An efficient procedure for preparation of 2-monoalkyl or 2-monoaryl-3-ethoxycyclobutanones

Article abstract of DOI:10.1016/j.tetlet.2010.05.031

Optimized reaction conditions for the preparation of various 2-monosubstituted 3-ethoxycyclobutanones are described. 2-Monoalkyl 3-ethoxycyclobutanones were efficiently prepared by the reaction of the corresponding carboxylic acid chlorides and an excess amount of ethyl vinyl ether in the presence of diisopropylethylamine at 90 °C in a sealed tube. 2-Monoaryl 3-ethoxycyclobutanones were prepared by using 2,6-lutidine as a base in the above-mentioned procedure.

Full text of DOI:10.1016/j.tetlet.2010.05.031

Tetrahedron Letters 51 (2010) 3736–3737
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An efficient procedure for preparation of 2-monoalkyl
or 2-monoaryl-3-ethoxycyclobutanones
*
Jun-ichi Matsuo , Ryosuke Okuno, Kosuke Takeuchi, Mizuki Kawano, Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimized reaction conditions for the preparation of various 2-monosubstituted 3-ethoxycyclobutanones
are described. 2-Monoalkyl 3-ethoxycyclobutanones were efficiently prepared by the reaction of the cor-
responding carboxylic acid chlorides and an excess amount of ethyl vinyl ether in the presence of diiso-
propylethylamine at 90 °C in a sealed tube. 2-Monoaryl 3-ethoxycyclobutanones were prepared by using
2,6-lutidine as a base in the above-mentioned procedure.
Received 13 April 2010
Revised 28 April 2010
Accepted 10 May 2010
Available online 12 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Cyclobutanones are important and versatile compounds in
organic synthesis.1 Among them, 3-ethoxycyclobutanones have
been employed for the preparation of bicyclobutanes2 and silyloxy
dienes.3 We recently found new synthetic utility of 3-ethoxycyclob-
utanones as a useful building block for the synthesis of various types
of six-membered cyclic compounds. Thus, Lewis acid activates 2,2-
disubstituted 3-ethoxycyclobutanones by cleaving the more substi-
tuted C2–C3 bond of the cyclobutanone ring to form a zwitterionic
intermediate, which reacts with carbonyl compounds,4 allylsilanes,5
or silyl enol ethers6 to afford the corresponding cyclic compounds. In
our investigation of these reactions, we encountered difficulty in the
preparation of 2-monosubstituted or nonsubstituted 3-ethoxycy-
clobutanones. That is, 3-ethoxy-2-monoalkylcyclobutanones were
synthesized in low yields (vide infra) by the conventional procedure
of employing the corresponding carboxylic acid chloride, triethyl-
amine, and ethyl vinyl ether (EVE) in refluxing acetonitrile.7 We
report here a widely applicable procedure for the preparation of
2-monosubstituted 3-ethoxycyclobutanones.
suitable amine for the cycloaddition reaction, and cyclobutanone 2
was obtained in 80% yield (entry 3).9 Tributylamine, triisobutyl-
amine, and 2,6-lutidine were not effective (entries 4–6). Decreasing
the amount of EVE from 10 to 5 equiv resulted in decrease in the
yield of 2 to 54% (entry 7). The use of inorganic bases such as
K2CO3 and Cs2CO3 in the presence of a catalytic amount of diisopro-
pylethylamine was not effective. Raising the reaction temperature
from 90 to 120 °C did not improve the yield of cyclobutanone 2,
and the reaction at 60 °C gave 2 in a trace amount.
Next, several 2-alkyl-3-ethoxycyclobutanones 7 were prepared
by using the corresponding carboxylic acid chloride 6, diisopropyl-
ethylamine, and 10 equiv of EVE in a sealed tube at 90 °C (Table 2).
It should be noted that 2-nonsubstituted 3-ethoxycyclobutanone
7a, which was not obtained by the conventional method of using tri-
Table 1
Optimization of reaction conditions
The conventional conditions for the synthesis of 3-ethoxycyclob-
utanones by [2 + 2] Cycloaddition of ethyl vinyl ether (EVE) and ke-
tene, which was generated in situ from carboxylic acid chloride 1
with triethylamine in refluxing acetonitrile, gave the desired 2-ben-
zyl-3-ethoxycyclobutanone 2 in 7% yield (Table 1, Entry 1). [2 + 2]
Cycloaddition using an excess amount (10 equiv) of EVE without
acetonitrile in a sealed tube gave 2 in a slightly improved yield
(12% yield, entry 2). It was thought that an undesired side reaction
such as dimerization of ketene via species 4, which was formed by
the addition of triethylamine hydrochloride to reactive monoalkyl
ketene 3,7a,8 was the reason for low yields of cyclobutanone 2
(Scheme 1). Therefore, hindered amines were employed in order
not to form 4. It was then found that diisopropylethylamine was a
Entry
Base
EVE (equiv)
Yielda (%)
cis/transb
1c
2
3
4
5
6
7
Et3N
Et3N
2
10
10
10
10
10
5
7
12
80
31
Trace
36b
54
10:90
17:83
62:38
10:90
—
i-Pr2NEt
Bu3N
i-Bu3N
2,6-Lutidine
i-Pr2NEt
61:39
61:39
a
b
c
Isolated yield unless otherwise mentioned.
Determined by 1H NMR.
The reaction was performed by using acetonitrile as a solvent at reflux under
* Corresponding author. Tel./fax: +81 76 234 4439.
E-mail address: jimatsuo@p.kanazawa-u.ac.jp (J. Matsuo).
N2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.031

