Ru-based Z-selective metathesis catalysts with modified cyclometalated carbene ligands

Article abstract of DOI:10.1039/c4sc01541j

A series of cyclometalated Z-selective ruthenium olefin metathesis catalysts with alterations to the N-heterocyclic carbene (NHC) ligand were prepared. X-Ray crystal structures of several new catalysts were obtained, elucidating the structural features of this class of cyclometalated complexes. The metathesis activity of each stable complex was evaluated, and one catalyst, bearing geminal dimethyl backbone substitution, was found to be comparable to our best Z-selective metathesis catalyst to date.

Full text of DOI:10.1039/c4sc01541j

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EDGEꢀARTICLE
Ru-Based Z-Selective Metathesis Catalysts with Modified
Cyclometalated Carbene Ligands†
Sarah M. Bronner, Myles B. Herbert, Paresma R. Patel, Vanessa M. Marx, and Robert H. Grubbs*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A series of cyclometalated Z-selective ruthenium olefin metathesis catalysts with alterations to the
N-heterocyclic carbene (NHC) ligand were prepared. X-Ray crystal structures of several new catalysts
were obtained, elucidating the structural features of this class of cyclometalated complexes. The
metathesis activity of each stable complex was evaluated, and one catalyst, bearing geminal dimethyl
backbone substitution, was found to be comparable to our best Z-selective metathesis catalyst to date.
1
0
11
Introduction
and subsequent metalation (e.g., 1 → 4 and 2 → 5, Scheme 1).
The resulting NHC-ligated complex then undergoes
carboxylate-driven C–H activation enabled by metal-bound
The olefin metathesis reaction is arguably one of the most
1
well-studied and useful tools in organic synthesis. The utility of
12
4
4
5
5
6
0
5
0
5
0
carboxylates. In our early reports, it was discovered that while
1
2
2
3
3
5
0
5
0
5
this powerful methodology is demonstrated by its prevalence in
9a,b
pivalate-ligated catalyst 6 was highly Z-selective,
nitrato
2
numerous applications, including natural product synthesis,
catalyst 7 had increased stability and selectivity with turnover
numbers (TONs) approaching 1000 and Z-selectivity of
3
4
materials science, and biochemistry. Recent metathesis
endeavors have addressed the challenge of stereoselectivity, as
productive metathesis reactions may construct carbon–carbon
double bonds with either Z- or E-stereochemistry. As a result of
the reversible nature of the olefin metathesis reaction, the
9c
approximately 90%. An analogous C–H activation strategy
could not be used on complexes containing more sterically
demanding NHCs; for example, treatment of 5, containing a
N-2,6-diisopropylphenyl (DIPP) group, with silver pivalate
5
thermodynamically favored E-olefin is generally formed. In
11
(
AgOPiv) led to complex mixtures. By employing the milder
contrast, selective generation of the Z-olefin, a motif found in
sodium pivalate (NaOPiv) in place of AgOPiv, it was discovered
2
b
many natural products and pharmaceutical targets, via olefin
metathesis has only recently been enabled by the development of
novel metathesis catalysts. The Schrock and Hoveyda groups
have achieved highly Z-selective metathesis utilizing
monoaryloxide pyrrolide (MAP) molybdenum and tungsten
catalysts, and have applied their systems to perform the
Z-selective homodimerization and cross-metathesis of terminal
that C–H activation of 5, as well as other challenging complexes,
12a
could occur cleanly to generate catalyst 8.
Gratifyingly,
catalyst 8 was found to perform a number of homodimerization
and cross-metathesis reactions with near perfect Z-selectivity
(
>95%) and unmatched TONs (≥ 7400). The power and industrial
relevance of this class of cyclometalated ruthenium compounds
has since been illustrated via applications in the synthesis of
6
7
olefins, ring-opening metathesis polymerization, as well as
13
14
insect pheromone natural products and macrocyclic musks, in
8
macrocyclic ring-closing metathesis.
15
addition to more complicated natural products.
Recently,
our
group
has
developed
Z-selective
Computational studies provide a model for the Z-selectivity
exhibited by cyclometalated metathesis catalysts 7 and 8, and also
provide guidance for further catalyst development. The Houk
ruthenium-based catalysts with cyclometalated N-heterocyclic
9,10
carbene (NHC) ligands. The general synthetic strategy used to
access these complexes involves in situ generation of a carbene
N
N
N
N
N
N
2
i. KOCMe Et
hexanes
R
R
R
AgOPiv
N
N
Cl
NH4NO3
THF
R
Ru
O
Ru
O O
Ru
O O
Cl
i-Pr
O
O
ii. 60 °C
Cl
THF
N
PCy
Ru
O
3
Cl
t-Bu
O
i-Pr
i-Pr
4: (41% yield)
5: (decomp.)
