From Box to Bench: Air-Stable Molybdenum Catalyst Tablets for Everyday Use in Olefin Metathesis

Article abstract of DOI:10.1021/acs.oprd.6b00161

Molybdenum- and tungsten-based olefin metathesis catalysts have demonstrated excellent results in the control of cis (Z-) selectivity as well as enantioselectivity. However, their air and moisture sensitivity, which requires the use of a glovebox, has prevented their more widespread use by organic chemists. Now we report on developed, preweighed Mo catalysts formulated in paraffin tablets. The significantly improved air stability, high homogeneity, and uniformity of the pellets allow researchers to carry out reactions on the bench avoiding the need of a glovebox. The two different Mo-based complexes which were packed into tablets are XiMoPac-Mo001 (1) that can be used to achieve endo-selective enyne ring-closing metathesis (RCM) reactions, inter alia; and XiMoPac-Mo003 (2) which was reported among the best catalysts to promote Z-selective cross-metathesis. For the evaluation of the wax-protected catalysts commonly used, highly reproducible robust model reactions were chosen: homo cross-metathesis (HCM) of functionalized (e.g., methyl 9-decenoate) and unfunctionalized (allylbenzene) terminal olefins, and ring closing metathesis (RCM) of diethyl diallylmalonate. The yields and conversions were comparable with those which can be achieved in glovebox with nonformulated catalysts. Exposure to air did not cause any significant reduction in conversion while the product selectivity (targeted product vs homologues derived from double bond isomerization) remained high. In contrast, exposure to air caused a measurable drop in the conversion with the nonprotected catalyst. Furthermore, the formulated catalysts remained unaffected even after 4 h of exposure to air, showing its enhanced air stability. In conclusion, these commercially available air-stable Mo-catalyst tablets allow the reactions to be accomplished using ordinary Schlenk techniques, and hence simplify catalyst handling in pilot laboratories and plants.

Full text of DOI:10.1021/acs.oprd.6b00161

Article
pubs.acs.org/OPRD
From Box to Bench: Air-Stable Molybdenum Catalyst Tablets for
Everyday Use in Olefin Metathesis
,
†
†
†
†
‡
Levente Ondi,* Gergely M. Nagy, Janos B. Czirok, Agota Bucsai, and Georg E. Frater
†
XiMo Hungary Ltd., 7. Zahony Str., Budapest HU-1031, Hungary
‡
XiMo AG, 3. Altsagenstrasse, Horw/Luzern CH-6048, Switzerland
ABSTRACT: Molybdenum- and tungsten-based olefin metathesis catalysts have demonstrated excellent results in the control of
cis (Z-) selectivity as well as enantioselectivity. However, their air and moisture sensitivity, which requires the use of a glovebox,
has prevented their more widespread use by organic chemists. Now we report on developed, preweighed Mo catalysts formulated
in paraffin tablets. The significantly improved air stability, high homogeneity, and uniformity of the pellets allow researchers to
carry out reactions on the bench avoiding the need of a glovebox. The two different Mo-based complexes which were packed into
tablets are XiMoPac-Mo001 (1) that can be used to achieve endo-selective enyne ring-closing metathesis (RCM) reactions, inter
alia; and XiMoPac-Mo003 (2) which was reported among the best catalysts to promote Z-selective cross-metathesis. For the
evaluation of the wax-protected catalysts commonly used, highly reproducible robust model reactions were chosen: homo cross-
metathesis (HCM) of functionalized (e.g., methyl 9-decenoate) and unfunctionalized (allylbenzene) terminal olefins, and ring
closing metathesis (RCM) of diethyl diallylmalonate. The yields and conversions were comparable with those which can be
achieved in glovebox with nonformulated catalysts. Exposure to air did not cause any significant reduction in conversion while
the product selectivity (targeted product vs homologues derived from double bond isomerization) remained high. In contrast,
exposure to air caused a measurable drop in the conversion with the nonprotected catalyst. Furthermore, the formulated catalysts
remained unaffected even after 4 h of exposure to air, showing its enhanced air stability. In conclusion, these commercially
available air-stable Mo-catalyst tablets allow the reactions to be accomplished using ordinary Schlenk techniques, and hence
simplify catalyst handling in pilot laboratories and plants.
INTRODUCTION
bidentate N-heterocycles. The active catalyst can be efficiently
■
11,12
recovered with the addition of a Lewis acid.
The suggested
Mo and W metathesis catalysts are useful reagents in organic
1
−4
solution works well for the given examples since the prepared
bidentate complexes can be stored on bench for weeks, without
any extra care, however, the applicability of this approach for
other, e.g., sterically demanding complexes, might be
challenging. Very recently, Buchwald and colleagues reported
a more general solution. They prepared several handmade air
sensitive reagent “cocktails” sealed in paraffin-wax capsules for
synthesis.
The increased interest in the past decade resulted
in the synthesis of numerous highly active and tunable catalysts,
now available to researchers. Many of these unique complexes
5
,6
enable excellent control of enantioselectivity as well as cis
7
selectivity. The capability to induce stereoselectivity is a
particularly valuable feature of these complexes since several
properties of a substance, including reactivity, polarity,
mechanical characteristics, and/or biological activity, depend
on molecular geometry. To have a well-defined molecular
structure is especially important in synthesis of biologically
active compounds, such as flavors, fragrances, pheromones, and
pharmaceuticals, where usually only the right enantiomer
delivers the expected biological activity. To illustrate the
advantages and usefulness of these complexes, several
applications of enantioselective/Z-selective ring closing meta-
thesis (RCM) to natural products synthesis have been
1
3
important coupling reactions. Such capsules provide a
protection for the air and moisture-sensitive reagents to some
extent (depending on the nature of the active ingredient), thus,
facilitating the work of organic chemists and at the same time
14
diminishing the waste of decomposed reagents. In other
historical examples the moisture-sensitive reagents, such as
sodium or potassium hydride, were protected by mineral oil or
8
,9
15
developed by the research groups of Schrock and Hoveyda.
paraffin. The same approach has also been applied for
However, their air and moisture sensitivity, which necessitates
the handling of these complexes under a strictly controlled,
inert atmosphere, using a glovebox, has certainly prevented
their widespread use by organic chemists.
A more practical approach is the preparation of an air-stable
Grubbs’ Ru-catalyst to prevent the loss of its catalytic activity
16,17
during a long-term storage to open air.
Paraffin wax is
particularly attractive as a protective matrix or carrier for
reagents since it releases the active ingredients upon melting
and/or adding appropriate solvents, while it is generally
unreactive, inexpensive, and easy to handle and remove.
