Difluoromethyl heteroaromatic compound and preparation method thereof

Abstract

The invention provides a preparation method of a difluoromethyl heteroaromatic compound, which comprises the following steps: by taking a heteroaromatic compound and iododifluoromethyl phenyl sulfone as raw materials, reacting for a certain time under the action of a palladium catalyst, a ligand, alkali, an organic solvent and temperature, thereby obtaining the difluoromethyl heteroaromatic compound. A series of difluoromethyl heteroaromatic compounds are generated; the heteroaromatic compound is an indole compound 1 or a pyrrole compound or a thiourea compound. The invention provides a novel method for generating the difluoromethyl heteroaromatic compounds by using palladium catalytic reaction under mild conditions, the method uses iodine difluoromethyl phenyl sulfone as a difluoromethylation reagent, the wide substrate compatibility is shown, and the excellent yield is obtained.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a difluoromethyl heteroaromatic compound and a preparation method thereof. Background Art

[0002] Fluorinated organic compounds have a wide range of applications in the fields of pharmaceuticals, pesticides, and advanced materials. Due to the unique properties of fluorine atoms, the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules can improve the lipid solubility, bioavailability, and metabolic stability of the target molecules. In recent years, people have focused on the selective introduction of fluorine atoms or -CF3 groups; however, especially for heteroaromatic systems, the selective introduction of -CF2 groups has been less studied. The -CF2 group is not only a bioisostere of hydroxymethyl and thiol groups, but also a lipophilic hydrogen bond donor. In addition, it can serve as a substitute for oxygen and is an important structural unit in various drugs, pesticides, and functional molecules. Therefore, the selective and efficient introduction of this group into organic molecules has important synthetic value, and the development of difluoromethylation methods remains a research hotspot and frontier in modern fluorinated organic chemistry.

[0003] Traditionally, the preferred strategy for the synthesis of difluoromethylated (hetero)arenes is deoxyfluorination of aldehydes. However, these reactions are often plagued by harsh reaction conditions and the need for pre-functionalization. Hartwig and Prakash reported direct copper-mediated nucleophilic difluoromethylation, but the application of this method to heteroaromatic substrates is limited, mainly to certain pyridine derivatives. In 2010, Reutrakul's group described a palladium-catalyzed Heck-type coupling reaction between PhSO2CF2Br and styrene. However, the reaction conditions are harsh and the substrate range is narrow. In the past decade, free radical-based difluoromethylation has become an important platform for the introduction of difluoromethyl groups into a variety of organic compounds. Due to the inherently high reactivity of these open-shell radical species, fairly mild reaction conditions and excellent functional group compatibility have been achieved. Among these radical-type reactions, PhSO2CF2I is widely used as an efficient, cost-effective and easily accessible radical (benzenesulfonyl) difluoromethylation reagent, and the generated (benzenesulfonyl) difluoromethylation products can be converted into the corresponding difluoromethylated compounds by simple transformation. In 2007, Hu's group first reported the radical (benzenesulfonyl) difluoromethylation reaction of olefins using PhSO2CF2I. Wang's group used PhSO2CF2I as a good precursor to form (benzenesulfonyl) difluoromethyl radicals. In 2014, the aromatic difluoromethylation reaction of activated olefins using Pd(0) catalysis and Fe catalysis was reported. The group also developed a new method to achieve the difluoromethylation of electron-rich nitrogen (N), oxygen (O) and sulfur (S) heteroaromatics under visible light photoreduction catalysis, but this method has low yields and harsh reaction conditions. Summary of the invention

[0004] The technical problem to be solved by the present invention is how to provide a preparation method for generating difluoromethyl heteroaromatic compounds by reaction under mild conditions to improve the product yield.

