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WO2009122408A1 - STABLE C - (sup3) - CYCLOMETALATED PINCER COMPLEXES, THEIR PREPARATION AND USE AS CATALYSTS - Google Patents

STABLE C - (sup3) - CYCLOMETALATED PINCER COMPLEXES, THEIR PREPARATION AND USE AS CATALYSTS Download PDF

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WO2009122408A1
WO2009122408A1 PCT/IL2009/000356 IL2009000356W WO2009122408A1 WO 2009122408 A1 WO2009122408 A1 WO 2009122408A1 IL 2009000356 W IL2009000356 W IL 2009000356W WO 2009122408 A1 WO2009122408 A1 WO 2009122408A1
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complex
carbon
independently selected
alkyl
complexes
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Dmitri Gelman
Clarite Azerraf
Olga Grossman
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Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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    • C—CHEMISTRY; METALLURGY
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    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • C07F9/50—Organo-phosphines
    • C07F9/5027—Polyphosphines
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    • 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)
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    • 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
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B01J2531/0244—Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-bonds
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    • 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
    • B01J2531/822—Rhodium
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • B01J2531/827—Iridium
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    • C07C2603/86—Ring systems containing bridged rings containing four rings
    • C07C2603/88—Ethanoanthracenes; Hydrogenated ethanoanthracenes

Definitions

  • the invention relates to a novel class of stable pincer complexes comprising an sp3-cyclometalated carbon, and use thereof as catalysts in transfer hydrogenation reactions such as reduction of ketones for the production of chiral and achiral alcohols, reduction of imines to produce chiral and achiral amines and reduction of olefins to produce alkanes.
  • Transition metal catalysts are used for a variety of organic processes and have an immense importance in some industrial fields, such as in the reduction of ketones to alcohols, or of imines to amines, and in the hydrogenation of olefins to alkanes.
  • the reduction of ketones to alcohols by transfer hydrogenation, catalyzed by transition metals represents a simple and much safer method compared to the use of molecular hydrogen.
  • enantiomerically enriched products can be prepared by asymmetric transfer hydrogenation when the transition metal catalyst comprises an enantiomerically enriched ligand (also defined as “optically active” or “chiral non racemic” ligand), ensuring that the double bond of a prochiral compound is asymmetrically reduced.
  • this asymmetric transfer hydrogenation is often employed for the preparation of enantiomerically enriched alcohols from prochiral ketones.
  • DCD pincer ligands are ligands which bind to the metal through at least three coplanar sites: two donor atoms (denoted D in scheme 1 below) and a metalated carbon (marked as C in Scheme 1 below) which is linked to the metal (M) in a ⁇ (sigma) metal-carbon bond.
  • A Sp2 pincer complex
  • B Sp3 pincer complex
  • the Donor atoms in the pincer ligands can be oxygen, sulfur, nitrogen or phosphorus, thereby forming complexes which are respectively termed OCO, SCS, NCN or PCP.
  • the pincer ligand is not necessarily symmetrical.
  • one of the donor atoms may be phosphorus while the other is oxygen, thereby forming a PCO pincer ligand.
  • pincer complex refers to a complex containing a pincer ligand. Pincer complexes are usually characterized by a high thermal stability and high reactivity.
  • sp2 and sp3 refer to hybridization states of a carbon atom: sp2- carbon (also termed sp2-hybridized) refers to a carbon atom which is linked to three substituents placed around it, and therefore involves one double bond.
  • sp3- carbon also termed sp3 -hybridized refers to a carbon atom which forms four bonds to four substituents placed in a tetrahedral fashion around this carbon atom.
  • the disbalance in the number of existing sp2- versus sp3 -complexes originates from a greater thermal, conformational and stability of the sp2 complexes compared to the sp3 complexes.
  • the thermal decomposition of sp2- metalated PCP complexes averages at about 250 °C, (e.g. Morales-Morales et al, Inorganica Chimica Acta (2004), 357(10), 2953-2956).
  • Empsall et al. J Chem. Soc, Chem. Commun. 1977, 589) describe the decomposition of sp3- metalated complexes at much lower temperatures: 150-170 0 C.
  • C(sp 3 )-based complexes The reactivity of C(sp 3 )-based complexes is significantly higher compared to that of C(sp )-based complexes due to electronic factors, such as stronger trans influence of the metalated carbon and higher nucleophilicity of the metal center in the C(sp 3 )-based complexes. While these are desirable features for an efficient transfer hydrogenation catalyst, such complexes have so far been too unstable to be used in industrial catalysis (see for example McLoughlin et al. Organometallics, 1994, 13, 3816; Lesueur, E. et al., Inorg. Chem., 1997, 36, 3354; and Sjovall, S. et al.,J Chern. Soc, Dalton Trans., 2002, 1396).
  • Ra is selected from among Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 5 -C 7 - cycloalkoxy, phenyl, phenoxy and pentafluorophenyl, where the phenyl- and phenoxy radicals may bear a substituent selected from among carboxyl, carboxylate, -SO 3 H and sulfonate, Rc is selected from among hydrogen, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 1 -C 6 - alkoxycarbonyl and aryl, Rd is selected from among hydrogen and Ci-C 6 -alkyl, and A 1 and A 2 are each, independently of one another, N or CR 5 , where R 5 is hydrogen or Ci- C ⁇ -alkyl.
  • Another aim of the present invention is the use of such complexes to provide catalysis processes which circumvent the need to use specially designed reactors and high dilution conditions.
  • a transition metal complex containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms Wi and W 2 , wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three C ⁇ carbons; each of the C ⁇ carbons is linked to non-hydrogen atoms; and Wi and W 2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
  • the complex is characterized by: a) the complex having a decomposition temperature higher than 260 0 C and/or b) the complex maintaining its structure after dissolving 10 mg thereof in 2 ml of deuterated DMSO, heating it to about 190 °C, and keeping it at this temperature for 2 days.
  • the decomposition temperature is equal to or higher than 350 0 C.
  • the transition metal is Ir or Rh.
  • M is selected from Ir or Rh
  • Z is selected from:
  • R 1 and R 2 are independently selected from: Ci-C 6 -alkyl, aryl, alkoxy, aryloxy, Cj-C ⁇ -alkylamine, arylamine, halogen, N, O or null;
  • R 3 and R 4 are independently selected from: Ci-C ⁇ -alkyl, aryl, alkoxy, aryloxy, Ci-C 6 -alkylamine and arylamine;
  • W) and W 2 are independently selected from P, As, N and O;
  • X 1 and X 2 are independently selected from: halogen, H, d-C 6 -alkyl or null; Y is selected from CO, RCN, N 2 , alkene or null; and
  • R is selected from: Cj-C 6 -alkyl, aryl, alkoxy, aryloxy, Ci-C ⁇ -alkylamine and arylamine.
  • Z is Z 1 .
  • W] and W 2 are both P.
  • R 3 and R 4 are independently selected from C t -C ⁇ -alkyl and aryl.
  • the complex described herein has the structure of formula II:
  • M is Ir
  • M is Rh.
  • X 1 is Cl and X 2 is hydrogen.
  • each of X 1 and X 2 is Cl.
  • each of R and R 4 is isopropyl.
  • R is different from R 4 .
  • R 3 is isopropyl and R 4 is phenyl.
  • the complexes described herein have a chiral center. According to additional aspects of the invention, there are provided the complexes: 1 ,8-Bis(diisopropylphosphino)triptycene [IrCl 2 CO( ⁇ 3 -PCP)],
  • the complex described herein is provided for use in the catalytic preparation of alcohols from ketones, for use in the catalytic preparation of amines from imines and for use in the catalytic preparation of alkanes from alkenes.
  • a method for the preparation of a complex having the structure of formula I comprising: a) mixing a precursor complex of the formula MXL 2 and/or hydrates thereof, wherein X is a halogen and L is a monodentate ligand, or wherein L 2 is a bidentate ligand, with a ligand having the structure of Formula III in a solvent to obtain a reaction mixture;
  • the solvent is selected from high-boiling polar solvents.
  • the heating is conducted at a temperature selected from about 100 °C till about 200 °C.
  • the heating is conducted for at least 12 hours.
  • the method further comprises purifying the complex to obtain the complex in a purified form.
  • a process for the catalytic transfer hydrogenation of a substrate having a multiple bond comprising: a) providing a substrate having a multiple bond, b) hydrogenating the substrate in the presence of a hydrogen donor, a base and further in the presence of a complex selected from:
  • a transition metal complex containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms W 1 and W 2 , wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three C ⁇ carbons; each of the C ⁇ carbons is linked to non-hydrogen atoms; and Wi and W 2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
  • the multiple bond of the substrate is selected from a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-carbon double bond or a carbon-carbon triple bond.
  • the substrate is a ketone, an imine or an alkene, thereby respectively obtaining an alcohol, an amine or an alkane.
  • the process described herein is an asymmetric catalytic transfer hydrogenation process of a substrate, wherein the substrate is a prochiral substrate, and wherein the complex has a chiral center.
  • the process is conducted in a closed reactor.
  • the process described herein is conducted under air.
  • the process described herein is characterized by turnover frequency (TOF) values which are equal to or higher than 10,000 hour "1 .
  • the process described herein is characterized by turnover number (TON) values which are equal to or higher than 2000.
  • FIGs. 1 A and B are ORTEP representations of complex IA.
  • the present invention describes a new family of stable pincer complexes comprising an sp3 hybridized cyclometalated carbon, and further having no ⁇ - or ⁇ - hydrogens, relative to the metal center. These complexes combine excellent thermal stability and high reactivity in catalytic reactions, such as in hydrogen transfer reactions. For example, in ketone reduction catalysis, using 2-propanol as the hydrogen source, the complexes of the present invention yielded TOF values ranging from 50,000 to 900,000 h '1 .
  • the catalysts of the invention were found to maintain their activity in closed reactors and were found to be unaffected by the presence of air.
  • novel pincer complexes of the present invention have been surprisingly found to be thermally and structurally stable, although they possess an sp3 cyclometalated carbon as part of its pincer ligand, quite in contrast to presently known C(sp3) cyclometalated pincer complexes.
  • the complexes of the present invention form a new class of stable pincer complexes which comprise an sp3 -hybridized cyclometalated carbon, according to one aspect of the invention, there is now provided a stable C(sp3) cyclometalated pincer complex.
  • the existence of the sp3 cyclometalated carbon has been confirmed by both
  • the enhanced stability of the complexes of the present invention can be confirmed in multiple ways, for example: a) these complexes are characterized by a decomposition temperature which is higher than 260 0 C and sometimes exceeds 350 0 C, as determined through thermo gravimetric analysis. In contrast, many known sp2 pincer complexes have a decomposition temperature of about 250 0 C and previously known unstable sp3 pincer complexes have a decomposition temperature of up to about 170 °C. b) these complexes maintain their structure even after prolonged heating in a solvent. Thus, the structure of the complex can be compared before and after a prolonged heating in a solvent, for example by using the "boiling DMSO test".
  • the structure of the complex is verified by comparing an NMR spectra before and after the prolonged heating in the solvent.
  • the two spectra have to be identical, in order to prove the stability of the complex.
  • the type of distinguishing NMR 1 H NMR, 13 C NMR, 31 P NME etc.
  • a 31 P NMR is preferable over an 1 H NMR.
  • the structure of the complex can also be compared using a variety of analytical methods known in art.
  • the complexes of the present invention have successfully withstood the boiling DMSO test and have further been shown to have decomposition temperatures as high as 350 0 C, demonstrating their high stability. Nonetheless, these complexes have shown remarkable reactivity in various catalytic hydrogenation processes (TOF values in the range of 50,000-900,000 h "1 ), thereby marking their applicability as industrial transfer hydrogenation catalysts.
  • pincer ligands there must be at least one pincer ligand, which would be linked to the transition metal center through a carbon, termed Ca, and through two donor atoms Wi and W 2 .
  • pincer ligands combine bulkiness and steric hindrance with controllable electronic effects, and are also characterized in that the atoms Wl,
  • W2 and Ca are coplanar.
  • the carbon atom linked to the metal (Ca) has to be part of a ring system(s), making Ca a cyclometalated carbon.
