In Situ Generation of Ru-Based Metathesis Catalyst. A Systematic Study

Article abstract of DOI:10.1021/acscatal.9b00244

A systematic study for the in situ generation of Ru-based metathesis catalysts was described. Assembly of commercially available and inexpensive reagents [Ru(p-cymene)Cl₂]₂, SIPr·HCl, and n-BuLi led to the formation of 18 electron arene-ruthenium complexes that, in the presence of additives such as alkynes, cyclopropenes, and diazoesters, generated highly selective and efficient catalytic systems applicable to a variety of olefin metathesis transformations. Notably, we were able to achieve a productive TON of 4500 for the self-metathesis of methyl oleate, a reaction which could be easily upscaled to 2 kg.

Full text of DOI:10.1021/acscatal.9b00244

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Article
In Situ Generation of Ru-Based Metathesis Catalyst. A Systematic Study
Daniel S Müller, Yann Raoul, Jérôme Le Nôtre, Olivier Baslé, and Marc Mauduit
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00244 • Publication Date (Web): 08 Mar 2019
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ACS Catalysis
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In Situ Generation of Ru-Based Metathesis Catalyst. A Systematic
Study
a
b
c
a,†
a
Daniel S. Müller, Yann Raoul, Jérôme Le Nôtre, Olivier Baslé and Marc Mauduit *
a
Univ Rennes, Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France
b
OLEON SAS, Venette BP 20609, 60206 Compiègne Cedex, France
c
PIVERT SAS, Rue les Rives de l’Oise CS50149, 60201 Compiègne Cedex, France
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KEYWORDS: Olefin metathesis, Ruthenium, Arene complexes, in situ, NHC ligand
ABSTRACT: A practical and cost-effective protocol for the in situ generation of Ru-based metathesis catalysts was developed.
Assembly of commercially available and inexpensive reagents [Ru(p-cymene)Cl ] , SIPr.HCl and n-BuLi led to the formation of 18
2 2
electron arene-ruthenium complexes that, in the presence of additives such as alkynes, cyclopropenes and diazoesters, generated
highly selective and efficient catalytic systems applicable to a variety of olefin metathesis transformations. Notably, we were able
to achieve a productive TON of 4500 for the self-metathesis of methyl oleate, a reaction which could be easily upscaled to 2 kg.
Since its discovery in the mid 1950's, the metathesis reaction
gained significant importance for organic syntheses and
polymer chemistry. In its early days, the metathesis reaction
containing the saturated NHC ancillary ligand (SIMes) is quite
1
0,18
unstable and remains difficult to isolate.
Inspired by the
1
14a
14c,16
14b
pioneering work of Grubbs, Noels
and Dixneuf we
relied on ill-defined in situ generated catalysts. Only upon the
emergence of well-defined air stable Ru-complexes, such as
opted for a systematic study to generate 14 electron active
species by simply mixing a Ru(II) salt, an ancillary NHC
precursors and a carbene activator, thus avoiding any isolation
steps of unstable complexes (Figure 1).
st
the Grubbs 1 generation Ru-1a, and the more performant
nd
Grubbs 2 generation Ru-1b containing an N-heterocyclic
carbene (NHC) ligand, olefin metathesis started to
2
significantly impact organic synthesis. Since then the field
has grown steadily, resulting in numerous applications for
3
both academia and industry. An early mechanistic study from
Grubbs demonstrated that Ru-1a,b are in fact precatalysts
which, only after dissociation of the PCy ligand, provide the
3
corresponding catalytically active 14-electron benzylidene-
4
ruthenium species (Figure 1-A). Obviously the dissociated
3
ligand (e.g. PCy ) is no longer needed in the catalytic cycle
and has been shown to even be involved in catalyst
5
decomposition. In the light of this, several research groups
were interested to develop the in situ formation of metathesis
active species from alkylidene-free Ru-precatalysts. In that
respect, the 18-electron phosphine-based p-cymene-ruthenium
6
7
8
complex Ru-2, and its NHC ligated congeners Ru-3, Ru-4
9
,10
and Ru-5
showed metathesis activity in the presence of
carbene activator (Figure 1-B). This in situ protocol was
1
1
successfully
polymerization (ROMP),
closing metathesis (RCM) reactions. Of note, Thieuleux and
Basset demonstrated by H-NMR studies that the self-
illustrated
in
ring-opening
metathesis
and ring-
6
a,12
13,14d
self-metathesis
14
1
3
metathesis of ethyl oleate with PCy -based complex Ru-2 and
(trimethylsilyl) diazomethane (TMSD) as carbene activator
generated the same observable resting states as the Grubbs-1
1
3
15
catalyst (Ru-1). Moreover, independent studies by Fürstner
and Noels
1
2d,16
showed that light could also initiate metathesis
reactions with 18-electron arene-ruthenium complexes (e.g.
