Ruthenium olefin metathesis catalysts bearing N-heterocyclic carbene ligands with substituted backbone

This invention was supported by National Institutes of Health under Grant number GM031332. The U.S. government has certain rights in this invention.

This application claims priority to PCT Application No. PCT/US09/40109, filed Apr. 9, 2009, which claims priority under 35 U.S.C. §119 to U.S. provisional application Ser. No. 61/118,171, filed Nov. 26, 2008; and U.S. provisional application Ser. No. 61/123,477, filed Apr. 9, 2008.

This invention relates generally to olefin metathesis, more particularly, to tri- or tetra-substituted imidazolinium salts which are precursors to N-heterocyclic carbene (NHC) ligands with tri- or tetra-substituted imidazolinium rings, organometallic ruthenium complexes comprising gem di-substituted imidazolinium NHC ligands, organometallic ruthenium complexes comprising tri- or tetra-substituted imidazolinium NHC ligands, and to olefin metathesis methods using them. The catalysts and methods of the invention have utility in the fields of catalysis, organic synthesis, and industrial chemistry.

Olefin metathesis is an indispensable tool in making carbon-carbon bonds in modern organic synthesis. For recent reviews, see, e.g., (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. Aidrichimica Acta 2007, 40, 45-52; (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140; (e) Furstner, 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. Since the development of well-defined ruthenium-based metathesis catalysts, there has been significant effort directed towards improving the catalyst efficiency. Most notably, the substitution of a phosphine ligand of RuCl 2 (PCy 3 ) 2 (═CHC 6 H 5 ) for a bulky, electron-rich N-heterocyclic carbene (NHC) ligand led to metathesis catalysts with enhanced reactivity and stability. See, e.g., (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. the high reactivity of NHC complexes is often attributed to the superior electron donor ability of NHC ligands in comparison to the phosphine ligands. See, e.g., (a) Sussner, M. S.; Plenio, H. Chem. Comm. 2005, 5417-5419. (b) Hadei, N.; Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7, 1991-1994.)

In addition, the use of NHC ligand has allowed access to metathesis catalysts suitable for various applications through the modification of NHC ligand, such as water-soluble metathesis catalysts, solid-supported catalysts, and highly active catalysts suitable for hindered substrate. See, e.g., (a) Deshmukh, P. H.; Blechert, S. Dalton Trans. 2007, 2479-2491 and references therein; (b) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008, 10, 441-444; (c) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589-1592.)

Although a variety of metathesis catalysts are available to address a range of problems in chemistry, it is still a challenge to obtain more robust catalysts that can be reliably applied in industrial processes. Ruthenium NHC complexes, albeit significantly more stable than the corresponding bisphosphine complexes, have limited lifetime. Recent catalyst stability studies suggested that C—H activation within the catalyst framework is responsible for the decomposition of the active ruthenium complexes. For instance, the X-ray structure of thermally degraded of ruthenium complexes bearing N-mesityl or N-phenyl-substituted NHC ligand revealed that the N-aryl substituents of NHC ligand have been altered by the metal center (Compounds C1-5 below). See, e.g., (a) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H., J. Am. Chem. Soc. 2007, 129, 7961-7968. (b) Hong, S. H.; Chlenov, A.; Day, M. W.; Grubbs, R. H., Angew. Chem., Int. Ed. 2007, 46, 5148-5151. (c) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl, M.; Choi, T. L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 2546-2558. (d) Vehlow, K.; Gessler, S.; Blechert, S. Angew. Chem., Int. Ed. 2007, 46, 8082-8085.

To resolve the above issue, this invention discloses further development of efficient and stable metathesis catalysts based on ruthenium NHC complexes.

The present invention relates to imidazolinium salt NHC ligand precursor of formula (I):

wherein:

a) R 1 and R 4 are methyl; and

R 2 and R 3 are independently selected from methyl, ethyl, or allyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring;

R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II);

wherein,

n ranges from 1 to 3; with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons;

R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups;

R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride; with the proviso that R 8 and R 9 are not C 1 -C 10 alkyl at the same time; and,

wherein R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 ; or,

b) R 1 is methyl;

R 4 is H;

R 2 and R 3 are independently selected from methyl, ethyl, allyl, or isopropyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring; with the proviso that R 2 and R 3 are not both isopropyl at the same time;

R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II);

wherein,

n ranges from 1 to 3; with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons;

R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups;

R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride; and,

wherein R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 ; and,

X − is an anion for the imidazolinium salt.