6: (82% yield)
1
:
R = Mes
Cl
7: R = Mes
R = DIPP
2
:
R = DIPP
4
:
R = Mes
6: R = Mes
8
:
i-Pr
5: R = DIPP
3
1
:
(92% yield)
1
. NaOPiv, THF, MeOH, 50 °C
. NH NO , THF
2
: (90% yield)
2
4
3
4
:
(60% yield, 2 steps)
5
:
(20% yield, 2 steps)
Scheme 1. Synthetic Route to Previously Reported C–H Activated Metathesis Catalysts.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 4, 00–00 | 1

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18
group has previously shown that steric crowding over the
ruthenium center forces the forming side-bound metallacyle into
5-membered NHC analogue, thus implying that 16 may display
improved Z-selectivity. Furthermore, increasing the ring size of
all-cis geometry (11, Figure 1), resulting in selective formation of 50 the NHC could result in additional degrees of freedom, relieving
16
the Z-isomer (12) via kinetic control.
In the case of
ring strain of the NHC and leading to a more stable catalyst.
5
cyclometalated catalysts 7 and 8, the 5-membered imidazoline
NHC holds the N-aryl group in close proximity to the
intermediate metallacycle, thus explaining why the sterically
more hindered N-DIPP group imparts greater selectivity than the
N-Mes analogue.
N
N
N
N
N
N
N
N
Mes
Mes
Mes
DIPP
Ru
O O
O
Ru
O
Ru
O O
Ru
O O
O
O
O
N
N
O
N
N
O
i-Pr
O
O
O
i-Pr
i-Pr
i-Pr
1
0
1
6
17
18
19
‡
R'
N
N
R'
R''
Z-Selectivity
R
R
Ru
N
N
N
N
N
O
+
[Ru] CH
2
Mes
DIPP
DEP
N
O
O
12
13
Ru
O
Ru
O
Ru
O O
R
11
R
O
O
O
N
O
N
O
N
favored metallacyclobutane
intermediate
O
i-Pr
O
i-Pr
O
i-Pr
[Ru]
+
R
R
2
0
21
22
9
10
‡
R'
Figure 2. New ruthenium complexes with modified
N
N
55
cyclometalated carbene ligands.
R R'
R"
E-Selectivity
R
Ru
O
+
[Ru] CH
2
N
O
R
O
R
15
13
1
4
Backbone-substituted ruthenium complexes 17–19 were
disfavored metallacyclobutane
intermediate
expected to display extended catalyst lifetimes and increased
19
Figure 1. Steric crowding of metallacycle enforces Z-
Z-selectivity. It was hypothesized that the geminal dimethyl
stereochemistry.
60 substitution on compound 17 could push the N-adamantyl group
closer to the metal center, resulting in a more stable chelate,
1
1
1
2
2
5
0
5
Despite the recent advances in catalyst development, there
remains a need for more Z-selective ruthenium metathesis
catalysts with expanded substrate scopes. In previous generations
of ruthenium metathesis catalysts, modification of the NHC
ligand has been well explored and has led to insights on the
thereby disfavoring common decomposition pathways.
Alternatively, it was expected that the same substitution above
the N-aryl group (e.g., 18 and 19) could prevent N-aryl rotation
from occurring, and also position the aryl substituent closer to the
forming metallacyclobutane; both effects could result in
improved Z-selectivity.
6
7
7
8
5
0
5
0
1
9
relation of structure, activity, and stability;
however,
17
modifications to the NHC ligand of cyclometalated catalysts
have been largely unexplored, although proposed transition states
suggest that this group is critical in imparting stereochemistry to
In the past, metathesis catalysts with unsaturated NHC ligands
20
have been found to be less active than their saturated analogues.
While it was expected that they would be less active, backbone
unsaturated ruthenium complexes 20 and 21 were identified as
synthetic targets. Finally, we decided to pursue ruthenium cyclic
1
6
the forming metallacycle. We hypothesized that modification to
the identity of the NHC ligand could potentially lead to more
active and more Z-selective metathesis catalysts.
