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Electrophilic Activation and Cycloisomerization of Enynes A New Route to Functional Cyclopropanes.

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C. Bruneau
Cyclopropane Derivatives
Electrophilic Activation and Cycloisomerization of
Enynes: A New Route to Functional Cyclopropanes
Christian Bruneau*
carbocycles · cyclization · enynes ·
isomerization · transition metals
Transformations of enynes in the presence of transition-metal catalysts
have played an important role in the preparation of a variety of cyclic
compounds. Recent developments in the activation of triple carbon–
carbon bonds by electrophilic metal centers have provided a new entry
to the selective synthesis of cyclopropane derivatives from enynes. The
mechanisms of these reactions involve catalytic species with both ionic
and cyclopropylcarbenoid character. This type of activation will
undoubtedly be further developed for application to other unsaturated
hydrocarbons and inspire new catalytic cascade reaction sequences.
This Minireview discusses the recent developments in electrophilic
activation of enynes and shows that simple catalysts such as
[Ru3(CO)12], PtCl2, and cationic gold complexes are efficient precursors to promote the formation of functional polyclic compounds.
The cyclopropane ring is a quite common subunit of
natural products isolated from plants, fungi, and microorganisms.[1] Many of these natural products show biological
activity, and some of them have found applications as drugs
or insecticides.[1, 2] The most common biosynthesis processes
are based on cationic intermediates in interaction with
carbon–carbon double bonds, as illustrated in the production
of terpene from isoprenoid allylic pyrophosphates.[1, 3] Classical chemical syntheses of cyclopropane derivatives include
the halomethyl–metal-mediated cyclopropanation of olefins,
the transition-metal-catalyzed carbene-transfer reaction from
diazo compounds, and the nucleophilic-addition/ring-closing
sequence.[4] Recently, the very rich chemistry of enynes has
made possible the preparation of a variety of carbocycles,
depending on both the nature of the enyne and the metal
catalyst.[5–7] Various transformations of enynes through metal-
[*] Dr. C. Bruneau
Institut de Chimie
UMR 6509: CNRS-Universit de Rennes 1
Organomtalliques et Catalyse
Campus de Beaulieu-35042 Rennes Cedex (France)
Fax: (+ 33) 2-2323-6939
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
catalyzed cycloisomerization have
been reported which involve several
pathways (Scheme 1):
* the metathesis reaction usually
performed with metal–carbene active species which leads to conjugated vinylcycloalkene derivatives
A,[8, 9]
oxidative cyclometalation followed by b elimination,
which provides cycloalkanes that bear an exo-1,3- or
-1,4-diene motif, B and C, respectively,[10]
Scheme 1. Z = CH2, heteroatom; R1,R2 = alkyl.
DOI: 10.1002/anie.200462568
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
Cyclopropane Derivatives
Scheme 2. [M] = transition-metal catalyst. Z = CH2, heteroatom; R1,R2 = alkyl.
oxidative coupling followed by reductive elimination to
give cyclobutene derivatives D,[11]
coupling involving p-allyl–metal intermediates to form
nonconjugated dienes E.[12]
More recently, another mechanism based on the activation of enynes by electrophilic transition-metal derivatives
was suggested to rationalize the catalytic isomerization of 1,6and 1,5-enynes, and polyene-ynes not only into dienic
compounds such as A’, F, and H but also into cyclopropane
derivatives G (Scheme 2). To date, the most appropriate
Dr. Christian Bruneau graduated in
Chemistry from the Institut National
Suprieur de Chimie Industrielle de Rouen
(1974) and obtained his Doctorate degree
at the University of Rennes (1979). He then
took up a CNRS position in environmental
organic chemistry, and since 1986 he has
studied molecular catalysis at the Institute
of Chemistry in Rennes. His research interests include ruthenium-catalyzed selective
transformations of alkynes, alkenes, and
enynes, and transition-metal-catalyzed enantioselective hydrogenation and allylic substitution reactions. Since 2000, he is head of the Organometallics and
Catalysis research group at the CNRS-University of Rennes.
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
metal derivatives that efficiently perform this type of cycloisomerization are based on electrophilic ruthenium, platinum,
and gold complexes or salts. Recent developments of the
electrophilic activation of enynes to produce fused cyclopropane derivatives are presented herein.
