Rhenium-catalyzed synthesis of stereodefined cyclopentenes from β-ketoesters and aliphatic allenes

Article abstract of DOI:10.1002/anie.200803350

(Chemical Equation Presented) Come on allene: Commercially available [Re₂(CO)₁₀] as a catalyst provides five-membered carbocycles in moderate to excellent yields with high stereoselectivity (see scheme). The configuration at each of the three sp³ carbon centers of the ring is defined. The reaction proceeds at the β, γ, and adjacent methylene positions of the allene; previously, similar reactions usually occurred at the α, β, and γ positions of the allene.

Full text of DOI:10.1002/anie.200803350

Communications
DOI: 10.1002/anie.200803350
Cycloaddition
Rhenium-Catalyzed Synthesis of Stereodefined Cyclopentenes from
b-Ketoesters and Aliphatic Allenes**
Salprima Yudha S., Yoichiro Kuninobu,* and Kazuhiko Takai*
Approaches to construct complex organic molecules, such as
carbocyclic compounds, from simple starting materials as
building blocks are of great interest. Five-membered carbo-
cycles are especially important, and remarkable progress has
been made in their syntheses.[1] Among them, [3+2] cyclo-
addition reactions have been studied intensively because the
five-membered carbocycles can be derived from simpler
molecules.[2] The synthesis of five-membered carbocycles
starting from allenes have also been reported; for example
(trimethylsilyl)cyclopentene annulation mediated by titanium
complexes, gold-catalyzed [3+2] cycloaddition of enones/
enals with allenyl methoxymethyl ethers, and cobalt-cata-
lyzed reductive [3+2] cycloaddition of allenes and enones.[3]
Figure 1. X-ray crystal structure of 3a.[17] Thermal ellipsoids set at 50%
probability.
Herein, we report the unprecedented synthesis of polysubsti-
tuted cyclopentenes from b-ketoesters and aliphatic allenes.
Previous work on the use of rhenium complexes in organic
synthesis, including our own studies on the reactions of
acetylenes and olefins,[4,5] led us to envisage the reactivity of
rhenium complexes towards allenes. By heating a mixture of
b-ketoester 1a and allene 2a in toluene in the presence of
rhenium complex [{ReBr(CO)3(thf)}2], the insertion of 2a
into either the C H bond at the a-position[4a] or the carbon–
ꢀ
carbon bond[4b] of 1a was expected. After carrying out the
ꢀ
above reaction, C H insertion product 4a was produced in
27% yield in addition to the unexpected formation of
cyclopentene 3a in 32% yield [Eq. (1)].[3] The structure of
3a was determined by both NMR spectroscopy and single-
crystal X-ray crystallographic analysis (Figure 1). For struc-
ture 3a, both the regiochemistry and the stereochemistry at
the three carbon centers was defined.
peak in the GC-MS analysis, but it was less than 1% yield.
Changing the electronic properties of the rhenium complexes
by using phosphine ligands ([ReCl3(PPh3)2(NCMe)], [ReCl3-
(PMe2Ph)3], and [ReOCl3(PPh3)2]) afforded decomposition
products of allenes. Other metal complexes, such as
[Mn2(CO)10], [MnBr(CO)5], and [Ru3(CO)12] were also
ineffective.
Once the optimal catalyst and reaction conditions were
identified, we investigated the scope and limitations of this
new synthetic method for making cyclopentenes using
b-ketoesters and aliphatic allenes. Aliphatic allenes reacted
with b-ketoesters in the presence of 2.5 mol% of the
[Re2(CO)10] catalyst to furnish the corresponding cyclopen-
tene derivatives in moderate to excellent yields (61–91%)
(Table 1). Cyclopentene 3b was isolated in 80% yield from
the reaction of active methylene compound 1a with allene 2b
(entry 1). Ester and silyloxy groups are tolerated under the
reaction conditions as evidenced by the high yields of
products, 3c and 3d, respectively (entries 2 and 3).[6] Active
methylene compound 1b also served as a good coupling
partner to give cyclopentene 3e in 61% yield. (entry 4).
