Synthesis of some 3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-6-one derivatives

Article abstract of DOI:10.1039/b202640f

Reactions of o-quinones 16-18 with ylide 19 afforded compounds 5-7 in moderate to good yields (62-80%), which were further de-ethoxycarbonylated to compounds 28-30 in 53-66% yield. Compounds 6, 7 and 29 were further transformed into compounds 31-35. The preparation of the novel compounds 10, 11, 16 and 27 is also reported.

Full text of DOI:10.1039/b202640f

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Synthesis of some 3,4-dihydro-2H-benzo[f ]pyrano[2,3-h]chromen-
6-one derivatives
Demetrios N. Nicolaides,* Daman R. Gautam, Konstantinos E. Litinas and
Theodora Papamehael
1
Laboratory of Organic Chemistry, Department of Chemistry,
Aristotle University of Thessaloniki, Thessaloniki 54006, Greece
Received (in Cambridge, UK) 15th March 2002, Accepted 29th April 2002
First published as an Advance Article on the web 20th May 2002
Reactions of o-quinones 16–18 with ylide 19 afforded compounds 5–7 in moderate to good yields (62–80%), which
were further de-ethoxycarbonylated to compounds 28–30 in 53–66% yield. Compounds 6, 7 and 29 were further
transformed into compounds 31–35. The preparation of the novel compounds 10, 11, 16 and 27 is also reported.
Introduction
It is well known that calophyllum coumarins, such as the
calanolides1 1 and 2 and the inophyllums2 3,4 have attracted
considerable attention as potent inhibitors of human immune
deficiency virus-1 (HIV-1) reverse transcriptase (RT) and sev-
eral synthetic methods have been reported3–9 for their prepar-
ation as well as for the preparation of compounds modified in
their D ring . Our continuing interest in the synthesis of
coumarin derivatives through the reaction of the appropriate
o-quinone with alkoxycarbonylmethylene(triphenyl)phosphor-
anes10–13 prompted us to try the synthesis of compounds 6–8.
We therefore studied the reactions of ethoxycarbonylmethylene-
(triphenyl)phosphorane 19 with the known 2,2-dimethyl-3,4-
dihydro-2H-benzo[h]chromene-5,6-dione (β-lapachone)14 17
and 2-methyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione15 18
and the unknown 2,2,9,9-tetramethyl-2,3,4,7,8,9-hexahydro-
pyrano[3,2-h]chromene-5,6-dione 13 respectively, since the
A–C–B ring skeleton of the target compounds 6–8 can be
considered as similar enough to that of the biologically active
calophyllum coumarins.
Results and discussion
o-Quinones 17 and 18 were prepared according to the literature
starting from 2-hydroxy-1,4-naphthoquinone (Lausone).14,15
The synthesis of the unknown o-quinone 13 was attempted by
applying the method used for the preparation of o-quinone 17
(Scheme 1).
Treatment of 2,5-dihydroxy-1,4-benzoquinone 9 with lithium
hydride, lithium iodide and two equivalents of 4-bromo-2-
methylbut-2-ene afforded 2,5-dihydroxy-3,6-bis(3-methylbut-2-
enyl)-1,4-benzoquinone 10 in 30% yield (based on the quinone
9 consumed). When compound 10 was then treated with
concentrated sulfuric acid 2,2,7,7-tetramethyl-3,4,8,9-tetra-
hydropyrano[2,3-g]chromene-5(2H ),10(7H )-dione 11 and the
unexpected 2,2,9-trimethyl-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione 16 were obtained in 45% and 16% yield, respectively.
The expected o-quinone 13 was not detected or separated from
this reaction mixture. The analytical and spectral data of the
major product resembled that of symmetrical isomers 11 and
13. Reaction of this major product with ylide 19 gave a com-
pound whose mass and spectral data matched that of com-
pound 27 (Scheme 3). Thus the major product was identified as
NMR spectrum and the 13C NMR spectrum (three methyl
groups, aromatic protons and carbons) of the minor product
accord14 well with the structure 16 suggested for it.
Compound 11 is obviously formed by the predominant direct
bis-cyclization of compound 10 (Scheme 1). Although a bis-
cyclization of the expected tautomeric o-quinone 12 could also
give the desired o-quinone 13 (route a), it can be considered
that, instead of that transformation, a mono-cyclization of
12 takes place initially (route b), accompanied by air oxidation
to the intermediate 14, which by further cyclization to the
1
compound 11. The recorded mass spectrum (m/z 256), the H
DOI: 10.1039/b202640f
J. Chem. Soc., Perkin Trans. 1, 2002, 1455–1460
This journal is © The Royal Society of Chemistry 2002
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Scheme 2
Scheme 1 Reagents and conditions: i, dry DMSO, LiH, Ϫ78 ЊC: ii, LiI,
; iii, conc. H2SO4, 25 ЊC; iv, ice–water; v, air oxidation.
The formation of compounds 5–7 and 22 can be explained by
the mechanism suggested10,11,13 for the formation of similar
compounds from reactions of other o-quinones with ylide
19. Wittig mono-olefination of the C-6 carbonyl of o-quinones
16–18 followed by Michael addition of a second ylide species to
the o-quinone methanides 20a–c, initially formed, accompanied
by Hoffmann elimination of triphenylphosphine give the
intermediate 21a–c. δ-Lactonization of the latter can afford
products 5–7, while γ-lactonization of 21c can lead to the
formation of product 22 obtained (Scheme 2). Initial Wittig
mono-olefination of the 5-carbonyl of quinones used can
also lead, via a similar reaction sequence, to the formation of
products 23a–c and 24, isomeric to 5–7 and 22, respectively.
