Synthesis and photooxygenation of furo[3,2-c]coumarin derivatives as antibacterial and DNA intercalating agent

Article abstract of DOI:10.1002/cjoc.201180483

Syntheses of 2,3-dimethyl-4H-furo[3,2-c]coumarin and 3-phenyl-4H-furo[3,2- c]coumarin as angular furocoumarins were carried out through Williamson reaction of 4-hydroxycoumarin with α-haloketones followed by cyclization. Photooxygenation of the synthesized furocoumarin derivatives was performed and the photoproducts were isolated and characterized. The affinity of 2,3-dimethyl-4H-furo[3,2-c]coumarin towards DNA and the antibacterial activity were evaluated and compared with 8-methoxypsoralen (8-MOP). Syntheses of 2,3-dimethyl-4H-furo[3,2-c]coumarin and 3-phenyl-4H-furo[3,2-c]coumarin as angular furocoumarins were carried out through Williamson reaction of 4-hydroxycoumarin with α-haloketones followed by cyclization. Photooxygenation of the synthesized furocoumarin derivatives was performed and the photoproducts were isolated and characterized. The affinity of 2,3-dimethyl-4H-furo[3,2-c]coumarin towards DNA and the antibacterial activity were evaluated and compared with 8-methoxypsoralen (8-MOP). Copyright

Full text of DOI:10.1002/cjoc.201180483

FULL PAPER
DOI: 10.1002/cjoc.2011080483
Synthesis and Photooxygenation of Furo[3,2-c]coumarin
Derivatives as Antibacterial and DNA Intercalating Agent
a
,b
Al-Sehemi, Abdullah G.
El-Gogary, Sameh R.*
a
Chemistry Department, Faculty of Science (Abha), King Khaled University, Kingdom of Saudia Arabia
b
Chemistry Department, Faculty of Science (Damietta), Mansoura University, Egypt
Syntheses of 2,3-dimethyl-4H-furo[3,2-c]coumarin and 3-phenyl-4H-furo[3,2-c]coumarin as angular furocou-
marins were carried out through Williamson reaction of 4-hydroxycoumarin with α-haloketones followed by cycli-
zation. Photooxygenation of the synthesized furocoumarin derivatives was performed and the photoproducts were
isolated and characterized. The affinity of 2,3-dimethyl-4H-furo[3,2-c]coumarin towards DNA and the antibacterial
activity were evaluated and compared with 8-methoxypsoralen (8-MOP).
Keywords furocoumarins, psoralens, photooxygenation, antibacterial activity and DNA
Introduction
O
O
O
O
O
O
Coumarins are structural units of several natural
[
1]
R
products, and feature widely in pharmacologically and
[2]
biologically active compounds. Coumarins have been
1a: R = H
1b: R = OMe
2
[
3]
synthesized by several routes including von Pechman,
[
4]
[5,6]
[7]
Figure 1 Structure of psoralens (1) and angelicins (2).
Perkin, Knoevenagel,
Reformatsky and Wittig
[
8]
[9-14]
reactions. Besides functionalized coumarins,
fu-
psoralen, whose geometry does not permit the simulta-
neous alignment of the two photoreactive sites with
pyrimidine bases, thus allowing only monofunctional
photobinding.
The reactions of singlet molecular oxygen ( O )
rocoumarins such as psoralens (1) are photoactive drugs
which are extensively used in the PUVA (psoralen plus
UVA radiation) therapy for the treatment of human skin
[
18]
[15-22]
diseases.
Most prominent among the biological
l
[30-32]
2
activities associated with these photochemotherapeutic
agents (psoralens, linear furocoumarins) is their ability
to cross-link DNA via intercalation of the furocoumarin
with olefins may be categorized into three classes. The
first of these involves a [2＋2] cycloaddition to elec-
[
30-32]
[33,34]
[23]
tron-rich
or sterically hindered
olefins. The
between the base pairs of the nucleic acid and [2＋2]
resulting dioxetane is sometimes of moderate stability
but readily cleaves thermally or photolytically into two
carbonyl-containing fragments. The second type is the
photooxygenation of olefins that contain at least one
allylic hydrogen to yield allylic hydroperoxides in
which the double bond has shifted to a position adjacent
to the original double bond. This reaction bears a formal
photocycloaddition with the pyrimidine bases, particu-
[
24]
larly thymine.
