C S I R O P U B L I S H I N G

Australian Journal
of Chemistry
Volume 50, 1997
© CSIRO Australia 1997

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 Aust. J. Chem., 1997, 50, 189–192 .

Dimethyl Cubane-1,4-dicarboxylate:
A Practical Laboratory Scale Synthesis

Marianne Bliese A and John Tsanaktsidis A,B

A
Division of Chemicals and Polymers, CSIRO,
Private Bag 10, Clayton South MDC, Vic. 3169.
B
Author to whom correspondence should be addressed.

Complete experimental details for the preparation of dimethyl cubane-1,4-dicarboxylate (1) in multigram
quantities, from cyclopentanone (2), in an overall yield of c. 23% are presented.

Introduction Background Material

The fascination with cubane chemistry has continued The first successful synthesis of the cubane nucleus
unabated ever since the maiden construction of the was described by Eaton and Cole1 in 1964 in the guise
cubane nucleus by Eaton and Cole some 30 years ago.1 of the 1,4-dicarboxylic acid (3), and characterized as
Since then, an impressive array of knowledge and under- the dimethyl ester (1), in five steps starting from
standing leading to the preparation of many different cyclopent-2-enone (4) in an overall yield of c. 12%
cubane derivatives has been amassed.2,3 Indeed, recent (Scheme 1). Specifically, sequential treatment of (4)
reports have highlighted the potential of cubane com- with N -bromosuccinimide in refluxing CCl4 , followed
pounds as pharmaceuticals, novel polymeric materials, by molecular bromine in a mixture of pentane and
explosives and fuels.4 From a preparative point of view, CH2 Cl2 , produced a mixture of tribromides (5), which
however, the seminal development in the evolution of upon exposure to diethylamine in ether furnished the
cubane chemistry was the direct functionalization of the dicyclopentadienone (6) in an overall yield of c. 40%
cubane nucleus through ortho-metallation and subse- from (4). Ultraviolet irradiation of (6) in methanolic
quent elaboration of the derived metallocubane.5 Since HCl afforded the cage dione (7) after deketalization
then, Eaton6 and others7 have successfully employed
this technique, in its various modifications, to prepare O O O
an impressive range polysubstituted cubanes otherwise
(a) (b) Br
unaccessible. Furthermore, we have recently described
a general strategy that provides access to monoalky-
lated cubanes through the use of functionalized cubane
(4) Br Br Br
precursors.8 Despite these important developments,
(5)
routine access to multigram quantities of the versatile (c)
dimethyl cubane-1,4-dicarboxylate (1) (see below) is
problematic.∗ Indeed, Eaton3,9 has commented recently O
CO2X Br
that the Chapman-modified sequence has ‘evolved into O
Br
a simple five-step process providing 1 in about 25% (e) (d)
overall’; however, the details of this process are not
available in the literature. Herein, we disclose complete
XO2C Br
experimental details for the preparation of (1), from O
commercially available cyclopentanone (2) in multigram (1) X = Me O Br
quantities, through a streamlined synthetic route which (3) X = H (7) (6)

involves the isolation and purification of only three

Scheme 1. (a) N -Bromosuccinimide, CCl4 , azobisisobutyroni-
of the seven intermediates on route to (1) and which trile, ∆. (b) Br2 , pentane/CH2 Cl2 , 0–10◦ C. (c) Et2 NH, ether,
incorporates several improvements over the published −20◦ C. (d ) (i) hν, methanol, HCl; (ii) H2 O, ∆. (e) (i) 50%
procedures. aq. KOH, ∆; (ii) aq. HCl.

∗
Although (3) is now commercially available (Aldrich), its prohibitive cost is likely to impede further exploration.