Ru-2). More recently, Lewis acid assisted activation of 18-
electron arene-ruthenium complexes containing various
unsaturated NHCs was reported by Beller and coworkers as
well as the influence of trace impurities upon metathesis
Figure 1. Previous strategies used for the formation of 14-electron
Ru-active species toward olefin metathesis (A and B). The proposed
synthetic route involving inexpensive commercially available
reagents (this work). SIMes = N,N'-bis-mesityl-imidazolin-2-ylidene
17
activity. Despite all these cost-effective methodologies to
furnish active metathesis species from simple 18-electron Ru-
complexes, few drawbacks merit to be solved to render this
protocol more attractive. For instance, the most efficient Ru-5
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Page 2 of 9
IMes = N,N'-bis-mesityl-imidazol-2-ylidene, IPr = N,N'-bis-2,6-iPr-
-imidazol-2-ylidene.
Figure 2. Ratio of RCM-product 2 (blue) and cycloisomerization
product 3 (red) in the absence (a) and in the presence (b) of phenyl
acetylene A1. SIPr = N,N'-bis-2,6-iPr-C -imidazolin-2-ylidene.
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6 3
C H
We report herein that transient alkylidene Ru-species may be
readily formed by mixing inexpensive commercially available
6 3
H
This reaction was carried out in the presence (Figure 2-a) and
1
9
20
[(p-cymene)RuCl
2
]
2
,
an azolium salt, a base and a carbene
absence (Figure 2-b) of phenyl acetylene A1, which has been
activator (Figure 1-this work). The choice of the base and the
activator appeared to be pivotal factors in the quest for highly
active catalytic species towards the targeted metathesis
transformation. Furthermore, the results of this systematic
approach led to the development of in situ made ruthenium-
catalysts exhibiting catalytic performances that can compete
previously described as
a
convenient and efficient
14c,d
activator.
In the absence of phenylacetylene, the use of
SIPr.HCl salt as NHC precursor afforded the highest
selectivity towards the metathesis product 2 (Figure 2-a). In
fact, the noticeable activity observed using SIMes ligand
precursor led mostly to the cycloisomerization product 3.
Interestingly, in all examined cases a strong enhancement of
the metathesis reactivity and selectivity could be observed
st
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with some well-defined 1 generation catalysts (e.g. Ru-1a).
We began our study by in situ generation of ruthenium arene
complex Ru-NHC from four commercially available azolium
salts which were deprotonated with NaHMDS and then
1
4c,d
upon the addition of 20 mol% of phenyl acetylene,
with the
SIPr-based complex demonstrating the highest catalytic
activity (Figure 2-b). It should be noted that a reduction of the
2
0
2
exposed to [(p-cymene)RuCl ] (Figure 2). There is literature
4
:1 phenyl acetylene:ruthenium ratio significantly lowered
precedent on the exchange of p-cymene to deuterated benzene
9
yields and selectivities towards the metathesis product 2 (see
Supporting Information; SI). Encouraged by these initial
results, we decided to further investigate the influence of the
base on the outcome of the metathesis reaction. Therefore, the
catalytic activity obtained with 3 mol% of SIPr-based complex
generated using NaHMDS was compared in terms of
efficiency to catalytic systems generated from the use of other
bases such as ZnEt , KHMDS, n-BuLi and KOtBu (Figure 3).
