Synthesis and use of an air-stable ferrocenyl phosphasilinane ligand in c-x cross-coupling reactions

Abstract

The present invention relates to cyclic ferrocenyl phosphasilinanes and their use as ligands in palladium complexes in palladium-catalyzed cross-coupling reactions such as the Suzuki-Miyaura cross-coupling and Buchwald-Hartwig coupling reactions.

Description

[0001] Synthesis and use of an air-stable ferrocenylphosphasilinane ligand in CX cross-coupling reactions

[0002] Description

[0003] The present invention relates to cyclic ferrocenylphosphasilinanes and their use as ligands in palladium complexes in palladium-catalyzed cross-coupling reactions such as the Suzuki-Miyaura cross-coupling and the Buchwald-Hartwig coupling.

[0004] A cross-coupling reaction is a coupling reaction in which two different molecules react with each other in the presence of a suitable catalyst to form a carbon-carbon or carbon-heteroatom bond. Palladium-catalyzed cross-coupling reactions are of particular practical importance (e.g., in the synthesis of pharmaceutical agents). Examples include the Stille coupling, the Suzuki coupling (also known as the Suzuki-Miyaura coupling), and the Negishi coupling. In 2010, R.F. Heck, E. Negishi, and A. Suzuki were awarded the Nobel Prize in Chemistry for their work on coupling reactions.

[0005] The following review articles describe in more detail the use of cross-coupling reactions in the synthesis of pharmaceutical agents:

[0006] HC Shen, “Selected Applications of Transition Metal-Catalyzed Carbon-Carbon Cross-Coupling Reactions in the Pharmaceutical Industry”, pp. 25-96, in “Applications of Transition Metal Catalysis in Drug Discovery and Development: An Industrial Perspective”, Ed.: ML Crawley and BM Trost, 2012, John Wiley & Sons;

[0007] Q. Gu et al., “Palladium catalyzed CC and CN bond forming reactions: An update on the synthesis of pharmaceuticals from 2015-2020", Org. Chem. Front., 2021, 8, pp. 384-414.

[0008] Another coupling reaction known to those skilled in the art is the Buchwald-Hartwig coupling, in which an aryl or heteroaryl halide or pseudohalide and a primary or secondary amine react with each other in the presence of a base and a palladium-containing catalyst to form a CN bond. The following review articles summarize the current state of knowledge in the field of CN coupling reactions:

[0009] R. Dorel et al., „The Buchwald-Hartwig Amination After 25 Years", Angew. Chem. Int. Ed., 2019, 58, S. 17118-17129;

[0010] S.L. Buchwald et al., „Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide", Chem. Sei., 2011, 2, S. 27-50;

[0011] S.L. Buchwald et al., „Biaryl Phosphane Ligands in Palladium-Catalyzed Amination", Angew. Chem. Int. Ed., 2008, 47, S. 6338-6361;

[0012] S.L. Buchwald et al., „Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions", Chem. Rev., 2016 116, S. 12564-12649.

[0013] Common catalysts in the field of coupling reactions are palladium complexes containing one or more phosphine ligands and optionally other ligands. These Pd complexes with suitable phosphine ligands can be prepared in advance and stored until needed, or alternatively generated in situ during the reaction to be catalyzed, e.g., by separately adding a palladium salt and the phosphine to the reaction medium, so that the formation of a phosphine-containing Pd complex only occurs in the reaction medium.

[0014] It is known that non-cyclic biarylphosphines can act as ligands for Pd complexes in palladium-catalyzed coupling reactions (such as the Buchwald-Hartwig coupling), see e.g. S.L. Buchwald et al., 2011, supra. These non-cyclic phosphines lack a phosphorus-containing ring (i.e., no ring containing phosphorus as a ring atom).

[0015] Cyclic biarylphosphines (i.e., phosphines in which the phosphorus atom is one of the ring-forming atoms) are also known as ligands for Pd complexes in palladium-catalyzed coupling reactions.

[0016] S. Shekhar et al., ACS Catal., 2019, 9, pp. 11691-11708, and S. Shekhar et al., ACS Catal., 2020, 10, pp. 15008-15018, describe biarylphosphorinans and their use as Pd complex ligands for palladium-catalyzed coupling reactions. C. Maumela et al., RSC Adv., 2021, 11, pp. 26883-26891, describe biarylphobans and biarylphosphaterioxadamantanes and their use as Pd complex ligands for palladium-catalyzed Suzuki couplings.

[0017] WO 2012 / 009698 A1 describes a monocyclic, bicyclic or tricyclic biarylphosphine, wherein the heterocyclic ring system contains, in addition to the phosphorus atom, four carbon atoms and optionally at least one further ring atom selected from carbon, oxygen, nitrogen, phosphorus and sulfur.

[0018] The formation of a carbon-heteroatom bond (especially a CN bond) via a coupling reaction, particularly a Buchwald-Hartwig coupling, typically requires long reaction times when using N-heterocyclic aryl halides. Unless more efficient catalysts are available, the reaction temperature can be increased to achieve shorter reaction times. However, this usually leads to undesired side reactions that reduce the yield of the coupling product.

