Enantiopure terphenyls with two ortho-atropisomeric axes

Abstract

Enantiopure terphenyl presenting two ortho-located chiral axes having the following structural formula (I): their process of synthesis and their use as mono or bidentate ligands for asymmetric organometallic reactions, as organocatalysts, as chiral base and as generator, with metal, of isolable chiral metallic complexes for applications in asymmetric catalysis and others.

Claims

1. Enantiopure terphenyl presenting two ortho-located chiral axis having the following structural formula (I) ##STR00026## wherein R.sub.1 on the phenyl ring Ar1 represents a halogen atom, or a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted branched or straight alkoxy group, or a CH.sub.2F group, or a CHF.sub.2 group or a —CnF.sub.n+2 group with n=1 to 10 or, a substituted or unsubstituted aryl group or, a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group or forming a NH.sub.2-protecting group, or a BR.sub.aR.sub.b group with R.sub.a and R.sub.b, identical or different being as defined above or a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, R.sub.2 in position 4 or 5 of the phenyl ring Ar1 which bears it represents a hydrogen atom or a halogen atom, a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted branched or straight alkoxy group or a substituted or unsubstituted aryl group or a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or forming a NH.sub.2-protecting group or a —BR.sub.aRb group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with Rd and Re identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, R.sub.3 on the phenyl ring Ar1 represents a halogen atom or a substituted or unsubstituted branched or straight alkyl group or, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted branched or straight alkoxy group or a substituted or unsubstituted aryl group or a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or forming a NH.sub.2-protecting group, a —BR.sub.aR.sub.b group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, R.sub.4, which may be in position 2, 3, 4 or 5 on the phenyl ring Art which bears it, represents: a hydrogen atom or a halogen atom or a substituted or unsubstituted branched or straight alkyl group or, a substituted or unsubstituted cycloalkyl group, or a CH.sub.2F group, or a CHF.sub.2 group or —CnF.sub.n+2 group with n=1 to 10, or a substituted or unsubstituted aryl group, or a —OR.sub.a, a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or forming a NH.sub.2-protecting group, or a —BR.sub.aR.sub.b group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, R.sub.5 on the phenyl ring Art represents a coordinating group or a substituent that will be used to install a coordinating group, selected from: a halogen atom, an —OR.sub.b group with Rb selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or a NH.sub.2-protecting group or a —CH.sub.2OR.sub.b group with R.sub.b selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or a —CHO group or a —COOR.sub.b group with R.sub.b selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or a NH.sub.2-protecting group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or a NH.sub.2-protecting group, a —SOR.sub.a group or a —SR.sub.a group or a —SO.sub.2R.sub.a with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —PR.sub.aR.sub.d or a —P (O)R.sub.an.sub.d with R.sub.a and R.sub.d independently selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —C═NR.sub.b with R.sub.b as defined above or a substituted or unsubstituted oxazoline group or a substituted or unsubstituted indenyl group or a substituted or unsubstituted cyclopentadienyl group, R.sub.6 on the phenyl ring Ar3 is a coordinating group either represents a hydrogen atom or a halogen atom, an —OH group a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aryl group or a —SOR.sub.a group or a —SR.sub.a group or a —SO.sub.2R.sub.a with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —OR.sub.a, a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or forming a NH.sub.2-protecting group or, a —BR.sub.aR.sub.b group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, a —PR.sub.aR.sub.d or a —P (O)R.sub.aR.sub.d with R.sub.a and R.sub.d independently selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a substituted or unsubstituted or oxazoline group a substituted or unsubstituted indenyl group or a substituted or unsubstituted cyclopentadienyl group, or may form with R.sub.5 a bridged phosphoric acid or ester or phosphinate represented by formula ##STR00027## with X being a carbon or an oxygen atom and Ra selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group; or a bridged phosphoramidite or phosphoramine represented by formula ##STR00028## with X being a carbon or an oxygen atom and Ra and Rb selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, R.sub.7 which may be in position 3 or 4 on the phenyl ring Ar3 which bears it represents: a hydrogen atom or a halogen atom or a substituted or unsubstituted branched or straight alkyl group or, a substituted or unsubstituted branched or straight alkoxy group a substituted or unsubstituted cycloalkyl group, or a CH.sub.2F group, or a CHF.sub.2 group or —CnF.sub.n+2 group with n=1 to 10, or a substituted or unsubstituted aryl group, or a —OR.sub.a, a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or forming a NH.sub.2-protecting group, or a —BR.sub.aR.sub.b group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group, R.sub.8 on the phenyl ring Ar3 represents a halogen atom or a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted branched or straight alkoxy group or a —OR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl group or a —COR.sub.a or a —COOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight alkyl group or a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted aryl group, or a forming NH.sub.2-protecting group, or a —BR.sub.aR.sub.b group with R.sub.a and R.sub.b identical or different being as defined above or, a —B(OR.sub.d)(OR.sub.e) group with R.sub.d and R.sub.e identical or different being selected from a hydrogen atom or a substituted or unsubstituted branched or straight alkyl group.

