EP1153031A1 - Method for preparing chiral diphosphines - Google Patents

Abstract

The invention concerns a method for preparing a compound of formula (I) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2 independently represent a saturated or aromatic carbocyclic group, optionally substituted.

Description

 Process for the preparation of chiral diphosphines

The invention relates to a process for the preparation of chiral disphosphines useful as bidentate ligands in the synthesis of transition metal catalysts intended for asymmetric catalysis.

Asymmetric catalysis has experienced considerable growth in recent years. It has the advantage of leading directly to the preparation of optically pure isomers by asymmetric induction without it being necessary to carry out the resolution of racemic mixtures.

2,2'-bis (diphenylphosphino) -1 J '-binaphtyl (BINAP) is an example of a disphosporated ligand commonly used for the preparation of metal complexes for the asymmetric catalysis of hydrogenation, carbonylation, hydrosilylation reactions, CC bond formation (such as allylic substitutions or Grignard cross couplings) or even asymmetric isomerization of allylamines.

The development of new chiral ligands is desirable so as to improve the enantioselectivity of the reactions and more generally, the general conditions for carrying out these reactions. The present invention more specifically provides a process for the preparation of biphosphorus bidentate chiral ligands of the 2,2'-bis-diarylphosphino) -1, 1 '-binaphtyl and 2,2'-bis (diarylphosphino) -1, 1' - type. biphenyl functionalized at the binaphthyl group, respectively biphenyl. These ligands coordinated with transition metals such as ruthenium or rhodium form complexes useful in the asymmetric catalysis of various reactions and more particularly of asymmetric hydrogenation reactions.

The ligands prepared according to the process of the invention are in particular dicyano derivatives, of formula I:

in which :

A represents phenyl or naphthyl; and Ar-i and Ar ₂ independently represent a saturated or aromatic carbocyclic radical.

In the context of the invention, the phenyl and naphthyl radicals are optionally substituted.

By cabocyclic radical is meant according to the invention a monocyclic or polycyclic radical optionally substituted, preferably C ₃ -Cso. Preferably, it is a C ₃ -C-ι ₈ radical, preferably mono-, bi- or tricyclic.

The carbocyclic radical can comprise a saturated part and / or an aromatic part. When the carbocyclic radical comprises more than one cyclic nucleus (in the case of polycyclic carbocycles), the cyclic nuclei can be condensed two by two or attached two by two by σ bonds.

Examples of saturated carbocyclic radicals are cycloalkyl groups. Preferably, the cycloalkyl groups are saturated cyclic hydrocarbon radicals, preferably C ₃ -Ci ₈ , better still C ₃ - C-to, and in particular the cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norbomyl radicals.

Examples of aromatic carbocyclic radicals are the (C ₆ -Cι ₈ ) aryl groups and in particular phenyl, naphthyl, anthryl and phenanthryl.

The substituents of the phenyl, naphthyl and carbocyclic radicals are such that they do not interfere with the reactions involved in the process of the invention. These substituents are inert under the conditions involved in bromination (step i), esterification (step ii), nucleophilic substitution (step iii) and coupling reactions.

Preferably, the substituents are alkyl or alkoxy groups.

By alkyl is meant a saturated, linear or branched hydrocarbon radical, comprising in particular up to 25 carbon atoms, and, for example from 1 to 12 carbon atoms, better still from 1 to 6 carbon atoms.

Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1 -methylpentyle, 3- methylpentyle, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-1- ethylpropyl, heptyle, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyle, octyl, 1-methylheptyle, 2- ethyihexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl.

In a particularly advantageous manner, the dicyano derivatives of formula I are such that:

A represents naphthyl or phenyl, optionally substituted by one or more radicals chosen from (CrC ₆ ) alkyl and (Cι-C ₆ ) alkoxy; and

Ar-i, Ar ₂ independently represent a phenyl group optionally substituted by one or more (Cι-C ₆ ) alkyl or (CrC- ₆ ) alkoxy; or a (C ₄ - C ₈ ) cycloalkyl group optionally substituted by one or more (CC ₆ ) alkyl groups.

Examples of preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1 -methylpentyle, 3- methylpentyle, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl and 1-methyl-

1-ethylpropyl.

Advantageously, the alkyl radical comprises from 1 to 4 carbon atoms.

The term alkoxy designates the radical -O-alkyl where alkyl is as defined above.

Advantageously, the cycloalkyl groups are chosen from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It should be understood that, according to the invention, each of the naphthyl and phenyl groups representing A can be substituted.

Among the preferred ligands of formula I are those for which Ar- and Ar ₂ are independently phenyl optionally substituted by methyl or tert-butyl; or (C ₅ -C ₆ ) cycloalkyl optionally substituted by methyl or tert-butyl.

Particularly preferred are the compounds of formula I in which Ar-i and Ar ₂ are identical. A clearly preferred meaning of A and Ar ₂ is optionally substituted phenyl. Furthermore, it is preferred that A represents naphthyl optionally substituted by one to five, preferably one to two, groups chosen from (C 1 -C ₆ ) alkyl and (C 1 -C ₆ ) alkoxy. More preferably, A represents unsubstituted naphthyl.

When A represents optionally substituted phenyl, it is preferable for the latter to be substituted in the meta position relative to the group PAr-ιAr ₂ by (Ci-Ce) alkyl or (CrC ₆ ) alkoxy, better still by methyl or methoxy, the other positions of the phenyl radical being unsubstituted.

A more particularly preferred group of compounds consists of the compounds of formula I having an axis of symmetry C ₂ to the exclusion of any other element of symmetry. The concept of axis of symmetry C ₂ is described in "Elements of

Stereochemistry "Wiley, New York, 1969, and in" Advanced Organic Chemistry ", Jerry March, Stereochemistry, chapter 4.

Among this latter group of preferred compounds, there are in particular the following compounds of formulas la and Ib:

in which A and Ar ₂ are as defined above and S represents a substituent compatible with the reactions involved, and in particular alkyl or alkoxy, preferably Ci-Cβ, wherein Ar- _t and Ar ₂ are as defined above.

The process of the invention more precisely comprises the steps consisting in: i) carrying out the bromination of a diol of formula II:

in which A is as defined above, by means of an appropriate brominating agent so as to obtain a dibromo compound of formula III:

wherein A is as defined above; ii) esterifying the compound of formula III obtained in the preceding step by the action of a sulfonic acid or of an activated form thereof so as to obtain the corresponding disulfonate; iii) substituting the two bromine atoms for cyano groups by reacting the disulfonate obtained in the previous step with an appropriate nucleophilic agent so as to obtain the corresponding nitrile; iv) coupling of a phosphine of formula VI: XPAr ₁ Ar ₂ VI in which X represents a hydrogen atom of a halogen atom and An and Ar ₂ are as defined above, with the nitrile obtained in the preceding step in the presence of a catalyst based of a transition metal, so as to obtain the expected compound of formula I.

In step (i) the phenyl nucleus, respectively naphthyl, of the diol of formula

II, is brominated by the action of an appropriate brominating agent.

When A is a phenyl ring which is unsubstituted or bearing in the meta position relative to the OH group a substituent, such as (Cι-Cβ) alkyl or (dC ₆ ) alkoxy, the corresponding diol of formula Ma:

where Si and S ₂ are as defined for S above or independently represent a hydrogen atom, an alkyl or alkoxy group, preferably C-ι-C- ₆ , leads to the corresponding bromine compound of formula IIIa:

in which Si and S ₂ are as defined above. When A is a naphthyl ring, the bromination of the corresponding diol of formula Mb: leads to the following compound IIIb:

More generally, the hydroxyl groups present on the naphthyl and phenyl nuclei direct the electrophilic reaction so that the position of the bromine atoms on these nuclei is well determined.

The bromination reaction of phenyl or naphthyl rings is an electrophilic reaction which is easily carried out by the action of Br ₂ on the corresponding diol. This reaction can be carried out in the presence of a catalyst such as a Lewis acid and in particular iron chloride. However, insofar as the hydroxyl groups present on the phenyl and naphthyl rings activate these rings, bromination is easily carried out in the absence of any catalyst. The diols of formula II are so reactive that it is desirable to carry out the bromination at low temperature, for example between -78 ° and -30 ° C, preferably between -78 ° C and -50 ° C.

According to a preferred embodiment of the invention, the bromination takes place in an inert aprotic solvent such as a halogenated aromatic hydrocarbon (for example chlorobenzene and dichlorobenzene); a nitrated aromatic hydrocarbon such as nitrobenzene; an optionally halogenated aliphatic hydrocarbon such as hexane, heptane, methylene chloride, carbon tetrachloride or dichioroethane; or an alicyclic hydrocarbon. In general, aromatic hydrocarbons having aromatic nuclei depleted in electrons, that is to say carrying one or more electron-withdrawing substituents, can be used.

Mention may be made, as preferred solvent, of halogenated aliphatic hydrocarbons and in particular methylene chloride.

