Copper-Catalyzed Aza-Michael Addition of 2-Aminobenzoate to β-Substituted α,β-Unsaturated Ketones: One-Pot Synthesis of 3-Carbonyl-2-Substituted Quinolin-4(1H)-ones

Article abstract of DOI:10.1021/acs.joc.7b03162

We present a new and straightforward one-pot process for the synthesis of 3-carbonyl-4-quinolone derivatives through highly efficient Cu-catalyzed aza-Michael addition of 2-aminobenzoates to β-substituted α,β-unsaturated ketones/cyclization/mild oxidation

Full text of DOI:10.1021/acs.joc.7b03162

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Copper-Catalyzed Aza-Michael Addition of 2‑Aminobenzoate to
β‑Substituted α,β-Unsaturated Ketones: One-Pot Synthesis of
3‑Carbonyl-2-Substituted Quinolin-4(1H)‑ones
Seongil Kang,† Subin Park,† Kyung-su Kim,‡ Changsik Song,‡ and Yunmi Lee*,†
†Department of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea
‡Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea
S
* Supporting Information
ABSTRACT: We present a new and straightforward one-pot
process for the synthesis of 3-carbonyl-4-quinolone derivatives
through highly efficient Cu-catalyzed aza-Michael addition of
2-aminobenzoates to β-substituted α,β-unsaturated ketones/
cyclization/mild oxidation reactions. A broad range of new
versatile 3-carbonyl-quinolin-4(1H)-ones is prepared from
readily available chemicals under mild reaction conditions
with short reaction times, producing good to excellent yields (up to 99%).
The aza-Michael addition reaction of arylamines is one of the
most useful and simplest protocols for synthesizing β-amino
carbonyl compounds.8 Recently, we described an efficient and
mild catalytic conjugate addition of (hetero)aromatic amines to
α,β-unsaturated olefins in the presence of a Cu catalyst based
on an electron-donating Lewis base ligand. This reaction
afforded versatile β-amino nitriles, β-amino sulfones, and β-
amino carbonyl compounds with high efficiency and
selectivity.9 However, most of the substrate scopes were limited
to terminal olefins bearing a nitrile and sulfonyl group. In
addition, Gunnoe, Yamazaki, Kantam, and coworkers demon-
strated the Cu-catalyzed aza-Michael addition of anilines or
imidazoles to α,β-unsaturated carbonyl compounds in which
the reactions were also specific to terminal alkenes or highly
activated ethenetricarboxylates.10 With a goal to develop a
widely applicable aza-Michael addition reaction using a low-cost
and environmentally benign copper catalyst, we decided to
investigate Cu-catalyzed amine conjugate addition to more
sterically demanding β-substituted α,β-unsaturated ketones
with 2-aminobenzoates, affording functional β-amino carbonyl
compounds. Encouraged by our previous results, we intended
to utilize the catalytic protocol for the synthesis of novel and
highly functionalized 3-carbonyl-2-substituted 4-quinolones in a
single vessel, as shown in pathway 3 of Scheme 1.
INTRODUCTION
■
Quinolones are important scaffolds that are found in a variety
of biologically active molecules and pharmaceuticals.1 In
particular, substitution and diversity in the quinolone moiety
produces altered effects on their pharmacological and biological
activities. Although quinoline core structures have been
prepared by many classical syntheses including the Skraup,
Friedlander, Combes, Conrad−Limpach, Doebner−von Miller,
̈
and Pfitzinger reactions,2 the synthetic approaches for highly
functionalized 3-carbonyl-2-substituted 4-quinolones have been
less studied.3 The acyl-substituted 4-quinolones serve as
valuable building blocks for the synthesis of bioactive molecules
and color chemicals (Figure 1).4,5 In addition, they are readily
transformed to structurally modified quinoline derivatives,
which are ubiquitous in natural products and drugs. The
frequently used methods for preparing 3-carbonyl-4-quinolones
involve the thermal cyclization of β-anilinoacrylate derivatives
prepared from the condensation of ethoxymethylene acetoace-
tate intermediates with anilines (the Gould−Jacobs reaction in
pathway 1 of Scheme 1)6 and the intramolecular ring closure of
enaminoesters derived from reaction of β-ketonic enol ethers
with methyl anthranilates (pathway 2).7 However, the reactions
were carried out under harsh reaction conditions including high
temperatures and the use of high-boiling solvents, resulting in
low to moderate yields of the products and the generation of
side-products. In a recent report, Goggiamani and coworkers
described a palladium-catalyzed intramolecular cyclocarbonyla-
tion of N-(2-iodoaryl)-enaminoes derived from addition of 2-
iodoanilines to α,β-ynones using CO gas under reflux
conditions, affording 2-substituted 3-aroyl-4-quinolones.3a
Due to the significance and practical utilities of functionalized
3-carbonyl-4-quinolones, the development of a new and
effective method is highly desirable.
In this study, we developed a new and easy method for a
one-pot synthesis of biologically and synthetically valuable 3-
carbonyl-4-quinolones through Cu-catalyzed aza-Michael addi-
tion, followed by base-mediated cyclization and oxidation in
mild reaction conditions. The commercially available and
readily obtainable 2-aminobenzoates were efficiently added to
the β-substituted α,β-unsaturated ketones in the presence of 5
Received: December 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b03162
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Figure 1. Bioactive 3-carbonyl-4-quinolone derivatives.
Scheme 1. Methods for Preparation of 3-Carbonyl-Substituted Quinolin-4(1H)-ones
mol % CuCl, phosphine, and KOt-Bu, which in situ generated
Cu-amido catalytic species,11 at room temperature. After direct
treatment with KOt-Bu, the resulting β-amino ketone products
were cyclized to form 3-carbonyl-2,3-dihydroquinolin-4(1H)-
one intermediates. These subsequently underwent dehydrogen-
ation in acidic and open air conditions at ambient temperatures
within 1 h, providing the oxidized 3-carbonyl-quinolin-4(1H)-
ones with high efficiency. In previous reports, a few oxidation
conditions for the transformation of 2,3-dihydroquinolin-
4(1H)-ones to quinolin-4(1H)-ones have been studied, such
as the use of thallium(III)-tosylate,12 the use of a
(diacetoxyiodo)benzene oxidant and base,13 the use of I2 in
dimethyl sulfoxide,14 and the use of palladium on C with H2
and NaOH.15 Most of these oxidation reactions should be
performed under heating conditions. In contrast, we explored
the first example of the oxidation of 3-carbonyl-2,3-
dihydroquinolin-4(1H)-one to 3-carbonyl-quinolin-4(1H)-one
in both mild and simple reaction conditions.
Table 1. Optimization of the Cu-Catalyzed Aza-Michael
Addition of 1a to 2a
a
CuCl
entry (mol %)
KOt-Bu
(mol %)
time
(h)
conv
b
yield
b
phosphine
(%)
(%)
1
0
5
0
5
5
5
5
5
5
5
5
5
no
0
0
5
5
5
5
5
5
5
5
5
5
16
16
16
16
3
<2
<2
>98
>98
<2
14
<2
<2
<2
<2
<2
10
40
60
36
33
24
>98
2
no
3
no
4
no
5
PPh3
PCy3
dppe
dppp
dppb
binap
DPEphos
dppbz
6
3
7
3
42
8
3
62
9
3
37
10
11
12
3
35
3
25
RESULTS AND DISCUSSION
■
3
>98
We began our investigation by establishing the optimal
conditions for the catalytic aza-Michael addition of methyl 2-
aminobenzoate 1a to (E)-1-phenylbut-2-en-1-one (2a). On the
basis of our previous studies, we examined the necessity of
CuCl, phosphine ligand, and KOt-Bu. As shown in Table 1,
there is no reaction without CuCl or KOt-Bu. When the
addition of 1a to 2a was carried out in the presence of only 5
mol % KOt-Bu or a mixture of 5 mol % CuCl and KOt-Bu, the
β-substituted α,β-unsaturated ketone 2a was completely
decomposed, and the β-amino ketone product 3a was not
obtained (<2% of 3a, entries 3 and 4). However, the use of a
phosphine ligand combined with CuCl and KOt-Bu produced
a
Reaction conditions: aminobenzoate 1a (0.36 mmol), 2a (0.30
mmol), CuCl (0.015 mmol), phosphine (0.015 mmol), KOt-Bu
b
1
(0.015 mmol), and toluene (0.2 M) under N2. Determined by H
NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
the desired product 3a (entries 6−12). These findings explain
that the in situ generated CuOt-Bu complex based on
phosphine may play an important role in the formation of
Cu-amido catalytic species for promoting aryl amine addition to
α,β-unsaturated ketone 2a. As a result of evaluating a variety of
phosphines including monodentate and bidentate ligands,16
B
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a
Table 2. Cu-Catalyzed Aza-Michael Addition of β-Substituted α,β-Unsaturated Ketones
a
Reaction conditions: 2-aminobenzoate 1 (0.36 mmol), α,β-unsaturated ketone 2 (0.30 mmol), CuCl (0.015 mmol), dppbz (0.015 mmol), KOt-Bu
b
(0.015 mmol), and toluene (0.2 M) under N2. Isolated yields after purification. Reaction time was 5 h.
1,2-bis(diphenylphosphanyl)benzene (dppbz) was the most
effective and generally applicable, furnishing the β-amino
ketone 3a in >98% yield (entry 12).
Additions of 1a to (E)-4-phenylbut-3-en-2-one or (E)-chalcone
did not proceed (<2% conv).
