Method for synthesizing adamantane phosphine compound through carbon-phosphine bond cross-coupling reaction

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a method for synthesizing an adamantane phosphine compound through a carbon-phosphine bond cross-coupling reaction. The method comprises the following steps: under a protective atmosphere, mixing adamantane boric acid, a phosphorus reagent, a catalyst, a ligand, alkali, an additive and a mixed solvent, and carrying out a carbon-phosphine bond cross-coupling reaction to obtain the adamantane phosphine compound. According to the method, through the palladium-catalyzed carbon-phosphine bond cross-coupling reaction, adamantyl boric acid and a halogenated phosphorus reagent react under mild conditions, the adamantane phosphine compound is innovatively and efficiently generated in one step, and compared with a traditional synthesis route, the synthesis efficiency is greatly improved. Moreover, the synthesis method provided by the invention can avoid the use of a violent Grignard reagent or halide reaction under relatively mild conditions, effectively improve the selectivity and yield of the reaction, and reduce the reaction steps and the generation of by-products at the same time.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction. Background Art

[0002] The existing methods for synthesizing tri(1-adamantyl)phosphine (Chen, L.; Ren, P.; Carrow, B. P., Tri(1-adamantyl)phosphine: Expanding the Boundary of Electron-Releasing Character Available to Organophosphorus Compounds. Journal of the American Chemical Society 2016, 138(20), 6392-6395.) are as Figure 1 shown. Traditional methods mostly use adamantyl halides to react with phosphine reagents, or use traditional organometallic reagents such as Grignard reagents. However, traditional synthesis methods have problems such as complex steps, difficult control of reactive intermediates, and many side reactions. Summary of the Invention

[0003] The purpose of the present invention is to provide a method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, so as to solve the problems of complex steps, difficult control of reactive intermediates, and many side reactions existing in the existing methods for synthesizing adamantylphosphine compounds.

[0004] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0005] The present invention provides a method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, comprising the following steps:

[0006] Under a protective atmosphere, mix adamantylboronic acid, a phosphorus reagent, a catalyst, a ligand, a base, an additive and a mixed solvent, and carry out a carbon-phosphorus bond cross-coupling reaction to obtain an adamantylphosphine compound.

[0007] Preferably, in the method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, the phosphorus reagent includes phosphorus trihalide or phosphorus dihalide;

[0008] The phosphorus trihalide includes phosphorus trichloride;

[0009] The phosphorus dihalide includes phenylphosphorus dichloride or n-butylphosphorus dichloride;

[0010] The catalyst includes one or more of Pd(TFA)2, Pd2(dba)3, PdCl2, and Pd(PPh)4;

[0011] The ligand includes one or more of 4,6-bis(diphenylphosphino)-10H-phenoxazine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, bis(dicyclohexylphosphinophenyl) ether, and 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-xanthene;

[0012] The base includes one or more of cesium carbonate, potassium carbonate, rubidium carbonate, and potassium phosphate;

[0013] The additive includes one or more of pivalic acid, glacial acetic acid, and trifluoroacetic acid.

[0014] Preferably, in the method for synthesizing adamantylphosphine compounds by carbon-phosphorus bond cross-coupling reaction, the molar ratio of the adamantylboronic acid to the phosphorus reagent is 3-5:1;

[0015] The molar ratio of the adamantylboronic acid, the catalyst, the ligand, the base, and the additive is 3-5:0.001-0.01:0.002-0.02:1-1.8:1.

[0016] Preferably, in the method for synthesizing adamantylphosphine compounds by carbon-phosphorus bond cross-coupling reaction, the mixed solvent includes a mixture of mesitylene, ethanol, and water;

[0017] The volume ratio of the mesitylene, the ethanol, and the water is 3-5:0.5-1:1.

[0018] Preferably, in the method for synthesizing adamantylphosphine compounds by carbon-phosphorus bond cross-coupling reaction, the molar amount of the adamantylboronic acid to the volume of the mixed solvent is 2.5-4 mol:1 L.

