Preparation method of polyfluorinated biaryl compound

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a polyfluoro biaryl compound. The preparation method comprises the following steps: taking polyfluoroaryl zinc carboxylate as a raw material, or taking a polyfluoroaryl carboxylic acid / zinc hydroxide system as a raw material, reacting with aryl sulfosalt in a palladium catalyst and an organic solvent, and carrying out decarboxylation and Negishi coupling reaction to prepare the polyfluorobiaryl compound. Under the heating condition, zinc promotes decarboxylation of polyfluoroaryl carboxylic acid to generate a polyfluoroaryl zinc reagent in situ, then the polyfluoroaryl zinc reagent and aryl sulfosalt are subjected to Negishi coupling under the catalysis of palladium, and efficient preparation of the polyfluorobiaryl compound can be achieved. The preparation method of the polyfluoroaryl compound has the advantages of mild reaction conditions, wide compatibility of functional groups and very high application value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic catalytic synthesis, and in particular relates to a method for preparing a polyfluorobiaryl compound. Background Art

[0002] Polyfluorobiaryl compounds are an important class of organic structural units, and have important applications in the fields of medicine, pesticides, materials and organic catalysis. For example, the cyclooxygenase inhibitor diflunisal, the PIM kinase inhibitor PIM447, N-type semiconductor materials and liquid crystal display materials all contain important applications of polyfluorobiaryl fragments. The traditional method of constructing polyfluorobiaryl compounds is mainly to prepare them by cross-coupling reactions of polyfluoroaryl metal reagents with aromatic electrophiles or selective functionalization reactions of CH / F bonds of polyfluoroaromatic hydrocarbons. In recent years, the decarboxylation coupling reaction of aromatic carboxylic acids has gradually attracted the attention of chemists. Using this strategy, cheap and readily available polyfluorobenzoic acid is used as a raw material instead of expensive and sensitive polyfluoroaryl metal reagents, and polyfluorobiaryl compounds can be prepared by coupling with different aromatic electrophiles. [(a) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 9350-9354. (b) Shang, R .;Xu,Q.;Jiang,Y.-Y.;Wang,Y.;Liu,L.Org.Lett.2010,12,1000-1003.(c)Fu,L.;You,J.;Nishihara,Y.Chem.C ommun.2021,57,3696-3699.(d)Sardzinski,LW;Wertjes,WC;Schnaith,AM;Kalyani,D.Org.Lett.2015,17,1256-1259.(e)Chen,Q.;Wu,A.;Qin,S.;Zeng,M.;Le,Z.;Yan,Z.;Zhang,H.Adv.Synth.Catal.2018,360,3239-3244.]. These methods usually use palladium, copper, nickel, etc. as catalysts. However, since the energy required for decarbonation of polyfluorobenzoic acid is particularly high, the above method is usually achieved at a higher temperature (usually greater than 130°C), resulting in poor applicability of the reaction and the production of unwanted by-products, which limits the practical application of the above method in organic synthesis. Therefore, it is necessary to develop new catalytic methods with mild conditions and wide applicability to improve the efficiency of the reaction and reduce the formation of by-products, thereby promoting the widespread application of this reaction in organic synthesis. Summary of the invention

[0003] The purpose of the present invention is to solve the above problems existing in the current field and to provide a synthetic method for efficiently preparing polyfluorobiaryl compounds under mild conditions.