To highlight the synthetic utility of the present catalytic
system, we designed a new and highly efficient route for
producing functionalized 3-carbonyl-2-substituted 4-quinolones
using β-amino carbonyl products in a single vessel. As
illustrated in Scheme 2, when the Michael adduct 3a was
treated with 3 equiv of KOt-Bu in toluene at room temperature,
the cyclization reaction rapidly proceeded to complete
conversion within 1 h, resulting in different products according
to the quenching conditions. When the reaction was
immediately quenched by the addition of water, only the 3-
benzoyl-2,3-dihydroquinolin-4(1H)-one product 5a was ob-
tained in 98% yield, as was expected. In contrast, the addition of
aqueous hydrochloric acid to the resulting reaction solution in
open air conditions surprisingly delivered the oxidized 3-
benzoyl-quinolin-4(1H)-one product 4a within 1 h in 75%
yield. To confirm whether the oxidation reaction indeed
proceeded during the quenching process under the acidic and
aerobic conditions, the isolated 2,3-dihydroquinolin-4(1H)-one
5a was treated with 6 N HCl in toluene under open air
conditions. It was found that dehydrogenation smoothly
occurred to generate the desired 3-carbonyl-4-quinolone 4a
in 78% yield, as shown in Scheme 2. If the corresponding
reaction with 5a is performed under nitrogen conditions, the
oxidation does not proceed (<5% 4a). This result indicates that
After determining the optimized reaction conditions, the
scope of the Cu-catalyzed aza-Michael addition was inves-
tigated. A variety of β-substituted α,β-unsaturated ketones and
readily accessible 2-aminobenzoates was examined. All trans-
formations were performed at ambient temperature in the
presence of 5 mol % CuCl, dppbz, and KOt-Bu. The results are
illustrated in Table 2. The catalytic addition of methyl 2-amino-
4,5-dimethoxybenzoate to α,β-unsaturated ketones bearing a
methyl, propyl, or isobutyl substituent on the β-position of the
keto group efficiently proceeded to complete the conversion
within 3 h, giving the β-amino carbonyl compounds 3a−3c
with excellent yields (90−99%). Various alkene substrates with
a methoxy, bromo, or chloro moiety attached on the aryl unit
were smoothly converted to the desired products 3d−3f with
87−95% yields. In addition, the methyl, bromo, or chloro
substituent on the 2-aminobenzoate were well-tolerated in the
Cu-catalyzed aza-Michael addition to afford 3g−3k with
excellent yields ranging from 80 to 96%. When (E)-hex-4-en-
3-one was used as an alkyl enone substrate, the catalytic
reaction was proceeded to complete conversion to provide 92%
yield of the desired product 3l. However, α,β-unsaturated
ketones, including a sterically demanding aryl substituent on
the β-position, were not suitable for the present system.
C
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Because it is known that the keto−enol tautomerism between
4-quinolone and 4-hydroxyquinoline forms can proceed in
certain solvents,18 we decided to confirm the structure of our 3-
benzoyl-4-quinolone 4a using a 2D NMR (NOSEY) experi-
ment. The NMR study disclosed that only 4-quinolone existed
in the deuteriodimethyl sulfoxide solution. In addition, when
methyl iodide was introduced to 4a in DMF in the presence of
potassium carbonate, the N-methylated 4-quinolone, rather
than the O-alkylated product, was observed. Its structural
assignment that was determined by the 2D NMR study was
similar to the 3-benzoyl-quinolin-4(1H)-one product 4a.19
On the basis of the above findings, we attempted an easy
one-pot synthesis of 3-carbonyl-2-substituted 4-quinolones
from readily available 2-aminobenzoates via aza-Michael
addition/cyclization/oxidation sequential reactions, as depicted
in Table 3. Various 2-aminobenzoates 1 were reacted with β-
substituted α,β-unsaturated ketones 2 in the presence of a 5
mol % Cu catalyst. This reaction formed β-amino ketone
intermediates, which were directly treated with KOt-Bu
followed by the addition of 6 N HCl under open to air in a
single vessel. All one-pot reactions were successfully performed
in toluene under mild reaction conditions at room temperature
and were completed within a total of 5 h, producing new and
versatile 3-aroyl-2-substituted 4-quinolones 4a−4h. In general,
moderate to good yields were observed, except for the low yield
of the product 4g (49% yield) that was derived from 2-
aminobenzoate substituted with a chloro group because of the
sluggish oxidation reaction (Table 3). The one-pot process
using (E)-hex-4-en-3-one was also efficient to synthesize 3-acyl-
2-substituted 4-quinolone 4i in 82% yield.
Scheme 2. Cyclization of β-Amino Ketone 3a Followed by
Oxidation and Plausible Oxidation Mechanism
the oxidation reaction seems to be promoted by the presence of
acid and air. Although further investigation for the mechanism
of aerobic oxidation is necessary, it is likely to generate the
radical cation intermediate 5a-I via a single electron transfer
(SET) from dihydroquinolinone 5a to oxygen, followed by a
further SET step to form the dihydroquinolinium 5a-II.
Subsequently, deprotonation occurs to furnish the quinolinone
4a.17
Next, we explored the efficiency and generality of this simple
process. Thus, the scope of the one-pot reaction was further
extended to different α,β-unsaturated carbonyl compounds and
a
Table 3. One-Pot Synthesis of 3-Carbonyl-2-Substituted 4-Quinolones
a
Reaction conditions: 2-aminobenzoate 1 (0.36 mmol), α,β-unsaturated ketone 2 (0.30 mmol), CuCl (0.015 mmol), dppbz (0.015 mmol), KOt-Bu
(0.015 mmol), and toluene (0.2 M) under N2. In the cyclization step, KOt-Bu (0.90 mmol) was added, followed by the addition of 6 N HCl (1 mL).
Isolated yields after purification.
D
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a
Table 4. One-Pot Synthesis of 3-Acyl-quinolin-4(1H)-ones
a
Reaction conditions: 2-aminobenzoate 1 (0.30 mmol), vinyl ketone 6 (0.36 mmol), CuCl (0.015 mmol), DPEphos (0.015 mmol), KOt-Bu (0.015
mmol), and toluene (0.2 M) under N2. In the cyclization step, KOt-Bu (0.9 mmol) was added, followed by the addition of 6 N HCl (1 mL). Isolated
b
yields after purification (trituration or recrystallization). Dppbz used.
Scheme 3. Gram Scale Synthesis of 3-Carbonyl-4-quinolones 4a and 7l
a broad range of 2-aminobenzoates. The catalytic system also
proved to be effective in promoting the aza-Michael addition to
alkyl vinyl ketones or aryl vinyl ketones under the established
conditions, which were transformed to a wide range of 3-acyl-4-
quinolones with high efficiency and up to 99% yield, as
demonstrated in Table 4. It is noteworthy that the one-pot
process with vinyl ketone substrates is faster and more efficient
than that with sterically demanding β-substituted α,β-
unsaturated ketones. The oxidation of the in situ-generated 3-
acyl-2,3-dihydroquinolin-4(1H)-ones during acidic workup was
complete within 10 min, and the desired 3-acyl-quinolin-
4(1H)-one products were easily purified by trituration or
recrystallization (no silica gel column chromatography was
required) in high yields. It is also noted that DPEphos ligand is
more effective in catalyzing the conjugate addition with alkyl-
substituted vinyl ketones than the dppbz ligand. The 2-
aminobenzoates, bearing electron-donating methyl and me-
thoxy or electron-withdrawing fluoro, chloro, bromo, and iodo
E
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specified. All workup and purification procedures were carried out with
reagent grade solvents in air. A variety of vinyl ketones20 and
disubstituted α,β-unsaturated ketones21 were prepared according to
previously reported experimental procedures.
substituents performed well in this catalytic process with
methyl vinyl ketone to afford the corresponding 3-acyl-4-
oxoquinolines 7a−7l in 71−99% yields. Furthermore, we also
examined the substrate scope with various alkyl vinyl ketones as
Michael acceptors, including the ethyl, n-propyl, n-pentyl,
phenethyl, and phenylpropyl groups. All groups were suitable
for this one-pot reaction and smoothly reacted with methyl 2-
amino-5-bromobenzoate, providing the desired 4-quinolones
7m−7q, bearing a bromo unit on the phenyl ring, which can be
further functionalized as useful building blocks through cross-
coupling reactions, in high yields (80−96%). It was also found
that the vinyl ketones, which have sterically demanding
cyclohexyl, aryl, and furyl substituents, could efficiently take
part in this transformation, affording the corresponding
products 7r−7u in 84−92% yields. These results indicate that
the current reaction is a highly efficient way to synthesize a
wide range of 3-acyl-4-quinolones.
This methodology also allowed the gram-scale one-pot
synthesis of 3-cabonyl-4-quinolones with high efficiency, as
shown in Scheme 3. The reactions of 1.00 g of 2-
aminobenzoate 1a with (E)-1-phenylbut-2-en-1-one (2a) and
methyl vinyl ketone (6a) in the presence of 5 mol % Cu
catalyst provided the corresponding 3-carbonyl-4-quinolones
4a and 7l in 75 and 96% yields, respectively. The Cu-catalyzed
process was performed on a benchtop without using glovebox
techniques. The facile one-pot process on gram-scale highlights
a significant practical utility of this method.
Representative Experimental Procedure for Cu-Catalyzed
Aza-Michael Addition of 2-Aminobenzoate to β-Substituted
α,β-Unsaturated Ketones. Methyl 4,5-Dimethoxy-2-((4-oxo-4-
phenylbutan-2-yl)amino)benzoate (3a). Methyl 2-amino-4,5-dime-
thoxybenzoate (76.0 mg, 0.360 mmol), CuCl (1.50 mg, 0.0150 mmol),
dppbz (6.70 mg, 0.0150 mmol), and KOt-Bu (1.70 mg, 0.0150 mmol)
were added to a vial (8 mL) charged with a magnetic bar in the
glovebox. The vial was sealed with a cap (phenolic open top cap with
gray PTFE/silicone) and was removed from the glovebox. Then, the
vial was purged with N2 gas for 5 min, and toluene (0.7 mL) was
added. After being premixed for 10 min, a solution of (E)-1-phenylbut-
2-en-1-one (43.9 mg, 0.300 mmol) in toluene (0.8 mL) was added to
the mixture, which was allowed to stir at room temperature for 3 h.
After that time period, the reaction was quenched by adding a
saturated aqueous solution of NH4Cl (1 mL) and was washed with
EtOAc (3 × 3 mL). The organic layers were combined, dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified using silica gel column chromatography (hexanes:EtOAc =
4:1) to produce the desired β-amino product 3a (106.5 mg, 0.298
mmol, 99% yield) as a bright greenish solid. mp 166−167 °C; IR
1
(neat): 3318 (w), 1683 (s), 1608 (s) cm−1; H NMR (CDCl3, 400
MHz): δ 7.96 (dd, J = 7.3, 1.3 Hz, 2H), 7.78 (br s, 1H), 7.58 (dd, J =
7.3, 7.3 Hz, 1H), 7.47 (dd, J = 7.3, 7.3 Hz, 2H), 7.37 (s, 1H), 6.33 (s,
1H), 4.33−4.31 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.31
(dd, J = 16.5, 4.3 Hz, 1H), 3.16 (dd, J = 16.5, 7.9 Hz, 1H), 1.38 (d, J =
6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 198.9, 168.6, 155.5,
147.2, 139.3, 137.0, 133.2, 128.6, 128.0, 113.8, 101.1, 95.0, 56.4, 55.6,
51.0, 45.3, 44.9, 21.3; HRMS (ESI) m/z: [M + H]+ Calcd for
C20H24NO5 358.1654, Found 358.1641.
