A method for synthesizing allyl monofluoride compounds

Abstract

The present invention belongs to the technical field of organic synthesis, and relates to a method for synthesizing an allyl monofluoro compound. The method comprises the following steps: an allyl gem-difluoromethyl compound, an aryl boronic acid, a catalyst Pd(PPh3)4 and an alkaline substance undergo a Suzuki coupling reaction in an organic solvent under a nitrogen environment to generate the allyl monofluoro compound. The present invention uses an allyl gem-difluoromethyl compound and an aryl boronic acid reagent to convert them into an allyl monofluoro compound under the action of tetrakis(triphenylphosphine)palladium and lithium hydroxide; the operation is simple and safe; the method of the present invention can use a weaker nucleophilic reagent boric acid to carry out a Suzuki coupling reaction to defluorinate the allyl gem-difluoromethyl compound to form an allyl monofluoro compound. The main advantages are a wide range of applications and good regioselectivity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for synthesizing an allyl monofluoride compound. Background Art

[0002] In 1995, Guo-qiang Shi's group (GQ Shi*, XH Huang, FJ, Zhang;

[0003] Tetrahedron Lett., 1995, 6305.) used zero-valent palladium as a catalyst and tetrahydrofuran as a solvent, and used carbon nucleophiles to attack l,l-difluoroπ-allylpalladium complexes to construct monofluoroolefin compounds. However, this method used organic tin reagents as nucleophiles, which was relatively dangerous. Later, in 2007, the Fujii group (T. Narumi, K. Tomita, E. Inokuchi, K. Kobayashi, S. Oishi, H. Ohno, N. Fujii, Org. Lett. 2007, 9, 3465.) proposed that in the presence of an appropriate fluorine activating agent, the allyl geminal difluoride reacted with a homogeneous palladium catalyst to promote the breaking of the carbon-fluorine bond, thereby generating a fluorine-containing π-allylpalladium intermediate. By reacting with an appropriate nucleophile for chemical selection, the intermediate is expected to be converted into (Z)-monofluoroolefins. Thus, a palladium-catalyzed defluorination method for synthesizing monofluoroolefins from allyl difluoride compounds was proposed.

[0004] Jean- In 2011, the Paquin group (Bergeron, M., Johnson, T. and Paquin, J.-F.; Angew. Chem. Int. Ed., 2011, 50, 11112.) proposed the SN2' substitution of the CF bond, using 3,3-difluoropropylene to react with an organic lithium reagent to directly obtain a monofluoroallyl product. However, the reaction used an organic lithium as a nucleophile, and the reaction conditions were relatively complex and harsh. In 2017, Jean- The Paquin team (M Drouin, S Tremblaya and JF Paquin, Org. Biomol. Chem., 2017, 15, 2376.) used dimethyl malonic acid and its derivatives as nucleophiles and palladium-catalyzed 3,3-difluoropropylene to synthesize monofluoroallyl compounds, and reported a method for synthesizing monofluoroallyl compounds containing malonic acid or its derivatives at the β-position. Summary of the invention

[0005] Since the carbon-fluorine bond (CF) has a higher dissociation energy, its conversion is considered to be much more difficult than the conversion of other carbon-halogen bonds (CI, C-Br, and C-Cl). Fluoroolefins show unique reactivity during the activation of CF bonds, including the cleavage of CF bonds and the formation of new bonds, such as CC bonds, CO bonds, and CN bonds. In the reactions of carbon-fluorine bond activation, most of them use very strong nucleophiles to attack and obtain the corresponding defluorinated products. So far, no one has reported on the research of using aryl boronic acid as a coupling agent for the activation of carbon-fluorine bonds (CF). The present invention uses Pd(PPh3)4 as a catalyst and aryl boronic acid as a nucleophile, and no external ligand is required to carry out the activation reaction of the carbon-fluorine bond (CF) of allyl geminal difluoromethyl compounds to synthesize allylic monofluoroarylation products.

