Conformational Control of Initiation Rate in Hoveyda-Grubbs Precatalysts

Article abstract of DOI:10.1021/acs.organomet.8b00041

When the coordinating isopropyl ether of the Hoveyda precatalyst is replaced by a cyclohexyl ether, it is possible to control the substituent's conformation in either the equatorial or axial position. A stereodivergent synthesis of axial and equatorial cyclohexyl vinyl ethers provided access to new ruthenium metathesis precatalysts by carbene exchange. The conformational disposition of the coordinating aryl ether was found to have a significant effect on the reactivity of the precatalyst in alkene metathesis. The synthesis of four new Ru carbene complexes is reported, featuring either the 1,3-bis(2,4,6-trimethylphenyl)dihydroimidazolylidene (H₂IMes) or the 1,3-bis(2,6-diisopropylphenyl)dihydroimidazolylidene (SIPr) N-heterocyclic carbene ligand. The conformational isomers in the SIPr series were structurally characterized. Performance testing of all new precatalysts in three different ring-closing metatheses and an alkene cross metathesis illustrated superior performance by the precatalysts bearing axial coordinating ethers. Initiation rates with butyl vinyl ether were also measured, providing a useful comparison to existing Hoveyda-type metathesis precatalysts. Use of conformational control of the coordinating ether substituent provides a new way to modulate reactivity in this important class of alkene metathesis precatalysts.

Full text of DOI:10.1021/acs.organomet.8b00041

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Conformational Control of Initiation Rate in Hoveyda−Grubbs
Precatalysts
Zackary R. Gregg, Justin R. Griffiths, and Steven T. Diver*
Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, New York 14260-3000, United States
S
* Supporting Information
ABSTRACT: When the coordinating isopropyl ether of the Hoveyda precatalyst is
replaced by a cyclohexyl ether, it is possible to control the substituent’s conformation in
either the equatorial or axial position. A stereodivergent synthesis of axial and equatorial
cyclohexyl vinyl ethers provided access to new ruthenium metathesis precatalysts by
carbene exchange. The conformational disposition of the coordinating aryl ether was
found to have a significant effect on the reactivity of the precatalyst in alkene
metathesis. The synthesis of four new Ru carbene complexes is reported, featuring
either the 1,3-bis(2,4,6-trimethylphenyl)dihydroimidazolylidene (H2IMes) or the 1,3-bis(2,6-diisopropylphenyl)-
dihydroimidazolylidene (SIPr) N-heterocyclic carbene ligand. The conformational isomers in the SIPr series were structurally
characterized. Performance testing of all new precatalysts in three different ring-closing metatheses and an alkene cross
metathesis illustrated superior performance by the precatalysts bearing axial coordinating ethers. Initiation rates with butyl vinyl
ether were also measured, providing a useful comparison to existing Hoveyda-type metathesis precatalysts. Use of conformational
control of the coordinating ether substituent provides a new way to modulate reactivity in this important class of alkene
metathesis precatalysts.
Scheme 1. Hoveyda-Type Catalysts with Different Initiation
Rates
INTRODUCTION
■
New metathesis applications continue to drive the development
of new ruthenium carbene initiators, known widely as Grubbs
catalysts. A rapid initiation rate is critical for successful ring-
opening polymerizations and for promoting ring-closing
metathesis. In 1999, Hoveyda and co-workers1 developed a
chelated carbene catalyst, and shortly thereafter, the second-
generation catalyst Ru1 bearing a H2IMes N-heterocyclic
carbene (NHC) ligand was reported.2 The chelating ether
motif is extremely important and versatile, as it provides a
platform to control initiation rate, an important determinant of
metathesis activity. The parent complex Ru1 is known as the
Hoveyda or Hoveyda-Grubbs precatalyst, and other precatalysts
that contain the chelating ether motif fall into a superfamily of
metathesis initiators known as Hoveyda-type precatalysts.3
Hoveyda-type initiators have been utilized in some of the most
synthetically demanding metathesis applications in organic
synthesis.4
The Hoveyda chelate design has allowed access to diverse
precatalysts with different initiation profiles thereby suited to
particular metathesis applications. In most cases, the chelated
ruthenium carbene complex can be purified by column
chromatography and often can be recrystallized. The benzene
ring of the chelating ether can be modified to increase the
initiation rate. For instance, the addition of an electron-
withdrawing p-nitro group results in the electronically activated
precatalyst Ru2 known as the Grela catalyst5 (Scheme 1).
Other aromatic ring substituents also influence the initiation
reaction rate and affect the mechanism of initiation, as shown
by Plenio and co-workers.6 Steric effects also result in an
activated catalyst. An adjacent ring substituent can exert a steric
buttressing effect as in Ru3, forcing the isopropyl group into
greater steric clash with the RuCl2 fragment, leading to a
dramatic increase in initiation rate.7 If the isopropyl group of
Ru1 is replaced with an adamantyl group as in Ru5, there is a
profound steric effect, destabilizing the chelate and increasing
the initiation rate. Grubbs et al. showed this steric effect on
metathesis through measurement of initiation rates with vinyl
ethers.8 Recently, Grubbs and Ahmed used the phenyl
buttressing design of Blechert and Wakamatsu7 in catecholdi-
Received: January 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00041
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Scheme 2. Will Axial Disposition of the Chelating Ether Oxygen Increase Initiation Rate?
Scheme 3. Stereodivergent Synthesis of Conformers and Ru Carbene Catalysts
thiolate carbene Ru6 complexes to make more reactive
stereoretentive Ru carbene catalysts.9 A more extensive
discussion of all the modifications that have been made can
be found in a review10 and a recent book chapter.11
conformationally controlled initiation activity to a different
catalyst with a different NHC, the 1,3-bis(2,6-
diisopropylphenyl)dihydroimidazolylidene (SIPr) ligand. This
latter initiator proved highly effective for RCM reactions that
form tetrasubstituted cycloalkenes and for cross alkene
metathesis.
