Synthesis of 3,4-disubstituted quinolin-2-(1H)-ones via palladium-catalyzed decarboxylative arylation reactions

Article abstract of DOI:10.1002/adsc.201300299

The Pd-catalyzed decarboxylative cross-coupling reaction of 4-substituted quinolin-2(1H)-one-3-carboxylic acids with (hetero)aryl halides is described. With palladium(II) bromide and triphenylarsine ligand as the catalyst system, a variety of 4-substituted 3-(hetero)aryl quinolin-2(1 H)-ones and related heterocycles, such as 4-substituted 3-arylcoumarins can be prepared in good to excellent yields. Copyright

Full text of DOI:10.1002/adsc.201300299

FULL PAPERS
DOI: 10.1002/adsc.201300299
Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones via
Palladium-Catalyzed Decarboxylative Arylation Reactions
Amandine Carrꢀr,a Jean-Daniel Brion,a Samir Messaoudi,a,* and Mouad Alamia,*
a
Univ Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thꢁrapeutique, Facultꢁ de
Pharmacie, 5 rue J.-B. Clꢁment, 92296 Chꢂtenay-Malabry, France
Fax : (+33)-146-835-828; e-mail: samir.messaoudi@u-psud.fr or mouad.alami@u-psud.fr
Received: April 11, 2013; Published online: July 12, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300299.
Abstract: The Pd-catalyzed decarboxylative cross- related heterocycles, such as 4-substituted 3-arylcou-
coupling reaction of 4-substituted quinolin-2(1H)- marins can be prepared in good to excellent yields.
one-3-carboxylic acids with (hetero)aryl halides is
described. With palladium(II) bromide and triphenyl- Keywords: aryl halides; decarboxylative arylation;
arsine ligand as the catalyst system, a variety of 4- palladium catalysis; 4-substituted 3-(hetero)arylqui-
substituted 3-(hetero)aryl quinolin-2ACTHUNRGTNE(NUG 1H)-ones and nolin-2(1H)-ones
Introduction
Traditional strategies for the preparation of 3,4-dis-
ubstituted quinolin-2(1H)-ones involve the construc-
4-Substituted 3-(hetero)arylquinolin-2(1H)-ones rep- tion of the heterocycle rings by non-trivial multistep
resent an important class of fused heterocyclic com- reaction sequences.[2,4,5] In recent years, efforts to de-
pounds regarding their various pharmacological prop- velop new approaches to 3,4-disubstituted quinolin-
erties including antiviral,[1] antibacterial[2] and anti- 2(1H)-ones under transition metal catalysis have been
cancer[3] activities. Examples of biologically active reported, including the site-selective palladium-cata-
agents[4] containing this structural motif are depicted lyzed Suzuki cross-coupling of 3-bromo-4-tosylquino-
in Figure 1.
lin-2(1H)-one with arylboronic acids.[6] However, this
reaction requires the use of stoichiometric amounts of
organometallic compounds, thus generating waste
À
from reagents. Alternative routes involve C H activa-
tion/annulation of N-arylpropiolamides[7] under Pd
catalysis, tandem Pd-catalyzed amidation/aldol con-
densation of aryl halides having an ortho carbonyl
functional group with 2-phenylacetamide,[8] or annula-
tion of N-arylcarbamoyl chlorides with internal al-
kynes under Ir catalysis.[9] Although these methods
are suitable procedures, they are often moderate to
low yielding and suffer from issues of poor regioselec-
tivity,[7,8] thus limiting the substrate scope. Therefore,
it is of great interest to develop general and conver-
gent protocols for the synthesis 3,4-disubstituted qui-
nolin-2(1H)-ones.
In support of an ongoing medicinal chemistry pro-
gram directed toward antagonists of the N-methyl-d-
aspartate (NMDA) receptor,[10] we required the syn-
thesis of 4-substituted 3-(hetero)arylquinolin-2(1H)-
ones of type A. Their preparation was envisioned
through palladium-catalyzed decarboxylative aryla-
tion of 4-substituted quinolin-2(1H)-one-3-carboxylic
Figure 1. Chemical structures of bioactive 3,4-disubstituted
quinolin-2(1H)-ones.
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Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones
Scheme 1. Pd-catalyzed decarboxylative coupling of 2a with 1a–c under our previously optimized conditions.
acids. Such a procedure which generates minimum source and ligand. The results of this study are now
waste upon decarboxylation, places this transforma- reported.
tion[11] amongst the greenest alternatives to traditional
cross-couplings. Despite the great success of this reac-
tion in the coupling of s electron-poor benzoic acids Results and Discussion
with aryl halides for biaryl synthesis,[12] the corre-
sponding coupling with heterocyclic carboxylic acids, After considerable exploration of the reaction param-
has received much less attention. In this area, very re- eters (for more details, see the Supporting Informa-
cently, we have reported a highly efficient and versa- tion), optimal conditions for the coupling of 4-phenyl-
tile decarboxylative coupling reaction of quinolin- quinolin-2(1H)-one-3-carboxylic acid 1a with 2a, as
4(1H)-one-3-carboxylic acids[13] with (hetero)aryl hal- the model study, required the use of PdBr2 (5 mol%),
ides. The bimetallic system composed of PdBr2/DPE- AsPh3 (10 mol%) and Ag2CO3 (1 equiv.), toluene/
phos/Ag2CO3 enables high-yielding reactions with var- DMA (9:1) in a sealed Schlenk tube at 1508C for 1 h
ious (hetero)aryl halides. In addition, we demonstrat- under microwave irradiation. Accordingly, the desired
ed through a preliminary result that the use of these coupling product 3a was isolated in a good 84% yield
conditions also enabled, for the first time, decarboxy- (Scheme 2). It should be noted that carrying out the
lative arylation of quinolin-2(1H)-one-3-carboxylic reaction using traditional oil bath heating (1508C, 1 h,
acid 1a to provide 3a in an acceptable 44% yield sealed tube), induced a lowering of the conversion
(Scheme 1). However, according to this protocol,[13] rate, and 3a was isolated in only 74% yield. This
all our attempts to prepare 3b, c by coupling 1b, result clearly demonstrated the benefit to use micro-
c with 2a resulted in unsatisfactory yields. The target- wave irradiation.
ed 4-substituted 3-(4-methoxyphenyl)quinolin-2(1H)-
With this promissing result in hand, we started to
ones 3b, c were formed in yields never exceeding investigate the substrate scope for the Pd-catalyzed
35%, regardless of the nature of the substituent at the decarboxylative coupling of 1a with various (hetero)-
C-4 position of the quinolin-2(1H)-one moiety aryl halides possessing different steric and electronic
(Scheme 1). Two others by-products were obtained as properties. As illustrated in Scheme 2, both aryl io-
a mixture: (i) quinolinones 3aa derived from protode- dides and bromides reacted well providing the desired
carboxylation of 1 and (ii) compounds 3ab which re- compound 3b in excellent yields. Electron-rich and
sulted from the phenyl migration from the phosphine electron-deficient, meta and para substituted aryl hal-
ligand.[14]
ides all underwent efficiently the decarboxylative cou-
Our attempts to increase the yields of 3b, c by pling with 1a in good yields (products 3a–e and 3g–k).