[0006] In order to achieve the purpose of the present invention, the technical solution adopted is:

[0007] A method for synthesizing an allyl monofluoro compound comprises the following steps: a geminal difluoromethyl compound as shown in general formula (1), an aromatic boronic acid as shown in general formula (2), a catalyst Pd(PPh3)4 and an alkaline substance undergo a Suzuki coupling reaction in a 1,4-dioxane solvent under a nitrogen environment to generate the allyl monofluoro compound as shown in general formula (3);

[0008]

[0009] In the general formula (1) and the general formula (2), Ar and Ar' are independently selected from substituted or unsubstituted phenyl and heteroaryl groups, wherein the substituent is an alkyl group, a halogen group, an alkoxy group or an aldehyde group.

[0010] Furthermore, the reaction temperature is 60-70° C., and the reaction time is at least 24 hours.

[0011] Furthermore, the molar ratio of the allyl geminal difluoromethyl compound to the arylboronic acid is 1:2;

[0012] The molar ratio of the allyl gem-difluoromethyl compound reagent to lithium hydroxide is 1:1.2-1.5;

[0013] The molar ratio of the allyl gem-difluoromethyl compound reagent to the catalyst is 1:0.01-0.05.

[0014] Furthermore, the method further comprises a purification step: adding an organic solvent and an aqueous solution to the system after the reaction is completed for extraction, drying and concentrating the organic phase, and then purifying (column chromatography).

[0015] Preferably, the material adding method comprises: firstly adding lithium hydroxide, the allyl geminal difluoromethyl compound of the general formula (1) and the aromatic boronic acid of the general formula (2) into the reactor; and then adding the Pd(PPh3)4 catalyst and the 1,4-dioxane solvent under anaerobic conditions.

[0016] Preferably, the organic solvent for extraction is ethyl acetate.

[0017] Preferably, the reaction is assisted with vigorous stirring.

[0018] Preferably, water is added to quench the reaction after the reaction is completed.

[0019] Furthermore, the organic solvent in the reaction system is selected from one or a combination of two or more of alkane, cycloalkane, aromatic hydrocarbon, ether, and cyclic ether solvents;

[0020] Preferably, the organic solvent is selected from any one or more of 1,4-dioxane, tetrahydrofuran (THF), and N,N-dimethylaniline (DMA);

[0021] The compound of general formula (3) is preferably the following specific compound of general formula (3) (Ar = 4-PhC6H4):

[0022]

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] (1) The present invention uses allyl geminal difluoromethyl compounds and aryl boronic acid reagents to convert into allyl monofluoro compounds under the action of tetrakis(triphenylphosphine)palladium and lithium hydroxide; the operation is simple and safe;

[0025] (2) The method of the present invention can use a weaker nucleophilic reagent, boric acid, to carry out a Suzuki coupling reaction to defluorinate allyl geminal difluoromethyl compounds to form allyl monofluoro compounds. The main advantages are a wide range of applications and good regioselectivity. DETAILED DESCRIPTION

[0026] The specific implementation modes of the present invention are further described in detail below in conjunction with the embodiments.

[0027] Example 1

[0028]

[0029] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2l 24 mg (0.2 mmol), a base, and then add 6 mg (5 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 100 ° C for 24 h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3l.

[0030] When potassium carbonate was used as the base, the reaction yield was 59%;

[0031] When potassium phosphate was used as the base, the reaction yield was 41%;

[0032] When sodium methoxide was used as the base, the reaction yield was 28%;

[0033] When potassium dihydrogen phosphate was used as the base, the reaction yield was 22%;

[0034] When lithium tert-butoxide was used as the base, the reaction yield was 43%;

[0035] When lithium hydroxide was used as the base, the reaction yield was 82%.

[0036] The target product 3l obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.60(d,J=2.2Hz,6H),7.45(dd,J=8.5,6.8Hz,2H),7.39–7.27( m,5H),7.27–7.20(m,1H),5.64(dt,J=36.3,7.7Hz,1H),3.67(dd,J=7.7,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.96 (d, J=35.7Hz). 13 C NMR (101MHz, CDCl3) δ158.09,155.64,141.48,140.45,140.29,131.58,128.96,128.69,128.57,12 7.70,127.35–126.86(m),126.35,124.56(d,J=7.0Hz),105.13(d,J=17.1Hz),30.59(d,J=5.7Hz).

