WO1999011648A1

WO1999011648A1 - Organometallic compounds, their preparation and use

Info

Publication number: WO1999011648A1
Application number: PCT/GB1998/002548
Authority: WO
Inventors: Colin White; Paul Beagley; Philip John Davies; Andrew John Blacker; Ben James Mellor
Original assignee: Zeneca Limited
Priority date: 1997-08-28
Filing date: 1998-08-24
Publication date: 1999-03-11
Also published as: GB9718073D0; AU8871698A

Abstract

Organometallic compounds of Formula (1), wherein R?1, R2, R3, and R4¿ are independently hydrogen, alkyl, aryl, or one of R?1 and R2 or R2 and R3 or R3 and R4¿ together with the atoms to which they are attached forms a 5- or 6- membered ring; R?5, R6, R7 and R8¿ are independently hydrogen, alkyl or aryl, or is a group of formula -Si(R11)3, -P(R12)2 or -N(R13)2, where each R?11, R12 and R13¿ are independently alkyl or aryl, provided that at least one of R?5, R6, R7 and R8¿ is an alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring, or is a group of formula -Si(R11)3, -P(R12)2 or -N(R13)2; R?9 and R10¿ are independently alkyl or aryl; M is a metal selected from the group consisting of Ti, Zr and Hf; n is 2; and X is halo or aryloxy, or (X)¿n? may with the metal atom to which it is attached form a 5-, 6- or 7-membered ring are provided. Preferred compounds contain a menthyl or neomenthyl group. Compounds of Formula (1) are useful as catalysts, particularly in optically active form.

Description

ORGANOMETALLIC COMPOUNDS. THEIR PREPARATION AND USE

The present invention relates to organometallic compounds, more particularly to optically active organometallic compounds, their use as catalysts, methods for their preparation and their use in synthesis particularly in asymmetric synthesis.

Ansa-bridged organometallocenes in which the bridging atom is silicon and the metal is lutetium or yttrium (J. Am. Chem. Soc. 112(26), 9558 [1990]) or samarium (J. Am. Chem. Soc. 114, 2761 [1992]) are known but such compounds suffer the disadvantage of employing lanthanide metals which are expensive and environmentally unacceptable particularly for use in industrial processes. Additionally, such catalysts are extremely difficult to purify and are susceptible to deactivation by oxygen, which makes them unsuitable for use in industrial processes.

It would therefore be desirable to identify organometallic compounds which achieve one or more of the objectives of being relatively inexpensive to prepare, effective catalysts for use in organic syntheses, particularly asymmetric syntheses and which are less sensitive to oxygen. According to a first aspect of the present invention there is provided an organometallic compound of Formula(1):

wherein: R¹, R², R³, and R⁴ each independently is -H or optionally substituted alkyl or optionally substituted aryl; or one of R¹ and R² or R² and R³ or R³ and R⁴ together with the atoms to which they are attached forms a 5- or 6- membered ring;

R⁵, R⁶, R⁷ and R⁸ each independently is -H or optionally substituted alkyl or optionally substituted aryl, or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, where each R¹¹, R¹² and R¹³ independently represents alkyl or aryl, provided that at least one of

R⁵, R⁶, R⁷ and R⁸ is a substituted or unsubstituted alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring or is a group of formula -Si(R ¹)₃, -P(R¹²)₂ or -N(R¹³)₂; R⁹ and R¹⁰ each independently is optionally substituted alkyl or aryl; M is a metal selected from the group consisting of Ti, Zr and Hf; n is 2; and

X is halo or aryloxy, or (X)_n may with the metal atom to which it is attached form a 5, 6 or 7-membered ring.

Hereinafter, the cyclopentadienyl ring bearing the groups R¹-R⁴ shall be referred to as ring A, and the cyclopentadienyl ring bearing the groups R⁵-R⁸ shall be referred to as ring B.

Alkyl groups which may be represented by R\ R², R³, R⁴, R⁹, R¹⁰ R¹¹, R¹² and R¹³ are preferably C_1-6-alkyl, more preferably a C^-alkyl and especially methyl or ethyl groups. Aryl groups which may be represented by R¹, R², R³, R⁴, R⁹, R¹⁰ R¹¹, R¹² and R¹³ are preferably phenyl or naphthyl, more preferably phenyl groups.

Where one of R¹ and R² or R² and R³ or R³ and R⁴ together with the atoms to which they are attached form a 5- or 6- membered ring, the 5- or 6- membered ring may be alicyclic, heteroalicyclic, aryl or heteroaryl. The 5- or 6- membered ring may be optionally substituted cyclohexyl, but is preferably a phenyl ring. In certain preferred embodiments, each of R¹, R², R³ and R⁴ represents an alkyl group, particularly a C_1-4 alkyl group and especially a methyl group.

