WO1999052915A1 - Chiral phosphorated ligands useful in catalysts - Google Patents

Chiral phosphorated ligands useful in catalysts Download PDF

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Publication number
WO1999052915A1
WO1999052915A1 PCT/EP1999/002432 EP9902432W WO9952915A1 WO 1999052915 A1 WO1999052915 A1 WO 1999052915A1 EP 9902432 W EP9902432 W EP 9902432W WO 9952915 A1 WO9952915 A1 WO 9952915A1
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Prior art keywords
group
formula
alkyl
ligand
phosphorated
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PCT/EP1999/002432
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French (fr)
Inventor
Oreste Piccolo
Emanuela Gancia
Andrea Zaliani
Fausto Bonifacio
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Chemi SpA
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Chemi SpA
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Priority to AT99920633T priority Critical patent/ATE251634T1/en
Priority to DE69911936T priority patent/DE69911936T2/en
Priority to EP99920633A priority patent/EP1070075B1/en
Priority to JP2000543471A priority patent/JP2002511473A/en
Priority to AU38147/99A priority patent/AU3814799A/en
Publication of WO1999052915A1 publication Critical patent/WO1999052915A1/en
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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Definitions

  • the present invention refers to new atropo-isomeric chiral phosphorated ligands having C, symmetry, the procedure for their preparation, the organometallic complexes containing said phosphorated ligands in optically active form, and the use of these complexes as catalysts in stereoselective organic syntheses.
  • Prior art Stereoselective reactions catalysed by enantiomerically pure complexes of transition metals, such as enantio- and/or diastereo-selective reactions of reduction, isomerization, hydroformylation, hydroboration, hydrosilylation, hydrocyanation, allylation, vinylation, and other reactions of formation of the C-C bond, are the subject of considerable interest from the scientific and application standpoints.
  • the catalysts containing C 2 -symmetry atropo-isomeric biheterocyclic ligands described by WO 96/01831 are endowed with a good capacity for inducing stereoselection in the reactions referred to above, they prove less efficient in certain stereoselective reactions, such as hydroformylation, hydrocyanation or hydrosilylation. Consequently, even though the number of organometallic catalysts is high and constantly increasing, the need is felt for identifying new chiral catalysts that are selective, easy to prepare, economical, stable, provided with high productivity, and may be possibly recycled without racemizing and without losing stereoselectivity.
  • the applicant has unexpectedly found a critical selection of molecular parameters which enables the properties of phosphorated ligands to be foreseen, and hence selective and efficient organometallic catalysts to be synthesized, determining a priori the structures of interest, and thus avoiding a purely experimental approach based upon the synthesis and a posteriori verification of the properties of the ligands.
  • a fundamental feature of the present invention hence consists in atropo-isomeric chiral phosphorated ligands of formula (I), having C, symmetry, in the optically active form or in the racemic form, i.e., as individual atropo-isomers or mixtures of these :
  • R 1 and R 2 bound to the phosphorous atoms, equal to or different from one another, are selected from a linear, branched or cyclic C 3 -C 10 alkyl group, a carbocyclic aromatic group (for example, phenyl or naphthyl), and a heterocyclic aromatic group having 5-6 members in the cycle, containing one or more hetero- atoms (for example, 1-2) chosen among oxygen, sulphur and nitrogen, where said carbocyclic or heterocyclic aromatic group is possibly substituted with one or more groups selected from a linear or branched 0,-0, 0 alkyl group, a linear or branched C C 10 alkoxyl group, an halogen, -COOR 4 , -SO 3 R 4 and -NR ⁇ where R 4 is chosen among H, alkyl (for example, C C 10 ), aryl (for example, phenyl), alkaline or alkaline-earth metal, -NH 4 + and alkyl ammonium c
  • R together with the phosphorous atom, or R 2 together with the phosphorus atom, form a heterocycle having 3-6 atoms in the cycle, possibly substituted with linear or branched C r C 10 alkyl groups ;
  • X is an -O- group or an -N(R 7 )- group, where R 7 is chosen among H, alkyl (for example, C C 6 alkyl) and phenyl ; n may have one of the following values : is 0 or 1 , when Ar is a heterocyclic aromatic residue, and n is 1 , when Ar is phenyl ; 4
  • Q,, Q 2 , Z, and Z 2 are selected from the group consisting of H, linear, branched or cyclic 0,-0, 0 alkyl, linear or branched
  • C,-C 10 alkoxyl a carbocyclic aromatic residue (for example, phenyl) and halogen, or Q, taken together with Z,, or Q 2 taken together with Z 2 , form a carbocyclic aromatic ring (for example, phenyl or naphthyl), possibly substituted with one or more T groups (for example, one or two T groups), where T is chosen among halogen, C,-C, 0 alkyl, C,-C, 0 alkokyl, -COOR 4 , -SO 3 R 4 and -NR 5 R 6> where R 4 is selected from H, alkyl (for example, C,-C, 0 alkyl), aryl (for example, phenyl), alkaline or alkaline-earth metal, -NH 4 + or alkyl ammonium cation having from 4 to
  • R 5 and R 6 are selected from H and alkyl (for example, C,-C, 0 alkyl).
  • the groups -P 1 (R 1 ) 2 and -(X) n -P 2 (R 2 ) 2 are bound to the corresponding carbocyclic or heterocyclic aromatic residue by means of a carbon atom of said aromatic residue or by means of a nitrogen atom comprised as hetero-atom in a pentatomic heterocyclic residue.
  • a further subject of the present invention is the procedure of preparation of the above-mentioned ligands of formula (I), comprising: a) construction of the molecular model of a series of structures of ligands of formula (I) as defined above, indicated as (I),, (l) 2 , (l) 3 , — , (l) ZI where z is the number of structures created, carried out by using the computation program SYBYL, Version 6.2; b) conformational analysis, comprising the determination, for each structure from (I), to (l) z , of the minimum-energy conformer, followed by optimisation using the program MOPAC, Version 6.0, Method MNDO; c) calculation, for each minimum-energy conformer structure, of the above defined difference
  • M(diphosphine) imposing that M should be Rh and that the bending constant of the bond P,-M-P 2 should be 0 Kcal/mol, and calculated by using the program SYBYL, Version 6.2, and adopting the parameters of the force field of the program TRIPOS, modified by entering the parameters developed for the Rh-diphosphine complexes by M. Kranenburg et al. [Organometallics, 14, 3081 , 1995]; f) selection of the structures from (I), to (l) n having: 6
  • ⁇ Q(P) Q(P, ) - Q(P 2 ) > 0.05 (preferably > 0.15) ; ii) a cone angle ⁇ n ranging from 80° and 130° (preferably between 83° and
  • organometallic complexes between the optically active form (enanatiomerically pure or at least enriched) of a ligand of formula (I) and a transition metal the procedure for their preparation, and their use in the preparation of an optically active chiral catalyst.
  • Further subjects of the present invention are the use of the present catalyst in stereoselective (diastereoselective or enantioselective) reactions, and therefore the processes of synthesis for the preparation of organic compounds in the form of stereo-isomers, which comprise at least one strereocontrolled reaction carried out in the presence of one of the present optically active chiral catalysts.
  • optically active chiral catalysts of the present invention have unexpectedly been found to be superior to those described by WO 96/01831 in some stereoselective reactions. Brief description of the figures
  • Figures 1-3 show the structures of some examples of phosphorated ligands according to the present invention, indicated as compounds (1 ) - (15). Detailed description
  • the atoms engaged in the bond between the two aromatic cycles are carbon atoms or nitrogen atoms.
  • the present ligands of formula (I) having C, symmetry in which Ar is a heterocycle and those in which Ar is phenyl are represented by the following formulas (l)a and (l)b, respectively :
  • Het, and Het 2 are pentatomic heterocyclic aromatic rings, equal to or different from one another, defined as Het is defined above ; n is 0 or 1 ; and X, A, B, C, D, E, Q,, Q 2 , Z, and Z 2 are as defined above.
  • Het, Het, and Het 2 heterocyclic residues are thiophene, pyrrole, furan, imidazole, isoxazole, isothiazole, pyrazole and triazole.
  • the Het, Het, or Het 2 pentatomic heterocyclic ring is condensed with phenyl or naphthyl.
  • Het, Het, or Het 2 may be, for example, benzothiophene, naphthothiophene, indole, benzofuran or benzoimidazole.
  • Q,, Q 2 , Z, and Z 2 are, for example, methyl.
  • heterocyclic aromatic residues present in the ligands of the present invention are 2,5-dimethyl-thien-3-yl, 4,6-dimethyl-benzofur-3-yl, 3-methyl-indol-2- yl, 1-N-methyl-indol-2-yl and benzothien-3-yl.
  • the carbocyclic aromatic residue is, for example, phenyl.
  • n is, for example, 0.
  • X is, for example, -O-.
  • the groups R, and R 2 are, for example, phenyl or cyclohexyl, hence -P ⁇ R ⁇ and - P 2 (R 2 ) 2 are, for instance, diphenyl phosphine or dicyclohexyl phosphine.
