4-Aryl-2-quinolones from 3,3-diarylacrylamides through intramolecular copper-catalyzed C-H functionalization/C-N bond formation

Article abstract of DOI:10.1021/jo202427m

Free NH 3,3-diarylacrylamides are cyclized to substituted 2-quinolones in the presence of CuI, PPh₃, and KO-t-Bu in o-xylene at 100 °C. The reaction proceeds through a C-H functionalization/C-N bond formation process. With unsymmetrical 3,3-diarylacrylamides, high selectivity is observed using substrates where the aromatic ring trans to the amide group bears o-methyl, -chloro, or -bromo substituents.

Full text of DOI:10.1021/jo202427m

Note
pubs.acs.org/joc
4-Aryl-2-quinolones from 3,3-Diarylacrylamides through
Intramolecular Copper-Catalyzed C−H Functionalization/C−N Bond
Formation
Roberta Berrino, Sandro Cacchi,* Giancarlo Fabrizi, and Antonella Goggiamani
̀
Dipartimento di Chimica e Tecnologie del Farmaco, La Sapienza, Universita di Roma, P. le A. Moro 5, 00185 Rome, Italy
S
* Supporting Information
ABSTRACT: Free NH 3,3-diarylacrylamides are cyclized to substituted 2-quinolones in the presence of CuI, PPh3, and KO-t-Bu
in o-xylene at 100 °C. The reaction proceeds through a C−H functionalization/C−N bond formation process. With
unsymmetrical 3,3-diarylacrylamides, high selectivity is observed using substrates where the aromatic ring trans to the amide
group bears o-methyl, -chloro, or -bromo substituents.
n recent years, direct transition-metal-catalyzed functional-
ization reactions of (hetero)arenes through the activation of
2-Quinolone subunits are prevalent in a vast array of
biologically active compounds.24−26 The 4-aryl-2-quinolone
derivative tipifarnib exhibits anticancer activity.27 Furthermore,
2-quinolones are useful synthetic intermediates.28 Conse-
quently, several methods for the construction of the 2-
quinolone ring have been developed.29 However, relatively
few of them are based on transition-metal catalysis and
palladium catalysis plays a major role.30−34 To the best of
our knowledge, only one example of a copper-catalyzed
approach to this class of compounds was described.35 In that
case, the 2-quinolone scaffold was prepared via cyclization of
acrylamides bearing a β-aryl group containing an ortho bromo
substituent, a process requiring a preactivated arene that can
react selectively with the metal catalyst. Thus, the development
of new transition-metal-catalyzed procedures is a subject of
great interest, particularly when they do not need wasteful
preactivation steps, are based on simple protocols, inexpensive
catalyst systems, and readily available starting materials.
I
inert C−H bonds, for the most part involving palladium-,
rhodium-, and ruthenium-based catalysts, has been intensively
investigated.1−3 Several reports have shown the potential of this
chemistry as an attractive, greener alternative to the more
commonly employed cross-coupling reactions using preacti-
vated (hetero)arenes (usually halo derivatives). More recently,
because of the economic advantages and good functional
tolerance of copper-catalyzed methods, several groups have
dedicated a growing attention to the use of copper catalysis4,5
in the formation of C−C,6−12 C−N,13−20 C−O,21−23 and C−
Cl21 bonds via catalytic functionalization of (hetero)aryl C−H
bonds.
Herein we report on a new synthesis of 4-aryl-2-quinolones
from free NH 3,3-diarylacrylamides that involves an intra-
molecular copper-catalyzed aryl C−H functionalization through
C−N bond formation (Scheme 1).
The starting 3,3-diarylacrylamides 1 were prepared via Heck
reaction of cinnamylamides with aryl iodides35 or hydro-
arylation of 3-arylpropiolamides with aryl iodides.36
We started our study by examining the conversion of 3,3-
diphenylacrylamide 1a (R1 = R2 = H) into the corresponding
quinolone 2a. Cyclization reactions were typically carried out
under an atmosphere of air. After an initial screen of copper-
based catalysts [CuI/L-proline,37 Cu(OTf)2, Cu(OAc)2/PPh3,
CuNO3(PPh3)2, CuNO3(1,10-phenanthroline)(PPh3)2,38 CuI/
Scheme 1. Copper-Catalyzed Construction of the 2-
Quinolone Ring from 3,3-Diarylacrylamides
Received: December 13, 2011
Published: January 24, 2012
© 2012 American Chemical Society
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Note
1,10-phenanthroline, CuI/pyridine], solvents (DMF, toluene,
xylene), bases (KO-t-Bu, K2CO3, Na2CO3, Cs2CO3, NaH), and
reaction temperatures (100−140 °C), we found that 2a could
be isolated in 75% yield by using 0.1 equiv of recrystallized
CuI39 and 0.2 equiv of PPh3 in the presence of 2 equiv of KO-t-
Bu in o-xylene at 100 °C after 5 h under aerobic conditions.
