A bulky c-c coupling palladium ligand and a synthesis method thereof

Abstract

The application discloses a kind of big steric hindrance C-C coupling palladium ligand and synthesis method, ligand is used naphthyl as the main group of stable ligand, this group provides big plane rigid configuration during ligand use, simultaneously, it provides big π electron for complex molecule to stabilize complex;In addition, the configuration of pyridofuran is used, the N coordination point of traditional N-P bidentate ligand is introduced O by furan this functional group in ortho position to adjust the chemical environment of intramolecular N coordination point, so as to modify the traditional N-P bidentate ligand to tridentate ligand, this change can effectively increase the penetration ability of Pd active center in actual ligand use to improve catalytic activity.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a sterically hindered CC-coupled palladium ligand and its synthesis method. Background Technology

[0002] Carbon-carbon coupling reactions are an important part of current organic chemical synthesis, especially directed coupling synthesis processes using palladium as a catalyst, which have been widely studied and recognized for their efficiency and environmental friendliness. When using palladium as the catalytic active center, the use and selection of palladium ligands have a crucial impact on the specific reaction results and are currently a hot research area in palladium catalysis.

[0003] The synthesis of aromatic compounds via C-C coupling is a very important method for the synthesis of drugs and materials. Classic named synthesis reactions for this type of reaction include the Suzuki reaction, the Heck reaction, and the Sonogashira reaction.

[0004] Considering the wide range of applications of palladium catalysis and the current supply and promotion of ligands in the market, the number of commercially available palladium ligands is relatively small, some of which have poor stability and low compatibility with sterically hindered substrates, making it difficult to achieve sterically hindered catalytic docking reactions. Halogen or boric acid loss is easily achieved during this process. Currently, the most popular OLED materials research focuses on the stacking and organic arrangement of aromatic fused rings and heterocyclic rings. In the development of such materials, the presence of sterically hindered substituents at the ortho position is frequently encountered. Commercially available catalysts such as Pd(PPh3)4, Xphos-Pd2(dba)3, Sphos-Pd2(dba)3, and X-Antphos-Pd2(dba)3 often fail to achieve the C / C coupling process, or the conversion rate is very low, easily leading to halogen or boric acid loss. For example, to achieve the coupling of 2,6-dimethylphenylboronic acid with 2,6-dimethylbromobenzene, the ortho-methyl substitution makes it difficult to achieve C / C coupling to obtain 2,2',6,6'-tetramethylbiphenyl; the same applies to the coupling of 2-biphenylboronic acid with 2-bromonaphthalene. Therefore, developing a ligand compatible with large steric hindrance is of great significance for the successful synthesis of the aforementioned compounds.

[0005] Currently available catalyst ligands are difficult to use for C-C coupling processes involving sterically hindered or electron-donating groups at the ortho position of aromatic benzene rings. Although some literature reports the synthesis of related catalysts, their complex structures and synthetic processes hinder market adoption. To effectively address these issues, a novel ligand needs to be designed to solve these coupling problems. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a large steric hindrance CC-coupled palladium ligand and its synthesis method.

[0007] To solve the technical problem, the technical solution of the present invention is: a method for synthesizing a large steric hindrance CC-coupled palladium ligand, comprising the following steps:

[0008] Step 1: 2-Naphthyl methyl ether is first subjected to hydrogen lithiation with n-butyllithium, and then reacted with tributyl borate followed by acid hydrolysis to obtain compound B. The molar ratio of 2-naphthyl methyl ether: n-butyllithium: tributyl borate is 1:1.1~1.2:1.2~1.3. The structural formula of compound B is as follows: ;

[0009] Step 2: Compound B and bromobenzene are reacted via a Suzuki reaction to prepare compound C. The molar ratio of compound B to bromobenzene is 1:1~1.1. The structure of compound C is as follows: ;

[0010] Step 3: Compound C undergoes a halogenation reaction to yield compound D. The structural formula of compound D is as follows: ;

[0011] Step 4: The amino group of 2-amino-6-methylpyridine is protected with di-tert-butyl dicarbonate to obtain compound F. The molar ratio of 2-amino-6-methylpyridine to di-tert-butyl dicarbonate is 1:1.1~1.2. The structural formula of compound F is as follows: ;

[0012] Step 5: Compound F is selectively dehydrolithiated to the 3-position of the pyridine ring in the presence of N,N-tetramethylethylenediamine, followed by reaction with triisopropyl borate and acid hydrolysis to obtain compound G. The molar ratio of compound F:N,N-tetramethylethylenediamine:triisopropyl borate is 1:1.2~1.3:1.2~1.25. The structural formula of compound G is as follows: ;

[0013] Step 6: Compound D and compound G undergo a Suzuki reaction to generate compound H. The molar ratio of compound D to compound G is 1:1~1.05. The structural formula of compound H is... ;

[0014] Step 7: The amino group of compound H undergoes a diazotization reaction with tert-butyl nitrite under copper acetate catalysis, resulting in intramolecular ether cyclization to give compound J. The molar ratio of compound H:copper acetate:tert-butyl nitrite is 1:0.01~0.1:1.2~1.5. The structural formula of compound J is as follows: ;

[0015] Step 8: Compound J reacts with tetramethylpiperidine lithium to first lithium-ionize and remove the methyl hydrogen from the pyridine ring, then reacts with di-tert-butylphosphine chloride to obtain compound K. The molar ratio of compound J:tetramethylpiperidine lithium:di-tert-butylphosphine chloride is 1:1.1~1.2:1.2~1.25. The structural formula of compound K is [insert structural formula here]. .