Manuscript received 7 February 1997 10.1071/CH97021 0004-9425/97/030189$05.00

190
and dehydration. It is worth noting, however, that the
entity undergoing photocyclization is not the dione (6)
itself, but either its hemiketal and/or its dimethyl ketal.
Exposure of (7) to boiling 50% aqueous KOH produced
the diacid (3) through two consecutive Favorskii ring
contractions.
A significant improvement to the original protocol
of Eaton and Cole was introduced by Chapman and
coworkers10 in 1970 (Scheme 2). Starting with the
cheaper and more accessible cyclopentanone (2), these
workers developed a more convenient approach to the
key dicyclopentadienone intermediate (6). Protection
of (2) with ethane-1,2-diol furnished the ethylene ketal
(8), which upon treatment with 3 equiv. of molecular
bromine in dry 1,4-dioxan produced the tribromide
(9). Exposure of (9) to NaOMe in methanol afforded
the bisketal dimer (10), the bisethylene ketal of (6).
Selective deprotection of the less strained ketal in (10)
with concentrated HCl in tetrahydrofuran at room
temperature delivered the monoketal (12), which upon
irradiation in deoxygenated benzene with a Hanovia
450 W medium-pressure mercury lamp afforded the
cage ketal (13). Further deprotection with concen-
trated H2 SO4 delivered the cage dione (7) which was
collapsed to the diacid (3) in the normal way. It should
be mentioned, however, that Chapman and workers
experienced considerable difficulty with the conversion
of (7) into (3) and were not able to reproduce the yields
reported by Eaton and Cole.1 A subsequent report by
Luh and Stock11 provided full experimental detail for
the preparation of (3), and its dimethyl ester (1), by
the Eaton and Cole protocol and suggested that the
difficulties encountered by Chapman and coworkers
were a result of the workup procedure and not the
ring-contraction process itself.
O solution was more conveniently effected by adding the
O O
Br
(a) (b)
(2) (8)
O 1,4-dioxan, room temperature; (ii) NaOH, methanol, ∆.
Br
O O
O
Br
(e)
Br
O O
(13) (12) O
(f)
(g)
(7) (3)
Scheme 2. (a) Ethane-1,2-diol, benzene, TsOH, ∆. (b) 3 equiv.
Br2 , 1,4-dioxan, room temperature. (c) NaOMe, methanol,
∆. (d ) Conc. HCl, tetrahydrofuran, room temperature. (e)
hν, benzene, room temperature. (f ) Conc. H2 SO4 , room
temperature. (g) 50% aq. KOH, ∆.
M. Bliese and J. Tsanaktsidis
Results and Discussion
In the present work (Scheme 3), the ketal (8) was pre-
pared through condensation of (2) with ethane-1,2-diol
in the presence of a sulfonic acid resin which was found
to be a superior catalyst to p-toluenesulfonic acid.10
Treatment of (8) with bromine in 1,4-dioxan produced
the corresponding tribromide (9) which was immedi-
ately exposed to excess NaOH, in boiling methanol
(or ethanol) thus producing the bisethylene ketal (10),
in c. 60% overall yield from (8), after trituration with
hot ethanol. The residue obtained upon evaporation of
these mother liquors contained the isomeric bisethylene
ketal (11), which could be isolated in pure form upon
recrystallization from methanol in yields up to 10%.12
Exposure of (10) to concentrated H2 SO4 led to the
production of the dione (6) in high yield (c. 90%)
after recrystallization thereby establishing a new route
to this key intermediate. It is important to note
that this double deketalization is quite temperature-
sensitive, with optimum conversions requiring reaction
temperatures between 20 and 25◦ C. Irradiation of (6) at
room temperature in methanol containing concentrated
HCl with a 450 W Hanovia medium-pressure mercury
lamp through Pyrex produced the cage dione (7) as a
mixture of hemiketals and ketals. Hydrolysis of this
mixture with hot (acidic) water, followed by treatment
with refluxing aqueous NaOH for 4 h furnished the
diacid (3) as a tan solid. Careful investigation of this
latter process showed that the highest yields of (3)