Evidence in favour of structures 5–7 for the products in
question is their strong fluorescence, a property characteristic
of coumarins substituted with an alkoxy substituent16 at the
7-position and not at the 6-position of their skeleton. The sug-
gested structure 6 was further supported by NOE experiments
on its derivative 29 (see Scheme 4), as we will see in the follow-
ing. The analytical and spectral data of the products obtained
intermediate 15 and dehydration of the latter can afford the
o-quinone 16, obtained from the reaction (Scheme 1).
Our unsuccessful attempts to synthesize o-quinone 13 did not
allow us to synthesize 8. However having quinones 16–18
on hand did allow us to synthesize the desired coumarins 5–7
(Scheme 2).
Treatment of quinone 16 with ylide 19 (2 equivalents) in dry
DCM under reflux for 5 h and separation of the reaction
mixture by column chromatography gave ethyl 2,2,11-trimethyl-
6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano[2,3-h]chromene-8-
carboxylate 5 in 80% yield. By a similar treatment of quinone
17 with ylide 19 ethyl 2,2-dimethyl-6-oxo-3,4-dihydro-2H,6H-
benzo[f]pyrano[2,3-h]chromene-8-carboxylate 6 was obtained
in 66% yield. In contrast to these reactions treatment of
quinone 18 with ylide 19, under similar conditions, resulted
in ethyl 2-methyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano-
[2,3-h]chromene-8-carboxylate 7 (62%) accompanied by ethyl
2-[2-methyl-6-oxo-3,4,6,7-tetrahydro-2H-benzo[h]furo[2,3-f]-
chromen-7-ylidene]acetate 22 in 6% yield.
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are consistent with the structures suggested for them. The
coumarin derivatives 5–7 exhibited absorptions at 1725–1720
and 1710–1680 cmϪ1 in their IR spectra and a singlet at δ 6.33–
1
6.39 in their H NMR spectra for the 7-H (3-H of pyranone
ring), in contrast to the IR and 1H NMR spectra of compound
22, which exhibited an absorption at 1780 cmϪ1, characteristic
of a five-membered lactone carbonyl10 and a singlet at δ 7.01.
When quinone 11 was treated with ylide 19 under the
conditions described above no reaction was observed, even
under refluxing in ethyl acetate or toluene, as indicated by TLC
examination after prolonged heating. When the mixture was
then heated without solvent at ∼150 ЊC (melted) for 1 h, diethyl
2-(10-hydroxy-2,2,7,7-tetramethyl-2,3,4,7,8,9-
hexahydropyrano[2,3-g]chromen-5-yl)but-2-enedioate 27 was
obtained in 69% yield, via the intermediates 25, 26 (Scheme
3).17,18 The stability of the product in question, under the con-
Scheme 3
ditions applied for its preparation is strong evidence that the
hydroxy group of this product is well separated from the ester
groups, in agreement with the product expected17,18 from the
p-quinone 11, since the formation of an o-hydroxy butenedioate
intermediate, similar to 21, from the isomeric o-quinone 13
ought to undergo a δ-, and/or γ-lactonization.
Scheme 4 Reagents and conditions: i, Cu, dry quinoline, 190–235 ЊC,
4–14 h; ii, NBS, CCl4, (C6H5CO)2O2, reflux.
De-ethoxycarbonylation of compounds 5–7 with copper
powder in dry quinoline at 190–235 ЊC for 4–14 h gave 2,2,11-
trimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-6-one
28 (61%), 2,2-dimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-
h]chromen-6-one 29 (59–66%, three attempts) and 2-methyl-
3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-6-one 30 (53%),
respectively (Scheme 4). NOE experiments on the de-ethoxy-
carbonylation product of compound 6 showed an interaction
between 8-H (8.41 ppm) and 9-H (8.13 ppm, 13.5%) and
between 4-H (3.02 ppm) and 3-H (1.97 ppm, 7%) in agreement
with structure 29 suggested for it. This proves beyond any
doubt the identity of the structures 5–7 and 22.
Treatment of compound 6 with NBS and a catalytic amount
of benzoyl peroxide in refluxing carbon tetrachloride for 6 h
and separation of the reaction mixture by column chromato-
graphy gave ethyl 2,2-dimethyl-6-oxo-2H,6H-benzo[f]pyrano-
[2,3-h]chromene-8-carboxylate31andethyl3-bromo-4-hydroxy-
2,2-dimethyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano[2,3-h]-
chromene-8-carboxylate 32 in 23% and 64% yield, respectively.
By a similar treatment of compound 7 with NBS ethyl
4-hydroxy-2-methyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano-
[2,3-h]chromene-8-carboxylate 33 was obtained in 67% yield.
