Ruthenium-catalyzed cycloisomerization of cis-3-en-1-ynes to cyclopentadiene and related derivatives through a 1,5-sigmatropic hydrogen shift of ruthenium vinylidene intermediates

Article abstract of DOI:10.1021/ja053674o

We report a new ruthenium-catalyzed cycloisomerization of unactivated cis-3-en-1-ynes, which produces substituted cyclopentadiene and related derivatives. The mechanism of this cyclization is proposed to involve a [1,5]-sigmatropic hydrogen shift of ruthenium-vinylidene intermediates on the basis of deuterium-labeling experiments. Copyright

Full text of DOI:10.1021/ja053674o

Published on Web 07/27/2005
Ruthenium-Catalyzed Cycloisomerization of cis-3-En-1-ynes to
Cyclopentadiene and Related Derivatives through a 1,5-Sigmatropic Hydrogen
Shift of Ruthenium-Vinylidene Intermediates
Swarup Datta, Arjan Odedra, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, ROC
Received June 4, 2005; E-mail: rsliu@mx.nthu.edu.tw.
Scheme 1
The [1,5]-sigmatropic hydrogen shift is a useful tool in organic
synthesis,1-4 and it has been employed frequently in the synthesis
of complex bioactive molecules.1 This process occurs very ef-
ficiently with cis-1,3-dienes,1,2 cis-1-alkyl-2-vinylcyclopropanes1,3
and cis-1-allen-4-enes1,4 at suitable conditions (Scheme 1, eqs 1-3),
but it proceeds sluggishly with cis-3-en-1-ynes even at elevated
temperatures.3a One possible approach to realize the [1,5]-hydrogen
shift of cis-3-en-1-ynes is to mimic the thermal rearrangement of
cis-1-allen-4-enes, using a suitable metal species to generate metal-
vinylidene intermediates (eq 4). To the best of our knowledge,
examples of such reactions have never been documented, even
Scheme 2
though there is considerable interest in metal-vinylidene chemis-
try.5 On the basis of this strategy, we report here a new ruthenium-
catalyzed cycloisomerization of cis-3-en-1-ynes into cyclopenta-
diene and related derivatives, which are appealing building blocks
to construct the skeletons of complex molecules.6,7
As shown in Scheme 2, treatment of 1-ethynyl-3-ols 1 and 2
with p-toluenesulfonic acid (p-TSA, 5 mol %) in hot toluene (110
°C, 12 h) gave cis-3-en-1-ynes 3 (91%) and 4 (92%), respectively.
The cis-configuration of enynes 3,4 was confirmed by proton NOE
spectra.8 Heating a benzene solution (80 °C) of alcohol 1 (Ar )
2-methoxyphenyl, 0.15 M) with TpRuPPh3(CH3CN)2PF69 (10 mol
%, Tp ) tris(1-pyrazolyl)borate) for 4 h gave cyclopentadiene 5
in 51% yield and enyne 3 (40%). At a longer period (12 h, entry
a [Ru] ) 10 mol % TpRuPPh3(CH3CN)2PF6. b[substrate] ) 0.15 M, 80
2), the desired diene 5 was obtained up to 79% yield with complete
consumption of enyne 3. Entry 3 confirms that cis-enyne 3 is truly
c
°C. Yields were reported after separation from a silica column.
the active intermediate in the cyclization of alcohol 1 to diene 5.
Heating species 3 with the catalyst (10 mol %) in benzene (80 °C,
12 h) produced diene 5 in 80% yield; structural assignment of diene
5 was based on the 1H NOE spectra.8 Similarly, the alcohol 2 (Ar
) 2-thienyl) and its cis-enyne derivative 4 were shown to be equally
active in this catalytic cyclization; they each gave diene 6 in 65-
66% yields (entries 4 and 5). The ruthenium catalyst has dual roles
in catalytic activities: dehydration of 1-ethynyl-3-ols and cyclization
of cis-enyne.
To examine the generality of this cycloisomerization, we used
various 1-ethynyl-3-ols 7-16 (Table 1) in the catalytic cyclization
because these alcohols are equally active as their dehydrated cis-
enyne derivatives. Most of these alcohols bear aryl or heteroaryl
substituents at their C(3) and C(5) carbons to ensure the formation
of a single and thermally stable cyclopentadiene regioisomer.10
Entries 1-3 reveal that the C(5)-phenyl substituent of alcohols 7
was catalytically as active as their 4-MeOPh and 4-CF3Ph analogues
8 and 9. This ruthenium catalyst is also active in the cyclizations
of alcohols 10-11 bearing a furyl group and gave cyclopentadienes
27-28 in 62-65% yields. Entries 6-8 indicate the effects of
alternating the C(3)-phenyl substituent of the alcohols 12-14; the
benzene group (12) produces a greater yield of cyclized product
