CN114632552A - Buchwald pre-catalyst, preparation method and application thereof - Google Patents
Buchwald pre-catalyst, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a Buchwald pre-catalyst, a preparation method and application thereof. The preparation method comprises the following steps: mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first step of reaction is finished, adding quaternary ammonium salt containing biphenyl groups to carry out a second step of reaction; after the second step reaction is finished, adding a second solvent, separating out solid, carrying out solid-liquid separation, and retaining a solid phase; wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer; the first solvent is toluene and/or xylene; the second solvent is n-hexane and/or diethyl ether. The preparation method has the advantages of simple process, low precious metal loss, high product yield, low solvent residue of the prepared pre-catalyst finished product, high catalytic activity and accurate measurement.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a Buchwald pre-catalyst, a preparation method and application thereof.
Background
The cross-coupling reaction refers to the reaction of RX and non-transition metal organic compound R ' M ' to form carbon-carbon bond (R-R ') under the catalysis of transition metal. The cross-coupling reaction has high efficiency, good selectivity and mild reaction conditions, and occupies a significant position in modern organic synthesis. Palladium catalysts are a class of catalysts widely used in cross-coupling reactions, and in order to control reaction rates, regioselectivities and stereoselectivities of different reactions, a series of ligands are often introduced into the palladium catalysts to achieve adjustability of the palladium catalysts. Currently, phosphine ligand derived palladium precatalysts, typically represented by ligand derived palladium catalyst precursors such as Buchwald precatalysts (dialkylarylphosphines, trialkylphosphines, triarylmono/bisphosphines, etc.), are used to form C-C, C-N, C-O, C-F, C-CF due to their higher stability and reactivity3And C-S bond, and the reactions can be carried out under mild alkaline conditions, thus having wide application prospect.
However, in the conventional technology, the preparation method of the Buchwald pre-catalyst is complex, the loss of noble metals is high, the product yield is low, and the prepared pre-catalyst finished product often has solvent residues, which easily causes misjudgment on the catalytic reaction metering and influences the catalytic activity.
Disclosure of Invention
Based on the above, the Buchwald precatalyst and the preparation method and application thereof are needed to be provided, the preparation method has the advantages of simple process, low precious metal loss, high product yield, low solvent residue of the prepared precatalyst finished product, high catalytic activity and accurate metering, the defects of the preparation method of the Buchwald precatalyst in the traditional technology can be effectively overcome, and the quality of the precatalyst finished product is improved.
In one aspect of the present invention, there is provided a method for preparing a Buchwald pre-catalyst, comprising the steps of:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first-step reaction is finished, adding quaternary ammonium salt containing biphenyl groups to perform a second-step reaction; after the second-step reaction is finished, adding a second solvent, separating out a solid, carrying out solid-liquid separation, and keeping a solid phase;
wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer, and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether.
In another aspect of the present invention, there is also provided a Buchwald precatalyst, which is prepared by the preparation method according to any one of the previous embodiments.
In another aspect of the invention, the use of the aforementioned Buchwald precatalyst in cross-coupling reactions is also provided.
The Buchwald precatalyst can be directly prepared by adopting one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer as a palladium source and reacting the palladium source with phosphine ligand and quaternary ammonium salt containing biphenyl groups through a one-pot method, has the advantages of simple and convenient process flow, few steps, mild reaction conditions, contribution to industrial amplification production and less loss, avoids noble metal loss caused by the need of separating a cyclic palladium intermediate in the traditional method, and greatly reduces the production cost; in addition, the scheme of the invention also optimizes a palladium source and a solvent, avoids the harsh requirement on the quality of the palladium acetate source in the traditional technology, does not use solvents such as tetrahydrofuran, dichloromethane and the like which are easy to coordinate with the product, and effectively reduces the residue of the solvent in the finished catalyst product.
The Buchwald pre-catalyst prepared by the invention has low solvent residue and small influence of a palladium source on the quality of a finished product, and the finished product has higher catalytic activity and more accurate catalytic reaction metering compared with the Buchwald pre-catalyst prepared by the traditional technology, can effectively improve the efficiency of cross coupling reaction, and promotes the further development of the field.
