Synthesis and characterization of new 3-acyl-7-hydroxy-6,8-substituted- coumarin and 3-acyl-7-benzyloxy-6,8-substituted-coumarin derivatives

Article abstract of DOI:10.1002/jhet.362

(Chemical Equation Presented) A new series of 3-acyl-6,7,8-substituted coumarin derivatives has been synthesized in high yields (79-99%) and characterized by means of elemental analysis, mass spectrometry, IR, and ¹H NMR spectroscopy. We examined with particular attention the presence of an acyl group at position 3 (ethyl ester, carboxylic acid, and acyl chloride), and of a hydroxyl group at position 7 or a functionalized one like benzyloxy or phthalimido. The hydroxyl group has been modified by an etherification in presence of crown ether with substituted benzyl bromide or chloride to evaluate the influence on chemical characteristics and lipophilicity of coumarin nucleus. Halogens (Cl, Br) and methyl group were introduced in position 6 and 8 of the coumarin ring, respectively, in order to study their effect on reaction feasibility. Some of these 3-acyl derivatives have been recently assayed as MAO inhibitors and as intermediates (i.e. reactive chloride derivative) to design new anti-Helicobacter pylori agents.

Full text of DOI:10.1002/jhet.362

May 2010
Synthesis and Characterization of New 3-Acyl-7-hydroxy-6,8-
substituted-coumarin and 3-Acyl-7-benzyloxy-6,8-substituted-
coumarin Derivatives
729
Franco Chimenti, Adriana Bolasco,* Daniela Secci, Bruna Bizzarri,
Paola Chimenti, Arianna Granese, and Simone Carradori
`
Dipartimento di Chimica e Tecnologie del Farmaco, Universita degli Studi di Roma
‘‘La Sapienza’’, P.le A. Moro 5, 00185 Rome, Italy
*E-mail: adriana.bolasco@uniroma1.it
Received September 25, 2009
DOI 10.1002/jhet.362
Published online 29 April 2010 in Wiley InterScience (www.interscience.wiley.com).
A new series of 3-acyl-6,7,8-substituted coumarin derivatives has been synthesized in high yields
1
(79–99%) and characterized by means of elemental analysis, mass spectrometry, IR, and H NMR spec-
troscopy. We examined with particular attention the presence of an acyl group at position 3 (ethyl ester,
carboxylic acid, and acyl chloride), and of a hydroxyl group at position 7 or a functionalized one like
benzyloxy or phthalimido. The hydroxyl group has been modified by an etherification in presence of
crown ether with substituted benzyl bromide or chloride to evaluate the influence on chemical character-
istics and lipophilicity of coumarin nucleus. Halogens (Cl, Br) and methyl group were introduced in
position 6 and 8 of the coumarin ring, respectively, in order to study their effect on reaction feasibility.
Some of these 3-acyl derivatives have been recently assayed as MAO inhibitors and as intermediates
(i.e. reactive chloride derivative) to design new anti-Helicobacter pylori agents.
J. Heterocyclic Chem., 47, 729 (2010).
INTRODUCTION
Coumarins, (2H)-1-benzopyran-2-ones, represent
opment of new reliable high-yielding methods for the synthe-
sis of coumarins an important matter. For these reasons, we
synthesized many molecules based on the coumarin ring sys-
tem by utilizing classic and innovative synthetic techniques
such as carbon suboxide [8] and microwave [9].
a
common type of phytochemicals, frequently encountered
in plants of the Apiaceae, Rutaceae, Fabaceae, and
Hyppocastanaceae [1]. Interest in this scaffold arose from
the identification of both natural or synthetic pharmaco-
logically active derivatives, which have been found to be
useful in photochemotherapy, antitumor [2], and anti-HIV
[3] therapy, and as stimulants for central nervous system,
antibacterials, antioxidants [4], anti-inflammatory [5], anti-
coagulants, and dyes according to the nature and the sub-
stitution pattern. In particular we recently demonstrated
that 3-acyl and 3-carboxyamido coumarins could be con-
sidered good lead compounds as reversible and effective
human monoamine oxidase (hMAO) inhibitors [6,7].
