WO1995013284A1

WO1995013284A1 - Asymmetric hydroboration

Info

Publication number: WO1995013284A1
Application number: PCT/GB1994/002461
Authority: WO
Inventors: John Michael Brown
Original assignee: Isis Innovation Limited
Priority date: 1993-11-09
Filing date: 1994-11-09
Publication date: 1995-05-18
Also published as: AU8112694A; GB9323028D0

Abstract

A process for the reaction of an alkene, allene or alkyne with a borane in the presence of a catalyst to form an optically active alkylboronate which may then be reacted with an oxidising agent to form an optically active alcohol or amine. The catalyst may have formula (4), where Q is a Group VIIIA metal ion and R?10 - R19¿ are organic groups.

Description

ASYMMETRIC HYDROBORATION

The present invention relates to a catalytic process for preparation of optically active alcohols and amines, a catalyst and a process for preparation of the catalyst.

An asymmetric hydroboration reaction of styrene with catecholborane in the presence of Rhodium bisdiphenylphosphine catalysts is known (Burgess

Tetrahedron: Asymmetry (1991), pg 601) but this reaction suffers from a number of disadvantages in that either low yields or low enantiomeric excesses (e.e.) are obtained or that the reaction is carried out at lower temperatures.

According to the present invention there is provided a process for the reaction of an alkene, allene or an alkyne with a borane in the presence of a catalyst to form an optically active alkylboronate characterised in that the catalyst is a neutral or cationic complex of a metal from Group VIIIA of the Periodic Table wherein the metal is co-ordinated with at least one nitrogen atom and at least one phosphorus atom and at least one of the catalyst and the borane is optically active.

The alkene or allene may be a straight or branched-chain alkene or allene or a cyclic alkene or allene and each of the alkenyl carbon atoms may carry up to 2 substituent groups. Preferred alkenes are those in which there are one or more substituent groups on one or on both of the alkenyl carbon atoms and if the substituents are on the same alkenyl carbon atom they are different.

The alkyne may be a straight or branched- chain alkyne or a cyclic alkyne and each of the alkynyl carbon atoms may carry a substituent group. Preferred alkynes are those which carry substituent groups on the alkynyl carbon atoms and that these substituents are different. The linear chain alkene is preferably of Formula ( 1 ) :

in which R1, R2, R3 and R4 each independently

is -H, or an alkyl, alkenyl, alkynyl, aryl or

heterocyclic radical each of which may optionally carry one or more substituents or is -NO2, -F, -Cl, -Br, -I, -CF3, -CC13, -OR5, -SR5, -OCOR5, -COR5, -SOR5, -SO2R5, -SO3R5, -PR5R6, -P(O)R5R6, -P(O)OR5R6, -P(O)OR5OR6, -NR5R6, -SiR5R6R7 in which R5, R6 and R7 each

independently is -H, C1-6-alkyl or phenyl.

The linear chain allene is preferably of Formula ( 1A) :

in which R1, R2, R3 and R4 are as

hereinbefore defined.

Where any one of R1, R2, R3 and R4 is an alkyl radical it is preferably C1-18-alkyl.

Where any one of R1, R2, R3 and R4 is an alkenyl radical it is preferably C2-18-alkenyl, more preferably C2-18-alk-1-enyl.

Where any one of R1, R2, R3 and R4 is an alkynyl radical it is preferably C2-18-alkynyl, more preferably C2-18-alk-1-ynyl.

The alkyl, alkenyl, alkynyl groups represented by R1, R2, R3 and R4 may be straight- or branched-chain or cyclic.

Where any one of R1, R2, R3 and R4 is an aryl radical it is preferably phenyl, naphthyl,

phenanthranyl, benzanthranyl or anthranyl, more preferably phenyl and naphthyl.

Where any one of R1, R2, R3 and R4 is a heterocyclic radical it may be saturated, unsaturated or partially saturated, preferably an unsaturated heterocyclic radical and especially selected from pyridyl, quinolinyl, furanyl, thienyl and pyrrolyl.

Where any of the groups represented by R1, R2, R3 or R4 carries one or more substituents the substituents may be selected from C1-6-alkyl, phenyl, C1-4-alkylphenyl, -F, -Cl, -Br, -I, -OR5, -OCOR5, -SR5,-SOR5, -SO2R5, -SO3R5, -NR5R6, -NO2, -CN, -COR5, -CO2R5 and -P(O)OR5OR6 in which R5 and R6 are as hereinbefore defined.

Examples of open chain alkenes include: 1-phenyl-2-bromoethene, 1-phenyl-3-chloroprop-1-ene, methyl 1-phenylprop-1-enoate, benzyl propenoate, 1-(2-phenylprop-1-en-3-yl)-1,2,4-triazole, hex-1-ene, 1-phenyl-but-2-ene, 3-phenoxyprop-1-ene, 1,1,1-trifluoropropene, (triethylsilyl)ethene, phenylethene, 4-methoxyphenylethene, 4-chloro phenylethene, 2-chlorophenylethene, trans-2-heptenaldimethyl acetal, 2-oxiranylethene, methylchrysanthamate and 1-phenyl-1-propyne, naphthylethene, cis and trans-1-phenylprop-1-ene,

cis and trans stilbene, trans-1-phenyl-3

-(trimethylsilyloxy)prop-1-ene.

The cyclic alkene is preferably a C3-8-cycloalkene or an alkene of Formula (2):

wherein:

J is -O-, -S-, -CR8R9 -C=C-, -C=O or -NR8 in which R8 and R9 each independently is H, C1-8-alkyl or phenyl;

M is a direct link or is any of the groups represented by L;

K is -H or any one of the substituents for R1 defined above; and

n is from 1 to 4.

Examples of cyclic alkenes include: 1- phenylcyclopent-1-ene, indene, 1-methylcyclohept-1-ene, benzo[2,3]cyclohept-1-ene, 2-coumaranone,

benzo[2,3]cyclooct-1-ene, cyclopentadiene,

cyclooctadiene, benzopyran, benzofuran, cyclohexene, 6-methyl-5,6-dihydropyran-2-one, N-benzyl-2,3-dihydropyrrole, 1,2-dihydronaphthalene and 7-methoxy-1,4-dihydronaphthalene.

The borane may be a primary or a secondary borane and is preferably a secondary borane of Formula (3):

wherein:

X and Y each independently is halogen, -OR8, -NR8R9 in which R8 and R9 are as hereinbefore defined; or

X and Y form a 5- or 6-membered ring which is optionally substituted.

The halogen represented by X and Y is preferably -Cl, -Br or -F, more preferably -Cl.

Examples of suitable boranes include catecholborane, 3, 4-benzocatecholborane, 4,5-benzocatecholborane, 1,8-naphthalenediolborane, dichloroborane, and N-alkyloxazaborolidines such as ephedrineborane, pseudoephedrineborane, N- methyloxazaborolidine, N-benzyl-4-isopropyloxazaborolidine, N-isopropyloxazaborolidine, 4-alkylsubstituted oxazaborolidines such as 4-isopropyloxazaborolidine, 4-arylsubstituted

oxazoborolidines such as 4-phenyloxazaborolidine, boranes based on dihydroxydihydrocyclohexadienes such as 1R,2S-dihydroxy-1,2-dihydro-3-methylcyclohexa-3,5-diene.

The catalyst is preferably of Formula (4):

wherein :

Q is Fe , Co , Ni , Ru, Rh, Pd , Os , I r or Pt ;

P is 0 or is an integer from 1 to 4 ; x is an integer f rom 1 to 3 ;

L is a ligand ;

r is 0 or an integer from 1 to 5;

n is 0 or an integer from 1 to 5;

q is an integer from 1 to 5; and

Z is a counter ion;

R10 and R1leach independently is alkyl, alkoxy, aryl or aryloxy each of which may be optionally substituted;

or R10 and R11 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered heterocyclic ring which may be optionally substituted;

R12, R13, R14, R15, R16, R17, R18 and R19 each independently is any of the

substituents described above for R1;

or R14 and R15 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted;

and/or R16 and R17 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted;

and/or R15 and R16 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted.

and/or R12 and R13 together with the carbon atoms to which they are attached are combined to form a 5- or 6- membered carbocyclic ring which may be optionally substituted

and/or R18 and R19 together with the carbon atoms to which they are attached are combined to form a 5- or 6- membered carbocyclic ring which may be optionally substituted.

