Efficient syntheses of new chromone- And chromanequinoline hybrids and their aza-analogs

Article abstract of DOI:10.2174/157017811796064494

Some novel chromone- and chromanequinoline hybrids and their aza-analogs were synthesized from 2-chloro-3-quinolinecarboxaldehydes as starting materials. The cyclization of 2-hydroxychalcones in the presence of AcONa yielded chroman-4-ones, while, in the typical AFO conditions, the 2-corresponding quinolyl-3-hydroxyflavonols were obtained. These approaches were extended to 2-aminochalcones, which delivered the 3-hydroxy-2,3-dihydroquinolin- 4(1H)-one via an epoxy-ketone and 2-quinolyl-2,3-dihydroquinoline-4(1H)-one under microwave irradiation in the presence of silica gel impregnated with indium (III) chloride.

Full text of DOI:10.2174/157017811796064494

374
Letters in Organic Chemistry, 2011, 8, 374-379
Efficient Syntheses of New Chromone- and Chromanequinoline Hybrids
and their Aza-analogs
Abelmalek Bouraioua, Fabienne Berréeb, Sofiane Bouacidac, Bertrand Carbonib,
Abdelmadjid Debachea, Thierry Royneld and Ali Belfaitah*,a
aLaboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences Exactes,
Campus de Chaabat Ersas, Université Mentouri-Constantine, 25000, Algeria
b
Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes
CEDEX, France
cUnité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, CHEMS, Université Mentouri-
Constantine 25000, Algeria
dCentre de Difractométrie X, UMR 6226 CNRS Unité Sciences Chimiques de Rennes, Universite´ de Rennes I,
Campus de Beaulieu, 35042 Rennes CEDEX, France
Received August 30, 2010: Revised March 29, 2011: Accepted April 13, 2011
Abstract: Some novel chromone- and chromanequinoline hybrids and their aza-analogs were synthesized from 2-chloro-
3-quinolinecarboxaldehydes as starting materials. The cyclization of 2-hydroxychalcones in the presence of AcONa
yielded chroman-4-ones, while, in the typical AFO conditions, the 2-corresponding quinolyl-3-hydroxyflavonols were
obtained. These approaches were extended to 2-aminochalcones, which delivered the 3-hydroxy-2,3-dihydroquinolin-
4(1H)-one via an epoxy-ketone and 2-quinolyl-2,3-dihydroquinoline-4(1H)-one under microwave irradiation in the
presence of silica gel impregnated with indium (III) chloride.
Keywords: Quinoline, chalcones, flavonoid, quinolinone, bis-heterocycles.
Flavonoids are naturally occurring polyphenol
derivatives present in substantial amounts in plants, fruits
and vegetables [1]. Since food products derived from plants
inflammatory, anti-tumor activities [3]. Flavonoids have
been classified into several subgroups, such as flavonols and
flavanones (Fig. 1).
R'
R'
R
R
X
X
OH
O
O
Flavanones
Flavonols
X=O
Fig. (1). Some subgroups of the flavonoid family.
