WO2008148202A1 - Method for the preparation of aminophosphine ligands and their use in metal catalysts - Google Patents

Method for the preparation of aminophosphine ligands and their use in metal catalysts Download PDF

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WO2008148202A1
WO2008148202A1 PCT/CA2008/001076 CA2008001076W WO2008148202A1 WO 2008148202 A1 WO2008148202 A1 WO 2008148202A1 CA 2008001076 W CA2008001076 W CA 2008001076W WO 2008148202 A1 WO2008148202 A1 WO 2008148202A1
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groups
optionally substituted
alkyl
ring system
linked
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PCT/CA2008/001076
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French (fr)
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WO2008148202A4 (en
WO2008148202A8 (en
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Kamaluddin Abdur-Rashid
Rongwei Guo
Xuanhua Chen
Wenli Jia
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Kanata Chemical Technologies Inc.
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Priority to CA002689239A priority Critical patent/CA2689239A1/en
Priority to JP2010510624A priority patent/JP5466152B2/en
Priority to EP08757212A priority patent/EP2167515A4/en
Priority to AU2008258233A priority patent/AU2008258233C1/en
Priority to US12/663,369 priority patent/US8658825B2/en
Publication of WO2008148202A1 publication Critical patent/WO2008148202A1/en
Publication of WO2008148202A4 publication Critical patent/WO2008148202A4/en
Publication of WO2008148202A8 publication Critical patent/WO2008148202A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J31/2419—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5004—Acyclic saturated phosphines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/65719—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonous acid derivative
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium

Definitions

  • TITLE METHOD FOR THE PREPARATION OF AMINOPHOSPHINE
  • the present disclosure relates to a general procedure for the synthesis of a wide range of achiral and chiral aminophosphine ligands, and their use for the preparation of chiral and achiral metal aminophosphine catalysts, for example, for the hydrogenation of ketones, aldehydes and imines.
  • Catalytic hydrogenation is a fundamental reaction in chemistry, and is used in a large number of chemical processes. Catalytic hydrogenation of ketones and aldehydes are useful and indispensable processes for the synthesis of alcohols, which are valuable end products and precursor chemicals in the pharmaceutical, agrochemical, flavor, fragrance, material and fine chemical industries. 1
  • molecular hydrogen (H 2 ) is used. However, for the hydrogenation process to proceed, a catalyst or catalytic system is needed to activate the molecular hydrogen.
  • Noyori and co-workers developed the versatile RuCl 2 (PR 3 ) 2 (diamine) and RuCl 2 (diphosphine)(diamine) hydrogenation catalyst system that are highly effective for the hydrogenation of ketones. 2 It was subsequently discovered that the Noyori catalysts were effective for the reductive hydrogenation of imines to amines. 3
  • RuCl 2 (aminophosphine)2 and RuCl 2 (diphosphine)(aminophosphine) are also very effective catalysts for the hydrogenation of ketones, aldehydes and imines, including the preparation of chiral compounds. 4 Hence, these catalysts are versatile alternatives to the Noyori-type catalysts.
  • the present disclosure includes a method for preparing aminophosphine ligands comprising reacting a compound of the formula I
  • LG 1 is a suitable leaving group; q is 0 or 1 ; p is 1 or 2, where when p is 1, the N atom is further linked to R 7 or any one of R 1 , R 2 , R 3 , R 4 , R 5 R 6 or LG, and when N is linked to any one of R 1 , R 2 , R 3 , R 4 , R 5 R 6 or LG, or if p is 2, q is 0; n is O, 1, 2, 3 or 4; PG is a suitable amine protecting group and, when p is 2, PG is the same or different; Y is a cation;
  • R 1 to R 6 are simultaneously or independently selected from H, Ci -2O alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R 7 is selected from d ⁇ alkyl and aryl, said latter two groups being optionally substituted;
  • R and R are simultaneously or independently selected from H, C 1-20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 10 and N(R I0 ) 2 , said latter 7 groups being optionally substituted, or R 8 and R 9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R and R 9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl;
  • R 10 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH 2 , OR 1 1 , N(R ⁇ ) 2 and R n ; and
  • R 11 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
  • the present disclosure includes a method for preparing aminophosphine ligands comprising reacting a compound of the formula II
  • one of q and r is 1 , while the other is 0; n is 0, 1, 2, 3 or 4;
  • R 1 to R 6 are simultaneously or independently selected from H, Ci -2 oalkyl, C 2- 2 oalkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R 7 is selected from Ci -6 alkyl and aryl, said latter two groups being optionally substituted; R and R are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 10 and N(R 10 ) 2 , said latter 7 groups being optionally substituted, or R 8 and R 9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 8 and R 9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S.
  • R 10 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH 2 , OR 11 , N(R ⁇ ) 2 and R ⁇ ; and R 11 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; and
  • R 12 and R 13 are simultaneously or independently selected from H, Ci. 2 oalkyl, C 2- 20 alkenyl, C 2-2 oalkynyl, aryl, heteroaryl, OR 10 and N(R 10 ) 2 , said latter 7 groups being optionally substituted, or R 12 and R 13 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 12 and R 13 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC 1-6 alkyl.
  • aminophosphine ligands are complexed with a metal to form aminophosphine metal catalysts.
  • aminophosphine metal catalysts are useful for the hydrogenation of ketones, aldehydes and imines.
  • R 14 and R 15 are simultaneously or independently selected from H, C 1-20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted;
  • R 16 is selected from H, Ci -6 alkyl and aryl, said latter two groups being optionally substituted or R 16 is PR 19 R 20 ; or two of R 14 , R 15 and R 16 are linked to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R and R are linked together with the phosphorous atom to which said R and R groups are linked to form an optionally substituted polycyclic ring of the formula
  • R 19 and R 20 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 2 oalkenyl, C 2-2 oalkynyl, aryl, heteroaryl, OR 21 and N(R 2 ') 2 , said latter 7 groups being optionally substituted, or R 19 and R 20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 19 and R 20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl; the optional substituents are selected from one or more of halo, OH,
  • R 23 and R 24 are simultaneously or independently selected from H, Ci -6 alkyl and aryl, said latter two groups being optionally substituted or one of R 23 and R 24 is PR 28 R 29 ;
  • R 25 and R 26 are simultaneously or independently selected from H, Ci -2 oalkyl, C 2- 2O alkenyl, C 2-2 oalkynyl, aryl, heteroaryl, OR 30 and N(R 30 ) 2 , said latter 7 groups being optionally substituted, or R 25 and R 26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 25 and R 26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC 1-6 alkyl;
  • R 27 represents optional substituents selected from one or more of OH
  • R 28 and R 29 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 2 oalkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 32 and N(R 32 ) 2 , said latter 7 groups being optionally substituted, or R 28 and R 29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 28 and R 29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl; R 30 , R 31 and R 32 are independently selected from Ci -6 alkyl, C 2-6 alkenyl, C ⁇ alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of
  • R 33 is selected from Ci- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
  • metal complexes suitably a transition metal complex comprising a ligand of the formula II, IV, V, VI or VII.
  • Figure 1 is a schematic showing the method of producing an aminophosphine ligand in accordance with one embodiment of the disclosure
  • Figure 2 is a schematic showing the method of producing an aminophosphine ligand in accordance with an embodiment of the disclosure
  • Figure 3 is a schematic showing the method of producing an aminophosphine ligand in accordance with an embodiment of the disclosure.
  • Ci -n alkyl as used herein means straight and/or branched chain, saturated alkyl groups containing from one to "n" carbon atoms and includes
  • n (depending on the identity of n) methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, n-hexyl and the like, where the variable n is an integer representing the largest number of carbon atoms in the alkyl radical.
  • C 2-n alkenyl as used herein means straight and/or branched chain, unsaturated alkyl groups containing from one to n carbon atoms and one to three double bonds, and includes (depending on the identity of n) vinyl, allyl, 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methylbut-l-enyl, 2- methylpent-1-enyl, 4-methylpent-l-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpenta-l,3-dienyl, hexen-1-yl and the like, where the variable n is an integer representing the largest number of carbon atoms in the alkenyl radical.
  • C 2-n alkynyl as used herein means straight and/or branched chain, unsaturated alkyl groups containing from one to n carbon atoms and one to three triple bonds, and includes (depending on the identity of n) ethynyl, 1-propynyl, 2- propynyl, 2-methylprop-l-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3- methylbut-1-ynyl, 4-methylbut-ynyl, 4-methylbut-2-ynyl, 2-methylbut-l-ynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,3-pentadiynyl, 1 ,4-pentadiynyl, 3- methylpent-1-ynyl, 4-methylpent-2-ynyl4-methyl
  • C 3-2 ocycloalkyl as used herein means a monocyclic or polycyclic saturated carbocylic group containing from three to twenty carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclodecyl and the like.
  • aryl as used herein means a monocyclic or polycyclic aromatic ring system containing from 6 to 14 carbon atoms and at least one aromatic group and includes phenyl, naphthyl, anthracenyl, 1 ,2-dihydronaphthyl, 1,2,3,4- tetrahydronaphthyl, fluorenyl, indanyl, indenyl, ferrocenyl and the like.
  • heteroaryl as used herein means a monocyclic or polycyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteromoieties independently selected from N. NH, N(Ci. 6 alkyl), O and S and includes thienyl, furyl, pyrrolyl, pyrididyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
  • ring system refers to any type of cyclic structure that comprises one or more rings and any type of saturation and optionally includes, where indicated, heteromoieties or metals. Ring systems formed between two R groups or an R group and a heteroatom, include within the system the atoms to which the R groups and/or heteroatoms are attached and any atoms linking the atoms to which the R groups and/or heteroatoms are attached.
  • fluoro- substituted with respect to any specified group as used herein means that the one or more, including all, of the hydrogen atoms in the group have been replaced with a fluorine, and includes trifluoromethyl, pentafluoroethyl, fluoromethyl and the like.
  • halo as used herein means halogen and includes chloro, flouro, bromo and iodo.
  • a method for preparing aminophosphine ligands comprising reacting a compound of the formula I )p
  • LG 1 is a suitable leaving group; q is O or l; p is 1 or 2, where when p is 1, the N atom is further linked to R 7 or any one of R 1 , R 2 ,
  • R 3 , R 4 , R 5 R 6 or LG when N is linked to any one of R 1 , R 2 , R 3 , R 4 , R 5 R 6 or LG, or if p is 2, q is 0; n is O, 1, 2, 3 or 4; PG is a suitable amine protecting group and, when p is 2, PG is the same or different;
  • Y is a cation
  • R 1 to R 6 are simultaneously or independently selected from H, Ci -20 alkyl, C 2-
  • alkenyl, C 2-2 oalkynyl, C 3-2 ocycloalkyl, aryl and heteroaryl said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R 7 is selected from Ci -6 alkyl and aryl, said latter two groups being optionally substituted;
  • R 8 and R 9 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 10 and N(R 10 ) 2 , said latter 7 groups being optionally substituted, or R 8 and R 9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 8 and R 9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl;
  • R 10 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH 2 , OR 11 ,
  • R 11 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
  • R 1 to R 6 are simultaneously or independently selected from H, Ci.i O alkyl, C 2- i 0 alkenyl, C 2- i 0 alkynyl, C 3- iocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
  • R 1 to R 6 are simultaneously or independently selected from H, d ⁇ alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the carbons to which these groups are attached and/or the nitrogen atom of the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
  • R 1 to R 6 are simultaneously or independently selected from H, methyl, phenyl, or two adjacent or geminal groups and the carbons to which said groups are attached and/or the nitrogen atom of the amino group, are linked together to form phenyl, indanyl or ferrocenyl, or a pyrrolidinyl ring.
  • n is equal to 0, 1 or 2. In further embodiments of the disclosure, n is 0 or 1. In other embodiments of the present disclosure, R 7 is Ci -4 alkyl or phenyl, said latter two groups being optionally substituted. In another embodiment, R 7 is methyl.
  • R 8 and R 9 are simultaneously or independently selected from H, Ci.i O alkyl, C 2- i 0 alkenyl, C- 2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R and R are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R 8 and R 9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi -6 alkyl.
  • R 8 and R 9 are simultaneously or independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R 8 and R 9 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R 8 and R 9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi -6 alkyl.
  • R 8 and R 9 are simultaneously Ci -6 alkyl or phenyl, in particular, methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl or phenyl. In further embodiments, R 8 and R 9 are simultaneously or independently isopropyl, t- butyl, or phenyl.
  • R 8 and R 9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R 8 and R 9 are linked.
  • R 10 is selected from C 2-4 alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R 10 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
  • the optional substituents are selected from one or more of halo, OH, NH 2> OR 1 1 , N(R U ) 2 and R 11 , in which R 11 is selected from Ci -4 alkyl, C 2-4 alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted.
  • R 11 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
  • PG means a suitable protecting group.
  • suitable protecting group would be understood by a person skilled in the art to means any moiety that, when linked to the amine functional group, prevents the amine functionality from participating in unwanted side reactions and which can be readily removed under conditions that do not degrade, decompose or otherwise interfere with the process of the disclosure to lower the yield and purity of the compounds of formula II.
  • suitable protecting groups would be well within the abilities of a person skilled in the art. For example, a person skilled in the art may refer to "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W.
  • protecting groups include, but are not limited to trimethylsilyl (TMS), acetyl, tert- butyldimethylsilyl (TBDMS), tert-butoxycarbonyl (BOC), benzyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (FMOC), benzyl and the like.
  • LG 1 means “leaving group”.
  • suitable leaving group as it applies to LG 1 would be understood by a person skilled in the art to mean any group attached to an atom that can be displaced by the nucleophilic phosphorus atom of the metal phosphide reagent under the conditions of the method of the disclosure.
  • Suitable leaving groups for LG 1 include, but are not limited to, halides, including chloro, bromo, and iodo, tosylates, mesylates, and triflates and the like.
  • LG 1 is a cyclic leaving group that is linked to another atom in the compound of formula I, including the nitrogen atom of the amine.
  • a portion of the leaving group remains linked to the other atom of the compound of formula I after nucleophilic displacement by the metal phosphide reagent, and those remaining portions may be removed, for example, during removal of the PG, to provide compounds of formula II.
  • a cyclic leaving group includes cyclic sulfamidates that are formed between the amine nitrogen and the carbon to which the LG is attached.
  • Y is any suitable cation, for example any metal that can complex with a nucleophilic phosphide reagent.
  • metals include the alkaline metals, for example lithium, sodium, potassium and the like, the alkaline earth metals. Suitable metals are the alkaline metals lithium, sodium and potassium.
  • Y is Li or K.
  • p is 1 or 2, where when p is 1, the N atom is further linked to R 7 or any one of R 1 , R 2 , R 3 , R 4 , R 5 R 6 or LG 1 , and when N is linked to any one of R 1 , R 2 , R 3 , R 4 , R 5 R 6 or LG 1 , or if p is 2, q is 0.
  • p is 1 when a cyclic leaving group is used.
  • p is 2 and the protecting group can be the same or different.
  • the conditions to provide a compound of the formula II are nucleophilic reaction conditions that would be known to a person skilled in the art.
  • the conditions to provide a compound of formula II comprise adding a compound of the formula I to a metal phosphide reagent of the formula Y-PR 8 R 9 , at a temperature of about -50 0 C to about 0 0 C over a period of about 1 hour to about 4 hours.
  • the solution of a compound of the formula I and a metal phosphide reagent of the formula Y-PR 8 R 9 is stirred at a temperature of about 10 0 C to about 70 0 C for a period of about 2 to about 24 hours.
  • the conditions, including time and temperature may be varied, depending, for example, on the structure of the compound of formula I and the metal phosphide reagent.
  • the conditions to provide a compound of the formula II comprise the reaction between the compound of the formula I and the metal phosphide reagent under anhydrous conditions and in an inert atmosphere (e.g. in the absence of oxygen).
  • the conditions to provide a compound of the formula II comprise the reaction between a compound of the formula I and a metal phosphide reagent in an aprotic solvent.
  • the reaction between a compound of the formula I and a metal phosphide reagent is performed in a polar, aprotic solvent.
  • the reaction between a compound of the formula I and a metal phosphide reagent is performed in a variety of solvents, including ethers such as tetrahydrofuran or diethyl ether, acetonitrile, benzene, toluene, hexanes, dimethyformamide and the like.
  • the reaction between a compound of the formula I and a metal phosphide reagent is performed in tetrahydrofuran.
  • the compounds of formula I are commercially available or may be prepared using methods known in the art.
  • compounds of formula I may be prepared from the corresponding amino alcohols.
  • Methods for attaching protecting groups onto amino groups are known in the art, in particular in the presence of a hydroxyl group or a latent or protected hydroxyl group (see for example, "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P. G. M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999).
  • amino alcohols may be converted into a compound of formula I comprising a cyclic sulfamidate leaving group by first monoprotecting the amine nitrogen with any suitable PG, for example, t- butoxycarbonyl (t-BOC), followed by reaction of the resulting derivative according to the procedure described by Qin et al. (J. Org. Chem.
