5,
135.8, 131.8, 130.2, 129.7, 129.2, 128.6, 127.9, 126.3, 126.1, 123.7,
118.2, 112.6, 21.2.
2-Phenyl-1-[3-(trifluoromethyl)phenyl]quinolin-4(1H)-one
(3ad)13b
White solid; yield: 46 mg (63%); mp 234–236 °C.
1-(4-Methoxyphenyl)-2-phenylquinolin-4(1H)-one (3aj)12h
1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0
Hz, 1 H), 7.55–7.48 (m, 2 H), 7.44–7.38 (m, 3 H), 7.21–7.20 (m, 3 H),
7.15–7.12 (m, 2 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 178.1, 153.8, 142.4, 140.0, 135.3,
133.7, 132.5 (q, JC–F = 22 Hz), 132.4, 130.5, 129.3, 129.1, 128.3, 127.5
(d, 127.50, 127.47, JC–F = 3 Hz), 126.8, 126.1, 125.9 (d, 125.93, 125.90,
JC–F = 3 Hz), 124.3, 123.3 (d, 124.2, 122.4, JC–F = 180 Hz), 117.7, 113.0.
Yellow solid; yield: 43.8 mg (67%); mp 198–200 °C.
1H NMR (400 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.2 Hz, 1 H), 7.52–7.46
(m, 1 H), 7.40–7.36 (m, 1 H), 7.22–7.17 (m, 5 H), 7.05 (d, J = 8.8 Hz, 2
H), 6.93 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.44 (s, 1 H), 3.79
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.9, 159.4, 154.5, 143.0, 135.8,
132.3, 131.9, 131.8, 129.2, 128.6, 127.9, 126.3, 126.1, 123.8, 118.1,
114.6, 112.5, 55.5.
1-(3,5-Dimethylphenyl)-2-phenylquinolin-4(1H)-one (3ae)
White solid; yield: 53.3 mg (82%); mp 214–216 °C.
IR (KBr): 1630, 1596, 1479, 1462, 1404, 1306, 1133, 766, 711 cm–1
1-Cyclohexyl-2-phenylquinolin-4(1H)-one (3ak)13b
.
White solid; yield: 37 mg (61%); mp 197–199 °C.
1H NMR (400 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.2 Hz, 1 H), 7.48–7.46
(m, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.21–7.18 (m, 5 H), 6.97–6.93 (m, 2
H), 6.76 (s, 2 H), 6.42 (s, 1 H), 2.24 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 177.9, 142.6, 139.3, 138.9, 135.8,
131.7, 130.4, 129.7, 129.1, 128.5, 127.7, 127.5, 126.2, 126.1, 123.6,
118.3, 112.5, 21.0.
1H NMR (400 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.6 Hz, 1 H), 7.96 (d,
J = 8.8 Hz, 1 H), 7.63 (dt, J = 8.0, 1.6 Hz, 1 H), 7.50–7.48 (m, 3 H), 7.40–
7.36 (m, 3 H), 6.22 (s, 1 H), 4.19–4.13 (m, 1 H), 2.46–2.37 (m, 2 H),
1.88–1.80 (m, 4 H), 1.63–1.60 (m, 1 H), 1.23–0.86 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.3, 155.7, 141.0, 137.3, 130.9,
129.3, 128.8, 128.1, 127.6, 127.1, 123.3, 118.8, 113.4, 63.5, 31.1, 26.5,
25.1.
ESI-MS: m/z = 325 [M+], 326 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C23H19NNaO: 348.1364; found:
348.1366.
1-Cyclopropyl-2-phenylquinolin-4(1H)-one (3al)12h
Yellow solid; yield: 32.4 mg (62%); mp 166–168 °C.
1-(4-Chlorophenyl)-2-phenylquinolin-4(1H)-one (3af)12e
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.8
Hz, 1 H), 7.73–7.64 (m, 1 H), 7.55–7.46 (m, 5 H), 7.41 (t, J = 7.6 Hz, 1
H), 6.35 (s, 1 H), 3.37–3.33 (m, 1 H), 0.94 (d, J = 1.6 Hz, 2 H), 0.58 (d, J =
1.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 178.2, 155.6, 143.1, 136.9, 131.8,
129.3, 128.6, 128.4, 126.7, 126.5, 123.7, 117.9, 113.2, 32.5, 12.9.
