The synthesis of 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione, a novel metabolite isolated from Crescentia cujete

Article abstract of DOI:10.1016/j.tet.2009.03.091

The title natural product 1, which possesses a new ring skeleton, has been synthesised by a sequence in which the key steps involve a tandem intramolecular Diels-Alder/reverse Diels-Alder reaction sequence. Thus 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol wa

Full text of DOI:10.1016/j.tet.2009.03.091

Tetrahedron 65 (2009) 4569–4577
Contents lists available at ScienceDirect
Tetrahedron
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The synthesis of 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione,
a novel metabolite isolated from Crescentia cujete
*
Linda B. Nielsen, Riskiono Slamet, Dieter Wege
Chemistry M313, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The title natural product 1, which possesses a new ring skeleton, has been synthesised by a sequence in
which the key steps involve a tandem intramolecular Diels–Alder/reverse Diels–Alder reaction sequence.
Thus 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol was treated with ethyl 3-bromopropiolate, and without
isolation, the resulting acetylenic ether was heated in the presence of 3,6-di(pyridin-2-yl)-1,2,4,5-tetra-
zine. Intramolecular addition of the pendant acetylenic chain to the furan ring followed by cycloaddition of
the electron-deficient tetrazine and subsequent cycloreversion delivered ethyl 5,10-dimethoxyfuro[3,2-
b]naphtho[2,3-d]furan-3-carboxylate, which has the ring system of the natural product. Functional group
manipulation then provided 1.
Received 18 December 2008
Received in revised form 10 March 2009
Accepted 26 March 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The common tropical American tree Crescentia cujete has been
an important source of folk medicine across Central America, the
northern half of South America and the Caribbean,1 with both ex-
tracts and pulp of the seeds, fruit, leaves and flowers being used to
treat a variety of ailments. These include colds and other re-
spiratory illnesses,2–4 hypertension5 and the haemorrhagic effect of
venomous snake bites.6 Like many other plant species used in
traditional medicine, C. cujete has also attracted increasing interest
as a source of novel and biologically active compounds, which could
provide possible lead structures in the development of new phar-
maceuticals.7–10
During an investigation into potentially useful anticancer agents
from the wood of C. cujete, Kingston and co-workers isolated a series
of nine related furo[b]-fused naphthoquinone derivatives.7,8 Of
particular interest are two tetracyclic naphthoquinones, which were
isolated as red pigments and assigned structures 3-hydroxy-
methylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (1) and 9-hy-
droxy-3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione
(2) (Fig. 1) on the basis of extensive spectroscopic analysis.7 Both
compounds were found to be cytotoxic and 1 exhibited selective
DNA-damaging activity in an assay involving a DNA repair-deficient
strain of yeast,7 suggesting that 1 may be useful in the development
of new antitumour drugs. Kingston and co-workers have also noted
that the planar structure of naphthoquinones 1 and 2 means that
Figure 1. Two novel furo[3,2-b]naphtho[2,3-d]furan-5,10-diones isolated from
C. cujete.7
intercalation into DNA is likely to contribute to their mode of action
for DNA damage.11
As well as having potentially useful biological activity, naph-
thoquinones 1 and 2 are interesting in terms of their structure. The
tetracyclic ring system, composed of a naphthoquinone ring fused
to a fully aromatic furo[3,2-b]furan moiety, represents a new nat-
ural product skeleton. Synthetic compounds incorporating a fully
aromatic furo[3,2-b]furan ring are also rare. The parent furo[3,2-
b]furan (3) (Fig. 2) has not been synthesised to date, although it has
been included in a number of computational studies on fused
heterocycles.12–15 Similarly, the benzo-fused and naphtho-fused
compounds 4 and 5 have not been prepared. Only two reports
* Corresponding author. Fax: þ61 8 6488 1005.
E-mail address: dwege@cyllene.uwa.edu.au (D. Wege).
Figure 2. Unknown parent compounds containing the furo[3,2-b]furan ring system.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.091

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L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
describing the preparation of several related benzo-fused de-
rivatives have appeared.
Tolmach and co-workers have synthesised benzofuro[3,2-
b]benzofuran (8) from ‘hydrosalicyloin’ 6 according to the route
in Scheme 1.16 The fused furofuran framework was constructed
in the first step by a simple dehydrative cyclisation of 6 with
dicyclohexylcarbodiimide (DCC). The resulting dihydro com-
pound 7 was then treated with N-bromosuccinimide (NBS),
which delivered the fully aromatic compound 8 via a bromina-
tion–dehydrobromination sequence in 32% yield. Vaidya and
Agasimundin have achieved the synthesis of three related benzo-
furo[3,2-b]furan derivatives 10/11 via Dieckmann condensa-
tion of benzofuran 9.17 A positive ferric chloride colour test
suggests that these compounds exist at least partially in the enol
form 11.
Scheme 3. Retrosynthetic analysis for the synthesis of 1.
2. Results and discussion
Before embarking on the synthesis of the naphthalene de-
rivative 20, we investigated a simpler model system (Scheme 4).
Treatment of 2-bromophenyl acetate (22) with 2-furanylboronic
acid in the presence of Pd(OAc)2 and PPh3 gave the coupled product
23, which on hydrolysis afforded 2-(2-furyl)phenol (24) in good
overall yield. The reaction of the lithium salt of 24 with tri-
chloroethylene in DMF20 then provided the dichlorovinyl ether 25.
Treatment of 25 with 2 equiv of BuLi followed by addition of methyl
chloroformate gave the acetylenic ester 26.21–23 When the latter
was heated in refluxing toluene in the presence of 3,6-di(pyridin-2-
yl)-1,2,4,5-tetrazine (14), the desired methyl furo[3,2-b]benzofu-
ran-3-carboxylate (29) was isolated in 93% yield after simple
chromatographic separation. This product had the expected spec-
troscopic properties and the carbon and proton resonances in the
NMR spectra were assigned with the aid of 2D experiments (see
Experimental).
On the basis of these successful model reactions, attention was
directed to the preparation of furyl-substituted naphthol 21 required
for the synthesis of the natural product 1. Our initial approach in-
volved a Hauser–Kraus annulation,24 as this would conceivably also
permit the synthesis of the hydroxy-substituted derivative 2. Thus
addition of the anion derived from the cyanophthalide 30 to 3-(2-
furyl)acrolein (31) followed by acidification and methylation pro-
vided the naphthaldehyde 32 in good yield (Scheme 5). However, the
Baeyer–Villiger oxidation of 32 to give the naphthol 21 was not
straightforward, presumably due to the presence of the electron-rich
naphthalene and furan rings. The use of m-chloroperoxybenzoic acid
afforded complex mixtures, but the action of hydrogen peroxide in
the presence of diphenyl selenide25 followed by hydrolysis gave 21 in
modest yield.