2
The catalytic systems generated from the various bases
evidenced tremendous metathesis activity differences after 15
and based on this observation, it is reasonable to assume that
2
1
p-cymene is rapidly replaced by toluene at 80 °C. The
solution of the in situ generated 18-electron complex Ru-NHC
was then immediately tested for the ring-closing metathesis
(RCM) of diethyl diallylmalonate 1.
used in situ
Me
NaHMDS (1.0 equiv)
toluene
+
Azolium salt
80 °C, 15 min
EtO2C CO2Et
Ru
2
min of reaction. Whereas Et Zn gave a very modest 7% yield
(
1.0 equiv)
-
p-cymene
Cl
Cl
+
NHC
of the desired RCM-product 2, NaHMDS and KOtBu gave
significantly improved results (37% and 63% yield). The best
performances were obtained with KHMDS and n-BuLi (~90
% GC-yield), which compare favorably to the previous
procedure described by Grubbs requiring prolonged reaction
times and higher catalyst loading for similar results (5 mol%,
[
(p-cymene)RuCl2]2
(0.5 equiv)
Ru-NHC (5 mol %)
3
EtO2C CO2Et
EtO2C CO2Et
+
Ph
toluene, 80 °C, 2 h
A1
1
2
(0 or 20 mol%)
1
4a
1
0 h). With the objective to provide catalytic systems of
Azolium salt
broad application, we therefore decided to continue our study
with n-BuLi, which has the advantage of only producing
butane and LiCl side products with low potential for
interfering with the metathesis catalytic cycle.
N
N
N
N
Cl
IMes.HCl
Cl
IPr.HCl
used in situ
base (1.0 equiv)
+
toluene
80 °C, 15 min
Me
SIPr.HCl (1.0 equiv)
N
N
N
N
Ru
- p-cymene
Cl
Cl
+
SIPr
Cl
SIMes.HCl
[(p-cymene)RuCl2]2
Cl
SIPr.HCl
(0.5 equiv)
Ru-6 (3 mol %)
EtO2C CO2Et
EtO2C CO2Et
+
Ph
toluene, 80 °C, 15 min.
A1
1
2
(12 mol%)
Et
2
Zn
NaHMDS KOtBu KHMDS
n-BuLi
(0.5 equiv)
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Figure 3. Influence of the base on the catalytic efficiency after 15
min in the RCM of diethyl diallylmalonate 1 using 3 mol% of in
situ generated Ru-6. In all cases, the 2:3 ratio was >98:2.
Concerning the activation of 18 electron arene-ruthenium-
complex Ru-6 with alkyne, cyclopropene and diazo activators
we propose the mechanistic scenarios described in Scheme 1.
1
2
3
4
5
6
7
8
9
2
3
24
Based on the work of Werner
and Ozawa
on
Next, we evaluated and compared the catalytic activity
resulting from the use of nine different activators; 3
representatives of each activator type shown in Figure 4. First,
the electronic properties of alkyne activators demonstrated an
influence on the catalyst activity. While electron neutral or
rich alkynes (A1 and A2) afforded the desired RCM product 2
in good 87 and 79% yield, modest 42% yield was obtained
with the electron poor alkyne A3. Then, cyclopropenes
additives, which have never been previously considered as
activator for 18 electron arene-ruthenium complexes, proved
beneficial to the performance of the metathesis reaction.
Again, the electronic property of the carbene source is
reflected in the catalytic activity: electron rich cyclopropene
A4 generated a metathesis catalytic system, affording
product 2 in high 96% yield, whereas the more electron
deficient cyclopropenes A5 and A6 gave inferior results.
Finally, the addition of diazocompounds such as A7 or A8
showed similar activity to produce the RCM product in 70%
yield, whereas TMSD (A9) gave only sluggish reactivity.
vinylideneruthenium complexes it was speculated in the past
that the addition of alkynes to 18 electron Ru-complexes
would lead to vinylidene species as the active catalyst.
