Tetrahydrobenzo- and benzofurobenzopyrones as a new class of potential photoreagents toward DNA

Article abstract of DOI:10.1016/j.ejmech.2008.03.041

The synthesis and the photobiological activity of new tetrahydrobenzo- and benzofurobenzopyrone derivatives carrying at position 4 of benzopyrone ring of furobenzopyrone moiety a phenyl, or a methyl group with a linear structure or with various angular ar

Full text of DOI:10.1016/j.ejmech.2008.03.041

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 18e24
http://www.elsevier.com/locate/ejmech
Original article
Tetrahydrobenzo- and benzofurobenzopyrones as a new class
of potential photoreagents toward DNA
*
Nahla Ahmed Hasan Farag
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University,
El-Kasr El-Aini Street, Cairo 11562, Egypt
Received 26 May 2007; received in revised form 3 March 2008; accepted 6 March 2008
Available online 10 April 2008
Abstract
The synthesis and the photobiological activity of new tetrahydrobenzo- and benzofurobenzopyrone derivatives carrying at position 4 of ben-
zopyrone ring of furobenzopyrone moiety a phenyl, or a methyl group with a linear structure or with various angular arrangements, are reported.
The new compounds are characterized by having an additional cyclohexene or phenyl ring condensed at the 2, 3 double bond of the furan ring of
furobenzopyrone nucleus. The syntheses were performed starting from the appropriate hydroxybenzopyrones on which the tetrahydrobenzofuran
or benzofuran moiety was built, which look most promising for enhancement of photoreactivity of compounds toward DNA. All the synthesized
compounds were screened for photosensitizing activity and some of them exhibited good activity also a certain effect was observed in the dark.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Tetrahydrobenzofurobenzopyrone; Benzofurobenzopyrone; Photochemotherapeutic agents; Photobiological activity
1. Introduction
photobinding and for the biological activity [8]. In addition, it
is reported that, genotoxicity is the undesirable side effect of
furobenzopyrones and it is developed from the formation of
DNA bi-functional adducts [9e11].
Photochemotherapy using psoralens and UVA; 320e
400 nm (PUVA) is a treatment used widely in some skin
diseases including vitiligo, a skin depigmentational disorder
and psoriasis, a disease of accelerated epidermal cell prolifer-
ation [1], in cutaneous lymphomas and in autoimmune
diseases, assuming that the major site of action is DNA [2].
The photobiological activity of furobenzo-a-pyrones (furocou-
marins) is the result of the covalent bonding they undergo with
nucleic acid [3e7]. The process is believed to involve three
major steps: noncovalent intercalative binding to DNA helix
[5], formation of a number of monoadditional products
between the furobenzopyrone and DNA based upon long
wave length UV-irradiation [7], absorption of a second photon
by some of the mono-adducts to form bi-adducts resulting in
interstrand cross-linkages [7]. Therefore, the 2, 3 and 5, 6 dou-
ble bonds are the two photoreactive sites responsible for DNA
Extensive photochemical and photobiological studies have
been performed mainly on two series of furobenzopyrones,
that is psoralens (linear furobenzopyrone) [1,12,13] and,
angelicins (angular furobenzopyrone) [14e18]. In addition,
new DNA monofunctional furobenzopyrones as 6-carbethoxy
analogues [19], furobenzopyrones with modified annulations
geometry [20] as well as pyridopsoralen [21e23], azapsora-
lens [24], and furoquinolinones [25] have been prepared.
They prevent interstrand cross-link formation, consequently
lack skin phototoxicity [21e25], and at the same time main-
tain the photosensitizing activity. Synthesis of different series
of tetrahydrobenzo- and benzofurobenzopyrone derivatives as
new monofunctional DNA photobinding agents was reported
[26,27] and it was interesting for the development of new,
less phototoxic chemotherapeutic agents that interact with
DNA better than 8-methoxypsoralen (8-MOP) (xanthotoxin)
[28].
* Tel.: þ20 24534418, 0123378871; fax: þ20 23628426.
