A fast-initiating ionically tagged ruthenium complex: A robust supported pre-catalyst for batch-process and continuous-flow olefin metathesis

Article abstract of DOI:10.1002/chem.201201589

In this study, a new pyridinium-tagged Ru complex was designed and anchored onto sulfonated silica, thereby forming a robust and highly active supported olefin-metathesis pre-catalyst for applications under batch and continuous-flow conditions. The involvement of an oxazine-benzylidene ligand allowed the reactivity of the formed Ru pre-catalyst to be efficiently controlled through both steric and electronic activation. The oxazine scaffold facilitated the introduction of the pyridinium tag, thereby affording the corresponding cationic pre-catalyst in good yield. Excellent activities in ring-closing (RCM), cross (CM), and enyne metathesis were observed with only 0.5mol % loading of the pre-catalyst. When this powerful pre-catalyst was immobilized onto a silica-based cationic-exchange resin, a versatile catalytically active material for batch reactions was generated that also served as fixed-bed material for flow reactors. This system could be reused at 1mol % loading to afford metathesis products in high purity with very low ruthenium contamination under batch conditions (below 5ppm). Scavenging procedures for both batch and flow processes were conducted, which led to a lowering of the ruthenium content to as little as one tenth of the original values. Tag! You're it! A pyridinium-tagged Ru complex (see figure) that was anchored to sulfonated silica formed a robust and highly active supported olefin-metathesis pre-catalyst for applications under batch and continuous-flow conditions with low ruthenium leaching.

Full text of DOI:10.1002/chem.201201589

FULL PAPER
DOI: 10.1002/chem.201201589
A Fast-Initiating Ionically Tagged Ruthenium Complex: A Robust Supported
Pre-catalyst for Batch-Process and Continuous-Flow Olefin Metathesis
Etienne Borrꢀ,[a] Mathieu Rouen,[a] Isabelle Laurent,[a] Magaly Magrez,[a]
Frꢀderic Caijo,[a] Christophe Crꢀvisy,[a] Wladimir Solodenko,[b] Loic Toupet,[c]
Renꢀ Frankfurter,[d] Carla Vogt,[d] Andreas Kirschning,*[b] and Marc Mauduit*[a]
Abstract: In this study, a new pyridini-
um-tagged Ru complex was designed
and anchored onto sulfonated silica,
thereby forming a robust and highly
active supported olefin-metathesis pre-
catalyst for applications under batch
and continuous-flow conditions. The in-
volvement of an oxazine–benzylidene
ligand allowed the reactivity of the
formed Ru pre-catalyst to be efficiently
controlled through both steric and elec-
tronic activation. The oxazine scaffold
facilitated the introduction of the pyri-
dinium tag, thereby affording the cor-
responding cationic pre-catalyst in
good yield. Excellent activities in ring-
closing (RCM), cross (CM), and enyne
metathesis were observed with only
0.5 mol% loading of the pre-catalyst.
When this powerful pre-catalyst was
immobilized onto a silica-based cation-
ic-exchange resin, a versatile catalyti-
cally active material for batch reactions
was generated that also served as
fixed-bed material for flow reactors.
This system could be reused at 1 mol%
loading to afford metathesis products
in high purity with very low ruthenium
contamination under batch conditions
(below 5 ppm). Scavenging procedures
for both batch and flow processes were
conducted, which led to a lowering of
the ruthenium content to as little as
one tenth of the original values.
Keywords: flow reactors · immobi-
lization · olefin metathesis · rutheni-
um · supported catalysts
Introduction
goal of controlling E/Z selectivity[3] has considerably in-
creased the interest of both academic and industrial groups
in this efficient and sustainable technology for their own
synthetic targets.[4] Despite these spectacular breakthroughs,
some hurdles remain to be tackled, such as catalyst recycling
and keeping metallic contamination in the metathesis prod-
ucts as low as possible.[5] The high price of commercially
available catalysts, combined with the pronounced toxicity
of transition metals (ruthenium, molybdenum, tungsten,
etc.), hamper their future prospects in industrial applica-
tions, notably for pharmaceutical ingredients.[6] Several proc-
esses for removing metallic contamination have been pro-
posed, typically involving oxidative treatments[7] or captive
ligands[8] followed by chromatography purification. These
methods either suffer from limited efficiency or prohibitive
cost. An attractive solution to both the recycling problem
and undesired leaching of the catalytic species is to make
the pre-catalyst heterogeneous through immobilization on
solid (or liquid) supports.[5] Since 2000, a large number of
supported catalysts have been reported (most of which have
involved Ru-based catalysts) that can be divided into two
main concepts of grafting: covalent[9] or non-covalent an-
chorage.[10] Although the former type has enabled a signifi-
cant decrease in the amount of metallic waste in the prod-
ucts (below 1 ppm), most of these covalently linked pre-cat-
alysts show lower reactivity, even at high loading, and their
reusability remains quite low. Moreover, the cost of these
specially designed supports becomes prohibitive, especially
if their recycling is difficult or impossible after the death of
the catalyst. Non-covalent anchorage, which is based on
Over the past two decades, olefin metathesis has become
one of the most important organometallic reactions in
modern organic synthesis because it forms C=C double
bonds from simple to highly functionalized alkenes and/or
alkynes.[1] The continuous development of well-defined ho-
mogeneous catalysts that show improved reactivity at low
loading[2] or, more recently, that facilitate the challenging
[a] Dr. E. Borrꢀ, Dr. M. Rouen, I. Laurent, M. Magrez, Dr. F. Caijo,
Dr. C. Crꢀvisy, Dr. M. Mauduit
Ecole Nationale Supꢀrieure de Chimie de Rennes, CNRS
UMR 6226, Av. du Gꢀnꢀral Leclerc
CS 50837, 35708 Rennes Cedex 7 (France)
Fax : (+33)223238108
E-mail: marc.mauduit@ensc-rennes.fr
[b] Dr. W. Solodenko, Prof. Dr. A. Kirschning
Institut fꢁr Organische Chemie, Leibniz Universitꢂt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax : (+49)511-7623011
E-mail: andreas.kirschning@oci.uni-hannover.de
[c] L. Toupet
Institut de Physique de Rennes Universitꢀ Rennes 1
CNRS, UMR 6251 - Campus de Beaulieu
Bꢃtiment 11A 263 Av. Gꢀnꢀral Leclerc
35042 Rennes Cedex (France)
[d] R. Frankfurter, Prof. Dr. C. Vogt
Institut fꢁr Anorganische Chemie
Leibniz Universitꢂt Hannover Callinstrasse 1
D-30167 Hannover (Germany)
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electrostatic interactions[10–12] or, more recently, on reversi-
[13]
À
ble p p interactions, has been more successful in terms of
recycling (up to 20 cycles in the best cases) and reactivity,
notably with Hoveyda-type complexes, which afford the re-
lease and return of the homogeneous Ru–alkylidene reac-
tive species.[14] Interestingly, such reloading was effective for
both solid and soluble supports (e.g., resins or ionic liquids),
thus allowing the possibility of reuse and minimizing the
drawbacks that arise from their high cost and difficult
design. However, the main problem that is associated with
cationically tagged catalysts that are immobilized on resin
supports is their continual leaching over multiple cycles,
caused by non-covalent attachment. This feature has led to
a dramatic drop in activity after only a few cycles, combined
with Ru-contamination levels of 100–200 ppm.[11] Surprising-
ly, a strategy that was based on the impregnation of cationi-
cally tagged catalysts in ionic liquids (ILs), combined with
liquid/liquid separation, was found to be more efficient,
thereby affording significantly higher longevity (even at
1 mol% of catalyst loading)[12] and, above all, lower Ru
Figure 1. Previously reported ionically tagged Hoveyda-type complexes
1–6; Cy=cyclohexyl, SIMes=1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
versus complex 3).[12f] However, the synthetic route for an-
choring the cationic tag onto the benzylidene fragment re-
mained laborious as well as non-modular.
Based on this experience, we decided to use an aminocar-
bonyl-based linker because it had previously been shown
that the electronic properties of this group allowed efficient
control over catalyst initiation (M71 catalysts, 7;[17]
Scheme 1). Therefore, pyridinium-tagged M7-type Ru com-
plex 11 was synthesized from functionalized styrenylether 8,
which was prepared in five steps on a large scale.[17a] As de-
picted in Scheme 1, aniline 8 was reacted with 4-(bromo-
wastACHTUNGTRENNUNG
age in the metathesis products (below 5 ppm[12b]). In ad-
dition, a mixed strategy that involved IL phases and silica
supports (namely, supported ionic-liquid catalyst or SILC)
has led to promising “greener” supported catalytic systems,
with the need for much lower amounts of expensive ILs.[15]
Preliminary results in this area were really attractive, nota-
bly for olefin metathesis under batch and continuous-flow
conditions.[16] On the other hand, reversible p p anchorage,
ACHTUNGTRENmNUNG ethyl)benzoyl chloride in the presence of pyridine, thereby
À
which has recently been highlighted in the literature,[13] has
opened up a new area that makes non-covalent strategies
more attractive in terms of catalyst grafting and in facilitat-
ing catalyst recovery after use. Despite these promising de-
velopments, there remains a quest for more efficient immo-
bilized catalysts. Based on our preceding work,[12a–g] we rein-
vestigated the design of cationically tagged Hoveyda-type
complexes to overcome the inherent problem of their lower
activity after immobilization on resin supports. Our main
objective was to develop highly active, robust, and long-last-
ing non-covalently supported Ru-based catalysts with appli-
cations in olefin metathesis under batch and continuous-
flow conditions.
yielding the corresponding amide in 66% yield. Treatment
with pyridine, followed by anionic metathesis, afforded the
expected PF6–pyridinium-tagged ligand (9) in 85% yield
over two steps; its complexation with Umicore M21 Ru–in-
Results and Discussion
Pyridinium-tagged Ru complexes that involve an aminocar-
bonyl linker: Our pioneering work on ionically grafted Hov-
eyda-type pre-catalysts 1–6 (Figure 1) has revealed two im-
portant features regarding their reactivity/longevity:[12a–e]
1) Firstly, the length of the alkyl chain between the cationic
moiety and the styrenyl ether fragment plays a crucial role
in determining the antinomic properties of the catalyst (ac-
tivity versus reusability); that is, the shorter the chain length
(complex 5 versus complexes 2–4), the faster the initiation
and, therefore, the lower the recyclability. 2) Secondly, the
longevity of the catalyst can be greatly improved by using a
SIPr ligand instead of the usual SIMes ligand (complex 6
Scheme 1. Synthetic route to ionically tagged M7-type Ru complex 11,
which contains an aminocarbonyl linker: a) 4-(Bromomethyl)benzoyl
chloride, pyridine, CH2Cl2, RT, 3 h, 66% yield. b) Pyridine, toluene,
reflux, overnight. c) KPF6, water, 30 min (85% over 2 steps). d) Umicore
M21 complex (10), CuCl, CH2Cl2, 358C, 1.5 h (40%).
