Synthesis of Biheterocycles Based on Quinolinone, Chromone, and Coumarin Scaffolds by Palladium-Catalyzed Decarboxylative Couplings

Article abstract of DOI:10.1021/acs.joc.5b02103

An efficient Pd-catalyzed decarboxylative coupling of heterocyclic carboxylic acids with heterocyclic halides to achieve the synthesis of biheterocycles of biological interest has been reported. In all cases, the cross-coupling reactions take place rapidl

Full text of DOI:10.1021/acs.joc.5b02103

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Article
Synthesis of Biheterocycles based on Quinolinone, Chromone and
Coumarin Scaffolds by Palladium-Catalyzed Decarboxylative Couplings
K. Harsha Vardhan Reddy, Jean-Daniel Brion, Samir Messaoudi, and Mouad Alami
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02103 • Publication Date (Web): 21 Dec 2015
Downloaded from http://pubs.acs.org on December 21, 2015
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The Journal of Organic Chemistry
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Synthesis of Biheterocycles based on Quinolinone,
Chromone and Coumarin Scaffolds by Palladiumꢀ
Catalyzed Decarboxylative Couplings
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K. Harsha Vardhan Reddy, Jean-Daniel Brion, Samir Messaoudi* and Mouad Alami*
Univ. ParisꢀSud, CNRS, BioCISꢀUMR 8076, Laboratoire de Chimie Thérapeutique, Equipe
Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 rue J.ꢀB. Clément,
ChâtenayꢀMalabry, Fꢀ92296, France.
samir.messaoudi@uꢀpsud.fr, mouad.alami@uꢀpsud.fr
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
An efficient Pdꢀcatalyzed decarboxylative coupling of heterocyclic carboxylic acids with
heterocyclic halides to achieve the synthesis of biheterocycles of biological interests has been
reported. In all cases, the crossꢀcoupling reactions take place rapidly in DMSO in good yields,
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and efficiently proceed in the presence of a PdBr2/DPEphos catalytic system, furnishing the
novel biheterocycles based on quinolinꢀ4ꢀone, quinolinꢀ2ꢀone, chromone and coumarin
scaffolds.
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KEYWORDS. Decarboxylative coupling, biheterocycles, palladium catalysis, quinolone,
quinolinꢀ2(1H)ꢀone, chromone and coumarin.
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1. Introduction
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Biheterocycles represent an important class of organic derivatives, which have attracted
considerable attention due to their largest application in organic synthesis, advanced materials,
and pharmaceuticals.1 On one hand, quinolinone containingꢀ biheterocycle is an important
constituent of various biologically active compounds, including topoisomerase inhibitors,2
adenosine A2B antagonists3 as well as multikinase inhibitors4 (Figure 1). On the other hand, the
quinolinꢀ2(1H)ꢀone5 and coumarin6 frameworks as well as chromone units7 are present in a very
broad range of natural and non natural products of biological interest. Over the past decades,
synthesis and screening of these heterocyclic compounds for drug discovery has been a subject
of constant interest in medicinal chemistry. Derivatisation of these heterocyclic pharmacophores
represents a convenient approach to generate chemical diversity during lead identification and
optimization. Thus, the combination of these privileged structures in single chemical entities, as
depicted in Figure 1, may lead to the identification of novel “multifunctional ligands“ able to
interfere with different biological pathways in a dual way.
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FIGURE 1. Chemical structures of bioactive bi-heterocycles and targeted products
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Traditional strategies for the preparation of such molecules employ the coupling of an
heterocyclic halide with an organometallic heterocyclic derivative under palladium catalysis.
However, this strategy requires the preparation and use of stoichiometric amounts of
organometallic derivatives such as HetArB(OR)2, HetArZnX, HetArMgX or HetArSnR3, in
which instability of the C−M bond, in some cases, lessens their synthetic utility.
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As part of our continuing efforts at the functionalization of heterocycles via transition metalꢀ
catalyzed reactions,8 combined with our interest in discovering novel scaffolds of biological
interest, we required the synthesis of biheterocycles based on quinolinꢀ2ꢀone, quinolinꢀ4ꢀone
coumarin, or chromone scaffolds (Figure 1). Their preparation was envisioned through a
palladiumꢀcatalyzed decarboxylative coupling of an heterocyclic carboxylic acid with another
heterocyclic halide. Such procedure which generated minimum waste upon decarboxylation,
places this transformation amongst the greenest alternatives to traditional crossꢀcouplings.9
Despite the great success of this reaction in the formation of heteroarene−aryl units via the
coupling of heteroarene carboxylic acids with aryl halides,10 similar strategies for the
construction of “heterocycle-heterocycle” such as quinolinoneꢀcoumarin remain far less
explored. In this area, very recently, we have reported a highly efficient and versatile
decarboxylative coupling reaction of quinolinoneꢀ3ꢀcarboxylic acids8e with (hetero)aryl halides.
The bimetallic system composed of PdBr2/DPEphos/Ag2CO3 enables highꢀyielding reactions
with various (hetero)aryl halides. In addition, we demonstrated through a preliminary result that
the use of these conditions also enabled, for the first time, decarboxylative coupling of
quinolinoneꢀ3ꢀcarboxylic acid 1a with 3ꢀbromocoumarin or quinolinꢀ2(1H)ꢀone to provide 3a
and 4a in moderate yields (40% and 56%, respectively, Scheme 1).
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SCHEME 1. Pd-Catalyzed Decarboxylative Coupling of 1a with 3-bromocoumarin and
quinolinone under our Previously Optimized Conditions.
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Given the practical importance of efficient biheterocycles syntheses for the purpose of our
medicinal chemistry program, we were interested in extending the scope of the palladiumꢀ
catalyzed decarboxylative coupling of quinolinꢀ4ꢀoneꢀ3ꢀcarboxylic acids with various coumarins
and quinolinꢀ2ꢀones. In these cases, all our attempts to increase the yields of 3a and 4a by using
high catalyst loading (up to 20 mol %) and elevated temperatures (up to 170 °C) combined with
a prolonged reaction time did not lead to any improvement. These unsuccessful results clearly
demonstrate that the nature of the heterocyclic substrates play a critical role in the outcome of
this decarboxylative coupling reaction. To address difficulties associated with the reactivity of
coumarin and quinolinꢀ2(1H)ꢀone derivatives, we decided to investigate these challenging
couplings by fineꢀtuning of the reaction conditions. The results of this study are now reported.
2. Results and Discussion
Initial investigations were performed coupling quinolinꢀ4ꢀone 3ꢀcarboxylic acid 1a with 3ꢀ
bromocoumarin 2a as a model study (Table 1). When the reaction was performed using our
previously reported procedure [PdBr2 (5 mol%), DPEphos (10 mol%); Ag2CO3 (1 equiv) in
toluene:DMA at 150 °C for 1 h under microwave irradiation], only 40% yield of 3a were
obtained (Table 1, entry 1). A similar yield was obtained when the reaction was heated in an oil
bath at 150 °C for 3 h in a mixture toluene/DMA 1:1 (entry 2) or in DMSO (entry 3).
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Table 1: Optimization of the coupling reaction of 1a with 3ꢀbromocoumarin
2aa
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Entry
[Pd]
Ligand
Solvent
Time
(min)
Yieldb (%)
1
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdCl2
DPEphosc PhMe:DMA
DPEphosc PhMe:DMA
DPEphosc DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMSO
DPEphos DMA
60
180
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30
10
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10
10
40
2
41
3
40
4
60
5
61
6
76d,e,f,g
62
7
8
PdI2
60
9
Pd(OAc)2
Pd(acac)2
PdBr2
PdBr2
72
10
11
12
40
29
DPEphos Mesitylene
22
a) Reaction conditions: 1a (1 equiv, 0.188 mmol), 2a (2 equiv), [Pd] (5 mol%), ligand
(20 mol%), base (1 equiv) in solvent (2 mL) were heated in a sealed tube at indicated
temperature. Yield of isolated 3a. c) 10 mol% of DPEphos was used. d) For control
b)
e)
experiments, no conversion at all was observed in the absence of PdBr2 or Ag2CO3.
Compound 3a was formed in 60% yield when reaction was carried out with Pddba2 (5
f)
mol%) instead PdBr2. 40% yield of 3a were obtained when using only 5 mol% of
PdBr2 and 5 mol% of DPEPhos, and 66% yield of 3a were obtained when using only 3
g)
mol% of PdBr2 and 20 mol% of DPEPhos. Only 24% yield of 3a were obtained
when the reaction was carried out in a mixture of DMA:Toluene (1.8 mL:0.2 mL) as
the solvent.