  • the two R, residues bound together with the atom P, (or the two R 2 residues bound together with the atoms P 2 ) represent a cyclic residue J, or J 2
  • Examples of sub-structures contained in the phosphorated ligands of the present invention are: (4-diphenylphosphine)- or (4-dicyclohexylphosphine)-2,5-dimethyl- thien-3-yl; (1-N-diphenylphosphine)- or (1-N-dicyclohexylphosphine)-3- methylindol-2-yl; (3-diphenylphosphine)- or (3-dicyclohexylphosphine)-1-N- methylindol-2-yl; 2-(diphenylphosphine)- or 2-(dicyclohexylphosphine)-benzothien- 3-yl; 2-(diphenylphosphine-oxy)- or 2-(dicyclohexylphosphine-oxy)-phenyl-1-yl; 4- (diphenylphosphine-oxy)- or 4-(dichenylphosphine-
  • Het, and Het 2 are defined as Het ;
  • A, B, C, D, E, Q,, Z,, P,, R,, Q 2 , Z 2 , P 2 , R 2 and T are as defined as for the formula (I) ;
  • m is 0, 1 or 2.
  • transition metals contained in the organometallic complexes of the present invention are Rh, Ru, Ir, Pt, Pd and Ni.
  • the structures of the ligands of formula (I) were created according to step a) of the present procedure by using the SYBYL modelling software, Version 6.2. Then, according to procedures known to the person skilled in the art, a structural investigation was carried out to determine the minimum- energy conformation associated to each individual structure. The reliability of the forecast of the minimum-energy conformer was then increased by subjecting the conformations thus identified to a further structural investigation, defined as 11
  • This ⁇ E corresponds to the maximum possible extension, given by the difference between the energy of the maximum-energy conformers E trans and the energy of the minimum-energy conformer E min , for each ligand examined, and was calculated by imposing that the said maximum energy should be the one associated to the conformer in which the two aromatic rings (the two heterocycles, or the heterocycle and the carbocyclic system) are coplanar.
  • the cone angle ⁇ n is as defined in the article by Casey et al., Isr. J. Chem., 30, 299-304, 1990, and is determined uniquely by the steric compression of the ligand structure, and not by the valence angle of the transition metal chosen for the complexation. However, it was calculated by using a program other than the software program AMBER which was employed according to the said article.
  • Atom i Atom j Type of bond L (A) k i,j (Kcal/mol)
  • the introduction of the groups containing the phosphorous atom may precede or follow the reaction of formation of the inter-annular bond.
  • [M] is an organometallic group, such as for example Li, MgX, ZnX and an organoboron residue, where X is a halogen ;
  • Z is an alkaline metal, such as Li, Na and K ;
  • R, and R 2 are alkyl or aryl residues.
  • Ar is a carbocyclic aromatic or hetero-aromatic residue comprised in the structure of formula (I) ;
  • Ind is an indole residue ;
  • X is a halogen ;
  • Z is an alkaline metal, such as Li, Na and K, or Z is a MgX group ;
  • R, is an alkyl or aryl group ;
  • R 2 is H or an alkyl or aryl group.
  • the present phosphorated ligands comprise basic or acidic groups, for example, amine, carboxyl or sulphone groups
  • the diastereo-isomeric adducts are, for example, the corresponding salts with enantiomerically pure chiral acids or bases.
  • the diastereo-isomeric adducts may be, for example, the diastereo- isomeric salts among enantiomerically pure chiral acids, and the phosphinoxides corresponding to the phosphorated ligands, obtained by phosphorous oxidation according to conventional methods : in this case, optical resolution is followed by reduction of the optically active phosphinoxides to phosphine, by means of a treatment with suitable reducing agents, such as sylans, in non-racemising reaction conditions, for example, according to the procedure described in WO 96/01831.
  • suitable reducing agents such as sylans
  • the complexes between ligands of formula (I) in the optically active form and transition metals are useful as catalysts in enantio- and/or diastereoselective reactions of reduction, hydroformylation, hydroboration, hydrosilylation, hydrocyanation, allylation, vynylation and other reactions of formation of the C-C bond.
  • the aqueous phase is separated, and the organic phase is washed, in order, with an aqueous solution of sodium chloride (10 g in 68.5 ml), an alkaline solution of sodium hyposulphite (6.8 g in 70 ml of 1% sodium hydroxide), and again with an aqueous solution of sodium 18
  • racemic disphosphine is obtained by reduction with trichlorosilane, and is resolved via HPLC on stationary chiral phase.
  • the mixture is then filtered on celite and concentrated under vacuum ; the residue is treated with 30 ml of diethyl ether, and the solution, in inert atmosphere, is fed drop by drop into 5 ml of a t-BuLi solution 1.6 M in penthane at the temperature of -30°C ; then 1.4 ml of chlorodiphenyl phosphine is added, and the reaction mixture is allowed to reconstitute at room temperature.
  • the organic phase is concentrated under vacuum, and the crude reaction product is purified by means of silica chromatography to yield the 4- bromo-2,5-dimethyl-3-propionyl-thiophene phenylhydrazone, which is dissolved in 350 ml of isopropanol/HCI (7.5 M) and kept stirred at room temperature until the reaction is completed.
  • the solvent is removed under reduced pressure, and the residue is treated with methylene chloride.
  • the organic phase is subjected to washings with a saturated solution of sodium bicarbonate, then with water, and finally concentrated under reduced pressure to yield 4.7 g of 2-[3'(4'-bromo-2',5'- dimethyl)-thienyl]-3-methyl-indole.
  • (+)(15) is added under stirring to a 4.2 mmol solution of hexahydrated NiCI 2 in 30 ml of ethanol. After 1 h the mixture is concentrated to a small volume, and the residue is squashed with ethanol and subsequently dried under vacuum.
  • the complex is used as such in enantoselective reactions of formation of C-C bonds. It is assumed that the complex obtained has the following structure:
  • (+)(15) and 2.6 mmol of PdCI 2 (benzonitrile) 2 is kept under stirring for 1 h at room temperature.
  • the mixture is concentrated to a small volume and the residue is squashed with ethanol and subsequently dried under vacuum.
  • the complex obtained is used as such in enantioselective reactions of formation of C-C bonds. It is assumed that the complex obtained has the following structure: [PdCI 2 (compound (+)(15)]. Using the same procedure, similar complexes of palladium were prepared with the other optically active phosphines of Table 7.

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Abstract

Described herein are new atropo-isomeric chiral phosphorated ligands having C1 symmetry, the procedure for their preparation, the organometallic complexes containing said ligands in optically active form, and the use of said complexes as catalysts in stereoselective syntheses.

Description

1
CHIRAL PHOSPHORATED LIGANDS USEFUL IN CATALYSTS
Scope of invention
The present invention refers to new atropo-isomeric chiral phosphorated ligands having C, symmetry, the procedure for their preparation, the organometallic complexes containing said phosphorated ligands in optically active form, and the use of these complexes as catalysts in stereoselective organic syntheses. Prior art Stereoselective reactions catalysed by enantiomerically pure complexes of transition metals, such as enantio- and/or diastereo-selective reactions of reduction, isomerization, hydroformylation, hydroboration, hydrosilylation, hydrocyanation, allylation, vinylation, and other reactions of formation of the C-C bond, are the subject of considerable interest from the scientific and application standpoints. The patent application WO 96/01831 describes chiral diphosphines consisting of a C2-symmetry atropo-isomeric biheterocyclic pentatomic aromatic system, which, by complexation with transition metals, give rise to chiral catalysts capable of inducing good stereoselection in enantio- and/or diastereo-selective reduction and isomerization reactions. Technical problem
For the use on an industrial scale of chiral organometallic catalysts, in addition to the stereoselectivity induced by these catalysts, of great importance are factors such as their cost, stability, productivity (kg of product per kg of catalyst per day), and the possibility of efficient recycling in the absence of racemization and loss of stereoselection. In addition, there does not exist a catalyst which is suitable for any reaction, nor, given the same reaction, for any substrate. For example, even though the catalysts containing C2-symmetry atropo-isomeric biheterocyclic ligands described by WO 96/01831 are endowed with a good capacity for inducing stereoselection in the reactions referred to above, they prove less efficient in certain stereoselective reactions, such as hydroformylation, hydrocyanation or hydrosilylation. Consequently, even though the number of organometallic catalysts is high and constantly increasing, the need is felt for identifying new chiral catalysts that are selective, easy to prepare, economical, stable, provided with high productivity, and may be possibly recycled without racemizing and without losing stereoselectivity. The search for new and efficient asymmetric catalysts is still based upon the synthesis and experimental verification of a large number of compounds. Even though an approach of this kind may be fruitful in some cases, it entails numerous disadvantages in terms of work and costs, and often leads to unsatisfactory results. Summary
Now the applicant has unexpectedly found a critical selection of molecular parameters which enables the properties of phosphorated ligands to be foreseen, and hence selective and efficient organometallic catalysts to be synthesized, determining a priori the structures of interest, and thus avoiding a purely experimental approach based upon the synthesis and a posteriori verification of the properties of the ligands.
