Palladium cyclocatalyst precursor, palladium cyclocatalyst, preparation method and application thereof

Abstract

The present invention relates to the technical field of chemical synthesis, and specifically discloses a palladium cyclocatalyst precursor, a palladium cyclocatalyst, a preparation method, and an application thereof. The structure of the palladium cyclocatalyst precursor is shown in formula (I), and the structure of the palladium cyclocatalyst is shown in formula (II). The palladium cyclocatalyst provided by the present invention generates 12e L-Pd(0), which has stronger kinetic activity than the traditional 14e L2Pd(0) species, can effectively reduce the amount of catalyst used and the temperature of the cross-coupling reaction, improve the catalytic efficiency, and enable the reaction to be carried out efficiently under milder reaction conditions. The dimethylindane generated during the activation process is an inert molecule and will not participate in the cross-coupling reaction, that is, it will not introduce derivative impurities and will not have an adverse effect on the cross-coupling reaction. At the same time, the dimethylindane has low polarity and a small molecular weight, and is easier to remove from the reaction system, which is beneficial to improving the purity of the target product. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a palladium cyclocatalyst precursor, a palladium cyclocatalyst, a preparation method and an application thereof. Background Art

[0002] Most Pd-catalyzed cross-coupling reactions are achieved through the combination of catalytically active Pd(0) species and ligands. The general catalytic cycle is: oxidative addition, transmetallation, and reductive elimination. Currently, phosphine ligands are widely used in ligand applications due to their ease of design and synthesis, and their suitable bonding with Pd. According to their structural characteristics, common ligands include dialkylarylphosphines, trialkylphosphines, triaryl mono / diphosphines, and Buchwald-type biphenyl monodentate phosphines. Phosphine ligands are widely used in cross-coupling reactions to form CC, CN, CO, CF, C-CF3, and CS bonds.

[0003] Pd-catalyzed cross-coupling reactions are often achieved by in-situ catalysis with the simultaneous addition of a palladium precursor and a ligand. Examples include Pd(II) precursors such as PdCl2, Pd(OAc)2, [(cinnamyl)PdCl]2, or more stable Pd(0) precursors such as Pd2(dba)3, Pd(dba)2 (dba = dibenzylideneacetone, cinnamyl = cinnamyl, the same below). However, in-situ catalysis has the following disadvantages: the use of Pd(II) precursors requires in-situ reduction to obtain catalytically active Pd(0), which is inefficient in many cases and can easily generate potentially active byproducts such as Cl - or OAC - . Pd has been commercialized n (dba) m Pd(0) is obtained by releasing dba, but there are literature reports that dba ligands can significantly inhibit the progress of some cross-coupling reactions under certain conditions, and their applicability is relatively narrow. In addition to the shortcomings of the palladium source, many highly active electron-rich monophosphine ligands are sensitive to air and even prone to spontaneous combustion (such as P(t-Bu)3). These shortcomings limit the application of in situ catalysis in actual industrialization. In addition, the mixing method of the palladium source and the ligand can also lead to the formation of different catalytic species, which may have an adverse effect on the reaction and may also affect the selectivity of specific cross-coupling reactions. In addition, excess ligands may also participate in competition and affect catalytic activity.

[0004] Compared with in situ catalysis, the development and use of preformed palladium catalysts (precatalysts) are more conducive to improving the activity and selectivity of the reaction, and are more conducive to large-scale production. Precatalysts are often in the form of PdL2X2, which releases 14e catalytically active form L2Pd(0) after activation, catalyzing the cyclic cross-coupling reaction. With further research, it was found that the 12e catalytically active form of L-Pd(0) has stronger kinetic activity than L2Pd(0), which can achieve the effect of thorough reaction, low precious metal dosage (low residual amount), and applicability to relatively inert substrates. At present, there are not many types of precatalysts that can be activated to generate L-Pd(0), mainly concentrated in the Buchwald Palladacycle series, [Pd(μ-Br)(P t Precatalysts for the synthesis of catalytic reactions have been proposed, including the Bu3)]2 type and the Pd(crotyl)(L)Cl (crotyl = butenyl, the same below) type. However, these precatalysts have drawbacks such as complex preparation and the potential generation of harmful substances (such as carbazole) during activation. Therefore, it is of great significance to design a novel, widely applicable palladium complex with precatalytic properties to reduce reaction temperature, improve catalytic efficiency and reaction selectivity. Summary of the Invention

[0005] In response to the problems of complex preparation methods and possible generation of harmful substances during activation of existing palladium pre-catalysts, the present invention provides a palladium cyclocatalyst precursor, a palladium cyclocatalyst, a preparation method and an application thereof.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] In a first aspect, the present invention provides a palladium ring catalyst precursor, the structure of which is shown in formula (I):

[0008]