Thus, undesirable side effects of
photoreactions with DNA and RNA lead to mutagenic-
[
25]
ity and carcinogenicity.
For this reason, considerable efforts have been ex-
pended to develop furocoumarins which only permit
monofunctional photobinding with DNA and thereby
diminish undesirable side effects. This has been accom-
plished by using angular furocoumarins such as an-
gelicins (2), which on account of their geometry cannot
[35]
resemblance to the Alder ene reaction.
The third
mode involves the addition of singlet oxygen to diene
systems to produce endoperoxides. The reaction is
analogous to a photo-induced Diels-Alder reaction in
which the oxygen is the dienophile.
In this work a new furo[3,2-c]coumarin derivatives,
isomers of angilicins, were synthesized by construction
of furano rings on pyrone moiety. The photooxygena-
tion of synthesized furocoumarin derivatives was per-
formed. The affinity of 2,3-dimethyl-4H-furo[3,2-c]-
coumarin towards DNA and the antibacterial activity
[
26]
crosslink with DNA, and by blocking the photoreac-
tive α-pyrone double bond with appropriate substitu-
[27]
ents 28,29o]r by annelation of an additional aromatic
[
ring.
To improve the photobinding capability and at the
same time to decrease the phototoxicity of psoralens,
several monofunctional derivatives have been prepared
and studied, such as angelicins, angular isomer of
*
E-mail: samehelgogary@yahoo.com
Received May 27, 2011; accepted September 26, 2011.
316
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 316—320

Synthesis and Photooxygenation of Furo[3,2-c]coumarin Derivatives
were evaluated and compared with 8-methoxypsoralen
5.26 and 5.70 with a coupling constant of 1.5 Hz and a
(8-MOP).
singlet peak at δ 8.25 for OOH which is exchangeable
with D O. The hydroperoxy stretching band at 3500—
2
－
l
Results and Discussion
3250 cm in the IR was appeared.
Under the photooxygenation conditions, the di-
oxetane 7 could be converted to 3-acetyl-2-oxo-2H-
chromen-4-yl acetate (8). The structure of 8 was con-
firmed by the presence of the three carbonyl carbons
resonance at δ 167.7, 178.7 and 206.1 in C NMR.
Further confirmation of compound 8 was obtained via
acid hydrolysis of compound 8 to afford 3-acetyl-4-
The synthetic route for the preparation of the furo-
coumarin derivative is displayed in Scheme 1. Phenol
was converted in 50% yield to the 4-hydroxycoumarin
(
3) by the reaction with malonic acid in the presence of
13
[36]
phosphorous oxychloride as described in literature.
The reaction of compound 3 with 3-chloro-2-butanone
in acetone in the presence of anhydrous K CO gave 4
2
3
hydroxy-2H-chromen-2-one (9) whose melting point is
in 75% yield. The absence of the OH group absorption
[38]
similar to the published data.
An additional confir-
－
1
and appearance of a new band at 1704.3 cm for new
carbonyl group in the IR, and the aliphatic protons
resonance at δ 1.66 (d, J＝6.6 Hz, 3H), 2.28 (s, 3H), and
mation of structure 9 was obtained through the treat-
ment of compound 3 with glacial acetic acid and phos-
phorous oxychloride (POCl ) to give 9.
3
4
.84 (q, J＝6.6 Hz, 1H) for 4'-H, 1'-H, and 3'-H respec-
Synthesis of 3-phenyl-4H-furo[3,2-c]chromen-4-one
1
tively in H NMR confirm the ether group in the keto
ether 4.
(11) (Scheme 2) was achieved in two steps by the same
manner as in case of 5. 4-Hydroxycoumarin was con-
verted to the β-keto ether 10 by reaction with phenacyl
chloride in refluxing acetone in the presence of K CO .
