WO2019170163A1 - 三联芳单膦配体、它们的制备方法和在催化偶联反应中的用途 - Google Patents

三联芳单膦配体、它们的制备方法和在催化偶联反应中的用途 Download PDF

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WO2019170163A1
WO2019170163A1 PCT/CN2019/079966 CN2019079966W WO2019170163A1 WO 2019170163 A1 WO2019170163 A1 WO 2019170163A1 CN 2019079966 W CN2019079966 W CN 2019079966W WO 2019170163 A1 WO2019170163 A1 WO 2019170163A1
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phenyl
bis
tert
biphenyl
mmol
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PCT/CN2019/079966
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French (fr)
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施继成
周发斌
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东莞市均成高新材料有限公司
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Priority to US16/977,390 priority Critical patent/US11420987B2/en
Priority to EP19764436.2A priority patent/EP3766891B1/en
Priority to JP2020547057A priority patent/JP7070873B2/ja
Publication of WO2019170163A1 publication Critical patent/WO2019170163A1/zh
Priority to US17/738,532 priority patent/US11787827B2/en

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Definitions

  • the present invention relates to novel triple aryl monophosphine ligands (including P-chiral), processes for their preparation, their catalytic systems as key components and late transition metals, and their palladium catalyzed organic reactions, especially in catalysis. Coupling reactions, including the use of CC and CX bond formation reactions.
  • transition metal catalysts are often found to play an important role in the preparation of pharmaceuticals and organic materials.
  • the properties of transition metal catalysts are essentially dependent on the metal elements themselves, but are highly efficient. Achieve a wide variety of organic transformations, including asymmetric transformations, as well as contributions from the surrounding ligands to the regulation of metal-centered properties.
  • organic ligands, especially phosphine ligands, metal-centered electronic properties and metals The regulation of the three-dimensional environment around the center plays an important role.
  • the ⁇ electron donating ability of the coordination atom and the ability of ⁇ to accept the feedback electrons regulate the electronic properties of the metal center and affect the coordination strength of the coordination atom and the metal center of the alignment.
  • the radius of the atom and its surrounding size affect the coordination number of the metal center and the coordination arrangement of other ligands (including the substrate). Therefore, the electronic properties of the ligand cooperate with the steric properties to comprehensively affect the catalysis.
  • the various steps of the reaction play a key role in the efficient catalytic conversion of transition metals.
  • 1,1' -Di-naphthalene-2-phosphines such as diarylphosphines have superior catalytic properties in palladium-catalyzed Kumada coupling reactions, but Buchwald The human has expanded to diphenylphosphine, and has developed a series of excellent diphenylphosphines (SL Buchwald, et al., US 6,307,087; WO 2009/076622). In addition to the characteristics of rich electrons and large steric hindrance. The ⁇ electron in the benzene ring B in the diphenylphosphine can also form a weak coordination with the palladium center, which is an important reason for the excellent catalytic performance of the diarylphosphine ligand.
  • K. Tsuji et al. prepared a compound with a 2,6-bis(2,4,6-trimethylphenyl)phenylphosphorus skeleton (K. Tsuji, et al., Tetrahedron Lett., 1999, 40, 3203).
  • Smith et al. reported a triarylphosphine, 2,6-bis(2,4,6-trimethylphenyl)phenyl diphosphine (DmpPMe 2 , RCSmith, et al., Tetrahedron).
  • Aromatic phosphine (A. Kondoh, et al., J. Am. Chem. Soc., 2007, 129, 6996-6997, see below), including 8b-S ligand, and found 8b-S in Buchwald-Hartwig
  • the reaction has higher catalytic activity, but the preparation route of the phosphine ligand is long, the preparation of the raw material is not easy, and the application of expensive ruthenium as a catalyst is involved, and the two phenyl groups on the side of the phosphorus atom cannot avoid the formation of Pd. Defects of the -C bond dormant species. Recently, Sasaki et al.
  • Phenyl]phosphine S. Sasaki, et al., Sulfur and Silicon, 2014, 189, 1207-1215
  • Zhong Rao et al. disclose a method for forming a Grignard reagent with 2,6-diphenyl-1-bromobenzene and magnesium, and then reacting with diphenylphosphine chloride or di-tert-butylphosphine chloride under palladium catalysis.
  • Ortega-Moreno et al. prepared a series of terphenyldioxyl (alkynyl) phosphines in two pots (L. Ortega-Moreno, et al., Polyhedron, 2016, 116, 170-181. See the figure below).
  • the other two substituents on the phosphorus atom are limited to groups with less steric hindrance: methyl, ethyl, propenyl, 3-butenyl or ethynyl.
  • the present invention is specifically designed to prepare triarylphosphines in view of the twistable defects of the diphenylphosphine conformation of Buchwald et al.
  • the inventive concept also includes the introduction of inexpensive and readily available starting materials such as m-dichlorobenzene, especially in phosphorus atoms.
  • m-dichlorobenzene especially in phosphorus atoms.
  • Inventives of large steric hindrance a variety of new triarylphosphines have been prepared "one pot”.
  • the aromatic rings on both sides have a hetero atom (oxygen, nitrogen) substituent, a triarylphosphine, such as a methoxy group. The isopropoxy group is not reported.
  • the present invention provides a method which is carried out in two steps. That is, the process in which the terphenyl phenyl anion is first reacted with dichloro-tert-butylphosphine and then reacted with a t-butyl anion, which is also a feature of the present invention for preparing a triarylphosphine having a tertiary sterically hindered substituent such as a t-butyl group.
  • the 2,6-bis(2,4,6-triisopropylphenyl)phenyl-dicyclohexylphosphine (ZTPhos) provided by the invention is superior to the palladium-catalyzed amination reaction of chlorinated aromatic hydrocarbons.
  • the catalytic properties of the 8b-S ligand developed by Kondoh et al. These also embody the inventiveness of the present invention.
  • the present invention relates to: (1) a triaryl aryl monophosphine ligand; (2) a preparation method of a triaryl aryl monophosphine ligand; (3) a triaryl aryl monophosphorus palladium complex; (4) a triaryl aryl phosphine a catalytic system formed by combining a palladium salt or a complex; (5) a catalytic system of a combination of a triaryl arylphosphine ligand and a palladium, including a palladium complex coordinated by a triaryl phosphine, which is catalyzed by a halogenated aromatic hydrocarbon The use of the substrate in the coupling reaction.
  • the present invention provides a triple aryl monophosphine ligand having the formula Ia, Ib or a mixture thereof.
  • Ar is selected from the group consisting of (C6-C20) aryl groups, which may have 1 to 3 independently selected from (C1-C6)alkyl, -O(C1-C6)alkoxy, -N(C1-C6) a substituent of 2 dialkylamino or (C6-C10) aryl (the aryl group herein may also have 1 to 3 independently selected from (C1-C6) alkyl, -O(C1-C6) alkoxy or -N(C1-C6) 2 substituent of dialkylamino), even Ar can be selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-isopropylphenyl, 4- Tert-butylphenyl, 4-(dimethylamino)phenyl, 4-fluorophenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 2-methylphenyl, 2-methoxyphenyl, 2-(dimethyla
  • R 1 is selected from H, (C1-C6)alkyl, -O(C1-C6)alkoxy or -N(C1-C6) 2 dialkylamino, and may even be selected from methyl, methoxy, One of dimethylamino, isopropyl or tert-butyl;
  • R 2 and R 3 are each independently selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, (5-11 membered)heterocycloalkyl, (C6-C20)aryl, (C4-C20) a heteroaryl or -CH 2 (C6-C10) arylmethylene group, here (C3-C10)cycloalkyl, (5-11 membered)heterocycloalkyl, (C6-C20)aryl, (C4) -C20) Heteroaryl and -CH 2 (C6-C10) arylmethylene may have 1 to 3 independently selected from (C1-C6)alkyl, -oxy(C1-C6)alkoxy or- a substituent of a N(C1-C6) 2 dialkylamino group, wherein the hetero atom in the heteroaryl group is selected from an O, N or S atom, and even R 2 and R 3 may each independently be selected from a methyl group or an e
  • propyl isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, 2-methylphenyl, 2-isopropylphenyl, 2-methoxybenzene , 2-(dimethylamino)phenyl, 4-methylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 3,5-dimethyl Phenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-difluorophenyl, 3,5-di-tert-butylphenyl, 2,6-dimethylphenyl, 2,6 -dimethoxyphenyl, 2,6-diisopropylphenyl, 2,4,6-trimethoxyphenyl, 2-biphenyl, 2',6'-dimethyl-2-linking Phenyl, 2',6'-d
  • Ar is not 2,6-dimethylphenyl, 2,6-diisopropylphenyl, 2,4,6-trimethyl Phenyl or 2,4,6-triisopropylphenyl;
  • Ar is not 2,6-dimethylphenyl, 2,4,6-trimethylphenyl or 2,6-diisopropyl Phenyl.
  • the present invention provides a process for the preparation of the above described triarylarylphosphine ligands (Formula Ia, Ib or mixtures thereof).
  • the preparation thereof can be summarized as follows: a substituent R 1 or an unsubstituted group 3,5-Dichlorobenzene or 3-fluoro-5-chlorobenzene can be reacted with butyl lithium or sec-butyl at -100 to -70 ° C, followed by ArMgX (X can be Cl, Br or I) at - After a stepwise temperature increase reaction in the temperature range of 100 to 140 ° C, then, CuX 1 may be added with or without addition (X 1 may be Cl, Br or I), or tetrakis(triphenylphosphine) may or may not be added.
  • the preparation method provided by the invention One of the characteristics is that the preparation of the triaryl arylphosphine ligand can be achieved by "one pot" without separating and purifying the intermediate.
  • 2,6-diarylphenyl bromide can also be used as a raw material (Mark C. Lipke, et al., Organometallics, 2009, 28, 188-196), by being generally known in the art and positive (secondary or uncle)
  • the reaction of butyllithium, magnesium metal or isopropyl format reagent to prepare 2,6-diarylphenyl lithium or magnesium reagent, and then with PCl 3 , R 2 PCl 2 , R 3 PCl 2 or R 2 R 3 PCl Reaction, then, you can choose to add or not add CuX (X can be Cl, Br or I), you can also choose to add or not add tetrakis(triphenylphosphine) palladium, and then according to the added phosphorus chloride reagent , optionally R 2 M and / or R 3 M (M li, Na, MgX 1 or CuX 1 , where X 1 may be Cl, Br or I).
  • the substituent selected from the triple aryl monophosphine ligand provided by the present invention may constitute the following specific phosphine compound:
  • the present invention provides a triplet arylphosphine as a supporting metal with a transition metal complex of an element of Group VIII or Group IB of the Periodic Table of Elements, such as palladium, nickel, platinum, rhodium, ruthenium, osmium, cobalt or gold. Or a combination of a transition metal salt is used as a catalyst.
  • the triple aryl monophosphine provided by the present invention can be added to a suitable transition metal precursor to generate a catalytic system in situ.
  • the invention provides a series of triplo-aryl monophosphine coordinated palladium complexes having the formula II, III, IV, V, VI or VII:
  • L is a triple aryl monophosphine ligand as defined above;
  • X 2 is Cl, Br, I, methanesulfonate, benzenesulfonate, p-toluenesulfonate, formate, acetate or benzoate;
  • R 4 , R 5 , R 6 , R 7 or R 8 are each independently selected from H, methyl or phenyl.
  • the invention still further provides the use of an in situ generated palladium catalytic system and a palladium complex for catalyzing Suzuki coupling and Buchwald-Hartwig amination, while other transition metals are apparent to those skilled in the art.
  • Catalytic reactions especially Negishi coupling, Kumada coupling, Sonogashira acetylation and Heck coupling, can also use the catalytic system provided by the present invention.
  • the use of a palladium complex as a precursor of the catalyst is more advantageous for the catalytic reaction, and in some cases shortens the induction period of the catalytic system. Even if the palladium complex is directly used as a catalyst precursor, sometimes it is additionally Adding 0.5 to 100 times the triple aryl monophosphine ligand according to the present invention relative to palladium generally increases the life of the catalytic system.
  • palladium sources which can form catalysts in situ with the phosphine ligands of the present invention, including palladium acetate, palladium chloride, palladium acetylacetonate, palladium diphenylmethyleneacetone, palladium tetrakis(triphenylphosphine), diacetonitrile.
  • the phosphine ligand of the invention has good thermal stability under an inert atmosphere, so that the catalytic system provided by the invention can be used at temperatures up to 200 ° C or higher.
  • the reaction temperature is 20 to 180 ° C, or even 40. It is advantageous to carry out the catalytic reaction at 130 ° C.
  • the triple aryl monophosphine ligand of the present invention can also be used in a repressurization reaction, usually at a pressure of up to 100 atm, but preferably at a pressure of not higher than 60 to atmospheric pressure. Carry out the reaction.
  • THF represents tetrahydrofuran
  • TMEDA represents N,N,N',N'-tetramethylethylenediamine.
  • Phenylmagnesium bromide reagent was prepared from magnesium chips (0.29 g, 12.0 mmol), THF (10 mL) and bromobenzene (1.73 g, 11.0 mmol). Add 3,5 to another dry 250 mL two-neck bottle. - Dichlorotoluene (0.81 g, 5.0 mmol) and THF (15 mL), cooled to -78 ° C, then added 2.4 mL of n-butyllithium (2.5 M n-hexane solution, 6.0 mmol), stirred for 30 min, still at this temperature The above prepared format reagent was added by double needle tip, raised to room temperature and refluxed at 70 ° C for 6 h in an oil bath.
  • diphenylchlorophosphine (1.32 g, 6.0 mmol) was added by syringe, and the cold bath was removed. The mixture was stirred at room temperature for 6 h. 50 mL of a saturated sodium chloride solution was added and extracted with dichloromethane (3 mL). The organic layer was dried over Na 2 SO 4 Off), obtained white solid 1.39g, yield 65%.