[0009] Compared with the prior art, the present invention provides a novel structure of a palladium cyclocatalyst precursor, which can be coordinated with a variety of phosphine ligands to form a palladium cyclocatalyst. The palladium cyclocatalyst forms a 12e L-Pd(0) species by reduction elimination activation in the cross-coupling reaction. Compared with the traditional PdL2X2 type pre-catalyst that generates 14e L2Pd(0) when activated, it has higher kinetic catalytic activity, can quickly catalyze and start the cross-coupling reaction, improve reaction efficiency, and reduce reaction temperature. In addition, compared with the currently commonly used Palladacycle When pre-catalysts such as G1, G2, and G3 are activated, small NH-containing molecules such as carbazole are generated, which may participate in the coupling competition. The cyclic palladium catalyst formed by the catalyst precursor provided by the present invention generates inert dimethylindane when activated, which will not have an adverse effect on the cross-coupling reaction. In addition, compared with the traditional in-situ catalysis in which the palladium source and ligand are directly added to the reaction system according to the stoichiometric ratio, the catalyst precursor provided by the present invention is stable in nature, avoids the problem of difficulty in using air-sensitive ligands alone, and also avoids the adverse effects of dba and COD removed during the reaction of commonly used palladium sources such as Pd2(dba)3, Pd(dba)2, (COD)PdCl2 (COD = 1,5-cyclooctadiene, the same below) that interfere with the coordination. The cyclic palladium catalyst formed by the precursor and a variety of phosphine ligands has good solubility in organic solvents, which is conducive to catalyzing a variety of cross-coupling reactions, has wide applicability, and has high practical value.

[0010] In a second aspect, the present invention further provides a method for preparing the above-mentioned palladium cyclopentadienyl catalyst precursor, comprising the following steps:

[0011] S1, under an inert atmosphere, in an organic solvent, 3-methyl-3-phenyl-1-chlorobutane and metallic magnesium undergo a Grignard reaction to obtain 3-methyl-3-phenyl-1-butylmagnesium chloride;

[0012] S2, under an inert atmosphere, in the presence of an organic solvent and a soluble zinc salt, 3-methyl-3-phenyl-1-butylmagnesium chloride and 1,5-cyclooctadiene palladium dichloride undergo an exchange reaction to obtain an intermediate represented by formula (V);

[0013]

[0014] S3, the intermediate represented by formula (V) undergoes a ring-closing reaction under alkaline conditions to obtain a palladium cyclocatalyst precursor represented by formula (I).

[0015] The present invention is the first to use 3-methyl-3-phenyl-1-butylmagnesium chloride and 1,5-cyclooctadiene palladium dichloride through exchange reaction and ring-closure reaction to prepare a series of palladium cyclocatalyst precursors with novel structures that have not been reported in the literature. The preparation method is simple, the reaction conditions are mild, and the palladium cyclocatalysts prepared from the catalyst precursors through industrial scale-up production have high catalytic activity and wide applicability, which is of great value in expanding the application of palladium cyclocatalysts in the field of cross-coupling reactions.

[0016] Furthermore, the preparation method of the palladium cyclopentadiene catalyst precursor specifically comprises the following steps:

[0017] S1, under an inert atmosphere, adding metallic magnesium to an organic solvent, adding dropwise a 3-methyl-3-phenyl-1-chlorobutane solution, heating and refluxing to obtain a 3-methyl-3-phenyl-1-butylmagnesium chloride solution;

[0018] S2, under an inert atmosphere, adding a soluble zinc salt to an organic solvent, adding dropwise the 3-methyl-3-phenyl-1-butylmagnesium chloride solution, adding 1,5-cyclooctadienepalladium dichloride after the addition is complete, stirring to react, and filtering to obtain a reaction solution of the intermediate represented by formula (V);

[0019] S3, adding a strong base solution to the reaction solution of the intermediate represented by formula (V), stirring and reacting to obtain the palladium cyclopentadiene catalyst precursor represented by formula (I). The reaction equation is as follows:

[0020]

[0021] The present invention first prepares a Grignard reagent of 3-methyl-3-phenyl-1-butylmagnesium chloride by reacting 3-methyl-3-phenyl-1-chlorobutane with metallic magnesium, then reacts the Grignard reagent with 1,5-cyclooctadiene palladium dichloride under the action of a soluble zinc salt, removes magnesium chloride to generate an intermediate represented by formula (V), and removes a molecule of sodium chloride from the intermediate under the action of a strong base to obtain a palladium cyclocatalyst precursor. The preparation process is simple, suitable for industrial large-scale production and application, and provides a new idea for the design and synthesis of a new palladium cyclocatalyst.

[0022] It should be noted that 3-methyl-3-phenyl-1-chlorobutane can be synthesized by referring to the methods disclosed in existing literature, such as Journal of the American Chemical Society, 1956, vol. 78, p. 5406, 5408.

[0023] In some embodiments, in S1 and S2, the organic solvent is tetrahydrofuran.

[0024] In some embodiments, in S1, the mass-to-volume ratio of the 3-methyl-3-phenyl-1-chlorobutane to the organic solvent is 1:3-10, wherein the unit of mass is gram and the unit of volume is milliliter.

[0025] Illustratively, in S1, the 3-methyl-3-phenyl-1-chlorobutane solution is a tetrahydrofuran solution of 3-methyl-3-phenyl-1-chlorobutane.

[0026] In some embodiments, in S1, the molar ratio of the magnesium metal to 3-methyl-3-phenyl-1-chlorobutane is 1 to 1.3:1.

[0027] In some embodiments, in S1, the molar ratio of metallic magnesium to 3-methyl-3-phenyl-1-chlorobutane is 1.2:1.

[0028] In some embodiments, in S2, the mass-to-volume ratio of the 1,5-cyclooctadienepalladium dichloride to the organic solvent is 1:5-20, wherein the unit of mass is gram and the unit of volume is milliliter.

[0029] In some embodiments, in S2, the soluble zinc salt is anhydrous zinc chloride.