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Interestingly, increasing the amount of the phosphine (up to 20 mol%) in the same otherwise
conditions drives the coupling to completion, and 3ꢀcoumarinoꢀ3ꢀylꢀquinolinone 3a was
obtained in a 60% yield (entry 4). This result is consistent with the possibility of the phosphine
ligand to act as a reducing agent to convert Pd to Pd(0). Moreover, decreasing the reaction time
into 30 min led to a similar yield (entry 5), whereas the yield of 3a increases to 76% when the
reaction was run in only 10 min (entry 6). It should be noted that the palladium catalyst is
necessary to achieve this transformation since no reaction occurs when the coupling is
conducted in the absence of PdBr2. A brief survey of palladium catalysts revealed that the source
of the catalyst has an influence in the outcome of the reaction. We were delighted to find that the
use of PdBr2 in combination with DPEphos for only 10 min heating at 150 °C is the best
combination of the coupling reaction with yield of 3a up to 76% (entry 6). A similar yield was
obtained when the reaction of 1a and 2a was performed with Pd(OAc)2 (entry 9), whereas
PdCl2, PdI2 and Pd(acac)2 were less efficient (entries 7, 8 and 10). The screening of other
solvents revealed that DMSO is the most effective (entries 6 and 11, 12). In summary, the best
conditions were found to require 1a (1 equiv), 2a (2 equiv), PdBr2 (5 mol%), DPEphos (20
mol%), Ag2CO3 (1 equiv), DMSO in a sealed tube at 150 °C for 10 min (entry 6). It should be
noted that this coupling of 1a with 2a is not limited to a small scale (0.56 mmol) as it could be
conveniently performed on a gramꢀscale (2 mmol, 4ꢀfold scale up) in a slightly lower yield.
With a viable coupling procedure in hand, attention was turned to the generality of the process,
and the couplings of structurally diverse heterocyclic carboxylic acids with diverse heterocyclic
halides. Remarkably, this heterocycle-heterocycle coupling reaction appeared to be quite general
with respect to both heterocyclic partners (Tables 2 and 3) and in all cases no homocoupled byꢀ
products were detected. First, we investigated the scope of the the Pdꢀcatalyzed decarboxylative
coupling of various substituted quinolinꢀ4ꢀones 3ꢀcarboxylic acids 1 with 3ꢀbromoꢀcoumarins
and 3ꢀbromoquinolinꢀ2ꢀones 2 possessing different steric and electronic properties.
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Gratifyingly, all the couplings proceeded cleanly and selectively in good to excellent yields
regardless the nature of the substituents on the aromatic ring of the quinolinꢀ4ꢀone 3ꢀcarboxylic
acid or coumarin/quinolinꢀ2ꢀone moities (compounds 3a-o, Table 2). Under our optimal
conditions, the reaction selectivity was investigated with coumarin and quinolinꢀ2ꢀone substrates
containing two carbonꢀbromine bonds. The coupling proceeded at the more activated Cꢀ3
position and yielded the monoꢀcoupling products 3c, 3h, 3k, and 3o in good yields, without any
trace of the side product arising from the coupling at 6ꢀBr position. The selectivity of this
procedure in the case of other heterocyclic substrates must be especially underlined, since the
reaction with 3,5ꢀdibromopyridinone gives only 3ꢀquinoylꢀ5ꢀbromopyridinone 3p in a 63%
yield. The presence of carbon−halogen bond in 3c, 3h, 3k, 3o and 3p provided a handle for
further structural diversifications using metalꢀcatalyzed cross coupling reactions.
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TABLE 2. Pd-catalyzed Decarboxylative Coupling of Quinolinone 3-carboxylic acids 1
With 3-Bromocoumarins and 3-Bromoquinolin-2(1H)-onesa
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8
R3
O
PdBr2 (5 mol%)
COOH
Br
O
DPEphos (20 mol%)
Ag2CO3 (1 equiv)
R1
R3
Z
9
R1
N
R2
O
Z
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O
N
R2
3
2 (Z = O, NMe)
1
Me
Br
O
O
O
O
O
O
O
O
O
O
N
O
O
N
N
Cl
N
3a, 76%b
52%b (750 mg scale)
Ph
Ph
Ph
Ph
3b, 64%b
3c, 59%b
Me
3d, 68%b
Br
Me
O
N
O
O
N
O
O
O
O
O
O
O
O
F
F
N
F
O
Cl
N
3e, 72%b
3f, 70%b
Me
3g,81%b
Br
3h, 61%b
Ph
F
F
F
O
N
O
O
O
MeO
O
MeO
O
O
MeO
O
O
N
O
O
N
N
N
3i, 64%b
3j, 72%b
3k, 61%b
Br
3l, 66%b
OMe
O
OMe
O
OMe
Br
MeO
N
O
N
O
O
O
N
O
N
O
N
F
N
N
N
3m, 70%b
3n, 85%b
3o, 71%b
3p, 63%b
Ph
OMe
F
a A solution of 1 (0.56 mmol) and 2 (2 equiv) in DMSO (2 mL) was added PdBr2 (5.0 mol%), DPEphos
(20 mol %) and Ag2CO3 (1equiv). The reaction vessel was capped with a rubber septum, evacuated and
backfilled with argon. The reaction vessel was sealed, then placed in the Emrys Optimizer and exposed
to microwave irradiation according to the following specifications: temperature: 150 °C; 10 minutes. b
Yield of isolated products 3a-p.
To further expand the scope of our methodology, we used this catalytic system in direct coupling
of other heterocyclic carboxylic acids with various heterocyclic halides (Table 3). Overall, we
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were pleased with the generality of our protocol. The reactions proceeded in good yields with
substituted naphthyridinꢀ4ꢀone, affording the corresponding 3ꢀnaphthyridinꢀ4ꢀoneꢀcoumarin
biheterocycle 4a with an acceptable 41% yield (Table 3). Remarkably, chromꢀ4ꢀone 2ꢀ
carboxylic acids and coumarin 3ꢀcarboxylic acids also undergoes clean selective coupling with
various halogenated heterocyclic compounds such as 3ꢀbromoquinolinꢀ2ꢀones, 3ꢀ
bromocoumarins, 3ꢀiodoquinolinones as well as 3ꢀbromopyridinones, providing the desired
coupling products 4b-l in yields ranging from 64 to 84%.
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TABLE 3 Pd-catalyzed Decarboxylative Coupling of Various Heterocyclic Carboxylic
Acids with Substituted Heterocyclic Halidesa
PdBr2 (5 mol%)
Heterocycle
COOH
COOH
Br
DPEphos (20 mol%)
Ag2CO3 (1 equiv)
Heterocycle
Heterocycle
Heterocycle
4a-l
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
Bn
Et
4a, 41%b
4b, 66%b
4c, 70%b
4d, 72%b
O
O
O
O
O
O
O
N
OMe
OMe
Br
CH3
MeO
CH3
O
N
O
O
O
O
MeO
O
O
4e, 71%b
4f, 77%b
4g, 84%b
4h, 81%b
Et
N
O
N
O
N
O
N
Br
O
O
O
O
O
O
O
O
O
4i, 72%b
4j, 64%b
4k, 68%b,c
4l, 75%b
a A solution of heterocycle carboxylic acid (0.56 mmol mmol) and heterocycle halide (2 equiv) in
DMSO (2 mL) was added PdBr2 (5.0 mol%), DPEphos (20 mol %) and Ag2CO3 (1equiv). The reaction
vessel was capped with a rubber septum, evacuated and backfilled with argon. The reaction vessel was
sealed, then placed in the Emrys Optimizer and exposed to microwave irradiation according to the
b
following specifications: temperature: 150 °C; 10 minutes. All yields given are yields of isolated
products after column purification. c3ꢀiodoquinlone was used as the coupling partner.
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The proposed reaction mechanism is outlined in Scheme 2. The reaction starts with the
extrusion of CO2 from a silvercarboxylate A which is generated from the carboxylic acid
heterocycle and silver carbonate. The resulting intermediate B transfers its heterocycle group to
an heterocyclepalladium(II) complex C generated by oxidative addition of an heterocycle
bromide to a palladium catalyst, giving rise to a biheterocyclepalladium(II) species D. The
catalytic cycle for the palladium is closed by reductive elimination of the bisꢀheterocycle, thus
also regenerating the initial palladium(0) species.
