Short and tandem syntheses of spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione via diethyl acetonedicarboxylate

Article abstract of DOI:10.1016/j.tetlet.2015.09.132

A general synthetic route to spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione that involves cyclization of the related acrylates and diethyl acetonedicarboxylate, followed by decarboxylation, has been developed. Compared with previous synthetic methods, the developed protocol avoids the use of column chromatography in each of the synthetic steps. Therefore, it can be readily scaled-up. The use of diethyl acetonedicarboxylate under mild conditions to build the skeleton of 1,3-cyclohexanedione has proved to be very efficient.

Full text of DOI:10.1016/j.tetlet.2015.09.132

Tetrahedron Letters 56 (2015) 6287–6289
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Short and tandem syntheses of spiro[2.5]octane-5,7-dione and spiro
[3.5]nonane-6,8-dione via diethyl acetonedicarboxylate
⇑
Xiangle Jin, Wei Xu, Jinsong Yang, Jun Lu, Yan Fu, Le Xie, Qian Zhu, Weitong Dong
Center of Competence, Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd, 1010 Longdong Ave., Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2015
Revised 25 September 2015
Accepted 28 September 2015
Available online 30 September 2015
A general synthetic route to spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione that involves
cyclization of the related acrylates and diethyl acetonedicarboxylate, followed by decarboxylation, has
been developed. Compared with previous synthetic methods, the developed protocol avoids the use of
column chromatography in each of the synthetic steps. Therefore, it can be readily scaled-up. The use
of diethyl acetonedicarboxylate under mild conditions to build the skeleton of 1,3-cyclohexanedione
has proved to be very efficient.
Keywords:
Spiro-1,3-cyclohexanedione
Cyclization
Ó 2015 Elsevier Ltd. All rights reserved.
Tandem
Decarboxylation
Diethyl acetonedicarboxylate
Compounds spiro[2.5]octane-5,7-dione (1) and spiro[3.5]non-
ane-6,8-dione (2, Fig. 1) are very useful and key intermediates of
pharmaceutical development products.1–3 Several routes to them
are known, although they are all quite challenging. Moreover, they
all suffer from severe drawbacks from a chemical synthetic point of
view.1–4 Therefore, there is a demand for developing efficient and
robust methods to synthesize 1 and 2 in order to circumvent these
problems.
One example is a four-step synthesis of spiro[2.5]octane-5,7-
dione (1) through Wittig reaction, Michael/Claisen reaction, fol-
lowed by hydrolysis and decarboxylation using (1-ethoxycyclo-
propoxy)trimethylsilane (3) as the starting material (Scheme 1),
as described in patent literature.1,2 However, this approach
requires flash chromatography for the purification of intermediates
and the final product. In addition, the overall yield was in the range
30–35% and needed improvement.
One published Letter described the synthesis of spiro[3.5]non-
ane-6,8-dione (2) by a similar protocol as above.3 Due to the high
volatility of the starting material cyclobutanone (5), the first step
could only be carried out in silicon oil to avoid the loss of cyclobu-
tanone from the reaction system. After the reaction, the resulting
enone (6) had to be distilled out from the silicon oil in order to pro-
ceed to the next step (Scheme 2).
For short and practical preparations of 1 and 2, it was decided to
use the same starting materials (3 and 5) as in Schemes 1 and 2 for
the new syntheses. For the first steps of both syntheses, it was also
decided that the corresponding acrylate esters should be prepared
instead of the enones (4 and 6), because we realized that 4 and 6
could further react with the Wittig reagent (MeC(O)CH@PPh3),
thereby decreasing the yields of the desired products.5
For the Wittig reaction between (1-ethoxycyclopropoxy)
trimethylsilane (3) and (2-ethoxy-2-oxoethylidene)triphenylphos-
phorane (7), a high-boiling-point solvent (tetraethylene glycol
dimethyl ether) was used. Therefore, the product (8) could be
easily distilled out from the reaction mixture in 76% yield.6 For
the reaction with cyclobutanone (5), the corresponding Horner–
Wadsworth–Emmons protocol was developed, which allowed the
process to be completed at lower temperature in 79% yield. Hence,
the problem of the high volatility of cyclobutanone was overcome
(Scheme 3).7
For the next step, our initial plan was to let the produced acry-
lates (8 or 9) react with ethyl acetoacetate. Based on the proposed
mechanism, the in situ generated dianion of ethyl acetoacetate was
O
O
O
O
Therefore, there is a strong demand for developing a novel and
practical protocol to synthesize both 1 and 2.