10
“dosage form” of the catalyst allowing researchers to carry out
reactions on the bench, avoiding the need of a glovebox. In this
context Furstner et al. demonstrated that sensitive Mo-based
̈
bisalkoxide metathesis catalysts can be converted into a bench-
stable but catalytically inactive form through complexation with
Received: May 4, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.6b00161
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Organic Process Research & Development
Article
Figure 1. Structure of the active catalyst of XiMoPac-Mo001 (1) and XiMoPac-Mo003 (2).
Table 1. Characteristics of XiMoPac-Mo001 and XiMoPac-Mo003
b
amount of the assumed substrate /pellet [mg] @
various catalyst loadings
weight of the pellet
mg]
MW of the catalyst
[g/mol]
[
amount of active catalyst/pellet [wt%] [mg] [mmole] 5.0 mol% 1.0 mol% 0.3 mol%
XiMoPac-
Mo001
200
895.03
5
10
0.0112
90
448
1493
XiMoPac-
Mo003
100
1062.98
10
10
0.0094
75
376
1253
a
b
Concentration and the potential substrate use at various catalyst loadings. Molecular weight of the hypothetical substrate: 400 g/mol.
RESULTS AND DISCUSSIONS
pretreatment of commercial grade olefins used later in various
metathesis reactions while the handling and storage of the
former one were incomparably safer and simpler.
■
We investigated a similar approach and now report a further
advancement of the original concept. The new technology can
provide a solution for difficulties accompanied by handling of
the otherwise particularly sensitive Mo-based metathesis
catalysts by making them “air-stable”. Our method enables
their use outside the glovebox without any risk of deterioration
of the catalysts’ activity.
In this study, beside TEAL, the following Mo-complexes
iPr
were selected for air-stable paraffin formulations: Mo(N Ph)-
iPr
(
(
CHCMe2Ph)(2,5-Me Pyrr)(OTPP) (1), Mo(N Ph)-
2
CHCMe2Ph)(Me Pyrr)(OBitet) (2) bearing R -octahydro-
2
ax
BINOL, the so-called R -Bitet ligand (Figure 1.).
ax
The developed formulation technology allowed to generate
accurately weighed tablets with high homogeneity. The main
characteristics of the tablets are summarized in Table 1 together
with an approximation of the potential substrate use/tablet at
different catalyst loadings (e.g., 5 mol%, 1 mol%, 0.3 mol%).
Due to the high homogeneity and uniformity of the tablets they
can readily be cut into smaller portions according to the exact
synthesis demand.
Our advanced procedure, in which the metathetically active
Mo-complexes are perfectly dissolved or dispersed in melted
macrocrystalline paraffin before formulation leads to homoge-
neous, preweighed paraffin droplets, containing predetermined,
constant amount of active ingredient. The process is suitable for
automation and to this end we developed an apparatus which
can produce pills with very low standard deviation of mass
(
typically less than 3%). This elaborated formulation
The stereogenic-at-Mo monoaryloxide/monoalkoxide
technology proved to be a broadly applicable tool for
converting air and moisture sensitive reagents, such as
triethylaluminum (TEAL), to stable and safe alternatives.
(
MAP) type of catalysts (including 1) were the first high
oxidation state complexes that efficiently catalyze enyne ring-
closing metathesis (RCM) reactions, affording the correspond-
18
Our earlier studies revealed that the amount of polar
impurities, which can irreversibly react with and inactivate Mo/
W-alkylidenes, can be efficiently reduced in various feedstocks
prior to metathesis by the addition of an appropriate amount of
triethylaluminum. Although this versatile organoaluminum
reagent can be purchased as a stock solution in various
concentrations working with this highly pyrophoric substance
requires much care therefore bench chemists try to avoid it.
Moreover, generally only a few mol% of TEAL is needed for an
efficient pretreatment therefore further dilution of the
commercially available material and safe storage of the prepared
manageable stock solution is required, which, once again, is an
additional encumbrance. To provide the community with a
universal solution for the above hurdle, formulation of neat
TEAL into macrocrystalline paraffin was attempted. As a result,
20
ing endo products with high selectivity. The previously
reported enyne metathesis catalysts were mostly ruthenium
21
complexes that, in most instances, provided exo products. In
contrast, the MAP Mo-alkylidenes are the first complexes that
20
allow for selective formation of endo products, with a >98:<2
22
endo:exo ratio in the case of (1). According to our experiences
catalyst (1) could also be used for performing various cross-
metathesis reactions with high conversion.
The active catalyst of XiMoPac-Mo003 (2) was reported to
be among the best catalysts to promote catalytic Z-selective
cross-metathesis of terminal enol ethers, and allylic amides. It is
important to note that thus far the cross metathesis of allylic
amides has only been realized in E-selective processes. Using
the active catalyst of XiMoPac-Mo003, Schrock, Hoveyda, et al.
obtained the corresponding disubstituted alkenes in up to
19
preweighed, “air-stable”, nonpyrophoric wax droplets of
TEAL were obtained. The formulated reagent turned out to
be equally efficient as the toluene stock solution for the
23
>98% Z-selectivity and 82% yield. A close analogue of catalyst
2 (bearing a chlorine instead of bromine in the 3,3′-position of
B
DOI: 10.1021/acs.oprd.6b00161
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Organic Process Research & Development
Article
the Bitet ligand) was also successfully applied for enantiose-
lective RCM of natural products’ intermediates.
1). Analysis of the reaction mixture indicated that under the
applied reaction conditions no detectable double bond
isomerization occurred. Isolation and purification of the crude
product by a simple flash chromatography, in a single run gave
the paraffin-free 4 in 69% yield. It should also be noted that at
1.0 mol% catalyst loading the amount of the expected product
and paraffin were practically identical which explains the
somewhat lower than expected isolated yield. In contrast to the
experiment carried out in toluene, in a “solvent-free” reaction,
at 65 °C, and under continuous argon flow (Table 2, entry 2),
migration of the double-bond took place and the homologous
products formed in ca. 6%. However, this double-bond
migration can be considerably suppressed if either a lower
catalyst loading or continuous dynamic vacuum is used (Table
24
In order to evaluate the applicability of our wax-stabilized
catalysts and to compare their efficiencies to that of the parent
ones we chose simple, highly reproducible metathesis trans-
formations that apply commercially available substrates. During
the design of the model reactions attention was paid to the ease
of monitoring conversion as well as product ratio (selectivity).
