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  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
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  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
  • C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
  • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
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  • C12C11/00—Fermentation processes for beer
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  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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  • C07B2200/07—Optical isomers
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  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• DIPHOSPHINS OF 6 ⁇ '-BIS- (l-PHOSPHANORBORNADIENE)
• the present invention relates to new 6,6'-bis- (1-phosphanorbornadiene) diphosphines and their preparation process.
• Another object of the invention are said optically active diphosphines.
• the difficulty is that the diphosphine-type chiral ligands are not easily accessible, due to their complex synthesis, as well as the difficulty in separating the diastereoisomers and / or enantiomers.
• a first objective of the invention is to provide new diphosphines and a process for their preparation.
• Another objective is to provide optically active diphosphines, chiral on phosphorus and non-racemizable.
• Another objective is to provide modified diphosphines, making it possible to obtain better results in asymmetric catalysis reactions.
• Rf, R2, R3, R4, R5, identical or different represent a hydrogen atom or a hydrocarbon radical, optionally substituted, having from 1 to 40 carbon atoms which can be a saturated or unsaturated acyclic aliphatic radical, linear or branched; a saturated, unsaturated or aromatic, monocyclic or pycycyclic carbocyclic or heterocyclic radical; a saturated or unsaturated, linear or branched aliphatic radical, carrying a cyclic substituent, - R2 and R 3 can form, together with the carbon atoms which carry them, a saturated or unsaturated cycle,
• R 5 can represent a radical of type
• R2 and R3 ' have the same meaning as that given for R 1 ( R 2 and R 3 ,
• Ri, R2, R3, R4, R5, identical or different can take various meanings. Various examples are given below, but they are in no way limiting.
• R ⁇ to R5, can represent an acyclic aliphatic radical, saturated or unsaturated, linear or branched.
• to R5 represent a linear or branched acyclic aliphatic radical preferably having from 1 to 12 carbon atoms, saturated or comprising one to several, generally, 1 to 3, double bonds.
• the hydrocarbon chain can optionally be interrupted by a group, preferably a heteroatom, and more particularly, an oxygen or nitrogen atom or alternatively carrying substituents, for example, a halogen atom, in particular, chlorine or a group -CF 3 .
• R 1 to R 5 represent an acyclic, saturated or unsaturated, linear or branched aliphatic radical which may optionally carry a cyclic substituent.
• cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
• cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzene, these cyclic substituents themselves being optionally carriers of one or more substituents.
• the radicals R 1 to R 5 may also represent a carbocyclic radical saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 8 carbon atoms, preferably 6 atoms carbon in the cycle; said cycle can be substituted.
• radicals R 1 to R 5 mention may be made of cyclohexyl radicals optionally substituted by linear or branched alkyl radicals having from 1 to 4 carbon atoms.
• R 1 to R 5 may be polycyclic, saturated or unsaturated, preferably bicyclic, carbocyclic radicals, which means that at least two rings have two carbon atoms in common.
• the number of carbon atoms in each cycle preferably varies between 3 and 6: the total number of carbon atoms being preferably equal to 7.
• the radicals R ⁇ to R5, preferably represent an aromatic, and in particular benzene, hydrocarbon radical corresponding to the general formula (II):
• - n is an integer from 0 to 5, preferably from 0 to 3,
• R Q represents R Q , one of the following groups or functions:
• a linear or branched alkenyl radical having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyl,.
• a linear or branched alkoxy radical having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, radicals.
• an acyl group having from 2 to 6 carbon atoms,
• Rg represents a valence bond or a divalent hydrocarbon radical, linear or branched, saturated or unsaturated, having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, propylene, isopropylene, isopropylidene; the radicals R7, which are identical or different, represent a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X symbolizes a halogen atom, preferably a chlorine, bromine or fluorine atom.
• - Q represents R n 'one of the following more complex radicals:
• - m is an integer from 0 to 5, preferably from 0 to 3,.
• R_ having the meaning given above,
• R ⁇ represents a valential bond; a divalent, linear or branched, saturated or unsaturated hydrocarbon group having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, propylene, isopropylene, isopropylidene or one of the following groups called Z: -O-; -CO-; COO-; -NR 7 -; -CO-NR 7 -; -S-; -S0 2 -; -NR 7 -CO-; in said formulas R 7 represents a hydrogen atom, a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably a methyl or ethyl radical.
• the radicals Q can be identical or different and 2 successive carbon atoms of the benzenic cycle can be linked together by a ketal bridge such as the extranuclear methylene dioxy or ethylene dioxy radicals.
• the preferred diphosphines correspond to the general formula (I) in which R-
• - n is equal to 0, 1, 2 or 3
• - Q represents one of the following groups or functions:
• the compounds of formula (I) are chosen in which the identical or different Q radicals are a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms.
• to R5 corresponding to formula (I)
• phenyl, tolyl or xylyl radicals 1-methoxyphenyl, 2-nitrophenyl and the biphenyl, 1,1'-methylenebiphenyl, 1,1'-isopropylidenebiphenyl radicals, 1,1'-carboxybiphenyl, 1,1'-oxybiphenyl, 1, 1'-iminobiphenyl: said radicals being able to be substituted by one or more substituents.
• R1 to R5 can also represent a polycyclic aromatic hydrocarbon radical; the cycles being able to form between them ortho-condensed, ortho- and peri-condensed systems. Mention may more particularly be made of a naphthyl radical; said cycles being able to be substituted.
• R 1 to R 5 may also represent a saturated, unsaturated or aromatic heterocyclic radical, comprising in particular 5 or 6 atoms in the ring including 1 or 2 heteroatoms such as nitrogen atoms, sulfur and oxygen; the carbon atoms of the heterocycle possibly being substituted.
• R 1 to R 5 can also represent a heterocyclic polycyclic radical defined as being either a radical consisting of at least 2 aromatic heterocyclic rings or not containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri- condensed or either a radical consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and per-condensed systems; the carbon atoms of said rings possibly being substituted ,.
• a heterocyclic polycyclic radical defined as being either a radical consisting of at least 2 aromatic heterocyclic rings or not containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri- condensed or either a radical consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and per-condensed systems; the carbon atoms of said rings possibly being substituted
• groups - ⁇ to R5 of heterocyclic type there may be mentioned, among others, the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl and quinolyl radicals. , naphthyridinyl, benzopyrannyl, benzofurannyl, indolyl.
• R 5 represents a radical of type Ri 'preferably represents a hydrogen atom and R2 * and R 3 ' preferably represent a methyl radical.
• the number of substituents present on the cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturations on the cycle.
