EP1305324A1

EP1305324A1 - Use of chiral diphosphines as optically active ligands

Info

Publication number: EP1305324A1
Application number: EP01960868A
Authority: EP
Inventors: Michel Bulliard; Blandine Laboue; Sonia Roussiasse
Original assignee: PPG Sipsy SAS
Current assignee: Zach System SA
Priority date: 2000-08-03
Filing date: 2001-08-03
Publication date: 2003-05-02
Also published as: BR0112970A; US20030195369A1; IL154263A0; AU2001282264A1; US6794525B2; WO2002012253A1; FR2812638B1; CA2417836A1; FR2812638A1; JP2004505985A; CN1468248A

Abstract

The invention concerns the use of chiral diphosphines as optically active ligands for preparing diphosphino-metal complexes. The invention also concerns diphosphino-metal complexes comprising a chiral diphosphine as ligands and asymmetrical catalysis methods using said complexes. More particularly, the invention concerns the use of said diphosphino-metal complexes in asymmetrical hydrogenation or isomerization processes for the synthesis of organic products with desired chirality.

Description

USE OF CHIRAL DIPHOSPHINES AS OPTICALLY ACTIVE LIGANDS

The subject of the present invention is the use of irid diphosphines as optically active ligands for the preparation of diphosphino-metallic complexes. The invention also relates to diphosphino-metallic complexes comprising a chiral disphophin as a ligand and the asymmetric catalysis methods using these complexes. The invention more particularly contemplates the use of these diphosphino-metallic complexes in asymmetric hydrogenation or isomerization processes for the synthesis of organic products with desired chirality.

We know in the prior art, various ligands used for the synthesis of diphosphino-metallic complexes, having catalytic properties in asymmetric hydrogenation. We can cite for example the compound BINAP described by the company Ta asago in European patent applications No. 444 930, No. 295 109, the compound MeOBIPHEP described by the company Hoffmann-La-Roche in European patent applications No. 398132 and PCT No.

WO93 / 15090.

The Applicant has now designed new diphosphino-metallic complexes comprising a chiral disphophine as an optically active ligand which are particularly useful for the synthesis of organic products with desired chirality with very high yields and enantioselectivity. The subject of the invention is therefore the use of a chiral diphosphine (R) or (S) of formula (I):

in which :

R and Ri, identical or different, represent a C ₁ _ ₁₀ alkyl group, saturated or unsaturated, a C ₃ cycloalkyl group. ₉ saturated or unsaturated, a C ₅ _ ₁₀ aryl group, said groups being optionally substituted by a halogen, a hydroxy, a C _x ₅ alkoxy, an amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said alkyl, cycloalkyl or aryl groups possibly comprising one or more heteroatoms such as 0, N, S, Si, or also R and Ri, together , represent a substituted or unsaturated C ₂ _ ₆ alkyl group, a saturated or unsaturated C ₃ _ ₉ cycloalkyl group, a C ₅ _ ₁₀ aryl group, said cycloalkyl or aryl groups being optionally substituted by a C _ alkyl ₅ , halogen, hydroxy, C _x ₅ alkoxy, amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , sulfino, sulfonyl, with R ₄ representing an alkyl, an alkoxy or a alkylcarbonyl, said alkyl, cycloalkyl or aryl groups optionally comprise one or more heteroatom e such that 0, N, S, Si;

R2 and R3, identical or different, represent a C ₃ cycloalkyl group. ₈ saturated or no, an aryl eh C ₆ _ ₁₀ , said groups being optionally substituted by a halogen, a hydroxy, a C ₁ _ ₅ alkoxy, an amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said cycloalkyl or aryl groups optionally comprising one or more heteroatoms such as 0, N, S, Si, or also, R2 and R3 together form a carbocycle group at C ₄ _ ₈ saturated or not, a C ₅ _ ₁₀ aryl group, said groups being optionally substituted by a halogen, a hydroxy, a C _x ₅ alkoxy, an amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said carbocycle or aryl groups optionally comprising one or more heteroatoms such as 0, N, S, Si; as an optically active ligand for the preparation of a diphosphino-metallic complex.

The chiral diphosphines of formula (I) can be used according to the invention for the preparation of several types of diphosphino-metallic complexes.

A first group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (II):

M _x E _y K _z () ₂ (Sv) _p (II) in which, M represents a metal such as ruthenium, rhodium or irridium;

X represents a halogen such as chlorine, bromine, fluorine or iodine; Sv represents a tertiary amine, a ketone, an ether;

L represents a chiral diphosphine (R) or (S), of formula (I) above; y is an integer, 0 or 1; x is an integer, equal to 1 or 2; z is an integer, equal to 1 or 4; p is an integer, equal to 0 or 1.

Among the diphosphino-metallic complexes of formula (II), the invention more particularly contemplates the complexes of formulas (IIA) and (IIB).

The complexes of formula (IIA) are those where y = 0 and then x = 2, z = 4 and p = l, these complexes correspond to the following formula (IIA): M ₂ X ₄ L ₂ (Sv) (IIA) in which M, X, L and Sv have the same meaning as in formula (II).