Changing the substituent from the ethyl group of the
Additional investigation of the catalysts showed that
treatment of b-ketoester 1a and allene 2a with [ReBr(CO)5]
(5.0 mol%) furnished the desired product in 35% yield. The
yield of 3a was improved to 76% by using [Re2(CO)10]
(2.5 mol%) instead of [ReBr(CO)5]. Gratifyingly, the yield
was improved to 85% by heating 1a and 2a under solvent free
conditions [Eq. (1)]. Notably, we detected another isomer
[*] Dr. S. Yudha S., Dr. Y. Kuninobu, Prof. Dr. K. Takai
Division of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology
Okayama University, Tsushima, Okayama 700-8530
E-mail: kuninobu@cc.okayama-u.ac.jp
ktakai@cc.okayama-u.ac.jp
[**] Financial support from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan, the Asahi Glass Foundation, and
the Okayama Foundation for Science and Technology. S.Y.S. also
thanks the Japan Society for the Promotion of Science (JSPS) for a
Postdoctoral Research Fellowship
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803350.
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Chemie
Table 1: Rhenium-catalyzed formation of cyclopentenes.[a]
3l, were obtained in 76%, 91%,
and 63% yields, respectively
(entries 9–11).[7]
The utility of the present annu-
lation reaction was demonstrated in
the stereoselective synthesis of the
spirocyclic compound 3m as shown
in Equation (2).[8]
Entry
1
1
2 (R4)
3
Yield [%][b]
Transition-metal-catalyzed
hydrocarbonation reactions of
allenes with active methylene com-
pounds have been reported,[9] and
the reactions formally occur at
three carbon atoms (a-, b-, and
g-positions) (Figure 2, left).[10] In
contrast, the reaction in Equa-
tion (1) proceeded at the b, g, and
adjacent methylene positions of the
allene (Figure 2, right).[11]
We conducted several experi-
ments to obtain information on the
reaction mechanism because the
annulation occurs at an unusual
site of the terminal allenes. Firstly,
the possibility of a rhenium-cata-
lyzed isomerization of aliphatic
allenes to 1,3-dienes[12] at the initial
step was examined. Treatment of
allene 2a with a catalytic amount of
1a
2b (nC9H19)
3b
80
2
3
4
5
1a
1a
1b
2c (AcO(CH2)3)
2d (tBuMe2SiO(CH2)3)
2a (PhCH2)
3c
3d
3e
73
74
61
1c R3 =tBu
1d R =CH2CH CH2
1e R =(CH2)4CH CH2
2a
2a
2a
3 f R3 =tBu
3g R =CH2CH CH2
3h R =(CH2)4CH CH2
68
3
3
62[c]
76[d]
=
=
6
7
3
3
=
=
[Re2(CO)10]
(2.5 mol%
or
8
25 mol%) at 1158C in the absence
of a b-ketoester, did not produce
1,3-diene derivative 5. In addition,
heating a mixture of 5 (E/Z 1:1.2)
and 1a in the presence of
1 f
1g
1g
2a
2a
2c
3i
3j
3k
69
76
91
9
[Re2(CO)10]
(2.5 mol%)
for
30 hours did not produce the corre-
sponding cyclopentene derivative
3a; the starting materials were
recovered almost quantitatively.[13]
These results clearly suggest that
the present annulation reaction
does not proceed by the isomeriza-
tion of allene to 1,3-butadiene
derivative 5.
10
11
1h
2a
3l
63[3]
[a] 1a (1.0 equiv), 2 (1.2 equiv). [b] Yield of isolated product. [c] 1d (1.2 equiv), 2a (1.0 equiv). 48 h.
[d] 48 h. [e] 48 h, see Ref. [7].
Since compound 4a was
obtained as a by-product, its role
in the synthesis was investigated by
b-ketoester to a bulkier tert-butyl group (entry 5) did not
affect the reaction significantly, and cyclopentene 3 f was
obtained in 68% yield. The use of 1d and 1e as substrates
indicated that the presence of an olefin within the ester group
did not disrupt the reaction and cyclopentenes 3g and 3h
were obtained in 62% and 76% yields, respectively (entries 6
and 7). Changing the substituent at the ketone part of the
b-ketoester afforded a cycloadduct 3j in 69% yield (entry 8).