In particular, microwave irradiation usually acceler-
ates some chemical transformations and offers numerous
benefits for performing solventless procedures (green
chemistry) and improving reaction yields, especially in
heterocyclic chemistry [10].
Hence, in this article, we report on synthesis and
1
characterization by spectral data, such as IR, H NMR,
and mass spectroscopy of coumarin analogues bearing
an acyl function (ethyl ester, carboxylic acid, and acyl
chloride) at position 3, halogens (Cl, Br) at position 6,
different unsubstituted or substituted benzyloxy moieties
at position 7, and methyl group at position 8 (Table 1).
The interesting biological properties of coumarins made
these compounds very attractive for organic synthesis. There
are many developed methods of coumarins synthesis, e.g.
Pechman reaction, Perkin reaction, Knoevenagel condensa-
tion, and many others [1]. However, it is important to high-
light that all the reported procedures have some disadvan-
tages, as they lack generality and efficiency making the devel-
RESULTS AND DISCUSSION
Coumarin derivatives were synthesized starting from
substituted salicylic aldehydes according to the pathway
reported in Scheme 1.
C
V
2010 HeteroCorporation

730
F. Chimenti, A. Bolasco, D. Secci, B. Bizzarri, P. Chimenti, A. Granese, and S. Carradori
Vol 47
Table 1
Structure and CLogP (ChemDraw Ultra 8.0) of synthesized coumarin derivatives.
Comp
R
R1
R2
X
ClogP
m/z
3a
3b
3c
3d
3e
3f
3g
3h
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
7a
7b
7c
7d
7e
7f
Cl
Br
H
CH2Ph
OCH2Ph
OCH2Ph
H
H
CH3
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OH
OH
OH
OH
OH
OH
OH
Cl
4.52
4.67
4.53
4.74
4.17
4.74
3.77
3.15
3.80
3.95
3.81
4.02
3.45
4.02
3.05
1.46
1.66
1.49
3.43
3.58
3.43
3.65
3.08
3.65
2.68
358.77
403.22
338.35
358.77
342.31
358.77
369.32
393.35
330.71
375.17
310.30
330.72
314.26
330.72
341.27
259.04
303.49
238.32
349.16
393.61
328.74
349.16
332.71
349.16
359.72
H
H
OCH2(2-Cl-Ph)
OCH2(4-F-Ph)
OCH2(4-Cl-Ph)
OCH2(4-NO2-Ph)
OCH2phtalimido
OCH2Ph
H
H
H
H
H
H
H
Cl
Br
H
H
H
OCH2Ph
OCH2Ph
CH3
H
H
OCH2(2-Cl-Ph)
OCH2(4-F-Ph)
OCH2(4-Cl-Ph)
OCH2(4-NO2-Ph)
OH
H
H
H
H
H
H
Cl
Br
H
Cl
Br
H
H
H
OH
OH
OCH2Ph
OCH2Ph
OCH2Ph
Cl
Cl
Cl
Cl
Cl
Cl
CH3
H
H
CH3
H
H
OCH2(2-Cl-Ph)
OCH2(4-F-Ph)
OCH2(4-Cl-Ph)
OCH2(4-NO2-Ph)
H
H
H
H
Cl
Cl
7g
H
H
Cl
The corresponding salicylic aldehydes were obtained
by a Gattermann aromatic formylation starting from 2-
or 4-substituted resorcinol in a strongly acidic environ-
ment (1a–1c). Ethyl esters of (2H)-1-benzopyran-2-one-
3-carboxylic acids (2a–2c), were easily obtained by a
Knoevenagel cyclization in 15–20 min (80ꢀC) under
microwave irradiation with an automatic single-mode re-
actor. All reactions were performed solventless in vials
of 10 mL, confirming that the focused microwave irradi-
ation was a very effective technique for accelerating
thermal organic reactions and limiting solvent wasting,
not being affected by substituents. These compounds,
bearing a hydroxyl group at position 7, were subse-
quently functionalized by benzylation in the presence of
N,N0-dicyclohexyl-18-crown-6-ether, which by chelating
potassium ion facilitated the nucleophilic attack to
improve the yields of the related compounds (3a–3h).
