Synthesis and photooxygenation of linear and angular furocoumarin derivatives as a hydroxyl radical source: Psoralen, pseudopsoralen, isopseudopsoralen, and allopsoralen

Article abstract of DOI:10.1002/jhet.2084

Synthesis of linear and angular furocoumarins with new skeleton structure of potential photobiological feature interest was carried out through Williamson reaction of hydroxycoumarins with 3-chloro-2-butanone followed by cyclization with polyphosphoric acid or by heating in a strongly alkaline solution. The photooxygenation reactions of synthesized furocoumarins were performed in chloroform and in the presence of tetraphenylporphyrin as singlet oxygen sensitizer (¹O₂). The photooxygenation reactions afforded the photocleaved product through [2 + 2] cycloaddition and the photooxygenated products through ene reaction and [4 + 2] cycloaddition. The photoproducts were isolated and fully characterized by spectral analyses.

Full text of DOI:10.1002/jhet.2084

Month 2014
Synthesis and Photooxygenation of Linear and Angular Furocoumarin
Derivatives as a Hydroxyl Radical Source: Psoralen, Pseudopsoralen,
Isopseudopsoralen, and Allopsoralen
a
a
Sameh Ramadan Elgogary,a,b Neveen Mohamed Hashem, and Mohamed Nabeel Khodeir
*
aChemistry Department, Faculty of Science, Damietta University, Egypt
bChemistry Department, Faculty of Science (Jazan), Jazan University, Kingdom of Saudi Arabia
*
E-mail: selgogary@gmail.com
Received March 24, 2013
DOI 10.1002/jhet.2084
Published online in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of linear and angular furocoumarins with new skeleton structure of potential photobiological
feature interest was carried out through Williamson reaction of hydroxycoumarins with 3-chloro-2-
butanone followed by cyclization with polyphosphoric acid or by heating in a strongly alkaline solution.
The photooxygenation reactions of synthesized furocoumarins were performed in chloroform and in the
presence of tetraphenylporphyrin as singlet oxygen sensitizer (1O2). The photooxygenation reactions
afforded the photocleaved product through [2 + 2] cycloaddition and the photooxygenated products
through ene reaction and [4 + 2] cycloaddition. The photoproducts were isolated and fully characterized by
spectral analyses.
J. Heterocyclic Chem., 00, 00 (2014).
have been attempted to obtain furocoumarins able to behave
as essentially monofunctional agents [6]. To date, this has
been accomplished in three different ways: (a) using angular
furocoumarins such as angelicins 2, which on account of
their geometry cannot cross-link with DNA [7], (b) blocking
of the photoreactive α-pyrone double bond by appropriate
substituents [8] or by annelation of an additional aromatic
ring [9], and (c) incorporating an additional benzene ring
between active double bonds of the α-pyrone and furan
moiety [10].
The differences of photobiological and mutagenic activities
between psoralens and angelicins [7,11] indicate that the
geometries of active double bonds of α-pyrone and furan
moieties play a crucial role in their properties.
In the last decade, intensive investigations have been
carried out on the chemical, biochemical, and biological
aspects of DNA oxidations caused by reactive oxygen
INTRODUCTION
Furocoumarins such as psoralens 1 are photoactive drugs,
which are commonly used in the PUVA therapy (psoralen
plus UVA radiation) for the treatment of human skin
diseases [1]. The potency and effectiveness of these
photochemotherapeutic agents depend on their photobinding
ability with DNA. Although PUVA therapy proves to be
very effective, some undesirable side effects are present such
as a persistant erythema [2], genotoxicity [3], phototoxicity,
and a possible risk of skin cancer [4]. These side effects are
mostly attributed to psoralen interstrand cross-links with
DNA rather than to monofunctional adducts [5], a conse-
quence of their bifunctional nature (photoactive α-pyrone
and furan sites).
To enhance the photobinding properties and reduce side
effects, a wide range of structural modifications of psoralens
© 2014 HeteroCorporation

S. R. Elgogary, N. M. Hashem, and M. N. Khodeir
Vol 000
Scheme 1. Synthesis of linear and angular furocoumarin derivatives.
species such as hydroxyl and alkoxyl radicals [12,13], singlet
oxygen [14], and superoxide ion [13], which are involved in
oxidative stress [15]. Among the reactive oxygen species,
hydroxyl radicals are implicated as the key oxidizing
reagents of DNA and other biological molecules [12,15,16].
The conventional chemical sources of hydroxyl radicals,
for example H2O2/Fe2+ (Fenton reaction) [17] or radiolysis
of aqueous solutions [18], are not properly suited for bio-
chemical or biological investigations because they generate,
besides hydroxyl radicals, other reactive oxygen species [18].
It has been reported that the furocoumarin hydroperoxides
[19,20], which are readily available by photooxygenation of
imperatorin or the alloimperatorin derivative, cause DNA
damage through generation of hydroxyl radicals under pho-
tolytic conditions, and they intercalated into the DNA [21].
In this context, our strategy has been focused on synthe-
sizing linear and angular furocoumarins and incorporating
the photolabile hydroperoxide group into their skeleton
through photooxygenation to provide an effective hydroxyl
radical source.