Scheme 1. Preparation of benzofuro[3,2-b]benzofuran (8)16 and the benzofuro[3,2-
b]furan derivatives 10/11.17
In examining possible synthetic approaches to 3-hydroxy-
methylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (1), we decided
to adapt a pathway previously used in our laboratory to construct
a number of thieno[3,4-b]furan and furo[3,4-b]furan derivatives by
means of a tandem intramolecular Diels–Alder/retro Diels–Alder
reaction sequence (Scheme 2).18,19
A better route to 21 proceeded as follows. Treatment of 2,3-
dibromonaphthoquinone (33) with 1 equiv of the lithium salt of
benzyl alcohol in THF gave the benzyl ether 34 (Scheme 5). Stille
coupling with 2-(tri-n-butylstannyl)furan (35) provided 36, which
was reduced and methylated to afford 37. Finally, hydrogenolysis of
the benzyl group gave 21.
The preparation of the dichlorovinyl ether 38 was attempted
under conditions used for the formation of the model compound 25
by treatment of the lithium salt of naphthol 21 with tri-
chloroethylene in DMF at 80 ꢀC. This afforded compound 39, the
intramolecular Diels–Alder adduct of 38 (Scheme 6). The structure
of 39 was apparent from its spectroscopic properties, and the exo-
orientation of the chloro substituent at C4 follows from the 1H NMR
spectrum, in which there is an absence of significant coupling be-
tween H4 and the bridgehead proton H3 within the 7-oxabicy-
clo[2.2.1]heptenyl moiety. The desired dichlorovinyl ether 38 could
be obtained satisfactorily by carrying out the reaction at room
temperature.
Scheme 2. Preparation of the thieno[3,4-b]furan and furo[3,4-b]furan derivatives
17.18,19
When furans of general structure 12 possessing a pendant
acetylenic ester moiety are heated in the presence of 3,6-
di(pyridin-2-yl)-1,2,4,5-tetrazine (14), the intramolecular Diels–
Alder adduct 13 is intercepted by the electron-deficient diene 14.
Loss of dinitrogen gives 15, which undergoes cycloreversion to
deliver 17. Extension of this concept suggests that compound 20
would serve as a suitable precursor to the natural product 1
(Scheme 3), and this forms the basis of the work outlined in the
current paper.

L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
4571
Scheme 4. Synthesis of the model compound 29.
Scheme 5. Synthesis of the naphthol 21.
Scheme 6. Intramolecular Diels–Alder reaction of the dichlorovinyl ether 38.

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L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
When the dichlorovinyl ether 38 was heated in CDCl3 at 60 ꢀC,
In an initial experiment, the lithium salt of 21 was treated
with ethyl 3-bromopropiolate in THF. This gave a complex mix-
ture from which a product isomeric with the desired compound
49 was isolated in 30% yield (Scheme 8). This product was
assigned structure 48 on the basis of its spectroscopic properties.
In particular, the 13C NMR spectrum showed the presence of
a ketonic carbonyl carbon at 190.7 ppm and the absence of
a signal at ca. 90 ppm expected for the acetylenic ether carbon
atom in 49 (in model compound 26 this resonance is at 88.7 ppm
while in simple alkoxy acetylenic esters22 the signal occurs at ca.
96 ppm). Compound 48 arises by C-alkynylation of the ambident
naphthoxide derived from 21, following a well-known outcome
in the alkylation of 2-naphthols.28,29
When the naphthol 21 was treated with ethyl 3-bromopropio-
late in the presence of K2CO3 in acetone under reflux, the phenolic
ester 51 was isolated in 28% yield after chromatography of the
complex reaction mixture (Scheme 8). Clearly the desired acetyle-
nic ether 49 was formed under these conditions and underwent
intramolecular Diels–Alder reaction to give 50, which then suffered
acid-catalysed ring opening, presumably during workup or chro-
matographic separation, by a pathway similar to that shown in
Scheme 6 for adduct 39.
The apparent formation of the two required intermediates 49
and 50 was encouraging as it seemed that the synthesis of the
furofuronaphthalene 52 might be achievable if the adduct 50 could
be trapped with 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (14) in the
reaction mixture. Towards this end, a stirred suspension of the
naphthol 21, ethyl 3-bromopropiolate and K2CO3 in acetone was
gently heated until 21 had been consumed. Without hydrolytic
workup, the mixture was filtered, diluted with toluene and most of
the acetone removed by distillation. The solution of the presumed
adduct 50 was then subjected to the action of tetrazine 14 in
refluxing toluene (Scheme 9). Gratifyingly, this afforded the target
furofuronaphthalene 52, albeit in only 11% yield. Attempts to in-
crease this yield by varying the reaction conditions were
unrewarding.
adduct 39 was not detected and the ring-opened product 41 was
formed instead, clearly as a result of acid-catalysed cleavage of the
epoxy bridge within the strained ring system of 39 (Scheme 6).
With the appropriately substituted dichlorovinyl ether 38 in
hand, we next attempted the construction of the acetylenic ester of
general structure 20 required for the projected synthesis of 1
depicted in Scheme 3. Compound 38 was treated sequentially with
BuLi and methyl or ethyl chloroformate under conditions, which
were successful for the preparation of the model acetylenic ester 26
(Scheme 4). This gave a complex mixture from which no pure
product could be isolated. The reaction was examined under vari-
ous reaction conditions,21,22 with similar outcomes. On some oc-
casions evidence was obtained for competitive metallation and
electrophilic capture at the a-position of the furan ring. The pres-
ence of the methoxy groups in 38 could also activate the peri-po-
sitions in the naphthalene system towards metallation, a feature
not present in the model system. Because of this disappointing
outcome, we reluctantly abandoned this approach to 20.
In view of the ready availability of the bromopropiolates 42,26
we wondered whether the desired acetylenic ester 44 could be
obtained by the simple substitution reaction as shown in (1) in
Scheme 7. Such an approach to esters of this type does not appear to
have been investigated before, presumably because of the high
reactivity of the product towards further nucleophilic addition. For
example, the acetylenic ether 46 resulting from the base-catalysed
reaction of phenol and the bromoacetylenic ketone 45 was too
reactive to be isolated and underwent further nucleophilic addition
to deliver the ethylenic ether 47 in high yield.27 However, we felt
that this approach was worth examining since the pendant furan
ring within 20 could potentially intercept the reactive alkyne
moiety in competition with further nucleophilic addition.
The remaining steps of the synthesis were carried out as shown
in Scheme 9. Oxidative demethylation of 52 with ceric ammonium
nitrate (CAN) gave quinone 53. Reduction of the ester group with
LiAlH4 followed by re-oxidation of the resulting naphthalene-1,4-
diol moiety with Fremy’s salt delivered the target 3-hydroxy-
methylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (1) as a red solid
in 49% yield over two steps.
The NMR spectral properties of 1 are summarised in Table 1. It
can be seen that there is excellent agreement between the data
Scheme 7. (1) A possible approach to compounds of structure 44 and (2) further
nucleophilic addition to such activated alkynes.27
Scheme 8. Formation of the undesired products 48 and 51.