  • the Ca carbon has to be in an sp3 hybridization. Finally, the Ca carbon has to be bonded to three C ⁇ carbons and each of these
  • C ⁇ carbons has to be linked only to non-hydrogen atoms. Namely, there should be no hydrogens linked to either Ca or to any carbon atom adjacent to Ca. Hence, no a- hydrogens or ⁇ -hydrogens, relative to the metal center, are allowed.
  • the complexes designed by the inventors are in fact the first successful group of pincer complexes having an sp3 -hybridized cyclometalated carbon, and having no ⁇ - or ⁇ -hydrogens. It appears that this novel group of complexes acts as exceptionally good catalyst in hydrogenation reactions, demonstrating both high reactivity and high stability, never before exhibited for sp3-type-pincer complexes of transition metals.
  • a transition metal complex containing at least one pincer ligand linked to said metal via a Ca cyclometalated carbon and via two donor atoms W 1 and W 2 , wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three C ⁇ carbons; each of the C ⁇ carbons is linked to non-hydrogen atoms; and W 1 and W 2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
  • the complexes may be formed with a variety of transition metals, in particular with any metal from Group VIII of the Periodic Table of Elements.
  • transition metals examples include silver (Ag), palladium (Pd), platinum (Pt), ruthenium (Ru), rhodium (Rh), iridium (Ir), copper (Cu), nickel (Ni), cobalt (Co), osmium (Os), and combinations thereof.
  • a complex as described herein being a complex of Ir or Rh.
  • the metal can be in several oxidation states, depending on the identity of the ligands attached thereto.
  • the inventors of the present invention have indeed successfully prepared a series of novel pincer complexes of Ir and Rh, which can act as successful catalysts in transfer hydrogenation processes.
  • a pincer complex of formula I is provided:
  • M is a metal selected from iridium (Ir) or rhodium (Rh).
  • Ir iridium
  • Rh rhodium
  • the metal is directly bound to an sp3 hybridized cyclic carbon which is part of a pincer ligand.
  • the direct metal-carbon bond renders this carbon an ⁇ -carbon relative to the metal center. It should be noted that neither this ⁇ -carbon, nor the carbons adjacent to it ( ⁇ -carbons) have any hydrogens thereon.
  • the pincer complex of formula I belongs to a special and novel class of pincer complexes, adding to the steric and electronic characteristics of the pincer ligand, two additional features: the pincer complex has, on one hand, neither ⁇ - nor ⁇ - hydrogens and, on the other hand, the cyclometalated carbon of the pincer ligand is in an sp3 hybridization.
  • pincer complexes combining these features are characterized by an unprecedented combination of stability and reactivity in catalytic hydrogenation reactions.
  • X 1 and X 2 are independently selected from: halogen, hydrogen, d-C 6 -alkyl, or null; When either X 1 or X 2 is a halogen, it can be fluorine, chlorine, bromine, iodine or combination thereof, but is preferably one of the first three mentioned, more preferably chlorine.
  • Y is selected from CO, RCN, N 2 , alkene or null. It should be noted that converting any of these groups to another can be done according to known chemical procedures, and therefore complexes containing any of these Y groups are interchangeable with one another. Although complexes containing CO as a Y group have been successfully employed in hydrogenation reactions, it is expected that having another substituent or having no Y at all, may even improve the properies of the complex.
  • R is selected from: Ci-C 6 -alkyl, aryl, alkoxy, aryloxy, d-C ⁇ -alkylamine and arylamine. Preferably the aryl is phenyl.
  • Wi and W 2 are donor atoms, independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
  • P phosphorus
  • As arsenic
  • N nitrogen
  • O oxygen
  • at least one donor atom is a phosphorus (P) atom. More preferably, both donor atoms are phosphorus (P) atoms.
  • R 3 and R 4 are independently selected from: Ci-C 6 -alkyl, aryl, alkoxy, aryloxy,
  • Ci-C ⁇ -alkylamine and arylamine are independently selected from Ci-C 6 -alkyl or aryl groups. More preferably, the aryl is phenyl.
  • R 3 and R 4 cannot be hydrogen, there are no ⁇ -hydrogens (relative to the metal center) on the donor atoms W.
  • R 3 and R 4 are chosen such that there will be also no ⁇ -hydrogens on the substituents.
  • R 1 and R 2 represent one or more substituent on the rings, whereas these substituents are independently selected from: CpC ⁇ -alky!, aryl, alkoxy, aryloxy, C 1 - C 6 -alkylamine, arylamine, halogen, N, O or null;
  • Z is selected from aryl, C t -C ⁇ -alkyl or alkenyl groups.
  • Z is selected from one of groups Z 1 '-Z 3 , as depicted below:
  • groups Z 1 -Z 3 act as bridging groups.
  • the complex having the general formula I is characterized by an enhanced thermal and conformational stability, quite in contrast to presently known sp3 -pincer type complexes.
  • the stability of these complexes is determined as described hereinabove, according to their decomposition temperature, by thermo-gravimetric analysis, and by comparing their structure before and after a prolonged heating test, such as the boiling
  • a preferable group of complexes of general formula I are those wherein Z is a substituted or unsubstituted phenyl ring linked (Z 1 ) to the other rings, thereby forming a triptycene ring system as a steric sp3 pincer ligand on the metallic center, as depicted below in formula I ⁇ :
  • phosphorus is a preferable donor atom in the pincer complexes of the present invention.
  • complexes having P as a donor, CO as a Y ligand and unsubstituted Z 1 as a bridging group have been synthesized, thereby obtaining complexes having the general formula II, as depicted below:
  • Preferable complexes of general formula II have been synthesized having an iridium metal center, or having a rhodium metal center.
  • R 3 and R 4 groups on the phosphorus atoms determines the asymmetry, and hence the chirality of the triprycene ligand.
  • R 3 and R 4 are the same, a symmetric, non-chiral ligand is formed.
  • Another class of complexes are obtained when the complexes described herein have a chiral center, for example when R 3 is different from R 4 , such as for the ligand l-(di-isopropylphosphino)-8-(diphenylphosphino)triptycene, wherein R 3 is isopropyl and R 4 is phenyl, as depicted in Formula HB below (* denotes a chiral center):
  • enantiomerically enriched product means that one of the enantiomers of the compound is present in excess compared to the other enantiomer.
  • enantiomeric excess or e.e. (as for example determined by chiral GLC or HPLC analysis).
  • the enantiomeric excess e.e. is equal to the difference between the amounts of enantiomers divided by the sum of the amounts of the enantiomers, which quotient can be expressed as a percentage after multiplication by 100.
  • the cyclometalated carbon has an sp2 hybridization rather than an sp3 hybridization, due to instability of the sp3 type complexes.
  • the inventors of the present invention have now devised a novel class of complexes, as described herein, by successfully attaching a bulky, bidentate ligand through a third center on an sp3 cyclometalated carbon, a synthesis which had not seemed feasible in the past, thereby forming a tridentate pincer-type ligand having an sp3 cyclometalated carbon, attached to the metal center.
  • the bidentate ligand is chosen such that the obtained complex would have no ⁇ - or ⁇ -hydrogens, relative to the metal center.
  • This method first comprises mixing a precursor complex of the formula MXL 2 and/or hydrates thereof, wherein X is a halogen and L is a monodentate ligand, or wherein L 2 is a bidentate ligand, with a ligand having the structure of Formula III in a solvent, wherein R 1 , R 2 , R 3 , R 4 , Z, W 1 and W 2 are as defined for formula I hereinabove,
  • X can be fluorine, chlorine, bromine, iodine or combination thereof, but is preferably chlorine.
  • L 2 may refer to a combination of two similar or different monodentate ligands, and may also indicate one bidentate ligand.
  • monodentate ligand refers to a ligand that has one point of attachment to the metal, and may have a valence of one or two.
  • H 2 O aqua
  • NH 3 ammine
  • CH 3 NH 2 methylamine
  • CO carbonyl
  • NO nitrogen
  • fluoro fluoro
  • CN cyano
  • CF chloro
  • Br bromo
  • F iodo
  • NO 2 nitro
  • OH hydroxo
  • COE cyclooctene
  • TFT tetrahydrothiophene
  • bidentate ligand refers to a compound that possesses two points at which it attaches to the metal.
  • bidentate ligands include, but are not limited to, acetylacetonate (ACAC), 1,5-cyclooctadiene (COD) and norbornadiene (NBD).
  • tridentate ligand refers to a compound that possesses three points at which it attaches to the metal, such as W]CaW 2 pincer ligands attached to the complexes of the present invention.
  • precursor complexes for the preparation of complexes having the structure of Formula I include, but are not limited to: MCl 3 , MCl(COD) or MCl(COE) or MCl 2 (CO).
  • the precursor complexes may further be used in their hydrated forms, for example as IrCl 3 (H 2 O).
  • the ligands of Formula III are prepared by a process such as that described in US Patent No. 6,977,312, or may be prepared by processes known to those skilled in the art. Suitable processes are mentioned, for example, in Walborsky and Bohnert (Org. Chem. 1968, 33, 3934), Sugihashi, M. et al. (Bull. Chem. Soc. Jap. 1972, 45, 2836), Ueda, K et al. (Chem. Express 1992, 7, 401) and Rybacek, J et al. (Synthesis 2008, 3615). Some of the suitable ligands of Formula III may be commercially available.
  • the bidentate ligands of formula III are chosen such that the obtained complex would have no ⁇ - or ⁇ -hydrogens, relative to the metal center.
  • Suitable solvents for the process of preparing the complexes of Formula I are preferably chosen to be high-boiling polar solvents.
  • polar solvent refers to a solvent that tends to provide protons, such as an alcohol, or a solvent polarized due to the presence of an electron withdrawing group, such as acetonitrile or tetrahydrofuran (THF), dimethylformamide (DMF), and the like.
  • an electron withdrawing group such as acetonitrile or tetrahydrofuran (THF), dimethylformamide (DMF), and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges.
  • high-boiling polar solvents includes all polar solvents whose boiling point at normal pressure is above 75 °C, preferably above 90 0 C, in particular above 120 0 C.
  • polar solvents of this type are high- boiling alcohols and additional solvents, such as dimethyl sulfoxide (DMSO), N 5 N- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or anisole.
  • DMSO dimethyl sulfoxide
  • DMF N 5 N- dimethylformamide
  • DMA N,N-dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • High-boiling alcohols are a group of high-boiling polar solvents.
  • the term "high-boiling alcohols” includes all alcohols whose boiling point at normal pressure is above 75 0 C, preferably above 90 °C, in particular above 120 °C.
  • alcohols of this type are ethanol, n-propanol, isopropanol, n-butanol, sec- butanol, isobutanol, tert-butanol, n-pentanol and its isomers, n-hexanol and its isomers, heptanol, octanol, nonanol or decanol and the respective isomeric haloalcohols such as 2-chloroethanol, 3-chloropropanol, 4-chlorobutanol, 5- chloropentanol, 6-chlorohexanol, 7-chloroheptanol, 8-chlorooctanol or 9- chlorononanol and the respective isomers and also alkoxyalkanols such as 2- methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol, 3-ethoxypropanol, 4- methoxybutanol, 4-
  • a preferable solvent is DMF.
  • Another preferable solvent is methoxyethanol.
  • the amount of alcohol to be used as solvent is preferably used in an excess of at least 20 moles, preferably at least 10 moles, in particular at least 5 moles, per mole of precursor complex MXL 2 .
  • reaction mixture obtained from the reaction of MXL 2 and the ligand of Formula III is then heated to form the complex of formula I in the reaction mixture.
  • heating is conducted by reflux.
  • the heating, or refluxing, temperature is chosen according to the solvent used in the process, and is usually selected to be at least 100 °C.
  • the heating is conducted at a temperature selected from about 100 °C till about 200 0 C. More preferably, for example when conducting the process in DMF, the heating is conducted at a temperature of about 150 °C.
  • the heating is conducted for at least 12 hours, but may of course be longer and up to a few days.
  • the heating is conducted either in an inert atmosphere (for example under nitrogen or argon atmosphere), or under air.
  • reaction is carried out at atmospheric pressure or at the autogenous pressure of the respective reaction mixture.
  • a higher or lower pressure is also possible but in general does not offer any additional advantage .
  • the complex of Formula I is isolated from said reaction mixture, for example by distilling the solvent from the reaction mixture until dryness.