Q is preferably Ru, Rh, Pd, Pt, Ir and Ni and more preferably Rh, Pd, Pt, Ru or Ir.

Suitable optional substituents for R10 and R11 and for the 5- or 6-membered rings formed by combining R10 and R11 and/or R14 and R15 and/or R16 and R17 and/or R15 and R16, and/or R12 and R13 and/or R18 and

R19 are any of the substituents defined for R1.

The alkyl groups represented by any one of

R10 to R19 and the alkoxy groups represented by R10 or R11 may be straight or branched chain groups.

Where any one of R10 to R19 represents alkyl it is preferably C1-10-alkyl or C1-10-alkyl substituted by 2- or 3-furyl, 2- or 3-thienyl, phenyl, more preferably C1-6-alkyl or -CPh3.

Where R10 or R11 is alkoxy it is preferably C1-6-alkoxy, more preferably methoxy, ethoxy, t-butoxy or benzyloxy.

Where R10 or R11 is aryl it is preferably phenyl, naphthyl or anthranyl each of which is optionally substituted by a group selected from F, Cl, N(R5)2 in which R5 is as hereinbefore defined, -CH3-OCH3, -NO2, -CN, -COOH, -COOCH3 or -COOC2H5.

Where R10 or R11 is aryloxy it is preferably phenoxy or naphthoxy each of which is optionally substituted by a group selected from -CH3, -OCH3, -NO2,-CN, -COOH, -COOCH3, -COOC2H5, more preferably phenoxy, p-methoxyphenoxy and trityloxy (Ph3CO-).

Where R10 and R11 are combined to form a five membered ring the derived phosphole can be further fused to form a mono or dibenzophosphole which can be optionally substituted by from 1 to 4 substituents selected from the substituents defined above for R1.

Where R14 and R15 and/or R16 and R17 and/or

R15 and R16 are combined to form a 5- or 6-membered ring the ring is preferably phenyl, naphthyl,

cyclohexyl or pyridyl each of which is optionally substituted by from 1 to 4 substituents selected from the substituents defined above for R1.

Where R12 and R13 and/or R18 and R19 are combined to form a 5- or 6- membered ring the ring is preferably phenyl, naphthyl, cyclohexyl each of which is optionally substituted by from 1 to 4 substituents selected

from the substituents defined above for R1

Suitable monodentate ligands represented by L are species which have at least one region of

relatively high electron density such as those having a halogen, C, O, N, S or P atom or a double or triple bond with C, O or N atoms, the monodentate ligand preferably has at least one alkenic bond. Suitable bidentate ligands represented by L are species which have at least two regions of relatively high electron density such as species having at least two C-C double, -C=N-, -C=O or -C=N bonds or any combination thereof. Similarly, suitable tridentate or tetradentate ligands represented by L are species having at least three or at least four, respectively, regions of relatively high electron density. It will be appreciated that the metals represented by Q may occur in a number of oxidation states and the particular oxidation state affects the number and geometric arrangement of the ligands, L, around the metal, Q.

For example where the metal, Q is Fell, CoII, NiII, FeIII, CoIII or NiO 4 or 6 donor atoms or groups in donor atoms may co-ordinate with the metal in a tetrahedral, square planar or octahedral arrangement; where the metal is RhI, RhIII, IrI or IrIII 4, 5 or 6 may co-ordinate with the metal in a tetrahedral or square planar, pentagonal or octahedral arrangement; where the metal is PdO or PdII 3 or 4 donor atoms may co-ordinate with the metal in a trigonal, tetrahedral or square planar arrangement; where the metal is RuO RuII or RuIII 6 donor atoms or groups may co-ordinate with the metal in an octahedral arrangement; where the metal is OsIII or OsIV 4 or 6 donor atoms may co- ordinate with the metal in a tetrahedral or octahedral arrangement, where the metal is PtO or PtII 3 or 4 maa co-ordinate with the metal in a trigonal, tetrahedral or square planar arrangement.

In the preferred catalyst of Formula (4) 2 of the 4 or 6 available positions co-ordinate with the N and P atoms, when x=1, and 4 of the 4 or 6 available positions co-ordinate with the N and P atoms when x=2. Where there are 2 remaining positions these may be co-ordinated with 2 monodentate or 1 bidentate ligand, where there are 4 remaining positions these may be co-ordinated with 4 monodentate, or 2 bidentate or 2 monodentate and 1 bidentate ligands. Where more than one mono- or bidentate ligands co-ordinate with the metal, Q, these may be the same or different. Suitable ligands are alkenes such as ethene, propene, styrene, norbornene and cyclohexene, alkynes such as ethyne, carbonyls such as acetoacetonate, nitriles such as acetonitrile, halides such as chloride and iodide, cyanide or carbon monoxide which are monodentate, dienes such as cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, norbornadiene, aryls such as benzene and xylene which may act as mono- or bi-dentate ligands or compounds of Formula (5):

in which R10 to R19 each independently is as

hereinbefore defined. Particularly preferred ligands, L, are cyclopentadiene, benzene, cycloheptadiene, cyclooctadiene, norbornadiene, ethene, propene, styrene and 1-(2-diphenylphosphino-1-naphthyl)isoquinoline (i.e. the compound of Formula (5) in which

R10=R11=phenyl, R12=R13=R18=R19=H, R14 and R15 are combined to form a six membered carbocyclic ring and R16 and R17 are combined to form a six membered carbocyclic ring).

The counter ion represented by Z may be any monovalent anion. Suitable anions include halides such as C1-, F-, Br-, I-, fluoroborates such as BF4-; sulphonates such as HSO3-, CF3SO3-; fluorophosphates such as PF6-.

Preferred anions represented by Z are CF3SO3- BF4-, PF6-, BPh4- and ClO4-.

An especially preferred catalyst is of Formula (6):

in which:

R10 and R11each independently is C1-4-alkyl or phenyl;

Q is Rh or Ru;

p is 0 to 3;

Z is PF6-, CF3SO3-, BF4-, C104- or I-;

r is 0, 1 or 2;

m is 0, 1 or 2;

L1 and L2 are combined to form a bidentate ligand selected from cyclooctadiene, norbornadiene or a group of Formula (7):

in which R10 and R11 each independently is C1-4-alkyl or phenyl.

The process may be performed by reaction of the alkene and the hydroborane in the presence of the catalyst optionally in a liquid medium followed by treatment with an oxidising agent. Where a liquid medium is used it is preferably an ether, more preferably diethylether, tetrahydrofuran, dioxan, t-butylmethylether, dimethoxyethane, diethoxyethane, an aromatic hydrocarbon, or its mono- or di-substituted derivative more preferably toluene, benzene, xylene, chlorobenzene, anisole or nitrobenzene, an aliphatic hydrocarbon, more preferably hexane, heptane, octane or isooctane, a halogenated aliphatic hydrocarbon, more preferably 1,2-dichloroethane, dichloromethane, trichloromethane, tetrachloromethane, or a cyclic sulphur compound, more preferably sulpholane, or a primary, secondary or tertiary amide more preferably dimethylacetamide.

The reaction is conveniently carried out at -100C to +100C preferably from -78C to 100C, more preferably from -50C to +50C and especially at -30C to +50C

The alkylboronate thus formed may be isolated

by standard procedures such as solvent extraction, crystallisation or chromatography or more conveniently by reacting the alkylboronate to form a more useful compound.