  • the metal phosphide reagents are either commercially available or may be prepared using methods known in the art as described hereinbelow. Typically the metal phosphide reagent is prepared in situ by reacting the corresponding phosphine, Z-PR 8 R 9 , where Z is for example, H or Cl, or the corresponding phosphepine borane, with a strong base, for example an alkyl lithium or lithium metal, at reduced temperatures, for example at about -80 0 C to about 10 0 C. In another embodiment, the method further comprises the step of reacting a compound of formula II as defined above, with a compound of the formula III
  • R 12 and R 13 are as defined for R 8 and R 9 in formula II and R 1 - R 9 are as defined in formula II, LG 2 is a suitable leaving group, and one of q and r is 1, while the other of q and r is 0.
  • R 12 and R 13 are simultaneously or independently selected from H, Ci-ioalkyl, C 2- i 0 alkenyl, C- 2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R 12 and R 13 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R 12 and R 13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi -6 alkyl.
  • R 12 and R 13 are simultaneously or independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R 12 and R 13 are linked to form an optionally substituted monocytic, fused bicylic, fused tricyclic, fused quadracyclic, fused pentacyclic, fused hexacyclic or fused heptacyclic ring system having 4-32 atoms, including the phosphorous atom to which R 12 and R 13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi_ 6 alkyl.
  • the compound of formula III is
  • LG 2 is a suitable leaving group
  • a method for preparing aminophosphine ligands comprising reacting a compound of the formula II
  • LG 2 is a suitable leaving group; one of q and r is 1, while the other is 0; n is 0, 1, 2, 3 or 4;
  • R 1 to R 6 are simultaneously or independently selected from H, Ci -2 oalkyl, C 2- 20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R 7 is selected from Ci -6 alkyl and aryl, said latter two groups being optionally substituted;
  • R 8 and R 9 are simultaneously or independently selected from H, Ci- 20 alkyl, C 2 . 20 alkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 10 and N(R 10 ) 2 , said latter 7 groups being optionally substituted, or R 8 and R 9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 8 and R 9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC )-6 alkyl;
  • R 10 is selected from C h alky!, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH 2 , OR 11 ,
  • R 11 is selected from C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted;
  • R 12 and R 13 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 2 oalkenyl, C 2-2 oalkynyl, aryl, heteroaryl, OR 10 and N(R 1 °) 2 , said latter 7 groups being optionally substituted, or R 12 and R 13 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 12 and R 13 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC 1-6 alkyl.
  • R 1 to R 6 are simultaneously or independently selected from H, Ci.ioalkyl, C 2- ioalkenyl, C 2- ioalkynyl, C 3 .i 0 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
  • R 1 to R 6 are simultaneously or independently selected from H, Ci -4 alkyl, C 2-4 alkenyl, C 2 .
  • R 1 to R 6 are simultaneously or independently selected from H, methyl, or phenyl, or two adjacent or geminal groups, are linked together with the carbons to which said groups are attached, and/or with the nitrogen atom of the amino group, to form a phenyl, indanyl or ferrocenyl ring.
  • n is equal to 0, 1 or 2. In a further embodiment, n is equal to 0 or 1.
  • R 7 is selected from or phenyl, said latter two groups being optionally substituted. In another embodiment, R 7 is methyl.
  • R and R are simultaneously or independently selected from H, Ci.i O alkyl, C 2- i 0 alkenyl, C- 2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R 8 and R 9 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R 8 and R 9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and
  • R 8 and R 9 are simultaneously or independently selected from H, Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R 8 and R 9 are linked to form an optionally substituted monocylic, fuse
  • R 8 and R 9 are simultaneously or independently isopropyl, t-butyl, or phenyl.
  • R 8 and R 9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R 8 and R 9 are linked.
  • the fused pentacyclic ring system is
  • R 10 is selected from Ci -4 alkyl, C 2-4 alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R 10 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro- substituted.
  • the optional substituents are selected from one or more of halo, OH, NH 2, OR 11 , N(R U ) 2 and R 11 , in which R 1 1 is selected from the group consisting of Ci-4alkyl, C 2-4 alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted.
  • R 11 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
  • R 12 and R 13 are simultaneously or independently selected from H, Ci -10 alkyl, C 2 -i 0 alkenyl, C- 2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R 12 and R 13 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R 11 and R 12 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi. 6 alkyl.
  • R 12 and R 13 are simultaneously or independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R 12 and R 13 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic, fused pentacyclic, fused hexacyclic or fused heptacyclic ring system having 4-32 atoms, including the phosphorous atom to which R 12 and R 13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi -6 alkyl.
  • the compound of formula III is
  • LG 2 in a compound of formula III is a suiable leaving group.
  • suitable leaving group in a compound of formula III would be understood by a person skilled in the art to mean any group attached to a phosphorous atom that can be displaced by the nucleophilic nitrogen atom of the compound of formula II.
  • Suitable leaving groups include, but are not limited to, halides, including chloro, bromo, and iodo, tosylates, mesylates, and triflates and the like.
  • the conditions to provide a compound of the formula IV are nucleophilic reaction conditions that would be known to a person skilled in the art.
  • the conditions to provide a compound of formula IV comprise adding a compound of the formula III to a compound of the formula II at about room temperature.
  • the solution of a compound of the formula II and formula III is stirred at about room temperature for a period of about 2 to about 24 hours.
  • the conditions, including time and temperature may be varied, depending, for example, on the structure of the compounds of formula II and formula III.
  • the conditions to provide a compound of the IV comprise the reaction between the compound of the formula II and a compound of formula III under anhydrous conditions and in an inert atmosphere (e.g. in the absence of oxygen).
  • the conditions to provide a compound of the formula IV comprise the reaction between a compound of the formula II and a compound of the formula III in an aprotic solvent.
  • the reaction between a compound of the formula II and a compound of the formula III is performed in a polar, aprotic solvent.
  • the reaction between a compound of the formula II and a compound of the formula III is performed in a variety of solvents, including chlorinated solvents such as dichloromethane, ethers such as tetrahydrofuran or diethyl ether, acetonitrile, benzene, toluene, hexanes, dimethyformamide and the like.
  • the reaction between a compound of the formula II and a compound of the formula III is performed in dichloromethane.
  • the aminophosphine ligands prepared using the method of the present disclosure are complexed with any metal for use as catalysts.
  • the metal is any transition metal of groups 3 through 12 of the periodic table, suitably groups 4 through 10, plus the lanthanides and actinides. Examples of suitable metals include, but are not limited to Co, Rh, Ir, Ru, Os and Re.
  • the metal is Ru.
  • the aminophosphine ligands of formula II are complexed with an RuCl 2 group to form RuCl 2 (aminophosphine) 2 and RuCl 2 (diphosphine)(aminophosphine) catalysts.
  • the aminophospine metal catalysts are those useful for the hydrogenation of ketones, aldehydes and imines.
  • R 14 and R 15 are simultaneously or independently selected from H, Ci -2 oalkyl, C 2 .
  • R 16 is selected from H, and aryl, said latter two groups being optionally substituted or R 16 is PR 19 R 20 ; or two of R 14 , R 15 and R 16 are linked to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
  • R 17 and R 18 are linked together with the phosphorous atom to which said R 17 and R 18 groups are linked to form an optionally substituted polycyclic ring of the formula
  • R 19 and R 20 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 2 oalkenyl, C2 -20 alkynyl, aryl, heteroaryl, OR 21 and N(R 21 ) 2 , said latter 7 groups being optionally substituted, or R 19 and R 20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 19 and R 20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC 1-6 alkyl; the optional substituents are selected from one or more of halo, OH, NH 2
  • R 14 and R 15 are simultaneously or independently selected from H, Ci -10 alkyl, C 2- ioalkenyl, C 2- i 0 alkynyl, C 3- iocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted.
  • R 14 and R 15 are simultaneously or independently selected from H, Ci- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted.
  • R 14 and R 15 are simultaneously or independently selected from H, methyl, or phenyl.
  • R 16 is H, Ci -4 alkyl or phenyl, said latter two groups being optionally substituted. In a further embodiment, R 16 is H or methyl.
  • R 16 is PR 19 R 20 , where R 19 and R 20 are simultaneously or independently selected from H, Ci.i O alkyl, C 2- i 0 alkenyl, C 2- l oalkynyl, aryl, heteroaryl, OR 21 and N(R 21 ) 2 , said latter 7 groups being optionally substituted, or R 19 and R 20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R 19 and R 20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -4 alkyl.
  • R 19 and R 20 are simultaneously or independently selected from H, Ci -6 alkyl, phenyl and OR 21 , said latter 3 groups being optionally substituted, or R 19 and R 20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R 19 and R 20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
  • R 16 is selected from:
  • R 14 , R 15 and R 16 are linked to form an optionally substituted monocyclic, bicyclic, tricyclic, saturated, unsaturated and/or aromatic ring system having 5 to 14 atoms.
  • R 15 and R 16 are linked to form an optionally substituted monocyclic or bicyclic, saturated, and/or aromatic ring system having 5 to 10 atoms.
  • the optional substituents on the compounds of formula V are selected from one or more of Cl, F, OR 22 and N(R 22 ) 2 and R 22 , where R 22 is selected from Ci -6 alkyl, and phenyl, said latter 4 groups being optionally fluoro-substituted.
  • the optional substituents on the compounds of formula V are selected from one or more of CH 3 , CF 3 , OCH 3 , and OCF 3 .
  • R 23 and R 24 are simultaneously or independently selected from H, Ci -6 alkyl and aryl, said latter two groups being optionally substituted or one of R 23 and R 24 is PR 28 R 29 ;
  • R 25 and R 26 are simultaneously or independently selected from H, Ci -2 oalkyl, C 2- 20 alkenyl, C 2-2 oalkynyl, aryl, heteroaryl, OR 30 and N(R 30 ) 2 , said latter 7 groups being optionally substituted, or R 25 and R 26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 25 and R 26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl;
  • R 27 represents optional substituents selected from one or more of OH
  • R 28 and R 29 are simultaneously or independently selected from H, Ci -20 alkyl, C 2- 20 alkenyl, C 2-20 alkynyl, aryl, heteroaryl, OR 32 and N(R 32 ) 2 , said latter 7 groups being optionally substituted, or R 28 and R 29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R 28 and R 29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl; R 30 , R 31 and R 32 are independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of
  • R 33 is selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
  • R 23 and R 24 are simultaneously or independently selected from H, Ci -4 alkyl, phenyl and naphthyl.
  • R 23 and R 24 are simultaneously or independently selected from H, methyl and phenyl.
  • R 23 and R 24 are simultaneously selected from H, methyl and phenyl.
  • one of R 23 and R 24 is PR 28 R 29 and R 28 and R 29 are simultaneously or independently selected from H, Ci.
  • R 28 and R 29 are simultaneously or independently selected from H, Ci -6 alkyl, phenyl and OR 32 , said latter 3 groups being optionally substituted, or R 28 and R 29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R 28 and R 29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
  • PR 28 R 29 is selected from:
  • R 25 and R 26 are simultaneously or independently selected from H, Ci-ioalkyl, C 2- i 0 alkenyl, C 2- l oalkynyl, aryl, heteroaryl, OR 30 and N(R 30 ) 2 , said latter 7 groups being optionally substituted, or R 25 and R 26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 or more atoms, including the phosphorous atom to which said R 25 and R 26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi -6 alkyl.
  • R 25 and R 26 are simultaneously or independently selected from H, Ci -6 alkyl, phenyl and OR 30 , said latter 3 groups being optionally substituted, or R 25 and R 26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R 25 and R 26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
  • R 27 represents optional substituents selected from one or five of OR 31 , N(R 31 ⁇ and R 31 is independently selected from Ci- 4 alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted. In a further embodiment, R 27 is H.
  • R 30 and R 32 are independently selected from Ci -4 alkyl, and phenyl, said latter 2 groups being optionally fluoro- substituted.
  • the optional substituents are selected from one or five of Cl, F, OR 33 , N(R 33 ) 2 and R 33 , and R 33 is selected from Ci- 4 alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
  • amino phosphine ligand of the formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethy
  • aminophnosphine ligand of formula VI is
  • aminophosphine ligand of formula VII is
  • metal complexes suitably a transition metal complex comprising a ligand of the formula II, IV, V, VI or VII.
  • the transition metal complex is of the type MCl 2 (aminophosphine) 2 and MCl 2 (diphosphine)(aminophosphine), where aminophosphine is of the formula Ha, lib, Hc or Hd.
  • M is Ru.
  • Example 1 Preparation of aminophosphine ligands
  • Example 1.1 2-(Diphenylphosphino)ethanamine
  • Butyl lithium (155 ml of a 1.6 M solution in hexane) was added dropwise to a cold (O 0 C) solution of diphenylphosphine (45 g, 0.24 mole) in THF (200 ml). The mixture was stirred for 2 hours at room temperature and a solution of N,N'-bis(trimethylsilyl)- 2-chloroethanamine (54 g, 0.24 mole) added slowly at O 0 C. The mixture was refluxed for 4 hours then cooled to room temperature. Water (50 ml) was added, followed by 2.0 M H 2 SO 4 solution (200 ml).
  • Example 4 General Procedures for the preparation of aminophosphine ligands from sulfamidates A solution of potassium diphenylphosphide (28 ml, 0.5 M in hexane, 14 mmol) was added slowly to a solution of the sulfamidate (12 mmol) in THF (100 ml) at -5O 0 C and the mixture was stirred at that temperature for 2h, then the mixture was slowly warmed to RT and stirred overnight. De-gassed H 2 SO 4 solution (2M, 30ml) in brine (50 ml) was added and the mixture was stirred for Ih, after which, de-gassed saturated Na 2 CO 3 solution (50 ml) was added to neutralize the acid.
  • K diphenylphosphide 28 ml, 0.5 M in hexane, 14 mmol
  • Butyl lithium (34 ml of a 2.5 M solution in hexane) was added to a solution of (l lbR)-4,5-dihydro-3H-dinaphtho[2,l-c:l',2'-e]phosphepine borane (28.0 g, 86 mmol) in THF (250 ml) at -78 0 C.
  • the mixture was stirred at -78 0 C for 1.5 hour, and a solution of N,N'-bis(trimethylsilyl)-2-chloroethanamine (19.2 g, 86 mmol) in THF (20 ml) added.
  • the reaction mixture was allowed to slowly warm to room temperature and refluxed for 24 hours.
  • Tetrafluoroboric acid (HBF 41 Et 2 O, 3.4 ml) was added to the solution of 2- ((l lbR)-3H-dinaphtho[2,l-c: l',2'-e]phos ⁇ hepin-4(5H)-yl)ethanamine borane (2.0 g) in CH 2 Cl 2 (50 ml) at O 0 C. The mixture was stirred at room temperature overnight. Saturated NaHCO 3 solution (2 x 100 ml) was added and the mixture stirred for 1 hour.
  • Trifloroacetic acid (30 ml) was added to the solution Of (IiS 1 , 25)- 1, 2-diphenyl-2-(S)- phosphepine ethyleneamine-N-Boc (12 g) in CH 2 Cl 2 (100 ml) at 0 0 C. The mixture was stirred at RT overnight. The volatiles were removed under vacuum and the residue was dissolved in CH 2 Cl 2 (150 ml). It was neutralized with Na 2 CO 3 (saturated, 50 ml) in brine (20 %, 100 ml). The aqueous layer was extracted with CH 2 Cl 2 (100 ml). The combined organic layer was washed with brine (20 %) and dried over MgSO 4 for 3h.
  • Trifluoroacetic acid (30 ml) was added to a solution Of (I 1 S, 25)-l-methyl-2-diphenyl- 2-(S)-phosphepinoethylamine-N-Boc (10.7 g) in CH 2 Cl 2 (100 ml) at 0 0 C. The mixture was stirred at RT overnight. The volatiles were removed under vacuum and the residue was dissolved in CH 2 Cl 2 (200 ml). It was neutralized with Na 2 CO 3 (saturated, 50 ml) in brine (20 %, 100 ml). The aqueous layer was extracted with CH 2 Cl 2 (100 ml). The combined organic layer was washed with brine (20 %) and dried over MgSO 4 for 3h.
  • the solvent was removed to give the crude product as a white solid (8.3 g) which was purified by filtering through a silica gel pad (eluent: CH 2 Cl 2 /hexane, 1/1, 300 ml to remove impurities, CH 2 C1 2 /THF, 9/1, 200 ml to elute the product).
  • the solvent was removed from the filtrate to give the product as a colorless solid (7.2 g, yield: 82.4 %).
  • Trifluoroacetic acid (3.5 ml) was added to a solution of tert-butyl-2-((l lbS)-3H- dinaphtho[2,l-c:l',2'-e]phosphepin-4(5H)-yl)ethylcarbamate (1.6 g) in CH 2 Cl 2 (30 ml) at room temperature. The mixture was stirred at RT overnight following which all volatiles were removed. The residue was dissolved in CH 2 Cl 2 (50 ml) and the solution was neutralized with Na 2 CO 3 (saturated, 50 ml) in brine (20%, 50 ml).