[0037] Example 2

[0038]

[0039] In a 4 mL vial, 1a 23 mg (0.1 mmol), 2l 24 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol) were added, and then 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml solvent were added in a glove box. The reaction mixture was stirred at 60°C for 24 h. Water was then added to quench the reaction. Ethyl acetate and water were added for extraction, and the organic phase was dried and concentrated to obtain the target compound 3l.

[0040] When tetrahydrofuran (THF) was used as solvent, the reaction yield was 80%;

[0041] When N,N-dimethylaniline (DMA) was used as the solvent, the reaction yield was 80%;

[0042] When 1,4-dioxane was used as the solvent, the reaction yield was 84%.

[0043] When toluene was used as solvent, the reaction yield was 39%.

[0044] When 1,2-dichloroethane (DCE) was used as the solvent, the reaction yield was 38%.

[0045] The target product 3l obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.60(d,J=2.2Hz,6H),7.45(dd,J=8.5,6.8Hz,2H),7.39–7.27( m,5H),7.27–7.20(m,1H),5.64(dt,J=36.3,7.7Hz,1H),3.67(dd,J=7.7,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.96 (d, J=35.7Hz). 13 C NMR (101MHz, CDCl3) δ158.09,155.64,141.48,140.45,140.29,131.58,128.96,128.69,128.57,12 7.70,127.35–126.86(m),126.35,124.56(d,J=7.0Hz),105.13(d,J=17.1Hz),30.59(d,J=5.7Hz).

[0046] Example 3

[0047]

[0048] In a 4 mL vial, 1a 23 mg (0.1 mmol), 2l 24 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol) were added, and then 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml solvent were added in a glove box. The reaction mixture was stirred at 60°C for 24 h. Water was then added to quench the reaction. Ethyl acetate and water were added for extraction, and the organic phase was dried and concentrated to obtain the target compound 3l.

[0049] When the molar ratio of the allyl geminal difluoromethyl compound reagent to the catalyst is 1:0.01, the yield of the product is 94%;

[0050] When the molar ratio of the allyl geminal difluoromethyl compound reagent to the catalyst is 1:0.02, the yield of the product is 96%;

[0051] When the molar ratio of the allyl gem-difluoromethyl compound reagent to the catalyst is 1:0.05, the yield of the product is 90%.

[0052] When the molar ratio of the allyl geminyl difluoromethyl compound reagent to the catalyst is 1:0.01, the yield of the product can reach 94%. The less the amount of catalyst used, the more obvious the advantage of the method. Therefore, the molar ratio of the allyl geminyl difluoromethyl compound reagent to the catalyst is 1:0.01 as the optimal condition.

[0053] The target product 3l obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.60(d,J=2.2Hz,6H),7.45(dd,J=8.5,6.8Hz,2H),7.39–7.27( m,5H),7.27–7.20(m,1H),5.64(dt,J=36.3,7.7Hz,1H),3.67(dd,J=7.7,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.96 (d, J=35.7Hz). 13 C NMR (101MHz, CDCl3) δ158.09,155.64,141.48,140.45,140.29,131.58,128.96,128.69,128.57,12 7.70,127.35–126.86(m),126.35,124.56(d,J=7.0Hz),105.13(d,J=17.1Hz),30.59(d,J=5.7Hz).

