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  • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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  • C07F9/28—Phosphorus compounds with one or more P—C bonds
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  • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/32—Addition reactions to C=C or C-C triple bonds
  • B01J2231/321—Hydroformylation, metalformylation, carbonylation or hydroaminomethylation
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  • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
  • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
  • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
  • B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
  • B01J2231/4227—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group with Y= Cl
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  • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
  • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
  • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
  • B01J2231/4266—Sonogashira-type, i.e. RY + HC-CR' triple bonds, in which R=aryl, alkenyl, alkyl and R'=H, alkyl or aryl
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  • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
  • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
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  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
  • B01J2531/82—Metals of the platinum group
  • B01J2531/824—Palladium

Definitions

• the present invention relates to new phosphine ligands, to their preparation and to their use in catalytic reactions, especially organic coupling reactions employing aryl, heteroaryl or vinyl halides and pseudohalides as educts.
• Suitable reactants for the coupling reactions are aryl, heteroaryl and vinyl halides, triflates, and other pseudohalides.
• the coupling reactions are catalyzed by transition metal compounds, typically palladium or nickel compounds.
• Palladium catalysts are generally advantageous in terms of the breadth of applicability of coupling substrates and in some cases the catalyst activity, while nickel catalysts have advantages in the area of the conversion of chloroaromatics and vinyl chlorides and the price of the metal.
• Palladium and nickel catalysts used to activate the aryl, heteroaryl and vinyl halides/pseudohalides are palladium ( II ) and/or nickel (II) as well as palladium(O) and/or nickel (0) complexes, although it is known that palladium (0) /nickel (0) compounds are the actual reaction catalysts.
• palladium (0) /nickel (0) compounds are the actual reaction catalysts.
• coordinatively unsaturated 14-electron and 16-electron palladium ( 0 ) /nickel ( 0 ) complexes stabilized with donor ligands such as phosphines are formulated as active species.
• the iodides are the most reactive ones. It is even possible to use palladium or nickel compounds that are not stabilized by a phosphine or a similar donor ligand when iodides are employed as educts in coupling reactions.
• aryl and vinyl iodides are very expensive starting compounds and moreover produce stoichiometric amounts of iodine salt waste.
• the remaining educts, i.e. the aryl, heteroaryl and vinyl bromides, chlorides, triflates and other pseudohalides require the use of stabilizing and activating ligands in order to become effective in catalytic production.
• transition metal catalyst complexes are recognized to be influenced by both the characteristics of the metal and those of the ligands associated with the metal atom. For example, structural features of the ligands can influence reaction rate, regioselectivity, and stereoselectivity.
• Trialkylphosphines with bulky substituents are highly useful ligands for transition metal complexes, especially palladium complexes, as catalysts in various types of coupling reactions.
• the main reasons for the favorable catalytic properties of trialkylphosphine palladium complexes are the electron-richness and the steric bulk of trialkylphosphine ligands, which favor the formation of low coordinate and highly active Pd complexes also observed with N-heterocyclic carbenes as Pd ligands in cross-coupling reactions.
• Prominent examples of phosphines are PCy3, P (tert.
• One object of the present invention is to provide new phosphines preferably exhibiting crucial properties for good ligands such as electron-richness and efficient -donation as perfectly met in trialkylphosphines, but lacking the disadvantages of the trialkylphosphines, i.e. they should have a variable ligand backbone.
• the new phosphines should be useful as ligands in new catalyst systems that possess greater substrate flexibility, e.g., the ability to utilize cost-effective organic chlorides as educts, and are suitable for a great variety of industrial scale reactions, preferably coupling reactions, that produce the desired products in high yield, with high catalytic productivity, and/or with high purity.
• R' and R" independently are selected from alkyl, cycloalkyl and 2-furyl radicals, or R' and R" are joined together to form with the phosphorous atom a carbon-phosphorous monocycle comprising at least 3 carbon atoms or a carbon- phosphorous bicycle; the alkyl radicals, cycloalkyl radicals, and carbon-phosphorous monocycle being unsubstituted or substituted by at least one radical selected from the group of alkyl, cycloalkyl, aryl, alkoxy, and aryloxy radicals;
• Cp s is a partially substituted or completely substituted cyclopentadien-1-yl group, including substitutions resulting in a fused ring system, and wherein a substitution at the 1- position of the cyclopentadien-1-yl group is mandatory when the cyclopentadien-1-yl group is not part of a fused ring system or is part of an indenyl group; and Y ⁇ represents an anion; excluding a phosphine compound represented by formula (A)
• the present invention is also directed to a coordination compound comprising (i) a phosphine compound represented by the general formula (1) wherein R', R", and Cp s are defined as above, and (ii) a transition metal selected from groups 8, 9, 10 and 11 of the Periodic Table of the Elements.