are an integral part of the human diet, the potential
bioactivity of these compounds has been largely investigated
ever since their discovery. Flavonoids exert various effects
on health that explains the considerable interest aroused by
this family. Numerous studies have shown their capacity to
absorb oxygen radicals, their antioxidant potential and
radical-scavenging properties [2]. Other benefits have since
been described: anti-viral, anti-allergic, anti-platelet, anti-
From a chemical point of view, 2,3-dihydro-2-aryl-
4(1H)-quinolinones can be considered as aza-analogs of
flavanones (X=NH instead of X=O, Fig. 1). They are known
for the wide-range of their biological activity, as anticancer
and immunosuppressive agents [4]. They also serve as
valuable precursors for the synthesis of other medicinally
important compounds [5]. To improve the pharmacological
profile of these important families of bioactive molecules, a
number of investigations have been carried out which
involved the replacement of the 2-aryl substituent by various
heterocycles [6]. The introduction of quinoline nucleus has
*Address correspondence to this author at the Laboratoire des Produits
Naturels d’Origine Végétale et de Synthèse Organique. Faculté des Sciences
Exactes, Campus de Chaabat Ersas, Université Mentouri-Constantine,
25000, Algeria; Tel/Fax: (213) (0) 31 81 88 62;
already been used successfully in
a
number of
pharmacomodulations [7]. In relation to these endeavours,
E-mail: abelbelfaitah@yahoo.fr
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Efficient Syntheses of New Chromone- and Chromanequinoline Hybrids
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
375
O
R4
R1
R1
CHO
X
R2
R2
R3
N
Y
N
Cl
R3
4, 5, 10, 11
1
R1, R2, R3= H, OMe, Me
Cl, O-(CH2)-O
X = O, NH
H, OH
Y= Cl, OMe
R4=
Scheme 1. Synthesis of chromone- and chromanequinoline hybrids and analogues.
Ibrahim et al. have recently published the synthesis of a 2-
(3-quinolinyl)-substituted chromone [8]. Analogously,
Chang et al. have reported the synthesis and evaluation of
antitubulin activity of a 2-(quinolin-3-yl)quinolin-4(1H)-one
[9].
treatment with AcONa in refluxing ethanol via
intramolecular attack of the phenoxide moiety at the ꢀ-
position of the ꢀ,ꢁ-unsaturated ketone [12], while 5a-e were
obtained albeit in lower yields, when subjected to the typical
Algar-Flynn-Oymanda (AFO) conditions, [13] aqueous
hydrogen peroxide in the presence of sodium hydroxide
Following our previous works related to the use of
substituted 2-chloro-3-formylquinolines 1 as precursors of
different quinoline-containing heterocycles, [10] we wish to
report herein our preliminary results concerning the
synthesis of chromone- and chromanequinoline hybrids and
their aza-analogs (Scheme 1).
1
(Scheme 2, Table 1) [14]. Both H and 13C NMR spectra are
in full agreement with those reported in the literature for
similar structures [15].
In contrast, if the base-catalyzed condensation of 2-
hydroxy-4,6-dimethoxyacetophenone effectively yielded the
desired chalcone 6, the major product detected after
treatment with H2O2/NaOH was a benzofuran-3(2H)-one 7
(aurone). The structure of 7 was established by detailed
examination of 1H and 13C spectra which showed
characteristic signals at 7.28 ppm assigned to the vinylic
proton and at 104.0 ppm for the corresponding carbon [16-
17]. In agreement with the literature, this result suggests that
the cyclization occurred at the ꢁ-position of an epoxide
intermediate due to the presence of a substituent at the
We first chose 2-methoxy-3-formylquinolines 2 as
starting material. They were easily prepared in good yields
from the corresponding 2-chloro-3-formylquinolines 1 in
refluxing methanol in the presence of sodium methoxide (2.0
equiv) [11]. Their conversion to the corresponding 2-
hydroxychalcones 3 proceeded cleanly in 73–90% yields by
treatment with 2-hydroxyacetophenone in the presence of
Ba(OH)2/MeOH. The flavanones 4a-e were synthesized on
OH
O
R1
R1
R2
CHO
ii
N
OMe
R2
N
Cl
3 (73-90%)
1
2
Y=Cl
Y=OMe
i
O
O
R1
R2
iii
N
OMe
3
4 (48-67%)
O
HO
R1
R2
iv
O
N
OMe
5 (30-61%)
Scheme 2. Reagents and conditions: (i) MeONa (2.0 eq.), MeOH, reflux. (ii) 2-hydroxyacetophenone, Ba(OH)2, MeOH, 40°C, 24h. (iii)
AcONa, EtOH, reflux, 48h. (iv) H2O2, NaOH, MeOH-THF, rt, 24h.

376 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Bouraiou et al.
