Synthesis and photochromism of a series of new 2-unsubstituted 3-(2-benzylbenzoyl)quinolin-4(1H)-ones

Article abstract of DOI:10.1016/j.tet.2010.08.039

Synthesis and characterization of a series of new 2-unsubstituted 3-(2-benzylbenzoyl)quinolin-4(1H)-ones is described. In addition to their potential biological activity, these compounds exhibit photoreversible photochromic properties in anaerobic conditions. Using the 1 and 2D NMR techniques we demonstrated that the coloration occurred owing to the formation of fluorescent 5a,6-dihydrobenzo[b]acridin-(5H)-ones. The photoreaction is stereoselective and the S,R-isomers are the major products (83%) whereas the S,S-isomers are the minor (6%). In addition, the irreversible formation of two oxidation products, 3-(2-benzoylbenzoyl)quinolin-4(1H)-ones, and acridin-12(5H)-one derivatives was observed in the presence of air.

Full text of DOI:10.1016/j.tet.2010.08.039

Tetrahedron 66 (2010) 8291e8299
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and photochromism of a series of new 2-unsubstituted
3-(2-benzylbenzoyl)quinolin-4(1H)-ones
,
y
Nina A. Larina a, Vladimir Lokshin a, Jerome Berthet b, Stephanie Delbaere b, Gaston Vermeersch b
,
,
Vladimir Khodorkovsky a
*
a Interdisciplinary Center of Nanoscience of Marseille CINaM (CNRS UPR 3118), 13288 Marseille Cedex 9, France
b Université Lille Nord de France, CNRS UMR 8516, UDSL, Faculté des Sciences Pharmaceutiques et Biologiques, F-59006, Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Received in revised form 11 August 2010
Accepted 13 August 2010
Available online 19 August 2010
Synthesis and characterization of a series of new 2-unsubstituted 3-(2-benzylbenzoyl)quinolin-4(1H)-
ones is described. In addition to their potential biological activity, these compounds exhibit photo-
reversible photochromic properties in anaerobic conditions. Using the 1 and 2D NMR techniques we
demonstrated that the coloration occurred owing to the formation of fluorescent 5a,6-dihydrobenzo[b]
acridin-(5H)-ones. The photoreaction is stereoselective and the S,R-isomers are the major products (83%)
whereas the S,S-isomers are the minor (6%). In addition, the irreversible formation of two oxidation
products, 3-(2-benzoylbenzoyl)quinolin-4(1H)-ones, and acridin-12(5H)-one derivatives was observed in
the presence of air.
Keywords:
Quinolin-4(1H)-one
Photochromism
Acridine
Ó 2010 Elsevier Ltd. All rights reserved.
Fluorescence
Hydrogen bonding
1. Introduction
Further varying the structure of the quinolone derivatives
afforded a new type of photochemically reversible and thermally
During the past decades, the main synthetic activities related to
the chemistry of quinolin-4(1H)-ones have been concentrated on
the 3-carboxy substituted derivatives 1 owing to their powerful
antibiotic properties.1 Much less information is available on de-
rivatives involving other substituents with the carbonyl group in
3-position, such as the aroyl substituents 2.
stable photochromes based on 2-substituted 3-(2-benzylbenzoyl)
derivatives.10 The colored photoproducts, unlike those from fur-
ylfulgides11 and dithienyl ethenes12, are fluorescent, which is im-
portant for non-destructive readout in information storage
applications. It was noted that even minor variations of sub-
stituents at 2-position noticeably affect the photochromic behavior
of 3-(2-benzylbenzoyl) derivatives.13
Here we report on the synthesis of a series of hitherto unknown 2-
unsubstituted-3-(2-benzylbenzoyl) derivatives 3 and provide a pre-
liminary account on their photoreversible photochromic behavior.
Recently, it was demonstrated2e4 that derivatives of type 2 ex-
hibit various kinds of biological activity as well. Moreover, these
compounds are known to serve as versatile precursors for achiev-
ing further structural modifications of quinolinones providing new
bioactive derivatives involving the quinoline moiety.5e7
Special interest toward the 3-aroyl-4(1H)-quinolones is also
related to their photochromic properties. Thus, 2-benzyl-3-ben-
zoyl-4(1H)-quinolones undergo photoenolization as a result of
hydrogen transfer to the excited carbonyl group to form the colored
photoenols, whose lifetimes are considerably enhanced by the
intramolecular hydrogen bond.8 Recently, we have demonstrated
that the stability of the photoenols depends strongly on the sub-
stituents at the quinolone moiety and solvent.9
2. Results and discussion
2.1. Synthesis
The synthetic approaches toward 3-carboxy substituted quino-
lones of type 1, including their esters, have been investigated in
depth. However, their applicability to the synthesis of 3-aroyl de-
rivatives 2 is limited.14 Insignificant, at the first glance, structural
modifications give rise to a severe decrease in yields and appear-
ance of byproducts, in many cases as the result of changes in re-
activity of precursors.15,16 Moreover, our experiments showed that
the methods suitable for the preparation of 2-substituted 3-aroyl
derivatives do not afford satisfactory results when applied for the
* Corresponding
author.
E-mail address:
khodor@cinam.univ-mrs.fr
(V. Khodorkovsky).
y
Deceased.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.039

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N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
synthesis of 2-unsubstituted derivatives. In particular, the method
of Grohe15e17 and the method based on thermolysis of 1-aroyl-2,3-
dihydro-2,3-pyrroldiones18e20 turned out to be problematic.
substituents in the quinolone moiety. Alkylation of 10bee on the
nitrogen atom occurred smoothly in yields of 60e80% in DME in the
presence of sodium hydride (Scheme 2). We did not observe
the formation of any noticeable quantities of the O-alkylated iso-
mers, although O-alkylation in such cases is a known problem.8,20
The new derivatives were characterized by elemental analysis
and their 1H and 13C NMR spectra. The X-ray structure of 3g was
also determined (Fig. 1). An interesting feature of the molecular
structure is the presence of the intramolecular hydrogen bond
C17-H17b/O2 (C/O distance 3.044 Å) analogous to the one
observed in the 2-methyl derivative.10
We found that the only two approaches, which are enough gen-
eral and appeared suitable for the preparation of precursors 10, are
the GouldeJacobs approach21 (Scheme 1, route A) and the recently
elaborated approach based on the cyclization of o-methoxycarbonyl
substituted enaminones 134,14 (Scheme 1, route B).
Scheme 2. Alkylation of derivatives 10bee.
Figure 1. The molecular structure of 3g. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (Å): C1eC2: 1.392(4); C1eN1: 1.396(3);
C2eC3: 1.381(4); C3eO3: 1.360(4); C3eC4: 1.389(4); C4eC5: 1.379(4); C5eO4: 1.358
(4); C5eC6: 1.422(4); C6eC7: 1.465(4); C7eO1: 1.237(4); C7eC8: 1.455(4); C8eC9:
1.358(4); C9eN1: 1.345(4); C17eO2: 3.044.
However, methylation of 10f, beside the target 3h, yielded two
byproducts (Scheme 3), resulting from the substitution of the
fluorine atom in position 5. The overall yield of the methylation
products was 67e70% and the product ratio depended on the re-
sidual water concentration. Even traces of water in freshly distilled
dimethoxyethane gave rise to the formation of 3i and 3j.
Scheme 1. Synthetic routes toward derivatives 10.
Most of the known 3-aroyl quinolinones of type 2 were pre-
pared using the GouldeJacobs approach.2,3,5e7,22 The precursors 9
were prepared by the reaction of ketoester 4a (R¼H) with alkyl
orthoformates 5 with subsequent substitution of the alkoxy group
by the aniline fragment. However, in our hands, the best results
were obtained using DMF dimethyl acetal 6, probably, owing to the
less drastic conditions of the reaction with 4. Alternatively, the
intermediate 8 can be prepared from 11, although the yields are
somewhat lower.
We also explored the possibility to prepare derivatives 10 by
route B, which involves the cyclization of enamine 13. A variety of
reaction conditions has been verified in14 and the reported opti-
mized yields were 40e61%. Derivative 10a (R¼R2¼H) was obtained
later in 70% yield in 3 min using a domestic microwave oven.23
We found that the cyclization can be achieved in higher yields
(80e90%) by heating a methanol solution of 13 in the presence of
sodium methanolate in a sealed tube at 120 ꢀC. The intermediates
13 can easily be prepared from enaminones 12.