Despite this expansive set of ruthenium carbene precatalysts,
to our knowledge, modulation of initiation rate has never been
achieved by placing the coordinating ether in conformationally
distinct positions in a chair cyclohexane ring. The arylidene
containing the coordinating isopropyl ether is dislodged by an
alkene in the initiation step.12,6b For some reactions, such as
ring-closing metathesis (RCM) of diethyl diallylmalonate
(DEDAM), the rate of initiation dictates the rate of alkene
metathesis.13,6a By modification of the isopropyl group into a
cyclohexyl group, the coordinating ether substituent can be
either equatorial or axial. For simple substituents, such as an
ether, the A value is about 0.8 kcal/mol, which means that the
axial conformer is 0.8 kcal/mol higher in energy than the
equatorial isomer due to destabilizing 1,3-diaxial interactions. In
the coordinated ether substituent −O(Ar)(RuLn), the sub-
stituent is larger and likely has a larger A value, see axial-A in
Scheme 2. We hypothesized that if the ether oxygen was held
into an axial position such as in axial-A (Scheme 2), the greater
conformational strain experienced by the −O(Ar)(RuLn)
substituent would favor loss of the RuLn group, resulting in a
faster initiation rate. In this work, we validated this hypothesis
by synthesizing new Hoveyda complexes bearing either axial or
equatorial cyclohexyl aryl ethers. Performance testing in RCM
and initiation studies with an alkyl vinyl ether showed that the
axial conformer had increased metathesis activity. We utilized
this knowledge to efficiently run challenging ring-closing and
cross-metathesis reactions. We applied this new concept of
RESULTS AND DISCUSSION
■
Conformational control was achieved through a conformation-
ally locked cyclohexane ring. To restrict the aryl ether to an
axial or equatorial position, a tert-butyl group was attached at
the 4-position, where it resides in the equatorial position due to
its steric bulk. If the cyclohexane features trans-1,4-
disubstitution, the oxygen will be forced equatorial as in
equatorial-A. In the cis-1,4-disubstituted isomer axial-A
(Scheme 2b), the ether oxygen is forced exclusively in the
axial position. This expected steric strain will raise the energy of
the cis diastereomer; loss of Ru from oxygen binding will
reduce the A value of the cyclohexyl ether and lower the energy
of Ru−O dissociation relative to the equatorial isomer.
Initiation of the parent Hoveyda complex with small alkenes
proceeds by an associative mechanism, leading to a higher
energy alkene complex.14a,b,6b,14c The higher ground state
energy of the axial-A conformer will result in a lower activation
energy en route to the higher energy reactive intermediates in
the initiation pathway. This thinking formed the basis for the
design of the catalysts in this study.
The stereodivergent synthesis of the cis and trans isomers
proceeded from a common commercially available starting
material, 4-tert-butylcyclohexanone (Scheme 3). Equatorial
hydride delivery with the bulky complex metal hydride L-
B
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Selectride gave the axial alcohol 1 with high stereocontrol. A
Mitsunobu reaction with phenol 2 gave the equatorial aryl ether
3 in 76% yield. Reaction of the Grubbs carbene Ru4 with 3 in
the presence of CuCl gave the equatorial catalyst 4 in good
overall yield. The corresponding axial conformer (diaster-
eomer) was produced by LiAlH4 reduction to give 5 in a 9:1
diastereomeric ratio (equatorial:axial). A Mitsunobu reaction
with phenol 2 was employed to install the axial ether, giving 6.
This was a more difficult reaction that resulted in lower yield
and lower dr; however, pure diastereomer 6 was obtained after
careful column chromatography. Carbene exchange by reaction
of 6 with Ru4 mediated by CuCl gave the axial conformer 7 in
good yield. The carbene complexes 4 and 7 were purified by
flash chromatography on silica gel, and the equatorial 4 was
recrystallized by layering in dichloromethane−hexanes and
allowing the mixture to stand at room temperature over several
days in the glovebox.
equatorial isomer performed similarly to that of the Ru1
complex, though slightly slower. In contrast, the axial
precatalyst 7 promoted this reaction more quickly than Ru1
and significantly more quickly than the equatorial isomer 4. For
the RCM of DEDAM, axial catalyst 7 was superior.
After observing a rate enhancement in the RCM of diethyl
diallylmalonate for the axial catalyst, we wondered whether the
same concept could be applied to a different Grubbs catalyst
with a different N-heterocyclic carbene supporting ligand.
Using the same axial and equatorial starting materials 3 and 6,
the CuCl-mediated carbene exchange reaction with the
commercially available Grubbs catalyst Ru7 produced two
new diastereomeric precatalysts in excellent yield (Scheme 4).
Precatalysts 8 and 9 bear a sterically hindered NHC, the 1,3-
bis(2,6-diisopropylphenyl)dihyrdoimidazole (SIPr) ligand. As
with the previous carbene complexes, these were purified by
flash chromatography on silica gel. Recrystallization by
dissolving in dichloromethane and layering with hexanes
yielded X-ray-quality crystals.
With conformational isomers 4 and 7 in hand, we checked
the rate of ring-closing metathesis of the simple diene, diethyl
diallylmalonate (DEDAM) (eq 1). In terms of performance
The X-ray crystal structures were obtained for the axial and
equatorial conformers of the SIPr carbene precatalysts. The
equatorial Ru complex 8 is shown in Chart 1, and the axial Ru
Chart 1. X-ray Structure of Ru Carbene Complex 8
a
(Equatorial Aryl Ether)
testing, this rate profile is commonly examined for new catalysts
because the slowest step of this reaction is the initiation step.15
Typically this reaction is monitored by in situ 1H NMR, but we
used in situ IR spectroscopy. In this way, the concentration of
product was measured by observing the IR absorption at 1254
cm−1 for a C−O bond in the RCM product. The benchmark
rate profile of the Ru1 precatalyst was also determined and
found to lie between the conformers 4 and 7 (Figure 1). The
a
Ellipsoids drawn at 50% probability. Hydrogen atoms have been
omitted for clarity. Selected bond lengths: Ru−Cl1, 2.3343(9) Å; Ru−
Cl2, 2.3445(9) Å; Ru−O1, 2.217(3) Å; Ru−C1, 1.966(4) Å; Ru−C28,
1.832(4) Å; O1−C35 1.470(4) Å.
Figure 1. Percent conversion of diethyl diallylmalonate to its ring-
closing metathesis product (eq 1), monitored by in situ IR versus time.
Conditions: 0.05 M DEDAM, 0.5 mM Ru catalyst, toluene, 30 °C;
reactant 1215 cm−1, product, 1254 cm−1.
complex 9 is shown in Chart 2. First, the solid-state structures
confirm the equatorial and axial orientations of the aryl ether
Scheme 4. Synthesis of New Precatalysts Bearing a Different NHC Ligand
C
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the RCM shown in eq 2 is illustrated in Figure 2. A large
number of data were obtained by in situ IR monitoring of the
Chart 2. X-ray Structure of Ru Carbene Complex 9 (Axial
Aryl Ether)
a
Figure 2. Conversion of dimethyl allyl(methylallyl)malonate to its
ring-closing metathesis product, 4,4-dicarboethoxy-1-methylcyclopen-
tene, monitored by in situ IR versus time. Conditions: 0.05 M diene,
0.5 mM Ru catalyst, toluene, 30 °C; reactant 1215 cm−1, product, 1254
cm−1.
a
Ellipsoids drawn at 50% probability. Hydrogen atoms have been
omitted for clarity. Selected bond lengths: Ru−Cl1, 2.3199(4) Å; Ru−
Cl2, 2.3396(5) Å; Ru−O1, 2.3118(13) Å; Ru−C1, 1.9736(17) Å; Ru−
C28, 1.8181(19) Å, O1−C35, 1.477(2) Å.
reactant and product concentrations, by the distinctive C−O
absorbances at 1215 and 1245 cm−1, respectively. The rate
profile of the Ru1-promoted reaction provides a reference for
this ring-closing metathesis. As expected, the equatorial H2IMes
precatalyst 4 showed a rate profile almost identical with that of
the Ru1 precatalyst. The SIPr equatorial precatalyst 8
promoted this RCM at a much slower rate. Interestingly,
both axial precatalysts 7 and 9 showed pronounced rates of
catalysis for this transformation even though they have different
initiation rates (see below).