[0004] To achieve the above object, the present invention adopts the following technical solutions:

[0005] A preparation method of a polyfluorobiaryl compound, the synthesis method comprising the following steps: under the protection of an inert gas and in a solvent, using a polyfluoroaryl carboxylate zinc as a raw material, or using a polyfluoroaryl carboxylic acid / zinc hydroxide system as a raw material, and heating a reaction with an aryl sulfide salt in the presence of a palladium catalyst to obtain a polyfluorobiaryl compound; wherein the structural formula of the polyfluoroaryl carboxylate zinc is shown in formula I, the structural formula of the aryl sulfide salt is shown in formula II, the structural formula of the polyfluorobiaryl compound is shown in formula III, the structural formula of the polyfluoroaryl carboxylic acid is shown in formula IV, and the reaction formula of the reaction is shown in the following formula:

[0006]

[0007] In formula I, n is a natural number of 2-5, and R is selected from at least one of anhydrous, hydrogen, bromine, chlorine, phenyl, C1-C6 alkoxy, C1-C6 alkyl substituted ester, and nitro; more preferably, when n is 2 and 3, R is one of nitro or ester, which can further improve the activity of the carboxylic acid;

[0008] In formula II, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, and substituted or unsubstituted heterocyclic aryl; the substituent of the substituted phenyl or heterocyclic aryl includes at least one of fluorine, chlorine, bromine, C1-C10 alkyl, C1-C6 alkoxy, substituted or unsubstituted phenoxy, allyl, hydroxyl, C1-C6 alkyl substituted ester, aldehyde, and cyano, and the substituent of the substituted phenoxy is at least one of fluorine, chlorine, bromine and cyano; the substituent of the substituted biphenyl is selected from at least one of chlorine and methyl ester; the heterocyclic aryl is selected from benzodihydrofuran, benzo-1,3-dioxole, xanthone, etc.; X is S, MeN or no atom; Y is OTf or BF4.

[0009] Preferably, the palladium catalyst described in the present invention includes at least one of tetrakis(triphenylphosphine)palladium, palladium acetate, palladium trifluoroacetate, tris(acetylacetone)dipalladium and di(acetylacetone)palladium, and the palladium catalyst can also be equipped with a phosphine ligand, and the molar feed ratio of the palladium catalyst to the phosphine ligand is 1:1.0-1:1.5; the phosphine ligand is at least one of triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, and triisopropylphosphine, and more preferably the palladium catalyst is tetrakis(triphenylphosphine)palladium.

[0010] Preferably, the solvent of the present invention is selected from at least one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylpropylene urea (DMPU), 1,1,3,3-tetramethylurea, acetonitrile (MeCN), ethyl acetate (EA), isopropyl acetate (IPA) and 1,2-dichloroethane (DCE), preferably N,N-dimethylformamide.

[0011] Preferably, the reaction temperature of the present invention is 40-100°C, preferably 60-80°C.

[0012] Preferably, the molar feed ratio of the aryl sulfide salt II to the palladium catalyst of the present invention is 1:0.01 to 1:0.1, preferably 1:0.05.

[0013] Preferably, in the present invention, in order to ensure the full reaction of the aryl sulfide salt II, the molar feed ratio of polyfluoroaryl carboxylic acid zinc I, or polyfluoroaryl carboxylic acid IV and aryl sulfide salt II is 1:1 to 3:1, preferably 1:1. For some polyfluoroaryl zinc carboxylates with relatively poor activity, it is necessary to appropriately increase the feed amount of zinc salt or increase the reaction temperature.

[0014] Preferably, when the polyfluoroaryl carboxylic acid / zinc hydroxide system is used as the raw material, the molar feed ratio of the polyfluoroaryl carboxylic acid to zinc hydroxide is 2: 1 to 3: 1, preferably 2: 1. The polyfluoroaryl carboxylic acid / zinc hydroxide system is used as the raw material for the reaction, and the polyfluorobiaryl compound can be directly synthesized in a one-pot method with high efficiency.

[0015] Preferably, when the polyfluoroaryl carboxylic acid / zinc hydroxide system is used as the raw material, a molecular sieve is also added to the reaction system, and the molecular sieve includes at least one of 3A, 4A and 5A molecular sieves. More preferably, the amount of the molecular sieve added is 30-100 mg, preferably 40-50 mg, per 1 mmol of polyfluoroaryl carboxylic acid.