Alkaline hydrolysis with 10% sodium hydroxide gave
carboxylic acid compounds (4a–4c and 5a–5f), which
were treated with thionyl chloride at reflux to yield the
desired and reactive acyl chloride derivatives (6a–6c
and 7a–7g). In general this synthetic procedure allowed
us to obtain the desired compounds in high yields and
simplify reaction work up, limiting the presence of by-
products.
The compounds, correctly analyzed for their molecu-
lar formula, showed in the IR spectrum strong bands at
1695–1720 cmꢁ1 due to the presence of a d-lactone
C¼¼O and eventually a carbonyl group, and characteris-
tic bands at 1655, 1615, 1575, and 1500 cmꢁ1 (double
bonds in the aromatic ring).
The lipophilicity (ClogP) of this coumarin scaffold
has been calculated with the suitable algorithm for each
molecule by using ChemDraw Ultra 8.0. because of its
importance in modulating biological activity and phar-
macodynamic profile of the molecules [11]. As
expected, the introduction of a benzyloxy group at posi-
tion 7 of the coumarin ring deeply affects this parame-
ter. All compounds, and above all compound 5g, which
was insoluble in common organic solvents (dimethyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis and Characterization of New 3-Acyl-7-hydroxy-6,8-substituted-coumarin
and 3-Acyl-7-benzyloxy-6,8-substituted-coumarin Derivatives
731
Scheme 1. General synthetic pattern of coumarin derivatives.
EXPERIMENTAL
Starting materials and reagents were obtained from commer-
cial suppliers and were used without purification. Melting
points (mp) were determined by the capillary method on an
FP62 apparatus (Mettler-Toledo) and are uncorrected. 1H
NMR spectra were recorded at 400 MHz on a Bruker spec-
trometer using DMSO-d6 as solvent. Chemical shifts are
expressed as d units (ppm) relative to TMS. Coupling con-
stants J are expressed in hertz (Hz). Elemental analyses for C,
H, and N were determined with a PerkinElmer 240 B micro-
analyzer and the analytical results were within 60.4% of the
theoretical values for all compounds. All reactions were moni-
tored by TLC performed on 0.2 mm thick silica gel plates (60
F254 Merck). Preparative flash column chromatography was
carried out on silica gel (230–400 mesh, G60 Merck). Organic
solutions were dried over anhydrous sodium sulphate. Concen-
tration and evaporation of the solvent after reaction or extrac-
tion was carried out on a rotary evaporator (Bu¨chi Rotavapor)
operating at reduced pressure. IR spectra were registered on a
PerkinElmer FTIR Spectrometer Spectrum 1000 in potassium
bromide. Mass spectra (EI) were obtained with a Fisons QMD
1000 mass spectrometer (70 ev, 200 lA, ion source tempera-
ture 200ꢀC). The samples were introduced directly into the ion
source. Compounds 2a–2c, synthesized with the microwave
method, were obtained with a Biotage InitiatorTM 2.0.
The synthesis of some compounds (1a–1c, 2a–2c, and 4a–
4c) has been previously described and was performed with
slight changes. Their analytical and spectral data were in full
agreement with those reported in the literature.
sulfoxide, chloroform, and acetone), have been charac-
terized by mass spectral studies. In the mass spectra the
fragment ion at m/z (%) ¼ 173 (90) corresponding to
the 3-acyl coumarin structure was always the most
abundant observed. The fragmentation pattern of deriva-
tive 5g was described in Figure 1. This compound
showed the fragment at m/z (%) 341 (10), which likely
represented the molecular ion. In fact, the base peak,
referred to the 40-nitro-benzyl fragment, was always
present at 134 (100). In addition the mass spectrum
revealed ion suggestive at m/z 297 (5), 250 (5), and 205
(20) because of the loss of COOH, CO2, and NO2.