using high catalyst loading (up to 15 mol%) and ele- In addition, the sterically demanding ortho substitu-
vated temperatures (up to 1708C) combined with tion pattern was tolerated toward coupling reaction of
a prolonged reaction times did not lead to any im- 1a, leading to 4-phenyl-3-arylquinolin-2(1H)-ones 3f
provement. These unsuccessful results clearly demon- and 3l in yields up to 82%, regardless of the electron-
strate that the nature of the heterocyclic substrate ic nature of the substituents. Interestingly, product 3i
and its substituent at the C-4 position play a critical revealed excellent chemical selectivity preserving the
À
role in the outcome of this decarboxylative coupling C Cl bond, which could undergo further metal-cata-
reaction. To address difficulties associated with the re- lyzed functionalization processes.[15] In addition, reac-
activity of 4-substituted quinolin-2(1H)-one-3-carbox- tions of 1a with aryl iodides bearing an enolizable
ylic acids 1, we decided to investigate this challenging methyl ketone or ethoxycarbonyl functions were also
coupling reaction by fine-tuning of the palladium efficient furnishing in good yields the coupling prod-
ucts 3e, 3j and 3k, which could then be subject to fur-
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Amandine Carrꢀr et al.
FULL PAPERS
Scheme 2. Pd-catalyzed decarboxylative coupling of 1a with various (hetero)aryl halides.
ther synthetic transformations. Heteroaromatic hal- We were pleased to observe that this procedure is
ides could be employed in this coupling reaction as compatible with a wide range of substituents at the C-
well. Thus, 3-iodo-6-methoxypyridine and 3-bromo- 4 position of the quinolin-2-one moiety such as aryl,
quinoline gave rise the heteroarylated quinolin-2- alkyl and benzyl groups, clearly indicating that the re-
A
action does not seems to be sensitive to steric hin-
Motivated by these results, we then examined drance. In this way, excellent yields of (hetero)arylat-
under our optimized conditions the efficiency of this ed quinolin-2(1H)-ones 3o–u were obtained. More-
catalytic system on the coupling of a range of quino- over, the presence of base-sensitive substituents on
lin-2(1H)-one-3-carboxylic acids containing other im- the C-4 position such cyclopropylmethyl as well as
portant groups at the C-4 position or on the aromatic a methoxy group[17] on substrates 3v–y were tolerated
ring of the quinolin-2(1H)-one moeity. As summar- under our catalytic system, however, the yields de-
ized in Scheme 3, all the substrates studied efficiently crease slightly. Noteworthy, the reaction is not effec-
undergo the coupling reaction with various aryl hal- tive with quinolin-2(1H)-one-3-carboxylic acid bear-
ides under the PdBr2/AsPh3 catalytic system, provid- ing a free hydroxy group at the C-4 position. In this
ing the corresponding 3,4-disubstituted quinolin- case, compound 3z has never been obtained and only
2(1H)-one products in yields ranging from 33 to 99%. a mixture of protodecarboxylative by-product and
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Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones
Scheme 3. Pd-catalyzed decarboxylative coupling of quinolin-2(1H)-one-carboxylic acid derivatives[16] with various (hetero)-
aryl iodides.
starting materials was isolated. Next, we used this cat- arylquinolin2(1H)-ones 6a and 6b in 48% and 56%
alytic system in decarboxylative coupling of other het- yields, respectively.
erocyclic carboxylic acids. Overall, this system could
be successfully applied to 4-substituted coumarin-3-
carboxylic acids,[18] leading to 3,4-disubstituted cou- Conclusions
marins 5a-c in yields ranging from 65% to 88%, re-
gardless of the nature of the aryl halide partner.
In conclusion, we have developed an efficient and
Finally, to illustrate the synthetic potential of our practical PdBr2/AsPh3 catalytic system for the decar-
protocol, substrate 1d enables the synthesis of N-me- boxylative coupling of various 4-substituted quinolin-
thylated 3-arylquinolin-2(1H)-ones 6a, b related to 2(1H)-one-3-carboxylic acids with (hetero)aryl hal-
MDL 140,653 and L 707-1317 as potential antagonists ides. This transformation exhibited broad substrate
at the glycine site of the NMDA receptor (Scheme 4). scope with respect to both the heterocyclic carboxylic
The key step was the coupling of 1d with iodobenzene acids and (hetero)aryl halides. It provides an attrac-
and 1-iodo-3-(3-methoxybenzyl)benzene under our tive alternative to the existing methods for the synthe-
optimized conditions to give selectively 4-methoxy-3- sis of 4-substituted 3-(hetero)arylquinolin-2(1H)-ones
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Scheme 4. Synthesis of 6a, b, as analogues of MDL 140,653 and L 707-1317.
lowing specifications: temperature: 1508C; 1 h; fixed hold
time: on; high absorption: high; pre-stirring: 60 s. The re-
sulting suspension was cooled to room temperature and fil-
tered through a pad of Celite eluting with ethyl acetate, and
the inorganic salts were removed. The filtrate was washed
with water. The aqueous layer was extracted twice with
EtOAc. The combined organic layers were washed with a sa-
turated solution of NH4Cl then brine, dried over MgSO4, fil-
tered and evaporated under reduced pressure. The residue
was purified by flash chromatography over silica gel to
afford the desired product.
3 and related heterocycles 5 of biological interest. We
believe that this methodology should find broad ap-
plications in synthetic organic chemistry, as well as in
the combinatorial and pharmaceutical sciences.
Experimental Section
General Experimental Methods
The compounds were all identified by the usual physical
methods, that is, 1H NMR, 13C NMR (J-MOD), IR, MS
1
(ESI). H and 13C NMR spectra were measured in CDCl3 or
Analytical Data for 4-Substituted 3-
(Hetero)arylquinolin-2(1H)-ones 3
DMSO-d6 with a Bruker Avance-300. 1H NMR chemical
shifts are reported in ppm from an internal standard TMS
or of residual chloroform (7.27 ppm). The following abrevia-
tions are used: m (multiplet), s (singlet), bs (broad singlet),
d (doublet), t (triplet) dd (doublet of doublet), td (triplet of
doublet), q (quadruplet), qui (quintuplet), sex (sextuplet).
13C NMR chemical shifts are reported in ppm from the cen-
tral peak of deuteriochloroform (77.14). IR spectra were
measured on a Bruker Vector 22 spectrophotometer. Mass
spectra were recorded on a Micromass spectrometer. Ana-
lytical TLC was performed on Merck precoated silica gel
60F plates. Merck silica gel 60 (0.015–0.040 mm) was used
for column chromatography. Melting points were recorded
on a Bꢄchi B-450 apparatus and are uncorrected.
3-(4-Methoxyphenyl)-1-methyl-4-phenylquinolin-2(1H)-
one (3a): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 1-iodo-4-methoxybenzene (234 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
80:20) to afford the desired product 3a as a beige solid;
yield: 143 mg, 0.42 mmol (84%); Rf 0.27 (cyclohexane/ethyl
acetate 70:30); mp 1658C (recrystallized from ethyl acetate
1
to give beige crystals). H NMR (300 MHz, CDCl3): d=7.56
(t, J=7.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.30–7.26 (m,
4H), 7.14–7.10 (m, 3H), 7.03 (d, J=8.4 Hz, 2H), 6.70 (d, J=
8.7 Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=162.2, 158.4, 147.5, 139.6, 136.7, 132.0 (2C),
131.7, 130.2, 130.0 (2C), 128.5, 128.3, 128.1 (2C), 127.6,
121.9, 121.7, 114.1, 113.1 (2C), 55.2, 30.3; IR (film): n=
1640, 1601, 1512, 1458, 1312, 1291,1248, 1177 cmÀ1; HR-MS
(ES+): m/z=364.1310, calculated for C23H19NO2Na [M+
Na]+: 364.1313.
