Synthesis of air-stable biaryl-phosphasilinane ligands via a radical-initiated double giese reaction

Abstract

The present invention relates to a novel efficient synthesis method for the preparation of biaryl-phosphasilinane ligands by a radical-initiated double Giese reaction of biarylphosphines with divinyl compounds.

Description

[0001] Synthesis of air-stable biaryl-phosphosphasilinane ligands via radical-initiated, double Giese reaction

[0002] Description

[0003] The present invention relates to a new efficient synthesis method for the preparation of biaryl-phosphasilinane ligands by a radical-initiated double Giese reaction of biarylphosphines on divinyl compounds.

[0004] A Giese reaction is defined as 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.

[0005] 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;

[0006] 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;

[0007] c) G. Bar, AF Parsons, “Stereoselective radical reactions” Chem. Soc. Rev. 2003, 32, 251-263;

[0008] d) GSC Srikanth, SL Castle, “Advances in radical conjugate additions” Tetrahedron 2005, 61, 10377-10441.

[0009] 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.

[0010] One object of the present invention is to solve the following problems / disadvantages of the aforementioned synthetic routes. The preparation of the dihalide compounds from the divinyl compounds is preparatively complex and leads to low or no yields for various substrates. Therefore, this class of substrates should be avoided whenever possible, and commercially available divinyl compounds should be used. Furthermore, the reactions of biarylphosphine via deprotonation and nucleophilic substitution with a dihalide compound have disadvantages. This method of preparation leads to low or no yields for various substrates. Moreover, the biaryl-phosphasilinane ligands obtained in this way are often difficult or impossible to isolate cleanly using this method.

[0011] The problem is solved by using a Giese reaction to prepare a biaryl-phosphosphasilinane compound of formula (1):

[0012]

[0013] where

[0014] Ar 1 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted;

[0015] Ar 2 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted;

[0016] R 3 , R 4 and R 5 independent of each other are hydrogen, alkyl, e.g., Ci-4-alkyl, cycloalkyl, e.g., Cs-7-cycloalkyl, or aryl, e.g., phenyl; or R 3 and R 4 each is a bivalent alkylene group and together with the carbon atom to which they are bonded forms a ring, e.g. a 4- to 7-membered ring and in particular a 5- to 6-membered ring; or, provided that two R groups 3 or R 4, which are bonded to different carbon atoms, each form a bivalent alkylene group and together with the carbon atoms to which they are bonded form a ring, e.g. a 4- to 8-membered ring and in particular a 5- to 6-membered ring;

[0017] Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is; and

[0018] 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.

[0019] In the Giese reaction mentioned above, a phosphine of formula (2) is formed.

[0020] Ar 1 -Ar 2 -PH2(2)

[0021] where

[0022] Ar 1Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted;

[0023] Ar 2 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted;

[0024] with a radical initiator and a divinyl compound of formula (3)

[0025]

[0026] where

[0027] R 3 , R 4 and R 5 are independently alkyl, e.g., Ci-4-alkyl, cycloalkyl, e.g., C5-7-cycloalkyl, or aryl, e.g., phenyl; or R 3 and R 4 each is a bivalent alkylene group and together with the carbon atom to which they are bonded forms a ring, e.g. a 4- to 7-membered ring and in particular a 5- to 6-membered ring; or, provided that two R groups 3 or R 4, which are bonded to different carbon atoms, each form a bivalent alkylene group and together with the carbon atoms to which they are bonded form a ring, e.g. a 4- to 8-membered ring and in particular a 5- to 6-membered ring;

[0028] Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is; and

[0029] 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,

[0030] implemented.

[0031] Suitable radical initiators with which a primary phosphine can be converted into a phosphorus radical by homolytic hydrogen abstraction are known to those skilled in the art. Examples of radical initiators include azobis(isobutyronitrile), azobis(cyclohexanecarbonitrile), and dibenzoyl peroxide.

[0032] The phosphine of formula (2) can be obtained, for example, by reacting a compound of formula (4)

[0033] >

[0034] <>

[0035]

[0036] where

[0037] Ar 1 and Ar 2 each have the meaning described above;

[0038] in the presence of a reducing agent is reduced to the phosphine of formula (2).

