High-Yield Synthesis of a Long-Sought, Labile Ru-NHC Complex and Its Application to the Concise Synthesis of Second-Generation Olefin Metathesis Catalysts

Article abstract of DOI:10.1021/acs.organomet.8b00745

The controlled reaction of [RuCl₂(p-cymene)]₂ with H₂IMes generates the previously challenging precatalyst and Ru synthon RuCl₂(p-cymene)(H₂IMes) (Ru-2) in 96% isolated yield. Critical to success is inhibiting premature p-cymene displacement. This is achieved by carrying out the synthesis at ambient temperatures, protected from light, and at sufficient dilutions (25 mM in THF) to enable stoichiometric control and inhibit bimolecular decomposition. The ease with which p-cymene loss can be deliberately induced, however, is key to the utility of Ru-2 in both catalysis and catalyst synthesis. The transformation of Ru-2 into two second-generation olefin metathesis catalysts is described. RuCl₂(H₂IMes)(=CH(o-C₆H₄-OⁱPr)) (HII) and RuCl₂(H₂IMes)(PPh₃)(=CHPh) GII′ (a desirable, faster-initiating analogue of GII) are accessible in ca. 80% yield over two steps from commercially available [RuCl₂(p-cymene)]₂. Synthesis from RuCl₂(PPh₃)₃, in comparison, requires three or four steps for HII or GII′, respectively, and proceeds in lower yields.

Full text of DOI:10.1021/acs.organomet.8b00745

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Cite This: Organometallics XXXX, XXX, XXX−XXX
High-Yield Synthesis of a Long-Sought, Labile Ru-NHC Complex and
Its Application to the Concise Synthesis of Second-Generation Olefin
Metathesis Catalysts
Craig S. Day and Deryn E. Fogg*
Center for Catalysis Research and Innovation and Department of Chemistry and Biomolecular Sciences, University of Ottawa,
Ottawa, Ontario, Canada K1N 6N5
*
S Supporting Information
ABSTRACT: The controlled reaction of [RuCl (p-cymene)] with H IMes
2
2
2
generates the previously challenging precatalyst and Ru synthon RuCl (p-
2
cymene)(H IMes) (Ru-2) in 96% isolated yield. Critical to success is inhibiting
2
premature p-cymene displacement. This is achieved by carrying out the
synthesis at ambient temperatures, protected from light, and at sufficient
dilutions (25 mM in THF) to enable stoichiometric control and inhibit
bimolecular decomposition. The ease with which p-cymene loss can be
deliberately induced, however, is key to the utility of Ru-2 in both catalysis and
catalyst synthesis. The transformation of Ru-2 into two second-generation olefin metathesis catalysts is described.
i
RuCl (H IMes)(CH(o-C H -O Pr)) (HII) and RuCl (H IMes)(PPh )(CHPh) GII′ (a desirable, faster-initiating
2
2
6
4
2
2
3
analogue of GII) are accessible in ca. 80% yield over two steps from commercially available [RuCl (p-cymene)] . Synthesis
2
2
from RuCl (PPh ) , in comparison, requires three or four steps for HII or GII′, respectively, and proceeds in lower yields.
2
3 3
iano-stool complexes of the group 8 metals are privileged
structures in catalysis, and in bioinorganic and medicinal
The behavioral difference between these complexes is critical
P
to their informed deployment. In some cases (e.g., outer-
1
−7
21
chemistry.
owing to their ease of access from commercially available
RuCl (p-cymene)] (Ru-1), although expanding roles for iron
p-Cymene complexes of ruthenium dominate,
sphere transfer hydrogenation), retention of the arene ligand
is required. In other contexts (e.g., metathesis, arylation,
alkylation or hydrogen-borrowing catalysis, or synthesis of new
[
2
2
8
9
complexes and functionalized arene derivatives have been
documented in recent reviews. In particular, attention has
focused on catalysis via N-heterocyclic carbene (NHC)
catalysts by elaboration of the RuCl (H IMes) core), p-
2 2
cymene loss is necessary, and its facile, controlled displacement
represents a key potential asset. In the present work, we sought
to clarify and control the instability of Ru-2, as an essential
step toward harnessing the potential of this and related p-
cymene complexes in synthesis and catalysis. Here we identify
key factors that promote loss of the p-cymene ring; we report
the successful development of a high-yield route to Ru-2, and
we demonstrate the exceptional utility of this complex in
enabling a concise, efficient route to high-performing second-
generation Ru metathesis catalysts.
1
−6
derivatives of Ru-1 (Chart 1).
10−15
Chart 1. Exemplary p-Cymene/NHC Catalysts
Literature reports describe the use of thermal and photolytic
22
triggers to displace the p-cymene ligand from phosphine and
12,13
NHC derivatives of Ru-1.
