WO2010085638A1

WO2010085638A1 - Olefin metathesis catalytic system

Info

Publication number: WO2010085638A1
Application number: PCT/US2010/021794
Authority: WO
Inventors: Peng Wang; Mathew Michael Yanik
Original assignee: Phenomix Corporation
Priority date: 2009-01-26
Filing date: 2010-01-22
Publication date: 2010-07-29

Abstract

The invention provides new, more effective olefin metathesis catalytic systems and catalysts, suitable for catalyzing olefin metathesis reactions. Addition of imidazolium ions to ruthenium-based olefin metathesis catalysts results in higher yields and greater purities of products. The catalysts are useful for the formation of macrocyclic products. Methods are provided for using the catalysts, such as in formation of a key intermediate in the synthesis of a macrocyclic hepatitis C virus protease inhibitor.

Description

OLEFIN METATHESIS CATALYTIC SYSTEM

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. Serial No. 61/205,944, filed Jan. 26, 2009, which is incorporated by reference herein in its entirety.

BACKGROUND

As was first discovered, olefin metathesis catalysts can catalyze a cross- reaction between two olefins, exchanging olefinic pairs such that A=B + D=E — * A=D + B=E or A=E + B=D in the presence of the catalyst. In 2005, Robert H. Grubbs, Richard R. Schrock and Yves Chauvin won the Nobel Prize in Chemistry for the development of olefin metathesis catalysts.

A number of olefin metathesis reactions have since been elucidated, not all of them restricted to olefins having double bonds, as some involve alkynes having triple bonds as well. However, a unifying feature of what are termed olefin metathesis reactions herein is the breaking of existing unsaturated bonds and the formation of new unsaturated bonds. It is believed that these reactions proceed via alkylidene species bound to the metal center, ruthenium in the present series of catalysts.

Among the types of olefin metathesis reactions now known, there are ring-opening metathesis, ring-opening polymerization metathesis (ROMP), 1- alkyne polymerization, cyclopolymerication, acyclic diene metathesis (ADMET), cross-metathesis, tandem metathesis, enyne metathesis including enyne ring closing metathesis, acyclic diene ring closing metathesis, and ring- opening metathesis. See Michael R. Bushmeiser, Chemical Reviews, Web publication 10.1021/cr800207n American Chemical Society , Nov. 4, 2008.

Olefin metathesis catalysts can be used in the forming of a macrocyclic product from an acyclic precursor, in a ring closing metathesis (RCM) reaction. As macrocyclic rings are otherwise difficult to form synthetically, these metathesis reactions have been found to be of great value in preparing these types of structures. For example, see U.S. Pat. No. 5,936,100 (issued Aug. 10, 1999).

One catalyst that can be used in RCM synthetic conversions is the Hoveyda-Grubbs 2^nd generation catalyst, (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium; see for example U.S. Pat. No. 6,921,735 (issued July 26, 2005). The structure of this catalyst is:

(I)

Another catalyst that can be used in RCM reactions is known as Zhan Catalyst- IB, see for example http://www.zannanpharma.com/Zannan/Zannan/Zhan%20Catalysts%20&%20M etathesis.pdf. The Zhan Catalyst- IB is further described in published patent applications US2007/0043180 and WO2007/003135. The structure of Zhan Catalyst- IB is:

(II).

The Zhan Catalyst- IB is reported to have a higher activity and to produce a greater yield in certain RCM reactions than does Hoveyda-Grubbs 2^nd generation catalyst. Nevertheless, there is a need for improved olefin metathesis catalysts, such as for RCM reactions in producing macrocyclic compounds.

For example, macrocyclic inhibitors of the Hepatitis C virus are known, so efficient synthesis routes to this class of compounds are desired. Hepatitis C virus ("HCV") is the causative agent for hepatitis C, a chronic infection characterized by jaundice, fatigue, abdominal pain, loss of appetite, nausea, and darkening of the urine. HCV, belonging to the hepacivirus genus of the Flaviviriae family, is an enveloped, single-stranded positive-sense RNA- containing virus. The long-term effects of hepatitis C infection as a percentage of infected subjects include chronic infection (55-85%), chronic liver disease (70%), and death (1-5%). Furthermore, HCV is the leading indication for liver transplant. In chronic infection, there usually presents progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma.

The NS3 (i.e., non-structural protein 3) protein of HCV exhibits serine protease activity, the N-terminus of which is produced by the action of a NS2- NS3 metal-dependent protease, and the C-terminus of which is produced by auto-pro teoly sis. The HCV NS3 serine protease and its associated cofactor, NS4a, process all of the other non-structural viral proteins of HCV. Accordingly, the HCV NS3 protease is essential for viral replication.

Several compounds have been shown to inhibit the hepatitis C serine protease (HCV protease), but all of these have limitations in relation to the potency, stability, selectivity, toxicity, and/or pharmacodynamic properties. Such compounds have been disclosed, for example, in published U.S. Patent Application Nos. 2004/0266731, 2002/0032175, 2005/0137139, 2005/0119189, and 2004/0077600A1, and in published PCT patent applications WO 2005/037214 and WO 2005/035525.

A series of macrocyclic inhibitors of the HCV protease enzyme have been prepared and characterized chemically and biologically, as described in published patent applications WO2008/070733 and WO2008/086161, and in applications incorporated by reference therein, as well as in U.S. Ser. Nos. 61/028,941, 61/088,585, 61/060,876, 61/088934, and 61/097,414. Certain of these macrocyclic inhibitors have been prepared using a ring closing metathesis (RCM) step, as described in the above-cited patent applications.

SUMMARY

The present invention is directed to an olefin metathesis catalytic system with improved properties compared to other ruthenium-based olefin metathesis catalysts, to methods of preparation, and methods of use, of the catalytic system.