The cyclization of 4 in the presence of poly phos-
phoric acid (PPA) or alcoholic KOH (3%) gave
2
3
2
,3-dimethyl-4H-furo[3,2-c]chromen-4-one (5) in 77%
Treatment of compound 8 with PPA at 70 ℃ affords
1, whose melting point is consistent with the published
1
yield. The structure of 5 was characterized by IR, H
NMR, C NMR, mass spectroscopy and elemental
analysis.
1
13
[39]
data.
The photooxygenation of compound 11 gave
-benzoyl-4-hydroxy-2H-chromen-2-one (14) via for-
The photooxygenation of the furocoumarin 5 in
chloroform and in the presence of tetraphenylporphine
3
mation of dioxetane 12 as intermediate which was
photo-cleaved into intermediate 13 and finally into 14
(TPP) as singlet oxygen sensitizer at room temperature
gave the stable allylic hydroperoxide 6 and the di-
oxetane 7 as intermediate which was photolized rapidly
under the photooxygenation conditions to give 8. The
(
Scheme 2). Further confirmation of structure 14 was
obtained unambiguously via benzoylation of compound
followed by Fries rearrangement at 140 ℃ to pro-
3
formation of the allylic hydroperoxide is achieved by
duce 14 whose structure was confirmed through melting
points, mixed melting points and TLC.
1
the reaction of singlet oxygen O with an olefin bearing
2
allylic hydrogens in the so-called Schenck-ene reaction
and leads via a double bond shift to an allylic hydrop-
Biological evaluation
[
37]
eroxide.
While the formation of the dioxitane 7 is
The furocoumarin 5 was preliminarily evaluated and
compared to 8-MOP for its in vitro antibacterial activity
against two Gram positive bacteria (Bacillus subtilus
and Bacillus cereus) and two Gram negative bacteria
(Escherichia coli and Klebsiella pneumoniae). The an-
tibacterial activity of 5 and 8-MOP against two Gram
positive and two Gram negative bacteria is presented in
Table 1.
carried out by the [2＋2] cycloaddition of singlet oxy-
gen with the double bond of the furan moiety.
The stable allylic hydroperoxide 6 was isolated and
1
13
fully characterized by IR, H NMR and C NMR spec-
1
troscopy. The most conspicuous features in the H NMR
spectrum of stable allylic hydroperoxide are two distinct
doublets which correspond to two olefinic protons at δ
Scheme 1
OH
O
Cl
O
O
K CO
2
3
PPA or KOH
+
O
O
Acetone
O
3
O
O
5
O
O
4
TPP/hu/ 1O2
AcOH
POCl3
[
2+2] Cycloaddition
O
Ene reaction
O
O
OH O
O
O
HOO
O
O
O
HCl
O
9
O
O
O
O
O
O
8
7
6
7
3%
1
8%
Chin. J. Chem. 2012, 30, 316—320
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
317

Al-Sehemi & El-Gogary
FULL PAPER
Scheme 2
OH
O
Ph
O
O
O
Ph
O
O
O
Ph
K CO
+
2
3
PPA
O
Acetone
Cl
O
O
3
1
0
1
1
(
(
i) PhCOCl/K CO3
2
TPP/hv
1O
ii) AlCl /150 o
C
3
2
O
OH
O
O
O
O
O
O
O
Ph
Ph
O
Ph
O
O
O
O
1
4
1
2
1
3
7
1%
Table 1 Antibacterial effect of compounds 5 and 8-MOP
against two Gram positive bacteria (Bacillus subtilus and Bacillus
cereus) and two Gram negative bacteria (Escherichia coli and
a
Klebsiella pneumoniae)
Gram positive bacteria
Gram negative bacteria
Compound
B. subtilus B. cereus E. coli K. pneumonia
8
-MOP
－ve
－ve
－ve
－ve
－ve
－ve
5
5 mm
1 mm
a
Inhibition zone was recorded as mm.