[0030] In some embodiments, in S2, the molar ratio of 1,5-cyclooctadienepalladium dichloride, 3-methyl-3-phenyl-1-butylmagnesium chloride and soluble zinc salt is 1:1:1 to 1.2.

[0031] In some embodiments, in S2, the temperature of the stirring reaction is 5°C to 30°C.

[0032] In some embodiments, in S2, after the dropwise addition of the 3-methyl-3-phenyl-1-butylmagnesium chloride solution is completed, the stirring reaction time is 30 minutes to 60 minutes, and after the addition of 1,5-cyclooctadiene palladium dichloride, the stirring reaction time is 10 hours to 20 hours.

[0033] The preferred ratio of reactants and reaction temperature can promote efficient reaction and increase the yield of target product.

[0034] In some embodiments, after the reaction in step S2 is completed, the reaction solution is filtered using silica gel, and then the solid phase is washed with the same solvent as the reaction solvent. The filtrate and the washing solution are combined and concentrated before the next ring-closing reaction.

[0035] In some embodiments, in S3, the strong alkaline solution is a sodium hydroxide solution.

[0036] In some embodiments, the molar ratio of the 1,5-cyclooctadiene palladium dichloride to sodium hydroxide is 1:4-6.

[0037] In some embodiments, the molar ratio of 1,5-cyclooctadiene palladium dichloride, 3-methyl-3-phenyl-1-butylmagnesium chloride, soluble zinc salt, and sodium hydroxide is 1:1:1:4. This ratio not only promotes a more thorough reaction, but also helps reduce costs.

[0038] In some embodiments, in S3, the stirring reaction temperature is 5°C to 30°C, and the reaction time is 1 hour to 4 hours.

[0039] In some embodiments, in S3, the stirring reaction temperature is 20° C. to 30° C., and the reaction time is 2 h.

[0040] In some embodiments, after the reaction in step S3 is completed, solid-liquid separation is performed, and the solid phase is washed. The filtrate and the washing liquid are combined, concentrated to dryness, and then recrystallized in cold cyclohexane.

[0041] The inert atmosphere in the present invention is provided by an inert gas commonly used in the art. An inert gas refers to a gas that does not participate in the reaction of the reaction system, such as nitrogen, argon or helium.

[0042] It should be noted that, after each step of the reaction in S1-S3, solid-liquid separation is performed, the conditions must be kept anhydrous and oxygen-free. Preferably, after the solid-liquid separation is completed, the solid phase is washed with the same solvent as the reaction solvent.

[0043] In some embodiments, after washing the solid phase obtained by solid-liquid separation, vacuum extraction is performed to remove residual solvent.

[0044] The preparation method of the palladium cyclocatalyst precursor provided by the present invention has a simple process, few reaction steps, and mild reaction conditions, which is conducive to industrial scale-up production. In addition, the prepared palladium cyclocatalyst precursor has stable properties, exhibits high coordination activity towards different phosphine ligands, has wide applicability, and has broad application prospects in the field of cross-coupling reactions.

[0045] In a third aspect, the present invention further provides a palladium cyclocatalyst, the structure of which is shown in formula (II):

[0046]

[0047] Wherein, L is a phosphine ligand.

[0048] Currently available pre-catalysts for cross-coupling reactions generally undergo an alkaline activation process with L-Pd to generate Pd(0) active centers in situ. When such catalysts are used in the coupling reaction of polyaromatic or complex amino compounds with halogenated aromatic hydrocarbons, they are generally added in large quantities and require additional ligand supplementation to avoid oxidative inactivation of zero-valent palladium.

[0049] During the cross-coupling reaction, the palladium cyclocatalyst provided by the present invention generates 12e L-Pd(0), which has stronger kinetic activity than the traditional 14e L2Pd(0) species, can effectively reduce the amount of catalyst used and the temperature of the cross-coupling reaction, improve the catalytic efficiency, and enable the reaction to be efficiently carried out under milder reaction conditions. Moreover, the dimethylindane generated during the activation process is an inert molecule and will not participate in the cross-coupling reaction, that is, it will not introduce derivative impurities and will not have an adverse effect on the cross-coupling reaction. At the same time, dimethylindane has low polarity and small molecular weight, and is easier to remove from the reaction system, thereby facilitating the improvement of the purity of the target product. Therefore, the palladium cyclocatalyst provided by the present invention has broad application prospects in various cross-coupling reactions and has high practical value.

[0050] The activation process of the palladium cyclopentadiene catalyst provided by the present invention during the catalytic reaction is as follows:

[0051]

[0052] The palladium cyclocatalyst provided by the present invention coordinates a phosphine ligand with zero-valent palladium to obtain an L-Pd(0) catalyst species with high catalytic activity. In a cross-reaction system, L-Pd(0) can rapidly undergo an oxidative addition reaction with a halide to form a transition state compound of divalent palladium. This compound then reacts with a substrate, deprotonates under the action of a base, and undergoes reduction and elimination to obtain a product and L-Pd(0), rapidly completing a catalytic cycle.

[0053] The palladium cyclocatalyst provided by the present invention has stable performance, high catalytic activity, more accurate catalytic reaction measurement, and is conducive to repeated and stable reactions. It avoids the problem of poor reaction repetition stability caused by the uneven quality of palladium acetate palladium sources in traditional in-situ catalysis technology, and also avoids the problem of palladium chloride being difficult to use in organic solvents. The catalyst is suitable for various cross-coupling reactions and has broader coupling applicability.