(
alkyl)(amino)carbene (CAAC) complex 22, bearing
a
2
,6-diethylphenyl (DEP) substituent. In addition to being
structurally interesting with a unique spiro-binding mode, CAAC
ligands have been shown to impart a unique reactivity to catalysts
Results and discussion
21
of previous generations. In the case of each target shown in
Figure 2, the carbene was synthesized using modifications of
Selection and Synthesis of Catalysts. Herein, we report the
preparation, characterization, and metathesis activity of seven
new cyclometalated ruthenium metathesis catalysts with varying
carbene ligands. While modifying the identity of the
cyclometalated carbene, other features of the catalyst were left
unaltered for the purpose of consistency. Although alternative
X-type ligands have been explored, the nitrate ligand was
selected for our catalyst series because it has been shown to
3
3
4
4
0
5
0
5
22
previously reported procedures.
Elaboration to the
cyclometalated complex was accomplished using strategies
analogous to those shown in Scheme 1, involving
metal-carboxylate mediated C–H activation, followed by ligand
23
exchange with the addition of ammonium nitrate.
A number of formamidinium salts were synthesized that could
9
c
85 not be elaborated to the desired cyclometalated ruthenium
complexes (Figure 3). Previously, non-cyclometalated metathesis
catalysts with acyclic diaminocarbenes have provided metathesis
products with lower E:Z ratios than analogous catalysts
impart exceptional stability and selectivity. In the past, we have
1
2a
seen that the N-1-adamantyl chelate is most stable, and for the
purposes of this study this feature was left unchanged. Finally,
our previous most promising Z-selective metathesis catalysts
have possessed either N-Mes or N-DIPP substituents.
24
containing NHC ligands. Based on these observations, it was
anticipated that C–H activation of these acyclic diaminocarbene
ruthenium complexes might lead to improved Z-selective
metathesis catalysts. However, acyclic formamidinium salts 23
and 24 underwent metalation to produce an unstable dichloride
that could not be isolated without substantial decomposition. We
also attempted to synthesize a DIPP analogue to catalyst 16 with
9
0
Cyclometalated complexes 16–22, bearing a number of unique
carbene motifs, were selected as catalyst targets for our studies
(
Figure 2). Complex 16, possessing a 6-membered NHC, was of
interest because crystal structures of similar non-cyclometalated
ruthenium complexes have revealed that the N-aryl component
exerts a larger steric influence on the benzylidene than with the
9
5
a
6-membered NHC, but found that the corresponding
2
| Chem. Sci., 2014, 5, 00–00
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formamidinium salt (25) did not undergo successful metalation.
Cyclometalated ruthenium complexes with 7-membered NHCs
were also targeted because, like the 6-membered NHC complex,
the N-aryl component was expected to have an increased steric
effect on the forming metallacyclobutane. However, attempts to
metalate 7-membered formamidinium salts 26 and 27 were
unsuccessful, as was the metalation of previously reported CAAC
5
25
salt 28.
N
N
N
N
N
N
Mes
DIPP
DIPP
BF4
BF4
BF4
2
3
24
25
40
Figure 4. ORTEP drawing of 8. Displacement ellipsoids are
drawn at 50% probability. For clarity, hydrogen atoms have been
omitted.
N
N
N
N
Mes
DIPP
N
BF4
Br
DIPP
BF4
2
6
27
28
1
0
Figure 3. Formamidinium salts that could not be elaborated to
cyclometalated ruthenium metathesis catalysts.
Structural Analyses. To probe the steric and electronic effects of
cyclometalated carbene modification, crystals of 19, 21, and 22
were grown and their molecular structures were confirmed by
single-crystal X-ray crystallographic analysis (Figures 5, 6, and 7,
respectively). For comparison purposes, a crystal structure of 8,
which previously had not been reported, was also obtained
(Figure 4). The crystal structure of 8 did not vary significantly
1
5
2
2
3
3
0
5
0
5
9
c
from the previously disclosed structure of 7. A comparison
between structures reveals that the distance between Ru and the
chelating adamantyl-carbon does not change significantly, with
the exception of CAAC-ligated 22, which possesses a slightly
longer bond length. Other key structural features are summarized
in Table 1. Of note, catalyst 8, bearing a 5-membered saturated
NHC, has the ability to kink its backbone, as shown by the N(1)–
C(2)–C(3)–N(2) torsional angle of 23.33°. This kinked geometry
relieves ring strain and allows for a more stable catalyst.
Interestingly, catalyst 19 possesses an approximately equal but
opposite torsional angle (–23.66°). As expected, unsaturation of
the NHC results in a nearly planar geometry, as indicated by 21’s
torsional angle of 1.16°. Furthermore, from the crystal structure
of CAAC-ligated 22, it is apparent that the N-aryl ring is situated
further away from the benzylidene moiety. This structural feature
may explain the diminished Z-selectivity observed in metathesis
studies, along with the fact that 22 is a less stable complex.