[0019] WO 2023 / 088620 A1 describes a process for the production of air-stable biaryl phosphasilinane ligands by the partial deprotonation of a phosphine and reaction with a dihalide compound. Furthermore, the application of phosphasilinane ligands with carbon substitution exclusively in the biaryl moiety in Pd-catalyzed cross-coupling reactions, such as the Suzuki-Miyaura cross-coupling reaction and the Buchwald-Hartwig coupling, is described.

[0020] Korb et al. (Eur. J. Inorg. Chem. 2020, 2968-2982) describe 2-phenylvinyl-1-phosphinoferrocene compounds and their use as catalysts for Suzuki-Miyaura cross-coupling reactions. In one of these compounds, the phosphorus atom bonded to the phenyl moiety is linked via two oxygen atoms to a 1,1'-bisnaphthol (BI₂NOL) unit.

[0021] Chen et al. (Organometallics 2011, 30, 5248-5257) describe o-diarylphosphino-sulfo-ferrocene compounds and their use as catalysts for ethene / CO copolymerizations. In one of these compounds, the diarylphosphino group is 2,8-dimethyl-1 OH-phenoxaphosphine. The synthesis of cyclic ferrocenylphosphasilinanes can be achieved via a Giese reaction, in which a ferrocenylphosphine reacts with a diolefin in an intermolecular and subsequent intramolecular reaction.

[0022] A Giese reaction is the reaction of a carbon or heteroatom radical to an unsaturated carbon-carbon, carbon-heteroatom, or heteroatom-heteroatom bond, forming a new carbon-carbon, heteroatom-carbon, carbon-carbon, or heteroatom-heteroatom bond. In addition to this bond, a new carbon-hydrogen or heteroatom-hydrogen bond is also formed.

[0023] The Giese reaction is described in more detail in the following review articles: a) B. Giese, “Formation of CC Bonds by Addition of Free Radicals to Alkenes” Angew. Chem. Int. Ed. Engi. 1983, 22, 753-764;

[0024] b) B. Giese, “Syntheses with Radicals — CC Bond Formation via Organotin and Organomercury Compounds [New Synthetic Methods (52)]” Angew. Chem. Int. Ed. Engl. 1985, 24, 553-565;

[0025] c) G. Bar, AF Parsons, “Stereoselective radical reactions” Chem. Soc. Rev. 2003, 32, 251-263;

[0026] d) GSC Srikanth, SL Castle, “Advances in radical conjugate additions” Tetrahedron 2005, 61, 10377-10441.

[0027] An object of the present invention is to provide suitable, highly electron-rich phosphines that can be used as highly active ligands in metal complexes, particularly in palladium complexes, in palladium-catalyzed cross-coupling reactions. In particular, these phosphines should enable efficient C-C coupling reactions, e.g., in the form of a Suzuki-Miyaura coupling, or C-N coupling reactions, e.g., in the form of a Buchwald-Hartwig coupling, even when N-heterocyclic aryl halides or pseudohalides are used as reactants.

[0028] A first aspect of the invention is a phosphine of formula (1)

[0029]

[0030] where

[0031] R 1 , R 2 , R 3 and R 4 independent of each other are hydrogen, alkyl, e.g. Ci-4-alkyl, cycloalkyl, e.g. Cs-7-cycloalkyl, or aryl, e.g. phenyl;

[0032] R 1 ', R 2 ', R 3 ' and R 4 ' independent of each other are hydrogen, alkyl, e.g. Ci-4-alkyl, cycloalkyl, e.g. Cs-7-cycloalkyl, or aryl, e.g. phenyl;

[0033] R 5 each is independent of hydrogen, alkyl or aryl;

[0034] Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is;

[0035] R 6 and R 7are independently alkyl, e.g. Ci-4-alkyl, cycloalkyl, e.g. C5-7-cycloalkyl or aryl, e.g. phenyl; or Re and R7 are each a bivalent alkylene group and together with a Si, Ge or Sn atom form a ring, in particular a 4- to 7-membered ring.

[0036] Another aspect of the invention is a metal complex, in particular a palladium or nickel complex, comprising a phosphine of formula (1) as ligand L 1 contains.

[0037] Another aspect of the invention is a combination containing

[0038] a metal compound, in particular a palladium or nickel compound and a phosphine of formula (1).

[0039] Another aspect of the invention is the use of a metal complex, in particular a palladium or nickel complex containing a phosphine of formula (1) as a ligand, as a catalyst, in particular as a catalyst for a coupling reaction, especially for a cross-coupling reaction. Yet another aspect of the invention is a method for carrying out a coupling reaction, wherein the reactants of the coupling reaction are reacted in the presence of a metal complex according to the invention, in particular a palladium or nickel complex containing a phosphine of formula (1), or a combination according to the invention, and the product of the coupling reaction is optionally isolated.

[0040] For the purposes of this invention, the term halogen means F, CI, Br or I.