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SCHEME 2. Proposed mechanism for the Pd-catalyzed bis-heterocycle synthesis
3. Conclusion
In summary, we have reported a novel palladiumꢀcatalyzed direct decarboxylative coupling
process to form a series of biheterocycle derivatives in good yields. This protocol exhibited
broad substrate scope with respect to both the heterocyclic carboxylic acids and halide partners.
It provides an attractive alternative to the existing methods for the synthesis of substituted
biheterocycles of biological interests. We believe that this methodology should find broad
applications in synthetic organic chemistry, as well as in the combinatorial and pharmaceutical
sciences.
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4. Experimental Section
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General. All reactions were conducted under an argon atmosphere. Solvents: cyclohexane, ethyl
acetate (EtOAc) for extraction and chromatography were technical grade. These compounds
were all identified by the usual physical methods that are 1H NMR, 13C NMR (JꢀMOD), IR, HRꢀ
MS (ESI or APCI). 1H NMR, 13C NMR spectra were measured in CDCl3. 1H chemical shift are
reported in ppm from an internal standard TMS or of residual chloroform (7.27 ppm). The
following abreviations are used: m (multiplet), s (singlet), bs (broad singlet), d (doublet), t
(triplet), dd (doublet of doublet), td (triplet of doublet), q (quartet), qui (quintet), sex (sextet).
13C chemical shift are reported in ppm from central peak of deuteriochloroform (77.14). Highꢀ
resolution mass spectra (HRꢀMS) were recorded on a MicroTOF spectrometer, using ESI or
APCI with methanol as the carrier solvent. Nominal and exact m/z values are reported in
Daltons. IR spectra were measured are reported in wave numbers (cmꢀ1). Analytical TLC was
performed on precoated silica gel plates. Silica gel 60 (0.0150 – 0.040 mm) was used for flash
chromatoghraphy. Carboxylic acids 1 are commercially available or prepared as it was reported
in the literature.11 3ꢀBromocoumarins and 3ꢀbromoquinolinones are prepared as it was reported
in the literature.12
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General procedure for decarboxylative arylation of quinolone-3-carboxylic acid 1 and
related heterocyclic carboxylic acid with hetero aryl halides 2 under microwave
irradiation:
A flameꢀdried resealable 2–5 mL Pyrex reaction vessel was charged with the solid reactant(s):
PdBr2 (5.0 mol%), DPEphos (20 mol %), heterocyclic carboxylic acid (1 equiv), hetero aryl
halide (2 equiv) and Ag2CO3 (1equiv). The reaction vessel was capped with a rubber septum,
evacuated and backfilled with argon; this evacuation/backfill sequence was repeated one
additional time. DMSO (2 mL) was added through the septum. The septum was replaced with a
Teflon screwcap. The reaction vessel was sealed, then placed in the Emrys Optimizer and
exposed to microwave irradiation according to the following specifications: temperature: 150
°C; 10 minutes; fixed hold time: on; high absorption: high; preꢀstirring: 30 seconds. The
resulting suspension was cooled to room temperature and filtered through a pad of Celite
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eluting with ethyl acetate, and the inorganic salts were removed. The crude reaction mixture was
diluted with sat. aq. NaCl solution (7.5 mL) and extracted with ethyl acetate (3x7.5 mL). The
combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The
organic layers were evaporated under reduced pressure and the resulting crude was concentrated
and purification of the residue by silica gel column chromatography gave the desired product.
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3-(2-oxo-2H-chromen-3-yl)-1-phenylquinolin-4(1H)-one (3a)8e: The reaction was carried out
from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and 3ꢀbromocoumarin 2a12a.
Yield: 76% (155.4 mg, 0.56 mmol); white solid; mp: 249ꢀ251°C; TLC : R
0.44 (cꢀ
f
hexane/EtOAc 70/30); IR (neat): ν (cmꢀ1) 3064, 1717, 1619, 1609, 1585, 1548, 1477, 1451,
1
1373, 1344, 1321, 1279, 1255, 1195, 1160, 1122, 1099, 1028; H NMR (300 MHz, CDCl3) δ
9.03 (s, 1H), 8.77 (s, 1H), 8.58 (dd, J = 8.0, 1.3 Hz, 1H), 7.67 – 7.39 (m, 9H), 7.30 (dd, J = 10.7,
4.3 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 175.8 (C), 161.2 (C), 153.0
(C), 144.9 (CH), 142.3 (CH), 141.4 (C), 140.2 (C), 132.1 (CH), 131.1 (CH), 130.4 (2CH), 129.8
(CH), 128.4 (CH), 127.6 (2CH), 127.3 (CH), 126.7 (C), 124.6 (CH), 124.5 (CH), 120.0 (2C),
117.5 (CH), 116.2 (CH), 113.4 (C). HRMS (ESI): m/z calc. for C24H15NO3 (M+H)+ 366.1130,
found: 366.1134.
3-(6-methyl-2-oxo-2H-chromen-3-yl)-1-phenylquinolin-4(1H)-one (3b): The reaction was
carried out from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and 3ꢀbromoꢀ6ꢀ
methylꢀ2Hꢀchromenꢀ2ꢀone 2b12a. Yield: 64% (135.9 mg, 0.56 mmol); White solid; mp: 233ꢀ
235°C; TLC: R f 0.37 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ1)1713, 1622, 1607, 1589, 1552,
1493, 1477, 1402, 1373, 1317, 1276, 1245, 1227, 1199, 1167, 1151, 1133, 1119, 1098, 1068,
1
1
1041, 1028, 1000; H NMR (300 MHz, CDCl3) δ H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H),
8.79 (s, 1H), 8.61 (dd, J = 8.0, 1.3 Hz, 1H), 7.72 – 7.21 (m, 10H), 7.11 (d, J = 8.5 Hz, 1H), 2.46
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.8 (C), 161.3 (C), 151.1 (C), 144.8 (CH), 142.2 (CH),
141.3 (C), 140.1 (C), 134.0 (C), 132.1 (CH), 131.9 (CH), 130.3 (CH), 129.6 (CH), 128.1 (CH),
127.6 (2CH), 127.1 (CH), 126.6 (C), 124.4 (CH), 123.8 (CH), 119.8 (C), 119.7 (C), 117.4 (CH),
+
115.8 (CH), 113.4 (C), 20.9 (CH3). HRMS (ESI): m/z calc. for C25H17NO3 (M+H) 380.1287,
found: 380.1281.
3-(6-bromo-2-oxo-2H-chromen-3-yl)-1-phenylquinolin-4(1H)-one (3c): The reaction was
carried out from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and 3,6ꢀdibromoꢀ
2Hꢀchromenꢀ2ꢀone 2c12a. Yield: 59% (146.7 mg, 0.56 mmol); Yellow solid; mp: 253ꢀ255°C;
TLC : R f 0.45 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ1) 3072, 1716, 1618, 1607, 1576,
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1546, 1493, 1476, 1397, 1372, 1338, 1310, 1266, 1248, 1186, 1128, 1119, 1096, 1067, 1039,
1
2
3
1
1022; H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.76 (s, 1H), 8.56 (dd, J = 8.0, 1.5 Hz, 1H),
7.72 (d, J = 2.3 Hz, 1H), 7.67 – 7.37 (m, 8H), 7.20 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.0 Hz,
1H).13C NMR (75 MHz, CDCl3) δ 175.8 (C), 160.6 (C), 151.7 (C), 145.1 (CH), 141.3 (C), 140.5
(CH), 140.2 (C), 134.2 (CH), 133.7 (CH), 132.2 (CH), 130.5 (CH), 130.5 (CH), 129.8 (CH),
127.6 (CH), 127.2 (CH), 126.7 (C), 124.7 (CH), 121.6 (C), 121.1 (2C), 117.9 (CH), 117.6 (CH),
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117.1 (C), 112.9 (CH). HRMS (ESI): m/z calc. for C24H1479BrNO3 (M+H) 444.0235, found:
+
444.0240. and m/z calc. for C24H1481BrNO3 (M+H) + 446.0055, found: 446.0052.
