Efficient, durable and reusable olefin metathesis catalysts with high affinity to silica gel

Article abstract of DOI:10.1016/j.tet.2013.06.056

The new Scorpio type olefin metathesis catalysts with very high affinity to silica gel are reported. After completion of the reaction, those complexes can be efficiently separated from reaction product by direct filtration of reaction mixture through a sh

Full text of DOI:10.1016/j.tet.2013.06.056

Tetrahedron 69 (2013) 7408e7415
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient, durable and reusable olefin metathesis catalysts with high
affinity to silica gel
,
a
a
b,
Krzysztof Skowerski a , Piotr Kasprzycki , Micha1 Bieniek , Tomasz K. Olszewski
*
*
a
ꢀ
Apeiron Synthesis Sp. z o.o., Klecinska 125, 54-413 Wrocław, Poland
Wrocław University of Technology, Faculty of Chemistry, Department of Organic Chemistry, Wybrzeze St. Wyspianskiego 27, 50-370 Wrocław, Poland
b
_
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
The new Scorpio type olefin metathesis catalysts with very high affinity to silica gel are reported. After
completion of the reaction, those complexes can be efficiently separated from reaction product by
direct filtration of reaction mixture through a short pad of silica gel. Products obtained by this
methodology are contaminated with low amounts of residual ruthenium. Especially, catalyst
(H2IPr)(Cl)2Ru]C(H)(C6H4OR) (5b, R¼CH(Me)(C(O)N(Me)OMe) exhibited very high activity and could
be easily recovered and reused. Additionally, this catalyst was found to be effective already at
0.1e0.5 mol % and showed good compatibility with environmentally benign solvents.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 February 2013
Received in revised form 7 June 2013
Accepted 17 June 2013
Available online 24 June 2013
Keywords:
Olefin metathesis
Catalysis
Reusable catalyst
Ruthenium removal
Organometallic reagents
1. Introduction
For current applications, commercially available first- and
second-generation catalysts G1 and G2 are already remarkably ef-
Olefin metathesis is a powerful transformation that is widely
used in organic synthesis for the formation of carbonecarbon
double bonds.1e5 The continuing success of olefin metathesis is due
to the development of efficient and stable catalysts for this trans-
formation (Fig. 1).
ficient.1,2 The Hoveyda catalyst H1,6 and its second-generation
congener H2, possess reactivity comparable to that of G2 and
they are efficient for the metathesis of highly electron-deficient
substrates (e.g., acrylonitrile).7 Grela et al. demonstrated that the
4-nitro-substituted complex N2 initiates olefin metathesis dra-
matically faster than the parent HoveydaeGrubbs catalyst H2.8,9
Later on, it was reported that replacement of the terminal iso-
propyl substituent of the hemilabile ether functionality by an ester
group, originally selected also on account of its electron-
withdrawing properties led to the isolation of the new complex
E2 (Fig. 2).
E2 was the first example of the so called Scorpio catalyst, where
the added ester group coordinates to the metal, thereby contrib-
uting to the overall stability of the complex.10,11 Recently, Grela
published further catalysts with other functional groups installed
as terminal substituents of the benzylidene ether ligand, such as
E20, Kme2, Ket2 and Carb2 that were found to be very active.12,13
One of the major problems in the application of olefin metathesis,
particularly in pharmaceutical industry, is related to the residual
ruthenium removal.2 Ruthenium level in orally administrative
drugs must not exceed 10 ppm. Additionally ruthenium hydride
complexes, formed after decomposition of metathesis catalysts can
also lead to unwanted side reactions during product isolation and
purification.14 Several protocols for separation of metal containing
impurities from metathesis products have been developed so far.15
Fig. 1. Classical metathesis catalysts and NHC ligands.
* Corresponding authors. Tel.: þ48 71 7985 621; fax: þ48 71 7985 622 (K.S.); tel.:
þ48 320 3210; fax: þ48 71 320 2427 (T.K.O.); e-mail addresses: krzysztof.sko-
werski@apeiron-synthesis.com (K. Skowerski), tomasz.olszewski@pwr.wroc.pl (T.K.
Olszewski).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.056

K. Skowerski et al. / Tetrahedron 69 (2013) 7408e7415
7409
O
Cl
O
K2CO3
DMF, 50 oC
O
HO
O
N
O
R
N
R
1
2a: R = H
2b: R = Me
3a: R = H, 98%
3b: R = Me, 88%
Scheme 1. Preparation of benzylidene ligands 3a and 3b.
Fig. 2. Modified olefin metathesis catalysts.