It will be appreciated by a person skilled in

the art that the alkylboronate may be used in

substitution reactions to form a number of useful intermediates such as alcohols, sulphides, amines, carboxylic acids, alkenes, and alkanes. These reactions are

illustrated in Borane Reagents by A. Pelter, K. Smith,

H.C. Brown, Academic Press, 1988.

A further aspect of the invention is a process for the reaction of an optically active alkyl boronate with an oxidising agent to form an optically active alcohol

or an optically active amine in which the configuration of the optically active alkyl boronate is retained.

The oxidising agent to produce secondary

alcohols may be an organic or inorganic oxidising agent is preferably a peroxide, more preferably hydrogen peroxide, a salt of perborate or percarbonic acid, t-butylhydroperoxide, cumene

hydroperoxide, a peracid more preferably perbenzoic acid, m-chloroperbenzoic acid, monoperphthalic acid, a chlorate more preferably sodium or potassium

perchlorate, a hypochlorite, more preferably sodium hypochlorite or a periodate more preferably sodium or potassium periodate or molecular oxygen; The oxidising reagent used to form secondary amines may be of the type X1-Y1N(Z1)R1, in which X1 is -SiR5R6R7, -CCl3, -CF3, -R5, -SOR5, -SO2R5, -SO3H, -PR5R6, -P(O)R5R6, -P(O)OR5R6, -P(O)OR5OR6, -NR5R6, -COR5; Y1 is an atom or group selected from O, NR1, S ;

Z1 is either H or an alkali metal salt preferably Li+, Na+, K+ ; R1, R5, R6, R7 are as

hereinbefore defined, R1 is preferably optionally substituted alkyl, alkaryl or aryl. When R1 is alkyl it is more preferably methyl or ethyl, when R1 is alkaryl it is more preferably benzyl, and when R1 is aryl it is more preferably phenyl.

Examples of the more prefered oxidising reagents of the type X-YN(Z)R1 are lithium

trimethylsilyloxyaminomethane,

O-hydroxylaminesulphonic acid,

O-mesityloxyaminesulphonic acid.

A further example of an oxidising reagent to form a secondary amine is chloramine.

The oxidation reaction is conveniently carried on the unisolated alkylboronate in the same solvent. The secondary alcohol or amine is formed either by addition of a mixture of a co-solvent, a base, and a solution of a peroxide or oxidising reagent, or by addition of each component separately.

The co-solvent is added to improve miscibility of the organic solvent with an aqueous solutions. A prefered co-solvent is an alcohol such as methanol, ethanol or isopropanol, or an ether such as tetrahydrofuran (thf). The base is preferably an aqueous solution of sodium or potassium hydroxide, or a strong base used in anhydrous conditions such as n-butyl lithium dissolved in hexane. The reaction is conveniently stirred and can be carried out at between -78C and 30C, preferably from between -50C and 25C. After the oxidation is completed the product may be conveniently isolated by standard methods such as solvent extraction, crystallisation or

chromatography. In the present process one of the catalyst

and the borane is optically active or both the catalyst and the borane are optically active.

The catalyst may be purified before use in the process, for example by reprecipitation of a tetrahydrofuran solution of the catalyst with petroleum spirit, this has the advantage of generally improving the enantiomeric excess (e.e.) of the desired product.

A further feature of the invention is use of an oxidising agent to hydrolyse the optically active alkylboronate to an optically active alcohol or amine by retention of configuration and is illustrated in the examples below.

The catalysts used in the hydroboration reaction are novel compounds except for (-)-cis-[(R)- Dimethyl(1-(1-naphthyl)ethyl)aminato-C2,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II) hexafluorophosphate, (+)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[(R)-1(2-diphenylphosphino-1-naphthyl)isoquinoline]

palladium(II) hexafluorophosphate, 1:1 mixture of (S,S) and (S,R)-cis-[dimethyl(1-phenylethyl)aminato-C2,N]-[1- (2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II) hexafluorophosphate, and these novel catalysts form a further feature of the present invention.

The catalysts of the invention may be generally prepared by reacting one or more mole equivalents of the bidentate ligand having one nitrogen and one phosphorus atom, with a group VIII metal coordinated with at least two labile ligands in an inert solvent in which the reactants are soluble, optionally in the presence of a reducing or alkylating reagent, in an inert atmosphere at ambient temperature.

Suitable labile ligands include halides, cyanide, acetate, acetylacetonate, carbonyl isocyanate,

dinitrogen or nitrous oxide. Suitable reducing reagents include zinc in methanol, triphenyl tin hydride, sodium borohydride, tri-tertiary butylalane.

Suitable alkylating reagents include trimethylsilyl trifluoromethane sulphonate, methyl trifluoromethane sulphonate and methyl iodide. The

catalyst can be isolated by any convenient means such as precipitation or crystallisation.

The invention is further illustrated by the following examples: Example 1

Preparation of (R) and (S) -1-(2-diphenylphosphino-1-naphthyl)isoquinoline

i) 1-Chloroisoquinoline. Phosphoryl chloride (150ml, 1.6 mol) was added slowly to a solution of isoquinoline N-oxide (82g, 0.50mol) in chloroform. The resulting orange solution was heated at reflux for two hours, allowed to cool to room temperature, then cautiously poured into ice. Concentrated aqueous ammonia was added slowly until the solution was basic. The layers were separated, then the aqueous layer washed with dichloromethane (2×500cm3). The combined organic extracts were dried with sodium sulphate, then concentrated in vacuo to give a dark red oil.

Kugelrohr distillation (0.4mmHg, 130oC) gave 1- chloroisoquinoline (74g, 80%) as a low melting white solid. ii) 2-Methoxy-1-naphthylboronic acid. Magnesium (5g, 208mmol) was activated by stirring overnight under argon. A solution of 1-bromo-2-methoxynaphthalene (30g, 190mmol) in tetrahydrofuran (THF) (200cm3) was added slowly via cannula to the magnesium in THF (50cm3), a vigorous reaction occurred giving a black suspension. The Grignard reagent was added, via cannula filtration, to trimethyl borate (47cm3

570mmol) at -78oC THF (100cm3) was added and the mixture allowed to warm to room temperature, then stirred overnight. Water (40cm3) was added and stirred to give a clear solution with a grey precipitate. THF was removed in vacuo, then water (200cm3) added and the mixture extracted with dichloromethane (3×200cm3). The combined organic extracts were dried with magnesium sulphate then the solvent removed in vacuo to give a brown solid. Recrystallisation from dichloromethane gave 2-methoxy-1-naphthylboronic acid (18g, 70%), as white granular solid, m.p. 117-119oC. Found: C, 65.2;

H, 5.26. C11H11BO3 requires C, 65.4; H, 5.49%. iii) 1-(2-Methoxy-1-naphthyl)isoquinoline. 1-Chloroisoquinoline (52.9g, 0.324mol) was added as a solid to a solution of tetrakis

(triphenylphosphine)palladium[O] (11.2g, 9.7mmol) in DME (600ml), and stirred for 10 minutes under an argon atmosphere to give a yellow/green solution. 2-Methoxy-1-naphthylboronic acid (65.4g, 0.324mol) in the minimum amount of ethanol was added to give a yellow solution.