[0016] Preferably, the reaction time is 8-24 hours, preferably 12 hours.

[0017] Preferably, the inert gas is any one or more of nitrogen, argon and helium.

[0018] Preferably, the present invention can separate the polyfluorobiaryl compound by the following post-treatment method: add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, dry with a desiccant such as anhydrous sodium sulfate, concentrate under reduced pressure and separate the product by column chromatography (eluent is petroleum ether or a mixture of petroleum ether and ethyl acetate).

[0019] Compared with the prior art, the present invention has the following beneficial effects: the present invention utilizes zinc to promote the decarboxylation of polyfluorobenzoic acid, realizes the in-situ preparation of polyfluoroaryl zinc under mild conditions, and then couples with aryl sulfide salts under palladium catalysis to realize the efficient preparation of polyfluorobiaryl compounds. The sensitivity of polyfluoroaryl zinc reagents to air and moisture in the preparation process is solved, the reaction conditions are mild, the substrate has a wide range of applicability, and is suitable for large-scale industrial production. This strategy can be used for the late polyfluoroarylation modification of complex molecules and bioactive molecules, and has strong application potential. DETAILED DESCRIPTION

[0020] In order to better clarify and understand the purpose, process scheme and advantages of the present invention, the technical scheme and implementation mode of the present invention are further described clearly, completely and in detail through specific examples. The embodiments presented in the present invention are all based on the core technical scheme of the present invention and only represent a part of the embodiments of the present invention, not all. The specific implementation details are intended to illustrate the present invention, not to limit it. All other implementation forms derived by ordinary technicians in the field without involving creative changes on the basis of the embodiments of the present invention belong to the protection scope of the present invention.

[0021] The experimental methods and conditions used in the embodiments of the present invention are conventional methods and conventional conditions unless otherwise specified. The materials, reagents or instruments used in the embodiments, unless otherwise specified, can be obtained from commercial sources or prepared by conventional methods. The reaction conditions embodied in the content of the invention of the present invention can achieve the reaction and obtain the product of the expected effect. Due to space limitations, some embodiments are listed below to further illustrate the advantages of the technical solution of the present invention.

[0022] Example 1

[0023]

[0024] Zinc pentafluorobenzoate (0.5mmol), p-methylphenylthianthrene trifluoromethanesulfonate (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIa was separated by column chromatography with a yield of 84%.

[0025] Product testing data: 1 H NMR (400MHz, CDCl3) δ7.36–7.26(m,4H),2.42(s,3H). 19FNMR (376MHz, CDCl3) δ-143.38 (dd, J=23.0, 8.2Hz, 2F), -156.15 (t, J=21.0Hz, 1F), -162.47 (dt, J=22.9, 8.2Hz, 2F).

[0026] 13 C NMR (100MHz, CDCl3) δ144.3 (dm, J = 245.4Hz), 140.3 (dm, J = 251.6Hz), 139.6, 1 38.0 (dm, J = 249.4Hz), 130.1, 129.6, 123.5, 116.1 (dt, J = 17.2, 4.1Hz), 21.5.

[0027] Example 2

[0028]

[0029] The thiocyanate IIb was used instead of the thianthrene salt IIa, and the other conditions were the same as those in Example 1. The yield of the target compound was 79%.

[0030] Example 3

[0031]

[0032] The thiocyanate IIc was used instead of the thianthrene salt IIa. The other conditions were the same as those in Example 1. The yield of the target compound was 69%.

[0033] Example 4

[0034] DMSO was used as the solvent instead of DMF, and the other conditions were the same as those in Example 1. The yield of the target compound was 82%.

[0035] Example 5

[0036] NMP was used as the solvent instead of DMF, and the other conditions were the same as those in Example 1. The yield of the target compound was 80%.

[0037] Example 6

[0038] DMF / DCE (volume ratio 1 / 1) was used as the solvent instead of DMF, and the other conditions were the same as those in Example 1. The yield of the target compound was 42%.

