Chemodivergent metathesis of dienynes catalyzed by ruthenium-indenylidene complexes: An experimental and computational study

Article abstract of DOI:10.1002/chem.200900976

A study on the enyne meta-thesis reaction leading to the formation cyclic compounds using ruthenium-in-denylidene complexes is presented. Several l, 11-dien-6-ynes have been subjected to ruthenium metathesis cyc-lization by using ruthenium-indenyli-dene c

Full text of DOI:10.1002/chem.200900976

DOI: 10.1002/chem.200900976
Chemodivergent Metathesis of Dienynes Catalyzed by Ruthenium–
IndenylACHTUNGTRENNUNGidene Complexes: An Experimental and Computational Study
Hervꢀ Clavier,[a, b] Andrea Correa,[c] Eduardo C. Escudero-Adꢁn,[b]
Jordi Benet-Buchholz,[b] Luigi Cavallo,*[c] and Steven P. Nolan*[a, b]
Abstract: A study on the enyne meta-
occurs and is a function of the catalyst
employed. This led us to investigate
the competing “ene-then-yne” or “yne-
then-ene” reaction pathways apparent-
ly at play in these systems using both
experimental observations and DFT
thesis reaction leading to the formation
cyclic compounds using ruthenium–in-
denylidene complexes is presented.
Several 1,11-dien-6-ynes have been
subjected to ruthenium metathesis cyc-
lization by using ruthenium–indenyli-
dene complexes bearing various phos-
phine and N-heterocyclic carbene
(NHC) ligands. Interestingly, for some
substrates chemodivergent metathesis
calculations. Experimental and compu-
tational studies were found in good
agreement and permit to conclude that
for phosphine-containing catalysts, the
“ene-then-yne” pathway is exclusively
adopted. On the other hand, for cata-
lysts bearing NHC ligands, both path-
ways are possible.
Keywords: density functional calcu-
lations · enynes · homogeneous cat-
alysis · metathesis · N-heterocyclic
carbenes · ruthenium
Introduction
rangement metathesis (RRM),[7] or also tandem processes.[8]
This explains the enormous activity aimed at attempting to
develop ever more active catalysts. Thus, several types of
ruthenium-based complexes have been investigated includ-
ing Ru–benzylidene[9] or –indenylidene,[10] “boomerang”
type catalysts,[11] or latent catalysts,[12] but also Ru species
bearing various phosphines,[13] N-heterocyclic carbenes
(NHCs),[14] pyridine derivatives,[15] or anionic ligands.[16]
Chiral Ru complexes[17] for asymmetric reactions have also
been synthesized, as well as supported catalysts that have
been used in a various reaction media.[18]
Surprisingly, considering the large number of ruthenium-
based complexes developed, only rare examples of reactivity
difference have been reported so far. Usually, variations are
observed in product conversions, but rarely in product distri-
butions. For instance, a limited number of studies have re-
ported the formation of self-cross-metathesis products, in
poor to quantitative yields, whereas other catalysts provided
only the expected RCM products using the same sub-
strates.[19] As a general example, a first-generation catalyst,
bearing two PCy3 ligands, led to the formation of dimers
and a second-generation catalyst, bearing 1,3-bis(2,4,6-tri-
Ruthenium-mediated olefin metathesis has emerged as an
indispensable tool in organic synthesis for the formation
carbon–carbon double bonds[1] as exemplified by the large
number of applications in natural product synthesis.[2] One
fascinating feature of olefin metathesis is the access to nu-
merous variations on the theme achieved as a function of
both substrates and reaction conditions. These metathesis
transformations include, for instance, polymerization reac-
tions (ROMP, ADMET),[3] cross metathesis (CM),[4] ring-
closing metathesis (RCM),[5] enyne metathesis,[6] ring-rear-
[a] Dr. H. Clavier, Prof. Dr. S. P. Nolan
School of Chemistry, University of St-Andrews
North Haugh, St Andrews, KY16 9ST (UK)
Fax : (+44)01334-463808
E-mail: snolan@st-andrews.ac.uk
[b] Dr. H. Clavier, E. C. Escudero-Adꢀn, Dr. J. Benet-Buchholz,
Prof. Dr. S. P. Nolan
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
[c] Dr. A. Correa, Prof. Dr. L. Cavallo
Dipartmento of Chimica, Universitꢀ di Salerno
Via Salvador Allende, Baronissi (SA), 84081 (Italy)
Fax : (+39)089-969603
AHCTUNGTREGmNNUN ethylphenyl)imidazol-2-ylidene (SIMes) NHC, led to
RCM products. As a proposed explanation for these obser-
vations, the reversible nature of the metathesis process is
thought to be responsible for the thermodynamic control of
the reaction and formation of the metathesis product. Thus,
E-mail: lcavallo@unisa.i
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900976.
