Mild and Efficient Silver(I) Triflate Catalyzed Synthesis of 2-Aryl-2,3-dihydroquinolin-4(1 H)-ones, and Their Antioxidant Activities

Article abstract of DOI:10.1055/s-0035-1560322

Biologically interesting 2-aryl-2,3-dihydroquinolin-4(1H)-ones were synthesized using a mild and efficient one-pot procedure starting from o-aminoacetophenones and aromatic aldehydes in the presence of silver(I) triflate. This synthetic protocol provides rapid access to a variety of 2-aryl-2,3-dihydroquinolin-4(1H)-ones. This technique has several advantages, such as the use of easily available starting materials, the efficiency of the catalyst, a simple operation, and tolerance of a wide range of functionality in the aldehydes. Screening of the synthesized compounds for their antioxidant properties revealed that two compounds (with EC₅₀ = 15.42 μM and 15.16 μM) exhibit a potent free-radical scavenging ability towards TEAC free radicals compared to the standard, Trolox.

Full text of DOI:10.1055/s-0035-1560322

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3881–3890
paper
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Paper
Synthesis
Mild and Efficient Silver(I) Triflate Catalyzed Synthesis of 2-Aryl-
2,3-dihydroquinolin-4(1H)-ones, and Their Antioxidant Activities
O
O
Rameshwar Prasad Pandit
Kavita Sharma
H
O
N
H
Yong Rok Lee*
R
AgOTf
MeOH
or
or
O
+
O
H
R
mild reaction conditions
wide functional group tolerance
20 examples
School of Chemical Engineering, Yeungnam University,
Gyeongsan 712-749, Republic of Korea
yrlee@yu.ac.kr
NH2
X
77–98% yield
N
H
X = NMe, O, S
O
X
FRAP test
O
most potent antioxidants
N
H
N
H
OMe
EC50 = 15.42 μM
EC50 = 15.16 μM
Received: 04.08.2015
Accepted after revision: 31.08.2015
Published online: 30.09.2015
based on intra- and intermolecular cyclization reactions
have been developed.7–25 Representative intramolecular ap-
proaches for 2,3-dihydroquinolin-4(1H)-ones include the
cyclization of 2-aminochalcones under a range of reaction
conditions, such as antimony(III) chloride,7,8 ytterbium(III)
triflate,9 indium(III) chloride,10 zinc chloride,11 phosphorous
acid,12 phosphomolybdic acid–silica gel,13 silica gel sup-
ported sodium bisulfite,14 silica gel supported tantalum(V)
bromide,15 silica chloride with microwave irradiation,16
PEG-400,17 montmorillonite,18 alumina-supported ceri-
um(III) chloride heptahydrate–sodium iodide,19 piperidine
with potassium hydroxide,20 sodium ethoxide,21 and ionic
liquids22 (Scheme 1, path a). Several intermolecular ap-
proaches have also been reported for 2,3-dihydroquinolin-
4(1H)-ones, which include the condensation of o-aminoac-
etophenones and aryl aldehydes in the presence of L-pro-
line,23 per-6-amino-β-cyclodextrin,24 and amino acid de-
rived sulfonamides25 as organocatalysts (Scheme 1, path b).
Despite their merits, many of the methods reported
thus far suffer from long reaction times, low yields, the
need for expensive catalysts, and harsh reaction conditions.
Therefore, more efficient and general methods are needed
to overcome these limitations, which prompted this study
into the development of a new approach using silver(I) tri-
flate (AgOTf) as a mild and efficient catalyst. Recently,
AgOTf has been widely used as a potential Lewis acid cata-
lyst.26 In this context, the use of AgOTf has attracted consid-
DOI: 10.1055/s-0035-1560322; Art ID: ss-2015-f0468-op
Abstract Biologically interesting 2-aryl-2,3-dihydroquinolin-4(1H)-
ones were synthesized using a mild and efficient one-pot procedure
starting from o-aminoacetophenones and aromatic aldehydes in the
presence of silver(I) triflate. This synthetic protocol provides rapid ac-
cess to a variety of 2-aryl-2,3-dihydroquinolin-4(1H)-ones. This tech-
nique has several advantages, such as the use of easily available starting
materials, the efficiency of the catalyst, a simple operation, and toler-
ance of a wide range of functionality in the aldehydes. Screening of the
synthesized compounds for their antioxidant properties revealed that
two compounds (with EC50 = 15.42 μM and 15.16 μM) exhibit a potent
free-radical scavenging ability towards TEAC free radicals compared to
the standard, Trolox.
Key words o-aminoacetophenones, aldehydes, silver(I) triflate, con-
densation, quinolinones, antioxidants
Aza analogues of flavonoids are an important class of
heterocycles that display a range of potent biological prop-
erties, such as antibacterial, antitumor, antifungal, anti-in-
flammatory, anthelmintic, antibiotic, and antihypertensive
activities.1,2 Among them, molecules bearing a dihydro-
quinolin-4(1H)-one moiety have been used as building
blocks in the synthesis of medically important compounds3
and natural products.4–6 A number of synthetic approaches
for the construction of 2,3-dihydroquinolin-4(1H)-ones
O
O
O
O
path a
path b
R
H
R
R
+
NH2
N
H
NH2
Scheme 1 General methods for the preparation of 2-aryl-2,3-dihydroquinolin-4(1H)-ones
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Synthesis
O
O
O
AgOTf
R1
H
R1
+
N
H
NH2
R2
R2
Scheme 2 AgOTf-catalyzed synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-ones
erable attention because of its easy availability and ease of
handling, and the enhanced reaction rates in organic reac-
tions.27
thaldehyde (2l) and 2-naphthaldehyde (2m), the desired
products 3l and 3m were also formed, in 84% and 87% yield,
respectively.