From Table 1 the compound 5 has no effect against
－5
Figure 2 DPV curves for 5.0×10 8-MOP solution obtained
two Gram positive bacteria (namely, Bacillus subtilus
and Bacillus cereus) while it has antimicrobial activity
towards two Gram negative bacteria (i.e., Escherichia
coli and Klebsiella pneumoniae). The compound has
moderate effect against Escherichia coli (5 mm) while it
has low effect against Klebsiella pneumonia (1 mm). On
the other hand, 8-MOP has no effect towards the tested
Gram positive and Gram negative bacteria.
in phosphate buffer (pH 7.0, 0.2 mol/L) in absence (a) and pres-
ence of (b) 1.1×10 , (c) 1.4×10 , (d) 1.8×10 mol/L DNA.
－4
－4
－4
Intercalation with DNA
The intercalation of 8-MOP and furocoumarin 5 with
DNA was studied by differential pulse voltammetry
(
DPV), which is a more sensitive electrochemical
method (Figures 1 and 2). According to Eq. 1, the sta-
bility constant (K ) was calculated through the decrease
S
of peak currents with increasing concentration of DNA.
－
Figure 3 DPV curves for 2.0×10 furocoumarin 5 solution
5
The stability constant (K
S
), which is usually used to
obtained in phosphate buffer (pH 7.0, 0.2 mol/L) in absence (a)
characterize the intercalation phenomena of DNA sys-
－
1
－4
－4
and presence of (b) 1.1×10 , (c) 1.8×10 mol/L DNA.
tems, was 204 and 7954 L•mol for 8-MOP and furo-
coumarin 5 respectively as calculated from the
y-intercept. The calculated value of K of the synthe-
S
sized furocoumarin (5) demonstrates an enhancement of
complex formation with DNA by a factor of 39 com-
pared to 8-MOP.
melting point apparatus. NMR spectra were performed
1
on a Varian Mercury-VX-300 (300 and 75 MHz for H
1
3
NMR and C NMR respectively) at Chemistry De-
partment, Faculty of Science, Cairo University using
(
3
TMS) as an internal stander and CDCl as solvents.
The IR spectra were performed on a Jasco 4100 FTIR
spectrophotometer (KBr pellet) at the Department of
Chemistry, Faculty of Science at New Damietta, Man-
Experimental
Melting points were obtained on a Gallenkamp
318
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 316—320

Synthesis and Photooxygenation of Furo[3,2-c]coumarin Derivatives
soura University, Damietta branch. The electron impact
A solution of 3 (1.3 g, 0.008 mol), 3-chloro-2-
butanone (1.0 g, 0.0094 mol) and potassium carbonate
anhydrous (2.5 g) in acetone (30 mL) was refluxed for
24 h. The inorganic salts that separated were filtered off.
The acetone solution was evaporated under reduced
pressure to give a gummy material which was recrystal-
(EI) mass spectra were performed on a Shimadzu
GCMS-QP 1000 EX mass spectrometer at 70 eV at the
Micro Analytical Unit, Cairo University. The Elemental
analyses were performed on a PERKIN-ELMER 2400
C, H Elemental Analyzer at the Micro Analytical Unit,
Cairo University. For the photolysis, a sodium lamp
lized from absolute ethanol to give 4 (1.5 g, yield 80%)
l
(
OSRAM, VIALOX 400 W) was used. For thin layer
as a white crystals, m.p. 150—152 ℃; H NMR (CDCl
3
,
chromatography (TLC), silica gel GF/UV 254 was used.
300 MHz) δ: 1.66 (d, J＝6.6 Hz, 3H, 4'-CH
3
), 2.28 (s,
For column choromatography, silica gel 60 (0.063—
3H, 1'-CH ), 4.84 (q, J＝6.6 Hz, lH, 3'-CH), 5.51 (s, lH,
3
0
.200 mm), Merck, was used. For the removal of sol-
3-H), 7.34 (m, 2H), 7.60 (dd, J＝7.2, 1.2 Hz, 1H), 7.90
(dd, J＝7.2, 1.2 Hz, lH); IR (KBr) ν: 3085.0, 1704.3,
vent a rotary evaporator (at 20 ℃/15 Torr) was used.
