Siloxy(trialkoxy)ethene undergoes regioselective [2+2] cycloaddition to ynones and ynoates en route to functionalized cyclobutenediones

Article abstract of DOI:10.1039/c0cc00883d

Regioselective [2+2] cycloaddition of ynones or ynoates to siloxy(trialkoxy)ethene (KSA) is described. A siloxy group on the KSA directs the perfect regioselectivity, allowing rapid construction of various functionalized cyclobutenedione derivatives.

Full text of DOI:10.1039/c0cc00883d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Siloxy(trialkoxy)ethene undergoes regioselective [2+2] cycloaddition
to ynones and ynoates en route to functionalized cyclobutenedionesw
Shin Iwata, Toshiyuki Hamuraz and Keisuke Suzuki*
Received 12th April 2010, Accepted 21st May 2010
First published as an Advance Article on the web 17th June 2010
DOI: 10.1039/c0cc00883d
Regioselective [2+2] cycloaddition of ynones or ynoates to
siloxy(trialkoxy)ethene (KSA) is described. A siloxy group on
the KSA directs the perfect regioselectivity, allowing rapid con-
struction of various functionalized cyclobutenedione derivatives.
makes the LUMO coefficient larger at the distal site to accept
the incoming KSA B. We are even tempted to regard the
reaction as a s-conjugate addition. (2) At the following cycliza-
tion stage, the more stabilized, and thus more contributing
zwitterion C is responsible, leading to the head-to-head
cycloadduct D.
Highly oxidized four-membered carbocycles are useful in
organic synthesis;1 squarates III and the derivatives, IV and
V, have been extensively used for the synthesis of complex
molecules by exploiting molecular strain, and also as a scaffold
for the hybrid assembly for biological studies.2
Analogy 2. Of further interest was the finding that, in spite
of pseudo-symmetry, fully oxygenated KSA E reacts with A in
a completely regioselective manner (Scheme 2).7 Thus, a
question arose whether or not such a selectivity also applies
to the triple bond in electrophilic alkyne G that resembles A in
polarity.
This paper describes an affirmative answer to this question:
tetraoxyethene E indeed undergoes fully regioselective [2+2]
cycloaddition to alkynone (or alkynoate) G, providing efficient
access to highly functionalized cyclobutenedione derivatives H
with considerable synthetic potentials.
If flexible de novo access to such oxidized cyclobutanes
became possible, new possibilities in organic synthesis would
be opened. We report herein ready, selective access to a class
of compounds related to I in its selectively protected form II,
starting with several analogies as the background of the idea.
The [2+2] cycloaddition of two ethenes is a simple proto-
type to construct cyclobutenes. While the parent system needs
photo-activation,3 the corresponding donor/acceptor pair, VI
and VII, reacts thermally through a polar two-step mechanism
(Scheme 1).4 The observed head-to-head regiochemistry could
be expressed either by the incipient HOMO–LUMO inter-
action or the relative stability of the intermediary zwitterionic
species VIII (vs. VIII0), and the two factors are usually closely
related.
Table 1 illustrates the initial model experiments. Upon
heating ynone 1 and KSA 2 (1.3 equiv.) in toluene at 90 1C
for 12 h, the [2+2] cycloaddition smoothly proceeded to give
cycloadduct 3 in 54% yield (entry 1).8 Importantly, the reaction
was completely regioselective, giving 3 as a single regioisomer.9
1,3-Diene 4 was obtained in 26% yield as a side product,
arising from the ring opening of the four-membered ring
followed by silyl group migration.11 As diene 4 was highly
prone to hydrolysis by silica-gel chromatography, the yields of
3 and 4 were assessed by 1H NMR analysis. Formation of
diene 4 was almost completely suppressed by performing the
reaction at lower temperature (entry 2).12 Moreover, the
reaction was even more efficient under solvent-free condi-
tions, giving cycloadduct 3 in almost quantitative yield.
