Fluorenyl bisphosphine ligands, methods for their preparation and use

Abstract

The application belongs to the technical field of organic phosphine ligands, and particularly relates to a fluorenyl biphosphine ligand and a preparation method and application thereof. The fluorenyl biphosphine ligand is prepared by using an easily available aryl halide as a starting material, constructing a phosphine-containing intermediate, and further converting the phosphine-containing intermediate to realize efficient construction of a fluorene skeleton biphosphine structure. The method has a clear reaction route, the raw materials are widely available, the reaction can be completed under mild conditions, is suitable for synthesis of different biphosphine substitution systems, and the prepared fluorenyl biphosphine ligand exhibits excellent catalytic performance in a Sonogashira coupling reaction, and has good practicability and promotional value.

Description

Technical Field

[0001] This invention belongs to the field of organophosphine ligand technology, and particularly relates to a fluorenyl bisphosphine ligand, its preparation method and application. Background Technology

[0002] Bisphosphine ligands, as an important class of organophosphine ligands, have wide applications in transition metal catalysis, asymmetric synthesis, and the preparation of fine chemicals. The fluorene framework, due to its strong structural rigidity and stable spatial configuration, is widely used in the construction of functional organic molecules and ligand structures. Introducing bisphosphine groups into the fluorene framework can form symmetrical bisphosphine ligands centered on the bridgehead carbon. These ligands have a well-defined spatial orientation and tunable steric hindrance, showing promising application prospects in catalytic systems such as coupling reactions, hydrogenation reactions, and CH bond activation reactions.

[0003] In existing technologies, fluorene-based bisphosphine ligands are typically synthesized using fluorene or its derivatives as starting materials. However, fluorene-based starting materials generally suffer from high prices, limited availability, or numerous pretreatment steps, which to some extent restricts the large-scale preparation and further application of these ligands. Furthermore, some reported synthetic methods involve harsh reaction conditions, cumbersome procedures, and limited applicability to bisphosphine substituents, making it difficult to simultaneously achieve both versatility and practicality.

[0004] Therefore, there is an urgent need to provide a method for preparing fluorenyl bisphosphine ligands that is readily available, has mild reaction conditions, is easy to operate, and has good versatility, so as to achieve effective compatibility with different bisphosphine substitution systems, thereby providing a reliable synthetic route for the development of high-performance bisphosphine ligands and their application in the field of catalysis. Summary of the Invention

[0005] The purpose of this invention is to provide a fluorene-based bisphosphine ligand, its preparation method, and its applications. This method uses readily available aryl halides as starting materials, and through the construction of phosphine-containing intermediates and further transformation, achieves efficient construction of the fluorene-based bisphosphine structure. The method has a clear reaction route, widely available raw materials, and can be carried out under mild conditions, making it suitable for the synthesis of different bisphosphine substitution systems.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing fluorene-based bisphosphine ligands includes the following steps:

[0008] S1. Dissolve triphosgene in an organic solvent and add it to an organic solution containing dialkylphosphine to react and generate bis(dialkylphosphino) ketone intermediate;

[0009] S2. The aryl halide is reacted with an organometallic reagent to generate an aryl metal intermediate; then the bis(dialkylphosphine) methyl ketone intermediate prepared in step S1 is added to the reaction system to undergo a nucleophilic addition reaction, and the target fluorenyl bisphosphine ligand is obtained after acid treatment and purification.

[0010] Furthermore, the synthetic route of the present invention is as follows:

[0011] Where R is n-butyl, tert-butyl, or adamantyl.

[0012] Furthermore, the organic solvent in step S1 is dichloromethane or tetrahydrofuran.

[0013] Furthermore, the bis(dialkylphosphine) methyl ketone intermediate generated in step S1 is used after processing, and the purification process includes dissolving in water, extraction, drying and concentration.

[0014] Furthermore, the reaction conditions in step S1 are: stirring at 0~25℃ for 1~4 hours.

[0015] Furthermore, the preparation method of the aryl metal intermediate in step S2 is as follows: 2-bromo-1,1'-biphenyl and tetrahydrofuran are mixed and cooled, and then n-butyllithium is added dropwise to the mixture to react and obtain the intermediate.

[0016] Furthermore, the acid treatment operation in step S2 is as follows: acetic acid and hydrochloric acid are added to the reaction system sequentially or in combination, and stirred at 75~80℃ for 3~4 hours.

[0017] Another object of the present invention is to provide a fluorene-based bisphosphine ligand prepared by the above method.

[0018] Another objective of this invention is to provide an application of fluorenyl bisphosphine ligands, which exhibits excellent catalytic performance in the Sonogashira coupling reaction and has good practicality and promotional value.