45
Figure 5. ORTEP drawing of 19. Displacement ellipsoids are
drawn at 50% probability. For clarity, hydrogen atoms have been
omitted.
50
Figure 6. ORTEP drawing of 21. Displacement ellipsoids are
drawn at 50% probability. For clarity, hydrogen atoms have been
omitted.
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preserving Z-selectivity highlights this new catalyst structure’s
unique attributes. However, complex 16, with a 6-membered
NHC, was not metathesis active, while CAAC-ligated 22 was
found to be highly unstable under the reaction conditions.
35
Table 2. Homodimerization of allyl benzene (29).
Ph
catalyst (0.1 mol%)
Ph
+
Ph
THF (3.35 M), 35 °C
Ph
2
9
30
31
catalyst time (h)
conversion (%)a
Z-selectivity (%)a
30/31a
7
1
3
7
93
98
>99
>99
92
98
>99
>99
0
92
84
>50
>50
>50
>50
>50
>50
>50
>50
n/a
n/a
n/a
n/a
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
17
N
N
Mes
DIPP
Mes
66
Figure 7. ORTEP drawing of 22. Displacement ellipsoids are
drawn at 50% probability. For clarity, hydrogen atoms have been
omitted.
[
Ru]
1
2
45
1
>95
>95
91
8
5
3
N
N
Table 1. Selected X-Ray Data for 8, 19, 21, and 22.
7
[
Ru]
8
19
21
22
12
1
83
n/a
n/a
n/a
n/a
>95
95
1
6
Bond Lengths (Å)
3
0
Ruthenium-NHC
Carbene Carbon
Ru(1)–C(1)
1.954
1.974
1.965
1.939
N
N
7
0
[Ru]
1
1
2
0
72
92
97
99
82
94
97
99
75
91
97
98
84
95
>99
>99
13
75
95
98
>99
4
Ruthenium-Chelating
Isopropoxy Group
Ru(1)–O(1)
1
7
2.311
2.320
2.064
2.317
2.060
2.329
3
N
N
Mes
7
72
[Ru]
12
1
53
Ruthenium-Chelating
Adamantyl Carbon
2.062
2.096
Ru(1)–C(5)
Ru(1)–C(7)
Ru(1)–C(7)
Ru(1)–C(18)
18
>95
95
3
N
N
Mes
7
90
Ruthenium Alkylidene
Styrene Carbon
1.849
1.851
1.841
1.852
[Ru]
Ru(1)–C(26)
Ru(1)–C(28)
Ru(1)–C(28)
Ru(1)–C(26)
12
1
79
>95
>95
>95
92
1
9
3
Torsional Angle (deg)
–23.66 1.16
N
N
DIPP
7
N(1)–C(2)–C(3)–N(2)
23.33
n/a
[Ru]
1
1
2
2
0
97
Homodimerization Metathesis Activity. To probe the
metathesis ability of each new cyclometalated complex,
homodimerization studies were performed using three standard
substrates. Allyl benzene (29) was selected for our initial studies
because this substrate is prone to double bond migration and the
extent of isomerization to form 31 is a good litmus test to assess
3
7
90
1
1
2
2
3
0
5
0
5
0
N
N
Mes
54
[
Ru]
12
1
25
>95
>95
>95
93
2
1
3
7
26
N
N
the overall stability of new metathesis catalysts.
homodimerization reactions were performed in tetrahydrofuran
THF) at 35 °C with an olefin concentration of 3.35 M and 0.1
mol% catalyst loading. Aliquots were removed at 1-, 3-, 7-, and
2-hour time points, and conversion as well as Z-selectivity were
All
DIPP
1
2
[Ru]
2
1
3
7
5
74
(
50
2
2
6
49
2
1
N
10
15
49
1
1
DEP
calculated by analysis of the H NMR spectra of the unpurified
reaction mixtures (Table 2). Complexes 7 and 8 were able to
catalyze the homodimerization of allyl benzene with excellent
conversions and high selectivities, and were in good agreement
1
2
49
0.6
[Ru]
aDetermined from analysis of the 1H NMR spectrum.
1
2a
with previously published data. A number of catalysts were
found to homodimerize allyl benzene with similar efficacy. While
catalysts 17, 20, and 21 demonstrated erosion of Z-selectivity
over time, catalyst 19, bearing geminal dimethyl substitution on
the NHC backbone, displayed higher Z-selectivities than 8 (98%
40
Next, the efficacy of our new complexes was further examined
using two more challenging homodimerization substrates.