At least one of R⁵ to R⁸ represents a substituted or unsubstituted alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, the remainder being H or alkyl or aryl groups as defined above for R¹-R⁴. Substituted or unsubstituted alkyl groups comprising 5 or more carbon atoms and which are branched at the carbon alpha to the cyclopentadienyl ring are preferred, and examples which may be represented by R⁵ to R⁸ include non-cyclic and cyclic groups. The total number of carbon atoms is often no more than 30 and commonly no more than 20. Examples of non-cyclic groups include 2-pentyl, tert-pentyl, 2-hexyl, tert-hexyl, 2-heptyl, tert-heptyl, 2-octyl, tert- heptyl, 2-nonyl, tert-nonyl, diphenylmethyl and triphenylmethyl groups. Examples of cyclic groups include cyclopentyl, cyclohexyl and indenyl groups, and groups derived from alkaloids such as camphor, borneol, fenchol, pinene, verbenol and iso-menthol.

Preferred cyclic groups include menthyl and neomenthyl groups. In an especially preferred embodiment, the alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring which may be represented by

R⁵ to R⁸ is an enantiopure auxiliary. The enantiopure auxiliary provides steric discrimination and diastereoisomeric complexes that allow physical separation, and may be any asymmetric group. The enantiopure auxiliary is preferably menthyl or neomenthyl, more preferably (-)-menthyl and (+)-neomenthyl. Groups of Formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, which may be represented by R⁵ to R⁸ include t-butyldimethylsilyl, trimethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylphosphinyl, diphenylamino and piperidinyl.

It is preferred that each of R¹ to R⁸ are chosen such that the pattern of substitution around cyclopentadienyl ring B is different from that of cyclopentadienyl ring A.

It is preferred that only one or two of R⁵, R⁶, R⁷, and R⁸ and particularly preferably only one, represents an alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring, or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, where R¹¹, R¹² and R¹³ are as defined above. When two of R⁵, R⁶, R⁷, and R⁸ represent an alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring, or are groups of formula -Si(R¹ )₃, -P(R¹²)₂ or -N(R¹³)₂, it is especially preferred that the two groups so defined are selected from the pairings R⁵ and R⁶, R⁵ and R⁷, R⁶ and R⁸ or R⁷ and R⁸. When only one of R⁵, R⁶, R⁷, and R⁸ represents an alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring, or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, it is particularly preferred that R⁶ or R⁷ represents menthyl or neomenthyl, and more preferably (-)-menthyl and (+)-neomenthyl, and that the remainder of R⁵ to R⁸ represent H. Where any of the groups represented by R¹ to R¹³ is optionally substituted, the substituent is often selected from -F, -Cl, -Br, -I, alkyl, preferably C_1-4 alkyl, aryl, alkoxy, preferably C_M alkoxy, -NO₂, -CN, -OH, -NHSO₂CH₃, -NHSO₂aryl or -NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ each independently are -H, methyl, ethyl, phenyl or benzyl. Preferred substituents include alkyl, especially C_1-4 alkyl, phenyl, alkoxy, especially C_1-4 alkoxy, NHSO₂CH₃, -NHSO₂phenyl or -NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ each independently are -H, methyl, ethyl, phenyl or benzyl. In many embodiments, the groups represented by R¹ to R ³ are unsubstituted or are substituted only by alkyl or aryl substituents. The metal represented by M is preferably titanium. The halo represented by X is preferably -F, -Cl or -Br. The aryloxy represented by X is preferably phenoxy or naphthoxy, more preferably phenoxy. When (X)_n together with M forms a 5, 6 or 7-membered ring, (X)_n preferably, comprises two O or S, or one O and one S, atoms coordinated to M, preferably two O atoms. Most preferably, (X)_n together with M is a 5-membered ring, especially where (X)_n is a catechol or a dihydroxynaphthalene. Especially preferred compounds of Formula (1) are those in which R¹ to R⁴ are all methyl, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R ⁰ are both methyl, M is titanium and X is -Cl. The compound of Formula (1) may be prepared by reaction of a compound of Formula (2), or isomers thereof in which the cyclopentadienyl double bonds are in different positions around the rings:

Formula (2) first with an organometallic compound and secondly with a compound of formula M(X)_πX¹ in which R¹ to R¹⁰, X and n are as hereinbefore defined and X¹ is halo. X¹ is preferably -Cl, -Br or -I, more preferably -F or -Cl. The organometallic compound is preferably an organolithium compound, more preferably an alkyllithium compound and especially n-butyllithium. The compound of Formula (1) is preferably prepared in a liquid medium. The liquid medium is preferably an ether, more preferably a diaikyl ether such as a diethyl ether or a cyclic ether such as tetrahydrofuran (THF). The liquid medium is preferably dried before use. The organometallic compound is preferably added to the compound of Formula (2) at a temperature of from -30°C to 10°C, more preferably at. from -10°C to 0°C. The compound of formula M(X)_nX¹ is preferably added to the reaction mixture after cooling the reaction mixture to a temperature of from -100°C to -50°C, more preferably at from -80°C to -70°C. The reaction temperature may then be increased to 20°C to 60°C, or conveniently to the boiling point of the liquid medium. The preparation of the compound of Formula (1) is preferably carried out in an inert atmosphere of for example nitrogen or argon. The compound of Formula (1) may be isolated from the reaction mixture by any convenient means for example by adding an acid such as hydrochloric acid and separating the organic and aqueous layers followed by evaporation of the liquid medium. The compound of Formula (1) may be purified by any convenient means for example by flash chromatography or distillation under reduced pressure. The process for preparing compounds of Formula (1) provides a second aspect of the present invention.

The compounds of Formula (2) may be prepared by reaction of a compound of Formula (3) or isomers thereof in which the cyclopentadienyl double bonds are in different positions around the rings:

Formula (3) with a compound of Formula (4) or isomers thereof in which the cyclopentadienyl double bonds are in different positions around the ring:

Formula (4)

in which R¹ to R¹⁰ and X¹ are as hereinbefore defined. The compound of Formula (4) preferably in a liquid medium, more preferably in an ether such as THF, is firstly reacted with an organometallic compound preferably an organolithium compound, more preferably an alkyllithium compound and especially n-butyllithium at a temperature of from -20°C to 10°C and secondly with a compound of Formula (3) preferably at a temperature from 20°C to 60°C and conveniently at the boiling point of the liquid medium. The compound of Formula (2) may be isolated by removing the precipitated lithium chloride by filtration and evaporating the liquid medium. Any excess compound of Formula (3) may be removed by heating under reduced pressure. The compound of Formula (3) may be prepared by reacting a compound of

Formula (5) or isomers or mixtures of isomers thereof in which the cyclopentadienyl double bonds are in different positions around the ring:

Formula (5) in which R¹ to R⁴ are as hereinbefore defined, with an organometallic compound preferably an organolithium compound, more preferably an alkyllithium compound and especially n-butyllithium and then with a compound represented by CI₂SiR⁹R¹⁰ in which R⁹ and R ⁰ are as hereinbefore defined. The compound of Formula (3) may be recovered and purified by any convenient means such as distillation.

The compound of Formula (4) may be prepared by reaction of a cyclopentadienyl salt with an alkylating agent, particularly an alkylating agent comprising an enantiopure auxiliary, such as menthyl tosylate or neomenthyl tosylate. The cyclopentadienyl salt is formed from the corresponding cyclopentadiene and an alkyllithium such as butyllithium, a metal hydride, such as an alkali metal hydride, particularly sodium hydride, or an alkali metal such as sodium, sodium metal being preferred.

The cyclopentadiene is preferably freshly prepared before use by cracking dicyclopentadiene.

The compound of Formula (5) may be prepared by reducing the corresponding cyclopent-2-enone with a reducing agent or by the method of Garner et al, Tett. Letts. 35, 16, 2463. Suitable reducing agents include lithium aluminium hydride, lithium diisobutyl aluminium hydride or preferably a combination of sodium borohydride with a lanthanyl halide such as CeCI₃. The compound of Formula (4) may be isolated and purified by distillation. It will be recognised that when cyclopentadiene ring A in Formula (1) comprises a symmetrical moiety, and that when the substituents represented by R⁵ and R⁶ are not the same as those represented by R⁸ and R⁷, respectively, the compound of Formula (1) will have planar asymmetry through the cyclopentadienyl-Si and cyclopentadienyl-M bonds, and that it will therefore exist in 2 enantiomeric forms, R and S. During the studies resulting in the present invention, and especially for those compounds of Formula (1) in which R¹ to R⁴ are all methyl, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, and especially , R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -Cl, it was surprisingly found that one diastereomer was more active as a catalyst than the other. It would therefore be desirable for the less active isomer to be converted to the more active isomer. It has now been found that the less active isomers of compounds of Formula (1) in which R¹ to R⁴ are all methyl, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -Cl can be converted to the more active isomer by irradiation with uv-visible light. This interconversion process is also applicable to compounds having the same general formula as those of Formula (1) except that both of the pairings R¹ and R² and R³ and R⁴ together with the carbon atoms to which they are attached form a phenyl ring, such that ring A comprises part of a fluorenyl moiety, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -Cl. This process of conversion of less active isomer to more active isomer forms a third aspect of the present invention. The conversion is preferably achieved by irradiating the less active isomer with uv-visible light having wavelengths in the range of from 200nm to 800nm, and preferably from 220nm to 450nm. A uv-visible lamp emitting the desired wavelength range is preferably employed. The conversion preferably takes place with the less active isomer dissolved in an inert hydrocarbon solvent such as benzene, toluene, xylene, hexane or heptane, and at ambient or sub-ambient temperature, such as no less than -40°C particularly no less than -25°C, and up to no more than 25°C, such as no more than 10°C. It has been found that often the less active isomer is the R isomer.

