Sulfoxide-Chelated Ruthenium Benzylidene Catalyst: a Synthetic Study on the Utility of Olefin Metathesis

Article abstract of DOI:10.1002/cctc.201600538

We provide an experimental summary of selected advances in olefin metathesis methodology that were reported over the past decades. A stable and universal sulfoxide-chelated ruthenium olefin metathesis catalyst [RuCl₂(SIMes)(=CH?C₆H₄?S(O)Ph)], SIMes=1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene, was introduced and its application profile was studied in detail. A range of model substrates of natural origin was developed and successfully metathesized with variants of the reaction, such as ene–yne, cross, or ring-closing metathesis. All reported reactions were performed in non-pretreated solvents and in air to demonstrate the user-friendliness of the system. Besides the great functional group tolerance exhibited by the reported complex, its compatibility with multiple solvents was determined along with its air and moisture stability. Additionally, an interesting effect increasing the reaction efficiency was observed, if reactions were performed at temperatures around the solvent boiling point.

Full text of DOI:10.1002/cctc.201600538

DOI: 10.1002/cctc.201600538
Full Papers
Sulfoxide-Chelated Ruthenium Benzylidene Catalyst:
a Synthetic Study on the Utility of Olefin Metathesis
[a]
[a]
[a, b]
˙
Karolina Zukowska,* Łukasz P a˛ czek, and Karol Grela
We provide an experimental summary of selected advances in
olefin metathesis methodology that were reported over the
past decades. A stable and universal sulfoxide-chelated ruthe-
All reported reactions were performed in non-pretreated sol-
vents and in air to demonstrate the user-friendliness of the
system. Besides the great functional group tolerance exhibited
nium olefin metathesis catalyst [RuCl (SIMes)(=CHÀC H À by the reported complex, its compatibility with multiple sol-
2
6
4
S(O)Ph)], SIMes=1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimi-
dazol-2-ylidene, was introduced and its application profile was
studied in detail. A range of model substrates of natural origin
was developed and successfully metathesized with variants of
the reaction, such as ene–yne, cross, or ring-closing metathesis.
vents was determined along with its air and moisture stability.
Additionally, an interesting effect increasing the reaction effi-
ciency was observed, if reactions were performed at tempera-
tures around the solvent boiling point.
Introduction
[
7]
The growing importance of catalysis is evident in the chemical
molybdenum, tungsten, and ruthenium were found suitable
to perform this task, however, the last class is assumed to be
the most user-friendly. The most beneficial characteristics of
ruthenium-based complexes are their air and moisture stability
[
1]
processes reality. This is particularly visible in the industry,
where a growing number of catalytic methods became virtual-
[
2]
ly irreplaceable. Application of catalysis has several advantag-
es, which constitute decrease of generated waste, overall time,
and cost reduction and, consequently, production in the spirit
of green chemistry, which considers catalysis one of its key
points. Additional benefits come from the ease of compound
modification or diversification enabled by catalytic process, re-
sulting in shorter synthetic routes leading to high-value prod-
ucts of increased complexity.
[8]
making them easy to handle. Over the years many catalyst
classes have been developed to serve different purposes
(Figure 1).
[9]
Complexes 1–6 were among the first obtained structures
and served as a basis for further modifications. Many interest-
ing classes of compounds have been obtained, for example,
[10]
containing two N-heterocyclic carbenes such as 7, but com-
pounds bearing bidentate alkylidene ligands are perhaps the
[
3]
Olefin metathesis is among the most commonly employed
catalytic methods of C=C bond formation. It is a fairly mature
field of science that has been finding its way to industrial pro-
[
4]
cesses over recent decades. There are numerous examples of
[5]
applications in both industry and fine-chemicals synthesis.
A
great advantage of this method is that it gives access to
straightforward derivatization leading to compound libraries
with potentially diverse activity making it ideal for pharma-
[
6]
ceutical research.