Quantitative data such as the kobs rate constants can be
extracted from the reaction progress plots. By a plot of ln
[diene] versus time, kobs can be obtained as the slopes of the
lines (see the Supporting Information for the plot), as
summarized in Table 1. The rate constant for the Hoveyda
substituent on the cyclohexane ring. Second, some bond length
differences are consistent with greater steric strain in the axial
conformer. Axial isomer 9 has a slightly longer Ru−O bond in
the chelate: 2.3118(13) vs 2.217(3) Å for the equatorial isomer
8. For comparison, the Ru−O bond length in the Grubbs 2-
adamantyl complex Ru5 is 2.338(3) Å.8 The NHC ligand is
slightly more distant from the Ru center in the axial isomer:
1.9736(17) vs 1.966(4) Å for the equatorial isomer. This may
be due to the greater face strain between the Cl−Ru−Cl moiety
and the cyclohexyl ether in the axial conformer. Finally, the
equatorial ether substituent holds the chair cyclohexane ring
closer to the aromatic ring of the NHC. For instance, the Ru−
O1−C35 bond angle is 127.07°, whereas the same bond angle
in the axial conformer is 131.16°. The axial conformer features
a slightly greater separation of the cyclohexane ring and the
aromatic ring of the N-heterocyclic carbene, which provides
greater access to the Ru center by an approaching alkene. Other
small structural differences are also noted, such as slightly
longer Ru−Cl bonds in the equatorial isomer and a shorter
RuC bond (Ru−C28) in the axial isomer. The difference in
Ru−O bond length between the conformational isomers is
most likely due to the steric strain imposed due to the
conformation of the cyclohexyl ether; some of the smaller
differences may result from additional interactions arising from
crystal packing.16
Table 1. Apparent Rate Constants (kobs) for the RCM of
a
Dimethyl Allyl(Methylallyl)Malonate
b
c
entry
precatalyst
kobs (10−3 s−1
)
krel
1
2
3
4
5
Ru1 (Hoveyda)
equatorial-4
axial-7
1.70
2.09
3.95
4.86
11.14
0.432
12.33
25.9
1.00
28.7
equatorial-8
axial-9
a
Conditions: 0.05 M dimethyl allyl(methylallyl)malonate, 1 mol %
b
catalyst loading, 30 °C. kobs is determined from the slope of the linear
region after the induction period. krel is based on 8 in entry 4.
c
When a more challenging diene substrate was used for the
RCM reaction, performance testing for the new precatalysts
revealed a significant difference in the equatorial and axial
conformational isomers. A more challenging RCM may magnify
catalyst differences, making it easier to compare them through
reaction progress graphs (time−conversion plots). Ultimately,
conversion data obtained from the Grubbs tests17 helps
compare new metathesis precatalysts with the available
precatalysts; rate comparisons also aid catalyst selection for
future synthetic applications. The reaction progress graph for
complex Ru1 provides a point of reference (entry 1). Each of
the precatalysts 7 and 9 promoted this reaction about 7 times
faster than Ru1. When equatorial is compared to axial (entry 2
vs 3; entry 4 vs 5), the axial conformer performed better. In the
H2IMes series, the rate difference for axial vs equatorial is a
factor of 6; in the SIPr series, the rate difference is a factor of
28. The conformation of the ether ligand with respect to the
cyclohexane ring affects the reaction rate. Interestingly, the axial
SIPr precatalyst performed almost identically with the axial
D
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H2IMes precatalyst. A similar profile was previously observed
by Nelson et al. for an SIPr catalyst in a comparative study of
SIPr and H2IMes-based Ru precatalysts.18
The new carbene precatalysts were evaluated for their
performance in promoting a challenging RCM to form a
tetrasubstituted cycloalkene (eq 3, Table 2). There are few
Table 3. Results of Alkene Cross Metathesis Using New
Precatalysts
a
b
entry
precatalyst
yield (%)
E:Z ratio
1
2
3
Ru1 (Hoveyda)
Ru2 (Grela)
equatorial-4
axial-7
67
77
70
75
66
86
69
>20:1
>20:1
>20:1
>20:1
3.8:1
c
4
5
6
equatorial-8
axial-9
6.4:1
7
Ru8
4.7:1
a
Conditions: 0.17 M B with 4.9 equiv of methyl acrylate in CH2Cl2, 1
b
1
mol % Ru cat, 25 °C, 30 min. Yield determined by H NMR vs
mesitylene internal standard. For this entry, yield and E:Z ratio
a
c
Table 2. Formation of a Tetrasubstituted Cycloalkene
represent the average of two runs.
b
entry
precatalyst
yield (%)
1
2
3
4
equatorial-4
axial-7
59
45
precatalyst Ru2. In the SIPr series, the difference was more
significant: 86% yield obtained with the axial conformer 9 was
superior to the corresponding equatorial catalyst 8, which gave
66% yield. The similarity of the performance of the axial
H2IMes precatalyst 7 to that displayed by the Grela precatalyst
Ru2 suggested that these carbene complexes may have similar
initiation rates. On the basis of this suspicion, we investigated
initiation rates next.
c
equatorial-8
axial-9
40 (69)
82
30
0
d
5
Ru1 (Hoveyda)
Ru2 (Grela)
e
6
a
Conditions: 0.1 M dimethyl bis(methylallyl)malonate, 5 mol %
b
catalyst loading, C6D6, 60 °C, 24 h reaction time. Average of two
c
d
runs; determined by 1H NMR spectroscopy. After 91 h. Taken from
Finally, the initiation rate with butyl vinyl ether was
measured (eq 5). We followed standard conditions so that
Grubbs et al.19 Taken from Grela et al.,5 where the reaction was
e
performed at 40 °C for 24 h.
catalysts that are proficient for this difficult RCM. We adopted
the standard conditions used by Grubbs et al.,19 who
determined the conversion to product after 24 h at 60 °C.
The yields are shown in Table 2. Surprisingly, the equatorial
H2IMes 4 proved superior to the axial conformer 7 (59% vs
47%, respectively). In comparison to the Hoveyda precatalyst
Ru1 (entry 5), all of the new precatalysts gave better yields.
The shortcoming of the axial initiator 7 may be a result of rapid
initiation, leading to a greater extent of catalyst decomposition.