  • Example 7 N-((lS,2S)-2-((4R,llbS)-3H-dinaphtho[2,l-c:l ⁇ 2 '-e]phosphepin-4(5H)- yl)-l, 2-diphenylethyl)-l , l-bis(3, 5-(trifluoromethylphenyl)phosphinamine
  • Example 8 (HbS)-N-((lS,2S)-2-((4R, llbS)-3H-dinaphtho[2,l-c:l ⁇ 2 '-e]phosphepin- 4(5H)-yl)-l, 2-diphenylethyl)dinaphtho[2, 1 -d: 1 ', 2 '-J][1, 3, 2]dioxaphosphepin-4-amine
  • Example 13 General Procedure for Preparation of new aminophosphine catalysts
  • the new catalysts (S-Binap)((l S,2S)-2-(diphenylphosphino)-l ,2-diphenylethanamine) and (S-Binap)((l S,2S)-2-(Diphenylphosphino)-2,3-dihydro-lH-inden-l -amine) were prepared using the general procedure below.
  • Tetrahydrofuran (20 ml) was added to a mixture of the S-binap ligand (0.5 g, 0.8 mmol) and [RuCl 2 (benzene)] 2 (200 mg, 0.4 mmol), followed by DMF (0.5 ml) and the mixture refluxed for 6 hours under argon.
  • the solvent was removed under reduced pressure and a solution of the aminophosphine (0.8 mmol) in toluene 20 added.
  • Ether (10 ml) was then added and the mixture stirred for 2 hours under argon.
  • the solids were filtered, washed with ether and dried under vacuum.
  • the catalysts were used for the hydrogenation of acetophenone without further purification.
  • Example 14 Catalytic hydrogenation of acetophenone using new catalysts
  • Ligand Solvent Con v. % e.e. %

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Abstract

The present application is directed to i) a method for synthesizing aminophosphine (P,N) and phosphine-aminophosphine (P,N,P) ligands, ii) the use of such ligands in the preparation of metal complexes as hydrogenation catalysts, and iii) aminophosphine (P,N) and phosphine-aminophosphine (P,N,P) ligands of various structures. In particular, the methods in i) involve reacting a protected tertiary amine of formula (I) with a metal phosphide of the formula Y-PR8R9 to afford an aminophosphine of formula (II), which can then be optionally further reacted with a phosphine of the formula (III) to afford the phosphine-aminophosphine of formula (IV).

Description

TITLE: METHOD FOR THE PREPARATION OF AMINOPHOSPHINE
LIGANDS AND THEIR USE IN METAL CATALYSTS
FIELD OF THE DISCLOSURE The present disclosure relates to a general procedure for the synthesis of a wide range of achiral and chiral aminophosphine ligands, and their use for the preparation of chiral and achiral metal aminophosphine catalysts, for example, for the hydrogenation of ketones, aldehydes and imines.
BACKGROUND OF THE DISCLOSURE Catalytic hydrogenation is a fundamental reaction in chemistry, and is used in a large number of chemical processes. Catalytic hydrogenation of ketones and aldehydes are useful and indispensable processes for the synthesis of alcohols, which are valuable end products and precursor chemicals in the pharmaceutical, agrochemical, flavor, fragrance, material and fine chemical industries.1 To achieve a catalytic hydrogenation transformation in the reduction of ketones and aldehydes, molecular hydrogen (H2) is used. However, for the hydrogenation process to proceed, a catalyst or catalytic system is needed to activate the molecular hydrogen.
Noyori and co-workers developed the versatile RuCl2(PR3)2(diamine) and RuCl2(diphosphine)(diamine) hydrogenation catalyst system that are highly effective for the hydrogenation of ketones.2 It was subsequently discovered that the Noyori catalysts were effective for the reductive hydrogenation of imines to amines.3
It was also determined that ruthenium aminophosphine complexes of the type
RuCl2(aminophosphine)2 and RuCl2(diphosphine)(aminophosphine) are also very effective catalysts for the hydrogenation of ketones, aldehydes and imines, including the preparation of chiral compounds.4 Hence, these catalysts are versatile alternatives to the Noyori-type catalysts.
Currently, the availability of chiral and achiral aminophosphine ligands are severely limited which restricts the development and exploitation of RuCl2(aminophosphine)2 and RuCl2(diphosphine)(aminophosphine) catalysts in catalytic hydrogenation processes. The few reported syntheses of aminophosphine ligands are either low yielding or involve the use of aziridines.5 Hence, there remains a need for a facile synthesis of chiral and achiral aminophosphine ligands in high yields and purity, and suitable for large scale applications.
SUMMARY OF THE DISCLOSURE It has now been found that achiral and chiral aminophosphine ligands can be synthesized in high yield and with high purity, allowing access to a wide variety of ligands from readily available and inexpensive starting materials.
Accordingly, the present disclosure includes a method for preparing aminophosphine ligands comprising reacting a compound of the formula I
Figure imgf000003_0001
with a metal phosphide reagent of the formula Y-PR R under conditions to provide, after removal of PG, a compound of the formula II, )P
Figure imgf000003_0002
wherein
LG1 is a suitable leaving group; q is 0 or 1 ; p is 1 or 2, where when p is 1, the N atom is further linked to R7 or any one of R1, R2, R3, R4, R5 R6 or LG, and when N is linked to any one of R1, R2, R3, R4, R5 R6 or LG, or if p is 2, q is 0; n is O, 1, 2, 3 or 4; PG is a suitable amine protecting group and, when p is 2, PG is the same or different; Y is a cation;
R1 to R6 are simultaneously or independently selected from H, Ci-2Oalkyl, C2- 20alkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R7 is selected from d^alkyl and aryl, said latter two groups being optionally substituted; R and R are simultaneously or independently selected from H, C1-20alkyl, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(RI0)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R and R9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl;
R10 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR1 1, N(Rπ)2 and Rn; and
R11 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
In another aspect, the present disclosure includes a method for preparing aminophosphine ligands comprising reacting a compound of the formula II
Figure imgf000004_0001
with a compound of the formula III
R13
P LG2
/
R12
III
under conditions to provide a compound of the formula IV
Figure imgf000005_0001
IV
wherein
one of q and r is 1 , while the other is 0; n is 0, 1, 2, 3 or 4;
R1 to R6 are simultaneously or independently selected from H, Ci-2oalkyl, C2- 2oalkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R7 is selected from Ci-6alkyl and aryl, said latter two groups being optionally substituted; R and R are simultaneously or independently selected from H, Ci-20alkyl, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R8 and R9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S. N. NH and NCi-βalkyl; R10 is selected from Ci-6alkyl, C2-6alkenyl, C2.6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR11, N(Rπ)2 and Rπ; and R11 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; and
R12 and R13 are simultaneously or independently selected from H, Ci.2oalkyl, C2- 20alkenyl, C2-2oalkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R12 and R13 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC1-6alkyl.
In another aspect of the disclosure, the aminophosphine ligands are complexed with a metal to form aminophosphine metal catalysts.
In another aspect of the disclosure, the aminophosphine metal catalysts are useful for the hydrogenation of ketones, aldehydes and imines.
In another aspect of the disclosure, there is included novel aminophosphepine ligands of the formula V
Figure imgf000006_0001
V
wherein R14 and R15 are simultaneously or independently selected from H, C1-20alkyl, C2- 20alkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted;
R16 is selected from H, Ci-6alkyl and aryl, said latter two groups being optionally substituted or R16 is PR19R20; or two of R14, R15 and R16 are linked to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R and R are linked together with the phosphorous atom to which said R and R groups are linked to form an optionally substituted polycyclic ring of the formula
Figure imgf000007_0001
in which one or more carbon atoms in said polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; R19 and R20 are simultaneously or independently selected from H, Ci-20alkyl, C2- 2oalkenyl, C2-2oalkynyl, aryl, heteroaryl, OR21 and N(R2 ')2, said latter 7 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; the optional substituents are selected from one or more of halo, OH, NH2, OR22, N(R22)2 and R22; and R21 and R22 are independently selected from C1-6alkyl, C2.6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
In an embodiment of the disclosure, there is included a novel aminophosphine ligand of the Formulae VI or VII
Figure imgf000008_0001
VI VII
wherein
R23 and R24 are simultaneously or independently selected from H, Ci-6alkyl and aryl, said latter two groups being optionally substituted or one of R23 and R24 is PR28R29; R25 and R26 are simultaneously or independently selected from H, Ci-2oalkyl, C2- 2Oalkenyl, C2-2oalkynyl, aryl, heteroaryl, OR30 and N(R30)2, said latter 7 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC1-6alkyl; R27 represents optional substituents selected from one or more of OH, NH2, OR31, N(R3 ')2 and R3 \ alternatively, R27 is H;
R28 and R29 are simultaneously or independently selected from H, Ci-20alkyl, C2- 2oalkenyl, C2-20alkynyl, aryl, heteroaryl, OR32 and N(R32)2, said latter 7 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; R30, R31 and R32 are independently selected from Ci-6alkyl, C2-6alkenyl, C^alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR33,
N(R33)2 and R33; and
R33 is selected from Ci-όalkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted. Also included within the disclosure are metal complexes, suitably a transition metal complex comprising a ligand of the formula II, IV, V, VI or VII.
Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The disclosure will now be described in greater detail with reference to the following drawings in which:
Figure 1 is a schematic showing the method of producing an aminophosphine ligand in accordance with one embodiment of the disclosure;
Figure 2 is a schematic showing the method of producing an aminophosphine ligand in accordance with an embodiment of the disclosure; Figure 3 is a schematic showing the method of producing an aminophosphine ligand in accordance with an embodiment of the disclosure.
DETAILED DESCRIPTION OF THE DISCLOSURE
DEFINITIONS
The term "Ci-nalkyl" as used herein means straight and/or branched chain, saturated alkyl groups containing from one to "n" carbon atoms and includes
(depending on the identity of n) methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, n-hexyl and the like, where the variable n is an integer representing the largest number of carbon atoms in the alkyl radical. The term "C2-nalkenyl" as used herein means straight and/or branched chain, unsaturated alkyl groups containing from one to n carbon atoms and one to three double bonds, and includes (depending on the identity of n) vinyl, allyl, 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methylbut-l-enyl, 2- methylpent-1-enyl, 4-methylpent-l-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpenta-l,3-dienyl, hexen-1-yl and the like, where the variable n is an integer representing the largest number of carbon atoms in the alkenyl radical. The term "C2-nalkynyl" as used herein means straight and/or branched chain, unsaturated alkyl groups containing from one to n carbon atoms and one to three triple bonds, and includes (depending on the identity of n) ethynyl, 1-propynyl, 2- propynyl, 2-methylprop-l-ynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiynyl, 3- methylbut-1-ynyl, 4-methylbut-ynyl, 4-methylbut-2-ynyl, 2-methylbut-l-ynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,3-pentadiynyl, 1 ,4-pentadiynyl, 3- methylpent-1-ynyl, 4-methylpent-2-ynyl4-methylpent-2-ynyl, 1-hexynyl and the like, where the variable n is an integer representing the largest number of carbon atoms in the alkynyl radical.
The term "C3-2ocycloalkyl" as used herein means a monocyclic or polycyclic saturated carbocylic group containing from three to twenty carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclodecyl and the like.
The term "aryl" as used herein means a monocyclic or polycyclic aromatic ring system containing from 6 to 14 carbon atoms and at least one aromatic group and includes phenyl, naphthyl, anthracenyl, 1 ,2-dihydronaphthyl, 1,2,3,4- tetrahydronaphthyl, fluorenyl, indanyl, indenyl, ferrocenyl and the like.
The term "heteroaryl" as used herein means a monocyclic or polycyclic ring system containing one or two aromatic rings and from 5 to 14 atoms of which, unless otherwise specified, one, two, three, four or five are heteromoieties independently selected from N. NH, N(Ci.6alkyl), O and S and includes thienyl, furyl, pyrrolyl, pyrididyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
The term "ring system" as used herein refers to any type of cyclic structure that comprises one or more rings and any type of saturation and optionally includes, where indicated, heteromoieties or metals. Ring systems formed between two R groups or an R group and a heteroatom, include within the system the atoms to which the R groups and/or heteroatoms are attached and any atoms linking the atoms to which the R groups and/or heteroatoms are attached. The term "fluoro- substituted" with respect to any specified group as used herein means that the one or more, including all, of the hydrogen atoms in the group have been replaced with a fluorine, and includes trifluoromethyl, pentafluoroethyl, fluoromethyl and the like. The term "halo" as used herein means halogen and includes chloro, flouro, bromo and iodo.
All compounds and groups having the general formulae disclosed and described herein, unless otherwise indicated, comprise carbon atoms and where no substitution is indicated in the structural formulae, the carbon atoms comprise hydrogen atoms to fulfill the valency requirements of carbon. In certain embodiments, and where indicated, one or more, although not all, of the carbon atoms in the group are replaced with another atom.
In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. Finally, terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies. METHOD OF THE DISCLOSURE It has been found that achiral and chiral aminophosphine ligands can be synthesized in high yield and with high purity, allowing access to a wide variety of ligands from readily available and inexpensive starting materials. Accordingly, a method for producing achiral and chiral aminophosphine ligands is disclosed.
In an embodiment of the disclosure, a method for preparing aminophosphine ligands comprising reacting a compound of the formula I )p
Figure imgf000012_0001
I
with a metal phosphide reagent of the formula Y-PR8R9 under conditions to provide, after removal of PG, a compound of the formula II,
Figure imgf000012_0002
wherein
LG1 is a suitable leaving group; q is O or l; p is 1 or 2, where when p is 1, the N atom is further linked to R7 or any one of R1, R2,
R3, R4, R5 R6 or LG, and when N is linked to any one of R1, R2, R3, R4, R5 R6 or LG, or if p is 2, q is 0; n is O, 1, 2, 3 or 4; PG is a suitable amine protecting group and, when p is 2, PG is the same or different;
Y is a cation;
R1 to R6 are simultaneously or independently selected from H, Ci-20alkyl, C2-
20alkenyl, C2-2oalkynyl, C3-2ocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms; R7 is selected from Ci-6alkyl and aryl, said latter two groups being optionally substituted;
R8 and R9 are simultaneously or independently selected from H, Ci-20alkyl, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R8 and R9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl;
R10 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR11,
N(Rπ)2 and Rπ; and R11 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
In an embodiment of the present disclosure, R1 to R6 are simultaneously or independently selected from H, Ci.iOalkyl, C2-i0alkenyl, C2-i0alkynyl, C3-iocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms. In further embodiments of the disclosure, R1 to R6 are simultaneously or independently selected from H, d^alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the carbons to which these groups are attached and/or the nitrogen atom of the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms. In further embodiments of the disclosure, R1 to R6 are simultaneously or independently selected from H, methyl, phenyl, or two adjacent or geminal groups and the carbons to which said groups are attached and/or the nitrogen atom of the amino group, are linked together to form phenyl, indanyl or ferrocenyl, or a pyrrolidinyl ring.
In embodiments of the present disclosure, n is equal to 0, 1 or 2. In further embodiments of the disclosure, n is 0 or 1. In other embodiments of the present disclosure, R7 is Ci-4alkyl or phenyl, said latter two groups being optionally substituted. In another embodiment, R7 is methyl.
In further embodiments of the present disclosure, R8 and R9 are simultaneously or independently selected from H, Ci.iOalkyl, C2-i0alkenyl, C-2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R and R are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl. In further embodiments of the disclosure, R8 and R9 are simultaneously or independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R8 and R9 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl.
In an embodiment of the disclosure, R8 and R9 are simultaneously Ci-6 alkyl or phenyl, in particular, methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl or phenyl. In further embodiments, R8 and R9 are simultaneously or independently isopropyl, t- butyl, or phenyl.
In another embodiment of the disclosure, R8 and R9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R8 and R9 are linked. In a further embodiment, the fused
pentacyclic ring system is
Figure imgf000015_0001
In another embodiment of the present disclosure, R10 is selected from
Figure imgf000015_0002
C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R10 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
According to other embodiments of the disclosure, the optional substituents are selected from one or more of halo, OH, NH2> OR1 1, N(RU)2 and R11, in which R11 is selected from Ci-4alkyl, C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R11 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
In the present disclosure PG means a suitable protecting group. The term "suitable protecting group" would be understood by a person skilled in the art to means any moiety that, when linked to the amine functional group, prevents the amine functionality from participating in unwanted side reactions and which can be readily removed under conditions that do not degrade, decompose or otherwise interfere with the process of the disclosure to lower the yield and purity of the compounds of formula II. The selection of suitable protecting groups would be well within the abilities of a person skilled in the art. For example, a person skilled in the art may refer to "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999. Examples of suitable protecting groups include, but are not limited to trimethylsilyl (TMS), acetyl, tert- butyldimethylsilyl (TBDMS), tert-butoxycarbonyl (BOC), benzyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (FMOC), benzyl and the like.
