Alkoxide-catalyzed ring expansion of 1,3-cyclobutanediones with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2020.151804

1,3-Cyclobutanediones (dialkyl ketene dimer) reacted with various aromatic aldehydes to give six-membered cyclic β-keto esters by using a catalytic amount of potassium ethoxide. Effects of alkoxide catalysts and spiro cyclic groups at the 2,4-positions of 1,3-cyclobutanediones were investigated.

Full text of DOI:10.1016/j.tetlet.2020.151804

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Alkoxide-catalyzed ring expansion of 1,3-cyclobutanediones with aldehydes
Mizuki Yamazaki, Tomoyuki Yoshimura, Jun-ichi Matsuo
PII:
S0040-4039(20)30239-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151804
TETL 151804
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 February 2020
29 February 2020
3 March 2020
Please cite this article as: Yamazaki, M., Yoshimura, T., Matsuo, J-i., Alkoxide-catalyzed ring expansion of 1,3-
cyclobutanediones with aldehydes, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151804
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Alkoxide-catalyzed ring expansion of 1,3-
cyclobutanediones with aldehydes
Leave this area blank for abstract info.
Mizuki Yamazaki, Tomoyuki Yoshimura, and Jun-ichi Matsuo
O
O
KOEt
(cat.)
R
R
R
R
R
O
O
R
+
R
Ar
THF
rt, 1 h
O
Ar
O
R
14 examples
up to 99% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Alkoxide-catalyzed ring expansion of 1,3-cyclobutanediones with aldehydes
Mizuki Yamazaki, Tomoyuki Yoshimura, and Jun-ichi Matsuo
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +81-76-234-4474; fax: +81-76-234-4474; e-mail: jimatsuo@kanazawa-u.ac.jp
Article history:
Received
1,3-Cyclobutanediones (dialkyl ketene dimer) reacted with various aromatic aldehydes to give
six-membered cyclic β-keto esters by using a catalytic amount of potassium ethoxide. Effects of
Received in revised form
Accepted
alkoxide catalysts and spiro cyclic groups at the 2,4-positions of 1,3-cyclobutanediones were
investigated.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
cyclobutanedione
potassium ethoxide
ring expansion
cyclic β-keto ester
O
R
R
R
R
O
O
LB
R
O
R
R
R
Cyclobutane derivatives are important synthetic blocks and
they show unique reactivities by cleaving their strained four-
membered rings.1 Tetraalkyl 1,3-cyclobutanediones have been
prepared by dimerization of dialkyl ketene, and their ring-
cleavage reactions have been studied by using alcohols,2 amines,3
phosphites,4 and phosphorus amides.5 Ring expansions of the
R
R
O
LB
O
R
LB
R
1
2
3
O
O
R
R
R
R
– LB
R'CHO
R
R
R
R
four-membered ring of 1,3-cyclobutanediones to
a five-
O
O
R'
membered compounds were reported in syntheses of -lactams,6
a -lactone,7 and a cyclopentanone derivative.8 However, there
has been no report about ring expansion to six-membered
compounds from 1,3-cyclobutanediones except formation of
1,3,5-cyclohexanetriones.9 We report here a new ring expansion
reaction of tetraalkyl 1,3-cyclobutanediones 1 to six-membered
cyclic β-keto esters 5 by reactions with aldehydes (Scheme 1).
We envisioned that a Lewis base catalyst would react with 1,3-
cyclobutanedione 1 to form 2 and that ring cleavage of
cyclobutanone 2 would give an enolate 3. Aldol reaction of 3
with an aldehyde would afford 4, and its intramolecular
cyclization would give 5 with regeneration of the catalyst.
Highly substituted β-keto δ-lactones 5, which are seen in some
bioactive natural products such as lankacidine C10 and
magromicins,11 have been prepared by Reformatsky reactions of
halo β-keto esters12 and Claisen-aldol tandem reactions.13
O
O
R'
LB
4
5
Scheme 1. Lewis base-catalyzed ring expansion of 1,3-
cyclobutanediones 1 with aldehydes to β-keto esters 5.
A suitable Lewis base catalyst for the ring expansion reaction
was explored in the reaction of 1.5 equivalents of tetramethyl-
1,3-cyclobutanedione (1a) with benzaldehyde (Table 1). It was
found that potassium alkoxides catalyzed the expected reaction
and potassium ethoxide was the most effective one (entry 2).14
Potassium ethoxide in THF solution was freshly prepared by the
reaction of KH and ethanol in THF and the solution was stirred at
room temperature for 1-2 h.15 Gram-scale synthesis of 5a was
performed by using KOEt as a catalyst and 1.2 g (97%) of 5a was
obtained. Sodium ethoxide did not catalyze the present reaction
(entry 7), and other Lewis bases including DABCO and Bu3P did
not catalyze the reaction even in refluxing THF (entries 8 and 9).
The use of an equimolar amount of 1a resulted in lowering the
yield of 5a (entry 10).

