EP2079752A1

EP2079752A1 - Preparation of optically pure ferrocenediphosphines

Info

Publication number: EP2079752A1
Application number: EP07847124A
Authority: EP
Inventors: Weiping Chen
Original assignee: Solvias AG
Current assignee: Solvias AG
Priority date: 2006-11-10
Filing date: 2007-11-08
Publication date: 2009-07-22
Also published as: WO2008055942A1

Abstract

[(RcRc)-, (SFc,SFc)-, (SP,SP)-1,1'-Bis(2-sec-aminoalkyl)-1-ferrocenyl]phosphino-ferrocene or the enantiomer [(Sc,Sc)-, (RFc,RFc)-, (RP,RP)-1,1'-bis (2-sec-aminoalkyl)-1-ferrocenyl]phosphinoferrocene are enriched by heating a mixture of optical isomers formed in the reaction of 1,1'-dilithioferrocene-amine complexes with at least 2 equivalents of a ferrocenylhalophosphine and are then separated off as optically pure compounds.

Description

Preparation of optically pure ferrocenediphosphines

The present invention relates to a process for preparing or enriching [(RcRc)-, (SF_CSFC)-, (Sp,Sp)-1 ,1 '-bis(2-sec-aminoalkyl)-1-ferrocenyl]phosphinoferrocene or the enantiomer [(S_C,S_C)-, (RF_CRFC)-, (RP, RP)-I , 1 '-bis(2-sec-aminoalkyl)-1- ferrocenyl]phosphinoferrocene by heating a mixture of optical isomers which are formed in the reaction of 1 ,1 '-dilithioferrocene-amine complexes with at least 2 equivalents of a haloferrocene.

WO 2006/075166 describes phosphine ligands based on metallocenes which contain asymmetric C and P atoms and in which i-sec-aminoalkylferrocen-2-yl is bound to the P atom. Two of the centres of chirality have the (RcRc) and (S_Fc,S_Fc) or (S_C,S_C) and (R_FCR_FC) configuration. To prepare optically pure or highly enriched phosphine ligands having a (S_P,S_P) or (R_PR_P) configuration of the two asymmetric P atoms, it is important that a 1 ,1 '-dibromoferrocene is lithiated by means of an alkyllithium and the product is then reacted with two equivalents of ferrocenemonochlorophosphine. This reaction displays a good stereoselectivity. However, this process is uneconomical because of the expensive 1 ,1 '-dibromoferrocene. To obtain good yields, it is also necessary to use the expensive and very highly flammable tert-butyllithium for the lithiation of the 1 ,1 '-dibromoferrocene. Mixtures of metallocenediphosphines having a predominant proportion of the desired (R,R) configuration and a smaller proportion of the undesirable (R,S) configuration of the two P atoms are always obtained and these have to be purified further by chromatography. The process also has to be carried out at low temperatures.

If an economical process is sought, it is necessary to start out from 1 ,1 '-dilithio- ferrocene which is not prepared via 1 ,1 '-dibromoferrocene. One known possibility is the reaction of ferrocene with alkyllithium in the presence of aliphatic polyamines, for example tetramethylethylenediamine, to form complexes of 1 ,1 '-dilithioferrocene with aliphatic polyamines. However, the reaction of such dilithioferrocene-amine complexes with ferrocenylhalophosphine is not stereoselective and leads to a mixture of diastereomers which contains, depending on the process conditions, varying proportions of ferrocenediphosphines having the desired (R_P,R_P) or (S_P,S_P) configura- tion. The possible separation of the diastereomers is then too complicated for the economics of a process based on amine complexes of dilithioferrocene as starting material and the yield of desired product is much too small because of the poor selectivity to the desired diastereomer.

The thermal epimerization of P-chiral, tertiary phospholanes is described, for example, in WO 2005/095424. However, the ratio of enantiomers which can be achieved cannot be predicted, particularly when acyclic, P-chiral and tertiary phosphines are used.

It has now been found that simple heating of the reaction product of the reaction of dilithioferrocene-amine complexes with ferrocenylhalophosphines surprisingly results in the desired diastereomers being formed in highly enriched form or exclusively. The isomerization of optical isomers leads to a simple, practical and economical preparation. A surprising advantage of the process is that even relatively high reaction temperatures which can be above room temperature can be employed to form the reaction products of dilithioferrocene-amine complexes and ferrocenylhalophosphines.

