Rational design and evaluation of upgraded Grubbs/Hoveyda olefin metathesis catalysts: Polyfunctional benzylidene ethers on the test bench

Article abstract of DOI:10.1021/om200463u

The series of upgraded Grubbs/Hoveyda second-generation catalysts (H ₂IMes)(Cl)₂Ru=C(H)(C₆H₄OR) (E2 (71% yield), R = CH(Me)(C(O)OMe); M2 (58% yield), R = CH(C(O)OMe)₂; Kme2 (88% yield), R = CH₂

Full text of DOI:10.1021/om200463u

ARTICLE
pubs.acs.org/Organometallics
Rational Design and Evaluation of Upgraded Grubbs/Hoveyda Olefin
Metathesis Catalysts: Polyfunctional Benzylidene Ethers on the
Test Bench†
‡
Michaz Bieniek,‡ Cezary Samojzowicz,‡ Volodymyr Sashuk,‡,^ Robert Bujok, Pawez Sledꢀz,‡,r No€el Lugan,§
ꢀ
Guy Lavigne,*,§ Dieter Arlt,||,# and Karol Grela*,‡
‡Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
§Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France
University of Cologne, Albertus-Magnus-Platz, 50923 K€oln, Germany
S Supporting Information
b
ABSTRACT: The series of upgraded Grubbs/Hoveyda second-generation catalysts
(H2IMes)(Cl)2RudC(H)(C6H4OR) (E2 (71% yield), R = CH(Me)(C(O)OMe);
M2 (58% yield), R = CH(C(O)OMe)2; Kme2 (88% yield), R = CH2C(O)Me; Ket2
(63% yield), R = CH2C(O)Et); C2 (58% yield), R = C(Me)CN) were prepared by the
reaction of the Grubbs second-generation catalyst (H2IMes)(Cl)2Ru(CHPh)(PCy3)
(G2) with the appropriate ortho-substituted ether H(Me)CdCHC6H4OR in the
presence of CuCl as a phosphine scavenger. The X-ray structures of these complexes
reveal that the terminal oxygen of the ester, ketone, or malonate group installed as the
terminal substituent of the benzylidene ether is coordinated to the metal, giving an octahedral structure. In contrast, the nitrile
group of the complex C2 remains uncoordinated. Even more sophisticated complexes, incorporating both a coordinating group
R (ester or ketone) as a terminal substituent of the ether and an electron-withdrawing group X (NO2 or C(O)Me) on the
aromatic ring, were synthesized: (H2IMes)(Cl)2RudC(H)[(C6H3X)OR] (NE2 (69% yield), R = CH(Me)(C(O)OMe), X =
NO2; KE2 (57% yield), R = CH(Me)(C(O)OMe), X = C(O)Me; KK2 (56% yield), R = CH2C(O)Me, X = C(O)Me). All these
complexes were used as catalyst precursors in standard metathesis reactions and compared with commercial catalysts such as
Grubbs II (G2), Grubbs/Hoveyda II (H2), and Nitro catalyst (N2). The catalysts NE2, KE2, N2, and M2 exhibit excellent
performances in the RCM of diallyl malonate or the RCM of diallyltosylamide at 0 ꢀC. The catalysts M2, N2, and Kme2 are also
very efficient for the RCM of allyl methallyl malonate to yield a trisubstituted olefin. The same complexes are also active for cross-
metathesis, and several low-loading tests are also presented. Finally, a very challenging example of the synthesis of BILN 2061
(hepatitis C virus HCV NS3 protease inhibitor having antiviral effect in infected humans) is presented, where the best
performances are recorded with E2 (95% conversion) and N2 (93% conversion). The enhanced activity of the reported
complexes is understood in terms of their enhanced stability and their ability to liberate progressively and continuously the active
species in solution.
Chart 1
’ INTRODUCTION
A major outcome of modern discoveries in the field of olefin
metathesis1 is certainly elevation of the art and science of
chemical synthesis and a significant enlargement of chemists’
view of their own synthetic possibilities.2 Indeed, with Grubbs
catalysts offering a proper solution to most current olefinic CdC
bond activation problems, investigators can now envision more
innovative and environmentally compatible synthetic procedures
at lower time, energy, and money costs.3,4 For current applica-
tions, commercially available first- and second-generation cata-
lysts G1 ((PCy3)2(Cl)2RudC(H)(C6H5)) and G2 are already
remarkably efficient in terms of activity, selectivity, and func-
tional group tolerance (Chart 1).5 As underscored by several
authors,6,7 the user’s choice may need to be guided when more
challenging transformations are to be achieved, due to the very
large “galaxy”7 of contemporary enhanced catalysts8 which are
now available from the literature.
Within the latter category, Hoveyda catalysts H1 ((PCy3)-
(Cl)2RudC(H)(C6H4-2-OPri), not shown in Chart 1) and their
Received: May 30, 2011
Published: July 11, 2011
r
2011 American Chemical Society
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Scheme 1. Basic Working Principle of Hoveyda Catalysts
relevant second-generation Grubbs/Hoveyda congeners H29
(now existing in upgraded chiral versions)10 also including
Blechert catalysts B211 continue to attract considerable attention
from both academic and applied viewpoints, because, at least on
their basic working principle, they are intrinsically offering a
conceptually original solution to the problem of catalyst recovery.
Hoveyda type precatalysts (drawing A in Scheme 1) incorporate
a chelating o-isopropoxybenzylidene moiety, in which the lightly
coordinating ether function serves as a lock for the active site.
Though the enhanced activity of such catalysts was originally
ascribed to a dissociative mechanistic pathway,9,12 some intriguing
observations13 and recent kinetic studies by Plenio14 have led to
the proposal that the olefinic substrate participates in the rate-
limiting step of the initiation reaction. According to such studies
(Scheme 1), decoordination of the ether in the presence of an
incoming olefin gives the adduct B and triggers the initiation step
by allowing formation of the key metallacyclobutane C via [2 + 2]
cycloaddition.15 Subsequent cycloreversion leads to D, from
which the styrenyl ether can be released in solution, thereby
generating the key 14e complex16 arising as the active propagating
species. After total consumption and transformation of the
olefinic substrate, the styrenyl ether may be recaptured by
the active species in the termination step, thus regenerating
the precatalyst in its resting state A. However, at least for the
unmodified Hoveyda catalysts H2, the practical effectiveness of
the “return” process has been recently questioned, on the basis of
simple and reliable experimental observations.17
Therefore, a fast release of the styrenyl ether corresponds to a
high initiation rate, whereas its ability to catch back the propagat-
ing species in the return process (reverse sequence from D to A)
is crucial for catalyst recovery. In the footprints of Hoveyda and
Blechert, we have attempted to enhance the leaving-group
properties of the ether through various approaches. The original
modifications made in Warsaw consisted of the introduction of
certain electron-withdrawing substituents, such as NO2, on the
aromatic ring in a para position relative to the isopropoxy unit,
with the aim of labilizing the bonding interaction between the
oxygen of the ether function and the metal. Such a strategy
proved to be valuable, giving in particular our very efficient
“nitro-Hoveyda” catalyst N2 shown in Chart 1,18 exhibiting a
high initiation rate and a broad application scope.19 In this
context, recent DFT calculations have led to the proposal that
both the enhanced activity of this catalyst and its recovery are
dependent on the π delocalization between the phenyl and the
carbene.20
Hoveyda catalyst, where the added ester group coordinates to
the metal, thereby contributing to the overall stability of the
complex.
The very positive catalytic tests carried out from such a
prototype led us to realize that, as also noted by other authors,23
the global efficiency of an olefin metathesis catalyst is not only
due to its ability to generate rapidly the active 14e species, but is
in fact the result of a subtle balance between antinomic properties,
where the stability of the precatalyst plays an important role.22 In
line with these observations, we see in the very recent literature a
renewed interest in precatalysts exhibiting enhanced stability (in
which, for example, the leaving group is an N-heterocyclic
carbene,24 reminiscent of the pioneering work of Herrmann),25
also including latent photo- or thermoswitchable catalysts.26
In a logical continuation of our preliminary investigation,22
other functional groups were installed as terminal substituents of
the benzylidene ether ligand and their respective benefits were
evaluated in a series of test reactions presented here. As shown
below, we also explored the possibility of obtaining upgraded
versions of our various catalysts combining their respective
characteristics: namely, the presence of an electron-withdrawing
group as a terminal substituent of the ether and of a second group
on the aromatic ring of the benzylidene group. The full results of
this collaborative investigation22 are disclosed in the present
paper, where the performances of the new catalysts, some of
which are now at the point of being commercialized, are also
compared with those of the known benchmark prototypes G2,
H2, N2, and B2.