[0016] Preferably, step 1 specifically involves: dissolving compound A 2-naphthyl methyl ether in THF solvent, adding 2.5 mol / L n-butyllithium dropwise under an argon atmosphere between -20°C and -10°C, maintaining the temperature for 2-3 hours to remove hydrogen, then cooling to -85°C to -80°C, and then adding tributyl borate dropwise. After completion, the temperature is naturally raised to an internal temperature above -10°C. Once the reaction is complete, the reaction solution is concentrated under reduced pressure, acidified with hydrochloric acid, and crystallized in PE to obtain a white solid compound B.

[0017] Preferably, step 2 specifically involves: adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water, and Pd(PPh3)4 sequentially to a three-necked flask, and reacting in a one-pot manner under an argon atmosphere at 70°C~75°C for 6h~8h until compound B reacts completely. The reaction solution is first washed with water and separated, then the organic phase is evaporated under reduced pressure, and then crystallized with methanol to obtain a white solid compound C. The molar ratio of compound B:bromobenzene:potassium carbonate:Pd(PPh3)4 is 1:1~1.1:1.5~2:0.005~0.01, and the volume ratio of compound B to toluene, ethanol, and water is 100g:600~615ml:200~210ml:200~210ml.

[0018] Preferably, step 3 specifically involves: under argon protection, adding compound C and DMF to a reaction flask, using N-bromosuccinimide as a brominating agent, adding N-bromosuccinimide in batches at 0~10℃, and after the reaction is completed, pouring the reaction solution into a large amount of water, filtering to precipitate the solid, and then dispersing it with ethanol to obtain a white solid compound D. The molar ratio of compound C to N-bromosuccinimide is 1:1~1.1, and the ratio of compound C to DMF is 100g:510~520ml.

[0019] Preferably, step 4 specifically involves: adding 2-amino-6-methylpyridine, 4-dimethylaminopyridine, and dichloromethane to a three-necked flask under an argon atmosphere, maintaining the internal temperature at 15~25℃, adding a DCM solution of Boc2O dropwise, and reacting at this temperature for 24 hours until the raw materials are almost completely removed. Then, the solvent and low-boiling-point substances are concentrated under reduced pressure to obtain a crude product, which is then dispersed and filtered using PE to obtain compound F. The molar ratio of 2-amino-6-methylpyridine:DMAP:Boc2O is 1:1~1.05:1.1~1.2, and the ratio of 2-amino-6-methylpyridine to DCM is 10g:92~95ml.

[0020] Preferably, step 5 specifically involves: dissolving compound F in THF, adding N,N-tetramethylethylenediamine, cooling to -80℃ to -75℃ under an argon atmosphere, adding 2.5 mol / L n-BuLi dropwise, stirring for 1 to 2 hours, then further cooling to -95℃ to -85℃, adding triisopropyl borate dropwise, and then heating back to room temperature. After the reaction is completed, the reaction solution is concentrated, ammonium chloride aqueous solution is dissociated, and PE is dispersed and crystallized to obtain a grayish-brown solid compound G. The molar ratio of compound F: N,N-tetramethylethylenediamine: n-BuLi: triisopropyl borate is 1:1.2~1.3:1.1~1.2:1.2~1.25, and the ratio of compound F to THF is 10 g:100 ml.

[0021] Preferably, step 6 specifically involves: adding compound D, compound G, potassium carbonate, dioxane, and water sequentially to a three-necked flask; replacing the system with argon gas; adding catalyst Pd(PPh3)4; and reacting in a one-pot manner at 75℃~80℃ for 12 hours until the reactant D is completely reacted. The reaction solution is concentrated under reduced pressure, dissolved in toluene, washed with deionized water, and then dried. After completion, the organic phase is filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound H. The molar ratio of compound D: compound G: potassium carbonate: Pd(PPh3)4 is 1:1~1.05:1.5~2:0.005~0.01, and the ratio of compound D to dioxane and water is 10g:100ml:16~18ml.

[0022] Preferably, step 7 specifically involves: dissolving compound H in THF in a three-necked flask, heating to an internal temperature of 55°C~60°C, stopping heating, adding copper acetate, and then carefully adding a THF solution containing tert-butyl nitrite dropwise into the system. The system releases heat and gas. After the addition is complete, the mixture is kept warm for 1~2 hours to complete the reaction. The reaction solution is directly concentrated to dryness under reduced pressure, then toluene is added and refluxed to dissolve and clarify the solution. The solution is passed through a silica gel column, and the product column liquid is collected and concentrated under reduced pressure until solid precipitates. After cooling to below 20°C, the mixture is filtered, dried under vacuum, and then dried to obtain a slightly yellow solid powder compound J. The molar ratio of compound H: copper acetate: tert-butyl nitrite is 1:0.01~0.1:1.2~1.5, the molar ratio of compound H to THF is 10g:78~80ml, and the molar ratio of tert-butyl nitrite to THF is 10g:24~26ml.

[0023] Preferably, step 8 specifically involves: dissolving compound J in THF under an argon atmosphere, cooling to -50°C to -60°C, then adding a tetramethylpiperidine lithium solution dropwise. After completion, maintaining the temperature between -55°C and -50°C for 2 to 3 hours until the system turns dark brown, then cooling to an internal temperature between -90°C and -80°C and adding a di-tert-butylphosphine chloride solution dropwise. After completion, naturally heating to an internal temperature of 0°C, and directly concentrating the reaction solution under negative pressure after the reaction is complete. Adding n-heptane, and refluxing the concentrated solution under an argon atmosphere, then... The solution was cooled to an internal temperature of 20℃~30℃ and rapidly passed through diatomaceous earth under an argon atmosphere to remove insoluble salts. The filtrate was collected and concentrated under reduced pressure to a very small amount of solvent. Under argon protection, the solution was stirred and cooled to 0℃~5℃, precipitating a white solid. The solid was filtered and dried under an inert gas atmosphere to obtain a white to slightly yellow waxy solid compound K. The molar ratio of compound J: lithium tetramethylpiperidine: di-tert-butylphosphine chloride was 1:1.1~1.2:1.2~1.25, and the molar ratio of compound J to THF was 10g:96~100ml.