2
Tetrahedron Letters
Table 1. Screening of catalysts.a
A proposed mechanism for the present ring-enlargement of 1,3-
cyclobutanediones 1 with aldehydes to six-membered β-keto esters
5 is shown in Scheme 2. Nucleophilic addition of potassium
ethoxide to the 1,3-butanedione 1 forms 6 and a retro-Claisen
reaction which is accelerated by cleaving a four-membered ring
gives an enolate 7. As the steric hindrance of alkoxides increases,
the nucleophilic addition of alkoxides is thought to proceed more
sluggishly (Table 1, entries 2-5). The excellent activity of an
ethoxide ion might be explained by relative nucleophilicity of
alkoxides.14b A weak nucleophile such as potassium phenoxide
can not attack to the 1,3-butanedione 1 to form 2 (Table 1, entries
6-9). Aldol reaction of 7 with an aldehyde gives 8 and its
O
cat.
(20 mol%)
O
O
+
Ph
THF
rt, 1 h
O
O
Ph
O
1a
5a
entry
cat.
conditions
yield
(%)
35
95 (97)b
21
10
23
0
0
0
0
55
1
2
3
4
5
6
7
8c
9c
10c
KOMe
KOEt
KOPr
KOiPr
KOtBu
KOPh
NaOEt
DABCO
Bu3P
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
rt, 1 h
intramolecular cyclization affords 5.
In the experiments
described above, a linear aldol product 9 was not obtained even
in the cases which gave low yields of desired products 5.
Therefore, the intramolecular cyclization of 8 proceeds smoothly
and a reverse reaction of 5 with potassium ethoxide to 8 is
suppressed by the presence of a more electrophilic compound 1
toward potassium ethoxide.
reflux, 6 h
reflux, 4 h
rt, 12 h
KOEt
a
Reaction conditions: 1,3-cyclobutanedione 1a (1.5 equiv), benzaldehyde
(1.0 equiv, 0.2 mmol), catalyst (20 mol%), THF, rt, 1 h.
b Benzaldehyde (5.0 mmol) was used.
c 1,3-Cyclobutanedione 1a (1.0 equiv) was used.
R
K
R
O
R
O
O
R
KOEt
R
O
R
R
R
R
R
K
O
R
OEt
O
OEt
R
The scope and limitations of the present reaction were studied
by using various aldehydes and cyclobutanediones (Table 2).
Various benzaldehyde derivatives having electron-withdrawing
groups or electron-donating groups smoothly reacted with 1,3-
cyclobutanedione 1a to give corresponding six-membered β-keto
esters 5b-f in high yields (94-99%). It was noted that the
carbomethoxy group of 5c was not affected under the present
1
6
7
O
O
R
R
R
R
–
R
R'CHO
KOEt
R
R
R
O
O
R'
O
O
R'
OEt
K
5
8
H2O
OH
R'
reaction
conditions.
1-Naphthylaldehyde
and
2-
naphthylaldehyde also reacted effectively with 1a to afford 5g
and 5h in 98% and 97% yields, respectively. The reaction of
cinnamaldehyde, an α,β-unsaturated aldehyde, proceeded
incompletely even in refluxing THF and 5i was obtained in 44%
yield. The reaction of 3-thiophenecarboxaldehyde proceeded
smoothly at room temperature to give 5j in 99% yield, but the
reaction of 2-furfural proceeded slowly at room temperature.
Addition of a catalytic amount of 18-crown-6 in refluxing THF
slightly improved the yield of the product 5k from 2-furfural.
However, the reaction with aliphatic aldehydes and ketones did
O
O
EtO
R
R R R
9
Scheme 2. Potassium ethoxide-catalyzed ring expansion of 1,3-
cyclobutanediones 1 with aldehydes to six-membered β-keto esters
5.
not give the desired products.
phenylpropanal afforded complex mixtures, and the reactions
with isobutyraldehyde, pivalaldehyde, benzophenone, and
The reaction with 3-
In conclusion, we have developed a KOEt-catalyzed ring-
enlargement reaction of 1,3-cyclobutanediones with aldehydes to
six-membered β-keto esters. Aromatic aldehydes including acid-
labile ones reacted to give the desired products. Potassium
ethoxide showed outstanding catalytic activity in the present ring
enlargement reaction.
cyclohexanone did not proceed.
In the reactions of
spirocyclobutanediones, it was found that the yields of products
5l-n were lower as the ring sizes of spiro rings were larger. In
these cases, the starting materials were detected even after a
prolonged reaction time, and raising the reaction temperature to
refluxing THF did not improve the yields of the desired products
5l-n.16
Table 2. Scope and limitations.a