The invention provides a process for preparing [(RcRc)-, (SF_CSFC)-, (SP, SP)-I , 1 '-bis(2- sec-aminoalkyl)-1-ferrocenyl]phosphinoferrocene of the formula I

the enantiomer [(ScSc)-, (RF_CRFC)-, (Rp, Rp)-1 , 1 '-bis(2-sec-aminoalkyl)-1 - ferrocenyl]phosphinoferrocene of the formula II,

where

R is an unsubstituted or substituted hydrocarbon radical which has from 1 to 40 carbon atoms and may contain heteroatoms selected from the group consisting of O, S and N,

Ri is d-Ce-alkyl, C₃-C₆-cycloalkyl or phenyl, and the two radicals R2 bound to an N atom are identical or different and are each d-Cs- alkyl, C₄-Cs-CyClOaI kyl, C₄-C₈-cycloal kyl-Ci-C₂-alkyl, phenyl, phenyl-Ci-C₂-alkyl or the two radicals R2 bound to an N atom together form C2-C₇-alkylene, -(CH₂)2-O-(CH₂)2 or -(CH₂J₂-N(Ci-C₄-AI kyl)-(CH₂)2-, which is characterized in that an aliphatic tertiary polyamine complex of 1 ,1 '-dilithio- ferrocene is reacted with at least 2 equivalents of a ferrocenylhalophosphine of the formula III or IV,

where R, Ri and R2 are as defined above and X is Cl, Br or I and the optionally isolated reaction product is then heated to a temperature of at least 50⁰C.

The hydrocarbon radicals R preferably contain from 1 to 30, particularly preferably from 1 to 24, carbon atoms. The radical R is preferably selected from the group consisting of linear or branched Ci-Ci2-alkyl; unsubstituted or Ci-Cβ-alkyl- or Ci-Cβ- alkoxy-substituted C₅-Ci2-cycloalkyl or C₅-Ci2-cycloalkyl-CH₂-; phenyl, naphthyl, furyl or benzyl and phenyl or benzyl substituted by halogen (for example F, Cl and Br), d-Ce-alkyl, Ci-C₆-haloalkyl (for example trifluoromethyl), Ci-C₆-alkoxy, Ci-C₆-halo- - A -

alkoxy (for example trifluoromethoxy), (C₆H₅)3Si, (Ci-Ci₂-alkyl)₃Si, sec-amino or -CO₂-Ci-C₆-alkyl (for example -CO₂CH₃).

Examples of alkyl radicals R which preferably contain from 1 to 6 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and the isomers of pentyl and hexyl. Examples of unsubstituted or alkyl-substituted cycloalkyl radicals R are cyclo- pentyl, cyclohexyl, methylcyclopentyl and ethylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl and ethylcyclohexyl and dimethylcyclohexyl. Examples of alkyl-, alkoxy-, haloalkyl-, haloalkoxy- and halogen-substituted phenyl and benzyl radicals R are o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, difluorophenyl or dichloro- phenyl, pentafluorophenyl, methylphenyl, dimethylphenyl, trimethylphenyl, ethyl- phenyl, methylbenzyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl, bistrifluoromethylphenyl, tristrifluoromethylphenyl, trifluoromethoxyphenyl, bis- trifluoromethoxyphenyl and 3,5-dimethyl-4-methoxyphenyl.

Preferred radicals R are radicals selected from the group consisting of d-Cβ-alkyl, unsubstituted cyclopentyl or cyclohexyl and cyclopentyl or cyclohexyl substituted by from 1 to 3 Ci-C₄-alkyl or Ci-C₄-alkoxy groups, benzyl and in particular phenyl which is unsubstituted or substituted by from 1 to 3 CrC₄-alkyl, Ci-C₄-alkoxy, F, Cl, CrC₄- fluoroalkyl or Ci-C₄-fluoroalkoxy substituents. The substituent F can also be present four or five times in the benzene ring.

The radicals R preferably correspond to a hydrocarbon radical which has from 1 to 24 carbon atoms and is unsubstituted or substituted by halogen, Ci-C₆-alkyl, CrC₆- haloalkyl, CrC₆-alkoxy, CrC₆-haloalkoxy, (Ci-C₄-alkyl)₂amino, (C₆H₅)3Si, (CrCi₂- alkyl)₃Si or -CO₂-Ci -C₆-alkyl and/or contains heteroatoms O.