In the present disclosure LG1, means "leaving group". The term "suitable leaving group" as it applies to LG1 would be understood by a person skilled in the art to mean any group attached to an atom that can be displaced by the nucleophilic phosphorus atom of the metal phosphide reagent under the conditions of the method of the disclosure. Suitable leaving groups for LG1 include, but are not limited to, halides, including chloro, bromo, and iodo, tosylates, mesylates, and triflates and the like. In a further embodiment, LG1 is a cyclic leaving group that is linked to another atom in the compound of formula I, including the nitrogen atom of the amine. In this latter instance, a portion of the leaving group remains linked to the other atom of the compound of formula I after nucleophilic displacement by the metal phosphide reagent, and those remaining portions may be removed, for example, during removal of the PG, to provide compounds of formula II. For example, a cyclic leaving group includes cyclic sulfamidates that are formed between the amine nitrogen and the carbon to which the LG is attached.
In the present disclosure, Y is any suitable cation, for example any metal that can complex with a nucleophilic phosphide reagent. Such metals include the alkaline metals, for example lithium, sodium, potassium and the like, the alkaline earth metals. Suitable metals are the alkaline metals lithium, sodium and potassium. In embodiment of the disclosure, Y is Li or K.
In the present disclosure, p is 1 or 2, where when p is 1, the N atom is further linked to R7 or any one of R1, R2, R3, R4, R5 R6 or LG1, and when N is linked to any one of R1, R2, R3, R4, R5 R6 or LG1, or if p is 2, q is 0. In an embodiment of the disclosure, p is 1 when a cyclic leaving group is used. In another embodiment, when p is 1, q is 1. In a further embodiment of the disclosure, p is 2 and the protecting group can be the same or different.
In an embodiment of the disclosure, the conditions to provide a compound of the formula II are nucleophilic reaction conditions that would be known to a person skilled in the art. In an embodiment of the method, the conditions to provide a compound of formula II comprise adding a compound of the formula I to a metal phosphide reagent of the formula Y-PR8R9, at a temperature of about -500C to about 00C over a period of about 1 hour to about 4 hours. In a further embodiment of the disclosure, the solution of a compound of the formula I and a metal phosphide reagent of the formula Y-PR8R9 is stirred at a temperature of about 100C to about 700C for a period of about 2 to about 24 hours. A person skilled in the art would understand that the conditions, including time and temperature may be varied, depending, for example, on the structure of the compound of formula I and the metal phosphide reagent.
In another embodiment of the disclosure, the conditions to provide a compound of the formula II comprise the reaction between the compound of the formula I and the metal phosphide reagent under anhydrous conditions and in an inert atmosphere (e.g. in the absence of oxygen).
In an embodiment of the method, the conditions to provide a compound of the formula II comprise the reaction between a compound of the formula I and a metal phosphide reagent in an aprotic solvent. In a subsequent embodiment of the method, the reaction between a compound of the formula I and a metal phosphide reagent is performed in a polar, aprotic solvent. In a further embodiment of the method, the reaction between a compound of the formula I and a metal phosphide reagent is performed in a variety of solvents, including ethers such as tetrahydrofuran or diethyl ether, acetonitrile, benzene, toluene, hexanes, dimethyformamide and the like. In a suitable embodiment of the method, the reaction between a compound of the formula I and a metal phosphide reagent is performed in tetrahydrofuran.
The compounds of formula I are commercially available or may be prepared using methods known in the art. For example, compounds of formula I may be prepared from the corresponding amino alcohols. Methods for attaching protecting groups onto amino groups are known in the art, in particular in the presence of a hydroxyl group or a latent or protected hydroxyl group (see for example, "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P. G. M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd Edition, 1999). Conversions of hydroxyl groups into leaving groups are also well known in the art (see for example, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, December 2006, Smith M.B. and March, J. Authors, John Wiley & Sons, New Jersey, Publisher). In a specific example of the present disclosure, amino alcohols may be converted into a compound of formula I comprising a cyclic sulfamidate leaving group by first monoprotecting the amine nitrogen with any suitable PG, for example, t- butoxycarbonyl (t-BOC), followed by reaction of the resulting derivative according to the procedure described by Qin et al. (J. Org. Chem. 2004, 69:8533-8536), that is, with thionyl chloride (SOCl2) under conditions to provide the cyclic sulfamidite which is converted to the corresponding sulfamidate by oxidation, for example with RuCl3ZNaIO4. This method is depicted schematically in Figure 1.
The metal phosphide reagents are either commercially available or may be prepared using methods known in the art as described hereinbelow. Typically the metal phosphide reagent is prepared in situ by reacting the corresponding phosphine, Z-PR8R9, where Z is for example, H or Cl, or the corresponding phosphepine borane, with a strong base, for example an alkyl lithium or lithium metal, at reduced temperatures, for example at about -80 0C to about 10 0C. In another embodiment, the method further comprises the step of reacting a compound of formula II as defined above, with a compound of the formula III
R13
P LG2
/
R12
III
under conditions to provide a compound of the formula IV
Figure imgf000018_0001
IV
wherein R12 and R13 are as defined for R8 and R9 in formula II and R1 - R9 are as defined in formula II, LG2 is a suitable leaving group, and one of q and r is 1, while the other of q and r is 0.
In another embodiment, R12 and R13 are simultaneously or independently selected from H, Ci-ioalkyl, C2-i0alkenyl, C-2-ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R12 and R13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl. In a further embodiment, R12 and R13 are simultaneously or independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R12 and R13 are linked to form an optionally substituted monocytic, fused bicylic, fused tricyclic, fused quadracyclic, fused pentacyclic, fused hexacyclic or fused heptacyclic ring system having 4-32 atoms, including the phosphorous atom to which R12 and R13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi_6alkyl. In another embodiment, the compound of formula III is
Figure imgf000019_0001
wherein LG2 is a suitable leaving group.
In an embodiment of the disclosure, a method for preparing aminophosphine ligands comprising reacting a compound of the formula II
Figure imgf000020_0001
with a compound of the formula III
R13
P LG2
/
R12
III
under conditions to provide a compound of the formula IV
Figure imgf000020_0002
wherein
LG2 is a suitable leaving group; one of q and r is 1, while the other is 0; n is 0, 1, 2, 3 or 4;
R1 to R6 are simultaneously or independently selected from H, Ci-2oalkyl, C2- 20alkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms; R7 is selected from Ci-6alkyl and aryl, said latter two groups being optionally substituted;
R8 and R9 are simultaneously or independently selected from H, Ci-20alkyl, C2. 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R8 and R9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC)-6alkyl;
R10 is selected from Chalky!, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR11,
N(Rπ)2 and Rπ; R11 is selected from
Figure imgf000021_0001
C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; and
R12 and R13 are simultaneously or independently selected from H, Ci-20alkyl, C2- 2oalkenyl, C2-2oalkynyl, aryl, heteroaryl, OR10 and N(R1 °)2, said latter 7 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R12 and R13 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC1-6alkyl. In another embodiment, R1 to R6 are simultaneously or independently selected from H, Ci.ioalkyl, C2-ioalkenyl, C2-ioalkynyl, C3.i0cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms. In another embodiment, R1 to R6 are simultaneously or independently selected from H, Ci-4alkyl, C2-4alkenyl, C2. 4alkynyl, C3-6cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the carbons to which these groups are attached and/or the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms. In a further embodiment, R1 to R6 are simultaneously or independently selected from H, methyl, or phenyl, or two adjacent or geminal groups, are linked together with the carbons to which said groups are attached, and/or with the nitrogen atom of the amino group, to form a phenyl, indanyl or ferrocenyl ring.
In another embodiment of the disclosure, n is equal to 0, 1 or 2. In a further embodiment, n is equal to 0 or 1.
In another embodiment of the disclosure, R7 is selected from
Figure imgf000022_0001
or phenyl, said latter two groups being optionally substituted. In another embodiment, R7 is methyl.
In a further embodiment of the disclosure, R and R are simultaneously or independently selected from H, Ci.iOalkyl, C2-i0alkenyl, C-2-ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and
Figure imgf000022_0002
In another embodiment, R8 and R9 are simultaneously or independently selected from H, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R8 and R9 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl. In a further embodiment, R8 and R9 are simultaneously or independently isopropyl, t-butyl, or phenyl. In another embodiment of the disclosure, R8 and R9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R8 and R9 are linked. In a further embodiment, wherein the fused pentacyclic ring system is
Figure imgf000023_0001
In the present disclosure, R10 is selected from Ci-4alkyl, C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R10 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro- substituted.
In embodiments of the disclosure, the optional substituents are selected from one or more of halo, OH, NH2, OR11, N(RU)2 and R11, in which R1 1 is selected from the group consisting of Ci-4alkyl, C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro-substituted. In an embodiment, R11 is selected from methyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
In another embodiment, R12 and R13 are simultaneously or independently selected from H, Ci-10alkyl, C2-i0alkenyl, C-2-ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R11 and R12 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi.6alkyl. In a further embodiment, R12 and R13 are simultaneously or independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R12 and R13 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic, fused pentacyclic, fused hexacyclic or fused heptacyclic ring system having 4-32 atoms, including the phosphorous atom to which R12 and R13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi-6alkyl. In another embodiment, the compound of formula III is
Figure imgf000024_0001
In the present disclosure LG2 in a compound of formula III, is a suiable leaving group. The term "suitable leaving group" in a compound of formula III would be understood by a person skilled in the art to mean any group attached to a phosphorous atom that can be displaced by the nucleophilic nitrogen atom of the compound of formula II. Suitable leaving groups include, but are not limited to, halides, including chloro, bromo, and iodo, tosylates, mesylates, and triflates and the like. In an embodiment of the disclosure, the conditions to provide a compound of the formula IV are nucleophilic reaction conditions that would be known to a person skilled in the art. In an embodiment of the method, the conditions to provide a compound of formula IV comprise adding a compound of the formula III to a compound of the formula II at about room temperature. In a further embodiment of the disclosure, the solution of a compound of the formula II and formula III is stirred at about room temperature for a period of about 2 to about 24 hours. A person skilled in the art would understand that the conditions, including time and temperature may be varied, depending, for example, on the structure of the compounds of formula II and formula III. In another embodiment of the disclosure, the conditions to provide a compound of the IV comprise the reaction between the compound of the formula II and a compound of formula III under anhydrous conditions and in an inert atmosphere (e.g. in the absence of oxygen). In an embodiment of the method, the conditions to provide a compound of the formula IV comprise the reaction between a compound of the formula II and a compound of the formula III in an aprotic solvent. In a subsequent embodiment of the method, the reaction between a compound of the formula II and a compound of the formula III is performed in a polar, aprotic solvent. In a further embodiment of the method, the reaction between a compound of the formula II and a compound of the formula III is performed in a variety of solvents, including chlorinated solvents such as dichloromethane, ethers such as tetrahydrofuran or diethyl ether, acetonitrile, benzene, toluene, hexanes, dimethyformamide and the like. In a suitable embodiment of the method, the reaction between a compound of the formula II and a compound of the formula III is performed in dichloromethane.
In an embodiment of the disclosure, the aminophosphine ligands prepared using the method of the present disclosure are complexed with any metal for use as catalysts. In an embodiment of the invention, the metal is any transition metal of groups 3 through 12 of the periodic table, suitably groups 4 through 10, plus the lanthanides and actinides. Examples of suitable metals include, but are not limited to Co, Rh, Ir, Ru, Os and Re. In an embodiment of the disclosure, the metal is Ru. In a further embodiment of the disclosure, the aminophosphine ligands of formula II are complexed with an RuCl2 group to form RuCl2(aminophosphine)2 and RuCl2(diphosphine)(aminophosphine) catalysts. In another embodiment of the disclosure, the aminophospine metal catalysts are those useful for the hydrogenation of ketones, aldehydes and imines.
In a further embodiment of the disclosure, there is included novel aminophosphepine ligands of the formula V
Figure imgf000026_0001
V
wherein R14 and R15 are simultaneously or independently selected from H, Ci-2oalkyl, C2.
20alkenyl, C2-2oalkynyl, C3-2ocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted;
R16 is selected from H,
Figure imgf000026_0002
and aryl, said latter two groups being optionally substituted or R16 is PR19R20; or two of R14, R15 and R16 are linked to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R17 and R18 are linked together with the phosphorous atom to which said R17 and R18 groups are linked to form an optionally substituted polycyclic ring of the formula
Figure imgf000026_0003
in which one or more carbon atoms in said polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; R19 and R20 are simultaneously or independently selected from H, Ci-20alkyl, C2- 2oalkenyl, C2-20alkynyl, aryl, heteroaryl, OR21 and N(R21)2, said latter 7 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC1-6alkyl; the optional substituents are selected from one or more of halo, OH, NH2, OR22, N(R22)2 and R22; and R21 and R22 are independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
In another embodiment of the disclosure, R14 and R15 are simultaneously or independently selected from H, Ci-10alkyl, C2-ioalkenyl, C2-i0alkynyl, C3-iocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted. In a further embodiment, R14 and R15 are simultaneously or independently selected from H, Ci- 4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted. In another embodiment, R14 and R15 are simultaneously or independently selected from H, methyl, or phenyl.
In another embodiment of the disclosure, R16 is H, Ci-4alkyl or phenyl, said latter two groups being optionally substituted. In a further embodiment, R16 is H or methyl.
In yet another embodiment, R16 is PR19R20, where R19 and R20 are simultaneously or independently selected from H, Ci.iOalkyl, C2-i0alkenyl, C2- loalkynyl, aryl, heteroaryl, OR21 and N(R21)2, said latter 7 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-4alkyl. In a further embodiment, R19 and R20 are simultaneously or independently selected from H, Ci-6alkyl, phenyl and OR21, said latter 3 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O. In yet another embodiment R16 is selected from:
Figure imgf000028_0001
In another embodiment, two of R14, R15 and R16 are linked to form an optionally substituted monocyclic, bicyclic, tricyclic, saturated, unsaturated and/or aromatic ring system having 5 to 14 atoms. In a further embodiment, R15 and R16 are linked to form an optionally substituted monocyclic or bicyclic, saturated, and/or aromatic ring system having 5 to 10 atoms.
In a further embodiment of the disclosure the optional substituents on the compounds of formula V are selected from one or more of Cl, F, OR22 and N(R22)2 and R22, where R22 is selected from Ci-6alkyl, and phenyl, said latter 4 groups being optionally fluoro-substituted. In yet another embodiment, the optional substituents on the compounds of formula V are selected from one or more of CH3, CF3, OCH3, and OCF3.
In yet another embodiment of the present disclosure, the stereochemistry of the compounds of formula V is as follows:
Figure imgf000028_0002
In an embodiment of the disclosure, there is included a novel aminophosphine ligand of the Formulae VI or VII
Figure imgf000029_0001
VI VII
wherein
R23 and R24 are simultaneously or independently selected from H, Ci-6alkyl and aryl, said latter two groups being optionally substituted or one of R23 and R24 is PR28R29; R25 and R26 are simultaneously or independently selected from H, Ci-2oalkyl, C2- 20alkenyl, C2-2oalkynyl, aryl, heteroaryl, OR30 and N(R30)2, said latter 7 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; R27 represents optional substituents selected from one or more of OH, NH2, OR31, N(R3 ' )2 and R3 ' , alternatively, R27 is H;
R28 and R29 are simultaneously or independently selected from H, Ci-20alkyl, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR32 and N(R32)2, said latter 7 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl; R30, R31 and R32 are independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR33, N(R33)2 and R33; and
R33 is selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted. In an embodiment of the disclosure, R23 and R24 are simultaneously or independently selected from H, Ci-4alkyl, phenyl and naphthyl. In yet another embodiment, R23 and R24 are simultaneously or independently selected from H, methyl and phenyl. In yet another embodiment, R23 and R24 are simultaneously selected from H, methyl and phenyl. In yet another embodiment, one of R23 and R24 is PR28R29 and R28 and R29 are simultaneously or independently selected from H, Ci.10alkyl, C2-i0alkenyl, C2- 20alkynyl, aryl, heteroaryl, OR32 and N(R32)2, said latter 7 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 or more atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl. In a further embodiment, R28 and R29 are simultaneously or independently selected from H, Ci-6alkyl, phenyl and OR32, said latter 3 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O. In yet another embodiment PR28R29 is selected from:
Figure imgf000031_0001
In further embodiments of the present disclosure, R25 and R26 are simultaneously or independently selected from H, Ci-ioalkyl, C2-i0alkenyl, C2- loalkynyl, aryl, heteroaryl, OR30 and N(R30)2, said latter 7 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 or more atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl. In a further embodiment, R25 and R26 are simultaneously or independently selected from H, Ci-6alkyl, phenyl and OR30, said latter 3 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
In an embodiment of the disclosure R27 represents optional substituents selected from one or five of OR31, N(R31^ and R31 is independently selected from Ci- 4alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted. In a further embodiment, R27 is H.