Table 1. Synthesis of Substituted Flavanones (4) and Flavonols (5) from 2-hydroxychalcones (3)
Entry
R1
R2
Yield 3 (%)
Yield 4 (%)a
Yield 5 (%)a
a
b
c
H
H
H
OMe
H
90
73
76
74
86
50
56
67
51
48
49
45
61
30
50
OMe
d
e
-O-(CH2)-O-
H
Cl
aYield of isolated product after purification by column chromatography.
O
OMe
MeO
OMe
O
ii
i
N
OMe
HO
MeO
OMe
OH
6
OMe
OMe
O
O
via
O
OMe
OMe
MeO
N
OMe
Ar
O
O
7
Scheme 3. Reagents and conditions: (i) 2b, Ba(OH)2, MeOH, 40°C, 24h, 80%. (ii) H2O2, NaOH, MeOH-THF, rt, 24h, 36%.
6’position to yield exclusively the Z-geometrical isomer
(Scheme 3) [17-18].
was condensed with 2-chloro-3-formylquinolines 1a-d to
deliver the 2-aminochalcones 8a-d in 70-87% yields
according to the procedure described by Schlenoff and co-
workers [19]. Oxidation with hydrogen peroxide performed
Another aim of this study was to expand this work to
some aza-analogs of flavanones. First, 2-aminoacetophenone
NH2
O
R1
R2
CHO
Cl
R1
R2
i
N
Cl
N
R3
8 (70-87%)
R3
1
O
O
NH2
HO
O
R1
R2
ii R1
N
H
iii
N
Cl
R2
N
Cl
R3
10 (49-56%)
R3
9 (70-89%)
8
O
R1
R2
iv
N
H
N
Cl
R3
11 (58-71%)
Scheme 4. Reagents and conditions: (i) 2-aminoacetophenone, NaOH, EtOH, r.t., 24h. (ii) H2O2, NaOH, MeOH, THF, rt, 24h. (iii) H2O,
MeOH, reflux, 24h. (iv) InCl3, silica gel, μw, 5 min.

Efficient Syntheses of New Chromone- and Chromanequinoline Hybrids
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
377
Table 2. Synthesis of Substituted 3-hydroxy-2,3-dihydroquinolin-4(1H)-ones (10) and 2,3-dihydroquinolin-4(1H)-ones (11) from
2-aminochalcones (3)
Entry
R1
R2
R3
Yield 8 (%)
Yield 9 (%)
Yield 10 (%)a
Yield 11 (%)a
a
b
c
H
H
H
H
H
Me
H
80
70
74
87
81
70
77
89
56
49
51
53
58
71
69
63
Me
H
d
Me
Me
H
aYield of isolated product after purification by column chromatography.
in the presence of sodium hydroxide afforded epoxides 9a-d
(Scheme 4, Table 2).
dihydroquinolin-4(1H)-ones 11c-d were indeed obtained, but
in relatively low yields (40-43%).
The structure of compound 9a-d has been established by
spectroscopic methods. In the epoxy ring, the quinoline
group at C-2 and the aroyl group at C-3 adopt a 2,3-trans
arrangement. Suitable crystal of 9b compound was obtained
by recrystallization and X-ray crystallographic analysis
confirmed the structural assignment (Fig. 2).
Fig. (3). ORTEP plot of the X-ray crystal structure of 10b [20].
Recent studies on the Lewis acid catalyzed reactions with
indium halides revealed that InCl3 adsorbed on silica gel has
often better catalytic properties than InCl3 in solution [24]. In
this context, a mixture of 2-aminochalcones 8a-d and silica
gel impregnated with indium (III) chloride (20 mol%) was
irradiated in domestic microwave oven at 360 W for 5
minutes. Under these conditions, 11a-d was successfully
synthesized in good yields (58-71%) (Scheme 4, Table 2)
[25].
Fig. (2). ORTEP plot of the X-ray crystal structure of 9b [20].