In this article, we have synthesized, by using readily
available and inexpensive reagents, and fully character-
ized a new series of heterocyclic derivatives (3-acyl-
6,7,8-substituted coumarins), which could reveal their
potentials as versatile biodynamic agents. The most im-
portant results of our approach are the optimization of
the yields and of the reaction times using microwave
irradiation. In addition, lower amount of solvent was
used and a better workup was obtained. The introduction
of a substituted benzyloxy group at position 7 could
influence not only the physical–chemical properties, but
also their biological activity. Halogens (Cl, Br) and
methyl group were introduced in position 6 and 8 of the
coumarin ring, respectively, to study their effect on
reaction feasibility.
Figure 1. The fragmentation pattern of derivative 5g.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

732
F. Chimenti, A. Bolasco, D. Secci, B. Bizzarri, P. Chimenti, A. Granese, and S. Carradori
Vol 47
General procedure for the synthesis of coumarin deriva-
tives 1a–1c. The substituted salicylic aldehydes were prepared
in a 500 mL bottle, fitted with a mechanical stirrer, a reflux
water condenser and an inlet tube, with wide mouth to prevent
clogging from the precipitate. Resorcinol derivatives (1 mmol),
zinc cyanide (2 mmol), and potassium chloride (0.3 mmol)
were suspended in anhydrous diethyl ether (40 mL). Gaseous
HCl was bubbled inside the bottle and then water was added
to hydrolyze the immine product into aldehyde. The zinc chlo-
ride, which was produced at the same time, acted as an effec-
tive condensing agent.
General procedure for the synthesis of coumarin deriva-
tives 2a–2c. The starting ethyl ester of coumarin-3-carboxylic
acid was prepared by Knoevenagel reaction between diethyl
malonate (1 mmol) and the appropriate salicylic aldehyde
(1 mmol) with catalytic amounts of piperidine (0.5 mL) in a
10 mL vial suitable for an automatic single-mode microwave
reactor (2.45 GHz high-frequency microwaves, power range 0–
300 W). The mixture was prestirred for 30 sec and then heated
by microwave irradiation for 15–20 min at 80ꢀC (irradiation
power reaches its maximum at the beginning of reaction, then
it decreases to lower and quite constant values). The internal
vial temperature was controlled by an IR sensor. After cooling
with pressurized air, the reaction mixture was poured onto ice,
filtered, and dried under vacuum.
Ethyl 7-(4-fluorobenzyloxy)-2-oxo-2H-chromene-3-carboxy-
late (3e). 87% yield; mp 159–160 ꢀC; 1H NMR (DMSO-d6)
1.29 (t, 3H, CH3), 4.33 (q, 2H, CH2), 5.23 (s, 2H, OCH2Ar),
7.15 (s, 1H, C8H-chrom.), 7.26–7.28 (m, 1H, C6H-chrom.),
7.61–7.65 (m, 2H, C3H-Ar and C5H-Ar), 7.72–7.74 (m, 1H,
C5H-chrom.), 7.89–7.92 (m, 2H, C2H-Ar and C6H-Ar), 8.85 (s,
1H, C4H-chrom.). Anal. Calcd. for C19H15FO5: C, 66.66; H,
4.42. Found: C, 66.68; H, 4.43.
Ethyl 7-(4-chlorobenzyloxy)-2-oxo-2H-chromene-3-carbox-
ylate (3f). 79% yield; mp 160–161ꢀC; 1H NMR (DMSO-d6)