[0054] Example 4

[0055]

[0056] In a 4mL cillin bottle, add 1a 23mg (0.1mmol), 2a 34mg (0.2mmol), lithium hydroxide 3.6mg (0.15mmol), and then add 1.2mg (1mol%) tetrakis (triphenylphosphine) palladium and 1ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 60°C for 24h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3a with a yield of 75%. The target product 3a obtained by the above synthesis method is tested by nuclear magnetic resonance hydrogen spectrum, fluorine spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.53–7.50(m,6H),7.39–7.34(m,2H),7.29–7.25(m,1H),7.11–7.09(d,J=8.4Hz,2H),6.79–6.75(m,2H), 5.59–5.46(dt,J=36.4,7.6Hz,1H), 3.96–3.91(q,J=6.8Hz,2H), 3.52–3.50(dd,J=7.4,1.6Hz,2H), 1.34–1.31(t,J=7.2Hz,3H). 19 F NMR (376MHz, CDCl3) δ-121.42–-121.51 (d, J=36.8Hz). 13 CNMR(101MHz, CDCl3)δ140.93(d,J=94.8Hz),132.24–131.25(m),129.47,128.96,127.74(d,J=10.7Hz),1 27.28–127.01(m),124.52(d,J=6.9Hz),114.68,105.61(d,J=17.2Hz),63.56,29.70(d,J=5.7Hz),15.00.

[0057] Example 5

[0058]

[0059] In a 4mL cillin bottle, add 1b 23mg (0.1mmol), 2b 34mg (0.2mmol), lithium hydroxide 3.6mg (0.15mmol), and then add 1.2mg (1mol%) tetrakis(triphenylphosphine)palladium and 1ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 60°C for 24h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3b with a yield of 79%. The target product 3b obtained by the above synthesis method is tested by hydrogen, fluorine and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.61–7.58(m,7H),7.47–7.43(m,2H),7.39–7.34(m,3H),5.65–5.52(dt,J=35.6,7.6Hz,1H),3.71–3.69(dd,J=8.0,1.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-119.01 (d, J=36.6Hz). 13 C NMR (101MHz, CDCl3) δ159.07,145.90,141.94,140.28,132.51,129.17(d,J=34.7Hz),127.83,127 .50–126.73(m),124.67(d,J=7.1Hz),119.11,110.28,103.09(d,J=17.3Hz),30.68(d,J=6.1Hz).

[0060] Example 6

[0061]

[0062] To a 4mL cillin bottle, add 1a 23mg (0.1mmol), 2c 38mg (0.2mmol), lithium hydroxide 3.6mg (0.15mmol), and then add 1.2mg (1mol%) tetrakis (triphenylphosphine) palladium and 1ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 60°C for 24h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3c with a yield of 85%. The target product 3c obtained by the above synthesis method is tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1H NMR (400MHz, CDCl3) δ7.61–7.55(m,8H),7.46–7.36(m,5H),5.60(ddd,J=36.0,8.0,7.2Hz,1H),3.70(d,J=7.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-62.22,-119.68 (d, J=36.2Hz). 13 C NMR (101MHz, CDCl3) δ158.71, 156.24, 144.38, 141.78, 140.34, 128.92 (d, J = 11.9Hz), 127.77, 127.4 3–126.74(m),125.59(d,J=3.9Hz),124.62(d,J=7.0Hz),103.83(d,J=17.2Hz),30.40(d,J=6.0Hz).

[0063] Example 7

[0064]

[0065] In a 4mL cillin bottle, add 1a 23mg (0.1mmol), 2d 28mg (0.2mmol), lithium hydroxide 3.6mg (0.15mmol), and then add 1.2mg (1mol%) tetrakis (triphenylphosphine) palladium and 1ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 60°C for 24h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3d with a yield of 72%. The target product 3d obtained by the above synthesis method is tested by hydrogen, fluorine and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.61–7.58(m,7H),7.46–7.43(m,2H),7.38–7.33(m,1H),7.25–7. 21(m,3H),7.02–6.97(m,2H),5.60(dt,J=36.4,8.0Hz,1H),3.62(dd,J=7.6,1.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-117.01,-120.72 (d, J=34.9Hz). 13C NMR (101MHz, CDCl3) δ162.81,160.38,158.22,155.75,141.60,140.40,135.88,131.28(d,J=29.1Hz), 129.92(d,J=7.9Hz), 128.97, 127.73, 127.58–126.66 (m), 124.57 (d, J = 7.0Hz), 115.41 (d, J = 21.3Hz), 104.88 (d, J = 17.2Hz), 29.76 (d, J = 6.1Hz).