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FULL PAPER
formation of thermodynamic products is favored when more
active, second-generation catalysts are used. Moreover, this
thermodynamic control influences the E/Z selectivity in
RCM macrocyclizations.[20] The (PCy3)2-containing catalysts
afforded mainly the E-isomer macrocycle, resulting from a
kinetic control, whereas complexes bearing NHC gave the
more thermodynamically stable Z macrocycle. Competition
between RCM and RRM as a function of catalyst genera-
tion employed has also been observed.[21] Recently, Grubbs
reported that NHC steric hindrance influences the product
distribution for RCM of trienes.[22] Less bulky disymmetrical
NHCs led to the formation of a tetrasubstituted double
bond, whereas trisubtituted C=C bonds were obtained with
a second-generation Hoveyda–Grubbs catalyst. In enyne
metathesis (ring-closing or ring-rearrangement), this selec-
tivity problem is expected;[23] however, only few examples
emphasizing the difference between first- and second-gener-
ation catalysts have been reported.[24]
Herein, we report Ru-catalyzed metathesis of dienynes
using indenylidene-based complexes. We have observed the
formation of a variation of products as a function of the sub-
strates, but more interestingly as a function of the catalyst
employed. These differences were observed not only be-
tween first- and second-generation metathesis catalysts, but
also between complexes bearing distinct NHC ligands.
These experimental results and associated DFT calculations
provide insights into the mechanism of the enyne metathesis
and lead to the determination of a reaction sequence follow-
ing the “ene-then-yne” or “yne-then-ene” scenario as a
function of catalyst.
cally relevant molecules.[26] As depicted in Table 1, the study
was initiated with the unhindered dienyne 6 and subjected
to phosphine-containing complexes 1 and 2. In cases in
which 1, bearing triphenylphosphine ligands, was found to-
Table 1. Influence of the catalyst on the enyne metathesis of 6.[a]
Catalyst
Reaction
Product
conditions
(isolated yield [%])
[b]
1
2
3
4
5
6
7
8
1
1
2
3
4
4
4
5
DCM, 408C, 24 h
toluene, 808C, 5 h
DCM, 258C, 1 h
DCM, 408C, 4 h
DCM, 408C, 4 h
toluene, 608C, 1 h
toluene, 808C, 0.5 h
DCM, 408C, 2 h
–
–
[b]
7a (90)
7a (49)/7d (10)
7a (72)/7d (17)
7a (75)/7d (18)
7a (69)/7d (18)
7a (70)/7b (18)
[a] Reaction conditions: substrate (0.5 mmol), catalyst (2 mol%), solvent
(5 mL; c=0.1m) in a Schlenk flask under Ar atmosphere. [b] Starting
material recovered.
tally ineffective in metathesis, even at high temperature (en-
tries 1 and 2), its tricyclohexylphosphine analogue afforded,
in good isolated yield, the expected double five-membered
cycle 7a under mild conditions and short reaction time
(entry 3). When the second-generation catalysts 3 and 4
were employed, an unknown product was isolated in poor
yields (entries 4 and 5). A search of the literature revealed
this product to be the unexpected six-membered ring 7d—a
compound the Grela group had obtained in similar yields
when catalysts bearing 1,3-bis(2,4,6-trimethylphenyl)imida-
zol-2-ylidene ligand (SIMes) were used.[11f,27] Interestingly,
the formation of 7d appears to occur only when second-gen-
eration catalysts are used.[28] Moreover, 7d was also ob-
tained when benzylidene- or “boomerang”-type second-gen-
eration catalysts were employed.[27] Of note, IMes-contain-
ing complex 3 (IMes=1,3-bis(2,4,6-trimethylphenyl)imida-
zol-2-ylidene) is less active than 4 and so the yield of prod-
ucts 7a and 7d is lower, but the 7a/7d ratio is similar. Using
4, the effect of reaction temperature was then investigated
(entries 5–7). At 60 and 808C, conversion of the dienyne 6
was found to proceed faster, but no influence on products
distribution was observed. In order to evaluate the effect of
the NHC ligand—IMes and SIMes having similar stereo-
electronic properties[29]—the metathesis reaction was per-
formed by using complex 5, bearing the more sterically
Results and Discussion
Investigation and identification of product formation: In the
course of investigations dealing with the scope of RCM re-
actions involving Ru-complexes bearing the indenylidene
scaffold 1–5,[25] we became interested in dienynes as sub-
strates, since this transformation is very useful for the con-
struction of double-ringed systems from acyclic materials
and has been successfully applied to the synthesis of biologi-
bulky
1,3-bis(2,6-isopropylphenyl)imidazol-2-ylidene
(IPr).[30] As shown in entry 8 of Table 1, 7d is not formed,
but another unexpected compound, showing a very similar
1
but distinct H NMR spectrum, identified as 7b was isolated
in low yield. Compound 7b results from the monocylization
of dienyne 6 and has not been reported to date. To the best
of our knowledge, only one example of selectivity difference
between ruthenium-complexes bearing these NHCs is re-
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S. P. Nolan, L. Cavallo et al.
