Highly efficient ruthenium catalysts for the formation of tetrasubstituted olefins via Ring-Closing Metathesis

Article abstract of DOI:10.1021/ol0705144

Equation presented A series of ruthenium-based metathesis catalysts with N-heterocyclic carbene (NHC) ligands have been prepared in which the N-aryl groups have been changed from mesityl to mono-ortho-substituted phenyl (e.g., tolyl). These new catalysts

Full text of DOI:10.1021/ol0705144

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1589-1592
Highly Efficient Ruthenium Catalysts for
the Formation of Tetrasubstituted
Olefins via Ring-Closing Metathesis
Ian C. Stewart,† Thay Ung,‡ Alexandre A. Pletnev,‡ Jacob M. Berlin,†
Robert H. Grubbs,† and Yann Schrodi*,‡
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, and Materia Inc., Pasadena, California 91107
yschrodi@materia-inc.com
Received February 28, 2007
ABSTRACT
A series of ruthenium-based metathesis catalysts with N-heterocyclic carbene (NHC) ligands have been prepared in which the N-aryl groups
have been changed from mesityl to mono-ortho-substituted phenyl (e.g., tolyl). These new catalysts offer an exceptional increase in activity
for the formation of tetrasubstituted olefins via ring-closing metathesis (RCM), while maintaining high levels of activity in ring-closing metathesis
(RCM) reactions that generate di- and trisubstituted olefins.
The formation of carbon-carbon bonds by olefin metathesis
has become one of the most powerful and broadly applicable
synthetic tools of modern chemists.1 In particular, ring-
closing metathesis (RCM) reactions promoted by ruthenium-
based catalysts have been widely utilized by synthetic organic
chemists in the construction of small, medium, and large ring
systems from acyclic precursors.2 The formation of cyclic,
disubstituted olefins from terminal dienes is generally
effectively catalyzed by diphosphine ruthenium complexes,3
and the synthesis of cyclic trisubstituted olefins can be readily
achieved using second-generation systems such as 1 (Figure
† California Institute of Technology.
‡ Materia Inc.
(1) (a) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740-3747. (b)
Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748-3759. (c) Grubbs,
R. H. Angew. Chem., Int. Ed. 2006, 45, 3760-3765. (d) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. (e)
Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140. (f) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003. (g) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (h)
Frenzel, U.; Nuyken, O. J. Polym. Sci. Part A: Polym. Chem. 2002, 40,
2895-2916. (i) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29. (j) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (k)
Buchmeiser, M. R. Chem. ReV. 2000, 100, 1565-1604.
Figure 1. Ruthenium-based olefin metathesis catalysts.
10.1021/ol0705144 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/23/2007

conditions within very short reaction times (Table 1, Figure
3). Methyl-substituted catalysts 5a and 6a performed better
Figure 2. Ru catalysts with mono-ortho-substituted NHCs.
Table 1. RCM to Form Tetrasubstituted Olefin 8
1).4 However, a ruthenium catalyst capable of producing ring
structures that contain a tetrasubstituted carbon-carbon
double bond with high efficiency remains elusive.5,6 Recent
efforts toward this goal have focused on the development
of N-heterocyclic carbene (NHC) ruthenium complexes
where both ortho positions of the N-aryl rings are substituted
with small atoms (e.g., H).7 Although these new catalysts,
including compound 4, are more efficient than previous
ruthenium-based systems in the formation of cyclic tetra-
substituted olefins, they tend to require long reaction times
and their production is difficult and not economical on a
large scale.8
a
Monitored by GC. See Supporting Information for additional details
and time points.
In pursuit of more efficient and more easily prepared cata-
lysts, we continued to investigate the effects of the N-aryl
group substitution patterns on the catalytic activity of the
corresponding ruthenium complexes. Because removing both
ortho substituents of the N-aryl ring (e.g., 4) led to a large
increase in reactivity for the formation of tetrasubstituted
olefins, we were interested in studying catalysts derived from
NHC ligands with only one ortho substituent on the aryl rings
(Figure 2).9
than their ethyl- and isopropyl-substituted analogues, re-
spectively.
A series of catalysts (5a-c and 6a-c) were synthesized,
and their activity was initially tested in the ring closing of
dimethallylmalonates 7 and 9 (eq 1).10 Phosphine-based
catalysts 5a-c gave high conversions to 8 under mild
(2) (a) Blechert, S.; Schuster, M. Angew. Chem., Int. Ed. 1997, 36, 2036-
2056. (b) Fu¨rstner, A. Top. Catal. 1997, 4, 285-299. (c) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413-4450. (d) Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2073-2077. (e) Yet, L. Chem. ReV. 2000, 100,
2963-3007. (f) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826-2830.
(3) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856-9857.
(4) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
Figure 3. RCM to form tetrasubstituted olefin 8.
(5) (a) Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann,
W. A. Tetrahedron Lett. 1999, 40, 4787-4790. (b) Huang, J. K.; Schanz,
H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5375-5380.
(c) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics
1999, 18, 5416-5419. (d) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz,
H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207. (e) Kirkland, T.
A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-7318. (f) Scholl, M.;
Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
2247-2250. (g) Briot, A.; Bujard, M.; Governeur, V.; Nolan, S.; Miosk-
owski, C. Org. Lett. 2000, 2, 1517-1519. (h) Fu¨rstner, A.; Ackermann,
L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel,
O. R. Chem.-Eur. J. 2001, 7, 3236-3253. (i) Andreana, P. R.; McLellan,
J. S.; Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875-3878. (j) Michrowska,
A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J.
Am. Chem. Soc. 2004, 126, 9318-9325.
Ether-based systems11 6a-c were found to require longer
reaction times than phosphine-based systems 5a-c under the
same conditions (Table 1). The kinetics of RCM to form
tetrasubstituted olefins were monitored for catalysts 5a and
(9) Chiral ruthenium metathesis catalysts have been reported with only
one ortho substituent on each N-bound aryl ring. These catalysts are
significantly less efficient for the preparation of tetrasubstituted olefins by
RCM than the catalysts reported in this communication. See ref 7.
(10) The optimum temperature for RCM reactions using catalyst 4 is
60 °C; see ref 7.
(11) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.; Kingsbury,
J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179.
(6) For examples of RCM to form tetrasubstituted olefins catalyzed by
molybdenum catalysts, see ref 5e and references therein.
(7) Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.;
Grubbs, R. H. Org. Lett. 2007, ASAP.
(8) Pletnev, A. A.; Ung, T.; Schrodi, Y., unpublished results.
1590
Org. Lett., Vol. 9, No. 8, 2007

6a by NMR spectroscopy in closed tubes according to our
recently published standard characterization system.12 The
results indicated that catalyst 5a initiates rapidly but also
decomposes readily under the reaction conditions.13 We
believe that the build-up of ethylene in this closed system
increases the concentration of intermediate ruthenium
methylidene complexes, which are susceptible to decomposi-
tion upon attack by free PCy3.14 The analogous ether-based
catalyst 6a appeared to initiate more slowly but was longer-
lived.
Catalyst 6a efficiently affords a variety of five-, six-, and
seven-membered tetrasubstituted RCM products within much
shorter reaction times than 3 (Table 2). Diene 11 was
Table 2. RCM Reactions Using Catalysts 3 and 6a
Increasing the temperature at which the metathesis reaction
was run led to sufficient initiation rates. When run at 60 °C,
catalyst 6a quantitatively afforded tetrasubstituted product
10 within 30 min. Unreacted or regenerated 6a was detected
1
by H NMR spectroscopy upon completion of the RCM
reaction, suggesting that the catalyst loading could likely be
decreased. Indeed, the ring closure of 9 was accomplished
in >95% conversion within 1 h using only 2.5 mol % of
catalyst 6a in C6D6 at 60 °C. The addition of water or
performing the reactions in air did not significantly affect
the yields of the RCM.
We propose that the remarkable increase in catalytic
activity of 6a compared to 3 in the RCM of 7 results from
the significantly more open steric environment around the
ruthenium center, which allows the catalytic site to accom-
modate larger organic fragments. The X-ray crystal structure
of 6a illustrates the reduced steric hindrance around the metal
compared to that in 3 (Figure 4).11b Interestingly, two
a
E ) CO2Et. b Isolated yield. c Performed in an open system. Conversion
in a closed system (NMR tube) was 62%.
quantitatively cyclized within 1 h, and full conversion was
also achieved within 1 h in the RCM of sulfonamide 13 and
ether 14. Ring closing of 12, which generates a seven-
membered ring, was most efficient when ethylene was
removed from the system. However, despite the higher
reactivity of 6a, the ring closing of ester 16 or the
macrocyclization of ester 17 was not realized.
A rather simple modification, removal of an ortho
substituent from the N-aryl ring of the NHC ligand, has
resulted in a complex that efficiently catalyzes the for-
mation of tetrasubstituted olefins by ring-closing metath-
esis. The synthesis of these catalysts can be performed on a
large scale, and metathesis reactions do not require any
special handling, a hallmark of ruthenium-based metath-
esis catalysts. In contrast to expectations, these less-
substituted systems were sufficiently stable to provide
efficient conversion to highly substituted products. A com-
Figure 4. ORTEP diagram of 6a.
conformers are present in the single crystal in a 91:9 ratio.
The major conformer corresponds to the complex where the
o-tolyl substituents of the NHC ligand adopt a syn conforma-
tion, whereas the o-tolyl substituents of the minor conformer
have an anti conformation. It is not clear whether the syn or
the anti conformer is more active in RCM. Studies related
to the conformation of catalysts 5a-c and 6a-c in solution
are underway.
(12) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.
Organometallics 2006, 25, 5740-5745.
(13) See Supporting Information.
(14) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414-7415.
Org. Lett., Vol. 9, No. 8, 2007
1591

plete discussion of catalyst development and reaction condi-
tion optimization will be reported in due course. The
application of these catalysts to other metathesis reactions
is ongoing in our laboratories.
Henling and Dr. Michael Day (California Institute of
Technology) for X-ray structural analysis.
Supporting Information Available: Experimental pro-
cedures and characterization for catalysts 5a-c and 6a-c
and procedures for the RCM reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge financial
support from NIH Grant 5RO1GM31332 to R.H.G. and an
NIH postdoctoral fellowship to I.C.S. We thank Larry
OL0705144
1592
Org. Lett., Vol. 9, No. 8, 2007