[0041] The term alkyl, especially for one of the R groups 1 , R 2 , R 3 , R 4 , R 1 ', R 2 ', R3 ', R 4 'R 5 , R 6 and R 7 means a straight-chain or branched, unsubstituted or substituted C1-C10 alkyl, preferably C1-6 alkyl and particularly preferably C1-4 alkyl, wherein each alkyl may bear one or more substituents independently selected from halogen, cycloalkyl, aryl, O-alkyl, O-cycloalkyl or O-aryl.

[0042] The term cycloalkyl, especially for one of the R groups 1 , R 2 , R 3 , R 4 , R 1 ', R 2 ', R 3 ', R 4 'R 5 , R 6 and R 7Cycloalkyl means a C3-8 cycloalkyl, preferably a C5-7 cycloalkyl, and particularly preferably a Ce cycloalkyl, wherein each cycloalkyl may bear one or more substituents independently selected from halogen, alkyl, O-alkyl, O-cycloalkyl, or O-aryl. In certain embodiments, cycloalkyl may also represent a heterocyclic ring system with one or more heteroatoms in the ring, e.g., N, O, or S. In further embodiments, cycloalkyl means a carbocyclic ring system.

[0043] The term aryl, especially for one of the residues R 1 , R 2 , R 3 , R 4 , R 1 ', R 2 ', R 3 ', R 4 'R 5 , R 6 and R 7Aryl means C5-C14 aryl or C6-C14 aryl, preferably phenyl or naphthyl, and particularly preferably phenyl, wherein each aryl may bear one or more substituents independently selected from halogen, alkyl, O-alkyl, cycloalkyl, O-cycloalkyl, aryl, or O-aryl. In certain embodiments, aryl may also represent a heterocyclic ring system with one or more heteroatoms in the ring, e.g., N, O, or S. In further embodiments, aryl means a carbocyclic ring system.

[0044] The cyclic ferrocenylphosphines of the present invention contain, in addition to the phosphorus atom, a further heteroatom as a ring atom in the heterocyclic ring according to formula (1), wherein this additional heteroring atom is Si, Ge, Sn, As or Se. 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 and R 4' are preferably each independently selected from H, Ci-4-alkyl, Cs-7-cycloalkyl, or phenyl, which is optionally substituted with one or more C1-6 alkyl groups. R are particularly preferred. 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 and R 4 ' H.

[0045] R 5 is preferably each independently selected from H, phenyl and methyl.

[0046] Q is preferably selected from SiR 6 R 7 .

[0047] R 6 and R 7 are preferably each independently selected from methyl, phenyl, which is optionally substituted with one or more Ci-6 alkyl groups and / or heteroatom groups, e.g., O-alkyl. R are particularly preferred. 6 and R 7 Phenyl, optionally substituted with an O-C1-6 alkyl group, e.g., O-methyl.

[0048] In the phosphines of formula (1), the phosphorus atom is bonded only to carbon atoms and is part of a saturated heterocyclic ring system. There are fundamental structural differences compared to the BINOL compound described by Korb et al., supra, in which the phosphorus atom is bonded to two oxygen atoms, and to the sulfo compound described by Chen et al., supra. Therefore, there is no comparability with the phosphines according to the invention.

[0049] As will be described in more detail below, the use of the phosphine according to the invention as a ligand in metal complexes, e.g. in Pd complexes, enables the carrying out of a CC cross-coupling reaction or a CN cross-coupling reaction, for example the Buchwald-Hartwig coupling, which leads to high yields at relatively low reaction temperatures and relatively short reaction times, even when an N-heterocyclic aryl halide or pseudohalide is used as a reactant.

[0050] The metal complex, e.g., a palladium or nickel complex, containing the phosphine according to the invention as a ligand, can be prepared prior to the reaction to be catalyzed and optionally stored until its use. Alternatively, it is also possible to add the phosphine according to the invention and a metal compound acting as a precursor, e.g., a palladium or nickel compound, to the reaction medium, so that the formation of a metal complex, e.g., a palladium or nickel complex, containing the phosphine according to the invention as a ligand, takes place in situ in the reaction medium of the coupling reaction.

[0051] The metal complex according to the invention, e.g. a palladium or nickel complex, which includes a ligand L 1 the above-described phosphine according to the invention contains, may additionally contain one or more, e.g. 1, 2 or 3 ligands L 2 containing none of which are phosphines according to the invention. Suitable ligands L2 for metal complexes, e.g. palladium or nickel complexes are known to those skilled in the art.

[0052] For example, the other ligands L 2 of the metal complex according to the invention, e.g. Pd complex, selected independently of one another from a halide (e.g. CI - , Br - or I - ); an aryl (e.g., phenyl), a nitrile (e.g., acetonitrile, propionitrile, or benzonitrile); a carboxylate (e.g., acetate); a conjugated dienone (e.g., a 1,4-dien-3-one such as dibenzylideneacetone (dba)); a phosphine that is not a phosphine according to the invention (e.g., a non-cyclic phosphine); a pseudohalide (e.g., CN _ or OCN - ) an amine or acetylacetonate.