2
1
⇑
Corresponding author. Tel.: +86 21 20600167.
E-mail address: weitong.dong@boehringer-ingelheim.com (W. Dong).
Figure 1. The structures of 1 and 2.
http://dx.doi.org/10.1016/j.tetlet.2015.09.132
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6288
X. Jin et al. / Tetrahedron Letters 56 (2015) 6287–6289
O
O
O
O
O
O
Ph
P
O
O
MeO
(1) NaH/THF
OMe
Ph
Ph
O
O
OEt
K2CO3/THF
OEt
EtO
OTMS
EtO
OEt
OEt
p-TsOH
(2) KOH (aq.)
(3) HCl (aq.)
54%
O
O
1,2-Dichlorobenzene
8
10
3
100 oC, 64%
4
1
O
Scheme 1. Synthesis of 1 via the enone intermediate 4.
O
O
O
O
O
OEt
NaO
OEt
OEt
NaH/THF
O
O
O
OEt
Ph
P
O
O
O
MeO
OMe
Ph
Ph
O
9
(1) MeONa/MeOH
12
(2) KOH (aq.)
(3) HCl(aq.)
99%
PhCOOH (cat.)
Silicon oil
O
ONa
O O
EtO
EtO
100 oC, 87%
5
2
6
OEt
OEt
O
Scheme 2. Synthesis of 2 via the enone intermediate 6.
O
O
NaO
OEt
OEt
14
13
Ph
P
O
O
Ph
Ph
7
OEt
EtO
OTMS
OEt
OEt
EtO
OEt
O
ONa O
HOAc
+
Tetraethylene glycol
dimethyl ether
87%
3
8
OEt
O
O
O
P
O
11
EtO
EtO
O
OEt
Scheme 5. Products formed by reaction of acrylates (8 and 9) and ethyl
acetoacetate.
NaH/THF
79%
5
9
Scheme 3. Synthesis of the acrylate intermediates 8 and 9.
O
O
O
O
OEt
O
EtO
OEt
O
(1) KOH
(2) HCl
O
O
O
OEt
(1) K2CO3/THF
OEt
44% from 8
(2) EtONa
O
O
O
O
O
O
O
8
15
1
OEt
OEt
CO2Et
Scheme 6. Synthesis of 1 from 8 via diethyl 1,3-acetonedicarboxylate.
n = 0,1
OEt
O
O
n = 0,1
n = 0,1
+
CO2Et
O
O
O
O
O
O
O
OEt
O
O
n = 0,1
OEt
O
O
O
EtO
OEt
O
(1) KOH
(2) HCl
O
OEt
O
O-
OEt
(1) NaH/THF
n = 0,1
OEt
n = 0,1
45% from 9
(2) EtONa
O
Scheme 4. Proposed synthetic pathways to 1 and 2 via ethyl acetoacetate.
9
16
2
Scheme 7. Synthesis of 2 from 9 via diethyl 1,3-acetonedicarboxylate.
envisaged as building the 1,3-cyclohexanedione skeleton directly
via either one of two plausible pathways (Scheme 4).
To our surprise, neither of the above two substrates (8 and 9)
afforded the desired product with the dianion of ethyl acetoac-
etate, giving only complex mixtures. It was further realized that
cyclopropylidene carboxylic acid ethyl ester (8) only produced 10
in 60% yield under milder Michael addition conditions (Scheme 5).
Even more surprisingly, cyclobutylidene carboxylic acid ethyl ester
(9) could only produce 11 with ethyl acetoacetate under basic con-
ditions. It was assumed that the Michael addition intermediates 12
and 13 underwent a process akin to a Baylis–Hillman-type reaction
via 14 to generate the product 11 (Scheme 5).
Gratifyingly, it was quickly found that by replacing ethyl ace-
toacetate with diethyl acetonedicarboxylate, the original goals
could be achieved. As shown in Scheme 6, the cyclization to form
the six-membered ring could be accomplished by treating cyclo-
propylidene carboxylic acid ethyl ester (8) and diethyl 1,3-ace-
tonedicarboxylate with potassium carbonate (K2CO3) in
tetrahydrofuran (THF), followed by addition of sodium ethoxide
(EtONa). Without any isolation, compound 15 was directly hydro-
lyzed by potassium hydroxide (KOH) and the product was sub-
jected to decarboxylation under acidic conditions. The obtained
crude spiro[2.5]octane-5,7-dione (1) was further purified by crys-
tallization from methyl tert-butyl ether (MTBE), which afforded
the desired product with 99% purity. The overall yield from cyclo-
propylidene carboxylic acid ethyl ester (8) was 44%.8
The above protocol could also be used for the synthesis of spiro
[3.5]nonane-6,8-dione (2). For the cyclization step, sodium hydride
(NaH) was used instead of K2CO3. For this, cyclobutylidene car-
boxylic acid ethyl ester (9) was added to a solution of diethyl
1,3-acetonedicarboxylate in THF containing NaH and then EtONa
was added, which led to the formation of compound 16. As above,
without any isolation, compound 16 was directly hydrolyzed with
KOH and the product was decarboxylated under acidic conditions.

