Imidazolium salt diphosphine ligand, and preparation method and application thereof

Abstract

The application belongs to the technical field of organic synthesis and metal catalytic ligand, and particularly relates to an imidazolium salt biphosphine ligand, a preparation method and application thereof, a structural formula of which is shown in the following formula: wherein R is a cyclohexyl group, a tert-butyl group or an adamantyl group; the preparation method is clear in steps, has mild reaction conditions, does not need high-pressure equipment, is simple in operation and suitable for scale-up production; and the large steric hindrance substituent (the cyclohexyl group, the tert-butyl group or the adamantyl group) is helpful to regulating the catalytic performance of a metal center, and has potential application value in metal catalytic reactions.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and metal catalytic ligand technology, and particularly relates to an imidazolium salt bisphosphine ligand, its preparation method and application. Background Technology

[0002] Nitrogen heterocyclic carbenes (NHCs) are a class of strong σ-electron-donating ligands with wide applications in metal catalysis, small organic molecule catalysis, and functional materials. Phosphine ligands are also a commonly used class of ligands in transition metal catalysis, playing an important role in stabilizing metal centers and modulating electronic effects.

[0003] Introducing phosphine groups into the NHC framework allows for the construction of multidentate ligands containing both phosphine and NHC structural units. Among these, NHC bisphosphine tridentate ligands are a class of ligands in which one NHC unit and two phosphine units coordinate with the metal center. Through the synergistic effect of multiple coordination sites, these ligands can more effectively stabilize the metal center, thus contributing to the stability and activity of the catalyst. Compared to monodentate or bidentate ligands, tridentate ligands may exhibit stronger resistance to dissociation and longer catalytic lifetime in catalytic systems.

[0004] This invention designs a novel class of imidazolium salt bisphosphine ligands that can serve as precursors for NHC bisphosphine tridentate ligands. Developing these novel imidazolium salt bisphosphine ligands and their efficient and safe preparation methods, and exploring their applications in metal catalysis, has significant innovative value and practical implications. Summary of the Invention

[0005] The purpose of this invention is to provide an imidazolium salt bisphosphine ligand, its preparation method, and its application.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: An imidazolium salt bisphosphine ligand has the following structural formula: Where R is cyclohexyl, tert-butyl, or adamantyl, the synthetic route is shown below: .

[0007] Another object of the present invention is to provide a method for preparing imidazolium salt bisphosphine ligands, comprising the following steps: 1) Using 2-bromoaniline and glyoxal as raw materials, methanol as solvent, and formic acid as catalyst, diimine is obtained by condensation.

[0008] 2) The diimine was reacted with chloromethyl ethyl ether at 80°C under nitrogen protection to give 1,3-bis(2-bromophenyl)-1H-imidazolium chloride.

[0009] 3) The above imidazolium chloride was deprotonated in tetrahydrofuran under alkaline conditions, and then recrystallized from toluene and n-hexane to obtain free carbene. The C-Br bond on the aromatic ring of the free carbene underwent lithium-bromine exchange with n-butyllithium at low temperature to form a lithium intermediate, which was then reacted with dialkylphosphine chloride (PR2Cl). After quenching with saturated ammonium chloride, acidification with hydrochloric acid, and recrystallization, the target compound 1,3-bis(2-(dialkylphosphino)phenyl)-1H-imidazolium-3-onium chloride was obtained.

[0010] The advantages of this invention are: it provides a novel 1,3-bis(2-(dialkylphosphino)phenyl)-1H-imidazol-3-onium chloride, the preparation method of which has clear steps, mild reaction conditions, no need for high-pressure equipment, simple operation, and is suitable for large-scale production; moreover, the sterically hindered substituents (cyclohexyl, tert-butyl, adamantyl) help to regulate the catalytic performance of the metal center, and have potential application value in metal catalytic reactions. Detailed Implementation

[0011] Example 1: Synthesis of diimine intermediate In a 250 mL round-bottom flask, 2-bromoaniline (6.88 g, 40.0 mmol, 2.0 equiv) was dissolved in methanol (100 mL). Glyoxal (1.16 g, 20.0 mmol, 1.0 equiv) and formic acid (approximately 0.1 mL, 2.6 mmol, 0.13 equiv) were added sequentially with stirring. The resulting mixture was stirred at 60 °C for 12 hours, during which a yellow solid gradually precipitated. After the reaction was complete, the yellow suspension was filtered, and the filter cake was treated with a solution at 0–5 °C. Wash with cold methanol (about 20 mL), and dry under vacuum to obtain a diimine intermediate, which can be used directly in the next reaction step.