E-mail address: anahla_69@yahoo.com
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.03.041

N.A. Hasan Farag / European Journal of Medicinal Chemistry 44 (2009) 18e24
19
The single-crystal structures 1FHY and 1FHZ are presented
for two DNA sequences with the thymine bases covalently
cross-linked across the complementary strands by 40-
hyroxymethyl-4, 50,8-trimethylpsoralen (HMT). The HMT-
adduct of d(CCGCTAGCGG) forms a psoralen-induced
Holliday junction showing the effect of this important class of
chemotherapeutics on the structure of the recombination inter-
mediate. In contrast HMT-d(CCGGTACCGG) forms a se-
quence-dependent junction. In both structures, the DNA
duplex is highly distorted at the thymine base linked to the
six-membered pyrone ring of the drug. The psoralen cross-
link defines the intramolecular interactions of the drug-induced
junction, while the sequence-dependent structure is nearly
identical to the native Holliday junction, suggesting a role for
psoralen in the mechanism to initiate repair of psoralen-lesion
in mammalian DNA [29].
furobenzopyrone (psoralen type, 1) 8, which is supported by
the absence of ortho coupling of H-5, H-6 protons of furoben-
zopyrone moiety and the presence of separate signals for H-5,
H-11 of furobenzopyrone moiety.
Analogously, the cyclized 4-methyl analogues 13, 14 are
obtained from the corresponding ether derivative 12, Scheme
2, to yield the angular structure (isopseudopsoralen type 4)
13 and the linearly annulated furobenzopyrone (type 3) 14.
3. Photosensitizing activity
The new derivatives (7e10, 13e16) obtained from the
reaction sequencewere screened for their antimicrobial and pho-
toreactivity toward DNA and the results are presented in Table 1.
Owing to our interest for drug molecules able to photoreact
monofunctional with DNA and their biological activity, we
planned to prepare a new series of tetracyclic furobenzopyrone
derivatives. These new compounds derive from the condensa-
tion of a cyclohexene or phenyl ring at 2, 3 double bond of the
furan ring of the furobenzopyrone nucleus and may have both
a linear geometry 1, 3 and angular structures 2, 4.
4. Isoelectric potential studies
Chem3D Ultra-models have been simulated using ChemO-
ffice 2004 software. First the structure models were generated
then fully minimized to obtain the optimum structures with
least energy. The charges were calculated by MNDO method
[37].
O
O
O
O
O
O
O
O
O
O
O
O
1
2
3
4
2. Chemistry
5. Results and discussion
Generally the synthetic pathway followed by MacLeod
et al. [30] to obtain the unsubstituted tetrahydrobenzofuroben-
zopyrone and benzofurobenzopyrone has been employed to
prepare the designed compounds as illustrated by the formulae
1, 2, 3, 4.
The appropriate hydroxybenzopyrones 5, 11 were condensed
with 2-bromocyclohexanone to yield the corresponding ethers
6, 12 [31e33], which were cyclized in alkaline medium [34]
obtaining the linearly annulated 8, 14 and the angular derivatives
7, 13. Dehydrogenation of the appropriate compounds 7, 8, 13,
14 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
[35,36] yielded the corresponding benzofurobenzopyrones 9,
10, 15, 16 (Schemes 1 and 2).
With dark controlled screening, data concerning antimicro-
bial activity which are reported in Table 1, it was noticed that
compounds 8e10, 15, 16 are active as antimicrobial against
Bacillus subtilis where compound 9 was the most active one,
while comparing activity as photosensitizer, compounds 7, 9,
10, 15, 16 have photosensitizing activity.
Isoelectric potential studies (Figs. 1e5) reveal that there
may be a relationship between photosensitizing activity and
coplanarity of the molecule may be due to its noncovalent in-
tercalative binding with DNA helix where, benzo group is co-
planar with furobenzopyrone moieties 9, 10, 15, 16.
Based on this finding, compounds 7, 10, 15, 16 may be
good candidates as new, monofunctional, less phototoxic
chemotherapeutic agents that interact with DNA.
