WO2010061350A1 - Hydrogenation of ester, ketone or aldehyde groups with ruthenium complexes having a di-amine and a phosphorous-nitrogen bidentate ligand - Google Patents

Hydrogenation of ester, ketone or aldehyde groups with ruthenium complexes having a di-amine and a phosphorous-nitrogen bidentate ligand Download PDF

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WO2010061350A1
WO2010061350A1 PCT/IB2009/055368 IB2009055368W WO2010061350A1 WO 2010061350 A1 WO2010061350 A1 WO 2010061350A1 IB 2009055368 W IB2009055368 W IB 2009055368W WO 2010061350 A1 WO2010061350 A1 WO 2010061350A1
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optionally substituted
group
groups
alkyl
atoms
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PCT/IB2009/055368
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WO2010061350A8 (en
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Lionel Saudan
Christophe Saudan
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Firmenich Sa
Saudan, Michel, Alfred, Joseph
SAUDAN, Sylvia, joyeuse, Adélaïde, Ada
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Priority to CN2009801478272A priority Critical patent/CN102227261A/en
Priority to EP09793584A priority patent/EP2370207A1/en
Publication of WO2010061350A1 publication Critical patent/WO2010061350A1/en
Publication of WO2010061350A8 publication Critical patent/WO2010061350A8/en

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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
    • B01J31/182—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine comprising aliphatic or saturated rings
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—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
    • 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
    • C07C29/14—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 a —CHO group
    • C07C29/141—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 a —CHO group with hydrogen or hydrogen-containing gases
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    • C07C29/132—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
    • 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
    • C07C29/145—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 with hydrogen or hydrogen-containing gases
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    • C07C29/132—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
    • 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
    • C07C29/147—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 carboxylic acids or derivatives thereof
    • C07C29/149—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 carboxylic acids or derivatives thereof with hydrogen or hydrogen-containing gases
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
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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
    • B01J2531/0213—Complexes without C-metal linkages
    • B01J2531/0216—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0263—Planar chiral ligands, e.g. derived from donor-substituted paracyclophanes and metallocenes or from substituted arenes
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • B—PERFORMING OPERATIONS; TRANSPORTING
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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
    • B01J2531/821—Ruthenium
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    • C07C2601/14—The ring being saturated
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to the field of catalytic hydrogenation and, more particularly, to the use of specific ruthenium catalysts, or pre-catalysts, in hydrogenation processes for the reduction of ketones, aldehydes and esters or lactones into the corresponding alcohol or diol respectively.
  • a ketone, aldehyde or ester functional group is one of the fundamental reactions in organic chemistry, and is used in a large number of chemical processes.
  • two main types of processes are known to achieve such a transformation.
  • Such types of processes are the following: a) hydride processes, in which a silyl or metal hydride salt, such as LiAlH 4 , or PMHS (polymethylhydrosiloxane) is used; b) hydrogenation processes, in which molecular hydrogen is used.
  • One of the mandatory and characterizing elements of hydrogenation processes is the catalyst or the catalytic system which is used to activate the molecular hydrogen in view of the reduction.
  • the development of useful catalysts or catalytic systems for the hydrogenation of a ketone, aldehyde or ester functional group represents an important, difficult and unpredictable task in chemistry.
  • the widely used and described catalysts or catalytic systems known to perform such reductions are all based on ruthenium complexes containing a P 2 N 2 coordination sphere; in particular of the (PP)(NN) type (see EP 0901997 and EP 1813621 for ketones and aldehydes, or more recently WO08/065588 for esters), or (PN)(PN) type (see WO02/022526 or WO02/40155 for ketones or aldehydes and WO2006/106483 or WO2006/106484 for esters).
  • the present invention relates to processes for the reduction by hydrogenation, using molecular H 2 , of a C 3 -C 70 substrate containing a ketone, aldehyde or ester/lactone functional group into the corresponding alcohol or diol, characterized in that said process is carried out in the presence of - at least one catalyst or pre-catalyst in the form of a ruthenium complex comprising: a C 2 - 40 diamino bidentate ligand (N-N) wherein at least one of said amino groups is a secondary or primary amine (i.e.
  • a C 5 _ 5 o bidentate ligand comprising a coordinating phosphorous atom and a coordinating nitrogen atom belonging to a N,N,N' trisubstituted carboxiamide (i.e. a
  • diamino bidentate it is understood that said ligand coordinates the Ru metal with two nitrogen atoms.
  • said (P-N) ligand coordinates the Ru metal with one phosphorous atom and one specific type of nitrogen atom, and in particular said N,N,N' trisubstituted carboxiamide or N-substituted imidoate are part of a 5,6 or 7 member ring.
  • the Ru complex possesses a coordination sphere comprising two bidentate ligands which bind the Ru metal, in total, with three nitrogen atoms and one P atom.
  • the substrate can be a C 3 _ 3 o compound, in particular of formula of formula (I)
  • n 0 or 1 ;
  • R a represents a hydrogen atom or a R b group
  • R b represents a Ci-C 30 hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens; or
  • R a and R b taken together, represent a C 3 -C 20 , preferably C 4 -C 20, saturated or unsaturated hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens.
  • said R a or R b groups optionally comprise one carbonyl and/or carboxylic groups.
  • the substrate is a ketone or aldehyde
  • the corresponding alcohols i.e (II-a)
  • R a and R b are defined as in formula (I).
  • the corresponding alcohols (i.e (II-b) and (II-c)), or the corresponding diol (II-d), of said substrate (I), are of formula
  • a compound of formula (II-b or II-c) will be obtained in the case where n is 1 and R a and R b are not bonded together, while a compound of formula (II-d) will be obtained in the case where n is 1 and R a and R b are bonded together.
  • said compounds (II-a) or (II-b)/(II-c)/(II-d) can be in a racemic or optically active form, depending on the nature of the substrate and on the catalyst/pre- catalyst used.
  • the substrate (I) is a racemic or optically active compound.
  • R a or R b can be in the form of a linear, branched or cyclic aromatic, alkyl, alkenyl, or alkynyl group, e.g., a linear alkyl group, or can also be in the form of a mixture of said type of groups, e.g.
  • a specific R a may comprise a linear alkyl, a branched alkenyl (e.g. having one or more carbon-carbon double bonds), a (poly)cyclic alkyl and an aryl moiety, unless a specific limitation to only one type is mentioned.
  • a group when a group is mentioned as being in the form of more than one type of topology (e.g. linear, cyclic or branched) and/or unsaturation (e.g. satured, unsatured or aromatic or more specifically alkyl, aromatic or alkenyl), it is meant also a group which may comprise moieties having any one of said topologies or unsaturations, as explained above.
  • a group when a group is mentioned as being in the form of one type of unsaturation, (e.g. alkyl), it is meant that said group can be in any type of topology (e.g. linear, cyclic or branched) or having several moieties with various topologies.
  • unsaturation e.g. alkyl
  • topology e.g. linear, cyclic or branched
  • the substrate is a ketone, an aldehyde or an ester, or a lactone, that will provide an alcohol, or a diol, that is useful in the pharmaceutical, agrochemical or perfumery industry as final product or as an intermediate.
  • Particularly preferred substrates are ketones, aldehydes, esters or lactones, that will provide an alcohol, or diol, which is useful in the perfumery industry as final product or as an intermediate.
  • the substrate is a C 5 -C 20 compound of formula (I), and in particular one may cite those wherein R a represent a hydrogen atom or a R b group, R b representing a linear, branched or cyclic C 1 -C 20 hydrocarbon group optionally substituted and optionally comprising one, two or three oxygen or nitrogen atoms; or R a and R b , taken together, represent a C 3 -C 20 hydrocarbon group, optionally substituted and optionally comprising one, two or three oxygen or nitrogen atoms.
  • the substrate is a C 5 -C 20 compound of formula (I)
  • R a represents a hydrogen atom or a R b group
  • R b representing a linear, branched or cyclic C3-C 1 8 alkyl group, optionally substituted, or a C 4 -C 1 8 alkenyl or alkynyl group, optionally substituted or a C ⁇ -Cio aromatic group, optionally substituted
  • R a represents a hydrogen atom or a R b group
  • R b representing a linear, branched or cyclic C3-C 1 8 alkyl group, optionally substituted, or a C 4 -C 1 8 alkenyl or alkynyl group, optionally substituted or a C ⁇ -Cio aromatic group, optionally substituted
  • R a represents a hydrogen atom or a R b group
  • R b representing a linear, branched or cyclic C3-C 1 8 alkyl group, optional
  • R a and R b taken together, represent a C 3 -C 18 hydrocarbon group, optionally substituted.
  • R a and R b are one, two or three halogens, OR C , NR° 2 or R c groups, in which R c is a hydrogen atom, a halogenated C 1 -C 2 group or a Ci to C 1 O cyclic, linear or branched alkyl, or alkenyl group, preferably a Ci to C 4 linear or branched alkyl or alkenyl group.
  • said substituents are one, two or three halogens, OR C , or R c groups, in which R c is a hydrogen atom, or a Ci to Ce cyclic, linear or branched alkyl, or alkenyl group.
  • R a and R b groups may comprise up to four oxygen, nitrogen or halogen atoms.
  • oxygen in particular, it is understood that said oxygen atoms may be also part of an additional ketone, aldehyde or ester/lactone functional group, which can also be reduced to the corresponding alcohol during the invention's process, according to the molar amount of H 2 used, as well known by a person skilled in the art.
  • the substrate possesses only one ketone, aldehyde or ester/lactone functional group, i.e. the one reduced in the invention's process.
  • Non-limiting examples of substrates of formula (I) are the following: C 3 _i 4 aldehydes such as: a C3_io alkanal, a Cj -1 Q 2-alkenal, a C3_io 2-methyl-2-alkenal, a Cs -1 Q 2,4-dienal, a 3-alkyl- 3-benzene-prop-2-enal, a 3-alkyl-2-methyl-3-benzene-prop-2-enal, a C ⁇ -io-benzene- carbaldehyde, a C 4- I? 2-methylen-aldehyde; wherein the underlined compounds are known to be particularly base-sensitive substrates; and
  • C 3 _i 4 ketones such as: a di(Ci-i 2 alkyl) ketone, a C 4 -C 12 cyclic-ketone, a cyclopentenone alpha substituted by a Cs-r? hydrocarbon group, a cyclohexenone alpha substituted by a C 6-12 hydrocarbon group, a substituted aryl Ci_i 2 -alkyl ketone, a C 2 -i 2 -l-alkene methyl ketone, a C ⁇ -1 2 -l-alkyne methyl ketone, a 2-trimethylsilyl- 1 -ethynyl Cuio-alkyl ketone, 2-trimethylsilyl- 1 -ethynyl phenyl ketone, a 2-trimethylsilyl-l-ethvnyl C_u j 9-(un)substituted aryl ketone, a Cum (un)substituted
  • the substrate can be selected from the group consisting of sclareolide, C 9 -C 15 spirolactones and C 1 -C 4 alkyl esters of 4-methyl-6- (2,6,6-trimethyl-l-cyclohexen-l-yl)-3-hexenoic acid.
  • the substrate is a compound of formula
  • R a represents a hydrogen atom or a d_ 4 alkyl or alkenyl group
  • R b represents a C 5 -C 14 hydrocarbon group, preferably alkyl or alkenyl, optionally substituted and optionally comprising one or two oxygen or nitrogen atoms
  • R a and R b taken together, represent a C 4 -C 16 , hydrocarbon group, preferably alkyl, alkenyl or alkadienyl, optionally substituted and optionally substituted and optionally comprising one or two oxygen or nitrogen atoms.
  • the compound of formula (III) is a ketone.
  • R a and R b are one or two OR C , CONR° 2 or R c groups, in which R c is a hydrogen atom or a Ci to C 4 linear or branched alkyl or alkenyl group.
  • R c is a hydrogen atom or a Ci to C 4 linear or branched alkyl or alkenyl group.
  • one may also cite a group COOR 0 which can also be reduced to the corresponding alcohol during the invention's process, according to the molar amount of H 2 used, as well known by a person skilled in the art.
  • Non-limiting examples of substrates of formula (II) are the following:
  • Cn-C is ketones comprising the trimethyl-cyclohexyl or trimethyl-cyclohexenyl moiety, in particular the 2,6,6 trimethyl ones; such as : Ci-C 4 alkyl 2,6,6-trimethyl-4-oxo-2- cyclohexene-1-carboxylate, Ci-C 4 alkyl 4,6,6-trimethyl-2-oxo-3-cyclohexene-l- carboxylate, beta ionone or irone, l-(2,2,3,6-tetramethyl-l-cyclohexyl)-l-hexen-3-one, l-(2,2,6-trimethyl-l-cyclohexyl)-l-hexen-3-one or 4-acetyl-3,5,5-trimethyl-2- cyclohexen- 1 -one ;
  • C 9 -C 16 ketones comprising the 2,2,3-trimethyl-cyclopentenyl or 2,2,3-trimethyl- cyclopentyl moiety; such as : 4,4-dimethyl-6-(2,2,3-trimethyl-3-cyclopenten-l-yl)-5- hexen-3-one or 4,4-diethyl-6-(2,2,3-trimethyl-3-cyclopenten-l-yl)-5-hexen-3-one;
  • C 1O -C 16 ketones comprising hydronaphthalenone moiety; such as : dihydro, tetrahydro, hexahydro or perhydronaphthalenone, e.g. 3,4,4a,5,8,8a-hexahydro-2,2,6,8- tetramethyl- 1 (2H)-naphthalenone ;
  • C 5 -C 14 ketones comprising cyclopentanone , cyclohexanone, cyclopentenone or cyclohexenone moiety; such as : 2-pentyl-l -cyclopentanone, 3,3,5- trimethylcyclohexanone, 2-ethyl-4,4-dimethyl-cyclohexanone, 2-tert- butylcyclohexanone or 4-tert-butylcyclohexanone ;
  • C 9 -C 1 8 ketones comprising a phenyl moiety, such as : 5-(3,4-dimethylphenyl)-2,2,4,5- tetramethyl-3-hexanone , 4-phenyl-3-buten-2-one, 4-phenyl-2-butanone, l-phenyl-2- pentanone, 4-methyl-l-phenyl-2-pentanone or 2-methoxy-l -phenyl- 1-ethanone; or
  • the presence of a base is not mandatory. This is an advantage, since it allows significant increases in yields for the production of alcohols from base-sensitive substrates. Therefore, according to a particular embodiment of the invention, the substrate is a base- sensitive compound and the process is carried out in the absence of a base.
  • n 0, i.e. aldehydes or ketones.
  • the ruthenium catalyst or pre-catalyst (also referred to from herein as complex) can be of the general formula
  • the monodentate ligands can be a C 3 _ 24 mono-phosphine, like PPh 3 , CO or even a solvent.
  • solvent it has to be understood the usual meaning in the art and in particular compounds used as diluent in the preparation of the complex or during the invention's process.
  • Non limiting examples of such solvent are dimethylsulfoxide, acetonitrile, dimethylformamide, an alcohol (e.g. an C 1 -C 4 alcohol), or also THF, acetone, pyridine or a C 3 -Cs ester or the substrate of the invention's process.
  • each Y represents, simultaneously or independently, a hydrogen atom, a hydroxyl, a Ci to C 10 alkoxyl group, such as a methoxyl, ethoxyl or isopropoxyl group, a halogen atom (such as Cl, Br or I), BH 4 , or a C 3 -CO allyl group group, such as allyl (i.e. propenyl), 2-methyl-allyl (i.e. 2- methyl-propenyl) .