  • Grignard reagent was prepared from magnesium turnings (0.06 g, 2.2 mmol), THF (5 mL) and 2,6-diphenyl-4-methyliodobenzene (0.74 g, 2.0 mmol). Cooled to -78 ° C, passed To the syringe was added diphenylchlorophosphine (0.49 g, 2.2 mmol), and the reaction was cooled to room temperature for 6 h. 20 mL of saturated sodium chloride solution was added, and extracted with dichloromethane (20 mL), and the organic layer was dried over Na 2 SO 4 After concentration under reduced pressure, the residue was purified by silica gel column chromatography eluting eluted
  • Grignard reagent was prepared from magnesium chips (0.61 g, 25.0 mmol), THF (10 mL) and 2,6-dimethylbromobenzene (4.44 g, 24.0 mmol). Add another two to a dry 250 mL two-neck bottle. Chlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stirred for 1h, still passed at this temperature The double-tip was added to the format reagent prepared above, and the mixture was warmed to room temperature and refluxed at 80 ° C for 6 h.
  • reaction solution was transferred to a 250 mL two-necked flask containing cuprous chloride (1.20 g, 12.0 mmol). After stirring for 20 min, it was cooled to -78 ° C, diphenylchlorophosphine (2.64 g, 12 mmol) was added by syringe, and the reaction was continued to room temperature for 6 h.
  • cuprous chloride (0.48 g, 4.8 mmol)
  • lithium reagent was added through a double needle tip.
  • diphenyl chlorophosphine (0.99 g, 4.5 mmol) was added by syringe, and the reaction was continued to room temperature for 6 h.
  • Grignard reagent was prepared from magnesium chips (0.61 g, 25.0 mmol), THF (10 mL) and 2,6-dimethylbromobenzene (4.44 g, 24.0 mmol). Add another two to a dry 250 mL two-neck bottle. Chlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stirred for 1h, still passed at this temperature The double-tip was added to the format reagent prepared above, and the mixture was warmed to room temperature and refluxed at 80 ° C for 6 h.
  • reaction solution was transferred to a 250 mL two-necked flask containing cuprous chloride (1.20 g, 12.0 mmol). After stirring for 20 min, it was cooled to -78 ° C, and a mixture of dichlorocyclohexylphosphine (2.22 g, 12.0 mmol) and THF (5 mL) was added, and the mixture was warmed to room temperature and refluxed at 40 ° C for 6 h. cooled to -80 ° C Add 2-thienylmagnesium bromide format reagent (36.0mmol), react in oil bath at 70 ° C for 12h.
  • Grignard reagent was prepared from magnesium chips (0.61 g, 25.0 mmol), THF (10 mL) and 2,4,6-trimethylbromobenzene (4.78 g, 24.0 mmol). Add to another dry 250 mL two-neck bottle. m-Dichlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stirred for 1h, still at this temperature The format reagent prepared above was added through a double needle tip, raised to room temperature, and refluxed in an oil bath at 80 ° C for 6 h.
  • reaction solution was transferred to a 250 mL two-pack containing cuprous chloride (1.20 g, 12.0 mmol). The mixture was stirred for 20 min, cooled to -78 ° C, and a mixture of dichlorophenylphosphine (2.15 g, 12.0 mmol) and THF (5 mL) was added, and the mixture was warmed to room temperature and refluxed at 40 ° C for 6 h. At -80 ° C, 2-dimethylaminophenyl magnesium bromide format reagent (30.0 mmol) was added, and the oil bath was reacted at 70 ° C for 12 h.
  • Grignard reagent was prepared from magnesium chips (0.29 g, 12 mmol), THF (10.0 mL) and 2,6-dimethoxybromobenzene (2.39 g, 11.0 mmol).
  • Grignard reagent was prepared from magnesium turnings (0.67 g, 27.5 mmol), THF (10.0 mL) and 2,6-dimethoxybromobenzene (5.40 g, 25.0 mmol). Another dry 250 mL two-necked bottle was added. Dichlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 5.0mL n-butyl lithium (2.4M n-hexane solution, 12.0mmol), stirred for 1h, the above preparation format reagent Transfer to a two-necked via a double needle tip, remove the cold bath and naturally warm to room temperature, then reflux at 70 ° C for 6 h in an oil bath.
  • Grignard reagent was prepared from magnesium turnings (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,6-dimethoxyiodobenzene (5.81 g, 22.0 mmol). Another dry 250 mL two-necked bottle was added.
  • Grignard reagent was prepared from magnesium chips (0.67 g, 27.5 mmol), THF (10 mL) and 2,4,6-triisopropylbromobenzene (7.08 g, 25.0 mmol).
  • THF 10 mL
  • 2,4,6-triisopropylbromobenzene 7.08 g, 25.0 mmol.
  • m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL)
  • cool to -78 ° C add 5.0mL n-butyl lithium (2.4M n-hexane solution, 12.0mmol) stir the reaction for 1h, still in At this temperature, the above-mentioned format reagent was added through a double needle tip, raised to room temperature, and refluxed at 80 ° C for 6 h in an oil bath.
  • reaction solution was transferred to another 250 mL with cuprous bromide (2.15 g, 15.0).
  • cuprous bromide (2.15 g, 15.0).
  • Grignard reagent was prepared from magnesium chips (0.67 g, 27.5 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (7.08 g, 25.0 mmol).
  • THF 1,2,4-triisopropylbromobenzene
  • reaction solution was transferred to another 250 mL of cuprous bromide (2.15 g, 15.0 mmol). After stirring for 15 min in a two-necked flask, the mixture was cooled to -78 ° C, and a solution of dichlorophenylphosphine (2.68 g, 15.0 mmol) in THF (5.0 mL) was added, and the mixture was warmed to room temperature for 12 h and then refluxed in an oil bath at 70 ° C for 6 h.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 10 mL
  • 2,4,6-triisopropylbromobenzene 6.23 g, 22.0 mmol.
  • m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL)
  • cool to -78 ° C add 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stir the reaction for 1h, still At this temperature, the above-mentioned format reagent was added through a double needle tip, and the temperature was raised to room temperature and refluxed at 80 ° C for 6 h in an oil bath.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 1,2,4-triisopropylbromobenzene
  • m-dichlorobenzene (1.47g, 10.0mmol)
  • THF 15mL
  • 4.8mL n-butyl lithium 2.5M n-hexane solution, 12.0mmol
  • the reaction solution was cooled to room temperature and transferred to a cuprous bromide (1.72 g, 12.0).
  • a cuprous bromide (1.72 g, 12.0).
  • stir the reaction for 15 min, then cool to -78 ° C, add a mixture of dichlorophenylphosphine (2.15 g, 12.0 mmol) and THF (5.0 mL), and warm to room temperature for 12 h, then oil
  • the mixture was refluxed at 70 ° C for 6 h. cooled to -78 ° C, 4.0 mL of isopropylmagnesium bromide solution (3.0 M in THF, 12.0 mmol) was added by syringe, and then allowed to react for 12 h.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 1,2,4-triisopropylbromobenzene
  • To another dry 250 mL two-neck bottle Add m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL), cool to -78 ° C, add 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stir the reaction for 2h, still in At this temperature, the above prepared format reagent was added through a double needle tip, raised to room temperature, and refluxed in an oil bath at 70 ° C for 12 h.
  • reaction solution was transferred to a cuprous bromide (1.72 g, 12.0 mmol).
  • a cuprous bromide (1.72 g, 12.0 mmol).
  • the mixture was stirred for 15 min, cooled to -78 ° C, and a mixture of dicyclohexylchlorophosphonane (2.79 g, 12.0 mmol) and THF (5.0 mL) was added, and the mixture was warmed to room temperature for 12 h and then in oil bath 70 It was refluxed for 6 h at ° C.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 1,2,46-triisopropylbromobenzene
  • m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL)
  • 4.8mL n-butyl lithium 2.5M n-hexane solution, 12.0mmol
  • stir the reaction for 2h still At this temperature, the format reagent prepared above was added through a double needle tip, the cold bath was removed, and the temperature was raised to room temperature, and then refluxed at 70 ° C for 12 h in an oil bath.
  • phosphorus trichloride (1.65 g, 12.0 mmol) was added by syringe. ), add to the room temperature and react for 6h, use.
  • Grignard reagent was prepared from magnesium turnings (0.39 g, 16.0 mmol), THF (15.0 mL) and 2,6-dimethoxy-2'-bromobiphenyl (4.39 g, 15.0 mmol). The reaction was carried out at room temperature. The liquid was transferred to another 250 mL two-necked flask containing cuprous chloride (1.49 g, 15.0 mmol), stirred for 15 min, and then cooled to -78 ° C. At this temperature, the reaction solution in the 250 mL two-necked flask was transferred through a double needle tip. To the bottle, remove the cold bath and warm to room temperature, then reflux at 110 ° C for 12 h in an oil bath.
  • Grignard reagent was prepared from magnesium chips (0.67 g, 27.5 mmol), THF (10 mL) and 1-bromo-2-methoxynaphthalene (5.93 g, 25.0 mmol). Add another dry 250 mL two-neck bottle. Dichlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 5.0mL n-butyl lithium (2.4M n-hexane solution, 12.0mmol), stirred for 2h, still at this temperature The format reagent prepared above was added to the above-prepared format reagent by double needle tip, and the mixture was refluxed to room temperature and refluxed at 70 ° C for 12 h.
  • reaction solution was transferred to a 100 mL portion of tetratriphenylphosphine palladium (0.17 g, 0.15 mmol).
  • the reaction was stirred for 20 min, cooled to -78 ° C, diphenylchlorophosphine (3.31 g, 15.0 mmol) was added by syringe, and the mixture was warmed to room temperature and refluxed at 70 ° C for 6 h.
  • Grignard reagent was prepared from magnesium turnings (0.56 g, 23.0 mmol), THF (10 mL) and 1-bromo-2-methoxynaphthalene (5.22 g, 22.0 mmol). Another dry 250 mL two-necked bottle was added to the two. Chlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stirred for 2h, still passed at this temperature The tip was added to the format reagent prepared above, and the mixture was warmed to room temperature and refluxed at 70 ° C for 12 h.
  • reaction solution was transferred to a 100 mL two-necked flask containing cuprous bromide (1.72 g, 12.0 mmol). After stirring for 20 min, it was cooled to -78 ° C, and a mixture of dicyclohexylchlorophosphonane (2.79 g, 12.0 mmol) and THF (5 mL) was added, and the mixture was warmed to room temperature and refluxed at 40 ° C for 12 h.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10 mL) and 1-bromo-2-methoxynaphthalene (5.22 g, 22.0 mmol). Add another dry 250 mL two-neck bottle Dichlorobenzene (1.47g, 10.0mmol) and THF (15mL), cooled to -78 ° C, added 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol), stirred for 2h, still at this temperature The format reagent prepared above was added through a double needle tip, raised to room temperature and refluxed at 70 ° C for 12 h in an oil bath.
  • reaction solution was transferred to a 250 mL two-necked flask containing cuprous chloride (1.20 g, 12.0 mmol). After stirring for 20 min, it was cooled to -78 ° C, and a mixture of dichlorocyclohexylphosphine (2.22 g, 12.0 mmol) and THF (5 mL) was added, and the mixture was warmed to room temperature and refluxed at 40 ° C for 6 h. °C, add 4-N,N-dimethylaminophenylmagnesium bromide solution (24.0mmol), oil bath 70 ° C reaction for 3 days.
  • Grignard reagent was prepared from magnesium chips (0.29 g, 12.0 mmol), THF (5 mL) and 1-bromo-2-methoxynaphthalene (2.61 g, 11.0 mmol). Add to another dry 250 mL two-neck bottle. Dichlorobenzene (0.74g, 5.0mmol) and THF (10mL), cooled to -78 ° C, added 2.4mL n-butyl lithium (2.5M n-hexane solution, 6.0mmol), stirred for 2h, still at this temperature The reagent prepared above was added to the above-prepared format reagent by double needle tip, and the mixture was refluxed to room temperature, and refluxed at 70 ° C for 12 h.
  • Grignard reagent was prepared from magnesium turnings (0.56 g, 23.0 mmol), THF (10.0 mL) and 2-methoxy(6-dimethylamino)iodobenzene (6.10 g, 22.0 mmol).
  • Dichlorobenzene (1.47g, 10.0mmol) and THF (15mL) were added to a 250mL two-necked flask, cooled to -78 ° C, 4.8mL n-butyl lithium (2.5M n-hexane solution, 12.0mmol) was added, and the reaction was stirred for 2 hours.
  • the above-prepared format reagent was added through a double needle tip, and the mixture was warmed to room temperature and refluxed at 70 ° C for 12 h.
  • the reaction solution was transferred to a cuprous chloride (1.20 g, 12.0).
  • a cuprous chloride (1.20 g, 12.0).
  • diphenylchlorophosphine (2.65 g, 12.0 mmol) by syringe, and warm to room temperature for 6 h.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 1,2,46-triisopropylbromobenzene
  • m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL)
  • 4.8mL n-butyl lithium 2.5M n-hexane solution, 12.0mmol
  • stir the reaction for 2h still At this temperature, the format reagent prepared above was added through a double needle tip, the cold bath was removed, and the temperature was raised to room temperature, and then refluxed at 70 ° C for 12 h in an oil bath.
  • phosphorus trichloride (1.65 g, 12.0 mmol) was added by syringe. ), add to the room temperature and react for 6h, use.
  • Grignard reagent was prepared from magnesium turnings (0.90 g, 37.0 mmol), THF (15.0 mL) and 2-bromothiophene (5.87 g, 36.0 mmol). The reaction solution was transferred to another 250 mL with chloride. Copper (1.19g, 12.0mmol) in a two-necked bottle, stirred for 15min, cooled to -78 ° C, at this temperature the reaction solution in the above 250mL two-necked bottle was transferred to the bottle through a double needle tip, remove the cold bath and rise to room temperature And refluxed in an oil bath at 70 ° C for 12 h.
  • Grignard reagent was prepared from magnesium chips (0.67 g, 27.5 mmol), THF (10.0 mL) and 2,6-dimethoxybromobenzene (5.40 g, 25.0 mmol). Add to another dry 250 mL two-neck bottle.
  • THF (5.0 mL) solution remove the cold bath and naturally warm to room temperature, then reflux at 70 ° C for 6 h in an oil bath. Cool to -78 ° C, then pass 15.0 mL of cyclohexylmagnesium bromide (1.0 M in THF, 15.0 mmol) and cuprous chloride (1.49 g, 15.0 mmol) in THF (10.0 mL) were transferred to a two-necked flask, removed from the cold bath and allowed to warm to room temperature, and then refluxed in an oil bath at 70 ° C for 12 h.