－
1
1
623.5 cm .
,3-Dimethyl-4H-furo[3,2-c]chromen-4-one (5)
Antimicrobial activities
2
Nutrient Agar (NA) medium was used for culturing
of the tested bacteria and for studying the effect of the
compounds on the bacterial growth. NA medium con-
taining (g/L), peptone, 5.0; beef extract, 3; NaCl, 8.0
and agar 12.0 and the pH 7.3±0.2, was used for
screening the effect of the compounds on the bacterial
growth. The medium was inoculated with the tested
bacteria (Bacillus subtilus, Bacillus cereus, Escherichia
coli and Klebsiella pneumoniae) and the compounds
A solution of 4 (2.32 g, 0.01 mol) in 0.1 mol/L KOH
(50 mL) was heated at reflux for 2 h. The reaction mix-
ture was cold and acidified with 1 mol/L HCl, and the
precipitate was filtered out by suction and recrystalized
from ethanol to give 1.65 g of 5 (m.p. 170—174 ℃,
l
yield 77%). H NMR (CDCl
) δ: 2.27 (s, 3H, CH
), 2.39
3
3
(s, 3H, CH
Hz, 1H); 7.78 (dd, J＝7.6, 1.2 Hz, 1H); C NMR
(CDCl , 75 MHz) δ: 8.6, 11.5, 111.4, 113.1, 114.0,
), 7.21—7.30 (m, 2H), 7.45 (dd, J＝7.6, 1.2
3
1
3
3
(
about 200 μL) were loaded into holes (1 cm diameter)
117.0, 120.4, 124.3, 129.8, 150.8, 152.2, 155.6, 159.0;
at a concentration of 50 μg/mL. The plates were incu-
bated at 37 ℃ for 24—48 h and the zones of inhibition
were measured.
IR (KBr) ν: 2920.3, 1735.5 (C＝O), 1620.3 (C＝C)
－
1
＋
＋
cm ; MS m/z (%): 214 (M , 22), 199 (M －CH , 26),
3
＋
＋
＋
185 (M －C H , 13), 186 (M －CO, 15), 187 (M －
2 5
＋
＋
CO＋H, 99), 92 (M －C
7
H
6
O
2
7 5 3
, 12), 77 (M －C H O ).
Intercalation with DNA
Anal. calcd for C13
73.11, H 4.81.
10 3
H O : C 72.89, H 4.71; found C
Differential pulse voltammetry (DPV) experiment
was performed for (2.0—5.0)×10 mol/L of furocou-
marin in phosphate buffer (0.2 mol/L, pH 7.0) contain-
ing various concentrations of DNA [(0.0—1.18)×10
－
5
Photooxygenation of 2,3-dimethyl-4H-furo[3,2-
c]chromen-4-one (5) A solution of 5 (2.14 g, 0.01
mol) and tetraphenylporphine (TPP) (5 mg) in CHCl3
(30 mL) was irradiated externally by means of a 500 W
sodium lamp at room temperature for 3 h. During the
－
4
mol/L]. The current titration-equation was described as
[
40]
follows:
irradiation a continuous stream of dry oxygen gas was
allowed to pass through the reaction mixture at a slow
rate to avoid solvent evaporation. The reaction progress
was monitored with TLC. After complete consumption
of the starting material, the solvent was removed at 20
℃/15 torr. The crude products were purified by column
chromatography on silica gel by eluting with a 7∶3
mixture of petroleum ether and ethyl acetate to give the
photoproducts 6 and 8.
(
1－A) －KS
1
/CDNA＝KS
(1)
1－i /io
where CDNA is the concentration of DNA, K
parent stability constant, i
without and with DNA, A is the proportional constant.
The condition of using this equation is that a 1∶1 asso-
ciation complex is formed and DNA is much larger than
the total concentration of furocoumarin in solution. K
was estimated via plotting 1/CDNA vs. 1/(1－i/i ) and the
data were linear fitted with an y-intercept equal to K
-Hydroxy-2H-chromen-2-one (3) A mixture of
S
is the ap-
and i are the peak current
o
S
o
2-Hydroperoxy-2-methyl-3-methylene-2H-furo-
S
.