White solid; yield: 38.4 mg (58%); mp 206–208 °C.
1H NMR (400 MHz, CDCl3): δ = 8.51 (d, J = 8.0 Hz, 1 H), 7.49 (m, 1 H),
7.40–7.10 (m, 10 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 178.1, 153.9, 142.6, 137.9, 135.6,
135.1, 132.3, 131.5, 130.1, 129.3, 129.1, 128.3, 126.6, 126.3, 124.2,
117.9, 113.0.
1-Methyl-2-phenylquinolin-4(1H)-one (3am)23
1-(4-Fluorophenyl)-2-phenylquinolin-4(1H)-one (3ag)12h
White solid; yield: 26.3 mg (56%); mp 61–63 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 7.6 Hz, 1 H), 7.73 (t, J = 8.0
Hz, 1 H), 7.58–7.51 (m, 4 H), 7.46–7.43 (m, 3 H), 6.32 (s, 1 H), 3.63 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 206.9, 154.8, 142.0, 135.9, 132.4,
White solid; yield: 43.5 mg (69%); mp 219–221 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.0
Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.23–7.14 (m, 6 H), 7.05 (t, J = 8.0 Hz,
2 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 178.0, 163.1, 161.4 (d, 1JC–F = 174 Hz),
130.9, 129.6, 128.6, 128.5, 126.8, 123.7, 115.9, 112.7, 37.3.
3
154.0, 142.7, 135.6, 135.2, 132.1, 131.9, 131.8 (d, JC–F = 6 Hz), 129.2,
128.8, 128.1, 126.5, 126.2, 124.0, 117.8, 116.8, 116.7 (d, 2JC–F = 15 Hz),
1-Isopropyl-2-phenylquinolin-4(1H)-one (3an)8h
112.8.
White solid; yield: 24.7 mg (47%); mp 95–97 °C.
1H NMR (400 MHz, CDCl3): δ = 8.53 (dd, J = 8.0, 1.6 Hz, 1 H), 7.85–7.82
(m, 1 H), 7.69–7.61 (m, 1 H), 7.56–7.36 (m, 6 H), 6.20 (s, 1 H), 4.72–
4.65 (m, 1 H), 1.60 (d, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 176.2, 154.4, 139.1, 136.1, 130.0,
128.3, 127.9, 127.2, 126.7, 126.3, 122.4, 117.5, 112.1, 52.6, 20.4.
4-(4-Oxo-2-phenylquinolin-1(4H)-yl)benzonitrile (3ah)13b
White solid; yield: 56 mg (87%); mp 254–255 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.2 Hz, 1 H), 7.72–7.64
(m, 3 H), 7.55–7.46 (m, 6 H), 7.43–7.39 (m, 3 H), 6.25 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 177.4, 154.6, 140.6, 136.1, 132.2,
132.1, 131.9, 129.4, 128.8, 128.7, 128.6, 128.4, 128.3, 127.5, 127.1,
123.5, 116.2, 112.9.
1-Butyl-2-phenylquinolin-4(1H)-one (3ao)13b
Yellow solid; yield: 45.4 mg (82%); mp 73–75 °C.
2-Phenyl-1-(4-tolyl)quinolin-4(1H)-one (3ai)12e
Yellow solid; yield: 39.8 mg (64%); mp 211–213 °C.
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1H NMR (400 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.6 Hz, 1 H), 7.72–7.65
(m, 2 H), 7.56–7.46 (m, 4 H), 7.43–7.38 (m, 2 H), 6.25 (s, 1 H), 4.02 (t,
J = 8.0 Hz, 2 H), 1.72–1.64 (m, 2 H), 1.28–1.13 (m, 2 H), 0.76 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.3, 163.2 (d, 1JC–F = 249 Hz), 153.5,
4
3
140.6, 132.3, 132.1 (d, JC–F = 3.0 Hz), 130.3 (d, JC–F = 8.0 Hz), 127.4,
2
127.1, 123.7, 116.2, 115.9 (d, JC–F = 22.0 Hz), 113.1, 47.9, 30.8, 19.7,
13.4.