• the maximum number of substituents likely to be carried by a cycle is easily determined by a person skilled in the art.
• the nature of the substituent is arbitrary insofar as it does not interfere with the desired product.
• RQ illustrates the type of substituents commonly encountered.
• the substituents most often carried by the ring are one or more alkyl or alkoxy radicals preferably having from 1 to 4 carbon atoms and / or a halogen atom.
• to R5 comprise an unsaturation such as a double bond
• one of the carbon atoms of the double bond is a disubstituted carbon, that is to say carrier of two substituents and one can cite , in particular alkyl radicals preferably having from 1 to 4 carbon atoms.
• the radicals R2 and R3 they can form, together with the carbon atoms which carry them, a saturated or unsaturated ring, preferably having from 5 to 7 carbon atoms and more preferably 6 carbon atoms.
• the radicals R2 and R 3 can form a cyclohexane.
• the different radicals represent more particularly:
• a radical other than a hydrogen atom preferably a linear or branched alkyl radical having from 1 to 4 carbon atoms, a phenyl radical,
• a hydrogen atom a linear or branched alkyl radical having from 1 to 4 carbon atoms, . a phenyl radical or a phenyl radical bearing one to several substituents, preferably from 1 to 3 alkyl or alkoxy radicals, linear or branched, having from 1 to 4 carbon atoms, a naphthyl radical, - R 4 and R 5 ne cannot simultaneously represent a phenyl group.
• the invention in its preferred form, resides in new diphosphines corresponding to the formula (D in which the radical R5 can represent a sterically hindered group such as a substituted phenyl radical or a tertiary radical, that is to say the carbon atom located in position ⁇ with respect to the phosphorus atom carries three substituents (for example a tert-butyl radical).
• sterically hindered group is intended to mean a group which has a steric hindrance greater than that of a phenyl radical and which can be appreciated by the molecular volume.
• diphosphines corresponding more particularly to the following formula (I ′) have characteristics which are specific to them:
• R2, R3, R4, identical or different represent a hydrogen atom or a hydrocarbon radical, optionally substituted, having from 1 to 40 carbon atoms which can be a saturated or unsaturated, linear or branched acyclic aliphatic radical a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic radical; a saturated or unsaturated, linear or branched aliphatic radical, carrying a cyclic substituent,
• R and R3 can form, together with the carbon atoms which carry them, a saturated or unsaturated cycle
• - R5 represents a branched, saturated or unsaturated aliphatic radical, the characteristic of which is to have a tertiary radical located in the ⁇ position with respect to the phosphorus atom and mention may be made in particular of a tert-butyl radical; a phenyl radical bearing at least one substituent, preferably one or more alkyl or alkoxy radicals having from 1 to 4 carbon atoms or a naphthyl radical, - R4 and R5 cannot simultaneously represent a phenyl group.
• Another object of the invention lies in the process for the preparation of diphosphines of formula (I) characterized in that it consists in reacting:
• R 1 f R 2 and R 3 have the meaning given above, - and an acetylene compound of formula (V):
• R 4 and R 5 have the meaning given above.
• diphosphines of formula (I) are therefore obtained by reaction between a diphosphole of formula (III) and an acetylene compound of formula (V).
• the diphospholes of formula (III) are prepared from diphospholes of formula (IV) according to a rearrangement obtained by heat treatment carried out at a temperature between 100 ° C and 200 ° C, preferably between 130 ° C and 150 ° C .
• diphospholes of formula (IV) preferably used there may be mentioned:
• acetylenic compounds of formula (V) are products which can be obtained according to the methods described in the literature [in particular Journal of the American Chemical Society 25, p. 3080-3081 (1973) and J. Org. Chem SS, p. 3520 et seq. (1971)].
• the amount of acetylene compound of formula (V) expressed in moles of acetylene compound per mole of diphosphole of formula (IV) can also vary within wide limits.
• the molar ratio of acetylene compound of formula (V) / diphosphole of formula (IV) can vary between 1 and 4, preferably between 1 and 1.5.
• reaction is advantageously carried out without solvent.
• an organic, preferably apolar, aprotic solvent when it is desired to dissolve the acetylene compound.
• solvents suitable for the present invention there may be mentioned in particular aliphatic, cycloaliphatic or aromatic hydrocarbons.
• aliphatic or cycloaliphatic hydrocarbons there may be mentioned more particularly paraffins such as in particular, hexane, heptane, octane, nonane, decane, undecane, dodecane, tetradecane or cyclohexane, and aromatic hydrocarbons such as in particular benzene, toluene, xylenes, cumene, petroleum fractions made up of a mixture of alkylbenzenes, in particular cuts of the Solvesso® type.
• the preferred solvents are toluene and xylenes. It is also possible to use a mixture of organic solvents.
• the concentration of diphosphole in the medium is chosen to be as high as possible. It can most often be between 1 and 25 mol per liter of medium and, preferably, between 5 and 10 mol per liter.
• the reaction temperature is as mentioned above, between 100 ° C and 200 ° C, preferably between 130 ° C and 150 ° C.
• reaction is carried out at atmospheric pressure, but higher pressures may also be suitable, ranging from 1 to 50 bar, preferably from 1 to 25 bar.
• pressures may also be suitable, ranging from 1 to 50 bar, preferably from 1 to 25 bar.
• reaction it is preferred to carry out the reaction under a controlled atmosphere of inert gases such as nitrogen or rare gases, for example argon.
• inert gases such as nitrogen or rare gases, for example argon.
• the duration of the reaction can be very variable. It is most often between 15 minutes and 10 hours, preferably between 30 minutes and 5 hours.
• the process can be carried out batchwise or continuously.
• a practical embodiment consists in loading the diphosphole of formula (IV), the acetylene compound of formula (V) preferably, diluted in the organic solvent. The atmosphere of inert gases is established and then heated in a closed atmosphere.
• Ri. R2, R3 have the meanings given above, and Y represents any group, preferably an aromatic carbocylic radical, and more preferably a phenyl radical or an aromatic heterocyclic radical, with an alkali metal, leading to a compound of formula ( VII):
• R ⁇ R, R3, have the meanings given above, and M represents an alkali metal, preferably, lithium or sodium. - dimerizing the compound of formula (VII) into a compound of formula (IV).
• the phosphole of formula (VI) is reacted with an alkali metal which may be sodium or any other alkali metal, but more preferably lithium.
• the metal is generally in excess.
• the ratio between the number of gram atoms of alkali metal and the number of moles of compound of formula (VI) advantageously varies between 2 and 3.