In further embodiments of the disclosure, R30 and R32 are independently selected from Ci-4alkyl, and phenyl, said latter 2 groups being optionally fluoro- substituted. In other embodiments if the present disclosure, the optional substituents are selected from one or five of Cl, F, OR33, N(R33)2 and R33, and R33 is selected from Ci- 4alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
In a further embodiment of the present disclosure, the amino phosphine ligand of the formula V is
Figure imgf000032_0001
, or the compounds as shown above, substituted on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl, CMalkyl, OCF3 and OCi-4alkyl.
In another embodiment of the disclosure, the aminophnosphine ligand of formula VI is
Figure imgf000033_0001
or the compounds as shown above, substituted on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl, Ci-4alkyl, OCF3 and OCi-4alkyl. In another embodiment, the aminophosphine ligand of formula VII is
Figure imgf000033_0002
or the compounds as shown above, substituted on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl, Ci-4alkyl, OCF3 and OCi^alkyl.
Also included as embodiments of the present disclosure are metal complexes, suitably a transition metal complex comprising a ligand of the formula II, IV, V, VI or VII. In particular the transition metal complex is of the type MCl2(aminophosphine)2 and MCl2(diphosphine)(aminophosphine), where aminophosphine is of the formula Ha, lib, Hc or Hd. Suitably M is Ru. The following non-limiting examples are illustrative of the present disclosure: EXAMPLES
All preparations and manipulations were carried out under hydrogen or argon atmospheres with the use of standard Schlenk, vacuum line and glove box techniques in dry, oxygen-free solvents. Tetrahydrofuran (THF), diethyl ether (Et2O) and hexanes were purified and dried using an Innovative Technologies solvent purification system. Deuterated solvents were degassed and dried before use. Precursor chemicals were supplied by Aldrich Chemical Company, Dalchem, Digital Specialty Chemicals and ChemPacific. NMR spectra were recorded on either a Varian Unity Inova 300 MHz spectrometer (300 MHz for 1H, 75 MHz for 13C and 121.5 for 31P) or a Bruker Avance 500 MHz DRX spectrometer. All 31P chemical shifts were measured relative to 85% H3PO4 as an external reference. The 1H and 13C chemical shifts were measured relative to partially deuterated solvent peaks but are reported relative to tetramethylsilane. The alcohol products obtained from the catalytic hydrogenation of ketones were characterized by their 1H and 13C NMR spectra. Example 1: Preparation of aminophosphine ligands Example 1.1: 2-(Diphenylphosphino)ethanamine
cr ^^ 2. H2o (ph)2p ^^
Butyl lithium (155 ml of a 1.6 M solution in hexane) was added dropwise to a cold (O0C) solution of diphenylphosphine (45 g, 0.24 mole) in THF (200 ml). The mixture was stirred for 2 hours at room temperature and a solution of N,N'-bis(trimethylsilyl)- 2-chloroethanamine (54 g, 0.24 mole) added slowly at O0C. The mixture was refluxed for 4 hours then cooled to room temperature. Water (50 ml) was added, followed by 2.0 M H2SO4 solution (200 ml). After stirring for 1 hour at room temperature a solution of 4.0 M NaOH solution (220 ml) was then added, and the mixture stirred for 1 hour. Hexane (200 ml) was added and the aqueous phase was separated and removed. The organic layer was dried (Na2SO4), filtered through a pad of silica gel, and evaporated to yield the aminophosphine, which was purified by vacuum distillation. Yield = 52.3 g. 1H NMR (C6D6): δ 7.72-7.32 (m, 10H), 2.95 (quartet, 2H, CH2), 2.26 (triplet, 2H, CH2), 0.92 (br, 2H, NH2). 31P NMR (C6D6): δ -23.3 (s).
Example 1.2: 2-(Diisopropylphosphino)ethanamine
1. LiP(1Pr)2
.N(TMS)2 ^
2. H2O 2
A THF (100 ml) solution of chlorodiisopropylphosphine (30 g, 0.20 mole) was added dropwise to a suspension of lithium granules (5.0 g, 0.72 mol) in THF (100 ml) maintained at room temperature, and the mixture stirred for 72 hours. The mixture was filtered and the filtrate cooled to O0C and a solution of N,N'-bis(trimethylsilyl)-2- chloroethanamine (44.2 g, 0.20 mole) added slowly. The mixture was refluxed for 4 hours then cooled to room temperature. Water (50 ml) was added, followed by 2.0 M H2SO4 solution (160 ml). After stirring for 1 hour at room temperature a solution of 4.0 M NaOH solution (180 ml) was then added, and the mixture stirred for 1 hour. Hexane (200 ml) was added and the aqueous phase was separated and removed. The organic layer was dried (Na2SO4), filtered through a pad of silica gel, and evaporated to yield the aminophosphine, which was purified by vacuum distillation. Yield = 28.2 g. 1H NMR (C6D6): δ 2.71 (m, 2H, CH2), 1.52 (doublet of septet, 2H, CH), 1.31 (m, 2H, CH2), 0.96 (m, 12H, CH3), 0.90 (br, 2H, NH2). 31P NMR (C6D6): δ -5.6 (s).
Example 1.3: 2-(Di-tert-butylρhosphino)ethanamine
1. LiP(NBu)2
,N(TMS)2 »- ,NH7
2. H2O <'-BukP '
A THF (100 ml) solution of chlorodi-tert-butylphosphine (42 g, 0.23 mole) was added dropwise to a suspension of lithium granules (5.0 g, 0.72 mol) in THF (100 ml) maintained at room temperature, and the mixture stirred for 72 hours. The mixture was filtered and the filtrate cooled to O0C and a solution of N,N'-bis(trimethylsilyl)-2- chloroethanamine (51.7 g, 0.23 mole) added slowly. The mixture was refluxed for 4 hours then cooled to room temperature. Water (50 ml) was added, followed by 2.0 M H2SO4 solution (200 ml). After stirring for 1 hour at room temperature a solution of 4.0 M NaOH solution (220 ml) was then added, and the mixture stirred for 1 hour. Hexane (200 ml) was added and the aqueous phase was separated and removed. The organic layer was dried (Na2SO4), filtered through a pad of silica gel, and evaporated to yield the aminophosphine, which was purified by vacuum distillation. Yield = 40.3 g. 1H NMR (C6D6): δ 2.76 (m, 2H, CH2), 1.35 (m, 2H, CH2), 1.02 (d, 18H, CH3), 0.84 (br, 2H, NH2). 31P NMR (C6D6): δ 17.5 (s).
Preparation of aminophosphine ligands from amino alcohols
Example 2: General Procedures for the preparation of N-tert-butoxycarbonylamino alcohol
A solution of (Boc)2O (44 mmol) in THF (50ml) was added to the mixture of the amino alcohol (40 mmol) and sodium carbonate (80 mmol) in THF/H2O (1/1, 300 ml) at O0C. The mixture was stirred at O0C for Ih and then at room temperature for another two 2h (TLC was used to monitor the reactions). Water (200 ml) was added to the mixture upon completion. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers was washed with brine (300 ml) and dried with anhydrous MgSO4 for Ih. It was then filtered and the solvent was removed under vacuum to give the product (yield = 90 - 99 %). It was sufficiently pure for the next step. The pure product was obtained by recrystallization from the THF and hexane, or by purification with silica gel chromatography.
Example 2.1: Tert-butyl (lS,2R)-2-hydroxy-l,2-diphenylethylcarbamate
Ph Ph
BocHN OH
Yield: 90 %. 1H NMR (CD2Cl2): δ 7.25-7.27 (m, 6H), 7.08-7.1 1 (m, 4H), 5.33 (m, IH), 5.04 (m, IH), 4.92 (b, IH), 2.60 (b, IH), 1.38 (s, 9H). Example 2.2: Tert-butyl (lS,2R)-2-hydroxy-l-phenylpropylcarbamate
Figure imgf000037_0001
Yield: 98 %. 1H NMR (CD2Cl2): δ 7.34-7.36 (m, 5H), 4.80-4.82 (m, 2H), 3.94 (b, IH), 3.60 (b, IH), 1.45 (s, 9H), 9.70 (d, J = 6.9 Hz, 3H).
Example 2.3: Tert-butyl (1 R, 2S)-2-methyl-l -hydroxy- 1 -phenylethylcarbamate
Me Ph
BocHN OH
Yield: quantitative yield. 1H NMR (CDCl3) δ 7.27-7.35 (m, 5H), 4.85 (d, IH), 4.62
(b, IH), 3.99 (b, IH), 3.24 (b, IH), 1.46 (s, 9H), 0.99 (d, J = 6.9 Hz, 3H).
Example 2.4: Tert-butyl ( J S,2R)-2-hydroxy-2,3-dihydro- 1 H-inden- 1 -ylcarbamate
Figure imgf000037_0002
Yield: 98 %. 1H NMR (CD2Cl2) δ 7.49 (d, IH), 7.25-7.28 (m. 3H), 5.64 (d, J = 5.4 Hz, IH), 5.44 (m, IH), 3.30 (b, 2H), 1.53 (s, 9H). Example 3: General Procedure for the preparation of sulfamidates An aliquot of SOCl2 (30 mmol) was added to the solution of N-alkoxycarbonylamino alcohol (30 mmol) and dimethylaminopyridine (DMAP, 90 mmol) in CH2Cl2 (200 ml) at -45 0C. The reaction was stirred at -45 0C for 1 -2 h and then water (2 ml) was added to quench the reaction. Another potion of water (150 ml) was added and the mixture was stirred at RT for 30 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (100 ml x 2). The combined organic layers was washed with water (150 ml x 2) and dried with anhydrous MgSO4. It was filtered through a silica gel pad (eluent: CH2Cl2). The filtration was dried under vacuum to give the sulfamidite which was sufficiently pure to be used for the next step without further purification.
To an ice-cold solution of the sulfamidite in a mixture of CH3CN (80 ml), CH2Cl2 (20ml) and water (80 ml) was added ruthenium(III) chloride (20mg) and NaIO4 (40 mmol). The mixture was stirred at O0C for 2-4h (TLC was used to monitor the reactions), and water (50 ml) was added. The organic layer was separated and the aqueous phase was extracted with ether (60 ml x 2). The combined organic layers was washed with brine (150 ml x 2) and dried with anhydrous MgSO4. It was filtered and the solvent was removed to give the crude product which was purified by recrystallization (THF/hexane) or by silica gel flash chromatography. The overall yield for the two steps was 40-60 %.
Example 3.1:
Figure imgf000038_0001
The overall yield for the two steps is 86%. 1H NMR (CD2Cl2) δ 7.14-7.24 (m, 6H), 7.06-7.10 (m, 2H), 6.95-7.00 (m, 2H), 6.20 (d, J = 5.6 Hz, IH), 5.45 (b, J = 5.6 Hz, IH), 1.46 (s, 9H).
Example 3.2:
Figure imgf000039_0001
Yield: 50 %. 1H NMR (CD2Cl2): δ 7.36-7 '.47 (m, 3H), 7.33-7.35 (m, 2H), 5.99 (d, J = 5.1 Hz, IH), 4.59 (dq, J = 5.1 Hz, J = 6.5 Hz, IH), 1.57 (s, 9H), 1.06 (d, J = 6.4 Hz, 3H).
Example 3.3
Figure imgf000039_0002
Yield: 34 %, two steps. 1H NMR (CDCl3) δ 7.42-7.45 (m, 3H), 7.30-7.33 (m, 2H), 5.96 (d, J = 5.2 Hz, IH), 4.52-4.62 (m, IH), 1.58 (s, 9H), 1.08 (d, J = 6.6 Hz, 3H). Example 3.4:
Figure imgf000040_0001
Yield: 40 %, two steps. 1H NMR (CD2Cl2) δ 7.49 (d, IH), 7.25-7.28 (m. 3H), 5.64 (d, J = 5.4 Hz, IH), 5.44 (m, IH), 3.30 (b, 2H), 1.53 (s, 9H).
Example 4: General Procedures for the preparation of aminophosphine ligands from sulfamidates A solution of potassium diphenylphosphide (28 ml, 0.5 M in hexane, 14 mmol) was added slowly to a solution of the sulfamidate (12 mmol) in THF (100 ml) at -5O0C and the mixture was stirred at that temperature for 2h, then the mixture was slowly warmed to RT and stirred overnight. De-gassed H2SO4 solution (2M, 30ml) in brine (50 ml) was added and the mixture was stirred for Ih, after which, de-gassed saturated Na2CO3 solution (50 ml) was added to neutralize the acid. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The combined organic layer was washed with brine and dried with anhydrous MgSO4. It was filtered and the solvent was removed under vacuum to give the crude product as a viscous oil which was dissolved in CH2Cl2 (50 ml). To the ice-cooled solution CF3CO2H (20 ml) was added and the mixture was stirred at RT overnight. All the volatiles were removed under vacuum and the residue was neutralized with de-gassed saturated Na2CO3 solution (50 ml). The product was extracted with CH2Cl2 (100ml x 2). The combined organic layers was washed with brine and dried with anhydrous MgSO4. It was filtered with a silica gel pad (eluent: CH2Cl2 to remove impurities, then CH2C12/THF to elute the product). The solvent was removed to give the pure aminophosphine product. The yields are 85-90 %. Example 4.1: (lS,2S)-2-(Diphenylphosphino)-l,2-diphenylethanamine
Figure imgf000041_0001
Yield = 85 %. 1H NMR (CD2Cl2) δ 7.81-7.88 (m, 2H), 7.42-7.50 (m, 3H), 6.88-7.22 (m, 15H), 4.43 (dd, IH), 4.05 (dd, IH), 1.6 (b, 2H), 31P NMR (CD2Cl2) δ -7.15 ppm.
Example 4.2: (IR, 2R)-2-(Diphenylphosphino)-l, 2-diphenylethanamine
Figure imgf000041_0002
The 1H NMR spectrum for this compound was similar to that of (lS,2S)-2- (diphenylphosphino)-l, 2-diphenylethanamine (Example 4.1).
Example 4.3: (1 S,2S)-2-(Diphenylphosphino)-2, 3-dihydro- 1 H-inden- 1 -amine
Figure imgf000041_0003
Yield = 87 %. 1H NMR (CD2Cl2): δ 7.54-7.66 (m, 4H), 7.38-7.42 (m. 6H), 7.26-7.32 (m, IH), 7.16-7.22 (m, 3H), 4.36 (dd, IH), 3.18-3.31 (m, IH), 2.73-2.97 (m, 2H), 1.19 (b, 2H). 31P NMR (CD2Cl2): δ -5.84 ppm. Example 4.4: (IR, 2R) -2- (Diphenylphosphino)-2, 3-dihydro- 1 H-inden- 1 -amine
Figure imgf000042_0001
The 1H NMR spectrum for this compound was similar to that of (lS,2S)-2- (diphenylphosphino)-2,3-dihydro-l H-inden- 1 -amine (Example 4.5).
Example 4.5: (S)-2-((Diphenylphosphino)methyl)pyrrolidine
Figure imgf000042_0002
The 1H NMR spectra was similar to that reported by Guo et al. J. Am. Chem. Soc. 2005, 127, 516-517.
Example 4.6: (R)-2-((Diphenylphosphino)methyl)pyrrolidine
Figure imgf000042_0003
The 1H NMR spectra was similar to that reported by Guo et al. J. Am. Chem. Soc. 2005, 127, 516-517.
Example 4.7: (1 S, 2S)- 1 -(Diphenylphosphino)- 1 -phenylpropan-2-amine
Figure imgf000043_0001
Yield: 93.2%. 1H NMR (CD2Cl2) δ 7.53-7.62 (m, 2H), 7.01-7.50 (m, 13H), 2.93-3.02 (m, IH), 1.65 (b, 2H), 1.00 (d, J = 6.6 Hz, 3H). 31P NMR (CD2Cl2) δ -8.7 ppm.
Example 4.8: (IR, 2R)-l-(Diphenylphosphino)-l-phenylpropan-2-amine
Figure imgf000043_0002
The 1H NMR spectrum for this compound was similar to that of (lS,2S)-2- (diphenylphosphino)-l-phenylpropan-l -amine (Example 4.7).
Preparation of Aminophosphephine Ligands
Example 5.1: 2-((l lbR)-3H-Dinaphtho[2, l-c:l \2'-e]phosphepin-4(5H)- yl) ethanam ine
Figure imgf000043_0003
Butyl lithium (34 ml of a 2.5 M solution in hexane) was added to a solution of (l lbR)-4,5-dihydro-3H-dinaphtho[2,l-c:l',2'-e]phosphepine borane (28.0 g, 86 mmol) in THF (250 ml) at -780C. The mixture was stirred at -780C for 1.5 hour, and a solution of N,N'-bis(trimethylsilyl)-2-chloroethanamine (19.2 g, 86 mmol) in THF (20 ml) added. The reaction mixture was allowed to slowly warm to room temperature and refluxed for 24 hours. The mixture was hydrolyzed with H2SO4 solution, then neutralized with NaOH solution. Work-up resulted in crude 2-((1 IbR)- 3H-dinaphtho[2,l-c:r,2'-e]phosphepin-4(5H)-yl)ethanamine borane (36.6 g), which was purified by silica gel chromatography (eluent = EA/CH2C12 (1 :8, then 1 :6)) to give pure 2-((l lbR)-3H-dinaphtho[2,l-c: l',2l-e]phosphepin-4(5H)-yl)ethanamine borane (17.5 g). A general procedure for the method of producing aminophosphepine ligands is shown in Figure 2.