This paper reports the synthesis of a variety of 2-aryl-
2,3-dihydroquinolin-4(1H)-ones starting from commercial-
ly available o-aminoacetophenones and aryl aldehydes, us-
ing AgOTf as a mild and efficient catalyst (Scheme 2). In ad-
dition, we also report the antioxidant activities of the syn-
thesized 2-aryl-2,3-dihydroquinolin-4(1H)-ones. To the
best of our knowledge, the antioxidant properties of these
synthetic compounds have not been previously investigat-
ed.
In order to identify the optimal reaction conditions, cy-
clization of o-aminoacetophenone (1a, 1.0 mmol) with
benzaldehyde (2a, 1.2 mmol) was first examined in the
presence of several silver catalysts and various solvents (Ta-
ble 1). The reaction of 1a with 2a using silver(II) oxide (20
mol%) or silver(I) oxide (20 mol%) in refluxing methanol for
24 hours gave none of the desired product (Table 1, entries
1 and 2). With silver carbonate (20 mol%) and silver nitrate
(20 mol%), product 3a was produced in 51% and 72% yield,
respectively (Table 1, entries 3 and 4). Importantly, the
treatment of 1a and 2a in the presence of AgOTf in reflux-
ing methanol for 24 hours provided 3a in the best yield
(88%; Table 1, entry 6). With other solvents (EtOH, toluene,
DMF), the yield of 3a was lower than that with methanol.
When 20 mol% of copper(II) triflate as another catalyst was
used, 3a was produced in low yield (21%; Table 1, entry 10).
The structure of 3a was confirmed by an analysis of the
spectroscopic data and by a comparison with the literature
values.28
To explore the generality and scope of this methodolo-
gy, additional reactions between o-aminoacetophenone
(1a) and different aryl aldehydes 2b–m were carried out
under the optimized conditions (Table 2, entries 1–12). The
reactions between 1a and aryl aldehydes 2b–f bearing elec-
tron-donating groups, such as methyl or methoxy groups,
on the benzene ring in refluxing methanol for 12 hours pro-
duced 3b–f in 86–98% yield. When aryl aldehydes 2g–k
bearing an electron-withdrawing group, such as a fluoro,
chloro, bromo, or nitro group, on the benzene ring were
used, the desired products 3g–k were produced in 80–87%
yield after longer reaction times (18–24 h). With 1-naph-
To further demonstrate the versatility of this protocol,
additional reactions with several substituted o-aminoace-
tophenones bearing an additional electron-donating or
electron-withdrawing group on the benzene ring were next
explored (Table 2, entries 13–16). Reaction of 1b or 1c bear-
ing an electron-donating group (4-Me and 3-OMe) with
benzaldehyde (2a) provided the desired products 3n (85%)
and 3o (77%), respectively, whereas those of 1d or 1e bear-
ing an electron-withdrawing group (5-Cl and 5-Br) with 2a
gave compounds 3p and 3q in 92% and 90% yield, respec-
tively. These reactions provided a rapid route to the prepa-
ration of a variety of 2-aryl-2,3-dihydroquinolin-4(H)-ones
in a one-pot procedure.
Next, control experiments to identify the potential in-
termediate that allows the cyclization to product 3a were
carried out (Scheme 3). For example, the reaction of o-ami-
noacetophenone (1a) and benzaldehyde (2a) in the pres-
Table 1 Effect of Catalyst and Solvent in the Synthesis of 3aa
O
O
O
catalyst
H
+
N
NH2
1a
H
3a
2a
Entry
Catalyst (mol%)
Conditions
Yieldb (%)
1
2
AgO (20 mol%)
MeOH, reflux, 24 h
MeOH, reflux, 24 h
MeOH, reflux, 24 h
MeOH, reflux, 24 h
MeOH, reflux, 24 h
MeOH, reflux, 24 h
EtOH, reflux, 24 h
toluene, reflux, 12 h
DMF, 100 °C, 24 h
MeOH, reflux, 24 h
0
0
Ag2O (20 mol%)
Ag2CO3 (20 mol%)
AgNO3 (20 mol%)
AgOTf (20 mol%)
AgOTf (10 mol%)
AgOTf (10 mol%)
AgOTf (10 mol%)
AgOTf (10 mol%)
Cu(OTf)2 (20 mol%)
3
51
72
79
88
73
37
12
21
4
5
6
7
8
9
10
a Reaction conditions: o-aminoacetophenone (1.0 mmol), benzaldehyde (1.2
mmol), solvent (5.0 mL).
b Isolated yield.
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Synthesis
ence of silver catalyst in refluxing methanol for 3 hours
provided products 3a (8%) and 4a (13%), together with the
recovered starting material 1a (77%). Importantly, treat-
ment of 4a with 10 mol% of silver catalyst in refluxing
methanol for 20 hours afforded the desired product 3a in
91% yield. The observation of intermediate 4a shows that
the cycloaddition for the product 3a proceeds through an
aldol reaction.