[0039] The reducing agent is, for example, a metal hydride (e.g., lithium aluminum hydride).

[0040] The compound of formula (4) can be made, for example, by a compound of formula (5)Ar 1 -Ar 2 -X (5)

[0041] where

[0042] X Halogen, e.g. CI, Br or I, is, and

[0043] Ar 1 and Ar 2 each have the meaning described above,

[0044] 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 (6)

[0045] O=P(O-Ci-4-Alkyl)2X (6)

[0046] where

[0047] X Halogen, e.g. CI, Br or I.

[0048] The term halogen in the context of the present invention means F, CI, Br or I. Preferably, halogen means as a substituent, e.g. as a substituent of the R groups. 3 , R 4 , R 5 , R 6 and R7 CI, Br or I. In compounds of formula (5) or (6), halogen means in particular CI, Br or I.

[0049] The term alkyl, especially for one of the R groups 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.

[0050] The term cycloalkyl, especially for one of the R groups 3 , R 4 , R 5 , R 6 and R 7 denotes a C3-8 cycloalkyl, where R 1 , R 2 , R 6 and R 7preferably a C3-8 cycloalkyl, R 3 and R 4 preferably a C3-5 cycloalkyl and R 5 preferably represent 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.

[0051] The term aryl, especially for one of the residues 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, amine, 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.

[0052] Ar 1 is selected from phenyl and naphthyl, wherein the phenyl or naphthyl is optionally singly or multiply substituted, e.g. with alkyl, in particular with one or more Ci-Ce alkyl groups or heteroatom groups, such as O-alkyl and amines.

[0053] Ar 2is selected from phenyl and naphthyl, wherein the phenyl or naphthyl is optionally singly or multiply substituted, e.g. with alkyl, in particular with one or more Ci-Ce alkyl groups or heteroatom groups.

[0054] Preferably Ar 1 and Ar 2 Each independently selected from possibly substituted phenyl.

[0055] R 3 , R 4 and R 5 are preferably selected from H, Methyl and Trimethylsilyl.

[0056] Q is preferably SiR 6 R 7 .

[0057] 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-aryl groups.

[0058] The phosphine produced by the process according to the invention can be used as a ligand for metal complexes, in particular palladium or nickel complexes. These metal complexes can in turn be used as catalysts for carrying out chemical reactions, especially coupling reactions. Thus, the use of phosphine as a ligand in metal complexes, e.g., Pd complexes, enables the performance of a C-C cross-coupling reaction or a C-N cross-coupling reaction, for example, the Buchwald-Hartwig coupling.

[0059] The invention will be explained in more detail below by means of the following examples.

[0060] Examples

[0061] Inventive production of a cyclic biarylphosphine

[0062] A biarylphosphosphinane of the following formula (7)

[0063]

[0064] was produced according to the following reaction scheme:

[0065]

[0066] Chemical name of the cyclic biarylphosphine of formula (7):

[0067] 4,4-Dimethyl-1-(2',4',6'-triisopropyl-[1,T-biphenyl]-2-yl)-1,4-phosphasilinan2'-iodo-2, 4, 6-triisopropyl-1,1'-biphenyl:

[0068] Magnesium shavings (1.75 g, 72.0 mmol, 2.40 equiv.) and 2-bromo-1,3,5-triisopropylbenzene (0.76 mL, 3.0 mmol, 0.10 equiv.) were placed in THF (5 mL). The Grignard reaction was started after stirring at room temperature (RT) for 10 min. A solution of 2-bromo-1,3,5-triisopropylbenzene (6.8 mL, 27 mmol, 0.90 equiv.) in THF (45 mL) was added dropwise, and the solution was stirred for one hour at 70 °C. 1-Bromo-2-chlorobenzene (3.3 mL, 28 mmol, 0.95 equiv.) was added dropwise over 40 minutes, and the mixture was stirred again for one hour at 70 °C. Iodine (8.4 g, 33 mmol, 1.1 equiv.) was dissolved in THF (50 mL), and the solution was slowly added to the ice-cooled reaction mixture. The mixture was filtered, the filtrate was concentrated, and the residue was dissolved in Et₂O (300 mL).The organic phase was washed with saturated aqueous Na₂S₂S₂S₃ solution (50 mL) and saturated aqueous Na₂Cl solution (50 mL), dried over MgSCl₂, and the organic solvent was removed under reduced pressure. The resulting solid was washed with methanol, yielding 2'-iodo-2,4,6-triisopropyl-1,1'-biphenyl (8.79 g, 21.6 mmol, 72%) as a colorless solid.