[0005] The present invention solves the above technical problems through the following technical means:

[0006] The first aspect of the present invention provides a method for preparing difluoromethyl heteroaromatic compounds, which uses heteroaromatic compounds and iododifluoromethylphenylsulfone as raw materials, reacts for a certain period of time under the action of a palladium catalyst, a ligand, a base, an organic solvent and temperature to generate a series of difluoromethyl heteroaromatic compounds; the heteroaromatic compounds are indole compounds 1 or pyrrole compounds or thiourea compounds.

[0007] Beneficial effects: The present invention provides a new method for generating difluoromethyl heteroaromatic compounds using palladium-catalyzed reactions under mild conditions. The method uses iododifluoromethylphenylsulfone as a difluoromethylating agent, exhibits broad substrate compatibility, and achieves excellent yields.

[0008] Preferably, the specific preparation method is as follows: palladium catalyst, ligand, base and iodine difluoromethyl phenyl sulfone are added to a reaction container in sequence, the reaction container is evacuated and backfilled with inert gas for protection, indole compound 1 and organic solvent are added for stirring, and the reaction container is placed in an oil bath preheated to 30-80°C for reaction for 24-48h, wherein: the equivalent ratio of the indole compound 1 to iodine difluoromethyl phenyl sulfone is 1:1.6, the molar ratio of the indole compound 1 to the palladium catalyst is 1:0.05, the molar ratio of the indole compound 1 to the ligand is 1:0.2, the equivalent ratio of the indole compound 1 to the base is 1:2, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature and separated by column chromatography to obtain the corresponding difluoromethyl indole compound 2; the synthetic route is as follows:

[0009]

[0010] R 1 is alkyl or halogen, R 2 is an alkyl or aryl group, R 3 is an alkyl group or a benzyl group.

[0011] Preferably, the halogen is fluorine, chlorine or bromine.

[0012] Preferably, the specific preparation method is as follows: palladium catalyst, ligand, base and iodine difluoromethyl phenyl sulfone are added to a reaction container in sequence, the reaction container is evacuated and backfilled with inert gas for protection, pyrrole compound and organic solvent are added for stirring, and the reaction container is placed in an oil bath preheated to 30-80°C for reaction for 24-48h, wherein: the equivalent ratio of the pyrrole compound to iodine difluoromethyl phenyl sulfone is 2.5:1, the molar ratio of the pyrrole compound to the palladium catalyst is 50:1, the molar ratio of the pyrrole compound to the ligand is 12.5:1, the equivalent ratio of the pyrrole compound to the base is 1.25:1, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature and separated by column chromatography to obtain the corresponding difluoromethyl pyrrole compound, the pyrrole compound is The product obtained is

[0013] Preferably, the specific preparation method is as follows: a palladium catalyst, a ligand, a base and iodine difluoromethyl phenyl sulfone are added to a reaction container in sequence, the reaction container is evacuated and backfilled with an inert gas for protection, a thiourea compound and an organic solvent are added for stirring, and the reaction container is placed in an oil bath preheated to 30-80°C for reaction for 24-48h, wherein: the equivalent ratio of the thiourea compound to iodine difluoromethyl phenyl sulfone is 2.5:1, the molar ratio of the thiourea compound to the palladium catalyst is 50:1, the molar ratio of the thiourea compound to the ligand is 12.5:1, the equivalent ratio of the thiourea compound to the base is 1.25:1, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature and separated by column chromatography to obtain the corresponding difluoromethyl thiourea compound, the thiourea compound is The product obtained is

[0014] Preferably, the palladium catalyst is selected from tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium acetate, palladium trifluoroacetate, palladium trifluoromethanesulfonate, palladium / carbon, palladium hydroxide on carbon, di(acetylacetone)palladium, di(benzylideneacetone)palladium, tri(benzylideneacetone)dipalladium, di(triphenyltris(dibenzylideneacetone)dipalladiumphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, and (1,5-cyclooctadiene)palladium dichloride.