13C NMR (100 MHz, CDCl3): δ = 177.4, 154.6, 140.6, 136.0, 132.2,
129.4, 128.7, 128.3, 127.3, 127.1, 123.6, 116.3, 112.8, 47.9, 30.8, 19.7,
13.4.
1,2-Dibutylquinolin-4(1H)-one (3eo)
Yellow solid; yield: 25.2 mg (49%); mp 91–93 °C.
IR (KBr): 2959, 2931, 2872, 1629, 1599, 1488, 1466, 1429, 761 cm–1
.
1-Hexyl-2-phenylquinolin-4(1H)-one (3ap)
1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 8.4 Hz, 1 H), 7.65 (t, J = 7.6
Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 6.28 (s, 1 H),
4.14 (t, J = 8.0 Hz, 2 H), 2.70 (t, J = 7.6 Hz, 2 H), 1.71–1.68 (m, 4 H),
1.51–1.48 (m, 4 H), 1.10–0.90 (m, 6 H).
Yellow solid; yield: 36 mg (59%); mp 75–77 °C.
IR (KBr): 2964, 2935, 2878, 1627, 1595, 1486, 1464, 1417, 1304, 1175,
764, 705 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 8.0 Hz, 1 H), 7.73–7.68 (m, 1
H), 7.55–7.50 (m, 4 H), 7.43–7.39 (m, 3 H), 6.26 (s, 1 H), 4.01 (t, J = 8.0
Hz, 2 H), 1.68–1.63 (m, 2 H), 1.45–1.11 (m, 6 H), 0.84 (t, J = 6.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 176.3, 153.6, 139.5, 135.0, 131.3,
128.4, 127.7, 127.3, 126.3, 126.1, 122.5, 115.2, 111.8, 47.2, 29.9, 27.6,
25.0, 21.3, 12.8.
13C NMR (100 MHz, CDCl3): δ = 178.0, 154.9, 141.1, 132.3, 127.2,
127.1, 123.5, 115.9, 111.3, 46.0, 33.9, 31.5, 31.0, 22.4, 20.1, 14.0, 13.8.
ESI-MS: m/z = 257 [M+], 258 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C17H23NNaO: 280.1677; found:
280.1681.
1-Butyl-5-fluoro-2-phenylquinolin-4(1H)-one (3fo)
Yellow solid; yield: 40.1 mg (68%); mp 164–166 °C.
ESI-MS: m/z = 305 [M+], 306 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C21H23NNaO: 328.1677; found:
IR (KBr): 2962, 2931, 2873, 1629, 1597, 1509, 1483, 1465, 1422, 847,
328.1681.
761 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.51 (dd, J = 8.8, 6.8 Hz, 1 H), 7.52–7.50
(m, 3 H), 7.40–7.38 (m, 2 H), 7.19–7.11 (m, 2 H), 6.22 (s, 1 H), 3.94 (t,
J = 8.0 Hz, 2 H), 1.67–1.63 (m, 2 H), 1.23–1.13 (m, 2 H), 0.77 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.7, 165.3 (d, 1JC–F = 249 Hz), 155.0,
142.1 (d, 3JC–F = 11.0 Hz), 135.7, 130.0 (d, 3JC–F = 11.0 Hz), 129.6, 128.8,
128.3, 124.1, 113.2, 112.3 (d, 2JC–F = 22.0 Hz), 102.4 (d, 2JC–F = 27.0 Hz),
48.2, 30.5, 19.6, 13.4.
1-Butyl-2-(2-chlorophenyl)quinolin-4(1H)-one (3bo)8h
Yellow solid; yield: 26.8 mg (43%); mp 141–143 °C.