[3,2-c]chromen-4(3H)-one (6) Obtained as semi oil
1
4
(0.45 g, 18%); H NMR (CDCl ) δ: 2.45 (s, 3H), 5.26 (d,
3
phenol (2.25 g, 0.024 mol), malonic acid (2.5 g, 0.024
mol), anhydrous zinc chloride (9.79 g), and phosphorus
oxychloride (7 mL) was heated with stirring at 60—65
J＝1.2 Hz, 1H), 5.70 (d, J＝1.2 Hz, 1H), 7.30—7.35 (m,
2H), 7.60 (dd, J＝7.6 Hz, 1H), 8.05 (dd, J＝7.6 Hz, 1H),
1
3
8.25 (s, 1H, OOH); C NMR (CDCl ) δ: 23.0 (CH ),
3
3
℃
for 48 h, cooled and decomposed with ice and water
101.4, 115.3, 117.1, 124.6, 125.6, 128.8, 130.9, 132.5,
and allowed to stand. The resulting crude 4-hydroxy-
coumarin (3) was collected, dissolved in 10% sodium
carbonate and acidified. At about the neutral point some
oily byproduct separated out and was removed. Acidifi-
cation of the remaining solution gave 4-hydroxy-
coumarin which recrystallized from water or dilute al-
136.0, 154.8, 160.1, 168.7; IR ν: 3500—3270 (OH),
3020.4 (＝CH), 2980.6 (CH), 1670.8 (C＝O) cm .
－
1
3-Acetyl-2-oxo-2H-chromen-4-yl acetate (8) 1.8
1
g, 73%; H NMR (CDCl ) δ: 2.27 (s, 3H), 2.79 (s, 3H),
3
7.30 (ddd, J＝7.8, 7.2, 1.2 Hz, 1H), 7.35 (ddd, J＝7.8,
7.2, 1.2 Hz, 1H) 7.71 (dd, J＝7.8, 1.2 Hz, 1H), 8.06 (dd,
[
36]
13
cohol giving 1.9 g (m.p. 209—210 ℃, yield 50%).
-(3-Oxobutan-2-yloxy)-2H-chromen-2-one (4)
J＝7.8, 1.2 Hz, 1H); C NMR (CDCl ) δ: 22.7, 24.7,
3
4
101.4, 115.2, 117.0, 124.5, 125.6, 136.1, 154.7, 160.0,
Chin. J. Chem. 2012, 30, 316—320
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
319

Al-Sehemi & El-Gogary
FULL PAPER
1
67.7, 178.7 and 206.1; IR ν: 3015.8 (＝CH), 2950.7
[9] Singer, L. A.; Long, N. P. J. Am. Chem. Soc. 1996, 88, 5213.
10] Zahradnik, M. The Production and Application of Flourescent
Brightening Agents, Wiley & Sons, New York, 1992.
11] Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins:
Occurrence, Chemistry and Biochemistry; Wiley & Sons, New York,
[
[
(
CH), 1700.6 (C＝O), 1705.8 (C＝O), 1610 (C＝C)
－
1
cm .
3
-Acetyl-4-hydroxy-chromen-2-one (9) To a so-
lution of 3 (3 g, 0.018 mol) in acetic acid (16 mL)
phosphorous oxychloride (5.6 mL) was added. The mix-
ture was heated at reflux for 30 min. After cooling, the
precipitate was collected and recrystallized from ethanol,
to give 3-acetyl-4-hydroxy-chromen-2-one (9), as white
needles, in a yield of 3.4 g (90%), m.p. 133—135 ℃
1
982.
[
12] Maria, J. B.; Santos, C.; Susana, N.; Barbara, G.; Mario, N. B. S.
Tetrahedron Lett. 2004, 45, 6927.
[13] Hara, K.; Sayama, K.; Ogha, Y.; Shinpo, A.; Suga, S.; Arakawa, H.