2. The enantiopure terphenyl according to claim 1, wherein R.sub.1 represents a halogen atom, a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted branched or straight alkoxy group, or a CF.sub.3 group, R.sub.2 represents a hydrogen atom, or a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted branched or straight alkoxy group, R.sub.3 represents a substituted or unsubstituted branched or straight alkyl group, or a substituted or unsubstituted branched or straight alkoxy group, R.sub.4 represents a hydrogen atom, or a halogen atom, or a substituted or unsubstituted branched or straight alkoxy group, or a substituted or unsubstituted branched or straight alkyl group, or an aryl group, or a CH.sub.2F group, or a CHF.sub.2 group or —CnF.sub.n+2 group with n=1 to 10, R.sub.5 represents a SOR.sub.a group with R.sub.a selected from a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkyl group, or a substituted or unsubstituted aryl group, or a OH group, or PR.sub.aR.sub.d or a —P (O)R.sub.aR.sub.d with R.sub.a and R.sub.d independently selected from a substituted or unsubstituted branched or straight alkyl group and a substituted or unsubstituted aryl group, R.sub.6 represents a hydrogen atom, a halogen atom, or a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkyl group, or a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkoxy group, or PR.sub.aR.sub.d or a —P (O)Rand with R.sub.a and R.sub.d independently selected from a substituted or unsubstituted branched or straight alkyl group and a substituted or unsubstituted aryl group, or a —NR.sub.bR.sub.c group with R.sub.b and R.sub.c independently selected from a hydrogen atom, a substituted or unsubstituted branched or straight alkyl group, and a substituted or unsubstituted aryl group, or a NH.sub.2-protecting group, R.sub.7 represents a hydrogen atom, a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkyl group, or a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkoxy group, or a CF.sub.3 group, R.sub.8 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkyl group, or a substituted or unsubstituted branched or straight-(C.sub.1-C.sub.4) alkoxy group, or a CF.sub.3 group.

3. Process for preparing the compounds of formula (I) according to claim 1, said process comprising the step of: reacting an enantiopure compound of formula (1) ##STR00029## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in claim 1 and Ar is selected from substituted or unsubstituted aryl groups, with a compound of formula (2) ##STR00030## with R.sub.6, R.sub.7 and R.sub.8 as defined in claim 1, in presence of a silver salt comprising a mixture of Ag.sub.2CO.sub.3 and AgTFA, a N-heterocyclic carbene precursor, a palladium catalyst and a molecular sieve of 3 Å to 5 Å in a solvent selected from the flurorinated alcools and the fluorinated ethers at a temperature comprised between 40 and 120° C. during 2 to 24 hours to obtain a compound of formula (Ia) ##STR00031## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are as defined in claim 1 and Ar is selected from substituted or unsubstituted aryl groups, replacing or substituting the —SOAr group in order to obtain a compound of formula (I) ##STR00032## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are as defined in claim 1 and R.sub.5 is as defined in claim 1 and is not —SOAr.

4. A method for performing asymmetric organometallic reactions, comprising providing the compound of formula (I) of claim 1, and applying the compound (I) as a mono or bidentate ligand.

5. Enantiopure compounds of formula (1) ##STR00033## wherein R.sub.1, R.sub.2 and R.sub.4 are as defined in claim 1, R.sub.3 is as defined in claim 1 but is not a hydrogen and Ar is selected from substituted or unsubstituted aryl groups.

6. The process of claim 3, wherein the molecular sieve is of 4 Å.

7. The process of claim 3, wherein the reacting step is performed at a temperature between 75 and 85° C.

8. The process of claim 6, wherein the reacting step is performed at a temperature between 75 and 85° C.

9. The process of claim 3, wherein the reacting step is performed for 2 to 10 hours.

10. The process of claim 6, wherein the reacting step is performed for 2 to 10 hours.

11. The process of claim 7, wherein the reacting step is performed for 2 to 10 hours.

12. The process of claim 8, wherein the reacting step is performed for 2 to 10 hours.

13. A method for performing asymmetric catalysis, comprising providing the compound (I) of claim 1, and applying the compound of formula (I) as organocatalyst, as chiral base and as generator, with metal, of isolable chiral metallic complexes.

14. A method for performing asymmetric hydrogenation comprising providing the compound (I) of claim 1, and applying the compound of formula (I) as organocatalyst.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) The sole drawing figure illustrates the terphenyls disclosed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(2) The following examples 1 to 7 illustrate the invention.

(3) General Experimental Part

(4) Unless otherwise noted, all reagents were purchased from commercial suppliers (Sigma-Aldrich, Acros, Alfa Aesar, Fluorochem) and were used without further purification.

(5) Anhydrous solvents term denotes solvents dried over molecular Sieves (to the fresh commercial solvent bottle were added 3 or 4 angstrom MS in beads form, followed by static drying for at least 48 hours before use), kept under Argon and handle using the standard Schlenk techniques: Tetrahydrofuran (THF) was dried using 10% (m/v) 3 or 4 Å MS Diethylether was dried using 10% (m/v) 3 or 4 Å MS Dichloromethane and Toluene were purchased from Aldrich (Sure/Seal packaging, kept over 3 Å molecular sieves). 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was purchased from Fluorochem and dried sequentially 2 times over 3 Å MS (each time 20% (m/v), static drying for 72 hours). Molecular sieves were activated by heating at ˜300° C. under vacuum overnight.

(6) Organolithium and organomagnesium reagents were titrated before use.

(7) Flash chromatography refers to column chromatography using silica gel (Merck 60, 40-63 μm size), driven by pressurized air.

(8) Thin layer chromatography (TLC): was carried out using Merck Kieselgel 60 F.sub.254 silica gel plates.

(9) NMR: recorded on Brücker Avance 500, 400 or 300, the FID was treated with MestRec Nova, TopSpin. The chemical shift (δ) is given relative to the residual signal of the solvent (CHCl.sub.3: δ (.sup.1H)=7.26 ppm; δ (.sup.13C)=77.16 ppm. CD.sub.3CN: δ (.sup.1H)=1.94 ppm; δ (.sup.13C)=1.32 ppm), or relative to an external standard (CFCl.sub.3: δ (.sup.19F)=0 ppm; H.sub.3PO.sub.4 (85%)=0 ppm). Broad=Br, singulet=s, doublet=d, triplet=t, quadruplet=q, multiplet=m.

(10) Specific description of signals: 7.06-7.03 (AA′BB′, 2H) refers to an AA′BB′ spin system, where the AA′ multiplet part covers from 7.06 to 7.03 ppm and integrates for 2 protons.