Thus, combining the both approaches we prepared a series of
derivatives 10aef involving both electron donating and accepting
Scheme 3. Alkylation of derivative 10f.

N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
8293
Whereas the nucleophilic substitution of the 5-fluorine atom in
4-quinolinone derivatives is known,24 the easiness and unusual
selectivity of the reaction is noteworthy. The X-ray structure de-
termination of 3i shows the presence of two intramolecular hy-
drogen bonds: O28eH28/O26 (O/O distance 2.496 Å) and
C13eH13/O27 (C/O distance 3.036 Å) (Fig. 2).
compound 3b are shown in Figure 3. The photostationary state is
reached within 35 min and the decoloration takes about 1 h. The
reaction can also be followed by the developing fluorescence bands.
The photocoloration is fully photoreversible (with the exception of
3f) in deoxygenated solutions, but in the presence of air, colored
oxidation products with the absorption maxima at about 480 nm
are accumulated.
Table 1
Absorption and fluorescence maxima of derivatives 3 and the respective photoin-
duced colored forms
l
(
3
10ꢂ3
)
l
colored
max
lfmaxcolored
abs
abs
max
ꢁ
nm
forms, nm
forms, nm
3a
3b
3c
3d
332 (14.3)
329 (16.2)
328 (15.1)
375 (1.9)
320 (11.9)
330 (14)
336 (10.1)
325 (12.5)
329 (14.6)
335 (16)
503
489
467
Inactive
571
553
540
3e
3f
3g
3h
3i
515
412, 510
459
473
Inactive
473
582
605
541
542
Figure 2. The molecular structure of 3i. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (Å): C2eN1: 1.397(3); C2eC3: 1.406(4);
C2eC7: 1.399(4); C3eC4: 1.368(4); C4eF30: 1.346(3); C4eC5: 1.370(5); C5eF29: 1.344
(3); C5eC6: 1.387(4); C6eO28: 1.329(3); C6eC7: 1.420(3); C7eC8: 1.459(3); C8eO26:
1.262(3); C8eC9: 1.428(3); C9eC24: 1.368(3); C24eN1: 1.341(3); O26eO28: 2.496;
C13eO27: 3.036.
3j
332 (12.5)
553
2.2. Photochromic behavior of derivatives 3
All derivatives 3 (except 3d and 3i) exhibited the appearance of
yellow to red color upon irradiation of their solutions at the
wavelengths corresponding to the absorption maxima. Their ab-
sorption spectra are very similar to those of the 3-benzoyl de-
rivatives described previously by us,9 and the longest wavelength
absorption maxima observed as a weak shoulder about 360 nm can
be ascribed to the n/
p transition located mostly on the carbonyl
*
group of the 3-benzoyl substituent. A possible reaction sequence,
giving rise to the colored products, is shown in Scheme 4. On the
contrary, the longest wavelength absorption maximum of de-
rivative 3d at 375 nm is relatively strong and can be interpreted as
a charge transfer transition within the p-NO2eC6H4eN moiety. This
can account for the lack of photochromism in this derivative. The
photochemical inertness of derivative 3i is more difficult to ratio-
nalize. Probably, the quinolone carbonyl group, being already in-
volved in one hydrogen bond, cannot sufficiently stabilize the
intermediate that forms upon photo-induced hydrogen atom
transfer by the formation of the second hydrogen bond (Scheme 4).
Figure 3. Spectral changes upon irradiation of 3b (c¼1.1ꢁ10ꢂ4 M) at 330 nm during
35 min (solid curves), fluorescence of the colored form (dashed curve) in toluene;
inset: subsequent irradiation at 505 nm during 60 min.
The amount of the colored oxidation products identified using
the NMR technique (see below) as the respective benzoacridine
derivatives depends on the substituents at the N atom and the
benzene ring of the quinolone moiety. Whereas only traces of them
were observed in the cases when R1 is a relatively bulky substituent
(3b and c), oxidation of 3f into 16 occurred with the remarkable
easiness (Fig. 4).
2.3. Identification of the photoproducts using NMR
spectroscopy
The photoconversion of 3f in deuterated toluene solution was
investigated in detail using NMR spectroscopy. The primary and the
main colored product appearing after 40 min of irradiation at
313 nm was identified as one of the two S,R-isomers of the
enols 14a (either (5aS,6R)-12-hydroxy-2,3-dimethoxy-5-methyl-6-
Scheme 4. A tentative mechanism for photocyclization of 3.
The relevant data on optical properties of derivatives 3 are
collated in Table 1. The absorption spectral changes corresponding
to the appearance of the colored photoproducts upon irradiation of

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N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
Figure 4. Spectral changes upon irradiation of 3f (c¼0.92ꢁ10ꢂ4 M) at 330 nm in tol-
uene during 30 min in the presence of air; inset: subsequent irradiation at 525 nm
during 40 min.
phenyl-5a,6-dihydrobenzo[b]acridin-11(5H)-one or (5aS,6R)-11-
hydroxy-2,3-dimethoxy-5-methyl-6-phenyl-5a,6-dihydrobenzo[b]-
acridin-12(5H)-one) in both deoxygenated solution (83%) and in the
presence of air (48%) (Figs. 5 and 6, Scheme 5). The minor product
(6% in both deoxygenated solution and in the presence of air) is one
of the two S,S-isomers 14b (either (5aS,6S)-12-hydroxy-2,3-dime-
thoxy-5-methyl-6-phenyl-5a,6-dihydrobenzo[b]acridin-11(5H)-
Figure 6. The NCH3 part of 1H NMR spectra of 3f in toluene-d8: (a) before irradiation,
(b) after 40 min of irradiation at 313 nm and (c) after 3 days in dark.
one or (5aS,6S)-11-hydroxy-2,3-dimethoxy-5-methyl-6-phenyl-
5a,6-dihydrobenzo[b]acridin-12(5H)-one). The enol 14a was
partially converted into the S,R,S-isomer of the diketo form 15a
(20%) when the sample was kept in dark for three days
(Scheme 5). The diketo form corresponding to the enol 14b was not
observed. Even in a thoroughly deoxygenated solution, some
amount of the oxidation product, the acridin-12(5H)-one derivative
16 (5%), was detected. This compound is photochemically inactive
and remains in the reaction mixture after decoloration at 546 nm
exhibiting the absorption band at about 480 nm (Fig. 4). It is worth
noting that a product of the same type was detected after photolysis
of the 2-benzyl-3-benzoylquinolinone derivative.25 In the presence
of oxygen, in addition to 16 (21%) we found another oxidation
product 17 (20%). Similar results were obtained for derivative 3g,
although the propensity of the corresponding enol to oxidation is
much less pronounced.
The above structural assignments were done using both 1 and
2D NMR experiments (see Supplementary data). The photo-
reversible derivatives 14a and 14b are formed via hydrogen mi-
gration from the methylene group in position Ca toward the
carbonyl group leading to the enol formation. In the 1H spectrum,
the OH groups were observed at 17.15 ppm and 17.54 ppm, for 14a
and 14b, respectively. The cyclization occurs between carbons C2
and Ca as proved by scalar coupling between the protons Ha at
4.15 ppm and H2 at 4.60 ppm in 14a and Ha at 4.04 ppm, and H2 at
4.87 ppm in 14b. Compounds 14a and 14b are two diastereoisomers
with Ha and H2 in anti position in 14a (3JHaeH2¼12.4 Hz) and with Ha
and H2 in syn position in 14b (3JHaeH2¼5.4 Hz). In the HMBC map
recorded at 263 K, carbon C4 at 178.2 ppm was identified from
correlation with OH at 17.43 ppm and H5 at 7.61 ppm, whereas
carbon Cb at 174.4 ppm was attributed from the coupling with OH
0
and H6 at 8.25 ppm. This result indicates that the OH group of the
photoproduct 14a is located between the two carbons C4 and Cb. As
for the photoproduct 14b, the exact enol position could not be de-
termined accurately due to its low concentration. However, one can
Figure 5. The NCH3 part of 1H NMR spectra of 3f in deoxygenated toluene-d8: (a)
before irradiation, (b) after 40 min of irradiation at 313 nm and (c) after 40 min of
irradiation at 546 nm.