The radical R is preferably selected from the group consisting of linear or branched d-Cβ-alkyl, unsubstituted cyclopentyl or cyclohexyl and cyclopentyl or cyclohexyl substituted by from one to three CrC₄-alkyl or Ci-C₄-alkoxy groups, furyl, norbornyl, adamantyl, unsubstituted benzyl and benzyl substituted by from one to three CrC₄- alkyl or Ci-C₄-alkoxy groups and in particular unsubstituted phenyl and phenyl substituted by from one to three Ci-C₄-alkyl, Ci-C₄-alkoxy, -NH₂, -N(Ci-C₆-alkyl)₂, OH, F, Cl, Ci-C₄-fluoroalkyl or Ci-C₄-fluoroalkoxy substituents.

The radical R is particularly preferably Ci-C₆-alkyl, cyclopentyl, cyclohexyl, furyl or unsubstituted phenyl or phenyl substituted by from one to three Ci-C₄-alkyl, CrC₄- alkoxy and/or Ci-C₄-fluoroalkyl groups.

An alkyl group Ri is preferably Ci-C₄-alkyl such as methyl, ethyl, n- and i-propyl, n-, i- and t-butyl. Linear Ci-C₄-alkyl is particularly suitable. A cycloalkyl radical Ri is preferably cyclopentyl or cyclohexyl.

The two radicals R₂ bound to an N atom can be identical or different and are preferably Ci-Cβ-alkyl, Cs-Cs-cycloalkyl (for example cyclopentyl or cyclohexyl), Cs-Cβ- cycloalkyl-CH₂- (for example cyclopentylmethyl or cyclohexyl methyl), phenyl or phenyl-CH₂-, or the two radicals R₂ bound to an N atom together preferably form C3-C6-alkylene (for example trimethylene, tetramethylene or pentamethylene), -(CH₂)₂-O-(CH₂)₂ or -(CH₂)₂-N(Ci-C₂-alkyl)-(CH₂)₂-.

The cyclic radicals R₂ or the two radicals R₂ on the N atom can be substituted, for example by Ci-C₄-alkyl.

An alkyl radical R₂ is preferably linear Ci-C₄-alkyl and can be, for example, methyl, ethyl, n-propyl or butyl.

In a preferred embodiment, both Ri and R₂ are each methyl.

In another preferred embodiment, both Ri and R₂ are each methyl and R is CrC₄- alkyl, cyclopentyl, cyclohexyl, furyl or unsubstituted phenyl or phenyl substituted by from one to three CrC₄-alkyl, Ci-C₄-alkoxy and/or CrC₄-fluoroalkyl groups.

Aliphatic tertiary polyamines for forming complexes with 1 ,1 '-dilithioferrocene are known. They can be, for example, ditertiary 1 ,2- or 1 ,3-diamines of C₂-Cβ- and preferably C2-C₄-alkanes. The N atoms are preferably substituted by ethyl and in particular methyl. They can also be N-methylated polyethylene amines. Some examples are N,N-tetramethylethylenediamine (TMEDA), N,N-tetramethyl-1 ,2- or 1 ,3- diaminopropane, N,N-tetramethyl-1 ,2- or -1 ,3-diaminobutane, N,N,N-pentamethyl- diethylenetriamine and N,N,N,N-hexamethylthethylenetetramine. N,N-Tetramethyl- ethylenediamine (TMEDA) is frequently used as complexing agent.

The metallation of ferrocenes is a known reaction which is described, for example, by W. Weissensteiner et al., J. Org. Chem., 66 (2001 ) 8912-9, W. Weissensteiner et al., Synthesis 8 (1999), pages 1354-1362, T. Hayashi et al., Bull. Chem. Soc. Jpn. 53 (1980), pages 1138 to 1151 , or in Jonathan Clayden Organolithiums: Selectivity for Synthesis (Tetrahedron Organic Chemistry Series), Pergamon Press (2002). The alkyl in the alkyllithium can contain, for example, from 1 to 4 carbon atoms. Use is frequently made of methyllithium and n-butyllithium or s-butyllithium.

The preparation of the amine complexes is known per se and is carried out in a simple manner by reaction of ferrocene with alkyllithium suspended in a solvent such as hydrocarbons (cyclohexane, pentane, methylcyclohexane, benzene, toluene or xylene) in the presence of an aliphatic tertiary polyamine such as N,N-tetramethyl- ethylenediamine. The reaction products are generally used directly in the next stage. The addition of the components is advantageously carried out at room temperature. The reaction temperature can then be increased and the reaction mixture can be stirred at temperatures of from 30 to 80⁰C, preferably from 40 to 60⁰C, to complete the reaction. The reaction mixture can then be used directly in the next stage.