’ RESULTS AND DISCUSSION
According to a general procedure originally disclosed by
Hoveyda,9 second-generation Grubbs/Hoveyda type catalysts
are directly accessible from a Grubbs second-generation catalyst
through a straightforward stoichiometric ligand exchange based
on a metathesis cycle where an incoming styrenyl ether serves as
the source of the benzylidene ether ligand.
A. Original Design of a New Grubbs/Hoveyda Catalyst by
Reaction of G2 with an Ester-Substituted Styrenyl Ether. In
the present approach, the appropriate carbene ligand precursor,
an ester-substituted styrenyl ether, was prepared by reaction of
the commercially available 2-(1-propenyl)phenol with methyl
bromopropionate in the presence of a base (Scheme 2, eq 1). It
was then reacted with Grubbs II catalyst in the presence of
copper(I) chloride, commonly used as a phosphine scavenger,9
Encouraged by the success of catalyst N2, we were prompted
to replace the terminal isopropyl substituent of the hemilabile
ether functionality by an ester group, originally selected also on
account of its electron-withdrawing properties. These initial
experiments21,22 led to the isolation of the new complex E2,
representing an unprecedented structural type of modified
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Scheme 2. Stepwise Preparative Procedure of the Catalyst E2
purification through a chromatographic column, with both of
these properties representing a beneficial practical advantage.
B. Extended Design of Malonic-, Ketyl-, and Nitrile-Func-
tionalized Grubbs/Hoveyda Catalysts. In a logical extension of
the above synthetic route, we were prompted to devise a full
palette of new catalysts differing in the nature of the potential
donor group installed as a terminal substituent of the benzylidene
ether (Scheme 3).
Scheme 3. New Precatalysts Generated from
Monofunctionalized Styrenyl Ethers
The procedure used for their individual preparation was
directly inspired from that shown in Scheme 2 for catalyst E2,
using the specific experimental conditions given in Table 1 for
the organic ligand precursors and in Table 3 for the complexes.
Thus, in a series of parallel typical experiments, commercially
available 2-(1-propenyl)phenol was coupled with the appropri-
ate substrate RꢀX, in the presence of a base. In most cases, using
carbonate as a base produced the coupled product in satisfactory
yields, except when dimethyl 2-chloromalonate was used as a
coupling partner (entry 2, 37% yield). Even in that case, however,
a major improvement was possible by using NaH as a stronger
base and a slightly higher temperature, affording the malonate
product in 81% yield. The syntheses of the corresponding
precatalysts from these ligands proceeded cleanly in dichloro-
methane, on the model of eq 2 in Scheme 2. The progress of
these reactions was monitored by thin-layer chromatography in
order to optimize the reaction time. A comparative analysis of the
optimized yields and experimental conditions necessary for the
generation of these precatalysts is provided in Table 3. It is
noteworthy that the ketonic catalysts can be generated under
milder conditions and within a shorter time than the others. In
contrast, and very strangely, the presence of a phenyl ring as a
substituent of the ketonic fragment (Table 3, entry 7) led to a
very unstable catalyst which could not be isolated, possibly due to
its steric hindrance, an observation revealing the importance of
subtle ligand modifications on the reactivity of Hoveyda catalysts.
As mentioned in the Introduction, an additional series of
“upgraded” precatalysts incorporating two electron-withdrawing
groups, namely, X (esteric or ketonic) on the ether and Y (nitro
or acyl) on the para position of the aromatic ring relative to the
ether, were also synthesized (Scheme 4).
to afford the desired precatalyst E2 (Scheme 2, eq 2), recovered
in 71% yield in the form of a green crystalline compound.
An X-ray structure analysis of complex E222 revealed that the
global arrangement of ligands around the metal center has
characteristics in common with those found in a classical
Grubbs/Hoveyda II-type complex, similarly showing the NHC
in an apical position, the two mutually trans halides and the
carbenic carbon of the chelating carbene ligand occupying the
equatorial plane, and the ether group of the chelating carbene
occupying the trans position relative to the NHC, with a
Ru(1)ꢀO(1) distance of 2.207(2) Å, which is significantly
shorter than the corresponding distance of 2.256(1) Å found
in the parent H2 complex. An additional characteristic geome-
trical feature, however, was found to be the occurrence of a weak
bonding interaction, Ru(1)ꢀO(2) = 2.535(1) Å, between the
terminal oxygen of the ester functionality and the ruthenium
center, thus completing an octahedral basis set.27 Intuitively,
these geometrical parameters might be indicative of a better
stabilization of the metal center, and further manipulation of the
complex effectively revealed its enhanced stability in air, parti-
cularly in the solid state, as well as in solution, allowing its easy
The bifunctionalized styrenyl ethers required for their pre-
paration were obtained according to the experimental proce-
dures shown in Table 2. It is noteworthy that the preparation of
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Table 1. Syntheses of Monofunctionalized Styrenyl Ethers
The respective molecular structures of the two complexes are
shown in Figure 1, along with a selection of interatomic distances
and bond angles.
Both of these complexes are isostructural with the ester
derivative E2, with the metal being in the same distorted-
octahedral environment. Here, the interatomic distance Ru(1)ꢀ
O(1) between the ether oxygen and the metal is only 2.1991(19)
Å for Ket2 and 2.2232(18) Å for Kme2, which to our
knowledge28 represents the shortest RuꢀO distances reported
so far for a chelating Hoveyda-type carbene. In addition, the
interatomic distance (Ru(1)ꢀO(2) = 2.551 Å for Ket2 and
Ru(1)ꢀO(2) = 2.529 Å for Kme2) between the carbonyl group
and the metal center are similar to that for E2 (Ru(1)ꢀO(2) =
2.536 Å), though the difference between the two is probably not
chemically significant. The structure of the malonate derivative
M2 is shown in Figure 2.
Since we have here a more electron-withdrawing group as a
terminal substituent of the ether, one would intuitively expect the
RuꢀO(ether) distance to be longer, and this is effectively the
case, since the actual value, Ru(1)ꢀO(1) = 2.2780(9) Å, is about
0.1 Å longer than those for the keto complexes (vide supra).
Nevertheless, the malonate group adopts a geometry where one
of its carbonyl groups lies in the plane of the chelating carbene
and is pointing toward the Ru center, even if, in that case, the
corresponding interatomic distance Ru(1)ꢀO(2) = 2.775 Å,
geometrically correlated with the magnitude of Ru(1)ꢀO(1), is
necessarily longer than in the previous case.
The structure of the nitrile-substituted derivative C2, shown in
Figure 3, is peculiar, since it does not show any “side-on” bonding
interation between the nitrile group and the metal center, the
nitrile group being oriented away from the main plane of the
chelating carbene ligand. Here, the Ru(1)ꢀO(1) distance is
2.2753(11) Å, the longest of the whole series of complexes
reported here and also slightly longer than that in the Hoveyda
prototype, but shorter than that in many of its congeners.26
D. Catalytic Activity of the New Complexes in RCM. Having
in hand a palette of benzylidene-modified ruthenium complexes
(Schemes 3 and 4), we first attempted to evaluate their respective
catalytic activities in RCM. The overall results are reported in
Table 4, whereas the kinetic plot of some specific entries are also
shown in Figures 4ꢀ6.
Scheme 4. New Catalysts Generated from Bifunctionalized
Styrenyl Ethers
a. RCM at 0 ꢀC. In order to compare the respective efficiencies
of the above complexes, we first used them in two parallel
standard RCM reactions, carried out in identical Schlenk tubes,
using diallyl malonate (Figure 4) and diallyltosylamide
(Figure 5) as substrates. Since the RCM in the presence of our
catalysts appeared to be too fast at room temperature to allow
accurate kinetic measurements, we were led to work at 0 ꢀC in
such a way to maximize possible differences between the
respective efficiencies of the precatalysts. The course of the
reactions was monitored by GC, and ethyl vinyl ether was
employed to quench the reactions at given time intervals.