Drawings
FIG. 1 is a NMR chart of a precatalyst obtained in example 1 (1HNMR）；
FIG. 2 shows the NMR phosphorus spectrum of the precatalyst obtained in example 131PNMR）；
FIG. 3 is a NMR spectrum of the precatalyst obtained in example 2: (1HNMR）；
FIG. 4 is a graph obtained in example 2Nuclear magnetic resonance phosphorus spectrum of the precatalyst of (a)31PNMR）；
FIG. 5 is a NMR spectrum of the precatalyst obtained in example 3: (1HNMR）；
FIG. 6 shows the NMR phosphorus spectrum of the pre-catalyst obtained in example 331PNMR）；
FIG. 7 is a NMR chart of the precatalyst obtained in example 4 (1HNMR）；
FIG. 8 shows the NMR phosphorus spectrum of the precatalyst obtained in example 4: (31PNMR）；
FIG. 9 is a NMR spectrum of the precatalyst obtained in example 5: (1HNMR）；
FIG. 10 shows the NMR phosphorus spectrum of the precatalyst obtained in example 5: (31PNMR）；
FIG. 11 is a NMR spectrum of the precatalyst obtained in example 6: (1HNMR）；
FIG. 12 is the NMR phosphorus spectrum of the precatalyst obtained in example 6 (31PNMR）；
FIG. 13 is a NMR spectrum of a precatalyst obtained in example 7: (1HNMR）；
FIG. 14 shows the NMR phosphorus spectrum of the precatalyst obtained in example 7: (31PNMR）；
FIG. 15 is a NMR spectrum of the precatalyst obtained in example 8: (1HNMR）；
FIG. 16 is a NMR phosphorus spectrum of the precatalyst obtained in example 8: (31PNMR）；
FIG. 17 is a NMR spectrum of the precatalyst obtained in example 9: (1HNMR）；
FIG. 18 shows the NMR phosphorus spectrum of the precatalyst obtained in example 931PNMR）；
FIG. 19 is a NMR spectrum of the precatalyst obtained in example 10: (1HNMR）；
FIG. 20 shows the NMR phosphorus spectrum of the precatalyst obtained in example 10: (31PNMR）；
FIG. 21 is a photograph of a film obtained in example 11NMR spectrum of precatalyst: (1HNMR）；
FIG. 22 is a NMR phosphorus spectrum of the precatalyst obtained in example 11: (31PNMR）；
FIG. 23 is a NMR chart of an intermediate obtained in step (1) of comparative example 11HNMR）；
FIG. 24 shows the NMR phosphorus spectrum of the intermediate obtained in step (1) of comparative example 131PNMR）。
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or to implicitly indicate the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless explicitly specified otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, the numerical intervals are regarded as continuous, and include the minimum and maximum values of the range and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
The percentage contents referred to in the present invention mean, unless otherwise specified, mass percentages for solid-liquid mixing and solid-solid mixing, and volume percentages for liquid-liquid mixing.
The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the added component in the system after the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C1~C6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms, which may be independently at each occurrence C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl group (b)n-Pr、n-propyl, n-propyl, -CH2CH2CH3) 2-propyl group (c) ((ii))i-Pr、i-propyl, isopropyl, -CH (CH)3)2) 1-butyl group (b)n-Bu、n-butyl, -CH2CH2CH2CH3) 2-methyl-1-propyl group(s) ((s))i-Bu、i-butyl, -CH2CH(CH3)2) 2-butyl group (b)s-Bu、s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl group(s) ((s))t-Bu、t-butyl, -C (CH)3)3) 1-pentyl group(s) ((s))n-pentyl, -CH2CH2CH2CH2CH3) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) And 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3。
The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing ring carbon atoms and may be a monocycloalkyl, or spirocycloalkyl, or bridged cycloalkyl. Phrases containing the term, e.g., "C3~C6Cycloalkyl "refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which may be independently C3A cycloalkyl group, a,C4Cycloalkyl radical, C5Cycloalkyl or C6A cycloalkyl group. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclo and cyclohexyl (Cy). In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl groups containing a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.
The term "alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C1~C6Alkoxy "means that the alkyl moiety contains 1 to 6 carbon atoms and, at each occurrence, may be independently C1Alkoxy radical, C4Alkoxy radical, C5Alkoxy or C6An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH)3or-OMe), ethoxy (-O-CH)2CH3or-OEt) and tert-butoxy (-O-C (CH)3)3or-OtBu).
"aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from the aromatic ring compound and may be a monocyclic aryl group, or a fused ring aryl group, or a polycyclic aryl group, at least one of which is an aromatic ring system for polycyclic ring species. For example, "C5~C20Aryl "refers to an aryl group containing 5 to 20 carbon atoms, which at each occurrence, independently of each other, can be C5Aryl radical, C6Aryl radical, C10Aryl radical, C14Aryl radical, C18Aryl or C20And (4) an aryl group. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof. It will be appreciated that multiple aryl groups may also be interrupted by short non-aromatic units (e.g. by<10% of atoms other than H, such as C, N or O atoms), such as in particular acenaphthene, fluorene, or 9, 9-diarylfluorene, triarylamine, diarylether systems should also be included in the definition of aryl.
"heteroaryl" means that on the basis of an aryl at least one carbon atom is replaced by a non-carbon atom which may be a N atom, an O atom, an S atom, etc. For example, "C3~C10Heteroaryl "meansHeteroaryl having 3 to 10 carbon atoms, which at each occurrence may be independently of one another C3Heteroaryl group, C4Heteroaryl group, C5Heteroaryl group, C6Heteroaryl, C7Heteroaryl or C8A 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, phthalazine, quinoxaline, phenanthridine, primadine, quinazoline, and quinazolinone.
"bonded to form a ring or not" means that the two groups may be present independently or may form a ring structure together with the surrounding atoms through a chemical bond. The bonding to the ring may be, for example, to form a five-membered ring, a six-membered ring or a seven-membered ring, and the ring forming species may be, for example, a cycloalkane, an aromatic ring or a heteroaromatic ring. For example,
in the case where R ' and R ' ' form a ring, they may form
(cyclohexane condensed with benzene ring is formed by bonding two ethyl groups on benzene ring),
(1, 3-dioxolane fused with a benzene ring formed by bonding one methoxy group and one hydroxyl group on the benzene ring),
(1, 4-dioxane fused with benzene ring is formed by bonding two methoxy groups on benzene ring) or
(formed by bonding two vinyl groups on a benzene ring with each otherBenzene ring in which benzene rings are fused).
"non-reactive gas" means a gas which does not participate in the reaction system, and may be, for example, nitrogen, argon or other inert gas.
In one aspect of the invention, a preparation method of the Buchwald pre-catalyst is provided, which comprises the following steps:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first step of reaction is finished, adding quaternary ammonium salt containing biphenyl groups to carry out a second step of reaction; after the second step reaction is finished, adding a second solvent, separating out solid, carrying out solid-liquid separation, and retaining a solid phase;
wherein the palladium source comprises one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether.
At present, researchers have developed multiple generations of Buchwald pre-catalysts, and four more mature generations of Buchwald pre-catalysts exist. Among these, the deprotonation of the first generation (G1) precatalyst under basic conditions enables the generation of the active Pd (0) species and the resulting catalyst activity is very high. Even at low temperatures of-40 ℃, various cross-coupling reactions can still occur. The improvement that the second generation (G2) precatalyst replaces the phenethylamine skeleton in the (G1) complex with biphenyl ligands, enables researchers to generate active Pd species using weak phosphates or carbonates at room temperature, and the second generation (G2) catalyst is significantly more useful for accelerating a large number of Suzuki-Miyaura couplings in other cross-coupling reactions. The versatility of third generation (G3) precatalysts is the greatest compared to the first two, are highly soluble in a variety of common organic solvents, are able to accommodate a large number of ligands, such as the BrettPhos family, and their efficacy in solution is also significantly extended. In some special cases, carbazole leaving groups may inhibit the catalytic reaction, and to avoid this problem, the Buchwald group prepared a G4 precatalyst on the basis of a G3 precatalyst by methylating the amino group on the biphenyl backbone. It has higher solubility in cross-coupling reaction, and retains the excellent catalytic activity of G3 catalyst.
At present, the G2-G4 catalyst containing biphenyl groups is mainly prepared by the following method:
g2: o-aminobiphenyl forms corresponding salt with trimethylchlorosilane under proper conditions, and the salt is treated with Pd (OAc)2The cyclic palladium dimer is obtained through reaction, and the cyclic palladium dimer further reacts with the ligand to obtain the needed precatalyst.
G3: o-aminobiphenyl forms a corresponding salt with MsOH under appropriate conditions, and the salt is treated with Pd (OAc)2The reaction is carried out to obtain a cyclic palladium dimer, and the cyclic palladium dimer further reacts with a ligand to obtain the required precatalyst.