[0019] Preferably, in the method for synthesizing adamantylphosphine compounds by carbon-phosphorus bond cross-coupling reaction, the conditions of the carbon-phosphorus bond cross-coupling reaction include: carried out under an oil bath, the reaction temperature is 60-90 °C, and the reaction time is 8-12 h.

[0020] Preferably, in the method for synthesizing adamantylphosphine compounds by carbon-phosphorus bond cross-coupling reaction, the protective atmosphere includes helium, argon, or nitrogen.

[0021] Preferably, in the method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, after the carbon-phosphorus bond cross-coupling reaction, post-treatment is also carried out, including the following steps: the reaction solution after the carbon-phosphorus bond cross-coupling reaction is successively filtered and ethanol is removed; the reaction solution after ethanol removal is extracted, and the organic phase is collected; the organic phase is recrystallized to obtain adamantylphosphine compounds.

[0022] Preferably, in the method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, the extraction method is as follows: saturated brine is added to the reaction solution after ethanol removal, and extraction is carried out using ethyl acetate.

[0023] Preferably, in the method for synthesizing adamantylphosphine compounds through carbon-phosphorus bond cross-coupling reaction, the number of times of extraction using ethyl acetate is 1 to 5 times.

[0024] It can be seen from the above technical solutions that compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention uses palladium-catalyzed carbon-phosphorus bond cross-coupling reaction to react adamantylboronic acid with halogenated phosphorus reagents under mild conditions, and innovatively generates adamantylphosphine compounds efficiently in one step. Compared with the traditional synthesis route, the synthesis method of the present invention can obtain the target product in only one step, greatly improving the synthesis efficiency. Moreover, the synthesis method provided by the present invention can avoid using violent Grignard reagents or halogenated reactions under relatively mild conditions, effectively improving the selectivity and yield of the reaction, while reducing the reaction steps and the generation of by-products. Description of the Drawings

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for description in the embodiments or the prior art.

[0027] Figure 1 Schematic diagram of the traditional synthesis method of tris(1-adamantyl)phosphine;

[0028] Figure 2 Schematic diagram of the synthesis method of tris(1-adamantyl)phosphine in Example 1;

[0029] Figure 3 Schematic diagram of the synthesis method of phenyldi(1-adamantyl)phosphine in Example 2;

[0030] Figure 4 Schematic diagram of the synthesis method of n-butyldi(1-adamantyl)phosphine in Example 3. Detailed Embodiments

[0031] The present invention provides a method for synthesizing adamantylphosphine compounds through a carbon-phosphorus bond cross-coupling reaction, comprising the following steps:

[0032] Under a protective atmosphere, adamantylboronic acid, a phosphorus reagent, a catalyst, a ligand, a base, an additive and a mixed solvent are mixed to carry out a carbon-phosphorus bond cross-coupling reaction to obtain an adamantylphosphine compound.

[0033] In the present invention, the specific process of mixing adamantylboronic acid, a phosphorus reagent, a catalyst, a ligand, a base, an additive and a mixed solvent comprises: mixing adamantylboronic acid, a catalyst, a ligand, a base and an additive, adding the mixed solvent thereto for mixing, and finally adding the phosphorus reagent for mixing.

[0034] In the present invention, the phosphorus reagent preferably comprises a trihalophosphine or a dihalophosphine.

[0035] In the present invention, the trihalophosphine preferably comprises phosphorus trichloride.

[0036] In the present invention, the dihalophosphine preferably comprises phenyl dichlorophosphine or n-butyl dichlorophosphine.

[0037] In the present invention, the catalyst preferably comprises one or more of Pd(TFA)2, Pd2(dba)3, PdCl2, Pd(PPh)4, more preferably comprises Pd(TFA)2, Pd2(dba)3, PdCl2 or Pd(PPh)4, and still more preferably is Pd2(dba)3.

[0038] In the present invention, the ligand preferably comprises one or more of 4,6-bis(diphenylphosphino)-10H-phenoxazine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, bis(dicyclohexylphosphinophenyl) ether, 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-oxanthene, more preferably comprises 4,6-bis(diphenylphosphino)-10H-phenoxazine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, bis(dicyclohexylphosphinophenyl) ether or 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-oxanthene, and still more preferably is 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-oxanthene.

