Synthesis and application of air-stable oxygen-substituted biaryl phosphasilinane ligands in c-x cross-coupling reactions

Abstract

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

Description

[0001] Synthesis and application of air-stable oxygen-substituted biaryl-phosphosphasilinane ligands in CX cross-coupling reactions

[0002] Description

[0003] The present invention relates to cyclic biarylphosphines and their use as ligands in metal complexes and in particular in palladium complexes in palladium-catalyzed cross-coupling reactions such as the Buchwald-Hartwig coupling and the Suzuki-Miyaura cross-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 biarylphosphorinanes and their use as Pd complex ligands for palladium-catalyzed coupling reactions. C. Maumela et al., RSC Adv., 2021, 11, pp. 26883-26891, describe biarylphosphanes and biarylphosphate rioxadamantanes 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] An object of the present invention is to provide suitable phosphines that can be used as ligands in metal complexes, in particular 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.

[0020] 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 and the Buchwald-Hartwig coupling, is described.

[0021] One object of the present invention is the description and protection of phosphasilinane ligands which have oxygen substituents in their biaryl moiety. This solves the problem of producing more active ligands for metal complexes, e.g., for palladium complexes, particularly for use as ligands for Pd-catalyzed cross-coupling reactions.

[0022] A first aspect of the invention is a phosphine of formula (1)

[0023]

[0024] where

[0025] R 1 each is independent of alkyl or aryl;

[0026] R 2 each is independent of alkyl or aryl;

[0027] p 0, 1, 2, 3 or 4 is,

[0028] q 1, 2, 3, 4, or 5 is,

[0029] R 3 , R 4 and R 5Each is independently of the other hydrogen, alkyl, e.g. C1-4-alkyl, cycloalkyl, e.g. Cs-7-cycloalkyl, or aryl, e.g. phenyl;

[0030] Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is;

[0031] R 6 and R 7 are 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.

[0032] Another aspect of the invention is a metal complex, in particular a palladium or nickel complex,

[0033] which uses a phosphine of formula (1) as ligand L 1 contains.

[0034] Another aspect of the invention is a combination containing

[0035] a metal compound, in particular a palladium or nickel compound and a phosphine of formula (1). 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.

[0036] 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.

[0037] The term halogen in the context of the present invention means F, CI, Br or I. Preferably halogen means Br or I.

[0038] The term alkyl, especially for one of the R groups 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 means a straight-chain or branched, unsubstituted or substituted C1-C10 alkyl, where R 1 , R 2 , R 6 and R 7 preferably a C1-8 alkyl, R 3 and R 4 preferably a C1-4 alkyl and R 5 preferably represent a C1-5 alkyl, wherein each alkyl may bear one or more substituents independently selected from halogen, amine, cycloalkyl, aryl, O-alkyl, O-cycloalkyl or O-aryl.

[0039] The term cycloalkyl, especially for one of the R groups 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 denotes a C3-8 cycloalkyl, where R 1 , R 2 , R 6 and R 7 preferably a C3-8 cycloalkyl, R 3and R 4 preferably a C3-5 cycloalkyl and R 5 Preferably, the cycloalkyl represents a C3-6 cycloalkyl, wherein each cycloalkyl may bear one or more substituents independently selected from halogen, amine, 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 signifies a carbocyclic ring system.

[0040] The term aryl, especially for one of the residues R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7C5-C14 means aryl or Ce-Ci4 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.

[0041] The cyclic biarylphosphines of the present invention contain in the heterocyclic ring according to formula (1) in addition to the phosphorus atom a further heteroatom as a ring atom, wherein this additional heteroring atom is selected from the group consisting of Si, Ge, Sn, As or Se.

[0042] The phosphine of formula (1) contains p residues OR 1 and q remainders OR 2, where p is 0, 1, 2, 3 or 4, and q is 1, 2, 3, 4, or 5. The sum of p + q is at least 1. Preferably, the sum of p + q is at least 2. Particularly preferred is p 1, 2, 3 or 4 and / or q is 1, 2, 3, 4 or 5.

[0043] OR 1 and OR 2 are preferably selected from O-methyl, O-phenyl, O-iso-propyl and O-tert-butyl.

[0044] R 3 , R 4 and R 5 are preferably selected from H, Methyl and Trimethylsilyl.

[0045] Q is preferably SiR 6 R 7 . R 6 and R 7 are preferably each independently selected from methyl, phenyl, which is optionally substituted with one or more Ci-6-alkyl, O-Ci-6-alkyl or O-C1-6-aryl groups.