Table 3. RCM of tosylamine-containing dienynes.[a]
ported in the literature and deals with the problem of mac-
rocyclization versus dimerization for substituted dienes.[19a.31]
With the aim of gaining information on the parameters di-
recting the formation of these “side-products”, similar meta-
thesis reactions were carried out with dienyne 8 possessing
ꢀ
the double C C bonds encumbered by an extra methyl
group (Table 2). Tricyclohexylphosphine-containing catalyst
Table 2. Influence of the catalyst on the enyne metathesis of 8.[a]
Substrate
Catalyst
Reaction
Product
conditions
(isolated yield [%])
[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
10
10
10
10
10
10
10
10
10
12
12
12
12
1
1
2
3
3
4
4
5
5
2
3
4
5
DCM, 408C, 24 h
toluene, 808C, 5 h
DCM, 258C, 0.5 h
DCM, 408C, 5 h
toluene, 808C, 0.5 h
DCM, 408C, 2 h
–
–
Catalyst
Reaction
product
[b]
conditions
(isolated yield [%])
11a (88)
11a (51)
[b]
1
2
3
4
5
2
2
3
4
5
DCM, 408C, 8 h
toluene, 808C, 8 h
DCM, 408C, 8 h
DCM, 408C, 5 h
DCM, 408C, 5 h
–
–
[b]
11a/11c 91:9 (97)[c]
11a/11c 80:20 (94)[c]
11a/11c 80:20 (96)[c]
11a (81)/11b (13)
11a (88)
9b (9)/9d (73)
9d (92)
9b (24)/9d (70)
toluene, 808C, 0.5 h
DCM, 408C, 2 h
toluene, 808C, 0.5 h
toluene, 808C, 2 h
toluene, 808C, 2 h
toluene, 808C, 2 h
toluene, 808C, 2 h
[a] Reaction conditions: substrate (0.5 mmol), catalyst (2 mol%), solvent
(5 mL; c=0.1m) in a Schlenk flask under Ar atmosphere. [b] Starting
material recovered.
[b]
–
13a (67)/13b (13)
13c (19)/13d (78)
13a (19)/13b (45)
[a] Reaction conditions: substrate (0.5 mmol), catalyst (2 mol%), solvent
(5 mL; c=0.1m) in a Schlenk flask under Ar atmosphere. [b] Starting
material recovered. [c] Products could not be separated, products ratio
2 was found inactive, leaving the starting material un-
changed and this despite 8 h of heating at 808C (entries 1
and 2). With NHC complexes 3–5, no anticipated bicyclic
compounds were obtained and the major product was found
be the six-membered ring 9d (entries 3–5).
1
determined by H NMR spectroscopy.
However, with the NHCs IMes and IPr small to signifi-
cant amounts of the five-membered cycle 9b were isolated.
Of note, with catalyst 4, bearing SIMes, traces of product 9b
(less than 5%) were detected in the crude mixture, but
could not be isolated. In terms of activity, it should be noted
that with complexes 3 and 4, reactions require a slight ther-
mal activation to proceed with both unhindered dienyne 6
and its more sterically congested analogue 8.[26] Catalyst 5 is
efficient at room temperature, nevertheless for a thorough
comparison similar reaction conditions were employed.
Indeed, it appears that the bulkiness of IPr appears to favor
the phosphine release leading to the 14-electron active spe-
cies.