The results of the two conformers in the SIPr series showed the
expected trend (entries 3 and 4): the equatorial 8 gave 40%
yield, whereas the axial conformer 9 resulted in 82% yield after
the standard reaction time. For this transformation, the
structure of the catalyst’s NHC ligand has a significant effect
on the yield and a faster initiation rate alone is not adequate for
the reaction of hindered diene substrates. To the best of our
k n o w l e d g e , t h e b i s ( 1 , 3 - d i i s o p r o p y l p h e n y l ) -
dihydroimidazolylidine ligand has not previously been shown
to be a good NHC ligand for ring-closing metatheses that form
tetrasubstituted cycloalkenes.20
Table 4. Initiation Rates of New Precatalysts with Butyl
Vinyl Ether
a
b
d
entry
precatalyst
kobs (10−4 s‑1)
krel
2
2
equatorial-4
axial-7
0.16 0.05
9.41
2000
1.00
82.4
1.29
34
2
c
3
equatorial-8
axial-9
0.017 0.004
1.4 0.2
4
c
5
Ru8
0.022 0.008
a
Conditions: 10−4 M Ru-cat, 3 × 10−3 M butyl vinyl ether (BuVE), 10
°C, in distilled toluene, measured by absorbance at 380 nm by UV−
b
vis. kobs is the average of three trials. kobs was determined through the
c
slope of ln(At − Ainf) − ln(A0 − Ainf) vs time. kobs was determined
from the linear region of ln [catalyst] vs time, and [catalyst] was
d
determined through the Beer−Lambert law. krel is equal to kobs/(kobs
The new precatalysts proved highly effective in promoting a
difficult cross alkene metathesis. We adopted conditions similar
to those reported by Grela, as shown in eq 4.5 A 67% yield
of 8).
we could make comparisons to known Hoveyda-type
precatalysts. We monitored the disappearance of the Ru
precatalyst by measuring the absorbance at 380 nm, which
gave kobs under pseudo-first-order conditions.8 Similarly to the
data obtained above, the equatorial and axial precatalysts
showed significant differences in the initiation rates (Table 4).
In entry 1, the equatorial precatalyst 4 registered a kobs value
similar to the reported literature value for the Hoveyda complex
Ru1.8 The axial precatalyst 7 registered a krel value of 2000
(entry 2). On comparison of the equatorial and axial
conformers (entries 1 and 2), the axial precatalyst 7 reacted
>200 times faster than 4. In the SIPr series, equatorial 8 was the
slowest initiator with a krel value of 1.00 (entry 3), whereas the
obtained with the Hoveyda precatalyst Ru1 gives a baseline
yield for comparison (entry 1, Table 3). The Grela precatalyst
Ru2 is highly proficient for this transformation, giving a 77%
yield. A slight difference in the effectiveness of the conformers 4
and 7 was found (entries 3 and 4). The yield with the
equatorial precatalyst was similar to that obtained with the
Hoveyda precatalyst Ru1, and the yield obtained with the axial
precatalyst was similar to that obtained with the Grela
E
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axial precatalyst 9 reacted 82 times faster (entry 4). In the SIPr
series, comparison was made to a commercially available
catalyst, Ru8. As expected, Ru8 showed a rate similar to that for
equatorial 8. On comparison of the equatorial conformers in
entries 1 and 3, it is not surprising that the equatorial H2IMes
precatalyst 4 is a faster initiator. The mechanism for initiation
with small alkenes such as butyl vinyl ether are associative and
bimolecular; the greater steric bulk of the 2,6-diisopropyl
substitution of 8 impedes alkene association, resulting in a
slower initiation rate. However, the greater steric bulk of the
NHC ligand alone does not control the initiation rate: SIPr-
based 9 reacts about 9 times faster than H2IMes-based 4 (82.4
vs 9.41, entries 4 and 1, respectively).
improve the initiation rate may prove useful for challenging
cross alkene metathesis applications. Future catalyst design
using conformational control of the ether substituent is
foreseeable.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise stated, all reactions
were performed using standard Schlenk line techniques under nitrogen
with oven or flame-dried glassware. Solvents used in reactions were
obtained from an anhydrous column purification system. Grubbs
carbenes were obtained from Materia Inc. (Pasadena, CA) and used as
received. Commercially available reagents were used as received unless
otherwise noted. Diethyl diallylmalonate, butyl vinyl ether, methyl
acrylate, and benzene-d6 were distilled before use. Copper(I) chloride
was recrystallized from concentrated hydrochloric acid, washed with
deionized water, and dried in vacuo. Flash chromatography was carried
out on untreated silica gel 60 from Sorbtech Technologies Inc. (230−
400 mesh) under air pressure. Thin-layer chromatography (TLC) was
performed on glass-backed silica plates (F254, 250 μm thickness, EMD
Millipore), visualized with UV light, phosphomolybdic acid, iodine, or
potassium permanganate. IR kinetics were obtained using a ReactIR
iC10 instrument equipped with a K4 conduit and a SiComp sensor
Comparison to other Hoveyda-type precatalysts was possible,
giving a direct measure of the effectiveness of the arylidene
linker in the initiation step of alkene metathesis. For instance,
literature data show that Ru1 has kobs = 0.401 × 10−4 s−1 and
Ru2 (Grela precatalyst) has kobs = 0.757 × 10−4 s−1, giving a krel
value of 23.6 for Ru1 and krel value of 44.5 for Ru2. This
comparison, on the basis of separate measurements made by
Grubbs et al.8 and ourselves under identical conditions,
illustrates that the fastest initiating new axial precatalyst 7 is
about 84 times more reactive than Ru1 and 45 times more
reactive than Ru2. In addition, comparison to Grubbs’ 2-
adamantyl precatalyst Ru5 is possible. The 2-adamantyl
precatalyst Ru5 has its aryl ether locked into an axial position;
1
(2.5 cm × 10 cm) running iC IR software. H NMR spectra were
recorded at 300, 400, or 500 MHz; proton-decoupled 13C NMR
spectra were recorded at 75, 101, or 125 MHz using Varian Mercury
300, Inova 400, and Inova 500 instruments, and proton-decoupled 31P
NMR spectra were recorded at 121 MHz on a Varian Inova 400
1
spectometer. H NMR chemical shifts are reported in ppm relative to
obs was determined to be 54.4 × 10−4 s−1,8 which would give a
1
the solvent used (chloroform-d, H 7.26 ppm, 13C 77 ppm; benzene-
k
d6, 1H 7.15 ppm, 13C 128.06 ppm; dichloromethane-d2, 1H 5.32 ppm),
and 31P was referenced using H3PO4 as an external reference. Infrared
spectra were recorded using a PerkinElmer Spectrum Two FTIR-ATR
instrument. Mass analysis was performed on a Bruker SolariX 12T
FTMS apparatus using electrospray ionization with acetonitrile or
dichloromethane as solvent. UV−vis studies were performed using a
Cary 3E or a Cary 300 Bio UV−visible spectrometer, with temperature
control. Computer-generated first-order fits were performed using the
Cary WinUV kinetics software.
krel value of 3200 (based on 8) in comparison to the set of
precatalysts in Table 4. Ru5 is a faster initiator than axial 7 by a
factor of 1.5. Ru5 and axial 7 should have similar rates of
initiation, but small differences in ring strain and rotamer
population may account for the observed difference between
these two initiation rates.