[0039] Example 7

[0040] DMF / MeCN (volume ratio 1 / 1) was used as the solvent instead of DMF, and the other conditions were the same as those in Example 1. The yield of the target compound was 25%.

[0041] Example 8

[0042] The reaction temperature was raised to 80° C., and the other conditions were the same as in Example 1. The yield of the target compound was 78%.

[0043] Example 9

[0044] The reaction temperature was lowered to 40° C., and the other conditions were the same as in Example 1. The yield of the target compound was 58%.

[0045] Example 10

[0046] The reaction temperature was lowered to room temperature (25° C.), and the other conditions were the same as in Example 1. The yield of the target compound was 39%.

[0047] Embodiment 11

[0048] The catalysts palladium acetate (0.025 mmol) and triphenylphosphine (0.05 mmol) were used to replace tetrakis(triphenylphosphine)palladium. The other conditions were the same as those in Example 1. The yield of the target compound was 79%.

[0049] Example 12

[0050] The catalyst di(acetylacetonate)palladium (0.025 mmol) and tricyclohexylphosphine (0.05 mmol) were used to replace tetrakis(triphenylphosphine)palladium. The other conditions were the same as those in Example 1. The yield of the target compound was 55%.

[0051] Example 13

[0052]

[0053] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IId (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIb was separated by column chromatography with a yield of 91%. 1 HNMR (400MHz, CDCl3) δ7.72(d,J=8.2Hz,2H),7.65(d,J=7.3Hz,2H),7.56–7.44(m,4H),7.44–7.36(m,1H). 19F NMR (376MHz, CDCl3) δ-143.14 (dd, J=23.0, 8.0Hz, 2F), -155.47 (t, J=21.0Hz, 1F), -162.09 (td, J=22.8, 8.2Hz, 2F). 13 C NMR (100MHz, CDCl3) δ 144.3 (dm, J = 246.0Hz), 143.1, 140.5 (dm, J = 252.0Hz), 140.3, 138. 0(dm,J=251.3Hz),130.7,129.1,128.0,127.6,127.3,125.4,115.8(dt,J=17.1,4.2Hz).

[0054] Embodiment 14

[0055]

[0056] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIe (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIc was separated by column chromatography with a yield of 88%. 1 HNMR (400MHz, CDCl3) δ7.68(d,J=7.3Hz,2H),7.57(d,J=7.5Hz,2H),7.51(d,J=7.0Hz,2H),7.45(d,J=7.4Hz,2H). 19 F NMR (376MHz, CDCl3) δ-143.14 (dd, J=22.8, 7.4Hz, 2F), -155.23 (t, J=21.0Hz, 1F), -161.98 (td, J=22.2, 7.7Hz, 2F). 13 C NMR (100MHz, CDCl3) δ144.3 (dm, J=250.2Hz), 141.1, 140.6 (dm, J=252.7Hz), 138.7, 138.0 (dm, J= 249.3Hz),134.2,130.8,129.2,128.5,127.4,125.8,115.6(dt,J=17.1,4.2Hz).HRMS(ESI):m / z calculated for C 18 H9ClF5 +[M+H] + :355.0307,found:355.0255.

[0057] Embodiment 15

[0058]

[0059] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIf (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIId was separated by column chromatography with a yield of 98%. 1 HNMR (400MHz, CDCl3) δ8.14(d,J=8.3Hz,2H),7.75(d,J=8.3Hz,2H),7.71(d,J=8.3Hz,2H),7.53(d,J=8.1Hz,2H),3.95(s,3H). 19 F NMR (376MHz, CDCl3) δ-143.10 (dd, J=22.9, 8.1Hz, 2F), -155.07 (t, J=20.9Hz, 1F), -161.91 (td, J=22.6, 8.2Hz, 2F). 13 C NMR (100MHz, CDCl3) δ167.0, 144.6, 144.3 (dm, J = 250.5Hz), 141.0, 140.6 (dm, J = 253.0Hz), 138.0 (dm, J =251.5Hz),130.8,130.3,129.6,127.7,127.2,126.3,115.5(dt,J=17.2,4.1Hz),52.3.HRMS(ESI):m / z calculated for C 20 H 12 F5O2 + [M+H] + :379.0752,found:379.0747.