Alternatively, it is possible to operate in glacial acetic acid as a solvent. Under these conditions, a solution of bromine in acetic acid is generally added dropwise to a solution of diol II in acetic acid. Whether operating in the presence of acetic acid or not, an excess of the brominating agent is used relative to the diol II.

Preferably, the molar ratio of the brominating agent to the diol II varies between 2 and 5, better still between 2 and 3.

When working in solution, the concentration of reagents can vary widely between 0.01 and 10 mol / l, for example between 0.05 and 1 mol / l.

In step (ii), the hydroxyl functions of the diol III are esterified by the action of a sulfonic acid or of an activated form thereof, so as to obtain the corresponding disulfonate.

According to the invention, the nature of the sulfonic acid used is not decisive in itself.

Advantageously, the sulfonic acid has the formula:

P-S0 ₂ -OH where P represents an aliphatic hydrocarbon group; an aromatic carbocyclic group; or an aliphatic group substituted by an aromatic carbocyclic group.

The term “aliphatic hydrocarbon group” is understood to mean in particular an alkyl group as defined above, optionally substituted. The nature of the substituent is such that it does not react under the conditions of the esterification reaction. A preferred example of an alkyl group substituent is a halogen atom such as fluorine, chlorine, bromine or iodine.

By aromatic carbocyclic group is meant the mono- or polycyclic aromatic groups and in particular the mono-, bi- or tricyclic defined above and for example, phenyl, naphthyl, anthryl or phenanthryl.

The aromatic carbocyclic group is optionally substituted. The nature of the substituent is not critical since it does not react under the conditions of esterification. Advantageously, the substituent is optionally halogenated alkyl, alkyl being as defined above and halogen representing chlorine, fluorine, bromine or iodine and, preferably chlorine. By way of example, optionally halogenated alkyl denotes perfluorinated alkyl such as trifluoromethyl or pentafluoroethyl. According to a preferred embodiment of the invention, the sulfonic acid has the formula:

P-S0 ₂ -OH where P represents (C- ₆ -C-ιo) aryl optionally substituted by one or more (C-ι-C ₆ ) optionally halogenated alkyl; (C-ι-C ₆ ) optionally halogenated alkyl; or (C ₆ -Cι ₀ ) aryl- (Cι-C ₆ ) alkyl in which the aryl group is optionally substituted by one or more (Cι-Ce) optionally halogenated alkyl and the alkyl group is optionally halogenated.

Suitable examples of such sulfonic acids are paratoluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, the latter being more particularly preferred.

According to a preferred embodiment of the invention, an activated derivative of sulfonic acid is used. By activated derivative is meant a sulfonic acid in which the acid function -S0 ₃ H is activated, for example by formation of an anhydride bond or of the group -S0 ₃ CI. A particularly advantageous sulfonic acid derivative is the symmetrical anhydride of trifluoromethanesulfonic acid, of formula (CF ₃ -SO ₂ ) ₂ θ.

When the sulfonic acid used has the formula P-S0 ₃ H above or is an activated form of this acid, the disulfonate obtained at the end of step ii) corresponds to formula IV:

in which A and P are as defined above. The conditions for the esterification reaction will be easily developed by a person skilled in the art. These depend in particular on the nature of the esterification agent. When the esterifying agent is a sulfonic acid, a higher reaction temperature, between 20 and 100 ° C, may be necessary. Conversely, starting from an activated form of this acid, such as an anhydride or sulfonyl chloride, a lower temperature may be suitable. Generally, a temperature between -30 ° C and 50 ° C, preferably between -15 and 20 ° C, may in this case suffice.

The esterification is preferably carried out in a solvent. Suitable solvents are in particular aliphatic, aromatic or cyclic optionally halogenated hydrocarbons, such as those defined above. Mention may be made of carbon tetrachloride and dichloromethane. Dichloromethane is particularly preferred. The ethers can also be used as a solvent. Examples include dialkyl ethers C-ι-C- ₆ (diethyl ether and diisopropyl ether), cyclic ethers (tetrahydrofuran and dioxane), dimethoxyethane and dimethyl ether of diethylene glycol. When the esterifying agent is an activated form of a sulfonic acid, it is desirable to introduce a base into the reaction medium. Basic examples are N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-dimethylpyridine, 4- (1 -pyrrolidinyl) pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl-4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline.

As preferred bases, essentially pyridine and 4-dimethylaminopyridine will be used. The reaction can also be carried out in a two-phase mixture of water and an organic solvent such as a halogenated aliphatic hydrocarbon (for example carbon tetrachloride). In this case, it is preferable to use an esterifying agent in the form of anhydride and to operate in the presence of a water-soluble base such as KOH, NaOH or K ₂ C0 ₃ , preferably KOH.

The reaction of sulfonic acid or its activated derivative on the bromine diol

III is stoichiometric. Nevertheless, it is preferable to operate in the presence of an excess of the acid or of its activated form. Thus, a ratio of the acid, possibly in activated form, to the diol III of between 2 and 5, better still between 2 and 3, is it recommended.

When the reaction is carried out in solution, the concentration of the reactants, which is not a critical parameter according to the invention, may vary between 0.1 and 10 mol / l, advantageously between 1 and 5 mol / l.

Those skilled in the art can draw inspiration from the operating conditions illustrated in J. Org. Chem. , flight. 58, n ° 7, 1993, 1945-1948 and Tetrahedron Letters, vol. 31, No. 7, 985-988, 1990 for the implementation of esterification.

The next step (iii) is a nucleophilic substitution. The two bromine atoms carried by the A nuclei are displaced by cyano groups by the action of an appropriate nucleophilic agent. In order to carry out this substitution, a person skilled in the art can use any of the methods known in the art.

According to a preferred embodiment of the invention, the nucleophilic agent used is copper cyanide.

The molar ratio of copper cyanide to disulfonate is preferably greater than 2, it can advantageously vary between 2 and 4, preferably between 2 and 3.

The reaction is preferably carried out in a solvent. Examples of solvents that may be mentioned are amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone and hexamethylphosphorylamide. Dimethylformamide is much preferred. Pyridine is also a suitable solvent. The reaction temperature is advantageously maintained between 50 and 200 ° C, for example between 70 and 190 ° C, better still between 80 and 180 ° C. A more particularly suitable temperature is between 100 and 190 ° C.

The concentration of reagents in the reaction medium generally varies between 0.1 and 10 mol / l, for example between 2 and 7 mol / l. The isolation of the nitrile involves the decomposition of the intermediate complex formed and the trapping of the excess cyanide.

The hydrolysis of the intermediate complex can be carried out either by the action of hydrated iron chloride, or by the action of aqueous ethylenediamine.

In the first case, the reaction medium is poured into an aqueous solution of iron chloride at 50-80% (g / ml) containing concentrated hydrochloric acid. The resulting solution is heated to 40-80 ° C until complete decomposition of the complex. Then the medium is decanted and extracted in a conventional manner.

In the second case, the reaction medium is poured into an aqueous solution of ethylenediamine (ethylenediamine / water: 1/5 - 1/1 (v / v), for example 1/3) then the whole is vigorously stirred. The medium is then decanted and extracted in a manner known per se.

Those skilled in the art can draw inspiration from the work of L. Friedman et al. published in J.O.C. 1961, 26, 1522, to isolate nitrile. Starting from the disulfonate of formula IV mentioned above, the nitrile of formula V is obtained at the end of this step:

in which A and P are as defined above and the position of the cyano group on the nucleus A is the same as that of bromine in compound IV.

In the next step (iv), cross-coupling of a phosphine of formula VI is carried out: XPArιAr ₂ VI in which X is a halogen or hydrogen atom and Ar-i, Ar ₂ are as defined above with the nitrile obtained in the preceding step, in the presence of a catalyst based on a transition metal. This coupling leads directly to the expected compound of formula I.

Examples of suitable catalysts are catalysts based on nickel, palladium, rhodium, ruthenium, platinum or a mixture of these metals.

The preferred catalysts are nickel-based catalysts such as those selected from NiCI ₂ ; NiBr ₂ ; NiCI (dppp); NiCI ₂ (dppb); NiCI ₂ (dppf); NiCI ₂ (dppe); NiCI ₂ (PPh ₃ ) ₂ ; Ni (CO) ₂ (PPh ₃ ) ₂ ; Ni (PPh ₃ ) and Ni [P (PhO) ₃ ] ₄ where dppe means (diphenylphosphino) ethane, dppp means (diphenylphosphino) propane, dppb means (diphenylphosphino) butane, and dppf means

(diphenylphosphino) ferrocenyl. Among these catalysts, NiCI ₂ (dppe) is preferred.

The reaction is generally carried out at a temperature of 50 to 200 ° C, preferably from 80 to 130 ° C.

The molar ratio of compound VI to nitrile is at least 2. It generally varies between 2 and 4, for example between 2 and 3. The amount of catalyst is preferably such that the molar ratio of nitrile to catalyst varies between 5 and 100, especially between 5 and 80.