[0046] The biarylphosphines according to the invention exhibit different electronic properties compared to the biarylphosphines described in WO 2023 / 088620, which are due to the presence of the substituents OR 1 and OR 2 are due to the aryl residues and result in completely new properties with regard to activity.

[0047] 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 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. The Metal I complex, e.g., a palladium or nickel complex, which contains the phosphine according to the invention as a ligand, can be prepared before the reaction to be catalyzed and optionally stored until it is used. 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.,The coupling reaction takes place in situ in the reaction medium of the palladium or nickel complex containing the phosphine according to the invention as a ligand.

[0048] 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 L 2 for metal complexes, e.g. palladium or nickel complexes are known to those skilled in the art.

[0049] 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.

[0050] The ligand L 2 The 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.

[0051] 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.

[0052] 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) and / or C1-4 alkoxy groups (e.g. methoxy).

[0053] For example, the phosphine ligand L 2 one of the following formulas (2), (3) or (4):

[0054]

[0055]

[0056] (4)

[0057] Alternatively, the phosphine ligand L 2 to be a phosphine of the following formula (5):

[0058] P(R 1 )(R 2 )(R 3 ) (5)

[0059] where R 1 and R2 are independently selected from Ci-6-alkyl and Cs-7-cycloalkyl, e.g., cyclohexyl, R 3 Biphenyl is optionally substituted by one or more Ci-6 alkyl or C1-6 haloalkyl groups, Ci-6 alkoxy or Ci-6 haloalkoxy groups, phenyl groups or pyridyl groups.

[0060] For example, the phosphine ligand L 2 one of the following formulas (6), (7), (8) or (9):

[0061]

[0062]

[0063] For example, a palladium complex according to the invention has the following formula (10):

[0064] L 1 — Pd - L 2a

[0065] L 2b (10)

[0066] where

[0067] L 1 a phosphine of formula (1) according to the invention, and

[0068] L 2a and L 2b each is a ligand that is not a phosphine according to the invention.

[0069] Regarding suitable ligands L 2a 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 I-; an aryl; a nitrile (e.g., acetonitrile, propionitrile, or benzonitrile); a carboxylate (e.g., acetate); a conjugated dienone, e.g., a 1,4-diene-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.

[0070] An exemplary palladium complex of the present invention has the following formula (11):

[0071]

[0072] where p, q, R 1 , R 2 , R 6 and R7 as well as the ligands L 2a and L 2b have the meanings given above.

[0073] 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.

[0074] Another exemplary palladium complex of the present invention exhibits the following

[0075]

[0076] where p, q, R 1 , R 2 , R 6 and R 7 have the meanings given above.

[0077] Another exemplary palladium complex of the present invention has the following formula (13):

[0078]

[0079] (13)

[0080] where p, q, R 1 , R 2 , 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 I-); a phosphine that is not a phosphine of 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] With regard to 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 relevant sections. 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), 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 formula (8) described above.

[0091] The following can be mentioned as exemplary palladium compounds of the combination according to the invention: a palladium dibenzylidene complex, e.g. Pd2(dba)3 or Pd(dba)2; PdCh(PR3)2, wherein R is a phenyl which is 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)3; 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 a cross-coupling reaction.

[0093] The cross-coupling reaction is, for example, a CC or CN cross-coupling reaction. 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 palladium-containing catalyst (and preferably a base) to form a CN bond.

[0094] 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.

[0095] The present invention also relates to a process for the production of an aryl or heteroarylamine, wherein a compound of formula (14)

[0096] Ar-X (14)

[0097] where

[0098] Ar is an aryl or heteroaryl

[0099] X is a halogen atom, a sulfonate group (e.g. trifluoromethanesulfonate-O-Tf) or a pseudohalogen group (e.g. -CN, -OCN or -NCO),

[0100] 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.

[0101] 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.

[0102] The invention will be explained in more detail below using the following examples.

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

[0104] A biaryl-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-Dimethyl-1-(2',,6'-dimethoxy-[1,T-biphenyl]-2-yl)-1,4-phosphasilinan

[0110] u.

