CN115894556A - Synthesis method of beta-fluoroallylphosphine - Google Patents
Synthesis method of beta-fluoroallylphosphine Download PDFInfo
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Abstract
The application discloses a synthesis method of beta-fluoro allyl phosphine, belonging to the technical field of organic synthesis. The method takes difluorocyclopropane derivative and phosphite ester or diaryl phosphine oxide as raw materials, under the catalytic action of palladium and ligand, takes dioxane as solvent, and adds alkali to prepare the beta-fluoroallylphosphine derivative. The method has the advantages of low reaction cost, simple operation, less side reaction and the like. The method can construct the beta-fluoroallylphosphine compound in one step, is suitable for large-scale production, and has the yield of 89 percent.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of beta-fluoro allyl phosphine.
Background
The phosphine-containing compound is an important composition structure in many bioactive substances and is closely related to life activities. Fluoroolefins are important reaction blocks in organic synthesis and can also be used as monomers for preparing fluoropolymer materials. Therefore, the beta-fluoroallylphosphine coexisting with phosphine and fluorine has important scientific research and application values.
The types of synthesized phosphorus-containing organic compounds reported at present mainly comprise aryl phosphine, alkyl phosphine, alkynyl phosphine, alkenyl phosphine and the like, and no effective synthesis method is invented for synthesizing fluorine-containing allyl phosphine compounds.
In addition, the literature review shows that in the reported synthetic method for preparing the phosphorus-containing organic compound, toxic phosphorus halide is often used as a phosphine source or unstable metal organic matters are used as reaction components to participate in conversion, and the disadvantages of harsh reaction process conditions and environmental unfriendliness exist.
In view of the above, there is still no effective method for preparing fluorinated allylphosphine derivatives from a phosphine source which is safe, readily available and highly operable.
Disclosure of Invention
The technical problem to be solved is as follows:
aiming at the defects of the prior art, the method solves the technical problems of harsh reaction process conditions, environmental friendliness and the like at present, and provides a synthesis method of beta-fluoroallylphosphine, which has the advantages of safe and easily obtained required raw materials, low cost, mild reaction conditions, high yield and simple post-treatment.
The technical scheme is as follows:
in order to achieve the purpose, the application is realized by the following technical scheme:
a process for synthesizing beta-fluoroallylphosphine includes such steps as reaction between 1, 1-difluorocyclopropane derivative and phosphite ester or diarylphosphine oxide under the action of palladium catalyst, phosphine ligand, alkali and solvent.
Further, the synthesis method comprises the following specific steps:
the first step is as follows: adding a 1, 1-difluorocyclopropane derivative and phosphite ester or diaryl phosphine oxide derivative into a reaction tube, and sequentially adding a palladium catalyst, a phosphine ligand and alkali; the reaction vessel is vented and replaced with an inert gas, followed by addition of solvent, sealing,
stirring for 15 minutes at room temperature, and then heating to 90-120 ℃ for reaction, wherein the reaction time is 12-16 hours;
the second step is that: detecting the reaction progress by using thin-layer chromatography until the reaction raw materials disappear completely; cooling the reaction system, extracting, washing twice with ethyl acetate as an extractant, collecting an organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then carrying out column chromatography separation to obtain the beta-fluoroallylphosphine derivative.
Further, the reaction formula of the method is as follows:
in the formula, R 1 ,R 2 And R 3 Including but not limited to aryl, heteroaryl, and alkyl.
Further, the 1, 1-difluorocyclopropane derivative is 2- (2, 2-difluorocyclopropyl) naphthalene, 4- (2, 2-difluorocyclopropyl) -N, N-dimethylaniline, 1- (2, 2-difluorocyclopropyl) -2-methoxybenzene, (1r, 2s, 5r) -2-isopropyl-5-methylcyclohexyl-4- (2, 2-difluorocyclopropyl) benzoate, or 8r,9s,13s, 14s) -3- (2, 2-difluorocyclopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one; the phosphite ester is diisopropyl phosphite or ethyl phenylphosphonate; the diarylphosphine oxide is bis (p-methoxyphenyl) phosphine oxide.
Further, the palladium catalyst is palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, ditriphenylphosphine palladium dichloride, allyl palladium chloride or tetrariphenylphosphine palladium.
