A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones through [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with ring expansion

Article abstract of DOI:10.1016/j.tetlet.2005.03.155

Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields. Heating

Full text of DOI:10.1016/j.tetlet.2005.03.155

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3767–3770
A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from
cyclobutanones through [chloro(p-tolylsulfinyl)-
methylidene]cyclobutanes with ring expansion
Tadashi Kawashima, Hiroaki Kashima, Daisuke Wakasugi and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku Tokyo 162-8601, Japan
Received 16 February 2005; revised 10 March 2005; accepted 18 March 2005
Available online 8 April 2005
Abstract—Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloro-
methyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields.
Heating of these enaminonitriles with H3PO4 in acetic acid gave 2-cyanobicyclo[3.3.0]oct-1-en-3-ones in good yield. On the other
hand, treatment of the [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with cyanomethyllithium followed by lithium carbanion
of the homologues of acetonitrile afforded enaminonitriles having a substituent at the 3-position. Heating of the enaminonitriles
with H3PO4 in acetic acid gave 2-substituted bicyclo[3.3.0]oct-1-en-3-ones in good to high yields. This method offers a novel and
versatile procedure for synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in good overall yields.
Ó 2005 Elsevier Ltd. All rights reserved.
The bicyclo[3.3.0]octane ring system is one of the most
widely distributed carbon structures in natural and
unnatural organic compounds. Especially, cyclopenta-
noid natural products such as angular triquinanes and
linear triquinanes contain bicyclo[3.3.0]octane rings in
their structure.1 Many methods have already been re-
ported for the construction of the bicyclo[3.3.0]octane
ring system and for the total synthesis of cyclopentanoid
natural products,2 including Nazarov cyclization3 and
Pauson–Khand reaction;4 however, in view of the
importance of the bicyclo[3.3.0]octane ring system,
new methods are still eagerly sought.
a novel method for construction of 2-substituted bi-
cyclo[3.3.0]oct-1-en-3-ones in good overall yields.
Thus, [chloro(p-tolylsulfinyl)methylidene]cyclobutane 2
was synthesized from cyclobutanone 1 in three steps in
quantitative yield. Treatment of this vinyl sulfoxide 2
with 5 equiv of cyanomethyllithium gave enaminonitrile
3 in high yield. The enaminonitrile 3 was heated in acetic
acid containing H3PO4 and water to give 2-cyanobi-
cyclo[3.3.0]oct-1-en-3-one 4 with ring expansion of the
cyclobutane ring (Scheme 1). The vinyl sulfoxide 2 was
first treated with cyanomethyllithium at À78 °C to give
the adduct 5 in quantitative yield. The adduct was then
treated with LDA followed by lithium a-carbanion of
the homologue of acetonitrile to give 3-substituted
enaminonitrile 6 in high yield.6 Finally, heating of 6 in
acetic acid containing H3PO4 and water resulted in the
formation of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones
7 in good yield. These reactions offer a novel and
versatile procedure for the preparation of various
bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in
good overall yield.
Previously, we reported a new synthesis of spiro[4.n]-
alkenones from three components: cyclic ketones, chlo-
romethyl p-tolyl sulfoxide and acetonitrile.5 In
continuation of our interest in the development of new
synthetic methods by using chloromethyl p-tolyl sulfox-
ide as a one-carbon homologating agent, we recently
investigated the above-mentioned reaction with cyclobu-
tanones and it was found that the reaction proved to be
A representative example of the synthesis of 2-cyanobi-
cyclo[3.3.0]oct-1-en-3-one 4a starting from cyclobuta-
none 1a is reported as an example (Scheme 2).
[Chloro(p-tolylsulfinyl)methylidene]cyclobutane 2a was
synthesized from cyclobutanone 1a and chloromethyl
Keywords: Cyclobutanone; Sulfoxide; Ring expansion; Bicyclo-
[3.3.0]octane; Bicyclo[3.3.0]oct-1-en-3-one.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235
2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.155