Upon heating in refluxing methanol/water, intramole-
cular cyclization occurred at the ꢀ-position of epoxides to
give the corresponding 3-hydroxy-2,3-dihydroquinolin-
4(1H)-ones 10a-d [21]. The relative position of the hydroxyl
and quinoline unit on the new heterocyclic ring could not be
determined efficiently by NMR spectroscopy (J H2-H3 = 12.5-
12.8 Hz). However, an X-ray structure determination of
quinolone 10b (Fig. 3) revealed a trans-configuration which
showed that the new ring was formed with inversion of
configuration at C-2 [22]. X-ray crystallography of 10b
showed an asymmetric unit which contains only one
stereoisomer and the analysis of the unit cell demonstrate
that the second stereoisomer is generated via a symmetry
element. The two stereoisomers have for each one, the
absolute stereochemistry 2S, 3S and 2R, 3R of the new
stereocenters created in the cyclization reactions.
Single crystal of compound 11b was obtained and X-ray
crystallographic analysis confirmed the structural assign-
ments (Fig. 4). The unit cell contains two independent
molecules and the analysis demonstrates that the two
stereoisomers have for each one, the absolute stereo-
chemistry (2R) and (2S).
Finally, we turned our attention to the synthesis of the
2,3-dihydroquinolin-4(1H)-ones. Most of the reported
procedures dealing with the synthesis of such compounds
involved the use of corrosive reagents, such as
orthophosphoric acid, acetic acid or strong alkalis [23]. The
high efficiency of InCl3 as catalyst in the synthesis of the
2,3-dihydroquinolin-4(1H)-ones [24] and the ease of product
isolation prompted us to investigate its use in the synthesis of
11. The reaction of the 2-aminochalcones 8a-d with InCl3 in
CH3CN was firstly examined. The corresponding 2,3-
Fig. (4). ORTEP plot of the X-ray crystal structure of 11b [20].

378 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Bouraiou et al.
Trisubstituted 3-Hydroxychromone Derivatives as Fluorophores for
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In conclusion, as demonstrated herein, the approaches
developed in this work allow an easy and efficient access to
structural analogs of flavonols and flavanones combining
these important substructures with quinolyl moieties. Further
biological evaluation of these compounds is currently
underway and will be reported in due course.
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ACKNOWLEDGMENT
We thank MESRS, Algeria, for the financial support.
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Efficient Syntheses of New Chromone- and Chromanequinoline Hybrids
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
379
135.1, 129.1, 127.5, 125.6, 123.7, 122.1, 121.4, 121.1, 118.4,
106.6, 75.2, 55.9, 54.2, 43.5. HRMS (EI): m/z [M+] Calc. for
C20H17NO4: 335.1158; found: 335,1174.
[20]
[21]
Crystallographic data (excluding structure factors) for compounds
9b, 10b and 11b have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC786116, CCDC786117, CCDC786115. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13]
(a) Moriarty, R. M.; Grubjesic, S.; Surve, B. C.; Chandersekera, S.
N.; Prakash, O.; Naithani, R. Synthesis of Abyssinone II
and related compounds as potential chemopreventive agents. Eur.
J. Med. Chem. 2006, 41(2), 263-267. (b) Yang, J. H.; Zhao, Y. M.;
Ji, C. B. First total synthesis of (±)-abyssinoflavanone V. Chin.
Chem. Lett. 2008, 19(6), 658-660. (c) Dong, X.; Liu, T.; Yan, J.;
Wu, P.; Chen, J.; Hu, Y. Synthesis, biological evaluation and
quantitative structure-activities relationship of flavonoids as
vasorelaxant agents. Bioorg. Med. Chem. 2009, 17(2), 716-726.