CONCLUSION
■
Preparation of 6. In a flame-dried 50 mL round-bottom flask
equipped with magnetic stirbar were successively placed triphenyl-
phosphine (1.10 g, 4.2 mmol), 4-trans-tert-butylcyclohexanol (984.7
mg, 6.3 mmol), 2 (282.4 mg, 2.1 mmol), triethylamine (580 μL, 4.2
mmol), and THF (7.05 mL). The reaction mixture was then stirred at
room temperature for 1 h. The solution was cooled to 0 °C, and then
diisopropyl azodicarboxylate (820 μL, 4.2 mmol) was added dropwise,
allowing the orange color to dissipate between drops. The reaction
mixture was maintained at 0 °C for 2 h then warmed to room
temperature and stirred overnight. The mixture was concentrated by
rotary evaporation and triturated with CH2Cl2 and hexanes to afford a
colorless oil. Flash chromatography (0−20% gradient ethyl acetate−
hexanes) afforded 6 (344 mg, 60%, >95% Z, and a single diastereomer
In summary, we synthesized four new Ru carbene complexes
that bear arylidene ethers in conformationally distinct positions
on a cyclohexane ring. The conformation of the aryl ether was
found to affect the reactivity of the new precatalysts. A simple
stereodivergent synthesis starting from commercially available
4-tert-butylcyclohexanone provided access to the equatorial and
axial conformers. The modular nature of the synthesis allows
for conformationally disposed ethers to be installed in different
Grubbs catalyst environments, such as those bearing different
N-heterocyclic carbene ligands. The axial or equatorial
conformation of the coordinated ether was found to have a
significant influence on the rate of ring-closing metathesis and
on the initiation rate. In three different ring-closing metatheses,
in an alkene cross metathesis, and in reaction with butyl vinyl
ether, the precatalysts with the axially disposed aryl ether
performed better than the corresponding equatorial con-
formers. Solid-state structures for the conformational isomers
in the SIPr series both confirmed the structure and showed
differences in the Ru−O bond length. Interestingly, the SIPr
catalysts performed well for the synthesis of tetrasubstituted
cycloalkenes and the axial SIPr catalyst proved to be superior
for a cross alkene metathesis. In the axial position, the Ru-
coordinated aryl ether has a higher steric strain which is
partially alleviated upon decoordination of the Ru atom, leading
to a lower activation energy for the initiation step. Overall, the
conformation of the aryl ether was found to be an important
determinant affecting alkene metathesis reactivity of different
Hoveyda-type catalysts. Use of a defined conformation to
1
by H NMR) as a colorless oil. Analytical TLC: Rf 0.6 (10% EtOAc−
hexanes); 1H NMR (400 MHz, CDCl3, ppm): δ 7.28 (d, 3J = 7.2 Hz, 1
H, aromatic), 7.17 (t, 3J = 8.4, 1 H, aromatic), 6.90 (t, 3J = 7.8 Hz, 2 H,
3
3
aromatic), 6.60 (d, J = 11.1 Hz, 1 H, α-vinylic), 5.79 (dq, J = 15.4
Hz, 3J = 9.4 Hz, 1 H, β-vinylic), 4.58 (s, 1 H, CHOAr), 2.19−2.01 (m,
2 H, cyclohexyl), 1.84 (d, 3J = 6.9 Hz, 3 H, CH3), 1.58−1.38 (m, 6 H,
cyclohexyl), 1.11−0.95 (m, 1 H, cyclohexyl), 0.87 (s, 9 H, tert-butyl).
13C{1H} NMR (75 MHz, CDCl3, ppm): δ 154.95, 130.28, 127.86,
127.60, 126.10, 125.69, 119.68, 113.89, 71.28, 47.64, 32.57, 30.19,
27.48, 21.37, 14.73. FT-IR (ATR, cm−1): 3024, 2940, 2866, 1596,
1483, 1449, 1393, 1365, 1285, 1230, 1177, 1111, 1032, 1005, 962, 928,
853, 749, 699. High-resolution MS (EI+, m/z): molecular ion
calculated for C19H28O [M+] 272.2135, found 272.2137, error 0.9
ppm.
Preparation of 3. In a 50 mL Schlenk tube containing a magnetic
stirbar were placed 650 mg of cyclohexanol 1 (4.15 mmol, 3 equiv),
186 mg of Z-2 (1.39 mmol, 1.00 equiv), 729 mg of triphenylphosphine
(2.78 mmol, 2 equiv), 0.39 mL of triethylamine (0.28 g, 2.78 mmol,
F
DOI: 10.1021/acs.organomet.8b00041
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
2.0 equiv), and 5 mL of THF. The solution was cooled to 0 °C,
whereupon 0.55 mL of diisopropylazodicarboxylate (0.56 g, 2.78
mmol, 2 equiv) was added dropwise via microliter syringe. After 2.5 h,
TLC indicated complete consumption of the limiting reagent. The
crude reaction mixture was concentrated in vacuo (rotary evaporator)
and dissolved in ca. 0.5 mL of CH2Cl2, and the solids were crashed out
by addition of 50 mL of hexanes. After the filtrate was decanted, the
process was repeated, keeping the filtrate and evaporating solvents.
The crude product was purified by flash chromatography (gradient
elution 0−10% ethyl acetate−hexanes) to give 287 mg of Z-3 (76%).
Analytical TLC: Rf 0.6 (10% ethyl acetate−hexanes). 1H NMR
122.75, 114.70, 79.22, 51.96, 48.74, 33.59, 30.80, 30.51, 28.99, 28.21,
22.36, 21.83, 19.17. FT-IR (ATR, cm−1): 2932, 2858, 2230, 1726,
1585, 1576, 1478, 1451, 1419, 1398, 1381, 1336, 1293, 1262, 1211,
1181, 1156, 1111, 1035, 1002, 915, 873, 852, 834, 780, 732, 645, 591,
580. High-resolution MS (ESI+, m/z): molecular ion calculated for
C38H50Cl2N2ORu [M + formate] 767.2320, found 768.2361, error 6.2
ppm.