3768
T. Kawashima et al. / Tetrahedron Letters 46 (2005) 3767–3770
O
CN
CN
NH2
5 eq.
LiCH2CN
H+
TolSCH2Cl
R
R
R
Cl
R
R
R
R
O
O
S(O)Tol
heating
R
1
2
3
4
Li
CN
NH2
R1
LiCH2CN
H+
R
R
R
R
R
CN
S(O)Tol
R1CHCN
O
2
heating
R
Cl
R1
6
5
7
Scheme 1.
O
CN
CN
NH2
5 eq.
LiCH2CN
TolSCH2Cl
H3PO4, H2O
Cl
S(O)Tol
O
O
AcOH, reflux 1 h
THF, -78 ˚C ~ r.t.
91%
3 steps, 93%
99%
2a
1a
4a
4a
3a
O
CN
H
H
H2 / Pd-C
H3PO4, H2O
AcOH, reflux 20 h
O
O
8
H
H
9
10
CN
CN
CN
NH2
NH2
EtO
H3PO4, H2O
EtO
EtO
EtO
EtO
O
O
O
O
2b
2c
AcOH, reflux 1 h
84%
84%
EtO
1b
1c
66%
4b
3b
3c
CN
AcO
AcO
O
O
O
O
62%
4c
Scheme 2.
p-tolyl sulfoxide in three steps in 93% overall yield.5 The
vinyl sulfoxide 2a was treated with 5 equiv of cyano-
methyllithium in THF to give the enaminonitrile 3a in
91% yield.5 The enaminonitrile was treated with
H3PO4 in the presence of water in acetic acid to give
the bicyclooctenone 4a in 99% yield.
H+
CN
CN
H
O
NH2
H+, H2O
3a
A
CN
CN
We expected that this reaction would give spiro[3.4]
alkenone 8 at first;5 however, the product obtained
had no olefinic hydrogen. The product showed 147 as
the molecular weight and the presence of a nitrile group
(2229 cmÀ1) and a carbonyl group (1724 cmÀ1) in its IR
spectrum. From the 1H and 13C NMR, the product
was presumed to be 2-cyanobicyclo[3.3.0]oct-1-en-3-one
4a. In order to confirm the structure, 4a was hydroge-
nated to 9 and the product was hydrolyzed and decarbox-
ylated to give the known bicyclo[3.3.0]octan-3-one 10.7
O
OH
4a
B
Scheme 3. Presumed mechanism for the formation of bicyclo-
[3.3.0]oct-1-en-3-one 4a from the enaminonitrile 3a by the treatment
with acid.
rile 3a gives the enone A. Protonation of the carbonyl
oxygen of the enone A followed by the ring expansion
of the cyclobutane ring would give bicyclo[3.3.0]octane
The presumed mechanism of this reaction is illustrated
in Scheme 3. Thus, acidic hydrolysis of the enaminonit-