General Procedure for Palladium-Catalyzed
Decarboxylative Coupling
A flame-dried resealable 2–5 mL Pyrex reaction vessel was
charged with the solid reactant(s): PdBr2 (5.0 mol%), AsPh3
(10 mol%), heterocyclic carboxylic acid (1 equiv.), (hetero)-
aryl halide (2 equiv.) and Ag2CO3 (1 equiv.). The reaction
vessel was capped with a rubber septum, evacuated and
backfilled with argon; this evacuation/backfill sequence was
repeated one additional time. The liquid reactant(s) and tol-
uene/DMA (9:1, 0.05M) were added through the septum.
The septum was replaced with a Teflon screwcap. The reac-
tion vessel was sealed, then placed in the Emrys Optimizer
and exposed to microwave irradiation according to the fol-
1-Methyl-3,4-diphenylquinolin-2(1H)-one (3b):[19] Fol-
lowing the general procedure for decarboxylative coupling,
a mixture of 1-methyl-2-oxo-4-phenyl-1,2-dihydroquinoline-
3-carboxylic acid 1a (139.5 mg, 0.5 mmol) and iodobenzene
(204 mg, 1.0 mmol) was heated for 1 h. The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 85:15 to 80:20) to afford the desired product
3b as a beige solid; yield: 140 mg, 0.45 mmol (90%); Rf 0.36
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Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones
(cyclohexane/ethyl acetate 70:30), mp 2208C (recrystallized
from ethyl acetate to give white crystals). 1H NMR
(300 MHz, CDCl3): d=7.58 (t, J=8.1 Hz, 1H), 7.46 (d, J=
8.4 Hz, 1H), 7.32–7.24 (m, 4H), 7.19–7.09 (m, 8H), 3.86 (s,
3H); 13C NMR (75 MHz, CDCl3): d=161.9, 147.8, 139.6,
136.4, 136.0, 132.1, 130.7 (2C), 130.4, 130.0 (2C), 128.6,
128.0 (2C), 127.6, 127.5 (2C), 127.0, 122.0, 121.6, 114.1,
30.20; IR (film): n=1630, 1601, 1589, 1457, 1311 cmÀ1.
127.9, 127.7, 122.2, 121.5, 114.2, 60.9, 30.3, 14.4; IR (film):
n=1715, 1635, 1602, 1313, 1291, 1262, 1226 cmÀ1; HR-MS
(ES+): m/z=406.1420, calculated for C25H21NO3Na [M+
Na]+: 406.1419.
1-Methyl-4-phenyl-3-(o-tolyl)quinolin-2(1H)-one (3f):
Following the general procedure for decarboxylative cou-
pling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-dihydroqui-
noline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol) and 1-iodo-
2-methylbenzene (218 mg, 1.0 mmol) was heated for 1 h.
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to
afford the desired product 3f as a beige solid; yield: 134 mg,
0.41 mmol (82%); Rf 0.39 (cyclohexane/ethyl acetate 70:30);
mp 1958C (recrystallized from ethyl acetate to give beige
1-Methyl-3-(naphthalen-2-yl)-4-phenylquinolin-2(1H)-
one (3c): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 2-iodo-4-naphthalene (254 mg, 1.0 mmol) was heated
for 1 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to
afford the desired product 3c as an orange solid,; yield:
113 mg, 0.31 mmol (63%); Rf 0.37 (cyclohexane/ethyl ace-
tate 70:30); mp 2118C (recrystallized from ethyl acetate to
1
crystals). H NMR (300 MHz, CDCl3): d=7.59 (t, J=7.8 Hz,
1H), 7.48 (d, J=8.4 Hz, 1H), 7.31–7.12 (m, 6H), 7.08–6.95
(m, 4H), 6.90 (d, J=7.2 Hz, 1H), 3.86 (s, 3H), 2.17 (s, 3H);
13C NMR (75 MHz, CDCl3): d=161.4, 148.1, 139.9, 136.8,
136.4, 136.0, 132.5, 130.6, 130.4, 130.1, 129.6, 128.6, 128.4,
128.2, 127.8, 127.8, 127.5, 125.3, 122.0, 121.6, 114.2, 30.2,
20.1; IR (film): n=1640, 1601, 1459, 1312 cmÀ1; HR-MS
(ES+): m/z= 348.1361, calculated for C23H19NONa [M+
Na]+: 348.1364.
1
give pale orange crystals). H NMR (300 MHz, CDCl3): d=
7.73–7.70 (m, 1H), 7.66–7.57 (m, 4H), 7.48 (d, J=8.4 Hz,
1H), 7.41–7.32 (m, 3H), 7.27–7.12 (m, 7H), 3.88 (s, 3H);
13C NMR (75 MHz, CDCl3): d=162.1, 148.1, 139.7, 136.4,
133.6, 133.1, 132.4, 132.0, 130.5, 130.2, 130.0 (2C), 128.7,
128.6, 128.2 (2C), 127.7, 127.6, 127.0, 125.8, 125.6, 122.1,
121.7, 114.2, 30.3; IR (film): n=1640, 1600, 1313 cmÀ1; HR-
MS (ES+): m/z=384.1362, calculated for C26H19NONa [M+
Na]+: 384.1364.
1-Methyl-3-(4-nitrophenyl)-4-phenylquinolin-2(1H)-one
(3g): Following the general procedure for decarboxylative
coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-dihydro-
quinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol) and 1-
iodo-4-nitrobenzene (248 mg, 1.0 mmol) was heated for 1 h.
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to
afford the desired product 3g as a yellow solid; yield:
117 mg, 0.33 mmol (66%); Rf 0.28 (cyclohexane/ethyl ace-
tate 70:30); mp 2168C (recrystallized from ethyl acetate to
3-(3-Methoxyphenyl)-1-methyl-4-phenylquinolin-2(1H)-
one (3d): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 1-iodo-3-methoxybenzene (234 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
70:30) to afford the desired product 3d as a beige solid;
yield: 148.1 mg, 0.43 mmol (87%); Rf 0.27 (cyclohexane/
ethyl acetate 70:30); mp 1468C (recrystallized from ethyl
1
give pale yellow crystals). H NMR (300 MHz, CDCl3): d=
8.03 (d, J=8.4 Hz, 2H), 7.63 (t, J=7.5 Hz, 1H), 7.49 (d, J=
8.1 Hz, 1H), 7.31–7.28 (m, 6H), 7.17 (t, J=7.2 Hz, 1H),
7.11–7.08 (m, 2H), 3.86 (s, 3H), 13C NMR (75 MHz, CDCl3):
d=161.1, 148.9, 146.7, 143.4, 139.9, 135.6, 131.9 (3C), 131.3,
129.8 (2C), 128.9, 128.5 (2C), 128.3, 122.8 (2C), 122.4, 121.2,
114.4, 30.3, IR (film): n=1631, 1602, 1588, 1515, 1314,
1236 cmÀ1; HR-MS (ES+): m/z=379.1053, calculated for
C22H16N2O3Na [M+H]+: 379.1059.
