Synthesis of cyclobutanones and four-membered enol ethers by using a rearrangement reaction of enol triflates

Article abstract of DOI:10.1016/j.tetlet.2004.12.060

A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the β′-position, were synthesized from the corresponding β-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.

Full text of DOI:10.1016/j.tetlet.2004.12.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1169–1172
Synthesis of cyclobutanones and four-membered enol ethers
by using a rearrangement reaction of enol triflates
Keiji Tanino,* Kotaro Aoyagi, Yasuhiro Kirihara, Yoshikazu Ito and Masaaki Miyashita*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 23 November 2004; revised 13 December 2004; accepted 15 December 2004
Available online 8 January 2005
Abstract—A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of
a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the b0-position, were synthesized
from the corresponding b-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under
the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the
trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
-
Development of an efficient method for constructing
highly strained molecules is one of the most challenging
subjects in synthetic organic chemistry. Although for-
mation of three-membered rings, for example, cyclopro-
panes and epoxides, is a kinetically favored process,
cyclization reactions giving rise to four-membered com-
pounds are far more difficult. Therefore, four-membered
ketones are commonly prepared through a [2+2] cyclo-
addition reaction of a ketene with an olefin,1 while there
are only a few methods for synthesizing cyclobutanones
via a direct intramolecular cyclization reaction. For
example, solvolysis of a trifluoromethanesulfonyl ester
of a 1-alkyn-4-ol affords a cyclobutanone derivative
via a p-cyclization reaction.2 An intramolecular alkyl-
ation reaction of a ketone enolate having a good leaving
group at the b0-position provides an alternative way for
cyclobutanone synthesis (path a in Scheme 1).3 This type
of approach, however, suffers from generation of a regio
isomer of the enolate, which merely lead to an enone via
a b-elimination reaction (path b). Indeed, successful
results have been reported only in the cases that an
a,a-disubstituted ketone, which cannot choose path b,
is used as a cyclization precursor.
O
O
O
X
X
path a
path b
R'
R'
R
R
R
R'
O
X
base
-
R'
O
R
R'
R
Scheme 1. Reactions of enolates generated from a ketone having a
leaving group at the b-position.
With a view to overcome the limitation mentioned
above, we designed enol triflate I having a siloxy group
at the b0-position as a cyclization precursor (Scheme 2).
O
-
SO2CF3
O
O
CF3
O
S
-
-
OTf OSiR3
O
O
F
R'
R'
R'
R
R
R
I
II
SO2CF3
O
O
-
O
R
Keywords: Cyclobutanone; Oxetane; Enol ether; Cyclization; Enol
triflate.
R'
IV
R'
*
R
Corresponding authors. Tel.: +81 117062703; fax: +81 117064920
(K.T.); tel.: +81 117062705; fax: +81 117064920 (M.M.); e-mail
addresses: ktanino@sci.hokudai.ac.jp; miyasita@sci.hokudai.ac.jp
III
Scheme 2. Enol triflates as a precursor of a cyclobutanone derivatives.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.060

1170
K. Tanino et al. / Tetrahedron Letters 46 (2005) 1169–1172
Since determination of the stereochemistry of the prod-
uct was difficult, cyclobutanone 3a was transformed into
cyclopentanone derivative 4 through one-carbon ring
expansion by diazomethane.9 The syn-configuration be-
tween the phenyl group and the ketone moiety was
unambiguously confirmed by an NOE experiment of 4,
which indicates that the cyclization step giving rise to
3a involves inversion of the configuration at the benzylic
carbon. High reactivity at the benzylic position to
enhance the cyclization step seems not essential for the
cyclobutanone synthesis, because enol triflate 2d having
an aliphatic side chain instead of a phenyl group also
afforded 3d in good yield.
1) TBSCl, imidazole / DMF
2) LDA / THF, -78 ˚C
then Comins reagent
O
O
OH
TfO
OTBS
Ph
H
H
H
Ph
81% from 1a
1a
2a
OH
Ph
TfO
OTBS
Ph
H
Cl
2 steps
N
N(Tf)2
85%
Comins reagent
from 1b
1b
2b
O
OH
TfO
OTBS
2 steps
Ph
1c
Ph
2c
68%
from 1c
On the other hand, the reaction of the corresponding
diastereomer 2b resulted in the formation of a mixture
containing no desired cyclobutanone derivative. Silica
gel column chromatography of the mixture afforded
aldol 1a as the major product, although it was never
Scheme 3. Preparation of cyclization precursors from aldol
derivatives.