Where the process for the preparation of compounds of Formula (1) having planar asymmetry produces a mixture of both isomers, the product so obtained can be treated by the uv-visible process of conversion to convert substantially all of the less active isomer to the more active isomer. Alternatively, it may be possible to separate the less active isomer from a mixture of isomers by differential crystallisation from a suitable solvent, for example a hydrocarbon solvent such as hexane. Temperatures of from 0°C to -40°C may be employed. A further method of separating the R from the S isomer is by HPLC, for example using a cyclodextrin column such as Chiralcel CD™, available from Daicel Inc., using mixtures of alkane, preferably hexane, and ether, preferably t-butylmethyl ether. The less active isomer obtained by crystallisation or HPLC can then be converted to the more active isomer by the use of the uv-visible process of conversion.

The compounds are useful as catalysts for a number of asymmetric syntheses such as in hydrogenations, alkylations, hydrosilylations, polymerisations and cycloadditions. Use of these compounds as catalysts generally has the advantage that mild reaction conditions may be used and that high yields and good enantiomeric excesses (ee) may be obtained. The use of a compound of Formula (1) as a catalyst forms a further feature of the present invention.

According to a fourth aspect of the present invention there is provided a process for asymmetric hydrogenation of a compound having a double or triple bond which comprises reacting the compound with hydrogen in the presence of a compound of Formula (1).

Compounds having a double bond which may be asymmetrically hydrogenated include alkenes, imines, vinylamides, ketones and vinylesters, and particularly alkenes, ketones and imines.

The asymmetric hydrogenation is preferably carried out in a liquid medium. Suitable liquid media include alkanes and arenes. Where the liquid medium is an alkane it is preferably a C₅.₁₅-alkane, more preferably n-hexane, n-heptane, isomers of octane, cyclohexane or decalin. Where the liquid medium is an arene it is preferably toluene, xylene or mesitylene. It has surprisingly been found that the addition of water, for example at an amount up to 1 equivalent based on the catalyst can increase the enantiomeric excess of one of the isomers of the asymmetric reaction product. Hydrogen gas is preferably used in the hydrogenation process. The hydrogenation process is preferably carried out at temperatures of from -80°C to 110°C, more preferably at from -50°C to 90°C and especially at from -40°C to 80°C. The hydrogenation process is preferably carried out at a pressure of from 1 to 100 atmospheres, more preferably at from 1 to 25 atmospheres.

The catalyst is preferably present at a concentration of 0.001 to 5.0 mol% of the compound having the double bond, more preferably at from 0.01 to 1.0 mol%. A co-catalyst is preferably used. Preferred co-catalysts are alkali metal aluminium dihydride dialkoxides such as lithium aluminium dihydride di(tertiary butoxide), or an alkali metal hydride such as sodium hydride, or a metal such as sodium or magnesium, or an alkyllithium such as butyllithium, or a Grignard Reagent of formula R'MgX² in which R' is alkyl or aryl and X² is -Cl, -Br or -I. A preferred co-catalyst is sodium bis(2methoxyethoxy) aluminium hydride. Relative amounts of co-catalyst to catalyst are preferably in a ratio of from 0.1 to 20:1 , more preferably from 1 to 10:1. Additionally, an activator such as a metal fluoride, preferably an alkali metal, such as potassium, fluoride can be employed. The activator may be employed in an amount equivalent in molar terms to the catalyst or may be employed in a molar excess. The hydrogenation process may take place in the presence of a stabilising reagent. An example of such a reagent is PhSiH₃. The stabilising reagent may be present in an amount of from equimolar to a fifty-fold molar excess based on the amount of catalyst.

According to a fifth aspect of the present invention, there is provided a process for the asymmetric hydrosilylation of a compound having a double or triple bond which comprises reacting the compound with a hydrosilylating agent in the presence of a compound of Formula (1).

Compounds having a double bond which can be hydrosilylated in the presence of a catalyst of Formula (1) include alkenes, imines, vinylamides, ketones, vinylketones and vinylesters, and particularly alkenes, ketones and imines.