7-chloro-3-(2-oxo-2H-chromen-3-yl)-1-phenylquinolin-4(1H)-one (3d): The reaction was
carried out from 7ꢀchloroꢀ4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1b11d and 3ꢀ
bromocoumarin 2a12a. Yield: 68% (135.9 mg, 0.50 mmol); White solid; mp: 253ꢀ255°C; TLC:
R
0.36 (cꢀhexane/EtOAc 30/70); IR (neat): ν (cmꢀ1) 3104, 2923, 2851, 1718, 1620, 1606,
f
1585, 1541, 1487, 1458, 1446, 1363, 1319, 1306, 1278, 1223, 1192, 1175, 1160, 1121, 1103,
1
1028, 1000; H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.73 (s, 1H), 8.50 (d, J = 8.7 Hz, 1H),
7.70 – 7.56 (m, 4H), 7.49 (ddd, J = 7.5, 5.2, 1.5 Hz, 3H), 7.41 – 7.29 (m, 3H), 7.04 (d, J = 1.8
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 175.3 (C), 161.1 (C), 153.0 (C), 145.2 (CH), 142.5
(CH), 140.9 (C), 138.6 (C), 132.7 (C), 131.3 (CH), 130.7 (2CH), 130.1 (CH), 129.0 (CH), 128.5
(CH), 127.5 (2CH), 125.3 (CH), 125.0 (C), 124.6 (CH), 119.9 (C), 119.6 (C), 117.1 (CH), 116.3
(CH), 114.0 (C). HRMS (ESI): m/z calc. for C24H14NO3Cl (M+H) + 400.0740, found: 400.0738.
7-chloro-3-(6-methyl-2-oxo-2H-chromen-3-yl)-1-phenylquinolin-4(1H)-one
(3e):
The
reaction was carried out from 7ꢀchloroꢀ4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid
1b11d and 3ꢀbromoꢀ6ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone 2b12a. Yield: 72% (148.9 mg, 0.50 mmol);
White solid; mp: 264ꢀ266°C; TLC : R f 0.32 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ1) 3103,
3078, 2925, 1921, 1712 ,1624, 1591, 1544, 1492, 1464, 1446, 1387, 1361 ,1309, 1277 , 1224
1
,1195, 1160, 1133, 1102, 1030, 1003; H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.77 (s, 1H),
8.53 (d, J = 8.5 Hz, 1H), 7.77 – 7.15 (m, 10H), 7.08 (s, 1H), 2.45 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 175.2 (C), 161.2 (C), 151.2 (C), 145.1 (CH), 142.4 (CH), 140.9 (C), 140.8 (C), 138.5
(C), 134.2 (C), 132.3 (CH), 130.6 (2CH), 130.0 (CH), 129.0 (CH), 128.2 (CH), 127.5 (2CH),
125.1 (CH), 125.0 (C), 119.6 (CH), 119.4 (C), 117.0 (C), 115.9 (CH), 114.1 (C), 20.9 (CH3).
HRMS (ESI): m/z calc. for C25H16ClNO3 (M+H) + 414.0897, found: 414.0899.
7-fluoro-1-(4-fluorophenyl)-3-(2-oxo-2H-chromen-3-yl)quinolin-4(1H)-one
(3f):
The
reaction was carried out from 7ꢀfluoroꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ3ꢀ
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carboxylic acid 1c11a and 3ꢀbromocoumarin 2a12a. Yield: 70% (137.6 mg, 0.49 mmol); White
solid; mp: 249ꢀ251°C; TLC : R f 0.35 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ1) 3065, 1688,
1615, 1558, 1506, 1485, 1374, 1339, 1323, 1280, 1246, 1218, 1199, 1160, 1147, 1121, 1094,
1
2
3
4
5
6
1
1018; H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.70 (s, 1H), 8.14 (dd, J = 9.0, 2.9 Hz, 1H),
7
8
9
7.56 (d, J = 7.8 Hz, 1H), 7.51 – 7.41 (m, 3H), 7.35 – 7.17 (m, 5H), 7.00 (dd, J = 9.3, 4.3 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ 174.9 (C), 164.6 (C), 161.3 (C), 158.1 (C), 152.9 (C), 144.8
(CH), 142.4 (CH), 137.2 (C), 136.7 (C), 131.3 (CH), 129.6 (CH), 128.4 (CH), 128.1 (C), 128.0
(C), 124.6 (CH), 120.9 (CH), 120.6 (CH), 119.8 (C), 119.7 (CH), 119.6 (CH), 117.8 (CH), 116.2
(CH), 112.9 (C), 112.1 (CH). 19F NMR (376 MHz, CDCl3) δ ꢀ109.75, ꢀ116.00. HRMS (ESI):
m/z calc. for C24H13NO3F2 (M+H) + 402.0942, found: 402.0945.
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7-fluoro-1-(4-fluorophenyl)-3-(6-methyl-2-oxo-2H-chromen-3-yl)quinolin-4(1H)-one (3g):
The reaction was carried out from 7ꢀfluoroꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ3ꢀ
carboxylic acid 1c11a and 3ꢀbromoꢀ6ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone 2b12a. Yield: 81% (164.8 mg,
0.49 mmol); White solid; mp: 206ꢀ208°C; TLC : R f 0.43 (cꢀhexane/EtOAc 70/30); IR (neat): ν
(cmꢀ1) 3444, 3065, 2927, 2251, 1912, 1717, 1622 ,1607 ,1589, 1569, 1557, 1509, 1485, 1415,
1374, 1342, 1320, 1281, 1248, 1223, 1201, 1173, 1157, 1135, 1094, 1020; 1H NMR (300 MHz,
CDCl3) δ 8.96 (s, 1H), 8.78 (d, J = 6.5 Hz, 1H), 8.22 (dd, J = 9.0, 3.0 Hz, 1H), 7.54 (ddd, J =
10.1, 5.1, 2.8 Hz, 2H), 7.44 – 7.18 (m, 6H), 7.08 (dd, J = 9.3, 4.3 Hz, 1H), 2.46 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 174.9 (C), 164.6 (C), 161.3 (C), 158.0 (C), 151.1 (C), 144.7 (CH),
142.5 (CH), 137.2 (C), 136.7 (C), 134.2 (C), 132.4 (CH), 129.6 (CH), 128.2 (C), 120.9 (CH),
120.6 (CH), 119.6 (C), 119.5 (CH), 119.4 (C), 117.7 CH), 117.4 (CH), 115.9 (CH), 113.0 (C),
112.1 (CH), 111.8 (CH), 20.9 (CH3). 19F NMR (376 MHz, CDCl3) δ ꢀ109.82, ꢀ116.11. HRMS
+
(ESI): m/z calc. for C25H15NO3F2 (M+H) 416.1098, found: 416.1103; for C25H15F2NO3
(M+Na) + 438.0918, found: 438.0929.
3-(6-bromo-2-oxo-2H-chromen-3-yl)-7-fluoro-1-(4-fluorophenyl)quinolin-4(1H)-one (3h):
The reaction was carried out from 7ꢀfluoroꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ3ꢀ
carboxylic acid 1c11a and 3,6ꢀdibromoꢀ2Hꢀchromenꢀ2ꢀone 2c12a. Yield: 61% (143.5 mg, 0.49
mmol); White solid; mp: 241ꢀ243°C; TLC : R f 0.48 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ
1) 2918, 2849, 2242,1715, 1612, 1581, 1553, 1505, 1485, 1405, 1373, 1342, 1314, 1221, 1197,
1
1152, 1129, 1089, 1066, 1015; H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 8.74 (s, 1H), 8.19
(dd, J = 9.0, 2.9 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 7.53 – 7.42
(m, 2H), 7.37 – 7.25 (m, 3H), 7.21 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 9.3, 4.3 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 174.9 (C), 164.7 (C), 161.4 (C), 160.5 (C), 158.2 (C), 151.7 (C), 145.0
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(CH), 140.8 (CH), 137.1 (C), 136.7 (C), 134.0 (CH), 130.6 (CH), 129.6 (CH), 128.2 (C), 121.5
(C), 121.1 (CH), 120.8 (CH), 119.7 (CH), 118.0 (CH), 117.5 (C), 117.2 (CH), 112.5 (C), 112.2
1
2
3
4
19
(CH), 111.9 (CH). F NMR (376 MHz, CDCl3) δ ꢀ109.59, ꢀ115.72. HRMS (ESI): m/z calc. for
5
6
79
81
C24H12NF2O3 Br (M+H) + 480.0044, found: 480.0038 and C24H12NF2O3 Br (M+H) +482.0013,
7
8
found: 482.0017.