  • the method described herein may optionally further comprise purifying the complex to obtain a purified form thereof.
  • the purification can be conducted in any number of industrially known processes, such as crystallization, recrystallization, filtration and distillation.
  • the process is preferably conducted by distillation.
  • Example 5 the complexes described herein have been successfully used in catalytic processes, exhibiting both high stability and high reactivity towards the substrate.
  • the complexes described herein are provided for use in the catalytic preparation of alcohols from ketones, for use in the catalytic preparation of amines from imines and for use in the catalytic preparation of alkanes from alkenes.
  • the catalyst was also active at low catalyst/substrate (C/S) molar ratios.
  • run 5 in Table 1 represents a concentration of 0.01 mol% of complex IA (C/S ratio of 1 : 10,000), resulting in complete conversion detected after only 5 minutes with an halogenated acetophenone substrate.
  • the catalyst/substrate ratio ranges from 1:2,000 and up to 1:100,000, thereby indicating a TON range of 2,000-100,000.
  • These complexes were advantageously characterized by high TOF values (in the range of 12,500-3,600,000 h "1 , more preferably 50,000-900,000 h "1 ), a remarkable insensitivity to air, and a high activity of the catalysts in concentrated solutions (up to
  • a catalytic transfer hydrogenation process of a substrate having a multiple bond comprising: a) providing a substrate having a multiple bond, b) hydrogenating this substrate in the presence of a base, a hydrogen donor, and further in the presence of a complex selected from:
  • a transition metal complex containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms W 1 and W 2 , wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three C ⁇ carbons; each of the C ⁇ carbons is linked to non-hydrogen atoms; and Wi and W 2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O). , or
  • hydrogen donor refers to a chemical agent that is capable of donating hydrogen in a catalytic transfer hydrogenation reaction.
  • hydrogen donors include: cyclooctane, various alcohols, such as ethanol and 1,2-ethanediol, iso-propanol and certain acids, such as ascorbic acid and formic acid and their salts e.g. sodium or ammonium formates Additional hydrogen donors are disclosed in: Brieger and Nestrick (Chemical Reviews, (1974), Vol. 74, No.5, pages 567-580) and Johnstone et al. ⁇ Chemical Reviews, (1985), Vol. 85, No. 2, pages 129-170).
  • the hydrogen donor may also be used as a solvent in the catalytic system, and may be referred as such in Example 5 below.
  • this process is conducted in a closed reactor and/or under air.
  • the base used for the hydrogenation process is selected from a variety of alkali metals, alkali metal alkoxides and alkali metal hydroxides.
  • alkali metals include, but are not limited to potassium, lithium or sodium.
  • alkali metal alkoxides include, but are not limited to, an alkali tert-butoxide, a metal methoxide or ethoxide.
  • the alkali tert-butoxide is NaO 1 Bu or KO 1 Bu.
  • alkali metal hydroxides examples include potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and mixtures thereof.
  • the base may be included in a relatively large range.
  • the solvent employed in the hydrogenation process is chosen according to the substrate and in accordance with industrial reactor requirements.
  • ketones and imines are conducted using a polar solvent.
  • polar solvents can be used for the catalytic hydrogenation reaction of ketones and imines.
  • Non-limiting examples include ethers and esters such as tetrahydrofuran, diethyl ether and ethyl acetate, primary or secondary alcohols such as methanol, ethanol and isopropanol, chlorinated solvents such as dichloromethane and chloroform, or mixtures thereof.
  • the industrially-acceptable isopropanol is used as solvent in these processes.
  • Hydrogenation of alkenes and alkynes is conducted using an alkane solvent.
  • the alkane solvent will normally contain from 5 to about 15 carbon atoms per molecule and will be a liquid under the conditions of the hydrogenation reaction.
  • alkane solvents which can be employed include pentane, hexane, heptane, octane, nonane, decane, undecane, docecane, pentadecane, 3-methylpentane, 2-methylpentane, 2,3-dimethylbutane, and 2,2-dimethylbutane.
  • a catalyst system comprising a complex as described hereinabove, a substrate, a hydrogen donor, a base and a solvent.
  • catalyst is also often referred to as catalyst precursor, precatalyst, catalyst precursor, catalyst compound, transition metal compound and/or transition metal complex. These words are used interchangeably. Unless otherwise clear from its context, the term “catalyst” is used interchangeably herein to refer both to the metal complexes or precatalysts before their activation as catalytic species, and to the active catalytic species themselves.
  • substrate refers to any compound which may undergo a catalytic hydrogenation/ reduction process. Preferably, the substrate is such that has a multiple bond.
  • the substrate of the catalytic transfer hydrogenation process according to the present invention is such that the multiple bond is selected from a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-carbon double bond or a carbon-carbon triple bond.
  • the substrate examples include ketones, aldehydes, imines, alkenes and akynes.
  • the substrate is a ketone, which may undergo transfer hydrogenation to obtain an alcohol, or an imine, which may undergo transfer hydrogenation to obtain an amine, or an alkene (olefin), which may undergo transfer hydrogenation to obtain an alkane.
  • the hydrogenation process of a prochiral substrate becomes an asymmetric transfer hydrogenation process, and results in enantiomerically rich products.
  • a method for enantioselectively hydrogenating a prochiral substrate to obtain an enantiomerically enriched product this method being conducted in the presence of a complex having a chiral center, as described hereinabove.
  • prochiral substrate refers to a substrate that may become a chiral product.
  • the hydrogenation process is conducted at pressures typically up to 200 psig, and at ambient temperature or higher.
  • the process described herein is characterized by turnover frequency (TOF) values which are equal to or higher than 50,000 hour "1 , and even values which are equal to or higher than 500,000 hour "1 , reaching values which are about 900,000 hour '1 and may even be higher.
  • TOF turnover frequency
  • These reactions are further characterized by high (>93%) yield of the product, and by a relatively high TON value of the complex (1 *10 5 ), quite remarkable for sp3 pincer complexes.
  • an alcohol prepared by a catalytic transfer hydrogenation of a ketone with a catalytic system comprising a base, a hydrogen source and a complex selected from: I) a transition metal complex, containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms Wi and W 2 , wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three C ⁇ carbons; each of the C ⁇ carbons is linked to non-hydrogen atoms; and Wi and W 2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
  • P phosphorus
  • As arsenic
  • N nitrogen
  • O oxygen
  • an amine prepared by a catalytic transfer hydrogenation of an imine with the same catalytic system and an alkane prepared by a catalytic transfer hydrogenation of an alkene with the same catalytic system.
  • the chirality of the metal center in the catalytic complex will determine the enantio-purity of the product.
  • the hydrogenation process is an asymmetric transfer process, and enantiomerically rich products are obtained. Therefore, according to a preferred embodiment of the present invention, enantiomerically enriched (ee) products, such as ee alcohols, ee amines and ee alkanes, formed in the presence of a complex having a chiral center, are provided.
  • ee enantiomerically enriched products
  • the inventors have successfully synthesized a novel class of stable C(sp3)-cyclometalated pincer complexes and have further successfully used these complexes as catalysts in transfer hydrogenation reactions such as reduction of ketones for the production of chiral and achiral alcohols.
  • These complexes can also be used for the reduction of imines to produce chiral and achiral amines and for the hydrogenation of olefins to produce chiral and achiral alkanes.
  • Yields refer to isolated yields of compounds having purity greater than 95% as determined by proton Nuclear Magnetic Resonance spectroscopy ( 1 H-NMR) analysis.
  • Figures 1 A and B are ORTEP representations of the structure (from different angles), wherein thermal ellipsoids are shown at 50% probability, and hydrogen atoms have been moved for clarity.
  • Example 1 (complex IB). The process of Example 1 was repeated starting from RhCVH 2 O (0.14 grams, 0.67 mmol) and the same amounts of 1,8-Bis(diisopropylphosphino)triptycene and DMF.
  • Diastereomer 1 (1 gram) was dissolved in dry THF at -78 °C and 4 equivalents of sec- BuLi were added. After stirring the reaction mixture for 5 minutes 4 equivalents of di- isopropylchlorophosphine were added and the resulting red to brown solution was stirred overnight to obtain a yellow solution which was diluted with water (30 ml) and extracted with dichloromethane (30 ml).
  • Turnover frequency moles of ketone converted to alcohol per mole of catalyst per hour

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Abstract

The invention relates to a novel class of stable pincer complexes comprising a pinσer ligand linked to the metal via a Calfa cyclometalated carbon and via two donor atoms W1 and W2, wherein said Calfa carbon has a sp3 hybridization; said Calfa carbon is bonded to three Cbeta carbons; each of said Cbeta carbons is linked to the non-hydrogen atoms,- and W1 and W2 are independently selected from P, As, N or O. Said complexes are used as catalyst in transfer hydrogenation reactions such as reduction of ketones, reductions of imines and reductions of olefines.

Description

STABLE C-(sp3)-CYCLOMETALATED PINCER COMPLEXES, THEIR PREPARATION
AND USE AS CATALYSTS Field of the invention
The invention relates to a novel class of stable pincer complexes comprising an sp3-cyclometalated carbon, and use thereof as catalysts in transfer hydrogenation reactions such as reduction of ketones for the production of chiral and achiral alcohols, reduction of imines to produce chiral and achiral amines and reduction of olefins to produce alkanes.
Background of the Invention
Transition metal catalysts are used for a variety of organic processes and have an immense importance in some industrial fields, such as in the reduction of ketones to alcohols, or of imines to amines, and in the hydrogenation of olefins to alkanes. For example, the reduction of ketones to alcohols by transfer hydrogenation, catalyzed by transition metals, represents a simple and much safer method compared to the use of molecular hydrogen.
Furthermore, enantiomerically enriched products can be prepared by asymmetric transfer hydrogenation when the transition metal catalyst comprises an enantiomerically enriched ligand (also defined as "optically active" or "chiral non racemic" ligand), ensuring that the double bond of a prochiral compound is asymmetrically reduced. In practice, this asymmetric transfer hydrogenation is often employed for the preparation of enantiomerically enriched alcohols from prochiral ketones.
Although highly enantioselective ketone-reducing catalysts have been prepared, these catalysts suffer major disadvantages since:
1) they generally demonstrate relatively low TOF values (turnover frequency = number of moles of substrate (for example, ketone) converted to a product (in this example, alcohol) per mole of catalyst per hour at 50 % conversion); and
2) they are also easily degradable during the catalytic process, demonstrating Low TON values (turnover number = the number of moles of substrate that a mole of catalyst can convert before becoming inactivated). Several examples of more efficient new catalysts, which are able to produce products with substrate/catalyst ratios of over 1000 have been developed in recent years. For example, Thoumaze et al. (Organometallics 2003, 22, 1580) reported a novel ruthenium arene catalyst, containing the bidentate N5P ligand l-(2- methylpyridine)-2,5-diphenylphosphole, which displays TOF values of up to 106 hr"1 for a variety of ketones. However the extremely long time required for conversion (days at 900C) limits its practical use.
DCD pincer ligands are ligands which bind to the metal through at least three coplanar sites: two donor atoms (denoted D in scheme 1 below) and a metalated carbon (marked as C in Scheme 1 below) which is linked to the metal (M) in a σ (sigma) metal-carbon bond.
Figure imgf000003_0001
A: Sp2 pincer complex B: Sp3 pincer complex
Scheme 1
The Donor atoms in the pincer ligands can be oxygen, sulfur, nitrogen or phosphorus, thereby forming complexes which are respectively termed OCO, SCS, NCN or PCP.
It should be noted that the pincer ligand is not necessarily symmetrical. For example, one of the donor atoms may be phosphorus while the other is oxygen, thereby forming a PCO pincer ligand.
The term "pincer complex" as used herein, refers to a complex containing a pincer ligand. Pincer complexes are usually characterized by a high thermal stability and high reactivity.
The carbon atom attached to the metal in most of the presently known and researched pincer complexes is in an sp2 form (for example, as complex A in Scheme 1) rather than in an sp3 form (as in complex B of Scheme 1).
The terms sp2 and sp3 refer to hybridization states of a carbon atom: sp2- carbon (also termed sp2-hybridized) refers to a carbon atom which is linked to three substituents placed around it, and therefore involves one double bond. The term sp3- carbon (also termed sp3 -hybridized) refers to a carbon atom which forms four bonds to four substituents placed in a tetrahedral fashion around this carbon atom.