• the compound of formula (VI) and the alkali metal are reacted at a temperature between 10 ° C and 40 ° C, preferably between 10 ° C and 20 ° C.
• the reaction usually lasts between 30 min and 2 h.
• the reaction is advantageously carried out in an organic solvent, preferably an aprotic polar solvent.
• diethyl ether dipropyl ether, diisopropyl ether, dibutyl ether, methyltertiobutyl ether, ether oxide dipentyl, diisopentyl oxide, dimethyl ether of ethylene glycol (or 1,2-dimethoxyethane), dimethyl ether of diethylene glycol (or 1,5-dime
• tetrahydrofuran is preferably used.
• the amount of organic solvent used can vary widely.
• the ratio between the number of moles of solvent and the number of moles of substrate can range from 10 to 40 and it is preferably between 20 and 25.
• a preferred variant consists in trapping the YM compound which has formed.
• a Lewis acid preferably AICI3 and optionally a tertiary alkyl halide, preferably tert-butyl chloride.
• Said reagents are used in an amount equal to or close to the stoichiometric amount.
• the phosphole of formula (VI), the excess alkali metal, can be charged. It is left to react for 30 min to 2 h. The excess metal is removed (solid / liquid separation), then the Lewis acid and / or the tertiary alkyl halide is added, between 0 ° C. and 20 ° C.
• the compound of formula (VII) is dimerized.
• the diiode is used as coupling agent, preferably used in stoichiometric quantity.
• the reaction is generally carried out in the same type of organic solvent as in the previous step.
• the reaction is carried out at room temperature (most often between 15 ° C and 25 ° C).
• the compound of formula (VI) can be obtained by reaction of a diene of formula (VIII) with a dihaloarylphosphine:
• R-j, R2, R3, have the meanings given above.
• dihaloarylphosphines use is generally made of dichlorophenylphosphine, dibromophenylphosphine or their mixtures preferably comprising equimolar amounts of each of the dihalogenophosphines.
• the compound of formula (VIII) and the dihaloarylphosphine used are mixed in stoichiometric or similar quantities. According to a practical embodiment, the diene compound of formula (VIII) is reacted with the dihaloarylphosphine generally dissolved in an appropriate solvent, preferably an aliphatic or aromatic halogenated hydrocarbon.
• dichloromethane 1,2-dichloroethane; monochlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene or mixtures of different chlorobenzenes; monobromobenzene or mixtures of monobromobenzene with one or more dibromobenzenes; 1- bromonaphthalene.
• Dichloromethane is more preferably chosen.
• the concentration of dihaloarylphosphine in the medium can vary within wide limits. Thus it can be between 5 and 20 mol per liter of medium and, preferably, is approximately 10 mol per liter.
• the reaction is advantageously carried out between 0 ° C and 20 ° C, preferably in the absence of air. It lasts from 1 to several days, for example, 15 days.
• the phosphole of formula (VI) results from the elimination of 2 moles of HX per mole of dihaloarylphosphine which is carried out by the presence of an amine, preferably a tertiary amine.
• the amount of amine is generally equal to twice the stoichiometric amount of the dihaloarylphosphine, or even in excess of 2 to 3 times the stoichiometry.
• the reaction is advantageously carried out in a mixture of two organic solvents, one dissolving the phosphole obtained, the other, the amine salts formed, which facilitates subsequent separation.
• solvents suitable for extracting the phosphole obtained there may be mentioned in particular aliphatic, cycloaliphatic or aromatic hydrocarbons.
• solvents suitable for extracting the phosphole obtained there may be mentioned in particular aliphatic, cycloaliphatic or aromatic hydrocarbons.
• solubilization of the amine salts obtained use may be made inter alia of halogenated aliphatic or aromatic hydrocarbons, as mentioned above.
• the preferred pair of solvents is hexane and dichloromethane preferably used, in volume quantities close to or equal.
• the concentration of diphosphole in the medium can vary within wide limits. Thus, it can be between 1 and 5 months per liter of medium and, preferably, between 2 and 3 mol per liter. '
• a mixture of organic solvents as specified above is introduced and a base, preferably an amine.
• the excess amine is neutralized with an acid solution, preferably a solution of mineral acid, such as, for example, hydrochloric acid.
• an acid solution preferably a solution of mineral acid, such as, for example, hydrochloric acid.
• the organic phases are then separated.
• the treatment consists of an extraction with a solvent of the phosphole, washing of the organic phase, generally with water and most often followed by conventional drying on a desiccant, for example sodium or magnesium sulfate.
• Diphosphine dioxides in meso or racemic form are in meso or racemic form.
• Another subject of the invention resides in the dioxides of diphosphines in meso and racemic form as well as their process for obtaining.
• the diastereoisomers can be separated according to a process which consists in subjecting the mixture of diastereoisomers to an oxidation reaction thus transforming them into dioxides of diphosphines, then in separating the dioxides of diphosphines from the two diastereoisomers.
• the diastereoisomers are transformed into the oxide form.
• diphosphine oxides of formula (IX) are obtained by oxidation of the two diastereoisomers of formula dm) and (lr) using an oxidizing agent.
• an oxidizing agent any type of oxidizing agent can be used, a chemical oxidant, for example potassium permanganate or molecular oxygen or a gas containing it, it is preferred to use hydrogen peroxide, preferably in the form of an aqueous solution.
• concentration of the hydrogen peroxide solution is advantageously between 10% and 35% by weight.
• the amount of oxidizing agent used can vary widely from the stoichiometric amount to an excess representing, for example, 20 times the stoichiometry.
• an organic solvent which dissolves all the reactants
• the solvent can be chosen from aliphatic, cycloaliphatic or aromatic, preferably aromatic, hydrocarbons. Examples are given above. Among all these solvents, toluene and xylenes are preferred.
• the concentration of diphosphine in the reaction solvent is preferably between 0.05 and 1 mole / liter and even more particularly between 0.05 and 0.2 mole / liter.
• the diastereoisomers generally dissolved in an appropriate solvent are therefore brought into contact with the oxidizing agent.
• the reaction is advantageously carried out between 50 ° C and 100 ° C.
• the reaction time is generally between 30 min and 4 h.
• the diphosphine oxides are recovered in the organic phase.
• the aqueous and organic phases are separated.
• a conventional phase treatment is carried out.
• the aqueous phase is washed several times (from 1 to 3) with an organic solvent for extracting the diphosphine oxides, for example ethyl ether.
• an organic solvent for extracting the diphosphine oxides for example ethyl ether.