Tetrafluoroboric acid (HBF41Et2O, 3.4 ml) was added to the solution of 2- ((l lbR)-3H-dinaphtho[2,l-c: l',2'-e]phosρhepin-4(5H)-yl)ethanamine borane (2.0 g) in CH2Cl2 (50 ml) at O0C. The mixture was stirred at room temperature overnight. Saturated NaHCO3 solution (2 x 100 ml) was added and the mixture stirred for 1 hour. The aqueous layer was extracted with CH2Cl2 (2 x 50 ml) and the combined organic layer was washed with 4.0 M NaOH solution (2 x 100 ml) and brine, then dried (MgSO4). The mixture was filtered and evaporated under reduced pressure to give the crude product as a white foamy solid. Purification by silica gel chromatography (eluent = ethyl acetate (EA)/CH2C12 (1 :2)) gave the pure product. Yield = 1.7 g. 1H NMR (C6D6): δ 7.03-7.88 (m, 12H), 2.85 (m, 2H, CH2), 2.05 (m, 2H, CH2), 1.76 (br, 2H, NH2), 1.53 (m, 2H, CH2), 1.35 (m, 2H, CH2). 31P NMR (C6D6): δ 2.0 (s).
Example 5.2.1: (IS, 2S)-I, 2-diphenyl-2-(S)-phosphepinoethyleneamine-N-Boc-P- borane complex
Figure imgf000044_0001
A solution of n-Butyllithium (12 ml, 2.5 M in Hexane) was slowly added to a solution of (l lbS)-4,5-dihydro-3H-dinaphtho[2,l-C:l',2'-e]-phosphepine borane complex (9.4 g) in THF (100 ml) in a dry ice/acetone bath. The mixture was stirred for Ih in the dry ice/acetone bath, then it was added to the suspension of (45, SR)-A, 5-diphenyl-3- alkoxycarbonyl-1, 2, 3-oxathiazolidine-2-dioxide (10 g) in THF (200 ml) cooled in a dry-ice/acetone bath. The mixture was stirred for 1 h. It was slowly warmed up to the RT and was stirred for 24 h. H2SO4 (20 ml, 2N) was added to the mixture which was stirred at RT for Ih. Na2CO3 (saturated 50 ml) in brine (20 %, 100 ml) was added to neutralize the mixture and make the solution basic. The aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic layer was washed with brine (100 ml x 2) and dried over MgSO4 for 2h. It was filtered and the filtrate was concentrated to almost dryness to give the crude product as a pale yellow solid (17 g) which was dissolved in CH2Cl2 (100 ml). Hexane (400 ml) was added slowly to precipitate the product. The resulting slurry was stirred at RT for 4 h. The solid was filtered and washed with Hexane (50 ml). It was dried under vacuum to give the product as a colorless crystalline solid (12.4 g). Another potion of product obtained from mother liquor (1.6 g). Overall yield is 84.7 %. 1H NMR (CD2Cl2) δ 7.89-7.94 (m, 2H), 7.79- 7.83 (m, 2H), 6.90-7.43 (m, 18H), 6.26 (b, IH), 5.24 (m, IH), 3.6 (m, IH), 2.46-2.56 (m, IH), 2.38 (b, IH), 2.04-2.14 (m, IH). 31P NMR (CD2Cl2) δ 49.8 ppm.
Example 5.2.2: (IS, 2S)-I, 2-diphenyl-2-(S)-phosphepineethyleneamine-N-Boc
Figure imgf000045_0001
DABCO (3.1 g) was added to the suspension of (IS, 2S)-I, 2-diphenyl-2-(S> phosphepine ethyleneamine-N-Boc-P-borane complex (13.5 g) in toluene (150 ml). The mixture was stirred at 90-95 0C under argon overnight. All the volatiles were removed under vacuum. To the residue, CH3CNZMeOH (1 :1, 80 ml) was added and the mixture was stirred for. It was filtered and the solid was washed with CH3CN/MeOH (1 :1, 30 ml) to give the pure product as a white solid (12 g, yield: 90.9 %). 1H NMR (CD2Cl2) δ 8.01 (dd, J1 = 5.1 Hz, J2 = 8.4 Hz, 2H), 7.87 (dd, Jy = 8.4 Hz, J2 = 14.7 Hz, 2H), 7.06-7.46 (m, 16H), 6.83 (b, 2H), 5.48 (b, IH), 5.34 (b, IH), 3.12-3.15 (m, IH), 2.50-2.71 (m, 2H), 1.83-1.95 (m, 2H), 1.47 (s, 9H). 31P NMR (CD2Cl2) δ 9.08 ppm. Example 5.2.3: (IS, 2S)-I, 2-diphenyl-2-(S)-phosphepineethyleneamine
Figure imgf000046_0001
Trifloroacetic acid (30 ml) was added to the solution Of (IiS1, 25)- 1, 2-diphenyl-2-(S)- phosphepine ethyleneamine-N-Boc (12 g) in CH2Cl2 (100 ml) at 0 0C. The mixture was stirred at RT overnight. The volatiles were removed under vacuum and the residue was dissolved in CH2Cl2 (150 ml). It was neutralized with Na2CO3 (saturated, 50 ml) in brine (20 %, 100 ml). The aqueous layer was extracted with CH2Cl2 (100 ml). The combined organic layer was washed with brine (20 %) and dried over MgSO4 for 3h. The solvent was removed to give the crude product as a white solid (9 g) which was purified by dissolving in CH3CN/MeOH (1 :1, 80 ml), then water (100 ml) was added slowly to precipitate the product. It was filtered and dried to give the pure product as a white solid (7.2 g, yield: 72 %). 1H NMR (CD2Cl2) δ 8.05 (dd, J1 = 8.3 Hz, J2 = 22.2 Hz, 2H), 7.88 (dd, J, = 7.2 Hz, J2 = 15.5 HZ, 2H), 7.63 (d, J - 7.2 Hz, IH), 6.73-7.47 (m, 17H), 4.47 (dd, J, = 5.1 Hz, J2 = 9.2 Hz, IH), 3.31 (dd, J, = 5.0 Hz, J2 = 14.0 Hz, IH), 3.06 (dd, J, = 6.6 Hz, J2 = 9.3 Hz, IH), 2.61 (dd, J1 = W A Hz, J2 = 14.3 Hz, IH), 1.89 (m, 4H). 31P NMR (CD2Cl2) δ 14.9 ppm.
Example 5.3.1: (IS, 2S)-l-methyl-2-diphenyl-2-(S)-phosphepinoethyleneamine-N- Boc-P-borane complex
Figure imgf000046_0002
A solution of n-Butyllithium (17 ml, 2.5 M in Hexane) was slowly added to a solution of (l lbS)-4,5-dihydro-3H-dinaphtho[2,l-C:l',2'-e]-phosphepine borane complex (13.8 g) in THF (100 ml) cooled in a dry ice/acetone bath. The mixture was stirred for Ih with cooling in a dry ice/acetone bath, then it was added to a suspension of (45, 5/?)-4-methyl- 5-phenyl-3-alkoxycarbonyl-l, 2, 3-oxathiazolidine-2, 2-dioxide (12.1 g) in THF (100 ml) cooled in a dry-ice/acetone bath. The mixture was stirred for 1 h. It was slowly warmed up to the RT and was stirred for 24 h. H2SO4 (20 ml, 2N) was added to the mixture which was stirred at RT for Ih. Na2CO3 (saturated 50 ml) in brine (20 %, 100 ml) was added to neutralize the mixture and make the solution basic. The aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic layer was washed with brine (100 ml x 2) and dried over MgSO4 for 2h. It was filtered and the filtrate was concentrated to almost dryness to give the crude product as a white solid (20 g) which was dissolved in CH2Cl2 (80 ml), hexane (400 ml) was added slowly to precipitate the product. The resulting slurry was stirred at RT for 4 h. The solid was filtered and washed with Hexane (50 ml). It was dried under vacuum to give the product as a colorless crystalline solid (15.5 g, yield: 71.8 %). 1H NMR (CD2Cl2) δ 7.83-7.97 (m, 6H), 7.30-7.40 (m, 4H), 6.96-7.16 (m, 7H), 4.90 (b, IH), 4.08 (m, IH), 3.46 (m, IH), 3.12 (dd, J = 5.0 Hz, J = 14.6 Hz, IH), 2.67 (dd, J = 6.4 Hz, J = 14.6 Hz, IH), 1.90-2.34 (m, 2H). 31P NMR (CD2Cl2) δ 50.2 ppm.
Example 5.3.2: (IS, 2S)-l-methyl-2-diphenyl-2-(S)-phosphepinoethyleneamine-N-Boc
Figure imgf000047_0001
DABCO (6.4 g) was added to a suspension of (IS, 2S)-l-methyl-2-diphenyl-2-(S)- phosphepinoethyleneamine-N-Boc-Phosphepine-borane complex (15.5 g) in toluene (250 ml). The mixture was stirred at 90-95 0C under argon overnight. All the volatiles were removed under vacuum. To the residue, CH3CN/MeOH (1 :1, 80 ml) was added and the mixture was stirred for 6h to remove impurities. It was filtered and the solid was washed with CH3CN/MeOH (1 :1, 30 ml) to give the pure product as a white solid (10.7 g, yield: 70.1 %). 1H NMR (CD2Cl2) δ 7.74-7.91 (m, 5H), 6.95-7.35 (m, 12H), 4.15-4.38 (m, 2H), 2.78-2.85 (m, 2H), 2.50 (dd, J =10.6 Hz, J = 14.4 Hz, IH), 1.96 (dd, J = 1 1.8 Hz, J = 14.9 Hz, IH), 1.75 (dd, J = 3.1 Hz, 1 1.9 Hz, IH), 1.43 (s, 9H), (m, 2H), 1.11 (d, J - 6.7 Hz, 3H). 31P NMR (CD2Cl2) δ 10.6 ppm.
Example 5.3.3: (IS, 2S)-l-methyl-2-diphenyl-2-(S)-phosphepinoethylamine
Figure imgf000048_0001
Trifluoroacetic acid (30 ml) was added to a solution Of (I1S, 25)-l-methyl-2-diphenyl- 2-(S)-phosphepinoethylamine-N-Boc (10.7 g) in CH2Cl2 (100 ml) at 0 0C. The mixture was stirred at RT overnight. The volatiles were removed under vacuum and the residue was dissolved in CH2Cl2 (200 ml). It was neutralized with Na2CO3 (saturated, 50 ml) in brine (20 %, 100 ml). The aqueous layer was extracted with CH2Cl2 (100 ml). The combined organic layer was washed with brine (20 %) and dried over MgSO4 for 3h. The solvent was removed to give the crude product as a white solid (8.3 g) which was purified by filtering through a silica gel pad (eluent: CH2Cl2/hexane, 1/1, 300 ml to remove impurities, CH2C12/THF, 9/1, 200 ml to elute the product). The solvent was removed from the filtrate to give the product as a colorless solid (7.2 g, yield: 82.4 %). 1H NMR (CD2Cl2) δ 7.83-8.04 (m, 4H), 6.94- 7.58 (m, 13H), 3.43-3.53 (m, IH), 3.16 (dd, J = 5.2 Hz, J = 14.2 Hz, IH), 2.53-2.62 (m, 2H), 1.86-1.90 (m, 2H), 1.29 (b, 2H), 1.07 (d, J = 6.3 Hz, 3H), 1.89 (m, 4H). 31P NMR (CD2Cl2) δ 14.6 ppm.
Example 5.4.1: tert-Butyl-2-((llbS)-3H-dinaphtho[2, 1-c: 1 ', 2 '-e]phosphepin-4(5H)- yl)ethylcarbamate-P-borane complex
Figure imgf000049_0001
A solution of n-Butyllithium (2.1 ml, 2.5 M in Hexane) was added to the solution of (l lbS)-4,5-dihydro-3H-dinaphtho[2,l-C:r,2'-e]-phosphepine borane complex (1.6 g) in THF (30 ml) with a dry ice/acetone bath at -50 °C. The mixture was stirred for 20 minutes at -50 °C and was then added to a solution of 3-alkoxycarbonyl-l, 2, 3- oxathiazolidine-2, 2-dioxide (1.0 g) in THF (20 ml). The mixture was slowly warmed to RT and was stirred overnight. A solution of H2SO4 (5 ml, 2N) followed by brine (10 ml) were added and the resulting solution was stirred at RT for 20 minutes. A solution of Na2CO3 (saturated, 10 ml) was added to neutralize the mixture. The aqueous layer was extracted using CH2Cl2 (50 ml) and the combined organic layer was washed with brine (100 ml x2) and dried over MgSO4 for 2 hours. The solution was filtered and concentrated under vacuum to generate the crude residue. This was dissolved in CH2Cl2 (50 ml) and filtered using a silica gel pad with CH2Cl2 as the eluent (200 ml). The solvent was removed under vacuum to give the pure product (2.0 g, yield: 90%). 1H NMR (CD2Cl2) δ 5.0 (b, IH), 7.1-8.0 (m, 16 H) 31P NMR (CD2Cl2) δ 44.9 ppm (b).
Example 5.4.2: tert-Butyl-2-((l lbS)-3H-dinaphtho[2,l-c: 1 \2 '-e]phosphepin-4(5H)- yl)ethylcarbamate
Figure imgf000049_0002
DABCO (0.62 g) was added to a solution of tert-butyl-2-((l lbS)-3H-dinaphtho[2,l- c:l ',2'-e]phosphepin-4(5H)-yl)ethylcarbamate-P-borane complex (2.0 g) in toluene (50 ml). The solution mixture was stirred at 90 °C overnight. The solvent was removed under vacuum to give a solid crude product which was then dissolved in CH3CN/MeOH 1:1 (30 ml). Water (20 ml) was added and the solvent was decanted. The remaining residue was dried under vacuum to give the product as a white solid (1.6 g, yield: 82.4%). 31P NMR (CD2Cl2) δ -0.1 ppm.
Example 5.4.3: 2-((llbS)-3H-dinaphtho[2, 1-c: 1 ', 2 '-e]phosphepin-4(5H)- yl)ethanamine
Figure imgf000050_0001
Trifluoroacetic acid (3.5 ml) was added to a solution of tert-butyl-2-((l lbS)-3H- dinaphtho[2,l-c:l',2'-e]phosphepin-4(5H)-yl)ethylcarbamate (1.6 g) in CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT overnight following which all volatiles were removed. The residue was dissolved in CH2Cl2 (50 ml) and the solution was neutralized with Na2CO3 (saturated, 50 ml) in brine (20%, 50 ml). The aqueous layer was then extracted with CH2Cl2 (60 ml) and the combined organic layer was washed with brine (20%, 150 ml) and dried over MgSO4 for 2 hours. The organic solution was filtered and concentrated under vacuum to give a crude white product (1.1 g, yield: 88 %). The product was washed with hexane (100 ml) to give a pure white solid product (0.8 g, yield: 64.3%). 31P NMR (CD2Cl2) δ 0.6, -1.4 ppm.
Example 6: N-((lS,2S)-2-((4R, llbS)-3H-dinaphtho[2, l-c:l \2 '-e]phosphepin-4{5H)- yl)-l, 2-diphenylethyl)- 1 , 2-diphenylphosphinamine
Figure imgf000051_0001
Chlorodiphenyl phosphine (121 mg) was added to a solution of (IS1, 2S)-I, 2- diphenyl-2-(S)-phosphepine ethyleneamine (254 mg) in triethylamine (101 mg), DMAP (5 mg) and CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT overnight. The solvent was removed and the residue was filtered using a silica gel pad with CH2Cl2 as the eluent (60 ml). The filtered solution was concentrated and dried under vacuum to give the colourless solid product (185 mg, yield: 53.5%). 31P NMR (CD2Cl2) δ 42.52 (d, J = 5.1 ppm); 12.02 (d, J = 5.1 ppm).
