GB2410026A - Sulfur-containing metallocenylphosphines and metallocenylarsines and their metal complexes - Google Patents

Abstract

A chiral metallocene ligand for use in homogeneous catalysis, the ligand having the formula (I): <EMI ID=1.1 HE=76 WI=52 LX=823 LY=803 TI=CF> <PC>or its enantiomer wherein M is a suitable metal, preferably iron, W is P or As, preferably P, R<1> is selected from substituted aryl or heteroaryl, preferably substituted phenyl; R<2>, R<3> are preferably phenyl; R<4> is a substituent, preferably methyl; Rn is a substituent, preferably hydrogen. The compounds of formula (I) can be used as catalysts in ARO or asymmetric hydrogenation reactions or asymmetric ring-opening reactions. Also, a transition metal complex containing a metal (preferably rhodium or iridium) co-ordinated to a ligand of formula (I) and the use of said complex as a catalyst or pre-catalyst. Also described is a method of preparing the transition metal complex comprising contacting the ligand of formula (I) with a halogen-containing transition metal complex in the presence of a halogen exchange or abstraction agent.

Description

LIGANDS FOR USE IN HOMOGENEOUS CATALYSIS

The present invention relates to homogeneous catalysis and to novel ligands for use therein, in particular to (arylthia) alkylmetallocene ligands, and to a process for their production, and to uses thereof.

The Josiphos_ ligand is well known in the field of homogeneous catalysis, in particular for the hydrogenation of imines.

PRR 5:PRR Fe

wherein R is selected from various radical groups. The Josiphos_ ligand is one of a class of chiral metallocene ligands which have been the subject of much interest, in particular in connection with the production of pharmaceutical compounds and intermediates, but also in other commercial applications, for example in agrochemicals and perfumery.

United States Patent No. 6,590,115 discloses bisphosphine metallocenyl compounds having both a carbon-bonded phosphine and a nitrogen-bonded phosphine, and describes potential uses of such ligands in asymmetric catalysis.

Phosphine amide metallocenyl ligands and their use in asymmetric catalysis are described in United States Patent No. 6,620,954.

Bisphosphine ferrocenyl ligands and metal-ligand complexes are disclosed in United States Patent No. 6,191,284.

United States Patent No. 6,348,620 relates to a method for the homogeneous, catalytic, enantioselective hydrogenation of unsaturated esters, catalysis being effected with the aid of a bisphosphine ferrocenyl ligand complex.

Chiral metallocenes with bisphosphine substitutions are therefore well documented in the prior art. United States Patent No. 5,565,594 provides another example. However, the prior art also discloses disubstituted chiral metallocenes in which different radicals substitute the metallocene ring at the 1 and 1' positions. For example, United States Patent No. 6,133,464 (and its equivalent WO-A-98/15565) teaches a number of compounds substituted in this way, further radical substituents in the 2 position also being disclosed.

Nishibayashi et al disclose 1,2-disubstituted metallocene ligands in which a phosphine radical is substituted at the 1 position and a sulphurcontaining radical is substituted at the 2 position on one of the metallocene rings.

It is an object of the invention to provide improved ligands for use in homogeneous catalysis, in particular ligands capable of catalysing asymmetric reactions and giving rise to good yields and high levels of enantioselectivity.

There is also a need to "tailor" individual ligand catalysts to meet the requirements of a particular asymmetric hydrogenation reaction. Therefore, it would be desirable to provide a general class of ligands found to be suitable in homogeneous catalysis, and for there to be an improved degree of flexibility within the general class for bespoke tailoring of the ligand. It is an object of the present invention to provide such a general class of ligands, as well as suitably tailored ligands within the class.

According to the present invention there is provided a chiral metallocene ligand for use in homogeneous catalysis, the ligand having the general formula (1): R4 SR1 RnZ - WR2R3

M torn

Formula (1) or its enantiomer, wherein W is P or As (preferably P); M is a suitable metal; R. is selected from substituted aryl and heteroaryl groups; R2 and R3 are, independently, selected from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heterocycloalkyl groups; R4 is selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl; or wherein R4 and R' together form a substituted polyaromatic group; and Rn indicates any possible number of substituents on the or each cyclopentadiene ring, with n being from 0 to 3 on the top ring and from 0 to 5 on the bottom ring, R being, independently selected from alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl, OR', SR', NHR', NR'R", wherein R' and R" are the same or different and are independently selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups and wherein each R may be the same or different, with the exception that when the bottom ring has a single R substituent, the single R substituent on the bottom ring is not P(R5R6), SR7, CH=NR7, CH2- NH-R7 or CH2-o-P(R5R6), wherein R5 and R6 are, independently of each other, C4-C8 alkylene, C4-C8 alkylene substituted by C,-C4 alkyl or by phenyl, or annelated C4-C8 alkylene, and wherein R7 is hyd rogen, C, -C, 2 alkyl, C, -Cl 2 alkyl substituted by C, -C4 alkoxy, C5-C, 2 alkyl or by phenyl, C5-C,2 cycloalkyl, phenyl, C5-C,2 cycloalkyl substituted by C,-C4 alkyl or by C4-C4 alkoxy, or phenyl substituted by from one to three substituents selected from C, -C4 alkyl, C, -C4 alkoxy, SiR8R9R'0, halogen, SO3Z, CO2Z, PO3Z, NR"R'2, [+NR"R'2R'3]X- and C,-C5 fluoroalkyl, wherein R8, R9 and R4 are each independently of the others C'-C,2 alkyl or phenyl, R" and R,2 together are tetramethylene, pentamethylene or 3- oxa-1,5 pentylene, wherein R'3 is hydrogen or C,-C4 alkyl, wherein Z is hydrogen or an alkali metal, and wherein X is the anion of an acid.