Ferrocenylhalophosphines of the formula III or IV are known (see WO 2006/075166) or can be prepared by analogous methods by reaction of 1-sec-aminoalkylferrocene with alkyllithium and then with a dihalophosphine RPX₂. The reaction product can be used directly in the last process step.

The reaction of the aliphatic tertiary polyamine complexes of 1 ,1 '-dilithioferrocene with at least 2 equivalents of a ferrocenylhalophosphine of the formula III or IV is carried out by methods known per se under process conditions known per se. The reaction can be carried out at low temperatures up to above room temperature, for example from -100 to 80⁰C, preferably from -40 to 60⁰C and particularly preferably from -40 to 40°C. The use of relatively high temperatures compared to the known reaction with 1 ,1 '-dibromoferrocene is a considerable process engineering and economic advantage. After the components have been mixed, the mixture is frequently allowed to warm slowly to room temperature while stirring. The reaction time is from about 0.5 to 20 hours. The reactions with lithium compounds are advantageously carried out under an inert protective gas, for example nitrogen or noble gases such as argon.

The reactions with lithium compounds are preferably carried out in the presence of inert solvents. Such solvents can be used either alone or as combinations of at least two solvents. Examples of solvents are aliphatic, cycloaliphatic and aromatic hydrocarbons and also open-chain or cyclic ethers. Specific examples are petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl or diethyl ether, tetrahydrofuran and dioxane.

The ratio of optical isomers in the reaction product of the reaction of the 1 ,1 '-dilithio- ferrocene-amine complex with the ferrocenylphosphine halide depends mainly on the reaction conditions and the optical purity of the ferrocenylphosphine halide. In the preparation of [(RcRc), (S_Fc,S_Fc), (Sp,S_P)]-1 ,1 '-bis[2-(1 -N,N-di(methylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene [hereinafter referred to as (Sp₁Sp) for short], [(RcRc), (S_FOS_FC), (Sp,R_P)]-1 , 1 '-bis[2-(1 -N, N-di(methylaminoethyl)-1- ferrocenyl]phenylphosphinoferrocene [hereinafter referred to as (Sp₁Rp) for short] and [(RcRc), (SFCSFC), (Rp,Rp)]-1 , 1 '-bis[2-(1 -N, N-di(methylaminoethyl)-1- ferrocenyl]phenylphosphinoferrocene [hereinafter referred to as (Rp₁Rp) for short] are additionally formed. Our own studies have found that the ratio of (Sp₁Sp): (Sp₁Rp): (Rp₁Rp) can range from 0:5:95 to 1 :2:1.

The optionally isolated reaction product is heated to a temperature of at least 50⁰C. The upper temperature limit depends on the thermal stability of the ferrocene- diphosphines and is below the decomposition temperature and is preferably not more than 250⁰C, more preferably not more than 200⁰C and particularly preferably not more than 180°C. The minimum temperature is preferably 60⁰C, particularly preferably 80°C and very particularly preferably 100°C. A preferred temperature range for the heating step is from 80 to 200⁰C and particularly preferably from 100 to 180°C. The thermal treatment can be carried out immediately after the reaction of the reaction mixture, with either relatively high-boiling solvents being present or low- boiling solvents being displaced by addition of relatively high-boiling solvents when the temperature is increased.

The ferrocenediphosphines formed can also be isolated and then heated either in bulk or in an inert, liquid carrier. Suitable liquid carriers are relatively high-boiling hydrocarbons (toluene, xylene, thmethylbenzene, alkanes and cycloalkanes having boiling points of at least from 80 to 100°C), ethers (dipropyl ether, dibutyl ether, ethylene glycol dimethyl or diethyl ether, triethylene glycol dimethyl ether and dioxane) and alcohols (ethanol, n- and i-propanol, n-, i- and t-butanol, pentanol, hexanol, ethylene glycol monomethyl or monoethyl ether and diethylene glycol monomethyl or monoethyl ether).

The duration of the thermal treatment depends essentially on the temperature selected, the amount use and the way in which the reaction is carried out. Reaction techniques such as microwaves or microreactors which allow substances to be heated quickly and in a controlled fashion to high temperatures and be cooled quickly can be advantageous. The treatment time can range from about 1 to 30 minutes up to from 4 to 20 hours.