The standardized procedures together with the simple
analytical techniques made comparison of the surveyed
25
catalysts very simple and reliable.
As the first model reaction for demonstrating the value of the
formulated Mo catalyst tablets homo cross-metathesis (HCM)
of 9-decenoic acid methyl ester (9-DAME, 3) was chosen. The
widespread efforts in renewable resources increased the
significance of using natural oil derivatives. Unsaturated fatty
acid methyl esters (FAME) derived from glycerides can be
converted to short fatty acids and then to their derivatives, thus
yielding various important intermediates through manipulations
2
, entries 3, 4). In these cases the amount of double bond
migration derived products was less than 3%. Metathesis
reactions assisted by Mo- as well as W-based complexes are
28
known to be sensitive to polar impurities, such as water,
alcohols, or organic hydroperoxides. Removal of the last traces
of these catalyst poisons from the feedstock is crucial for a
successful transformation, but can be far from trivial when one
works in small quantities. To overcome this difficulty we
envisioned the use of triethylaluminum as an in situ
18
via metathesis reaction. Mo- and W-based MAP catalysts can
efficiently couple terminal olefins even in a Z-selective
2
6,27
manner.
However, up to now, all of these transformations
were carried out in an N -filled glovebox. In this study
2
homocoupling of 9-DAME (3) (Scheme 1) was performed out
18
pretreatment agent When the commercial grade decenoate
treated with 3.0 mol% toluene solution of TEAL was submitted
to HCM with 1 mol% XiMOPac-Mo001 again close to
complete conversion was realized (Table 2, entry 5). To
illustrate the positive impact of TEAL on substrate quality and
thus on catalyst performance reactions using untreated and in
situ purified feedstock at reduced catalyst loading were
compared. The obtained conversion values (Table 2, entries
Scheme 1. Homocoupling of 3 with XiMoPac-Mo001
6
, 7) clearly showed the utility of this simple pretreatment.
To evaluate the synthetic utility of paraffin formulated
catalysts, air stability of XiMoPac-Mo001 was thoroughly
investigated and compared to that of the nonformulated
metal complex, used as a control sample. In this study both
formulated and nonformulated catalyst samples were exposed
to air for various time periods before the extent of catalyst’s
decomposition and the retained catalytic performance were
determined (Figure 3). To this end, after the given time of
exposure each sample was divided into two partspellets were
of a glovebox, in a regular fume hood with 1.0 mol% of
XiMoPac-Mo001 using simplified Schlenk techniques. To
successfully accomplish these reactions only an inert gas supply
and not even Schlenk-type vacuum-inert gas manifold is
required (Figure 2).
Homocoupling performed in a toluene solution at 40 °C,
using a distilled, predried ester (3) proceeded to nearly
complete conversion within 4 h, affording the targeted C18
diester (9-ODDAME, 4) with perfect selectivity (Table 2, entry
1
cut in halfand one part was submitted to H NMR study in
anhydrous deuterated benzene while the other part was used in
HCM of 9-DAME (3), according to Method A. Exposure to air
for up to 24 h did not reduce the catalytic performance of
XiMoPac-Mo001 at all, in each case the conversion remained
close to quantitative (96%). On the contrary, only 5 min
“
aeration” of the nonformulated control sample resulted in
detectable decomposition and measurable drop of its catalytic
activity. The attainable conversion using the aforementioned
1
sample did not exceed 79%. The H NMR experiments carried
out parallel with the metathesis reactions revealed that up to 4
h no decomposition can be detected in case of the paraffin
pellets. However, after 4 h a slow decomposition starts and
some decomposition products can appear in 4−6 mol%, after
2
4 h. Nevertheless the metal complex of XiMoPac-Mo001 is so
active that this level of decomposition is not noticeable at the
applied 1.0 mol% catalyst loading (Table 3). NMR data
collected from the parallel experiment applying nonformulated
catalyst suggest that beside detectable decomposition some
other factors must have effect on catalysts performance (e.g.,
moisture can more readily adsorb onto the surface of a
Figure 2. Typical reaction setup.
C
DOI: 10.1021/acs.oprd.6b00161
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Table 2. Homocoupling of 9-Decenoic Acid Methyl Ester (9-DAME, 3) with XiMoPac-Mo001 (1) under Various Conditions
a
b,
c
d
entry
method
loading [mol %]
solvent
substrate
T [°C]
reaction time [h]
conv. [%]
sel. [%]
e
1
2
3
4
5
6
7
A
B
1.0
1.0
0.3
1.0
1.0
0.3
0.3
dry toluene
neat
purified (distilled, mol. sieves dried)
purified (distilled, mol. sieves dried)
purified (distilled, mol. sieves dried)
purified (distilled, mol. sieves dried)
40
65
65
65
40
40
40
4
2
2
2
4
4
4
93
99
99
94
B
neat
88
99
C
D
A
D
neat
99
97
f
dry toluene
dry toluene
dry toluene
in situ purified with TEAL
96
97
commercial grade
0−42
89
> 99
99
f
in situ purified with TEAL
a
Method A: Under argon atmosphere, into a predried 10 mL glass vessel equipped with an oil-bubbler and an inert gas inlet (a Schlenk tube or a
two-neck round-bottom flask) one tablet of XiMoPac-Mo001 catalyst was placed while a continuous argon flow was maintained. Then, 9-DAME (or
allylbenzene or allyltrimethylsilane) and dry toluene were added consecutively via automatic pipet before the reaction mixture was heated to 40 °C
and stirred for 4 h. In order to purge out the evolving ethylene the inert gas flow was kept constant during the reaction. Workup/removal of the
paraffin: to the reaction mixture wet acetonitrile was added, which led to the precipitation of over 90% of the paraffin. The resulting slurry was
intensively mixed before filtered through a short silica column. Method B: Same as Method A, with the exception that the reaction was performed at
6
5 °C for 2 h with no additional solvent. Method C: Same as Method B, except that after the additions the vessel was closed with a glass stopper, Ar
flow was discontinued, and the gas inlet was connected to a membrane pump. The vacuum was set to 25 mbar and the reaction mixture was heated
to 65 °C for 2 h. Method D: Under argon atmosphere, into a predried Schlenk tube (equipped with an oil-bubbler) 9-DAME (or allyl-benzene), dry
toluene, and a stock solution of triethylaluminum in anhydrous toluene were added successively by automatic pipet and the reaction mixture was
stirred for 30 min at room temperature while a continuous slow argon flow was maintained. After the pretreatment the procedure was continued as
b
c
Method A. Conv.: [2 × area(9-ODDAME)/(area(9-DAME) + 2 × area(9-ODDAME)] × 100%. The conversion values are the average of 3
parallel reactions in entries 2−4 and that of 2 parallel reactions in entries 1, 5−7. The results are based on noncalibrated results (GC peak areas).
d
e
Sel.: [ area(9-ODDAME)/(area(9-ODDAME) + area(9-ODDAME homologues))] × 100%. C18-diester (4) was isolated by flash
f
chromatography; yield: 69% (132 mg). Addition of 3.0 mol% TEAL to the commercial grade substrate as pretreatment agent makes its prior
distillation and drying dispensable.