The enantiomer has the general formula (11): WR2R3 Rn 4_.,.,\\\\R4 torn Formula (11) Wherein Rn, R', R,i, R., R2, R3, R4 R5 R6 R7 R8 R9 R4 R'' R'2 R'3 M W and X have the same meanings as defined above in respect of Formula (1).

Preferably, M is Fe.

In one preferred ligand according to the invention having a single R substituent on the bottom ring, the single R substituent does not contain any heteroatoms. In another preferred ligand according to the invention the bottom ring contains no heteroatom substituents. In another preferred ligand according to the invention the bottom ring contains no substituents, in which case n=0 on the bottom ring. Preferably n=0 on the top ring also.

Preferably the ligand of the invention has the Formula (111): R4 1SR1 t:PR2R3 Fe A57 Formula (111) Wherein R'-4 each have the meanings assigned hereinabove.

Some preferred ligands according to the invention have the Formula (IV): 1 SRi iPR2R3 Fe Formula (IV) wherein R'-3 have the same meanings assigned in Formula (1).

Preferred R' substituents include optionally further substituted alkylphenyl, dialkylphenyl, pyrimidinyl, alkoxyphenyl, naphthyl, halophenyl, dihalophenyl and nitrophenyl groups.

The substitution on R' has been found to confer unexpected advantages on the ligand activity compared to comparable ligands in which R' is not a substituted aryl or heteroaryl group.

Preferably, the R' substituent is substituted at the meta- and/or pareposition with respect to the sulphur group. Such ligands appear particularly suited for ARO reactions. However, for other transformations, such as asymmetric hydrogenation, it may in some cases be preferable for the R' substituent to be substituted at the or/ho-position with respect to the sulphur group. In certain cases it may be preferable for R' to be unsubstituted at the or/ho-position with respect to the sulphur group.

Preferred R2 and R3 substituents include, independently, optionally substituted phenyl, t-butyl, and cyclohexyl groups.

Also provided in accordance with the invention is the use of the ligand of Formula I, or its enantiomer, in combination with a metal source as a catalyst in asymmetric hydrogenation reactions. Suitable substrates include imines, allylic alcohols and esters, a, p-unsaturated esters, olefins, and substrates giving rise to a-amino acids and p-amino acids. The ligand of the invention also finds application as a catalyst in asymmetric ring opening (ARO) reactions.

The invention also provides a method for asymmetrically hydrogenating an organic substrate comprising contacting the substrate under suitable hydrogenation conditions with a suitable hydrogenation reagent in the presence of the ligand of Formula I as catalyst.

The invention also provides a method for performing an ARO reaction comprising contacting a cyclic substrate under suitable ARO conditions with a suitable ARO reagent in the presence of the ligand of Formula I as catalyst.

Also provided in accordance with the invention is the use the ligand of Formula 1, or its enantiomer in combination with a metal source as a catalyst in asymmetric ring opening reactions reactions. Suitable substrates include oxa/azabicyclic norbornadienes and oxa/azabicyclic alkenes: R:R R:C Z= 0, N Suitable nucleophiles for the catalysed addition to the above substrates include alcohols, carboxylates, aliphatic and aromatic amines and carbon 1 5 nucleophiles.

The invention also provides a method for carrying out asymmetric ring opening reactions comprising contacting the substrates under suitable conditions with a suitable metal source in the presence of the ligand of Formula I to comprise the catalyst.

Also provided in accordance with the invention is a transition metal complex containing as ligand a compound of Formula (1), (11), (111) or (IV).

In the course of experimental work, reported below, the inventors noted that the formation of stable transition metal complexes in accordance with the invention was assisted by the use of a halogen exchange or abstraction agent in the synthesis involving contacting the ligand of the invention with a transition metal (suitably rhodium or iridium) itself coordinated with cyclooctadiene and chlorine. Suitable halogen exchange or abstraction agents were found to be iodides, such as sodium iodide, and tetraaryl borate anions, such as tetrakis(3,5-bis(trifluormethyl) phenyl)borate. Other suitable halogen abstraction salts include, by way of example, silver (1) triflate, silver tetrafluoroborate, ammonium hexafluorophosphate and sodium hexafluoroantimonate. Trifluoromethyl compounds are also suitable.

Accordingly, the invention also provides a method for preparing transition metal complexes in accordance with the invention comprising contacting the ligand of the invention with a halogen-containing transition metal complex in the presence of a halogen exchange or abstraction agent. This method can be used to prepare the inventive complex in situ for use in an ARO or hydrogenation reaction, or for pre- preparation of the catalytic complex.