Equatorial 8. Following the general procedure and using Ru7
(115.7 mg, 0.124 mmol), CuCl (13.9 mg, 0.14 mmol), and 6 (65.4 mg,
0.24 mmol) for the reaction, 97.0 mg of 8 (97% yield) was isolated as a
green solid. Analytical TLC: Rf 0.42 (50% CH2Cl2−hexanes). 1H
NMR (323 K, 400 MHz, CDCl3, ppm): δ 16.57 (s, 1 H, RuCHAr),
7.41 (t, 3J = 7.8 Hz, 2 H, aromatic), 7.31 (d, 3J = 7.6 Hz, 4 H,
(CDCl3, 300 MHz, ppm): δ 7.30−7.26 (m, 1H, aromatic), 7.17 (t, 3J =
3
7.5 Hz, 1H, aromatic), 6.93−6.89 (m, 2H, aromatic), 6.54 (d, Jcis
=
3
4
3
3
aromatic), 7.17−7.10 (m, 1 H, aromatic), 7.04 (dd, J = 7.6 Hz, J =
1.6 Hz, 1 H, aromatic), 6.63 (t, 3J = 7.6 Hz, 1 H, aromatic), 6.48 (d, 3J
= 8.4 Hz, 1 H, aromatic), 4.29−4.18 (m, 1 H, CHOAr), 3.87 (br s, 4
H, −CH2CH2−), 3.84 (sept, 3J = 6.8 Hz, isopropyl CH), 2.26 (d, 3J =
10.4 Hz, 2 H, cyclohexyl), 1.87 (q, 3J = 12.4 Hz, 2 H, cyclohexyl), 1.59
(d, 3J = 12.8, 2 H, cyclohexyl), 1.43 (d, 3J = 5.2 Hz, 12 H, CH3), 1.19
(d, 3J = 6.8 Hz, 12 H, CH3), 0.96 (t, 3J = 12 Hz, 1 H, cyclohexyl), 0.79
11.1 Hz, 1H, α-vinyl), 5.79 (dq, Jcis = 11.1, J = 7.2 Hz, 1H, β-vinyl),
4.12−4.02 (m, 1H, CHOAr), 2.18 (br d, 3J = 12.3 Hz, 2H, cyclohexyl),
1.86−1.82 (m, 5H, methyl and cyclohexyl), 1.48−1.36 (m, 2H,
cyclohexyl), 1.16−1.08 (m, 3H, cyclohexyl), 0.87 (s, 9H, tert-butyl).
13C NMR (75 MHz, CD2Cl2, ppm): δ 155.60, 130.25, 127.79, 127.63,
126.24, 125.58, 120.01, 114.49, 77.79, 47.32, 32.60, 32.31, 27.63,
25.57, 14.75. FT-IR (ATR, cm−1): 2941, 2862, 1597, 1576, 1482,
1449, 1365, 1286, 1229, 1159, 1105, 1048, 1029, 982, 928, 901, 834,
748, 699. HR-MS (ESI): [M + Na+] calcd for C19H28O 295.2032,
found 295.2032, error 0.1 ppm.
3
(s, 9 H, tert-butyl), 0.76−0.62 (q, J = 14.8 Hz, 2 H, cyclohexyl). 13C
NMR (323 K, 101 MHz, C6D6, ppm): δ 288.88, 216.56, 153.74,
150.52, 145.65, 138.07, 130.48, 129.57, 125.20, 122.94, 122.84, 113.75,
81.90, 55.40, 53.90, 47.66, 32.80, 32.35, 29.85, 28.30, 27.41, 26.46,
24.31. FT-IR (ATR, cm−1): 2945, 1586, 1472, 1452, 1408, 1387, 1296,
1263, 1234, 1219, 1109, 1010, 964, 866, 801, 757, 744. HR-MS (FT-
ICR ESI): C44H62ON2Cl2Ru, calcd for [M+] 806.3277, found
806.3280, error 0.4 ppm.
General Procedure for the Synthesis of Ruthenium Carbene
Complexes. In the glovebox, a 50 mL Schlenk flask equipped with a
magnetic stirbar was charged with Grubbs catalyst Ru4 or Ru7 (0.205
mmol, 1 equiv) and copper(I) chloride (22.3 mg, 0.226 mmol, 1.1
equiv). The flask was sealed, removed from the glovebox, placed under
argon, and then the solids were dissolved in CH2Cl2 (16.4 mL). The
corresponding styrenyl ether (0.24 mmol, 1.9 equiv) was injected, and
the resulting solution was stirred at 40 °C or room temperature until
complete consumption of the phosphine-containing precatalyst was
observed by TLC (50% CH2Cl2−hexanes). Upon reaction completion,
the reaction was concentrated in vacuo (rotary evaporator), and the
resulting dark solid was purified by column chromatography (30−70%
CH2Cl2−hexanes) to obtain the desired precatalyst as a green solid. Ru
carbene complexes 4, 8, and 9 were recrystallized by slow diffusion of
CH2Cl2 and hexanes in the glovebox over the course of several days.
Equatorial 4. Following the general procedure and using Ru4 (50
mg, 0.059 mmol, 1.00 equiv), CuCl (6.4 mg, 0.065 mmol, 1.1 equiv),
and Z-3 (0.115 mmol, 1.95 equiv) for the reaction, 30.1 mg of 4 (71%
yield) was isolated as a green solid. Analytical TLC: Rf 0.24 (50%
Axial 9. Following the general procedure and using Ru7 (115.7 mg,
0.124 mmol), CuCl (13.9 mg, 0.14 mmol), and 6 (65.4 mg, 0.24
mmol) for the reaction, 91.7 mg of 9 (92% yield) was isolated as a
green solid. Analytical TLC: Rf 0.4 (50% CH2Cl2−hexanes). 1H NMR
(323 K, 400 MHz, C6D6, ppm): δ 16.69 (s, 1 H, Ru = CHAr), 7.40 (t,
3J = 7.6 Hz, 2 H, aromatic), 7.29 (d, 3J = 7.6 Hz, 4 H, aromatic), 7.11
3
3
(t, J = 7.8 Hz, 1 H, aromatic), 6.98 (d, J = 7.6 Hz, 1 H, aromatic),
3
3
6.62 (t, J = 7.6 Hz, 1 H, aromatic), 6.48 (d, J = 8.4, 1 H, aromatic),
4.56−4.50 (m, 1 H, CHOAr), 3.89−3.77 (m, 8 H, isopropyl CH,
3
4
−CH2CH2−), 2.59 (dd, J = 14.4 Hz, J = 3.2 Hz, 2 H, cyclohexyl),
3
1.67 (q, J = 12 Hz, 2 H, cyclohexyl), 1.46−1.31 (m, 14 H, 4CH3,
cyclohexyl), 1.22−1.14 (m, 14 H, 4CH3, cyclohexyl), 0.89 (s, 9 H, tert-
butyl), 0.85−0.77 (m, 1 H, cyclohexyl). 13C{1H} NMR (323 K, 101
MHz, C6D6, ppm): δ 289.61, 215.13, 154.60, 150.02, 145.30, 138.26,
130.75, 130.01, 125.49, 123.38, 122.80, 114.54, 114.27, 79.43, 55.55,
53.91, 48.41, 33.48, 30.52, 29.74, 28.99, 28.22, 27.23, 24.50, 22.38. FT-
IR (ATR, cm−1): 2964, 2867, 2280, 1585, 1475, 1453, 1440, 1409,
1386, 1362, 1326, 1297, 1260, 1232, 1211, 1181, 1157, 1111, 1049,
1002, 928, 874, 835, 803, 746. HR-MS (FT-ICR ESI):
C44H62ON2Cl2Ru, calcd for [M+] 806.3277, found 806.3289, error
−0.7 ppm.