• a further aspect of the present invention is the use of said coordination compound as a catalyst or a part of a catalyst system for the preparation of an organic compound.
• Yet another aspect of the present invention is the use of a phosphine compound represented by the general formula (1) or a corresponding phosphonium salt represented by the general formula (Ia) wherein R', R", Cp s and Y ⁇ are defined as above, in combination with a transition metal compound as a catalyst or a part of a catalyst system for the preparation of an organic compound wherein the transition metal is selected from groups 8, 9, 10, and 11 of the Periodic Table of the Elements.
• the present invention is further directed to process for the preparation of said phosphine compound comprising the steps of: deprotonating a compound according to the formula HCp s by the use of a strong base and reacting the resulting anion with a phosphinous halide according to the formula R'R"PX to form the phosphine compound R'R"PCp ⁇ , wherein Cp ⁇ , R' and R" are defined as above and X is Cl or Br.
• the present invention is also directed to an alternative process for the preparation of said phosphine compound comprising the steps of: deprotonating a compound according to the formula HCp ⁇ by the use of a strong base and reacting the resulting anion with a phosphonous dihalide according to the formula R'PX2 to form the phosphinous halide according to the formula Cp s R'PX, and alkylating the phosphinous halide with an appropriate organometallic alkylation agent to introduce the R" group and to form the phosphine compound R'R"PCp s , wherein Cp ⁇ , R' and R" are defined as above and X is Cl or Br.
• the Cp s group is a monocycle (i.e. a cyclopentadienyl group) or a multicycle (e.g. an indenyl group when one benzene ring is fused to the cyclopentadienyl group or a fluorenyl group when two benzene rings are fused to the cyclopentadienyl group) .
• Phosphine compounds comprising an unsubstituted cyclopentadienyl group or an unsubstituted indenyl group as one substituent as well as transition metal complexes comprising those phosphines as ligands are known from the literature (Kolodyazhnyi, O. I., "Reaction of phosphorylated phosphorus ( III ) carbon acids with carbon tetrahalides” in Zhurnal Obshchei Khimii (1980), 50(8), 1885-6; Kolodyazhnyi, O. I., "Reaction of sterically hindered phosphines with carbon tetrahalides” in Zhurnal Obshchei Khimii (1981),
• metallocene type coordination compounds e.g. a ferrocene type coordination compound, wherein one or two cyclopentadienyl dialkyl or diarylphosphine ligands are bound to the metal atom, e.g.
• the cyclopentadienyl dialkyl or diaryl phosphine ligands formally are aromatic anions; hence, the electronic structure of those compounds is completely different to that in a coordination compound according to the present invention .
• a phosphine compound according to formula (A) above comprising a pentamethylcyclopentadienyl group as one substituent is also known from the prior art (Jutzi, Peter; Saleske, Hartmut; Nadler, Doris, "The synthesis of thermally stable pentamethylcyclopentadienyl-substituted phosphorus compounds” in Journal of Organometallic Chemistry (1976), 118(1), C8-C10; and Jutzi, Peter; Saleske, Hartmut, "Synthesis and dynamic behavior of pentamethylcyclopentadienylphosphines" in Chemische Berichte (1984), 117(1), 222-33).
• phosphine ligand in transition metal complexes nor its use in catalytic reactions has been mentioned.
• Another group of known compounds comprising a pentamethylcyclopentadienyl-substituted phosphorous atom are P-pentamethy1cyclopentadienyl-substituted lH-phosphirenes that are employed as ligands in tungsten complexes
• phosphine compounds according to the present invention can be used as ligands in transition metal complexes that may function as highly efficient catalysts.
• R' and R" may independently be selected from alkyl, preferably Ci to Cis alkyl, more preferably Ci to C 5 alkyl, most preferably C3 to C 5 alkyl; cycloalkyl, preferably C 5 to C12 cycloalkyl, more preferably C 5 to Cio cycloalkyl, most preferably C6 to Cs cycloalkyl; and 2-furyl.
• the alkyl radicals may be branched or unbranched.
• Preferred alkyl radicals are selected from isopropyl, n-butyl, t-butyl, and neopentyl . Most preferred is isopropyl.
• the cycloalkyl radicals may be monocyclic or multicyclic, such as adamantyl and norbornyl .
• Preferred cycloalkyl radicals are cyclohexyl and adamantly.
• R' and R" represent the same radicals, more preferably both are isopropyl or cyclohexyl. All the foregoing radicals represented by R' and R" are unsubstituted or may be substituted by at least one radical selected from the group of alkyl, cycloalkyl, aryl, alkoxy, and aryloxy radicals. Preferably, the radicals represented by R' and R" are unsubstituted.
