Addition of silyloxydienes to 2,6-dibromo-1,4-benzoquinone: An approach to highly oxygenated bromonaphthoquinones for the synthesis of thysanone

Article abstract of DOI:10.1016/S0040-4020(03)00291-6

The synthesis of tetraoxygenated bromonaphthoquinones 6a, 6b, 6c, 6d, key intermediates for a synthesis of the 3C protease inhibitor, thysanone, were investigated. Addition of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene 8 to 2,6-dibromo-1,4-benzoquinone 10 in benzene afforded a mixture of naphthoquinone 6a, arising from Diels-Alder addition followed by aromatisation, and Michael adduct 12. The Michael adduct 12 predominated when THF was used as solvent whereas 6a predominated when benzene was used. Naphthoquinone 6a underwent benzylation to naphthoquinone 6c. Addition of 1,1-dimethoxy-3-trimethylsilyloxy-1,3-butadiene 9 to 2,6-dibromo-1,4-benzoquinone 10 followed by benzylation failed to afford the desired bromonaphthoquinone 6d yet methylation did afford naphthoquinone 6b. Bromonaphthoquinone 6d was finally prepared from naphthol 18, obtained from addition of diene 9 to 1,4-benzoquinone 17, followed by ortho-bromination and oxidation. Attempted Sakurai allylation of bromonaphthoquinone 6d afforded naphthodihydrofuran 21. A similar observation was observed for 2-carbomethoxy-1,4-naphthoquinone 22 that also underwent Sakurai allylation to afford naphthodihydrofuran 23. The structure of Michael adduct 12 was confirmed by X-ray crystallography.

Full text of DOI:10.1016/S0040-4020(03)00291-6

Tetrahedron 59 (2003) 2441–2449
Addition of silyloxydienes to 2,6-dibromo-1,4-benzoquinone:
an approach to highly oxygenated bromonaphthoquinones
for the synthesis of thysanone
a
a
David Barker,a Margaret A. Brimble,b Peter Do and Peter Turner
,
*
aSchool of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
bDepartment of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 25 November 2002; revised 28 January 2003; accepted 20 February 2003
Abstract—The synthesis of tetraoxygenated bromonaphthoquinones 6a, 6b, 6c, 6d, key intermediates for a synthesis of the 3C protease
inhibitor, thysanone, were investigated. Addition of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene 8 to 2,6-dibromo-1,4-benzoquinone
10 in benzene afforded a mixture of naphthoquinone 6a, arising from Diels–Alder addition followed by aromatisation, and Michael adduct
12. The Michael adduct 12 predominated when THF was used as solvent whereas 6a predominated when benzene was used. Naphthoquinone
6a underwent benzylation to naphthoquinone 6c. Addition of 1,1-dimethoxy-3-trimethylsilyloxy-1,3-butadiene 9 to 2,6-dibromo-1,4-
benzoquinone 10 followed by benzylation failed to afford the desired bromonaphthoquinone 6d yet methylation did afford naphthoquinone
6b. Bromonaphthoquinone 6d was finally prepared from naphthol 18, obtained from addition of diene 9 to 1,4-benzoquinone 17, followed by
ortho-bromination and oxidation. Attempted Sakurai allylation of bromonaphthoquinone 6d afforded naphthodihydrofuran 21. A similar
observation was observed for 2-carbomethoxy-1,4-naphthoquinone 22 that also underwent Sakurai allylation to afford naphthodihydrofuran
23. The structure of Michael adduct 12 was confirmed by X-ray crystallography. q 2003 Elsevier Science Ltd. All rights reserved.
The replication of many animal and plant viruses relies on
proteolytic processing and is dependent upon two virally
encoded proteases 3C-protease and 2A-protease. Human
rhinoviruses belong to a family of picornaviruses that are
responsible for causing common colds1 as well as polio,
hepatitis A and foot and mouth disease.2 Human rhinovirus
3C-protease is therefore an attractive target for the screen-
ing of lead compounds for eventual control or cure of the
common cold. Thysanone 1, isolated from Thysanophora
penicilloides3 was found to exhibit potent activity (IC50
13 ug/ml) against human rhinovirus 3C-protease by scien-
tists at Merck, Sharp and Dohme who were screening
microbial extracts against this enzyme. Thysanone 1 is
closely related to the pyranonaphthoquinone family of
antibiotics4 and the absolute stereochemistry of thysanone 1
was established to be (1R,3S) by an elegant total synthesis
recently reported by Donner and Gill.5
In the synthesis of thysanone 1 by Donner and Gill5 the
(S)-stereochemistry at C-3 was derived in nine steps from
(S)-mellein which in turn was prepared in several steps from
(S)-propylene oxide. The oxygenated naphthalene ring was
assembled at a late stage via Diels–Alder addition of a
silyloxydiene to a bromobenzoquinone that already con-
tained a dihydrobenzopyran ring appended to it. Our
synthetic approach to thysanone 1 was based on a strategy
wherein the stereochemistry at C-3 is controlled using an
asymmetric reduction and an efficient synthesis of
(1S,3R)-dideoxythysanone 2 was recently reported6 using
this strategy. This approach to thysanone 1 differed from
that used by Donner and Gill5 in that construction of the
dihydrobenzopyran was envisaged to take place from
bromoalcohol 3 that is derived from reduction of ketone
4. Ketone 4 is formed from allylbromonaphthalene 5 via
Wacker oxidation. Allylbromonaphthalene 5 in turn is
available from Sakurai allylation of a suitably oxygenated
bromonaphthoquinone 6 that is obtained by oxidative
demethylation of tetraoxygenated bromonaphthalene 7
(Scheme 1). We therefore herein report our efforts to
prepare suitable oxygenated bromonaphthoquinones 6 that
will enable us to complete our synthesis of thysanone 1
based on our initial synthesis of dideoxythysanone 2.
Thysanone 1 0has the same oxygenation pattern as quinone
A, quinone A and deoxyquinone A which are derivatives of
the aphid pigments protoaphin-fb,17 protoaphid-sl,7 and
deoxyprotoaphin.8 Giles et al.9,10 have developed a
Keywords: bromonaphthoquinone; Michael adduct; thysanone.