In particular, the synthesis of phenyl derivatives of tetrahy-
drobenzofurobenzopyrones 7, 8 was performed starting from
7-hydroxybenzopyrone derivative with phenyl group in 4-
position Scheme 1. Thus, cyclization of 20-oxocyclohexenyl
ethers of 7-hydroxybenzopyrone 6, yielded the angular struc-
6. Experimental protocols
6.1. Chemistry
1
ture (angelicin type, 2) 7 which is supported by H NMR
which reveals the presence of ortho coupling of H-5, H-6
protons of furobenzopyrone moiety, and the linearly annulated
Remarks: melting points (mp) were determined in one-end
open capillary tubes on Gallenkamp and Kofler melting point

20
N.A. Hasan Farag / European Journal of Medicinal Chemistry 44 (2009) 18e24
C6H5
CH3
HO
O
O
HO
O
O
5
11
2-Bromocyclohexanone
K2CO3/ dry acetone
2-Bromocyclohexanone
K2CO3/ dry acetone
C6H5
CH3
O
O
O
O
O
O
O
O
6
12
Ethanolic KOH
Ethanolic KOH
C6H5
C6H5
CH3
O
CH3
O
O
O
O
O
O
O
O
O
O
O
13
14
7
8
DDQ/ dry benzene
CH3
DDQ/ dry benzene
CH3
DDQ/ dry benzene
C6H5
DDQ/ dry benzene
C6H5
O
O
O
O
O
O
O
O
O
15
16
O
O
O
Scheme 2.
9
10
Scheme 1.
anhydrous potassium carbonate (2.76 g, 0.02 mol) by refluxing
the mixture for 20 h. After chilling the potassium carbonate
was filtered off and washed with acetone. The pooled filtrate
and acetone washings were concentrated to dryness and the
residue crystallized from methanol giving 6 as yellow crystals
(2.2 g, 66%), mp 173 ꢁC.
apparatus and are uncorrected. Elemental analyses (C, H) were
undertaken with PerkineElmer model 240Canalyser and
performed by microanalytical center, Cairo University (within
ꢀ0.4%). Infrared spectra were determined on Shimadzu IR
435 Spectrophotometer using KBr disc. Nuclear magnetic
resonance spectra were scanned on Joel NMR and Varian
Gemini 300 MHz and 90 MHz spectrometer. Mass spectra
were taken with a Finigan Mat 212-spectrometer (ei 120 eV,
R 1000). The homogeneity of the compounds was monitored
by thin-layer chromatography (TLC) using precoated silica
gel-G plates 60-F-254 (Merk; 0.25 mm). Developing solvent
was chloroform.
1
Compound 6 H NMR. (90 MHz, d): 1.80e2.65 (m, 8H, e
(CH2)4ꢂ), 4.74e4.79 (m, 1H, ]CHeOe), 6.22 (s, 1H, H-3),
6.78 (d, 1H, H-8, J8,6 ¼ 2.1), 6.80 (d, 1H, H-6, J6,8 ¼ 2.1), 7.37
(d, 1H, H-6, J6,5 ¼ 9.6), 7.43 (d, 1H, H-5, J5,6 ¼ 9.6), 7.45e
7.52 (m, 5H, ar. protons). Anal. Calcd for C21H17O4: C,
75.68; H, 5.11. Found: C, 75.60; H, 5.02.
6.1.2. Synthesis of 4-methyl-6-(20-oxocyclohexyloxy)-
2H-1-benzopyran-2-one (12)
Reaction of 6-hydroxy-4-methyl-2H-1-benzopyran-2-one
11 (1.76 g, 0.01 mol), and 2-bromocyclohexanone (3.52 g,
0.02 mol) as described for compound 6 was adopted, crystal-
lization from methanol giving 12 as yellow crystals (3.5 g,
65%), mp 212 ꢁC.
6.1.1. Synthesis of 7-(20-oxocyclohexyloxy)-
4-phenyl-2H-1-benzopyran-2-one (6)
A solution of 7-hydroxy-4-phenyl-2H-1-benzopyran-2-one
5 (2.38 g, 0.01 mol) in 120 ml of acetone was reacted with
2-bromo-cyclohexanone (3.52 g, 0.02 mol) in the presence of

N.A. Hasan Farag / European Journal of Medicinal Chemistry 44 (2009) 18e24
21
Table 1
Preliminary screening of furobenzopyrone derivatives (7e10, 13e16) as
antimicrobial and photosensitizing agents
Compound
Control
(before UV-irradiation)
inhibition zone (mm)
Test
(after UV-irradiation)
inhibition zone (mm)
Xanthotoxin (8-MOP)
7
e
12.0
5.0
e
8
9.0
13.0
10.0
e
7.0
9
14.0
13.0
e
10
13
14
15
16
e
11.0
12.0
e
14.0
16.0
Compound 12 1H NMR. (90 MHz, d): 1.15e2.64 (m,
(CH2)4, 8H), 2.37 (s, 3H, CH3-4), 4.74e4.79 (m, 1H,
]CHeOe), 6.34 (s, 1H, H-3), 7.00e7.29 (m, 3H, H-6,
H-5, H-8), m/z ¼ (272.15, 25.77), (176.00, 93.96), (147.00,
100). Anal.Calcd for C16H15O4: C, 70.85; H, 5.54. Found:
C, 71.11; H, 5.36.
