A method for synthesizing 6-trifluoromethylthiophenanthridine compounds

Abstract

The invention discloses a kind of synthetic method of 6-trifluoromethylthiophenanthridine compounds, belong to the field of organic synthesis technology.The present invention uses phenanthridinethione as raw material, with cheap and easily available trifluorobromomethane as fluorination reagent, under the action of visible light induction and photocatalyst and alkali, by the free radical addition reaction of C=S, prepares the phenanthridine compounds containing trifluoromethylthio in one step.The method has the characteristics of green safety, cheap and easy to obtain raw materials, high atom economy, good regioselectivity of reaction, mild reaction conditions, wide application range of substrate, high yield and easy purification of product, belongs to green synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 6-trifluoromethylthiophenanthridine compounds. Background Art

[0002] Phenanthridines are an important class of nitrogen-containing heterocyclic compounds that are widely found in natural alkaloids and drug molecules. For example, a relatively representative natural benzophenanthridine alkaloid was isolated from the Amaryllidaceae plant Narcissus asturiensis. Proven anti-HIV-1 protease activity; Humidinium bromide salt It is a commonly used multifunctional DNA / RNA intercalator; nitidine chloride with a benzophenanthridine structure It has many activities including anti-inflammatory, anti-tumor and anti-malarial.

[0003] Among various fluorinated groups, the trifluoromethylthio group (SCF3) exhibits high lipid solubility and strong electron-withdrawing ability. As shown by the Hansch hydrophobicity parameter, the trifluoromethylthio group has the highest π coefficient among common fluorinated groups. Its introduction into drug molecules can significantly improve lipid solubility, enhance cell membrane permeability, and enhance drug bioavailability. Furthermore, due to the strong electron-withdrawing ability of the trifluoromethylthio group, the modified drug molecules possess high metabolic stability. Currently, the synthesis of trifluoromethylthio-containing phenanthridine compounds has been limited. Reported literature primarily uses phenanthridine N-oxide as a raw material. The 2,4-dinitrobenzenesulfonyl chloride used in the synthesis process can react explosively in organic solvents, posing a significant safety hazard. Furthermore, only one trifluoromethylthiophenanthridine compound has been synthesized, resulting in a narrow substrate range. Therefore, the development of novel, efficient, and facile synthetic methods for preparing more trifluoromethylthio-containing phenanthridine compounds is highly desirable. Summary of the Invention

[0004] The present invention aims to provide a method for synthesizing 6-trifluoromethylthiophenanthridine compounds to address the problems of the prior art. Using phenanthridinethione as a raw material and inexpensive and readily available trifluorobromomethane as a fluorination agent, the present invention uses visible light-induced, photocatalyst- and base-induced C=S free radical addition reaction to prepare a phenanthridine compound containing a trifluoromethylthio group in a single step. This method is characterized by its environmental friendliness and safety, its readily available and inexpensive raw materials, its high atom economy, its good regioselectivity, its mild reaction conditions, its wide substrate applicability, its high yield, and its ease of product purification, making it a green synthesis.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] One of the technical solutions of the present invention is a 6-trifluoromethylthiophenanthridine compound, the structural formula of which is shown in formula (1):

[0007]

[0008] Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

[0009] The second technical solution of the present invention is a method for synthesizing the above-mentioned 6-trifluoromethylthiophenanthridine compound, comprising the following steps:

[0010] Phenanthridinethione, a photocatalyst and a base are added to an organic solvent, and then CF3Br is introduced to carry out a visible light-induced reaction, and the 6-trifluoromethylthiophenanthridine compound is obtained after purification by column chromatography;

[0011] The structural formula of the phenanthridinethione is as follows:

[0012]

[0013] Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

[0014] The chemical reaction formula is as follows:

[0015]

[0016] Furthermore, the photocatalyst (PC) includes fac-Ir III (ppy)3 (tris(2-phenylpyridine)iridium), Ru(bpy)3Cl2 (terpyridylruthenium chloride hexahydrate), or 4CzIPN (2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile);

[0017] The base includes K2CO3, KHCO 3、 Na2CO3, K3PO4, K2HPO4, Li2CO3, NaOAc, Et3N or 2,6-lutidine;

[0018] The organic solvent includes CH3CN, DMF, DMSO (dimethyl sulfoxide), THF, acetone or 1,4-dioxane.

[0019] Furthermore, the photocatalyst is fac-Ir III (ppy) 3; the base is 2,6-lutidine; and the organic solvent is DMSO.

[0020] Furthermore, the molar ratio of the phenanthridinethione to the base is (1-3):(2-6).

[0021] Furthermore, the molar ratio of the phenanthridinethione to the base is 1:2.