1
acetate to give beige crystals). H NMR (300 MHz, CDCl3):
d=7.58 (t, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.32–
7.26 (m, 4H), 7.15–7.06 (m, 4H), 6.74–6.63 (m, 2H), 3.85 (s,
3H), 3.63 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.8,
158.9, 147.8, 139.7, 137.3, 136.5, 132.0, 130.4, 129.9 (2C),
128.6, 128.5, 128.1 (2C), 127.7, 123.4, 122.0, 121.6, 116.1,
114.2, 113.2, 55.2, 30.2, IR (film) n 1639, 1601, 1461, 1287,
1253, 1212, 1049; HR-MS (ES+): m/z=364.1307, calculated
for C23H19NO2Na [M+H]+: 364.1313.
1-Methyl-4-phenyl-3-[4-(trifluoromethyl)phenyl]quino-
lin-2(1H)-one (3h): Following the general procedure for de-
carboxylative coupling,
a mixture of 1-methyl-2-oxo-4-
phenyl-1,2-dihydroquinoline-3-carboxylic acid 1a (139.5 mg,
0.5 mmol) and 1-iodo-4-(trifluoromethyl)benzene (272 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 90:10 to 80:20) to afford the desired product 3h as an
off-white solid; yield: 170.6 mg, 0.45 mmol (90%); Rf 0.32
(cyclohexane/ethyl acetate 70:30); mp 1968C (recrystallized
from ethyl acetate to give white crystals). 1H NMR
(300 MHz, CDCl3): d=7.64–7.58 (m, 1H), 7.48 (d, J=
8.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.33–7.27 (m, 4H),
7.23 (d, J=8.1 Hz, 2H), 7.15 (t, J=7.2 Hz, 1H), 7.11–7.08
(m, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
161.5, 148.5, 140.0, 139.8, 135.9, 131.2 (2C), 130.9, 130.7,
129.9 (2C), 129.0 (q, J=32 Hz), 128.8, 128.3 (2C), 128.1,
124.5 (2C, q, J=3.75 Hz), 124.3 (q, J=271 Hz), 122.3, 121.4,
114.3, 30.3, 19F NMR (188 MHz, CDCl3): d=À63.0; IR
(film): n=1639, 1602, 1491, 1458, 1264 cmÀ1; HR-MS (ES+):
Ethyl 3-(1-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-
3-yl)benzoate (3e): Following the general procedure for de-
carboxylative coupling,
a mixture of 1-methyl-2-oxo-4-
phenyl-1,2-dihydroquinoline-3-carboxylic acid 1a (139.5 mg,
0.5 mmol) and ethyl 3-iodobenzoate (275 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 80:20) to
afford the desired product 3e as a beige solid; yield: 184 mg,
0.48 mmol (96%); Rf 0.30 (cyclohexane/ethyl acetate 70:30);
mp 154–1558C (recrystallized from ethyl acetate to give
beige crystals): 1H NMR (300 MHz, CDCl3): d=7.76–7.73
(m, 2H), 7.55–7.49 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.24–
7.13 (m, 6H), 7.09–7.02 (m, 3H), 4.22 (q, J=7.2 Hz, 2H),
3.78 (s, 3H), 1.26 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=166.6, 161.7, 148.4, 139.7, 136.3, 136.1, 135.2,
132.1, 131.1, 130.7, 129.9 (2C), 128.7, 128.3, 128.2 (2C),
Adv. Synth. Catal. 2013, 355, 2044 – 2054
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2049

Amandine Carrꢀr et al.
FULL PAPERS
m/z=402.1085, calculated for C23H16NOF3Na [M+Na]+:
402.1082.
3-(2-Fluorophenyl)-1-methyl-4-phenylquinolin-2(1H)-
one (3l): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 1-fluoro-2-iodobenzene (222 mg, 1.0 mmol) was heated
for 1 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to
afford the desired product 3l as a white solid; yield:
141.2 mg, 0.43 mmol (86%); Rf 0.42 (cyclohexane/ethyl ace-
tate 70:30); mp 1928C (recrystallized from ethyl acetate to
3-(4-Chlorophenyl)-1-methyl-4-phenylquinolin-2(1H)-
one (3i): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 1-chloro-4-iodobenzene (238.5 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
80:20) to afford the desired product 3i as a white solid;
yield: 159.1 mg, 0.46 mmol (92%); Rf 0.41 (cyclohexane/
ethyl acetate 70:30); mp 2028C (recrystallized from ethyl
1
give white crystals). H NMR (400 MHz, CDCl3): d=7.62–
7.58 (m, 1H), 7.47 (d, J=6.0 Hz, 1H), 7.32–7.25 (m, 4H),
7.16–7.14 (m, 4H), 7.01–6.91 (m, 3H), 3.86 (s, 3H);
13C NMR (100 MHz, CDCl3): d=161.2, 160.4 (d, J=
244 Hz), 149.6, 140.0, 136.1, 132.3 (d, J=3.0 Hz), 130.8,
129.5, 129.4 (d, J=8.0 Hz), 129.2, 128.7, 128.4, 128.0, 127.8,
127.1, 124.3 (d, J=17 Hz), 123.6 (d, J=3.0 Hz), 122.1, 121.4,
115.2 (d, J=22 Hz), 30.2; 19F NMR (188 MHz, CDCl3): d
À113.4; IR (film): n=1636, 1602, 1323, 1163, 1123,
1070 cmÀ1; HR-MS (ES+): m/z=352.1113, calculated for
C22H16NOFNa [M+Na]+: 352.1114.
1
acetate to give white crystals). H NMR (300 MHz, CDCl3):
d=7.59 (t, J=7.2 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.31–
7.28 (m, 4H), 7.16–7.08 (m, 5H), 7.05 (d, J=8.4 Hz, 2H),
3.85 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.7, 148.2,
139.7, 136.2, 134.6, 132.9, 132.2 (2C), 130.9, 130.7, 129.9
(2C), 128.7, 128.3 (2C), 127.9, 127.8 (2C), 122.1, 121.5,
114.2, 30.3; IR (film): n=1635, 1601, 1491, 1458, 1313,
1090 cmÀ1; HR-MS (ES+): m/z=368.0836, calculated for
C22H16NONa35Cl [M+Na]+: 368.0818.