L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
4573
3. Experimental
3.1. General
General details have been given previously.30
3.1.1. 2-(2-Furyl)phenol (24)
A mixture of 2-bromophenyl acetate (540 mg, 2.53 mmol),
2-furanylboronic acid (425 mg, 3.80 mmol), Et3N (1.05 mL,
7.50 mmol), palladium acetate (117 mg, 0.757 mmol) and Ph3P
(40 mg, 1.53 mmol) in anhydrous DMF (10 mL) was heated at
100 ꢀC under Ar for 3 h. The solvent was evaporated and the residue
dissolved in CH2Cl2. The solution was washed sequentially with
aqueous NH3 (10%), water, brine and was dried. Evaporation
followed by radial chromatography using EtOAc/light petroleum
(0–3%) gave 2-(2-furyl)phenyl acetate (23) (420 mg, 83%) as a col-
ourless oil. dH (200 MHz, CDCl3) 7.83 (1H, dd, J 5.8, 3.7, ArH), 7.49
(1H, d, J 1.8, furyl H), 7.35–7.26 (2H, m, ArH), 7.13 (1H, dd, J 6.0, 3.3,
ArH), 6.68 (1H, d, J 3.4, furyl H), 6.49 (1H, dd, J 3.4, 1.8, furyl H). This
spectrum is similar to that reported for 23 prepared by another
route.31 The foregoing acetate (303 mg, 1.50 mmol) and NaOH
(60 mg, 1.5 mmol) in aqueous MeOH (1:1, 20 mL) was stirred under
Ar at room temperature overnight. The MeOH was evaporated and
the residue acidified with dilute HCl. Extraction with CH2Cl2 fol-
lowed by radial chromatography eluting with EtOAc/light petro-
leum (0–7%) gave 2-(2-furyl)phenol (24) (208 mg, 86%) as pale
yellow plates, mp 40–41 ꢀC, after recrystallisation from CH2Cl2/light
petroleum. EIMS m/z 161 (Mþ1, 30%), 160 (M, 100), 149 (19), 131
(11). dH (300 MHz, CDCl3) 7.58 (1H, ddd, J 9.8, 7.2, 0.4, ArH), 7.52 (1H,
dd, J 1.8, 0.7, furyl H), 7.23 (1H, ddd, J 9.8, 7.2, 1.7, ArH), 7.13 (1H, br,
OH), 7.01–6.97 (1H, m, ArH), 6.75 (1H, dd, J 3.4, 0.7, furyl H), 6.54
(1H, dd J 3.4, 1.8, furyl H). dC (75.5 MHz, CDCl3) 152.4 (C), 152.3 (C),
141.2 (CH), 129.1 (CH), 126.1 (CH), 120.5 (CH), 117.1 (CH), 116.5 (C),
111.7 (CH), 106.7 (CH). Anal. Calcd for C10H8O2: C, 74.99; H, 5.03.
Found: C, 74.75; H, 4.96.
Scheme 9. Final steps in the synthesis of 1.
reported7 for the natural product and those observed for the
synthetic material, except for the value for the 13C chemical shift
of the CH2 group. We recorded the spectrum of synthetic 1 at
three different concentrations and consistently observed the
value of 52.3 ppm, ruling out any possible concentration de-
pendence due to, for example, intermolecular hydrogen-bonding
effects. We note that for the naturally occurring hydroxy de-
rivative 2, the reported chemical shift for the methylene carbon is
52.3 ppm,7 a value identical to that observed by us for synthetic
1. As the hydroxyl group in 2 is unlikely to interact with the
distant CH2 group, we conclude that the correct shift for this
carbon atom in 1 is 52.3 ppm.
In summary, we have confirmed the nature of the novel ring
skeleton of 1 by synthesis. The propensity of the naphthyl
dichlorovinyl ether 38 to undergo facile intramolecular Diels–Alder
addition (relative to the model ether 25) may be a consequence of
a buttressing effect due to the methoxy groups. These groups also
appear to interfere with the metallation and further trans-
formations of the dichlorovinyl moiety, which proceeded smoothly
with the model ether 25.
3.1.2. (E)-1,2-Dichloroethenyl 2-(2-furyl)phenyl ether (25)
Methanolic LiOMe (2.50 mL of 1.5 M solution, 3.75 mmol) was
added to a solution of 2-(2-furyl)phenol (24) (586 mg, 3.65 mmol)
in MeOH (20 mL) under Ar. The MeOH was evaporated and the
residue dissolved in DMF (20 mL), trichloroethylene (1.40 g,
11.1 mmol) was added, and the solution stirred at 80 ꢀC for 14 h.
The mixture was diluted with water and extracted thoroughly with
light petroleum. The extract was washed sequentially with dilute
NaOH and water, dried and then concentrated. Distillation gave (E)-
1,2-dichloroethenyl 2-(2-furyl)phenyl ether (25) as a colourless
liquid (780 mg, 93%) bp 190 ꢀC/0.05 Torr (Kugelrohr). EIMS m/z 258
(Mþ4, 3%), 256 (Mþ2,18), 254 (M, 30), 221 (43), 220 (20), 219 (100),
193 (15), 191 (46). dH (300 MHz, CDCl3) 7.97–7.94 (1H, m, ArH), 7.53
(1H, dd, J 1.8, 0.7, furyl H), 7.29–7.25 (1H, m, ArH), 7.10–7.07 (1H, m,
ArH), 6.98 (1H, dd, J 3.3, 0.7, furyl H), 6.55 (1H, dd, J 3.3, 1.7, furyl H),
6.04 (1H, s, vinyl H). dC (75.5 MHz, CDCl3) 149.1 (C), 148.6 (C), 141.8
(CH), 139.5 (C), 127.8 (CH), 126.6 (CH), 124.7 (CH), 121.6 (C), 116.2
(CH), 111.9 (CH), 110.7 (CH), 103.8 (CH). Anal. Calcd for C12H8Cl2O2:
C, 56.50; H, 3.16; Cl, 27.80. Found: C, 56.30; H, 3.22; Cl, 27.66.
Table 1
Comparison of the NMR spectral data in (CD3)2SO for natural7 and synthetic 3-hy-
droxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (1)
Posn
Natural 1
Synthetic 1
a
b
c
d
dH
dC
dH
dC
2
3
8.18 (br s)
150.8
116.5
151.9
153.3
173.0
132.0
126.42
134.0
134.5
126.35
132.2
179.1
117.9
141.2
54.5
8.16 (t, 1.0)
150.8
116.5
151.9
153.3
173.0
132.0
126.42
134.0
134.5
126.35
132.2
179.2
117.9
141.2
52.3
3a
4a
5
5a
6
7
8
9
9a
10
10a
10b
CH2
OH
8.11 (m)
7.87 (m)
7.88 (m)
8.09 (m)
8.11 (m, J6,7 7.73, J6,8 1.24, J6,9 0.42)e
7.90 (m, J6,7 7.73, J7,8 7.27, J7,9 1.25)e
7.87 (m, J8,9 7.74, J7.8 7.27, J6,8 1.24)e
8.09 (m, J8,9 7.74, J7,9 1.25, J6,9 0.42)e
3.1.3. Methyl 3-[2-(2-furyl)phenoxy]propynoate (26)
A solution of BuLi in hexane (3.0 mL of 0.80 M, 2.40 mmol) was
added dropwise over 20 min to a stirred solution of 1,2-dichloro-
ethenyl 2-(2-furyl)phenyl ether (25) (280 mg, 1.10 mmol) in ether
(15 mL) at ꢁ78 ꢀC. The mixture was allowed to warm to ꢁ10 ꢀC,
stirred for 10 min and then transferred via cannula to a solution of
methyl chloroformate (1.16 g, 12.3 mmol) in ether at ꢁ78 ꢀC. The
mixture was stirred at ꢁ40 ꢀC for 15 min and then added to
phosphate buffer22 (40 mL) and ether (75 mL). The organic layer
was separated, dried, concentrated and the residue subjected to
4.59 (d, 5.2)
5.51 (t, 5.2)
4.58 (dd, 5.4, 1.0)
5.49 (t, 5.4)
a
400 MHz.
100.57 MHz.
500 MHz.
125.75 MHz.
b
c
d
e
Simulated using the program gNMR version 4.0 (Cherwell Scientific Publishing
Limited).