Benzophenone was isolated in 8% yield. Most probably, its
formation involves a copper-catalyzed oxidative cleavage of the
carbon−carbon double bond,40 a reaction that is favored by
molecular oxygen. Accordingly, 2a and benzophenone were
isolated in 50 and 20% yield, respectively, when 1a was
subjected to CuI under the above-mentioned conditions for 24
h under a balloon of molecular oxygen. To prevent this side
reaction, we then attempted the cyclization under an
atmosphere of nitrogen. However, 2a was isolated only in
15% yield, and the starting material was recovered in 61% yield.
These results imply that an excess of oxygen is detrimental to
the reaction increasing the amount of benzophenone. Never-
theless, oxygen is needed to get the best results, most probably
acting in reoxidation steps that involve the copper catalyst.
Therefore, when the method was extended to the
preparation of other quinolone derivatives, we decided to
carry out the reactions under an atmosphere of air, the simplest
way to reach a satisfactory concentration of oxygen.
Table 1. Copper-Catalyzed Synthesis of 4-Arylquinolones
from Symmetrical 3,3-Diarylacrylamides
a
As shown in Table 1, moderate to high yields of the desired
products were obtained from symmetrical 3,3-diarylacrylamides
(R1 = R2) bearing neutral, electron-rich, and moderately
electron-poor aromatic rings. No evidence of 2-quinolone
formation was obtained in the presence of strongly electron-
withdrawing groups (Table 1, entry 9), suggesting that the
nucleophilicity of the aromatic ring plays a key role in the
cyclization event. Accordingly, an acrylamide containing
appropriately protected ketone groups on the 3-aryl rings
gave the desired product in good yield (Table 1, entry 10). The
presence of substituents at both meta positions of the aromatic
fragment does not hamper the reaction (Table 1, entry 6).
When there is only one meta substituent, the cyclization affords
regioisomeric derivatives (Table 1, entry 3).
We next explored the cyclization of unsymmetrical 3,3-
diarylacrylamides (R1 ≠ R2). Rather disappointingly, both the
substrates 1k and its diastereoisomer 1k′, selected as model
systems, afforded mixtures of isomeric quinolones (Scheme 2).
Compound 1k gave an almost equimolar amount of 2k and 3k
in high overall yield, whereas a high selectivity was observed
with 1k′ but 2k and 3k were isolated in low overall yield. The
low overall yield of the isomeric quinolones in the cyclization of
1k′ is due to its the strong tendency (higher than that of 1k) to
undergo the oxidative cleavage of the carbon−carbon double
bond. The substrate 1k afforded a 18% yield of the
corresponding benzophenone whereas the latter was isolated
in 45% yield starting from 1k′. The reasons for this behavior are
unclear at the moment.
A couple of considerations can be drawn from these results.
The first one is that an E/Z isomerization of the starting
acrylamides is likely to take place under the reaction conditions.
This notion is supported by the recovery of the starting
material 1k′ and its diastereoisomer 1k in 13% overall yield as
an approximately 87:13 1k′/1k mixture when the cyclization of
1k′ was attempted. Control experiments revealed that the
isomerization is due to the presence of KO-t-Bu. Indeed, an
approximately 85:15 1k′/1k mixture is formed upon treatment
of 1k′ with KO-t-Bu in o-xylene omitting CuI and PPh3 after 24
h at 100 °C. No isomerization was observed when 1k′ was
a
Unless otherwise stated, reactions were carried out under an
atmosphere of air on a 0.45 mmol scale at 100 °C using 0.1 equiv
of recrystallized CuI, 0.2 equiv of PPh3, and 2 equiv of KO-t-Bu in 3
mL of o-xylene. Yields are given for isolated products.
b
subjected to CuI and PPh3 in xylene at 100 °C for 24 h in the
absence of KO-t-Bu.
The second one is that the ratio between the isomeric
quinolone products appears to depend on a subtle balance
between the equilibration and the cyclization rate, the latter in
turn depending on the nature of the substituents on the
aromatic rings. With 1k′, the cyclization reaction is faster than
the equilibration reaction. As a consequence, a good 3k:2k ratio
is observed. In the cyclization of 1k, the lower reactivity (as
compared to that of the phenyl ring) of the aromatic ring
bearing a methoxy group meta to the carbon involved in the
copper-catalyzed C−N bond formation makes it the cyclization
rate comparable to (or lower than) the equilibration rate and
the isomeric quinolones are obtained in an approximately 1:1
ratio.
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Note
carbon−carbon double bond as the amide group) in an overall
18% yield as an approximately 91:9 mixture.