3-(6-Methoxypyridin-3-yl)-1-methyl-4-phenylquinolin-
2(1H)-one (3m): Following the general procedure for decar-
boxylative coupling, a mixture of 1-methyl-2-oxo-4-phenyl-
3-(4-Acetylphenyl)-1-methyl-4-phenylquinolin-2(1H)-
one (3j): Following the general procedure for decarboxyla-
tive coupling, a mixture of 1-methyl-2-oxo-4-phenyl-1,2-di-
hydroquinoline-3-carboxylic acid 1a (139.5 mg, 0.5 mmol)
and 1-(4-iodophenyl)ethanone (246 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
70:30) to afford the desired product 3j as a yellow solid;
yield: 134 mg, 0.38 mmol (76%); Rf 0.15 (cyclohexane/ethyl
acetate 70:30); mp 1968C (recrystallized from ethyl acetate
1,2-dihydroquinoline-3-carboxylic
0.5 mmol) and 5-iodo-2-methoxypyridine
acid
1a
(139.5 mg,
(235 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 85:15 to 80:20) to afford the desired product 3m as
a yellow oil; yield: 134 mg, 0.39 mmol (78%); Rf 0.27 (cyclo-
hexane/ethyl acetate 70:30). 1H NMR (300 MHz, CDCl3):
d=7.86 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.45–7.40 (m, 2H),
7.33–7.27 (m, 4H), 7.14–7.11 (m, 3H), 6.58 (d, J=8.4 Hz,
1H), 3.84 (s, 6H); 13C NMR (75 MHz, CDCl3): d=162.8,
161.8, 148.5, 148.4, 141.1, 139.6, 136.2, 130.6 (2C), 129.9
(2C), 128.6, 128.4 (2C), 127.9, 125.0, 122.1, 121.5, 114.2,
1
to give beige crystals). H NMR (300 MHz, CDCl3): d=7.76
(d, J=8.1 Hz, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.47 (d, J=
8.4 Hz, 1H), 7.33–7.26 (m, 4H), 7.22 (d, J=8.1 Hz, 2H),
7.16 (d, J=7.5 Hz, 1H), 7.12–7.09 (m, 2H), 3.86 (s, 3H),
2.53 (s, 3H); 13C NMR (75 MHz, CDCl3): d=198.0, 161.5,
148.3, 141.4, 139.8, 136.0, 135.6, 131.1 (2C), 131.0, 130.8,
129.9 (2C), 128.7, 128.3 (2C), 128.0, 127.7, 122.2, 121.4,
114.3, 30.2, 26.7; IR (film): n=1680, 1633, 1602, 1458, 1363,
1313, 1268; HR-MS (ES+): m/z=376.1313, calculated for
C24H19NO2Na [M+Na]+: 376.1313.
109.6, 53.5, 30.3; IR (film): n=1634, 1602, 1493, 1285cmÀ1
;
HR-MS (ES+): m/z=343.1428, calculated for C22H19N2O2
[M+H]+: 343.1441.
1-Methyl-4-phenyl-3,3’-biquinolin-2(1H)-one (3n): Fol-
lowing the general procedure for decarboxylative coupling,
a mixture of 1-methyl-2-oxo-4-phenyl-1,2-dihydroquinoline-
3-carboxylic acid 1a (139.5 mg, 0.5 mmol) and 3-bromoqui-
noline (208 mg, 1.0 mmol) was heated for 1 h. The residue
was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 85:15 to 80:20) to afford the desired
product 3n as a pale yellow solid; yield: 141 mg, 0.39 mmol
(78%); Rf 0.11 (cyclohexane/ethyl acetate 70:30); mp 207–
2098C (recrystallized from ethyl acetate to give pale yellow
crystals). 1H NMR (300 MHz, CDCl3):; d=8.64 (d, J=
1.8 Hz, 1H), 8.11–8.08 (m, 2H), 7.71–7.62 (m, 3H), 7.52–
7.47 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.28–7.25 (m, 2H),
7.21–7.16 (m, 4H), 3.89 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=152.1, 149.4, 146.4 (2C), 139.9, 138.3, 135.8,
131.1, 130.0 (2C), 129.6, 129.4, 128.9 (2C), 128.8, 128.6 (2C),
128.3, 128.1, 127.5, 126.5, 122.4, 121.5, 114.4, 30.4 (CO not
Ethyl 4-(1-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-
3-yl)benzoate (3k): Following the general procedure for de-
carboxylative coupling,
a mixture of 1-methyl-2-oxo-4-
phenyl-1,2-dihydroquinoline-3-carboxylic acid 1a (139.5 mg,
0.5 mmol) and ethyl 4-iodobenzoate (275 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
80:20) to afford the desired product 3k as an off-white solid;
yield: 177.5 mg, 0.46 mmol (93%); Rf 0.29 (cyclohexane/
ethyl acetate 70:30); mp 1658C (recrystallized from ethyl
1
acetate to give white crystals): H NMR (300 MHz, CDCl3):
d=7.85 (d, J=8.1 Hz, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.47 (d,
J=8.4 Hz, 1H), 7.32–7.26 (m, 3H), 7.20–7.08 (m, 6H), 4.32
(q, J=7.2 Hz, 2H), 3.85 (s, 3H), 1.35 (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=166.7, 161.5, 148.3, 141.1,
139.8, 136.0, 131.2, 130.9 (2C), 130.8, 129.9 (2C), 128.9,
128.8 (2C), 128.7, 128.3 (2C), 128.0, 122.2, 121.4, 114.3, 60.9,
30.2, 14.4; IR (film): n=1712, 1632, 1602, 1589, 1271,
1101 cmÀ1; HR-MS (ES+): m/z=406.1416, calculated for
C25H21NO3Na [M+Na]+: 406.1419.
observed); IR (film): n=2924, 1634, 1600, 1490, 1313 cmÀ1
;
HR-MS (ES+): m/z=363.1496, calculated for C25H19N2O
[M+H]+: 363.1497.
6-Chloro-3-(4-fluorophenyl)-1-methyl-4-phenylquinolin-
2(1H)-one (3o): Following general procedure for decarboxy-
lative coupling, a mixture of 6-chloro-1-methyl-2-oxo-4-
2050
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2044 – 2054

Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones
phenyl-1,2-dihydroquinoline-3-carboxylic
acid
1b
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 80:20) to afford the desired product 3r as an off-white
solid; yield: 159 mg, 0.42 mmol (85%); Rf 0.37 (cyclohexane/
ethyl acetate 70:30); mp 1978C (recrystallized from ethyl
(156.75 mg, 0.5 mmol) and 1-fluoro-4-iodobenzene (222 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 80:20) to afford the desired product 3o as an off-white
solid; yield: 180 mg, 0.49 mmol (99%); Rf 0.31 (cyclohexane/
ethyl acetate 70:30); mp 1918C (recrystallized from ethyl
1
acetate to give white crystals): H NMR (300 MHz, CDCl3):
d=7.58 (t, J=7.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.35 (d,
J=7.5 Hz, 1H), 7.17–7.12 (m, 3H), 7.05 (d, J=8.4 Hz, 2H),
7.00 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.84 (s,
3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.7,
159.1, 148.0, 139.7, 134.8, 132.8, 132.2 (2C), 131.2 (2C),
131.0, 130.6, 128.7, 128.3, 127.9 (2C), 122.1, 121.8, 114.2,
113.8 (2C), 55.3, 30.2; IR (film): n=1634, 1598, 1513, 1495,
1456, 1314, 1176 cmÀ1; HR-MS (ES+): m/z=398.0924, calcu-
lated for C23H18NO2Na35Cl [M+Na]+: 398.0924.