Fig. 2. Isoelectric potential of 10.
obtaining 7 as greenish brown needles (1.17 g, 37%), mp
235 ꢁC.
6.1.3. Synthesis of 4-phenyl-8,9,10,11-tetrahydro-
2H-benzofuro[2,3-h]-1-benzopyran-2-one (7)
and 4-phenyl-6,7,8,9-tetrahydro-2H-benzofuro
1
Compound 7 H NMR. (300 MHz, d): 1.81e1.96 (m, 4H,
H-9, H-10), 2.52e2.76 (m, 4H, H-8, H-11), 6.26 (s, 1H,
H-3), 7.49 (d, 1H, H-6, J6,5 ¼ 9.6), 7.54 (d, 1H, H-5,
J5,6 ¼ 9.6), 7.56e7.57 (m, 5H, Ar-H).
[3,2-g]-1-benzopyran-2-one (8)
7-(20-Oxocyclohexyloxy)-4-phenyl-2H-1-benzopyran-2-one 6
(3.33 g, 0.01 mol) was dissolved in 0.1 N potassium hydroxide
solution (0.56 g, 100 ml absolute ethanol) and was refluxed for
18 h. The reaction was TLC controlled and left overnight at
room temperature, then filtered.
Compound 7 13C NMR. d 19.5, 21.0, 23.9, 23.9 (C-11, C-9,
C-10, C-8), 103.8e112.5, 112.7, 117.6, 122.1, 122.5 (C-6,
C-3, C-11a, C-11b, C-5, C-4a), 126.4 (C-20, C- 60), 128.0
(C-30, C-50), 128.7(C-40), 140 (C-10), 148.6, 152.1, 154.0
(C-11c, C-6a, C-7a), 155.5 (C-4), 160.9 (C-2). Anal. Calcd
for C21H16O3: C, 79.75; H, 5.06. Found: C, 79.66; H, 5.35.
The residue was collected, acidified with dilute hydro-
chloric acid and filtered, washed with water and dried under
vacuum. The crude product was crystallized from ethanol
Fig. 1. Isoelectric potential of 9.
Fig. 3. Isoelectric potential of 15.

22
N.A. Hasan Farag / European Journal of Medicinal Chemistry 44 (2009) 18e24
9a), 155.5 (C-4), 160.9 (C-2). Anal. Calcd for C21H16O3: C,
79.75; H, 5.06. Found: C, 79.49; H, 4.83.
6.1.4. Synthesis of 4-methyl-5,6,7,8-tetrahydro-
2H-benzofuro[3,2-f]-1-benzopyran-2-one (13)
4-methyl-7,8,9,10-tetrahydro-2H-benzofuro
[2,3-g]-1-benzopyran-2-one (14)
These compounds were prepared from 4-methyl 6-(20-
oxocyclohexyloxy)-2H-1-benzopyran-2-one
0.01 mol) as described for compounds 7, 8.
12
(2.71 g,
The residue was collected, acidified with dilute hydro-
chloric acid and filtered, washed with water and dried under
vacuum. The crude product was crystallized from ethanol
obtaining 13 (1.33 g, 52%), mp above 350 ꢁC.
1
Compound 13 H NMR. (300 MHz, d): 1.74e1.98 (m, 4H,
H-6, H-7), 2.39 (s, 3H, CH3-4), 2.62e2.87 (m, 4H, H-5, H-8),
6. 33 (s, 1H, H-3), 7.26 (d, 1H, H-10, J6,5 ¼ 9.6), 7.27 (d, 1H,
H-11, J5,6 ¼ 9.6). Anal. Calcd for C16H14O3: C, 75.59; H,
5.51. Found: C, 75.93; H, 5.02.
Then, the obtained mother liquor was acidified with dilute
hydrochloric acid and the precipitate obtained was filtered,
washed with water and dried under vacuum. The crude
product was crystallized from benzene/pet.ether obtaining
light brown powder (1.17 g, 46%) of 14 mp 247 ꢁC.