14
However, recent reports by Delaude on homobimetallic
ruthenium complexes suggest that the initially generated
vinylidene species C undergoes ene-yne metathesis with
excess alkyne to produce after cycloaddition/cycloreversion
benyzlidene complex E which is very likely responsible for
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0
1
2
3
4
5
6
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0
1
2
3
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0
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0
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0
25
the catalytic activity (Scheme 1-a). This hypothesis is further
supported by our experimental findings that an alkyne:Ru ratio
inferior to 4:1 resulted in a strong drop of activity and
20
selectivity. For the reaction with cyclopropenes, we propose
the following mechanism (Scheme 1-b). First, thermal de-
2
2
6b
coordination of toluene gives the coordinately unsaturated,
highly reactive 12 electron ruthenium complex B which
rapidly reacts with cyclopropene A4 to give the more stable

-complex F. In fact a recent report by Occhipinti and Jensen
described species B to be responsible for common catalyst
degradation by intramolecular C−H activation and hydride-
9
mechanism isomerization. Hydride ruthenium species were
n-BuLi (1.0 equiv)
+
used in situ
Me
toluene
0 °C, 15 min
evoked by Beller as the responsible species for producing
8
17a
SIPr.HCl (1.0 equiv)
cycloisomerization products (e.g. 3; Figure 2).
An
Ru
+
- p-cymene
Cl
Cl
alternative isomerization pathway was proposed by Dixneuf
who reported that B can promote cycloisomerization of dienes
via formation of a bis--complex followed by oxidative
SIPr
[
(p-cymene)RuCl2]2
(0.5 equiv)
Ru-6 (3 mol %)
EtO2C CO2Et
1
4b
addition, -elimination and reductive elimination. This is
very likely the reason why in the absence of activator the
cycloisomerized product 3 was formed as the major species
EtO2C CO2Et
A1-9
(12 mol%)
+
toluene, 80 °C, 15 min.
1
2
(Figure 2). In analogy to the corresponding tungsten
complexes we then propose the subsequent formation of
MeO
F3C
metallacyclopropane G which then rearranges to give the
A1
A2
A3
26
active vinyl alkylidene complex H.
Cl Cl
O
Me
Cl
A5
O
Cl
Ph
Ph
A4
A6
O
TMS
OEt
N2
OBn
N2
N2
A7
A8
A9
A
A
d
d
d
d
i ti t
i
i
v
v
e
e
:
none
A1
A2
A3
A4
A5
A6
A7
A8
A9
Figure 4. Screening of activators for the RCM of diethyl
diallylmalonate 1.
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case of alkynes. Another explanation for the sluggish
Page 4 of 9
H
decomposition
catalysis
Ph
Cl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ph
C
reactivity with A1 and A7 at 22 °C might be that these
catalytic systems require thermal activation. Trisubstituted
Ru
30
H
Cl
NHC
olefin 6 reacted cleanly in the presence of cyclopropene A4
(entry 11). Surprisingly, in the absence of activator very high
RCM selectivity was observed (entry 9). This illustrates the
unpredictable behavior of Ru-6 in the absence of activator,
which often results in mixtures of metathesis,
cycloisomerization and isomerization products (e.g. entries 13,
17 and 21) but in some cases, can also afford relatively clean
reactions (entries 9 and 33). Interestingly, 6-membered RCM
product 9 was obtained in high yields independent on the
source of activator (entries 14-16). RCM reactions with
substrate 10 were carried out either under standard conditions
with non-degassed toluene (entries 17-20) or using degassed
toluene (entries 21-24). In general yields and conversions were
similar in the two cases. However, we found the reaction with
activator A7 to be more selective towards the metathesis
product 11 with degassed toluene (entries 20 and 24). For the
synthesis of macrocycle 13 we noticed that the use of degassed
toluene gave better reproducibility compared to standard
conditions. The yields were somewhat lower compared to
E
proposed active catalyst
Ph
Me
H
Ph
Ph
H
C
Ru
C
Cl
Cl
Cl
NHC
A1
Cl
Ru
Ru
Ph
Cl
Cl
NHC
NHC
A
C
D
(
a)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
thermal
dissociation
-
toluene
Cl
OEt
decomposition
catalysis
O
Cl
N2
(c)
Ru
O
Cl
Cl
OEt
NHC
Ru
A7 - N2
B
NHC
I
proposed active catalyst
(b)
decomposition
Me Ph
Me Ph
Me Ph
Cl
NHC
Cl
A4
Ru
Ru
Cl
NHC
Cl
7
-membered cycle 11 (entries 25-28), very likely due to the
F
G
31
formation of oligomeric side products.