Chem. Commun. 2001, 569.
14] Jiao, C.; Chen, L.; Shen, G.; Yu, R. Sens. Actuators 2003, 94, 176.
[15] Dall’Acqua, F.; Vedaldi, D.; Caffieri, S.; Guiotto, A.; Rodighiero, P.;
[
[
38]
(
lit. 134—136 ℃).
-Phenyl-4H-furo[3,2-c]chromen-4-one (11)
Baccichetti, F.; Carlassare F.; Bordin, F. J. Med. Chem. 1981, 24,
1
3
A
78.
solution of 3 (1.3 g, 0.008 mol), phenacyl bromide (1.57
g, 0.008 mol) and potassium carbonate anhydrous (2.5 g)
in acetone (30 mL) was refluxed overnight. The acetone
solution was evaporated under reduced pressure to give
crude product of 4-(2-oxo-2-phenylethoxy)-H-chromen-
[
16] Guiotto, A.; Rodighiero, P.; Manzini, P.; Pastorini, G.; Bordin, F.;
Baccichetti, F.; Carlassare, F.; Vedaldi, D.; Dall’Acqua, F.; Tamaro,
M.; Recchia, G.; Cristofolini, M. J. Med. Chem. 1984, 27, 959.
[17] Bordin, F.; Carlassare, F.; Baccichetti, F.; Guiotto, A.; Rodighiero,
P.; Vedaldi, D.; Dall’Acqua, F. Photochem., Photobiol. 1979, 29,
1
063.
2
-one (10) (1.5 g, 67%) which was cyclized with PPA to
[
[
18] Dall’Acqua, F.; Vedaldi, D.; Guiotto, A.; Rodighiero, P.; Carlassare,
F.; Baccichetti, F.; Bordin, F. J. Med. Chem. 1981, 24, 806.
19] Guiotto, A.; Rodighiero, P.; Pastorini, G.; Manzini, P.; Bordin, F.;
Baccichetti, F.; Carlassare, F.; Vedaldi D.; Dall’Acqua, F. Eur. J.
Med. Chem.-Chim. Ther. 1981, 16, 489.
afford 11 (1.1 g, yield 80%) as a white crystals,
[
39]
m.p.176—178 ℃ (ethanol) (lit. m.p. 177 ℃).
-Benzoyl-4-hydroxy-2H-chromen-2-one
O-Benzoylation of 3 was obtained as previously de-
3
(14)
[41]
scribed. A solution of 3 (0.01 mol) and benzoyl chlo-
ride (0.02 mol) in aqueous sodium carbonate (40%) was
stirred for 24 h to give 4-benzoyloxycoumarin. A mix-
ture of 4-benzoyloxycoumarin (2.66 g, 0.01 mol) and
aluminum chloride (0.02 mol) was heated for 1 h at 140
[20] Dall’Acqua, F.; Vedaldi, D.; Bordin, F.; Baccichetti, F.; Carlassare,
F.; Tamaro, M.; Rodighiero, P.; Pastorini, G.; Guiotto, A.; Recchia,
G.; Cristofolini, M. J. Med. Chem. 1983, 26, 870.
[
21] Vedaldi, D.; Dall’Acqua, F.; Carlassare, F.; Baccichetti, F.; Bordin,
F.; Rodighiero, P.; Manzini, P.; Guiotto, A. Farmaco 1991, 46,
1
381.
℃
. After cooling to 50 ℃ the melt was treated with
[
22] Bethea, D.; Fullmer, B.; Syed, S.; Seltzer, G.; Tiano, J.; Rischko, C.;
diluted hydrochloric acid to obtain a precipitate, which
was separated by suction, washed with water and crys-
tallized from ethanol to give 2.2 g of 14. Yield 82%,
Gillespie, L.; Brown, D.; Gasparro, F. P. J. Dermatol. Sci. 1999, 19,
78.
[23] Dall'Acqua, F.; Terbojevich, M.; Marciani, S.; Vedaldi, D.; Recher,
[
41]
M. Chem. Biol. Inter. 1987, 21, 103.
m.p. 150 ℃ (lit. 148—151 ℃).