Further, the phosphine ligand is a triphenylphosphine ligand derivative, a trialkyl phosphine ligand derivative, a bidentate phosphine ligand, a Buchwald ligand or a carbene ligand.
Further, the base is cesium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate, or lithium tert-butoxide.
Further, the solvent is dioxane, acetonitrile, toluene, ethylene glycol dimethyl ether, tetrahydrofuran or 1, 2-dichloroethane.
Further, the reaction in the first step is a stirring reaction of 500-700 revolutions per minute by a magnetic stirrer for 12-16 hours; mobile phase eluent adopted by column chromatography in the second step: the volume ratio of the petroleum ether to the ethyl acetate is 2:1 to 1:2.
further, the molar ratio of the palladium catalyst to the ligand is 1; the molar ratio of the palladium catalyst to the 1, 1-difluorocyclopropane derivative is 1; the molar ratio of the base to the 1, 1-difluorocyclopropane derivative is 3; the concentration of the 1, 1-difluorocyclopropane derivative in the mixed solution of the solvent is 0.1mol/L.
The principle of the synthesis method of the beta-fluoroallylphosphine is as follows: under the action of a palladium catalyst, the difluorocyclopropane derivative is subjected to ring opening and elimination reaction to generate a beta-fluoroallyl palladium intermediate, and then under the action of alkali, a phosphine atom in a phosphite ester or diaryl phosphine oxide derivative is used as a nucleophilic center to perform nucleophilic attack on the beta-fluoroallyl palladium intermediate, so that the beta-fluoroallyl phosphine compound is finally generated.
Has the advantages that:
compared with the prior art, the synthesis method of beta-fluoroallylphosphine has the following beneficial effects:
1. the synthesis method of the beta-fluoroallylphosphine provided by the invention has the advantages of low cost, simple operation steps, easy obtainment of raw materials, no need of further treatment of a solvent, high reaction efficiency and high yield of 89%, and the product can be applied to the synthesis of medicaments.
2. The method can realize the active drug molecules containing the beta-fluoroallyl phosphine with high yield in one step, and overcomes the defects of multiple steps and low yield in the conventional synthesis of the molecules.
3. The Z/E selectivity ratio of the beta-fluoroallylphosphine produced by the invention is greater than 30:1; this excellent selectivity is difficult to achieve with the current prior art processes.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A method for synthesizing beta-fluoro allyl phosphine is shown as the following formula:
in the formula, R 1 ,R 2 And R 3 Including but not limited to aryl and alkyl.
The method comprises the following specific steps:
(1) Adding a 1, 1-difluorocyclopropane derivative and phosphite ester or diaryl phosphine oxide derivative into a reaction tube, and sequentially adding a palladium catalyst, a phosphine ligand and alkali; and (3) exhausting the air in the reaction container, replacing the air with inert gas (such as argon, nitrogen and the like), then adding a solvent, sealing, stirring for 10 minutes at room temperature, and then heating to 90-120 ℃ for reaction, wherein the reaction time is 12-16 hours.
(2) And detecting the reaction progress by using thin-layer chromatography until the reaction raw materials disappear completely. Cooling the reaction system, extracting, washing twice with ethyl acetate as an extracting agent, collecting an organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then carrying out column chromatography separation to obtain the beta-fluoroallylphosphine derivative.
The palladium catalyst is one of palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, palladium ditriphenylphosphine dichloride, allyl palladium chloride or tetrakistriphenylphosphine palladium.
The phosphine ligand is one of triphenylphosphine ligand derivatives, bidentate phosphine ligands, buchwald ligands or carbene ligands.
The alkali is one of cesium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate or lithium tert-butoxide.
The solvent is one of dioxane, acetonitrile, toluene, glycol dimethyl ether, tetrahydrofuran or 1, 2-dichloroethane.
The molar ratio of the palladium catalyst to the ligand is 1; the molar ratio of the palladium catalyst to the 1, 1-difluorocyclopropane derivative is 1; the molar ratio of base to 1, 1-difluorocyclopropane derivative is 3; the concentration of the 1, 1-difluorocyclopropane derivative in the mixed solution of the solvent is 0.1mol/L.