Ethyl 4-(4-benzyl-1-methyl-2-oxo-1,2-dihydroquinolin-
3-yl)benzoate (3s): Following the general procedure for de-
carboxylative coupling, a mixture of 4-benzyl-1-methyl-2-
oxo-1,2-dihydroquinoline-3-carboxylic acid 1e (146.5 mg,
0.5 mmol) and ethyl 4-iodobenzoate (275 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 85:15 to
80:20) to afford the desired product 3s as a yellow solid;
yield: 129 mg, 0.32 mmol (65%); Rf 0.28 (cyclohexane/ethyl
acetate 70:30); mp 988C (precipitated from ethyl acetate/
hexane to give a white powder). 1H NMR (300 MHz,
CDCl3): d=8.05 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.1 Hz, 1H),
7.55 (t, J=8.1 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (d, J=
8.4 Hz, 2H), 7.26–7.12 (m, 4H), 7.04 (d, J=7.5 Hz, 2H),
4.37 (q, J=7.2 Hz, 2H), 4.12 (s, 2H), 3.81 (s, 3H), 1.38 (t,
J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=166.6,
161.6, 144.1, 141.4, 139.9, 138.9, 133.3, 130.6, 129.9 (2C),
129.6, 128.8, 128.0, 127.2, 126.5, 122.4, 120.6, 114.6, 61.1,
36.0, 30.2, 14.5; IR (film): n=2979, 1713, 1634, 1593, 1453,
1271, 1101 cmÀ1; HR-MS (ES+): m/z=420.1573, calculated
for C26H23NO3Na [M+Na]+: 420.1576.
3-(4-Methoxyphenyl)-1,4-dimethylquinolin-2(1H)-one
(3t): Following the general procedure for decarboxylative
coupling, a mixture of 1,4-dimethyl-2-oxo-1,2-dihydroquino-
line-3-carboxylic acid 1f (108.5 mg, 0.5 mmol) and 1-iodo-4-
methoxybenzene (234 mg, 1.0 mmol) was heated for 1 h.
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 90:10 to 80:20) to
afford the desired product 3t as a beige solid; yield: 85 mg,
0.30 mmol (61%); Rf 0.19 (cyclohexane/ethyl acetate 70:30);
mp 1418C (recrystallized from ethyl acetate to give beige
crystals). 1H NMR (300 MHz, CDCl3): d=7.81 (d, J=
7.8 Hz, 1H), 7.58 (t, J=8.1 Hz, 1H), 7.40 (d, J=8.4 Hz,
1H), 7.28 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 6.98
(d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H);
13C NMR (75 MHz, CDCl3): d=162.0, 159.0, 142.3, 139.1,
132.1, 131.4 (2C), 130.0, 129.0, 125.7, 122.0, 121.7, 114.2,
113.7 (2C), 55.4, 29.9, 17.0; IR (film): n=1635, 1608, 1513,
1461, 1312, 1290, 1245 cmÀ1; HR-MS (ES+): m/z=302.1158,
calculated for C18H17NO2Na [M+Na]+: 302.1157.
1
acetate to give white crystals). H NMR (300 MHz, CDCl3):
d =7.44 (dd, J=2.4–9.9 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H),
7.25–7.17 (m, 4H), 7.01–6.96 (m, 4H), 6.77 (t, J=8.7 Hz,
2H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.9 (d,
J=244 Hz), 161.6, 147.1, 138.2, 135.6, 132.4 (d, J=8.25 Hz,
2C), 132.2, 131.5 (d, J=3.75 Hz), 130.6, 129.8 (2C), 128.5
(2C), 128.2, 127.8, 127.7, 122.7, 115.7, 114.7 (d, J=22 Hz,
2C), 30.5, IR (film): n=1640, 1601, 1510, 1489, 1230 cmÀ1
;
HR-MS
C22H16NOF35Cl [M+H]+: 364.0904.
6-Chloro-3-(6-methoxypyridin-3-yl)-1-methyl-4-phenyl-
quinolin-2(1H)-one (3p): Following the general procedure
for decarboxylative coupling, mixture of 6-chloro-1-
(ES+):
m/z=364.0911,
calculated
for
a
methyl-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylic
acid 1b (156.75 mg, 0.5 mmol) and 5-iodo-2-methoxypyridine
(235 mg, 1.0 mmol) was heated for 1 h. The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 80:20 to 60:40) to afford the desired product
3p as a yellow oil; yield: 128.5 mg, 0.34 mmol (68%); Rf 0.24
(cyclohexane/ethyl acetate 70:30). 1H NMR (300 MHz,
CDCl3): d=7.85 (d, J=2.1 Hz, 1H), 7.50 (dd, J=2.4–9.0 Hz,
1H), 7.41–7.30 (m, 5H), 7.23 (d, J=2.1 Hz, 1H), 7.11–7.08
(m, 2H), 6.58 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H);
13C NMR (75 MHz, CDCl3): d=162.9, 161.5, 148.4, 147.5,
141.0, 138.2, 135.5, 130.6, 129.8 (2C), 128.7 (2C), 128.3,
127.8, 127.7, 124.6, 122.7, 115.7, 109.7, 53.5, 30.5; IR (film):
n=1634, 1601, 1488, 1284, 1026 cmÀ1; HR-MS (ES+): m/z=
377.1060, calculated for C22H18N2O235Cl [M+H]+: 377.1057.
4-(2-Methoxyphenyl)-3-(4-methoxyphenyl)-1-methylqui-
nolin-2(1H)-one (3q): Following the general procedure for
decarboxylative coupling, a mixture of 4-(2-methoxyphen-
yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1c
(154.5 mg,
0.5 mmol)
and
1-iodo-4-methoxybenzene
(234 mg, 1.0 mmol) was heated for 1 h. The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 85:15 to 80:20) to afford the desired product
3q as an off-white solid; yield: 157.7 mg, 0.42 mmol (85%);
Rf 0.18 (cyclohexane/ethyl acetate 70:30); mp 1688C (recrys-
1
tallized from ethyl acetate to give white crystals). H NMR
(300 MHz, CDCl3): d=7.53 (t, J=7.2 Hz, 1H), 7.42 (d, J=
8.4 Hz, 1H), 7.28–7.18 (m, 2H), 7.12–7.06 (m, 3H), 6.98–
6.94 (m, 1H), 6.90–6.83 (m, 2H), 6.69 (d, J=8.7 Hz, 2H)
3.84 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=162.2, 158.5, 156.8, 144.9, 139.5, 132.3, 131.2
(2C), 131.1, 130.0, 129.5, 128.8, 128.0, 125.9, 121.9, 121.6,
120.5, 114.1, 112.9 (2C), 110.8, 55.5, 55.2, 30.2; IR (film): n=
1636, 1606, 1513, 1491, 1461, 1312, 1291, 1247, 1177, 1027;
HR-MS (ES+): m/z=372.1603, calculated for C24H22NO3
[M+H]+: 372.1600.
3-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-methylqui-
nolin-2(1H)-one (3r): Following the general procedure for
decarboxylative coupling, a mixture of 4-(4-methoxyphen-
yl)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1d
(154.5 mg, 0.5 mmol) and 1-chloro-4-iodobenzene (238.5 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
3-(3-Chlorophenyl)-1,4-dimethylquinolin-2(1H)-one
(3u): Following the general procedure for decarboxylative
coupling, a mixture of 1,4-dimethyl-2-oxo-1,2-dihydroquino-
line-3-carboxylic acid 1f (108.5 mg, 0.5 mmol) and 1-chloro-
3-iodobenzene (238.5 mg, 1.0 mmol) was heated for 1 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane/ethyl acetate 85:15) to afford the desired prod-
uct 3u as a beige solid; yield: 124.5 mg, 0.44 mmol (88%); Rf
Adv. Synth. Catal. 2013, 355, 2044 – 2054
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2051

Amandine Carrꢀr et al.