The invention also relates to novel N-heterocyclic carbene (NHC) ruthenium olefin metathesis catalyst of formula (III):

The catalysts of formula (III) contain the NHC ligand from the tri- or tetra-substituted imidizoladinium salt NHC ligand precursor described in formula (I) as well as the other ligands shown. The catalysts of formula (III) may also contain NHC ligands from gem di-substituted imidizoladinium salt NHC ligand precursors having the structure of formula (I) in which R 1 and R 2 are C 1 -C 10 alkyl, or together form a cyclic structure, and R 3 and R 4 are hydrogen. In formula (III), X 1 and X 2 are independently anionic ligands; R 10 and R 11 are each independently hydrogen or a substituted or unsubstituted substituent selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, C 1 -C 20 carboxylate, C 1 -C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, C 1 -C 20 alkylthio, C 1 -C 20 alkylsulfonyl and C 1 -C 20 alkylsulfinyl; L is a neutral 2-electron donor ligand; and “m” is 1 or 2. R 10 and R 11 may optionally be linked together to form a cyclic structure via one of the substituents mentioned above. L may optionally be linked to R 11 to form a chelating carbene ligand.

Another embodiment of the invention relates to an olefin metathesis reaction which contacts an olefin with an N-heterocyclic carbene (NHC) ruthenium olefin metathesis catalyst of the invention under metathesis conditions. The catalysts of the invention may be used in, for example, ring-closing metathesis (RCM), cross metathesis (CM), ring-opening metathesis polymerization (ROMP), and acyclic diene metathesis polymerization (ADMET).

FIG. 1 depicts the standard activity tests of the Ruthenium catalysts in Ring Closing Metathesis (RCM) reactions to form a di-substituted olefin.

FIG. 2 depicts the standard activity tests of the Ruthenium catalysts in RCM reactions to form a tri-substituted olefin.

FIG. 3 depicts the standard activity tests of the Ruthenium catalysts in RCM reactions to form a di-substituted olefin.

FIG. 4 depicts the standard activity tests of the Ruthenium catalysts in RCM reactions to form a tri-substituted olefin.

FIG. 5 depicts charts showing the standard activity tests of the Ruthenium catalysts in RCM reactions to form a di-substituted olefin and a tri-substituted olefin at 60° C.

FIG. 6 depicts charts showing the standard activity tests of the Ruthenium catalysts in RCM reactions to form a tetra-substituted olefin at different temperatures.

FIG. 7 depicts charts comparing the catalytic activity of compound H6 and H8 in RCM reactions to form a di-substituted olefin ( FIG. 7 a ), a tri-substituted olefin ( FIG. 7 b ) and a tetra-substituted olefin ( FIG. 7 c ).

FIG. 8 depicts the catalytic activity of the Ruthenium catalysts in Cross-Metathesis (CM) reactions.

FIG. 9 depicts the catalytic activity of the Ruthenium catalysts in Ring Opening Metathesis Polymerization (ROMP) reactions.

FIG. 10 depicts the initiation kinetics studies of the compound H6.

FIG. 11 depicts the catalytic activity of the Ruthenium catalysts in RCM reactions using low catalysts loadings.

FIG. 12 depicts the catalytic activity of the Ruthenium catalysts in RCM reactions using low catalysts loadings.

FIG. 13 depicts the X-Ray structural analysis of the compound H6.

1. Tri- and Tetra-Substituted Imidazolinium Salts

In the first embodiment, the invention relates to an imidazolinium salt NHC ligand precursor of formula (I):

The imidazolinium salts of the invention may be tetra-substituted or tri-substituted on the backbone of the NHC ligand—the adjacent ring carbons of the imidazole ring. The substituents are defined by R 1 , R 2 , R 3 and R 4 . As shown in the Scheme 1 below, restricting the N-aryl ring prevents the ruthenium complex comprising the NHC ligand from entering into the unwanted processes discussed above. The invention places bulky substituents, such as alkyl groups, on the backbone of the NHC ligands. In addition to the stabilization effect, the backbone substitution renders the NHCs more σ-donating than the non-substituted analogues, since it was conceivable that the direct backbone substitution would have greater influence on the donor ability of NHC than the substitution on the N-aryl groups.