Table 2 Additional Syntheses of a Variety of 2-Aryl-2,3-dihydroquinolin-4(1H)-ones
Entry
o-Aminoacetophenone
Aryl aldehyde
Time (h)
Product
Yield (%)
O
O
O
H
1
12
86
N
H
NH2
2b
1a
3b
O
O
H
2
1a
12
90
N
H
2c
3c
O
O
H
3
1a
12
95
N
H
OMe
2d
OMe
3d
O
O
H
4
1a
12
N
H
98
OMe
OMe
OMe
OMe
OMe
2e
OMe
3e
O
O
H
5
1a
12
98
N
H
OMe
2f
OMe
3f
O
O
H
6
1a
18
85
N
H
F
2g
F
3g
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Table 2 (continued)
Entry
o-Aminoacetophenone
Aryl aldehyde
Time (h)
Product
Yield (%)
O
O
Cl
Cl
H
7
1a
1a
1a
18
87
N
H
2h
3h
O
O
H
8
18
18
24
84
81
80
N
H
Cl
2i
Cl
3i
O
O
H
9
N
H
Br
2j
Br
3j
O
O
H
10
1a
N
H
NO2
2k
NO2
3k
O
O
O
O
H
N
H
11
1a
20
84
2l
3l
O
H
N
H
12
1a
20
87
2m
3m
O
O
H
13
18
85
N
H
NH2
2a
1b
3n
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Table 2 (continued)
Entry
o-Aminoacetophenone
Aryl aldehyde
Time (h)
Product
Yield (%)
O
O
14
2a
2a
2a
24
77
N
H
NH2
OMe
OMe
1c
3o
O
O
Cl
Cl
15
12
92
N
H
NH2
1d
3p
O
O
Br
Br
16
12
90
N
H
NH2
1e
3q
Based on the results of the control experiments, the for-
mation of 3a can be explained by the mechanism shown in
Scheme 4. In the presence of AgOTf catalyst, benzaldehyde
(2a) initially forms an activated complex 2a′, which is at-
tacked by enolizable 1a to afford the intermediate 4a
through the protonation of aldol adduct 4 with methanol or
a proton (path a). The AgOTf-catalyzed elimination of water
from 4a produces another intermediate 5, which undergoes
intramolecular cyclization to yield final product 3a via 5a.
Although intermediate 4a was isolated, it may be possible
to proceed through another mechanistic pathway, via tau-
tomerization of 4 followed by E1cB reaction of 4b to give 5
(path b).
role-2-carboxaldehyde in the presence of 10 mol% of AgOTf
in refluxing methanol for 20 hours provided the desired
To explore the applications of this methodology, further
reactions with heteroaryl aldehydes for the synthesis of di-
hydroquinolin-4(1H)-ones bearing heteroaromatics were
attempted (Scheme 5). Reaction of 1a with N-methylpyr-
Figure 1 FRAP test results of the synthesized compounds 3a–q and 6–
8 as TEAC values
O
OH
O
O
AgOTf
H
+
1a
3a
+
+
MeOH
77%
8%
NH2
NH2
reflux, 3 h
4a 13%
2a
1a
(recovered)
O
O
OH
AgOTf
N
H
MeOH
reflux, 20 h
NH2
4a
3a 91%
Scheme 3 Control experiments
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Synthesis
OTf
Ag
AgOTf
O
O
OH
O
O
O
H+
H
+
H
NH2
path a
NH2
NH2
– H+
1a
4
2a'
4a
path b
AgOTf
tautomerization
AgOTf
2a
OTf
Ag
O
H+
O
OH
E1cB
NH2
– AgOTf
– H2O
NH2
5
4b
AgOTf
AgOTf
O
O
NH2
N
H
AgOTf
5a
3a
Scheme 4 Proposed mechanism for the formation of 3a
product 6 in 80% yield, whereas treatment with furan-2-
carboxaldehyde and thiofuran-2-carboxaldehyde for 20
hours afforded 7 and 8 in 85% and 89% yield, respectively.
The antioxidant activity of organic compounds seems to
be related to their molecular structure, more precisely to
the presence of hydroxy groups, double bond conjugation,
and resonance effects.29 The synthesized 2-aryl-2,3-dihy-
droquinolin-4(1H)-ones contain C=O and NH groups, and
aromatic substitution at C2. Results of FRAP (ferric reducing
antioxidant power) assays are given in Figure 1 as TEAC
(Trolox equivalent antioxidant capacity) values, which were
obtained from the calibration graph prepared with Trolox.
The Trolox concentration giving the same absorbance val-
ues as the test sample and the higher value of TEAC means
higher antioxidant capacity. All the compounds were active
in the FRAP test and the EC50 values are presented in Figure
2. The starting material o-aminoacetophenone showed
slightly lower activity as compared to the synthesized com-
pounds.
O
H
O
O
X
AgOTf
20 h
N
H
NH2
X
1a
6: X = NMe (80%)
7: X = O (85%)
8: X = S (89%)
Scheme 5 Synthesis of dihydroquinolin-4(1H)-ones bearing heteroaro-
matics
The regression line drawn with Microsoft Excel for syn-
thesized compounds 3a–q and 6–8 is in agreement with
the FRAP test results. The haloaryl derivatives 3i and 3j and
naphthyl-substituted 2,3-dihydroquinolin-4(1H)-ones 3l
and 3m exhibited lower activity as compared to aryl- and
heteroaryl-substituted
2,3-dihydroquinolin-4(1H)-ones
3a–h,k,n–q, and 6–8. The antioxidant activities of the com-
pounds are well correlated with their EC50 values.