Analogy 1. We noted a close resemblance of such a stepwise
[2+2] cycloaddition to the reaction of a-alkoxybenzyne A
with ketene silyl acetal (KSA) B on two counts.5,6 (1) The
inductive electron-withdrawal of the a-alkoxy group in A
Department of Chemistry, Tokyo Institute of Technology,
and SORST, JST Agency, 2-12-1 O-okayama, Meguro-ku,
Tokyo 152-8551, Japan. E-mail: ksuzuki@chem.titech.ac.jp;
Fax: (+81)3-5734-2788
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. CCDC 662792 and 709482. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc00883d
z Present address: Department of Chemistry, School of Science and
Technology, Kwansei Gakuin University, and PRESTO, JST Agency,
2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
Scheme 1 Polar [2+2] cycloaddition.
ꢀc
This journal is The Royal Society of Chemistry 2010
5316 | Chem. Commun., 2010, 46, 5316–5318

View Article Online
Table 2 Thermal [2+2] cycloaddition
Yield of
6 (%)
Entrya
1
Alkyne
R
Time/h
2
5a
Ph
93
89
2
5b
1
Scheme 2 Possible access to functionalized cyclobutenediones.
Isolation by silica-gel chromatography afforded 93% yield of 3
(entry 3).
3
5c
8
75
As shown in Table 2, the regioselectivity persisted in the
reactions of various other ynones (and a ynoate). Upon
heating of ynone 5a with KSA 2, the [2+2] cycloaddition
cleanly proceeded to give cycloadduct 6a in excellent yield
(entry 1).
4b
5d
5e
0.2
19
98
94
5
PhO
a
b
The molar ratio of KSA 2 to alkyne 5 is 1.3–1.4. Performed at
room temperature.
Interestingly, ynones 5b and 5c with an additional alkene
moiety, reacted smoothly at the triple bond, while the alkenyl
groups remained intact, giving dialkenyl ketones 6b and 6c,
respectively, in high yield (entries 2 and 3). Diynyl substrate 5d
also underwent rapid cycloaddition at room temperature to
give mono-cycloadduct 6d in 98% yield (entry 4). It should be
noted that the reaction occurred selectively at the terminal
alkynyl group: there was neither indication of the double
cycloaddition nor a reaction at the phenylethynyl moiety.
Moreover, phenyl propiolate (5e) was also a good substrate,
affording 6e in 94% yield (entry 5).13
Table 4 shows the Me3Al-promoted [2+2] cycloaddition of
2 to various phenyl esters 10a–10e, giving the corresponding
cyclobutenes 11a–11e, respectively, in high yields.16–18
Thus, the various cycloadducts are synthetically useful
cyclobutenedione derivatives with two selectively protected
carbonyl groups on the four-membered ring. Scheme 3
exemplifies some possibilities. Careful treatment of cycloadduct
11b with BF3ꢂEt2O and water in CH2Cl2 allowed selective
hydrolysis of the silyl acetal, giving mono-ketone 12 in 85%
yield.19 Reduction of 11b with LiAlH4 afforded alcohol 13.
Bis-acetal 13 was selectively hydrolyzed with aq. KF and
n-Bu4NCl to give mono-one 14, which was further converted
to cyclobutenedione 15 by treatment with BF3ꢂEt2O and water
in CH2Cl2 (0 1C).
In summary, regioselective [2+2] cycloaddition of electro-
philic alkynes and fully oxygenated ketene silyl acetals
allows rapid access to synthetically attractive cyclobutene-
dione derivatives. Further studies on selective transformation
en route to polycyclic compounds are underway in our
laboratories.
Upon further attempts to examine the substrate scope, we
found that b-substituted propiolate 7a failed to react. Only the
starting material was recovered, even when the reaction was
performed at 110 1C for a prolonged reaction time (entry 1,
Table 3). We were pleased to find, however, that the cyclo-
addition could be achieved under Lewis acid promoted con-
ditions, and ynoate 7a reacted with KSA 2 in the presence of
Me3Al (CH2Cl2, ꢁ78 - ꢁ20 1C) to give the desired [2+2]
cycloadduct 8a in 41% yield (entry 2).14 In this case, however,
the 1,2-addition competed, producing 9a in 29% yield.15 We
found that this side reaction was suppressed by increasing the
sterics of the ester moiety. The 1,2-addition was partially
suppressed by replacing methyl by ethyl (entry 3) or isopropyl
(entry 4), and completely suppressed by phenyl, giving the
corresponding phenyl ester 8d in good yield (entry 5).