A halogen-containing metal complex can be reacted with a halogen abstraction agent to yield a halogen-free metal source after filtration of any formed halogen salt. The halogen-free metal source can then be combined with an appropriate ligand. Such halogen-free metal sources are commercially available as [M(cod)2][counterion]. In situ preparation of complexes for hydrogenation can be made by reacting a suitable ligand L with [M(cod)2][counterion] to give [M(L)(cod)][counterion].

The invention will now be more particularly described with reference to the

Examples.

Example 1

A number of ligands in accordance with the invention were synthesised according to one of the following methods: Ligands syntheses were carried out using two methods depending on the reactivity of the thiol nucleophile.

Method 1 This method was used with the less reactive thiols with the phosphine-acetate A used as the starting ferrocene precursor G:OAc RSH, THF/H'O (4:1) 6:SR PPh2 Reflux, 6H e I,

A

Method 2 This method was used for more reactive thiols with the phosphine dimethylamine B used as the starting ferrocene precursor.

:NMe2 RSH,AcOH, 80 C, 2h 6 - \SR Fe PPh

B

The following ligands, designated L2, L3, L5-L13 and L15, were synthesised: PPh2PPh2 PPh2 SitFe SitFe SO L2 L3L5 Fe Sit;Fe Sin\ L6 L7L8 :ÓCH3 Fe S:CI 7 7 Cl L9 L10 L11 PPh2 Cl PPh2 PPh2 Fe S Fe SNO2 Fe SF Cl 6 L12 L13 L15 General Procedure for the syntheses of (Arylthia) alkyl metallocenes via Method 1: The phosphine-acetate A (1mmol) was dissolved in a mixture of THF/H2O (4:1, 20 ml) in a 2-necked round bottom flask equipped with a reflux condenser and a septum. The appropriate aryl thiol (1.2 mmol) was syringed into the flask via the septum and the resulting mixture reflexed for 6 h. After cooling to room temperature water was added and the mixture extracted with ether. The organic layer was dried over anhydrous sodium sulfate and after filtration the ether was removed under reduced pressure to give a crude product. This crude product was purified by flash chromatography on SiO2 eluting with a solvent mixture of Et3N/ethyl acetate/hexane or ethyl acetate/hexane to give the pure product. L2

The reaction was performed using the general procedure outlined above with 2-methylthiophenol as nucleophile, and column chromatography using Et3N/ EtOAc/hexane (2:5:93) to give the pure product as yellow foam in 40% yield.

MS: 521 (M++1); 1H NMR (400MHz, CDCI3): 1.67 (3H, d, -CH-5), 2.21 (3H, s, CH3-Ph), 3.94-4.48 (8H, m, Fc), 4.52 (1H, q, -CH-CH3), 7.08-7.63 (14H, m, Ar); 3iP NMR (162MHz, CDCI3): -23.58; Cald for C3'H29FePS: C, 71.54; H. 5.62. Found: C, 71.34; H. 5.64. L3

The reaction was performed using the general procedure outlined above with 3-methylthiophenol as nucleophile, and column chromatography using Et3N/ EtOAc/hexane (2:5:93) to give the pure product as a yellow foam in 51% yield.

MS: 520 (M++1); OH NMR (400MHz, CDCI3): 1.70 (3H, d, -CH-), 2.24 (3H, s, CH3-Ph), 3.92-4.39 (8H, m, Fc), 4.50 (1H, q, -CH-CH3), 6.98-7.64 (14H, m, Ar); 3'P NMR (162MHz, CDCI3): X -23.58; Cald for C3,H29FePS: C, 71.54; H. 5.62. Found: C, 71.52; H. 5.64. L5

The reaction was performed using the general procedure outlined above with 2,6-dimethylthiophenol as nucleophile, and column chromatography using Et3N/ EtOAc/hexane (2:5:93) to give the pure product as a yellow foam in 20% yield. MS: 534 (M+); lH NMR (400MHz, CDCI3): 61.47 (3H, d, -CH-), 2.40 (6H, s, 2xCH-Ph), 3.94-4.40 (8H, m, Fc), 4.54 (1H, q, -CH-CH3), 7.01-7.64 (15H, m, Ar); 34P NMR (162MHz, CDCI3): -23.70; Cald for C32H3,FePS: C, 71.91; H. 5.85. Found: C, 71.90; H. 6.00. L6

The reaction was performed using the general procedure outlined above with 2,4-dimethylbenzenethiol as nucleophile, and column chromatography using Et3N/ EtOAc/hexane (2:5:93) to give the pure product as a yellow foam in 35% yield. MS: 534 (M+); OH NMR (400MHz, CDCI3): 61.63 (3H, d, -CH-CH3), 2.24 (3H, s, CH3-Ph), 2.26 (3H, s, CH3-Ph) 3.92-4.45 (8H, m, Fc), 4.48 (1H, q, -CH CH3), 6 92-7.64 (13H, m, Ar); 3'P NMR (162MHz, CDCI3): -23.58; Cald for C32H31FePS: C, 71.91; H. 5.85. Found: C, 71.88; H. 5.90 L8 The reaction was performed using the general procedure outlined above with 2-mercaptopyrimidine as nucleophile, and column chromatography using EtOAc/hexane (20:80) to give the pure product as yellow foam in 94% yield.