*
Corresponding author. Tel.: þ64-93737599; fax: þ64-937374422;
e-mail: m.brimble@auckland.ac.nz
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00291-6

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D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
Scheme 1.
synthesis of these aphid derivatives and have established
that a benzyl ether was a suitable protecting group for 7-OH.
However, the use of methyl or isopropyl ethers at this
position led to destruction of the sensitive pyran ring during
deprotection in related synthetic studies towards quinone
A.11 A benzyl ether at the C-7 position is thought be to more
suitable as it can be removed by hydrogenolysis over
palladium on charcoal. This milder deprotection would be
less damaging to the pyran ring in thysanone 1. The 9-OH
group can be protected as either a methyl or benzyl ether, as
Table 1. Addition of silyloxydienes 8 and 9 to 2,6-dibromo-1,4-benzoquinone 10
Diene
Quinone
Conditions
Products, yield (%)
Entry 1
Entry 2
Entry 3
Entry 4
Entry 5
Benzene, room temperature, 18 h.
Benzene, reflux, 4 h.
CH2Cl2 reflux, 12 h.
THF, room temperature, 4 h
THF, 2788C, 2 h. then HCl
32
19
26
6
12
8
12
15
40
14
Entry 6
Entry 7
Entry 8
(i) Benzene, reflux, 1 h,
(ii) MeOH, 5% HCl, (iii) MeI, Ag2O
25
(i) Benzene, reflux, 1 h,
(ii) MeOH, 5% HCl, (iii) BnBr, Ag2O
Complex mixture no 6d isolated
(i) Benzene, room temperature, 1 h,
(ii) BnBr, K2CO3 DMF, 608C
31

D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
2443
Scheme 2.
it is peri to the quinone carbonyl group at C-10 and can
therefore be more easily removed than a 7-OMe group using
boron tribromide.
trimethylsilyl chloride afforded diene 8 in over 90% yield.
Diene 8 could only be stored in the freezer at 258C for 1
week due to the facile migration25 of the trimethylsilyl
group attached to the oxygen at C-1 to C-4.
Bromonaphthoquinones 6c and 6d in which the hydroxyl
group at C-7 is protected as a benzyl ether were considered
suitable intermediates for our synthesis of thysanone 1.
These compounds were envisaged to be assembled by
Diels–Alder addition of 1-methoxy-1,3-bis(trimethylsilyl-
oxy)-1,3-butadiene 8 or 1,1-dimethoxy-3-trimethylsilyloxy-
1,3-butadiene 9 to 2,6-dibromo-1,4-benzoquinone 10 (Table
1). The presence of strategically placed halogen substituents
in benzoquinone and naphthoquinone dienophiles controls
the regiochemistry of the cycloaddition such that the
nucleophilic end of an electron rich diene adds to the
unsubstituted carbon of the quinone.12–18
Addition of diene 8 to 2,6-dibromo-1,4-benzoquinone 10 in
dry benzene under nitrogen for 18 h. afforded the Diels–
Alder adduct 6a as an orange solid in 32% yield together
with the conjugate addition product 12 in 12% yield.
Bromonaphthoquinone 6a exhibited a broad absorbance at
3400–3500 cm21 consistent with the presence of the two
hydroxyl groups and an absorbance at 1653 cm21 due to the
quinonoid carbonyls. The 1H NMR spectrum of 6a
exhibited meta-coupled aromatic doublets at dH 6.63 and
dH 7.04 (J 2.5 Hz), assigned to 8-H and 6-H, respectively,
and a singlet at dH 7.49 was assigned to the quinonoid
proton, 2-H. The two hydroxyl protons, 7-OH and 5-OH
resonated at dH 10.32 and dH 11.87, respectively, with 5-OH
resonating further downfield due to hydrogen bonding to the
C-4 quinone carbonyl group.
Our initial attention focused on the synthesis of bromo-
naphthoquinone 6c available from benzylation of bromo-
naphthoquinone 6a, the anticipated Diels–Alder adduct
formed from 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
butadiene 8 and 2,6-dibromo-1,4-benzoquinone 10 (entries
1–5, Table 1). 2,6-Dibromo-1,4-benzoquinone 10 was
prepared uneventfully from 2,4-dibromo-4-nitrophenol
using the procedure reported by van Erp.19 Diene 8 was
prepared20–22 from silyl enol ether 11 (Scheme 2) that in
turn was available from methyl acetoacetate.23,24 In the
reported procedure24 for the preparation of silyl enol ether
11, a mixture of methyl acetoacetate, zinc chloride and
triethylamine in benzene was treated with trimethylsilyl
chloride and the reaction left to stir overnight. In our hands
we found that the reaction required stirring for 2–3 days in
order to obtain an acceptable 70% yield of the silyl ether 11.
Reaction of silyl ether 11 with lithium diisopropylamide in
THF at 2788C for 2 min followed by the addition of
Considerable effort was made to improve the yield of the
desired naphthoquinone 6a by conducting the reaction in a
variety of solvents and at different temperatures, however
these efforts were fruitless. Representative examples of
these attempts are summarized (entries 1–5, Table 1).
Adding base to the initial reaction mixture (pyridine or
NaHCO3) in order to mop up any hydrogen bromide formed
did not improve the yield. Alternatively, use of an acidic
workup or the addition of silica gel to the reaction in an
effort to facilitate the aromatization step, did not help.
It was found that use of THF as the solvent increased the
yield of the conjugate addition product 12 (entries 4 and 5,
Table 1) that was only observed as a minor product when
benzene was used as the solvent. The formation of Michael
adducts such as 12 is not without precedence in related
1
systems using highly electrophilic dienophiles.6,12 The H
NMR spectrum of Michael adduct 12 was difficult to assign
due to the presence of tautomers, however the structure of
12 was confirmed by X-ray crystallography (Fig. 1).
Benzylation of dihydroxynaphthoquinone 6a was carried
out using freshly prepared silver(I) oxide and benzyl
bromide in chloroform in the dark for 3 days (Scheme 3).
Although this procedure only afforded bis(benzyloxy)-
naphthoquinone 6c in 30% yield, alternative conditions
such as the use of sodium hydride in DMF or potassium
Figure 1.