Scheme 2. Copper-Catalyzed Cyclization of Unsymmetrical
3,3-Diarylacrylamides 1k and 1k′
Control experiments revealed that treatment of 1m with KO-
t-Bu in o-xylene omitting CuI and PPh3 affords an
approximately 93:7 1m/1m′ mixture after 24 h at 100 °C
whereas an approximately 94:6 1m′/1m mixture is obtained
from its diastereoisomer 1m′ under the same conditions. These
data support the notion that with ortho substituted 3,3-
diarylacrylamides the composition of the quinolone mixture is
mostly dependent on a relatively high energy barrier for the E/
Z isomerization.
Building on the reactivity of 1mwith the idea of exploiting
the effect of ortho substituents to develop a highly selective
synthesis and, at the same time, providing a route to quinolones
that might allow for increasing their molecular complexity via
transition-metal-catalyzed coupling reactionswe explored the
use of substrates bearing 3-(o-chlorophenyl)- and 3-(o-
bromophenyl)- substituents trans to the amide group. To our
delight, these substrates underwent selectively the cyclization to
the corresponding quinolones in acceptable to high yields
(Table 2, entries 2−7). The cyclization of 1q (Table 2, entry 7)
is of particular interest in that the contemporary presence of
chloro and bromo substituents in the quinolone product may
pave the way to selective double functionalizations (C−Cl and
C−Br bonds show different reactivity in oxidative additions to
transition metals).
On the basis of the above results and literature precedent of
related processes,10,13,18 a possible rationale for the copper-
catalyzed synthesis of 2-quinolones from 3,3-diarylacrylamides
is outlined in Scheme 3.42 The reaction of the acrylamide 1
with the copper salt under basic conditions (pathway a) is
expected to afford the intermediate A that is converted to B
upon oxidation. A subsequent intramolecular electrophilic
attack to the aromatic ring produces C. Base-promoted
rearomatization generates D from which the quinolone product
2 is formed via reductive elimination with the catalyst
regenerated by oxidation.43,44 Alternatively (pathway b),
oxidation of Cu(I) to Cu(II) can take place. The reaction of
1 with Cu(II) under basic conditions affords B.
On the basis of these results, we hypothesized that slowing
down the equilibration rate by an appropriate choice of the
substituents at the aromatic rings might produce a highly
selective cyclization process. Further investigations on the
reactivity of unsymmetrical substrates revealed that such a
selective cyclization process could be achieved by taking
advantage of the steric effects41 of the substituents on the
aromatic rings.
In particular, the substrate 1m, a 3,3-diarylacrylamide
containing an o-methyl group on the aromatic ring trans to
the amide group, was found to possess a strong tendency to
preserve its configuration under the reaction conditions.
Indeed, the quinolone product was obtained in acceptable
yield and high 2m/3m ratio when the cyclization of 1m was
attempted (Table 2, entry 1). The starting acrylamide was
recovered along with its diastereoisomer 1m′ (containing the
ortho substituted aromatic ring on the same side of the
a
Table 2. Copper-Catalyzed Cyclization of Unsymmetrical 3,3-Diarylacrylamides
3,3-diarylacrylamide 1
b
c
entry
R1
4-F
R2
overall yield (%)
2/3 ratio
1
2
3
4
5
6
7
2-Me
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Br
1m
1n
1o
1p
1q
1r
50
75
63
61
43
41
53
2m/3m = 96:4
2n/3n = 92:8
2o/3o > 99:1
2p/3p = 97:3
2q/3q > 99:1
2r/3r > 99:1
2s/3s > 99:1
H
4-MeO
4-Me
4-Br
4-F
4-Me
1s
a
Unless otherwise stated, reactions were carried out under an atmosphere of air on a 0.45 mmol scale at 100 °C for 24 h using 0.1 equiv of
b
c
recrystallized CuI, 0.2 equiv of PPh3, and 2 equiv of KO-t-Bu in 3 mL of o-xylene. Yields are given for isolated products. Molar ratios were
determined by NMR analysis.