The results shown in Figure 4 indicate first that all the ligand
modifications introduced in the present work result in an
enhancement of activity relative to that of the unmodified
Hoveyda catalyst, which appears as the least efficient of the
whole series. Though slightly better, Grubbs catalyst G2 is only
moderately efficient under such low-temperature conditions,
since its activity reaches a plateau after about 1 h (Figure 4),
giving a maximum conversion of 30%. Such a limitation, ob-
servable at low temperature, has already been noted by Grubbs
himself in a previous comparative analysis of a series of olefin
the ligands for keto esteric and keto ketonic catalysts required an
additional step consisting of a well established Ru-catalyzed
isomerization of the double bond. From these ligands, the
preparation of the complexes proceeded straightforwardly under
the experimental conditions depicted in Table 3.
C. Structural Analyses of the New Complexes. Some of the
precatalysts reported here, namely, E2, M2, Ket2, Kme2, and C2,
gave suitable crystals, which were subjected to X-ray structure
analyses. The structure of the prototype E2 has been briefly
described above and in a preliminary account of this work.22
Crystals of the new ketonic complexes Ket2 and Kme2 were
grown by slow evaporation of CH2Cl2/MeOH solvent mixtures.
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Table 2. Syntheses of Bifunctionalized Styrenyl Ethers
metathesis catalysts, where the same plateau was observed;6 it
may be due to catalyst decomposition via further attack of the
liberated phosphine onto the carbene center, with formation of a
phosphorus ylide,29 an observation which has been made in
several instances and highlights the advantage of working with
phosphine-free olefin metathesis catalysts.30 It is also noteworthy
that Blechert’s catalyst systematically exhibits excellent perfor-
mance and is (only slightly) surpassed by the polyfunctional
“nitro-ester” (NE2) and “keto-ester” (KE2) catalysts. The
monofunctionalized nitro catalyst N2 initiates slightly less ra-
pidly than Blechert’s but leads to a final conversion of 85%, which
is 10% superior to the latter. In addition, the ester catalyst E2
exhibits very good performance, remaining the most efficient of
the series of monofunctionalized catalysts having a coordinating
group as the terminal substituent of the ether. Very character-
istically, it initiates more slowly than Blechert’s catalyst B2 but
reaches almost the same conversion after 6 h. Also interesting is
the observation that a catalyst such as the nitrile derivative C2,
whose terminal CN ligand has no interaction with the metal
(side-on coordination is inoperative for nitriles), initiates more
rapidly than E2 but is surpassed by the latter after 4 h. For the
present series of catalysts, a glance at the shape of kinetic plots
indicates that the catalysts having a coordinating group as
terminal substituent of the ether are initiating at slightly lower
rate than the others but are reaching a comparable efficiency in
the long run, which seems to indicate that they have a longer
lifetime. This may reflect the fact that the active species is more
progressively generated from such stable precursors or may be also
indicative of a better ability of the pendant terminal donor group
of the styrenyl ether to catch back the metal center, resulting in a
more efficient precatalyst regeneration. About the same order of
activities is observed for the closely related RCM reaction shown
in Figure 4, which includes the case of the malonic derivative:
H2 < Kme2 < M2 < E2 < N2 < B2 < NE2. Also characteristically,
the malonic derivative, for which the interaction between the
malonic group and the metal center was noted to be very weak,
initiates very rapidly but is surpassed by the ester derivative E2
after less than 2 h.
b. RCM at Room Temperature (25 or 30 ꢀC). Under such
conditions, which are those of normal utilization, the differences
noted above between the performances of the new catalysts
examined here are reduced, whereas very good to excellent activities
are recorded. Of particular interest is the specific example of the
RCM of 2-allyl-2-methallylmalonate (entry 3 of Table 4 and
Figure 6), a more challenging case, since it involves the difficult
formation of a relatively sterically crowded trisubstituted double
bond. Whereas the conversion reached by the Hoveyda catalyst H2
after 30 min is still only 7%, the malonic catalyst M2 reaches 97%
conversion within the same time, which represents a spectacular
performance. Not surprisingly, and due to their close structural
similarities, the catalysts E2, M2, and Kme2 often exhibit very
comparably high performances, as illustrated in particular by the
RCM reactions of the substrates shown in entries 5 and 6.
E. Catalytic Activity in Cross-Metathesis Reactions. At the
present stage of our investigation, it was also of interest to test the
ability of our complexes to promote the CM reaction of electron-
deficient olefins, which are rather challenging substrates for
ruthenium catalysts. As shown in Table 5, almost all the reactions
were found to work at room temperature, with relatively low
catalyst loadings. A general analysis of the results shows that our
catalysts regularly match the performances of Blechert’s catalyst,
a very good reference for CM reactions. Here, the excellent
performances of the catalysts Ket2 and E2 (entries 2 and 3) and
NE2 (entry 5) are noteworthy. Substrate-dependent differences
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Table 3. Experimental Conditions for the Preparation of the Polyfunctional Precatalysts
a unstable complex seen to decompose during its attempted isolation.
from one catalyst to the other may be observed but remain
difficult to rationalize. In practice, it is noteworthy that the
catalysts generated from the monofunctionalized styrenyl esters,
exemplified by E2, already give very satisfactory results, indicat-
ing that there is no real systematic need to invest time in the
generation of the polyfunctionalized species. Furthermore, one
advantage of E2 is that it is insensitive to the presence of
impurities and can thus even work in an open tube in commer-
cial-grade dichloromethane solvent (Table 5, entry 1).
F. Low-Loading Tests. Attempts to reduce the catalyst
loading in metathesis transformations have been an important
area of research in recent years; this achievement would lower the
process costs, those associated not only with the catalyst but also
with the removal of residual ruthenium from products.3b,15 While
several catalysts can efficiently convert di- and trisubstituted
dienes into the corresponding RCM product in short reaction
times using classical catalyst loadings (1ꢀ5 mol %), at very low
loadings the catalyst loading limits are 0.0025 and 0.0250 mol %,
respectively, for the formation of di- and trisubstituted olefins;
however, these limits are under drybox conditions.31
Catalysts made by us were able to promote a number of model
reactions (Table 6) at loadings from 1.0 to 0.03 mol % outside of a
drybox. However, a further decrease of the catalyst loading
(below 0.03 mol %) showed the limit of these complexes. It
seems that, at loadings this low, the careful exclusion of air
becomes very important. This is especially visible for reactions
done on a relatively small scale (e1 mmol). We were pleased,
however, to observe that the more challenging CM reaction of
the sulfone S16 (Table 6, entry 4) could be achieved in air, using
only 0.2 mol % of the ester catalyst. This transformation run on a
preparative scale (3 g) produced P16 in excellent yield.
G. Synthesis of BILN2061 Precursor by RCM. Metathesis has
been successfully applied by Boehringer Ingelheim Pharma Inc.
in the synthesis of BILN 2061 (Ciluprevir), the first reported
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Figure 2. Perspective view of the catalyst M2, represented with
ellipsoids drawn at the 50% probability level. Selected interatomic
distances (Å) and bond angles (deg): Ru(1)ꢀC(1) = 1.9822(11),
Ru(1)ꢀC(4) = 1.8285(13), Ru(1)ꢀO(1) = 2.2780(9), Ru(1)ꢀ
Cl(1) = 2.3603(3), Ru(1)ꢀCl(2) = 2.3364(3); Cl(1)ꢀRu(1)ꢀ
Cl(2) = 163.629(14), C(1)ꢀRu(1)ꢀO(1) = 179.65(4), C(4)ꢀRu-
(1)ꢀO(1) = 80.16(5), C(1)ꢀRu(1)ꢀCl(2) = 93.28(3), O(1)ꢀRu-
(1)ꢀCl(1) = 85.29(3).