Scheme 3. Reagents and conditions: (i) Ag2O, CHCl3, BnBr, room temperature, 3 days, 30%; (ii) Na2S2O4, Bu4NI, Me2So4, 50% KOH, THF, 75%.

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D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
Scheme 4. Reagents and conditions: (i) vinylidence chloride, AlCl3, 82%; (ii) NaOMe, MeOH, 08C, 63%; (iii) 1508C, 5 h, 44%; (iv) LDA, Me3SiCl, 2788C,
97%.
carbonate in acetone, only resulted in decomposition of
the starting material. Bis(benzyloxy)naphthoquine 6c was
unstable, thus in order to facilitate characterisation,
reductive methylation to dimethoxynaphthalene 13 was
carried out in 75% yield using sodium dithionite in aqueous
THF with tetrabutylammonium iodide followed by the
addition of potassium hydroxide and dimethyl sulfate.
literature procedure which involved heating the orthoester
15 at 1508C for exactly 5 h. Finally, enone 16 was treated
with lithium diisopropylamide and trimethylsilyl chloride to
afforded diene 9 in 97% yield. This procedure proved better
than using the literature method26 that used triethylamine
and trimethylsilyl chloride in benzene to effect the final
silylation step. Diene 9 needed to be redistilled immediately
before use in order to remove trace quantities of enone 15
that formed upon storage.
Given the disappointing yield of naphthoquinone 6a from
the addition of diene 8 to 2,6-dibromo-1,4-benzoquinone
10, we next focused our attention on the synthesis of
naphthoquinone 6d from reaction of diene 9 with 2,6-di-
bromo-1,4-benzoquinone 10 followed by benzylation of the
C-7 hydroxyl group (entry 7, Table 1). 1,1-Dimethoxy-3-
trimethylsilyloxy-1,3-butadiene 9 was prepared in four steps
from acetyl chloride (Scheme 4) using procedures that were
slightly modified from that given in the literature.26
Grandmaison and Brassard28 reported a procedure wherein
diene 9 and 2,6-dibromo-1,4-benzoquinone 10 were reacted
to form a Diels–Alder adduct that was hydrolysed using
methanol and 5% HCl. The crude adduct was not isolated
but immediately treated with methyl iodide and silver(I)
oxide to produce dimethoxynaphthoquinone 6b in 25%
yield. In order to generate naphthoquinone 6d in which
7-OH is protected as a benzyl ether rather than a methyl
ether, it was thought that the above procedure could be used
replacing methyl iodide with benzyl bromide. Disappoint-
ingly, substituting benzyl bromide for methyl iodide in this
procedure, afforded a complex mixture of products with
none of the desired product 6d being isolated (entry 7, Table
1). On the other hand, when the literature procedure with
methyl iodide was used the desired product 6b was afforded
in the anticipated 25% yield (entry 6, Table 1). Considerable
experimentation did not avail us of the desired naphtho-
quinone 6d when using benzyl bromide in the alkylation
step thereby leading us to conclude that addition of diene 9
to 2,6-dibromo-1,4-benzoquinone 10 is an unfavourable
process and other side products are generated in preference
to the required product 6d.
The first step in the synthesis of diene 9 involved
preparation of 4,4-dichlorobut-3-en-2-one 14 in 82% yield
via Friedel–Craft acylation of vinylidene chloride by acetyl
chloride using aluminium trichloride as reported by
Heilbron et al.27 In our hands, a slightly modified procedure
was used. Finely powdered aluminium chloride was added
to acetyl chloride at 298C. Conversion of enone 14 into the
trimethyl orthoester 15 was then effected using the method
of Banville and Brassard26 upon treatment with sodium
methoxide in methanol at 08C. Pyrolysis of orthoester 15 to
enone 16 proved to be the most difficult step. Banville and
Brassard26 reported that this pyrolysis proceeded in 35%
yield, however, it was hoped that modification of the
procedure might increase the yield of the desired product.
The literature procedure involved heating orthoester 15 in
a pear-shaped flask at 1608C for 5 h. After cooling, the
mixture was distilled at reduced pressure to afford the
product 16 in 44% yield together with recovered 15 in 25%
yield. It was found that leaving the pyrolysis for longer
periods of time led to decreased yields of enone 16 whilst
the yield of recovered starting material 15 did not change.
The reaction was also carried out at a higher temperature,
namely 1908C for 5 h, however this also led to decompo-
sition of the desired product. Thus it was found that the
optimum yield of enone 16 was obtained by adhering to the
We next considered that the desired bromonaphthoquinone
6d could be formed by bromination and oxidation of
naphthol 18 (Scheme 5). Naphthol 18 in turn, has been
prepared albeit in low yield, from cycloaddition of diene 9
to 1,4-benzoquinone 17 followed by benzylation.10 Follow-
ing the procedure described by Giles et al.10 a solution of
diene 9 and 1,4-benzoquinone 17 in benzene was stirred at
room temperature for 12 h. The solvent was removed and
the crude adduct redissolved in DMF then treated with
benzyl bromide and anhydrous potassium carbonate. After
Scheme 5. Reagents and conditions: (i) Br2, CCl4, 08C, 83%; (ii) NAH, Mel, DMF, 83%; (iii) Ce(NH4)2(NO3)6, CH3CN, 1 h, 08C, 79%; (iv) MeAlCl2, CH2Cl2,
2788C, allyltrimethylsilane, 48%.

D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
2445
further stirring at 408C for 18 h. naphthol 18 was isolated in
31% yield after purification by flash chromatography and
was found to be unstable when stored at room temperature.
the early stages of a longer synthesis, have now prompted us
to rethink our synthetic strategy to thysanone 1 in a direction
far removed from our original synthesis of dideoxythysa-
none 2.6 The formation of the unusual naphthodihydro-
furans 21 and 23 upon attempts to effect Sakurai reaction
of the highly electrophilic benzoquinones 6d and 22
with allyltrimethylsilane, have also provided impetus for
development of an alternative strategy.
