The synthesis of bicyclo[2.2.2]octan-2,6-dione revisited

Article abstract of DOI:10.1055/s-2006-942532

The cyclisation conditions for the formation of bicyclo[2.2.2]octan-2,6- dione (1) from 3-substituted cyclohexanones 2 and 3 have been re-investigated. Use of a medium consisting of isobutyric anhydride and trifluoroacetic acid resulted in a simplified an

Full text of DOI:10.1055/s-2006-942532

PRACTICAL SYNTHETIC PROCEDURES
3527
The Synthesis of Bicyclo[2.2.2]octan-2,6-dione Revisited
Revised Synthesis of
B
a
icyclo[2.2.
g
2]octan-2,6-d
n
ione us Widegren,a Melanie Dietz,a Annika Friberg,a Torbjörn Frejd,*a Bärbel Hahn-Hägerdal,b
Marie F. Gorwa-Grauslund,b Mikael Katzb
a
Division of Organic Chemistry, Center for Chemistry and Chemical Engineering,
Lund University, P.O. Box 124, 22100 Lund, Sweden
Fax +46(46)2224119; E-mail: Torbjorn.Frejd@organic.lu.se
Department of Applied Microbiology, Center for Chemistry and Chemical Engineering,
b
PSP
Lund University, P.O. Box 124, 22100 Lund, Sweden
Received 26 April 2006; revised 26 June 2006
No71
Abstract: The cyclisation conditions for the formation of bicyclo[2.2.2]octan-2,6-dione (1) from 3-substituted cyclohexanones 2 and 3
have been re-investigated. Use of a medium consisting of isobutyric anhydride and trifluoroacetic acid resulted in a simplified and repro-
ducible method for large-scale synthesis of this compound.
Key words: bicyclic compounds, cyclisations, diketones, carboxylic acids, anhydrides
O
O
PPA/HOAc
A)
100 °C
1 h
O
O
O
2
1
O
O
68% yield
O
O
IBA/TFA
B)
1
r.t. (2–4 h) →
125 °C (1–4 h)
OH
71–77% yield
3
O
OH
Scheme 1
Bicyclo[2.2.2]octane derivatives are frequently used in tion in PPA/AcOH using 2 was hampered by low yields at
total synthesis and as ligands for asymmetric catalysis, larger scales, synthesis of 1 had to be performed repeated-
and they are also found in many natural products.1 One of ly. The neutralisation of rather large amounts of PPA/
the simpler derivatives for synthesis among the bicy- AcOH was also inconvenient. We present here a more
clo[2.2.2]octanes is bicyclo[2.2.2]octane-2,6-dione (1). convenient large-scale method for the synthesis of 1.
Synthetic procedures for this dione have been presented in
The reasons for the scale-up problems with 2 are not clear.
We noticed that higher proportions of acetic acid in the
the literature,2,3 none of which are entirely satisfactory.
Our need for larger amounts of 1 could not be met by these
medium to make it less viscous adversely influenced the
procedures. This problem was partially solved by the cy-
yields of 1 despite consumption of 2.4 An important factor
clisation of 2 (Scheme 1, A).4
to consider was the ‘anhydridic’ medium. It is likely that
Keeping the output scale below 5 g, the yields were repro- acetic anhydride or mixed acetic-PPA anhydrides are
ducible around 60%, sometimes even higher. However, a formed to some extent when acetic acid and PPA are
very serious limitation was that the yields dropped drasti- mixed.5 This indicated that it would be reasonable to per-
cally when the scale was increased, e.g. at 10 g scale the form the reaction of 2 in acetic anhydride in the presence
yields seldom exceeded 40% and at larger scales the of an acidic catalyst. The best results were achieved using
yields were even lower.
trifluoroacetic acid (TFA) (35% yield) or PPA (36%
yield). Alternative acids were tested and the results are
given in Table 1 (see also experimental). Further experi-
mentation with 2 as starting material was abandoned at
this point since the yields were not satisfactory.
A further impracticality was the use of polyphosphoric
acid (PPA). Its viscosity is perhaps tolerable a few times
but not repetitively and since the scale-up of the cyclisa-
Earlier experiments with the malonic acid 3 in PPA/
AcOH were not rewarding, but since 3 is very easy to syn-
thesise in large amounts it is indeed an attractive starting
SYNTHESIS 2006, No. 20, pp 3527–3530
Advanced online publication: 02.08.2006
DOI: 10.1055/s-2006-942532; Art ID: T07206SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

3528
M. Widegren et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Cyclisation Experiments of 2 in Acetic Anhydridea
by removing the excess of the reaction medium directly
from the reaction vessel by low-pressure distillation,
which left a residue that could be purified by crystallisa-
tion from heptane–EtOAc to give a high quality of 1, di-
rectly useful for further transformations, e.g.
stereoselective baker’s yeast reduction.4,6 Thus, the proce-
dure does not require column chromatography.