X. Jin et al. / Tetrahedron Letters 56 (2015) 6287–6289
6289
1.18–1.13 (m, 2H); 13C NMR (100 MHz, CDCl3): d 166.1, 144.8, 110.8, 60.0, 14.2,
4.4, 1.8; MS: (m/z) [MÀ28] 98.1.
The obtained crude spiro[3.5]nonane-6,8-dione (2) was further
purified by crystallization from MTBE, which afforded the desired
product with 98% purity. The overall yield from cyclobutylidene
carboxylic acid ethyl ester (9) was 45% (Scheme 7).9
7. Synthesis of acrylate 9: A solution of triethyl phosphonoacetate (44.8 g) in THF
(25 mL) was added dropwise to a slurry of NaH (8.0 g, 60% in oil) in THF
(150 mL) at 0–10 °C over a period of 40 min. The reaction mixture was stirred at
0–10 °C for a further 0.5 h. A solution of cyclobutanone (14.0 g) in THF (25 mL)
was then added dropwise at 0–10 °C over a period of 30 min. The reaction
mixture was stirred at 0–10 °C for 2 h. Water (50 mL) was then slowly added at
20–30 °C. The organic solvent was removed under reduced pressure and then
further water (150 mL) was added. The aqueous solution was extracted with
MTBE (3 Â 100 mL). The combined organic phases were washed with water
(100 mL) and then dried over anhydrous MgSO4. Filtration followed by
evaporation of the solvent gave the crude product, which was purified by
fractional distillation at 81–82 °C/19 mbar to give 22.2 g (79% yield) of
compound 9 as a colorless liquid. 1H NMR (500 MHz, CDCl3): d 5.58 (m, 1H),
4.13 (q, 2H, J = 7.1 Hz), 3.14 (m, 2H), 2.84 (m, 2H), 2.09 (m, 2H), 1.26 (t, 3H,
J = 7.1 Hz); 13C NMR (125 MHz, CDCl3): d 167.6, 166.6, 112.4, 59.5, 33.8, 32.3,
17.7, 14.4; MS: (m/z) 140.1.
In conclusion, it has been demonstrated that both spiro[2.5]oc-
tane-5,7-dione (1) and spiro[3.5]nonane-6,8-dione (2) could be
synthesized by using diethyl 1,3-acetonedicarboxylate as the key
material to build up the skeleton of the 1,3-cyclohexanedione. This
developed protocol is superior to the previously reported synthe-
ses of spiro[2.5]octane-5,7-dione (1) and spiro[3.5]nonane-6,8-
dione (2) in terms of the reaction conditions and the corresponding
purification methods. Application of the same methodology to
other substrates to generate spiro 1,3-cyclohexanediones is being
investigated, and the corresponding experimental results will be
reported in due course.
8. Synthesis of 1: Diethyl 1,3-acetonedicarboxylate (76.9 g) and compound
8
(40.0 g) were each added dropwise to a slurry of K2CO3 (43.8 g) in THF (200 mL)
at 20–30 °C, and the mixture was stirred for 1 h. NaOEt solution (20% in EtOH;
215.7 g) was added dropwise at below 40 °C over a period of 30 min. The
mixture was then heated under reflux for 3 h. KOH solution (20% in water;
354.7 g) was slowly added to keep the reaction mixture under slight reflux, and
reflux conditions were maintained for a further 5 h. The organic solvent in the
mixture was then removed under reduced pressure. The resulting aqueous
phase was washed with MTBE (2 Â 100 mL). The aqueous phase was then
heated at 50–60 °C. At this temperature, concd aq HCl was added dropwise until
pH 2.5–3.0 was attained. The mixture was stirred for a further 1 h and then
cooled to 20–30 °C. Water (200 mL) was added and the resulting aqueous
solution was extracted with MTBE (3 Â 300 mL). The combined organic phases
were concentrated under reduced pressure. A further portion of MTBE (30 mL)
was then added to the residue, and the slurry was stirred for 30 min at 0–10 °C.