Surprisingly,
activators A1 and A7 performed significantly better than A4
(entries 26-28). Cross-metathesis reactions between 14 and 15
were very sluggish and low yielding (entries 29-32). We
noticed that upon addition of Ru-6 to a mixture of 14 and 15 a
black slimy residue appeared within seconds. The observed
degradation might be similar to the corresponding PCy3
ligated complex which was reported to decompose in the
Ph
Me
decomposition
catalysis
Cl
NHC
proposed active catalyst
Ru
Cl
H
Scheme 1. Postulated mechanisms for the activation with
alkynes, cyclopropenes and diazocompounds
3
2
presence of allylic alcohols.
Alternatively, the -complex F could also react to H without
formation of the metallacyclopropane intermediate. Due to
the known lack of stability of complex H we can expect that
there will be a partial loss of material due to decomposition.
Therefore the in situ generated 18-electron complex A needs
to be added to the activator and the substrate at the same time.
In this case the transiently generated active species H will
immediately enter the catalytic cycle thus diminishing
inadvertent decomposition. According to reactions between
Ru-complexes and diazocompounds described in the
2
7
Table 1. Reaction scope.a
4
d
28
10,29
literature,
we propose the formation of I from B and A7
under concomitant nitrogen evolution (Scheme 1-c). Indeed,
gas evolution is observed even at room temperature upon
addition of A7 to Ru-6.
With the optimized conditions in hand for the in situ
generation of the complex Ru-6 that use n-BuLi as the base to
deprotonate the SIPr ligand precursor, we investigated the
substrate scope (Table 1). In order to minimize the risk of
potential mismatch between substrates and activators, we
decided to evaluate several activators (or no activator) for each
of the metathesis reactions. RCM reactions with diallyl-N-
tosylamine 4 was carried out at 80 °C and 22 °C (entries 1-8).
At 80 °C complete conversion was observed with only 2 mol
%
of Ru-6 in combination with activator A1 (entry 2). In
contrast, carrying out the same reactions at 22 °C (entries 5-8)
gave similar results only with cyclopropene A4 (entry 7). This
indicates that the rate determining step in the in situ formation
of active 14-electron ruthenium complexes is very likely not
the thermal dissociation of the toluene substituent (A → B;
Scheme 1) but rather the formation of E (Scheme 1-a) in the
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important chemical feedstock from biomass, leading to
n-BuLi (1.0 equiv)
+
used in situ
Me
toluene
0 °C, 15 min
1
2
3
4
5
6
7
8
9
valuable hydrocarbon 21 and mono-unsaturated diester 22
8
SIPr.HCl (1.0 equiv)
Ru
33
+
- p-cymene
Cl
Cl
(Table 2). Surprisingly, activators like phenyl acetylene A1
SIPr
[
(p-cymene)RuCl2]2
and cyclopropene A4, which were among the best activators
for RCM or CM reactions with terminal alkenes, gave poor or
no conversion in the self-metathesis of (Z)-20 (entries 3 and
(0.5 equiv)
Ru-6 (y mol %)
A1, A4 or A7
4 x y mol%)
metathesis
product
substrate
+
6
). In contrast, when the reaction was carried out in the
(
toluene, 80 °C, time
absence of activator the self-metathesis still proceeded,
however producing many isomerization side-products (entry
Ru-6
AX
Time conv. (%) /
Entry
Substrate
Product
(
y mol %)
(min)
yield (%)
1
). The best productivity was found at low catalyst loading in
1
2
2
2
2
none
A1
15
15
15
15
45 / 36b
>98 / 91
97 / 89
the presence of diazocompounds A7 and A8 (entries 9-14).