1
CH2Cl2−pentane). H NMR (400 MHz, CDCl3, ppm): δ 16.54 (s,
3
1H, RuCHAr), 7.46 (t, J = 7.6 Hz, 1 H, aromatic), 7.07 (s, 4 H,
mesityl aromatic CH), 6.92 (d, 3J = 7.2 Hz, 1 H, aromatic), 6.84 (t, 3J
3
= 7.2 Hz, 1 H, aromatic), 6.78 (d, J = 8.8 Hz, 1 H, aromatic), 4.51−
4.43 (m, 1 H, CHOAr), 4.18 (s, 4 H, −CH2CH2−), 2.66−2.22 (br m,
18H, mesityl CH3), 2.16 (d, 3J = 11.6 Hz, 2 H, cyclohexyl), 1.75−1.63
(m, 2 H, cyclohexyl), 1.51−1.38 (m, 2 H, cyclohexyl), 1.01−0.91 (m, 3
H, cyclohexyl), 0.86 (s, 9 H, tert-butyl). 13C{1H} NMR (75 MHz,
CD2Cl2, ppm): δ 296.67, 211.40, 152.42, 145.47, 139.15 (br, 2 C),
129.60, 129.57 (2C), 122.60, 122.41, 113.12, 81.63, 51.83, 47.16,
32.51, 31.42, 27.71, 25.89, 21.33, 19.68. FT-IR (ATR, cm−1): 2950,
1587, 1438, 1453, 1395, 1259, 1217, 1016, 967, 913, 850, 744. HR-MS
(FT-ICR ESI): C38H50ON2Cl2Ru, calcd for [M + Na+] 745.2236,
found 745.2265, error 3.9 ppm.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00041.
Axial 7. Following the general procedure and using Ru4 (174.0 mg,
0.205 mmol), CuCl (22.3 mg, 0.226 mmol), and 6 (109.0 mg, 0.4
mmol) for the reaction, 119.5 mg of 7 (81% yield) was isolated as a
green solid. Analytical TLC: Rf 0.13 (50% CH2Cl2−pentanes); Rf 0.63
(100% CH2Cl2). 1H NMR (400 MHz, 323 K, C6D6, ppm): δ 16.84 (s,
1H, RuCHAr), 7.16 (m, 1 H), 7.08 (dd, 3J = 7.2 Hz, 4J = 1.2 Hz, 1
Preparation of organic starting materials, procedure for
kinetic monitoring of RCM reactions, procedure for
cross alkene metathesis, and initiation procedure using
the alkene butyl vinyl ether (PDF)
3
H, aromatic), 7.00−6.90 (br s, 4 H, mesityl aromatic), 6.68 (t, J =
Accession Codes
3
10.4 Hz, 1 H, aromatic), 6.51 (d, J = 8.4 Hz, 1 H, aromatic), 4.57−
CCDC 1828210−1828211 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
4.49 (m, 1 H, CHOAr), 3.46 (s, 4 H, −CH2CH2−), 2.80−2.40 (m, 12
H, mesityl o−CH3), 2.28 (s, 6 H, mesityl p-CH3), 1.77 (q, 3J = 10 Hz,
2 H, cyclohexyl), 1.43−1.26 (m, 3 H, cyclohexyl), 1.25−1.15 (m, 2H,
cyclohexyl), 1.01 (s, 9 H, tert-butyl), 0.79−0.88 (m, 3 H, cyclohexyl).
13C{1H} NMR (75 MHz, C6D6, ppm): δ 294.43, 212.06, 154.40,
146.34, 139.05, 135.88, 130.55, 129.97, 128.94, 128.62, 128.30, 123.28,
G
DOI: 10.1021/acs.organomet.8b00041
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(5) Grela, K.; Harutyunyan, S.; Michrowska, A. A highly efficient
ruthenium catalyst for metathesis reactions. Angew. Chem., Int. Ed.
2002, 41, 4038−4040.
(6) (a) Vorfalt, T.; Wannowius, K.-J.; Plenio, H. Probing the
Mechanism of Olefin Metathesis in Grubbs−Hoveyda and Grela Type
Complexes. Angew. Chem., Int. Ed. 2010, 49, 5533−5536. (b) Thiel, V.;
Hendann, M.; Wannowius, K.-J.; Plenio, H. On the Mechanism of the
Initiation Reaction in Grubbs-Hoveyda Complexes. J. Am. Chem. Soc.
2012, 134, 1104−1114.
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.T.D.: diver@buffalo.edu.
ORCID
Steven T. Diver: 0000-0003-2840-6726
Notes
The authors declare no competing financial interest.
■
(7) Wakamatsu, H.; Blechert, S. A New Highly Efficient Ruthenium
Metathesis Catalyst. Angew. Chem., Int. Ed. 2002, 41, 2403−2405.
(8) Engle, K. M.; Lu, G.; Luo, S.-X.; Henling, L. M.; Takase, M. K.;
Liu, P.; Houk, K. N.; Grubbs, R. H. Origins of Initiation Rate
Differences in Ruthenium Olefin Metathesis Catalysts Containing
Chelating Benzylidenes. J. Am. Chem. Soc. 2015, 137, 5782−5792.
(9) Ahmed, T. S.; Grubbs, R. H. Fast-Initiating, Ruthenium-based
Catalysts for Improved Activity in Highly E-Selective Cross Meta-
thesis. J. Am. Chem. Soc. 2017, 139, 1532−1537.
ACKNOWLEDGMENTS
■
This work was supported by the NSF (CHE-1300702). The
authors thank Eric Sylvester and Prof. Jason Benedict for
solving the crystal structures of 8 and 9 and Prof. Jerry Keister
for helpful discussions. We gratefully acknowledge Materia, Inc.
(Pasadena, CA), for supplying the Grubbs catalysts used in this
work.
(10) Vougioukalakis, G. C.; Grubbs, R. H. Ruthenium-Based Olefin
Metathesis Catalysts Coordinated with Unsymmetrical N-Heterocyclic
Carbene Ligands: Synthesis, Structure, and Catalytic Activity. Chem. -
Eur. J. 2008, 14, 7545−7556.
REFERENCES
■
(1) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. A Recyclable Ru-Based Metathesis Catalyst. J. Am. Chem. Soc. 1999,
121, 791−799.
(11) Diver, S. T.; Griffiths, J. R. Factors Affecting Initiation Rates;
Wiley: New York, 2014; Vol. 1, Catalyst Development and
Mechanism.
(2) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
Efficient and Recyclable Monomeric and Dendritic Ru-Based Meta-
thesis Catalysts. J. Am. Chem. Soc. 2000, 122, 8168−8179. (b) Gessler,
S.; Randl, S.; Blechert, S. Synthesis and metathesis reactions of a
phosphine-free dihydroimidazole carbene ruthenium complex. Tetra-
hedron Lett. 2000, 41, 9973−9976.