Typical procedure for the synthesis of 3-hydroxy-2-(2,7-
Selected data for 2'-chloro-3-hydroxy-6'-methyl-2,3-dihydro-2,3'-
biquinolin-4(1H)-one 10c (mp. 172°C); 1H NMR (300 MHz,
CDCl3) ꢀ 8.43 (s, 1H), 7.89 (m, 2H), 7.59-7.29 (m, 3H), 6.90-6.83
(m, 2H), 5.15 (d, J = 12.8 Hz, 1H), 4.94 (s, 1H), 4.67 (d, J = 12.8
Hz, 1H), 3.75 (s, 1H), 2.53 (s, 3H). 13C NMR (75 MHz, CDCl3) ꢀ
194.3, 151.4, 145.7, 137.7, 137.5, 137.4, 136.3, 133.4, 129.5,
128.2, 127.9, 127.6, 126.6, 119.2, 116.5, 116.0, 74.9, 60.2, 21.6.
HRMS (EI): m/z [M+] Calc. for C19H15ClN2O2: 338.0822; found:
338.0820.
(a) Chen, W. P.; Egar, A. L.; Hursthouse, M. B.; Abdul Malik,
K.M.; Mathews J. E.; Roberts S. M. Synthesis of optically active
2,3-substituted-1,2,3,4-tetrahydro-4-quinolones using polyleucine.
Tetrahedron Lett. 1998, 39(46), 8495-8498. (b) Donnelly, J. A.;
Farrell D. F. The chemistry of 2'-amino analogs of 2'-
hydroxychalcone and its derivatives. J. Org. Chem. 1990, 55(6),
1757-1761.
(a) Donnelly, J. A.; Farrell, D. F. Chalcone derivatives as
precursors of 1,2,3,4-tetrahydro-4-quinolones. Tetrahedron 1990,
46(3), 885. (b) Tokes, A. L.; Litkei, G. Schmidt Reaction on 2-
Aryl-1,2,3,4-tetrahydro-4-quinolone. Synth. Commun. 1993, 23(7),
895-902 and references cited therein.
Hemanth Kumar, K.; Muralidharan, D.; Perumal, P. T. Indium (III)
Chloride/Silica Gel-Promoted Facile and Rapid Cyclization of 2-
Aminochalcones to 2-Aryl-2,3-dihydroquinolin-4(1H)-ones under
Solvent-Free Conditions. Synthesis 2004, (1), 1, 63-69.
Typical procedure for the synthesis of 2,3-dihydro-2-(2-chloro-6-
methylquinolin-3-yl)quinolin-4(1H)-one 11c: To 2-aminochalcone
8c (100 mg, 0.31 mmol) in DCM (5 mL) was added silica gel
impregnated with InCl3 (13.6 mg, 20% mol), prepared by addition
of a solution of InCl3 in a minimum of THF to silica gel (1 g, 100-
200 mesh activated by heating for 4 h at 150°C before use). The
resulting mixture was homogenized by stirring for 5 min. After
complete evaporation of the solvent, it was transferred to a glass
tube which was inserted in an alumina bath (100 g, 60 GF254,
fisher scientific bath 6.5 cm diameter) inside the microwave oven.
The compound was irradiated at 350 W for 5 min. On completion,
the resulting product was directly charged on a small pad of silica
gel and eluted with DCM to afford 11c as yellow solid (65 mg,
0.20 mmol, 69%, mp. 205°C); 1H NMR (300 MHz, CDCl3) ꢀ 8.29
(s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.59-7.55 (m, 2H), 7.40 (t, J = 7.2
Hz, 1H), 6.87-6.75 (m, 2H), 5.28 (dd, J = 11.2, 4.0 Hz, 1H), 4.90
(s, 1H), 3.12 (dd, J = 13.3, 3.5 Hz, 1H), 2.82 (dd, J = 16.2, 11.8 Hz,
1H), 2.52 (s, 3H). 13C NMR (75 MHz, CDCl3) ꢀ 192.3, 151.0,
148.0, 145.5, 137.6, 135.4, 133.1, 132.4, 127.8, 127.7, 127.5,
127.1, 126.5, 119.0, 118.9, 116.2, 53.9, 43.8, 21.6. HRMS (EI):
m/z [M+] Calc. for C19H15ClN2O: 322.0872; found: 322.0864.