Sodium carbonate solution (324cm3, 2M) was added and the solution refluxed overnight (16 hours). The solution was allowed to cool, and the solid filtered off. The solid was washed with dichloromethane until it was white. The solvent was removed in vacuo to give a brown oil. The oil was dissolved is dichloromethane (600cm3), washed with saturated brine (2×300cm3), dried with sodium sulphate, and solvent removed in vacuo to give a brown viscous oil. Diethyl ether (500cm3) was added and a white solid formed. The solid was collected by filtration, then the filtrate concentrated in vacuo and the process repeated. Recrystallisation from chloroform gave 1-(2-methoxy-1-naphthyl)isoquinoline (72g, 78%), as white needles, m.p. 130-133oC. 1H NMR (500 MHz): s(CDCl3) 8.74

(d,1H, J=6Hz,H3), 8.03 (d, 1H, J=9Hz, H4'), 7.93

(d,1H,J=8.5Hz,H8), 7.88 (d, 1H, J=8.5Hz,H8'), 7.77

(d,1H, J=6Hz,H4), 7.68 (t, 1H, J=7Hz, H7) , 7.52

(d,1H, J=8.5Hz,H5), 7.45 (d, 1H, J=9Hz, H3'), 7.41

(t,1H, J=7Hz,H6), 7.32 (t, 1H, J=8Hz, H7'), 7.25

(t,1H, J=8.5Hz,H6'). iv) 1-(2-Hydroxy-1-naphthyl)isoquinoline. Boron tribromide (45cm3, 0.48mol) was placed in a pressure equalising dropping funnel under argon and added, dropwise with stirring to a solution of 1-(2-methoxy-1-naphthyl)isoquinoline (68.4g, 0.24mol) in dry

dichloromethane (1 litre). The yellow solution heated up and turned black. The solution was allowed to cool overnight, then water (500cm3) was added cautiously, white fumes were evolved and a yellow precipitate formed. The mixture was stirred for 15 minutes, then the solid was collected by filtration. The aqueous layer was neutralised with sodium hydroxide solution, then extracted with dichloromethane. Aqueous

hydrochloric acid (10%) was stirred with the

dichloromethane extracts, and more yellow precipitate formed which was collected by filtration. The yellow solid was stirred with dichloromethane (500cm3) and sodium carbonate solution (200cm3, 2M) to give a pale pink solution. The organic phase was separated, and the aqueous phase washed with dichloromethane (200cm3). The combined organic extracts were concentrated to

200cm3 and a solid precipitated. This was filtered and washed with dichloromethane to give 1-(2-hydroxy-1-naphthyl) isoquinoline (56g, 86%), as a white solid, m.p. 244-245oC. Found: C, 844.4; H, 4.65; N, 5.1.

C19H13NO requires C, 84.1; H, 4.83; N, 5.2%. v) 1-(2-Trifluoromethanesulphonyloxy-1-naphthyl)isoquinoline.

Trifluoromethanesulphonicanhydride (60g, 211mmol) was placed in a pressure equalising dropping funnel under argon and added, dropwise with stirring, to a solution of 1-(2-hydroxy-1-naphthyl) isoquinoline (52g, 192mmol) and 4-dimethylaminopyridine (71g, 576mmol) in dry dichloromethane (1 litre). The resulting brown solution was left overnight, then washed with 1M hydrochloric acid (3×1 litre), water (2×1 litre), and saturated brine (1 litre). The solution was dried with magnesium sulphate, then the solvent removed in vacuo to give 1-(2-trifluoromethanesulphonyloxy-1-naphthyl) isoquinoline (64.6g, 84%), as a white solid, m.p. 89-100oC. Found: C, 59.7; H, 2.87; N, 3.6.

C20H12NO3SF3 requires C, 59.5; H, 3.00; N, 3.5%. vi) 1-(2-Diphenylphosphinyl-1-naphthyl)

isoquinoline. Dry dimethylsulphoxide (1 litre) was placed in a 2 litre 3-necked flask, equipped with an overhead stirrer, and argon bubbled through for 20 minutes. 1-(2-Trifluoromethanesulphonyloxy-1- naphthyl)isoquinoline (64.6g, 124mmol), diphenylphosphine oxide (100.2g, 496mmol), 1,3-bis(diphenylphosphino)propane (5.11g, 12,4mmol), palladium acetate (2.78g, 12.4mmol), and sodium hydrogencarbonate (63.5g, 744mmol) were added as solids against an argon counterflow. The mixture was heated at 85oC, with stirring, for 20 hours. The dark solution was allowed to cool to room temperature then added to dichloromethane (2.5 litre), washed with water (2×2.5 litre), saturated sodium carbonate solution (2.5 litre), water (2×2.5 litre) and saturated brine (2.5 litre). The solution was dried with magnesium sulphate then the solvent removed in vacuo to give a dark red viscous oil. Toluene (250cm3) was added and an off-white solid precipitated which was collected by filtration. The filtrate was concentrated in vacuo and the process repeated several times. The combined solids were recrystallised from toluene to give 1-(2-diphenylphosρhinyl-1-naphthyl)isoquinoline (34g, 60%), as a white powder, m.p. 215-218oC. Found: C, 81.6; H, 5.05; N, 2.9. C31H22NOP requires C, 81.7; H, 4.87; N,

3.1%. vii) (R,S)-1-(2-Diphenylphosphino-1-naphthyl) isoquinoline. 1-(2-Diphenylphosphinyl-1-naphthyl)isoquinoline (12g, 26.4mmol) was placed in a 2 litre 2-necked flask under argon, then toluene (1 litre) added and stirred to give a white suspension. Trichlorosilane (20cm3, 200mmol) then triethylamine (35cm3, 250mmol) were added, and white fumes were evolved. The solution was refluxed for 2 hours, then cooled to 0oC and 2N sodium hydroxide solution (1 litre) added cautiously with vigorous stirring. The layers were separated and the aqueous layer extracted with dichloromethane (1 litre). The combined organic extracts were dried with magnesium sulphate, then the solvent removed in vacuo to give a pale orange solid. Recrystallisation from dichloromethane gave 1-(2-diphenylphosphino-1-naphthyl)isoquinoline (9.7g, 84%), as a white solid, m.p. 217-219oC. Found: C, 8.49; H, 5.02; N, 3.0. C31H22NP requires C, 84.7; H, 5.05; N,

3.2%. viii) Resolution of the product of vii) above.

Formation of diastereomers. (+)-Di-u-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]dipalladium (II) (160mg, 0.235mmol) and 1-(2-diphenyl phosphino-1-naphthyl) isoquinoline (210mg, 0.478mmol) were placed in a Schlenk tube under argon. Degassed methanol (25ml) was added via syringe and stirred until the solids had dissolved to give a pale yellow/green solution.

Potassium hexafluorophosphate (85mg, 0.462mmol) in water 920ml) was added via syringe with vigorous stirring, and a very pale green solid precipitated. The solid was collected by filtration, and washed with ether to give a 1:1 mixture of (R,R)- and (R,S)-cis-[dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[1-(2-diphenyl phosphino-1-naphthyl)isoquinoline] palladium

(II) hexafluorophosphate as a very pale green solid (389mg, 92%). ix) (-)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl) isoquinoline] palladium (II) hexaflulorophosphate.

Crystallisation of the racemic mixture with chloroform gave (-)-cis-[(R)-dimethyl(1-(1-naphthyl)ethyl) aminato- C2,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II)

hexaflulorophosphate as very pale green hexagonal prisms, m.p. 228-230oC. x) (+)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[(R)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II) hexafluorophosphate. After crystallisation of the (R,S)-diastereomer the residual solution was reduced in vacuo to a solid. Crystallisation from

butanone/diethylether gave (+) -cis-[(R)-dimethyl(1-(1-naphthyl) ethyl) aminato-C2,N]-[(R)-1-(2-diphenylphosphino-1-naphthyl) isoquinoline]palladium (II) hexafluorophosphate butanone solvate as yellow cubes, m.p. 216-219oC. Found: C, 61.4; H, 4.89; N, 2.8. C49H46N2OP2PdF6 requires C, 61.2; H, 4.82; N,

2.9%. xi ) ( - ) - ( S ) - 1- ( 2-Diphenylphosphino-1-naphthyl ) -isoquinoline . 1 , 2-Bis (diphenylphosphino) ethane ( 201mg, 0.51mmol) was added to a solution of (-)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II) hexafluorophosphate (450mg, 0.51mmol) in

dichloromethane (50ml). The solution was stirred for ten minutes then the volume reduced in vacuo to ~10ml. Toluene (20ml) was added then the solvent removed in vacuo to leave a white solid. Toluene (20ml) was added and the suspension stirred for 5 minutes. The solid was removed by filtration then solvent removed in vacuo to leave a white solid. Methanol (10ml) was added and the suspension stirred for five minutes. The solid was collected by filtration to give (-)-(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline (195mg, 88%) as a white powder, mp 226-231oC. [a]D21 = -153.0 (c=1,CHCl3). xii) (+)-(R)-1-(2-Diphenylphosphino-1-naphthyl) isoquinoline. The same procedure as for the (S)-4 was followed to give (+)-(R)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline. [a]D22 = +153.2 (c=1,CHCl3).