The reaction is preferably carried out in a polar aprotic solvent and in particular an amide such as those mentioned above. Again, N, N-dimethylformamide is preferred. Other types of polar solvents can nevertheless be used such as (CrC ₆ ) alkanols (ethanol), aromatic hydrocarbons (toluene, xylene and benzene), ethers (dioxane) and acetonitrile.

The precise reaction conditions depend on the nature of the compound of formula VI involved in the reaction.

When compound VI is HPArιAr ₂ , the reaction is advantageously carried out in the presence of a base.

Particularly suitable bases are pyridine, 4-dimethylaminopyridine, 2,6-di-tertbutylpyridine, 1,8-diazabicyclo [5.4.0] - undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1, 4- diazabicyclo [2.2.2] octane (DABCO or triethylenediamine). Advantageously, DABCO will be used as a base. In this case, it is preferred that the molar ratio of the nitrile to the catalyst is between 5 and 20, for example between 7 and

15. When the compound of formula VI is halPAr ₁ Ar where hal is a halogen atom, preferably Cl or Br (better still Cl), it is necessary to add zinc to the reaction medium.

The amount of zinc is preferably such that the molar ratio of zinc to halPAr- | Ar ₂ varies between 1 and 2, preferably between 1, 2 and 1, 7. In this case, it is desirable to cool the reaction mixture containing the solvent, the nitrile and the compound VI to a temperature between

-10 and 20 ° C throughout the addition of zinc to the reaction medium. Then, the reaction takes place by heating to an appropriate temperature of between 50 and

200 ° C. When the compound of formula VI is halPArιAr ₂ , it is preferred that the molar ratio of the nitrile to the catalyst is between 40 and 80, for example between 50 and 70.

For more details on the implementation of these coupling reactions, the skilled person will refer to D. Cai et al. J.O.C. 1994, 59, 7180 and D. J. Ager et al. Chem. Comm. 1997, 2359.

When A represents phenyl optionally substituted preferably by (CrCe) alkyl or (CC ₆ ) alkoxy, the compound obtained at the end of step (iv) has the formula:

in which Ar- ^* , Ar ₂ , Si and S2 are as defined above for the formula IIa.

When A represents naphthyl, the compound obtained at the end of step (iv) has the formula Ib: in which An and Ar ₂ are as defined above.

The compounds of formula I are ligands capable of coordinating with transition metals of the ruthenium and rhodium type. Associated with these metals, the ligands form complexes useful in the asymmetric catalysis of enantioselective hydrogenation reactions from various substrates such as β-ketoesters, α-ketoesters and dehydroamino acids.

The present invention further provides a process for transforming the compounds of formula I (which have two cyano functions) into corresponding diaminomethylated compounds.

As a variant, it is possible to transform the two cyano functions of the compounds of formula I into carboxylic acid, imine, hydroxymethyl or amide functions.

The products resulting from these transformations are all ligands which can be used in asymmetric catalysis.

Thus, according to another of its aspects, the invention relates to a process comprising in addition to steps (i) to (iv) defined above, the step consisting in reducing the nitrile function of the compound of formula I by the action of a reducing agent so as to obtain a compound of formula VII:

in which A, A and Ar ₂ are as defined above. A suitable reducing agent is lithium aluminum hydride

(AILiH ₄ ).

The invention is not intended to be limited to the use of this particular reducing agent.

The reaction is preferably carried out in a solvent or a mixture of solvents.

When the reducing agent is AILiH ₄ , the solvent advantageously comprises one or more aromatic hydrocarbons (such as benzene, toluene and xylene) in admixture with one or more ethers.

Mention may be made, as ether, of CrC ₆ alkyl ethers (diethyl and diisopropyl ether), cyclic ethers (dioxane, tetrahydrofuran), dimethoxyethane and diethylene glycol dimethyl ether.

Cyclic ethers of the tetrahydrofuran type are preferred.

When the reducing agent is AILiH, we will more preferably opt for a mixture of toluene and tetrahydrofuran in proportions varying between (v / v) 70-50 / 30-50: toluene / tetrahydrofuran (for example 60/40: toluene / THF).

The reduction can be carried out at a temperature between 20 ° C and 100 ° C, preferably between 40 ° C and 80 ° C.

Usually, a large excess of the reducing agent is used. Thus, the molar ratio of the reducing agent to the compound of formula I generally varies between 1 and 30, for example between 2 and 20, in particular between 5 and 18.

The concentration of reagents in the medium is variable; it can be maintained between 0.005 and 1 mol / l.

The compounds of formula VII obtained according to the process of the invention are new and form another subject of the invention. Among these compounds, prefers those for which A represents naphthyl which correspond to the following formula:

in which An and Ar ₂ are as defined in claim 1.

A preferred group of these diamines consists of the compounds of formula VIIa in which An and Ar ₂ are independently chosen from phenyl optionally substituted by methyl or tert-butyl; and (C ₅ -C ₆ ) cycloalkyl optionally substituted by methyl or tert-butyl. More preferably, the compounds in which An and Ar ₂ are identical and represent optionally substituted phenyl are preferred.

As a variant, the invention provides a process comprising, in addition to steps (i) to (iv) defined above, the step consisting in treating in an acidic or basic medium, the compound of formula I, so as to obtain the corresponding carboxylic acid of formula VIII:

in which A, An and Ar ₂ are as defined above.

The transformation of a nitrile function into a carboxylic acid function is described in the basic works of organic chemistry. Also, a person skilled in the art can easily determine the appropriate reaction conditions.

An easy way to do this is to use aqueous sodium hydroxide as the hydrolysis agent. The process of the invention can be carried out starting from an optically active compound II with conservation of the chirality from one end to the other of the synthesis.

In order to conserve chirality, the compound of formula III will be esterified under anhydrous conditions in the presence of appropriate bases chosen from N-methylmorpholine, triethylamine, tributylamine, diisopropylethamine, dicyclohexylamine, N-methylpiperidine , pyridine, 2,6-dimethylpyridine, 4- (1-pyrrolidinyl) pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl-4-methylpyridine , quinoline, N, N-dimethylaniline and N, N-diethyaniline.

Thus, starting from (S) -2,2'-dihydroxy-1, 1 '-binaphtyle, we successively obtain (S) -6,6'-dibromo-2,2'-dihydroxy-1, 1' - binaphthyl and (S) -6,6'- dicyano-2,2'-bis (diarylphosphino) -1, 1 '-binaphtyle.

The same process applied to (R) -2,2'-dihydroxy-1 J '-binaphtyle, leads to (R) -6,6'-dicyano-2,2'-bis (diarylphosphino) -1, 1' - binaphthyle.

The optically active isomers of the compounds of formula II are isolated in a conventional manner from the corresponding racemic mixtures. Usually, an optically active resolving agent is used for this.

In the case of 1, 1 '-bi-2-naphthol, the resolution of the enantiomers can be carried out by formation of an inclusion complex with the (R, R) -1, 2-cyclohexanediamine, the (R, R ) or (S, S) -2,3 - (+) - dimethoxy-N, N, N ', N'- tetramethylsuccinamide, or else (R, R) or (S, S) - (+) - N , N, N ', N'-tetramethyl-2,2'-dimethyl-1, 3-dioxolane-trans-dicarboxamide. These methods have been described in the literature. Another way of proceeding consists in forming an inclusion complex of 1, 1 '-bi-2-naphthol with N-benzylcinchonidinium chloride. By using acetonitrile as solvent, only the complex with one of the enantiomers precipitates, which allows the separation of the two enantiomers. We will refer in this regard to the works of D. Cai published in Tetrahedron

Letters, vol. 36, n ° 44, 7991 -7994, 1995. As a variant, it is possible, with a view to preparing an optically active compound of formula I, to carry out step a) starting from a diol of racemic formula II , to carry out the splitting of the bromine derivative obtained of formula III, then continue the synthesis starting from the appropriate optically active brane III compound.

The bifunctional ligands obtained according to the methods of the invention can be used in the preparation of metal complexes intended for the asymmetric catalysis of hydrogenation, hydrosilylation, hydroboration of unsaturated compounds, epoxidation of allyl alcohols, d vicinal hydroxylation, hydrovinylation, hydroformylation, cyclopropanation, isomerization of olefins, polymerization of propylene, addition of organometallic compounds to aldehydes, allyl alkylation, aldol-type reactions, reactions of Diels-Alder and, in general, reactions of formation of bonds CC (such as the allylic substitutions or the cross couplings of Grignard).

According to a preferred embodiment of the invention, the complexes are used for the hydrogenation of the C = O, C = C and C = N bonds. The complexes which can be used in this type of reaction are complexes of rhodium, ruthenium, palladium, platinum, iridium, cobalt, nickel or rhenium, preferably complexes of rhodium, ruthenium, iridium, palladium and platinum. Even more advantageously, rhodium, ruthenium or iridium complexes are used. Specific examples of said complexes of the present invention are given below, without limitation.