[0019] The advantages of this invention are: it uses readily available aryl halides as starting materials, and achieves efficient construction of fluorene-based bisphosphine structures by constructing phosphine-containing intermediates and further transforming them. It does not require expensive fluorene or its derivatives as direct starting materials. By rationally designing the reaction pathway, it achieves efficient synthesis of fluorene-based bisphosphine ligands. While ensuring the reaction yield, it improves the versatility and practicality of the method and has good potential for scale-up preparation. Detailed Implementation

[0020] Example 1 (using di-n-butylphosphine as an example)

[0021] A method for preparing fluorene-based bisphosphine ligands includes the following steps:

[0022] Step 1: Preparation of the bis(di-n-butylphosphino) ketone intermediate. At 0°C, triphosgene (10 mmol) was dissolved in 5 mL of anhydrous dichloromethane and slowly added dropwise to 25 mL of anhydrous dichloromethane solution of di-n-butylphosphine. After the addition was complete, the mixture was stirred for 1 hour, then heated to 25°C and stirred for another 2 hours. After the reaction was complete, 100 mL of water was added to the reaction system to dissolve the precipitate. The mixture was extracted twice with dichloromethane (25 mL each time), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the bis(di-n-butylphosphino) ketone intermediate, which can be directly used in the next reaction step.

[0023] Step 2: Construction of fluorene-bisphosphine ligand. In a 100 mL flask, 2-bromo-1,1'-biphenyl (11 mmol) and 30 mL tetrahydrofuran were added. The mixture was cooled to -78 °C, and 1.6 M n-butyllithium (12 mmol) was slowly added dropwise while stirring for 1 hour. Then, the bis(di-n-butylphosphine) methyl ketone intermediate (10 mmol) obtained in Step 1 was dissolved in 10 mL tetrahydrofuran and slowly added to the reaction system. After the reaction was complete, the temperature was slowly raised to 25 °C, quenched with saturated ammonium chloride solution, and the solvent was removed by rotary evaporation. 2 mL of acetic acid was added to the residue, followed by 2 mL of hydrochloric acid, and the mixture was heated to 75 °C and reacted for 4 hours. The mixture was cooled to 25 °C, the precipitate was collected by suction filtration and washed 2-3 times with methanol to obtain (9H-fluorene-9,9-diyl)bis(di-n-butylphosphine), with a single-step yield of 91%. 1 HNMR (500 MHz, CDCl3) δ 8.23 ​​(d, J = 7.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.0 Hz, 2H), 2.30 (m, 8H), 1.49 (m,8H), 1.24 (m, 8H), 0.77 (t, J = 6.8 Hz, 12H). 13 C NMR (125 MHz, CDCl3)δ144.74,143.92, 129.25, 128.86, 124.95, 120.74, 77.57, 32.07, 29.91, 23.66, 14.52.

[0024] Example 2

[0025] The procedure was followed as in Example 1, but di-n-butylphosphine was replaced with di-tert-butylphosphine. All other conditions were the same, yielding (9H-fluorene-9,9-diyl)bis(di-tert-butylphosphine) in approximately 85% yield. 1H NMR (500 MHz, CDCl3) δ8.11 (d, J= 7.2 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.02 (t, J = 7.0 Hz, 2H), 6.56 (t, J= 7.2 Hz, 2H), 1.02 (m, 36H). 13 C NMR (125 MHz, CDCl3)δ151.59, 141.92, 129.18,129.17, 125.51, 120.87, 71.76, 32.10, 30.78.

[0026] Example 3

[0027] The procedure was followed as in Example 1, but di-n-butylphosphine was replaced with diadamantylphosphine. All other conditions were the same, yielding (9H-fluorene-9,9-diyl)bis(dadamantylphosphine) in approximately 72% yield. 1 H NMR (500 MHz, CDCl3)δ8.32 (d,J = 7.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 7.2 Hz, 2H), 6.70 (t,J = 7.6 Hz, 2H), 2.02 (m, 6H), 1.95 (m, 6H), 1.88 -1.71 (m, 24H), 1.71 -1.53 ​​(m, 24H). 13 C NMR (125 MHz, CDCl3)-δ-154.62, 141.68, 129.32, 129.17, 125.44,120.77, 90.19, 46.48, 44.60, 37.97, 29.91.

[0028] Example 4

[0029] Step 1: At 10°C, triphosgene was dissolved in 5 mL of anhydrous dichloromethane and slowly added dropwise to a 25 mL solution of di-n-butylphosphine in dichloromethane. After stirring for 1 hour, the temperature was raised to 25°C and stirred for 2 hours. Step 2: Same as Example 1, acid treatment at 75°C for 4 hours. Product: (9H-fluorene-9,9-diyl)bis(di-n-butylphosphine), yield approximately 90%.