  • Grignard reagent was prepared from magnesium chips (0.56 g, 23.0 mmol), THF (10.0 mL) and 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol).
  • THF 1,2,46-triisopropylbromobenzene
  • m-dichlorobenzene (1.47g, 10.0mmol) and THF (15mL)
  • 4.8mL n-butyl lithium 2.5M n-hexane solution, 12.0mmol
  • stir the reaction for 2h still in At this temperature, the above-prepared format reagent was added through a double needle tip, raised to room temperature, refluxed at 70 ° C for 12 h in an oil bath, cooled to -78 ° C, and added with phosphorus trichloride (1.65 g, 12.0 mmol) by syringe. Raise to room temperature for 6h, set aside.
  • the Grignard reagent was prepared from magnesium turnings (0.39 g, 16.0 mmol), THF (10.0 mL) and 3,5-bis(trifluoromethyl)bromobenzene (4.40 g, 15.0 mmol). The reaction solution was transferred to room temperature. To another 250 mL two-necked flask with cuprous chloride (1.48 g, 15.0 mmol), stir the reaction for 30 min, then cool to -78 ° C, at which temperature the reaction solution in the 250 mL two-necked vial was transferred to the In the bottle, remove the cold bath and warm to room temperature, then reflux at 110 ° C for 12 h in the oil bath.

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Abstract

针对Buchwald等人发明的二联芳单膦(biaryl phosphine)配体存在的不足,本发明提供了间三联芳单膦配体,通式为Ia和Ib或它们的混合物,和它们的制备方法.本发明还描述了三联芳单膦配位的钯络合物.三联芳单膦配体与钯盐或络合物组成的体系、以及三联芳单膦配位的钯络合物在催化有机反应中的用途亦是本发明的一部分,特别是在催化涉及(拟)卤代芳烃为底物的偶联反应中的用途.

Description

三联芳单膦配体、它们的制备方法和在催化偶联反应中的用途 技术领域
本发明涉及新颖的三联芳单膦配体(包括P-手性),它们的制备方法,它们作为关键组分和后过渡金属组成的催化体系,以及它们在钯催化的有机反应特别是在催化偶联反应,包括C-C和C-X键形成反应,中的用途.
背景技术
多种有机反应可由过渡金属络合物高效催化实现,因此在药物和有机材料的制备过程中常常见到过渡金属催化剂起到重要作用.过渡金属催化剂的性能本质上取决于金属元素本身,但能高效地实现丰富多样的有机转化,包括不对称转化,还有来自于其周边的配体的对金属中心性质调控的贡献.其中,有机配体,尤其是膦配体,对金属中心电子性质和金属中心周围立体环境的调控起到重要作用.配位原子的σ给电子能力和π接受反馈电子能力调控了金属中心的电子性质以及影响了对位的配位原子与金属中心的配位强度,配位原子的半径及其占据的周边尺寸影响到金属中心的配位数和其它配体(包括底物)的配位排布.因此,配体的电子性质与立体性质协同、综合地影响了催化反应的各个步骤,对过渡金属能高效地催化有机转化起到了关键作用.
在过渡金属催化的许多有机反应中,偶联反应是非常重要的一类反应.因此,研发高效的手性或非手性膦配体以实现高效的催化偶联反应受到人们重视.下图列出几类用于钯催化偶联反应而性能优异的富电子、大立体位阻有机膦配体.Fu等人发现富电子、大立体位阻的三特丁基膦在Pd催化的偶联反应中具有优异的性能,掀起了开发这类新型膦配体的热潮(A.F.Littke,et al.,J.Am.Chem.Soc.，2000,122,4020).德国的Beller和耶鲁大学的Hartwig分别开发了富电子、大立体位阻的二金刚基膦(M.Beller,et al.,CN 101195641)和多取代苯基二茂铁膦QPhos(J.F.Hartwig,et al.,WO2002/011883),都已成为商业化产品.日本Takasago公司研发出带芳基环丙基骨架的膦配体(cBRIDP)(K.Suzuki，et al，WO2013/032035).虽然Hiyashi等人早就发现了1,1’-二联萘-2-膦这类二联芳膦在钯催化的Kumada偶联反应中具有优越的催 化性能,但是Buchwald等人扩展了到二联苯膦,又出研发一系列性能卓越的二联苯膦(S.L.Buchwald,et al.,US6,307,087；WO 2009/076622).除了富电子、大立体位阻的特点外,二联苯膦中的苯环B中的π电子还可以与钯中心产生弱配位作用,这是二联芳膦配体具有卓越催化性能重要原因.
Figure PCTCN2019079966-appb-000001
虽然Pd中心朝向苯环B,并与芳基电子产生配位作用是能量最低的优势构象,见下图,但是还存在构象扭转导致Pd中心背向苯环B(T.E.Barder,et al.,J.Am.Chem.Soc.,2007,129,5096).而这类钯背向苯环B的物种的催化活性仅相当于二环己基苯基膦钯,甚至,可以形成Pd-C键而成为休眠催态物种.这是这类二联芳膦存在的一个缺陷.
Figure PCTCN2019079966-appb-000002
为了克服磷上的孤对电子或其配位的钯中心背向苯环B的这种构象而导致的缺陷问题.Buchwald等人又制备了在苯环A上引入甲基或甲氧基的二联芳膦,见下图,据称能有利于孤对电子或其配位的钯中心朝向苯环B的这种构象.但引入的甲基或甲氧基,由于它们与磷原子上的取代基之间的相互排斥作用或/和氧原子与钯中心的配位作用,还是没能彻底弥补这个缺陷；在实际催化过程中,钯中心背向苯环B的这种构象可高达33％(B.P.Fors,D.A.Watson,M.R.Biscoe,S.L.Buchwald,J.Am.Chem.Soc.,2008,130,13552-13554).当然引入的甲基或甲氧基在防止钯与苯环A形成Pd-C键而阻止休眠态的形成上发挥了作用.Haddad等人利用氧亚甲基链固定构象使得孤对电子只能朝向苯环B,而彻底解决了二联苯膦的这个构象可扭转的缺陷(WO 2011/126917).这种通过氧亚甲基链固定构象的二联苯膦配体具有优越的催化性能,但是存在合成步骤长达10步以上的问题.
Figure PCTCN2019079966-appb-000003
三联芳膦配体,在磷原子的两边都有苯环,使得磷原子上的孤对电子总有一个苯环B可以朝向,则可以解决Buchwald等人的二联芳膦构象扭转的缺陷.出于为了获得稳定的P＝P双键物种的需要,B.Twamley等人制备了2,6-双(2,4,6-三异丙基苯基)苯基二氯化膦(B.Twamley,et al.,J.Am.Chem.Soc.,1999,121,3357-3367).出于研发光电材料的目的,利用三联苯膦的大立体位阻来稳定的P＝P双键物种,K.Tsuji等人制备了带2,6-双(2,4,6-三甲基苯基)苯基磷骨架的化合物(K.Tsuji,et al.,Tetrahedron Lett.,1999,40,3203).2004年,Smith等人报道了一种三联芳膦,2,6-双(2,4,6-三甲基苯基)苯基二甲膦(DmpPMe 2,R.C.Smith,et al.,Tetrahedron Letters,2004,45,8327-8330,见下图),在钯催化的Suzuki偶联反应中应用,但由于磷原子上有2个立体位阻较小的甲基基团,这个三联芳膦的催化性能明显不如Buchwald的二联膦.Buster等人也制备出三联芳膦(B.Buster,et al.,Inorganica Chimica Acta,2009,362,3465-3474),但磷原子上的另外2个取代基也都同时为甲基.Kondoh等人通过三炔烃在铑催化下成环的研究,制备了几种三联芳膦(A.Kondoh,et al.,J.Am.Chem.Soc.,2007,129,6996-6997,见下图),包括8b-S配体,同时发现8b-S在Buchwald-Hartwig偶联反应中具有较高的催化活性,但这种膦配体的制备路线长、原料制备不易以及涉及到应用贵重的铑作为催化剂等问题,另外磷原子边上是两个苯基不能避免形成Pd-C键休眠态物种的缺陷.最近,Sasaki等人制备出双(2,4,6-三异丙基苯基)[4-溴-2,6-双(4-叔丁基苯基)苯基]膦(S.Sasaki,et al.,Sulfur and Silicon,2014,189,1207-1215),其特征是磷原子对位是溴原子取代基,也未见到用于组成过渡金属催化体系中.饶等人公开了2,6-二苯基-1-溴苯与镁形成格氏试剂,再在钯催化下与二苯基氯化膦或二特丁基氯化膦反应得到方法,制备出(2,6-二苯基)-苯基二苯基膦配体和(2,6-二苯基)-苯基二特丁基膦配体(CN 105859774),但未给出该化合物的任何结构鉴定或理化数据.实际上，饶等人所要表述的是四(三苯基膦)钯在具有立体位阻的格氏试剂与 有大立体位阻的一氯化膦反应中的作用.
Figure PCTCN2019079966-appb-000004
2016年,Ortega-Moreno等人分“2锅”制备了一系列三联苯二烷(炔)基膦(L.Ortega-Moreno,et al.,Polyhedron,2016,116,170-181.见下图),但磷原子上的另外2个取代基限于立体位阻较小的基团：甲基、乙基、丙烯基、3-丁烯基或乙炔基.
Figure PCTCN2019079966-appb-000005
R＝Me,R’＝H:R”＝Me,Et,CH 2CH＝CH 2,CH 2CH 2CH＝CH 2；R＝Pr i,R’＝H:R”＝Me,Et,CH 2CH＝CH 2；R＝R’＝Pr i:R”＝Me；R＝R’＝Me:R”＝乙炔基.
本发明针对Buchwald等人的二联苯膦构象可扭转的缺陷而专门设计制备三联芳膦,本发明的创造性还包括可以从价廉易得原料,如间二氯苯,特别是在磷原子引进大立体位阻的取代基发明的,“一锅”地制备出多种新的三联芳膦.另外,两边的芳环上带杂原子(氧、氮)取代基三联芳膦,如甲氧基、异丙氧基,则未见到报道.在制备磷原子上同时带2个叔丁基这种立体位阻大的三联芳膦配体时,本发明提供了分2步来进行的方法,也就是三联苯基负离子先与二氯叔丁基膦反应再与叔丁基负离子反应的过程,这也是本发明得以制备带如叔丁基大立体位阻取代基的三联芳膦的特征.
本发明研制的2,6-双(2,4,6-三异丙基苯基)苯基-二环己基膦(XTPhos)在钯催化的Suzuki-Miyaura偶联反应中的催化性能明显优于Smith等人研制的DmpPMe 2的催化性能，另外在催化咔唑与4-氯甲苯的偶联反应中，性能优于Takasago公司的cBRIDP膦配体(其优于Buchwald的XPhos膦配体).而本发明提供的2,6-双(2,4,6-三异丙基苯基)苯基-二环己基膦(ZTPhos)在钯催化的氯代芳烃的胺化反应中的性能明显优于Kondoh等人所研制的8b-S配体的催化性能. 这些亦体现了本发明的创造性.
发明概述
本发明涉及：(1)三联芳单膦配体；(2)三联芳单膦配体的制备方法；(3)三联芳单膦配位的钯络合物；(4)三联芳单膦配体和钯盐或络合物组合形成的催化体系；(5)三联芳单膦配体和钯组合的催化体系,包括三联芳单膦配位的钯络合物,在催化涉及卤代芳烃为底物的偶联反应中的用途.
发明公开
第一方面,本发明提供了三联芳单膦配体,它们通式为Ia、Ib或它们的混合物,
Figure PCTCN2019079966-appb-000006
其中,Ar选自(C6-C20)芳基,其可以有1到3个独立地选自(C1-C6)烷基、-O(C1-C6)烷氧基、-N(C1-C6) 2二烷氨基或(C6-C10)芳基的取代基(这里的芳基同样可以有1到3个独立地选自(C1-C6)烷基、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷氨基的取代基),甚至Ar可以精选自苯基、4-甲基苯基、4-甲氧基苯基、4-异丙基苯基、4-叔丁基苯基、4-(二甲氨基)苯基、4-氟苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、2-甲基苯基、2-甲氧基苯基、2-(二甲氨基)苯基、2-异丙基苯基、2,6-二甲基苯基、2,6-二异丙基苯基、2,6-二甲氧基苯基、2,6-二异丙氧基苯基、2,6-双(二甲氨基)苯基、2,6-二甲氧基-3,5-二苯基-苯基、2,6-二甲氧基-3,5-双(3,5-二甲基苯基)-苯基、2,6-二异丙氧基-3,5-二苯基-苯基、2,6-二甲氧基-3,5-双(2,4,6-三异丙基苯基)-苯基、2-甲氧基-6-(二甲氨基)苯基、2,4,6-三甲基苯基、2,4,6-三甲氧基苯基、2,4,6-三异丙基苯基、二茂铁基、1-萘基、2-萘基、2-甲氧基-1-萘基或9-蒽基的一种；
R 1选自H、(C1-C6)烷基、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷基氨基,甚至可精选自甲基、甲氧基、二甲氨基、异丙基或叔丁基中的一种；
R 2和R 3各自独立地选自(C1-C10)烷基、(C3-C10)环烷基、(5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基或-CH 2(C6-C10)芳亚甲基,这里的(C3-C10)环烷基、 (5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基和-CH 2(C6-C10)芳亚甲基中可以有1到3个独立地选自(C1-C6)烷基、-氧(C1-C6)烷氧基或-N(C1-C6) 2二烷氨基的取代基,这里的杂芳基中的杂原子选自O、N或S原子,甚至R 2和R 3可以各自独立地精选自甲基、乙基、丙基、异丙基、正丁基、叔丁基、环戊基、环己基、金刚基、苯基、2-甲基苯基、2-异丙基苯基、2-甲氧基苯基、2-(二甲氨基)苯基、4-甲基苯基、4-氟苯基、4-甲氧基苯基、4-(二甲氨基)苯基、3,5-二甲基苯基、3,5-双(三氟甲基)苯基、3,5-二氟苯基、3,5-二叔丁基苯基、2,6-二甲基苯基、2,6-二甲氧基苯基、2,6-二异丙基苯基、2,4,6-三甲氧基苯基、2-联苯基、2’,6’-二甲基-2-联苯基、2’,6’-二甲氧基-2-联苯基、2’,6’-二异丙氧基-2-联苯基、2’,6’-双二甲氨基基-2-联苯基、2’,6’-二异丙基-2-联苯基、2’,4’,6’-三异丙基-2-联苯基、二茂铁基、2-呋喃基、2-噻吩基、2-苯并呋喃基、2-苯并噻吩基、2-吡啶基或2-四氢呋喃基；
当R 1＝H且Ar＝苯基时,R 2或和R 3不同时为叔丁基；
当R 1＝H且当R 2＝R 3＝甲基时,Ar不为2,6-二甲基苯基、2,6-二异丙基苯基、2,4,6-三甲基苯基或2,4,6-三异丙基苯基；
当R 1＝H且当R 2＝R 3＝乙基时,Ar不为2,6-二甲基苯基、2,4,6-三甲基苯基或2,6-二异丙基苯基.
