Synthesis of the reported structure of crassiflorone, a naturally occurring quinone isolated from the African ebony Diospyros crassiflora, and regioisomeric pentacyclic furocoumarin naphthoquinones

Article abstract of DOI:10.1039/c0ob01231a

A synthesis of the structure reported for the natural product crassiflorone, a furocoumarin naphthoquinone, is described. The key steps are a Diels-Alder reaction to form 2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and copper(ii) mediated coupling to 4-hydroxy-5-methylcoumarin to establish the pentacyclic framework whose structure was unambiguously confirmed by X-ray crystallography. Since the spectroscopic data of the synthetic material did not match those reported for the natural product, three further regioisomeric furocoumarin naphthoquinones were prepared by copper(ii) mediated coupling of 4-hydroxy-5- or 8-methyl coumarins with 5-benzyloxy-2-bromo-7-methyl- or 8-benzyloxy-2-bromo-6-methyl-1,4- naphthoquinone. Again the spectroscopic data did not match those of the natural material and therefore the true structure of crassiflorone remains unknown.

Full text of DOI:10.1039/c0ob01231a

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PAPER
Synthesis of the reported structure of crassiflorone, a naturally occurring
quinone isolated from the African ebony Diospyros crassiflora, and
regioisomeric pentacyclic furocoumarin naphthoquinones
Jalindar Padwal, William Lewis and Christopher J. Moody*
Received 22nd December 2010, Accepted 1st February 2011
DOI: 10.1039/c0ob01231a
A synthesis of the structure reported for the natural product crassiflorone, a furocoumarin
naphthoquinone, is described. The key steps are a Diels–Alder reaction to form
2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and copper(II) mediated
coupling to 4-hydroxy-5-methylcoumarin to establish the pentacyclic framework whose structure was
unambiguously confirmed by X-ray crystallography. Since the spectroscopic data of the synthetic
material did not match those reported for the natural product, three further regioisomeric
furocoumarin naphthoquinones were prepared by copper(II) mediated coupling of 4-hydroxy-5- or
8-methyl coumarins with 5-benzyloxy-2-bromo-7-methyl- or 8-benzyloxy-2-bromo-6-methyl-1,4-
naphthoquinone. Again the spectroscopic data did not match those of the natural material and
therefore the true structure of crassiflorone remains unknown.
Introduction
Quinones occur widely in Nature and constitute a large group
of natural pigments,1–4 although their contribution to natural
colouring is relatively small. Many quinones have important
functions in living systems where they participate in a range
of important biological redox processes. Prominent amongst
quinone natural products are the naphthoquinones, for example,
phylloquinone (vitamin K1) (Fig. 1) that occurs in green plants
and participates in photosynthetic electron transport processes.1,2
Recently, a new naphthoquinone with antibacterial properties
was isolated from the stem bark of the African ebony (per-
simmon) tree Diospyros crassiflora.5,6 The compound, named
crassiflorone, was assigned the pentacyclic naphthoquinone struc-
ture 1 (Fig. 1) on the basis of NMR spectroscopic studies.5 In
addition to the naphthoquinone chromophore, crassiflorone also
contains a furocoumarin ring system, in common with other
Fig. 1 Structures of phylloquinone, the reported structure of the naph-
natural products such as the phytoestrogens coumestan and
thoquinone crassiflorone 1, and the furocoumarin coumestrol.
coumestrol (Fig. 1).7 We recently described the first synthesis
of structure 1,8 which unfortunately appeared to cast some
Results and discussion
doubt on the original structural assignment of the natural
product. We now report the details of this work, together with
the synthesis of three regioisomeric pentacyclic furocoumarin
naphthoquinones as possible candidate structures for the natural
product.
For the synthesis of the furocoumarin naphthoquinone 1 we
planned to couple together a bromonaphthoquinone fragment
2 with 4-hydroxy-5-methylcoumarin 3. To this end, Diels–Alder
reaction of 1-methoxy-3-methyl-1-trimethylsiloxy-1,3-butadiene,
obtained by silylation of the LDA-generated enolate of methyl
3,3-dimethylacrylate,9 with 2,6-dibromoquinone10 in benzene at
room temperature, followed by aromatization of the initial
adduct by stirring over silica gel, delivered the known naph-
thoquinone 211 in 50% yield (Scheme 1). Although the bromine
in 2-bromobenzoquinones is known to direct the regiochemical
School of Chemistry, University of Nottingham, University Park, Notting-
ham, U.K. NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk; Fax: 44 115
951 3564
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protected as its benzyl ether 4 in order to avoid potential problems
in ensuing coupling reactions.
4-Hydroxy-5-methylcoumarin 3 was also readily accessible,
and was prepared from ethyl 6-methylsalicylate 5 by addition
of the lithium enolate of tert-butyl acetate followed by acid
mediated cyclization according to the literature procedure.13
Hence we were ready for the pivotal union of quinone 4 and
hydroxycoumarin 3 fragments. The bromine in bromo-benzo- and
naphtho-quinones is known to be readily displaced under basic
(K2CO3) conditions by various nucleophiles, including phenols,14
and enamines. In the latter case, in the presence of copper(II)
salts, the intermediate adducts can undergo oxidative cyclization
onto the quinone ring.15–17 Therefore 4-hydroxy-5-methylcoumarin
3 and the bromonaphthoquinone 4 were coupled in the presence
of potassium carbonate and copper(II) acetate, and gave directly
the pentacyclic framework 6 in 56% yield. Removal of the benzyl
ether protecting group by hydrogenolysis over Pearlman’s catalyst
gave the desired furocoumarin naphthoquinone 1 (Scheme 1),
the structure of which was unambiguously confirmed by X-ray
crystallography (Fig. 3).