With naphthol 18 in hand, a bromine can now be introduced
at the ortho position as required for a synthesis of thysanone
1, that then serves as a vital tool for introduction of an
aldehyde group. ortho-Bromination of naphthol 18 was
therefore effected smoothly using bromine in carbon
tetrachloride at 08C affording unstable bromonaphthol 19
in 83% yield that then underwent methylation under
standard conditions to tetraoxygenated bromonaphthalene
20. The 1H NMR spectrum for bromonaphthol 19 exhibited
two meta-coupled doublets with J¼2 Hz at dH 6.64 ppm and
dH 7.25 ppm assigned to 6-H and 8-H respectively, together
with a singlet at dH 7.02 ppm assigned to H-2, thereby
providing strong evidence for introduction of a bromine at
C-3. Bromonaphthol 19 also underwent smooth oxidation
with ceric ammonium nitrate (2.5 equiv.) in acetonitrile to
bromonaphthoquinone 6d thereby providing a suitable
intermediate for our projected synthesis of thysanone 1.
Successful introduction of a bromine substituent onto the
quinonoid nucleus was important in order to control the
regiochemistry of the subsequent allylation step by
bidentate coordination with the quinone carbonyl group at
C-4 to a Lewis acid.
1. Experimental
1.1. General details
All reactions were conducted in flame-dried or oven-dried
glassware under a dry nitrogen atmosphere unless otherwise
noted. Tetrahydrofuran was dried over sodium/benzo-
phenone and distilled prior to use. Flash chromatography
was performed using Merck Kieselgel 60 (230–400 mesh)
with the indicated solvents. Thin layer chromatography
(TLC) was carried out on precoated silica plates (Merck
Kieselgel 60F254) and compounds were visualized by UV
fluorescence or by staining with vanillin in methanolic
sulfuric acid and heating. Infrared spectra were recorded
with a Perkin–Elmer 1600 series Fourier-transform infrared
spectrometer as thin films between sodium chloride plates.
Absorption maxima are expressed in wavenumbers (cm21
)
With bromonaphthoquinone 6d finally in hand, our attention
turned to the introduction of an allyl group at C-2. Attempts
to effect oxidative allylation of bromonaphthoquinone 6d
with vinylacetic acid, potassium persulfate and silver nitrate
as successfully used by Kometani et al.29 on a simpler
system, was unsuccessful and only starting material was
recovered from the reaction. We therefore turned to the use
of allyltrimethylsilane with methylaluminium dichloride as
the Lewis acid at 2788C as these conditions had been
successfully used by us in our earlier synthesis of
dideoxythysanone 2.6
with the following abbreviations: s¼strong, m¼medium,
1
w¼weak and br¼broad. H and 13C NMR spectra were
obtained using a Bruker AC 200B or a Bruker AM 400
spectrometer. All chemical shifts are given in parts per
million (ppm) downfield from tetramethylsilane as internal
standard (1H) or relative to CDCl3 (13C) and J values are
1
given in Hz. H NMR data are tabulated as s, singlet; d,
doublet; t, triplet; q, quartet, m, multiplet, br, broad. High-
resolution mass spectra were recorded using a VG70-SE
spectrometer operating at nominal accelerating voltage of
70 eV. Chemical ionisation (CI) mass spectra were obtained
with ammonia as the reagent gas.
More recently, attempted allylation of bromonaphtho-
quinone 6d using these same conditions afforded the highly
unstable naphthodihydrofuran 21. Naphthodihydrofuran 21
arises from trapping of the initial b-silyl carbocation formed
upon Michael addition of the allylsilane to the naphtho-
quinone, by the incumbent naphthol OH group at C-1 that is
generated upon aromatization of the aromatic ring. Further
support for the formation of naphthodihydrofuran 21 was
also observed by us when attempted Sakurai allylation
of naphthoquinone 22 afforded naphthodihydrofuran 23
(Scheme 6).
1.1.1. Methyl 3-trimethylsilyloxybut-2-enoate 11. Anhy-
drous powered zinc chloride (0.2 g, 1.47 mmol) was added
to triethylamine (15.8 cm3, 0.11 mol) and the mixture
stirred at room temperature for 1 h. or until the salt had
become suspended in the amine. To this suspension was
added a solution of methyl acetoacetate (10.8 cm3,
0.05 mol) in dry benzene (15 cm3) followed by trimethyl-
silyl chloride (10.85 g, 0.1 mol). The reaction mixture was
heated to 408C and stirred for 30 min, after which time the
reaction mixture was cooled to room temperature and stirred
for 2 days. Ether (100 cm3) was added and the reaction
mixture filtered. The filtrate and ether washes were
combined and concentrated in vacuo to give a yellowish
oil. Distillation of the crude oil at reduced pressure using a
Vigreux column gave the title compound 11 (13.9 g, 70%)
as a clear oil, bp 82–848C/30 mm Hg (lit.20 bp 71–
728C/9 mm Hg).
The difficulties described herein with our attempts to obtain
bromonaphthoquinones 6a, 6b, 6c or 6d in a respectable
yield, as required for the synthesis of a key intermediate at
1.1.2. 1-Methoxy-1,3-bis(trimethylsilyloxy)-buta-1,3-
diene 8. Butyllithium in hexanes (9 cm3, 22.5 mmol,
2.5 mol l21) was added dropwise to a stirred solution of
diisopropylamine (2.16 g, 3 cm3, 21.3 mmol) in THF
(75 cm3) under nitrogen at 08C. The solution was then
Scheme 6. Reagents and conditions: (i) MeAlCl2, CH2Cl2, 2788C,
allyltrimethylsilane, 51%.

2446
D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
cooled to 2788C and methyl 3-trimethylsilyloxybut-2-
enoate 11 (3.3 g, 17.7 mmol) added dropwise, over 5 min.
After stirring for 3 min, trimethylsilyl chloride (3.07 g,
3.6 cm3, 28.5 mmol) was added. The reaction mixture was
allowed to warm to room temperature and the solvent
removed in vacuo. The residue was washed with dry hexane,
filtered and concentrated in vacuo to yield the title
residue was washed with dry hexane, filtered and concen-
trated in vacuo to yield the title compound 9 (5.21 g, 97%)
as a clear oil for which the 1H NMR spectrum was in
agreement with the literature.26
1.1.7. 2,6-Dibromo-1,4-benzoquinone 10. Tin granules
(8 g) were slowly added to a solution of 2,4-dibromo-4-
nitrophenol (10 g, 0.33 mol) in acetic acid (40 cm3) over
10 min. and the reaction mixture stirred until most of the tin
was consumed (approx. 2 h). The reaction mixture was then
filtered and the solid residue washed with boiling acetic acid
(5 cm3). The combined filtrate and washes were then
quickly added to a solution of chromium trioxide (11 g) in
conc. H2SO4 (50 cm3) and water (500 cm3). The solution
instantly darkened and a yellow precipitate was formed.