Under the influence of a fluoride ion, silyl ether I will
give alkoxide II that could be transformed into enolate
III through an intramolecular rearrangement of the tri-
fluoromethanesulfonyl group.4 The resulting enolate III
having a trifluoromethanesulfonyloxy group, a very
good leaving group,5 at the b0-position would rapidly
undergo a cyclization reaction to afford a cyclobutanone
derivative IV.
1
detected in the H NMR spectra of the crude mixture.
Careful analysis of the reaction of 2b led us to find oxe-
tane derivative 5b, a highly strained enol ether10 that
easily undergoes hydrolysis during column chromato-
graphy to give aldol 1a, as a main product. Since the ste-
reochemistry of oxetane 5b confirmed by an NOE exper-
iment was identical with that of aldol 1a, conversion of
the former to the latter would proceed through proton-
ation of the olefin moiety.
To this end, cyclization precursors were successfully syn-
thesized from the corresponding b-hydroxy ketones,
which are readily accessible via an aldol reaction of a
ketone and an aldehyde,6 in two steps (Scheme 3). Thus,
after protection of the hydroxyl group with a tert-butyl-
dimethylsilyl group,7 the ketone was converted to an
enol triflate8 through regioselective formation of a
lithium enolate under kinetic control.
Next, scope and limitation of the fluoride-mediated
intramolecular cyclization reaction was investigated
(Scheme 5). Acyclic enol triflate 2c failed to give any
cyclization product, and alkynyl alcohol 6 arising from
a b-elimination reaction was obtained almost quantita-
tively. The result suggests that the use of an enol triflate
prepared from a cycloalkanone is effective to avoid a b-
elimination reaction giving rise to a highly strained
cycloalkyne.
The cyclization reaction was performed by treating the
substrate with tetrabutylammonium fluoride7 (TBAF)
in THF, and the desired cyclobutanone 3a was obtained
from enol triflate 2a as a single isomer in high yield
(Scheme 4).
OH
Ph
TfO
OTBS
Ph
TBAF (6 eq)
THF, rt
96%
2c
6
R
O
O
H
TfO
OTBS
R
Ph
OTBS
OH
TfO
O
O
O
O
H
H
H
TBAF (6 eq)
THF, rt
H
H
H
H
H
H
TBAF (6 eq)
HCl
H
Ph
Ph
R
THF, rt
94%
2e
5e
2a: R = Ph
2d: R = CH2CH2Ph
3a 86%
3d 72%
R
OTBS
R
OH
TfO
H
H
O
NOE
TBAF (6 eq)
THF, rt
HCl
R
H
H
O
CH2N2
3a
H
H
Ph
MeOH
H
4
2f: R = Ph
2g: R = CH2CH2Ph
5f 91%
5g 92%
78%
Ph
O
TfO
OTBS
Ph
O
OH
O
TfO
OTBS
Ph
CO2H
H
H
H
TBAF (3 eq)
TBAF (6 eq)
THF, rt
H
H
SiO2
H
Ph
Ph
+
Ph
THF, rt
H
55% (NMR yield)
2h
3h 14%
2b
5b
1a
7 41%
Scheme 4. Cyclization reactions of six-membered enol triflates.
Scheme 5. Cyclization reactions of various enol triflates.

K. Tanino et al. / Tetrahedron Letters 46 (2005) 1169–1172
1171
Ph
Interestingly, the ring size of substrates was found to
H
O
-
O
play an important role in selection of the reaction path-
way, namely, C-alkylation versus O-alkylation. Thus,
both enol triflates 2e and 2f derived from cyclohepta-
none underwent an O-alkylation reaction regardless of
their stereochemistry in excellent yields, while five-mem-
bered substrate 2h afforded cyclobutanone 3h in low
yield along with fragmentation product 7. It is notewor-
thy that oxetanes 5e, 5f, and 5g exhibited much higher
stability than 5b, which allowed us to isolate them in
high yield after silica gel column chromatography. In
order to determine the stereochemistry, the enol ethers
were subjected to hydrolysis promoted by diluted hydro-
chloric acid and the corresponding syn and anti aldol
derivatives were obtained, respectively.