In various embodiments, the invention provides olefin metathesis catalytic systems comprising a ruthenium-based metathesis catalyst and an imidazolium ion in a solvent, adapted for catalyzing an olefin metathesis reaction. For example, the ruthenium-based metathesis catalyst can be a Grubbs first generation catalyst, a Grubbs second generation catalyst, a Hoveyda-Grubbs first generation catalyst, a Hoveyda-Grubbs second generation catalyst or a Zhan catalyst. The inventors herein have unexpectedly discovered that addition of imidazolium ions in various forms to reaction mixtures containing olefinic substrates and a ruthenium-based metathesis catalysts such as one of the above can provide both improved yields and diminished proportions of byproducts in olefin metathesis reactions. For example, ring closing metathesis reactions forming macrocyclic products from acyclic precursors can be carried out using the inventive catalytic systems.

In various embodiments, a purified or isolated reaction product of a ruthenium-based olefin metathesis catalyst and an imidazolium ion is provided.

In various embodiments, methods of forming a catalytic system of the invention are provided.

In various embodiments, methods of carrying out olefin metathesis reactions using a catalytic system of the invention, or a catalytic system prepared by a method of the invention, or a reaction product of the invention, are provided.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows a graph of the time course of the conversion of the compound of formula (IX) to a mixture of the compounds of formula (XZ) and formula (XE) using four catalysts of the invention in comparison with two art catalysts. The dark blue diamonds and the aquamarine Xs represent the percent conversion versus time using the art catalyst compounds of formula (I) (HG-II) and of formula (II) (Zhan Catalyst- IB) respectively. The mauve stars represent the reaction course using HG-II in combination with the trifluoromethanesulfonic acid (triflate) salt of imidazole, the brown circles using HG-II in combination with the trifluoroacetic acid (TFA) salt of imidazole; the yellow triangles using Zhan Catalyst- IB in combination with the triflate salt of imidazole; and the reddish squares using Zhan Catalyst- IB in combination with the TFA salt of imidazole; under conditions described in the specification.

Figure 2 shows a graph of the time course of the conversion of the compound of formula (IX) to a mixture of the compounds of formula (XZ) and formula (XE) using Zhan Catalyst- IB in combination with imidazole tosylate (triangles), imidazole trifluoroacetate (diamonds), and imidazole acetate (squares) under the reaction conditions shown.

Fig. 3 shows a graph of the time course of the conversion of the compound of formula (IX) to a mixture of the compounds of formula (XZ) and formula (XE) using Zhan Catalyst- IB in combination with imidazole tosylate (triangles), imidazole trifluoroacetate (diamonds), imidazole triflate (Xs), and imidazole acetate (squares) under the reaction conditions shown.

Fig. 4 shows a graph of a percent conversion of the compound of formula (IX) to a mixture of the compounds of formula (XZ) and formula (XE) using Zhan Catalyst- IB in combination with imidazole trifluoroacetate at various molar ratios of the imidazole trifluoroacetate relative to the Zhan Catalyst- IB.

Fig. 5 shows the E/Z ratio of the compound of formula (XE) to the compound of formula (XZ) produced using the indicated catalysts of the invention HG-II / imidazole triflate, HG-II / imidazole trifluoroacetate, Zhan / imidazole triflate, and Zhan / imidazole trifluoroacetate, over a range of catalyst concentrations.

DETAILED DESCRIPTION OF THE INVENTION

All chiral, diastereomeric, racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.

By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.

When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other by a chemically feasible bonding configuration.

In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboyxlate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR', OC(O)N(R')₂, CN, CF₃, OCF₃, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')₂, SR', SOR, SO₂R, SO₂N(R)₂, SO₃R, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R, C(S)R', C(O)OR, OC(O)R, C(O)N(R)₂, 0C(0)N(R')₂, C(S)N(R')₂, (CH₂V₂NHC(O)R, N(R)N(R)C(O)R, N(R')N(R')C(0)0R', N(R')N(R')C0N(R)₂, N(R')S0₂R', N(R)SO₂N(R)₂, N(R')C(0)0R', N(R')C(O)R', N(R')C(S)R, N(R)C(0)N(R')₂, N(R')C(S)N(R)₂, N(COR)COR', N(0R')R, C(=NH)N(R')₂, C(O)N(OR)R', or C(=N0R)R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=O, wherein the C and the O are double bonded. Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(O)₂ can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH₂)_n or (CRy_n wherein n is 1, 2, 3, or more, and each R' is independently selected.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.

By a "ring system" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyclic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.

Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec -butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include poly cyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N-I substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃),

-C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃), and -CH₂C≡C(CH₂CH₃) among others.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Heterocyclyl groups include aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C₂-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5- ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group designated as a C₂-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroaryl can be a 5 -ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2 -pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2- thiazolyl, 4-thiazolyl, 5 -thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6- isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro- benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro- benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b] thiophenyl, 3 -benzo[b] thiophenyl, 4-benzo[b]thiophenyl, 5 -benzo [b] thiopheny 1, 6-benzo [b] thiopheny 1, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3- dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7 -(2,3- dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2- benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine- 5-yl), 10,l l-dihydro-5H-dibenz[b,f]azepine (10,l l-dihydro-5H- dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11- dihydro-5H-dibenz[b,f]azepine-3-yl, 10,l l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydro furan-2-yl ethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.

The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein.

"Halo" as the term is used herein includes fluoro, chloro, bromo, and iodo. A "haloalkyl" group includes mono-halo alkyl groups, and poly-halo alkyl groups wherein all halo atoms can be the same or different. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3- dibromo-3,3-difluoropropyl and the like.

The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moeity. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.

An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3 -carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)₃ wherein each group can independently be H or non-H, such as alkyl, alkenyl, or alkynyl as defined herein, cycloalkyl or heterocyclyl as defined herein, aryl or heteroaryl as defined herein,, and the like. Amines include but are not limited to R-NH₂, for example, alkylamines, arylamines, alkylarylamines; R₂NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

An "amino" group is a substituent of the form -NH₂, -NHR, -NR₂, -NR3⁺, wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.

An "ammonium" ion includes the unsubstituted ammonium ion NH₄ ⁺, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR₂, and -NRC(O)R groups, respectively. Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH₂) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term "urethane" (or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR₂ groups, respectively.

The term "sulfonamide" (or "sulfonamido") includes S- and N- sulfonamide groups, i.e., -SO₂NR₂ and -NRSO₂R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO₂NH₂). An organosulfur structure represented by the formula -S(O)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.

The term "amidine" or "amidino" includes groups of the formula -C(NR)NR₂. Typically, an amidino group is -C(NH)NH₂.

The term "guanidine" or "guanidino" includes groups of the formula -NRC(NR)NR₂. Typically, a guanidino group is -NHC(NH)NH₂.

A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH₄ ⁺ or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein.

As the term is used herein, a "ruthenium-based" metathesis catalyst refers to a catalyst that is structurally a complex of the transition metal ruthenium, such as Grubbs, Hoveyda-Grubbs, and Zhan catalysts are.

An "imidazolium ion" is a cationic species, with any of a variety of counterions, wherein the imidazole ring bears a positive charge. An imidazolium ion can be a protonated imidazole, such as results from contacting an imidazole with an acid of sufficient strength to protonate the imidazole ring. An imidazole, within the meaning herein, is a five-membered heterocyclic ring containing two nitrogen atoms in a 1,3-orientation. The ring can bear substituents, such as alkyl groups, on carbon atoms or on nitrogen atoms, or both. The imidazole can be protonated by a strong acid or by a weak acid, as the pKa of the parent compound imidazole is about 6.9. Accordingly, a weak acid such as acetic acid, pKa of about 5, will protonate imidazole, as will a strong acid such as trifluoroacetic acid with a pKa of about 0.5.

As the term is used herein, a "strong acid" is an acidic material with a pKa substantially lower, i.e., more acidic, than about 3. The pKa of acetic acid is about 5, and a strong acid is more acidic, more readily ionized to provide a proton and the conjugate base of the acid, than is acetic acid. Examples of strong acids include sulfonic acids such as p-toluenesulfonic acid (tosic acid) and trifluoromethanesulfonic acid (triflic acid), trifluoracetic acid (TFA), and mineral acids such as HCl, H₂SO₄, and H3PO₄, all of which have pKa values of less than about 3. An imidazole salt of a strong acid refers to a protonated form of imidazole wherein the counterion is a weak base. It is the product of combination of the free base form of imidazole and the strong acid. The trifluoroacetic acid salt of imidazole is also known as imidazole trifluoroacetate; the triflic acid salt of imidazole as imidazole triflate, the tosic acid salt of imidazole as imidazole tosylate, the acetic acid salt of imidazole as imidazole acetate; as is well-known in the art. Specific examples of imidazole salts of strong acids as used herein include imidazole tosylate, imidazole triflate, and imidazole trifluoroacetate. Imidazole can also form salts with weaker acids, such as acetic acid, as is well known in the art.

The term "imidazolium ion" also includes quaternarized imidazole, that is, structures wherein the imidazole ring bears a cationic nitrogen atom as a result of alkylation of a ring nitrogen atom. For example, 1,3- dimethylimidazolium ion is an example of an imidazolium ion within the meaning here.

In both instances of imidazolium ions, i.e., protonated and alkylated imidazoles, a counterion is present. Examples include inorganic anions such as halides, sulfate, phosphate, and the like, as well as organic anions such as trifluoroacetate, tosylate, trifluoromethanesulfonate ("triflate") and the like. In the catalytic system of the invention, any anion that does not interfere with the catalytic efficacy of the combination of the ruthenium-based metathesis catalyst and imidazolium ion can be used.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.

In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.

In various embodiments, the invention provides an olefin metathesis catalytic system comprising a ruthenium-based metathesis catalyst and an imidazolium ion in a solvent, adapted for catalyzing an olefin metathesis reaction. For example, the ruthenium-based metathesis catalyst can be a Grubbs first generation catalyst, a Grubbs second generation catalyst, a Hoveyda-Grubbs first generation catalyst, a Hoveyda-Grubbs second generation catalyst or a Zhan catalyst. Or, the ruthenium-based metathesis catalyst can be a polymer-bound immobilized metathesis catalyst. An example is Zhan Catalyst-II, a polymer- bound analog of Zhan Catalyst-IC or Zhan Catalyst- IB; see: http://www.zannanpharma.com/Zannan/Zannan/Zhan%20Catalysts%20&%20M etathesis.pdf.

For example, the imidazolium ion can be an imidazole salt of an acid. More specifically, the acid can be a strong acid, such as p-toluenesulfonic (tosic) acid, trifluoroacetic acid, or trifluoromethanesulfonic (triflic) acid.

In various other embodiments, the imidazolium ion can be a quaterarized imidazole, such as an N-(Ci-Ci₂)-alkyl-imidazolium ion. More specifically, the imidazolium ion can be an N-methyl, N-ethyl, or N-benzyl imidazolium ion.

In various embodiments, at least about one molar equivalent of the imidazolium ion is present, or at least about two molar equivalents of the imidazolium ion are present, relative to the ruthenium-based metathesis catalyst. In various embodiments no more than about sixteen molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst. In various embodiments about two molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst. In various embodiments, the ruthenium-based catalyst comprises a compound of formula (I):

(I, Hoveyda-Grubbs second generation catalyst) or a compound of formula (II):

(II, Zhan Catalyst- IB).

The compound of formula (I) is generally known as Hoveyda-Grubbs second generation catalyst, and the compound of formula (II) is generally known as Zhan Catalyst- IB.

In various embodiments, the inventive catalytic system can be adapted to catalyze a ring closing metathesis reaction, such as are shown in the Examples, below.

In various embodiments, the solvent can comprise an organic solvent. More specifically, the organic solvent can comprise isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof. For example, the inventive catalytic system can be formed at a concentration of less than about 0.1 M of the ruthenium-based catalyst in the organic solvent.

In various embodiments, the solvent can comprise an ionic liquid, as are well known in the art. For example, the ionic liquid can comprise a l-butyl-3- methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof. It is well known that ionic liquids can dissolve a wide range of substrates. An ionic liquid used as a solvent or a component thereof can also serve as a source of the imidazolium ion herein; for instance the above-listed l-butyl-3-methylimidazolium with a counterion is both an ionic liquid and an imidazolium ion. For example, the inventive catalytic system can be formed at a concentration of less than about 0.1 M of the ruthenium-based catalyst in the ionic liquid solvent

In various embodiments, with either organic solvent or ionic liquid solvent, the catalytic system can be formed at a temperature of at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

In various embodiments, the invention provides a reaction product of a ruthenium-based olefin metathesis catalyst and an imidazolium ion in a solvent, wherein the reaction product is adapted for catalyzing an olefin metathesis reaction. In various embodiments, the reaction product can be formed under any of the conditions discussed above for the catalytic system. Without wishing to be bound by theory, the inventors herein believe that the catalytic system of the invention incorporates a reaction product of the ruthenium-basis metathesis catalyst and the imidazolium ion formed under the range of conditions described herein.

In various embodiment, a reaction product of the invention can be formed by contacting a ruthenium-based metathesis catalyst such as Hoveyda- Grubbs type II (HG-II) (the compound of formula (I) shown below) or Zhan Catalyst- IB (Zhan) (the compound of formula (II) shown below) olefin metathesis catalysts

(I) or

(H) with an imidazolium salt in a solvent.

In various embodiments, the imidazolium ion can be an imidazole salt of a strong acid, such as imidazole tosylate, imidazole triflate, or imidazole trifluoroacetate, or any combination thereof.

For example, at least about one molar equivalent of the imidazole salt can be present, or at least about two molar equivalents of the imidazole salt can be present relative to the compound of formula (I), HG-II, or the compound of formula (II), Zhan Catalyst- IB. Or, no more than about sixteen molar equivalents of the imidazole salt are present. In various embodiments, about two molar equivalents of the imidazole salt are present.

The inventive catalytically-active reaction product can be formed in an organic solvent. More specifically, the organic solvent can comprise isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof. The catalytic system can be formed in the organic solvent at a concentration of less than about 0.1 M of the compound of formula (I) or formula (II) respectively, with about 1 to about 8 equivalents of the imidazole salt. Preferably about 1 -3 equivalents of the imidazole salt are present in solution. The catalytic system can be formed at a temperature of at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

Or, the catalytically-active reaction product can be formed in an ionic liquid solvent. Examples of ionic liquids, which are known in the art to dissolve a wide range of organic compounds, include l-butyl-3-methylimidazolium, 1- alkylpyridinium, N-methyl-N-allkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof. It has been surprisingly found by the inventors herein that such catalytic systems or reaction products of the invention provide higher yields and fewer byproducts in certain metathesis reactions, such as ring-closing metathesis reactions, compared to use of the ruthenium-based metathesis catalyzed reactions in the absence of the imidazolium ions. For example, HG-II and Zhan catalysts in combination with imidazolium ions have unexpectedly been found to provide more effective catalysis, with a lower percentage of the impurities derived from loss of a carbon atom or of two carbon atoms from the newly formed macrocyclic ring being formed.

It is believed that the imidazole salts react with the ruthenium-based metathesis catalyst, such as the HG-II catalyst and the Zhan Catalyst- IB, to produce new molecular species. A possible structure for the new catalyst species that may be formed in situ may include a ruthenium complex wherein one or more imidazolium groups displace one or more ligands of the ruthenium in the starting structures to provide discrete molecular species.

In various embodiments, a reaction product of the invention can be purified or isolated or both, by techniques well known in the art for purification of organometallic compounds.

In various embodiments, the inventive catalytic system or reaction product is adapted for catalyzing a ring-closing metathesis reaction.

In various embodiments, the inventive catalytic system or reaction product is adapted for catalyzing a ring-opening metathesis reaction.

In various embodiments, the inventive catalytic system or reaction product is adapted for catalyzing a ring-opening polymerization metathesis reaction.

In various embodiments, the inventive catalytic system or reaction product is adapted for catalyzing a 1-alkyne polymerization metathesis reaction.

In various embodiments, the inventive catalytic system or reaction product is adapted for catalyzing a cross metathesis reaction.

Various embodiments of the invention provide a method of forming the inventive catalytic system, the method comprising contacting ruthenium-based olefin metathesis catalyst and the imidazolium ion in a suitable solvent, at a temperature, and for a duration of time sufficient to bring about formation of the catalytic system. For example, the temperature at which the catalytic system is formed can be at least about 50⁰C, or at least about 65°C, or at least about 80⁰C. For example, the period of time that can be employed for formation of the catalytic system can be about 1 to about 3 hours.

In various embodiments, as discussed above, the imidazolium ion can be an imidazolium salt of an acid. For example, the acid can be a strong acid. More specifically, the acid can be trifluoroacetic acid, tosic acid, or triflic acid.

In various embodiments, as discussed above, the imidazolium ion can be a quaternarized imidazolium, such as an N-alkylimidazolium. More specifically, the N-alkylimidazolium can be an N-(Ci-Ci₂)alkylimidazolium, such as an N- methyl- or N-ethylimidazolium. Alternatively, the quaternarized imidazolium can be an N-aralkylimidazolium, such as an N-benzylimidazolium.

In various embodiments, the catalytic system can be formed in a solvent wherein the solvent comprises an organic solvent. For example, the organic solvent can comprise isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof.

Or, in various embodiments, the catalytic system can be formed in a solvent wherein the solvent comprises an ionic liquid. For example, the ionic liquid can comprise a l-butyl-3-methylimidazolium, 1 -alkylpyridinium, N- methyl-N-allkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof.

In various embodiments, the catalytic system can be formed in a solvent wherein a concentration of the ruthenium-based catalyst is less than about 0.1 M in the solvent.

In various embodiments, the invention provides a method for carrying out an olefin metathesis reaction comprising contacting a suitable amount of a catalytic system of the invention, or of a reaction product of the invention, or of an inventive catalytic system prepared by a method of the invention; and a first unsaturated compound, and, optionally, a second unsaturated compound, in a solvent, at a temperature, and for a duration of time sufficient to produce a third unsaturated compound.

For example, the olefin metathesis reaction can be a ring-closing metathesis reaction, a ring-opening metathesis reaction, a ring-opening polymerization metathesis reaction, a 1-alkyne polymerization reaction, or a cross-metathesis reaction, as are all well known in the art. In various embodiments, the invention provides a method for carrying out a ring closing metathesis reaction, comprising contacting a precursor di- olefin of formula (III)

(III) wherein L comprises a linking moiety, and a suitable amount of the catalytic system of the invention, or of the reaction product of the invention, in a solvent, at a temperature, and for a duration of time sufficient to produce a cyclic product of formula (IV)

(IV).

For example, the solvent can comprise an organic solvent such as isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof. Or, the solvent can comprise an ionic liquid solvent such as l-butyl-3-methylimidazolium, 1-alkylpyridinium, N- methyl-N-allkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof. A suitable temperature can be, for example, at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C. A suitable period of time can be, for example, about 1 to about 3 hours.

In various embodiments, the catalytic system or the reaction product of the invention is present in less than about 5 mole percent relative to an amount of the compound of formula (III) initially present. Or, the catalytic system or the reaction product is present in less than about 2 mole percent relative to an amount of the compound of formula (III) initially present, or the catalytic system or the reaction product is present in less than about 1 mole percent relative to an amount of the compound of formula (III) initially present. In various embodiments, the compound of formula (III) comprises a compound of formula (VII)

(VII), wherein R comprises, H, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, or two R groups taken together form together with a nitrogen atom to which they are attached form a heterocyclyl ring that can unsubstituted or substituted, or fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; PR comprises a nitrogen protecting group; each PR' independently comprises an oxygen protecting group or taken together with the oxygen atoms to which they are attached and a boron atom to which the oxygen atoms are both attached together form a cyclic boronate ester; m is 0 to about 4; and n is 0 to about 8. In various embodiments, the compound of formula (VII) comprises a compound of formula (IX)

(IX). In various embodiments, the compound of formula (IV) comprises a compound of formula (VIIIE)

E

(VIIIE) or a compound of formula (VIIIZ),

or a mixture of the compound of formula (VIIIE) and the compound of formula (VIIIZ); wherein R comprises, H, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, or two R groups taken together form together with a nitrogen atom to which they are attached form a heterocyclyl ring that can unsubstituted or substituted, or fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; PR comprises a nitrogen protecting group; each PR' independently comprises an oxygen protecting group or taken together with the oxygen atoms to which they are attached and a boron atom to which the oxygen atoms are both attached form a cyclic boronate ester; m is 0 to about 4; and n is 0 to about 8. In various embodiments, the compound of formula (VIII) comprises a compound of formula (XZ)

(XZ) or a compound of formula (XE)

(XE) or a mixture thereof.

In various embodiments of the method of the invention, the compound of formula (IV) is provided in a greater proportion of the total reaction product with respect of a compound of formula (V)

(V) or a compound of formula (VI)

(VI), or both, using a catalyst or a reaction product of the invention, compared to when an equivalent amount of a catalyst of formula (I) or formula (II) is used in the absence of the imidazole salt of a strong acid. The compounds of formula (V), fore example, are believed to be derived from an olefin isomerization reaction that takes place prior to ring closure, for example as shown below:

In various embodiments of the method of the invention, the compound of formula (IV) is formed in a higher yield using a catalyst or a reaction product of the invention compared to when an equivalent amount of a catalyst of formula (I) or formula (II) is used in the absence of the imidazole salt of a strong acid.

In various embodiments the invention provides compounds of formula (VIIIE) and of formula (VIIIZ) prepared by a method of the invention.

In various embodiments the invention provides a method further comprising, after formation of the compound of formula (IV), contacting the compound of formula (IV) and hydrogen in the presence of a suitable hydrogenation catalyst under conditions suitable to bring about formation of a compound of formula (IVH)

(IVH). For example, the compound of formula (IVH) can comprise a compound of (VIIIH)

(VIIIH), wherein R comprises, H, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, or two R groups taken together form together with a nitrogen atom to which they are attached form a heterocyclyl ring that can unsubstituted or substituted, or fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; PR comprises a nitrogen protecting group; each PR' independently comprises an oxygen protecting group or taken together with the oxygen atoms to which they are attached and a boron atom to which the oxygen atoms are both attached form a cyclic boronate ester; m is 0 to about 4; and n is 0 to about 8.

In various embodiments the compound of formula (VIIIH) comprises a compound of formula (XH)

(XH).

Figure 1 shows the results of the experiment described below in Example 1, wherein both HG-II and Zhan Catalyst- IB were evaluated in the ring closing metathesis reaction as shown:

(IX) (XE)+(XZ)

The reaction was carried out under the conditions stated, and it is clear that in all four experimental results (HG-II plus imidazole triflate, HG-II plus imidazole trifluoroacetate, Zhan plus imidazole triflate, Zhan plus imidazole trifluoroacetate) that substantially higher yields were achieved than in the control experiments wherein no imidazole salts were present. In all four experimental reactions, yields in excess of about 80%, ranging up to a maximum of over 90% in the case of HG-II plus imidazole triflate and in the case of Zhan plus imidazole triflate. In comparison, yields of only about 60% were achieved using the art catalysts HG-II and Zhan Catalyst- IB with no added imidazole salts.

Figures 2 and 3 show that the compounds of formula (I) and formula (II) in the presence of imidazole salts of strong acids are significantly more effect olefin metathesis catalysts than are those compounds in the presence of imidazole salts of weaker acids, for example, the imidazole salt of acetic acid. Imidazole tosylate, triflate, and trifluroacetate are shows to result in higher conversions than does imidazole acetate under the reaction conditions shows, discussed below in Example 2.

Figure 4 shows a plot of the yields obtained in the above reaction varying the molar ratio of imidazole trifluoroacetate relative to Zhan Catalyst- IB. As can be seen, an optimum ratio appears to be about 1 -5 equivalents of the imidazole salt per mole of Zhan catalyst, with conversions approaching 100%.

Figure 5 shows a plot of the E/Z isomer ratios obtained using the indicated catalysts, which are in the range of about 3.5 to about 5. It can be seen that the greatest isomeric purity of the preferred E isomer is obtained using HG- II / imidazole triflate.

If the saturated macrocyclic ring is the desired product, the mixture of Z and E isomers of the macrocyclic olefin can be hydrogenated in the presence of a suitable hydrogenation catalyst, for example platinum or palladium, without separation or purification, to provide the saturated macrocyclic ring product. See, for example, Example 4.

Examples

The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

The following abbreviations are used throughout this document.

DCM Dichloromethane eq Equivalents

EtOAc Ethyl acetate h Hours

HCT Hvdrochloric acid IPAc Isopropylacetate mg Milligrams min Minutes mL Milliliters μL Microliters mmole Millimoles

MS Mass spectroscopy rb Round-bottom

RT Room temperature sat. Saturated

TFA Trifluoroacetic acid

THF Tetrahydrofuran

Tosic, tosyl p-Toluenesulfonic

Triflic Trifluoromethanesulfonic to (range, e.g., X-Y = X to Y)

Example 1

Scheme 1

(IX) (XE)+(XZ)

A comparative study of the effect of catalyst type on the rate and yield of the conversion shown in Scheme 1 was carried out. Six catalysts were evaluated, including three sets of conditions using Hoveyda-Grubbs 2ⁿ generation catalyst (compound of formula (I)), and three sets of conditions using Zhan Catalyst- IB (compound of formula (II)). With each catalyst, the conversion was run under standardized conditions in the absence of any imidazole salt (two controls), and in the presence of two equivalents of imidazole triflate salt or imidazole trifluoroacetate salt in both cases (four experimental) . Starting material (IX) was dissolved in isopropylacetate at a concentration of 1 gm / 100 mL, and the solution warmed to 85°C. Two equivalents of each of the imidazole salts were added to their respective reaction mixtures. Stock solutions of HG-II and Zhan catalyst were prepared and added to each of the six reaction mixtures defined above to provide a catalyst loading of 0.25 mol%. Aliquots were collect at time points 0.25, 0.5, 1, 2, and 4 hours, and the reaction mixtures analyzed by HPLC at each time point. Then, after 4 hours, an additional 0.25 mol% of each catalyst, and an additional 0.5 mol% of each salt, was added to the respective reaction mixture and monitoring continued at time points 6 h and 8 h. The results are shown in Figure 1.

Example 2

Scheme 1.

(IX) (XE)+(XZ)

A comparative study of the effect of salt type on the rate and yield of the conversion shown in Scheme 1 was carried out. Two sets of experiments were conducted. The Zhan Catalyst IB (compound formula (H)) was fixed at 2.5 mol% in the first set of experiments and 1.0 mol% in the second set of experiments. The series of experiments with 2.5 mol% of Zhan IB catalyst used three imidazole salts (TFA, AcOH, and TsOH) while experiments with 1 mol% of Zhan IB catalyst used a total of four salts: 2.5mol% of imidazole salts (TFA, AcOH, TsOH) and 2.0 mol% of the triflic acid imidazole salt (Tf). Temperature for both sets of experiments was held constant at 75 ⁰C, and concentration was also constant at 0.013 M in isopropyl acetate. All reactions were performed under an inert atmosphere of nitrogen. A stock solution of diene (IX) was prepared by dissolving in isopropyl acetate at a concentration of 1 g/100 mL (0.013 M). For each experiment a portion of the stock solution, 10 mL per experiment, was placed in a 20 mL vial with a magnetic stir bar and septum. The solutions were warmed to 75°C in a thermostated aluminum block. The requisite amount of imidazole salt was added to each respective reaction mixture. A stock solution of Zhan IB catalyst, 1 mg/mL, in isopropyl acetate was prepared and an appropriate volume of the stock catalyst solution was added to each of the seven reaction mixtures defined above to provide a catalyst loading of 1.0 or 2.5 mol%. Aliquots from the reaction were collected at time points 0.25, 0.5, 1, and 2 hours and diluted with acetonitrile. The reaction aliquots were quantitatively analyzed by HPLC at each time point. The results are shown in Figures 2 and 3.

Example 3.

(IX) (XEMXZ)

A comparative study between imidazole salt stoichiometry and catalyst stoichiometry in order to determine the optimal ratio of salt and catalyst was conducted. Stock solutions of diene (IX), 1 g/100 mL, Zhan IB catalyst 1 mg/mL, and imidazole-TFA salt, 1 mg/mL, were prepared in isopropyl acetate. Catalyst loading was fixed at 1 mol% for all experiments. Concentration was fixed at 0.013 M, and temperature was fixed at 75 ⁰C by means of a thermostated aluminum reaction block. All reactions were conducted under an inert atmosphere of nitrogen. A portion of the stock diene (IX) solution (10 mL) was charged into a vial along with the appropriate quantity of imidazole-TFA salt solution and Zhan IB catalyst solution for each experiment. Ahquots were withdrawn at the 2 h time point for each individual experiment and quantitatively analyzed by HPLC to determine the level of conversion and yield. Figure 4. plots the total RCM conversion based on 1 mol% of Zhan IB catalyst and varying amounts of imidazole-TFA salt (0-16 mol%).

Example 4

E+Z

A heavy walled glass pressure vessel was purged with nitrogen and Pd-C (Degussa ElOl NE/W, 10wt% Pd, 50wt% water, 3.0 g) was charged. A solution of 10 g of compound (XE+XZ) arising from the RCM reaction of compound (X), in isopropylacetate (300 mL) was charged to the pressure vessel. The atmosphere was changed to hydrogen (2 bar, -30 psi) and the mixture was stirred vigorously for 24 h. Hydrogenation of the double bond was judged complete by HPLC analysis and the catalyst was removed by filtration through a pad of Celite washing with isopropyl acetate (600 mL). The filtrate was concentrated affording an oil. Recrystalhzation from a mixture of acetonitπle and water afforded 5.5 g of compound (XH) with additional product being recovered from the mother liquors by chromatography.

While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.

All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. An olefin metathesis catalytic system comprising a ruthenium-based metathesis catalyst and an imidazolium ion in a solvent, adapted for catalyzing an olefin metathesis reaction.

2. The catalytic system of claim 1 wherein the ruthenium-based metathesis catalyst is a Grubbs first generation catalyst, a Grubbs second generation catalyst, a Hoveyda-Grubbs first generation catalyst, a Hoveyda-Grubbs second generation catalyst or a Zhan catalyst.

3. The catalytic system of claim 1 wherein the ruthenium-based metathesis catalyst is a polymer-bound immobilized metathesis catalyst.

4. The catalytic system of claim 1 wherein the imidazolium ion is an imidazole salt of an acid.

5. The catalytic system of claim 4 wherein the acid is a strong acid.

6. The catalytic system of claim 5 wherein the acid is tosic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid.

7. The catalytic system of claim 1 wherein the imidazolium ion is a quaternarized imidazolium ion.

8. The catalytic system of claim 1 wherein the imidazolium ion is an N-(Ci- Ci₂)-alkyl-imidazolium ion or an N-benzyl-imidazolium ion.

9. The catalytic system of claim 1 wherein at least about one molar equivalent of the imidazolium ion is present, or at least about two molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst.

10. The catalytic system of claim 1 wherein no more than about sixteen molar equivalents of the imidazolium ion are present relative to the ruthenium- based metathesis catalyst.

11. The catalytic system of claim 1 wherein about two molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst.

12. The catalytic system of claim 1 wherein the ruthenium-based catalyst comprises a compound of formula (I):

(I, Hoveyda-Grubbs second generation catalyst) or a compound of formula (II):

(II, Zhan Catalyst- IB).

13. The catalytic system of claim 1 wherein the catalytic system is adapted to catalyze a ring closing metathesis reaction.

14. The catalytic system of claim 1 wherein the solvent comprises an organic solvent.

15. The catalytic system of claim 14 wherein the organic solvent comprises isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof.

16. The catalytic system of claim 14 formed at a concentration of less than about 0.1 M of the ruthenium-based catalyst.

17. The catalytic system of claim 1 wherein the solvent comprises an ionic liquid.

18. The catalytic system of claim 17 wherein the ionic liquid comprises a 1- butyl-3-methylimidazolium, 1-alkylpyridinium, N-methyl-N- allkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof.

19. The catalytic system of claim 17 formed at a concentration of less than about 0.1 M of the ruthenium-based catalyst.

20. The catalytic system of claim 1 formed at a temperature of at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

21. A reaction product of a ruthenium-based olefin metathesis catalyst and an imidazolium ion in a solvent, wherein the reaction product is adapted for catalyzing an olefin metathesis reaction.

22. The reaction product of claim 21 wherein the ruthenium-based metathesis catalyst is a Grubbs first generation catalyst, a Grubbs second generation catalyst, a Hoveyda-Grubbs first generation catalyst, a Hoveyda-Grubbs second generation catalyst or a Zhan catalyst, and wherein the imidazolium ion can be an imidazolium salt of an acid or a quaternarized imidazolium ion.

23. The reaction product of claim 21 wherein the ruthenium-based metathesis catalyst is a polymer-bound immobilized metathesis catalyst.

24. The reaction product of claim 21 wherein at least about one molar equivalent of the imidazolium ion is present, or at least about two molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst.

25. The reaction product of claim 21 wherein no more than about sixteen molar equivalents of the imidazolium ion are present relative to the ruthenium- based metathesis catalyst.

26. The reaction product of claim 21 wherein about two molar equivalents of the imidazolium ion are present relative to the ruthenium-based metathesis catalyst.

27. The reaction product of claim 21 wherein the ruthenium-based catalyst comprises a compound of formula (I):

(I) or a compound of formula (II):

(II).

28. The reaction product of claim 21 wherein the catalytic system is adapted to catalyze a ring closing metathesis reaction, a ring opening metathesis reaction, a ring opening polymerization metathesis reaction, a 1-alkyne polymerization reaction, or a cross metathesis reaction.

29. The reaction product of claim 21 wherein the solvent comprises an organic solvent.

30. The reaction product of claim 29 wherein the organic solvent comprises isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof.

31. The reaction product of claim 21 wherein the solvent comprises an organic liquid.

32. The reaction product of claim 31 wherein the ionic liquid comprises a 1- butyl-3 -methylimidazolium, 1 -alkylpyridinium, N-methyl-N-alkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof.

33. The reaction product of claim 21 formed at a concentration of less than about 0.1 M of the ruthenium-based catalyst in the solvent.

34. The reaction product of claim 21 formed at a temperature of at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

35. An isolated or purified reaction product of claim 21 comprising a ruthenium-containing olefin metathesis catalyst.

36. The catalytic system of claim 1 or the reaction product of claim 21 or 35 adapted for catalyzing a ring-closing metathesis reaction.

37. The catalytic system of claim 1 or the reaction product of claim 21 or 35 adapted for catalyzing a ring-opening metathesis reaction.

38. The catalytic system of claim 1 or the reaction product of claim 21 or 35 adapted for catalyzing a ring-opening polymerization metathesis reaction.

39. The catalytic system of claim 1 or the reaction product of claim 21 or 35 adapted for catalyzing a 1 -alkyne polymerization metathesis reaction.

40. The catalytic system of claim 1 or the reaction product of claim 21 or 35 adapted for catalyzing a cross metathesis reaction.

41. A method of forming the catalytic system of claim 1 comprising contacting ruthenium-based olefin metathesis catalyst and the imidazolium ion in a suitable solvent, at a temperature, and for a duration of time sufficient to bring about formation of the catalytic system.

42. The method of claim 41 wherein the temperature is at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

43. The method of claim 41 wherein the period of time is about 1 to about 3 hours.

44. The method of claim 41 wherein the imidazolium ion is an imidazolium salt of an acid.

45. The method of claim 41 wherein the imidazolium ion is an N- alkylimidazolium.

46. The method of claim 41 wherein the solvent comprises an organic solvent.

47. The method of claim 46 wherein the organic solvent comprises isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof.

48. The method of claim 41 wherein the solvent comprises an ionic liquid.

49. The method of claim 48 wherein the ionic liquid comprises a l-butyl-3- methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidinium, or tetralkylammonium salt, or any combination thereof.

50. The method of claim 41 wherein a concentration of the ruthenium-based catalyst is less than about 0.1 M in the solvent.

51. A method for carrying out an olefin metathesis reaction comprising contacting a suitable amount of the catalytic system of any one of claims 1-20, or of the reaction product of any one of claims 21-35, or of the catalytic system prepared by the method of any one of claims 41-50; and a first unsaturated compound, and, optionally, a second unsaturated compound, in a solvent, at a temperature, and for a duration of time sufficient to produce a third unsaturated compound.

52. The method of claim 51 comprising a ring-closing metathesis reaction.

53. The method of claim 51 comprising a ring-opening metathesis reaction.

54. The method of claim 51 comprising a ring-opening polymerization metathesis reaction.

55. The method of claim 51 comprising a 1-alkyne polymerization reaction.

56. The method of claim 51 comprising a cross-metathesis reaction.

57. The method of claim 52 comprising contacting a precursor di-olefin of formula (III)

(III) wherein L comprises a linking moiety, to produce a cyclic product of formula (IV)

(IV).

58. The method of claim 57 wherein the solvent comprises isopropyl acetate, ethyl acetate, dichloromethane, dichloroethylene, toluene, or tetrahydrofuran, or any combination thereof.

59. The method of claim 57 wherein the temperature is at least about 50⁰C, or is at least about 65°C, or is at least about 80⁰C.

60. The method of claim 57 wherein the period of time is about 1 to about 3 hours.

61. The method of claim 57 wherein the catalyst or the reaction product is present in less than about 5 mole percent relative to an amount of the compound of formula (III) initially present.

62. The method of claim 61 wherein the catalyst or the reaction product is present in less than about 2 mole percent relative to an amount of the compound of formula (III) initially present.

63. The method of claim 62 wherein the catalyst or the reaction product is present in less than about 1 mole percent relative to an amount of the compound of formula (III) initially present.

64. The method of claim 57, wherein a compound of formula (V)

(V) or formula VI

(VI) is also produced, wherein a quantity of the compound of formula (IV) produced relative to a quantity of the compound of formula (V) or a quantity of the compound of formula (VI) or a quantity of both taken together, is greater, compared to a quantity of the compound of formula (V) or a quantity of the compound of formula (VI) or a quantity of both taken together, produced in a ring closing metathesis reaction of the compound of formula (III) carried out using a equivalent quantity of the ruthenium-based olefin metathesis catalyst in the absence of the imidazolium ion.

65. The method of claim 57 wherein a yield of a compound of formula (IV) from a compound of formula (III) is greater than a yield of a compound of formula (IV) from a compound of formula (III) when carried out using an equivalent amount of the ruthenium-based olefin metathesis compound in the absence of the imidazolium ion.

66. The method of claim 57 wherein the compound of formula (III) comprises a compound of formula (VII)

(VII), wherein

R comprises, H, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, or two R groups taken together form together with a nitrogen atom to which they are attached form a heterocyclyl ring that can unsubstituted or substituted, or fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring;

PR comprises a nitrogen protecting group; each PR' independently comprises an oxygen protecting group or taken together with the oxygen atoms to which they are attached and a boron atom to which the oxygen atoms are both attached together form a cyclic boronate ester; m is 0 to about 4; and n is 0 to about 8.

67. The method of claim 66 wherein the compound of formula (VII) comprises a compound of formula (IX)

(IX).

68. The method of claim 57 wherein the compound of formula (IV) comprises a compound of formula (VIIIE)

E

(VIIIE) or a compound of formula (VIIIZ),

or a mixture of the compound of formula (VIIIE) and the compound of formula

(VIIIZ); wherein

PR comprises a nitrogen protecting group; each PR' independently comprises an oxygen protecting group or taken together with the oxygen atoms to which they are attached and a boron atom to which the oxygen atoms are both attached form a cyclic boronate ester; m is 0 to about 4; and n is 0 to about 8.

69. The method of claim 68 wherein the compound of formula (VIIIE) or (VIIIZ) respectively comprises a compound of formula (XE)

(XE)

a compound of formula (XZ)

(XZ) or a mixture thereof.

70. The method claim 57 further comprising, after formation of the compound of formula (IV), contacting the compound of formula (IV) and hydrogen in the presence of a suitable hydrogenation catalyst under conditions suitable to bring about formation of a compound of formula (IVH)

(IVH).

71. The method of claim 70 wherein the compound of formula (IVH) comprises a compound of (VIIIH)

(VIIIH) wherein

72. The method of claim 71 wherein the compound of formula (VIIIH) comprises a compound of formula (XH)

(XH).