• the solvent is concentrated by evaporation and then the separation is carried out in a known manner [A. Bertheillier - Dunod Paris (1972)] by liquid column chromatography, preferably with a silica support.
• the column is eluted with a mixture of suitable solvents.
• Solvents suitable for separation are determined by simple execution operations for a person skilled in the art which consists in performing chromatography on a silica plate.
• the solvents are generally chosen from ethyl acetate, methanol, ethyl ether or their mixtures.
• diphosphine dioxide in meso form (IXm) and diphosphine dioxide in racemic form (IXr) are recovered in a variable order from the elution solvents.
• Diphosphine disulfides in racemic or meso form are examples of Diphosphine disulfides in racemic or meso form.
• Another subject of the invention resides in diphosphine disulfides in meso and racemic form as well as their process for obtaining.
• the diastereoisomers can be separated according to a process which consists in reacting with sulfur, the mixture of diastereoisomers dm) and (lr), thus transforming them into diphosphine disulfides (IX'm) and (IX ' r), then separating the diphosphine disulfides from the two diastereoisomers.
• the diastereoisomers are transformed into the form of sulphide.
• the quantity of sulfur used defined with respect to each phosphorus atom varies from the stoichiometric quantity to a slight excess of 10%.
• the reaction takes place at a temperature ranging from ambient temperature to approximately 100 ° C., preferably around 80 ° C., in a solvent preferably of the aromatic hydrocarbon type, and in particular toluene.
• the mixture of diastereoisomers is separated on a silica column as previously described.
• diphosphine disulfide is recovered in meso form (IX′m) and the diphosphin disulfide
• Another object of the present invention are the optically active diphosphines of 6,6′-bis- (1-phosphanorbomadiene) corresponding to the following formulas:
• a first variant for obtaining an optically active diphosphine of formula (la) or (Ib) consists in carrying out the doubling of the diphosphine dioxide in racemic form (IXr) then in carrying out separately the reduction of the enantiomers of diphosphine dioxide obtained (IXa) or (IXb).
• Another variant of the invention consists in first performing the reduction of diphosphine dioxide in racemic form (IXr) to diphosphine in racemic form (lr), then in performing the splitting of diphosphine in racemic form (lr) into enantiomers (la) and (Ib).
• Another variant of the invention consists in carrying out the resolution of the racemic mixture of diphosphine disulfides (IX'r) preferably on a chiral column and then in reducing the enantiomers of diphosphine disulfides (IX'a) and (IX'b) enantiomers of disphosphines (la) and (Ib).
• Another variant consists in reducing the racemic mixture of diphosphine disulphides (IX'r) to the racemic mixture of diphosphines (lr) and then performing the splitting of the racemic mixture of diphosphines into enantiomers (la) and (Ib).
• Another variant of the invention is to transform the racemic mixture of diphosphine disulfides (IX'r) into a racemic mixture of diphosphine dioxides (IXr) and then to obtain the optically active diphosphines (la) and (Ib) according to the previously described modes.
• the racemic mixture of dioxides of diphosphines (IXr) is split.
• the resolution can be carried out by separation of the two enantiomers, by chiral liquid chromatography.
• a chiral column is used, for example Chirosebond C1® (chiral graft of polyholoside type on spherical silica 5 ⁇ m - 100 ⁇ ) and the elution solvents can in particular be a water / acetonitrile mixture.
• Another variant consists first of all in carrying out the reduction of the diphosphine dioxide in racemic form and then in carrying out the doubling of the diphosphine in racemic form, obtained.
• the reduction can be carried out with a reducing agent such as, for example, trichlorosilane, hexachlorodisilazane, phenyltrisiiane, a hydride, in particular LiAIH 4 or NaBH 4 .
• a reducing agent such as, for example, trichlorosilane, hexachlorodisilazane, phenyltrisiiane, a hydride, in particular LiAIH 4 or NaBH 4 .
• the amount of reducing agent used can vary widely from the stoichiometric amount to an excess representing, for example, 20 times the stoichiometry.
• a reducing agent which leads to the release of a halogen acid for example trichlorosilane or hexachlorodisilazane
• a base is added, preferably an amine so that it traps the halogen acid (hydrochloric ) released.
• picolines pyridine, 2-ethylpyridine, 4-ethylpyridine, 2-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, imidazole, 1-methylimidazole, TMEDA
• the amount of amine is at least equal to the amount necessary to trap the halogenated acid released and is more often in excess of up to 3 times the stoichiometric amount.
• the reaction is carried out in an organic solvent which dissolves all the reactants.
• the solvent can be chosen from aliphatic, aromatic, halogenated or not. Among all these solvents, toluene and dichloromethane are preferred.
• the concentration of diphosphine in the reaction solvent is preferably between 0.05 and 1 mole / liter and even more particularly between 0.05 and 0.2 mole / liter.
• the racemic compound is added, in the form of oxides, then the reducing agent.
• the reaction is advantageously carried out between 50 ° C and 100 ° C.
• the reaction time is generally between 30 min and 4 h.
• the racemic mixture is in the organic phase.
• a base is then added, preferably sodium hydroxide, potassium hydroxide or sodium carbonate, until a basic pH is obtained (pH of at least 8).
• a basic aqueous solution preferably a sodium hydroxide solution having a concentration of 10% to 30%.
• the enantiomers of diphosphines are recovered in the organic phase which is subjected to the conventional treatment described above, solvent extraction, washing with brine and optionally drying.
• the racemic mixture of 6,6'-bis- (1-phosphanorbomadiene) is split in accordance with a process which consists in reacting it with a palladium and / or platinum complex as an auxiliary chiral, in an organic solvent thus forming diastereoisomeric complexes, then in splitting said optically pure complexes.
• - M represents palladium and / or platinum
• , R2, R3 and R4 represent a hydrogen atom or an alkyl radical having from 1 to 10 carbon atoms or a cycloalkyl radical having from 3 to 10 carbon atoms
• R3 and R4 are different and at least one of the two represents a hydrogen atom
• - X represents a halogen atom
• - n is a number from 0 to 4,
• the complex used corresponds to the above formula in which R-j, R2.
• R3 and R4 represent a hydrogen atom or a methyl radical
• X represents a chlorine atom and n is equal to 0.
• the amount of complex of the aforementioned metals expressed in metal is generally from 0.5 to 1 atom of metal per atom of phosphorus.
• An organic solvent is used which solubilizes all the reactants.
• the solvent must be inert towards diphosphine.
• solvents suitable for the process of the invention mention may be made of aliphatic or aromatic hydrocarbons, halogenated or not, as mentioned above.
• benzene and toluene are preferred.