In the case of Ru-2, we
suspected that steric pressure exerted by the H IMes mesityl
2
Notably sparse, however, are reports of high-performing p-
cymene catalysts containing N,N’-diarylimidazolidin-2-yli-
6
groups could add to the lability of the η -arene ligand. While
2
3−25
rotation about the Ru−H IMes bond is restricted
(a
2
denes, of which the H IMes complex Ru-2 (Chart 1) may
2
consequence of the π-acceptor character of the saturated
be regarded as an exemplar. This is particularly striking given
early advances establishing a convenient in situ synthesis of
26,27
NHC),
N−Mes bond rotation is facile. In contrast, the
28,29
1
3
IMes ligand has a higher barrier to N−Mes rotation,
as
Ru-2, for use in olefin metathesis and atom-transfer radical
30
1
3,16−18
well as a lower buried volume. These factors could account
for the improved stability of Ru-2′. NOE experiments on
isolated Ru-2 (Figure S2; generated as described below)
polymerization.
Ledoux and co-workers subsequently
19
described Ru-2 as too unstable to isolate. The Jensen group
recently succeeded in isolating the complex,
10,20
albeit in yields
(
26%) that support this view. The N-o-phenol analogue of Ru-
19
2
also decomposes rapidly. In contrast, IMes analogue Ru-2′
Received: October 11, 2018
11,12
is stable, and indeed isolable in ca. 80−90% yield.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00745
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
confirm the presence of steric interactions between the mesityl
o-Me groups and the p-cymene ligand in solution.
We bore these points in mind in seeking to synthesize Ru-2
for direct study. The thermal lability of the p-cymene ring rules
out, for example, in situ production of H IMes from its
2
19
imidazolinium salt, which typically requires high temper-
atures as well as strong base. Instead, Ru-2 was prepared by
adding free H IMes to dimeric Ru-1, under conditions
2
designed to minimize exposure of the product to light and
heat: that is, at 22 °C in a foil-wrapped vessel, with the
glovebox light switched off.
The stoichiometry of the reactionand hence the solubility
of Ru-1emerged as a key additional criterion. Synthesis of
Ru-2 in CH Cl , in which Ru-1 is fully soluble, is precluded by
2
2
31
the rapid reaction of H IMes with CH Cl . THF was
2
2
2
therefore employed, despite only partial solubility of Ru-1 in
this solvent even at millimolar concentrations. An important
insight was offered by the observation of negligible yields of
Ru-2 when solid H IMes was added to the Ru-1 suspension,
Figure 1. (a−c) Decomposition of Ru-2 (20 mM; C D , room
2
6
6
but greatly improved yields when THF solutions of H IMes
temperature), showing plausible initial products, and (d) first-order
dependence of decomposition on [Ru] in the light, vs second-order
dependence in the dark.
2
were added. We infer that a local excess of H IMes is able to
2
displace the p-cymene ligand from Ru-2. In an optimized
synthetic protocol (Scheme 1), we therefore slowly infused a
From a complementary perspective, the ease with which the
p-cymene ring can be displaced is a core asset that enables use
of Ru-2 as a clean source of “RuCl (H IMes)” in catalysis or
Scheme 1. High-Yield Synthesis of Ru-2
2
2
catalyst synthesis. A final aspect of this work focused on the
latter opportunity: specifically, use of Ru-2 as an entry point to
olefin metathesis catalysts. The important “second-generation”
metathesis catalysts are typically accessed via multiple steps
3
3−39
(
Scheme 2),
commencing with transformation of
,
a b
Scheme 2. Dominant Routes to HII and GII′
solution of the free carbene (1 mL/min; 25 mM) into a THF
suspension of Ru-1 (ca. 15 mg/mL). Addition was complete
after 30 min, at which point a clear deep red solution was
present. Evaporation of the solvent and reprecipitation of the
residue from CH Cl −hexanes afforded Ru-2 as a dark red
2
2
powder, in 96% yield.
With clean Ru-2 in hand, we examined its stability. As
anticipated from the experiments above, adding H IMes to Ru-
2
2
caused extensive loss of the p-cymene ring (minutes at room
temperature; Figure 1a). Exposing C D solutions of Ru-2 to
6
6
fluorescent laboratory light at room temperature caused nearly
0% decomposition over 5 h, vs 10% for a foil-wrapped sample
over the same period (Figure 1b,c). Of note, the photolytic
reaction showed a first-order rate dependence on [Ru-2], while
decomposition in the dark was second order, albeit slower
7
a
Overall yields 34−52% for HII and 29−33% for GII’: see the
b
41
Supporting Information. Conditions: (1) 6 PPh , refluxing MeOH;
3
36a
(
(
2) 2 PhCHN + 2.2 PCy , CH Cl , −78 °C to room temperature;
2
3
2
2
38
3) 1.1 H IMes, THF, Merrifield resin; (4) 1.1 ArCHCH , 1.3
2
2
(Figure 1d). The latter, bimolecular reaction underscores the
37
42
CuCl, refluxing CH Cl ; (4′) 1/3 toluene/py: the product is a
2
2
4
3
42
importance of maintaining low concentrations during the
mono/bis-py mixture; (5′) 1.1 PPh , C H . For further details, see
3
6
6
synthesis of Ru-2. Irradiating CH Cl solutions of Ru-2 at 465
the Supporting Information. Steps 3 and 4 in the synthesis of HII can
2
2
38,39
or 365 nm led to broadening of the absorption bands (Figure
S7) and formation of a black suspension, suggesting nano-
be advantageously reversed.