The thermal treatment at least enriches the desired diastereomer or its enantiomer or even gives it in pure form. The enrichment makes it possible to avoid an excessively high loss of the substance when the product of the thermal treatment is to be purified further, for example by crystallization or chromatographic methods on achiral columns, for example silica gel, silicate or SiO2 columns. The enantiomers [(Rc₁Rc), (S_Fc,S_Fc), (Sp.SpM-i .i '-bisp-ti 1 -ferrocenyl]phosphinoferrocene and [(ScSc), (RFC.RFC), (Rp,Rp)]-1 ,1 '-bis[2-(1 -N,N- di((Ci-C₄)alkyl))alkyl-1-ferrocenyl]phosphinoferrocene are, surprisingly, more thermo- dynamically stable than the corresponding diastereomers having a (Rp₁Rp) or (Sp₁Sp) configuration.

The ferrocenediphosphines prepared according to the invention are valuable ligands for metal complexes which are used as homogeneous catalysts in stereoselective syntheses, for example the hydrogenation of prochiral compounds.

The following examples illustrate the invention.

Example 1 : [(RcRc), (S_Fc,S_Fc), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene of the formula

a) 13.7 ml (22 mmol, 1.6 M in hexane) of n-butyllithium are added to a suspension of 1.86 g of ferrocene (10 mmol) and 3.20 ml of TMDEA (20 mmol) in 20 ml of hexane over a period of 10 minutes. The mixture is stirred at 50⁰C for 2 hours and then used in the next step.

b) 15.4 ml of a cyclohexane solution of s-butyllithium (1.3 M, 22 mmol) are added to a solution of 5.14 g (20 mmol) of (R)-N, N-dimethyl-1 -ferrocenylethylamine [(R)-ugi- amine] in 30 ml of t-butyl methyl ether (TBME) at -78°C over a period of 10 minutes. The mixture is then heated to room temperature while stirring and maintained at this temperature for 1.5 hours. It is then cooled back down to -78 ⁰C and 2.71 ml

(20 mmol) of dichlorophenylphosphine are added over a period of 10 minutes. After stirring at -78°C for 10 minutes, the mixture is allowed to warm slowly to room temperature and is stirred at this temperature for 1.5 hours. c) The suspension prepared as described in a) is added at below -70⁰C to the reaction mixture prepared as described in b). The mixture is stirred overnight at from -70⁰C to room temperature and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently evaporated off to dryness. This gives an orange solid comprising a mixture of the 3 diastereomers (Sp₁Sp), (Sp₁Rp) and (Rp₁Rp) in a ratio of 1 :2:1. The ratio is determined by means of ³¹ P NMR. ³¹ P NMR (CDCI₃, 101 MHz) {R_P,R_P) isomer: δ -31.8 (s); {Sp,Rp) isomer: δ -32.0 (s) and -34.8 (s); {S_P,S_P) isomer: δ -35.2 (s).

d) The solid obtained as described in c) is taken up in 20 ml of toluene and refluxed for 4 hours. After removal of the toluene, the residue is purified by chromatography (SiO2, hexane : ethyl acetate = 3:1 ). This gives 6.47 g (71 % of theory) of the pure title compound. ¹H NMR (CDCI₃, 300 MHz): δ 1.14 (d, 6H, J = 6.7 Hz), 1.50 (s, 12H);

3.43 (m, 2H); 3.83 (m, 2H); 3.87 (m, 2H); 4.01 (s, 10H), 4.09 (t, 2H, J = 2.4 Hz); 4.11 (m, 2H); 4.20 (m, 2H); 4.28 (m, 2H); 4.61 (m, 2H); 7.18 (m, 6H); 7.42 (m, 4H) ppm. ³¹P NMR (CDCI₃, 101 MHz): δ -35.2 (s).

Example 2: [(Rc₁Rc), (SFC,S_FC), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene

a) 13.7 ml (22 mmol, 1.6 M in hexane) of n-butyllithium are added to a suspension of 1.86 g of ferrocene (10 mmol) and 3.20 ml of TMDEA (20 mmol) in 20 ml of hexane over a period of 10 minutes. The mixture is stirred at 50°C for 2 hours and then used in the next step.