1.28 (t, 3H, CH3), 4.23 (q, 2H, CH2), 5.26 (s, 2H, OCH2Ar),
7.19 (s, 1H, C8H-chrom.), 7.25–7.28 (m, 1H, C6H-chrom.),
7.31–7.36 (m, 2H, C3H-Ar and C5H-Ar), 7.41–7.43 (m, 1H,
C5H-chrom.), 7.54–7.58 (m, 2H, C2H-Ar and C6H-Ar), 8.80 (s,
1H, C4H-chrom.). Anal. Calcd. for C19H15ClO5: C, 63.61; H,
4.21. Found: C, 63.63; H, 4.22.
Ethyl 7-(4-nitrobenzyloxy)-2-oxo-2H-chromene-3-carboxy-
late (3g). 87% yield; mp 210–211ꢀC; 1H NMR (DMSO-d6)
1.29 (t, 3H, CH3), 4.33 (q, 2H, CH2), 5.45 (s, 2H, OCH2Ar),
7.26 (s, 1H, C8H-chrom.), 7.30–7.32 (m, 1H, C6H-chrom.),
7.41–7.44 (m, 2H, C2H-Ar and C6H-Ar), 7.51–7.53 (m, 1H,
C5H-chrom.), 8.26–8.30 (m, 2H, C3H-Ar and C5H-Ar), 8.83 (s,
1H, C4H-chrom.). Anal. Calcd. for C19H15NO7: C, 61.79; H,
4.09; N, 3.79. Found: C, 61.77; H, 4.10; N, 3.80.
Ethyl 7-[(1,3-dioxoisoindolin-2-yl)methoxy]-2-oxo-2H-chro-
mene-3-carboxylate (3h). 98% yield; mp 284–285ꢀC; 1H
NMR (DMSO-d6) 1.27–1.31 (t, 3H, CH3), 4.26-4.28 (q, 2H,
CH2), 5.73 (s, 2H, OCH2Ar), 7.29 (s, 1H, C8H-chrom.), 7.33–
7.35 (m, 1H, C6H-chrom.), 7.49–7.51 (m, 1H, C5H-chrom.),
7.86–7.92 (m, 4H, Ar), 8.73 (s, 1H, C4H-chrom.). Anal. Calcd.
for C21H15NO7: C, 64.12; H, 3.84; N, 3.56. Found: C, 64.10;
H, 3.83; N, 3.57.
General procedure for the synthesis of coumarin deriva-
tives 3a–3h. The etherification at position 7 was performed
by adding suitable benzyl bromide (1 mmol) and potassium
carbonate (1 mmol) in dry acetone (50 mL) for 48 h at room
temperature, using N,N0-dicyclohexyl-18-crown-6-ether (1
mmol) as a chelating agent. The resulting reaction mixture
was filtered and the crude product was purified by
chromatography.
General procedure for the synthesis of coumarin deriva-
tives 4a–4c and 5a–5g. All ethyl ester derivatives were dis-
solved in NaOH 10% (50 mL) and added of HCl 3N (50 mL).
The resulting suspension was filtered and dried under vacuum.
7-(Benzyloxy)-6-chloro-2-oxo-2H-chromen-3-carboxylic acid
Ethyl 7-(benzyloxy)-6-chloro-2-oxo-2H-chromene-3-carbox-
1
ylate (3a). 85% yield; mp 211–212ꢀC; H NMR (DMSO-d6) d
1.27–1.29 (t, 3H, CH3), 4.29–4.31 (q, 2H, CH2), 5.31 (s, 2H,
OCH2Ar), 7.30 (s, 1H, C8H-chrom.), 7.31–7.50 (m, 5H, Ar),
8.18 (s, 1H, C5H-chrom.), 8.68 (s, 1H, C4H-chrom.). Anal.
Calcd. for C19H15ClO5: C, 63.61; H, 4.21. Found: C, 63.63; H,
4.22.
1
(5a). 87% yield; mp 233–234ꢀC; H NMR (DMSO-d6) d 5.34
(s, 2H, OCH2Ar), 7.41 (s, 1H, C8H-chrom.), 7.43–7.48 (m,
5H, Ar), 8.18 (s, 1H, C5H-chrom.), 8.43 (s, 1H, C4H-chrom.),
13.24 (bs, 1H, COOH, D2O exch.). Anal. Calcd. for
C17H11ClO5: C, 61.74; H, 3.35. Found: C, 61.76; H, 3.36.