[0024] Preferably, a sterically hindered CC-coupled palladium ligand, wherein the ligand is a tripentate ligand of NPO, and its structural formula is as follows: The tridentate ligand of NPO is synthesized by a method for synthesizing a sterically hindered CC-coupled palladium ligand as described in any one of claims 1 to 9, and the tridentate ligand of NPO is used to synthesize catalysts compound1 and compound2.

[0025] The structural formula for compoud1 is: ,

[0026] The structural formula of compound2 is: ;

[0027] The synthesis process of compound1 or compound2 is as follows: THF is measured into a three-necked flask, and after purging the system with argon, palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine) is weighed and dissolved in the solution. The temperature is raised to 45℃~55℃, and the solution is stirred thoroughly until clear. Under an argon atmosphere, the solution of NPO tridentate ligand dissolved in THF is slowly added dropwise to the above system. The NPO tridentate ligand reacts with palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine) The molar ratio of palladium is 1:0.4~0.6, and the dropping rate is controlled at 0.5h~1h. After the reaction is completed, the reaction is stirred for 3h~4h until the reaction is complete. Then the reaction system is concentrated under reduced pressure at 30℃~40℃ until most of the solid precipitates out. Then n-heptane is added, and under argon atmosphere protection, the system is stirred and crystallized for another 2h~3h at room temperature. Then the mixture is filtered, dried under vacuum, washed with n-heptane, and dried under vacuum to obtain a light brownish-red solid powder compouud1 or a dark blackish-red solid powder compouud2.

[0028] Compared with the prior art, the advantages of the present invention are as follows:

[0029] (1) The ligand of the present invention uses naphthyl as the main group of the stabilizing ligand. During the use of the ligand, this group provides a rigid configuration with a large plane and provides a large π electron to stabilize the complex molecule. In addition, the configuration of pyridofuran is adopted, and the N coordination site of the traditional NP bidentate ligand is introduced into O via the furan functional group to regulate the chemical environment of the N coordination site in the molecule, thereby modifying the traditional NP bidentate ligand into a tridentate ligand. This change can effectively increase the penetration ability of the Pd active center in actual ligand use, thereby improving the catalytic activity.

[0030] (2) In practical applications, the ligands of the present invention need to be used in combination with palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine) in the process of application. The process of use is convenient and has good compatibility with the steric hindrance coupling catalysis effect. When used in the steric hindrance CC coupling process, its conversion rate is significantly better than that of traditional ligands.

[0031] (3) This invention discloses a large steric hindrance CC-coupled palladium ligand. The ligand is solid at room temperature, is not sensitive to oxygen in the air at room temperature, is easy to store and transport, and is convenient to use.

[0032] (4) The raw materials used in the preparation process of the ligands of the present invention are all commercially available and widely sourced. The synthesis process is mostly carried out using conventional reaction processes, and the large-scale preparation and promotion are expected to be good. Attached Figure Description

[0033] Figure 1 The NMR spectrum of a large steric hindrance CC-coupled palladium ligand of the present invention. Detailed Implementation

[0034] The present invention will be described below with reference to specific embodiments. The raw materials, solvents and catalysts used are all conventional commercial products. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0035] This invention discloses a method for synthesizing a sterically hindered CC-coupled palladium ligand, comprising the following steps:

[0036] Step 1: 2-Naphthyl methyl ether is first subjected to hydrogen lithiation with n-butyllithium, and then reacted with tributyl borate followed by acid hydrolysis to obtain compound B. The molar ratio of 2-naphthyl methyl ether: n-butyllithium: tributyl borate is 1:1.1~1.2:1.2~1.3. The structural formula of compound B is as follows: ;

[0037] Step 2: Compound B and bromobenzene are reacted via a Suzuki reaction to prepare compound C. The molar ratio of compound B to bromobenzene is 1:1~1.1. The structure of compound C is as follows: ;

[0038] Step 3: Compound C undergoes a halogenation reaction to yield compound D. The structural formula of compound D is as follows: ;

[0039] Step 4: The amino group of 2-amino-6-methylpyridine is protected with di-tert-butyl dicarbonate to obtain compound F. The molar ratio of 2-amino-6-methylpyridine to di-tert-butyl dicarbonate is 1:1.1~1.2. The structural formula of compound F is as follows: ;

[0040] Step 5: Compound F is selectively dehydrolithiated to the 3-position of the pyridine ring in the presence of N,N-tetramethylethylenediamine, followed by reaction with triisopropyl borate and acid hydrolysis to obtain compound G. The molar ratio of compound F:N,N-tetramethylethylenediamine:triisopropyl borate is 1:1.2~1.3:1.2~1.25. The structural formula of compound G is as follows: ;

[0041] Step 6: Compound D and compound G undergo a Suzuki reaction to generate compound H. The molar ratio of compound D to compound G is 1:1~1.05. The structural formula of compound H is... ;

[0042] Step 7: The amino group of compound H undergoes a diazotization reaction with tert-butyl nitrite under copper acetate catalysis, resulting in intramolecular ether cyclization to give compound J. The molar ratio of compound H:copper acetate:tert-butyl nitrite is 1:0.01~0.1:1.2~1.5. The structural formula of compound J is as follows: ;

[0043] Step 8: Compound J reacts with tetramethylpiperidine lithium to first lithium-ionize and remove the methyl hydrogen from the pyridine ring, then reacts with di-tert-butylphosphine chloride to obtain compound K. The molar ratio of compound J:tetramethylpiperidine lithium:di-tert-butylphosphine chloride is 1:1.1~1.2:1.2~1.25. The structural formula of compound K is [insert structural formula here]. .