The reasons for the dramatic decrease of activity with alkyne
and cyclopropene activators are still unclear. We postulate that
the intermediate E generated from phenyl acetylene (Scheme
1a) is too sterically encumbered to efficiently react with the
internal olefin of (Z)-20. In contrast, steric arguments cannot
be evoked to explain the lack of efficiency with cyclopropene
A4. In this case, the sterically more demanding cyclopropene
A5 shows in fact better efficiency (entries 6-7). However, an
electronic argument might be considered: Internal alkenes are
more electron rich compared to terminal alkenes. Therefore,
we postulate that electron poor cyclopropenes A5 and A6 lead
to a better electronic match for in situ generated ruthenium
catalyst with (Z)-20. On the other hand, we observed that, at
high catalyst loading, the in situ generated ruthenium catalyst
produces significant amounts of isomerization side-product
(entries 9 and 13; see SI). Fortunately, lowering the catalyst
loading to less than 500 ppm favors the metathesis reaction
over undesired isomerization (entries 10-12 and 14).
2
3
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ts
N
Ts
N
A4
55 / 64b
A7
5c
6
2
2
2
2
none
A1
15
15
15
15
18 / 12
23 / 18
90 / 81
29 / 22
c
4
5
7c
8c
A4
A7
E
E
2 2
EtO C CO Et
9
3
3
3
3
none 120
19 / 18
76 / 73
>98 / 95
92 / 86
10
A1
A4
A7
120
120
120
11
E = CO2Et
12
6
7
E
E
EtO2C CO2Et
>98 / 24b
>98 / 98
>98 / 99
96 / 88b
13
3
3
3
3
none 120
1
1
4
5
A1
A4
A7
120
120
120
E = CO2Et
16
8
9
84 / 27b
88 / 78
17
3
3
3
3
none 240
18
A1
A4
A7
240
240
240
EtO2C CO2Et
1
2
9
0
E
E
88 / 74
84 / 62b
91 / 6b
88 / 81
90 / 72
93 / 81
d
d
d
d
2
22
1
E = CO2Et
10
3
3
3
3
none 240
A1
A4
A7
240
240
240
11
2
2
3
4
Table 2: Screening of activators for the self-metathesis of
methyl (Z)-9-octadecenoate (Z)-20 (99% purity)a
used in situ
O
O
O
5d
6
10
10
10
10
none 120
>98 / 18b,e
>98 / 55b,e
>98 / 40e
>98 / 54e
2
2
O
d
A1
A4
A7
120
120
120
27d
Me
6
2
8d
O
Ru
O
Cl
Cl
1
2
13
SIPr
6
OMe
6
OMe
(E/Z)-21
2 f
( )9
+
14 / <2g
6
Ru-6 (y mol %)
9
0
1
14
5
5
5
5
none 240
( )9
O
+
+
f
g
3
3
A1
A4
A7
240
240
240
18 / 5
6
toluene, 80 °C, 2 h
f
47 / 33g
23 / 10g
16
OH
OMe
HO
OH
2.0 equiv) 15
(Z)-20
6
6
32f
A1-9
(4 x y mol%)
MeO
(
6
90 / 84g
O
(E/Z)-20
3
3
35
3
4
3
3
3
3
none 240
(
)11
17
(E/Z)-22
( )11
g
A1
A4
A7
240
240
240
85 / 75
+
91 / 81g
90 / 84g
20 (%)b
(Z:E ratio)
Ru-6
(y mol %)
22 (%)b
(Z:E ratio)
19
OAc
Entry
1
21 (%)b
AX
AcO
OAc
2.0 equiv) 18
36
(
2
0.1
2
2
2
2
2
2
none
none
36 (21:79)
93 (59:41)
15
3
0
0
0
4
20
16
18
24
24
22
19
24
14
15 (25:75)
3 (32:68)
c
2
aReactions carried out in argon-flushed vials with dry solvents (MBraun®
solvent system). Conversions and yields were determined by GC-analysis
with internal standards (see SI). Significant amounts of side products
from cycloisomerization and isomerization processes were observed (see
SI). Reactions carried out at room temperature. Reactions carried out in
the glove-box with degassed solvents. Low yield due to oligomeric side
3
4
5
6
7
8
9
10
11
12
A1
A2
A3
A4
A5
A6
A7
A7
A7
A7
A8
A8
A9
100 (>99:1)
100 (>99:1)
100 (>99:1)
92 (82:18)
51 (24:76)
68 (35:65)
38 (21:79)
51 (21:79)
51 (21:79)
55 (30:70)
15 (13:87)
50 (21:79)
72 (32:68)
0
0
0
b
4 (30:70)
21 (22:78)
16 (24:76)
18 (25:75)
24 (23:77)
25 (22:78)
23 (24:76)
16 (19:81)
24 (24:76)
14 (27:73)
c
d
e
f
products. Ru-6 was synthesized in toluene and then added to a solution of
2
g
c
1
4 and 15 in THF. Reactions in toluene afforded even lower yields. Apart
0.05
0.02
0.01
2
0.05
2
d
from the desired products (16 or 19) we observed products from
isomerization and self-metathesis of the terminal alkene substrates (14 or
d
1
7).