The disbalance in the number of existing sp2- versus sp3 -complexes, originates from a greater thermal, conformational and stability of the sp2 complexes compared to the sp3 complexes. For example, the thermal decomposition of sp2- metalated PCP complexes averages at about 250 °C, (e.g. Morales-Morales et al, Inorganica Chimica Acta (2004), 357(10), 2953-2956). In comparison, Empsall et al. (J Chem. Soc, Chem. Commun. 1977, 589) describe the decomposition of sp3- metalated complexes at much lower temperatures: 150-170 0C.
An example for sp2 pincer complexes is described by Dani et al. (Angew. Chem., Int. Engl. 2000, 39, 743) who have reported C-(sp2) metalated terdentate complexes of ruthenium (II) having a stable aryl Ru-C bond, which display TOF values of up to 27,000 h"1. Some of their complexes are displayed in Scheme 2 below.
Figure imgf000004_0001
Scheme 2
However, in all of these cases the catalyst degradation over the course of the process was still significant, standing for low TON values.
An additional disadvantage of the existing transition metal catalysts is the necessity to carry out the reactions under high dilution conditions in open reactors, and often under air-free conditions, in order to reach high TON values. For example, in ketone reduction processes, it is necessary to remove the acetone by-product for this purpose. This raises overall process costs due to the need in specially designed reactors and solvent recovery (see for example, Zanfir, M.; Gavriilidis, A. Org. Process Res. Dev. 2007, 11, 966).
The reactivity of C(sp3)-based complexes is significantly higher compared to that of C(sp )-based complexes due to electronic factors, such as stronger trans influence of the metalated carbon and higher nucleophilicity of the metal center in the C(sp3)-based complexes. While these are desirable features for an efficient transfer hydrogenation catalyst, such complexes have so far been too unstable to be used in industrial catalysis (see for example McLoughlin et al. Organometallics, 1994, 13, 3816; Lesueur, E. et al., Inorg. Chem., 1997, 36, 3354; and Sjovall, S. et al.,J Chern. Soc, Dalton Trans., 2002, 1396). Some of the presently known unstable sp3 pincer Ir, Rh and Pd complexes are presented in scheme 3 below:
Figure imgf000005_0001
McLoughlin sp3 pincer complex
Figure imgf000005_0002
Sjovall sp3 pincer complex Lesueur sp3 pincer complex
Scheme 3
US Patent No. 6,977,312 (to BASF) discloses a new class of ligands having the structure
For example,
Figure imgf000005_0003
wherein Ra is selected from among Ci-C6-alkyl, Ci-C6-alkoxy, C5-C7- cycloalkoxy, phenyl, phenoxy and pentafluorophenyl, where the phenyl- and phenoxy radicals may bear a substituent selected from among carboxyl, carboxylate, -SO3H and sulfonate, Rc is selected from among hydrogen, Ci-C6-alkyl, Ci-C6-alkoxy, C1-C6- alkoxycarbonyl and aryl, Rd is selected from among hydrogen and Ci-C6-alkyl, and A1 and A2 are each, independently of one another, N or CR5, where R5 is hydrogen or Ci- Cβ-alkyl.
Given the enormous potential of transition metal catalysts in industrial processes, as well as the shortage in stable yet reactive catalysts suitable for this purpose, it is an aim of the present invention to obtain more powerful and yet more stable pincer complexes of rhodium and indium, that will be useful as catalysts in various reactions, such as in the reduction reactions of ketones by transfer hydrogenation, in the reduction of imines to produce amines and in the reduction of olefins to produce alkanes.
Another aim of the present invention is the use of such complexes to provide catalysis processes which circumvent the need to use specially designed reactors and high dilution conditions.
Summary of the invention
According to one aspect of the invention there is provided a transition metal complex, containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms Wi and W2, wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three Cβ carbons; each of the Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
According to a preferred embodiment of the present invention, the complex is characterized by: a) the complex having a decomposition temperature higher than 260 0C and/or b) the complex maintaining its structure after dissolving 10 mg thereof in 2 ml of deuterated DMSO, heating it to about 190 °C, and keeping it at this temperature for 2 days.
Preferably, the decomposition temperature is equal to or higher than 350 0C. According to a preferred embodiment of the present invention, the transition metal is Ir or Rh.
According to another aspect of the invention there is provided a pincer complex of general formula I:
Figure imgf000007_0001
Formula I
Wherein M is selected from Ir or Rh;
Z is selected from:
Figure imgf000007_0002
R1 and R2 are independently selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy, Cj-Cό-alkylamine, arylamine, halogen, N, O or null;
R3 and R4 are independently selected from: Ci-Cβ-alkyl, aryl, alkoxy, aryloxy, Ci-C6-alkylamine and arylamine;
W) and W2 are independently selected from P, As, N and O;
X1 and X2 are independently selected from: halogen, H, d-C6-alkyl or null; Y is selected from CO, RCN, N2, alkene or null; and
R is selected from: Cj-C6-alkyl, aryl, alkoxy, aryloxy, Ci-Cβ-alkylamine and arylamine.
Preferably, Z is Z1. Further preferably, W] and W2 are both P.
Further preferably, R3 and R4 are independently selected from Ct-Cό-alkyl and aryl.
Preferably, The complex described herein has the structure of formula II:
Figure imgf000008_0001
Formula II.
According to a preferred embodiment of the present invention, M is Ir
According to a preferred embodiment of the present invention, M is Rh. According to a preferred embodiment of the present invention, X1 is Cl and X2 is hydrogen.
According to a preferred embodiment of the present invention, each of X1 and X2 is Cl.
According to a preferred embodiment of the present invention, each of R and R4 is isopropyl.
According to a preferred embodiment of the present invention, R is different from R4. According to a preferred embodiment of the present invention, R3 is isopropyl and R4 is phenyl.
According to another preferred embodiment of the present invention, the complexes described herein have a chiral center. According to additional aspects of the invention, there are provided the complexes: 1 ,8-Bis(diisopropylphosphino)triptycene [IrCl2CO(κ3-PCP)],
1,8-Bis(diisopropylphosphino)triptycene [RhCl2CO(κ3-PCP)], and
1 ,8-Bis(diisopropylphosphino)triptycene [IrCl(H)CO(κ3-PCP)]. According to a preferred embodiment of the present invention, the complex described herein is provided for use in the catalytic preparation of alcohols from ketones, for use in the catalytic preparation of amines from imines and for use in the catalytic preparation of alkanes from alkenes.
According to yet another aspect of the invention there is provided a method for the preparation of a complex having the structure of formula I, as it is described hereinabove, the method comprising: a) mixing a precursor complex of the formula MXL2 and/or hydrates thereof, wherein X is a halogen and L is a monodentate ligand, or wherein L2 is a bidentate ligand, with a ligand having the structure of Formula III in a solvent to obtain a reaction mixture;
Figure imgf000009_0001
Formula III b) heating the reaction mixture to form the complex of formula I in the reaction mixture; c) isolating the complex from the reaction mixture.
According to a preferred embodiment of the present invention, the solvent is selected from high-boiling polar solvents.
According to a preferred embodiment of the present invention, the heating is conducted at a temperature selected from about 100 °C till about 200 °C.
According to a preferred embodiment of the present invention, the heating is conducted for at least 12 hours. According to a preferred embodiment of the present invention, the method further comprises purifying the complex to obtain the complex in a purified form.
According to yet an additional aspect of the invention there is provided a process for the catalytic transfer hydrogenation of a substrate having a multiple bond, the process comprising: a) providing a substrate having a multiple bond, b) hydrogenating the substrate in the presence of a hydrogen donor, a base and further in the presence of a complex selected from:
I) a transition metal complex, containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms W1 and W2, wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three Cβ carbons; each of the Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
, or II) a complex of general formula I, as it is described hereinabove.
According to another preferred embodiment of the present invention, the multiple bond of the substrate is selected from a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-carbon double bond or a carbon-carbon triple bond.
According to another preferred embodiment of the present invention, the substrate is a ketone, an imine or an alkene, thereby respectively obtaining an alcohol, an amine or an alkane.
According to yet another preferred embodiment of the present invention, the process described herein is an asymmetric catalytic transfer hydrogenation process of a substrate, wherein the substrate is a prochiral substrate, and wherein the complex has a chiral center. According to a preferred embodiment of the present invention, the process is conducted in a closed reactor.
According to a preferred embodiment of the present invention, the process described herein is conducted under air. According to a preferred embodiment of the present invention, the process described herein is characterized by turnover frequency (TOF) values which are equal to or higher than 10,000 hour"1.
According to a preferred embodiment of the present invention, the process described herein is characterized by turnover number (TON) values which are equal to or higher than 2000.
Brief Description of The Drawings In the drawings:
FIGs. 1 A and B are ORTEP representations of complex IA.
Detailed Description of the invention As mentioned above, although many successful transition metal complexes are known to catalyze transfer hydrogenation reactions, it is a continuing effort to find catalysts that will exhibit both a high activity rate and a high thermal and structural stability (expressed as combined high TON and high TOF values).
The present invention describes a new family of stable pincer complexes comprising an sp3 hybridized cyclometalated carbon, and further having no α- or β- hydrogens, relative to the metal center. These complexes combine excellent thermal stability and high reactivity in catalytic reactions, such as in hydrogen transfer reactions. For example, in ketone reduction catalysis, using 2-propanol as the hydrogen source, the complexes of the present invention yielded TOF values ranging from 50,000 to 900,000 h'1.
In addition, the catalysts of the invention were found to maintain their activity in closed reactors and were found to be unaffected by the presence of air. These features advantageously circumvent the need to remove any by-produced compounds, work under inert atmospheres or use specially-built reactors, thus enabling the industrial exploitation of the new complexes.
The novel pincer complexes of the present invention have been surprisingly found to be thermally and structurally stable, although they possess an sp3 cyclometalated carbon as part of its pincer ligand, quite in contrast to presently known C(sp3) cyclometalated pincer complexes. As the complexes of the present invention form a new class of stable pincer complexes which comprise an sp3 -hybridized cyclometalated carbon, according to one aspect of the invention, there is now provided a stable C(sp3) cyclometalated pincer complex. The existence of the sp3 cyclometalated carbon has been confirmed by both
NMR and X-ray data.
H NMR spectra of all non-metalated complexes bearing triptycene-based ligands show a very characteristic low-field resonance (9-10 ppm) for the central methine hydrogen (Azerraf et al., Inorg. Chem. 2006, 45, 7010-7017 ox Azerraf et al., J Organomet. Chem. 2007, 692, 761-767). This signal does not appear in the 1H
NMR spectrum of complex IA, as can be seen in Example 1 below.
Furthermore, X-ray crystallographic analysis of this complex unequivocally proved its structural arrangement (Figures IA and IB). Indeed, X-ray crystallography is often the best analytical method to prove the structure of a suspected sp3- cyclometalated pincer complex.
The enhanced stability of the complexes of the present invention can be confirmed in multiple ways, for example: a) these complexes are characterized by a decomposition temperature which is higher than 260 0C and sometimes exceeds 350 0C, as determined through thermo gravimetric analysis. In contrast, many known sp2 pincer complexes have a decomposition temperature of about 250 0C and previously known unstable sp3 pincer complexes have a decomposition temperature of up to about 170 °C. b) these complexes maintain their structure even after prolonged heating in a solvent. Thus, the structure of the complex can be compared before and after a prolonged heating in a solvent, for example by using the "boiling DMSO test".
In this test, 10 mg of the complex are dissolved in an NMR tube with 2 ml of deuterated DMSO, heated to about 190 0C, and the solution is kept in the closed NMR tube, at this temperature, for 2 days. After this period the solution is subjected to
NMR analysis to re-confirm the structure of the complex. Preferably, the structure is verified by comparing an NMR spectra before and after the prolonged heating in the solvent. The two spectra have to be identical, in order to prove the stability of the complex. The type of distinguishing NMR (1H NMR, 13C NMR, 31P NME etc.) is chosen according to the specific complex, and is preferably an NMR type other than 1H NMR. For example, in complexes containing phosphorus, a 31P NMR is preferable over an 1H NMR. Alternatively, the structure of the complex can also be compared using a variety of analytical methods known in art.