After stirring for 15 min, the solution was filtered, the solid
washed with water (2£50 cm3) then left to dry in air
overnight. The crude solid was recrystallized from ethanol
to give the title compound 10 (5.52 g, 61%) as golden flakes,
mp 126–1278C (lit.19 129–1308C).
1
compound 8 (4.57 g, 99%) as a clear oil for which the H
NMR spectrum was in agreement with the literature.20
1.1.3. 4,4-Dichlorobut-3-en-2-one 14. Finely powered
aluminium chloride (100.3 g, 0.75 mol) was added in
portions, over 10 min, to acetyl chloride (100.8 g, 91 cm3,
1.27 mol) at 298C (ice/salt bath). Upon completion of the
addition, the reaction was allowed to warm to room
temperature. Vinylidene chloride (60.1 g, 50 cm3,
0.62 mol) was then added dropwise over 1.5 h, with
continuous stirring, forming a fine yellow precipitate. The
reaction mixture was stirred for 1 h before quenching by
slow addition of ice, then water (100 cm3). After extraction
into dichloromethane (4£100 cm3), the combined organic
layers were washed with water (3£100 cm3), dried (MgSO4)
and concentrated in vacuo to yield the crude product.
Further purification by distillation under vacuum using a
Vigreux column yielded the title compound 14 (70.6 g,
82%), as a pale yellow oil, bp 53–558C/26 mm Hg (lit.27 bp
588C/32 mm Hg).
1.1.8. 3-Bromo-5,7-dihydroxy-1,4-naphthoquinone 6a
and methyl 3-oxo-4-(2,4 dibromo-3,6-dihydroxyphenyl)-
butanoate 12. To a solution of 2,6-dibromo-1,4-benzo-
quinone 10 (0.47 g, 1.75 mmol) in dry benzene (5 cm3)
under nitrogen, at room temperature, was added, dropwise
over 10 min, a solution of diene 8 (0.5 g, 2 mmol) in dry
benzene (5 cm3). The reaction mixture was stirred for 18 h,
after which time the solvent was removed in vacuo to yield a
crude residue. The residue was purified by flash chroma-
tography (20–30% ethyl acetate–hexane) to afford the title
compound 6a (0.15 g, 32%) as a bright orange solid, mp
192–1948C. (Found: Mþ, 269.9383; 267.9388. C10H5O841Br
and C10H5O749Br require 269.9350; 267.9371); nmax (NaCl
plates)/cm21 3425 (OH), 1699 and 1653 (CvO) and 1599
(CvC); dH (200 MHz, d6-acetone) 6.63 and 7.04 (each 1H,
d, J¼2.5 Hz, 6-H and 8-H), 7.49 (1H, s, 2-H), 10.32 (1H, bs,
7-OH) and 11.87 (1H, s, 5-OH); m/z (%) 270 (81Br Mþ, 81),
268 (79Br Mþ, 83), 189 (M2Br, 26) and 161 (100)
and methyl 3-oxo-4-(2,4-dibromo-3,6-dihydroxyphenyl)-
butanoate 12 (0.08 g, 12%) as pale crystals, mp 137–
1388C. (Found: Mþ, 383.8878; 381.8880; 379.8899.
C11H10O581Br2, C11H10O581Br79Br and C11H10O759Br2 require
383.8854; 381.8875; 379.8895); nmax (NaCl plates)/cm21
3300–3500 (OH), 1740 (CvO) and 1696 (CvC); m/z (%)
382 (79Br81Br Mþ, 10), 350 (M2MeOH, 23), 308 (73), 281
(56) and 101 (100). The structure of 12 was confirmed by
X-ray crystallography (vide infra).
1.1.4. 4,4,4-Trimethoxybutan-2-one 15. Freshly cut
sodium metal (6.98 g, 0.302 mol) was added to dry
methanol (120 cm3) with vigorous stirring. Upon complete
dissolution 4,4-dichlorobut-3-ene-2-one 14 (20 g, 0.144 mol)
was added dropwise over 1 h. The reaction mixture was then
stirred for 2 h., then quenched by pouring into water
(100 cm3) and extracting with dichloromethane (6£50 cm3).
The combined organic extracts were washed with water
(2£50 cm3), dried (MgSO4) and evaporated in vacuo to
yield an oil. The crude oil was purified by distillation under
vacuum to yield the title compound 15 (14.9 g, 63%) as
a
12 mm Hg).