13
14
c
15
This assumption gains further credence when compared to the
reactions with diacetate 18 which afforded CM product 19 in
good yields with all activators (entries 33-36). Having tested
several RCM and cross-metathesis reactions with substrates
containing terminal olefins, we then decided to focus our
attention on the self-metathesis of methyl oleate (i.e. methyl
aReactions performed in argon flushed vials on a 0.3 mmol scale (MO
of 99% purity, Sigma Aldrich; used as received). The other products
b
observed are unidentified isomerization products; see SI. Determined by
c
d
GC. Carried out on a 8.0 mmol scale. Reactions were carried out in the
glove box (See SI for details).
When working with degassed solvents in a glove box, we even
achieved 45% productive conversion (50% being the
(
Z)-9-octadecenoate) (Z)-20 (99% purity) which is an
ACS Paragon Plus Environment

ACS Catalysis
maximum) with only 100 ppm of in situ generated Ru-6 and
Page 6 of 9
competitive and cost-effective catalytic process is underway in
other valuable metathesis transformations.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
400 ppm of activator A7 (entry 12). It is noteworthy that this
is currently the best effective turn over number (TON = 4500)
1
3
achieved with in situ generated ruthenium catalysts. This
TON is even higher compared to effective TON previously
ASSOCIATED CONTENT
Supporting Information. Optimization reactions, experimental
procedures and characterization data ( H NMR, C NMR, GC-
traces). This material is available free of charge via the Internet at
http://pubs.acs.org.
3
4
1
13
achieved with the Grubbs-1 catalyst Ru-1 (TON = 2500). To
demonstrate the robustness of in situ generated catalyst Ru-6,
we tested the optimized catalytic system towards a non-refined
methyl oleate Z-20 (technical grade, 85% purity) derived from
very high oleic sunflower oils (VHOSO) on a 2-kg scale
AUTHOR INFORMATION
Corresponding Author
(Scheme 2). We were delighted that with only 400 ppm of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
catalyst full equilibrium of 20, 21 and 22 was achieved within
only 1 hour at 80 °C (See SI for a detailed description of the
experiments including pictures). Of note, due to the low cost
*
E-mail: marc.mauduit@ensc-rennes.fr
ORCID
of [(p-cymene)RuCl
2
]
2
,
n-BuLi, SIPr.HCl and ethyl
Daniel S. Müller: 0000-0001-8184-1474
Olivier Baslé : 0000-0002-4551-473X
Marc Mauduit : 0000-0002-7080-9708
diazoacetate A7, this catalytic system showing a TON of 1250
appeared quite competitive to the most efficient well-defined
3
3
Ru-catalysts.
Present Addresses
†
Laboratoire de Chimie de Coordination, CNRS, UPR 8241, 205
used in situ
Me
route de Narbonne, 31077 Toulouse Cedex 04, France
6
O
Ru
O
Cl
Cl
Notes
SIPr
6
OMe
6
OMe
(E/Z)-21
The authors declare no competing financial interests
6
Ru-6 (0.04 mol %)
+
O
+
6
toluene, 80 °C, 1 h
O
ACKNOWLEDGMENT
OMe
6
6
(
Z)-20
from non-refined
MeO
This work was supported by the FASO (grant to DSM;
Z-SELECT) and the Région Bretagne (SAD 2016 N° 9639 –
RZSELECT; grant to OB and DSM). OB and MM acknowledge
the Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)
and the Centre National de la Recherche Scientifique (CNRS) for
financial support. Umicore AG & Co is acknowledged for a
a
OEt
6
VHOSO (Radia 7072)
O
(E/Z)-20
(
85% purity)b
N2
(E/Z)-22
@ 2 kg scale
A7 (0.16 mol%)
20 42 % (Z:E 21:79)
olefin distribution @ equilibriumc: 21 21 % (Z:E 21:79)
2
2 21 % (Z:E 21:79)
2
generous gift of [(p-cymene)RuCl ] complex.