Methyl 4,5-Dimethoxy-2-((1-oxo-1-phenylhexan-3-yl)amino)-
benzoate (3b). Compound 3b was synthesized from methyl 2-
amino-4,5-dimethoxybenzoate (76.0 mg, 0.360 mmol) and (E)-1-
phenylhex-2-en-1-on (52.3 mg, 0.300 mmol) in 99% yield (114.5 mg,
0.297 mmol) as a greenish oil. IR (neat): 3325 (w), 1645 (s), 1616 (s)
cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.93 (dd, J = 7.3, 1.3 Hz, 2H),
7.77 (br s, 1H), 7.53 (dd, J = 7.3, 7.3 Hz, 1H), 7.42 (dd, J = 7.3, 7.3
Hz, 2H), 7.34 (s, 1H), 6.34 (s, 1H), 4.28−4.19 (m, 1H), 3.85 (s, 3H),
3.81 (s, 3H), 3.79 (s, 3H), 3.24−3.12 (m, 2H), 1.70−1.62 (m, 2H),
1.51−1.42 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100
MHz): δ 199.3, 168.7, 155.5, 147.8, 139.2, 137.1, 133.2, 128.6, 128.0,
113.8, 101.0, 95.0, 56.4, 55.6, 51.0, 49.1, 44.1, 38.1, 19.2, 13.8; HRMS
(ESI) m/z: [M + H]+ Calcd for C22H28NO5 386.1967, Found
386.1962.
Methyl 4,5-Dimethoxy-2-((5-methyl-1-oxo-1-phenylhexan-3-yl)-
amino)benzoate (3c). Compound 3c was synthesized from methyl
2-amino-4,5-dimethoxybenzoate (76.0 mg, 0.360 mmol) and (E)-5-
methyl-1-phenylhex-2-en-1-one (56.5 mg, 0.300 mmol) in 90% yield
(108.3 mg, 0.271 mmol) as a greenish oil. IR (neat): 3425 (w), 1710
(s), 1685 (s) cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.93 (dd, J = 7.3,
1.5 Hz, 2H), 7.74 (br s, 1H), 7.56 (dd, J = 7.3, 7.3 Hz, 1H), 7.45 (dd, J
= 7.3, 7.3 Hz, 2H), 7.35 (s, 1H), 6.37 (s, 1H), 4.32−4.22 (m, 1H),
3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.22 (dd, J = 16.5, 4.3 Hz,
1H), 3.14 (dd, J = 16.5, 7.9 Hz, 1H), 1.85−1.78 (m, 1H), 1.66−1.59
(m, 1H), 1.53−1.46 (m, 1H), 0.95 (d, J = 7.3 Hz, 3H), 0.92 (d, J = 7.3
Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 199.3, 168.6, 155.4, 147.6,
139.1, 137.0, 133.2, 128.6, 128.0, 113.6, 100.8, 94.7, 56.3, 55.6, 51.0,
47.4, 45.4, 44.5, 24.8, 23.1, 21.8; HRMS (ESI) m/z: [M + H]+ Calcd
for C23H30NO5 400.2124, Found 400.2120.
CONCLUSIONS
■
In summary, we demonstrated a mild and efficient method for
Cu-catalyzed aza-Michael addition of 2-aminobenzoates to β-
substituted α,β-unsaturated ketones and successfully inves-
tigated the synthetic utility of the Michael adduct by developing
a novel approach to highly functionalized 3-carbonyl-4-
quinolones in a single vessel. Specifically, we suggested a new
and efficient way to oxidize 3-carbonyl-2,3-dihydroquinolin-
4(1H)-ones to 3-carbonyl-4-quinolones under mild reaction
conditions. The use of easily accessible or commercially
available substrates and inexpensive Cu catalysts, the
applicability of the straightforward and mild one-pot process,
the broad substrate scope, and the synthetic potential of the β-
amino ketone and 3-carbonyl-4-quinolone products make this
methodology very attractive and practical.
EXPERIMENTAL SECTION
■
General. Infrared (IR) spectra were recorded in reciprocal
centimeters (cm−1). Bands are characterized as broad (br), strong
(s), medium (m), and weak (w). 1H NMR spectra were recorded on a
400 MHz spectrometer. Chemical shifts are reported in ppm from
tetramethylsilane, with the solvent resonance as the internal standard
(CDCl3: δ 7.27 ppm and DMSO-d6: 2.50 ppm). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, and m = multiplet), coupling constants (Hz), and
integration. 13C NMR spectra were recorded on a 100 MHz
spectrometer with complete proton decoupling. Chemical shifts are
reported in ppm from tetramethylsilane with the solvent resonance as
the internal standard (CDCl3: δ 77.00 ppm and DMSO-d6: 39.51
ppm). High-resolution mass spectra (HRMS) were obtained using an
electrospray ionization (ESI) time-of-flight mass spectrometer.
Melting points were determined using a melting point apparatus and
are uncorrected. Unless otherwise noted, all reactions were carried out
with distilled solvents under an atmosphere of dry N2 in oven-dried
(130 °C) glassware. Toluene was purified by distillation from sodium
benzophenone ketyl immediately prior to use, unless otherwise
Methyl 4,5-Dimethoxy-2-((1-(4-methoxyphenyl)-5-methyl-1-oxo-
hexan-3-yl)amino)benzoate (3d). Compound 3d was synthesized
from methyl 2-amino-4,5-dimethoxybenzoate (76.0 mg, 0.360 mmol)
and (E)-1-(4-methoxyphenyl)-5-methylhex-2-en-1-one (65.5 mg,
0.300 mmol) in 95% yield (122.8 mg, 0.286 mmol) as a greenish
1
oil. IR (neat): 3345 (w), 1696 (s), 1618 (s) cm−1; H NMR (CDCl3,
400 MHz): δ 7.91 (dd, J = 7.0, 1.9 Hz, 2H), 7.71 (br s, 1H), 7.34 (s,
1H), 6.90 (dd, J = 7.0, 1.9 Hz, 2H), 6.36 (s, 1H), 4.30−4.20 (m, 1H),
F
DOI: 10.1021/acs.joc.7b03162
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.86 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.14 (dd, J =
16.3, 4.6 Hz, 1H), 3.07 (dd, J = 16.3, 6.9 Hz, 1H), 1.88−1.74 (m, 1H),
1.64−1.57 (m, 1H), 1.51−1.44 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H), 0.90
(d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 197.9, 168.7,
163.7, 155.6, 147.8, 139.1, 130.4, 130.3, 113.8, 113.7, 100.8, 94.9, 56.4,
55.7, 55.3, 51.1, 47.7, 45.5, 44.2, 24.9, 23.2, 21.9; HRMS (ESI) m/z:
[M + H]+ Calcd for C24H32NO6 430.2230, Found 430.2230.
Hz, 1H), 7.47 (dd, J = 7.8, 7.8 Hz, 2H), 7.40 (dd, J = 9.1, 2.5 Hz, 1H),
6.68 (d, J = 9.1 Hz, 1H), 4.30−4.26 (m, 1H), 3.86 (s, 3H), 3.30 (dd, J
= 16.8, 4.3 Hz, 1H), 3.14 (dd, J = 16.8, 8.0 Hz, 1H), 1.36 (d, J = 6.4
Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 198.5, 168.1, 148.7, 137.3,
137.0, 134.1, 133.3, 128.7, 128.1, 113.5, 111.5, 105.9, 51.6, 44.7, 44.4,
21.0; HRMS (ESI) m/z: [M + H]+ Calcd for C18H19BrNO3 376.0548,
Found 376.0549.
Methyl 4-Chloro-2-((4-oxo-4-phenylbutan-2-yl)amino)benzoate
(3j). Compound 3j was synthesized from methyl 2-amino-4-
chlorobenzoate (66.8 mg, 0.360 mmol) and (E)-1-phenylbut-2-en-1-
one (43.9 mg, 0.300 mmol) in 94% yield (93.9 mg, 0.283 mmol) as a
yellow solid. mp 176−177 °C. IR (neat): 3389 (w), 1676 (s), 1612 (s)
cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.96 (dd, J = 7.3, 1.6 Hz, 2H),
7.95 (br s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.58 (td, J = 7.3, 1.6 Hz, 1H),
7.47 (dd, J = 7.3, 7.3 Hz, 2H), 6.76 (d, J = 2.0 Hz, 1H), 6.54 (dd, J =
8.5, 2.0 Hz, 1H), 4.27−4.23 (m, 1H), 3.84 (s, 3H), 3.31 (dd, J = 16.9,
4.4 Hz, 1H), 3.15 (dd, J = 16.9, 8.0 Hz, 1H), 1.37 (d, J = 6.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 198.6, 168.2, 148.5, 137.1, 134.7,
Methyl 2-((1-(4-Bromophenyl)-5-methyl-1-oxohexan-3-yl)-
amino)-4,5-dimethoxybenzoate (3e). Compound 3e was synthesized
from methyl 2-amino-4,5-dimethoxybenzoate (76.0 mg, 0.360 mmol)
and (E)-1-(4-bromophenyl)-5-methylhex-2-en-1-one (80.2 mg, 0.300
mmol) in 87% yield (125.3 mg, 0.262 mmol) as a sticky oil. IR (neat):
1
3248 (w), 1686 (s), 1621 (s) cm−1; H NMR (CDCl3, 400 MHz): δ
7.78 (d, J = 8.5 Hz, 2H), 7.77 (br s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.34
(s, 1H), 6.34 (s, 1H), 4.32−4.21 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H),
3.81 (s, 3H), 3.16 (dd, J = 16.3, 4.9 Hz, 1H), 3.11 (dd, J = 16.3, 6.6
Hz, 1H), 1.85−1.75 (m, 1H), 1.66−1.56 (m, 1H), 1.50−1.46 (m, 1H),
0.95 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 198.6, 168.8, 155.5, 147.6, 139.3, 135.9, 132.0, 129.7,
128.5, 113.6, 101.0, 94.9, 56.4, 55.7, 51.2, 47.7, 45.5, 44.5, 24.9. 23.2,
21.9; HRMS (ESI) m/z: [M + H]+ Calcd for C23H29BrNO5 478.1229,
Found 478.1229.