N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
8295
expect a similar behavior of exchange of the enol proton between
the two carbonyl groups.
The compound 15a corresponds to the diketone formed from
14a after the thermal ketoeenol equilibrium is established. The
2D 1He1H COSY experiment exhibited new scalar correlations
between aliphatic protons H3, H2, and Ha, at 4.06 ppm, 3.50 ppm,
and 4.68 ppm, respectively, with the coupling constant
3JH3eH2¼5.1 Hz (syn position) and with the coupling constant
3JH2eHa¼10.8 Hz (anti position). In the HMBC map recorded at
263 K (to slow the OH exchange between both carbons), the
carbon C4 at 184.8 ppm was identified by the long-range corre-
lations with the proton H3 at 4.08 ppm and the proton H5 at
7.67 ppm, while the carbon Cb at 191.6 ppm was identified by the
long-range correlations with the proton H3 at 4.08 ppm and the
3. Conclusions
The new series of 2-unsubstituted 3-aroyl 4(1H)-quinolones 3
was synthesized using two different approaches. These com-
pounds, in addition to their potential biological activity, exhibit
photoreversible photochromic properties. We have demonstrated
that the colored photoproducts are the acridine derivatives, which,
depending on the substituents, exhibit the absorption maxima
between 460 and 515 nm and fluorescence maxima between 540
and 605 nm. The absence of photochromism in derivative 3i and
dependence of the product ratio on the presence of oxygen are
noteworthy and may serve as clues to understanding the mecha-
nism of the reaction. The kinetic and mechanistic details of the
photochemical processes leading to the remarkable stereo-
selectivity in the colored species formation are currently under
investigation in our laboratories.
0
proton H6 at 8.41 ppm.
4. Experimental section
4.1. General
The 1H and 13C NMR spectra used for characterization of the
products were recorded on a Bruker AC 250 spectrometer (250 and
62.5 MHz for 1H and 13C, respectively), using TMS as an internal
standard. Chemical shifts (
d) are given in parts per million and
coupling constants J in hertz.
The 1H and 13C NMR spectra used for analysis of photoproducts
were recorded on a Bruker 300 spectrometer (300 and 75 MHz for
1H and 13C, respectively) equipped with BBI or QNP probes and on
a Bruker 500 spectrometer (500 and 125 MHz for 1H and 13C, re-
spectively) equipped with TXI probe, using standard sequences.
Data sets were processed using Bruker Topspin 1.3 software. Solu-
tions (10ꢂ3 M in toluene-d8) were degassed by the freezee
pumpethaw technique (five cycles at 2.25ꢁ10ꢂ6 Torr) in Young valve
NMR sample tubes (Wilmad 507-JY-7), which were irradiated in
a home-built setup using a 1000 W high-pressure HgeXe lamp
equipped with the Schott 11FG09 and differential filters.
Melting points were measured in open capillaries on a Buchi 510
apparatus and are uncorrected. Column chromatography was per-
formed on silica gel Merck (70e230 mesh). The elemental analyses
were performed by the Microanalytical Center of the University of
Aix-Marseille III. Identification of known compounds was made by
1H NMR and the melting points comparison with the literature
data. The solvents used for the synthesis (Carlo Erba, Aldrich) were
dried according to the standard procedures.
The UVevis absorption spectra were recorded on a spectropho-
tometer Ocean Optics USB 4000 combined with UVeViseNIR Light
Source Micropack DH-2000. LED sources LUMOS 43 (Atlas Pho-
tonics) with available wavelengths 300, 315, 330, 350, 405, 450,
505, 525 nm were used for irradiation for qualitative photochromic
measurements. The fluorescence spectra were recorded on a Cary
ECLIPSE spectrofluorometer. Toluene of the spectroscopic grade
(Carlo Erba) was used as the solvent for all spectroscopic studies.
Crystallographic data were collected on a BrukereNonius Kap-
Scheme 5. Photoproduct structures.
Compound 16 formed from 14a as a result of oxidation with
the loss of protons H2 and Ha. In the 1H spectrum, the OH group
was observed at 17.20 ppm. The 2D HMBC experiment recorded
at 263 K evidenced a correlation between OH at 17.42 ppm (a
weak shift of this signal was observed due to temperature ef-
fects) and carbon Cb at 163.1 ppm, thus positioning the OH group
at carbon Cb, while a correlation between carbon C4 at 182.7 ppm
and proton H5 at 7.97 ppm was also observed (Supplementary
data).
The oxidized photoproduct 17 features three carbonyl groups. In
the 1He13C HMBC recorded at 263 K, the carbonyl Ca at 195.8 ppm
paCCD diffractometer with Mo K
pound 3g: monoclinic from methanol. C26H23NO4. Unit cell
a
radiation,
l
¼0.71073 Å. Com-
00 00
was correlated with H2 /6 at 8.29 ppm, while the carbonyl Cb at
0
195.4 ppm was coupled with H6 at 7.45 ppm and, finally, the car-
parameters: a¼9.4144(1), b¼20.5690(4), c¼10.8158(2),
b
¼95.006
bonyl C4 at 173.0 ppm was coupled with H5 and H2 at 7.86 ppm and
7.79 ppm, respectively.
(2), space group P 21/n. Compound 3i: triclinic from chloroform.
C25H18Cl3F2NO3. Unit cell parameters: a¼7.7741(2), b¼12.0946(4),

8296
N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
c¼13.3545(5),
a
¼85.835(1),
b
¼74.789(1),
g
¼79.869(1), space
142.7 (C); 167.1 (COOMe); 190.5 (C]O). E-isomer: 1H NMR (CDCl3):
group P-1. The crystal structures have been deposited at the Cam-
bridge Crystallographic Data Centre and allocated the deposition
numbers CCDC 782450 and 782451, respectively.
3.90 (s, 3H, CH3); 6.57 (d, 1H, J¼12.6, H2a); 10.86 (d, 1H, J¼12.9,
NH); 6.94e8.10 (m, 10H).
Methyl anthranilate, ethyl 3-(dimethylamino)acrylate (11),
methyl 2-amino-4,5-dimethoxybenzoate, methyl 2-amino-5-fluo-
robenzoate, 3,4,5-trifluoroaniline, and 3,5-dimethoxyaniline are
available from Alfa Aesar and o-benzylbenzoic acid from Aldrich.
1-(2-Benzylphenyl)ethanone,26 o-benzylbenzoic acid chlo-
ride,27 ethyl 2-benzoyl-3-(dimethylamino)propenoate 8a,28 and
ethyl 2-benzoyl-3-(phenylamino)propenoate 9a29 were prepared
according to the known procedures.
4.2.2.2. Methyl
2-[(3-(2-benzylphenyl)-3-oxoprop-1-en-1-yl)
amino]benzoate (13b). From 12b and methyl anthranilate. Yield
64%, pale yellow needles (from cyclohexaneeethyl acetate mix-
ture), mp 102e104 ꢀC. Two isomers, Z/E: 4/1.
Z-isomer: 1H NMR (CDCl3): 4.03 (s, 3H, CH3); 4.31 (s, 2H, CH2);
5.70 (d, 1H, J¼8.1, H2a); 7.06 (ddd, 1H, J¼8.0, J¼7.2, J¼0.8, H5);
7.11e7.35 (m, 9H, HAr); 7.41 (dd, 1H, J¼12.2, J¼8.2, H1a); 7.48e7.56
(m, 2H, HAr); 8.08 (dd, 1H, J¼8.0, J¼1.6, H6); 13.27 (d, 1H, J¼12.2,
NH). 13C NMR (CDCl3): 38.8 (CH2); 52.6 (CH3); 100.5 (C2a); 114.2
(CH); 116.5 (C1); 122.0 (CH); 125.9 (CH); 126.0 (CH); 127.8 (CH);
128.4 (2ꢁCH); 129.4 (2ꢁCH); 129.9 (CH); 130.9 (CH); 132.4 (CH);
134.3 (CH); 139.3 (C); 141.3 (C); 141.4 (C); 141.5 (C); 142.5 (C1a);
167.1 (COOMe); 195.6 (C]O). E-isomer: 1H NMR (CDCl3): 3.93 (s,
3H, CH3); 4.19 (s, 2H, CH2); 6.13 (d, 1H, J¼12.9, H2a); 8.00 (dd, 1H,
J¼7.9, J¼1.3, H6); 10.77 (d, 1H, J¼12.9, NH); 7.02e7.56 (m, 13H).