At this stage, the difficulties associated with crude mix-
ture analysis, product isolation, and identification were
judged a crucial issue[24,32] and led us to examine a similar
substrate, but one that could be crystallized to unambigu-
ously establish the structure of each product. Thus catalysis
was performed using dienynes 10 and 12 as substrates; re-
sults are depicted in Table 3. Once again, triphenylphos-
phine complex 1 did not lead to metathesis product, in spite
of using harsh reaction conditions (entries 1 and 2). Catalyst
2 gave a sole product, the bicyclic compound 11a as con-
firmed by single-crystal X-ray analysis. A ball-and-stick rep-
resentation of this compound is presented in Figure 1
(entry 3). With the IMes-containing complex 3, the reaction
was found to be slow and after 5 h at 408C, only 51% of
Figure 1. Ball-and-stick representation of metathesis product 11a.
product 11a was isolated (entry 4). To accelerate the reac-
tion, this experiment was repeated at 808C giving complete
conversion after only 30 min (entry 5). As indicated by
1H NMR spectroscopy, two products were observed in the
reaction crude. Compound 11a is the major product, but
1
small amounts of another product having similar H NMR
chemical shifts, differing only by a few tenths of a ppm, was
identified as the fused bicycle 11c. Unfortunately, the poor
solubility of these products prevents their separation. To the
best of our knowledge, this type of fused bicyclic compound
has not been reported to date as a metathesis product of
linear dienynes. Compound 11c was also detected in the re-
action products performed by using catalyst 4 in a more im-
portant ratio (entries 6 and 7). Compound 5 bearing IPr
showed a different activity with 10, since the bicyclic com-
pound 11a is still the major product, but the byproduct was
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Homogeneous Catalysis
FULL PAPER
identified as the five-membered cycle 11b when the reaction
was conducted at 408C (entry 8). Repeating the reaction at
808C allowed the reaction to reach completion and 11b was
not detected under these conditions.
When the more hindered di-
Mechanistic studies: In enyne metathesis, the mechanism[6b]
at play is still a matter of debate. The question asked is
whether an “ene-then-yne”[34] or a “yne-then-ene” pathway
is involved.[35] In order to shed more light on the matter, we
enyne 12 was employed, cata-
lyst 2 led to unchanged starting
material after 2 h at 808C
(entry 10, Table 3). It seems
that phosphine-containing com-
plexes are not capable of acting
on dienynes possessing sterical-
ly hindred C=C bonds. When
NHC-based
catalysts
were
used, surprisingly, completely
different products were isolated
as a function of the NHC (en-
tries 11–13).
Whereas
the
SIMes complex 4 led only to
the formation of six-membered
ring products, the bicycle 13c
and the monocycle 13d, IMes-
and IPr catalysts 3 and 5, re-
Scheme 1. Proposed mechanism for the formation of isolated products A–D.
spectively, gave only the five-
membered cycles 13a and 13b.
It should be noted that poor
yields with 5 are due to a rapid degradation of the catalyst
and so 29% of unreacted starting material were also isolat-
ed in this instance (entry 13). While the explanation of activ-
ity difference between complexes bearing IMes and SIMes
ligands is still a matter of debate,[33] for the first time these
catalysts were found to exhibit a totally different reactivity.
For all products 13 suitable crystals for single-crystal diffrac-
tion studies were obtained. Ball-and-stick representations
considered both pathways with the dienyne substrates
shown in Scheme 1. According to the “ene-then-yne” path-
way, the intermediate E is obtained and a first metathesis
cyclization leads to the second intermediate F. A second
cyclization allows for the formation of product A, whereas
an elimination of the methylidene species through a meta-
thesis reaction with another substrate molecule yields prod-
uct B. Following the “yne-then-ene” pathway, intermediate
G is generated which could produce either a five-membered
ring cyclization leading to B or the six-membered ring cycli-
zation affording D. Further cyclization of B and D allow for
the formation of the corresponding bicyclic compounds A
and C. Interestingly, this second pathway can explain the
formation of all products obtained here, whereas the “ene-
then-yne” mechanism permits to explain only the formation
of five-membered ring compounds A and B.
1
are presented in Figure 2. Moreover, the H NMR spectra of
The reversibility of the metathesis process was consid-
ered; however, since unstrained five- or six-membered rings
containing conjugated C=C double bonds are formed, this
reversibility seems unlikely. The alternative “ene-then-ene”
pathway presented in Scheme 2 was also considered. How-
Figure 2. Ball-and-stick representations of products 13.
each product permits, by analogy, to confirm the correct
identity of all other cyclized products obtained in the course
of this study.
Scheme 2. Alternative “ene-then-ene” pathway.
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S. P. Nolan, L. Cavallo et al.
ever, in the course of this study products of the J structure
could not be observed. At this point, we conclude that the
unambiguously established structures of 13c and 13d are a
testimony to the existence of the “yne-then-ene” pathway.
Nevertheless these six-membered products were obtained
only when second-generation catalysts were used, suggesting
that this pathway might be applicable only to NHC-contain-
ing complexes. Moreover, products of types C and D were
observed in higher amounts when substrates possessing ster-
ically hindered C=C bonds were employed, suggesting that
for unhindered substrates the “ene-then-yne” pathway may
be preferred.