The analytical and spectral data of the products in question
accord well the structures suggested for them. The recorded 1H
NMR spectrum of compound 32 exhibited two doublets at
δ 4.27 (1H, d, J = 4.6 Hz, exchangeable with D2O) and 4.41 (1H,
d, J = 4.6 Hz) and a triplet at δ 5.50 (1H, t, J = 4.6 Hz) indicative
of the –OH and the two protons of the pyran ring, with the
hydroxy and bromo substituents in aa, ae or ea positions. The
1
recorded H NMR spectrum of product 33 exhibited absorp-
tions at δ 1.85 (1H, ddd, J = 3.8, 3.8, 14.0 Hz), 2.26 (1H, d,
J = 14.0 Hz), 3.15 (br s, 1H), 4.62 (1H, dq, J = 3.8, 6.4 Hz) and
5.32 (1H, d, J = 3.8 Hz) for the –OH and the pyran protons, in
agreement with the structure 33 suggested for it.
J. Chem. Soc., Perkin Trans. 1, 2002, 1455–1460
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Obviously, compound 31 is formed via an initial benzylic
bromination of 6, followed by dehydrobromination, while com-
pound 32 can be formed by further addition of hypobromous
acid (HOBr) formed in situ from the NBS and H2O,19 to com-
pound 31, with the –OH group being introduced into the
4-position, due to the more stable benzylic carbonium inter-
mediate formed after the addition of the Brϩ. When, in a con-
trol experiment, compound 31 was treated with NBS under the
conditions applied for the reaction of the latter with compound
6, compound 32 was obtained in 63% yield. The formation of
compound 33 can be explained by assuming a further substi-
tution of the bromine of the 4-bromo derivative, initially
formed, by the hydroxy group.
sodium bicarbonate solution (4 × 100 cm3). The combined
aqueous layers were acidified accurately to pH = 2, by addition
of concentrated hydrochloric acid and the unreacted quinone 9
was precipitated (3.2 g, 22.84 mmol, 32%). The organic extracts
were concentrated on a rotary evaporator, ether (250 cm3) was
added to the residue, the mixture was filtered and the filtrate
was washed with 2 M sodium hydroxide solution (3 × 150 cm3).
The combined alkaline extractions were then acidified accur-
ately to pH = 2 by addition of concentrated hydrochloric acid
and cooled in an ice–water bath to give a precipitate of com-
pound 10 (3.965 g, 14.38 mmol, 20%), mp 176–178 ЊC (from
ethanol) (Found: C, 69.8; H, 7.1. C16H20O4 requires C, 69.5;
H, 7.3%); νmax/cmϪ1 3305, 1610; δH 1.68 (s, 6H), 1.73 (s, 6H),
3.11 (d, 4H, J = 7.6), 5.13 (t, 2H, J = 7.6), 7.61 (s, 2H, –OH,
exchanged with D2O); δC 17.7, 21.5, 25.7, 102.2, 119.4, 133.7,
149.3, 175.1; EI MS: m/z 276 (Mϩ, 65%), 261 (68), 220 (100),
205 (40), 55 (70); ESI MS: m/z 277 [M ϩ H]ϩ, 275 [M Ϫ H]ϩ.
Treatment of compound 29 with NBS, under the same
conditions, gave 7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo-
[f]pyrano[2,3-h]chromen-6-one 34 and 3-bromo-4-hydroxy-2,2-
dimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-6-one
35, in 30% and 12% yield, respectively. The 1H NMR spectrum
of compound 35 is very similar to that of compound 32, with
two absorptions at δ 4.41 (1H, d, J = 5.1 Hz) and 5.52 (1H, d,
Transformation of compound 10 to 2,2,7,7-tetramethyl-3,4,8,9-
tetrahydropyrano[2,3-g]chromene-5(2H),10(7H)-dione 11 and
2,2,9-trimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione 16
1
J = 5.1 Hz). The H NMR of the major product showed a
singlet at δ 8.73 for its 8-H and two triplets at δ 3.00 (2H, t, J =
6.8 Hz) and 1.97 (2H, t, J = 6.8 Hz) without any absorption for
7-H at δ ∼ 6.4, in agreement with the structure 34 suggested for
it. A similar bromination of the 3-position of the coumarin
skeleton has also been reported in the case of the treatment of
coumarin with NBS.20
In conclusion, the title compounds can be easily prepared
in moderate to good yields, starting from the appropriate
o-quinones, by using the reactions depicted in Schemes 2 and 4,
and can further transformed into other derivatives modified in
their pyran ring.
A mixture of quinone 10 (0.82 g, 2.97 mmol) in concentrated
sulfuric acid (6 cm3) was stirred at 25 ЊC for 1 h and then poured
into an ice–water mixture (100 g). The yellow precipitate
formed was filtered off, washed with water, dried and recrystal-
lized from ethanol to give compound 11 (0.24 g). The filtrate
was concentrated and the residue was separated by column
chromatography (DCM) to give an additional amount of com-
pound 11 (0.132 g, total amount 0.372 g, 45%), mp 246–247 ЊC
(sealed tube) (from ethanol); νmax/cmϪ1 1635, 1590; δH 1.38 (s,
12H), 1.73 (t, 4H, J = 6.6), 2.42 (t, 4H, J = 6.6); δC 15.9, 26.4,
31.5, 78.2, 114.5, 152.9 181.3; ESI MS: m/z 277 [M ϩ H]ϩ, 299
[M ϩ Na]ϩ; MALDI HRMS (DHB): m/z 277.1424 [M ϩ H]ϩ.
C16H21O4 requires m/z 277.1434.