• the concentration of diphosphine in the reaction solvent is preferably between 0.05 and 1 mole / liter and even more particularly between 0.05 and 0.2 mole / liter.
• the separation is advantageously carried out at room temperature generally between 15 ° C and 25 ° C. It preferably takes place under a controlled atmosphere of inert gases.
• inert gases One can establish an atmosphere of rare gases, preferably argon, but it is more economical to use nitrogen.
• Another object of the invention is are the intermediate products, namely the metal complexes with the diphosphines.
• complexes of two forms are obtained either corresponding to the formulas (Xlla) and (Xllb), or to the formulas (Xllla) and (Xlllb):
• the column is eluted with a mixture of suitable solvents.
• the solvent or a mixture of solvents is chosen in a conventional manner by a person skilled in the art.
• solvents generally use is made of ethyl acetate, methanol, hexane, cylclohexane, dichloromethane. The examples illustrate the use of a mixture of solvents.
• the two enantiomers of the diphosphines are recovered by carrying out the decomplexation.
• hydrocyanic acid salt preferably an alkaline salt and even more preferably sodium: the said salt being dissolved in the minimum amount of water required.
• the complexes are solubilized in an organic solvent such as, for example, dichloromethane, then the salt of hydrocyanic acid used generally in excess representing 2 to 5 mol per metal atom, with stirring.
• organic solvent such as, for example, dichloromethane
• the operation is also carried out under a controlled atmosphere and at room temperature.
• the enantiomer is recovered in the organic phase which is separated, washed with water and dried, for example over sodium sulfate.
• the racemic mixture of diphosphine disulfides (IX'r) is split on a chiral column allowing the optically active diphosphine disulfides (IX'a) and (IX ') to be obtained. b), then they are reduced to disphosphines thus leading to the optically active diphosphines (la) and (Ib).
• diphosphine disulfides is carried out by reaction with a phosphorous reagent of PBu 3 or P (CH 2 CH 2 CN) 3 type: the reaction being carried out in an organic solvent medium, for example an aromatic hydrocarbon, preferably toluene.
• a phosphorous reagent of PBu 3 or P (CH 2 CH 2 CN) 3 type the reaction being carried out in an organic solvent medium, for example an aromatic hydrocarbon, preferably toluene.
• the reaction is generally carried out at the reflux temperature of the reaction solvent.
• Another variant consists in reducing the racemic mixture of diphosphine disulfides (IX'r) into a racemic mixture of diphosphines (lr) and then in performing the splitting of the racemic mixture of diphosphines into optically active phosphines (la) and (Ib).
• the reduction of the racemic mixture of diphosphine disulfides is carried out as specified for optically active diphosphine disulfides.
• another variant of the invention consists in transforming the racemic mixture of diphosphine disulfides (IX'r) into a racemic mixture of diphosphine dioxides (IXr) and then in obtaining the optically active diphosphines (la) and (Ib) according to the routes mentioned above. It is possible to convert the diphosphine disulfides into diphosphine dioxides by any suitable means, in particular by reaction of the diphosphine disulfides with cyclohexene oxide, in trifluoroacetic acid and in an organic solvent medium, in particular in a halogenated aliphatic hydrocarbon, preferably methylene chloride.
• the racemic mixture (IXr) is obtained which is treated as previously mentioned.
• optically active diphosphines according to the present invention are of particular interest in organic chemistry, in asymmetric synthesis methods.
• optically active diphosphines according to the invention can be used for the preparation of metal complexes, allowing asymmetric hydrogenation of unsaturated derivatives or allylic substitution (Tsuji-Trost type reaction). More particularly, they can be used to carry out asymmetric hydrogenation reactions.
• optically active diphosphines according to the invention can be used for the preparation of metal complexes, allowing the asymmetric hydrogenation of ⁇ , ⁇ -unsaturated and / or derived carboxylic acids.
• optically active diphosphines of formula (la) or (Ib) serve as ligands in the formation of complex ligands with transition metals.
• An object of the invention is therefore new complexes comprising an optically active diphosphine and a transition metal which are characterized by the fact that the ligand corresponds to one of the following formulas (la) or (Ib).
• transition metals capable of forming complexes mention may in particular be made of metals such as rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum, palladium.
• metals such as rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum, palladium.
• rhodium, ruthenium and iridium are preferred.
• (P * P) represents the diphosphine of formula (la) or (Ib).
• the rhodium and iridium complexes can be represented by the following formulas:
• - M represents rhodium or iridium
• - Y represents an coordinating anionic ligand
• - L represents a neutral ligand
• the preferred rhodium or iridium complexes correspond to the formula (XlVa) or (XlVb) in which:
• L represents an olefin having 2 to 12 carbon atoms and two L ligands can be linked together to form a polyunsaturated, linear or cyclic hydrocarbon chain; L preferably representing 1,5-cyclooctadiene, norbornadiene, ethylene,
• - Y represents an anion PF 6 -, PCI 6 -, BF 4 -, BCI 4 -, SbF 6 ", SbCI 6 -, BPh 4 " , CIO 4 -, CN _ , CF3SO3 ", preferably halogen, CI " or Br, a 1,3-diketonate anion, alkylcarboxylate, haloalkylcarboxylate with a lower alkyl radical, a phenylcarboxylate or phenolate anion in which the benzenic ring can be substituted by lower alkyl radicals and / or halogen atoms.
• lower alkyl radicals is generally meant a linear or branched alkyl radical having from 1 to 4 carbon atoms.
• iridium complexes can be represented by the formulas:
• Y 2 identical or different, preferably represent a PFg-, PCI 6 -, BF 4 -, BCI 4 -, SbF 6 " , SbCI 6 -, BPh 4 " , CIO 4 -, CF 3 SO anion 3 -, a halogen atom, more particularly, chlorine or bromine or a carboxylate anion, preferably acetate, trifluoroacetate.
• Ar represents benzene, p-methylisopropylbenzene, hexamethylbenzene,
• Yi represents a halogen atom, preferably chlorine or bromine
• - Y2 preferably represents an anion, a PFg “, PCIg “ , BF “ , BCI 4 ", SbFg “ , SbCl “ , BPh 4 “ , CIO 4 “ , CF3SO3- anion.
• They can be prepared in particular by reaction of the diphosphine of formula (la) or (Ib) with the transition metal compound, in a suitable organic solvent.
• the reaction is carried out at a temperature between room temperature (15 to 25 ° C) and the reflux temperature of the reaction solvent.