[0054] Furthermore, the structural formula of the phosphine ligand is as shown in formula (III) or formula (IV):

[0055]

[0056] wherein R is selected from cyclohexyl, 1-adamantyl or tert-butyl;

[0057] R 1 ~R 9 Each is independently selected from H, D, NMe2, CF3, CN, F, 1-adamantyl, C1-C6 alkyl or alkoxy, C3-C6 cycloalkyl, phenyl, and a six-membered heteroaryl containing one or two N, O, or S;

[0058] R 10 is selected from 1-adamantyl or tert-butyl;

[0059] R 11 Selected from C1-C8 alkyl, C3-C8 cycloalkyl, benzyl, phenyl, phenethyl, 4-methylaminophenyl, 3-dimethylaminophenyl, 2-dimethylaminophenyl, 2-(N-morpholinyl)phenyl, 3-(N-morpholinyl)phenyl, 4-(N-morpholinyl)phenyl.

[0060] The present invention uses the above-mentioned phosphine ligand with higher reactivity to improve the catalytic activity of the palladium cyclocatalyst and also improve the stability of the palladium cyclocatalyst, which is beneficial to further improve the catalytic activity of the palladium cyclocatalyst for the cross-coupling reaction.

[0061] Preferably, the phosphine ligand is selected from one or more of compounds L1-L36:

[0062]

[0063] It should be noted that the abbreviated functional groups in the above structural formula are standard abbreviations of organic functional groups in the art, such as Cy is cyclohexyl, Pr is propyl, Me is methyl, Bu is butyl, and Ad is 1-adamantyl.

[0064] In a fourth aspect, the present invention also provides a method for preparing the aforementioned palladium cyclohexane catalyst, comprising the steps of: adding the palladium cyclohexane catalyst precursor and a phosphine ligand to an organic solvent under an inert atmosphere, and stirring the mixture to react to obtain the palladium cyclohexane catalyst of formula (II). The reaction equation is as follows:

[0065]

[0066] Furthermore, in combination with the above, the mass-to-volume ratio of the palladium cyclopentadiene catalyst precursor to the organic solvent is 1:15-50, wherein the unit of mass is gram and the unit of volume is milliliter.

[0067] Furthermore, in combination with the above, the molar ratio of the palladium ring catalyst precursor to the phosphine ligand is 1:1 to 1.2.

[0068] In some embodiments, the molar ratio of the palladium cyclopentadiene catalyst precursor to the phosphine ligand is 1:1.05.

[0069] Furthermore, in combination with the above, the temperature of the stirring reaction is 30° C. to 60° C., and the reaction time is 1 h to 2 h.

[0070] Furthermore, in combination with the above, the temperature of the stirring reaction is 50°C to 60°C.

[0071] Furthermore, in combination with the above, the organic solvent is cyclohexane.

[0072] Cyclohexane is used as the reaction solvent. Compared with diethyl ether and tetrahydrofuran, cyclohexane is less likely to coordinate with the palladium cyclohexane catalyst precursor, which is conducive to the coordination of the palladium cyclohexane catalyst precursor with the phosphine ligand.

[0073] The palladium ring catalyst prepared by the above method has little effect of the palladium source on the quality of the finished catalyst product, is more accurately measured than the in-situ catalyst, and has significantly better catalytic activity than the in-situ catalyst and the existing pre-catalyst. It can effectively improve the efficiency of the cross-coupling reaction, and the catalyst dosage is small, will not cause adverse effects on the cross-coupling reaction, and will not produce toxic and harmful substances, and has high practical value.

[0074] In a fifth aspect, the present invention further provides the use of the aforementioned palladium cyclocatalyst precursor or the aforementioned palladium cyclocatalyst in a cross-coupling reaction.

[0075] Furthermore, the cross-coupling reaction is a cross-coupling reaction to form a CC bond or a CN bond.

[0076] The present invention provides a novel structure of a palladium cyclocatalyst, which has a catalytic activity significantly superior to that of existing in-situ catalysts and pre-catalysts, can effectively improve the reaction efficiency of a cross-coupling reaction, reduce the reaction temperature and the amount of catalyst used, and is more in line with the development trend of energy conservation and consumption reduction. In addition, the preparation process is simple, the raw materials are readily available, and industrial production is facilitated. At the same time, the catalyst has good substrate adaptability and can effectively catalyze a variety of cross-coupling reactions. This provides a new approach for the design and synthesis of novel palladium cyclocatalysts, and is of great significance for promoting the development of the field of cross-coupling reactions. DETAILED DESCRIPTION

[0077] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0078] It should be noted that the term "alkyl" in the present invention refers to a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s -butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-Methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl 3)3.

[0079] The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing ring carbon atoms, which can be a monocyclic alkyl, a spirocyclic alkyl, or a bridged cycloalkyl. Phrases containing this term, for example, "C3-C6 cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, each occurrence of which can be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl or C6 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cy). In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. The term "alkoxy" refers to a group having -O-alkyl, i.e., an alkyl group as defined above connected to a parent core structure via an oxygen atom. Phrases containing this term, for example, "C1-C6 alkoxy" means that the alkyl portion contains 1 to 6 carbon atoms and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy or C6 alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt) and tert-butoxy (-OC(CH3)3 or -OtBu).

