Improvement in Olefin Metathesis Using a New Generation of Ruthenium Catalyst Bearing an Imidazolylidene Ligand: Synthesis of Heterocycles

Article abstract of DOI:10.1021/ol005651e

(Equation Presented) A number of heterocycles have been prepared in very good yields using 1,3-dimesitylimidazol-2-ylidene ruthenium benzylidene 1. This catalyst displays increased activity for ring-closing metathesis of some hindered heterodienes which d

Full text of DOI:10.1021/ol005651e

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1517-1519
Improvement in Olefin Metathesis Using
a New Generation of Ruthenium
Catalyst Bearing an Imidazolylidene
Ligand: Synthesis of Heterocycles
Anne Briot, Murielle Bujard, Ve´ronique Gouverneur,§ Steven P. Nolan,† and
Charles Mioskowski*
Laboratoire de Synthe`se Bio-Organique, CNRS et UniVersite´ Louis Pasteur,
Faculte´ de Pharmacie, 74 route du Rhin, 67401 Illkirch-Graffenstaden, France
mioskow@bioorga.u-strasbg.fr
Received February 11, 2000
ABSTRACT
A number of heterocycles have been prepared in very good yields using 1,3-dimesitylimidazol-2-ylidene ruthenium benzylidene 1. This catalyst
displays increased activity for ring-closing metathesis of some hindered heterodienes which did not cyclize using the Grubbs catalyst 2. The
scope of the olefin metathesis has been expanded.
Ring-closing metathesis (RCM) has been shown to be a
highly effective and practical method in organic synthesis.
It has emerged as an efficient strategy to prepare, usually in
excellent yields, various functionalized carbocycles and
heterocycles from acyclic dienes precursors.1 This success
hinges on the development of stable metal carbenes as olefin
metathesis catalysts. The benzylidene ruthenium carbene
initiator 2 developed by Grubbs2 and the alkoxy imido
molybdenum catalyst 3 developed by Schrock3 have proven
to be the best suited and the most widely used systems to
perform RCM. The ruthenium complex exhibits greater
functional group tolerance and higher moisture and atmo-
spheric oxygen stability relative to those of the extremely
sensitive molybdenum system. Nevertheless, this latter
(3) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886.
(4) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310-7318.
(5) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674-2678. (b) Huang, J.; Schanz, H.-J.; Stevens,
E. D.; Nolan, S. P. Organometallics 1999, 18, 5375-5380. (c) Fu¨rstner,
A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204-2207.
(6) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805. (b) Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999,
121, 9889-9890.
(7) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309.
(8) (a) For the first carbene of this type, see: Wanzlick, H.-W. Angew.
Chem., Int. Ed. Engl. 1962, 1, 75-80. (b) Arduengo, A. J., III; Dias, H. V.
R.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1992, 114, 5530-5534.
† Department of Chemistry, University of New Orleans, New Orleans,
LA 70148. Email: snolan@uno.edu.
§ University of Oxford, Dyson Perrins Laboratory, South Parks Road,
Oxford OX1 3QY, U.K.
(1) For recent reviews on olefin metathesis, see the following and
references cited within these articles: (a) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (c) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371-388.
(2) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
10.1021/ol005651e CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/05/2000

exhibits better reactivity toward a broad range of substrates
with important steric and electronic demands.4
Table 1. Results of Ring-Closing Metathesis11 Using the New
Generation Initiator 1 and the Initial Grubbs Catalyst 2
Further advances in catalyst development leading to
complexes with enhanced activity and stability are expected
to extend the scope of the RCM reaction. Recent investiga-
tions in this area have led to the development of a new
generation of catalysts. Catalyst precursors bearing nucleo-
philic N-heterocyclic carbene ligands have been introduced.
As reported by Nolan and co-workers, the use of these
versatile imidazol-2-ylidenes ligands, so-called “phosphine
mimics”, has opened new opportunities in optimizing the
efficiency of catalyst able to mediate RCM5 as well as C-C6
and C-N7 bond formation. Indeed, the 1,3-bis(2,4,6-tri-
methylphenyl)imidazol-2-ylidene ligand (IMes) developed
by Arduengo et al.8 not only stabilizes the catalyst 1 but
also enhances its catalytic activity toward RCM, as shown
in early experiments.5,9 This new ruthenium derivative has
also been reported to display improved thermal stability
compared to existing initiators.5b These attractive improve-
ments prompted us to examine the scope and the potential
of RCM reactions mediated by this new catalyst 1.
Grubbs and co-workers have explored the reactivity of 1,3-
dimesitylimidazol-2-ylidene ruthenium benzylidene 1 with
some sterically demanding dienes. Submitted to cyclization
in the presence of 1, diverse substrates afford carbocycles
that could not be obtained with catalyst 2.10a Similarly, the
4,5-dihydroimidazol-2-ylidenes ruthenium derivative has
been shown to also exhibit high olefin metathesis activity.10b
Herein we report the use of initiator 1 in RCM as a new
route to prepare various substituted heterocycles.
We intended to test the selectivity and the limitation of
the reactivity displayed by benzylidene 1 compared to its
parent complex 2. The present study aims at providing some
guidelines for the use of this new catalyst in the preparation
of polyfunctionalized molecules.
a Reaction conditions: 0.02 M in refluxing dichloromethane. b Yields
in parentheses are isolated. c No RCM means that no RCM product could
be detected after several days by 1H NMR and starting materials were
recovered. d Neither substrates of entries 1 and 3 undergo cyclization with
12
the Schrock catalyst 3.
As shown in Table 1 we initially investigated the activity
of benzylidene 1 in the RCM of phosphinic acids (entry 1).
Whereas the diallylphosphinic acid did not undergo cycliza-
tion with catalysts 2 and 3, the use of 5% of 1 led to a
quantitative conversion to the desired heterocycle within 4
h. However, benzylidene 1 failed to promote the cyclization
of a phosphinic acid to form a tetrasubstituted double bond
(entry 2), although it permits cyclization to the corresponding
benzyl phosphinate (entry 3).
With another sterically demanding phosphinate bearing a
double bond containing a phenyl group (entry 4), catalyst 1
has shown interesting RCM activity compared to that of 2
which proved inactive. The reaction required 10 h and 10
mol % of catalyst to proceed to completion.
(9) Similar results were reported by the Grubbs laboratory.
(10) (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250. (b) Scholl, M.; Ding, S.; Lee, C.
W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
As far as amino templates are concerned, benzylidene 1
was unable to cyclize free amine (entry 5). Nevertheless,
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Org. Lett., Vol. 2, No. 11, 2000

ring closure of an N-protected substrate leading to a five-
membered structure with a tetrasubstituted double bond
proved feasible (entry 6). The compatibility with additional
steric bulk of phenyl and methyl groups was quite surprising
and underlines the efficiency of this catalytic system (requir-
ing however the protection of the amino moiety). In entry 7
no reaction occurred with allylic disubstituted carbamate. It
can be assumed that either the diene conformation is not
favorable for the cyclization or the initiation reaction of the
benzylidene with the monosubstituted olefin remains impos-
sible due to steric hindrance.
To illustrate another useful application, the closing of some
silaketals has been investigated (entries 8-10) to prepare
precursors to allylic diols. The use of silicon tethering
methodology with RCM has already been reported. 13 With
the silaketals studied here, we intended to underscore the
new possibilities opened in this field by initiator 1. The
substrates chosen include sterically hindered structures. Only
the substrate outlined in entry 8 underwent cyclization with
Grubbs catalyst 2 in 57% yield, while the other substrates
proved inactive (entries 9 and 10). With initiator 1, the
cyclization in entry 8 proceeded in quantitative yield after 2
h with 5% catalyst. Moreover, ring closure could be achieved
in 90% yield with the substrate from entry 9 leading to a
seven-membered ring containing a trisubstituted double bond
and an alkyl residue in the allylic position. Not surprisingly,
the substrate presented in entry 10 failed to cyclize. These
results are very promising for the temporary silicon-tethered
methodology and for the preparation of asymmetric alkene-
1,4-diols, which are useful for the elaboration of asymmetric
catalysts or chiral auxiliaries.14
Finally we examined one example of ether (entry 11) to
show the selectivity displayed by catalyst 1. Whereas we
observed only a dimerization product using Grubbs catalyst
2, the cyclized product was the only one obtained in good
yield with the new catalyst.
Herein we have presented a brief survey of the behavior
of ruthenium catalyst 1 bearing an imidazolylidene ligand.
Various heterodienes, which failed to react with Grubbs
catalyst, cyclize in good to excellent yields through RCM.
Even with the Schrock catalyst 3, substrates from entries 1
and 3 failed to react, proving the high potential of this new
initiator. The improvement in catalyst activity appears to be
sufficient to overcome some steric deactivation and the
inhibition effect of some functional groups. Moreover, the
catalyst displays a remarkable thermal stability compared to
that of existing initiators and proves to be easy to handle.
Hence this complex could provide new access to polysub-
stituted targets and widen the scope and synthetic applications
of the RCM reaction. Ongoing efforts are directed toward
the use of catalyst 1 in various RCM protocols.
Acknowledgment is made to Hoechst Marion Roussel for
financial support to M.B., to the National Science Foundation
(CHE-9985213) and the Louisiana Board of Regents for
support to S.P.N., and to A. Valleix for obtaining mass
spectra.
(11) Representative procedure: In a typical reaction a stirred solution
of diene (typical concentration 0.02 M) in dry dichloromethane with a
catalytic amount of ruthenium benzylidene (3-15 mol %) was heated to
reflux. The reaction was followed by TLC or 1H NMR monitoring the
disappearance of the starting material. After heating, the reaction mixture
was concentrated under vacuum. Purification was performed by chroma-
tography on silica gel providing the desired cycloadduct in yields indicated
in Table 1.
(12) Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org. Chem. 1999,
64, 2119-2123.
(13) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769.
(14) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518-8519. (b) Chong,
J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J. Tetrahedron:
Asymmetry 1995, 6, 409-418.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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