• R' and R" are joined together to form with the phosphorous atom a carbon-phosphorous monocycle comprising at least 3 carbon atoms or a carbon- phosphorous bicycle.
• the carbon-phosphorous monocycle is typically unsubstituted, but may also be substituted by at least one radical selected from the group of alkyl, cycloalkyl, aryl, alkoxy, and aryloxy radicals.
• R' and R" are joined together to form a [3.3.1]- or [4.2.1] phobyl radical with the phosphorous atom as depicted below.
• Cp s in formulae (1) and (Ia) is a monocycle, i.e. a partially substituted or completely substituted cyclopentadien-1-yl group.
• the phosphine compound and its corresponding phosphonium salt according to this embodiment are represented by formulae (2] and (2a) :
• R is selected from the group consisting of aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, heteroatom-containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the cyclopentadienyl group, all the foregoing radicals being unsubstituted or substituted by further carbon and/or heteroatoms; and organosilyl radicals;
• R 1 , R 2 , R 3 , and R 4 independently are selected from the group consisting of hydrogen; aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, heteroatom- containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the cyclopentadienyl group, all the foregoing radicals being unsubstituted or substituted by further carbon and/or heteroatoms; halogens; and heteroatom- containing groups .
• aliphatic radicals include alkyl, alkenyl, and alkynyl radicals; the radicals may be branched or unbranched.
• Heteroaliphatic radicals include alkyl, alkenyl, and alkynyl radicals additionally comprising at least one heteroatom, e.g. oxygen or sulfur, within their backbone or as linking atom; the radicals may be branched or unbranched.
• Alicyclic radicals include cycloalkyl, cycloalkenyl, and cycloalkynyl radicals; the term "alicyclic" also encompasses multicyclic systems.
• Aromatic radicals include monocyclic and multicyclic systems.
• Heterocyclic radicals include alicyclic radicals containing at least one heteroatom within the ring structure and aromatic radicals containing at least one heteroatom within the ring structure.
• "Unsubstituted” means substituted by only hydrogen atoms.
• "Substituted by further carbon atoms” means that at least one further carbon atom is bonded to the radical.
• Said carbon atom may be part of a hydrocarbyl group, e.g. aliphatic radicals may be substituted by aromatic radicals forming aralkyl radicals, and vice versa aromatic radicals may be substituted by aliphatic radicals forming alkylaryl radicals.
• Said carbon atom may also be part of a group comprising heteroatom (s) , e.g.
• heteroatom-containing group is any group that comprises at least one heteroatom, including groups that impart functionality and/or water-solubility to the molecule.
• heteroatom-containing groups are -SO 3 H, -OSO 2 Ph, -CN, -PO 3 H 2 , -OP(O)Ph 2 , -NO 2 , organosilyl, e.g. - SiMe 3 and SiPhMe 2 .
• R is preferably selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, alkenyl, alkynyl, alkoxy, and alkylsilyl radicals that are unsubstituted or substituted by further carbon and/or heteroatoms. More preferably, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-octadecyl, benzyl, and phenyl radicals that are unsubstituted or substituted, preferably unsubstituted. Even more preferably, R is an unbranched alkyl radical or a benzyl radical. Most preferably R is a methyl or ethyl radical with methyl being even more preferred .
• R 1 , R 2 , R 3 , and R 4 are preferably independently selected from the group consisting of hydrogen; alkyl, cycloalkyl, aryl, and alkoxy radicals that are unsubstituted or substituted; halogens; and heteroatom-containing groups. More preferably, R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, a methyl radical, a methoxy radical, and -SO 3 H. Even more preferably, R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen and methyl radicals. Most preferably R 1 , R 2 , R 3 , and R 4 are each a methyl radical.
• cyclopentadienyl-substituted phosphine compounds according to formulae (2) and (2a) are compounds wherein the radicals R, R', R", R 1 , R 2 , R 3 , and R 4 are defined as in the following table:
• cyclopentadienyl-substituted phosphine compounds according to formulae (2) and (2a) are those wherein R, R 1 , R 2 , R 3 , and R 4 are each a methyl radical.