For example, extraction with supercritical carbon dioxide,16 treat-
ment with aqueous hydrogen peroxide and filtration through silica
gel17 as well as the use of various scavengers18 allow to reduce the
ruthenium content to 10e60 ppm. Alternatively, two cycles of
chromatography combined with 12 h incubation with activated
charcoal was shown to reduce the amount of residual ruthenium to
60 ppm.19 However, those methods are time consuming and in
some cases can provoke side reactions. In a different approach
catalysts with high affinity to silica gel, such as A220 and Q221
(Fig. 2) or heterogenic complexes, such as Het-222 and Het-323
and others were synthesized.24e37 Homogeneous catalysts with
classical NHC ligand and modified benzylidene ligand allow to
obtain product having from 12 to 420 ppm of ruthenium with the
use of simple purification step. Heterogenic catalysts can give su-
perior results, but their synthesis is much more complicated. In-
spired by those reports we developed novel catalysts bearing
a hydroxamic ester group as terminal substituent of the styrenyl
ether. Our intention was to combine high activity observed for
Scorpio type catalysts with the possibility of simple purification of
products from catalyst and ruthenium containing impurities. Ad-
ditionally, we were interested in developing an easy and efficient
method for catalyst recovery and reuse. The introduction of
a hydroxamic ester into the catalyst structure resulted in a very
high affinity to silica gel, which depends however on the solvent
used. Herein we present the results on the synthesis and activity of
those new catalysts. Additionally, the removal of residual ruthe-
nium from products as well as catalyst recovery and reuse experi-
ments is reported. Finally, experiments showing high activity of the
catalyst when performing reaction in green solvents are presented.
Scheme 2. Preparation of catalysts 5a,b.
Activity of complexes 5a and 5b was tested using standard RCM
substrate 6 and results were compared with those obtained with
commercially available H2 and N2 (Fig. 3). Those reactions were run
in dry, degassed dichloromethane under argon. Catalyst 5b exhibi-
ted activity comparable to that presented by N2, which is known to
be a fast initiator, giving almost full conversion of substrate after
20 min. Interestingly, the activity of 5a was low when compared
with 5b and was comparable with that observed for H2 catalyst.
Fig. 3. RCM of diethyl allylmethallylmalonate (6).
Next complexes 5a and 5b were tested in various metathetical
transformations to establish the scope of their application (Table 1).
Noteworthy, those reactions were run in non-degassed DCM
without protective atmosphere of inert gas. For comparison re-
actions under the same conditions with the use of N2 and H2 were
also carried out. In turn, results obtained with the use of E2, Q2 and
A2 are presented as reported in the literature.
2. Results and discussion
In the presented approach, the appropriate carbene ligand
precursors 3a and 3b, being hydroxamic ester-substituted styrenyl
ethers, were prepared in Williamson reaction using commercially
available 2-propenylphenol 1 and suitable alkylating agents 2a and
2b, respectively (Scheme 1).
In general, catalysts 5a and 5b were found to give better results
than H2, E2, A2, Het-2 and Het-3 in all the tested reactions. The
obtained results with the use 5a and 5b were comparable with Q2,
this includes the residual ruthenium levels found in the reaction
products. The latter however binds to the silica gel strongly and this
fact makes impossible its recovery and reuse. Noticeably, the re-
sidual ruthenium level in all products obtained using our new
catalysts was from 5 to 400 times lower than that observed in the
products synthesized with N2 or H2. For product purification, we
used a straightforward procedure, which involved only filtration of
It is quite well known that SIPr ligand provide higher catalyst
stability.38 Therefore, we decided to synthesize new catalysts
bearing SIPr ligand. New complexes were obtained in the reaction
of ligands 3a and 3b with indenylidene complex 4 (Scheme 2). The
reaction was carried out in toluene at 80 ꢀC in the presence of
copper(I) chloride, commonly used as a phosphine scavenger6
affording the desired catalysts 5a and 5b with good yields. Com-
plexes 5a and 5b were stable during purification on silica gel. Both
5a and 5b were very stable in the solid statedno signs of de-
composition were observed after 3 months storage.

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K. Skowerski et al. / Tetrahedron 69 (2013) 7408e7415
Table 1
Activity tests in various metathesis transformations catalyzed by 5a, 5b, N2 and H2 on air and in non-degassed solvent.a For comparison, results obtained with E2, Q2 and A2
reported in the literature
Entry
1
Substrate
Product
Cat.
Time [min]
60
Yieldb [%]
94
Ruc [ppm]
41
5a
EtOOC
COOEt
EtOOC
COOEt
2
3
4
5
5b
30
30
360
60
98
99
(70)
(99)
14
N2
2180
ND
12
E2d
Q2e
8
9
6
5a
150
97
17
EtOOC
COOEt
EtOOC
COOEt
7
8
5b
N2
60
50
96
98
9
1950
3640
ND
ND
ND
9
H2
120
1080
90
94
10
11
12
A2f
(75)
(96)
(41)
6
7
Q2e
Het-2g
180
13
5b
20
>98
36
Ts
N
Ts
N
14
15
16
17
18
N2
10
60
30
420
120
99
(55)
99
(95)
(>95)
1980
ND
68
ND
<5 ppb
E2d
Q2e
Het-2g
Het-3h
10
11
Ts
N
Ts
N
19
20
5b
40
20
>98
32
N2
99
2210
12
14
13
21
5a
45
99
37
15
Ph
Ph
22
23
24
25
5b
30
30
15
30
>98
99
99
15
O
N2
1430
ND
ND
E2d
Q2e
O
Ph
Ph
98
26
5a
120
93
113
16
TBSO
COOMe
4
27
28
29
30
5b
50
15
40
92
94
87
89
143
704
2550
ND
4
N2
H2
E2d
COOMe
18
OTBS
17[i]
960
a
Reaction conditions: catalyst 1 mol %, CH2Cl2, reflux, C¼0.05 M.