were obtained when 12 ml of 25% aqueous NaOH per
gram of (6) were employed. Indeed, more concen-
trated conditions [<12 ml of 25% aq. NaOH/g of (6)]
resulted in considerably lower yields of (3), whereas
lower concentrations [>12 ml of 25% aq. NaOH/g of
(6)] offered no additional benefit. Additionally, it was
found that acidification of the strongly basic Favorskii
O O chilled basic solution to a freshly prepared mixture
Br
Br (a) (b) (c) (d)
(2) (8) (10) (6) (1)
(9)
(c) Scheme 3. (a) Ethane-1,2-diol, benzene, Dowex 50W-
X8 (H) cation exchange resin, ∆. (b) (i) 3 equiv. Br2 ,
O O (c) Conc. H2 SO4 , 20–25◦ C. (d ) (i) hν, methanol, conc.
Br
HCl, room temperature; (ii) H2 O, ∆; (iii) 25% aq. NaOH,
(d) ∆; (iv) methanol, Dowex 50W-X8 (H) cation exchange
resin, ∆.
Br O Br
O O
(10)
Br
O
O Br
(11)
Dimethyl Cubane-1,4-dicarboxylate
of concentrated HCl and ice chips. Purification of
crude (3) was best accomplished by esterification with
methanol followed by sublimation and recrystallization
of the corresponding dimethyl ester (1). This final
sequence, (6) through (1), proceeds in an overall yield
between 42 and 47%.
In summary, we have detailed an operationally sim-
ple protocol for the preparation of (1) in multigram
quantities from (2) in an overall yield of c. 23%. The
key innovations of this study are (i) the double dekatal-
ization of the bisethylene ketal (10) with concentrated
H2 SO4 and (ii) the optimized conversion of dione (6)
into (1), through a four-step sequence without the
need for purification of intermediate substrates.
Experimental
Melting points were determined on a Gallenkamp apparatus
and are uncorrected. 1 H n.m.r. spectra were recorded on a
Bruker AC200 spectrometer operating at 200 · 132 MHz. 1 H
chemical shifts (δ) are relative to tetramethylsilane as internal
standard. Gas chromatographic analyses were performed with
a Hewlett Packard 5890A gas chromatograph and an HP-17
(10 m by 0 · 53 mm by 2 · 0 µm) column. Commercial reagents
were purified according to standard procedures.13 1,4-Dioxan
was distilled from potassium benzophenone ketyl immediately
prior to use.
Cyclopentanone Ethylene Ketal (8)
A mixture of cyclopentanone (2) (250 ml, 237 · 8 g, 3 mol),
ethane-1,2-diol (200 ml, 222 · 6 g, 3 · 59 mol), Dowex 50W-X8
(H) cation exchange resin (3 g) and benzene (500 ml) was
heated under reflux with concomitant azeotropic removal of
water over 30 h. The resulting clear yellow solution was cooled
to room temperature, filtered and washed successively with
portions of 4% aqueous NaOH (250 ml) and brine (500 ml),
then dried (MgSO4 ) and concentrated by distillation through
a Vigreux column (35 cm). Simple distillation of the residue
(59–63◦ C/23 mmHg) (lit.14 57◦ C/18 mmHg) delivered the title
ketal (8) (326 · 2 g, 90%) as a colourless liquid which was shown
to be 99 · 2% pure by gas chromatographic analysis. 1 H n.m.r.
δ 1 · 58–1 · 81, m, 8H, ring protons; 3 · 87, s, 4H, ketal protons.
endo-2,4-Dibromodicyclopentadiene-1,8-dione ∗ Bisethylene
Ketal (10)
Molecular bromine (200 ml, 620 g, 3 · 88 mol) was added
dropwise (c. 1 h) to a stirred solution of cyclopentanone ethylene
ketal (8) (160 g, 1 · 25 mol) in dry 1,4-dioxan (1 litre), under
nitrogen and with protection from light, so that the temperature
of the reaction mixture was maintained between 10 and 20◦ C.
The resultant red solution was stirred at room temperature for
a further 2 days with a slow stream of dry nitrogen passing over
the solution, and then poured into saturated aqueous NaHCO3
(6 litres) and treated with sufficient Na2 S2 O5 to discharge the
orange-red colour of this solution. The precipitated material
was collected by filtration at the pump and washed successively
with water (1 litre) and ice-cold methanol (600 ml). The
resulting colourless solid [tribromide (9)] was suspended in