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6-methoxy-1-(4-methoxyphenyl)-3-(2-oxo-2H-chromen-3-yl)quinolin-4(1H)-one (3i): The
reaction was carried out from 6ꢀmethoxyꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ3ꢀ
carboxylic acid 1d11c and 3ꢀbromocoumarin 2a12a. Yield: 64% (125.2 mg, 0.46 mmol); Yellow
solid; mp: 206ꢀ208°C; TLC : R f 0.60 (cꢀhexane/EtOAc 50/50); IR (neat): ν (cmꢀ1) 3079, 3007,
2988, 2954, 2910, 2832, 2062, 1702, 1612, 1579, 1554, 1511, 1488, 1436, 1382, 1353, 1322,
1
1303, 1282, 1265, 1234, 1217, 1197, 1184, 1168, 1157, 1120, 1093, 1037, 1019; H NMR (300
MHz, CDCl3) δ 8.93 (s, 1H), 8.59 (s, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.57 – 7.12 (m, 6H), 7.08 –
13
6.86 (m, , 4H), 3.82 (d, J = 12.8 Hz, 6H). C NMR (75 MHz, CDCl3) δ 175.2 (C), 161.3 (C),
160.3 (C), 156.9 (C), 153.0 (C), 144.3 (CH), 142.0 (CH), 135.2 (C), 134.2 (C), 131.0 (CH),
128.7 (2CH), 128.3 (CH), 127.9 (C), 124.5 (CH), 122.7 (CH), 120.3 (C), 120.1 (C), 119.4 (CH),
116.2 (CH), 115.4 (2CH), 112.3 (C), 106.0 (CH), 55.9 (CH3), 55.84 (CH3). HRMS (ESI): m/z
calc. for C26H19NO5 (M+H) + 426.1341, found: 426.1349.
6-methoxy-1-(4-methoxyphenyl)-3-(6-methyl-2-oxo-2H-chromen-3-yl)quinolin-4(1H)-one
(3j):
dihydroquinolineꢀ3ꢀcarboxylic acid 1d11c and 3ꢀbromoꢀ6ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone 2b12a.
Yield: 72% (145.5 mg, 0.46 mmol); White solid; mp: 230ꢀ232°C; TLC : R 0.51 (cꢀ
The reaction was carried out from 6ꢀmethoxyꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀoxoꢀ1,4ꢀ
f
hexane/EtOAc 50/50); IR (neat): ν(cmꢀ1) 3002, 2937, 2840, 2242, 1712, 1623, 1612, 1565,
1547, 1509, 1487, 1439, 1380, 1352, 1321, 1300, 1278, 1267, 1251, 1242, 1223, 1198, 1166,
1
1130, 1108, 1096, 1025; H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.71 (s, 1H), 7.99 (d, J =
2.9 Hz, 1H), 7.53 – 6.99 (m, 9H), 3.96 (d, J = 13.4 Hz, 6H), 2.45 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 175.2 (C), 161.5 (C), 160.2 (C), 156.8 (C), 151.1 (C), 144.6 (CH), 144.2 (CH), 142.1
(CH), 135.2 (C), 134.2 (C), 134.1 (C), 132.1 (CH), 128.7 (CH), 128.0 (CH), 127.8 (C), 122.7
(2CH), 120.2 (C), 119.8 (C), 119.3 (CH), 115.9 (CH), 115.3 (CH), 112.4 (C), 106.0 (CH), 55.9
+
(CH3), 55.8 (CH3), 20.9 (CH3). HRMS (ESI): m/z calc. for C27H21NO5 (M+H) 440.1487,
found: 440.1490.
3-(6-bromo-2-oxo-2H-chromen-3-yl)-6-methoxy-1-(4-methoxyphenyl)quinolin-4(1H)-one
(3k): The reaction was carried out from 6ꢀmethoxyꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀoxoꢀ1,4ꢀ
12a
dihydroquinolineꢀ3ꢀcarboxylic acid 1d11c and 3,6ꢀdibromoꢀ2Hꢀchromenꢀ2ꢀone 2c . Yield:
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61% (141.5 mg, 0.46 mmol); Yellow solid; mp: 255ꢀ257°C; TLC : R f 0.81 (cꢀhexane/EtOAc
50/50); IR(neat):ν(cmꢀ1) 2998, 2837, 1716, 1628, 1610, 1601, 1582, 1552, 1510, 1487, 1452,
1437, 1407, 1374, 1348, 1320, 1301, 1268, 1249, 1210, 1194, 1163, 1137, 1096, 1067, 1036,
1022; 1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 8.60 (d, J = 1.3 Hz, 1H), 7.84 (s, 1H), 7.60 (s,
1
2
3
4
5
6
13
7
8
1H), 7.46 (d, J = 8.7 Hz, 1H), 7.39 – 6.82 (m, 7H), 3.83 (dd, J = 12.3, 1.2 Hz, 6H). C NMR
9
(75 MHz, CDCl3) δ 175.0 (C), 160.5 (C), 160.2 (C), 156.9 (C), 151.6 (C), 144.3 (2CH), 140.2
(CH), 135.0 (C), 134.0 (C), 133.5 (CH), 130.3 (CH), 128.54 (CH), 127.7 (C), 122.7 (2CH),
121.6 (C), 121.4 (C), 119.3 (CH), 117.7 (CH), 116.9 (C), 115.2 (CH), 111.7 (C), 105.9 (CH),
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55.8 (CH3), 55.7 (CH3). HRMS (ESI): m/z calc. for C26H18NO5 Br (M+H) 504.0447, found:
81
504.0446 and m/z calc. for C26H18NO5 Br (M+H) + 506.0426, found: 506.0432.
1-methyl-1'-phenyl-[3,3'-biquinoline]-2,4'(1H,1'H)-dione (3l): The reaction was carried out
from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and 3ꢀbromoꢀ1ꢀ
methylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 66% (139.8 mg, 0.56 mmol); white solid; mp: 218ꢀ
220°C; TLC : R f 0.26 (cꢀhexane/EtOAc 50/50); IR (neat): ν (cmꢀ1) 2923, 1621, 1583, 1548,
1493, 1476, 1452, 1401, 1372, 1333,1318, 1292, 1236, 1198, 1165, 1104, 1062; 1H NMR (300
MHz, CDCl3) δ 8.79 (d, J = 8.8 Hz, 2H), 8.58 (dt, J = 12.3, 6.1 Hz, 1H), 7.68 (dd, J = 7.8, 1.3
Hz, 1H), 7.64 – 7.46 (m, 7H), 7.38 (ddd, J = 15.6, 11.3, 4.8 Hz, 2H), 7.23 (dd, J = 10.9, 3.7 Hz,
1H), 7.06 (d, J = 8.0 Hz, 1H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 176.0 (C), 161.9 (C),
144.9 (CH), 141.6 (C), 140.3 (C), 139.3 (CH), 139.1 (C), 131.7 (CH), 130.3 (2CH), 130.2 (CH),
129.5 (CH), 129.4 (CH), 127.7 (2CH), 127.3 (CH), 126.9 (C), 124.1 (CH), 123.9 (C), 122.3
(CH), 121.0 (C), 117.4 (CH), 115.2 (C), 113.9 (CH), 30.2 (CH3). HRMS (ESI): m/z calc. for
C25H18N2O2 (M+H) + 379.1447, found: 379.1450.
6'-methoxy-1'-(4-methoxyphenyl)-1-methyl-[3,3'-biquinoline]-2,4'(1H,1'H)-dione
(3m):
The reaction was carried out from 6ꢀmethoxyꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ
3ꢀcarboxylic acid 1d11c and 3ꢀbromoꢀ1ꢀmethylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 70% (141.1 mg,
0.46 mmol); White solid; mp: 231ꢀ233°C; TLC : R f 0.18 (cꢀhexane/EtOAc 50/50); IR (neat): ν
(cmꢀ1) 3117, 3079, 3010, 2934, 2837, 1630, 1612, 1584, 1547, 1512, 1490, 1458, 1435, 1414,
1374, 1350, 1328, 1292, 1267, 1252, 1232, 1212, 1187 ,1163, 1099, 1060, 10221H NMR (300
MHz, CDCl3) δ 8.84 (s, 1H), 8.75 (s, 1H), 8.01 (d, J = 2.9 Hz, 1H), 7.66 (t, J = 12.7 Hz, 1H),
7.62 – 7.50 (m, 1H), 7.40 (dt, J = 13.9, 5.9 Hz, 3H), 7.27 (dd, J = 13.5, 5.9 Hz, 1H), 7.21 – 6.98
(m, 4H), 3.96 (s, 3H), 3.91 (s, 3H), 3.78 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.3 (C), 161.9
(C), 160.1 (C), 156.5 (C), 144.4 (CH), 139.1 (CH), 139.0 (C), 135.3 (C), 134.4 (C), 130.0 (CH),
129.2 (CH), 128.7 (2CH), 127.9 (C), 124.2 (C), 122.3 (CH), 122.2 (CH), 121.0 (C), 119.2
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(CH), 115.2 (2CH), 114.1 (C), 113.8 (CH), 106.0 (CH), 55.8 (CH3), 55.7 (CH3), 30.1 (CH3).