Table 3 Effect of the alkoxy moiety in the ester
Table 1 Model experiments
Entrya Alkyne
R
Time/h Yield of 8 (%) Yield of 9 (%)
1c
2
3
4
7a
7a
7b
7c
7d
Me 40
Me 69
—
44
49
59
74
—
29
29
10
—
Entrya
Conditions
Yield of 3 (%)b
Yield of 4 (%)b
1
2
3
toluene, 90 1C, 12 h
toluene, 60 1C, 17 h
neat, 60 1C, 8 h
54
84
26
3
—
Et
i-Pr 11
Ph 19
58
quant. (93)c
5
a
b
The molar ratio of KSA 2 to alkyne 1 is 1.3. NMR yield (internal
a
b
c
The molar ratio of KSA 2 to alkyne 7 is 1.2–1.3. 1.0 equiv. The
reaction was performed in toluene at 110 1C.
c
standard: p-bromoanisole). Isolated yield.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5316–5318 | 5317

View Article Online
Table 4 Lewis acid mediated [2+2] cycloaddition
7 (a) T. Hosoya, T. Hamura, Y. Kuriyama, T. Matsumoto and
K. Suzuki, Synlett, 2000, 520; (b) T. Hamura, T. Hosoya,
H. Yamaguchi, Y. Kuriyama, M. Tanabe, M. Miyamoto,
Y. Yasui, T. Matsumoto and K. Suzuki, Helv. Chim. Acta, 2002,
85, 3589.
8 For related thermal [2+2] cycloadditions, see: (a) M. Miesch and
F. Wendling, Eur. J. Org. Chem., 2000, 3381, and the references
cited therein. For preparation of cyclobutenedione derivatives via
[2+2] cycloaddition of alkynylalkoxycarbene metal complexes
with tetraalkoxyethylenes, see: (b) F. Camps, A. Liebaria,
J. M. Moreto, S. Ricart and J. M. Vinas, Tetrahedron Lett.,
1990, 31, 2479.
Yield of
11 (%)
Entrya
Alkyne
R
Time/h
1
2
10a
10b
n-Bu
Ph
20
68
92
81
9 Cycloadduct 3 was reduced under Luche conditions10 to give
the alcohol as a 1 : 1 diastereomer mixture. One of the dia-
stereomers gave single crystals suitable for X-ray analysis, thereby
confirming the structure of compound 3. For details, see
ESIw.
3
4
10c
23
1
85
87
92
10dc
10ec
5
1
10 (a) J.-L. Luche, J. Am. Chem. Soc., 1978, 100, 2226;
(b) A. L. Gemal and J.-L. Luche, J. Am. Chem. Soc., 1981, 103,
5454.
a
b
The molar ratio of KSA 2 to alkyne 10 is 1.2–1.3. The molar ratio
c
of Me3Al to alkyne 10 is 1.0–1.1. PMB: p-methoxybenzyl.
11 For related thermal ring openings of cyclobutene acetals, see:
(a) M. L. Graziano, M. R. Iesce and F. Cermola, Synthesis,
1994, 149; (b) E. V. Dehmlow and A. L. Veretenov, Synthesis,
1992, 939.
12 The reaction at higher temperatures (110 1C, 5 h) gave the ring-
opened 1,3-diene 4 in quantitative yield. The stereochemistry of 4
was determined by an NOE study. See ESIw.
13 Choice of the substituent on the ester group was important: methyl
ester reacted slowly (neat, 60 1C, 31 h, 67%).