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Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
denylidene catalyst 10[18] gave the corresponding pyridini-
um-tagged Ru complex (11), which was isolated as a green
powder in 40% yield after column chromatography on silica
gel.
With this new tagged Ru complex in hand, we started its
evaluation in the RCM of metallylallyl diethylmalonate 12
under standard homogeneous conditions[19] (i.e., CH2Cl2,
308C, 1 mol%). Unfortunately, pre-catalyst 11 showed a
very poor kinetic profile: only 15% conversion was reached
1
after 1 h (measured by H NMR spectroscopy, see Figure 5),
*
Figure 3. RCM kinetic profiles of Hoveyda–Grubs II ( ) and oxazine-
~
&
^
based Ru complexes 14a (ꢅ), 14b ( ), 14c ( ), and 14d ( ) for the
RCM of metallylallyl diethylmalonate 12; reaction conditions: 1 mol%
catalyst, CH2Cl2 (0.1m), 308C, 1 h.
oxaACTHNUGRTENUNGzine ring (15), which could be easily obtained from func-
tionalized 2-aminophenols (17) and various 2-bromoacyl
chlorides (18), followed by the reduction of the resulting
cyclic amide (16; Figure 2).
Commercially available 2-bromo-6-aminophenol (17a)
was condensed with 2-bromobutyroyl chloride (18a) in the
presence of pyridine and the resulting product was heated in
DMF in the presence of potassium carbonate to give the ex-
pected 2-bromo-oxazinone (16a) in 79% overall yield after
column chromatography on silica gel (Scheme 2). The intro-
duction of the propenyl fragment was achieved in 98%
yield by Stille coupling with propenyltributyltin catalyzed by
Figure 2. New design for increasing the initiation rate of ionically tagged
Ru complexes: The oxazine chelating moiety (FG=functionalized
group).
whereas complete conversion into compound 13 was ob-
served under similar conditions with our initial cationically
tagged complex 6. This dramatic lack of reactivity, which is
incompatible with continuous-flow applications, could be ex-
plained by the weak electron-withdrawing-group (EWG)
effect of the benzylpyridinium fragment. One solution to in-
crease the EWG effect could be to synthesize a per-fluori-
nated phenyl linker. However, the corresponding 4-(bromo-
methyl)-2,3,5,6-tetrafluorobenzoic acid was not commercial-
ly available and required a long and expensive multi-step se-
quence. In light of this disappointing result, we decided to
revise our design of the benzylidene ligand.
[PdACHTNURTGNEUGN(PPh3)4] in refluxing toluene for 12 h. The resulting 2-
Design of complexes to accelerate catalyst initiation: Our
new strategy to increase the initiation rate of the ionically
tagged catalyst was inspired by the well-defined Blechert
catalyst[20] (Figure 2). We expected that a rigid link between
a chelating ether group and an aminocarbonyl function at
the ortho position (e.g., complex 14) should promote a ben-
eficial activation through steric hindrance, similar to that in
Blechert’s catalyst. Therefore, we anticipated that the lack
of an EWG effect from the aminocarbonyl/ionic-tag frag-
ment could be counter-balanced by the steric activation. The
simple framework that afforded these properties was the
Scheme 2. Synthetic route to oxazine-type Ru–benzylidene complexes
14a–14d: a) Pyridine, CH2Cl2, RT, 2 h, 98% yield. b) K2CO3, DMF,
reflux, 3 h, 81%. c) Propenyltributyltin, [PdACHTNURTGNE(UNG PPh3)4], toluene, 1108C,
12 h, 84%. d) LiAlH4, THF, RT, 1 h, 99%. e) Appropriate halogen com-
pound, NaH, THF, RT, 3 h, 61–99%. f) M21 complex (10), CuCl, CH2Cl2,
358C, 2 h, 22–45%.
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A. Kirschning, M. Mauduit et al.
propenyl benzo-oxazinone was then reduced by LiAlH4 at
room temperature in THF to afford compound 15a in 99%
yield, without the need for further purification. The amino
function was then reacted with methyl iodide or various
Pyridium-tagged oxazine-based Ru complex: synthesis, char-
acterization, kinetic profile, and activity: Amine 15a was
acylated by using bromomethylbenzoyl chloride in the pres-
ence of lutidine to afford amide 20. Treatment with pyridine
in refluxing toluene, followed by anionic metathesis with
KPF6, yielded the corresponding PF6–pyridinium-tagged
ligand (19e) in 50% overall yield over two steps after
column chromatography on silica gel. Lastly, the complexa-
tion step, starting from M21 complex 10, led to the isolation
of up to 1.2 g of the desired pyridinium-tagged oxazine-
based Ru complex (13e), which was collected as pale-green
micro-crystals in excellent yield (76% after column chroma-
tography on silica gel). However, attempts to form nicotoyli-
um complex 14 f from PF6–pyridinium-tagged ligand 19 f
failed, probably owing to the low chemical stability of com-
plex 13 f (Scheme 3).
acylACHTUNGTRENNUNGating reagents in the presence of a suspension of NaH in
THF at room temperature. The corresponding amine (19a,
R=Me), carbamate (19b, R=CO2iBu), and amides (19c,
R=COPh and 19d, R=COC6F5) were isolated in moder-
ate-to-excellent yields (71, 99, 78, and 61%, respectively).
Finally, these ligands were reacted with M21 complex 10 in
the presence of CuCl to give the expected oxazine-based Ru
pre-catalysts (14a–14d) in low-to-moderate yields (22–45%)
after column chromatography on silica gel.
Having these new complexes in hand, we evaluated their
initiation rate in the RCM of metallylallyl diethylmalonate
12 under homogeneous standard conditions (CH2Cl2, 308C,
1 mol%). As depicted in Figure 3, in comparison with the
Figure 4. X-ray structure (ORTEP) of ionically tagged complex 13e.
well-known Hoveyda–Grubbs II complex, the association of
steric activation with an electronic one within oxazine-based
complexes 14a–14d appears to be beneficial for controlling
their initiation rates. Indeed, with a methyl group (14a), the
catalyst initiation was very slow, reaching only 2–3% after
20 min and 30% after 1 h. In the presence of an EWG
group, such as an isobutoxycarbonyl group (complex 14b),
the conversion only slightly improved to 20% after 10 min;
however, the catalyst remained active, thereby allowing the
conversion to reach 83% after 60 min. Nevertheless, both
complexes had poorer initiation rates than the Hoveyda–
Grubbs II complex. On the contrary, when a bulkier sub-
stituent, such as a benzoyl group, was employed (14c), the
activation was more pronounced and conversions of 63%
and 100% were reached after 20 and 50 min, respectively.
In the presence of a highly EWG per-fluorinated benzoyl
group (14d), the best initiation rate was reached: Complete
conversion was obtained after only 20 min. From these re-
sults, we have clearly demonstrated the significant benefit
that arises from a combination of both steric and electronic
activation within the benzylidene ligand. Therefore, the ex-
tension of this strategy to ionically tagged catalysts should
lead to an efficient immobilization concept.
Scheme 3. Synthetic route to pyridinium-tagged oxazine-based Ru com-
plex 14e: e) (Bromomethyl)benzoyl chloride, 2,6-lutidine, THF, RT, 3 h,
99% yield. f) Pyridine, toluene, reflux, 12 h. g) KPF6, water, RT, 10 min,
50%. h) M21 complex (10), CuCl, CH2Cl2, 358C, 2 h, 76%. i) NaH,
K2CO3, isonicotinoyl chloride hydrochloride, DMF, RT, 12 h, 78%.
j) MeI, toluene, reflux, 12 h. k) KPF6, water, RT, 10 min, 62% over
2 steps. l) M21 complex (10), CuCl, CH2Cl2, 358C, 2 h.
The structure of pyridinium-tagged complex 14e was con-
firmed by single-crystal X-ray diffraction (Figure 4)[21] and,
interestingly, some important structural information was
gained. Complex 14e showed the expected distorted-square-
based-pyramidal geometry around the metal center with co-
ordination of the oxygen atom to the ruthenium center. The
À
Ru=C and Ru CACTHUNTGRNEUNG(NHC) bond lengths (1.83 and 1.98 ꢆ, re-
spectively) were comparable to those reported previously
for Hoveyda-type complexes.[12h,22] However, the Ru O
À
bond length was shorter than that in the SIPr-Hoveyda-type
catalyst that contained an aminocarbonyl function in the po-
sition para from the ether group (2.18 vs. 2.30 ꢆ).[17b] More-
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Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
Scheme 4. Substrates for the olefin-metathesis reaction and their corre-
sponding products (see Table 1).
Figure 5. RCM kinetic profiles of Hoveyda–Grubbs II and pyridinium-
~
^
tagged Ru complexes 6, 11, and 14e:
14e (1 mol%),
14e
&
(0.1 mol%),
(1 mol%).
6 (1 mol%), ꢅ 11 (1 mol%), and Hoveyda–Grubbs II
*
Table 1. Evaluation of catalyst 13e in the RCM, CM, and enyne meta-
thesis at 0.5 mol% catalyst loading.[a]
Entry
Substrate
Product
t [h][b]
Yield [%][c]
3
À
over, the buried volume of the SIPr unit was 37.1 ꢆ (Ru
NHC 2.00 ꢆ, sphere radius: 3.50 ꢆ).[23a] This value is one of
the largest reported in the literature for this kind of
1
2
3
4
5
6
21
23
25
27
22
24
26
28
5
4
1
1
3.5
3.5
86
87
79
NHC.[23b] Lastly, the values for the Cl1 Ru1 Cl2, C1 Ru1
À
À
À
À
88
29/30[d]
32/30[d]
31 (E/Z>20:1)
33 (E/Z>20:1)
70[e]
82[f]
À
À
C25, and C25 Ru1 O1 angles were 158.6, 103.1, and 174.18,
respectively; these values were in the same range as those
found in most Hoveyda-type catalysts.[12h,22]
[a] Reaction conditions: Compound 14e (0.5 mol%), CH2Cl2, 0.1m,
208C; [b] reactions were run until the starting material had been com-
pletely consumed (monitored by 1H NMR spectroscopy); [c] yield of iso-
lated product after column chromatography on silica gel; [d] 4 equiv of
compound 30 were used; [e] 10% of the self-metathesis product of com-
pound 29 was also formed; [f] no self-metathesis product of compound 32
The kinetic profile of newly tagged catalyst 14e was first
studied in the RCM of methallylallyl diethylmalonate 12 ac-
cording to a literature procedure (CH2Cl2, 308C, 1 mol%;
Figure 5). As expected, an excellent initiation rate was ob-
served, which surpassed those obtained with pyridium-
tagged complexes 6 and 11 and complete conversion into
metathesis product 13 was observed after only 20 min.