Figure 1. Perspective views of the catalysts Ket2 (top) and Kme2
(bottom). Ellipsoids are drawn at the 50% probability level. Selected
interatomic distances (Å) and bond angles (deg) are as follows. Ket2:
Ru(1)ꢀC(1) = 1.980(3), Ru(1)ꢀC(4) = 1.832(3), Ru(1)ꢀO(1) =
2.1991(19), Ru(1)ꢀCl(1) = 2.3608(9), Ru(1)ꢀCl(2) = 2.3620(9);
Cl(1)ꢀRu(1)ꢀCl(2) = 165.17(3), C(1)ꢀRu(1)ꢀO(1) = 176.05(10),
C(4)ꢀRu(1)ꢀO(1) = 80.58(10), C(1)ꢀRu(1)ꢀCl(2) = 90.43(8),
O(1)ꢀRu(1)ꢀCl(1) = 88.76(7). Kme2: Ru(1)ꢀC(1) = 1.985(2),
Ru(1)ꢀC(4) = 1.834(3), Ru(1)ꢀO(1) = 2.2232(18), Ru(1)ꢀ
Cl(1) = 2.3734(14), Ru(1)ꢀCl(2) = 2.3520(15); Cl(1)ꢀRu(1)ꢀ
Cl(2) = 165.79(3), C(1)ꢀRu(1)ꢀO(1) = 179.06(7), C(4)ꢀRu-
(1)ꢀO(1) = 80.56(10), C(1)ꢀRu(1)ꢀCl(2) = 95.51(8), O(1)ꢀRu-
(1)ꢀCl(1) = 84.71(7).
Figure 3. Perspective view of the catalyst C2. Ellipsoids are drawn at the
50% probability level. Selected interatomic distances (Å) and bond
angles (deg): Ru(1)ꢀC(1) = 1.9677(15), Ru(1)ꢀC(4) = 1.8290(16),
Ru(1)ꢀO(1) = 2.2753(11), Ru(1)ꢀCl(1) = 2.3300(4), Ru(1)ꢀ
Cl(2) = 2.3264(4); Cl(1)ꢀRu(1)ꢀCl(2) = 158.509(18), C(1)ꢀRu-
(1)ꢀO(1) = 176.73(5), C(4)ꢀRu(1)ꢀO(1) = 79.64(6), C(1)ꢀRu-
(1)ꢀCl(2) = 91.84(4), O(1)ꢀRu(1)ꢀCl(1) = 86.01(3).
hepatitis C virus (HCV) NS3 protease inhibitor to have shown
an antiviral effect in infected humans.32 The HCV infection is a
serious cause of chronic liver disease worldwide. The macrocycle
peptide BILN 2061 is the first compound of its class to have
reached clinical trials and to have shown oral bioavailability and
antiviral effects in infected humans. The key step in its prepara-
tion is the RCM of the diolefinic compound BILN1 (Table 7),
leading to the cyclic 15-membered olefinic compound BILN2.
The results show that the ester catalyst E2 is much more efficient
for this reaction than the parent Hoveyda complex H1 and even
outperforms the nitro catalyst N2 (Figure 7). This figure also
reveals that a highly beneficial protocol is to add the catalyst
stepwise in two portions, the first one initially (0.4 mol % Ru)
and the second one (0.2 mol % Ru) after 1 h.
H2, the ester complex E2 stabilized by the extra Ru
O
3 3 3
chelation (representative 18-electron complex), and the cyano-
substituted catalyst C2 as an example of an activated complex,
where additional stabilization via chelation is not possible
(Figure 8). Dichloromethane, a privileged solvent for olefin
metathesis, was logically selected as a solvent for these experi-
mental tests. It is noteworthy that the time over which we
followed the decomposition of these precatalysts is much longer
than the time required for most catalytic reactions reported here.
Thus, at least for the most stable precatalysts tested here, the
observed intrinsic decomposition has very little incidence on the
course of the catalytic reaction. Importantly, it appears that the
ester catalyst E2 is the most stable of the whole series, immedi-
ately followed by the unmodified second-generation Hoveyda
catalyst H2. As expected, catalyst C2, bearing a cyano group with
no extra stabilizing interaction with the metal center, undergoes
more rapid decomposition.
H. Digression on the Stability of Our Precatalysts in
Solution. During the course of the present work, we decided
to study the respective stabilities of our complexes in solution, in
the absence of olefinic substrate. To do so, three representative
complexes were chosen by us: the unmodified Hoveyda catalyst
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Table 4. RCM Reactions (0.02 M in CH2Cl2)
Figure 4. Catalytic activity of NE2 (b), KE2 (b), N2 (4), B2 (2), E2
([), C2 (ꢁ), Kme2 (]), Ket2 (O), KK2 (b), G2 (0), and H2 (9) in
the RCM of diallyl diethylmalonate (S1 f P1, dichloromethane, 1 mol %
of ruthenium precatalyst, 0 ꢀC, 6 h, conversion according to GC using
internal standard).
a Isolated yields after silica gel chromatography. Yields determined by
GC using an internal standard are given in parentheses.
Figure 5. Catalytic activity of NE2 (b),B2 (4),N2 (2), E2 (O),M2 (]),
Kme2 ([), and H2 (9) in RCM involving the formation of a disubstituted
double bond (S2 f P2, dichloromethane, 1 mol % of ruthenium precatalyst,
0 ꢀC, 6 h, conversion according to GC using internal standard).
’ CONCLUSION
Whereas the primary objective of the present work was to boost
the activity of Hoveyda catalysts by introducing an electron-with-
drawing group as a terminal substituent of the “leaving” benzylidene
ether group, we have learned that, in cases where such a substituent
is an ester group, a ketonic group ,or a malonic group, it functions as
an additional coordinating functionality binding the metal center.
They constitute a new structural variety of Grubbs/Hoveyda
precatalysts having an octahedral geometry and yet exhibiting
enhanced catalytic performance. When they are dissolved in
dichloromethane in the absence of olefin, the resulting precatalysts
differing in the nature of the installed donor group appear to exhibit
a stability which, at least for the ester derivative, matches that of the
parent Hoveyda complex. A further valuable advantage of these
upgraded catalysts is that the presence of an additional coordinating
group (ester, ketone, malonate) brings additional protection to the
metal center, allowing in particular their manipulation in air and
their purification by chromatography. Interestingly, however, their
enhanced stability is not detrimental, since these catalysts were
found to exhibit systematically higher activity than the unmodified
Hoveyda prototype in RCM and CM, for both standard and
challenging substrates. The overall excellent performance of these
new catalysts may be rationalized in terms of a more progressive
liberation of the active propagating species in the reaction medium and
possibly also (but this remains to be demonstrated) to a better
ability of the functionalized styrenyl ether to use its additional
pendant coordinating group to recapture the metal center in the
“return” process leading to catalyst regeneration. Even more
sophisticated upgraded polyfunctional catalysts were accessed by
introducing both a coordinating group as a terminal substituent of
the ether and an electron-withdrawing group as a substituent of the
aromatic ring of the benzylidene moiety.33 In the latter case,
however, we reach a point where the catalyst’s efficiency starts to
be affected by its lower stability. It also appears that minor
differences that are becoming detectable from one precatalyst to
the other for a given substrate cannot be fully rationalized and can be
only evaluated by experimental catalytic tests, not necessarily
transposable from one substrate to the other.
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Table 5. CM Reactions
Figure 6. Catalytic activity of M2 ([), N2 (2), Kme2 (0), and H2
(9) in RCM involving the formation of a trisubstituted double bond
(S3 f P3, dichloromethane, 1 mol % of ruthenium precatalyst, 30 ꢀC, 6
h, conversion according to GC using internal standard).
’ EXPERIMENTAL SECTION34
General Procedure for Preparation of Ligands. To a suspen-
sion of K2CO3 (5.64 g, 40.8 mmol) and Cs2CO3 (2.65 g, 8.14 mmol) in
DMF (100 mL) was added 2-[(1E,Z)-prop-1-en-1-yl)phenol (2.5 mL,
20.0 mmol). After the mixture was stirred for 30 min at 40 ꢀC, alkylation
reagent (24.0 mmol) was added and the reaction mixture was stirred (for
1 h to 4 days) at the same temperature. The reaction mixture was poured
into water (40 mL) and extracted with Et2O (3 ꢁ 40 mL). The
combined organic phases were washed with water (30 mL) and brine
(30 mL). The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure to afford a crude product. The
crude product was purified by column chromatography (using eluents:
cyclohexane/ethyl acetate, 10:1 to 5:1 v/v).