第二方面,本发明提供了上面描述的三联芳单膦配体(通式为Ia、Ib或它们的混合物)的制备方法.其制备可以概括如下：带取代基R 1或未带取代基的3,5-二氯苯或3-氟-5-氯苯在-100到-70℃下与丁基锂或仲丁基作用后,再与ArMgX(X可以是Cl,Br或I)在-100到140℃温度范围内分阶段升温反应后,然后,可以选择再加入或不加入CuX 1(X 1可以是Cl,Br或I),也可以选择再加入或不加入四(三苯基膦)钯,根据加入氯化磷试剂的种类可选择在-100到30℃的温度范围内再加入PCl 3、R 2PCl 2、R 3PCl 2或R 2R 3PCl反应,再根据所加入的氯化磷试剂不同,选择加入R 2M和/或R 3M(M＝li,Na,MgX 1,CuX 1,这里的X 1可以是Cl,Br或I).本发明所提供的制备方法的特征之一是可以不需要分离提纯中间体“一锅”地实现制备三联芳单膦配体.
也可用2,6-二芳基苯基溴(碘)为原料(Mark C.Lipke,et al., Organometallics,2009,28,188-196),通过通常被本领域所熟知的与正(仲或叔)丁基锂、金属镁或异丙基格式试剂反应制得2,6-二芳基苯基锂或镁试剂,再与PCl 3、R 2PCl 2、R 3PCl 2或R 2R 3PCl反应,然后,可以选择再加入或不加入CuX(X可以是Cl,Br或I),也可以选择再加入或不加入四(三苯基膦)钯,再根据所加入的氯化磷试剂不同,选择加入R 2M和/或R 3M(M＝li,Na,MgX 1或CuX 1,这里的X 1可以是Cl,Br或I).
第三方面,本发明提供的三联芳单膦配体所选自的取代基可以构成下面具体膦化合物：
(2,6-二苯基-4-甲基苯基)-二苯基膦；
(2,6-二苯基-4-甲基苯基)-二环己基膦；
(2,6-二苯基-4-甲基苯基)-二叔丁基膦；
[2,6-双(2-甲基苯基)苯基]-二苯基膦；
[2,6-双(2-甲基苯基)苯基]-二环己基膦；
[2,6-双(2-甲基苯基)苯基]-二叔丁基膦；
[2,6-双(2,6-二甲基苯基)苯基]-二苯基膦；
[2,6-双(2,6-二甲基苯基)苯基]-二环己基膦；
[2,6-双(2,6-二甲基苯基)苯基]-环己基-2-噻吩基膦；
[2,6-双(2,6-二甲基苯基)苯基]-叔丁基-2-呋喃基膦；
[2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-苯基膦；
[2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-环己基膦；
[2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-叔丁基膦；
[2,6-双(2-甲氧基苯基)苯基]-二苯基膦；
[2,6-双(2-甲氧基苯基)苯基]-二环己基膦；
[2,6-双(2-甲氧基苯基)苯基]-二叔丁基膦；
[2,6-双(2-甲氧基苯基)苯基]-环己基-2-噻吩基膦；
[2,6-双(2-甲氧基苯基)苯基]-甲基-叔丁基膦；
[2,6-双(2-甲氧基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2-甲氧基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-二苯基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-二环己基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-苯基-异丙基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-环己基-2-噻吩基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-环己基-金刚基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-甲基-叔丁基膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,6-二甲氧基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,6-二异丙氧基苯基)苯基]-二苯基膦；
[2,6-双(2,6-二异丙氧基苯基)苯基]-二环己基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-二环己基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-苯基-环己基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-甲基-叔丁基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-苯基-异丙基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲基-2-联苯基]-甲基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-甲基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-环己基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二异丙基-2-联苯基]-环己基膦；
[2,6-双(2,6-二异丙基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,6-二异丙基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-二环己基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-苯基-环己基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-甲基-叔丁基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-环己基-异丙基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲基-2-联苯基]-正丁基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-甲基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-环己基 膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二异丙基-2-联苯基]-叔丁基膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2,4,6-三异丙基苯基)苯基]-环己基-[3,5-双(三氟甲基)苯基]膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-二苯基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-二环己基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-二叔丁基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-(2-二甲氨基苯基)-环己基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-(4-二甲氨基苯基)-环己基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-[2’,6’-二甲氧基-2-联苯基]-正丁基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-[2’,6’-二异丙基-2-联苯基]-环己基膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-双[3,5-二(三氟甲基)苯基]膦；
[2,6-双(2-甲氧基-1-萘基)苯基]-[3,5-双(三氟甲基)苯基]-甲基膦；
[2,6-双(2-异丙氧基-1-萘基)苯基]-二苯基膦；
[2,6-双(2-异丙氧基-1-萘基)苯基]-二环己基膦；
[2,6-双(2-甲氧基-6-二甲氨基苯基)苯基]-二苯基膦；
[2,6-双(2-甲氧基-6-二甲氨基苯基)苯基]-二环己基膦；
[2,6-双(2,6-二甲氨基苯基)苯基]-二苯基膦；
[2,6-双(2,6-二甲氨基苯基)苯基]-二环己基膦.
第四方面,本发明提供了三联芳单膦作为支持配体与元素周期表VIII族或IB族的元素,例如钯、镍、铂、铑、铱、钌、钴或金的过渡金属络合物或过渡金属盐结合用作催化剂.通常地,本发明提供的三联芳单膦可以加入到合适的过渡金属前体中原位地产生催化体系.
第五方面,本发明提供了一系列三联芳单膦配位的钯络合物,具有通式II、III、IV、V、VI或VII：
Figure PCTCN2019079966-appb-000007
其中
L为上面定义的三联芳单膦配体；
X 2为Cl、Br、I、甲磺酸基、苯磺酸基、对甲苯磺酸基、甲酸基、乙酸基或苯甲酸基；
R 4、R 5、R 6、R 7或R 8各自独立地选自H、甲基或苯基.
本发明还进一步提供了原位产生的钯催化体系和钯络合物在催化Suzuki偶联和Buchwald-Hartwig胺化反应中的用途.同时,对于那些本领域技术人员来说很明显的其它过渡金属催化反应,特别是Negishi偶联、Kumada偶联、Sonogashira炔化及Heck偶联,也可使用本发明提供的催化体系.
一般说来,利用钯络合物作为催化剂的前体对于催化反应是更为有利的,在一些情况中会缩短催化体系诱导期.即使是直接应用钯络合物作为催化剂前体,有时也额外相对钯来说加入0.5到100倍根据本发明的三联芳单膦配体,这样一般会增加催化体系的寿命.
可以与本发明的膦配体原位形成催化剂的钯源有很多,包括醋酸钯、氯化钯、乙酰丙酮钯、二苯基亚甲基丙酮钯、四(三苯基膦)钯、二乙腈氯化钯、2-氨基联苯-2-氯化钯,或其它对于那些本领域技术人员来说熟知的钯源.
本发明的膦配体在惰性气氛下有很好的热稳定性,因此能在高达200℃或更高的温度下使用本发明提供的催化体系.优选反应温度为20至180℃,甚至是40至130℃进行催化反应是有利的.本发明的三联芳单膦配体还可以再加压反应中使用,通常压力可以到100个大气压,但优选在不高于60的大气压到常压的范围进行反应.
以下举例说明本发明的具体实施例,而不意味着本发明仅限于以下的举例说明.
THF表示四氢呋喃；TMEDA代表N,N,N’,N’-四甲基乙二胺。
格氏试剂的制备方法.惰气气氛下,往一个干燥的100mL三口瓶中,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入镁屑.将THF与溴带芳烃的混合液置于恒压漏斗中,先加入约1mL到三口瓶中,反应引发后,在保持微沸的情况下将剩余的混合液滴加到三口瓶中(约15min),加毕在油浴70℃下反应2-5h,冷却到室温备用.
实施例1.(2,6-二苯基-4-甲基-苯基)-二苯基膦
Figure PCTCN2019079966-appb-000008
实施例1-1.
由镁屑(0.29g,12.0mmol)、THF(10mL)与溴苯(1.73g,11.0mmol)的制得苯基溴化镁格氏试剂.往另一个干燥的250mL两口瓶中加入3,5-二氯甲苯(0.81g,5.0mmol)和THF(15mL),冷却到-78℃,加入2.4mL正丁基锂(2.5M正己烷溶液,6.0mmol),搅拌反应30min后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴70℃下回流6h.再冷却到-78℃,通过注射器加入二苯基氯膦(1.32g,6.0mmol),撤去冷浴升至室温反应6h.加入50mL饱和氯化钠溶液,用二氯甲烷萃取三次(40mL),有机层用Na 2SO 4干燥后减压浓缩,残余物用硅胶柱层析分离提纯(石油醚洗脱),得白色固体1.39g,产率65％.
MP:144.3-145.9℃.
1H NMR(400MHz,CDCl 3)δ:7.14(d,J＝2.7Hz,3H),7.13(s,1H),7.12–7.07(m,10H),7.06(t,J＝4.3Hz,8H),2.46(s,3H).
13C NMR(101MHz,CDCl 3)δ:150.29,150.13,143.10,143.05,138.80,137.65,137.53,132.45,132.26,131.70,131.66,129.24,129.22,127.65,127.59,127.31,127.00,126.46,21.12.
31P NMR(162MHz,CDCl 3)δ:-6.85.
HR-MS m/z(％):Calcd for C 31H 25P[M]428.1688；Found 428.1671(100).
实施例1-2.
惰气气氛下,往一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二苯基-4-甲基碘苯(0.74g,2.0mmol),加入THF(3.0mL),冷却至-78℃,通过恒压漏斗滴加0.89mL正丁基锂(2.7M正己烷溶液,2.4mmol)到反应液中(约8min),加毕后继续在此温度下反应2h,然后再通过注射器加入二苯基氯膦(0.44g,2.0mmol),撤去冷浴升至室温反应6h.加入20mL饱和氯化钠溶液,用二氯甲烷萃取三次(20mL),有机层用Na 2SO 4干燥后减压浓缩,残余物用硅胶柱层析分离提纯(石油醚洗脱),得白色固体0.60g,产率71％.
实施例1-3.
由镁屑(0.06g,2.2mmol)、THF(5mL)和2,6-二苯基-4-甲基碘苯(0.74g,2.0mmol)制得格氏试剂.冷却至-78℃,通过注射器加入二苯基氯膦(0.49g,2.2mmol),撤去冷浴升至室温反应6h.加入20mL饱和氯化钠溶液,用二氯甲烷萃取三次(20mL),有机层用Na 2SO 4干燥后减压浓缩,残余物用硅胶柱层析分离提纯(石油醚洗脱),得白色固体0.59g,产率69％.
实施例2.(2,6-二苯基-4-甲基苯基)-二环己基膦
Figure PCTCN2019079966-appb-000009
惰气气氛下,往一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二苯基-4-甲基碘苯(1.85g,5.0mmol)和THF(10.0mL),冷却至-78℃,通过恒压漏斗滴加2.04mL正丁基锂(2.7M正己烷溶液,5.5mmol)到反应液中(约8min),加毕后继续后继续反应2h,通过双针尖加入另一个史莱克瓶中的二环己基氯膦(1.16g,5.0mmol)和THF(3.0mL)的混合液,撤去冷浴升至室温反应6h,加入20mL饱和氯化钠溶液,用二氯甲烷萃取三次(20mL).有机相用Na 2SO 4干燥后减压浓缩,残余物用硅胶柱层析分离提纯(石油醚),得白色固体1.21g,产率55％.
MP:138.3-139.6℃.
1H NMR(500MHz,CDCl 3)δ:7.41(s,6H),7.31(s,4H),7.06–7.02(m,2H),2.39(s,3H),1.31(s,22H).
13C NMR(126MHz,CDCl 3)δ:144.44,144.40,137.22,131.20,131.18,129.89, 129.87,127.22,126.61,35.80,35.69,32.91,32.71,31.96,31.53,31.45,29.72,29.68,29.39,27.06,26.99,26.97,26.86,26.26,22.71,20.90,14.13.
31P NMR(202MHz,CDCl 3)δ:-0.53.
HR-MS m/z(％):Calcd for C 31H 38P[M ++H]441.2705；Found 441.2734(100).
实施例3.[2,6-双(2-甲基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000010
惰气气氛下,往一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二(2-甲基苯基)碘苯(1.54g,4.0mmol)和THF(5.0mL),冷却至-78℃,通过恒压漏斗滴加6.8mL叔丁基锂(1.3M正戊烷溶液,8.8mmol)到反应液中(约20min),加毕后继续反应2h,回至室温待用.另一个干燥的100mL两口瓶中加入氯化亚铜(0.48g,4.8mmol),通过双针尖加入上述待用的锂试剂,加毕后继续搅拌20min后再冷却到-78℃,通过注射器加入二苯基氯膦(0.88g,4.0mmol),撤去冷浴回至室温反应6h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机层用50mL饱和氯化钠溶液洗涤,再用二氯甲烷萃取氯化钠洗涤液三次(30mL),合并的有机层用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体0.91g,产率52％.
MP:146.5-147.3℃.
1H NMR(400MHz,CDCl 3)δ:7.49(dd,J＝14.6,7.0Hz,1H),7.22–6.70(m,20H),1.92(d,J＝30.1Hz,6H).
