Olefin metathesis catalyst: Stabilization effect of backbone substitutions of N-heterocyclic carbene

Article abstract of DOI:10.1021/ol800824h

(Chemical Equation Presented) Ruthenium olefin metathesis catalysts bearing an N-phenyl-substituted N-heterocyclic carbene (NHC) ligand that are resistant to decomposition through C-H activation have been prepared and tested in ring closing metathesis (RC

Full text of DOI:10.1021/ol800824h

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2693-2696
Olefin Metathesis Catalyst: Stabilization
Effect of Backbone Substitutions of
N-Heterocyclic Carbene
Cheol K. Chung and Robert H. Grubbs*
The Arnold and Mabel Beckman Laboratories for Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
rhg@caltech.edu
Received April 10, 2008
ABSTRACT
Ruthenium olefin metathesis catalysts bearing an N-phenyl-substituted N-heterocyclic carbene (NHC) ligand that are resistant to decomposition
through C-H activation have been prepared and tested in ring closing metathesis (RCM), cross metathesis (CM), and ROMP reactions. The
N,N′-diphenyl-substituted NHC complex proved to be one of the most efficient catalysts in RCM to form tetrasubstituted olefins.
Olefin metathesis has become an indispensable tool in
making carbon-carbon bonds in organic synthesis.1 Since
the development of well-defined ruthenium-based metathesis
catalysts, there has been significant effort directed toward
improving the catalyst efficiency. Most notably, the substitu-
tion of a phosphine ligand of RuCl2(PCy3)2(dCHC6H5) for
a bulky, electron-rich N-heterocyclic carbene (NHC) ligand
led to metathesis catalysts with enhanced reactivity and
stability (Figure 1, 1).2
Figure 1. Ruthenium-based olefin metathesis catalysts.
While the modification of the NHC ligand allowed access
to metathesis catalysts suitable for various applications,3 our
group recently demonstrated that decreasing the size of the
aryl groups on the NHC ligand by the removal of one ortho
substituent was beneficial for the ring closing metathesis
(RCM) and cross metathesis (CM) of hindered substrates
(Figure 1, 3).4
However, attempts to further enhance the efficiency of the
catalyst by removing both ortho substituents on the NHC
ligand met with either difficulty in synthesis or catalyst
instability. For instance, N,N′-diphenyl-substituted NHC
derived from 5 failed to form a detectable amount of
ruthenium complex such as 6 under various conditions (eq
(1) (a) Grubbs, R. H. Handbook of metathesis; Wiley-VCH: Weinheim,
Germany, 2003. (b) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450,
243–251. (c) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45–
52. (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. (e) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3013–3043. (f) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
(2) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100–110. (c) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H. Angew. Chem., Int. Ed. 1995, 34, 2039–2041.
(4) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (b) White, D. E.; Stewart,
I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810–811.
(c) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441–
444.
(3) For examples, see: Deshmukh, P. H.; Blechert, S. Dalton Trans.
2007, 2479–2491, and references therein.
10.1021/ol800824h CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society