HRMS (ESI): m/z calc. for C27H22N2O4 (M+H) + 439.1658, found: 439.1663
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7'-fluoro-1'-(4-fluorophenyl)-1-methyl-[3,3'-biquinoline]-2,4'(1H,1'H)-dione (3n): The
reaction was carried out from 7ꢀfluoroꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydroquinolineꢀ3ꢀ
carboxylic acid 1c11a and 3ꢀbromoꢀ1ꢀmethylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 85% (172.5 mg,
0.49 mmol); White solid; mp: 251ꢀ253°C; TLC : R f 0.44 (cꢀhexane/EtOAc 50/50); IR (neat): ν
(cmꢀ1) 3035, 2919, 2851, 1638, 1615, 1588, 1561, 1503, 1484, 1461, 1417, 1393, 1372, 1354,
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1334, 1317, 1296, 1259, 1243, 1215, 1202, 1163,1101, 1039, 1015; H NMR (300 MHz,
CDCl3) δ 8.73 (d, J = 2.3 Hz, 2H), 8.16 (dd, J = 9.1, 3.0 Hz, 1H), 7.64 (dd, J = 7.8, 1.1 Hz, 1H),
7.56 – 7.41 (m, 3H), 7.37 – 7.15 (m, 5H), 6.98 (dd, J = 9.3, 4.3 Hz, 1H), 3.72 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 175.1 (C), 164.5 (C), 161.8 (C), 161.1 (C), 157.9 (C), 144.9 (CH), 139.4
(CH), 139.1 (C), 136.9 (C), 130.3 (CH), 129.7 (CH), 129.4 (CH), 128.2 (C), 123.4 (C), 122.4
(CH), 120.9 (C), 120.6 (CH), 119.5 (CH), 117.6 (CH), 117.3 (CH), 114.7 (C), 113.9 (CH), 112.1
19
(CH), 111.8 (CH), 30.1 (CH3). F NMR (376 MHz, CDCl3) δ ꢀ110.25, ꢀ116.73. HRMS (ESI):
m/z calc. for C25H16N2F2O2 (M+H) + 415.1258, found: 415.1254.
6-bromo-1-methyl-1'-phenyl-[3,3'-biquinoline]-2,4'(1H,1'H)-dione (3o): The reaction was
carried out from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and 3,6ꢀdibromoꢀ
1ꢀmethylquinolinꢀ2(1H)ꢀone 2e12c. Yield: 71% (150.4 mg, 0.56 mmol); White solid; mp: 289ꢀ
291°C; TLC:Rf 0.37 (cꢀhexane/EtOAc 50/50);IR (neat): ν (cmꢀ1) 3076, 1621, 1587, 1575, 1547,
1492, 1475, 1449, 1412, 1395, 1368, 1337, 1313, 1290, 1265, 1251, 1236, 1220, 1199, 1161,
1122, 1104, 1084, 1072, 1038, 1023, 1002; 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.70 (s,
1H), 8.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.64 – 7.44 (m, 7H), 7.43 – 7.32
(m, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 175.8 (C), 161.5 (C), 145.0 (CH), 141.5 (C), 140.2 (C), 137.9 (C), 137.7 (CH), 132.7
(CH), 131.8 (CH), 131.2 (CH), 130.3 (2CH), 129.5 (CH), 127.6 (2CH), 127.3 (CH), 126.8 (C),
125.1 (C), 124.2 (CH), 122.5 (C), 117.4 (CH), 115.5 (CH), 115.0 (C), 114.7 (C), 30.3 (CH3).
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HRMS (ESI): m/z calc. for C25H17N2O2 Br (M+H) 457.0552, found: 457.0559 and m/z calc.
81
for C25H17N2O2 Br (M+H) + 459.0531, found: 459.0552.
3-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1-phenylquinolin-4(1H)-one(3p): The
reaction was carried out from 4ꢀoxoꢀ1ꢀphenylꢀ1,4ꢀdihydroquinolineꢀ3ꢀcarboxylic acid 1a11c and
3,5ꢀdibromoꢀ1ꢀmethylpyridinꢀ2(1H)ꢀone 2f12d. Yield: 63% (143.6 mg, 0.56 mmol); Yellow
solid; mp: 273ꢀ275°C; TLC : R 0.26 (cꢀhexane/EtOAc 20/80); IR (neat): ν (cmꢀ1) 3057,
f
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1775, 1636, 1619, 1603, 1586, 1570, 1548, 1533, 1493, 1478, 1448, 1422, 1404, 1367, 1348,
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1317, 1304, 1247, 1207, 1155, 1120, 1089, 1073, 1038, 1001; H NMR (300 MHz, CDCl3) δ
8.91 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.53 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 – 7.32 (m, 8H), 7.03
(d, J = 8.5 Hz, 1H), 3.54 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.7 (C), 160.7 (C), 144.8
(CH), 142.2 (CH), 141.5 (C), 140.2 (C), 136.0 (CH), 131.7 (CH), 130.3 (2CH), 129.5 (CH),
127.6 (2CH), 127.2 (CH), 126.8 (C), 124.7 (C), 124.2 (CH), 117.4 (CH), 113.9 (C), 98.7 (CH),
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38.5 (CH3). HRMS (ESI): m/z calc. for C21H1579BrN2O2 (M+H) 407.0395, found: 407.0400
+
and m/z calc. for C21H1581BrN2O2 (M+H) + 409.0375, found: 409.0385.
1-ethyl-7-methyl-3-(2-oxo-2H-chromen-3-yl)-1,8-naphthyridin-4(1H)-one (4a): The reaction
was carried out from 1ꢀethylꢀ7ꢀmethylꢀ4ꢀoxoꢀ1,4ꢀdihydroꢀ1,8ꢀnaphthyridineꢀ3ꢀcarboxylic acid
(commercially available) and 3ꢀbromocoumarin 2a12a. Yield: 41% (87.2 mg, 0.64 mmol);
White solid; mp: 220ꢀ222°C; TLC : R 0.515 (cꢀhexane/EtOAc 50/50); IR (neat): ν (cmꢀ1)
f
3086, 2965, 2919, 2849, 1714, 1619, 1604, 1573, 1540, 1498, 1485, 1444, 1375, 1347, 1316,
1
1263, 1234, 1184, 1151, 1136, 1118, 1098, 1052, 1021; H NMR (400 MHz, CDCl3) δ 9.01 (s,
1H), 8.88 (s, 1H), 8.67 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H),
7.32 (dd, J = 18.3, 7.9 Hz, 3H), 4.55 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 176.2 (C), 173.4 (C), 162.5 (C), 161.3 (C), 152.9 (C), 148.0 (C),
144.6 (C), 141.9 (CH), 136.6 (CH), 136.0 (CH), 131.1 (CH), 128.4 (CH), 124.5 (CH), 120.5 (C),
120.0 (CH), 116.2 (CH), 114.1 (C), 46.4 (CH2), 30.4 (CH3), 15.4 (CH3). HRMS (ESI): m/z calc.
for C20H16N2O3 (M+H) + 333.1239, found: 333.1233.
2'H,4H-[2,3'-bichromene]-2',4-dione(4b): The reaction was carried out from 4ꢀoxoꢀ4Hꢀ
chromeneꢀ2ꢀcarboxylic acid (commercially available) and 3ꢀbromocoumarin 2a12a. Yield: 66%
(149.4 mg, 0.78 mmol); White solid; mp: 243ꢀ245°C; TLC : R f 0.14(cꢀhexane/EtOAc70/30);
IR(neat): ν(cmꢀ1); 3064, 1722, 1701, 1633, 1608, 1563, 1488, 1465, 1450, 1397, 1349, 1330,
1280, 1244, 1208, 1187, 1163, 1136, 1120, 1092, 1026: 1H NMR (300 MHz, CDCl3) δ 8.60 (d,
J = 7.0 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.75 – 7.54 (m, 5H), 7.47 – 7.29 (m, 3H). 13C NMR
(75 MHz, CDCl3) δ 178.5 (C), 156.6 (C), 156.2 (C), 154.1 (C), 143.8 (CH), 142.8 (CH), 134.1
(CH), 134.0 (CH), 129.4 (CH), 126.0 (CH), 125.4 (CH), 125.2 (CH), 124.0 (2C), 118.4 (C),
+
117.8 (CH), 116.8 (CH), 112.9 (CH). HRMS (ESI): m/z calc. for C18H10O4 (M+H) 291.0657,
found: 291.0666.