As examples of complexes of formula (IIA), there may be mentioned: - Ru ₄ Cl ₂ [(R) or (S) CH ₃ C00-Binap] ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) - 6, 6' - diacé t oxybiphenyl] -tetrachloro diruthenium triethy lamine,

- Ru ₄ Cl ₂ ((Me) ₂ CHCOO-Binap) ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) -6,6'-di- is obutanoyl oxybiphenyl] -tetrachloro diruthenium triethylamine,

- Ru ₄ Cl ₂ ((CH ₃ ) ₃ CCOO-Binap) ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) -6,6'- ditrimethylacetoxybiphenyl] -tetrachloro diruthenium triethylamine,

- Ru ₄ Cl ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Cl ₂ (CH ₃ COO-Binap) ₂ . C0 (Me) ₂ ,

- Ru ₄ Br ₂ (CH ₃ COO-Binap) ₂ . N (And) ₃ , - Ru ₄ Br ₂ ((Me) ₂ CHCOO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ ((CH ₃ ) ₃ CCOO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ (CH ₃ COO-Binap) ₂ . CO (Me) ₂ , - Ru ₄ Br ₂ ((Me) ₂ CHCOO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ ((CH ₃ ) ₃ CCOO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ (C ₆ H ₅ COO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ (C _s H ₁₁ COO-Binap) ₂ - CO (Me) ₂ , - Ru ₄ Br ₂ (C ₄ H ₃ OCOO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ (CH ₃ OCH ₂ COO-Binap) ₂ . CO (Me) ₂ .

The compounds of formula (IIB) are those where y = l then x = l, z = l and p = 0, these complexes correspond to the following formula (IIB): MHXL ₂ (IIB) in which M, X and L have the same meaning as in formula (II) and H represents a hydrogen atom.

A second group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (III):

MX _d (Ar) _m LY _n (III) in which, M, X, L have the same meaning as in formula (II);

Ar represents an olefin such as ethylene, 1, 3-butadiene, cyclohexadiene, norbonadiene, cycloocta-1, 5-diene, a pi-allyl, a nitrile such as acetonitrile, an arene of formula ( IV):

where R5, R6, R7, R8, R9 and RIO, identical or different, are chosen from a hydrogen atom, a ¹ alkyl group in ₁ _ ₅ , an isoalkyl group, a tertioalkyl group ^, an alkoxy group, said groups comprising one or more heteroatoms such as 0, N and Si;

Y represents an anion, such as C10 ₄ ^" , BF ₄ ^" , PF ₆ ^" ; j is an integer equal to 0 or 1; m is an integer equal to 1.2 or 4; n is an integer equal to 1 or 2.

A third group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (V):

[MX (P (R ₁₁ ) ₂ (R ₁₂ )) L] ₂ X (V) in which

M, X and L have the same definitions as in formula (II), and R _1X and R ₁₂ , identical or different, represent a phenyl or a phenyl substituted by an alkyl, an alkoxy or a dialkylamino.

A fourth group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (VI):

M (L) Z ₂ (VI) in which,

M and L have the same meaning as in formula (II) and Z represents an acetate group of formula R ₁₃ C00 ^~ , diacetate of formula ^" OOCR ₁₃ COO ^" , an aminoacetate of formula R ₁₃ CH (NH ₂ ) C00 ^~ , wherein R ₁₃ represents a C _x _ ₄ haloalkyl C _x _ _4, a phenyl substituted or not. A fifth group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (VII):

[M (L) WX _k ] _n Z ' _p (VII) in which:

M, L and X have the same meaning as in formula (II); W represents zinc, aluminum, titanium or tin;

Z 'represents:

- Or an acetate group of formula R ₁₄ C00 ^" where R ₁₄ represents a C ₁ ^ alkyl, a C ₁ _ ₄ haloalkyl, a substituted or unsubstituted phenyl, and in this case n = 1 and p = 2, and when W is Zn then k = 2, when W is Al then k = -3, and when W is Ti or Sn then k = 4, or a tertiary amine, such as triethylamine, and in this case n = 2 and p = l, and when W is Zn then k = 4, when W is Al then k = -5 and when W is Ti or Sn then k -6.

A sixth group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (VIII):

MH (L) ₂ Y (VIII) in which the H expresses a atom of hydrogen, M and L have the same meaning as in formula (II);

Y represents an anion, such as C10 ₄ ^_ , BF ₄ ^" , PF ₆ ^~ .

A seventh group of diphosphino-metallic complexes prepared using chiral diphosphines of formula (I) according to the invention corresponds to the following formula (IX):

M (L) Y ₂ (IX) in which M and L have the same meaning as in formula (II) and Y represents an anion, such that

CIO BP_ PF,

An eighth group of diphosphino-metallic complexes prepared using the chiral diphosphines of formula (I) according to the invention corresponds to the following formula (X):

M (L) ₂ Y (X) in which M and L have the same meaning as in formula (II) and Y represents an anion, such as C10 ₄ -, BF ₄ ^" , PF ₆ ^~ .

The chiral diphosphines (R) or (S) of formula (I) can be prepared by methods well known to those skilled in the art from compounds of formula (XI):

in which, R2 and R3 have the same meanings as in formula (I).

These methods consist in bringing together a compound of formula (XI) and a compound derived from an acid halide of formula RCOX or R1COX, where R and Ri have the same meaning as in formula (I) and X having the same meaning as in formula (II). The compound of formula (XI) is prepared, according to the method described in PCT patent application No. WO9315090, from the compound of formula (XII):

in which, R2 and R3 have the same meanings as in formula (I).