[0060] Example 16

[0061]

[0062] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIg (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIe was separated by column chromatography with a yield of 88%. 1 HNMR (400MHz, CDCl3) δ7.46–7.35(m,4H),7.19(t,J=7.4Hz,1H),7.11(d,J=8.5Hz,4H). 19 F NMR (376MHz, CDCl3) δ-143.40 (dd, J=23.0, 8.1Hz), -155.88 (t, J=21.0Hz), -162.25 (td, J=22.4, 8.2Hz). 13 C NMR (100MHz, CDCl3) δ158.7, 156.3, 144.3 (dm, J=249.4Hz), 140.4 (dm, J=252.2Hz), 138.0 (dm, J= 248.8Hz),131.8,130.1,124.3,120.7,120.0,118.4,115.6(dt,J=16.9,3.9Hz).HRMS(ESI):m / z calculated for C 18 H 10 F5O + [M+H] + :337.0646,found:337.0593.

[0063] Embodiment 17

[0064]

[0065] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIh (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIf was separated by column chromatography with a yield of 67%. 1HNMR (400MHz, CDCl3) δ7.65 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.0Hz, 2H), 7.18 (d, J = 8.3Hz, 2H), 7.11 (d, J = 8.4Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-143.29 (dd, J=22.9, 8.0Hz, 2F), -155.07 (t, J=21.0Hz, 1F), -161.88 (td, J=22.5, 8.1Hz, 2F). 13 C NMR (100MHz, CDCl3) δ160.8, 156.0, 144.2 (dm, J = 246.0Hz), 140.5 (dm, J = 257.7Hz), 138.0 (dm, J = 256 .4Hz),134.4,132.2,122.9,120.2,118.8,118.7,115.0(dt,J=16.8,3.9Hz),106.8.HRMS(ESI):m / z calculated for C 19 H9F5NO + [M+H] + :362.0599,found:362.0560.

[0066] Embodiment 18

[0067]

[0068] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIi (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIg was separated by column chromatography with a yield of 43%. 1 H NMR (400MHz, CDCl3) δ7.10 (s, 2H), 4.99 (s, 1H), 3.35–3.02 (m, 2H), 1.29 (d, J = 6.9Hz, 12H). 19 F NMR (376MHz, CDCl3) δ-143.38 (dd, J=23.4, 8.0Hz, 2F), -157.15 (t, J=21.0Hz, 1F), -162.84 (dt, J=23.0, 8.0Hz, 2F). 13C NMR (100MHz, CDCl3) δ151.0, 144.3 (dm, J = 244.4Hz), 140.0 (dm, J = 250.7Hz), 138.0 (dm, J =248.7Hz),134.2,125.8,118.5,116.7(dt,J=16.7,4.1Hz),27.3,22.8.HRMS(ESI):m / z calculated forC 18 H 18 F5O + [M+H] + :345.1272,found:345.1216.

[0069] Embodiment 19

[0070]

