A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant and lipoxygenase inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2010.05.022

A series of coumarin analogues bearing a substituted phenyl ring on position 3 were synthesized via a novel methodology, through an intermolecular condensation reaction of 2-hydroxyacetophenones and 2-hydroxybenzaldehyde, with imidazolyl phenylacetic acid active intermediates. The in vitro antioxidant activity of the synthesized compounds was evaluated using two different antioxidant assays (radical scavenging ability of DPPH stable free radical and inhibition of lipid peroxidation induced by the thermal free radical AAPH). Moreover, the ability of the compounds to inhibit soybean lipoxygenase was determined as an indication of potential anti-inflammatory activity.

Full text of DOI:10.1016/j.bmcl.2010.05.022

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3889–3892
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant
and lipoxygenase inhibitory activity
Marina Roussaki a, Christos A. Kontogiorgis b, Dimitra Hadjipavlou-Litina b, Stylianos Hamilakis a,
,
*
Anastasia Detsi a
a Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens, Heroon Polytechniou 9, Zografou Campus, GR 15773 Athens, Greece
b Aristotle University of Thessaloniki, School of Pharmacy, Department of Pharmaceutical Chemistry, 54124 Thessaloniki, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of coumarin analogues bearing a substituted phenyl ring on position 3 were synthesized via a
novel methodology, through an intermolecular condensation reaction of 2-hydroxyacetophenones and
2-hydroxybenzaldehyde, with imidazolyl phenylacetic acid active intermediates. The in vitro antioxidant
activity of the synthesized compounds was evaluated using two different antioxidant assays (radical
scavenging ability of DPPH stable free radical and inhibition of lipid peroxidation induced by the thermal
free radical AAPH). Moreover, the ability of the compounds to inhibit soybean lipoxygenase was deter-
mined as an indication of potential anti-inflammatory activity.
Received 19 March 2010
Revised 10 May 2010
Accepted 11 May 2010
Available online 2 June 2010
Keywords:
3-Aryl-coumarins
Lipoxygenase
Antioxidant
Ó 2010 Elsevier Ltd. All rights reserved.
Coumarins are benzopyrone analogues widely distributed in
nature.1 The fused heterocyclic framework of coumarins has served
as the prototype scaffold for the synthesis of a wide variety of ana-
logues in order to investigate their biological activity. In the liter-
ature, coumarins are reported to possess a remarkable range of
biological properties including antioxidant,2 anticancer,3 vasore-
laxant,4 antiviral5 and anti-inflammatory activities.6,7 Moreover,
several synthetic coumarin derivatives have important pharmaco-
logical potential as they proved to be efficient inhibitors of a vari-
ety of enzymes such as the human 5-lipoxygenase,8 aromatase,9
horseradish peroxidase,10 hAChE/BACE111 and 17b-hydroxysteroid
dehydrogenase type 3.12
Reactive oxygen species (ROS) are formed by aerobic organisms
as an unavoidable consequence of cell metabolism. Although effec-
tive natural defense mechanisms against these highly reactive spe-
cies exist (e.g., natural antioxidants such as vitamins E and C,
b-carotene and polyphenolic flavonoids), excessive ROS production
which escorts many pathophysiological conditions (oxidative
stress) poses the need of further antioxidant protection. As a result,
the research for the development of novel, small molecules with
antioxidant activity is constantly attracting attention.
physiology of several inflammatory and allergic diseases. Inhibitors
of lipoxygenases have attracted attention initially as potential
agents for the treatment of inflammatory and allergic diseases,
but their therapeutic potential has now been expanded to certain
types of cancer and cardiovascular diseases.13
This work aims at the development of a novel synthetic
approach towards 3-aryl-coumarin derivatives and the evaluation
of their antioxidant and lipoxygenase inhibitory activity.