The complexes of formulas (II), (III) and (V) can be prepared by analogy according to methods described in the prior art.

Indeed, according to the process described in European patent application No. 174 057, the complexes of formulas (II) can be prepared from a compound of formula (XIII):

MX ₂ (C0D) ₂ (XIII) in which M, X have the same meanings as in formula (II) and COD represents cyclooctadiene.

Likewise, according to the process described in European patent application No. 366 390, the complexes of formulas (III) can be prepared from a compound of formula (XIV):

[MX ₂ (Ar)] ₂ (XIV) in which M, X and Ar have the same meanings as in formula (III).

Finally, according to the process described in European patent application No. 470 756, the compounds of formulas (V) can be prepared from a compound of formula (XV):

[MX (P (R11) ₂ (R12)) (DMA)] ₂ X (XV) in which M, X, R11 and R12 have the same definitions as in formula (V) and DMA represents dimethylacetamide.

The complexes of formulas (VI), (VII), (VIII), (IX) and (X) can also be prepared by analogy according to methods described in the prior art.

In fact, the complexes of formulas (VI) and (VII) can be obtained from the compounds of formulas (IIA) by analogy to the methods described in European patent applications No. 245 960 and No. 271 310. The complexes of Formulas (VIII), (IX) and (X) can be obtained from the compounds of formulas (IIB) by analogy to the methods described in European patent applications No. 256 634, No. 245 959 and No. 271 310.

The present invention also relates to the diphosphino-metallic complexes of formulas (II), (III),

(V), (VI), (VII), (VIII), (IX) and (X), as well as their use as a catalyst in asymmetric catalysis processes. Thus, the invention more particularly contemplates their use in asymmetric hydrogenation or asymmetric isomerization processes.

The invention especially relates to their use in an asymmetric hydrogenation process of unsaturated compounds carrying functional groups of formula (XVI) below:

in which :

A and B are different and chosen from a C ₁ _ ₅ alkyl group, an aryl group, a C _x hydroxycarbonyl group, _η , a C _x _ _η alkoxycarbonyl group, a C aryloxycarbonyl group. _K ), a C _± ₇ halogenoalkyl group, a heteroaryl group, a saturated or unsaturated cycloalkyl group, said alkyl, aryl or cycloalkyl groups optionally comprising one or more substituents chosen from a halogen such as chlorine, fluorine, bromine, a -N0 ₂ group, an alkyl C _x _ ₅ alkoxy C _x. ₅ , a C ₁ _ ₁ cycloalkyl fused or not, a aryl group, fused or not, optionally substituted by a halogen, a C _ ₅ alkyl, a C ₁ _ ₅ alkoxy, said alkyl, cycloalkyl or aryl groups comprising possibly one or more heteroatoms such as 0, N or Si,

Or A and B together form a substituted C ₂ _ ₆ alkyl group, a C ₃ _ ₉ cycloalkyl group saturated or not, a C ₅ _ ₁₀ aryl group, said groups being optionally substituted by a C ₁ _ alkyl ₅ , halogen, hydroxy, C ₅ alkoxy, amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , sulfino, sulfonyl, where R ₄ represents alkyl, alkoxy or alkylcarbonyl , said alkyl, cycloalkyl or aryl groups optionally comprising one or more heteroatoms such as 0, N, S, Si;

Q represents an oxygen, a group -NR16, -NOR16 or -C (R16) ₂ , where R16 is chosen from alkyl C _j. _ ₅ , an aryl group, a heteroaryl group substituted by a C ₁ _ ₄ alkyl.

Among the compounds of formulas (XVI), non-limiting examples that may be mentioned include the following compounds: ene-acid or ester derivatives, ene-alcohol or ether derivatives, ene-derivatives amide, e-amine derivatives, beta-ketoacid or ester derivatives, gam a-ketoacid or ester derivatives, beta, gamma-dicetoacid or ester derivatives, alpha-amido-beta derivatives cetoacid or ester, halogeno-ketone derivatives, hydroxy or alkoxy-ketone derivatives, i ine derivatives.

A preferred asymmetric hydrogenation process according to the invention comprises the treatment of a compound of formula (XVI), in an appropriate solvent, in the presence of a catalytic complex of formulas (II), (III), (V), (VI), (VII), (VIII), (IX) or (X), as a catalyst, under the operating conditions preferably as follows: - A temperature between 0 and +150 ° C.

- A hydrogen pressure between 1 and 20 bars or between 1 and 100 bars.

- An amount of catalyst relative to the amount of substrate between 1/50000 and 1/10, preferably between 10/10000 and 1/10, most preferably 10/100 and 1/10.

The hydrogenation time will generally be greater than or equal to 1 hour. Depending on the substrate and the catalyst, it may, for example, be between 1 hour and 70 hours.