• Examples of these pentamethylcycopentadienyl-substituted phosphine compounds are :
• Cp s in formulae (1) and (Ia) is a bicycle, i. e. a partially substituted or completely substituted ind- 2-en-l-yl or ind-2-en-2-yl group, preferably a partially substituted or completely substituted ind-2-en-l-yl group. More preferably, the phosphine compound and its corresponding phosphonium salt according to this embodiment are represented by formulae (3) and (3a) :
• R is selected from the group consisting of aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, and aromatic, alicyclic, and heteroatom-containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the indenyl group, all the foregoing radicals being unsubstituted or substituted by further carbon or heteroatoms; and organosilyl radicals;
• R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 independently are selected from the group consisting of hydrogen; aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, heteroatom-containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the indenyl group, all the foregoing radicals being unsubstituted or substituted by further carbon and/or heteroatoms; halogens; and heteroatom- containing groups .
• R is preferably selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, alkenyl, alkynyl, alkoxy, and alkylsilyl radicals that are unsubstituted or substituted by further carbon and/or heteroatoms. More preferably, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-octadecyl, benzyl, and phenyl radicals that are unsubstituted or substituted, preferably unsubstituted. Even more preferably, R is an unbranched alkyl radical or a benzyl radical. Most preferably R is a methyl or ethyl radical with methyl being even more preferred .
• R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are preferably independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and alkoxy radicals that are unsubstituted or substituted; halogens, and heteroatom-containing groups. More preferably, R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen, a methyl radical, a methoxy radical, and -SO 3 H. Most preferably, R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen, a methyl radical, and a methoxy radical.
• indenyl-substituted phosphine compounds according to formulae (3) and (3a) are compounds wherein the radicals R, R', R", R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are defined as in the following table:
• R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, a methyl radical and a methoxy radical.
• R 7 , R 8 , R 9 and R 10 are either each hydrogen or R 8 and R 9 are each hydrogen and R 7 and R 10 are non-hydrogen radicals.
• Examples of this embodiment of indenyl-substituted phosphine compounds are:
• Cp s in formulae (1) and (Ia) is a tricycle, i. e. an unsubstituted, partially substituted or completely substituted fluoren-9-yl group, including substitutions resulting in an enlarged fused ring system.
• the phosphine compound and its corresponding phosphonium salt according to this embodiment are represented by formulae (4) and (4a) :
• R is selected from the group consisting of hydrogen; aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, and heteroatom-containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the fluorenyl group, all the foregoing radicals being unsubstituted or substituted by further carbon and/or heteroatoms; and organosilyl radicals;
• R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 independently are selected from the group consisting of hydrogen; aliphatic, heteroaliphatic, aromatic, alicyclic, heterocyclic radicals, heteroatom-containing radicals comprising an aromatic, alicyclic, or heterocyclic radical and an additional heteroatom linking the aromatic, alicyclic, or heterocyclic radical atom with the carbon atom of the fluorenyl group, all the foregoing radicals being unsubstituted or substituted by further carbon and/or heteroatoms; halogens, and heteroatom-containing groups.
• R is preferably selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, alkenyl, alkynyl, alkoxy, and alkylsilyl radicals that are unsubstituted or substituted by further carbon and/or heteroatoms. More preferably, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-octadecyl, benzyl, and phenyl radicals that are unsubstituted or substituted, preferably unsubstituted. Even more preferably, R is an unbranched alkyl radical or a benzyl radical. Most preferably R is a methyl or ethyl radical with ethyl being even more preferred .
• R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are preferably independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and alkoxy radicals that are unsubstituted or substituted; halogens, and heteroatom-containing groups. More preferably, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently selected from the group consisting of hydrogen, a methyl radical, a methoxy radical, and -SO3H.
• R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently selected from the group consisting of hydrogen, a methyl radical, and a methoxy radical. Still more preferably, R 14 and R 15 are each hydrogen and R 11 , R 12 , R 13 , R 16 , R 17 , and R 18 are independently selected from hydrogen and methyl radicals. Still more preferably R 13 , R 14 , R 15 , and R 16 are each hydrogen. Most preferably R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R are each hydrogen.
• R 12 and/or R 17 in formulae (4) or (4a) are a halogen or a heteroatom- containing group, preferably both are Br or one of them is -
• R 17 and R ,18 are each hydrogen.
• fluorenyl-substituted phosphine compounds according to formulae (4) and (4a) are compounds wherein the radicals R, R', R", R 11 R 12 R 13 R 14 R 15 R 16
• R 17 , and R 18 are def ined as in the fol lowing table :
• the bromine radicals (e.g. in phosphine compound no. 31) allow an easy introduction of additional functional groups.
• Y ⁇ represents an anion, preferably a non-coordinating, non-basic anion such as BF 4 " .
• a general route for the preparation of the new phosphine compounds is as follows: A compound according to the formula HCp s having the desired substitutions, typically a substituted cyclopentadiene, a substituted indene, or an unsubstituted or substituted fluorene, is first reacted with a strong base, typically n-BuLi, to abstract a proton and a resonance stabilized carbanion is formed.
