Thermally induced [2+2] cycloadditions of (benzyloxymethylene)cyclopropane with alkylidenemalononitriles

Article abstract of DOI:10.1002/ejoc.200700531

The reaction of (benzyloxymethylene)cyclopropane (1a) with alkylidenemalononitriles 2 at ambient pressure afforded the corresponding cyclobutane derivatives 3 in good-to-high yields. For example, the reaction of 1a with benzylidenemalononitrile (2a), (2-n

Full text of DOI:10.1002/ejoc.200700531

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700531
Thermally Induced [2+2] Cycloadditions of (Benzyloxymethylene)cyclopropane
with Alkylidenemalononitriles[‡]
Itaru Nakamura,*[a] Ryoko Nagata,[a] Tetsuya Nemoto,[a] Masahiro Terada,[a]
Yoshinori Yamamoto,[a] Thomas Späth,[b] and Armin de Meijere[b]
Keywords: Cycloaddition / Cyclobutanes / Enols / Cyclopropanes
The reaction of (benzyloxymethylene)cyclopropane (1a) with
alkylidenemalononitriles 2 at ambient pressure afforded the
corresponding cyclobutane derivatives 3 in good-to-high
yields. For example, the reaction of 1a with benzylidenema-
lononitrile (2a), (2-naphthylmethylene)malononitrile (2e),
and tert-butylmethylenemalononitrile (2f) in acetonitrile at
80 °C gave the corresponding cyclobutanes 3a, 3e, and 3f in
96, 96, and 91% yield, respectively. Control experiments
proved that the reaction proceeds via well-stabilized zwitter-
ionic intermediate 6.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
of enol ethers with α,β-unsaturated esters that were enabled
by acid catalysts [Scheme 2, type (c)].[5] Some time ago,
Scheeren’s group reported that the cycloaddition of 1,1-di-
cyanoalkenes to enol ethers required high pressure [12 kbar,
Scheme 2, type (e)],[6] whereas that of tetracyanoethylene
proceeded at ambient pressure [Scheme 2, type (d)].[7]
Introduction
Cyclobutane moieties are present in a variety of biolo-
gically active compounds,[1] and cyclobutane derivatives are
widely utilized as starting materials in organic synthesis.[2]
These molecules have been primarily synthesized by photo-
chemical [2+2] cycloadditions of alkenes and enones
[Scheme 1, type (a)][3] as well as thermal [2+2] cycload-
ditions of ketenes and alkenes [Staudinger ketene cycload-
ditions, Scheme 1, type (b)].[4] However, [2+2] cycload-
ditions of enol ethers have rarely been utilized owing to the
insufficient nucleophilicity of the enol ethers. Recently, the
group of Takasu and Ihara reported [2+2] cycloadditions
Scheme 2. [2+2] Cycloadditions of enol ethers: (c) with α,β-unsatu-
rated esters in the presence of Lewis acid catalysts; (d) with tetra-
cyanoethylene at ambient pressure; and (e) with methylene-
malononitrile under high pressure.
Scheme 1. Various known [2+2] cycloadditions: (a) photochemical
reactions of alkenes with enones; (b) Staudinger ketene cycload-
ditions.
Recently, we found that [2+2] cycloadditions of (alkoxy-
[‡] For A. d. M.: Cyclopropyl Building Blocks for Organic Synthe-
methylene)cyclopropanes 1, which are easily accessible and
sis, 144. Part 143: B. Yücel, N. V. Valentic´, A. de Meijere, Eur.
J. Org. Chem. 2007, in press. Part 142: H. Schill, A. de Meijere, storable at room temperature,[8] with imines proceeded at
ambient pressure [Equation (1)].[9] We envisioned that the
Org. Lett. 2007, in press.
[a] Department of Chemistry, Graduate School of Science, Tohoku
formation of the zwitterionic intermediate A, in which the
cation center is doubly stabilized by the cyclopropyl and
the alkoxy groups, facilitated the cycloaddition. Herein, we
report that the [2+2] cycloaddition of (benzyloxymethylene)-
cyclopropane (1a) with alkylidenemalononitriles 2 proceeds
at ambient pressure to afford the corresponding cyclobu-
tanes 3 in good-to-high yields [Equation (2)].
University,
Sendai 980-8578, Japan
Fax: +81-22-795-6602
E-mail: itaru-n@mail.tains.tohoku.ac.jp
[b] Institut fuer Organische und Biomolekulare Chemie, Georg-
August-Universitat Goettingen,
Tammannstrasse 2, 37077 Goettingen, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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I. Nakamura et al.