The most widely applied approaches towards the synthesis of
coumarin analogues include the Perkin reaction, that uses
2-hydroxyacetophenone and phenylacetic acid as starting materi-
als, and the Pechmann reaction, which involves the condensation
of phenols with b-keto-esters in the presence of strong acids. Vari-
ations of these methodologies have been developed in an attempt
to improve reaction conditions and yields.14–19
In order to synthesize the coumarin analogues desired for this
study, we developed a smooth, clean and effective procedure toward
these heterocyclic compounds, using mild reaction conditions. The
major drawbacks of the Perkin and Pechmann procedures include
the use of excess acetic anhydride, acyl chlorides, high temperatures
and strong acids. In addition, many functional groups cannot stand
these harsh conditions. Therefore the scope of the synthesis is lim-
ited. Moreover, the availability and safety of acyl chlorides is prob-
lematic: certain types of acyl chlorides are unstable, are prepared
and isolated with difficulty and give products of hydrolysis in basic
or acidic conditions.
Lipoxygenases (LOs) are a family of iron-containing enzymes
that catalyse the dioxygenation of polyunsaturated fatty acids in
lipids. Lipoxygenases have recently become of interest, as they
are considered the key enzymes in the biosynthesis of leukotrienes
that have been postulated to play an important role in the patho-
We have previously reported extensive studies on the use of 1,1-
carbonyldiimidazole (CDI) activated
tic acids as acylating agents and in that research, the formation of the
a-amino-acids and phenylace-
* Corresponding author. Tel.: +30 2107723258; fax: +30 210773072.
E-mail address: hamil@chemeng.ntua.gr (S. Hamilakis).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.022

3890
M. Roussaki et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3889–3892
corresponding imidazolyl intermediates was undoubtedly proven
by 1H NMR spectroscopy.20,21 Therefore, in order to circumvent the
aforementioned problems concerning the synthesis of coumarin
derivatives, we decided to investigate the potential use of CDI acti-
vated phenylacetic acids as acylating agents.
In this work, we found that reaction of a variety of phenylacetic
acids with CDI provided sufficient activation and enabled them to
smoothly react with 2-hydroxy-acetophenone in the presence of
an organic base, DBU, in CH2Cl2. The reaction proceeds at room
temperature and is completed in 1–2 h (monitoring by TLC is use-
ful). Quenching with aqueous HCl (10%) with vigorous stirring for
10 min, followed by separation of the organic phase and evapora-
tion of the solvent, results to the isolation of the crude product.
Purification using flash column chromatography yields the desired
coumarin in satisfactory yields (40–60%).22
OH
OH
OCH3
OCH3
R
R
O
(i)
R'
R'
O
O
O
14
R=R'=H
15 R=CH3, R'=Cl
4
R=R'=H
5 R=CH3, R'=Cl
Scheme 2. Reagents and conditions: (i) BBr3, CH2Cl2, 0 °C (1 h), rt (3 h).
bit lipid peroxidation induced by the thermal free radical producer
2,20-azobis(2-amidinopropane) dihydrochloride (AAPH) was evalu-
ated. Moreover, the ability of the synthesized coumarins to inhibit
soybean lipoxygenase was determined. The results are presented
in Table 1.
The scope of the reaction was investigated using a variety of
substituted phenylacetic acids containing either electron-with-
drawing or electron-donating substituents, 2-hydroxy-acetophe-
none (1a), 5-chloro-2-hydroxy-acetophenone (1b), 5-bromo-2-
hydroxy-acetophenone (1c) and 2-hydroxy-benzaldehyde (2)
(Scheme 1). It is interesting to note that our methodology is appli-
cable even in the case of 5-chloro- and 5-bromo-2-hydroxy-aceto-
phenone, which contain electron-withdrawing substituents.