133.4, 131.2, 128.7, 128.1, 119.3, 113.2, 111.0, 51.7, 44.8, 44.5, 21.0;
HRMS (ESI) m/z: [M + H]+ Calcd for C18H19ClNO3 332.1053,
Found 332.1054.
Methyl 5-Chloro-2-((5-methyl-1-oxo-1-phenylhexan-3-yl)amino)-
benzoate (3k). Compound 3k was synthesized from methyl 2-amino-
5-chlorobenzoate (66.8 mg, 0.360 mmol) and (E)-5-methyl-1-
phenylhex-2-en-1-one (56.5 mg, 0.300 mmol) in 80% yield (90.1
mg, 0.241 mmol) as a greenish oil. IR (neat): 3275 (w), 1655 (s),
Methyl 2-((1-(3-Chlorophenyl)-5-methyl-1-oxohexan-3-yl)-
amino)-4,5-dimethoxybenzoate (3f). Compound 3f was synthesized
from methyl 2-amino-4,5-dimethoxybenzoate (76.0 mg, 0.360 mmol)
and (E)-1-(3-chlorophenyl)-5-methylhex-2-en-1-one (66.8 mg, 0.300
mmol) in 90% yield (117.6 mg, 0.271 mmol) as a greenish oil. IR
1
1602 (s) cm−1; H NMR (CDCl3, 400 MHz): δ 7.99 (d, J = 2.3 Hz,
1
(neat): 3412 (w), 1673 (s), 1612(s) cm−1; H NMR (CDCl3, 400
1H), 7.92 (dd, J = 7.3, 1.5 Hz, 2H), 7.79 (br s, 1H), 7.55 (dd, J = 7.3,
7.3 Hz, 1H), 7.46 (dd, J = 7.8, 7.8 Hz, 2H), 7.38 (dd, J = 9.0, 2.3 Hz,
1H), 6.72 (d, J = 9.0 Hz, 1H), 4.33−4.22 (m, 1H), 3.84 (s, 3H), 3.20
(dd, J = 17.1, 4.6 Hz, 1H), 3.14 (dd, J = 17.1, 7.3 Hz, 1H), 1.87−1.75
(m, 1H), 1.62−1.47 (m, 2H), 0.95 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6
Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 198.8, 168.1, 149.2, 137.3,
134.0, 133.2, 132.5, 128.6, 128.0, 113.3, 111.3, 105.6, 51.6, 47.0, 45.0,
24.9, 23.2, 22.3, 21.8; HRMS (ESI) m/z: [M + H]+ Calcd for
C21H25ClNO3 374.1523, Found 374.1519.
MHz): δ 7.89 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.8 Hz,
1H), 7.39 (dd, J = 7.8, 7.5 Hz, 1H), 7.34 (s, 1H), 6.36 (s, 1H), 4.27 (br
s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.22 (dd, J = 16.6, 4.6
Hz, 1H), 3.12 (dd, J = 16.6, 6.6 Hz, 1H), 1.85−1.75 (m, 1H), 1.66−
1.60 (m, 2H), 1.51−1.43 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J
= 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 198.6, 169.1, 155.8,
147.9, 139.0, 135.3, 133.5, 130.3, 128.6, 128.5, 126.5, 114.0, 101.3,
95.1, 56.7, 56.0, 51.5, 47.8, 45.8, 45.0, 25.2, 23.5, 22.2; HRMS (ESI)
m/z: [M + H]+ Calcd for C23H29ClNO5 434.1734, Found 434.1732.
Methyl 2-((4-Oxo-4-phenylbutan-2-yl)amino)benzoate (3g).
Compound 3g was synthesized from methyl 2-aminobenzoate (54.4
mg, 0.360 mmol) and (E)-1-phenylbut-2-en-1-one (43.9 mg, 0.300
mmol) in 96% yield (85.9 mg, 0.289 mmol) as a greenish oil. IR
Methyl 4,5-Dimethoxy-2-((4-oxohexan-2-yl)amino)benzoate (3l).
Compound 3l was synthesized from methyl 2-amino-4,5-dimethox-
ybenzoate (76.0 mg, 0.360 mmol) and (E)-hex-4-en-3-one (34.3 μL,
0.300 mmol) in 92% yield (85.8 mg, 0.276 mmol) as an ivory solid.
1
mp 86−87 °C; IR (neat): 3078 (w), 1612 (s), 1566 (s) cm−1; H
1
(neat): 3356 (w), 1663 (s), 1633 (s) cm−1; H NMR (CDCl3, 400
NMR (CDCl3, 400 MHz): δ 7.66 (s, 1H), 7.36 (s, 1H), 6.27 (s, 1H),
4.13 (br s, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.78 (dd, J =
16.1, 4.8 Hz, 1H), 2.56 (dd, J = 16.1, 7.3 Hz, 1H), 2.49−2.44 (m, 2H),
1.29 (d, J = 6.3 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 210.6, 168.8, 155.4, 147.3, 139.3, 113.5, 101.1, 95.0, 56.4,
55.8, 51.2, 49.3, 44.7, 37.4, 21.3, 7.5; HRMS (ESI) m/z: [M + H]+
Calcd for C16H24NO5 310.1654, Found 310.1648.
MHz): δ 8.00−7.95 (m, 3H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.86 (br s,
1H), 7.57 (dd, J = 8.0, 8.0 Hz, 1H), 7.46 (dd, J = 7.7, 7.7 Hz, 2H), 6.78
(d, J = 8.0 Hz, 1H), 6.59 (dd, J = 7.7, 7.7 Hz, 1H), 4.39−4.28 (m, 1H),
3.80 (s, 3H), 3.35 (dd, J = 16.8, 3.9 Hz, 1H), 3.16 (dd, J = 16.8, 8.4
Hz, 1H), 1.36 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ
198.8, 169.2, 149.9, 137.1, 134.8, 133.3, 131.9, 128.7, 128.2, 114.7,
111.7, 110.1, 51.4, 44.9, 44.3, 21.1; HRMS (ESI) m/z: [M + H]+ Calcd
for C18H20NO3 298.1443, Found 298.1443.
Representative Experimental Procedure for the One-Pot
Synthesis of 3-Aroyl-2-Substituted 4-Quinolones. 3-Benzoyl-
6,7-dimethoxy-2-methylquinolin-4(1H)-one (4a). In the glovebox,
methyl 2-amino-4,5-dimethoxybenzoate (1a) (76.0 mg, 0.360 mmol),
CuCl (1.50 mg, 0.0150 mmol), dppbz (6.70 mg, 0.0150 mmol), and
KOt-Bu (1.70 mg, 0.0150 mmol) were added to a vial (8 mL) charged
with a magnetic bar. The vial was sealed with a cap (phenolic open top
cap with gray PTFE/silicone) and taken out of the glovebox. The vial
was purged with N2 gas for 5 min. Toluene (0.7 mL) was added to the
mixture, which was allowed to premix for 10 min. Then, a solution of
(E)-1-phenylbut-2-en-1-one (2a) (43.9 mg, 0.300 mmol) in toluene
(0.8 mL) was added to the mixture, which was allowed to stir at room
temperature for 3 h. After that time, KOt-Bu (101 mg, 0.900 mmol)
was added, and the reaction was allowed to stir for an additional 1 h at
22 °C. In open air conditions, an aqueous solution of 6 N HCl (1.5
mL) was added to the resulting solution, which was allowed to stir for
1 h. The reaction was quenched by adding a saturated aqueous
solution of K2CO3 (2 mL) and was washed with CH2Cl2 (3 × 2 mL).
The organic layers were combined, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by silica gel
column chromatography (MeOH:CH2Cl2 = 5:95) to afford the
desired product 4a (72.7 mg, 0.225 mmol, 75% yield) as a yellow solid.
Methyl 5-Methyl-2-((4-oxo-4-phenylbutan-2-yl)amino)benzoate
(3h). Compound 3h was synthesized from methyl 2-amino-5-
methylbenzoate (59.5 mg, 0.360 mmol) and (E)-1-phenylbut-2-en-1-
one (43.9 mg, 0.300 mmol) in 96% yield (90.0 mg, 0.289 mmol) as a
1
yellow oil. IR (neat): 3386 (w), 1673 (s), 1611 (s) cm−1; H NMR
(CDCl3, 400 MHz): δ 7.78 (d, J = 7.3 Hz, 2H), 7.57 (br s, 1H), 7.50
(br, 1H), 7.37 (dd, J = 7.4, 7.4 Hz, 1H), 7.27 (dd, J = 7.7, 7.7 Hz, 2H),
7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 4.17−4.12 (m,
1H), 3.68 (s, 3H), 3.16 (dd, J = 16.7, 4.0 Hz, 1H), 2.95 (dd, J = 16.7,
8.3 Hz, 1H), 2.06 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 198.7, 169.0, 147.9, 135.7, 133.0, 131.5, 128.5, 127.9,
123.5, 116.7, 111.7, 109.9, 51.1, 44.8, 44.3, 21.0, 19.9; HRMS (ESI)
m/z: [M + H]+ Calcd for C19H22NO3 312.1600, Found 312.1604.
Methyl 5-Bromo-2-((4-oxo-4-phenylbutan-2-yl)amino)benzoate
(3i). Compound 3i was synthesized from methyl 2-amino-5-
bromobenzoate (82.8 mg, 0.360 mmol) and (E)-1-phenylbut-2-en-1-
one (43.9 mg, 0.300 mmol) in 95% yield (107 mg, 0.284 mmol) as a
bright yellow solid. mp 155−156 °C. IR (neat): 3425 (w), 1683 (s),
1
1601 (s) cm−1; H NMR (CDCl3, 400 MHz): δ 8.01 (d, J = 2.5 Hz,
1H), 7.95 (d, J = 7.8 Hz, 2H), 7.84 (br s, 1H), 7.58 (dd, J = 7.4, 7.4
G
DOI: 10.1021/acs.joc.7b03162
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The Journal of Organic Chemistry
Article
mp 252−253 °C; IR (neat): 3417 (w), 1664 (s), 1603 (s) cm−1; H
NMR (DMSO-d6, 400 MHz): δ 11.85 (s, 1H), 7.76 (d, J = 7.6 Hz,
2H), 7.59 (dd, J = 7.6, 7.6 Hz, 1H), 7.46 (dd, J = 7.6 7.6 Hz, 2H), 7.36
(s, 1H), 7.01 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.24 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz): δ 196.1, 171.8, 153.8, 147.8, 137.9,
135.5, 133.0, 128.9,128.6, 128.5, 118.6, 117.6, 104.1, 99.3, 55.8, 55.6,
17.5; HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO4 324.1236,
Found 324.1235.