1-methyl-3-(4-oxo-4H-chromen-2-yl)quinolin-2(1H)-one (4c): The reaction was carried out
from 4ꢀoxoꢀ4Hꢀchromeneꢀ2ꢀcarboxylic acid (commercially available) and 3ꢀbromoꢀ1ꢀ
methylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 70% (165.4 mg, 0.78 mmol); Yellow solid; mp: 249ꢀ
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251°C;TLC : R f 0.35 (cꢀhexane/EtOAc 50/50); IR (neat): ν (cmꢀ1): 1651, 1632, 1612, 1597,
1586, 1566, 1497, 1473, 1454, 1415, 1392, 1351, 1328, 1305, 1233, 1198, 1167, 1126, 1104,
1056, 1022; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.20 (dt, J = 10.3, 5.2 Hz, 1H), 7.88 (s,
1H), 7.78 – 7.64 (m, 3H), 7.56 (dd, J = 8.4, 0.7 Hz, 1H), 7.43 – 7.28 (m, 3H), 3.80 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 178.9 (C), 159.3 (C), 158.3 (C), 156.3 (C), 140.5 (C), 139.2 (CH),
133.7 (CH), 132.8 (CH), 130.5 (CH), 125.9 (CH), 125.0 (CH), 124.1 (C), 122.8 (C), 122.2 (CH),
119.4 (C), 117.93(CH), 114.4 (CH), 112.9 (CH), 30.1 (CH3). HRMS (ESI): m/z calc. for
C19H13NO3 (M+H) + 304.0974, found: 304.0981.
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1-benzyl-3-(4-oxo-4H-chromen-2-yl)quinolin-4(1H)-one (4d): The reaction was carried out
from 4ꢀoxoꢀ4Hꢀchromeneꢀ2ꢀcarboxylic acid (commercially available) and 1ꢀbenzylꢀ3ꢀ
bromoquinolinꢀ4(1H)ꢀone 2g12c. Yield: 72% (212.9 mg, 0.78 mmol); White solid; mp:273ꢀ
275°C; TLC:Rf0.16(cꢀhexane/EtOAc50/50); IR(neat): ν(cmꢀ1) 2917, 2849, 2360, 1637, 1605,
1583, 1562, 1546, 1486, 1451, 1429, 1408, 1351, 1320, 1265, 1227, 1187, 1129, 1060, 1024; 1H
NMR (300 MHz, CDCl3) δ 9.59 (s, 1H), 8.65 – 8.51 (m, 2H), 8.08 (s, 1H), 7.71 – 7.47 (m, 2H),
7.46 – 7.18 (m, 9H), 5.51 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 178.6 (C), 159.7 (C), 158.6 (C),
155.8 (C), 145.9 (CH), 143.9 (CH), 139.5 (C), 138.8 (C), 135.6 (C), 134.3 (C), 133.3 (CH),
129.6 (CH), 129.2 (CH), 128.8 (CH), 128.2 (CH), 127.9 (CH), 127.4 (CH), 126.4 (CH), 125.9
(CH), 125.2 (CH), 124.8 (CH), 117.5 (CH), 111.6 (C), 110.6 (CH), 57.7 (CH2). HRMS (ESI):
m/z calc. for C25H17NO3 (M+H) + 380.1287, found: 380.1291.
5-bromo-1-methyl-3-(4-oxo-4H-chromen-2-yl)pyridin-2(1H)-on (4e): The reaction was
carried out from 4ꢀoxoꢀ4Hꢀchromeneꢀ2ꢀcarboxylic acid (commercially available) and 3,5ꢀ
dibromoꢀ1ꢀmethylpyridinꢀ2(1H)ꢀone 2f12d. Yield: 71% (183.9 mg, 0.78 mmol); Yellow solid;
mp: 212ꢀ214°C; TLC : Rf 0.32(cꢀhexane/EtOAc 30/70); IR (neat): ν (cmꢀ1) 3056, 2918, 1656,
1630, 1596, 1580, 1564, 1533, 1527, 1470, 1433, 1416, 1394, 1377, 1352, 1301, 1278, 1234,
1
1205, 1157, 1127, 1068; H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 2.8 Hz, 1H), 8.21 (dd, J =
8.0, 1.6 Hz, 1H), 7.92 (s, 1H), 7.67 (dt, J = 4.8, 1.7 Hz, 2H), 7.57 – 7.48 (m, 1H), 7.44 – 7.34
(m, 1H), 3.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.8 (C), 158.4 (C), 157.0 (C), 141.8 (C),
140.7 (CH), 133.9 (CH), 125.9 (CH), 125.2 (CH), 124.1 (C), 122.1 (C), 119.1 (C), 117.8 (CH),
+
112.4 (CH), 97.1 (CH), 38.8 (CH3). HRMS (ESI): m/z calc. for C15H1079BrNO3 (M+H)
+
331.9922, found: 331.9929 and m/z calc. for C15H1081BrNO3 (M+H)
333.9902, found:
333.9909.
6-methyl-2H,2'H-[3,3'-bichromene]-2,2'-dione (4f): The reaction was carried out from 2ꢀoxoꢀ
2Hꢀchromeneꢀ3ꢀcarboxylic acid (commercially available) and 3ꢀbromoꢀ6ꢀmethylꢀ2Hꢀ
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chromenꢀ2ꢀone 2b12a. Yield: 77% (182.7 mg, 0.78 mmol); White solid; mp: 244ꢀ246°C;
TLC:Rf0.40(cꢀhexane/EtOAc70/30); IR(neat): ν(cmꢀ1) 2957, 2923, 2853, 1729, 1690, 1622,
1605, 1567, 1491, 1458, 1363, 1346, 1307, 1277, 1249, 1221, 1172, 1157, 1125, 1080; 1H NMR
(300 MHz, CDCl3) δ 8.55 (d, J = 15.8 Hz, 2H), 7.57 (dd, J = 13.9, 7.2 Hz, 2H), 7.45 – 7.18 (m,
5H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.41 (C), 160.2 (C), 153.4 (C), 151.6 (C),
143.8 (CH), 143.7 (CH), 134.5 (C), 133.5 (CH), 133.5 (CH), 132.4 (CH), 128.9 (CH), 124.8
(CH), 120.3 (C), 120.0 (C), 119.2 (C), 118.9 (C), 116.5 (CH), 116.2 (CH), 20.9 (CH3). HRMS
(ESI): m/z calc. for C19H12O4 (M+H) + 305.0814, found: 305.0819.
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5,7-dimethoxy-6'-methyl-2H,2'H-[3,3'-bichromene]-2,2'-dione (4g): The reaction was carried
out from 5,7ꢀdimethoxyꢀ2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid 1e11b and 3ꢀbromoꢀ6ꢀmethylꢀ2Hꢀ
chromenꢀ2ꢀone 2b12a. Yield: 84% (180.5mg, 0.59mmol); White solid; mp: 229ꢀ231°C; TLC :
R 0.62 (cꢀhexane/EtOAc 50/50); IR (neat): ν (cmꢀ1) 2956, 2923, 2853, 1728, 1714, 1632,
f
1619, 1605, 1581, 1566, 1494, 1471, 1417, 1365, 1341, 1306, 1294, 1257, 1207, 1155, 1114,
1081, 1044, 1000; 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.41 (s, 1H), 7.40 – 7.30 (m, 2H),
7.30 – 7.20 (m, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 3.89 (dd, J = 10.3, 2.4
Hz, 6H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.3 (C), 160.6 (C), 160.4 (C), 157.6 (C),
156.1 (C), 151.3 (C), 142.5 (CH), 139.1 (CH), 134.2 (C), 132.8 (CH), 128.2 (CH), 120.9 (C),
119.0 (C), 116.0 (CH), 114.8 (C), 104.4 (C), 95.0 (CH), 92.3 (CH), 56.0 (CH3), 55.8 (CH3), 20.7
(CH3). HRMS (ESI): m/z calc. for C21H16O6(M+H) + 365.1025, found: 365.1033.