RESULTS AND DISCUSSION
Construction of furan ring on the benzene ring of cou-
marin gives six possible structures of furocoumarins. The
two possible linear geometry are 7H-furo[3,2-g]chromen-
7-one (psoralen, 1) and 6H-furo[2,3-g]chromen-6-one
(pseudopsoralen, 3), while the four angular structures
are 2H-furo[2,3-h]chromen-2-one (angelicin, 2), 7H-furo
[3,2-f]chromen-7-one (isopseudopsoralen, 4), 7H-furo
[2,3-f]chromen-7-one (allopsoralen, 5), and 8H-furo[3,2-
h]chromen-8-one (pseudoisopsoralen, 6) (Fig. 1). We
prepared, successfully, new linear and angular furocoumarins
with new skeleton structure and potentially interesting pho-
tobiological features.
Synthesis of linear and angular furocoumarin derivatives.
The synthetic methodology for the preparation of the
furocoumarins is displayed in Scheme 1. The first step was
Pechmann condensation of resorcinol [22], quinol [23],
and orcinol [15] with ethyl acetoacetate in sulfuric acid,
affording the corresponding hydroxycoumarins 7, 8,
and 9 in 95, 35, and 78% yields, respectively. Next, the
Williamson reaction of 7, 8, and 9 with 3-chloro-2-
butanone in refluxing acetone and in the presence of
K2CO3 for 24 h gave the keto ethers 10, 11, and 12 in
51, 65, and 83% yields, respectively (Scheme 1).
The structure of keto ether 10, for example, was confirmed
by the disappearance of the hydroxyl group absorption band
and appearance of the new absorption band related to
carbonyl group at 1712.48cmÀ1. The 1H NMR of this com-
pound revealed that new signals corresponding to aliphatic
protons resonates at δ 4.69 (q, J = 6.9 Hz), 2.19 (s), and
1.54 (d, J = 6.9 Hz) for 1′-H, 3′-H, and 4′-H respectively.
Further confirmation of 10 was the detection of the molecular
ion (M+) at m/z 246 (M+, 54%) in the mass spectrum.
Finally, compounds 10, 11, and 12 were cyclized by
treatment with polyphosphoric acid (PPA) at 70°C for 5 h
or by heating in a strongly alkaline solution (3% KOH)
for 2 h.
Cyclization of 10 gave the linear furocoumarin 13 exclu-
sively in 80% yield (psoralen type). The structure of 13
was established for the reaction product based on the spectral
1
[IR, H NMR, 13C NMR, and mass spectroscopy (MS)]
and elemental analyses, while the structure of angular
furocoumarin 13a was excluded.
1H NMR spectrum of 13 showed two singlet signals for
two aromatic protons (C-5 and C-8) at δ 7.49 and 7.28 ppm.
The multiplicity of the aromatic protons (singlet signals),
Figure 1. Structure of linear and angular furocoumarins (psoralens).
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and the absence of ortho coupling, confirmed the exclusive
cyclization to the linear furocoumarin skeleton.
Schenck-ene reaction [24] through the ene mechanism from
peroxirane transition state (A) that led to the formation of an
allylic hydroperoxide. On the other hand, the formation of
the dioxetane (B) was carried out by the [2 + 2] cycloaddition
of singlet oxygen with the double bond of the furan moiety.
The dioxetane (B) was photolized rapidly under the
photooxygenation conditions to give 18 via broken O–O
and C–C bond (Scheme 2).
Compound 11 was cyclized with PPA to yield 1,2,9-
trimethyl-7H-furo[3,2-f]chromen-7-one (14) (isopseudopsoralen
type) and 2,3,8-trimethyl-6H-furo[2,3-g]chromen-6-one (16)
(pseudopsoralen type) in 43 and 10% yields, respectively
(Scheme 1). The structures of 14 and 16 were supported
1
by spectral analyses. H NMR spectrum of 14 showed
separated two signals for two aromatic protons (H-7 and H-8)
as doublet with coupling constant 9 Hz at δ 7.52 and
7.19 ppm (presence of ortho coupling). On the other hand,
1H NMR spectrum of 16 showed two singlet signals for
two aromatic protons (H-5 and H-8) at δ 7.54 and
7.31 ppm (absence of ortho coupling).
The stable allylic hydroperoxide 17 was isolated and fully
characterized by spectral analyses (cf. Experimental section).
The most conspicuous features in H NMR spectrum of
stable allylic hydroperoxide were two distinct doublets that
correspond to two olefinic protons at δ 6.33 and 6.19 ppm
with a coupling constant of 1.2 Hz and a singlet peak at
δ 12.62ppm for OOH, which was exchangeable with D2O.
The IR spectrum of 17 showed that hydroperoxy stretching
broad band was at 3500–3250 cmÀl.
1
The cyclization of 12 gave the angular furocoumarin 15
(allopsoralen type) in 54% yield. The structure of 15 was
1
confirmed by spectral (IR, H NMR, 13C NMR, and MS)
1
and elemental analyses. H NMR spectrum of 15 showed
The structure of 18 was confirmed by the presence of new
two bands at 1754.9 and 1685.48 cmÀ1 for two carbonyl
moieties in IR and the three singlet signals of three methyl
singlet signal for one aromatic proton at δ 6.89 ppm (C-8)
and four singlet signals at δ 2.68, 2.64, 2.39, and 2.31ppm
assigned to four methyl groups (each signal integrating for
three protons), with resonance at δ 22.0, 19.6, 11.7, and
10.5 ppm in 13C NMR.
1
groups at δ 2.61, 2.49, and 2.40 ppm in H NMR. Further
confirmation of compound 18 was obtained through acid
hydrolysis of compound 18 to afford 6-acetyl-7-hydroxy-
4-methyl-2H-chromen-2-one (20), which was obtained
through Fries rearrangement of 19 (Scheme 3).