[0053] The ligand L 2The ligand, which is not a phosphine according to the invention, can be a monodentate or, alternatively, a polydentate ligand. Examples of such polydentate ligands include arylalkylamines or arylamines (e.g., phenethylamine or naphthylamine) and monoanions thereof.

[0054] Provided the ligand L 2 If the phosphine is a phosphine, it is preferably a non-cyclic phosphine, i.e., a phosphine that does not have a phosphorus-containing ring. Suitable non-cyclic phosphine ligands for metal or palladium complexes are known to those skilled in the art.

[0055] The phosphine ligand L 2, which is not a phosphine according to the invention, is for example a tri-Ci-6-alkylphosphine, a tri-Cs-7-cycloalkylphosphine or a triarylphosphine (in particular a triphenylphosphine), wherein each of the aryl groups (which are preferably phenyl groups) is optionally substituted by one or more Ci-4-haloalkyl groups (e.g. -CF3), Ci-4-alkyl groups (e.g. Methyl) or Ci-4-alkoxy groups (e.g. Methoxy).

[0056] For example, the phosphine ligand L 2 one of the following formulas (2), (3) or (4):

[0057]

[0058] Alternatively, the phosphine ligand L 2 to be a phosphine of the following formula (5):

[0059] P(R 1 )(R 2 )(R 3 ) (5)

[0060] where R 1 and R 2are independently selected from alkyl, in particular Ci-6-alkyl and cycloalkyl, in particular Cs-7-cycloalkyl (e.g. cyclohexyl), and R 3 Biphenyl is optionally substituted by one or more Ci-6 alkyl groups, Ci-6 alkoxy groups, phenyl groups and / or pyridyl groups.

[0061] For example, the phosphine ligand L 2 one of the following formulas (6), (7), (8) or (9):

[0062]

[0063]

[0064] (9)

[0065] For example, a palladium complex according to the invention has the following formula (10):

[0066]

[0067] where

[0068] L 1 a phosphine according to the invention, and

[0069] L 2a and L 2b each is a ligand that is not a phosphine according to the invention.

[0070] Regarding suitable ligands L2a and L 2b The above statements regarding the ligand L can be referred to. 2 be referred to. For example, the ligands L 2a and L 2b of the Pd complex according to the invention selected independently of one another from a halide (e.g. CI - , Br - or T); an aryl; a nitrile (e.g., acetonitrile, propionitrile, or benzonitrile); a carboxylate (e.g., acetate); a conjugated dienone (e.g., a 1,4-dien-3-one such as dibenzylideneacetone (dba)); a phosphine that is not a phosphine according to the invention (e.g., a non-cyclic phosphine); a pseudohalide (e.g., CN _ or OCN - ) an amine or acetylacetonate.

[0071] An exemplary palladium complex of the present invention has the following formula (11):

[0072]

[0073] where R 5 , R 6 and R 7 as well as the ligands L 2a and L 2bhave the meanings given above.

[0074] For example, the ligand L 2a Dibenzylideneacetone (dba) or acetonitrile and the ligand L 2b will be from one of the above for L 2 The specified ligands were selected.

[0075] Another exemplary palladium complex of the present invention has the following formula (12):

[0076]

[0077] where R 5 , R 6 and R 7 have the meanings given above.

[0078] Another exemplary palladium complex of the present invention has the following formula (13):

[0079]

[0080] where R 5 , R 6 and R 7 have the meanings given above.

[0081] As mentioned above, the phosphine according to the invention and a metal or palladium compound acting as a precursor, which does not yet contain the phosphine according to the invention, can be added to the reaction medium, so that the formation of a metal or palladium complex containing the phosphine according to the invention as a ligand takes place in situ in the reaction medium of the coupling reaction.

[0082] The present invention therefore also relates to a combination comprising

[0083] a metal, palladium, or nickel compound and

[0084] the phosphine according to the invention as described above.

[0085] The metal, palladium, or nickel compound of the combination according to the invention typically does not contain phosphine according to the invention.

[0086] The combination can be contained in a single container that holds both the metal, palladium, or nickel compound and the phosphine according to the invention. Optionally, the combination can be provided as a kit containing the metal, palladium, or nickel compound and the phosphine according to the invention in separate containers.

[0087] The metal or palladium compound is, for example, a metal or palladium salt or a metal or palladium complex whose ligands are not phosphine according to the invention.

[0088] The metal or palladium salt is, for example, a palladium acetate, a palladium halide (e.g., a palladium chloride, palladium bromide, or palladium iodide), a palladium pseudohalide, or a mixture of at least two of these salts.

[0089] If the metal or palladium compound is a metal or palladium complex, its ligands are selected independently of one another, for example from a halide (e.g., CI), Br - or T); a phosphine that is not a phosphine according to the invention (e.g., a non-cyclic phosphine); a conjugated dienone, e.g., a 1,4-dien-3-one such as dibenzylideneacetone (dba); a nitrile, e.g., acetonitrile, propionitrile, or benzonitrile; an acetylacetonate; a carboxylate, e.g., acetate; a pseudohalide, e.g., CN _ or OCN - , an amine or an aryl.