13C NMR(101MHz,CDCl 3)δ:149.02,148.85,142.06,135.30,132.86,132.66,130.33,130.29,129.48,129.24,129.22,129.10,127.42,127.35,127.22,127.06,124.55,20.82,1.05.
31P NMR(162MHz,CDCl 3)δ:-5.37,-7.65.
HR-MS m/z(％):Calcd for C 32H 28P[M ++H]443.1923；Found 443.1903(100).
实施例4.[2,6-双(2,6-二甲基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000011
实施例4-1.
由镁屑(0.61g,25.0mmol)、THF(10mL)与2,6-二甲基溴苯(4.44g,24.0mmol)制得格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应1h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴80℃下回流6h.冷至室温后将反应液转移到一个装有氯化亚铜(1.20g,12.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,通过注射器加入二苯基氯膦(2.64g,12mmol),升至室温继续反应6h.加入50mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相用50mL饱和氯化钠溶液洗涤,再用二氯甲烷萃取氯化钠洗涤液三次(30mL),合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体2.91g,产率62％.
MP:149.5-150.9℃.
1H NMR(400MHz,CDCl 3)δ:7.51(t,J＝7.6Hz,1H),7.16–7.06(m,8H),7.05–6.99(m,4H),6.99–6.92(m,2H),6.82(d,J＝7.6Hz,4H),2.05(s,12H).
13C NMR(101MHz,CDCl 3)δ:147.15,147.00,141.32,141.28,136.72,136.60,136.00,135.99,134.71,134.48,130.39,130.36,129.16,127.92,127.32,127.23,127.18,21.55,21.52.
31P NMR(162MHz,CDCl 3)δ:-2.18.
HR-MS m/z(％):Calcd for C 34H 32P[M ++H]471.2251；Found 471.2239(100).
实施例4-2.
惰气气氛下,往一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-双(2,6-二甲基苯基)碘苯(1.24g,3.0mmol)和THF(5.0mL),冷却至-78℃,通过恒压漏斗滴加5.1mL叔丁基锂(1.3M正戊烷,6.6mmol)到反应液中(约20min),加毕后继续反应30min,撤去冷浴回至室温待用.另一个干燥的100mL两口瓶中加入氯化亚铜(0.48g,4.8mmol),通过双针尖加入上 述待用的锂试剂,加毕后搅拌20min再冷到-78℃,通过注射器加入二苯基氯膦(0.99g,4.5mmol),升至室温继续反应6h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相用50mL饱和氯化钠溶液洗涤,再用二氯甲烷萃取氯化钠洗涤液三次(30mL),合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体0.90g,产率64％.
实施例5.[2,6-双(2,6-二甲基苯基)苯基]-环己基-噻吩基膦
Figure PCTCN2019079966-appb-000012
由镁屑(0.61g,25.0mmol)、THF(10mL)与2,6-二甲基溴苯(4.44g,24.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应1h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴80℃下回流6h.冷至室温后将反应液转移到一个装有氯化亚铜(1.20g,12.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,加入二氯环己基膦(2.22g,12.0mmol)和THF(5mL)的混合液,升至室温再于油浴40℃下回流6h.冷却至-80℃,加入2-噻吩基溴化镁格式试剂(36.0mmol),油浴70℃反应12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.45g,产率48％.
MP:149.9-151.6℃.
1H NMR(400MHz,CDCl 3)δ:7.60–7.52(m,1H),7.49–7.44(m,1H),7.40–7.32(m,2H),7.31–7.25(m,2H),7.12–6.99(m,4H),6.85–6.78(m,1H),6.02–5.94(m,1H),2.42–2.27(m,1H),2.20(s,6H),1.81–1.74(m,1H),1.69(s,6H),1.66–1.58(m,3H),1.56–1.46(m,2H),1.38–1.29(m,1H),1.27–1.18(m,1H),1.15–1.00(m,2H).
13C NMR(101MHz,CDCl 3)δ:148.63,148.49,139.81,139.74,137.22,136.47,136.43,134.82,132.62,132.55,131.87,131.85,131.18,131.11,128.99,128.58, 128.49,128.19,128.11,127.54,127.17,126.90,126.56,34.87,34.58,31.67,31.57,30.21,30.13,26.39,26.23,26.19,26.03,25.45,21.50,20.76.
31P NMR(162MHz,CDCl 3)δ:-13.70.
实施例6.[2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲基氨基苯基]-苯基膦
Figure PCTCN2019079966-appb-000013
由镁屑(0.61g,25.0mmol)、THF(10mL)与2,4,6-三甲基溴苯(4.78g,24.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应1h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴80℃下回流6h.冷至室温后将反应液转移到一个装有氯化亚铜(1.20g,12.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,加入二氯苯基基膦(2.15g,12.0mmol)和THF(5mL)的混合液,升至室温再于油浴40℃下回流6h.冷却至-80℃,加入2-二甲氨基苯基溴化镁格式试剂(30.0mmol),油浴70℃反应12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体3.08g,产率57％.
MP:151.2-152.9℃.
1H NMR(400MHz,CDCl 3)δ:7.62–7.47(m,2H),7.46–7.30(m,2H),7.26–7.17(m,2H),7.09–6.96(m,4H),6.94–6.86(m,2H),6.85–6.75(m,2H),6.39–6.24(m,2H),2.39(s,9H),2.16(s,9H),1.51(s,6H).
31P NMR(162MHz,CDCl 3)δ:-19.14(s).
HR-MS m/z(％):Calcd for C 38H 41NP[M ++H]542.2971；Found 542.2975(100).
实施例7.[2,6-双(2-甲氧基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000014
惰气气氛下,往一个干燥的100mL三口瓶中,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二(2-甲氧基苯基)碘苯(0.83g,2.0mmol)和THF(5mL),冷却至-78℃,通过恒压漏斗滴加3.4mL叔丁基锂(1.3M正戊烷,4.4mmol)到反应液中(约15min),加毕后继续反应1h,仍在-78℃下通过注射器加入二苯基氯膦(0.44g,2.0mmol),撤去冷浴自然升至室温再反应6h.加入15mL饱和氯化钠溶液,用二氯甲烷萃取三次(每次30mL),有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝20:1),得白色固体0.76g,产率80％.
MP:144.6-146.1℃.
1H NMR(500MHz,CDCl 3)δ:7.50–7.44(m,1H),7.25–7.17(m,3H),7.15–7.13(m,1H),7.11–6.96(m,12H),6.91–6.85(m,2H),6.74–6.63(m,2H),6.52–6.46(m,2H),3.59(s,3H),3.38(s,3H).
13C NMR(126MHz,CDCl 3)δ:156.48,155.81,145.99,145.86,145.72,145.60,133.09,132.98,132.92,132.83,132.59,132.43,131.72,131.68,131.65,131.25,131.24,131.08,131.05,130.98,130.95,130.87,130.85,128.46,128.30,127.25,127.20,127.17,127.12,126.94,126.88,126.78,126.65,126.58,119.37,109.89,109.71,54.65,54.46.
31P NMR(162MHz,CDCl 3)δ:-3.40,-5.52.
HR-MS m/z(％):Calcd for C 32H 28O 2P[M ++H]475.1821；Found475.1856(100).
实施例8.[2,6-双(2-甲氧基苯基)苯基]-二环己基膦(HTPhos)
Figure PCTCN2019079966-appb-000015
惰气气氛下,一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二(2-甲氧基苯基)碘苯(0.83g,2.0mmol)和THF(5mL),冷却至-78℃,通过恒压漏斗滴加3.4mL叔丁基锂(1.3M正戊烷,4.4mmol)到反应液中(约15min),加毕后继续反应1h,仍在此温度下通过双针尖加入二环己基氯膦(0.47g,2.0mmol)和THF(3.0mL)的混合液,撤去冷浴自然升至室温再反应6h.加入15mL饱和氯化钠溶液,用二氯甲烷萃取三次,每次30mL,有机相用 Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝20:1),得白色固体0.76g,产率78％.
MP:143.2-145.1℃.
1H NMR(500MHz,CDCl 3)δ:7.37–7.31(m,3H),7.17–7.06(m,4H),7.00–6.95(m,2H),6.94–6.90(m,2H),3.75(s,6H),1.63–1.58(m,2H),1.55–1.46(m,6H),1.46–1.35(m,3H),1.12–1.00(m,5H),0.97–0.91(m,3H),0.87–0.79(m,3H).
31P NMR(202MHz,CDCl 3)δ:5.75,5.24.
HR-MS m/z(％):Calcd for C 32H 40O 2P[M ++H]487.2760；Found487.2762(100).
实施例9.[2,6-双(2-甲氧基苯基)苯基]-二叔丁基膦
Figure PCTCN2019079966-appb-000016
惰气气氛下,一个干燥的100mL三口瓶,加入搅拌子,装上冷凝管、恒压漏斗和抽气接头,加入2,6-二(2-甲氧基苯基)碘苯(0.83g,2.0mmol)和THF(5mL),冷却至-78℃,通过恒压漏斗滴加3.4mL叔丁基锂(1.3M正戊烷,4.4mmol)到反应液中(约15min),加毕后继续反应1h,仍在此温度下通过双针尖加入二氯叔丁基膦(0.32g,2.0mmol)和THF(3.0mL)的混合液,撤去冷浴自然升至室温再反应6h.再加入CuCl(0.25g,2.5mmol)和2.2mL叔丁基锂(1.3M正戊烷,2.9mmol)搅拌反应1h后,再回流反应24h.冷至室温加入15mL饱和氯化钠溶液,用二氯甲烷萃取三次,每次30mL,有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝20:1),得白色固体0.27g,产率31％.
31P NMR(162MHz,CDCl 3)δ:23.69.
实施例10.[2,6-双(2,6-二甲氧基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000017
实施例10-1.
由镁屑(0.29g,12mmol)、THF(10.0mL)与2,6-二甲氧基溴苯(2.39g,11.0mmol)制成格氏试剂.另一个干燥的250mL两口瓶中加入3-氯氟苯(1.47g,5.0mmol)和THF(15mL),冷却到-78℃,加入2.4mL正丁基锂(2.5M正己烷溶液,6.0mmol),搅拌反应1h后,将上述制备格式试剂通过双针尖转移至两口瓶中,撤去冷浴自然升至室温,再于油浴80℃下回流6h.冷至室温后将反应液转移到一个装有氯化亚铜(0.60g,6.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,通过注射器加入二苯基氯膦(1.32g,6.0mmol),加毕油浴加热至70℃反应3h.室温下加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),合并的有机相再用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL),有机层用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体1.15g,产率43％.
MP:154.2-156.2℃.
1H NMR(400MHz,CDCl 3)δ:7.52(dd,J＝10.6,4.5Hz,1H),7.16–6.85(m,14H),6.29–6.13(m,4H),3.53(d,J＝1.5Hz,12H).
13C NMR(101MHz,CDCl 3)δ:157.42,141.41,141.24,137.46,137.33,135.37,135.17,133.96,133.75,131.34,128.79,128.57,126.77,126.70,119.92,119.86,103.08,55.12.
31P NMR(162MHz,CDCl 3)δ:-2.99.
HR-MS m/z(％):Calcd for C 34H 32O 4P[M ++H]535.2032；Found 535.2029(100).
实施例10-2.
由镁屑(0.67g,27.5mmol)、THF(10.0mL)与2,6-二甲氧基溴苯(5.40g,25.0mmol)制成格氏试剂.另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入5.0mL正丁基锂(2.4M正己烷溶液,12.0mmol),搅拌反应1h后,将上述制备格式试剂通过双针尖转移至两口瓶中,撤去冷浴自然升至室温,再于油浴70℃下回流6h.冷至室温,通过双针尖加入四三苯基膦钯(0.17g,0.15mmol)与THF(5mL)的溶液,搅拌反应2h.通过注射器加入二苯基氯膦(3.3g,15.0mmol),加毕油浴加热至70℃反应3h.室温下加入 40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),合并的有机相再用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL),有机层用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.56g,产率48％.
实施例11.[2,6-双(2,6-二甲氧基苯基)苯基]-苯基异丙基膦
Figure PCTCN2019079966-appb-000018
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,6-二甲氧基碘苯(5.81g,22.0mmol)制成格氏试剂.另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,滴加4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,通过双针尖加入上述待用的格式试剂,升至室温,再于油浴70℃下回流12h后,冷至室温,再转移至另一个冷至-78℃的含有溴化亚铜(1.72g,12.0mmol)的100mL两口瓶中,加毕继续搅拌20min后.通过注射器加入二氯苯基膦(2.15g,12.0mmol),加毕升至室温再反应12h.再冷却到-78℃,通过注射器加入4.0mL异丙基溴化镁(3.0M的THF溶液,12.0mmol),加毕升至室温反应12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),合并的有机相用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL),有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝20:1),得白色固体2.90g,产率58％.
MP:153.2-154.9℃.
1H NMR(400MHz,CDCl 3)δ:7.47(t,J＝7.5Hz,1H),7.34(ddd,J＝18.9,13.8,6.7Hz,4H),7.18(d,J＝7.4Hz,3H),6.70(d,J＝8.3Hz,6H),3.80(s,12H),3.77(s,6H),1.82(s,1H).
13C NMR(101MHz,CDCl 3)δ:157.90,157.68,141.00,136.99,134.01,129.75,129.31,129.22,128.44,127.52,124.60,123.87,120.04,109.60,104.45,104.32,56.15,55.96,16.88.
31P NMR(162MHz,CDCl 3)δ:-13.29.
实施例12.[2,6-双(2,4,6-三异丙基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000019
由镁屑(0.67g,27.5mmol)、THF(10mL)与2,4,6-三异丙基溴苯(7.08g,25.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,滴加5.0mL正丁基锂(2.4M正己烷溶液,12.0mmol),搅拌反应1h后,仍在此温度下通过双针尖加入上述待用的格式试剂,升至室温,再于油浴80℃下回流6h.冷却至室温将反应液转移到另一个250mL带有溴化亚铜(2.15g,15.0mmol)两口瓶中,搅拌反应15min后冷却到-78℃,通过注射器加入二苯基氯膦(3.31g,15.0mmol),加毕升至室温反应6h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),合并的有机相用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL),有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体5.53g,产率83％.
MP:148.4-149.6℃.