1). It is presumably due to the rapid and irreversible
dimerization of the corresponding carbene to form an
enetetramine byproduct (“Wanzlick dimerization”).5
the direct backbone substitution would have greater influence
on the donor ability of NHC than the substitution on the
N-aryl groups. Herein, we report the synthesis and reactivity
of ruthenium complex 13 bearing a tetramethyl-substituted
NHC ligand.
The synthesis of 13 began with the condensation of 2,3-
butandione with aniline (Scheme 1). Treatment of the
Scheme 1. Synthesis of Ruthenium Complex 13
In the case of the 1,3-diphenylbenzimidazol-2-ylidene
ligand, the ruthenium complexes were synthesized success-
fully and shown to have good catalytic activity for hindered
olefin synthesis.6 However, these complexes are rather
unstable and decompose to metathesis inactive compounds
7a and 7b through the activation of ortho C-H bonds of
the N-phenyl groups (Figure 2).7 A related oxidative
resulting diimine with methyl Grignard reagent furnished
diamine 9, which was subsequently converted to imidazo-
lidinium salt 10 in high yield in the presence of excess
triethylorthoformate. The corresponding free carbene 11 was
generated by treating 10 with potassium hexamethyldisilazide
at room temperature, judged by the appearance of the
characteristic free carbene 13C NMR signal (245.1 ppm). This
carbene displaces a phosphine ligand when mixed with
RuCl2(PCy3)2(dCHC6H5) at room temperature, affording
monophosphine complex 12, which was promptly trans-
formed to phosphine-free complex 13 by the reaction with
14.
Figure 2. Decomposition of N-phenyl-substituted NHC complexes.
degradation product 8 has been reported recently by Blech-
ert’s group.8 These observations suggest N-phenyl-substituted
NHC complexes are more prone to decomposition in
comparison to complexes bearing ortho-substituted N-
substituents.9
Compound 13 was stable under air in the solid state and
could be purified by flash chromatography. Its structure was
fully characterized by NMR and mass spectroscopy as well
as single crystal X-ray analysis (Figure 3). The crystal
structure shows that the length of the C(1)-Ru is shorter in
13 (1.959 Å) than in 2 (1.980 Å), indicating a stronger
NHC-ruthenium interaction. Notably, the two phenyl sub-
stituents are slightly tilted away from the neighboring gem-
dimethyl groups as can be seen from the bond angles
C(2)-N(1)-C(8) and C(3)-N(2)-C(14) (124.83° and
121.36°, respectively, compared with 118.33° and 118.22°
for 2).
To the best of our knowledge, 13 is the first stable
ruthenium olefin metathesis catalyst bearing N,N′-diphenyl-
substituted NHC with a saturated backbone. It appears that
the combination of the shorter NHC-Ru bond and canted
N-phenyl groups to the metal center helps to stabilize the
complex by providing sufficient shielding despite its smaller
size.
These decomposition pathways are likely facilitated by
facile rotation of the N-phenyl group relative to bulkier aryl
groups, which can bring an aryl C-H bond closer to the
ruthenium center. It was therefore anticipated that restriction
of the N-phenyl ring would raise the barrier for decomposi-
tion processes. A straightforward approach to achieve this
goal would be to place bulky substituents, such as gem-
dialkyl groups, on the backbone of the NHC ligand. The
backbone substitution was also expected to slow down
unfavorable Wanzlick dimerization by providing increased
steric hindrance around the carbene.5d Furthermore, the
substitution on the backbone should affect the electron-
donating properties of NHC, since it was conceivable that
(5) (a) Wanzlick, H. W.; Schikora, E. Chem. Ber. 1961, 94, 2389–2393.
(b) Liu, Y. F.; Lemal, D. M. Tetrahedron Lett. 2000, 41, 599–602. (c) Denk,
M. K.; Hatano, K.; Ma, M. Tetrahedron Lett. 1999, 40, 2057–2060. (d)
Denk, M. K.; Thadani, A.; Hatano, K.; Lough, A. J. Angew. Chem., Int.
Ed. 1997, 36, 2607–2609. (e) Alder, R. W.; Blake, M. E.; Chaker, L.;
Harvey, J. N.; Paolini, F.; Schutz, J. Angew. Chem., Int. Ed. 2004, 43, 5896–
5911.
Encouraged by the successful preparation of 13, we
became curious whether the similar approach could be used
to stabilize Blechert’s 1-mesityl-3-phenyl-substituted NHC
system.8 Therefore, compound 19 with an unsymmetrically
substituted NHC that has a gem-dimethyl group adjacent to
the N-phenyl substituent was synthesized as described in
(6) Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.;
Grubbs, R. H. Org. Lett. 2007, 9, 1339–1342.
(7) Hong, S. H.; Chlenov, A.; Day, M. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2007, 46, 5148–5151.
(8) Vehlow, K.; Gessler, S.; Blechert, S. Angew. Chem., Int. Ed. 2007,
46, 8082–8085.
(9) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2007, 129, 7961–7968.
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Org. Lett., Vol. 10, No. 13, 2008

Scheme 3
.
RCM Reactions with Backbone-Substituted
Catalystsa
aReactions were performed in NMR tubes with closed caps and
conversions were determined by NMR. bReactions were performed at 60
°C in C6D6.
Figure 3. X-ray structure of 13 (ORTEP drawing, thermal ellipsoids
are shown at 50% probability). Selected bond length (Å) and angles
(°): Ru-C(20) 1.822(2), Ru-C(1) 1.959(2), Ru-O(1) 2.3068(14),
Ru(1)-Cl(1) 2.3549(5), Ru-Cl(2) 2.3354(5), Cl(1)-Ru-Cl(2)
157.668(19), C(2)-N(1)-C(8) 124.83(15), C(3)-N(2)-C(14)
121.36(15).
slower rate compared to phosphine-free second-generation
complex 2. When more challenging substrate 22 was
employed, the RCM proceeded at a noticeably slower rate
with 13 or 19, furnishing the cycloalkene 23 in 82% and
32% yield, respectively, whereas 2 completed the cyclization
in one hour. The plots of conversion versus time revealed
an induction period with backbone-substituted catalysts. This
could originate from different initiation behavior for each
catalyst, and indeed 13 initiated about 30% slower than 2 as
determined by the irreversible metathesis reaction with
n-butyl vinyl ether (see Supporting Information).12
Scheme 2. Compound 19 was isolated as an air-stable
crystalline green solid after flash column chromatography,
Scheme 2. Synthesis of 19
Remarkably, 13 was highly effective in the ring closing
metathesis reaction of 24 forming a tetrasubstituted cycloalk-
ene, completing the cyclization in 4 h at 30 °C. Complex 13
is among the most efficient catalyst in the RCM of 24.
Complexes 3 and 4, which are also efficient catalysts for
hindered substrates, required 15 and 43 h, respectively, to
attain 95% (Figure 4).4a
and its structure was confirmed by NMR, HRMS, and X-ray
analysis. Unlike its parent compound, 19 was quite stable
under air and did not readily degrade to the oxidative
insertion product analogous to 8, as judged from the retention
of the benzylidene proton signal in the 1H NMR spectrum.10
With complexes 13 and 19 in hand, their catalytic activity
in various metathesis reactions was tested according to the
standard characterization system.11 First, the catalysts were
examined for the ring closing metathesis of diethyl diallyl-
malonate 20, diethyl allylmethallylmalonate 22, and diethyl
dimethallylmalonate 24 (Scheme 3). Both 13 and 19 ef-
ficiently cyclized 20 in several hours at 30 °C, a slightly
Figure 4. RCM of diethyl dimethallylmalonate (24).
(10) A solution of 19 in CD2Cl2 was aerated and subjected to NMR
analysis. This was repeated over the period of 4 days without noticeable
degradation of the benzylidene signal compared with an internal standard
(anthracene).
(11) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.
Organometallics 2006, 25, 5740–5745.
Contrary to the high reactivity of 13 in hindered olefin
formation, the unsymmetrical complex 19 failed to cyclize
(12) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543–6554.
Org. Lett., Vol. 10, No. 13, 2008
2695

24 at 30 °C. However, at higher reaction temperature (60
°C in benzene), 19 afforded 25 in 55% conversion after 31 h.
Next, we examined the catalytic activity of 13 and 19 in
the cross metathesis using allylbenzene (26) and cis-1,4-
diacetoxy-2-butene (27) (Scheme 4, eq 1).13 Again, both 13
electron donor ability of 11 and 17 is comparable to that of
H2IMes, indicating that the backbone substitution contributes
to the donor ability of NHC slighltly more than substitution
on N-aryl groups (Table 1).
Table 1. Carbonyl Frequencies of cis-[(NHC)RhCl(CO)2]
Scheme 4.
Cross Metathesisa and ROMPb with
NHC
νCO (cm-1
)
ref
Backbone-Substituted Catalysts
11
17
H2IMes
2078, 1996
2079, 1996
2081, 1996
this work
this work
15b
In conclusion, we have successfully prepared a stable
ruthenium complex bearing an N,N′-diphenyl-substituted
NHC with a saturated backbone, the synthesis of which has
long been elusive. The addition of substituents on the
backbone of the NHC ligand, based on our hypothesis that
restricting rotation of the N-aryl group would prevent catalyst
decomposition, allowed access to these species. The catalytic
activity of these backbone-substituted complexes was tested
in RCM, CM, and ROMP reactions, and 13 emerged as one
of the most efficient catalysts in the tetrasubstituted olefin
forming RCM reaction. Currently, synthesis of ruthenium-
based metathesis catalysts with various substitution patterns
on the backbone in combination with different N-aryl groups
to further enhance the efficiency of olefin metathesis reactions
is underway.
aConversion and E/Z ratio was determined by GC analysis. bReactions
were performed in NMR tubes with closed caps, and conversions were
determined by NMR.
and 19 catalyzed the reaction at slower rates compared to 2,
but 13 outperformed 2 in terms of overall conversion at the
end of the reaction, whereas 19 lost its activity at around
57% conversion. The complex 13 was also an efficient
catalyst in the ring opening metathesis polymerization of
cyclooctadiene providing 30 cleanly in 20 min at 0.1 mol %
of the catalyst loading (Scheme 4, eq 2).
While we believe that the observed reactivity difference
mainly stems from steric factors, we were interested in the
influence of backbone substitution on the electron-donating
ability of the NHC, since its strong σ-donating ability is often
discussed in conjunction with the catalytic activity of its
metal complexes.14 To evaluate the electronic properties of
carbenes 11 and 17, cis-[RhCl(CO)2(NHC)] was prepared
via [(NHC)RhCl(COD)] by displacing COD with excess
CO.15 IR carbonyl stretching frequencies show that the
Acknowledgment. This research was supported by the
National Institutes of Health. The authors thank Larry M.
Henling and Dr. Michael W. Day, Beckman Institute for
X-ray crystallographic analysis. Dr. Jean-Baptiste Bourg and
Dr. Ian C. Stewart, California Institute of Technology, are
greatly acknowledged for helpful discussion.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. X-ray
analysis of compounds 13 and 19. Procedures for RCM, CM,
and ROMP reactions. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800824H
(13) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
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