Dimethyl {2-[(1E,Z)-Prop-1-en-1-yl]phenoxy}malonate (3b). Yield:
37%, yellow oil. Isomer mixture E/Z = 7/3. IR (film): ν 2959, 2852,
1
1751, 1487, 1437, 1227, 1200, 1161, 1019, 754 cmꢀ1. H NMR (500
a Isolated yields after silica gel chromatography. Yields determined by
GC are given in parentheses. b Reaction in commercial-grade CH2Cl2,
on air.
MHz, CDCl3): E isomer, δ 1.92 (dd, J = 6.6, 1.8 Hz, 3H), 3.85 (s, 6H),
5.20 (s, 1H), 6.30 (dq, J = 15.8, 6.6 Hz, 1H), 6.76 (dd, J = 8.3, 1.1 Hz, 1H),
6.82 (dd, J = 15.8, 1.8 Hz, 1H), 6.98ꢀ7.06 (m, 1H), 7.08ꢀ7.15 (m, 1H),
7.44 (dd, J = 7.7, 1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): E isomer, δ
18.9 (CH3), 53.2 (CH3), 77.4 (CH), 113.8 (CH), 123.0 (CH), 125.0
(CH), 126.9 (CH), 127.5 (CH), 127.6 (CH), 128.5 (C), 153.5 (C),
166.1 (C); MS (EI): m/z (relative intensity) 264 (28, [M]•+), 200 (8),
173 (9), 145 (37), 133 (100), 131 (42), 115 (27), 105 (52), 91 (15), 77
(15), 59 (9), 51 (9) 39 (10). HRMS (EI): m/z calcd for C14H16O5
([M]•+) 264.099 77, found 264.098 89.
1-{2-[(1E,Z)-Prop-1-en-1-yl]phenoxy}acetone (3c). Yield: 73%, col-
orless oil. Isomer mixture E/Z = 7/3. IR (film): ν 3033, 2914, 1722,
1598, 1487, 1452, 1433, 1357, 1229, 1117, 1061, 970, 751, 615,
512 cmꢀ1. 1H NMR (500 MHz, CDCl3): E isomer, δ 1.92 (dd, J = 6.6,
1.7 Hz, 3H), 2.30 (s, 3H), 4.53 (s, 2H), 6.26 (dq, J = 15.9, 6.6 Hz, 1H), 6.68
(dd, J = 8.2, 1.0 Hz, 1H), 6.78 (dd, J = 15.9, 1.7 Hz, 1H), 6.91ꢀ7.02 (m,
1H), 7.11ꢀ7.17 (m, 1H, E), 7.44 (dd, J = 7.7, 1.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3): E isomer, δ 18.9 (CH3), 26.7 (CH3), 73.3 (CH2),
111.7 (CH2), 121.7 (CH), 125.1 (C), 126.6 (CH), 127.0 (CH), 127.7
(CH), 130.5 (CH), 154.2 (C), 206.1 (C); MS (EI): m/z (relative
intensity) 190 (39, [M]•+), 147 (11), 133 (52), 132 (19), 131 (31), 119
(10), 115 (23), 105 (15), 103 (10), 91 (100), 77 (17), 51 (10), 43 (44),
41 (10), 39 (14). HRMS (EI): m/z calcd for C12H14O2 ([M]•+)
190.099 38, found 190.099 01. Anal. Calcd for C12H14O2: C, 75.76; H,
7.42. Found: C, 75.32; H, 7.31.
1-{2-[(1E,Z)-Prop-1-en-1-yl]phenoxy}butan-2-one (3d). Yield: 90%,
colorless oil. Isomer mixture E/Z = 7/3. IR (film): ν 3073, 3033, 2978,
2938, 2912, 2881, 2855, 1722, 1598, 1579, 1487, 1453, 1434, 1406,
1378, 1292, 1245, 1224, 1160, 1114, 1055, 1024, 973, 944, 752 cmꢀ1
.
1H NMR (500 MHz, CDCl3): E isomer, δ 1.11 (t, J = 7.3 Hz, 3H), 1.92
(dd, J = 6.6, 1.8 Hz, 3H), 2.66 (q, J = 7.3 Hz, 2H), 4.55 (s, 2H), 6.26
(dq, J = 15.8, 6.6 Hz, 1H), 6.67 (dd, J = 8.3, 1.0 Hz, 1H), 6.78 (dq, J =
15.8, 1.8 Hz, 1H), 6.91ꢀ6.97 (m, 1H), 7.11ꢀ7.16 (m, 1H), 7.43 (dd, J =
7.7, 1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): E isomer, δ 7.0 (CH3),
18.9 (CH3), 32.3 (CH2), 73.0 (CH2), 111.6 (CH), 121.6 (CH), 125.1 (C),
126.6 (CH), 127.4 (CH), 127.7 (CH), 130.4 (CH), 154.3 (C), 208.5 (C);
MS (EI): m/z (relative intensity) 204 (72, [M]•+), 148 (6), 147 (25), 134
(13), 133 (100), 132 (20), 131 (32), 119 (11), 115 (16), 105 (9), 103 (5),
91 (54), 77 (7), 57 (26), 41 (5). Anal. Calcd for C13H16O2: C, 76.44; H,
7.90. Found: C, 76.45; H, 7.93.
2-(2-Propenylphenoxy)propionitrile (3e). Yield: 90%, yellow oil.
Isomer mixture E/Z = 5/2. IR (film): ν 3034, 2966, 2916, 2854, 1651,
1600, 1580, 1487, 1447, 1368, 1296, 1264, 1220, 1195, 1165, 1115, 1090,
1057, 1040, 968, 946, 897, 751 cmꢀ1. 1H NMR (400 MHz, CDCl3): E
isomer, δ 1.83 (d, J = 6.7 Hz, 3H), 1.91 (dd, J = 6.6, 1.7 Hz, 3H), 4.84 (q, J =
6.7 Hz, 1H), 6.25 (dq, J = 15.9, 6.7 Hz, 1H), 6.64 (dd, J = 15.9, 1.7 Hz, 1H),
6.98ꢀ7.12 (m, 2H), 7.18ꢀ7.33 (m, 1H), 7.45 (dd, J = 7.7, 1.7 Hz, 1H).
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Table 6. “Low Loading” Tests of Metathesis Transformations
(0.02 M in CH2Cl2)
13C NMR (100 MHz, CDCl3): E isomer, δ 18.8 (CH3), 19.9 (CH3),
63.4 (CH), 114.8 (CH), 123.5 (CH), 124.6 (CH), 126.8 (CH), 127.7
(CH), 127.8 (C), 128.1 (C), 130.7 (CH), 153.9 (C). MS (EI): m/z
(relative intensity) 187 (54, [M]•+), 158 (7), 133 (23), 105 (100), 77
(18). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C,
76.98; H, 7.11; N, 7.53.
Methyl 2-(4-Acetyl-2-propenylphenoxy)propionate (3g). Yield: 96%,
yellow oil. Isomer mixture E/Z = 10/1. IR (film): ν 1732, 1670, 1597,
1573, 1492, 1448, 1436, 1358, 1325, 1302, 1278, 1247, 1133, 1102,
1054, 971, 825, 585 cmꢀ1. 1H NMR (400 MHz, CDCl3): E isomer, δ
1.68 (d, J = 7.0 Hz, 3H), 1.92 (dd, J = 6.7, 1.7 Hz, 3H), 2.56 (s, 3H),
3.76 (s, 3H), 4,63 (q, J = 7.0 Hz, 1H), 6.36 (dq, J = 16.0, 6.7 Hz, 1H),
6.70 (d, J = 8.6 Hz, 1H), 6.76 (dd, J = 16.0, 1.7 Hz, 1H), 7.75 (dd, J = 8.6,
2.2 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): E
isomer, δ 18.5 (CH3), 18.9 (CH3), 26.3 (CH3), 52.4 (CH3), 72.9 (CH),
111.5 (CH), 124.6 (CH), 127.2 (CH3), 127.6 (C), 128.1 (CH), 128.5
(CH), 130.8 (C), 157.8 (C), 172.0 (C), 196.9 (C). MS (EI): m/z (relative
intensity) 262 (30, [M]•+), 247 (11), 203 (12), 161 (38), 43 (100); HRMS
(EI): m/z calcd for C15H18O4 ([M]•+) 262.12 051, found 262.119 72.