[0080] "Aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom. It can be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. For example, "C6-C20 aryl" refers to an aromatic group containing 6 to 20 carbon atoms. Each occurrence can be independently a C6 aryl, a C10 aryl, a C12 aryl, a C14 aryl, a C18 aryl, or a C20 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and their derivatives. It is understood that multiple aryl groups can also be interrupted by short non-aromatic units (e.g., <10% non-H atoms, such as C, N, or O atoms), such as acenaphthene, fluorene, or 9,9-diarylfluorene, triarylamine, and diaryl ether systems should also be included in the definition of aryl.

[0081] "Heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. For example, "C3-C10 heteroaryl" refers to a heteroaryl group containing 3 to 10 carbon atoms, and each occurrence thereof can independently be a C3 heteroaryl group, a C4 heteroaryl group, a C5 heteroaryl group, a C6 heteroaryl group, a C7 heteroaryl group, or a C8 heteroaryl group. Suitable examples include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primidine, quinazoline, and quinazolinone.

[0082] "Bonded to form a ring or not" means that the two groups can exist independently or form a ring structure with the surrounding atoms through chemical bonds. The bonded ring can form a five-membered ring, a six-membered ring or a seven-membered ring, and the ring type can be, for example, a cycloalkane, an aromatic ring or a heteroaromatic ring. For example, when R' and R" form a ring, they can form (two ethyl groups on the benzene ring bonded to form a cyclohexane fused to the benzene ring), (a methoxy group and a hydroxyl group on the benzene ring bonded to form a 1,3-dioxolane fused to the benzene ring), (two methoxy groups on the benzene ring bonded to form a 1,4-dioxane fused to the benzene ring) or (two vinyl groups on the benzene ring bonded to form a benzene ring fused to the benzene ring).

[0083] In order to better illustrate the present invention, further examples are given below.

[0084] Example 1

[0085] This embodiment provides a method for preparing a palladium cyclopentadiene catalyst, comprising the following steps:

[0086] (1) Preparation of 3-methyl-3-phenyl-1-butyl magnesium chloride

[0087] Under inert gas protection, 2.9g magnesium chips (120mmol, 1.2 equivalents) and 10mL tetrahydrofuran (THF) were added to a 250mL dry three-necked flask. Under stirring, 10mL 3-methyl-3-phenyl-1-chlorobutane solution (18.3g (100mmol, 1 equivalent) 3-methyl-3-phenyl-1-chlorobutane+73mL tetrahydrofuran) was added thereto. The mixture was stirred and heated to micro-reflux. After the Grignard reagent was triggered, heating was turned off and the remaining 3-methyl-3-phenyl-1-chlorobutane solution was added dropwise. The reaction system was kept in a micro-reflux state. The addition was completed in about 1h. After completion of the addition, the system was controlled to react at micro-reflux for 1h and cooled to room temperature to obtain 3-methyl-3-phenyl-1-butylmagnesium chloride solution. The mixture was temporarily stored under inert gas protection for use.

[0088] (2) Preparation of palladium cyclocatalyst precursor:

[0089] Under inert gas protection, 15.0 g of anhydrous zinc chloride (110 mmol, 1.1 equivalents) was added to a dry 500 mL three-necked flask, and then 300 mL of tetrahydrofuran was added. The prepared 3-methyl-3-phenyl-1-butylmagnesium chloride solution was added to a constant pressure dropping funnel and slowly added dropwise to the three-necked flask. The addition time was about 20 min. After the addition was completed, the constant pressure funnel was rinsed with 10 mL of anhydrous tetrahydrofuran, and stirring was continued for 30 min. Then 28.5 g of 1,5-cyclooctadiene palladium dichloride (100 mmol, 1.0 equivalent), the light brown solution was stirred at room temperature for 15h to 16h, and then the reaction solution was filtered with 40.0g silica gel, 450mL tetrahydrofuran was used to wash the silica gel, and all the filtrates were combined into a 1L round-bottom flask. Then, 30mL water and 16.0g sodium hydroxide (400mmol, 4.0 equivalent) were added to the round-bottom flask, and the reaction was stirred at room temperature for 4h. The reaction solution was concentrated to dryness with a rotary evaporator, and the resulting solid was added to 500mL tetrahydrofuran, filtered with 40.0g silica gel, and the silica gel was washed with 250mL tetrahydrofuran. The filtrates were combined and concentrated to dryness in vacuo with a rotary evaporator. 200mL of cold cyclohexane at 0°C was added to the resulting orange solid, stirred and slurried to obtain a suspension. The resulting suspension was vacuum filtered and washed with 150mL cyclohexane at 0°C to obtain 23.4g of an off-white palladium cyclohexane precursor with a yield of 64.8%;

[0090] The filtrate was concentrated in vacuo using a rotary evaporator, and 50 mL of 0°C cold cyclohexane was added to the resulting solid. The solid was sealed and placed in a -25°C refrigerator for recrystallization for 2 h. The solid was filtered through a glass funnel and washed twice with cold cyclohexane (-25°C, 20 mL*2) to obtain a gray-brown palladium cyclohexane precursor (1.8 g). The two-step palladium cyclohexane precursors were combined to give a total of 25.2 g, with a yield of 69.8%.