Photooxygenation reactions of furocoumarin derivatives
13–15. Our strategy to obtain an effective hydroxyl radical
source has been oriented to incorporate the photolabile
hydroperoxide group into an intercalating chromophore such
as furocoumarins (13–15) through the photooxygenation
reactions.
The photooxygenation of the linear furocoumarin derivative
13 in chloroform and in the presence of tetraphenylporphyrin
(TPP) as singlet oxygen sensitizer at room temperature gave
the stable allylic hydroperoxide 17 and 6-acetyl-4-methyl-
2-oxo-2H-chromen-7-yl acetate (18) in 10 and 60% yields,
respectively (Scheme 2).
Similarly, under the photooxygenation conditions
(chloroform/TPP/1O2), the photooxygenation reaction of
14 gave the photooxygenated product 22 (allylic hydroper-
oxide) and the photocleaved product 5-acetyl-4-methyl-2-
oxo-2H-chromen-6-yl acetate (23) in 6 and 55% yields,
respectively (Scheme 4).
The IR spectrum of 22 showed the hydroperoxy (OOH)
stretching broad band at 3600–3200 cmÀl. The most
1
important signals in the H NMR spectrum of 22 were
two distinct doublets that attributed to two olefinic protons
at δ 6.33 and 5.16 ppm with coupling constant J = 0.9 Hz
and a singlet peak at δ 7.30 ppm for OOH, which was
exchangeable with D2O.
The mechanism of the formation of the allylic hydroperox-
ide 17 was achieved by the reaction of singlet oxygen (1O2)
with an olefin bearing allylic hydrogens in the so-called
The photocleaved product 23 was isolated and fully
1
characterized by IR, H NMR, and MS (cf. Experimental
section). The appearance of two new stretching bands at
Scheme 2. Photooxygenation mechanisms of 13.
Scheme 3. Fries rearrangement of 19.
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S. R. Elgogary, N. M. Hashem, and M. N. Khodeir
Vol 000
Scheme 4. Photooxygenation of 14.
Acid hydrolysis of the photocleaved product 24 gave the
corresponding hydroxyacetyl derivative 28. Compound 28
was further confirmed through Fries rearrangement of 27,
which was obtained by acetylation of 9 (Scheme 6).
CONCLUSION
Linear and angular furocoumarin derivatives were synthe-
sized through Williamson reaction of hydroxycoumarins
with 3-chloro-2-butanone followed by cyclization with
PPA or by heating in a strongly alkaline solution. The
photooxygenation reactions of synthesized furocoumarins
were performed in the presence of TPP as singlet oxygen
sensitizer (1O2). The photooxygenation reactions afforded
the photocleaved product through [2 + 2] cycloaddition and
the photooxygenated products through ene reaction and
[4 + 2] cycloaddition.
1770.33 and 1708.62 cmÀ1 that were assigned to two new
carbonyl groups in IR and the presence of three singlet
signal of three methyl moieties at δ 2.62, 2.31, and 2.30 ppm
in 1H NMR confirmed the structure of 23.
In the same way, the photooxygenation reaction of 15
afforded the photocleaved product 6-acetyl-4,7-dimethyl-2-
oxo-2H-chromen-5-yl acetate (24) ([2 + 2] cycloaddition)
and the photooxygenated products 2-hydroperoxy-2,4,9-
trimethyl-3-methylene-2H-furo[2,3-f]chromen-7(3H)-one (25)
[ene reaction] and endoperoxide of 2,3,4,9-tetramethyl-7H-
furo[2,3-f]chromen-7-one (26) ([4 + 2] cycloaddition) in
44, 7, and 37% yields, respectively (Scheme 5).
All photoproducts were isolated and fully characterized by
IR, 1H NMR, and MS (cf. Experimental section). The mass
spectra of compounds 24–26 showed a molecular ion M+
m/z, 274 indicating that the singlet oxygen is inserting in
the molecule without losing any fragments. The hydroperox-
ide 25 gave a broad band at 3600–3250 cmÀ1 in IR spectrum
assigned to OOH that resonates at δ 13.07 ppm, exchange-
able with D2O, in 1H NMR spectrum.
EXPERIMENTAL
Melting points were obtained on a Gallenkamp melting point
apparatus (open capillary tubes) and were uncorrected. Silica
gel (ADWIC 60 GF254) was used for thin layer chromatography
(TLC). Silica gel (ADWIC 60–120 mesh, size 0.13–0.25 nm)
was used for column chromatography. 1H NMR spectra were
performed on a Varian Mercury-VX-300 (300 MHz) at the Micro
Analytical Unit, Cairo University and a BRUKER (600 MHz)
ultra shield Avance III spectrometer at the Faculty of Science,
King Abd-Elaziz University, Jeddah, KSA, using TMS as an
internal stander and DMSO or CDCl3 as solvents. Chemical shifts
were expressed as δ ppm. IR spectra were performed on a Jasco
4100 FTIR spectrophotometer (KBr pellet) at the Department of
Chemistry, Faculty of Science at New Damietta, Mansoura
University, Damietta branch. The electron impact 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, within 0.4 deviation from the calculated value.
1H NMR spectrum of the endoperoxide 26 showed a singlet
signal at δ 3.32 ppm for one proton assigned to H-8.
On the other hand, compound 24 showed a broad band
for two new carbonyl groups at 1758.76 cmÀ1 in the IR
spectrum. Moreover, 1H NMR spectrum of 24 showed four
singlet signals of four methyl moieties protons at δ 2.48,
2.45, 2.38, and 2.31 ppm.
Synthesis of 7-hydroxy-4-methyl-2H-chromen-2-one (7).