[0030] Example 5

[0031] Step 1: At 0°C, triphosgene was dissolved in 5 mL of tetrahydrofuran and added dropwise to 25 mL of di-tert-butylphosphine tetrahydrofuran solution. The mixture was stirred for 1 hour, then heated to 25°C and stirred for 2 hours. Step 2: Same as Example 3, acid treatment at 75°C for 4 hours. Product: (9H-fluorene-9,9-diyl)bis(di-tert-butylphosphine), yield approximately 85%.

[0032] Example 6

[0033] Step 1: Same as Example 4. Step 2: Acid treatment temperature increased to 80°C, held for 4 hours, other conditions unchanged. Product: (9H-fluorene-9,9-diyl)bis(diadamantylphosphine), yield approximately 66%.

[0034] Example 7 (Di-n-Butylphosphine, shortened acid treatment time in step two)

[0035] Step 1: Same as Example 1. Step 2: Acid treatment at 75°C for 3 hours, with all other conditions unchanged. Product: (9H-fluorene-9,9-diyl)bis(di-n-butylphosphine), yield approximately 91%.

[0036] Application examples

[0037] The reaction route is as follows:

[0038]

[0039] Under nitrogen protection, tris(dibenzylacetone)palladium (Pd2dba3, 0.1 mmol), cuprous iodide (CuI, 0.1 mmol), and (9H-fluorene-9,9-diyl)bis(di-n-butylphosphine) (the product of Example 1, 0.2 mmol) were mixed. 20 mL of triethylamine was added, followed by 2-iodo-1,3-diisopropylbenzene (1 mmol) and phenylacetylene (2 mmol), and the mixture was bubbled with nitrogen for 10 minutes.

[0040] The mixture was heated at 90°C for 24 hours under a nitrogen atmosphere and then cooled to 25°C. Volatile substances were removed by vacuum evaporation, and the residue was partitioned between 10 mL of dichloromethane and 10 mL of 1 N hydrochloric acid aqueous solution. The aqueous phase was discarded, and the organic phase was washed successively with 1 N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the volatile substances were removed by vacuum evaporation. The residue was purified by rapid column chromatography (silica gel, n-hexane) to give a colorless liquid, 1,3-diisopropyl-2-(phenylethynyl)benzene (97% yield).

Claims

1. A method for preparing a fluorene-based bisphosphine ligand, characterized in that, Includes the following steps: S1. Dissolve triphosgene in an organic solvent and add it to an organic solution containing phosphine to react and generate a bis(phosphono) ketone intermediate; S2. Reaction of aryl halides with n-butyllithium generates aryl metal intermediates; The bis(phosphine) methyl ketone intermediate prepared in step S1 is then added to the reaction system to undergo a nucleophilic addition reaction. After acid treatment, the target fluorenyl bisphosphine ligand is obtained by separation and purification. Its synthetic route is as follows: Where R is n-butyl, tert-butyl, or adamantyl; aryl halides are... .

2. The method for preparing fluorene-based bisphosphine ligands as described in claim 1, characterized in that: The organic solvent in step S1 is dichloromethane or tetrahydrofuran.

3. The method for preparing fluorene-based bisphosphine ligands as described in claim 1, characterized in that: The bis(phosphono) methyl ketone intermediate generated in step S1 is used after processing. The purification process includes dissolving in water, extraction, drying, and concentration.

4. The method for preparing fluorene-based bisphosphine ligands as described in claim 1, characterized in that: The reaction conditions in step S1 are: stirring at 0~25℃ for 1~4 hours.

5. The method for preparing fluorene-based bisphosphine ligands as described in claim 1, characterized in that: The preparation method of the aryl metal intermediate in step S2 is as follows: 2-bromo-1,1'-biphenyl and tetrahydrofuran are mixed and cooled, and then n-butyllithium is added dropwise to the mixture to react and obtain the intermediate.

6. The method for preparing fluorene-based bisphosphine ligands as described in claim 1, characterized in that: The acid treatment operation in step S2 is as follows: acetic acid and hydrochloric acid are added to the reaction system in sequence, and the mixture is stirred at 75~80℃ for 3~4 hours.

7. A fluorenyl bisphosphine ligand prepared by the preparation method according to any one of claims 1-6.

8. The application of the fluorene-based bisphosphine ligand as described in claim 7, characterized in that, It is used as a catalyst in the Sonogashira coupling reaction.

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