Although the structure of synthetic naphthoquinone 1 is not in
1
doubt, we note that its H NMR data are completely consistent
with its structure. However, there are some significant differences
between these data and those reported for the natural product
(Table 1).5 Likewise the 13C NMR data (in CDCl3) are at
variance with those reported for the natural material (in DMSO-
d6),5 although accurate comparison was hampered by the fact
that the synthetic material was insufficiently soluble in DMSO
to obtain good 13C NMR spectroscopic data. Unfortunately
it has proved impossible to obtain a sample of the natural
material for direct comparison, and therefore our short syn-
thesis of the furocoumarin naphthoquinone structure 1, rather
than confirming the structure of the unusual natural product
crassiflorone, suggests that the original structural assignment is
incorrect.
Scheme 1 Synthesis of the reported furocoumarin naphthoquinone
structure 1 of crassiflorone.
outcome of Diels–Alder reactions,12 the structure of 2-bromo-8-
hydroxy-6-methyl-1,4-naphthoquinone 2 was confirmed by X-ray
crystallography (Fig. 2). The H-bonded phenol 2 was subsequently
Fig. 2 X-Ray crystal structure of 2-bromo-8-hydroxy-6-methyl-1,4-naphthoquinone 2.
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Fig. 3 X-Ray crystal structure of the synthetic furocoumarin naphthoquinone 1.
In view of the above data, we considered other possible
structures for the natural product crassiflorone based around
the furocoumarin naphthoquinone framework (Fig. 4). Given
the original data for the natural material and comparison with
the synthetic sample, in particular the intramolecular H-bonded
phenol, and the aromatic protons H-8 and H-10, it seemed
fairly clear that the methyl substituted hydroxy naphthoquinone
fragment was correct, and that the structural misassignment lay in
the furocoumarin part of the molecule. Therefore we considered
three structural variations of compound 1 as candidate structures
for the natural material: the 4,9-dimethyl isomer 7, and the
corresponding two structures 8 and 9 with the furocoumarin
inverted with respect to the naphthoquinone.
The synthesis of the 11-hydroxy-4,9-dimethyl isomer
7
required the coupling of 8-benzyloxy-2-bromo-6-methyl-1,4-
naphthoquinone 4 with 4-hydroxy-8-methylcoumarin 10. The
coumarin was readily prepared by the reaction of o-cresol with
Meldrum’s acid followed by cyclization using Eaton’s reagent
(phosphorus pentoxide in methanesulfonic acid) following a
literature protocol.18 Thereafter the synthesis (Scheme 2) fol-
lowed the methodology described for the isomeric furocoumarin
naphthoquinone 1, and delivered the desired isomer 7, following
deprotection of the intermediate benzyl ether 11.
The synthesis of the 8-hydroxy-1,10- and 4,10-dimethyl furo-
coumarin naphthoquinones regioisomers 8 and 9 necessitated
the use of 5-benzyloxy-2-bromo-7-methyl-1,4-naphthoquinone 13
in place of bromonaphthoquinone 4. The quinone was readily
prepared by an analogous Diels–Alder reaction of 1-methoxy-3-
methyl-1-trimethylsiloxy-1,3-butadiene with 2,5-dibromoquinone
in benzene at room temperature to give the known naphtho-
quinone 1219 in 45% yield (Scheme 3), followed by benzylation
to yield the bromoquinone coupling partner 13, the structure
of which was confirmed by X-ray crystallography (Fig. 5).
Copper mediated coupling of bromoquinone 13 with the 4-
hydroxycoumarins 3 and 10 delivered the required furocoumarin
naphthoquinones 14 and 15 in good yield (Scheme 3), subse-
quently deprotected by hydrogenolysis over Pearlman’s catalyst
to provide the desired furocoumarin naphthoquinones 8 and 9
(Scheme 3). The structures of pentacycles 14 and 9 were confirmed
by X-ray crystallography (Fig. 6 and 7) verifying that they were
Scheme 2 Synthesis of the 11-hydroxy-4,9-dimethyl furocoumarin naph-
thoquinone 7.
indeed regioisomers of each other (albeit one benzyl protected),
and also regioisomeric with the previously described furocoumarin
naphthoquinones 1 and 7.
With three new furocoumarin naphthoquinones available, we
were able to compare their spectroscopic data with those reported
for the natural product crassiflorone. Unfortunately none of the
data were in agreement (Table 1), and therefore, based on the 1H
NMR spectroscopic data, we conclude that crassiflorone is not
represented by structures 1, 7, 8, or 9. Again it was impossible
to compare accurately the 13C NMR data since the synthetic
materials were insufficiently soluble in DMSO to obtain good
13C NMR spectroscopic data. Differences in the IR spectra were
also noted, in particular the lactone C O stretching frequency
reported as 1678 cm-1 (KBr) for the natural product, compared
with the synthetic materials 1, 7, 8, and 9 that have their coumarin
carbonyl absorptions in KBr at 1760, 1754, 1772 and 1753 cm-1
respectively. These latter values compare favourably with data
reported for furocoumarins of the coumestan and coumestrol
family (1740–1717 cm-1),20,21 and hence the value reported for the
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Fig. 4 Hydroxy-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-c]chromene-6,7,
12-triones: structure reported for crassiflorone 1, and three regioisomers
7–9 thereof, possible structures for the natural product.
natural product is unlikely to be compatible with any coumarin
structure. In view of the combination of spectroscopic data on our
four furocoumarin naphthoquinones, obtained by unambiguous
chemical synthesis with additional confirmation by X-ray crys-
tallography, we suggest that the structural misassignment of the
natural product probably lies in the furocoumarin part of the
molecule. Unfortunately, for the moment, the true structure of
crassiflorone remains unknown.
Experimental section
General experimental information
Commercially available reagents were used throughout with-
out further purification unless otherwise stated. Anhydrous
tetrahydrofuran and dichloromethane were freshly distilled. Light
petroleum refers to the fraction of petroleum boiling between
40 and 60 ◦C. All reactions were carried out under nitrogen or
argon atmosphere. Thin layer chromatography was carried out
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Fig. 5 X-Ray crystal structure of 2-bromo-5-benzyloxy-7-methyl-1,4-
naphthoquinone 13.