Example 2

(i) Preparation of Rhodium(I) (1,5-cyclooctadiene) (2,4-pentanedionate).

Rhodium(III) chloride and 1,5-cyclooctadiene are reacted to give rhodium(III) chloride cyclooctadiene which is then reacted with acetylacetonate.

( ii ) Preparation of Rhodium(I ) cyclooctadiene ( ( S ) - 1- ( 2-diphenylphosphinoisoquinoline ) trifluoromethyl-sulphonate ) .

Rhodium(I) (1,5-cyclooctadiene (2,4- pentanedionate) (93mg) was dissolved in tetrahydrofuran (THF) (3cm3) over argon in a Schlenk tube to give a yellow solution. To this 1.1 mole equivalents of trimethylsilyl triflate (trimethylsilyltrifluoromethylsulphonate) (64ul) were added by syringe and the colour darkened slightly. One mole equivalent of the ligand (-)-(S)-1-(2-diphenylphospino-1-naphthyl) isoquinoline

(132mg) was added as a solid to the vigorously stirred solution over argon, the solution turned orange.

Stirring was continued for five minutes and then the solution was concentrated to one third volume. To this concentrated solution 30-40oC petroleum fraction was added to precipitate an orange solid. The solvent was removed by syringe and the solid washed a further twice with the 30-40oC petroleum fraction. The orange solid was dried under reduced pressure to give a 100% yield of Rhodium(l) (cyclooctadiene) ((S)-1-(2- diphenylphosphino-1-naphthyl)isoquinoline)- trifluoromethanesulphonate.

m.p. 135-140_C. 1H NMR (500 MHz) : δ (CDCl3) 8.92 (d, 1H, J = 6.3Hz, H3) , 8.26 (d, 1H, J = 8.5 Hz, H4'), 8.11 (d, 1H, J = 8.3 Hz,

H8'), 7.94 (d, 1H, J = 6.3 Hz, H4), 7.75 (t, 1H, J = 8.2 Hz,

H3'), 7.74 (d, 1H, J = 8.2 Hz, H8), 7.68 (t, 1H, J = 7.5 Hz,

H7), 7.60 (t, 1H, J = 7.2 Hz, H7 '), 7.56 (td, 1H, J = 1.7, 7.3

Hz, p-H[A]), 7.49 (td, 2H, JH,H = 7.6 Hz, JP,H = 2.4 Hz, m-Ph[A] ) , 7.42 (t, 1H, J = 7.7 Hz, H6'), 7.31 (dd, JH,H = 7.2 Hz,

JP,H = 10.4 Hz, o-Ph[A]), 7.12 (d, 1H, J = 8.4 Hz, H5'), 6.88

(d, 1H, J = 8.6 Hz, H5), 6.85-6.75 (br m, Ph[B]), 5.40 (br s,

1H, =CH; , 5.17 (br s, 1H, =CH), 4.75 (br s, 1H, =CH), 4.00 (br s, 1H, =CH), 3.15 (m, CH2), 2.55 (m, CH2), 2.20 (m, CH2) , 1.80

(m, CH2); 13C NMR (62.9 MHz) : δ (CDCl3) 157.1 (d, JP,C = 10 Hz,

C1), 143.0 (C3), 140.0 (d, J = 15 Hz, C1'), 137-123 (Ar-C) ,

103.3 (d, J = 12 Hz, CH), 100.5 (d, J = 12 Hz, CH), 78.6 (d, J =

12 Hz, CH), 76.1 (d, J = 12 Hz, CH), 35.6 (s, CH2), 31.6 (s,

CH2), 28.5 (s, CH2), 26.4 (s, CH2); 31P NMR (101.3 MHz) : δ (THF)

32.4 (d, J = 141 Hz); vmax (KBr) 1437 (w) (P-Ph), 1273 (br, s)

(S-O), 1153 (br, m), 1031 (s), 752 (m) (Ar-H), 702 (m) (Ar-H)

and 638 (s) cm-1; m/z (Eiectrospray) 650 (100%, M+) .

Example 3

Preparation of Rhodium(I)bis ((S)-1-(2-diphenylphosphino- 1-naphthylisoquinoline)trifluoromethanesulphonate

Rhodium(I) (1,5-cyclooctadiene) (2,4- pentanedionate) (93mg) was dissolved in THF (3cm3) under argon in a Schlenk tube to give a yellow solution. To this 1.1 mole equivalents of

trimethylsilyl triflate (64ul) were added by syringe and the colour darkened slightly. Two mole equivalents of the ligand (S)-1-(2-diphenylphosphino-1- naphthyl)isoquinoline were added as a solid to the vigorously stirred solution over argon, the solution turned deep red. Stirring was continued for five minutes and then the solution was concentrated to one third volume. To this concentrated solution 30-40oC petroleum fraction was added to precipitate an dark red solid. The solvent was removed by syringe and the solid washed a further twice with the 30-40oC petroleum fraction. The orange solid was dried under reduced pressure to give a 100% yield of Rhodium(I) bis ((S)-1- (2-diphenylphosphino-1-naphthyl)isoquinoline)- trifluoromethylsulphonate.

m.p. 228-231_C. ¹H NMR (500 MHz) : δ (CDCl₃) 8.59 (c, 1H, J = 6.3 Hz, H₃), 8.07 (d, 1H, J = 8.3 Hz, H₆,), 8.06 (d, 1H, J = 8.4 Hz,

H₄,), 7.67 (d, 1H, H₆), 7.63 (t, 1H, J = 7.6 Hz, H₇), 7.54 (t,

1H, J = 7.2 Hz, H₇,), 7.51 (d, 1H, J = 6.3 Hz, H₄), 7.33 (t, 1H,

J = 7.7 Hz, H₆,), 7.30 (br s, Ph-H), 7.19 (m, 1H, H₆), 7.15-7.05

(m, Ar-H), 6.88 (d, J = 7.6 Hz, Ph-H), 6.8-6.7 (m, Ar-H), 6.70

(d, 1H, J = 8.6 Hz, H₅); ¹³C NMR (62.9 MHz) : δ (CD₂Cl₂) 157.6

(C₁), 143.3 (C₃), 140-125 (Ar-C), 122.4 (C₄); ³¹P NMR (101.3 MHz) :

δ (CH₂Cl₂) 60.5 (d, J = 178 Hz); v_max (KBr) 3054 (w) (Ar-H), 1620 (br m) (Ar), 1436 ιm) (P-Ph), 1263 (br s) (C-F), 1150 (br, m) (-SO₃), 1031 (s), 746 (m) (Ar-H), 702 (m) (Ar-H) and 638 (m) (Ar

-H) cm^-1; m/z (FAB+ or electrospray) 981 (100%, M⁺) . Example 4

Preparation of Rhodium( I ) ( cyclooctadiene ) ( ( R) -1- ( 2-diphenylphosphino-1-naphthyl ) isoquinolinetrifluoro-methylsulphonate .