Compound 16 was eluted next (0.122 g, 16%), mp 172–174 ЊC
(from ethanol); νmax/cmϪ1 1680, 1630,1565; δH 1.47 (s, 6H), 1.85
(t, 2H, J = 6.4), 2.46 (s, 3H), 2.56 (t, 2H, J = 6.4), 7.29 (d, 1H,
J = 7.6), 7.59 (s, 1H), 7.95 (d, 1H, J = 7.6); δC 16.2, 22.1, 26.7,
31.7, 79.1, 112.6, 124.6, 127.9, 128.9, 131.2, 132.6, 146.0, 162.0,
174.4, 178.9; ESI MS: m/z 257 [M ϩ H]ϩ, 255 [M Ϫ H]ϩ, 279
[M ϩ Na]ϩ; MALDI HRMS (DHB): m/z 257.1176 [M ϩ H]ϩ.
C16H17O3 requires m/z 257.1172.
Experimental
Mps were determined on a Kofler hot-stage apparatus and are
uncorrected. IR spectra were obtained with a Perkin–Elmer
1310 spectrophotometer as Nujol mulls. NMR spectra were
1
recorded on a Bruker AM 300 (300 MHz and 75 MHz for H
and 13C respectively, using CDCl3 as the solvent and TMS as an
internal standard. J values are reported in Hz. Mass spectra
were determined on a VG-250 spectrometer at 70 eV under
electron impact (EI) conditions, or on a Perkin Elmer API 100
Sciex Simple Quadrupole under electronspray ionization (ESI)
conditions. High resolution mass spectra (HRMS) were
recorded on an Ionspec mass spectrometer under matrix-
assisted laser desorption-ionization Fourier transform mass
spectrometer (MALDI-FTMS) conditions with 2,5-dihydroxy-
benzoic acid (DHB) as the matrix. Microanalyses were deter-
mined on a Perkin–Elmer 2400-II Element analyser. Silica gel
No. 60, Merck AG was used for column chromatography.
Compounds 1714 and 1815 were prepared according to the
literature.
Ethyl 2,2,11-trimethyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]-
pyrano[2,3-h]chromene-8-carboxylate 5
A solution of quinone 16 (59 mg, 0.23 mmol) and ylide 19
(77 mg, 0.51 mmol) in dry DCM (5 cm3) was refluxed for 5 h and
the solvent was removed on a rotary evaporator. Separation of
the residue by column chromatography (hexane–ethyl acetate
10 : 1) gave compound 5 (67 mg, 80%), mp 161–163 ЊC (ether–
hexane); νmax/cmϪ1 3050, 1725, 1680, 1578; δH 1.40 (t, 3H, J =
7.6), 1.48 (s, 6H), 1.96 (t, 2H, J = 6.4), 2.53 (s, 3H), 2.99 (t, 2H,
J = 6.4), 4.52 (q, 2H, J = 7.6), 6.33 (s, 1H, 7-H), 7.36 (d, 1H, J =
8.9), 7.65 (d, 1H, J = 8.9), 8.07 (s, 1H); δC 13.8, 17.1, 21.4, 26.6,
31.6, 62.7, 76.5, 103.1, 105.9, 110.3, 121.9, 123.0, 123.7, 125.2,
129.5, 135.0, 146.7, 153.9, 154.7, 160.4, 167.9; ESI MS: m/z 367
[M ϩ H]ϩ, 365 [M Ϫ H]ϩ, 389 [M ϩ Na]ϩ; MALDI HRMS
(DHB): m/z 367.1528 [M ϩ H]ϩ. C22H23O5 requires 367.1540.
2,5-Dihydroxy-3,6-bis(3-methylbut-2-enyl)-1,4-benzoquinone 10
Lithium hydride (1.192 g, 144.9 mmol) was added to a stirred
solution of 2,5-dihydroxy-1,4-benzoquinone 9 (10.0 g, 71.38
mmol) in dry DMSO (83 cm3) at Ϫ78 ЊC and the mixture was
heated gradually up to 25 ЊC. When the hydrogen gas evolution
ceased, anhydrous lithium iodide (4.777 g, 35.7 mmol) was
added, followed by 3,3-dimethylallyl bromide (21.276 g,
16.45 cm3, 142.76 mmol). The mixture was then heated at 45 ЊC
for 7 h and left at 25 ЊC for 15 h. A mixture of ice (95 g) and
water (35 cm3) was then added and the initial red colour was
discharged within 5 min. The mixture was treated with concen-
trated hydrochloric acid (35 cm3) and then stirred with ethyl
acetate (240 cm3) for 5 min. The organic layer was separated
and the aqueous layer extracted with ethyl acetate (3 × 200
cm3). The combined organic extracts were washed with 5%
Ethyl 2,2-dimethyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano-
[2,3-h]chromene-8-carboxylate 6
A. A solution of β-lapachone 17 (0.478 g, 1.975 mmol) and
ylide 19 (2.062 g, 5.93 mmol) in dry DCM (25 cm3) was heated
under reflux for 1 h, until the quinone was consumed. The sol-
vent was evaporated off on a rotary evaporator and the residue
was separated by column chromatography (hexane–ethyl
acetate 10 : 1) to give, after the elution of triphenylphosphine
(0.367 g, 71%), compound 6 (0.459 g, 66%).