MS: 508 (M+); 'H NMR (400MHz, CDC13): 1.92 (3H, d, -CH-CH3), 3.94-4.52 (8H, m, Fc), 5.25 (1H, q, -CH-CH3), 6.80 (1H, t, J. 4.83, Hey); 8.38 (2H, d, J. 4.84, Hpy); 7.08-7.62 (10H, m, Ar); UP NMR (162MHz, CDCI3): -22.81; Cald for C28H25FePSN2: C, 66.15; H. 4.96; N. 5.51. Found: C, 65.91; H. 5.01; N. 5.38. L9

The reaction was performed using the general procedure outlined above with p-methoxybenzenethiol as nucieophile, and column chromatography using Et3N/ EtOAc/hexane (2:10:88) to give the pure product as yellow foam in 44% yield. MS: 537 (M++1); 1H NMR (400MHz, CDCI3): 61.65 (3H, d, CH-CH3), 3.77-4.34 (8H, m, Fc), 4.37 (1H, q, -CH-CH3), 6.73-7.65 (14H, m, Ar); 31p NMR (162MHz, CDCI3): -23.58; Cald for C31H2eFePSO: C, 69.28; H. 5.44; Found: C, 69.12; H. 5.43. L10

The reaction was performed using the general procedure outlined above with naphthylthiol as nucleophile, and column chromatography using EtOAc/hexane (20:80) to give the pure product as a yellow foam in 65% yield.

Acc Mass: 557 (M++1); 1H NMR (400MHz, CDCI3): 1.74 (3H, d, -CH-CH3), 3.92-4.39 (8H, m, Fc), 4.63 (1H, q, -CH-CH3), 7.18-7.97 (17H, m, Ar); 3'P NMR (162MHz, CDCI3): 6-23.54. L11

The reaction was performed using the general procedure outlined above with 3,4-dichlorobenzenethiol as nucleophle, and column chromatography using EtOAc/hexane (10:90) to give gave the pure product as a yellow foam in 77% yield. MS: 575 (M+); 'H NMR (400MHz, CDCI3): 61.56 (3H, d, -CH-CH3), 3.97 4.45 (8H, m, Fc), 4.90 (1H, q, -CH-CH3), 6.94-7.62 (13H, m, Ar); 31p NMR (162MHz, CDCI3): -23.71; Cald for C30H25FePSCI2: C, 62.63; H. 4.37.

Found: C, 62.75; H. 4.45 L12 The reaction was performed using the general procedure outlined above with 2,6-dichlorobenzenethiol as nucleophile, and column chromatography using EtOAc/hexane (10:90) to give the pure product as a yellow foam in 88% yield.

MS: 575 (M+); 1H NMR (400MHz, CDCI3): 31.73 (3H, d, -CH-CH3), 3.97-4.45 (8H, m, Fc), 4.54 (1H, q, -CH-CH3), 6.94-7.62 (13H, m, Ar); 31p NMR (162MHz, CDCI3): -24.09; Cald for: C30H25FePSCI2 C, 62.63; H. 4.37.

Found: C, 63.05; H. 4.37 L13 The reaction was performed using the general procedure outlined above with p-nitrobenzenethiol as nucleophile, and column chromatography using EtOAc/hexane (10:90) to give the pure product as yellow foam in 55% yield.

MS: 552 (M++1); 1H NMR (400MHz, CDCI3): 1.84 (3H, d, -CH-CH3), 3.97 4.46 (8H, m, Fc), 4.80 (1H, q, -CH-CH3), 7.12-7.99 (14H, m, Ar); 31p NMR (162MHz, CDCI3): -24.11; Cald for C30H26FePSNO2: C, 65.34; H. 4.75; N. 2.54. Found: C, 64.97; H. 4.72; N. 2.52.

tButyl Mercaptan- (15) The reaction was performed using the general procedure outlined above with tbutylmercaptan as nucleophile, and column chromatography using EtOAc/hexane (20:80) to give the pure product as a yellow foam in 70% yield.

MS: 487 (M++1), 1H NMR (400MHz, CDCI3): 1.08 (9H, s, tBu) 1.87 (3H, d, CHCH3), 3.90-4.41 (8H, m, Fc), 4.50 (1H, q, -CH-CH3), 7.17-7.63 (10H, m, r Ar); 3'P NMR (162MHz, CDCI3): -22.99; Cald for C2H3,FePS: C, 69.15; H. 6.42. Found: C, 68.88; H. 6.45.