Compound 14 1H NMR. (300 MHz, d): 1.80e1.90 (m, 4H, H-
8, H-9), 2.37e2.60 (m, 4H, H-7, H-10), 2.38 (s, 3H, CH3-4),
6.34 (s, 1H, H-3), 7.00 (s, 1H, H-5), 7.30 (s, 1H, H-11), m/
z ¼ (256.25, 1.92), (176.00, 76.62), (147.00, 100). Anal. Calcd
for C16H14O3: C, 75.59; H, 5.51. Found: C, 75.93; H, 5.39.
Fig. 4. Isoelectric potential of 16.
Then, the obtained mother liquor was acidified with dilute
hydrochloric acid and the precipitate obtained was filtered,
washed with water and dried under vacuum. The crude prod-
uct was crystallized from benzene/pet.ether obtaining 8 as
light brown powder (0.95 g, 30%), mp 157 ꢁC.
1
Compound 8 H NMR. (300 MHz, d): 1.81e1.96 (m, 4H,
H-7, H-8), 2.52e2.78 (m, 4H, H-6, H-9), 6.31 (s, 1H, H-3),
7.27 (s, 1H, H-5), 7.40 (s, 1H, H-11), 7.44e7.57 (m, 5H, Ar-H).
Compound 8 13C NMR. d 19.5, 21.0, 23.9 (C-6, C-8), 23.9
(C-7, C-9), 103.6, 112.5, 112.7, 119.5 122.5, 134.0 (C-5a, C-3,
C-5b, C-5, C-4a, C-11), 126.4 (C-20, C-60), 128.0 (C-30, C-50),
128.7 (C-40), 140 (C-10), 151.5, 152.1, 154.6 (C-11a, C-10a, C-
6.1.5. Synthesis of 4-phenyl-2H-benzofuro
[2,3-h]-1-benzopyran-2-one (9)
A solution of 4-phenyl-8,9,10,11-tetrahydro-2H-benzo-
furo[2,3-h]-1-benzopyran-2-one 7 (0.60 g, 0.0018 mol) and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ (1.4 g,
0.007 mol) in 300 ml of benzene was refluxed for 20 h. After
cooling, the solid was filtered off and the solution was concen-
trated to dryness. The obtained residue was collected and
chromatographed on silica gel column eluting with chlorofor-
m:ethanol 8:2. From the pooled fractions containing a pure
product (TLC), the solvent was evaporated and the residue
crystallized from methanol/benzene giving 9 as dark red
powder (0.18 g, 36%), mp 170 ꢁC, Rf ¼ 0.68.
1
Compound 9 H NMR. (300 MHz, d): 6.39 (s, 1H, H-3),
7.27 (s, 5H, C6H5-4), 7.04e7.08 (d, 1H, H-6, J6,5 ¼ 9.3),
7.24e7.37 (d, 1H, H-5, J5,6 ¼ 9.9), 7.57e7.99 (m, 9H, Ar-H).
Compound 9 13C NMR. d 106.5, 108.3, 111.6, 112.7, 121.0,
122.1, 122.5, 123.3, 124.7 (C-11, C-9, C-10, C-8, C-6, C-3,
C-11a, C-11b, C-5, C-4a), 126.4 (C-20, C-60), 128.0 (C-30,
C-50), 128.7 (C-40), 140 (C-10), 145.8, 148.6, 155.5 (C-11c,
C-6a, C-7a), 156.3 (C-4), 160.9 (C-2). Anal. Calcd for
C21H12O3: C, 80.77; H, 3.85. Found: C, 81.13; H, 3.83.
6.1.6. Synthesis of 4-phenyl-2H-benzofuro
[3,2-g]-1-benzopyran-2-one (10)
This compound was prepared from 4-phenyl-6,7,8,9-tetrahy-
dro-2H-benzofuro[3,2-g]-1-benzopyran-2-one 8 (0.50 g, 0.0016
Fig. 5. Isoelectric potential of 8.

N.A. Hasan Farag / European Journal of Medicinal Chemistry 44 (2009) 18e24
23
mol) as described for the synthesis of compound 9 giving 10 as
dark red powder (0.14 g, 28%), mp 123 ꢁC, Rf ¼ 0.58.