Mobile phase eluent for column chromatography: the volume ratio of the petroleum ether to the ethyl acetate is 2:1 to 1:2.
example 1:
synthesis method of beta-fluoro allyl phosphine, and synthesis of (Z) - (2-fluoro-3- (naphthalene-2-yl) allyl) diisopropyl phosphonate
2- (2, 2-Difluorocyclopropyl) naphthalene (81.6mg, 0.4mmol), diisopropyl phosphite (76.4mg, 0.46mmol), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) were sequentially added to a 25mL pressure-resistant reaction tube, and argon gas was introduced by vacuum evacuation. Then 4 ml of 1, 4-dioxane was added, sealed and stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110 ℃ and stirred for 12 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying, and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (102 mg, 74% yield).
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.71(t,J＝7.5Hz,3H),7.56(d,J＝8.6Hz,1H),7.40–7.33(m,2H),5.73(dd,J＝38.4,4.5Hz,1H),4.70(h,J＝6.4Hz,2H),2.85(dd,J＝21.5,19.1Hz,2H),1.26(dd,J＝6.3,2.7Hz,12H). 13 C NMR(101MHz,CDCl 3 )δ133.46,132.51,130.81,128.13,128.05,127.61,127.55,127.50,127.48,126.55,126.54,126.48,126.23,126.06,109.89,109.81,109.78,109.70,71.41,71.35,34.01,33.72,32.59,32.30,24.18,24.14,24.04,23.99. 19 F NMR(376MHz,CDCl 3 )δ-95.87(d,J＝5.2Hz). 31 P NMR(162MHz,CDCl 3 )δ20.38(d,J＝5.2Hz).HRMS(ESI)m/z:[M+H] + calcd for C 19 H 25 FO 3 P 351.1520；found:351.1533.
Example 2:
synthesis method of beta-fluoroallylphosphine and synthesis of (Z) - (3- (4- (dimethylamino) phenyl) -2-fluoroallyl) diisopropyl phosphonate
To a 25mL pressure-resistant reaction tube were added 4- (2, 2-difluorocyclopropyl) -N, N-dimethylaniline (78.8mg, 0.4mmol), diisopropyl phosphite (76.4mg, 0.46mmol), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) in this order, and the mixture was evacuated and purged with argon. 4 ml of 1, 4-dioxane was then added, sealed and stirred at room temperature for 15 minutes, after which it was placed in a magnetic stirrer at 110 ℃ and stirred for 14 hours. After the reaction is completed, adding 1mL of water for quenching, extracting by ethyl acetate for 3 times, combining organic phases, and adding anhydrous Na 2 SO 4 Drying, spin-drying, and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (118 mg, 86% yield).
1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝8.6Hz,2H),6.60(d,J＝8.7Hz,2H),5.47(dd,J＝39.4,4.6Hz,1H),4.79–4.56(m,2H),2.88(s,6H),2.78(dd,J＝21.3,19.1Hz,2H),1.26(dd,J＝6.2,4.2Hz,12H). 13 C NMR(101MHz,CDCl 3 )δ149.59,129.59,129.57,129.52,129.50,121.76,112.29,109.65,109.57,109.54,109.46,71.25,71.19,40.53,33.84,33.55,32.42,32.13,24.23,24.19,24.07,24.02. 19 F NMR(376MHz,CDCl 3 )δ-101.34(d,J＝6.1Hz). 31 P NMR(162MHz,CDCl 3 )δ21.03(d,J＝5.7Hz).HRMS(ESI)m/z:[M+H] + calcd for C 17 H 28 FO 3 PN 344.1785；found:344.1779.
Example 3:
synthesis method of beta-fluoro allyl phosphine, and synthesis of (Z) - (2-fluoro-3- (2-methoxyphenyl) allyl) diisopropyl phosphonate
To a 25mL pressure-resistant reaction tube were added 1- (2, 2-difluorocyclopropyl) -2-methoxybenzene (73.6 mg,0.4 mmol) and diisopropyl phosphite (76.4 mg, 0.46mmo) in this orderl), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol), and argon was introduced by evacuation. 4 ml of 1, 4-dioxane was then added, sealed and stirred at room temperature for 15 minutes, after which it was placed in a magnetic stirrer at 110 ℃ and stirred for 14 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (94 mg, 71% yield).