The presence of a catechol system is well known to improve the
antioxidant activity of a compound. Especially in the case of flavo-
noid analogues as well as in coumarin derivatives, it has been
shown that the ortho-dihydroxy system forms a resonance stabi-
lized radical which enhances the radical scavenging ability of the
compound.4,10,23 In order to examine the influence of this struc-
tural feature on the biological activity of the new coumarin ana-
logues 4 and 5, the methyl group was removed, using BBr3 in
CH2Cl2, providing coumarins 14 and 15, respectively (Scheme 2).24
The structure of all the synthesized coumarin analogues was elu-
cidated using spectroscopic techniques (1H and 13C NMR, ESI/MS).25
The in vitro antioxidant activity of the new compounds was
evaluated using two antioxidant assays: the radical scavenging
ability of the compounds was tested against the 1,1-diphenyl-2-
picryl-hydrazyl (DPPH) stable free radical and their ability to inhi-
The scavenging effect of the synthesized compounds on the
DPPH radical was evaluated according to the methods of Hadjipav-
lou-Litina and co-worker.30 The interaction of the synthesized
compounds with the stable free radical DPPH indicates their radi-
cal scavenging ability in an iron-free system. The majority of the
tested coumarins presented low interaction with the DPPH radical
at 50 lM concentration. However, compounds 14 and 15, which
possess the catechol structural feature are potent DPPH radical
scavengers, showing high activity comparable to the reference
compound NDGA. It is evident that, for this series of compounds,
the presence of the catechol system is crucial for this type of activ-
ity: the corresponding methoxylated analogues 4 and 5 have very
low activity which is remarkably enhanced when the methyl
groups are removed (compounds 14 and 15). In addition, the pres-
ence of only one free phenolic hydroxyl group (as in the case of
compound 9), does not favour activity. The observation that the
catechol structural feature favours radical scavenging and antioxi-
dant ability of coumarin derivatives is in accordance with previous
findings of other research groups studying analogous systems.10,23
AAPH induced linoleic acid oxidation is based on the inhibition
of lipid peroxidation (LP), and provides a measure of how effi-
ciently antioxidants protect against lipid peroxidation in vitro. Oxi-
dation of exogenous linoleic acid by a thermal free radical producer
COOH
R3
R1
3
R3
O
R
R2
R
R3
R'
R2
O
O
R'
R'
R
R1
(i),(ii)
O
R2
OH
O
O
R1
1a R=CH3, R'=H
1b
4-13
R=CH3, R'=Cl
1c R=CH3, R'=Br
R=R'=H
R
R'
R1
R2
R3
2
4
5
H
H
H
H
OCH3
OCH3
OCH3
H
OCH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Cl
H
H
H
H
H
H
H
Br
OCH3
OCH3
OCH3
NO2
OH
6
H
7
H
8
H
H
9
H
H
10
11
12
13
H
H
Br
OCH3
Br
H
H
H
H
H
OCH3
OCH3
Scheme 1. Reagents and conditions: (i) CDI, CH2Cl2, rt; (ii) DBU, CH2Cl2, rt.

M. Roussaki et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3889–3892
3891
Table 1
The synthesized coumarins were tested for their ability to in-
hibit soybean lipoxygenase using the UV absorbance based en-
zyme assay.30 Although the results of this assay cannot be
extrapolated to the inhibition of mammalian 5-LO, it has been
shown that inhibition of plant LO activity by non-steroidal
anti-inflammatory agents is qualitatively similar to the inhibition
they cause to the rat mast cell LO. Therefore, the soybean inhi-
bition assay can be used as a simple qualitative assay for such
activity. Amongst the tested coumarin analogues, compound 13
(86%) was the most efficient soybean LO inhibitor, as compared
to the reference compounds NDGA. This highly active LO inhib-
itor, may not be a good DPPH radical scavenger but possesses
also the best LP inhibitory activity amongst the tested com-
pounds. Moreover, coumarin derivative 7 showed satisfactory
LO inhibition (62%), although it is neither a good DPPH scaven-
ger nor a good LP inhibitor.
In conclusion, this study presents the development of an effi-
cient one-step approach towards the synthesis of new coumarin
analogues, using commercially available and affordable starting
materials which leads to structurally diverse compounds. This
new method is straightforward, simple, involves mild reaction con-
ditions easy work-up and isolation procedure of the compounds.