A
mixture of resorcinol (11 g, 100 mmol) and ethyl acetoacetate
(12.8 g, 100 mmol) was stirring in ice bath, and 70% sulfuric acid
(100 mL) was added dropwise and refluxed for 1 h. The reaction
mixture was poured onto ice/water, and the separated solid was
Scheme 5. Photooxygenation of 15.
Scheme 6. Fries rearrangement of 27.
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filtered off. The product was purified by recrystallization from
aqueous methanol 80% to give white crystals of 7 (16.73 g, 95%),
MP 184–186°C (lit [22], 184–186°C, 89%).
1.6 (d, 3H, J = 7.2 Hz). 13C NMR (125MHz, CDCl3) ppm: 208.8,
160.7, 155.5, 153.5, 143.2, 114.0, 111.2, 108.3, 107.9, 107.7,
79.7, 24.7, 24.6, 22.0, and 17.6. MS (m/z, %): 260 (M+, 61), 218
(M+-C2H2O, 18), 217 [M+-(CH3 + CO), 100], 190 (M+-C3H2O2, 11),
175 (M+-C4H5O2, 6), 174 (M+-C5H10O, 8), 161 (M+-C5H7O2,
40.74), 146 (M+-C6H10O2, 15.29), 133 (M+-C7H11O2, 13.57),
132 (M+-C7H12O2, 6), and 131 (M+-C7H13O2, 10). Anal. calcd
for C15H16O4 (260.29): C, 69.22; H, 6.20. Found: C, 69.32; H,
5.80.
Synthesis of 2,3,5-trimethyl-7H-furo[3,2-g]chromen-7-one (13).
A solution of 10 (1 g, 4.06 mmol) in 10-mL absolute ethanol was
added to 30 mL of alcoholic 3% potassium hydroxide (KOH), and
the mixture was refluxed for 2 h. The reaction mixture was poured
onto ice/diluted hydrochloric acid (HCl). The separated solid was
filtered off and crystallized from methanol, giving pale yellow
crystals of 13 (0.74 g, 80%), MP 200–204°C. IR (KBr, cmÀ1):
3068.26 (CH arom.), 2921.32 (CH aliph.), 1702.53 (CO), and
1627.74 (C=C). 1H NMR (600 MHz, CDCl3): δ 7.49 (s, 1H), 7.28
(s, 1H), 6.21 (s, 1H), 2.49 (s, 3H), 2.39 (s, 3H), and 2.18 (s, 3H).
13C NMR (125 MHz, CDCl3) ppm: 161.4, 155.3, 153.0, 152.7,
151.0, 127.9, 114.9, 113.2, 112.5, 109.6, 98.9, 19.2, 11.9, and
7.9. MS (m/z, %): 228 (M+, 72), 171 (M+-C3H5O, 72), 147 (M+-
C5H5O, 86), and 146 (M+-C5H6O, 100). Anal. calcd for C14H12O3
(228.24): C, 73.67; H, 5.30. Found: C, 73.90; H, 4.90.
Synthesis of 1,2,9-trimethyl-7H-furo[3,2-f]chromen-7-one (14)
and 2,3,8-trimethyl-6H-furo[2,3-g]chromen-6-one (16). Compound
11 (1 g, 4.06 mmol) was added to PPA (5 g), and the mixture was
heated for 2 h at 80°C. The reaction mixture was cold and poured
onto ice/water. The separated solid was filtered off with suction and
recrystallized from methanol to afford 14. The filtrate was evaporated
and purified through column chromatography by eluting with 70% of
a mixture of petroleum ether 40–60 and ethyl acetate to give 16.
Compound 14 (0.4 g, 43%), pale yellow crystals, MP 204–208°C. IR
(KBr, cmÀ1): 3066.26 (CH arom.), 2977.55 (CH aliph.), 1708.62
(CO), and 1592.91 (C=C). 1H NMR (600 MHz, CDCl3): δ 7.52
(d, 1H, J= 9 Hz), 7.19 (d, 1H, J= 9 Hz), 6.28 (s, 1H), 2.70 (s, 3H),
2.46 (s, 3H), and 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3) ppm:
160.9, 154.6, 152.8, 151.6, 151.1, 125.4, 115.0, 114.7, 114.1, 113.0,
109.8, 25.5, 15.1, and 12.7. MS (m/z, %): 228 (M+, 61), 200 (M+-CO
or M+-C2H4, 43), 199 (M+-C2H5, 33), 186 (M+-C3H6, 22), 185 [M+-
(CH3 +CO) or M+-C3H7, 100], 184 (M+-C3H8, 19), and 171 (M+-
C3H5O, 20). Anal. calcd for C14H12O3 (228.08): C, 73.67; H, 5.30.
Found: C, 73.35; H, 4.89. Compound 16 (0.094 g, 10%), white
powder, MP 140–144°C. IR (KBr, cmÀ1): 3081.69 (CH arom.),
2962.13 (CH aliph.), and 1639.2 (CO). 1H NMR (300 MHz, CDCl3):
δ 7.54 (s, 1H), 7.31 (s, 1H), 6.26 (s, 1H), 2.48 (s, 3H), 2.36 (s, 3H),
and 2.17 (s, 3H). Anal. calcd for C14H12O3 (228.08): C, 73.67; H,
5.30. Found: C, 73.41; H, 5.44
Synthesis of 6-hydroxy-4-methyl-2H-chromen-2-one (8).