(11) Mixture of atropisomer on the NMR time scale: compounds that are not considered atropisomeric, in the sense that each atropisomer can be isolated, might exhibit atropisomeric feature on the NMR time scale. Indeed, if two atropodiastereoisomers are possible by symmetry consideration, each can give well-defined and resolved spectra. This is dependent on the rate of interconversion between the two atropodiastereoisomers, the chemical shift difference between the signals, and the temperature.

(12) HRMS measurements were performed by Service de Spectromètrie de Masse de L′institut de Chimie at the University of Strasbourg.

(13) Elemental Analysis measurements were performed by the Analytical, Physical Measurements and Optical Spectroscopy Service of the University of Strasbourg.

EXAMPLE 1: BIARYL PRECURSORS

1.1. (−)-Menthyl-(S)-p-toluenesulfinate

(14) Said Compound is Commercially Available

1.2. (S)-1-bromo-2-(p-tolylsulfinyl)benzene

(15) ##STR00012##

(16) 2-bromoiodobenzene (1 eq., 20 g, 9.08 mL, 70.7 mmol) was dissolved in THF (40 mL) and cooled down to 0° C. A solution of i-PrMgCl (35.35 mL, 70.7 mmol, 2M in THF) was added dropwise and the resulting mixture stirred for 1 hour at 0° C. It was then cannulated on a solution of (−)-(1R,2S,5R)-menthyl (S)-p-toluenesulfinate (1 equiv, 0.25M in anhydrous THF) (1 eq., 20.8 g, 70.7 mmol) in THF (200 mL) at −40° C. The reaction was then allowed to come back to 0° C. over 2-3 hours when it was diluted with Et.sub.2O and quenched by a sat.sol. of NH.sub.4Cl. The phases were separated, the aqueous phase extracted once with Et.sub.2O and the combined organic phases dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and the crude oily product was quickly dissolved in 100 mL of Et.sub.2O and allowed to crystallize at 4-6° C. for several hours. The crystals were collected and washed with n-pentane. The mother liquor was concentrated and again dissolved Et.sub.2O to afford a second batch of equal purity (.sup.1H NMR), yielding a total of (S)-1-bromo-4-methyl-2-(p-tolylsulfinyl)benzene as colorless crystals (18.06 g, 61.2 mmol, 86.5%).

(17) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.06 (dd, J=7.8, 1.6 Hz, 1 H), 7.63 (d, J=8.2 Hz, 2 H), 7.56 (ddd, J=7.8, 7.4, 1.0 Hz, 1 H), 7.51 (dd, J=8.0, 1.0 Hz, 1 H), 7.32 (ddd, J=8.0, 7.4, 1.6 Hz, 1 H), 7.24 (d, J=8.2 Hz, 2 H), 2.36 (s, 3 H) ppm.

(18) .sup.13C-NMR (101 MHz, CDCl.sub.3): δ=145.1, 142.1, 141.3, 133.1, 132.2, 130.0 (2 C.sub.pTol), 128.5, 126.4 (2 C.sub.pTol), 126.3, 120.0, 21.5 ppm.

(19) R.sub.f (EtOAc/c-Hex 1:2)=0.42.

(20) [α].sub.D.sup.20=−161 (c=1, CHCl.sub.3).

(21) Chiral HPLC e.r. >99% [OD-H column, n-Hex/i-PrOH 80:20, 0.5 mL/min, (R) r.sub.t=13.49 min, (S) r.sub.t=16.01 min].

1.3. 2-bromo-4-methoxy-1-methylbenzene

(22) ##STR00013##

(23) 3-bromo-4-methylphenol (1 eq., 5 g, 26.7 mmol) was dissolved in DCM (200 mL) along with triethylbenzylammonium chloride (5%, 0.304 g, 1.34 mmol) and dimethyl sulfate (1.2 eq., 4.05 g, 3.04 mL, 32.1 mmol). Then, under vigorous stirring, NaOH (19 M, 2.5 eq.,3.5 mL) was added dopwise at room temperature. The reaction mixture became orange and turbid, then after 2 hours it regained its original greenish color. Water was then added (100 mL), and the mixture was stirred for 1 more hour. Then an ammonium hydroxide solution (10 mL) was added to quench the excess dimethyl sulfate, and the mixture was stirred for 1 more hour. The phases were then separated and the organic phase was washed with a 1M NaOH solution (1M), a sat. sol. of NaHCO.sub.3, and with a 1M HCl solution (2 times). The product 2-bromo-4-methoxy-1-methylbenzene (5.02 g, 25 mmol, 93%), isolated as an orange oil, is pure enough to be used in the next step (the crude .sup.1H NMR is given in the SI).

(24) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ=7.12 (d, J=8.4 Hz, 1H), 7.10 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.4, 2.7 Hz, 1H), 3.77 (s, 3H), 2.33 (s, 3H) ppm. Spectral data matched the literature.

1.4. (5-methoxy-2-methylphenyl)boronic acid

(25) ##STR00014##

(26) Mg turnings (3 eq., 3.97 g, 163 mmol) were loaded in a two-necked flask, followed by THF (10 mL) at room temperature. The magnesium was activated by dibromoethane (0.0531 eq., 0.543 g, 0.25 mL, 2.89 mmol), and then under stirring a solution of 2-bromo-4-methoxy-1-methylbenzene (1 eq., 11 g, 54.5 mmol) in THF (40 mL) was added dropwise at a rate sufficient to obtain a refluxing solution. After the addition, the light grey solution was stirred for a further 1 h. at 50° C. Then, after cooling to room temperature, the reaction mixture was diluted with THF (50 mL), and cooled down to 0° C. Then, under vigorous stirring, neat B(OMe).sub.3 (3.5 eq., 19.8 g, 21.6 mL, 190 mmol) was quickly added in one portion, which caused a white precipitate to appear. After 15 min. of stirring at 0° C., the cooling bath was removed and the reaction mixture was stirred for 1 h. at room temperature. The reaction was then quenched by a 1M HCI solution, and stirred for 1h., diluted with Et.sub.2O, and the phases were separated. The aqueous phase was extracted with an Et.sub.2O/THF mixture (1:1, v/v), and the combined organic phases were dried over Na.sub.2SO.sub.4. The volatile were removed under reduced pressure and the crude off-white solid thus obtained was triturated with n-pentane under sonication. The crude product is then recrystallized from MeCN (reflux to room temperature to 4-6° C. The titled compound (5-methoxy-2-methylphenyl)boronic acid (7.33 g, 44.2 mmol, 81%) was obtained as a white solid. The title compound as a low solubility in most water-free organic solvents except for THF.