7-(Benzyloxy)-6-bromo-2-oxo-2H-chromene-3-carboxylic acid
Ethyl 7-(benzyloxy)-6-bromo-2-oxo-2H-chromene-3-carbox-
1
ylate (3b). 87% yield; mp 215–216ꢀC; H NMR (DMSO-d6) d
1.30–1.32 (t, 3H, CH3), 4.32–4.34 (q, 2H, CH2), 5.40 (s, 2H,
OCH2Ar), 7.19 (s, 1H, C8H-chrom.), 7.21–7.49 (m, 5H, Ar),
8.10 (s, 1H, C5H-chrom.), 8.60 (s, 1H, C4H-chrom.). Anal.
Calcd. for C19H15BrO5: C, 56.59; H, 3.75. Found: C, 56.57; H,
3.76.
1
(5b). 92% yield; mp 255–256ꢀC; H NMR (DMSO-d6) d 5.30
(s, 2H, OCH2Ar), 7.30 (s, 1H, C8H-chrom.), 7.41–7.47 (m,
5H, Ar), 8.20 (s, 1H, C5H-chrom.), 8.59 (s, 1H, C4H-chrom.),
13.15 (bs, 1H, COOH, D2O exch.). Anal. Calcd. for
C17H11BrO5: C, 54.42; H, 2.96. Found: C, 54.44; H, 2.95.
7-(Benzyloxy)-8-methyl-2-oxo-2H-chromene-3-carboxylic acid
Ethyl
7-(benzyloxy)-8-methyl-2-oxo-2H-chromene-3-car-
boxylate (3c). 89% yield; mp 154–155ꢀC; 1H NMR (DMSO-
d6) d 1.27–1.29 (t, 3H, CH3), 2.20 (s, 3H, ArCH3), 4.22–4.27
(q, 2H, CH2), 5.31 (s, 2H, OCH2Ar), 7.39 (s, 1H, C8H-
chrom.), 7.40–7.45 (m, 5H, Ar), 7.46 (s, 1H, C5H-chrom.),
8.72 (s, 1H, C4H-chrom.). Anal. Calcd. for C20H18O5: C,
70.99; H, 5.36. Found: C, 71.01; H, 5.37.
1
(5c). 90% yield; mp 204–205ꢀC; H NMR (DMSO-d6) d 2.23
(s, 3H, ArCH3), 5.28 (s, 2H, OCH2Ar), 7.21 (s, 1H, C8H-
chrom.), 7.47–7.53 (m, 5H, Ar), 7.77 (s, 1H, C5H-chrom.),
8.70 (s, 1H, C4H-chrom.), 12.98 (bs, 1H, COOH, D2O exch.).
Anal. Calcd. for C18H14O5: C, 69.67; H, 4.55. Found: C,
69.69; H, 4.54.
Ethyl 7-(2-chlorobenzyloxy)-2-oxo-2H-chromene-3-carbox-
ylate (3d). 79% yield; mp 126–127ꢀC; 1H NMR (DMSO-d6)
1.28–1.30 (t, 3H, CH3), 4.29–4.31 (q, 2H, CH2), 5.44 (s, 2H,
OCH2Ar), 7.19 (s, 1H, C8H-chrom.), 7.21–7.22 (m, 1H, C6H-
chrom.), 7.23–7.27 (m, 4H, Ar), 7.28–7.29 (m, 1H, C5H-
chrom.), 8.70 (s, 1H, C4H-chrom.). Anal. Calcd. for
C19H15ClO5: C, 63.61; H, 4.21. Found: C, 63.63; H, 4.22.