Found, %: C 77.66; H 5.78; N 3.69. C24H21NO3. Calculated, %: C 77.61;
H 5.70; N 3.77; O 12.92. M 371.43.
4.2. Synthesis of quinolin-4(1H)-ones 10 by route B
4.2.1. Enaminones 12a,b. Dimethylformamide dimethyl acetal
(12.13 g, 102 mmol) was added to the solution of the corresponding
acetophenone (33.9 mmol) in DMF (30 ml), the resulting mixture
was stirred at reflux for 3e7 h (TLC control). Upon cooling, water
(30 ml) was added, and the stirring continued at room temperature
for another 30 min, then the product was extracted with diethyl
ether (4ꢁ75 ml), organic layer washed with brine and water, dried
with MgSO4, and the solvent evaporated in vacuo. Compound 12b
was also purified by column chromatography (cyclohexane/ethyl
acetate 1:1 to 0:1).
4.2.2.3. Methyl 2-[(3-(2-benzylphenyl)-3-oxoprop-1-en-1-yl)
amino]-5-fluorobenzoate (13c). From 12b and methyl 2-amino-5-
fluorobenzoate. Yield 86%, bright yellow needles (from methanol),
mp 101e103 ꢀC. The Z-isomer only. 1H NMR (CDCl3): 4.02 (s, 3H,
CH3); 4.31 (s, 2H, CH2); 5.69 (d, 1H, J¼8.1, H2a); 7.11e7.32 (m, 11H,
HAr); 7.33 (dd, 1H, J¼12.5, J¼8.1, H1a); 7,52 (dd, 1H, J¼7.4, J¼1.6,
H60); 7.75e7.79 (m, 1H, H6); 13.21 (d, 1H, J¼12.5, NH). 13C NMR
(CDCl3): 38.8 (CH2); 52.9 (CH3); 100.5 (C2a); 115.9 (d, J¼7.5, C3);
117.5 (d, J¼6.9, C1); 118.3 (d, J¼24.1), 121.7 (d, J¼23.1, C4, and C6);
125.9 (CH); 126.0 (CH); 127.8 (CH); 128.4 (2ꢁCH); 129.4 (2ꢁCH);
130.0 (CH); 130.9 (CH); 139.0 (d, J¼2.5, C2); 139.3 (C); 141.3 (C);
141.51 (C); 141.53 (C1a); 157.5 (d, J¼243, C5); 166.0 (d, J¼2.5,
COOMe); 195.6 (C]O). Found, %: C 73.93; H 5.22; N 3.53.
C24H20FNO3. Calculated, %: C 74.02; H 5.18; F 4.88; N 3.60; O 12.33.
M 389.42.
4.2.1.1. 3-(Dimethylamino)-1-phenylprop-2-en-1-one
(12a). From acetophenone. Yield 51%, bright yellow needles, mp
91e92 ꢀC (lit. 90e92 ꢀC30). Only the E-isomer was observed. 1H
NMR (CDCl3): 2.91 (s, 3H, NCH3), 3.12 (s, 3H, NCH3), 5.71 (d, 1H,
J¼12.4, H2), 7.36e7.49 (m, 3H, H30eH50), 7.79 (d, 1H, J¼12.4, H3),
7.87e7.93 (m, 2H, H20, H60). 13C NMR (CDCl3): 37.3 (CH3), 45.0 (CH3),
92.2 (C2), 127.5 (2ꢁCH), 128.1 (2ꢁCH), 130.9 (CH), 140.6 (C), 154.3
(C3), 188.7 (C]O).
4.2.1.2. 1-(2-Benzylphenyl)-3-(dimethylamino)prop-2-en-1-one
(12b). From 1-(2-benzylphenyl)ethanone. Yield 55%, pale yellow
prisms (from ether), mp 70e72 ꢀC. The E-isomer only. 1H NMR
(CDCl3): 2.74 (s, 3H, NCH3), 2.95 (s, 3H, NCH3), 4.13 (s, 2H, CH2), 5.20
(d, 1H, J¼12.8, H2), 7.10e7.36 (m, 10H, H3, and 9HAr). 13C NMR
(CDCl3): 37.2 (CH3), 38.8 (CH2), 45.0 (CH3), 90.3 (C2), 125.8 (CH),
125.9 (CH), 127.4 (CH), 128.3 (2ꢁCH), 128.9 (CH), 129.3 (2ꢁCH);
130.6 (CH), 138.2 (C), 141.4 (C), 142.3 (C), 155.3 (C3), 188.1 (C]O).
Found, %: C 81.52, H 7.24, N 5.19. C18H19NO. Calculated, %: C 81.47, H
7.22, N 5.28, O 6.03. M 265.35.
4.2.2.4. Methyl
2-[(3-(2-benzylphenyl)-3-oxoprop-1-en-1-yl)
amino]-4,5-dimethoxybenzoate (13d). From 12b and methyl 2-
amino-4,5-dimethoxybenzoate. Yield 71%, bright yellow needles
(from methanol), mp 135e137 ꢀC. The Z-isomer only. 1H NMR
(CDCl3): 3.91 (s, 3H, CH3); 3.97 (s, 3H, CH3); 4.01 (s, 3H, CH3); 4.31 (s,
2H, CH2); 5.67 (d, 1H, J¼8.0, H2a); 6.72 (s, 1H, H3); 7.11e7.29 (m, 8H,
HAr); 7,34 (dd, 1H, J¼12.2, J¼8.0, H1a); 7.51 (s, 1H, H6); 7.52 (dd, 1H,
J¼7.0, J¼1.7, H60); 13.28 (d, 1H, J¼12.2, NH). 13C NMR (CDCl3): 38.8
(CH2); 52.4 (CH3); 56.2 (CH3); 56.3 (CH3); 97.5 (C2a); 99.8 (CH);
108.3 (C); 113.6 (CH); 125.9 (CH), 126.0 (CH), 127.8 (CH); 128.4
(2ꢁCH); 129.3 (CH); 129.4 (2ꢁCH); 130.9 (CH); 138.0 (C); 139.2 (C);
141.5 (C1a); 141.56 (C); 141.57 (C); 144.3 (C); 154.2 (C); 166.7
(COOMe); 195.2 (C]O). Found, %: C 72.45; H 5.94; N 3.32.
C26H25NO5. Calculated, %: C 72.37; H 5.84; N 3.25; O 18.54. M
431.48.
4.2.2. Enaminones 13aed. A mixture of 12 (1 mmol), the corre-
sponding substituted methyl anthranilate (1 mmol) and acetic acid
(3 ml) was stirred at 45e50 ꢀC for 5 h (TLC control). The reaction
mixture was then poured into water (50 ml), and sodium hydro-
carbonate was added till pH¼8. After extraction with ether
(2ꢁ30 ml), the ether layer was washed with water and dried over
MgSO4. The solvent was evaporated in vacuo, the dry residue pu-
rified by column chromatography using pentaneedichloromethane
mixture as the eluent.
4.2.3. Cyclization of 13aed into 10aed. In an Ace pressure tube, Na
(115 mg, 5 mmol) was dissolved in methanol (5 ml), then the cor-
responding derivative 13 (1 mmol) was added. The tube was sealed,
placed in the oil bath and heated overnight at 120 ꢀC. Upon cooling
the reaction mixture was poured into water, acidified with HCl till pH
5e6, the precipitate was filtered and washed with water and ether.
4.2.2.1. Methyl 2-[(3-oxo-3-phenylprop-1-en-1-yl)amino]benzo-
ate (13a). From 12a and methyl anthranilate. Yield 70%, bright
yellow prisms (from ethanol), mp 108e109 ꢀC (lit. 108e110 ꢀC14).
Two isomers, Z/E: 10/1.