[0069] 1 H NMR (400 MHz, CDCI3) ö [ppm] = 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.38 (td, J = 7.5, 1.3 Hz, 1H), 7.19 (dd, J = 7.5, 1.7 Hz, 1H), 7.06 - 7.04 (s, 2H), 7.03 - 7.01 (m, 1H), 2.95 (p, J = 6.9 Hz, 1H), 2.39 (hept, J = 6.9 Hz, 2H), 1.31 (d, J = 6.9 Hz, 6H), 1.22 (d, J = 6.9 Hz, 6H), 1.01 (d, J = 6.9Hz, 6H).

[0070] 13 C{ 1 H} NMR (101 MHz, CDCI3) ö [ppm] = 148.7, 146.0, 145.9, 139.3, 138.9, 130.7, 128.4, 127.9, 120.9, 102.6, 34.3, 30.8, 25.0, 24.2, 23.6.

[0071] Diethyl(2',4',6'-triisopropyl-[1,T-biphenyl]-2-yl)phosphonat:

[0072] 2'-Ido-2,4,6-triisopropyl-1,1'-biphenyl (8.13 g, 20.0 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to -78 °C. nBuLi (2.5 M in hexane, 8.8 mL, 22 mmol, 1.1 equiv.) was added dropwise. The solution was stirred for one hour, and then diethyl chlorophosphate (3.5 mL, 24 mmol, 1.2 equiv.) was slowly added dropwise. The reaction mixture was warmed to room temperature overnight and then stirred for twelve hours at room temperature. The solution was treated with saturated aqueous NH4Cl solution (150 mL), the aqueous phase was separated, and the organic phase was extracted with AcOEt (3 x 150 mL). The combined organic phases were washed with saturated aqueous NaCl solution (50 mL), dried over Na₂SC>4, and the solvent was removed under reduced pressure. Column chromatography (silica, pentane / EtOAc = 10 / 1 then 1 / 1) was performed to detect diethyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonate (5.06 g, 12).1 mmol, 61%) to obtain a colorless solid.

[0073] 1 H NMR (400 MHz, CDCI3) o [ppm] = 8.09 - 7.93 (m, 1 H), 7.51 (tt, J = 7.5, 1.5 Hz, 1 H), 7.43 (tdd, J= 7.6, 3.6, 1.3 Hz, 1H), 7.02 (s, 2H), 3.85 (ddq, J= 10.3, 8.7, 7.1 Hz, 2H), 3.63 (ddq, J= 10.3, 8.9, 7.1 Hz, 2H), 2.92 (hept, J= 6.9 Hz, 14.8 Hz, 2Hz, 2.6 Hz). 2H), 1.27 (d, J= 7.0 Hz, 6H), 1.20 (d, J= 6.8 Hz, 6H), 1.08 (t, J= 7.1 Hz, 6H), 0.95 (d, J = 6.8 Hz, 6H).

[0074] 13 C{ 1 H} NMR (101 MHz, CDCh) ö [ppm] =148.1, 146.5, 143.8 (d, J= 9.9 Hz), 135.9 (d, J= 3.6 Hz), 133.1 (d, J = 10.1 Hz), 131.9 (d, J = 10.1 Hz), (d, J = 3.0 Hz), 128.7 (d, J = 191.5 Hz), 126.7 (d, J= 14.9 Hz), 120.2, 61.5 (d, J= 6.6 Hz), 34.4, 30.7, 25.5, 24.2, d, J = 16.2 (d, 26.6). 5.5 Hz).

[0075] 31 P{ 1 H} NMR (162 MHz, CDCh) o [ppm] = 18.2.

