Intramolecular formal [4+2] cycloaddition of 3-ethoxycyclobutanones and alkenes

Article abstract of DOI:10.1039/b919332d

Intramolecular formal [4+2] cycloaddition between 3-ethoxycyclobutanones and a carbon-carbon double bond to the corresponding bicyclo[4.n.0]alkan-2-one derivatives proceeded effectively by using ethylaluminium dichloride. The Royal Society of Chemistry 20

Full text of DOI:10.1039/b919332d

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Intramolecular formal [4+2] cycloaddition of 3-ethoxycyclobutanones
and alkenesw
Jun-ichi Matsuo,* Shun Sasaki, Takaya Hoshikawa and Hiroyuki Ishibashi
Received (in College Park, MD, USA) 16th September 2009, Accepted 3rd December 2009
First published as an Advance Article on the web 6th January 2010
DOI: 10.1039/b919332d
Intramolecular formal [4+2] cycloaddition between 3-ethoxy-
cyclobutanones and a carbon–carbon double bond to the corres-
ponding bicyclo[4.n.0]alkan-2-one derivatives proceeded effectively
by using ethylaluminium dichloride.
Table 1 Intramolecular formal [4+2] cycloaddition of 2-allyl-3-
ethoxycyclobutanones 1 to 4a
Intramolecular cycloaddition is a powerful tool for efficient
and stereoselective construction of complex molecules.1
Especially, [4+2] cycloaddition reactions such as intramolecular
Diels–Alder (IMDA) reaction have been successfully employed
for the synthesis of biologically active compounds and natural
products under the condition of a well-designed combination
between diene and dienophile.2 The utility of intramolecular
[4+2] cycloaddition is expected to be enhanced by discovering
a more potent and readily available C4 unit.
Entry
1 (R)
cis/transb
Product (%yieldc)
cis/transb
1
2d
3
4
5
6
7
8
1a (allyl)
1a (allyl)
1b (H)
1c (Me)
1d (Bn)
1e (i-Pr)
1f (Ph)
—
—
4a (92)
84 : 16
27 : 73
—
89 : 11
85 : 15
82 : 18
—
4a (89), 5 (3)
4b (0), 6 (41)
4c (72)
4d (81)
4e (88)
30 : 70
56 : 44
34 : 66
28 : 72
100 : 0
0 : 100
4f (0), 7 (70)
4f (0), 7 (74)
1f (Ph)
—
We have recently reported that intermolecular [4+2] cyclo-
addition between 3-alkoxycyclobutanone and aldehyde or
ketone proceeds to afford tetrahydro- or dihydro-g-pyrone
derivatives by catalysis with boron trifluoride etherate.3 In the
course of our study on this cycloaddition, we examined a
reaction between 2,2-diallyl-3-ethoxycyclobutanone (1a) and
benzaldehyde (Scheme 1). It was found that catalysis with
boron trifluoride etherate gave expected adducts 2 and 3 in
67% and 13% yields, respectively, whereas the employment of
ethylaluminium dichloride gave intramolecular cycloadduct
4a as the major product (66% yield). The finding of unprece-
dented intramolecular cycloaddition of an allyl group into the
C2–C3 bond of a cyclobutanone ring4–6 as well as the observed
interesting chemoselectivity prompted us to investigate this
intramolecular cycloaddition further. We report herein formal
a
b
EtAlCl2 (1.2 equiv.) was employed. The ratios were determined by
1H NMR analysis. For determination of relative stereochemistry, see
c
supporting information.w Isolated yield unless otherwise noted.
Conditions: Tin(IV) chloride (1.2 equiv.), allyltriisopropylsilane
d
(1.5 equiv.), ꢀ45 to 0 1C, 80 min. Yield of 4a was determined by 1H NMR.
[4+2] cycloaddition between a cyclobutanone skeleton and
carbon–carbon double bond of the alkenyl group at the
2-position of 3-ethoxycyclobutanones.