[
[
[
24] Kanne, D.; Straub, K.; Hearst, E. J.; Rapoport, H. J. Am Chem. Soc.
982, 104, 6754.
Photooxygenation of 3-phenyl-4H-furo[3,2-c]-
chromen-4-one (11) A solution of 11 (2.62 g, 0.01
mol) was photooxygenated as in case of 5 for 3 h. The
crude product was purified by column chromatography
on silica gel by eluting with 7∶3 mixture of petroleum
ether and ethyl acetate to give 3-benzoyl-4-hydroxy-
1
25] Saffran, W. A. In Psoralen DNA Photobiology, Ed.: Gasparro, F. P.,
CRC Press, Inc., Boca Raton, FL, 1988, Vol. II, Chapter 6, p. 73.
26] Dall'Acqua, F.; Vedaldi, D.; Caffieri, S.; Guitto, A.; Bordin, F.;
Rodighiero, P. Natl. Cancer Inst. Monogr. 1984, 66, 55.
[27] Carlassare, F.; Baccichetti, F.; Guiotto, A.; Rodighiero, P.; Gia, O.;
Capozzi, A.; Pastorine, G.; Bordin, F. J. Photochem. Photobiol., B:
Biol. 1990, 5, 25.
28] Blais, J.; Averbeck, D.; Moron, J.; Bisagni, E.; Vigny, P. Photochem.
Photobiol. 1987, 45, 465.
29] Adam, W.; Qian, X.; Saha-Mtiller, C. R. J. Org. Chem. 1993, 58,
2
℃
H-chromen-2-one (14), (1.9 g, yield 71%), m.p. 150
[
41]
(lit. 148—151 ℃).
[
Acknowledgement
[
3
769.
Special thanks go to Dr. Mohamed Abou Dobara,
assistant professor in Department of Botany, Faculty of
Science (Damietta), Mansoura University, Egypt, for his
help and practical assistance in the antimicrobial study.
[
[
[
[
[
[
30] Kahn, A. U. J. Phys. Chem. 1976, 80, 2219.
31] Shlaypintokh, V. Y.; Ivanov, V. B. Russ. Chem. Rev. 1976, 45, 99.
32] Matsumoto, M.; Kondo, K. J. Syn. Org. Chem. Jpn. 1977, 35, 188.
33] Bartlett, P. D.; Ho, M. S. J. Am. Chem. Soc. 1974, 96, 627.
34] Takeshita, H.; Hatsui, T.; Jinnai, O. Chem. Lett. 1976, 1059.
35] Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76,
References
2
7.
[
[
1] Murray, R. D. H. Prog. Chem. Org. Nat. Prod. 1991, 58, 84.
2] O`Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications
and Mode of Action, Wiley & Sons, Chichester, 1997.
3] von Pechmann, H.; Duisberg, C. Chem. Ber. 1884, 17, 929.
4] Johnson, J. R. Org. React. 1942, 1, 210.
[36] Shah, V.; Bose, J.; Shah, R. J. Org. Chem. 1960, 25, 677.
[37] Schenck, G. O. Naturwissenschaften 1948, 35, 28.
[38] Sukdolak, S.; Solujić, S.; Manojlović, N.; Vuković, N. J. Heterocyc-
lic Chem. 2004, 41, 593.
[39] Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron Lett. 2001,
42, 3503.
[
[
[
[
5] Jones, G. Org. React. 1967, 15, 204.
6] Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles
[40] Zhao, G. C.; Zhu, J. J.; Zhang, J. J.; Chen, H. Y. Anal. Chim. Acta
1999, 394, 337.
1
996, 43, 1257.
[
[
7] Shriner, R. L. Org. React. 1942, 1, 1.
8] Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. Tetrahedron Lett. 1998,
[41] Kappe, T.; Schnell, B. J. Heterocyclic Chem. 1996, 33, 663.
(E1105274 Sun, H.; Lu, Y.)
3
9, 2391.
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