According to the invention an allylic compound is reacted with an organozinc compound Zn(R6)2 to eliminate a group (the leaving group) from the allylic compound and to add a group from the organozinc compound to it in the presence of a copper salt catalyst and a chiral organic ligand for the copper. Preferably the ligand is a primary or secondary amine in which the nitrogen atom is directly linked to the chiral centre.

The allylic compound is suitably of formula where X is the leaving group for example a chlorine atom and in which A is hydrogen or an alkyl or aryl group, preferably having 0-20 carbon atoms. If substitution occurs at the carbon atom marked * a chiral centre may be formed. This process is known as Sn2'substitution ; an alternative substitution at the carbon atom marked t may occur in which case there may be no chiral centre, this process is known as Sn2 substitution.

The reactions are shown as follows : where R6 is a group from the organozinc compound. Surprisingly, in this process the former reaction is generally favoured and is influence by the leaving group, ligands and solvents as shown below, tetrahydofuran being a particularly favourable solvent. The process is normally chemoselective for Sn2'substitution and/or stereoselective.

In a preferred form of the invention the reaction is as shown below : - R'- R6 are alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl groups optionally substituted by for example halogen, alkoxy, aryloxy, acyboxy, nitro, amide, acetamide, carboxylate, cyano, acetal, sulphide, sulphonate, sulfone, sulfoxide, phosphite, phosphonate, phosphine groups, each preferably having at most 20 and preferably less than 10 carbon atoms, or R'to R5 may be H, R7 is an aryl for example a phenyl or ferrocenyl or

substituted aryl or ferrocenyl group of which the substituents may be for example 1- aminobenzyl, 1-amino-2-naphthylmethyl, 1-amino- (4-tert-butylphenyl) methyl, trimethylsilyl, phosphite, phosphine, alkyl, alkoxy, thiophosphonate, amino and/or halogen (eg Cl or Br) atoms and R is an alkyl or aryl, preferably a methyl, ethyl, propyl, tert-butyl, phenyl or naphthyl for example 2-naphthyl group which may be substituted for example by nitro, alkoxy, alkyl and/or haloalkyl group. X is halogen, OR9, OCOR9, OC02R9, OS02R9, OCS2R9 CH (OR'O) 2, OPO (OR9)2, SOR9, or SO2R9where R9 and R'° are optionally substituted Ci-Cio atkyt or aryl, of which the substituents may be halogen, nitro, methoxy, trifluoromethoxy, methyl, ethyl, tert butyl or sulphonate groups e. g. methyl, ethyl, trifluoromethyl, phenyl, tosyl, p-bromophenyl, p-nitrophenyl, p- methoxyphenyl. or R7 and R8 may together form a 5 or 6 membered carbocyclic or heterocyclic ring providing that a carbon atom to which the nitrogen is attached is chiral. for example R7 and R8 together may be 1-indane, bornylamine or 2-cyclohexylamine. Y is halogen, carboxylate for example, acetate, acetoacetate, cyanide, or thiocyanate and Z is an ether or thioether for example dimethylsulfide, tetrahydrofuran or diethylether.

Preferably R' - R2 and R3 and one of R4 or R5 are H and the other one of R4 or R5 is aryl, for example phenyl, 4-chlorophenyl or 4-trifluoromethyl phenyl or is a trialkyl (e. g. tri- isopropyl) silyl oxymethyl groups R5 is alkyl, tri-alkyl (e.g. trimethyl) silyl methyl, phenyl or 2,2-dimethylbut-3-enyl. R7 is ferrocenyl, R3 is naphthyl, X is chloride, Y is chloride or bromide and Z is dimethylsulfide. R5 is preferably phenyl and R6 is preferably neopentyl.

The substituents of R'preferably have at most 10 carbon atoms in total and those of R preferably at most 8 carbon atoms in total. Alkanes, cyclo alkanes and/or aromatic solvents for example toluene may be present.