b) 15.4 ml of a cyclohexane solution of s-butyllithium (1.3 M, 22 mmol) are added to a solution of 5.14 g (20 mmol) of (R)-N, N-dimethyl-1 -ferrocenylethylamine [(R)-ugi- amine] in 30 ml of t-butyl methyl ether (TBME) at <20°C over a period of 10 minutes. The mixture is then heated to 0⁰C while stirring and maintained at this temperature for 1.5 hours. It is then cooled to <60°C and 2.71 ml (20 mmol) of dichlorophenyl- phosphine are added over a period of 10 minutes. After stirring at -78°C for

30 minutes, the mixture is allowed to warm slowly to room temperature and is stirred at this temperature for 1.5 hours. c) The suspension prepared as described in a) is added at below -40⁰C to the reaction mixture prepared as described in b). The cooling is removed, the mixture is stirred at room temperature for 2.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising a mixture of 3 diastereomers (Sp₁Sp), (Sp₁Rp) and (Rp₁Rp) in a ratio of 1 :3.5:4.

d) The solid obtained as described in c) is maintained at 140⁰C for 1 hour and then purified by chromatography (SiO2, firstly hexane : ethyl acetate = 3:1 , then hexane : ethyl acetate = 3:1 containing 1 % of triethylamine). This gives a first fraction containing 6.22 g (68.2% of theory) of the pure title compound. The second fraction contains a mixture of the diastereomers (Sp₁Sp) and (Sp₁Rp) in a ratio of 1 :2 (1.71 g, 18.7% of theory).

Example 3: [{R_c,Rc), {S_Fc,S_Fc), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene

b) 15.4 ml of a cyclohexane solution of s-butyllithium (1.3 M, 22 mmol) are added to a solution of 5.14 g (20 mmol) of (R)-N, N-dimethyl-1 -ferrocenylethylamine [(R)-ugi-amine] in 30 ml of t-butyl methyl ether (TBME) at <20°C over a period of 10 minutes. The mixture is then heated to 0⁰C while stirring and maintained at this temperature for

1.5 hours. It is then cooled to <60°C and 2.71 ml (20 mmol) of dichlorophenylphosphine are added over a period of 10 minutes. After stirring at -78°C for 30 minutes, the mixture is allowed to warm slowly to room temperature and is stirred at this temperature for 1.5 hours.

c) The suspension prepared as described in a) is added at below -20⁰C to the reaction mixture prepared as described in b). The cooling is removed, the mixture is stirred at room temperature for 2.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising a mixture of 3 diastereomers (S_P,S_P), (S_P,R_P) and (R_P,R_P) in a ratio of 1 :3.5:5.2.

d) The solid obtained as described in c) is maintained at 130⁰C for 2 hours and then purified by chromatography (SiO2, hexane : ethyl acetate = 3:1 ). This gives 6.41 g (70% of theory) of the pure title compound.

Example 4: [{R_c,Rc), {S_Fc,S_Fc), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene a) 13.7 ml (22 mmol, 1.6 M in hexane) of n-butyllithium are added to a suspension of 1.86 g of ferrocene (10 mmol) and 3.20 ml of TMDEA (20 mmol) in 20 ml of hexane over a period of 10 minutes. The mixture is stirred at 50⁰C for 2 hours and then used in the next step.

c) The suspension prepared as described in a) is added at below 40⁰C to the reaction mixture prepared as described in b). The mixture is stirred at room temperature for 1.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising a mixture of

3 diastereomers (S_P,S_P), (S_P,R_P) and (R_P,R_P) in a ratio of 1 :4:10.

d) The solid obtained as described in c) is maintained at 150⁰C for 30 minutes and then purified by chromatography (SiO2, hexane : ethyl acetate = 3:1 ). This gives 6.36 g (69.7% of theory) of the pure title compound.

Example 5: [(RcRc), (S_Fc,S_Fc), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]phenylphosphinoferrocene

c) The suspension prepared as described in a) is added at below 40⁰C to the reaction mixture prepared as described in b). The mixture is stirred at room temperature for

1.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising a mixture of 3 diastereomers (Sp,S_P), (S_P,R_P) and (Rp₁Rp) in a ratio of 1 :6:20. The product is purified by chromatography (SiO₂, hexane: ethyl acetate = 3:1 containing 1 % of triethylamine). This gives 7.93 g (88% of theory) of a yellow foam comprising the 3 diastereomers (Sp,S_P), (S_P,R_P) and (R_P1R_P) in a ratio of 1 :6.5:34.

d) 0.5 g of the product is maintained at 130⁰C and the ratio of the 3 diastereomers is determined at intervals of 20 minutes. The result is shown in the table below.