[0015] Preferably, the ligand is selected from triphenylphosphine, tri(2-methylphenyl)phosphine, tri(dimethylamino)phosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, tri-(1-adamantyl)phosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tri(4-trifluoromethylphenyl)phosphine, 2-diphenylphosphine-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, tri(2-furyl)phosphine, 2-diphenylphosphine-2',4',6'-triisopropylbiphenyl, (2-methoxyphenyl)diphenylphosphine, 4,5-bis(dicyclohexylphosphine)-9,9-dimethyloxanthene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, bis(2-(diphenylphosphino)phenyl)ether.

[0016] Preferably, the base is selected from sodium hydroxide, potassium fluoride, phosphates, carbonates, triethylamine and cesium carbonate.

[0017] Preferably, the organic solvent is selected from dichloromethane, N,N-dimethylformamide, acetonitrile and chloroform.

[0018] Preferably, the palladium catalyst is tris(dibenzylideneacetone)dipalladium.

[0019] Preferably, the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0020] Preferably, the base is cesium carbonate.

[0021] Preferably, the organic solvent is chloroform.

[0022] The second aspect of the present invention provides a difluoromethyl heteroaromatic compound prepared according to the above-mentioned method for preparing difluoromethyl indole compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the product 2a in Example 1 1 H NMR;

[0024] Figure 2 is the product 2a in Example 1 13 C NMR;

[0025] Figure 3 is the product 2a in Example 1 19 F NMR;

[0026] Figure 4 is the product 2b in Example 2 1 H NMR;

[0027] Figure 5 is the product 2b in Example 2 13 C NMR;

[0028] Figure 6 is the product 2b in Example 2 19 F NMR;

[0029] Figure 7 is the product 2c in Example 3 1 H NMR;

[0030] Figure 8 is the product 2c in Example 3 13 C NMR;

[0031] Fig. 9 is the product 2c in Example 3 19 F NMR;

[0032] Fig.10 is the product 2d in Example 4 1 H NMR;

[0033] Fig.11 is the product 2d in Example 4 13 C NMR;

[0034] Fig.12 is the product 2d in Example 4 19 F NMR;

[0035] Fig.13 is the product 2e in Example 5 1 H NMR;

[0036] Fig.14 is the product 2e in Example 5 13 C NMR;

[0037] Fig.15 is the product 2e in Example 5 19 F NMR;

[0038] Fig.16 is the product 2f in Example 6 1 H NMR;

[0039] Fig.17 is the product 2f in Example 6 13 C NMR;

[0040] Fig.18 is the product 2f in Example 6 19 F NMR;

[0041] Fig.19 is the product 2f in Example 7 1 H NMR;

[0042] Fig. 20 is the product 2f in Example 7 13 C NMR;

[0043] Fig.21 is the product 2f in Example 7 19 F NMR;

[0044] Fig. 22 is the product 2f in Example 8 1 H NMR;

[0045] Fig.23 is the product 2f in Example 8 13 C NMR;

[0046] Fig.24 is the product 2f in Example 8 19 F NMR. DETAILED DESCRIPTION

[0047] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0048] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0049] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0050] The embodiment provides a method for preparing a difluoromethyl heteroaromatic compound, using a heteroaromatic compound and iododifluoromethyl phenylsulfone as raw materials, reacting for a certain time under the action of a palladium catalyst, a ligand, a base, an organic solvent and temperature to generate a series of difluoromethyl heteroaromatic compounds; the heteroaromatic compound is an indole compound 1 or a pyrrole compound or a thiourea compound. For specific embodiments, please refer to Table 1. When the heteroaromatic compound is an indole compound 1, the specific synthesis route is as follows:

[0051]

[0052] Table 1

[0053]

[0054]

[0055] The above only lists several representative compounds and gives a detailed preparation process, as follows:

[0056] Example 1

[0057] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added to the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1a (145.2 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40°C for reaction for 30 h. After the reaction, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2a with a yield of 84%.