In the following formulas, P represents a ligand according to the invention. A preferred group of rhodium and iridium complexes is defined by the formula: [MeLig ₂ P] Yι IX in which:

P represents a ligand according to the invention; Yι represents an coordinating anionic ligand; Me represents iridium or rhodium; and Lig represents a neutral ligand.

Among these compounds, those in which:

- Lig represents an olefin having from 2 to 12 carbon atoms; - Y, represents an anion PF ₆ ^" , PCI ₆ ^" , BF ₄ ^" , BCI ₄ ^" , SbF ₆ ^" , SbCI ₆ ^" , BPh ^" , CI0 ₄ ^" , CN ^" , CF ₃ S0 ₃ ^" , preferably halogen CI ^" or Br ^" , an anion 1, 3-diketonate, alkylcarboxylate, haloalkylcarboxylate with a lower alkyl radical (preferably in C-ι-C ₆ ), a phenylcarboxylate or phenolate anion whose benzene ring can be substituted by alkyl radicals lower (preferably C Cβ) and / or halogen atoms, are particularly preferred.

In formula IX, Lig ₂ can represent two ligands Lig as defined above or a bidental ligand such as bidental ligand, linear or cyclic, polyunsaturated and comprising at least two unsaturations.

It is preferred according to the invention that Lig ₂ represents 1,5-cyclooctadiene, norbornadiene or that Lig represents ethylene.

By lower alkyl radicals is generally meant a linear or branched alkyl radical having from 1 to 4 carbon atoms. Other iridium complexes are those of formula:

[IrLigPjY, X where Lig, P and Y | are as defined for formula IX.

A preferred group of ruthenium complexes consists of the compounds of formula: [RuYι ¹ Y, ² P] XI in which:

- P represents a ligand according to the invention;

- Yι ¹ and Y | ² , identical or different, represent an anion PF ₆ ^" , PCl6 ^" , BF ^" , BCI ₄ ^" , SbF ₆ ^" , SbCI ₆ ^" , BPh ₄ ^" , CIO ₄ ^" , CF ₃ S0 ₃ ^" , a halogen atom , more particularly chlorine or bromine or a carboxylate anion, preferably acetate, trifluoroacetate.

Other ruthenium complexes are those corresponding to the following formula XIV:

[RuY, ³ arPY | ⁴ ] XII in which:

- P represents a ligand according to the invention;

- Ar represents benzene, p-methylisopropylbenzene or hexamethylbenzene; Yι ³ represents a halogen atom, preferably chlorine or bromine; Yι ⁴ represents an anion, preferably an anion PF ₆ ^" , PCI ₆ ^" , BF ₄ ^" , BCI ₄ ^" , SbF ₆ ^" , SbCI ₆ ^" , BPh ₄ ^" , CIO ₄ ^" , CF ₃ SO ₃ ^" .

It is also possible to use in the process of the invention complexes based on palladium and platinum.

As more specific examples of said complexes, there may be mentioned, inter alia, Pd (hal) ₂ P and Pt (hal) ₂ P where P represents a ligand according to the invention and hal represents halogen such as, for example, chlorine.

The complexes comprising a ligand according to the invention and the transition metal can be prepared according to the known methods described in the literature.

The complexes are generally prepared from a precatalyst, the nature of which varies according to the transition metal selected.

In the case of rhodium complexes, the precatalyst is for example one of the following compounds: [Rh '(CO) ₂ CI] 2; [Rh '(COD) CI] ₂ where COD denotes cyclooctadiene; or Rh '(acac) (CO) ₂ where acac denotes acetylacetonate.

In the case of ruthenium complexes, particularly suitable precatalysts are bis- (2-methylallyl) -cycloocta-1, 5-diene ruthenium and [RuCI ₂ (benzene)] ₂ . We can also cite the Ru (COD) (η ³ - (CH ₂ ) ₂ CHCH ₃ ) ₂ . By way of example, starting from bis- (2-methylallyl) -cycloocta-1,5-diene ruthenium, a solution or suspension is prepared containing the metal precatalyst, a ligand and a perfectly degassed solvent such as acetone ( the ligand concentration of the solution or suspension varying between 0.001 and 1 mol / l), to which a methanolic solution of hydrobromic acid is added. The ratio of ruthenium to bromine advantageously varies between 1: 1 and 1: 4, preferably between 1: 2 and 1: 3. The molar ratio of the ligand to the transition metal is about 1. It can be between 0.8 and 1.2.

When the precatalyst is [RuCl ₂ (benzene)] ₂ , the complex is prepared by mixing the precatalyst, the ligand and an organic solvent and optionally maintaining at a temperature between 15 and 150 ° C for

1 minute to 24 hours, preferably 30 to 120 ° C for 10 minutes to 5 hours.

As solvent, mention may be made of aromatic hydrocarbons

(such as benzene, toluene and xylene), amides (such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorylamide), alcohols (such as ethanol, methanol, n-propanol and isopropanol) and their mixtures.

Preferably, when the solvent is an amide, in particular dimethylformamide, the mixture of the ligand, the precatalyst and the solvent is heated to between 80 and 120 ° C.

As a variant, when the solvent is a mixture of an aromatic hydrocarbon (such as benzene) with an alcohol (such as ethanol), the reaction medium is heated to a temperature between 30 and 70 ° C. The catalyst is then recovered according to conventional techniques

(filtration or crystallization) and used in asymmetric reactions. However, the reaction to be catalyzed by the complex thus prepared can be carried out without intermediate isolation of the catalyst complex.

In the following, the case of hydrogenation is explained in detail. The unsaturated substrate, in solution in a solvent comprising the catalyst, is placed under hydrogen pressure.

The hydrogenation is for example carried out at a pressure varying between 1, 5 and 100 bar, and at a temperature between 20 ° C and 100 ° C.

The exact conditions of implementation depend on the nature of the substrate to be hydrogenated. However, in the general case, a pressure of 20 to 80 bars, preferably 40 to 60 bars, and a temperature of 30 to 70 ° C, are particularly suitable.

The reaction medium can consist of the reaction medium in which the catalyst was obtained. The hydrogenation reaction then takes place in situ. Alternatively, the catalyst is isolated from the reaction medium in which it was obtained. In this case, the reaction medium for the hydrogenation reaction consists of one or more solvents, in particular chosen from C ₁ -C ₅ aliphatic alcohols such as methanol or propanol and an amide as defined above. above, for example dimethylformamide, optionally in admixture with benzene.

When the hydrogenation reaction takes place in situ, it is desirable to add to the reaction medium one or more solvents chosen from those mentioned above, and more particularly one or more aliphatic alcohols.

According to a preferred embodiment, perfectly degassed methanol and the substrate are added to the reaction medium containing the complex. The amount of methanol, or more generally of solvent, which can be added is such that the concentration of the substrate in the hydrogenation reaction medium is between 1 J 0 ^"3 and 10 mol / l, preferably between 0.01 and 1 mol / l.

The molar ratio of the substrate to the catalyst generally varies from 1/100 to 1/100,000, preferably from 1/20 to 1/2000. This ratio is for example of 1/1000.

The rhodium complexes prepared from the ligands of the invention are more particularly suitable for the asymmetric catalysis of isomerization reactions of olefins.

The ruthenium complexes prepared from the ligands of the invention are more particularly suitable for the asymmetric catalysis of the hydrogenation reactions of carbonyl bonds, of C = C bonds and of C = N bonds.

As regards the hydrogenation of double bonds, the suitable substrates are of the α, β-unsaturated carboxylic acid type and / or derivatives of α, β-unsaturated carboxylic acid. These substrates are described in EP 95943260.0. The α, β-unsaturated carboxylic acid and / or its derivative more particularly corresponds to formula A:

in which :

- R- | , R2, R3 and R4, represent a hydrogen atom or any hydrocarbon group, insofar as:

. if R- | is different from R2 and different from a hydrogen atom then R3 can be any hydrocarbon or functional group designated by R,

. if R- | where R2 represents a hydrogen atom and if R- | is different from R2, then R3 is different from a hydrogen atom and different from -COOR4, . if Rj is identical to R2 and represents any hydrocarbon or functional group designated by R, then R3 is different from -CH- (R) 2 and different from -COOR4, - one of the groups R- | , R2 and R3 can represent a functional group. As a specific example, there may be mentioned, inter alia, 2-methyl-2-butenoic acid.

A first group of preferred substrates is formed by substituted acrylic acids which are precursors of amino acids and / or derivatives.

Under the term substituted acrylic acids is meant all of the compounds whose formula derives from that of acrylic acid by substitution of at most two of the hydrogen atoms carried by the ethylenic carbon atoms by a hydrocarbon group or by a functional group. They can be symbolized by the following chemical formula:

in which :

- Rg, R'g, identical or different, represent a hydrogen atom, an alkyl group, linear or branched having from 1 to 12 carbon atoms, a phenyl group or an acyl group preferably having from 2 to 12 carbon atoms , an acetyl or benzoyl group, - Rβ represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, a cycloalkyl radical having from 3 to 8 carbon atoms, an arylalkyl radical having from 6 to 12 carbon atoms carbon, an aryl radical having from 6 to 12 carbon atoms, a heterocyclic radical having from 4 to 7 carbon atoms, - R- | o represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms. We can cite more particularly:

- methyl -acetamidocinnamate,

- methyl acetamidoacryiate, - benzamidocinnamic acid, - α-acetamidocinnamic acid.

