Synthesis of cyclopentenones from cyclopropanes and silyl ynol ethers

Article abstract of DOI:10.1002/anie.200801957

(Chemical Equation Presented) Exploiting an opening: Lewis acid promoted ring-opening of donor-acceptor cyclopropanes generates a 1,3-zwitterion; cycloaddition with a silyl ynol ether leads to a general synthesis of cyclopentenones (see scheme). Substitution is tolerated on the ynol and on all positions of the cyclopropane to give tri-, tetra-, and penta-substituted cyclopentenones in high yield.

Full text of DOI:10.1002/anie.200801957

Communications
DOI: 10.1002/anie.200801957
Cycloadditions
Synthesis of Cyclopentenones from Cyclopropanes and Silyl Ynol
Ethers**
Xiangbing Qi and Joseph M. Ready*
Five-membered carbocyclic rings appear in all classes of
organic materials including pharmaceutical agents, polymers,
natural products, and catalysts. Accordingly, their preparation
has challenged synthetic chemists since the inception of the
field.[1] In this regard, [3+2] cycloadditions—both concerted
and stepwise—represent convergent strategies for the for-
mation of the cyclopentane nucleus.[2] Dipolar cycloadditions,
in particular, have proven especially successful for this
construction. Of the various all-carbon dipolar synthons
available, donor–acceptor cyclopropanes (1) have proven
especially versatile.[3] In the presence of Lewis acids, donor–
acceptor cyclopropanes undergo ring-opening to yield 1,3-
zwitterions. Pursuing a general interest in the reactivity of
derivatives has not been documented. Indeed, these alkynes
have hardly been explored in the context of [3+2] cyclo-
additions.[9]
Exploratory studies examined the reaction of cyclopro-
pane 1a (R1 = R2 = H) with ynol ether 2a (R3 = nBu), which is
prepared in a single step from n-hexyne.[10] Several Bronsted
and Lewis acids, including Me3SiOTf (Tf = SO2CF3),
HN(Tf)2, and BBr3, promoted the formation of cyclopenta-
diene 5aa and cyclopentenone 4aa in moderate yield.
However, despite substantial efforts to optimize the reaction
conditions we were unable to develop a protocol that
returned the cycloadducts in synthetically useful yields. Our
early experiments suggested similarly mediocre performance
with Me2AlCl; therefore, when we reinvestigated the use of
this Lewis acid several months after our initial experiments
we were surprised to find that it promoted the cycloaddition
cleanly and rapidly.[11] Our hope that the increase in yield
reflected improved technique was quickly dispelled when we
found substantial differences in reactivity between aged and
freshly opened bottles of reagent.
electron-rich alkynes,[4] we envisioned
a cycloaddition
between such intermediates and ynol ethers (2, Scheme 1).
In analogy to Diels–Alder reactions involving the diene
Reactions involving Me2AlCl from freshly opened bottles
required more than 24 h to go to completion (Table 1,
entry 1). Under otherwise identical conditions, reagent
drawn from bottles aged for several months displayed
markedly superior reactivity (Table 1, entry 2). Reasoning
that this observation could be accounted for by evaporation
(solutions of Me2AlCl in hexanes were used), adventitious air,
or water, we performed a series of control experiments.
Modest changes to the charge of Me2AlCl had little effect on
Scheme 1. Cycloaddition of ynol ethers with 1,3-zwitterions derived
from the opening of donor–acceptor cyclopropanes. EWG=electron-
withdrawing group.
Table 1: Effects of additives on the aluminum(III)-mediated reaction of
silyl ynol ethers with cyclopropanes.[a]
developed by Danishefsky,[5] we postulated that the inter-
mediate vinylogous acetal 3 might decompose to give cyclo-
pentenone 4 during the reaction. While donor–acceptor
cyclopropanes have been shown to combine with indoles,[6]
enol ethers,[7] and aryl acetylenes,[8] a condensation with ynol
Entry
Me2AlCl[b]
Additive
t [h]
Yield [%][c]
[*] X. Qi, Prof. J. M. Ready
1
2
3
4
5
6
freshly opened
aged[d]
freshly opened
freshly opened
freshly opened
aged[d]
none
none
28
6
24
5
3
5
74
76
64
77
70
74
Department of Biochemistry
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-0320
E-mail: joseph.ready@utsouthwestern.edu
Homepage: http://www.swmed.edu/readylab/
H2O (10 mol%)
air[e]
MeOH (1 equiv)
air[e]
[**] Financial support was provided by the NIGMS (grant no.
GM074822) and the Welch Foundation.