G4: adding solvent, o-aminobiphenyl, dropwise adding n-BuLi into ice salt bath, stirring for 1h after dropwise adding, and adding CH3I, after complete reaction, carrying out post-treatment to obtain N-methyl-2-aminobiphenyl; adding N-methyl-2-aminobiphenyl and MsOH under proper conditions to form salt in a corresponding solvent, and adding Pd (OAc) after the reaction is completed2The reaction is complete, the required target compound is obtained after post treatment, and the cyclic palladium dimer further reacts with the ligand to obtain the required pre-catalyst.
Therefore, in the traditional methods, palladium acetate is basically used as a palladium source, however, polymeric palladium acetate or nitrogen-containing palladium acetate has a significant influence on the product quality and yield, so that the preparation methods have high requirements on the quality of the palladium acetate source, and if the quality of the palladium source does not meet the requirements, a high-quality pre-catalyst is difficult to prepare. In addition, the methods need to form a cyclic palladium intermediate, and the next reaction can be carried out after separation, so that the loss of noble metals is easily caused, the operation is complex and time-consuming, and the production cost is greatly increased. Furthermore, these processes often use tetrahydrofuran or dichloromethane as solvent, and both of these solvents are very easily coordinated with palladium, so that a large amount of residues remain in the finished product of the pre-catalyst, which affects the reactivity and accuracy of the catalytic reaction metering.
In order to solve the problems in the prior art, researchers of the invention find through a large number of researches that Buchwald precatalyst can be directly prepared by adopting one or more of allyl palladium chloride dimer, crotyl palladium chloride dimer and cinnamyl palladium chloride dimer as a palladium source and reacting with phosphine ligand and quaternary ammonium salt containing biphenyl groups through a one-pot method, the process flow is simple and convenient, the steps are few, the reaction condition is mild, the industrial amplification production is facilitated, the loss is low, the loss of precious metal caused by the need of separating a cyclic palladium intermediate in the traditional method is avoided, and the production cost is greatly reduced; in addition, the scheme of the invention also optimizes the palladium source and the solvent, avoids the strict requirement on the quality of the palladium source of palladium acetate in the traditional technology, does not use solvents which are easy to coordinate with products, such as tetrahydrofuran, dichloromethane and the like, and effectively reduces the residue of the solvent in the finished catalyst product.
In some embodiments, the reaction temperature of the first step reaction is 5 ℃ to 25 ℃. Preferably, the temperature of the first step reaction is 10 ℃ to 15 ℃. The reaction temperature of the first step reaction is controlled within a proper range, so that the reaction is kept efficient, and the intermediate is not decomposed to form a simple substance palladium byproduct due to the excessively high reaction speed.
It will be appreciated that the first step reaction may be monitored by monitoring means conventional in the art, for example by HPLC (high performance liquid chromatography) or GC (gas chromatography). In particular, can be prepared by31P is monitored until the peak of the phosphine ligand is completely disappeared, indicating that the reaction has been carried out completely.
In some embodiments, the reaction temperature of the second step reaction is 20 ℃ to 30 ℃. Preferably, the temperature of the second reaction is 25 ℃. The reaction temperature of the second step is controlled within a suitable range, so that the reaction can be completed without causing decomposition of the intermediate.
In some embodiments, the time of the second step reaction is 10 h to 14 h, preferably 12 h.
In some embodiments, the second solvent is added and stirred for 20 min to 40 min to precipitate a solid, preferably for 30 min.
In some embodiments, the solid-liquid separation is maintained anhydrous and oxygen free. Preferably, after the solid-liquid separation is completed, the solid phase is washed with the second solvent.
In some embodiments, the resulting solid phase is subjected to vacuum extraction to remove residual solvent.
Preferably, the second solvent is n-hexane. The n-hexane is used as a poor solvent to separate out the pre-catalyst, and compared with the ether, the pre-catalyst is not easy to coordinate with the ether, so that the solvent residue in a finished product is less, and the quality is higher.
In some embodiments, the ratio of the amounts of the palladium source, the phosphine ligand, and the quaternary ammonium salt having a biphenyl group is 1 (2-2.5) to (2-2.5). The ratio of the amounts of the palladium source, the phosphine ligand and the quaternary ammonium salt having a biphenyl group may also be, for example, 1: 2.1: 2.1, 1: 2.1: 2.2, 1: 2.1: 2.3, 1: 2.1: 2.4, 1: 2.2: 2.1, 1: 2.2: 2.2, 1: 2.2: 2.3, 1: 2.2: 2.4, 1: 2.3: 2.1, 1: 2.3: 2.2, 1: 2.3: 2.3, 1: 2.3: 2.4, 1: 2.4: 2.1, 1: 2.4: 2.2, 1: 2.4: 2.3 or 1: 2.4: 2.4. The ratio of the three substances is controlled within a proper range, so that the reaction can be carried out more thoroughly; preferably, the ratio of the three substances is 1 (2-2.1) to 2-2.1, which not only allows the reaction to proceed completely, but also reduces the cost.