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B. A solution of 17 (0.484 g, 2 mmol) and ylide 19 (1.462 g,
4.20 mmol) in dry DCM (15 cm3) was stirred at room temper-
ature for 14 h to give compound 6 (0.367 g, 53%), mp 137–138
ЊC (ether–hexane) (Found: C, 71.4; H, 5.7. C21H20O5 requires C,
71.6; H, 5.7%); νmax/cmϪ1 1725, 1710, 1690; δH 1.40 (t, 3H, J =
7.6), 1.47 (s, 6H), 1.96 (t, 2H, J = 6.4), 3.00 (t, 2H, J = 6.4), 4.52
(q, 2H, J = 7.6), 6.36 (s, 1H, 7-H), 7.46–7.56 (m, 2H), 7.76 (d,
1H, J = 7.6), 8.31 (d, 1H, J = 7.6); δC 13.9, 17.1, 26.6, 31.5, 62.7,
103.1, 105.9, 110.4, 122.7, 123.1, 123.6, 125.1, 127.2, 127.6,
146.7, 154.3, 155.2, 160.3, 167.9; EI MS: m/z 352 (Mϩ, 100%),
297 (33), 296 (58), 268 (61), 240 (20), 223 (18), 167 (20), 139
(26).
mmol) in dry quinoline (10 cm3) was heated at 195–235 ЊC
under a nitrogen atmosphere for 4–14 h. Ethyl acetate (3 ×
10 cm3) was then added to the cooled mixture and this was
filtered. The combined filtrates were treated with 10% hydro-
chloric acid (4 × 15 cm3) and the organic layer was washed with
water (2 × 10 cm3), dried with anhydrous sodium sulfate and
concentrated on a rotary evaporator. The residue was separated
by column chromatography (hexane–ethyl acetate 15 : 1) to give
the products 28–30.
2,2,11-Trimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]-
chromen-6-one 28. This was obtained from compound 5 which
was heated at 190–195 ЊC for 5 h, (90 mg, 61%), mp 211–212 ЊC
(ethyl acetate–hexane) (Found: C, 77.75; H, 6.2. C19H18O3
requires C, 77.5; H, 6.2%); νmax/cmϪ1 3060, 1710, 1560, 1510;
δH 1.48 (s, 6H), 1.96 (t, 2H, J = 6.9, 3-H), 2.55 (s, 3H), 3.01
(t, 2H, J = 6.9, 4-H), 6.35 (d, 1H, J = 9.5, 7-H), 7.47 (d, 1H,
J = 8.6), 8.02 (d, 1H, J = 8.6), 8.05 (s, 1H), 8.39 (d, 1H, J = 9.5,
8-H); δC 16.9, 21.6, 26.7, 31.7, 76.2, 105.8, 106.3, 110.7, 120.9,
121.8, 123.2, 126.3, 129.9, 135.0, 139.7, 153.0, 153.7, 162.0;
EI MS: m/z 294 (Mϩ, 75%), 238 (100), 210 (35), 84 (90).
Ethyl 2-methyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]pyrano-
[2,3-h]chromene-8-carboxylate 7
A solution of quinone 18 (0.55 g, 2.41 mmol) and ylide 19
(2.098 g, 6.03 mmol) in dry DCM (20 cm3) was stirred at room
temperature for 1 h during which time the quinone was con-
sumed. The solvent was evaporated off on a rotary evaporator
and the residue was chromatographed on a column (hexane–
ethyl acetate 6 : 1) to give, after the elution of compound 22,
compound 7 (0.509 g, 62%), mp 170–172 ЊC (ethyl acetate–
hexane) (Found: C, 70.8; H, 5.3. C20H18O5 requires C, 71.0; H,
5.4%); νmax/cmϪ1 3060, 1720, 1690, 1580; δH 1.42 (t, 3H, J = 7.2),
1.60 (d, 3H, J = 6.3), 1.82–1.90 (m, 1H), 2.20–2.28 (m, 1H),
2.91–2.99 (m, 1H), 3.13–3.19 (m, 1H), 4.40–4.46 (m, 1H), 4.55
(q, 2H, J = 7.2), 6.39 (s, 1H, 7-H), 7.51–7.58 (m, 2H), 7.75
(d, 1H, J = 7.6), 8.30 (d, 1H, J = 7.6); δC 13.9, 19.1, 20.9,
27.8, 62.7, 73.6, 103.4, 106.9. 110.6, 122.6, 123.1, 123.2, 125.2,
127.1, 127.6, 146.7, 155.1, 155.2, 160.2, 167.8; ESI MS: m/z 339
[M ϩ H]ϩ, 361 [M ϩ Na]ϩ.
2,2-Dimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-
6-one 29. This was obtained from compound 6 which was
heated at 230–235 ЊC for 4 h, (93 mg, 66%), mp 144–145 ЊC
(ether–hexane) (Found: C, 77.15; H, 5.4. C18H16O3 requires C,
77.1; H, 5.75%); νmax/cmϪ1 3030, 1715, 1575, 1560, 1510; δH 1.47
(s, 6H), 1.97 (t, 2H, J = 6.5, 3-H), 3.02 (t, 2H, J = 6.5, 4-H), 6.36
(d, 1H, J = 9.7, 7-H), 7.51 (t, 1H, J = 7.6), 7.63 (t, 1H, J = 7.6),
8.13 (d, 1H, J = 7.6, 9-H), 8.28 (d, 1H, J = 7.6), 8.41 (d, 1H, J =
9.7, 8-H); δC 16.8, 26.6, 31.5, 76.2, 105.7, 106.1, 110.6, 120.8,
122.5, 123.0, 125.0, 127.8, 128.1, 139.5, 153.3, 154.0, 161.6; EI
MS: m/z 280 (Mϩ, 100%), 265 (7), 225 (35), 224 (83), 196 (58),
139 (30), 115 (18), 114 (15).