The asymmetric hydrosilylation process is preferably carried out in a liquid medium. Suitable liquid media include alkanes, arenes and ethers. Preferred alkanes include C_5-15 alkanes, and more preferably n-hexane, n-heptane, isomers of octane, cyclohexane or decalin. Preferred arenes include toluene, xylene and mesitylene. Preferred ethers include those having the general formula R^x-O-R^y, wherein R^x and R^y each independently represents a C_1-6 alkyl or an aryl group or R^x and R^y together with the O atom form a 5, 6 or 7 membered saturated ring, and more preferably diethylether, diisopropylether, t-butylmethylether, diphenylether or tetrahydrofuran. It has surprisingly been found that the addition of water, for example at an amount up to 1 equivalent based on the catalyst can increase the enantiomeric excess of one of the isomers of the asymmetric reaction product.

The hydrosilylating agent may be a compound known in the art to hydrosilylate double or triple bonds. Preferred hydrosilylating agents include those of the formula R^aR^bR^cSiH, wherein each of R^{a c} independently represents an alkyl, aryl or halo group, or H, provided at least one of R^{a c} represents alkyl, aryl or halo, such as dichlorosilane, Ph₃SiH, Ph₂SiH₂ and PhSiH₃. Other preferred hydrosilylating agents include polymeric silanes, such as poly(methylhydrosiloxane) and poly(phenylhydrosiioxane).

The hydrosilylation process can be carried out at temperatures of from -80°C to 110°C, more preferably at from -50°C to 90°C and especially at from -40°C to 80°C. The hydrogenation process is preferably carried out at ambient pressure.

In the hydrosilylation process of the present invention, the catalyst of Formula (1) is most often present at a concentration of about 0.001 mol% to 5 mol%, preferably from 0.01 mol% to 1 mol%, based on the amount of the compound having the double or triple bond. The amount of catalyst employed can be varied appropriately in situations where the compound being hydrosilylated comprises two or more double bonds which it is desired to hydrosilylate, or where it is desired to hydrosilylate twice at a triple bond.

A co-catalyst is preferably used. Preferred co-catalysts are alkali metal aluminium dihydride dialkoxides such as lithium aluminium dihydride di(tertiary butoxide), or an alkali metal hydride such as sodium hydride, or a metal such as sodium or magnesium, or an alkyllithium such as butyllithium, or a Grignard Reagent of formula

R'MgX² in which R' is alkyl or aryl and X² is -Cl, -Br or -I. A preferred co-catalyst is sodium bis(2methoxyethoxy) aluminium hydride. Relative amounts of co-catalyst to catalyst are preferably in a ratio of from 0.1 to 20:1 , more preferably from 1 to 10:1. Additionally, an activator such as a metal fluoride, preferably an alkali metal, such as potassium, fluoride can be employed. The activator may be employed in an amount equivalent in molar terms to the catalyst or may be employed in a molar excess.

The present invention is further illustrated by the following examples:

Example 1

Preparation of (R,S)-dichloro{1 -(η⁵-2,3,4,5-tetramethylcyclopentadienyl)-1 '-fn⁵-3'-(+)- neomenthylcyclopentadienylldimethylsilaneltitanium i) Preparation of (-)-menthyltosylate

Toluenesuiphonylchloride (32.7g) was added to a solution of (-)-menthol (25. Og) in pyridine (75 cm³). The mixture was stirred for 46 hours before quenching with ice/water

(50 cm³). Crystals were deposited and collected by filtration and washed with water.

Recrystallisation gave (-)-menthyltosylate (46.0g, 93%). ii) Preparation of (+)-neomenthylcyclopentadiene

Sodium hydride (9.6, 0.2 mol, 50% dispersion) was washed with hexane (3 x 50 cm³) then THF (150 cm³) was added. Freshly cracked cyclopentadiene (26g, 0.4 mol) in THF (50 cm³) was added over a 1 hour period and the mixture was stirred for 3 hours. The resulting red solution of cyclopentadienylsodium was added to a solution of

(+)-menthyltosylate (31.7g, 0.1 mol) in THF (100 cm³) via cannula. The mixture was heated under reflux for 6 hours producing a precipitate of sodium tosylate. After cooling, the mixture was filtered and the solvent removed in vacuo to produce a brown viscous residue which was redissolved in diethyl ether and washed with water (3 x 100 cm³). The organic layer was dried over Na₂SO₄, filtered and the solvent removed in vacuo to yield a brown oil which was distilled at reduced pressure to yield the product as a colourless liquid (3.07g, 15%, 95% pure G.C.) b.p._{o 05} 70°C; δH(25 MHz; solvent CDCI₃) 0.79-0.90 (9H, m, CH₃), 0.90-1.86 (9H, m, CH₂'s and CH's), 2.90-3.12 (3H, m, CH and allylic), 6.08-6.58 (3H, m, vinylic).