[0012] Example 2: Synthesis of 1,3-bis(2-bromophenyl)-1H-imidazolium chloride The diimine intermediate was placed in a 250 mL round-bottom flask under nitrogen protection. Chloromethyl ethyl ether (56 mL, 600 mmol, 30 equiv) was added, serving as both a reactant and solvent in the reaction. The reaction mixture was heated to 80 °C and stirred for 6 hours. After the reaction was complete, excess solvent and low-boiling byproducts were removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane and methanol (v / v 10:1). The target fractions were collected, combined, and evaporated to dryness under reduced pressure to obtain a pale yellow to white solid, 1,3-bis(2-bromophenyl)-1H-imidazolium chloride (7.21 g, 87% yield). 1H NMR (400 MHz, CDCl3)δ9.66 (t, J = 1.6 Hz, 1H), 8.05 (d,J = 1.6 Hz, 2H), 8.00 (dd, J = 7.8, 1.6 Hz, 2H), 7.81 (dd, J = 7.7,1.9 Hz,2H), 7.77–7.64 (m, 4H). 13 C NMR (101 MHz, CDCl3)δ138.3, 134.4, 133.8, 133.1,129.6, 128.3, 124.5, 119.2. HRMS (ESI) m / z: [M-Cl-] + Calculated for [C 15 H 11 Br2N2]+378.9263; Found378.9272. Example 3: Synthesis of 1,3-bis[2-(dicyclohexylphosphino)phenyl]-1H-imidazol-3-onium chloride Inside a glove box, imidazolium chloride (4.15 g, 10.0 mmol, 1.0 equiv) and potassium tert-butoxide (2.24 g, 20.0 mmol, 2.0 equiv) were added to a 100 mL round-bottom flask, followed by anhydrous tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 12 hours, during which the system gradually changed from a milky white suspension to a pale yellow solution. The solvent was removed under reduced pressure to obtain a white solid. Toluene (20 mL) was added to the solid, and the mixture was heated slightly to ensure homogeneity. Subsequently, n-hexane (approximately 40 mL) was slowly added, precipitating a large amount of white solid. The suspension was filtered, and the filter cake was washed with a small amount of toluene. All filtrates were combined, and the solvent was removed under reduced pressure to obtain colorless microcrystalline free nitrogen heterocyclic carbene, which was used directly in the next step.

[0013] Under nitrogen protection, the above-mentioned free carbene (10.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and cooled to -78 °C. A hexane solution of n-butyllithium (2.5 M, 10.0 mL, 25.0 mmol, 2.5 equiv) was slowly added dropwise, and after stirring for 30 minutes, dicyclohexylphosphine chloride (4.89 g, 21.0 mmol, 2.1 equiv) was added dropwise. The reaction mixture was stirred at -78 °C for 30 minutes, then allowed to warm naturally to room temperature and stirred for 16 hours.