The new molecules have been further evaluated for their antioxi-
dant and soybean LO inhibitory activity. The catechol moiety has
been identified as the structural requirement for efficient DPPH
radical scavenging and lipid peroxidation activity, however it does
not favour LO inhibitory ability. The best combined pharmacolog-
ical profile is exhibited by compound 13, which is a potent LO
inhibitor and efficiently inhibits lipid peroxidation. Synthesis of
analogues of 13 in order to perform more detailed structure–activ-
ity relationship studies are currently underway.
Interaction % with DPPH, % inhibition of LP induced by AAPH and inhibition of
soybean lipoxygenase (LO) at 100
l
M for coumarins 4–15
Compound
DPPH (%)
% inhibition of LP
induced by AAPH % at
100 lM
% inhibition of
LO % at 100 lM
50
lM
20 min 60 min
4
5
6
7
8
9
10
11
12
13
14
15
4
4
8
5
5
5
3
3
4
7
5
10
2
4
9
4
3
3
6
47
100
36
24
36
20
70
12
20
90
68
48
No
12
31
62
No
No
No
No
6
86
9
No
40
3
85
84
84
85
83
83
NDGAa
Trolox
63
Each in vitro experiment was performed at least in triplicate and the standard
deviation of absorbance was less than 10% of the mean.
a
NDGA—nordihydroguaiaretic acid; No—no activity under the reported experi-
mental conditions.
(AAPH) is followed by UV spectrophotometry in a highly diluted
sample.31
Amongst the 12 tested coumarins, five exhibited significant LP
inhibition, higher than the reference compound trolox. The most
efficient LP inhibitor compared to trolox is compound 5, followed
by the coumarins 13, 10 and 14. For the compounds which do
not have a substituent on the aromatic ring of the benzopyranone
moiety, the presence of electron-donating groups on the phenyl
ring of position 3 does not favour activity: compounds 6, 7, 9, 11,
which contain methoxy or hydroxy-groups, present low to moder-
ate inhibition potency (12.3–36%). The number and the position of
substituents do not significantly increase activity as can be de-
duced by comparing compounds 6 and 7 as well as 7 and 11. Sub-
stitution of the methoxy-group with bromine dramatically
enhances activity as can be seen by comparison of compound 7
with compound 10. In this case, the position of the substituent
plays a major role: a bromine substituent on the para-position
(compound 10) gives an active compound (70%) whereas a bro-
mine substituent on the ortho-position (compound 12) leads to a
compound with moderate activity (20%). Thus, the lipophilic con-
Acknowledgement
Financial support by the Basic Research Committee Programme
‘PEBE 2009, 65/1796’ is gratefully acknowledged (M. Roussaki).
References and notes
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I.-C.; Chang, C.-W.; Tang, W.-F.; Tseng, S.-N.; Chen, C.-J.; Shih, S.-R.; Hsu, J. T. A.;
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Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Guay, J.; Hamel, P.; Riendeau, D.;
Soucy-Breau, C.; Tagari, P.; Girard, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2528.
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10. Kabeya, L. M.; de Marchi, A. A.; Kanashiro, A.; Lopes, N. P.; da Silva, C. H. T. P.;
Pupo, M. T.; Lucisano-Valima, Y. M. Bioorg. Med. Chem. 2007, 15, 1516.
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Inoue, S.; Kojima, A. Bioorg. Med. Chem. Lett. 2010, 20, 272.
tribution
way the LP inhibition (
p
of the substituent affects significantly in a positive
value for CH3O-group = ꢀ0.02 whereas
p
p
value for Br-group = 0.86). The nature of the electron-withdrawing
group is also important, as coumarin derivative 8, which bears a ni-
tro-group on the para-position exhibits only 36% inhibition of LP.