Example 6: [(RcRc), (SFC,S_FC), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyl]cyclohexylphosphinoferrocene

b) 15.4 ml of a cyclohexane solution of s-butyllithium (1.3 M, 22 mmol) are added to a solution of 5.14 g (20 mmol) of (R)-N, N-dimethyl-1 -ferrocenylethylamine [(R)-ugi- amine] in 30 ml of t-butyl methyl ether (TBME) at <20°C over a period of 10 minutes. The mixture is then heated to 0⁰C while stirring and maintained at this temperature for 1.5 hours. It is then cooled to <60°C and 3.0 ml (20 mmol) of dichlorocyclohexyl- phosphine are added over a period of 10 minutes. After stirring at -78°C for

30 minutes, the mixture is allowed to warm slowly to room temperature and is stirred at this temperature for 1.5 hours.

c) The suspension prepared as described in a) is added at below -20⁰C to the reaction mixture prepared as described in b). The mixture is stirred at room temperature for 2.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising at mixture of

3 diastereomers (Sp₁Sp), (Sp₁Rp) and (Rp₁Rp) in a ratio of 1 :4:6. The ratio is determined by means of ³¹P NMR. ³¹P NMR (CDCI₃, 101 MHz): (R_P,R_P) isomer: δ -21.6 (s), (S_P,R_P) isomer: δ -21.3 (s) and -26.9 (s); (S_P,S_P) isomer: δ -26.5 (s). d) The solid obtained as described in c) is maintained at 150⁰C for 2 hours. The ratio of (Sp₁Sp) : (Sp₁Rp) : (R_P1R_P) is then 2.5:1 :0. The product is then purified by chromatography (SiO2, firstly hexane : ethyl acetate = 3:1 , then hexane : ethyl acetate = 3:1 containing 1 % of triethylamine). This gives a first fraction containing 5.43 g (58.7% of theory) of the pure title compound. ¹H NMR (CDCI₃, 300 MHz): δ 1.30 (d, 6H, J = 6.6 Hz), 1.28-2.40 (m, 18H), 2.26 (s, 12H); 2.68 (m, 2H), 3.99 (m, 2H); 4.09 (s, 12H, overlapping), 4.21 (m, 2H); 4.30 (m, 2H); 4.53 (m, 2H); 4.56 (m, 2H); 4.63 (m, 2H); 4.86 (m, 2H) ppm. ³¹P NMR (CDCI₃, 101 MHz): δ -26.5 (s). The second fraction contains a mixture of the diastereomers (S_P,S_P) and (S_P,R_P) (2.96 g, 32.0% of theory).

Example 7: [(Rc₁Rc), (SFC,S_FC), (S_P,S_P)]-1 ,1 '-Bis[2-(1-N,N-dimethylaminoethyl)-1 - ferrocenyφsopropylphosphinoferrocene

b) 15.4 ml of a cyclohexane solution of s-butyllithium (1.3 M, 22 mmol) are added to a solution of 5.14 g (20 mmol) of (R)-N, N-dimethyl-1 -ferrocenylethylamine [(R)-ugi- amine] in 30 ml of t-butyl methyl ether (TBME) at <20°C over a period of 10 minutes. The mixture is then heated to 0⁰C while stirring and maintained at this temperature for 1.5 hours. It is then cooled to <60°C and 2.47 ml (20 mmol) of dichlororopropyl- phosphine are added over a period of 10 mintues. After stirring at -78°C for

c) The suspension prepared as described in a) is added at below -20⁰C to the reaction mixture prepared as described in b). The mixture is stirred at room temperature for 2.5 hours and 20 ml of water are then added. The organic phase is then separated off, dried over sodium sulphate and the solvent is subsequently removed to dryness. This gives an orange solid comprising a mixture of 3 diastereomers (Sp,S_P), (S_P,R_P) and (R_P1R_P) in a ratio of 1 :4.8:7.7. The ratio is determined by means of ³¹P NMR. ¹³P NMR (CDCI₃, 101 MHz): (R_P,R_P) isomer: δ -16.4 (s), {Sp,Rp) isomer: δ -18.8 (s) and -24.1 (s); {S_P,S_P) isomer: δ -23.8 (s).