[0071] Zinc pentafluorobenzoate (0.5mmol), thianthrene salt IIj (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIh was separated by column chromatography with a yield of 68%. 1 HNMR (400MHz, CDCl3) δ7.23–7.13(m,1H),6.97(d,J=1.6Hz,1H),6.88(d,J=8.5H z,1H),6.03–5.75(m,1H),5.12–4.80(m,2H),3.71(s,3H),3.30(d,J=6.6Hz,2H). 19 F NMR (376MHz, CDCl3) δ-140.18 (dd, J=23.1, 8.0Hz, 2F), -156.27 (t, J=21.0Hz, 1F), -163.23 (dt, J=23.2, 8.1Hz, 2F). 13C NMR (100MHz, CDCl3) δ155.7, 144.6 (dm, J = 249.0Hz), 140.6 (dm, J = 251.0Hz), 137.7 (dm, J = 250.2Hz), 13 7.4,132.3,131.9,131.2,116.2,115.2,113.0(dt,J=19.3,3.8Hz),111.4,55.9,39.2.HRMS(ESI):m / z calculatedfor C 16 H 12 F5O + [M+H] + :315.0803,found:315.0748.

[0072] Embodiment 20

[0073]

[0074] Zinc pentafluorobenzoate (0.5 mmol), thianthrene salt IIk (0.5 mmol) and tetrakis(triphenylphosphine)palladium (0.025 mmol) were added to the reaction tube in sequence, and anhydrous DMF (2 mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12 h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10 mL) was added, and ethyl acetate was added for extraction three times (5 mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIi was separated by column chromatography with a yield of 94%. 1 HNMR (400MHz, CDCl3) δ7.66–7.59 (m, 2H), 7.12 (d, J = 8.6Hz, 1H), 4.00 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-143.39 (dd, J=22.8, 8.0Hz, 2F), -154.22 (t, J=21.0Hz, 1F), -161.43 (dt, J=22.6, 8.2Hz, 2F). 13 C NMR (100MHz, CDCl3) δ161.8, 144.3 (dm, J = 246.7Hz), 140.8 (dm, J = 253.6Hz), 138.0 (dm, J =252.0Hz), 136.3, 135.4, 119.1, 115.7, 113.7 (dt, J = 16.5, 4.1Hz), 112.0, 102.7, 56.5.

[0075] Embodiment 21

[0076]

[0077] 2,3,5,6-tetrafluorobenzoic acid zinc Ib (0.5mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIj was separated by column chromatography with a yield of 62%. 1 HNMR (400MHz, CDCl3) δ7.77–7.51(m,2H),7.19–6.97(m,2H),4.01(s,3H). 19 F NMR (376MHz, CDCl3) δ-137.56–-139.14(m,2F),-142.82–-145.51(m,2F). 13 C NMR (100MHz, CDCl3) δ161.7,146.4(dm,J=256.2Hz),143.7(dm,J=245.8Hz),136.3,135.5,1 20.3,119.1(t,J=16.2Hz),115.8,111.8,105.6(t,J=22.2Hz),102.7,56.5.HRMS(ESI):m / z calculated for C 14 H8F4NO + [M+H] + :282.0537,found:282.0533.

[0078] Embodiment 22

[0079]

[0080] Zinc salt Ic (0.5mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIk was separated by column chromatography with a yield of 65%. 1HNMR (400MHz, CDCl3) δ7.71(s,1H),7.67(d,J=8.9Hz,1H),7.13(d,J=8.8Hz,1H),4.01(s,3H),4.01(s,3H). 19 F NMR (376MHz, CDCl3) δ-138.85 (td, J=14.7, 3.4Hz, 2F), -142.81 (dd, J=20.8, 11.6Hz, 2F). 13 CNMR (100MHz, CDCl3) δ162.0, 160.1, 145.1 (dm, J = 239.8Hz), 143.9 (dm, J = 234.1Hz), 136.2, 135.4, 121.3(t,J=15.9Hz),119.3,115.6,112.0,111.9(t,J=16.1Hz),102.8,56.5,53.5.HRMS(ESI):m / z calculated forC 16 H 10 F4NO3 + [M+H] + :340.0591,found:340.0573.