In some embodiments, the amount of the palladium source is 0.5 mol to 1mol per 1L of the first solvent. The amount of the palladium source used per 1L of the first solvent may be, for example, 0.6 mol, 0.7 mol, 0.8 mol, or 0.9 mol. The concentration of the palladium source in the solvent is controlled within a proper range, so that the reaction rate of the first step is moderate, and the intermediate product is better generated.
In some embodiments, the volume ratio of the first solvent to the second solvent is 1 (2-5). The volume ratio of the first solvent to the second solvent may also be, for example, 1:2.5, 1:3, 1:3.5, 1:4, or 1: 4.5. The volume ratio of the first solvent to the second solvent is controlled in a proper range, so that the pre-catalyst can be completely precipitated, the loss is small, and more waste liquid is not generated.
In some embodiments, the phosphine ligand has a structure according to any one of formulas I-IV:
wherein m is 1, 2,3 or 4;
n is 1, 2,3, 4 or 5;
R1~R13each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3-CN, halogen, adamantyl, unsubstituted or R19Substituted C1~C6Alkyl or alkoxy, unsubstituted or R20Substituted C3~C6Cycloalkyl, unsubstituted or R21Substituted C5~C20Aryl, unsubstituted or R22Substituted C3~C10A heteroaryl group;
preferably, R1~R13Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, adamantyl, unsubstituted C1~C6Alkyl or alkoxy, unsubstituted C3~C6Cycloalkyl, unsubstituted C5~C10Aryl, unsubstituted C3~C5A heteroaryl group;
further preferably, R1~R13Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl or pyridyl;
even more preferably, R1~R13Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, isopropyl, n-butyl, t-butyl, methoxy, isopropoxy, cyclohexyl, phenyl or furanyl.
R14Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3-CN, halogen, adamantyl, unsubstituted or R19Substituted C1~C6Alkyl or alkoxy, unsubstituted or R20Substituted C3~C6Cycloalkyl, unsubstituted or R21Substituted C5~C20Aryl, unsubstituted or R22Substituted C3~C10Heteroaryl, -PR23R24；
Preferably, R14Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, adamantyl, unsubstituted C1~C6Alkyl or alkoxy, unsubstituted C3~C6Cycloalkyl, unsubstituted C5~C10Aryl, unsubstituted C3~C5Heteroaryl or-PR23R24；
Further preferably, R14Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl, pyridyl or-PR23R24；
Even more preferably, R14Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, isopropyl, n-butyl, t-butyl, methoxy, isopropoxy, cyclohexyl, phenyl, furyl or-PR23R24；
R15~R18Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R15And R16、R16And R17、R17And R18Independently bonding to form a ring or not to form a ring;
preferably, R15~R18Each occurrence is independently selected from-H, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R is15And R16、R16And R17、R17And R18Independently bonding to form a ring or not to form a ring;
further preferably, R15~R18Each occurrence is independently selected from-H, -Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy or methoxy, and R15And R16、R16And R17、R17And R18Independently bonded to form a ring or not.
In some embodiments, R15And R16、R16And R17、R17And R18Are not bonded to form a ring.
In some embodiments, R15And R16、R16And R17、R17And R18Are respectively and independently bonded to form a five-membered ring or a six-membered ring.
A is independently selected from the group consisting of a single bond, -O-, -NH-, -C (= O) -, CR, for each occurrence25R26Or is absent;
preferably, A is independently selected for each occurrence from the group consisting of-O-, -NH-, and CR25R26Or is absent.
R19~R26Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, halogen, methyl, ethyl, methoxy, cyclohexyl or phenyl.
Preferably, R19~R26Each occurrence is independently selected from-H, -CF3-Br, -Cl, methyl, ethyl, methoxy, cyclohexyl or phenyl.
In some embodiments, the phosphine ligand is selected from one or more of the following compounds:
in the above-listed phosphine ligands, the racemic structure also includes chiral versions of the phosphine ligands, e.g., L25 includes racemic L25 itself,
and
。
in some embodiments, the quaternary ammonium salt containing a biphenyl group has the structure shown in formula V:
wherein p is 1, 2,3 or 4;
q is 1, 2,3, 4 or 5;
X-is selected from F-、Cl-、Br-、I-Or OMs-；
R27~R28Each occurrence is independently selected from-H, -D, methyl, ethyl, or methoxy;
preferably, R27~R28Each occurrence is independently selected from-H or methyl.
