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  • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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  • B01J31/2457—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings, e.g. Xantphos
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Definitions

• This invention relates to novel metallocene-based phosphine ligands incorporating up to four elements of chirality, planar chirality, chirality at phosphorus, and optionally chirality at carbon and axial chirality, and methods for their preparation.
• this invention relates to the metal-ligand complexes that can be used as catalysts or precatalysts for asymmetric transformation reactions to generate products of high enantiomeric excess.
• structured arsines are also within the scope of this invention.
• Ferrocene as a backbone for diphosphine ligands was introduced by Kumada and Hayashi based on the pioneering work of Ugi related to the synthesis of enantiopure substituted metallocenes 1 .
• a number of these ligands are shown below:
• Ppfa as well as bppfa and bppfoh proved to be effective ligands for the catalysis of a variety of asymmetric transformations. From this starting point, many chiral ferrocene-based bisphosphine ligands with a range of structural variation have been developed in the last few years.
• Josiphos-type ligands are in widespread commercial use, having been found effective for Rh-catalyzed hydrogenation of ⁇ -acetamidocinnamate, dimethyl itaconate, and ⁇ -ketoesters. Because the two phosphine groups are introduced into the ligand in consecutive steps with high yields, a variety of ligands are available with widely differing steric and electronic properties. The ligands have already been applied in three production processes 3 , several pilot processes and many other syntheses.
• PPF-tBu2 a Josiphos type ligand with a di-(tert-butyl)phosphino group
• XyliPhos is another notable example.
• Bophoz 6 is a combination of a phosphine and an aminophosphine and is prepared in 3 steps from ppfa with high overall yields.
• the ligand is air stable and effective for the hydrogenation of enamides, itaconates and ⁇ -keto acid derivatives. As observed for several ligands forming seven-mem bered chelates, high activities can be reached and TONs up to 10,000 have been claimed. The full scope of this modular ligand class has not yet been explored.
• Taniaphos A class of non-C 2 -symmetrical, ferrocene-based 1 ,5-diphosphine ligands, Taniaphos, has been developed by Knochel 7 ' 8 . Compared to the Josiphos ligands, Taniaphos has an additional phenyl ring inserted at the side chain of the Ugi amine. Taniaphos gave excellent results in Rh- and Ru-catalyzed asymmetric hydrogenation. The configuration of ⁇ -position of Taniaphos plays an important role in the enantioselectivities and activities. The Taniaphos 1b with ⁇ S configuration leads to higher enantioselectivities and activities than 1a with ⁇ R configuration in a wide range of asymmetric transformations.
• Mandyphos is a bidentate version of ppfa with C 2 symmetry, where in addition to the PPh 2 moieties, R and R' can be used for fine tuning the functionality of the ligand 10 .
• the scope of this ligand family has not yet been fully explored, but preliminary results indicate high enantioselectivities for the Rh-catalyzed hydrogenation of enamides, itaconates and enol acetates.
• the TRAP ligands developed by Ito 11 form 9-membered metallocycles. However, it is not clear whether the cis-isomer, present in small amounts, or the major trans-isomer is responsible for the catalytic activity. Up to now only a few different PR2 fragments have been tested, but it is clear that the choice of R strongly affects the catalytic performance.
• the Rh complexes work best at very low pressures of 0.5 ⁇ 1 bar and effectively reduces indole-derivatives, enamides and itaconic acid derivatives.
• Kang 12 reported the C 2- symmetry FerroPHOS with only planar chirality. FerroPHOS ligands are air-stable and are very efficient for the asymmetric hydrogenation of various dehydroamino acid derivitives (up to 99% ee).
• JAFAPhos Another C 2 -symmetry planar chiral diphosphine, JAFAPhos, has been developed by Jendralla 13 . JAFAPhos gave excellent results in asymmetric hydrogenation, allylic alkylation, Grignard cross coupling and aldol reactions.
