Much interest has been shown in the synthesis and use of orthometallated complexes as catalysts in coupling reactions such as the Suzuki, Stille, Heck, Grignard cross-coupling, Buchwald-Hartwig amination reactions, and a number of others.

The Suzuki reaction, for example, involves carbon-carbon bond formation in the presence of a catalyst under basic conditions: catalyst Q-base wc-Q basa R R R, i wherein R and R'are variously defined. The reaction is catalysed by palladium, and various types of organo-palladium catalysts have been disclosed in GB-A-2376946. CA-A-2419023 is directed to a transition metal catalyst, comprising a Group 8 metal and a ligand having the structure (a), wherein R', R'and R"are organic groups having 1-15 carbon atoms, n = 1-5, and m = 0-4.

Structure (a) This document also discloses a method of forming a compound having an aromatic or vinylic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond using the above catalyst. The catalyst and the method of using the catalyst are said to be advantageous in preparation of compounds under mild conditions of approximately room temperature and pressure.

It would be advantageous to provide improved catalytic compounds for use in carbon-carbon and carbon-heteroatom bond-forming reactions. It would also be desirable to provide chiral catalysts of this type that can be useful in enantioselective catalysis, that give rise to good yields and conversion rates, and that provide good ee ratios in enantioselective applications. It would also be desirable to provide such catalysts that can be used at low loadings in coupling reactions. It would also be desirable to provide an improved method for effecting coupling reactions in the presence of a catalyst to give good product yields and fast reaction times. According to the present invention there is provided a ferrocene derivative useful in the catalysis of carbon-carbon and/or carbon-heteroatom bond forming reactions, the derivative having the Formula (I) :

Formula (I) or its enantiomer, wherein R'has 3 or more contiguous carbon atoms and a branched chain structure providing bulk to the substituent and is selected from optionally substituted alkyl, alkenyl, aryl, cycloalkyl, alkaryl, aralkyl, heteroaryl and heterocycloalkyl groups, with the exception that R'is not an amide, an amine, a phosphine or an ester; R2 and R3 are, independently, selected from optionally substituted alkyl, alkenyl, aryl, cycloalkyl, alkaryl, aralkyl, heteroaryl and heterocycloalkyl groups, with the exception that R2 and R3 are not together C4-C8 alkylen, C4- C8 alkylen substituted by Ci-C4 aryl or by phenyl, or annelated C4-C8 alkylen ; and R4 is selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, cycloalkyl, alkaryl, aralkyl, heteroaryl and heterocycloalkyl groups, n is from 0 to 5, and each R4 may be the same or different, with the exception that no R4 is a phosphine.

The invention also provides a transition metal complex comprising a transition metal coordinated with the ligand or Formula (I). Preferably the transition metal is coordinated to the phosphine group.

Preferred R'substituents include alkyl and aryl groups, optionally substituted.

Preferably R'is a somewhat bulky substituent comprising at least three, preferably at least four, preferably at least five carbon atoms, and preferably has at least one, preferably at least two chain branches. Preferred R1 substituents include isopropyl, secondary butyl, isobutyl, tertiary butyl and non-primary pentyl and hexyl groups.

Preferred R2 and R3 substituents include, independently of each other, phenyl and t-butyl. Preferably R2 = R3.

Preferred R4 substituents include, independently of each other, hydrogen, methyl and phenyl.

Also provided in accordance with the invention is a catalytic composition for use in coupling reactions comprising a ferrocene derivative in accordance with Formula (I) in combination with an organo-transition metal, preferably organo- palladium, complex capable of coordinating with the phosphine moiety of the ferrocene derivative.

Also provided in accordance with the invention is a catalytic composition for use in coupling reactions comprising a ferrocene derivative in accordance with Formula (I) coordinated with an organo-transition metal, preferably organo- palladium, complex capable of coordinating with the phosphine moiety of the ferrocene derivative.

During the course of experimental work, reported below, the inventors noted that surprisingly fast reaction times and/or conversion rates in coupling reactions catalysed by the transition metal complex of the invention could be obtained by heating the reaction mixture with microwave radiation.

Accordingly, there is provided in accordance with the invention the use of microwave radiation to speed up the reaction rate and/or improve the conversion rate of a coupling reaction catalysed by the transition metal complex disclosed herein.