Wherein, OMs-Refers to methylsulfonate.
R29~R30Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl.
Preferably, R29~R30Each occurrence is independently selected from-H, -NMe2Halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or methoxy.
Even more preferably, R29~R30Is selected from-H.
In some embodiments, the quaternary ammonium salt containing biphenyl groups is selected from one or more of the following compounds:
in another aspect of the present invention, there is also provided a Buchwald precatalyst, which is prepared by the preparation method according to any one of the previous embodiments.
The Buchwald pre-catalyst prepared by the invention has low solvent residue and small influence of a palladium source on the quality of a finished product, and the finished product has higher catalytic activity and more accurate catalytic reaction metering compared with the Buchwald pre-catalyst prepared by the traditional technology, can effectively improve the efficiency of cross coupling reaction, and promotes the further development of the field.
In another aspect of the invention, the use of the aforementioned Buchwald precatalyst in cross-coupling reactions is also provided.
The present invention will be described in further detail with reference to specific examples and comparative examples. Experimental parameters not described in the following specific examples are preferably referred to the guidelines given in the present application, and may be referred to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by the manufacturer. It is understood that the following examples are specific to the particular apparatus and materials used, and in other embodiments, are not limited thereto; the weight of the related components mentioned in the embodiments of the present specification may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the embodiments of the present specification according to the present specification. Specifically, the weight described in the description of the embodiment of the present invention may be a mass unit known in the chemical engineering field such as μ g, mg, g, kg, etc.
And (3) reagent sources:
allyl palladium chloride dimer, crotyl palladium chloride dimer, cinnamyl palladium chloride dimer and palladium acetate were purchased from the noble platinum industry, and the other reagents were analytically pure.
Example 1
（1）Ar2Adding allyl palladium chloride dimer (36.6g,0.1mol), L18 (71.7g,0.2mol) and 183 ml of toluene into a 1L three-neck flask under the atmosphere, stirring at 10-15 ℃, continuously releasing allyl chloride gas along with the continuous reaction, gradually turning yellow precipitate into white, and reacting in the process of reaction by31P monitoring until the peak of phosphine ligand completely disappeared;
(2) adding 2-aminobiphenyl hydrochloride (41.1 g,0.2mol) into the reaction system with the phosphine ligand peak completely disappeared in the step (1), stirring for 12h at 25 ℃, then adding 366 ml of n-hexane, stirring for 30min, filtering without water and oxygen, washing with n-hexane, and vacuum-drying the solvent to obtain Ad2P(n-Bu) Pd G2 precatalyst as an off-white powder (128.2G, 95.9% yield).
Example 2
Substantially the same as in example 1 except that the palladium source in step (1) was replaced with crotyl palladium chloride dimer in an equivalent amount to that of product Ad2P(n-Bu) Pd G2 precatalyst as an off-white powder (125.0G, 93.5% yield).
Example 3
Essentially the same as in example 1, except that the palladium source in step (1) was replaced with an equivalent amount of cinnamyl palladium chloride dimer, product Ad2P(n-Bu) Pd G2 precatalyst as an off-white powder (125.8G, 94.1% yield).
Example 4
Substantially the same as in example 1 except that 2-aminobiphenyl hydrochloride in step (2) was replaced with 2-aminobiphenyl methanesulfonate in an equivalent amount to that of product Ad2P(n-Bu) Pd G3 catalyst was an off-white powder (137.9G, 94.7% yield).
Example 5
Essentially as in example 1, with the difference that in step (2) the 2-aminobiphenyl hydrochloride is replaced by 2-methylaminobiphenyl methanesulfonate in an equivalent amount to that of product Ad2P(n-Bu) Pd G4 catalyst was an off-white powder (138.4G, 93.2% yield).
Example 6
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L5, the product XPhos Pd G2 catalyst was an off-white powder (152.8G, 97.2% yield).
Example 7
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L3, the 2-aminobiphenyl hydrochloride in step (2) was replaced with an equivalent amount of 2-aminobiphenyl methanesulfonate, and the product SPhos Pd G3 catalyst was an off-white powder (150.3G, 96.3% yield).
