One known catalyst used in the formation of carbon-carbon double bonds is that described by Grubbs et al in J. Am. Chem. Soc., 1992, 114, 3974. This is a ruthenium catalyst, not bound onto a polymer support, that is useful in the catalysis of carbon-carbon double bond forming reactions. However, a major problem with this catalyst is that it cannot be recovered from the reaction mixture and hence, the final reaction product is usually contaminated with ruthenium compounds, thereby requiring extensive purification by chromatography.

Ultimately, the lack of recyclability of this catalyst has the effect of increasing the overall expense of using this catalyst in carbon-carbon double bond formation reactions.

Another catalyst used in the formation of carbon-carbon double bonds is that described by Grubbs et al, in Tet. Lett., 1999, 40, 2247-2250. This is also a ruthenium catalyst, wherein one of the phosphine ligands of the catalyst described above is replaced with an imidazole carbene ligand, resulting in catalysts with improved potency.

A method of improving catalyst efficacy and recyclability in carbon-carbon double bond forming reactions has been achieved by attaching a ruthenium catalyst to a polymer support. Such catalysts are described by Grubbs and Nguyen in J. Organometallic Chem., 1995, 497, 195-200, wherein a series of 2% cross-linked polystyrene-divinylbenzene-supported ruthenium bis-phosphine diphenylvinylcarbene catalysts have been synthesised. The catalyst is attached to the polymer support via both of its phosphine groups. However, these catalysts were found to be at least two orders of magnitude less active than the first mentioned homogeneous Grubbs catalyst.

Polymer supported ruthenium catalysts wherein the catalyst is attached to the polymer support via the ruthenium itself have been reported by Barrett et al, in Tet. Lett., 1999, 40, 8657-8662. These catalysts have improved activity over the Grubbs and Nguyen catalyst and they allow for a reduction in catalyst residue.

They are recyclable but only to the extent that they may be used twice in independent reactions, without a significant loss of activity. Hence, the use of such catalysts in carbon-carbon double bond forming reactions is still relatively expensive due to their restricted lifetime of only two ring closing reactions and this precludes economic use of these catalysts on a large scale.

The aim of the present invention is to overcome the limitations of the above- mentioned catalysts by providing solid phase supported ruthenium catalysts that have extended lifetimes by way of recycling, with little or no loss in catalytic activity, for use in carbon-carbon double bond forming reactions. These catalysts are"boomerang"type catalysts, wherein the ruthenium catalyst is released from the support during the bond forming reaction and then recaptured once the reaction is complete. Recycling of these catalysts can be achieved very easily, with no purification necessary once the catalysts have been isolated from the previous reaction mixture. Such catalysts allow for the economic execution of carbon-carbon double bond forming reactions on a large scale.

In addition, the use of such catalysts can lead to the amount of catalyst required for carbon-carbon double bond forming reactions to be lowered, i. e. lower catalyst loadings, resulting in lower quantities of ruthenium residues in the reaction mixtures and in reducing the expense of these reactions.

According to the present invention there is provided a catalyst for alkene metathesis reactions obtainable by reacting a solid phase support functionalised to contain aryl vinyl groups with a ruthenium compound having the general formula I

wherein W is C6-14aryl, optionally substituted with C14alkyl or C4alkoxy, diphenylvinyl, allenyl or phenylindenyl ; Xr, X2, and X3 are selected independently from a C"8alkyl group, a C6-10aryl group, optionally substituted by a C1-4alkyl, or a C1-4alkoxy group, a C3 7 cycloalkyl group, optionally substituted by a C » alkyl or a C1-4alkoxy group or a C7-20alkylaryl group, optionally substituted by a C14alkyl or a C » alkoxy group ; Y is a halogen atom ; Z is a group of formulae wherein Ri and R2 are selected independently from a C3-7cycloalkyl group, optionally substituted by C1-4alkyl or C6-10 aryl groups, a C1-10alkyl group, a ¬7-20 alkylaryl group, or a C7-20arylalkyl group, optionally substituted with C, 4alkyl, C6-10aryl or C3-7cycloalkyl groups, and wherein R\'and R2 may be racemic or chiral non-racemic ; R3 and R4 are selected independently from hydrogen, a C » alkyl group, a C6 r0 aryl group, optionally substituted by a C » alkyl or a C » alkoxy group, or together