A fundamental feature of the present invention hence consists in atropo-isomeric chiral phosphorated ligands of formula (I), having C, symmetry, in the optically active form or in the racemic form, i.e., as individual atropo-isomers or mixtures of these :
P2(R2)2
Figure imgf000004_0001
(I)
wherein the atoms A, B, C, D, E and F, which are equal to or different from one another, 3
are carbon atoms or hetero-atoms chosen from among oxygen, nitrogen and sulphur, which form together an Ar of Het aromatic residue, where Ar is chosen between pentatomic heterocyclic residue and phenyl, and Het is a pentatomic heterocyclic residue, and where said pentatomic heterocyclic aromatic residue contains 1 or 2 hetero-atoms, equal to or different from one another, selected from the group consisting of -O-, -S- and -NR3-, wherein R3 = H, an alkyl group (for example, C^Ce), an aromatic group (for example, phenyl), a group -P1(R1)2, or a nitrogen atom comprised as hetero-atom in the other pentatomic heterocyclic residue belonging to the structure of formula (I) ; 1 = 0, 1 ; when I =1 , F is a carbon atom ;
R1 and R2, bound to the phosphorous atoms, equal to or different from one another, are selected from a linear, branched or cyclic C3-C10 alkyl group, a carbocyclic aromatic group (for example, phenyl or naphthyl), and a heterocyclic aromatic group having 5-6 members in the cycle, containing one or more hetero- atoms (for example, 1-2) chosen among oxygen, sulphur and nitrogen, where said carbocyclic or heterocyclic aromatic group is possibly substituted with one or more groups selected from a linear or branched 0,-0,0 alkyl group, a linear or branched C C10 alkoxyl group, an halogen, -COOR4, -SO3R4 and -NR^ where R4 is chosen among H, alkyl (for example, C C10), aryl (for example, phenyl), alkaline or alkaline-earth metal, -NH4 + and alkyl ammonium cation having from 4 to 20 carbon atoms ; and where R5 and R6, equal to or different from one another, are H or alkyl (for example, C C10 alkyl) ; or
R, together with the phosphorous atom, or R2 together with the phosphorus atom, form a heterocycle having 3-6 atoms in the cycle, possibly substituted with linear or branched CrC10 alkyl groups ;
X is an -O- group or an -N(R7)- group, where R7 is chosen among H, alkyl (for example, C C6 alkyl) and phenyl ; n may have one of the following values : is 0 or 1 , when Ar is a heterocyclic aromatic residue, and n is 1 , when Ar is phenyl ; 4
Q,, Q2, Z, and Z2, equal to or different from one another, are selected from the group consisting of H, linear, branched or cyclic 0,-0,0 alkyl, linear or branched
C,-C10 alkoxyl, a carbocyclic aromatic residue (for example, phenyl) and halogen, or Q, taken together with Z,, or Q2 taken together with Z2, form a carbocyclic aromatic ring (for example, phenyl or naphthyl), possibly substituted with one or more T groups (for example, one or two T groups), where T is chosen among halogen, C,-C,0 alkyl, C,-C,0 alkokyl, -COOR4, -SO3R4 and -NR5R6> where R4 is selected from H, alkyl (for example, C,-C,0 alkyl), aryl (for example, phenyl), alkaline or alkaline-earth metal, -NH4 + or alkyl ammonium cation having from 4 to
12 carbon atoms, and where R5 and R6, equal to or different from one another, are selected from H and alkyl (for example, C,-C,0 alkyl).
The groups -P1(R1)2 and -(X)n-P2(R2)2 are bound to the corresponding carbocyclic or heterocyclic aromatic residue by means of a carbon atom of said aromatic residue or by means of a nitrogen atom comprised as hetero-atom in a pentatomic heterocyclic residue.
The ligands in question moreover present: i) a difference between the residual charges of the phosphorous atoms ΔQ(P) = Q(P,) - Q(P2) > 0.05 (preferably > 0.15), where Q(P,) and Q(P2) are the values of difference between the number of valence electrons and the number of electrons actually present for the phosphorous atoms P, and P2; ii) a cone angle βn ("natural bite angle" according to Casey), ranging from 80° to
130°, preferably from 83° to 120°, defined as preferred chelation angle P,-M-P2 , between the phosphorous atoms P, and P2 and a transition metal M, obtained by minimization of the strain energy of the fragment M(diphosphine), choosing Rh as transition metal; iii) a value of the barrier of interconversion energy between the two enantiomers of a given iigand ΔE = E^- - Emin > 28 Kcal/mol, 5
where E^- is the energy value for the transition state, and Emin is the energy value for the state of minimum energy of the enantiomers, expressed in Kcal/mol. A further subject of the present invention is the procedure of preparation of the above-mentioned ligands of formula (I), comprising: a) construction of the molecular model of a series of structures of ligands of formula (I) as defined above, indicated as (I),, (l)2, (l)3, — , (l)ZI where z is the number of structures created, carried out by using the computation program SYBYL, Version 6.2; b) conformational analysis, comprising the determination, for each structure from (I), to (l)z, of the minimum-energy conformer, followed by optimisation using the program MOPAC, Version 6.0, Method MNDO; c) calculation, for each minimum-energy conformer structure, of the above defined difference
ΔQ(P) = Q(P,) - Q(P2), by using the computation program MOPAC, Version 6.0, Method MNDO; d) calculation, for each structure from (I), to (l)z, of the value of the above defined interconversion energy barrier between the two enantiomers (atropo-isomers) of formula (I)
* '— ~" '-trans " *-min> by means of the computation program MOPAC, Version 6.0, Method MNDO, imposing that the value E^.. should be that of the maximum-energy conformer having the two rings Ar and Het of the structure (I) coplanar with respect to one another; e) calculation, for each structure from (I), to (l)z, of the natural bite angle βn, as defined above, obtained by minimization of the strain energy of the fragment
M(diphosphine), imposing that M should be Rh and that the bending constant of the bond P,-M-P2 should be 0 Kcal/mol, and calculated by using the program SYBYL, Version 6.2, and adopting the parameters of the force field of the program TRIPOS, modified by entering the parameters developed for the Rh-diphosphine complexes by M. Kranenburg et al. [Organometallics, 14, 3081 , 1995]; f) selection of the structures from (I), to (l)n having: 6
i) ΔQ(P) = Q(P, ) - Q(P2) > 0.05 (preferably > 0.15) ; ii) a cone angle βn ranging from 80° and 130° (preferably between 83° and
120°) ; iii) an interconversion energy barrier between the two enantiomers of one and the same structure ΔE > 28 Kcal/mol ; g) chemical synthesis of the phosphorated ligands of formula (I) thus selected. The structure of the compounds of formula (I) in which n is 1 , and X is -O- or -NR7 has been identified by setting by approximation that
C.3 - P2 ≡ N- P2 = O- P2I i.e., that the phosphorous atom P2 is directly bound to a tetrahedral carbon atom C.3, instead of to oxygen or nitrogen, and hence by using for the bonds N-P2 and O-P2 the same calculation parameters as those used for the bond C.3 -P2 . Once resolved into their optical antipodes, the present atropo-isomeric chiral phosphorated ligands of formula (I), having C, symmetry, are useful in the preparation of complexes with transition metals, which are in turn useful as catalysts in stereoselective reactions.
Further aspects of the present invention are therefore represented by the organometallic complexes between the optically active form (enanatiomerically pure or at least enriched) of a ligand of formula (I) and a transition metal, the procedure for their preparation, and their use in the preparation of an optically active chiral catalyst. Further subjects of the present invention are the use of the present catalyst in stereoselective (diastereoselective or enantioselective) reactions, and therefore the processes of synthesis for the preparation of organic compounds in the form of stereo-isomers, which comprise at least one strereocontrolled reaction carried out in the presence of one of the present optically active chiral catalysts.
The optically active chiral catalysts of the present invention have unexpectedly been found to be superior to those described by WO 96/01831 in some stereoselective reactions. Brief description of the figures
Figures 1-3 show the structures of some examples of phosphorated ligands according to the present invention, indicated as compounds (1 ) - (15). Detailed description
In the phosphorated ligands of the present invention, the atoms engaged in the bond between the two aromatic cycles are carbon atoms or nitrogen atoms. The present ligands of formula (I) having C, symmetry in which Ar is a heterocycle and those in which Ar is phenyl are represented by the following formulas (l)a and (l)b, respectively :
Figure imgf000009_0001
Het,
Figure imgf000009_0002
(l)a (l)b wherein
Het, and Het2 are pentatomic heterocyclic aromatic rings, equal to or different from one another, defined as Het is defined above ; n is 0 or 1 ; and X, A, B, C, D, E, Q,, Q2, Z, and Z2 are as defined above.