Scheme 2. Homocoupling of 5 with XiMoPac-Mo001
In this series of experiments the conversion and selectivity of
the HCM reaction was comparable when applying triethylalu-
minum (TEAL) pretreatments, either in toluene stock solution
(
conv.: 80%, Table 4, entry 2) or in preformulated paraffin
tablets (conv.: 78%, Table 4, entry 3). Moreover, using the
paraffin formulated TEAL is a safer and more practical method
for this transformation. Isolation and purification of the highly
apolar 1,4-diphenylbut-2-ene (6) was accomplished by a reverse
phase flash chromatography.
RCM of diethyl diallylmalonate (DEDAM, 7) (Scheme 3.)
was carried out under constant argon flow (Method A, 40 °C, 4
h) using XiMoPac-Mo001 and XiMoPac-Mo003 tablets. GC-
Figure 3. Isolated catalysts and their air-stable “successors”.
nonformulated catalyst), however, these still have to be
investigated more thoroughly.
16
In another model study, the HCM reactions of allylbenzene
5; Scheme 2) were carried out using XiMoPac-Mo001 tablets
(
at various loadings and conditions (Table 4).
Table 3. Air-Stability Study of XiMoPac-Mo001 (1)
1H NMR study
HCM of 9-DAME
a
b
c
entry
exposure to air [h]
0 (control)
observation
2,3,5,6-Ph PhOH [n/n%] 2,5-Me2-pyrrole [n/n%] conv. (GC%) sel. (GC%)
4
1
2
3
4
5
6
no detectable decomp.high
99
98
99
98
97
79
97
conv.
2
99
4
96
8
detectable decomp.high conv.
4
8
2
3
2
3
97
24
> 99
99
nonformulate catalyst
detectable decomp.decreased
(ca. 5 min)
conv.
a
b
The reactions were accomplished according to Method A. The results are based on noncalibrated results (GC peak areas). Conv. = [2 × area(9-
c
ODDAME)/(area(9-DAME) + 2 × area(9-ODDAME))] × 100%. Sel.= [area(9-ODDAME)/(area(9-ODDAME) + area(9-ODDAME
homologues))] × 100%.
D
DOI: 10.1021/acs.oprd.6b00161
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Article
Table 4. Homocoupling of 5 with XiMoPac-Mo001 with and without TEAL Pretreatments
a
b
c
d
entry method loading [mol%]
solvent
substrate
TEAL pretreatment
T [°C] reaction time [h] conv. [%] sel. [%]
1
2
3
A
D
E
1.0
1.0
1.0
dry toluene
dry toluene
dry toluene
commercial grade
40
40
40
4
4
4
22−31
> 99
> 99
> 99
in situ purified with TEAL
3.0 mol% in toluene
80
e
3.0 mol% in paraffin
78
a
The results based on 2 parallel reactions in entries 1−3. The given conversion and selectivity based on noncalibrated results (GC peak areas).
b
Method E: Method D, except a preformulated 5 wt% triethylaluminum (TEAL) paraffin tablet (3.42 mg, 0.03 mmol, triethylaluminum in 64 mg
c
macrocrystalline paraffin) was applied instead of a toluene stock solution. Conv. = [2 × area(product)/(area(allylbenzene) + 2 x area(product))] ×
1
d
e
00%. Sel. = [area(1,4-diphenylbut-2-ene)/(area(1,4-diphenylbut-2-ene) + area(1,4-diphenylbut-2-ene homologues + isomers))] × 100%. Scale-
up experiment at ca. 8.0 mmol scale gave 99% conv.; 1,4-diphenylbut-2-ene (648 mg) was isolated with 79% yield.
Scheme 3. RCM of 7 with XiMoPac-Mo001 and XiMoPac-
Mo003
Scheme 4. Homocoupling of 9 with XiMoPac-Mo001/
XiMoPac-Mo003
MS analysis confirmed the high conversion (XiMoPac-
Mo001:86%; XiMoPac-Mo003:99%) even at 1.0 mol% catalyst
loading.
In the RCM reaction of 7, XiMoPac-Mo003 yielded higher
conversions compared to XiMoPac-Mo001, although in the
former cases untreated, commercial grade substrate was used
reagents can be readily handled. By encapsulation of the
otherwise air and moisture sensitive molybdenum monoalkox-
id-monopyrrolides (MAP) catalysts to macrocrystalline wax we
generated “air-stable”, easy-to-handle metathesis pills (XiMo-
Pac-Mo001/-Mo003) which can be used outside the glovebox.
To demonstrate the practical importance of our solution the
stabilized reagents were tested on the bench, in various, well-
known metathetic transformations. The achieved high con-
versions, good yields, and excellent selectivities show clearly the
utility of our method. We proved that a catalyst which lasts only
minutes under air without any extra protection can be readily
rendered to preweighed pills which remain unaffected for up to
(
Table 5). This observation highlights that metathesis catalysts
29
are strongly substrate- and reaction-specific, which also means
that their activity and sensitivity toward impurities might vary a
lot. Once again, addition of TEAL pellets to the untreated
substrate resulted in higher conversion, highlighting the
advantage of this additive.
An additional HCM example of allyltrimethylsilane (9)
(
(
Scheme 4) was carried out under constant argon flow
Method A, 40 °C, 4 h) using XiMoPac-Mo001 and
XiMoPac-Mo003 tablets. GC-MS analysis confirmed the high
4
h. We also showed that homogeneity of the tablets provides
users with the possibility to cut it into pieces and adjust the
catalyst/substrate ratio accordingly. The designed encapsula-
tion method turned out to be broadly applicable which allows
the conversion of various air sensitive reagents into stable
alternatives as it is demonstrated by the formulation of the
highly reactive and pyrophoric triethylaluminum.
conversion of the starting material to the desired product
(
XiMoPac-Mo001:99%; XiMoPac-Mo003:98%). However, iso-
lation of the paraffin-free bis(trimetlysilyl)but-2-ene having
polarity akin to paraffin was not feasible at such a scale.