Isolated yield after column chromatography. In parentheses yield determined by GC.
Determined by ICP-MS.
b
c
d
e
f
Ref. 13, reaction conditions: catalyst 1 mol %, CH2Cl2 (for entry 30 reaction was performed in commercially grade CH2Cl2), 0 ꢀC (45 ꢀC for entry 24), C¼0.02 M.
Ref. 21, reaction conditions: catalyst 5 mol %, CH2Cl2 25 ꢀC, C¼0.02 M.
Ref. 20, reaction conditions: catalyst 2.5 mol %, CH2Cl2 25 ꢀC.
g
h
Ref. 22, reaction conditions: catalyst 5.0 mol %, CH2Cl2 45 ꢀC, C¼0.02 M.
Ref. 23, reaction conditions: catalyst 0.4 mol %, C6H6 30 ꢀC. NDdnot determined.
reaction mixture through a short pad of silica gel (SiO2/substrate
mass ratio¼7) (Fig. 4). When DCM was used as an eluent, 5a and
particularly 5b showed high affinity to silica gel what allowed to
obtain products with low residual ruthenium (determined by in-
ductively coupled plasma mass spectroscopy, ICP-MS). Only in the
case of the CM was the ruthenium content in the product over
100 ppm (Table 1, entries 26, 27).
protective atmosphere of inert gas. Dropwise addition of catalyst
allows for reduction of its loading to 0.1 mol % in the case of RCM
reactions (entries 2, 4). We observed a positive effect of slow
addition of catalyst also in CM and this reaction was completed
with 0.3 mol % of catalyst (entry 8). Interestingly, enyne ring
closing proceeded better when the catalyst was added in one
portion (entry 5). This transformation turned out to be quite
challenging and 0.5 mol % of catalyst was necessary to achieve a
good yield.
In Table 2 we present few examples of reactions catalyzed by
low amount of catalyst 5b in non-degassed toluene and without

K. Skowerski et al. / Tetrahedron 69 (2013) 7408e7415
7411
Fig. 4. Filtration of the reaction mixture through a short pad of silica. (a) Mixture after metathesis reaction with the use of H2 (on the left) and 5b (on the right) before filtration; (b)
mixture after filtration and washed with DCM (H2 on the left and 5b on the right); (c) catalyst 5b can be subsequently washed with EtOAc and reused (H2 on the left and 5b on the
right).
Table 2
Table 3
Low loading experiments in non-degassed toluene and without protective atmo-
Recovery and reuse of catalyst 5ba
sphere of inert gas.a NIdnot isolated
Cycle Substrate Product Time Product
[min]
5b Yield
[%], (mg)
Entry
Substrate
Product
5b mol %
Time
[min]
Conversionb
[%]
Yield
[%]
Yieldb
(mg)
%
Purityc Ru
[%] [ppm]
1
2
10
11
0.1
60
60
76
97
NI
94
0.1c
1
2
3
4
5
10
14
12
16, 17
10
11
15
13
18
11
20
30
50
50
35
97 (983) >99
>99 (962) >99
>99 (825)
77d (610) >99
97 (553) 98
161
58
86 (61)
89 (54)
85 (46)
97 (40)
90 (36)
3
4
12
13
15
18
0.1
60
60
55
98
NI
96
98
113
ND
184
0.1c
5
6
14
0.5
300
300
94
86
92
NI
0.5c
a
b
c
Conditions: 5b 2 mol %, C¼0.05 M, dry DCM, 40 ꢀC.
Isolated yield.
Determined by GC.
7
8
16, 17d
0.3
180
180
68
94
NI
90
0.3c
d
Reaction with 2 equiv of 17, after separation of catalyst, product was purified by
a
Reaction conditions: toluene, 70 ꢀC, C¼0.1 M.
column chromatography; 17% of a dimer of 16 was obtained as well.
b
c
Determined by GC.
Added dropwise with the use of syringe pump.
17 (5 equiv) was used.
by 1H NMR and an equimolar mixture of 5b and dimer of 3b was
observed. Nonetheless, this mixture still efficiently mediate me-
tathesis reactions and no sign of 3b was observed in products. As
shown in Fig. 4 the classical H2 complex does not provide such an
opportunity. Relatively high catalysts loadings (2 mol %) are needed
in recovery/reuse experiments. This fact can be explained by the
lack of the previously suggested boomerang effect in Hoveyda-type
catalysts.7b,c Experiments with lower catalyst loadings resulted
a decrease in the yields of the reaction products.