FULL PAPERS
0.34 (cyclohexane/ethyl acetate 70:30); mp 135–1378C (re-
crystallized from ethyl acetate to give beige crystals).
1H NMR (300 MHz, CDCl3): d=7.81 (d, J=8.1 Hz, 1H),
7.61 (t, J=8.1 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.38–7.26
(m, 4H), 7.17–7.15 (m, 1H), 3.77 (s, 3H), 2.33 (s, 3H);
13C NMR (75 MHz, CDCl3): d=161.3, 142.9, 139.2, 138.7,
134.1, 131.1, 130.5, 130.3, 129.5, 128.4, 127.7, 125.8, 122.2,
121.3, 114.3, 29.9, 16.9; IR (film): n=1634, 1594, 1566, 1460,
1313 cmÀ1; HR-MS (ES+): m/z=306.0661, calculated for
C17H14NONa35Cl [M+Na]+: 306.0662.
Ethyl 3-(4-methoxy-1-methyl-2-oxo-1,2-dihydroquino-
lin-3-yl)benzoate (3x): Following the general procedure for
decarboxylative coupling, a mixture of 4-methoxy-1-methyl-
2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1h (116.5 mg,
0.5 mmol) and ethyl 3-iodobenzoate (275 mg, 1.0 mmol) was
heated for 1 h. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/ethyl acetate 80:20 to
70:30) to afford the desired product 3x as a beige solid;
yield: 94 mg, 0.28 mmol (56%); Rf 0.27 (cyclohexane/ethyl
acetate 70:30); mp 868C (precipitated from ethyl acetate/cy-
clohexane to give a beige powder). 1H NMR (300 MHz,
CDCl3): d=8.18 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.00 (d,
J=7.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.8 Hz,
1H), 7.52 (t, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.28
(t, J=7.5 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.75 (s, 3H),
3.51 (s, 3H), 1.39 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=166.7, 163.3, 160.9, 139.6, 135.4, 134.0, 132.0,
131.3, 130.6, 129.1, 128.2, 124.4, 122.2, 118.7, 118.2, 114.1,
61.2, 61.1, 30.0, 14.5, IR (film) n 1716, 1637, 1593, 1463,
1354, 1292, 1263, 1225, 1107, HR-MS (ES+): m/z=360.1218,
calculated for C20H19NO4Na [M+Na]+: 360.1212.
4-(Cyclopropylmethyl)-1-methyl-3-phenylquinolin-
2(1H)-one (3v): Following the general procedure for decar-
boxylative coupling, a mixture of 4-(cyclopropylmethyl)-1-
methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1g
(128.5 mg, 0.5 mmol) and iodobenzene (204 mg, 1.0 mmol)
was heated for 1 h. The residue was purified by flash chro-
matography over silica gel (cyclohexane/ethyl acetate 90:10
to 80:20) to afford the desired product 3v as an orange
solid; yield: 84 mg, 0.29 mmol (58%); Rf 0.33 (cyclohexane/
ethyl acetate 70:30); mp 122–1248C (precipitated from ethyl
acetate/hexane to give an orange powder). 1H NMR
(300 MHz, CDCl3): d=7.96 (d, J=8.1 Hz, 1H), 7.59 (t, J=
8.4 Hz, 1H), 7.45–7.24 (m, 7H), 3.77 (s, 3H), 2.69 (d, J=
6.3 Hz, 2H), 0.98–0.87 (m, 1H), 0.40–0.36 (m, 2H), À0.01–
0.03 (m, 2H); 13C NMR (75 MHz, CDCl3): d=162.2, 146.4,
139.8, 137.0, 132.7, 130.3 (2C), 130.2, 128.3 (2C), 127.6,
126.5, 122.0, 120.9, 114.6, 33.8, 30.0, 11.2, 5.6 (2C); IR
(film): n=1630, 1589, 1458, 1312 cmÀ1; HR-MS (ES+): m/z=
312.1355, calculated for C20H19NONa [M+Na]+: 312.1359.
4-Methoxy-3-(4-methoxyphenyl)-1-methylquinolin-
3-(3-Chlorophenyl)-4,6,7-trimethoxy-1-methylquinolin-
2(1H)-one (3y): Following the general procedure for decar-
boxylative coupling, a mixture of 4,6,7-trimethoxy-1-methyl-
2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1i (146.5 mg,
0.5 mmol) and 1-chloro-3-iodobenzene (238.5 mg, 1.0 mmol)
was heated for 1 h. The residue was purified by flash chro-
matography over silica gel (cyclohexane/ethyl acetate 80:20
to 70:30) to afford the desired product 3y as a beige solid;
yield: 59 mg, 0.16 mmol (33%); Rf 0.10 (cyclohexane/ethyl
acetate 70:30); mp 165–1668C (recrystallized from ethyl ace-
2(1H)-one (3w): Following the general procedure for decar-
boxylative coupling, a mixture of 4-methoxy-1-methyl-2-
oxo-1,2-dihydroquinoline-3-carboxylic acid 1h (116.5 mg,
1
tate to give beige crystals); H NMR (300 MHz, CDCl3): d=
7.51 (s, 1H), 7.39–7.33 (m, 4H), 6.81 (s, 1H), 4.04 (s, 3H),
3.97 (s, 3H), 3.74 (s, 3H), 3.52 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=163.1, 160.7, 152.8, 145.4, 135.9, 135.3, 134.0,
131.1, 129.4, 129.3, 127.8, 116.0, 111.0, 105.0, 97.2, 61.1, 56.4
(2C), 30.3; IR (film): n=2936, 1623, 1517, 1250, 1206,
1004 cmÀ1; HR-MS (ES+): m/z=382.0817, calculated for
C19H18NO4Na35Cl [M+Na]+: 382.0822.
0.5 mmol)
and
1-iodo-4-methoxybenzene
(234 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 85:15 to 70:30) to afford the desired product 3w as
a beige solid; yield: 73 mg, 0.25 mmol (50%); Rf 0.25 (cyclo-
hexane/ethyl acetate 70:30); mp 1218C (recrystallized from
ethyl acetate to give beige crystals). 1H NMR (300 MHz,
CDCl3): d=8.00 (d, J=7.8 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H),
7.44 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 1H), 7.27 (t, J=
7.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.75 (s,
3H), 3.52 (s, 3H); 13C NMR (75 MHz, CDCl3): d=163.6,
160.2, 159.1, 139.2, 132.0, 130.8, 125.6, 124.1, 121.9, 119.0,
118.3, 113.9, 113.6, 60.7, 55.3, 29.9, IR (film): n=1633, 1607,
1512, 1462, 1352, 1307, 1290, 1247, 1178, 1105 cmÀ1; HR-MS
(ES+): m/z=318.1098, calculated for C18H17NO3Na [M+
Na]+: 318.1106.