• Kagan 14 reported plane chiral ferrocene-based bisphosphorus ligands 2 and 3, and up to 95% ee's have been obtained in asymmetric hydrogenation of dimethyl itaconate using these ligands as catalyst.
• Another class of known diphosphine ligands exhibit chirality only at the
• Mezzetti 18 and van Leeuwen 19 have independently reported P-chiral ferrocenyl bisphosphines 4a and 4b. These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric hydrogenation of ⁇ - dehydroamino acid derivatives.
• Zhang has reported a 1 ,1'-bis(Phospholanyl) ferrocene ligand 5 with ketal substitutes at the 3 and 4 positions.
• the ligand has shown excellent enantioselectivities in hydrogenation of ⁇ -dehydroamino acid derivatives.
• the ketal groups of the ligand are important for achieving the high enantioselectivity, since the corresponding ligand without ketal groups only provides moderate ee's.
• Zhang has also developed a 1 ,1'-bis(dinaphthophosphepinyl) ferrocene ligand, f-binaphane, which has been successfully applied in the Ir-catalyzed hydrogenation of acyclic aryl imines. 21
• Reetz has developed a binaphthol-derived ferrocene-based bisphosphonite ligand 6 22 , which has shown excellent reactivities and enantioselectivities in Rh- catalyzed hydrogenation of itaconates and ⁇ -dehydroamino acid derivatives.
• Another class of known ligands exhibits both planar and phosphorus chirality:
• Van Leeuwen has reported ferrocene-based bisphosphines combining planar and phosphorus chirality 4a and 4b 23 . These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric allylic alkylations. Thus, most of the known ferrocene-based diphosphines contain planar and carbon chirality, only planar chirality or only phosphorus chirality. More recently, Togni reported the first tridentate ferrocene-based phosphine ligand 12 combining planar, phosphorus and carbon chirality. 24
• bisphosphine ligands incorporating up to three elements of chirality, planar chirality, chirality at phosphorus, and chirality at carbon for use in enantioselective catalysis. It would also be advantageous to design ligands that exhibit three different types of chirality; carbon, planar and phosphorus.
• a metallocene-based phosphine having up to three or four elements of chirality; planar chirality, chirality at phosphorus, and optionally chirality at carbon and axial chirality.
• the invention also provides a metallocene-based arsine having up to three elements of chirality; planar chirality, chirality at arsenic, and optionally chirality at carbon.
• a metallocene-based arsine having up to three elements of chirality; planar chirality, chirality at arsenic, and optionally chirality at carbon.
• ferrocene based ligands are preferred, other suitable metals may be used in the ligands of the invention, and hence reference is made herein to metallocenes generally.
• the invention further provides a metallocene-based diphosphine having planar, phosphorus and carbon chirality.
• Ligands according to the invention have particular advantages over prior art ligands because the provision of up to three or four chiralities allows the designer of a ligand greater scope than has hitherto been the case to design ligands for a particular purpose.
• Preferred ligands in accordance with the invention are selected from ligands having Formula (I), (II) or (III):
• W is phosphorus or arsenic
• M is a metal
• R 1 and R 2 are different from each other, and are independently selected from from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; R 3 and R 4 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl,
• W is phosphorus or arsenic
• R 6 and R 7 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and R 8 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted
• W is phosphorus or arsenic
• R 6 , R 7 and R 8 are, independently, as previously defined; and R 9 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or
• Q is selected from:
• R 6 , R 7 , R 8 and R 9 are, independently, as previously defined; and R 10 is selected from hydrogen, substituted and unsubstituted, branched- and straight- chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or
• Q is selected from:
• W is phosphorus or arsenic;
• R 6 , R 7 are, as previously defined;
• R 11 is selected from OR 13 , SR 13 , NHR 13 , NR 13 R 14 , wherein R 13 and R 14 are the same or different and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight- chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen;
• R 12 is selected from hydrogen, halogen, OR 13 , SR 13 ,
• NR 13 R 14 substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; wherein R 13 , R 14 are, as previously defined and n' is 0 to 4; or Q is selected from:
• R 8 and R 9 are as previously defined; R 5 is selected from:
• R 15 , R 16 and R 17 are the same or different and are independently selected from hydrogen, OR 13 , SR 13 , NR 13 R 14 , substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; wherein R 13 , R 14 are, as previously defined; or R 5 is selected from:
• R 19 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or (R 19 )2 is -(CH2V- , n' is 0 to 4; and m' is 1 to 8;
• the invention also relates to the enantiomers of the ligands described above, the enantiomers having the Formulae (IV), (V) and (VI):
• diastereomers of the ligands described above the diastereomers having the Formulae (VII), (VIII) and (IX):
• transition metal complex containing transition metal coordinated to the ligand of the invention.