Z-isomer: 1H NMR (CDCl3): 4.02 (s, 3H, CH3); 6.12 (d, 1H, J¼8.3,
H2a); 7.01 (ddd, 1H, J¼8.0, J¼7.2, J¼0.9, H5); 7.29 (d, 1H, J¼9.3, H3);
7.38e7.57 (m, 5H, H1a, H30eH50, H4); 7.99e8.09 (m, 3H, H6, H20,
H60); 13.45 (d, 1H, J¼12.1, NH). 13C NMR (CDCl3): 52.6 (CH3); 96.4
(C2a); 113.9 (CH); 115.8 (C1); 121.7 (CH); 127.7 (2ꢁCH); 128.3
(2ꢁCH); 131.7 (CH); 132.1 (CH); 134.3 (CH); 139.1 (C); 141.6 (C1a);
4.2.3.1. 3-Benzoylquinolin-4(1H)-one (10a). Yield 86%, white
powder, mp 259e260 ꢀC (lit. 230e232 ꢀC23). 1H NMR (DMSO-d6):
7.38e7.51 (m, 3H, H30, H50, H6); 7.53e7.62 (m,1H, H40); 7.67 (dd,1H,
J¼8.3, J¼0.9, H8); 7.70e7.78 (m, 3H, H20, H60, H7); 8.12 (dd, 1H,
J¼8.1, J¼0.8, H5); 8.36 (s, 1H, H2); 12.53 (br s, 1H, NH).

N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
8297
4.2.3.2. 3-(2-Benzylbenzoyl)quinolin-4(1H)-one (10b). Yield 79%,
white powder, mp 254e256 ꢀC. 1H NMR (DMSO-d6): 4.04 (s, 2H,
CH2); 7.06e7.26 (m, 7H, HAr); 7.30 (dd, 1H, J¼7.7, J¼1.4, H30); 7.34
(dd, 1H, J¼7.3, J¼1.7, H60); 7.42 (ddd, 1H, J¼8.0, J¼6.9, J¼1.0, H6);
7.64 (dd, 1H, J¼8.2, J¼1.0, H8); 7.73 (ddd, 1H, J¼8.2, J¼6.9, J¼1.2,
H7); 8.08 (dd, 1H, J¼8.0, J¼1.2, H5); 8.38 (s, 1H, H2); 12.55 (br s, 1H,
NH). 13C NMR (DMSO-d6): 37.8 (CH2); 118.8 (C8); 119.1 (C3); 124.9
(CH); 125.6 (CH); 125.7 (CH); 125.8 (CH); 127.6 (C); 127.9 (CH);
128.2 (2ꢁCH); 129.0 (2ꢁCH); 129.6 (CH); 130.3 (CH); 132.6 (CH);
138.4 (C); 139.3 (C); 141.0 (C); 141.1 (C); 145.0 (C2); 174.2 (C(4)]O);
195.7 (C]O). Found, %: C 81.46; H 5.12; N 4.09. C23H17NO2. Calcu-
lated, %: C 81.40; H 5.05; N 4.13; O 9.43. M 339.39.
(1.64 g, 7.14 mmol) in toluene (10 ml), and the mixture was heated
at 90 ꢀC during 4e5 h (TLC control). The precipitate was filtered off,
and the filtrate evaporated in vacuo. The dry residue was distrib-
uted between water and ethyl acetate, after separation of the layers
the water layer was extracted with ethyl acetate once again. The
united organic phase was washed with brine and dried over MgSO4.
The solvent was evaporated in vacuo, and the product purified by
column chromatography using cyclohexaneeethyl acetate mixture
as the eluent. Yield 21%, identical to the compound obtained by
method (a).
4.3.2. Conversion of 8b into 9b,c.
4.3.2.1. Ethyl
2-(2-benzylbenzoyl)-3-[(3,5-dimethoxyphenyl)
4.2.3.3. 3-(2-Benzylbenzoyl)-6-fluoroquinolin-4(1H)-one
(10c). Yield 89%, white powder, mp 254e255 ꢀC (darkens at
243 ꢀC). 1H NMR (DMSO-d6): 4.03 (s, 2H, CH2); 7.05e7.21 (m, 7H,
HAr); 7.23 (dd, 1H, J¼7.5, J¼1.1, H30); 7.30 (dd, 1H, J¼7.6, J¼1.4, H60);
7.32e7.40 (m, 1H, H40); 7.64 (ddd, 1H, J¼9.0, J¼8.6, J¼2.9, H7); 7.74
(dd, 1H, J¼9.1, J¼2.9, H5); 7.80 (dd, 1H, J¼9.0, J¼4.7, H8); 8.35 (s, 1H,
H2); 13.01 (br s, 1H, NH). 13C NMR (DMSO-d6): 37.8 (CH2); 110.0 (d,
J¼23.3, C5); 117.9 (C3); 121.2 (d, J¼25.4, C7); 121.9 (d, J¼8.4, C8);
125.7 (CH); 125.8 (CH); 127.9 (CH); 128.1 (2ꢁCH); 128.9 (2ꢁCH);
129.1 (d, J¼6.6, C4a); 129.6 (CH); 130.3 (CH); 136.0 (d, J¼1.3, C8a);
138.4 (C); 140.9 (2ꢁC); 144.8 (C2); 159.3 (d, J¼243, C6); 173.4 (d,
J¼2.4, C(4)]O); 195.5 (C]O). Found, %: C 77.41; H 4.58; N 3.85.
C23H16FNO2. Calculated, %: C 77.30; H 4.51; F 5.32; N 3.92; O 8.95. M
357.38.
amino] propenoate (9b). A solution of 8b (1 g, 2.96 mmol) and 3,5-
dimethoxyaniline (0.46 g, 3.0 mmol) in ethanol (10 ml) was stir-
red at rt for 24 h, then the solvent was evaporated in vacuo and the
residue separated on the column by eluting with cyclo-
hexaneeethyl acetate mixture. Yield 96%, pale yellow oil. Two
isomers, E/Z: 5/2. E-isomer: 1H NMR (CDCl3): 0.84 (t, 3H, J¼7.1,
CH2CH3); 3.82 (s, 6H, 2ꢁOCH3); 3.91 (q, 2H, J¼7.1, CH2CH3); 4.04 (s,
2H, CH2Ph); 6.32 (t, 1H, J¼2.0, H4a); 6.39 (d, 2H, J¼2.0, H2a, and
H6a); 7.09e7.31 (m, 9H, HAr); 8.52 (d, 1H, J¼13.3, H3); 12.57 (br d,
1H, J¼13.3, NH). 13C NMR (CDCl3): 13.8 (CH3); 38.9 (CH2Ph); 55.7
(2ꢁOCH3); 60.0 (CH2CH3); 96.6 (2ꢁCH, C2a, and C6a); 97.9 (C3);
103.9 (CH); 125.5 (CH); 125.9 (CH); 126.0 (CH); 128.3 (2ꢁCH);
128.7 (CH); 129.4 (2ꢁCH); 130.0 (CH); 137.2 (C); 140.7 (C); 140.9
(C); 143.1 (C); 152.6 (C); 162.0 (2ꢁC, C3a, and C5a); 167.0 (COOEt);
198.5 (C]O). Z-isomer: 1H NMR (CDCl3): 0,82 (t, 3H, J¼7.1,
CH2CH3); 3.78 (s, 6H, 2ꢁOCH3); 3.89 (q, 2H, J¼7.1, CH2CH3); 4.09 (s,
2H, CH2Ph); 6.24 (d, 2H, J¼2.0, H2a, and H6a); 6.27 (t, 1H, J¼2.0,
H4a); 7.09e7.31 (m, 9H, HAr); 8.32 (d, 1H, J¼13.8, H3); 10.98 (br d,
1H, J¼13.8, NH). Found, %: C 72.87; H 6.13; N 3.06. C27H27NO5.
Calculated, %: C 72.79; H 6.11; N 3.14; O 17.96. M 445.51.
4.2.3.4. 3-(2-Benzylbenzoyl)-6,7-dimethoxyquinolin-4(1H)-one
(10d). Yield 79%, colorless needles (from DMF), mp 288 ꢀC (dec). 1H
NMR (DMSO-d6): 3.82 (s, 3H, OCH3), 3.88 (s, 3H, OCH3); 4.03 (s, 2H,
CH2); 7.07e7.29 (m, 9H, HAr); 7.30e7.38 (m, 1H, H40); 7.46 (s, 1H,
H5); 8.28 (s, 1H, H2); 12.43 (br s, 1H, NH). 13C NMR (DMSO-d6): 37.8
(CH2), 55.5 (OCH3), 55.8 (OCH3), 100.1 (CH), 105.0 (CH), 118.1 (C),
121.4 (C), 125.6 (CH), 125.8 (CH), 127.7 (CH), 128.1 (2ꢁCH), 128.9
(2ꢁCH), 129.4 (C), 130.2 (CH), 134.6 (CH), 138.3 (C), 141.1 (C), 141.4
(C), 143.2 (C(2)H), 147.5 (C); 153.2 (C), 173.1 (C(4)]O), 195.9 (C]O).