than do the reactions of its 4-tolyl (13) and 4-CF3Ph counterparts
(14). The value of this cyclization is highlighted by its applicability
to the activation of a non-benzylic C-H bond, as represented by
substrates 15 and 16. The corresponding cylopentene products 32
and 33 were obtained in 71% and 53% yields, respectively (entries
9 and 10). The molecular structures of cyclopentadiene 29 and
cyclopentene 33 were also characterized by X-ray diffraction
studies.8 The high efficiencies were maintained when this cycliza-
tion was applied to the synthesis of trisubstituted cyclopentene 34-
35 (80-84%) and cyclopentene 36 (89%) from cis-enyne substrates
17-19. Entries 14-17 show additional instances for cyclization
of cis-enynes 20-23 via a non-benzylic C-H bond activation, and
the cyclized products 37-39 and 34 were obtained in 71-79%
yields. This new approach is very useful to construct bicyclic
carbocyclic skeletons because only one regioisomer was formed
exclusively (entries 11, 12, 14-17).
As shown in Scheme 3 (eq 1), the alkynyl deuterium of d1-3
produced the diene d1-5 bearing only 21% deuterium excess at the
CHdCPh carbon. The remaining three diene protons of d1-5
contained a total 0.42D content according to mass analysis.11 The
1,5-hydrogen shift2,6-7 of the cyclopentadiene framework hampers
a precise interpretation of 2H NMR labeling studies. Using a highly
deuterated enyne d3-3 circumvented this problem. Equation 2 shows
the deuterium distribution of diene d3-5 generated from this d3-3
enyne. The kinetic isotope effect of the CD2 group of d3-5 inhibits
this 1,5-hydrogen shift.12 Notably, one CeD2Ph deuterium of species
9
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J. AM. CHEM. SOC. 2005, 127, 11606-11607
10.1021/ja053674o CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Ruthenium-Catalyzed Cyclization of 1-Ethynyl-3-ols and
cis-Enynes
a reaction intermediate, which equilibrates with its σ-allyl species
F and would ultimately generate diene d3-5 bearing a deuterium
distribution inconsistent with our observation.
Although cis-3-en-1-yne is a common and practical functional-
ity,14 cycloisomerization of this moiety into a cyclopentadiene or
related framework is unprecedented before our findings. Here we
report that TpRuPPh3(CH3CN)2PF6 implements the cycloisomer-
ization of unactivated cis-3-en-1-ynes and efficiently produces stable
cyclopentadiene and related derivatives. The mechanism of this
cyclization is proposed to involve a [1,5]- sigmatropic hydrogen
shift of ruthenium-vinylidene intermediates on the basis of
deuterium-labeling experiments.
Acknowledgment. We thank the National Science Council,
Taiwan, for supporting this work.
Supporting Information Available: NMR spectra, spectral data
2
1
of compounds 1-39, NMR spectra of H-labeled d3-3 and d3-5, H
NOE spectra of 3, 5, 37, and 39, and X-ray structural data of cyclized
products 29 and 33. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Scheme 3
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Scheme 4
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cycloaddition under catalytic conditions.
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metal-vinylidene chemistry; see our related work.9
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d3-3 relocates to the CD2 fragment of diene d3-5, and the other
deuterium is present at the Ca-carbon of d3-5. In this transformation,
the alkynyl proton of d3-3 undergoes a 1,2-shift to relocate to the
Cb-carbon of d3-5.
Scheme 4 shows a plausible mechanism to rationalize the
deuterium-labeling experiments. The 1,2-shift of the alkynyl
hydrogen of d3-3 indicates the formation of ruthenium-vinylidene
intermediate5 A, which undergoes a subsequent 1,5-sigmatropic shift
to generate ruthenahaxa-3,5-triene B. A subsequent 6π-electro-
cyclization13 of species B gives ruthenacyclohexa-2,4-diene species
C. Reductive elimination of this Ru(IV)-triene species produces
cyclopentadiene D and ultimately yields the most stable regioisomer
d3-5 via a 1,5-hydrogen shift. The deuterium distribution of d3-5
in Scheme 3 precludes an involvement of ruthenium-π-allyl E as
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