Moreover, in comparison with untagged analogue 14c (R=
COPh), the presence of the benzylpyridinium fragment
drastically improved the initiation rate at 10 min (93% con-
version versus 23%, respectively). Interestingly, 14e showed
a similar kinetic profile to the Hoveyda–Grubbs II catalyst
but at tenfold-lower catalyst loading (0.1 vs. 1 mol%).
Therefore, the oxazine-based ligand enabled an efficient
control of the initiation rate of the catalyst, whilst allowing
the ionic tag to be grafted without any loss of activity (com-
pare, for instance, to compound 11).
Next, the scope of the metathesis transformations cata-
lyzed by pyridinium-tagged oxazine-based Ru complex 14e
was investigated (Scheme 4). Owing to its remarkable activi-
ty, we decided to fix the catalyst loading at 0.5 mol%. As
shown in Table 1, we selected three main types of olefin
metathesis, namely RCM, CM, and enyne metathesis, and
performed the reactions without any thermal activation.
Concerning the RCM transformations (Table 1, entries 1
and 2), 4 and 5 h were required to completely consume the
starting materials and afford seven-membered-ringed ether
22 and amide 24 in 86 and 87% yield, respectively. Enynes
25 and 27 reacted faster, thereby affording their correspond-
ing cyclic ethers in good yields (79 and 88%, respectively;
1
was detected by H NMR spectroscopy.
Table 1, entries 4 and 5). Pyridinium-tagged complex 14e
was also efficient in the cross-metathesis reactions of termi-
nal alkenes 29 and 32 with n-butyl acrylate (30) as a deacti-
vated olefin partner (Table 1, entries 5 and 6); complete
transformation occurred within 3.5 h. Notably, in the case of
electron-rich olefin 29, 10% of the corresponding self-meta-
thesis product was formed, whilst this side-reaction was not
observed with olefin partner 32.
Immobilization of pyridinium-tagged oxazine-based Ru
complex 14e and evaluation of the corresponding supported
pre-catalyst 34: Next, pyridinium-tagged Ru complex 14e
was immobilized by ion-exchange on silica gel that was func-
tionalized with lithium p-toluenesulfonate. Immobilization
proceeded quickly in an acetone/water mixture. Immobilized
pre-catalyst 34 was formed in quantitative yield as a dark-
green powder with a loading of 0.09 mmolgÀ1, as judged by
gravimetric analysis (Scheme 5). It is known that supports
that are based on silica can also trap Ru–alkylidene com-
plexes by physisorption. However, the loadings are typically
about 0.01 mmolgÀ1, as reported by van Berlo et al.;[24] thus,
we assume that, herein, the prevailing mode of interaction
between the solid phase and the pre-catalyst involves elec-
trostatic forces.
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A. Kirschning, M. Mauduit et al.
hexane CH2Cl2, and toluene) at 40–458C. In all cases, com-
plete consumption of compound 35 was achieved within 1 h
and the highest yield (90%) was afforded in n-hexane
(Table 2, entry 1). For more sterically demanding substrate
12, 6.5 h were required to achieve 76% conversion (70%
yield) when the reaction was run in n-hexane at 458C
(Table 2, entry 4). Heterogeneous pre-catalyst 34 was also
active in the cross-metathesis reactions of alkenes 29 and 39
with methyl acrylate 37 as the olefinic partner (Table 2, en-
tries 3 and 4). In both cases, the cross-metathesis reactions
also provided minor amounts (10%) of the olefinic self-
metathesis reactions of compounds 29 and 39, respectively.
The pure trans-configured cross-metathesis products (38 and
40) were isolated after flash chromatography in very good
yields. Finally, enyne metathesis of substrates 25 and 27
were carried out in toluene at 608C and afforded dienes 26
and 28 after 2 h, again in very good yields (87 and 77%, re-
spectively; Table 2, entries 5 and 6).
Scheme 5. Immobilization of Ru complex 14e, leading to supported pre-
catalyst 34.
Initially, the catalytic activity of immobilized catalyst 34
was tested under batch conditions. The ring-closing metathe-
sis of diethyl diallylmalonate 35 and diethyl allylmethallyl-
malonate 12, the cross-metathesis reactions of terminal al-
kenes 29 and 39 with methyl acrylate 37, and the enyne
metathesis of enynes 25 and 27 served as test reactions
(Scheme 6).
To study the stability and, thus, recyclability, of pre-cata-
lyst 34, the ring-closing metathesis of diethyl diallylmalonate
35 served as a test reaction. Heterogeneous pre-catalyst 34
was not only found to be highly active in n-hexane at 458C
but it could also be reused in ten consecutive runs. After
each run, compound 34 was thoroughly washed with n-
hexane and used in the next run. The results are listed in
Figure 6.
Scheme 6. Metathesis reactions with supported pre-catalyst 34.
The performance of this heterogeneous catalyst is sum-
marized in Table 2. The ring-closing metathesis of diethyl di-
allylmalonate 35 was conducted in different solvents (n-
Figure 6. Consecutive RCM of diethyl diallylmalonate 35 in the batch
mode with catalyst 34; conditions: substrate (0.2 mmol) in n-hexane
(2 mL), 1 mol% catalyst, 458C.
Table 2. Evaluation of supported pre-catalyst 34 in the RCM, CM, and
enyne metathesis under batch conditions.
Although it is usually difficult to combine both high initia-
tion rates and good stability with Hoveyda-type pre-cata-
Entry
Substrate
Product
T [8C]
t [h]
Yield [%][a]
AHCTUNGTRENNUNG
lysts,[12e] we were pleased to observe some interesting behav-
1[b]
2[c]
3[d]
4[g]
5[j]
35
12
29/37
39/37
25
36
13
45
45
80
80
60
60
1.25
6.5
1.5
1.5
2
90
70
ior of supported pre-catalyst 34. In the first eight runs, con-
versions of 80% or higher were achieved between 30 min
and 4 h and conversions of 88% and 72% were reached for
the 9th and 10th runs, respectively, after 24 h. From these
ten consecutive runs, a turnover number (TON) of 868 was
calculated for catalyst 34. We also conducted the so-called
“split test”[23] during the 2nd run. For this purpose, a sample
of the supernatant was removed from the reaction mixture
after 15 min and the formation of the product was moni-
tored by GC. The supernatant did not show any measurable
catalytic activity, which confirmed the heterogeneous char-
acter of immobilized pre-catalyst 34 under the conditions
38[e] (E/Z=9:1)
72[f]
72[i]
87
40[h] (E/Z=9:1)
26
28
6[k]
27
2
77
[a] Yield of isolated product; [b] 1 mol% catalyst 34, 0.1m compound 35
in n-hexane; [c] 1 mol% catalyst 34, 0.1m compound 12 in n-hexane;
[d] 2.5 mol% catalyst 34, 0.1m compound 29 in toluene, 4 equiv of com-
pound 37; [e] 9% of the self-metathesis product of compound 29 was
also formed; [f] yield of pure trans-38; [g] 2.5 mol% catalyst 34, 0.1m
compound 39 in toluene, 4 equiv of compound 37; [h] 11% of the self-
metathesis product from compound 39 was also formed; [i] yield of pure
trans-40; [j] 1 mol% catalyst 34, 0.1m compound 25 in toluene;
[k] 1 mol% catalyst 34, 0.1m compound 27 in toluene.
16374
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Chem. Eur. J. 2012, 18, 16369 – 16382

Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
that were employed in this study. Pre-catalyst 34 performed
even better in toluene at 458C. The RCM reaction was con-
ducted eleven times with the same batch of pre-catalyst and
diallylmalonate 35 and conversions started at 96% and were
still 75% for the 11th run after reaction times of 1.5–3 h
(Figure 7). Again, a split test that was conducted during the
first run revealed no catalytic activity in the supernatant.
The TON for this set of eleven RCM reactions was 968.
the course of the ring-closing-metathesis reactions, we ex-
tensively analyzed ruthenium contamination in the crude
products by inductively coupled plasma–mass spectrometry
(ICP-MS); the results are listed in Table 3.
Table 3. Ruthenium leaching during consecutive RCM reactions of dieth-
yl diallylmalonate 35 catalyzed by pre-catalyst 34 under batch conditions.
Entry
Solvent
Ru content in the
product [ppm][a]
Ru leaching
[%][b]
1
n-hexane[c]
1st run: 2
2nd run: 3
3rd run: 1
1st run: 92
2nd run: 59
0.04
0.07
0.03
1.54
1.18
0.90
1.62
0.91
0.33
4.6
2
3
toluene[d]
3rd run: 48
4th–6th runs:[e] 30
7th–9th runs:[e] 17
10th–11th runs:[e]
9
[f]
CH2Cl2
1st run: 217
2nd run: 105
3rd run: 105
2.2
2.2
[a] Determined by ICP-MS; [b] calculated as a percentage of the starting
Ru content in catalyst 34; [c] for conditions, see Figure 6; [d] for condi-
tions, see Figure 7; [e] products from the given runs were combined
before ICP-MS analysis; [f] for conditions, see Figure 8.
Figure 7. Consecutive RCM of diethyl diallylmalonate 35 in the batch
mode with pre-catalyst 34; conditions: substrate (0.2 mmol) in toluene
(2 mL), 1 mol% catalyst, 458C.
The leaching was found to depend on the solvent. As ex-
pected, the most pronounced leaching was observed in
CH2Cl2 (Table 3, entry 3), less so in toluene (Table 3,
entry 2). In n-hexane, ruthenium contamination of the crude
product was almost negligible (Table 3, entry 1). Even after
prolonged reaction times, very low degrees of leaching were
encountered in n-hexane, for example, in the RCM of dieth-
yl allylmethallylmalonate 12 (Table 2, entry 2). After 6.5 h,
only 0.1% of the initial ruthenium content was present in
the product, which was equivalent to 5 ppm Ru.
Heterogeneous pre-catalyst 34 was also active in CH2Cl2
at 408C. These recycling experiments only revealed high ac-
tivity for the first six runs, which was comparable to when n-
hexane was used as the solvent. However, a sharp drop in
activity occurred, beginning during the 7th run (Figure 8).