Figure 2 EC50 (μg/mL) values of the synthesized compounds 3a–q and
6–8
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In conclusion, a novel and efficient methodology was
developed for the synthesis of a variety of 2-aryl-2,3-dihy-
droquinolin-4(1H)-ones by the silver(I) triflate catalyzed
reaction of o-aminoacetophenones with aryl aldehydes.
The advantage of this protocol over existing methods lies in
the simplicity of the procedure, milder reaction conditions,
easily available catalyst, and improved substrate scope, as
well as eliminating the need for preparation of any chal-
cones. Compounds 3c and 3d (with EC50 = 15.42 μM and
15.16 μM, respectively) showed potent antioxidant activi-
ties towards TEAC free radicals compared to the standard,
Trolox. These bioactive compounds can potentially be uti-
lized as antioxidants in the future.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.8 Hz, 1 H), 7.33–7.28 (m, 3
H), 7.21–7.15 (m, 2 H), 6.76 (t, J = 7.5 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H),
4.69 (dd, J = 13.8, 3.6 Hz, 1 H), 4.44 (s, 1 H, NH), 2.91–2.71 (m, 2 H),
2.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 193.6, 151.8, 138.3, 138.1, 135.5, 129.7,
129.6, 127.7, 126.6, 119.1, 118.4, 116.0, 58.3, 46.6, 21.3.
HRMS (EI): m/z [M+] calcd for C16H15NO: 237.1154; found: 237.1154.
2-(2,5-Dimethylphenyl)-2,3-dihydroquinolin-4(1H)-one (3c)
Yellow solid; yield: 225 mg (90%); mp 95–97 °C.
IR (KBr): 3311, 2927, 1602, 1492, 1315, 1244, 752 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.87 (dd, J = 7.8, 1.2 Hz, 1 H), 7.46 (s, 1
H), 7.32 (td, J = 8.4, 1.2 Hz, 1 H), 7.07–7.03 (m, 2 H), 6.77 (t, J = 7.2 Hz,
1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.97 (dd, J = 14.4, 3.6 Hz, 1 H), 4.37 (s, 1
H, NH), 2.78 (dd, J = 16.8, 14.4 Hz, 1 H), 2.72–2.69 (m, 1 H), 2.36 (s, 3
H), 2.30 (s, 3 H).
All experiments were carried out under a nitrogen atmosphere.
Merck silica gel plates (Art. 5554) precoated with fluorescent indica-
tor were used for analytical TLC. Flash column chromatography was
performed using Merck silica gel 9385. Melting points are uncorrect-
ed and were determined on a Fisher-Johns melting point apparatus.
1H NMR and 13C NMR spectra were recorded in CDCl3 on a Varian VNS
spectrometer (600 and 150 MHz, or 300 and 75 MHz, respectively),
using δ = 7.24 and 77.0 ppm as the solvent chemical shift. Multiplici-
ties are abbreviated as s = singlet, d = doublet, t = triplet, m = multi-
plet, dd = doublet of doublets, and dt = doublet of triplets. IR spectra
were recorded on a Bio-Rad FTIR or PerkinElmer Spectrum 2 ATR
spectrophotometer. HRMS was carried out at the Korea Basic Science
Institute.
13C NMR (75 MHz, CDCl3): δ = 193.6, 152.2, 138.9, 136.3, 135.4, 131.9,
130.9, 128.8, 127.7, 126.6, 119.0, 118.4, 116.1, 54.6, 45.4, 21.2, 18.7.
HRMS (EI): m/z [M+] calcd for C17H17NO: 251.1310; found: 251.1308.
2-(4-Methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (3d)
Brown solid; yield: 240 mg (95%); mp 145–147 °C.
IR (KBr): 3330, 2978, 1663, 1585, 1305, 1224 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.85 (dd, J = 7.8, 1.5 Hz, 1 H), 7.37–7.33
(m, 2 H), 7.31–7.28 (m, 1 H), 6.93–6.88 (m, 2 H), 6.79–6.74 (m, 1 H),
6.68 (d, J = 8.1 Hz, 1 H), 4.68 (dd, J = 13.5, 3.6 Hz, 1 H), 4.41 (s, 1 H,
NH), 3.80 (s, 3 H), 2.90–2.69 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 193.5, 159.8, 151.8, 135.5, 133.2, 127.9,
2-Aryl-2,3-dihydroquinolin-4(1H)-ones 3 and 6–8; General Proce-
127.7, 119.1, 118.4, 116.0, 114.1, 58.0, 55.5, 46.6.
dure
HRMS (EI): m/z [M+] calcd for C16H15NO2: 253.1103; found: 253.1102.
AgOTf (26 mg, 10 mol%) was added to a solution of an o-aminoace-
tophenone (1.0 mmol) and an aryl aldehyde (1.2 mmol) in MeOH (5
mL) at r.t. The reaction mixture was stirred under reflux for 12–24 h.
After the reaction was complete, as indicated by TLC, the excess sol-
vent was removed under reduced pressure and the residue was puri-
fied by silica gel column chromatography (hexanes–EtOAc, 20:1) to
yield the desired product.
2-(3,4-Dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (3e)
Off-white semisolid; yield: 277 mg (98%).