(27) .sup.1H NMR (NCCD.sub.3, 400 MHz): δ=7.07 (d, J=8.3 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.82 (dd, J=8.3, 2.9 Hz, 1H), 6.14 (s, 2H), 4.87 (s, 2H signal corresponding to the hydrated boronic acid, due the water-contaminated NCCD.sub.3), 3.75 (s, 3H), 2.36 (s, 3H) ppm.

EXAMPLE 2: DI-ORTHO-SUBSTITUTED BIPHENYLS

2. (S)-5-methoxy-2-methyl-2′-(p-tolylsulfinyl)-1,1′-biphenyl

(28) ##STR00015##

(29) (S)-1-bromo-2-(p-tolylsulfinyl)benzene (1 eq., 3.87 g, 13.1 mmol), Pd(OAc).sub.2 (2.5 mol %, 0.0735 g, 0.327 mmol), TBAB (0.999 eq., 4.22 g, 13.1 mmol) and Na.sub.2CO.sub.3 (3 eq., 4.16 g, 39.3 mmol) were loaded under air in a round-bottom flask. EtOH (8 mL) was then added under gentle stirring in order to dissolve the organic reagents and to obtain a thick paste. The resulting heterogeneous solution was heated at 100° C., water (75 mL) was added and the reaction mixture was stirred vigorously for 3 hours at 100° C. After having cooled down to room temperature, the reaction was diluted with Et.sub.2O and stirred for 10-15 min. It was then transferred to a separating funnel; diluted with more Et.sub.2O and a 1M NaOH solution, and the phases were separated. The organic phase was dried over Na.sub.2SO.sub.4 and the solvent removed under reduced pressure. The crude product was then purified by flash chromatography. The crude product was purified quickly by careful filtration on silica gel, followed by recrystallization from a 95:5 heptane/toluene mixture (reflux to room temperature then to 4-6° C.). The solution is seeded while hot and left undisturbed, yielding (S)-5-methoxy-2-methyl-2′-(p-tolylsulfinyl)-1,1′-biphenyl (3.8 g, 11.3 mmol, 86%) as white crystals. The seed crystals are obtained by careful recrystallization of the pure product after column chromatography from a 95:5 heptane/toluene mixture (reflux to room temperature then to 4-6° C.). Mixture of two atropisomer (1:1) on the NMR time scale.

(30) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.25 (dd, J=7.9, 1.2 Hz, 1H), 8.21 (dd, J=7.9, 1.3 Hz, 1H), 7.62 (td, J=7.7, 1.4 Hz, 1H), 7.61 (td, J=7.7, 1.3 Hz, 1H), 7.51 (td, J=7.4, 1.3 Hz, 1H), 7.46 (td, J=7.5, 1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.15-7.11 (m, 2H), 7.08-7.04 (A.sub.1A.sub.1′B.sub.1B.sub.1′, 2H), 7.05-6.96 (m, 5H), 6.95-6.91 (A.sub.1A.sub.1′B.sub.1B.sub.1′, 2H), 6.91-6.81 (m, 3H), 5.90 (d, J=2.8 Hz, .sup.1H), 3.84 (s, 3H), 3.52 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.26 (s, 3H) ppm.

(31) .sup.13C-NMR (CDCl.sub.3, 101 MHz): δ=157.24, 157.22, 143.73, 143.68, 141.85, 141.55, 141.47, 140.96, 139.53, 139.32, 138.02, 137.41, 131.22, 130.96, 130.75, 130.49, 129.89, 129.78, 129.35 (2C), 129.32 (2C), 128.55, 128.42, 128.30, 127.74, 126.23 (2C), 126.20 (2C), 123.52, 123.46, 114.90, 114.79, 114.72, 114.60, 55.42, 54.81, 21.32, 21.29, 18.99, 18.25 ppm

(32) HRMS (ESI): calc. for C.sub.21H.sub.21O.sub.2S.sup.+ 337.1257; found 337.1251

EXAMPLE 3: ARYLATION WITH DOUBLE CONTROL OF AXIAL CHIRALITY

3.1 (1′S,2′R)-5-bromo-6′-methoxy-2,3′-dimethyl-2″-((S)-p-tolylsulfinyl)-1,1′:2′,1″-terphenyl

(33) ##STR00016##

(34) Under air, in a an oven-dried pressure tube closed by a teflon screw cap were loaded (S)-5-methoxy-2-methyl-2′-(p-tolylsulfinyl)-1,1′-biphenyl (1 eq., 120 mg, 0.357 mmol), AgTFA (1 eq., 79 mg, 0.358 mmol), Ag.sub.2CO.sub.3 (2.5 eq., 246 mg, 0.892 mmol), 4 Å powdered molecular sieves (85 mg), Pd(TFA).sub.2 (25.3 mol %, 30 mg, 0.0902 mmol) and 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium chloride (50.1%, 76 mg, 0.179 mmol). HFIP (3400 μL) was then added and the resulting heterogeneous mixture was stirred at room temperature for 10 min. The reactor was then submerged in a 85° C. bath and stirred for 4 hours. After cooling down to room temperature the mixture was diluted with CH.sub.2Cl.sub.2, filtered on a silica gel pad (eluted with Et.sub.2O) and the volatiles were removed under reduced pressure. Subsequent chromatography yielded (1′S,2′R)-5-bromo-6′-methoxy-2,3′-dimethyl-2″-((S)-p-tolylsulfinyl)-1,1′:2′,1″-terphenyl (92 mg, 0.182 mmol, 51%) as a yellow powder with a d.r. ≥98:2 (>95% conversion, crude d.r.=20.4: n.d. :1 overlapping signals).