[0044] Preferably, step 1 specifically involves: dissolving compound A 2-naphthyl methyl ether in THF solvent, adding 2.5 mol / L n-butyllithium dropwise under an argon atmosphere between -20°C and -10°C, maintaining the temperature for 2-3 hours to remove hydrogen, then cooling to -85°C to -80°C, and then adding tributyl borate dropwise. After completion, the temperature is naturally raised to an internal temperature above -10°C. Once the reaction is complete, the reaction solution is concentrated under reduced pressure, acidified with hydrochloric acid, and crystallized in PE to obtain a white solid compound B.

[0045] Preferably, step 2 specifically involves: adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water, and Pd(PPh3)4 sequentially to a three-necked flask, and reacting in a one-pot manner under an argon atmosphere at 70°C~75°C for 6h~8h until compound B reacts completely. The reaction solution is first washed with water and separated, then the organic phase is evaporated under reduced pressure, and then crystallized with methanol to obtain a white solid compound C. The molar ratio of compound B:bromobenzene:potassium carbonate:Pd(PPh3)4 is 1:1~1.1:1.5~2:0.005~0.01, and the volume ratio of compound B to toluene, ethanol, and water is 100g:600~615ml:200~210ml:200~210ml.

[0046] Preferably, step 3 specifically involves: under argon protection, adding compound C and DMF to a reaction flask, using N-bromosuccinimide as a brominating agent, adding N-bromosuccinimide in batches at 0~10℃, and after the reaction is completed, pouring the reaction solution into a large amount of water, filtering to precipitate the solid, and then dispersing it with ethanol to obtain a white solid compound D. The molar ratio of compound C to N-bromosuccinimide is 1:1~1.1, and the ratio of compound C to DMF is 100g:510~520ml.

[0047] Preferably, step 4 specifically involves: adding 2-amino-6-methylpyridine, 4-dimethylaminopyridine, and dichloromethane to a three-necked flask under an argon atmosphere, maintaining the internal temperature at 15~25℃, adding a DCM solution of Boc2O dropwise, and reacting at this temperature for 24 hours until the raw materials are almost completely removed. Then, the solvent and low-boiling-point substances are concentrated under reduced pressure to obtain a crude product, which is then dispersed and filtered using PE to obtain compound F. The molar ratio of 2-amino-6-methylpyridine:DMAP:Boc2O is 1:1~1.05:1.1~1.2, and the ratio of 2-amino-6-methylpyridine to DCM is 10g:92~95ml.

[0048] Preferably, step 5 specifically involves: dissolving compound F in THF, adding N,N-tetramethylethylenediamine, cooling to -80℃ to -75℃ under an argon atmosphere, adding 2.5 mol / L n-BuLi dropwise, stirring for 1 to 2 hours, then further cooling to -95℃ to -85℃, adding triisopropyl borate dropwise, and then heating back to room temperature. After the reaction is completed, the reaction solution is concentrated, ammonium chloride aqueous solution is dissociated, and PE is dispersed and crystallized to obtain a grayish-brown solid compound G. The molar ratio of compound F: N,N-tetramethylethylenediamine: n-BuLi: triisopropyl borate is 1:1.2~1.3:1.1~1.2:1.2~1.25, and the ratio of compound F to THF is 10 g:100 ml.

[0049] Preferably, step 6 specifically involves: adding compound D, compound G, potassium carbonate, dioxane, and water sequentially to a three-necked flask; replacing the system with argon gas; adding catalyst Pd(PPh3)4; and reacting in a one-pot manner at 75℃~80℃ for 12 hours until the reactant D is completely reacted. The reaction solution is concentrated under reduced pressure, dissolved in toluene, washed with deionized water, and then dried. After completion, the organic phase is filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound H. The molar ratio of compound D: compound G: potassium carbonate: Pd(PPh3)4 is 1:1~1.05:1.5~2:0.005~0.01, and the ratio of compound D to dioxane and water is 10g:100ml:16~18ml.

[0050] Preferably, step 7 specifically involves: dissolving compound H in THF in a three-necked flask, heating to an internal temperature of 55°C~60°C, stopping heating, adding copper acetate, and then carefully adding a THF solution containing tert-butyl nitrite dropwise into the system. The system releases heat and gas. After the addition is complete, the mixture is kept warm for 1~2 hours to complete the reaction. The reaction solution is directly concentrated to dryness under reduced pressure, then toluene is added and refluxed to dissolve and clarify the solution. The solution is passed through a silica gel column, and the product column liquid is collected and concentrated under reduced pressure until solid precipitates. After cooling to below 20°C, the mixture is filtered, dried under vacuum, and then dried to obtain a slightly yellow solid powder compound J. The molar ratio of compound H: copper acetate: tert-butyl nitrite is 1:0.01~0.1:1.2~1.5, the molar ratio of compound H to THF is 10g:78~80ml, and the molar ratio of tert-butyl nitrite to THF is 10g:24~26ml.

[0051] Preferably, step 8 specifically involves: dissolving compound J in THF under an argon atmosphere, cooling to -50°C to -60°C, then adding a tetramethylpiperidine lithium solution dropwise. After completion, maintaining the temperature between -55°C and -50°C for 2 to 3 hours until the system turns dark brown, then cooling to an internal temperature between -90°C and -80°C and adding a di-tert-butylphosphine chloride solution dropwise. After completion, naturally heating to an internal temperature of 0°C, and directly concentrating the reaction solution under negative pressure after the reaction is complete. Adding n-heptane, and refluxing the concentrated solution under an argon atmosphere, then... The solution was cooled to an internal temperature of 20℃~30℃ and rapidly passed through diatomaceous earth under an argon atmosphere to remove insoluble salts. The filtrate was collected and concentrated under reduced pressure to a very small amount of solvent. Under argon protection, the solution was stirred and cooled to 0℃~5℃, precipitating a white solid. The solid was filtered and dried under an inert gas atmosphere to obtain a white to slightly yellow waxy solid compound K. The molar ratio of compound J: lithium tetramethylpiperidine: di-tert-butylphosphine chloride was 1:1.1~1.2:1.2~1.25, and the molar ratio of compound J to THF was 10g:96~100ml.