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L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
radial chromatography. Elution with EtOAc/light petroleum (0–
20%) gave methyl 3-[2-(2-furyl)phenoxy]propynoate (26) (109 mg,
41%) as a colourless oil. EIMS m/z 242 (M, 33%), 211 (21), 210 (100),
182 (33), 126 (32), 77 (11). dH (300 MHz, CDCl3) 7.89–7.86 (1H, m,
ArH), 7.64–7.60 (1H, m, ArH), 7.51 (1H, dd, J 1.8, 0.7, furyl H), 7.34–
7.25 (2H, m, ArH), 6.87 (1H, dd, J 3.4, 0.7, furyl H), 6.52 (1H, dd, J 3.5,
1.8, furyl H), 3.84 (3H, s, OCH3). dC (75.5 MHz, CDCl3) 154.6 (CO),
150.1 (C), 147.4 (C), 147.3 (CH), 142.3 (CH), 128.3 (CH), 126.7 (CH),
126.0 (CH), 120.0 (C), 114.8 (CH), 112.0 (CH), 111.1 (CH), 88.7 (C), 52.6
(OCH3), 41.1 (C). HRMS calcd for C14H10O4 Mþ: 242.0579, found:
242.0576.
(500 mL) and extracted with ethyl acetate (3ꢂ100 mL). The com-
bined organic extracts were washed with water, followed by brine,
dried and concentrated to give a yellow residue, which was sub-
jected to silica gel filtration. Elution with 5–30% EtOAc/light pe-
troleum gave a yellow solid, which recrystallised from CH2Cl2/light
petroleum to give 2-benzyloxy-3-bromonaphthalene-1,4-dione
(34) as yellow needles (15.4 g, 75%), mp 103–104 ꢀC. EIMS m/z 345
(Mþ3, 19%), 344 (Mþ2, 100), 343 (Mþ1, 19), 342 (M, 94), 265 (13),
264 (25), 255 (61), 254 (44), 253 (58). dH (300 MHz, CDCl3) 8.10–
8.04 (2H, m, ArH), 7.72–7.69 (2H, m, ArH), 7.49–7.46 (2H, m, ArH),
7.39–7.31 (3H, m, ArH), 5.64 (2H, s, OCH2). dC (75.5 MHz, CDCl3)
179.3 (CO), 178.5 (CO), 158.4 (C), 136.0 (C), 134.3 (CH), 138.8 (CH),
130.8 (C), 129.7 (C), 128.6 (CH), 128.2 (2ꢂCH), 127.2 (CH),126.9 (CH),
123.9 (C), 75.7 (OCH2). nmax (Nujol)/cmꢁ1 1669 (C]O). Anal. Calcd
for C17H11BrO3: C, 59.50; H, 3.23. Found: C, 59.35; H, 3.40.
3.1.4. Methyl furo[3,2-b]benzofuran-3-carboxylate (29)
A solution of methyl 3-[2-(2-furyl)phenoxy]propynoate (26)
(50 mg, 0.21 mmol) and 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (14)
(49 mg, 0.21 mmol) in toluene (25 mL) was heated under reflux
under Ar for 16 h. The solvent was evaporated and the residue
subjected to radial chromatography. Elution with CH2Cl2/light pe-
troleum (0–10%) gave methyl furo[3,2-b]benzofuran-3-carboxylate
(29) (40 mg, 93%) as colourless needles mp 105–107 ꢀC. EIMS m/z
216 (M, 100%), 185 (31), 158 (17), 157 (18), 149 (31), 101 (19), 86 (15),
84 (26). dH (500 MHz, CDCl3) 8.11 (1H, s, furyl H2), 7.70–7.61 (2H, m,
ArH5 and ArH8), 7.34–7.30 (2H, m, ArH6 and ArH7), 3.97 (3H, s,
OCH3). dC (125.75 MHz, CDCl3) 161.9 (CO), 159.5 (C4a), 150.8 (C2),
145.5 (C8b), 143.8 (C3a), 124.3 (C6), 123.7 (C7), 117.2 (C8a), 117.5
(C5), 113.3 (C8), 109.9 (C3), 52.2 (OCH3). nmax (KBr)/cmꢁ1 1720
(C]O). Anal. Calcd for C12H8O4: C, 66.67; H, 3.73. Found: C, 66.53;
H, 3.87.
3.1.7. 2-Benzyloxy-3-(2-furyl)naphthalene-1,4-dione (36)
A mixture of 2-benzyloxy-3-bromonaphthalene-1,4-dione (34)
(4.38 g, 12.8 mmol), 2-(tri-n-butylstannyl)furan33 (5.61 g, 15.7 mmol),
Pd(PPh3)4 (546 mg, 0.473 mmol) and CuBr (531 mg, 3.70 mmol) in
dioxane (60 mL) was heated at reflux for 30 min under Ar. The reaction
mixture was diluted with water (500 mL) and extracted with EtOAc
(3ꢂ60 mL). The combined organic extracts were washed with water
(60 mL), followed by brine (50 mL), dried and concentrated to give
a red-brown residue, which crystallised from CH2Cl2/light petroleum
to give 2-benzyloxy-3-(2-furyl)naphthalene-1,4-dione (36) as dark red
plates (2.92 g), mp 141 ꢀC. The mother liquor was concentrated under
reduced pressure, adsorbed onto silica and subjected to silica gel fil-
tration. Elution with 2.5–5% EtOAc/light petroleum gave a further
portion of the title compound as a bright red solid (0.825 g, total yield
89%). EIMS m/z 330 (M, 42%), 302 (29), 241 (11), 240 (11), 183 (17), 127
(11), 91 (100). dH (300 MHz, CDCl3) 8.13–8.05 (2H, m, ArH), 7.76–7.68
(2H, m, ArH), 7.61 (1H, dd, J 1.8, 0.7, furyl H), 7.47–7.41 (2H, m, ArH),
7.38–7.30 (3H, m, ArH), 7.22 (1H, dd, J3.5, 0.7, furyl H), 6.56 (1H, dd, J3.5,
1.8, furyl H), 5.42 (2H, s, OCH2). dC (75.5 MHz, CDCl3) 183.4 (CO), 181.5
(CO), 154.1 (C), 145.1 (C), 144.2 (CH), 136.4 (C), 133.9 (CH), 133.5 (CH),
132.1 (C), 131.2 (C), 128.4 (CH), 128.3 (CH), 126.6 (CH), 125.9 (CH), 123.3
(C), 117.9 (CH), 111.9 (CH), 75.6 (OCH2). nmax (Nujol)/cmꢁ1 1661 (C]O).