[0039] In the present invention, the base preferably comprises one or more of cesium carbonate, potassium carbonate, rubidium carbonate, potassium phosphate, more preferably comprises cesium carbonate, potassium carbonate, rubidium carbonate or potassium phosphate, and still more preferably is cesium carbonate. The base can enhance the coordination ability of the ligand with the catalyst and promote transmetalation.

[0040] In the present invention, the additive preferably includes one or more of pivalic acid, glacial acetic acid, and trifluoroacetic acid, more preferably includes pivalic acid, glacial acetic acid, or trifluoroacetic acid, and most preferably is pivalic acid. The additive can coordinate with the metal center of the catalyst, adjust the electronic state of the catalyst, and maintain the catalytic activity.

[0041] In the present invention, the mixed solvent preferably includes a mixture of mesitylene, ethanol, and water.

[0042] In the present invention, the volume ratio of mesitylene, ethanol, and water is preferably 3 - 5:0.5 - 1:1, more preferably 3 - 4:0.8 - 1:1, and most preferably 3:1:1.

[0043] In the present invention, the molar ratio of adamantylboronic acid to the phosphorus reagent is preferably 3 - 5:1, more preferably 3 - 4:1, and most preferably 3.5:1.

[0044] In the present invention, the molar ratio of adamantylboronic acid, the catalyst, the ligand, the base, and the additive is preferably 3 - 5:0.001 - 0.01:0.002 - 0.02:1 - 1.8:1, more preferably 3 - 4:0.002 - 0.006:0.005 - 0.015:1.1 - 1.5:1, and most preferably 3.5:0.005:0.01:1.2:1.

[0045] In the present invention, the molar amount of adamantylboronic acid to the volume of the mixed solvent is preferably 2.5 - 4 mol:1 L, more preferably 3 - 4 mol:1 L, and most preferably 3.5 mol:1 L.

[0046] In the present invention, the conditions for the carbon - phosphorus bond cross - coupling reaction preferably include: carried out under an oil bath; the reaction temperature is preferably 60 - 90 °C, more preferably 60 - 75 °C, and most preferably 60 °C; the reaction time is preferably 8 - 12 h, more preferably 10 - 12 h, and most preferably 12 h.

[0047] In the present invention, the protective atmosphere preferably includes helium, argon, or nitrogen, and more preferably is argon.

[0048] In the present invention, after the carbon - phosphorus bond cross - coupling reaction, post - treatment is also carried out, which preferably includes the following steps: the reaction solution after the carbon - phosphorus bond cross - coupling reaction is sequentially filtered to remove ethanol; the reaction solution after removing ethanol is extracted, and the organic phase is collected; the organic phase is recrystallized to obtain adamantylphosphine compounds.

[0049] In the present invention, the conditions for the filtration preferably include: filtering with diatomaceous earth.

[0050] In the present invention, the method for removing ethanol is preferably rotary evaporation.

[0051] In the present invention, the conditions for rotary evaporation are not limited, and the well-known methods in the art can be adopted. Specifically in the examples, the temperature for rotary evaporation is preferably 45°C.

[0052] In the present invention, the extraction method is preferably as follows: saturated brine is added to the reaction solution from which ethanol has been removed, and extraction is carried out using ethyl acetate.

[0053] In the present invention, the number of times of extraction using ethyl acetate is preferably 1 to 5 times, more preferably 2 to 4 times, and even more preferably 3 times.

[0054] In the present invention, the recrystallization method is preferably as follows: the organic phase is added to a mixed solvent of dichloromethane - n-hexane and allowed to stand.

[0055] In the present invention, the ratio in the mixed solvent of dichloromethane - n-hexane is not limited, and the well-known methods in the art can be adopted. Specifically in the examples, the volume ratio of dichloromethane to n-hexane is preferably 1:50.

[0056] In the present invention, the conditions for standing are not limited, and the well-known methods in the art can be adopted. Specifically in the examples, the temperature for standing is preferably 0°C, and the standing time ≥ 5 h.