The most important structural feature that affects the LP inhibition
potency of this series of compounds seems to be the presence of a
halogen on the aromatic ring of the benzopyranone fused ring sys-
tem: compound 6, without a halogen substituent on the aromatic
ring, is a moderate inhibitor (36%) whereas the analogous com-
pounds 5 and 13 (bearing a Cl and a Br substituent, respectively)
are very potent inhibitors of LP.
13. Werz, O.; Steinhilber, D. Pharmacol. Ther. 2006, 112, 701.
14. Sabitha, G.; Rao-Subha, A. V. Synth. Commun. 1987, 17, 341.
15. Ming, Y.; Boykin, D. W. Heterocycles 1987, 26, 3229.
The majority of LO inhibitors are antioxidants or free radical
scavengers,32 since lipoxygenation occurs via a carbon centred rad-
ical. LOs contain a ‘non-heme’ iron per molecule in the enzyme ac-
tive site as high-spin Fe2+ in the native state and the high-spin in
the activated state Fe3+. Some studies suggest a relationship be-
tween LO inhibition and the ability of the inhibitors to reduce
16. Gallastegui, D. J.; Lago, J. M.; Palomo, C. J. Chem. Res. S. 1984, 170.
17. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285.
18. Waldmann, H.; Kühn, M.; Liuab, W.; Kumar, K. Chem. Commun. 2008, 1211.
19. Li, X.; Reuman, M.; Russell, R. K.; Youells, S.; Beish, S.; Hu, Z.; Branum, S.; Jain,
N.; Sui, Z. Org. Process Res. Dev. 2007, 11, 731.
20. Hamilakis, S.; Kontonassios, D.; Sandris, C. J. Heterocycl. Chem. 1996, 33, 825.
21. Hamilakis, S.; Tsolomitis, A. Heterocycl. Commun. 2005, 11, 149.
the Fe3+ at the active site to the catalytically inactive Fe2+ 33,34
.

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M. Roussaki et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3889–3892
22. General procedure for the synthesis of coumarin analogues 4–13: A solution of
phenylacetic acid (1 equiv) in CH2Cl2 (5 mL) and 1,1-carbonyldiimidazole (CDI)
(1.2 equiv) was stirred at room temperature for 30 min. That solution was
added dropwise to a mixture of the appropriate 2-hydroxyacetophenone (1a,
1b or 1c) or 2-hydroxybenzaldehyde (2) (1 equiv) in CH2Cl2 (5 mL) and DBU
(1 equiv). The reaction mixture was stirred for 1–2 h at room temperature. The
mixture was acidified with HCl 10%, stirred vigorously for 10 min. The organic
phase was separated, dried over anhydrous Na2SO4, filtered and evaporated to
give the crude product. Purification by flash column chromatography
(petroleum ether/ethyl acetate 9:1) affords the pure coumarin.