1H NMR(400MHz,CDCl 3)δ:7.42(t,J＝7.5Hz,1H),7.20(dd,J＝7.5,2.2Hz,2H),7.00(t,J＝6.9Hz,2H),6.96–6.83(m,8H),6.78(s,4H),2.89–2.77(m,6H),1.26(d,J＝6.9Hz,12H),0.91(dd,J＝34.9,6.7Hz,24H).
13C NMR(101MHz,CDCl 3)δ:147.48,147.26,145.84,138.05,137.91,137.27,137.22,134.65,134.43,132.29,132.26,127.64,127.35,127.31,127.28,120.51,34.03,30.91,25.59,24.03,22.61.
31P NMR(162MHz,CDCl 3)δ:-5.89.
HR-MS m/z(％):Calcd for C 48H 60P[M ++H]667.4427；Found 667.4479(100).
实施例13.[2,6-双(2,4,6-三异丙基苯基)苯基]-苯基-环己基膦
Figure PCTCN2019079966-appb-000020
由镁屑(0.67g,27.5mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(7.08g,25.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g, 10.0mmol)和THF(15.0mL),冷却到-78℃,滴加5.0mL正丁基锂(2.4M正己烷溶液,12.0mmol),搅拌反应1h后,通过双针尖加入上述待用的格式试剂,升至室温再于油浴80℃下回流6h.冷却至室温再将反应液转移到另一个带有溴化亚铜(2.15g,15.0mmol)的250mL两口瓶中,搅拌反应15min后冷却到-78℃,加入二氯苯基膦(2.68g,15.0mmol)的THF(5.0mL)溶液,升至室温反应12h后再于油浴70℃下回流6h.冷却至-78℃,再通过注射器加入15.0mL环己基溴化镁(1.0M in THF,15.0mmol)溶液,室温反应12h后再回流12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体4.91g,产率73％.
MP:146.5-148.1℃.
1H NMR(400MHz,CDCl 3)δ:7.36–7.30(m,1H),7.15(dd,J＝7.6,1.8Hz,3H),7.06–6.96(m,6H),6.88(s,2H),2.97(s,4H),2.69–2.60(m,2H),1.34(d,J＝6.9Hz,17H),1.29–1.20(m,1H),1.02(ddd,J＝16.8,13.2,6.7Hz,27H),0.89–0.78(m,2H).
13C NMR(101MHz,CDCl 3)δ:147.80,146.67,146.52,146.20,146.05,146.05,138.10,138.05,135.25,135.03,132.04,132.02,127.75,127.13,127.05,126.53,120.84,120.45,34.23,33.01,32.68,32.04,31.91,31.02,30.95,30.93,30.68,30.61,26.86,26.81,26.74,26.68,25.98,25.85,24.21,24.15,22.58,22.44.
31P NMR(162MHz,CDCl 3)δ:6.72.
HR-MS m/z(％):Calcd for C 48H 66P[M ++H]673.4897；Found 673.4944(100).
实施例14.[2,6-双(2,4,6-三异丙基苯基)苯基]-甲基-叔丁基膦(ZTPhos)
Figure PCTCN2019079966-appb-000021
由镁屑(0.56g,23.0mmol)、THF(10mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,滴加4.8mL正丁基锂(2.5M正己烷溶 液,12.0mmol),搅拌反应1h后,仍在此温度下通过双针尖加入上述待用的格式试剂,升至室温再于油浴80℃下回流6h.冷却至室温转移到另一个带有溴化亚铜(1.72g,12.0mmol)干燥的250mL两口瓶中,搅拌反应15min再冷却到-78℃,通过双针尖加入二氯叔丁基膦(1.90g,12.0mmol)和THF(5mL)的溶液,升至室温反应12h后再于油浴70℃下回流6h.冷却至-78℃,通过注射器加入12.0mL甲基溴化镁溶液(1.0M in THF,12.0mmol),升至室温反应12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝50:1),得白色固体3.09g,产率53％.
MP:145.3-146.7℃.
1H NMR(400MHz,CDCl 3)δ:7.33–7.27(m,1H),7.16(d,J＝7.5Hz,2H),7.05(d,J＝5.9Hz,4H),2.98(dp,J＝13.5,6.5Hz,2H),2.80(ddq,J＝26.6,13.1,6.6Hz,4H),1.45–1.25(m,24H),1.04(dd,J＝10.1,6.8Hz,12H),0.96(d,J＝7.0Hz,3H),0.76(t,J＝14.2Hz,9H)；
13C NMR(101MHz,CDCl 3)δ:148.15,147.96,147.82,146.22,145.92,139.18,139.13,137.37,136.95,131.90,131.87,126.54,120.64,120.09,34.19,31.02,30.97,30.95,29.87,29.68,29.51,29.35,26.15,25.83,24.29,24.05,22.62,8.33,8.11；
31P NMR(162MHz,CDCl 3)δ:-3.33；
HR-MS m/z(％):Calcd for C 41H 62P[M ++H]585.4853；Found 585.4857(100).
实施例15.[2,6-双(2,4,6-三异丙基苯基)苯基]-苯基-异丙基膦
Figure PCTCN2019079966-appb-000022
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,滴加4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,撤去冷浴升至室温,再于油浴70℃下回流12h.冷却至室温将反应液转移 到装有溴化亚铜(1.72g,12.0mmol)的250mL两口瓶中,搅拌反应15min后冷却到-78℃,加入二氯苯基膦(2.15g,12.0mmol)和THF(5.0mL)的混合液,升至室温反应12h,再于油浴70℃下回流6h.冷却至-78℃,通过注射器加入4.0mL异丙基溴化镁溶液(3.0M in THF,12.0mmol),升至室温后再反应12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体3.98g,产率63％.
MP:144.3-146.2℃.
1H NMR(400MHz,CDCl 3)δ:7.40–7.34(m,1H),7.21(d,J＝7.0Hz,4H),7.16–7.07(m,2H),6.99(t,J＝9.5Hz,4H),6.66(s,1H),3.28–3.17(m,1H),3.06(s,2H),2.89(s,2H),2.72–2.62(m,1H),2.55(s,1H),1.47–1.39(m,15H),1.35(d,J＝6.9Hz,6H),1.32(d,J＝6.8Hz,3H),1.06(d,J＝6.6Hz,4H),1.00–0.90(m,5H),0.77(d,J＝6.7Hz,5H),0.66(dd,J＝15.5,6.7Hz,3H).
31P NMR(162MHz,CDCl 3)δ:-4.19.
HR-MS m/z(％):Calcd for C 45H 62P[M ++H]633.4583；Found 633.4580(100).
实施例16.[2,6-双(2,4,6-三异丙基苯基)苯基]-二环己基膦(XTPhos)
Figure PCTCN2019079966-appb-000023
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温,再于油浴70℃下回流12h.冷至室温后将反应液转移到一个装有溴化亚铜(1.72g,12.0mmol)的250mL两口瓶中,搅拌反应15min后冷却到-78℃,加入二环己基氯膦(2.79g,12.0mmol)和THF(5.0mL)的混合液,升至室温反应12h,再于油浴70℃下回流6h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水 层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得白色固体4.13g,产率61％.
MP:147.5-149.1℃.
1H NMR(400MHz,CDCl 3)δ:7.30–7.25(m,1H),7.14–7.12(m,1H),7.11–7.10(m,1H),7.07(s,4H),3.01–2.92(m,2H),2.84–2.72(m,4H),1.83–1.71(m,3H),1.63–1.53(m,5H),1.48–1.40(m,5H),1.36(dd,J＝11.7,6.9Hz,24H),1.22–1.15(m,2H),1.11–1.04(m,2H),1.00(d,J＝6.7Hz,13H),0.89–0.81(m,4H).
13C NMR(101MHz,CDCl 3)δ:147.55,147.38,145.70,139.30,139.25,131.82,131.79,126.53,120.79,34.16,34.06,33.79,31.92,31.75,30.74,30.62,30.50,27.35,27.27,27.17,27.01,26.38,25.98,24.16,23.12.
31P NMR(162MHz,CDCl 3)δ:9.62,9.52.
HR-MS m/z(％):Calcd for C 48H 72P[M ++H]679.5366；Found 679.5367(100).
实施例17.[2,6-双(2,4,6-三异丙基苯基)苯基]-(2’,6’-二甲氧基-2-联苯基)-甲基膦
Figure PCTCN2019079966-appb-000024
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,滴加4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,撤去冷浴升至室温,再于油浴70℃下回流12h.冷却到-78℃,通过注射器加入三氯化膦(1.65g,12.0mmol),加毕升至室温反应6h,待用.
由镁屑(0.39g,16.0mmol)、THF(15.0mL)与2,6-二甲氧基-2’-溴联苯(4.39g,15.0mmol)制成格氏试剂.在室温下将反应液转移到另一个250mL带有氯化亚铜(1.49g,15.0mmol)两口瓶中,搅拌反应15min后冷却到-78℃,在此温度下通过双针尖将上述250mL两口瓶中的反应液转移至该瓶中,撤去冷浴升至室温,再于油浴70℃下回流12h.冷却至-78℃,通过注射器加入15.0mL甲基溴化镁溶 液(1.0M in THF,15.0mmol),撤去冷浴升至室温,再于油浴70℃下回流12h.加入60mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(80mL),有机相再用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.89g,产率39％.
31P NMR(162MHz,CDCl 3)δ:7.12.
实施例18.[2,6-双(2-甲氧基-1-萘基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000025
由镁屑(0.67g,27.5mmol)、THF(10mL)与1-溴-2-甲氧基萘(5.93g,25.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入5.0mL正丁基锂(2.4M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴70℃下回流12h.冷却至室温后将反应液转移到一个装有四三苯基膦钯(0.17g,0.15mmol)的100mL两口瓶中,搅拌反应20min后冷却到-78℃,通过注射器加入二苯基氯膦(3.31g,15.0mmol),升至室温再于油浴70℃下回流6h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体3.05g,产率53％.
MP:153.2-155.0℃.
1H NMR(400MHz,CDCl 3)δ:7.72–7.57(m,5H),7.42(dd,J＝7.5,5.7Hz,4H),7.30(ddd,J＝7.4,4.5,2.5Hz,4H),7.06–6.98(m,2H),6.90–6.77(m,6H),6.72(t,J＝7.4Hz,4H),3.55(d,J＝4.4Hz,6H).
13C NMR(101MHz,CDCl 3)δ:154.07,143.67,143.51,136.63,136.39,136.20,136.07,134.03,133.71,133.50,132.14,132.12,129.27,128.51,127.73,126.76,126.44,126.36,126.06,125.46,124.77,124.72,122.98,112.16,55.26.
31P NMR(162MHz,CDCl 3)δ:-4.54.
HR-MS m/z(％):Calcd for C 40H 32O 2P[M ++H]575.2134；Found 575.2151(100).
实施例19.[2,6-双(2-甲氧基-1-萘基)苯基]-二环己基膦
Figure PCTCN2019079966-appb-000026
由镁屑(0.56g,23.0mmol)、THF(10mL)与1-溴-2-甲氧基萘(5.22g,22.0mmol)制成格氏试剂.另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol)搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴70℃下回流12h.冷至室温后将反应液转移到一个装有溴化亚铜(1.72g,12.0mmol)的100mL两口瓶中,搅拌20min后冷却到-78℃,加入二环己基氯膦(2.79g,12.0mmol)和THF(5mL)的混合液,升至室温再于油浴40℃下回流12h.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.58g,产率44％.
MP:156.3-157.6℃.
1H NMR(400MHz,CDCl 3)δ:7.94(d,J＝9.0Hz,2H),7.86(d,J＝7.8Hz,2H),7.43–7.33(m,8H),7.27(d,J＝8.0Hz,3H),3.98–3.90(m,6H),1.48–1.19(m,11H),0.95–0.41(m,11H).
13C NMR(101MHz,CDCl 3)δ:153.59,144.78,144.62,139.65,139.34,134.59,131.61,131.57,128.87,128.69,128.40,127.80,127.15,127.10,126.06,125.81,123.19,112.86,57.01,56.03,33.11,32.95,32.93,32.71,31.55,31.38,29.74,27.07,27.01,26.94,26.91,26.35.
31P NMR(162MHz,CDCl 3)δ:9.76.
HR-MS m/z(％):Calcd for C 40H 43P[M]586.2995；Found 586.2965(100).
实施例20.[2,6-双(2-甲氧基-1-萘基)苯基]-(4-二甲氨基苯基)-环己基膦
Figure PCTCN2019079966-appb-000027
由镁屑(0.56g,23.0mmol)、THF(10mL)与1-溴-2-甲氧基萘(5.22g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴70℃下回流12h.冷至室温后将反应液转移到一个装有氯化亚铜(1.20g,12.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,加入二氯环己基膦(2.22g,12.0mmol)和THF(5mL)的混合液,升至室温再于油浴40℃下回流6h.冷却至-50℃,加入4-N,N-二甲基氨基苯基溴化镁溶液(24.0mmol),油浴70℃反应3天.加入40mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.84g,产率45％.
MP:157.2-158.9℃.
1H NMR(400MHz,CDCl 3)δ:7.93(dd,J＝8.9,6.3Hz,3H),7.77–7.69(m,1H),7.57–7.51(m,3H),7.44(d,J＝9.1Hz,2H),7.29–7.24(m,2H),7.20–7.13(m,2H),7.10–7.05(m,1H),7.02–6.98(m,1H),6.28(s,2H),5.98(d,J＝8.0Hz,2H),4.01(s,3H),3.76(s,3H),2.80(s,6H),2.11–2.00(m,1H),1.82–1.54(m,4H),1.48–1.17(m,4H),1.11–0.86(m,3H).
13C NMR(101MHz,CDCl 3)δ:153.76,153.74,153.59,149.15,145.11,144.86,144.02,143.93,138.73,138.42,134.59,134.42,134.40,134.28,134.07,132.03,132.01,131.36,131.31,129.10,128.82,128.72,128.71,128.47,127.95,126.99,126.22,126.16,125.98,125.50,123.07,122.81,120.29,120.18,112.57,112.49,111.56,111.49,56.27,55.34,50.80,40.37,32.13,32.06,30.36,30.19,30.14,26.94,26.84,26.71,26.60.
31P NMR(162MHz,CDCl 3)δ:-9.15.
HR-MS m/z(％):Calcd for C 42H 42NO 2P[M]623.2947；Found 623.2930(100).