Our preweighed homogeneous tablets have the following
advantageous characteristics: (a) their uniformity and homo-
geneity assures a robustness and resistance to any mechanical
impacts; (b) their homogeneity and accurate active ingredient
content allows the user to cut them into smaller pieces, thus
adjusting the loading according to their needs; (c) the
CONCLUSIONS
■
In the present article we are reporting a new approach to Mo-
based alkylidene assisted olefin metathesis and giving a hand to
scientists who would like to use this versatile transformation
but have no access to an expensive glovebox in which sensitive
Table 5. Ring Closing Metathesis of 7 with XiMoPac-Mo001,-Mo003
a,b
entry
XiMoPac-
method loading [mol%]
solvent
substrate
T [°C] reaction time [h] conv. [%]
1
2
3
4
5
6
7
Mo001 (1)
Mo001 (1)
Mo001 (1)
Mo003 (2)
Mo003 (2)
Mo003 (2)
Mo003 (2)
A
A
A
A
A
A
E
5.0
1.0
0.3
5.0
1.0
0.3
0.3
dry toluene
purified (distilled, molecular sieves dried)
40
40
40
40
40
40
40
4
4
4
4
4
4
4
> 99
86
9
dry toluene
commercial grade
> 99
> 99
33
c
in situ purified with TEAL
57
a
b
Conv.: [area(8)/ {area(DEDAM, 7) + area(8)}] × 100%. The conversion values are the average of 3 parallel reactions. The results are based on
c
noncalibrated results (GC peak areas). Addition of 3.0 mol% TEAL to the commercial grade substrate as pretreatment agent makes its prior
distillation and drying dispensable.
E
DOI: 10.1021/acs.oprd.6b00161
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Organic Process Research & Development
Article
automatized mass-production guarantees high reproducibility
for weight and loading accuracy.
h while a continuous slow argon flow was applied. After 4 h the
reaction mixture was diluted to 25 mL with acetonitrile (of
technical grade, containing some water to decompose catalyst).
At this step, the majority of the paraffin precipitated. The
obtained slurry was thoroughly stirred, then filtered through a
short silica column (2.0 mL), finally the silica pad was washed
with further 15 mL acetonitrile. The combined elute was
analyzed by GC-MS-FID (column: Phenomenex Zebron-
Inferno 35HT (30 m x I.D.:0.25 mm); method: 100 °C for 5
min, 50 °C/min until 250 °C, 250 °C for 10 min, 50 °C/min
until 340 °C, 340 °C for 5 min). Conversion: 93%; selectivity:
> 99%; E/Z-ratio: 85/15.
In summary, our commercially available air-stable Mo-
catalyst tablets prepared by a well-controlled formulation
technology has many practical advantages (uniformity,
accurately preweighed units), facilitating not only the
experimental process in laboratory, but can simplify the
everyday work with highly sensitive reagents in pilot
laboratories and plants. (Note: See a very recent successful
application of this new approach: Nguyen, T. T., Koh, M. J.;
Shen, X.; Romiti, F.; Schrock, R. R.; Hoveyda, A. H. Science
2
016, 352, 369.) A more comprehensive analysis of the utility
of Mo-, W-, and certain Ru-based complexes that are part of the
portfolio of XiMo AG is planned for publication in the near
future.
Isolation of Product 4. The volatiles were removed in
vacuum, the obtained crude product was purified by flash (silica
gel) column chromatography (heptane:EtOAc = 50:1) to afford
the product as a colorless oil. (TLC visualization reagent:
EXPERIMENTAL SECTION
potassium permanganate.)
■
1
Isolated Yield: 132 mg (69%) of Pure 4. H NMR (CDCl ,
Materials and Methods. All reactions were carried out in
oven-dried (140 °C, for 4 h) or flame-dried glassware under an
inert atmosphere of dry argon unless otherwise stated.
Molecular sieve (3 Å) was purchased from Merck and
activated at 300 °C, under <1 mbar vacuum for 18 h.
Allylbenzene (5), diethyl diallylmalonate (DEDAM, 7), and
3
3
00 MHz): 5.44−5.27 (2H, m, CH), 3.66 (6H, s, CH ), 2.29
3
(
4H, t, J = 7.5 Hz, CH ), 1.81 (4H, m, CH ) 1.68−1.52 (4H, m,
2
2
13
CH ), 1.39−1.16 (16H, m, CH ); C NMR (CDCl , 75 MHz):
1
2
2
3
74.5 (C1), 130.5 (C9), 51.6 (O−CH ), 34.2 (C2), 29.7 (C8),
3
2
9.2, 29.1, 25.1 (C3); MS (m/z): 340, 308, 276.
HCM of Commercial Grade 9-DAME (3) with 0.3 mol%
XiMoPac-Mo001, According to Method A (Table 2, Entry 6).
Analogously to the above procedure but used commercial grade
triethylaluminum were purchased from Sigma-Aldrich. C D6
6
(
99.98%) and CDCl (99.8%) were purchased from Euriso-top,
3
and 9-decenoic acid methyl ester (9-DAME, 3) from Elevance
Renewable Science.
9
(
-DAME (3; 776 μL, 686 mg, 3.72 mmol), anhydr. toluene
1224 μL), and one piece of XiMoPac-Mo001catalyst (200 mg
pellet: 10 mg, 0.011 mmol 1 in 190 mg macrocrystalline wax;
.3 mol%). Workup as described above. Conversion: 42%;
Each substrate was purified by atmospheric (for 5) or
vacuum distillation (3, 7) under inert atmosphere before they
were stored on 10 wt% activated 3 Å molecular sieves for 24 h
in an ordinary Schlenk tube. Toluene was distilled from
potassium under dry nitrogen, and stored over activated 3 Å
molecular sieves in a Schlenk tube.
Prior to use, all substrates (purified and commercial grade),
the triethylaluminum stock solution (TEAL, 5.18 wt % in
toluene), and abs. toluene were stored in Schlenk tube on the
bench.
0
selectivity: > 99%; E/Z-ratio: 87/13.
HCM of Purified 9-DAME (3) with 1.0 mol% XiMoPac-
Mo001, According to Method B (Table 2, Entry 2). Similar to
Method A, with the following modifications: purified 9-DAME
(5; 234 μL, 206 mg, 1.12 mmol) and one piece (200 mg) of
XiMoPac-Mo001catalyst (10 mg, 0.011 mmol 1 in 190 mg
macrocrystalline wax; 1.0 mol%) were placed in a Schlenk tube
and the neat reaction mixture was heated to 65 °C for 2 h in a
continuous dry argon stream before the reaction was quenched.