Anal. Calcd for C21H14O4: C, 76.36; H, 4.27. Found: C, 76.50; H, 4.33.
3.1.5. 3-(2-Furyl)-1,4-dimethoxynaphthalene-2-
carboxaldehyde (32)
A
stirred solution of diisopropylamine (1.0 mL, 0.722 g,
7.71 mmol) in THF (20 mL) at ꢁ78 ꢀC was treated dropwise with
BuLi in hexane (5.20 mL of 1.5 M, 7.80 mmol) under Ar. To the
mixture was then added over 20 min a solution of 3-cyanoph-
thalide (30) (1.23 g, 7.73 mmol) in THF (50 mL). Stirring was con-
tinued for 45 min and then a solution of 3-(2-furyl)acrolein (31)
(944 mg, 7.74 mmol) in THF (30 mL) was added. The mixture was
allowed to warm to room temperature, stirred for 6 h and then
acidified with HCl (1 M, 100 mL) and extracted thoroughly with
EtOAc. The dried extract was evaporated and the residue dissolved
in anhydrous acetone (100 mL) and treated with K2CO3 (4.0 g,
29 mmol) and MeI (7.0 mL, 16 g, 113 mmol) and refluxed under Ar
for 18 h. The cooled mixture was filtered through Celite and the
filtrate evaporated. The residue was subjected to silica gel filtration.
Elution with CH2Cl2/light petroleum (0–5%) gave 3-(2-furyl)-1,4-
dimethoxynaphthalene-2-carboxaldehyde (32) (1.65 g, 76%), mp
84–86 ꢀC, after recrystallisation from Et2O/light petroleum. EIMS
m/z 282 (M, 77%), 267 (29), 240 (17), 239 (100), 224 (17), 223 (18),
139 (19). dH (300 MHz, CDCl3) 10.20 (1H, s, CHO), 8.29–8.18 (2H, m,
ArH), 7.75–7.56 (2H, m, ArH), 7.60 (1H, dd, J 1.8, 0.7, furyl H), 6.74
(1H, dd, J 3.3, 0.7, furyl H), 6.60 (1H, dd, J 3.3, 1.8, furyl H), 4.10 (3H, s,
OCH3), 3.71 (3H, s, OCH3). dC (75.5 MHz, CDCl3) 190.7 (CHO), 155.3
(C), 151.2 (C), 147.1 (C), 142.9 (CH), 131.3 (C), 129.2 (CH), 129.1 (C),
127.6 (CH), 125.1 (C), 123.9 (CH), 123.2 (CH), 118.9 (C), 111.7 (CH),
111.5 (CH), 65.0 (OCH3), 61.9 (OCH3). nmax (KBr)/cmꢁ1 1695 (C]O).
Anal. Calcd for C17H14O4: C, 59.20; H, 3.86. Found: C, 59.42; H, 4.08.
3.1.8. 2-Benzyloxy-3-(2-furyl)-1,4-dimethoxynaphthalene (37)
A mixture of 2-benzyloxy-3-(2-furyl)naphthalene-1,4-dione
(36) (1.71 g, 5.18 mmol), tetrabutylammonium bromide (109 mg,
0.295 mmol) and sodium dithionite (2.87 g, 16.5 mmol) in CH2Cl2
(45 mL) and H2O (45 mL) was stirred vigorously under Ar. After
30 min the reaction mixture was treated sequentially with a so-
lution of NaOH (2.31 g, 57.8 mmol) in H2O (7 mL) and dimethyl
sulfate (3.5 mL, 4.7 g, 37 mmol) and the resulting solution was left
to stir for 17 h. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2ꢂ40 mL). The combined organic
extracts were washed with H2O (40 mL), followed by brine
(40 mL), dried and concentrated to give a light brown oil, which
was subjected to silica gel filtration. Elution with 2.5% EtOAc/light
petroleum gave 2-benzyloxy-3-(2-furyl)-1,4-dimethoxynaph-
thalene (37) (1.80 g, 96%) as a pale yellow oil. EIMS m/z 361 (Mþ1,
39%), 360 (M, 88), 345 (19), 269 (34), 242 (25), 241 (100), 226 (45),
211 (26), 183 (32), 127 (12), 91 (41). dH (300 MHz, CDCl3) 8.20–8.17
(2H, m, ArH), 7.65 (1H, dd, J 1.8, 0.7, furyl H), 7.59–7.48 (2H, m,
ArH), 7.39–7.30 (5H, m, ArH), 6.77 (1H, dd, J 3.3, 0.7, furyl H), 6.59
(1H, dd, J 3.3, 1.8, furyl H), 5.02 (2H, s, OCH2), 4.08 (3H, s, OCH3),
3.73 (3H, s, OCH3). dC (75.5 MHz, CDCl3) 150.9 (C), 146.8 (C), 145.9
(C), 144.3 (C), 142.2 (CH), 137.2 (C), 129.2 (C), 128.4 (CH), 128.3
(CH), 128.1 (CH), 127.7 (CH), 126.7 (CH), 125.8 (C), 125.3 (CH), 122.6
(CH), 121.5 (CH), 117.2 (C), 111.6 (CH), 110.9 (CH), 75.4 (OCH2), 61.7
(OCH3), 61.3 (OCH3). HRMS calcd for C23H20O4 Mþ: 360.1361,
found: 360.1364.
3.1.6. 2-Benzyloxy-3-bromonaphthalene-1,4-dione (34)
BuLi in hexane (1.6 M, 35 mL, 56 mmol) was added dropwise
under Ar to a stirred solution of benzyl alcohol (7.41 g, 68.6 mmol)
in anhydrous THF (180 mL) cooled in an ice bath. After 20 min the
solution was treated with a slurry 2,3-dibromonaphthalene-1,4-
dione (33)32 (16.4 g, 52.0 mmol) in anhydrous THF (50 mL) and the
resulting mixture was stirred for a further 1.5 h. The reaction
mixture was quenched with a little ice, then diluted with water

L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
4575
3.1.9. 3-(2-Furyl)-1,4-dimethoxynaphthalen-2-ol (21)
(C), 126.6 (C), 126.5 (CH), 123.0 (CH), 121.9 (CH), 112.4 (CH), 111.3 (C),
111.1 (CH), 94.9 (CH), 62.4 (OCH3), 61.8 (OCH3). HRMS calcd for
C18H14Cl2O4 Mþ: 364.0269, found: 364.0271.
(a) To a solution of 3-(2-furyl)-1,4-dimethoxynaphthalene-2-carb-
oxaldehyde (32) (1.92 g, 6.80 mmol) in CH2Cl2 (80 mL) were
added aqueous H2O2 (1.8 g of 35%) and diphenyl diselenide
(88 mg, 0.28 mmol). The mixture was stirred under Ar at room
temperature with periodic monitoring by 1H NMR spectroscopy
(the Rf values of the starting material and the product formate
were identical). After 16 h the mixture was diluted with H2O
(100 mL) and the organic layer was separated and dried.