• organic solvents there may be mentioned, inter alia, aliphatic hydrocarbons, halogenated or not and more particularly, hexane, heptane, isooctane, decane, benzene, toluene, methylene chloride, chloroform; solvents of ether or ketone type and in particular diethyl ether, tetrahydrofuran, acetone, methyl ethyl ketone; alcohol type solvents, preferably methanol or ethanol.
• aliphatic hydrocarbons halogenated or not and more particularly, hexane, heptane, isooctane, decane, benzene, toluene, methylene chloride, chloroform
• alcohol type solvents preferably methanol or ethanol
• the metal complexes according to the invention recovered according to conventional techniques (filtration or crystallization) are used in asymmetric hydrogenation reactions of substrates specified below.
• Another object of the present invention is to provide a process for the preparation of an optically active carboxylic and / or derivative acid, which process is characterized in that the asymmetric hydrogenation of an ⁇ carboxylic acid is carried out, ⁇ -unsaturated and / or its derivatives in the presence of an effective amount of a metal complex comprising, as ligand, the optically active diphosphine of formula (la) or (Ib) and a transition metal.
• R 1 f R 2 , R3 and R 4 represent a hydrogen atom or any hydrocarbon group, insofar as:
• R 3 can be any hydrocarbon or functional group designated by. . if R ⁇ or R represents a hydrogen atom and if R 1 is different from R2, then R 3 is different from a hydrogen atom and different from -COOR,. if R] is identical to R2 and represents any hydrocarbon or functional group designated by then R3 is different from -CH - ( ⁇ .) 2 and different from -COOR 4 ,
• one of the groups R f R2 and R3 can represent a functional group.
• the radicals R-j to R4 which are identical or different represent an optionally substituted hydrocarbon radical having from 1 to 20 carbon atoms which can be a saturated or unsaturated, linear or branched acyclic aliphatic radical; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic radical; a saturated or unsaturated, linear or branched aliphatic radical, carrying a cyclic substituent.
• R- in R4, identical or different can take various meanings. Various examples are given below, but they are in no way limiting.
• radicals R-j to R4 preferably represent an aromatic hydrocarbon radical, and in particular benzenic radical corresponding to the general formula (XVIII):
• - n is an integer from 0 to 5, preferably from 0 to 3,
• R Q represents R Q , one of the following groups or functions:
• an alkyl radical linear or branched, having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
• a linear or branched alkenyl radical having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyl,
• a linear or branched alkoxy radical having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy radicals,
• R5 represents a valence bond or a divalent, linear or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, propylene, isopropylene, isopropylidene
• R7 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms
• X symbolizes a halogen atom, preferably a chlorine, bromine or fluorine atom.
• R Q represents a value link; a divalent, linear or branched, saturated or unsaturated hydrocarbon group having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, propylene, isopropylene, isopropylidene or one of the following groups called Z: -O-; -CO-; -COO-; -NR 7 -; -CO-NR r ; -S-; -S0 2 -; -NR 7 -
• R 7 represents a hydrogen atom, a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably a methyl or ethyl radical.
• the radicals Q can be identical or different and 2 successive carbon atoms of the benzenic cycle can be linked together by a ketal bridge such as the extranuclear methylene dioxy or ethylene dioxy radicals.
• n is equal to 0, 1, 2 or 3.
• Rj to R4 very preferably in the process of the invention, the carboxylic acids or derivatives corresponding to the general formula (XVII) are used.
• Rj to R4 represent an aromatic radical corresponding to the general formula (XVIII) in which:
• - n is equal to 0, 1, 2 or 3,
• - Q represents one of the following groups or functions:. a hydrogen atom,
• a halogen atom . a CF3 group.
• the compounds of formula (XVII) are chosen in which the identical or different radicals Q are a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, a methoxy radical, a benzoyl group, a group NO2.
• to R4 corresponding to the formula (XVII)
• the phenyl, tolyl or xylyl radicals 1-methoxyphenyl, 2-nitrophenyl and the biphenyl, 1,1'-methylenebiphenyl, 1,1'-isopropylidenebiphenyl radicals, 1 , 1'-carboxybiphenyl, 1,1'-oxybiphenyl, 1,1'-iminobiphenyl: the said radicals being able to be substituted by one or more radicals Q as defined above.
• Rj to R4 can also represent a polycyclic aromatic hydrocarbon radical; the cycles being able to form between them ortho-condensed, ortho- and peri-condensed systems. Mention may more particularly be made of a naphthalene radical; said rings being able to be substituted by 1 to 4 radicals R Q , preferably 1 to 3, R Q having the meanings stated previously for the substituents of the aromatic hydrocarbon radical of general formula (XVIII).
• R 1 to R 4 may also represent a carbocyclic radical saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 7 carbon atoms, preferably 6 carbon atoms in the cycle; said cycle possibly being substituted by 1 to 5 radicals R Q , preferably 1 to 3, R Q having the meanings previously stated for the substituents of the aromatic hydrocarbon radical of general formula (XVIII).
• radicals R-j to R4 mention may be made of cyclohexyl or cyclohexene-yl radicals, optionally substituted by linear or branched alkyl radicals, having from 1 to 4 carbon atoms.
• R-j to R4 can represent an acyclic aliphatic, saturated or unsaturated, linear or branched radieal.
• R 1 to R 4 represent a linear or branched acyclic aliphatic radical preferably having from 1 to 12 carbon atoms, saturated or comprising one to several unsaturations on the chain, generally, 1 to 3 unsaturations which may be single double bonds or conjugates or triple bonds.
• the hydrocarbon chain can optionally be:
• R represents a hydrogen atom, a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably a methyl or ethyl radical,
• R-j to R4 represent an acyclic aliphatic radical, saturated or unsaturated, linear or branched which can optionally carry a cyclic substituent.
• cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.
• the acyclic aliphatic radical can be linked to the ring by a valential bond or by one of the abovementioned Z groups.
• cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of 1, 2, 3, 4 or 5 radicals R Q , identical or different, R Q having the meanings stated above for the substituents of the aromatic hydrocarbon radical of general formula (XVIII).
• R 1 to R 4 may also represent a heterocyclic radical, saturated or not, comprising in particular 5 or 6 atoms in the ring including 1 or 2 hetero atoms such as the nitrogen, sulfur and oxygen; the carbon atoms of the heterocycle possibly being substituted, in their entirety or for a part of them only by radicals R Q , R Q having the meanings stated above for the substituents of the aromatic hydrocarbon radical of general formula (XVIII ).