[0090] Regarding the phosphine ligand, which is not a phosphine according to the invention, reference can be made to the above statements concerning ligand L. 2Reference is made to the above. Preferably, the phosphine ligand, which is not a phosphine according to the invention, is a non-cyclic phosphine, i.e., a phosphine that does not have a phosphorus-containing ring. Suitable non-cyclic phosphine ligands for palladium complexes are known to those skilled in the art. The phosphine ligand, which is not a phosphine according to the invention, is, for example, a tri-Ci-6-alkylphosphine, a tri-Cs-7-cycloalkylphosphine, or a triarylphosphine, in particular a triphenylphosphine, wherein each of the aryl groups, which are preferably phenyl groups, is optionally substituted by one or more Ci-4-haloalkyl groups (e.g., -CF3), Ci-4-alkyl groups (e.g., methyl), and / or C1-4-alkoxy groups (e.g., methoxy). Alternatively, the phosphine ligand, which is not a phosphine according to the invention, can, for example, be a phosphine of the formula (8) described above.

[0091] Examples of palladium compounds of the combination according to the invention include: a palladium dibenzylidene complex (e.g., Pd2(dba)3 or Pd(dba)2); PdCh(PR3)2, wherein R is a phenyl (optionally substituted with one or more C1-6 alkyl groups), a Cs-7 cycloalkyl, or a Ci-6 alkyl; a palladium acetate (e.g., Pd2(OAc)s); a palladium acetylacetonate; a PdX2, wherein X is a halide or pseudohalide; a Pd(RCN)2Ch, wherein R is a phenyl or methyl.

[0092] The present invention also relates to the use of the metal complex described above according to the invention, e.g. palladium or nickel complex, or the combination described above according to the invention as a catalyst, in particular as a catalyst in a cross-coupling reaction.

[0093] The cross-coupling reaction is, for example, a CC or CN cross-coupling reaction. The CC cross-coupling reaction is, for example, a Suzuki-Miyaura coupling. As is known to those skilled in the art, the Suzuki-Miyaura coupling is a coupling reaction in which an organoboron compound and, for example, an aryl or heteroaryl halide, pseudohalide, or sulfonate are reacted with each other in the presence of a catalyst, e.g., a palladium-containing catalyst, forming a CC bond.

[0094] A preferred CN cross-coupling reaction is the Buchwald-Hartwig coupling. As is known to those skilled in the art, the Buchwald-Hartwig coupling is a coupling reaction in which an aryl or heteroaryl halide, pseudohalide, or sulfonate and a primary or secondary amine are reacted with one another in the presence of a catalyst, e.g., a palladium-containing catalyst (and preferably a base), to form a CN bond. The present invention further relates to a process for the preparation of an aryl or heteroaryl amine, wherein a compound of formula (14)

[0095] Ar-X (14)

[0096] where

[0097] Ar is an aryl or heteroaryl

[0098] X is a halogen atom, a sulfonate group (e.g. trifluoromethanesulfonate-O-Tf) or a pseudohalogen group (e.g. -CN, -OCN or -NCO),

[0099] reacted with a primary or secondary amine in the presence of the metallocomplex according to the invention described above, e.g. palladium or nickel complex, or the combination according to the invention described above.

[0100] Suitable reaction conditions for the Buchwald-Hartwig coupling are known to those skilled in the art. The reaction preferably takes place in the presence of a base.

[0101] The invention will be explained in more detail below by means of the following examples.

[0102] Examples

[0103] Production of a cyclic ferrocenylphosphine according to the invention

[0104] A ferrocenyl phosphosphasilinane according to the invention of the following formula (15)

[0105]

[0106] was produced according to the following reaction scheme:

[0107]

[0108] Chemical name of the cyclic biarylphosphine of formula (15):

[0109] 4,4-Bis(4-methoxyphenyl)-1-ferrocenyl-1,4-phosphasilinan

[0110] tl

[0111] Diethylferrocenylphosphonate (17)

[0112]

[0113] Ferrocene (4.65 g, 25.0 mmol, 1.00 equiv.) was placed in THF (12.5 mL, 2.0 M) at 0°C, and fBuLi (1.70 M in n-pentane, 14.7 mL, 25.0 mmol, 1.00 equiv.) was added over 5 min. This solution was stirred for 20 min, then diethyl chlorophosphate (3.64 mL, 25.0 mmol, 1.00 equiv.) was added and stirred for 30 min. The reaction solution was heated to room temperature (RT) and stirred for 18 h. Then MeOH (5 mL) was added, and the solvent was removed under reduced pressure. The crude product was then purified by column chromatography (SiO₂, Et₂O₂ - EtOAc - EtOAc:EtOH = 20:1 - 10:1). The product (17) was obtained as a reddish-brown oil (5.13 g, 15.9 mmol, 63%).