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Typical Procedure for the Preparation of Unsymmetrical
3,3-Diarylacrylamides: (Z)-3-(4-Methoxyphenyl)-3-phenylacry-
lamide (1k). 3-(4-Methoxyphenyl)propiolamide (175.2 mg, 1 mmol),
iodobenzene (0.22 mL, 2 mmol), and Pd2(dba)3 (22.9 mg, 0.025
mmol) were dissolved in AcOEt (50 mL). Et2NH (0.31 mL, 3 mmol)
was added, followed by HCO2H (0.08 mL, 2 mmol), and the solution
was heated to reflux until reaction completion. The reaction mixture
was then cooled to room temperature and washed with HCl 2 N, a
saturated NaHCO3 solution, and finally brine. The organic layer was
separated, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography (silica gel; 20/
80 v/v n-hexane/AcOEt) to give 177.1 mg (70% yield) of 1k: yellow
solid; mp 164−166 °C; IR (KBr) 3234, 1680, 1597, 1422, 1164, 1082
cm−1; 1H NMR (CDCl3) δ 7.36−7.24 (m, 7H), 6.98 (m, J = 8.4 Hz, 2
H), 6.34 (s, 1 H), 5.41 (br s, 1 H), 5.17 (br s, 1 H), 3.88 (s, 3 H); 13C
NMR (CDCl3) δ 168.6, 151.2, 140.7, 138.6, 135.2, 129.6, 129.2, 128.4,
128.0, 121.6, 55.5. Anal. Calcd for C16H15 NO2: C, 75.87; H, 5.97 97.
Found: C, 76.09; H, 5.96.
Scheme 3. Proposed Mechanism
Typical Procedure for the Preparation of 2: 4-Phenyl-
quinolin-2(1H)-one (2a). To a stirred solution of CuI (8.6 mg,
0.05 mmol) and PPh3 (23.6 mg, 0.09 mmol) in 1.0 mL of anhydrous
o-xylene were added 3,3-diarylacrylamide 1a (99.5 mg, 0.45 mmol)
and KO-t-Bu (101.0 mg, 0.90 mmol) at room temperature with 2.0
mL of the solvent. Then the mixture was stirred for 24 h at 100 °C.
After this time, the reaction mixture was cooled to room temperature,
diluted with AcOEt, and washed with brine. The organic layer was
separated, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography (silica gel, n-
hexane/AcOEt 15/85 v/v) to afford 66.3 mg (75% yield) of 2a: white
solid; mp 262−264 °C (lit.33 mp 259−260 °C); IR (KBr) 2954, 1654
cm−1; 1H NMR (DMSO-d6) δ 11.91 (br s, 1 H), 7.56−7.47 (m, 6 H),
7.42−7.37 (m, 2 H), 7.17−7.13 (m, 1 H), 6.40 (s, 1 H); 13C NMR
(DMSO-d6) δ 161.8, 151.9, 139.8, 137.2, 131.0, 129.2, 129.16, 129.14,
126.6, 122.3, 121.7, 118.8, 116.3. Anal. Calcd for C15H11 NO: C,
81.43; H, 5.01. Found: C, 81.52; H, 4.99.
In summary, we have developed a novel copper-catalyzed
approach for the construction of the 2-quinolone ring from free
NH 3,3-diarylacrylamides that is based on an intramolecular
C−H functionalization/C−N bond forming process. With
unsymmetrical 3,3-diarylacrylamides high selectivity is observed
using substrates where the aromatic ring trans to the amide
group bears o-methyl, -chloro, or -bromo substituents. Our
procedure is simple, uses readily available starting materials and
an inexpensive catalyst system. Although moderate yields are
obtained in some cases, it can be a useful complement to
commonly used strategies.
7-Methyl-4-p-tolylquinolin-2(1H)-one (2b): yellow solid; mp
1
193−195 °C; IR (KBr) 3450, 1655 cm−1. H NMR (DMSO-d6) δ
11.76 (br s, 1 H); 7.35 (s, 4 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1
H), 6.97 (d, J = 8.0 Hz, 1 H), 6.29 (s, 1 H), 2.40 (s, 3 H), 2.38 (s, 3
H); 13C NMR (DMSO-d6) δ 162.0, 151.9, 141.1, 139.9, 138.7, 134.4,
129.7, 128.9, 126.5, 123.7, 120.3, 116.8, 115.9, 21.6, 21.3. Anal. Calcd
for C17H15NO: C, 81.90; H, 6.06. Found: C, 81.87; H, 6.07.
8-Methyl-4-m-tolylquinolin-2(1H)-one (2c) and 6-Methyl-4-
m-tolylquinolin-2(1H)-one (2c′). The two regioisomeric quinolones
were obtained in a 70:30 molar ratio. The ratio of two isomers was
determined by 1H NMR; they were separated by semipreparative
HPLC. 2c: yellow solid; mp 204−207 °C; IR (KBr) 2983, 1656 cm−1;
1H NMR (DMSO-d6) δ 10.95 (br s, 1 H), 7.44−7.38 (m, 2 H), 7.32
EXPERIMENTAL SECTION
■
Melting points are uncorrected. All of the reagents, catalysts, and
solvents are commercially available and were used as purchased,
without further purification. CuI used in the general procedure was
recrystallized according to literature.39 Reaction products were purified
by flash column chromatography using SiO2 25−40 μm and eluting
with n-hexane/ethyl acetate/methanol mixtures. 1H NMR and 13C
NMR spectra were recorded at 400 and 100.6 MHz, respectively.