The split test revealed low catalytic activity in the superna-
tant of about 1% conversion within 5 h. The calculated
TON was 611 for seven runs.
Determining the degree of Ru leaching in batch reactions
with heterogenized pre-catalyst 34: A key issue in hetero-
genized homogeneous catalysts is metal leaching. If the im-
mobilization is not strong enough, the solution will be conta-
minated with metal traces, which is unsuitable for many
uses, in particular for pharmaceutical applications. During
RCM with heterogenized pre-catalyst 34 under flow condi-
tions: Based on the very good properties of pre-catalyst 34
with respect to its reactivity and recyclability, we devised a
circulating-flow process.[26] Very few examples of metathesis
reactions in flow regimes have been reported so far and, in
these few cases, the flow processes were conducted with het-
erogenized ruthenium complexes.[11,16,27] Grela, Kirschning,
and co-workers reported an ionically tagged Ru complex
41[11] that was formed by the protonation of a diethylamino-
substituted Hoveyda–Grubbs complex (Figure 9). Their
complex could also be immobilized by ion-exchange and
used in flow experiments. However, both of these homoge-
neous and heterogenized Ru complexes were much less
active than compounds 14e and 34, respectively.
Herein, a solution of diethyl diallylmalonate 35 was circu-
lated at a rather high flow rate of 2.5 mLminÀ1 through a re-
actor (100 mmꢅ2.5 mm) that was packed with immobilized
pre-catalyst 34 (111 mg, 2.5 mol%). First, the reactor was
pre-heated to the given temperature and the reaction mix-
ture in n-hexane was pumped through the system in a circu-
lating-flow mode at 458C. We found that the RCM proceed-
Figure 8. Consecutive RCM of diethyl diallylmalonate 35 in the batch
mode with pre-catalyst 34; conditions: substrate (0.2 mmol) in CH2Cl2
(2 mL), 1 mol% catalyst, 408C.
Chem. Eur. J. 2012, 18, 16369 – 16382
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16375

A. Kirschning, M. Mauduit et al.
Table 4. Ruthenium leaching during consecutive RCM reactions of dieth-
yl diallylmalonate 35 catalyzed by heterogenized pre-catalyst 34 under
circulating-flow conditions.
Solvent
Ru content in the product [ppm][a]
Ru leaching [%][b]
toluene[c]
1st run: 196
2nd run: 75
3rd run: 87
1.72
0.63
0.73
[a] Determined by ICP-MS; [b] calculated as a percentage of the starting
Ru content in catalyst 34; [c] for conditions, see Figure 10.
Figure 9. Structure of ionically tagged Ru complex 41 and its activation.
highest for the first run. Nevertheless, the recyclability of
supported pre-catalyst 34 appears to be insufficient for con-
tinuous-flow conditions. A solution to improve this catalytic
system would be to introduce an additional ionic tag onto
the diaminocarbene ancillary ligand.[28] In this case, the re-
formation of the pre-catalyst at the end of the catalytic cycle
should be significantly favored.
ed substantially slower compared to the batch process. Thus,
after 6 h, only 68% conversion was achieved. The split test
revealed no catalytic activity in solution. When the flow
process was performed in CH2Cl2 at 408C, again, the RCM
only proceeded sluggishly, affording 53% conversion after
6 h. Improved performance was achieved in toluene at
608C. Under these conditions, three consecutive runs in the
RCM of diethyl diallylmalonate 35 were carried out with
the same portion of pre-catalyst 34. After each run, the cata-
lyst in the reactor was thoroughly washed with toluene and
used for the next run. The results are summarized in
Figure 10.
Ruthenium scavenging from the crude metathesis products:
Clearly, non-polar solvents, such as n-hexane, are desirable
for preventing the desorption of the ruthenium species from
the solid support. However, polar starting materials or prod-
ucts require more polar solvents, particularly when blocking
in the flow devices has to be avoided. In selected examples,
we also found that toluene was more beneficial than n-
hexane, such as in the cross-metathesis reaction of terminal
alkene 39 with methyl acrylate 37, when catalyzed by
heteroACHTNUTRGNEgNUG enized ruthenium pre-catalyst 34. However, the use
of toluene as solvent resulted in considerable contamination
of the solution. Therefore, we also investigated the use of
scavenging systems.
To confirm this concept, commercial QuadraSil AP
(silica-bearing aminopropyl groups) was tested as a possible
scavenger for ruthenium. For this purpose, we employed the
crude products that were collected from metathesis reac-
tions with pre-catalyst 34 under both batch and continuous-
Figure 10. Consecutive RCM of diethyl diallylmalonate 35 in a circulat-
ing-flow mode with pre-catalyst 34; conditions: 2.5 mol% catalyst,
flow conditions. First,
a solution (Ru contamination:
0.4 mmol substrate per run (0.05m in toluene), flow rate: 2.5 mLminÀ1
,
195.8 ppm) of compound 36 in toluene was shaken with
QuadraSil AP at 608C for 3 h. After filtration and evapora-
tion of the solvent, the product was analyzed with respect to
ruthenium content by using ICP-MS. We found that the
product 36 only contained 15.5 ppm of ruthenium impurities
after this scavenging process. In a second batch experiment,
a solution of compound 36 in CH2Cl2 that initially contained
86.7 ppm Ru was shaken with QuadraSil AP at room tem-
perature for 3.5 h; after filtration and evaporation of the sol-
vent, ICP-MS analysis revealed 22.6 ppm of ruthenium im-
purities. Likewise, the scavenging process was conducted
under flow conditions. A solution of compound 36 in tol-
uene that contained 74.5 ppm Ru was pumped through a re-
actor that was filled with QuadraSil AP in one pass at a
flow rate of 0.05 mLminÀ1. The reactor was locally heated at
608C. As a result, the ruthenium content in the crude mate-
rial decreased to 8.5 ppm. In essence, the scavenging process
lowered the ruthenium contamination to about one fifth and
one tenth of the original values under batch and flow condi-
tions, respectively. Next, we screened for other scavenging
~
&
^
608C: 1st run, 2nd run, ꢅ 3rd run, split test.
After 3 h of circulation, the conversion reached 82% in
the first run, 68% in the second run, and 38% in the third
run. In contrast, conversions of above 80% were commonly
achieved in the batch mode within 1.5 to 3 h for the first ten
consecutive runs (see Figure 8). For the 3rd run, the conver-
sion reached 60% after 10 h of continuous circulation. A
split test was conducted during the first run when about
52% of the starting diene (35) had been consumed. This
test revealed no catalytic activity outside the reactor. More-
over, the leaching was moderate (Table 4). The batch and
the circulating-flow modes showed similar profiles of ruthe-
nium leaching. However, because a higher catalyst/substrate
ratio was used in the flow experiment (2.5 mol% versus
1 mol%), the crude product was more contaminated with
ruthenium in the latter case. Irrespective of whether batch
or flow conditions were employed, ruthenium leaching was
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Chem. Eur. J. 2012, 18, 16369 – 16382

Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
systems in a similar manner as that described above. Tol-
uene was chosen as the solvent and the scavenging process
was conducted at room temperature for 18 h. After filtration
and evaporation of the solvent, the products were analyzed
by using ICP-MS. The results of these experiments are sum-
marized in Table 5 and in Figure 11; these data show that
the ruthenium content can be easily decreased to below
5 ppm by treatment of the crude metathesis products with
suitable commercial scavenger resins.
change of pre-catalyst 14e. Pre-catalyst 34 could be used for
consecutive metathesis reactions both under batch and cir-
culating-flow conditions. Ruthenium leaching was very low
to moderate, depending on the solvent used. Metallic wastes
could be lowered further for batch and flow systems by
using common scavenging systems. Finally, it must be noted
that heterogenized pre-catalyst 34 is insensitive to water and
air and it can be stored for a long time. However, the lack
of recyclability of supported pre-catalyst 34 hampers its effi-
cient application in continuous-flow processes. The introduc-
tion of an additional ionic tag onto the diaminocarbene an-
cillary ligand,[28] which should improve its performance, it
currently being investigated in our laboratories.
Table 5. Scavenging of ruthenium impurities from crude compound 36 in
toluene, which was obtained from the RCM reaction catalyzed by pre-
catalyst 34.
Scavenger
Initial Ru content
Ru content
in compound 36
after treatment
AHCTUNGTRENNUNG
[ppm][a]
with scavenger [ppm][a]
Experimental Section
QuadraSil MP[b]
QuadraSil MTU[c]
QuadraSil TA[d]
QudraPure TU[e]
QudraPure BDZ[f]
48
30
30
17
17
5
4
2
3
5
General information: 1H NMR spectra were recorded on Bruker
AVANCE 500 or Bruker ARX400 spectrometers. Chemical shifts are re-
ported in ppm relative to the solvent resonance as an internal standard
(CDCl3; 1H: d=7.26 ppm, 13C: d=77.00 ppm). The data are reported as
follows: chemical shift (d) in ppm, multiplicity (s=singlet, d=doublet,
t=triplet, q=quadruplet, hept=heptuplet, m=multiplet), coupling con-
stants (J) in Hz, integration, and attribution. GC analysis was conducted
on a Hewlett–Packard HP 6890 Series GC System equipped with an
OPTIMAꢇ-5 0.25 mm fused silica capillary column (30 mꢅ0.32 mm ID,
stationary phase thickness 0.25 mm, Macherey–Nagel). The following
heating mode was used: 1 min at 508C, then heating to 3008C with a gra-
dient 258CminÀ1 (10 min), then 9 min at 3008C. Under these conditions,
the analyzed compounds had the following retention times (tR): 8.9 min
for compound 12, 8.5 min for compound 13, 10.8 min for compound 25,
11.6 min for compound 26, 7.7 min for compound 27, 8.8 min for com-
pound 28, 8.4 min for compound 35, 8.1 min for compound 36, 10.8 min
for compound cis-38, 11.0 min for compound trans-38, 11.1 min for com-
pound cis-40, 11.4 min for compound trans-40. The Ru content was deter-
mined by inductively coupled plasma–mass spectrometry (ICP-MS XSer-
ies 2, “Thermo Scientific”). HRMS analysis (ESI) was performed on a
Waters Q-Tof 2 at the Centre Rꢀgional de Mesures Physiques de l’Ouest
(CRMPO), Universitꢀ de Rennes 1. All glassware was pre-dried in an
oven and the reactions were performed under a nitrogen atmosphere
unless otherwise noted. All organic solvents were dried by being passed
through solvent purification columns that contained activated alumina,
except for n-hexane, which was used as received (“Rotisolv for HPLC”,
Roth), and degassed. All commercial chemicals were used as received
unless otherwise noted. Toluene and THF were dried by being passed
through solvent purification columns that contained activated alumina.