1-(4-Acetyl-2-propenylphenoxy)propan-2-one (3h). Yield: 32%, yel-
low oil. Isomer mixture E/Z = 11/1. IR (film): ν 1738, 1669, 1595, 1495,
1
1426, 1353, 1259, 1180, 1138, 1085, 973, 811, 602 cmꢀ1. H NMR
(400 MHz, CDCl3): E isomer, δ 1.94 (dd, J = 6.6, 1.6 Hz, 3H), 2.32 (s,
3H), 2.57 (s, 3H), 4.63 (s, 2H), 6.39 (dq, J = 15.9, 6.6 Hz, 1H), 6.70 (d,
J = 8.7 Hz, 1H), 6.75 (dq, J = 15.9, 1.6 Hz, 1H), 7.78 (dd, J = 8.7, 2.2 Hz,
1H), 8.07 (d, J = 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): E isomer, δ
18.9 (CH3), 26.4 (CH3), 26.7 (CH3), 73.1 (CH2), 110.9 (CH), 124.4
(CH), 127.2 (CH), 127.5 (C), 128.6 (CH), 128.7 (CH), 131.0 (C),
157.7 (C), 196.9 (C), 204.6 (C). MS (EI): m/z (relative intensity) 232
(36, [M]•+), 217 (20), 189 (4), 175 (11), 161 (10), 131 (6), 115 (6), 103
(3), 91 (4), 77 (4), 43 (100). Anal. Calcd for C14H16O3: C, 72.39; H,
6.94. Found: C, 72.13; H, 6.93.
a Reactions performed outside of a glovebox. b Isolated yields after silica
gel chromatography. Yields determined by GC using an internal
standard are given in paretheses. c Reaction performed on a 15
mmol scale.
Table 7. Comparative Study of the Activities of Catalysts E2, H1, and N2 in the RCM of BILN1
a Conversion is determined by HPLC after 2 h. b Conversion is determined by HPLC after 1 h.
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2-(4-Acetyl-2-propenylphenoxy)propionitrile (3k). Yield: 62%, yellow
oil. Isomer mixture E/Z = 9/1. IR (film): ν 1735, 1651, 1600, 1580, 1487,
1447, 1368, 1296, 1264, 1220, 1195, 1165, 1115, 1090, 1057, 1040, 968, 946,
897, 751 cmꢀ1.1H NMR (400 MHz, CDCl3):Eisomer, δ1.87 (d, J=6.7Hz,
3H), 1.94 (dd, J = 6.7, 1.8 Hz, 3H), 2.58 (s, 3H), 4,97 (q,
J = 6.9 Hz, 1H), 6.36 (dq, J = 15.9, 6.6 Hz, 1H), 6.65 (dd, J = 16.0, 1.7
Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7, 2.2 Hz, 1H), 8.07 (d, J =
2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): E isomer, δ 18.9 (CH3), 19.8
(CH3), 26.4 (CH3), 62.4 (CH), 112.7 (CH), 117.7 (CH), 123.9 (CH),
127.3 (C), 128.3 (C), 128.5 (CH), 129.1 (CH), 132.1 (C), 156.1 (C),
196.8 (C). MS (EI): m/z (relative intensity) 229 (36, [M]•+), 214 (20),
161 (5), 145 (4), 131 (6), 103 (4), 77 (5), 43 (100). Anal. Calcd for
C14H15NO2: C, 73.34; H, 6.59;N, 6.11. Found: C, 73.08; H, 6.58; N, 5.96.
General Syntheses of Catalysts. A Schlenk tube equipped with a
stirring bar was charged with styrene ligand 3a (0.054 g, 0.24 mmol) and
CuCl (0.022 g, 0.22 mmol). The tube was flushed with argon and charged
with anhydrous CH2Cl2 (10 mL). The ruthenium complex G2 (0.170 g,
0.20 mmol) was added, and the resulting mixture was stirred at 40 ꢀC for
20 min. After this time, TLC indicated complete conversion of the substrate.
The resulting mixture was concentrated in vacuo, the residue was redissolved
in AcOEt, and the solution was passed through a Paster pipet containing a
small amount of cotton and evaporated to dryness. The crude product was
purified by column chromatography (using cyclohexane/ethyl acetate as
eluent, 10/1 to 1/1 v/v). After evaporation of the solvents, the resulting solid
was collected and washed a few times with AcOEt and with cold n-pentane.
Catalyst M2. Yield: 58%, green microcrystalline solid. IR (KBr): ν
2953, 2919, 2854, 1743, 1597, 1479, 1415, 1264, 1116, 1080, 1034, 852,
748, 580 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 2.38 (br s, 6H), 2.50 (br
s, 12H), 3.67 (s, 6H), 4.12 (s, 4H), 5.28 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H),
6.94ꢀ7.09 (m, 6H), 7.47 (td, J = 9.2, 1.5 Hz, 1H), 16.62 (s, 1H). 13C
NMR (125 MHz, CDCl3): δ 21.1, 51.8, 54.1, 75.6, 112.6, 122.8, 125.0,
128.8, 129.5, 138.1, 145.8, 151.5, 164.9, 209.4, 301.7. MS (ESI+ from
MeOH/CH2Cl2 m/z 714): the molecular formula was confirmed by
comparing the theoretical and experimental isotopic patterns for the
[M]+ ion (C33H38N2O5Cl2Ru), and these were found to be identical
within the experimental error limits.
Catalyst Ket2. Yield: 63%, green microcrystalline solid. IR (KBr): ν
3425, 3041, 2912, 1714, 1593, 1573, 1478, 1451, 1415, 1262, 1226, 1107,
1034, 1016 849, 753, 729, 579 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
0.97 (t, J = 7.2 Hz, 3H), 2.32 (q, J = 7.2 Hz, 2H), 2.41 (s, 6H), 2.50
(s, 12H), 4.12 (s, 4H), 4.71 (s, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.93ꢀ7.00
(m, 2H), 7.07 (s, 4H), 7.45ꢀ7.50 (m, 1H), 16.63 (s, 1H). 13C NMR
(125 MHz, CDCl3): δ 6.8, 19.2, 21.2, 32.5, 51.8, 71.9, 113.0, 122.6,
124.6, 128.7, 129.5, 138.2, 138.6, 146.3, 152.1, 204.6, 210.0, 300.8. MS
(EI): m/z (relative intensity) 654 (2, [M]•+), 406 (3), 404 (3), 305 (32),
304 (62), 289 (12), 190 (15), 176 (16), 158 (18), 148 (28), 133 (21),
118 (100), 107 (19), 91 (57), 77 (18), 63 (20), 57 (91), 43 (31), 39
(19). HRMS (EI): m/z calcd for C32H38N2O235Cl2102Ru ([M]•+)
654.135 38, found 654.137 90.
Catalyst Kme2. Yield 88%, green microcrystalline solid. IR (KBr):
ν 3448, 2916, 1719, 1594, 1573, 1479, 1415, 1263, 1189, 1110, 1046,
851, 748, 579 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 2.03 (s, 3H), 2.41
(s, 6H), 2.48 (s, 12H), 4.14 (s, 4H), 4.70 (s, 2H), 6.68 (d, J = 8.2 Hz,
1H), 6.94ꢀ7.00 (m, 2H), 7.07 (s, 4H), 7.46ꢀ7.51 (m, 1H), 16.57 (s,
1H). 13C NMR (125 MHz, CDCl3): δ 19.2, 21.1, 26.6, 51.7, 73.2, 113.0,
122.7, 124.6, 128.9, 129.4, 138.3, 138.7, 146.1, 152.2, 202.4, 209.8. MS
(EI): m/z (relative intensity) 640 (1, [M]•+), 324 (6), 305 (22), 198
(34), 145 (7), 131 (11), 118 (100), 115 (16), 105 (9), 89 (38), 83 (13),
73 (18), 63 (19), 55 (22), 43 (39), 36 (30). HRMS (EI): m/z calcd for
C31H36N2O235Cl2102Ru ([M]•+) 640.119 73, found 640.118 09.