A
mixture of quinol (15 g, 136.36 mmol) and ethylacetoacetate
(17.73g, 136.36 mmol) was stirring in ice bath, and 80%
sulfuric acid (150 mL) was added dropwise within half an hour.
The reaction mixture was stirred overnight at room temperature.
The reaction mixture was poured onto ice/water, and the
separated solid was filtered off. The crude product was purified
by recrystallization from ethanol to give white crystals of
8 (8.4g, 35%), MP 239–241°C (lit [23], 243–245°C, 40%).
Synthesis of 5-hydroxy-4,7-dimethyl-2H-chromen-2-one (9).
Compound 9 was prepared from orcinol (10g, 80.6 mmol) and
ethyl acetoacetate (10.5 g, 80.77 mmol) according to the method
given for 8 to afford a crude product that was purified by
crystallization from methanol to give white crystals of 9 (11.95g,
78%), MP 246–250°C (lit [15], 245–247°C, 71%).
Synthesis of 4-methyl-7-(3-oxobutan-2-yloxy)-2H-chromen-
2-one (10). To a solution of 7 (4 g, 22.73 mmol) in dry acetone
(70 mL), anhydrous potassium carbonate (10g) and 3-chloro-2-
butanone (2.44 g, 22.9mmol) were added. The mixture was
refluxed at 80°C for 24 h. The reaction was monitored by TLC for
the disappearance of reactants. The inorganic salt was filtered off,
and the solvent was concentrated under reduced pressure and
poured onto ice/water. The separated solid was filtered off and
washed with excess of water. The crude product was purified by
recrystallization from ethanol to afford white crystals of 10
(2.85g, 51%), MP 95–97°C. IR (KBr, cmÀ1): 3066.26 (CH arom.),
1
2931.27 (CH aliph.), 1712.48 (br, 2CO), and 1608.34 (C=C). H
NMR (300 MHz, CDCl3): δ 7.49 (d, 1H, J= 9 Hz), 6.81 (d, 1H,
J= 9 Hz), 6.73 (s, 1H), 6.14 (s, 1H), 4.69 (q, 1H, J=6.9Hz), 2.39
(s, 3H), 2.19 (s, 3H), and 1.54 (d, 3H, J=6.9Hz). MS (m/z, %):
246 (M+, 54), 204 (M+-C2H2O, 12), 203 [M+-(CH3+CO), 90], 189
(M+-C3H5O, 6), 176 (M+-C3H2O2, 5), 175 (M+-C4H7O, 19), 161
(M+-C4H5O2, 2), 160 (M+-C5H10O, 7), 147 (M+-C5H7O2, 54),
and 132 (M+-C6H10O2, 4). Anal. calcd for C14H14O4 (246.26):
C, 68.82; H, 5.73. Found: C, 69.20; H, 5.40.
Synthesis of 4-methyl-6-(3-oxobutan-2-yloxy)-2H-chromen-2-
one (11). Compound 11 was prepared from 8 (4 g, 22.73 mmol)
and 3-chloro-2-butanone (2.44 g, 22.9 mmol) according to the
method given for 10. The crude product was recrystallized from
ethanol to give white crystals of 11 (3.63 g, 65%), MP 76°C. IR
(KBr, cmÀ1): 3089.4 (CH arom.), 2923.56 (CH aliph.), 1735.62
(CO), 1712.48 (CO), and 1616.06 (C=C). 1H NMR (300 MHz,
CDCl3): δ 7.26 (d, 1H, J= 9 Hz), 7.04 (d, 1H, J= 9 Hz), 6.99
(s, 1H), 6.30 (s, 1H), 4.64 (q, 1H, J= 6.9 Hz), 2.39 (s, 3H), 2.19
(s, 3H), and 1.53 (d, 3H, J=6.9Hz). MS (m/z, %): 246 (M+, 40),
204 (M+-C2H2O, 14), 203 [M+-(CH3 + CO), 100], 189 (M+-
C3H5O, 4), 176 (M+-C3H2O2, 8), 175 (M+-C4H7O, 30), 161 (M+-
C4H5O2, 3), 160 (M+-C5H10O, 7), 147 (M+-C5H7O2, 47), and 132
(M+-C6H10O2, 6). Anal. calcd for C14H14O4 (246.26): C, 68.28;
H, 5.73. Found: C, 67.77; H, 5.70.
Synthesis of 2,3,4,9-tetramethyl-7H-furo[2,3-f]chromen-7-
one (15).
Compound 15 was synthesized from 12 (3.3 g,
13.52 mmol) according to the method given for 14. The crude
product was purified by crystallization from ethanol to give buff
crystals of 15 (1.77 g, 54%), MP 208–210°C. IR (KBr, cmÀ1):
3066.26 (CH arom.), 2927.41 (CH aliph.), 1712.48 (CO), and
1616.06 (C=C). 1H NMR (600 MHz, CDCl3): δ 6.89 (s, 1H),
6.15 (s, 1H), 2.68 (s, 3H), 2.64 (s, 3H), 2.39 (s, 3H), and 2.31
(s, 3H). 13C NMR (125 MHz, CDCl3) ppm: 161.4, 152.1, 150.9,
150.8, 149.3, 135.2, 125.0, 113.2, 112.9, 110.4, 104.8, 22.0,
19.6, 11.7, and 10.5. MS (m/z, %): 242 (M+, 100), 214 (M+-CO or
M+-C2H4, 91), 213 (M+-HCO or M+-C2H5, 91), 186 (M+-C3H4O,
11), and 185 (M+-C3H5O, 11). Anal. calcd for C15H14O3 (242.27):
C, 74.36; H, 5.82. Found: C, 73.82; H, 5.99.