1 H NMR(400MHz,CDCl 3 )δ7.67(dd,J＝7.8,1.6Hz,1H),7.14(td,J＝7.9,1.7Hz,1H),6.86(t,J＝7.6Hz,1H),6.78(d,J＝8.3Hz,1H),6.01(dd,J＝39.4,4.6Hz,1H),4.69(dp,J＝7.8,6.2Hz,2H),3.74(s,3H),2.83(dd,J＝21.4,19.1Hz,2H),1.27(dd,J＝6.2,2.2Hz,12H). 13 C NMR(101MHz,CDCl 3 )δ156.02,129.94,129.92,129.81,129.79,128.43,128.41,120.65,110.46,103.34,103.27,103.23,103.16,71.32,71.25,55.54,34.13,33.84,32.71,32.42,24.19,24.15,24.01,23.96. 19 F NMR(376MHz,CDCl 3 )δ-98.46(d,J＝5.9Hz). 31 P NMR(162MHz,CDCl 3 )δ20.58(d,J＝5.9Hz).HRMS(ESI)m/z:[M+H] + calcd for C 16 H 25 FO 4 P 331.1469；found:331.1458.
Example 4
Synthesis method of beta-fluoroallylphosphine and synthesis of diisopropyl (Z) - (3- (3-chlorophenyl) -2-fluoroallyl) phosphonate
To a 25mL pressure-resistant reaction tube were added 1- (2, 2-difluorocyclopropyl) -2-methoxybenzene (75.2mg, 0.4mmol), diisopropyl phosphite (76.4mg, 0.46mmol), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) in this order, and the mixture was evacuated and purged with argon. Then 4 ml of 1, 4-dioxane are addedAfter stirring for 15 minutes at room temperature, the mixture was stirred for 14 hours in a magnetic stirrer at 110 ℃. After the reaction is completed, adding 1mL of water for quenching, extracting by ethyl acetate for 3 times, combining organic phases, and adding anhydrous Na 2 SO 4 Drying, spin-drying, and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (92 mg, 69% yield).
1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝2.0Hz,1H),7.35–7.31(m,1H),7.22(dd,J＝14.5,7.8Hz,2H),5.63(dd,J＝37.6,4.5Hz,1H),4.76(ddt,J＝12.2,7.5,6.1Hz,2H),2.88(dd,J＝21.6,19.2Hz,2H),1.34(dd,J＝6.2,4.4Hz,12H). 13 C NMR(101MHz,CDCl 3 )δ134.87,134.31,129.68,128.36,128.34,128.28,128.26,127.28,127.26,126.62,126.60,126.55,108.59,108.51,108.48,108.41,71.42,71.35,33.82,33.53,32.40,32.12,24.11,24.07,23.98,23.93. 19 F NMR(376MHz,CDCl 3 )δ-94.05(d,J＝4.6Hz). 31 P NMR(162MHz,CDCl 3 )δ19.96(d,J＝4.4Hz).HRMS(ESI)m/z:[M+H] + calcd for C 15 H 22 FClO 3 P 355.0974；found:355.0977.
Example 5
Synthesis method of beta-fluoroallylphosphine and synthesis of (Z) - (2-fluoro-3- (naphthalene-2-yl) allyl) diethyl phosphonate
2- (2, 2-Difluorocyclopropyl) naphthalene (81.6mg, 0.4mmol), diethyl phosphite (63.5mg, 0.46mmol), allylpalladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) were sequentially added to a 25mL pressure-resistant reaction tube, and argon gas was introduced by evacuation. Then 4 ml of 1, 4-dioxane was added, sealed and stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110 ℃ and stirred for 12 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying, and passing through columnChromatographic separation (petroleum ether/ethyl acetate = 1) purification afforded the product as a colorless liquid (115 mg, 89% yield).