3
2
particle formation.
The historical difficulties in isolating Ru-2 noted above are
unsurprising, given the need to inhibit loss of p-cymene by
protecting from (i) light and heat, (ii) uptake of a second
hydrated RuCl3 into RuCl (PPh ) and then the first-
2 3 3
36a
generation Grubbs catalyst GI. RuCl (PPh ) is attractive
2
3 3
relative to many alternative Ru precursors for its ease of
36b
H IMes ligand, and (iii) bimolecular decomposition. Once
handling, and because the bulk of the stabilizing phosphine
2
40
recognized, however, these conditions are readily met, as
indicated by near-quantitative isolation of Ru-2 on a nearly 1 g
scale via the protocol of Scheme 1.
ligands provides leverage for ligand exchange.
A major drawback, however, is the need to first install, and
then remove, the PPh ligands and one or more PCy ligands.
3
3
B
DOI: 10.1021/acs.organomet.8b00745
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
While phosphine scavengers can significantly improve isolated
yields, the net process is laborious and wasteful. More
bimolecular displacement of the p-cymene ring. We anticipate
that these precautions may likewise afford access to related p-
cymene complexes bearing bulky, inflexible imidazolidene or
other donors, and hence expand the deployment of such
complexes in catalysis.
3
8
44
efficient routes to Ru metathesis catalysts, which circumvent
3
6b
reliance on RuCl (PPh ) as a precursor,
are highly
2
3 3
desirable.
6
In important early work, metathesis-active allenylidene or
Importantly, the lability of the η -arene ring represents a
indenylidene complexes were generated by treating [RuCl(p-
major asset in use of Ru-2 as a precatalyst or a building block.
An exceptionally efficient route to high-performing phosphine-
free and phosphine-stabilized metathesis catalysts from Ru-2 is
demonstrated. Attractive features are its brevity (just two
synthetic steps from commercially available Ru-1), time
11,45,46
cymene)(PCy )](OTf) or Ru-2′ with terminal alkynes,
3
while benzylidene species were generated by treating piano-
47,48
stool Os complexes with phenyldiazomethane.
Here we
sought to build on these advances by displacing the arene ring
from Ru-2, while simultaneously introducing a benzylidene
ligand and a stabilizing donor. We envisaged that this could
offer access to the second-generation Hoveyda catalyst HII
efficiency, and high yields (ca. 70% from RuCl ). In
3
comparison, existing routes proceed in overall yields of ca.
30−50% over four to five steps and require up to 1 week.
3
3,34
These findings are anticipated to open the door to new,
efficient transformations based on Ru-2 as a precatalyst, and to
improve the efficiency, economy, and reliability of synthetic
routes to leading metathesis catalysts.
(Scheme 3a),
for example, in a single step.
Scheme 3. One-Step Synthesis of High-Performing
Metathesis Catalysts from Ru-2
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.8b00745.
Experimental procedures and NMR and UV−vis spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
E-mail for D.E.F.: dfogg@uottawa.ca.
*
Accordingly, we adapted to Ru-2 a procedure used by the
ORCID
Hoveyda group to install chelating benzylidene ether ligands
3
3
i
49
on RuCl (PPh ) . Adding ArCHN (Ar = o-C H -O Pr) to
Deryn E. Fogg: 0000-0002-4528-1139
Notes
The authors declare no competing financial interest.
2
3 3
2
6
4
a CH Cl solution of Ru-2 at −78 °C caused evolution of N ,
2
2
2
accompanied by a color change from red to green over the ca.
0 min time of addition. The solution was then warmed to 0
C and briefly (10 min) irradiated with a standard portable UV
2
°
ACKNOWLEDGMENTS
■
lamp mounted 5 cm away. HII was obtained after flash
chromatography in 82% isolated yield, or ca. 70% overall yield
This work was funded by the NSERC of Canada.
from the ultimate precursor RuCl . This compares favorably
with the dominant route shown in Scheme 1 (four steps and
3
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(
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3 3
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3
perhaps owing to the difficulty of the final relay-ring closing
̈
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2
initiate catalyst decomposition. See: Amoroso, D.; Fogg, D. E. Ring-
E
DOI: 10.1021/acs.organomet.8b00745
Organometallics XXXX, XXX, XXX−XXX