[0058] The data of product 2a are as follows:

[0059] 1H NMR (400MHz, CDCl3) δ7.96 (d, J=8.0Hz, 2H), 7.76 (tt, J=7.2, 1.2Hz, 1H), 7.61-7.57 (m, 3H),7.36-7.35(m,2H),7.18-7.14(m,1H),3.91(t,J=1.6Hz,3H),2.26(t,J=3.2Hz,3H).

[0060] 13 C NMR (101MHz, CDCl3) δ139.0,135.4,133.1,130.9,129.4,127.4,125.1,121.2(t,J=287.4Hz),12 0.2, 120.0, 119.7 (t, J = 3.5Hz), 119.5 (t, J = 25.4Hz), 109.9, 31.9 (t, J = 4.9Hz), 9.1 (t, J = 3.4Hz).

[0061] 19 F NMR(376MHz, CDCl3)δ-94.5.HRMS EI(m / z):[M] + calcd.for C 17 H 15 F2NO2S:335.0792,found:335.0799.

[0062] Example 2

[0063] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added into the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1b (221.3 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40°C for reaction for 30 h. After the reaction, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2b with a yield of 78%.

[0064] The data of product 2b are as follows:

[0065] 1H NMR(400MHz, CDCl3) δ7.96(d,J=7.6Hz,2H),7.74(tt,J=7.2,1.2Hz,1H),7.65(d,J=8.0Hz,1H), 7.56-7.61(m,2H),7.30-7.15(m,6H),6.96(d,J=6.8Hz,2H),5.62(s,2H),2.34(t,J=2.8Hz,3H).

[0066] 13 C NMR (101MHz, CDCl3) δ138.9,138.3,135.4,133.0,130.9,129.4,128.6,127.8,127.2,125.6,125.4,121.1(t,J =287.0Hz), 120.4, 120.3, 120.3 (t, J = 3.3Hz), 119.5 (t, J = 25.8Hz), 110.7, 49.0 (t, J = 3.7Hz), 9.3 (t, J = 3.4Hz).

[0067] 19 F NMR(376MHz, CDCl3)δ-94.0(d,J=3.4Hz).HRMS ESI(m / z):[M+H] + calcd.forC 23 H 20 F2NO2S:412.1105,found:412.1169.

[0068] Example 3

[0069] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added to the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1c (179.6 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40°C for reaction for 30 h. After the reaction, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2c with a yield of 84%.

[0070] The data of product 2c are as follows:

[0071] 1H NMR (400MHz, CDCl3) δ7.99 (d, J=8.0Hz, 2H), 7.78 (tt, J=7.2, 1.2Hz, 1H), 7.64-7.59 (m, 2H), 7.48 (dd, J=8 .0,1.2Hz,1H),7.29(d,J=7.6Hz,1H),7.03(t,J=7.6Hz,1H),4.31(t,J=1.2Hz,3H),2.27(t,J=3.2Hz,3H).

[0072] 13 C NMR (101MHz, CDCl3) δ135.5,134.3,133.0,131.0,130.5,129.5,127.2,121.6(t,J=25.0Hz),120 .9(t,J=287.9Hz),120.5,120.3(t,J=3.5Hz),119.1,117.3,34.7(t,J=5.4Hz),9.4(t,J=3.9Hz).

[0073] 19 F NMR(376MHz, CDCl3)δ-93.0.HRMS EI(m / z):[M] + calcd.for C 17 H 14 ClF2NO2S:369.0402,found:369.0398.

[0074] Example 4

[0075] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added to the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1d (179.6 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40° C. for reaction for 30 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2d with a yield of 76%.

[0076] The data of product 2d are as follows:

[0077] 1H NMR (400MHz, CDCl3) δ7.95 (d, J=8.0Hz, 2H), 7.77 (tt, J=7.6, 1.6Hz, 1H), 7.63-7.58 (m, 2H ),7.56(d,J=1.6Hz,1H),7.32-7.28(m,2H),3.90(t,J=1.6Hz,3H),2.21(t,J=3.2Hz,3H).