General Procedure for the syntheses of this alkyl metallocene-ligands via Method 2: The phosphine-amine B (1 mmol) was dissolved in warm acetic acid (7 ml) in a two necked round bottom flask equipped with a reflux condenser and a septum. The appropriate thiol (2 mmol) was syringed into the flask via the septum and the resulting mixture was stirred at 80 C for 2h. After cooling to room temperature the mixture was slowly and very carefully (caution: copious gas evolution) poured into a cold saturated aqueous solution of Na2CO3. This was extracted with DCM and the aqueous layer washed with more DCM. The combined organic layers were dried over anhydrous Na2SO4 and after filtration; the solvent was removed under reduced pressure to give a crude product. This crude product was purified by flash chromatography on SiO2 eluting with a solvent mixture of Et3N/ethyl acetate/hexane or ethyl acetate/hexane to give the pure product. L16

The reaction was carried out as described above using cyclohexylmercaptan as nucleophile and the crude product columned on silica, eluting with EtOAc/hexane (10:90) to give the pure product as a yellow solid, 38% yield.

MS: 513 (M++1); 'H NMR (400MHz, CDCI3): 31.07-1.52 (11H, m, Hcy), 1.79 (3H, d, -CH-CH3), 3.93-4.43 (8H, m, Fc), 4.14 (1H, q, -CH-CH3), 7.19-7.61 (10H, m, Ar); 3,P NMR (162MHz, CDCI3): -23.64; Cald for C30H33FePS: C, 70.32; H. 6.49. Found: C, 70.17; H. 6.55.

J

Example 2

The efficacy of a number of these ligands (L) was tested in an asymmetric ring opening (ARO) of oxanorbornadiene type substrates such as 1 reaction using methanol as the nucleophilic reagent. The ARO reaction was carried out in THE at 80 C, in the presence of a rhodium-containing catalytic complex [Rh(COD)2CI]2, 0.5mol%. The ligand catalyst of the invention was also added at 0.5mol% and 4-5 equivalents of the nucleophile were used. It was discovered that the addition of sodium iodide to the reaction mixture improved reaction rates, possibly due to a halogen exchange in the rhodium-containing complex.

Accordingly, the invention also provides the use of an iodide, preferably sodium iodide, in combination with the ligand of the invention as rate enhancer in asymmetric ARO and hydrogenation reactions.

:3 L, MeOH, 1 OH The conversions quoted in Table 1 for these alcoholic nucleophiles were calculated from GO analyses of the reaction mixtures and relate to the % of starting material consumed. When the reaction product mixtures were purified by flash chromatography, the isolated yield of product was generally found to be above 65%. 1 1

General procedure for asymmetric ring opening reactions of 1 with alcohols: All reactor tubes were dried at 1 50 C prior to use. 1 (0.694 mmol), [Rh(COD)CI]2 (3.4 x 10-3 mmol), ligand (6.94 x 10-3 mmol) and Nal (11-15 mg) were weighed into the reactor tube and then placed under vacuum/ N2 backfill cycles 3 times. A previously degassed solvenVreagent mixture of THF/alcohol (0.7:0.3, 1 ml) was then added and the mixture stirred at 80 C under N2 for 2 3h. After this time the solvent was removed under reduced pressure and the residue was purified on SiO2 eluting with EtOAc/hexane (20:80).

Table 1 Conversions and enantioselectivities for the Rh catalysed ring opening reaction of oxanorbornadiene 1 with MeOH Ligand Time (h) Conversion (%) Eel%) L5 4 20 9 L6 4 75 75 L8 3 25 50 L9 4 95 99 L10 3 95 97 L11 3 96 95 L12 4 35 40 L13 3 70 71

Example 3

The three best performing ligands (L9, L10 and L11) were tested further with different nucleophiles, ethanol, benzyl alcohol and anisyl alcohol. BnO' L, OH

L, EtOH, 1 OH L, AnsylOH AnsylO'

OH

Using a similar method to that outlined above in Example 1, and with the addition of iodide, all these oxygen nucleophiles investigated gave complete substrate conversion. Allyl alcohol and isopropyl alcohol were found to be unreactive. The results, shown in Table 2, demonstrate that the preferred ligands in accordance with the invention can be used in ARO reactions with high conversion and high enantiomeric excess.

Table 2Conversions and enantioselectivities for the Rh catalysed ring opening reaction of oxanorbornadiene 1 with various alcohols Ligand Nucleophile Time(h) Conversion (%) ee(%) L9 EtOH 3 >95 98 L1 0 EtOH 4-5 > 95 96 L1 1 EtOH 4-5 >95 97 L9 BzOH 3 >95 94 L1 0 BzOH 4-5 >95 92 L1 1 BzOH 4-5 >95 93 L9 AnsylOH 3 >95 92 L1 0 AnisylOH 4-5 >95 94 L1 1 AnisylOH 4-5 >95 91

Example 4

A similar ARO scheme was then investigated using amine nucleophiles in place of the oxygen nucleophiles.

BnN' J Oll OH ' _ Nit'

OH

OF OH

The nitrogen nucleophiles in combination with ligands 9, 10 and 11, gave high yields of substrate conversion in most cases. Phthalimide and benzenesulfonamide were found to be unreactive. The results, shown in Table 3, demonstrate that the preferred ligands in accordance with the invention can be used in ARO reactions with high conversion and high enantiomeric excess.