• the metal is preferably a Group Vlb or a Group VIII metal, especially rhodium, ruthenium, iridium, palladium, platinum and nickel.
• Synthesis of ferrocene-based phosphorus chiral phosphines may be effected with the use of a suitable chiral ortho-d irecting group, for example in accordance with the following schemes:
• the invention provides a method for preparing a phosphine ligand chiral at phosphorus comprising providing a metallocene-based substrate having a chiral or achiral directing substituent on one or both rings, and subjecting the substituted metallocene to an ortho-lithiation step before subsequently converting the ortho-lithiated substrate to a phosphine chiral at phosphorus.
• one such method comprises providing a compound of the Formula (X) (optionally substituted on one or both cyclopentadiene rings with R 3 n (top ring) and/or R 4 m (bottom ring)):
• X* is chiral directing group, and is preferably selected from the group consisting of :
• R, R a and R b are same or different, and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; ortho-lithiating the substrate; reacting the ortholithiated substrate with an R 1 substituted phosphine or arsine, and then with an R 2 -bearing Grignard reagent or organolithium compound, and converting X* to Q or G as appropriate.
• One particularly preferred X* group is R ⁇ NMe 2
• the ortho-lithiation step is preferably a mono-ortho-lithiation step using n- butyllithium, sec-butyllithium or tert- butyllithium.
• the resulting monolithium compound is preferably reacted in situ with a dichlorophosphine of the formula R 1 PCI 2 followed by reacting with an organometallic reagent of the formula R 2 Z, wherein R 1 and R 2 are as defined above; Z is Li or MgY wherein Y is a halide.
• R 19 is an acyl group, and R 1 , R 2 are as previously defined; and then: reacting compound XII with a secondary phosphine of the formula R 6 R 7 PH wherein R 6 , R 7 are, as previously defined, to obtain the diphosphine combining planar, phosphorus and carbon chirality having formula XV:
• Compound XVI may be reacted with a halophosphine of the formula R 6 R 7 PY wherein R 6 , R 7 are, as previously defined, and Y is chlorine, bromine or iodine, to obtain compound XXIII:
• compound XVI may be reacted with an acid derivative of the formula R 10 COY wherein R 10 is, as previously defined, and Y is a halide, a sulphate, an imidazole, R 10 COO- or hydrogen, to obtain compound XXIV:
• compound XVI (in which R 9 is hydrogen) may be reacted with an aldehyde of the formula OHC-R*-CHO or OHC-R-CHO wherein R* and R are, as previously defined, to obtain the compounds having Formulae XXV and XXVI:
• XXIX Compounds XIX, XX, XXI, XXII, XXV, XXVI, XXVII, XXVIII may be reduced to obtain respective compounds XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII:
• the invention provides a method for preparing a chiral diphosphine ligand comprising a metallocene-based substrate having an achiral directing substituent on one or both rings, and subjecting the substituted metallocene to an enantioselective ortho-lithiation step before subsequently converting the ortho-lithiated substrate to phosphorus chiral phosphines.