[0114] Rf (SiO2, EtOAc: EtOH = 10:1) = 0.65.

[0115] 1H NMR (401 MHz, CDCI3): 5 = 4.49-4 .52 (m, 2H), 4.38-4.41 (m, 2H), 4.31 (s, 5H), 4.08-4.15 (m, 4H,), 1.34 (t, 3 J H ,H = 6.4 Hz, 6H) ppm.

[0116] 31 P NMR (162 MHz, CDCI3): 5 = 25.8 (s, 1P) ppm.

[0117] T2

[0118] Divinylbis(para-methoxyphenyl)silan (18)

[0119]

[0120] Magnesium chips (3.65 g, 150 mmol, 6.00 equiv.) were placed in a flask and heated. They were then layered with THF (5 mL) and para-bromoanisole (9.41 mL, 75.0 mmol, 3.00 equiv.) was added portionwise along with THF (70 mL, 2.0 M). This solution was refluxed for 2 h at 80°C. Divinyldichlorosilane (3.55 mL, 25.0 mmol, 1.00 equiv.) was dissolved in THF (25 mL, 1.0 M) at 0°C and Grignard's solution was added. The resulting solution was stirred for 1 h at 0°C and 16 h at 23°C. The reaction mixture was quenched with H₂O (100 mL) and the aqueous phase was extracted with Et₂O (3 x 50 mL). The combined organic phases were dried over MgSO₄ and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (SiO₂, nPentane:Et₂O 20:1–10:1). The product (18) was obtained as a yellowish oil (6.45 g, 23.1 mmol, 92%).

[0121] Rf (SiO2, nPentane:Et2O = 20:1) = 0.25.

[0122] 1H NMR (401 MHz, CDCI3): 5 = 7.45 (d, 2 J H ,H = 8.8 Hz, 4H), 6.92 (d, 2 JH,H = 8.8 Hz, 4H), 6.20-6.52 (m, 4H), 5.74-5.81 (m, 2H), 3.82 (s, 6H, OCH3) ppm.1.3

[0123] 4,4-Bis(4-methoxyphenyl)-1-ferrocenyl-1,4-phosphasilinan (15)

[0124]

[0125] UAIH4 (2.28 g, 60.0 mmol, 3.0 equiv.) was placed in 46.7 mL of Et₂O at 0°C and slowly mixed with a solution of 17 (6.44 g, 20.0 mmol, 1.00 equiv.) in 20 mL of Et₂O. This solution was stirred for 1 h at 0°C and then for 18 h at room temperature. The solution was then cooled to 0°C, mixed with 80 g of Na₂SC>4-10 H₂O, stirred for 1 h at 0°C and 3 h at room temperature. The mixture was then filtered through a frit, the residue was washed with 200 mL of Et₂O, and the filtrate was subsequently concentrated under reduced pressure. The residue was dissolved in toluene (200 mL) and treated with 1,1'-azobis(cyclohexanecarbonitrile) (22) (489 mg, 2.00 mmol, 10.0 mol%) and 18 (8.29 g, 28.0 mmol, 1.4 equiv.). This reaction mixture was heated at 100°C for 20 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (SiC>2, nPentane:EtOAc = 10:1). The product (15) was obtained as an orange solid (3.90 g, 7.58 mmol, 38%).

[0126] Rf (SiC>2, nPentan:EtOAc = 10:1) = 0.50.

[0127] 1 H NMR (801 MHz, C6D6): 5 = 7.67 (d, 2 J H ,H = 8.8 Hz, 2H), 7.56 (d, 2 J H ,H = 8.8 Hz, 2H), 7.02 (d, 2 J H ,H = 8.0 Hz, 2H), 6.93 (d, 2 J H ,H = 8.0 Hz, 2H), 4.20-4.22 (m, 2H), 4.13-^1.15 (m, 2H), 4.12 (s, 5H), 3.41 (s, 3H), 3.38 (s, 3H), 2.30-2.34 (m, 2H), 2.10-2.16 (m, 2H), 1.76-1.84 (m, 2H), 1.62-1.69 (m, 2H) ppm.

[0128] 13 C NMR (201 MHz, C6D6): 5 = 161.6 (s, 1C), 161.5 (s, 1C), 136.8 (s, 2C), 136.2 (s, 2C), 128.5 (s, 2C) 114.7 (s, 2C), 114.3 (s, 2C), 80.1 (d, 1 Jc,p = 14 Hz, 1C), 71.3 (d, 2 J C -H = 13 Hz, 2C), 70.2 (d, 3 Jc- P = 3.6 Hz, 2C), 69.2 (s, 5C), 54.7 (s, 1C), 54.7 (1s, 1C), 24.7 (d, 1 J C -p = 11 Hz, 2C), 10.0 (s, 1C), 9.95 (s, 1C) ppm. 31 P NMR (256 MHz, C6D6): 5 = -34.0 (s, 1P).