[0078] 13 C NMR (101MHz, CDCl3) δ137.3,135.5,132.9,130.9,129.4,128.2,125.8,125.4,120.8(t,J=287.0 Hz), 120.8 (t, J = 25.6Hz), 119.5, 119.0 (t, J = 3.5Hz), 111.1, 32.2 (t, J = 4.9Hz), 9.1 (t, J = 3.4Hz).

[0079] 19 F NMR(376MHz, CDCl3)δ-95.0.HRMS EI(m / z):[M] + calcd.for C 17 H 14 ClF2NO2S:369.0402,found:369.0399.

[0080] Example 5

[0081] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added into the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1f (173.3 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40°C for reaction for 30 h. After the reaction, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2e with a yield of 64%.

[0082] The data of product 2e are as follows:

[0083] 1H NMR (400MHz, CDCl3) δ8.06(d,J=8.0Hz,2H),7.90(d,J=8.0Hz,1H),7.78(tt,J=7.6,1.2Hz,1H),7.66-7.62(m,2H),7.37(d,J=8.0Hz,1H ),7.33(ddd,J=7.6,6.8,1.2Hz,1H),7.12(ddd,J=8.4,6.8,1.6Hz,1H),3.87(t,J=2.0Hz,3H),3.56-3.45(m,1H),1.45(d,J=6.8Hz,6H).

[0084] 13 C NMR (101MHz, CDCl3) δ139.8,135.4,133.4,130.9,130.6(t,J=3.1Hz),129.5,125.2,124.6,122.7, 121.3(t,J=287.8Hz),119.5,118.1(t,J=23.9),110.4,32.0(t,J=5.7Hz),26.4(t,J=4.2Hz),23.2.

[0085] 19 F NMR(376MHz, CDCl3)δ-91.8.HRMS EI(m / z):[M] + calcd.for C 19 H 19 F2NO2S:363.1105,found:363.1100.

[0086] Example 6

[0087] Tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (508.9 mg, 1.6 mmol) were accurately weighed and added to the reaction vessel in sequence. The reaction vessel was evacuated and backfilled with nitrogen for protection. Indole compound 1f (159.2 mg, 1.0 mmol) and 0.1 M chloroform were added and stirred. The reaction vessel was placed in an oil bath preheated to 40°C for reaction for 30 h. After the reaction, the mixture was cooled to room temperature and separated by column chromatography to obtain product 2f with a yield of 60%.

[0088] The data of product 2f are as follows:

[0089] 1H NMR (400MHz, CDCl3) δ7.98(d,J=7.6,Hz,2H),7.76(tt,J=7.6,1.2Hz,1H),7.65(d,J=8.0Hz,1H),7.63-7.58(m,2H ),7.37-7.35(m,2H),7.17-7.13(m,1H),3.91(t,J=1.6Hz,3H),2.75(qt,J=7.6,2.4Hz,2H),1.22(t,J=7.6Hz,3H).

[0090] 13 C NMR (101MHz, CDCl3) δ139.2, 135.4, 133.1, 131.0, 129.4, 126.6, 126.5 (t, J = 3.3Hz), 125.0, 121.2 (t ,J=287.5Hz),120.3,120.0,118.8(t,J=25.6Hz),110.1,31.9(t,J=4.9Hz),17.9(t,J=3.0Hz),16.4.

[0091] 19 F NMR(376MHz, CDCl3)δ-93.7.HRMS ESI(m / z):[M+H] + calcd.for C 18 H 18 F2NO2S:350.0948,found:350.1010.

[0092] Example 7

[0093] Accurately weigh tri(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (318.1 mg, 1.0 mmol) and add them to the reaction vessel in sequence. Evacuate the reaction vessel and backfill with nitrogen for protection. Add 1 g of pyrrole compound (202.8 mg, 2.5 mmol) and 0.1 M chloroform and stir. Place the reaction vessel in an oil bath preheated to 60 ° C to react for 24 h. After the reaction, cool the mixture to room temperature and separate by column chromatography to obtain 2 g of product with a yield of 94%.