To a solution of 2,6-dibromobenzoquinone10 (3.00 g, 11.3 mmol)
in benzene (60 mL) was added dropwise 1-methoxy-3-methyl-1-
trimethylsiloxy-1,3-butadiene22 (3.15 g, 16.9 mmol) with constant
◦
◦
stirring at 0 C. After being stirred for 1 h at 0 C, the reaction
mixture was allowed to warm to room temperature and stirred for
another 7 h. The reaction mixture was poured onto silica gel (100 g)
in dichloromethane (400 mL). The suspension was stirred for 24 h
at room temperature. After removing the solvent under reduced
pressure the silica gel was eluted with dichloromethane and
methanol (10 : 1). The eluant was concentrated in vacuo and the
residue was subjected to silica gel flash column chromatography in
10% ethyl acetate and light petroleum to give the title compound
Scheme 3 Synthesis of the 8-hydroxy-1,10- and 4,10-dimethyl furo-
coumarin naphthoquinones 8 and 9.
using aluminium backed plates coated with silica gel. The plates
were visualized under UV light at 254 nm and/or by vanillin or
permanganate stains. Flash column chromatography was carried
out using silica gel with the eluent specified.
IR spectra were recorded using a Perkin ELMER 1600 FTIR
spectrometer. Ultra-violet spectra were recorded in the range of
220–450 nm using either Perkin Elmer Lambda 5 spectropho-
tometer or ATI Unicam UV4. Mass spectra were carried out on
Agilent 6890 series GC, micromass GCT, VG Autospec or Bruker
microTOF (for ESI) spectrometers, using electron impact (EI) or
electrospray ionization (ESI) techniques. 1H NMR and 13C NMR
spectra were recorded using Bruker instruments (1H frequencies
300, 400 and 500 MHz, corresponding 13C frequencies are 75, 100,
125 MHz, respectively). Chemical shifts are quoted in parts per
million (ppm). J values are recorded in Hz.
◦
(1.50 g, 50%); mp 188–189 C (lit.,11 mp 186–187 ◦C); (Found:
M + Na+, 288.9460. C11H779BrO3 + Na+ requires 288.9471); nmax
(CHCl3)/cm-1 3011, 1664, 1642, 1587, 1385, 1302, 1257, 1175,
1143, 866; dH (400 MHz; CDCl3) 11.71 (1 H, s, OH), 7.48 (1 H,
d, J 1.6, ArH), 7.47 (1 H, s, H-3), 7.12 (1 H, d, J 1.6, ArH), 2.47
(3 H, s, Me); dC (100 MHz; CDCl3) 182.3 (C), 181.9 (C), 162.3
(C), 149.3 (C), 140.9 (CH), 139.6 (C), 131.4 (C), 124.3 (CH), 121.3
(CH), 111.0 (C), 22.3 (Me); m/z (ESI) 288 (M + Na+, 100%), 266
(38), 251 (35), 226 (76), 192 (24) 190 (47), 185 (51), 158 (45), 151
(43), 149 (73).
2-Bromo-8-hydroxy-6-methyl-1,4-naphthoquinone 2
8-Benzyloxy-2-bromo-6-methyl-1,4-naphthoquinone 4
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Fig. 6 X-Ray crystal structure of 8-benzyloxy-1,10-dimethyl furocoumarin naphthoquinone 14.
Fig. 7 X-Ray crystal structure of 8-hydroxy-4,10-dimethyl furocoumarin naphthoquinone 9.
Benzyl bromide (0.09 mL, 0.75 mmol), was added to a
mixture of 2-bromo-8-hydroxy-6-methyl-1,4-naphthoquinone 2
(0.10 g, 0.37 mmol), and silver(I) oxide (0.17 g, 0.74 mmol) in
dichloromethane (5 mL) and the resulting suspension was stirred
for 48 h at room temperature. Then, additional silver(I) oxide
(0.17 g, 0.74 mmol) and benzyl bromide (0.09 mL, 0.75 mmol)
were added and stirring was continued for another 24 h. The
mixture was filtered through a plug of Celite and rinsed with
dichloromethane. After removal of the solvent under reduced
pressure the crude product was subjected to silica gel flash column
chromatography in 20% ethyl acetate and light petroleum to give
the title compound (90 mg, 68%); mp 146–148 ◦C; (Found: C,
61.11; H, 3.75. C18H13BrO3 requires C, 61.03, H, 3.70); (Found:
M + H+, 358.0025. C18H1379BrO3 + H+ requires 358.0027); nmax
(CHCl3)/cm-1 3011, 1671, 1600, 1456, 1329, 1260, 1239, 1155,
1056, 851; dH (400 MHz; CDCl3) 7.62 (2 H, m, ArH), 7.57 (1 H, s,
H-3), 7.45 (3 H, m, ArH), 7.37 (1 H, m, ArH), 7.18 (1 H, s, ArH),
5.29 (2 H, s, CH2), 2.47 (3 H, s, Me); dC (100 MHz; CDCl3) 182.9
(C), 175.6 (C), 159.5 (C), 147.1 (C), 142.9 (C), 138.2 (CH), 135.8
(C), 133.7 (C), 128.7 (CH), 128.0 (CH), 126.7 (CH), 120.7 (CH),
119.9 (CH), 116.7 (C), 70.9 (CH2), 22.3 (Me); m/z (EI) 358/356
(M+, 3%), 108 (14), 91 (100), 79 (11).