[0076] (2',4',6'-Trisopropyl-[1,T-biphenyl]-2-yl)phosphane:

[0077] Diethyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonate (2.92 g, 7.00 mmol, 1.00 equiv.) was dissolved in THF (20 mL). UAIH4 (2 M in THF, 9.0 mL, 18 mmol, 2.5 equiv.) was cooled to 0 °C in a separate flask, and TMSCI (chloro(trimethyl)silane) (2.3 mL, 18 mmol, 2.5 equiv.) was added dropwise. The solution was stirred at 0 °C for 30 min, and then the phosphonate solution was added dropwise. The reaction mixture was stirred for 12 hours and then quenched with degassed EtOAc (70 mL), followed by degassed hydrochloric acid (1 M, 70 mL), and stirred for 30 min. The solution was extracted with EtOAc (2x80 mL), the combined organic phases were washed with saturated aqueous NaCl solution (20 mL), dried over Na2SU4, and the solvent was removed under reduced pressure to obtain (2',4',6'-Triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (2.12 g, 6.79 mmol, 97%) as a colorless solid.

[0078] 1 H NMR (400 MHz, CDCI3) ö [ppm] = 7.60 (tdd, J= 6.6, 1.5, 0.7 Hz, 1H), 7.32 (td, J= 7.5, 1.6 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.13 (ddd, J = 7.4, 2.9, 1.5 Hz, 1H), 7.06 (s, 2H), 3.57 (d, J = 204.3 Hz, 2H), 2.95 (hept, J= 7.1 Hz, 1H), 2.52 -2.32 (hept, J= 7.1 Hz, 2H), 1.31 (d, J= 7.0 Hz, 6H), 1.19 (d, J= 6.9 Hz, 6H), 1.01 (d, J= 6.8 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCI3) ö [ppm] = 148.6, 146.1, 144.9 (d, J= 13.5 Hz), 136.2 (d, J = 3.4 Hz), 134.5 (d, J= 11.9 Hz), 130.8 (d, J= 7.0 Hz), 130.4 (d, J= 2.3 Hz), 128.0, 126.87 (d, J= 4.1 Hz), 121.0, 34.4, 30.6, 25.3, 24.2, 23.6 (d, J= 1.6 Hz).

[0079] 31 P{ 1 H} NMR (162 MHz, CDCI3) ö [ppm] = -127.28.

[0080] 4,4-Dimethyl-1-(2',4',6'-triisopropyl-[1,T-biphenyl]-2-yl)-1,4-phosphasilinan:

[0081] (2',4',6'-Triisopropyl-[1,T-biphenyl]-2-yl)phosphine (312 mg, 1.00 mmol, 1.00 equiv.) was mixed with ABCN (24.4 mg, 100 pmol, 10 mol%) and dimethyldivinylsilane (0.21 mL, 1.4 mmol, 1.4 equiv.) in a 10 mL Schlenk tube. Toluene (10 mL) was then added, the Schlenk tube was completely sealed, and the mixture was stirred at 100 °C for twelve hours. The solvent was removed under reduced pressure, and cold acetone was added to the residue. The obtained solid was filtered and washed with a little cold acetone to obtain 4,4-Dimethyl-1-(2',4',6'-triisopropyl-[1 , 1'-biphenyl]-2-yl)-1 ,4-phosphasilinane (233 mg, 0.550 mmol, 55%) as a colorless solid.

[0082] 1H NMR (400 MHz, CDCI3) ö [ppm] = 7.68 (ddd, J = 7.6, 3.4, 1.5 Hz, 1H), 7.50 - 7.28 (m, 2H), 7.16 - 7.06 (he (m, 1H), 7.9, 7.2 H 6.9 Hz, 1H), 2.40 (hept, J= 6.7 Hz, 2H), 2.00 - 1.63 (m, 4H), 1.31 (d, J= 6.9 Hz, 6H), 1.14 (d, J= 6.9 Hz, J=6H. 8), 1. 0.98 − 0.71 (m, 3H), 0.11 (s, 3H), −0.06 (s, 3H).