3-(5,7-dimethoxy-2-oxo-2H-chromen-3-yl)-1-methylquinolin-2(1H)-one (4h): The reaction
was carried out from 5,7ꢀdimethoxyꢀ2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid 1e11b and 3ꢀbromoꢀ
1ꢀmethylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 81% (173.6 mg, 0.59 mmol); Yellow solid; mp: 251ꢀ
253°C; TLC : R 0.45 (cꢀhexane/EtOAc 50/50); IR (neat): ν(cmꢀ1) 1721, 1648, 1610, 1593,
f
1564, 1495, 1469, 1452, 1424, 1371, 1345, 1306, 1286, 1254, 1237, 1227, 1199, 1155, 1140,
1
1116, 1085, 1044, 1025; H NMR (300 MHz, CDCl3) δ 8.64 (d, J = 7.1 Hz, 1H), 8.25 (s, 1H),
7.68 – 7.47 (m, 2H), 7.32 (t, J = 12.4 Hz, 1H), 7.23 (dd, J = 11.8, 4.5 Hz, 1H), 6.43 (d, J = 2.1
Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 3.87 (d, J = 7.8 Hz, 6H), 3.77 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 163.9 (C), 161.1 (C), 161.0 (C), 157.5 (C), 156.3 (C), 139.5 (C), 139.1 (CH), 138.7
(CH), 130.8 (CH), 129.4 (CH), 125.5 (C), 122.3 (CH), 120.3 (C), 117.2 (C), 114.0 (CH), 104.6
(C), 94.9 (CH), 92.4 (CH), 56.0 (CH3), 55.9 (CH3), 30.1 (CH3). HRMS (ESI): m/z calc. for
C21H17NO5 (M+H) + 364.1185, found: 364.1191.
1-methyl-3-(2-oxo-2H-chromen-3-yl)quinolin-2(1H)-one(4i): The reaction was carried out
from 2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid (commercially available) and 3ꢀbromoꢀ1ꢀ
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methylquinolinꢀ2(1H)ꢀone 2d12b. Yield: 72% (170.3 mg, 0.78 mmol); White solid; mp: 210ꢀ
213°C; TLC : Rf 0.22 (cꢀhexane/EtOAc70/30); IR(neat): ν(cmꢀ1): 1719, 1641, 1619, 1592, 1564,
1487, 1446, 1416, 1352, 1294, 1271, 1237, 1222, 1205, 1155,1 139, 1121, 1088, 1031, 1022; 1H
NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.32 (s, 1H), 7.69 – 7.47 (m, 4H), 7.43 – 7.21 (m, 4H),
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3.79 (s, 3H). C NMR (75 MHz, CDCl3) δ 161.0 (C), 160.5 (C), 153.5 (C), 143.2 (CH), 139.9
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(C), 139.7 (CH), 131.8 (CH), 131.3 (CH), 129.7 (CH), 128.5 (CH), 124.7 (C), 124.5 (CH), 122.5
(CH), 120.1 (2C), 119.4 (C), 116.4 (CH), 114.1 (CH), 30.2 (CH3). HRMS (ESI): m/z calc. for
C19H13NO3 (M+H) + 304.0974, found: 304.0986
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1-ethyl-3-(2-oxo-2H-chromen-3-yl)quinolin-2(1H)-one(4j): The reaction was carried out from
2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid (commercially available) and 3ꢀbromoꢀ1ꢀethylquinolinꢀ
2(1H)ꢀone 2h12d. Yield: 64% (158.4 mg, 0.78 mmol); Yellow solid; mp: 217ꢀ219°C; TLC : R f
0.28 (cꢀhexane/EtOAc 70/30); IR (neat): ν (cmꢀ1) 2961, 2925, 2853, 1720, 1641, 1619, 1591,
1562, 1486, 1462, 1443, 1371, 1349, 1293, 1276, 1241, 1221, 1198, 1156, 1138, 1123, 1084,
1038; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.72 – 7.46 (m, 4H), 7.43 – 7.20
(m, 4H), 4.42 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 160.5
(C), 153.5 (C), 143.3 (CH), 140.0 (CH), 138.7(C), 131.7 (CH), 131.2 (CH), 130.0 (CH), 128.5
(CH), 124.5 (CH), 124.3 (C), 122.3 (CH), 120.4 (2C), 119.4 (2C), 116.4 (CH), 113.9 (CH), 38.2
(CH2), 12.7 (CH3). HRMS (ESI): m/z calc. for C20H15NO3 (M+H) + 318.1130, found: 318.1137.
1-methyl-3-(2-oxo-2H-chromen-3-yl)quinolin-4(1H)-one (4k): The reaction was carried out
from 2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid (commercially available) and 3ꢀiodoꢀ1ꢀ
methylquinolinꢀ4(1H)ꢀone 2i12b. Yield: 68% (160.8 mg, 0.78 mmol); White solid; mp: 214ꢀ
216°C; TLC: Rf 0.42(cꢀhexane/EtOAc50/50); IR(neat): ν(cmꢀ1) 3062, 2360, 1714, 1 628, 1612,
1583, 1552, 1501, 1476, 1455, 1411, 1379, 1342, 1327, 1277, 1253, 1242 , 1200, 1157, 1141,
1121, 1101, 1039 ;1H NMR (300 MHz, CDCl3) δ 9.03 (s, 1H), 8.73 (s, 1H), 8.55 (dd, J = 8.3,
1.6 Hz, 1H), 7.71 (ddd, J = 8.7, 7.1, 1.6 Hz, 1H), 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.53 – 7.40 (m,
3H), 7.28 (ddd, J = 7.5, 5.8, 4.8 Hz, 2H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.8 (C),
161.5 (C), 152.9 (C), 145.9 (CH), 142.0 (CH), 139.4 (C), 132.4 (CH), 131.0 (CH), 128.4 (CH),
127.6 (CH), 127.2 (C), 124.5 (CH), 124.5 (CH), 120.1 (C), 120.0 (C), 116.2 (CH), 115.5 (CH),
+
113.0 (C), 41.5 (CH3). HRMS (ESI): m/z calc. for C19H13NO3 (M+H) 304.0974, found:
304.0976.
5-bromo-1-methyl-3-(2-oxo-2H-chromen-3-yl)pyridin-2(1H)-one (4l): The reaction was
carried out from 2ꢀoxoꢀ2Hꢀchromeneꢀ3ꢀcarboxylic acid (commercially available) and 3,5ꢀ
dibromoꢀ1ꢀmethylpyridinꢀ2(1H)ꢀone 2f12d. Yield: 75% (194.3 mg, 0.78 mmol); White solid;
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mp: 223ꢀ225°C; TLC: Rf 0.45 (cꢀhexane/EtOAc50/50); IR(neat): ν(cmꢀ1) 1718, 1649, 1609,
1587, 1536, 1456, 1419, 1347, 1301, 1232, 1210, 1163, 1127, 1042, 1016 ; 1H NMR (300 MHz,
CDCl3) δ 8.59 (s, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.52 (dd, J = 14.2, 5.1 Hz, 3H), 7.41 – 7.19 (m,
2H), 3.61 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.2 (C), 153.5 (C), 143.3 (CH), 143.1 (CH),
138.1 (CH), 132.0 (CH), 128.7 (CH), 124.9 (C), 124.6 (CH), 121.1 (C), 119.3 (C), 116.4 (CH),
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97.8 (C), 38.7 (CH3). HRMS (ESI): m/z calc. for C15H1079BrNO3 (M+H) 331.9922, found:
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331.9922 and m/z calc. for C15H1081BrNO3 (M+H) + 333.9902, found: 333.9901.
Supporting Information Available: 1H and 13C NMR spectra of new compounds 3a-p and 4a-
l. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment.
Authors acknowledge support of this project by CNRS, University Paris Sud and by La Ligue
Nationale Contre le Cancer throughout an Equipe Labellisée 2014 grant. We also thank
CEFIPRA (Raman Charpak fellowship) for the Ph.D. grant to K. H. V. R. Our laboratory
BioCISꢀUMR 8076 is a member of the Laboratory of Excellence LERMIT supported by a grant
from ANR (Agence Nationale de la Recherche, ANRꢀ10ꢀLABXꢀ33).
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