Typical Procedure for the Preparation of Symmetrical 3,3-
Diarylacrylamides: 3,3-Diphenylacrylamide (1a). To a stirred
solution of acrylamide (1.0 g, 13.9 mmol) in MeCN (10.0 mL),
iodobenzene (1.71 mL, 15.3 mmol), and Et3N (5.79 mL, 41.7 mmol)
was added Hermann’s catalyst (130.2 mg, 0.139 mmol). The reaction
mixture was stirred overnight at 100 °C. After this time, the reaction
mixture was cooled, diluted with EtOAc, and washed with HCl 2 N, a
saturated NaHCO3 solution, and finally brine. The organic layer was
separated, dried over Na2SO4, and concentrated under reduced
pressure. The residue was dissolved in Et3N (10 mL), iodobenzene
(2.33 mL, 20.86 mmol) and Pd(OAc)2 (156.0 mg, 0.695 mmol) were
added, and the resulting reaction mixture was stirred overnight at 100
°C. After this time, the reaction mixture was cooled, diluted with
EtOAc, and washed with HCl 2 N, a saturated NaHCO3 solution, and
finally brine. The organic layer was separated, dried over Na2SO4, and
concentrated under reduced pressure. The crude was purified by
chromatography (silica gel, 40/60 v/v n-hexane/AcOEt) to give 2.67 g
(86% yield) of 1a: white solid; mp 147−151 °C (lit.39 mp 150−153
(d, J = 7.6 Hz, 1 H), 7.26−7.21 (m, 3 H) 7.05 (t, J = 7.6 Hz, 1 H), 6.38
(s, 1 H), 2.48 (s, 3 H), 2.39 (s, 3 H); 13C NMR (DMSO-d6) δ 162.1,
152.6, 138.4, 138.0, 137.5, 132.3, 129.8, 129.6, 128.9, 126.2, 124.8,
124.4, 121.9, 121.3, 119.1, 21.4, 17.9. Anal. Calcd for C17H15NO, C,
81.90; H, 6.06. Found: C, 81.93; H, 6.07. 2c′: yellow solid; mp 212−
1
215 °C; IR (KBr) 2986, 1565 cm−1; H NMR (400 MHz) (DMSO-
d6) δ 11.78 (br s, 1 H); 7.45−7.41 (m, 1 H), 7.37−7.21 (m, 6 H), 6.33
(s, 1 H), 2.40 (s, 3 H), 2.26 (s, 3 H); 13C NMR (100.6 MHz)
(DMSO-d6) δ 161.6, 151.9, 138.5, 137.8, 137.3, 132.2, 131.2, 129.8,
129.6, 128.9, 126.2, 126.1, 121.6, 118.8, 116.2, 21.5, 21.1. Anal. Calcd
for C17H15NO: C, 81.90; H, 6.06. Found: C, 81.87; H, 6.07.
7-tert-Butyl-4-(4-tert-butylphenyl)quinolin-2(1H)-one (2d):
yellow solid; mp 289−291 °C; IR (KBr) 2962, 1656, 1621 cm−1;
1H NMR (CDCl3) δ 12.57 (br s, 1 H), 7.59−7.44 (m, 6 H), 7.26−7.23
(m, 1 H), 6.71 (s, 1 H), 1.43 (s, 9 H), 1.40 (s, 9 H); 13C NMR
(CDCl3) δ 166.7, 154.5, 151.8, 139.0, 134.5, 128.6, 126.5, 125.5, 120.4,
117.5, 112.9, 35.0, 34.8, 31.4, 31.1. Anal. Calcd for C23H27NO: C,
82.84; H, 8.16. Found: C, 82.73; H, 8.17.
°C); IR (KBr) 3285, 1654, 1611 cm−1; H NMR (CDCl3) δ 7.46−
1
7.44 (m, 3H), 7.38−7.28 (m, 7 H), 6.41 (s, 1 H), 5.99 (br s, 1 H), 5.24
(br s, 1 H); 13C NMR (CDCl3) δ 168.5, 151.0, 140.5, 138.0, 129.2,
129.0, 128.8, 128.7, 128.3, 127.9, 121.7. Anal. Calcd for C15H13 NO: C,
80.69; H, 5.87. Found: C, 80.96; H, 5.85.
7-Methoxy-4-(4-methoxyphenyl)quinolin-2(1H)-one (2e):
white solid;39 mp 229−232 °C; IR (KBr) 3448, 1654, 1608, 1216
cm−1; 1H NMR (DMSO-d6) δ 11.68 (br s, 1 H), 7.41 (d, J = 8.8 Hz, 2
H), 7.35 (d, J = 9.2 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 2.0
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Note
1
Hz, 1 H), 6.77 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz 1 H), 3.83 (s, 3 H), 3.82
(s, 3 H); 13C NMR (DMSO-d6) δ 162.2, 161.5, 160.1, 151.6, 141.6,
130.4, 129.6, 128.1, 118.3, 114.6, 113.1, 110.1, 99.0, 55.8, 55.7. Anal.