4-Hydroxy-5-methylcoumarin 3
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(a) To a 100 mL 2 neck round bottomed flask equipped with mag-
netic stirrer, nitrogen inlet and thermometer; diisopropylamine
(4.45 mL, 31.8 mmol), N-benzylbenzamide (5 mg) and dry THF
(20 mL) were added. The solution was cooled to -78 ◦C and
n-BuLi (2.5 M in hexanes; 17.17 mL, 42.92 mmol) was added
slowly. The solution becomes dark blue immediately with addition
of n-BuLi. After 1.5 h, a solution of tert-butyl acetate (2.26 g,
19.5 mmol) in THF (5 mL) was added over 5 min during which
time◦ the solution turned yellow. The solution was stirred at
-78 C for 1 h and a solution ethyl 2-hydroxy-6-methylbenzoate
523 (1.0 g, 5.58 mmol) in THF (5 mL) was added over 5 min. The
colour changes from yellow to orange; after warming to room
temperature overnight, the reaction was quenched by addition of
ice cooled saturated aqueous ammonium chloride (40 mL) and
ethyl acetate (80 mL). The organic layer was washed with brine
(100 mL) dried over MgSO4 and concentrated in vacuo. The residue
was purified by flash column chromatography (10% ethyl acetate in
light petroleum) to give tert-butyl 3-(2-hydroxy-6-methylphenyl)-
3-oxopropanoate as a pale yellow oil (0.95 g, 68%); (Found: M+,
250.1205. C14H18O4 requires 250.1205); nmax (CHCl3)/cm-1 2983,
1730, 1627, 1443, 1370, 1254, 1145; dH (400 MHz; CDCl3) 11.01
(1 H, s, OH), 7.29 (1 H, dd, J 8.1, 7.6, ArH), 6.85 (1 H, d, J 8.1,
ArH), 6.75 (1 H, d, J 7.6, ArH), 3.93 (2 H, s, CH2), 2.53 (3 H, s,
CH3), 1.47 (9 H, s, CMe3); dC (100 MHz; CDCl3) 200.6 (C), 166.7
(C), 161.2 (C), 138.6 (C), 134.4 (CH), 123.2 (CH), 122.3 (C), 116.2
(CH), 82.4 (C), 52.1 (CH2), 27.9 (Me), 23.2 (Me); m/z (ESI) 194
(M+, 41%), 176 (76), 135 (97), 134 (100).
(100 mL). The filtrate was concentrated under reduced pressure
and the residue was purified by flash column chromatography to
give the title compound (0.14 g, 56%), mp 236–238 ◦C; (Found:
M + Na+, 473.0985. C28H18O6 + Na+ requires 473.0996); nmax
(CHCl3)/cm-1 2985, 1731, 1446, 1374, 1249, 1045; dH (400 MHz;
CDCl3) 7.71 (1 H, s, H-10), 7.62 (2 H, d, J 7.4, ArH), 7.52 (1 H,
dd, J 7.3, 7.7, H-3), 7.42 (2 H, dd, 7.3, 7.7, ArH), 7.33 (2 H, d, J
7.6, ArH), 7.22 (1 H, d, J 7.5, H-4), 7.18 (1 H, s, H-8), 5.28 (2 H, s,
CH2), 2.94 (3 H, s, Me), 2.50 (3 H, s, Me); dC (100 MHz; CDCl3)
177.9 (C), 172.2 (C), 162.0 (C), 159.8 (C), 155.2 (C), 154.9 (C),
154.3 (C), 147.4 (C), 136.0 (C), 135.9 (C), 136.6 (C), 132.5 (CH),
128.7 (CH), 127.9 (CH), 127.1 (CH), 126.7 (CH), 124.2 (C), 121.9
(C), 120.1 (CH), 117.2 (C), 115.2 (CH), 110.7 (C), 107.3 (C), 70.8
(CH2), 22.5 (Me), 21.5 (Me).
11-Hydroxy-1,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,7,12-trione (“crassiflorone”) 1
The benzyl ether 6 (0.10 g) was dissolved in ethyl acetate (10 mL)
and Pearlman’s catalyst (20 mg) was added. The reaction mixture
was flushed with nitrogen followed by hydrogen. The reaction
mixture was stirred for 16 h under a hydrogen atmosphere. The re-
action mixture was filtered through a Celite pad while exhaustively
washing with 5% methanol in dichloromethane (100 mL). The
filtrate was concentrated under reduced pressure and the residue
was subjected to silica gel flash column chromatography to give
(b) A small reaction vial was charged with tert-butyl 3-(2-
hydroxy-6-methylphenyl)-3-oxopropanoate (1.7 g, 6.8 mmol) and
trifluoroacetic acid (0.9 mL). The reaction mixture was stirred
vigorously for 15 min and allowed to settle at room temperature
for 4 h. A pale yellow solid was formed which was collected on a
sintered glass funnel and washed with a mixture of light petroleum
and ether (3 : 1) to give 4-hydroxy-5-methylcoumarin. The filtrate
was concentrated a◦nd cooled to give a second crop (total 1.1 g,
◦
the title compound (0.09 g, 93%), mp 230 C (decomp) (lit.,5 mp
230–232 ◦C); (Found: M + H+, 361.0700. C21H12O6 + H+ requires
361.0707; M + Na+, 383.0537. C21H12O6 + Na+ requires 383.0526);
nmax (CHCl3)/cm-1 3689, 3604, 3043, 1755, 1644, 1603, 1239; nmax
(KBr)/cm-1 1760, 1640, 1606, 1541, 1460, 1384, 1235, 1193, 1064;
lmax (MeOH) 305 (log e 4.056) and 440 nm (log e 3.54); dH (400
MHz; CDCl3) (400 MHz; CDCl3) 11.84 (1 H, s, 11-OH), 7.66 (1
H, s, H-8), 7.58 (1 H, dd, J 8.2, 7.6, H-3), 7.38 (1 H, d, J 8.2,
H-4), 7.28 (1 H, d, J 7.6, H-2), 7.13 (1 H, s, H-10), 2.96 (3 H, s,
14-Me), 2.50 (3 H, s, 15-Me); dH (400 MHz; DMSO-d6) 11.60 (1
H, s, 11-OH), 7.66 (1 H, t, J 7.6, H-3), 7.55 (1 H, s, H-8), 7.43 (1 H,
d, J 8.0, H-2), 7.37 (1 H, dd, J 7.6, 0.8, H-4), 7.23 (1 H, s, H-10),
2.88 (3 H, s, 14-Me), 2.50 (3 H, s, 15-Me); dC (100 MHz; CDCl3)
177.6 (C), 177.3 (C), 162.84(C), 162.8 (C), 155.1 (C), 154.7 (C),
152. 9 (C), 149.4 (C), 136.0 (C), 133.2 (CH), 133.1 (CH), 127.3
(CH), 127.2 (C), 124.7 (CH), 122.5 (C), 115.4 (CH), 112.4 (C),
110.5 (C), 107.9 (C), 22.4 (Me), 21.4 (Me).