Catalyst C2. Yield: 58%,green microcrystalline solid. IR (KBr): ν
3456, 2922, 2851, 1738, 1594, 1572, 1478, 1451, 1424, 1399, 1378, 1295,
1261, 1200, 1158, 1130, 1109, 1034, 941, 853, 797, 750, 579 cmꢀ1. 1H
NMR (600 MHz, CDCl3): δ 1.60 (d, J = 6.6 Hz, 3H), 2.40 (s, 6H), 2.46
Figure 7. Activity of E2 ([), N2 (2), and H1 (9) complexes in the
RCM of BILN1 (in toluene, 80 ꢀC, 2 h; catalysts added in two portions
(0.4 + 0.2 mol % Ru)). Conversions were determined by HPLC.
Figure 8. Degradation of representative catalysts in CD2Cl2 solution
1
(deoxygenated with argon) at 25 ꢀC using H NMR with durene as
internal standard. E2 ([), H2 (9), C2 (4).
(2-Propenylphenoxy)acetonitrile (3i). Yield: 42%, yellow oil. Isomer
mixture E/Z = 6/3. IR (film): ν 3034, 2966, 2916, 2854, 1651, 1600,
1580, 1487, 1447, 1368, 1296, 1264, 1220, 1195, 1165, 1115, 1090, 1057,
1040, 968, 946, 897, 751 cmꢀ1. 1H NMR (400 MHz, CDCl3): E isomer,
δ 1.91 (dd, J = 6.7, 1.8 Hz, 3H), 4.76 (s, 2H), 6.24 (dq, J = 15.8, 6.7 Hz,
1H), 6.65 (dd, J = 15.9, 1.7 Hz, 1H), 6.90ꢀ7.12 (m, 2H), 7.18ꢀ7.35 (m,
1H), 7.45 (dd, J = 7.7, 1.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): E
isomer, δ 18.8 (CH3), 54.2 (CH2), 113.0 (CH), 115.2 (C), 123.4 (CH),
124.5 (CH), 127.0 (CH), 127.8 (CH), 128.2 (C), 130.8 (CH), 153.2
(C); MS (EI): m/z (relative intensity) 173 (50, [M]•+), 144 (20), 105
(100), 77 (21). HRMS (EI): m/z calcd for C11H11ON ([M]•+)
173.0841, found 173.0846. Anal. Calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.50; H, 6.36; N, 7.87.
1-Phenyl-2-{2-[(1E,Z)-prop-1-en-1-yl]phenoxy}propan-1-one (3j).
Yield: 89%, white solid. Mp: 79ꢀ81 ꢀC. Isomer mixture E/Z = 7/3.
IR (KBr): ν 3033, 2960, 1690, 1595, 1578, 1486, 1449, 1379, 1301, 1238,
1
1137, 1090, 1032, 965, 932, 794, 744, 703, 605, 537 cmꢀ1. H NMR
(500 MHz, CDCl3): E isomer, δ 1.73 (d, J = 6.9 Hz, 3H), 1.89 (dd, J =
6.6, 1.7 Hz, 3H), 5.45 (q, J = 6.9 Hz, 1H), 6.22 (dq, J = 15.9, 6.6 Hz, 1H),
6.69 (dd, J = 8.3, 0.8 Hz, 1H), 6.78 (dd, J = 15.9, 1.7 Hz, 1H), 6.86ꢀ6.94
(m, 1H), 7.02ꢀ7.12 (m, 1H), 7.40 (dd, J = 7.8, 1.7 Hz, 1H), 7.42ꢀ7.48
(m, 2H), 7.53ꢀ7.60 (m, 1H), 8.01ꢀ8.09 (m, 2H). 13C NMR (125 MHz,
CDCl3): E isomer, δ 18.7 (CH3), 18.9 (CH3), 77.5 (CH), 112.9 (CH),
121.5 (CH), 125.6 (CH), 126.6 (CH), 126.7 (CH), 127.6 (CH), 128.7
(CH3), 128.9 (CH), 130.5 (CH), 133.5 (CH), 134.3 (C), 154.0 (C), 198.9
(C); MS (EI): m/z (relative intensity) 266 (32, [M]•+), 161 (55), 134
(16), 133 (93), 131 (16), 119 (100), 115 (41), 105 (74), 103 (12), 91 (78),
79 (14), 77 (83), 65 (10), 51 (25), 43 (39), 39 (12); HRMS (EI): m/z
calcd for C18H18O2 ([M]•+) 266.130 68, found 266.129 55.
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Organometallics
ARTICLE
Table 8. Crystal Data and Structure Refinement Details for Complexes Ket2, Kme2, M2, and C2
Ket2 0.5MeOH
Kme2 2CH2Cl2
M2 1.5CH2Cl2 C6H14
C2 2CH2Cl2
3
3
3
3
3
empirical formula
mol wt (g)
temp (K)
λ (Å)
C32.5H40Cl2N2O2.5Ru
C33H40Cl6N2 O2Ru
1549.45
C40.50H54Cl5N2O5Ru
C38H35Cl4NP2Ru
810.48
1341.27
180
927.18
180
180
180
0.71073
cryst syst
space group
a (Å)
triclinic
triclinic
triclinic
monoclinic
P21/c (No. 14)
11.9763(4)
16.6003(6)
18.6197(6)
P1 (No. 2)
10.9701(11)
11.0589(13)
15.1717(15)
74.472(9)
73.584(9)
70.246(10)
1631.2(3)
2
P1 (No. 2)
11.913(9)
11.970(7)
15.284(10)
106.60(4)
93.07(5)
C2/c (No. 15)
34.4881(11)
15.1596(5)
18.2349(6)
b (Å)
c (Å)
R (deg)
β (deg)
γ (deg)
V (Å3)
116.1310(10)
102.306(2)
117.141(11)
1815(2)
8559.2(5)
8
3616.7(2)
4
Z
2
Dcalcd (g cmꢀ3
)
1.365
1.483
1.439
1.483
μ (mmꢀ1
)
0.676
0.905
0.723
0.907
F000
694
828
3840
1648
instrument
Oxford Instruments Xcalibur
32.06
Oxford Instruments Xcalibur
38.34
Bruker D8 Apex II
37.76
Bruker D8 Apex II
33.05
θmax (deg)
completeness to θmax (%)
99.0
99.0
92.0
99.0
index ranges
ꢀ13 < h < 13
ꢀ12 < k < 13
ꢀ18 < l < 18
70 524
ꢀ16 < h < 16
ꢀ16 < l < 16
ꢀ21 < l < 21
54 028
ꢀ57 < h < 52
ꢀ22 < k < 25
ꢀ30 < l < 29
76 718
ꢀ15 < h < 18
ꢀ25 < k < 25
ꢀ28 < l < 25
75 885
no. of rflns collected
no. of indep rflns
no. of data/restraints/params
GOF
6608
10 379
21 013
13 617
6608/0/377
1.03
10 379/0/404
1.07
21 013/0/423
1.116
13 617/0/351
1.027
R, Rw (I > 2σ(I))
R1 = 0.0407
wR2 = 0.859
R1 = 0.0543
wR2 = 0.0903
1.18/ꢀ0.86
R1 = 0.0363
wR2 = 0.087
R1 = 0.0408
wR2 = 0.092
2.05/ꢀ1.66
R1 = 0.0377
wR2 = 0.1109
R1 = 0.0521
wR2 = 0.1179
1.212/ꢀ0.098
R1 = 0.0359
wR2 = 0.0893
R1 = 0.0559
wR2 = 0.0952
0.756/ꢀ0.411
R, Rw (all data)
resid electr dens (e Åꢀ3
)
(s, 12H), 4.19 (s, 4H), 5.04ꢀ5.08 (m, 1H), 6.95ꢀ7.10 (m, 7H),
7.56ꢀ7.61 (m, 1H), 16.56 (s, 1H). 13C NMR (150 MHz, CDCl3): δ
14.1, 18.2, 19.3, 21.0, 21.1, 26.9, 51.5, 60.3, 62.9, 112.4, 123.1, 124.8,
129.3, 129.4, 129.5, 139.0, 144.1, 150.4, 171.1, 209.5, 293.9. MS (TOF
FD+ from CH2Cl2, m/z 637): the molecular formula was confirmed by
comparing the theoretical and experimental isotopic patterns for the
[M]+ ion (C31H35N3OCl2Ru), and these were found to be identical
within the experimental error limits.