Ethyl 2-[2-methyl-6-oxo-3,4,6,7-tetrahydro-2H-benzo[h]furo-
[2,3-f ]chromen-7-ylidene]acetate 22
2-Methyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]chromen-6-
one 30. This was obtained from compound 7 which was heated
at 190–195 ЊC for 14 h, (71 mg, 53%), mp 195–196 ЊC (ethyl
acetate–hexane) (Found: C, 76.9; H, 5.2. C17H14O3 requires C,
76.7; H, 5.3%); νmax/cmϪ1 3040, 1705, 1575, 1555, 1505; δH 1.57
(d, 3H, J = 6.9), 1.74–1.92 (m, 1H), 2.19–2.28 (m, 1H), 2.82–
2.99 (m, 1H), 3.07–3.19 (m, 1H), 4.31–4.45 (m, 1H), 6.35 (d,
1H, J = 9.5, 7-H), 7.51 (t, 1H, J = 8.6), 7.63 (t, 1H, J = 8.6), 8.11
(d, 1H, J = 8.6), 8.27 (d, 1H, J = 8.6), 8.38 (d, 1H, J = 9.5, 8-H);
δC 18.9, 21.0, 27.9, 73.4, 106.5, 106.8, 111.0, 120.9, 122.5, 122.7,
125.2, 128.0, 128.1, 139.6, 154.1, 154.4, 161.7; EI MS: m/z 266
(Mϩ, 100%), 251 (12), 237 (20), 224 (70), 196 (65).
Acetate 22 was obtained from the reaction between compounds
18 and 19 described above (0.052 g, 6%), mp 181–182 ЊC
(DCM–hexane); νmax/cmϪ1 3060, 1780, 1705, 1590; δH 1.39 (t,
3H, J = 7.6), 1.55 (d, 3H, J = 6.4), 1.72–1.86 (m, 1H), 2.10–2.23
(m, 1H), 2.71–2.98 (m, 2H), 4.32–4.50 (m, 3H), 7.01 (s, 1H),
7.41 (t, 1H, J = 7.6), 7.56 (t, 1H, J = 7.6), 7.87 (d, 1H, J = 8.9),
8.23 (d, 1H, J = 8.9); δC 14.0, 18.8, 21.0, 27.7, 61.7, 73.7, 103.3,
105.6, 121.8, 122.8, 123.5, 124.3, 125.5, 127.7, 128.8, 129.2,
154.5, 155.4, 165.2, 165.6; EI MS: m/z 338 (Mϩ, 100%), 310
(14), 293 (22), 268 (51), 267 (13), 266 (52), 251 (14), 167 (51),
139 (53); MALDI HRMS (DHB): m/z 339.1228 [M ϩ H]ϩ.
C20H19O5 requires 339.1227.
Ethyl 2,2-dimethyl-6-oxo-2H,6H-benzo[f]pyrano[2,3-h]-
chromene-8-carboxylate 31
Diethyl 2-(10-hydroxy-2,2,7,7-tetramethyl-2,3,4,7,8,9-hexa-
hydropyrano[2,3-g]chromen-5-yl)but-2-enedioate 27
A mixture of compound 6 (0.332 g, 0.942 mmol), NBS (0.168 g,
0.943 mmol) and benzoyl peroxide (3 mg, 0.0095 mmol) in
carbon tetrachloride (20 cm3) was heated under reflux for 3 h.
Additional amounts of NBS (0.168 g, 0.943 mmol) and benzoyl
peroxide (3 mg) were then added and the mixture was heated for
a further 3 h and then cooled to room temperature. The precipi-
tated succinimide was filtered off and washed with carbon
tetrachloride (5 cm3). The filtrate was concentrated on a rotary
evaporator and the residue was separated by column chrom-
atography (hexane–ethyl acetate 10 : 1 up to 4 : 1) to give first
compound 31 (76 mg, 23%), yellow crystals, mp 112–113 ЊC
(from hexane) (Found: C, 72.0; H, 5.1. C21H18O5 requires C,
72.0; H, 5.2%); νmax/cmϪ1 3050, 1730, 1690; δH 1.40 (t, 3H, J =
7.2), 1.58 (s, 6H), 4.53 (q, 2H, J = 7.2), 5.79 (d, 1H, J = 10.0),
6.38 (s, 1H, 7-H), 6.99 (d, 1H, J = 10.0), 7.50–7.59 (m, 2H), 7.74
(d, 1H, J = 8.5), 8.30 (d, 1H, J = 7.9); δC 13.9, 28.2, 62.9, 78.8,
106.4, 107.3, 111.3, 115.6, 123.0, 123.2, 123.4, 125.5, 126.6,
128.3, 129.5, 146.7, 152.2, 153.5, 160.0, 167.7; EI MS: m/z 350
(Mϩ, 100%), 336 (14), 335 (78), 307 (8), 261 (8), 235 (7), 205 (5),
178 (8).