[0066] Example 8

[0067]

[0068] In a 4mL cillin bottle, add 1a 23mg (0.1mmol), 2e 28mg (0.2mmol), lithium hydroxide 3.6mg (0.15mmol), and then add 1.2mg (1mol%) tetrakis (triphenylphosphine) palladium and 1ml 1,4-dioxane solvent in a glove box. The reaction mixture is stirred at 60°C for 24h. Then water is added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3e with a yield of 63%. The target product 3e obtained by the above synthesis method is tested by nuclear magnetic resonance hydrogen spectrum, fluorine spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.61–7.59(m,6H),7.47–7.42(m,2H),7.38–7.34(m,1H) ,7.29–7.19(m,4H),5.59(dt,J=36.1,7.6Hz,1H),3.62(dd,J=7.6,1.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.31 (d, J=36.8Hz). 13 CNMR (101MHz, CDCl3) δ158.41, 155.95, 141.66, 140.38, 138.72, 132.10, 131.20 (d, J = 29.2Hz), 129.90, 128.8 6(d,J=22.5Hz),127.75,127.33–127.01(m),124.59(d,J=6.9Hz),104.46(d,J=17.3Hz),29.93(d,J=5.9Hz).

[0069] Example 9

[0070]

[0071] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2f 30 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol), then add 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box, and stir the reaction mixture at 60 ° C for 24 h. Then add water to quench the reaction. Add ethyl acetate and water for extraction, and dry and concentrate the organic phase to obtain the target compound 3f with a yield of 72%.

[0072] The target product 3f obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.83 (d, J = 8.2Hz, 2H), 7.63–7.54 (m, 6H), 7.49–7.4 1(m,5H),7.38–7.33(m,1H),5.62(dt,J=35.8,7.8Hz,1H),3.73(dd,J=7.8,1.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-119.01 (d, J=36.6Hz). 13 C NMR(101MHz, CDCl3)δ192.08,158.84,147.61,141.83,140.33,134.92,131.02(d,J=29.0Hz),130.26,129.1 1(d,J=24.5Hz),127.79,127.52–126.58(m),124.65(d,J=7.0Hz),103.54(d,J=17.3Hz),30.78(d,J=6.1Hz).

[0073] Example 10

[0074]

[0075] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2g 39 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol), then add 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box, and stir the reaction mixture at 60 ° C for 24 h. Then add water to quench the reaction. Add ethyl acetate and water for extraction, dry and concentrate the organic phase to obtain 3 g of the target compound with a yield of 96%.

[0076] The target product 3g obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows:1 H NMR(400MHz, CDCl3)δ8.00(d,J=8.4Hz,1H),7.64–7.56(m,6H),7.48–7.42(m,2H),7.40–7.31(m,3H ),5.62(dt,J=36.0,7.7Hz,1H),4.38(q,J=7.1Hz,2H),3.71(d,J=7.6Hz,2H),1.39(t,J=7.1Hz,3H). 19 F NMR (376 MHz, CDCl3) δ 20.53. 13 C NMR (101MHz, CDCl3) δ166.58,158.52,156.06,131.23,130.95,129.90,128.88,128.63,128.43, 127.66,127.18,127.02,124.54(d,J=7.0Hz),104.02,103.85,60.87,30.53(d,J=5.8Hz),14.37.

[0077] When other conditions remain unchanged, the reaction temperature is 100℃, the reaction time is 24h, and the reaction yield is 47%;

[0078] When the reaction temperature was 70°C and the reaction time was 24 h, the reaction yield was 96%.

[0079] When the reaction temperature was 60°C and the reaction time was 12 h, the reaction yield was 44%.

[0080] Embodiment 11

[0081]

[0082] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2h 31 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol), then add 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box, and stir the reaction mixture at 60 ° C for 24 h. Then add water to quench the reaction. Add ethyl acetate and water for extraction, dry and concentrate the organic phase to obtain the target compound 3h with a yield of 79%.