Suitable organo-palladium complexes for use in the catalytic composition of the invention are disclosed in GB-A-2376946 and may be of Formula (ll) : Formula (II) Wherein: Rn indicates from 0 to 4 substituents on the benzene ring wherein the or each substituent is independently selected from alkyl, alkenyl, aryl, alkaryl,

alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or one or more of the substituents together with the metallated benzene ring form a larger substituted or unsubstituted polyaromatic or heterocyclic group; R5 and R6 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups; R7 and R8 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or from OR', SR', NHR'and 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 L is an anionic ligand The coordinated catalytic composition in accordance with the invention may comprise a complex of Formula (III) Formula (III)

Wherein Rn, R2, R3, R4, R5, R6, R7 and R3 have the meanings assigned hereinabove.

Further suitable organo-palladium complexes for use in the catalytic composition of the invention are disclosed in GB-A-2376946 and may be of Formula (IV) : Formula (IV) Wherein: Rn indicates from 0 to 4 substituents on the benzene ring wherein the or each substituent is independently selected from alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or wherein at least one of the substituents together with the metallated benzene ring forms a larger substituted or unsubstituted polyaromatic or heterocyclic group; R9 is selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or from OR', SR', NHR'and 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;

Rlo is selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or R9 and Rlo are together incorporated in an optionally substituted cyclic or heterocyclic structure; and L is an anionic ligand The coordinated catalytic composition in accordance with the invention may comprise a complex of Formula (V)

Formula (V) Wherein Rn, R', R2, R3, R4, R9 and R10 have the meanings assigned hereinabove.

Yet further suitable organo-palladium complexes for use in the catalytic composition of the invention are disclosed in GB-A-2376946 and may be of Formula (VI) :

Formula (VI) Wherein: Rn indicates from 0 to 4 substituents on the benzene ring wherein the or each substituent is independently selected from alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or wherein one or more of the substituents together with the metallated benzene ring form a larger substituted or unsubstituted polyaromatic or heterocyclic group; R7 and R8 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or from OR', SR', NHR'and 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; R"is selected from alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups; and L is an anionic ligand The coordinated catalytic composition in accordance with the invention may comprise a complex of Formula (VII)

Formula (Vil) Wherein Rn, R', R2, R3, R4, R7, R8 and R11 have the meanings assigned hereinabove.

The invention will now be more particularly described with reference to the Examples which follow.

Example 1 Novel ligands in accordance with the invention were prepared by a diastereoselective route giving rise to a single planar chiral enantiomer. (pS)-2-bromoferrocenecarboxaldehyde (A) was synthesised as described by Kagan (J. Org. Chem., 1997,62, 6733).

R in the above scheme is a cyclohexyl group.

(S, pS)-2-(2, 2-dimethylpropan-1-ol)-1-bromoferrocene (B) A solution of (pS)-2-bromoferrocenecarboxaldehyde (0.99 g, 3.39 mmol) in Et20 (20 ml) was added slowly via syringe to a solution of tBuMgCi (2M, 3.39 ml, 6.78 mmol) in Et20 (20 ml) cooled to-78 °C. The resulting mixture was allowed to warm slowly to rt overnight. The crude mixture was washed with aqueous ammonium chloride solution (3 x 20 ml). The combined aqueous washes were extracted with DCM (20 ml). The combined organic extracts were dried (MgS04), filtered and the solvent was removed in vacuo. The residue was purified by column chromatography (Si02, DCM) to afford the title

compound (0.842 g, 71 %) as yellow crystals.'H NMR (CDCl3, 250 MHz): 5 0.91 (s, 9H); 2.8 (d, 1 H, J = 1. 5 Hz); 4.15 (t, 1 H, J = 2.9) ; 4.25 (s, 5H); 4.28 (brs, 1 H); 4.49 (dd, 1 H, J = 2. 5,1. 5 Hz).