118.3, 117.8, 104.1, 99.6, 55.8, 55.6, 28.2, 21.9; HRMS (ESI) m/z: [M
+ H]+ Calcd for C22H23BrNO4 444.0810, Found 444.0805.
1
3-Benzoyl-6-chloro-2-isobutylquinolin-4(1H)-one (4g). Com-
pound 4g was synthesized from methyl 2-amino-5-chlorobenzoate
(66.8 mg, 0.360 mmol) and (E)-5-methyl-1-phenylhex-2-en-1-one
(56.5 mg, 0.300 mmol) in 49% yield (50.3 mg, 0.148 mmol) as a
yellow solid. mp 215−216 °C; IR (neat): 3373 (w), 1682 (s), 1621 (s)
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.04 (s, 1H), 7.95 (d, J =
3-Benzoyl-6,7-dimethoxy-2-propylquinolin-4(1H)-one (4b). Com-
pound 4b was synthesized from methyl 2-amino-4,5-dimethoxyben-
zoate (76.0 mg, 0.360 mmol) and (E)-1-phenylhex-2-en-1-one (52.3
mg, 0.300 mmol) in 89% yield (94.2 mg, 0.268 mmol) as a yellow
solid. mp 248−249 °C; IR (neat): 3408 (w), 1644 (s), 1635 (s) cm−1;
1H NMR (DMSO-d6, 400 MHz): δ 12.82 (s, 1H), 7.79 (d, J = 7.3 Hz,
2H), 7.61 (dd, J = 7.3, 7.3 Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J = 7.3, 7.3
Hz, 2H), 7.32 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.58 (t, J = 7.3 Hz,
2H), 1.60 (qt, J = 7.3, 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 196.3 172.3 153.8, 151.3, 147.5, 138.0,
135.7, 133.1, 128.9, 128.6, 118.5, 117.7, 104.1, 99.5, 55.8, 55.7, 32.9,
22.2, 13.3; HRMS (ESI) m/z: [M + H]+ Calcd for C21H22NO4
352.1549, Found 352.1545.
3-Benzoyl-2-isobutyl-6,7-dimethoxyquinolin-4(1H)-one (4c).
Compound 4c was synthesized from methyl 2-amino-4,5-dimethox-
ybenzoate (76.0 mg, 0.360 mmol) and (E)-5-methyl-1-phenylhex-2-
en-1-one (56.5 mg, 0.300 mmol) in 80% yield (88.1 mg, 0.241 mmol)
as a dark yellow solid. mp 257−258 °C; IR (neat): 3369 (w), 1687 (s),
1626 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.16 (s, 1H), 7.76
(d, J = 7.3 Hz, 2H), 7.58 (dd, J = 7.3, 7.3 Hz, 1H), 7.46 (dd, J = 7.3,
7.3 Hz, 2H), 7.41 (s, 1H), 7.25 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H),
2.49 (d, J = 6.6 Hz, 2H), 2.02−1.91 (m, 1H), 0.81 (d, J = 6.6 Hz, 6H);
13C NMR (DMSO-d6, 100 MHz): δ 197.2, 174.2, 153.3, 150.8, 147.0,
2.3 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.76 (dd, J = 8.8, 2.3 Hz, 1H),
7.70 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 7.5, 7.5 Hz, 1H), 7.47 (dd, J =
7.5, 7.5 Hz, 2H), 2.48 (d, J = 6.6 Hz, 2H), 2.00−1.91 (m, 1H), 0.82 (d,
J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 100 MHz): δ 197.0, 175.2,
151.4, 138.2, 137.7, 133.7, 133.2, 133.0, 128.9, 128.6, 124.7, 124.2,
119.8, 118.3, 28.1, 22.0, 20.7; HRMS (ESI) m/z: [M + H]+ Calcd for
C20H19ClNO2 340.1104, Found 340.1103.
3-Benzoyl-2,6-dimethylquinolin-4(1H)-one (4h). Compound 4h
was synthesized from methyl 2-amino-5-methylbenzoate (59.5 mg,
0.360 mmol) and (E)-1-phenylbut-2-en-1-one (43.8 mg, 0.300 mmol)
in 61% yield (51.0 mg, 0.184 mmol) as a dark yellow solid. mp 223−
1
224 °C. IR (neat): 3413 (w), 1674 (s), 1624 (s) cm−1; H NMR
(DMSO-d6, 400 MHz): δ 11.95 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 7.5
Hz, 2H), 7.60 (d, J = 7.5 Hz, 1H), 7.54 (dd, J = 8.5, 1.9 Hz, 2H), 7.50
(d, J = 8.5 Hz, 2H), 2.40 (s, 3H), 2.27 (s, 3H); 13C NMR (DMSO-d6,
100 MHz): δ 197.1, 174.9, 148.7, 138.1, 137.7, 133.8, 133.2, 133.1,
129.1, 128.7, 124.8, 124.3, 119.5, 118.2, 20.8, 17.8; HRMS (ESI) m/z:
[M + H]+ Calcd for C18H16NO2 278.1181, Found 278.1176.
6,7-Dimethoxy-2-methyl-3-propionylquinolin-4(1H)-one (4i).
Compound 4i was synthesized from 2-amino-4,5-dimethoxybenzoate
(76.0 mg, 0.360 mmol) and (E)-hex-4-en-3-one (34.3 μL, 0.300
mmol) in 82% yield (67.7 mg, 0.246 mmol) as a yellow solid. mp
248−249 °C; IR (neat): 3340 (w), 1696 (s), 1674 (s) cm−1; 1H NMR
(DMSO-d6, 400 MHz): δ 11.75 (s, 1H), 7.46(s, 1H), 6.96 (s, 1H),
3.87 (s, 3H), 3.84 (s, 3H), 2.92 (q, J = 7.3 Hz, 2H), 2.34 (s, 3H), 1.02
(t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 207.1, 175.3,
154.2, 149.3, 148.0, 135.1, 120.6, 119.4, 101.4, 98.9, 56.1, 56.0, 37.4,
19.5, 8.4; HRMS (ESI) m/z: [M + H]+ Calcd for C15H18NO4
276.1236, Found 276.1231.
138.3, 135.3, 132.9, 128.9, 128.6, 118.8, 118.6, 104.2, 99.3, 55.7, 55.5,
33.1, 22.3, 13.5; HRMS (ESI) m/z: [M + H]+ Calcd for C22H24NO4
366.1705, Found 366.1703.
6,7-Dimethoxy-3-(4-methoxybenzoyl)-2-propylquinolin-4(1H)-
one (4d). Compound 4d was synthesized from methyl 2-amino-4,5-
dimethoxybenzoate (76.0 mg, 0.360 mmol) and (E)-1-(4-
methoxyphenyl)hex-2-en-1-one (61.3 mg, 0.300 mmol) in 81% yield
(93.1 mg, 0.244 mmol) as an ivory solid. mp 243−244 °C; IR (neat):
3423 (w), 1658 (s), 1614 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz):
δ 11.69 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 7.04 (s, 1H),
6.99 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.82 (s, 6H), 2.46 (t, J = 7.6 Hz,
2H), 1.57 (qt, J = 7.5, 7.5 Hz, 2H), 0.82 (t, J = 7.5 Hz, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 195.5, 174.0, 163.2, 153.3, 150.1, 146.9,
135.3, 131.5, 131.2, 119.2, 118.5, 113.9, 104.2, 99.3, 55.7, 55.6, 55.5,
33.1, 22.3, 13.6; HRMS (ESI) m/z: [M + H]+ Calcd for C22H24NO5
382.1654, Found 382.1649.
2-Isobutyl-6,7-dimethoxy-3-(4-methoxybenzoyl)quinolin-4(1H)-
one (4e). Compound 4e was synthesized from methyl 2-amino-4,5-
dimethoxybenzoate (76.0 mg, 0.360 mmol) and (E)-1-(4-methox-
yphenyl)-5-methylhex-2-en-1-one (65.5 mg, 0.300 mmol) in 74% yield
(88.2 mg, 0.223 mmol) as a bright ivory solid. mp 253−254 °C; IR
(neat): 3385 (w), 1675 (s), 1628 (s) cm−1; 1H NMR (DMSO-d6, 400
MHz): δ 11.16 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.37 (s, 1H), 7.07 (s,
1H), 6.98 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 3.82 (s, 6H), 2.42 (d, J =
7.6 Hz, 2H), 1.92 (m, 1H), 0.80 (d, J = 6.6 Hz, 6H); 13C NMR
(DMSO-d6, 100 MHz): δ 195.4, 174.0, 163.2, 153.3, 149.5, 147.0,
135.3, 131.5, 131.2, 119.6, 118.2, 113.8, 104.2, 99.3, 55.7, 55.6, 55.5,
28.0, 22.1; HRMS (ESI) m/z: [M + H]+ Calcd for C23H26NO5
396.1811, Found 396.1810.
3-Benzoyl-6,7-dimethoxy-2-methyl-2,3-dihydroquinolin-4(1H)-
one (5a). Methyl 4,5-dimethoxy-2-((4-oxo-4-phenylbutan-2-yl)-
amino)benzoate (3a) (85.9 mg, 0.300 mmol) and KOt-Bu (101 mg,
0.900 mmol) were added to a vial (8 mL) charged with a magnetic bar.