7-(2-Chlorobenzyloxy)-2-oxo-2H-chromene-3-carboxylic acid
1
(5d). 92% yield; mp 218–219ꢀC; H NMR (DMSO-d6) 5.32 (s,
2H, OCH2Ar), 7.12 (s, 1H, C8H-chrom.), 7.13–7.15 (m, 1H,
Ar) 7.40–7.41 (m, 1H, C6H-chrom.), 7.42–7.44 (m, 1H, Ar),
7.65–7.67 (m, 1H, Ar), 7.77–7.79 (m, 1H, Ar), 7.85–7.86 (m,
1H, C5H-chrom.), 8.72 (s, 1H, C4H-chrom.), 13.12 (bs, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis and Characterization of New 3-Acyl-7-hydroxy-6,8-substituted-coumarin
and 3-Acyl-7-benzyloxy-6,8-substituted-coumarin Derivatives
733
COOH, D2O exch.). Anal. Calcd. for C17H11ClO5: C, 61.74;
H, 3.35. Found: C, 61.72; H, 3.36.
7-(4-Fluorobenzyloxy)-2-oxo-2H-chromene-3-carboxylic acid
5.30 (s, 2H, OCH2Ar), 7.30 (s, 1H, C8H-chrom.), 7.41–7.47
(m, 5H, Ar), 8.20 (s, 1H, C5H-chrom.), 8.60 (s, 1H, C4H-
chrom.). Anal. Calcd. for C17H10BrClO4: C, 51.87; H, 2.56.
Found: C, 51.89; H, 2.57.
1
(5e). 91% yield; mp 228–229ꢀC; H NMR (DMSO-d6) 5.33 (s,
2H, OCH2Ar), 7.12 (s, 1H, C8H-chrom.), 7.25–7.27 (m, 1H,
C6H-chrom.), 7.37–7.40 (m, 2H, C3H-Ar and C5H-Ar), 7.53–
7.56 (m, 2H, C2H-Ar and C6H-Ar), 7.82–7.84 (m, 1H, C5H-
chrom.), 8.85 (s, 1H, C4H-chrom.), 13.02 (s, 1H, COOH, D2O
exch.). Anal. Calcd. for C17H11FO5: C, 64.97; H, 3.53. Found:
C, 64.98; H, 3.54.
7-(2-Chlorobenzyloxy)-2-oxo-2H-chromene-3-carbonyl chlo-
ride (7d). 91% yield; mp 171–172ꢀC; 1H NMR (DMSO-d6) d
5.29 (s, 2H, ArCH2), 7.18 (s, 1H, C8H-chrom.), 7.19–7.21 (m,
1H, Ar), 7.40–7.41 (m, 1H, C6H-chrom.), 7.42–7.44 (m, 1H,
Ar), 7.50–7.53 (m, 1H, Ar), 7.59–7.61 (m, 1H, Ar), 7.85–7.86
(m, 1H, C5H-chrom.), 8.73 (s, 1H, C4H-chrom.). Anal. Calcd.
for C17H10Cl2O4: C, 58.48; H, 2.89. Found: C, 58.50; H, 2.90.
7-(4-Nitrobenzyloxy)-2-oxo-2H-chromene-3-carbonyl chlo-
7-(4-Chlorobenzyloxy)-2-oxo-2H-chromene-3-carboxylic acid
1
(5f). 93% yield; mp 251–252ꢀC; H NMR (DMSO-d6) 5.26 (s,
1
2H, OCH2Ar), 7.07 (s, 1H, C8H-chrom.), 7.09–7.12 (m, 1H,
C6H-chrom.), 7.47–7.53 (m, 4H, Ar), 7.84–7.86 (m, 1H, C5H-
chrom.), 8.72 (s, 1H, C4H-chrom.), 13.12 (bs, 1H, COOH,
D2O exch.). Anal. Calcd. for C17H11ClO5: C, 61.74; H, 3.35.
Found: C, 61.75; H, 3.34.