IR (neat): 3329, 2971, 1665, 1594, 1313, 1235 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.85 (dd, J = 7.8, 0.9 Hz, 1 H), 7.35–7.29
(m, 1 H), 6.98–6.94 (m, 2 H), 6.85 (d, J = 8.1 Hz, 1 H), 6.79–6.75 (m, 1
H), 6.69 (d, J = 8.1 Hz, 1 H), 4.67 (dd, J = 13.8, 3.9 Hz, 1 H), 4.47 (s, 1 H,
NH), 3.88 (s, 3 H), 3.87 (s, 3 H), 2.91–2.70 (m, 2 H).
2-Phenyl-2,3-dihydroquinolin-4(1H)-one (3a)
13C NMR (75 MHz, CDCl3): δ = 193.6, 151.7, 149.3, 149.0, 135.5, 133.6,
Off-white solid; yield: 196 mg (88%); mp 155–157 °C.
127.6, 119.0, 118.5, 116.1, 111.3, 109.4, 58.4, 56.1, 56.0, 46.8.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found: 283.1209.
IR (KBr): 3321, 2978, 1666, 1591, 1233 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.83 (dd, J = 8.4, 1.2 Hz, 1 H), 7.42 (d,
J = 7.2 Hz, 2 H), 7.38–7.35 (m, 2 H), 7.33–7.30 (m, 2 H), 6.75 (t, J = 7.2
Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.69 (dd, J = 13.8, 3.6 Hz, 1 H), 4.64 (s,
1 H, NH), 2.82 (dd, J = 16.2, 14.4 Hz, 1 H), 2.70 (dd, J = 16.8, 3.6 Hz, 1
H).
13C NMR (150 MHz, CDCl3): δ = 193.2, 151.5, 140.9, 135.3, 128.8,
128.3, 127.4, 126.5, 118.8, 118.2, 115.8, 58.3, 46.2.
2-(3,5-Dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (3f)
Off-white semisolid; yield: 277 mg (98%).
IR (neat): 3335, 2839, 1674, 1602, 1320, 1138, 752 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.83 (dd, J = 8.4, 1.2 Hz, 1 H), 7.31 (td,
J = 9.0, 1.8 Hz, 1 H), 6.76 (t, J = 6.6 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H),
6.57 (d, J = 2.4 Hz, 2 H), 6.39 (t, J = 2.4 Hz, 1 H), 4.63 (dd, J = 13.8, 3.6
Hz, 1 H), 4.57 (s, 1 H, NH), 3.77 (s, 6 H), 2.82 (dd, J = 15.6, 13.2 Hz, 1 H),
2.73 (dd, J = 16.2, 3.6 Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C15H13NO: 223.0997; found: 223.0994.
2-(p-Tolyl)-2,3-dihydroquinolin-4(1H)-one (3b)
13C NMR (150 MHz, CDCl3): δ = 193.2, 161.1, 151.4, 143.4, 135.3,
Pale yellow solid; yield: 203 mg (86%); mp 145–147 °C.
127.5, 118.9, 118.4, 115.9, 104.4, 99.9, 58.5, 55.3, 46.3.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found: 283.1210.
IR (KBr): 3340, 2965, 1660, 1555, 1230, 910 cm–1
.
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2-(4-Fluorophenyl)-2,3-dihydroquinolin-4(1H)-one (3g)
1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 8.1
Hz, 1 H), 7.63 (d, J = 8.1 Hz, 2 H), 7.38–7.33 (m, 1 H), 6.84 (m, 1 H),
6.75 (d, J = 8.1 Hz, 1 H), 4.90–4.84 (m, 1 H), 4.55 (s, 1 H, NH), 2.82–
2.79 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 192.0, 151.1, 148.4, 135.9, 127.8, 127.7,
124.5, 119.3, 116.2, 58.1, 46.3.
Off-white solid; yield: 204 mg (85%); mp 135–137 °C.
IR (KBr): 3339, 2966, 1662, 1553, 1228, 911 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.83 (dd, J = 8.4, 1.8 Hz, 1 H), 7.42–7.39
(m, 2 H), 7.32 (dd, J = 7.2, 1.8 Hz, 1 H), 7.07–7.03 (m, 2 H), 6.77 (t, J =
7.8 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 4.70 (dd, J = 13.8, 3.6 Hz, 1 H),
4.54 (s, 1 H, NH), 2.80 (dd, J = 15.6, 13.2 Hz, 1 H), 2.71 (dd, J = 16.8, 3.6
Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C15H12N2O3: 268.0848; found:
268.0846.
13C NMR (150 MHz, CDCl3): δ = 192.9, 162.5 (JC-F = 246.0 Hz), 151.3,
136.7, 135.4, 128.3 (JC-F = 8.1 Hz), 127.5, 119.0, 118.6, 115.9 (JC-F = 5.8
Hz), 115.7, 57.8, 46.4.
2-(Naphthalen-1-yl)-2,3-dihydroquinolin-4(1H)-one (3l)
Yellow solid; yield: 230 mg (84%); mp 176–177 °C.
IR (KBr): 3332, 3056, 1647, 1490, 1318, 765, 630 cm–1
.
HRMS (EI): m/z [M+] calcd for C15H12FNO: 241.0903; found: 241.0902.
1H NMR (300 MHz, CDCl3): δ = 8.12–8.09 (m, 1 H), 7.93–7.88 (m, 2 H),
7.83 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.56–7.47 (m, 3 H),
7.38–7.32 (m, 1 H), 6.83–6.78 (m, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.56
(dd, J = 11.4, 6.0 Hz, 1 H), 4.60 (s, 1 H, NH), 3.08–2.91 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 193.5, 152.0, 136.6, 134.2, 130.5, 129.4,
129.0, 127.9, 126.8, 126.2, 125.7, 123.9, 122.5, 119.3, 118.7, 116.3,
54.6, 45.5.
2-(2-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (3h)
Yellow solid; yield: 223 mg (87%); mp 146–147 °C.
IR (KBr): 3340, 2970, 1664, 1586, 1222, 758 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.86 (dd, J = 7.8, 1.2 Hz, 1 H), 7.65 (dd, J
= 7.8, 1.8 Hz, 1 H), 7.38 (dd, J = 8.4, 1.2 Hz, 1 H), 7.34–7.31 (m, 1 H),
7.29 (dd, J = 7.8, 1.2 Hz, 1 H), 7.27–7.24 (m, 1 H), 6.79 (t, J = 7.2 Hz, 1
H), 6.72 (d, J = 7.8 Hz, 1 H), 5.24 (dd, J = 13.2, 4.2 Hz, 1 H), 4.51 (s, 1 H,
NH), 2.93 (dd, J = 16.2, 4.2 Hz, 1 H), 2.75 (dd, J = 16.2, 12.0 Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C19H15NO: 273.1154; found: 273.1154.
2-(Naphthalen-2-yl)-2,3-dihydroquinolin-4(1H)-one (3m)
13C NMR (150 MHz, CDCl3): δ = 192.7, 151.4, 138.2, 135.4, 132.7,
Pale yellow solid; yield: 238 mg (87%); mp 160–162 °C.
130.0, 129.3, 127.6, 127.5, 127.4, 119.1, 118.6, 116.0, 54.2, 44.0.
IR (KBr): 3333, 3053, 1654, 1492, 1325, 754 cm–1
.
HRMS (EI): m/z [M+] calcd for C15H12ClNO: 257.0607; found:
1H NMR (300 MHz, CDCl3): δ = 7.89–7.82 (m, 5 H), 7.56 (d, J = 8.7 Hz, 1
H), 7.53–7.47 (m, 2 H), 7.37–7.32 (m, 1 H), 6.82–6.77 (m, 1 H), 6.73 (d,
J = 8.4 Hz, 1 H), 4.90 (dd, J = 13.5, 3.6 Hz, 1 H), 4.60 (s, 1 H, NH), 3.02–
2.91 (m, 1 H), 2.86–2.79 (m, 1 H).
257.0604.
2-(4-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (3i)
Orange solid; yield: 215 mg (84%); mp 168–170 °C.
13C NMR (75 MHz, CDCl3): δ = 193.6, 151.9, 138.6, 135.8, 133.6, 133.5,
129.2, 128.2, 128.1, 127.9, 126.8, 126.7, 125.9, 124.6, 119.3, 118.8,
116.3, 58.9, 46.7.
IR (KBr): 3343, 2971, 1666, 1585, 1221, 750 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.83 (dd, J = 7.8, 1.2 Hz, 1 H), 7.38–7.31
(m, 5 H), 6.78 (t, J = 7.2 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 4.69 (dd, J =
13.8, 4.2 Hz, 1 H), 4.54 (s, 1 H, NH), 2.79 (dd, J = 16.8, 13.8 Hz, 1 H),
2.71 (dd, J = 16.8, 4.2 Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C19H15NO: 273.1154; found: 273.1151.
7-Methyl-2-phenyl-2,3-dihydroquinolin-4(1H)-one (3n)
13C NMR (150 MHz, CDCl3): δ = 192.8, 151.3, 139.5, 135.4, 134.1,
Yellow solid; yield: 201 mg (85%); mp 140–142 °C.
129.1, 127.9, 127.5, 119.0, 118.6, 115.9, 57.8, 46.3.
IR (ATR): 3337, 2840, 1609, 1464, 1302, 624 cm–1
.
HRMS (EI): m/z [M+] calcd for C15H12ClNO: 257.0607; found:
1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 8.1 Hz, 1 H), 7.42–7.29 (m, 5
H), 6.58 (d, J = 8.1 Hz, 1 H), 6.50 (s, 1 H), 4.67 (dd, J = 13.2, 3.9 Hz, 1 H),
4.42 (s, 1 H, NH), 2.79 (dd, J = 16.2, 15.0 Hz, 1 H), 2.71–2.64 (m, 1 H),
2.27 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.8, 151.6, 146.8, 141.1, 128.8, 128.2,
127.4, 126.5, 119.9, 116.8, 115.8, 58.3, 46.3, 21.8.
257.0605.
2-(4-Bromophenyl)-2,3-dihydroquinolin-4(1H)-one (3j)
Brown solid; yield: 244 mg (81%); mp 165–167 °C.
IR (KBr): 3324, 3053, 1654, 1492, 1325, 754 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.85 (dd, J = 7.8, 1.5 Hz, 1 H), 7.53–7.48
(m, 2 H), 7.36–7.30 (m, 3 H), 6.81–6.76 (m, 1 H), 6.70 (d, J = 8.2 Hz, 1
H), 4.71 (dd, J = 17.4, 4.8 Hz, 1 H), 4.44 (s, 1 H, NH), 2.87–2.77 (m, 1 H),
2.77–2.70 (m, 1 H).
.
HRMS (EI): m/z [M+] calcd for C16H15NO: 237.1154; found: 237.1152.
8-Methoxy-2-phenyl-2,3-dihydroquinolin-4(1H)-one (3o)
13C NMR (75 MHz, CDCl3): δ = 192.9, 151.5, 140.3, 135.6, 132.3, 128.5,
Yellow solid; yield: 195 mg (77%); mp 151–153 °C.