H
OTf
-
H
Ph
O
OTf
H
H
"highly strained"
Ph
Ph
O
Ph
H
H
OTf
H
generated
from 2a
H
-
O
3a
Ph
Ph
O
-
O
H
OTf
-
H
H
O
OTf
H
H
5b
"highly strained"
Ph
H
Ph
Ph
Ph
The different behavior of the cyclic enol triflates 2a, 2b,
2e, 2f, and 2h can be rationalized as follows. The cycli-
zation step proceeds through an intermediate having a
quaternary ammonium enolate moiety and an alkyl tri-
flate moiety (III in Scheme 2). It should be noted that a
quaternary ammonium enolate and an alkyl triflate are
classified as a Ôhard nucleophileÕ and a Ôhard electro-
phileÕ, respectively.11 Combination of these ÔhardÕ spe-
cies should be advantageous to an O-alkylation
reaction, and oxetanes 5b, 5e, and 5f are formed via this
pathway. On the other hand, these four-membered enol
ethers having an sp2 carbon at the angular position are
highly strained especially in the case that the size of
the carbocycle is small. Indeed, cyclohexene derivative
5b exhibits higher lability than the seven-membered ana-
logues 5e and 5f, and an O-alkylation pathway from
five-membered enol triflate 2h suffered from extremely
high strain energy of a bicyclo[3.2.0]heptane skeleton.
OTf
generated
H
H
from 2b
H
-
O
O
OTf
H
H
O
-
"sterically hindered"
Scheme 6. Transition state models of the cyclization reactions.
O
TfO
OH
Me
H
Me
TBAF (5 eq)
THF, rt
H
Me
+
O
2i
3i 48%
8 34%
-
-
O
OTf
Me
O
Selective formation of cyclobutanones from six-mem-
bered enol triflates 2a and 2d can also be explained simi-
larly, although the corresponding syn-isomer 2b yielded
enol ether 5b. As depicted in Scheme 6, the exceptional
behavior of enol triflate 2b would come from steric
repulsion between the phenyl group and the ring carbon
in the transition state leading to a cyclobutanone
derivative.
2i
8
+
Me
V
VI
Scheme 7. Cyclization reaction of a0-substituted enol triflate 2i.
stabilize the zwitter ion intermediate like VI in Scheme
7, which leads to selective formation of the cyclization
product with a bicyclo[3.2.0]heptane skeleton. Indeed,
the reaction of triflate 2j afforded the expected cyclobu-
tanone 9 via a ring expansion pathway, while the corre-
sponding anti-isomer 2k underwent an O-alkylation
reaction. The different behavior between these syn- and
anti-isomers is quite similar with that of 2a and 2b in
Scheme 6, and the results can be rationalized by using
a similar transition state model. While the ring expan-
sion reaction of 2j proceeds through a transition state
in which the ring carbon and the triflate moiety are anti-
parallel to each other, 2k cannot undergo a similar reac-
tion because of steric repulsion between the side chain
and the six-membered ring.
Finally, a cyclization reaction of a six-membered enol
triflate having a substituent at the a0-position was exam-
ined (Scheme 7). In this case, increased steric hindrance
around the silyloxy group prevented the desilylation
step, and the substrate was previously treated with HF
to remove the silyl group under more mild conditions.
The reaction of b0-hydroxy enol triflate 2i with TBAF
afforded cyclobutanone 3i along with unusual product
8 in high combined yield. It is reported that a similar re-
sult was obtained from the reaction of 2-methyl-2-(tosyl-
oxymethyl)cyclohexanone with a base.3,12 We assumed
that the unusual product 8 would arise from ring expan-
sion of enolate V to give zwitter ion intermediate VI fol-
lowed by transannular cyclization.
In order to prove the hypothesis, we designed enol tri-
flates 2j and 2k having a methoxyl group at the a0-posi-
tion, as a substrate (Scheme 8). We envisioned that the
electron donation by the methoxyl group would strongly
In conclusion, a new synthetic method of cyclobutanone
derivatives and four-membered enol ethers was devel-
oped on the basis of intramolecular cyclization of a
ketone enolate. The cyclization precursors, enol triflates

1172
K. Tanino et al. / Tetrahedron Letters 46 (2005) 1169–1172
References and notes
H
O
TfO
TfO
OH
Ph
OMe
Bu4NF (5 eq)
Ph
Ph
1. For a review, see: Hyatt, J. A.; Raynolds, P. W. Org.
React. 1994, 45, 159–646.