(35) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ=8.00 (dd, J=8.0, 1.1 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.39 (td, J=7.7, 1.3 Hz, 1H), 7.26 (td, J=7.8, 1.4 Hz, 1H), 7.15 (td, J=8.3, 2.0 Hz, 1H), 7.15-7.04 (m, 5H), 6.98 (d, J=8.5 Hz, 1H), 6.96 (dd, J=7.5, 1.1 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.76 (s, 3H), 2.33 (s, 3H), 1.84 (s, 3H), 1.14 (s, 3H) ppm.

(36) .sup.13C-NMR (CDCl.sub.3, 101 MHz): δ=154.92, 143.28, 141.61, 141.14, 138.32, 136.95, 134.72, 132.78, 130.57, 130.11, 130.03, 129.79, 129.39 (2C), 129.37, 129.19, 128.34, 128.05, 126.45 (2C), 123.30, 118.54, 111.17, 55.78, 21.34, 19.44, 19.16 ppm. (1C overlapping not identified)

(37) [α].sub.D.sup.20=−6.4° (C=0.54, CHCl.sub.3)

(38) HRMS (ESI): calc. for C.sub.28H.sub.26BrO.sub.2S.sup.+ 505.0831; found 505.0822

(39) ##STR00017##

3.2. 2-(1′.SUB.a.S,2′.SUB.a.R)-6′-methoxy-3′,6-dimethyl-2″-((S)-p-tolylsulfinyl)-[1,1′:2′,1″-terphenyl]-3-yl)isoindoline-1,3-dione

(40) An optimized procedure was conducted, giving a more synthetically useful yield, from (S)-5-dimethoxy-2-methyl-2′-(p-tolylsulfinyl)-1,1′-biphenyl (1 eq., 287 mg, 0.853 mmol), AgTFA (0.998 eq., 188 mg, 0.851 mmol), Ag.sub.2CO.sub.3 (2.34 eq., 551 mg, 2 mmol), 2-(4-iodo-3-methylphenyl)isoindoline-1,3-dione (1.28 eq., 396 mg, 1.09 mmol), 4 Å powdered molecular sieves (200 mg), Pd(TFA).sub.2 (30%, 85 mg, 0.256 mmol), 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ium chloride (30.1%, 109 mg, 0.256 mmol) in hfip (9000 μL) for 5 hours. After cooling down to room temperature the mixture was diluted with CH.sub.2Cl.sub.2, filtered on a silica gel pad (eluted with Et.sub.2O) and the volatiles were removed under reduced pressure. Subsequent chromatography yielded, affording 2-(1′S,2′R)-6′-methoxy-3′,6-dimethyl-2″-((S)-p-tolylsulfinyl)-[1,1′:2′,1″-terphenyl]-3-yl)isoindoline-1,3-dione (358 mg, 0.626 mmol, 73%) as an off-white powder and with a d.r.≥98:2 (95% conversion, crude d.r.=n.d., overlapping signals).

(41) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ=8.05 (dd, J=7.9, 1.3 Hz, 1H), 7.94-7.87 (m, 2H), 7.75-7.70 (m, 2H), 7.69 (d, J=2.2 Hz, 1H), 7.43 (td, J=7.7, 1.3 Hz, 1H), 7.28 (td, J=7.5, 1.3 Hz, 1H), 7.18 (dd, J=8.2, 2.3 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.07-7.04 (m, 4H), 7.03 (d, J=15.7 Hz, 1H), 7.01 (dd, J=7.5, 1.2 Hz, 1H), 6.97 (d, J=4.3 Hz, 1H), 3.79 (s, 3H), 2.31 (s, 3H), 1.94 (s, 3H), 1.05 (s, 3H) ppm.

(42) .sup.13C-NMR (CDCl.sub.3, 101 MHz): δ=167.17 (2C), 155.26, 143.16, 141.51, 141.31, 137.39, 137.03 (2C), 135.78, 133.92 (2C), 131.93, 130.05, 129.69, 129.67, 129.43 (2C), 129.27 (2C), 128.84, 128.66, 128.29, 127.87, 126.82 (2C), 125.45, 124.88, 123.55 (2C), 123.32, 111.43, 56.00, 21.37, 19.78, 19.09 ppm. [α].sub.D.sup.20 =−5.54° (c=0.148, CHCl.sub.3).

(43) HRMS (ESI): calc. for C.sub.36H.sub.29NNaO.sub.4S.sup.+ 594.1701; found 594.1685

EXAMPLE 4: FUNCTIONAL GROUP INTERCONVERSION OF THE SULFINYL GROUP

4.1 ((1′R,2′S)-3′-methoxy-6′,6″-dimethyl-[1,1′:2′,1″-terphenyl]-2,3″-diyl)bis(diphenylphosphane)

(44) ##STR00018##

(45) Anhydrous conditions: A solution of (1′S,2′R)-5-bromo-6′-methoxy-2,3′-dimethyl-2″-((S)-p-tolylsulfinyl)-1,1′:2′,1″-terphenyl (1 eq., 300 mg, 0.594 mmol) in Et.sub.2O (6 mL) was cooled to −94° C. A solution of t-BuLi (5 eq., 1.55 M in pentane, 1.91 mL, 2.97 mmol) was then added dropwise (color changed to dark blue/maroon, some precipitate). The resulting mixture was stirred at −94° C. for 20 min., when a solution of ClPPh.sub.2 (4.22 eq., 553 mg, 0.45 mL, 2.51 mmol) in toluene (0.5 mL) was slowly cannulated. The resulting mixture was allowed to reach −78° C. over 30 min., and was quenched by filtration over a silica gel pad under argon (washed with Et.sub.2O, some DCM can be added to solubilize the reaction mixture). Solvent was removed under reduced pressure, and flash chromatography under argon (Et.sub.2O/n-pentane 10:90, product loaded as 20:80 DCM/n-pentane solution) afforded ((1′R,2′S)-3′-methoxy-6′,6″-dimethyl-[1,1′:2′,1″-terphenyl]-2,3″-diyl)bis(diphenylphosphane) (210 mg, 0.32 mmol, 54%) as a white powder. Recrystallization by layering a concentrated 80:20 CHCl.sub.3/Et.sub.2O solution with n-pentane afforded colorless crystals suitable for X-Ray analysis.