  • each Z represents, simultaneously or independently, ClO 4 " , BF 4 “, PF 6 “, SbCl 6 “, AsCl 6 “, SbF 6 “, AsF 6 “, a R d SO 3 " wherein R d is a chlorine of fluoride atom or a CF 3 group, or a BR e 4 " wherein R e is a phenyl group optionally substituted by one, two or three groups such as halide atoms and/or methyl and/or CF 3 groups.
  • the complexes of the invention can be added into the reaction medium of the invention's process in a large range of concentrations.
  • concentration values those ranging from 50 ppm to 50000 ppm, relative to the amount of substrate.
  • the complex concentration will be comprised between 100 and 10000, or even 1000, ppm. It goes without saying that the optimum concentration of complex will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, of the temperature and on the pressure of H 2 used during the process, as well as the desired time of reaction.
  • the hydrogenation processes of the invention may be carried out in the absence of a base, or in the absence of a significant amount of a base, or in the presence of a base.
  • the base can be added in particular for those processes wherein neither the starting product nor the final product is sensible to a base (e.g. does not undergo isomerisation, degradation, ring opening, polymerisation reactions, etc).
  • Said base can be the substrate itself, if the latter is basic, a corresponding alcoholate or any organic or inorganic base having preferentially a pK a above 10.
  • said base may have a pK a above 14. It is also understood that preferably said base does not reduce itself a substrate of formula (I).
  • Ci_s alcoholates As non-limiting examples one may cite the following types of base: Ci_s alcoholates, hydroxides, alkaline or alkaline-earth carbonates, Cio- 26 phosphazenes, C 1-1O amides, basic alox, siliconates (i.e. silicium derivatives having SiO " or SiRO " groups), or an inorganic hydride such as NaBH 4 , NaH or KH.
  • alkaline or alkaline-earth metal carbonates such as cesium carbonate, an alkaline or alkaline-earth metal hydroxide, C 1-1O amides, Cio- 26 phosphazene or an alcoholate of formula (R 31 O) 2 M or R 31 OM', wherein M is an alkaline-earth metal, M' is an alkaline metal or an ammonium NR 32 4 + , R 31 stands for hydrogen or a Ci to Ce linear or branched alkyl radical and R 32 stands for a Ci to C 1O linear or branched alkyl radical, such as sodium or potassium alcoholates.
  • other suitable bases can be used.
  • said base is an alkaline alcoholate of formula R 31 OM'.
  • Useful quantities of base, added to the reaction mixture, may be comprised in a relatively large range.
  • the hydrogenation reaction can be carried out in the presence or absence of a solvent.
  • a solvent is required or used for practical reasons, then any solvent current in hydrogenation reactions can be used for the purposes of the invention.
  • Non-limiting examples include C 6-1O aromatic solvents such as toluene or xylene, Cs_s hydrocarbon solvents such as hexane or cyclohexane, C 3 _g ethers such as tetrahydrofuran or MTBE, polar solvents such as C 1-S primary or secondary alcohols such as isopropanol or ethanol, or mixtures thereof.
  • the choice of the solvent is a function of the nature of the complex and the person skilled in the art is well able to select the solvent most convenient in each case to optimize the hydrogenation reaction.
  • the reaction can be carried out at a
  • H 2 pressure comprised between 10 Pa and 80x10 Pa (1 to 80 bars) or even more if desired.
  • a person skilled in the art is well able to adjust the pressure as a function of the catalyst load and of the dilution of the substrate in the solvent.
  • typical pressures 1 to 50xl0 5 Pa (1 to 50 bar).
  • the temperature at which the hydrogenation can be carried out is comprised between -20 0 C and 120 0 C. More preferably in the range of between 0 0 C and 100 0 C.
  • a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.
  • the diamino bidentate ligand (N-N) can be a racemic or an optically active compound of formula
  • each a simultaneously or independently, represents 0 or 1 ;
  • the R 1 taken separately, represent, simultaneously or independently, a hydrogen atom or a C 1-1O alkyl or alkenyl group optionally substituted;
  • two R 1 taken together, may form a saturated heterocycle containing 5 to 10 atoms and including the atoms to which said R 1 are bonded, said heterocycle being optionally substituted;
  • R 2 and R 3 taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci-io alkyl or alkenyl group optionally substituted or a C 6-1 O aromatic group optionally substituted; a R 1 and an adjacent R 2 , taken together, may form a saturated or unsatured heterocycle containing 5 to 12 atoms and including the atoms to which said R 1 and R 2 are bonded, and being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; a R and an adjacent R 2 , taken together, may form an aromatic heterocycle containing 5 to 12 atoms and including the atoms to which said R 1 and R 2 are bonded, two R 2 , or a R 2 and a R 3 , taken together, may form a saturated or unsaturated ring having 5 to 12 atoms and including the carbon atom to which said R or R 3 groups are bonded, said ring being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; and Q represents
  • R 5 and R 6 represent, simultaneously or independently, a hydrogen atom, a C 1-1O alkyl or alkenyl group optionally substituted, a C 6-1O aromatic group optionally substituted, or an OR 7 group, R 7 being a C 1-1O alkyl or alkenyl group;
  • two distinct R 6 and/or R 5 groups, or R 5 or R 6 and R 1 or R 2 , taken together, may form a C 3 _s , or even up to Cio, saturated or unsaturated ring optionally substituted, including the atoms to which said R 6 , R 5 , R 1 , R 2 groups are bonded, and optionally containing one or two additional nitrogen, oxygen or sulfur atoms; or
  • aromatic group or ring it is preferably meant a phenyl or naphthyl group.
  • the atoms which may coordinate the Ru atom are the two N atoms bearing the R 1 groups. Therefore, it is also understood that whenever said R 1 , R 2 , R 3 , R 5 , R 6 or any other group comprises heteroatoms such as N, O or S, said heteroatoms are not coordinating.
  • R , R 2 , R 3 , R , R or Q are one, two, three or four groups selected amongst i) halogens (in particular when said substituents are an aromatic moiety), ii) Cs -12 cycloalkyl or cycloalkenyl, iii) C 1-1 O alkoxy, alkyl, alkenyl, polyalkyleneglycols or halo- or perhalo-hydrocarbon, iv) COOR 4 wherein R 4 is a Ci_ 6 alkyl, or v) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, C 1- S alkyl, alkoxy, amino, nitro, ester, sulfonate or halo- or perhalo-hydrocarbon groups.
  • the Q group may also be substituted by one or two groups of formula O-(CR 8 2 ) b -O or O-(CR 8 2 ) b -NR 4 wherein b is 1 or 2 and R 8 being a hydrogen atom or a d_ 4 alkyl group.
  • halo- or perhalo-hydrocarbon has here the usual meaning in the art, e.g. a group such as CF 3 or CClH 2 for instance.
  • said compound (B) is one wherein each a, simultaneously or independently, represents 0 or 1 ; the R 1 , taken separately, represent, simultaneously or independently, a hydrogen atom or a Ci_ 6 alkyl or alkenyl group optionally substituted; two R 1 , taken together, may form a saturated heterocycle containing 5 to 10 atoms and including the atoms to which said R 1 are bonded, said heterocycle being optionally substituted;
  • R 2 and R 3 taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_ 6 alkyl or alkenyl group optionally substituted or a phenyl group optionally substituted; a R 1 and an adjacent R 2 , taken together, may form a saturated heterocycle containing 5 or 10 atoms and including the atoms to which said R 1 and R 2 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atoms; a R 1 and an adjacent R 2 , taken together, may form an a pyridinyl group including the atoms to which said R 1 and R 2 are bonded, and being optionally substituted; two R 2 , or a R 2 and a R 3 , taken together, may form a saturated or unsaturated ring having 5 or 6 atoms and including the atoms to which said R 2 or R 3 groups are bonded, said ring being optionally substituted and optionally containing one additional oxygen atoms; and Q represents a
  • R 5 and R 6 represent, simultaneously or independently, a hydrogen atom, a Ci_ 6 alkyl or alkenyl group optionally substituted or a phenyl group optionally substituted; two distinct R 6 and/or R 5 groups, or R 6 or R 5 and a R 1 or R 2 , taken together, may form a
  • C 3 _ 6 saturated or unsaturated ring optionally substituted, including the atoms to which said R 6 , R 5 , R 1 , R 2 groups are bonded and optionally containing one or two additional oxygen atoms.
  • R 1 , R 2 , R 3 , R 5 , R 6 or Q are one, two or three groups selected amongst i) halogens (in particular when said substituents are an aromatic moiety), ii) Cs_ 6 cycloalkyl or cycloalkenyl , iii) Cue alkoxy or alkyl, iv) COOR 4 wherein
  • R 4 is a Ci_ 4 alkyl, or v) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, d_ 4 alkyl, alkoxy, amino, nitro, ester or sulfonate groups.
  • the Q group may also be substituted by one or two groups of formula O-(CR 8 2 ) b -O, b being lor 2 and R 8 being a hydrogen atom or a methyl or ethyl group group.
  • halo- or perhalo-hydrocarbon it is meant groups such as CF 3 or CClH 2 for instance.
  • a represents 0 or 1 ; and each R 1 , simultaneously or independently, represents a hydrogen atom or a d_ 4 alkyl group optionally substituted;
  • R 2 and R 3 taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_ 4 alkyl group optionally substituted or a phenyl group optionally substituted; a R 1 and an adjacent R , taken together, may form a saturated heterocycle containing 5 or 6 atoms and including the atoms to which said R 1 and R 2 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atoms; two R 2 , or a R 2 and a R 3 , taken together, may form a saturated or unsaturated ring having 5 or 6 atoms and including the atoms to which said R 2 or R 3 groups are bonded, said ring being optionally substituted and optionally containing one additional oxygen atom; and Q represents a
  • R 5 and R 6 represent, simultaneously or independently, a hydrogen atom, a C 1-4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct
  • R 6 and/or R 5 groups, or R 6 or R 5 and a R 1 or R 2 , taken together, may form a C 3 _ 6, saturated or unsaturated ring optionally substituted, including the atoms to which said R 6 , R 5 , R 1 , R 2 groups are bonded and optionally containing one or two additional oxygen atoms.
  • formula (B) a particular embodiment of formula (B) is represented by formula
  • RVe presents a hydrogen atom or a C 1-4 alkyl group optionally substituted
  • R 2 and R 3 taken separately, represent, simultaneously or independently, a hydrogen atom, a C M alkyl group optionally substituted or a phenyl group optionally substituted
  • R and R 2 , or R 2 and R 3 taken together, may form a saturated cycle containing 5 or 6 atoms and including the atoms to which said R 1 , R 2 , R 3 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atom
  • each R 9 represents a hydrogen atom, a Ci_ 6 alkyl group or a substituted or unsubstituted phenyl or benzyl group optionally substituted
  • two R 9 or, R 6 and a R 9 taken together, may form a saturated or unsaturated or aromatic, preferably saturated, ring comprising 5 or 6 atoms
  • Q represents a
  • R 5 and R 6 represent, simultaneously or independently, a hydrogen atom, a C 1-4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct R 6 and/or R 5 groups, or R 5 and a R 1 or R 2 , taken together, may form a C 3 _ 6, saturated or unsaturated ring optionally substituted, including the atoms to which said R 6 , R 5 , R 1 , R 2 groups are bonded and optionally containing one or two additional oxygen atoms.
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 9 or Q of formulae (B') or (B") are as defined above, or more specifically are one or two i) halogens (in particular when said substituents are an aromatic moiety), ii) Ci_s alkyl or alkoxy groups, iii) COOR 4 wherein R 4 is a C M alkyl, or iv) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, Q- 4 alkyl or alkoxy groups, esters or sulfonate groups.
  • Non-limiting examples of said optionally substituted pyridyl group of formula (B") or (B) are: a such as a 2-pyridyl, 2-quinolinyl or a methyl-2-pyridinyl.
  • cycle or ring can be a mono, bi or tri-cyclic group.
  • said Q can be a group of formula (i) wherein m is 1 or 2, R 5 is a hydrogen atom and R 6 is as defined above.
  • at least one coordinating amino group of the N-N ligand is a primary amino group (i.e. NH 2 ) or in other words in formula (B), (B') or (B") one, two or three R 1 represent a hydrogen atom.
  • the N-N ligand is of formula (B'), and preferably the two R 1 represent a hydrogen atom.
  • said compounds being in an optically active form or in a racemic form, if applicable.
  • the bidentate ligand (P-N) can be a racemic or an optically active compound of formula
  • d is 1 or 0,
  • U is an oxygen atom or a NR 14 group, R 14 being a CM alkyl group
  • R 11 and R 12 when taken separately, represent, simultaneously or independently, a Ci_s alkyl or alkenyl group optionally substituted or a C 6-1O aromatic group optionally substituted; or the R and R 2 bounded to the same phosphorous atom, when taken together, may form a saturated or unsaturated ring optionally substituted, having 4 to 8 atoms and including the phosphorous atom to which said R 11 and R 12 groups are bonded;
  • X' represents an unsaturated group of formula
  • each R 9 represents a hydrogen atom, a C 1-1O alkyl group optionally substituted or a phenyl group optionally substituted; two R 9 , taken together, may form a saturated, unsaturated or aromatic ring comprising 5 or 6 atoms;
  • V is an oxygen atom or a NR 17 group, R 17 a C 1-1 O alkyl group or a C 1-1 O hydrocarbon group comprising an acyl, carbamate or sulfonate functional group (P-N ligand); and Q' represents:
  • m' is 1, 2, 3 or 4 and
  • R 5 and R 6 represent, simultaneously or independently, a hydrogen atom, a C 1-1O alkyl or alkenyl group optionally substituted or a C 6-1O aromatic group optionally substituted, or an OR 7 group, R 7 being a C 1-1O alkyl or alkenyl group;
  • two distinct R 6 and/or R 5 groups, or a R 6 and a R 11 or R 13 groups, or a R 6 and a R 9 in formula (b), taken together, may form a C 3 - 8, or even up to C 1O , saturated or unsaturated ring optionally substituted, including the atoms to which said R , R , R 9 , R 11 , R 13 groups are bonded, and optionally containing one additional nitrogen or oxygen atom; or a R 6 and R 14 , taken together, may form a C 3 - 8 saturated, unsaturated or aromatic ring optionally substituted, including the atoms to which said R 6 , R 14 groups are bonded; or
  • aromatic group or ring for (P-N) it is also preferably meant a phenyl or naphthyl derivative.
  • the atoms which may coordinate the Ru atom are the P atom of the PR 11 R 12 group and the N atom of the X group. Therefore, it is also understood that whenever said R 5 , R 6 , R 11 , R 12 , Q' or any other group comprises heteroatoms such as N or O, said heteroatoms are not coordinating.
  • R 5 , R 6 , R 9 , R 11 and R 12 are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) C 1-1O alkyl alkenyl, alkoxy, polyalkyleneglycols groups or halo- or perhalo-hydrocarbon, amine or quaternary amine groups, ii) COOR h wherein R h is a Ci_ 6 alkyl group, iii) Cs_i 2 cycloalkyl or cycloalkenyl groups, iv) NO 2 group, or v) benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups optionally substituted by one, two or three halogens, nitro, Ci_s alkyl, alkoxy, amino, ester, sulfonate or halo
  • halo- or perhalo-hydrocarbon groups such as CF 3 or CClH 2 for instance.
  • the Q' group may be also substituted by one or two groups of formula 0-(CR 8' 2 ) b >-0 or O-(CR 8 2 ) b >-NR 4> wherein b' is 1 or 2, R 4> being a Ci_ 4 alkyl group and R 8 being a hydrogen atom or a C 1 - 4 alkyl group.