1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 8.0 Hz, 1 H), 7.73–7.69 (m, 1
H), 7.56–7.52 (m, 2 H), 7.49–7.41 (m, 4 H), 6.22 (s, 1 H), 4.18–4.11 (m,
1 H), 3.78–3.75 (m, 1 H), 1.77–1.68 (m, 1 H), 1.51–1.48 (m, 1 H), 1.18–
1.11 (m, 2 H), 0.77 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.6, 151.3, 140.4, 134.8, 132.9,
132.3, 131.0, 130.6, 129.9, 127.3, 127.2, 127.1, 123.7, 116.2, 112.7,
47.8, 30.5, 19.7, 13.4.
ESI-MS: m/z = 295 [M+], 296 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C19H18FNNaO: 318.1270; found:
318.1272.
1-Butyl-2-(4-tolyl)quinolin-4(1H)-one (3co)
Yellow solid; yield: 32.6 mg (56%); mp 85–87 °C.
1-Butyl-7-fluoro-2-phenylquinolin-4(1H)-one (3go)
Yellow solid; yield: 47.2 mg (80%); mp 162–165 °C.
IR (KBr): 2961, 2932, 2871, 1627, 1597, 1508, 1484, 1465, 1421, 1379,
841 cm–1
.
IR (KBr): 2961, 2932, 2871, 1626, 1598, 1507, 1485, 1467, 1421, 844,
1H NMR (400 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.6 Hz, 1 H), 7.71–7.67
(m, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.31–7.27 (m, 4
H), 6.25 (s, 1 H), 4.04 (t, J = 8.0 Hz, 2 H), 2.44, (s, 3 H), 1.67–1.64 (m, 2
H), 1.26–1.14 (m, 2 H), 0.77 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.4, 154.9, 140.6, 139.5, 133.2,
132.1, 129.3, 128.2, 127.3, 127.0, 123.5, 116.3, 112.9, 47.9, 30.8, 21.4,
19.7, 13.5.
761 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.51 (dd, J = 8.8, 6.8 Hz, 1 H), 7.52–7.50
(m, 3 H), 7.40–7.38 (m, 2 H), 7.20–7.16 (m, 1 H), 7.15–7.10 (m, 1 H),
6.22 (s, 1 H), 3.94 (t, J = 8.0 Hz, 2 H), 1.66–1.63 (m, 2 H), 1.18–1.13 (m,
2 H), 0.76 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.7, 165.2 (d, 1JC–F = 166 Hz), 155.0,
3
3
142.1 (d, JC–F = 8.0 Hz), 135.7, 129.9 (d, JC–F = 7.0 Hz), 129.6, 128.8,
ESI-MS: m/z = 291 [M+], 292 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C20H21NNaO: 314.1521; found:
4
2
128.3, 124.0, 113.1 (d, JC–F = 3.0 Hz), 112.3 (d, JC–F = 15.0 Hz), 102.5
(d, 2JC–F = 18.0 Hz), 48.2, 30.5, 19.6, 13.4.
314.1524.
ESI-MS: m/z = 295 [M+], 296 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C19H18FNNaO: 318.1270; found:
318.1273.
1-Butyl-2-(4-fluorophenyl)quinolin-4(1H)-one (3do)8h
Yellow solid; yield: 36.6 mg (62%); mp 98–100 °C.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 8.0 Hz, 1 H), 7.73–7.68 (m, 1
H), 7.55–7.52 (m, 1 H), 7.44–7.38 (m, 3 H), 7.22–7.18 (m, 2 H), 6.23 (s,
1 H), 4.01 (t, J = 8.0 Hz, 2 H), 1.65 (m, 2 H), 1.22–1.17 (m, 2 H), 0.79 (t,
J = 7.2 Hz, 3 H).
1-Butyl-6-methoxy-2-phenylquinolin-4(1H)-one (3io)
Yellow solid; yield: 35.6 mg (58%); mp 108–111 °C.