may form a C68cycloalkyl or aromatic ring, optionally substituted by C » alkyl or a C1-4alkoxy group ; R5, R6, R7 and R8 are independently selected from hydrogen, a C1-4 alkyl group, a C6 r0aryl group, optionally substituted by a C1-4alkyl or a C1-4alkoxy group, or together form a six-membered cycloalkyl ring, optionally substituted by a C14 alkyl or a C » alkoxy group, wherein R5, r6, R7 and R8 may be cis or trans and may be racemic or chiral non-racemic ; in a molar ratio of 100 : 1 to 5 : 1 (free vinyl groups : ruthenium compound).

In a preferred aspect of the invention, W may represent phenyl.

In a further preferred aspect of the invention, X\', X2 and X3 may represent cyclohexyl or phenyl.

In a further preferred aspect of the invention, R1 and R2 may represent isopropyl, 1-ethylphenyl or mesityl. Particularly preferred is mesityl.

In a further preferred aspect of the invention R3 and R4 may represent hydrogen.

In a further preferred aspect of the invention R5, R6, R7 and R8 may represent hydrogen.

A C »4alkyl group may be a straight chain or branched chain alkyl group and may be, for example, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, or tert-butyl.

A C1-10 alkyl group may be a straight chain or branched chain alkyl group and may be, for example, those alkyl groups exemplified above for a C »4alkyl group or pentyl, hexyl, heptyl, octyl, nonyl or decyl.

A C,, 8alkyl group may be a straight chain or branched chain alkyl group and may be, for example, those alkyl groups exemplified abovefor a C1-10alkyl group

or undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.

A C » alkoxy group may be a straight chain or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2- methylprop-1-oxy.

A C3 7 cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A C6 r0aryl group may be, for example, a phenyl or a naphthyl group.

A C6, 4aryl group may be, for example, a phenyl, a naphthyl or an anthracenyl group.

A C720alkylaryl group may be, for example,-CHMePh and-CHMe (naphthyl).

A halogen atom may be a chlorine, bromine or iodine atom. Particularly preferred is chlorine.

The solid phase support to be functionalised to contain arylvinyl groups may be any suitable inert insoluble support material such as polymers, for example, Merrifield resin@, Wang resin@, TentaGel@, ArgoGel@, or QuadraGel@. A particularly preferred solid phase support is polystyrene with 1 to 20% cross- linked divinylbenzene, such as 1 to 10%, and preferably 1-2%.

In order to functionalise polymeric resins to contain arylvinyl groups, the polymeric resin is, for example, converted to the chloromethyl resin and reacted with, for example, trimethyl sulphonium iodide under basic conditions to introduce the vinyl groups.

For the purpose of this invention, the term"inert"is applied in the context that the support material is inert to any solvents or reagents used during the course of metathesis reactions.

For the purpose of this invention, the term"insoluble"is applied in the context that the support material is insoluble in non-polar organic solvents well known for metathesis reactions, for example dichloromethane, benzene, toluene, hexane, xylene, dichloroethane, and also other solvents used in the further manipulation of the reaction products.

Particularly preferred catalysts according to the invention are (tricyclohexylphosphine) (1, 3-dimesityl-imidazol-2-ylidene) (polystyrylmethylidene) ruthenium dichloride and (tricyclohexylphosphine) (1, 3-dimesityl-4, 5- dihydroimidazol-2-ylidene) (polystyrylmethylidene) ruthenium dichloride. Such catalysts may either have a polystyrene support having a high percentage of cross-linked divinylbenzene e. g. 20% or a low percentage of cross-linked divinylbenzene e. g. 1-2%.