2H), 7.49 (pseudotriplet, 1H), 7.64 (dd, J = 8.1 Hz, J = 1.2 Hz, 1H). 13C NMR
(75 MHz, CDCl3–MeOH): d 16.5, 115.3, 116.6, 120.6, 124.2, 125.0, 125.3, 126.9,
131.1, 131.2, 147.7, 152.3, 153.7, 156.7, 161.7; 3-(4-bromophenyl)-4-methyl-
2H-chromen-2-one (10) Yield 46%. Mp 156–159 °C.14 1H NMR (300 MHz,
CDCl3): d 2.33 (s, 3H), 7.20 (d, J = 8.4 Hz, 2H), 7.39–7.27 (m, 2H), 7.61–7.54 (m,
3H), 7.69 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 16.6, 116.9, 120.4,
122.5, 124.4, 125.1, 126.2, 131.6, 131.7, 131.8, 133.3, 147.9, 152.7, 160.6; 3-(2-
methoxyphenyl)-4-methyl-2H-chromen-2-one (11)28
: Yield 42%. Mp 160–
161 °C. 1H NMR (300 MHz, CDCl3): d 2.25 (s, 3H), 3.78 (s, 3H), 6.99–7.07 (m,
2H), 7.19 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 7.29–7.42 (m, 3H), 7.53 (pseudotriplet,
1H), 7.68 (dd, J = 8.1 Hz, J = 0.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 16.3, 55.6,
111.2, 116.8, 120.5, 120.6, 123.4, 124.0, 124.3, 124.9, 129.9, 131.0, 131.2, 148.5,
152.8, 157.2, 160.5; 3-(2-bromophenyl)-4-methyl-2H-chromen-2-one (12):
Yield 43%. Mp 119–122 °C. 1H NMR (300 MHz, CDCl3): d 2.23 (s, 3H), 7.44–7.25
(m, 5H), 7.60–7.55 (m, 1H), 7.70 (d, J = 7.8 Hz, 2H). 13C NMR (75 MHz, CDCl3): d
16.2, 117.0, 120.1, 124.3, 125.2, 126.9, 127.7, 129.9, 131.3, 131.7, 132.9, 135.6,
149.1, 152.9, 159.8. ESI-HRMS Calcd for C16H1279BrO2+H: m/z: 315.0015,
found: 314.9998; 6-bromo-3-(3,4-dimethoxyphenyl)-4-methyl-2H-chromen-
2-one (13): Yield 44%. Mp 185–186 °C. 1H NMR (300 MHz, CDCl3): d 2.32 (s,
3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.84 (d, J = 10.2 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H),
7.24–7.27 (m, 1H), 7.62 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 7.78 (s, 1H); MS (ESI) m/
z = 375/377 [M+H]+/[M+2+H]+. ESI-HRMS Calcd for C18H1579BrO4+H: m/z:
375.0226, found: 375.0221; 3-(3,4-dihydroxyphenyl)-2H-chromen-2-one
(14)29: Yield 89%. Mp 176–178 °C. 1H NMR (300 MHz, CD3OD): d 6.83 (d,
J = 8.1 Hz, 1H), 7.09 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.33
(d, J = 7.8 Hz, 2H), 7.51–7.55 (m, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H); 13C
NMR (75 MHz, CD3OD): d 116.2, 116.8, 116.9, 121.3, 121.5, 125.7, 127.7, 128.9,
129.2, 132.1, 140.0, 146.0, 147.4, 154.4, 162.6; MS (ESI) m/z = 255 [M+H]+. ESI-
HRMS Calcd for C15H10O4+H: m/z: 255.0652, found: 255.0640; 6-chloro-3-(3,4-
dihydroxyphenyl)-4-methyl-2H-chromen-2-one (15): Yield 88%. Mp 297–
23. Raj, H. G.; Parmar, V. S.; Jain, S. C.; Goel, S.; Himansu, P.; Malhotra, S.; Singh, A.;
Olsen, C. E.; Wengel, J. Bioorg. Med. Chem. 1998, 6, 833.
24. Demethylation of compounds 4 and 5: To a stirred solution of the appropriate
coumarin (1 equiv) in CH2Cl2 (1.5 mL) at 0 °C was added boron tribromide
(BBr3, 1 M solution in hexane) (16 equiv). After 1 h, the resulting mixture was
stirred for 3 more hours at room temperature. The yellow mixture was poured
into ice water and dissolved in MeOH. The mixture was then extracted with
CH2Cl2 and the organic phase was dried over anhydrous Na2SO4, filtered and
evaporated to give the final product.