IR (KBr): 2953, 2933, 2870, 2837, 1623, 1601, 1507, 1483, 1420, 1380,
840 cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 3.2 Hz, 1 H), 7.54–7.49 (m, 4
H), 7.41–7.38 (m, 2 H), 7.32 (dd, J = 9.2, 3.2 Hz, 1 H), 6.24 (s, 1 H), 4.02
(t, J = 8.0 Hz, 2 H), 3.96 (s, 3 H), 1.67–1.63 (m, 2 H), 1.19–1.12 (m, 2 H),
0.75 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.6, 156.1, 153.7, 136.1, 135.2,
129.4, 128.7, 128.6, 128.4, 122.9, 118.0, 111.9, 105.9, 55.8, 48.1, 30.9,
19.7, 13.4.
References
(1) (a) Höfle, G.; Kunze, B. J. Nat. Prod. 2008, 71, 1843. (b) Abe, H.;
Kawada, M.; Inoue, H.; Ohba, S.-i.; Nomoto, A.; Watanabe, T.;
Shibasaki, M. Org. Lett. 2013, 15, 2124. (c) Jadulco, R. C.; Pond, C.
D.; Van Wagoner, R. M.; Koch, M.; Gideon, O. G.; Matainaho, T.
K.; Piskaut, P.; Barrows, L. R. J. Nat. Prod. 2014, 77, 183.
(2) (a) Krishnamurthy, M.; Gooch, B. D.; Beal, P. A. Org. Lett. 2004, 6,
63. (b) Krishnamurthy, M.; Simon, K.; Orendt, A. M.; Beal, P. A.
Angew. Chem. Int. Ed. 2007, 46, 7044. (c) Cross, R. M.; Manetsch,
R. J. Org. Chem. 2010, 75, 8654. (d) Audisio, D.; Messaoudi, S.;
Peyrat, J.-F.; Brion, J.-D.; Alami, M. J. Org. Chem. 2011, 76, 4995.
(e) Chen, F.; Feng, Z.; He, C.-Y.; Wang, H.-Y.; Guo, Y.-l.; Zhang, X.
Org. Lett. 2012, 14, 1176. (f) Klier, L.; Bresser, T.; Nigst, T. A.;
Karaghiosoff, K.; Knochel, P. J. Am. Chem. Soc. 2012, 134, 13584.
(3) (a) Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C.
J. Med. Chem. 2001, 44, 2374. (b) Asahina, Y.; Iwase, K.; Iinuma,
F.; Hosaka, M.; Ishizaki, T. J. Med. Chem. 2005, 48, 3194.
(c) Odagiri, T.; Inagaki, H.; Sugimoto, Y.; Nagamochi, M.;
Miyauchi, R. N.; Kuroyanagi, J.; Kitamura, T.; Komoriya, S.;
Takahashi, H. J. Med. Chem. 2013, 56, 1974.
(4) (a) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-S.; Mauger, A.; Lin, C.
M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37, 3400.
(b) Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda, H.; Nishino,
H.; Suzuki, M.; Tatsuzaki, J.; Natschke, S. L. M.; Kuo, S.-C.; Lee,
K.-H. Bioorg. Med. Chem. 2005, 13, 4396. (c) Chang, Y.-H.; Hsu,
M.-H.; Wang, S.-H.; Huang, L.-J.; Qian, K.; Morris-Natschke, S. L.;
Hamel, E.; Kuo, S.-C.; Lee, K.-H. J. Med. Chem. 2009, 52, 4883.
(5) (a) Cross, R. M.; Monastyrskyi, A.; Mutka, T. S.; Burrows, J. N.;
Kyle, D. E.; Manetsch, R. J. Med. Chem. 2010, 53, 7076. (b) Cross,
R. M.; Namelikonda, N. K.; Mutka, T. S.; Luong, L.; Kyle, D. E.;
Manetsch, R. J. Med. Chem. 2011, 54, 8321. (c) Zhang, Y.; Clark, J.
A.; Connelly, M. C.; Zhu, F.; Min, J.; Guiguemde, W. A.; Pradhan,
A.; Iyer, L.; Furimsky, A.; Gow, J.; Parman, T.; Mazouni, F. E.;
Phillips, M. A.; Kyle, D. E.; Mirsalis, J.; Guy, R. K. J. Med. Chem.
2012, 55, 4205.