iii) Preparation of 1 ,2,3,4-tetramethylcvclopentadiene

2,3,4,5-Tetramethylcyclopent-2-enone (18.8g, 0.13 mol in diethyl ether (50 cm³) was added over 1 hour to a suspension of lithium aluminium hydride (2.5g 0.07 mol) in diethyl ether (200 cm³) and the mixture was stirred for a further 2 hours. Aqueous hydrochloric acid (1.0 M, 300 cm³) was added slowly and when the addition was complete the mixture was stirred overnight in air. The organic layer was separated and the aqueous layer washed with diethyl ether (3 x 100 cm³). The ether washings were combined with the organic layer, washed with a saturated sodium carbonate solution (2 x 50 cm³) and dried over Na₂SO₄. Removal of the solvent in vacuo gave a yellow liquid that was distilled at reduced pressure to produce the title product as a colourless liquid (6.59g yield 37%) b.p.₀₅ 30-35°C; δH(250 MHz; solvent CDCI₃) 1.80 (6H, br s, 2 CH₃), 1.95 (6H, br s, 2CH₃), 2.75 (2H, br s, C₅Me₄H₂).

iv) Preparation of 1-(chlorodimethylsilyl)-2,3,4,5-tetramethylcvclopentadiene 1 ,2,3,4-Tetramethyicyclopentadiene (6g, 0.05 mol) was dissolved in petroleum ether (b.p. 40°-60°) and a solution of n-butyllithium (2.5M, 20 cm³, 0.05 mol) was added at 0°C over 1 hour. The mixture was stirred for 15 hours at room temperature to produce a milky white suspension which was thinned by the addition of THF (45 cm³). A solution of dichlorodimethylsilane (9.7g, 0.075 mol) in THF (30 cm³) was added at 0°C over 1 hour and the mixture was stirred for a further 15 hours. The lithium chloride precipitate was filtered off through Cellite under nitrogen producing a yellow solution. Removal of solvent in vacuo gave the crude product as yellow/brown oil. The crude product was distilled under reduced pressure to give the title product as yellow/green liquid b.p.₀₀₅ 56- 60°C; δH(250 MHz; solvent CDCI₃) 0.30 (6H, s, 2Si-CH₃), 0.9 (6H, s, 2CH₃), 2.06 (6H, s, 2CH₃).

v) Preparation of 1 -(2,3,4,5-tetramethylcvclopentadienyl)-1 '-r3'-(+)-neomenthyl- cyclopentadienyll dimethylsilane

(+)-Neomenthylcyclopentadienyllithium (3.07g, 0.015 mol) was prepared by the addition of a solution of n-butyllithium (2.5 M, 10.8 cm³, 0.27 mol) in hexane to a solution of (+)-neomenthylcyclopentadiene (5.51 g, 0.027 mol) in THF (50 cm³) at 0°C followed by stirring at room temperature for 30 minutes. This solution was transferred at room temperature via cannula to a solution of 1-(chlorodimethylsilyl)-2, 3,4,5- tetramethylcyclopentadiene (4.29g, 0.02 mol) in of THF (50 cm³). The mixture was heated at reflux temperature for 12 hours, cooled to room temperature and the solution filtered to remove lithium chloride. Solvent was removed in vacuo and the yellow oil obtained redissolved in diethyl ether and washed with water (3 x 20 cm³), dried over Na₂SO₄ and the solvent removed in vacuo to yield a yellow oil. Heating of the yellow oil in a vacuum distillation apparatus to 80°C under high vacuum removed excess 1- (chlorodimethylsilyl)-2,3,4,5-tetramethyicyclopentadiene and left the title product as a yellow oil (4.73, 83%) δ_H (250 MHz; solvent CDCI₃), -0.05-0.33 (6H, m, Si-CH₃), 0.90-1.11 (9H, m, neomenthyl CH₃), 1.07-1.85 (9H, m, CH₂'s, CH's), 1.85-2.20 (12H, m, Cp-CH₃'s). 3.00-3.40 (3H, m, allylic, neomenthyl CH), 6.15 (1 H, br s, olefinic), 6.36-6.48 (1 H, m, olefinic), 6.61-6.72 (1 H, m, olefinic), δ_c (63 MHz, solvent CDCI₃, reference SiMe₄) 156.5, 147.7, 147.3, 142.6, 136.1 , 135.2, 133.2, 132.4, 129.0, 119.7 (Cp's), 48.0, 47.9, 37.8, 37.7, (CH's), 42.4, 35.8, 26.1 (neomenthyl CH₂'s), 30.2, 26.5, 22.8, 21.4, 21.3, 14.7, 11.3 (CH₃'s), 1.1 , -2.6 (Si-CH₃'s), m/z [GC/MS (El)] 382 (M+, 12%), 261 (78, M-TMCp), 179 (100, M-nmCp).