Electrophilic Activation: Mechanistic
Considerations and Model Calculations
The activation of the triple bond of enynes by a metal
center generates highly electrophilic species and triggers the
nucleophilic attack of a double bond to the activated triple
bond by an endo- or exo-dig pathway. As illustrated in
Scheme 2, a large number of resonance structures result from
these two possible pathways. The carbon skeleton can adopt
the canonical cationic homoallyl, cyclopropylmethyl, or
cyclobutyl forms, all of them in resonance with a neutral
cyclopropylmethylidene form. As already underlined by
Frstner and co-workers,[13] the congruence between ionic
and carbenoid species is obvious in these activation processes.
It is thus pertinent to suggest that the reactivity of enynes
activated by electrophilic metals is governed by the formation
of cyclopropylcarbene–metal intermediates (Scheme 3).[13–15]
DFT calculations based on PtCl2·H2O/6-octen-1-yne models suggest that the triple bond is h2-coordinated to the metal
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
C. Bruneau
Scheme 3.
Scheme 4.
center and that the slippage toward an h1-coordinated vinyl
cation is not favored.[16] Furthermore, bicyclic cyclopropane
intermediates of type b and i are expected to be formed
directly in a single step by nucleophilic attack of the double
bond to the activated triple bond.[16] With the same model, it
was also found that the six-membered intermediate b
(Scheme 2, Z = CH2, R1 = H, R2 = Me) was more stable than
the exo-dig intermediate i by 8.1 kcal mol 1, but a higher
activation energy of about 1 kcal mol 1 was required.[15, 16]
When an oxygen atom was introduced in the tether between
the triple and the double bonds ((E)-HCCCH2OCH2CH=
CHMe; Scheme 2, Z = O), the endo-dig pathway leading to b
was both kinetically and thermodynamically favored.[17] With
[Au(PH3)]+/6-octen-1-yne as a model, calculations show a
highly polarized activated triple bond that easily reacts with
the double bond with a low activation energy (0.1 kcal mol 1)
to give the exo-dig cyclization form g. However, depending on
the nature of the starting enyne, the endo-dig cyclization,
which requires a higher activation energy (6.1 kcal mol 1), but
generates a more stable gold carbene intermediate b, can also
take place.[18]
Echavarren and co-workers have shown that in the
presence of external nucleophiles such as water or alcohols,
which are able to intercept cationic intermediate species,
cyclic homoallylic alcohols and ethers can be obtained.[19] In
the absence of external nucleophiles, catalytic transformations that involve 1,2-hydrogen migration and release of the
metal catalyst are observed. From 1,6-enynes (Scheme 2), the
only pathway that leads to the formation of cyclopropane
compounds involves as the first step the endo-dig cyclization
to form bicyclic [4.1.0] heteroheptenes. This reactivity is
mainly driven by the presence of a heteroatom at the
propargylic position which facilitates the 1,2-hydrogen migration and implies the presence of at least one hydrogen atom at
the propargylic position.
Scheme 5. R1 = Me, Et, Ph; R2 = Ph, 1-naphthyl, iPr, tBu, p-tolyl, CH=
atives 6 in the presence of PtCl2 as catalyst at 60–80 8C in
toluene (Scheme 6).[21, 23]
Scheme 6. Ts = p-toluenesulfonyl, TMS = trimethylsilyl.
Cycloisomerization of 1,6- and 1,5-Enynes Catalyzed
by Electrophilic Metal Centers
The first examples of cycloisomerization of 1,6 and 1,5enynes were reported by Blum et al. in 1995.[20] PtCl4 was used
as catalyst to promote the selective formation of 3-oxabicyclo[4.1.0]hept-4-enes 2 from allyl propargyl ethers 1 (Scheme 4).
Other reactions of this type were further reported in which
PtCl2 was used as catalyst[21] and the reaction was extended to
enol ethers as starting compounds (Scheme 5).[22] The presence of a protected nitrogen atom at the propargyl position in
1,6-enynes 5 also orientates the rearrangement of the skeleton
of these compounds into 3-azabicyclo[4.1.0]hept-4-ene deriv-
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Tricyclic structures such as 8 and 10 are also obtained from
allyl propargyl tosylamides, such as 7 and 9, which respectively contain an endo- or exocyclic double bond. In this
context, catalytic systems based on gold complexes such as
[AuCl(PPh3)]/AgSbF6 were more active under milder conditions and these reactions could be performed in dichloromethane at room temperature with very short reaction
times.[18] In the absence of a heteroatom in the bridge
between the triple and the double bonds of 1,6-enynes, a
skeletal rearrangement leading to 1,3-dienes such as A’ and H
is observed (Scheme 2),[13, 14, 18] but cyclopropanation usually
does not take place. However, when a carbene intermediate
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
Cyclopropane Derivatives
can be intramolecularly transferred to another double bond,
the generation of polycyclic compounds that contain two
cyclopropane structures is possible from the exo-dig intermediates that feature the less hindered metal–carbene
moieties i (Scheme 2). This type of cascade reaction was first
observed by Murai and co-workers with the skeleton rearrangement of 11 into 12, when the starting compound was
heated at 80 8C in the presence of catalytic amounts of
[{RuCl2(CO)3}2], PtCl2, or [{Rh(O2CCF3)2}2] (Scheme 7).[24]
Scheme 9.
