Cyclic biarylphosphines as ligands for palladium-containing catalysts in cross-clutch reactions

Description

[0001] The present invention relates to cyclic biarylphosphines and their use as ligands in palladium complexes in palladium-catalyzed coupling reactions (such as the Buchwald-Hartwig coupling).

[0002] 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.

[0003] The following review articles describe in more detail the use of cross-coupling reactions in the synthesis of pharmaceutical agents: 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; 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.

[0004] 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 are reacted together in the presence of a base and a palladium-containing catalyst to form a CN bond.

[0005] The following review articles summarize the current state of knowledge in the field of CN coupling reactions: R. Dorel et al., “The Buchwald-Hartwig Amination After 25 Years,” Angew. Chem. Int. Ed., 2019, 58, pp. 17118-17129; SL Buchwald et al., "Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide", Chem. Sci., 2011, 2, pp. 27-50; SL Buchwald et al., “Biaryl Phosphane Ligands in Palladium-Catalyzed Amination,” Angew. Chem. Int. Ed., 2008, 47, pp. 6338-6361; SL Buchwald et al., "Applications of Palladium-Catalyzed CN Cross-Coupling Reactions", Chem. Rev., 2016 116, pp. 12564-12649.

[0006] 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 in situ during the reaction to be catalyzed (e.g. by separate addition of a palladium salt and the phosphine to the reaction medium, so that the formation of a phosphine-containing Pd complex only takes place in the reaction medium).

[0007] It is known that non-cyclic biaryl phosphines 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., "Dialkylbiaryl phosphines in Pd-catalyzed irination: a user's guide", Chem. Sci., 2011, 2, pp. 27-50. These non-cyclic phosphines lack a phosphorus-containing ring (i.e., no ring containing phosphorus as a ring atom).

[0008] 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.

[0009] 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.

[0010] 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. US2014 / 371446 A1 discloses ligands that can be used for complexes in catalysis.

[0011] Y.A. Vereshchagina et al., Russian Journal of General Chemistry, 2007, Volume 77, No. 1, pp. 36-39, describe the conformation of various monoaryl-1,4-heterophosphinanes. One of the 1,4-heterophosphinanes features a silicon atom as a ring atom. Possible uses of the compounds are not mentioned.

[0012] The formation of a carbon-heteroatom bond (especially a CN bond) via a coupling reaction, particularly a Buchwald-Hartwig coupling, typically requires relatively 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 further reduce the yield of the desired coupling product.

[0013] One object of the present invention is to provide suitable phosphines that can be used as ligands in palladium complexes in palladium-catalyzed cross-coupling reactions. In particular, these phosphines should enable efficient CN coupling reactions (e.g., in the form of a Buchwald-Hartwig coupling) as ligands in palladium complexes even when N-heterocyclic aryl halides or pseudohalides are used as reactants.

[0014] The problem is solved by a phosphine of formula (1) where Q SiR 3< R 4< is; m is 1, 2 or 3; n is 1, 2 or 3; provided that the following relationship is satisfied: 3 ≤ m + n ≤ 5; the R groups are independently a hydrogen atom or a C 1-4 alkyl group; or two R groups bonded to the same carbon atom are each a bivalent alkylene group and together with the carbon atom to which they are bonded form a 4- to 7-membered (in particular 5- to 6-membered) ring; or two R groups bonded to different carbon atoms are each a bivalent alkylene group and together with the carbon atoms to which they are bonded form a 4- to 7-membered (in particular 5- to 6-membered) ring; Ar 1< is a phenyl or naphthyl compound that is optionally substituted with one or more C 1-6 alkyl groups; Ar 2< is a phenyl or naphthyl compound that is optionally substituted with one or more C 1-6 alkyl groups;R3< and R4< are independently of each other a C1-4 alkyl or a phenyl that is optionally substituted with one or more C1-6 alkyl groups.

[0015] The cyclic biarylphosphines of the present invention contain, in addition to the phosphorus atom, a further heteroatom as a ring atom in the heterocyclic ring, wherein this additional heteroring atom is Si. As will be described in more detail below, the use of the phosphine according to the invention as a ligand in Pd complexes enables the carrying out of a C-C cross-coupling reaction or a C-N 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 the reactant.

[0016] The palladium 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 palladium compound acting as a precursor to the reaction medium, so that the formation of a palladium complex containing the phosphine according to the invention as a ligand, in situ This occurs in the reaction medium of the coupling reaction.