vi) Preparation of (R,S)-dichloro{1 -,η⁵-2,3,4,5-tetramethylcvclopentadienyl)-1 '-fn⁵-3'- (+)-neomenthylcvclopentadienvπdimethylsilane)titanium

1-(2,3,4,5-Tetramethylcyclopentadienyl)-1'-[3'-(+)-neomenthylcyclopentadienyl] dimethylsilane (3.07g, 8 mmol) was dissolved in THF (45 cm³). A solution of n- butyllithium (2.5M, 6.4 cm³, 16 mmol) in hexane was added at 0°C via syringe and the mixture stirred at room temperature for 30 minutes. The solution was cooled to -78°C and TiCI₃.3THF (3.1g, 8 mmol) was added rapidly against a stream of nitrogen, the mixture was allowed to warm to room temperature and then heated to reflux for 6 hours. After cooling to room temperature, chloroform (45 cm³), together with concentrated aqueous hydrochloric acid (30 cm³) was added and the mixture stirred at room temperature in air for 30 minutes. The organic layer was separated, dried over Na₂SO₄ and the solvent removed in vacuo to yield a red, viscous oil. This was chromatographed on a silanised column eluting with hexane to remove organic residues and then a 4% diethyl ether/hexane mixture to elute a red band consisting of a 1.2:1 mixture of more active to less active diastereo ers (2.74g, 67%).

Example 2 Hydrogenation of 1-ethylstyrene

A mixture of 1 -ethylstyrene (0.5 cm³) and hexane (5 cm³) was hydrogenated at - 30°C and 1 bar with hydrogen gas in the presence of (R,S)-dichloro{1-(n⁵-2, 3,4,5- tetramethylcyclopentadienyl)-1'-[η⁵-3'-(+)-neomenthylcyclopentadienyl]dimethylsilane} titanium (10mg) and lithium aluminium dihydride di-t-butoxide (60mg) in THF (0.5 cm³) to give (S)-2-phenylbutane ( 0.1 g, 21 %, 52% ee).

Example 3

Hydrogenation of 1-pyrollidinylstyrene

(R)-dichloro{1-(η⁵-2,3,4,5-tetramethylcyclophentadienyl)-1'-[η⁵.3'-(+)- neomenthylcyclopentadienyl]dimethylsilane} titanium (18mg) in a dry stirred 10ml flask flushed with argon gas, was dissolved in dry, argon flushed, tetrahydrofuran (5ml). 1- pyrollidinylstyrene (200μm) was added, then the flask sparged first with argon for 20 minutes and then hydrogen for 10 minutes. A 1.0M argon-flushed toluene solution of sodium bis(2-methoxyethoxy)aluminium hydride (250μl) was added to the reaction solution which changed colour to green/grey, and the hydrogen sparge was continued for a further 6 hours after which the hydrogen flow was stopped, and replaced by a static hydrogen atmosphere for 16 hours. Analysis of the reaction by Chiral GC indicated 15% of the starting material had been converted to 1-methylbenzylpyrrolidine of 62% e.e. The identity of the product was confirmed by ¹HNMR and GC-mass spectrometry purification by column chromatography using silica and elution with diethyl ether.

Example 4

Hydrosilylation of acetophenone

(R)-dichloro{1-(η⁵-2,3,4,5-tetramethyicyclopentadienyl)-1 '-[η⁵-3'-(+)- neomenthylcyclopentadienyl]dimethylsilane} titanium (22mg) in a dry stirred 10ml flask flushed with argon gas, was dissolved in dry, freshly distilled toluene (1 ml). A 1.0M argon-flushed toluene solution of sodium bis(2-methoxyethoxy)aluminium hydride (90 μl) was added dropwise to the reaction solution at 5°C which became green/grey colour. Phenylsilane (16.5 μl) was then added dropwise and the solution was warmed to ambient temperature. Acetophenone (100 μl) was added dropwise and the solution was warmed to 50°C. After 3 hours the reaction mixture analysed by Chiral GC and found to contain only phenylethanol product of 94.5% (R) enantiomer and 5.5% (S) enantiomer. Example 5

Hydrosilylation of acetophenone

(R)-dichloro{1-(η⁵-2,3,4,5-tetramethylcyclopentadienyl)-1 '-[η⁵-3'-(+)- neomenthylcyclopentadienyljdimethylsilane} titanium (0.02 mol equiv.) in a dry, stirred flask flushed with argon gas, was dissolved in hexane (2ml). 2.0M hexane solution of n- butyllithium (0.02 mol equiv.) was added dropwise to the solution at 0°C which became green/grey colour. Poly(methylhydrosiloxane) (1.5 mol equiv.) was then added dropwise and the solution warmed to ambient temperature. Acetophenone (1.0 mol equiv.) was added dropwise and the solution stirred for 18 hours. GC analysis showed that 99% of the acetophenone had been converted to 1-phenylethanol of 76.5% (S) and 23.5% (R).