  • Possible optional substituents of R 13 are one or two groups selected amongst C 1-1O alkoxy or alkyl groups, or one or two phenyl groups optionally substituted by one, two or three halogens, nitro or Ci-Cs alkyl, alkoxy, amino, acyl, sulfonate, or ester groups, or one or two benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups.
  • cycle or ring can be a mono or bi-cyclic group.
  • P-N is a bidentate ligand wherein, d is 0; R and R 2 represent, simultaneously or independently, a Ci_ 6 alkyl group optionally substituted, a phenyl or naphthyl group optionally substituted; or the R 11 and R 12 bounded to the same phosphorous atom, taken together, form a saturated or unsaturated ring optionally substituted, having 4 to 7 atoms and including the phosphorous atom to which said R 11 and R 12 groups are bonded; X' represents an unsaturated group of formula
  • each R 9 represents a hydrogen atom, a Cue alkyl group optionally substituted or a phenyl group optionally substituted; two R 9 , taken together, may form a saturated, unsaturated or comprising 5 or 6 atoms; and
  • V is an oxygen atom (P-N ligand); such as a 2-oxazolidinyl or 8,8a-dihydro-3aH- indeno[l,2-d][l,3]oxazol-2-yl; and Q' represents: - a group of formula
  • m' is 1, 2, 3 or 4 and R and R represent, simultaneously or independently, a hydrogen atom, a Ci_ 6 alkyl or alkenyl group optionally substituted or a phenyl or naphthyl group optionally substituted; two distinct R 6 and/or R 5 groups, or a R 6 and a R 11 or R 13 groups, or a R 6 and a R 9 in formula (b), taken together, may form a C 3 - O saturated or unsaturated ring optionally substituted, including the atoms to which said R 6 , R 5 ,
  • R 9 , R 11 , R 13 groups are bonded, and optionally containing one additional nitrogen or oxygen atoms; or a R and R 4 , taken together, may form a C 3 - 6 saturated, unsaturated or aromatic ring optionally substituted, including the atoms to which said R 6 , R 14 groups are bonded; or - a C 1O -C 12 metallocenediyl, a 2,2'-diphenyl, a l,l'-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, l-benzofuran-2,3-diyl, a 2-ylomethylphenyl, a 4,12- [2:2]-paracyclophanediyl, a l,6-spiro[4:4]nonanediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6
  • halo- or perhalo-hydrocarbon groups such as CF 3 or CClH 2 for instance.
  • the Q' group may be also substituted by one or two groups of formula O-(CR 8' 2 ) b -O or O-(CR 8' 2 ) b -NR 4> wherein b' is 1 or 2, R 4> being a C i_ 4 alkyl group and R 8 being a hydrogen atom or a C 1 - 4 alkyl group.
  • Possible optional substituents of R 13 are one or two groups selected amongst Ci_ 6 alkoxy or alkyl groups, or one or two phenyl groups optionally substituted by one, two or three halogen, nitro or Ci_ 6 alkyl, alkoxy, amino, acyl, sulfonate, or ester groups, or one or two benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups.
  • Q' may represent a linear C 1 -Cs alkanediyl radical optionally substituted, a 2,2'-diphenyl, a 1,1'- (bis(naphthyl)-2,2'-diyl, a 1 ,2-benzenediyl, a 2-ylomethylphenyl or a 1,8- or 1,2- naphthalenediyl group optionally substituted.
  • X' represents a group (a') or (a").
  • said P-N ligand is of formula
  • R 11 and R 12 represent, simultaneously or independently, a phenyl group optionally substituted
  • Q' represents a C 1 -C 2 alkanediyl radical optionally substituted, a 2,2'-diphenyl, a l,l'-(bis(naphthyl)-2,2'-diyl, a 2-ylomethylphenyl, a 1 ,2-benzenediyl or a 1,8- naphthalenediyl group optionally substituted; and each R represents, simultaneously or independently, a hydrogen atom, a Ci- 6 alkyl group optionally substituted or a phenyl group optionally substituted; two R 18 , when taken together, may form a fused indane or tetraline group optionally substituted and including the carbon atoms to which said R 18 groups are bonded.
  • R Possible optional substituents of R are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) CM alkyl, alkenyl or alkoxy groups , ii) COOR h wherein R h is a C 1 - 4 alkyl group, iii) C 5 - 6 cycloalkyl or cycloalkenyl groups, iv) NO 2 or Ci_ 6 alkyl, alkoxy, amino, ester or sulfonate groups or v) benzyl or phenyl groups.
  • P-N ligands of formula (C) or (C) one can cite the one in the following scheme: Scheme B
  • said compounds being in an optically active form or in a racemic form, if applicable.
  • said P-N ligand is of formula
  • R 11 and R 12 represent, simultaneously or independently, a phenyl group optionally substituted
  • Q' represents a CpC 2 alkanediyl radical optionally substituted, a 2,2'-diphenyl, a l,l'-(bis(naphthyl)-2,2'-diyl, a 2-ylomethylphenyl, a 1 ,2-benzenediyl or a 1,8- naphthalenediyl group optionally substituted; and each R 19 , taken separately, represents simultaneously or independently, a hydrogen atom, a Ci to Ce alkyl group optionally substituted or a phenyl group optionally substituted.
  • Possible optional substituents of R 11 , R 12 and Q' are as described above for formula (C).
  • R 1 1 i 9 y are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) d_ 4 alkyl, alkenyl or alkoxy groups , ii) COOR h wherein R h is a d_ 4 alkyl group, iii) Cs_ 6 cycloalkyl or cycloalkenyl groups, iv) NO 2 or Ci_ 6 alkyl, alkoxy, amino, ester or sulfonate groups or v) benzyl or phenyl groups.
  • ligands (B) or (C) described above can be obtained by applying standard general methods which are well known in the state of the art and by the person skilled in the art. Many of said ligands N-N or P-N are even commercially available.
  • the complexes of formula (A) or (A'), as described above, as well as those wherein Y and/or Z is also a Ci-C 8 acyloxyl or a halogen atom (such as Cl, Br or I), which are precursors (as below described) of said complexes (A) or (A'), are new compounds and are therefore another object of the present invention.
  • the complex (A) of the invention can be used in the form of a preformed complex or can be generated in situ, in the reaction medium of the hydrogenation.
  • the catalyst or pre-catalyst is obtained or obtainable by a process comprising reacting together: 1) a ruthenium precursor of formula
  • E represents a mono anion
  • iene represents a linear or branched C 4 -C 15 hydrocarbon group comprising two carbon-carbon double bonds, optionally substituted, or a cyclic C 7 -C 20 hydrocarbon group comprising two carbon-carbon double bonds, optionally substituted;
  • L represents a C 3 -C 15 allyl, a CO-C 12 aromatic ring optionally substituted or a C 7 -C 15 triene; T) with a C 2 - 40 diamino bidentate ligand (N-N), defined as above, and a Cs_ 5 o bidentate ligand (P-N), defined as above; and 3) optionally a base, in an amount comprised between approximately 0.5 and 15 molar equivalent relative to the ruthenium metal.
  • Optional substituent of the "diene" or of L are one or two C 1 -C 10 alkyl or aryl groups, Ci-C 6 alkoxy groups or -C(O)O-(Ci-C 6 alkyl) groups.
  • triene possesses the usual meaning in the art, i.e. a group comprising three non aromatic carbon- carbon double bonds.
  • E represents a mono anion selected amongst the group consisting of halides (e.g. Cl, Br, I,), BF 4 “, Cl(V, PF 6 “, SbCl 6 “, AsCl 6 “, SbF 6 “, AsF 6 “, hydroxylate, Ci-Ci 0 carboxylates (e.g.
  • R 1 SOs wherein R 1 is a chlorine of fluoride atom or a Ci-Cs alkyl, aryl, fluoroalkyl or fluoroaryl group, or BR J 4 " wherein R J is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF 3 groups.
  • Suitable ruthenium precursors one can cite the compound (D) wherein "diene” stands for a C 7 -C 10 , hydrocarbon group comprising two carbon-carbon double bonds, such as for example COD (cycloocta-l,5-diene) or NBD (norbornadiene) , or yet cyclohepta- 1 ,4-diene .
  • Suitable ruthenium precursors one can cite the compound (D) wherein "aromatic ring” stands for a CO-C 12 group comprising a benzene ring, such as an indane, para-cymene (6-isopropyl-toluene) or hexamethyl benzene.
  • aromatic ring stands for a CO-C 12 group comprising a benzene ring, such as an indane, para-cymene (6-isopropyl-toluene) or hexamethyl benzene.
  • triene stands for a C ⁇ -Cio hydrocarbon group comprising three non aromatic carbon-carbon double bonds, such as for example COT (cyclooctatriene).
  • the preparation of the catalyst may benefit from the presence of a base, in particular when in compound (D) E represents a halogen or a carboxylate group.
  • Said base can be defined as for the base of the hydrogenation process described herein above.
  • ruthenium precursor (D) examples include the following: [Ru("diene”)("allyl") 2 ] such as [Ru(COD)(2-methallyl) 2 ] , [Ru(COD)(allyl) 2 ],
  • the preparation of the catalyst/pre-catalyst can be carried out in a suitable solvent.
  • the solvent is preferably anhydrous, e.g. containing less that 0.1 % of water.
  • Said solvent could be the substrate of the hydrogenation processes itself or another one.
  • the same solvent as for the subsequent hydrogenation as described herein above. Typical non-limiting examples are given herein below, when describing the hydrogenation process.
  • said catalyst or pre-catalyst is a complex which can be obtained by a process comprising reacting together a complex of formula [Ru(P-N)(Arene)(Y) 2 ] or [Ru(P-N)(Arene)Y]Z with a (N-N) ligand in a manner similar to the one described in N.
  • the autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 6O 0 C. After 1 hour, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite ® 560 and analyzed by GC (DB-Wax).
  • Table a Structure of phenyl-oxazolie ligands (La-Lc) used in Table 1
  • Ph is a C O H S group.
  • Com/Base complex/base molar ratio in ppm relative to the substrate.
  • Conv. conversion (in %, analysed by GC) of acetophenone into (S)-phenylethanol after the indicated time.
  • r The (lS,2S)-l,2-diphenylethylenediamine (5,5-L) was used in this case
  • the autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 60 0 C. After 1 hour, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite ® 560 and analyzed by GC (DB-Wax). Under these conditions several diamine (Table b), as reported in Table 2, were tested. Table b : Structure of diamine ligands (Le-Lr) used
  • Ph is a C O H S group.
  • Com/Base molar ratio in ppm relative to the substrate.
  • Conv. conversion (in %, analysed by GC) of acetophenone into (S)-phenylethanol after the indicated time.
  • Example 3 Catalytic hydrogenation of acetophenone using various invention ruthenium precursors: formation in-situ, from various Ru precursor with oxazoline derivative (R-La) as (P-N) and diamine (R,R-Le) as (N-N) and optionally in the presence of a base.
  • R-La oxazoline derivative
  • R,R-Le diamine
  • the autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 60 0 C. After 30 min, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite 560 and analyzed by GC (DB -Wax). Under these conditions several ruthenium complexes were tested with or without bases (Table 3).
  • Com/Base molar ratio in ppm relative to the substrate.
  • Conv. conversion (in %, analysed by GC) of acetophenone into phenylethanol after the indicated time. Reaction conditions: H 2 gas (50 bar), 60 0 C, iPrOH (2 M). r ) When the ratio Com / Base is equal 2, it is considered that the base is consumed to achieve the conversion of the precursor into the complex/pre-catalyst of the invention, and thus the hydrogenation process is carried out in the absence of a base.
  • Catalytic hydrogenation of various substrates using various invention ruthenium precursors formation in-situ from Ru(COD)(C 4 Hy) 2 as precursor with (5)-2-[2- (diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydrooxazole (5-La) as (P-N) and several diamines (Le, Lp and Lr) as (N-N), the hydrogenation process carried out in the absence of a base, or using the preformed [RuQ 2 (2-[2-(diphenylphosphino)phenyl]-4-(l- methylethyl)-4,5-dihydrooxazole)(l,2-diphenylethylenediamine)] in presence of the base.
  • a typical experimental procedure is as follows for the base free hydrogenation: In a glove box under argon, a 5 ml screw-cap glass vial equipped with a magnetic stirring bar was charged with Ru(COD)(C 4 Hy) 2 (3.2 mg, 0.01 mmol, 0.2 mol%), (S)-La (4 mg, 0.011 mmol, 0.22 mol%), and the appropriate diamine in solution in iPrOH (ImI at 0.011 M, 0.011 mmol, 0.22 mol%). The vial was sealed with a Teflon coated screw-cap and heated in a hot plate at 60 0 C for Ih with stirring.
  • the vial was charged with the appropriate ketone or aldehyde (5 mmol), n-tridecane (0.4 mmol), and more iPrOH (ImI), then the vial was placed in a Keim autoclave
  • the autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 60 0 C. After 1 hour, the autoclave was removed from the oil bath, and cooled in an ice-water bath. The autoclave was vented and opened; an aliquot (0.05 ml) was taken from the vial, diluted with MTBE (1 ml), and analysed by GC (DB-Wax).
  • the autoclave was vented and opened; an aliquot was taken, diluted with MTBE, washed with aq. sat. NH 4 Cl, filtered over a plug of celite ® 560 and analyzed by GC (DB-Wax).
  • Com/Base molar ratio in ppm relative to the substrate.
  • Conv. conversion (in %, analysed by GC) of ketones, aldehydes and esters into alcohol after the indicated time. Reaction conditions: H 2 gas (50 bar), 60 0 C. nd: not determined ⁇ 5 min
  • Example 5 Catalytic hydrogenation of acetophenone (Ka) with various preformed complexes not part of the invention for comparison.
  • a typical experimental procedure is as follows using the preformed catalyst in presence of base:
  • Com/Base molar ratio in ppm relative to the substrate.
  • Conv. conversion (in %, analysed by GC) of ketone into alcohol after the indicated time. Reaction conditions: H 2 gas (50 bar), 50 0 C.
  • the present invention's catalysts are as effective as the catalysts of the (PP)(NN) type (see EP 0901997 and EP 1813621 for ketones) and by far more effective than the prior art complexes comprising oxazoline groups (see WO02/055195).
  • Example 6 Catalytic hydrogenation of a substrate with various complexes part of the invention.

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Abstract

The present invention relates to the field of catalytic hydrogenation and, more particularly, to the use of specific ruthenium catalysts, or pre-catalysts, in hydrogenation processes with molecular H2 for the reduction of ketones, aldehydes and esters or lactones into the corresponding alcohol or diol respectively. Said catalysts are ruthenium complexes comprising a ligand of the type (N-N) type, in which at least one of said amino groups is a secondary or primary amine (i.e. a NH or NH2) and a ligand of the type (P-N) in which N belongs to a tertiary amino group, a N, N, N' trisubstituted carboxiamide (a C(=N)N moiety) or a N-substituted imidoate (a C(=N)O moiety).

Description

HYDROGENATION OF ESTER, KETONE OR ALDEHYDE GROUPS WITH RUTHENIUM COMPLEXES HAVING A DI-AMINE AND A PHOSPHOROUS- NITROGEN BIDENTATE LIGAND
Technical field
The present invention relates to the field of catalytic hydrogenation and, more particularly, to the use of specific ruthenium catalysts, or pre-catalysts, in hydrogenation processes for the reduction of ketones, aldehydes and esters or lactones into the corresponding alcohol or diol respectively.