Nowadays, the chemical industry, in particular fine-chemical
and pharmaceutical industry, use large amounts of solvents per
mass of final products. Therefore, solvents define a major part of
the environmental performance of a process and also impact on
cost, safety and health issues. The goal to minimize the environ-
mental impact resulting from the use of solvents in chemical
production as well as their impact on safety and health is
expressed by the idea of ‘green’ solvents.43,44 In that respect,
straight-chain alkanes (e.g., hexane, heptane), ethers (diethyl
ether, methyl tert-butyl ether [TBME] or cyclopentyl methyl ether
[CPME]), simple alcohols and esters (e.g., ethyl acetate) are con-
sidered as green solvents. In Table 4 we show an example of RCM
reaction catalyzed by 5b carried out in such green solvents. In the
tested reaction good to excellent conversions are observed after
60 min reaction time at 40 ꢀC. It should be noted that all reactions
were performed in ACS grade solvents and under an air atmo-
sphere. These results clearly show that catalyst 5b is suitable for
industrial applications where the need to perform reactions under
eco-friendly conditions is very important. It has to be added that
d
Examples of much lower loadings are known from the literature
however, they usually require special conditions, such as running
the reaction at high concentration,39 robotic equipment40 or per-
forming reaction in a glove box.41 Recently, fast olefin metathesis at
low catalyst loading was reported by Plenio et al., but still all these
reactions needed an argon atmosphere and the use of dry solvents
to go to completion.42 The use of our catalysts therefore, is ad-
vantageous because it does not require a protective atmosphere of
an inert gas, nor specially dried and degassed solvents, thus making
our catalysts especially suitable for industrial applications.
High stability, activity and efficiency of 5b give us the oppor-
tunity to its recovery and reuse. For this experiment we used pro-
tocol reported by Grela et al.21 After filtration of reaction mixture
through silica gel and removal of product with an additional por-
tion of DCM, the catalyst was eluted with ethyl acetate. The se-
quence consisting of RCM, enyne, RCM, CM and RCM was
performed. Similar approach was previously reported for hetero-
genic catalyst Het-2.22 However, both Het-223 and Het-323 as well
as A220 showed noticeable decrease in activity after 3e4 cycles and
were relatively slow initiators. Notably, in our case the products
were eluted quantitatively and did not contaminate the subsequent
reaction mixture, moreover we did not observe any traces of
isomerization by-products and full conversion of substrate was
noted in each run. The results of 5b recycling and reuse are pre-
sented in Table 3. After fifth run the purity of crude 5b was checked

7412
K. Skowerski et al. / Tetrahedron 69 (2013) 7408e7415
the use of catalysts H2 and E2 resulted in much lower conversions
(Table 4).
In order to further test the performance and utility of catalyst 5b
in green solvents, we have applied it in the RCM reaction of bio-like
substrate 19 to obtain the desired cyclic compound 20 (Table 5
entry 2). Catalyst 5b was also very efficient in the RCM reaction
leading to 14- and 16-membered lactones 22 and 24, respectively
(Table 5 entries 3 and 4). These results are important because the
macrocyclic motif is widely prevalent in a number of natural
products and pharmaceuticals45 and also provides the backbone for
a
unique class of olfactory compounds, termed macrocyclic
musks.46 Finally, 5b was used in the CM reaction of methyl 10-
undecenoate (25) with methyl acrylate (17) yielding the desired
product 26 using i-PrOH as solvent (Table 5 entry 5). This result is
valuable because 10-undecylenic acid derivatives constitute feed-
stock readily available from castor oil and have already been used
for the industrial production of C11-polyamide (PA11) in the
RilsanÒ process.
Table 4
RCM of 8 promoted by 5b, E2 and H2 in ACS grade green solvents on aira
Entry
Solvent
Catalyst
(mol %)
Conversionb
[%]
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
i-PrOH
i-PrOH
i-PrOH
CPME
CPME
CPME
n-Heptane
AcOEt
AcOEt
AcOEt
5b (0.5)
E2 (0.5)
H2 (0.5)
5b (0.5)
E2 (0.5)
H2 (0.5)
5b (0.2)
E2 (0.2)
H2 (0.2)
5b (0.2)
5b (0.2)
E2 (0.2)
H2 (0.2)
52
7
17
94
10
30
98
36
54
96
>99
65
88
3. Conclusions
In conclusion, we presented new Scorpio type catalysts bearing
hydroxamic ester group. Those catalysts can be easily obtained
from commercially available substrates. Particularly, complex 5b
exhibited high activity and efficiency. Recovered, crude 5b main-
tained activity and efficiency for at least five subsequent reactions.