Synthesis of 4,7-dimethyl-5-(3-oxobutan-2-yloxy)-2H-chromen-
2-one (12).
Compound 12 was synthesized from 9 (3 g,
15.79 mmol) and 3-chloro-2-butanone (1.67 g, 15.67 mmol)
according to the method given for 10. The crude product was
crystallized from ethanol to give white crystals of 12 (3.2g, 83%),
MP 152–154°C. IR (KBr, cmÀ1): 3062.41 (CH arom.), 2931.27
(CH aliph.), 1720.19 (br, 2CO), and 1616.06 (C=C). 1H NMR
(600MHz, CDCl3): δ 6.78 (s, 1H), 6.26 (s, 1H), 6.10 (s, 1H), 4.74
(q, 1H, J = 7.2Hz), 2.65 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H), and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. R. Elgogary, N. M. Hashem, and M. N. Khodeir
Vol 000
General procedure of the photooxygenation of furocoumarins.
A solution of the furocoumarin (1 g) and (2 mg) of TPP in
chloroform (30mL) was irradiated externally by means of a
sodium lamp at room temperature. During the 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 irradiated solution was monitored by TLC for the
disappearance of reactants, and the solvent was evaporated at 20°
C/15torr. The photoproducts were isolated and purified by
column chromatography on silica gel by eluting with a 70%
mixture of petroleum ether 40–60 and ethyl acetate.
Photooxygenation of 13. According to the general procedure
of the photooxygenation, the irradiation of 13 (1g, 4.39mmol)
yielded 2-hydroperoxy-2,5-dimethyl-3-methylene-2H-furo[3,2-g]
chromen-7(3H)-one (17) and 6-acetyl-4-methyl-2-oxo-2H-chromen-7-yl
acetate (18). Compound 17, white powder (0.114 g, 10%), MP
144–148°C. IR (KBr, cmÀ1): 3500–3250 (br, OOH), 3085.55
(CH arom.), 2931.27 (CH aliph.), 1685.48 (CO), and 1621.58
(C=C). 1H NMR (300 MHz, CDCl3): δ 12.62 (s, 1H, exchangeable
with D2O, OOH), 8.08 (s, 1H), 7.97 (s, 1H), 6.87 (s, 1H), 6.33
(d, 1H, J = 1.2 Hz), 6.19 (d, 1H, J = 1.2 Hz), 2.61 (s, 3H), and
1.56 (s, 3H). Compound 18, white powder (0.684 g, 60%), M.P.
160–162°C. IR (KBr, cmÀ1): 3043.12 (CH arom.), 2927.41
(CH aliph.), 1754.9 (CO), 1685.48 (CO), 1631.48 (CO), and
1623.77 (C=C). 1H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H),
7.12 (s, 1H), 6.33 (s, 1H), 2.61 (s, 3H), 2.49 (s, 3H), and 2.40
(s, 3H). Anal. calcd for C14H12O5 (260.24): C, 64.61; H, 4.65.
Found: C, 65.10; H, 4.96.
204.5, 166.7, 159.5, 155.2, 153.1, 131.3, 115.2, 111.9, 111.3,
109.3, 33.9, and 19.4. MS (m/z, %): 218 (M+, 100), 204 (M+-
CH2, 65), 203 (M+-CH3, 100), 190 (M+-CO, 97), 189 (M+-
C2H5, 11), 176 [M+-(CH2 + CO), 22], 175 [M+-(CH3 + CO),
100], 161 (M+-C3H5O, 7), and 147 (M+-C3H3O2, 20).
Compound 7, white powder (0.017 g, 2%), MP 184–186°C.
Acid hydrolysis of 6-acetyl-4-methyl-2-oxo-2H-chromen-7-yl
acetate (18).
A solution of 18 (0.8g, 3.08 mmol) in 20-mL
HCl was refluxed for half an hour and then cool in air to obtain a
precipitate that was separated with suction, washed with water,
dried, and recrystalized from ethanol to give white crystals of
6-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one (20) (0.6 g, 90%),
MP 203–204°C.
Photooxygenation of 14. According to the general procedure
of the photooxygenation, the irradiation of 14 (1 g, 4.39 mmol)
for 5 h yielded 2-hydroperoxy-2,9-dimethyl-1-methylene-1H-furo
[3,2-f]chromen-7(2H)-one (22) and 5-acetyl-4-methyl-2-oxo-2H-
chromen-6-yl acetate (23). Compound 22, white powder (0.07 g,
6%), MP 76–80°C. IR (KBr cmÀ1): 3600–3200 (br, OOH), 3087
(CH arom.), 2928 (CH aliph.), 1700.48 (CO), and 1620 (C=C).
1H NMR (300MHz, CDCl3): δ 7.32 (d, 1H, J = 9.6 Hz), 7.30 (s,
1H, exchangeable with D2O, OOH), 7.11 (d, 1H, J = 9.6 Hz), 6.33
(d, 1H, J = 0.9 Hz), 6.32 (s, 1H), 5.16 (d, 1H, J = 0.9 Hz), 2.62 (s,
3H), and 1.27 (s, 3H). MS (m/z, %): 227 (M+-OOH, 19), 199
[M+-(OOH + CO) or M+-(OOH + C2H4), 8], and 185 [M+-
(OOH + CO+ CH2), 25]. Compound 23, pale yellow powder
(0.63 g, 55%), MP 126°C. IR (KBr, cmÀ1): 3081.69 (CH arom.),
2927.41 (CH aliph.), 1770.33 (CO), 1708.62 (CO), 1648 (CO),
1
Synthesis of 4-methyl-2-oxo-2H-chromen-7-yl acetate (19). A
solution of 7 (1.7 g, 9.66 mmol) in 20-mL acetic anhydride was
refluxed for 1 h. The reaction mixture was poured onto water,
and the separated solid was filtered off. The solid was purified
by recrystallization from ethanol to give white crystals of 19
(2 g, 95%), MP 152°C. IR (KBr, cmÀ1): 3050.83 (CH arom.),
2931.27 (CH aliph.), 1762.62 (CO), 1720.19 (CO), and 1623.77
(C=C).