CH2Cl2 was distilled over CaH2. All commercial chemicals were used as
received unless otherwise noted. After isolation by using flash chroma-
tography on silica gel, the known compounds 13,[29b] 26,[29c] 28,[29c] 36,[29a]
38,[17a] and 40[29d] were identified by full characterization (1H- and 13C-
NMR, mass-spectrometry) and comparison with the literature data.
[a] Determined by ICP-MS; [b] Quadrasil MP: mercaptopropyl;
[c] Quadrasil MTU: methylthiourea; [d] Quadrasil TA: triamine;
[e] Quadrasil TU: thiourea; [f] Quadrasil BDZ: propylimidazole.
Figure 11. Minimization of ruthenium impurities (in ppm) with different
scavengers. Bars to the left represent the starting content of Ru and bars
to the right Ru content after treatment.
Conclusion
In summary, the introduction of an oxazine chelating func-
tion onto the styrenyl fragment of Ru-based complexes has
allowed us to efficiently control the reactivity of their corre-
sponding pre-catalysts (14a–14d). Both steric and electronic
activation led to various kinetic initiation profiles that
ranged from slow to high. Interestingly, the oxazine function
facilitated the introduction of an ionic tag, which provided
the expected ionically tagged Ru-pre-catalyst (14e). This
complex showed an unprecedentedly fast kinetic initiation
at 1 mol%, thereby reaching full conversion within 20 min.
Good activities were reached at a low loading of 0.5 mol%
in both the RCM and CM transformations. Finally, a new
heterogeneous pre-catalyst 34 was developed that could be
prepared in a very straightforward manner by the ion-ex-
1-(4-(4-Isopropoxy-3-(prop-1-enyl)phenylcarbamoyl)benzyl)-pyridinium
hexafluorophosphate(V) (9): 4-(Bromomethyl)benzoyl chloride (1.08 g,
4.65 mmol, 1.2 equiv) was added at 08C to a solution of compound 7
(882 mg, 3.87 mmol) and pyridine 1.6 mL, 19.35 mmol, 5 equiv) in
CH2Cl2 (50 mL) and the reaction mixture was stirred for 3 h at RT. The
organic layer was washed successively with 1m HCl (ꢅ2) and saturated
solutions of NaHCO3 and brine, dried over MgSO4, and evaporated
under reduce pressure to afford 1 g of the desired product (yield: 66%).
Next, the previously prepared amide (1 g, 2.5 mmol) was added to pyri-
dine (4 mL, 20 equiv) in toluene (70 mL) and the mixture was heated at
reflux overnight. The volatile compounds were removed, potassium hexa-
fluorophosphate (462 mg, 1 equiv) and water (100 mL) were added, and
the mixture was stirred for 10 min. The desired product was extracted
with CH2Cl2. After concentration under vacuum, 1.13 g of compound 9
Chem. Eur. J. 2012, 18, 16369 – 16382
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16377

A. Kirschning, M. Mauduit et al.
was obtained (yield: 85%). 1H NMR (400 MHz, CDCl3, E/Z mixture
25:75): d=8.67 (br s, 1H; Z), 8.63 (br s, 1H; E), 8.53 (d, J=6.4 Hz, 2H;
E), 8.46 (d, J=5.9 Hz, 2H; Z), 8.19 (dd, J=7.9, 7.0 Hz, 1H), 7.71 (dd,
J=7.3, 6.8 Hz, 2H), 7.59 (d, J=7.7 Hz, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.31
(d, J=8.1 Hz, 1H), 7.21 (s, 1H), 6.65 (d, J=9.5 Hz, 1H; Z), 6.60 (d, J=
8.6 Hz, 1H; E), 6.47 (dd, J=15.8, 2.2 Hz, 1H; E); 6.32 (dd, J=11.4, 1.8,
1H; Z), 6.01 (dq, J=15.8, 6.6 Hz, 1H; E), 5.61 (dq, J=11.4, 6.4 Hz, 1H;
Z), 5.56 (s, 1H), 4.28 (sept, J=6.2 Hz, 1H), 1.68–1.61 (m, 3H), 1.59 (s,
2H), 1.15 ppm (d, J=6.2 Hz, 6H); 19F NMR (376 MHz, CDCl3): d=
À70.9 ppm (d, J=718 Hz, 6F); 31P NMR (162 MHz, CDCl3): d=
À144.4 ppm (sept, J=718 Hz, 1P); 13C NMR (101 MHz, CDCl3, E/Z mix-
ture): d=167.61, 154.03, 147.56, 146.18, 137.93, 137.78, 134.63, 132.04,
130.20, 129.88, 129.81, 129.57, 129.27, 127.45, 126.59, 124.83, 122.25,
115.80, 72.34, 65.17, 29.37, 27.99, 22.46, 14.95, 14.03 ppm.
CDCl3, E/Z mixture): d=162.27, 141.48, 140.80, 133.27, 133.12, 126.63,
126.39, 126.15, 125.85, 125.42, 124.84, 120.55, 119.88, 119.86, 116.11,
113.94, 113.64, 75.37, 45.13, 25.97, 25.93, 18.98, 14.89, 9.85, 9.78 ppm;
HRMS: calcd for C13H18NO: 204.1388 [M+H]+; found: 204.1386.
General procedure for synthesis of oxazine ligand 19: An appropriate
halogen compound (1.2 equiv) was added to a mixture of NaH (4 equiv)
and the oxazine in THF (1 mL per 0.1 mmol of oxazinone) at 08C and
the mixture was stirred at RT for 3 h. THF was removed under reduce
pressure and EtOAc was added. The organic layer was washed with satu-
rated solutions of NaHCO3 and brine, dried over MgSO4, and evaporated
to dryness. The products were purified by column chromatography on
silica gel (cyclohexane/EtOAc, 9:1).
2-Ethyl-4-methyl-8-(prop-1-enyl)-3,4-dihydro-2H-benzo[b]ACTHNUGRTNEUNG[1,4]oxazine
(19a): Following the general procedure for the synthesis of the oxazine
ligand with methyl iodide (287 mL, 4.6 mmol, 10 equiv), NaH (74 mg,
1.28 mmol, 4 equiv), and compound 15a (100 mg, 0.46 mmol), the expect-
ed compound was isolated as a white solid as a mixture of E/Z isomers
(20:80, 75 mg, yield: 71%). 1H NMR (400 MHz, CDCl3, E/Z mixture):
d=6.71 (t, J=8.1 Hz, 1H), 6.68–6.64 (m, 1H; E), 6.61 (dd, J=7.5,
1.3 Hz, 1H; Z), 6.59–6.53 (m, 1H; E), 6.50 (dd, J=7.9, 1.3 Hz, 1H; Z),
6.48–6.42 (m, 1H), 6.12 (dq, J=15.8, 6.6 Hz, 1H; E), 5.70 (dq, J=11.4,
7.0 Hz, 1H; Z), 4.06–3.98 (m, 1H), 3.11 (dd, J=11.4, 2.4 Hz, 1H), 2.91
(dd, J=11.4, 7.9 Hz, 1H), 2.79 (s, 3H), 1.80 (dd, J=6.6, 1.8 Hz, 1H; E),
1.77 (dd, J=7.0, 1.8 Hz, 1H; Z), 1.73–1.47 (m, 2H), 1.00 (t, J=7.3 Hz
3H; E), 0.97 ppm (t, J=7.4 Hz 3H; Z); 13C NMR (101 MHz, CDCl3, E/Z
mixture): d=136.14, 126.37, 125.86, 125.68, 125.30, 120.61, 119.90, 119.34,
115.46, 110.90, 110.61, 74.92, 53.55, 39.08, 26.11, 14.90, 9.85, 9.79 ppm;
HRMS: m/z calcd for C14H20NO: 218.1545 [M+H]+; found: 218.1540.
8-Bromo-2-ethyl-2H-benzo[b]ACTHNUGRTENUNG[1,4]oxazin-3(4H)-one (16a): To a stirring
solution of 2-bromo butyric acid (10.0 mL, 0.0936 mole) in dry CH2Cl2
(100 mL) under a nitrogen atmosphere at 08C was added dropwise oxalyl
chloride (8.16 mL, 0.0936 mole) and 2 drops of DMF. The reaction mix-
ture was stirred at RT for 2 h. Then, the volatile compounds were con-
centrated under vacuum to give the crude material, which was dissolved
in CH2Cl2 (75 mL). This solution of acid chloride 18a was slowly added
to a mixture of amine 17a (16 g, 0.0851 mole) and pyridine (6.8 mL,
0.085 mole) at 08C over a period of 30 min. The reaction mixture was
stirred at RT for 2 h and then diluted with CH2Cl2. The organic layer was
washed with water, dried with anhydrous Na2SO4, and concentrated
under reduced pressure to afford a brown-colored semi-solid that was
used in the next step without further purification (28.0 g, yield: 98%).
The brown-colored semi-solid (34.0 g, 0.1008 mole) and K2CO3 (28.54 g,
0.2068 mole) were heated at reflux in DMF (800 mL) for 3 h. After the
completion of the reaction, the mixture was cooled to RT and poured
into a mixture of water and EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure to
give a crude residue that was purified by column chromatography on
silica gel (EtOAc/n-hexane, 15%) to obtain a pale-orange-colored solid
(14a, 21.0 g, yield: 79%). 1H NMR (400 MHz, CDCl3): d=7.84 (s, 1H),
7.14 (dd, J=8.1, 1.4 Hz, 1H), 6.76 (dd, J=8.1, 7.9 Hz, 1H), 6.65 (dd, J=
7.9, 1.4 Hz, 1H), 4.54 (dd, J=9.1, 4.2 Hz, 1H), 2.00–1.71 (m, 2H),
1.08 ppm (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=167.20,
139.69, 127.75, 127.27, 123.17, 114.43, 111.37, 79.04, 23.95, 9.61 ppm.