[0022] Furthermore, the amount of the photocatalyst used is 0.5 to 1.5 mol% of the molar amount of phenanthridinethione.

[0023] The pressure of the CF3Br in the reaction system is 1.0 to 1.5 atm.

[0024] Furthermore, the amount of the photocatalyst used is 1.0 mol% of the molar amount of phenanthridinethione; and the pressure of the CF3Br in the reaction system is 1.0 atm.

[0025] Furthermore, the wavelength of the visible light is 390 to 460 nm;

[0026] The induction reaction time is 12 to 48 hours.

[0027] Furthermore, the induction reaction temperature is 25° C. and the time is 24 hours.

[0028] Furthermore, the visible light is 5W, 10W, 15W or 20W blue light.

[0029] Furthermore, the visible light is 15W blue light.

[0030] Furthermore, the usage ratio of the phenanthridinethione and the organic solvent is 0.2 mmol:1-5 mL.

[0031] Furthermore, the usage ratio of the phenanthridinethione and the organic solvent is 0.2 mmol:3 mL.

[0032] Furthermore, the eluent used in the column chromatography purification is petroleum ether (PE) and ethyl acetate (EA) in a volume ratio of (100-60):1.

[0033] The third technical solution of the present invention: a use of the above-mentioned 6-trifluoromethylthiophenanthridine compound in the preparation of anti-inflammatory, anti-tumor or anti-malarial drugs.

[0034] The 6-trifluoromethylthiophenanthridine compound prepared by the present invention is a kind of nitrogen-containing heterocyclic compound, and nitrogen-containing heterocyclic compound generally has biological activity, such as anti-inflammatory, antibacterial and antitumor, therefore, the 6-trifluoromethylthiophenanthridine compound prepared by the present invention also has the above-mentioned biological activity. Simultaneously, because trifluoromethylthio (SCF3) has higher fat solubility and stronger electron-withdrawing ability, this just makes the drug molecule after being modified by trifluoromethylthio have higher metabolic stability, and can improve the bioavailability of medicine. Therefore, the phenanthridine compound containing trifluoromethylthio also possesses the above-mentioned biological activity.

[0035] The present invention discloses the following technical effects:

[0036] (1) The 6-trifluoromethylthiophenanthridine compounds of the present invention have anti-inflammatory, antibacterial or anti-tumor activities and can be used to prepare anti-inflammatory, anti-tumor or anti-malarial drugs.

[0037] (2) The present invention uses phenanthridinethione as a raw material and trifluorobromomethane as a fluorination agent. Under the induction of visible light and the action of a photocatalyst and a base, the trifluoromethyl radical generated by trifluorobromomethane undergoes a free radical addition reaction with C=S to prepare a phenanthridine compound containing a trifluoromethylthio group in one step.

[0038] (3) The present invention is the first to use a free radical addition reaction involving phenanthridinethione for the synthesis of 6-trifluoromethylthiophenanthridine compounds, and the first to use trifluorobromomethane (CF3Br is a non-toxic, odorless, cheap and easily available industrial raw material. Compared with other fluorination reagents, its greatest advantages are low price, easy availability and high atom economy) for the free radical addition reaction of C=S to construct a trifluoromethylthio group, providing a new raw material selection for the synthesis of 6-trifluoromethylthiophenanthridine compounds.

[0039] (4) The synthesis method provided by the present invention has a high degree of regioselectivity (i.e., all 6-trifluoromethylthiophenanthridine compounds are obtained), has the characteristics of short reaction steps, cheap and readily available raw materials, simple operation, mild reaction conditions, high reaction yield, and high purity of the obtained products, which conforms to the concept of green synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0041] Figure 1 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 1 H NMR spectra;

[0042] Figure 2 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 13 C NMR spectrum;

[0043] Figure 3 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 19 F NMR spectrum;

[0044] Figure 4This is a high-resolution mass spectrometry monitoring diagram of 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention;

[0045] Figure 5 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 1 H NMR spectra;

[0046] Figure 6 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 13 C NMR spectrum;

[0047] Figure 7 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 19 F NMR spectrum;

[0048] Figure 8 This is a high-resolution mass spectrometry monitoring diagram of 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention;

[0049] Figure 9 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 1 H NMR spectra;

[0050] Figure 10 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 13 C NMR spectrum;

[0051] Figure 11 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 19 F NMR spectrum;

[0052] Figure 12 This is a high-resolution mass spectrometry monitoring diagram of 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention;

[0053] Figure 13 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 1 H NMR spectra;

[0054] Figure 14 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 13 C NMR spectrum;

[0055] Figure 15 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 19 F NMR spectrum;

[0056] Figure 16 This is a high-resolution mass spectrometry monitoring diagram of 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention;

[0057] Figure 17 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 1 H NMR spectra;