Evaporation gave the crude formate, which was stirred for 2 h
under Ar with a solution of NaOH (400 mg) in H2O (40 mL) and
MeOH (40 mL). The MeOH was evaporated and the residue
acidified with dilute HCl and extracted with CH2Cl2 (3ꢂ50 mL),
and the extract was dried and concentrated. The residue was
subjected to radial chromatography. Elution with 0–5% EtOAc/
light petroleum gave 3-(2-furyl)-1,4-dimethoxynaphthalen-2-
ol (21) (750 mg, 41%) as a pale yellow oil possessing a strong
blue fluorescence under 254 nm irradiation. EIMS m/z 270 (M,
100%), 255 (78), 241 (13), 212 (17), 199 (30), 183 (29), 149 (22),
128 (16), 139 (12). dH (300 MHz, CDCl3) 8.11 (1H, d, J 8.4, ArH),
7.99 (1H, d, J 8.4, ArH), 7.65 (1H, dd, J 1.8, 0.7, furyl H) 7.56–7.32
(2H, m, ArH), 7.04 (1H, dd, J 3.3, 0.7, furyl H), 6.64 (1H, dd, J 3.3,
1.8, furyl H), 4.00 (3H, s, OCH3), 3.78 (3H, s, OCH3). dC (75.5 MHz,
CDCl3) 150.4 (C), 147.5 (C), 143.3 (C), 141.8 (CH), 137.0 (C), 128.2
(C),127.0 (CH),123.9 (CH),123.4 (C),122.9 (CH),120.6 (CH),112.0
(CH), 111.7 (C), 111.6 (CH), 61.5 (OCH3), 61.2 (OCH3). HRMS calcd
for C16H14O4 Mþ: 270.0892, found: 270.0888.
(b) A solution of 2-benzyloxy-3-(2-furyl)-1,4-dimethoxynaph-
thalene (37) (1.86 g, 5.17 mmol) in EtOAc (50 mL) was hydro-
genated in the presence of 10% Pd/C (280 mg) until TLC
indicated that most of the starting material had been con-
sumed (ca. 3.5 h). The reaction mixture was filtered through
a plug of Celite and the filtrate was concentrated to give a yel-
low oil, which was subjected to silica gel filtration. Elution with
3% EtOAc/light petroleum returned starting material (157 mg)
as a pale yellow oil. Further elution with 7.5% EtOAc/light pe-
troleum afforded 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol
(21) (1.27 g, 91%) as a yellow oil spectroscopically identical to
the material prepared in (a).
3.1.11. Intramolecular Diels–Alder reactions of (E)-1,2-dichloroethenyl
3-(2-furyl)-1,4-dimethoxynaphthalen-2-yl ether (38)
(a) To a solution of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol (21)
(450 mg, 1.66 mmol) in MeOH (20 mL) was added methanolic
LiOMe (1.2 mL of 1.58 M solution, 1.90 mmol) and the mixture
was stirred under Ar for 10 min and the solvent was then evap-
orated. To the residue was added DMF (50 mL) and tri-
chloroethylene (1.5 mL, 2.19 g, 16.7 mmol) and the solution was
heated at 80 ꢀC for 5 h. The cooled mixture was diluted with H2O
(300 mL) and extracted with light petroleum (3ꢂ75 mL). The
extract was dried, concentrated and the residue subjected to
radial chromatography. Elutionwith 0–3% EtOAc/light petroleum
gave (3a,4a,4ab,11ba)-4,4b-dichloro-6,11-dimethoxy-3,4,4a,11b-
tetrahydro-3,11b-epoxybenzo[b]naphtho[2,3-d]furan (39) as
a colourless solid (270 mg, 60%), which crystallised from CH2Cl2/
light petroleum as prisms, mp100–101 ꢀC. EIMS m/z 368 (Mþ4,
10%), 367 (12), 366 (Mþ2, 59), 365 (18), 364 (M, 93), 349 (26), 329
(100) and numerous peaks of intensity >10% at lower m/z values.
dH (300 MHz, CDCl3) 8.19–8.14 (2H, m, ArH), 7.56–7.53 (1H, m,
ArH), 7.47–7.43 (1H, m, ArH), 7.88 (1H, d, J 5.7, vinyl H1), 6.71 (1H,
dd, J 5.7,1.9, vinyl H2), 5.15 (1H, d, J 1.9, bridgehead H2a), 4.41 (1H,
s, chloromethine H3), 4.14 (3H, s, OCH3), 4.03 (3H, s, OCH3). dC
(75.5 MHz, CDCl3) 150.8 (C), 146.1 (C), 137.2 (CH), 135.6 (CH),
135.2 (C), 131.1 (C), 127.5 (CH), 125.4 (C), 124.9 (CH), 122.6 (CH),
121.9 (CH), 111.1 (C), 110.7 (C), 97.5 (C), 87.8 (CH), 64.5 (CH), 63.5
(OCH3), 61.2 (OCH3). Anal. Calcd for C18H14Cl2O4: C, 72.33; H,
5.00. Found: C, 72.50; H, 5.02.
(b) A solution of the ether 38 (48 mg) in CDCl3 (1 mL) was heated
at 60 ꢀC with periodic monitoring of the 1H NMR spectrum.
Adduct 39 was not detected but a new product was formed
slowly (t1/2 ca. 65 h). After 115 h the mixture was subjected to
radial chromatography. Elution with 2% EtOAc/light petroleum
gave starting material (9 mg). Elution with 2–5% EtOAc/light
petroleum afforded 4-chloro-6,11-dimethoxybenzo[b]naph-
tho[2,3-d]furan-3-ol (41) as a colourless solid (27 mg, 63%)
possessing
a blue fluorescence under 254 nm radiation.
Recrystallisation from CH2Cl2/light petroleum gave 41 as plates,
mp 196–197 ꢀC. EIMS m/z 330 (Mþ2, 16%), 328 (M, 44), 315
(34), 314 (19), 313 (100), 300 (13), 298 (39), 86 (19). dH
(600 MHz, CDCl3) 8.36–8.34 (1H, m, ArH), 8.26–8.24 (1H, m,
ArH), 7.97 (1H, d, J 8.3, ArH), 7.56–7.52 (2H, m, ArH), 7.09 (1H, d,
J 8.3, ArH), 5.85 (1H, br s, OH), 4.38 (3H, s, OCH3), 4.10 (3H, s,
OCH3). dC (150.9 MHz, CDCl3) 153.4 (C), 152.1 (C), 144.7 (C),
143.6 (C), 135.2 (C), 126.7 (C), 125.4 (CH), 125.3 (C), 124.8 (CH),
122.3 (CH), 121.9 (CH), 121.6 (CH), 117.9 (C), 116.9 (C), 111.7 (CH),
103.4 (C), 61.6 (OCH3), 61.3 (OCH3). HRMS calcd for C18H13ClO4
Mþ: 328.0502, found: 328.0498.