Isobutyl-2-ethyl-8-(prop-1-enyl)-2H-benzo[b]ACTHNUTRGNE[UNG 1,4]oxazine-4(3H)-carboxy-
late (19b): Following the general procedure for the synthesis of the oxa-
zine ligand with isobutyl chloroformate (392 mL, 3 mmol, 2.5 equiv), NaH
(192 mg, 4.8 mmol, 4 equiv), and compound 15a (261 mg, 1.2 mmol), the
expected compound was isolated as a white solid as a mixture of E/Z iso-
mers (60:40, 380 mg, yield: 99%); 1H NMR (400 MHz, CDCl3, E/Z mix-
ture): d=7.67–7.49 (m, 1H), 7.06 (dd, J=7.7, 1.3 Hz, 1H; E), 6.94 (dd,
J=7.5, 1.5 Hz, 1H; Z), 6.83–6.69 (m, 1H), 6.61 (dd, J=15.6, 1.8 Hz, 1H;
E), 6.43 (dd, J=11.4, 1.8 Hz, 1H; Z), 6.15 (dq, J=15.6, 6.8 Hz, 1H; E),
5.74 (dq, J=11.4, 7.3 Hz, 1H; Z), 4.19–3.97 (m, 2H), 3.97–3.86 (m, 2H),
3.29–3.16 (m, 1H), 2.00–1.88 (m, 1H), 1.82 (dd, J=6.6, 1.8 Hz, 3H; E),
1.77 (dd, J=7.0, 1.8 Hz, 3H; Z), 1.72–1.54 (m, 2H), 1.02 (t, J=7.7 Hz,
3H; E), 0.99 (t, J=7.7 Hz, 3H; Z), 0.90 (d, J=6.8 Hz, 6H; E) 0.88 ppm
(d, J=6.6 Hz, 6H; Z); 13C NMR (101 MHz, CDCl3, E/Z mixture): d=
154.07, 143.8, 143.1, 126.9, 126.6, 126.6, 125.9, 125.6, 125.5, 125.5, 125.3,
124.8, 121.7, 119.5, 118.9, 76.2, 72.4, 45.8, 30.3, 29.7, 27.9, 26.9, 25.7, 25.6,
22.7, 19.2, 19.2, 18.9, 14.8, 9.6, 9.5 ppm; HRMS: m/z calcd for
C18H25NO3Na: 326.1732 [M+Na]+; found: 326.1762.
2-Ethyl-8-(prop-1-enyl)-3,4-dihydro-2H-benzo[b]ACHTNUTRGNE[NUG 1,4]oxazine (15a): To a
stirring solution of tetrakis(triphenylphosphine)palladium(0) (6.16 g,
5.32 mmol) in toluene (150 mL) was added a solution of compound 16a
(21.0 g, 0.0819 mol) in toluene (100 mL). The mixture was degassed for
15 min, then propenyltri-n-butyltin (44.36 g, 0.1352 mol) was added and
the mixture was stirred at 1108C for 12 h under a nitrogen atmosphere.
After filtration through a bed of celite followed by column chromatogra-
phy on silica gel (EtOAc/n-hexane, 15%), the expected 2-ethyl-8-(prop-
1-enyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (14.7 g) was obtained (yield:
84%) as pale-orange solid. 1H NMR (400 MHz, CDCl3, E isomer): d=
7.65 (s, 1H), 7.04 (dd, J=7.9, 1.3 Hz, 1H), 6.83 (dd, J=7.9, 7.7 Hz, 1H),
6.59 (dq, J=15.9, 1.7 Hz, 1H), 6.53 (dd, J=7.7, 1.3 Hz, 1H), 6.26 (dq, J=
15.9, 6.7 Hz, 1H), 4.45 (dd, J=8.7, 4.3 Hz, 1H), 1.97–1.71 (m, 5H),
0.85 ppm (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=168.67,
140.26, 128.31, 126.71, 124.29, 123.63, 121.53, 114.37, 78.22, 23.85, 18.97,
14.80, 9.82 ppm.
(2-Ethyl-8-(prop-1-enyl)-2H-benzo[b]
ACHTUNGERTN[NUNG 1,4]oxazin-4(3H)-yl)-
AHCTUNGTRENNUNG
thesis of oxazine ligand with benzoyl chloride (348 mL, 3 mmol,
2.5 equiv), NaH (192 mg, 4.8 mmol, 4 equiv), and compound 15a
(261 mg, 1.2 mmol), the expected compound was isolated as a white solid
as a mixture of E/Z isomers (65:35, 300 mg, yield: 78%); 1H NMR
(400 MHz, CDCl3): d=7.46–7.38 (m, 2H), 7.38–7.31 (m, 1H), 7.31–7.22
(m, 2H), 7.03 (dd, J=7.7, 1.1 Hz, 1H; E), 6.93 (dd, J=7.7, 1.1 Hz, 1H;
Z), 6.70–6.39 (m, 3H), 6.23 (dq, J=16.1, 6.4 Hz, 1H; E), 5.78 (dq, J=
11.4, 7.4 Hz, 1H; Z), 4.28–4.12 (m, 2H), 3.38 (dd, J=7.7, 6.1 Hz, 1H),
1.84 (dd, J=6.6, 1.5 Hz, 3H; E), 1.78 (dd, J=7.0, 2.0 Hz, 3H; Z), 1.76–
1.53 (m, 2H), 1.01 ppm (t, J=7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3,
E/Z mixture): d=168.90, 143.35, 135.43, 135.30, 130.64, 130.67, 128.62,
128.66, 128.45, 128.33, 127.34, 127.14, 126.81, 126.38, 126.27, 125.03,
124.58, 123.07, 122.92, 122.67, 119.18, 118.53, 25.95, 18.98, 14.88, 9.67,
9.52 ppm; HRMS: m/z calcd for C20H21NO2Na: 310.1470 [M+Na]+;
found: 330.1458.
Next, the previously prepared 2-ethyl-8-(prop-1-enyl)-2H-benzo[b]-
ACHTUNGTRENNUNG[1,4]oxazin-3(4H)-one (1.2 g, 5.5 mmol) was added to a suspension of
LAH (418 mg, 2 equiv, 11 mmol) in THF (50 mL) at 08C. The resulting
suspension was stirred at RT for 1 h. Water and a 1m solution of NaOH
were slowly added at 08C. The resulting precipitate was filtered through
a bed of celite and washed with warm THF. After concentration under
vacuum, compound 15a (1.1 g) was obtained as a mixture of E/Z isomers
(60:40, yield: 99%) without further purification. 1H NMR (400 MHz,
CDCl3): d=6.75–6.34 (m, 4H), 6.16 (dq, J=15.8, 6.6 Hz, 1H; E), 5.72
(dq, J=11.4, 7.0 Hz, 1H; Z), 3.98–3.91 (m, 1H), 3.28 (ddd, J=11.4, 2.9,
2.9 Hz, 1H), 3.04 (ddd, J=11.4, 7.7, 1.1 Hz, 1H), 1.81 (dd, J=6.6, 1.5 Hz,
3H; E), 1.77 (dd, J=7.0, 1.8 Hz, 3H; Z), 1.75–1.49 (m, 2H), 1.01 (t, J=
7.5 Hz, 3H; E), 0.98 ppm (t, J=7.5 Hz, 3H; Z); 13C NMR (101 MHz,
(2-Ethyl-8-(prop-1-enyl)-2H-benzo[b]ACTHNUGTRNEUNG[1,4]oxazin-4(3H)-yl)(perfluoro-
phenyl)methanone (19d): Following the general procedure for the syn-
thesis of the oxazine ligand with pentafluorobenzoyl chloride (141 mL,
0.98 mmol, 2 equiv), NaH (78 mg, 1.96 mmol, 4 equiv), and compound
15a (100 mg, 0.49 mmol), the expected compound was isolated as a white
16378
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16369 – 16382

Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
solid as a mixture of E/Z isomers (80:20, 118 mg, yield: 61%). Atro-
poisomers were observed in the NMR spectra. 1H NMR (400 MHz,
CDCl3): d=7.11 (dd, J=7.9, 1.3 Hz, 1H; E), 6.99 (dd, J=7.7, 1.1 Hz,
1H; Z), 6.64–6.37 (m, 2H), 6.30 (dd, J=8.1, 1.1 Hz, 1H; Z), 6.26 (dd, J=
7.9, 1.1 Hz, 1H; E), 6.22–5.72 (m, 1H), 4.59 (dd, J=3.1, 1.4 Hz, 1H),
4.28–4.04 (m, 1H), 3.38–3.17 (m, 1H), 1.87–1.64 (m, 5H), 1.07 (t, J=
7.5 Hz, 3H; E), 1.04 ppm (t, J=7.5 Hz, 3H; Z); 13C NMR (101 MHz,
CDCl3): d=156.90, 145.29, 144.48, 143.94, 143.54, 142.91, 141.35, 141.31,
140.99, 139.17, 139.02, 138.60, 138.43, 136.61, 136.49, 136.06, 135.90,
128.10, 127.94, 127.79, 127.60, 127.45, 127.26, 126.72, 126.43, 124.56,
124.37, 124.21, 123.96, 123.71, 122.08, 120.35, 120.18, 119.36, 119.18,
118.58, 112.19, 111.99, 111.79, 77.90, 77.83, 75.84, 48.64, 44.11, 26.08,
25.32, 18.93, 14.77, 14.68, 9.43, 9.34, 9.26 ppm; 19F NMR (376 MHz,
CDCl3): d=À139.59 to À140.69 (m, 2F), À150.30 to À151.23 (m, 1F),
À158.61 to À160.29 ppm (m, 2F); HRMS: m/z calcd for C20H16F5NO2Na:
420.0999 [M+Na]+; found: 420.0986.
114 mg, 0.11 mmol, 1.1 equiv), and copper chloride (12 mg, 0.12 mmol,
1.2 equiv), the expected catalyst (42 mg, yield: 40%) was isolated as a
green solid. 1H NMR (400 MHz, CD2Cl2): d=16.32 (s, 1H), 8.70 (d, J=
6.1 Hz, 2H), 8.55–8.45 (m, 1H), 8.08–8.00 (m, 2H), 7.96 (s, 1H), 7.92 (d,
J=8.0 Hz, 3H), 7.57–7.47 (m, 5H), 7.37 (s, 2H), 6.99 (d, J=2.1 Hz, 1H),
6.83–6.77 (m, 1H), 5.76 (s, 2H), 4.87 (sept, J=6.1 Hz, 1H), 4.17 (s, 4H),
3.55 (sept, J=6.8 Hz, 4H), 1.31 (d, J=6.1 Hz, 6H), 1.22 (d, J=6.9 Hz,
12H), 1.20 ppm (d, J=6.1 Hz, 12H); 19F NMR (376 MHz, CD2Cl2): d=
À72.6 ppm (d, J=711 Hz, 6F); 31P NMR (162 MHz, CD2Cl2): d=
À144.5 ppm (sept, J=711 Hz, 1P); HRMS: m/z calcd for
C50H61Cl2N4O2Ru: 921.3215 [MÀPF6]À; found: 921.2698.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(14a): Following the general procedure for the synthesis of the catalyst
with compound 19a (39 mg, 0.18 mmol), M21 (10, 186 mg, 0.18 mmol,
1.2 equiv), and copper chloride (20 mg, 0.20 mmol, 1.1 equiv), the expect-
ed catalyst (34 mg, yield: 25%) was isolated as a green solid. 1H NMR
(400 MHz, CD2Cl2): d=16.22 (s, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.28 (dt,
J=7.7, 1.5 Hz, 4H), 6.71 (dd, J=8.0, 1.7 Hz, 1H), 6.68 (d, J=7.2 Hz,
1H), 6.14 (dd, J=7.2, 1.7 Hz, 1H), 4.32–4.17 (m, 1H), 4.13–4.05 (m, 4H),
3.56–3.41 (m, 4H), 3.16 (dd, J=12.1, 2.3 Hz, 1H), 3.01 (dd, J=12.1,
9.2 Hz, 1H), 2.74 (s, 3H), 1.80–1.68 (m, 2H), 1.20–1.06 (m, 24H),
0.70 ppm (t, J=7.6 Hz, 3H); HRMS: m/z calcd for C39H53N3OClRu:
716.2915 [MÀCl]À; found: 716.2919.