◦
92%), mp 232–234 C (lit.,13 mp 229–230 C); (Found: M + H+,
177.0547. C10H8O3 + H+ requires 177.0546);nmax (solid)/cm-1 1599,
1324, 1204, 1256, 828; dH (400 MHz; CDCl3) 12.36 (1 H, s, br, OH),
7.46 (1 H, t, J 8.0, ArH), 7.18 (1 H, d, J, 7.6, ArH), 7.10 (1 H, d,
J, 7.6, ArH), 5.56 (1 H, s, ArH), 2.67 (3 H, s, Me); dC (100 MHz;
CDCl3) 169.1 (C), 161.9 (C), 155.4 (C), 137.6 (C), 132.2 (CH),
127.6 (CH), 115.2 (CH), 114.7 (C), 91.6 (CH), 23.1 (Me).
11-Benzyloxy-1,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,7,12-trione 6
4-Hydroxy-8-methylcoumarin 10
Amixture of 8-benzyloxy-2-bromo-6-methyl-1,4-naphthoquinone
4 (0.20 g, 0.56 mmol), copper(II) acetate (0.33 g, 1.7 mmol), 4-
hydroxy-5-methyl coumarin 3 (0.12 g, 1.7 mmol) and potassium
carbonate (0.23 g, 1.7 mmol) in acetonitrile (10 mL) was heated
to reflux for 8 h with constant stirring. After 8 h the mixture was
diluted with dichloromethane (100 mL) and filtered through Celite
while exhaustively washing with dichloromethane–methanol (9 : 1)
A mixture of o-cresol (0.50 g, 4.6 mmol) and Meldrum’s acid
(0.66 g, 4.6 mmol) was heated at 110 ◦C for 3 h. After cooling to
room temperature, the acetone formed was removed under vacuum
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to give 3-oxo-3-phenoxypropanoic acid (0.89 g, 100%) as viscous
oil that was used directly for the next step.
11-Hydroxy-4,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,7,12-trione 7
To the above product 3-oxo-3-phenoxypropanoic acid (0.89 g,
4.9 mmol), Eaton’s reagent (7.7 wt% phosphorus pentoxide
solution in methanesulfonic acid (5 mL)) was added and the
reaction mixture was heated at 70 ◦C with constant stirring for
5 h. After cooling to room temperature the reaction mixture was
poured into ice-cooled water (50 mL) with vigorous stirring. The
aqueous solution was stirred for 30 min at 0 ◦C and then filtered.
The solid was washed with cold water, dried under high vacuum,
and purified by recrystallization from 20% acetone in n-pentane
gave◦pure 4-hydroxy-8-methyl-coumarin (0.85 g, 98%); mp 238–
239 C (lit.,18 mp 231.1–233.4 ◦C); (Found: C, 68.01, H, 4.57.
C10H8O3 requires C, 68.18, H, 4.58); (Found: M + H+, 177.0554.
C10H8O3 + H+ requires 177.0546; M + Na+, 199.0378. C10H8O3
+ Na+ requires 199.0366); nmax (CHCl3)/cm-1 3691, 3906, 1720,
1602, 1265, 1239; dH (400 MHz; DMSO-d6) 12.39 (1 H, s, OH),
7.63 (1 H, dd, J 0.8, 7.6, ArH), 7.46 (1 H, dd, J 0.8, 7.6, ArH),
7.19 (1 H, t, J 7.6, ArH), 5.59 (1 H, s, H-3), 2.33 (3 H, s, Me);
dC (100 MHz; DMSO-d6) 166.3 (C), 162.3 (C), 152.2 (C), 133.7
(CH), 125.6 (C), 123.9 (CH), 121.4 (CH), 115.9 (C), 91.2 (CH),
15.7 (Me).
The benzyl ether 11 (0.14 g, 0.31 mmol) was dissolved in the
ethyl acetate (10 mL) and dichloromethane (5 mL) and then
Pearlman’s catalyst (30 mg) was added. The reaction mixture was
flushed carefully with nitrogen followed by hydrogen. The reaction
mixture was stirred for 16 h under a hydrogen atmosphere. The
reaction mixture was filtered through a Celite while exhaustively
washing with 5% methanol in dichloromethane (100 mL). The
filtrate was concentrated under reduced pressure and the residue
was subjected to silica gel flash column chromatography to give the
title compound (0.10 g, 91%); mp 304–306 ◦C (decomp); (Found:
M + Na+, 383.0546. C21H12O6 + Na+ requires 383.0526); nmax
(CHCl3)/cm-1 3011, 1757, 1644, 1621, 1552, 1386, 1239, 1260,
1188, 1056, 1018; nmax (KBr)/cm-1 3442, 1754, 1643, 1550, 1459,
1384, 1292, 1184, 1054, 1015; lmax (MeOH) 295 (log e 4.25) and
300 nm (log e 4.25); dH (500 MHz; CDCl3) 11.81 (1 H, s, 11-OH),
7.96 (1 H, d, J 8.0, H-1), 7.64 (1 H, s, H-8), 7.55 (1 H, d, J 7.5,
H-3), 7.36 (1 H, t, J 7.5, H-2), 7.13 (1 H, s, H-10), 2.56 (3 H, s,
14-Me), 2.49 (3 H, s, 15-Me); dH (400 MHz; DMSO-d6) 11.65 (1
H, s, 11-OH), 7.98 (1 H, d, J 7.2, H-1), 7.69 (1 H, d, J 7.2, H-3),
7.51 (1 H, s, H-8), 7.45 (1 H, t, J 7.6, H-2), 7.24 (1 H, s, H-10), 2.51
(3 H, s, 14-Me), 2.48 (3 H, s, 15-Me); dC (125 MHz; CDCl3) 177.8
(C), 177.4 (C), 162.9 (C), 162.3 (C), 154.6 (C), 153.0 (C), 152.8
(C), 149.4 (C), 135.0 (CH), 133.0 (C), 127.7 (C), 127.5 (C), 124.8
(2 ¥ CH), 122.6 (CH), 119.9 (CH), 112.4 (C), 110.8 (C), 107.6 (C),
22.4 (Me), 16.1 (Me).