Example 7: N-((lS,2S)-2-((4R,llbS)-3H-dinaphtho[2,l-c:l \2 '-e]phosphepin-4(5H)- yl)-l, 2-diphenylethyl)-l , l-bis(3, 5-(trifluoromethylphenyl)phosphinamine
Figure imgf000051_0002
Chlorodi(3,5-trifluoromethylphenyl) phosphine (270 mg) was added to the solution of (15, 25)-l, 2-diphenyl-2-(S)-phosphepine ethyleneamine (254 mg) in triethylamine (101 mg), DMAP (5 mg) and CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT for four hours. The solvent was removed under vacuum and the crude product was purified using a silica gel pad with CH2Cl2 as the eluent (60 ml). The filtered solution was dried under vacuum to give the product as a pale-yellow solid (335 mg, yield: 69.6%). 31P NMR
Example 8: (HbS)-N-((lS,2S)-2-((4R, llbS)-3H-dinaphtho[2,l-c:l \2 '-e]phosphepin- 4(5H)-yl)-l, 2-diphenylethyl)dinaphtho[2, 1 -d: 1 ', 2 '-J][1, 3, 2]dioxaphosphepin-4-amine
Figure imgf000052_0001
A portion of (l lbR)-4-chlorodinaphtho[2,l-(i:l ',2'-/J[l,3,2]dioxaphosphepine (210 mg) was added to the solution of (15, 2S)-I, 2-diphenyl-2-(S)- phosphepineethyleneamine (254 mg) in triethylamine (101 mg), DMAP (5 mg) and
CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT for three hours.
The solvent was removed under vacuum and the crude product was filtered using a silica gel pad with CH2Cl2 as the eluent (60 ml). The filtered solution was dried under vacuum to give the product as a white solid product (260 mg, yield: 64%). 31P NMR
(CD2Cl2) δ 152.4 (d, J = 26.7 Hz); 14.4 (d, J = 26.7 Hz).
Example 9:
Figure imgf000052_0002
Chlorodi(3,5-trifluoroniethylphenyl) phosphine (270 mg) was added to a solution of (IS, 2S)-l-methyl-2-diphenyl-2-(S)-phosphepinoethylamine (223 mg) in triethylamine (101 mg), DMAP (5 mg) and CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT for four hours. The solvent was removed under vacuum and the crude product was purified using a silica gel pad with CH2Cl2 as the eluent (60 ml). The filtered solution was dried under vacuum to give the product as a pale- yellow solid (320 mg, yield: 71%). 31P NMR (CD2Cl2) δ 39.10 (d, J = 1.9 Hz); 10.83 (d, J = 1.9 Hz).
Example 10:
Figure imgf000053_0001
A portion of (l lbS)-4-chlorodinaphtho[2,l-t/:l ',2'-/J[l,3,2]dioxaphosphepine (210 mg) was added to a solution of (IS, 25)-l-methyl-2-diphenyl-2-(S)- phosphepinoethylamine (223 mg) in triethylamine (101 mg), DMAP (5 mg) and CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT for three hours. The solvent was removed under vacuum and the crude product was filtered using a silica gel pad with CH2Cl2 as the eluent (60 ml). The filtered solution was dried under vacuum to give the product as a white solid (230 mg, yield: 61.6%). 31P NMR (CD2Cl2) δ 152.88 (d, J = 25.5 Hz); 13.87 (d, J = 25.5 Hz).
Preparation of Aminophosphine Ligands from Ephedrine Example 11.1: (4S, 5R)-3, 4-dimethyl-5-phenyl-l, 2, 3-oxathiazolidine-2-oxide
Me Ph MeN ^O O A solution of SOCl2 (7.2 g) in CH2Cl2 (50 ml) was added to a solution of (IR, 2S)- ephedrine (8.3 g) and triethylamine (20 g) in CH2Cl2 (300 ml) at -40 0C. The mixture was stirred at —40 0C for 2 h. Water (50 ml) was added to quench the reaction. The mixture was allowed to warm up to RT, then water (500 ml) was added. The aqueous layer was extracted with CH2CI2 (100 ml x 2). The combined organic layer was washed with brine (20 %, 800 ml) and was dried over MgSO4. It was filtered with a silica gel pad (eluent: CH2Cl2/ethyl acetate = 1 :1). The solvent was removed to give the crude cyclic sulfamidite as a brown oil which solidified upon standing (6.4 g). The product was sufficiently pure for the next step. A general procedure for the method of producing aminophosphine ligands from ephedrine is shown in Figure 3.
Example 11.2: (4S, 5RJ-3, 4-dimethyl-5-phenyl-l , 2, 3-oxathiazolidine-2, 2-dioxide Me Ph
MeN , ,0 O -A O A weighed amount of RuCl3 «H2O (20 mg) was added to a mixture of (AS, 5R)-2>, A- dimethyl-5-phenyl-l, 2, 3-oxathiazolidine-2-oxide (6.4 g) in CH3CN (150 ml), CH2Cl2 (20 ml) and H2O (150 ml). This was followed by the addition Of NaIO4 (8 g) at 0 0C. The color of mixture changed to yellow. It was stirred at 0 0C for 1 h, then RT for Ih. The aqueous layer was extracted with ether (100 ml x 2). The combined organic layer was washed with brine (200 ml x 3) and dried over MgSO4. The filtrate was concentrated to almost dryness. The residue was crystallized from ethyl acetate (15 ml) and Hexane (300 ml). The crystalline solid was filtered and dried to give the product (6g, yield: 52 % two steps). 1H NMR (CD2Cl2) δ 7.38-7.45 (m, 5H), 5.71 (d, J = 6.75 Hz, IH), 3.88-3.93 (m, IH), 2.76 (s, 3H), 0.87 (d, J = 6.6 Hz, 3H).
Example 11.3: (IS, 2S)-l-methyl-2-phenyl-2-diphenylphosphino-N- methylethyleneamine
Me Ph
/ \ MeHN PPh2 A solution of KPPh2 (54 ml, 0.5 M in THF) was added dropwise to a suspension of (4S, 5R)-3, 4-dimethyl-5-phenyl-l, 2, 3-oxathiazolidine-2, 2-dioxide (5.9 g) in THF (150 ml) cooled in an acetone/dry- ice bath. The mixture was stirred at -60 0C for 0.5 h. It was slowly warmed up to the RT and stirred overnight. A solution Of H2SO4 (10 ml, 2N) in brine (20 %, 100 ml) was added to the mixture and it was stirred at RT for Ih. Na2CO3 (saturated 50 ml) was added to neutralize the mixture and make the solution basic. The aqueous layer was extracted with CH2Cl2 (50 ml x 2). The combined organic layer was washed with brine (150 ml x 2) and dried over MgSO4 for 2h. It was filtered and the filtrate was concentrated to almost dryness. The residue was purified with a silica gel pad (eluent: CH2C12/Hexane 1/1 to remove the impurities, then CH2C12/THF 19/1 to washed out the product. The solvent was removed to give the product as a colorless solid (7.3 g, yield: 84 %). 1H NMR (CD2Cl2) δ 7.60-7.70 (m, 2H), 7.06-7.39 (m, 13H), 3.91 (dd, J = 4.4 Hz, J = 6.4 Hz, IH), 2.63-2.68 (m, IH), 2.33 (s, 3H), 1.11 (d, J= 6.6 Hz, 3H). 31P NMR (CD2Cl2) δ - 9.9.
Example 12: (UbS)-N-((lS,2S)-2-(diphenylphosphino)-l,2- diphenylethyl)dinaphtho[2, l-d:l ', 2 '-J][J, 3, 2]dioxaphosphepin-4-amine
Figure imgf000055_0001
A portion of (l lbR)-4-chlorodinaphmo[2,l-tf:l \2'-/][l,3,2]dioxaphosphepine (210 mg) was added to a solution of (IS, 2S)- 1, 2-diphenyl-2- diphenylphosphinoethyleneamine (190 mg) in triethylamine (101 mg), DMAP (5 mg) and CH2Cl2 (30 ml) at room temperature. The mixture was stirred at RT for three hours. The solvent was removed under vacuum and the crude product residue was filtered using a silica gel pad with CH2Cl2 as the eluent (60 ml). The remaining eluent in the filtered solution was evaporated under vacuum to give the white solid product (251 mg, yield: 72.1%). 31P NMR (CD2Cl2) δ 153.4 (d, J = 12.1 Hz); 13.87 (d, J = 12.1 Hz).
Example 13: General Procedure for Preparation of new aminophosphine catalysts The new catalysts (S-Binap)((l S,2S)-2-(diphenylphosphino)-l ,2-diphenylethanamine) and (S-Binap)((l S,2S)-2-(Diphenylphosphino)-2,3-dihydro-lH-inden-l -amine) were prepared using the general procedure below.
Tetrahydrofuran (20 ml) was added to a mixture of the S-binap ligand (0.5 g, 0.8 mmol) and [RuCl2(benzene)]2 (200 mg, 0.4 mmol), followed by DMF (0.5 ml) and the mixture refluxed for 6 hours under argon. The solvent was removed under reduced pressure and a solution of the aminophosphine (0.8 mmol) in toluene 20 added. The mixture was refluxed for 4 hours and the solvent removed under reduced pressure. Ether (10 ml) was then added and the mixture stirred for 2 hours under argon. The solids were filtered, washed with ether and dried under vacuum. The catalysts were used for the hydrogenation of acetophenone without further purification.
Example 14: Catalytic hydrogenation of acetophenone using new catalysts
Figure imgf000056_0001
A solution of acetophenone (1.0 g, 8.3mmol) in 2-propanol (10 ml) was added to a 50 mL Schlenk flask. After degassing and refilling with argon, a mixture of the catalyst (0.01 mmol) and K1OBu (0.18mmol) were added. The resulting mixture was then injected into a 100 mL autoclave under an atmosphere of H2 gas. The autoclave was pressurized to 200 psig and the reaction mixture was stirred at ambient temperature. Upon completion of the reaction, the solvent was removed under vacuum and the mixture was filtered through a silica gel pad (ca. 6 cm) using 3:1 hexane:ethyl acetate. The solvent was removed from the filtrate affording the product as a colorless liquid. Results are shown in Table 1. Example 15: General Procedure for Enamide Hydrogenation
Figure imgf000057_0001
> 99 % Conv.
Figure imgf000057_0002
A solution of the substrate (lmmol) was injected into an autoclave and the desired solvent (7 ml) was added. The resulting mixture was degassed with hydrogen several times. The rhodium catalyst (0.002 mmol) in the corresponding solvent (1 ml) was added. The mixture was pressured with hydrogen (100 psi) and stirred at ambient temperature for 1O h. The conversion and enantiomeric excess was determined with GC. The results are shown in Table 2.
While the present disclosure has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the disclosure is not limited to the disclosed examples. To the contrary, the disclosure is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION
(1) (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495-497. (b) Doucet, H.; Ohkuma, T.; Murata, K.;
Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A.F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed 1998, 37, 1703-1707. (c) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417-10418.
(2) (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120,
13529-13530. (b) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 1086-1087. (c) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J Org. Chem. 1996, 61, 4872-4873.
(3) (a) Abdur-Rashid, K.; Lough, A.J.; Morris, R.H. Organometallics 2001, 20, 1047-1049. (b) Abdur-Rashid. K; Lough, A.J.; Morris, R.H. Organometallics 2000,
19, 2655-2657.
(4) (a) PCT Int. Appl. WO 02/22526 A2. (b) Abdur-Rashid, K.; Guo, R.; Lough, A.J.; Morris, R.H. Adv. Synth. Catal. 2005, 347, 571-579. (c) Guo, R.; Lough, A.J.; Morris, R.H.; Song, D. Organometallics 2004, 23, 5524-5529. (d) Guo, R.; Lough, A.J.; Morris, A.J.; Song, D. Organometallics 2005, 24 3354 - 3354.
Table 1 : Results of Hydrogenation of Acetophenone
Figure imgf000059_0001
Figure imgf000060_0001
Table 2: Results for Enamide Hydrogenation
Ligand Solvent Con v. % e.e. %
Ll MeOH >99 55
Ll Acetone >99 40
Ll CH2Cl2 >99 66
L2 MeOH >99 45
L2 Acetone >99 58
L2 CH2Cl2 >99 74

Claims

WE CLAIM:
1. A method for preparing aminophosphine ligands comprising reacting a compound of the formula I )p
Figure imgf000062_0001
with a metal phosphide reagent of the formula Y-PR R under conditions to provide, after removal of PG, a compound of the formula II, )p
Figure imgf000062_0002
II wherein
LG1 is a suitable leaving group; q is 0 or 1 ; p is 1 or 2, where when p is 1, the N atom is further linked to R7 or any one of R1, R2,
R3, R4, R5 R6 or LG, and when N is linked to any one of R1, R2, R3, R4, R5 R6 or LG, or if p is 2, q is 0; n is O, 1, 2, 3 or 4;
PG is a suitable amine protecting group and, when p is 2, PG is the same or different;
Y is a cation;
R1 to R6 are simultaneously or independently selected from H, Ci-20alkyl, C2-
2oalkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R7 is selected from C1-6alkyl and aryl, said latter two groups being optionally substituted;
R8 and R9 are simultaneously or independently selected from H, Ci-20alkyl, C2-
2oalkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R and
R9 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O,
S, N, NH and NCi-6alkyl;
R10 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR11,
N(Rπ)2 and R"; and
R11 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
2. The method according to claim 1, wherein R1 to R6 are simultaneously or independently selected from the group consisting of H, Ci.iOalkyl, C2-i0alkenyl, C2- loalkynyl, C3-i0cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
3. The method according to claim 2, wherein R1 to R6 are simultaneously or independently selected from H,
Figure imgf000063_0001
aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the carbons to which these groups are attached and/or the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
4. The method according to claim 3, wherein R1 to R are simultaneously or independently selected from H, methyl, or phenyl, or two adjacent or geminal groups, are linked together with the carbons to which said groups are attached, and/or with the nitrogen atom of the amino group, to form a phenyl, indanyl, ferrocenyl or pyrrolidinyl ring, or.
5. The method according to any one of claims 1 to 4, wherein n is equal to 0 or 1.
6. The method according to any one of claims 1 to 5, wherein R7 is Ci-4alkyl or phenyl, said latter two groups being optionally substituted.
7. The method according to claim 6, wherein R7 is methyl.
8. The method according to any one of claims 1 to 7, wherein R and R are simultaneously or independently selected from H, Ci.ioalkyl, C2-iOalkenyl, C-2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl.
9. The method according to claim 8, wherein R8 and R9 are simultaneously or independently selected from H,
Figure imgf000064_0001
C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R8 and R9 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic, fused pentacyclic, fused hexacyclic or fused heptacyclic ring system having 4-32 atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl.
10. The method according to claim 9, wherein R8 and R9 are simultaneously or independently isopropyl, t-butyl, or phenyl.
11. The method according to claim 9, wherein R8 and R9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R and R are linked.
12. The method according to claim 11, wherein the fused pentacyclic ring system comprises
Figure imgf000065_0001
13. The method according to any one of claims 1 to 12, wherein R11 is selected from Ci_4alkyl, C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro- substituted.
14. The method according to claim 13, wherein R11 comprises methyl or phenyl.
15. The method according to any one of claims 1 to 14, wherein LG1 is selected from halo, triflate, mesylate and tosylate.
16. The method according to claim 15, wherein LG1 comprises chloro, bromo or iodo.
17. The method according to claim 16, wherein LG1 comprises chloro.
18. The method according to any one of claims 1 to 14, wherein LG1 is a cyclic leaving group said cycle being formed by bonding with another atom in the compound of formula I.
19. The method according to claim 18, wherein the cyclic leaving group is a sulfamidate formed by bonding with the nitrogen atom of the amine.
20. The method according to any one of claims 1 to 19, wherein PG comprises trimethylsilyl (TMS), acetyl, tert-butyldimethylsilyl (TBDMS), tert-butoxycarbonyl (BOC), benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl (FMOC).
21. The method according to claim 20, wherein PG is trimethylsilyl (TMS) or tert-butoxycarbonyl (BOC).
22. The method according to claim 1, wherein when p comprises 1 the leaving group is a cyclic leaving group.
23. The method according to claim 1, wherein Y is any metal that can complex with a negatively charged phosphide reagent.
24. The method according to claim 23, wherein the metal is any alkaline or alkaline earth metal.
25. The method according to claim 24, wherein the metal is lithium or potassium.
26. The method according to any one of claims 1-25, wherein a compound of the formula I is added to a metal phosphide reagent of the formula Y-PR8R9, at a temperature of about -500C to about 00C over a period of about 1 hour to about 4 hours.
27. The method according to any one of claims 1-26, wherein the solution of a compound of the formula I and a metal phosphide reagent of the formula Y-PR8R9 is stirred at a temperature of about 1O0C to about 700C for a period of between about 2 to 24 hours.
28. The method according to any one of claims 1-27, wherein reaction between a compound of the formula I and a metal phosphide reagent of the formula Y-PR8R9 is performed in an aprotic solvent under anhydrous conditions in an inert atmosphere.
29. The method according to claim 28, wherein the aprotic solvent is tetrahydrofuran, diethyl ether or acetonitrile.
30. The method according to claim 29, wherein the aprotic solvent is tetrahydrofuran.
31. The method according to any one of claims 1-30, further comprising reacting a compound of formula II as defined in claim 1 , with a compound of the formula III
R13
F - LG2 /
R12
III
to provide a compound of the formula IV
Figure imgf000067_0001
wherein R12 and R13 are as defined for R8 and R9 in formula II; R1 - R9 are as defined in formula II; LG2 is a suitable leaving group; and one of q and r is 1 , while the other is 0.