[0014] After the reaction was complete, the reaction flask was cooled back to 0°C (ice-water bath), and excess n-butyllithium was quenched by slowly adding 20 mL of saturated ammonium chloride solution. After complete quenching, 15 mL of 1 M hydrochloric acid aqueous solution was added, and stirring was continued for 15 minutes. The mixture was transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted with dichloromethane (3 × 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from a mixture of dichloromethane and n-hexane (volume ratio 1:3), filtered, and dried under vacuum to give 1,3-bis[2-(dicyclohexylphosphine)phenyl]-1H-imidazol-3-onium chloride (5.78 g, yield 89%). 1 H NMR (400 MHz, CDCl3)δ9.69 (t, J = 1.6 Hz, 1H), 8.06 (dd,J = 8.8, 1.4 Hz, 1H), 8.04–7.87 (m, 2H), 7.75 (td, J = 7.7, 1.5Hz, 1H), 7.65(dd, J = 7.7, 1.4 Hz, 1H), 7.58–7.47 (m, 2H), 7.47–7.37 (m, 2H), 7.21 (ddd, J= 7.9, 6.6, 1.3 Hz, 1H), 2.43 (pd, J = 7.2, 3.7 Hz, 4H), 1.80–1.66 (m, 8H), 1.60–1.32 (m, 32H). 13 C NMR (101 MHz, CDCl3)δ139.2, 135.0, 131.5, 129.6, 126.6,126.2, 125.1, 117.9, 34.8, 34.4, 31.4, 27.2. HRMS (ESI) m / z: [M-Cl-] + Calcdfor [C 39 H 55 N2P2] + 613.3835; Found 613.3832. Example 4: Synthesis of 1,3-bis[2-(di-tert-butylphosphino)phenyl]-1H-imidazol-3-onium chloride Similar to Example 3, dicyclohexylphosphine chloride was replaced with an equimolar amount of di-tert-butylphosphine chloride (3.79 g, 21.0 mmol), and the remaining operations were the same as in Example 3, to obtain the target compound (4.47 g, yield 82%). 1H NMR (400 MHz, CDCl3) δ9.71 (t, J = 1.7 Hz, 1H), 8.05–7.96 (m, 2H), 7.79– 7.67 (m, 2H), 7.61–7.49 (m, 3H), 7.46–7.29 (m, 2H), 7.23 (ddd, J= 6.7, 5.4, 1.3 Hz, 1H), 1.12(s, 36H). 13 C NMR (101 MHz, CDCl3)δ137.5, 135.1, 132.8, 130.1, 128.9, 127.7,126.7, 120.6, 31.4, 29.3. HRMS (ESI) m / z: [M-Cl-] + Calculated for [C 31 H 47 N2P2] + 509.3209; Found 509.3207. Example 5: Synthesis of 1,3-bis[2-(diadamantylphosphino)phenyl]-1H-imidazol-3-onium chloride Similar to Example 3, dicyclohexylphosphine chloride was replaced with an equimolar amount of diadamantylphosphine chloride (7.07 g, 21.0 mmol), and the remaining operations were the same as in Example 3, to obtain the target compound (6.77 g, 79% yield). 1 H NMR (400MHz, CDCl3)δ9.69 (t, J = 1.7 Hz, 1H), 8.05–7.96 (m, 2H), 7.82– 7.70 (m, 2H), 7.63–7.49 (m, 4H), 7.47–7.36 (m, 1H), 7.23 (ddd, J= 6.7, 5.4, 1.4 Hz, 1H), 1.91–1.90 (m, 12H), 1.74–1.52 (m, 48H). 13 C NMR (101 MHz, CDCl3) δ138.1, 134.1,132.4, 131.1, 129.2, 128.3, 126.4, 124.1, 50.18, 43.91, 37.97, 29.67. HRMS(ESI) m / z:[M-Cl-] + Calculated for [C 55 H 71 N2P2] + 821.5087; Found 821.5089. Example 6: Similar to Example 3, potassium tert-butoxide was replaced with sodium tert-butoxide (1.92 g, 20.0 mmol, 2.0 equiv), and the rest of the operation was the same as in Example 3, to obtain free nitrogen heterocyclic carbene. The subsequent phosphineization steps were the same as in Example 3, and finally 1,3-bis(2-(dicyclohexylphosphino)phenyl)-1H-imidazol-3-onium chloride (5.91 g, yield 91%) was obtained.

[0015] Example 7: Similar to Example 3, potassium tert-butoxide was replaced with potassium carbonate (2.76 g, 20.0 mmol, 2.0 equiv), and the rest of the operation was the same as in Example 3, to obtain free nitrogen heterocyclic carbene. The subsequent phosphineization steps were the same as in Example 3, and finally 1,3-bis(2-(dicyclohexylphosphino)phenyl)-1H-imidazol-3-onium chloride (5.71 g, yield 88%) was obtained.

[0016] Example 8: Similar to Example 3, potassium tert-butoxide was replaced with sodium hydroxide (0.80 g, 20.0 mmol, 2.0 equiv), and the rest of the operation was the same as in Example 3, to obtain free nitrogen heterocyclic carbene. The subsequent phosphineization steps were the same as in Example 3, and finally 1,3-bis(2-(dicyclohexylphosphino)phenyl)-1H-imidazol-3-onium chloride (4.80 g, yield 74%) was obtained.

[0017] The differences in yield among different bases in Examples 6-8 are mainly due to their different nucleophilicity and solubility: Sodium hydroxide, due to its strong nucleophilicity and insolubility in tetrahydrofuran, easily triggers the ring-opening side reaction of imidazolium and leads to incomplete deprotonation, while sterically hindered tert-butoxide or mild potassium carbonate can generate free carbene more efficiently, thus resulting in higher yields.