Importantly, products obtained using complex 5b have low level of
residual ruthenium after implementation of simple purification
step. This fact along with the possibility of using low loadings of 5b
and its high efficiency in ACS grade green solvents (TON up to 920)
make this catalyst especially suitable for industrial applications, in
particular in fine-chemical and pharmaceutical industry.
9
10
11
12
13
a
Reaction conditions: 40 ꢀC, C¼0.1 M, 60 min.
b
Determined by GC.
Table 5
RCM and CM products obtained in ACS grade AcOEt under an air atmospherea
Entry
Substrate
Product
5b
Yieldb
[%]
(mol %)
4. Experimental part
O
N
O
N
1c
2c
8
9
0.1
0.1
93
92
4.1. General information
N
N
Boc
O
Boc
Solvents were dried by distillation over the following drying
agents and were transferred under argon: toluene (Na), n-pentane,
CH2Cl2 (CaH2). Column chromatography was performed with the
use of Merck silica gel 60 (230e400 mesh). NMR spectra were
recorded on Bruker Avance 300 MHz spectrometer in CDCl3;
20
19
O
O
O
3d,e
0.5
97
chemical shifts (d) are given in parts per million (ppm) downfield
from trimethylsilane as referenced to residual protio solvent peaks,
coupling constants (J) are reported in hertz (Hz). GC analysis: Trace
GC Ultra, Thermo Electron Corporation, HP-5 column. MS (ESI): LCT
PremierXE Waters mass spectrometer. Ru content was evaluated
using ICP-MS. IR spectra were recorded on a PerkineElmer 1600
FTIR spectrometer.
21
22
O
O
O
O
4d,f
0.5
95
4.2. Preparation of catalyst 4
A 100 mL Schlenk flask was purged with argon and charged
with dry hexane (10 mL) and commercially available 1,3-bis(2,6-
diisopropylphenyl)-4,5-dihydroimidazolium tetrafluoroborate [SI
Pr$BF4, CAS 282109-83-5] (182 mg, 0.379 mmol) followed by the
addition of potassium tert-pentoxide (0.207 mL of 1.7 M solution in
toluene, 0.352 mmol). The resulting mixture was stirred at room
temperature for 1 h. After that time commercially available
dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohex-
ylphosphine) ruthenium(II) [M1, CAS 250220-36-1] (250 mg,
0.271 mmol) was added and the resulting mixture was stirred at
reflux for 30 min. After completion of the reaction the reaction
mixture was cooled down to room temperature and concentrated
in vacuo. Crude product was purified by column chromatography
(EtOAc/cyclohexane 1/10) affording the desired ruthenium com-
plex 4 as a red solid (260 mg, 92.9% yield). Spectroscopic analysis
was consistent with the literature data.47 1H NMR (300 MHz,
23
24
25
MeOOC
COOMe
5g
8
0.5
88
8
COOMe
26
COOMe
17
a
Reaction conditions: catalyst added with the syringe pump over 1 h, reaction
time 1.5 h.
b
c
d
e
f
Yields for isolated products.
C¼0.1 M, 40 ꢀC.
C¼0.005 M, 70 ꢀC.
E/Z 9/1.
E/Z 8/2.
g
17 (6 equiv), catalyst added over 2 h with syringe pump, reaction time 3 h,
CD2Cl2):
d
8.90 (d, J¼7.0 Hz, 1H), 7.62 (d, J¼7.0 Hz, 2H), 7.50e7.49
C¼0.1 M, 70 ꢀC, solvent i-PrOH, E/Z 9/1, selectivity towards CM product (96%),
conversion (92%) and yield were determined by GC using dodecane as internal
standard.
(m, 1H), 7.44e7.36 (m, 6H), 7.25 (t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.3 Hz,
1H), 7.11 (d, J¼7.1 Hz, 1H), 6.82 (s, 1H), 6.80 (d, J¼7.7 Hz, 1H), 6.69 (d,

K. Skowerski et al. / Tetrahedron 69 (2013) 7408e7415
7413
J¼6.5 Hz, 1H), 6.62 (d, J¼7.5 Hz, 1H), 4.41e4.35 (m, 1H), 4.18e4.09
(m, 2H), 4.05e4.00 (m, 1H), 3.90e3.80 (m, 2H), 3.61e3.55 (m, 1H),
3.03e2.95 (m, 1H), 2.00e1.94 (m, 3H), 1.75e0.90 (m, 51H), 0.65 (d,
J¼6.2 Hz, 3H).
128.1, 124.9, 122.6, 112.5, 72.1, 61.4, 54.6, 32.5, 29.6, 26.4, 23.6, 17.6.
IR, nmax (KBr): 3439, 3069, 2968, 2864, 1792, 1663, 1592, 1574, 1455,
1400, 1391, 1327, 1296, 1400, 1252, 1216, 1176, 1107, 1045, 993, 936,
850, 860, 803, 743, 648, 556, 461, 438 cmꢁ1. HRMS calcd for
C39H53N3O3ClRu (MꢁCl)þ 748.2819 found 748.2844.