Prior Art
The reduction of a ketone, aldehyde or ester functional group to the corresponding alcohol is one of the fundamental reactions in organic chemistry, and is used in a large number of chemical processes. In general, two main types of processes are known to achieve such a transformation. Such types of processes are the following: a) hydride processes, in which a silyl or metal hydride salt, such as LiAlH4, or PMHS (polymethylhydrosiloxane) is used; b) hydrogenation processes, in which molecular hydrogen is used.
From a practical point of view, hydrogenation processes are more attractive as they can be run using small amounts of catalyst (typically 10 to 1000 ppm relative to the substrate) and in the presence of small quantities or even in the absence of solvent.
Furthermore, hydrogenation processes do not require the use of highly reactive and expensive hydrides, and do not produce important amounts of aqueous waste.
One of the mandatory and characterizing elements of hydrogenation processes is the catalyst or the catalytic system which is used to activate the molecular hydrogen in view of the reduction. The development of useful catalysts or catalytic systems for the hydrogenation of a ketone, aldehyde or ester functional group represents an important, difficult and unpredictable task in chemistry.
The widely used and described catalysts or catalytic systems known to perform such reductions are all based on ruthenium complexes containing a P2N2 coordination sphere; in particular of the (PP)(NN) type (see EP 0901997 and EP 1813621 for ketones and aldehydes, or more recently WO08/065588 for esters), or (PN)(PN) type (see WO02/022526 or WO02/40155 for ketones or aldehydes and WO2006/106483 or WO2006/106484 for esters).
From the examples cited herein above, one can notice that the catalysts reported always have a similar coordination sphere and there is no example where is used a different coordination sphere providing a larger choice of electronic effect on the metal centre, allowing thus a greater flexibility in the tuning of the activity of the catalyst.
Furthermore, from the examples cited herein above, one can notice that the catalysts reported used a strong base in the catalytic systems, which hampered such catalytic systems to be used with base sensitive ketones. Only two catalytic systems have been reported to avoid such a problem (see R. Noyori & al., in J. Am. Chem. Soc. 2002, 124, 6508-6509; J. Am. Chem. Soc. 2006, 128, 8724-8725 or Nagoya Industrial Science Research Institute US 6720439 and US 2007/0225528), but still the diversity is very low and moreover the first one is based on the synthesis of a non-air stable ruthenium complex and the second one showed a low reactivity. Whenever the coordination sphere of the Ru complexes reported in the prior art deviates from the above-mentioned P2N2 type, then the reported structure of the complex is totally different, i.e. having only one bidentate ligand (see, WO07/104690, Teller D.M et al in Tetrahedron Asymmetry, 2009, 550, or Miyake Y. et al in Synlett 2008, 1747, which disclose coordination sphere of the (PN)(P) type - and in the latter reference requires also a silane as co-reducing agent), or in addition the reactivity is very poor (see WO02/055195 disclosing a N4 type complex).
Therefore there is a need for hydrogenation processes using catalysts or pre- catalysts allowing a greater diversity in the ligand structure allowing additional tuning of the steric hindrance and electronic properties around the metal and moreover which are effective (yields) and can operate under base free conditions by using easily available ruthenium precursors.
Description of the invention
In order to overcome the problems aforementioned, the present invention relates to processes for the reduction by hydrogenation, using molecular H2, of a C3-C70 substrate containing a ketone, aldehyde or ester/lactone functional group into the corresponding alcohol or diol, characterized in that said process is carried out in the presence of - at least one catalyst or pre-catalyst in the form of a ruthenium complex comprising: a C2-40 diamino bidentate ligand (N-N) wherein at least one of said amino groups is a secondary or primary amine (i.e. a NH or NH2); and a C5_5o bidentate ligand comprising a coordinating phosphorous atom and a coordinating nitrogen atom belonging to a N,N,N' trisubstituted carboxiamide (i.e. a
C(=N)N moiety) or a N-substituted imidoate (i.e. a C(=N)O moiety) group (P-N ligand); and
- optionally of a base.
As well understood by a person skilled in the art, by "diamino bidentate" it is understood that said ligand coordinates the Ru metal with two nitrogen atoms. Similarly, it is understood that said (P-N) ligand coordinates the Ru metal with one phosphorous atom and one specific type of nitrogen atom, and in particular said N,N,N' trisubstituted carboxiamide or N-substituted imidoate are part of a 5,6 or 7 member ring.
Therefore in the present invention the Ru complex possesses a coordination sphere comprising two bidentate ligands which bind the Ru metal, in total, with three nitrogen atoms and one P atom.
According to a particular embodiment of the invention, the substrate can be a C3_3o compound, in particular of formula of formula (I)
O
R O^1 Rc (D \ ' n
wherein n represents 0 or 1 ;
Ra represents a hydrogen atom or a Rb group;
Rb represents a Ci-C30 hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens; or
Ra and Rb, taken together, represent a C3-C20, preferably C4-C20, saturated or unsaturated hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens. In a particular embodiment of the invention said Ra or Rb groups optionally comprise one carbonyl and/or carboxylic groups. In the case where the substrate is a ketone or aldehyde, the corresponding alcohols (i.e (II-a)), are of formula
H
I (II-a)
R a-CH-~_R b
wherein Ra and Rb are defined as in formula (I).
In the case where the substrate is an ester/lactone, the corresponding alcohols (i.e (II-b) and (II-c)), or the corresponding diol (II-d), of said substrate (I), are of formula
H
H V
/ p
/ No H
/
Ra — CH2 Rb^O R a- CH2
I
Rκ
(II-b) (II-c) <π-d) wherein Ra and Rb are defined as in formula (I).
A compound of formula (II-b or II-c) will be obtained in the case where n is 1 and Ra and Rb are not bonded together, while a compound of formula (II-d) will be obtained in the case where n is 1 and Ra and Rb are bonded together.
It is understood that said compounds (II-a) or (II-b)/(II-c)/(II-d) can be in a racemic or optically active form, depending on the nature of the substrate and on the catalyst/pre- catalyst used. According to a particular embodiment of the invention, the substrate (I) is a racemic or optically active compound. It is understood that by "... hydrocarbon group ..." it is meant that said Ra or Rb can be in the form of a linear, branched or cyclic aromatic, alkyl, alkenyl, or alkynyl group, e.g., a linear alkyl group, or can also be in the form of a mixture of said type of groups, e.g. a specific Ra may comprise a linear alkyl, a branched alkenyl (e.g. having one or more carbon-carbon double bonds), a (poly)cyclic alkyl and an aryl moiety, unless a specific limitation to only one type is mentioned. Similarly, in all the below embodiments of the invention, when a group is mentioned as being in the form of more than one type of topology (e.g. linear, cyclic or branched) and/or unsaturation (e.g. satured, unsatured or aromatic or more specifically alkyl, aromatic or alkenyl), it is meant also a group which may comprise moieties having any one of said topologies or unsaturations, as explained above. Similarly, in all the below embodiments of the invention, when a group is mentioned as being in the form of one type of unsaturation, (e.g. alkyl), it is meant that said group can be in any type of topology (e.g. linear, cyclic or branched) or having several moieties with various topologies.
According to a further embodiment of the invention, the substrate is a ketone, an aldehyde or an ester, or a lactone, that will provide an alcohol, or a diol, that is useful in the pharmaceutical, agrochemical or perfumery industry as final product or as an intermediate. Particularly preferred substrates are ketones, aldehydes, esters or lactones, that will provide an alcohol, or diol, which is useful in the perfumery industry as final product or as an intermediate.
According to another embodiment of the invention, the substrate is a C5-C20 compound of formula (I), and in particular one may cite those wherein Ra represent a hydrogen atom or a Rb group, Rb representing a linear, branched or cyclic C1-C20 hydrocarbon group optionally substituted and optionally comprising one, two or three oxygen or nitrogen atoms; or Ra and Rb, taken together, represent a C3-C20 hydrocarbon group, optionally substituted and optionally comprising one, two or three oxygen or nitrogen atoms.
According to a further embodiment of the invention, the substrate is a C5-C20 compound of formula (I), Ra represents a hydrogen atom or a Rb group, Rb representing a linear, branched or cyclic C3-C18 alkyl group, optionally substituted, or a C4-C18 alkenyl or alkynyl group, optionally substituted or a Cό-Cio aromatic group, optionally substituted; or
Ra and Rb , taken together, represent a C3-C18 hydrocarbon group, optionally substituted.
Possible substituents of Ra and Rb are one, two or three halogens, ORC, NR°2 or Rc groups, in which Rc is a hydrogen atom, a halogenated C1-C2 group or a Ci to C1O cyclic, linear or branched alkyl, or alkenyl group, preferably a Ci to C4 linear or branched alkyl or alkenyl group.
According to a further embodiment of the invention, said substituents are one, two or three halogens, ORC, or Rc groups, in which Rc is a hydrogen atom, or a Ci to Ce cyclic, linear or branched alkyl, or alkenyl group.
As mentioned above, Ra and Rb groups may comprise up to four oxygen, nitrogen or halogen atoms. In the case of oxygen, in particular, it is understood that said oxygen atoms may be also part of an additional ketone, aldehyde or ester/lactone functional group, which can also be reduced to the corresponding alcohol during the invention's process, according to the molar amount of H2 used, as well known by a person skilled in the art. According to an embodiment of the invention, the substrate possesses only one ketone, aldehyde or ester/lactone functional group, i.e. the one reduced in the invention's process.
Non-limiting examples of substrates of formula (I) are the following: C3_i4 aldehydes such as: a C3_io alkanal, a Cj-1Q 2-alkenal, a C3_io 2-methyl-2-alkenal, a Cs-1Q 2,4-dienal, a 3-alkyl- 3-benzene-prop-2-enal, a 3-alkyl-2-methyl-3-benzene-prop-2-enal, a Cγ-io-benzene- carbaldehyde, a C4-I? 2-methylen-aldehyde; wherein the underlined compounds are known to be particularly base-sensitive substrates; and
C3_i4 ketones such as: a di(Ci-i2 alkyl) ketone, a C4-C12 cyclic-ketone, a cyclopentenone alpha substituted by a Cs-r? hydrocarbon group, a cyclohexenone alpha substituted by a C6-12 hydrocarbon group, a substituted aryl Ci_i2-alkyl ketone, a C2-i2-l-alkene methyl ketone, a Cτ-12-l-alkyne methyl ketone, a 2-trimethylsilyl- 1 -ethynyl Cuio-alkyl ketone, 2-trimethylsilyl- 1 -ethynyl phenyl ketone, a 2-trimethylsilyl-l-ethvnyl C_uj9-(un)substituted aryl ketone, a Cum (un)substituted aryl chloromethyl ketone, a Ci-ι?-(un)substituted aryl chloromethyl ketone, a C4-s-heteroaryl chloromethyl ketone, C_ui?-(un)substituted aryl dichloromethyl ketone, a Cj-n-alkyl dichloromethyl ketone, a C4-s-heteroaryl dichloromethyl ketone, a Cum (un)substituted aryl trichloromethyl ketone, a Q-n-alkyl trichloromethyl ketone, a £4-5- heteroaryl trichloromethyl ketone, a Ci-i2-(un)substituted 1-indanone, a Cum (un)substituted 1-tetralone, a Ci-i2-(un)substituted 2-tetralone, a Ci-i2-(un)substituted 1- benzosuberone, a Ci-i2-(un)substituted 2-benzosuberone, a Ci-i2-(un)substituted benzofuran-3(2H)-one, a Ci-i2-(un)substituted 4-chromanone; and wherein the underlined compounds are known to be particularly base-sensitive substrates, by, "Ci_i2-(un)substituted" it is meant here a group such as an aryl (phenyl or naphthyl) which can be substituted by one or more groups which have in total between 1 and 12 carbon atoms; and C6-14 esters such as: alkyl cinnamates or sorbates, alkyl or glycolic esters of natural (fatty or not) acids, Sclareolide, spirolactones, allylic ester, di alkyl diesters, (un)substituted benzoic esters, and β-γ unsaturated esters. In particular, the substrate can be selected from the group consisting of sclareolide, C9-C15 spirolactones and C1-C4 alkyl esters of 4-methyl-6- (2,6,6-trimethyl-l-cyclohexen-l-yl)-3-hexenoic acid. One can also cite the di alkyl esters of 1 ,4-dicarboxylate-cyclohexane, the di C1-S alkyl esters of the C2-10 alkanediyl- dicarboxylates, Ci_s alkyl cyclopropanecarboxylates, mono-, di- or tri-methoxybenzoic esters.
According to a further embodiment of the invention, the substrate is a compound of formula
Figure imgf000008_0001
wherein Ra represents a hydrogen atom or a d_4 alkyl or alkenyl group; Rb represents a C5-C14 hydrocarbon group, preferably alkyl or alkenyl, optionally substituted and optionally comprising one or two oxygen or nitrogen atoms; or
Ra and Rb , taken together, represent a C4-C16, hydrocarbon group, preferably alkyl, alkenyl or alkadienyl, optionally substituted and optionally substituted and optionally comprising one or two oxygen or nitrogen atoms.
According to a particular embodiment of the invention, the compound of formula (III) is a ketone.
Possible substituents of Ra and Rb are one or two ORC, CONR°2 or Rc groups, in which Rc is a hydrogen atom or a Ci to C4 linear or branched alkyl or alkenyl group. As other possible substituents, one may also cite a group COOR0, which can also be reduced to the corresponding alcohol during the invention's process, according to the molar amount of H2 used, as well known by a person skilled in the art.
Non-limiting examples of substrates of formula (II) are the following:
• Cn-C is ketones comprising the trimethyl-cyclohexyl or trimethyl-cyclohexenyl moiety, in particular the 2,6,6 trimethyl ones; such as : Ci-C4 alkyl 2,6,6-trimethyl-4-oxo-2- cyclohexene-1-carboxylate, Ci-C4 alkyl 4,6,6-trimethyl-2-oxo-3-cyclohexene-l- carboxylate, beta ionone or irone, l-(2,2,3,6-tetramethyl-l-cyclohexyl)-l-hexen-3-one, l-(2,2,6-trimethyl-l-cyclohexyl)-l-hexen-3-one or 4-acetyl-3,5,5-trimethyl-2- cyclohexen- 1 -one ;
• C9-C16 ketones comprising the 2,2,3-trimethyl-cyclopentenyl or 2,2,3-trimethyl- cyclopentyl moiety; such as : 4,4-dimethyl-6-(2,2,3-trimethyl-3-cyclopenten-l-yl)-5- hexen-3-one or 4,4-diethyl-6-(2,2,3-trimethyl-3-cyclopenten-l-yl)-5-hexen-3-one;
• C1O-C16 ketones comprising hydronaphthalenone moiety; such as : dihydro, tetrahydro, hexahydro or perhydronaphthalenone, e.g. 3,4,4a,5,8,8a-hexahydro-2,2,6,8- tetramethyl- 1 (2H)-naphthalenone ;
• C5-C14 ketones comprising cyclopentanone , cyclohexanone, cyclopentenone or cyclohexenone moiety; such as : 2-pentyl-l -cyclopentanone, 3,3,5- trimethylcyclohexanone, 2-ethyl-4,4-dimethyl-cyclohexanone, 2-tert- butylcyclohexanone or 4-tert-butylcyclohexanone ;
• C9-C18 ketones comprising a phenyl moiety, such as : 5-(3,4-dimethylphenyl)-2,2,4,5- tetramethyl-3-hexanone , 4-phenyl-3-buten-2-one, 4-phenyl-2-butanone, l-phenyl-2- pentanone, 4-methyl-l-phenyl-2-pentanone or 2-methoxy-l -phenyl- 1-ethanone; or
• C7-C12 acyclic ketones, such as : l-octen-3-one.