Calcd for C17H15NO3: C, 72.58; H, 5.37. Found: C, 72.44; H, 5.38.
4-(3,5-Dimethylphenyl)-6,8-dimethylquinolin-2(1H)-one
1666 cm−1; H NMR (CDCl3) δ 13.02 (br s, 1 H), 7.61−7.53 (m, 3
H), 7−49−7−36 (m, 3 H), 7.20−7.14 (m, 2 H), 6.72 (s, 1 H); 13C
NMR (CDCl3) δ 164.2, 151.0, 138.6, 135.9, 132.9, 130.8, 130.7, 130.1,
129.9, 126.9, 126.5, 122.7, 121.7, 119.5, 116.7. Anal. Calcd for
C15H10ClNO: C, 70.46; H, 3.94. Found: C, 70.29; H, 3.96.
1
(2f): white solid; mp 235−239 °C; IR (KBr) 3565, 1655 cm−1; H
4-(2-Chlorophenyl)-7-methoxyquinolin-2(1H)-one (2o): yel-
low solid; mp 189−192 °C; IR (KBr) 3415, 2235, 1665 cm−1; H
1
NMR (CDCl3) δ 9.32 (br s, 1 H), 7.20 (d, J = 10.4 Hz, 2 H), 7.14 (s, 1
H), 7.05 (s, 1 H), 6.58 (s, 1 H), 2.51 (s, 3 H), 2.42 (s, 6 H), 2.32 (s, 3
H); 13C NMR (CDCl3) δ 162.8, 153.7, 138.1, 137.6, 135.2, 133.3,
131.3, 130.2, 126.6, 125.8, 124.8, 123.3, 119.7, 21.4, 17.1. Anal. Calcd
for C19H19NO: C, 82.28; H, 6.90. Found: C, 81.99; H, 6.92.
7-Chloro-4-(4-chlorophenyl)quinolin-2(1H)-one (2g): white
solid;33 mp 270−274 °C; IR (KBr) 3448, 1673 cm−1; 1H NMR
(DMSO-d6) δ 12.03 (br s, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.52 (d, J =
8.4 Hz, 2 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.20
(dd, J1 = 8.8 Hz, J2 = 2.2 Hz 1 H), 6.45 (s, 1H); 13C NMR (DMSO-
d6) δ 161.6, 150.2, 140.7, 135.6, 134.3, 131.07, 131.06, 129.3, 128.4,
122.5, 122.2, 117.6, 115.4. Anal. Calcd for C15H9Cl2NO: C, 62.09; H,
3.13. Found: C, 62.16; H, 3.11.
NMR (CDCl3) δ 12.59 (br s, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.49−
7.39 (m, 2 H), 7.34 (dd, J1 = 7.6, J2 = 1.2 Hz, 1 H), 7.06 (d, J = 8.8 Hz,
1 H), 6.94 (s, 1 H), 6.76 (dd, J1 = 8.8, J2 = 2.0 Hz, 1 H), 6.52 (s,1 H),
3.93 (s, 3H); 13C NMR (CDCl3) δ 162.0, 150.9, 140.3, 136.2, 132.8,
130.6, 129.9, 129.8, 127.9, 126.9, 118.5, 113.7, 112.6, 98.6, 55.7. Anal.
Calcd for C16H12ClNO2: C, 67.26; H, 4.23. Found: C, 67.32; H, 4.21.
4-(2-Chlorophenyl)-7-methylquinolin-2(1H)-one (2p) and 5-
Chloro-4-p-tolylquinolin-2-(1H)-one (3p). Obtained as a mixture
of two isomers. The ratio of two isomers was determined by 1H NMR
spectrum as 2p/3p = 97:3. Compound 2p could be separated from the
mixture by semipreparative HPLC: yellow solid; mp 210−212 °C; IR
(KBr) 3450, 1665, 1430 cm−1; H NMR (CDCl3) δ 12.89 (br s, 1H)
1
7.58−7.55 (m, 1 H), 7.48−7.40 (m, 2 H), 7.38−7.35 (m, 2 H), 7.06
(d, J = 8.0 Hz, 1 H), 6.98 (dd, J1 = 8.4, J2 = 1.2 Hz, 1 H), 6.65 (s, 1 H),
2.48 (s, 3 H); 13C NMR (CDCl3) δ 164.4, 150.9, 141.8, 138.7, 136.1,
132.9, 130.6, 130.0, 129.9, 126.9, 126.3, 124.4, 120.5, 117.4, 116.4,
21.6. Anal. Calcd for C16H12ClNO: C, 71.25; H, 4.48. Found: C,
71.22; H, 4.49.