Any solvent can be used, isolated or mixed, as long as it can dissolve the substrate and does not affect the reaction. Among the solvents which may be used in the above process, mention may be made of water, a hydrocarbon such as hexane, heptane, octane, nonane, decane, benzene, toluene and xylene, an ether such as tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, diisopropyl ether and diethylene glycol dimethyl ether, an ester such as a formate or an alkyl acetate such as ethyl formate, ethyl acetate, butyl acetate and ethyl propionate, a ketone such as acetone, diethylketone, diisopropylce t one, methylisobutylket one, methylethylketone and acetylacetone, an alcohol such as methanol, ethanol, n-propanol and 1 isopropanol, a nitrile such as acetonitrile, an alkyl halide such as dichloromethane, chloroform and 1,2-dichloroethane, an amine such as dimethylamine, triethylamine, diisobutylamine, triethylamine, N-methylpiperidine, ethyldiisopropylamine, N-methylcyclohexylamine and pyridine , an organic acid like ac ide acetic, propionic acid and formic acid, an ide like dimethylformamide and N-methylformamide.

When carrying out the reaction, it is recommended to use the substrate at a concentration, in the solvent of 0.1 to 2 moles / liter.

Other advantages and characteristics of the invention will appear in the examples which follow, given without implied limitation.

I - Preparation of ligands.

Example 1: Preparation of the ligand (R) -HOBIPHEP: (R) -6, 6 '-Dihydroxybiphenyl-2, 2' -diyl bis (diphenylphosphine).

The method described in PCT patent application No. WO9315090 is applied. The compound (R) -HOBIPHEP is ^''. Obtained with a quantitative yield.

Example 2: Preparation of the ligand (R) - CH ₂ COOBIPHEP (Abstract A): (R) -6, 6 '-acetoxybiphenyl-2, 2' - diyl bis (diphenylphosphine).

Under nitrogen, in a four-necked 250 ml flask, suspending the (R) -HOBIPHEP (5.65 _g;. 1 01.10 ^"2 mol) in 100 ml of DMF .Additionner to 20/24 ° C K ₂ C0 ₃ (7 g) After 10 minutes of stirring, slowly introduce acetyl chloride (1.7 g; 2.14.10 ^{~ 2} mol) dropwise. Maintain at a temperature of 24/25 ° C for 48 hours.

The reaction medium is concentrated. The residue is taken up with a solution of 220 ml of ethyl acetate and 50 ml of water.

After decantation, the organic phase is washed with a sodium chloride solution (3 times 30 ml). The organic phase is dried, filtered and then concentrated in vacuo. 4.5 g of product are obtained in the form of clear brown crystals.

The product is purified by column chromatography. Eluent: CH ₂ C1 ₂ / Hexane (1/2)

3.35 g of product are obtained in the form of white crystals.

Yield: 59% in purified product. [α] _D ²³ : + 52.4 °

NMR spectrum ^X H: 7.4 to 7.05 ppm (m, 26H, arom H.); 1.7 ppm (S, 6H, CH ₃ CO). ¹³ C NMR spectrum: 168.9 (CO); 122.8-148.9 (C arom.); 20.5 (C methyl). Example 3: Preparation of the ligand (R) - (CH „), CHCOOBIPHEP (Abstract B): (R) - 6,6 '-isobutanoyloxy biphenyl-2, 2' -diyl bis (diphenylphosphine).

In a 250 ml tetracol flask, with stirring, the (R) -HOBIPHEP (4 g; 7.21 × 10 ⁻³ mol) is suspended in 72 ml of THF. The medium is cooled to -20 ° C. and added NaH (0.61 g; 0.025 mol) The medium is left stirring, at -20 ° C., for 1 hour. The medium is cooled to -30 ° C., to add dropwise the chloride of 1 ' 98% acid isobutyric acid (1.6 ml; 0.025 mol) The medium is allowed to return to ambient temperature, ie 20 ° C. (after 1 hour). The medium is hydrolyzed with 50 ml of water. is exothermic. Extraction is carried out with 40 ml of ethyl acetate. The organic phase is washed with water (20 ml) then with an aqueous solution of sodium chloride (twice 20 ml). The organic phase is dried, filtered and then concentrated in vacuo.

5.6 g of product are obtained in the form of a brown gum.

2.36 g of product are obtained in the form of white crystals. Yield: 31.4% in purified product.

[α] _D ²³ : + 49.6 °

NMR spectrum ^X H: 7.2 to 7.55 ppm (m, 26H, arom H.); 2.2-2.35 ppm (m, 2H, -CH-), 0.8-1.05 ppm (m, 12H, (CH ₃ ) ₂ -).

¹³ C NMR spectrum: 175 (CO); 123-149 (C arom.); 34 (CH-); 19 (C methyl).

Example 4: Preparation of the ligand (R) -

(CH ₃ ) CCOQBIPHEP (Abbreviated ÇJ: (R) - 6,6 '- tertiobutanoyloxybiphenyl-2, 2' -diyl bis (diphenylphosphine). According to the same process as 1 example 2.

YId: 58%.

¹ H NMR spectrum: 7.05-7.4 ppm (m, 26H, aromatic H); 0.8 ppm (m, 18H, (CH ₃ )). ¹³ C NMR spectrum: 176 (CO); 122.8-149 (C arom.); 39.5 (C); 28 (C methyl).

Example 5.-Preparation of the ligand (R) -

(CH,), CHCH _Z C OOBIPHEP (Abstract D): (R) -6,6 '- isovaleroyloxybiphenyl-2, 2' -diyl bis (diphenylphosphine).

According to the procedure of Example 3.