and 1596.77 (C=C). H NMR (300 MHz, CDCl3): δ 7.39 (d, 1H,
J = 9 Hz), 7.31 (d, 1H, J = 9 Hz), 6.33 (s, 1H), 2.62 (s, 3H), 2.31
(s, 3H), and 2.30 (s, 3H). MS (m/z, %): 218 (M+-C2H2O, 63), 204
(M+-C3H4O, 2), 203 (M+-C3H5O, 12), 190 (M+-C3H2O2, 6), 189
(M+-C4H7O, 5), 176 (M+-C4H4O2, 100), 175 (M+-C4H5O2, 7),
161 (M+-C5H7O2, 6), and 147 (M+-C5H5O3, 10). Anal. calcd for
C14H12O5 (260.24): C, 64.61; H, 4.65. Found: C, 64.92; H, 4.88.
Photooxygenation of 15.
According to the general
Synthesis of 6-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one
(20) and 8-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one (21).
Compound 19 (1 g, 4.59 mmol) was mixed with AlCl3 powder
(2 g, 15.2 mmol), and the mixture was heated at 155–170°C for
2 h. After cooling to 50°C, the melt was treated with diluted
HCl. The deposited product was filtered off, washed with water,
and purified by column chromatography by eluting with 70% of
a mixture of petroleum ether 40–60 and ethyl acetate to give 20,
21, and 7. Compound 20, white powder (0.33 g, 33%), MP
203–204°C. IR (KBr, cmÀ1): 3430 (OH), 3054.69 (CH arom.),
2927.41 (CH aliph.), 1739.48 (br, 2CO), and 1619.91 (C=C).
1H NMR (600 MHz, CDCl3): δ 12.65 (s, 1H, exchangeable with
D2O, OH), 7.97 (s, 1H), 6.86 (s, 1H), 6.19 (s, 1H), 2.71 (s, 3H),
and 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3) ppm: 203.3,
165.3, 159.9, 158.7, 151.6, 128.1, 117.0, 113.0, 112.8, 105.4,
26.7, and 18.6. MS (m/z, %): 218 (M+, 45), 204 (M+-CH2, 14),
203 (M+-CH3, 100), 190 (M+-CO, 11), 189 (M+-C2H5, 3), 176
(M+-C2H2O, 11), 175 [M+-(CH3 + CO), 96], 161 (M+-C3H5O,
4.7), and 147 (M+-C3H3O2, 37). Anal. calcd for C12H10O4
(218.21): C, 66.05; H, 4.62. Found: C, 66.16; H, 4.67.
Compound 21, white powder (0.57 g, 57%), MP 164°C. IR
(KBr, cmÀ1): 3440.39 (OH), 3090 (CH arom.), 2920 (CH aliph.),
1739.48 (br, 2CO), and 1608.34 (C=C). 1H NMR (600 MHz,
CDCl3): δ 13.57 (s, 1H, exchangeable with D2O, OH), 7.68
(d, IH, J = 9 Hz), 6.91 (d, 1H, J = 9 Hz), 6.17 (s, 1H), 2.96
(s, 3H), and 2.43 (s, 3H). 13C NMR (125 MHz, CDCl3) ppm:
procedure of the photooxygenation, the irradiation of 15 (1 g,
4.13 mmol) for 4 h yielded 6-acetyl-4,7-dimethyl-2-oxo-2H-
chromen-5-yl acetate (24), 2-hydroperoxy-2,4,9-trimethyl-3-
methylene-2H-furo[2,3-f]chromen-7(3H)-one (25), and endoperoxide
of 2,3,4,9-tetramethyl-7H-furo[2,3-f]chromen-7-one (26). Compound
24, yellow crystals (0.5 g, 44%), MP 120–122°C. IR (KBr cmÀ1):
3058.55 (CH arom.), 2935.13 (CH aliph.), 1758.76 (br, 2CO),
1693.19 (CO), and 1608.34 (C=C). 1H NMR (300 MHz,
CDCl3): δ 7.11 (s, 1H), 6.21 (s, 1H), 2.48 (s, 3H), 2.45 (s, 3H),
2.38 (s, 3H), and 2.31 (s, 3H). MS (m/z, %): 274 (M+, 10), 232
(M+-C2H2O, 69), 231 [M+-(CO + CH3), 9], 218 (M+-C3H4O,
15), 217 (M+-C3H5O, 100), 204 (M+-C3H2O2 or M+-C4H6O,
18), 203 (M+-C4H7O, 6), 190 (M+-C4H4O2, 6), 189 (M+-
C4H5O2, 30) , and 161 (M+-C5H5O3, 15). Anal. calcd for
C15H14O5 (274.27): C, 65.69; H, 5.15. Found: C, 65.91; H, 4.97.