[0052] Preferably, a sterically hindered CC-coupled palladium ligand, wherein the ligand is a tripentate ligand of NPO, and its structural formula is as follows: The tridentate ligand of NPO is synthesized by a method for synthesizing a sterically hindered CC-coupled palladium ligand as described in any one of claims 1 to 9, and the tridentate ligand of NPO is used to synthesize catalysts compound1 and compound2.

[0053] The structural formula for compoud1 is: ,

[0054] The structural formula of compound2 is: ;

[0055] The synthesis process of compound1 or compound2 is as follows: THF is measured into a three-necked flask, and after purging the system with argon, palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine) is weighed and dissolved in the solution. The temperature is raised to 45℃~55℃, and the solution is stirred thoroughly until clear. Under an argon atmosphere, the solution of NPO tridentate ligand dissolved in THF is slowly added dropwise to the above system. The NPO tridentate ligand reacts with palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine) The molar ratio of palladium is 1:0.4~0.6, and the dropping rate is controlled at 0.5h~1h. After the reaction is completed, the reaction is stirred for 3h~4h until the reaction is complete. Then the reaction system is concentrated under reduced pressure at 30℃~40℃ until most of the solid precipitates out. Then n-heptane is added, and under argon atmosphere protection, the system is stirred and crystallized for another 2h~3h at room temperature. Then the mixture is filtered, dried under vacuum, washed with n-heptane, and dried under vacuum to obtain a light brownish-red solid powder compouud1 or a dark blackish-red solid powder compouud2.

[0056] Example 1

[0057] Compound A (2-naphthyl methyl ether) is a commercially available, conventional intermediate with a purity greater than 99.5% as determined by GC analysis.

[0058] Synthesis of Compound B: Compound A (158.2 g, 1.0 mol) was dissolved in 1.5 L of THF solvent. Under an argon atmosphere, 0.48 L of n-BuLi (2.5 mol / L) was added dropwise between -20 °C and -10 °C. After maintaining the temperature for 2-3 hours to remove hydrogen, the temperature was lowered to -85 °C to -80 °C, and then B(C4H9)3 (288 g, 1.25 mol) was added dropwise. After completion, the temperature was naturally raised to an internal temperature above -10 °C, and the reaction was complete. The reaction solution was concentrated under reduced pressure, acidified with hydrochloric acid, and crystallized by PE to obtain a white solid. LC analysis showed that the main content was greater than 98%, yielding 157 g (78% yield).

[0059] Synthesis of compound C: 147.8 g of B, 157 g of bromobenzene, 138 g of potassium carbonate, 900 mL of toluene, 300 mL of ethanol, 300 mL of water, and 43.5 g of Pd (PPh3) were added sequentially to a 3 L three-necked flask. The mixture was refluxed under an argon atmosphere for 6–8 h until B was completely reacted. The reaction solution was first washed with water and separated, then the organic phase was evaporated to dryness under reduced pressure, and finally crystallized from methanol to obtain 131 g of an off-white solid (yield 93%) with a GC content >98%.

[0060] Synthesis of compound D: Under argon protection, 117g of C and 600mL of DMF were added to a 2L flask. 98g of NBS was added in batches at 0℃~10℃. After the reaction was completed, the reaction solution was poured into a large amount of water, filtered to precipitate the solid, and then dispersed with ethanol to obtain 138g of off-white solid (yield 88%).

[0061] Synthesis of compound F: Under an argon atmosphere, 54g of E, 12g of DMAP, and 500mL of DCM were added to a 2L three-necked flask. The internal temperature was maintained at 15℃~25℃. 164g of Boc2O in DCM solution was added dropwise. The reaction was maintained at this temperature for 24h until the starting material was almost completely removed. The solvent and low-boiling-point substances were then concentrated under reduced pressure to obtain a semi-solid substance. The substance was then dispersed and filtered with PE to obtain compound F, weighing 70.5g (yield 73%).

[0062] Synthesis of compound G: 50 g of compound F was dissolved in 500 mL of THF, and 39 g of N,N-tetramethylethylenediamine was added. Under an argon atmosphere, the temperature was lowered to -80℃ to -75℃, and 115 mL of n-BuLi (2.5 mol / L) was added dropwise. After stirring for 1 h, the temperature was further lowered to -85℃ to -80℃, and 65 g of triisopropyl borate was added dropwise. Then, the temperature was raised to room temperature, and the reaction was completed. The reaction solution was concentrated, and the ammonium chloride aqueous solution was dissociated. PE was dispersed and crystallized to obtain a grayish-brown solid weighing 21.2 g (yield 53%). The LC main content was 95%, and the molecular weight was 152 as determined by LC-MS.

[0063] Synthesis of Compound H: Compound D 30.0 g, Compound G 16.7 g, potassium carbonate 20.7 g, dioxane 300 mL, and water 50 mL were added sequentially to a 500 mL three-necked flask. After purging the system with argon, 41.2 g of catalyst Pd (PPh3) was added. The temperature was raised to 72℃~75℃ and maintained for 12 h until the reactant D was completely reacted. The reaction solution was concentrated under reduced pressure, and 500 mL of toluene was added to dissolve the concentrated product. The product was then washed three times with 200 mL of deionized water each time, followed by drying with anhydrous sodium sulfate. After completion, the organic phase was filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to obtain crude compound H, weighing 38 g. LC analysis showed a purity of 91%, requiring no purification and ready for the next step.