Preferred solvents are ethers for example diethylether, 1, 4-dioxane, tertbutylmethylether and especially tetrahydrofuran. Preferred temperatures are -120°C to 25°C more preferably -100°C to 20°C and especially -90°C to -50°C.

Preferred concentrations of catalyst are 0. 1 atom% to 20 atom%, especially 0. 5 atom% to 5 atom% expressed as copper atoms based on moles of the allylic compound.

The ratio of copper atoms to the amine ligand molecules is suitably 1 : 10 to 2 : 1.

Compounds for formula in which A is a ferrocenyl or substituted ferrocenyl group and B is a group R$ other than a methyl or phenyl group are believed to be novel. The groups A and B should be different in order to obtain stereospecificity. B is preferably a 2-naphthyl group.

Example 1 Preparation of (R) - (1-amino-2-naphthylmethyl) ferrocene Step1 Ferrocene (4. 5 g, 24 mmol) and aluminium trichloride (3. 5 g, 26 mmol) were combined in dry dichloromethane (100 ml) at 0°C under argon. To the greenish suspension was added a solution of 2-naphthoyl chloride (5. 0 g, 26 mmol) in dichloromethane (20 ml) at 0°C over a period of 20 min to obtain a dark purple solution.

The reaction was stirred for 2h at room temperature and then quenched by careful addition of saturated aqueous ammonium chloride solution (100 ml). The organic layer was separated, washed with sat. aqueous sodium bicarbonate solution (2 x 30 ml), dried (MgS04) and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 1 : 1 pentane : diethyl ether by volume as eluent to give the ketone (5. 6 g, 69%) as a red solid.

Step 2 The ferrocenyl ketone (4. 5 g, 13.2 mol) and borane dimethyl sulfide complex (1. 4 ml, 14 mmol) were added simultaneously over a period of 30 minutes to a solution of the CBS catalyst (0. 70 g, 2. 5 mmol) in THF (80 ml) at 0°C under argon. CBS catalyst is The catalyst is prepared from 1, 1-diphenyl pyrrolidine methanol and borane (see Synlett 1993,929) After stirring for an additional 30 min the mixture was quenched with aq. ammonium chloride solution (70 ml). The organic layer was separated, dried (MgS04) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 1 : 1 pentane : ether as eluent affording the desired alchohol (4. 0 g, 89%) as an orange solid.

Step 3 The ferrocenyl alcohol (4. 0 g, 11. 6 mmol) was dissolve in dry pyridine (30 ml) and acetic anhydride (20 ml) at room temperature. After stirring for 18h at room temperature all volatiles were removed under high vacuum at 50°C furnishing the pure acetylated alcohol (4. 5 g, 100 %) as a red glue, that smoothly crystallised on standing to a red solid.

The acetylated alcohol (3. 0 g, 8 mmol) was dissolve in acetonitrile (200 ml) and 37% aqueous ammonia solution (40 ml). After stirring for 24h at room temperature the mixture was poured into 10% aqueous hydrochloric acid (200 ml). The resulting precipitate was removed by filtration and washed with ether (4 x 20 ml). The residue was

dissolved in 20% aqueous sodium hydroxide solution (200 ml) and the desired product re-extracted with ether (5 x 50 ml). After drying (MgS04), the solvent was removed under reduced pressure and the pure (R)-(1-amino-2-naphthylmethyl) ferrocene (1. 8 g, 66%) was obtained as an orange solid.

The corresponding compounds in which the naphthyl group is replace by phenyl, o-tolyl, 1-naphthyl, 2-naphthyl, methyl, cyclohexyl, o-biphenyl, p-biphenyl, phenanthrenyl, o-bromophenyl and p-butylphenyl were prepared similarly. Compounds in which the ferrocenyl is symmetrically 1, 1' disubstituted with 1-aminobenzyl, 1-amino-2- naphthylmethyl, 1-amino- (4-tert-butylphenyl) methyl, or 2-substituted with trimethylsilyl were prepared using the method given in example 1 except that two mole equivalents of aluminium chloride and acylchloride were used in step 1, two mole equivalents borane dimethylsulfide and 30 mol% CBS catalyst were used in step 2, and two mole equivalents acetic anhydride, pyridine and ammonia were used in step 3. The enantiomeric excess was in each case greater than 99%.