IR (ATR): 3373, 2924, 1674, 1486, 1231, 1030, 616 cm–1
.
127.7, 122.4, 119.2, 118.8, 116.1, 58.1, 46.5.
HRMS (EI): m/z [M+] calcd for C15H12BrNO: 301.0102; found:
301.0102.
1H NMR (600 MHz, CDCl3): δ = 7.49–7.46 (m, 3 H), 7.39 (t, J = 6.6 Hz, 2
H), 7.34 (t, J = 6.0 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.70 (t, J = 7.2 Hz, 1
H), 5.07 (s, 1 H, NH), 4.71 (dd, J = 13.8, 4.2 Hz, 1 H), 3.84 (s, 3 H), 2.88
(dd, J = 16.2, 14.4 Hz, 1 H), 2.76 (dd, J = 16.2, 3.6 Hz, 1 H).
2-(4-Nitrophenyl)-2,3-dihydroquinolin-4(1H)-one (3k)
13C NMR (150 MHz, CDCl3): δ = 193.2, 147.0, 142.6, 141.1, 128.9,
Pale yellow solid; yield: 214 mg (80%); mp 198–200 °C.
IR (KBr): 3357, 2911, 1670, 1466, 1187, 761 cm–1
.
128.3, 126.6, 118.9, 118.7, 116.9, 113.8, 58.4, 55.6, 46.3.
HRMS (EI): m/z [M+] calcd for C16H15NO2: 253.1103; found: 253.1103.
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6-Chloro-2-phenyl-2,3-dihydroquinolin-4(1H)-one (3p)
Control Experiment for the Formation of 4a
Yellow solid; yield: 236 mg (92%); mp 155–157 °C.
IR (ATR): 3336, 1657, 1490, 1197, 701, 612, 490 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 1.8 Hz, 1 H), 7.35–7.25 (m, 5
H), 7.17 (dd, J = 8.7, 1.8 Hz, 1 H), 6.57 (d, J = 8.7 Hz, 1 H), 4.63 (dd, J =
13.2, 4.5 Hz, 1 H), 4.48 (s, 1 H, NH), 2.76 (dd, J = 16.5, 13.2 Hz, 1 H),
2.67 (dd, J = 16.2, 4.5 Hz, 1 H).
AgOTf (26 mg, 10 mol%) was added to a solution of o-aminoacetophe-
none (1a; 135 mg, 1.0 mmol) and benzaldehyde (2a; 127 mg, 1.2
mmol) in MeOH (5 mL) at r.t. The reaction mixture was stirred under
reflux for 3 h only. The excess solvent was removed under reduced
pressure and the residue was purified by silica gel gradient column
chromatography (hexanes–EtOAc, 20:1–5:1) to yield 1a (104 mg, 77%,
recovered), 3a (17 mg, 8%), and 4a (31 mg, 13%).
.
13C NMR (75 MHz, CDCl3): δ = 192.1, 149.8, 140.5, 135.2, 129.0, 128.6,
126.5, 123.7, 119.6, 117.4, 58.3, 45.9.
HRMS (EI): m/z [M+] calcd for C15H12ClNO: 257.0607; found:
257.0605.
1-(2-Aminophenyl)-3-hydroxy-3-phenylpropan-1-one (4a)
Yellow liquid; yield: 31 mg (13%).
IR (ATR): 3471, 3349, 1755, 1619, 1210, 754 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.63 (d, J = 7.8 Hz, 1 H), 7.42 (d, J = 7.8
Hz, 2 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.29–7.24 (m, 2 H), 6.64 (d, J = 8.4 Hz,
1 H), 6.59 (t, J = 7.2 Hz, 1 H), 6.29 (s, 2 H, NH2), 5.29 (dd, J = 9.6, 3.0 Hz,
1 H), 3.73 (s, 1 H, OH), 3.34 (dd, J = 17.4, 3.0 Hz, 1 H), 3.29 (dd, J = 18.0,
9.6 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 202.0, 150.6, 143.1, 134.8, 131.1,
128.5, 127.5, 125.8, 117.6, 117.4, 115.9, 70.3, 47.6.
6-Bromo-2-phenyl-2,3-dihydroquinolin-4(1H)-one (3q)
Yellow solid; yield: 272 mg (90%); mp 165–167 °C.
IR (ATR): 3333, 3045, 1656, 1493, 1285, 595 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 2.1 Hz, 1 H), 7.42–7.33 (m, 6
H), 6.60 (d, J = 8.7 Hz, 1 H), 4.70 (dd, J = 12.9, 4.5 Hz, 1 H), 4.59 (s, 1 H,
NH), 2.83 (dd, J = 16.5, 13.5 Hz, 1 H), 2.73 (dd, J = 16.2, 4.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 191.9, 150.2, 140.4, 137.9, 129.9, 129.0,
HRMS (EI): m/z [M+] calcd for C15H15NO2: 241.1103; found: 241.1105.
128.6, 126.5, 120.1, 117.7, 110.6, 58.2, 45.8.
HRMS (EI): m/z [M+] calcd for C15H12BrNO: 301.0102; found:
Control Experiment for the Conversion of 4a into 3a
301.0100.