4.3. Protocol for the synthesis of ligands 3a and 3b
4.5. General procedure for olefin metathesis
To the solution of 2-propenylphenol (1), (1 equiv, mixture of E
and Z isomers) in DMF (C¼0.5 M) solid K2CO3 (2 equiv) was added,
and the resulting mixture was stirred at room temperature for
15 min. Next, the appropriate alkylating reagent 2a or 2b (1.2 equiv)
was added and the reaction mixture was heated at 50 ꢀC for 20 h
with vigorous stirring. After that time, solvent was removed under
vacuum and water was added to the residue. The aqueous phase
was extracted with EtOAc and the organic layer was washed with
brine and dried over MgSO4. Crude products were purified by col-
umn chromatography using mixture of EtOAc/c-hexane as eluent.
Under argon the substrate (1 mmol) was dissolved in dry,
degassed DCM (20 mL, C¼0.05 M), and solid catalyst (1 mol %) was
added in one portion. The reaction mixture was stirred at reflux and
the reaction progress was monitored by GC. After cooling down, the
reaction mixture was filtered through a pad of silica gel (SiO2/
substrate mass ratio¼7). The product was eluted with additional
portion of reagent grade DCM (20 mL). The solvent was removed,
the product was dried on vacuum and its purity was determined
by GC.
4.3.1. (E/Z)-N-Methoxy-N-methyl-2-(2-[prop-1-en-1-yl]phenoxy)
acetamide (3a). Yield 97%, light yellow oil. Isomer mixture E/Z¼5/1.
4.6. General procedure for low catalyst loading experiments
E isomer, 1H NMR (300 MHz, CDCl3)
d
7.45 (dd, J¼7.5, 1.6 Hz, 1H),
7.20e6.80 (m, 4H), 6.30 (dq, J¼16.0, 6.4 Hz, 1H), 4.83 (s, 2H), 3.73 (s,
The substrate (1 mmol) was dissolved in dry, non-degassed
toluene (C¼0.1 M), and catalyst was added (in one portion or
drop by drop with the use of syringe pump). The reaction mixture
was stirred at 70 ꢀC and the reaction progress was monitored by GC.
After cooling down, the reaction mixture was filtered through a pad
of silica gel (SiO2/substrate mass ratio¼7). The product was eluted
with additional portion of reagent grade toluene. The solvent was
removed, product was dried on vacuum.
3H), 3.25 (s, 3H), 1.89 (dd, J¼6.7, 1.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3)
d 154.9, 130.4, 127.6, 127.0, 126.8, 126.6, 125.6, 120.9, 112.3,
66.3, 61.6, 32.4, 19.0. IR, nmax (KBr): 3501, 2937, 1688, 1598, 1579,
1487, 1446, 1328, 1294, 1226, 1178, 1122, 1062, 989, 855, 750, 629,
591, 466, 434 cmꢁ1. HRMS calcd for C13H17NO3 (M)þ m/z 236.1287
found 236.1290.
4.3.2. (E/Z)-N-Methoxy-N-methyl-2-(2-[prop-1-en-1-yl]phenoxy)
propanamide (3b). Yield 88%, yellow oil. Isomer mixture E/Z¼6/1. E
isomer, 1H NMR (300 MHz, CDCl3)
d
7.42 (dd, J¼7.7, 1.7 Hz, 1H),
4.7. General procedure for catalyst recovery experiment
7.30e6.70 (m, 4H), 6.24 (dq, J¼15.9, 6.6 Hz, 1H), 5.15e5.08 (m, 1H),
3.70 (s, 3H), 3.22 (s, 3H), 1.90 (dd, J¼6.6, 1.8 Hz, 3H), 1.60 (d,
The substrate was dissolved in dry DCM (C¼0.05 M), and solid
catalyst (2 mol %) was added in one portion. The reaction mixture
was stirred at reflux and the reaction progress was monitored by
GC. After cooling down, the reaction mixture was filtered through
a pad of silica gel (SiO2/substrate mass ratio¼7). The product was
eluted with additional portion of reagent grade DCM. The solvent
was removed, the product was dried on vacuum and its purity was
determined by GC. Catalyst was removed from silica gel with re-
agent grade AcOEt. After removal of solvent, the crude catalyst was
washed with n-pentane and dried on vacuum. The recovered cat-
alyst was used in next reaction without additional purification.
J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 154.3, 130.4, 127.6, 126.8,
126.4, 125.7, 121.6, 121.0, 113.4, 71.8, 61.5, 32.6, 18.9, 17.7. IR, nmax
(KBr): 3501, 3345, 2937, 1682, 1597, 1579, 1486, 1452, 1387, 1295,
1239, 1176, 1148, 1078, 1039, 992, 944, 751, 620, 555, 433 cmꢁ1
.