J. Matsuo et al. / Tetrahedron Letters 51 (2010) 3736–3737
3737
The use of diisopropylethylamine gave the desired cyclobutanone
9a in a trace amount, whereas the use of 2,6-lutidine gave 9a in
75% yield (entry 1). It was assumed that diisopropylethylamine-
mediated formation of phenyl ketene took place too rapidly before
cycloaddition with EVE because of increased acidity of the
a-pro-
Scheme 1. Undesired formation of reactive intermediate 4.
ton of carboxylic acid chloride 8a. Other -aryl carboxylic acid
a
chlorides 8b–i also reacted with EVE smoothly in the presence of
2,6-lutidine (entries 2–9).
Table 2
Synthesis of various 2-monoalkyl 3-ethoxycyclobutanones 7a–i
In summary, we have developed a convenient method for the
synthesis of 2-monoalkyl or 2-monoaryl 3-ethoxycyclobutanones
by using the corresponding carboxylic acid chlorides and EVE in
the presence of sterically hindered amines such as diisopropyleth-
ylamine and 2,6-lutidine.11 Two points are thought to be important
for the efficient synthesis of 2-monosubsituted 3-ethoxycyclobuta-
nones from carboxylic acid chloride and EVE. One is smooth gener-
ation of ketene at 90 °C, a temperature at which ketene can react
readily with EVE. The other is to avoid a reaction between ketene
and amine hydrochloride to form intermediate 4.
Entry
R
7
Yielda (%)
cis/transb
1
2
3
4
5
6
7
8
9
H
Me
Et
Pr
Bu
Hex
i-Bu
i-Pr
t-Bu
7a
7b
7c
7d
7e
7f
7g
7h
7i
37
77
78
71
76
77
77
50
—
53:47
16:84
27:73
30:70
58:42
24:76
31:69
36:64
(54:46)c
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan.
48
(74)c
a
b
c
Isolated yield.
Determined by 1H NMR.
Supplementary data
Triethylamine was used instead of diisopropylethylamine.
Supplementary data (full characterization of all new cyclobuta-
nones (2, 7a–i, and 9a–i) and their 1H and 13C NMR spectra) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.05.031.
Table 3
Synthesis of various 2-monoaryl 3-ethoxycyclobutanones 9a–i
References and notes
1. (a) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1483; (b) Namyslo, J.
C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485–1537; (c) Belluš, D.; Ernst, B.
Angew. Chem., Int. Ed. Engl. 1988, 27, 797–827.
Entry
Ar
9
Yielda (%)
cis/transb
1
2
3
4
5
6
7
8
9
Ph
9a
9b
9c
9d
9e
9f
9g
9h
9i
75 (trace)c
11:89
14:86
11:89
6:94
12:88
7:93
6:94
7:93
7:93
2. Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 130–136.
p-MeOC6H4
p-MeC6H4
o-MeC6H4
p-ClC6H4
1-Naph
2-Naph
2-Thienyl
3-Thienyl
74
56
74
56
83
64
62
70
3. Aben, R. W.; Scheeren, H. W. J. Chem. Soc., Perkin Trans. 1 1979, 3132–3138.
4. Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc. 2008, 130,
11600–11601.
5. Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett. 2009, 11, 3822–
3825.
6. Matsuo, J.; Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 5831–5833.
7. (a) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159–646; (b) Ward, R. S.
Chem. Ketenes, Allenes Relat. Compd. 1980, 1, 223–277.