[a] 0.33m in 2. Reactions were carried out on a 0.5 mmol scale. [b] 1m
solution in hexanes. [c] Yield of isolated compound 4aa. [d] Opened
several months prior to use. [e] Dry air (20 mL) was bubbled through the
reaction mixture at 238C.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801957.
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Chemie
Table 2: Synthesis of cyclopentenes from silyl enol ethers and cyclo-
the rate of the reaction (results not shown), and small
amounts of water (Table 1, entry 3) had no effect. In contrast,
when dry air was bubbled through solutions containing the
Lewis acid we could recapitulate the phenomenon observed
with aged bottles of reagent and isolate 4aa in good yield
(Table 1, entry 4).[12]
propanes.[a]
Under optimized reaction conditions, air was bubbled
through a solution of Me2AlCl (1 equiv) at room temperature.
Then at À788C, cyclopropane (1.3 equiv) and ynol ether
(1 equiv) were added, and the mixture was stirred until the
reaction was complete (2–24 h). Subsequently, HF·pyridine
was added, and after an aqueous workup, the residue was
purified by column chromatography to give cyclopentenone
4. In this way, a series of substituted donor–acceptor cyclo-
propanes were combined with a range of ynol ethers to yield
enones in generally good yields (Table 2). Silyl ynol ethers
bearing olefins, alkynes, ethers, halides, and aromatic rings all
functioned effectively in the transformation (Table 2,
entries 1–12). Unfortunately, the ynol derived from phenyl
acetylene was a poor substrate (Table 2, entry 13). Both cis-
and trans-disubstituted cyclopropanes appear to behave
identically (Table 2, entries 1 and 2). Likewise, substitution
at C3 (Table 2, entries 14–16), C1 (Table 2, entry 17), or both
(Table 2, entries 18 and 19) are accommodated in the cyclo-
addition. Thus, tri-, tetra-, and even penta-substituted cyclo-
pentenones can be formed in good yields and in a convergent
manner. When two stereocenters were generated in the
reaction (Table 2, entries 14–16, 18, and 19), we observed
greater than 10:1 diastereoselectivity favoring the more stable
trans isomer. Furthermore, both partners in the cycloaddition
can be accessed in a single operation from readily available
materials.
Entry Cyclopropane
Ynol Ether (2) Product (4)
Yield [%][b]
77
1
cis-1a
2a
R3 =nBu
2
3
trans-1a
cis-1a
2a
2b
R3 =nBu
75
67
4
cis-1a
2c
71
5
6
7
cis-1a
cis-1a
cis-1a
2d
72
72
79
2e
2 f[c]
8
9
cis-1a
cis-1a
2g
2h
R3 =(CH2)2Ph
R3 =CH2-
54
82
(cPent)
10
11
12
13
cis-1a
cis-1a
cis-1a
cis-1a
2i
2j
2k
2l
R3 =cHex
76
72
R3 =CH2OBn
R3 =(CH2)2OBn 54
R3 =Ph
24
14
1b[d]
2a
70
15
16
17
1
The H NMR spectra of anaerobic solutions of Me2AlCl
revealed one singlet at d = À0.31 ppm (CDCl3). After oxy-
genation, the same solution displays two upfield singlets at
d = À0.39 and À0.43 ppm and two downfield resonances
which are suggestive of a methoxide group (d = 3.87 and
3.85 ppm). We interpret these signals as arising from
(MeO)AlMeCl, the product of aerobic oxidation of one
methyl–aluminum bond. The two sets of signals (ca. 1:2 ratio)
likely correspond to diastereomeric cyclic trimers.[13] Indeed,
addition of 1 equivalent of methanol to Me2AlCl yielded a
substance with substantially the same spectrum, and the
reagent thus produced is a better Lewis acid for the cyclo-
addition than Me2AlCl (Table 1, entry 5). Interestingly, while
the major products formed upon addition of either methanol
or air to Me2AlCl are the same, the reaction resulting from the
addition of methanol is noticeably messier: an unidentified
precipitate is formed, and the 1H NMR spectrum of the
filtrate indicates several minor products. Perhaps as a
consequence, the cycloadditions carried out using this reagent
are lower yielding and generate more side products. Thus,
aerobic oxidation of dialkyl alanes constitutes a clean and
efficient method to generate a strong but selective Lewis acid.
Finally, it is important to note that we observe no difference in
reactivity between the (MeO)AlMeCl generated from freshly
opened versus aged bottles of Me2AlCl (Table 1, compare
entries 4 and 6).