clear oil, bp 48–508C/2 mm Hg (lit.26 82–848C/
1.1.5. 4,4-Dimethoxybut-3-en-2-one 16. 4,4,4-Trimethoxy-
butan-2-one 15 (12 g, 0.07 mol) was pyrolyzed, by heating
in a pear-shaped flask, at 1608C for 5 h. After cooling to
room temperature, distillation under reduced pressure
afforded the title compound 16 (4.2 g, 44%) as a yellow
oil, bp 80–828C/0.8 mm Hg (lit.26 bp 104–1058C/
1
10 mm Hg) and starting material 15 (3.03 g, 25%). The H
NMR spectrum of enone 16 was in agreement with the
1.1.9. 5,7-Bis(benzyloxy)-3-bromo-1,4-naphthoquinone
6c. To a suspension of 3-bromo-5,7-dihydroxy-1,4-naphtho-
quinone 6a (140 mg, 0.52 mmol) in chloroform (8 cm3)
under nitrogen, was added silver(I) oxide (0.72 g,
3.12 mmol)33 and benzyl bromide (0.53 g, 0.37 cm3,
3.12 mmol). The reaction mixture was vigorously stirred
for 3 days, within which time two subsequent portions of
silver(I) oxide (0.36 g, 1.56 mmol) and benzyl bromide
(0.26 g, 0.18 cm3, 1.56 mmol) were added. After this time
the reaction mixture was diluted with chloroform (15 cm3),
filtered through a small Celite pad and the solvent removed
in vacuo to yield an oily residue. The residue was purified
by flash chromatography (5–20% ethyl acetate–hexane) to
afford the title compound 6c (69 mg, 30%) as an orange
literature.26
1.1.6. 1,1-Dimethoxy-3-trimethylsilyloxy-1,3-butadiene
9. Butyllithium in hexanes (12.8 cm3, 32 mmol,
2.5 mol l21) was added dropwise to a stirred solution of
diisopropylamine (8.64 g, 12 cm3, 21.3 mmol) in THF
(75 cm3) under nitrogen at 08C. The reaction mixture was
then cooled to 2788C and a solution of 4,4-dimethoxy-
butan-2-one 16 (3.45 g, 26.5 mmol) in dry THF (10 cm3)
added dropwise, over 10 min. After stirring for 30 min,
trimethylsilyl chloride (4.43 g, 5.2 cm3, 39.8 mmol) was
added and the reaction mixture allowed to warm to room
temperature before the solvent was removed in vacuo. The

D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
2447
oil. (Found: Mþ, 450.0154; 448.0288. C24H17O841Br and
C24H17O749Br require 450.0290; 448.0310); nmax (NaCl
plates)/cm21 1660 (CvO) and 1592 (CvC); dH (400 MHz,
CDCl3) 5.18 (2H, s, 5-OCH2Ph), 5.22 (2H, s, 7-OCH2Ph),
7.12 (1H, s, 2-H) and 7.12–7.65 (12H, m, Ar-H); m/z (%)
450 (81Br Mþ, 2), 448 (79Br Mþ, 2), 357 (M2CH2Ph 10)
and 91 (CH2Ph 100).
464.0662. C25H21O841Br and C26H23O749Br require
466.0603; 464.0623); nmax (NaCl plates)/cm21 3382
(OH), 1619 (CvC); dH (400 MHz, CDCl3) 4.03 (3H, s,
5-OMe), 5.13 (4H, s, 2£OCH2Ph), 6.64 (1H, d, J¼2.3 Hz,
6-H), 7.02 (1H, s, 2-H), 7.25 (1H, d, J¼2.3 Hz, 8-H), 7.35–
7.48 (10H, m, Ar-H) and 9.43 (1-H, s, 4-OH); dC (100 MHz,
CDCl3) 57.2, 70.9, 71.9, 96.7, 100.5, 100.9, 112.3, 113.5,
127.7, 128.2, 128.5, 128.7, 128.9, 129.0, 129.3, 129.4,
137.3, 137.7, 145.6, 147.3, 157.2 and 157.6; m/z (%) 466
(81Br Mþ, 14), 464 (79Br Mþ, 15), 373 (52), 375 (53), 91
(PhCH2, 100).
1.1.10. 5,7-Bis(benzyloxy)-3-bromo-1,4-dimethoxynaph-
thalene 13. To a stirred solution of naphthoquinone 6c
(30 mg, 0.07 mmol) and tetrabutylammonium iodide (5 mg,
0.02 mmol) in aqueous THF (30% water–70% THF) was
added a solution of sodium dithionite (70 mg, 0.4 mmol) in
water (0.2 cm3). After 30 min a solution of potassium
hydroxide (50%, 1 cm3) was added followed 10 min later by
dimethyl sulfate (1.3 cm3, 13.75 mmol). After 12 h. the
reaction mixture was poured into water (15 cm3), extracted
with dichloromethane (2£10 cm3), dried (MgSO4) and the
solvent removed in vacuo. The crude residue was purified
by flash chromatography (10% ethyl acetate–hexane) to
yield the title compound 13 (34 mg, 75%) as a yellow–
green oil. (Found: Mþ, 480.0743; 478.0758. C26H23O841Br
and C26H23O749Br require 480.0759; 478.0780); nmax (NaCl
plates)/cm21 1592 (CvC); dH (200 MHz, CDCl3) 3.95 (3H,
s, 4-OMe), 3.97 (3H, s, 1-OMe), 5.18 (2H, s, 5-OCH2Ph),
5.21 (2H, s, 7-OCH2Ph), 6.92–7.63 (13H, m, Ar-H); m/z
(%) 480 (81Br Mþ, 2), 478 (79Br Mþ, 2), 389 (81Br
M2CH2Ph, 5), 387 (79Br M2CH2Ph, 5), 91 (PhCH2, 100).
1.1.13. 1,7-Bis(benzyloxy)-3-bromo-4,5-dimethoxy-
naphthalene 20. To a stirred solution of bromonaphthol
19 (35 mg, 0.076 mmol) and methyl iodide (1.14 g,
0.5 cm3) in dry dimethylformamide (2 cm3) under hydro-
gen, was added a slurry of sodium hydride (4 mg,
0.15 mmol) in dry dimethylformamide (0.5 cm3). After
5 min, ice (2 cm3) was added to quench the reaction. The
reaction mixture was extracted with dichloromethane
(2£5 cm3), washed with water (10 cm3), dried (MgSO4)
and the solvent removed in vacuo. The resultant residue was
purified by flash chromatography (10% ethyl acetate–
hexane) to yield the title compound 20 (30 mg, 83%) as a
yellow oil. (Found: Mþ, 480.0766; 478.0712. C26H23O841Br
and C26H23O749Br require 480.0759; 478.0779); nmax (NaCl
plates)/cm21 1581 (CvC); dH (200 MHz, CDCl3) 3.86 (3H,
s, 5-OMe), 3.96 (3H, s, 4-OMe), 5.14 (2H, s, 7-OCH2Ph),
5.16 (2H, s, 5-OCH2Ph), 6.68 (1H, d, J¼2.4 Hz, 6-H), 7.01
(1H, s, 2-H), 7.21 (1H, d, J¼2.4 Hz, 8-H), 7.35–7.52 (10H,
m, Ar-H); m/z (%) 480 (81Br Mþ, 3), 478 (79Br Mþ, 3), 389
(81Br M2CH2Ph, 7), 387 (79Br M2CH2Ph, 7), 91 (PhCH2,
100).