Example 6

As for Example 5 except 0.01 mol equiv. of catalyst were used in the reaction heated at 65°C for 18 hours. GC analysis showed that 92% of the acetophenone had been converted to 1-phenylethanol of 82.5% (S) and 17.5% (R).

Example 7

Preparation of (R,S)-dichloro(1-(n⁵-2.3,4.5-tetramethylcvclopentadienyl)-1'-[η⁵-3'-(-)- menthylcvclopentadienylldimethylsilaneltitanium The title compound was prepared by following the general method of Example 1 , except employing (+)-neomenthol in place of the (-)-menthol.

Example 8

A diastereomeric sample of the the product of Example 7 above wherein the ratio of less active isomer: more active isomer was 1.2:1 was dissolved in dry toluene and irradiated with a 125W Hanovair UV Lamp at a temperature of -20°C for approximately

4.5 weeks. Complete conversion from less active isomer to more active isomer was observed.

Example 9

500mg of diastereomeric product of Example 1 was dissolved in pet ether (200cm³, bpt 60-80°C) was irradiated with a 125W Hanovair UV Lamp at a temperature of -20°C for 2 weeks. The solvent was removed in vacuo, the residue dissolved in hexane (10cm³) and filtered through silanised silica. Removal of the solvent gave 260mg of pure product, having a ratio of active : less active isomers of 3:1.

Claims

1. An organometallic compound of Formula(1):

wherein:

R¹, R², R³, and R⁴ each independently is -H or optionally substituted alkyl or optionally substituted aryl; or one of R¹ and R² or R² and R³ or R³ and R⁴ together with the atoms to which they are attached forms a 5- or 6- membered ring; R⁵, R⁶, R⁷ and R⁸ each independently is -H or optionally substituted alkyl or optionally substituted aryl, or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂, where each R¹¹, R ² and R¹³ independently represents alkyl or aryl, provided that at least one of R⁵, R⁶, R⁷ and R⁸ is a substituted or unsubstituted alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂;

R⁹ and R¹⁰ each independently is optionally substituted alkyl or aryl;

M is a metal selected from the group consisting of Ti, Zr and Hf; n is 2; and

2. A compound according to claim 1 , wherein only one or two of R⁵, R⁶, R⁷, and R⁸ and preferably only one, represents an alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring, or is a group of formula -Si(R¹¹)₃, -P(R¹²)₂ or -N(R¹³)₂.

3. A compound according to either preceding claim, wherein the alkyl group comprising 5 or more carbon atoms and which is branched at the carbon alpha to the cyclopentadienyl ring represented by R⁵, R⁶, R⁷, and R⁸ is (-)-menthyl or (+)-neomenthyl.

4. A compound according to any one preceding claim wherein R¹ to R⁴ are all methyl, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -Cl.

5. A process for asymmetric hydrogenation of a substrate compound having a double or triple bond which comprises reacting the compound with hydrogen in the presence of a compound of Formula (1) as defined in claim 1.

6. A process for asymmetric hydrosilylation of a substrate compound having a double or triple bond which comprises reacting the compound with a hydrosilylating agent in the presence of a compound of Formula (1) as defined in claim 1.

7. A process according to claim 5 or 6, wherein R¹ to R⁴ are all methyl, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -CI.

8. A process according to any one of claims 5 to 7, wherein the substrate compound is selected from the group consisting of alkenes, imines, vinylamides, ketones and vinylesters, and preferably alkenes, ketones and imines.

9. The use of a compound of Formula (1) as defined in claim 1 as a catalyst.

10. A process for the conversion of less active isomers of compounds of Formula (1) as defined in claim 1 , in which R¹ to R⁴ are all methyl or both of the pairings R¹ and R² and R³ and R⁴ together with the carbon atoms to which they are attached form a phenyl ring, such that ring A comprisise part of a fluorenyl moiety, R⁵ and R⁸ are both -H, R⁶ is menthyl or neomenthyl, R⁷ is -H, R⁹ and R¹⁰ are both methyl, M is titanium and X is -Cl to the more active isomer in which the less active isomer is irradiated with uv-visible light.