In the present invention, contrary to almost all the examples in the prior art, the presence of a base is not mandatory. This is an advantage, since it allows significant increases in yields for the production of alcohols from base-sensitive substrates. Therefore, according to a particular embodiment of the invention, the substrate is a base- sensitive compound and the process is carried out in the absence of a base.
According to a particular embodiment of the invention, particularly suitable substrates as those of formula (I) wherein n is 0, i.e. aldehydes or ketones.
According to a particular embodiment of the invention, the ruthenium catalyst or pre-catalyst (also referred to from herein as complex) can be of the general formula
[Ru(P-N)(N-N)(S)2_rYr](Z)2.r (A) wherein r represents 0, 1 or 2; S represents a neutral C1-C26 monodentate ligand; (P-N) represents a ligand as defined above; (N-N) represents a ligand as defined above; and each Y represents, simultaneously or independently, a hydrogen atom, a hydroxyl, a Ci-Cio alkoxyl, a halogen atom (such as Cl, Br or I), BH4, or an C3-C15 allyl group; and each Z represents, simultaneously or independently, ClO4 ", BF4-, PF6-, SbCl6", AsCl6", SbF6", AsF6", a RdSθ3 ~ wherein Rd is a chlorine of fluoride atom or an Ci-Cs alkyl, aryl, fluoroalkyl or fluoroaryl group, or a BRe 4 " wherein Re is a phenyl group optionally substituted by one to five groups such as halide atoms and/or methyl and/or CF3 groups.
The monodentate ligands can be a C3_24 mono-phosphine, like PPh3, CO or even a solvent. By the term "solvent" it has to be understood the usual meaning in the art and in particular compounds used as diluent in the preparation of the complex or during the invention's process. Non limiting examples of such solvent are dimethylsulfoxide, acetonitrile, dimethylformamide, an alcohol (e.g. an C1-C4 alcohol), or also THF, acetone, pyridine or a C3-Cs ester or the substrate of the invention's process.
In a particular embodiment of the invention, in formula (A), each Y represents, simultaneously or independently, a hydrogen atom, a hydroxyl, a Ci to C 10 alkoxyl group, such as a methoxyl, ethoxyl or isopropoxyl group, a halogen atom (such as Cl, Br or I), BH4, or a C3-CO allyl group group, such as allyl (i.e. propenyl), 2-methyl-allyl (i.e. 2- methyl-propenyl) .
In a particular embodiment of the invention, in formula (A), each Z represents, simultaneously or independently, ClO4 ", BF4", PF6", SbCl6", AsCl6", SbF6", AsF6", a RdSO3 " wherein Rd is a chlorine of fluoride atom or a CF3 group, or a BRe 4 " wherein Re is a phenyl group optionally substituted by one, two or three groups such as halide atoms and/or methyl and/or CF3 groups.
According to a particular embodiment of the invention, there can be used as complex a compound of formula [Ru(P-N)(N-N)Y2] (A') wherein P-N, N-N and Y have the meaning indicated above.
The complexes of the invention can be added into the reaction medium of the invention's process in a large range of concentrations. As non- limiting examples, one can cite as complex concentration values those ranging from 50 ppm to 50000 ppm, relative to the amount of substrate. Preferably, the complex concentration will be comprised between 100 and 10000, or even 1000, ppm. It goes without saying that the optimum concentration of complex will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, of the temperature and on the pressure of H2 used during the process, as well as the desired time of reaction.
The hydrogenation processes of the invention may be carried out in the absence of a base, or in the absence of a significant amount of a base, or in the presence of a base. The base can be added in particular for those processes wherein neither the starting product nor the final product is sensible to a base (e.g. does not undergo isomerisation, degradation, ring opening, polymerisation reactions, etc). Said base can be the substrate itself, if the latter is basic, a corresponding alcoholate or any organic or inorganic base having preferentially a pKa above 10. According to a particular embodiment of the invention, said base may have a pKa above 14. It is also understood that preferably said base does not reduce itself a substrate of formula (I). As non-limiting examples one may cite the following types of base: Ci_s alcoholates, hydroxides, alkaline or alkaline-earth carbonates, Cio-26 phosphazenes, C1-1O amides, basic alox, siliconates (i.e. silicium derivatives having SiO" or SiRO" groups), or an inorganic hydride such as NaBH4, NaH or KH.
One can cite, as non-limiting examples, alkaline or alkaline-earth metal carbonates, such as cesium carbonate, an alkaline or alkaline-earth metal hydroxide, C1-1O amides, Cio-26 phosphazene or an alcoholate of formula (R31O)2M or R31OM', wherein M is an alkaline-earth metal, M' is an alkaline metal or an ammonium NR32 4 +, R31 stands for hydrogen or a Ci to Ce linear or branched alkyl radical and R32 stands for a Ci to C1O linear or branched alkyl radical, such as sodium or potassium alcoholates. Of course, other suitable bases can be used.
According to an embodiment of the invention, said base is an alkaline alcoholate of formula R31OM'. Useful quantities of base, added to the reaction mixture, may be comprised in a relatively large range. One can cite, as non-limiting examples, ranges between 0 to
50000 molar equivalents, relative to the complex (e.g. base/com = up to 50000), preferably 20 to 2000, and even more preferably between 50 and 1000 molar equivalents.
The hydrogenation reaction can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent current in hydrogenation reactions can be used for the purposes of the invention. Non-limiting examples include C6-1O aromatic solvents such as toluene or xylene, Cs_s hydrocarbon solvents such as hexane or cyclohexane, C3_g ethers such as tetrahydrofuran or MTBE, polar solvents such as C1-S primary or secondary alcohols such as isopropanol or ethanol, or mixtures thereof. The choice of the solvent is a function of the nature of the complex and the person skilled in the art is well able to select the solvent most convenient in each case to optimize the hydrogenation reaction.
In the hydrogenation process of the invention, the reaction can be carried out at a
H2 pressure comprised between 10 Pa and 80x10 Pa (1 to 80 bars) or even more if desired. Again, a person skilled in the art is well able to adjust the pressure as a function of the catalyst load and of the dilution of the substrate in the solvent. As examples, one can cite typical pressures of 1 to 50xl05 Pa (1 to 50 bar).
The temperature at which the hydrogenation can be carried out is comprised between -200C and 1200C. More preferably in the range of between 00C and 1000C. Of course, a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.
According to any of the embodiments of the present invention, the diamino bidentate ligand (N-N) can be a racemic or an optically active compound of formula
Figure imgf000012_0001
wherein each a, simultaneously or independently, represents 0 or 1 ; the R1, taken separately, represent, simultaneously or independently, a hydrogen atom or a C1-1O alkyl or alkenyl group optionally substituted; two R1, taken together, may form a saturated heterocycle containing 5 to 10 atoms and including the atoms to which said R1 are bonded, said heterocycle being optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci-io alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted; a R1 and an adjacent R2, taken together, may form a saturated or unsatured heterocycle containing 5 to 12 atoms and including the atoms to which said R1 and R2 are bonded, and being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; a R and an adjacent R2, taken together, may form an aromatic heterocycle containing 5 to 12 atoms and including the atoms to which said R1 and R2 are bonded, two R2, or a R2 and a R3, taken together, may form a saturated or unsaturated ring having 5 to 12 atoms and including the carbon atom to which said R or R3 groups are bonded, said ring being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; and Q represents a
- a group of formula
Figure imgf000013_0001
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-1O alkyl or alkenyl group optionally substituted, a C6-1O aromatic group optionally substituted, or an OR7 group, R7 being a C1-1O alkyl or alkenyl group; two distinct R6 and/or R5 groups, or R5 or R6 and R1 or R2, taken together, may form a C3_s, or even up to Cio, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded, and optionally containing one or two additional nitrogen, oxygen or sulfur atoms; or
- a C1O-C16 metallocenediyl, a 2,2'-diphenyl, a l,l'-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, a 4,12-[2:2]-paracyclophanediyl, a 1,6- spiro[4:4]nonanediyl, 3,4-(l-benzyl)-pyrrolidinediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6-phenoxazinediyl, 4,5-(9,9-dimethyl)-xanthenediyl, 3,3'-bipyri-4,4'-diyl or 2,2'-(l,l'-bicyclopentyl)-diyl group optionally substituted.
According to an embodiment, by "aromatic group or ring" it is preferably meant a phenyl or naphthyl group.
As mentioned above, in said ligand (B) the atoms which may coordinate the Ru atom are the two N atoms bearing the R1 groups. Therefore, it is also understood that whenever said R1, R2, R3, R5, R6 or any other group comprises heteroatoms such as N, O or S, said heteroatoms are not coordinating. Possible optional substituents of R , R2, R3, R , R or Q are one, two, three or four groups selected amongst i) halogens (in particular when said substituents are an aromatic moiety), ii) Cs-12 cycloalkyl or cycloalkenyl, iii) C1-1O alkoxy, alkyl, alkenyl, polyalkyleneglycols or halo- or perhalo-hydrocarbon, iv) COOR4 wherein R4 is a Ci_6 alkyl, or v) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, C1-S alkyl, alkoxy, amino, nitro, ester, sulfonate or halo- or perhalo-hydrocarbon groups. The Q group may also be substituted by one or two groups of formula O-(CR8 2)b-O or O-(CR8 2)b-NR4 wherein b is 1 or 2 and R8 being a hydrogen atom or a d_4 alkyl group. The expression "halo- or perhalo-hydrocarbon" has here the usual meaning in the art, e.g. a group such as CF3 or CClH2 for instance. According to a particular embodiment, said compound (B) is one wherein each a, simultaneously or independently, represents 0 or 1 ; the R1, taken separately, represent, simultaneously or independently, a hydrogen atom or a Ci_6 alkyl or alkenyl group optionally substituted; two R1, taken together, may form a saturated heterocycle containing 5 to 10 atoms and including the atoms to which said R1 are bonded, said heterocycle being optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_6 alkyl or alkenyl group optionally substituted or a phenyl group optionally substituted; a R1 and an adjacent R2, taken together, may form a saturated heterocycle containing 5 or 10 atoms and including the atoms to which said R1 and R2 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atoms; a R1 and an adjacent R2, taken together, may form an a pyridinyl group including the atoms to which said R1 and R2 are bonded, and being optionally substituted; two R2, or a R2 and a R3, taken together, may form a saturated or unsaturated ring having 5 or 6 atoms and including the atoms to which said R2 or R3 groups are bonded, said ring being optionally substituted and optionally containing one additional oxygen atoms; and Q represents a
- a group of formula
Figure imgf000014_0001
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a Ci_6 alkyl or alkenyl group optionally substituted or a phenyl group optionally substituted; two distinct R6 and/or R5 groups, or R6 or R5 and a R1 or R2, taken together, may form a
C3_6, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded and optionally containing one or two additional oxygen atoms.
Possible optional substituents of R1, R2, R3, R5, R6 or Q are one, two or three groups selected amongst i) halogens (in particular when said substituents are an aromatic moiety), ii) Cs_6 cycloalkyl or cycloalkenyl , iii) Cue alkoxy or alkyl, iv) COOR4 wherein
R4 is a Ci_4 alkyl, or v) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, d_4 alkyl, alkoxy, amino, nitro, ester or sulfonate groups. The Q group may also be substituted by one or two groups of formula O-(CR8 2)b-O, b being lor 2 and R8 being a hydrogen atom or a methyl or ethyl group group. By "halo- or perhalo-hydrocarbon" it is meant groups such as CF3 or CClH2 for instance.
According to any embodiments of the present invention, a particular embodiment of formula (B) is represented by formula
Figure imgf000015_0001
wherein a represents 0 or 1 ; and each R1, simultaneously or independently, represents a hydrogen atom or a d_4 alkyl group optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_4 alkyl group optionally substituted or a phenyl group optionally substituted; a R1 and an adjacent R , taken together, may form a saturated heterocycle containing 5 or 6 atoms and including the atoms to which said R1 and R2 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atoms; two R2, or a R2 and a R3, taken together, may form a saturated or unsaturated ring having 5 or 6 atoms and including the atoms to which said R2 or R3 groups are bonded, said ring being optionally substituted and optionally containing one additional oxygen atom; and Q represents a
- a group of formula
Figure imgf000016_0001
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct
R6 and/or R5 groups, or R6 or R5 and a R1 or R2, taken together, may form a C3_6, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded and optionally containing one or two additional oxygen atoms. Alternatively, according to any embodiments of the present invention, a particular embodiment of formula (B) is represented by formula
Figure imgf000016_0002
wherein a represents 0 or 1 ; and
RVepresents a hydrogen atom or a C1-4 alkyl group optionally substituted; R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a CM alkyl group optionally substituted or a phenyl group optionally substituted; R and R2, or R2 and R3, taken together, may form a saturated cycle containing 5 or 6 atoms and including the atoms to which said R1, R2, R3 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atom; and each R9 represents a hydrogen atom, a Ci_6 alkyl group or a substituted or unsubstituted phenyl or benzyl group optionally substituted; two R9 or, R6 and a R9, taken together, may form a saturated or unsaturated or aromatic, preferably saturated, ring comprising 5 or 6 atoms; and Q represents a
- a group of formula
Figure imgf000017_0001
wherein m is 1 or 2, and R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct R6 and/or R5 groups, or R5 and a R1 or R2, taken together, may form a C3_6, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded and optionally containing one or two additional oxygen atoms.
Possible optional substituents of R1, R2, R3, R5, R6, R9 or Q of formulae (B') or (B") are as defined above, or more specifically are one or two i) halogens (in particular when said substituents are an aromatic moiety), ii) Ci_s alkyl or alkoxy groups, iii) COOR4 wherein R4 is a CM alkyl, or iv) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, Q-4 alkyl or alkoxy groups, esters or sulfonate groups.
Non-limiting examples of said optionally substituted pyridyl group of formula (B") or (B) are: a such as a 2-pyridyl, 2-quinolinyl or a methyl-2-pyridinyl.
For the sake of clarity, and as mentioned above, in any one of the embodiment of the present invention, whenever two groups of formula (B) are taken together to form a cycle or ring, said cycle or ring can be a mono, bi or tri-cyclic group.
According to any one of the above-mentioned embodiments of the invention, said Q can be a group of formula (i) wherein m is 1 or 2, R5 is a hydrogen atom and R6 is as defined above. According to any one of the above-mentioned embodiments, at least one coordinating amino group of the N-N ligand is a primary amino group (i.e. NH2) or in other words in formula (B), (B') or (B") one, two or three R1 represent a hydrogen atom.
According to any one of the above-mentioned embodiments, the N-N ligand is of formula (B'), and preferably the two R1 represent a hydrogen atom.
As non limiting examples of N-N ligands, one can cite the one in the following scheme: Scheme A
Figure imgf000018_0001
said compounds being in an optically active form or in a racemic form, if applicable.