[0017] If in formula (1) two R groups, which are bonded to the same carbon atom, together with this carbon atom form a 4- to 7-membered ring, a spiro ring system is present.

[0018] If in formula (1) two residues R, which are bonded to two adjacent carbon atoms, together with these adjacent carbon atoms form a 4- to 7-membered ring, an fused ring system is present.

[0019] If in formula (1) two residues R, which are bonded to two non-adjacent carbon atoms, together with these non-adjacent carbon atoms form a 4- to 7-membered ring, a bridged ring system is present.

[0020] Preferably, the phosphine according to the invention has the following formula (1a): where m is 0 or 1 (preferred m=1) and n is 1 or 2 (preferred n=1); k is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5; Q and R each have the meaning given above.

[0021] In a preferred embodiment of the present invention, the phosphine has the following formula (1b): where p is 0, 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4.

[0022] Furthermore, the present invention relates to a process for producing the phosphine described above according to the invention, wherein a phosphine of formula (5) Ar 1< -Ar 2< -PH 2 (5) where Ar 1< and Ar 2< each have the meaning described above; is at least partially deprotonated with a base and the phosphide obtained is reacted with a compound of formula (6) where X is a halogen atom (e.g. Cl, Br or I), Q, R, m and n each have the meaning described above.

[0023] Suitable bases with which a primary phosphine can be converted into a phosphide by deprotonation are known to those skilled in the art. For example, the base is an organolithium compound (e.g., butyllithium).

[0024] Phosphine of formula (5) can be obtained, for example, by reacting a compound of formula (4) where Ar 1< and Ar 2< each have the meaning described above; is reduced in the presence of a reducing agent to the phosphine of formula (5).

[0025] The reducing agent is, for example, a metal hydride (e.g., lithium aluminum hydride).

[0026] If the phosphine of the above formula (1a) is produced using the process according to the invention, the phosphide obtained after deprotonation of the phosphine of formula (5) is reacted with a compound of formula (6a): where m 0 or 1 (preferred m=1) and n 1 or 2 (preferred n=1); X is a halogen atom (e.g. Cl, Br or I); Q and R have the meanings given above for formula (1a).

[0027] If the phosphine of the above formula (1b) is produced using the process according to the invention, the phosphide obtained after deprotonation of the phosphine of formula (5) is reacted with a compound of formula (6b): where X is a halogen atom (e.g. Cl, Br or I).

[0028] The compound of formula (4) can be made, for example, by a compound of formula (2) Ar 1< -Ar 2< -X (2) where X is a halogen atom (e.g. Cl, Br or I), Ar 1< and Ar 2< each have the meaning described above, is reacted with a metal-organic compound, preferably an organolithium compound (e.g. butyllithium), to form an intermediate, and the intermediate is subsequently reacted with a compound of formula (3) O=P(OC 1-4 -Alkyl) 2 X (3) where X is a halogen atom (e.g. Cl, Br or I).

[0029] Furthermore, the present invention relates to a palladium complex which contains the phosphine described above as a ligand L 1<.

[0030] The palladium complex can additionally contain one or more ligands L 2<, none of which are phosphines according to the invention. Suitable ligands for palladium complexes are known to those skilled in the art.

[0031] For example, the further ligands L 2< of the Pd complex according to the invention are independently selected from a halide (e.g. Cl -< , Br -< or I -< ); 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.

[0032] The ligand L 2<, 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.

[0033] If the ligand L2< 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 palladium complexes are known to those skilled in the art.

[0034] The phosphine ligand L 2< , which is not a phosphine according to the invention, is for example a tri-C 1-6 alkylphosphine, a tri-C 5-7 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 C 1-4 haloalkyl groups (e.g. -CF 3 ), C 1-4 alkyl groups (e.g. methyl) or C 1-4 alkoxy groups (e.g. methoxy).

[0035] For example, the phosphine ligand L 2< has one of the following formulas (7.1), (7.2) or (7.3):

[0036] Alternatively, the phosphine ligand L 2< can be a phosphine of the following formula (8): P(R 1< )(R 2< )(R 3< ) (8) where R 1< and R 2< are independently selected from C 1-6 alkyl and C 5-7 cycloalkyl (e.g. cyclohexyl), R 3< is biphenyl, which is optionally substituted by one or more C 1-6 alkyl groups, C 1-6 alkoxy groups, phenyl groups or pyridyl groups.