[0094] The data of product 2g are as follows:

[0095] 1H NMR (400MHz, CDCl3) δ7.95-7.93(m,2H),7.74(tt,J=7.6,1.6Hz,1H),7.62-7.57(m,2H ),6.80(t,J=2.0Hz,1H),6.54-6.52(m,1H),6.16-6.14(m,1H),3.84(t,J=1.2Hz,3H).

[0096] 13 C NMR (101MHz, CDCl3) δ135.2, 133.3, 130.8, 129.3 (t, J = 2.3Hz), 129.3, 120.2 (t, J=285.3Hz), 116.9 (t, J=29.4Hz), 116.6 (t, J=4.7Hz), 108.5, 36.2 (t, J=3.3Hz).

[0097] 19 F NMR(376MHz, CDCl3)δ-96.8.HRMS ESI(m / z):[M+H] + calcd.for C 12 H 12 F2NO2S:272.0479,found:272.0548.

[0098] Example 8

[0099] Accurately weigh tris(dibenzylideneacetone)dipalladium (45.8 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.7 mg, 0.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol) and iododifluoromethylphenylsulfone (318.1 mg, 1.0 mmol) were added to the reaction vessel in sequence, the reaction vessel was evacuated and backfilled with nitrogen for protection, thiourea compound 1h (282.9 mg, 2.5 mmol) and 0.1 M chloroform were added for stirring, and the reaction vessel was placed in an oil bath preheated to 60°C for reaction for 24 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain the product 2h with a yield of 84%.

[0100] The data of product 2h are as follows:

[0101] 1 H NMR (400MHz, CDCl3) δ8.01(d,J=7.6Hz,2H),7.78(tt,J=7.6,1.2Hz,1H),7.65-7.61(m,2H),2.71(s,3H),2.51(t,J=2.4Hz,3H).

[0102] 13 C NMR (101MHz, CDCl3) δ 169.3, 157.4 (t, J = 2.4Hz), 135.6, 132.6, 131.0, 129.5, 121.0 (t, J = 287.4Hz), 115.6 (t, J = 26.0Hz), 19.4, 16.6 (t, J = 2.2Hz).

[0103] 19 F NMR(376MHz, CDCl3)δ-91.0.HRMS EI(m / z):[M] + calcd.for C 12 H 11 F2NO2S2:303.0199,found:303.0215.

[0104] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a difluoromethyl heteroaromatic compound, characterized in that: Using heteroaromatic compounds and iododifluoromethylphenylsulfone as raw materials, under the action of palladium catalyst, ligand, base, organic solvent and temperature, the reaction is carried out for a certain time to generate a series of difluoromethyl heteroaromatic compounds; the heteroaromatic compounds are indole compounds 1 or pyrrole compounds or thiourea compounds.

2. The method for preparing difluoromethyl heteroaromatic compounds according to claim 1, characterized in that: The specific preparation method is as follows: palladium catalyst, ligand, base and iodine difluoromethyl phenyl sulfone are added to a reaction container in sequence, the reaction container is evacuated and backfilled with inert gas for protection, indole compound 1 and organic solvent are added and stirred, and the reaction container is placed in an oil bath preheated to 30-80°C for reaction for 24-48h, wherein: the equivalent ratio of the indole compound 1 to iodine difluoromethyl phenyl sulfone is 1:1.6, the molar ratio of the indole compound 1 to the palladium catalyst is 1:0.05, the molar ratio of the indole compound 1 to the ligand is 1:0.2, the equivalent ratio of the indole compound 1 to the base is 1:2, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature, separated by column chromatography, and the corresponding difluoromethyl indole compound 2 is obtained. The synthesis route is as follows: R 1 is alkyl or halogen, R 2 is an alkyl or aryl group, R 3 is an alkyl group or a benzyl group.