7-(4-Nitrobenzyloxy)-2-oxo-2H-chromene-3-carboxylic acid
(5g). 89% yield; mp 281–282ꢀC. Insoluble in DMSO, chloro-
form, and acetone. ms: m/z 134 (100), 205 (20), 250 (5), 297
(5), 341 (10). Anal. Calcd. for C17H11NO7: C, 59.83; H, 3.25;
N, 4.10. Found: C, 59.84; H, 3.26; N, 4.09.
ride (7g). 79% yield; mp 220–221ꢀC; H NMR (DMSO-d6) d
5.45 (s, 2H, ArCH2), 7.20 (s, 1H, C8H-chrom.), 7.33–7.35 (m,
1H, C6H-chrom.), 7.49–7.52 (m, 2H, C2H-Ar and C6H-Ar),
7.95–7.97 (m, 1H, C5H-chrom.), 8.25–8.29 (m, 2H, C3H-Ar
and C5H-Ar), 8.81 (s, 1H, C4H-chrom.). Anal. Calcd. for
C17H10ClNO6: C, 56.76; H, 2.80. Found: C, 56.74; H, 2.79.
Acknowledgment. This work was supported by MURST (Italy).
General procedure for the synthesis of coumarin deriva-
tives 6a–6c and 7a–7g. Carboxylic acid derivatives were
refluxed under magnetic stirring with thionyl chloride (40 mL)
for 3 h to give the desired compound. The obtained solutions
were added with hexane and the resulting suspensions were
then filtered and dried under vacuum.
REFERENCES AND NOTES
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6-Chloro-7-hydroxy-2-oxo-2H-chromene-3-carbonyl chlo-
1
ride (6a). 95% yield; mp >300ꢀC; H NMR (DMSO-d6) d 6.92
[3] Kostova, I.; Mojzis, J. Futur HIV Ther 2007, 1, 315.
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(s, 1H, C8H-chrom.), 7.99 (s, 1H, C5H-chrom.), 8.62 (s, 1H,
C4H-chrom.), 11.96 (bs, 1H, OH, D2O exch.). Anal. Calcd. for
C10H4Cl2O4: C, 46.37; H, 1.56. Found: C, 46.39; H, 1.57.
6-Bromo-7-hydroxy-2-oxo-2H-chromene-3-carbonyl chlo-
1
ride (6b). 91% yield; mp >300ꢀC; H NMR (DMSO-d6) d 6.87
(s, 1H, C8H-chrom.), 8.11 (s, 1H, C5H-chrom.), 8.63 (s, 1H,
C4H-chrom.), 11.92 (bs, 1H, OH, D2O exch.). Anal. Calcd. for
C10H4BrClO4: C, 39.57; H, 1.33. Found: C, 39.55; H, 1.32.
7-Hydroxy-8-methyl-2-oxo-2H-chromene-3-carbonyl chlo-
[7] Chimenti, F.; Secci, D.; Bolasco, D.; Chimenti, P.; Bizzarri,
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Secci, D. Farmaco 1998, 53, 693.
1
ꢀ
ride (6c). 87% yield; mp >300 C; H NMR (DMSO-d6) d 2.16
(s, 3H, ArCH3), 6.96–6.98 (m, 1H, C6H-chrom.), 7.58–7.60 (m,
1H, C5H-chrom.), 8.69 (s, 1H, C8H-chrom.). Anal. Calcd. for
C11H7ClO4: C, 55.37; H, 2.96. Found: C, 55.39; H, 2.95.
7-(Benzyloxy)-6-chloro-2-oxo-2H-chromene-3-carbonyl chlo-
ride (7a). 95% yield; mp 214–215ꢀC; 1H NMR (DMSO-d6) d
5.34 (s, 2H, OCH2Ar), 7.41 (s, 1H, C8H-chrom.), 7.43–7.48
(m, 5H, Ar), 8.18 (s, 1H, C5H-chrom.), 8.43 (s, 1H, C4H-
chrom.). Anal. Calcd. for C17H10Cl2O4: C, 58.48; H, 2.89.
Found: C, 58.50; H, 2.90.
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Moreau, G.; Vandycke, C. Eur J Med Chem,1984, 19, 71.
7-(Benzyloxy)-6-bromo-2-oxo-2H-chromene-3-carbonyl chlo-
ride (7b). 85% yield; mp 214–215ꢀC; 1H NMR (DMSO-d6) d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet