Merrifield resin-assisted routes to second-generation catalysts for olefin metathesis

Article abstract of DOI:10.1039/c7cy02278f

Phosphine-scavenging resins can significantly facilitate the synthesis of highly active Ru metathesis catalysts, including the second-generation Grubbs, Hoveyda, and indenylidene catalysts (GII, HII, InII). These catalysts are customarily prepared by ligand exchange of the corresponding first-generation catalysts with the N-heterocyclic carbene (NHC) H₂IMes. The PCy₃ coproduct is conventionally removed by pentane extraction, but the partial solubility of the desired Ru products can cause product losses of over 20%. Sequestration of the PCy₃ coproduct with CuCl is more efficient, but is undesirable given the potential for non-innocent copper residues. Use of the arylsulfonic acid resin Amberlyst-15 delivers near-quantitative catalyst yields, but the high acidity of the resin leads to problems with reproducibility and decomposition. An alternative approach is described, in which a neutral Merrifield resin (crosslinked polystyrene with pendant p-C₆H₄CH₂I groups; MF-I) is used to sequester PCy₃ as the covalently-tethered benzylphosphonium salt. Addition of MF-I following complete ligand exchange effects quantitative uptake of free PCy₃ (and any residual free NHC) within 45 min at RT: the clean products are isolated by filtration, in ca. 95% yield. These yields compare well with those obtained via the Amberlyst-15 route, without the challenges due to resin acidity. The efficacy of this methodology is demonstrated in the synthesis of isotopically-labelled derivatives of HII, in which the H₂IMes ligand bears a ¹³C-label at the carbene carbon, or perdeuterated mesityl rings.

Full text of DOI:10.1039/c7cy02278f

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Qingzhu Zhang et al.
Catalytic mechanism of C–F bond cleavage: insights from QM/MM
analysis of fluoroacetate dehalogenase
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Merrifield Resin-Assisted Routes to Second-Generation Catalysts
for Olefin Metathesis
Received 00th January 20xx,
Accepted 00th January 20xx
Daniel L. Nascimento, Emma C. Davy and Deryn E. Fogg*
DOI: 10.1039/x0xx00000x
Phosphine-scavenging resins can significantly facilitate the synthesis of highly active Ru metathesis catalysts, including the
second-generation Grubbs, Hoveyda, and indenylidene catalysts (GII, HII, InII). These catalysts are customarily prepared by
www.rsc.org/
ligand exchange of the corresponding first-generation catalysts with the N-heterocyclic carbene (NHC) H
coproduct is conventionally removed by pentane extraction, but the partial solubility of the desired Ru products can cause
product losses of over 20%. Sequestration of the PCy coproduct with CuCl is more efficient, but is undesirable given the
2 3
IMes. The PCy ,
3
potential for non-innocent copper residues. Use of the arylsulfonic acid resin Amberlyst-15 delivers near-quantitative
catalyst yields, but the high acidity of the resin leads to problems with reproducibility and decomposition. An alternative
approach is described, in which a neutral Merrifield resin (crosslinked polystyrene with pendant p-C
is used to sequester PCy as the covalently-tethered benzylphosphonium salt. Addition of MF-I following complete ligand
exchange effects quantitative uptake of free PCy (and any residual free NHC) within 45 min at RT: the clean products are
6 4 2
H CH I groups; MF-I)
3
3
isolated by filtration, in ca. 95% yield. These yields compare well with those obtained via the Amberlyst-15 route, without
the challenges due to resin acidity. The efficacy of this methodology is demonstrated in the synthesis of isotopically-
1
3
labelled derivatives of HII, in which the H
2
IMes ligand bears a C-label at the carbene carbon, or perdeuterated mesityl
rings.
Ph
Introduction
Olefin metathesis offers powerful, versatile methodologies for
Ph
PCy
1,2
Cl
Cl
Cl
the catalytic assembly of carbon-carbon bonds. Ruthenium
metathesis catalysts bearing an N-heterocyclic carbene (NHC)
ligand, long embraced for synthetic purposes in academia,
i
3
Cy P
Ru
PCy3
Cy
3
P
Ru
3
3
Cy P
Ru O Pr
InI Cl Ph
GI Cl
HI Cl
have now begun to see uptake in pharmaceutical
3
Ph
PCy
Cl
IMes
Cl
Cl
manufacturing.
Despite prominent recent advances
i
H
2
Ru
3
H IMes
Ru O Pr
HII
Figure 1. Metathesis catalysts discussed. Top: first-generation Ru catalysts, precursors
H IMes
Ru
PCy3
2
2
highlighting the potential of alternative ligand sets, particularly
4
cyclic (alkyl)(amino) carbenes, the "second-generation"
GII Cl
InII
Cl
Cl
Grubbs and Hoveyda catalysts GII and HII (Figure 1) continue to (bottom) the second-generation catalysts in dominant use.
to dominate current use. Clean, reproducible, high-yield routes
These catalysts are typically accessed via ligand exchange
reactions, in which a PCy ligand present in the corresponding
first-generation complex is replaced with H IMes. Classically,
such routes rely on in situ generation and installation of
to such complexes, as well as indenylidene analogue InII, are
3
therefore of interest.
2
H
2 2
IMes, via treatment of the imidazolinium salt H IMes•HX (X
t
=
4
Cl or HBF ) with a strong base such as KO Bu, NaH, or
5
2
potassium t-amylate (KOCMe Et). Depicted in Scheme 1 is the
5
c
original, still widely cited, synthesis of GII via this approach.
Mes
BF
4
t
1
2
) KO Bu, THF, RT, 1 h
) 0.7 GI, C , 80 °C, 0.5 h
N
N
6 6
H
H
GII
75%, based on GI)
3
) MeOH extraction
(
Mes
Scheme 1. Synthesis of GII via in situ liberation and installation of H
2
IMes.
The continuing popularity of in situ NHC generation is
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6
surprising, given problems pointed out in early reports. The chromatographic workup (Table 1, entries 1-2).
,7
15,17
metathesis activity of GII, for example, was reported to be We previously reported a convenient route involving reaction
reduced by unreacted NHC•HX (Scheme 2a; this reagent is with free H
2
IMes, and workup by addition of the acidic resin
1
4
used in excess to ensure full conversion of GI), as well as Amberlyst-15 (Figure 2a) to scavenge the PCy
3
byproduct.
6
residual alkali metal salts, likewise used in excess. In the This procedure offered two key advances over standard
t
specific case of KO Bu, the side-reaction with GI generates methods. First, use of the isolated free NHC (an approach
t
Ru(O Bu)
6
)(=CHPh) (Scheme 2b), a complex known to pioneered by Nolan with IMes as pro-ligand)
11,18
2
(PCy
3
prevents side-
19
8
exhibit minimal metathesis activity. Quenching excess base reactions arising from in situ liberation of the NHC. Secondly,
with methanol is also problematic, as this generates Ru the use of Amberlyst-15 as a PCy
3
scavenger, originally
20
described in a patent procedure by Verpoort and co-workers,
6
hydride contaminants, including isomerization-active Ru-1
,7
9
:
Scheme 2c. (Such hydrides may plausibly originate in the and subsequently adopted by our group and others for
1
4,21,22
conversion of methanol to methoxide ion, which reacts with GI removal of PCy
1
3
or nitrogen bases,
was attractive for the
0
and GII much more rapidly than does methanol itself).
simplicity and convenience of workup. Thus, workup requires
Further, loss of the benzylidene ligand has been observed on only filtering off the resin once scavenging is complete, and
6
adventitious admission of air during synthesis of GII (Scheme evaporation of the filtrate.
2d). Unintended exposure to air is a perennial risk for Schlenk Such straightforward purification procedures are considerably
reactions carried out at reflux, underscoring the convenience more time- and resource-efficient than removing the PCy
3
5
and reliability of the room-temperature, glovebox operations byproduct by column chromatography or extracting with
d
5
pentane or hexanes. Amberlyst-assisted workup was initially
c
below.
Finally, no consensus exists on the reliability of the NHC•HCl found to improve isolated yields by 20% or more for GII, and
1
4
salts, as compared to NHCs•HBF
4
. Bantreil and Nolan reported ca. 15% for HII, vs. pentane extraction (though see below).
lower yields for the IMes analogue of GII on using IMes•HCl, Also attractive was the elimination of concerns arising from
1
1
vs. IMes•HBF
4
,
but the opposite claim has also been the use of CuCl as a phosphine scavenger (Table 1, entries 2, 3,
6,12
made. Relevant in this context is Grela’s comment that the 5), as detailed below.
yield of GII is extremely sensitive to the purity of the
1
3
Table 1. Reported high-yield routes (>90%) to GII, HII, and InII
H
2
IMes•HBF
4
reagent. It should be noted that although the
IMes•HBF is a valuable aid to
this salt must be rigorously dried to remove
water remaining from its synthesis, which otherwise
high crystallinity of H
2
4
entry catalyst NHC source
(precursor)
PCy removal
method
yield
a
(scale)
ref.
3
5
a,11
purification,
1
1
1
5
5
3
1
2
3
GII (GI)
HII (HI)
HII (HI)
H
2
IMes•CO
(1.5 equiv)
IMes•CO
1.2 equiv)
2
chromatography
90%
(1 g)
95%
(0.4 g)
92%
1
4
hydrolyzes the free NHC as it is generated (Scheme 2e).
H
2
2
1.2 CuCl
chromatography
1.8 CuCl
(
(
2
a) residual H IMes•HX
decreased metathesis activity
Ph
2 4
H IMes•HBF
(
1.2 equiv) + KO-
CMe
IMes•HC
(1.5 equiv)
recrystallize from
Et (1.3 equiv) CH Cl –MeOH
2 2
(17.6 g)
2
2
3
tBuO
t
4
5
6
7
8
GII (GI)
H
2
6
F
5
chromatography
91%
(0.16 g)
97%
(
b) residual KO Bu
Ru
PCy
3
GII via
tBuO
b
24
14
HII (GII) n/a
1.3 CuCl
low metathesis activity
H
H
2
2
IMes•HX
IMes
chromatography
Amberlyst;
"filter-and-strip"
Amberlyst;
"filter-and-strip"
Amberlyst;
"filter-and-strip"
(0.05 g)
96%
(2.4 g)
98%
H
GII (GI)
HII (HI)
InII (InI)
1 H
2
IMes
(c) extract salts
Cl
(1.1 equiv)
H
2
IMes
Ru
Ru-1 CO
isomerization catalyst
PCy
3
1
1
4
4
(MeOH)
H IMes
2
(
1.1 equiv)
IMes
1.1 equiv)
(4 g)
H
(
2
95%
(1 g)
(
e) trace
H O
2
(
d) air exposure
Mes
a
b
Scale based on mass of Ru precursor as limiting reagent. Accessed by cross-
Cl
N
N
metathesis (CM) of GII with 1,2 isoproxy-2-propenylbenzene. For strategic
limitations to synthesis of HII via ligand exchange of GI, followed by metathesis of
GII, see Scheme 5 and associated discussion.
Ru
PCy
CO
3
Mes
N
H
N
H
O
Mes
not metathesis-active
NHC hydrolysis
Scheme 2. Exemplary problems in synthesis of GII via in situ liberation of H
CuCl is widely used to assist workup in the synthesis of
metathesis catalysts, although Hoveyda’s original report noted
2
IMes.
5
. Grela
d
that it complicates chromatographic purification of HII
High-yield routes to the leading Ru-H IMes metathesis
2
and co-workers circumvented any such problems by
developing a successful recrystallization procedure, used in
one of the largest-scale syntheses of HII reported in the open
catalysts (Table 1) typically utilize alternative sources of
1
5
H IMes. Such sources include H IMes•CO , which stands out
2
2
2
1
3
among the many NHC adducts used to access metal-NHC
literature (Table 1, entry 3). More generally, copper-free
scavenging protocols are desirable for deployment of
metathesis catalysts in the pharmaceutical sector in
compliance with current Good Manufacturing Practices
1
6
derivatives for the innocuousness of the CO2 byproduct.
Delaude and coworkers reported the synthesis of GII and HII
by refluxing GI or HI with H IMes•CO , followed by
2
2
2
| J. Name., 2012, 00, 1-3
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(
cGMP).
Cu(I)
halides
mediate
many
catalytic the glovebox atmosphere. Beyond the requirement for
2
5
transformations, and copper residues are notorious for additional resin when using Amberlyst-15 handled under these
2
6
promoting unanticipated catalytic and/or redox chemistry.
Copper, along with iron, is indeed the one of the usual culprits
in unplanned oxidations of pharmaceutical compounds material (Figure S9). Best practices thus involve bringing in
conditions, additional, unidentified signals were evident in
3
1
1
P{ H} NMR spectra of GII “purified” via workup with this
2
6d
catalyzed by trace metal impurities.
fresh resin for each use, and ensuring that the stock supply is
stored in a cabinet free of chemical vapours.
Even with clean resin, however, decomposition was
occasionally apparent on treating GII with Amberlyst-15 in
THF. In one case, 15% loss of GII was detected by integration
of the alkylidene singlet against an internal standard, after
stirring a clean sample of the catalyst with the resin in THF for
(a)
(b)
n
n
X
I
MF-I
Cl MF-Cl
SO3H
CH2X
Amberlyst-15
2
h. While Amberlyst-15 is much more aggressive toward GII
Figure 2. Molecular structures of the (a) Amberlyst and (b) Merrifield resins.
alone than during workup, when free PCy3 and GII are
simultaneously present, this highlights undesirable potential
Sustained use of the alternative Amberlyst scavenging risks.
protocols, however, revealed limitations arising from the high Synthesis of the Merrifield-Iodide Resin.
2
7
acidity of the resin p-toluene sulfonic acid (pTSA) groups.
While the original experiments suggested that GII was stable
Preliminary experiments indicated that the benzyl chloride
resin MF-Cl can sequester free PCy , but that reaction is
3
1
4
toward Amberlyst-15 over 2 h in THF at RT, problems with
reproducibility and catalyst decomposition emerged in
subsequent use, as detailed below. We therefore sought an
alternative approach aimed at retaining the high yields and
convenience of resin-enabled "filter-and-strip" workup, while
circumventing the problems arising from the highly acidic pTSA
scavenger.
inconveniently slow. Even for resin that is relatively lightly (1%)
crosslinked with divinylbenzene, which permits better
swelling, 30% PCy
at RT in THF. We therefore abandoned direct use of MF-Cl
instead converting it into the more electrophilic iodide resin
3
remained after 20 h exposure to the resin
,
30,31
MF-I via the established
reaction with NaI. Sub-
stoichiometric proportions of NaI were used (Scheme 3), to
ensure that the product resin is free of residual alkali iodide,
which could contribute to formation of ruthenium iodide
Attractive from this perspective are Merrifield resins (e.g. MF-
I
, Figure 2b), benzyl halide-functionalized polystyrenes
2
8,29
originally developed to assist solid-phase synthesis.
The
31-33
products.
Lipshutz group successfully employed in situ-generated MF-I to
purify cross-coupling products synthesized via Ni or Pd
3
0
catalysis. Morris and co-workers found it advantageous to
isolate the resin, which they used to sequester PPh3
byproducts (and trace phosphine oxides) generated during
n
n
0
.9 NaI
acetone
RT, 12 h
3
1
synthesis of ruthenium hydride complexes. Inspired by these
successes, we examined the utility of the Merrifield resin MF-I
2
CH Cl
CH2I
in ligand-exchange routes to GII
,
HII, and InII, selected as the
MF-Cl
MF-I
dominant metathesis catalysts in current use. Here we report Scheme 3. Synthesis of the Merrifield Iodide Resin.
the success of this approach, illustrated with synthesis of all
three of these benchmark catalysts, as well as isotopically- Merrifield Resin-Assisted Synthesis of GII.
1
labelled HII, in which the H IMes ligand bears a C-label at the
3
2
In examining the capacity of MF-I as an aid to workup, we first
focused on the transformation of GI into GII by reaction with
carbene carbon, or perdeuterated mesityl rings.
free H IMes (Scheme 4). Adding the resin once exchange is
2
complete enables removal of both the PCy byproduct, and
3
Results and discussion
residual free NHC (which is used in 10% excess in these
reactions, to ensure complete conversion of GI). THF was
chosen as the reaction medium: chlorinated solvents are
Problems with Amberlyst-15.
Initial problems with the Amberlyst-15 methodology were
manifested in stoichiometric irreproducibility. Specifically,
higher proportions of Amberlyst-15 were required (relative to
our originally-optimized 4:1 ratio of resin pTSA groups vs.
1
4,34
precluded by their reactivity toward the free NHC,
3
while
5,36
aromatic solvents limit resin swelling,
retarding the SN2
1
4
scavenging reaction. It should be noted that greater bead
fragility results from the choice of lightly crosslinked resins to
aid in swelling. Controlled stirring rates (ca. 240 rpm) were
therefore employed, to limit mechanical damage to the beads,
and conserve consistent reaction stoichiometry and rates.
1
4
Ru),
3
to completely scavenge free PCy . The reaction
stoichiometry is, unsurprisingly, highly sensitive to resin
storage conditions. While glovebox storage maximizes
convenience, the avidity of the resin for volatile base
(pyridines, amines) was apparent even when Amberlyst-15
was stored in well-taped vials, and opened only after purging
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from self-metathesis). To remove these byproducts, the Ru
product must be purified by chromatography or extraction,
Ph
Ph
Cl
Cy3P
1.1 H2IMes
Cl
H2IMes
Ru
GI
PCy3
Cl
Ru
GII
PCy3
Cl
3
either of which removes the PCy coproduct along with
THF, RT, 2 h
styrene. There is thus no benefit to using the resin for post-
metathesis workup (that is, after step 1 of Route A, or step 2 of
Route B).
+
PCy3
n
Finally, losses of 15-20% (extraction) or up to 10%
(chromatography) are typically incurred in purification. Route
A is therefore strategically preferable, in that maximum loss
occurs in the first step, where the premium on materials and
labour is least. The NHC ligand – synthesis of which is more
workup
MF-I, 45 min
GII
+
3
(
94%, isolated)
A
PCy3 I
Scheme 4. Merrifield Resin-Assisted Synthesis of GII.
demanding than that of
1, even when the NHC is not
isotopically labelled – is then installed in the second stage of
reaction. Accordingly, the studies below focused on the
capacity of MF-I to improve yields in the second step of Route
A, the transformation of HI into HII via ligand exchange.
A challenge in the synthesis of HII, described in the original
Addition of a twofold excess of MF-I, relative to GI, effected
complete removal of free PCy within 1.5 h, as judged by
3
3
1
1
P{ H} NMR analysis. This period was reduced to 45 min by
increasing the resin stoichiometry to 3:1. Reactions on
preparative scale (3 g; Scheme 4) proceeded smoothly under
these conditions, with complete reaction after 45 min. The
mixture was immediately filtered through Celite to remove the
3
7
study by Blechert and co-workers, is slow chelation of the
ether group following reaction of HI with H IMes. The initial
-isopropoxystyrene intermediate with a dangling
2
1
product is a
ether oxygen (HII ; Scheme 6), chelation of which is inhibited
by the low lability characteristic of PCy trans to an NHC
Formation of HII is commonly driven by addition of
κ
phosphonium iodide-bearing resin
A. (Minimizing exposure
P
times of the catalyst to the resin is a precaution against salt
3
1-33
metathesis,
the onset of which can be observed on
3
3
8,39
ligand.
extended reaction: e.g. 1% at 8 h; see below). The product was
washed through the Celite pad with further THF, and the
filtrate was evaporated. This procedure afforded clean GII (for
spectra, see Figure S1) as a microcrystalline powder in 94%
yield after drying. This is comparable to the yields obtained
using the Amberlyst-15 resin. In comparison, workup by
CuCl and heating. Resin treatment proves an effective
alternative. In this approach, a more specific embodiment of
the strategy exemplified in Scheme 5 above, HI was treated
P
with H
2
IMes for 2 h at RT to effect transformation to HII
.
Addition of excess MF-I and heating for 2 h at 40 °C afforded
clean HII as a green powder in 96% yield (Figure S2), after the
usual filter-and-strip workup. In comparison, the original route
5
c
pentane extraction afforded GII in 75% isolated yield.
Merrifield Resin-Assisted Synthesis of HII.
5
d
gave HII in 85% yield after chromatographic purification.
The second-generation Hoveyda catalyst HII can be accessed
from GI by either of the pathways shown in Scheme 5. Route A
commences with synthesis of the first-generation Hoveyda
catalyst HI via cross-metathesis of GI with o-isopropoxystyrene
HI + 1.2
iPrO
H
2
IMes
1
.
HI is then converted into the target HII by ligand exchange
Cl
IMes
Cl
IMes
3
MF-I
i
H
2
Ru
PCy3
H
2
Ru O Pr
with H IMes. In the alternative Route B, ligand exchange of GI
2
4
0 °C, 2 h
RT, 2 h
THF
HIIP Cl
HII Cl
is carried out first, forming GII, and the styrenyl ether ligand is
then installed via cross-metathesis with
1.
(96%, isolated)
+
HII + PCy
3
Scheme 6. Merrifield Resin-Assisted Synthesis of HII.
Route A
Ph
Merrifield Resin-Assisted Synthesis of InII.
Cl
1.1 ArCH=CH
2
(1)
Cl
i
Synthesis of InII was undertaken via the procedure established
3
Cy P
Ru
PCy
Cl
3
Cy
3
P
Ru O Pr
4
for the IMes analogue. Accordingly, an orange-brown
0
GI
HI
Cl
solution of InI and H IMes in hexanes was heated at 60 °C
2
1
2
.1 H IMes
1
–
.1 H
PCy
2
IMes
(Scheme 7). Within ca. 10 min, the InII product began to
Route B
PCy
3
Ph
– PCy
3
31
deposit as a red-brown precipitate. P{ H} NMR analysis of the
1
3
+
supernatant confirmed conversion of InI to InII and free PCy3
Ph
after 2.5 h. Also present were two minor, unidentified singlets
41
Cl
IMes
Cl
IMes
(
45.7 and –4.6 ppm in CDCl ; 3% of total integration.
3
H
2
Ru
GII Cl
Scheme 5. Strategies for synthesis of HII. Route A (preferred): metathesis with 1, then
PCy
3
H
Ru OPr
i
2
1.1 ArCH=CH2 (1)
HII
Cl
i
6 4
ligand exchange. Route B: ligand exchange, then metathesis. Ar = o-C H -O Pr.
Importantly, however, the styrene co-product of metathesis
has no affinity for the resin (and nor do any stilbenes resulting
4
| J. Name., 2012, 00, 1-3
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underscores the importance of removing MF-I promptly,
Ph
Ph
Cl
3
particularly for GII, once PCy scavenging is complete.
1
2
.2 H IMes
Cl
Ph
hexanes
0 °C, 2.5 h
(a)
Cy
3
P
Ru PCy
3
H
2
IMes
Ru PCy
3
+ PCy
3
6
Cl
InII Cl
InI
Ph
PCy3
Cl
H2IMes
Cl
PCy3 H2IMes
Cl
Ru O Pr H2IMes
+
unidentified byproducts
i
Ru
InII-I
Ru
GII-I
workup
I
HII-I
δH 16.29
(HII: 16.71)
I
I
InII
(
96% isolated) 1) evaporate; redissolve in THF
not formed
δH 19.14
(GII: 19.64)
ca. 4 MF-I, RT, 1 h
2
) ca. 5 MF-I; RT, 40 min
(b)
00
1
Scheme 7. Synthesis of InII.
%
To scavenge the free PCy , the solvent was evaporated on the
3
Schlenk line, the residue was dissolved in THF, and a fourfold
excess of MF-I was added. No free PCy remained after stirring
3
0
at RT for 1 h, as judged by NMR analysis, though traces of the
byproducts remained (ca. 1% of total integration). Filtering and
stirring with further MF-I for 40 min completely removed these
Figure 3. (a) Observed (GII-I, HII-I) or prospective (InII-I) mono-iodide species following
h, RT). (b) Assessing
species. Workup as before, by filtering through Celite to reaction of isolated GII, HII, or InII with MF-I (4 equiv;
8
remove the resin, washing the product through with THF, and decomposition and halide exchange vs. DMT as internal standard.
evaporating the filtrate, afforded clean InII as microcrystalline
red-brown powder in 96% yield. In comparison, the Amberlyst
route gave InII in 95% isolated yield; Delaude’s H IMes•CO
2
2
Merrifield Resin-Assisted Synthesis of Isotopically-Labelled
Metathesis Catalysts.
In final set of experiments, we deployed these
1
5
route, with chromatographic workup, gave 86%, and Nolan’s
synthesis of the IMes analogue, with pentane extraction of the
4
0
a
PCy byproduct, proceeded in 79% yield.
3
methodologies to aid in synthesis of isotopically labelled
metathesis catalysts. We were particularly interested in
Halide Exchange.
1
3
derivatives of HII containing C-labelled H
IMes, which could (respectively) report on the retention
and/or activation of the NHC ligand during catalysis. The Piers
group described a route to d22-H IMes, in which the mesityl
2
IMes and d22-
A potential concern at the outset of these studies was
formation of Ru-iodide derivatives of the targeted metathesis
catalysts, via exchange of the chloride ligands (Figure 3a).
Halide exchange was observed in the Morris study, which
deliberately exploited the phenomenon to synthesize the iodo
H
2
2
44
groups are fully deuterated, and used this ligand to confirm
that C–H activation of the Mes o-methyl groups is key to
3
1
catalyst RuHI(BINAP)(PPh3). In the context of metathesis,
control over exchange is essential, given the impact of the
decomposition of the Piers catalyst, [RuCl
13
2
(H
2 3
IMes)(=CHPCy ]X
(
X = various counter-anions). C-labelled H IMes, in which the
2
3
2,33,42
anionic ligands on catalyst activity.
label is sited at the carbene carbon, has not been reported,
although a number of reports describe the corresponding
To probe the potential for resin-induced halide exchange, the
catalysts were stirred with a fourfold excess of MF-I at RT in
THF, with dimethyl phthalate (DMT) present as an NMR
integration standard. This test, carried out with the isolated
13
13
45
unsaturated, C-labelled NHCs, including C-IMes. Studies
with the latter have demonstrated the potential for important
insights into reaction chemistry involving the NHC ligand
during catalysis. Ruthenium catalysts for olefin metathesis
catalysts in the absence of any free PCy , is deliberately more
3
aggressive than the scavenging reaction, in which uptake of
13
46,47
have been prepared with a C label at the benzylidene,
49
PCy damps the reactivity of the resin, as noted above. As
3
48
methylidene,
and indenylidene
carbons, and at the
The present work is the
shown in Figure 3b, no change was observed for InII after 8 h.
For HII, no change was evident at 6 h, although 1% of the
50,51
metallacyclobutane ring carbons.
first report of a metathesis catalyst in which the NHC ligand
13
bears a C-label at the carbene carbon, directly bound to the
13
Ru center. The C-NHC ligand can thus report directly on the
3
2
known mono-iodide species HII-I was detected at 8 h, as a
singlet at 16.29 ppm. For GII, 1% GII-I was likewise present at 8
h (assigned based on its transient observation on the
independently-examined reaction of GII with NaI, en route to
stability of the Ru-NHC bond, on oxidation or attack at the NHC
3
carbon, and (via, e.g.,
JCH coupling) on other spin-active
4
3
known GII-I2). Of greater concern was the observation of an
as-yet unidentified decomposition pathway for GII, which
caused slow loss of the benzylidene signal. No decomposition
was evident at 2 h, however, or – more pertinently – on the
ligands present on the metal.
2
Arduengo’s now-classic synthetic route to non-labelled H IMes
begins with cyclization of diamine
2
with triethyl
orthoformate, the latter being used as both solvent and
5a,52
45-minute timescale of the Merrifield-scavenging chemistry
carbon source.
As use of the labelled orthoformate as
described above (see Figures S1–3). Nevertheless, this
solvent is cost-prohibitive, and probe reactions in alternative
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C7CY02278F
ARTICLE
Journal Name
1
solvents proved unsatisfactory, we turned to C-labelled these catalysts in pharmaceutical manufacturing. The efficacy
3
1
paraformaldehyde, (CH
3
2
O)
n
, the carbon source utilized to of the new methodology was demonstrated in the synthesis of
13
45c–e
13
Thus, a isotopically-labelled derivatives of HII, bearing a C label at
access C-IMes and related unsaturated NHCs.
13
13
suspension of diamine
in DME was stirred for 20 h at RT, after which the crude rings (d22-H
product was treated with N-bromosuccinimide to afford adds powerful capabilities for the mechanistic exploration of
2 n 2
2 and (CH O) (1.2 equiv; Scheme 8a) the carbene carbon ( C-H IMes), or perdeuterated mesityl
2
IMes). Efficient access to the labelled catalysts
1
3
labelled imidazolinium bromide C-H
2
IMes•HBr. The latter catalyst performance, including studies of catalyst
was converted into the labelled free carbene by treatment decomposition, which will be reported in due course.
1
with NaH. Ligand exchange of HI with C-H
3
2
IMes was carried
out as described above, with the MF-I workup enabling access
1
3
Experimental
to clean C-HII in 93% yield (Scheme 8b). The corresponding
reaction with d22-H IMes was carried out to obtain deuterium-
HII in 92% yield.
2
Materials and methods.
labelled d22
-
2
Reactions were carried out under N in a glovebox at room
temperature (25
, hexanes, CH
a Glass Contour solvent purification system and stored under
over 4 Å molecular sieves. C , CDCl (Cambridge Isotopes)
and deionized H O were freeze-pump-thaw degassed (5x), and
the deuterated solvents were stored under N over 4 Å
±
2 °C), unless otherwise specified. Solvents
(
C
6
H
6
2
2
Cl and THF) were dried and degassed using
(
a)
1
) 1.2 (13CH
MeOH, HOAc
0 h, RT
2 n
O)
H
13C
Br
N
2
6
D
6
3
H
N
H
N
2
Mes
Mes
Mes
N
N
Mes
2
2
) NBS, DME,
40 h, RT
2
13C-H
IMes•HBr
2
2
molecular sieves for at least 12 h prior to use. NaI (99.5%
purity) and Merrifield resin MF-Cl (4.5 mmol/g Cl loading; 1%
cross-linked with divinylbenzene; 200–400 mesh) were
HBF
4 2
, H O
2
0 min
5
3
H
13C
purchased from Sigma-Aldrich and used as received. GI, N,N’-
13C
54
55
2 NaH
BF
Mes
4
dimesitylethane-1,2-diamine
prepared by the reported methods. Free H
the freezer (–35 °C) under N . NMR spectra were recorded on
2,
and free H
2
IMes were
Mes
N
N
Mes
Mes
N
N
IMes was stored in
THF, 20 h
2
13C-H
IMes
13
2
2
C-H IMes•HBF4
2
an Bruker Avance 300 NMR spectrometer at 23 ± 2 °C, and
referenced to the residual proton signals of the deuterated
1
solvents ( H). Chemical shifts (
13C-HII
(b)
13C-H
IMes
2
δ
ppm), are reported relative to TMS ( H, C) or 85% external
), measured in parts per million
1
D
1) RT, THF, 2 h
13
(
3
D C
HI
3
1
CD
3
2) 3 MF-I, 40 °C, 2 h
3 4
H PO ( P) at 0 ppm.
d
11-Mes
N
N
d22-HII
Synthetic procedures.
D
CD
3
Synthesis of MF-I from MF-Cl. Reaction carried out using the
d
22-H
2
IMes
3
1
13
a
reported procedure, using lower proportions of NaI. MF-Cl
(4.24 g, 19.1 mmol) was suspended in acetone (20 mL), and
NaI (2.28 g, 17.2 mmol; 0.9 equiv) was added. The suspension
was stirred for 16 h in air, after which the resin was filtered off
Scheme 8. (a) Synthesis of C-labelled
H
2
IMes. (b) Resin-assisted synthesis of
a
isotopically-labelled HII. NBS = N-bromosuccinimide, DME = dimethoxyethane.
and washed successively with degassed H
acetone (2 x 100 mL). Yield after drying: 6.11 g (quantitative)
Resin-Assisted Synthesis of GII by Ligand Exchange. Solid
white H IMes (1.23 g, 4.01 mmol, 1.1 equiv) was added to a
2
O (4 x 100 mL), and
Conclusions
.
The foregoing describes an efficient route to second-
generation metathesis catalysts, in which the neutral
Merrifield resin MF-I greatly improves the convenience and
reliability of purification. Addition of resin once ligand
2
solution of GI (3.00 g, 3.64 mmol, 1 equiv) in 80 mL THF. A
colour change from purple to red occurred on stirring for 5 min
at RT. Stirring was continued for 2 h, after which conversion to
GII was complete (NMR). MF-I (3.63 g, 10.9 mmol, 3 equiv)
exchange of GI
,
HI or InI with free H
2
IMes is complete results
in sequestration of the free PCy
3
coproduct as the covalently-
tethered benzylphosphonium salt. Excess NHC is likewise
removed, and the clean products can be isolated by filtration
in near-quantitative yields. The high yields are due to the
convenient "filter-and-strip" workup, in place of standard
pentane extraction or chromatographic purification methods,
which are cumbersome and reduce final yields by up to ca.
was then added to sequester free PCy
3
, and the mixture was
stirred for 45 min. No free PCy remained after this time. The
3
resin was then filtered off (Celite), and GII was washed
through with THF (3 x 3 mL). The filtrate was evaporated under
vacuum to afford 2.91 g of clean red GII (94%). NMR chemical
38
.
shifts agree with values reported in C
6
D
1
6
Key values are
, 121
3 6 6
δ 30.1 (s, PCy ). H NMR (C D , 300 MHz): δ 19.64 (s, 1H,
20%. The Merrifield resin-assisted synthesis improves on
31
6 6
reproduced here for convenience. P{ H} NMR (C D
process reliability relative to the prior resin workup, in which
the highly acidic Amberlyst-15 resin was used to sequester
1
MHz):
Ru=CHPh).
Resin-Assisted Synthesis of HII by Ligand Exchange. Solid
3
PCy : it also obviates use of CuCl, residues of which are
undesirable, particularly from the perspective of deploying
H
2
IMes (1.84 g, 5.99 mmol, 1.2 equiv) was added to a brown
6
| J. Name., 2012, 00, 1-3
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C Pa l tea al ys se i sd So c ni eo nt c ae d &j u Ts et cmh an rog l ion gs y
View Article Online
DOI: 10.1039/C7CY02278F
Journal Name
solution of HI (3.00 g, 4.99 mmol, 1 equiv) in 30 mL THF. The Synthesis of C-H
ARTICLE
1
3
2
IMes•HBF
4
.
In air; variant on the method
1
1
solution was stirred for 2 h at RT, at which point no colour reported for the unsaturated salt. The dibromide salt (0.460
P
change was evident, but conversion to HII and HII was g, 1.18 mmol) was stirred vigorously in 50 mL water to effect
3
1
1
P
complete. P{ H} NMR (THF, 300 MHz):
PCy ); ratio 4:1. MF-I (4.65 g, 14.0 mmol, 2.8 equiv) was added, w/w in water; 0.80 mL, 4.37 mmol; 3.4 equiv) was added
and the reaction was heated at 40 °C. After 2 h, the solution dropwise. The product precipitated as a white solid, which was
was dark green, and both transformation to HII and filtered off, suspended in Et O, filtered again, and dried for two
sequestration of PCy were complete. The mixture was filtered days to ensure complete removal of water prior to liberating
through Celite, and the product was washed through with THF the free carbene. Yield: 0.420 g (90%). H NMR (CDCl
4
δ 30.6 (s, HII ), 10.9 (s, complete dissolution. After 20 min, a solution of HBF (40%
3
2
3
1
3
, 300
7.90 (d, JHC = 205 Hz, 1H, NCHN), 6.96 (br s, 4H,
afford HII as a spectroscopically clean green solid (2.99 mg, Mes CH), 4.52 (s, 4H, CH ), 2.34 (s, 12H, Mes o-CH , 2.29 (s, 6H,
). C{ H} NMR (CDCl , 75.5 MHz, 298K):  158.6
That for the benzylidene proton is provided here for (NCHN), 141.2 (Mes C), 134.9 (Mes C), 130.2 (Mes C), 51.9
1
(
3 x 3 mL). The combined filtrate was stripped of solvent to mHz, 298 K): δ
2
3
5
d
13
1
9
6%; Figure S2). NMR values agree with those reported.
Mes p-CH
3
3
δ
1
convenience. H NMR (C
6
D
6
, 300 MHz):
δ
16.71 (s, 1H, (CH
2
), 21.1 (Mes p-CH
3
), 17.7 (Mes o-CH
3
).
1
Synthesis of Free C-H
3
Ru=CHPh).
2
IMes. In the glovebox, NaH (33 mg,
1
Resin-Assisted Synthesis of InII by Ligand Exchange. Reaction 1.31 mmol; 3.3 equiv) was added to a suspension of C-
3
4
0
adapted from the reported procedure for the IMes analogue.
Thus, solid InI (0.31 g, 0.33 mmol, 1 equiv) was added to a reaction was stirred for 18 h before filtering through Celite.
stirred solution of H IMes (0.12 g, 0.39 mmol, 1.2 equiv) in The filtrate was stripped to dryness. The residue was
hexanes (40 mL), and the mixture was heated to 60 °C. After redissolved in benzene, filtered through Celite, and stripped of
.5 h, the colour had changed from orange-brown to dark red, solvent to yield a tan solid. Yield: 88 mg (63%). NMR chemical
2 4
labelled H IMes•HBF (156 mg (0.425 mmol) in 15 mL THF. The
2
2
5
2
and a red-brown precipitate had deposited. No InI remained in shifts are consistent with reported values, with the addition
1
3
1
the solution, but two unassigned PCy
3
derivatives were of the C splitting indicated. H NMR (C
, 300 MHz): 45.7 (s), – 4.6 (s); ratio  6.82 (s, 4H, Mes CH), 3.26 (s, 4H, CH ), 2.29 (s, 12H, Mes o-
:1; 3% of total integrated intensity. Evaporation of the solvent CH ). C{ H} NMR (C , 75.5 MHz,
gave a dark red powder. This was re-suspended in THF (20 mL) 298 K):  243.5 (NCN), 139.2 (d, JCC = 9.7 Hz, Mes C ), 135.8 (d,
), 129.4 (Mes CH), 50.3 (d, JCC = 75.6 Hz,
), 20.5 (Mes p-CH ), 17.7 (Mes o-CH ).
Celite). The product was washed through with THF (3 x 2 mL). Resin-Assisted Synthesis of C-HII. As for the synthesis of HII
6 6
D , 300 MHz, 298 K):
3
1
1
present; P{ H} NMR (CDCl
3
δ
2
1
3
1
3
3
), 2.16 (s, 6H, Mes p-CH
3
6 6
D
2
δ
i
3
2
to form a slurry, to which MF-I (0.47 g, 1.43 mmol, 4.3 equiv)
JCC = 1.3 Hz, Mes C
i
was added. The mixture was stirred at RT for 1 h, then filtered CH
2
3
3
13
(
1
3
3 2
No free PCy remained in the filtrate, though traces of the above, but by reaction of C-H IMes (8 mg, 0.013 mmol, 1.1
byproducts remained (ca. 1% of total integration). These equiv) with HI (14 mg, 0.023 mmol, 1 equiv) in 2 mL THF, and
disappeared on adding further MF-I (0.59 g, 1.77 mmol, 5.4 workup with MF-I (25 mg, 0.075 mmol, 3 equiv). Yield: 14 mg,
equiv) and stirring for 40 min. The resin was separated as 93%. NMR chemical shifts agree with those above, barring
1
3
before. Evaporation of the filtrate gave 0.30 g InII as a additional splitting due to the C label.
spectroscopically clean red-brown solid (96%; Figure S3). The Resin-Assisted Synthesis of d22-HII. As for HII, using d22
3
-
1
1
P{ H} NMR chemical shift is in good agreement with that
H
2
IMes (11.5 mg, 0.035 mmol, 1.4 equiv) with HI (15.1 mg,
5
6
31
1
P{ H} NMR (CDCl
reported in C
PCy ).
Synthesis of
6
D
6
.
3
, 121 MHz):
δ
26.9 (s, 0.025 mmol, 1 equiv) in 3 mL THF, and treating with MF-I (25
mg, 0.075 mmol, 3 equiv). Yield of 22-HII: 15 mg, 92%. NMR
C- chemical shifts agree with the values above for non-labelled
3
d
1
3
13
C-Labelled IMes•HBr. In air.
H
2
Paraformaldehyde (61 mg, 1.97 mmol, 1.3 equiv) was added to HII, barring the absence of those due to the mesityl rings.
a solution of N,N’-dimesitylethane-1,2-diamine (434 mg, 1.46
Control Experiments: Halide Exchange with MF-I.
mmol) in 10 mL methanol. Acetic acid (0.17 mL, 2.97 mmol; 2.0
equiv) in 2 mL methanol was added dropwise to the stirred Representative procedure. A solution of GII (10 mg, 0.01
reaction mixture. Stirring was continued for 10 h, after which mmol, 1 equiv) and DMT (2.3 mg, 0.01 mmol, 1 equiv) in THF
1
the solvent was removed under vacuum to afford the cyclic (1 mL) was stirred at RT for 5 min. H NMR analysis of an
6 6
product. This was dissolved in DME (6 mL) and treated with N- aliquot (stripped to dryness and suspended in C D ) was used
bromosuccinimide (305 mg, 1.71 mmol; 1.1 equiv). A white to establish the initial integration ratio of substrate to DMT.