• one method according to the present invention for preparing the ligand of Formula (I) or (III) comprises providing a compound of the formula XXXVII: (XXXVII)
• X is an achiral directing group, and is preferably selected from: and subjecting the compound to enantioselective mono-ortho-lithiation using n- butyllithium or sec-butyllithium or tert- butyllithium in the presence of a homochiral tertiary amine, and reacting the resulting chiral monolithium compound in situ with a dichlorophosphine of the formula R 1 PCI 2 followed by reacting with an organometallic reagent of the formula R 2 M, wherein R 1 and R 2 are as defined hereinabove; M is Li or MgX wherein X is a halide, to obtain phosphorus chiral compound having formula XXXVIII:
• One method according to the invention for preparing the ligand of Formula (II) comprises providing a compound of the Formula XXXIX: Fe 4 ⁇ - ⁇ * (XXXIX)
• X* is as previously defined; and subjecting the compound to bis-ortho- lithiation using n-butyllithium, sec-butyllithium or tert- butyllithium, and reacting the resulting bislithium compound in situ with a dichlorophosphine of the formula R 1 PC followed by reacting with an organometallic reagent of the formula R 2 Z, wherein R 1 and R 2 are as previously defined; Z is Li or MgY wherein Y is a halide, to obtain a phosphorus chiral compound having formula XXXX:
• PhPCI 2 (746 uL, 5.5 mmoL) was added via a syringe
• the mixture was warmed to room temperature and stirred for 1 h at room temperature, the mixture was cooled to - 78 °C again, and a suspension of o-AnLi [prepared from 2-bromoanisole (805 uL, 6.5 mmol) and 1.7 M t-BuLi (7.6 mL, 13 mmol) in Et 2 O (30 mL) at -78 °C] was added via a cannula, then the mixture was stirred overnight at -78 °C to room temperature.
• Example 60 N-Acetyl L-alanine methyl ester via Hydrogenation in THF: MHAr H2 (5 ° PSl) NHAC NHAc Rh(COD) 2 OTf/L* AC A CO .MMes — ; . , ** C0 2 Me solvent, rt, 2.5 h
• Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1 ,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , S P )-23 (3.8 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 18.6% conversion to amino acid derivative with 88.6% ee as determined by chiral GC analysis.
• Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1 ,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , S P )-24 (4.0 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with 98.3% ee as determined by chiral GC analysis.
• Example 62 N-Acetyi L-alanine methyl ester via Hydrogenation in THF:
• Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1 ,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , Rp)-25 (4.0 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with 92.3% ee as determined by chiral GC analysis.
• Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in MeOH using bis(1,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , S P )-24 (4.0 mg; 6 mumol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with >99% ee as determined by chiral GC analysis.
• Example 64 N-Acetyl L-alanine methyl ester via Hydrogenation in THF wit
• Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1 ,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe )-BoaPhoz (3.7 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 99% conversion to amino acid derivative with 94.5% ee as determined by chiral GC analysis.
• Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , S P )-23 (3.8 mg; 6 umol; 0.012 equiv) for 2 hour to afford 100% conversion to amino acid derivative with 88.0% ee as determined by chiral GC analysis.
• Example 66 N-Acetyl L-phenylalanine methyl ester via Hydrogenation in THF:
• Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe , S P )-24 (4.0 mg; 6 mumol; 0.012 equiv) for 2 hour to afford 100% conversion to amino acid derivative with 97.0% ee as determined by chiral GC analysis.
• Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5-
• Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (R c , S Fe )-BoaPhoz (3.7 mg; 6 umol; 0.012 equiv) for 2 hour to afford 100% conversion to amino acid derivative with 95.7% ee as determined by chiral GC analysis.
• Nettekoven U.; Kamer, P. C. J.; Widhalm, M.; van Leeuwen, P. W. N. M. Organometallics 2000, 19, 4596.

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