The condition that the above-mentioned ligands should have C, symmetry imposes that the two substituted aromatic residues present in formula (I) are not mutually specular. Hence, in the case of the ligands of formula (l)a, at least one of the following requirements must be met : R, ≠ R2,
Het, ≠ Het2,
Q ≠ Q2, Z, ≠ Z2, or n = 1. In the case where Het, = Het2, R, = R2, Q, = Q2, Z, = Z2, and n = 0, the C,-type asymmetry occurs, for example, when the two pentatomic cyclic residues, even if they derive from the same type of aromatic heterocycle, are bound together via two different relative positions with respect to the hetero-atom, for example via the position 2' of Het, and the position 3' of Het2.
Examples of Het, Het, and Het2 heterocyclic residues are thiophene, pyrrole, furan, imidazole, isoxazole, isothiazole, pyrazole and triazole. When the substituents Q, and Z, taken together, or Q2 and Z2 taken together, form a carbocyclic aromatic ring, the Het, Het, or Het2 pentatomic heterocyclic ring is condensed with phenyl or naphthyl. In this case Het, Het, or Het2 may be, for example, benzothiophene, naphthothiophene, indole, benzofuran or benzoimidazole.
Q,, Q2, Z, and Z2 are, for example, methyl. Examples of heterocyclic aromatic residues present in the ligands of the present invention are 2,5-dimethyl-thien-3-yl, 4,6-dimethyl-benzofur-3-yl, 3-methyl-indol-2- yl, 1-N-methyl-indol-2-yl and benzothien-3-yl. The carbocyclic aromatic residue is, for example, phenyl. n is, for example, 0. When n = 1 , X is, for example, -O-. For example, in certain compounds Ar = phenyl, n = 1 and X = -O-.
The groups R, and R2 are, for example, phenyl or cyclohexyl, hence -P^R^ and - P2(R2)2 are, for instance, diphenyl phosphine or dicyclohexyl phosphine. According to other embodiments of the present invention, the two R, residues bound together with the atom P, (or the two R2 residues bound together with the atoms P2) represent a cyclic residue J, or J2
P"
Figure imgf000010_0001
(phospholyl) (2\5'-dimethyl-phospholyl) or a polycyclic aromatic residue, for example, of formula J3
Figure imgf000011_0001
(dibenzophospholyl) Examples of sub-structures contained in the phosphorated ligands of the present invention are: (4-diphenylphosphine)- or (4-dicyclohexylphosphine)-2,5-dimethyl- thien-3-yl; (1-N-diphenylphosphine)- or (1-N-dicyclohexylphosphine)-3- methylindol-2-yl; (3-diphenylphosphine)- or (3-dicyclohexylphosphine)-1-N- methylindol-2-yl; 2-(diphenylphosphine)- or 2-(dicyclohexylphosphine)-benzothien- 3-yl; 2-(diphenylphosphine-oxy)- or 2-(dicyclohexylphosphine-oxy)-phenyl-1-yl; 4- (diphenylphosphine-oxy)- or 4-(dicyclohexylphosphine-oxy)-2,5-dimethyl-thien-3- yl; 4-(2',5,-dimethyl-phospholyl)- or 4-(dibenzophospholyl)-2,5-dimethyl-thien-3-yl; 1 -N-(2',5'-dimethyl-phospholyl)- or 1 -N-(dibenzophospholyl)-3-methyl-indol-2-yl. Examples of the present C,-symmetry atropo-isomeric ligands are the ligands of formulas (l)c, (l)d, and (l)e represented below:
.p2.
Figure imgf000011_0003
"cy;. Rι
E— — D
Figure imgf000011_0002
Figure imgf000011_0004
10
Figure imgf000012_0001
(|)e
In the structures (l)c, (l)d and (l)e, Het, and Het2 are defined as Het ; A, B, C, D, E, Q,, Z,, P,, R,, Q2 , Z2, P2, R2 and T are as defined as for the formula (I) ; m is 0, 1 or 2. Examples of transition metals contained in the organometallic complexes of the present invention are Rh, Ru, Ir, Pt, Pd and Ni.
Construction of the molecular models, conformational analysis, and calculation of the "natural bite angle" were carried out by using the S/W program SYBYL, Version 6.2 [Sybyl; Tripos Associates, 193 S. Hasley Road, Suite 363, St. Louis MO 63144].
Minimisation of the structures, calculation of the energy levels associated to the ground state and to the transition state, and the value of the atomic charges were determined by using the program MOPAC, Version 6.0, Method MNDO [J.P. Stewart, J. Comp. - Aideed Molec. Design, 4 (1), 1990 ; QCPE, Quantum Chemistry Program Exchange - QCMP019 Indiana University - Chemistry Department].
More particularly, the structures of the ligands of formula (I) were created according to step a) of the present procedure by using the SYBYL modelling software, Version 6.2. Then, according to procedures known to the person skilled in the art, a structural investigation was carried out to determine the minimum- energy conformation associated to each individual structure. The reliability of the forecast of the minimum-energy conformer was then increased by subjecting the conformations thus identified to a further structural investigation, defined as 11
"optimisation", by using the program MOPAC, Version 6.0, method MNDO, via which the energy levels of the conformers were calculated, as well as the values of the residual charge quantities Q(P,) and Q(P2) for the phosphorous atoms P, and P2, and then the ΔQ(P) as defined above. A further parallel optimisation investigation was carried out, again using the program MOPAC, Version 6.0, method MNDO, to determine the value of the interconversion energy barrier ΔE between the two enanatiomers (atropo- isomers), or racemisation energy barrier, for each structure of formula (I). This ΔE, as defined above, corresponds to the maximum possible extension, given by the difference between the energy of the maximum-energy conformers Etrans and the energy of the minimum-energy conformer Emin, for each ligand examined, and was calculated by imposing that the said maximum energy should be the one associated to the conformer in which the two aromatic rings (the two heterocycles, or the heterocycle and the carbocyclic system) are coplanar. For the purposes of the present invention, the cone angle βn is as defined in the article by Casey et al., Isr. J. Chem., 30, 299-304, 1990, and is determined uniquely by the steric compression of the ligand structure, and not by the valence angle of the transition metal chosen for the complexation. However, it was calculated by using a program other than the software program AMBER which was employed according to the said article.
In fact, according to the present procedure, the cone angle is calculated by using the program SYBYL, Version 6.2, assuming that M = Rh and using the force field parameters of the program TRIPOS, modified by entering the parameters developed for the Rh-diphosphine complexes by M. Kranenburg et al. [Organometallics, 14, 3081 , 1995] : by means of this modified program, the optimal geometry of the ligand-metal complex was determined, associating the preferred cone angle to the structure of the minimum-energy conformer. The parameters developed by M. Kranenburg and entered in the TRIPOS force field, which are used in the procedure of the present invention, are given in the following Tables 1-6, in which: H = hydrogen; A = angstrom 12
P.p = phosphorous atom
C.3 = saturated carbon atom (sp3) bound to the phosphorous Car = aromatic carbon atom bound to the phosphorous Rh = rhodium; s = single bond; ar =aromatic bond 11
Table 1
BOND LENGTHS
Atom i Atom j Type of bond Bond length (A)
H P-P s 1.43
C.3 P-P s 1.85
Car P-P s 1.83
Rh P-P s 2.315
Figure imgf000014_0001
Table 2
BOND TYPES
Atom i Atom j Type of bond Ambiguity
H P-P s no
C.3 P.p s no
Car P-P s no
Rh P-P s no
Figure imgf000014_0002
13
Table 3
BENDING ANGLE
Atom i Atom j Atom k Theta k (Kcal/mol-degrees2)
H P-P H 93.4 0.02
C.3 P-P H 95 0.02
Car P-P C.3 96 0.02
Rh P-P Car 100 0.02
P-P Rh P.p 120 0.02
Car P-P Rh 109.5 0.02
Figure imgf000015_0001
Theta = bending angle between the atoms considered, expressed in degrees k (kcal/mol-degrees2) = bending force
Table 4
STRETCHING ANGLE - Calculation parameters
Atom i Atom j Type of bond L (A) k i,j (Kcal/mol)
C3 P-P s 1.85 350
H P-P s 1.43 700
Car P-P s 1.83 1000
P.p Rh s 2.315 700
Figure imgf000015_0002
L (A) = bond length in angstrom k i,j = stretching force 14
Table 5
ROTATIONAL BARRIER - Calculation parameters
Atom i Atom j Atom k Atom 1 Type of bond k (Kcal/mol) P
* C.3 *
P-P s 0.4 3
* Car *
P-P s 1 3
* Car *
P-P ar 1 3
C.3 P-P Rh P.P s 0.2 3
Car P-P Rh P.P s 0.2 3
Car Car Rh P.P s 0.2 3
Car C.3 P-P Rh s 0.2 3
Figure imgf000016_0001
k = rotational force P = periodicity
Table 6
Van der Waals radius
Atom r (A) k (kcal/mol)
P-P 1.8 0.314
Rh 1.844 0.63
Figure imgf000016_0002
r (A) = Van der Waals radius expressed in angstrom k = Van der Waals force
The chemical synthesis of the phosphorated ligands according to the present invention is carried out according to one of the following general procedures, in themselves known:
A) coupling reaction between aromatic or hetero-aromatic halides with organometallic aryl or hetero-aryl reactants, such as organolithium, organomagnesium, organozinc, organoboron, etc., in the presence of catalytic 15
quantities of salts or complexes of copper, nickel, or palladium [see, for example,
Takao Sakamoto, Yoshinori Kondo, Nobuo Takazawa, Hiroshi Yamanaka, J.