The complexes of the present invention have successfully withstood the boiling DMSO test and have further been shown to have decomposition temperatures as high as 350 0C, demonstrating their high stability. Nonetheless, these complexes have shown remarkable reactivity in various catalytic hydrogenation processes (TOF values in the range of 50,000-900,000 h"1), thereby marking their applicability as industrial transfer hydrogenation catalysts.
It should be emphasized that structurally, these complexes are characterized by a unique combination of requirements on the ligands and substituents linked to the transition metal center.
First, there must be at least one pincer ligand, which would be linked to the transition metal center through a carbon, termed Ca, and through two donor atoms Wi and W2. As noted hereinabove, pincer ligands combine bulkiness and steric hindrance with controllable electronic effects, and are also characterized in that the atoms Wl,
W2 and Ca are coplanar.
Secondly, the carbon atom linked to the metal (Ca) has to be part of a ring system(s), making Ca a cyclometalated carbon.
Thirdly, the Ca carbon has to be in an sp3 hybridization. Finally, the Ca carbon has to be bonded to three Cβ carbons and each of these
Cβ carbons has to be linked only to non-hydrogen atoms. Namely, there should be no hydrogens linked to either Ca or to any carbon atom adjacent to Ca. Hence, no a- hydrogens or β-hydrogens, relative to the metal center, are allowed.
The complexes designed by the inventors are in fact the first successful group of pincer complexes having an sp3 -hybridized cyclometalated carbon, and having no α- or β-hydrogens. It appears that this novel group of complexes acts as exceptionally good catalyst in hydrogenation reactions, demonstrating both high reactivity and high stability, never before exhibited for sp3-type-pincer complexes of transition metals. Therefore, according to another aspect of the invention, there is provided a transition metal complex, containing at least one pincer ligand linked to said metal via a Ca cyclometalated carbon and via two donor atoms W1 and W2, wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three Cβ carbons; each of the Cβ carbons is linked to non-hydrogen atoms; and W1 and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
The complexes may be formed with a variety of transition metals, in particular with any metal from Group VIII of the Periodic Table of Elements.
Examples of such transition metals include silver (Ag), palladium (Pd), platinum (Pt), ruthenium (Ru), rhodium (Rh), iridium (Ir), copper (Cu), nickel (Ni), cobalt (Co), osmium (Os), and combinations thereof.
As can be seen in the examples section which follows, especially successful complexes have been prepared with Ir and Rh. Therefore, according to a preferred embodiment of the present invention, there is provided a complex as described herein, being a complex of Ir or Rh.
The metal can be in several oxidation states, depending on the identity of the ligands attached thereto. The inventors of the present invention have indeed successfully prepared a series of novel pincer complexes of Ir and Rh, which can act as successful catalysts in transfer hydrogenation processes. Thus, according to another aspect of the invention, there is provided a pincer complex of formula I:
Figure imgf000014_0001
Formula I wherein M is a metal selected from iridium (Ir) or rhodium (Rh). As demonstrated in formula I, the metal is directly bound to an sp3 hybridized cyclic carbon which is part of a pincer ligand. The direct metal-carbon bond renders this carbon an α-carbon relative to the metal center. It should be noted that neither this α-carbon, nor the carbons adjacent to it (β-carbons) have any hydrogens thereon. Thus, the pincer complex of formula I belongs to a special and novel class of pincer complexes, adding to the steric and electronic characteristics of the pincer ligand, two additional features: the pincer complex has, on one hand, neither α- nor β- hydrogens and, on the other hand, the cyclometalated carbon of the pincer ligand is in an sp3 hybridization.
The inventors have now found that pincer complexes combining these features are characterized by an unprecedented combination of stability and reactivity in catalytic hydrogenation reactions.
X1 and X2 are independently selected from: halogen, hydrogen, d-C6-alkyl, or null; When either X1 or X2 is a halogen, it can be fluorine, chlorine, bromine, iodine or combination thereof, but is preferably one of the first three mentioned, more preferably chlorine.
Y is selected from CO, RCN, N2, alkene or null. It should be noted that converting any of these groups to another can be done according to known chemical procedures, and therefore complexes containing any of these Y groups are interchangeable with one another. Although complexes containing CO as a Y group have been successfully employed in hydrogenation reactions, it is expected that having another substituent or having no Y at all, may even improve the properies of the complex. R is selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy, d-Cό-alkylamine and arylamine. Preferably the aryl is phenyl.
Wi and W2 are donor atoms, independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O). Preferably, at least one donor atom is a phosphorus (P) atom. More preferably, both donor atoms are phosphorus (P) atoms. R3 and R4 are independently selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy,
Ci-Cό-alkylamine and arylamine; Preferably, R3 and R4 are independently selected from Ci-C6-alkyl or aryl groups. More preferably, the aryl is phenyl. Again, it should be noted that since R3 and R4 cannot be hydrogen, there are no α-hydrogens (relative to the metal center) on the donor atoms W. Preferably, but not necessarily, R3 and R4 are chosen such that there will be also no β-hydrogens on the substituents. As noted hereinabove, it has now been found that the combination of a pincer ligand having a cyclometalated carbon which is in an sp3 hybridization, and the absence of α- and β-hydrogens, results in pincer complexes which combine stability and reactivity in catalytic hydrogenation reactions.
R1 and R2 represent one or more substituent on the rings, whereas these substituents are independently selected from: CpCό-alky!, aryl, alkoxy, aryloxy, C1- C6-alkylamine, arylamine, halogen, N, O or null;
Z is selected from aryl, Ct-Cό-alkyl or alkenyl groups. Preferably, Z is selected from one of groups Z1 '-Z3, as depicted below:
Figure imgf000016_0001
It can be seen that groups Z1 -Z3 act as bridging groups.
As noted hereinabove, it has now been found by the inventors that the complex having the general formula I is characterized by an enhanced thermal and conformational stability, quite in contrast to presently known sp3 -pincer type complexes. The stability of these complexes is determined as described hereinabove, according to their decomposition temperature, by thermo-gravimetric analysis, and by comparing their structure before and after a prolonged heating test, such as the boiling
DMSO test.
A preferable group of complexes of general formula I are those wherein Z is a substituted or unsubstituted phenyl ring linked (Z1) to the other rings, thereby forming a triptycene ring system as a steric sp3 pincer ligand on the metallic center, as depicted below in formula Iχ:
Figure imgf000017_0001
Formula Iχ
As noted before, phosphorus is a preferable donor atom in the pincer complexes of the present invention. Several complexes having P as a donor, CO as a Y ligand and unsubstituted Z1 as a bridging group have been synthesized, thereby obtaining complexes having the general formula II, as depicted below:
Figure imgf000017_0002
Formula II
Preferable complexes of general formula II have been synthesized having an iridium metal center, or having a rhodium metal center.
As can be seen from Examples 1-5 below, preferable complexes have been synthesized such that X1 is Cl and X2 is hydrogen (for the Ir complex), or when both X1 and X2 are Cl (for the Ir and Rh complexes).
The identity of the R3 and R4 groups on the phosphorus atoms determines the asymmetry, and hence the chirality of the triprycene ligand. When R3 and R4 are the same, a symmetric, non-chiral ligand is formed.
Exemplary complexes of this type are 1,8-Bis(diisopropylphosphino)triptycene
[IrCl2CO(κ3-PCP)], 1,8-Bis(diisopropylphosphino)triptycene [RhCl2CO(κ3-PCP)] and
1,8-Bis(diisopropylphosphino)triptycene [IrCl(H)CO(κ3-PCP)] wherein both R3 and R4 are isopropyl.
Another class of complexes are obtained when the complexes described herein have a chiral center, for example when R3 is different from R4, such as for the ligand l-(di-isopropylphosphino)-8-(diphenylphosphino)triptycene, wherein R3 is isopropyl and R4 is phenyl, as depicted in Formula HB below (* denotes a chiral center):
Figure imgf000018_0001
Formula HB
This in turn influences the specifity of the metal complex in subsequent catalytic processes, resulting in an enantiomerically enriched product.
The term "enantiomerically enriched product" means that one of the enantiomers of the compound is present in excess compared to the other enantiomer.
This excess will hereinafter be referred to as "enantiomeric excess" or e.e. (as for example determined by chiral GLC or HPLC analysis). The enantiomeric excess e.e. is equal to the difference between the amounts of enantiomers divided by the sum of the amounts of the enantiomers, which quotient can be expressed as a percentage after multiplication by 100.
As discussed in the background section hereinabove, up to date, in most pincer-type complexes the cyclometalated carbon has an sp2 hybridization rather than an sp3 hybridization, due to instability of the sp3 type complexes. The inventors of the present invention have now devised a novel class of complexes, as described herein, by successfully attaching a bulky, bidentate ligand through a third center on an sp3 cyclometalated carbon, a synthesis which had not seemed feasible in the past, thereby forming a tridentate pincer-type ligand having an sp3 cyclometalated carbon, attached to the metal center. Furthermore, the bidentate ligand is chosen such that the obtained complex would have no α- or β-hydrogens, relative to the metal center.
Thus, according to another aspect of the present invention, there is provided a method for the preparation of a complex having the structure of formula I, as depicted above.
This method first comprises mixing a precursor complex of the formula MXL2 and/or hydrates thereof, wherein X is a halogen and L is a monodentate ligand, or wherein L2 is a bidentate ligand, with a ligand having the structure of Formula III in a solvent, wherein R1, R2, R3, R4, Z, W1 and W2 are as defined for formula I hereinabove,
Figure imgf000019_0001
Formula HI to obtain a reaction mixture.
X can be fluorine, chlorine, bromine, iodine or combination thereof, but is preferably chlorine.
As defined herein, L2 may refer to a combination of two similar or different monodentate ligands, and may also indicate one bidentate ligand. As used herein, the term "monodentate ligand" refers to a ligand that has one point of attachment to the metal, and may have a valence of one or two. Some examples of common monodentate ligands are H2O (aqua), NH3 (ammine), CH3NH2 (methylamine), CO (carbonyl), NO (nitrosyl), F" (fluoro), CN" (cyano), CF (chloro), Br" (bromo), F (iodo), NO2 " (nitro), OH" (hydroxo), cyclooctene (COE) and tetrahydrothiophene (THT).
The term "bidentate ligand" refers to a compound that possesses two points at which it attaches to the metal. Examples of bidentate ligands include, but are not limited to, acetylacetonate (ACAC), 1,5-cyclooctadiene (COD) and norbornadiene (NBD).
The term "tridentate ligand", as used herein, refers to a compound that possesses three points at which it attaches to the metal, such as W]CaW2 pincer ligands attached to the complexes of the present invention.
Some examples of precursor complexes for the preparation of complexes having the structure of Formula I, include, but are not limited to: MCl3, MCl(COD) or MCl(COE) or MCl2(CO).
The precursor complexes may further be used in their hydrated forms, for example as IrCl3(H2O).
The ligands of Formula III are prepared by a process such as that described in US Patent No. 6,977,312, or may be prepared by processes known to those skilled in the art. Suitable processes are mentioned, for example, in Walborsky and Bohnert (Org. Chem. 1968, 33, 3934), Sugihashi, M. et al. (Bull. Chem. Soc. Jap. 1972, 45, 2836), Ueda, K et al. (Chem. Express 1992, 7, 401) and Rybacek, J et al. (Synthesis 2008, 3615). Some of the suitable ligands of Formula III may be commercially available. As noted hereinabove, the bidentate ligands of formula III are chosen such that the obtained complex would have no α- or β-hydrogens, relative to the metal center. Suitable solvents for the process of preparing the complexes of Formula I are preferably chosen to be high-boiling polar solvents.
The term "polar solvent" as used herein, refers to a solvent that tends to provide protons, such as an alcohol, or a solvent polarized due to the presence of an electron withdrawing group, such as acetonitrile or tetrahydrofuran (THF), dimethylformamide (DMF), and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges. As defined herein, the term "high-boiling polar solvents" includes all polar solvents whose boiling point at normal pressure is above 75 °C, preferably above 90 0C, in particular above 120 0C. Examples of polar solvents of this type are high- boiling alcohols and additional solvents, such as dimethyl sulfoxide (DMSO), N5N- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or anisole. These polar solvents have high boiling points. For example, the boiling point of DMSO is 189°C, that of DMA is 165°C and of NMP is 202°C.