[0091] (3) Preparation of palladium cyclocatalyst:

[0092] To a 50 mL round-bottom flask equipped with a magnetic stirrer were added 360 mg (1.0 mmol, 1.0 equivalent) of the palladium cyclohexyl catalyst precursor prepared above and 501 mg (1.05 mmol, 1.05 equivalent) of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (abbreviated as XPhos, structure as shown in L1), and then 15 mL of cyclohexane was added to the flask via a pipette. The mixture was stirred at room temperature for 1 hour, and crystals gradually precipitated. The mixture was filtered through a glass funnel and washed with 30 mL of cyclohexane. The resulting solid was dried in vacuo at 30°C-35°C overnight (about 15 hours) to give an off-white powder. 583 mg of the palladium cyclohexyl catalyst shown below was obtained in a yield of 79.9%.

[0093]

[0094] 1 H NMR (400MHz, CDCl3): δ7.75 (ddd, J=7.3, 5.1, 1.6Hz, 1H), 7.42 (td, J=7.4, 1.6Hz, 1H), 7.41-7.36 (m, 1H), 7.15 (s, 2H), 7.09 (ddd, J=7. 4,4.0,1.4Hz,1H),6.88(ddd,J=7.6,3.5,1.6Hz,1H),6.78(td,J=7.3,1.4Hz,1H),6.73(tt,J=7.3,1.4Hz,1H),6.62(dt,J=7.3,1.4Hz, 1H),2.89(hept,J=6.9Hz,1H),2.47(h,J=6.8Hz,2H),2.32-2.23(m,2H),2.18-2.11(m,2H),1.86-1.76(m,6H),1.70(d,J=14.9Hz,4H) ,1.60(qt,J=13.2,4.0Hz,2H),1.55(s,2H),1.48(d,J=6.8Hz,6H),1.36-1.23(m,7H),1.21(m,7H),1.14(s,6H),0.90(d,J=6.7Hz,6H).

[0095] Example 2

[0096] This example provides a method for preparing a palladium cyclocatalyst, the steps and reaction conditions of which are exactly the same as those of Example 1, except that the XPhos ligand in step 3 of Example 1 is replaced with an equimolar amount of n-butyldi(1-adamantyl)phosphine ligand (abbreviated as Ad2P(n-Bu), with a structure as shown in L31).

[0097] The structural formula of the prepared product is shown below. The product mass is 557.8 mg, and the yield is 91.3%.

[0098]

[0099] Example 3

[0100] This example provides a method for preparing a palladium cyclocatalyst, the steps and reaction conditions of which are exactly the same as those in Example 1, except that the XPhos ligand in step 3 of Example 1 is replaced with an equimolar amount of 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (abbreviated as RuPhos, structure shown in L4).

[0101] The structural formula of the prepared product is shown below. The product mass is 633.5 mg, and the yield is 88.1%.

[0102]

[0103] Example 4

[0104] This embodiment provides a method for preparing a palladium cyclocatalyst, the steps, reaction conditions, etc. of which are exactly the same as those of Example 1, except that the XPhos ligand in step 3 of Example 1 is replaced with an equimolar amount of 2-di(1-adamantyl)phosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (structure shown in L13).

[0105] The structural formula of the prepared product is shown below. The product mass is 853.5 mg and the yield is 95.5%.

[0106]

[0107] Example 5

[0108] This example provides a method for preparing a palladium cyclocatalyst, the steps and reaction conditions of which are exactly the same as those of Example 1, except that the XPhos ligand in step 3 of Example 1 is replaced with an equimolar amount of 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (abbreviated as t-BuXPhos, structure shown in L21).

[0109] The structural formula of the prepared product is shown below. The product mass is 611.4 mg, and the yield is 90.1%.

[0110]

[0111] By replacing the XPhos ligand in Example 1 with an equimolar amount of other phosphine ligands defined in the present invention (phosphine ligands in L1 to L31), a palladium cyclocatalyst containing the corresponding phosphine ligand can be prepared.

[0112] Applied to CC cross-coupling reaction

[0113] Application Example 1

[0114] Under nitrogen protection, 4-propyl bromobenzene (39.8 g, 0.2 mol, 1 eq), 4-ethoxy-2,3-difluorophenylboric acid (44.4 g, 0.22 mol, 1.1 eq), sodium carbonate (42.4 g, 0.4 mol, 2 eq), 300 mL of toluene and 100 mL of ethanol were added to a 1 L three-necked flask, and then stirred to dissolve. The palladium cyclohexane catalyst prepared in Example 1 (0.2 g, 0.27 mmol, 0.00135eq), heated with stirring to reflux, reacted for 8h, sampled raw material 4-propyl bromobenzene and reacted completely, the reaction solution was cooled to room temperature, 200mL of water was added to the reaction solution, separated, extracted, washed with water, and concentrated to obtain a khaki crude product, which was subjected to vacuum distillation and recrystallization from anhydrous ethanol to obtain 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl as white crystals, 49.1g, with a yield of 88.9% and a GC purity of 99.91%.

[0115] Application Example 2

[0116] The reaction was the same as in Application Example 1, except that the added palladium cyclopentane catalyst was replaced with an equal amount of the catalyst prepared in Example 2. The coupling reaction time was 4 h, and the sampled raw material 4-propyl bromobenzene reacted completely. The final product, 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl, had a mass of 51.5 g, a yield of 93.3%, and a GC purity of 99.93%.