[0129] Use of a composition containing a ferrocenylphosphasilinane according to the invention and a palladium compound as a catalyst in a Suzuki-Miyaura cross-coupling mechanism

[0130] In the following described examples 1-12 according to the invention, the ferrocenylphosphasilinane of formula (15) was used, i.e.:

[0131]

[0132] In comparative example 1, a non-cyclic ferrocenylphosphine of the following formula (23) was used:

[0133]

[0134] Using a ferrocenylphosphine of formula (15) according to the invention, a Suzuki-Miyaura coupling was carried out in Examples 1-12 according to the invention with the reactants and reaction conditions specified in the following reaction scheme and in Table 1. The yields are given in Table 1.

[0135] In Example 1, 4-chloroquinoline and phenylboronic acid were used as reactants for the Suzuki-Miyaura cross-coupling reaction. Pd(OAc)₂ (1.0 mol%), RaabPhos (15) (1.5 mol%), Ba(OH)₂ (2.0 equiv.), THF / H₂O (9:1, 0.2 M), 80°C, 18 h

[0136]

[0137] 24 (1.0 equiv.) 25 (1.5 equiv.) C9H6CIN C6H7BO2

[0138]

[0139] 163.6 g / mol 121.9 g / mol 205.3 g / mol

[0140] Examples 1-12 and comparative example 1:

[0141] Pd(OAc)₂ (1.12 mg, 5.00 pmol, 1.00 mol%) and the ferrocenylphosphine of formula 15 (3.86 mg, 7.50 pmol, 1.50 mol%) were placed in a degassed mixture of THF / H₂O (10:1, 2.5 mL, 0.2 M) at room temperature and stirred for 10 min. Subsequently, 4-chloroquinoline (24) (81.8 mg, 0.500 mmol, 1.00 equiv.), phenylboronic acid (25) (91.4 mg, 0.750 mmol, 1.50 equiv.), and Ba(OH)₂ (171 mg, 1.00 mmol, 2.00 equiv.) were added. The reaction mixture was heated at 80 °C for 6 h. The solvent was removed under reduced pressure. The product was purified by column chromatography (Cis-SiC>2, MeCN / FLO = 5:95 - 100:0). 4-(Phenyl-l-yl)quinoline (26) (99.0 mg 0.482 mmol, 96%) was isolated as a colorless solid.

[0142] In Examples 1-12 according to the invention, the reactants were varied (see Table 1 below), but the synthesis conditions were identical to those used in Example 1.

[0143] In comparative example 1, the reactants and synthesis conditions were identical to those used in Example 1. However, instead of the phosphine of formula (15) according to the invention, the phosphine of formula (23) was used.

[0144] The results of Examples 1-12 according to the invention are summarized in Table 1 below. Table 1: Boronic acids used as reactants, reaction products obtained by the Suzuki-Miyaura cross-coupling reaction and product yields in Examples 1-12 according to the invention.

[0145]

[0146]

[0147]

[0148] Although in many examples one of the reactants was an N-heterocyclic aryl chloride and a rather short reaction time was chosen at a relatively mild reaction temperature, the use of the cyclic biarylphosphine according to the invention as a ligand of a palladium complex in a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction led to high product yields.

[0149] The result of comparison example 1 is shown in Table 2 below.

[0150] Table 2: Phenylboron used as reactant and product yield in the Suzuki-Miyaura cross coupling in comparative example 1.

[0151]

[0152] In comparative example 1, the product yield was considerably lower at 38% than in example 1 according to the invention at 96%.

[0153] Use of compositions containing a ferrocenylphosphasilinane according to the invention and a palladium compound as a catalyst in a Buchwald-Hartwig coupling

[0154] In the following examples 13-20 according to the invention, the ferrocenylphosphasilinane of formula (15) was used, i.e.:

[0155]

[0156] In comparative example 2, a non-cyclic ferrocenylphosphine of the following formula (23) was used:

[0157]

[0158] In all examples (i.e., examples 13-20 according to the invention and comparative example 2), a palladium dibenzylidene complex (Pd2(dba)s) was used as the palladium compound. This palladium compound and the phosphine of formula (15) or (23) were added to the reaction medium so that a palladium complex containing the phosphine as one of its ligands could form in situ.

[0159] In Example 13, 4-chloroquinoline and pyrrolidine were used as reactants for the Buchwald-Hartwig coupling.

[0160] Pd2dba3(1.0 mol%), RaabPhos (15) (3.0 mol%) NaOfBu(2.0 equiv), toluene (0.2 M), 80 °C, 6 h

[0161]

[0162] 24 (1.0 equiv.) 27 (1.5 equiv.) C9H6CIN C4H9N

[0163]

[0164] 163.6 g / mol 71.1 g / mol 198.3 g / mol

[0165] Examples 13-20 and comparative example 2:

[0166] In Example 13, Pd₂dba₃ (4.56 mg, 5.00 pmol, 1.00 mol%) and the ferrocenylphosphine of formula 15 (7.72 mg, 150 pmol, 3.00 mol%) were placed in degassed and dry toluene (2.5 mL, 0.2 M) at room temperature and stirred for 10 min. Then, 4-chloroquinoline (24) (81.8 mg, 0.500 mmol, 1.00 equiv.), NaOfBu (96.1 mg, 1.00 mmol, 2.00 equiv.), and pyrrolidine (27) (62.0 pL, 53.3 mg, 0.750 mmol, 1.50 equiv.) were added. The reaction mixture was heated at 80 °C for 6 h. The solvent was removed under reduced pressure. The product was purified by column chromatography (C18-SiC>2, MeCN / H2O = 5:95 - 100:0). 4-(Pyrrolidin-1-yl)quinoline (28) (98.8 mg 0.498 mmol, 99%) was isolated as a colorless solid.