SHORT COMMUNICATION
recovered quantitatively, whereas 1a decomposed under the
reaction conditions. The constitutions of the spirocyclopro-
panated cyclobutanes 3 were confirmed by spectroscopic
methods (see Supporting Information). Furthermore, the
structure of the trans isomer of 3e was unambiguously es-
tablished by an X-ray crystallographic analysis (Fig-
ure 1).[10]
(1)
(2)
Table 2. [2+2] Cycloadditions of (benzyloxymethylene)cyclopro-
pane (1a) with alkylidenemalononitriles 2.[a]
Entry
2
R1
R2
Time Product Yield trans/cis[c]
[h]
[%][b]
Results and Discussion
1
2
3
4
5
6
7
2a Ph
H
H
H
H
H
H
Me
2
1
3a
3b
3c
3d
3e
3f
96
93
91
89
96
91
54
1.5:1
2.0:1
1.3:1
1.3:1
1.8:1
3.4:1
–
2b p-O2NC6H4
2c p-MeOC6H4
2d 2-furyl
2e 2-naphthyl
2f tBu
Treatment of (benzyloxymethylene)cyclopropane (1a)
with benzylidenemalononitrile (2a) in acetonitrile at 80 °C
for 2 h afforded 4-benzyloxy-6-phenylspiro[2.3]hexane-5,5-
dicarbonitrile (3a) in 96% yield with a trans/cis ratio of
1.5:1 (Table 1, Entry 2). The trans/cis ratio depended on the
reaction temperature; when the reaction was carried out at
30 °C, the trans/cis ratio was 3.7:1, whereas the reaction at
130 °C gave 3a with a trans/cis ratio of 1.4:1 (Table 1, En-
tries 2 and 3). At 0 °C, the reaction was very slow (8 d, 65%
yield; Table 1, Entry 4).
54
50
15
33
72
2g Me
3g
[a] The reactions of 1a (0.2 mmol) and 2 (0.2 mmol) were carried
out in acetonitrile (2 mL) at 80 °C. [b] Yields of isolated products.
[c] The diastereomeric ratio was determined by 1H NMR spec-
troscopy.
Table 1. [2+2] Cycloaddition of 1a to 2a.[a]
Entry
Temperature [°C]
Time [h]
Yield [%][b]
trans/cis[c]
1
2
3
4
130
80
30
0
1.5
2
50
8 d
Ͼ99
96
Ͼ99
65
1.4:1
1.5:1
3.7:1
3.6:1
[a] The reaction of 1a (0.2 mmol) and 2a (0.2 mmol) was carried
out in acetonitrile. [b] Yields were determined by NMR spec-
troscopy by using 1,4-dioxane as an internal standard. [c] The dia-
1
stereomeric ratio was determined by H NMR spectroscopy.
The results of the reaction of 1a with different alkylid-
enemalononitriles at 80 °C are summarized in Table 2. The
reaction of (arylmethylene)malononitrile 2b bearing an
electron-withdrawing group on the aryl moiety proceeded
smoothly, whereas the reaction of 2c having an electron-
donating group was very slow (Table 2, Entries 2 and 3).
Figure 1. Crystal structure of 4-benzyloxy-6-(2-naphthyl)spiro[2.3]-
hexane-5,5-dicarbonitrile (trans-3e). ORTEP representation with
thermal ellipsoids set at 50% probability.
A plausible mechanism for the [2+2] cycloadditions of 1a
The reaction of 2d, which had an electron-rich furan ring to 2 is illustrated in Scheme 3. Initially, nucleophilic attack
as R1, also proceeded slowly (Table 2, Entry 4). The reac- of the carbon–carbon double bond in 1a on the β-position
tion of (2-naphthylmethylene)malononitrile (2e) with 1a of the alkylidenemalononitrile would lead to the anti-ori-
gave 3e in a high yield (Table 2, Entry 5). Substrate 2f hav- ented zwitterion anti-6, which, after internal rotation, cy-
ing a bulky tert-butyl group as R1 was smoothly converted clizes to the cyclobutane trans-3 or cis-3. The stabilization
into the corresponding cyclobutane 3f in 91% yield, of the zwitterionic intermediate 6 by the cyclopropyl group
whereas the reaction of 2g, which had a geminal dimethyl adjacent to the cationic center is essential, as the enol ether
group, with 1a took 3 d to afford 3g in 54% yield (Table 2, 7, which does not contain a cyclopropane ring, did not re-
Entries 6 and 7). Other substrates, such as dimethyl benzyl- act with benzylidenemalononitrile 2a under thermal condi-
idenemalonate (4) and 3-benzylidenepentane-2,4-dione (5), tions. When the reaction of 1a and 2a was carried out in
did not react with (benzyloxymethylene)cyclopropane (1a); methanol, the open chain benzyl methyl acetal 8 was ob-
in the attempted reaction of 1a with 4 or 5, the latter were tained in 69% yield [Equation (3)] and [Equation (4)].[11]
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[2+2] Cycloadditions of (Benzyloxymethylene)cyclopropane
This result proves that the 1,4-zwitterion anti-6 is an inter- lononitrile (2b) at 80 °C for 40 h; however, 3a was quantita-
mediate that can be captured by an external nucleophile tively recovered, and none of the expected crossover prod-
1
such as methanol.[12]
uct 3b was observed by H NMR spectroscopy or GC–MS
[Equation (6)].