(46) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ=7.69 (dd, J=10.7, 1.5 Hz, 1H), 7.36-6.94 (m, 29H), 6.92 (d, J=8.4 Hz, 1H), 6.80-6.73 (m, 1H), 3.72 (s, 3H), 2.03 (s, 3H), 1.25 (s, 3H) ppm.

(47) .sup.13C-NMR (CDCl.sub.3, 101 MHz): δ=154.88, 146.42, 146.09, 140.97, 140.91, 138.42, 138.40, 138.37, 138.29, 138.25, 137.78, 137.71, 137.58, 137.28, 137.15, 137.12, 137.05, 136.75, 136.68, 136.52, 136.38, 135.22, 135.00, 133.85, 133.83, 133.80, 133.60, 133.21, 133.09, 133.06, 133.03, 132.91, 132.88, 131.92, 131.82, 131.56, 131.53, 129.65, 129.63, 129.54, 129.52, 129.20, 129.03, 128.97, 128.75, 128.47, 128.18, 128.16, 128.14, 128.11, 128.04, 128.00, 127.95, 127.79, 127.44, 126.79, 110.51, 55.83, 20.07, 19.41, 19.40 ppm.

(48) .sup.31P-NMR (CDCl.sub.3, 162 MHz): δ=−6.94, −14.90 ppm.

(49) [α].sub.D.sup.20=+31.1 (c=1, CHCl.sub.3)

(50) HRMS (ESI): calc. for C.sub.45H.sub.39OP.sub.2.sup.+657.2471; found 657.2463

4.2. 1′R,2′S)-5″-chloro-3′-methoxy-2″,6′-dimethyl-[1,1′:2′,1″-terphenyl]-2-carboxylic acid

(51) ##STR00019##

(52) To a solution of (1S,1″R)-5-chloro-6′-methoxy-2,3′-dimethyl-2″-((S)-p-tolylsulfinyl)-1,1′:2′,1″-terphenyl (1 eq., 80 mg, 0.174 mmol) in THF (2000 μL) at −78° C. was added dropwise n-BuLi (4.15 eq., 1.6 M, 450 μL, 0.72 mmol). The mixture was stirred 3 min. at −78° C. (color changed from light yellow to darker orange), when gaseous CO.sub.2 was bubbled into the reaction mixture, causing discoloration after few minutes. The resulting mixture was stirred at −78° C. for 30 min. with continuous CO.sub.2 bubbling. It was quenched at −78° C. by addition of a MeOH solution in Et.sub.2O, allowed back to room temperature, acidified to pH 1 by the addition of 1M HCl solution. The phases were separated and the organic phase was dried over Na.sub.2SO.sub.4. The volatiles were removed under reduced pressure and flash chromatography (CyH/EtOAc/AcOH 70:30:1) afforded (1′R,2′S)-5″-chloro-3′-methoxy-2″,6′-dimethyl-[1,1′:2′,1″-terphenyl]-2-carboxylic acid (47 mg, 0.128 mmol, 74%) as a yellowish solid with a d.r. >95:5 by .sup.1H NMR, and a d.r. >99:1 by chiral HPLC.

(53) Crystals suitable for X-ray analysis were grown in a round-bottom flask by layering a diluted DCM solution with n-pentane and letting the resulting mixture equilibrate at 4-6° C.

(54) .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ=10.96 (brd s, 1H), 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.30 (td, J=7.5, 1.4 Hz, 1H), 7.25-7.18 (m, 2H), 7.02-6.96 (m, 1H), 6.96-6.89 (m, 2H), 6.87 (d, J=8.2 Hz, 2H), 3.75 (s, 3H), 2.02 (s, 3H), 1.96 (s, 3H) ppm.

(55) .sup.13C-NMR (CDCl.sub.3, 101 MHz): δ=171.49, 154.62, 141.97, 141.51, 139.06, 134.87, 132.19, 130.59, 130.48, 129.99, 129.95, 129.76, 129.47, 129.18, 127.68, 127.20, 126.93, 126.61, 109.37, 55.60, 19.87, 19.33 ppm.

(56) [α].sub.D.sup.20=−42.3° (c=0.230, CHCl.sub.3).

(57) HRMS (ESI): calc. for C.sub.22H.sub.19NaO.sub.3.sup.+389.0915; found 389.0892

EXAMPLE 5: SYNTHESIS OF MONOPHOSPHINE LIGAND

(58) A selective functionalization of the triarylic bromosulfoxyde skeleton is realized by chemoselectif sulfoxide/Li exchange followed by the condensation with a methoxydiarylphosphine according to the following scheme

(59) ##STR00020##

(60) To a solution of 2-(5-bromo-2-methylphenyl)-1-methoxy-4-methyl-3-{2-[(S)-(4-methylphenyl)sulfinyl]phenyl}benzene (1 eq., 290 mg, 0.574 mmol) in toluene (5 mL) at −78° C., was added n-BuLi (3.35 eq., 1.6 M, 1.2 mL, 1.92 mmol) dropwise. The mixture was stirred 2 min when Et.sub.2O (1 mL) cooled down to −78° C. was added and stirred 5 min at −78° C. A solution of CIPPh2 (3.4 eq., 430 mg, 0.35 mL, 1.95 mmol) in Et.sub.2O (0.4 mL) was then added in one portion and stirred 15 min. at −78° C., then allowed to come back at 0° C. when the cooling bath was removed. The mixture was diluted with Et.sub.2O and filtered under argon on silica plug. The solution was concentrated and purified by chromatography on silica gel push with argon (Et.sub.2O/n-pentane 5:95, product loaded as 20:80 DCM/n-pentane solution) to afford ((1′R,2′S)-5″-bromo-3′-methoxy-2″,6′-dimethyl-[1,1′:2′,1″-terphenyl]-2-yl)diphenylphosphane (152 mg, 0.276 mmol, 48%) as a white powder.