Another question that arises is whether the monocyclized
products B or D are intermediates in the formation of bicy-
clic compounds A and C. To attempt to provide an answer
to this question, the cyclization reaction from the nonsteri-
cally congested 11b was carried out by using catalysts 2 and
4 (Scheme 3). After 24 h at 408C, complex 2, bearing two
that catalyst 2 is ineffective towards a hindered substrate,
because it reacts exclusively according to the “ene-then-
yne” mechanism. The active species is apparently unable to
ꢁ
coordinate to C C triple bonds, if this was not the case, in-
termediate G would lead to the formation of at least one
monocyclic product.
Concerning second-generation catalysts, we believe a
competition between both mechanisms exists. Thus the
products isolated at the end of dienyne metathesis depend
on the mechanism and consequently on several parameters.
Increasing the steric hindrance around the C=C bonds will
favor the “yne-then-ene” pathway. However, as will be pre-
sented in the following section, increasing the congestion
ꢁ
around C C bond should lead to a preference for the “ene-
then-yne” mechanism. NHC steric parameters should also
play a crucial role in the cyclization of the intermediate G
affording five- or six-membered ring when the “yne-then-
ene” pathway is adopted.
DFT calculations: To achieve more meaningful insights into
this complex mechanistic manifold we performed focused
DFT calculations. In fact, due to the size and number of spe-
cies to locate for a complete characterization of the chemis-
try shown in Scheme 1 (approximately 30 structures for each
catalyst for a total of 100 structures if 2, 4, and 5 are com-
pared) we focused on some selected steps. We thus concen-
trated on the starting reaction of substrates 6 and 8 with cat-
alysts 2, 4, and 5, leading to intermediates E and G. The ele-
mentary steps and the relative labeling are shown in
Scheme 5. The indenylidene group of the starting pre-cata-
lyst was replaced by a methylidene, as should occur during
the majority of the productive steps.
Scheme 3. Formation of A product form from monocycle B.
tricyclohexylphosphine ligands, did not afford the bicycle
11a. This, in addition to the fact that with catalyst 2 no mon-
ocylized products B were isolated, demonstrates that for 2
the sequence E!F!A is a nonstop process. On the other
hand, after 4 h at 408C, 87% of 11a was isolated when the
SIMes-containing catalyst 4 was employed. This is support-
ing evidence for the higher activity of second-generation
catalysts.
We were intrigued by the lack of activity of PCy3-contain-
ing complex 2 towards hindered substrates such as 8 and 12,
whereas for their non-hindered congeners, reactions were
found straightforward. Catalyst 2 was employed for the
metathesis of the dissymmetrical dienyne 14 (Scheme 4).
Since 46% of bicycle 15a was isolated, we conclude that the
presence of a methyl group at one terminal olefinic position
does permit the second ring-closing metathesis. We reasoned
Scheme 5. Reaction steps leading to intermediates E and G.
Figure 3 displays the energy profile of the steps shown in
Scheme 5 for the smaller substrate 6. Focusing on the sub-
strate capture step from the naked 14 e [LCl2Ru=CH2] spe-
cies, yne coordination is favored relative to ene coordination
by 5.3, 1.9, and 4.3 kcalmolꢀ1 with 2, 4, and 5, respectively,
leading to the corresponding coordination intermediates
CO-ene and CO-yne. In terms of absolute coordination en-
Scheme 4. Metathesis of dissymmetric dienyne 14.
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Homogeneous Catalysis
FULL PAPER
alysts.[36] Coordination of the O atom of the substrate
(Ecoord =ꢀ9.3, ꢀ13.7, and ꢀ9.6 kcalmolꢀ1 for 2, 4, and 5, re-
spectively) is not competing with ene and yne coordination
in 4 and 5, while it competes with yne coordination in 2.
Moving to the first metathesis step, in all cases the transi-
tion state originating from yne coordination (TS1-yne in
Figure 3) is higher in energy relative to the transition state
originating from ene-coordination (TS1-ene in Figure 3).
This preference is 3.5, 3.3, and 5.5 kcalmolꢀ1 in 2, 4, and 5,
respectively. Importantly, for the NHC-based catalysts 4 and
5 both transition states are well below in energy relative to
the naked 14e species plus uncoordinated 6, whereas for the
PCy3-based catalyst
2
transition state TS1-ene is
3.8 kcalmolꢀ1 below the naked 14e species plus 6 and, re-
markably, transition state TS1-yne is almost isoenergetic
with the naked 14e species plus uncoordinated 6. Consider-
ing that entropic effects (not included in the present calcula-
tions) would add a TDS contribution that would decrease
the free energy of coordination of the substrate, it is possi-
ble to conclude that 6 would dissociate from the metal
rather than proceeding through TS1-yne, and thus the yne-
then-ene pathway with 2.