3
O
O
O
O
5b: X = 4-NO2 (96%)
5c: X = 4-MeO2C (99%)
5d: X = 4-Br (99%)
5e: X = 2-Me (94%)
5f: X = 4-MeO (95%)
O
O
O
O
O
X
5g (98%)
5h (97%)
O
O
O
O
O
O
Ph
O
O
O
O
5i (44%)b
S
5k (55%)c
5j (99%)
O
O
O
O
O
O
O
O
O
5l (75%)d
5n
(15%)
d
5m (47%)d
a
Reaction conditions: 1,3-cyclobutanedione 1 (1.5 equiv), aldehyde (1.0 equiv), KOEt (20 mol%), THF, rt, 1 h. Numbers in parentheses are isolated yields.
b Reaction conditions: rt to reflux, 6 h.
c Reaction conditions: KOEt (20 mol%) and 18-crown-6 (20 mol%) , reflux, 22 h.
d Reaction conditions: rt, 3 h.
2001, 37, 374-375; (d) Shchepin, V. V.; Sazhneva, Y. K.;
Litvinov, D. N., Russ. J. Gen. Chem. 2003, 73, 596-602.
13. Tanabe, Y.; Hamasaki, R.; Funakoshi, S., Chem. Comm. 2001,
1674-1675.
Acknowledgments
14. (a) Phan, T. B.; Mayr, H., Can. J. Chem. 2005, 83, 1554-1560; (b)
Reeve, W.; Erikson, C. M.; Aluotto, P. F., Can. J. Chem. 1979, 57,
2747-2754.
15. Agitation of KOEt solution in THF at room temperature for 5 min
did not give satisfactory results (5a 15%).
This work was supported by JSPS KAKENHI Grant Number
JP19K05473 and Kanazawa University SAKIGAKE project.
References and notes
16. The use of KOMe instead of KOEt did not improve the yield of 5n
(11%).
1.
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Supplementary Material
Supplementary data associated this article can be found in the
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cyclobutanediones and aldehydes
• Effects of nucleophilic catalysts for activation of
1,3-cyclobutanediones
• Mechanism of the ring enlargement of 1,3-
cyclobutanediones to six-membered β-keto esters
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