10-Methyl undecenoate (32, Table 3) was selected because the
ester functionality is far removed from the double bond, while 4-
pentenol (34, Table 4) has been linked to decomposition
27
conversion, 92% Z-selectivity vs. >99% conversion, 83% Z- 45 pathways of prior generations of Ru-metathesis catalysts.
selectivity at 12 h of reaction time). The efficacy of 19 at
Furthermore, pronounced Z-content degradation has been
4
| Chem. Sci., 2014, 5, 00–00
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DOI: 10.1039/C4SC01541J
observed in the homodimerization of 4-pentenol with previous Z-
selective metathesis catalysts 7 and 8. Metathesis reactions were
executed utilizing the standard conditions described above.
Catalyst 19 effected the homodimerization of 10-methyl
undecenoate with approximately the same conversions and near-
perfect selectivities as catalyst 8 (96% vs. 97% conversion at 12 h
for 19 and 8, respectively), and 21 showed a similar level of Z-
selectivity and efficiency. As expected, 4-pentenol was a difficult
substrate and erosion of Z-selectivity was observed for all
catalysts. Of note, 20 and 21 have improved solubility compared
Table 4. Homodimerization of 4-pentenol (34).
OH
3
catalyst (0.1 mol%)
OH
3
THF (3.35 M), 35 °C
3
HO
5
34
catalyst time (h)
35
conversion (%)a Z-selectivity (%)a
7
1
3
7
52
92
96
99
37
87
94
97
0
>95
88
N
N
Mes
DIPP
Mes
58
1
0
[
Ru]
1
1
3
7
2
24
to
homodimerizations of allylbenzene (29), 10-methyl undecenoate
32), and pentenol (34) without reduced activity.
7
and 8, and could perform neat, homogeneous
8
>95
80
(
N
N
33
[
Ru]
1
1
3
7
2
21
1
5
Table 3. Homodimerization of 10-methyl undecenoate (32).
1
6
n/a
n/a
n/a
n/a
>95
88
O
O
0
catalyst (0.1 mol%)
THF (3.35 M), 35 °C
OMe
8
N
N
OMe
8
0
O
8
[Ru]
1
2
0
3
2
33
OMe
1
7
1
6
3
55
73
85
20
63
71
81
14
63
79
86
22
84
95
catalyst time (h)
conversion (%)a Z-selectivity (%)a
N
N
7
78
Mes
7
1
85
94
96
97
70
91
96
97
0
92
89
[
Ru]
12
1
76
3
N
N
18
>96
95
Mes
DIPP
Mes
7
88
3
[Ru]
12
1
83
N
N
Mes
7
82
8
>95
>95
>95
>95
n/a
n/a
n/a
n/a
>95
>95
94
[
Ru]
1
1
2
63
3
N
N
>95
82
7
19
[Ru]
12
1
3
N
N
DIPP
7
30
1
6
3
0
[Ru]
12
1
29
N
N
7
0
20
n/a
75
[Ru]
12
1
0
3
N
N
18
56
79
86
35
65
78
82
68
88
94
96
28
56
75
82
5
7
35
1
7
Mes
3
[Ru]
12
1
significant isomerization
N
N
7
n/a
Mes
21
0
[Ru]
12
1
91
10
49
65
88
0
>95
72
3
>95
>95
>95
94
1
8
7
N
N
DIPP
3
47
1
2
N
N
[Ru]
Mes
7
27
2
1
3
7
5
[Ru]
12
1
n/a
n/a
n/a
n/a
2
2
>95
>95
>95
>95
>95
92
1
9
0
3
N
0
N
N
DEP
DIPP
7
1
2
0
[Ru]
12
1
[Ru]
aDetermined from analysis of the 1H NMR spectrum.
2
0
3
20
N
N
7
85
Mes
Cross-Metathesis Activity. Based on the results of the
homodimerization studies, our two most active and selective new
catalysts 19 and 21 were selected to be evaluated in more
complicated cross-metathesis reactions. Cross-metathesis with
[Ru]
12
1
78
>95
>95
>95
>95
>95
n/a
n/a
n/a
n/a
2
1
3
27
65
81
85
0
7
N
N
25 allylic-substituted olefins is a particularly difficult transformation
DIPP
1
2
because increased steric bulk further destabilizes the Z-geometry
[Ru]
2
1
3
7
5
28
of the cross product. However, the utility of Z-selective
2
2
cyclometalated metathesis catalyst
8 has previously been
0
illustrated in the cross-metathesis of vinyl pinacol boronate (36)
N
0
29
DEP
30 with 1-dodecene (37). In the case of catalyst 8, the reaction
1
2
0
[Ru]
proceeds with 81% yield and 92% Z-selectivity. Catalyst 19
aDetermined from analysis of the 1H NMR spectrum.
performed with comparable yields and selectivities, while
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DOI: 10.1039/C4SC01541J
unsaturated catalyst 21 displayed low activity under these
Acknowledgements
conditions.