11-Benzyloxy-4,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,7,12-trione 11
2-Bromo-5-hydroxy-7-methyl-1,4-naphthoquinone 12
Amixture of 8-benzyloxy-2-bromo-6-methyl-1,4-naphthoquinone
4 (0.10 g, 0.28 mmol), copper(II) acetate monohydrate (0.17 g,
0.84 mmol), 4-hydroxy-8-methyl coumarin 10 (0.06 g, 0.34 mmol)
and potassium carbonate (0.12 g, 0.84 mmol) in acetonitrile
(10 mL) was heated under reflux for 8 h with constant stir-
ring. The reaction mixture was diluted with dichloromethane
(100 mL) and filtered through Celite with exhaustive washing
by dichloromethane: methanol (9 : 1) (100 mL). The filtrate was
concentrated under reduced pressure and the residue was purified
by flash column chromatography to give the title compound (0.06 g,
To a solution of 2,5-dibromobenzoquinone24 (0.20 g, 0.75 mmol)
in toluene (10 mL) was added dropwise 1-methoxy-3-methyl-1-
trimethylsilyloxy-1,3-butadiene (0.21 g, 1.13 mmol) with constant
◦
◦
stirring at 0 C. After being stirred for 1 h at 0 C, the reaction
mixture was allowed to warm to room temperature and stirred
for another 7 h, and then poured onto silica gel (50 g) in
dichloromethane (100 mL). The suspension was stirred for 24 h
at room temperature. After removing the solvent under reduced
pressure the silica gel was eluted with dichloromethane and
methanol (10 : 1). The organic layer was concentrated in vacuo. The
residue was subjected to silica gel flash column chromatography in
10% ethyl acetate and light petroleum to give 2-bromo-5-hydroxy-
7-methyl-1,4-n◦aphthoquinone (0.09 g, 45%); mp 114–116 ◦C (lit.,19
mp 132–133.5 C); (Found: M - H+, 264.9493. C11H779BrO3 - H+
requires 264.9506); nmax (CHCl3)/cm-1 3009, 1678, 1639, 1584,
1373, 1312, 1257; dH (400 MHz; CDCl3) 11.73 (1 H, s, ArOH),
7.56 (1 H, d, J 1.6, ArH), 7.48 (1 H, s, H-3), 7.12 (1 H, d, J 1.6,
◦
50%); mp 236–238 C; (Found: M + Na+, 473.0998. C28H18O6 +
Na+ requires 473.0996; M + H+, 451.1187. C28H18O6 + H+ requires
451.1176); nmax (CHCl3)/cm-1 3690, 3008, 1751, 1664, 1600, 1529,
1295, 1021; lmax (MeOH) 298 (log e 4.07) and 404 nm (log e 4.53);
dH (400 MHz; CDCl3) 7.98 (1 H, d, J 7.2, ArH), 7.78 (1 H, s,
ArH), 7.68 (2 H, d, J 7.2, ArH), 7.53 (1 H, d, 7.2, ArH), 7.45 (2 H,
t, J 7.2, ArH), 7.35 (2 H, t, J 7.6, ArH), 7.24 (1 H, s, ArH), 5.34
(2 H, s, CH2), 2.56 (3 H, s, Me), 2.53 (3 H, s, Me); dC (100 MHz;
CDCl3) 178.1 (C), 172.7 (C), 161.6 (C), 159.9 (C), 155.0 (C), 154.4
(C), 152.6 (C), 147.5 (C), 135.9 (C), 135.6 (C), 134.6 (CH), 128.7
(CH), 127.9 (CH), 127.3 (C), 126.6 (CH), 124.9 (C), 124.6 (CH),
122.0 (CH), 120.2 (CH), 119.9 (CH), 117.2 (C), 112.5 (C), 111.0
(C), 70.9 (CH2), 22.5 (Me), 16.1 (Me).
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ArH), 2.47 (3 H, s, Me); dC (100 MHz; CDCl3) 186.9 (C), 177.5
(C), 161.9 (C), 148.5 (C), 140.5 (C), 140.4 (CH), 130.4 (C), 124.8
(CH), 122.4 (CH), 112.7 (C), 22.2 (Me).
(2 H, m, ArH), 7.25 (1 H, d, J 7.6, ArH), 7.21 (1 H, s, ArH), 5.36
(2 H, s, CH2), 2.96 (3 H, s, Me), 2.48 (3 H, s, Me); dC (100 MHz;
CDCl3) 176.8 (C), 173.5 (C), 162.7 (C), 159.9 (C), 155.1 (C), 154.7
(C), 151.8 (C), 146.3 (C), 136.1 (C), 136.0 (C), 133.9 (C), 132.8
(CH), 128.8 (CH), 128.3 (C), 128.0 (CH), 127.1 (CH), 126.9 (CH),
121.4 (CH), 120.7 (CH), 119.0 (C), 115.2 (CH), 110.7 (C), 108.1
(C), 71.0 (CH2), 22.2 (Me), 21.5 (Me).