Entry 2 (g)
Ac2O Acid
(mL)
Yield (%)
1
2
1
5
5
15
50
7.5
11
14
45
35
5
TFA, 5 mL
35
21
9
TFA, 15 mL
3
10
1
TFA, 50 mL
Table 2 Cyclisation of 3 in the IBA/TFA Medium
b
4
TFA, 7.5 mL
-
Entry
3 (g)
1
IBA (mL)
TFA (mL) Yield (%)
5
1
PPA, 11 g
36
33
17
1
2
3
4
1
1
0.1
0.5
10a,b
68a,b
72b,c
77c,d
6
3
PPA, 14 g
1
7
10
5
PPA, 50 g
50
500
50
25
250
c
8
MgCl2, 2 g
-
500
9
1
TFA, 5 mL/MgCl2, 0.4 g
BF3·AcOH, 0.05 mL
PPA, 43 g/AcOH, 40 mLd
17
18
23
a Isolated by aqueous work-up followed by column chromatography.
b Reaction time: 2 h at r.t., then 1 h at 125 °C.
c Isolated by removal of excess reagent by distillation followed by re-
crystallisation.
10
11
5
35
-
5
d Reaction time: 4 h at r.t., then 4 h at 125 °C.
a Conditions: Compound 2 was added in one portion to the reaction
medium at r.t. and then the temperature was increased to 100 °C, re-
action time, 1 h.
Since small amounts of 1 are lost due to sublimation at re-
duced pressure, the yields are noticeably affected when
the reaction is run at smaller scales. Therefore, the low-
pressure distillation is best suited for large-scale opera-
tions (≥50 g). For small-scale reactions an aqueous work-
up followed by column chromatography is recommended.
b The addition of 2 was made over 1 h, but 1 could not be detected by
TLC.
c No product could be isolated.
d PPA and AcOH were stirred at 100 °C for 24 h before addition of 2.
material. The synthesis of 3 was carried out by the Micha-
el reaction of cyclohex-2-ene-1-one with dimethyl mal-
onate followed by hydrolysis of the ester groups in the
addition product 4 (Scheme 2).
Other reaction media can also be used. The reaction was
run using trifluoroacetic anhydride (TFAA) with a cata-
lytic amount (5 mol%) of TFA (Table 3). A slight excess
(1.1 equiv) of TFAA was required to obtain yields compa-
rable to those obtained in the IBA-mediated cyclisations.
However, using two equivalents of TFAA was detrimen-
tal for the reaction, resulting in a significantly lower yield
and large amounts of labile by-products, which decom-
posed during column chromatography.
The best results in the cyclisation of 3 were achieved with
isobutyric anhydride (IBA) in combination with TFA
(Scheme 1, B and Table 2). Using this reaction medium
the yields were reproducible and in the range of 70–80%,
and the scaling-up of the reaction was possible without a
drop in yield. The highest yields were obtained using a
1:1.1 molar ratio of IBA/TFA, in slight excess with re-
spect to 3. At scales £50 g, stirring at room temperature
Table 3 Cyclisation Experiments of 3 in TFAA in the Presence of
TFA (5 mol%)
for two hours before increasing the temperature to 125 °C Entry
3 (g)
TFAA (equiv) Yield (%)a
was necessary to obtain good yields. During this period,
formation of 1 was not detected. However, a slightly exo-
1
1
1
5
1
49
19
69
thermic process was observed. As decarboxylation gently
began at a temperature just above 100 °C, formation of 1
was observed. The reaction was performed in up to 500 g
scale with standard laboratory equipment. However, at
this scale a longer reaction time was required (see experi-
mental part). Isolation of the product was accomplished
2
2
3
1.1
a Isolated yield.
In the IBA-mediated cyclisation, a by-product was formed
in up to 20% yield, which we failed to isolate in the pure
state due to partial decomposition in solution and on silica
gel. The by-product did not originate from further reaction
of 1 with the medium, since a pure sample of 1 on heating
for three hours in the IBA/TFA mixture was indifferent as
checked by TLC analysis. IR and NMR spectroscopic ev-
idence of an impure sample of the by-product gave indi-
cations that pointed to structure 5 (Figure 1). A similar
O
O
dimethyl malonate
O
2 M NaOH
96%
3
Et3N, LiCl
toluene
95%
OMe
OMe
4
O
Scheme 2
Synthesis 2006, No. 20, 3527–3530 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Revised Synthesis of Bicyclo[2.2.2]octan-2,6-dione
3529
Dimethyl (3-Oxocyclohexyl)malonate (4)
ester-acetal-lactone formed under similar conditions was
reported by Mori.7
Et3N (8 mL) and LiCl (24.6 g, 0.582 mol) were added to a solution
of dimethyl malonate (100 mL, 0.872 mol) in toluene (100 mL).