[14]
dimethoxyquinolin-3-yl)-4H-chromen-4-one 5c: To
a stirring
solution of chalcone 3c (200 mg, 0.59 mmol) in MeOH-THF (10
mL, 1/1) was added NaOH 16% (2 mL) at 0°C, followed by the
solution of 30% H2O2 (2 mL). The solution was stirred for 24 h at
rt. The reaction mixture was acidified with 2 N HCl and extracted
with DCM. The extracts were washed with water, brine, and dried
over anhydrous Na2SO4. Purification by silica gel column
chromatography (CH2Cl2), afforded 5c as a yellow solid (112 mg,
[22]
[23]
0.32 mmol, 61%) mp. 195°C. 1H NMR (300 MHz, CDCl3) ꢀ 8.33-
8.30 (m, 2H), 7.73-7.70 (m, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.46 (d,
J = 8.2 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.12-7.08 (m, 2H), 6.50
(s, 1H), 4.13 (s, 3H), 4.00 (s, 3H). 13C NMR (75 MHz, CDCl3) ꢀ
172.1, 161.2, 158.5, 154.9, 148.2, 143.4, 139.4, 138.1, 132.4,
128.2, 124.5, 123.4, 120.2, 118.0, 117.4, 116.0, 111.5, 105.2, 54.5,
52.8. HRMS (EI): m/z [M+] Calc. for C20H15NO5: 349.0950; found:
349.0945.
[24]
[25]
[15]
[16]
Ibrahim, A. S.; Abul-Hajj, Y. J. Microbiological Transformation of
(±)-Flavanone and (±)-Isoflavanone. J. Nat. Prod. 1990, 53(3),
644-656.
Spectral data for selected products: 2-[(2,7-dimethoxyquinolin-3-
yl)methylene]-4,6-dimethoxy-1-benzofuran-3(2H)-one
7 (yellow
solid: mp. 237°C): 1H NMR (500 MHz, CDCl3) ꢀ 8.80 (s, 1H), 7.72
(d, J = 8.8 Hz, 1H), 7.28 (s, 1H) 7.21 (s, 1H), 7.06 (dd, J = 8.9 and
2.4 Hz, 1H), 6.46 (s, 1H), 6.17 (s, 1H), 4.15 (s, 3H), 3.98 (s, 3H),
3.96 (s, 3H), 3.96 (s, 3H). 13C NMR (125 MHz, CDCl3) ꢀ 180.2,
168.9, 168.8, 161.9, 160.7, 159.4, 148.7, 148.3, 139.7, 129.4,
120.0, 116.8, 114.9, 106.2, 105.4, 104.0, 94.0, 89.3, 56.2, 56.1,
55.5, 53.7. HRMS (EI): m/z [M+H]+ Calc. for C22H20NO6:
394.12906; found: 394.1291.
[17]
Detsi, A.; Majdalani, M.; Kontogiorgis, C.; Hadjipavlou-Litina, D.;
Kefalas, P. Natural and synthetic 2ꢁ-hydroxy-chalcones and
aurones: Synthesis, characterization and evaluation of the
antioxidant and soybean lipoxygenase inhibitory activity. Bioorg.
Med. Chem. 2009, 17(23), 8073-8085.
[18]
[19]
Adams, C. J.; Main, L. Cyclisation and subsequent reactions of 2ꢁ-
hydroxy-6ꢁ-methoxychalcone
epoxide
and
related
compounds. Tetrahedon 1991, 47(27), 4979-4990.
Gao, F.; Johnson, K. F.; Schlenoff, J. B. Ring closing and
photooxidation in nitrogen analogues of 3-hydroxyflavone. J.
Chem. Soc. Perkin Trans. 2 1996, (2), 269-273.