Conclusions
For the [2+2] cycloadditions of (benzyloxymethylene)-
cyclopropane with alkylidenemalononitriles, which proceed
at ambient pressure, the twofold stabilization of the cationic
center in the zwitterionic intermediates 6 plays a crucial
role.[12] Further development of these cycloaddition reac-
tions by employing (alkoxymethylene)cyclopropanes is now
in progress in our laboratory.
Scheme 3. Mechanistic rationalization of the [2+2] cycloadditions
of (benzyloxymethylene)cyclopropane (1a) with alkylidenema-
lononitriles 2.
Experimental Section
Preparation of (Benzyloxymethylene)cyclopropane (1a)
(1-Bromocyclopropyl)methanol:[13] A solution of methyl 1-bromocy-
clopropanecarboxylate[14] (100.0 g, 0.50 mol) in anhydrous diethyl
ether (200 mL) was added dropwise to a suspension of lithium alu-
minum hydride (12.00 g, 0.30 mol) in diethyl ether (500 mL) at such
a rate that the ether kept boiling gently under reflux. The mixture
was then stirred at ambient temperature for an additional 24 h be-
fore the excess amount of LiAlH4 was hydrolyzed by the addition
of a slurry of magnesium sulfate (20 g) and water. The solids were
filtered off and carefully washed with diethyl ether (250 mL). The
combined organic phase was dried with MgSO4 and concentrated
in vacuo. The residue was distilled under reduced pressure through
a 20-cm Vigreux column to give 69.93 g (83%) of (1-bromocy-
clopropyl)methanol, b.p. 86–89 °C/10 mbar (ref.[13] 64–70 °C/
12 Torr). The spectroscopic data were identical with the published
ones.[13]
(3)
(4)
When the isolated trans and cis isomers of 3a were heated
at 80 °C individually, both were converted to a 1.1:1 mix-
ture of trans and cis isomers, which suggests that the ring
closure is reversible [Equation (5)]. To test whether a com-
plete [2+2] cycloreversion can occur, 3a in acetonitrile was
heated in the presence of (p-nitrophenylmethylene)ma-
(1-Bromocyclopropyl)methanol was converted to (benzyloxymeth-
ylene)cyclopropane (1a) (Scheme 4) according to a literature pro-
cedure.[8]
Scheme 4. Preparation of (benzyloxymethylene)cyclopropane (1a):
(a) LiAlH4, Et2O; (b) PhCH2Br, NaH, nBu4NI (cat.), THF, 0 to
25 °C, then 25 °C, 70 h; (c) tBuOK, DMSO, 10 to 25 °C, then
25 °C, 2 h.[8]
(5)
General Procedure for the [2+2] Cycloaddition of (Benzyloxymethyl-
ene)cyclopropane (1a) to Alkylidenemalononitriles 2: To the alkylid-
enemalononitrile 2 (0.2 mmol) in acetonitrile (2 mL) was added
(benzyloxymethylene)cyclopropane 1a (0.2 mmol). The mixture
was stirred at 80 °C with monitoring by GC–MS. After the starting
materials were consumed completely, the solvent was removed in
vacuo, and the crude product was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate) to afford product 3.
trans-4-(Benzyloxy)-6-phenylspiro[2.3]hexane-5,5-dicarbonitrile (trans-
3a): 1H NMR (270.05 MHz, CDCl3): δ = 0.62–0.81 (m, 3 H), 1.40–
1.48 (m, 1 H), 3.94 (s, 1 H), 4.56 (d, J = 11.7 Hz, 1 H), 4.80 (s, 1
H), 4.83 (d, J = 11.7 Hz, 1 H), 7.32–7.46 (m, 10 H) ppm. 13C NMR
(67.80 MHz, CDCl3): δ = 8.8, 9.7, 28.3, 39.4, 52.3, 72.4, 81.4, 113.0,
(6) 114.0, 128.3, 128.6, 128.7, 128.9, 129.1, 134.5, 135.6 ppm. IR
Eur. J. Org. Chem. 2007, 4479–4482
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I. Nakamura et al.