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under award numbers F32GM102984
Table 5. Cross-metathesis of vinyl pinacol boronate (36) and
1-dodecene (37).
40
5
(
fellowship to S.M.B.) and NIH R01-GM031332, the NSF under
award number CHE-1212767, and the NSERC of Canada
fellowship to V.M.M.). NMR spectra were obtained by
O
B
O
O
B
catalyst (2.0 mol%)
9
+
O
9
(
THF (0.5 M), 35 °C, 5 h
3
6
37
38
instruments supported by the NIH (RR027690). The Bruker
KAPPA APEXII X-ray diffractometer was purchased via an
NSF:CRIF:MU award to the California Institution of Technology
45
catalyst
yield (%)a
Z-selectivity (%)b
(
CHE-0639094). Lawrence Henling and Dr. Michael Takase are
8
81
81
92
acknowledged for X-ray crystallographic analysis. Naseem
Torian and Dr. Mona Shahgholi are acknowledged for high-
1
9
>95
n/a
<
5
50 resolution mass spectrometry assistance. Dr. David VanderVelde
is acknowledged for NMR assistance. Brendan Quigley, Dr. Jeff
Cannon, and Dr. Daryl Allen are acknowledged for helpful
discussions. David Weinberger (Bertrand Group) is gratefully
acknowledged for providing CAACs. Materia, Inc. is thanked for
2
1
aIsolated yields. bZ-Selectivity determined by analysis of the
1H NMR spectrum of the purified product.
Chemoselective cross-metathesis of dienes is another 55 its donation of 3 and metathesis catalysts 7 and 8.
30
underdeveloped reaction
that can be accomplished by
1
0
cyclometalated ruthenium metathesis catalysts. Previously, 8 was
demonstrated to catalyze the Z-selective cross-metathesis of 39
Notes and references
31
and 40 with complete chemoselectivity.
Under identical
Arnold and Mabel Beckman Laboratories of Chemical Synthesis,
Division of Chemistry and Chemical Engineering, California Institute of
reaction conditions, the catalytic abilities of 8, 19, and 21 were
compared (Table 6). Catalysts 8 and 19 afforded cross-product in
similar yields (77% and 64%, respectively), with near perfect
Z-selectivities, while 21 was again found to be an ineffective
catalyst.
60
Technology,
rhg@caltech.edu; Fax: +1 626-564-9297
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
Pasadena,
California,
91125,
USA.
E-mail:
1
5
†
Table 6. Chemoselective cross-metathesis of 8-nonenol (39) and
trans-1,4-hexadiene (40).
1
2
(a) A. Fürstner, Angew. Chem. Int. Ed., 2000, 39, 3012–3043; (b) T.
M. Trnka, R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18–29; (c) R. R.
(a) A. Fürstner, Chem. Commun., 2011, 47, 6505–6511; (b) J. Cossy,
S. Arseniyadis, C. Meyer, Metathesis in Natural Product Synthesis:
Strategies, Substrates, and Catalysts, Wiley-VCH, Weinheim, 2010.
(a) A. Leitgeb, J. Wappel, C. Slugovc, Polymer, 2010, 51, 2927–
2
0
OH
catalyst (0.5 mol%)
+
OH
7
7
THF (0.5 M), 23 °C, 5 h
3
9
40
41
3
2
9
946; (b) S. Sutthasupa, M. Shiotsuki, F. Sanda, Polym. J., 2010, 42,
05–915; (c) X. Liu, A. Basu, J. Organomet. Chem., 2006, 691,
catalyst
yield (%)a
Z-selectivity (%)b
8
77
64
<5
>95
>95
n/a
5148–5154.
4
5
6
J. B. Binder, R. T. Raines, Curr. Opin. Chem. Biol., 2008, 12, 767–
1
9
7
73.
2
1
Handbook of Metathesis (Ed.: R. H. Grubbs), Wiley-VCH,
Weinheim, 2003.
(a) S. J. Meek, R. V. O’Brien, J. Llaveria, R. R. Schrock, A. H.