Among Lewis acids we tested,7 ethylaluminium dichloride
most efficiently promoted intramolecular cycloaddition of 1a
to give cis- and trans-4a in 92% combined yield (cis/trans =
84 : 16, Table 1, entry 1).8 Neither regioisomeric cycloaddition
nor elimination of ethanol from 4a were observed. It is notable
that the activation of 1a with tin(IV) chloride in the presence of
allyltriisopropylsilane inverted the ratio of cis- and trans-4a
(cis/trans = 27 : 73), and intermolecular cycloadduct 59
was obtained in 3% yield (entry 2). Cycloaddition of
several 2-alkyl-2-allyl-3-ethoxycyclobutanones 1b–e was next
performed in order to investigate stereospecificity as well as
generality of the intramolecular reaction (entries 3–6). Treat-
ment of a mixture of diastereomers (cis/trans = 30 : 70) of
2-allyl-3-ethoxycyclobutanone 1b with ethylaluminium
dichloride did not give a cycloadduct 4b, but a self-
cycloadduct 6 was obtained in 41% yield (entry 3).3 2-Allyl-
cyclobutanones 1c–e gave the desired products 4c–e in
72–88% yields, and the reactions were found to proceed
nonstereospecifically since cis/trans ratios of 1c–e did not
correspond to the efficiency of the cycloaddition nor cis/trans
Scheme 1 Lewis acid (LA)-controlled chemoselectivity: intermolecular
formal [4+2] cycloaddition between 1a and benzaldehyde to 2 and 3
and intramolecular formal [4+2] cycloaddition of 1a to 4a.
School of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan.
E-mail: jimatsuo@p.kanazawa-u.ac.jp; Fax: +81-76-234-4439;
Tel: +81-76-234-4439
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. CCDC 735720, 735721, 735722. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b919332d
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Table
2 EtAlCl2-catalyzed intramolecular formal [4+2] cyclo-
addition of various 2-alkenyl-3-ethoxycyclobutanones 8a
Entry
Cyclobutanone
Major product (%yieldb)
d.r.
Scheme 2 Plausible mechanism for EtAlCl2-catalyzed [4+2] cyclo-
addition of 2-alkenyl-3-ethoxycyclobutanones 10 to 4-ethoxybicyclo-
[4.n.0]alkan-2-ones 12.
1
2
3
8a (n = 1)
8b (n = 2)
8c (n = 3)
9a (18)
9b (86)
9c (0)
499 : 1
499 : 1
—
of cyclobutanone 10,3 and [4+2] cycloaddition of a terminal
alkenyl group proceeds to give an adduct 12.
Two isomers
65 : 35
4
5
8dc
9d (67)
9e (89)
In summary, we have developed ethylaluminium dichloride-
promoted intramolecular insertion of a carbon–carbon double
bond into 3-ethoxycyclobutanones. This intramolecular [4+2]
cycloaddition shows high regioselectivity and stereoselectivity.
Studies on the nature of zwitterionic intermediates generated
by activation of 3-ethoxycyclobutanones and the reaction
mechanism for the present intramolecular cycloaddition is
currently under way.
Two isomers
95 : 5
8ed
6
499 : 1
The authors thank Prof. Shuhei Fujinami (Kanazawa
University) for X-ray crystallographic analysis. This study
was supported by a SUMBOR grant and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
8fd
9f (87)
a
b
Conditions: see Table 1. Combined yield of diastereomers.
d
A mixture of diastereomers (53 : 47). A mixture of four diastereomers
c
was treated at ꢀ45 to 0 1C.
Notes and references
z CCDC 735720 for 9d, CCDC 735721 for 9d0, and CCDC 735722 for
a derivative of 9f contain the supplementary crystallographic data.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ratios of 4c–e. Also, cyclobutanones bearing a bulky alkyl
group tended to give the cycloadducts more efficiently
(entries 4–6). On the other hand, both isolated diastereomers
of 2-allyl-3-ethoxy-2-phenylcyclobutanones 1f gave no
1 (a) W. Carruthers, Cycloaddition Reactions in Organic Synthesis,
Pergamon, Oxford, 1990; (b) W. Oppolzer, Angew. Chem., Int. Ed.
Engl., 1977, 16, 10.
2 (a) B. R. Bear, S. M. Sparks and K. J. Shea, Angew. Chem., Int.
Ed., 2001, 40, 820; (b) W. R. Roush, Adv. Cycloaddit., 1990, 2, 91;
(c) D. Craig, Chem. Soc. Rev., 1987, 16, 187; (d) E. Ciganek, Org.
React. (N. Y.), 1984, 32, 1; (e) G. Brieger and J. N. Bennett, Chem.
Rev., 1980, 80, 63.
[4+2] cycloadduct 4f but afforded 1-allyl-2-naphthol
7
(entries 7 and 8). These results suggest that cyclization of the
phenyl group10 followed by aromatization to the 2-naphthol
derivative 7 took place selectively rather than insertion of the
allyl group.
Preparation of bicyclic or tricyclic compounds other than
bicyclo[4.1.0]heptan-2-ones 4 was next investigated (Table 2).