1c[e]
1c[e]
2a
R3 =nBu
76
81
2 f[c]
1d[d,f]
2a
R2 =R3 =nBu
63
18
19
1e[d]
2a
2a
46[g]
1 f[d]
79[g]
[a] Reactions were carried out on a 1.0 mmol scale. Dry air (40 mL) was
bubbled through A solution of Me2AlCl at 238C prior to use (cHex=
cyclohexyl, cPent=cyclopentyl). See the Supporting Information for
complete experimental details. [b] Yield of isolated product. [c] The
ynolate 2 f used was bis(iPr)3Si-ether. [d] Single unassigned diastereo-
mer. [e] Mixture of diastereomers. [f] 1d (2.5 equiv). [g] d.r.> 20:1.
With respect to the utility of the methodology described
here, comparisons to two standard syntheses of cyclopenten-
ones are appropriate. This cycloaddition is more direct than
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121, 4516 – 4517; j) H. M. L. Davies, B. Xiang, N. Kong, D. G.
Stefford, J. Am. Chem. Soc. 2001, 123, 7461 – 7462; k) O.
Kitagawa, S. Miyaji, C. Sakuma, T. Taguchi, J. Org. Chem.
2004, 69, 2607 – 2610; l) J. C. Methot, W. R. Roush, Adv. Synth.
Catal. 2004, 346, 1035 – 1050; m) S. E. Gibson, S. E. Lewis, N.
Mainolfi, J. Organomet. Chem. 2004, 689, 3873 – 3890; n) Y. T.
Wu, T. Kurahashi, A. De Meijere, J. Organomet. Chem. 2005,
690, 5900 – 5911; o) A. Herath, J. Montgomery, J. Am. Chem.
Soc. 2006, 128, 14030 – 14031; p) D. Struebing, M. Beller, Top.
Organomet. Chem. 2006, 18, 165 – 178; q) P.-C. Chiang, J.
Kaeobamrung, J. W. Bode, J. Am. Chem. Soc. 2007, 129, 3520 –
3521; r) X. Huang, L. Zhang, J. Am. Chem. Soc. 2007, 129, 6398 –
6399; s) J. Barluenga, P. Barrio, L. Riesgo, L. A. Lopez, M.
Tomas, J. Am. Chem. Soc. 2007, 129, 14422 – 14426.
the Nazarov cyclization, and in contrast to that cyclization,
yields a single olefin positional isomer.[14] Likewise, while the
Pauson–Khand reaction is generally limited to intramolecular
cyclizations, the reactivity described above functions effi-
ciently in an intermolecular context.[15]
While (MeO)AlMeCl has been characterized previously,
it has found infrequent use as a Lewis acid.[16] In the present
transformation, this species appears strong enough to activate
the cyclopropane towards ring-opening and to mediate the
decomposition of the vinylogous acetal (3); fortunately it is
mild enough to coexist with the ynol ether and the cyclo-
pentenone. Whether this favorable reactivity profile extends
to other classes of cycloadditions and, more broadly, to other
Lewis acid promoted reactions remains the subject of future
investigations.
[3] For reviews, see: a) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003,
103, 1151 – 1196; b) M. Yu, B. L. Pagenkopf, Tetrahedron 2005,
61, 321 – 347.
[4] X. Qi, J. M. Ready, Angew. Chem. 2007, 119, 3306 – 3308; Angew.
Chem. Int. Ed. 2007, 46, 3242 – 3244.
[5] S. Danishefsky, Acc. Chem. Res. 1981, 14, 400 – 406.
[6] B. Bajtos, M. Yu, H. Zhao, B. L. Pagenkopf, J. Am. Chem. Soc.
2007, 129, 9631 – 9634.
[7] a) K. Saigo, S. Shimada, T. Shibasaki, M. Hasegawa, Chem. Lett.
1990, 1093 – 1096; b) M. Komatsu, I. Suehiro, Y. Horiguchi, I.
Kuwajima, Synlett 1991, 771 – 773.
Experimental Section
A dried test tube was charged with anhydrous dichloromethane
(1 mL) and Me2AlCl (0.5 mL of a 1m solution in hexanes, 1 equiv).
Dry air (20 mL) was bubbled through the solution at room tempera-
ture. The resulting solution then was cooled to À788C before
cyclopropane (0.65 mmol, 1.3 equiv) and silyl ynol ether (0.5 mmol,
1 equiv) were added sequentially. The reaction mixture was stirred at
À788C and upon completion (as evident by TLC), the reaction was
quenched by adding 30% HF·pyridine solution (0.5 mL). After
stirring at À788C for 5 min, the mixture was diluted with diethyl ether
and water. The aqueous layer was washed with 30 mL diethyl ether
and the combined organic extracts were washed with brine (50 mL),
dried over anhydrous MgSO4, concentrated in vacuo and the resulting
residue was purified by column chromatography on silica gel to afford
the product.
[8] V. K. Yadav, V. Sriramurthy, Angew. Chem. 2004, 116, 2723 –
2725; Angew. Chem. Int. Ed. 2004, 43, 2669 – 2671.