• a strong base typically n-BuLi
• phosphinous halide according to the formula R'R"PX, wherein R' and R" are defined as above and X is Cl or Br, preferably Cl, to result in the respective Cp s - substituted phosphine which is conveniently converted into the respective phosphonium salts for easier storage and handling (e.g. by reacting with HBF 4 ) .
• This method is advantageously used to prepare phosphine compounds wherein R' and R' ' in formulae (1) or (Ia) are the same radicals as the corresponding phosphinous halides are easily available.
• a cyclopentadienyl-, indenyl- or fluorenyl-substituted phosphine compound it is required in some cases to prepare first a cyclopentadienyl-, indenyl- or fluorenyl-substituted phosphine compound and then perform the appropriate reactions to result in the desired substitutions at the Cp s ring system.
• An example is the preparation of a sulfonated fluorenyl-substituted phosphine wherein a fluorenyl- substituted phosphonium salt is reacted with sulfuric acid to introduce an -SO3 group at the fluorenyl radical.
• R' and R" radicals are different and the corresponding phosphinous halide R'R"PX is not readily available.
• a compound according to the formula HCp s having the desired substitutions typically a substituted cyclopentadiene, a substituted indene, or an unsubstituted or substituted fluorene, is first reacted with a strong base, typically n-BuLi, to abstract a proton and a resonance stabilized carbanion is formed.
• a strong base typically n-BuLi
• R'PX2 a phosphonous dihalide according to the formula R'PX2 wherein R' is defined as above and X is Cl or Br, preferably Cl, to result in the phosphinous halide according to the formula Cp ⁇ R'PX as intermediate product.
• Cp ⁇ R'PX can easily be converted to the desired phosphine R'R"PCp s by simple alkylation with an appropriate organometallic reagent, such as R 11 MgX or R"Li wherein R" is a defined above.
• One aspect of the present invention is a coordination compound comprising a phosphine compound as described before (including phosphine compounds according to formulae (A) and (B)) and a transition metal selected from groups 8, 9, 10, and 11 of the Periodic Table of the Elements.
• Said coordination compounds are effective catalysts or effective parts of catalyst systems for organic synthesis.
• Said coordination compounds can either be prepared in advance and then used for catalytic reactions or can be formed in situ by adding the phosphine compound or its corresponding phosphonium salt in combination with an appropriate transition metal precursor compound.
• another aspect of the present invention is the use the phosphine compound (including phosphine compounds according to formulae (A) and (B) ) or its corresponding phosphonium salt (including phosphonium salts according to formulae (Aa) and (Ba) ) in combination with a transition metal compound as a catalyst or a part of a catalyst system for the preparation of an organic compound, wherein the transition metal is selected from groups 8, 9, 10, and 11 of the Periodic Table of the Elements.
• the in situ formation of the catalytically active coordination compound comprising the phosphine compound according to the invention as ligand is often more convenient; however it may also be advantageous to prepare the catalytically active coordination compound comprising the phosphine compound according to the invention as ligand directly and then use it for catalytic applications as this increases the initial catalytic activity in some instances. If it is referred to the "present catalyst” or “catalyst according to the invention” both alternative routes are included.
• the transition metal is preferably selected from Pd, Ni, Pt, Rh, Ir, Ru, Co, Fe, Cu, and Au, more preferably it is Pd or Ni and most preferably it is Pd.
• palladium compounds that can be used together with the phosphine compounds according to the invention in order to form in situ the catalytically active coordination compound comprising the phosphine compound as a ligand are palladium (II) acetate, palladium (II) chloride, palladium (II) bromide, sodium tetrachloropalladate (II), palladium (II) acetylacetonate, palladium (0) dibenzylidenacetone complexes, palladium(O) tetrakis (triphenylphosphine) , palladium(O) bis (tri-o-tolylphosphine) , palladium (II) propionate, palladium (II) (cyclooctadiene-1, 5) dichloride, palladium (0) - diallyl ether complexes, palladium (II) nitrate, palladium (II) chloride bis (aceton
• the phosphine ligand is used in excess relative to the transition metal.
• the ratio of transition metal to ligand is preferably from 1:1 to 1:1000. Ratios of transition metal to ligand of 1:1 to 1:100 are particularly preferred.
• the exact transition metal/ligand ratio to be used depends on the specific application and also on the amount of catalyst used. Thus, in general, it is conventional to use lower transition metal/ligand ratios in the case of very low transition metal concentrations ( ⁇ 0.01 mol %) than in the case of transition metal concentrations of between 0.5 and 0.01 mol % of transition metal.