Rhodium(I) (1,5-cyclooctadiene) (2,4-pentanedionate) (93mg) was dissolved in THF (3cm3) over argon in a Schlenk tube to give a yellow solution. To this 1.1 mole equivalents of trimethylsilyl triflate (64ul) were added by syringe and the colour darkened slightly. One mole equivalent of the ligand (R)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline was added as a solid to the vigorously stirred solution over argon, the solution turned orange. Stirring was continued for five minutes and then the solution was concentrated to one third volume. To this concentrated solution 30-40oC

petroleum fraction was added to precipitate an orange solid. The solvent was removed by syringe and the solid washed a further twice with the 30-40oC petroleum fraction. The orange solid was dried under reduced pressure to give a 100% yield of

Rhodium(I) (cyclooctadiene(R)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline)trifluoromethylsulphonate.

Example 5

Preparation of (1,5-cyclooctadiene)platinum (II) dichloride

Potassium tetrachloroplatinite (1.25 g, 3 mmol) was dissolved in water (20 ml) and the residual solid removed by filtering through a plug of cotton wool. Acetic acid (30 ml)

and 1,5-cyclooctadiene (1.25 ml, 10 mmol) were added and the mixture heated at 90 C for 30 minutes. The mixture was allowed to cool to room temperature and then reduced in vacuo to ~15 ml.

The precipitate was collected by filtration and washed with water, ethanol, then diethyl ether. The product was dried in vacuo at 80_C for 1 hour to give (1,5

-cyclooctadiene) platinum

(II) dichloride (979 mg, 87%) as a white solid.

Preparation of [(S)-1-(2-Diphenylphosphino- 1-naphthyl)isoquinoline]platinum (II) Dichloride

(S)-1-(2-Diphenylphosphino-1-naphthyl)isoquinoline (87.9 mg, 2 mmol) and 1,5-cyclooctadieneplatinum (II) dichloride (74.8 mg, 2 mmol) were placed in an 8mm NMR tube and dichloromethane (2 ml) added. The solids dissolved to give a yellow solution and ³¹P NMR showed complete reaction. Diethyl ether was added to

precipitate a yellow solid which was

collected by filtration, washed with diethyl ether, then dried in vacuo to at 80_C to give [(S)-1-(2- diphenylphosphino-1-naphthyl)isoquinoline]platinum (II) dichloride (106 mg, 75%).

m.p. >320_C. Found: C, 52.5; H, 2.9; N, 1.9. C₃₁H₂₂NPPtCl₂

requires C, 52.8; H, 3.1; N, 2.0%; ¹H NMR (500 MHz): δ (CDCl₃)

9.37 (d, 1H, J = 6.7 Hz, H₃), 7.87 (dd, 1H, J_3',4' = 8.5, J_P,M =

2.0 Hz, H_4'), 7.78 (d, 1H, J = 8.3 Hz, H_6' ) , 7.43 (c, 1H, J = 3.2

Hz, H₆), 7.41 (t, 1H, J = 7.9 Hz, H₇), 7.39-7.20 (m, Ar-H), 7.06

(t, 1H, J = 8.2 Hz, H_6'), 7.05 (t, 1H, J = 8.8 Hz, H_3'), 6.98 (t,

1H, J = 8.2 Hz, H₆), 6.77 (t, 1H, J = 7.4 Hz, Ph-H), 6.75 (d, J

= 8.7 Hz, H_5'), 6.65 (d, 1H, J = 8.4 Hz, H₅) ; ¹³C NMR (62.9 MHz):

δ (CDCl₃) 154.6 (d, J_P,C = 10 Hz, C₁), 145.5 (s, C₃), 140.3 (d,

J_P,C = 13 Hz, C_1'), 136-118 (Ar-C); ³¹P NMR (101.3 MHz): 5 (CDCl₃)

10.3 (s, J_P,Pt = 3718 Hz); λ_max (MeOH) 345 (∈/dm3 mol^-1 cm^-1 = 10

600), 233 (76 900) nm; λ_max (KBr) 3058 (w) (Ar-H), 1620 (m) (conj

C=C), 1595 (m) (conj C=C), 1437 (s) (P-Ph), 748 (s) (Ar-H), 704

(s) (Ar-H) and 694 (s) (Ar-H) cm^-1; m/z (ES+) 670 (100%, M-Cl );

= -66.2 (c = 1, CHCl₃) . Example 6

Preparation of (Bicyclo[2.2.1]hepta-2,5-diene) (π-allyl) (1,1,1,5,5,5-hexafluoro-2,4

-pentanedionato)ruthenium

Sodium hexafluoroacetylacetonate (0.716 g, 3.3 mmol) in acetone (25 ml) was added to a solution of

bis (acetonitrile) (bicyclo[2.2.1]hepta-2,5-diene) (π -allyl) ruthenium (1.315 g, 4.2 mmol) in acetone (25 ml) and the mixture stirred overnight. The solvent was removed in vacuo to leave a brown oil which was dissolved in 30-40 petrol and filtered through celite. The solvent was removed in vacuo to

leave a dark red viscous oil. Kugelrohr distillation (130_C, 0.01 mmHg) gave (bicyclo[2.2.1]hepta-2,5-diene) (π -allyl) (1,1,1,5,5,5-hexafluoro-2,4

-pentanedionato) ruthenium

(650 mg, 41%) as a dark red solid.

Preparation of [(S)-1-(2-Diphenylphosphino-1- naphthyl)isoquinoline] (π-allyl) (1,1,1,5,5,5-hexafluoro -2,4-pentanedionato) ruthenium

(S)-1-(2-Diphenylphosphino-1-naphthyl)isoquinoline (184.6 mg, 0.42 mmol) and (bicyclo[2.2.1]hepta-2,5 -diene) (π-allyl) (1,1,1,6,6,6-hexafluoro-2,4- pentanedionato) ruthenium

(162.5 mg, 0.4 mmol) were dissolved in THF (10 ml) and heated at

60_C for 40 hours. The solvent was removed in vacuo then hexane (10 ml) added and the solid removed by cannula filtration. The solid was washed repeatedly with hexane until the washings were clear. The combined washings were reduced in vacuo to a very dark purple solid (222 mg, 70%). ¹H NMR showed

one major complex (>80%) and several minor products which were not separated. Major product ¹H NMR (200

MHz) :δ (CDCl3 9.67(d,1H,J = 6.6 Hz, H₅), 8.0-6.7 (m, Ar-H), 5.73 (s, 1H);

31P NMR (101.3 MHz): δ (CDCl₃) 76.6 (s). Example 7

Preparation of (1,5-Cyclooctadiene) [1-(2

-diphenylphosphino-1

-naphthyl)isoquinoline]iridium (I) Hexafluorophosphate

1-(2-Diphenylphosphino-1-naphthyl)isoquinoline (100 mg, 0.227mmol) and di--╡-chloro-bis(1,5- cyclooctadiene)diiridium (76 mg, 0.113 mmol) were dissolved in methanol (10 ml) and stirred for

30 minutes under argon. Potassium hexafluorophosphate (42 mg, 0.227 mmol) in water (3 ml) was added via syringe followed by more water to precipitate a red solid which was collected by filtration and then washed with water. The solid was dried in vacuo to give (1,5- cyclooctadiene) [1-(2-diphenylphosphino-1

-naphthyl)isoquinoline]iridium (I) hexafluoro phosphate (144 mg,72%),

m.p. >290_C. ¹H NMR (500 MHz): δ (CDCl₃) 3.77 (d, 1H, J =

6.4 Hz, H₃), 8.25 (d, 1H, J = 8.4 Hz, H_4'), 8.09 (d, 1H, J = 8.3

Hz, H_4'), 7.96 (d, 1H, J = 6.4 Hz, H₄), 7.75 (d, 1H, J = 8.2 Hz,

H₄), 7.73 (t, 1H, J = 8.2 Hz, H₃,), 7.67 (t, 1H, J = 7.6 Hz, H₇,), 7.61 (t, 1H, J = 7.6 Hz, H₇), 7.57 (td, J = 7.2, 1.6 Hz, p