25. Structural characterization data for the synthesized compounds: 3-(3,4-
Dimethoxyphenyl)-2H-chromen-2-one (4): Yield 59%. Mp 132–136 °C.26 1H
NMR (300 MHz, CDCl3): d 3.92 (s, 1H), 3.94 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H),
7.36–7.26 (m, 3H), 7.54–7.47 (m, 2H), 7.77 (s, 1H). 13C NMR (75 MHz, CDCl3): d
55.9, 56.0, 111.0, 111.8, 116.3, 119.7, 121.2, 124.4, 127.4, 127.7, 127.8, 131.0,
138.6, 148.7, 149.7, 153.2, 160.6; 6-chloro-3-(3,4-dimethoxyphenyl)-4-
methyl-2H-chromen-2-one (5): Yield 47%. Mp 179–182 °C. 1H NMR
(300 MHz, CDCl3): d 2.32 (s, 3H), 3.90 (d, J = 11.4 Hz, 6H), 6.82–6.86 (m, 2H),
6.96 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.46–7.50 (m, 1H), 7.63 (d,
J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 16.6, 55.9, 111.1, 113.1, 118.2,
122.6, 124.7, 126.4, 128.1, 129.6, 131.1, 146.4, 148.9, 149.2, 151.0, 153.7, 160.5.
ESI-HRMS Calcd for C18H16ClO4+H: m/z: 331.0732, found: 331.0720; 3-(3,4-
dimethoxyphenyl)-4-methyl-2H-chromen-2-one (6): Yield 45%. Mp 156–
160 °C.16 1H NMR (300 MHz, CDCl3): d 7.67 (dd, J5,6 = 8.1 Hz, J5,7 = 1.5 Hz, 1H),
7.54 (pseudotriplet, 1H), 7.38–7.29 (m,2H), 6.95 (d, J = 8.1 Hz, 1H), 6.87–6.82
(m, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3): d 16.6,
55.9, 111.0, 113.1, 116.8, 120.6, 122.6, 124.2, 125.0, 126.8, 127.0, 131.2, 147.7,
148.7, 148.9, 152.6, 161.2; 3-(4-methoxyphenyl)-4-methyl-2H-chromen-2-
one (7): Yield 44%. Mp 190–193 °C.14 1H NMR (300 MHz, CDCl3): d 2.34 (s, 3H),
3.85 (s, 3H), 6.99 (d, J = 8.4 Hz, 2H), 7.23 (br s, 1H), 7.38–7.29 (m, 3H), 7.53
(pseudotriplet, 1H), 7.67 (d, J = 6.6 Hz, 1H); 13C NMR (75 MHz, CDCL3): d 16.6,
55.3, 113.9, 116.8, 120.7, 124.2, 125.0, 126.6, 127.0, 131.1, 131.3, 147.3, 152.6,
153.7, 159.4, 161.2; 4-methyl-3-(4-nitrophenyl)-2H-chromen-2-one (8): Yield
51%. Mp 200–202 °C. 1H NMR (300 MHz, CDCl3): d 2.35 (s, 3H), 7.35–7.42 (m,
2H), 7.51 (s, 1H), 7.54 (s, 1H), 7.61 (pseudotriplet, 1H), 7.72 (dd, J = 8.1 Hz,
J = 1.2 Hz, 1H), 8.33 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 16.6, 117.1,
120.0, 123.6, 124.6, 125.2, 125.3, 131.4, 132.2, 141.3, 147.6, 148.7, 152.8, 153.7,
160.1. ESI-HRMS Calcd for C16H12NO4+H: m/z: 282.0761, found: 282.0758; 3-
(4-hydroxyphenyl)-4-methyl-2H-chromen-2-one (9): Yield 54%. Mp 243–
299 °C. 1H NMR (300 MHz, CD3OD):
d 2.34 (s, 3H), 6.62 (dd, J = 8.4 Hz,
J = 2.1 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.7 Hz,
1H), 7.58 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), MS (ESI) m/
z = 303/305 [M+H]+/[M+2+H]+. ESI-HRMS Calcd for C16H11ClO4+H: m/z:
303.0419, found: 303.0403.
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246 °C.27 1H NMR (300 MHz, CDCl3–MeOH):
J = 6.6 Hz, J = 1.8 Hz, 2H), 7.09 (dd, J = 8.7 Hz, J = 2.1 Hz, 2H), 7.28–7.33 (m,
d
2.29 (s, 3H), 6.86 (dd,