7-Fluoro-4-(4-fluorophenyl)quinolin-2(1H)-one (2h): yellow
solid;39 mp 302−306 °C; IR (KBr) 2981, 1654 cm−1; 1H NMR
(CDCl3) δ 12.65 (br s, 1 H), 7.54−7.45 (m, 3 H), 7.27−7.22 (m, 3
H), 6.94 (ddt, J1 = 8.8 Hz, J2 = 2.4 Hz, J3 = 0.8 Hz, 1 H), 6.63 (s, 1 H);
13C NMR (CDCl3) δ 164.2, 164.1 (d, J = 250.6 Hz), 163.2 (d, J =
249.3 Hz), 152.1, 140.5 (d, J = 12.1 Hz), 132.9 (d, J = 3.3 Hz), 130.6
(d, J = 8.3 Hz), 128.9 (d, J = 10.2 Hz), 119.9 (d, J = 3.4 Hz), 116.3 (d,
J = 2.6 Hz), 115.9 (d, J = 21.7 Hz), 111.2 (d, J = 23.0 Hz), 102.7 (d, J
= 25.0 Hz); 19F NMR (376.5 MHz) δ −107.6, −112.1. Anal. Calcd for
C15H9F2NO: C, 70.04; H, 3.53. Found: C, 70.21; H, 3.52.
7-Bromo-4-(2-chlorophenyl)quinolin-2(1H)-one (2q): yellow
1
solid; mp 231−235 °C; IR (KBr) 3378, 2334, 1651 cm−1; H NMR
(CDCl3) δ 13.01 (br s, 1 H), 7.74 (s, 1 H), 7.57 (d, J = 7.6, 1 H),
7.49−7.42 (m, 2 H), 7.36 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1 H), 7.27 (dd,
J1 = 8.8 Hz, J2 = 1.2 Hz, 1 H) 7.034 (d, J = 8.8, 1 H), 6.67 (s, 1 H); 13
C
7-(2-Methyl-1,3-dioxolan-2-yl)-4-(2-methyl-1,3-dioxolan-2-
NMR (CDCl3) δ 164.2, 150.7, 139.3, 135.4, 132.8, 130.6, 130.3, 130.0,
127.9, 127.1, 126.2, 125.3, 119.19, 119.18, 118.4. Anal. Calcd for
C15H9BrClNO: C, 53.84; H, 2.71. Found: C, 53.76; H, 2.72.
4-(2-Chlorophenyl)-7-fluoroquinolin-2(1H)-one (2r): yellow
solid; mp 253−255 °C; IR (neat) 3399, 1594 cm−1; 1H NMR
(DMSO-d6) δ 12.04 (br s, 1 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.57−7.44
(m, 3 H), 7.14 (d, J = 10.0, 1 H), 6.98 (d, J = 6.8, 2 H), 6.37 (s, 1 H);
13C NMR (DMSO-d6) δ 163.6 (d, J = 247.5 Hz), 161.9, 149.2, 140.9
(d, J = 12.4 Hz), 135.6, 132.0, 131.3, 131.2, 130.1, 129.0 (d, J = 10.5
Hz), 128.1, 121.6 (d, J = 2.3 Hz), 115.9 (d, J = 1.9 Hz), 110,7 (d, J =
23.4 Hz), 102.0 (d, J = 25.6 Hz); 19F NMR (376.5 MHz) δ −108.8.
Anal. Calcd for C15H9ClFNO: C, 65.83; H, 3.31. Found: C, 65.79; H,
3.32.
yl)phenyl)quinolin-2(1H)-one (2j): white solid; mp 272−275 °C;
1
IR (neat) 2985, 1654, 1124, 1038 cm−1; H NMR (CDCl3) δ 11.80
(br s, 1 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 2H), 7.47 (d,
J = 8.0 Hz, 2 H), 7.30 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz 1 H), 6.69 (s, 1 H),
4.17−4.05 (m, 4 H), 3.95−3.79 (m, 4 H), 1.76 (s, 3 H), 1.71 (s, 3 H);
13C NMR (CDCl3) δ 163.6, 152.8, 146.7, 144.2, 138.8, 136.6, 128.7,
127.0, 125.6, 119.9, 119.1, 113.0, 108.7, 108.4, 64.7, 27.6, 27.5. Anal.
Calcd for C23H23NO5: C, 70.21; H, 5.89. Found: C, 70.34; H, 5.87.