The reaction conveniently takes place in a suitable solvent such as an aromatic hydrocarbon, such as toluene or benzene or chlorinated hydrocarbons, for example, dichloromethane or dichloroethane, at a temperature ranging from 0°C to the reflux temperature of the reaction mixture. A particularly preferred solvent is dichloromethane.

The molar ratio of ruthenium compound of formula I to free vinyl groups of the solid phase support is in the range of 1 : 100 to 1 : 5 (1% to 20%). Preferably, the molar ratio is 1 : 20 (5%).

The present invention also provides a process for preparing solid phase supported catalysts as defined above.

W groups may be exchanged in solution to W groups prior to their attachment on to the solid phase support and such exchange will be understood by the person skilled in the art. W groups, whilst being stable in the solution phase, may not necessarily be stable in the solid phase, but may still be used for the above process. For example, W may be an alkyl, cycloalkyl, arylalkyl or aryl group. W may not be hydrogen.

The present invention also provides the use of solid phase catalysts as defined above.

Compounds of formula I may be prepared according to methods known to the person skilled in the art, for example, the methods described in Grubbs et al, Tet. Lett., 1999, 40, 2247-2250 and Grubbs et al., Org. Letters, 1999, 1, 953- 956.

The above-mentioned supported ruthenium catalysts are useful in the catalysis of carbon-carbon double bond formation. They are particularly useful in the catalysis of ring closing metathesis of suitable substrates, such as dienes, for example, diethyl diallylmalonate, diethyl allylcrotylmalonate, N, N-diallyl-4-methyl- 1-benzenesulfonamide, diethyl 2, 2-di- (3-butenyl) malonate, and allyl 1-phenyl-3- butenyl ether. These catalysts are particularly useful in the catalysis of enyne metathesis (the reaction between an acetylene and an alkene), dienyne metathesis (the reaction between an acetylene and dialkene) and cross- metathesis (the intermolecular reaction between two different alkenes). For cross-metathesis reactions, one of the coupling alkenes must be monosubstituted and the other alkene must either be disubstituted at the same carbon atom or be a styrene.

Such carbon-carbon double bond forming reactions may be performed by reacting the desired substrates in the presence of such ruthenium catalysts. The reaction conveniently takes place in a suitable solvent such as an aromatic hydrocarbon, for example, toluene or benzene or chlorinated hydrocarbons, for example, dichloromethane or dichloroethane, at a temperature ranging from 0°C to the reflux temperature of the reaction mixture, in a suitable reaction vessel under an inert atmosphere, for example, nitrogen. Preferably, the temperature is maintained between 20-70°C, more preferably at 20-50°C.

The reaction vessel may be selected from a continuous flow or a batch reactor, such as a flask containing an Irori kan, a U tube, or a glass-frit containing Schlenk flask. A batch reactor is particularly preferred.

The supported catalyst may be present in an amount ranging from 0. 01 to 30 mol% with respect to the substrate. Preferably, the catalyst is present in 1 to 3 mol% with respect to the substrate.

Following completion of the reaction, the supported catalyst may be isolated from the reaction mixture via filtration. If required, the isolated catalyst may be subsequently re-used in the next metathesis reaction without further purification.

In order to obtain the optimum longevity and recyclability of the supported catalyst, one or more additives may be added to the reaction mixture containing the substrate and the supported catalyst. The additives are selected from a terminal alkene RCH=CH2, and PX\'X2X3, wherein R is selected from a C,, 5alkyl group, such as 1-hexene or 1-octene, or a C3 r0cycloalkyl group, for example, cyclohexyl, C6 rOaryl, for example phenyl, and X, X2, and X3 are as defined before. Preferably, the terminal alkene is a volatile lower alkyl alkene, such as 1-hexene or 1-octene. Preferably, PX1X2X3 is trialkylphosphine, tricycloalkyl phosphine or triaryl phosphine, for example triphenyl, triisopropylphosphine, tricyclohexylphosphine, or triphenylphosphine covalently attached to solid phase support as defined before.