This fine methodology requires transition-metal complexes
to promote the catalytic cycle. Various compounds based on
[
a] K. Z˙ ukowska, Ł. P a˛ czek, Prof. K. Grela
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/54
0
1-224 Warsaw (Poland)
E-mail: karolina.zukowska@gmail.com
[b] Prof. K. Grela
Biological and Chemical Research Centre, Faculty of Chemistry
University of Warsaw
Z˙ wirki i Wigury 101
0
2-089 Warsaw (Poland)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/cctc.201600538.
Figure 1. Selected ruthenium-based metathesis complexes.
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[11]
most interesting for further applied research nowadays. The
[
12]
excellent performance of complex 8 triggered various stud-
[
13]
ies on optimization of oxygen substituents (9), other types
[
14]
of heteroatoms (10–11), or oxidation level of thereof (12–
[
15]
14).
Variety of those complexes turned out to be stable and
Scheme 2. Model RCM reaction.
promising (e.g., 7, 9, 10, 13), but reports on their applications
towards advanced synthetic targets are still quite scarce, even
[16]
though such catalysts are known to be easily scalable. Most
reports contain only a brief description of their activity in
model reactions. Tests of solvent compatibility and more ad-
vanced substrates remain mostly unavailable thus discouraging
the use of novel complexes. Finding one of our complexes in
such a situation motivated us to provide a more detailed
study.
Table 1. Initial screening of RCM conditions.
Ru loading
mol%]
Temperature
[8C]
Conditions
Conversion
[%]
[
a]
[
0.5
80
100
100
100
100
toluene as received,
on air
anhydrous toluene,
argon atmosphere
toluene as received,
on air
anhydrous toluene,
argon atmosphere
toluene as received,
on air
90
0.5
0.5
0.1
0.1
98
99
79
22
Compound 13 was a very promising member of a sulfoxide-
[15b]
chelated catalyst series, unfortunately, the original study
did
not entirely reveal the advantages of the catalyst class. There-
fore, we decided to conduct a more thorough investigation.
[
a] Conversion determined by GC after 1 hour.
Results and Discussion
[
15b]
Based on the reported study,
we initially believed that the
p-nitrophenyl derivative of complex 13 was the most promis-
ing member of the sulfoxide complex family, but the high cata-
lyst loading in that study prevented accurate comparison. A
recent study on the same class of compounds revealed that
the phenyl-substituted complex performed almost two times
was reached. To push the system even further we elevated the
[7]
temperature of the transformation to 1008C. Irrespective of
the reaction conditions, maximum conversions were achieved
in 1 h, and over time (8 h heating) no decomposition or iso-
merization of the formed product was observed. Subsequently,
the loading was decreased by five times to 0.1 mol%. Only in
this conditions the application of the pretreated solvent in
inert conditions proved significantly better than the non-pre-
treated one (79 vs. 22%). Interestingly, in all cases the maxi-
mum conversion was reached within an hour of the reaction
start and no side reactions were observed during prolonged
heating time.
[
17]
better in low loadings. It was also indicated that the catalyst
bearing a saturated N-heterocyclic carbene initiates faster than
its unsaturated congener providing very similar end results.
Therefore, we decided to synthesize complex 16 that would
combine those beneficial structural features (Scheme 1).
As toluene is not a particularly difficult solvent to conduct
metathesis reactions, we selected a number of solvents that
tend to be more challenging and typically require pretreat-
[18]
ment. Usually, the aim of such operation is to evacuate any
stabilizers, possibly formed decomposition products, or traces
of water that may be detrimental to the metathesis reaction.
The solvents were selected to enable working with polar com-
pounds. Additionally, the screening took into consideration the
Scheme 1. Synthesis of the studied complex 16.