32. The method according to claim 31, wherein R12 and R13 are simultaneously or independently selected from H, Ci-ioalkyl, C2-i0alkenyl, C-2-10alkynyl and aryl, said latter 4 groups being optionally substituted, or R and R are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R12 and R1 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl.
33. The method according to claim 32, wherein R12 and R13 are simultaneously or independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R12 and R13 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R12 and R13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi-6alkyl.
34. The method according to any one of claims 31 to 33, wherein the compound of formula III is
Figure imgf000069_0001
wherein LG2 is a leaving group.
35. A method for preparing aminophosphine ligands comprising reacting a compound of the formula II p
Figure imgf000069_0002
II with a compound of the formula III
Figure imgf000069_0003
III
under conditions to provide a compound of the formula IV
Figure imgf000070_0001
IV
wherein
LG2 is a suitable leaving group; one of q and r is 1 , while the other is 0; n is O, 1, 2, 3 or 4;
R1 to R6 are simultaneously or independently selected from H, Ci-20alkyl, C2-
2oalkenyl, C2-20alkynyl, C3-20cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
R7 is selected from Ci-6alkyl and aryl, said latter two groups being optionally substituted;
R8 and R9 are simultaneously or independently selected from H, Ci-20alkyl, C2.
20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R1 °)2, said latter 7 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R and
R groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O,
S, N, NH and NCi-6alkyl;
R10 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR1 1,
N(R1 ')2 and R";
R11 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; and R12 and R13 are simultaneously or independently selected from H, Ci-20alkyl, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR10 and N(R10)2, said latter 7 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R12 and R13 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCi-6alkyl.
36. The method according to claim 35, wherein R1 to R6 are simultaneously or independently selected from the group consisting of H, Ci-iOalkyl, C2-ioalkenyl, C2- loalkynyl, C3-i0cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
37. The method according to claim 36, wherein R1 to R6 are simultaneously or independently selected from H, Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted, or two adjacent or geminal groups, including the carbons to which these groups are attached and/or the nitrogen atom of the amino group, are linked together to form an optionally substituted monocyclic or polycyclic, metallated, saturated, unsaturated and/or aromatic ring system having 5 or more atoms.
38. The method according to claim 37, wherein R1 to R6 are simultaneously or independently selected from H, methyl, or phenyl, or two adjacent or geminal groups, are linked together with the carbons to which said groups are attached, and/or with the nitrogen atom of the amino group, to form a phenyl, indanyl or ferrocenyl ring.
39. The method according to any one of claims 35 to 38, wherein n is equal to 0 or 1.
40. The method according to any one of claims 35 to 39, wherein R7 is Ci-4alkyl or phenyl, said latter two groups being optionally substituted.
41. The method according to claim 40, wherein R7 is methyl.
42. The method according to any one of claims 35 to 41, wherein R8 and R9 are simultaneously or independently selected from H, Ci.iOalkyl, C2-i0alkenyl, C-2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R8 and R9 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and
Figure imgf000072_0001
43. The method according to claim 42, wherein R8 and R9 are simultaneously or independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R8 and R9 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R8 and R9 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NCi-6alkyl.
44. The method according to claim 43, wherein R8 and R9 are simultaneously or independently isopropyl, t-butyl, or phenyl.
45. The method according to claim 43, wherein R8 and R9 are linked to form an optionally substituted fused pentacyclic ring system having 23 atoms, including the phosphorous atom to which R8 and R9 are linked.
46. The method according to claim 45, wherein the fused pentacyclic ring system is
Figure imgf000073_0001
47. The method according to any one of claims 35 to 46, wherein R11 is selected from C1-4alkyl, C2-4alkenyl and phenyl, said latter 3 groups being optionally fluoro- substituted.
48. The method according to claim 47, wherein R11 is methyl or phenyl.
49. The method according to any one of claims 35 to 48, wherein R12 and R13 are simultaneously or independently selected from H, Ci-ioalkyl, C2-i0alkenyl, C-2- ioalkynyl and aryl, said latter 4 groups being optionally substituted, or R12 and R13 are linked together to form an optionally substituted monocyclic or polycyclic ring system having 4 or more atoms, including the phosphorous atom to which R1 ' and R12 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, N, NH and NC1-6alkyl.
50. The method according to claim 49, wherein R12 and R13 are simultaneously or independently selected from H,
Figure imgf000073_0002
C2-6alkenyl, C2-6alkynyl, phenyl, and naphthyl, said latter 5 groups being optionally substituted, or R12 and R13 are linked to form an optionally substituted monocylic, fused bicylic, fused tricyclic, fused quadracyclic or fused pentacyclic ring system having 4-23 atoms, including the phosphorous atom to which R12 and R13 are linked, in which the rings are saturated, unsaturated and/or aromatic and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteroatom selected from O, N, NH and NCi-6alkyl.
51. The method according to any one of claims 35 to 50, wherein the compound of formula III is
Figure imgf000074_0001
wherein LG2 is a leaving group.
52. The method according to any one of claims 35 to 51, wherein LG2 is selected from halo, triflate, mesylate and tosylate.
53. The method according to claim 52, wherein LG2 is chloro, bromo or iodo.
54. The method according to claim 53, wherein LG2 is chloro.
55. A use of an aminophosphine ligand prepared using the method according to any one of claims 1-54 to prepare a metal catalyst.
56. The use according to claim 55, wherein the catalyst is used for hydrogenation of ketones, aldehydes, enamides or imines.
57. An aminophosphepine ligand of the Formula V
Figure imgf000074_0002
V wherein
R14 and R15 are simultaneously or independently selected from H, Ci-2oalkyl, C2-
20alkenyl, C2.20alkynyl, C3-2ocycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted;
R16 is selected from H, Ci-6alkyl and aryl, said latter two groups being optionally substituted or R16 is PR19R20; or two of R14, R15 and R16 are linked to form an optionally substituted monocyclic or polycyclic, metalated, saturated, unsaturated and/or aromatic ring system having 3 or more atoms;
RR17 aanndd RR18 z are linked together with the phosphorous atom to which said R and R groups are linked to form an optionally substituted polycyclic ring of the formula
Figure imgf000075_0001
in which one or more carbon atoms in said polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and
Figure imgf000075_0002
R19 and R20 are simultaneously or independently selected from H, Ci-2oalkyl, C2-
20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR21 and N(R21)2, said latter 7 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from
O, S, N, NH and NC1-6alkyl; the optional substituents are selected from one or more of halo, OH, NH2, OR22,
N(R22)2 and R22; and
R21 and R22 are independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
58. The aminophosphepine ligand according to claim 57, wherein R14 and R15 are simultaneously or independently selected from H, Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, aryl and heteroaryl, said latter 6 groups being optionally substituted.
59. The aminophosphepine ligand according to claim 57, wherein R14 and R15 are simultaneously or independently selected from H, methyl, or phenyl.
60. The aminophosphepine ligand according to any one of claims 57-59, wherein R16 is H, Ci-4alkyl or phenyl, said latter two groups being optionally substituted.
61. The aminophosphepine ligand according to any one of claims 57-59, wherein R16 is PR19R20, where R19 and R20 are simultaneously or independently selected from H, Ci.ioalkyl, C2-i0alkenyl, C2-i0alkynyl, aryl, heteroaryl, OR21 and N(R21)2, said latter 7 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NCMalkyl.
62. The aminophosphepine ligand according to claim 61, wherein R19 and R20 are simultaneously or independently selected from H, Ci-6alkyl, phenyl and OR21, said latter 3 groups being optionally substituted, or R19 and R20 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R19 and R20 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
63. The aminophosphepine ligand according to any one of claims 57-59, wherein R15 and R16 are linked to form an optionally substituted monocyclic or bicyclic, saturated, and/or aromatic ring system having 5 to 10 atoms.
64. The aminophosphepine ligand according to any one of claims 57-63, wherein the optional substituents on the compounds of formula V are selected from one or more of Cl, F, OR22 and N(R22)2 and R22, where R22 is selected from Ci.6alkyl, and phenyl, said latter 4 groups being optionally fluoro-substituted.
65. The aminophosphepine ligand according to claim 57, wherein the stereochemistry of the compounds of formula V is as follows:
Figure imgf000077_0001
66. An aminophosphine ligand of the formula VI or VII
Figure imgf000077_0002
VI VII
wherein
R23 and R24 are simultaneously or independently selected from H, Ci-6alkyl and aryl, said latter two groups being optionally substituted or one of R23 and R24 is PR28R29; R25 and R26 are simultaneously or independently selected from H, C1-2OaIlCyI, C2- 20alkenyl, C2-20alkynyl, aryl, heteroaryl, OR30 and N(R30)2, said latter 7 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from
O, S, N, NH and NCi^alkyl;
R27 represents optional substituents selected from one or more of OH, NH2, OR31,
N(R31)2 and R31, alternatively, R27 is H;
R28 and R29 are simultaneously or independently selected from H, Ci-2oalkyl, C2-
2oalkenyl, C2-20alkynyl, aryl, heteroaryl, OR32 and N(R32)2, said latter 7 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 4 or more atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from
O, S, N, NH and NCi-6alkyl;
R30, R31 and R32 are independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted; the optional substituents are selected from one or more of halo, OH, NH2, OR33,
N(R33)2 and R33; and
R33 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and aryl, said latter 4 groups being optionally fluoro-substituted.
67. The aminophosphine ligand according to claim 66, wherein R23 and R24 are simultaneously or independently selected from H, Ci^alkyl, phenyl and naphthyl.
68. The aminophosphine ligand according to claim 66 or 67, wherein one of R23 and R24 is PR28R29 and R28 and R29 are simultaneously or independently selected from H, Ci.ioalkyl, C2-i0alkenyl, C2-20alkynyl, aryl, heteroaryl, OR32 and N(R32)2, said latter 7 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 or more atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with a heteromoiety selected from O, S, N, NH and NC!-6alkyl.
69. The aminophosphine ligand according to claim 68, wherein R28 and R29 are simultaneously or independently selected from H, Ci-6alkyl, phenyl and OR32, said latter 3 groups being optionally substituted, or R28 and R29 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R28 and R29 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
70. The aminophosphine ligand according to any one of claims 66-69, wherein R25 and R26 are simultaneously or independently selected from H, Ci.6alkyl, phenyl and OR30, said latter 3 groups being optionally substituted, or R25 and R26 are linked together to form an optionally substituted monocyclic or polycylic, saturated, unsaturated and/or aromatic ring system having 5 to 23 atoms, including the phosphorous atom to which said R25 and R26 groups are linked, and in which one or more carbon atoms in said monocyclic or polycyclic ring system are optionally replaced with O.
71. The aminophosphine ligand according to any one of claims 66-69, wherein R27 represents optional substituents selected from one or five of OR31, N(R3 ')2 and R31 is independently selected from C1-4alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
72. The aminophosphine ligand according to any one of claims 66-69, wherein R27 is H.
73. The aminophosphine ligand according to any one of claims 66-72, wherein R30 and R32 are independently selected from Ci-4alkyl, and phenyl, said latter 2 groups being optionally fluoro-substituted.
74. The aminophosphine ligand according to any one of claims 66-69, wherein the optional substituents are selected from one or five of Cl, F, OR33, N(R33)2 and R33, and R33 is selected from Ci-4alkyl and phenyl, said latter 2 groups being optionally fluoro-substituted.
75. The aminophosphine ligand according to claim 57, wherein the amino phosphine ligand of the formula V is
Figure imgf000080_0001
on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl, Ci-4alkyl, OCF3 and OC1-4alkyl.
76. The aminophosphine ligand according to claim 66, wherein the aminophnosphine ligand of formula VI is
Figure imgf000081_0001
the compounds as shown above, substituted on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl,
Figure imgf000081_0002
77. The aminophosphine ligand according to claim 66, wherein the aminophosphine ligand of formula VII is
Figure imgf000081_0003
or the compounds as shown above, substituted on the naphthyl, phenyl or alkyl groups by one or more, suitably one or three, more suitably one or two substituents independently selected from F, Cl,
Figure imgf000081_0004
78. A metal complex comprising a ligand of the formula V, VI or VII according to any one of claims 57 to 77.
79. The metal complex according to claim 78, wherein the metal is a transition metal.
80. The metal complex according to claim 78 or 79 wherein the complex is of the type MCl2(aminophosphine)2 and MCl2(diphosphine)(aminophosphine), wherein M is a metal.
81. The metal complex according to claim 79 or 80 wherein the metal, M, is Ru.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112824421A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral phosphine-phosphoramidite ligand and preparation method and application thereof
CN114539319A (en) * 2020-11-24 2022-05-27 中国科学院大连化学物理研究所 Novel chiral phosphine-dicyclic phosphoramidite ligand and preparation method and application thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2215101A4 (en) * 2007-10-30 2013-04-24 Kanata Chemical Technologies Inc Cationic transition metal catalysts
CN114106057B (en) 2016-10-19 2023-06-23 优美科股份公司及两合公司 Synthesis and characterization of Ru alkylene complexes
WO2019193483A1 (en) 2018-04-06 2019-10-10 Kamal Pharmachem Inc. Catalytic conversion of carbon dioxide to methanol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US115A (en) 1837-01-31 Machine fob boring and mortising
US6590A (en) 1849-07-17 tisdale
US6590115B2 (en) * 2000-09-29 2003-07-08 Eastman Chemical Company Phosphino-aminophosphines

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000128891A (en) * 1998-10-22 2000-05-09 Kyowa Yuka Kk Production of cycloalkyldiarylphosphines
ES2305095T3 (en) 2000-09-13 2008-11-01 Firmenich S.A. CATALYTIC HYDROGENATION PROCESSES.
WO2004096735A2 (en) * 2003-05-02 2004-11-11 Kamaluddin Abdur-Rashid Transfer hydrogenation processes and catalysts
CN1768944A (en) * 2004-11-01 2006-05-10 中国科学院大连化学物理研究所 Catalyst using phosphine-phosphoramidite ester as ligand, its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US115A (en) 1837-01-31 Machine fob boring and mortising
US6590A (en) 1849-07-17 tisdale
US6590115B2 (en) * 2000-09-29 2003-07-08 Eastman Chemical Company Phosphino-aminophosphines

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
ANDRIEU ET AL., INORG. CHEM., vol. 41, no. 15, 2002, pages 3876 - 85
ISSLEIB ET AL., CHEM. BER., vol. 100, 1967, pages 2685 - 93
ISSLEIB K. ET AL.: "Syntheses und Reaktionsverhalten des [beta-amino-äthyl]-phenyl-phosphins", CHEM. BER., vol. 100, 1967, pages 2685 - 2693, XP008127307 *
JIANG Q. ET AL.: "Synthesis of (1R,1R')-2,6-Bis[1-(diphenylphosphino)ethyl]pyridine and its Application in Asymmetric Transfer Hydrogenation", TETRAHEDRON LETTERS, vol. 37, no. 6, 1996, pages 797 - 800, XP002088600 *
JIANG, Q ET AL., TETRAHEDRON LETTERS, vol. 37, no. 6, 1996, pages 797 - 800
KRAWIECKA ET AL., TETRAHEDRON LETT., vol. 46, no. 25, 2005, pages 4381 - 4
KÜHNLEIN C.: "Ruthenium(II) Complexes bearing Bis(phosphine) and beta-Aminophosphine Ligands and their Application to Homogeneous>C=O Reduction", UNIVERSITÄT ERLANGE-NURNBERG, 14 December 2005 (2005-12-14) *
KUHNLEIN, C., DOCTORAL THESIS, 14 December 2005 (2005-12-14)
MIKHAEL ET AL., TETRAHEDRON ASYM, vol. 17, no. 12, 2006, pages 1853 - 8
RONNHOLM P. ET AL.: "Improved and Efficient Synthesis of Chiral N,P-Ligands via Cyclic Sulfamidates for Asymmetric Addition of Butylithium to Benzaldehyde", ORG. LETT., vol. 9, no. 19, 16 August 2007 (2007-08-16), pages 3781 - 3783, XP008127301 *
See also references of EP2167515A4 *
SOETA ET AL., J. ORG. CHEM., vol. 68, no. 25, 2003, pages 9723 - 7

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112824421A (en) * 2019-11-21 2021-05-21 中国科学院大连化学物理研究所 Chiral phosphine-phosphoramidite ligand and preparation method and application thereof
CN114539319A (en) * 2020-11-24 2022-05-27 中国科学院大连化学物理研究所 Novel chiral phosphine-dicyclic phosphoramidite ligand and preparation method and application thereof
CN114539319B (en) * 2020-11-24 2024-04-12 中国科学院大连化学物理研究所 Chiral phosphine-dicyclophosphoramidite ligand and preparation method and application thereof

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