According to any of the embodiments of the present invention, the bidentate ligand (P-N) can be a racemic or an optically active compound of formula
Figure imgf000018_0002
wherein d is 1 or 0, U is an oxygen atom or a NR14 group, R14 being a CM alkyl group; R11 and R12, when taken separately, represent, simultaneously or independently, a Ci_s alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted; or the R and R 2 bounded to the same phosphorous atom, when taken together, may form a saturated or unsaturated ring optionally substituted, having 4 to 8 atoms and including the phosphorous atom to which said R11 and R12 groups are bonded; X' represents an unsaturated group of formula
Figure imgf000019_0001
(a') (b') wherein d" is 0 if the dotted line indicates a double bond or d" is 1 if the dotted line indicates a single bond; each R9 represents a hydrogen atom, a C1-1O alkyl group optionally substituted or a phenyl group optionally substituted; two R9 , taken together, may form a saturated, unsaturated or aromatic ring comprising 5 or 6 atoms; and
V is an oxygen atom or a NR17 group, R17 a C1-1O alkyl group or a C1-1O hydrocarbon group comprising an acyl, carbamate or sulfonate functional group (P-N ligand); and Q' represents:
- a group of formula
Figure imgf000019_0002
wherein m' is 1, 2, 3 or 4 and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-1O alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted, or an OR7 group, R7 being a C1-1O alkyl or alkenyl group; two distinct R6 and/or R5 groups, or a R6 and a R11 or R13 groups, or a R6 and a R9 in formula (b), taken together, may form a C3-8, or even up to C1O, saturated or unsaturated ring optionally substituted, including the atoms to which said R , R , R9 , R11, R13 groups are bonded, and optionally containing one additional nitrogen or oxygen atom; or a R6 and R14, taken together, may form a C3-8 saturated, unsaturated or aromatic ring optionally substituted, including the atoms to which said R6 , R14 groups are bonded; or
- a C10-C16 metallocenediyl, a 2,2'-diphenyl, a l,l'-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, a 4,12-[2:2]-paracyclophanediyl, a 1,6- spiro[4:4]nonanediyl, 3,4-(l-benzyl)-pyrrolidinediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6-phenoxazinediyl, 4,5-(9,9-dimethyl)-xanthenediyl, 3,3'-bipyri-4,4'-diyl, a l-benzofuran-2,3-diyl, a 2-ylomethylphenyl or 2,2'-(l,l'-bicyclopentyl)-diyl group optionally substituted.
As mentioned above, according to a particular embodiment of the invention, by "aromatic group or ring" for (P-N) it is also preferably meant a phenyl or naphthyl derivative. As mentioned above, in said ligand (C) the atoms which may coordinate the Ru atom are the P atom of the PR11R12 group and the N atom of the X group. Therefore, it is also understood that whenever said R5 , R6 , R11, R12, Q' or any other group comprises heteroatoms such as N or O, said heteroatoms are not coordinating.
Possible optional substituents of R5 , R6 , R9 , R11 and R12 are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) C1-1O alkyl alkenyl, alkoxy, polyalkyleneglycols groups or halo- or perhalo-hydrocarbon, amine or quaternary amine groups, ii) COORh wherein Rh is a Ci_6 alkyl group, iii) Cs_i2 cycloalkyl or cycloalkenyl groups, iv) NO2 group, or v) benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups optionally substituted by one, two or three halogens, nitro, Ci_s alkyl, alkoxy, amino, ester, sulfonate or halo- or perhalo-hydrocarbon groups. By "halo- or perhalo-hydrocarbon" it is meant groups such as CF3 or CClH2 for instance. The Q' group may be also substituted by one or two groups of formula 0-(CR8' 2)b>-0 or O-(CR8 2)b>-NR4> wherein b' is 1 or 2, R4> being a Ci_4 alkyl group and R8 being a hydrogen atom or a C 1-4 alkyl group. Possible optional substituents of R13 are one or two groups selected amongst C1-1O alkoxy or alkyl groups, or one or two phenyl groups optionally substituted by one, two or three halogens, nitro or Ci-Cs alkyl, alkoxy, amino, acyl, sulfonate, or ester groups, or one or two benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups.
For the sake of clarity, and as mentioned above, in any one of the embodiments of the present invention, whenever two groups of formula (C) are taken together to form a cycle or ring, said cycle or ring can be a mono or bi-cyclic group.
In a particular embodiment of formula (C), P-N is a bidentate ligand wherein, d is 0; R and R 2 represent, simultaneously or independently, a Ci_6 alkyl group optionally substituted, a phenyl or naphthyl group optionally substituted; or the R11 and R12 bounded to the same phosphorous atom, taken together, form a saturated or unsaturated ring optionally substituted, having 4 to 7 atoms and including the phosphorous atom to which said R11 and R12 groups are bonded; X' represents an unsaturated group of formula
Figure imgf000021_0001
wherein each R9 represents a hydrogen atom, a Cue alkyl group optionally substituted or a phenyl group optionally substituted; two R9 , taken together, may form a saturated, unsaturated or comprising 5 or 6 atoms; and
V is an oxygen atom (P-N ligand); such as a 2-oxazolidinyl or 8,8a-dihydro-3aH- indeno[l,2-d][l,3]oxazol-2-yl; and Q' represents: - a group of formula
Figure imgf000021_0002
wherein m' is 1, 2, 3 or 4 and R and R represent, simultaneously or independently, a hydrogen atom, a Ci_6 alkyl or alkenyl group optionally substituted or a phenyl or naphthyl group optionally substituted; two distinct R6 and/or R5 groups, or a R6 and a R11 or R13 groups, or a R6 and a R9 in formula (b), taken together, may form a C3-O saturated or unsaturated ring optionally substituted, including the atoms to which said R6 , R5 ,
R9 , R11, R13 groups are bonded, and optionally containing one additional nitrogen or oxygen atoms; or a R and R 4, taken together, may form a C3-6 saturated, unsaturated or aromatic ring optionally substituted, including the atoms to which said R6 , R14 groups are bonded; or - a C1O-C12 metallocenediyl, a 2,2'-diphenyl, a l,l'-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, l-benzofuran-2,3-diyl, a 2-ylomethylphenyl, a 4,12- [2:2]-paracyclophanediyl, a l,6-spiro[4:4]nonanediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6-phenoxazinediyl, 4,5-(9,9-dimethyl)-xanthenediyl group optionally substituted. Possible optional substituents of R5 , R6 , R9 , R11 and R12 are one to five halogens
(in particular when said substituents are an aromatic moiety), or one, two or three i) Ci_6 alkyl alkenyl, alkoxy, polyalkyleneglycols groups or halo- or perhalo-hydrocarbon, amine or quaternary amine groups, ii) COORh wherein Rh is a Ci_6 alkyl group, iii) Cs_s cycloalkyl or cycloalkenyl groups, iv) NO2 group, or v) benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups optionally substituted by one, two or three halogens, nitro groups or Ci_6 alkyl, alkoxy, amino, ester, sulfonate or halo- or perhalo-hydrocarbon groups. By "halo- or perhalo-hydrocarbon" it is meant groups such as CF3 or CClH2 for instance. The Q' group may be also substituted by one or two groups of formula O-(CR8' 2)b-O or O-(CR8' 2)b-NR4> wherein b' is 1 or 2, R4> being a C i_4 alkyl group and R8 being a hydrogen atom or a C 1-4 alkyl group.
Possible optional substituents of R13 are one or two groups selected amongst Ci_6 alkoxy or alkyl groups, or one or two phenyl groups optionally substituted by one, two or three halogen, nitro or Ci_6 alkyl, alkoxy, amino, acyl, sulfonate, or ester groups, or one or two benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups.
According to any embodiment of the invention, for this P-N ligands, Q' may represent a linear C1-Cs alkanediyl radical optionally substituted, a 2,2'-diphenyl, a 1,1'- (bis(naphthyl)-2,2'-diyl, a 1 ,2-benzenediyl, a 2-ylomethylphenyl or a 1,8- or 1,2- naphthalenediyl group optionally substituted.
Furthermore, in all the above embodiments, a particularly appreciated mode of realization is the one where said R11 and R12 groups are aromatic groups optionally substituted.
According to any embodiment of the invention, X' represents a group (a') or (a").
According to a particular embodiment of the invention, said P-N ligand is of formula
Figure imgf000023_0001
wherein R11 and R12 represent, simultaneously or independently, a phenyl group optionally substituted; and
Q' represents a C1-C2 alkanediyl radical optionally substituted, a 2,2'-diphenyl, a l,l'-(bis(naphthyl)-2,2'-diyl, a 2-ylomethylphenyl, a 1 ,2-benzenediyl or a 1,8- naphthalenediyl group optionally substituted; and each R represents, simultaneously or independently, a hydrogen atom, a Ci-6 alkyl group optionally substituted or a phenyl group optionally substituted; two R18, when taken together, may form a fused indane or tetraline group optionally substituted and including the carbon atoms to which said R18 groups are bonded.
Possible substituents of R11, R12 and Q' are as described above.
Possible optional substituents of R are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) CM alkyl, alkenyl or alkoxy groups , ii) COORh wherein Rh is a C 1-4 alkyl group, iii) C5-6 cycloalkyl or cycloalkenyl groups, iv) NO2 or Ci_6 alkyl, alkoxy, amino, ester or sulfonate groups or v) benzyl or phenyl groups. As non limiting examples of P-N ligands of formula (C) or (C), one can cite the one in the following scheme: Scheme B
Figure imgf000024_0001
said compounds being in an optically active form or in a racemic form, if applicable.
According to a particular embodiment of the invention, said P-N ligand is of formula
Figure imgf000025_0001
(C")
wherein R11 and R12 represent, simultaneously or independently, a phenyl group optionally substituted; and
Q' represents a CpC2 alkanediyl radical optionally substituted, a 2,2'-diphenyl, a l,l'-(bis(naphthyl)-2,2'-diyl, a 2-ylomethylphenyl, a 1 ,2-benzenediyl or a 1,8- naphthalenediyl group optionally substituted; and each R19, taken separately, represents simultaneously or independently, a hydrogen atom, a Ci to Ce alkyl group optionally substituted or a phenyl group optionally substituted. Possible optional substituents of R11, R12 and Q' are as described above for formula (C).
Possible optional substituents of R 1 1i9y are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) d_4 alkyl, alkenyl or alkoxy groups , ii) COORh wherein Rh is a d_4 alkyl group, iii) Cs_6 cycloalkyl or cycloalkenyl groups, iv) NO2 or Ci_6 alkyl, alkoxy, amino, ester or sulfonate groups or v) benzyl or phenyl groups.
As non limiting examples of P-N ligands of formula, (C) or (C"), one can cite the one in the following scheme:
Figure imgf000025_0002
said compounds being in an optically active form or in a racemic form, if applicable. The ligands (B) or (C) described above can be obtained by applying standard general methods which are well known in the state of the art and by the person skilled in the art. Many of said ligands N-N or P-N are even commercially available.
The complexes of formula (A) or (A'), as described above, as well as those wherein Y and/or Z is also a Ci-C8 acyloxyl or a halogen atom (such as Cl, Br or I), which are precursors (as below described) of said complexes (A) or (A'), are new compounds and are therefore another object of the present invention.
The complex (A) of the invention can be used in the form of a preformed complex or can be generated in situ, in the reaction medium of the hydrogenation. In any case, according to a particular embodiment of the invention, the catalyst or pre-catalyst is obtained or obtainable by a process comprising reacting together: 1) a ruthenium precursor of formula
[Ru("diene")(L)vE2-y] (D) wherein v represents 0, 1 or 2;
E represents a mono anion;
"diene" represents a linear or branched C4-C15 hydrocarbon group comprising two carbon-carbon double bonds, optionally substituted, or a cyclic C7-C20 hydrocarbon group comprising two carbon-carbon double bonds, optionally substituted; and
L represents a C3-C15 allyl, a CO-C 12 aromatic ring optionally substituted or a C7-C15 triene; T) with a C2-40 diamino bidentate ligand (N-N), defined as above, and a Cs_5o bidentate ligand (P-N), defined as above; and 3) optionally a base, in an amount comprised between approximately 0.5 and 15 molar equivalent relative to the ruthenium metal.
Optional substituent of the "diene" or of L are one or two C1-C10 alkyl or aryl groups, Ci-C6 alkoxy groups or -C(O)O-(Ci-C6 alkyl) groups.
It is understood that "allyl" possesses the usual meaning in the art, i.e. a group comprising a fragment C=C-C , or C=C-C. Similarly, it is understood that "triene" possesses the usual meaning in the art, i.e. a group comprising three non aromatic carbon- carbon double bonds.
According to a particular embodiment of the invention, E represents a mono anion selected amongst the group consisting of halides (e.g. Cl, Br, I,), BF4", Cl(V, PF6", SbCl6", AsCl6", SbF6", AsF6", hydroxylate, Ci-Ci0 carboxylates (e.g. acetate, trifluoroacetate, proprionate, 2-Et-hexanoate), a C5-C10 1,3-diketonate, R1SOs" wherein R1 is a chlorine of fluoride atom or a Ci-Cs alkyl, aryl, fluoroalkyl or fluoroaryl group, or BRJ 4 " wherein RJ is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF3 groups.
As non-limiting examples of suitable ruthenium precursors, one can cite the compound (D) wherein "diene" stands for a C7-C10, hydrocarbon group comprising two carbon-carbon double bonds, such as for example COD (cycloocta-l,5-diene) or NBD (norbornadiene) , or yet cyclohepta- 1 ,4-diene .
As non-limiting examples of suitable ruthenium precursors, one can cite the compound (D) wherein "allyl" stands for a C3-Ci0, or even C3-CO, hydrocarbon group comprising a fragment C=C-C , or C=C-C, such as for example allyl or 2-methyl-allyl (see, for instance, J. Powell et al., in J. Chem. Soc, (A), 1968, 159; M.O. Albers et al., Inorganic Synth., 1989, 26, 249 ; R.R. Schrock et al., J. Chem. Soc. Dalton Trans., 1974, 951).
As non-limiting examples of suitable ruthenium precursors, one can cite the compound (D) wherein "aromatic ring" stands for a CO-C 12 group comprising a benzene ring, such as an indane, para-cymene (6-isopropyl-toluene) or hexamethyl benzene. As non-limiting examples of suitable ruthenium precursors, one can cite the compound (D) wherein "triene" stands for a Cγ-Cio hydrocarbon group comprising three non aromatic carbon-carbon double bonds, such as for example COT (cyclooctatriene).
The preparation of the catalyst may benefit from the presence of a base, in particular when in compound (D) E represents a halogen or a carboxylate group. Said base can be defined as for the base of the hydrogenation process described herein above.
As specific, but non limiting, examples of said ruthenium precursor (D), one may cite the following: [Ru("diene")("allyl")2] such as [Ru(COD)(2-methallyl)2] , [Ru(COD)(allyl)2],
[Ru(NBD)(2-methallyl)2] or [Ru(NBD)(allyl)2]; [Ru("diene")E2] such as [Ru(COD)(Cl)2] or [Ru(NBD)(Cl)2]; [Ru("diene")("triene")] such as [Ru(COD)(COT)]; or [Ru("diene") ("arene")] such as [Ru(COD)(C6H6)], [Ru(C6H6)(cyclohexadiene)] , [Ru(COD)(C8H8)], [Ru(COD)(1, 4-C6H4Me2)] or [Ru(COD)(1, 3,5-C6H3Me3)].
The preparation of the catalyst/pre-catalyst can be carried out in a suitable solvent. As a person skilled in the art is well aware, the solvent is preferably anhydrous, e.g. containing less that 0.1 % of water. Said solvent could be the substrate of the hydrogenation processes itself or another one. Typically there is used the same solvent as for the subsequent hydrogenation as described herein above. Typical non-limiting examples are given herein below, when describing the hydrogenation process.
A typical example of such procedure to prepare the invention's catalysts is provided in the examples.