Cyclobutanones 8a,b having a 3-butenyl or 4-pentenyl group
at the 2-position gave the corresponding cycloadducts 9a
and 9b in 18% and 86% yields, respectively, as a single
diastereomer (entries 1 and 2). Cyclobutanone 8c bearing a
5-hexenyl group did not give a cycloadduct 9c (entry 3),
whereas the reaction of 2-(o-allylbenzyl)cyclobutanone 8d
3 J. Matsuo, S. Sasaki, H. Tanaka and H. Ishibashi, J. Am. Chem.
Soc., 2008, 130, 11600.
4 Reviews for synthetic application of cyclobutanones: (a) E. Lee-
Ruff and G. Mladenova, Chem. Rev., 2003, 103, 1449;
(b) J. C. Namyslo and D. E. Kaufmann, Chem. Rev., 2003, 103,
1485; (c) D. Bellus and B. Ernst, Angew. Chem., Int. Ed. Engl.,
1988, 27, 797; (d) J. M. Conia and M. J. Robson, Angew. Chem.,
Int. Ed. Engl., 1975, 14, 473.
5 Thermal or acid treatment of 2-vinyl cyclobutanones caused
rearrangements such as 1,2- or 1,3-acyl migration:
(a) M. Bertrand, G. Gil and A. Junino, Tetrahedron Lett., 1977,
18, 1779; (b) M. Bertrand, G. Gil, A. Junino and R. Maurin,
J. Chem. Res. (S), 1980, 98; (c) J. R. Matz and T. Cohen,
Tetrahedron Lett., 1981, 22, 2459; (d) R. Huston, M. Rey and
A. S. Dreiding, Helv. Chim. Acta, 1982, 65, 1563;
(e) R. L. Danheiser, S. K. Gee and H. Sard, J. Am. Chem. Soc.,
1982, 104, 7670; (f) D. A. Jackson, M. Rey and A. S. Dreiding,
Tetrahedron Lett., 1983, 24, 4817; (g) D. A. Jackson, M. Rey and
A. S. Dreiding, Helv. Chim. Acta, 1985, 68, 439.
gave two products, 9d and its 4-epimer 9d0 (9d : 9d0
=
65 : 35) in 67% combined yield (entry 4).z Restricted
conformation of the o-allylbenzyl group might help the
successful cycloaddition of 8d. Intramolecular cycloaddition
of spirocyclobutanones 8e,f proceeded smoothly to afford the
corresponding tricyclic compounds 9e,f in good yields
(entries 5 and 6), and stereochemical convergence was
observed. That is, treatment of a mixture of four diastereo-
mers of 8f with ethylaluminium dichloride gave 9f as a single
diastereomer.11
6 Transition metal-catalyzed intramolecular olefin insertion into the
C1–C2 bond of
a cyclobutanone ring: (a) M. Murakami,
T. Itahashi and Y. Ito, J. Am. Chem. Soc., 2002, 124, 13976;
(b) M. Murakami and S. Ashida, Chem. Commun., 2006, 4599.
7 Conversion of 1a to 4a by using other Lewis acids: SnCl4 at ꢀ45 to
0 1C (80%); TiCl4 at ꢀ78 1C (77%); Me3SiOTf at ꢀ45 to 0 1C
(43%); BF3-OEt2 at ꢀ45 to 0 1C (70%); GaCl3 at ꢀ45 1C (65%).
A plausible mechanism for the present intramolecular cyclo-
addition is shown in Scheme 2. A zwitterionic intermediate 11
is regioselectively formed by EtAlCl2-catalyzed ring cleavage
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8 The use of 20 mol% of EtAlCl2 gave 4a in 19% yield.
9 J. Matsuo, S. Sasaki, T. Hoshikawa and H. Ishibashi, Org. Lett.,
2009, 11, 3822.
(c) V. P. Abegg, A. C. Hopkinson and E. Lee-Ruff, Can. J. Chem.,
1978, 56, 99; (d) P. Duperrouzel and E. Lee-Ruff, Can. J. Chem., 1980,
58, 51.
10 (a) R. Huisgen, L. A. Feiler and P. Otto, Chem. Ber., 1969, 102, 3405;
(b) L. A. Feiler and R. Huisgen, Chem. Ber., 1969, 102, 3428;
11 Preparation of cyclohexa[c]indele skeletones: J. Holtsclaw and
M. Koreeda, Org. Lett., 2004, 6, 3719.
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This journal is The Royal Society of Chemistry 2010
936 | Chem. Commun., 2010, 46, 934–936