[0064] Synthesis of Compound J: 38 g of crude compound H was dissolved in 300 mL of THF in a 500 mL three-necked flask. The temperature was raised to 55-57 °C, then heating was stopped. 0.35 g of copper acetate was added, followed by careful dropwise addition of 50 mL of THF solution containing 20.6 g of tert-butyl nitrite. The system was exothermic and gas-releasing. After the addition was complete, the mixture was kept at this temperature for 1 hour to complete the reaction. The reaction solution was directly concentrated to dryness under reduced pressure, and then 500 mL of toluene was added and refluxed until clear. The solution was passed through a silica gel column, and the column liquid was collected and concentrated under reduced pressure to approximately 60 mL. A solid precipitated out. The solution was cooled to below 20 °C, filtered, dried under vacuum, and then dried to obtain 19.5 g of a pale yellow solid powder (yield 63%). The LC purity was 97%, and the molecular weight was 309.1 as determined by LC-MS.

[0065] Synthesis of compound K: 15.5 g of compound J was dissolved in 150 mL of THF under an argon atmosphere, cooled to -55℃ to -50℃, and then 55 mmol of tetramethylpiperidine lithium salt solution was added dropwise. After completion, the mixture was kept at -55℃ to -50℃ for 2 h until the system turned dark brown. Then the internal temperature was lowered to -90℃ to -80℃ and 55 mmol of di-tert-butylphosphine chloride solution was added dropwise. After completion, the mixture was naturally heated to 0℃, and the reaction was completed. The reaction solution was directly concentrated to dryness under negative pressure. 1.2 L of n-heptane was added, and the concentrated solution was dissolved by reflux under an argon atmosphere. Then, the solution was cooled to an internal temperature of 20℃~30℃ and rapidly passed through diatomaceous earth under an argon atmosphere to remove insoluble salts. The filtrate was collected and concentrated under reduced pressure to about 100 mL. Under argon protection, the solution was stirred and cooled to 0℃~5℃, precipitating a white solid. The solid was filtered and dried under an inert gas atmosphere to obtain a white to slightly yellow waxy solid weighing 16.3 g (yield 72%) with a LC main content of 98.5%. The molecular weight was determined to be 453.1 by LC-MS.

[0066] like Figure 1 The image shown is the NMR spectrum of compound K in this embodiment.

[0067] Compound K was used to prepare catalysts compound1 and compound2 using the following method:

[0068] Synthesis process: Compound 1: Measure 400 mL of THF into a 1 L three-necked flask, purge the system with argon, weigh 2.0 g of palladium acetate, dissolve it in the solution, heat to 45℃~55℃, and stir thoroughly until dissolved, resulting in an orange solution; then, under an argon atmosphere, dissolve 4.5 g of compound K in 90 mL of the solution. The THF solution was slowly added dropwise to the above system over 0.5–1 hour. The system gradually changed from orange to light red, and a small amount of solid particles gradually precipitated out. After the addition was complete, the reaction was stirred for 3–4 hours until the reaction was complete. Then, the reaction system was concentrated under reduced pressure at 30–40 °C to remove most of the THF, stopping when about 50 mL of system remained. At this point, most of the solid had precipitated out. Then, 200 mL of n-heptane was added, and the mixture was stirred and crystallized at room temperature for another 2 hours. The mixture was then filtered, dried under vacuum, washed with 50 mL of n-heptane, and dried again to obtain a light brownish-red solid powder weighing 4.67 g (yield 83%). The compound was characterized by LC-MS, and the molecular weight was found to be between 631 and 633, which was in line with expectations.

[0069] The synthesis process of Compound2 is the same as that of Compound1, except that the source of palladium is changed to palladium dichloro(N,N,N',N'-tetramethylethylenediamine). The reaction process and processing flow are similar. The resulting Compound2 is dark reddish-black in color, with a yield of 87%. LC-MS analysis showed that the molecular weight was 675-677, which is in line with expectations.

[0070] The structural diagram of the synthesized palladium complex is shown below:

[0071]

[0072] compound1

[0073]

[0074] compound2

[0075] Catalysts compound 1 and compound 2 are compared with traditional catalytic ligands in the following synthesis process, as shown in Table 1 below:

[0076] Reaction process:

[0077]

[0078] Table 1 Catalytic effect of each catalyst

[0079]

[0080] Reaction conditions: anaerobic conditions; catalyst dosage was 1% molar equivalent; boric acid substrate to bromide substrate equivalent ratio was 1.2:1, KOH equivalent was 2.0; reaction temperature was 83℃~85℃. As can be seen from Table 1, the product concentration of the reaction using catalysts compound1 and compound2 can reach 88.6%, which is significantly better than other catalysts, and the boric acid concentration is 1.3~9.1%, which is significantly lower than other catalysts.

[0081] The following replacements can be made in the above content:

[0082] In the synthesis of compound K, replacing di-tert-butylphosphine chloride with diphenylphosphine chloride can alter the ligand structure, and similar effects may be achieved in practical applications.

[0083] In the synthesis of compound C, replacing bromobenzene with similar groups such as fluorobromobenzene or bromobiphenyl may produce products with similar effects.

[0084] The source of palladium was replaced by palladium acetate or palladium dichlorotetramethylethylenediamine, or other similar palladium sources.