For tetra-substituted imidazolinium salts of the invention, R 1 and R 4 are methyl; R 2 and R 3 are independently selected from methyl, ethyl, or allyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring; R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3; with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride: with the proviso that R 8 and R 9 are not C 1 -C 10 alkyl at the same time; and wherein R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 ; and X − is an anion for the imidazolinium salt.

For tri-substituted imidazolinium salts of the invention, R 1 is methyl; R 4 is H; R 2 and R 3 are independently selected from methyl, ethyl, allyl, or isopropyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring: with the proviso that R 2 and R 3 are not both isopropyl at the same time; R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3; with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride; wherein R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 ; and X − is an anion for the imidazolinium salt.

In preferred embodiments of these tri-substituted or tetra-substituted imidazolinium salts, R 2 and R 3 are methyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-membered carbocylic ring; and R 5 and R 6 are independently selected from the group consisting of isopropyl, tertbutyl, neopentyl, phenyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; and R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride: with the proviso that R 8 and R 9 of the tetra-substituted imidazolinium salts are not C 1 -C 10 alkyl at the same time. In even more preferred embodiments, R 2 and R 3 are methyl; R 5 and R 6 are independently selected from phenyl, mesityl, o-tolyl, m-tolyl, p-tolyl, o-difluorophenyl, o-dichlorophenyl or o-isopropylphenyl. For tetra-substituted imidazolinium salts, X − is preferably chloride, bromide, iodide, tetrafluoroborate (BF 4 ) or trifluoroacetate (CF 3 COO); for tri-substituted imidazolinium salts X − is preferably chloride, tetrafluoroborate (BF 4 ) or trifluoroacetate (CF 3 COO).

2. Preparation of Imidazolinium Salts

The tetra- or tri-substituted imidazolinium salts NHC ligand precursors of formulas (I) used to form the Ruthenium catalysts of the invention may be prepared from diamine derivatives bearing desired substituents and substitution pattern, as shown in the examples below. Typically, the diamine is dissolved in diethyl ether and treated with a solution of hydrogen chloride to precipitate the diamine hydrochloride salt. The diamine hydrochloride salt is reacted with large excess of triethyl orthoformate to give the desired imidazolinium chloride salts NHC ligand precursor of formula (I). Alternatively, the diamine compound can also form salt with trifluoroacetic acid or tetrafluoroborate acid, which is also reacted with large excess of triethyl orthoformate to give the desired imidazolidinium salts NHC ligand precursor of formula (I).

3. N-Heterocyclic Carbene (NHC) Ruthenium Catalysts of the Invention

The invention also relates to N-heterocyclic carbene (NHC) ruthenium olefin metathesis catalysts. Advantageously, the catalysts of the invention display greater efficiency/activity than current olefin metathesis catalysts for catalyzing ring-closing metathesis (RCM) reactions to form tetra-substituted cyclic olefins. The catalysts also perform the other known metathesis reactions in the family of metathesis reactions discussed above. The catalysts are also particularly useful in cross-metathesis to prepare tri-substituted olefins, and di-substituted olefins that are further substituted at the allylic carbon. The N-heterocyclic carbene (NHC) ruthenium olefin metathesis catalysts of the invention have the following general formula (III):

The NHC ligand in the ruthenium catalyst of formula (III) is derived from the imidazolinium salt NHC ligand precursor of formula (I) described above, with formula (IV):

For ruthenium catalyst derived from the tetra-substituted NHC ligand of the invention, R 1 and R 4 are methyl; R 2 and R 3 are independently selected from methyl, ethyl, or allyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring; R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3; with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride: with the proviso that R 8 and R 9 are not C 1 -C 10 alkyl at the same time; and wherein R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 .

For ruthenium catalyst derived from the tri-substituted NHC ligand of the invention, R 1 is methyl; R 4 is H; R 2 and R 3 are independently selected from methyl, ethyl, allyl, or isopropyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-, 7- or 8-membered carbocylic ring: with the proviso that R 2 and R 3 are not both isopropyl at the same time; R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3: with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride. R 2 and/or R 3 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 .

In preferred embodiments of the ruthenium catalyst derived from the tri-substituted or tetra-substituted NHC ligand of the invention, R 2 and R 3 are methyl, or R 2 and R 3 together with the carbons carrying them form a fused 6-membered carbocylic ring; and R 5 and R 6 are independently selected from the group consisting of isopropyl, tertbutyl, neopentyl, phenyl, or a group having the structure of formula (II):

wherein n ranges from 1 to 3; R 7 is methyl, fluoride or chloride; and R 8 and R 9 are independently selected from hydrogen, C 1 -C 10 alkyl, fluoride or chloride: with the proviso that R 8 and R 9 of the tetra-substituted imidazolinium salts are not C 1 -C 10 alkyl at the same time. In even more preferred embodiments, R 2 and R 3 are methyl; and R 5 and R 6 are independently selected from phenyl, mesityl, o-tolyl, m-tolyl, p-tolyl, o-difluorophenyl, o-dichlorophenyl or o-isopropylphenyl.

One embodiment of the NHC ligand in the ruthenium catalyst of formula (III) of the invention includes the ruthenium catalyst derived from the gem di-substituted N-heterocyclic carbene (NHC) ligand of formula (IV):

wherein R 1 and R 2 are C 1 -C 10 alkyl, or together form a cyclic structure; R 3 and R 4 are H; R 5 and R 6 are each independently a C 1 -C 10 alkyl, cycloalkyl, a fused or bridged ring, aralkyl, or a group having the structure of formula (II):

wherein, n ranges from 1 to 3: with the proviso that only one of R 5 or R 6 may be a linear alkyl group having 3 or less carbons; R 7 is independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, aryl, aralkyl, and one or more functional groups; R 8 and R 9 are hydrogen, C 1 -C 10 alkyl, fluoride or chloride. R 1 and/or R 2 may form a cyclic structure with one or both of R 5 and R 6 , or through one or more links with at least one of R 7 , R 8 and R 9 .

In the catalysts of formula (III), X 1 and X 2 are independently anionic ligands. Preferably, X 1 and X 2 are halide, or one of the following groups: C 1 -C 20 alkyl, aryl, C 1 -C 20 alkoxide, aryloxide, C 3 -C 20 alkyldiketonate, aryldiketonate, C 1 -C 20 carboxylate, arylsulfonate, C 1 -C 20 alkylsulfonate, C 1 -C 20 alkylthio, C 1 -C 20 alkylsulfonyl, or C 1 -C 20 alkylsulfinyl. Optionally, X 1 and X 2 may be substituted with one or more moieties selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 alkoxy, and aryl which in turn may each be further substituted with one or more groups selected from halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, and phenyl. In more preferred embodiments, X 1 and X 2 are halide, benzoate, C 1 -C 5 carboxylate, C 1 -C 5 alkyl, phenoxy, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, aryl, and C 1 -C 5 alkyl sulfonate. As discussed below, the other ligands in a catalyst of the invention, when substituted, may also contain such substituents. In even more preferred embodiments, X 1 and X 2 are each halide, CF 3 CO 2 , CH 3 , CO 2 , CFH 2 CO 2 , (CH 3 ) 3 CO, (CF 3 ) 2 (CH 3 )CO, (CF 3 )(CH 3 ) 2 CO, PhO, MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate. In the most preferred embodiments, X 1 and X 2 are each chloride.

R 10 and R 11 are each independently hydrogen or a substituted or unsubstituted group selected from the group consisting of C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, C 1 -C 20 carboxylate, C 1 -C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, C 1 -C 20 alkylthio, C 1 -C 20 20 alkylsulfonyl and C 1 -C 20 alkylsulfinyl. Optionally, each of the R 10 or R 11 substituent group may be substituted with one or more moieties selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 alkoxy, and aryl which in turn may each be further substituted with one or more groups selected from a halogen, a C 1 -C 5 alkyl, C 1 -C 15 alkoxy, and phenyl. Moreover, R 10 and R 11 , as well as any other of the catalyst ligands, may further include one or more functional groups as long as they do not defeat the activity of the catalyst. Examples of suitable functional groups include but are not limited to: hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen. R 10 and R 11 may optionally be linked together to form a cyclic structure via one of the substituents mentioned above.

In preferred embodiments of these catalysts, the R 10 substituent is hydrogen, C 1 -C 5 alkyl or aryl and the R 11 substituent is selected from the group consisting of C 1 -C 20 alkyl, C 2 -C 20 alkenyl, and aryl. In even more preferred embodiments, the R 11 substituent is phenyl or vinyl, optionally substituted with one or more moieties selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 alkoxy, phenyl, and a functional group. In especially preferred embodiments, R 11 is phenyl or vinyl substituted with one or more moieties selected from the group consisting of chloride, bromide, iodide, fluoride, —NO 2 , —NMe 2 , methyl, methoxy and phenyl. In the most preferred embodiments, the R 11 substituent is phenyl or —CH═C(CH 3 ) 2 .

L may be any neutral 2-electron donor ligand known in the art. The variable “m” defines the number of neutral donor ligands, L. The variable “m” is 1 or 2 and preferably 1. When “m” is 1, L is any neutral 2-electron donor ligand. L may be linked to R 11 forming a chelating arbine ligand. When “m” is 2, L is a heteroarene ligand such as pyridine or substituted pyridine. See U.S. Pat. Nos. 6,759,537 and 6,818,586, herein incorporated by reference in their entirety; for examples of suitable heteroarene ligands. Preferably, the heteroarene ligand is pyridine or substituted pyridine.

In a preferred embodiment, L is selected from the group consisting of phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, imine, sulfoxide, carboxyl, nitrosyl, pyridine, and thioether. In more preferred embodiments, L is a phosphine of the formula PR′R″R′″, where R′, R″, and R′″ are each independently aryl; C 1 -C 10 alkyl (in particular, a primary or secondary alkyl); or C 3 -C 6 cycloalkyl. In the most preferred embodiments, L is selected from the group consisting of P(cyclohexyl) 3 , P(cyclopentyl) 3 , P(isopropyl) 3 , and P(phenyl) 3 .

In a preferred embodiment, L may be linked to R 11 forming a chelating arbine ligand. The L portion of the chelating arbine ligand is still a 2-electron donor ligand when linked to R 11 . L may or may not be linked to R 11 through a spacer moiety. U.S. Pat. No. 6,921,735 describes chelating arbine ligands and is incorporated herein by reference for examples of how the ligand and R substituent on the arbine can be linked through various spacer moieties. The spacer moiety may be substituted or unsubstituted.

Preferred catalysts of the invention where L and R 11 are linked include those represented by formula (V):

In formula (V), NHC is an N-heterocyclic carbene (NHC) ligand of formula (IV). Y is a heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus. X 1 and X 2 are independently anionic ligands. Z is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, functionalized alkyl, or functionalized aryl, wherein the functional group(s) may independently be selected from alkoxy, aryloxy, halogen, carbonyl, carboxylic acid, ketone, aldehyde, nitrate, nitrile, nitro, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide, sulfonyl, sulfinyl, disulfide, sulfonate, carbamate, silane, siloxane, phosphine, phosphate, borate, or combinations thereof; each optionally substituted with an alkyl, halogen, alkoxy, aryl, aryloxy, or heteroaryl moiety. R d , R b , R c , and R d are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, functionalized alkyl, or functionalized aryl, wherein the functional group(s) may independently be selected from alkoxy, aryloxy, halogen, carbonyl, carboxylic acid, ketone, aldehyde, nitrate, nitrile, nitro, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide, sulfonyl, sulfinyl, disulfide, sulfonate, carbamate, silane, siloxane, phosphine, phosphate, borate, or combinations thereof; each optionally substituted with an alkyl, halogen, alkoxy, aryl, aryloxy, or heteroaryl moiety, wherein any two or more of R a , R b , R c , and R d may be independently linked through hydrocarbon or functionalized hydrocarbon groups forming an aliphatic or aromatic ring.

Preferred catalysts of the invention where L and R 11 are linked may also include the following:

Examples of ruthenium complexes with chelating arbine ligands, ligands linking the L ligand and the R 11 substitutent, are also described in Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791 and Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. Preferably, R 11 is linked to L via spacer group being 2-5 atoms in length between L and R 11 , for example via an alkyl group, a cycloloalkyl group, or an aryl group. A preferred spacer group is a substituted or unsubstituted phenyl group.

4. Synthesis of Catalysts

The ruthenium catalysts of the invention may be prepared using methods known in the art. In general, the catalysts of the present invention are prepared via a ligand exchange reaction, for example, by substituting an NHC ligand for one of the neutral electron donor ligands in a first generation ruthenium carbene complexes (discussed above). For example, a Ruthenium Phosphine complex of the invention can be prepared by replacing a phosphine ligand in a complex of the general formula (PCy 3 ) 2 (X) 2 Ru═CHC 6 H 5 with an NHC ligand described above. Example 2 illustrates preparation of ruthenium catalysts of the invention by this method. Ruthenium Ether complex of the invention can be prepared by replacing a phosphine ligand in a complex of the general formula (PCy 3 )(X) 2 Ru═CH-o-iPrC 6 H 5 with an NHC ligand described above. Examples 3, 6 illustrate preparation of ruthenium catalysts of the invention by this method. As discussed in the Background of the Invention, these synthetic procedures are known in the art.

5. Metathesis Reactions

The ruthenium catalysts of the invention are particularly efficient olefin metathesis catalysts. Accordingly, one embodiment of the invention is an olefin metathesis reaction which contacts an olefin with an N-heterocyclic carbene (NHC) ruthenium olefin metathesis catalyst of the invention under metathesis conditions. The catalysts of the invention may be used in, for example, ring-closing metathesis (RCM), cross metathesis (CM), self metathesis (which is a type of cross metathesis), ring-opening metathesis polymerization (ROMP), and acyclic diene metathesis polymerization (ADMET).

The metathesis conditions for the catalysts of the invention are the same as those used in other olefin metathesis reactions and with other known olefin metathesis catalysts. Generally speaking, the olefin metathesis reactions are run at a temperature ranging from about 10° C. to about 70° C. and for a time period ranging from about 5 minutes to about 24 hours. The catalysts of the invention may be used in the same amounts as know for other olefin metathesis catalysts. Typically, about 1 to about 10 mol % of the catalyst is used and more often about 1 to 5 mol %.

The ruthenium catalysts of the invention are particularly useful in metathesis reactions for the production of tetra-substituted cyclic olefins. The catalysts of the invention have significantly increased efficiency/activity for the preparation of tetra-substituted cyclic olefins via olefin metathesis.

General Experimental Conditions for Examples 1-8

All reactions involving metal complexes were conducted in oven-dried glassware under a nitrogen atmosphere with anhydrous solvents, using standard Schlenk and glovebox techniques. Anhydrous solvents were obtained via elution through a solvent column drying system. (See Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518-1520.) RuCl 2 (PCy 3 ) 2 (═CHC 6 H 5 ) was obtained from Materia, Inc. Silica gel used for the purification of organometallic complexes was obtained from TSI Scientific, Cambridge, Mass. (60 Å, pH 6.5-7.0). NMR chemical shifts are reported in ppm downfield from Me 4 Si, by using the residual solvent peak as internal standard for 1 H and 13 C, and H 3 PO 4 (δ 0.0) for 31 P. Data for NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz) and integration. IR spectra were recorded on a Perkin-Elmer Paragon 1000 Spectrophotometer. Gas chromatography data was obtained using an Agilent 6850 FID gas chromatograph equipped with a DB-Wax Polyethylene Glycol capillary column (J&W Scientific). X-ray crystallographic structures were obtained by the Beckman Institute X-ray Crystallography Laboratory of the California Institute of Technology. Unless otherwise stated, the screening of the catalysts, in ring-closing metathesis (RCM), cross metathesis (CM), and ring-opening metathesis polymerization reactions (ROMP), was conducted according to literature procedures. (see Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. Organometallics 2006, 25, 5740-5745.) The initiation kinetics studies were conducted according to literature procedures. (see Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543-6554.)