14 EtAlCl2 was much less effective and the yield was extremely low.
15 We recently reported the Mukaiyama aldol reactions of KSA to
simple methyl esters promoted by organoaluminium reagents,
giving 1,2-addition product, see: S. Iwata, T. Hamura,
T. Matsumoto and K. Suzuki, Chem. Lett., 2007, 36, 538.
16 For selective recent reports on acid promoted [2+2] cycloaddition
for efficient access to functionalized cyclobutenes, see:
(a) K. Takao, N. Hayakawa, R. Yamada, T. Yamaguchi,
H. Saegusa, M. Uchida, S. Samejima and K. Tadano, J. Org.
Chem., 2009, 74, 6452; (b) I. Hachiya, T. Yoshitomi, Y. Yamaguchi
and M. Shimizu, Org. Lett., 2009, 11, 3266; (c) K. Takao,
N. Hayakawa, R. Yamada, T. Yamaguchi, U. Morita,
S. Kawasaki and K. Tadano, Angew. Chem., Int. Ed., 2008, 47,
3426; (d) K. Ishihara and M. Fushimi, J. Am. Chem. Soc., 2008,
130, 7532; (e) K. Inanaga, K. Takasu and M. Ihara, J. Am. Chem.
Soc., 2005, 127, 3668; (f) H. Ito, M. Hasegawa, Y. Takenaka,
T. Kobayashi and K. Iguchi, J. Am. Chem. Soc., 2004, 126, 4520;
(g) R. F. Sweis, M. P. Schramm and S. A. Kozmin, J. Am. Chem.
Soc., 2004, 126, 7442.
Scheme 3 Selective hydrolysis of cycloadduct 11b.
The authors deeply appreciate Prof. Dieter Seebach for
helpful discussion on the subject.
Notes and references
1 J. C. Namyslo and D. E. Kaufmann, Chem. Rev., 2003, 103, 1485.
2 T. Shinada, Y. Nakagawa, K. Hayashi, G. Corzo, T. Nakajima
and Y. Ohfune, Amino Acids, 2003, 24, 293.
3 (a) R. B. Woodward and R. Hoffmann, The Conservation of
Orbital Symmetry, Academic Press, New York, 1970;
(b) K. Fukui, Acc. Chem. Res., 1971, 4, 57; (c) N. D. Epiotis,
Angew. Chem., Int. Ed. Engl., 1974, 13, 751.
4 (a) K. C. Brannock, A. Bell, R. D. Burpitt and C. A. Kelly, J. Org.
Chem., 1964, 29, 801; (b) R. Huisgen, Acc. Chem. Res., 1977, 10,
117; (c) R. Huisgen, Pure Appl. Chem., 1980, 52, 2283, and the
references cited therein.
17 For selective recent reports on transition-metal-catalyzed [2+2]
cycloaddition of alkynes, see: (a) N. Cockburn, E. Karimi and
W. Tam, J. Org. Chem., 2009, 74, 5762; (b) R. W. Jordan,
P. L. Marquand and W. Tam, Eur. J. Org. Chem., 2008, 80;
(c) N. Riddell, K. Villeneuve and W. Tam, Org. Lett., 2005, 7,
3681; (d) T. Shibata, K. Takami and A. Kawachi, Org. Lett., 2006,
8, 1343.
5 (a) T. Hosoya, T. Hasegawa, Y. Kuriyama, T. Matsumoto and
K. Suzuki, Synlett, 1995, 177; (b) T. Hosoya, T. Hasegawa,
Y. Kuriyama and K. Suzuki, Tetrahedron Lett., 1995, 36, 3377.
6 (a) D. M. Hayes and R. Hoffmann, J. Phys. Chem., 1972, 76, 656;
(b) S. Inagaki and K. Fukui, Bull. Chem. Soc. Jpn., 1973, 46, 2240.
18 Structure of 11a was determined by NMR study (HMBC). See
ESIw.
19 Ketone 12 gave single crystals suitable for X-ray analysis,
thereby proving the structure of compound 11b. For details, see
ESIw.
ꢀc
This journal is The Royal Society of Chemistry 2010
5318 | Chem. Commun., 2010, 46, 5316–5318