[0085] The reaction route for the synthesis of the sterically hindered ligands of this invention is as follows:

[0086]

[0087] This invention utilizes 2-naphthyl methyl ether, first undergoing dehydrolithiation with n-butyllithium, followed by reaction with tributyl borate and acid hydrolysis to obtain compound B. Compound B reacts with bromobenzene via a Suzuki reaction to prepare compound C. Compound C undergoes a halogenation reaction to obtain compound D. Compound F is selectively dehydrolithiated to the 3-position of the pyridine ring in the presence of N,N-tetramethylethylenediamine, then reacts with triisopropyl borate followed by acid hydrolysis to obtain compound G. Compound D and compound G undergo a Suzuki reaction to generate compound H. The amino group of compound H reacts with tert-butyl nitrite via a diazotization reaction catalyzed by copper acetate to close the intramolecular ether bond, yielding compound J. Compound J reacts with tetramethylpiperidinium to first lithiate and remove the methyl hydrogen from the pyridine ring, then reacts with dimethylpiperidinium... The reaction of tert-butylphosphine chloride yields compound K, which is then reacted with palladium acetate or dichloro(N,N,N',N'-tetramethylethylenediamine)palladium to synthesize compound1 or compound2. In this invention, the naphthyl group is used as the main stabilizing group. During ligand use, this group provides a large planar rigid configuration and simultaneously provides a large number of π electrons to stabilize the complex molecule. Furthermore, a pyridofuran configuration is employed, introducing the furan functional group into the O position of the N-coordination site of the traditional NP bidentate ligand to regulate the chemical environment of the intramolecular N-coordination site, thereby modifying the traditional NP bidentate ligand into a tridentate ligand. This modification effectively increases the penetration ability of the Pd active center in actual ligand use, thereby enhancing catalytic activity.

[0088] In practical applications, the ligands of this invention need to be used in combination with palladium acetate or palladium dichloro(N,N,N',N'-tetramethylethylenediamine)acetate. The process is convenient and has good compatibility with the sterically hindered coupling catalysis effect. When used in the sterically hindered CC coupling process, its conversion rate is significantly better than that of traditional ligands.

[0089] This invention discloses a large steric hindrance CC-coupled palladium ligand. The ligand is solid at room temperature, is insensitive to oxygen in the air at room temperature, is easy to store and transport, and is convenient to use.

[0090] The raw materials used in the preparation process of the ligands of this invention are all commercially available and widely sourced. The synthesis process is mostly carried out using conventional reaction processes, and the large-scale preparation and promotion are expected to be successful.

[0091] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

[0092] Many other changes and modifications can be made without departing from the concept and scope of this invention. It should be understood that this invention is not limited to the specific embodiments, and the scope of this invention is defined by the appended claims.

Claims

1. A method for synthesizing a sterically hindered CC-coupled palladium ligand, characterized in that, Includes the following steps: Step 1: 2-Naphthyl methyl ether is first subjected to hydrogen lithiation with n-butyllithium, and then reacted with tributyl borate followed by acid hydrolysis to obtain compound B. The molar ratio of 2-naphthyl methyl ether: n-butyllithium: tributyl borate is 1:1.1~1.2:1.2~1.

3. The structural formula of compound B is as follows: ; Step 2: Compound B and bromobenzene are reacted via a Suzuki reaction to prepare compound C. The molar ratio of compound B to bromobenzene is 1:1~1.

1. The structure of compound C is as follows: ; Step 3: Compound C undergoes a halogenation reaction to yield compound D. The structural formula of compound D is as follows: ; Step 4: The amino group of 2-amino-6-methylpyridine is protected with di-tert-butyl dicarbonate to obtain compound F. The molar ratio of 2-amino-6-methylpyridine to di-tert-butyl dicarbonate is 1:1.1~1.

2. The structural formula of compound F is as follows: ; Step 5: Compound F is selectively dehydrolithiated to the 3-position of the pyridine ring in the presence of N,N-tetramethylethylenediamine, followed by reaction with triisopropyl borate and acid hydrolysis to obtain compound G. The molar ratio of compound F:N,N-tetramethylethylenediamine:triisopropyl borate is 1:1.2~1.3:1.2~1.

25. The structural formula of compound G is as follows: ; Step 6: Compound D and compound G undergo a Suzuki reaction to generate compound H. The molar ratio of compound D to compound G is 1:1~1.

05. The structural formula of compound H is... ; Step 7: The amino group of compound H undergoes a diazotization reaction with tert-butyl nitrite under copper acetate catalysis, resulting in intramolecular ether cyclization to give compound J. The molar ratio of compound H:copper acetate:tert-butyl nitrite is 1:0.01~0.1:1.2~1.

5. The structural formula of compound J is as follows: ; Step 8: Compound J reacts with tetramethylpiperidine lithium to first lithium-ionize and remove the methyl hydrogen from the pyridine ring, then reacts with di-tert-butylphosphine chloride to obtain compound K. The molar ratio of compound J:tetramethylpiperidine lithium:di-tert-butylphosphine chloride is 1:1.1~1.2:1.2~1.

25. The structural formula of compound K is [insert structural formula here]. .

2. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 1 specifically involves dissolving 2-naphthyl methyl ether in THF solvent, adding 2.5 mol / L n-butyllithium dropwise under an argon atmosphere between -20°C and -10°C, maintaining the temperature for 2-3 hours to remove hydrogen, then cooling to -85°C to -80°C, and then adding tributyl borate dropwise. After completion, the temperature is naturally raised to an internal temperature above -10°C. Once the reaction is complete, the reaction solution is concentrated under reduced pressure, acidified with hydrochloric acid, and crystallized in PE to obtain a white solid compound B.

3. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 2 specifically involves adding compound B, bromobenzene, potassium carbonate, toluene, ethanol, water, and Pd(PPh3)4 sequentially to a three-necked flask. The mixture is then refluxed at 70°C–75°C for 6–8 hours under an argon atmosphere until compound B is completely reacted. The reaction solution is first washed with water and separated, then the organic phase is evaporated under reduced pressure. The resulting product is then crystallized from methanol to obtain a white solid compound C. The molar ratio of compound B:bromobenzene:potassium carbonate:Pd(PPh3)4 is 1:1–1.1:1.5–2:0.005–0.