The terminal alkene may be present in an amount ranging from 1 to 10 mol% with respect to the substrate. Preferably, the terminal olefin is present in an amount of 10 mol% with respect to the substrate. Preferably, the terminal olefin is selected from 1-hexene and 1-octene.

PX1X2X3 may be present in an amount ranging from 1 to 5 mol% with respect to the substrate. Preferably, PX1X2X3 is present in an amount of 5 mol% with respect to the substrate.

The following examples further describe and demonstrate embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as a limitation of the present invention, as many variations thereof are possible within the scope of the invention.

Reference Example 1 Vinyl Polystyrene (1 % cross-linked divinylbenzene) (Mioskowski et al., Tet. Lett., 1998, 39, 9679-9680) n-Butyllithium (2. 5M solution in hexane, 20 ml, 50mmol) was added to a mechanically stirred, cooled, suspension of trimethyl sulphonium iodide (10. 2 g, 84. 5 mmol) in dry THF (150 ml) at such rate as to maintain the temperature below 10°C. The mixture was stirred at 0-5°C for 45 min, Merrifield resine (100- 200 mesh, 1. 34 mmol Cl/g, 5g, 6. 7mmol) was added and the mixture was stirred at room temperature overnight. The resin was filtered and washed with methanol, methanol-acetic acid (4 : 1), water, and dichloromethane, and dried under vacuum at 40°C overnight to give vinyl polystyrene (5. 07g).

Vmax (cm-\', diffuse reflectance) 1628, 988, 906, 839.

Reference Example 2 (Grubbs et al, Tet. Lett., 1999, 40, 2247-2250) (Tricyclohexylphosphine) (1, 3-dimesityl-imidazol-2-ylidene) benzylidene ruthenium dichloride [1, 3-Dimesityl-(imidazol-2-yl)] carbene in toluene (0. 05M, 45ml) was added to the bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (411 mg, 0. 5 mmol) in the presence of cuprous chloride (3 mg, 0. 03 mmol). The dark solution was stirred for 3 hours at room temperature, followed by the removal of toluene under reduced pressure. The residue was dissolved in dry hexane (20 ml) and the solution was transferred under nitrogen via filter canula to another flask which was cooled to-79°C for 1 hour allowing the product to slowly precipitate. The solution was removed via filter canula and pentane (5 ml) was added to the solid where it stood for 1 hour at-78°C. After pentane was removed via filter canula, the solid was allowed to warm up to room temperature and was then dried under vacuum for 1 hour to yield the titled compound.

Reference Example 3 Chloromethyl polystyrene (20% cross-linked divinylbenzene) To degassed water (160 ml) was added a solution of divinylbenzene (80% tech., 7. 1 ml), styrene (16. 0 ml) and 4-vinylbenzylchloride (90% tech., 3. 1 ml).

Nitrogen gas was then bubbled into the biphasic solution which was then stirred at 350 rpm for 15 min. The mixture was then heated at 80-85°C for 24 h. The

resulting polymer was collected by filtration, washed with water, then toluene (five times), then alternately with toluene and methanol five times, then acetone, then ether, then petroleum ether, then ethyl acetate, then dichloromethane, followed by pentane twice. The polymer was dried in vacuo to give chloromethyl polystyrene (20% cross-linked divinylbenzene) (21. 90g).

Reference Example 4 Vinyl Polystyrene (20% cross-linked divinylbenzene) (Mioskowski et al., Tet Lett., 1998, 39, 9679-9680) To a solution of trimethyl sulfonium iodide (5. 5 g) in dry tetrahydrofuran (150 ml) was added a 2. 5M solution of n-butyl lithium (10. 8 ml) over 30 min at 0°C. The solution was stirred at 0°C for a further 1 h before chloromethyl polystyrene (20% cross-linked divinylbenzene) (5g) was added and the solution was then allowed to warm to room temperature and stirred for 40h. The beads were then filtered and washed with methanol, then methanol : acetic acid (4 : 1) twice, then alternately with methanol and water three times, then alternatively with methanol and dichloromethane twice, followed by dichloromethane. After drying in vacuo at 45°C overnight 4. 93 g of vinyl polystyrene (20% cross-linked divinylbenzene2 was obtained.