[0037] For example, the phosphine ligand L 2< has one of the following formulas (8.1), (8.2), (8.3) or (8.4):

[0038] The palladium complex according to the invention has, for example, the following formula (10): where L 1< is a phosphine according to the invention, L 2a< and L 2b< are each a ligand that is not a phosphine according to the invention.

[0039] Regarding suitable ligands L2a< and L2b<, reference can be made to the above descriptions of ligand L2<. For example, the ligands L2a< and L2b< of the Pd complex according to the invention are independently selected from a halide (e.g., Cl<, Br<, or I<); 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.

[0040] An exemplary palladium complex of the present invention has the following formula (10.1): where the ligands L 2a< and L 2b< have the meanings given above and p is 0, 1, 2, 3 or 4.

[0041] For example, the ligand L 2a< is dibenzylideneacetone (dba) or acetonitrile and the ligand L 2b< is selected from one of the ligands listed above for L 2<.

[0042] Another exemplary palladium complex of the present invention has the following formula (10.2): where p is 0, 1, 2, 3 or 4.

[0043] Another exemplary palladium complex of the present invention has the following formula (10.3): where p is 0, 1, 2, 3 or 4.

[0044] As mentioned above, the phosphine according to the invention and a 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 palladium complex containing the phosphine according to the invention as a ligand, in situ This occurs in the reaction medium of the coupling reaction.

[0045] The present invention therefore also relates to a composition containing a palladium compound and the phosphine according to the invention described above.

[0046] The palladium compound of the composition according to the invention typically does not contain any phosphine according to the invention.

[0047] Optionally, the composition can be in the form of a kit containing the palladium compound and the phosphine according to the invention in separate containers.

[0048] The palladium compound is, for example, a palladium salt or a palladium complex whose ligands are not a phosphine according to the invention.

[0049] The 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.

[0050] If the palladium compound is a palladium complex, its ligands are selected independently of one another, for example, from a halide (e.g., Cl⁻, Br⁻, or I⁻); 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 polyene (e.g., a polyene with 2-4 double bonds, preferably a cyclic polyene, in particular a cyclic polyene with 2-4 double bonds such as cyclooctadiene or cyclooctatetraene); 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.

[0051] Regarding the phosphine ligand, which is not a phosphine according to the invention, reference can be made to the above descriptions of ligand L2. 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-C1-6 alkylphosphine, a tri-C5-7 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 C1-4 haloalkyl groups (e.g., -CF3), C1-4 alkyl groups (e.g., methyl), or C1-4 alkoxy groups (e.g., methoxy).Alternatively, the phosphine ligand, which is not a phosphine according to the invention, can be, for example, a phosphine of the formula (8) described above.

[0052] Examples of palladium compounds of the composition according to the invention include: a palladium dibenzylidene complex (e.g., Pd2(dba)3 or Pd(dba)2); PdCl2(PR3)2, wherein R is a phenyl (optionally substituted with one or more C1-6 alkyl groups), a C5-7 cycloalkyl, or a C1-6 alkyl; a palladium acetate (e.g., Pd2(OAc)3); a palladium acetylacetonate; a PdX2, wherein X is a halide or pseudohalide; a Pd(RCN)2Cl2, wherein R is a phenyl or methyl.

[0053] The present invention also relates to the use of the above-described palladium complex or the above-described composition according to the invention as a catalyst in a cross-coupling reaction.

[0054] The cross-coupling reaction is, for example, a CC or CN cross-coupling reaction.

[0055] 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 each other in the presence of a palladium-containing catalyst (and preferably a base) to form a CN bond.

[0056] 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 palladium-containing catalyst to form a CC bond.

[0057] The present invention further relates to a process for the production of an aryl or heteroarylamine, wherein a compound of formula (9) Ar-X (9) wherein Ar is an aryl or heteroaryl, X is a halogen atom, a sulfonate group (e.g. trifluoromethanesulfonate -O-Tf) or a pseudohalogen group (e.g. -CN, -OCN or -NCO), reacted with a primary or secondary amine in the presence of the above-described palladium complex or the above-described composition according to the invention.