Acknowledgment
Dr. Klaus Rudolf (Boehringer Ingelheim) is gratefully acknowl-
edged for initial discussion and manuscript review of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
132.
A
first portion of the product was collected by filtration. The filtrate was
concentrated under reduced pressure once more and then MTBE (20 mL) was
added. After the slurry had been stirred at 0–10 °C for 0.5 h, a second portion of
the product was also collected by filtration. The combined product was washed
with MTBE (5 mL), and then dried under vacuum. A total of 19.5 g (44% yield) of
1 was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): d 11.04 (br s, 1H),
5.27 (s, 1H), 2.13 (br s, 4H), 0.37 (br s, 4H); 13C NMR (100 MHz, DMSO-d6): d
196.4, 178.6, 104.0, 41.7, 15.0, 10.8; MS: (m/z) 138.1.
References and notes
1. Abel, U.; Hechenberger, M.; Henrich, M.; Kauss, V.; Kubas, H.; Meyer, U.; Muller,
S.; Zemribo, R. World Patent 2,012,052,451 A1, 2012.
2. Abel, U.; Krueger, B.; Kubas, H.; Meyer, U.; Zemribo, R. World Patent
2,012,085,166 A1, 2012.
3. Paulsen, H.; Antons, S.; Brandes, A.; Loegers, M.; Mueller, S. N.; Naab, P.;
Schmeck, C.; Schneider, S.; Stoltefuss, J. Angew. Chem., Int. Ed. 1999, 38, 3373.
4. Busch, T.; Anklam, S.; Jung, J.; Ostermeier, M. World Patent 2,014,020,038 A1,
2014.
9. Synthesis of 2: Diethyl 1,3-acetonedicarboxylate (2.4 g) was slowly added to a
slurry of NaH (0.96 g, 60% in oil) in THF (5.0 mL) at 0–15 °C. After the mixture
had been stirred for 0.5 h, compound 9 (1.4 g) was slowly added at 0–15 °C. The
mixture was stirred at 20–30 °C for 1 h and then heated to reflux. EtOH (5 mL)
and NaOEt solution (20% in EtOH; 2.4 g) were then added. The resulting mixture
was heated under reflux for 5 h. Thereafter, KOH solution (20% in water; 11.2 g)
was slowly added, and the reaction mixture was heated under reflux for a
further 5 h. The organic solvent in the reaction mixture was removed under
reduced pressure. The aqueous solution was extracted with MTBE (2 Â 10 mL)
and then heated to 50–60 °C with the addition of concd HCl until pH 2.5–3.5 was
attained. The resulting mixture was stirred at 50–60 °C for 2 h and then cooled
to 20–30 °C. It was then extracted with dichloromethane (3 Â 25 mL). The
combined organic phases were concentrated under reduced pressure. MTBE
(5.0 mL) was then added to the residue and the resulting slurry was stirred for
0.5 h at 0–10 °C. The solid was collected by filtration, washed with MTBE
(5.0 mL), and dried under vacuum. A total of 0.68 g (45% yield) of 2 was obtained
as a white solid. 1H NMR (400 MHz, DMSO-d6): d 11.00 (br s, 1H), 5.17 (s, 1H),
2.36 (br s, 4H), 1.87–1.82 (m, 2H), 1.78–1.74 (m, 4H); 13C NMR (100 MHz,
DMSO-d6): d 186.2, 103.6, 44.7, 38.4, 31.5, 14.6; MS: (m/z) 152.1.
5. Our internal experimental observations.
6. Synthesis of acrylate 8:
A
solution of (2-ethoxy-2-oxoethylidene)
triphenylphosphorane in dichloromethane (270 mL) was added dropwise to a
solution of 1-ethoxy-1-(trimethylsiloxy)cyclopropane (3) (100 g) and AcOH
(17.1 g) in tetraethylene glycol dimethyl ether (400 mL) at 90–100 °C over a
period of 3 h under stirring. During the addition, dichloromethane was removed
by distillation to keep the process temperature at 90–100 °C. The mixture was
stirred at 90–100 °C for a further 1 h, which allowed complete removal of the
dichloromethane by distillation. The product was then purified by fractional
distillation at 10 mbar in the range 90–100 °C (cooling temperature of fluid in
condenser should not be above À10 °C; all distillate collected under these
conditions consisted of the product). A total of 50–55 g (yield: 69–76%) of
compound 8 was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3): d
6.15 (m, 1H), 4.13 (q, 2H, J = 7.1 Hz), 1.40–1.35 (m, 2H), 1.23 (t, 3H, J = 7.1 Hz),