The reaction medium is left for 24 hours at 20 ° C, before hydrolysis.

5.1 g of product are obtained in the form of an oil. After purification by column chromatography. Eluent: CH ₂ C1 ₂ / Hexane (1/2)

1.7 g of product are obtained in the form of white crystals.

Yid: 37% in purified product. ^Α H NMR spectrum: 7.2-7.55 ppm (m, 26H, aromatic H);

1.85-2.05 ppm (m, 6H, CH ₂ CH-), 0.95 ppm (d, 12H, (CH ₃ ) ₂ -).

^Α3 C NMR ^spectrum : 171 (CO); 123-149.4 (C arom.); 43.1 (CH-); 25.6 (CH ₂ ); 22.7 (C methyl).

Example 6: Preparation of the ligand (R) -

C.H ^ COOBIPHEP (Abstract E): (R) -6, 6 '-benzoyloxybiphenyl-2, 2' - diyl bis (diphenylphosphine).

In a 500 ml tetracol, under nitrogen, put NaH (2.6 g; 0.108 mol) in THF (64 ml). Add the (R) -HOBIPHEP (0.0257 mol) dissolved in DMF (64 ml) for 45 min at 20 ° C. Leave to stir at 20 ° C for 1 hour. Cool the medium to -40 ° C. Introduce benzoyl chloride (8.18 ml source Fluka) drop by drop for 20 min. Maintain the medium at -40 / 45 ° C for 45 min.

Add a 10% hydrochloric acid solution (75 ml). Let the temperature rise to 0 ° C for

1 introduction.

After the hydrolysis, bring back to room temperature. Extract the medium with ethyl acetate (50 ml and 40 ml). Wash the organic phase with water (twice 20 ml). The organic phase is dried, filtered and then concentrated in vacuo.

The expected product is obtained in the form of a brown oil.

After purification by column chromatography. Eluent: Hexane then Toluene.

The product is obtained in the form of white crystals.

Yield: 55.2% in purified product.

H NMR spectrum ^X: from 7 to 7.55 ppm (m, H arom.) ¹³ C-NMR spectrum: 164 (CO); 123-149 (C arom.).

Example 7: Preparation of the ligand (R) -

CJi C OOBIPHEP (Abstract 7): (R) - 6, 6 '-

Cyclohexanoyloxybiphenyl-2, 2 '-diyl bis (diphenylphosphine). According to the same process as that of Example 6, without purification by column chromatography.

The product is obtained in the form of white crystals.

Yid: 52.5% in product. NMR spectrum ^X H: 7.15 to 7.5 ppm (m, 26H, arom H.);

1.9 ppm (m, 2H, -CH-), 1-1.6 ppm (m, 20H, - (CH ₂ ) -).

¹³ C NMR spectrum: 172 (CO); 123-149.5 (C arom.); 43 (CH-); 26 and 28 ppm (CH ₂ ). Example 8: Preparation of the ligand (R) - (C ₄ H ₃ Q) COOBIPHEP (Abbreviated G): (R) -6,6'-2- Furanoyloxybiphenyl-2, 2 '-diyl bis (diphenylphosphine).

According to the same process as that of Example 6, with purification by column chromatography. Eluent CH ₂ CL ₂ .

The product is obtained in the form of white or pale yellow crystals.

Yield: 84.2% in purified product.

Η NMR spectrum: 7.6-6.35 ppm (m, H arom. + H furyl).

^Α3 C NMR ^spectrum : 156 (CO); 110-149 (C arom.).

Example 9: Preparation of the ligand (R) -

CH_0CH, C OOBIPHEP (Abbreviated H): (R) - 6, 6 '-

Methoxyacetyloxybiphenyl-2, 2 '-diyl bis (diphenylphosphine).

According to the same process as that of Example 6 without purification by column chromatography.

The product is obtained in the form of white or pale yellow crystals.

YId: 34.8% in product.

NMR spectrum ^X H: 7.4 to 7.08 ppm (m, 26H, arom H.); 3.6 ppm (s, 4H, -0CH ₂ 0-), 3.25 ppm (s, 6H, CH ₃ 0-).

¹³ C NMR spectrum: 169 (CO); 123-149 (C arom.); 69 (CH ₂ 0-); 60 (C ethoxy).

II - Preparation of catalysts

Example 10: Preparation of the catalyst: The complex [RuBr, (R) -CH ₃ COOBIPHEP)],. acetone.

In a hydrogenation bomb, introduce the ligand (R) - CH ₃ COOBIPHEP (20.8 mg; 0.032 mol) and 1,5- bis methylallylcyclooctadiene ruthenium (8.4 mg; 0.026 mol) in 1.5 ml of acetone. Hydrobromic acid dissolved in methanol (0.128 ml of a 0.5 M solution) is then added via a syringe. It is left for 15 min at 20 ° C., with stirring.

A catalytic solution of the complex [RuBr ₂ (R-CH ₃ COOBIPHEP)] _{2 is} obtained. acetone.

Example 11: Preparation of the catalyst: The Ru (R) -CTCOOBIPHEP) (OAc) complex.

In a 100 ml tetracol, under nitrogen, introduce the ligand (R) - CH ₃ COOBIPHEP (8 g) in toluene (50 ml).