(61) .sup.1H-NMR (500 MHz, Chloroform-d) δ: 7.67 (t, J=1.8 Hz, 1H), 7.48-7.10 (m, 15H), 7.07 (d, J=8.5 Hz, 1H), 7.00-6.91 (m, 2H), 3.74 (s, 3H), 2.00 (s, 3H), 1.26 (s, 3H) ppm

(62) .sup.13C-NMR (126 MHz, CDCl.sub.3) δ: 154.76, 146.40, 146.13, 141.10, 141.05, 140.00, 138.73, 138.64, 137.15, 137.06, 135.71, 135.37, 135.19, 134.11, 134.10, 132.96, 132.82, 132.24, 132.17, 130.67, 129.96, 129.63, 129.59, 129.57, 129.09, 128.82, 128.77, 128.53, 128.43, 128.36, 128.32, 127.65, 127.49, 127.20, 118.47, 110.40, 55.83, 19.73, 19.42 ppm

(63) .sup.31P-NMR (202 MHz, CDCl.sub.3) δ: −14.88 ppm

(64) [α].sub.D.sup.20=+5.0° (c=1, CHCl.sub.3)

EXAMPLE 6: SYNTHESIS OF DIPHOSPHINE LIGAND BEARING TWO DIFFERENT PHOSPHINE MOTIFS

(65) The synthesis is realized according to the following scheme

(66) ##STR00021##

EXAMPLE 6A

(67) ##STR00022##

(68) To a solution of {2-[2-(5-bromo-2-methylphenyl)-3-methoxy-6-methylphenyl]phenyl}diphenylphosphane (1 eq., 150 mg, 0.272 mmo) in anhydrous Et.sub.2O (3.1 mL) cooled down to −94° C., t-BuLi (2.1 eq., 1.6 M, 0.357 mL, 0.571 mmol) is added dropwise and the reaction is stirred 20 min. A solution of methyl bis(4-methoxy-3,5-dimethylphenyl)phosphinite (2 eq., 180 mg, 0.544 mmol) in anhydrous toluene (0.25 mL) cooled down to −78° C. is then added and the reaction is stirred 1h and was allowed to warm to 0° C. Then the mixture is filtered over a silica plug under argon and then concentrated. Chromatography on silica gel (Et.sub.2O/n-pentane 50:50, product loaded as 20:80 DCM/n-pentane solution) push with argon afforded {3-[2′-(diphenylphosphanyl)-3-methoxy-6-methyl-[1,1′-biphenyl]-2-yl]-4-methylphenyl}bis(4-methoxy-3,5-dimethylphenyl)phosphane (103 mg, 0.133 mmol, 49%) as a white solid.

(69) .sup.1H-NMR (400 MHz, Chloroform-d) δ: 7.61 (dd, J=10.2, 1.6 Hz, 1H), 7.20-7.15 (m, 4H), 7.13-6.86 (m, 12H), 6.81 (dd, J=8.2, 2.4 Hz, 3H), 6.75 (ddd, J=7.4, 5.2, 1.7 Hz, 1H), 6.69 (d, J=7.6 Hz, 2H), 3.62 (s, 3H), 3.61 (s, 3H), 3.59 (s, 3H), 2.09 (s, 6H), 2.07 (s, 6H), 1.94 (s, 3H), 1.09 (s, 3H) ppm

(70) .sup.13C-NMR (126 MHz, CDCl.sub.3) δ: 159.87, 157.92, 155.05, 155.02, 146.38, 146.11, 141.05, 141.00, 138.71, 138.61, 137.42, 137.31, 136.46, 136.39, 136.34, 136.22, 136.14, 135.82, 135.64, 135.58, 135.40, 134.58, 134.43, 134.28, 133.71, 133.28, 133.22, 133.14, 133.06, 132.98, 131.73, 130.91, 129.41, 129.07, 128.37, 128.31, 128.23, 128.20, 127.54, 127.03, 111.06, 110.87, 59.74, 59.69, 56.09, 20.34, 19.43, 16.25, 16.23 ppm

(71) .sup.31P-NMR (162 MHz, CDCl.sub.3) δ: −8.51, −15.18 ppm

(72) [α].sub.D.sup.20 =+426.0° (c=0.32, CHCl.sub.3)

EXAMPLE 6B

(73) ##STR00023##

(74) To a solution of {2-[2-(5-bromo-2-methylphenyl)-3-methoxy-6-methylphenyl]phenyl}diphenylphosphane (1 eq., 110 mg, 0.199 mmol) in anhydrous Et.sub.2O (2.3 mL) cooled down to −94° C., t-BuLi (2.1 eq., 1.6 M, 0.262 mL, 0.419 mmol) is added dropwise and the reaction is stirred 20 min. A solution of methyl bis(4-methylphenyl)phosphinite (2 eq., 97.5 mg, 0.399 mmol) in anhydrous toluene (0.6 mL) cooled down to −78° C. is then added and the reaction is stirred 1h and was allowed to warm to 0° C. Then the mixture is filtered over a silica plug under argon and then concentrated. Chromatography on silica gel (Et.sub.2O /n-pentane 10:90, product loaded as 20:80 DCM/n-pentane solution) push with argon afforded {3-[2′-(diphenylphosphanyl)-3-methoxy-6-methyl-[1,1′-biphenyl]-2-yl]-4-methylphenyl}bis(4-methylphenyl)phosphane (117 mg, 0.172 mmol, 86%) as a colorless oil.