实施例21.[2,6-双(2-甲氧基-1-萘基)苯基]-双[3,5-二(三氟甲基)苯基]膦
Figure PCTCN2019079966-appb-000028
由镁屑(0.29g,12.0mmol)、THF(5mL)与1-溴-2-甲氧基萘(2.61g,11.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(0.74g,5.0mmol)和THF(10mL),冷却到-78℃,加入2.4mL正丁基锂(2.5M正己烷溶液,6.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温,再于油浴70℃下回流12h.冷至室温后将反应液转移到一个装有氯化亚铜(0.6g,6.0mmol)的250mL两口瓶中,搅拌20min后冷却到-78℃,加入双[3,5-二(三氟甲基)苯基]氯化膦,升至室温再于油浴加热下回流6h.加入50mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体2.03g,产率48％.
MP:151.1-152.6℃.
1H NMR(400MHz,CDCl 3)δ:7.77–7.69(m,5H),7.55–7.49(m,2H),7.45–7.42(m,4H),7.41(d,J＝2.7Hz,1H),7.40–7.38(m,1H),7.38–7.36(m,1H),7.35(d,J＝1.2Hz,1H),7.33(d,J＝6.9Hz,4H),7.08(d,J＝9.1Hz,2H),3.68(s,6H).
13C NMR(101MHz,CDCl 3)δ:154.29,143.38,143.22,138.54,138.35,133.63,133.01,132.78,132.57,132.54,130.76,130.25,128.36,128.02,127.00,124.57,123.78,121.82,121.75,112.56,55.60,1.11.
31P NMR(162MHz,CDCl 3)δ:-3.12.
HR-MS m/z(％):Calcd for C 44H 27F 12O 2P[M]846.1552；Found 846.1552(100).
实施例22.[2,6-双(2-甲氧基-6-二甲氨基苯基)苯基]-二苯基膦
Figure PCTCN2019079966-appb-000029
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2-甲氧基(6-二甲基氨基)碘苯(6.10g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温再于油浴70℃下回流12h.至室温备后将反应液转移到一个装有氯化亚铜(1.20g,12.0mmol)干燥的250mL两口瓶中,搅拌反应15min后冷却到-78℃,通过注射器加入二苯基氯膦(2.65g,12.0mmol),升至室温反应6h.加入50mL氨水(26.0％-28.0％)并搅拌30min,用二氯甲烷萃取三次(50mL),有机相再用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(30mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体1.57g,产率28％.
1H NMR(400MHz,CDCl 3)δ:7.73–7.62(m,3H),7.35–7.27(m,7H),7.19–7.12(m,3H),6.41–6.28(m,6H),3.80(s,6H),2.94(s,12H).
31P NMR(162MHz,CDCl 3)δ:-13.62,-13.66.
实施例23.[2,6-双(2,4,6-三异丙基苯基)苯基]-二(2-噻吩基)膦
Figure PCTCN2019079966-appb-000030
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,滴加4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,撤去冷浴升至室温,再于油浴70℃下回流12h.冷却到-78℃,通过注射器加入三氯化膦(1.65g,12.0mmol),加毕升至室温反应6h,待用.
由镁屑(0.90g,37.0mmol)、THF(15.0mL)与2-溴噻吩(5.87g,36.0mmol)制 成格氏试剂.冷却到室温将反应液转移到另一个250mL带有氯化亚铜(1.19g,12.0mmol)两口瓶中,搅拌反应15min后冷却到-78℃,在此温度下通过双针尖将上述250mL两口瓶中的反应液转移至该瓶中,撤去冷浴升至室温,再于油浴70℃下回流12h.加入40mL氨水(26.0％-28.0％)并搅拌50min,用二氯甲烷萃取三次(150mL),合并的有机相用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(50mL),有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚),得蓝色固体3.59g,产率53％.
MP:144.3-145.5℃.
1H NMR(400MHz,CDCl 3)δ:7.47–7.40(m,1H),7.26–7.23(m,2H),7.23–7.18(m,2H),6.88(s,4H),6.79–6.75(m,2H),6.75–6.70(m,2H),2.85(s,6H),1.30(d,J＝6.9Hz,12H),1.04–0.92(m,24H).
13C NMR(101MHz,CDCl 3)δ:147.80,146.63,146.45,146.19,146.18,139.55,139.29,136.76,136.70,135.63,135.40,135.20,134.96,132.31,132.28,131.55,131.52,127.93,126.69,126.63,120.64,34.17,31.13,25.58,24.09,22.70.
31P NMR(162MHz,CDCl 3)δ:-33.31.
HR-MS m/z(％):Calcd for C 44H 56S 2P[M ++H]679.3555；Found 679.3560(100).
实施例24.[2,6-双(2,6-二甲氧基苯基)苯基]-二环己基膦(STPhos)
Figure PCTCN2019079966-appb-000031
由镁屑(0.67g,27.5mmol)、THF(10.0mL)与2,6-二甲氧基溴苯(5.40g,25.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15.0mL),冷却到-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,在次温度下将上述制备格式试剂通过双针尖转移至两口瓶中,撤去冷浴自然升至室温,再于油浴70℃下回流12h.冷却到-78℃,加入二氯环己基膦(2.68g,15.0mmol)的THF(5.0mL)溶液,撤去冷浴自然升至室温,再于油浴70℃下回流6h.冷却至-78℃,再通过双针尖将15.0mL环己基溴化镁(1.0M in THF,15.0mmol)和氯化亚铜(1.49g,15.0mmol)的THF(10.0mL)溶液转移至两口瓶中,撤去冷浴自然升至室温,再于油浴70℃下回流12 h.加入40mL氨水(26.0％-28.0％)并搅拌50min,用二氯甲烷萃取三次(100mL),有机相用50mL饱和氯化钠溶液洗涤,水相再用二氯甲烷萃取三次(50mL).合并的有机相用Na 2SO 4干燥后减压浓缩,残余物硅胶柱层析分离提纯(石油醚:乙酸乙酯＝10:1),得白色固体0.87g,产率16％.
1H NMR(400MHz,CDCl 3)δ:7.48–7.43(m,1H),7.39–7.34(m,1H),7.34–7.29(m,1H),7.19–7.14(m,2H),6.70–6.68(m,2H),6.68–6.65(m,2H),3.80–3.74(m,12H),1.81–1.52(m,9H),1.47–1.13(m,10H),1.01–0.82(m,3H).
31P NMR(162MHz,CDCl 3)δ:4.54.
实施例25.[2,6-双(2,4,6-三异丙基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦
Figure PCTCN2019079966-appb-000032
由镁屑(0.56g,23.0mmol)、THF(10.0mL)与2,4,6-三异丙基溴苯(6.23g,22.0mmol)制成格氏试剂.往另一个干燥的250mL两口瓶中加入间二氯苯(1.47g,10.0mmol)和THF(15mL),冷却至-78℃,加入4.8mL正丁基锂(2.5M正己烷溶液,12.0mmol),搅拌反应2h后,仍在此温度下通过双针尖加入上述制备的格式试剂,升至室温,再于油浴70℃下回流12h.冷却到-78℃,通过注射器加入三氯化膦(1.65g,12.0mmol),加毕升至室温反应6h,待用.
由镁屑(0.39g,16.0mmol)、THF(10.0mL)与3,5-二(三氟甲基)溴苯(4.40g,15.0mmol)制成格氏试剂.冷却到室温将反应液转移到另一个250mL带有氯化亚铜(1.48g,15.0mmol)两口瓶中,搅拌反应30min后冷却到-78℃,在此温度下通过双针尖将上述250mL两口瓶中的反应液转移至该瓶中,撤去冷浴升至室温,再于油浴70℃下回流12h.冷到室温后,加入40mL氨水(26.0％-28.0％)并搅拌50min,用二氯甲烷萃取三次(150mL),合并的有机相用50mL饱和氯化钠溶液洗涤,水层再用二氯甲烷萃取三次(50mL),有机相用Na 2SO 4干燥后减压浓缩,残余物经硅胶柱层析分离提纯(石油醚),得白色固体4.03g,产率43％.
MP:139.7-141.2℃.
1H NMR(400MHz,CDCl 3)δ:8.03(s,2H),7.80(d,J＝7.0Hz,4H),7.48–7.37 (m,1H),7.22(d,J＝7.4Hz,2H),7.10(d,J＝8.5Hz,4H),3.05–2.92(m,2H),2.82–2.72(m,1H),2.67–2.55(m,3H),1.40–1.34(m,12H),1.20(t,J＝6.0Hz,11H),1.16(t,J＝6.1Hz,11H),1.10(s,1H),1.08(s,1H).
13C NMR(101MHz,CDCl 3)δ:148.30,146.47,145.92,142.38,137.48,137.31,136.54,133.37,133.34,133.19,133.12,129.78,128.49,127.84,126.50,124.46,124.42,124.38,124.08,121.36,120.69,120.43,34.28,34.19,30.89,30.40,29.73,24.65,24.30,24.11,24.08,24.05,23.51.
31P NMR(162MHz,CDCl 3)δ:-4.15.
实施例26.反式-双[2,6-双(2-甲氧基苯基)苯基-二苯基膦]二氯化钯(II)
Figure PCTCN2019079966-appb-000033
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入[2,6-双(2-甲氧基苯基)苯基]-二苯基膦(240.0mg,0.5mmol)与双乙腈二氯化钯(65.0mg,0.25mmol),通过注射器加入5mL二氯甲烷,搅拌反应6h.减压浓缩除去溶剂,残余物硅胶柱层析分离提纯(二氯甲烷),得黄色固体0.23g,产率77％.
1H NMR(500MHz,DMSO)δ:7.50–7.44(m,1H),7.25–7.17(m,3H),7.15–7.13(m,1H),7.11–6.96(m,12H),6.91–6.85(m,2H),6.74–6.63(m,2H),6.52–6.46(m,2H),3.59(s,3H),3.38(s,3H).
31P NMR(162MHz,DMSO)δ:30.94.
实施例27.双[(4-甲基-2,6-二苯基-苯基)-二苯基膦]钯
Figure PCTCN2019079966-appb-000034
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入(2,6-二苯基-4-甲基苯基)-二苯基膦(236mg,0.55mmol)与Me 2Pd(Ⅱ)(TMEDA)(67mg,0.25mmol),通过注射器加入2mL二氯甲烷,搅拌反应6h.抽去溶剂,残余物用丙酮重结晶,得黑色固体0.21g,产率70％.
31P NMR(162MHz,CDCl 3)δ:26.04.
实施例28.(N,N-二甲基苯甲胺-2-基-η 2-C,N)-[(2,6-二苯基-4-甲基-苯基)-二苯基膦]氯化钯(Ⅱ)
Figure PCTCN2019079966-appb-000035
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入(2,6-二苯基-4-甲基苯基)-二苯基膦(214.0mg,0.5mmol)与二聚苄胺钯(138.0mg,0.25mmol),通过注射器加入5mL二氯甲烷,搅拌反应6h.减压浓缩除去溶剂,残余物硅胶柱层析分离提纯(二氯甲烷),得黄色固体0.31g,产率90％.
1H NMR(400MHz,CDCl 3)δ:7.50–7.33(m,5H),7.12–7.02(m,3H),7.02–6.94(m,3H),6.94–6.90(m,3H),6.89(s,2H),6.88–6.86(m,1H),6.85(d,J＝3.1Hz,3H),6.74–6.67(m,2H),6.17–6.10(m,1H),5.55–5.49(m,1H),3.99(d,J＝1.2Hz,2H),2.91(d,J＝2.4Hz,6H),2.30(s,3H).
13C NMR(101MHz,CDCl 3)δ:149.05,148.20,148.18,146.75,146.67,142.78,142.74,138.48,138.46,137.52,137.42,137.14,137.03,132.81,132.73,131.34,130.86,129.44,129.41,127.25,127.14,126.19,124.38,124.32,123.56,122.08,50.63,50.61,29.72,20.89.
31P NMR(162MHz,CDCl 3)δ:42.51.
HR-MS m/z(％):Calcd for C 40H 37NPPd[M +-Cl]668.1708；Found668.1755(100).
实施例29.(2’-氨基苯乙烷-2-η 2-C,N)-[(2,6-二苯基-4-甲基苯基)-二苯基膦]氯化钯(Ⅱ)
Figure PCTCN2019079966-appb-000036
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入(2,6-二苯基-4-甲基苯基)-二苯基膦(214.0mg,0.5mmol)与二聚苯乙胺钯(130.0mg,0.25mmol),通过注射器加入10mL二氯甲烷,搅拌反应6h.减压浓缩除去溶剂,残余物硅胶柱层析分离提纯(二氯甲烷),得黄色固体0.27g,产率80％.
1H NMR(400MHz,CDCl 3)δ:8.06–7.95(m,1H),7.76–7.69(m,1H),7.64–7.30(m,12H),7.21–7.10(m,4H),7.08–6.91(m,4H),6.65–6.58(m,2H),6.56–6.50(m,1H),6.49–6.42(m,2H),2.46–2.40(m,3H),1.58–1.52(m,4H),1.47–1.44(m,2H).
31P NMR(162MHz,CDCl 3)δ:22.69.
实施例30.(2’-甲氨基联苯-2-基-η 2-C,N)-[(2,6-双(2,4,6-三异丙基苯基)苯基)-二环己基膦]甲基磺酸钯(Ⅱ)
Figure PCTCN2019079966-appb-000037
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入[2,6-双(2,4,6-三异丙基苯基)苯基]-二环己基膦(271.0mg,0.4mmol)与[(2’-甲氨基联苯-2-基-C,N)氯化钯] 2(148.0mg,0.2mmol),及5mL二氯甲烷,搅拌反应6h.减压浓缩除去溶剂,残余物硅胶柱层析分离提纯(二氯甲烷洗脱),得黄色固体0.37g,产率89％.
31P NMR(162MHz,CDCl 3)δ:59.07,25.02.
实施例31.[(2,6-双(2,4,6-三异丙基苯基)苯基)-二环己基膦]-烯丙基-氯化钯(Ⅱ)[(XTPhos)(all)PdCl]
Figure PCTCN2019079966-appb-000038
惰气气氛下,往一个干燥的50mL史莱克瓶中,加入[2,6-双(2,4,6-三异丙基 苯基)苯基]-二环己基膦(135.0mg,0.2mmol)与烯丙基氯化钯(Ⅱ)二聚体(36.0mg,0.1mmol),及3mL二氯甲烷,搅拌反应6h.减压浓缩除去溶剂,残余物硅胶柱层析分离提纯(二氯甲烷),得黄色固体0.15g,产率90％.