High-boiling alcohols are a group of high-boiling polar solvents. As defined herein, the term "high-boiling alcohols" includes all alcohols whose boiling point at normal pressure is above 75 0C, preferably above 90 °C, in particular above 120 °C. Examples of alcohols of this type are ethanol, n-propanol, isopropanol, n-butanol, sec- butanol, isobutanol, tert-butanol, n-pentanol and its isomers, n-hexanol and its isomers, heptanol, octanol, nonanol or decanol and the respective isomeric haloalcohols such as 2-chloroethanol, 3-chloropropanol, 4-chlorobutanol, 5- chloropentanol, 6-chlorohexanol, 7-chloroheptanol, 8-chlorooctanol or 9- chlorononanol and the respective isomers and also alkoxyalkanols such as 2- methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol, 3-ethoxypropanol, 4- methoxybutanol, 4-ethoxybutanol, 5-methoxypentanol, 5-ethoxypentanol, 6- methoxyhexanol, 6-ethoxyhexanol, 7-methoxyheptanol, 7-ethoxyheptanol, 8- methoxyoctanol, 8-ethoxyoctanol, 9-methoxynonanol or 9-ethoxynonanol and the respective isomers.
As can be seen in Examples 1-4 which follow, a preferable solvent is DMF. Another preferable solvent is methoxyethanol. The amount of alcohol to be used as solvent is preferably used in an excess of at least 20 moles, preferably at least 10 moles, in particular at least 5 moles, per mole of precursor complex MXL2.
The reaction mixture obtained from the reaction of MXL2 and the ligand of Formula III, is then heated to form the complex of formula I in the reaction mixture. Preferably the heating is conducted by reflux.
The heating, or refluxing, temperature is chosen according to the solvent used in the process, and is usually selected to be at least 100 °C. Preferably, the heating is conducted at a temperature selected from about 100 °C till about 200 0C. More preferably, for example when conducting the process in DMF, the heating is conducted at a temperature of about 150 °C.
According to preferred embodiments of the present invention, the heating is conducted for at least 12 hours, but may of course be longer and up to a few days. The heating is conducted either in an inert atmosphere (for example under nitrogen or argon atmosphere), or under air.
As a rule, the reaction is carried out at atmospheric pressure or at the autogenous pressure of the respective reaction mixture. A higher or lower pressure is also possible but in general does not offer any additional advantage .
Once the heating stage is completed (as can be determined by consecutive analytical tests of the products), the complex of Formula I is isolated from said reaction mixture, for example by distilling the solvent from the reaction mixture until dryness. The method described herein may optionally further comprise purifying the complex to obtain a purified form thereof.
The purification can be conducted in any number of industrially known processes, such as crystallization, recrystallization, filtration and distillation. The process is preferably conducted by distillation.
As can be seen from Example 5 below, the complexes described herein have been successfully used in catalytic processes, exhibiting both high stability and high reactivity towards the substrate.
Therefore, according to additional aspects of the invention the complexes described herein are provided for use in the catalytic preparation of alcohols from ketones, for use in the catalytic preparation of amines from imines and for use in the catalytic preparation of alkanes from alkenes.
As can be seen from Tables 1 and 2 which follow, the catalyst was also active at low catalyst/substrate (C/S) molar ratios. For example, run 5 in Table 1 represents a concentration of 0.01 mol% of complex IA (C/S ratio of 1 : 10,000), resulting in complete conversion detected after only 5 minutes with an halogenated acetophenone substrate. Furthermore, the catalyst remains active and the reaction goes to completion even under extremely low loading conditions (C/S= 1:100,000, run 1 in Table 1).
Other experiments showed that a variety of ketones were converted in high yields to the corresponding alcohols within minutes at 82 0C and with a catalyst/substrate ratio of 1 :2000 or higher (Table 2).
Preferably, the catalyst/substrate ratio ranges from 1:2,000 and up to 1:100,000, thereby indicating a TON range of 2,000-100,000. These complexes were advantageously characterized by high TOF values (in the range of 12,500-3,600,000 h"1, more preferably 50,000-900,000 h"1), a remarkable insensitivity to air, and a high activity of the catalysts in concentrated solutions (up to
4M substrate solution) and in closed reactors. All of these properties can significantly reduce the reactor design and solvent recovery expenses.
Thus, according to yet another aspect of the invention, there is provided a catalytic transfer hydrogenation process of a substrate having a multiple bond, this process comprising: a) providing a substrate having a multiple bond, b) hydrogenating this substrate in the presence of a base, a hydrogen donor, and further in the presence of a complex selected from:
I) a transition metal complex, containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms W1 and W2, wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three Cβ carbons; each of the Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O). , or
II) a complex of general formula I:
Figure imgf000023_0001
Formula I As those complexes have been defined hereinabove. The term "hydrogen donor," as used herein, refers to a chemical agent that is capable of donating hydrogen in a catalytic transfer hydrogenation reaction. Non- limiting examples of hydrogen donors include: cyclooctane, various alcohols, such as ethanol and 1,2-ethanediol, iso-propanol and certain acids, such as ascorbic acid and formic acid and their salts e.g. sodium or ammonium formates Additional hydrogen donors are disclosed in: Brieger and Nestrick (Chemical Reviews, (1974), Vol. 74, No.5, pages 567-580) and Johnstone et al. {Chemical Reviews, (1985), Vol. 85, No. 2, pages 129-170).
It should be noted that the hydrogen donor may also be used as a solvent in the catalytic system, and may be referred as such in Example 5 below.
According to preferred embodiments of the present invention, this process is conducted in a closed reactor and/or under air.
In spite of these industrially convenient conditions, it has now been found that the process described herein is characterized by high turnover frequency (TOF) values, which are equal to or higher than 50,000 hour"1, thereby confirming the reactivity of the complexes of the invention, combined with their unique stability.
The base used for the hydrogenation process is selected from a variety of alkali metals, alkali metal alkoxides and alkali metal hydroxides.
Examples of alkali metals include, but are not limited to potassium, lithium or sodium.
Examples of alkali metal alkoxides include, but are not limited to, an alkali tert-butoxide, a metal methoxide or ethoxide. Preferably the alkali tert-butoxide is NaO1Bu or KO1Bu.
Examples of alkali metal hydroxides which may be used include potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and mixtures thereof.
In an embodiment of the disclosure, the base may be included in a relatively large range. One can cite, as non-limiting examples, ranges between 10 to 50,000 molar equivalents relative to the complex (e.g. base/catalyst=10:l to 50,000: 1), more preferably in the range or 50:1 to 5000:1 molar equivalents. However, it should be noted that it is also possible to add a small amount of base, meaning less than 10:1 base/catalyst (e.g. base/catalyst=l:l to 1:3) to achieve high yields. The solvent employed in the hydrogenation process is chosen according to the substrate and in accordance with industrial reactor requirements.
For example, hydrogenation of ketones and imines is conducted using a polar solvent. A wide variety of polar solvents can be used for the catalytic hydrogenation reaction of ketones and imines. Non-limiting examples include ethers and esters such as tetrahydrofuran, diethyl ether and ethyl acetate, primary or secondary alcohols such as methanol, ethanol and isopropanol, chlorinated solvents such as dichloromethane and chloroform, or mixtures thereof. Typically, the industrially-acceptable isopropanol is used as solvent in these processes. Hydrogenation of alkenes and alkynes is conducted using an alkane solvent.
The alkane solvent will normally contain from 5 to about 15 carbon atoms per molecule and will be a liquid under the conditions of the hydrogenation reaction.
Some representative examples of alkane solvents which can be employed include pentane, hexane, heptane, octane, nonane, decane, undecane, docecane, pentadecane, 3-methylpentane, 2-methylpentane, 2,3-dimethylbutane, and 2,2-dimethylbutane.
According to an additional aspect of the invention, there is provided a catalyst system comprising a complex as described hereinabove, a substrate, a hydrogen donor, a base and a solvent.
The term "catalyst" is also often referred to as catalyst precursor, precatalyst, catalyst precursor, catalyst compound, transition metal compound and/or transition metal complex. These words are used interchangeably. Unless otherwise clear from its context, the term "catalyst" is used interchangeably herein to refer both to the metal complexes or precatalysts before their activation as catalytic species, and to the active catalytic species themselves. The term "substrate" as used herein refers to any compound which may undergo a catalytic hydrogenation/ reduction process. Preferably, the substrate is such that has a multiple bond.
More preferably, the substrate of the catalytic transfer hydrogenation process according to the present invention, is such that the multiple bond is selected from a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-carbon double bond or a carbon-carbon triple bond.
Examples of such substrates include ketones, aldehydes, imines, alkenes and akynes. Preferably, the substrate is a ketone, which may undergo transfer hydrogenation to obtain an alcohol, or an imine, which may undergo transfer hydrogenation to obtain an amine, or an alkene (olefin), which may undergo transfer hydrogenation to obtain an alkane. As discussed hereinabove, when the complex of the present invention has a chiral center, the hydrogenation process of a prochiral substrate becomes an asymmetric transfer hydrogenation process, and results in enantiomerically rich products. Therefore, according to a preferred embodiment of the present invention, there is provided a method for enantioselectively hydrogenating a prochiral substrate to obtain an enantiomerically enriched product, this method being conducted in the presence of a complex having a chiral center, as described hereinabove.
The term "prochiral substrate" refers to a substrate that may become a chiral product.
The hydrogenation process is conducted at pressures typically up to 200 psig, and at ambient temperature or higher.
In all of these cases, the process can be conducted in a closed reactor, and even under air, thereby circumventing the need to use specially-built reactors, or work in controlled or inert atmosphere. Undoubtedly, these are major advances in the industrial applicability of such processes, which contribute immensely to lowering the costs associated therewith.
As noted in the Examples section below, the process described herein is characterized by turnover frequency (TOF) values which are equal to or higher than 50,000 hour"1, and even values which are equal to or higher than 500,000 hour"1, reaching values which are about 900,000 hour'1 and may even be higher. These reactions are further characterized by high (>93%) yield of the product, and by a relatively high TON value of the complex (1 *105), quite remarkable for sp3 pincer complexes.
As can be seen in Example 5 which follows, these catalytic processes resulted in chemically pure products, in affordable and high reactivity. Thus, according to additional aspects of the present invention, there is provided an alcohol prepared by a catalytic transfer hydrogenation of a ketone with a catalytic system comprising a base, a hydrogen source and a complex selected from: I) a transition metal complex, containing at least one pincer ligand linked to the metal via a Ca cyclometalated carbon and via two donor atoms Wi and W2, wherein the Ca carbon is in an sp3 hybridization; the Ca carbon is bonded to three Cβ carbons; each of the Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
, or II) a complex of general formula I:
Figure imgf000027_0001
Formula I as it has been defined hereinabove.
Furthermore, there is provided an amine prepared by a catalytic transfer hydrogenation of an imine with the same catalytic system and an alkane prepared by a catalytic transfer hydrogenation of an alkene with the same catalytic system. As described hereinabove, the chirality of the metal center in the catalytic complex will determine the enantio-purity of the product.
According to the catalytic processes described herein, it is possible to obtain both diastereomers as well as specific enantiomers, depending on the chosen complex.
When the complex of the present invention has a chiral center, the hydrogenation process is an asymmetric transfer process, and enantiomerically rich products are obtained. Therefore, according to a preferred embodiment of the present invention, enantiomerically enriched (ee) products, such as ee alcohols, ee amines and ee alkanes, formed in the presence of a complex having a chiral center, are provided. As has been demonstrated in the present application, the inventors have successfully synthesized a novel class of stable C(sp3)-cyclometalated pincer complexes and have further successfully used these complexes as catalysts in transfer hydrogenation reactions such as reduction of ketones for the production of chiral and achiral alcohols. These complexes can also be used for the reduction of imines to produce chiral and achiral amines and for the hydrogenation of olefins to produce chiral and achiral alkanes.
Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.
EXAMPLES
Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.