migration of the ester group and the formation of a metal–
vinylcarbene species, which transfers the carbene to one of
the two double bonds of 17 depending on the configuration of
the intermediate, as illustrated in the formation of 18 and 19
(Scheme 10).[25]
Scheme 7. L = ligand, E = CO2Et.
Scheme 10.
In this case, the exo-dig cyclization is probably the first
step followed by cyclopropanation with the pendant terminal
olefin. Note that the corresponding oxygen-tethered dienyne,
which in principle favors the endo-dig cyclization, is much less
reactive. Recently, less activated substrates 13 which contain
diene-yne substructures connected by only one C(CO2Me)2,
C(SO2Ph)2, or NTs group were efficiently isomerized into
tetracyclic derivatives 14 in the presence of cationic gold
catalysts in dichloromethane at 30 to 23 8C (Scheme 8).[18]
When the starting compound is a simple 1,n-enyne that
contains only one olefinic bond, isomerization takes place at
room temperature in the presence of PtCl2[25] or [AuCl(PPh3)]/AgSbF6[26]as catalyst and provides bicyclic enol esters
in good yields (Scheme 11). The stereoselectivity of this
reaction is especially interesting from a synthetic point of
view. The formation of the sole diastereoisomer 21 with
control of three asymmetric centers during the cycloisomerization of a diastereomeric mixture of 20 is a representative
example (Scheme 12).[25]
Scheme 8. Z = C(CO2Me)2, C(SO2Ph)2, NTs.
Upon treatment of tertiary propargylic alcohols or ethers
15 that bear two unsaturated chains at the propargylic
position with PtCl2 (5 mol %) at 80 8C, tetracyclic compounds
16 that result from electrophilic activation of the triple bond,
exo-dig cyclization, and cyclopropanation were also formed
(Scheme 9).[25] However, when a propargylic ester is submitted to similar reaction conditions (Y = MeCO, p-NO2C6H4CO), the formation of a metal–cyclopropylcarbene such as i is
inhibited, as the metal-stabilized vinyl cation intermediate is
trapped by the ester functionality, as shown from a more
simple enyne in Scheme 11.[25–27] This mechanism leads to the
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
Scheme 11. [M] = Pt or Au complexes.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
C. Bruneau
Scheme 12.
Note that the intermolecular coupling of propargylic
acetates with styrene and other olefins (1,2-diphenylethene,
1,2-diethylethene, 3-trimethylsilylprop-1-ene, tert-butoxyethene, vinyl acetate) which takes place in the presence of
[{RuCl2(CO)3}2], PtCl2, or AuCl3 as catalyst and leads to 1cyclopropylvinyl acetate derivatives 22 is reminiscent of this
general mechanism (Scheme 13).[28]
involve first, the formation of a 1,5-enyne through intramolecular carbon–carbon bond formation from a propargylic
moiety and an olefinic group catalyzed by [Cp*RuCl(m2SiPr)2RuCp*Cl] (Cp* = pentamethylcyclopentadienyl), followed by a 1,5-enyne cycloisomerization catalyzed by
PtCl2.[30] Among the other 1,5-enynes which have been
investigated, 3-hydroxy-1,5-enynes that bear propargyl and
allyl motifs represent an interesting class of compounds.
Indeed, the hydrogen migration that occurs for the formation
of the final organic compound directly provides cyclic
ketones. Terminal as well as substituted triple and double
bonds provide bicyclo[3.1.0]hexan-3-ones in good yields. The
stereochemical implication of this reaction is also very
valuable and can be rationalized and predicted on the basis
of the mechanism and structure of the starting enyne. Indeed,
excellent results have been obtained upon catalysis with PtCl2
in toluene at 60–80 8C (Scheme 15).[26, 31]
Scheme 13.