The reaction is illustrated below. The reaction was also carried out with the compounds indicated below, the % figures indicating the stated yields of pure material based on starting material, Ph ph 0 4 1. Ac2o, pyddine Fe RB H F Fe Re R8 /t\ BH3.DMS, THF lt\ R /t\ 2. NH3, acetonitrile R8 = Ph R8 = Ph; 88% R8 = Ph; 45% R8 = o-Tolyl R8 = o-Tolyl; 62% R8 = o-Tolyl; 48% R8 = 1-Naphth R8 = 1-Naphth;73% R8 = 1-Naphth ; 44% R8 = 2-Naphth R"= 2-Naphth ; 81% R"= 2-Naphth ; 66% R8 = Methyl R8 = Methyl R8 = Methyl R8 = Cyclohexyl R8 = Cyclohexyl; R8 = Cyclohexyl; R8 = 2-Biphenyl R8 = 2-Biphenyl R8 = 2-Biphenyl R8 = 4-Biphenyl R8 = 4-Biphenyl R8 = 4-Biphenyl R8 = phenanthrenyl R8 = phenanthrenyl R8 = phenanthrenyl R8 = 2-bromophenyl R8 = 2-bromophenyl R8 = 2-bromophenyl R8 = 4-bromophenyl R8 = 4-bromophenyl R8 = 4-bromophenyl DMS is dimethyl sulphide and THF is tetrahydrofuran.

Example 2 Enantioselective allylation. Preparation of (+) - (S) -5, 5-dimethyl-3 (4- trifluoromethylphenyl)-1-hexene This reaction is shown below

The chiral organic ligand R7=ferrocenyl, R8=2-naphthyl (70 mg, 0.2 mmol) and CuBr.Me2S (3 mg, 0.02 mmol) were dissolve in THF (5 ml) yielding a clear solution.

After cooling to -90°C, neo-Pent2Zn (0. 3 ml, 2. 4 mmol) and 4-trifluoromethylcinnamyl chloride were added successively. The reaction mixture was stirred for 18h at -90°C and was worked up. The crude residue obtained after evaporation of the solvents was purified by flash-chromatography (ether pentane 1 : 50) leading to the desired product (370 mg, 72% yield : SN2'/SN2 ratio : 97 : 3). The enantiomeric excess of the chiral product was determined by gas chromatography to be 87% using a Chiraldex capillary column.

Use of different substituents R7 and R8 in asymmetric allylation reaction The following Table 1 shows the use of different chiral organic tigands (iig*) R and R8 as indicated in table 1, in the reaction of cinnamyl chloride with di-neopentyl zinc at -50°C. The chiral organic ligands were prepared according to the methods in example 1 and are of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

Table 1 Entry R7 R8 Yield SN2X: SN2 ee (%) 1 Ferrocenyl Phenyl 73 95 : 5 32% 2 Ferrocenyl o-Tolyl 79 96:4 16% 3 Ferrocenyl 1-Naphthyl 72 93:7 33% 4Ferroceny!2-Naphthyt7795:542% 5Ferroceny)Methy!7488:127% 6 Ferrocenyl Cyclohexyl 74 92 : 8 15%' 7 Ferrocenyl o-Biphenyl n. d. 92 : 8 4% 8 Ferrocenyl p-Biphenyl 84 97:3 38% 9Ferroceny)Phenanthreny)6998:261% 10 Ferrocenyl 2-Naphthyl 75 97: 3 67% 11 Ferrocenyl o-Bromophenyl 67 96:4 38% 12 Ferrocenyl p-Butylphenyl 69 96 : 4 56% Entry R7 R8 Yield SN2' : SN2 ee (%) Ph Fe \ 13 R Ph 68 99 : 1 51 % Ph Fe NHZ sX N H 2 14 2 n2#"68 97 : 3 52% 8 H N% Fe H, N 15 tet) utylphen 69 96 : 445% R Fe -Q NH2 H N% H2N Fe s 17 phenyl methyl >95 94 : 6 44% 18 2-naphthyl methyl >95 95 : 5 42% 19 1-naphthyl methyl >95 95 : 5 52% 20 R7+R8= 80% 86: 14 18% (R) -2-bornyl 21 R7+R8 = (R)1- >95% 93 : 7 16% indany) 22 R+R 70% >99 : 1 0% trans-2- cyclohexylamine 23 (S)-2- phenyl 70% >99 : 1 0% aminobenzyl