(c) Paper discs: Whatman no. 1 filter paper disc (6 mm) was
sterilized and impregnated with the tested compounds
10 mg/ml dimethylformamide (DMF) and allowed to dry
overnight.
1
Compound 10 H NMR. (300 MHz, d): 6.39 (s, 1H, H-3),
7.27 (s, 1H, H-11), 7.35 (s, 5H, C6H5-4), 7.43 (m, 2H, H-7),
7.52 (s, 1H, H-8), 7.52 (s, 1H, H-6) 7.61 (s, 1H, H-5), 7.99
(s, 1H, H-9).
Compound 10 13C NMR. d 103.6, 111.6, 112.7, 113.0,
119.5, 121.0, 122.5, 123.3, 124.7 (C-6, C-8, C-7, C-9, C-5a,
C-3, C-5b, C-5, C-4a, C-11), 126.4 (C-20, C-60), 128.0 (C-30,
C-50), 128.7(C-40), 140 (C-10), 145.8, 151.5, 155.9 (C-11a,
C-10a, C-9a), 155.5 (C-4), 160.9 (C-2). Anal. Calcd for
C21H12O3: C, 80.77; H, 3.85. Found: C, 80.54; H, 3.92.
6.2.2. Experimental
Prepared broth culture 0.02 ml was added carefully in the
sterile Petri dishes, then 10 ml of the liquefied nutrient agar me-
dium was added, allowed to be mixed uniformly and solidified
agar layer. Each dish contains a disc impregnated with DMF (ne-
glect effect of the solvent) and another disc impregnated with
xanthotoxin and 10 mg/ml DMF as reference compound.
Two groups of plates were used, one as test plate was incu-
bated in the dark at 37 ꢁC for 3 h before irradiation to allow for
diffusion of the tested compounds through the agar layer, and
the duplicate plate was left in the incubator overnight as
control to determine the antimicrobial activity.
Covers were removed from the tested Petri dishes and
exposed to UV lamp (365 nm) for 20 min. After irradiation,
the plates were reincubated in the dark at 37 ꢁC overnight
and examined for antimicrobial and photosensitizing activities
by measuring the produced inhibition zones.
6.1.7. Synthesis of 4-methyl-2H-benzofuro
[3,2-f]-1-benzopyran-2-one (15)
A solution of 4-methyl-5,6,7,8-tetrahydro-2H-benzofuro[3,2-
f]-1-benzopyran-2-one 13 (0.6 g, 0.002 mol) and 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone DDQ (1.4 g, 0.007 mol) in 300
ml of benzene was treated as described for the synthesis of com-
pound 9. Crystallization from benzene gives 15 as red needles,
(0.29 g, 49%), mp 213 ꢁC.
Compound 15 1H NMR. (300 MHz, d): 2.41 (s, 3H, CH3-4),
6.31 (s, 1H, H-3), 7.04e7.08 (d, 1H, H-11, J11,10 ¼ 9.3),
7.22e7.25 (d, 1H, H-10, J10,11, ¼ 9.9), 7.23e7.27 (m, 4H,
H-5, H-6, H-7, H-8). Anal. Calcd for C16H10O3: C, 76.80;
H, 4.00. Found: C, 76.62; H, 4.17.
Acknowledgements
I wish to offer my deep gratitude to Yosra Ibrahim demon-
strator of Microbiology, Faculty of Pharmacy, Cairo University,
for carrying out the microbiological and photosensitizing
activities.
6.1.8. Synthesis of 4-methyl-2H-benzofuro
[2,3-g]-1-benzopyran-2-one (16)
This compound was prepared from 4-methyl-7,8,9,10-tetrahy-
dro-2H-benzofuro[2,3-g]-1-benzopyran-2-one 14(0.5 g, 0.0019
mol) as described for the synthesis of compound 9. Crystallization
from benzene gives 16 as orange red powder (0.21 g, 42%), mp
200 ꢁC.
Compound 16 1H NMR. (300 MHz, d): 2.41 (s, 3H, CH3-4),
6.31 (s, 1H, H-3), 7.06 (d, 1H, H-11, J11,5 ¼ 1.0), 7.08 (d, 1H,
H-5, J5,11 ¼ 0.9), 7.26e7.27 (m, 4H, H-7, H-8, H-9, H-10).
Anal. Calcd for C16H10O3: C, 76.80; H, 4.00. Found: C,
76.45; H, 4.38.
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