[0111] Diethyl (2',6'-dimethoxy-f1,T-biphenyl1-2-yl)phosphonat:

[0112] 1,3-Dimethoxybenzene (5.9 mL, 45 mmol, 1.2 equiv.) was dissolved in THF (150 mL). nBuLi (2.5 M in hexane, 18 mL, 45 mmol, 1.2 equiv.) was added dropwise at room temperature and stirred for one hour. 1,2-Dibromobenzene (4.5 mL, 38 mmol, 1.0 equiv.) was added slowly dropwise, and the solution was stirred at room temperature for four hours. THF (150 mL) and TMEDA (tetramethylethylenediamine) (6.1 mL, 41 mmol, 1.1 equiv.) were added to the solution, which was then cooled to -78 °C. nBuLi (2.5 M in hexane, 16 mL, 41 mmol, 1.1 equiv.) was added dropwise and the solution was stirred at 0 °C. The solution was then cooled again to -78 °C and diethyl chlorophosphate (6.5 mL, 45 mmol, 1.2 equiv.) was added dropwise. The solution was warmed very slowly to room temperature overnight and stirred for a total of twelve hours. The reaction solution was treated with aqueous saturated NH4Cl solution (150 mL) and extracted with EtOAc (3 x 150 mL).The combined organic phases were washed with saturated aqueous NaCl solution (50 mL) and dried over Na₂SC>4. The solvent was removed under reduced pressure, and the crude product was recrystallized in EtOAc to yield diethyl (2',6'-dimethoxy-[1,T-biphenyl]-2-yl)phosphonate (9.01 g, 25.7 mmol, 69%) as a colorless solid.

[0113] 1 H NMR (400 MHz, CDCI3) ö [ppm] = 8.07 (dddd, J= 14.2, 7.7, 1.5, 0.6 Hz, 1H), 7.57 (tt, J = 7.5, 1.5 Hz, 1H), 7.42 (tdd, J= 7.6, 3.7, 1.3 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.21 (dddd, J = 7.7, 5.3, 1.3, 0.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 4.12 (q, J = 7.1 Hz, 1H), 3.98 - 3.73 (m, 4H), 3.69 (s, 6H), 1.20 - 1.11 (m, 6H).

[0114] 13 C{ 1H} NMR (101 MHz, CDCI3) ö [ppm] = 158.1, 139.06 ( = 7.4 Hz), 134.2 ( = 10.4 Hz), 132.1 ( = 1.0 Hz), 132.0 (J = 10.4 Hz), 129.3,128.6 (J = 186.4 Hz), 127.7, 126.9 (J = 15.3 Hz), 118.6 (J = 4.3 , 103.4, 61.6 (J = 5.6 Hz), 55.7, 16.4 (J = 6.8 Hz).

[0115] 31 P{ 1 H} NMR (162 MHz, CDCI3) ö [ppm] = 18.2.

[0116] 12

[0117] (2',6'-Dimethoxy-[1,T-biphenyl1-2-yl)phosphan:

[0118] Diethyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphonate (3.50 g, 10.0 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and cooled to 0 °C. LiAIH4 suspension (2 M in THF, 13 mL, 26 mmol, 2.5 equiv.) was cooled to 0 °C in a separate flask, and TMSCI (chloro(trimethyl)silane) (3.8 mL, 4.8 mmol, 2.5 equiv.) was added dropwise. This solution was stirred for 30 min at 0 °C, and then the phosphonate solution was slowly added dropwise (caution: gas evolution). The reaction mixture was stirred at room temperature for twelve hours, then cooled to 0 °C and quenched with degassed EtOAc (100 mL), followed by degassed aqueous HCl solution (1 M, 100 mL). After stirring for 30 min, the solution was extracted with EtOAc (2 x 100 mL), and the combined organic phases were washed with saturated NaCl solution, dried over Na₂SC > 4, and the solvent was removed under reduced pressure to yield (2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (2.45 g, 9).80 mmol, 98%) als farblosen Feststoff zu erhalten.

[0119] 1 H NMR (400 MHz, CDCI3) ö [ppm] = 7.71 - 7.60 (m, 1H), 7.44 - 7.32 (m, 2H), 7.32 - 7.25 (m, 1H), 7.22 (ddd, J = 7.5, 2.8, 1.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 3.75 (s, 6H), 3.67 (d, J = 203.4 Hz. 2H).

[0120] 13 C{ 1 H} NMR (101 MHz, CDCI3) ö [ppm] = 157.6, 139.3 (d, J= 14.7 Hz), 135.0 (d, J= 10.6 Hz), 131.0 (d, J= 3.0 Hz), 130.6 (d, J= 6.9 Hz), 129.4, 128.1, 127.2 (d, J= 4.3 Hz), 119.2 (d, J= 3.6 Hz), 104.1, 56.0.

[0121] 31 P{ 1 H} NMR (162 MHz, CDCI3) ö [ppm] = -128.3.