Hoveyda, Nature, 2011, 471, 461–466; (b) M. M. Flook, A. J. Jiang,
R. R. Schrock, P. Müller, A. H. Hoveyda, J. Am. Chem. Soc., 2009,
aIsolated yields. bZ-Selectivity determined by analysis of the
1H NMR spectrum of the purified product.
1
31, 7962–7963; (c) S. C. Marinescu, D. S. Levine, Y. Zhao, R. R.
Conclusions
Schrock, A. H. Hoveyda, J. Am. Chem. Soc., 2011, 133, 11512–
11514; (d) A. J. Jiang, Y. Zhao, R. R. Schrock, A. H. Hoveyda, J.
Am. Chem. Soc., 2009, 131, 16630–16631; (e) M. Yu, I. Ibrahem, M.
Hasegawa, R. R. Schrock, A. H. Hoveyda, J. Am. Chem. Soc., 2012,
A variety of new cyclometalated ruthenium alkylidene complexes
have been prepared that exhibit high Z-selectivity. The use of
NaOPiv to perform C–H activation has allowed access to a
number of unique structures. This approach was used to
synthesize seven new cyclometalated species, which were
evaluated in a number of metathesis reactions. As expected, it
was found that N-DIPP-substituted catalysts were more
Z-selective than the analogous N-Mes-substituted complexes.
One catalyst in particular, 19, was found to be comparable to the
best Z-selective metathesis catalyst to date in this series (8) in
homodimerizations and more complicated cross-metathesis
reactions. Future studies into catalyst development will focus on
investigating modification of the X-type ligand, N-chelate, and
the chelating isopropoxy styrene group.
2
3
3
5
0
5
1
34, 2788–2799.
7
8
M. M. Flook, V. W. L. Ng, R. R. Schrock, J. Am. Chem. Soc., 2011,
133, 1784–1786.
(a) C. Wang, M. Yu, A. F. Kyle, P. Jakubec, D. J. Dixon, R. R.
Schrock, A. H. Hoveyda, Chem.–Eur. J., 2013, 19, 2726–2740; (b)
M. Yu, C. Wang, A. F. Kyle, P. Jakubec, D. J. Dixon, R. R. Schrock,
A. H. Hoveyda, Nature, 2011, 479, 88–93; (c) C. Wang, F. Haeffner,
R. R. Schrock, A. H. Hoveyda, Angew. Chem. Int. Ed.; 2013, 52,
1939–1943.
(a) K. Endo, R. H. Grubbs, J. Am. Chem. Soc., 2011, 133, 8525–
8
Chem. Soc., 2011, 133, 9686–9688; (c) B. K. Keitz, K. Endo, P. R.
9
527; (b) B. K. Keitz, K. Endo, M. B. Herbert, R. H. Grubbs, J. Am.
6
| Chem. Sci., 2014, 5, 00–00
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Patel, M. B. Herbert, R. H. Grubbs, J. Am. Chem. Soc., 2012, 134,
93–699.
31 J. S. Cannon, R. H. Grubbs, Angew. Chem. Int. Ed., 2013, 52, 9001–
6
9004.
1
0
For other Z-selective ruthenium metathesis catalysts, see: (a) R. K.
M. Khan, R. V. O’Brien, S. Torker, B. Li, A. H. Hoveyda, J. Am.
Chem. Soc., 2012, 134, 12774–12779; (b) R. K. M Khan, S. Torker,
A. H. Hoveyda, J. Am. Chem. Soc., 2013, 135, 10258–10261; (c) G.
Occhipinti, F. R. Hansen, K. W. Törnroos, V. R. Jensen, J. Am.
Chem. Soc., 2013, 135, 3331–3334.
1
1
1
2
For metalation of 1 see ref 9a. For metalation of 2, see: M. B.
Herbert, Y. Lan, B. K. Keitz, P. Liu, K. Endo, M. W. Day, J. Am.
Chem. Soc., 2012, 134, 7861–7866.
For the C–H activation of 4 see ref 9a. For the C–H activation of 8
see: (a) L. E. Rosebrugh, M. B. Herbert, V. M. Marx, B. K. Keitz, R.
H. Grubbs, J. Am. Chem. Soc., 2013, 135, 1276–1279. For more
detailed studies on carboxylate-assisted C–H activation, see: (b) J. S.
Cannon, L. Zou, P. Liu, D. J. O’Leary, K. N. Houk, R. H. Grubbs, J.
Am. Chem. Soc., 2014, 136, 6733–6743.