1.1.11. 1,7-Bis(benzyloxy)-5-methoxy-4-naphthol 18. A
solution of recrystallized 1,4-benzoquinone (52) (0.4 g,
3.7 mmol) and freshly distilled diene 9 (0.97 g, 4.8 mmol)
in dry benzene (6 cm3) was stirred for 14 h under nitrogen.
The initial dark reddish solution turned to dark yellow. The
solvent was evaporated under reduced pressure to afford
the crude material. The crude material was dissolved in
dimethylformamide (20 cm3) under nitrogen, anhydrous
potassium carbonate (3.48 g, 25.2 mmol) and benzyl
bromide (4.43 g, 3.07 cm3, 25.2 mmol) were added and
the mixture stirred vigorously at 408C. After 24 h. the
reaction mixture was cooled, quenched with water (20 cm3)
and extracted with 30% ether–ethyl acetate (5£30 cm3).
The combined organic layers were washed with water
(2£20 cm3), dried (MgSO4) and the solvent removed in
vacuo. The resultant residue was purified by flash
chromatography (10% ethyl actetate–hexane) to yield the
title compound 18 (438 mg, 31%) as silver flakes, mp 160–
1.1.14. 7-Benzyloxy-3-bromo-5-methoxy-1,4-naphtho-
quinone 6d. To a solution of naphthol 19 (409 mg,
0.88 mmol) in acetonitrile (40 cm3) at 08C, was added
dropwise a solution of ceric ammonium nitrate (1.21 g,
2.21 mmol) in water (10 cm3) to give a yellow coloured
solution. After stirring at room temperature for 1 h, the
reaction mixture was poured into water (100 cm3) and
extracted with dichloromethane (3£100 cm3). The com-
bined organic extracts were dried over anhydrous mag-
nesium sulfate and filtered through a layer of florisil. The
solvent was removed under reduced pressure to afford a
residue. Further purification of the residue by flash
chromatography (10% ethyl acetate–hexane) yielded the
title compound 6d (260 mg, 79%) as a yellow solid, mp
130–1318C (dec.). (Found: Mþ, 373.9987; 371.9963.
C18H13O841Br and C18H13O749Br require 373.9977;
371.9997); nmax (NaCl plates)/cm21 1668 (CvO) and
1591 (CvC); dH (400 MHz, CDCl3) 3.98 (3H, s, OMe),
5.20 (2H, s, OCH2Ph), 6.80 (1H, d, J¼2.0 Hz, 6-H), 7.30
(1H, d, J¼2.0 Hz, 8-H) and 7.35–7.46 (6H, m, Ar-H and
2-H); dH (100 MHz, CDCl3) 57.3, 71.7, 105.5, 106.0, 114.2,
129.0, 129.9, 130.1, 136.4, 139.1, 144.9, 163.9, 165.6, 176.6
and 184.2; m/z (%) 374 (81Br Mþ, 44), 376 (79Br Mþ, 44),
91 (PhCH2, 100).
1
1618C (lit.10 159–1608C). The H NMR spectrum of the
product was in agreement with the literature.10
1.1.12. 1,7-Bis(benzyloxy)-3-bromo-5-methoxy-4-naph-
thol 19. To a stirred solution of naphthol 18 (60 mg,
0.155 mmol) in carbon tetrachloride (2 cm3) at 08C was
added dropwise a solution of bromine (28.8 mg, 0.18 mmol)
in carbon tetrachloride (0.87 cm3). After 5 min 10%
aqueous sodium thiosulfate (10%, 2 cm3) was added and
the reaction mixture allowed to warm to room temperature.
The mixture was then extracted with dichloromethane
(10 cm3), washed with water (10 cm3), dried (MgSO4) and
the solvent removed in vacuo. The resultant residue was
purified by flash chromatography (15% ethyl acetate–
hexane) to yield the title compound 19 (60 mg, 83%) as a
colourless solid, mp 139–1398C. (Found: Mþ, 466.0664;
1.1.15. Methyl 5-hydroxy-2-(trimethylsilylmethyl)-2,3-
dihydronaphtho[1,2-b]furan-4-carboxylate 23. To methyl
1,4-dimethoxynaphthalene-2-carboxylate30 (0.89 g, 3.62
mmol) in acetonitrile (30 cm3) at 08C was added 10%

2448
D. Barker et al. / Tetrahedron 59 (2003) 2441–2449
aqueous ceric ammonium nitrate (3.97 g, 7.2 mmol) with
stirring. After 20 min, the mixture was diluted with
dichloromethane (60 cm3) and poured into water (100 cm3)
containing pH 7 phosphate buffer (0.1 M, 5 cm3). The
organic layer was washed with brine (3£50 cm3), dried over
anhydrous magnesium sulfate, passed through a short
florisil pad and the solvent removed at reduced pressure.
The residue (presumed to be naphthoquinone 22) was dried
under high vacuum for 30 min then dissolved in dry
dichloromethane (50 cm3) and cooled to 2788C. Methyl-
aluminium dichloride (4.1 cm3, 1.0 M, 4.1 mmol) was then
added dropwise with stirring under an atmosphere of
nitrogen. After 5 min allyltrimethylsilane (0.57 cm3,
3.6 mmol) was added and the mixture stirred for 90 min at
2788C, followed by gradual warming to room temperature.
The reaction was quenched by the dropwise addition of
water (1 cm3) with vigorous stirring until the green solution
turned yellow. Water (100 cm3) was added, the organic
layer washed with brine (3£100 cm3) and dried over
anhydrous magnesium sulfate. After concentration in
vacuo the crude product was purified by flash chroma-
tography (1% ethyl acetate–hexane) to afford the title
compound 23 (0.59 g, 51%) as an unstable pale yellow
solid, mp 71–738C. (Found: Mþ, 330.1296. C18H22O4Si
requires Mþ, 330.1287); nmax (film) (cm21) 3360–2900
(OH), 1662 (CvO, o-hydroxyl aryl ester) and 1235 (Si–
CH3); dH (200 MHz, CDCl3) 0.24 (9H, s, SiMe3), 1.15 (1H,
OMe), 5.02–5.10 (1H, m, 2-H), 6.62 (1H, s, 7-H), 7.01 (1H,
s, 8-H), 7.30–7.53 (5H, m, Ar-H) and 9.34 (1H, s, OH); m/z
(%) 488 (81Br Mþ, 11), 486 (79Br Mþ, 11), 408 (32), 91
(86), 73 (100).