Moving to the metallacycles MC-ene and MC-yne, they
represent quite stable intermediates with all the catalysts
considered, with the MC-yne species roughly 15 kcalmolꢀ1
more stable than the corresponding MC-ene species. The
higher energy gain associated with formation of MC-yne is
easily rationalized considering that the standard enthalpy of
formation of ethane, ethene, and acetylene[37] indicates that
the acetylene!ethene transformation, which can be associ-
ated with the metathesis of the yne functionality to yield the
MC-yne intermediate, is favored by 9.5 kcalmolꢀ1 relative to
the ethene!ethane transformation, which can be associated
with the metathesis of the ene functionality to yield the
MC-ene intermediate. Finally, opening of the MC-ene and
MC-yne intermediates through transition states TS2-ene and
TS2-yne leads to intermediates E and G of Scheme 1 and 5.
In all the cases these steps present a quite similar energy
barrier, which suggests the selectivity between the yne-then-
ene and ene-then-yne pathways occurs when the coordinat-
ed substrate 6 first reacts through transition states TS1-ene
or TS1-yne.
At this point, to fully rationalize the experimental data
we investigated the possible evolution of intermediate G,
which is considered to be the key intermediate leading to
formation of the monocyclic products 7b and 7d. Since G is
an intermediate along the “yne-then-ene” pathway, which is
viable only for the NHC catalysts, we focused on 4 and 5.
The corresponding energy profile is reported in Figure 4 and
sketched in Scheme 6. First of all, coordination of the C=C
bond at the end of short arm of the alkylidene of intermedi-
ate G (labeled as G-b in Scheme 6 and Figure 4 because it
leads to product 6b) is somewhat favored relative to coordi-
nation of the C=C bond at the end of long arm (labeled as
G-d in Scheme 6 and Figure 4 because it leads to product
6d). However, with catalyst 4 this order of stability is revert-
ed at the transition state of the metathesis step, with the
Figure 3. Energy profile for the steps leading to intermediates E and G
for substrate 6.
ergies, Ecoord, both the NHC-based active species (Ecoord
=
ꢀ17.3 and ꢀ15.8 kcalmolꢀ1 for 4 and 5, respectively) coordi-
nate the substrate better than the PCy3-based active species
(Ecoord =ꢀ9.9 kcalmolꢀ1) by more than 5 kcalmolꢀ1. This
result is in agreement with our previous report that NHC-
based catalysts bind ethene better than phosphine-based cat-
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S. P. Nolan, L. Cavallo et al.
Moving to the bulkier substrate 8, we only discuss the
first part of the energy profile shown in Scheme 5, up to
metallacycles MC-ene and MC-yne, since our analysis on
substrate 6 clearly indicates that the selectivity between the
“ene-then-yne” and the “yne-then-ene” pathways occurs at
the level of transition states TS1-ene and TS1-yne. The data
reported in Figure 5 indicate that, as expected, coordination
of 8 is somewhat destabilized relative to coordination of 6
by steric interactions between the catalyst framework and
Figure 4. Energy profile for the steps leading to five- and six-membered
products 6b and 6d, respectively, from intermediate G.
Scheme 6. Reaction steps leading to five- and six-membered products
from intermediate G.
transition state leading to formation of the six-membered
ring of TS-d is clearly favored. Differently, with catalyst 5 it
is the transition state leading to formation of the five-mem-
bered rings of TS-b that is favored, although only by
0.4 kcalmolꢀ1.
Our data suggest that with substrate 6 the only viable
pathway is the “ene-then-yne” pathway with catalyst 2, be-
cause substrate 6 prefers to dissociate rather than to proceed
through the “yne-then-ene” pathway. Differently, for the
NHC-based catalysts 4 and 5 both pathways are possible, al-
though the ene-then-yne pathway presents a transition state
that is lower in energy. Furthermore, starting from inter-
mediate G, we found that the formation of the six-mem-
bered ring of product 7d is favored with catalyst 4, whereas
formation of the five-membered ring of product 7b is fa-
vored with catalyst 5. These conclusions are in qualitative
agreement with experimental data reported in Table 1.