1
1
1
3
4
5
M. B. Herbert, V. M. Marx, R. L. Pederson, R. H. Grubbs, Angew.
Chem. Int. Ed., 2013, 52, 310–314.
V. M. Marx, M. B. Herbert, B. K. Keitz, R. H. Grubbs, J. Am. Chem.
Soc., 2013, 135, 94–97.
(a) W.-j. Chung, J. S. Carlson, D. K. Bedke, C. D. Vanderwal,
Angew. Chem. Int. Ed., 2013, 52, 10052–10055; (b) W.-j. Chung, J.
S. Carlson, C. D. Vanderwal, J. Org. Chem., 2014, 79, 2226–2241.
P. Liu, X. Xu, X. Dong, B. K. Keitz, M. B. Herbert, R. H. Grubbs, K.
N. Houk, J. Am. Chem. Soc., 2012, 134, 1464–1467.
1
1
6
7
For a discussion on the reactivity of various carbenes, see: D. Martin,
Y. Canac, V. Lavallo, G. Bertrand, J. Am. Chem. Soc., 2014, 136,
5
023–5030.
(a) J. Yun, E. R. Marinez, R. H. Grubbs, Organometallics, 2004, 23,
172–4173; (b) L. Yang, M. Mayr, K. Wurst, M. R. Buchmeiser,
1
1
8
9
4
Chem.–Eur. J., 2004, 10, 5761–5770.
For previous reports of non-cyclometalated metathesis catalysts with
back-bone substituted NHCs, see: (a) K. M. Kuhn, J.-B. Bourg, C. K.
Chung, S. C. Virgil, R. H. Grubbs, J. Am. Chem. Soc., 2009, 131,
5
2
313–5320; (b) C. K. Chung, R. H. Grubbs, Org. Lett., 2008, 10,
693–2696.
2
2
0
1
M. Scholl, T. M. Trnka, J. P. Morgan, R. H. Grubbs, Tetrahedron
Lett., 1999, 40, 2247–2250.
(a) D. R. Anderson, T. Ung, G. Mkrtumyan, G. Bertrand, R. H.
Grubbs, Y. Schrodi, Organometallics, 2008, 27, 563–566; (b) D. R.
Anderson, V. Lavallo, D. J. O’Leary, G. Bertrand, R. H. Grubbs,
Angew. Chem. Int. Ed., 2007, 46, 7262–7265.
2
2
For general procedures for the synthesis of imidazolium salts, see: (a)
K. M. Kuhn, R. H. Grubbs, Org. Lett., 2008, 10, 2075–2077; (b) K.
Hirano, S. Urban, C. Wang, F. Glorius, Org. Lett., 2009, 11, 1019–
1
022.
2
2
3
4
For catalyst synthesis details, see Supporting Information.
E. L. Rosen, D. H. Sung, Z. Chen, V. M. Lynch, C. W. Bielawski,
Organometallics, 2010, 29, 250–256.
2
2
2
5
6
7
V. Lavallo, G. D. Frey, S. Kousar, B. Donnadieu, G. Bertrand, Proc.
Nat. Acad. Sci., 2007, 104, 13569–13573.
T. Ritter, A. Heji, A. G. Wenzel, T. W. Funk, R. H. Grubbs,
Organometallics, 2006, 25, 5740–5745.
(a) T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E. Wilhelm, M.
Scholl, T.-L. Choi, S. Ding, M. W. Day, R. H. Grubbs, J. Am. Chem.
Soc., 2003, 125, 2546–2558; (b) N. J. Beach, J. A. M. Lummiss, J.
M. Bates, D. E. Fogg, Organometallics, 2012, 31, 2349–2356.
R. B. Turner, A. D. Jarrett, P. Goebel, B. J. Mallon, J. Am. Chem.
Soc., 1973, 95, 790–792.
2
8
2
3
9
0
B. L. Quigley, R. H. Grubbs, Chem. Sci., 2014, 5, 501–506.
(a) S. P. Nolan, H. Clavier, Chem. Soc. Rev., 2010, 39, 3305–3316;
(
b) Y. Zhang, C. C. Arpin, A. J. Cullen, M. J. Mitton-Fry, T.
Sammakia, J. Org. Chem., 2011, 76, 7641–7653; (c) K. P. Carter, D.
J. Moser, J. M. Storvick, G. W. O’Neil, Tetrahedron Lett., 2011, 52,
4
1
494–4496; (d) S. T. Diver, A. J. Giessert, Chem. Rev., 2004, 104,
317–1382.
This journal is © The Royal Society of Chemistry [year]
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