MA TERIALS AND ANAL YTICAL METHODS l-(bromo)-8-(diphenylphosphino)triptycene was prepared as described by D. Gelman et al. (Organometallics 2007, 25, 387). 1,8-Bis(diisopropylphosphino)triptycene can be synthesized as published by
Grossman et al., Organometallics 2006, 25, 375.
All other chemicals and metal precursors were purchased from Sigma-Aldrich and were used without further purifications.
1H-NMR, 31P-NMR and 13C-NMR spectra were recorded on a Bruker 400 MHz instrument with chemical shifts reported in ppm relative to the residual deuterated solvent or the internal standard tetramethylsilane. IR was measured using a Perkin Elmer 16PC FTIR.
Gas chromatography analyses were performed on a Hewlett Packard 5890 instrument with a FID detector and a Hewlett Packard 25 m x 0.2 mm i.d. Supelcowax-10 capillary column. Thermal stability of the complexes was determined using Thermogravimetric analysis (TSA) on a Perkin Elmer Pyris 1 TGA.
X-ray crystallographic analysis was performed on a Bruker APEX CCD X-ray system.
Yields refer to isolated yields of compounds having purity greater than 95% as determined by proton Nuclear Magnetic Resonance spectroscopy (1H-NMR) analysis.
Hydrogenation of imines is conducted according to known procedures, such as those described in Samec et al. (Chemistry-A European Journal, (2002), 8(13), pp. 2955-2961) or Wu et al. {Chemical Communications (2006), (16), pp. 1766-1768).
Hydrogenation of alkenes to alkanes is conducted according to known procedures, such as those described in Huang et al. (Advanced Synthesis & Catalysis (2009), 351(1+2), pp. 188-206) or Goldman et al. (Science 2006, 312(5771), pp. 257- 261).
EXAMPLE l Preparation of 1,8-Bis(diisopropylphosphino)triptycene [IrCl2CO(K? -PCP)] (complex IA).
IrCl3 *H2O (0.2 grams, 0.67 mmol) was mixed with 2 equivalents of 1,8- Bis(diisopropylphosphino)triptycene (0.65 grams, 1.34 mmol) in DMF (10 ml) and the solution was refluxed at 150 °C for 2 days under N2. The DMF was then distilled from the reaction mixture until dryness and the off-white product was twice crystallized from methanol affording 0.37 grams of complex IA (71% yield).
1H NMR, 400 MHz (CDCl3), δ: 1.02 (6H, dd, J=I, J=8); 1.29 (6H, dd, J=7, J=8); 1.71 (12H, m); 2.52 (H, m); 3.85 (2H, m); 5.35 (IH, s); 6.81 (IH, t, J=6.5); 6.88 (IH, t, J=7.3); 7.08 (2H, t, J=8.6); 7.17 (IH, d, J=6.5); 7.28 (2H, d); 7.3 (2H, t, J=7.3); 7.4 (IH, t, J=7.3); 13C NMR, 400 (CDCl3), δ: 19.60 (d, J=30.8), 20.80, 21.86, 26.63 (t, J=14.7), 28.29 (t, J=14.7), 34.81, 52.03, 54.66, 123.03, 124.3 (d, J=24.1), 125.03, 125.6 (d,J=16.1), 128.53, 130.70 (t,J=26.2), 144.39 (t,J=7.0), 149.02, 151.70, 164.3
(t, J=12.1), 167.27.31P NMR, 400 MHz (CDCl3), δ: 34.38.
IR (neat): 2020 cm"1 (s, CO).
X-ray crystallographic analysis unequivocally proved the structural arrangement of complex IA. Figures 1 A and B are ORTEP representations of the structure (from different angles), wherein thermal ellipsoids are shown at 50% probability, and hydrogen atoms have been moved for clarity. Selected bond lengths [A] and angles (°): Ir-Cl=2.154, Ir-C12=2.463, Ir-C33= 1.839, Ir-Pl= 2.365, Ir-P2= 2.364, Pl-Ir-P2= 164.74, Cl-Ir-Cl= 173.64, C33-Ir-Cll= 173.36, C15-Cl-Ir= 127.38 A thermal analysis of complex IA detected a first weight loss at 350 °C.
EXAMPLE 2
Preparation of 1,8-Bis(diisopropylphosphino)triptycene [RhCl2CO(κ? -PCP)]
(complex IB). The process of Example 1 was repeated starting from RhCVH2O (0.14 grams, 0.67 mmol) and the same amounts of 1,8-Bis(diisopropylphosphino)triptycene and DMF.
The off-white product was twice crystallized from methanol affording 0.23 grams of complex IB (60 % yield).
1H NMR, 400 MHz (CDCl3), δ: 1.1 (6H, dd, J=8, J=8); 1.3 (6H, dd, J=8, J=8); 1.7 (12H, m); 3.1 (H, m); 3.45 (2H, m); 5.12 (IH, s); 6.74 (IH, t, J=6.5); 6.98 (IH, t, j=7.3); 7.1 (2H, t, J=8.6); 7.23 (IH, d, J=6.5); 7.3 (2H, d); 7.3 (2H, t, J=7.3); 7.6 (IH, t, J=7.3).
IR (neat): 2002 cm'1 (s, CO).
EXAMPLE 3
Preparation of 1,8-Bis(diisopropylphosphino)triptycene [IrCl(H)CO(K? -PCP)]
(complex IC)
IrCl3 #H2O (0.2 grams, 0.67 mmol) was mixed with 2 equivalents of 1,8- Bis(diisopropylphosphino)triptycene (0.65 grams, 1.34 mmol) in methoxyethanol (10 ml) and the solution was refluxed at 150 °C) for 2 days under N2. The methoxyethanol solvent was distilled from the reaction mixture to dryness and the off-white product was crystallized from methanol affording 0.31 grams of complex IC (70% yield). 1H NMR, 400 MHz (CDCB), δ: -19.8 ppm (IH, t, J = 16 hz), 1.12 (12H, m); 1.20 (6H, dd, J=7, J=8); 1.45 (6H, dd, J=7, J=8); 2.79 (2H, m); 2.94 (2H, m); 5.34 (IH, s); 6.81 (IH, t, J=6.5); 6.84 (IH, t, J=7.3); 7.08 -7.28 (5H, m); 7.4 (2H, d, J=7); 9.14 (IH, d, J=7);
31P NMR, 120 MHz (CDC13), δ: 47.5 (d, J = 12 Hz). IR (neat): 2017 cm-1 (s, CO).
EXAMPLE 4
Preparation ofchiral non racemic (sp3)-carbometalated ligand l-(di- isopropylphosphino)-8-(diphenylphosphino)triptycene (ligand IV) and complexes thereof To a cold stirred solution (-78 °C) of l-(bromo)-8-(diphenylphosphino)triptycene (2.3 g, 4.45 mmol) and Tetramethylethylenediamine (TMEDA) (1.3 mL, 2.5 eqivalents) in dry THF (20 mL), n-BuLi in hexane (1.6 M, 5.5mL, 2 eq) was added over a period of 10-15 minutes. The resulting red to brown solution was stirred for additional 30 minutes and (-)-menthyl-(s)-toluenesulfϊnate (3.26 grams, 11.1 mmol, 2.5 equivalents) solution in THF (20 mL) was added dropwise over a period 30-35 minutes. The resulting red to brown solution was stirred overnight to obtain a yellow solution. This solution was diluted with water (30 ml) and extracted with dichloromethane (30 ml). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by flash chromatography on silica with ethyl acetate/hexane (10:90) to provide two separate diastereomers of ligand IV(26% yield each).
P NMR (diastereomer 1). -14.40 ppm. [α]D= -423.8 (C= 0.00302 gr/ml in CHCl3) P NMR (diastereomer 2) -15.18 ppm
Diastereomer 1 (1 gram) was dissolved in dry THF at -78 °C and 4 equivalents of sec- BuLi were added. After stirring the reaction mixture for 5 minutes 4 equivalents of di- isopropylchlorophosphine were added and the resulting red to brown solution was stirred overnight to obtain a yellow solution which was diluted with water (30 ml) and extracted with dichloromethane (30 ml). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by flash chromatography on silica with ethyl acetate/hexane (5:95) to provide enantiopure l-(di- isopropylphosphino)-8-(diphenylphosphino)triptycene separately in 10% yield (99% ee).
1H NMR (THF-J8): 7.33 (t, J) 7 Hz, 2H), 7.29-7.22 (m, 12H), 7.11 (d, J) 4 Hz, IH),
6.94 (t, J) 8 Hz, IH), 6.85-6.81 (m, 2H), 6.73 (t, J) 7 Hz, IH), 6.67 (d, 4 Hz, IH),
6.55-6.52 (m, IH), 5.46 (s, IH), 2.17-2.12 (m, IH), 2.04-1.99 (m, IH), 1.19 (dd, J) 7
Hz, J) 7 Hz, 3H), 1.02 (dd, J) 7 Hz, J) 7 Hz, 3H), 0.80 (dd, J) 7 Hz, J) 7 Hz, 3H),
0.71(dd, J) 7 Hz, J) 4 Hz, 3 H).
31P NMR(THF-c/8): -9.26 (dj) 21 Hz), -18.05 (d, J) 21Hz).
The synthesis of chiral non racemic (sp3)-carbometalated Ir or Rh complexes is performed according to the procedures described in Examples 1-3, according to scheme 4:
Figure imgf000032_0001
Scheme 4
EXAMPLE 5
Catalytic transfer hydrogenation of ketones by Complex I- general procedure
In a typical catalytic transfer hydrogenation procedure, an oven-dried screw caped reaction tube was charged with the complex I in NaO1Bu and was heated to 82 0C. A solution of the ketone substrate in 2-propanol (4M) was then injected into the reaction mixture and was monitored by GC. After attainment of equilibrium conversion or after the allotted time, the solvent was removed by evaporation under reduced pressure. Isolated yields were obtained after a standard workup and purification by flash chromatography. In all cases the reactions were carried out in the closed system under air. No difference in reactivity was observed under air-free conditions. No difference in reactivity was observed in the open reactor. The catalytic studies are summarized in Table 1 and 2. Yields reported in Table 1 and 2 are an average of two runs.
TABLE 1
Yield
TOF Conversion % entry Catalyst: Substrate ratio
(h-')a (minutes)b (%)
1
O TON:1*105
1 :100,000 94 (48 hours) 93
2
1 : 10,000 9*105 >99(5) 99
3
1 :10,000 9*105 96(5) 95
5 •-
1 :10,000 9*105 >99(5) 99
" Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion. b Determined by GC analysis.
TABLE 2 entry substrate Time Yield (minutes) (%)b
5 90
1 >99
Figure imgf000034_0001
1 96
Figure imgf000034_0002
5 93
Figure imgf000034_0003
0 The reaction was carried out with a catalyst/substrate/Base ratio of 1/2000/50 * Isolated.
Specific examples of products, which have been isolated and characterized by way of non-limiting examples of the following invention, are reported hereunder.