[19]
The obtained system was preliminarily checked in ring-clos-
current regulatory situation unfavorable for typically utilized
metathesis solvents such as DCM or toluene. Emphasis was
put on the environmental aspects so the chosen solvents can
ing metathesis (RCM) of a known model compound 17
(Scheme 2). This reaction leads to formation of a trisubstituted
[20,21]
double bond, providing a good basis for screening metathesis
systems. As one of the project aims was to get a user-friendly
system, the initial screening included runs in predried de-
gassed toluene under argon flow followed by runs in non-pre-
treated HPLC-grade solvent on air. The results are presented in
Table 1.
be described as green.
Considering the already reported
compatibility with other ruthenium systems we selected di-
[22]
methyl and diethyl carbonates (DMC and DEC),
alcohols
(1-butanol), ethers such as 2-methyltetrahydrofurane
[23]
[18b]
(2-MeTHF), cyclopentyl methyl ether (CPME),
and dimeth-
yl glycol (DMG). All of those were used as obtained, without
any purification with the tested ruthenium system. The results
are presented in Figure 2.
The first run was conducted in typical metathesis conditions
such as toluene, 808C. To stress the system, it was performed
in air- and moisture-containing environment. Although only
The outcome of this experiment was very interesting. Over
80% conversion was achieved in both tested carbonates and
0.5 mol% of the studied complex was used, 90% conversion
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Moreover, we focused on reporting isolated yields, because
isolation of the polar compound from the crude mixture may
also be difficult.
The first chosen model substrate, 21, is a precursor of a bicy-
clic member of b-lactam family of antibiotics. This class of com-
pounds is heavily used in medicine thanks to its broad spec-
trum of antibacterial and antifungal activity combined with
[25]
a relatively low toxicity. Our target molecule was the known
b-lactam-containing compound 22, which can be obtained by
a short sequence involving ene–yne metathesis (Scheme 3).
Figure 2. RCM of 17 conducted in various solvents (0.5 mol% 16, 808C).
CPME, whereas other tested ethers (2-MeTHF and DMG, 5%
and 22%, respectively) and 1-buthanol (9%) turned out to be
very poor. The very pronounced difference between CPME
(88%) and 2-MeTHF, which are known to be very similar in
their properties, drew our attention. As the reactions were per-
formed in a relatively low ruthenium loading, we have consid-
ered the potential presence of inhibiting stabilizers, such as
butylated hydroxytoluene (BHT) and the tendency of both sol-
vents to form peroxides as a possible source of this discrepan-
cy. Both of these issues can be excluded by additional solvent
purification, but the reactions run in distilled and degassed
Scheme 3. Synthesis of compound 22 containing a b-lactam core.
The metathesis substrate 21 was obtained from commercial-
[26]
ly available 19 by utilizing a two-step pathway. The previous-
2
-MeTHF and CPME gave the same tendency.
ly reported metathesis of this substrate utilized 10 mol% of
[27]
The difference between methyl and ethyl carbonate was
ruthenium complex 1 under completely inert conditions.
also interesting. The first of those gave the product in the
highest nearly quantitative conversion (98%), whereas the
second led to a noticeably lower conversion (86%).
Aware of the challenges, we initially employed 2.5 mol% of
complex 16, but this led only to 33% conversion after 1 h. In
another run, applied 2.5 mol% and after 1 h reaction time we
added the same dose of the Ru complex. Such treatment led
to a nearly complete conversion and allowed us to isolate the
desired compound in 87%. This success allowed us to employ
more challenging substrates to ensure that it is compatible
with more structurally diverse compounds.
This pronounced difference cannot be explained by the tem-
perature, which was the same in both experiments. A different
type of interaction with the reacting system is also highly un-
likely because of the similar chemical character of considered
solvents (DMC and DEC). We presume that the difference may
lie in the boiling points of the studied solvents. The conditions
utilized temperature near the boiling point of methyl carbon-
As another model system, we selected a compound bearing
[28,29]
a strongly chelating sulfoxide moiety:
modafinil, a pharma-
[24]
ate (908C) and that may have aided the ethylene removal
cologically active agent commonly used in treating of sleep
[30]
from the reaction media, and as no flow of inert gas was ap-
plied, the difference may be pronounced. This effect would
not be observable in the case of the diethyl carbonate which
boils at 1268C. To explore this possibility we decided to con-
duct an additional run under reflux with CPME (b.p.=1068C)
and toluene for comparison purpose. The yields after 1 h at
disorders.