[0081] Embodiment 23

[0082]

[0083] Zinc salt Id (0.75mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIm was separated by column chromatography with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ7.99 (dd, J=15.7, 7.9Hz, 1H), 7.73–7.57 (m, 2H), 7.15 (d, J=8.5Hz, 1H), 4.02 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-121.00–-122.01(m,1F),-123.81–-126.34(m,1F),-135.87–-137.10(m,1F). 13C NMR (100MHz, CDCl3) δ 162.1, 151.3 (ddd, J = 261.4, 14.1, 5.5Hz), 149.6 (ddd, J = 264.2, 5.0, 3.3Hz), 146.3 (ddd, J = 252.8, 14.5, 4.1Hz), 136.3 ,135.4,133.9–133.2(m),120.6(dd,J=19.4,16.0Hz),118.77(d,J=2.0Hz),115.5,113.7(d,J=23.2Hz),112.1,102.9,56.5.HRMS(ESI):m / z calculated forC 14 H8F3N2O3[M+H] + :309.0482,found:309.0471.

[0084] Embodiment 24

[0085]

[0086] Zinc salt Ie (0.75mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIn was separated by column chromatography with a yield of 61%. 1 H NMR (400MHz, CDCl3) δ8.19–8.08(m,1H),7.73–7.59(m,2H),7.22–7.07(m,2H),4.02(s,3H). 19 F NMR(376MHz, CDCl3)δ-98.04–-104.20(m,1F),-116.13(dd,J=13.4,8.4Hz,1F). 13C NMR (100MHz, CDCl3) δ162.7(dd,J=257.8,5.5Hz),161.8,153.9(dd,J=265.3,7.7Hz),136.4,135.6,135.1–134.9(m),126. 7(d,J=10.8Hz),119.7,119.2–118.7(m),115.7,112.4(dd,J=24.8,4.2Hz),111.9,102.8,56.5.HRMS(ESI):m / zcalculated for C 14 H9F2N2O3 + [M+H] + :291.0576,found:291.0558.

[0087] Embodiment 25

[0088]

[0089] Zinc salt If (0.5mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIo was separated by column chromatography with a yield of 71%. 1 HNMR (400MHz, CDCl3) δ7.65 (s, 1H), 7.62 (d, J = 9.1Hz, 1H), 7.09 (d, J = 8.8Hz, 1H), 4.13 (s, 3H), 4.00 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-145.39 (dd, J=21.8, 8.6Hz, 2F), -157.56 (dd, J=21.8, 8.3Hz, 2F). 13 CNMR(100MHz, CDCl3)δ161.5,144.4(dm,J=246.0Hz),141.4(dm,J=246.5Hz),138.4–137.8(m),13 6.3,135.5,120.1,115.9,112.1–111.4(m),111.8,102.6,62.3(t,J=3.6Hz),56.4.HRMS(ESI):m / z calculated forC 15 H 10 F4NO2+ [M+H] + :312.0642,found:312.0636.

[0090] Embodiment 26

[0091]

[0092] Zinc salt Ig (0.6mmol), thianthrene salt IIk (0.5mmol) and tetrakis(triphenylphosphine)palladium (0.025mmol) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIp was separated by column chromatography with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ7.75(s,1H),7.72(d,J=8.9Hz,1H),7.56–7.43(m,5H),7.13(d,J=8.8Hz,1H),4.02(s,3H). 19 FNMR (376MHz, CDCl3) δ-143.57 (dd, J=22.2, 12.3Hz, 2F), -144.58 (dd, J=22.2, 12.3Hz, 2F). 13 C NMR (101MHz, CDCl3) δ161.7,145.7–145.1(m),143.5–142.4(m),136.3,130.3,129.5,128. 8,127.3,120.7–119.9(m),117.2(t,J=16.3Hz),115.9,111.8,102.7,56.5.HRMS(ESI):m / z calculated for C 20 H 12 F4F + [M+H] + :358.0850,found:358.0847.