The workup was analogous to the one described above.
Conversion: 99%; selectivity: 94%; E/Z-ratio: 83/17.
HCM of Purified 9-DAME (3) with 0.3 mol% XiMoPac-
Mo001, According to Method B (Table 2, Entry 3).
Analogously to Method B but used purified 9-DAME (5; 776
μL, 686 mg, 3.72 mmol) and one piece of XiMoPac-
Mo001catalyst (200 mg pellet:10 mg, 0.011 mmol 1 in 190
mg macrocrystalline wax; 0.3 mol%). Workup was the same as
for Method A with 0.3 mol% catalyst loading. Conversion:
88%; selectivity: > 99%; E/Z-ratio: 84/16.
HCM of Purified 9-DAME (3) with 1.0 mol% XiMoPac-
Mo001, According to Method C (Table 2, Entry 4.).
Analogously to Method B described for 1.0 mol% catalyst
loading, except that after addition of the substrate and the
catalyst the reaction vessel was closed with a glass stopper, its
gas inlet was connected to a membrane vacuum pump set to 25
mbar, and the reaction was heated to 65 °C. Workup was the
same as for Method B at 0.3 mol% catalyst loading.
Conversion: 99%; selectivity: 97%; E/Z-ratio: 83/17.
The applied formulated catalysts (XiMoPac-Mo001 and
Mo003) are already available while the paraffin formulated
-
triethylaluminum will be accessible in January 2017 at Aspira
Scientific (www.aspirasci.com). They are sold in airtight, sealed
sachets and must be stored at 4 °C in a normal refrigerator.
Analysis of metathesis reactions was performed by GC-MS-
FID (Shimadzu GCMS QP2010Plus) or Agilent DB-23 (30 m
×
I.D.: 0.25 mm); the results of the reactions are given as ratio
of area of the corresponding GC-FID peaks.
Flash chromatography was performed by a Teledyne Isco
Combiflash Rf apparatus. Stationary phase: LiChroprep RP-18
(
25, 40 μm, Merck) or silica gel 60 (0.063−0.2 mm, spheric,
Molar Chemicals Ltd.).
Characterization of the isolated compound was performed by
NMR measured on a Bruker Avance 300 spectrometer.
Chemical shifts are reported in ppm using the residual peak
of the CDCl or C D as an internal reference.
3
6
6
Reactions. HCM of Purified 9-DAME (3) with 1.0 mol%
XiMoPac-Mo001, According to Method A (Table 2, Entry 1).
Under argon atmosphere, into a dry 10 mL Schlenk tube
(equipped with an oil-bubbler) purified 9-DAME (3; 234 μL,
2
06 mg, 1.12 mmol) and anhydr. toluene (1776 μL) were
HCM of Commercial Grade 9-DAME (3) with 1.0 mol%
XiMoPac-Mo001, According to Method D (Table 2, Entry 5).
Analogously to Method A applying 1 mol% catalyst loading, but
using commercial grade substrate which was treated with 3.0
mol% TEAL in toluene (85.9 μL, 5.18 w/w%, containing 3.83
measured by automatic pipettes. One piece of XiMoPac-
Mo001catalyst pellet (200 mg tablet containing 10 mg, 0.011
mmol 1 in 190 mg macrocrystalline wax; 1.0 mol%) was added,
the reaction mixture was heated up to 40 °C, and it stirred for 4
F
DOI: 10.1021/acs.oprd.6b00161
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Organic Process Research & Development
Article
mg, 0.033 mmol, TEAL) at 30 °C for 30 min prior to the
addition of the catalyst pellet. Conversion: 96%; selectivity:
evaporated, then extracted with dichloromethane, giving the
product as colorless oil after concentration. 1
97%; E/Z-ratio: 86/14.
Isolated Yield: 648 mg (79%) of Pure 6. H NMR (CDCl ,
3
HCM of Commercial Grade 9-DAME (3) with 0.3 mol%
300 MHz): δ 7.39−7.32 (m, 4H), 7.31−7.22 (m, 6H), 5.72 (m,
2H), 3.50 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 140.7,
130.4, 128.5, 128.4, 125.9, 38.9. MS (m/z): 208, 117, 91, 65.
RCM of DEDAM (7) with 1.0 mol% XiMoPac-Mo001,
According to Method A (Table 5, Entry 2). Analogous to
Method A but used purified DEDAM (7; 271 μL, 269 mg, 1.12
mmol), anhydr. toluene (1729 μL), and one piece of XiMoPac-
Mo001 catalyst (200 mg pellet: 10 mg, 0.11 mmol 1 in 190 mg
macrocrystalline wax; 1.0 mol%). After 4 h the reaction mixture
was diluted to 25 mL with wet acetonitrile. At that point the
majority of the paraffin (90−95%) precipitated. The obtained
slurry was thoroughly stirred before it was filtered through a
short silica column (2.0 mL), which was then washed with
further 15 mL of acetonitrile. From the combined elute 200 μL
was diluted to 1 mL with acetonitrile from which 1 μL was
injected and analyzed by GC-MS-FID (column: Phenomenex
Zebron-Inferno 5HT (30 m × I.D.: 0.25 mm); method details:
XiMoPac-Mo001, According to Method D (Table 2, Entry 7).
Analogously to Method A applying 0.3 mol% catalyst loading,
but used commercial grade substrate which was treated with 3.0
mol% TEAL in toluene (285 μL, 5.18 w/w%, containing 12.8
mg, 0.11 mmol, TEAL) at 30 °C for 30 min. Conversion: 89%;
selectivity: > 99%; E/Z-ratio: 90/10.
HCM of Commercial Grade Allylbenzene (5) with 1.0 mol
XiMoPac-Mo001, According to Method A (Table 4, Entry
). The reaction was performed according to Method A:
commercial grade allylbenzene (5, 148 μL, 132 mg, 1.12
mmol), anhydr. toluene (1776 μL), and one piece of XiMoPac-
Mo001 catalyst (200 mg pellet: 10 mg, 0.011 mmol 1 in 190
mg macrocrystalline wax; ca. 1.0 mol%). Workup: the reaction
mixture was diluted to 25 mL with further amount of wet
acetonitrile. At this step majority of the paraffin (90−95%)
precipitated. The obtained slurry was thoroughly stirred before
it was filtered through a short silica column (2.0 mL), which
was eluted with further 15 mL of acetonitrile. The combined
elute was diluted and analyzed by GC-MS-FID (column:
Phenomenex Zebron-Inferno 35HT (30 m × I.D.: 0.25 mm);
method details: 50 °C for 5 min, 18 °C/min until 275 °C, 20
%
1
5
0 °C for 5 min, 25 °C/min until 340 °C, 340 °C for 8.4 min).