Interestingly, cyclic b-ketoesters, 1g and 1h, participated in
the annulation reaction, and bicyclic compounds, 3j, 3k, and
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Communications
Figure 2. Reaction sites of terminal aliphatic allenes.
heating it in the presence of a catalytic amount of [Re2(CO)10]
or [{ReBr(CO)3(thf)}2]. Upon heating, the reaction did not
proceed and the recovery of 4a was almost quantitative
[Eq. (3)]. This result indicates that the cyclopentene adduct
3a was not generated by intramolecular cyclization of 4a.
Scheme 1. Proposed mechanism.
result provides new insights into the reactivity of unactivated
allenes bearing an adjacent methylene moiety.
We performed a deuterium labeling experiment using
(4,4-2H2)-phenethyl allenes ([D2]-2a), which would enable us
to determine where a proton of an adjacent methylene moiety
of the allene is transferred [Eq. (4)]. Formation of cyclo- Experimental Section
A mixture of 1a (72.1 mg, 0.500 mmol), 2a (87.0 mg, 0.600 mmol),
pentenes [D2]-3a having a monodeuterated methyl group at
C3 indicates that the proton of the methylene is transferred
exclusively to the terminal carbon atom of the allene.
and [Re2(CO)10] (8.2 mg, 0.0125 mmol) was stirred in an oil bath
heated to 1158C for 30 h. After completion of the reaction, the
mixture was purified by silica gel column chromatography using
hexane/ethyl acetate (20:1!10:1) as the eluent to give 3a (122 mg,
85% yield).
Received: July 10, 2008
Revised: September 17, 2008
Keywords: allenes · cyclopentenes · rhenium · synthetic methods
.
At present, we do not have enough experimental evidence
to fully describe the reaction mechanism, especially in terms
of the stereoselectivity at C5; however, we believe that the
mechanism shown in Scheme 1 is operative.[14] Although the
active rhenium species is not still clear,[15] we believe that the
initial step in the reaction is the formation of rhenacyclopen-
tane intermediate A from the rhenium catalyst, b-ketoester,
and allene.[4a,b,16] At this stage, the cis stereochemical relation-
ship between the hydroxy and ester groups of the product is
controlled by hydrogen bonding between the two groups.
b-Hydride elimination of A gives intermediate B having a
diene moiety. Insertion of an exo double bond of B into the
[1] For reviews on the synthesis of cyclopentanoid carbocycles, see:
a) L. A. Paquette, Chem. Rev. 1989, 89, 1051 – 1065; b) T.
Hudlicky, J. D. Price, Chem. Rev. 1989, 89, 1467 – 1486; c) G.
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Wilson, G. C. Fu, Angew. Chem. 2006, 118, 1454 – 1457; Angew.
Chem. Int. Ed. 2006, 45, 1426 – 1429, and references therein.
[2] For reviews, see: a) M. E. Welker, Chem. Rev. 1992, 92, 97 – 112;
b) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49 – 92.
[3] a) R. L. Danheiser, D. J. Carini, A. Basak, J. Am. Chem. Soc.
1981, 103, 1604 – 1606; b) R. L. Danheiser, D. M. Fink, Tetrahe-
dron Lett. 1985, 26, 2513 – 2516; c) R. L. Danheiser, C. A.
Kwasigroch, Y.-M. Tsai, J. Am. Chem. Soc. 1985, 107, 7233 –
7235; d) H.-T. Chang, T. T. Jayanth, C. C. Cheng, J. Am. Chem.
Soc. 2007, 129, 4166 – 4167; e) L. Zhang, X. Huang, J. Am. Chem.
Soc. 2007, 129, 6398 – 6399.
ꢀ
Re D gives p-allyl rhenium intermediate C. The s-allyl
intermediate D, derived by rearrangement of C, undergoes a
final reductive elimination to give the product and regenerate
the rhenium catalyst.
[4] a) Y. Kuninobu, A. Kawata, K. Takai, Org. Lett. 2005, 7, 4823 –
4825; b) Y. Kuninobu, A. Kawata, K. Takai, J. Am. Chem. Soc.
2006, 128, 11368 – 11369; c) S. Yudha S. , Y. Kuninobu, K. Takai,
Org. Lett. 2007, 9, 5609 – 5611.