• Rj to R4 can also represent a heterocyclic polycyclic radical defined as being either a radical consisting of at least 2 aromatic heterocyclic rings or not containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems or either a radical consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems; the carbon atoms of said rings possibly being substituted, in their entirety or for a part of them only by radicals R Q , R Q having the meanings stated above for the substituents of the aromatic hydrocarbon radical of general formula (XVIII).
• groups R 1 to R 4 of heterocyclic type there may be mentioned, among others, the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl and quinolyl radicals, naphthyridinyl, benzopyrannyl, benzofurannyl, indolyl.
• R ⁇ to R3 represents a functional group and mention may in particular be made of functional groups of the NRgR'g type in which R9, 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, a benzyl group or an acyl group having preferably from 2 to 12 carbon atoms, an acetyl group or benzoyl.
• a first class of substrates to which the process of the invention is more preferably applied are substituted acrylic acids which are precursors of amino acids and / or derivatives.
• substituted acrylic acids is meant all of the compounds whose formula derives from that of acrylic acid and by substituting 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 as follows:
• 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,
• R ⁇ 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, an aryl radical having from 6 to 12 carbon atoms, a heterocyclic radical having 4 to 7 carbon atoms,
• R-J O represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms.
• an alkyl group such as methyl, ethyl, isopropyl, isobutyl; a cycloalkyl group such as cyclopentyl, cyclohexyl; an aromatic group such as phenyl, naphthyl or a heterocyclic group such as furyl, pyrannyl, benzopyrannyl, pyrrolyl, pyridyl, indolyl.
• the R-jo group is preferably a hydrogen atom.
• substituted acrylic acids which are precursors of amino acids, there may be mentioned N-acetyl ⁇ -amino ⁇ -phenylacrylic acid, N-benzoyl ⁇ -amino ⁇ -phenylacrylic acid, in which the phenyl nucleus is optionally substituted with a or more alkyl, alkyloxy or hydroxy groups, N-acetyl ⁇ -amino ⁇ -indolylacrylic acid, N-benzoyl ⁇ -amino ⁇ -indolylacrylic acid, N-acetyl ⁇ -amino ⁇ -isobutyl acrylic acid.
• R 12 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, an 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, - Rio- '10 > identical or different represent a hydrogen atom or a linear alkyl group or branched, having from 1 to 4 carbon atoms.
• the preferred substrates correspond to the formula (XVIIb) in which Rj -j, Rj 2, identical or different, represent a hydrogen atom, an alkyl group having from 1 to 4 atoms carbon and RJ Q, R'-J O- identical or different represent a hydrogen atom or a methyl group.
• R-J O represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms,
• R-j 3 represents a phenyl or naphthyl group, optionally carrying a substituent or more substituents R:
• RQ can represent RQ, one of the following groups: a linear or branched alkyl or alkenyl group having from 1 to 12 carbon atoms, preferably a linear or branched alkyl group having from 1 to 4 carbon atoms,
• a linear or branched alkoxy group having from 1 to 12 carbon atoms preferably a linear or branched alkoxy group having from 1 to 4 carbon atoms
• acyloxy group having 2 to 8 carbon atoms, preferably an acetoxy group
• acylamido group having from 1 to 8 carbon atoms, preferably an acetamido group
• R 0 - R can represent R 0 ', one of the following more complex groups:. a formula group
• - RQ represents a value link; a divalent, linear or branched, saturated or unsaturated hydrocarbon group having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, propylene, isopropylene, isopropylidene or one of the following groups called Z: -0-; -CO-; -COO-; -NR 7 -; -CO-NR7-; -S-; -SO2-; -NR7-CO-; in said formulas R7 represents a hydrogen atom, a linear or branched alkyl group having from 1 to 6 carbon atoms,
• - m is an integer from 0 to 4.
• the selective asymmetric hydrogenation of said substrates is carried out using as catalysts the metal complexes of the invention liganded by the optically active diphosphines of general formula (la) or (Ib).
• diphosphine-transition metal When the complexes of the invention diphosphine-transition metal are used as a catalyst for asymmetric hydrogenation of unsaturated carboxylic acids, the desired product can be obtained with a high optical yield.
• the unsaturated carboxylic acid is hydrogenated into a compound having the desired absolute configuration, with a high optical yield.
• the hydrogenation is generally carried out at a temperature between
• the hydrogen pressure can be between 0.1 and 200 bar, and more preferably between 1 and 150 bar.
• the diphosphine / transition metal complex is used in such a way that the ratio between the number of metal atoms present in the complex and the number of moles of the compound to be hydrogenated is between 0.1 and 0.0001.
• the hydrogenation process is preferably carried out in an organic solvent. Any solvent is used insofar as it is stable under the reaction conditions.
• Use is preferably made of a polar organic solvent and more particularly of the following solvents: - aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyitertiobutyl ether, ditertiobutyl ether , ethylene glycol dimethyl ether, diethylene glycol dimethyl ether; diphenyl ether, dibenzyl ether, anisole, phenetole, 1,4-dimethoxybenzene, veratrole; 1, 4-dioxane, tetrahydrofuran O ⁇ F),
• aliphatic monoalcohols such as methanol, ethanol, propanol, butanol, sec-butanol, tert-butanol, pentanol, hexanol
• aliphatic dialcohols such as ethylene glycol, diethylene glycol, propylene glycol
• cycloaliphatic alcohols such as cyclopentanol, cyclohexanol
• - aliphatic ketones such as acetone, methyl ethyl ketone, diethyl ketone,
• Aliphatic esters such as in particular methyl acetate, ethyl acetate, propyl acetate.
• concentration of the substrate in the organic solvent advantageously varies between 0.01 and 1 mol / l.
• This basic compound may be an alkaline base such as sodium or potassium hydroxide or else a primary, secondary or tertiary amine, and more particularly, pyridine, piperidine, triethylamine and preferably triethylamine.
• the amount of base added is such that the ratio between the number of moles of base and the number of metal atoms present in the diphosphine / transition metal complex is between 0 and 25, preferably between 0 and 12. We gives below a preferred embodiment of the process of the invention.
• Said process is carried out in an autoclave which is purged using an inert gas, preferably nitrogen.
• the substrate is preferably loaded in solution in organic solvent, then the catalyst also in solution in organic solvent.
• Nitrogen is replaced by hydrogen.
• the hydrogenation is complete when the hydrogen pressure becomes stable.
• the hydrogenation process according to the invention allows access to the different enantiomers of many derivatives.
• the implementation of the new diphosphines of the invention makes it possible to obtain the improvement of the enantiomeric excess in certain reactions of asymmetric catalysis, in particular in the reactions of allylic substitution [M. YAMAGUSI et al, Tetrahedron Letters 21, p. 5049 (1990) and [M. MAYASHI et al, Tetrahedron Letters 27, p. 191 (1986)].