HRMS calcd for C14H19NNaO3 (MþNa)þ m/z 272.1263 found
272.1250.
4.4. General protocol for the synthesis of catalysts 5a,b
Ligand 3a or 3b (1.2 equiv) and CuCl (1.5 equiv) were placed in
an Schlenk flask. The flask was filled with argon and then dry tol-
uene (C¼0.1) was added. Afterwards complex 4 (1 equiv) was
added and the resulting solution was stirred at 80 ꢀC for 20 min.
Then reaction mixture was cooled down to room temperature and
concentrated under vacuum. The resulting material was dissolved
in a minimum amount of DCM and purified by flash chromatog-
raphy (c-hexane/EtOAc 7/3).
4.8. General procedure for RCM of substrates 19, 21 and 23
The substrate was dissolved in appropriate green solvent
(0.6 mmol, C¼0.1 M for 19 and C¼0.005 M in case of 21 and 23) and
was treated with catalyst 5b (stock solution prepared in DCM).
Reaction mixture was heated at 40 ꢀC (70 ꢀC for 21 and 23) and
conversions were measured by GC.
Catalyst 5a, yield 62%, green microcrystalline solid. 1H NMR
(300 MHz, CDCl3)
d 16.47 (s, 1H), 7.56e7.44 (m, 3H), 7.42e7.32 (m,
4H), 7.00e6.86 (m, 2H), 6.81 (d, J¼8.2 Hz, 1H), 4.83 (s, 2H), 4.14 (s,
4H), 3.63 (s, 7H), 3.04 (s, 3H), 1.31e1.16 (m, 24H). 13C NMR (75 MHz,
4.9. General procedure for CM reactions of 25 with 17
CDCl3)
d 298.5, 213.7, 167.8, 153.0, 149.1, 146.2, 138.2, 128.9, 128.1,
124.3, 122.2, 113.3, 65.4, 61.4, 54.6, 32.5, 28.6, 26.5, 23.7. IR, nmax
(KBr): 3440, 3066, 3039, 2963, 2928, 2867, 1935, 1652, 1592, 1475,
1454, 1404, 1327, 1296, 1260, 1232, 1105, 1048, 993, 931, 875, 804,
758, 748, 647, 598, 555, 434, 462 cmꢁ1 HRMS calcd for
C38H51ClN3O3Ru (MꢁCl)þ 734.2662 found 734.2662.
Substrate (0.6 mmol, C¼0.1 M) and dodecane (0.6 mmol) were
dissolved in i-PrOH and was treated with catalyst 5b (stock solution
prepared in DCM). Reaction mixture was heated at 70 ꢀC and
conversions and selectivity were measured by GC.
Catalyst 5b, yield 72%, green microcrystalline solid. 1H NMR
(300 MHz, CDCl3)
d
16.46 (s, 1H), 7.53e7.35 (m, 7H), 6.90e6.74 (m,
4.10. Characterization of the metathesis products
3H), 5.27 (q, J¼6.3 Hz, 1H), 4.14 (s, 4H), 3.70e3.61 (m, 7H), 2.97 (s,
3H), 1.55 (d, J¼6.3 Hz, 3H), 1.33e1.12 (d, J¼6.8 Hz, 24H). 13C NMR
4.10.1. Diethyl 3-methyl-3-cyclopentene-1,1-dicarboxylate (7).48 1H
(75 MHz, CDCl3)
d
297.7, 214.1, 170.6, 151.8, 149.0, 145.9, 138.1, 128.9,
NMR (300 MHz, CDCl3)
d: 5.10e5.09 (m, 2H), 4.07 (q, J¼7.2 Hz, 4H),

7414
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J¼7.2 Hz, 6H).
4.10.2. Diethyl 3-cyclopentene-1,1-dicarboxylate (9).48 1H NMR
6. Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc.
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(300 MHz, CDCl3)
2.92e2.89 (m, 4H), 1.15 (t, J¼7.2 Hz, 6H).
d
: 5.53e5.51 (m, 2H), 4.08 (q, J¼7.2 Hz, 4H),
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4.10.3. N-Tosyl-2,5-dihydropyrrole (11).49 1H NMR (300 MHz,
CDCl3) d ppm: 7.74e7.68 (m, 2H), 7.33e7.29 (m, 2H), 5.66e5.62 (m,
2H), 4.12e4.08 (m, 4H), 2.41 (s, 3H).
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4.10.4. N-Tosyl-3-methyl-2,5-dihydropyrrole (13).50 1H NMR (300
MHz, CDCl3)
d ppm: 7.72e7.69 (m, 2H), 7.32e7.29 (m, 2H),
10. (a) Priority date: August 2, 2003, DE 103 35 416, Inventor Dieter Arlt; (b)
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5.24e5.22 (m, 1H), 4.07e4.03 (m, 2H), 3.97e3.95 (m, 2H), 2.41 (s,
3H), 1.64 (s, 3H).