AgOTf (7 mg, 10 mol%) was added to a solution of 1-(2-aminophe-
nyl)-3-hydroxy-3-phenylpropan-1-one (4a; 60 mg, 0.25 mmol) in
MeOH (5 mL), and the mixture was stirred under reflux for 20 h. The
excess solvent was removed under reduced pressure and the residue
was purified by column chromatography (hexanes–EtOAc, 10:1) to af-
ford 3a (51 mg, 91%).
2-(1-Methyl-1H-pyrrol-2-yl)-2,3-dihydroquinolin-4(1H)-one (6)
Off-white solid; yield: 180 mg (80%); mp 160–162 °C.
IR (KBr): 3325, 1646, 1488, 1320, 733 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.84 (dd, J = 8.1, 1.2 Hz, 1 H), 7.31 (dt,
J = 8.4, 1.5 Hz, 1 H), 6.76 (t, J = 7.5 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H),
6.59 (s, 1 H), 6.20–6.19 (m, 1 H), 6.11–6.09 (m, 1 H), 4.80 (dd, J = 13.2,
3.9 Hz, 1 H), 4.58 (s, 1 H, NH), 3.64 (s, 3 H), 2.95–2.73 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 193.2, 151.2, 135.2, 131.3, 127.5, 123.2,
118.9, 118.3, 115.8, 107.2, 107.0, 50.3, 44.5, 34.0.
HRMS (EI): m/z [M+] calcd for C14H14N2O: 226.1106; found: 226.1105.
.
Antioxidant Activity Test
FRAP assays were performed as described by Benzie and Strain,30 and
were carried out using an Optizen 3220 UV spectrophotometer. Ex-
periments were conducted at 37 °C under low pH (3.6) with a blank
sample in parallel. At low pH, a complex of Fe3+–TPTZ (2,4,6-tripyr-
idyl-s-triazine) is reduced to the Fe2+–TPTZ form, with development
of an intense blue color at a wavelength maximum of 593 nm. The
FRAP working reagent was freshly prepared by mixing 300 mM ace-
tate buffer (pH 3.6), 10 mM TPTZ in 40 mM HCl, and 20 mM FeCl3·H2O
in the ratio of 10:1:1. For each assay, FRAP reagent (2.9 mL) and syn-
thetic compound in MeOH (1 mg/mL, 100 μL) were mixed. Absor-
bance of the reaction (incubated at 37 °C) was measured at 593 nm
after 30 min. The standard curve was linear between 125 and 2000
μM Trolox. All results are expressed in terms of TEAC (μM). In order to
calculate the EC50 value, the synthesized compound in MeOH was fur-
ther diluted and tested in the FRAP assay to establish 50% inhibition.
The EC50 value was calculated by the graph method. Data were ana-
lyzed statistically by using OriginPro 8.1 software (OriginLab,
Northampton, MA, USA).
2-(Furan-2-yl)-2,3-dihydroquinolin-4(1H)-one (7)
Brown solid; yield: 181 mg (85%); mp 95–97 °C.
IR (KBr): 3341, 1657, 1609, 1503, 1305, 1114, 767 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 8.1 Hz, 1 H), 7.35–7.27 (m, 2
H), 6.74 (t, J = 7.8 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 6.31–6.29 (m, 1 H),
6.23 (d, J = 2.7 Hz, 1 H), 4.79 (dd, J = 9.3, 5.8 Hz, 1 H), 4.74 (s, 1 H, NH),
3.02–2.87 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 192.5, 153.0, 150.4, 142.4, 135.3, 127.3,
119.1, 118.5, 115.9, 110.3, 106.7, 50.7, 41.9.
HRMS (EI): m/z [M+] calcd for C13H11NO2: 213.0790; found: 213.0790.
.
2-(Thiophen-2-yl)-2,3-dihydroquinolin-4(1H)-one (8)
Brown solid; yield: 203 mg (89%); mp 135–136 °C.
Acknowledgment
IR (KBr): 3343, 2985, 1659, 1577, 1313, 1225 cm–1
.
This research was supported by the Nano Material Technology Devel-
opment Program of the Korean National Research Foundation (NRF)
funded by the Korean Ministry of Education, Science, and Technology
(Grant no. 2012-049675). This work was also supported by the Kore-
an National Research Foundation (NRF) grant funded by the Korean
government (MSIP) (NRF-2014R1A2A1A11052391) and Priority Re-
search Centers Program (2014R1A6A1031189).
1H NMR (300 MHz, CDCl3): δ = 7.87 (dd, J = 8.1, 1.2 Hz, 1 H), 7.38–7.33
(m, 1 H), 7.28 (d, J = 5.1 Hz, 1 H), 7.07 (d, J = 3.0 Hz, 1 H), 7.01–6.98 (m,
1 H), 6.81 (t, J = 7.8 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 5.03 (dd, J = 10.5,
6.0 Hz, 1 H), 4.77 (s, 1 H, NH), 2.99–2.86 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 192.5, 150.7, 144.4, 135.3, 127.4, 126.7,
125.0, 124.9, 119.1, 118.6, 115.9, 53.5, 46.8.
HRMS (EI): m/z [M+] calcd for C13H11NOS: 229.0561; found: 229.0560.
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Synthesis
Supporting Information
(16) Muthkrishnan, M.; Mujahid, M.; Punitharasu, V.; Dnyaneshwar,
D. A. Synth. Commun. 2010, 40, 1391.
(17) Kumar, D.; Patel, G.; Mishra, B. G.; Varma, R. S. Tetrahedron Lett.
2008, 49, 6974.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560322.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3881–3890