The mixture was stirred at r.t. under argon for 10 min and a solution
of cyclohex-2-ene-1-one (58.8 mL, 0.582 mol) in toluene (100 mL)
was then added. The resulting mixture was stirred at r.t. overnight,
then H2O (50 mL) was added followed by conc. HCl (~20 mL) until
neutral pH. The phases were separated and the H2O phase was ex-
tracted with EtOAc (3 × 100 mL). The combined organic extracts
were dried (Na2SO4), filtered and the solvent was removed at re-
duced pressure. The resulting yellow oil was purified by distillation
to give 4 (126 g, 95%) as a colourless liquid; bp 140 °C/1 Torr (Lit.9
O
O
O
5
O
1
Figure 1 Structure of the by-product 5
bp 124–130 °C/0.4 Torr). The H NMR data of 4 were in accord
with literature values.9
Since the large-scale operations also required larger
amounts of 4 (Scheme 2), it was desirable to avoid chlori-
nated solvents (dichloromethane), which had been used
earlier in the conjugate addition of dimethyl malonate to
cyclohexenone. From an environmental point of view tol-
uene is more tolerable, and it is also superior to dichlo-
romethane. A close to quantitative yield of 4 was obtained
in toluene as compared to less than 80% in dichlo-
romethane or THF (see experimental part). Alternatively,
4 can be prepared by an electrochemically promoted
Michael addition reaction of cyclohex-2-ene-1-one and
dimethyl malonate under solvent-free conditions in high
yield.8
(3-Oxocyclohexyl)malonic Acid (3)
Dimethyl (3-oxocyclohexyl)malonate (4; 227 g, 1.00 mol) was dis-
solved in aq 2 M NaOH (1.8 L) and stirred at r.t. for 2 h. The mixture
was then acidified with conc. HCl (~360 mL), saturated with NaCl
and extracted with EtOAc (4 × 600 mL). The combined organic lay-
ers were dried (Na2SO4), filtered and the solvent removed at re-
duced pressure to give 3 (191 g, 96%) as a white solid powder,
which was used in the next step without further purification; mp
146–147 °C (melt and dec.) (Lit.2 mp 166–168 °C).
IR (KBr): 2955, 1724, 1684, 1302, 1219 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.82 (v br s, 2 H), 3.19 (m, 1
H), 2.35–2.06 (m, 5 H), 2.01–1.88 (m, 1 H), 1.81 (br d, J = 12.6 Hz,
1 H), 1.64–1.34 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 209.6, 169.6, 169.5, 56.9,
44.8, 40.5, 37.5, 28.1, 24.2.
In conclusion, a convenient method has been worked out
for the synthesis of 1 by the use of IBA/TFA as reaction
medium for the ring closure of 3. It is now possible to pro-
duce large amounts (>100 g) of 1 in less than two days
without the use of chromatography, starting from cyclo-
Note that complicated NMR patterns were obtained with MeOH as
solvent. Depending on concentration, partial acetal formation was
observed.
hex-2-ene-1-one. It is also possible to recover the solvents Bicyclo[2.2.2]octane-2,6-dione (1)
Method 1: Isobutyric anhydride (500 mL, 3.02 mol) and TFA (250
and reagents for recycling.
mL, 3.37 mol) were added under stirring to finely powdered 3 (500
g, 2.51 mol). The mixture was stirred at r.t. for 4 h and then the tem-
perature was slowly increased to 125 °C. After 4 h at 125 °C, evo-
lution of CO2 ceased and the mixture was cooled to r.t. A colourless
liquid (mostly excess IBA and TFA) was distilled off (bp 70 °C/1
Torr) and the remaining crude brown residue was crystallised from
EtOAc–heptane (1:1). On cooling with on solid CO2, diketone 1
(211 g, 61%) precipitated as colourless needles. From the mother li-
quor a second crop of 1 was obtained (56 g, 16%); mp 194–197 °C
(Lit.2 mp 190–191 °C). The total yield was 267 g (77%).
1H NMR (400 MHz, CDCl3): d = 3.19 (t, J = 2.9 Hz, 1 H), 2.66
(heptet, J = 3.0 Hz, 1 H), 2.52 (doublet of multiplets, J = 20.4 Hz, 1
H), 2.51–2.47 (m, 1 H), 2.38 (doublet of multiplets, J = 19.3 Hz, 1
H), 9.37–9.34 (m, 1 H), 2.16–2.09 (m, 2 H), 1.91–1.84 (m, 2 H).