A second preferred group of substrates consists of itaconic acid and its derivatives of formula:

A2 in which: - RH, R- | 2 _> identical or different represent a hydrogen atom, a linear or branched alkyl group having from 1 to 12 carbon atoms, a cycloalkyl radical having from 3 to 8 carbon atoms, a arylalkyl radical having from 6 to 12 carbon atoms, an aryl radical having from 6 to 12 carbon atoms, a heterocyclic radical having from 4 to 7 carbon atoms. - R- | o _> R'10 _> identical or different represent a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms.

As more specific examples, it may be mentioned in particular itaconic acid and dimethyl itaconate.

A third preferred group of substrates is defined by the formula A3:

A3 in which:

- R "- | Q represents a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms.

- R- | 3 represents a phenyl or naphthyl group, optionally carrying one or more substituents. As specific examples, there may be mentioned substrates by hydrogenation leading to 2- (3-benzoylphenyl) propionic acid (Ketoprofen ^®), 2- (4-isobutylphenyl) propionic (Ibuprofen ^® ), 2- (5-methoxynaphthyl-propionic acid (Naproxene ^® ).

As regards the hydrogenation of carbonyl bonds, the appropriate ketone type substrates more preferably correspond to formula B:

in which: - R5 is different from Rβ

- R5 and Rβ represent a hydrocarbon radical having from 1 to 30 carbon atoms optionally comprising one or more functional groups,

- R5 and Rβ can form a cycle optionally comprising another heteroatom, - Z is or comprises a heteroatom, oxygen or nitrogen or a functional group comprising at least one of these heteroatoms.

These compounds are precisely described in FR 96 08 060 and EP 97930607.3.

A first preferred group of such ketone substrates has the formula

in which :

- R5 is different from Rβ, the radicals R5 and Rβ represent a hydrocarbon radical having from 1 to 30 carbon atoms optionally comprising another ketone and / or acid function, ester, thioacid, thioester;

- R5 and Rβ can form a carbocyclic or heterocyclic ring, substituted or not, having 5 to 6 atoms.

Among these compounds, very particularly preferred are the ketones chosen from:

- methylphenylketone,

- isopropylphenylketone, - cyclopropylphenylketone,

- allylphenylketone,

- p-methylphenylmethylketone,

- benzylphenylketone, - phenyltriphenylmethylketone,

- o-bromoacetophenone,

- α- bromoacetone,

- α-dibromoacetone,

- α-chloroacetone, - α-dichloroacetone,

- α-trichloroacetone,

- 1 -chloro-3,3-dichloroacetone,

- 1 -chloro-2-oxobutane,

- 1-fluoro-2-oxobutane, - 1-chloro-3-methyl-2-butanone,

- α-chloroacetophenone,

- 1-chloro-3-phenylacetone,

- α-methylaminoacetone,

- α-dimethylaminoacetone, - 1 -butylamino-2-oxopropane,

- 1 -dibutylamino-2-oxopropane.

- 1-methylamino-2-oxobutane,

- 1-dimethylamino-2-oxobutane,

- 1-dimethylamino-3-methyl-2-oxobutane, - 1-dimethylamino-2-oxopentane,

- α-dimethylaminoacetophenone,

- α-hydroxyacetone,

- 1-hydroxy-3-methyl-2-butanone,

- 1-hydroxy-2-oxobutane, - 1-hydroxy-2-oxopentane,

- 1-hydroxy-2-oxohexane,

- 1-hydroxy-2-oxo-3-methyl butane, - α-hydroxyacetophenone,

- 1-hydroxy-3-phenylacetone,

- α-methoxyacetone,

- α-methoxyacetophenone, - α-ethoxyacetone,

- α-butoxyacetophenone,

- α-chloro-p-methoxyacetophenone,

- α-naphthenone,

- 1-ethoxy-2-oxobutane, - 1 -butoxy-2-oxobutane,

- α-dimethoxyphosphorylacetone,

- 3-oxotetrahydrothiophene.

Aldehyde / ketone type substrates having a second carbonyl group in position α, β, γ or δ relative to the first carbonyl group are also particularly suitable in the context of the invention. Examples of such diketonic compounds are:

- α-formylacetone,

- diacetyl,

- 3,4-dioxohexane, - 4,5-dioxooctane,

- 1-phenyl-1, 2-dioxopropane,

- 1-phenyl-2,3-dioxobutane,

- diphenylglyoxal,

- p-methoxydiphenylglyoxal, - 1, 2-cyciopentanedione,

- 1, 2-cyclohexanedione,

- acetylacetone,

- 3,5-heptanedione, - 4,6-nonanedione, - 5,7-undecadione,

- 2,4-hexanedione,

- 2,4-heptanedione, - 2,4-octanedione,

- 2,4-nonanedione,

- 3,5-nonanedione,

- 3,5-decanedione, - 2,4-dodecanedione,

- 1-phenyl-1, 3-butanedione,

- 1-phenyl-1, 3-pentanedione,

- 1-phenyl-1, 3-hexanedione,

- 1-phenyl-1, 3-heptanedione, - 3-methyl-2,4-pentanedione,

- 1, 3-diphenyl-1, 3-propanedione,

- 1,5-diphenyl-2,4-pentanedione,

- 1, 3-di (trifluoromethyl) -1, 3-propanedione,

- 3-chloro-2,4-pentanedione - 1,5-dichloro-2,4-pentanedione,

- 1,5-dihydroxy-2,4-pentanedione, - 1,5-dibenzyloxy-2,4-pentanedione,

- 1,5-diamino-2,4-pentanedione,

- 1,5-di (methylamino) 2,4-pentanedione, - 1,5-di (dimethylamino) -2,4-pentanedione,

- methyl 3,5-dioxo-hexanoate.

- 3-carbomethoxy-2,4-pentanedione,

- 3-carboethoxy-2,4-pentanedione,

- 1, 3-cyclopentanedione, - 1, 3-cyciohexanedione,

- 1, 3-cycloheptanedione,

- 5-carboethoxy-1, 3-cyclopentanedione,

- 2-acetyl-1-cyclopentanone,

- 2-acetyl-1-cyclohexanone. As other substrates which are particularly suitable, mention may be made of keto acids or their derivatives and ketothio acids or their derivatives with a functional group (acid, ester, thioacid or thioester) in the α, β, γ or δ position relative to the carbonyl group. Examples are: - 2-acetylbenzoic acid,

- pyruvic acid,

- 2-oxobutanoic acid,

- 3-methyl-2-oxobutanoic acid, - phenylglyoxylic acid,

- phenylpyruvic acid,

- p-methoxyphenylpyruvic acid,

- 3,4-dimethoxyphenylpyruvic acid,

- methyl acetoacetate, - ethyl acetoacetate,

- n-propyl acetoacetate,

- isopropyl acetoacetate,

- n-butyl acetoacetate,

- t-butyl acetoacetate, - n-pentyl acetoacetate,

- n-hexyl acetoacetate,

- n-heptyl acetoacetate,

- n-octyl acetoacetate,

- methyl 3-oxopentanoate, - methyl 3-oxohexanoate,

- methyl 3-oxoheptanoate,

- ethyl 3-oxooctanoate,

- ethyl 3-oxononanoate,

- ethyl 3-oxodecanoate, - ethyl 3-oxoundecanoate,

- ethyl 3-oxo-3-phenylpropanoate,

- ethyl 4-phenyl-3-oxobutanoate,

- methyl 5-phenyl-3-oxopentanoate,

- ethyl 3-oxo-3-p-methoxyphenylpropanoate, - methyl 4-chloroacetoacetate,

- ethyl 4-chloroacetoacetate,

- methyl 4-fluoroacetoacetate,

- ethyl 3-trifluoromethyl-3-oxopropanoate, - ethyl 4-hydroxy-3-oxobutanoate,

- methyl 4-methoxyacetoacetate,

- methyl 4-tert-butoxyacetoacetate,

- methyl 4-benzyloxy-3-oxobutanoate, - ethyl 4-benzyloxy-3-oxobutanoate,

- methyl 4-amino-3-oxobutanoate,

- ethyl 3-methylamino-3-oxobutanoate,

- methyl 4-dimethylamino-3-oxobutanoate,

- ethyl 4-dimethylamino-3-oxobutanoate, - methyl 2-methylacetoacetate,

- ethyl 2-methylacetoacetate,

- ethyl 2-chloroacetoacetate,

- diethyl 2-acetylsuccinate,

- diethyl 2-acetylglutarate, - dimethyl acetylmalonate,

- thiomethyl acetoacetate,

- thioethyl acetoacetate,

- thiophenyl acetoacetate,

- methyl pyruvate, - ethyl 3-methyl-2-oxobutanoate,

- ethyl phenylglyoxolate,

- methyl phenylpyruvate,

- ethyl phenylpyruvate,

- 3-oxobutanoic dimethylamide, - 3-oxobutanoic benzylamide,

- 2-carboethoxy-cyclopentanone,

- 2-carboethoxy-cyclohexanone,

- ketopentalactone.