-Ph[A]), 7.53 (td, 1H, J_M,M = 7.4 Hz, J_P,M = 2.4 Hz, m-Ph[A]),

7.41 (t, 1H, J = 7.7 Hz, H_6'), 7.30 (m, 2H, o-Ph(A]), 7.25 (t,

1H, J = 7.7 Hz, H₆), 7.10 (d, 1H, J = 9.6 Hz, H₅,), 6.95-6.8 (m,

Ph[B]), 6.77 (d, 1H, J = 8.7 Hz, H₅), 4.95 (br s, 1H, =CH), 4.80 (br s, 1H, =CH), 4.40 (br s, 1H, =CH), 3.65 (br s, 1H, =CH),

2.81 (m, CH₂), 2.57 (m, CH₂) , 2.40 (m, CH₂), 1.81 (m, CH₂); λ_max

(MeOH) 226 (∈/dm³ mol^-1 cm^-1 = 77 900) .nm; ʋ_max (KBr) 840 (vs) (P

-F), 751 (m) (Ar-H), and 700 (m) (Ar-H) cm^-1; m/z (FAB+) 740

(2%, M⁺), 632 (3%, M-C₆H₁₂), 440 (10%, M+H-C₆H₁₂-Ir) . Example 8

Procedure for hydroboration/oxidation of styrene. Freshly distilled styrene (0.86 cm³, 7.5 mmol) and freshly distilled catecholborane (0.80 cm³, 7.5 mmol) were added sequentially to a solution of (cycloocta-1,5-diene) (S)-1-(2-diphenylphosphino-1-naphthyl)isoquinolinerhodium (I) trifluoromethanesulphonate catalyst (0.012 g. 0.2 mol%) in thf

(5 cm³). The mixture was stirred under argon for 8h., then quenched with EtOH (2 cm³), NaOH (2M in H₂O, 10 cm³) and H₂O₂

(30% in H₂O, 1 cm³), with stirring for a further 2h. The reaction mixture was extracted with Et₂O, washed with 2M

NaOH, water and brine and dried (MgSO₄) . Metal residues were removed by chromatography through a small column of Florisil. Analysis of the crude reaction mixture by GC showed 90% reaction (secondary alcohol / primary alcohol / hydrocarbon 94 : 3 : 3)

Silica gel chromatography (1:1 Et₂O / pentane) gave S-1-phenylethanol (0.647 g., 71%), [α]_D ²³-50.2 (c = 1, CHCl₃) [ Lit [α]_D ²³ -54.0 ( c = 5.1, CHCl₃)]; optical yield 92.9%, e.e 91.1(CYDEX GC) .

Example 9

Procedure for hydroboration/oxidation of E- and Z- β-methylstyrene

E-o-methylstyrene (0.049 cm³, 0.38 mmol) and freshly distilled catecholborane (0.040 cm³, 0.375 mmol) were added to a solution of (cycloocta-1,5-diene) (S)-1-(2 -diphenylphosphino-1-naphthyl)-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst

(0.003 g. 1 mol%) in thf (0.5 cm³). The mixture was stirred under argon for 2h., then quenched with EtOH (0.5 cm³), NaOH (2M in H₂O, 0.5 cm³) and H₂O₂ (30% in H₂O, 0.5 cm³), with stirring for

a further 2h. The reaction mixture was extracted with

Et₂O, washed with 2M NaOH, water and brine and dried MgSO₄). Metal residues were removed by chromatography through a small column of Florisil. Analysis of the crude reaction mixture showed 92% reaction (secondary alcohol / hydrocarbon 98 :2) Preparative silica gel tic (1:1 Et₂O / pentane) gave S-1-phenylpropanol

(0.033 g., 64%), e.e 95.0 (CYDEX GC, 100_C, 10psi). Commencing from the Z-isomer, a sample of 93.2% e.e was similarly obtained. From the E-isomer, on 20 times this scale with 0.2 mol % catalyst, the reaction proceeded to 61% completion after 3 days (300 turnovers) and gave S-1-phenylpropanol in 93% e.e. Example 10

Procedure for hydroboration/oxidation of 2

-vinylnaphthalene 2-Vinylnaphthalene (0.058 mg, 0.38 mmol) and freshly distilled catecholborane (0.040 cm³, 0.375 mmol) were added to a solution of (cycloocta-1,5-diene) (S)-1-(2 -diphenylphosphino-1-naphthyl)

-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst (0.003 g. 1 mol%) in thf (0.5 cm³). The mixture was stirred under argon for 2h., then quenched with EtOH (0.5 cm³), NaOH(2M in H₂O, 0.5 cm³) and H₂O₂ (30% in H₂O, 0.5 cm³), with stirring for a further 2h. The reaction mixture was extracted with Et₂O,

washed with 2M NaOH, water and brine and dried (MgSO₄).

Metal residues were removed by chromatography through a small column of Florisil. Preparative silica gel tic (1:1 Et₂O / pentane) gave S-2-naphthylethanol (0.0042 g., 65%), e.e 89.0 (CYDEX GC, 150_C, lOpsi) .

Example 11

Procedure for isolation of a catecholborane adduct of 4-methoxystyrene

To freshly distilled 4-methoxystyrene (3.0 g., 22.4 mmol) and (cycloocta-1,5-diene) (S)-1-(2-diphenylphosphino-1-naphthyl)-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst

(0.160 g. 0.9 mol%) in thf (15 cm³). was added freshly distilled catecholborane (2.1 ml., 22.4 mmol). The solution was stirred for 1h at RT under argon whence the orange solution first turned red and then brown. Solvent was removed in vacuo and the residue was purified by short-path distillation giving B-(S-(4-methoxyphenyl)-1-ethyl)catecholborane (4.26 g., 75%, b.p. 90_C,0.05 mmHg). A sample oxidised with H₂O₂ as described above and analysed by CYDEX GC was of 86% e.e.

Example 12

Procedure for hydroboration/amination of 4

-methoxystyrene

B-(S-(4-methoxyphenyl)-1-ethyl)catecholborane, prepared as in Example 11 (0.127 g., 112 ╡l ) was dissolved in thf

(0.5 ml.) and added at -78_C under argon to a stirred solution prepared by adding BuLi (643 ╡l . 1.4 M) to a solution of O-trimethylsilyloxy-N-methylamine

(0.119 g., 151 ╡l, 1 mmol) in thf (0.5 ml) held at -78_C. The mixture was warmed to -20_C, stirred for lh., and warmed to RT. To the resulting solution was added 1M KOH (1 ml) and CH₂Cl₂ (2 ml) . The organic solution was dried (MgSO4) and

solvent removed in vacuo; crude yield 145 mg. Extraction with Et₂O / CH₂Cl₂ (100 : 1), washing with water and back-extraction of the aqueous layer with CH₂Cl₂ gave a combined yield of 0.042g as an approximately 1 : 1 mixture of S-4-methoxyphenylethan- 1- ol

and N-methyl-N-S-1-(4-methoxyphenyl)ethylamine.

Determination of enantiomeric purity by reaction with

RS-2-naphthyl-1-ethylisocyanate and estimation by ¹H NMR indicated an enantiomeric purity of 60%.

Example 13

Procedure for hydroboration/oxidation of chromene

Chromene (50 mg, 0.38 mmol) and freshly distilled catecholborane (0.040 cm³, 0.375 mmol) were added to a solution of (cycloocta-1,5-diene) (S)-1-(2

-diphenylphosphino-1-naphthyl)-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst (0.003 g., 1 mol%) in thf (0.5 cm³). The mixture was stirred under argon for 2h., then quenched with EtOH (0.5 cm³), NaOH (2M in H₂O, 0.5 cm³) and H₂O₂ (30% in H₂O, 0.5 cm³), with stirring for a further 2h. The reaction mixture was extracted with Et₂O, washed with 2M NaOH, water and brine and dried (MgSO₄). Metal residues were removed by chromatography through a small column of Florisil.