01. The volume ratio of compound B to toluene, ethanol, and water is 100g:600–615ml:200–210ml:200–210ml.

4. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 3 specifically involves: under argon protection, adding compound C and DMF to a reaction flask, using N-bromosuccinimide as a brominating agent, and adding N-bromosuccinimide in batches at 0-10°C. After the reaction is completed, the reaction solution is poured into a large amount of water, filtered to precipitate a solid, and then dispersed with ethanol to obtain a white solid compound D. The molar ratio of compound C to N-bromosuccinimide is 1:1-1.1, and the ratio of compound C to DMF is 100g:510-520ml.

5. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 4 specifically involves: adding 2-amino-6-methylpyridine, 4-dimethylaminopyridine, and dichloromethane to a three-necked flask under an argon atmosphere, maintaining the internal temperature at 15-25°C, adding a DCM solution of Boc2O dropwise, and maintaining the reaction temperature for 24 hours until the raw materials have basically reacted completely. Then, the solvent and low-boiling-point substances are concentrated under reduced pressure to obtain a crude product. The crude product is then dispersed and filtered using PE to obtain compound F. The molar ratio of 2-amino-6-methylpyridine: 4-dimethylaminopyridine: Boc2O is 1:1~1.05:1.1~1.2, and the ratio of 2-amino-6-methylpyridine to DCM is 10g:92~95ml.

6. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 5 specifically involves: dissolving compound F in THF, adding N,N-tetramethylethylenediamine, cooling to -80℃ to -75℃ under an argon atmosphere, adding 2.5 mol / L n-BuLi dropwise, stirring for 1 to 2 hours, then further cooling to -95℃ to -85℃, adding triisopropyl borate dropwise, and then heating back to room temperature. After the reaction is complete, the reaction solution is concentrated, ammonium chloride aqueous solution is dissociated, and PE is used to disperse and crystallize, yielding a grayish-brown solid compound G. The molar ratio of compound F: N,N-tetramethylethylenediamine: n-BuLi: triisopropyl borate is 1:1.2~1.3:1.1~1.2:1.2~1.25, and the ratio of compound F to THF is 10 g:100 ml.

7. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 6 specifically involves: adding compound D, compound G, potassium carbonate, dioxane, and water sequentially to a three-necked flask; replacing the system with argon gas; adding catalyst Pd(PPh3)4; and reacting in a one-pot manner at 75℃~80℃ for 12 hours until the reactant D is completely reacted. The reaction solution is concentrated under reduced pressure, dissolved in toluene, washed with deionized water, and then dried. After completion, the organic phase is filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound H. The molar ratio of compound D: compound G: potassium carbonate: Pd(PPh3)4 is 1:1~1.05:1.5~2:0.005~0.01, and the ratio of compound D to dioxane and water is 10g:100ml:16~18ml.

8. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 7 specifically involves dissolving compound H in a three-necked flask with THF, heating to an internal temperature of 55°C–60°C, stopping the heating, adding copper acetate, and then carefully adding a THF solution containing tert-butyl nitrite dropwise into the system. The system releases heat and gas. After the addition is complete, the mixture is kept warm for 1–2 hours to complete the reaction. The reaction solution is directly concentrated to dryness under reduced pressure, then toluene is added and refluxed to dissolve and clarify the solution. The solution is passed through a silica gel column, and the product column liquid is collected and concentrated under reduced pressure until solid precipitates. The solution is cooled to below 20°C, filtered, dried under vacuum, and then dried to obtain a slightly yellow solid powder, compound J. The molar ratio of compound H: copper acetate: tert-butyl nitrite is 1:0.01–0.1:1.2–1.5, the molar ratio of compound H to THF is 10 g:78–80 ml, and the molar ratio of tert-butyl nitrite to THF is 10 g:24–26 ml.

9. The method for synthesizing a large sterically hindered CC-coupled palladium ligand according to claim 1, characterized in that, Step 8 specifically involves: dissolving compound J in THF under an argon atmosphere, cooling to -50°C to -60°C, then adding a tetramethylpiperidine lithium solution dropwise. After completion, maintaining the temperature between -55°C and -50°C for 2 to 3 hours until the system turns dark brown. Then, cooling to an internal temperature between -90°C and -80°C, and adding a di-tert-butylphosphine chloride solution dropwise. After completion, allowing the temperature to rise naturally to an internal temperature of 0°C. Once the reaction is complete, the reaction solution is directly concentrated to dryness under negative pressure. Heptane is added, and the concentrated solution is dissolved under reflux in an argon atmosphere, followed by cooling. The solution was rapidly passed through diatomaceous earth at an internal temperature of 20℃~30℃ under an argon atmosphere to remove insoluble salts. The filtrate was collected and concentrated under reduced pressure to a very small amount of solvent. Then, under argon protection, the solution was stirred and cooled to 0℃~5℃, precipitating a white solid. The solid was filtered and dried under an inert gas atmosphere to obtain a white to slightly yellow waxy solid compound K. The molar ratio of compound J: lithium tetramethylpiperidine: di-tert-butylphosphine chloride was 1:1.1~1.2:1.2~1.25, and the molar ratio of compound J to THF was 10g:96~100ml.

10. A sterically hindered CC-coupled palladium ligand, characterized in that, The ligand is a tridentate ligand of NPO, and its structural formula is as follows: The tridentate ligand of NPO is synthesized by the method for synthesizing a large steric hindrance CC-coupled palladium ligand as described in any one of claims 1 to 9.

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