[9] a) For cycloaddition of ynolates with nitrones, see: M. Shindo, K.
Itoh, C. Tsuchiya, K. Shishido, Org. Lett. 2002, 4, 3119 – 3121;
b) M. Shindo, K. Ohtsuki, K. Shishido, Tetrahedron: Asymmetry
2005, 16, 2821 – 2831; c) with epoxides, see: H. Kai, K. Iwamoto,
N. Chatani, S. Murai, J. Am. Chem. Soc. 1996, 118, 7634 – 7635;
d) with aziridines, see: K. Iwamoto, M. Kojima, N. Chatani, S.
Murai, J. Org. Chem. 2001, 66, 169 – 174; e) cycloaddition of
ynamines with epoxides, see: M. Movassaghi, E. J. Jacobsen, J.
Am. Chem. Soc. 2002, 124, 2456 – 2457.
Received: April 25, 2008
[10] a) M. Julia, V. P. Saint-Jalmes, J. N. Verpeaux, Synlett 1993, 233 –
234; b) L. Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126,
11806 – 11807; c) M. Shindo, Tetrahedron 2007, 63, 10 – 36.
[11] MeAlCl2: 4aa in 34% yield; MAO (methylaluminoxane): 11%
yield; Et2AlCl: 53% yield; Me3Al, AlCl3, and (EtO)3Al: traces.
[12] Additional notes: a) The isolation of minor quantities of A from
the reaction mixture indicates that the cycloaddition is stepwise;
b) lower yields were obtained with tert-butyl-diphenylsilyl ethers
while tert-butyl-dimethylsilyl ethers could not be prepared in
satisfactory yields; c) similar yields are observed in dicholo-
ethane while substantially reduced yields were observed in
chloroform and no reaction occured in diethyl ether or THF.
Published online: July 30, 2008
Keywords: cycloaddition · cyclopentenones · cyclopropanes ·
.
ynols
[1] For reviews, see: a) T. Hudlicky, J. D. Price, Chem. Rev. 1989, 89,
1467 – 1486; b) U. M. Dzhemilev, R. I. Khusnutdinov, G. A.
Tolstikov, J. Organomet. Chem. 1991, 409, 15 – 65; c) G. Mehta,
A. Srikrishna, Chem. Rev. 1997, 97, 671 – 720; d) V. Singh, B.
Thomas, Tetrahedron 1998, 54, 3647 – 3692.
[2] For leading references, see: a) R. L. Danheiser, D. J. Carini, A.
Basak, J. Am. Chem. Soc. 1981, 103, 1604 – 1606; b) B. M. Trost,
Angew. Chem. 1986, 98, 1 – 20; Angew. Chem. Int. Ed. Engl.
1986, 25, 1 – 20; c) N. E. Schore, Chem. Rev. 1988, 88, 1081 –
1119; d) R. D. Little in Comprehensive Organic Synthesis,
Vol. 5 (Eds.: B. M. Trost, I. Fleming), Pergamon, New York,
1991, pp. 239 – 270; e) D. M. T. Chan in Comprehensive Organic
Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming), Pergamon, New
York, 1991, pp. 271 – 314; f) S. Yamago, S. Ejiri, M. Makamura,
E. Nakamura, J. Am. Chem. Soc. 1993, 115, 5344 – 5345; g) M.
Lautens, N. Klute, W. Tam, Chem. Rev. 1996, 96, 59 – 92; h) H. J.
Knolker, J. Prakt. Chem./Chem.-Ztg. 1997, 339, 304 – 314; i) J.
Barluenga, M. Tomas, A. Ballesteros, J. Santamaria, C. Brillet,
A. Pinera-Nicholas, A. J.-T. Vazquez, J. Am. Chem. Soc. 1999,
[13] A. Kunicki, W. Kosinska, M. Boleslawski, S. Pasynkiewcz, J.
Organomet. Chem. 1977, 141, 283 – 288.
[14] a) H. Pellissier, Tetrahedron 2005, 61, 6479 – 6517; b) A. J.
Frontier, C. Collison, Tetrahedron 2005, 61, 7557 – 7606.
[15] N. E. Schore in Comprehensive Organometallic ChemistryII,
Vol. 12 (Eds: E. W. Abel, F. G. Stone, G. Wilkinson), Elsevier,
New York, 1995, pp. 703 – 739.
[16] a) J. Fried, J. C. Sih, Tetrahedron Lett. 1973, 14, 3899 – 3902;
b) A. R. Daniewski, P. M. Wovkulich, M. R. Uskokivic, J. Org.
Chem. 1992, 57, 7133 – 7139.
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