Chem. Soc, Perkin Trans., 1 , 1996, Pages 1927-1929];
B) cyclisation and aromatisation, with formation of one of the two heterocyclic rings comprised in the structure of formula (I), of a suitable precursor already containing the other heterocyclic or carbocyclic system.
The introduction of the groups containing the phosphorous atom may precede or follow the reaction of formation of the inter-annular bond.
In the case of phosphine derivatives, for example, one of the following reactions in themselves known will be used:
Ar-[M] + XP(R,)2 → Ar-P(R,)2
Ar-[M] + XP(=O) (R,)2 → Ar-P(=O)(R,)2 → Ar-P(R,)2
Ar-[M] + (R20)2P(=O)(R,)- Ar2-P(=O)(R,) → Ar2-PR,
Ar-X + ZP(R,)2 → Ar-P(R,)2 wherein Ar is an aromatic residue comprised in the structure of formula (I) ; [M] is an organometallic group, such as for example Li, MgX, ZnX and an organoboron residue, where X is a halogen ; Z is an alkaline metal, such as Li, Na and K ; R, and R2 are alkyl or aryl residues.
In the case of phosphite or aminophosphine derivatives, for example, one of the following reactions, in themselves known, is used :
Ar-OH + XP(R,)2 -> Ar-OP(R,)2
Ind-NZ + XP(R,)2 → lnd-NP(R,)2
Ind-NZ + XP(=O)(R,)2 → lnd-NP(=O)(R,)2 → lnd-NP(R,)2
Ar-NHR2 + XP(R,)2 → Ar-NR2P(R,)2 Ar-X + ZOP(R,)2 → Ar-OP(R,)2 wherein Ar is a carbocyclic aromatic or hetero-aromatic residue comprised in the structure of formula (I) ; Ind is an indole residue ; X is a halogen ; Z is an alkaline metal, such as Li, Na and K, or Z is a MgX group ; R, is an alkyl or aryl group ; R2 is H or an alkyl or aryl group. The resolution of the present phosphorated ligands into their optical antipodes is carried out according to techniques in themselves known; for example, by 16
separation on chromatographic column or through membrane, by using a chiral stationary substrate or a chiral eluent, or by means of fractioned crystallisation of a corresponding diastereomeric adduct. If the present phosphorated ligands comprise basic or acidic groups, for example, amine, carboxyl or sulphone groups, the diastereo-isomeric adducts are, for example, the corresponding salts with enantiomerically pure chiral acids or bases. Alternatively, the diastereo-isomeric adducts may be, for example, the diastereo- isomeric salts among enantiomerically pure chiral acids, and the phosphinoxides corresponding to the phosphorated ligands, obtained by phosphorous oxidation according to conventional methods : in this case, optical resolution is followed by reduction of the optically active phosphinoxides to phosphine, by means of a treatment with suitable reducing agents, such as sylans, in non-racemising reaction conditions, for example, according to the procedure described in WO 96/01831. The preparation of the complexes with transition metals of the present phosphorated ligands is carried out according to techniques in themselves known. The complexes between ligands of formula (I) in the optically active form and transition metals are useful as catalysts in enantio- and/or diastereoselective reactions of reduction, hydroformylation, hydroboration, hydrosilylation, hydrocyanation, allylation, vynylation and other reactions of formation of the C-C bond.
There follow a number of examples given to provide a non-limiting illustration of the present invention. EXPERIMENTAL PART Calculation of the parameters of some phosphorated ligands
Applying the procedure of the present invention, the phosphorated ligands having the structures from (1 ) to (15) illustrated in Figures 1-3, a calculated interconversion energy barrier = 28 Kcal/mole, and the calculated values of ΔQ(P) and of the natural bite angle according to Casey as given in the following Table 7, have been identified : 17
Table 7
Compound ΔQ(P) Natural bite angle
(1 ) 0.07 86.7
(2) 0.35 97.3
(3) 0.47 108.6
(4) 0.18 97.1
(5) 0.37 88.3
(6) 0.23 83.7
(7) 0.46 97.5
(8) 0.23 93.3
(9) 0.41 99.7
(10) 0.18 87.3
(11 ) 0.27 98.7
(12) 0.24 84.4
(13) 0.20 118.8
(14) 0.45 104.1
(15) 0.27 99.3
Figure imgf000019_0001
Preparation of intermediate compounds
EXAMPLE 1
Preparation of 3-diphenyl phosDhine-2.5-dimethyl-thiophene
Into a flask, in the following order are introduced : 13.6 ml of water, 4.1 g of sodium iodate, 7.3 g of iodine, 26 ml of acetic acid, 91 ml of ethyl acetate, and 7.8 g of 2,5-dimethyl-thiophene. The mixture is kept under stirring at 25°C, while 3.2 g of 96% sulphuric acid are fed in slowly drop by drop The mixture is then kept under stirring for 10 hours, cooled down to 15°C, and an aqueous solution of sodium chloride (10 g in 68.5 ml) is added. The aqueous phase is separated, and the organic phase is washed, in order, with an aqueous solution of sodium chloride (10 g in 68.5 ml), an alkaline solution of sodium hyposulphite (6.8 g in 70 ml of 1% sodium hydroxide), and again with an aqueous solution of sodium 18
chloride (10 g in 68.5 ml). The organic phase is then dried on sodium sulphate and concentrated to yield 16.4 g of crude 3-iodo-2,5-dimethylthiophene. This residue, in inert atmosphere, is treated with 50 ml of DMF, and the following are added: 8.8 g of potassium acetate, 2 mg of palladium acetate, and 13.8 ml of diphenyl phosphine. The mixture is heated up to approximately 130°C and kept at this temperature until the reaction is completed (approximately 15 hours). The mixture is then cooled to approximately 30°C and diluted with 20 ml of water and 300 ml of methylene chloride. The dichloromethylene phase is separated and washed with 30 ml of water. After concentration to dry residue, 18.5 g are obtained of 3- diphenyl phosphine-2,5-dimethyl-thiophene. EXAMPLE 2
Preparation of 3-dicvclohexyl phosphine-2.5-dimethyl-thiophene 100 ml of a t-BuLi solution 1.5 M in penthane are fed drop by drop, in inert atmosphere and under stirring, into a solution containing 33.1 g of 3-iodo-2,5- dimethylthiophene prepared according to Example 1 and 18.7 g of tetramethylendiamine in 150 ml of THF anhydrous, at -50°C The temperature of the mixture is made to rise to -20°C in 30 minutes. A solution of chloro- dicyclohexyl-phosphine (36 g) in 40 ml of THF is then fed in drop by drop, and the mixture is kept under stirring while the temperature is brought to 20°C in 4 hours. The mixture is then treated with 50 ml of water and concentrated under vacuum. The residue is treated with 300 ml of methylene chloride. The dichloromethane phase is washed with water (30 ml x 2), then concentrated to residue to yield 28.5 g of crude 3-dicyclohexyl phosphine-2,5-dimethylthiophene. The product is purified by means of silica gel chromatography. EXAMPLE 3
Prepartion of 3-diphenylphosphinyl-4-bromo-2.5-dimethyl-thiophene Into a flask, in the following order are inserted : 1.5 g of 3-diphenyl phosphine-2,5- dimethyl-thiophene prepared according to Example 1 and 32 ml of methylene chloride. The mixture is kept stirred at -10°C, and at the same time 2.5 g of N- BROMOSUCCINIMIDE are added slowly in portions. The mixture is then kept under stirring for 15 h, at 25°C, then refluxed after addition of a further 1.3 g of N- 19
BROMOSUCCINIMIDE. After a further 20 h of reaction, 20 ml of water are added, and the phases are separated. The organic phase, re-united to the dichloromethane extract (15 ml) of the aqueous phase, is washed with an aqueous solution of sodium chloride (2 g in 15 ml). The organic phase is then dried on sodium sulphate and concentrated. The residue obtained is purified using silica chromatography to yield 0.9 g of 3-diphenylphosphiny!-4-bromo-2,5- dimethylthiophene. EXAMPLE 4 Preparation of 3-dicvclohexylphosphinyl-4-bromo-2.5-dimethyl-thiophene Proceeding as in Example 3 and using 1.8 g of 3-dicyclohexyl phosphine-2,5- dimethyl-thiophene instead of 1.5 g of 3-diphenyl phosphine-2,5-dimethyl- thiophene, 1.2 g of 3-dicyclohexylphosphinyl-4-bromo-2,5-dimethyl-thiophene are obtained. Preparation of phosphorated ligands of the invention EXAMPLE 5
Preparation of (+) and (-) 4-diohenyl phosphine-3-|"3'(4'-dicvclohexyl phosphine- 2'.5'-dimethyl(thienvm-2.5-dimethyl-thiophene rcompound (15)] A solution of 3-dicyclohexylphosphinyl-4-bromo-2,5-dimethyl-thiophene (3.4 g) prepared according to Example 4 in 20 ml of diethyl ether is fed drop by drop in inert atmosphere into 5 ml of a t-BuLi solution 1.5 M in penthane, at -30°C The mixture is kept under stirring for 2 h, then 2.5 g of zinc iodide are added to it, and the mixture is allowed to warm up to room temperature. Then a solution of 3- diphenylphosphinyl-4-bromo-2,5-dimethyl-thiophene (3.4 g), prepared according to Example 3, and palladium tetrakistriphenyl phosphine (87 mg) in 20 ml of anhydrous tetrahydrofuran is added to it, and the mixture is refluxed until completion of the reaction. The mixture is then treated with 200 ml of water, vacuum-concentrated to a small volume, and the residue treated with 200 ml of toluene; the organic phase is separated and washed with 30 ml of water, filtered on celite and concentrated to yield 2.8 g of crude (±) 4-diphenylphosphinyl-3-[3'- (4'-dicyclohexylphosphinyl-2',5'-dimethyl)thienyl]-2,5-dimethyl-thiophene. The product is purified via silica chromatography, and resolved in its optical antipodes 20
by crystallization of the diastereo-isomeric salts, using enantiomerically pure dibenzoyltartaric acid, for example, according to the procedure described in WO 96/01831. The diastereo-isomerically pure adducts are then unblocked using sodium hydroxide and reduced with trichlorosilane, according to the procedure described in Example 2 of the patent application WO 96/01831 , thus yielding approximately 0.7 g of (+) - and (-)-4-diphenyl phosphine-3-[3'(4'-dicyclohexyl phosphine^'.δ'-dimethyljthienyl^.δ-dimethyl-thiophene.