[0122] 13

[0123] 1-(2',6'-Dimethoxy-[1,T-biphenyl1-2-yl)-4,4-dimethyl-1,4-phosphasilinan:

[0124] The reaction was carried out in a 10 mL Young-Schlenk tube. (2',6'-Dimethoxy-[1,T-biphenyl]-2-yl)phosphine (246 mg, 1.00 mmol, 1.00 equiv.) and ABCN (24.4 mg, 100 pmol, 10 mol%) were dissolved in toluene (10 mL). Dimethyldivinylsilane (0.21 mL, 1.4 mmol, 1.4 equiv.) was added, the Schlenk tube was sealed, and the reaction was stirred at 100 °C for twelve hours. Column chromatography yielded 1-(2',6'-Dimethoxy-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-1,4-phosphasilinane (200 mg, 0.560 mmol, 56%) as a colorless solid.

[0125] 1 H NMR (400 MHz, C6D6) ö [ppm] = 7.63 (ddd, J = 7.7, 3.3, 1.9 Hz, 1H), 7.40 - 7.34 (m), 7.28 - 7.23 (m), 7.23 - 7.20 (m), 7.20 - 7.16 (m), 6.44 (d, J = 8.3 Hz, 2H), 3.30 (s, 6H), 2.07 - 1.78 (m, 4H), 0.99 - 0.71 (m, 4H), -0.01 (s, 3H), -0.16 (s, 3H).

[0126] 13 C{ 1H} NMR (101 MHz, C6D6) ö [ppm] = 158.5, 141.1 (d, J = 6.4 Hz), 141.1(d, J = 6.4 Hz,), 140.9 (d, J = 7.1 Hz), 131.8 (d, J = 5.3 Hz), 130.2, 129.1, 127.9, 127.4, 120.4 (d, J= 6.2 Hz), 104.1, 55.2, 24.0 (d, J= 13.7 Hz), 12.0 (d, J= 16.6 Hz), -2.2, -4.0.

[0127] 31 P{ 1 H} NMR (162 MHz, C6D6) ö [ppm] = -30.33.

[0128] HRMS (El) m / z: calculated for C2oH2602PSi [MH] + 357.1434, found: 357.1430. Use of compositions containing a biarylphosphine and a palladium compound as a catalyst in a Buchwald-Hartwig coupling

[0129] In the following described example 1 according to the invention, the cyclic biarylphosphine of formula (15) was used, i.e.:

[0130]

[0131] In comparative example 1, a non-cyclic biarylphosphine of the following formula (16) was used:

[0132]

[0133] In all examples (i.e., Example 1 according to the invention and Comparative Example 1), a palladium dibenzylidene complex (Pd2(dba)s) was used as the palladium compound. This palladium compound and the phosphine of formula (15) or (16) were added to the reaction medium so that a palladium complex containing the phosphine as one of its ligands could form in situ.

[0134] Example 1:

[0135] In Example 1, 2-chloroquinoline (17) and piperidine (18) were used as reactants for the Buchwald-Hartwig coupling. Pd2dba3 (1.0 mol%), 15 (3.0 mol%)

[0136] NaOtBu (1.4 equiv.)

[0137] Toluene (0.5 M), 60 °C, 3 h

[0138]

[0139] 97%

[0140] 17 (1.0 equiv.) 18 (1.2 equiv.)

[0141]

[0142] 4-Chloroquinoline (39 pL, 0.30 mmol, 1.0 equiv.), Pd₂dba₃ (2.8 mg, 3.0 pmol, 1 mol%), 1-(2',6'-Dimethoxy-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-1,4-phosphasilinane (15) (3.2 mg, 9.0 pmol, 3 mol%), and NaOtBu (40.4 mg, 0.420 mmol, 1.40 equiv.) were dissolved in toluene (0.6 mL). The solution was stirred at 60 °C for 15 min. Piperidine (36 pL, 0.36 mmol, 1.2 equiv.) was added, and the reaction was stirred at 60 °C for three hours. The solution was treated with H₂O (5 mL) and extracted with AcOEt₂ (3 x 5 mL). The combined organic phases were washed with saturated NaCl solution, dried over Na₂SO₄, and concentrated under reduced pressure. Column chromatography afforded the desired product (19) (61.7 mg, 0.290 mmol, 97%) as a colorless oil in almost quantitative yield.