Example 1 (Tricyclohexylphosphine) (1, 3-dimesityl-imidazol-2-ylidene) (polystyryl- methylidene) ruthenium dichloride (1% cross-linked divinylbenzene) 1 The catalyst (tricyclohexylphosphine) (1, 3-dimesityl-imidazol-2- ylidene) benzylidene ruthenium dichloride (84mg, 0. 1 mmol) was reacted in refluxing dichloromethane (20 ml) under gentle stirring with vinyl polystyrene (1g, 1mmol/g) for 2 hours, after which time the soluble catalyst had been completely consumed according to 31p NMR. Filtration and washing with dichloromethane (5 x 25 ml), then twice alternately with ether (25 ml) and dichloromethane (25mut) and finally with ether (2 x 25 ml), yielded the titled compound as a black resin.

The ruthenium content of the title compound 1 was determined by ICP to be 0. 43% w/w (weight of ruthenium/weight of compound). vmax (cm~1) 1124.

Example 2 (Tricyclohexylphosphine) (1, 3-dimesityl-4, 5-dihydroimidazol-2-ylidene) (polystyryl- methylidene) ruthenium dichloride (1% cross-linked divinylbenzene) 2 To a suspension of vinyl polystyrene (1g, theoretically 1. 51 mmol) in dichloromethane (20ml) was added (tricyclohexylphosphine) (1, 3-dimesityl-4, 5- dihydroimidazol-2-ylidene) benzylidene ruthenium dichloride (85mg, 0. 1 mmol).

The mixture was then gently stirred for 2 hours at room temperature. Filtration of the solution was followed by washing of the beads by dichloromethane (5 x 25ml), alternately with ether and dichloromethane (2 x 25ml each) then with ether (2 x 25ml). The brown resin was dried under vacuum at room temperature. The ruthenium content of the title compound 2 was determined by ICP to be 0. 19% w/w (weight of ruthenium/weight of compound). vmax (cm~1) 1120.

Example 3 (Tricyclohexylphosphine) (1, 3-dimesityl-4, 5-dihydroimidazol-2-ylidene) (polystyrylmethylidene) ruthenium dichloride (20% cross-linked divinylbenzene) 3 To. vinyl polystyrene (20% cross-linked divinylbenzene) (500 mg) and (tricyclohexylphosphine) (1, 3-dimesityl-4, 5-dihydroimidazol-2-ylidene) ruthenium dichloride (42 mg) was added dry dichloromethane (10 ml) under argon. The mixture was shaken for 2 h then filtered and washed with dichloromethane five times, then diethyl ether and dichloromethane twice, followed by diethyl ether twice to give the title catalyst 3 (500mg).

Example 4 Recyclability of catalyst 1 A solution of substrate (48 mg, 0. 2 mmol) and A [1-octene (10 mol%), then 10 min before filtration, triphenylphosphine (5 mol%)] or B [1-octene (10 mol%)] in toluene was mixed with the catalyst (tricyclohexylphosphine) (1, 3-dimesityl- imidazol-2-ylidene) (polystyrylmethylidene) ruthenium dichloride (1 % cross-linked divinylbenzene) 1 (100 mg, 5 mol%) by allowing argon to bubble through the glass frit of a Schlenk flask apparatus at 50°C for two hours. At the end of the reaction, the solution was separated from the catalyst using vacuum filtration, leaving the catalyst beads on the glass frit, ready for the next reaction. The results are shown in Table 1.

Table 1 Substrate Product Additive Conversion (%) 1 2 3 4 5 6 E E A 100 100 100 88 43 7 J ! B 100 100 97 86 60 32 E E A 100 100 90 68 35 14 S Wj. B 100 100 51 18 9 5 cis or trans A 100 100 100 89 42 16 Ts Ts B 100 90 79 53 26 11 I U Ex A 100 100 100 94 42 11 B 100 100 82 43 20 10 o A 100 100 100 85 31 9 o Ph B. 100 100 36 3 2 2 Ph E=C02Et. A : 1-Octene (10 mol%) and PPh3 (5 mol%). B : 1-octene (10 mol %).