Alternatively, starting from the racemic diphosphine oxide, the racemic disphosphine is obtained by reduction with trichlorosilane, and is resolved via HPLC on stationary chiral phase. EXAMPLE 6
Preparation of (+) and (-) 2-diphenyl phosphine-3-r3'(4'-dicvclohexyl phosohine- 2'.5'-dimethyl(thienvπi-4.6-dimethyl-benzofuran fcompound (2)1 A solution of 3-dicyclohexylphosphinyl-4-bromo-2,5-dimethyl-thiophene (3.4 g) prepared according to Example 4 in 20 ml of diethyl ether is fed drop by drop in inert atmosphere into 5 ml of a 1.6 M of t-BuLi solution in penthane at -30°C; the mixture is kept under stirring for 2 h, then 2.5 g of zinc iodide are added to it, and the mixture is allowed to warm up to room temperature. Then a solution of 3- bromo-4,6-dimethyl-benzofuran (1.7 g), prepared according to Example 23 of the patent application WO 96/01831 , and palladium tetrakis-triphenylphosphine (57 mg) in 20 ml of anhydrous tetrahydrofuran is added, and the mixture is refluxed until the reaction is completed. The mixture is then filtered on celite and concentrated under vacuum ; the residue is treated with 30 ml of diethyl ether, and the solution, in inert atmosphere, is fed drop by drop into 5 ml of a t-BuLi solution 1.6 M in penthane at the temperature of -30°C ; then 1.4 ml of chlorodiphenyl phosphine is added, and the reaction mixture is allowed to reconstitute at room temperature. After hydrolysis with water, the organic phase is separated and concentrated under reduced pressure; the residue is treated with xylene and reduced with trichlorosilane according to the procedure mentioned previously, to yield 2.5 g of (±) 2-diphenyl phosphine-3-[3'-(4,-dicyclohexylphosphinyl-2,,5'- dimethyl)thienyl]-4,6-dimethyl-benzofuran, which is resolved via HPLC on chiral 21
stationary phase.
EXAMPLE 7
Preparation of (+) and (-) 2-diphenyl phosphine-3-r3'(4'-diphenyl phosphine-2'.5'- dimethyl(thienylϊl-4,6-dimethyl-benzofuran [compound (1 )] The procedure of Example 6 is repeated using 3.3 g of 3-diphenylphosphinyl-4- bromo-2,5-dimethyl-thiophene, prepared as described in Example 3, instead of the
3.4 g of 3-dicyclohexylphosphinyl-4-bromo-2,5-dimethyl-thiophene, to recover 2.2 g of racemic 2-diphenyl phosphine-3-[3'(4'-diphenyl phosphine-2',5'- dimethyl(thienyl)]-4,6-dimethyl-benzofuran, which is resolved into its optical antipodes by means of HPLC on chiral stationary phase.
EXAMPLE 8
Preparation of (+) and (- N-diphenyl phosphine-2-[3'(4'-diphenyl phosphine-2'.5'- dimethyl(thienylY|-3-methyl-indole rcompound (6)]
To a solution of 4-bromo-2,5-dimethyl-3-propionyl-thiophene (12 g) and phenylhydrazine (34.9) in 250 ml of ethanol are added 61 ml of acetic acid. The mixture is reflux-heated for 4 h, then concentrated under reduced pressure and the residue treated with methylene chloride; the organic phase is washed with a saturated solution of sodium bicarbonate and subsequently with water until neutral pH is obtained. The organic phase is concentrated under vacuum, and the crude reaction product is purified by means of silica chromatography to yield the 4- bromo-2,5-dimethyl-3-propionyl-thiophene phenylhydrazone, which is dissolved in 350 ml of isopropanol/HCI (7.5 M) and kept stirred at room temperature until the reaction is completed. The solvent is removed under reduced pressure, and the residue is treated with methylene chloride. The organic phase is subjected to washings with a saturated solution of sodium bicarbonate, then with water, and finally concentrated under reduced pressure to yield 4.7 g of 2-[3'(4'-bromo-2',5'- dimethyl)-thienyl]-3-methyl-indole.
Into a solution of 4 g of indole derivative thus prepared in 150 ml of anhydrous diethyl ether and 2.2 ml of N,N,N',N'-tetramethylethylenediamine, cooled to -60°C, 16 ml of a t-BuLi solution 1.5 M in penthane are carefully fed in drop by drop. The mixture is allowed to reconstitute at -30°C, and 4.9 ml of chlorodiphenyl phosphine 22
are added to it. After being kept under stirring overnight at room temperature, the mixture is treated with water and concentrated to a small volume; the residue is treated with 150 ml of methylene chloride, and the organic phase washed with water. The solvent is removed to yield 3.3 g of racemic N-diphenyl phosphine-2-[ 3'(4'-diphenyl phosphine-2\5'-dimethyl)-thienyl]-3-methyl-indole, which is resolved into its optical antipodes using HPLC on chiral stationary phase. EXAMPLE 9
Preparation of the complex obtained from rRhd .δ-CODWICIO, and compound (*X15) In argon atmosphere, equimolar solutions of [Rh(1 ,5-COD)2]CIO4 (COD = cyclo- octadiene) and of the optically pure ligand (+)(15) in dichloromethane are prepared ; these two solutions are then mixed and kept under stirring for 30 minutes. The solution is then concentrated under reduced pressure to yield the Rh complex containing the chiral diphosphine which is used as such without further purification in the enantioselective reduction of olefins. It is assumed that the complex obtained has the following structure:
[Rh(1 ,5-COD)(compound (+)(15))]CIO4.
Using the same procedure, similar complexes of rhodium were prepared with the other optically active phosphines of Table 7. EXAMPLE 10
Preparation of the complex obtained from Hrd .δ-COD'.CIl . compound (+K15). and tetrabutylammonium iodide
In argon atmosphere, a solution is prepared of toluene/methanol 1/1 (3 ml) containing 2.5 x 10"3 mmol of [lr(1 ,5-COD)CI]2 and 6.0 x 10"3 mmol of optically pure ligand (+)(15). After 30 minutes, 1 x 10"2 mmol of tetrabutylammonium iodide are added under stirring. The solution thus obtained is used as such without further purification in the enantioselective reduction of imines. It is assumed that the complex obtained has the following structure: [lr(1 ,5-COD)(compound (+)(15))]l.
Using the same procedure, similar complexes of iridium were prepared with the other optically active phosphines of Table 7. 23
EXAMPLE 11
Preparation of the complex obtained from Hr .5-CODVCπ, and compound (+)(15).
In argon atmosphere, a solution is prepared of diethyl ether (3 ml) containing
2.5x10"3 mmol of [lr(1 ,5-COD)CI]2 and 5.0x10"3 mmol of optically pure ligand (+)(15). After 1 h under stirring, the solution thus obtained is used as such without further purification in the enanatioselective hydrosilylation of chetones. It is assumed that the complex obtained has the following structure:
[lr(1 ,5-COD)(compound (+)(15))]CI.