Figure 5. Energy profile for the steps leading to intermediates MC-ene
and MC-yne for substrate 8.
the additional methyl groups of 8. These additional steric in-
teractions are also responsible for the higher energy of the
TS1-ene and TS1-yne transition states and, as logical, are
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Homogeneous Catalysis
FULL PAPER
more severe for the TS1-ene transition state, since one of
the additional methyl group of 8 is directly involved in the
metathesis step. As a consequence, there is a clear reduction
of the preference for the TS1-ene versus the TS1-yne transi-
tion state, which suggests that with the bulkier substrate 8
the “yne-then-ene” pathway becomes more competitive. Al-
though it would have been nice to have the TS1-yne transi-
tion state lower in energy than the TS1-ene transition
state,[38] our results are in qualitative agreement with the ex-
perimental observation that with the NHC-based catalysts 4
and 5 the amount of the six-membered product is increased
when moving from substrate 6 to 8. Finally, in the case of
the PCy3-based catalyst 2, both the TS1-ene and TS1-yne
transition states are higher in energy than the naked 14 e
species plus uncoordinated 8, which could explain the ab-
sence of reactivity experimentally observed.
tion changed the product distribution and only product A
was obtained for all catalysts when these more hindered
substrates were tested. Dienyne 16 reacted rapidly and
quantitatively with catalyst 2 affording the bicyclic com-
pound 17a (entry 1). All NHC-containing complexes also
lead to the formation of 17a in good to excellent isolated
yields. While reactions proceeded in relatively short reaction
times with catalysts 3 and 5 (5 h at 408C, entries 2 and 4),
catalyst 4, bearing the SIMes ligand, required 24 h at 408C
to provide 82% of 17a. This lower activity could be ex-
plained by the fact that increasing the steric hindrance near
ꢁ
the C C bond may favor the “ene-then-yne” pathway, but
the formation of the intermediate F should be somewhat
ꢁ
more difficult. When the C C bond is more sterically en-
cumbered, such as in substrate 18, all complexes exhibited
an expected reduced activity and only product 19a was ob-
served. With catalyst 2, only a 42% yield was reached, and
even 5 h of reaction at 408C did not improve this conversion
(entries 5 and 6). Using complex 4, quantitative yield was
obtained but heating at 808C was required (entries 7 and 8).
The IPr-containing catalyst 5 afforded a 39% yield of prod-
uct 19a (entry 9). With these catalysts, comparable results
were obtained with dienyne 20
Scope of the reaction: Next, we investigated the scope of
this dienyne metathesis catalyzed by the indenylidene-based
complexes. We first examined the effect of substitution
ꢁ
around the C C triple bonds (Table 4). Overall, introduc-
tion of one or two methyl groups close to the alkyne func-
leading to the spirocycle 21a as
the unique product (entries 10–
13). These substrates attest to
Table 4. Influence of dienyne substitution.[a]
Substrate
Catalyst
Reaction
Product
(isolated yield [%])
conditions
the superior activity and/or
thermal stability of complex 4
bearing the SIMes ligand over
other catalysts. Thus, 4 is the
best catalyst choice for hin-
dered or less reactive substrates
necessitating an important ther-
mal activation.
1
2
3
4
2
3
4
5
DCM, 258C, 1 h
DCM, 408C, 5 h
DCM, 408C, 24 h
DCM, 408C, 5 h
17a (97)
17a (92)
17a (82)
17a (87)
5
6
7
8
9
10
11
12
13
2
2
4
4
5
2
4
4
5
DCM, 258C, 5 h
DCM, 408C, 5 h
DCM, 408C, 8 h
toluene, 808C, 1 h
toluene, 808C, 1 h
DCM, 258C, 5 h
DCM, 408C, 8 h
toluene, 808C, 1 h
toluene, 808C, 1 h
19a (42)
19a (37)
19a (54)
19a (93)
19a (34)
21a (33)
21a (29)
21a (74)
21a (43)
When the steric hindrance
ꢁ
around both C=C and C C
bonds of the dienyne was in-
creased, heating to 808C was
required (entry 15). Under
these conditions, catalysts 3 and
5 displayed moderate activity as
small amounts of the bicyclic
product 23a and modest quanti-
ties of its monocyclized relative
23b were isolated (entries 14
and 17). Using catalyst 4, the
product distribution was found
14
15
16
17
3
4
4
5
toluene, 808C, 2 h
DCM, 408C, 8 h
toluene, 808C, 1 h
toluene, 808C, 2 h
23a (10)/23b (44)
[b]
–
23a (16)/23b (70)/23d (11)
23a (7)/23b (31)
significantly
different
(entry 16). The six-membered
ring compound 23d was isolat-
ed, supporting the “yne-then-
ene” mechanism occuring for
this substrate/catalyst combina-
tion. With the very sterically
hindered dienyne 24, no prod-
uct formation could be detected
(entry 18).