(12) The mechanism is associative for small alkenes.
(13) Gatti, M.; Vieille-Petit, L.; Luan, X.; Mariz, R.; Drinkel, E.;
Linden, A.; Dorta, R. Impact of NHC Ligand Conformation and
Solvent Concentration on the Ruthenium-Catalyzed Ring-Closing
Metathesis Reaction. J. Am. Chem. Soc. 2009, 131, 9498−9499.
(14) (a) Ashworth, I. W.; Hillier, I. H.; Nelson, D. J.; Percy, J. M.;
Vincent, M. A. What is the initiation step of the Grubbs-Hoveyda
olefin metathesis catalyst? Chem. Commun. 2011, 47, 5428−5430.
(b) Nunez-Zarur, F.; Solans-Monfort, X.; Rodriguez-Santiago, L.;
Sodupe, M. Differences in the activation processes of phosphine-
containing and Grubbs-Hoveyda-type alkene metathesis catalysts.
Organometallics 2012, 31, 4203−4215. (c) Ashworth, I. W.; Hillier, I.
H.; Nelson, D. J.; Percy, J. M.; Vincent, M. A. Olefin Metathesis by
Grubbs−Hoveyda Complexes: Computational and Experimental
Studies of the Mechanism and Substrate-Dependent Kinetics. ACS
Catal. 2013, 3, 1929−1939.
(15) Vorfalt, T.; Wannowius, K.-J.; Plenio, H. Probing the
Mechanism of Olefin Metathesis in Grubbs−Hoveyda and Grela
Type Complexes. Angew. Chem., Int. Ed. 2010, 49, 5533−5536.
(16) Pump, E.; Leitgeb, A.; Kozłowska, A.; Torvisco, A.; Falivene, L.;
Cavallo, L.; Grela, K.; Slugovc, C. Variation of the Sterical Properties
of the N-Heterocyclic Carbene Coligand in Thermally Triggerable
Ruthenium-Based Olefin Metathesis Precatalysts/Initiators. Organo-
metallics 2015, 34, 5383−5392.
(17) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. A
Standard System of Characterization for Olefin Metathesis Catalysts.
Organometallics 2006, 25, 5740−5745.
(18) Nelson, D. J.; Queval, P.; Rouen, M.; Magrez, M.; Toupet, L.;
Caijo, F.; Borre, E.; Laurent, I.; Crevisy, C.; Basle, O.; Mauduit, M.;
́ ́ ́
Percy, J. M. Synergic Effects Between N-Heterocyclic Carbene and
Chelating Benzylidene−Ether Ligands Toward the Initiation Step of
Hoveyda−Grubbs Type Ru Complexes. ACS Catal. 2013, 3, 259−264.
(19) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R.
H.; Schrodi, Y. Highly Efficient Ruthenium Catalysts for the
Formation of Tetrasubstituted Olefins via Ring-Closing Metathesis.
Org. Lett. 2007, 9, 1589−1592.
(20) Urbina-Blanco, C. A.; Leitgeb, A.; Slugovc, C.; Bantreil, X.;
Clavier, H.; Slawin, A. M. Z.; Nolan, S. P. Olefin Metathesis Featuring
Ruthenium Indenylidene Complexes with a Sterically Demanding
NHC Ligand. Chem. - Eur. J. 2011, 17, 5045−5053.
(3) Throughout this paper metathesis initiators are called
“precatalysts”. Upon intiation with an alkene, they give rise to the
active carbene catalyst.
(4) (a) White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M. The
Catalytic Asymmetric Total Synthesis of Elatol. J. Am. Chem. Soc.
2008, 130, 810−811. (b) Jackson, K. L.; Henderson, J. A.; Motoyoshi,
H.; Phillips, A. J. A Total Synthesis of Norhalichondrin B. Angew.
Chem., Int. Ed. 2009, 48, 2346−2350. (c) Dieckmann, M.; Kretschmer,
M.; Li, P.; Rudolph, S.; Herkommer, D.; Menche, D. Total Synthesis
of Rhizopodin. Angew. Chem., Int. Ed. 2012, 51, 5667−5670.
(d) Ohyoshi, T.; Funakubo, S.; Miyazawa, Y.; Niida, K.; Hayakawa,
I.; Kigoshi, H. Total Synthesis of (−)-13-Oxyingenol and its Natural
Derivative. Angew. Chem., Int. Ed. 2012, 51, 4972−4975. (e) Gao, X.;
Woo, S. K.; Krische, M. J. Total Synthesis of 6-Deoxyerythronolide B
via C−C Bond-Forming Transfer Hydrogenation. J. Am. Chem. Soc.
2013, 135, 4223−4226. (f) Mewald, M.; Medley, J. W.; Movassaghi,
M. Concise and Enantioselective Total Synthesis of (−)-Mehranine,
(−)-Methylenebismehranine, and Related Aspidosperma Alkaloids.
Angew. Chem., Int. Ed. 2014, 53, 11634−11639. (g) Wang, H.;
Reisman, S. E. Enantioselective Total Synthesis of (−)-Lansai B and
(+)-Nocardioazines A and B. Angew. Chem., Int. Ed. 2014, 53, 6206−
6210. (h) Glaus, F.; Altmann, K.-H. Total Synthesis of the Tiacumicin
B (Lipiarmycin A3/Fidaxomicin) Aglycone. Angew. Chem., Int. Ed.
2015, 54, 1937−1940. (i) Harvey, R. S.; Mackay, E. G.; Roger, L.;
Paddon-Row, M. N.; Sherburn, M. S.; Lawrence, A. L. Total Synthesis
of Ramonanins A−D. Angew. Chem., Int. Ed. 2015, 54, 1795−1798.
(j) Jecs, E.; Diver, S. T. Two Ene−Yne Metathesis Approaches to the
Total Synthesis of Amphidinolide P. Org. Lett. 2015, 17, 3510−3513.
(k) Kita, M.; Oka, H.; Usui, A.; Ishitsuka, T.; Mogi, Y.; Watanabe, H.;
Tsunoda, M.; Kigoshi, H. Total Synthesis of Mycalolides A and B
through Olefin Metathesis. Angew. Chem., Int. Ed. 2015, 54, 14174−
14178. (l) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.;
Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and
α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric
Allylic Alkylation. Angew. Chem., Int. Ed. 2015, 54, 179−183.
̌
(m) Svenda, J.; Sheremet, M.; Kremer, L.; Maier, L.; Bauer, J. O.;
Strohmann, C.; Ziegler, S.; Kumar, K.; Waldmann, H. Biology-
Oriented Synthesis of a Withanolide-Inspired Compound Collection
Reveals Novel Modulators of Hedgehog Signaling. Angew. Chem., Int.
Ed. 2015, 54, 5596−5602.
H
DOI: 10.1021/acs.organomet.8b00041
Organometallics XXXX, XXX, XXX−XXX