Example 5 Diethyl 3-cyclopentene-1, 1-dicarboxylate (a) To a solution of diethyl diallylmalonate (50 mg, 0. 21 mmol) in

dichloromethane (10mL) was added (tricyclohexylphosphine) (1, 3- dimesitylimidazol-2-ylidene) (polystyrylmethylidene) ruthenium dichloride (1 % cross-linked divinylbenzene) 1 (100 mg, 0. 005 mmol). The mixture was gently stirred at reflux temperature for 2h. It was then filtered through a plug of cotton wool and the solution was concentrated and dried in vacuo to yield the title compound (43. 65 mg).

\'H NMR (CDC13) : 5. 62 (2H, s), 4. 21 (4H, q, J=7 Hz), 3. 03 (4H, s), 1. 27 (6H, t, J=7 Hz). 13C NMR (CDC13) : 172. 3, 127. 8, 61. 5, 58. 9, 40. 9, 14. 0.

(b) To a solution containing diethyl diallylmalonate (25 mg) in dry dichloromethane (5 ml) was added (tricyclohexylphosphine) (1, 3-dimesityl-4, 5- dihydroimidazol-2-ylidene) (polystyryl-methylidene) ruthenium dichloride (20% cross-linked divinylbenzene) 3 (100 mg). The reaction was stirred at room temperature and conversion monitored by TLC. After 48h the solution was filtered and evaporated and the conversion to the title compound was estimated to be 92% by\'H NMR.

Example 6 Ring closing methathesis examples using catalyst 2 A solution of substrate (48mg, 0. 2mmol) in dichloromethane was gently stirred with (tricyclohexylphosphine) (1, 3-dimesityl-4, 5-dihydroimidazol-2-ylidene) (polystyryl-methylidene) ruthenium dichloride (1 % cross-linked divinylbenzene) 2 (100mg, 5 mol%). At the end of the reaction, the solution was filtered through a plug of cotton wool and concentrated under vacuum. The residue was analysed by\'H NMR. The results are shown in Table 2.

Table 2 Substrate Product Conditions Conversion Conversion dichloromethane-100% f\020°C 1h E E dichloromethane 100% / 20°C 2h o dichloromethane 100% o I Pn v 20°C PhJ 2h

E=C02Et.

Example 7 Cross Metathesis of styrene and 1-allyloxybenzene To a solution containing styrene (115 pI) and 1-allyloxybenzene (69 pI) in dry dichloromethane (2. 5 ml) was added (tricyclohexylphosphine) (1, 3-dimesityl-4, 5- dihydroimidazol-2-ylidene) (polystyryl-methylidene) ruthenium dichloride (1 % cross-linked divinylbenzene) 2 (100 mg) and the reaction was refluxed for 24 h.

The conversion after 24 h was 69% by GC integration. The ratio of products stilbene (RT=8. 35min) : cinnamyl phenyl ether (RT=9. 27min) : 1, 4-diphenoxy-2- butene (10. 18min) was 28 : 58 : 14 determined by GC integration.

Comparative Data A solution of diethyl diallylmalonate (48 mg, 0. 2 mmol) in toluene was mixed with the catalyst (100 mg, 5 mol%) by allowing argon to bubble through the glass frit

of a Schlenk flask apparatus at 50°C for two hours. At the end of the reaction, the solution was separated from the catalyst using vacuum filtration, leaving the catalyst beads on the glass frit, ready for the next reaction. The results are shown in Table 3.

Table 3 Catalyst Additive Conversion (%) a 1 2 3 4 5 Xb None 100 40 0 0 2 None 91 61 40 13 1 4 1-octene 100 67 26 7 5

X bis (tricyclohexylphosphine) polystyrylmethylidene) ruthenium dichloride a1H NMR yield. Performed at 25°C for 40 minutes in dichloromethane.