d) The solid obtained as described in c) is maintained at 150⁰C for 2 hours. The ratio of (Sp₁Sp) : (Sp₁Rp) : (Rp₁Rp) is then 14:7:1. The product is then purified by chromatography (SiO2, firstly hexane : ethyl acetate = 3:1 , then hexane : ethyl acetate = 3:1 containing 1 % of triethylamine). This gives a first fraction containing 4.85 g (57.5% of theory) of the pure title compound. ¹H NMR (CDCI₃, 300 MHz): δ 1.25 (m, 12 H, overlapping), 1.68 (dd, 6H, J = 18.5 and 7.3 Hz), 2.25 (s, 12H); 2.85 (m, 2H), 3.96 (m, 2H); 4.10 (s, 12H, overlapping), 4.21 (m, 2H); 4.26 (m, 2H); 4.47 (m, 2H); 4.55 (m, 4H); 4.89 (m, 2H) ppm. ³¹P NMR (CDCI₃, 101 MHz): δ -23.8 (s). The second fraction contains a mixture of the 3 diastereomers (Sp₁Sp), (Sp₁Rp) and (RpRp) (2.2O g, 32.0% of theory).

Claims

1. Process for preparing [(RcRc)-, (SF_CSFC)-, (SP, SP)-I , 1 '-bis(2-sec-aminoalkyl)-1 - ferrocenyl]phosphinoferrocene of the formula I

where

Ri is d-Cβ-alkyl, Cs-Cβ-cycloalkyl or phenyl, and the two radicals R2 bound to an N atom are identical or different and are each d-Cs- alkyl, C₄-C₈-cycloalkyl, C₄-C₈-cycloalkyl-Ci-C₂-alkyl, phenyl, phenyl-Ci-C₂-alkyl or the two radicals R2 bound to an N atom together form C2-C₇-alkylene, -(CH₂)2-O-(CH₂)2 or -(CH₂)2-N(Ci-C₄-Alkyl)-(CH₂)2-, which is characterized in that an aliphatic tertiary polyamine complex of 1 ,1 '-dilithio- ferrocene is reacted with at least 2 equivalents of a ferrocenylhalophosphine of the formula III or IV, where R, Ri and R2 are as defined above and X is Cl, Br or I and the optionally isolated reaction product is then heated to a temperature of at least 50⁰C.

2. Process according to Claim 1 , characterized in that the radical R is linear or branched Ci-Ci₂-alkyl; unsubstituted or Ci-C₆-alkyl- or Ci-C₆-alkoxy-substituted C₅- Ci2-cycloalkyl or C₅-Ci2-cycloalkyl-CH₂-; phenyl, naphthyl, furyl or benzyl and phenyl or benzyl substituted by halogen, d-Cβ-alkyl, Ci-Cs-haloalkyl, CrCs-alkoxy, C1-C3- haloalkoxy, (CeHs)₃Si, (Ci-Ci2-alkyl)₃Si, sec-amino or -CO2-Ci-C3-alkyl.

3. Process according to Claim 1 , characterized in that R is Ci-Cs-alkyl, cyclopentyl, cyclohexyl, furyl, unsubstituted phenyl or phenyl substituted by from one to three Ci-C₄-alkyl, Ci-C₄-alkoxy and/or Ci-C₄-fluoroalkyl groups.

4. Process according to Claim 1 , characterized in that Ri is linear CrC₄-alkyl, preferably methyl.

5. Process according to Claim 1 , characterized in that R₂ is methyl.

6. Process according to Claim 1 , characterized in that both Ri and R₂ are each methyl and R is CrC₄-alkyl, cyclopentyl, cyclohexyl, furyl or unsubstituted phenyl or phenyl substituted by from one to three Ci-C₄-alkyl, Ci-C₄-alkoxy and/or CrC₄- fluoroalkyl groups.

7. Process according to Claim 1 , characterized in that the polyamine in the polyamine complex is N,N-tetramethylethylenediamine.

8. Process according to Claim 1 , characterized in that the optionally isolated reaction product is heated to a temperature of from 50⁰C to 250°C.

9. Process according to Claim 8, characterized in that the temperature is from 80 to 200⁰C, preferably from 100 to 180⁰C.

10. Process according to Claim 1 , characterized in that the thermal treatment is carried out immediately after the reaction of the reaction mixture, with either relatively high- boiling solvents being present or low-boiling solvents being displaced by addition of relatively high-boiling solvents when the temperature is increased.

11. Process according to Claim 1 , characterized in that the reaction mixture is isolated and then heated either in bulk or in an inert, liquid carrier.

12. Process according to Claim 1 , characterized in that the liquid carrier comprises relatively high-boiling hydrocarbons, ethers or alcohols.