(4-(Bromomethyl)phenyl)(2-ethyl-8-(prop-1-enyl)-2H-benzo[b]-
ACHTUNGTRENNUNG[1,4]oxazin-4(3H)-yl)methanone (20): Following the general procedure
for the synthesis of the oxazine ligand with 4-(bromomethyl)benzoyl
chloride (2.08 g, 8.9 mmol, 1.5 equiv), 2,6-lutidine (1.04 mL, 8.9 mmol,
1.5 equiv), and compound 15a (1.22 g, 5.9 mmol), the expected com-
pound was obtained as a as a mixture of E/Z isomers (20:80, 2.34 g,
yield: 99%). 1H NMR (400 MHz, C6D6): d=7.40–7.32 (m, 2H), 7.15 (dd,
J=7.7, 1.3 Hz, 1H; E), 7.07 (dd, J=7.5, 1.1 Hz, 1H; Z), 7.11–6.99 (m,
1H), 6.99–6.86 (m, 2H), 6.80 (d, J=12.1 Hz, 1H), 6.54–6.44 (m, 1H),
6.24 (dq, J=11.4, 7.0 Hz, 1H; Z), 5.84 (dq, J=15.8, 6.6 Hz, 1H; E), 4.03–
3.67 (m, 4H), 3.09–2.98 (m, 1H), 1.84–1.64 (m, 3H), 1.44–1.32 (m, 1H),
1.19–1.06 (m, 1H), 0.81–0.73 ppm (m, 3H); 13C NMR (101 MHz, C6D6,
E/Z mixture): d=166.34, 143.07, 142.31, 138.98, 138.61, 134.72, 134.68,
128.03, 127.99, 127.94, 127.73, 127.21, 125.97, 125.65, 125.41, 125.24,
125.06, 124.48, 123.95, 122.13, 121.99, 121.37, 118.07, 117.46, 75.93, 43.96,
30.98, 24.54, 24.49, 17.65, 13.49, 8.19, 8.12 ppm; HRMS: m/z calcd for
C21H22BrNO2Na: 422.0732 [M+Na]+; found: 422.0715.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
sis of the catalyst with compound 19b (50 mg, 0.17 mmol), M21 (10,
170 mg, 0.17 mmol, 1 equiv), and copper chloride (18 mg, 0.18 mmol,
1.1 equiv), the expected catalyst (59 mg, yield: 43%) was isolated as a
1
green solid. H NMR (400 MHz, CD2Cl2): d=16.22 (s, 1H), 8.04–7.93 (m,
1H), 7.45 (t, J=7.7 Hz, 2H), 7.29 (d, J=7.7 Hz, 4H), 6.82–6.73 (m, 1H),
6.53 (dd, J=7.6, 1.3 Hz, 1H), 4.23 (dd, J=13.9, 2.2 Hz, 1H), 4.13–4.06
(m, 6H), 3.92–3.79 (m, 2H), 3.54–3.41 (m, 4H), 3.22 (dd, J=13.9, 8.5 Hz,
1H), 1.92–1.75 (m, 2H), 1.17 (d, J=7.0 Hz, 24H), 0.84 (d, J=6.7 Hz,
6H), 0.75 ppm (t, J=7.6 Hz, 3H); HRMS: m/z calcd for
C43H59N3O3Cl2RuNa: 860.2869 [M+Na]+; found: 860.2863.
1-(4-(2-Ethyl-8-(prop-1-enyl)-3,4-dihydro-2H-benzo[b]ACTHUNRTGNEUNG[1,4]oxazine-4-car-
bonyl)benzyl)pyridinium hexafluorophosphate(V) (19e): Oxazine 20
(1.22 g, 3 mmol) was added to a solution of pyridine (5 mL, 20 equiv) in
toluene (50 mL) and the mixture was heated at reflux overnight. The vol-
atile compounds were removed under vacuum, potassium hexafluoro-
phosphate (828 mg, 1.5 equiv) and water (150 mL) were added, and the
mixture was stirred for 10 min. The crude mixture was extracted with
CH2Cl2 (3ꢅ50 mL). After concentration under vacuum, the desired prod-
uct was obtained as a mixture of E/Z isomers (25:75, 822 mg, yield:
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dichloride (14c): Following the general procedure for the synthesis of the
catalyst with compound 19c (50 mg, 0.17 mmol), M21 (10, 170 mg,
0.17 mmol, 1 equiv), and copper chloride (18 mg, 0.18 mmol, 1.1 equiv),
the expected catalyst (30 mg, yield: 22%) was isolated as a green solid.
1H NMR (400 MHz, CD2Cl2): d=16.24 (s, 1H), 7.45 (t, J=7.7 Hz, 2H),
7.40–7.32 (m, 4H), 7.31–7.25 (m, 6H), 6.61–6.50 (m, 2H), 4.37–4.26 (m,
1H), 4.17–4.05 (m, 4H), 4.01–3.92 (m, 1H), 3.58–3.53 (m, 1H), 3.53–3.42
(m, 4H), 1.88–1.76 (m, 2H), 1.25–1.06 (m, 24H), 0.64 ppm (t, J=7.6 Hz,
3H); HRMS: m/z calcd for C45H55N3O2Cl2RuNa: 864.2607 [M+Na]+;
found: 864.2610.
1
50%). H NMR (400 MHz, [D6]DMSO): d=9.19 (d, J=5.5 Hz, 2H), 8.64
(dd, J=7.9, 7.3 Hz, 1H), 8.19 (dd, J=7.7, 7.3 Hz, 2H), 7.58–7.52 (m,
4H), 7.17–6.74 (m, 2H), 6.68–6.54 (m, 1H), 6.6 (dd, J=15.8, 1.5 Hz, 1H;
E), 6.45 (dd, J=11.6, 2.0 Hz, 1H; Z), 6.26 (dq, J=15.8, 6.6 Hz, 1H; E),
5.9 (br s, 1H), 5.79 (dq, J=11.4, 7.0 Hz, 1H; Z), 4.31–4.21 (m, 1H), 4.09–
3.99 (m, 2H), 3.48–3.39 (m, 1H), 1.85 (dd, J=6.4, 1.8 Hz, 3H; E), 1.77
(dd, J=7.0, 1.7 Hz, 3H; Z), 1.70–1.52 (m, 2H), 1.00–0.90 ppm (m, 3H);
19F NMR (376 MHz, [D6]DMSO): d=À71.7 ppm (d, 6F, J=711 Hz);
31P NMR (162 MHz, [D6]DMSO): d=À144.5 ppm (sept, 1P, J=711 Hz);
13C NMR (101 MHz, [D6]DMSO, E/Z mixture): d=167.05, 146.09, 144.92
(2C), 143.53, 136.36, 136.12, 128.88 (2C), 128.73 (2C), 128.50 (2C),
126.68, 125.66, 125.35, 124.76, 124.29, 122.66, 118.21, 83.54, 76.32, 62.81,
24.95, 14.55, 9.18 ppm; HRMS: m/z calcd for C26H27N2O2: 399.2067
[MÀPF6]À; found: 399.2070.
General procedure for the synthesis of the catalyst: A solution of the
ligand in CH2Cl2 was added to a solution of M21 (10, 1.2 equiv) and
copper chloride (1.3 equiv) in dry CH2Cl2 (1 mL per 0.07 mmol of oxazi-
none). The resulting mixture was stirred at 358C for 1.5–2 h. The volatile
compounds were removed under reduce pressure, acetone was added to
the residue, and the solution was filtered through a plug of Celite. The
filtrate was concentrated and purified by column chromatography on
silica gel (n-pentane/acetone, 9:1 to 8:2).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
thenium(II) dichloride (14d): Following the general procedure for the
synthesis of the catalyst derivative of oxazinone/oxazine with compound
19d (118 mg, 0.297 mmol), M21 (10, 307 mg, 0.297 mmol, 1 equiv), and
copper chloride (32 mg, 0.32 mmol, 1.1 equiv), the expected catalyst
(125 mg, yield: 45%) was isolated as a green solid. 1H NMR (400 MHz,
CD2Cl2): d=16.22 (d, J=6.6 Hz, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.29 (d,
J=7.7 Hz, 4H), 7.22–6.82 (m, 1H), 6.72–6.59 (m, 1H), 6.57–6.44 (m,
1H), 4.33–4.21 (m, 1H), 4.16–4.04 (m, 4H), 3.70–3.59 (m, 1H), 3.57–3.41
(m, 4H), 3.41–3.29 (m, 1H), 1.96–1.71 (m, 2H), 1.27–1.02 (m, 24H),
0.60 ppm (t, J=7.6 Hz, 3H); 19F NMR (376 MHz, CD2Cl2): d=À142.94
(2F), À154.00, À161.93 ppm (2F); HRMS: m/z calcd for
C45H50Cl2N3O2F5RuNa: 954.2135 [M+Na]+; found: 954.2139.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
8-yl)methylene)ruthenium(II) dichloride hexafluorophosphate(V) (14e):
Following the general procedure for the synthesis of the catalyst deriva-
tive of oxazinone/oxazine with compound 19e (605 mg, 1.11 mmol), M21
ACHTUNGTRENNUNG
Chem. Eur. J. 2012, 18, 16369 – 16382
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16379

A. Kirschning, M. Mauduit et al.
(10, 1.148 g, 1.11 mmol), and copper chloride (330 mg, 1.3 equiv,
with periodic GC analyses of aliquots of the supernatant (10 mL) from
both reactors to determine the conversions.