7-Methoxy-4-phenylquinolin-2(1H)-one (2k): yellow solid;39
1
mp 234−237 °C; IR (KBr) 2910, 1654, 1610, 1220 cm−1; H NMR
(DMSO-d6) δ 11.75 (br s, 1H), 7.54−7.51 (m, 3 H), 7.46−7−44 (m,
2 H), 7.28 (d, J = 9.2 Hz, 1 H), 6.91 (d, J = 2.8 Hz, 1 H), 6.77 (dd, J1 =
9.2, J2 = 2.8 Hz, 1 H), 6.22 (s, 1 H), 3.82 (s, 3 H); 13C NMR (DMSO-
d6) δ 162.2, 161.5, 151.9, 141.6, 137.5, 129.2, 129.1, 129.0, 128.1,
118.5, 112.9, 111.2, 98.9, 55.9. Anal. Calcd for C16H13NO2: C, 76.48;
H, 5.21. Found: C, 76,40; H, 5.23.
4-(2-Bromophenyl)-7-methylquinolin-2(1H)-one (2s): white
1
solid; mp 228−231 °C; IR (KBr) 3440, 1564, 1450 cm−1; H NMR
(CDCl3) δ 12.81 (br s, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.49−7.46 (m,
1 H), 7.37−7.33 (m, 3 H), 7.026 (m, 2 H), 6.63 (s, 1 H), 2.48 (s, 3
H); 13C NMR (CDCl3) δ 164.3, 152.4, 141.8, 138.7, 138.2, 133.1,
130.6, 130.1, 127.5, 126.4, 124.4, 122.5, 120.4, 117.4, 116.4, 21.6. Anal.
Calcd for C16H12BrNO: C, 61.17; H, 3.85. Found: C, 61.22; H, 3.84.
4-(4-Methoxyphenyl)quinolin-2(1H)-one (3k): yellow solid;39
1
mp 228−231 °C IR (KBr) 2910, 1654, 1610, 1220 cm−1; H NMR
(DMSO-d6) δ 11.84 (br s, 1H), 7.55−7.51 (m, 1 H), 7.46−7−39 (m,
4 H), 7.17−7.10 (m, 3 H), 6.37 (d, 1 H), 3.84 (s, 3 H); 13C NMR
(DMSO-d6) δ 161.9, 160.1, 151.7, 139.8, 130.9, 130.5, 129.3, 126.7,
122.2, 121.4, 119.0, 116.2, 114.6, 55.7. Anal. Calcd for C16H13NO2: C,
76.48; H, 5.21. Found: C, 76,51; H, 5.20.
ASSOCIATED CONTENT
■
S
* Supporting Information
7-Fluoro-4-o-tolylquinolin-2(1H)-one (2m) and 4-(4-Fluoro-
phenyl)-5-methylquinolin-2(1H)-one (3m). Obtained as a mixture
of two isomers. The ratio of two isomers was determined by 1H NMR
as 2m/3m = 96:4.Compound 2m could be separated from the mixture
by semipreparative HPLC: white solid; mp 171−174 °C; IR (KBr)
3340, 1675, 1542 cm−1; 1H NMR (CDCl3) δ 13.12 (br s, 1 H), 7.44−
7.22 (m, 5 H), 7.16−7.12 (m, 1 H), 6.89−6.85 (m, 1 H), 6.61 (s, 1 H),
2.16 (s, 3 H); 13C NMR (CDCl3) δ 165.9, 164.8, 164.1 (d, J = 250.0
Hz), 153.4, 140.1 (d, J = 11.8 Hz), 136.4, 135.5, 130.4, 128.9 (d, J =
9.6 Hz), 128.8, 126.0, 119.8, 116.9, 111.3 (d, J = 23.2 Hz), 102.7 (d, J
= 25.2 Hz), 19.8; 19F NMR (376.5 MHz) δ −107.8. Anal. Calcd for
C16H12FNO: C, 75.88; H, 4.78. Found: C, 75.83; H, 4.80.
NMR spectra for all the compounds synthesized. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sandro.cacchi@uniroma1.it.
Notes
The authors declare no competing financial interest.
4-(2-Chlorophenyl)quinolin-2(1H)-one (2n) and 5-Chloro-4-
phenylquinolin-2-(1H)-one (3n). Obtained as a mixture of two
isomers. The ratio of two isomers was determined by 1H NMR as 2n/
3n = 92:8. Compound 2n could be separated from the mixture by
semipreparative HPLC: white solid; mp 213−216 °C; IR (KBr) 3386,
ACKNOWLEDGMENTS
■
We gratefully acknowledge MURST (FIRB 2008, Futuro in
ricerca) and La Sapienza, University of Rome, for their financial
support.
2541
dx.doi.org/10.1021/jo202427m | J. Org. Chem. 2012, 77, 2537−2542

The Journal of Organic Chemistry
Note
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