We envisioned a derivative of the parent com-
pound containing two allylic groups that through metathesis
would form a substituted pyrroline ring. To obtain the desired
[
31]
model we utilized benzhydrylisothiouronium chloride 25
and N,N-diallyl-2-chloroacetamide
[32]
as the substrates
(Scheme 4). Combining those compounds in a final alkylation
reaction resulted in the formation of a molecule that required
a final oxidation stage. Once it was completed two structurally
similar models, 29 and 31, were available for us to test in the
metathesis reaction, a thioether and its monooxidated version.
We decided to run metathesis on both of them to evaluate
the influence of sulfoxide and sulfide functional groups. We
adapted the initial conditions, non-pretreated toluene in 808C,
and gladly observed that both compounds underwent meta-
thesis readily allowing isolation of pure products in very good
yield. The studied thioether derivative resulted in quantitative
110 8C were 88% for CPME and 53% for toluene, providing
a hint that the described effect may be in operation.
Having obtained satisfactory results with the model diene
17 in non-innocent conditions we decided to utilize the devel-
oped catalytic system in the synthesis of selected, more chal-
lenging molecules containing pharmaceutically relevant frag-
ments. Our aim was to perform the study in conditions that
would reveal complex 16 as a user-friendly tool in target-ori-
ented organic synthesis. We decided against the application of
pretreated solvents, high vacuum, or inert gas atmosphere.
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facilitates removal of ruthenium residues in the final product
[33]
making it more suitable for pharmaceutical applications.
The next selected model was a-terpineol (38, Scheme 5),
a natural compound containing a substituted double bond.
One of its main characteristics is a very pleasant odor of this
compound, often associated with lilac, making it a very
common ingredient in the production of cosmetics and per-
[34]
fume. Owing to the high demand from the industry, many
[35]
large-scale methods of synthesis have been developed. We
did not envision metathesis becoming one of those for cost
reasons, but it remained a valid research model for evaluating
our catalytic system in metathetic reactions leading to a substi-
tuted double bond. We visualized a synthesis starting from
ethyl acetoacetate which after subsequent alkylation, saponifi-
[36]
[37]
cation, and a Grignard reaction yielded the model for the
metathesis study. Subjecting the substrate 37 to standard con-
ditions utilized in this study, we managed to obtain very good
yields irrespective of whether the reaction was conducted in
toluene or DMC.
Another class of compounds examined in our study were
the allyl barbiturate derivatives already explored in metathesis
[38]
reactions. We prepared two models with different number of
allyl functionalities. The first was the simple diallyl derivative
39, and the other molecule (40) had an additional allyl moiety
Scheme 4. Synthesis of a modafinil derivative 32.
substituted at the nitrogen atom (Scheme 6). By comparing
how those models undergo metathesis we wanted to check
the selectivity of the resulting process. A summary of the con-
ducted experiments is presented in Table 2.
conversion and 96% isolated yield. The sulfoxide compound
was also quantitatively converted to the product but because
of its high polarity its isolated yield was lower (84%). To enable
comparison with other known catalytic systems, reactions in
similar conditions were performed utilizing complex 2. In both
cases the results were inferior—the thioether 30 was obtained
with 88% yield and the sulfoxide 32 with 82% yield.
Interestingly, the sequence of metathesis and oxidation can
be performed equally successfully irrespective of the order. Ap-
plying RCM after the oxidation step results in 69% yield of
a two-step sequence. This approach has the advantage of
using the minimal quantity of the ruthenium compound, as
the catalytic step is the last one in the synthetic pathway. On
the other hand, conducting RCM prior to oxidation allows an
identical 69% yield of the sequence. The additional beneficial
aspect of the metathesis-then-oxidation is that the latter step
The experiment series begun with subjecting both com-
pounds to 1 mol% of catalyst 16 in toluene. Quantitative con-
version of the dimethyl compound led to the isolation of 41 in
[38]
99% yield, whereas in
a previously published report
10 mol% of complex 1 were used to provide product 41 with
only 88% yield. The molecule bearing the additional allyl
moiety yielded the RCM product in only 70% proving the reac-
tion more challenging as a result of the lower selectivity. De-
creasing the catalyst loading was the next step of the research.