Add sodium acetate (4.48 g), ruthenium cyclooctadiene dichloride (CODRuCl2) (3.85 g).

Quickly add the acetic acid (15.5 g). The mixture is heated at reflux (93 ° C) for 22 hours.

Cool to 65 ° C. Dispense under vacuum, the acetic acid / toluene azeotrope. Reload with toluene (40 ml) to entrain the acetic acid to a residual volume of 20 ml. Cool to 50 ° C and introduce acetone (112 ml). Let cool to 20 ° C and stir for 1 hour.

Filter and concentrate the filtrate. The residue is taken up with toluene and then concentrated (twice 20 ml).

At 70 ° C, add dropwise to the concentrate, with stirring, heptane (52 ml) (duration of the addition 52 min.).

Let cool to 20 ° C. Filter and rinse with heptane (2 times 20 ml). Dry in a bell.

Dark green crystals are obtained.

Yid: 30.2%.

Elemental analysis: 58.6% C; 4.6% H.

Example 12: Preparation of the catalyst: The Ru (R) - (CHJ, CHCQOBIPHEP) (OAc) complex.

According to the same process as that of Example 11. Dark green crystals are obtained. Yid: 83%.

Examples 13 to 19 follow the same procedure as that of Example 10.

III - Application in asymmetric hydrogenation.

Example 20: Asymmetric hydrogenation of ethylbenzoylacetate. Catalyst ligand: A.

To the catalytic solution of Example 10, ethyl benzoylacetate (0.5 g; 0.0026 mol) and 5 ml of ethanol are added. One puts under a pressure of 20 bars of hydrogen. The medium is heated to 50 ° C. and left stirring for 22 hours.

The medium is concentrated.

0.54 g of product is obtained in the form of a brown liquid.

Yield: Chemical purity: 82% e.e. : 97.8%

Examples 21 to 23: Same procedure as that of Example 20 with ligands B, C or D.

Example 24: Asymmetric hydrogenation of the hydroxyacetone compound. Ligand A.

5 bars, 60 ° C

Cat .: [Ru- (R) -PhosphineA-Br ₂ ] ₂ S / C = 1/3000

The same process is carried out as that of Example 20, taking into account the hydrogen pressure, the temperature and the substrate / catalyst ratio (S / C) indicated in the reaction.

The expected product is obtained in the form of a brown liquid.

Yield: Chemical purity: 72.7% ee: 96.1% Examples 25 to 33: Same procedure as that of Example 24 with ligands B, C, D, E, F, G or H. Catalyst [RuL * Br ₂ ].

Example 34: Asymmetric hydrogenation of the hydroxyacetone compound.

4 bars, 35 ° C

Ca: [Ru- (R) -PhosphineA-Br ₂ ] ₂ S / C = 1/300

The expected product is obtained in the form of a brown liquid.

Yid: 80-95% e.e. : 97%

Examples 35 to 39: Same procedure as that of Example 34 with ligands B, C, D, E, F, G or H. Catalyst [RuL * Br ₂ ].

Example 40: Asymmetric hydrogenation of the 4-chloroacetoacetate compound.

8 bar, 95 ° C And cal: Ru- (R) -PhosphineA- (OAc) ₂ S / C = 1/2000

The expected product is obtained in the form of an oil.

Yield: Quantitative Chemical purity: 52% e.e. : 94%.

Examples 41: Same procedure as that of Example 40 with the ligand B. Catalyst [RuL * Br,].

*: temperature condition: 75 ° C

Example 42: Asymmetric hydrogenation of the compound Acetamide, N- [1- (2-naphthaïenyl) ethenyl]. Ligand A.

The expected product is obtained in the form of an orange oil.

Yid: 80-90 e.e. : 85.8%.

Examples 43 to 47: Same procedure as that of Example 42 with ligands B, C, E, F and G. Catalyst [RuL * Br _? ].

Example 48: Asymmetric hydrogenation of the dimethyl Itaconate compound. Ligand A.

V CO ₂ CH ₃ 2 bars, 20 ° C Me _. , CO ₂ 2CH "" 3

^{> C0} 2 ^CH 3 cat: Ru- (R) -PhosphineA- (Br) ₂ OO ₂ CH ₃ S / C = 1/100 The same process is carried out as that of Example 20, taking into account the hydrogen pressure, the temperature and the substrate / catalyst ratio (S / C) indicated in the reaction.

The expected product is obtained in the form of a brown liquid.

Yid: 80-90% e.e. : 97.4%.

Examples 49 to 53: Same procedure as that of Example 48 with ligands C, E, F, G and H. Catalyst [RuL * Br,].