1-phenylethanol : 1H NMR, 400 MHz (CDCl3), δ: 1.5 (3H, d, J= 6.5 Hz); 2.02 (IH, s ); 4.89 (IH, q, J=6.5 Hz); 7.29-7.38 (5H,m). 13C NMR, 400 MHz (CDCl3), δ: 25.16, 70.30, 125.43, 127.40, 128.47, 145.94.
diphenylmethanol : 1H NMR, 400 MHz (CDCl3), δ: 2.09 (IH, s ); 5.84 (IH, s); 7.32- 7.43 (10H,m). 13C NMR, 400 MHz (CDCl3), δ: 76.25, 126.62, 127.58, 128.52, 143.90.
l-(naphthalen-6-yl)ethanol: 1H NMR, 400 MHz (CDCl3), δ: 1.61 (3H, d, J = 6.5
Hz); 1.97 (IH, br ); 5.10 (IH, q, J=6.5 Hz); 7.49-7.55 (3H,m); 7.84-7.87 (3H,m). 113J,C NMR, 400 MHz (CDCl3): 25.15, 70.55, 123.82, 125.81, 126.16, 127.68, 127.94, 128.33, 133.00, 133.36, 143.18.
l-(4-bromophenyl)ethanol: 1H NMR, 400 MHz (CDCl3), δ: 1.46 (3H, d, J = 6.5 Hz); 1.78 (IH, br ); 4.86 (IH, q, J=6.5 Hz); 7.23-7.26 (2H,m); 7.44-7.46 (2H,m). 13C NMR, 400 MHz (CDCl3), δ: 25.23, 69.75, 121.14, 127.16, 131.54, 144.80.
l-(2-chlorophenyl)ethanol: 1H NMR, 400 MHz (CDCl3), δ: 1.49 (3H, d, J = 6.5 Hz); 1.94 (IH, br ); 5.29 (IH, q, J=6.5 Hz); 7.19 (lH,td, 2J=1.5,3J=7.5 Hz); 7.27-7.33 (2H,m); 7.19 (lH,dd, 2J=1.7,3J=7.8 Hz). 13C NMR, 400 MHz (CDCl3), δ: 23.52, 66.89, 126.44, 127.20, 128.35, 129.37, 131.60, 143.13.
l-(2-bromophenyI)ethanol: 1H NMR, 500 MHz (CDCl3), δ: 1.51 (3 H, d, J = 6.5 Hz); 2.00 (IH, br ); 5.26 (IH, q, J=6.5 Hz); 7.15 (lH,t, J=8 Hz); 7.38 (lH,t, J=8 Hz); 7.54 (lH,t, J=8 Hz); 7.62 (lH,t, J=8 Hz). 13C NMR, 400 MHz (CDCl3), δ: 23.59, 69.17, 121.70, 126.70, 127.85, 128.75, 132.66, 144.76.
l-(3-bromophenyl)ethanol: 1H NMR, 500 MHz (CDCl3), δ: 1.51 (3 H, d, J = 6.5 Hz); 1.81 (IH, br ); 4.9 (IH, q, J=6.5 Hz); 7.24 (lH,t, J=7 Hz); 7.31 (lH,d, J=7 Hz); 7.42 (lH,t, J=7 Hz); 7.56 (lH,s,). 13C NMR, 400 MHz (CDCl3), δ: 25.20, 69.63, 122.58, 124.06, 128.58, 130.10, 130.42, 148.17.
l-(naphthalen-5-yl)ethanol: 1H NMR, 400 MHz (CDCl3), δ: 1.71 (3H, d, J = 6.5 Hz); 1.93 (IH, br ); 5.7 (IH, q, J=6.5 Hz); 7.49-7.56 (3H,m); 7.71 (lH,d, J=7 Hz); 7.81 (lH,d, J=8 Hz); 7.90 (lH,d, J=7 Hz); 8.15 (lH,d, J=8 Hz). 13C NMR, 400 MHz (CDCl3), δ: 24.39, 67.08, 76.80, 77.12, 77.44, 122.05, 123.23, 125.56, 126.04, 127.92, 128.92, 130.33, 133.85, 141.44.
l-(4-methoxyphenyl)ethanol: 1H NMR, 400 MHz (CDCl3), δ: 1.51 (3H, d, J = 6.3 Hz); 1.73 (IH, br ); 3.83(3H,s); 4.89 (IH, q, J=6.3 Hz); 6.91 (2H,d, J=8.6 Hz); 7.33 (2H,t, J=8.6 Hz). 13C NMR, 400 MHz (CDCl3), δ: 25.04, 55.26, 69.81,113.82, 126.69, 138.17, 158.90. 3-phenyl-l-propanol: 1H NMR, 400 MHz (CDCl3), δ: 1.92 (2H, m); 2.39 (IH, s );
2.74 (2H, t, J=7.8 Hz); 3.71 (2H, t, J=6.4 Hz); 7.20-7.24 (2H,m); 7.30-7.34 (3H,m).
13C NMR, 400 MHz (CDCl3), δ: 32.13, 34.25, 62.16, 125.90, 128.45, 128.48, 141.93.
cinnamyl alcohol: 1H NMR, 400 MHz (CDCl3), δ: 1.62 (IH, br); 4.35 (2H, t, J=5.6
Hz ); 6.4 (IH, dt, J=16, J=5.6 Hz); 3.71 (IH, t, J=16 Hz); 7.25-7.29 (lH,m); 7.5
(lH,t, J=7.2 Hz); 7.4 (lH,d, J=7.2 Hz). 13C NMR, 400 MHz (CDCl3), δ: 63.67,
126.49, 127.70, 128.55, 128.61, 131.13, 136.87.
bis(4-chlorophenyl)methanol: 1H NMR, 400 MHz (CDCl3), δ: 2.08 (IH, s ); 5.81
(IH, s); 7.29-7.34 (8H,m). 13C NMR, 400 MHz (CDCl3), δ: 74.92, 127.88, 128.5,
133.58, 141.86.

Claims

Claims
1. A transition metal complex, containing at least one pincer ligand linked to said metal via a Ca cyclometalated carbon and via two donor atoms Wi and W2, wherein said Ca carbon is in an sp3 hybridization; said Ca carbon is bonded to three Cβ carbons; each of said Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O).
2. The complex of claim 1, characterized by: a) said complex having a decomposition temperature higher than 260 0C and/or b) said complex maintaining its structure after dissolving 10 mg thereof in 2 ml of deuterated DMSO, heating it to about 190 °C, and keeping it at this temperature for 2 days.
3. The complex of claim 2, having a decomposition temperature equal to or higher than 350 0C.
4. The complex of claim 1 , wherein said transition metal is Ir or Rh.
5. A pincer complex of general formula I:
Figure imgf000037_0001
Wherein
M is selected from Ir or Rh;
Z is selected from:
Figure imgf000038_0001
Z1 Z2 Z3
R1 and R2 are independently selected from: Ci-Cό-alkyl, aryl, alkoxy, aryloxy, C1-C6- alkylamine, arylamine, halogen, N, O or null;
R3 and R4 are independently selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy, C1-C6- alkylamine and arylamine;
Wi and W2 are independently selected from P, As, N and O;
X1 and X2 are independently selected from: halogen, H, Ci-C6-alkyl or null;
Y is selected from CO, RCN, N2, alkene or null; and
R is selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy, Cj-Cό-alkylamine and arylamine.
6. The complex of claim 5, characterized by: a) said complex having a decomposition temperature higher than 260 0C and/or b) said complex maintaining its structure after dissolving 10 mg thereof in 2 ml of deuterated DMSO, heating it to about 190 0C, and keeping it at this temperature for 2 days.
7. The complex of claim 6, having a decomposition temperature equal to or higher than 350 0C.
8. The complex of any of claims 5-7 wherein Z is Z1.
9. The complex of any of claims 5-7 wherein W1 and W2 are both P.
10. The complex of claim 9, wherein R3 and R4 are independently selected from C1- C6-alkyl and aryl.
11. The complex of any of claims 1-10 having a chiral center.
12. The complex of claim 5 having the structure of formula II:
Figure imgf000039_0001
Formula II.
13. The complex of claim 12, wherein M is Ir.
14. The complex of claim 12, wherein M is Rh.
15. The complex of claim 13, wherein X1 is Cl and X2 is hydrogen.
16. The complex of claim 13, wherein each of X1 and X2 is Cl.
17. The complex of claim 14, wherein each of X1 and X2 is Cl.
18. The complex of any of claims 15-17, wherein each of R3 and R4 is isopropyl.
19. The complex of any of claims 15-17, wherein R3 is different from R4.
20. The complex of claim 19, wherein R3 is isopropyl and R4 is phenyl.
21. 1,8-Bis(diisopropylphosphino)triptycene [IrCl2CO(κ3-PCP)].
22. 1,8-Bis(diisopropylphosphino)triptycene [RhCl2CO(κ3-PCP)].
23. 1,8-Bis(diisopropylphosphino)triptycene [IrCl(H)CO(κ3-PCP)].
24. The complex of any of claims 1 -23 for use in the catalytic preparation of alcohols from ketones.
25. The complex of any of claims 1-23 for use in the catalytic preparation of amines from imines.
26. The complex of any of claims 1-23 for use in the catalytic preparation of alkanes from alkenes.
27. A method for the preparation of a complex having the structure of formula I:
Figure imgf000040_0001
Formula I wherein
M is selected from Ir or Rh;
Z is selected from:
Figure imgf000040_0002
Z3 R1 and R2 are independently selected from: d-C6-alkyl, aryl, alkoxy, aryloxy,
Ci-C6-alkylamine, arylamine, halogen, N, O or null;
R and R4 are independently selected from: C!-C6-alkyl, aryl, alkoxy, aryloxy,
Ci-Cό-alkylamine and arylamine;
Wi and W2 are independently selected from P, As, N and O;
X1 and X2 are independently selected from: halogen, H, Ci-C6-alkyl or null;
Y is selected from CO, RCN, N2, alkene or null; and
R is selected from: C!-C6-alkyl, aryl, alkoxy, aryloxy, Ci-C6-alkylamine and arylamine;
said method comprising: a) mixing a precursor complex of the formula MXL2 and/or hydrates thereof, wherein X is a halogen and L is a monodentate ligand, or wherein L2 is a bidentate ligand, with a ligand having the structure of Formula III in a solvent to obtain a reaction mixture;
Figure imgf000041_0001
b) heating said reaction mixture to form the complex of formula I in said reaction mixture; c) isolating said complex from said reaction mixture.
28) The method of claim 27, wherein said solvent is selected from high-boiling polar solvents.
29) The method of claim 27, wherein said heating is conducted at a temperature selected from about 100 °C till about 200 °C.
30) The method of claim 27 wherein said heating is conducted for at least 12 hours.
31) The method of claim 27, wherein said method further comprises purifying said complex to obtain said complex in a purified form.
32) A process for the catalytic transfer hydrogenation of a substrate having a multiple bond, said process comprising: a) providing a substrate having a multiple bond, b) hydrogenating said substrate in the presence of a hydrogen donor, a base and further in the presence of a complex selected from:
I) a transition metal complex, containing at least one pincer ligand linked to said metal via a Ca cyclometalated carbon and via two donor atoms Wi and W2, wherein said Ca carbon is in an sp3 hybridization; said Ca carbon is bonded to three Cβ carbons; each of said Cβ carbons is linked to non-hydrogen atoms; and Wi and W2 are independently selected from phosphorus (P), arsenic (As), nitrogen (N) or oxygen (O). , or
II) a complex of general formula I:
Figure imgf000042_0001
Formula I Wherein M is selected from Ir or Rh;
Figure imgf000043_0001
R1 and R2 are independently selected from: d-C6-alkyl, aryl, alkoxy, aryloxy,
Ci-C6-alkylamine, arylamine, halogen, N, O or null;
R3 and R4 are independently selected from: C]-C6-alkyl, aryl, alkoxy, aryloxy,
Cj-Cβ-alkylamine and arylamine;
Wi and W2 are independently selected from P, As, N and O;
X1 and X2 are independently selected from: halogen, H, Ci-C6-alkyl or null;
Y is selected from CO, RCN, N2, alkene or null; and
R is selected from: Ci-C6-alkyl, aryl, alkoxy, aryloxy, Ci-Cg-alkylamine and arylamine.
33. The process of claim 32 wherein said complex has a stability characterized by: a) said complex having a decomposition temperature higher than 260 0C and/or b) said complex maintaining its structure after dissolving 10 mg thereof in 2 ml of deuterated DMSO, heating it to about 190 °C, and keeping it at this temperature for 2 days.
34. The process of claim 32, wherein said multiple bond of said substrate is selected from a carbon-oxygen double bond, a carbon-nitrogen double bond, a carbon-carbon double bond or a carbon-carbon triple bond.
35. The process of claim 34, wherein said substrate is a ketone, an imine or an alkene, thereby respectively obtaining an alcohol, an amine or an alkane.
36. The process of claim 32, being an asymmetric catalytic transfer hydrogenation process of a substrate, wherein said substrate is a prochiral substrate, and wherein said complex has a chiral center.
37. The process of any of claims 32-36, wherein said process is conducted in a closed reactor.
38. The process of any of claims 33-37, wherein said process is conducted under air.
39. The process of any of claims 33-38, characterized by turnover frequency (TOF) values which are equal to or higher than 10,000 hour'1.
40. The process of any of claims 33-39, characterized by turnover number (TON) values which are equal to or higher than 2000.
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CN114891046B (en) * 2022-06-15 2023-12-26 国信宝威(北京)科技有限公司 Tri-discoene metallocene catalyst and application thereof

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