Catalyst KK2. Yield: 56%, green microcrystalline solid. IR (KBr): ν
2913, 1727, 1681, 1581, 1487, 1415, 1354, 1266, 1203, 1171, 1141, 1074,
1049, 861 cmꢀ1. 1H NMR (600 MHz, CDCl3): δ 2.02 (s, 3H), 2.43 (s,
6H), 2.47 (s, 12H), 2.52 (s, 3H), 4.17 (s, 4H), 4.74 (s, 2H), 6.73 (d, J= 8.6 Hz,
1H), 7.09 (s, 4H), 7.53 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 2.5, 8.6 Hz, 1H),
16.50 (s, 1H). 13C NMR (150 MHz, CDCl3): δ 19.2, 21.1, 26.3, 26.5, 51.6,
73.1, 113.0, 122.9, 128.9, 129.5, 133.8, 138.5, 138.7, 145.8, 155.2, 195.8, 201.3,
208.7, 298.5. MS (TOF FD+ from CH2Cl2, m/z 682): the molecular formula
was confirmed by comparing the theoretical and experimental isotopic patterns
for the [M]+ ion (C33H38N2O3Cl2Ru), and these were found to be identical
within the experimental error limits.
(m, 12H), 3.63 (s, 3H), 4.18 (s, 4H), 4.74 (q, J = 6.7 Hz, 1H), 6.70 (d, J =
8.7 Hz, 1H), 7.09 (bs, 4H), 7.56 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 2.0, 8.5
Hz, 1H), 16.50 (s, 1H). 13C NMR (150 MHz, CDCl3): δ 14.0, 17.3,
21.1, 26.2, 51.6, 53.1, 74.2, 112.4, 123.1, 129.1, 129.4, 133.0, 138.6, 139.0,
145.0, 154.6, 170.4, 195.7, 209.1, 296.9. MS (TOF FD+ from CH2Cl2,
m/z 712): the molecular formula was confirmed by comparing the
theoretical and experimental isotopic patterns for the [M]+ ion
(C34H40N2O4Cl2Ru), and these were found to be identical within the
experimental error limits.
General Procedure for Cross-Metathesis Reactions. To a
mixture of alkene (0.5 mmol) and cross-metathesis partner (1.0ꢀ
4.0 mmol) in CH2Cl2 (25 mL, c = 0.02 M) was added a Ru catalyst as
a solid (0.0015ꢀ0.0150 mmol, 0.2ꢀ5.0 mol %). The resulting mixture
was stirred at 25ꢀ40 ꢀC for 0.5ꢀ16 h. The solvent was removed under
reduced pressure. The crude product was purified by flash chromatog-
raphy (cyclohexane/EtOAc).
General Procedure for RCM and Enyne Metathesis Reac-
tions. To a solution of diene (0.5 mmol) in CH2Cl2 (25 mL, c = 0.02
M) was added a solution of a Ru catalyst (0.000 15ꢀ0.005 00 mmol,
0.03ꢀ1.00 mol %). The resulting mixture was stirred at 0ꢀ25 ꢀC for
0.5ꢀ6 h. The solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (cyclohexane/
EtOAc).
Catalyst KE2. Yield: 57%, green microcrystalline solid. IR (KBr): ν
2914, 1733, 1681, 1605, 1581, 1484, 1415, 1399, 1359,1296, 1264, 1230,
1196, 1177, 1128, 1107, 1088, 1046, 979, 960, 915, 899, 854, 579 cmꢀ1
.
1H NMR (600 MHz, CDCl3): δ 1.52 (s, J = 6.7 Hz, 3H), 2.50ꢀ2.40
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Organometallics
ARTICLE
X-ray Diffraction Studies. Crystals of Ket2 and Kme2, M2, and
C2 suitable for X-ray diffraction were obtained by recrystallization of
the relevant compounds from dichloromethane/methanol, dichloro-
methane/n-hexane, and dichloromethane/n-pentane solutions, respec-
tively. Intensity data were collected at low temperature on either an
Oxford Diffraction Xcalibur diffractometer (Ket2 and Kme2) or an
Bruker D8 Apex II diffractometer (M2 and C2). All calculations were
performed on a PC-compatible computer using the WinGX system.35
Full crystallographic data are given in Table 8. The structures were
solved by using the SIR92 program,36 which revealed in each instance
the positions of most non-hydrogen atoms. All remaining non-hydrogen
atoms were located by the usual combination of full-matrix least-squares
refinement and difference electron density syntheses by using the
SHELXL97 program.36 Atomic scattering factors were taken from the
usual tabulations. Anomalous dispersion terms for Ru, P, and Cl atoms
were included in Fc. All non-hydrogen atoms were allowed to vibrate
anisotropically. All hydrogen atoms were introduced in idealized posi-
tions (R3CH, CꢀH = 0.96 Å; R2CH2, CꢀH = 0.97 Å; RCH3, CꢀH,
0.98 Å; C(sp2)ꢀH = 0.93 Å; Uiso 1.2 or 1.5 times greater than the Ueq
value of the carbon atom to which the hydrogen atom is attached) and
refined as “riding” atoms. For M2 and C2, after the initial structure
solution was completed, it was found that 21%, and 23%, respectively, of
the total cell volume was filled with disordered solvent molecules, which
could not be modeled in terms of atomic sites. From this point on,
residual peaks were removed and the solvent region was refined as a
diffuse contribution without specific atom positions by using the
PLATON37 module SQUEEZE,38 which subtracts electron density
from the void regions by appropriately modifying the diffraction
intensities of the overall structure. An electron count over the solvent
region provided an estimate for the number of solvent molecules
removed from the cell. The number of electrons thus located was
assigned to 1.5 molecule of dichloromethane and 1 molecule of hexane
on two different sites per molecule of complex in the case of M2 and to 2
molecules of dichloromethane on two different sites per molecule of
complex in the case of C2. The contributions of the solvent molecules
were introduced in the formula, formula weight, calculated density,
absorption coefficient, and F(000). Applying this procedure led to a
dramatic improvement in all refinement parameters and a minimization
of residuals.
Action (Contract No. HPMT-CT-2001-00398). A gift of chemi-
cals from Chemetall GmbH (Frankfurt am Main, Germany) is
gratefully acknowledged. C.S. is grateful to the Foundation for
Polish Science for the award of a “Ventures” grant.
’ DEDICATION
†Dedicated to Christian Bruneau on the occasion of his 60th
birthday.
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’ ASSOCIATED CONTENT
S
Supporting Information. Figures giving NMR character-
b
ization data for all new compounds and CIF files giving crystal-
lographic data for Ket2, Kme2, M2, and C2. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: klgrela@gmail.com (K.G.); lavigne@lcc-toulouse.fr (G.L.).
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(7) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K. Chem. Eur.
J. 2008, 14, 806.
Present Addresses
^Institute of Physical Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
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catalysts exhibiting specific characteristics, see: (a) F€urstner, A.;
Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
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Love, J. A.; Grubbs, R. H. Organometallics 2001, 20, 5314. (c) Love, J. A.;
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#Guest of the Institute of Organic Chemistry, Polish Academy of
Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
rUniversity Chemical Laboratory, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW, United Kingdom
’ ACKNOWLEDGMENT
Research was supported by the Polish Academy of Sciences, by
the CNRS, and through a European Community Marie-Curie
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describing inter alia the interesting story of BILN 2061, see: Magano, J.;
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(33) The very characteristic geometry of complex E2 originally
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chelating group as terminal substituent of the ether; see for example: (a)
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A2: Puentener, K.; Scalone, M. U.S. Patent Application 2009/0275714
A1. (c) The keto catalyst Kme2 described here is now commercially
available from Umicore AG under the name Umicore M52: Artl, D.;
Bieniek, M.; Karch, R. U.S. Patent Application 2010/0113795A1.
(34) For full experimental details and other information, see the
Supporting Information.
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