ESI-MS: m/z = 307 [M+], 308 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C20H21NNaO2: 330.1470; found:
330.1472.
1-Butyl-6-chloro-2-phenylquinolin-4(1H)-one (3jo)
Yellow solid; yield: 50.4 mg (81%); mp 87–89 °C.
IR (KBr): 2967, 2935, 2874, 2858, 1627, 1593, 1502, 1482, 1453, 1436,
770 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.47–8.46 (m, 1 H), 7.63–7.60 (m, 1 H),
7.54–7.48 (m, 4 H), 7.40–7.38 (m, 2 H), 6.24 (s, 1 H), 4.00 (t, J = 8.0 Hz,
2 H), 1.65–1.61 (m, 2 H), 1.17–1.12 (m, 2 H), 0.75 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.1, 154.9, 139.0, 135.7, 132.4,
129.8, 129.6, 128.8, 128.4, 128.3, 126.3, 118.2, 113.0, 48.2, 30.7, 19.6,
13.4.
ESI-MS: m/z = 311 [M+], 312 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C19H18ClNNaO: 334.0975; found:
334.0977.
1-Butyl-6-methyl-2-phenylquinolin-4(1H)-one (3ko)
Viscous yellow liquid; yield: 50.7 mg (87%).
IR (KBr): 2965, 2937, 2875, 2859, 1628, 1595, 1481, 1417, 1175, 761
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.32 (s, 1 H), 7.53–7.44 (m, 5 H), 7.40–
7.38 (m, 2 H), 6.23 (s, 1 H), 4.00 (t, J = 8.0 Hz, 2 H), 2.49 (s, 3 H), 1.66–
1.62 (m, 2 H), 1.17–1.12 (m, 2 H), 0.77 (t, J = 7.2 Hz, 3 H).
(6) (a) Sui, Z.; Nguyen, V. N.; Altom, J.; Fernandez, J.; Hilliard, J. J.;
Bernstein, J. I.; Barrett, J. F.; Ohemeng, K. A. Eur. J. Med. Chem.
1999, 34, 381. (b) Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.;
Mauger, A.; Wu, J.-H.; Lee, K.-H. J. Med. Chem. 2001, 44, 3932.
(c) Hadjeri, M.; Peiller, E. L.; Beney, C.; Deka, N.; Lawson, M. A.;
Dumontet, C.; Boumendjel, A. J. Med. Chem. 2004, 47, 4964.
(7) (a) Cecchetti, V.; Parolin, C.; Moro, S.; Pecere, T.; Filipponi, E.;
Calistri, A.; Tabarrini, O.; Gatto, B.; Palumbo, M.; Fravolini, A.;
Palu, G. J. Med. Chem. 2000, 43, 3799. (b) Sato, M.; Motomura, T.;
Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.;
Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama,
E.; Matsuoka, M.; Shinkai, H. J. Med. Chem. 2006, 49, 1506.
(c) Pasquini, S.; Mugnaini, C.; Tintori, C.; Botta, M.; Trejos, A.;
Arvela, R. K.; Larhed, M.; Witvrouw, M.; Michiels, M.; Christ, F.;
Debyser, Z.; Corelli, F. J. Med. Chem. 2008, 51, 5125.
13C NMR (100 MHz, CDCl3): δ = 177.2, 154.3, 138.7, 136.1, 133.6,
133.5, 129.3, 128.7, 128.4, 127.2, 126.4, 116.2, 112.5, 47.9, 30.8, 20.8,
19.7, 13.4.
ESI-MS: m/z = 291 [M+], 293 [M + 1]+.
HRMS-ESI: m/z [M + Na]+ calcd for C20H21NNaO: 314.1521; found:
314.1523.
Acknowledgment
We are grateful for financial support from the Fundamental Research
Funds for the Central Universities (2572014DB04), the National Natu-
ral Science Foundation of China (31300286, 31400294), and the China
Postdoctoral Science Foundation (20110491013, 2012T50319).
(8) (a) Reitsema, R. H. Chem. Rev. 1948, 43, 43. (b) López, S. E.;
Rebollo, O.; Salazar, J.; Charris, J. E.; Yánez, C. J. Fluorine Chem.