[0018] Application Example 1 The palladium-catalyzed Negishi cross-coupling reaction is synthesized via the following route: Under nitrogen protection, palladium chloride (0.9 mg, 0.005 mmol), 1,3-bis[2-(dicyclohexylphosphino)phenyl]-1H-imidazol-3-onium chloride (3.2 mg, 0.005 mmol), and cesium carbonate (4.9 mg, 0.015 mmol) prepared in Example 3 were added to a dry Schlenk reaction tube. Anhydrous toluene (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The system gradually turned into a pale yellow homogeneous solution (in situ formation of an active palladium complex). The reaction flask was cooled in an ice-water bath at 0°C for 5 minutes, followed by the addition of 6-bromoquinoline (104 mg, 0.5 mmol), and then the slow dropwise addition of a toluene / tetrahydrofuran mixture of 3-pentylzinc bromide (approximately 1.2 mL, 0.6 mmol, concentration approximately 0.5 M). The ice bath was removed, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 1 M hydrochloric acid (0.6 mL) was added to quench the reaction, and the mixture was stirred for 2 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the target conjugate product (88 mg, yield 88%). 1 H NMR (400 MHz, CDCl3)δ8.84-8.83(m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.54-7.52 (m,2H), 7.34-7.32 (m,1H), 2.52-2.47 (m, 1H), 1.79-1.72 (m, 2H), 1.67-1.59 (m,2H), 0.77 (t, J = 7.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ149.4, 147.3, 144.0,135.5, 129.5, 129.4, 128.1, 126.1, 120.8, 49.6, 29.1, 12.1.

[0019] Comparative experiment The catalyst and ligand in Application Example 1 were replaced with an equimolar amount of tetra(triphenylphosphine)palladium (0.005 mmol, 1 mol%), and the rest of the operation was exactly the same as in Application Example 1, to obtain the target coupling product in 47% yield.

[0020] A comparison of Application Example 1 and the comparative experiment shows that the palladium complex formed by the imidazolium salt bisphosphine ligand prepared in this invention exhibits significantly superior catalytic activity to the conventional tetra(triphenylphosphine)palladium catalyst in this Negishi cross-coupling reaction. This is because the strongly electron-donating NHC group in the ligand effectively promotes oxidative addition, the sterically hindered substituents accelerate reductive elimination, and the stable tripentate chelate structure greatly extends the catalyst lifetime. This series of advantages determined by the ligand structure enables it to surpass the conventional Pd(PPh3)4 catalyst in both catalytic efficiency and stability.

Claims

1. An imidazolium salt bisphosphine ligand, characterized in that: Its structural formula is shown below: , where R is cyclohexyl, tert-butyl, or adamantyl.

2. The method for preparing the imidazolium salt bisphosphine ligand as described in claim 1, characterized in that, Includes the following steps: S1. Diimine is obtained by condensation of 2-bromoaniline and glyoxal under solvent and catalyst conditions; S2. The diimine is reacted with chloromethyl ethyl ether under nitrogen protection to give imidazolium chloride; S3. Imidazolium chloride is deprotonated in tetrahydrofuran under alkaline conditions, and then recrystallized from toluene and n-hexane to obtain free carbene. The free carbene undergoes lithium-bromine exchange with n-butyllithium to form a lithium intermediate, which is then reacted with dialkylphosphine chloride. After quenching with saturated ammonium chloride, acidification with hydrochloric acid, and recrystallization, imidazolium salt bisphosphine ligand is obtained.

3. The method as described in claim 2, characterized in that: In step S1, the solvent is methanol, the catalyst is formic acid, the condensation reaction temperature is 50~70℃, and the reaction time is 10~14 hours.

4. The method as described in claim 2, characterized in that: In step S2, the reaction temperature is 70-90℃ and the reaction time is 5-7 hours. After the reaction, the product is successively purified by vacuum distillation, silica gel column chromatography, and vacuum evaporation to obtain 1,3-bis(2-bromophenyl)-1H-imidazolium chloride.

5. The method as described in claim 2, characterized in that: In step S3, the alkali is one of potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, and sodium hydroxide.

6. The method as described in claim 5, characterized in that: In step S3, the dialkylphosphine chloride is dicyclohexylphosphine chloride, di-tert-butylphosphine chloride, or diadamantylphosphine chloride.

7. The application of the imidazolium salt bisphosphine ligand as described in claim 1 in transition metal catalytic reactions.

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