T. Kawashima et al. / Tetrahedron Letters 46 (2005) 3767–3770
3769
B. Tautomerization of the enol B gives the product
enone 4a.
product in 99% yield. Somewhat surprisingly, the
product was not the expected 2-cyano-4-phenylbicy-
clo[3.3.0]oct-1-en-3-one but 2-phenylbicyclo[3.3.0]oct-1-
en-3-one 7a. All the spectral data of 7a was highly
consistent with those reported.9
Generality of this reaction was investigated with two
cyclobutanones 1b and 1c8 and the results are shown
in Scheme 2. The enaminonitriles 3b and 3c were synthe-
sized from the cyclobutanones 1b and 1c via the vinyl
sulfoxides 2b and 2c in high overall yields by the same
procedure as described above. The acidic treatment of
the enaminonitriles gave the expected 7,7-disubstituted
2-cyanobicyclo[3.3.0]oct-1-en-3-ones 4b and 4c in some-
what variable yields.
A presumed mechanism of this reaction is as follows
(Scheme 4). At first, acidic hydrolysis of the enaminonit-
rile 6a would give the enone C, then the rearrangement
(ring expansion) takes place as described in Scheme 3 to
afford 2-cyano-4-phenylbicyclo[3.3.0]oct-1-en-3-one D.
Migration of the double bond under acidic conditions
proceeds to give 4-cyano-2-phenylbicyclo[3.3.0]oct-1-
en-3-one E. Finally, the cyano group is hydrolyzed
and decarboxylated to give 7a.
We previously reported a novel synthesis of 2,4,4-trisub-
stituted 2-cyclopentenones from 1-chlorovinyl p-tolyl
sulfoxides by consecutive reaction with acetonitrile and
its homologues.6 We applied this methodology to the
[chloro(p-tolylsulfinyl)methylidene]cyclobutane 2a and
quite interesting results were obtained (Table 1).
As this procedure is quite an interesting new method for
synthesis of various 2-substituted bicyclo[3.3.0]oct-1-en-
3-ones, we investigated the generality of the substituents
at the 2-position and the results are summarized in
Table 1. The reaction with 4-methoxyphenylacetonitrile
gave also 7b in good overall yield (entry 2). Entries 3 and
4 show that the alkyl groups can be introduced at the 2-
position of the bicyclo[3.3.0]oct-1-en-3-one system in
high yields. Interestingly, it was found that the enamino-
nitriles having alkyl groups need much longer time for
the acidic hydrolysis compared with those having aryl
groups (compare entries 1 and 2 with 3 and 4). A steri-
cally highly bulky group, a triphenylmethyl group, can
First, 2a was treated with 3 equiv of cyanomethyllithium
in THF at À78 °C for 10 min to give the adduct 5a in
95% yield. The adduct 5a was treated with LDA at
À78 °C followed by lithium a-carbanion of phenylaceto-
nitrile (7 equiv). The reaction mixture was slowly
allowed to warm to À40 °C and the reaction was
quenched to afford enaminonitrile 6a (Table 1, entry 1)
in 78% yield. Finally, 6a was heated under reflux in ace-
tic acid containing H3PO4 and water for 12 h to give the
Table 1. Synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-one 7 from the vinyl sulfoxide 2a with acetonitrile and its homologues through
enaminonitriles 6
CN
NH2
3 eq.
1) LDA
2) 7 eq.
H3PO4, H2O
LiCH2CN
CN
Cl
O
R1
THF, -78 ˚C,
10 min, 95%
S(O)Tol
1
AcOH, reflux
S(O)Tol
R C(Li)HCN
R1
Cl
2a
6
7
-78 ~ 0 ˚C
5a
Entry
1
R1CH2CN
Enaminonitrile 6, yield (%)
6a, 78a
Conditions for the hydrolysis
2-Substituted bicyclo[3.3.0]oct-1-
en-3-one 7 (yield, %)
O
12 h
(99)
CH2CN
7a
O
2
6b, 99
14 h
7b
(75)
H3CO
CH2CN
OCH3
O
O
3
4
CH3CH2CN
6c, 97
6d, 95
65 h
85 h
7c
7d
(78)
(83)
CH3
CH3(CH2)3CH2CN
(CH2)3CH3
O
5
Ph3CCH2CN
6e, 64
50 h
7e
(53)
CPh3
a Conditions: À78 to À40 °C and À40 °C for 1.5 h.

3770
T. Kawashima et al. / Tetrahedron Letters 46 (2005) 3767–3770
CN
CN
CN
NH2
Ph
O
H+, H2O
O
Ph
Ph
C
6a
D
CN
Ph
hydrolysis and
decarboxylation
migration of
double bond
O
O
Ph
E
7a
Scheme 4. Presumed mechanism for the formation of 2-phenylbicyclo[3.3.0]oct-1-en-3-one 7a from the enaminonitrile 6a by the treatment with acid.
(d) Martin, J. D. In Studies in Natural Products Chemistry;
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be introduced at the 2-position by this procedure to give
7e, though the overall yield was not satisfactory (entry
5).
It is worth noting that when cycloalkanones having lar-
ger than five-membered ring were used in this reaction,
the ring expansion did not proceed.5 The relief of strain
associated with the cyclobutane ring must be the driving
force of this reaction.10
3. (a) Stantelli-Rouvier, C.; Stantelli, M. Synthesis 1983, 429;
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Org. React. 1994, 45, 1.
In conclusion, we have discovered a novel procedure for
synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones and
2-substituted bicyclo[3.3.0]oct-1-en-3-ones from three
components: cyclobutanones, chloromethyl p-tolyl sulf-
oxide and nitriles, in good overall yields. We are contin-
uing to study the scope and limitations of this procedure
and its application to total synthesis of cyclopentanoid
natural products.
4. (a) Pauson, P. L. Tetrahedron 1985, 41, 5855; (b) Schore,
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56, 3263; (g) Perez-Serrano, L.; Blanco-Urgoiti, J.; Casar-
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Acknowledgements
This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan,
which is gratefully acknowledged.
5. Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K.
Tetrahedron 2003, 59, 9599.
6. (a) Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44,
7517; (b) Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61,
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