Found, %: C 75.21; H 5.41; N 3.48. C25H21NO4. Calculated, %: C 75.17;
H 5.30; N 3.51; O 16.02. M 399.44.
4.3.2.2. Ethyl
2-(2-benzylbenzoyl)-3-[(3,4,5-trifluorophenyl)
amino] propenoate (9c). A solution of 8b (2.4 g, 7.11 mmol) and
3,4,5-trifluoroaniline (1.1 g, 7.48 mmol) in a mixture of ethanol
(25 ml) and concentrated HCl (0.4 ml) was refluxed under the TLC
control (about 1 h). The precipitated product was filtered. Yield
86%, white voluminous solid, mp 125e127 ꢀC. Two isomers, E/Z: 5/
2. E-isomer: 1H NMR (CDCl3): 0.85 (t, 3H, J¼7.1, CH2CH3); 3.92 (q, 2H,
J¼7.1, CH2CH3); 4.03 (s, 2H, CH2Ph); 6.89 (dd, 2H, J¼8.4, J¼5.7, H2a,
and H6a); 7.08e7.37 (m, 9H, HAr); 8.34 (d, 1H, J¼12.8, H3); 12.51 (br
d, 1H, J¼12.8, NH). 13C NMR (CDCl3): 13.8 (CH3); 38.9 (CH2Ph); 60.4
(CH2CH3); 102.6 (2ꢁCH, C2a, and C6a); 105.4 (CH); 125.6 (CH);
126.0 (CH); 126.1 (CH); 128.3 (2ꢁCH); 129.1 (CH); 129.4 (2ꢁCH);
130.2 (CH); 135.0 (m, C1a); 137.3 (C); 140.7 (C); 142.5 (C); 151.9 (C);
152.1 (ddd, J¼252, J¼10, J¼5, C3a, and C5a); 166.5 (COOEt); 198.9
(C]O). Z-isomer: 1H NMR (CDCl3): 0.84 (t, 3H, J¼7.1, CH2CH3); 3.95
(t, 2H, J¼7.1, CH2CH3); 4.09 (s, 2H, CH2Ph); 6.69 (dd, 2H, J¼8.5, J¼5.7,
H2a, and H6a); 7.08e7.37 (m, 9H, HAr); 8.01 (d, 1H, J¼13.4, H3);
10.92 (br d, 1H, J¼13.4, NH). Found, %: C 68.39; H 4.64; N 3.17.
C25H20F3NO3. Calculated, %: C 68.33; H 4.59; F 12.97; N 3.19; O
10.92. M 439.43.
4.3. Synthesis of quinolin-4(1H)-ones 10 by route A
4.3.1. Ethyl 3-(2-benzylphenyl)-3-oxopropanoate (4b). Compound
(4b) was synthesized according to the procedure for the methyl
ester31 in 94% yield as pale yellow oil, keton/enol ratio 3:1.
The keto form: 1H NMR (CDCl3): 1.24 (t, 3H, J¼7.1, CH2CH3); 3.86
(s, 2H, C(2)H2); 4.19 (q, 2H, J¼7.1, CH2CH3); 4.31 (s, 2H, CH2Ph);
7.14e7.48 (m, 8H, Har); 7.67 (dd, 1H, J¼7.7, J¼1.6, H60). The enol
form: 1H NMR (CDCl3): 1.34 (t, 3H, J¼7.1, CH2CH3); 4.22 (s, 2H,
CH2Ph); 4.27 (q, 2H, J¼7.1, CH2CH3); 5.26 (s, 1H, CHeCOOEt); 12.53
(s, 1H, OH).
4.3.1.1. Ethyl
2-(2-benzylbenzoyl)-3-(dimethylamino)acrylate
8b. Method (a): A solution of 4b (1.5 g, 5.31 mmol) and dime-
thylformamide dimethyl acetal (0.7 g, 5.84 mmol) in toluene (7 ml)
was heated at 60 ꢀC for 24 h. The solvent was then evaporated in
vacuo, and the mixture separated by column chromatography using
cyclohexaneeethyl acetate mixture as the eluent. Yield 95%, yellow
oil. 1H NMR (CDCl3): 0.83 (t, 3H, J¼7.1, CH2CH3); 3.02 (br s, 6H, N
(CH3)2); 3.89 (q, 2H, J¼7.1, CH2CH3); 4.19 (s, 2H, CH2Ph); 7.04e7.40
(m, 9H, HAr); 7.55 (br s, 1H, H3). 13C NMR (CDCl3): Found, %: C 74.80;
H 6.95; N 4.09. C21H23NO3. Calculated, %: C 74.75; H 6.87; N 4.15; O
14.23. M 337.41.
4.3.3. Cyclization of enaminones 9aec. The corresponding enami-
none 9 (10 mmol) was added to the preheated till 200 ꢀC diphenyl
ether (200 ml), and the solution thus obtained was refluxed for
30 min. Upon cooling, the reaction mixture (with the precipitate, if
formed) was poured into hexane (300 ml) and stirred for another
30 min at rt. The precipitate was filtered, washed with hexane and
dried.
Method (b): To a solution of ethyl 3-(dimethylamino)acrylate
(11) (1.00 g, 7 mmol) and triethylamine (1.55 g, 15.4 mmol) in tol-
uene (5 ml) was added a solution of 2-benzylbenzoic acid chloride
4.3.3.1. 3-Benzoylquinolin-4(1H)-one 10a. Compound (10a) was
obtained from 9a in 51% yield. It was identical to the product
obtained by route B.

8298
N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
4.3.3.2. 3-(2-Benzylbenzoyl)-5,7-dimethoxyquinolin-4(1H)-one
1H, J¼8.5, J¼7.1, J¼1.6, H7); 8.13 (s, 1H, H2); 8.42 (dd, 1H, J¼8.0,
J¼1.6, H5). 13C NMR (CDCl3): 14.2 (CH3); 39.0 (CH2Ph); 54.6 (NCH2);
62.7 (CH2CH3); 115.2 (CH); 120.2 (C); 125.5 (CH); 125.9 (CH); 126.0
(CH); 127.9 (CH); 128.1 (CH); 128.3 (2ꢁCH); 129.1 (C); 129.4
(2ꢁCH); 130.3 (CH); 130.8 (CH); 133.1 (CH); 138.7 (C); 139.4 (C);
140.8 (C); 141.1 (C); 149.7 (C2); 166.6 (COOEt); 174.9 (C(4)]O);
195.9 (C]O). Found, %: C 76.30; H 5.51; N 3.21. C27H23NO4. Calcu-
lated, %: C 76.22; H 5.45; N 3.29; O 15.04. M 425.48.
(10e) from 9b. Yield 19%, white powder, mp 220e221 ꢀC. 1H NMR
(DMSO-d6): 3.74 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); 4.03 (s, 2H, CH2);
6.40 (d, 1H, J¼2.2, H6); 6.58 (d, 1H, J¼2.2, H8); 7.08e7.24 (m, 7H,
HAr); 7,27 (dd, 1H, J¼7.8, J¼1.7, H60); 7.29e7.37 (m, 1H, H40); 8.10 (s,
1H, H2); 12.03 (br s, 1H, NH). Found, %: C 75.11; H 5.35; N 3.48.
C25H21NO4. Calculated, %: C 75.17; H 5.30; N 3.51; O 16.02. M
399.44.
4.3.3.3. 3-(2-Benzylbenzoyl)-5,6,7-trifluoroquinolin-4(1H)-one
(10f) from 9c. Yield 66%, white powder, mp 271e272 ꢀC. 1H NMR
(DMSO-d6): 4.06 (s, 2H, CH2); 7.05e7.29 (m, 7H, HAr); 7.32e7.41 (m,
2H, H60, and H40); 7.46 (ddd, 1H, J¼10.9, J¼6.6, J¼1.8, H8); 8.34 (c,
1H, H2); 12.51 (br s, 1H, NH). 13C NMR (DMSO-d6): 37.8 (CH2); 101.9
(dd, J¼20.6, J¼4.9, C8); 114.9e115.0 (m, C4a); 120.1 (C3); 125.68
(CH); 125.71 (CH); 128.0 (CH); 128.1 (2ꢁCH); 128.8 (2ꢁCH); 129.8
(CH); 130.5 (CH); 136.3e136.6 (m, C8a); 138.4 (C); 140.4 (C); 140.9
(C); 144.6 (C2); 172.4 (d, J¼1.7, C(4)]O); 195.1 (C]O). Found, %: C
70.20; H 3.49; N 3.52. C23H14F3NO2. Calculated, %: C 70.23; H 3.59; F
14.49; N 3.56; O 8.13. M 393.36.