• the present phosphine compounds and their corresponding phosphonium salts are thermally very stable. It is thus possible to use the catalysts according to the invention at reaction temperatures of up to 250 0 C or more.
• the catalysts are preferably used at temperatures of 20 to 200 0 C; it has proved advantageous in many cases to work at temperatures of 30 to 180°C, preferably of 40 to 160 0 C.
• the ligands can also be used in pressure reactions without loss of activity, the operating pressure conventionally being up to only 100 bar, but preferably in the normal pressure range of up to 60 bar.
• the present catalysts are preferably used in couplings reactions wherein a C-C or C-heteroatom bond is formed.
• transition metal-catalyzed reactions such as the metathesis or hydrogenation of double bonds or carbonyl compounds can also be catalyzed by the present catalysts.
• R a is an aryl, alkenyl, or alkyl radical, or, although less preferred, a corresponding boronic acid ester.
• the reaction is conducted in the presence of the Pd complex and a base.
• the Suszuki cross-coupling is significant to couple aryl and heteroaryl boronic acid with aryl and heteroaryl halides, respectively, resulting in the formation of biaryl compounds.
• the carbon electrophile is an aryl, heteroaryl or vinyl halide/pseudohalide, although other electrophiles, such as acid halides, may be used.
• the organotin compound has the formula R b Sn(R c )3, wherein the R c radicals being not transferred are usually butyl or methyl radicals and the R b radical can be varied broadly, preferably it is an aryl, heteroaryl, alkenyl, alkynyl, or alkyl radical.
• the reaction is conducted in the presence of the Pd complex. Stille cross-coupling is a popular tool in the synthesis of complex natural products.
• the organosilane has the formula R d SiZ, wherein Z represents three radicals that are not transferred, e.g. MeCl2, Me3, and (OMe) 3, and R d is, for example, a vinyl, akynyl, or aryl radical.
• the reaction is conducted in the presence of the Pd catalyst.
• the Hiyama cross-coupling is an interesting alternative to the Stille cross-coupling as organosilicon compounds are non-toxic.
• the organozinc compound has the formual R e ZnX or R e 2 Zn, wherein X is a halogen or a phenyl radical and R e is, for example, an aryl, heteroaryl, or alkyl radical.
• the reaction is conducted in the presence of the Pd catalyst.
• the Negishi cross-coupling is an effective method for the formation of C-C bonds as organozinc compounds are readily accessible and show a high tolerance against functional groups.
• the compounds to be arylated include carbonyl compounds, such as ketones and esters, and nitro compounds.
• the reaction is conducted in the presence of the Pd catalyst and a base.
• the cyanation agent is an inorganic cyanide, such as Zn(CN) 2 or KCN.
• the reaction is conducted in the presence of the Pd catalyst.
• C-N coupling reaction An example of a C-N coupling reaction is the Buchwald- Hartwig coupling of an aryl or heteroaryl halide/pseudohalide with an amine (Buchwald-Hartwig amination) .
• the amine component can be varied broadly, it includes various secondary and primary alkyl (including cycloalkyl) amine and anilines.
• the reaction is conducted in the presence of the Pd catalyst and a base.
• the Buchwald- Hartwig amination is an effective tool for the synthesis of aniline derivatives that play an important role in the preparation of pharmaceuticals, agro chemicals, and in photography.
• An example of a reaction resulting in the formation of a C-O bond is the coupling of an aryl or heteroaryl halide/pseudohalide with an alcohol.
• the Pd catalyzed C-O coupling may be used for substrates that do not couple in the absence of the Pd catalyst under "normal" conditions of the well-known electrophilic substitution.
• the alkoxide employed is NaOtBu or a phenoxide.
• the reaction is conducted in the presence of the Pd catalyst (and a base, in case the alcohol is employed instead of the alkoxide) .
• the resulting diaryl and arylalkyl ethers play an important role in the synthesis of pharmaceuticals and natural products.
• pseudohalogen or "pseudohalide” has the standard meaning accepted in the art.
• Non-limiting examples of pseudohalogens/pseudohalides are -COCl, -SO2CI, -N 2 X, -OP(O) (OR) 2 , -OSO 2 CF 3 (-OTf, triflate) , and -OSO 2 ToI (-OTs, tosylate) .
• the preferred pseudohalides used in the above coupling reactions are the triflates.
• the above-mentioned coupling reactions are preferably conducted by using the corresponding chlorides, bromides, or triflates as starting materials, more preferably the corresponding chlorides or bromides are used.
• a further example of a reaction that can be catalyzed the by the catalysts according to the present invention is the dehydrohalogenation, especially dehydrochlorination, of aryl and heteroaryl halides, preferably chlorides and bromides.