Conversion: 86%.
RCM of Commercial Grade DEDAM (7) with 1.0 mol%
XiMoPac-Mo003, According to Method A (Table 5, Entry 5).
Analogous to Method A described above but used commercial
grade DEDAM (7; 455 μL, 452 mg, 1.88 mmol) and using two
pellets of XiMoPac-Mo003 catalyst (2 × 100 mg pellet: 20 mg,
°
C/min until 340 °C, 340 °C for 6.4 min). Conversion: 31%;
selectivity: > 99%; E/Z-ratio: 69/31.
HCM of Commercial Grade Allylbenzene (5) with 1.0 mol
XiMoPac-Mo001, According to Method D (Table 4, Entry
1
.88 mmol 2 in 180 mg macrocrystalline wax; 1.0 mol%) as
catalyst. Conversion: > 99%.
%
2
Isolation of Product 8. The volatiles were removed in
vacuum, the obtained crude product was purified by flash (RP
silica gel) column chromatography (methanol:water = 7:3→
). The reaction was performed according to Method D:
commercial grade allylbenzene (5, 148 μL, 132 mg, 1.12 mmol)
and anhydr. toluene (1776 μL). The toluene solution of the
substrate was pretreated with 3.0 mol% TEAL in toluene (85.9
μL, 5.18 w/w%, containing 3.83 mg, 0.033 mmol, TEAL)
before one piece of XiMoPac-Mo001 catalyst (200 mg pellet:
0 mg, 0.011 mmol 1 in 190 mg macrocrystalline wax; 1.0 mol
) was added and the reaction mixture was heated to 40 °C for
h. The workup was carried out analogously to the one
described above (8.). Conversion: 80%; selectivity: > 99%; E/
Z-ratio: 84/16.
1
:0). The combined fractions were extracted with dichloro-
methane, dried over MgSO and evaporated under vacuum
4
giving product 8 as colorless oil.
1
Isolated Yield: 337 mg (84%) of Pure 8. H NMR (CDCl ,
3
1
%
4
3
3
00 MHz): δ = 5.60 (pseudo s, 2H), 4.19 (q, J = 7.2 Hz, 4H),
.01 (pseudo s, 4H), 1.22 ppm (t, J = 6.6 Hz, 6H); C NMR
13
(
100 MHz, CDCl3): δ = 172.4, 127.9, 61.6, 59.0, 41.0, 14.1
ppm; MS (m/z): 212, 166, 138, 111.
RCM of Commercial Grade DEDAM (7) with 0.3 mol%
XiMoPac-Mo003, According to Method E (Table 5, Entry 7).
According to Method E: commercial grade DEDAM (7; 758
μL, 753 mg, 3.13 mmol) in anhydrous toluene (3242 μL) was
pretreated with 3.0 mol% TEAL in paraffin (10 × 22.8 mg; each
of them containing 1.14 mg, 0.01 mmol, triethylaluminum in
HCM of Commercial Grade Allylbenzene (5) with 1.0 mol
%
3
XiMoPac-Mo001, According to Method E (Table 4, Entry
). Analogous to Method D, but instead of a toluene stock
solution TEAL was added in 5 wt% paraffin formulated pellet
3.4 mg, 0.03 mmol, triethylaluminum in 64 mg macrocrystal-
line wax). Conversion: 78%; selectivity: > 99%; E/Z-ratio: 85/
5.
(
2
1.7 mg macrocrystalline wax) at 30 °C for 30 min before one
1
piece of XiMoPac-Mo003 catalyst (100 mg pellet: 10 mg, 0.094
mmol 2 in 90 mg macrocrystalline wax; 0.3 mol%) was added
and the reaction mixture was heated to 40 °C for 4 h. Workup
as described above (13). Conversion: 57%; selectivity: > 99%.
HCM of Purified Allyltrimethylsilane (9) with 1.0 mol%
XiMoPac-Mo001, According to Method A. Into a dry Schlenk
tube the following compounds were transferred: dry toluene (2
mL) via cannula, purified allyltrimethylsilane (180 μL, 129 mg,
1.13 mmol, 9) via syringe. An aliquot was taken for GCMS, one
piece of XiMoPac-Mo001 (200 mg pellet: 10 mg, 0.011 mmol 1
in 190 mg macrocrystalline wax; 1.0 mol%) was added, and the
mixture was stirred for 4 h at 40 °C under a slow constant
argon flow. Then, 8 mL of wet acetonitrile was added to the
reaction mixture and the resulting suspension was stirred for 20
min. The suspension was filtered over a pipet filled with glass
fiber filter and silica and a sample for GC was taken (column:
HCM of Commercial Grade Allylbenzene (5) with 1.0 mol
XiMoPac-Mo001, According to Method E (Scale-up).
%
Similarly, 5 wt% TEAL in paraffin pellet (16 mg, 0.24 mmol
triethylaluminum; 3.0 mol% in 540 mg macrocrystalline wax)
was added to allylbenzene (5, 1040 μL, 927 mg, 7.84 mmol) in
toluene (13 mL) at 30 °C, 30 min later 7 pieces of XiMoPac-
Mo001 (7*200 mg, 70 mg, 0.078 mmol 1 in 1330 mg
macrocrystalline wax; 1.0 mol%). After 4 h the reaction was
quenched with aq. MeOH. A sample was diluted with
dichloromethane for GC-MS-FID analysis. Conversion: 99%;
selectivity: 95%; E/Z-ratio: 86/14.
Isolation of Product 6. The volatiles were removed in
vacuum, the obtained crude product was purified by flash (RP
silica gel) column chromatography (methanol:water = 7:3→
8
:2). The combined fractions containing product 6 were partly
G
DOI: 10.1021/acs.oprd.6b00161
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Agilent DB-23 (30 m × I.D.:0.25 mm); method: 35 °C for 5
min, 35 °C/min until 100 °C, 7 °C/min until 130 °C, 35 °C/
min until 240 °C, 240 °C for 5.17 min). Conversion: 99%.