The vial was sealed with a cap (phenolic open top cap with gray
PTFE/silicone) and was purged with N2 gas. Toluene (1.5 mL) was
added to the mixture, which was allowed to stir at room temperature
for 1 h. The resulting solution was quenched by adding water (1 mL)
and was washed with CH2Cl2 (3 × 2 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by silica gel column chromatography
(CH2Cl2:MeOH = 95:5) to produce the 2,3-dihydroquinolin-4(1H)-
one 5a (95.8 mg, 0.294 mmol, 98% yield) as a yellow solid. mp 233−
1
234 °C; IR (neat): 3331 (w), 1694 (s), 1635 (s) cm−1; H NMR
(DMSO-d6, 400 MHz): δ 8.02 (d, J = 7.5 Hz, 2H), 7.66 (dd, J = 7.5,
7.5 Hz, 1H), 7.54 (dd, J = 7.5, 7.5 Hz, 2H), 6.98 (s, 1H), 6.73 (s, 1H),
6.35 (s, 1H), 4.57 (d, J = 10.8 Hz, 1H), 4.05−3.96 (m, 1H), 3.78 (s,
3H), 3.65 (s, 3H), 1.14 (d, J = 5.6 Hz, 3H); 13C NMR (DMSO-d6, 100
MHz): δ 199.3, 189.4, 156.3, 149.1, 141.8, 138.0, 133.6, 128.9, 128.7,
109.8, 107.1, 97.8, 59.6, 55.6, 55.6, 51.3, 19.1; HRMS (ESI) m/z: [M +
H]+ Calcd for C19H20NO4 326.1392, Found 326.1385.
3-Benzoyl-6,7-dimethoxy-1,2-dimethylquinolin-4(1H)-one (Me-
4a). 3-Benzoyl-6,7-dimethoxy-2-methylquinolin-4(1H)-one (4a)
(32.3 mg, 0.100 mmol), NaH (60% in mineral oil, 6.00 mg, 0.150
mmol), and DMF (1 mL) were added to a vial (4 mL) charged with a
magnetic bar. The mixture was allowed to stir at room temperature for
1 h under N2 gas. Then, methyl iodide (18.6 μL, 0.300 mmol) was
added to the mixture, which was allowed to stir at 80 °C for 4 h. The
reaction was quenched by adding water (1 mL) and was washed with
CH2Cl2 (3 × 1 mL). The organic layers were combined, dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified using silica gel column chromatography (Hexanes:EtOAc =
1:3) to produce the desired product (29.4 mg, 0.0872 mmol, 87%
3-(4-Bromobenzoyl)-2-isobutyl-6,7-dimethoxyquinolin-4(1H)-
one (4f). Compound 4f was synthesized from methyl 2-amino-4,5-
dimethoxybenzoate (76.0 mg, 0.360 mmol) and (E)-1-(4-bromo-
phenyl)-5-methylhex-2-en-1-one (80.1 mg, 0.300 mmol) in 74% yield
(99.1 mg, 0.223 mmol) as a dark yellow solid. mp 235−236 °C; IR
(neat): 3432 (w), 1695 (s), 1613 (s) cm−1; 1H NMR (DMSO-d6, 400
MHz): δ 12.74 (s, 1H), 7.72−7.67 (m, 4H), 7.53 (s, 1H), 7.33 (s, 1H),
3.91 (s, 3H), 3.84 (s, 3H), 2.56 (d, J = 7.6 Hz, 2H), 1.98−1.92 (m,
1H), 0.82 (d, J = 6.5 Hz, 6H); 13C NMR (DMSO-d6, 100 MHz): δ
195.4, 172.4, 153.8, 151.2, 147.6, 137.2, 135.6, 131.6, 130.8, 126.9,
H
DOI: 10.1021/acs.joc.7b03162
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The Journal of Organic Chemistry
Article
yield) as an ivory solid. mp 175−176 °C; IR (neat): 1684 (s), 1607 (s)
5-methylbenzoate (49.6 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 96% yield (57.8 mg, 0.287 mmol) as a dark
yellow solid. mp 207−208 °C; IR (neat): 3384 (w), 1648 (s), 1624 (s)
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 7.80 (d, J = 8.2 Hz, 2H),
7.62 (dd, J = 7.4, 7.4 Hz, 1H), 7.49 (dd, J = 7.4, 7.4 Hz, 2H), 7.49 (s,
1H), 7.23 (s, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.82, (s, 3H), 2.32 (S,
3H); 13C NMR (DMSO-d6, 100 MHz): δ 197.7, 173.0, 153.4, 148.4,
146.8, 137.9, 137.3, 133.4, 129.2, 128.9, 121.1, 119.8, 104.8, 99.3, 54.6,
54.5, 35.4, 18.8; HRMS (ESI) m/z: [M + H]+ Calcd for C20H20NO4
338.1392, Found 338.1391.
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.56 (br s, 1H), 8.47 (s,
1H), 8.02 (s, 1H), 7.55 (s, 2H), 2.61 (s, 3H), 2.43 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 200.0, 175.4, 143.8, 137.3, 134.8, 134.1,
127.8, 125.3, 119.0, 117.5, 31.2, 20.9; HRMS (ESI) m/z: [M + H]+
Calcd for C12H12NO2 202.0868, Found 202.0868.
3-Acetyl-6-fluoroquinolin-4(1H)-one (7d). Compound 7d was
synthesized according to general procedure A using methyl 2-amino-
5-fluorobenzoate (50.7 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) as an ivory solid in 94% yield (58.1 mg, 0.283
mmol). mp 207−208 °C; IR (neat): 3411 (w), 1635 (s), 1620 (s),
Representative Experimental Procedure for One-Pot Syn-
thesis of 3-Acyl Quinolin-4(1H)-ones. General Procedure A. In
the glovebox, methyl 2-amino-6-fluorobenzoate (50.8 mg, 0.300
mmol), CuCl (1.50 mg, 0.0150 mmol), DPEphos (8.10 mg, 0.0150
mmol), and KOt-Bu (1.70 mg, 0.0150 mmol) were added to a vial (8
mL) charged with a magnetic bar. The vial was sealed with a cap
(phenolic open top cap with gray PTFE/silicone) and taken out of the
glovebox. The vial was purged with N2 gas for 5 min. Toluene (1.5
mL) was added to the mixture, which was allowed to premix for 10
min. Then, methyl vinyl ketone (25.0 μL, 0.360 mmol) was added to
the reaction solution. After stirring at room temperature for 3 h, KOt-
Bu (101 mg, 0.900 mmol) was added, and the reaction was allowed to
stir for an additional 1 h at 22 °C. The resulting solution was
quenched with an aqueous solution of 6 N HCl (1 mL) and allowed to
stir for 10 min in open air conditions. The organic layers were washed
with CH2Cl2 (3 × 2 mL), combined, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was recrystallized from
dichloromethane and diethyl ether to afford the desired product 7b
(59.3 mg, 0.289 mmol, 96% yield) as an ivory solid.
General Procedure B. In the glovebox, methyl 2-amino-5-
bromobenzoate (82.8 mg, 0.360 mmol), CuCl (1.50 mg, 0.0150
mmol), dppbz (6.70 mg, 0.0150 mmol), and KOt-Bu (1.70 mg, 0.0150
mmol) were added to a vial (8 mL) charged with a magnetic bar. The
vial was sealed with a cap (phenolic open top cap with gray PTFE/
silicone) and taken out of the glovebox. The vial was purged with N2
gas for 5 min. Toluene (0.7 mL) was added to the mixture, which was
allowed to mix for 10 min. Then, a solution of 1-cyclohexylprop-2-en-
1-one (41.4 mg, 0.300 mmol) in toluene (0.8 mL) was added to the
mixture, which was allowed to stir at room temperature for 3 h. After
that time, KOt-Bu (101 mg, 0.900 mmol) was added to the reaction
solution, which was allowed to stir for an additional 1 h at 22 °C. The
resulting solution was quenched with an aqueous solution of 6 N HCl
(1 mL) and allowed to stir for 10 min in open air conditions. The
organic layers were washed with CH2Cl2 (3 × 2 mL), combined, dried
over MgSO4, filtered, and concentrated in vacuo. The crude product
was recrystallized from dichloromethane and diethyl ether to afford the
desired product 7r (89.3 mg, 0.267 mmol, 89% yield) as an ivory solid.
3-Acetylquinolin-4(1H)-one (7a). Compound 7a was synthesized
according to general procedure A using methyl 2-aminobenzoate (38.8
μL, 0.300 mmol) and methyl vinyl ketone (25.0 μL, 0.360 mmol) in
92% yield (51.9 mg, 0.277 mmol) as an ivory solid. This compound
has been previously reported, and spectral data match described.1f mp
252−253 °C. IR (neat): 3442 (w), 1643 (s), 1615 (s) cm−1; 1H NMR
(DMSO-d6, 400 MHz): δ 12.67 (br s, 1H), 8.51 (s, 1H), 8.23 (d, J =
8.0 Hz, 1H), 7.73 (dd, J = 8.0, 7.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.44 (dd, J = 8.0, 7.2 Hz, 1H), 2.61 (s, 3H); 13C NMR (DMSO-d6, 100
MHz): δ 196.6, 175.4, 144.2, 139.2, 132.7, 127.9, 125.9, 125.0, 119.0,
117.7, 31.1.
1
1616 (s) cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.53 (br s, 1H),
8.52 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.45
(dd, J = 8.8, 2.0 Hz, 1H), 2.59 (s, 3H); 13C NMR (DMSO-d6, 100
MHz): δ 196.6, 174.7 (d, J = 2.5 Hz), 160.8, 158.4, 144.3, 136.1, 122.0
(d, J = 8.3 Hz), 121.3 (d, J = 24.8 Hz), 117.1, 110.3 (d, J = 23.2 Hz),
31.3; HRMS (ESI) m/z: [M + H]+ Calcd for C11H9FNO2 206.0617,
Found 206.0618.
3-Acetyl-6-chloroquinolin-4(1H)-one (7e). Compound 7e was
synthesized according to general procedure A using methyl 2-amino-
5-chlorobenzoate (55.7 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 97% yield (64.5 mg, 0.291 mmol) as a
yellow solid. mp 243−244 °C; This compound has been previously
reported, and spectral data match described.1f IR (neat): 3411 (w),
1642 (s), 1606 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.68 (br
s, 1H), 8.52 (d, J = 6.7 Hz, 1H), 8.12 (s, 1H), 7.75 (dd, J = 8.7, 2.2 Hz,
1H), 7.66 (dd, J = 8.8, 2.2 Hz, 1H), 2.60 (s, 3H); 13C NMR (DMSO-
d6, 100 MHz): δ 196.3, 174.2, 144.6, 137.8, 132.6, 129.7, 129.1, 124.8,
121.4, 117.8, 31.1; HRMS (ESI) m/z: [M + H]+ Calcd for
C11H9ClNO2 222.0322, Found 222.0328.