The side product [the protodecarboxylated compound 4-
methoxy-1-methylquinolin-2(1H)-one] (3w’) was also isolat-
ed as beige solid; yield: 42 mg, 0.22 mmol (44%); Rf 0.18
(cyclohexane/ethyl acetate 50:50); mp 668C (recrystallized
from ethyl acetate to give beige crystals). 1H NMR
(300 MHz, CDCl3): d=7.97 (d, J=8.1 Hz, 1H), 7.59 (t, J=
7.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.24 (t, J=7.8 Hz,
1H), 6.11 (s, 1H), 3.95 (s, 3H), 3.68 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=164.0, 163.0, 139.8, 131.5, 123.6, 122.0,
116.7, 114.3, 96.4, 56.0, 29.3, IR (film): n=1635, 1587, 1391,
1234 cmÀ1; HR-MS (ES+): m/z=190.0859, calculated for
C11H12NO2 [M+H]+: 190.0863.
3-(4-Methoxyphenyl)-4-phenyl-2H-chromen-2-one
(5a):[20] Following the general procedure for decarboxylative
coupling, a mixture of 2-oxo-4-phenyl-2H-chromene-3-car-
boxylic acid 4a (133 mg, 0.5 mmol) and 1-iodo-4-methoxy-
benzene (234 mg, 1.0 mmol) was heated for 1 h. The residue
was purified by flash chromatography over silica gel (cyclo-
hexane/ethyl acetate 90:10 to 80:20) to afford the desired
product 5a as a yellow solid; yield: 123 mg, 0.37 mmol
(75%); Rf 0.57 (cyclohexane/ethyl acetate 70:30); mp 1758C
(recrystallized from ethyl acetate to give yellow crystals).
1H NMR (300 MHz, CDCl3): d=7.55–7.49 (m, 1H), 7.42 (d,
J=8.1 Hz, 1H), 7.35–7.31 (m, 3H), 7.22–7.12 (m, 4H), 7.06
(d, J=8.7 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 3.74 (s, 3H);
13C NMR (75 MHz, CDCl3): d=161.7, 159.0, 153.2, 151.2,
134.9, 132.0 (2C), 131.3, 129.5 (2C), 128.5 (2C), 128.4, 127.8,
126.7, 126.2, 124.2, 120.8, 116.8, 113.4 (2C), 55.3; IR (film):
n=1713, 1609, 1512, 1298, 1249 !cmÀ1.
3-(4-Chlorophenyl)-7-methoxy-4-(4-methoxyphenyl)-
2H-chromen-2-one (5b): Following the general procedure
for decarboxylative coupling, a mixture of 7-methoxy-4-(4-
methoxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid 4b
(163 mg, 0.5 mmol) and 1-chloro-4-iodobenzene (238.5 mg,
1.0 mmol) was heated for 1 h. The residue was purified by
2052
asc.wiley-vch.de
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2044 – 2054

Synthesis of 3,4-Disubstituted Quinolin-2-(1H)-ones
flash chromatography over silica gel (cyclohexane/ethyl ace-
tate 90:10) to afford the desired product 5b as a pale yellow
solid; yield: 173 mg, 0.44 mmol (88%); Rf 0.59 (cyclohexane/
ethyl acetate 70 :30); mp 173–1758C (recrystallized from
ethyl acetate to give white crystals); 1H NMR (300 MHz,
CDCl3): d=7.19–7.15 (m, 3H), 7.05 (d, J=8.4 Hz, 2H), 7.01
(d, J=8.4 Hz, 2H), 6.91 (d, J=2.4 Hz, 1H), 6.84 (d, J=
8.7 Hz, 2H), 6.76 (dd, J=2.4–8.7 Hz, 1H), 3.89 (s, 3H), 3.81
(s, 3H); 13C NMR (75 MHz, CDCl3): d=162.8, 161.6, 159.7,
155.1, 152.2, 133.4, 133.0, 132.3 (2C), 130.9, 129.1, 128.2,
126.7, 122.6, 114.2, 114.0 (2C), 112.4, 100.8, 55.9, 55.4; IR
(film): n=1714, 1615, 1548, 1294, 1266, 1032 cmÀ1; HR-MS
(ES+): m/z=415.0693, calculated for C23H17O4Na35Cl [M+
Na]+: 415.0708.
(m, 4H), 7.21 (dd, J=1.8–8.7 Hz, 1H), 7.19–7.15 (m, 1H),
7.12 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 3.98 (s,
2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.45 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=163.5, 159.8, 158.0, 141.4 (2C), 140.1,
137.1, 133.4, 131.3, 129.9 (2C), 128.6, 128.5, 128.3, 125.6,
122.3, 119.0, 116.9, 113.9 (3C), 60.9, 55.3, 41.1, 30.0; IR
(film): n=1641, 1614, 1589, 1511, 1246; HR-MS (ES+):
m/z=442.1163, calculated for C25H22NO3Na35Cl [M+Na]+:
442.1180.
Acknowledgements
3-(4-Methoxyphenyl)-4-propyl-2H-chromen-2-one (5c):
Following the general procedure for decarboxylative cou-
pling, a mixture of 2-oxo-4-propyl-2H-chromene-3-carboxyl-
ic acid 4c (116 mg, 0.5 mmol) and 1-iodo-4-methoxybenzene
(234 mg, 1.0 mmol) was heated for 1 h. The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 90:10 to 80:20) to afford the desired product
5c as a pale yellow solid; yield: 94 mg, 0.32 mmol (64%); Rf
0.55 (cyclohexane/ethyl acetate 70:30); mp 1538C (recrystal-
lized from ethyl acetate to give white crystals). 1H NMR
(300 MHz, CDCl3): d=7.66 (d, J=7.8 Hz, 1H), 7.52 (t, J=
8.1 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.31 (t, J=7.8 Hz,
1H), 7.21 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 3.86
(s, 3H), 2.68–2.63 (m, 2H), 1.67–1.55 (m, 2H), 0.91 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.6, 159.5,
153.3, 152.0, 131.2, 131.0 (2C), 127.0, 126.9, 125.3, 124.3,
119.8, 117.3, 114.1 (2C), 55.4, 31.7, 23.3, 14.5, IR (film): n=
2963, 1713, 1601, 1512, 1247 cmÀ1; HR-MS (ES+): m/z=
317.1128, calculated for C19H18O3Na [M+Na]+: 317.1148.
7-Chloro-4-methoxy-1-methyl-3-phenylquinolin-2(1H)-
one (6a): Following the general procedure for decarboxyla-
tive coupling, a mixture of 7-chloro-4-methoxy-1-methyl-2-
oxo-1,2-dihydroquinoline-3-carboxylic acid 1j (133.75 mg,
0.5 mmol) and iodobenzene (204 mg, 1.0 mmol) was heated
for 1 h. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 80:20) to afford
the desired product 6a as a beige solid; yield: 72.5 mg,
0.24 mmol (48%); Rf 0.50 (cyclohexane/ethyl acetate 70:30),
mp 127–1288C (recrystallized from hexane/dichloromethane
The CNRS is gratefully acknowledged for financial support
of this research. Our laboratory BioCIS-UMR 8076 is
a member of the laboratory of Excellence LERMIT support-
ed by a grant from ANR (ANR-10-LABX-33). The ANR is
also acknowledged for the postdoctoral fellowship to A.C.
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m/z=322.0603,
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for
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4-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic
acid 1j (125.8 mg, 0.47 mmol) and 1-iodo-3-(4-methoxyben-
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Adv. Synth. Catal. 2013, 355, 2044 – 2054