General procedure for asymmetric ring opening reactions of 1 with other nucleophiles (solid/liquid alcohols and amines) All reactor tubes were dried at 150 C prior to use. 1 (0.694 mmol), [Rh(COD)CI]2 (3.4 x 10-3 mmol), ligand (6.94 x 10-3 mmol) and Nal (11-15 mg) were weighed into the reactor tube and then placed under vacuum/ N2 backfill cycles 3 times. Degassed THF (1 ml) was then added and the liquid amine reagent was injected into the reaction mixture (solid nucleophiles were dissolved in degassed THE (1 ml) and then injected into the reaction mixture).

The reaction mixture was then stirred at 80 C under N2 for 2-24h and an aliquot removed, filtered through a small silica pad eluting with ether or DCM.

The solvent was removed under reduced pressure and the residue taken up in PrOH/hexane (10:90) for HPLC analysis.

Table 3 Conversions and enantioselecVvities for the Rh catalysed ring opening reaction of oxanorbomadiene 1 with venous amines Ligand Nucleophile Time(h) Conversion (%) ee (%) L9, L10, L11 Morpholine 2 91 95 L9, L10, L11 Pyrrolidine 2 87 97 L9, L10, L11 Benzylamine 2 85 91 L9, L10, L11 Indole 2 80 * L9, L10, L11 Tetrahydroisonuinoline 2 46 93 No conditions were found to analyse the ee of the Indole product

Example 5

Allylic alkylation of Ethyl-1,3-diphenyi-2-propenyl carbonate (Arylthia) alkyl metallocene ligands (L10 and L11) were tested further in the allylic alkylation reaction of the allyl precursor ethyl-1,3-diphenyi- 2-propenyl carbonate with the carbon based nucleophile derived from dimethylmalonate.

For comparison the (cyclohexylthia) alkyl metallocene L16 was prepared and tested in this reaction also It can be observed that the appropriate (arylthia) alkyl metallocene ligands (L10, L11) give a significantly higher enantioselectivity and a somewhat improved conversion in this reaction compared to the (alkylthia) alkyl metallocene ligands (L16).

MeO2C CO2Me OAc.

Pd2(dba)3, L, NaH, DCM FUJI Ph Ph MeO2C:'CO2Me Ph Ph

SM

IS = iSC iS PPh2, PPh2, PPh2 Fe Fe Fe L10 L11 L16 Procedure Solution A was prepared by dissolving NaH (1.45mmol) and dimethylmalonate (1.45mmol) in degassed dry DCM (3ml) and stirring the suspension at room temperature for 1 h under N2 Solution B was prepared by dissolving ethyl1,3-diphenyi-2-propenyl carbonate (SM) (1.05mmol), ligand (0.01mmol), and Pd2(dba)3 (0.005mmol) in degassed anhydrous dichloromethane (3ml) and stirring the resulting solution at room temperature under N2 for 1 h. Solution B was added to solution A via cannula and the resulting mixture stirred under N2 at 50 C for 24 h. The reaction was quenched in saturated aq.

NH4CI and extracted with ether. The organic layer was dried over MgSO4 and the ether removed under reduced pressure to obtain the crude product. This was columned on S'O2 eluting with 20% ethyl acetate in hexane.

The ee of the products were determined by HPLC using a Chiralcel AD column hexane/'PrOH 95:5 1 ml/min flow rate.

Table 4Conversions and enantioselectivities for the Pd catalysed allylic alkylation reaction of ethyl-1,3-diphenyi-2-propenyl carbonate (SM) with sodiodimethylmalonate Entry Ligands Conversion (%) Ee(%) 1 L10 54 73 2 L11 65 73 3 L16 47 52

Example 6

Allylic amination of Ethyl-1,3-diphenyi-2-propenyl carbonate (Arylthia) alkyl metallocene ligand L10 was tested further in the allylic amination reaction of the allyl precursor ethyl-1,3-diphenyi-2-propenyl carbonate with the nitrogen based nucleophile benzyl amine.

OAc HN Ph Phi Pd2(dba)3, L10, NaH, BzNH2, DCM 'Ph

SM S<W -PPh2 Fe L10

Procedure Ligand L10 (0.01 mmol) and Pd2(dba)3 (0.005 mmol) were placed in a Schlenk tube under N2. The tube was evacuated using a high vacuum oil pump and then the tube was backfilled with Nitrogen. This procedure was repeated three times. Degassed dichloromethane (3 ml) was then added and the mixture stirred under N2 at room temperature for 30 min. Ethyl-1,3diphenyi-2-propenyl carbonate (1.0 mmol) in degassed DCM (2 ml) and benzylamine (1.05 mmol) were then added. The mixture was stirred at room temperature under nitrogen for 15 h. The solvent was removed under reduced pressure. The residue was dissolved in hexane/ethanol 98:2 and analysed by HPLC (Diacel Chiralcel OJ column, hexane/ethanol 98:2 1 ml/min flow). The conversion was determined from the peak areas to be 65% and the ee of the product was determined to be 83%.

Example 7

A number of phosphorus-thio ligand metal complexes in accordance with the invention were prepared as potential hydrogenation pre-catalysts.