3-Acetyl-6-bromoquinolin-4(1H)-one (7f). Compound 7f was
synthesized according to general procedure A using methyl 2-amino-
5-bromobenzoate (69.0 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 98% yield (78.2 mg, 0.294 mmol) as a
yellow solid. This compound has been previously reported, and
spectral data match described.22 mp 287−288 °C; IR (neat): 3421
1
(w), 1636 (s), 1613 (s) cm−1; H NMR (DMSO-d6, 400 MHz): δ
12.66 (br s, 1H), 8.52 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.87 (dd, J =
8.8, 2.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 2.60 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 196.4, 174.2, 144.7, 138.2, 135.4, 129.4,
128.1, 121.6, 118.1, 117.9, 31.1.
3-Acetyl-6-iodoquinolin-4(1H)-one (7g). Compound 7g was
synthesized according to general procedure A using methyl 2-amino-
5-iodobenzoate (83.1 mg, 0.300 mmol) and methyl vinyl ketone (25.0
μL, 0.360 mmol) in 99% yield (93.3 mg, 0.298 mmol) as an ivory
solid. mp 293−294 °C; IR (neat): 3433 (w), 1660 (s), 1622 (s) cm−1;
1H NMR (DMSO-d6, 400 MHz): δ 12.64 (br s, 1H), 8.54 (d, J = 6.5
Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.6, 2.1 Hz, 1H), 7.46
(d, J = 8.6 Hz, 1H), 2.60 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ
196.3, 174.0, 144.6, 140.8, 140.7, 138.5, 134.3, 121.4, 121.3, 118.1,
31.1; HRMS (ESI) m/z: [M + H]+ Calcd for C11H9INO2 313.9678,
Found 313.9678.
3-Acetyl-6-methoxyquinolin-4(1H)-one (7h). Compound 7h was
synthesized according to general procedure A using methyl 2-amino-5-
methoxybenzoate (54.4 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 98% yield (63.6 mg, 0.293 mmol) as a bright
yellow solid. mp 210−211 °C; IR (neat): 3453 (w), 1648 (s), 1620 (s)
3-Acetyl-5-fluoroquinolin-4(1H)-one (7b). Compound 7b was
synthesized according to general procedure A using methyl 2-amino-
6-fluorobenzoate (50.8 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 96% yield (59.3 mg, 0.289 mmol) as an
ivory solid. mp 216−217 °C; IR (neat): 3376 (w), 1630 (s), 1618 (s)
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.69 (br s, 1H), 8.46 (s,
1H), 7.65 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.36 (dd, J =
8.8, 2.7 Hz, 1H), 3.86 (s, 3H), 2.62 (s, 3H); 13C NMR (DMSO-d6,
100 MHz): δ 196.6, 174.7, 156.8, 142.7, 133.5, 129.1, 122.2, 120.6,
116.7, 105.8, 55.4, 30.9; HRMS (ESI) m/z: [M + H]+ Calcd for
C12H12NO3 218.0817, Found 218.0815.
3-Acetyl-7-chloroquinolin-4(1H)-one (7i). Compound 7i was
synthesized according to general procedure A using methyl 2-amino-
4-chlorobenzoate (55.7 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 71% yield (47.2 mg, 0.213 mmol) as a
yellow solid. This compound has been previously reported, and
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.56 (br s, 1H), 8.41 (s,
1H), 7.69−7.64 (m, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.11 (dd, J = 8.1,
8.0 Hz, 1H), 2.55 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 196.5,
174.7, 162.6, 160.0, 144.0, 141.6 (d, J = 3.3 Hz), 133.5 (d, J = 10.7
Hz), 119.4, 115.1 (d, J = 4.2 Hz), 111.5 (d, J = 21.5 Hz), 31.1; HRMS
(ESI) m/z: [M + H]+ Calcd for C11H9FNO2 206.0617, Found
206.0618.
3-Acetyl-6-methylquinolin-4(1H)-one (7c). Compound 7c was
synthesized according to general procedure A using methyl 2-amino-
I
DOI: 10.1021/acs.joc.7b03162
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The Journal of Organic Chemistry
Article
spectral data match described.1f mp 260−261 °C; IR (neat): 3321
100 MHz): δ 199.0, 173.9, 144.5, 138.1, 135.2, 129.4, 128.0, 121.5,
117.8, 117.7, 42.4, 31.1, 23.4, 22.0, 13.8; HRMS (ESI) m/z: [M + H]+
Calcd for C15H17BrNO2 322.0443, Found 322.0456.
1
(m), 1660 (s), 1633 (s) cm−1; H NMR (DMSO-d6, 400 MHz): δ
12.52 (br s, 1H), 8.51 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.7
Hz, 1H), 7.45 (dd, J = 8.8, 1.7 Hz, 1H), 2.59 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz): δ 196.5, 174.9, 144.9, 140.0, 137.2, 128.2,
126.6, 125.3, 118.4, 118.2, 31.0.
6-Bromo-3-(3-phenylpropanoyl)quinolin-4(1H)-one (7p). Com-
pound 7p was synthesized according to general procedure B using
methyl 2-amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and 5-
phenylpent-1-en-3-one (48.1 mg, 0.300 mmol) in 81% yield (86.9 mg,
0.244 mmol) as a yellow solid. mp 264−265 °C; IR (neat): 3382 (m),
1643 (s), 1605 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.74 (br
s, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.30 (s, 1H), 7.89 (dd, J = 8.9, 1.4 Hz,
1H), 7.63 (d, J = 8.9 Hz, 1H), 7.30−7.27 (m, 4H), 7.21−7.18 (m,
1H), 3.41 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H); 13C NMR
(DMSO-d6, 100 MHz): δ 198.6, 173.9, 153.5, 147.8, 142.8, 141.9,
134.7, 128.4, 128.3, 125.8, 121.4, 116.3, 105.1, 100.0, 44.1, 29.8;
HRMS (ESI) m/z: [M + H]+ Calcd for C18H15BrNO2 356.0286,
Found 356.0295.
6-Bromo-3-(4-phenylbutanoyl)quinolin-4(1H)-one (7q). Com-
pound 7q was synthesized according to general procedure B using
methyl 2-amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and 6-
phenylhex-1-en-3-one (52.3 mg, 0.300 mmol) in 80% yield (89.2 mg,
0.241 mmol) as a yellow solid. mp 249−250 °C; IR (neat): 3389 (w),
1640 (s), 1613 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.68 (br
s, 1H), 8.56 (d, J = 6.8 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.87 (dd, J =
8.6, 2.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.29−7.25 (m, 2H), 7.30−
7.15 (m, 3H), 3.11 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.89−
1.85 (m, 2H); 13C NMR (DMSO-d6, 100 MHz): δ 198.7, 173.9, 144.7,
142.1, 138.1, 135.3, 129.4, 128.4, 128.3, 128.0, 125.8, 121.5, 117.8,
117.7, 42.0, 34.7, 25.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C19H17BrNO2 370.0443, Found 370.0431.
3-Acetyl-7-bromoquinolin-4(1H)-one (7j). Compound 7j was
synthesized according to general procedure A using methyl 2-amino-
4-bromobenzo ate (69.0 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 98% yield (78.5 mg, 0.295 mmol) as a
yellow solid. mp 263−264 °C; IR (neat): 3415 (w), 1644 (s), 1619 (s)
cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.48 (br s, 1H), 8.51 (d, J
= 6.6 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.56
(dd, J = 8.5, 1.7 Hz, 1H), 2.59 (s, 3H); 13C NMR (DMSO-d6, 100
MHz): δ 196.2, 174.8, 144.7, 140.0, 128.0, 127.8, 126.8, 125.8, 121.1,
118.2, 30.9; HRMS (ESI) m/z: [M + H]+ Calcd for C11H9BrNO2
265.9817, Found 265.9811.
3-Acetyl-8-chloroquinolin-4(1H)-one (7k). Compound 7k was
synthesized according to general procedure A using methyl 2-amino-
3-chlorobenzoate (55.7 mg, 0.300 mmol) and methyl vinyl ketone
(25.0 μL, 0.360 mmol) in 76% yield (50.8 mg, 0.229 mmol) as an
ivory solid. mp 257−258 °C; IR (neat): 3332 (w), 1666 (s), 1640 (s)
1
cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.66 (br s, 1H), 8.54 (s,
1H), 8.14 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.8, 2.5 Hz, 1H), 7.68 (d, J
= 8.8 Hz, 1H), 2.60 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ
196.3, 174.2, 144.6, 137.9 132.7, 129.7, 129.1, 124.8, 121.4, 117.9,
31.0; HRMS (ESI) m/z: [M + H]+ Calcd for C11H9ClNO2 222.0322,
Found 222.0321.
3-Acetyl-6,7-dimethoxyquinolin-4(1H)-one (7l). Compound 7l was
synthesized according to general procedure A using methyl 2-amino-
4,5-dimethoxybenzoate (63.4 mg, 0.300 mmol) and methyl vinyl
ketone (25.0 μL, 0.360 mmol) in >98% yield (74.2 mg, 0.300 mmol)
as an ivory solid. mp 230−231 °C; IR (neat): 3432 (w), 1648 (s),
6-Bromo-3-(cyclohexanecarbonyl)quinolin-4(1H)-one (7r). Com-
pound 7r was synthesized according to general procedure B using 2-
amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and 1-cyclo-
hexylprop-2-en-1-one (41.5 mg, 0.300 mmol) in 89% yield (89.3
mg, 0.267 mmol) as an ivory solid. mp 267−268 °C; IR (neat): 3432
1
1620 (s) cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.36 (br s, 1H),
1
(w), 1653 (s), 1615 (s) cm−1; H NMR (DMSO-d6, 400 MHz): δ
8.43 (d, J = 4.6 Hz, 1H), 7.60 (s, 1H), 7.08 (s, 1H), 3.89 (s, 3H), 3.87
(s, 3H), 2.62 (s, 3H); 13C NMR (DMSO-d6, 100 MHz): δ 197.5,
173.7, 153.7, 148.0, 142.7, 134.9, 121.0, 116.4, 104.8, 100.1, 56.0, 55.7,
30.8; HRMS (ESI) m/z: [M + H]+ Calcd for C13H14NO4 248.0923,
Found 248.0929.