5-Benzyloxy-2-bromo-7-methyl-1,4-naphthoquinone 13
8-Hydroxy-1,10-dimethyl-12H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,11,12-trione 8
Benzyl bromide (0.08 mL, 0.7 mmol), was added to a mixture
of 2-bromo-5-hydroxy-7-methyl-1,4-naphthoquinone (0.090 g,
0.34 mmol), and silver(I) oxide (0.23 g, 1.0 mmol) in
dichloromethane (5 mL) and the resulting suspension was stirred
for 48 h at room temperature. Then, additional silver(I) oxide
(0.076 g, 0.34 mmol) and benzyl bromide (0.04 mL, 0.34 mmol),
were added and stirring was continued for another 24 h. The
mixture was filtered through a plug of Celite and rinsed with
dichloromethane. After removal of the solvent under reduced
pressure, the residue was subjected to silica gel flash column
chromatography in 20% ethyl acetate and light petroleum to give
5-benzyloxy-2-bromo-6-methyl-1,4-naphthoquinone (90 mg, 75%);
The benzyl ether 14 (0.19 g, 0.42 mmol) was dissolved in the ethyl
acetate (20 mL) and methanol (5 mL) and then Pearlman’s catalyst
(20 mg) was added. The reaction mixture was flushed with nitrogen
followed by hydrogen. The reaction mixture was stirred for 16 h
under a hydrogen atmosphere. The reaction mixture was filtered
through a Celite pad while exhaustively washing with 5% methanol
in dichloromethane (100 mL). The filtrate was concentrated under
reduced pressure, and the residue was subjected to the silica gel
flash column chromatography to give the title compound (0.14 g,
93%); mp 300 ◦C (decomp); (Found: M + H+, 361.0724. C21H12O6
+ H+ requires 361.0707; M + Na+, 383.0523. C21H12O6 + Na+
requires 383.0526); nmax (CHCl3)/cm-1 3689, 3608, 3006, 1754,
1677, 1602, 1543, 1386, 1267, 1074; nmax (KBr)/cm-1 3440, 1772,
1675, 1638, 1604, 1541, 1384, 1267, 1079; lmax 202 (log e 4.27) and
305 nm (log e 4.092), dH (400 MHz; CDCl3) 12.29 (1 H, s, 8-OH),
7.67 (1 H, s, H-11), 7.59 (1 H, dd, J 8.2, 7.8, H-3), 7.40 (1 H, d, J
8.2, H-4), 7.28 (1 H, d, J 7.8, H-2), 7.18 (1 H, s, H-9), 2.97 (3 H, s,
14-Me), 2.51 (3 H, s, 15-Me); dH (400 MHz; DMSO-d6) 12.02 (1
H, s, 8-OH), 7.66 (1 H, t, J 8.0, H-3), 7.57 (1 H, s, H-11), 7.43 (1
H, d, J 8.0, H-4), 7.37 (1 H, d, J 7.6, H-2), 7.24 (1 H, s, H-9), 2.88
(3 H, s, 14-Me), 2.50 (3 H, s, 15-Me); dC (125 MHz; CDCl3) 183.7
(C), 172.8 (C), 163.1 (C), 162.8 (C), 155.1 (C), 154.8 (C), 153.3 (C),
148.6 (C), 136.1 (C), 133.1 (CH), 131.7 (CH), 127.3 (CH), 126.6
(C), 125.8 (CH), 121.6 (C), 115.3 (CH), 113.3 (C), 110.5 (C), 107.6
(C), 22.1 (Me), 21.5 (Me
◦
mp 131–133 C; (Found: C, 61.12; H, 3.79. C18H13BrO3 requires
C, 61.03, H, 3.70); (Found: M + H+, 356.0037. C18H1379BrO3 +
H+ requires 356.0048); nmax (CHCl3)/cm-1 3008, 1678, 1654, 1603,
1252, 1063, 899; lmax (MeOH) 212 (log e 4.53) and 250 nm (log e
4.016); dH (400 MHz; CDCl3) 7.65 (1 H, s, ArH), 7.60 (2 H, d, J
7.2, ArH), 7.44 (2 H, dd, J 7.2, 7.7, ArH), 7.38 (1 H, s, ArH), 7.36
(1 H, d, J 7.2, ArH), 7.18 (1 H, s, ArH), 5.29 (2 H, s, CH2), 2.47 (3
H, s, Me); dC (100 MHz; CDCl3) 181.0 (C), 178.5 (C), 159.0 (C),
146.5 (C), 142.4 (CH), 136.6 (C), 135.9 (C), 132.8 (C), 128.7 (CH),
128.0 (CH), 126.6 (CH), 121.8 (CH), 120.5 (CH), 117.6 (C), 70.9
(CH2), 22.3 (Me).