RSR' ! SR' 2)BARF [M ( cod)CI]2/DC M/2 he Fe P-M- Fe PR2 NaBARF/H2O/1 h:: R2 \ 3)4 M = Rh, Ir R' = 3,5 dichlorobenzene, benzyl, 2-naphthyl etc. R = Ph. cyclohexyl cod = cyclooctadiene Procedure Ligand L11 (0.080 g, 0.140 mmol) and [Ir(COD)CI]2 (0.050 g, 0.074 mmol) were placed in an round bottom flask under Ar. Degassed dichloromethane (3 ml) was then added and the mixture stirred under Ar at reflux for 2 h. The mixture was then cooled to room temperature and NaBARF (0.133 g, 0.15 mmol) was then added. An immediate colour change was observed from dark red to pale orange. The mixture was stirred at room temperature under Ar for 40 min after this time degassed water was added (2 ml) and the resulting mixture stirred vigorously for 20 min. The organic layer was then separated and the aqueous layer extracted with dichloromethane (3 x 5 ml). The combinedorganic phases were dried over MgSO4, filtered and then the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2-dichoromethane eluent) to give 0.177 9 (73%) of a red/orange foam [(L11)1r(COD)][BARF]. AH NMR (CDCI3, 400.13 MHz): o 0.73 (d, 3H, J = 6.9 Hz); 1.75 (br m, 2H); 2.07 (br m, 1 H); 2.20 (br m, 1 H); 2.3 2.55 (br m, 4H, overlap); 3.61 (br m, 2H, overlap); 4.14 (m, 1 H); 4.24 (m, 1 H); 4.46 (s, 5H); 4.48 (m, 1 H); 4.51 (m, 1 H); 4.63 (q, 1 H. J = 6.9 Hz); 4. 72 (br m, 1H); 7.30 7.75 (m, 25H); 34P NMR (CDCI3, 162 MHz): c 5.32. HRMS (35eV, ES+ , Solvent MeOH): Calcd for C38H37CI256Fe1911rPS cation: 873.0686; Found: 873.0700.

[(L 9) Rh (C OD)][BA RF] A procedure similar to that described above with the exception that [Ir(COD)CI]2 was replaced with [Rh(COD)CI]2 was used to give 0.183 9 (88%) of an orange foam [(L9)Rh(COD)][BARF]. 'H NMR (CDCI3, 400.13 MHz): 0 0.63 (d, 3H, J = 6.9 Hz); 2.05 (br m, 2H); 2.1 1 (br m, 1 H); 2.32 (br m, 1 H); 2.42 (br m, 2H); 2.6-2.75 (br m, 2H); 3.79 (s, 3H); 3.85 (br m, 1 H); 3. 94 (br m, 1H);4.10(m, 1H);4.20(q, 1H,J=6.9Hz);4.47 (m, 2H);4.52(s,5H);4.59 (m, 1 H); 4.48 (m, 1 H); 5.05 (m, 1 H); 6.94 (d, 2H, J = 8.78 Hz); 7.44 (d, 2H, J = 8.78 Hz); 7.48 7.73 (m, 12H); 7.74 7.80 (m, 10H); 34P NMR (CDCI3, 162 MHz) : 620.12 (d, JRhp= 139.92 Hz).

[(L 10)Rh(COD)][BARF] A procedure similar to that described above was used to give 0.134 g (78%) of an orange foam [(L10)Rh(COD)][BARF].

[(L10)Rh(COD)][BARF]. 'H NMR (CDCI3, 400.13 MHz): 0.75 (d, 3H, J = 6.9 Hz) ; 2.01 (br my 3H); 2.31 (br m, 3H); 2.71 (br m, 2H); 3.98 (br m, 1 H); 4. 09 (term, 1H); 4.14 (m, 1H); 4.38 (q, 1H, J= 6.9 Hz); 4.50 (m, 2H); 4.53 (s, 5H); 4.61 (br m, 1H); 5.12 (br m, 1 H); 7.30-8.15 (m, 29H); UP NMR (CDCI3, 162 MHz): o20.01(d, JRhp= 141.71 Hz). is PCy2 L17

A procedure similar to that described above was used to give 0.089g (64%) of an brown/orange foam [(L17)1r(COD)][BARF].'H NMR (CDCI3, 400.13 MHz): o 1.1-2.5 (br m, 33H overlap); 1.81 (d, 3H, J = 6.9 Hz overlap); 4.15 (m, 1H); 4.31 (s, 5H); 4.46 (m, 2H); 4.47 (m, 2H); 4.48 (m, 2H); 4.54 (q, 1 H. J = 6.9 Hz); 7.31 (m, 1H); 7.63 (m, 2H); 7.51 (m, 4H); 7.71 (m, 8H); 7.73-7. 89 (m, 4H); 3'P NMR (CDCI3, 162 MHz): o 4.40. HRMS (30eV, ES+, Solvent MeOH): Calcd for C34H53CI256Fe1931rPS cation: 869.2584; Found: 869.2567.

BARF refers to tetra(3, 5-bistrifluoromethylbenzene) borate Unlike bisphosphine and phosphine/oxazoline ligands, it appears that the P. S ligands of the invention do not react directly with [M(COD)CI]2 to form ligand-metal complexes. Only on addition of a chloride abstraction agent (in this case NaBARF) do stable P. S ligand metal complexes form in accordance J. with the invention. This observation is consistent with the use of an iodide additive in the ARO chemistry to attain good yields and turn-over factors.