[0083] The target product 3h obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1H NMR(400MHz, CDCl3)δ7.59(d,J=8.1Hz,6H),7.48–7.41(m,2H),7.38–7.31(m,1H),7.29–7.18(m ,2H),6.99–6.83(m,2H),5.66(dt,J=36.8,7.7Hz,1H),3.87(s,3H),3.65(dd,J=7.6,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-121.55 (d, J=36.9Hz). 13 C NMR (101MHz, CDCl3) δ158.00, 157.46, 155.55, 140.88 (d, J = 70.8Hz), 131.90, 131.60, 129.81, 128.94, 128.55, 127.62 (d ,J=2.4Hz),127.36–126.89(m),124.48(d,J=6.9Hz),120.68,110.38,104.81(d,J=16.9Hz),55.48,25.10(d,J=6.2Hz).

[0084] Example 12

[0085]

[0086] In a 4 mL vial, 1a 23 mg (0.1 mmol), 2i 33 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol) were added, and then 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent were added in a glove box. The reaction mixture was stirred at 60 ° C for 24 h. Water was then added to quench the reaction. Ethyl acetate and water were added for extraction, and the organic phase was dried and concentrated to obtain the target compound 3i with a yield of 79%.

[0087] The target product 3i obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.63–7.54(m,6H),7.48–7.41(m,2H),7.39–7.31(m,1H),6.88(s,2 H),5.36(dt,J=36.9,7.2Hz,1H),3.64(dd,J=7.2,1.8Hz,2H),2.35(s,6H),2.27(s,3H). 19 F NMR (376MHz, CDCl3) δ-120.23 (d, J=37.1Hz). 13C NMR (101MHz, CDCl3) δ156.41 (d, J = 246.1Hz), 140.88 (d, J = 84.1Hz), 136.24 (d, J = 83.0Hz), 133.70, 131.47 ( d,J=29.0Hz),130.27–128.04(m),127.13,124.41,104.15,24.58(d,J=5.8Hz),20.98,20.04(d,J=11.8Hz).

[0088] Embodiment 13

[0089]

[0090] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2J 35 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol), then add 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box, and stir the reaction mixture at 60 ° C for 24 h. Then add water to quench the reaction. Add ethyl acetate and water for extraction, and dry and concentrate the organic phase to obtain the target compound 3J with a yield of 76%.

[0091] The target product 3j obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.20–8.06(m,1H),7.89(dd,J=8.0,1.6Hz,1H),7.77(dd,J=6.8,2.7Hz,1H),7.62–7.54(m,6H),7.5 4–7.48(m,1H),7.44(dt,J=8.0,4.2Hz,4H),7.39–7.32(m,1H),5.70(dt,J=36.6,7.5Hz,1H),4.11(dd,J=7.4,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-119.74 (d, J=36.8Hz). 13C NMR (101MHz, CDCl3) δ157.86,155.40,141.49,140.43,136.30,134.02,132.05,131.35(d,J=29.1Hz),128.92(d,J=7.6Hz),127 .70,127.42–127.03(m),126.25,125.79(d,J=2.7Hz),124.58(d,J=6.9Hz),123.94,105.12(d,J=17.2Hz),28.30(d,J=5.9Hz).

[0092] Embodiment 14

[0093]

[0094] In a 4 mL vial, add 1a 23 mg (0.1 mmol), 2k 25 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol), then add 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent in a glove box, and stir the reaction mixture at 60 ° C for 24 h. Then add water to quench the reaction. Add ethyl acetate and water for extraction, and dry and concentrate the organic phase to obtain the target compound 3k with a yield of 72%.

[0095] The target product 5 obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.63–7.59(m,6H),7.48–7.42(m,2H),7.39–7.33(m,1H),7.29(dd,J=4 .9,3.0Hz,1H),7.07–6.99(m,2H),5.64(dt,J=36.2,7.7Hz,1H),3.66(dt,J=7.7,1.3Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.59 (d, J=37.0Hz). 13 C NMR (101MHz, CDCl3) δ158.16, 155.70, 140.98 (d, J = 111.7Hz), 131.38 (d, J = 29.2Hz), 128.97, 128.34, 127 .72,127.43–126.57(m),125.87,124.57(d,J=7.0Hz),120.82,104.51(d,J=17.2Hz),25.28(d,J=6.6Hz).