• esters preferably 1,3-diphenyl-3-acetoxypropene
• malonic acid preferably malonate dimethyl or diethyl
• the reaction is carried out in the presence of a complex comprising an optically active diphosphine and palladium: the ligand corresponding to one of the following formulas (la) or (Ib).
• the palladium precursor preferably chosen corresponds to the formula
• the reaction is preferably carried out in a polar aprotic solvent, in particular an aliphatic or aromatic halogenated hydrocarbon or a solvent of nitrile type, preferably acetonitrile, an aliphatic, cycloaliphatic or aromatic ether oxide and, more particularly, the diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyertertiobutyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2- dimethoxyethane), dimethyl ether of diethylene glycol (or 1,5-dimethoxy 3-oxapentane); benzyl oxide; dioxane, tetrahydrofuran (THF).
• a polar aprotic solvent in particular an aliphatic or aromatic halogenated hydrocarbon or a solvent of nitrile type, preferably acetonitrile, an ali
• tetrahydrofuran is preferably used.
• the amount of organic solvent used can vary widely.
• the ratio between the number of moles of solvent and the number of moles of substrate can range from 10 to 40 and it is preferably between 20 and 25.
• the molar ratio of the ester of malonic acid / unsaturated substrate generally varies between 1 and 5, preferably between 1 and 3.
• the ester of malonic acid which is reacted can be in the form of an anion.
• a nucleophile preferably sodium hydride.
• the hydride is used in an amount ranging from the stoichiometric amount to an excess, for example of 20%.
• the reaction is advantageously carried out at low temperature, preferably between -10 ° C and 10 ° C, preferably around 0 ° C.
• the anion of the malonic ester is first formed by reaction of the latter with sodium hydride, then the substrate and the catalyst obtained beforehand by reaction of the salt are added.
• palladium and ligand in an organic solvent, preferably tetrahydrofuran.
• the reaction is advantageously carried out at ambient temperature, that is to say at a temperature generally ranging from 15 ° C. to 25 ° C.
• the coupling product is obtained in the allylic position.
• Examples 5, 7 and 8 relate to the preparation of catalysts which are used in application examples 6, 9 and 10.
• a diphosphine is prepared corresponding to the following formula:
• the 1,1'-bis- (3,4-dimethylphosphole) is extracted under nitrogen from the medium, using hexane.
• the residue is then purified by chromatography on a silica column (elution with hexane to remove the excess methylphenylacetylene then with a hexane / dichloromethane mixture: 80/20 by volume).
• the overall yield is 30%.
• the two diastereoisomers are separated by chromatography on a silica column by elution with ethyl acetate and then with an ethyl acetate / methanol mixture (90/10 by volume).
• trichlorosilane is neutralized with an aqueous sodium hydroxide solution at 30% by weight, then the aqueous phase is extracted three times with ether, the organic phases are combined and then washed with a saturated solution of sodium chloride.
• the organic phase is dried over magnesium sulfate, and evaporated under reduced pressure.
• the phosphine (lr) thus obtained is purified on a column of deactivated silica gel (elution dichloromethane).
• the overall reduction yield is 95%.
• a diphosphine is prepared corresponding to the following formula:
• the spectrum is composed of 2 singlets corresponding to the two diastereoisomers.
• the mixture Im + lr previously obtained is dissolved in 50 ml of toluene and oxidized with 10 ml of a hydrogen peroxide solution at 30% by weight of hydrogen peroxide, introduced in excess. The mixture is then heated to 70 ° C with mechanical stirring for 30 min.
• the two diastereoisomers are separated by chromatography on a silica column by elution with ethyl acetate and then with an ethyl acetate / methanol mixture (90/10 by volume).
• the organic phase is dried over magnesium sulfate, and evaporated under reduced pressure.
• the phosphine (lr) thus obtained is purified on a column of deactivated silica gel (elution dichloromethane).
• the diphosphine (la) is then extracted with dichloromethane.
• the organic phase is washed with water and then dried over sodium sulfate.
• Example 3 In this example, a diphosphine is prepared corresponding to the following formula:
• the mixture (Im) + (lr) previously obtained is dissolved in 50 ml of toluene and oxidized with 4.5 g of a hydrogen peroxide solution at 30% by weight of hydrogen peroxide, introduced in excess. The mixture is then heated to 70 ° C with mechanical stirring for 3 h.
• the two diastereoisomers are separated by chromatography on a silica column by elution with ethyl acetate and then with an ethyl acetate / methanol mixture (95/05 by volume).
• the overall yield (IXm) + (IXr) is 100%.
• the overall reduction yield is 89%.
• the diphosphine is then extracted with dichloromethane.
• the organic phase is washed with water and then dried over sodium sulfate.
• the overall efficiency of the decomplexation is 85%.
• Example 4 In this example, a diphosphine is prepared corresponding to the following formula:
• the mixture dm) + (lr) previously obtained is dissolved in 50 ml of toluene and oxidized with 4.6 g of a hydrogen peroxide solution at 30% by weight of hydrogen peroxide, introduced in excess. The mixture is then heated to 70 ° C with mechanical stirring for 3 h.
• the overall reduction yield is 90%.
• a decomplexation is carried out with sodium cyanide, in dichloromethane, as previously described.
• the diphosphine is then extracted with dichloromethane.
• the organic phase is washed with water and then dried over sodium sulfate.
• the overall efficiency of the decomplexation is 85%.
• Example 5 In this example, the preparation of a complex of formula is described.
• the acetone is evaporated and the residue is dissolved in 5 ml of methanol.
• the 2 solutions are then introduced into an autoclave previously purged and maintained under a nitrogen atmosphere.
• the excess hydrogen is emptied and the reaction solution is recovered.
• the solvent is evaporated and the residue analyzed by NMR " ⁇ to check the progress of the reaction.
• the reaction is quantitative.
• the enantiomeric excess is determined by chiral high performance liquid chromatography (chiral column HSA protein 150 x 6.4 mm Shandon®) and the absolute configuration of the product by measurement of VCLQ, by polarimetry.
• the medium is heated to the reflux temperature of the solvent.
• reaction medium is hydrolyzed with 4 ml of acetic acid and then extracted with ether.
• the organic phase is washed with water, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure of 25 mm of mercury.
• the diphosphine of Example 1 is prepared according to the same procedure, with the difference that the meso and d / 1 diastereoisomers are separated according to a sulphide and then oxide route.

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