Scheme 2. Kg-scale self-metathesis of non-refined methyl
oleate (Z)-20 (technical grade, 85% purity) catalyzed by
optimized in situ catalytic system Ru-6/A7
REFERENCES
(1) Selected comprehensive books on olefin metathesis: (a) Handbook
of Metathesis, 2nd ed.; Grubbs, R. H.; Wenzel, A. G.; O’Leary, D. J.;
Khosravi E., Eds.; Wiley-VCH, Weinheim, Germany, 2015. (b)
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Alkylidene Moiety on Metathesis Activity. Synthesis and
Applications of RuCl
aRadia 7072 is commercialized by Oleon. bThe other compounds were
identified as saturated and mono- or poly-unsaturated fatty methyl esters:
C16:0 (3.4 wt.%); C16:1 (0.1 wt.%); C18:0 (1.8 wt.%); C18:2 (3.1 wt.%);
C18:3 (1.8 wt.%); C20:0 (0.2 wt.%) C22:0 (0.3 wt.%) and C22:1 (0.7
c
wt.%). Determined by GC.
2
(=CHR'(PR
3 2
) . J. Am. Chem. Soc. 1996, 118,
In conclusion, we have reported a systematic study
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1
(
00–110.
3) For applications in industry, see: (a) Higman, C. S.; Lummiss, J.
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2 2
available and inexpensive reagents [Ru(p-cymene)Cl ] ,
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arene-ruthenium complex promoted, in the presence of
activators such as alkynes, cyclopropenes and diazoesters,
highly selective and efficient catalytic systems toward a
variety of olefin metathesis transformations. Furthermore, we
introduced for the first time cyclopropenes as efficient
activators for the in situ generation of Ru-metathesis catalysts.
Our investigations concerning the self-metathesis of methyl
oleate (MO) showed an unprecedented substrate dependence
on the activators. The diazoester A7 was identified to be most
efficient to convert the MO (Z)-20 (@99% purity) into highly
valuable mono-unsaturated diester and hydrocarbon with a
catalyst loading as low as 100 ppm (TON of 4500). Moreover,
the robustness of the newly developed catalytic system was
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refined technical grade MO (Z)-20 (85% purity) using only
2
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4
00 ppm of catalyst loading (TON = 1250). This highly
ACS Paragon Plus Environment

Page 7 of 9
ACS Catalysis
(
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1
2
3
4
5
6
7
8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(6) (a) Demonceau, A.; Noels, A. F.; Saive, E. Hubert, A. J.
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3
Closely related, PPh ligated catalysts were synthesized previously by
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2
33–241. Ru-2 is commercially available; CAS: 145381-23-3.
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characterization of the complex was given: a) Stumpf, A. W.; Saive,
E.; Demonceau, A.; Noels, A. F. Ruthenium-Based Catalysts for the
Ring-Opening Metathesis Polymerisation of Low-Strain Cyclic
Olefins and of Functionalised Derivatives of Norbornene and
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report metathesis reactions with Ru-3 (see ref. 8).
(
(
8) Jafarpour, L.; Huang, J.; Stevens, E. D.; Nolan, S. P.;
p-cymene)RuLCl (L = 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-
2
ylidene and 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and
Related Complexes as Ring Closing Metathesis Catalysts.
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(19) Grubbs already reported that ([RuCl
2
(PPh
3
)
3
]
and
[{RuCl (cod)} ] were unsuitable precursors, see ref. 14a.
2
n
(20) See Supporting Information (SI) for additional screening
experiments.
(21) ESI mass spectrometry the Ru-stock solution confirmed the
presence of Ru-6 (see SI).
(
12) a) Demonceau, A.; Stumpf, A. W.; Saive, E.; Noels, A. F.; Novel
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3-Arylcyclopropenes.
Tetrahedron
2008,
64,
8610–8617.
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