4.4.4. 3-(2-Benzylbenzoyl)-1-(2,4-dinitrophenyl)quinolin-4(1H)-one
(3d). From 10b and 2,4-dinitrochlorobenzene (1.2 mmol). Yield
60%, bright yellow powder, mp 180e181ꢀC. 1H NMR (CDCl3): 4.18 (s,
2H, CH2); 6,64 (ddd, 1H, J¼8.2, J¼1.1, J¼0.5, H8); 7.04e7.32 (m, 7H,
HAr); 7.37e7.58 (m, 4H, HAr); 7,81 (d, 1H, J¼8.7, H6a); 8.07 (c, 1H,
H2); 8.44 (ddd, 1H, J¼7.9, J¼1.8, J¼0.5, H5); 8.71 (dd, 1H, J¼8.7,
J¼2.6, H5a); 9.10 (d, 1H, J¼2.6, H3a). 13C NMR (CDCl3): 38.9 (CH2);
115.8 (CH); 121.3 (CH); 122.2 (CH); 126.0 (CH); 126.1 (CH); 126.2
(CH); 128.1 (C); 128.2 (CH); 128.3 (2ꢁCH); 129.3 (2ꢁCH); 129.7
(CH); 130.8 (CH); 130.9 (CH); 133.1 (CH); 133.4 (CH); 138.3 (C);
139.2 (C); 139.8 (C); 140.1 (C); 141.0 (C); 146.10 (C); 146.13 (C); 146.9
(C2); 148.4 (C); 174.6 (C(4)]O); 195.4 (C]O). Found, %: C 68.98; H
3.88; N 8.23. C29H19N3O6. Calculated, %: C 68.91; H 3.79; N 8.31; O
18.99. M 505.48.
4.4. Synthesis of quinolin-4(1H)-ones 3aej by alkylation
of 10bef
The corresponding derivative 10 (1 mmol) was added in small
portions to the suspension of NaH (1.5 mmol) in dry DME (8 ml)
under argon, the mixture was stirred at rt for 1 h, then the alky-
lating agent R1eX (see below) and tetrabutylammonium iodide (for
X¼Cl, Br) (2 mg) were added in one portion. The mixture was then
heated at 70e80 ꢀC, the consumption of 10 was monitored by TLC
(4-8 h). When the reaction was completed, the content of the re-
action flask was poured into the mixture of water and ice (30 ml),
extracted with ether (2ꢁ20 ml), organic phase washed with brine,
and dried over MgSO4. The solvent was evaporated in vacuo and the
product purified by column chromatography.
4.4.5. 3-(2-Benzylbenzoyl)-6-fluoro-1-methylquinolin-4(1H)-one
(3e). From 10c and methyl iodide (3 mmol). Yield 65%, white
powder, mp 136e137 ꢀC. 1H NMR (CDCl3): 3.81 (s, 3H, CH3); 4.13 (s,
2H, CH2); 7.03e7.30 (m, 7H, HAr); 7.33e7.45 (m, 4H, HAr); 8.08 (ddd,
1H, J¼8.9, J¼2.2, J¼1.3, H5); 8.12 (s, 1H, H2). 13C NMR (CDCl3): 39.1
(CH2); 41.7 (CH3); 113.1 (d, J¼23.1, C5); 118.1 (d, J¼7.9, C8); 119.0
(C3); 121.2 (d, J¼25.0, C7); 125.9 (CH); 126.1 (CH); 127.8 (CH); 128.3
(2ꢁCH); 129.4 (2ꢁCH); 130.3 (CH); 130.8 (CH); 131.3 (d, J¼6.7, C4a);
136.5 (d, J¼1.8, C8a); 138.6 (C); 141.0 (C); 141.2 (C); 149.4 (C2); 160.3
(d, J¼248, C6); 173.9 (d, J¼2.4, C(4)]O); 195.8 (C]O). Found, %: C
77.70; H 4.93; N 3.71. C24H18FNO2. Calculated, %: C 77.61; H 4.88; F
5.12; N 3.77; O 8.62. M 371.40.
4.4.1. 3-(2-Benzylbenzoyl)-1-methylquinolin-4(1H)-one (3a). From
10b and methyl iodide (3 mmol). Yield 83%, white powder, mp
94e96 ꢀC. 1H NMR (CDCl3): 3.81 (s, 3H, CH3); 4.13 (s, 2H, CH2);
7.03e7.30 (m, 7H, HAr); 7.33e7.50 (m, 4H, HAr); 7.72 (ddd, 1H, J¼8.5,
J¼7.1, J¼1.5, H7); 8.16 (s, 1H, H2); 8.44 (ddd, 1H, J¼7.9, J¼1.5, J¼0.5,
H5). 13C NMR (CDCl3): 39.0 (CH2); 41.6 (CH3); 116.0 (C8); 119.3 (C);
125.6 (CH); 125.9 (CH); 126.1 (CH); 127.8 (CH); 127.9 (CH); 128.3
(2ꢁCH); 129.1 (C); 129.4 (2ꢁCH); 130.2 (CH); 130.8 (CH); 133.1
(CH); 138.6 (C); 140.0 (C); 140.9 (C); 141.2 (C); 149.7 (C2); 174.8 (C
(4)]O); 196.3 (C]O). Found, %: C 81.61; H 5.48; N 3.88. C24H19NO2.
Calculated, %: C 81.56; H 5.42; N 3.96; O 9.05. M 353.41.
4.4.6. 3-(2-Benzylbenzoyl)-6,7-dimethoxy-1-methylquinolin-4(1H)-
one (3f). From 10d and methyl iodide (3 mmol). Yield 68%, white
powder, mp 225e226 ꢀC. 1H NMR (CDCl3): 3.82 (s, 3H, NCH3); 3.95
(s, 3H, OCH3); 4.03 (s, 3H, OCH3); 4.13 (s, 2H, CH2); 6.74 (s, 1H, H8);
7.06e7.29 (m, 7H, HAr); 7.31e7.39 (m, 2H, H40, H60); 7.84 (s, 1H, H2);
8.13 (s, 1H, H5). 13C NMR (CDCl3): 39.0 (CH2); 41.6 (NCH3); 56.4
(OCH3); 56.5 (OCH3); 97.5 (C8); 107.5 (C5); 119.2 (C3); 123.5 (C4a);
125.8 (CH); 126.0 (CH); 127.6 (CH); 128.3 (2ꢁCH); 129.4 (2ꢁCH);
130.0 (CH); 130.6 (CH); 135.4 (C); 138.4 (C); 141.3 (C); 141.5 (C);
147.9 (C2); 148.1 (C6); 153.8 (C7); 173.9 (C(4)]O); 196.5 (C]O).
Found, %: C 75.58; H 5.69; N 3.34. C26H23NO4. Calculated, %: C
75.53; H 5.61; N 3.39; O 15.48. M 413.47.
4.4.2. 1-Benzyl-3-(2-benzylbenzoyl)quinolin-4(1H)-one (3b). From
10b and benzyl bromide (1.5 mmol). Yield 67%, white powder, mp
167e168 ꢀC. 1H NMR (CDCl3): 4.17 (s, 2H, CH2); 5.32 (s, 2H, NCH2);
7.03e7.42 (m, 16H, HAr); 7.55 (ddd, 1H, J¼8.5, J¼7.1, J¼1.6, H7); 8.32
(s, 1H, H2); 8.44 (dd, 1H, J¼8.0, J¼1.6, H5). 13C NMR (CDCl3): 39.0
(CH2); 50.6 (NCH2); 116.8 (C8); 119.7 (C3); 125.4 (CH); 125.9 (CH);
126.0 (CH); 126.2 (2ꢁCH); 127.9 (CH); 128.0 (CH); 128.3 (2ꢁCH);
128.7 (CH); 129.3 (C); 129.4 (2ꢁCH); 129.5 (2ꢁCH); 130.2 (CH);
130.8 (CH); 132.9 (CH); 134.2 (C); 138.7 (C); 139.4 (C); 141.0 (C);
141.2 (C); 149.6 (C2); 174.9 (C(4)]O); 196.0 (C]O). Found, %: C
83.99; H 5.44; N 3.22. C30H23NO2. Calculated, %: C 83.89; H 5.40; N
3.26; O 7.45. M 393.36.