3.1.10. (E)-1,2-Dichloroethenyl 3-(2-furyl)-1,4-dimethoxy-
naphthalen-2-yl ether (52)
BuLi in hexane (1.35 M, 1.2 mL, 1.6 mmol) was added dropwise
to a stirred solution of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol
(21) (393 mg, 1.46 mmol) in anhydrous THF (7 mL) cooled in an ice
bath under Ar. After 10 min the mixture was concentrated under
reduced pressure and the resulting yellow residue was dissolved in
DMF (10 mL). The reaction mixture was then treated with tri-
chloroethylene (1.74 g, 13.2 mmol) and left to stir overnight. The
mixture was diluted with water and extracted with 50% Et2O/light
petroleum (4ꢂ50 mL). The combined organic extracts were washed
successively with dilute NaOH solution and H2O, dried and con-
centrated to give a brown oil, which was subjected to silica gel
filtration. Elution with 2% EtOAc/light petroleum afforded (E)-1,2-
dichloroethenyl 3-(2-furyl)-1,4-dimethoxynaphthalen-2-yl ether
(38) (454 mg, 85%) as a colourless oil, which crystallised on
standing to afford plates mp 64–66 ꢀC. EIMS m/z 368 (Mþ4, 15%),
367 (17), 366 (Mþ2, 77), 365 (24), 364 (M, 100), 351 (15), 349 (23),
331 (32), 329 (83), 313 (28), 301 (27), 285 (40), 281 (40), 183 (557),
152 (39), 139 (68). dH (300 MHz, CDCl3) 8.26–8.09 (2H, m, ArH), 7.63
(1H, dd, J 1.8, 0.8, furyl H), 7.61–7.50 (2H, m, ArH), 6.82 (1H, d, J 0.8,
furyl H), 6.59 (1H, dd, J 3.4, 1.8, furyl H), 5.56 (1H, s, vinyl H), 4.03
(3H, s, OCH3), 3.75 (3H, s, OCH3). dC (75.5 MHz, CDCl3) 150.9 (C),
145.6 (C), 143.8 (C), 142.9 (CH), 141.3 (C), 128.4 (C), 127.4 (CH), 127.2
3.1.12. Attempted synthesis of ethyl 3-[3-(2-furyl)-1,4-dimethoxy-
naphthalen-2-yloxy]propynoate (49) by alkynylation of
3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol (21)
(a) BuLi in hexane (1.6 M, 0.65 mL, 1.0 mmol) was added dropwise
under Ar to a stirred solution of 3-(2-furyl)-1,4-dimethoxynaph-
thalen-2-ol (21) (261 mg, 0.967 mmol) in anhydrous THF (8 mL)
cooled in an ice bath. After 5 min the solution was treated with
ethyl 3-bromopropiolate (184 mg, 1.04 mmol) in anhydrous THF
(1 mL), then the ice bath was removed and the reaction mixture
was left to stir at room temperature for a further 22 h. The mixture
was diluted with H2O (80 mL) and extracted with CH2Cl2

4576
L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
(3ꢂ40 mL). The combined organic extracts were washed with
b]naphtho[2,3-d]furan-3-carboxylate (52) as a pale pink crystalline
solid (27 mg,11%), which recrystallised from CH2Cl2/light petroleum
as faint pink needles, mp 199–200 ꢀC. EIMS m/z: 341 (Mþ1, 21%),
340 (M, 87), 326 (31), 325 (100), 297 (65). dH (500 MHz, CDCl3) 8.33–
8.31 (1H, m, ArH), 8.28–8.26 (1H, m, ArH), 8.10 (1H, s, furyl H), 7.54–
7.47 (2H, m, ArH), 4.45 (2H, q, J 7.1, CH2), 4.39 (3H, s, OCH3), 4.30 (3H,
s, OCH3), 1.45 (3H, t, J 7.1, CH3). dC (125.75 MHz, CDCl3) 161.3 (C]O),
150.6 (CH, furyl), 148.7 (C), 146.2 (C), 142.3 (C), 141.5 (C), 134.4 (C),
125.6 (CH), 125.3 (C), 124.5 (CH), 123.1 (C), 122.3 (CH), 121.7 (CH),
110.4 (C), 106.0 (C), 61.6 (OCH3), 61.2 (CH2), 59.9 (OCH3), 14.3 (CH3).
nmax (CH2Cl2)/cmꢁ1 1724 (C]O). HRMS calcd for C19H16O6 Mþ:
340.0947, found: 340.0936.
brine (30 mL), dried and concentrated to give a brown oil, which
was subjected to radial chromatography. Elution with 10% EtOAc/
light petroleum returned unreacted starting material (36 mg).
Further elution with 20% EtOAc/petroleum gave ethyl 3-[3-(2-
furyl)-1,4-dimethoxy-2-oxo-1,2-dihydronaphthalen-1-yl]pro-
pynoate (48) as a yellow oil (105 mg, 30%, 34% based on
recovered starting material). EIMS m/z: 366 (M, 51%), 337 (29),
336 (46), 335 (100), 321 (23), 308 (16), 307 (69), 306 (34), 305
(16), 293 (45), 291 (17), 279(22), 277(26), 265 (24), 264 (18), 263
(38), 247 (19), 236 (19), 235 (48), 234 (15), 221 (15), 220 (40),165
(17), 164 (20), 163 (35), 152 (19), 151 (21). dH (300 MHz, CDCl3)
7.90–7.87 (1H, m, ArH), 7.80–7.77 (1H, m, ArH), 7.56–7.45 (3H, m,
2ꢂArH,1ꢂfuryl H), 6.64 (1H, dd, J 3.3, 0.7, furyl H), 6.52 (1H, dd, J
3.3, 1.8, furyl H), 4.22 (2H, q, J 7.1, CH2), 3.75 (3H, s, OCH3), 3.48
(3H, s, OCH3), 1.28 (3H, t, J 7.1, CH3). dC (75.5 MHz, CDCl3) 190.7
(ketone C]O),165.7 (ester C]O),152.8 (C),144.5 (C),142.6 (CH),
135.4 (C),131.1 (CH),129.7 (CH),128.8 (C),128.2 (CH),125.5 (CH),
113.5 (CH), 111.5 (CH), 107.4 (C), 82.3 (C), 79.3 (C), 76.0 (C), 62.3
(CH2), 60.5 (OCH3), 54.5 (OCH3), 13.9 (CH3). nmax (CH2Cl2)/cmꢁ1
1713 (C]O), 1676 (C]O), 2237 (alkyne). HRMS calcd for
C21H18O6 Mþ: 366.1103, found: 366.1104.
3.1.14. Ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-
carboxylate (53)
A solution of ceric ammonium nitrate (149 mg, 0.272 mmol) in
water (2 mL) was added dropwise under Ar to a stirred suspension
of ethyl 5,10-dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-carboxy-
late (64) (31 mg, 0.091 mmol) in CH3CN (2 mL) cooled in an ice
bath. The mixture was stirred vigorously for 10 min, then diluted
with H2O (20 mL) and extracted with EtOAc (3ꢂ20 mL). The com-
bined organic extracts were washed with brine, dried and con-
centrated to give a bright yellow solid, which was subjected to
radial chromatography. Elution with 20–50% EtOAc/light petroleum
gave the ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-carb-
oxylate (53) (14 mg, 50%), which recrystallised from dichloro-
methane/light petroleum as fine yellow needles, mp 219–220 ꢀC.