Alternatively, said catalyst or pre-catalyst is a complex which can be obtained by a process comprising reacting together a complex of formula [Ru(P-N)(Arene)(Y)2] or [Ru(P-N)(Arene)Y]Z with a (N-N) ligand in a manner similar to the one described in N.
B. Johnson, I. C. Lennon, P. H. Moran, J. A. Ramsden, Ace. Chem. Res. 2007, 40, 1291- 1299. Although in said reference the complexes prepared are of different formulae, the experimental procedure can be applied to prepare the invention's complexes. Typical examples for the synthesis of complexes of formula [Ru(P-N)(Arene)(Y)2] is D. Carmona,
C. Vega, N. Garcia, F. J. Lahoz, S. Elipe, L. A. Oro, M. P. Lamata, F. Viguri R. Borao, Organometallics 2006, 25, 1592-1606. It is also possible to react together a complex of formula [Ru(N-N)(Arene)(Y)2] or
[Ru(N-N)(Arene)Y]Z with a ligand P-N. A typical example for the synthesis of complex of formula [Ru(N-N)(Arene)(Y)2] is provided in M. D. Jones, F. A. Almeida Paz, J. E. Davies, R. Raja, J. Klinowski, B. F. G. Johnson, Inorg. Chimica Acta 2004, 357, 1247- 1255.
Examples
The invention will now be described in further detail by way of the following examples, wherein the temperatures are indicated in degrees centigrade and the abbreviations have the usual meaning in the art. All the procedures described hereafter have been carried out under an inert atmosphere unless stated otherwise. Hydrogenations were carried out in a stainless steel autoclave without glass liner. H2 gas (99.99990%) was used as received. All substrates and solvents were distilled from appropriate drying agents under argon. NMR spectra were recorded on a Bruker AM-400 (1H at 400.1 MHz, 13C at 100.6 MHz, and 31P at 161.9 MHz) spectrometer and normally measured at 300 K, in CDCI3 unless indicated otherwise. Chemical shifts are listed in ppm.
Example 1
Catalytic hydrogenation of acetophenone using various invention ruthenium complexes: formation in-situ, from Ru(COD)(C4Hy)2 as Ru precoursor with several oxazoline derivatives as (P-N) and (li?,2i?)-l,2-diphenylethylenediamine) (R,R-Le) as (N- N), the hydrogenation process was carried out in the absence of a base
A typical experimental procedure is as follows :
In a glove box under argon, a solution of acetophenone (2.404 g, 20 mmol) and
«-tridecane (187.8 mg, 1 mmol) in /PrOH (2 ml) were added, followed by more /PrOH (2x1 ml), to a Keim autoclave equipped with a magnetic stirring bar and containing RU(COD)(C4HT)2 (6.4 mg, 0.02 mmol, 0.1 mol%), the phosphine-oxazoline La (8.2 mg, 0.02 mmol, 0.1 mol%), (l#,2#)-l,2-diphenylethylenediamine (R,R-Le) (4.7 mg, 0.02 mmol, 0.1 mol%) and /PrOH (6 ml). The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 6O0C. After 1 hour, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite® 560 and analyzed by GC (DB-Wax).
Under these conditions several phosphine-oxazoline (Table a), as reported in Table 1, were tested.
Table a : Structure of phenyl-oxazolie ligands (La-Lc) used in Table 1
Figure imgf000029_0001
Figure imgf000030_0001
wherein Ph is a COHS group.
Table 1 : Hydrogenation of acetophenone into (S)-phenylethanol
Figure imgf000030_0002
Com/Base: complex/base molar ratio in ppm relative to the substrate. Conv. = conversion (in %, analysed by GC) of acetophenone into (S)-phenylethanol after the indicated time. r) The (lS,2S)-l,2-diphenylethylenediamine (5,5-L) was used in this case
2) The (i?)-phenylethanol was formed in this case
3) The ruthenium complex, the phosphine-oxazoline and the diamine were heated (600C) in iPrOH (2 ml) under argon for 1 hour prior to the hydrogenation reaction The reaction was performed on 5 mmol of acetophenone
5) The BH3 adduct of the phosphine was used here
Example 2
Catalytic hydrogenation of acetophenone using various invention ruthenium complexes: formation in-situ, from Ru(COD)(C4Hy)2 as precursor with (i?)-2-[2- (diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydrooxazole as (R-La) (P-N) and several diamines (Le-Lr) as (N-N), the hydrogenation process carried out in the absence of a base
A typical experimental procedure is as follows:
In a glove box under argon, a solution of acetophenone (2.415 g, 20 mmol) and
«-tridecane (179.1 mg, 1 mmol) in /PrOH (2 ml) were added, followed by more /PrOH (2x1 ml), to a Keim autoclave equipped with a magnetic stirring bar and containing Ru(COD)(C4H7)2 (6.4 mg, 0.02 mmol, 0.1 mol%), the phosphine-oxazoline La (8.4 mg, 0.02 mmol, 0.1 mol%), (li?,2i?)-l,2-bis(2,4,6-trimethylphenyl)ethylenediamine (6.3 mg, 0.02 mmol, 0.1 mol%) and /PrOH (6 ml). The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 600C. After 1 hour, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite® 560 and analyzed by GC (DB-Wax). Under these conditions several diamine (Table b), as reported in Table 2, were tested. Table b : Structure of diamine ligands (Le-Lr) used
Figure imgf000032_0001
wherein Ph is a COHS group.
Table 2 : Hydrogenation of acetophenone into (5)-phenylethanol
Figure imgf000032_0002
Figure imgf000033_0001
Com/Base: molar ratio in ppm relative to the substrate.
Conv. = conversion (in %, analysed by GC) of acetophenone into (S)-phenylethanol after the indicated time.
^ The (S)-2-[2-(diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydroxazole oxazoline was used here. 2) The (i?)-phenylethanol was formed in this case.
Example 3 Catalytic hydrogenation of acetophenone using various invention ruthenium precursors: formation in-situ, from various Ru precursor with oxazoline derivative (R-La) as (P-N) and diamine (R,R-Le) as (N-N) and optionally in the presence of a base. A typical experimental procedure is as follows:
In a glove box under argon, a solution of acetophenone (2.407 g, 20 mmol) and «-tridecane (188.6 mg, 1 mmol) in /PrOH (2 ml) were added, followed by more /PrOH (2x1 ml), to a Keim autoclave equipped with a magnetic stirring bar and containing [RuCl2(COD)In (5.6 mg, 0.02 mmol, 0.1 mol%), (#)-2-[2-(diphenylphosphino)phenyl]-4- (l-methylethyl)-4,5-dihydrooxazole (7.7 mg, 0.02 mmol, 0.1 mol%), {\R,2R)-l,2- diphenylethylenediamine (4.4 mg, 0.02 mmol, 0.1 mol%), potassium tørt-butylate (4.5 mg, 0.04 mmol, 0.2 mol%) and /PrOH (6 ml). The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 600C. After 30 min, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot (0.4 ml) was taken, diluted with MTBE (5 ml), filtered over a plug of celite 560 and analyzed by GC (DB -Wax). Under these conditions several ruthenium complexes were tested with or without bases (Table 3).
Table 3 : Hydrogenation of acetophenone into (S)-phenylethanol
Figure imgf000034_0001
Figure imgf000035_0001
Com/Base: molar ratio in ppm relative to the substrate.
Conv. = conversion (in %, analysed by GC) of acetophenone into phenylethanol after the indicated time. Reaction conditions: H2 gas (50 bar), 600C, iPrOH (2 M). r) When the ratio Com / Base is equal 2, it is considered that the base is consumed to achieve the conversion of the precursor into the complex/pre-catalyst of the invention, and thus the hydrogenation process is carried out in the absence of a base.
2) The diamine was omitted in this case and the reaction was performed with 0.2 mol% of (i?)-2-[2-(diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydrooxazole.
3) The (i?)-phenylethanol was formed in this case.
4) The phosphine-oxazoline was omitted in this case and the reaction was performed with 0.2 mol% of (li?,2i?)-l,2-diphenylethylenediamine.
5) The ruthenium complex, the phosphine-oxazoline and the diamine were heated (600C) in iPrOH (2 ml) under argon for 1 hour prior to the hydrogenation reaction.
6) The ruthenium complex and the phosphine-oxazoline were heated (600C) in iPrOH (2 ml) under argon for 1 hour prior to the hydrogenation reaction.
7) The ruthenium complex and the diamine were heated (600C) in 1PrOH (2 ml) under argon for 1 hour prior to the hydrogenation reaction.
As can be seen from Table 3, when instead of the claimed complexes (comprising both ligands (N-N) and (P.N)) are used other complexes (e.g. comprising only ligands (N-N) or (P.N)), the yield is strongly decreased and in the vast majority of the cases also the e.e. of the alcohol produced is strongly decreased. This is well shown, for instance, by comparing entry 2) (invention complex) with entry 4) or 5) (not invention complex), or by comparing entry 6) (invention complex) with entry 10) or 11) (not invention complex).
Example 4
Catalytic hydrogenation of various substrates using various invention ruthenium precursors: formation in-situ from Ru(COD)(C4Hy)2 as precursor with (5)-2-[2- (diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydrooxazole (5-La) as (P-N) and several diamines (Le, Lp and Lr) as (N-N), the hydrogenation process carried out in the absence of a base, or using the preformed [RuQ2(2-[2-(diphenylphosphino)phenyl]-4-(l- methylethyl)-4,5-dihydrooxazole)(l,2-diphenylethylenediamine)] in presence of the base.
A typical experimental procedure is as follows for the base free hydrogenation: In a glove box under argon, a 5 ml screw-cap glass vial equipped with a magnetic stirring bar was charged with Ru(COD)(C4Hy)2 (3.2 mg, 0.01 mmol, 0.2 mol%), (S)-La (4 mg, 0.011 mmol, 0.22 mol%), and the appropriate diamine in solution in iPrOH (ImI at 0.011 M, 0.011 mmol, 0.22 mol%). The vial was sealed with a Teflon coated screw-cap and heated in a hot plate at 600C for Ih with stirring. Then under argon in a glove box, the vial was charged with the appropriate ketone or aldehyde (5 mmol), n-tridecane (0.4 mmol), and more iPrOH (ImI), then the vial was placed in a Keim autoclave The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 600C. After 1 hour, the autoclave was removed from the oil bath, and cooled in an ice-water bath. The autoclave was vented and opened; an aliquot (0.05 ml) was taken from the vial, diluted with MTBE (1 ml), and analysed by GC (DB-Wax).
Synthesis of [RuCl2((R)-2-[2-(diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5- dihydrooxazole)((lR, 2R)-l,2-diphenylethylenediamine)]
A solution of ((i?)-2-[2-(diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5- dihydrooxazole) (59.7 mg, 0.16 mmol) and [RuQ2(pαra-cymene)]2 (49 mg, 0.08 mmol) in a mixture Of CH2Cl2 (0.8 niL) and EtOH (6.5 mL) was heated at 500C (oil bath) for Ih. Then, at room temperature, the solvent were removed in-vacuo and (\R,2R)-\,2- diphenylethylenediamine) (34.9 mg, 0.16 mmol) followed by THF (5 mL) were added. The following solution was then heated at 600C (oil bath) for 16h to give a dark purple solution. The solvent was removed in-vacuo to give a purple solid, which was triturated with hexane (5 mL), filtered and washed with more hexane (5 mL) and dried in-vacuo. The title complex was then obtained as a dark purple solid (75.6 mg, 63%). 31P{ 1H)-NMR (CD2Cl2, 162 MHz): δ = 63.8 ppm (singlet). A typical experimental procedure is as follows using the preformed catalyst in presence of base:
In a glove box under argon, the appropriate ketones or esters (5 mmol), «-tridecane (0.4 mmol) and the appropriate solvent (2 ml) were added to a glass vial equipped with a magnetic stirring bar and charged with the RuCl2(La)(Le) (0.05-0.2 mol%) and a base (0.5-5 mol%), then the vial was placed in a Keim autoclave. The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 600C. After the appropriate time, the autoclave was removed from the oil bath, and cooled in a cold-water bath. The autoclave was vented and opened; an aliquot was taken, diluted with MTBE, washed with aq. sat. NH4Cl, filtered over a plug of celite® 560 and analyzed by GC (DB-Wax).
Under these conditions several ketones (Table c), aldehydes (Table d) and esters (Table e) as reported in Table 5, were tested in presence of various diamine (Table b).
Table c : Structure of ketones (Ka-Kf) used
Figure imgf000037_0001
Table d : Structure of aldehydes (Aa-Ad) used
Structure Structure Structure Structure
Figure imgf000038_0001
Aa Ab Ac Ad
Table e : Structure of esters (Ea-Ae) used
Figure imgf000038_0002
Table 5 : Hydrogenation of various ketones, aldehydes and esters into their corresponding alcohols
Figure imgf000038_0003
Figure imgf000039_0001
Figure imgf000040_0001
Com/Base: molar ratio in ppm relative to the substrate.
Conv. = conversion (in %, analysed by GC) of ketones, aldehydes and esters into alcohol after the indicated time. Reaction conditions: H2 gas (50 bar), 600C. nd: not determined υ 5 min
2) The reactions were run in THF.
Example 5 Catalytic hydrogenation of acetophenone (Ka) with various preformed complexes not part of the invention for comparison.
A typical experimental procedure is as follows using the preformed catalyst in presence of base:
In a glove box under argon, acetophenone (5 mmol), «-tridecane (0.4 mmol) and /PrOH (2 ml) were added to a glass vial equipped with a magnetic stirring bar and charged with the appropriate preformed ruthenium complex (0.05 mol%) and KO^Bu base (2.5 mol%), then the vial was placed in a Keim autoclave. The autoclave was pressurized with hydrogen gas at 50 bar and placed in a thermostated oil bath set at 500C. After 15 min, the autoclave was removed from the oil bath, and cooled in an ice-water bath. The autoclave was vented and opened; an aliquot (0.1 ml) was taken, diluted with MTBE (2 ml), washed with aq. sat. NH4Cl (3 ml), filtered over a plug of celite® 560 and analysed by GC
(DB-Wax).
Under these conditions the following complexes were tested (Table T): Table f: Structure of the preformed complexes (Ca-Cb) used
Figure imgf000041_0001
Table 6 : Hydrogenation of acetophenone into 1-phenyl-ethanol with complexes Ca-Cd
Figure imgf000041_0002
Com/Base: molar ratio in ppm relative to the substrate.
Conv. = conversion (in %, analysed by GC) of ketone into alcohol after the indicated time. Reaction conditions: H2 gas (50 bar), 500C.
As can be seen from Table 6, despite the presence of an oxazoline group, the present invention's catalysts are as effective as the catalysts of the (PP)(NN) type (see EP 0901997 and EP 1813621 for ketones) and by far more effective than the prior art complexes comprising oxazoline groups (see WO02/055195).
Example 6 Catalytic hydrogenation of a substrate with various complexes part of the invention.
Using the same general procedures above, acetophenone or the substrates above are reduced with similar yields in an invention's process comprising catalysts wherein ligands (P-N) and/or (N-N) are the ones described in Scheme A, B or C.

Claims

Claims
1. A process for the reduction by hydrogenation, using molecular H2, of a C3-C70 substrate containing a ketone, aldehyde or ester/lactone functional group into the corresponding alcohol or diol, characterized in that said process is carried out in the presence of
- at least one catalyst or pre-catalyst in the form of a ruthenium complex comprising: a C2-40 diamino bidentate ligand (N-N) wherein at least one of said amino groups is a secondary or primary amine (i.e. a NH or NH2); and a C5_5o bidentate ligand comprising a coordinating phosphorous atom and a coordinating nitrogen atom belonging to a N,N,N' trisubstituted carboxiamide (a C(=N)N moiety) or a N-substituted imidoate (a C(=N)O moiety) group (P-N ligand); and
- optionally of a base.