Using the same procedure, similar complexes of iridium were prepared with the other optically active phosphines of Table 7.
EXAMPLE 12
Preparation of the complex obtained from [Ru(p-cvmene l ]g and compound
(÷)(15).
In argon atmosphere, a solution is prepared of methylene chloride/methanol 8/3 (11 ml) containing 1.6x10"2 mmol of [Ru(p-cymene)l2]2 and 3.5x10"2 mmol of optically pure ligand (+)(15); after 60 minutes at reflux under stirring, the mixture thus obtained is concentrated under reduced pressure to yield a residue containing the complex, which is used as such without further purification, dissolved in methanol or ethanol, in the enantioselective reduction of carbonyl compounds. It is assumed that the complex obtained has the following structure: [Ru(p-cymene)(compound (+)(15) l)]l.
Using the same procedure, similar complexes of ruthenium were prepared with the other optically active phosphines of Table 7. EXAMPLE 13 Preparation of the complex obtained from [Rh(acac (CO)5] and compound (+)(2) Into an autoclave in argon atmosphere are introduced a toluene solution (10 ml) containing 2.0 x 10"2 mmol of [Rh(acac)(CO)2] and 2.2x10"2 mmol of optically pure ligand (+)(2). The autoclave is purged, loaded with CO/H2 1/1 (pressure, approximately 20 bar) and kept at room temperature for 15 h to form the active catalyst suitable for enantioselective hydroformylation reactions. It is assumed that the complex obtained has the following structure: [H Rh (compound (+)(2)(CO)2]. 24
Using the same procedure, similar complexes of rhodium were prepared with the other optically active phosphines of Table 7.
EXAMPLE 14
Preparation of the complex obtained from NiC and compound (+)(15) A dichloromethane solution (10 ml) containing 4.2 mmol of optically pure ligand
(+)(15) is added under stirring to a 4.2 mmol solution of hexahydrated NiCI2 in 30 ml of ethanol. After 1 h the mixture is concentrated to a small volume, and the residue is squashed with ethanol and subsequently dried under vacuum.
The complex is used as such in enantoselective reactions of formation of C-C bonds. It is assumed that the complex obtained has the following structure:
[NiCI2(compound (+)(15)].
Using the same procedure, similar complexes of nickel were prepared with the other optically active phosphines of Table 7.
EXAMPLE 15 Preparation of the complex obtained from PdCI2(benzonitrile , and compound
(±X15)
A dichloromethane solution (10 ml) containing 2.6 mmol of optically pure ligand
(+)(15) and 2.6 mmol of PdCI2(benzonitrile)2 is kept under stirring for 1 h at room temperature. The mixture is concentrated to a small volume and the residue is squashed with ethanol and subsequently dried under vacuum.
The complex obtained is used as such in enantioselective reactions of formation of C-C bonds. It is assumed that the complex obtained has the following structure: [PdCI2(compound (+)(15)]. Using the same procedure, similar complexes of palladium were prepared with the other optically active phosphines of Table 7.

Claims

25
1. An atropo-isomeric chiral phosphorated ligand of formula (I), having C, symmetry, in the optically active form or in the racemic form
P2(R2)2
Figure imgf000027_0001
(|)
wherein the atoms A, B, C, D, E and F, equal to or different from one another, are carbon atoms or hetero-atoms chosen from among oxygen, nitrogen and sulphur, which form together an Ar of Het aromatic residue, where Ar is chosen between pentatomic heterocyclic residue and phenyl, and Het is a pentatomic heterocyclic residue, and where said pentatomic heterocyclic aromatic residue contains 1 or 2 hetero-atoms, equal to or different from one another, selected from the group consisting of -O-, -S- and -NR3-, wherein R3 = H, an alkyl group, an aromatic group, a group -P,(R,)2, or a nitrogen atom comprised as hetero-atom in the other pentatomic heterocyclic residue belonging to the structure of formula (I) ; I = 0, 1 ; when I =1 , F is a carbon atom ; R, and R2, bound to the phosphorous atoms, equal to or different from one another, are selected from a linear, branched or cyclic C3-C10 alkyl group, a carbocyclic aromatic group chosen between phenyl and naphthyl, and a heterocyclic aromatic group having 5-6 members in the cycle, containing 1-2 hetero-atoms chosen among oxygen, sulphur and nitrogen, where said carbocyclic or heterocyclic aromatic group is optionally substituted with one or more groups selected from a linear or branched C,-C,0 alkyl group, a linear or branched C,-C,0 alkoxyl group, an halogen, -COOR4, -SO3R4 and -NR5R6ι where 26
R4 is chosen among H, C,-C,0 alkyl, phenyl, alkaline or alkaline-earth metal, -NH4 + and alkyl ammonium cation ; and where R5 and R6, equal to or different from one another, are H or alkyl ; or R, and R2 together with the phosphorus atom, form a heterocycle having 3-6 atoms in the cycle, optionally substituted with linear or branched C,-C10 alkyl groups ; X is an -O- group or an -N(R7)- group, where R7 is chosen among H, alkyl and phenyl ; n is 0 or 1 , when Ar is a heterocyclic aromatic residue ; n is 1 , when Ar is phenyl ; Q,, Q2, Z, and Z2, equal to or different from one another, are selected from the group consisting of H, linear, branched or cyclic C,-C,0 alkyl, linear or branched C,-C,0 alkoxyl, phenyl and halogen, or Q, taken together with Z,, or Q2 taken together with Z2, form a carbocyclic aromatic ring selected from phenyl and naphthyl, said carbocyclic aromatic ring being optionally substituted with one or more T groups, where T is chosen among halogen, C,-C,0 alkyl, C,-C,0 alkokyl, -COOR4, -SO3R4 and -NR5Rβ, where R4 is selected from H, C,-C,0 alkyl, phenyl, alkaline or alkaline-earth metal, -NH4 + or C4- C,2 alkyl ammonium cation, and where R5 and R6, equal to or different from one another, are selected from H and C,-C,0 alkyl ; and wherein -Pι(Rι)2 and -(X)n-P2(R2)2 are bound to the corresponding carbocyclic or heterocyclic aromatic residue by means of a carbon atom of said aromatic residue or by means of a nitrogen atom comprised as hetero-atom in a pentatomic heterocyclic residue ; said phosphorated ligand further having : i) a difference between the residual charges of the phosphorous atoms ΔQ(P) = Q(P,) - Q(P2) > 0.05, where Q(P,) and Q(P2) are the values of difference between the number of valence electrons and the number of electrons actually present for the phosphorous atoms P, and P2, said difference between residual charges being calculated using the program MOPAC, Version 6.0, Method MNDO ; ii) a cone angle βn ("natural bite angle" according to Casey) ranging from 80° to 27
130°, defined as preferred chelation angle P,-M-P2 between the phosphorous atoms P, and P2 and a transition metal M, said angle being obtained by minimization of the strain energy of the fragment M(diphosphine), where M is Rh, and calculated by means of the program SYBYL, using the force field of TRIPOS modified by entering the parameters developed for the Rh-diphosphine complexes by M. Kranenburg et al., in Organometallics, 14, 3081 (1995) ; iii) an energy barrier value of interconversion between the two enantiomers of a given ligand
ΔE = Etran.- Emin > 28 Kcal/mol, where Etrans is the energy value for the transition state, and Emin is the value associated to the state of minimum energy of the enantiomers, expressed in Kcal/mol, said ΔE being calculated by using the program MOPAC, Version 6.0, Method MNDO, assuming that the energy of the maximum-energy conformer Etrans is that of the conformer in which the two aromatic rings are coplanar.
2. The phosphorated ligand according to claim 1 , wherein i) said difference ΔQ(P) = Q(P,) - Q(P2) is > 0.15 ; ii) said "natural bite angle" βn ranging from 83° and 120°.
3. The phosphorated ligand according to claim 1 , wherein said phosphorated ligand is chosen between a ligand of formula (l)a and a ligand of formula (l)b :
Figure imgf000029_0001
Figure imgf000029_0002
(l)a (l)b where 28
Het, and Het2 are pentatomic heterocyclic aromatic rings, equal to or different from one another, defined as Het in claim 1 ; n is 0 or 1 ;
X, A, B, C, D, E, Q„ Q2 Z, and Z2 are as defined in claim 1.
4. The phosphorated ligand according to claim 1 , wherein said heterocyclic residue is selected from the group consisting of thiophene, pyrrole, furan, imidazole, isoxazole, isothiazole, pyrazole and triazole.
5. The phosphorated ligand according to claim 1 , wherein Q, taken together with Z,, or Q2 taken together with Z2, form a carbocyclic ring, and Het is condensed with phenyl or naphthyl.
6. The phosphorated ligand according to claim 5, wherein said heterocyclic ring Het condensed with phenyl is selected from the group consisting of benzothiophene, naphthothiophene, indole, benzofuran and benzoimidazole.