2. (a) Hanack, M.; Bocher, S.; Herterich, I.; Hummel, K.;
Vott, V. Liebigs Ann. Chem. 1970, 733, 5; (b) Schumacher,
W.; Hanack, W. Synthesis 1981, 490–492.
3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.;
Schenk, H. P. J. Am. Chem. Soc. 1971, 93, 3208.
4. For intramolecular rearrangement of trifluoro-
methanesulfonyl group, see: Coe, J. W.; Bianco, K. E.;
Boscoe, B. P.; Brooks, P. R.; Cox, E. D.; Vetelino, M. G.
J. Org. Chem. 2003, 68, 9964–9970.
5. For a review of alkyl triflates, see: Stang, P. J.; Hanack,
M.; Subramanian, L. R. Synthesis 1982, 85–126.
6. Mukaiyama, T. Org. React. 1982, 28, 203–331.
7. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190.
8. Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P.
Org. Synth. Coll. 1998, IX, 165–168.
9. Majerski, Z.; Djigas, S.; Vinkovic, V. J. Org. Chem. 1979,
44, 4064.
10. A synthetic method for four-membered enol ethers from
b-lactones was reported. Dollinger, L. M.; Howell, A. R.
J. Org. Chem. 1996, 61, 7248–7249.
H
OMe
CH2Cl2, 0 ˚C
78%
2j
9
Ph
OH
O
Bu4NF (5 eq)
CH2Cl2, 0 ˚C
81%
H
OMe
OMe
2k
5k
-
O
OTf
R
H
R
OMe
2j
9
+
R
OMe
-
O
OTf
OMe
2k
H
-
O
"sterically hindered"
Scheme 8. Cyclization reactions of a0-methoxy enol triflates 2j and 2k.
11. Ho, T. Hard and Soft Acids and Bases Principle in Organic
Chemistry; Academic: New York, 1977.
12. Tsuda, Y.; Tanno, T.; Ukai, A.; Isobe, K. Tetrahedron
Lett. 1971, 2009–2012; See also: Zhang, L.; Koreeda, M.
Org. Lett. 2002, 4, 3755–3758.
having a silyloxy group at the b0-position, were synthe-
sized from the corresponding b-hydroxy ketones, which
were prepared via an aldol reaction of a cycloalkanone
and an aldehyde. Under the influence of TBAF, the enol
triflates afforded a cyclobutanone or a four-membered
enol ether through rearrangement of the trifluoro-
methanesulfonyl group followed by an intramolecular
C- or O-alkylation reaction.13 Synthetic applications of
the products having a highly strained skeleton are cur-
rently under investigation.
13. Typical procedure: enol triflate 2g (0.54 g, 1.1 mmol) was
diluted with a 1.0 M THF solution of TBAF (6.6 mL,
6.6 mmol) at room temperature. After being stirred for
1 h, aqueous NaHCO3 solution was added. The aqueous
layer was extracted with ether, and the combined organic
layer was washed with brine and dried over MgSO4.
Concentration under reduced pressure followed by silica
gel column chromatography (hexane–AcOEt, 20:1) affor-
1
ded oxetane 5g (0.23 g, 92%) as a colorless oil: H NMR
(270 MHz, CDCl3) d 1.19–2.25 (m, 10H), 2.60 (ddd,
J = 6.9, 9.6, 13.7 Hz, 1H), 2.79 (ddd, J = 5.1, 9.9, 13.7 Hz,
1H), 3.46–3.57 (m, 1H), 4.74 (ddd, J = 4.3, 7.6, 9.6 Hz,
1H), 4.79–4.85 (m, 1H), 7.16–7.32 (m, 5 H); 13C NMR
(67.5 MHz, CDCl3) d 25.36, 25.41, 29.72, 30.51, 31.44,
33.38, 44.95, 81.62, 95.25, 125.89, 128.33, 128.38, 141.26,
163.86.
Acknowledgements
Financial support from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan (a Grant-
in-Aid for Scientific Research (B) (No. 16350049 and
No. 14340191)) is gratefully acknowledged.