A solution of quinone 11 (0.2 g, 0.72 mmol) and ylide 19
(0.707 g, 2.03 mmol) was heated in an oil bath at ∼150 ЊC for 1 h
after which the reaction mixture was separated by column
chromatography (hexane–ethyl acetate 10 : 1) to give compound
27 (0.214 g, 69%), yellow oil; νmax/cmϪ1 3430, 1720, 1710, 1620,
1590; δH 1.13 (t, 3H, J = 7.2), 1.19 (s, 3H), 1.22 (s, 3H), 1.28 (t,
3H, J = 7.2), 1.31 (s, 3H), 1.37 (s, 3H), 1.72–1.79 (m, 4H), 2.36–
2.43 (m, 1H), 2.50–2.55 (m, 1H), 2.67–2.71 (m, 2H), 4.0–4.09
(m, 2H), 4.19–4.30 (m, 2H), 5.70 (s, 1H), 6.99 (s, 1H); δC 13.9,
14.1, 17.1, 20.4, 25.5, 26.0, 26.9, 27.5, 32.1, 33.1, 60.3, 61.3,
73.5, 74.3, 105.9, 112.4, 117.8, 129.3, 133.4, 141.4, 142.8, 144.4,
165.3, 167.1; ESI MS: m/z 433 [M ϩ H]ϩ, 431 [M Ϫ H]ϩ, 455
[M ϩ Na]ϩ; MALDI HRMS (DHB): m/z 432.2142 [M]ϩ.
C24H32O7 requires 432.2142. Unreacted starting quinone 11 was
eluted next (16 mg, 8%).
De-ethoxycarbonylation of compounds 5–7
Synthesis of compounds 28–30: general procedure. A mixture
of the ester 5–7 (0.5 mmol) and copper powder (220 mg, 3.5
J. Chem. Soc., Perkin Trans. 1, 2002, 1455–1460
1459

View Article Online
Ethyl 3-bromo-4-hydroxy-2,2-dimethyl-6-oxo-3,4-dihydro-
2H,6H-benzo[f]pyrano[2,3-h]chromene-8-carboxylate 32
1.97 (t, 2H, J = 6.8), 3.00 (t, 2H, J = 6.8), 7.53 (t, 1H, J = 7.8),
7.64 (t, 1H, J = 7.8), 8.08 (d, 1H, J = 7.8), 8.28 (d, 1H, J = 7.8),
8.73 (s, 1H, 8-H); δC 16.9, 26.7, 31.6, 78.6, 105.6, 105.8, 107.0,
120.9, 121.2, 122.8, 123.3, 125.5, 127.5, 128.3, 141.1, 153.9,
158.0; EI MS: m/z 360/358 (Mϩ, 100%), 343 (48), 341 (33), 304
(51), 302 (41), 223 (17), 152 (33), 139 (97); MALDI HRMS
(DHB): m/z 359.0288 [M ϩ H]ϩ. C18H16BrO3 requires 359.0277.
A. Compound 32 [0.257 g, 64%, yellow crystals, mp 71–73 ЊC
(ether–hexane)] was eluted after compound 31 from the
reaction of 6 described above.
B. A mixture of compound 31 (60 mg, 0.17 mmol), NBS
(31 mg, 0.17 mmol) and a few crystals of benzoyl peroxide in
carbon tetrachloride (3 cm3) was refluxed for 2 h. TLC exam-
ination of the reaction mixture showed the presence of unre-
acted starting quinone 31. An additional amount of NBS (31
mg, 0.17 mmol) was then added and the mixture was refluxed
for a further for 2 h, after which time the starting material
was consumed. The reaction mixture was cooled, the precipi-
tated succinimide was filtered off, the filtrate was concentrated
on a rotary evaporator and the residue was separated by col-
umn chromatography (hexane–ethyl acetate 7 : 1 up to 4 : 1)
to give compound 32, identical with that obtained by method
A, (48 mg, 63%) (Found: C, 56.5; H, 4.15. C21H19BrO6
requires C, 56.4; H, 4.3%); νmax/cmϪ1 3450, 3050, 1715, 1690;
δH 1.40 (t, 3H, J = 7.3), 1.67 (s, 3H), 1.74 (s, 3H), 4.27 (d, 1H,
J = 4.6, exchangeable with D2O), 4.41 (d, 1H, J = 4.6), 4.53
(q, 2H, J = 7.3), 5.50 (t, 1H, J = 4.6), 6.42 (s, 1H, 7-H), 7.53–
7.63 (m, 2H), 7.78 (d, 1H, J = 8.3), 8.35 (d, 1H, J = 8.3); δC
13.9, 25.4, 25.9, 57.2, 63.0, 67.3, 79.6, 104.9, 106.9, 111.3,
123.3, 123.6, 125.9, 128.4, 128.8, 133.8, 147.0, 153.0, 155.5,
159.8, 167.4; EI MS: m/z 448/446 (Mϩ, 100%), 432 (11), 430
(14), 367 (11), 350 (35), 349 (11), 336 (44), 312 (96), 284 (89),
256 (46), 126 (76).