[0117] Application Example 3

[0118] The reaction was the same as in Application Example 1, except that the added palladium cyclopentane catalyst was replaced with an equal amount of the catalyst prepared in Example 3. The coupling reaction time was 8 h, and the sampled raw material 4-propyl bromobenzene reacted completely. The final product, 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl, had a mass of 47.0 g, a yield of 85.1%, and a GC purity of 99.94%.

[0119] Application Example 4

[0120] The reaction was the same as in Application Example 1, except that the reaction temperature in Application Example 1 was replaced with 40°C to 45°C, the reaction time was 10 h, the sampled raw material 4-propyl bromobenzene was completely reacted, and the mass of the final product 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl was 49.0 g, the yield was 88.8%, and the GC purity was 99.93%.

[0121] Comparison of Application Example 1 and Application Example 4 demonstrates that the palladium cyclocatalyst provided by the embodiment of the present invention can achieve the effect of efficiently catalyzing the CC cross-coupling reaction even under low temperature conditions, without reducing the reaction yield and purity.

[0122] When the catalysts prepared in Examples 4-5 were applied to the same reaction system as in Application Example 1, the final product yields reached over 85% and purities reached over 99.9%. The corresponding palladium cyclohexane catalysts prepared according to Example 1 using other phosphine ligands of the present invention were applied to the same reaction system, and the final product yields reached over 80% and purities reached over 99.9%.

[0123] Comparative Example 1

[0124] This comparative example is the same as Application Example 1, except that the palladium cyclohexane catalyst in Application Example 1 is replaced with an equal amount of XPhos ligand and an equal amount of Pd(dba)2. The coupling reaction lasts for 8 hours, and approximately 15% of the sampled raw material 4-propyl bromobenzene remains. After 10 hours of coupling reaction, approximately 11% of the sampled raw material 4-propyl bromobenzene remains. The final product, 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl, weighs 39.2 g, with a yield of 71.0% and a GC purity of 99.88%.

[0125] Comparative Example 2

[0126] This comparative example is the same as Application Example 1, except that the palladium cyclocatalyst in Application Example 1 is replaced with an equal amount of XPhos ligand and an equal amount of Pd(OAc)2. The coupling reaction lasts for 8 hours, and approximately 14% of the raw material 4-propyl bromobenzene remains after sampling. After 10 hours of coupling reaction, approximately 12% of the raw material 4-propyl bromobenzene remains. The final product, 4-ethoxy-2,3-difluoro-4'-propyl-1,1'-biphenyl, weighs 37.8 g, with a yield of 68.5% and a GC purity of 99.85%.

[0127] Application in CN cross-coupling reactions

[0128] Application Example 1

[0129] Under nitrogen protection, 51.3 g of 4-bromobiphenyl (0.22 mol), 40.3 g (0.2 mol) of 2-chlorocarbazole, 38.4 g (0.4 mol) of sodium tert-butoxide and 400 mL of toluene were added to a 1 L three-necked flask and stirred to dissolve. 0.2 g (0.28 mmol) of the palladium cyclohexane catalyst prepared in Example 3 was added, and the mixture was heated and stirred to reflux. The reaction was allowed to proceed for 5 h. The reaction of the raw material 2-chlorocarbazole was complete (<0.01%). The reaction solution was cooled to room temperature, 300 mL of water was added to the reaction solution, the liquid was separated, extracted, washed with water, and concentrated to obtain a light yellow crude product. After dissolving with methylcycloalkyl, the product was purified by silica gel column. The purified solution was recrystallized from methylcyclohexane to obtain 65.8 g of white crystals of N-(4-biphenyl)-2-chlorocarbazole. The yield was 93.0% and the HPLC purity was 99.95%.

[0130] Application Example 2

[0131] The same as Application Example 1, except that the palladium cyclopentadiene catalyst was replaced by the palladium cyclopentadiene catalyst prepared in Example 2. The coupling reaction was carried out for 6 h. The sampled raw material 2-chlorocarbazole reacted completely (<0.02%). The final product, N-(4-biphenyl)-2-chlorocarbazole, was 64.5 g of white crystals with a yield of 91.1% and an HPLC purity of 99.96%.

[0132] When the catalysts prepared in Examples 1 and 4-5 were applied to the same reaction system as in Application Example 1, the final product yields reached over 90% and purities reached over 99.9%. When the corresponding palladium cyclohexane catalysts prepared according to Example 1 using other phosphine ligands of the present invention were applied to the same reaction system, the final product yields reached over 85% and purities reached over 99.9%.

[0133] Comparative Application Example 1

[0134] This comparative example is identical to Application Example 1, except that the palladium cyclocatalyst in Application Example 1 is replaced with an equal amount of RuPhos ligand and an equal amount of Pd(dba)2. The coupling reaction lasts 5 hours, leaving approximately 7% of the sampled 2-chlorocarbazole. After 8 hours of coupling reaction, approximately 3% of the sampled 2-chlorocarbazole remains. The final product, N-(4-biphenyl)-2-chlorocarbazole, has a mass of 53.9 g, a yield of 76.2%, and an HPLC purity of 99.74%.

[0135] Application Comparative Example 2

[0136] This comparative example is the same as Example 1, except that the palladium cyclohexyl catalyst in Example 1 is replaced with an equal amount of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) methanesulfonate (RuPhos Pd G3). The coupling reaction lasts 5 hours, leaving approximately 2.5% of the sampled 2-chlorocarbazole. After 8 hours of coupling reaction, approximately 0.4% of the sampled 2-chlorocarbazole remains. The final product, N-(4-biphenyl)-2-chlorocarbazole, has a mass of 63.0 g, an 89.0% yield, and a 99.72% HPLC purity. The product contains 0.065% N-(4-biphenyl)carbazole as an impurity, which originates from the carbazole generated during the activation of RuPhos Pd G3.