EIMS m/z: 311 (Mþ1, 20%), 310 (M, 100), 282 (33), 265 (33), 238
(20). dH (300 MHz, CDCl3) 8.33 (1H, s, furyl), 8.27–8.20 (2H, m, ArH),
7.84–7.75 (2H, m, ArH), 4.44 (2H, q, J 7.1, CH2), 1.43 (3H, t, J 7.1, CH3).
dC (75.5 MHz, CDCl3) 178.9 (C]O), 173.5 (C]O), 160.0 (C]O), 156.0
(CH, furyl), 154.3 (C), 149.1 (C), 142.6 (C), 134.3 (CH), 133.9 (CH),
132.2 (C), 132.1 (C), 127.1 (CH), 126.0 (CH), 118.2 (C), 110.5 (C), 61.6
(CH2), 14.2 (CH3). nmax (CH2Cl2)/cmꢁ1 1729 (C]O), 1674 (C]O).
HRMS calcd for C17H10O6 Mþ: 310.0477, found: 310.0478.
(b) A suspension of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-ol (21)
(137 mg, 0.507 mmol), ethyl 3-bromopropiolate (93 mg,
0.52 mmol) and K2CO3 (175 mg,1.27 mmol) in acetone (2.5 mL)
was stirred at room temperature for 2.5 h under Ar. TLC analysis
indicated that starting material still remained so the reaction
mixture was heated at 40 ꢀC (bath) for 3 h, then allowed to cool
to room temperature and left to stir for a further 16 h. The mix-
ture was diluted with H2O (40 mL) and extracted with CH2Cl2
(3ꢂ20 mL). The combined organic extracts were washed with
brine (20 mL), dried and concentrated to give a brown oil, which
was subjected to radial chromatography. Elution with 2.5%
EtOAc/light petroleum gave ethyl 3-hydroxy-6,11-dimethoxy-
benzo[b]naphtho[2,3-d]furan-2-carboxylate (51) as
a white
crystalline solid (52 mg, 28%), which recrystallised from CH2Cl2/
petroleum as prisms, mp 154–155 ꢀC. EIMS m/z: 366 (M, 41%),
351 (19), 320 (18), 306 (19), 305 (100), 290 (26). dH (500 MHz,
CDCl3) 11.55 (1H, s, OH), 8.36–8.34 (1H, m, ArH), 8.23–8.22 (2H,
m, ArH), 7.54–7.51 (2H, m, ArH), 7.03 (1H, d, J 8.5, ArH), 4.57 (2H,
q, J 7.2, OCH2), 4.45 (3H, s, OCH3), 4.09 (3H, s, OCH3), 1.56 (3H, t, J
7.2, CH3). dC (125.75 MHz, CDCl3) 169.7 (C]O), 162.8 (C), 156.2
(C), 143.9 (C), 142.8 (C), 134.9 (C), 129.3 (CH), 126.1 (C), 125.2 (C),
125.1 (CH), 124.7 (CH), 122.4 (CH), 121.4 (CH), 117.2 (C), 115.2 (C),
113.1 (CH), 99.6 (C), 62.0 (OCH2), 61.6 (OCH3), 60.6 (OCH3), 14.2
(CH3). nmax (CH2Cl2)/cmꢁ1 1670 (C]O). HRMS calcd for C21H18O6
Mþ: 366.1103, found: 366.1099.
3.1.15. 3-Hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-
5,10-dione (1)
A solution of ethyl 5,10-dioxofuro[3,2-b]naphtho[2,3-d]furan-3-
carboxylate (53) (12 mg, 0.039 mmol) in anhydrous THF (1.5 mL)
was added to a suspension of LiAlH4 (62 mg,1.6 mmol) in anhydrous
THF (1.5 mL) at 0 ꢀC under Ar and the resulting mixture was stirred
for 20 min. The reaction mixture was quenched with a little EtOAc
and ice, then diluted with water (5 mL) and extracted with CHCl3
(1ꢂ3 mL), followed by EtOAc (4ꢂ3 mL). The combined organic ex-
tracts were washed with brine and concentrated under reduced
pressure. To the resulting brown residue were added Fremy’s salt
(40 mg, 0.15 mmol), Et2O (3 mL) and an aqueous borax buffer so-
lution (0.025 M sodium tetraborate, 2.7 mL; 0.1 M NaOH, 1.3 mL)
and the resulting mixture was shaken vigorously for 20 min. The
organic layer was separated and the aqueous layer was extracted
with CHCl3 (4ꢂ3 mL). The combined organic extracts were washed
with brine, dried and concentrated to give a red residue, which was
subjected to radial chromatography. Elution with 50–70% EtOAc/
light petroleum afforded 3-hydroxymethylfuro[3,2-b]naphtho[2,3-
d]furan-5,10-dione (1) as a red solid (5 mg, 49%), mp 204 ꢀC onwards
(sublimed and underwent crystal phase change), 240–241 ꢀC
(melted) (lit.7 217–218 ꢀC). EIMS m/z: 269 (Mþ1, 22%), 268 (M, 100),
252 (17). The 1H and 13C NMR spectral data are given in Table 1. nmax
(KBr)/cmꢁ1 3485 (OH), 1672 (C]O), 1651 (C]O). HRMS calcd for
C15H8O5 Mþ: 268.0372, found: 268.0368.
3.1.13. Ethyl 5,10-dimethoxyfuro[3,2-b]naphtho[2,3-d]furan-3-
carboxylate (52)
A stirred suspension of 3-(2-furyl)-1,4-dimethoxynaphthalen-2-
ol (21) (193 mg, 0.715 mmol), ethyl 3-bromopropiolate (201 mg,
1.14 mmol) and K2CO3 (250 mg, 1.80 mmol) in acetone (5 mL) was
heated at 40 ꢀC (bath) under Ar until TLC indicated that the starting
material had been consumed (ca. 3.5 h). The reaction mixture was
filtered through a plug of Celite and washed through with a little
acetone. The filtrate was diluted with toluene (5 mL) and most of the
acetone was removed by distillation. Then the solution was treated
with 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (169 mg, 0.716 mmol)
and heated at reflux for 5.5 h under Ar. The resulting dark brown
mixture was adsorbed onto silica and subjected to silica gel filtra-
tion. Elution with 1% EtOAc/light petroleum gave a number of
fractions containing the impure title compound, which were com-
bined and further subjected to radial chromatography. Elution with
2.5–5% EtOAc/light petroleum gave ethyl 5,10-dimethoxyfuro[3,2-
Acknowledgements
We thank Dr. Lindsay Byrne for 2D NMR spectra and for the
spectral simulation. Thanks to Dr. Tony Reader for mass spectra and

L.B. Nielsen et al. / Tetrahedron 65 (2009) 4569–4577
4577
Professor David Kingston for correspondence regarding the 13C
NMR spectrum of 1.
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