3-Bromo-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo[f]-
pyrano[2,3-h]chromen-6-one 35
The hydroxy bromide 35 was obtained from the reaction of
compound 29 with NBS, described above (eluted after com-
pound 34), (18 mg, 12%), mp 210–212 ЊC (ethyl acetate–
hexane); νmax/cmϪ1 3320, 3070, 1730, 1580; δH 1.65 (s, 3H), 1.75
(s, 3H), 2.18 (br s, 1H), 4.41 (d, 1H, J = 5.1), 5.52 (d, 1H, J =
5.1), 6.42 (d, 1H, J = 10.2, 7-H), 7.57 (t, 1H, J = 8.9), 7.71 (t, 1H,
J = 8.9), 8.15 (d, 1H, J = 8.9), 8.32 (d, 1H, J = 8.9), 8.43 (d, 1H,
J = 10.2, 8-H); δC 24.7, 26.1, 57.4, 67.4, 79.5, 106.3, 106.8, 107.5,
111.6, 121.1, 122.7, 123.5, 125.8, 129.2, 139.8, 152.1, 154.0,
160.9; EI MS: m/z 376/374 (Mϩ, 23%), 278 (8), 277 (16), 263
(15), 240 (100), 212 (70), 184 (23), 128 (35); MALDI HRMS
(DHB): m/z 375.0228 [M ϩ H]ϩ. C18H16BrO4 requires 375.0226.
Acknowledgements
D. R. Gautam thanks the State Scholarships Foundation
(IKY), Greece for financial support and Tribhuvan University,
Kathmandu, Nepal for granting him the PhD study leave.
References
Ethyl 4-hydroxy-2-methyl-6-oxo-3,4-dihydro-2H,6H-benzo[f]-
pyrano[2,3-h]chromene-8-carboxylate 33
1 Y. Kashman, K. R. Gustafson, R. W. Fuller, J. H. Cardellina II,
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A mixture of compound 7 (0.3 g, 0.887 mmol), NBS (0.174 g,
0.976 mmol) and benzoyl peroxide (2.7 mg, 0.00855 mmol) in
carbon tetrachloride (15 cm3) was heated under reflux for 3 h.
Additional amounts of NBS (0.174 g, 0.976 mmol) and benzoyl
peroxide (2.7 mg, 0.00855 mmol) were added and the mixture
was heated for an additional 6 h. The mixture was cooled at
room temperature and the precipitated succinimide was filtered
off and washed with carbon tetrachloride (5 cm3). The solvent
was removed on a rotary evaporator and the residue was separ-
ated by column chromatography (hexane–ethyl acetate 10 : 1) to
give yellow crystals of compound 33 (0.21 g, 67%), mp 171–173
ЊC (ether–hexane) (Found: C, 67.7; H, 5.0. C20H18O6 requires C,
67.8; H, 5.1%); νmax/cmϪ1 3350, 3060, 1715, 1690; δH 1.39 (t, 3H,
J = 7.6), 1.63 (d, 3H, J = 6.4), 1.85 (ddd, 1H, J1 = 3.8, J2 = 3.8,
J3 = 14.0), 2.26 (d, 1H, J = 14.0), 3.15 (br s, 1H), 4.51 (q, 2H, J =
7.6), 4.62 (dq, 1H, J1 = 3.8, J2 = 6.4), 5.32 (d, 1H, J = 3.8), 6.37
(s, 1H, 7-H), 7.49–7.59 (m, 2H), 7.75 (d, 1H, J = 7.6), 8.35 (d,
1H, J = 7.6); δC 13.9, 20.8, 36.6, 58.3, 62.8, 69.7, 103.7, 109.0,
111.0, 123.2, 123.3, 123.4, 125.5, 128.1, 128.5, 146.9, 155.4,
155.9, 159.9, 167.6; EI MS: m/z 354 (Mϩ, 100%), 336 (10), 321
(29), 286 (50), 284 (83), 256 (59), 183 (48), 127 (91).
7-Bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[f]pyrano[2,3-h]-
chromen-6-one 34
13 K. C. Fylaktakidou, D. R. Gautam, D. J. Hadjipavlou-Litina,
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A mixture of compound 29 (0.117 g, 0.417 mmol), NBS (0.074 g,
0.417 mmol) and benzoyl peroxide (1 mg, 0.0042 mmol) in car-
bon tetrachloride (10 cm3) was refluxed for 30 min and addi-
tional amounts of NBS (0.038 g, 0.213 mmol) and benzoyl
peroxide (1 mg, 0.0042 mmol) were then added. The reaction
mixture was refluxed for further 30 min, cooled to room temper-
ature and the precipitated succinimide was filtered off and
washed with carbon tetrachloride (2 cm3). The filtrate was con-
centrated on a rotary evaporator and the residue was separated
by column chromatography (hexane–ethyl acetate 15 : 1 up to
4 : 1) to give compound 34 (45 mg, 30%), mp 226–228 ЊC (ethyl
acetate–hexane); νmax/cmϪ1 3050, 1710, 1570; δH 1.48 (s, 6H),
14 J. S. Sun, A. H. Geiser and B. Frydman, Tetrahedron Lett., 1998, 39,
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15 R. Cassis, R. Tapia and J. Valderrama, J. Heterocycl. Chem., 1982,
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1460
J. Chem. Soc., Perkin Trans. 1, 2002, 1455–1460