methanol (1 litre), treated with NaOH (150 g, 3 · 75 mol) and
stirred at reflux for 2 h, then poured onto ice chips (3 kg).
The resulting precipitate was collected by vacuum filtration,
∗
(3aα,4β,7α,7aα)-2,4-Dibromo-3a,4,7,7a-tetrahydro-4,7-methano-1H -indene-1,8-dione.
191
washed thoroughly with water (1 litre), triturated with boiling
ethanol (c. 500 ml), then cooled (−10◦ C) and filtered, thus
affording the bisketal (10) (152 · 6 g, 60%) as a colourless solid,
m.p. 174–176◦ C (lit.10 172–174◦ C). 1 H n.m.r. δ 2 · 69–2 · 76, m,
1H; 3 · 02–3 · 13, m, 1H; 3 · 46–3 · 55, m, 1H; 3 · 83–4 · 30, m, 8H,
ketal protons; 5 · 84, d, J 6 · 5 Hz, 1H; 6 · 07, d, J 2 · 3 Hz, 1H;
6 · 19, dd, J 6 · 5, 3 · 5 Hz, 1H.
endo-2,4-Dibromodicyclopentadiene-1,8-dione∗ (6)
The bisketal (10) (100 g, 246 mmol) was added in portions
over 20 min to 98% H2 SO4 (300 ml) with stirring at between
20 and 25◦ C. After 30 h the resulting solution was poured
into an ice-water slurry (1 · 5 litres). The resulting precipitate
was collected by vacuum filtration, washed with ice-cold water
(250 ml), then dried. Recrystallization (EtOAc/hexanes; two
crops) furnished the dione (6) (71 · 9 g, 92%) as colourless solid,
m.p. 156–157◦ C (lit.10 155–155 · 5◦ C). 1 H n.m.r. δ 3 · 15–3 · 25,
m, 1H; 3 · 48–3 · 63, m, 2H; 6 · 24–6 · 36, m, 2H; 7 · 67, d, J 2 · 9
Hz, 1H.
Dimethyl Cubane-1,4-dicarboxylate (1)
A solution of the dione (6) (50 g, 157 mmol) in methanol
(1 · 5 l) containing concentrated HCl (10 ml) was deoxygenated
by bubbling N2 through the solution for 30 min, then irradiated
at room temperature with a 450 W Hanovia mercury lamp in
a water-cooled Pyrex immersion well apparatus. The reaction,
which was sensitive to the lamp’s output, was monitored by
1
H n.m.r. When the reaction was complete, the methanol was
removed by rotary evaporation under reduced pressure. The
resulting acid-contaminated orange residue was then dissolved
in water (600 ml), and heated under reflux for 1 h and cooled
to ambient temperature. Solid NaOH (150 g) was then added
and the resultant solution heated under reflux for 4 h. The
resulting black solution was cooled in an ice bath and then
added slowly with stirring to a mixture of concentrated HCl
(330 ml) and ice chips (1 · 2 kg) so that the temperature of the
solution did not exceed c. 5◦ C. The resulting precipitate was
collected by vacuum filtration, and the crude diacid (3) washed
with a small volume of ice-cold water and dried in a vacuum
oven at 60◦ C. The combined filtrates were saturated with NaCl,
and extracted with 1 : 1 EtOAc/tetrahydrofuran (3×150 ml).
These extracts were dried (MgSO4 ) and concentrated under
reduced pressure and then by azeotropic evaporation with
toluene to remove the last traces of acetic acid. Trituration of
the resulting residue with Et2 O produced a further quantity
of crude (3). The combined material (24 · 5 g) was suspended
in dry methanol (600 ml), and heated under reflux for 24 h,
under N2 , in the presence of prewashed (dry methanol) Dowex
50W-X8 (H) cation exchange resin (3 g). The hot reaction
mixture was filtered, then concentrated by rotary evaporation
under reduced pressure. The crude diester (1) (25· 3 g) was
sublimed (100–120◦ C/0 · 01 mmHg), and the colourless subli-
mate recrystallized (methanol, two crops) furnishing the diester
(1) (16 · 35 g, 47 · 3%) as a colourless solid, m.p. 161–162◦ C
(lit.11 161–162◦ C). 1 H n.m.r. δ 3 · 7, s, 6H; 4 · 24, s, 6H, ring
protons.
References
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Eaton, P. E., and Cole, T. W., Jr., J. Am. Chem. Soc.,
1964, 86, 962, 3157.
2
Tsanaktsidis, J., in ‘Advances in Strain in Organic Chem-
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Griffin, G. W., and Marchand, A. P., Chem Rev ., 1989,
89, 997.
192 M. Bliese and J. Tsanaktsidis

3
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