[5] For a review, see: R. Hua, J.-L. Jiang, Curr. Org. Synth. 2007, 4,
151 – 174.
In summary, we have developed a novel stereoselective
annulation method for construction of cyclopentene frame-
works containing multiple stereogenic centers. The reaction
proceeds with a commercially available [Re2(CO)10] catalyst,
is operationally simple, and is atom economical. We hope the
[6] Internal allene, 1-phenyl-2,3-nonadiene, and 1,1-disubstituted
allene, 3-pentyl-octa-1,2-diene, did not give the corresponding
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Chemie
annulation products, and the allenes were recovered almost
[12] For a reaction of an aliphatic allene with carboxylic acid to form
1,3-butadiene derivatives, see: M. Al-Masum, Y. Yamamoto, J.
Am. Chem. Soc. 1998, 120, 3809 – 3810.
quantitatively.
[7] For the reaction in Table 1, entry 11, by-product 4b was isolated
[13] We could not detect other isomerization product that may be
produced from the allene, such as methyl alkyne derivative 6.
Indeed, when aliphatic methyl alkyne 6 was treated with
b-ketoester 1a in the presence of [Re2(CO)10] at 1158C, the
reaction did not give the corresponding cyclopentene product
3a.
in 7% yield.
[14] For a study on sigmatropic hydrogen shifts of allenes, see: F.
Jensen, J. Am. Chem. Soc. 1995, 117, 7487 – 7492.
[8] Inseparable by-product in Equation (2).
[15] For a discussion about photoreactions of [Re2(CO)10] and their
complexes with allenes, see: a) C. G. Kreiter, W. Michels, G.
Heeb, J. Organomet. Chem. 1995, 502, 9 – 18, and references
therein; b) H. Yang, P. T. Snee, K. T. Kotz, C. K. Payne, C. B.
Harris, J. Am. Chem. Soc. 2001, 123, 4204 – 4210.
[16] The mechanism can explain the appearances of by-products in
some cases, such as 4b; b-hydride elimination and reductive
elimination of intermediate A gives by-product 4b.
[9] For pioneering examples of hydrocarbonation reaction of
allenes, see: a) Y. Yamamoto, M. Al-Masum, N. Asao, J. Am.
Chem. Soc. 1994, 116, 6019 – 6020; b) B. M. Trost, V. J. Gerusz, J.
Am. Chem. Soc. 1995, 117, 5156 – 5157.
[10] For reviews on the synthesis and reactions of allenes, see: a) R.
Zimmer, C. U. Dinesh, E. Nandanan, F. A. Khan, Chem. Rev.
2000, 100, 3067 – 3125; b) Modern Allene Chemistry (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; c) S.
Ma, Chem. Rev. 2005, 105, 2829 – 2871; d) K. M. Brummond,
J. E. DeForrest, Synthesis 2007, 795 – 818; e) S. Ma, Aldrichimica
Acta 2007, 40, 91 – 102; f) H. H. A. M. Hassan, Curr. Org. Synth.
2007, 4, 413 – 439.
[11] For annulation reactions between activated allenes having an
adjacent methylene moiety and imines under phosphine catal-
ysis, see: a) X.-F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc. 2003,
125, 4716 – 4717; b) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005,
127, 12234 – 12235.
[17] Crystal data for 3a: The structure was solved by direct methods
and expanded using Fourier techniques. The non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were
refined using the riding model. C18H24O3, Mr = 288.39,
0.18x0.13x0.02 mm, triclinic, space group P-1 (#2), a =
7.5638(4) ꢀ, b = 10.4887(5) ꢀ, c = 11.2406(7) ꢀ, a = 70.915(3)o,
b = 75.657(3)o, g = 74.835(3)o, V= 800.45(7) ꢀ3, Z = 2, 1calcd
=
1.196 g/cm3, m = 6.374 cm-1, MoKaradiation (l = 1.54187 ꢀ) at
93(1) K, 2qmax = 136.3o, number of independent reflection 18099
(Rint = 0.060), R = 0.0659, wR2 = 0.1563, R1 = 0.0565. CCDC-
706439 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.
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