Compound 25, semi oil (0.08 g, 7%). IR (KBr, cmÀ1):
3600–3250 (br, OOH), 3072 (CH arom.), 2928.27 (CH aliph.),
1
1680.12 (CO), and 1620 (C=C). H NMR (300 MHz, CDCl3): δ
13.07 (s, 1H, exchangeable with D2O, OOH), 6.67 (s, 1H), 6.11
(s, 1H), 6.67 (d, 1H, J = 1.2 Hz), 6.05 (d, 1H, J = 1.2 Hz), 2.51
(s, 3H), 2.30 (s, 3H), and 1.46 (s, 3H). MS (m/z, %): 276
(M+ + 2, 69), 275 (M+ + 1, 7), 241 (M+-OOH, 4), 232 (M+-
C2H2O, 9), 231 [M+-(CO + CH3], 40), 216 (M+-C3H6O or M+-
C2H2O2, 19), and 215 (M+-C2H3O2, 5). Compound 26, yellow
powder (0.416 g, 37%), MP 120–126°C. IR (KBr, cmÀ1):
3062.41 (CH arom.), 2927.41 (CH aliph.), 1727.91 (CO), and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Organic Photochemistry and Photobiology
1619.91 (C=C). 1H NMR (300 MHz, CDCl3): δ 6.11 (s, 1H), 3.32
(s, 1H), 2.49 (s, 3H), 2.30 (s, 3H), 1.81 (s, 3H), and 1.64 (s, 3H).
MS (m/z, %): 274 (M+, 2), 231 [M+-(CH3 + CO), 100], 203 (M+-
C4H7O or M+-(CH3 + 2CO), 3), 189 (M+-C5H9O, 3), 175 (M+-
C5H7O2, 2), 161 (M+-C6H9O2, 11), 160 (M+-C6H10O2, 5), 105
(M+-C9H13O3, 4), and 104 (M+-C9H14O3, 3). Anal. calcd for
C15H14O5 (274.27): C, 65.69; H, 5.15. Found: C, 65.78; H, 5.28.
Synthesis of 4,7-dimethyl-2-oxo-2H-chromen-5-yl acetate (27).
Compound 27 was prepared from 9 (0.4g, 2.1 mmol) and 5-mL
acetic anhydride according to the method given for 19. The crude
product was purified by recrystallization from ethanol to give 27
(0.44 g, 90%) as white crystals, MP 194–196°C. IR (KBr, cmÀ1):
3062.41 (CH arom.), 2927.41 (CH aliph.), 1743.33 (br, 2CO), and
1677.77 (C=C). 1H NMR (600 MHz, CDCl3): δ 7.06 (s, 1H), 6.79
(s, 1H), 6.17 (s, 1H), 2.47 (s, 3H), 2.42 (s, 3H), and 2.37 (s, 3H).
13C NMR (125MHz, CDCl3) ppm: 169.2, 160.1, 154.6, 150.8,
147.3, 142.7, 120.4, 115.9, 115.6, 111.3, 22.7, 21.5, and 21.4. MS
(m/z, %): 232 (M+, 19), 190 (M+-C2H2O, 97), , 189 [M+-
(CH3 + CO), 8], 162 (M+-C3H2O2, 100), 161 (M+-C3H3O2, 36),
148 (M+-C4H4O2, 1), 147 (M+-C4H5O2, 6), 146 (M+-C4H6O2, 2),
133 (M+-C5H7O2, 7), and 132 (M+-C5H8O2, 2). Anal. calcd for
C13H12O4 (232.23): C, 67.23; H, 5.21. Found: C, 67.20; H, 4.65.
Synthesis of 6-acetyl-5-hydroxy-4,7-dimethyl-2H-chromen-2-
one (28). Compound 28 was prepared from 27 (0.4 g, 2.1 mmol)
according to the method given for 21. The crude product was
purified by column chromatography by eluting with 70% of a
mixture of petroleum ether 40–60 and ethyl acetate to give 28 and
9. Compound 28, white powder (0.42 g, 42%), MP 168–170°C.
IR (KBr, cmÀ1): 3432.67(OH), 3066.26 (CH arom.), 2931.27
(CH aliph.), 1727.91 (br, 2CO), and 1608.34 (C=C). 1H NMR
(600MHz, CDCl3): δ 14.61 (s, 1H, exchangeable with D2O, OH),
6.67 (s, 1H), 6.08 (s, 1H), 2.71 (s, 3H), 2.66 (s, 3H), and 2.65 (s,
3H). 13C NMR (125 MHz, CDCl3) ppm: 205.5, 165.2, 160.0,
158.0, 155.0, 144.0, 116.9, 113.6, 112.0, 108.5, 33.4, 25.3, and
24.3. MS (m/z, %): 232 (M+, 9), 218 (M+-CH2, 4), 217 (M+-CH3,
13), 204 (M+-CO or M+-C2H4, 11), 203 (M+-C2H5, 6), 190 (M+-
C2H2O, 4), 189 [M+-(CH3 + CO), 23], 161 [M+-(CO+ CH3 + CO),
52], and 131 (M+-C5H9O2, 49). Compound 9, white powder
(0.156g, 19%), MP 246–250°C.
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Acid hydrolysis of 6-acetyl-4,7-dimethyl-2-oxo-2H-chromen-5-
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product was purified by column chromatography on silica gel by
eluting with 70% of a mixture of petroleum ether 40–60 and ethyl
acetate to give white powder of 6-acetyl-5-hydroxy-4,7-dimethyl-
2H-chromen-2-one (28) (0.3g, 59%), MP 168–170°C.
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Acknowledgment. This work is gifted to the soul of Prof. Dr.
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of Science (new Dameitta), Mansoura University (Damietta branch).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet