Ruthenium catalyst

This application claims benefit from U.S. Provisional Application No. 60/531,774, filed Dec. 22, 2003.

This invention relates to ruthenium carbene complexes of formula 1, their synthesis and their practical use as catalysts for different types of metathesis reactions.

Great progress has been made in the last few years in the application of olefins metathesis in organic synthesis. Some ruthenium carbene complexes acting as (pre)catalysts have been developed, which possess a high activity in various metathesis reactions as well as a broad tolerance for a number of functional groups. This combination of characteristics is a basis for the usability of such (pre)catalysts in organic synthesis.

Moreover, for the practical application, especially in industrial scale, it is very desirable that these ruthenium complexes are stable for a longer period of time in the conditions of thermal load and that they can be stored, purified and applied without the atmosphere of protective gases.

Ruthenium complexes with the above mentioned characteristics are known in literature. See J. Am. Chem. Soc. 2000, 122, 8168–8179 or Tetrahedron Lett. 2000, 41, 9973–9976.

However, it has been discovered that a better stability is connected with a lower catalytic activity. Such a limitation was found for example for the (pre)catalyst of the formula A (see Angew. Chemie Int. Ed. 2002, 114, 832).

Next, (pre)catalysts of the formula B and C were described, which demonstrate a higher catalytic activity in comparison with the (pre)catalyst of the formula A. The catalysts A, B and C contain an iso-propoxy group chelating the metal atom. The reason for a higher activity of the systems B and C is a steric hindrance caused by the presence of a phenyl or a (substituted) naphthyl group in ortho-position to the iso-propoxy group ( Angew. Chemie Int. Ed. 2002, 114, 832 ; Angew. Chemie Int. Ed. 2002, 114, 2509).

It has been found surprisingly that ruthenium complex (pre)catalysts of general formula 1, demonstrate much higher catalytic activity in comparison to known highly active ruthenium complexes and that these complexes are at the same time thermal and air stable.

The present invention relates to novel ruthenium complexes of formula 1, their synthesis, the synthesis of all intermediates and the use of complexes of formula 1 as catalysts or as precatalysts,

wherein:

X 1 and X 2 are anionic ligands; L 1 is a neutral ligand; R 1 is —C 1-20 -alkyl, —C 1-20 -haloalkyl, —C 3-8 -cycloalkyl or —C 7-13 -aralkyl; R 2 is H, —C 1-20 -alkyl, —C 2-20 -alkenyl, —C 2-20 -alkynyl or aryl; R 3 is —C 1-6 alkyl, —C 1-6 -alkoxy, aryl, F or Cl; n is 0, 1, 2 or 3; Z is —CO—R 4 , —SO 2 —R 5 or —PO(R 6 ) 2 ; R 4 is —C 1-20 -alkyl or —C 3-8 -cycloalkyl, both optionally substituted by one or more group selected from each independently F, Cl, Br, I or —C 1-6 -alkoxycarbonyl, or aryl or heteroaryl both optionally substituted by one or more group selected from each independently F, Cl, Br, I, —C 1-6 -alkyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 or —C 1-6 alkoxycarbonyl R 5 is —C 1-8 -fluoroalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are both optionally substituted by one or more groups selected from each independently F, Cl, Br, I, —C 1-6 alkyl, —C 1-6 -alkenyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 , —C 1-6 -alkoxycarbonyl, —SO 2 —C 1-6 alkyl or —SO 2 -aryl, or R 6 are each independently —C 1-20 -alkyl, —C 3-8 -cycloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are both optionally substituted by one or more group selected from each independently F, Cl, Br, I, —C 1-6 -alkyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 , or —C 1-6 -alkoxycarbonyl; or R 4 , R 5 and R 6 are a group of formula 1′

wherein:

X 1′ and X 2′ are anionic ligands; L 1′ is a neutral ligand; R 1′ is —C 1-20 -alkyl, —C 1-20 -haloalkyl, —C 3-8 -cycloalkyl or —C 7-13 -aralkyl; R 2′ is H, —C 1-20 -alkyl, —C 2-20 -alkenyl, —C 2-20 -alkynyl or aryl; R 3′ is —C 1-6 alkyl, —C 1-6 -alkoxy, aryl, F or Cl; and n′ is 0, 1, 2 or 3

The compounds of formula 1 of the present invention may be used to catalyse olefin metathesis reactions including, but not limited to, ring opening metathesis polymerisation (ROMP), ring closing metathesis (RCM), depolymerisation of unsaturated polymers, synthesis of telechelic polymers, ene-ine metathesis and olefin synthesis.

Another embodiment of the present invention relates to novel 2-alkoxy-5-styrene derivatives of formula 2, which are intermediates for the preparation of complexes 1,

wherein:

wherein R 1 , R 2 , R 3 , n and Z are defined as above and R 12 is —C 1-4 -alkyl; m is 0, 1 or 2.

The partial formula

represents an alkylene group in which one or both hydrogen atoms of the methylene group may be replaced by the group R 12 . Accordingly it covers the following alkylene groups:

A further aspect of the invention is the preparation of novel 2-alkoxy-5-styrene derivatives of formula 2, wherein:

A substituted 2-hydroxy-5-benzaldehyde 3 is alkylated by a R 1 V, wherein R 1 has the meaning given for formula 1 and V is a leaving group selected from halogen atoms, C 1-6 -alkyl-S(O)—O—, C 1-6 -fluoroalkyl-S(O)—O—, aryl-S(O)—O— or aryl-S(O) 2 —O—.

The substituted 2-alkoxy-5-benzaldehyde of formula 4 is then treated with an olefination reagent of formula

wherein R 4 and m has the meaning given for formula 2 and W is a leaving group suitable for olefination reactions; to yield formula 2,

Compound 2 can then be reacted with a ruthenium complex of formula 5 to result in the ruthenium complex of the formula 1 in which L 1 and L 2 are neutral ligands; R 13 is H, —C 1-20 -alkyl, —C 2-20 -alkenyl, —C 2-20 -alkynyl or aryl; R 14 is aryl, vinyl or allenyl and X and X′ are anionic ligands.

Optionally, the obtained compound of formula 1 can then be reacted with a different neutral ligand L 1 to replace the neutral ligand L 1 that is present in the compound of formula 1 and thereby obtain a different compound of formula 1.

The compounds herein described may have asymmetric centres. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and Trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

FIG. 1 is a graph comparing the cyclisation speed of 22 when using a ruthenium catalyst according to the present invention versus using a known ruthenium catalyst 1i (see Example 9).

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, —C 1-6 alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Unless otherwise specified below, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.

The term “optionally substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.

The term “aryl” as used herein, either alone or in combination with another substituent, means either an aromatic monocarbocyclic system or aromatic multicarbocyclic systems. For example, aryl includes a phenyl or a naphthyl ring system.

The term “heteroaryl” as used herein, either alone or in combination with another substituent, means a monovalent substituent derived by removal of a hydrogen, especially if a the annelated connection noted, then it means a divalent substituent derived by removal of two hydrogen, from a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and from one to four ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of suitable heterocycles include: tetrahydrofuran, thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine, pyrimidine or

The term “heteroaryl” also includes a heterocycle as defined above fused to one or more other cycle be it a heterocycle or any other cycle. One such examples includes indole or thiazolo[4,5-b]-pyridine. Although generally covered under the term “Heteroaromatic ring”, the term “heteroaryl” as used herein precisely defines an unsaturated heterocycle for which the double bonds form an aromatic system. Suitable example of heteroaromatic system include: quinoline, indole, pyridine,

The term “halogen” as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.

The term “—C 1-20 -alkyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing from one to twenty carbon atoms. The term “—C 1-6 -alkyl” as used herein has the same meaning as the above mentioned term but contains less carbon atoms, precisely a maximum of six carbon atoms and is therefore preferred. The terms —C 1-20 -alkyl or —C 1-6 -alkyl can include i.e. methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

The term “—C 2-20 -alkenyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkenyl substituents containing from two to twenty carbon atoms and at least one double bond. The term “—C 2-6 -alkenyl” as used herein has the same meaning as the above mentioned term but contains less carbon atoms, precisely a maximum of six carbon atoms and is therefore preferred. The terms —C 1-20 -alkenyl or —C 1-6 -alkenyl can include i.e. vinyl or allenyl.

The term “—C 2-20 -alkynyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkynyl substituents containing from two to twenty carbon atoms and at least one triple bond. The term “—C 2-6 -alkynyl” as used herein has the same meaning then the above mentioned term but contains less carbon atoms, precisely a maximum of six carbon atoms and is therefore preferred.

The term “—C 3-8 -cycloalkyl” as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent containing five or six carbon atoms and includes i.e. cyclopentyl or cyclohexyl.

The term “—C 1-6 -alkoxy” as used herein, either alone or in combination with another substituent, means the substituent —C 1-6 -alkyl-O— wherein alkyl is as defined above containing up to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy or 1,1-dimethylethoxy.

The term “—C 7-13 -aralkyl” as used herein, either alone or in combination with another substituent, means the substituent -Aryl-C 1-6 -alkyl- wherein alkyl is as defined above containing up to six carbon atoms. Aralkyl includes benzyl, phenylethyl, phenylpropyl, 1-phenyl-1-methylethyl or phenylbutyl.

The term “—C 1-20 -haloalkyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing up to twenty carbon atoms having one or more hydrogens substituted for a halogen selected from bromo, chloro, fluoro or iodo. Preferably the term —C 1-20 -haloalkyl represents —C 1-8 -fluoroalkyl. The term “—C 1-8 -fluoroalkyl” as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing up to six carbon atoms having one or more hydrogens substituted by a flour atom such as 2-fluorethyl or 2,2,2-trifluorethyl. Preferably the terms —C 1-20 -haloalkyl and —C 1-8 -fluoroalkyl represent —C 1-6 -perflouroalkyl such as trifluoromethyl or pentafluoroethyl.

Additional Embodiments

Preferred are compounds of general formula 1, wherein

R 4 is —C 1-20 -alkyl or —C 3-8 -cycloalkyl, both optionally substituted by one or more group selected from each independently F, Cl, Br, I or —C 1-6 -alkoxycarbonyl, or aryl or heteroaryl both optionally substituted by one or more group selected from each independently F, Cl, Br, I, —C 1-6 alkyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 or —C 1-6 -alkoxycarbonyl R 5 is —C 1-8 -fluoroalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are both optionally substituted by one or more groups selected from each independently F, Cl, Br, I, —C 1-6 -alkyl, —C 1-6 -alkenyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 , —C 1-6 -alkoxycarbonyl, —SO 2 —C 1-6 -alkyl, —SO 2 -aryl or a group of formula 1′; R 6 are each independently —C 1-20 -alkyl, —C 3-8 -cycloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are both optionally substituted by one or more group selected from each independently F, Cl, Br, I, —C 1-6 -alkyl, —C 1-6 -alkoxy, —NO 2 , —CN, —CF 3 , —OCF 3 , or —C 1-6 -alkoxycarbonyl.

Also preferred are compounds of general formula 1, wherein

Z is —CO—R 4 or —PO(R 6 ) 2 ; and R 4 and R 6 are a group of formula 1′.

Preferred are compounds of formula 1a, wherein L 1 , X 1 , X 2 , R 1 , R 2 , R 3 , Z and n are defined as above.

More preferred are the above mentioned compounds of general formula 1 or 1a wherein

L 1 is P(R 11 ) 3 and R 11 are each independently —C 1-6 -alkyl, —C 3-8 -cycloalkyl or aryl; or L 1 is a ligand of formula 6a, 6b, 6c or 6d,

wherein

R 7 and R 8 are each independently H, —C 1-20 -alkyl, —C 2-20 -alkenyl or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from —C 1-6 -alkyl, —C 1-6 -alkoxy or halogen; particularly R 9 and R 10 are each independently H, —C 1-20 -alkyl, —C 2-20 -alkenyl or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from —C 1-6 -alkyl, —C 1-6 -alkoxy or halogen or R 9 and R 10 together with the carbon atoms to which they are attached are combined to form a carbocyclic 3 to 8 membered ring. Y and Y′ are halogen.

Particularly preferred are compounds wherein

R 7 and R 8 are each independently H, —C 1-6 -alkyl, —C 2-6 -alkenyl or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from —C 1-6 alkyl, —C 1-6 -alkoxy or halogen; R 9 and R 10 are each independently H, —C 1-6 -alkyl, —C 2-6 -alkenyl or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from —C 1-6 -alkyl, —C 1-6 -alkoxy or halogen or R 9 and R 10 together with the carbon atoms to which they are attached are combined to form a carbocyclic 5 to 7 membered ring.

Most preferred are compounds of general formula 1 or 1a, wherein

R 1 is iso-propyl; R 2 is H, —C 1-6 -alkyl or aryl, in particular H; X 1 and X′ 2 are halogen, particularly chlorine; L 1 is P(cyclohexyl) 3 or L 1 is a group of formula 6a, 6b, 6c or 6d, more preferred a group of formula 6a;

wherein R 7 and R 8 are each 2,4,6-trimethylphenyl; and R 9 and R 10 are each H.

R 7 and R 8 are 2-methylbenzene, 2,6-dimethylbenzene or 2,4,6-trimethylbenzene;

n is 0.

In particular most preferred are compounds of general formula 1 or 1a, wherein

R 1 is a iso-propyl; R 2 is H; X 1 and X′ 2 are chlorine; L 1 is a group of formula 6a;

wherein R 7 and R 8 are each 2,4,6-trimethylpheny and R 9 and R 10 are each H;

R 7 and R 8 are 2-methylbenzene, 2,6-dimethylbenzene or 2,4,6-trimethylbenzene;

n is 0.

Preferred compounds of formula 2 are compounds of formula 2a, wherein R 1 , R 2 , R 3 , R 12 , Z, m and n are defined as above.

More preferred are compounds of general formula 2 or 2a, wherein

R 1 is a isopropyl group; and/or R 2 is H, —C 1-6 -alkyl or aryl, in particular R 2 has the meaning of a hydrogen atom; and/or R 12 is —C 1-6 -alkyl, in particular methyl or ethyl; and/or n is 0 and/or m is 0.

Additional embodiments are compounds of formula 2 or 2a wherein:

R 1 is iso-propyl; R 2 is H; m is 0; and n is 0.

Furthermore preferred is a process for manufacturing complexes of formula 1 or 1a, wherein a compound of general formula 2 or 2a, is reacted with a ruthenium complex of formula 5

wherein

L 1 and L 2 are neutral ligands R 13 is H, —C 1-20 -alkyl, —C 2-20 -alkenyl, —C 2-20 -alkynyl or aryl; and R 14 is aryl, vinyl or allenyl; and X 1 and X′ 2 are anionic ligands;

optionally in the presence of a different neutral ligand L 1 .

More preferred is the above mentioned synthesis of a ruthenium complex of formula 1, when the process is carried out:

in the presence of a copper salt, in particular CuCl; and/or in a halogenated or an aromatic solvent, particularly selected from methylene chloride, chloroform, benzene, toluene, xylene, mesitylene or mixtures thereof; and/or at a temperature from 0 to 100° C., in particular at a temperature from 10 to 80° C., more particular at a temperature from 20 to 60° C.; and/or in a time period from 1 to 24 h, in particular 1 to 10 h, more particular 1 to 4 h.

Most preferred is the above mentioned synthesis of a ruthenium complex, wherein the reaction is carried out in one vessel by mixing the ligand of formula 6a, 6b, 6c or 6d with a solid complex of formula 5, wherein both ligands L 1 and L 2 are phosphines of formula P(R 11 ) 3 , wherein R 11 has the meaning as above and thereafter adding a ligand of formula 2 or 2a.

One preferred variation of the above mentioned synthesis of a ruthenium complex is the generation of the ligands of general formula 6a, 6b, 6c or 6d in situ from the stable salts of the formulae 7a, 7b, 7c or 7d,

wherein the anion is selected from formiate, acetate, trifluoro-acetate or another acid group, a halogen or [BF 4 ] − . Therefore, the salt is preferably in form of a suspension in solvents such as aliphatic or aromatic hydrocarbons, preferably hexane, reacted with a strong base, selected from alkali metal hydrides, alkaline earth metal hydrides or alcoholates, particularly potassium tert-pentanolate, potassium tert-amylate or potassium tert-butanolate. Thereafter reaction is continued by adding a solid complex of formula 5, wherein both ligands L 1 and L 2 are phosphines of formula P(R 11 ) 3 and thereafter adding a ligand of formula 2 or 2a, to yield a compound of general formula 1 or 1a.

Moreover preferred is a process for manufacturing intermediates, which comprises the steps of a) alkylating a compound of general formula 3, with a reagent of formula R 1 V (9) to form a intermediate of formula 4, and b) reacting 4 with an olefination reagent of formula 10 to yield a compound of the general formula 2,

wherein R 1 , R 2 , R 3 , R 12 , Z, m and n of formula 2a, 3, 4, 9 and 10 are defined as above and

W is a leaving group suitable for olefination reactions; and V is halogen, —C 1-6 alkyl-S(O)—O—, —C 1-6 -fluoroalkyl-S(O)—O—, aryl-S(O)—O— or aryl-S(O) 2 —O—.

More preferred is a process, wherein the above mentioned step a) is carried out:

in an aprotic solvent, in particular selected from DMF, DMSO, acetone, acetonitrile, ethyl acetate, glycol ether, methanol, ethanol or mixtures thereof, more particular the solvent is DMF; or in a biphasic solvent system fitted with a phase transfer catalyst; or in presence of a catalyst, in particular the catalyst is selected from Cs 2 CO 2 , CsF, quaternary ammonium salts, crown ethers or cryptands, more particular Cs 2 CO 3 ; or in the presence of an alkali metal carbonate or an alkali hydroxide, in particular selected from Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, LiOH, CsOH; or in a time period from 1 to 24 h, in particular 8 to 24 h, more particular 16 to 24 h. at a temperature from 0 to 150° C., in particular at a temperature from 10 to 100° C., more particular at a temperature from 20 to 80° C.; or

Starting from compound 4, compound 2 is available under Tebbe, Wittig, Wittig-Horner, Wittig-Horner-Emmons or Peterson conditions, but preferred is a process, wherein the above mentioned step b) is carried out:

in a solvent selected from alcohols, glycol ethers or cyclic ethers, preferred is THF; or W is a leaving group suitable for olefination reactions according to Tebbe, with Tebbe's titanium reagent, or according to Wittig, with Wiltig's phosphonium ylide reagent, more particular a leaving group selected from PPh 3 or TiCp 2 ; wherein Ph is substituted or unsubstituted phenyl and Cp is a substituted or unsubstituted cyclopentadienyl-anion, which can be found after reaction in its oxidised form.

Another preferred embodiment of the invention is a process for metathesis reactions of all types, comprising contacting an olefin with a catalyst of general formula 1; in particular wherein the metathesis reaction is a ring closing or cross metathesis reaction.

The following examples are to illustrate various embodiments of the present invention and are not to be understood as limiting the present invention in a way.