Isolation and purification of the product 10 was attempted
on a double scale reaction by means of reverse phase flash
chromatography (MeOH: water = 8:2→1:0), but remain
(8) Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock,
R. R.; Hoveyda, A. H. Nature 2011, 479, 88.
(
9) Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943.
10) van den Broek, S. B. A.; Meeuwissen, S. A.; van Delft, F. L.;
(
Rutjes, F. P. Natural Products Containing Medium-sized Nitrogen
Heterocycles Synthesized by Ring-closing Alkene Metathesis. In
Metathesis in Natural Product Synthesis: Strategies, Substrates and
Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.; Wiley-VCH Verlag
GmbH & Co KgaA: Weinheim, 2010; p 45.
unsuccessful.
1
H NMR (300 MHz, C D ) δ 5.41 and 5.28 (m, 2H), 1.4−
6
6
1
.6 (m, 4H), 0.03 and 0.00 (s, J = 0.8 Hz, 18H).
HCM of Purified Allyltrimethylsilane (9) with 1.0 mol%
(11) Heppekausen, J.; Fu
7829−7832.
12) Furstner, A.; Heppekausen, J. Metal complexes of molybdenum
and tungsten, and their use as pre-catalysts for olefin metathesis.
Patent WO 2012116695 A1, September 7, 2012.
̈
rstner, A. Angew. Chem., Int. Ed. 2011, 50,
XiMoPac-Mo003, According to Method A. Similar to the
above-described procedure, 153 μL of allyltrimethylsilane and
one piece of XiMoPac-Mo003 (100 mg pellet: 10 mg, 0.0094
mmol 2 in 90 mg macrocrystalline wax; 1 mol%) was used.
Conversion: 98%.
Air Stability of XimoPac-Mo001 (Table 3, Entry 5). A piece
of XiMoPac-Mo001 pellet (200 mg tablet containing 10 mg,
(
̈
(13) Sather, A. C.; Lee, H. G.; Colombe, J. R.; Zhang, A.; Buchwald,
S. L. Nature 2015, 524, 208.
(
(
(
14) Halford, B. Chem. Eng. News 2015, 93 (3), 6.
15) Taber, D. F.; Nelson, C. G. J. Org. Chem. 2006, 71, 8973.
16) Taber, D. F.; Frankowski, K. J. J. Org. Chem. 2003, 68, 6047.
0
.011 mmol 1 in 190 mg macrocrystalline wax; 5.0 wt%) was
stored on the bench without any protection for 2 h. Then it was
cut in half. One of the halves (75.3 mg) was dissolved at 45 °C
in 600 μL benzene-d6, an internal standard, 100 μL ferrocene
(17) Rule, J. D.; Brown, E. N.; Sottos, N. R.; White, S. R.; Moore, J.
S. Adv. Mater. 2005, 17, 205.
(18) Wampler, K. M.; Cohen, S. A.; Frater, G. E.; Ondi, L.; Varga, J.;
Methods for treating substrates prior to metathesis reactions, and
methods for metathesizing substrates. U.S. Patent US 2014275595 A1,
September 18, 2014.
(
0.0531 mol/L solution in benzene-d ) was added to it, and the
6
1
sample was measured by H NMR.
The other half (126 mg) was submitted to HCM (Scheme
), according to Method A using purified 9-DAME (3; 147 μL,
30 mg, 0.705 mmol), in anhydr. toluene (323 μL). XiMoPac-
(19) According to the statement of a certified laboratory which
1
1
carried out the necessary studies in line with Directive of the European
Communities: Methods for the Determination of Physico-Chemical
Properties (A.13), and the Principles of Good Laboratory Practice
Mo001 (after 24 h): conversion: 97%; selectivity: > 99%; E/Z-
ratio: 84/16.
(
Hungarian GLP Regulations: 42/2014. (VIII. 19.) EMMI decree of
the Ministry of Human Capacities which corresponds to the OECD
GLP, ENV/MC/CHEM (98) 17.) the obtained paraffin formulated
product is not pyrophoric, thus can be safely transported by airfreight.
AUTHOR INFORMATION
■
*
Corresponding Author
Telephone: (36) 1 580 2202; Fax: (36) 1-580 2201; E-mail:
levente.ondi@ximo-inc.com.
(
20) Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
009, 131, 10652.
(21) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55.
2
(
(
22) Ondi, L.; Nagy, G. M. Unpublished results.
23) Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda,
Notes
The authors declare no competing financial interest.
A. H. Nature 2011, 471, 461.
24) Hoveyda, A. H.; Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R.
Angew. Chem., Int. Ed. 2010, 49, 34.
25) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.
Organometallics 2006, 25, 5740.
26) Jiang, A. J.; Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 16630.
27) Marinescu, S. C.; Schrock, R. R.; Mu
Hoveyda, A. H. Organometallics 2011, 30, 1780.
28) Stenne, B.; Collins, S. K. Enantioselective Olefin Metathesis. In
(
ACKNOWLEDGMENTS
■
(
The authors are particularly grateful to Dr. Gyo
his competence and enthusiasm during compilation of this
̈
rgy Dorman
́
for
(
́
publication and thanks to Dr. Zsofia Dubrovay for her expert
assistance of NMR spectroscopy during the catalyst formula-
tion. We would also like to acknowledge the supporting
contribution of the Organocatalysis Research Group of the
(
̈
ller, P.; Takase, M. K.;
(
́
Hungarian Academy of Sciences, led by Dr. Tibor Soos and the
research group of the University of Stuttgart, Institute of
Polymer Chemistry led by Prof. Michael Buchmeiser.
Olefin Metathesis Theory and Practice; Grela, G., Ed.; John Wiley &
Sons, Inc.: Hoboken, NJ, 2014; p 234.
(29) Thorn-Csan
́
yi, E.; Zilles, J. U. J. Mol. Catal. A: Chem. 2002, 190,
8
5.
DEDICATION
■
To our boss and great mentor, Georg E. Frater. On the
occasion of his 75th birthday.
REFERENCES
1) Schrock, R. R. Chem. Rev. 2009, 109, 3211.
2) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
■
(
(
4
592.
(
(
(
3) Schrock, R. R.; Czekelius, C. Adv. Synth. Catal. 2007, 349, 55.
4) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
5) Hoveyda, A. H.; Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R.
Angew. Chem., Int. Ed. 2010, 49, 34.
(
6) Schrock, R. R. Chem. Commun. 2005, 2773.
(
7) Jiang, A. J.; Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 16630.
H
DOI: 10.1021/acs.oprd.6b00161
Org. Process Res. Dev. XXXX, XXX, XXX−XXX