[0167] In the examples 14-20 according to the invention, the reactants were varied (see Table 2 below), but the synthesis conditions were identical to those used in example 13.

[0168] In comparative example 2, the reactants and synthesis conditions were identical to those used in example 13. However, instead of the phosphine of formula (15) according to the invention, P ho sp hin of formula (23) was used.

[0169] The results of examples 13-20 according to the invention are summarized in Table 3 below.

[0170] Table 3: Amines used as reactants, reaction products obtained by the Buchwald-Hartwig coupling and product yields in Examples 13-20 according to the invention.

[0171]

[0172]

[0173] Although in all examples one of the reactants was an N-heterocyclic aryl chloride and a rather short reaction time was chosen at a relatively mild reaction temperature, the use of the cyclic biarylphosphine according to the invention as a ligand of a palladium complex in a palladium-catalyzed Buchwald-Hartwig coupling led to high product yields.

[0174] The result of comparison example 2 is shown in Table 4 below.

[0175] Table 4: Amines used as reactants and product yield in the Buchwald-Hartwig coupling in comparative example 2.

[0176]

[0177]

[0178] In comparative example 2, the product yield was considerably lower at 60% than in example 13 according to the invention, which was 99%.

Claims

Claims 1. Ferrocenylphosphasilinan of formula (1) where R 1 , R 2 , R 3 and R 4 independent of each other are hydrogen, alkyl, cycloalkyl or aryl; R 1 ', R 2 ', R 3 ' and R 4 ' are independent of each other hydrogen, alkyl, cycloalkyl or aryl; R 5 each is independent of hydrogen, alkyl or aryl; Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is; R 6 and R 7 are independently alkyl, cycloalkyl or aryl; or Re and R? are each a bivalent alkylene group and together with a Si, Ge or Sn atom form a ring.

2. Metal complex containing one ligand L 1 containing the phosphine according to claim 1.

3. Metal complex according to claim 2, which is a palladium or nickel complex.

4. Metal complex according to claim 2 or 3, further comprising at least one ligand L 2 contains, each of which is not a phosphine according to claim 1.

5. Metal complex according to claim 4, wherein the at least one ligand L 2 independently selected from a halide; an aryl; a nitrile; a carboxylate; a conjugated dienone; a phosphine other than a phosphine according to claim 1; an amine or acetylacetonate.

6. Combination containing a metal compound, in particular a palladium or nickel compound, and a phosphine of formula (1).

7. Combination according to claim 6, wherein the components of the combination are present together in one container or separately in several containers.

8. Combination according to claim 6 or 7, wherein the metal compound, in particular the palladium or nickel compound, is selected from a metal salt, in particular a palladium-nickel salt, a metal complex, in particular a palladium or nickel complex, which does not contain phosphine according to claim 1 as a ligand, or a combination of several salts and / or complexes.

9. Combination according to claim 8, wherein the metal salt is a palladium salt selected from a palladium acetate, a palladium halide, a palladium pseudohalide or a mixture of at least two of these salts.

10. Combination according to claim 8, wherein the metal complex, in particular the palladium or nickel complex, comprises one or more ligands independently selected from a halide; a phosphine other than a phosphine according to claim 1; a conjugated dienone, preferably a 1,4-dien-3-one such as dibenzylideneacetone; a nitrile; an acetylacetonate; a carboxylate; a pseudohalide; an amine; an aryl.

11. Use of a metal complex according to any one of claims 2 to 5, in particular a palladium or nickel complex, or a combination according to any one of claims 6 to 10, as a catalyst, e.g., as a catalyst in a coupling reaction, in particular in a cross-coupling reaction.

12. Use according to claim 11, wherein the cross-coupling reaction is a CC cross-coupling reaction, in particular a Suzuki-Miyaura cross-coupling, or a CN cross-coupling reaction, in particular a Buchwald-Hartwig coupling.

13. Method for carrying out a coupling reaction, comprising: Reacting the reactants of the coupling reaction in the presence of a metal complex according to one of claims 2 to 5, in particular a palladium or nickel complex, or a combination according to one of claims 6 to 10, and If necessary, isolate the reaction product.

14. Method according to claim 13 for the preparation of an aryl or heteroarylamine, wherein a compound of formula (14) Ar-X (14) where Ar is an aryl or heteroaryl, and X is a halogen, a sulfonate, or a pseudohalogen is reacted with a primary or secondary amine.

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