The spiro compounds 41 and 42 were then obtained in 84%
and 67%, respectively. Interestingly the decrease of loading
was far less detrimental to the substrate bearing three allyl
moieties. Presumably owing to the lower concentration of the
active ruthenium species, the number of unproductive turn-
Scheme 5. Metathesis step en route to a-terpineol.
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Scheme 6. Synthesis of chosen barbituric acid derivatives.
Table 2. Conditions utilized in metathesis of barbiturate derivatives.
[C]=0.1m.
Product
Loading [mol%]
Solvent
Isolated yield [%]
41
42
41
42
42
44
44
1
1
0.5
0.5
0.5
1
toluene
toluene
toluene
toluene
DMC
99
70
84
67
81
55
59
Scheme 7. Synthetic pathway towards selected kavalactones.
toluene
DMC
1
substrate self-cross metathesis (48) in 7% yield. Increasing
both the catalyst loading and the temperature increased the
yield to 18%, but the result was still the isolation of 48. To de-
termine if cross metathesis is a feasible method of obtaining
a cross product with 45 we decided to further increase the
loading to 2.5 mol% added twice and change the cross part-
ner. In the reaction with cis-1,4-diacetoxy-2-butene we ob-
served the formation of the expected cross product in 75%
yield. To check if a change of catalyst may provide better re-
sults we examined a known complex 2. Unfortunately it per-
formed in the examined reaction quite poorly leading to 56%
yield. In another attempt to increase the yield of the reaction
we conducted a run in toluene (1108C) and utilized CPME in
the very same conditions. We were hoping to observe a higher
yield in the reaction conducted in CPME, whereas we obtained
78% yield in toluene and only 64% yield in CPME. This result
seemed to be a bit out of place until we realized that the uti-
overs was reduced. Having in mind the beneficial effect of di-
methyl carbonate discussed before, we decided to employ it in
the described reaction. As a result we isolated the RCM prod-
uct 42 in very high, 81% yield. Having this compound in hand,
we decided to subject it into cross metathesis employing cis-
1,4-diacetoxy-2-butene as a cross partner. Utilizing 1 mol% of
the catalyst, we managed to isolate 55% of the substituted
product 44. Changing the solvent to DMC resulted in im-
proved yields of 59%. The results may stem from the very high
polarity of the product, making it relatively difficult to purify
by column chromatography.
The next group of studied compounds were members of
the kavalactone family. Compounds belonging to this class
were isolated from the Kava shrub and popularized because of
their healing properties. They are used for treating a range of
conditions, such as stress disorders, nervous tension,
[
39]
and restlessness, with minimal side effects.
The
Table 3. Conditions of cross metathesis (CM) leading to kavalactone
derivatives.
pharmacological potential made them interesting tar-
gets for the synthesis with complex 16 (Scheme 7).
The first step to obtain the substrate was aldol con-
densation of ethyl acetoacetate with acroleine and
a subsequent methylation of the resulting com-
Cross
partner
Loading
[mol%]
Catalyst
Solvent
Temperature
[8C]
Isolated yield [%]
dimer
CM
46
46
0.5
2.5
16
16
16
2
16
16
16
16
16
toluene
toluene
toluene
toluene
toluene
CPME
toluene
CPME
CPME
80
100
100
100
110
110
110
110
110
7
18
0
0
0
0
13
8
0
0
[
40]
pound. The obtained compound 45 was then cou-
pled with various compounds in metathesis reactions
and the results are summarized in Table 3.