• the dehalogenation of aryl and heteroaryl halides is not only important for the organic synthesis but also for environmental chemistry as the dechlorination of polychlorinated biphenyls (PCB) and related chlorinated arenes represents a mechanism to detoxicate these persistent harmful substances.
• the new phosphine compounds used as ligands in homogeneous transition metal complexes offer a new perspective to dehalogenate aryl and heteroaryl halides under mild conditions.
• a transition metal complex comprising a specific phosphine compound as a ligand has not the same effectiveness as catalyst in all different types of reactions with all different types of substrates.
• a significant advantage of the new phosphine compounds is that they have a variable backbone they allows "catalyst fine tuning", i.e. detailed structural and electronic modifications in order to adapt the ligand to the intended use.
• fluorenyl-substituted phosphine compounds can be varied readily: Substituents at the 1- and 8-positions (R 11 and R 18 ) allow to modulate the steric bulk close to the phosphorous atom and the 2- and 7-positions (R 12 and R 17 ) allow the easy introduction of the various functional groups. It is within the ordinary skill of an organic chemist to conduct some routine experiments in order to find out which specific phosphine compound according to the present invention will be the appropriate ligand in a transition metal catalyst to function as an highly effective catalyst for the preparation of a selected product. In general, reactions using the present catalysts produce the desired products in high yield, with high catalytic productivity, and/or with high purity.
• the new catalysts possess the ability to employ the less reactive, but cost-effective chlorides.
• the following examples illustrate the preparation of the new phosphine compounds and/or their corresponding phosphonium salts. The exemplary use of some of the synthesized compounds in various coupling reactions is also illustrated.
• Mass spectra were recorded on a Finigan MAT 95 magnetic sector spectrometer. Thin layer chromatograpy (TLC) was performed using Fluka silica gel 60 F 254 (0.2 mm) on aluminum plates. Silica gel columns for chromatography were prepared with E. Merck silica gel 60
• benzene (335 ml, 3.74 mol) and aluminum trichloride (90.78 g, 0.68 mol) were introduced into a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel and a reflux condenser.
• the stirred orange mixture was cooled to 7 0 C and tigloyl chloride (33) (40 g, 0.34 mol) was added dropwise via an addition funnel. After completion of the addition, the mixture was allowed to come to room temperature and then refluxed overnight. Then the reaction mixture was allowed to come to room temperature and poured onto mixture of ice (300 g) and cone. HCl (50 ml) .
• the brown reaction mixture was then refluxed for 3 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g) . Then the mixture was transferred into a separation funnel, the lower CS 2 layer was separated and the aqueous layer extracted with diethyl ether (3x100 ml) . The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed in a rotary evaporator to give a red brown liquid.
• p-Toluene sulfonic acid 50 mg, 0.26 mmol was added and the solution refluxed overnight. After completion of the removal of the water the excess toluene was removed via distillation through the Dean-Stark arm, the residue was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with a saturated solution of sodium bicarbonate (3x100 ml), dried over magnesium sulfate and filtered.
• the resulting mixture was transferred to a separation funnel and extracted with diethyl ether (3x200 ml) .
• the combined organic layers were stirred overnight with 15 ml concentrated HCl. After this time the reaction mixture was carefully adjusted to pH 7 with a saturated aqueous solution of sodium carbonate.
• the reaction mixture was transferred into a separation funnel.
• the organic layer was washed with H 2 O (3x100 ml), dried over MgSO 4 , filtered and the solvent removed under reduced pressure to give a yellow liquid.
• the residual liquid was purified via column chromatography [ (Si ⁇ 2, 35x9 cm), initial eluent: cyclohexane : ethylacetate (100:2))] to afford two fractions: 1, 2, 3-trimethyl-4, 7- dimethoxyindene (39) (4.63 g, 66 %) as a yellow liquid R f 0.42; (Change of eluents to cyclohexane : ethylacetate (2:1)): 4, 7-dimethoxy-2, 3-dimethyl-l-indanone (36) (starting material) R f 0.35 (cyclohexane : ethylacetate) (5:1)) as a pale yellow liquid.
• 1-Methylfluorene (47) 1-Methylfluoren-9-one (46) was prepared according to Mortier et al . (D. Tilly, S. S. Samanta, A. -S. Castanet, A. De, J. Mortier, Eur. J. Org. Chem. 2005, 174) .
• 1-Methylfluoren-9-one (46) was reduced according to the general procedure of Carruthers et al . (W. Carruthers, D. Whitmarsh, J. Chem. Soc.
• Reagents and conditions a) 1, 3-propanediol, ZrCl 4 ; n-BuLi,
• Benzaldehyde 50 (3.1 g, 15.6 mmol) and 3,5- dimethylphenylboronic acid were added and the mixture stirred for 2 h at 80 0 C (quantitative conversion, GC) .