[0058] 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. Examples Production of a cyclic biarylphosphine according to the invention

[0059] A cyclic biarylphosphine according to the invention of the following formula (I) was produced according to the following reaction scheme:

[0060] Chemical name of the cyclic biarylphosphine of formula (I): 4,4-Dimethyl-1-(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)-1,4-phosphasilinane. Preparation of the intermediates (chemical name: Diethyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonate) and (chemical name: 2',4',6'-Triisopropyl-[1,1'-biphenyl]-2-yl)phosphine) was carried out according to the syntheses described by S. Shekhar et al., ACS Catal., 2019, 9, pp. 11691-11708. Diethyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonate:

[0061] 2'-Iodo-2,4,6-triisopropyl-1,1'-biphenyl (438 mg; 1.08 mmol; 1.00 equiv.) under argon was dissolved in degassed, dry THF (5 mL), and n-BuLi (2.50 M in hexane; 0.47 mL; 1.10 mmol; 1.10 equiv.) was added dropwise at -78 °C for 30 minutes. The solution was stirred at -78 °C for 30 minutes. Diethyl chlorophosphate (0.19 mL; 1.29 mmol; 1.20 equiv.) was added at -78 °C, and the solution was stirred for another 30 minutes at -78 °C. The reaction solution was then stirred at room temperature for 5 hours. The reaction was quenched with a saturated aqueous solution of NH₄Cl (7 mL), filtered, and the aqueous phase extracted with EtOAc (3 × 7 mL). The combined organic phases were washed with saturated sodium chloride solution (7 mL) and dried over Na₂SO₄. The solvent was in vacuoThe residue was removed. It was purified by column chromatography (silica gel, hexane / EtOAc: 0-60% EtOAc). The product (335 mg; 0.80 mmol; 75%) was obtained as a colorless solid. (2',4',6'-Triisopropyl-[1,1'-biphenyl]-2-yl)phosphine:

[0062] LiAlH₄ (1.00 M in THF; 5.04 mL; 5.04 mmol; 3.00 equiv.) was added under argon at 0 °C to degassed, dry THF (5 mL). Trimethylchlorosilane (0.64 mL; 5.04 mmol; 3.00 equiv.) was added at 0 °C and the solution was stirred for 30 minutes at 0 °C. The solution was added dropwise to a solution of diethyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonate (335 mg; 0.80 mmol; 1.00 equiv.) in THF (5 mL) at 0 °C. The reaction solution was stirred overnight at room temperature, then cooled to 0 °C and quenched with EtOAc (10 mL) and an aqueous 1 M HCl solution (26 mL). The reaction mixture was stirred for one hour and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over Na₂SO₄, and the solvent was removed. in vacuo removed. The product (239 mg; 0.76 mmol; 95%) was obtained as a colorless solid. 4,4-Dimethyl-1-(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)-1,4-phosphasilinane:

[0063] (2',4',6'-Triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (200 mg; 0.64 mmol; 1.00 equiv.) was dissolved in dry, degassed THF (3 mL). n-BuLi (2.5 M in hexane; 0.51 mL; 1.28 mmol; 2.00 equiv.) was added dropwise at -78 °C. The mixture was stirred for 10 minutes at room temperature. Subsequently, bis(bromoethyl)dimethylsilane (175 mg; 0.64 mmol; 1.00 equiv.) was added at -78 °C. The reaction was stirred for 4 hours at room temperature. The reaction was quenched with a degassed, aqueous, saturated solution of NH₄Cl (5 mL). The aqueous phase was washed with degassed, dry EtOAc (3 × 7 mL) and the combined organic phases were dried over Na₂SO₄. The solvent was in vacuo removed. The product (259 mg; 0.61 mmol; 95%) could be isolated as a colorless, viscous liquid. Use of compositions containing a biarylphosphine and a palladium compound as a catalyst in a Buchwald-Hartwig coupling

[0064] In the following examples 1-13 according to the invention, the cyclic biarylphosphine of formula (I) was used, i.e.:

[0065] In comparison example 1, a non-cyclic biarylphosphine of the following formula (II) was used:

[0066] In all examples (i.e., examples 1-13 according to the invention and comparative example 1), a palladium dibenzylidene complex (Pd₂(dba)₃) was used as the palladium compound. This palladium compound and the phosphine of formula (I) or (II) were added to the reaction medium, such that in situ a palladium complex that contains phosphine as one of its ligands was able to form.