2003, 120, 71. (c) Boteva, A. A.; Krasnykh, O. P. Chem. Heterocycl.
Compd. (Engl. Transl.) 2009, 45, 757. (d) Romek, A.; Opatz, T. Eur.
J. Org. Chem. 2010, 5841. (e) Liu, Q.-L.; Li, Q.-L.; Fei, X.-D.; Zhu,
Y.-M. ACS Comb. Sci. 2011, 13, 19. (f) Zhao, J.; Zhao, Y.; Fu, H. Org.
Lett. 2012, 14, 2710. (g) Iaroshenko, V. O.; Knepper, I.; Zahid, M.;
Dudkin, S.; Kuzora, R.; Villinger, A.; Langer, P. Org. Biomol. Chem.
2012, 10, 2955. (h) Shao, J.; Huang, X.; Hong, X.; Liu, B.; Xu, B.
Synthesis 2012, 44, 1798. (i) Victor, N. J.; Muraleedharan, K. M.
Adv. Synth. Catal. 2014, 356, 3600.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380496.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(9) Camps, R. Ber. Dtsch. Chem. Ges. 1899, 32, 3228.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1851–1860

1860
Y. Wang et al.
Paper
Synthesis
(10) (a) Li, J. J. Name Reactions: A Collection of Detailed Reaction
Mechanisms, 2nd ed.; Springer: Berlin, 2003, 81. (b) Zewge, D.;
Chen, C.-y.; Deer, C.; Dormer, P. G.; Hughes, D. L. J. Org. Chem.
2007, 72, 4276.
118, 4284. (b) Paley, R. S.; de Dios, A.; Estroff, L. A.; Lafontaine, J.
A.; Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura, M. P.;
Weers, H. L.; Fernández de la Pradilla, R.; Castro, S.; Dorado, R.;
Morente, M. J. Org. Chem. 1997, 62, 6326. (c) Xi, C.; Kotora, M.;
Nakajima, K.; Takahashi, T. J. Org. Chem. 2000, 65, 945.
(d) Kotora, M.; Matsumura, H.; Gao, G.; Takahashi, T. Org. Lett.
2001, 3, 3467. (e) Haack, T.; Kurtkaya, S.; Snyder, J. P.; Georg, G.
I. Org. Lett. 2003, 5, 5019. (f) Bekele, T.; Brunette, S. R.; Lipton, M.
A. J. Org. Chem. 2003, 68, 8471. (g) Bates, C. G.; Saejueng, P.;
Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005.
(h) Liang, G.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7, 819.
(i) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2012,
134, 1268.
(11) (a) Niementowski, S. Ber. Dtsch. Chem. Ges. 1894, 27, 1394.
(b) Fuson, R. C.; Burness, D. M. J. Am. Chem. Soc. 1946, 68, 1270.
(c) Son, J. K.; Kim, S. I.; Jahng, Y. Heterocycles 2001, 55, 1981.
(12) (a) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B. Tetra-
hedron Lett. 1992, 33, 373. (b) Torii, S.; Okumoto, H.; Xu, L. H.;
Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin,
V. N. Tetrahedron 1993, 49, 6773. (c) Haddad, N.; Tan, J.; Farina,
V. J. Org. Chem. 2006, 71, 5031. (d) Huang, J.; Chen, Y.; King, A.
O.; Dilmeghani, M.; Larsen, R. D.; Faul, M. M. Org. Lett. 2008, 10,
2609. (e) Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212. (f) Takahashi, I.;
Morita, F.; Kusagaya, S.; Fukaya, H.; Kitagawa, O. Tetrahedron:
Asymmetry 2012, 23, 1657. (g) Iaroshenko, V. O.; Knepper, I.;
Zahid, M.; Kuzora, R.; Dudkin, S.; Villinger, A.; Langer, P. Org.
Biomol. Chem. 2012, 10, 2955. (h) Fei, X.-D.; Zhou, Z.; Li, W.;
Zhu, Y.-M.; Shen, J.-K. Eur. J. Org. Chem. 2012, 3001.