2. A process according to claim 1, characterised in that said ruthenium complex is of formula
[Ru(P-N)(N-N)(S)2_rYr](Z)2.r (A) wherein r represents 0, 1 or 2;
S represents a neutral C1-C26 monodentate ligand;
(P-N) represents a ligand as defined in claim 1 ;
(N-N) represents a ligand as defined in claim 1 ; and each Y represents, simultaneously or independently, a hydrogen atom, a hydroxyl, a Ci-Cio alkoxyl, a halogen atom, BH4, or an C3-C15 allyl group; and each Z represents, simultaneously or independently, Cl(V, BF4-, PF6-, SbCl6-, AsCl6-,
SbF6-, AsF6-, a RdSθ3 ~ wherein Rd is a chlorine of fluoride atom or an Ci-Cs alkyl, aryl, fluoroalkyl or fluoroaryl group, or a BRe 4 " wherein Re is a phenyl group optionally substituted by one to five halide atoms and/or methyl and/or CF3 groups.
3. A process according to claim 1 or 2, characterised in that said ligand (N-N) is of formula
Figure imgf000043_0001
wherein each a, simultaneously or independently, represents 0 or 1 ; the R1, taken separately, represent, simultaneously or independently, a hydrogen atom or a Ci-io alkyl or alkenyl group optionally substituted; two R1, taken together, may form a saturated heterocycle containing 5 to 10 atoms and including the atoms to which said R1 are bonded, said heterocycle being optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci-io alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted; a R1 and an adjacent R2, taken together, may form a saturated or unsatured heterocycle containing 5 to 12 atoms and including the atoms to which said R1 and R2 are bonded, and being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; a R1 and an adjacent R2, taken together, may form an aromatic heterocycle containing 5 to 12 atoms and including the atoms to which said R1 and R2 are bonded; two R2, or a R2 and a R3, taken together, may form a saturated or unsaturated ring having 5 to 12 atoms and including the carbon atom to which said R2 or R3 groups are bonded, said ring being optionally substituted and optionally containing one additional nitrogen, oxygen or sulfur atom; and Q represents a - a group of formula
Figure imgf000043_0002
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-1O alkyl or alkenyl group optionally substituted, a C6-1O aromatic group optionally substituted, or an OR7 group, R7 being a C1-1Q alkyl or alkenyl group; two distinct R and/or R groups, or R or R and R or R2, taken together, may form a C3_s, or even up to Cio, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded, and optionally containing one or two additional nitrogen, oxygen or sulfur atoms; or - a C1O-C16 metallocenediyl, a 2,2'-diphenyl, a l,l '-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, a 4,12-[2:2]-paracyclophanediyl, a 1,6- spiro[4:4]nonanediyl, 3,4-(l-benzyl)-pyrrolidinediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6-phenoxazinediyl, 4,5-(9,9-dimethyl)-xanthenediyl, 3,3'-bipyri-4,4'-diyl or 2,2'-(l,l '-bicyclopentyl)-diyl group optionally substituted; and the substituents of said R1, R2, R3, R5, R6 or Q are one, two, three or four groups selected amongst i) halogens, ii) Cs_i2 cycloalkyl or cycloalkenyl, iii) C1-1O alkoxy, alkyl, alkenyl, polyalkyleneglycols or halo- or perhalo-hydrocarbon, iv) COOR4 wherein R4 is a Ci_6 alkyl, or v) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, Ci_s alkyl, alkoxy, amino, nitro, ester, sulfonate or halo- or perhalo-hydrocarbon groups; said Q group may also be substituted by one or two groups of formula O-(CR8 2)b-O or O-(CR8 2)b-NR4 wherein b is 1 or 2 and R8 being a hydrogen atom or a d_4 alkyl group.
4. A process according to claim 3, characterised in that ligand (N-N) is of formula
R2 R2
I a R3 I
H H
wherein a represents 0 or 1 ; and each R1, simultaneously or independently, represents a hydrogen atom or a d_4 alkyl group optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_4 alkyl group optionally substituted or a phenyl group optionally substituted; a R1 and an adjacent R , taken together, may form a saturated heterocycle containing 5 or 6 atoms and including the atoms to which said R1 and R2 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atoms; two R2, or a R2 and a R3, taken together, may form a saturated or unsaturated ring having 5 or 6 atoms and including the atoms to which said R2 or R3 groups are bonded, said ring being optionally substituted and optionally containing one additional oxygen atom; and Q represents a
- a group of formula
Figure imgf000045_0001
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a C1-4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct
R6 and/or R5 groups, or R6 or R5 and a R1 or R2, taken together, may form a C3_6, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded and optionally containing one or two additional oxygen atoms; or is of formula
Figure imgf000045_0002
wherein a represents 0 or 1 ; and RVepresents a hydrogen atom or a C1-4 alkyl group optionally substituted;
R2 and R3, taken separately, represent, simultaneously or independently, a hydrogen atom, a Ci_4 alkyl group optionally substituted or a phenyl group optionally substituted; R1 and R2, or R2 and R3, taken together, may form a saturated cycle containing 5 or 6 atoms and including the atoms to which said R1, R2, R3 are bonded, and being optionally substituted and optionally containing one additional nitrogen or oxygen atom; and each R9 represents a hydrogen atom, a Ci_6 alkyl group or a substituted or unsubstituted phenyl or benzyl group optionally substituted; two R9 or, R6 and a R9, taken together, may form a saturated or unsaturated or aromatic ring comprising 5 or 6 atoms; and Q represents a
- a group of formula
Figure imgf000046_0001
wherein m is 1 or 2, and
R5 and R6 represent, simultaneously or independently, a hydrogen atom, a Ci_4 alkyl group optionally substituted or a phenyl group optionally substituted; two distinct R6 and/or R5 groups, or R5 and a R1 or R2, taken together, may form a C3_6, saturated or unsaturated ring optionally substituted, including the atoms to which said R6, R5, R1, R2 groups are bonded and optionally containing one or two additional oxygen atoms; and the substituents of R1, R2, R3, R5, R6, R9 or Q of formulae (B') or (B") are one or two i) halogens (in particular when said substituents are an aromatic moiety), ii) Ci_s alkyl or alkoxy groups, iii) COOR4 wherein R4 is a d_4 alkyl, or iv) benzyl, phenyl, indanyl, fused benzene or fused indane groups optionally substituted by one, two or three halogens, C 1-4 alkyl or alkoxy groups, esters or sulfonate groups.
5. A process according to claim 3 or 4, characterised in that said R1 are all hydrogen atoms.
6. A process according to any one of claims 1 or 5, characterised in that said ligand (P-N) is of formula
Figure imgf000046_0002
wherein d is 1 or 0, U is an oxygen atom or a NR14 group, R14 being a d_4 alkyl group; R and R 2, when taken separately, represent, simultaneously or independently, a Ci_s alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted; or the R11 and R12 bounded to the same phosphorous atom, when taken together, may form a saturated or unsaturated ring optionally substituted, having 4 to 8 atoms and including the phosphorous atom to which said R11 and R12 groups are bonded;
X' represents an unsaturated group of formula
Figure imgf000047_0001
(a') (b1) wherein d" is 0 if the dotted line indicates a double bond or d" is 1 if the dotted line indicates a single bond; each R9 represents a hydrogen atom, a C1-1O alkyl group optionally substituted or a phenyl group optionally substituted; two R9 , taken together, may form a saturated, unsaturated or aromatic ring comprising 5 or 6 atoms; and
V is an oxygen atom or a NR17 group, R17 a C1-1O alkyl group or a C1-1O hydrocarbon group comprising an acyl, carbamate or sulfonate functional group; and Q' represents: - a group of formula
Figure imgf000047_0002
wherein m' is 1, 2, 3 or 4 and
R and R represent, simultaneously or independently, a hydrogen atom, a C1-1O alkyl or alkenyl group optionally substituted or a C6-1O aromatic group optionally substituted, or an OR7 group, R7 being a C1-1O alkyl or alkenyl group; two distinct R6 and/or R5 groups, or a R6 and a R11 or R13 groups, or a R6 and a R9 in formula (b), taken together, may form a C3_s, or even up to C1O, saturated or unsaturated ring optionally substituted, including the atoms to which said R6 , R5 , R9 , R11, R13 groups are bonded, and optionally containing one additional nitrogen or oxygen atom ; or a R6 and R14, taken together, may form a C3-8 saturated, unsaturated or aromatic ring optionally substituted, including the atoms to which said R6 , R14 groups are bonded; or
- a C1O-C16 metallocenediyl, a 2,2'-diphenyl, a l,l '-binaphthalene-2,2'-diyl, a benzenediyl, a naphthalenediyl, a 4,12-[2:2]-paracyclophanediyl, a 1,6- spiro[4:4]nonanediyl, 3,4-(l-benzyl)-pyrrolidinediyl, 2,3-bicyclo [2:2:1 ]hept-5- enediyl, 4,6-phenoxazinediyl, 4,5-(9,9-dimethyl)-xanthenediyl, 3,3'-bipyri-4,4'-diyl, l-benzofuran-2,3-diyl, a 2-ylomethylphenyl, or 2,2'-(l,l '-bicyclopentyl)-diyl group optionally substituted; the substituents of R5 , R6 , R9 , R11 and R12 are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) C1-1O alkyl alkenyl, alkoxy, polyalkyleneglycols groups or halo- or perhalo-hydrocarbon, amine or quaternary amine groups, ii) COORh wherein Rh is a Ci_6 alkyl group, iii) Cs_i2 cycloalkyl or cycloalkenyl groups, iv) NO2 group, or v) benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups optionally substituted by one, two or three halogens, nitro, Ci_s alkyl, alkoxy, amino, ester, sulfonate or halo- or perhalo- hydrocarbon groups; said Q' group may be also substituted by one or two groups of formula O-(CR8' 2)b'-O or O-(CR8 2)b'-NR4> wherein b' is 1 or 2, R4> being a Ci_4 alkyl group and R8 being a hydrogen atom or a Ci_4 alkyl group; and the substituents of R13 are one or two groups selected amongst C1-1O alkoxy or alkyl groups, or one or two phenyl groups optionally substituted by one, two or three halogen, nitro or Ci-Cs alkyl, alkoxy, amino, acyl, sulfonate, or ester groups, or one or two benzyl, phenyl, indanyl, fused benzene, fused indane, fused tetraline or fused naphthalene groups.
7. A process according to claim 6, characterised in that said ligand (P-N) is of formula
Figure imgf000049_0001
wherein R11 and R12 represent, simultaneously or independently, a phenyl group optionally substituted; and Q' represents a C1-C2 alkanediyl radical optionally substituted, a 2,2'-diphenyl, a l,l '-(bis(naphthyl)-2,2'-diyl, a 2-ylomethylphenyl, a 1 ,2-benzenediyl or a 1,8- naphthalenediyl group optionally substituted; and each R18 represents, simultaneously or independently, a hydrogen atom, a Q-6 alkyl group optionally substituted or a phenyl group optionally substituted; two R , when taken together, may form a fused indane or tetraline group optionally substituted and including the carbon atoms to which said R18 groups are bonded; or each R19, taken separately, represents simultaneously or independently, a hydrogen atom, a Ci to Ce alkyl group optionally substituted or a phenyl group optionally substituted ; the substituents of R 8 or R 9 are one to five halogens (in particular when said substituents are an aromatic moiety), or one, two or three i) Ci_4 alkyl, alkenyl or alkoxy groups , ii) COORh wherein Rh is a CM alkyl group, iii) Cs_6 cycloalkyl or cycloalkenyl groups, iv) NO2 or Ci_6 alkyl, alkoxy, amino, ester or sulfonate groups or v) benzyl or phenyl groups.
8. A process according to any one of claims 1 to 7, characterised in that the substrate is of formula
O
> b (I)
«■
wherein n represents 0 or 1 ; Ra represents a hydrogen atom or a Rb group; R represents a C1-C30 hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens; or
Ra and Rb, taken together, represent a C3-C20, preferably C4-C20, saturated or unsaturated hydrocarbon group, optionally substituted and optionally comprising one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen or halogens; and the substituents of Ra and R are one, two or three halogens, ORC, NR°2 or Rc groups, in which Rc is a hydrogen atom, a halogenated Ci-C2 group or a Ci to Ci0 cyclic, linear or branched alkyl, or alkenyl group, or a group COOR0.
9. A process according to claim 8, characterised in that the substrate is of formula
Figure imgf000050_0001
wherein Ra represents a hydrogen atom or a C 1-4 alkyl or alkenyl group;
R represents a C5-C14 hydrocarbon group, preferably alkyl or alkenyl, optionally substituted and optionally comprising one or two oxygen or nitrogen atoms; or Ra and Rb , taken together, represent a C4-C16, hydrocarbon group, preferably alkyl, alkenyl or alkadienyl, optionally substituted and optionally substituted and optionally comprising one or two oxygen or nitrogen atoms; and the substituents of Ra and Rb are one or two OR0, C0NR°2 or Rc groups, in which Rc is a hydrogen atom or a Ci to C4 linear or branched alkyl or alkenyl group, or a group COOR0.
10. A process according to claim 8, characterised in that the substrate is selected amongst :
• the C11-C18 ketones comprising the trimethyl-cyclohexyl or trimethyl-cyclohexenyl moiety, in particular the 2,6,6 trimethyl ones;
• the C9-C16 ketones comprising the 2,2,3-trimethyl-cyclopentenyl or 2,2,3-trimethyl- cyclopentyl moiety;
• the Cio-C i6 ketones comprising hydronaphthalenone moiety; • the C5-C14 ketones comprising cyclopentanone , cyclohexanone, cyclopentenone or cyclohexenone moiety;
• the C9-C18 ketones comprising a phenyl moiety; or
• the C7-C12 acyclic ketones.
11. A ruthenium complex of formula
[Ru(P-N)(N-N)(S)2_rYr](Z)2_r (A) wherein r represents 0, 1 or 2;
S represents a neutral C1-C26 monodentate ligand;
(P-N) represents a ligand as defined in claim 1 ;
(N-N) represents a ligand as defined in claim 1 ; and each Y represents, simultaneously or independently, a hydrogen atom, a hydroxyl, a Ci-Cio alkoxyl, a halogen atom, BH4, or an C3-C15 allyl group; and each Z represents, simultaneously or independently, Cl(V, BF4", PF6", SbCl6", AsCl6",
SbF6", AsF6", a R SO3" wherein R is a chlorine of fluoride atom or an Ci-Cs alkyl, aryl, fluoroalkyl or fluoroaryl group, or a BRe 4 " wherein Re is a phenyl group optionally substituted by one to five halide atoms and/or methyl and/or CF3 groups.
12. A ruthenium complex according to claim 10, characterised in that it is of formula
[Ru(P-N)(N-N)Y2] (A')
wherein Y has the same meaning as in claim 11 , (P-N) is a ligand as defined in claim 6 or 7; and (N-N) is a ligand as defined in any one of claims 3 to 5.
PCT/IB2009/055368 2008-11-28 2009-11-26 Hydrogenation of ester, ketone or aldehyde groups with ruthenium complexes having a di-amine and a phosphorous-nitrogen bidentate ligand WO2010061350A1 (en)

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