43
43
43
2.5+2.5
2.5+2.5
2.5+2.5
2.5+2.5
2.5+2.5
2.5+2.5
2.5+2.5
75
56
78
64
48
56
55
Subjecting 45 and styrene to previously utilized
metathesis conditions resulted in only minor conver-
sion. After isolation of the obtained product and
analysis it was determined to be the result of the
43
46
46
7
4
0
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lized cross partner (43) had a boiling point of 1208C. As
a result the boiling CPME facilitated not only the removal of
ethylene, but also of 43 decreasing the concentration of the
cross partner in the reaction mixture and overall diminishing
the yield.
7.27–7.36 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.56–7.61 (m, 1H),
13
1
1
1
2
1
5
6
6.75 ppm (s, 1H). C NMR (CDCl ): d=21.3, 22.8, 29.1, 32.0, 52.2,
3
21.0, 127.0, 127.5, 127.7, 129.7, 130.0, 130.2, 130.7, 134.2, 138.0,
38.5, 138.8, 139.0, 142.3, 156.3, 206.1 ppm. IR (KBr) n˜ =3495, 3058,
951, 2916, 2853, 1697, 1606, 1581, 1478, 1442, 1397, 1306, 1284,
264, 1226, 1125, 1112, 1065, 1034, 996, 852, 798, 746, 688, 632,
Having in hand the conditions suitable to perform cross
metathesis we returned to the styrene as a cross partner to
obtain the desired kavalactone. In 1108C and toluene we ob-
served a very high conversion. After purification we observed
À1
+
93, 579, 539, 516, 493, 449, 419 cm . MS (ESI) m/z: [(M-Cl )]
57.13. Anal. calcd. for C H Cl N ORuS (692.70): C, 58.95; H, 5.24;
34
36
2
2
N, 4.04; S, 4.63. Found: C, 58.88; H, 5.24; N, 3.79; S, 4.48.
48% of the cross product and 13% of the self-CM product. Re-
peating the reaction with CPME as a solvent improved the Acknowledgements
ratio, resulting in 56% of kavain and 8% of the dimer.
˙
As the last applied conditions proved to be the best we uti-
lized them to obtain the yangonin precursor (51). In this reac-
tion we did not observe any trace of substrate dimerization.
The cross product was obtained selectively in 55%. Subse-
quent reaction of 51 with 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) resulted in the desired kavalactone–yangonin
with 77%.
K.Z. thanks for the “Diamond Grant” research project financed
from the governmental funds for science for 2012–2015.
Keywords: alkenes · homogeneous catalysis · metathesis ·
natural products · ruthenium
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1
8.2 Hz, 12H), 2.55 (s, 6H), 4.11 (s, 4H), 6.77 (d, J=7.6 Hz, 1H), 6.97
(
s, 2H), 7.05 (s, 2H), 7.08–7.12 ppm (m, 2H), 7.20- 7.25 (m, 2H),
&
ChemCatChem 2016, 8, 1 – 8
www.chemcatchem.org
6
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ÝÝ These are not the final page numbers!

Full Papers
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Received: May 5, 2016
Published online on && &&, 0000
ChemCatChem 2016, 8, 1 – 8
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&
These are not the final page numbers! ÞÞ

FULL PAPERS
˙
K. Zukowska,* Ł. P a˛ czek, K. Grela
&& – &&
Sulfoxide-Chelated Ruthenium
Benzylidene Catalyst: a Synthetic
Study on the Utility of Olefin
Metathesis
A new industry’s darling? The stable
and universal sulfoxide-chelated ruthe-
nium olefin metathesis catalyst
metathesis with respect to relevant
target natural compounds studied. The
catalyst offers great functional group
tolerance, compatibility with multiple
solvents, and air and moisture stability.
[
RuCl (SIMes)(=CHÀC H ÀS(O)Ph)] is in-
2
6
4
troduced and its application profile in
&
ChemCatChem 2016, 8, 1 – 8
www.chemcatchem.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!