31P NMR(162MHz,CDCl 3)δ:67.00.
实施例32-38.
Figure PCTCN2019079966-appb-000039
Figure PCTCN2019079966-appb-000040
[a]在手套箱中，将1.1mmol卤代芳烃、1.0mmol二苯胺、1.2mmol叔丁醇钠、适量的配体和钯(Ⅱ)、0.13mL十二烷(GC内标)和2mL无水甲苯置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
[b]氮气气氛下,往一个干燥的100mL三口瓶,加入搅拌子并装上冷凝管和恒压漏斗,加入二苯胺(0.846g,5.0mmol)、4-氯苯甲醚(0.784g,5.5mmol)和二甲苯(9.0mL),冰浴冷却至5℃,通过注射器滴加甲基氯化镁(1.7mL,3.0mol/L,5.1mmol),约需10min,再加入配体、钯(II)和0.26mL十二烷(GC分析的内标)的二甲苯(1.0mL)溶液.在145℃的油浴中反应.GC分析有机相.
实施例39-40.
Figure PCTCN2019079966-appb-000041
Figure PCTCN2019079966-appb-000042
[a]在手套箱中，将1.1mmol卤代芳烃、1.0mmol二苯胺、1.2mmol叔丁醇钠、适量的配体和钯(Ⅱ)、0.13mL十二烷(GC分析的内标)和2mL无水甲苯置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
实施例41.
Figure PCTCN2019079966-appb-000043
[a]在手套箱中,将1.0mmol卤代芳烃、1.5mmol苯硼酸、3.0mmol氟化铯、适量的配体和钯(Ⅱ)(P:Pd＝1:1)、0.13mL十二烷(作为GC分析的内标)和2mL无水二氧六环置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
[b]R.C.Smith,et al.,Tetrahedron Letters 2004,45,8327-8330.
[c]
Figure PCTCN2019079966-appb-000044
实施例42-43.
Figure PCTCN2019079966-appb-000045
Figure PCTCN2019079966-appb-000046
[a]在手套箱中，将1.1mmol卤代芳烃、1.0mmol咔唑、1.2mmol叔丁醇钠、适量的配体和钯(Ⅱ)、0.13mL十二烷(GC分析的内标)和2mL无水甲苯置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
[b]Ken Suzuki,et al.,Adv.Synth.Catal.2008,350,652-656.
[c]
Figure PCTCN2019079966-appb-000047
实施例44.
Figure PCTCN2019079966-appb-000048
Figure PCTCN2019079966-appb-000049
[a]在手套箱中，将1.0mmol卤代芳烃、1.5mmol吗啡啉、1.2mmol叔丁醇钠、适量的配体和钯(Ⅱ)、0.13mL十二烷(作为GC分析的内标)和2mL无水甲苯置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
[b]Azusa Kondon,et al.,J.Am.Chem.Soc.2007,129,6996-6997.
[c]
Figure PCTCN2019079966-appb-000050
实施例45.
Figure PCTCN2019079966-appb-000051
Figure PCTCN2019079966-appb-000052
Figure PCTCN2019079966-appb-000053
[a]在手套箱中，将1.0mmol卤代芳烃、1.5mmol苯硼酸、3.0mmol磷酸钾、适量的配体和钯(Ⅱ)、0.13mL十二烷(作为GC分析的内标)和2mL无水甲苯置于耐压管中.将该管密封并悬浮在100℃的油浴中.GC分析有机相.
[b]Stephen L.Buchwald,et al.,Angew.Chem.Int.Ed.2004,43,1871-1876.
[c]
Figure PCTCN2019079966-appb-000054

Claims (11)

  1. 通式为Ia和Ib或它们的混合物的三联芳单膦配体：
    Figure PCTCN2019079966-appb-100001
    其中
    Ar选自(C6-C20)芳基,其可以有1到3个独立地选自(C1-C6)烷基、-O(C1-C6)烷氧基、-N(C1-C6) 2二烷基氨基或(C6-C10)芳基的取代基(这里的芳基同样可以有1到3个独立地选自(C1-C6)烷基、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷氨基的取代基)；
    R 1选自H、(C1-C6)烷基、-O(C1-C6)烷氧基或-N(C1-C6) 2二烷基氨基；
    R 2和R 3各自独立地选自(C1-C10)烷基、(C3-C10)环烷基、(5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基或-CH 2(C6-C10)芳亚甲基,这里的(C3-C10)环烷基、(5-11元)杂环烷基、(C6-C20)芳基、(C4-C20)杂芳基和-CH 2(C6-C10)芳亚甲基中可以有1到3个独立地选自(C1-C6)烷基或-O(C1-C6)烷氧基-N(C1-C6) 2二烷氨基的取代基,这里的杂芳基中的杂原子选自O、N或S原子；
    当R 1＝H且Ar＝苯基时,R 2或和R 3不同时为叔丁基；
    当R 1＝H且当R 2＝R 3＝甲基时,Ar不为2,6-二甲基苯基、2,6-二异丙基苯基、2,4,6-三甲基苯基或2,4,6-三异丙基苯基；
    当R 1＝H且当R 2＝R 3＝乙基时,Ar不为2,6-二甲基苯基、2,4,6-三甲基苯基或2,6-二异丙基苯基.
  2. 根据权利要求1,Ar可以进一步选自苯基、4-甲基苯基、4-甲氧基苯基、4-异丙基苯基、4-叔丁基苯基、4-(二甲氨基)苯基、4-氟苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、2-甲基苯基、2-甲氧基苯基、2-(二甲氨基)苯基、2-异丙基苯基、2,6-二甲基苯基、2,6-二异丙基苯基、2,6-二甲氧基苯基、2,6-二异丙氧基苯基、2,6-双(二甲氨基)苯基、2,6-二甲氧基-3,5-二苯基-苯基、2,6-二甲氧基-3,5-双(3,5-二甲基苯基)-苯基、2,6-二异丙氧基-3,5-二苯基-苯基、2,6-二甲氧基-3,5-双(2,4,6-三异丙基苯基)-苯基、2-甲氧基-6-(二甲氨基)苯基、 2,4,6-三甲基苯基、2,4,6-三甲氧基苯基、2,4,6-三异丙基苯基、二茂铁基、1-萘基、2-萘基、2-甲氧基-1-萘基或9-蒽基的一种.
  3. 根据上述权利要求,R 1可以进一步选自H、甲基、甲氧基、二甲氨基、异丙基或叔丁基中的一种.
  4. 根据上述权利要求,R 2和R 3可以进一步各自独立地精选自甲基、乙基、丙基、异丙基、正丁基、叔丁基、环戊基、环己基、金刚基、苯基、2-甲基苯基、2-异丙基苯基、2-甲氧基苯基、2-(二甲氨基)苯基、4-甲基苯基、4-氟苯基、4-甲氧基苯基、4-(二甲氨基)苯基、3,5-二甲基苯基、3,5-双(三氟甲基)苯基、3,5-二氟苯基、3,5-二叔丁基苯基、2,6-二甲基苯基、2,6-二甲氧基苯基、2,6-二异丙基苯基、2,4,6-三甲氧基苯基、2-联苯基、2’,6’-二甲基-2-联苯基、2’,6’-二甲氧基-2-联苯基、2’,6’-二异丙氧基-2-联苯基、2’,6’-双二甲氨基基-2-联苯基、2’,6’-二异丙基-2-联苯基、2’,4’,6’-三异丙基-2-联苯基、二茂铁基、2-呋喃基、2-噻吩基、2-苯并呋喃基、2-苯并噻吩基、2-吡啶基或2-四氢呋喃基.
  5. 根据上述权利要求,本发明提供的三联芳单膦配体所选自的取代基可以构成下面具体膦化合物：
    (2,6-二苯基-4-甲基苯基)-二苯基膦；
    (2,6-二苯基-4-甲基苯基)-二环己基膦；
    (2,6-二苯基-4-甲基苯基)-二叔丁基膦；
    [2,6-双(2-甲基苯基)苯基]-二苯基膦；
    [2,6-双(2-甲基苯基)苯基]-二环己基膦；
    [2,6-双(2-甲基苯基)苯基]-二叔丁基膦；
    [2,6-双(2,6-二甲基苯基)苯基]-二苯基膦；
    [2,6-双(2,6-二甲基苯基)苯基]-二环己基膦；
    [2,6-双(2,6-二甲基苯基)苯基]-环己基-2-噻吩基膦；
    [2,6-双(2,6-二甲基苯基)苯基]-叔丁基-2-呋喃基膦；
    [2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-苯基膦；
    [2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-环己基膦；
    [2,6-双(2,4,6-三甲基苯基)苯基]-[2-二甲氨基苯基]-叔丁基膦；
    [2,6-双(2-甲氧基苯基)苯基]-二苯基膦；
    [2,6-双(2-甲氧基苯基)苯基]-二环己基膦；
    [2,6-双(2-甲氧基苯基)苯基]-二叔丁基膦；
    [2,6-双(2-甲氧基苯基)苯基]-环己基-2-噻吩基膦；
    [2,6-双(2-甲氧基苯基)苯基]-甲基-叔丁基膦；
    [2,6-双(2-甲氧基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2-甲氧基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-二苯基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-二环己基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-苯基-异丙基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-环己基-2-噻吩基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-环己基-金刚基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-甲基-叔丁基膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,6-二甲氧基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,6-二异丙氧基苯基)苯基]-二苯基膦；
    [2,6-双(2,6-二异丙氧基苯基)苯基]-二环己基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-二环己基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-苯基-环己基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-甲基-叔丁基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-苯基-异丙基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲基-2-联苯基]-甲基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-甲基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-环己基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-[2’,6’-二异丙基-2-联苯基]-环己基膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,6-二异丙基苯基)苯基]-苯基-[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-二环己基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-苯基-环己基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-甲基-叔丁基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-环己基-异丙基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲基-2-联苯基]-正丁基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-甲基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二甲氧基-2-联苯基]-环己基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-[2’,6’-二异丙基-2-联苯基]-叔丁基膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-双[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2,4,6-三异丙基苯基)苯基]-环己基-[3,5-双(三氟甲基)苯基]膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-二苯基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-二环己基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-二叔丁基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-(2-二甲氨基苯基)-环己基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-(4-二甲氨基苯基)-环己基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-[2’,6’-二甲氧基-2-联苯基]-正丁基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-[2’,6’-二异丙基-2-联苯基]-环己基膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-双[3,5-二(三氟甲基)苯基]膦；
    [2,6-双(2-甲氧基-1-萘基)苯基]-[3,5-双(三氟甲基)苯基]-甲基膦；
    [2,6-双(2-异丙氧基-1-萘基)苯基]-二苯基膦；
    [2,6-双(2-异丙氧基-1-萘基)苯基]-二环己基膦；
    [2,6-双(2-甲氧基-6-二甲氨基苯基)苯基]-二苯基膦；
    [2,6-双(2-甲氧基-6-二甲氨基苯基)苯基]-二环己基膦；
    [2,6-双(2,6-二甲氨基苯基)苯基]-二苯基膦；
    [2,6-双(2,6-二甲氨基苯基)苯基]-二环己基膦.
  6. 根据权利要求1至5项中一项所述的间三联芳单膦配体的制备方法,其特征是：用4-位带取代基或不带取代基的2,6-二氯苯或2-氟-6-氯苯在丁基锂作用下拔去1-位的氢原子继而发生消去反应形成苯炔类化合物,再与芳基负离子发生亲核加成反应，而后又发生消去反应可再一次形成苯炔类化合物，再与芳基负离子发生亲核加成反应形成2,6-二芳基苯基负离子，或者用2,6-二芳基苯基溴(碘)为原料与金属锂、正(仲,叔)丁基锂、金属镁或异丙基格式试剂反应制得2,6-二芳基苯基锂或镁试剂,再与PCl 3、R 2PCl 2、R 3PCl 2或R 2R 3PCl反应,这里可以加入或不加入CuX 1或Pd(PPh 3) 4,再根据所加入的氯化磷试剂的种类不同,选择分步加入R 2M和/或R 3M(M＝li,Na,MgX 1,CuX 1),X 1可以是Cl,Br或I.
  7. 根据权利要求1至5项中一项所描述的间三联芳单膦配体所配位的钯络合物,具有通式II、III、IV、V、VI或VII：
    Figure PCTCN2019079966-appb-100002
    其中
    L为权利要求1到4定义的三联芳单膦配体；
    X 2为Cl、Br、I、甲磺酸基、苯磺酸基、对甲苯磺酸基、甲酸基、乙酸基或苯甲酸基；
    R 4、R 5、R 6、R 7或R 8各自独立地选自H、甲基或苯基.
  8. 根据权利要求1至5项中一项所述的三联芳单膦配体和元素周期表VIII副族的过渡金属盐或络合物组合形成的体系用作催化剂的用途,其中,通常将所述膦配体原位加入到包含了合适的过渡金属前体化合物的反应体系中,或将所述膦配体先与过渡金属盐或配位络合物搅拌反应形成催化体系然后不经分离提纯直接加入到反应体系中.
  9. 根据权利要求8所述的用途,其特征在于所用的过渡金属是钯、镍、铂、铑、钴、铱和钌.
  10. 根据权利要求8或9所述的用途,其特征在于所用的过渡金属络合物是钯或镍络合物,优选钯络合物.
  11. 根据权利要求8至10所述的用途,其特征在于所述的膦配体用于催化(拟)卤代芳烃联芳烃为底物去形成新的C-C或C-N键的偶联反应中.
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CN114478627A (zh) * 2022-02-23 2022-05-13 湖北大学 一种烯丙基化单膦配体及其制备方法
CN114478627B (zh) * 2022-02-23 2023-06-20 湖北大学 一种烯丙基化单膦配体及其制备方法
CN115477630A (zh) * 2022-09-30 2022-12-16 大理大学 一类香豆素衍生物及其制备方法
CN115477630B (zh) * 2022-09-30 2023-10-27 大理大学 一类香豆素衍生物及其制备方法

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