- 4-oxopentanoic acid, - 4-oxohexanoic acid,

- 4-oxoheptanoic acid,

- 4-oxodecanoic acid,

- 4-oxododecanoic acid, - 4-phenyl-4-oxybutyric acid,

- 4-p-methoxyphenyl-4-oxybutyric acid,

- 4- (3,4-dimethoxyphenyl) -4-oxobutyric acid,

- 4- (3,4,5-trimethoxyphenyl) -4-oxobutyric acid,

- 4-p-chlorophenyl-4-oxybutyric acid,

- 4-phenyl-4-oxobutyric acid.

It should be noted that when one has to do the asymmetric hydrogenation of a γ-keto acid or derivative, the product obtained is generally a derivative of γ-butyrolactone and in the case of a δ-keto acid, it s' is a derivative of valerolactone.

As other examples of ketones, there may be mentioned, among others, the following cyclic, saturated or unsaturated, monocyclic or polycyclic ketone compounds:

where R represents a phenyl substituted or not by alkyl radicals, alkoxy or a halogen atom; or R represents an alkyl group or cycloalkyl substituted or not by alkyl radicals, alkoxy, or a halogen atom, a hydroxyl group, ether, amino; or R represents a halogen atom, a hydroxyl, alkoxy or amino group.

It is also possible to use ketones of steroid type (for example 3-cholestanone, 5-cholesten-3-one).

As other ketone substrates, mention may be made of the compounds of formula B2:

in which :

- R5 different from Rβ have the meaning given above,

- R7 represents:

• a hydrogen atom,

A hydroxyl group,

• an OR17 group,

• a hydrocarbon radical R-j 7,

^R 14 a group of formula - N. \

R -15

a formula group

with R14, R-15, Riβ and R-17 which represent a hydrogen atom or a hydrocarbon group having from 1 to 30 carbon atoms. Examples of compounds of formula B2 are: → N-alkylketoimine, such as: - N-isobutyl-2-iminopropane

- N-isobutyl-1-methoxy-2-iminopropane → N-arylalkyl ketoimine, such as:

- N-benzyl-1 -imino-1 - (phenyl) ethane

- N-benzyl-1 -imino-1 - (4-methoxyphenyl) ethane - N-benzyl-1-imino-1- (2-methoxyphenyl) ethane

- N-arylketoimine, such as:

- N-phenyl-2-iminopentane

- N- (2,6-dimethylphenyl) -2-iminopentane

- N- (2,4,6-trimethylphenyl) -2-iminopentane - N-phenyl-1-imino-1-phenylethane

- N-phenyl-1-methoxy-2-iminopropane

- N- (2,6-dimethylphenyl) -1-methoxy-2-iminopropane

- N- (2-methyl-6-ethylphenyl) -1 -methoxy-2-iminopropane

→ hydrazone type compounds, optionally N-acylated or N-benzoylated:

- 1 -cyclohexyl-1 - (2-benzoylhydrazono) ethane, - 1 -phenyl-1 - (2-benzoylhydrazono) ethane, - 1 -p-methoxyphenyl-1 - (2-benzoylhydrazono) ethane, - 1 -p-ethoxyphenyl -1 - (2-benzoylhydrazono) ethane, - 1-p-nitrophenyl-1- (2-benzoylhydrazono) ethane,

- 1 -p-bromophenyl-1 - (2-benzoylhydrazono) ethane, - 1 -p-carboethoxyphenyl-1 - (2-benzoylhydrazono) ethane,

- 1, 2-diphenyl-1- (2-benzoylhydrazono) ethane,

- 3-methyl-2- (2-p-dimethylaminobenzoylhydrazono) butane, - 1-phenyl-1- (2-p-methoxylbenzoylhydrazono) ethane,

- 1 -phenyl-1 - (2-p-dimethylaminobenzoylhydrazono) ethane,

- ethyl-2- (2-benzoylhydrazono) propionate

- methyl-2- (2-benzoylhydrazono) butyrate - methyl-2- (2-benzoylhydrazono) valerate

- methyl-2-phenyl-2- (2-benzoylhydrazono) acetate.

Other starting substrates are semi-carbazones and cyclic ketoimines with endo or exocyclic linkages, such as:

According to a particularly preferred embodiment of the invention, the substrate is a β-ketoester (such as methyl acetoacetate or methyl 3-oxovalerate), an α-ketoester (such as methyl benzoylformate or pyruvate methyl), a ketone (such as acetophenone), an olefin, an unsaturated amino acid or one of its derivatives (and in particular one of its esters). The complexes obtained from the ligands of formula I and their derivatives lead in particular to a good enantioselectivity of the hydrogenation reactions.

More particularly, the ruthenium complexes prepared from the ligands obtained according to the process of the invention are suitable for the asymmetric catalysis of the hydrogenation reactions of the C = 0 bonds of β-ketoesters.

The complexes of ruthenium and ligands of formula VII are particularly suitable for the asymmetric catalysis of hydrogenation reactions of the C = O bonds of ketones.

Thus, according to another of its aspects, the invention relates to the use of a compound of formula I or of formula VII or of formula VIII for the preparation of a metal complex intended for asymmetric catalysis, and more particularly of a ruthenium, iridium or rhodium complex. The use of a ligand of formula VII for the preparation of a metal complex and more specifically of a ruthenium complex, intended for the asymmetric catalysis of ketone hydrogenation reactions, forms a preferred object of the invention. The following examples illustrate the invention more precisely.

PREPARATION 1

Preparation of (Sî-δ.θ'-dibromo ^^ '- dihydroxy-l .l' -binaphtyle

7.7 g (26.9 moles) of (S) -2,2'-dihydroxy-1, 1 '-binaphthyle are dissolved in 145 ml of dichloromethane. The solution is cooled to -75 ° C. then 3.66 ml of Br ₂ (71.7 mmol) are added dropwise for 30 minutes with constant stirring. The solution is stirred for an additional 2.5 hours before being brought to room temperature. After adding 180 ml of sodium bisulfite (10% by mass), the organic phase is washed with a saturated NaCl solution and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the solid obtained is recrystallized from a mixture of tuuene / cyclohexane) at 80 ° C to give 9.8 g (22 mmol, 82% yield) of the expected product.

The rotary power as measured on a Perkin-Elmer-241 polahmeter (1 = 10 cm, 25 ° C, concentration c in g / dm ³ ) is 124.3 at c = 1.015 and 578 nm. For the preparation of the dibromo derivative of the title, reference may be made to G.

Dotsevi et al., J. Am. Chem. Soc, 1979, 101, 3035.

PREPARATION 2

Preparation of (S) -6,6'-dibromo-2,2'-bis (trifluoromethane-sulfonyloxyj-l .l '-binaphtyle

9.52 g (21.4 mml) of (S) -6,6'-dibromo-2,2'-dihydroxy-1, 1 '-binaphtyle are dissolved in a mixture of 40 ml of CH2Cl2 and 5.4 ml of pyridine. After cooling the mixture to 0 ° C, 8.7 ml (14.5 g, 51.5 mmol) of triflic anhydride ((CF ₃ - Sθ2) ₂ Û) are added slowly. After stirring for 6 h, the solvent is evaporated and the reaction mass is dissolved in 100 ml of ethyl acetate. After washing with a 5% aqueous solution of HCl, a saturated solution of NaHCO ₃ and a saturated solution of NaCl, the organic phase is dried over Na ₂ S0 ₄ then the solvent is evaporated under reduced pressure. The yellow oil is purified by chromatography on silica (CH ₂ CI ₂ ) to give 12.5 g (17.7 mmol, 83% yield) of the expected product.

[CX] D = 151, 3 (c = 1, 005, THF), the rotary power being measured under the same conditions as in preparation 1 but at the wavelength corresponding to the D line of sodium.

For the preparation of the title compound, reference may also be made to the work of M. Vondenhof, Tetrahedron Letters, 1990, 31, 985.