12.68 (br s, 1H), 8.52 (d, J = 6.6 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H),
7.88 (dd, J = 8.8, 2.2 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 1.86−1.60 (m,
11H); 13C NMR (DMSO-d6, 100 MHz): δ 202.1, 173.6, 144.9, 138.0,
135.2, 128.0, 121.4, 120.8, 117.6, 117.3, 45.6, 32.3, 28.2, 25.7, 25.5,
24.4; HRMS (ESI) m/z: [M + H]+ Calcd for C16H17BrNO2 334.0443,
Found 334.0446.
3-Benzoyl-6-bromoquinolin-4(1H)-one (7s). Compound 7s was
synthesized according to general procedure B using 2-amino-5-
bromobenzoate (82.8 mg, 0.360 mmol) and 1-phenylprop-2-en-1-one
(39.6 mg, 0.300 mmol) in 92% yield (90.7 mg, 0.276 mmol) as a
yellow solid. mp 234−235 °C; IR (neat): 2938 (m), 1638 (s), 1615 (s)
cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.66 (br s, 1H), 8.38 (d, J
= 6.5 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 7.90 (dd, J = 8.8,
2.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.46 (dd J = 7.6, 7.6 Hz, 3H);
13C NMR (DMSO-d6, 100 MHz): δ 194.2, 173.3, 143.6, 138.5, 138.3,
135.3, 132.5, 128.5, 127.7, 127.6, 121.5, 121.4, 119.8, 117.3; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H11BrNO2 327.9973, Found
327.9968.
6-Bromo-3-(4-methoxybenzoyl)quinolin-4(1H)-one (7t). Com-
pound 7t was synthesized according to general procedure B using
methyl 2-amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and 1-(4-
methoxyphenyl)prop-2-en-1-one (48.7 mg, 0.300 mmol) in 84% yield
(90.6 mg, 0.253 mmol) as a yellow solid. mp 254−255 °C; IR (neat):
3392 (w), 1649(s), 1616 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ
12.56 (br s, 1H), 8.33 (d, J = 6.3 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H),
7.90 (dd, J = 8.8, 2.3 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 8.8
Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (DMSO-d6,
100 MHz): δ 192.5, 173.2, 162.9, 142.9, 138.5, 135.1, 131.8, 130.8,
128.4, 127.7, 121.5, 120.5, 117.1, 113.4, 55.4; HRMS (ESI) m/z: [M +
H]+ Calcd for C17H13BrNO3 358.0079, Found 358.0084.
6-Bromo-3-(furan-2-carbonyl)quinolin-4(1H)-one (7u). Com-
pound 7u was synthesized according to general procedure B using
2-amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and 1-(furan-2-
yl)prop-2-en-1-one (36.6 mg, 0.300 mmol) in 91% yield (87.2 mg,
0.274 mmol) as an ivory solid. mp 255−256 °C; IR (neat): 3413 (w),
6-Bromo-3-propionylquinolin-4(1H)-one (7m). Compound 7m
was synthesized according to general procedure B using methyl 2-
amino-5-bromobenzoate (82.8 mg, 0.360 mmol) and ethyl vinyl
ketone (29.7 μL, 0.300 mmol) in 96% yield (81.0 mg, 0.289 mmol) as
a yellow solid. mp 240−241 °C; IR (neat): 3421 (m), 1646 (s), 1611
1
(s) cm−1; H NMR (DMSO-d6, 400 MHz): δ 12.66 (br s, 1H), 8.56
(d, J = 6.1 Hz, 1H), 8.30 (s, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.62
(d, J = 7.2 Hz, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 3H);
13C NMR (DMSO-d6, 100 MHz): δ 199.4, 173.8, 144.4, 138.0, 135.2,
129.3, 127.9, 121.4, 117.7, 117.6, 35.6, 8.01; HRMS (ESI) m/z: [M +
H]+ Calcd for C12H11BrNO2 279.9973, Found 279.9977.
6-Bromo-3-butyrylquinolin-4(1H)-one (7n). Compound 7n was
synthesized according to general procedure B using methyl 2-amino-5-
bromobenzoate (82.8 mg, 0.360 mmol) and hex-1-en-3-one (35.1 μL,
0.300 mmol) in 91% yield (80.6 mg, 0.274 mmol) as a yellow solid.
1
mp 250−251 °C; IR (neat): 3321 (w), 1649 (s), 1607 (s) cm−1; H
NMR (DMSO-d6, 400 MHz): δ 12.79 (br s, 1H), 8.52 (s, 1H), 8.28
(d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.8, 2.2 Hz, 1H), 7.62 (d, J = 8.7 Hz,
1H), 3.05 (t, J = 7.1 Hz, 2H), 1.60−1.53 (m, 2H), 0.91 (t, J = 7.3 Hz,
3H); 13C NMR (DMSO-d6, 100 MHz): δ 198.9, 173.9, 144.6, 138.2,
135.3, 129.4, 128.0, 121.6, 117.9, 117.8, 44.5, 17.1, 13.9.; HRMS (ESI)
m/z: [M + H]+ Calcd for C13H13BrNO2 294.0130, Found 294.0124.
6-Bromo-3-hexanoylquinolin-4(1H)-one (7o). Compound 7o was
synthesized according to general procedure B using methyl 2-amino-5-
bromobenzoate (82.8 mg, 0.360 mmol) and oct-1-en-3-one (45.5 μL,
0.300 mmol) in 91% yield (88.3 mg, 0.274 mmol) as a bright yellow
solid. mp 228−229 °C; IR (neat): 3416 (m), 1661 (s), 1605 (s) cm−1;
1H NMR (DMSO-d6, 400 MHz): δ 12.73 (br s, 1H), 8.55 (d, J = 6.6
Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 8.8, 2.2 Hz, 1H), 7.61
(d, J = 8.8 Hz, 1H), 3.07 (t, J = 7.3 Hz, 1H), 1.56 (d, J = 7.1 Hz, 2H),
1.30−1.27 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (DMSO-d6,
J
DOI: 10.1021/acs.joc.7b03162
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1630(s), 1616 (s) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 12.61 (br
s, 1H), 9.27 (s, 1H), 8.37 (d, J = 6.3 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H),
7.98 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 6.70
(d, J = 3.2 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz): δ 180.1, 172.9,
152.6, 147.7, 143.0, 138.5, 135.4, 128.4, 127.8, 121.5, 120.1, 119.7,
117.4, 112.5; HRMS (ESI) m/z: [M + H]+ Calcd for C14H9BrNO3
317.9766, Found 317.9772.
Development Program of the National Research Foundation
(NRF) and was funded by the Korean government
(MSIP&MOHW) (Grant NRF-2015M3A9E6029594) and by
the Research Grant of Kwangwoon University in 2017. The
authors thank the Korea Basic Science Institute for technical
assistance with mass spectrometry.
Experimental Procedures for the One-Pot, Gram Scale
Synthesis of 3-Carbonyl-4-quinolones. 3-Benzoyl-6,7-dime-
thoxy-2-methylquinolin-4(1H)-one (4a). Methyl 2-amino-4,5-dime-
thoxybenzoate (1a) (1.00 g, 4.73 mmol), CuCl (23.5 mg, 0.237
mmol), dppbz (106 mg, 0.237 mmol), and KOt-Bu (26.6 mg, 0.237
mmol) were added to a round-bottom flask (100 mL) charged with a
magnetic bar, which was sealed with a rubber septum. The flask was
purged with N2 gas for 5 min. Toluene (21.7 mL) was added to the
mixture, which was allowed to premix for 10 min. Then, a solution of
(E)-1-phenylbut-2-en-1-one (2a) (831 mg, 5.68 mmol) in toluene (2
mL) was added to the reaction solution. After the mixture was stirred
for 3 h at room temperature, KOt-Bu (1.59 g, 14.2 mmol) was added,
and the reaction was allowed to stir for an additional 1 h at 22 °C. In
open air conditions, an aqueous solution of 6 N HCl (16 mL) was
added to the resulting solution, which was allowed to stir for 1 h. The
reaction was quenched by adding a saturated aqueous solution of
K2CO3 (16 mL) and was washed with CH2Cl2 (3 × 30 mL). The
organic layers were combined, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by silica gel
column chromatography (MeOH:CH2Cl2 = 5:95) to afford the
desired product 4a (1.15 g, 3.56 mmol, 75% yield) as a yellow solid.
3-Acetyl-6,7-dimethoxyquinolin-4(1H)-one (7l). Methyl 2-amino-
4,5-dimethoxybenzoate (1a) (1.00 g, 4.73 mmol), CuCl (23.5 mg,
0.237 mmol), DPEphos (128 mg, 0.237 mmol), and KOt-Bu (26.6 mg,
0.237 mmol) were added to a round-bottom flask (100 mL) charged
with a magnetic bar. The round-bottom flask was sealed with a rubber
septum and purged with N2 gas for 5 min. Toluene (23.7 mL) was
added to the mixture, which was allowed to premix for 10 min. Then,
methyl vinyl ketone (6a) (473 μL, 5.68 mmol) was added to the
reaction solution. After the mixture was stirred for 3 h at room
temperature, KOt-Bu (1.59 g, 14.2 mmol) was added, and the reaction
was allowed to stir for an additional 1 h at 22 °C. The resulting
solution was quenched with an aqueous solution of 6 N HCl (16 mL)
and allowed to stir for 10 min in open air conditions. The organic
layers were washed with CH2Cl2 (3 × 30 mL), combined, dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
recrystallized from dichloromethane and diethyl ether to afford the
desired product 7l (1.12 g, 4.53 mmol, 96% yield) as an ivory solid.
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b03162.
1H NMR and 13C NMR spectra for all products (PDF)
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Corresponding Author
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ORCID
Changsik Song: 0000-0003-4754-1843
Yunmi Lee: 0000-0003-1315-4001
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ACKNOWLEDGMENTS
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This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) (Grant NRF-2017R1A2B4008310). This work was also
partially supported by the Bio & Medical Technology
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J. Org. Chem. XXXX, XXX, XXX−XXX