8-Benzyloxy-1,10-dimethyl-12H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,11,12-trione 14
8-Benzyloxy-4,10-dimethyl-12H-naphtho[2¢,3¢:4,5]furo[3,2-
c]chromene-6,11,12-trione 15
Amixture of 5-benzyloxy-2-bromo-7-methyl-1,4-naphthoquinone
13 (0.20 g, 0.56 mmol), copper(II) acetate (0.33 g, 1.7 mmol),
4-hydroxy-5-methylcoumarin 3 (0.12 g, 1.7 mmol) and potas-
sium carbonate (0.23 g, 1.7 mmol) acetonitrile was stirred at
room temperature for 2 h. After 2 h the mixture was diluted
with dichloromethane (100 mL) and filtered through Celite
while exhaustively washing with dichloromethane–methanol (9 : 1)
(100 mL). The filtrate was concentrated under reduced pressure
and the residue was purified by flash column chromatography to
give the title compound (0.21 g, 86%); mp 266–268 ◦C; (Found:
C, 74.74, H, 4.15. C28H18O6 requires C, 74.66, H, 4.03); (Found:
M + Na+, 473.0996. C28H18O6 + Na+ requires 473.0996); nmax
(CHCl3)/cm-1 3051, 1758, 1678, 1600, 1454, 1362, 1296, 1265,
1063; lmax (MeOH) 201 (log e 4.17) and 305 nm (log e 3.90); dH
(400 MHz; CDCl3) 7.74 (1 H, s, ArH), 7.63 (2 H, d, J 7.6, ArH),
7.56 (1 H, dd, J 8.2, 7.7, ArH), 7.45 (2 H, dd, 7.2, 7.7, ArH), 7.37
Amixture of 5-benzyloxy-2-bromo-7-methyl-1,4-naphthoquinone
13 (0.10 g, 0.28 mmol), copper(II) acetate monohydrate (0.17 g,
0.84 mmol), 4-hydroxy-8-methyl coumarin 10 (0.06 g, 0.34 mmol)
and potassium carbonate (0.12 g, 0.84 mmol) in acetonitrile
(10 mL) was stirred at room temperature under nitrogen atmo-
sphere. After 2 h the mixture was diluted with dichloromethane
(100 mL) and filtered through Celite while exhaustively washing
with dichloromethane: methanol (9 : 1) (100 mL). The filtrate
3492 | Org. Biomol. Chem., 2011, 9, 3484–3493
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was concentrated under reduced pressure and the residue was
purified by flash column chromatography (30% ethyl acetate in
light petroleum) to give the title compound (0.11 g, 87%); mp 260–
262 ◦C; (Found: C, 74.30; H, 3.89. C28H18O6 requires C, 74.66,
H, 4.03); (Found: M + Na+, 473.0999. C28H18O6 + Na+ requires
473.0996); nmax (CHCl3)/cm-1 1764, 1677, 1621, 1599, 1558, 1296,
1250, 1023; lmax (MeOH) 300 (log e 4.20) and 390 nm (log e 3.76);
dH (400 MHz; CDCl3) 7.96 (1 H, d, J 7.6, ArH), 7.74 (1 H, s, ArH),
7.62 (2 H, d, J 7.2, ArH), 7.53 (1 H, d, 7.2, ArH), 7.44 (2 H, dd, J
7.6, 7.2, ArH), 7.37–7.32 (2 H, m, ArH), 7.20 (1 H, s, ArH), 5.36
(2 H, s, CH2), 2.57 (3 H, s, Me), 2.47 (3 H, s, Me); dC (100 MHz;
CDCl3) 176.8 (C), 173.7 (C), 162.1 (C), 159.1 (C), 154.5 (C), 152.8
(C), 151.8 (C), 146.3 (C), 136.1 (C), 134.8 (CH), 133.8 (C), 128.8
(C), 128.7 (CH), 128.0 (CH), 127.3 (C), 126.9 (CH), 124.6 (CH),
121.5 (CH), 120.8 (CH), 119.9 (CH), 118.9 (C), 111.0 (C), 107.8
(C), 71.0 (CH2), 22.2 (Me), 16.1 (Me).
(1 H, d, J 7.6, H-3), 7.57 (1 H, s, H-11), 7.47 (1 H, t, J 7.6, H-2),
7.28 (1 H, s, H-9), 2.51 (3 H, s, 14-Me), 2.48 (3 H, s, 15-Me); dC
(125 MHz; CDCl3) 183.7 (C), 173.1 (C), 163.1 (C), 162.3 (C), 154.7
(C), 153.3 (C), 152.8 (C), 148.6 (C), 135.1 (CH), 131.6 (C), 127.5
(C), 127.2 (C), 125.9 (CH), 124.8 (C), 121.6 (CH), 119.9 (CH),
113.2 (C), 110.8 (C), 107.3 (C), 22.1 (Me), 16.1 (Me).
Acknowledgements
We thank Dr Martyn Inman for helpful discussions, and the
University of Nottingham for support of this work.
References
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c]chromene-6,11,12-trione 9
Chapman and Hall, 1987.
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The benzyl ether 15 (0.20 g, 0.44 mmol) was dissolved in the
ethyl acetate (15 mL) and dichloromethane (5 mL) and then
Pearlman’s catalyst (40 mg) was added. The reaction mixture was
flushed with nitrogen followed by hydrogen. The reaction mixture
was stirred for 16 h under hydrogen atmosphere. The reaction
mixture was filtered through Celite while exhaustively washing
with 5% methanol in dichloromethane (100 mL). The filtrate
was concentrated under reduced pressure and the residue was
subjected to silica gel flash column chromatography to give the title
compound (0.15 g, 94%) mp 310 ◦C (decomp); (Found: M + H+,
361.0688. C21H12O6 + H+ requires 361.0707; M + Na+, 383.0515.
C21H12O6 + Na+ requires 383.0526); nmax (CHCl3)/cm-1 3692, 3044,
2337, 1752, 1676, 1642, 1553, 1260, 1071; nmax (KBr)/cm-1 3441,
1753, 1675, 1638, 1551, 1501, 1384, 1258, 1183, 1071; lmax (MeOH)
295 (log e 4.25) and 302 nm (log e 4.27); dH (500 MHz; CDCl3)
12.25 (1 H, s, 8-OH), 7.97 (1 H, d, J 8.0, H-1), 7.65 (1 H, s, H-11),
7.55 (1 H, d, J 7.0, H-3), 7.36 (1 H, t, J 7.5, H-2), 7.16 (1 H, s,
H-9), 2.57 (3 H, s, 14-Me), 2.48 (3 H, s, 15-Me); dH (400 MHz;
DMSO-d6) 12.06 (1 H, s, 8-OH), 8.00 (1 H, d, J 7.2, H-1), 7.73
23 F. M. Hauser and S. A. Pogany, Synthesis, 1980, 814.
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The Royal Society of Chemistry 2011
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©