7. The phosphorated ligand according to claim 1 , wherein said phosphorated ligand is chosen from a ligand of formula (l)c, (l)d and (l)e :
■P2- y .B "N ^ Xn
■ Rι
Figure imgf000030_0001
Figure imgf000030_0002
(l)c (l)d 29
Figure imgf000031_0001
(l)e wherein Het, and Het2are defined as Het in claim 1 ; A, B, C, D, E, Q,, Z,, P,, R,,Q2, Z2 P2, R2 and T are as defined in claim 1 for formula (I) ; m is 0, 1 or 2. 8. The phosphorated ligand according to claim 1 , wherein said heterocyclic aromatic residue is selected from the group consisting of 2,5-dimethyl-thien-3-yl, 4,6-dimethyl-benzofur-3-yl, 3-methyl-indol-2-yl, 1-N-methyl-indol-2-yl, and benzothien-3-yl ; and said carbocyclic aromatic residue is phenyl. 9. The phosphorated ligand according to claim 1 , wherein said groups -P,(R,)2 and -P2(R2)2 are selected from diphenyl phosphine, dicyclohexyl phosphine, J,, J2 and J3 , where J,, J2 and J3 have the following formulas :
30
Figure imgf000032_0001
Figure imgf000032_0002
10. The phosphorated ligand according to claim 1 , containing one of the following sub-structures : (4-diphenylphosphine)- or (4-dicyclohexylphosphine)-2,5-dimethyl- thien-3-yl ; (1-N-diphenylphosphine)- or (1-N-dicyclohexylphosphine)-3- methylindol-2-yl; (3-diphenylphosphine)- or (3-dicyclohexylphosphine)-1-N- methylindol-2-yl; 2-(diphenylphosphine)- or 2-(dicyclohexylphosphine)-benzothien- 3-yl; 2-(diphenylphosphine-oxy)- or 2-(dicyclohexylphosphine-oxy)-phenyl-1-yl ; 4- (diphenylphosphine-oxy)- or 4-(dicyclohexylphosphine-oxy)-2,5-dimethyl-thien-3- yl ; 4-(2',5'-dimethyl-phospholyl)- or 4-(dibenzophospholyl)-2,5-dimethyl-thien-3-yl ; 1 -N-(2',5'-dimethyl-phospholyl)- or 1 -N-(dibenzophospholyl)-3-methyl-indol-2-yl. 11. The phosphorated ligand according to claim 1 , wherein said phosphorated ligand is chosen from the compounds from (1 ) to (15).
31
Figure imgf000033_0001
12
Figure imgf000033_0002
32
Figure imgf000034_0002
Figure imgf000034_0001
(7)
Figure imgf000034_0003
Figure imgf000034_0004
(10)
13
Figure imgf000034_0005
33
Figure imgf000035_0003
Figure imgf000035_0001
(12)
(11)
Figure imgf000035_0002
Figure imgf000035_0004
H3C CH
(14)
(13)
Figure imgf000035_0005
12. Procedure for the preparation of an atropo-isomeric phosphorated ligand of formula (I) having C, symmetry, as defined in claim 1 , comprising the following steps : 34
a) construction of the molecular model of a series of structures of ligands of formula (I), (I),, (l)2, (l)3, — , (l)z, where z is the number of structures created, by means of the computation program SYBYL, Version 6.2 ; b) conformational analysis, comprising the determination of the minimum-energy conformer for each structure from (I), to (l)z, followed by optimisation using the program MOPAC, Version 6.0, Method MNDO ; c) calculation of the difference ΔQ(P) = Q(P,) - Q(P2) as defined in claim 1 , for each minimum-energy conformer structure, by using the computation program MOPAC, Version 6.0, Method MNDO ; d) calculation, for each structure from (I), to (l)z, of the value of the energy barrier of interconversion between the two enantiomers (atropo-isomers) of formula (I) Δb - t:,,-,-.- - tmin as defined in claim 1 , made using the computation program MOPAC, Version 6.0, Method MNDO, assuming that the value E^ is that of the maximum-energy conformer having the two rings Ar and Het of the structure (I) coplanar with respect to one another ; e) calculation, for each structure from (I), to (l)z, of the "natural bite angle" βn, as defined in claim 1 , obtained by minimisation of the strain energy of the fragment M(diphosphine), imposing that M should be Rh and that the bending constant of the bond P,-M-P2 should be 0 Kcal mol"\ and calculated by using the program SYBYL, Version 6.2, adopting the parameters of the force field of the program TRIPOS, modified by entering the parameters developed for the Rh-diphosphine complexes by M. Kranenburg et al., in Organometallics, 14, 3081 , 1995 ; f) selection of the structures from (I), to (l)z having : i) ΔQ(P) = Q(P,) - Q(P2) > 0.05 i) a "natural bite angle" βn ranging between 80° and 130° ; ii) an energy barrier of interconversion between the two enantiomers of the same structure ΔE > 28 Kcal/mol; g) chemical synthesis of the phosphorated ligands of formula (I) thus selected. 13. The procedure according to claim 12, wherein said step f) consists in a selection of the structures from (I), to (l)z having : 35
i) the difference ΔQ(P) = Q(P,) - Q(P2) > 0.15 ; ii) the "natural bite angle" βn ranging between 83° and 120°. 14. The procedure according to claim 12, wherein said step g) is carried out according to one of the following procedure : A) coupling reaction between aromatic or hetero-aromatic halides with organometallic aryl or hetero-aryl reactants selected from organolithium, organomagnesium, organozinc, and organoboron, in the presence of catalytic quantities of salts or complexes of copper, nickel, or palladium; or B) cyclisation and aromatisation, with formation of one of the two heterocyclic rings comprised in the structure of formula (I), of a precursor already containing the other heterocyclic or carbocyclic system ; in said procedure the introduction of the groups containing the phosphorous atom preceding or following the reaction of formation of the inter-annular bond. 15. The procedure according to claim 14, wherein said introduction of the groups containing the phosphorous atom is carried out according one of the following reactions : in the case of phosphine derivatives : Ar-[M] + XP(R,)2 → Ar-P(R,)2 Ar-[M] + XP(=O) (R,)2 - Ar-P(=O)(R,)2 → Ar-P(R,)2 Ar-[M] + (R2O)2P(=O)(R,) → Ar2-P(=O)(R,) → Ar2-PR, Ar-X + ZP(R,)2 → Ar-P(R,)2 wherein Ar is an aromatic residue comprised in the structure of formula (I) ; [M] is an organometallic group ; X is a halogen ; Z is an alkaline metal ; R, and R2 are alkyl or aryl residues ; - in the case of phosphite or aminophosphine derivatives : Ar-OH + XP(R, )2 → Ar-OP(R, )2 Ind-NZ + XP(R,)2 → lnd-NP(R,)2 Ind-NZ + XP(=0)(R,)2 → lnd-NP(=O)(R,)2 → lnd-NP(R,)2 36
Ar-NHR2 + XP(R,)2 → Ar-NR2P(R,)2 Ar-X + ZOP(R,)2 → Ar-OP(R,)2 Ar is a carbocyclic aromatic or hetero-aromatic residue comprised in the structure of formula (I) ; Ind is an indole residue ; X is a halogen ; Z is an alkaline metal ; R, is an alkyl or aryl group ; R2 is H or an alkyl or aryl group. 16. The procedure according to claim 14, further comprising the resolution of a ligand of formula (I) into its optical antipodes, via separation on chromatographic column or through a membrane, using a chiral stationary substrate or a chiral eluent, or via fractioned crystallisation of a corresponding diastereo-isomeric adduct. 17. The procedure according to claim 16, wherein, if the ligand of formula (I) comprises basic or acidic groups, the diastereo-isomeric adduct is the corresponding salt with an entantiomerically pure chiral acid or base; alternatively, the said adduct is the diastereo-isomeric salt between an enantiomerically pure chiral acid and the phosphinoxide corresponding to the present phosphorated ligand. In this case, the optical resolution is followed by reduction of optically active phosphinoxides into phosphines, via treatment with a reducing agent. 18. An organometallic complex, comprising a chiral phosphorated ligand of formula (I) as defined in each of the claims from 1 to 11 , in the enanatiomerically pure or enriched form, and a transition metal.
1 19. The organometallic complex according to claim 18, wherein the transition metal is selected from the group consisting of Rh, Ru, Ir, Pt, Pd and Ni.
1 20. Use of an organometallic complex according to claim 18 for the preparation of
2 an optically active chiral catalyst. i 21. Procedure for the preparation of an organic compound in the form of stereo-
2 isomer, comprising at least one stereoselective reaction conducted in the
3 presence of at least one organometallic complex as defined in claim 18. l 22. The procedure according to claim 21 , wherein said stereoselective reaction is 37
selected from the group consisting of enantio- and/or diastereoselective reactions of reduction, hydroformylation, hydroboration, hydrosilylation, hydrocyanation, allylation, vinylation and other reactions of formation of the C-C bond.
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