PREPARATION 3 Preparation of (SJ-β ^ '- dibromo ^^' - bisftrifluoromethane- sulfonyloxy) -1, 1 '-binaphtyle

Alternatively, the title compound can be prepared from (R) -6,6'-dibromo-2,2'-dihydroxy-1, 1 '-binaphtyle by following the procedure described below. 10.0 g (22.52 mmol) of (R) -6,6'-dibromo-2,2'-dihydroxy-1, 1 '-binaphtyle are dissolved in a solution of 6.3 g (0.1 1 mol of KOH in 300 ml of degassed water The mixture is cooled to 0 ° C. and then a solution of 11.4 ml (19.1 g, 68 mmol) of triflic anhydride in 200 ml of CCI is added for 45 minutes so that the temperature does not exceed 10 ° C. After stirring for 30 min, 300 ml of CH ₂ CI ₂ are added.The organic phase is washed with water and then dried over MgS0. g of crude product are then purified by chromatography on silica (CH ₂ CI ₂ : cyclohexane 1: 1) to give 12.94 g (18.27 mmol, 81% yield) of pure product.

[α] _D = -153.2 ° (c = 0.945, THF), the rotary power being measured under the same conditions as in preparation 1 but at the wavelength corresponding to the line D of sodium.

¹ H NMR (CDCI ₃ , 200 MHz): δ (ppm): 7.07 (d (J _HH = 7.07), CH, 2H); 7.48 (dd (J ¹ _HH = 9.05; J ² _H- H = 1.94), CH, 2H); 7.62 (d (J _{H, H} = 9.1 1), CH, 2H); 8.06 (d (J _H -H = 9.13), CH, 2H); 8.18 (d (J _H- H = 1.90), CH, 2H). ¹³ C NMR (CDCI ₃ , 200 MHz): δ (ppm) = 11.1 (Cq (J _cF = 320)); 120.2

(Cq); 120.7 (CH); 122.0 (Cq); 123.4 (Cq); 128.2 (CH); 130.5 (CH); 131, 4 (CH); 131.6 (Cq); 131.7 (CH); 133.4 (Cq). PREPARATION 4

Preparation of (S) -6,6'-dicyano-2,2'-bis (trifluoromethane sulfonyloxy) -1, 1 '-binaphtyle

12.5 g (17.7 mmol) of the compound prepared in preparation 2 and 3.5 g (38.8 mmol) of CuCN are stirred at 180 ° C in 20 ml of N-methyl-pyrrolidone for 4 h. After having cooled to room temperature, the black suspension is poured into a solution of 15 ml of diaminoethane in 35 ml of water. The solution is extracted several times with 30 ml of CH ₂ CI ₂ , the organic phase is washed with a 10% aqueous solution of KCN, and a saturated NaCl solution. After drying over Na ₂ S0 ₄ , the solvent is evaporated off under reduced pressure. The black oil thus obtained is purified by chromatography on silica (CH ₂ Cl ₂ : cyclohexane 9: 1) to give 6.5 g (10.8 mmol, 61% yield) of pure product.

[δ] o = 171, 7 (c = 1, 15, THF), the rotary power being measured under the same conditions as in preparation 1 but at the wavelength corresponding to the D line of sodium.

¹ H NMR (CDCI ₃ , 200 MHz): δ (ppm) = 7.30 (d (J _H - _H = 9.81), CH, 2H); 7.59 (dd (J ¹ _H -H = 8.82, J ² _H- H = 1.65), CH, 2H); 7.78 (d (J _HH = 9.1 1), CH, 2H); 8.29 (d (J _H - _H = 8.09), CH, 2H); 8.46 (d (J _H- = _1.29 ), CH, 2H). ¹³ C NMR (CDCI ₃ , 200 MHz): δ (ppm) = 1 1 1, 7 (CN); 1 18.0 (Cq); 1 18.1

(Cq (J _c- F = 320)); 121, 6 (CH); 123.3 (Cq); 127.7 (CH); 128.9 (CH); 131, 4 (Cq); 133.2 (CH); 134.4 (Cq); 134.5 (CH); 147.4 (Cq).

For the preparation of the title compound, those skilled in the art can refer to the work of Friedman & coll., J. Org. Chem. 1961, 26, 2522 and M. S. Neuman & coll., J. Org. Chem., 1961, 26, 2525.

EXAMPLE 1

Preparation of (S) -6,6'-dicyano-2,2'-bis (diphenyl phosphino) -1, 1 '- binaphthyl (I: A = phenyl; A ^ = Ar ₂ = phenyl) In a three-necked flask 100 ml surmounted by an inlet of argon, a solution of NiCI ₂ dppe (371 mg, 0.7 mmol) and diphenylphosphine (3 ml, 17 mmol) in 14 ml of DMF (anhydrous and degassed) is heated for 30 minutes at 100 ° C. Le (S) -6,6'-dicyano-2,2'-bis (trifluorométhanesulfonyloxy) -1, 1 '- binaphthyl (4.4 g, 7.4 mmol) and DABCO (3.375 g, 30 mmol) dissolved in 20 ml of DMF are added dropwise. The reaction medium is left at 100 ° C. After 1, 3 and 7 hours, 0.75 ml of diphenylphosphine is added. The solution is left under stirring for 2 days. It is then cooled to 0 ° C, then filtered under argon, washed with methanol (2 x 10 ml). The solid is finally dried under vacuum to provide the expected product with a yield of 50%.

Elementary analysis for C ₄₆ H ₃ oN ₂ P ₂ calculated: C = 80.88; H = 4.43; N = 4.10; P = 9.07; found: C = 81.61; H = 4.45; N = 4.1 1; P = 8.99. ¹ H NMR (CDCI ₃ , 200 MHz) δ (ppm): 6.59 (d, 2H, CH); 6.87 (dd, 2H, CH);

6.92-6.99 (m, 4H, CH); 7.09 (t, 4H, CH); 7.17-7.31 (m, 12H, CH); 7.57 (d, 2H, CH); 7.95 (d, 2H, CH); 8.20 (s, 2H, CH).

¹³ C NMR (CDCI ₃ , 50 MHz) δ (ppm): 109.8 (CN); 11.0 (Cq); 126.3 (CH) 127.7 (CH); 128.4 (CH); 128.5 (CH); 128.5 (CH); 128.6 (CH); 128.8 (CH) 129.3 (CH); 132.0 (CH); 132.1 (Cq); 132.9 (CH (triplet J _C -P = 1 1, 7); 133.9 (Cq) 134.1 (Cq); 134.9 (CH (triplet J _cP = 9.9)); 136.8 (Cq); 140.6 (Cq).

³¹ P NMR (CDCI3, 81 MHz) δ (ppm): -12.75.

EXAMPLE 2

Preparation of (S) -6,6'-bis (aminomethyl) -2,2'-bis (diphenylphosphino) -1, 1 '-binaphthyl (VII: Ar- = Ar ₂ = C ₆ H ₅ )

In a 250 ml flask placed under an argon atmosphere, 557 mg (14.7 mmol) of LiAIH _{4 are} dissolved in a mixture of THF (30 ml) / toluene (60 ml). (S) -6,6'-dicyano-2,2'-bis (diphenylphosphino) -1, 1 '-binaphthyle (650 mg, 0.97 mmol) is added to this solution which is stirred and brought to reflux for 4 hours. It is then cooled to 0 ° C. 600 μl of water and 600 μl of 15% NaOH are added. Then 2 g of celite are added and the mixture is filtered through miilipore under argon. 60 ml of dichloromethane are added, the mixture is stirred and again filtered. This is done three times. The organic phase obtained is washed with a saturated aqueous NaCl solution and then dried over Na ₂ S0 ₄ . The solvent is evaporated to obtain a yellow solid (657 mg, yield quantitative) characterized by NMR (proton, carbon and phosphorus) corresponding to the expected structure.

Elementary analysis for C ₆ H ₃ 8N ₂ P2 calculated: C = 80.59; H = 6.00; N = 3.55; P = 7.84; found: C = 81, 14; H = 5.51; N = 3.13; P = 7.90.

¹ H NMR (CDCI ₃ , 200 MHz) δ (ppm): 1.68 (s, 4H, NH ₂ ); 3.81 (s, 4H, CH ₂ ); 6.72 (s, 4H, CH); 6.9-7.3 (m, 20H, CH); 7.33 (d, 2H, CH); 7.64 (s, 2H, CH); 7.76 (d, 2H, CH).

³¹ P NMR (CDCI ₃ , 81 MHz) δ (ppm): -15.08.

EXAMPLE 3

Preparation of a ruthenium catalyst

The catalyst is prepared in situ. All the solvents used have been carefully degassed and are anhydrous. The reaction medium is maintained under an argon atmosphere. The ligand and the metal precatalyst, bis- (2-methylallyl) cycloocta-1,5,5-diene ruthenium, are directly weighed in a 5 ml conical bottom glass reactor removed from the oven and equipped with a stirrer. in a ligand / metal molar ratio of 1: 1. The reactor is closed by a septum and the air is expelled by an inlet of argon. Acetone is then added (1 ml) to give a white suspension. This suspension is stirred for 30 minutes and then a 0.29 M methanolic HBr solution is added (Ru / Br ratio of 1 / 2.3). There is then a change in color of the solution which turns brown. This solution is further stirred for 1 hour then the solvent is evaporated. The catalyst is then obtained in the form of a brown solid. Two complexes were prepared following this procedure.