[0143] 1H NMR (400 MHz, CDCh) ö [ppm] = 8.69 (d, J= 5.1 Hz, 1H), 8.10 - 7.97 (m, 2H), 7.65 (ddd, J= 8.4, 6.8, 1.5 Hz, 1H), 7.47 (ddd, J= 8.3, 6.8, 1.3 Hz, 1H), 6.82 (d, J= 5.1 Hz, 1H), 3.21 (t, J = 5.2 Hz, 4H), 1.86 (dq, J = 11.0, 5.2 Hz, 4H), 1.71 (q, J = 6.0 Hz, 2H).

[0144] Comparative example 1:

[0145] 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 (16) was used:

[0146] Pd2dba3(1.0 mol%), 16 (3.0 mol%)

[0147] NaOtBu (1.4 equiv.)

[0148] Toluene (0.5 M), 60 °C, 3 h

[0149]

[0150] 41%

[0151] 17 (1.0 equiv.) 18 (1.2 equiv.)

[0152]

[0153] In comparative example 1, the yield of product (19) was considerably lower at 41% than in example 1 according to the invention at 97%.

[0154] 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.

[0155] The preparation of product (19) in the presence of Pd2dba3 and NaOtBu as base, but using a different biarylphosphine as ligand, is described in Example 12 (Table 1) of WO 2023 / 088620. The yield is only 40%.

[0156] Use of a composition containing a cyclic biarylphosphine according to the invention and a palladium compound as a catalyst in a Suzuki-Miyaura coupling

[0157] Using a cyclic biarylphosphine of formula (15) according to the invention, a Suzuki-Miyaura coupling was carried out in Example 2 according to the invention under the reaction conditions shown in the following reaction scheme. The yield is given in the reaction scheme.

[0158] Pd(OAc)2(2.0 mol%), 15 (2.4 mol%)

[0159] Ba(OH)2(2.0 equiv.) 2-Me-THF / H2O (9:1, 0.5 M), 100 °C, 16 h

[0160]

[0161] 89%

[0162] 17 (1.0 equiv.) 20 (1.4 equiv.)

[0163]

[0164] Example 2:

[0165] Phenylboronic acid (20) (51 mg, 0.42 mmol, 1.4 equiv), Pd(OAc)₂ (1.4 mg, 6.0 pmol, 2 mol%), 1-(2',6'-Dimethoxy-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-1,4-phosphasilinane (15) (2.5 mg, 7.2 pmol, 2.4 mol%), and Ba(OH)₂ (103 mg, 600 pmol, 2.0 equiv) were dissolved in a mixture of H₂O (0.06 mL) and 2-MeTHF (0.54 mL). 4-Chloroquinoline (17) (39 pL, 0.30 mmol, 1.0 equiv) was added, and the solution was stirred at 100 °C for 16 h. The solvents were removed under vacuum and the residue was purified by column chromatography. The desired product (21) (55.0 mg, 0.268 mmol, 89% yield) was obtained as a colorless solid in very high yield.

[0166] 1 H NMR (400 MHz, CD2CI2) ö [ppm] = 8.93 (d, J = 4.4 Hz, 1H), 8.21 - 8.13 (m, 1H), 7.94 (dd, J = 8.6, 1.5 Hz, 1H), 7.73 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.58 - 7.47 (m, 6H), 7.35 (d, J = 4.4 Hz, 1H).

[0167] Comparative example 2:

[0168] In comparative example 2, the reactants and synthesis conditions were identical to those used in Example 2. However, instead of the phosphine of formula (15) according to the invention, the phosphine of formula (16) was used.

[0169] Pd(OAc)2(2.0 mol%), 16 (2.4 mol%) Ba(OH)2(2.0 equiv.) 2-Me-THF / H2O (9:1, 0.5 M), 100 °C, 16 h

[0170]

[0171] 74%

[0172] 17 (1.0 equiv.) 20 (1.4 equiv.)

[0173]

[0174] In comparative example 2, the yield of product (21) was considerably lower at 74% than in example 2 according to the invention at 89%.

[0175] Although in both example reactions and the respective comparison example one of the reactants was an N-heterocyclic aryl chloride and a relatively short reaction time (4 hours) 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. Thus, an increased yield was also achieved compared to the two comparison examples.

Claims

Claims 1. Phosphine of formula (1) where R 1 each is independent of alkyl or aryl; R 2 each is independent of alkyl or aryl; p 0, 1, 2, 3 or 4 is, q 1, 2, 3, 4, or 5 is, R 3 , R 4 and R 5 independent of each other are hydrogen, alkyl, cycloalkyl 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 or 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 selected independently 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, in particular as a catalyst in a coupling reaction, in particular 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 reaction, or a CN cross-coupling reaction, in particular a Buchwald-Hartwig coupling reaction.

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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