precipitate deposited over 40 h, which was filtered off and This material was evaporated, redissolved (THF) and returned
washed with cold DME (3x). Yield: 468 mg (82%). NMR to the reaction mixture. MF-I (16.0 mg, 0.04 mmol, 4 equiv)
chemical shifts are in reasonable agreement with values was added, and the reaction was stirred at RT for 8 h. Aliquots
5
2
6
reported for the chloride salt in dmso-d , with the addition of were taken every 2 h to assess loss of GII and formation of GII-
1
3
1
1
1
C splitting. H NMR (CDCl
3
, 300 MHz, 298 K):
δ
8.87 (d, JHC
), 2.37 GII, 99%), 19.43 (s, 1H, Ru=CHPh for GII-I, 1%). A similar
). C{ H} NMR procedure was used for HII and InII. For InII, which has no
159.0 (NCHN), 140.6 (Mes C), 135.0 benzylidene proton, an isolated signal of the indenylidene ring
Mes C), 130.1 (Mes CH), 52.0 (CH ), 21.0 (Mes p-CH ), 18.1 protons was used (see Figure S3a).
Mes o-CH ).
=
6 6
I. H NMR (C D , 300 MHz, at 8 h): δ 19.64 (s, 1H, Ru=CHPh for
2
04 Hz, 1H, NCHN), 6.92 (s, 4H, Mes CH), 4.61 (s, 4H, CH
2
1
3
1
(
(
(
(
s, 12H, Mes o-CH
3 3
), 2.26 (s, 6H, Mes p-CH
CDCl , 75.5 Hz, 298 K):
3
δ
2
3
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Page 8 of 9
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DOI: 10.1039/C7CY02278F
ARTICLE
Journal Name
1
1
1
1
3. M. Bieniek, A. Michrowska, L. Gulajski and K. Grela,
Organometallics, 2007, 26, 1096–1099.
4. B. J. van Lierop, A. M. Reckling, J. A. M. Lummiss and D. E.
Fogg, ChemCatChem, 2012, 4, 2020–2025.
5. X. Sauvage, A. Demonceau and L. Delaude, Adv. Synth. Catal.,
2009, 351, 2031–2038.
6. A bicarbonate adduct (see: M. Fèvre, J. Pinaud, A. Leteneur, Y.
Gnanou, J. Vignolle, D. Taton, K. Miqueu and J.-M.
Sotiropoulos, J. Am. Chem. Soc., 2012, 134, 6776–6784) also
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
NSERC of Canada is thanked for financial support. The
University of Ottawa is thanked for an International
Scholarship to DLN.
holds promise. However, a recent report suggests the CO
2
adducts may be more efficient as sources of the free NHC. See:
M. Fevre, P. Coupillaud, K. Miqueu, J.-M. Sotiropoulos, J.
Vignolle and D. Taton, J. Org. Chem., 2012, 77, 10135–10144.
7. Z. J. Wang, W. R. Jackson and A. J. Robinson, Green Chem.,
2015, 17, 3407–3414.
Notes and references
1
1.
2.
3.
4.
K. Grela, ed., Olefin Metathesis-Theory and Practice, Wiley,
Hoboken, NJ, 2014.
R. H. Grubbs and A. G. Wenzel, eds., Handbook of Metathesis,
Wiley-VCH, Weinheim, 2015.
C. S. Higman, J. A. M. Lummiss and D. E. Fogg, Angew. Chem.,
Int. Ed., 2016, 55, 3552–3565.
(a) R. Gawin, A. Kozakiewicz, P. A. Guńka, P. Dąbrowski and K.
Skowerski, Angew. Chem., Int. Ed., 2017, 56, 981–986. (b) R.
18. J. Huang, E. D. Stevens, S. P. Nolan and J. L. Petersen, J. Am.
Chem. Soc., 1999, 121, 2674–2678.
19. Use of the free NHC offers a clean, straightforward alternative,
providing care is taken to use dry solvents. The free NHCs are
readily hydrolyzed by water, although they are stable to
oxygen. See ref 14 and: M. K. Denk, J. M. Rodezno, S. Gupta
and A. J. Lough, J. Organomet. Chem., 2001, 617-618, 242–253.
Gawin, A. Tracz, M. Chwalba, A. Kozakiewicz, B. Trzaskowski 20. Monsaert, S. F.; Verpoort, F. W. C. Process for preparation of
and K. Skowerski, ACS Catal., 2017, 7, 5443–5449. (c) U. S. D.
Paul and U. Radius, Eur. J. Inorg. Chem., 2017, 3362–3375. (d)
ruthenium-based carbene catalysts with chelating alkylidene
ligands. WO Patent App. WO 2011/091980 Al; CA+ 383210.
V. M. Marx, A. H. Sullivan, M. Melaimi, S. C. Virgil, B. K. Keitz, D. 21. K. M. Engle, G. Lu, S.-X. Luo, L. M. Henling, M. K. Takase, P. Liu,
S. Weinberger, G. Bertrand and R. H. Grubbs, Angew. Chem.,
Int. Ed., 2015, 54, 1919–1923. (e) J. Zhang, S. Song, X. Wang, J.
Jiao and M. Shi, Chem. Commun., 2013, 49, 9491–9493.
K. N. Houk and R. H. Grubbs, J. Am. Chem. Soc., 2015, 137,
5782−5792.
22. P. Kos, R. Savka and H. Plenio, Adv. Synth. Catal., 2013, 355,
5.
For a recent overview of synthetic routes to N-heterocyclic
439 – 447.
carbenes, see: (a) Hans, M.; Lorkowski, J.; Demonceau, A.; 23. A. P. Blum, T. Ritter and R. H. Grubbs, Organometallics, 2007,
Delaude, L. Beilstein J. Org. Chem. 2015, 11, 2318–2325. For a
26, 2122–2124.
review of such chemistry in the context of metathesis, see: (b) 24. R. Bujok, M. Bieniek, M. Masnyk, A. Michrowska, A. Sarosiek,
G. C. Vougioukalakis and R. H. Grubbs, Chem. Rev., 2010, 110,
746–1787. For use of these methods in the original syntheses
H. Stepowska, D. Arlt and K. Grela, J. Org. Chem., 2004, 69,
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1
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