3. The method for preparing difluoromethyl heteroaromatic compounds according to claim 2, wherein the specific preparation method is as follows: a palladium catalyst, a ligand, a base and iodine difluoromethyl phenyl sulfone are sequentially added to a reaction vessel, the reaction vessel is evacuated and backfilled with an inert gas for protection, a pyrrole compound and an organic solvent are added for stirring, and the reaction vessel is placed in an oil bath preheated to 30-80° C. for reaction for 24-48 hours, wherein: The equivalent ratio of the pyrrole compound to iododifluoromethylphenylsulfone is 2.5:1, the molar ratio of the pyrrole compound to the palladium catalyst is 50:1, the molar ratio of the pyrrole compound to the ligand is 12.5:1, the equivalent ratio of the pyrrole compound to the base is 1.25:1, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature and separated by column chromatography to obtain the corresponding difluoromethylpyrrole compound, the pyrrole compound is The product obtained is 4. The method for preparing difluoromethyl heteroaromatic compounds according to claim 2, characterized in that: The specific preparation method is as follows: a palladium catalyst, a ligand, a base and iodine difluoromethyl phenyl sulfone are added to a reaction container in sequence, the reaction container is evacuated and backfilled with an inert gas for protection, a thiourea compound and an organic solvent are added for stirring, and the reaction container is placed in an oil bath preheated to 30-80° C. for reaction for 24-48 hours, wherein: the equivalent ratio of the thiourea compound to iodine difluoromethyl phenyl sulfone is 2.5:1, the molar ratio of the thiourea compound to the palladium catalyst is 50:1, the molar ratio of the thiourea compound to the ligand is 12.5:1, the equivalent ratio of the thiourea compound to the base is 1.25:1, and the concentration of the organic solvent is 0.1M; after the reaction is completed, the mixture is cooled to room temperature, separated by column chromatography, and the corresponding difluoromethyl thiourea compound is obtained, and the thiourea compound is The product obtained is 5. The method for preparing difluoromethyl heteroaromatic compounds according to any one of claims 1 to 4, characterized in that: The palladium catalyst is selected from tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium acetate, palladium trifluoroacetate, palladium trifluoromethanesulfonate, palladium / carbon, palladium hydroxide on carbon, di(acetylacetone)palladium, di(benzylideneacetone)palladium, tri(benzylideneacetone)dipalladium, di(triphenyltris(dibenzylideneacetone)dipalladiumphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, and (1,5-cyclooctadiene)palladium dichloride.

6. The method for preparing a difluoromethyl heteroaromatic compound according to any one of claims 1 to 4, wherein the ligand is selected from triphenylphosphine, tri(2-methylphenyl)phosphine, tri(dimethylamino)phosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, tri-(1-adamantyl)phosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tri(4-trifluoromethylphenyl)phosphine, 2-diphenylphosphine-2'-(N,N-dimethylamino)phosphine, 1,2-Bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, bis(2-(diphenylphosphino)phenyl)ether.

7. The method for preparing a difluoromethyl heteroaromatic compound according to any one of claims 1 to 4, characterized in that: The base is selected from sodium hydroxide, potassium fluoride, phosphates, carbonates, triethylamine and cesium carbonate.

8. The method for preparing difluoromethyl heteroaromatic compounds according to any one of claims 1 to 4, characterized in that: The organic solvent is selected from the group consisting of dichloromethane, N,N-dimethylformamide, acetonitrile and chloroform.

9. The method for preparing difluoromethyl heteroaromatic compounds according to any one of claims 1 to 4, characterized in that: The palladium catalyst is tris(dibenzylideneacetone)dipalladium; the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; the base is cesium carbonate; and the organic solvent is chloroform.

10. A difluoromethyl heteroaromatic compound, characterized in that: The compound is prepared according to the method for preparing difluoromethyl indole compounds according to claims 1-9.

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