Entry 1-8 : Ratio CuBr Me2S/Lig*/Substrate = 1/1/20. Entry 9 - 23 : 1/10/100 Opposite stereoisomer in excess Use of different substrates for the substitution The following Tables 2 and 3 show the use of different allyl reagents R'and R2 and (except in entry 13 of Table 3) R3 = H, R4 and R5 as indicated in the tables, in the reaction with di-neopentyl zinc using the chiral ligand R7=ferrocenyl, R8=2-naphthyl of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

Reactions run at -50°C Table 2 Entry R4 R5 Yield(%) SN2':SN2 ee 1 H phenyl 75 97:3 67% 2 phenyl H 50 96:4 22% 3 H 2-trifluoromethyl 55 80 : 20 -' phenyl 4 H 4-trifluoromethyl 70 98:2 74% phenyl) 5 H 1-naphthyl 74 97: 3 58% 6 H cyclohexyl 70 (78 : 22) 59% 7 H phenylmethyl 50 18 : 82 4% 8 CH2OMe H 67 >99:1 2% 9 CH2OAc H 74 >99:1 14% 10 CH20SitBuMe2 H 30 > 99 : 1 29% 11 CH2OSi(iPr)3 H 53 >99: 1 47% 12 H ; CH2Osi(iPr)3 55 >99: 1 38% 13 CH2OSiPh2tBu H 70 >99: 1 12% Separation of enantiomers was not possible.

Reactions run at -90°C

Table 3 Entry R4 R5 R3 Yield SN2' : SN2 ee (%) 1 H phenyl H 68 95:5 82% 2 4-trifluoromethyl H 72 97: 3 87% phenyl 3H1-naphthytH6594:671% 4 2-naphthyl H 60 91: 9 70% 5 H cyclohexyl H 67 98:2 76% 6 H 3-thienyl H 70 94:6 63% 7 CH2OSi(iPr)3 H H 45 >99:1 64% 8H4-isopropy!pheny)H7090:1076% 9 H 4-chlorophenyl H 71 96:4 79% 10 H 3-chlorophenyl H 72 97: 3 70% 11 H 3,4-dichlorophenyl H 68 96: 4 22% 12 H 1-cyclopentenyl H 63 64:36 60% 13 phenyl H -CO2Et 71 87: 13 12%

Use of different diorganozincs at - 50°C The following Table 4 shows the use of different organozinc reagents Zn (R6) 2, in the reaction with trans-cinnamyl chloride using the chiral ligand R7=ferrocenyl, R8=2-naphthyl of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

Table 4 Entry R Yield (%) SN2' : SN2 ee 1 Methyl 90 98:2 10% 2 Ethyl 88 98:2 10% 3/soPropy!8798229% 4 isoButyl 69 98:2 45% 5 Pentyl 88 98:2 26% 6 neoPentyl 75 97:3 67% 7 1R-(+)-Pinane 65 97:3 41% 8 1S-(-)-Pinane 60 98:2 37% 9 PhMe2SiCH2 50 90 : 10 42% 10 Me3SiCH2 52 94:6 67% 11 Me2PhCCH2 @ 68:32 25% 12 Me2PhSi(CH2)27898:215% 13 H2C=CH2C(CH3)2CH2 65 95:5 79%² 'Reaction worked up before completion. 2 Reaction done at-85°C

98TJL01S - MS - 23 August 1999