(i) Iaroshenko, V. O.; Zahid, M.; Mkrtchyan, S.; Gevorgyan, A.;
Altenburger, K.; Knepper, I.; Villinger, A.; Sosnovskikh, V. Y.;
Langer, P. Tetrahedron 2013, 69, 2309.
(13) (a) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2007, 72, 7968. (b) Bernini, R.; Cacchi, S.; Fabrizi, G.; Sferrazza,
A. Synthesis 2009, 1209.
(14) Seppänen, O.; Muuronen, M.; Helaja, J. Eur. J. Org. Chem. 2014,
4044.
(15) (a) Peng, J.; Shang, G.; Chen, C.; Miao, Z.; Li, B. J. Org. Chem. 2013,
78, 1242. (b) Chen, C.; Shang, G.; Zhou, J.; Yu, Y.; Li, B.; Peng, J.
Org. Lett. 2014, 16, 1872. (c) Peng, J.; Zhao, Y.; Zhou, J.; Ding, Y.;
Chen, C. Synthesis 2014, 46, 2051.
(19) For selected examples of syntheses of nitrogen heterocycles
through Pd-catalyzed double aminations, see: (a) Willis, M. C.;
Brace, G. N.; Holmes, I. P. Angew. Chem. Int. Ed. 2005, 44, 403.
(b) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes, I. P. Adv.
Synth. Catal. 2006, 348, 851. (c) Fletcher, A. J.; Bax, M. N.; Willis,
M. C. Chem. Commun. 2007, 4764. (d) Kuwahara, A.; Nakano, K.;
Nozaki, K. J. Org. Chem. 2005, 70, 413. (e) Zhang, X.; Yang, Y.;
Liang, Y. Tetrahedron Lett. 2012, 53, 6406. (f) Ueno, A.; Kitawaki,
T.; Chida, N. Org. Lett. 2008, 10, 1999. (g) Zhou, Y.; Verkade, J. G.
Adv. Synth. Catal. 2010, 352, 616.
(20) (a) Chen, Q.-H.; Geng, Z. Chin. Sci. Bull. 1993, 38, 791.
(b) Esteban, J.; Costa, A. M.; Gómez, À.; Vilarrasa, J. Org. Lett.
2008, 10, 65. (c) Kashiwabara, T.; Fuse, K.; Hua, R.; Tanaka, M.
Org. Lett. 2008, 10, 5469. (d) Souibgui, A.; Gaucher, A.; Marrot,
J.; Bourdreux, F.; Aloui, F.; Ben Hassine, B.; Prim, D. Tetrahedron
2014, 70, 3042. (e) Clayden, J.; Greeves, N.; Warren, S.; Wothers,
P. Organic Chemistry; Oxford University Press: Oxford, 2001,
Chap. 23, 585.
(16) (a) Wang, B.; Wang, S.; Li, P.; Wang, L. Chem. Commun. 2010, 46,
5891. (b) Gandeepan, P.; Parthasarathy, K.; Su, T.-H.; Cheng, C.-
H. Adv. Synth. Catal. 2012, 354, 457.
(17) (a) Pohland, A. E.; Benson, W. R. Chem. Rev. 1966, 66, 161.
(b) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Angew. Chem. Int. Ed.
2009, 48, 9592; Angew. Chem. 2009, 121, 9770.
(21) (a) Eaton, P. E.; Stubbs, C. E. J. Am. Chem. Soc. 1967, 89, 5722.
(b) Kim, H. Y.; Li, J.-Y.; Oh, K. J. Org. Chem. 2012, 77, 11132.
(22) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47,
6338. (b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
(23) Shim, S. C.; Chae, S. A.; Lee, D. Y.; Lim, H. S.; Kalinin, V. N.
J. Korean Chem. Soc. 1994, 38, 774.
(18) For selected examples in which β-halovinyl ketones or ana-
logues are used as electrophilic coupling reagents, see:
(a) Xiang, J. S.; Mahadevan, A.; Fuchs, P. L. J. Am. Chem. Soc. 1996,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1851–1860