Preparative silica gel tic (1:1 Et₂O / pentane) separated the 4- and 3-hydroxy compounds which were present in 7 : 3 ratio giving S-4-chromanol (12 mg., 21%), e.e 52 % (CYDEX GC, 100_C, 10psi). Example 14

Procedure for hydroboration/oxidation of Z-stilbene

Z-stilbene (0. 68g, 0.38 mmol) and freshly distilled catecholborane (0.040 cm³, 0.375 mmol) were added to a solution of (cycloocta-1,5-diene) (S)-1-(2

-diphenylphosphino-1-naphthyl)-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst (0.003 g. 1 mol%)in thf (0.5 cm³). The mixture was stirred under argon for 2h., then quenched with EtOH (0.5 cm³), NaOH (2M in H₂O, 0.5 cm³) and H₂O₂ (30% in H₂O, 0.5 cm³), with stirring for a further 2h. The reaction mixture was extracted with Et₂O, washed with 2M NaOH, water and brine and dried (MgSO₄). Metal residues were removed by chromatography through a small column

of Florisil. Preparative silica gel tic (1:1 Et₂O / pentane) gave S-1-benzylphenylethanol, separated from ca. 40% of E-stilbene, e.e 69.0% (CYDEX GC). Example 15

Procedure for hydroboration/oxidation of 4

-methoxystyrene 4-methoxystyrene ( 50mg, 0.38 mmol) and freshly distilled catecholborane (0.040 cm³, 0.375 mmol) were added to a solution of (cycloocta-1,5-diene) (S)-1-(2-diphenylphosphino-1-naphthyl)-isoquinolinerhodium (I) trifluoromethanesulphonate catalyst

(0.003 g. 1 mol%) in thf (0.5 cm³). The mixture was stirred under argon for 2h., then quenched with EtOH (0.5 cm³), NaOH (2M in H₂O, 0.5 cm³) and H₂O₂ (30% in H₂O, 0.5 cm³), with stirring for a further 2h. The reaction mixture was extracted with Et₂O, washed with 2M NaOH, water and brine and dried (MgSO₄). Metal residues were removed by chromatography through a small column of Florisil. Preparative silica gel tic (1:1 Et₂O / pentane) gave S-4-methoxyphenylethanol (0.033g., 57%), e.e 94 % (CYDEX GC, 100_C, lOpsi) .

Example 16 Procedure for hydroboration/oxidation of indene

Indene (44ul, 0.377mmol) was added to a

solution of [Rh(cod) (P-N)]OTf (3.0mg, 3.83umol, catalyst of Example 1) in thf (0.5cm3) under argon, to give an orange solution. Catecholborane (40ul,

0.375mmol) was added and the resultant deep red solution was left to stand at room temperature for 1 hour. Ethanol (0.5cm3), sodium hydroxide solution (2M, 0.5cm3) and hydrogen peroxide (100vols, 0.5cm3) were added and the resultant stirred for 1 hour.

Diethylether (5cm3) was added and the organic layer was washed successively with sodium hydroxide solution (2M, 5cm3), water (5cm3), saturated brine (5cm3) and dried over MgS04. Filtration through a short column of reversed-phase silica and removal of the solvent in vacuo gave (S)-1-indanol as a white solid (28.4mg, 58%, 91%e.e.).

Example 17

In situ procedure for hydroboration/oxidation of 2-chlorostyrene

2-Chlorostyrene (48ul, 0.374mmol) was added

to a solution of [Rh2Cl2 (C2H4) 4] (0.8mg, 2.06uml) and

(-)-(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline (2.1mg, 4.78umol) in thf (0.5cm3) under argon, to give a yellow solution. Catecholborane (40ul, 0.375mmol) was added and the resultant deep red solution was left to stand at room temperature for 1 hour. Oxidative workup as in Example 16 gave (S)-1-(2'- chlorophenyl)ethanol as a colourless oil (34.5g, 59%, 55%e.e.). Examples 18-21

General Procedure for hydroboration/oxidation

An alkene (0.375mmol), catecholborane

(0.375mmol), the catalyst of Example 1 (3.8umol), tetrahydrofuran (0.5cm3) were stirred at ambient temperature for a period of from 1 up to 24 hours before oxidising with hydrogen peroxide and isolating the alcohol, e.e was determined by gas chromatography on a

20m permethylated cyclodextrin column or via 1HNMR using Brown's method in Tetrahedron Asymmetry [1992], 3, 261. Table 1 below summarises Examples 18-23 which use the catalyst of Example 2 and the General Procedure above.

Claims

1. A process for the reaction of an alkene, allene or an alkyne with a borane in the presence of a catalyst to form an optically active alkylboronate characterised in that the catalyst is a neutral or cationic complex of a metal from Group VIIIA of the Periodic Table wherein the metal is co-ordinated with at least one nitrogen atom and at least one phosphorus atom and at least one of the catalyst and the borane is optically active.

2. A process for the reaction of an optically active alkyl boronate with an oxidising agent to form an optically active alcohol or an optically active amine in which the configuration of the optically active alkyl boronate is retained.

3. A process according to claim 2 in which hydrogen peroxide is used as the oxidising agent to produce the optically active alcohol.

4. A process according to claim 2 in which an oxidising agent X1-Y1N (Z1) R1, wherein X1 is a functional group; Y1 is O, S, NR1 ; Z1 is a cationic counterion; R1 is H, alkyl, alkaryl or aryl, and the reagent is used to form the optically active amine.

5. A process according to claim 4 in which the oxidising agent is lithium O-trimethylsilyloxy-N- methylamine.

6. A compound of Formula (4)

wherein:

Q is Fe, Co, Ni, Ru, Rh, Pd, Os, Ir or Pt; p is 0 or is an integer from 1 to 4;

x is an integer from 1 to 3;

L is a ligand;

r is 0 or an integer from 1 to 5;

n is 0 or an integer from 1 to 5;

q is an integer from 1 to 5; and

Z is a counter ion;

R10 and R11 each independently is alkyl, alkoxy, aryl or aryloxy each of which may be optionally substituted;

R12, R13, R14, R15, R16, R17, R18 and R19 each independently is -H, or an alkyl, alkenyl, alkynyl, aryl or heterocyclic radical each of which may optionally carry one or more substituents or is -N02, -F, -Cl, -Br, -I, -CF3, -CCl3, -OR5, -SR5, -OCOR5, -COR5, -SOR5, -SO2R5, -SO3R5, -PR5R6, -P(O)R5R6, -P(O)OR5R6, -P(O)OR5OR6, -NR5R6, -SiR5R6R7 in which R5, R6 and R7 each independently is -H, C1-6 alkyl or phenyl;

or R14 and R15 together with the carbon atoms to which they are attached are combined for form a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted;

and/or R16 and R17 together with the carbon atoms to which they are attached are combined to from a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted;

and/or R15 and R16 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic or heterocyclic ring which may be optionally substituted;

and/or R12 and R13 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic ring which

may be optionally substituted;

and/or R18 and R19 together with the carbon atoms to which they are attached are combined to form a 5- or 6-membered carbocyclic ring which

may be optionally substituted;

except for (-)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl)aminato-C2,N]-[(S)-1-(2-diphenylphosphino-1-naphthyl)isoquinoline]palladium (II) hexafluorophosphate, (+)-cis-[(R)-Dimethyl(1-(1-naphthyl)ethyl) aminato-C2,N]-[(R)-1(2-diphenylphosphino-1-naphthyl)isoquinoline]

palladium(II) hexafluorophosphate, 1:1 mixture of (S,S) and (S,R)-cis-[dimethyl(1-phenylethyl)aminato-C2,N]-[1-(2-diphenylphosphino-1-naphthyl)isoquinoline]

palladium(II) hexafluorophosphate.