The first, Dicyano-BINAP, from (S) -6,6'-dicyano-2,2'- bis (diphenylphosphino) -1, 1 '-binaphtyle (obtained in Example 1).

The second, Diam-BINAP, starting from (S) -6,6'-diaminomethyl-2,2'- bis (diphenylphosphino) -1, 1 '-binaphtyle (obtained in Example 2).

EXAMPLE 4

This example illustrates the hydrogenation of a β-ketoester in the presence of the ruthenium complexes prepared in Example 3. The hydrogenation protocol is described below: The methanol which has been previously dried over magnesium, is added (2.5 ml) under argon in the conical reactor where the catalyst has just been prepared, the substrate is then added ( in a defined catalyst / substrate ratio). The operation of vacuuming and filling the argon reactor is repeated three times. The septum is then replaced by a pierced plug and the reactor is placed in an autoclave. The autoclave is purged three times under argon then three times under hydrogen before receiving 40 bar of hydrogen pressure. The autoclave is placed on a hot plate (50 ° C) and stirring is continued overnight. The conical reactor is finally recovered, the plug is replaced by a septum, and the argon is reinjected into this reactor. The reactor is placed in a centrifuge, then the solution is extracted using a syringe. It is placed in a 50 ml flask and diluted in 20 ml of methanol, ready then to be injected into a chromatography column for gas chromatography for analysis of the conversion rate and the enantioselectivity of the reaction.

More specifically, the determination of enantiomeric excesses is carried out by chiral gas chromatography on a column of Macheray-Nagel type (Lipodex A 25 m × 0.25 mm). The substrate tested is a β-ketoester, namely methyl acetoacetate. It leads, after hydrogenation, to methyl 3-hydroxybutanoate. The compound obtained is the S enantiomer, the catalysts being prepared from the compounds of Examples 1 and 2.

The results obtained for each of the complexes described in Example 3 above are reported in the following Table 1:

TABLE 1

By way of comparison, the hydrogenation of methyl acetoacetate is carried out in the presence of a ruthenium complex prepared from (R) -2,2'- bis (diphenylphosphino) -1, 1'-binaphtyle. The reaction conditions for hydrogenation and preparation of the metal catalyst are as described above. The results obtained are summarized in Table 2, it being understood that the hydrogenation product in this case is methyl (R) -3-hydroxybutanoate.

TABLE 2 (comparison)

As can be seen, the complexes prepared from the compounds of Examples 1 and 2 above lead to excellent enantiomeric excesses. The catalysts of the invention therefore allow the implementation of a highly enantioselective hydrogenation reaction.

EXAMPLE 5 This example illustrates the hydrogenation of an aromatic ketone in the presence of the ruthenium complexes prepared in Example 3. The hydrogenation protocol followed is as described in Example 4, except that the substrate used is acetophenone. It leads to phenylethanol.

The determination of enantiomeric excesses is carried out under the same conditions as in Example 4. The results obtained are reported in Table 3 below.

By way of comparison, the hydrogenation of this same substrate is carried out in the presence of the ruthenium complex with 2,2'-bis (diphenylphosphino) -1, 1 '- binaphthyl prepared in Example 4.

The hydrogenation reaction conditions are as described above.

The results obtained are a conversion rate of less than 1% (traces) and an enantiomeric excess of 0%.

This example shows very clearly the superiority of the catalysts of the invention.

Claims

CLAIMS 1 - Process for the preparation of a compound of formula I:

in which :

A represents naphthyl or phenyl; and

An and Ar ₂ independently represent a saturated or aromatic carbocyclic group; comprising the steps consisting in: i) carrying out the bromination of a diol of formula II:

in which A is as defined above, by means of an appropriate brominating agent so as to obtain a dibromo compound of formula III:

wherein A is as defined above; ii) esterifying the compound of formula III obtained in the preceding step by the action of a sulfonic acid or of an activated form thereof so as to obtain the corresponding disulfonate; iii) substituting the two bromine atoms for cyano groups by reacting the disulfonate obtained in the previous step with an appropriate nucleophilic agent so as to obtain the corresponding nitrile; iv) coupling of a phosphine of formula VI: XPArιAr ₂ VI in which X represents a hydrogen atom or a halogen atom and Ar-i and Ar ₂ are as defined above, with the nitrile obtained in l 'previous step in the presence of a catalyst based on a transition metal, so as to obtain the compound of formula (I) expected. 2 - Method according to claim 1, characterized in that:

A represents naphthyl or phenyl, optionally substituted by one or more radicals chosen from (CrC ₆ ) alkyl and (C C- ₆ ) alkoxy; and

Ar-i, Ar ₂ independently represent a phenyl group optionally substituted by one or more (CC ₆ ) alkyl or (CrC ₆ ) alkoxy; or a (C ₄ - C ₈ ) cycloalkyl group optionally substituted by one or more (C 1 -C ₆ ) alkyl groups.

3 - Process according to any one of claims 1 or 2, characterized in that A and Ar ₂ are independently chosen from phenyl optionally substituted by methyl or tert-butyl; and (C ₅ -C ₆ ) cycloalkyl optionally substituted by methyl or tert-butyl.

4 - Process according to any one of claims 1 or 2, characterized in that Ar-i and Ar ₂ are identical and preferably represent optionally substituted phenyl.

5 - Method according to one of the preceding claims, characterized in that A represents naphthyl.

6 - Process according to any one of the preceding claims for the preparation of a compound of formula I optically active from a diol of formula II optically active.

7 - Method according to any one of the preceding claims, characterized in that the bromination is carried out, in step (i), by the action of bromine, at a temperature between -78 ° and -30 ° C.

8 - Process according to any one of the preceding claims, characterized in that in step (ii) the esterification is carried out by the action of anhydride trifluoromethanesulfonic acid in the presence of a base, the base being preferably chosen from pyridine and 4-dimethylaminopyridine.

9 - Method according to any one of the preceding claims, characterized in that the nucleophilic agent used in step (iii) is CuCN. 10 - Process according to any one of the preceding claims, characterized in that in step (iv), HPAr-ιAr ₂ is reacted with the nitrile in the presence of nickel [bis (diphenylphosphino) ethane] dichloride and triethylenediamine, at a temperature of 50 to 200 ° C, preferably from 80 to 130 ° C. 11 - Process according to any one of claims 1 to 9, characterized in that in step (iv), reacting a compound of formula XPAr-ιAr ₂ (where X is a halogen atom) with the nitrile in the presence of nickel and zinc [bis (diphenylphosphino) ethane] dichloride, at a temperature between 50 and 200 ° C, preferably between 80 and 180 ° C. 12 - Method according to any one of claims 10 and 11, characterized in that the molar ratio of compound VI to nitrile is between 2 and 4.

13 - Process according to any one of claims 10 to 12, characterized in that the reaction of the compound of formula VI with the nitrile is carried out in N, N-dimethylformamide as solvent.

14 - Process for the preparation of a compound of formula VII:

in which A, An and Ar ₂ are as defined in claim 1 or in claim 2, characterized in that it comprises the reduction of the nitrile functions of the corresponding compound of formula I as defined in claim 1, respectively claim 2, by the action of an appropriate reducing agent. 15 - Process according to claim 14, characterized in that the reducing agent is lithium aluminum hydride, the reduction being carried out in a mixture of toluene and tetrahydrofuran as solvent.

16 - Method according to any one of claims 1 to 13, further comprising the step of treating in basic medium or in acidic medium the compound of formula I so as to obtain the corresponding carboxylic acid of formula:

wherein A, Aη and Ar ₂ are as defined in claim 1 or claim 2.

17 - Compound of formula VII:

in which A, Ar-t and Ar ₂ are as defined in any one of claims 1 to 5. 18 - Use of a compound of formula I obtained by carrying out the process according to any one of claims 1 to 13 as a ligand for the preparation of a metal complex useful in asymmetric catalysis.

19 - Use of a compound of formula VII according to claim 17 as a ligand for the preparation of a metal complex useful in asymmetric catalysis.

20 - Use according to claim 19, characterized in that said complex is intended to catalyze the asymmetric hydrogenation of ketones. 21 - Use according to any one of claims 18 to 20, characterized in that the metal complex is a complex of ruthenium, rhodium or iridium.

22 - Compound of formula IV:

wherein A is as defined in any one of claims 1 to 5 and P represents an aliphatic hydrocarbon group; an aromatic carbocyclic group; or an aliphatic group substituted by an aromatic carbocyclic group.

AMENDED CLAIMS

[received by the International Bureau on July 10, 2000 (10.07.00); claim 22 as amended; other claims unchanged

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21 - Use according to any one of claims 18 to 20, characterized in that the metal complex is a complex of ruthenium, rhodium or iridium.

22 - Compound of formula IV:

wherein A is as defined in any one of claims 1 to 5 and P represents an aliphatic hydrocarbon group; an aromatic carbocyclic group; or an aliphatic group substituted by an aromatic carbocyclic group, it being understood that P represents neither CF ₃ nor p-tolyl.