SHORT COMMUNICATION
(neat): ν = 3032–2867, 2248, 1455, 1345, 1091, 1014 cm–1. HRMS
(ESI): calcd for C21H18N2NaO 337.1317; found 337.1311.
of Organic Chemistry (Houben-Weyl) (Ed.: A. de Meijere),
Thieme, Stuttgart, 1996, vol. E17e, p. 118.
[4] a) H. Staudinger, E. Suter, Ber. Dtsch. Chem. Ges. 1920, 53,
1092–1105. For a review, see: b) T. T. Tidwell, Eur. J. Org.
Chem. 2006, 563–576.
[5] a) K. Takasu, M. Ueno, K. Inanaga, M. Ihara, J. Org. Chem.
2004, 69, 517–521; b) K. Inanaga, K. Takasu, M. Ihara, J. Am.
Chem. Soc. 2005, 127, 3668–3669.
[6] R. W. M. Aben, J. Goudriaan, J. M. M. Smits, J. W. Scheeren,
Synthesis 1993, 37–39.
[7] a) J. K. Williams, D. W. Wiley, B. C. McKusick, J. Am. Chem.
Soc. 1962, 84, 2210–2215; b) S. W. Staley, G. M. Cramer, W. G.
Kingsley, J. Am. Chem. Soc. 1973, 95, 5054–5055.
[8] A. de Meijere, A. Leonov, T. Heiner, M. Noltemeyer, M. T. Bes,
Eur. J. Org. Chem. 2003, 472–478.
[9] I. Nakamura, T. Nemoto, Y. Yamamoto, A. de Meijere, Angew.
Chem. Int. Ed. 2006, 45, 5176–5179.
˜
cis-4-(Benzyloxy)-6-phenylspiro[2.3]hexane-5,5-dicarbonitrile (cis-
3a): 1H NMR (270.05 MHz, CDCl3): δ = 0.52–0.80 (m, 3 H), 1.19–
1.27 (m, 1 H), 3.98 (s, 1 H), 4.58 (d, J = 11.7 Hz, 1 H), 4.65, (s, 1
H), 4.87 (d, J = 11.7 Hz, 1 H), 7.39–7.41 (m, 10 H) ppm. 13C NMR
(67.80 MHz, CDCl3): δ = 5.2, 8.8, 29.9, 40.1, 48.8, 72.5, 81.0, 111.8,
115.2, 128.4, 128.6, 128.7, 129.1, 129.4, 132.1, 135.6 ppm. IR
(neat): ν = 3032–2867, 2372, 2243, 1497, 1455, 1142, 1111, 1026,
˜
746 cm–1. HRMS (ESI): C21H18N2NaO 337.1317; found 337.1311.
Supporting Information (see footnote on the first page of this
article): General procedure for the [2+2] cycloadditions of (benzyl-
oxymethylene)cyclopropane (1a) to alkylidenemalononitriles 2,
spectroscopic data of 3 and 8.
[10] CCDC-643852 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[11] A 57:43 mixture of the diastereomers, the configuration of
which was not determined, was obtained.
[12] [2+2] Cycloadditions of various cyclophiles to bicyclopropyli-
dene have also been observed to proceed at ambient pressure
via well-stabilized 1,4-zwitterionic intermediates: a) W. Weber,
I. Erden, A. de Meijere, Angew. Chem. 1980, 92, 387–388; An-
gew. Chem. Int. Ed. Engl. 1980, 19, 387–388; b) A. de Meijere,
I. Erden, W. Weber, D. Kaufmann, J. Org. Chem. 1988, 53,
152–161.
[13] (1-Bromocyclopropyl)methanol was previously prepared by
bromohydroxylation of methylenecyclopropane: R. Köster, S.
Arora, P. Binger, Justus Liebigs Ann. Chem. 1973, 1219–1235.
[14] Methyl 1-bromocyclopropanecarboxylate can easily be pre-
pared on a large scale from inexpensive γ-butyrolactone in
three simple steps: H. M. R. Hoffmann, K. Eggert, A. Walenta,
D. Schomburg, R. Wartchow, F. H. Allen, J. Org. Chem. 1989,
54, 6096–6100.
Acknowledgments
This work was financially supported by a Grant-in-Aid for Scien-
tific Research from the Japan Society for the Promotion of Science
(JSPS).
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Received: June 9, 2007
Published Online: July 30, 2007
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