• the reaction mixture was allowed to cool to ambient temperature and treated with NaOH (100 ml of a 1 N solution) and diethylether (200 ml) and transferred into a separation funnel.
• the aqueous phase was extracted with Et 2 O (2 x 100 ml), the combined organic layers were subsequently washed with NaOH (100 ml, 1 N), brine (100 ml), dried over MgSO4, and the volatiles removed in vacuo.
• 1,3,8-Trimethylfluorene (54) 1, 3, 8-Trimethylfluoren-9- one (53) was reduced according to the general procedure of Carruthers et al . (W. Carruthers, D. Whitmarsh, J. Chem. Soc. Perkin Trans, I 1973, 1511). 1, 3, 8-Trimethylfluoren-9- one (53) (2.74 g, 12.3 mmol) was dissolved in propionic acid (235 ml) . Red phosphorus (3.0 g) and concentrated HI (40 ml) were added and the reaction mixture was refluxed for 24 h. Quantitative conversion was shown by TLC.
• reaction mixture was diluted with water (250 ml) , neutralized with NaOH and extracted with Et 2 O (4x125 ml) .
• the combined organic layers were washed with brine (2x125 ml) , dried over MgSO4, filtered and the volatiles removed in vacuo to afford 2.56 g (quant.) 54 as a white solid.
• Fluorene derivative 9-Ethylfluorene (41) (0.54 g, 2.78 mmol) , n-BuLi (1.35 ml, 2.0 M in hexane,
• 24a was isolated to give a white solid (4.13 g, 73 %) .
• Fluorene derivative 9- phenylfluorene (prepared according to a standard literature method, e.g. F. Ullman, R. von Wurstemberger, Chem. Ber.
• phosphine compounds were used as ligands in Pd complexes performing as catalysts in various cross-coupling reactions. All cross-coupling reaction were carried out under an argon atmosphere in degassed solvents (freeze and thaw). TON means catalytic turnover number and is defined as the ratio of the number of moles of product to the number of moles of catalyst.
• Ad 2 PBn is an adamantly-substituted phosphine and is available under the trademark cataCXium® A from Degussa AG.
• Reagents and conditions 10 mmol aryl bromide, 11 mmol phenylacetylene, 10 ml IPr 2 NH, 50 0 C, 24 h.
• Catalyst 0.02 mol % Na 2 PdCl 4 , 0.04 mol % EtFIuPCy 2 -HBF 4 (9a), 0.015 mol % CuI, catalyst mixture in IPr 2 NH 2 Br.
• the product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was determined via gaschromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard.
• Reagents and conditions 1.5 mmol aryl chloride, 2.1 mmol phenylacetylene, 3 mmol Na2CC>3, 5 ml DMSO, catalyst: 1 mol% Na 2 PdCl 4 / ligand / CuI (4:8:3).
• phosphonium salt MeFIuIPr 2 -HBF 4 (5a). Reaction conditions not been optimized.
• Reagents and conditions 1 mmol aryl bromide, 1.2 mmol acetylene, 1.5 mmol CS2CO3, 1 mol % Na2PdCl4, 2 mol % ligand ( ( 9-ethyl-2-sulfofluorenyl) dicyclohexyl-phosphonium-tetrafluoroborate; 9-Et-2-SO 3 HFluPCy 2 (13)), H 2 0/i-propanol (4 ml, 1:1), 100 0 C. Reaction times and temperatures were not optimized, [a] Average of 2 runs, determined by GC using hexadecane as internal standard.
• reaction mixture was stirred at 100 0 C in an aluminum block. After cooling to room temperature the reaction mixture was diluted with ether (15 ml), washed with water (10 ml), the organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was determined via gaschromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard.
• the catalyst stock solution was prepared as described for the aqueous Sonogshira reaction using 9-Et-2-SO 3 HFlu-PCy 2 • HBF 4 (13a).
• Cross-coupling reaction Aryl halide (1 mmol), boronic acid (1.2 mmol) and K 2 CC>3 (3.2 mmol) were first added to water (4 ml) , then the catalyst stock solution and two drops of Labrasol ® (caprylocaproyl macrogol-8 glyceride blend, saturated polyglycolized glycerides consisting of mono-, di- and triglycerides of mono- and di-fatty acids of polyethylene glycol (PEG) ) were added.
• Labrasol ® caprylocaproyl macrogol-8 glyceride blend, saturated polyglycolized glycerides consisting of mono-, di- and triglycerides of mono- and di-fatty acids of polyethylene glycol (PEG)

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