1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.71(dd,J＝7.2,3.6Hz,3H),7.56(dd,J＝8.6,1.7Hz,1H),7.37(td,J＝5.9,5.3,3.2Hz,2H),5.75(dd,J＝38.3,4.5Hz,1H),4.21–4.02(m,4H),2.89(dd,J＝21.5,19.4Hz,2H),1.27(t,J＝7.0Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ133.47,132.59,130.68,128.15,128.08,127.71,127.68,127.63,126.56,126.54,126.48,126.47,126.28,126.13,110.07,110.00,109.96,109.89,62.73,62.66,32.99,32.70,31.59,31.29,16.55,16.49. 19 F NMR(376MHz,CDCl 3 )δ-96.58(d,J＝6.0Hz). 31 P NMR(162MHz,CDCl 3 )δ22.35(d,J＝5.9Hz).HRMS(ESI)m/z:[M+H] + calcd for C 17 H 21 FO 3 P 323.1207；found:323.1216.
Example 6:
synthesis method of beta-fluoro allyl phosphine, and synthesis of (Z) - (2-fluoro-3- (naphthalene-2-yl) allyl) (phenyl) ethyl phosphonate
2- (2, 2-Difluorocyclopropyl) naphthalene (81.6mg, 0.4mmol), ethyl phenylphosphonate (78.2mg, 0.46mmol), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) were sequentially added to a 25mL pressure-resistant reaction tube, and argon gas was introduced by vacuum evacuation. Then 4 ml of 1, 4-dioxane was added, sealed and stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110 ℃ and stirred for 12 hours. After the reaction is completed, adding 1mL of water for quenching, extracting by ethyl acetate for 3 times, combining organic phases, and adding anhydrous Na 2 SO 4 Drying, spin-drying and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (93 mg, 66% yield).
1 H NMR(400MHz,CDCl 3 )δ7.89–7.73(m,6H),7.58–7.41(m,6H),5.66(dd,J＝38.4,4.3Hz,1H),4.20(dt,J＝10.1,7.2Hz,1H),4.03(dt,J＝10.1,7.3Hz,1H),3.23–3.00(m,2H),1.36(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ133.44,132.83,132.80,132.55,132.53,132.03,131.94,130.70,130.55,129.26,128.80,128.68,128.13,128.01,127.62,127.60,127.55,127.52,126.53,126.47,126.45,126.25,126.10,110.43,110.36,110.34,110.26,61.60,61.53,37.06,36.78,36.10,35.82,16.64,16.58. 19 F NMR(376MHz,CDCl 3 )δ-95.50(d,J＝8.0Hz). 31 P NMR(162MHz,CDCl 3 )δ36.50(d,J＝7.8Hz).HRMS(ESI)m/z:[M+H] + calcd for C 21 H 21 FO 2 P 355.1258；found:355.1258.
Example 7:
synthesis method of beta-fluoro allyl phosphine, and synthesis of (Z) - (2-fluoro-3- (naphthalene-2-yl) allyl) bis (4-methoxyphenyl) phosphine oxide
2- (2, 2-Difluorocyclopropyl) naphthalene (81.6 mg,0.4 mmol), bis (p-methoxyphenyl) phosphine oxide (120.5 mg, 0.46mmol), allylpalladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) were sequentially added to a 25mL pressure-resistant reaction tube, and argon gas was introduced by vacuum-pumping. 4 ml of 1, 4-dioxane was then added, sealed and stirred at room temperature for 15 minutes, after which it was placed in a magnetic stirrer at 110 ℃ and stirred for 12 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying, and finally purification by column chromatography (petroleum ether/ethyl acetate =2: 1-1) gave the product as a colorless liquid (139 mg, 78% yield).
1 H NMR(400MHz,CDCl 3 )δ7.80–7.68(m,8H),7.51(dd,J＝8.6,1.7Hz,1H),7.47–7.39(m,2H),6.98(dd,J＝8.8,2.4Hz,4H),5.76(dd,J＝39.0,3.7Hz,1H),3.82(s,6H),3.41(dd,J＝18.9,14.3Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ162.66,162.63,133.37,133.15,133.05,132.47,132.45,128.12,127.91,127.67,127.65,127.58,126.62,126.55,126.20,126.05,123.68,122.61,114.34,114.21,110.88,110.80,110.72,55.45,37.27,36.88,36.61. 19 F NMR(376MHz,CDCl 3 )δ-93.62(d,J＝6.1Hz). 31 P NMR(162MHz,CDCl 3 )δ27.70(d,J＝5.9Hz).HRMS(ESI)m/z:[M+H] + calcd for C 27 H 25 FO 3 P447.1520；found:447.1526.