Example 8
Substantially the same as in example 7 except that the phosphine ligand in step (1) was replaced with L11 in an equivalent amount, the productt-Bu3The Pd G3 catalyst was an off-white powder (105.3G, 92% yield).
Example 9
Essentially the same as in example 1, except that the phosphine ligand in step (1) was replaced by L20 in an equivalent amount, the 2-aminobiphenyl hydrochloride in step (2) was replaced by 2-methylaminobiphenyl methanesulfonate in an equivalent amount, and the product Xantphos Pd G4 catalyst was an off-white powder (187.3G, 97.3% yield).
Example 10
Essentially the same as example 1 except that the phosphine ligand in step (1) was replaced with an equivalent amount of L13, the 2-aminobiphenyl hydrochloride in step (2) was replaced with an equivalent amount of 2-aminobiphenyl methanesulfonate, and the product P (o-tol)3 Pd G3 catalyst was an off-white powder (126.9G, 94.1% yield).
Example 11
Substantially the same as in example 1 except that the phosphine ligand in step (1) was replaced with L27 in an equivalent amount, the 2-aminobiphenyl hydrochloride in step (2) was replaced with 2-aminobiphenyl methanesulfonate in an equivalent amount, and the product BINAP Pd G3 catalyst was an off-white powder (193.5G, 97.5% yield).
Comparative example 1
（1）Ar2Adding allyl palladium chloride dimer (36.6g,0.1mol), L18 (71.7g,0.2mol) and 183 ml of toluene into a 1L three-neck flask under the atmosphere, stirring at 10-15 ℃, continuously releasing allyl chloride gas along with the continuous reaction, gradually turning yellow precipitate into white, and reacting in the process of reaction by31Monitoring P until the peak of the phosphine ligand completely disappears, adding 366 ml of n-hexane for anhydrous and oxygen-free filtration, and performing vacuum drying to obtain a light yellow powder intermediate;
（2）Ar2adding the light yellow powder intermediate prepared in the step (1) and 2-aminobiphenyl hydrochloride (41.1 g,0.2mol) into a 1L three-neck flask under the atmosphere, stirring for 12h at 25 ℃, then adding 366 ml of n-hexane, stirring for 30min, carrying out anhydrous and oxygen-free filtration, washing with n-hexane, and carrying out vacuum drying on the solvent to obtain Ad2P(n-Bu) Pd G2 precatalyst as an off-white powder (121.0G, 90.5% yield).
Comparative example 2
Substantially the same as in example 1 except that the reaction temperature in step (1) was 30 ℃. In this comparative example, in step (1), due to the excessively high temperature, the formation of a black elemental palladium by-product in the system was observed, which significantly decreased the yield.
Comparative example 3
Substantially the same as in example 1 except that the palladium source was replaced with palladium acetate in an equivalent amount in step (1). In the comparative example, the boiling point of acetic acid is high, so that the process cannot be removed and the off-white reaction cannot be normally carried out.
The nuclear magnetic spectrum of each example shows that the pre-catalyst prepared by the method has high purity, less solvent residue, higher quality and more accurate catalytic reaction metering. As can be seen from the spectra (FIGS. 23 to 24) of the intermediate of comparative example 1, the intermediate can be isolated and stably exist. From the spectrograms (fig. 1-2) of the example 1, the preparation method of the invention does not need to separate the intermediate product, the one-pot two-step method can normally carry out the reaction to obtain the target product precatalyst, and the one-pot two-step method has higher yield than the comparative example 1 because the separation is not needed, thereby effectively reducing the loss of noble metals in the preparation process, simplifying the process and greatly reducing the production cost.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims, and the description and the drawings can be used for explaining the contents of the claims.
Claims (14)
1. A preparation method of a Buchwald pre-catalyst is characterized by comprising the following steps:
mixing a palladium source, a phosphine ligand and a first solvent in a non-reactive gas atmosphere to perform a first-step reaction; after the first-step reaction is finished, adding quaternary ammonium salt containing biphenyl groups to perform a second-step reaction; after the second step of reaction is finished, adding a second solvent, separating out a solid, carrying out solid-liquid separation, and retaining a solid phase;
wherein the palladium source comprises one or more of allylpalladium chloride dimer, crotyl palladium chloride dimer, and cinnamyl palladium chloride dimer;
the first solvent is toluene and/or xylene;
the second solvent is n-hexane and/or diethyl ether.