[0057] The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0058] Example 1

[0059] This example provides a method for synthesizing tris(1-adamantyl)phosphine through a carbon-phosphorus bond cross-coupling reaction, as shown by Figure 2 including the following steps:

[0060] Under an argon atmosphere, 3.5 mol of adamantylboronic acid, 0.005 mol of Pd2(dba)3 (manufacturer: TCI, T2184), 0.01 mol of 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-xanthene (manufacturer: Bide, BD165236), 1.2 mol of cesium carbonate, and 1 mol of pivalic acid were added to a 2 L reaction kettle. Then, a mixed solvent of 600 mL of mesitylene, 200 mL of ethanol, and 200 mL of water was added. Finally, 1 mol of phosphorus trichloride reagent was added, and the reaction was carried out in an oil bath at 90 °C for 12 h. After the reaction was completed, filtration was carried out using diatomaceous earth. The ethanol in the reaction solution was distilled off at 45 °C. Saturated brine was added thereto, and then extraction was carried out 3 times with 300 mL of ethyl acetate each time. The organic phase was collected, and then the target product was collected by recrystallization. The recrystallization conditions were as follows: the volume ratio of dichloromethane to n-hexane was 1:50, and the mixture was allowed to stand at 0 °C for 6 h to obtain 366.8 g of tris(1-adamantyl)phosphine with a yield of 84%.

[0061] After testing, the 1H NMR spectrum of the tris(1-adamantyl)phosphine obtained in Example 1 was as follows: 1 H NMR(400MHz,CD2Cl2)δ2.13(br,18H),1.84(br,9H),1.74-1.58(m,18H);

[0062] The 13C NMR spectrum was as follows: 13 C NMR(101MHz,CD2Cl2):δ42.7(br),41.1(d,J=34.3Hz),37.0,29.5(d,J=7.2Hz).

[0063] Example 2

[0064] This example provides a method for synthesizing phenyldi(1-adamantyl)phosphine through a carbon-phosphorus bond cross-coupling reaction, which consists of Figure 3 As shown, the method includes the following steps:

[0065] Under an argon atmosphere, 3.5 mol of adamantylboronic acid, 0.005 mol of Pd2(dba)3 (manufacturer: TCI, T2184), 0.01 mol of 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-xanthene (manufacturer: Bide, BD165236), 1.2 mol of cesium carbonate and 1 mol of pivalic acid were added to a 2 L reaction kettle respectively. Then, a mixed solvent of 600 mL of mesitylene, 200 mL of ethanol and 200 mL of water was added. Finally, 1 mol of phenylphosphorus dichloride reagent was added, and the reaction was carried out in an oil bath at 60 °C for 12 h. After the reaction was completed, filtration was carried out using diatomaceous earth, the ethanol in the reaction solution was spun out at 45 °C, saturated brine was added thereto, and extraction was carried out 3 times with 300 mL of ethyl acetate each time. The organic phase was collected, and then the target product was collected by recrystallization. The recrystallization conditions were as follows: the volume ratio of dichloromethane to n-hexane was 1:50, and it was allowed to stand at 0 °C for 6 h to obtain 344.5 g of phenylbis(1-adamantyl)phosphine with a yield of 91%.

[0066] After testing, the 1H NMR spectrum of the phenylbis(1-adamantyl)phosphine obtained in Example 2 was as follows: 1 H NMR(400MHz,CDCl3)δ7.65-7.45(m,2H),7.30-7.20(m,3H),2.10-1.55(m,30H);

[0067] The 13C NMR spectrum was as follows: 13 C NMR(101MHz,CDCl3):δ134.5,130.9,128.8,127.3,42.4,36.6,34.8,28.9。

[0068] Example 3

[0069] This example provides a method for synthesizing n-butylbis(1-adamantyl)phosphine by a carbon-phosphorus bond cross-coupling reaction, as shown by Figure 4 and includes the following steps:

[0070] Under an argon atmosphere, 3.5 mol of adamantylboronic acid, 0.005 mol of Pd2(dba)3 (manufacturer: TCI, T2184), 0.01 mol of 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-xanthene (manufacturer: Bidepharm, BD165236), 1.2 mol of cesium carbonate and 1 mol of pivalic acid were added into a 2 L reaction kettle respectively. Then, a mixed solvent of 600 mL of mesitylene, 200 mL of ethanol and 200 mL of water was added. Finally, 1 mol of n-butyldichlorophosphorus reagent was added, and the reaction was carried out in an oil bath at 60 °C for 12 h. After the reaction was completed, filtration was carried out using diatomite, the ethanol in the reaction solution was spun out at 45 °C, saturated brine was added thereto, and then extraction was carried out 3 times with 300 mL of ethyl acetate each time. The organic phase was collected, and then the target product was collected by recrystallization. The recrystallization conditions were as follows: the volume ratio of dichloromethane to n-hexane was 1:50, and it was left standing at 0 °C for 6 h to obtain 315.5 g of n-butylbis(1-adamantyl)phosphine with a yield of 88%.

[0071] It was tested that the 1H NMR spectrum of the n-butylbis(1-adamantyl)phosphine obtained in Example 3 was as follows: 1 H NMR(400MHz,CDCl3):δ0.96(t,3H,J=7.3Hz),1.35-2.03(m,36H);

[0072] The 13C NMR spectrum was as follows: 13 C NMR(101MHz,CDCl3):δ41.3,37.4,36.1,33.9,29.1,24.9,17.1,14.3。

[0073] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction, characterized in that: The following steps are involved: Under a protective atmosphere, adamantane boronic acid, a phosphorus reagent, a catalyst, a ligand, a base, an additive and a mixed solvent are mixed to carry out a carbon-phosphine bond cross-coupling reaction to obtain an adamantane phosphine compound.

2. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1, characterized in that: The phosphorus reagent includes trihalogenated phosphorus or dihalogenated phosphorus; The trihalogenated phosphorus includes phosphorus trichloride; The dihalogenated phosphorus includes phenyl phosphorus dichloride or n-butyl phosphorus dichloride; The catalyst includes one or more of Pd(TFA)2, Pd2(dba)3, PdCl2, and Pd(PPh)4; The ligand includes one or more of 4,6-bis(diphenylphosphino)-10H-phenoxazine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis(dicyclohexylphosphinophenyl) ether, and 4,5-bis(dicyclohexylphosphino)-9,9-dimethyl-9H-xanthene; The base includes one or more of cesium carbonate, potassium carbonate, rubidium carbonate, and potassium phosphate; The additive includes one or more of pivalic acid, glacial acetic acid, and trifluoroacetic acid.

3. A method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1 or 2, characterized in that: The molar ratio of the adamantane boronic acid to the phosphorus reagent is 3 to 5:1; The molar ratio of the adamantane boronic acid, the catalyst, the ligand, the base and the additive is 3-5: 0.001-0.01: 0.002-0.02: 1-1.8:

1.

4. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1, characterized in that: The mixed solvent includes a mixture of mesitylene, ethanol and water; The volume ratio of the mesitylene, the ethanol and the water is 3-5:0.5-1:

1.

5. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1 or 4, characterized in that: The ratio of the molar amount of the adamantane boronic acid to the volume of the mixed solvent is 2.5-4 mol:1L.

6. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1, characterized in that: The conditions of the carbon-phosphine bond cross-coupling reaction include: conducting the reaction under an oil bath, the reaction temperature is 60 to 90° C., and the reaction time is 8 to 12 hours.

7. A method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1 or 6, characterized in that: The protective atmosphere includes helium, argon or nitrogen.

8. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 1, characterized in that: After the carbon-phosphine cross-coupling reaction is completed, post-treatment is performed, which includes the following steps: filtering the reaction solution after the carbon-phosphine cross-coupling reaction is completed and removing ethanol; extracting the reaction solution after removing ethanol and collecting the organic phase; and recrystallizing the organic phase to obtain adamantane phosphine compounds.

9. The method for synthesizing adamantane phosphine compounds by carbon-phosphine bond cross-coupling reaction according to claim 8, characterized in that: The extraction method is: adding saturated brine to the reaction solution from which ethanol has been removed, and extracting with ethyl acetate.

10. The method for synthesizing adamantane phosphine compounds through carbon-phosphine bond cross-coupling reaction according to claim 9, characterized in that: The extraction with ethyl acetate is performed 1 to 5 times.

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