11. Bieniek, M. Substituted HoveydaeGrubbs Catalysts-activity Control and Applica-
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4.10.5. 2,2-Diphenyl-3-vinyl-2,5-dihydrofuran (15).51 Colourless oil.
1H NMR (300 MHz, CDCl3)
d ppm: 7.37e7.28 (m, 10H), 6.28e6.20
(m, 2H), 5.32 (d, J¼14.1 Hz, 1H), 5.11 (d, J¼8.4 Hz, 1H), 4.81e4.80
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4.10.6. 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-enoic acid methyl
ester (18).52 1H NMR (300 MHz, CDCl3)
d
ppm: 6.89 (dt, J ¼ 15.7, 7.0
Hz, 1H), 5.82 (dt, J ¼ 15.7, 1.6 Hz), 3.71 (s, 3H), 3.62e3.58 (m, 2H),
2.24e2.18 (m, 2H), 1.53e1.51 (m, 4H), 0.88 (s, 9H), 0.03 (s, 6H).
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4.10.7. 2-(2,5-Dihydropyrrole-1-carbonyl)-pyrrolidine-1-
carboxylicacid tert-butyl ester (20).53 1H NMR (300 MHz, CD2Cl2)
d
ppm: 5.87e5.69 (m, 2H), 4.54e4.08 (m, 5H), 3.61e3.29 (m, 2H),
Grela, K. Green Chem. 2006, 8, 685e688.
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Muihua, T.; Peng, S. C. Adv. Synth. Catal. 2009, 351, 2650e2656 and references
cited therein.
25. Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto, M. M.; Farrer, R.
A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem. Int., Ed. 2001, 40, 4251e4256.
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2.20e2.04 (m, 2H), 1.92e1.74 (m, 2H), 1.40e1.32 (m, 9H).
4.10.8. (E,Z)-Oxacyclotetradec-11-en-2-one (22).54
E
isomerd1H
NMR (300 MHz, CDCl3) ppm: 5.51e5.30 (m, 2H), 4.14e4.10 (m,
2H), 2.39e2.33 (m, 4H), 2.04e1.98 (m, 2H), 1.63e1.55 (m, 2H),
1.38e1.27 (m, 10H). 13C NMR (75.4 MHz, CDCl3)
ppm: 174.1, 132.8,
127.8, 64.3, 35.1, 31.9, 31.3, 26.6, 26.1, 25.8, 25.6, 23.88, 23.80.
d
d
4.10.9. (E,Z)-Oxacyclohexadec-11-en-2-one (24).49
E
isomerd1H
€
€
29. Michalek, F.; Madge, D.; Ruhe, J.; Bannwarth, W. Eur. J. Org. Chem. 2006,
577e581.
NMR (300 MHz, CDCl3) ppm: 5.40e5.25 (m, 2H), 4.16e4.04 (m, 2H),
2.35e2.25 (m, 2H), 2.06e1.96 (m, 4H), 1.66e1.56 (m, 4H), 1.41e1.20
(m,12H). 13C NMR (75.4 MHz, CDCl3)
ppm: 173.9,131.8,130.3, 63.9,
d
€
€
30. Michalek, F.; Madge, D.; Ruhe, J.; Bannwarth, W. J. Organomet. Chem. 2006, 691,
5172e5180.
d
31. Lim, J.; Lee, S. S.; Riduan, S. N.; Ying, J. Y. Adv. Synth. Catal. 2007, 349, 1066e1076.
32. Keraani, A.; Fischmeister, C.; Renouard, T.; Le Floch, M.; Baudry, A.; Bruneau, C.;
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33. Melis, K.; De Vos, D.; Jacobs, P.; Verpoort, F. J. Mol. Catal. A: Chem. 2001, 169,
47e56.
34.7, 32.06, 32.02, 28.37, 28.31, 28.2, 28.0, 27.2, 26.5, 25.5, 25.2.
4.10.10. (E,Z)-Dodec-2-enedioic acid dimethyl ester (26).55 E iso-
merd1H NMR (300 MHz, CDCl3)
d ppm: 7.01e6.91 (m, 1H),
34. Mayr, M.; Buchmeiser, M. R.; Wurst, K. Adv. Synth. Catal. 2002, 344,
712e719.
5.83e5.77 (m, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 2.32e2.27 (m, 2H),
2.21e2.14 (m, 2H),1.63e1.56 (m, 2H),1.49e1.39 (m, 2H) 1.28 (s, 8H).
35. Allen, D. P.; Van Wingerden, M. M.; Grubbs, R. H. Org. Lett. 2009, 11, 1261e1264.
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Apeiron Synthesis acknowledges the National Centre for Re-
search and Development for financial support within ‘IniTech’
programme. M.B. acknowledges the Foundation for Polish Science
for financial support within ‘INNOWATOR’ programme.
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Supplementary data
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Supplementary data related to this article can be found at http://
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