[0083] 13 C{ 1 H} NMR (101 MHz, CDCI3) ö [ppm] = 147.7, 146.5 (d, J= 31.3 Hz), 146.0, 139.9 (d, J = 14.1 Hz), 136.7 (d, J= 6.3 Hz), J.0,30. (d, J = 2.1 Hz), 128.2, 126.9, 120.6, 34.1, 31.1, 30.7, 25.2, 24.1, 23.9 (d, J = 12.4 Hz), 23.2 (d, J = 1.3 = Hz), 23.2 (d, J = 1.1 = Hz). −2.1, −4.0.

[0084] 31 P{ 1 H} NMR (162 MHz, CDCI3) ö [ppm] = −36.0.

[0085] HRMS (El) m / z: berechnet für C27H4oPSi [MH] + :423.2631, gefunden: 423.2631.

[0086] The preparation of 4,4-dimethyl-1-(2',4',6'-triisopropyl-[1,T-biphenyl]-2-yl)-1,4-phospha-silinan is also described in WO 2023 / 088620. There, the product was isolated as a colorless, viscous liquid and thus in a lower purity than in the process according to the invention.

Claims

Claims 1. Method for the preparation of a phosphasilinane compound of general formula (1) where Ar 1 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted; Ar 2 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted; R 3 , R 4 and R 5 independent of one another are hydrogen, alkyl, in particular C1-4-alkyl, cycloalkyl, in particular Cs-7-cycloalkyl, or aryl, in particular phenyl; or R 3 and R 4 each is a bivalent alkylene group and together with the carbon atom to which they are bonded forms a ring, e.g. a 4- to 7-membered ring and in particular a 5- to 6-membered ring; or, provided that two R groups 3 or R 4, which are bonded to different carbon atoms, each form a bivalent alkylene group and together with the carbon atoms to which they are bonded form a ring, e.g. a 4- to 8-membered ring and in particular a 5- to 6-membered ring; Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is; andR 6 and R 7 are independently alkyl, in particular Ci-4-alkyl, cycloalkyl, in particular Cs-7-cycloalkyl or aryl, in particular phenyl; or Re and R? 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, where a phosphine of formula (2) Ar 1 -Ar 2 -PH2(2) where Ar 1phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted; and Ar 2 Phenyl or naphthyl, where the phenyl or naphthyl may optionally be singly or multiply substituted; with a radical initiator and a divinyl compound of formula (3) where R 3 , R 4 and R 5 independent of each other are hydrogen, alkyl, cycloalkyl or aryl; or R 3 and R 4 each is a bivalent alkylene group and forms a ring together with the carbon atom to which it is bonded; or, provided that two R groups are present 3 or R 4 , which are bonded to different carbon atoms, each is a bivalent alkylene group and together with the carbon atoms to which they are bonded form a ring;Q SiR 6 R 7 , GER 6 R 7, SnR 6 R 7 , AsR 6 , S, SO2 or Se is; and 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; Q SiR 6 R 7 , GER 6 R 7 , SnR 6 R 7 , AsR 6 , S, SO2 or Se is; and 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, is being implemented.

2. The method of claim 1, wherein Ar 1 and Ar 2 Each is independently selected from possibly substituted phenyl.

3. Method according to claim 1 or 2, wherein Q SiR 6 R 7 is.

4. A method according to any one of claims 1-3, wherein the phosphine of formula (2) is produced by preparing a compound of formula (4) where Ar 1 and Ar 2 each have the meaning specified in claim 1 or 2; is reduced in the presence of a reducing agent.

5. Method according to any one of claims 1-4, wherein the compound of formula (4) is produced by reacting a compound of formula (5) Ar 1 -Ar 2 -X (5) where X is a halogen, and Ar 1 and Ar 2 each have the meaning specified in claim 1 or 2, is reacted with a metal-organic compound, preferably an organolithium compound, to form an intermediate, and the intermediate is subsequently reacted with a compound of formula (6) O=P(O-Ci-4-Alkyl)2X (6) where X is halogen.

6. Method according to claim 5, wherein X in the compounds of formula (5) and (6) is selected from CI, Br and I.

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