The cycloisomerization of 1,5-enynes into bicyclo[3.1.0]hexane derivatives has recently been performed by
using a gold catalyst.[29] In the presence of a cationic gold
precursor such as [Au(PPh3)]SbF6 or [AuCl(PPh3)]/AgBF4, a
very efficient endo-dig cyclization takes place with a variety of
substrates even if they do not contain a heteroatom in the
tether between the two unsaturated bonds. This observation
confirms that the catalytic activity of cationic gold catalysts is
superior to that of platinum catalysts. This transformation
includes terminal as well as substituted triple- and doublebond-containing enynes, and substitution at the allylic or
propargylic position does not constitute a drawback. Note
that the very electrophilic gold center tolerates oxygen
functionalities such as ethers, esters, and silyl ethers. The
stereochemistry of this reaction is also very well controlled as
exemplified by the transformation of 23 into 24 (Scheme 14).
Very recently, fused polycyclic cyclopropanes have been
obtained by sequential one-pot catalytic reactions that
Scheme 14. TIPS = triisopropylsilyl.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 15. TBS = tert-butyldimethylsilyl.
Formation of Cyclopropanes from Enynes through
Tandem Reactions
Other transformations that are not purely isomerizations
but also involve activation of enynes and lead to cyclopropane
derivatives have been recently reported and deserve to be
discussed here. The formation of cyclopropane derivatives
from enynes through tandem cyclopropanation and metathesis can compete with the formation of the products
expected from pure electrophilic activation. This is the case
when a ruthenium carbene, such as [RuCl2(PCy3)(MesH2Im)(=CHPh)]
(Cy = cyclohexyl,
MesH2Im = bis(mesityl)imidazolinylidene) or the system generated in situ from
[{RuCl2(p-cymene)}2], MesH2Im, and PCy3, is used as catalyst
to promote the tandem cyclopropanation and ring-closing
metathesis reactions of the dienyne 27 into 28 as the major
compound (Scheme 16).[32] Indeed, compound 28 does not
result from isomerization of the starting enyne, as a CH2
group is transferred to the ruthenium center to generate a
metathesis catalyst. This result contrasts with the expected
formation of 1,3-dienes and polycyclic compounds as obtained with RuCl3 and PtCl2 as electrophilic catalyst precursors.[32] From a more simple enyne such as 29, the quantitative
formation of the dimer 30 which contains two cyclopropane
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
Cyclopropane Derivatives
Scheme 18. Z = C(CO2Me)2.
Scheme 16. Cy = cyclohexyl, Mes = mesityl (2,4,6-trimethylphenyl),
Im = imidazole, p-cymene = 4-isopropyltoluene.
rings is observed from a cyclopropanation and cross-metathesis sequence.
The transformation of 1,6-enynes derived from propargylic alcohols into alkenylcyclopropane derivatives 32 promoted by [RuCl(Cp*)(cod)] (cod = cyclooctadiene) in the
presence of a carbene source such as trimethylsilyldiazomethane or ethyl diazoacetate proceeds with skeleton rearrangement and addition of the carbene moiety to the initial
enyne through a tandem alkenylation/cyclopropanation reaction (Scheme 17).[33] Unexpectedly, the metal carbene
generated in situ is not involved in the cyclopropanation
reaction but in the alkenylation reaction.
Scheme 17. X = O, NTs. Cp* = pentamethylcyclopentadienyl.
Another catalytic system based on tetrakis(methoxycarbonyl)palladacyclopentadiene has demonstrated a high efficiency to promote the dimerization of 1,6-enynes to form a
cyclopropane ring. This reaction results from the intermediate
formation of a palladium–cyclopropyl vinyl carbene which is
trapped by [4+2] cycloaddition with an external double
bond.[34] In the absence of any other olefin, the dimerization
product 34 is obtained from 33, whereas in the presence of a
second olefinic substrate such as a conjugated diene or enyne,
cyclopropane-containing cycloaddition products are obtained
(Scheme 18).[34, 35]
Conclusions and Outlook
The activation of the triple bond of enynes with electrophilic metal derivatives, especially cationic gold complexes,
Angew. Chem. Int. Ed. 2005, 44, 2328 –2334
platinum salts such as PtCl2, and ruthenium derivatives,
makes possible the nucleophilic addition of the double bond
to generate metal–cyclopropylcarbenoid intermediates. These
species are very reactive and key intermediates to promote
skeleton rearrangements and the formation of fused rings that
contain at least one cyclopropane subunit. Reactivity strongly
depends on the nature and geometry of the starting compounds, and both exo- and endocyclization modes provide
atom-economical skeleton rearrangements and cycloisomerizations. Most of these transformations take place under
stereochemical control and provide good routes to prepare
optically active compounds. At the dawn of this chemistry,
there is no doubt that further development will soon appear
for the stereocontrolled construction of functional cyclopropane derivatives.
Received: November 10, 2004
Published online: March 10, 2005
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