[b]
18
4
toluene, 808C, 5 h
–
[a] Reaction conditions: substrate (0.5 mmol), catalyst (2 mol%), solvent (5 mL; c=0.1m) in a Schlenk flask
under Ar atmosphere. [b] Starting material recovered.
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10251

S. P. Nolan, L. Cavallo et al.
Table 5. Influence of functional groups.[a]
Substrate Catalyst
required to reach any product
conversion (Scheme 8). Where-
as the IPr–indenylidene 5 could
Reaction
conditions
Product
(isolated yield [%])
1
2
3
4
5
6
2
3
4
4
5
5
DCM, 258C, 1 h
toluene, 808C, 2 h
DCM, 408C, 8 h
toluene, 808C, 0.5 h
DCM, 408C, 3 h
toluene, 808C, 4 h
26a (99) not lead to any product forma-
26a (98)
tion, its SIMes counterpart af-
forded after 24 h at 408C, 66%
of 31a and 25% of the mono-
26a (62)
26a (99)
26a (50)
cyclized product 31b. Of note,
the structure of 31b has been
confirmed by single-crystal X-
26a (96)
[b]
7
8
9
2
4
4
DCM, 408C, 24 h
DCM, 408C, 24 h
toluene, 808C, 5 h
–
[b]
–
[b]
ray analysis;
a ball-and-stick
–
representation is shown is
Figure 6. We recognize that the
formation of these products
could be a result of both reac-
tion pathways, since the cycliza-
[a] Reaction conditions: substrate (0.5 mmol), catalyst (2 mol%), solvent (5 mL; c=0.1m) in a Schlenk flask
under Ar atmosphere. [b] Starting material recovered.
Next, we turned our attention to the effect of functional
groups on the dienyne. These results are presented in
Table 5. With the malonate-based substrate 25, only the A-
type product 26a was isolated with all catalysts (entries 1–
6). Whereas using the first-generation catalyst, the reaction
reached completion easily at room temperature (entry 1),
second-generation catalysts gave moderate yields at 408C
(entries 3 and 5) and so heating to 808C was necessary to
provide complete conversion with these catalysts (entries 2,
4, and 6). We believe the ester functions increase the steric
Scheme 8. Reaction on the hindered dienyne 30.
ꢁ
bulk around the C C bond and consequently disfavor both
activity and the “yne-then-ene” pathway. Besides modulat-
ing steric hindrance of the alkene functions to encourage
ꢁ
the C C bond coordination, electronic effects can also be
examined. Dienyne 27 possessing electron poor C=C double
bonds was used as substrate; unfortunately neither the first-
generation complex 2 nor the best catalyst 4 were able to
promote any reaction (entries 7–9).
We were interested in examining if the competing forma-
tion of five- versus six-membered rings could also be present
in six- versus seven-membered rings. Thus dienyne 28 when
subjected to PCy3-containing catalyst 2 leads to the bicyclic
product 29a (Scheme 7). Catalyst 4, possessing the NHC
Figure 6. Ball-and-stick representation of metathesis product 31a.
tion of the intermediate G should lead to the thermodynam-
ically more stable six-membered ring.
Conclusions
Scheme 7. Reaction on dienyne 28.
In summary, we have presented a study on enyne metathesis
for the formation cyclic compounds using Ru-based com-
plexes bearing the indenylidene scaffold. Chemodivergent
metathesis transformations have been observed as a func-
tion of the substrate, but also as a function of the L ligand
borne on the active catalytic species. Differences were ob-
served between first- and second-generation metathesis cat-
alysts, bearing a phosphine and a N-heterocyclic carbene, re-
spectively. Unexpectedly, significant differences in products
ligand SIMes, which exhibited the best ability for the forma-
tion of larger rings, was also employed and 29a was equally
obtained in quantitative yield without traces of other prod-
ucts.
When 30, the hindered analogue of 28, was used as sub-
strate, the reaction proved difficult and 5 mol% catalyst was
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Homogeneous Catalysis
FULL PAPER
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Experimental Section
Details of the syntheses and characterization of the compounds reported
herein can be found in the Supporting Information.
Acknowledgements
Funding for this project was generously provided by the EC through the
seventh framework program through grant CP-FP-211468-2-EUMET.
Umicore AG is gratefully acknowledged for the generous gift of materi-
als. S.P.N. (research grant) and H.C. (postdoctoral fellowship) both ac-
knowledge the Ministerio de Educaciꢃn y Ciencia (Spain) as well as the
ICIQ Foundation for partial support of this work. S.P.N. is an ICREA
Research Professor.
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Received: April 13, 2009
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Published online: August 26, 2009
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