Claims (19)

LIl1. -'3 CLAIMS

1. A chiral metallocene ligand for use in homogeneous catalysis, the ligand having the general formula (I): R4 SR1 Rny'WR2R3 -r

M <?Rn

Formula (I) or its enantiomer, wherein WisPorAs; M is a suitable metal; Ri is selected from substituted aryl and heteroaryl groups; R2 and R3 are, independently, selected from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heterocycloalkyl groups; R4 is selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl; or wherein R4 and Ri together form a substituted polyaromatic group; and Rn indicates any possible number of substituents on the or each cyclopentadiene ring, R being selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl, OR', SR', NHR', NR'R", wherein R' and R" are the same or different and are independently selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups and wherein each R may be the same or different, with the exception that when the bottom ring has a single R substituent, the single R substituent on the bottom ring is not P(R5R6), SR7, CH=NR7, CH2-NH-R7 or CH2-o-P(R5R6), wherein R5 and R6 are, independently of each other, C4-C8 alkylene, C4-C8 alkylene substituted by C4-C4 alkyl or by phenyl, or annelated C4-C8 alkylene, and wherein R7 is hydrogen, C,-C,2 alkyl, C'-C'2 alkyl substituted by Ci-C4 alkoxy, C5-C, 2 alkyl or by phenyl, C5-C,2 cycloalkyl, phenyl, C5-C'2 cycloalkyl substituted by C,-C4 alkyl or by C4-C4 alkoxy, or phenyl substituted by from one to three substituents selected from C,-C4 alkyl, C'-C4 alkoxy, SiR3R9R40, halogen, SO3M, CO2M, PO3M, NR"R42, [+NR44R'2R,3]X- and C' C5 fluoroalkyl, wherein R8, R9 and R' are each independently of the others C,-C'2 alkyl or phenyl, R" and R'2 together are tetramethylene, pentamethylene or 3-oxa-1,5-pentylene, wherein R'3 is hydrogen or C,-C4 alkyl, wherein M is hydrogen or an alkali metal, and wherein X is the anion of an acid.

2. A ligand according to claim 1 wherein R' is selected from optionally further substituted alkylphenyl, dialkylphenyl, pyrimidinyl, alkoxyphenyl, naphthyl, halophenyl, dihalophenyl and nitrophenyl groups.

3. A ligand according to claim 1 or claim 2 wherein the R' substituent is substituted at the meta- and/or pare-position with respect to the sulphur group.

4. A ligand according to any one of claims 1 to 3 wherein the R. substituent is substituted at the or/ho-position with respect to the sulphur group.

5. A ligand according to any one of claims 1 to 4 wherein R2 and R3 are, independently, selected from optionally substituted phenyl, t-butyl, and cyclohexyl groups.

6. A ligand according to any one of claims 1 to 5 wherein M is Fe

7. A ligand according to any one of claims 1 to 6 having the Formula (111) : R4 SR1 PR2R3 Fe Formula (111) i wherein Ri-4 have the same meanings assigned in Formula (I).

8. A ligand according to claim 7 having the Formula (IV): SR' :PR2R3 Fe Formula (IV) wherein R'-3 have the same meanings assigned in Formula (I).

9. Use of the ligand of any one of claims 1 to 8 as a catalyst in ARO or asymmetric hydrogenation reactions.

10. Use according to claim 9 wherein the hydrogenation substrate is selected from imines, allylic alcohols and esters, a-, F- unsaturated esters, olefins, and substrates giving rise to Gamine acids, and substrates giving rise to P-amino acids.

11. A method for asymmetrically hydrogenating an organic substrate comprising contacting the substrate under suitable hydrogenation conditions with a suitable hydrogenation reagent in the presence of the ligand of any one of claims 1 to 8 as catalyst.

12. A method for performing an ARO transformation comprising contacting a cyclic substrate under suitable ARO conditions with a suitable ARO reagent in the presence of the ligand of any one of claims 1 to 8 as catalyst.

13. The use of an iodide in combination with the ligand of any one of claims 1 to 8 as a rate-enhancer in ARO or asymmetric hydrogenation reactions.

14. Use of the ligand of any one of claims 1 to 8 as a catalyst in asymmetric ring opening reactions reactions.

15. Use according to claim 14 wherein the ARO substrate is selected from oxabicyclic norbornadienes, and oxabicyclic alkenes.

16. Use according to claim 14 or claim 15 wherein the ARO reagent is a nucleophiles selected from amongst alcohols, carboxylates, aliphatic and aromatic amines and carbon-based nucleophiles.

17. A method for carrying out asymmetric ring opening reactions comprising contacting a suitable cyclic substrate under suitable ARO conditions with a suitable metal source in the presence of the ligand of any one of claims 1 to 8 as catalyst.

18. A transition metal complex containing a transition metal coordinated to a ligand according to any one of claims 1 to 8 for use as a catalyst or pre-catalyst.

19. A method for preparing a transition metal complex according to claim 18 comprising contacting the ligand of any one of claims 1 to 8 with a halogen-containing transition metal complex in the presence of a halogen exchange or abstraction agent.