Example 8
Synthesis method of beta-fluoroallylphosphine, (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-4- ((Z) -3- (diisopropoxyphosphoryl) -2-fluoroprop-1-en-1-yl) benzoate
To a 25mL pressure-resistant reaction tube were added (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-4- (2, 2-difluorocyclopropyl) benzoate (134.4mg, 0.4mmol), diisopropyl phosphite (76.4mg, 0.46mmol), allylpalladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol) in this order, and argon gas was introduced under vacuum. Then 4 ml of 1, 4-dioxane was added, sealed and stirred at room temperature for 15 minutes, and then placed in a magnetic stirrer at 110 ℃ to stir for 16 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying, and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (170 mg, 88% yield).
1 H NMR(400MHz,CDCl 3 )δ8.00(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),5.74(dd,J＝37.8,4.4Hz,1H),4.92(td,J＝10.9,4.4Hz,1H),4.77(dp,J＝7.8,6.2Hz,2H),2.91(dd,J＝21.7,19.2Hz,2H),2.16–2.10(m,1H),1.96(td,J＝7.0,2.7Hz,1H),1.73(dq,J＝15.4,3.4Hz,2H),1.62–1.48(m,2H),1.34(t,J＝5.7Hz,12H),1.20–1.03(m,2H),0.92(dd,J＝6.8,4.7Hz,6H),0.79(d,J＝6.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ165.80,137.51,129.74,129.23,128.28,128.26,128.20,128.18,109.12,109.04,109.01,108.94,74.77,71.42,71.35,47.24,40.95,34.30,33.94,33.66,32.52,32.24,31.44,26.46,24.09,24.05,23.94,23.89,23.59,22.08,20.79,16.51. 19 F NMR(376MHz,CDCl 3 )δ-92.59(d,J＝5.2Hz). 31 P NMR(162MHz,CDCl 3 )δ19.86(d,J＝4.8Hz).HRMS(ESI)m/z:[M+H] + calcd for C 26 H 41 FO 5 P483.2670；found:483.2679.
Example 9
Synthesis method of beta-fluoroallylphosphine, and synthesis method of (Z) -2-fluoro-3- ((8R, 9S,13S, 14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ alpha ] phenanthrene-3-yl) allyl) diisopropyl phosphonate
To a 25mL pressure-resistant reaction tube were added sequentially 8R,9S,13S, 14S) -3- (2, 2-difluorocyclopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopentane [ a]Phenanthrene-17-one (132.0mg, 0.4mmol), diisopropyl phosphite (76.4mg, 0.46mmol), allyl palladium chloride (21.8mg, 0.06mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (46.3mg, 0.08mmol), and potassium phosphate (168.8mg, 0.8mmol), and argon gas was introduced under vacuum. 4 ml of 1, 4-dioxane was then added, sealed and stirred at room temperature for 15 minutes, after which it was placed in a magnetic stirrer at 110 ℃ and stirred for 14 hours. After the reaction is completed, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases and anhydrous Na 2 SO 4 Drying, spin-drying, and final purification by column chromatography (petroleum ether/ethyl acetate = 1) gave the product as a colorless liquid (160 mg, 84% yield).
1 H NMR(400MHz,CDCl 3 )δ7.28–7.18(m,3H),5.61(dd,J＝38.6,4.5Hz,1H),4.76(dp,J＝7.9,6.1Hz,2H),2.93–2.81(m,4H),2.51(dd,J＝18.8,8.7Hz,1H),2.45–2.39(m,1H),2.29(td,J＝10.9,4.2Hz,1H),2.21–1.94(m,5H),1.63–1.48(m,5H),1.34(dd,J＝6.2,3.4Hz,12H),0.91(s,3H). 13 C NMR(101MHz,CDCl 3 )δ138.91,136.52,130.79,129.08,129.01,126.02,125.95,125.48,109.39,109.31,109.21,71.25,71.18,50.48,48.01,44.44,38.11,35.90,33.80,33.51,32.38,32.10,31.59,29.42,26.51,25.66,24.14,24.11,24.02,23.97,21.61,13.87. 19 F NMR(376MHz,CDCl 3 )δ-96.96(d,J＝5.3Hz). 31 P NMR(162MHz,CDCl 3 )δ20.47(d,J＝5.3Hz).HRMS(ESI)m/z:[M+H] + calcd for C 27 H 39 FO 4 P 477.2565；found:477.2568.