(75) .sup.1H NMR (400 MHz, Chloroform-d) δ: 7.60 (dd, J=10.3, 1.6 Hz, 1H), 7.26-7.16 (m, 5H), 7.12-6.87 (m, 17H), 6.83 (dd, J=8.1, 6.7 Hz, 3H), 6.73 (ddd, J=7.5, 5.3, 1.8 Hz, 1H), 3.63 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.94 (s, 3H), 1.16 (s, 3H) ppm

(76) .sup.31P-NMR (162 MHz, CDCl.sub.3) δ: −8.44, −14.84 ppm

(77) .sup.13C-NMR (101 MHz, CDCl.sub.3) δ: 155.02, 146.50, 146.17, 141.08, 141.02, 138.48, 138.24, 137.86, 137.74, 137.59, 137.35, 137.22, 136.73, 136.62, 136.49, 136.49, 135.34, 135.11, 133.95, 133.91, 133.72, 133.40, 133.22, 133.17, 133.13, 132.99, 132.96, 131.58, 131.54, 129.29, 129.23, 129.17, 129.06, 128.99, 128.86, 128.28, 128.22, 128.11, 128.06, 127.52, 126.90, 110.65, 55.96, 21.35, 21.32, 20.20, 19.51 ppm

(78) [α].sub.D.sup.°=+15.6° (c=1.2, CHCl.sub.3)

EXAMPLE 7: USE OF THE LIGANDS ACCORDING TO THE INVENTION

(79) The ligand according to the invention may be used in asymmetric hydrogenation according to the following scheme

(80) ##STR00024##

(81) General Procedure:

(82) In an oven-dried tube closed with a septum was loaded the substrate (1 equiv). Similarly an oven-dried schlenk closed with a septum was loaded with the metal (1.5-2 mol %) along with the ligand (2-2.5 mol %). Both vessels were evacuated under vacuum and back-filled with argon (4 times). Then the schlenk was put under vacuum, the stopcock closed and the vacuum was carefully broken with an hydrogen balloon. The required solvent was then added by mean of a syringe (˜0.01 M) and the catalyst stock solution was stirred for 15 min in order to properly activate the complex. Meanwhile the required solvent was added to the substrate under argon, a hydrogen balloon fitted with a needle was inserted in the septum, vigorous stirring was started, and the required amount of the solution of the catalyst was added to the substrate (final concentration 0.1 M). The reaction was followed by .sup.1H NMR and upon completion the solvent was removed under reduced pressure, the solid residue dissolved in DCM and filtrated over a silica gel plug to remove the catalyst (eluting with Et.sub.2O or EtOAc) affording the pure, by .sup.1H NMR, product with e.r. 99.5:0.5.

(83) Analysis of the optical purity: Chiral HPLC conditions: ODH column, n-Hex/iPrOH 90:10, 0.5 mL/min, (tr.sub.1: 19.8 min; tr.sub.2: 25.8 min)

(84) TABLE-US-00001 M (mol %) L (mol %) additives(mol %) T(° C.) Solvent Convrsion (%) Ee (%) [Ir(cod).sub.2Cl].sub.2 (2.5) Biaxphos(6) NaBARF(6.5) rt Mesitylene 80 90 [Ir(cod).sub.2Cl].sub.2 (2.5)* Biaxphos(7) NaBARF(7) rt Mesitylene 99 85 *catalyst initially prepared in DCM

(85) In the glove box, the bis(1,5-cyclooctadiene)diiridium(i) dichloride (2.55%, 2.73 mg, 0.00406 mmol), ligand 4.1 (7%, 7.32 mg, 0.0111 mmol) and NaBARF (7%, 9.87 mg, 0.0111 mmol) are placed in a schlenk. On the other hand, the (1E)-6-methoxy-N-phenyl-1,2,3,4-tetrahydronaphthalen-1-imine (1 eq., 40 mg, 0.159 mmol) is added to a tube. Both vessels were closed by a septum, removed from the glovebox and put under vacuum.

(86) The vacuum in the schlenk was broken with an hydrogen balloon and the DCM (0.4 mL) was added. The solution was stirred for 30 min and then the solvent was removed under vacuum. Afterwards, the vacuum is broken with an hydrogen balloon and the mesitylene (0.4 mL) is added. The solution is stirred for 30 min. The mesitylene (1.1 mL) is added to the tube with the substrate under argon and finally the catalyst. The tube is put under hydrogen with a balloon and the reaction is stirred at room temperature for 24 h.

(87) The reaction was followed by .sup.1H NMR and upon completion the solution was filtrated over a celite plug (eluting with DCM) and concentrated to afford the 6-methoxy-N-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine as a brown oil.

(88) Enantiomeric ratio determination was carried out by HPLC on a chiral stationary phase against a racemic reference prepared by reduction of the same substrate NaBH.sub.4 in EtOH.

(89) Analysis of the optical purity: Daicel Chiracel ODH, n-Hex/i-PrOH 99:1, 0.5 mL/min. injection of 1 μL of 5 mg/mL solution in n-Hex/i-PrOH 80:20 (tr.sub.1: 27.3 min; tr.sub.2: 39.8 min).

(90) .sup.1H-NMR (400 MHz, Chloroform-d) δ: 7.31 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 7.3 Hz, 2H), 6.82-6.60 (m, 5H), 4.59 (t, J=4.7 Hz, 1H), 3.80 (s, 3H), 2.99-2.54 (m, 2H), 2.16-1.71 (m, 4H) ppm.