[0096] Embodiment 15

[0097]

[0098] In a 4 mL vial, 1a 23 mg (0.1 mmol), 2l 24 mg (0.2 mmol), lithium hydroxide 3.6 mg (0.15 mmol) were added, and then 1.2 mg (1 mol%) tetrakis(triphenylphosphine)palladium and 1 ml 1,4-dioxane solvent were added in a glove box. The reaction mixture was stirred at 60 ° C for 24 h. Water was then added to quench the reaction. Ethyl acetate and water were added for extraction, and the organic phase was dried and concentrated to obtain the target compound 3l with a yield of 94%.

[0099] When the molar ratio of the allyl gem-difluoromethyl compound reagent to lithium hydroxide is 1:1.2, the yield of the allyl monofluoro compound is 73%.

[0100] The target product 3l obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.60(d,J=2.2Hz,6H),7.45(dd,J=8.5,6.8Hz,2H),7.39–7.27( m,5H),7.27–7.20(m,1H),5.64(dt,J=36.3,7.7Hz,1H),3.67(dd,J=7.7,1.8Hz,2H). 19 F NMR (376MHz, CDCl3) δ-120.96 (d, J=35.7Hz). 13 C NMR (101MHz, CDCl3) δ158.09,155.64,141.48,140.45,140.29,131.58,128.96,128.69,128.57,12 7.70,127.35–126.86(m),126.35,124.56(d,J=7.0Hz),105.13(d,J=17.1Hz),30.59(d,J=5.7Hz).

[0101] The above is only a preferred specific implementation of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field within the technical scope disclosed by the present invention, according to the technical solution and its concept of the present invention, shall be covered within the protection scope of the present invention. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A method for synthesizing an allyl monofluoro compound, characterized in that: The method comprises the following steps: a Suzuki coupling reaction is carried out in an organic solvent under a nitrogen environment with an allyl geminal difluoromethyl compound represented by the general formula (1), an aromatic boronic acid represented by the general formula (2), a catalyst Pd(PPh3)4 and an alkaline substance to generate the allyl monofluoro compound represented by the general formula (3); In the general formula (1) and the general formula (2), Ar and Ar' are independently selected from substituted or unsubstituted phenyl and heteroaryl, wherein the substituent is an alkyl, halogen, alkoxy or aldehyde group, Or Ar is 4-PhC6H4, the general formula (3) is 2. The method for synthesizing an allyl monofluoro compound according to claim 1, characterized in that: The reaction temperature is 60-70°C and the reaction time is at least 24 hours.

3. The method for synthesizing an allyl monofluoro compound according to claim 1, characterized in that: The molar ratio of the allyl gem-difluoromethyl compound to the aryl boronic acid is 1:2; And / or, the molar ratio of the allyl gem-difluoromethyl compound reagent to lithium hydroxide is: 1:1.2-1.5; And / or, the molar ratio of the allyl gem-difluoromethyl compound reagent to the catalyst is: 1:0.01-0.

05.

4. The method for synthesizing an allyl monofluoride compound according to claim 1, characterized in that: The material adding method comprises: firstly adding lithium hydroxide, an allyl geminal difluoromethyl compound of general formula (1) and an aromatic boronic acid of general formula (2) into a reactor; and then adding a Pd(PPh3)4 catalyst and an organic solvent under anaerobic conditions.

5. The method for synthesizing an allyl monofluoro compound according to claim 1, characterized in that: The organic solvent is selected from any one or more of 1,4-dioxane, tetrahydrofuran (THF) and N,N-dimethylaniline (DMA).

6. The method for synthesizing an allyl monofluoro compound according to claim 1, characterized in that: The method further comprises a purification step: adding ethyl acetate and aqueous solution to the system after the reaction is completed for extraction, drying and concentrating the organic phase, and then purifying.

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