[0067] In Example 1, 2-chloroquinoline and piperidine were used as reactants for the Buchwald-Hartwig coupling. Example 1:

[0068] 2-Chloroquinoline (150 mg; 0.92 mmol; 1.00 equiv.) was dissolved in dry, degassed toluene (6 mL). Pd₂(dba)₃ (16.8 mg; 0.02 mmol; 0.02 equiv.), NaOtBu (123 mg; 1.28 mmol; 1.40 equiv.), the cyclic biarylphosphine of formula (I) (0.5 M in toluene; 0.07 mL; 0.04 mmol; 0.04 equiv.), and piperidine (109 mL; 1.10 mmol; 1.20 equiv.) were added. The reaction was stirred at 60 °C for 2 hours and then quenched with an aqueous, saturated solution of NH₄Cl. The aqueous phase was washed with EtOAc (3 × 8 mL) and the combined organic phases were dried over Na₂SO₄. The solvent was in vacuo The product was removed. It was purified by column chromatography (silica gel, hexane / EtOAc: 20 / 1). 2-(Piperidin-1-yl)quinoline (173 mg; 0.81 mmol; 89%) was isolated as a colorless solid.

[0069] In Examples 2-13 according to the invention, the reactants were varied (see Table 1 below), but the synthesis conditions were identical to those used in Example 1.

[0070] In comparative example 1, the reactants and synthesis conditions were identical to those used in Example 1. However, instead of the phosphine of formula (I) according to the invention, the phosphine of formula (II) was used.

[0071] The results of examples 1-13 according to the invention are summarized in Table 1 below. Table 1: Amines used as reactants, reaction products obtained in the Buchwald-Hartwig coupling and product yields in Examples 1-13 according to the invention. Example Heteroaryl Amin reaction product Yield [%] 1 88 2 74 3 100 4 42 5 86 6 95 7 67 8 79 9 82 10 100 11 98 12 40 13 86

[0072] Although in all examples one of the reactants was an N-heterocyclic aryl halide 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.

[0073] The result of comparison example 1 is shown in Table 2 below. Table 2: Amines used as reactants and product yield in the Buchwald-Hartwig coupling in comparative example 1 Heteroaryl Amin Desired reaction product yield Example 1 0% Use of a composition containing a cyclic biarylphosphine according to the invention and a palladium compound as a catalyst in a Suzuki-Miyaura coupling

[0074] Using a cyclic biarylphosphine of formula (I) according to the invention, a Suzuki-Miyaura coupling was carried out in Examples 14-17 according to the invention with the reactants and reaction conditions given in the following reaction scheme and in Table 3. The yields are given in Table 3. R = H, Me

[0075] In Example 14, 2-(o-tolyl)quinoline (i.e., R=Me) was prepared as follows: 2-chloroquinoline (150 mg; 0.92 mmol; 1.00 equiv.) was dissolved in dry, degassed THF (5 mL) and degassed water (1 mL). Pd₂(dba)₃ (16.8 mg; 0.02 mmol; 0.02 equiv.), CsOH × H₂O (216 mg; 1.28 mmol; 1.40 equiv.), and the cyclic biarylphosphine of formula (I) were dissolved. (0.5 M in toluene; 0.07 mL; 0.04 mmol; 0.04 equiv.) and o-tolylboronic acid (150 mg; 1.10 mmol; 1.20 equiv.) were added. The reaction was stirred at 60 °C for 4 hours and then quenched with a saturated aqueous solution of NH₄Cl. The aqueous phase was washed with EtOAc (3 × 8 mL) and the combined organic phases were dried over Na₂SO₄. The solvent was in vacuo The product was removed. It was purified by column chromatography (silica gel, hexane / EtOAc: 10 / 1). 2-(o-Tolyl)quinoline (179 mg; 0.82 mmol; 89%) was isolated as a colorless solid.

[0076] The Suzuki-Miyaura coupling in Examples 15-17 according to the invention was based on Example 14, but with the variations in synthesis conditions shown in Table 3.

[0077] In each of examples 14-17, the cyclic biarylphosphine of formula (I) and a palladium compound (Pd 2 (dba) 3 ) or Pd(OAc) 2 ) were added to the reaction medium, such that in situ a palladium complex which contains the cyclic biarylphosphine according to the invention as one of its ligands. Table 3: Reaction yields in examples 14-17 Pd compound R base solvent Reaction temperature yield Example 14 Pd 2 (dba) 3 Me CsOH x H₂O THF / H2O 60°C 89 % Example 15 Pd 2 (dba) 3 H NaOtBu THF / H2O room temperature 35 % Example 16 Pd 2 (dba) 3 H CsOH x H₂O THF / H2O room temperature 54 % Example 17 Pd(OAc) 2 H CsOH x H₂O THF / H2O room temperature 46 %

[0078] Although in all examples one of the reactants was an N-heterocyclic aryl halide and a rather short reaction time (4 hrs) at a mild reaction temperature was chosen, the use of the cyclic biarylphosphine according to the invention as a ligand of a palladium complex in a palladium-catalyzed Suzuki-Miyaura coupling led to high product yields.