4.4.7. 3-(2-Benzylbenzoyl)-5,7-dimethoxy-1-methylquinolin-4(1H)-
one (3g). From 10e and methyl iodide (3 mmol). Yield 63%, white
powder, mp 139e140 ꢀC. 1H NMR (CDCl3): 3.65 (s, 3H, NCH3); 3.89
(s, 3H, OCH3); 3.91 (s, 3H, OCH3); 4.15 (s, 2H, CH2); 6.29 (d, 1H,
J¼2.2, H8); 6.40 (d, 1H, J¼2.2, H6); 7.07e7.24 (m, 7H, HAr); 7.30
(ddd, 1H, J¼7.5, J¼7.5, J¼1.6, H40); 7.40 (ddd, 1H, J¼7.4, J¼1.6, J¼0.4,
H60); 7.83 (s, 1H, H2). 13C NMR (CDCl3): 39.1 (CH2); 42.2 (NCH3);
55.7 (OCH3); 56.4 (OCH3); 91.3 (C8); 95.5 (C6); 113.8 (C4a); 122.2
(C3); 125.8 (CH); 126.0 (CH); 128.2 (CH); 128.3 (2ꢁCH); 129.4
(2ꢁCH); 130.0 (CH); 130.7 (CH); 138.7 (C); 141.2 (C); 141.5 (C); 144.2
(C); 147.8 (C2); 163.29,163.3 (C5, C7); 174.7 (C(4)]O); 196.7 (C]O).
Found, %: C 75.55; H 5.70; N 3.32. C26H23NO4. Calculated, %: C
75.53; H 5.61; N 3.39; O 15.48. M 413.47.
4.4.3. Ethyl 2-(3-(2-benzylbenzoyl)-4-oxoquinolin-1(4H)-yl)acetate
(3c). From 10b and ethyl bromoacetate (1.5 mmol). Yield 69%,
white powder, mp 155e156 ꢀC. 1H NMR (CDCl3): 1.26 (t, 3H, J¼7.1,
CH3); 4.14 (s, 2H, CH2Ph); 4.25 (q, 2H, J¼7.1, CH2CH3); 4.77 (s, 2H,
NCH2); 7.04e7.29 (m, 8H, HAr); 7.33e7.45 (m, 3H, HAr); 7.65 (ddd,
4.4.8. 3-(2-Benzylbenzoyl)-1-methyl-5,6,7-trifluoroquinolin-4(1H)-
one (3h). From 10f and methyl iodide. Yield 61 (25)%,32 white

N.A. Larina et al. / Tetrahedron 66 (2010) 8291e8299
8299
powder, mp 163e164 ꢀC. 1H NMR (CDCl3): 3.68 (s, 3H, CH3); 4.13 (s,
References and notes
2H, CH2); 6.99 (ddd, 1H, J¼11.1, J¼5.9, J¼2.1, H8); 7.04e7.29 (m, 7H,
HAr); 7.33e7.41 (m, 2H, H60, and H40); 7.96 (s, 1H, H2). 13C NMR
(CDCl3): 39.0 (CH2); 42.1 (CH3); 99.5 (dd, J¼21.7, J¼4.9, C8); 121.1
(C); 125.9 (CH); 126.2 (CH); 128.1 (CH); 128.3 (2ꢁCH); 129.3
(2ꢁCH); 130.6 (CH); 131.1 (CH); 138.7 (C); 141.1 (C); 149.1 (C2);
195.3 (C]O). Found, %: C 71.81; H 4.06; N 3.30. C24H16F3NO2. Cal-
culated, %: C 70.76; H 3.96; F 13.99; N 3.44; O 7.85. M 407.38.
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4.4.9. 3-(2-Benzylbenzoyl)-6,7-difluoro-5-hydroxy-1-methyl-
quinolin-4(1H)-one (3i). Yield: 4 (20)%,32 colorless prisms (from
CHCl3), mp 178e180 ꢀC (at 149e151 ꢀC chloroform evolution). 1H
NMR (CDCl3): 3.70 (s, 3H, CH3); 4.14 (s, 2H, CH2); 6.58 (dd,1H, J¼11.4,
J¼5.6, H8); 7.01e7.21 (m, 5H, HAr); 7.26e7.48 (m, 4H, HAr); 7.96 (s,1H,
H2); 14.87 (br s, 1H, OH). 13C NMR (CDCl3): 39.1 (CH2); 42.3 (CH3);
92.7 (d, J¼23.5, C8); 112.6 (dd, J¼6.2, J¼3.3, C4a); 118.1 (C3); 126.0
(CH); 126.2 (CH); 128.2 (CH); 128.3 (2ꢁCH); 129.3 (2ꢁCH); 130.8
(CH); 131.2 (CH); 136.3 (dd, J¼257, J¼10.3, C6); 136.5 (d, J¼9.7, C8a);
139.0(C);140.0(C); 140.8 (C);150.0 (C2); 153.3 (dd, J¼9.8, J¼6.6, C5);
154.7 (dd, J¼254, J¼11.0, C7); 179.7 (d, J¼2.7, C(4)]O); 194.1 (C]O).
Found, %: C 71.12; H 4.27; N 3.39. C24H17F2NO3. Calculated, %: C 71.11;
H 4.23; F 9.37; N 3.46; O 11.84. M 405.39.
10. Lokshin, V.; Valès, M.; Samat, A.; Pèpe, G.; Metelitsa, A.; Khodorkovsky, V. Chem.
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4.4.10. 3-(2-Benzylbenzoyl)-6,7-difluoro-5-methoxy-1-methyl quino-
lin-4(1H)-one (3j). Yield 5 (23)%,32 white powder, mp 182e184 ꢀC.
1H NMR (CDCl3): 3.62 (s, 3H, NCH3); 4.00 (d, 3H, J¼1.2, OCH3); 4.16
(s, 2H, CH2); 6.90 (dd, 1H, J¼11.3, J¼6.1, H8); 7.05e7.28 (m, 7H, HAr);
7.33e7.41 (m, 2H, H60, and H40); 7.76 (s, 1H, H2). 13C NMR (CDCl3):
39.1 (CH2); 42.1 (NCH3); 63.1 (d, J¼4.0, OCH3); 99.0 (d, J¼22.0, C8);
121.3 (C3); 125.8 (CH); 126.2 (CH); 128.3 (2ꢁCH); 128.4 (CH); 129.3
(2ꢁCH); 130.5 (CH); 131.2 (CH); 137.7 (dd, J¼11.5, J¼2.7, C8a); 139.0
(C); 140.1 (C); 141.2 (C); 148.6 (C2); 173.8 (d, J¼2.8, C(4)]O); 195.6
(C]O). Found, %: C 71.64; H 4.51; N 3.27. C25H19F2NO3. Calculated,
%: C 71.59; H 4.57; F 9.06; N 3.34; O 11.44. M 393.36.
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Acknowledgements
This work was supported by the Centre National de la Recherche
Scientifique (CNRS). The 300 and 500 MHz NMR facilities were
funded by the Région Nord-Pas de Calais (France), the Ministère de
la Jeunesse de l0Education Nationale et de la Recherche (MJENR),
and the Fonds Européens de Développement Régional (FEDER). Part
of this collaborative work was realized within the framework of the
International Research Group IRG CNRS 93 ‘Phenics’ (Photo-
switchable Organic Molecular Systems & Devices). N.A.L. is thankful
for the PhD fellowship to the ‘Reseau Formation-Recherche Franco-
Russe’ of the French Ministry for Education and Research.
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Supplementary data
28. Breaux, E. J.; Zwikelmaier, K. E. J. Heterocycl. Chem. 1981, 18, 183e184.
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These data include 1 and 2D NMR spectra used for the structure
assignments. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tet.2010.08.039.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
32. The yields obtained with dried and freshly distilled DME. Using this solvent few
days after distillation afforded the yields given in brackets.