Claims

1) Use of a chiral diphosphine (R) or (S) of formula (I):

in which :

R and R, identical or different, represent an alkyl group C ^ _o saturated or unsaturated cycloalkyl, C ₃ _ ₉ saturated or unsaturated, an aryl group, C ₅ _ _10, said groups being optionally substituted by halogen, hydroxy, C _ ₅ alkoxy _r amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , sulfino, sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said alkyl groups, cycloalkyl, aryl optionally comprising one or more heteroatoms such as 0, N, S, Si, or also R and Ri, together, represent a substituted C ₂ _ _s alkyl group, saturated or unsaturated, a C ₃ _ ₉ cycloalkyl group or not, a C ₅ _ ₁₀ aryl group, said cycloalkyl and aryl groups being optionally substituted by a C 1 -C 4 alkyl, a halogen, a hydroxy, a C ₁ -C ₅ alkoxy, an amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said alkyl, cycloalkyl or aryl groups optionally comprise one or more heteroatoms such as 0, N, S, Si; R2 and R3, identical or different, represent a C ₃ _ ₈ cycloalkyl group, saturated or unsaturated, a C ₅ _ ₁₀ aryl, said groups being optionally substituted by a halogen, a hydroxy, a C _x _ ₅ alkoxy, a amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said cycloalkyl or aryl groups possibly comprising one or more heteroatoms such as 0, N, S, Si, or also R2 and R3 together form a C ₄ _ ₈ carbocycle group, saturated or not, a C ₆ _ ₁₀ aryl group, said groups being optionally substituted by a halogen, a hydroxy, an alkoxy in C ₁ _ ₅ , an amino such as NH ₂ , NHR ₄ , N (R ₄ ) ₂ , a sulfino, a sulfonyl, with R ₄ representing an alkyl, an alkoxy or an alkylcarbonyl, said carbocycle or aryl groups optionally comprising one or several heteroatoms such as 0, N, S, Si; as an optically active ligand for the preparation of a diphosphino-metallic complex.

2) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (II): M _x H _y X _z (L) ₂ (Sv) _p (II) in which,

M represents a metal such as ruthenium, rhodium or irridium;

X represents a halogen such as chlorine, bromine, fluorine or iodine;

Sv represents a tertiary amine, a ketone, an ether;

L represents a chiral diphosphine (R) or (S), of formula (I) defined in claim 1; y is an integer, equal to 0 or 1 x is an integer, equal to 1 or 2 z is an integer, equal to 1 or 4 p is an integer, equal to 0 or 1.

3) Use according to one of claims 1 or 2, characterized in that the diphosphino-metallic complex corresponds to the following formula (IIA):

M ₂ X ₄ L ₂ (Sv) (IIA) in which M, X, L and Sv have the same meaning as in formula (II) defined in claim 2.

4) Use according to one of claims 1 to 3, characterized in that the diphosphino-metallic complex is chosen from:

- Ru ₄ Cl ₂ [(R) or (S) CH ₃ C00-Binap] ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) - 6,6' -di acé t oxybiphenyl] -tetrachloro diruthenium triethylamine,

- Ru ₄ Cl ₂ ((Me) ₂ CHC00-Binap) ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) -6,6'-di- is obutanoyl oxybiphenyl] -tetrachloro diruthenium triethylamine, - Ru ₄ Cl ₂ (( CH ₃ ) ₃ CCOO-Binap) ₂ . N (Et) ₃ , also designated Di [2, 2 '-bis (diphenylphosphino) (R) or (S) -6, 6'- di trimethylacetoxybiphenyl] -tetrachloro diruthenium triethylamine,

- Ru ₄ Cl ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . N (Et) ₃ , - Ru ₄ Cl ₂ (CH ₃ COO-Binap) ₂ . CO (Me) ₂ ,

- Ru ₄ Br ₂ (CH ₃ COO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ ((Me) ₂ CHCOO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ ((CH ₃ ) ₃ CCOO-Binap) ₂ . N (And) ₃ ,

- Ru ₄ Br ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . N (And) ₃ , Ru ₄ Br ₂ (CH ₃ COO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ ((Me) ₂ CHCOO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ ((CH ₃ ) ₃ CCOO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ ((Me) ₂ CHCH ₂ COO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ (C ₆ H ₅ COO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ (C ₆ H _{1: L} COO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ (C ₄ H ₃ OCOO-Binap) ₂ . CO (Me) ₂ , Ru ₄ Br ₂ (CH ₃ OCH ₂ COO-Binap) ₂ . CO (Me) ₂ .

5) Use according to one of claims 1 or 2, characterized in that the diphosphino-metallic complex corresponds to the following formula (IIB):

MHXL ₂ (IIB) in which M, X and L have the same meaning as in formula (II) defined in claim 2 and H represents a hydrogen atom.

6) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (III): X., (Ar) _n IY _n (III) in which,

M, X, L have the same meaning as in formula (II) defined in claim 2;

Ar represents an olefin such as ethylene, 1,3-butadiene, cyclohexadiene, norbonadiene, cycloocta-1,5-diene, a pi-allyl, a nitrile such as acetonitrile, an arene of formula ( IV):

where R5, R6, R7, R8, R9 and RIO, identical or different, are chosen from a hydrogen atom, a C ₁ _ ₅ alkyl group, an isoalkyl group, a tertioalkyl group, an alkoxy group, said groups comprising one or more heteroatoms such as O, N and Si;

Y represents an anion, such as C10 ₄ ^~ , BF ₄ ^~ , PF ₆ ^" ; j is an integer equal to 0 or 1; m is an integer equal to 1.2 or 4; n is an integer equal to 1 or 2.

7) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (V): [MX (P (R ₁₁ ) ₂ (R ₁₂ )) L] ₂ X (V) in which

M, X and L have the same definitions as in formula (II) defined in claim 2, and R _X1 and R ₁₂ , identical or different, represent a phenyl or a phenyl substituted by an alkyl, an alkoxy or a dialkylamino.

8) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (VI):

M (L) Z ₂ (VI) in which,

M and L have the same meaning as in formula (II) defined in claim 2 and Z represents an acetate group of formula R ₁₃ COO ^" , diacetate of formula ^" OOCR ₁₃ COO ^" , an aminoacetate of formula R ₁₃ CH (NH ₂₎ COO ^", where R ₁₃ is C _1-4 alkyl, halo C ₁ _ _4, a substituted or unsubstituted phenyl. 9) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (VII):

[M (L) WX _k ] _n Z ' _p (VII) in which:

M, L and X have the same meaning as in formula (II) defined in claim 2;

W represents zinc, aluminum, titanium or tin; Z 'represents:

- Or an acetate group of formula R ₁₄ COO ^~ where R ₁₄ represents a C ₁ _ ₄ alkyl, a haloalkyl C ₁ _ _â , a substituted or unsubstituted phenyl, and in this case n = 1 and p = 2, and when W is Zn then k = 2, when W is Al then k = 3, and when W is Ti or Sn then k = 4, ie a tertiary amine, such as triethylamine, and in this case n = 2 and p = l, and when W is Zn then k = 4, when W is Al then k = 5 and when W is Ti or Sn then k = 6.

10) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (VIII):

MH (L) ₂ Y (VIII) in which H represents a hydrogen atom, M and L have the same meaning as in formula (II) defined in claim 2;

Y represents an anion, such as C10 ₄ ^" , BF ₄ ^" , PF ₆ ^~ .

11) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (IX): M (L) Y ₂ (IX) in which M and L have the same meaning as in the formula (II) defined in claim 2 and Y represents an anion, such as C10 ₄ ^" , BF ₄ ^" , PF ₅ ^" .

12) Use according to claim 1, characterized in that the diphosphino-metallic complex corresponds to the following formula (X): M (L) ₂ Y (X) in which M and L have the same meaning as in formula (II ) defined in claim 2 and Y represents an anion, such as C10 ₄ ^_ , BF ₄ ^" , PF _ε ^" .

13) A diphosphino-metallic complex of formulas (II), (III), (V), (VI), (VII), (VIII), (IX) or (X), defined in one of claims 2 to 12.

14) Use of a diphosphino-metallic complex according to claim 13 as catalyst in an asymmetric catalysis process.

15) Use according to claim 14, characterized in that the asymmetric catalysis process is an asymmetric isomerization process.

16) Utilization according to claim 14, characterized in that the asymmetric catalysis process is an asymmetric hydrogenation process.

17) Use of a diphosphino-metallic complex according to claim 13 as catalyst in a process for asymmetric hydrogenation of unsaturated compounds carrying functional groups of formula (XVI) below:

in which :

A and B are different and chosen from a C ₁ _ ₅ alkyl group, an aryl group, a C _x _ _η hydroxycarbonyl group, a C _λ _ ₇ alkoxycarbonyl group, a C _xw aryloxycarbonyl group, an alogenoalkyl group in C _x _ ₇ , a heteroaryl group, a saturated or unsaturated cycloalkyl group, said alkyl, aryl or cycloalkyl groups optionally comprising one or more substituents chosen from a halogen such as chlorine, fluorine, bromine, a group -N0 ₂ , alkyl C _x _ ₅ alkoxy C _x _ ₅ cycloalkyl C _± _ ₇ merged or not, an aryl group, fused or unsaturated, optionally substituted by halogen, alkyl C _{x ^ 5} a C ^ alkoxy, said alkyl, cycloalkyl or aryl groups optionally comprising one or more heteroatoms such as O, N or Si,

Or A and B together form a substituted C ₂ _ ₆ alkyl group, a saturated or unsaturated C ₃ _ ₉ cycloalkyl group, a C ₅ _ ₁₀ aryl group, said groups being optionally substituted by a Cχ alkyl. _5, halogen, hydroxy, alkoxy, C ₁ _ _5, amino such as NH _2, NHR _4, N (R ₄₎ _2, sulfino, sulfonyl, wherein R ₄ represents alkyl, alkoxy or alkylcarbonyl, said alkyl, cycloalkyl or aryl groups optionally comprising one or more heteroatoms such as O, N, S, Si;

Q represents an oxygen, a group -NR16, -NOR16 or -C (R16) ₂ , where R16 is chosen from a C _x- alkyl. ₅ , an aryl group, a heteroaryl group substituted by a C 1 alkyl. 18) A process for asymmetric hydrogenation of a compound of formula (XVI) defined in claim 17, characterized in that it comprises the treatment of said compound of formula (XVI), in an appropriate solvent, in the presence of a complex according to claim 13, as a catalyst.

19) Method according to claim 18, characterized in that the operating conditions are the following:

- A temperature between 0 and +150 ° C.

- Hydrogen pressure between 1 and 100 bars.

- An amount of catalyst relative to the amount of compound of formula (XVI) between

1/50000 and 1/10, preferably 10/10000 and 1/10, very preferably 10/100 and 1/10.

20) Method according to one of claims 19 or 18, characterized in that the hydrogenation time is greater than or equal to 1 hour.

21) Method according to one of claims 18 to 20, characterized in that the concentration of the compound of formula (XVI) in the solvent is between 0.1 and 2 moles / liter.