Claims

1. A phosphine of formula (1) wherein - Q is SiR3R4; - m is 1, 2 or 3; n is 1, 2 or 3; under the proviso that the following relationship is met: 3 ≤ m + n ≤ 5; - the groups R are, independently of one another, a hydrogen atom or a C1-4 alkyl; or two groups R that bind to the same carbon atom are in each case a divalent alkylene group and together with the carbon atom to which they are bound form a 4- to 7-membered ring; or two groups R that bind to different carbon atoms are in each case a divalent alkylene group and together with the carbon atoms to which they are bound form a 4- to 7-membered ring; - Ar1 is a phenyl or naphthyl optionally substituted with one or more C1-6 alkyl groups; - Ar2 is a phenyl or naphthyl optionally substituted with one or more C1-6 alkyl groups; - R3 and R4 are, independently of one another, a C1-4 alkyl or a phenyl optionally substituted with one or more C1-6 alkyl groups.

2. The phosphine according to claim 1, having the following formula (1a): wherein m is 0 or 1 (more preferably m = 1) and n is 1 or 2 (more preferably n = 1); k is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, or 5; Q and R each have the meaning indicated in claim 1.

3. The phosphine according to any one of claims 1 to 2, having the following formula (1b): wherein p is 0, 1, 2, 3, 4 or 5, more preferably 1, 2, 3 or 4.

4. A method for preparing the phosphine according to any one of claims 1 to 3, wherein a phosphine of formula (5)         Ar1-Ar2-PH2     (5) wherein Ar1 and Ar2 each have the meaning indicated in any one of claims 1-3, is at least partially deprotonated with a base and the resulting phosphide is reacted with a compound of formula (6) wherein X is a halogen atom, Q, R, m and n each have the meaning indicated in any one of claims 1-3.

5. The method according to claim 4, wherein the phosphine of formula (5) is prepared by reducing a compound of formula (4) wherein Ar1 and Ar2 each have the meaning indicated in any one of claims 1-3; in the presence of a reducing agent.

6. The method according to claim 4 or 5, wherein the compound of formula (4) is prepared by reacting a compound of formula (2)         Ar1-Ar2-X     (2) wherein X is a halogen atom, Ar1 and Ar2 each have the meaning indicated in any one of claims 1-3, with an organometallic compound, preferably an organolithium compound, to form an intermediate product, and by subsequently reacting the intermediate product with a compound of formula (3)         O=P(O-C1-4 alkyl)2X     (3) wherein X is a halogen atom.

7. A palladium complex containing the phosphine according to any one of claims 1 to 3 as a ligand L1.

8. The palladium complex according to claim 7, additionally containing one or more ligands L2, each of which is not a phosphine according to any one of claims 1 to 3.

9. The palladium complex according to claim 8, wherein the ligands L2 are independently selected from a halide; an aryl; a nitrile; a carboxylate; a conjugated dienone; a phosphine which is not a phosphine according to any one of claims 1 to 3; an amine or acetylacetonate.

10. A composition containing - a palladium compound, and - the phosphine according to any one of claims 1-3.

11. The composition according to claim 10, wherein the palladium compound is a palladium salt or a palladium complex that does not contain a phosphine according to any one of claims 1-3 as a ligand.

12. The composition according to claim 10 or 11, wherein the palladium salt is a palladium acetate, a palladium halide, a palladium pseudohalide, or a mixture of at least two of these salts.

13. The composition according to claim 11, wherein the ligands of the palladium complex are independently selected from a halide; a phosphine which is not a phosphine according to any one of claims 1 to 3; a conjugated dienone; a polyene; a nitrile; an acetylacetonate; a carboxylate; a pseudohalide; an amine or an aryl.

14. A use of the palladium complex according to any one of claims 7 to 9 or the composition according to any one of claims 10 to 13 as a catalyst in a cross-coupling reaction.

15. The use according to claim 14, wherein the cross-coupling reaction is a C-C or a C-N cross-coupling reaction, in particular a Buchwald-Hartwig coupling.

16. A method for preparing an arylamine or heteroarylamine, wherein a compound of formula (9)         Ar-X     (9) wherein Ar is an aryl or heteroaryl, X is a halogen atom, a sulfonate group, or a pseudohalogen group, is reacted with a primary or secondary amine in the presence of the palladium complex according to any one of claims 7 to 9 or the composition according to any one of claims 10 to 13.