8. Farnum, D. G.; Johnson, J. R.; Hess, R. E.; Marshall, T. B.; Webster, B. J. Am. Chem.
Soc. 1965, 87, 5191–5197.
9. Typical procedure (Table 1, entry 3): To a solution of diisopropylethylamine
(0.28 mL, 1.64 mmol) and ethyl vinyl ether (1.28 mL, 13.4 mmol) was added 3-
phenylpropionyl chloride 1 (0.20 mL, 1.35 mmol) in a sealed tube. The reaction
mixture was heated with stirring at 90 °C (bath temperature) for 2 h. After
cooling to room temperature, the reaction was quenched with saturated
aqueous sodium hydrogen carbonate solution, and the mixture was extracted
with ethyl acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography on silica gel (hexane/ethyl
acetate = 30:1 to 8:1) to afford 2-benzyl-3-ethoxycyclobutanone 2 (220 mg,
80%). Characterization data and NMR spectra are shown in the Supplementary
data.
a
b
c
Isolated yield.
Determined by 1H NMR.
Diisopropylethylamine was used instead of 2,6-lutidine.
ethylamine as a base, was obtained in 37% yield (entry 1).10 This is a
convenient method for the preparation of 7a because a special appa-
ratus (ketene lamp) is not required in the present method. Linear
nonbranched ketenes such as methyl ketene, ethyl ketene, propyl
ketene, and butyl ketene, which were reported to dimerize easily,7a
reacted with EVE smoothly to afford the corresponding cyclobuta-
nones in good yields (entries 2–6). Ketenes bearing a b-branched
alkyl group generated from acid chloride 6g gave the corresponding
10. Preparation of 7a (10-time scale, Table 2, entry 1): To
a solution of
diisopropylethylamine (2.8 mL, 16.4 mmol) and ethyl vinyl ether (13.0 mL,
136 mmol) was added acetyl chloride (0.96 mL, 13.5 mmol) in a sealed tube.
The reaction mixture was heated with stirring at 90 °C (bath temperature) for
2 h. After cooling to room temperature, the reaction was quenched with
saturated aqueous sodium hydrogen carbonate solution, and the mixture was
extracted with ether. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography on silica gel (pentane/
ether = 8:1) to afford 3-ethoxycyclobutanone 7a (572 mg, 37%).
cyclobutanone 7g in 77% yield, whereas a-branched ketenes gener-
ated from acid chlorides 6h and 6i gave the corresponding cyclobu-
tanones 7h and 7i in 48–50% yields (entries 7–9). In the reaction of
6i, triethylamine was found to be more suitable than diisopropyleth-
ylamine probably because smooth abstraction of the a-proton of 6i
11. The present method was not suitable for the preparation of 2,2-dialkyl 3-
ethoxycyclobutanones. The reaction between isobutyryl chloride and EVE with
diisopropylethylamine or triethylamine under the present reaction conditions
gave 2,2-dimethyl-3-ethoxycyclobutaone in 8% or 46% yield, respectively.
with triethylamine took place, and formation of undesired 4 from
tert-butyl ketene was difficult due to its steric hindrance.
Preparation of 2-aryl-3-ethoxycyclobutanones 9 from the corre-
sponding
a-aryl carboxylic acid chlorides 8 is shown in Table 3.