(pS)-2- (2, 2-dimethylpropan)-1-bromoferrocene (C) A solution of (S, pS)-2-(2, 2-dimethylpropan-1-ol)-1-bromoferrocene (842 mg, 2.40 mmol) and triethylsilane (0.77 ml, 4.80 mmol) in DCM (10 ml) was cooled to 0 °C. Trifluoroacetic acid (1 ml) was added and the resulting mixture stirred for 1 hour. The reaction was quenched with aqueous NaHCO3 (20 ml) and extracted with DCM (3 x 10 ml). The combined organic extracts were dried (MgS04), filtered, and the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, 20% EtOAc/hexane) to give the title compound as a yellow oil.'H NMR (CDCl3, 250 MHz): 5 0.88 (s, 9H); 2.3 (d, 1H, J = 13. 8 Hz); 2.57 (d, 1H, J = 13. 8 Hz); 4.05 (t, 1H, J = 2.4 Hz); 4.11 (s, 6H, overlap); 4.37 (dd, 1 H, J = 2.1, 1.5 Hz).

(pS)-2-(2, 2-dimethylpropan)-1-dicyclohexylphosphinoferrocene (Fc1) A solution of (pS)-2-(2, 2-dimethylpropan)-1-bromoferrocene (1.00 g, 2.99 mmol) in Et20 (10 ml) was degassed under N2 and cooled to-78 °C. BuLi in hexanes (1.49 ml, 3.28 mmol) was added dropwise and the solution allowed to warm to-0 °C over 30 min. After cooling to-78 °C, CIPCy2 (0.72 ml, 3.28 mmol) was added via syringe and stirring continued for 30 min. After warming to rt over-1 h. the solvent was removed in vacuo and the resulting residue

was purified by column chromatography (Si02, 2% EtOAc/hexane).

Recrystallisation (hexane) afforded orange crystals (0.943 g, 70%). 1H NMR (CDCI3, 250 MHz): 5 0.93 (s, 9H); 1.13-2. 26 (m, 22H); 2.49 (d, 1H, J= 14.6) ; 2.68 (dd, 1 H, J = 14.6, 2.9 Hz); 4.07 (s, 6H, overlap) ; 4.25 (t, 1 H, J = 2. 5 Hz); 4.46-4. 83 (m, 1 H) ; 13C NMR (CDCI3, 62.9 MHz): 5 26.4 (CH2, Cy); 27.2 (CH2, Cy); 27.6 (CH2, Cy); 28.4 (CH2, Cy); 29.4 (CH2, Cy); 30.3 (CH2, Cy); 31.3 (CH2, Cy); 32.3 (CH2, Cy); 33.6 (CH2, Cy); 35.5 (CH, Cy); 37.7 (CH, Cy); 42.7 (CH2-tBu); 68.4 (CH, Fc); 69.7 (C5H5) ; 70.0 (CH, Fc); 71.0 (CH, Fc) 80.5 (ipso, Fc); 91.7 (ipso, Fc); 31p NMR (CDCI3, 101.2 MHz): S-15. 3. C27H42FeP : calculated 453.2374, found 453.2367 Example 2 The novel ligand designated Fc1 was tested for catalytic activity in a standard Suzuki reaction, namely the coupling of 4-chlorotoluene with phenylboronic acid : Ci (Pd] Fc1 B (OH) 2 \/base : Cs2CO3 or KF solvent : dioxane or THF The results are presented graphically below :

After stirring at room temperature for 22h the Buchwald system had given a 64% conversion. On heating to 60°C both Fc1 and the Bedford catalyst began rapidly to catalyse the reaction, with Fc1 obtaining complete conversion (no detectable aryl chloride remaining in the reaction product mixture). It was postulated that the higher temperature is required to break down the stable preformed complex before it can become involved in the catalytic cycle. The catalyst therefore acts as a palladium source.

Similar results are obtained when the more demanding 4-chloroanisole is used as substrate. Again the catalyst of the invention outperformed the known systems in parallel tests.

It was noted that particularly good reaction times and conversion rates were obtained following microwave heating of the reaction mixture.

Accordingly, there is also provided in accordance with the invention a method for effecting a coupling reaction, forming a carbon-carbon or carbon- heteroatom bond, between a first substrate and a second substrate, comprising contacting the first substrate with the second substrate in the presence of the ligand of Formula (I) and a palladium source under basic conditions and in a suitable solvent, the method comprising the step of heating the reaction mixture with microwave radiation.