[0137] In summary, the palladium cyclocatalyst provided by the present invention has excellent catalytic activity, can effectively improve the reaction efficiency of the cross-coupling reaction, reduce the reaction temperature, and enable the reaction to proceed efficiently under milder conditions. In addition, the catalyst dosage is low and the catalytic activity is stable, which is conducive to improving the repeatability of the reaction. At the same time, during the reaction process, the catalyst activation will not introduce derivative impurities and will not have an adverse effect on the cross-coupling reaction, thereby significantly improving the yield and purity of the target product. The application prospects in the field of cross-coupling reactions are extremely broad.

[0138] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A palladium cyclocatalyst precursor, characterized in that Its structure is shown in formula (I): Formula (I).

2. The method for preparing the palladium cyclopentadiene catalyst precursor according to claim 1, wherein The steps include: S1, under an inert atmosphere, in an organic solvent, 3-methyl-3-phenyl-1-chlorobutane and metallic magnesium undergo a Grignard reaction to obtain 3-methyl-3-phenyl-1-butylmagnesium chloride; S2, under an inert atmosphere, in the presence of an organic solvent and a soluble zinc salt, 3-methyl-3-phenyl-1-butylmagnesium chloride and 1,5-cyclooctadiene palladium dichloride undergo an exchange reaction to obtain an intermediate represented by formula (V); Formula (V) S3, the intermediate represented by formula (V) undergoes a ring-closing reaction under alkaline conditions to obtain a palladium cyclocatalyst precursor represented by formula (I).

3. The method for preparing a palladium cyclopentadiene catalyst precursor according to claim 2, wherein: The specific steps include: S1, under an inert atmosphere, adding metallic magnesium to an organic solvent, adding dropwise a 3-methyl-3-phenyl-1-chlorobutane solution, heating and refluxing to obtain a 3-methyl-3-phenyl-1-butylmagnesium chloride solution; S2, under an inert atmosphere, adding a soluble zinc salt to an organic solvent, adding dropwise the 3-methyl-3-phenyl-1-butylmagnesium chloride solution, adding 1,5-cyclooctadienepalladium dichloride after the addition is complete, stirring to react, and filtering to obtain a reaction solution of the intermediate represented by formula (V); S3, adding a strong base solution to the reaction solution of the intermediate represented by formula (V), stirring and reacting to obtain a palladium cyclopentadiene catalyst precursor represented by formula (I).

4. The method for preparing a palladium cyclopentadiene catalyst precursor according to claim 3, wherein: In S1 and S2, the organic solvents are both tetrahydrofuran; and / or In S1, the molar ratio of the magnesium metal to 3-methyl-3-phenyl-1-chlorobutane is 1 to 1.3:1; and / or In S2, the soluble zinc salt is anhydrous zinc chloride; and / or In S2, the molar ratio of 1,5-cyclooctadiene palladium dichloride, 3-methyl-3-phenyl-1-butylmagnesium chloride and soluble zinc salt is 1:1:1~1.2; and / or In S2, the stirring reaction temperature is 5°C to 30°C, and the reaction time is 10h to 20h; and / or In S3, the stirring reaction temperature is 5°C to 30°C, and the reaction time is 1h to 4h.

5. A palladium cyclocatalyst, characterized in that Its structure is shown in formula (II): Formula (II) Wherein, L is a phosphine ligand; The structural formula of the phosphine ligand is shown in formula (III) or formula (IV): Formula (III) Formula (IV) wherein R is selected from cyclohexyl, 1-adamantyl or tert-butyl; R 1 ~R 9 Each is independently selected from H, D, NMe2, CF3, CN, F, 1-adamantyl, C1~C6 alkyl or alkoxy, C3~C6 cycloalkyl, phenyl, and a six-membered heteroaryl containing one or two N, O, or S; R 10 is selected from 1-adamantyl or tert-butyl; R 11 Selected from C1~C8 alkyl, C3~C8 cycloalkyl, benzyl, phenyl, phenethyl, 4-methylaminophenyl, 3-dimethylaminophenyl, 2-dimethylaminophenyl, 2-(N-morpholinyl)phenyl, 3-(N-morpholinyl)phenyl, 4-(N-morpholinyl)phenyl.

6. The palladium cyclocatalyst according to claim 5, wherein The phosphine ligand is selected from one or more compounds such as L1-L36: 。 7. A method for preparing the palladium cyclocatalyst according to claim 5 or 6, characterized in that: The method comprises the following steps: adding the palladium cyclocatalyst precursor and the phosphine ligand according to claim 1 into an organic solvent under an inert atmosphere, stirring and reacting to obtain the palladium cyclocatalyst represented by formula (II); Formula (II).

8. The method for preparing the palladium cyclopentadiene catalyst according to claim 7, wherein The molar ratio of the palladium cyclocatalyst precursor to the phosphine ligand is 1:1 to 1.2; and / or The stirring reaction temperature is 30° C. to 60° C., and the reaction time is 1 h to 2 h.

9. Use of the palladium cyclocatalyst precursor according to claim 1 or the palladium cyclocatalyst according to claim 5 or 6 in a cross-coupling reaction.

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