3.33 mmol) in dry CH2Cl2 (4 mL), the expected product (1.2 g, yield:
76%) was obtained as a green powder. H NMR (400 MHz, CD2Cl2): d=
1
General procedure for the cross-metathesis: A mixture of heterogeneous
16.37 (s,1H), 8.61 (d, J=5.1 Hz, 2H), 8.33 (dd, J=8.0, 7.3 Hz,1H), 7.83
(dd, J=6.7, 6.2 Hz, 2H), 7.53 (dd, J=7.7, 7.7 Hz, 2H), 7.37–7.26 (m,
6H), 7.26–7.21 (m, 2H), 7.12–6.86 (m, 1H), 6.61 (d, J=2.9 Hz, 2H), 5.66
(s, 2H), 4.42 (s, 1H), 4.19 (s, 4H), 4.02 (d, J=13.6 Hz, 1H), 3.63–3.55 (m,
1H), 3.68–3.51 (m, 1H), 1.94–1.72 (m,2H), 1.28–1.14 (m, 24H), 0.72 ppm
(t, J=6.9 Hz, 3H); 19F NMR (376 MHz, CD2Cl2): d=À72.6 ppm (d, J=
711 Hz, 6F); 31P NMR (162 MHz, CD2Cl2): d=À144.5 ppm (sept, J=
711 Hz, 1P); HRMS: m/z calcd for C51H61Cl2N4O2Ru: 933.3209
[MÀPF6]À; found: 933.3214.
ruthenium pre-catalyst 34 (2.5 mmol) and the solvent (0.5 mL) in
a
Schlenk tube was pre-heated to the given temperature. Then, a solution
of alkene (0.1 mmol) and methyl acrylate (0.4 mmol) in the same solvent
(0.5 mL) was added and the mixture was stirred at the given temperature
under a nitrogen atmosphere (balloon). After the required time, the mix-
ture was filtered, the filtrate was concentrated in vacuum, and the residue
1
was analyzed by H NMR spectroscopy and by GC. Then, the cross-prod-
uct was isolated by flash chromatography on silica gel.
General procedure for the consecutive RCM runs in a circulating-flow
mode: Heterogeneous pre-catalyst 34 (111 mg, 0.01 mmol) was placed
into the reactor (glass column, 100 mmꢅ2.5 mm). The reactor was attach-
ed to the pump and flushed with the solvent (15 mL) in a one-way mode.
Then, a three-necked reservoir that contained the solvent (3 mL) and
was filled with nitrogen gas was incorporated to give a circulating-flow-
reactor system. The reactor was placed into the heating bath and the sol-
vent was circulated at a flow rate of 2.5 mLminÀ1. After pre-heating the
reactor to the given temperature, the diene substrate (0.4 mmol) was
added to the reservoir and the solution of the substrate was pumped
through the reactor in a cycle mode with a flow rate of 2.5 mLminÀ1. Pe-
riodically, aliquots of the supernatant (10 mL) were removed from the
reservoir and analyzed by GC. After the completion of the run, the reser-
voir was disconnected, the reactor was washed with the solvent (20 mL)
in a one-way mode, and the next run was carried out in a similar manner
after the incorporation of the three-necked reservoir that contained the
diene substrate (0.4 mmol) and the solvent (3 mL).
Preparation of immobilized pre-catalyst 34: Silica gel that was functional-
À
ized with p-toluenesulfonic acid groups (Si TsOH, “Biotage”,
0.64 mmolgÀ1) was shaken in excess 0.13m aqueous lithium carbonate
solution for 2 h at RT, washed thoroughly with water and MeOH, and
dried under vacuum at 808C to give silica gel that was functionalized
with lithium p-toluenesulfonate groups. This support (200 mg,
0.128 mmol) was shaken in a Schlenk tube under a nitrogen atmosphere
at RT with a solution of ruthenium catalyst 14e (21.6 mg, 0.020 mmol) in
acetone (4 mL) for 1 min, degassed water (4 mL) was added, and the
shaking was continued for a further 5 min. At this point, the solid phase
had turned green and the supernatant had become colorless. The super-
natant was removed by syringe and the solid was washed with acetone
(5ꢅ5 mL) and n-hexane (3ꢅ5 mL) and dried under vacuum at RT to
give heterogeneous pre-catalyst 34 (218 mg) as a dark-green powder. The
established catalyst loading was 0.09 mmolgÀ1, as determined by gravi-
metric analysis and by ruthenium-content analysis by using ICP-MS.
Split tests for continuous-flow reactions: For the split test, the superna-
tant of the reservoir was sampled (0.1 mL) at a given time and transfer-
red into a vial that was filled with nitrogen gas. The vial was shaken at
the given temperature and the solution was periodically analyzed by GC
(10 mL aliquots) to determine the degree of conversion.
General procedure for ring-closing and enyne metathesis in a batch
mode:
A
mixture of heterogeneous ruthenium pre-catalyst 34
(0.002 mmol) and degassed solvent (2 mL) in a Schlenk tube was pre-
heated to the desired temperature. The diene or enyne substrate
(0.2 mmol) was added and the mixture was stirred with heating under a
nitrogen atmosphere (a balloon was used to subdue the increase in pres-
sure during the course of ethylene formation). Periodically, aliquots of
the supernatant (10 mL) were removed and analyzed by GC. After the
completion of the reaction, the supernatant was removed by using a plas-
tic syringe that was equipped with a 0.45 mm PTFE filter. The heteroge-
neous catalyst was stirred with a fresh portion of solvent (2 mL) for
1 min and the supernatant was again removed by using a syringe with an
attached 0.45 mm PTFE filter. This procedure was repeated four further
times. The combined organic phases were concentrated under vacuum to
give a crude product that was then either analyzed for Ru content or pu-
rified by flash chromatography on silica gel.
Typical procedure for ruthenium scavenging under batch-mode condi-
tions: Crude compound 36 (40 mg) that contained 195.8 ppm of rutheni-
um that was collected from a RCM with heterogeneous pre-catalyst 34
was taken up in toluene (5 mL). QuadraSil AP (150 mg) was added to
this solution and the mixture was shaken at 608C for 3 h. Then, the solid
scavenger was filtered off, the filtrate was concentrated under vacuum,
and the ruthenium content of the remaining compound 36 (38 mg) was
analyzed by ICP-MS.
Typical procedure for ruthenium scavenging under continuous-flow con-
ditions in one pass: Crude compound 36 (39 mg) that contained 74.5 ppm
of ruthenium that was collected from a RCM with heterogeneous pre-
catalyst 34 was taken up in toluene (5 mL). This solution was pumped at
a flow rate of 0.05 mLminÀ1 through a preheated (608C) reactor (glass
column, 100 mmꢅ2.5 mm) that was filled with QuadraSil AP (200 mg).
After one pass, the reactor was washed with toluene (15 mL), the com-
bined eluate was concentrated under vacuum, and the ruthenium content
of compound 36 (38 mg) was analyzed by ICP-MS.
General procedure for the consecutive RCM runs in a batch mode: A
mixture of heterogeneous ruthenium pre-catalyst 34 (0.002 mmol) and
degassed solvent (2 mL) in a Schlenk tube was pre-heated to the desired
temperature. Diene substrate (0.2 mmol) was added and the mixture was
stirred at the given temperature under a nitrogen atmosphere. Periodical-
ly, aliquots of the supernatant (10 mL) were removed and analyzed by
GC. After completion of the first run, the supernatant was removed by
using a syringe and the catalyst was stirred with a new portion of the sol-
vent (2 mL) for 1 min, followed by the removal of the supernatant with
the syringe. This washing procedure was repeated four more times. Then,
the solvent (2 mL) was added to the catalyst, the mixture was pre-heated
to the given temperature, and the next run was initiated through the ad-
dition of the diene substrate (0.2 mmol) into the Schlenk tube.
Analytical determination of ruthenium concentration: All of the samples,
which ranged from colorless to black, were microwave digested in mi-
crobeakers by using sub-boiled HNO3 (about 60%, 0.5 mL) and 1 mL
HCl (35% p.a., Merck) and diluted by using 2% HCl. The microwave
program was set to a maximum beaker temperature of 2008C, after a
10 min heat-up period, for 20 min. Different sets of digestion methods, in-
cluding different combinations of acids, where tested on a single sample;
the combination of HNO3 and HCl was found to be superior in terms of
repeatability and maximum ruthenium signal. The determination of
ruthenium traces was carried out on an inductively coupled plasma–mass
spectrometer (ICP-MS) Thermo X2 ICP-QMS (Thermo Fisher Scientific,
Dreieich, Germany). The plasma power of the instrument was set to
1400 W throughout the measurements. The gas-flow rates were: nebuliser
0.98 LminÀ1, auxiliary 0.8 LminÀ1, and plasma gas 13 LminÀ1, argon with
a purity degree 5.0 (99.999%). The purging time was set to 40 s between
the sample measurements and 40 s on the sample solution before the
measurements. Peak-jump mode was used with a measurement time of
10 ms for 100 cycles for each isotope. For each solution, the measurement
General procedure for the split tests: The ring-closing and enyne meta-
thesis were carried out as described above. At a given time, the superna-
tant (0.1 mL) was removed by using a plastic syringe that was equipped
with a 0.45 mm PTFE filter (this procedure was carried out at the corre-
sponding reaction temperature to avoid the possible retrapping of the ho-
mogeneous catalyst as the temperature changes). The filtered superna-
tant was transferred into another Schlenk tube that was pre-filled with ni-
trogen and contained a magnetic stirring bar and GC analysis was imme-
diately performed to determine the conversion at the split time. The re-
actions in both Schlenk tubes were carried out under identical conditions,
16380
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Chem. Eur. J. 2012, 18, 16369 – 16382

Ionically Tagged Ru Complex for Olefin Metathesis
FULL PAPER
was repeated five times. Quantification was performed by averaging the
concentrations that were obtained for 99Ru, 102Ru, and 104Ru, by using at
least five liquid ruthenium standards that matched the respective sam-
ples, with concentrations that ranged from 90 ngLÀ1 to 10 mgLÀ1. The
standard solutions were prepared from a 1000 mgLÀ1 ruthenium solution
(Spex Certiprep) and diluted by using 2% HCl. Under the conditions
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Funding for this project was generously provided by the European Com-
munity through the Seventh Framework Program (CP-FP 211468–2
EUMET grant to E.B., M.R., and W.S.). This work was supported by the
CNRS and by the Ministꢈre de la Recherche et de la Technologie. M.M.
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nancial support related to the development of metathesis catalysts. Addi-
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Received: May 7, 2012
Published online: October 22, 2012
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