All chemicals were purified by standard methods, unless otherwise
stated. Dimethyl malonate (97%, Merck), LiCl (99%, Riedel-de-
Haen), cyclohex-2-ene-1-one (98.5%, Fluka), isobutyric anhydride
(97%, Acros), TFA (99%, Acros) and trifluoroacetic anhydride
(≥99%, Aldrich) were used as delivered. Column chromatography
was performed on Matrex (25–70 mm) silica gel. TLC was per-
formed on silica gel covered glass plates (60 F254, Merck) and the
plates were impregnated with a solution of p-methoxybenzaldehyde
(10 mL), conc. H2SO4 (50 mL) and EtOH (95%, 950 mL). The com-
pounds were visualized by heating. NMR data were recorded on a
Bruker DRX 400 MHz or Bruker ARX 300 MHz spectrometer, and
the chemical shifts were measured using the solvent peaks as inter-
nal references. Melting points were taken on a Sanyo Gallenkamp
melting point apparatus (MPD.350.BM3.5) and are uncorrected. IR
spectra were recorded on a Shimadzu FTIR-8300 spectrometer.
13C NMR (100 MHz, CDCl3): d = 206.7, 63.8, 44.0, 28.0, 23.7,
22.1.
HRMS-FAB+: m/z [M + H]+ calcd for C8H11O2: 139.0759; found:
139.0755.
Cyclisation of 2 in Acetic Anhydride; General Procedure
The Meldrum’s acid derivative 2 was added to a mixture of Ac2O
and co-reagent (Table 1) under argon at r.t. The temperature was in-
creased to 100 °C and held there for 1 h. The mixture was cooled to
r.t., then sat. NaHCO3 (50 mL) was added followed by further addi-
tion of sat. NaHCO3 until neutral pH. It was then saturated with
NaCl and extracted with toluene (5 × 50 mL). The combined organ-
ic phases were dried (Na2SO4), filtered and the solvent was removed
at reduced pressure. The residue was purified by column chroma-
tography [SiO2, heptane–EtOAc (1:1); Rf 0.3] to give 1 as a white
solid, which was analysed by IR and 1H NMR spectroscopy.
By-Product 5
A by-product was formed in up to 20% yield. Attempted purifica-
tion of an analytical sample, obtained from the mother liquor after
recrystallization of 1, by column chromatography (SiO2, heptane–
EtOAc, 1:1) gave the following spectroscopic data:
IR (film): 2937, 1751, 1215, 1142, 1099, 1074, 1042, 1003, 972
cm–1.
Synthesis 2006, No. 20, 3527–3530 © Thieme Stuttgart · New York

3530
M. Widegren et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (300 MHz, CDCl3): d = 2.77 (dd, J = 18.8, 6.9 Hz, 1 H),
2.64–2.36 (m, 4 H), 2.17–2.09 (m, 2 H), 2.00–1.88 (m, 1 H), 1.85–
1.74 (m, 1 H), 1.69–1.55 (m, 3 H), 1.16 (d, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 174.7, 170.1, 105.8, 35.6, 35.1,
34.9, 33.7, 30.2, 27.5, 18.9, 18.5.
Gluchowski, C.; Guinn, D. E.; Hartmann, M.; Tanaka, T.;
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For small-scale synthesis, it is recommended that an aqueous work-
up is applied as for the general procedure for the cyclisation of 2 in
Ac2O (see above).
Method 2: TFAA (3.84 mL, 27.6 mmol) and TFA (93 mL, 1.3 mmol)
were added under stirring to finely powdered 3 (5.00 g, 25.1 mmol).
The mixture was stirred at r.t. for 2 h and then the temperature was
increased to 125 °C and held there for 1 h. After cooling the mixture
to r.t., aq sat. NaHCO3 (150 mL) was added and the resulting H2O
phase was extracted with EtOAc (3 × 70 mL). The combined organ-
ic extracts were dried (Na2SO4), filtered and the solvent was re-
moved at reduced pressure. The residue was purified by column
chromatography (SiO2, heptane–EtOAc, 3:1 to 1:1) to give 1 (2.41
g, 69%) as a white solid; mp 192–195 °C (Lit.2 mp 190–191 °C);
Rf 0.3 (heptane–EtOAc, 1:1). The 1H NMR data were in accord with
those reported for 1 above.
Acknowledgment
The work was financially supported by grants from the Swedish
Foundation for Strategic Research, the Swedish Research Council,
the Royal Physiographic Society in Lund, the Crafoord Foundation,
the Knut and Alice Wallenberg Foundation, and the Research
School in Medicinal Science at Lund University (FLÄK).
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23, 1499.
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Synthesis 2006, No. 20, 3527–3530 © Thieme Stuttgart · New York