[0093] Example 27 One-pot Synthesis of Polyfluorobiaryl Compounds

[0094]

[0095] Pentafluorobenzoic acid (1.0mmol), zinc hydroxide (0.5mmol), thianthrene salt IIa (0.5mmol), tetrakis(triphenylphosphine)palladium (0.025mmol) and 4A molecular sieve (50mg) were added to the reaction tube in sequence, and anhydrous DMF (2mL) was added after argon replacement three times, and the reaction system was placed in an oil bath at 60°C and stirred for 12h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature and saturated ammonium chloride (10mL) was added, and ethyl acetate was added for extraction three times (5mL×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the target product IIIa was separated by column chromatography with a yield of 74%.

[0096] The above-described embodiments are only preferred embodiments of the present invention, and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a polyfluorobiaryl compound, characterized in that: The method comprises the following steps: under the protection of inert gas and in a solvent, using polyfluoroaryl carboxylic acid zinc (Formula I) as a raw material, or using polyfluoroaryl carboxylic acid (Formula IV) / zinc hydroxide system as a raw material, and heating reaction with aryl sulfide (Formula II) in the presence of a palladium catalyst to obtain a polyfluorobiaryl compound (Formula III); the reaction formula of the reaction is shown as follows: In formula I, n is a natural number of 2-5, and R is selected from at least one of anhydrous, hydrogen, bromine, chlorine, phenyl, C1-C6 alkoxy, C1-C6 alkyl substituted ester, and nitro; more preferably, when n is 2 and 3, R is one of nitro or ester, which can further improve the activity of the carboxylic acid; In formula II, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, and substituted or unsubstituted heterocyclic aryl; the substituent of the substituted phenyl or heterocyclic aryl includes at least one of fluorine, chlorine, bromine, C1-C10 alkyl, C1-C6 alkoxy, substituted or unsubstituted phenoxy, allyl, hydroxyl, C1-C6 alkyl substituted ester, aldehyde, and cyano, and the substituent of the substituted phenoxy is at least one of fluorine, chlorine, bromine and cyano; the substituent of the substituted biphenyl is selected from at least one of chlorine and methyl ester; the heterocyclic aryl is selected from one of benzodihydrofuran, benzo-1,3-dioxole, and xanthone; X is S, MeN or no atom; Y is OTf or BF4.

2. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The palladium catalyst comprises at least one of tetrakis(triphenylphosphine)palladium, palladium acetate / phosphine ligand, palladium trifluoroacetate / phosphine ligand, tris(acetylacetonate)dipalladium / phosphine ligand and di(acetylacetonate)palladium / phosphine ligand; the phosphine ligand is at least one of triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine and triisopropylphosphine.

3. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylpropylene urea, 1,1,3,3-tetramethyl urea, acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate and 1,2-dichloroethane.

4. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The reaction temperature is 40-100°C.

5. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The molar feed ratio of the aryl sulfide salt to the palladium catalyst is 1:0.01 to 1:0.

1.

6. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The molar feed ratio of polyfluoroaryl carboxylate zinc or polyfluoroaryl carboxylic acid and aryl sulfide salt is 1:1 to 3:

1.

7. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: When the polyfluoroaryl carboxylic acid / zinc hydroxide system is used as raw materials, the molar feed ratio of the polyfluoroaryl carboxylic acid to the zinc hydroxide is 2:1 to 3:

1.

8. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: When the polyfluoroaryl carboxylic acid / zinc hydroxide system is used as the raw material, molecular sieves are also added into the reaction system.

9. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The reaction time is 8-24 hours.

10. The method for preparing a polyfluorobiaryl compound according to claim 1, characterized in that: The palladium catalyst is tetrakis(triphenylphosphine)palladium, the solvent is N,N-dimethylformamide, the reaction temperature is 60-80°C, the molar feed ratio of the aryl sulfide salt and the palladium catalyst is 1:0.05, and the molar feed ratio of the polyfluoroaryl carboxylic acid zinc or the polyfluoroaryl carboxylic acid and the aryl sulfide salt is 1:1.

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