The above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention in any way, and any person skilled in the art can make any simple modification, equivalent replacement, and improvement on the above embodiment without departing from the technical spirit of the present invention, and still fall within the protection scope of the technical solution of the present invention.
Claims (10)
1. A method for synthesizing beta-fluoro allyl phosphine, which is characterized by comprising the following steps: 1, 1-difluorocyclopropane derivative and phosphite ester or diaryl phosphine oxide are used as reactants and react under the mixed action of palladium catalyst, phosphine ligand, alkali and solvent to obtain the beta-fluoroallylphosphine derivative.
2. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the synthesis method comprises the following specific steps:
the first step is as follows: adding a 1, 1-difluorocyclopropane derivative and phosphite ester or diaryl phosphine oxide derivative into a reaction tube, and sequentially adding a palladium catalyst, a phosphine ligand and alkali; discharging the air in the reaction container, replacing the air with inert gas, adding a solvent, sealing, stirring at room temperature for 15 minutes, heating to 90-120 ℃ for reaction, wherein the reaction time is 12-16 hours;
the second step is that: detecting the reaction progress by using thin-layer chromatography until the reaction raw materials disappear completely; cooling the reaction system, adding 1mL of water for quenching, extracting for 3 times by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, spin-drying, and then separating by column chromatography to obtain the beta-fluoroallylphosphine derivative.
3. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the reaction formula of the synthesis method is as follows:
in the formula, R 1 ,R 2 And R 3 Including but not limited to aryl, heteroaryl, and alkyl.
4. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the 1, 1-difluorocyclopropane derivative is 2- (2, 2-difluorocyclopropyl) naphthalene, 4- (2, 2-difluorocyclopropyl) -N, N-dimethylaniline, 1- (2, 2-difluorocyclopropyl) -2-methoxybenzene, (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl-4- (2, 2-difluorocyclopropyl) benzoate, or 8R,9S,13S, 14S) -3- (2, 2-difluorocyclopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one; the phosphite ester is diisopropyl phosphite or ethyl phenylphosphonate; the diarylphosphine oxide is bis (p-methoxyphenyl) phosphine oxide.
5. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the palladium catalyst is palladium acetate, palladium chloride, diacetonitrile palladium dichloride, palladium trifluoroacetate, palladium ditriphenylphosphine dichloride, allyl palladium chloride or palladium tetrakistriphenylphosphine.
6. The method for synthesizing beta-fluoroallylphosphine according to claim 1, wherein the phosphine ligand is a triphenylphosphine ligand derivative, a trialkylphosphine ligand derivative, a bidentate phosphine ligand, a Buchwald ligand or a carbene ligand.
7. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the alkali is cesium carbonate, potassium tert-butoxide, potassium phosphate, sodium phosphate or lithium tert-butoxide.
8. The method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the solvent is dioxane, acetonitrile, toluene, ethylene glycol dimethyl ether, tetrahydrofuran or 1, 2-dichloroethane.
9. The method of synthesizing β -fluoroallylphosphine of claim 2, wherein: the reaction in the first step is a stirring reaction of 500-700 r/min by a magnetic stirrer for 12-16 hours; mobile phase eluent adopted by column chromatography in the second step: the volume ratio of the petroleum ether to the ethyl acetate is 2:1 to 1:2.
10. the method of synthesizing β -fluoroallylphosphine of claim 1, wherein: the molar ratio of the palladium catalyst to the phosphine ligand is 1; the molar ratio of the palladium catalyst to the 1, 1-difluorocyclopropane derivative is 1; the molar ratio of the base to the 1, 1-difluorocyclopropane derivative is 3; the concentration of the 1, 1-difluorocyclopropane derivative in the mixed solution of the solvent is 0.1mol/L; the molar ratio of 1, 1-difluorocyclopropane derivative to phosphite or diarylphosphine oxide is 1.
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