1.1.17. Crystallographic details for Michael adduct 12. A
brown blade like crystal having approximate dimensions of
0.30£0.15£0.08 mm3 was attached to a thin glass fibre, and
mounted on a Rigaku AFC7R diffractometer employing
graphite monochromated Cu Ka radiation from a rotating
anode generator. Primitive orthorhombic cell constants
were obtained from a least-squares refinement using the
setting angles of 25 reflections in the range 93.88,
2u,109.208. Diffraction data were collected at a tempera-
ture of 21^18C using v–2u scans to a maximum 2u value of
130.08. Omega scans of several intense reflections made
prior to data collection, had an average width at half-height
of 0.218, and scans of (1.78þ0.35 tan u)8 were made at a
speed of 32.08/min (in omega). The weak reflections
(I,15.0u(I)) were rescanned up to 10 times. Stationary
background counts were recorded on each side of the
reflection, with a 2:1 ratio of peak to background counting
time. The intensities of three representative reflections
measured every 150 reflections, did not change significantly
during the data collection. An empirical absorption correc-
tion based on azimuthal scans of three reflections was
applied and the data were also corrected for Lorentz and
polarisation effects. All calculations were undertaken with
the teXsan31 crystallographic software package. Neutral
atom scattering factors were taken from Cromer and
Waber.32 Anomalous dispersion effects were included in
Fcalc33 and the values for Df0 and Df00 were those of Creagh
and McAuley.34 The values for the mass attenuation
coefficients were those of Creagh and Hubbell.35 The
structure was solved36 and elaborated in the acentric space
group Pna21 (#33) with Fourier techniques.37 Non-hydro-
gen atoms were modelled with anisotropic thermal para-
meters. Hydrogen atoms were included in the model at
calculated positions with group thermal parameters. Refine-
ment of the inversion related structures elevated the
residuals by approximately 0.003. An ORTEP projection
of the molecule is provided in Figure 1.38
dd, Jgem¼14.4 Hz, J1 ,2¼7.4 Hz, 10-HA or 10-HB), 1.33 (1H,
0
dd, Jgem¼14.4 Hz, J1 ,2¼7.4 Hz, 10-HB or 10-HA), 3.13 (1H,
0
dd, Jgem¼16.6 Hz, J3,2¼8.2 Hz, 3-HA or 3-HB), 3.67 (1H,
dd, Jgem¼16.6 Hz, J3,2¼8.0 Hz, 3-HB or 3-HA), 3.97 (3H, s,
aryl CO2Me), 5.01–5.12 (1H, m, 2-H), 7.44–7.63 (2H, m,
7-H and 8-H), 7.86 (1H, d, J9,8¼8.2 Hz, 9-H), 8.36 (1H, d,
J6,7¼8.0 Hz, 6-H), 11.78 (1H, s, OH); dC (100 MHz,
CDCl3) 20.09, 26.3, 42.7, 52.7, 82.7, 104.1, 117.0, 122.0,
124.6, 125.0, 125.6, 126.1, 129.7, 147.9, 156.4 and 172.5;
m/z (%) 330 (Mþ, 32), 299 (24), 298 (59), 283 (52), 73 (100).
1.1.16. 8-Benzyloxy-4-bromo-6-methoxy-5-hydroxy-2-
(trimethylsilylmethyl)-2,3-dihydronaphtho[1,2-b]furan
21. To a solution of bromonaphthoquinone 6d (0.19 g,
0.51 mmol) in dichloromethane (5 cm3), cooled to 2788C
under nitrogen was added methylaluminium dichloride
(0.77 cm3, 1.0 M, 0.77 mmol) dropwise with stirring.
After 5 min allyltrimethylsilane (0.097 cm3, 0.61 mmol)
was added and the mixture stirred for 1 h at 2788C. The
reaction was quenched by the dropwise addition of saturated
sodium bicarbonate solution (1 cm3) and extracted with
dichloromethane (2£10 cm3). The organic extract was
washed with brine (1 cm3), dried over anhydrous mag-
nesium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography (15% ethyl
acetate–hexane) using flash silica that had been pre-treated
with triethylamine, to afford the title compound 21 (0.12 g,
48%) as an unstable yellow oil that rapidly darkened upon
standing. (Found: Mþ, 488.0822; 486.0844. C24H27O4Si81Br
and C24H27O4Si79Br require 488.0842; 486.0862); nmax
(film) (cm21) 3389 (OH), and 1607 (CvC); dH (200 MHz,
CDCl3) 0.12 (9H, s, SiMe3), 1.03 (1H, dd, Jgem¼14.5 Hz,
1.2. Crystal data
Empirical formula C11H10Br2O5, M 382.01, orthorhombic,
˚
˚
space group Pna21 (#33), a¼12.148(1) A, b¼4.962(1) A,
3
c¼21.060(1) A, V¼1269.5(2) A , Dc 1.999 g cm23, Z 4,
˚
˚
3
˚
crystal size 0.30£0.15£0.08 mm , l (Cu Ka) 1.5418 A, m
(Cu Ka) 82.36 cm21, T(analytical)min,max 0.68, 0.99, umax
65.0, hkl range 0 14, 0 5, 224 0, N 1316, Nobs 1043, R(F)
P
P
0.038, Rw(F) 0.040. R¼ llFol2lFcll/ lFol; Rw¼
P
P
(
w(Fo2Fc)2/ (wFc)2)1/2; w¼1/[s 2(Fo)]. Tables of
atomic coordinates, bond angles and bond lengths have
been deposited at the Cambridge Crystallographic database.
References
J1 ,2¼7.4 Hz, 10-HA or 10-HB), 1.18 (1H, dd, Jgem¼14.5 Hz,
0
J1 ,2¼7.4 Hz, 10-HB or 10-HA), 2.40–2.61 (1H, dd, Jgem
¼
0
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Jgem¼16.6 Hz, J3,2¼7.9 Hz, 3-HB or 3-HA), 3.99 (3H, s,

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