2. The preparation method of claim 1, wherein the reaction temperature of the first step reaction is 5 ℃ to 25 ℃.
3. The preparation method of claim 1, wherein the reaction temperature of the second step reaction is 20 ℃ to 30 ℃.
4. The method according to claim 1, wherein the ratio of the amounts of the palladium source, the phosphine ligand and the quaternary ammonium salt having a biphenyl group is 1 (2-2.5) to (2-2.5).
5. The method according to claim 1, wherein the palladium source is used in an amount of 0.5 to 1mol per 1L of the first solvent.
6. The preparation method according to claim 1, wherein the volume ratio of the first solvent to the second solvent is 1 (2-5).
7. The method according to any one of claims 1 to 6, wherein the phosphine ligand has a structure represented by any one of formulae I to IV:
wherein m is 1, 2,3 or 4;
n is 1, 2,3, 4 or 5;
R1~R13each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, halogen, adamantyl, unsubstituted or R19Substituted C1~C6Alkyl or alkoxy, unsubstituted or R20Substituted C3~C6Cycloalkyl, unsubstituted or R21Substituted C5~C20Aryl, unsubstituted or R22Substituted C3~C10A heteroaryl group;
R14each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, halogen, adamantyl, unsubstituted or R19Substituted C1~C6Alkyl or alkoxy, unsubstituted or R20Substituted C3~C6Cycloalkyl, unsubstituted or R21Substituted C5~C20Aryl, unsubstituted or R22Substituted C3~C10Heteroaryl, -PR23R24；
R15~R18Each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl, and R15And R16、R16And R17、R17And R18Independently bonding to form a ring or not forming a ring;
a is independently selected for each occurrence from the group consisting of a single bond, -O-, -NH-, -C (= O) -, CR25R26Or is absent;
R19~R26each occurrence ofIndependently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, methyl, ethyl, methoxy, cyclohexyl or phenyl.
8. The method of claim 7, wherein R is1~R13Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl or pyridyl.
9. The method of claim 7, wherein R is14Each occurrence is independently selected from-H, -NMe2、-F、-Cl、-Br、-CF3Adamantyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopentyl, cyclohexyl, phenyl, naphthyl, furyl, thiazolyl, pyrrolyl, pyridyl or-PR23R24。
10. A preparation method according to any one of claims 1 to 6, wherein the phosphine ligand is selected from one or more of the following compounds:
11. the method according to any one of claims 1 to 6, wherein the quaternary ammonium salt containing a biphenyl group has a structure represented by formula V:
wherein p is 1, 2,3 or 4;
q is 1, 2,3, 4 or 5;
X-is selected from F-、Cl-、Br-、I-Or OMs-；
R27~R28Each occurrence is independently selected from-H, -D, methyl, ethyl, or methoxy;
R29~R30each occurrence is independently selected from-H, -D, -NMe2、-NO2、-CF3CN, -halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclohexyl or phenyl.
12. The method according to any one of claims 1 to 6, wherein the quaternary ammonium salt containing a biphenyl group is selected from one or more of the following compounds:
13. a Buchwald pre-catalyst, characterized by being prepared by the preparation method of any one of claims 1 to 12.
14. Use of a Buchwald precatalyst as defined in claim 13 in cross-coupling reactions.
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| US20130331566A1 (en) * | 2012-06-08 | 2013-12-12 | Massachusetts Institute Of Technology | Phosphine-Ligated Palladium Sulfonate Palladacycles |
| CN105801625A (en) * | 2016-05-30 | 2016-07-27 | 郑州大学 | Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction |
| JP2019011286A (en) * | 2017-06-30 | 2019-01-24 | 公益財団法人相模中央化学研究所 | Phosphine compound and catalyst for coupling containing the same as ligand |
| CN109400646A (en) * | 2018-12-31 | 2019-03-01 | 湖北大学 | A kind of novel B uchwald-type monophosphorus ligand and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20130331566A1 (en) * | 2012-06-08 | 2013-12-12 | Massachusetts Institute Of Technology | Phosphine-Ligated Palladium Sulfonate Palladacycles |
| CN105801625A (en) * | 2016-05-30 | 2016-07-27 | 郑州大学 | Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction |
| JP2019011286A (en) * | 2017-06-30 | 2019-01-24 | 公益財団法人相模中央化学研究所 | Phosphine compound and catalyst for coupling containing the same as ligand |
| CN109400646A (en) * | 2018-12-31 | 2019-03-01 | 湖北大学 | A kind of novel B uchwald-type monophosphorus ligand and preparation method thereof |
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