[0058] Figure 18 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 13 C NMR spectrum;

[0059] Figure 19 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 19 F NMR spectrum;

[0060] Figure 20 This is a high-resolution mass spectrometry monitoring chart of 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention. DETAILED DESCRIPTION

[0061] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0062] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0063] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0064] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0065] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0066] The phenanthridine-6(5H)-thione (1a) used in the examples of the present invention is a known compound. Its synthesis method and structural characterization data can be found in the literature: Zhao CL, Han QY, Zhang CP. TfOH-promoted transition-metal-free cascade trifluoroethylation / cyclization of organic isothiocyanates byphenyl(2,2,2-trifluoroethyl)iodonium triflate[J]. Organic letters, 2018, 20(20): 6480-6484.

[0067] The 8-methylphenanthridine-6(5H)-thione (1b), 8-methoxyphenanthridine-6(5H)-thione (1c), 8-fluorophenanthridine-6(5H)-thione (1d) and 8-chlorophenanthridine-6(5H)-thione (1e) used in the examples of the present invention are new compounds, and their synthesis methods are the same as those mentioned above.

[0068] The chemical reaction formula of the specific synthesis method is as follows:

[0069]

[0070] The specific synthesis steps of phenanthridinethiones 1b, 1c, 1d and 1e are as follows:

[0071] (1) Preparation of biphenyl-2-amine

[0072] A. Preparation of 4'-methyl-[1,1'-biphenyl]-2-amine: Under nitrogen atmosphere, 2-bromoaniline (0.86 g, 5.0 mmol), 4-methylphenylboronic acid (0.816 g, 6.0 mmol), Na2CO3 (1.33 g, 12.5 mmol), Pd(PPh3)4 (0.29 g, 0.25 mmol) and toluene / ethanol / H2O (24 mL, 1:1:1 (v / v / v)) solvent were added into a 100 mL Schlenk flask. The mixture was stirred at 80°C for 6 h. TLC indicated complete conversion of the starting material. The mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl solution, and extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and spin-dried to obtain a crude product, which was then purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=10:1, volume ratio) to obtain 4'-methyl-[1,1'-biphenyl]-2-amine as a yellow oily liquid, 0.732 g, with a yield of 80%.

[0073] B. The preparation method of 4'-methoxy-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboronic acid is replaced with an equal molar amount of 4-methoxyphenylboronic acid; the product is a yellow oily liquid, 0.816 g, with a yield of 82%.

[0074] C. The preparation method of 4'-fluoro-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboronic acid is replaced with an equal molar amount of 4-fluorophenylboronic acid. The product is a yellow oily liquid, 0.73 g, with a yield of 78%.

[0075] D. The preparation method of 4'-chloro-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboronic acid is replaced with an equal molar amount of 4-chlorophenylboronic acid. The product is a yellow oily liquid, 0.812 g, with a yield of 80%.

[0076] (2) Preparation of biphenyl-2-isothiocyanate

[0077] A. Preparation of 4'-Methyl-1,1'-biphenyl-2-isothiocyanate: 4'-Methyl-[1,1'-biphenyl]-2-amine (0.632 g, 4.0 mmol), thiocarbonyldiimidazole (0.854 g, 4.8 mmol), and CH2Cl2 (15 mL) were added to a 100 mL round-bottom flask under air. The mixture was stirred at room temperature for 2 h. TLC confirmed complete conversion of the starting material. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 15:1, volume ratio) as eluents to obtain 4'-methyl-1,1'-biphenyl-2-isothiocyanate as a colorless oily liquid (0.855 g, 95% yield).

[0078] B. Preparation of 4'-methoxy-1,1'-biphenyl-2-isothiocyanate: The preparation was the same as that of 4'-methyl-1,1'-biphenyl-2-isothiocyanate, except that 4'-methyl-[1,1'-biphenyl]-2-amine was replaced with an equal molar amount of 4'-methoxy-[1,1'-biphenyl]-2-amine. The product was a colorless oily liquid, 0.879 g, with a yield of 89%.

[0079] C. Preparation of 4'-Fluoro-1,1'-biphenyl-2-isothiocyanate: The preparation was the same as that of 4'-methyl-1,1'-biphenyl-2-isothiocyanate, except that 4'-methyl-[1,1'-biphenyl]-2-amine was replaced with an equal molar amount of 4'-fluoro-[1,1'-biphenyl]-2-amine. The product was a colorless oily liquid, 0.742 g, with a yield of 83%.

[0080] D. Preparation of 4'-chloro-1,1'-biphenyl-2-isothiocyanate: The preparation was the same as that of 4'-methyl-1,1'-biphenyl-2-isothiocyanate, except that 4'-methyl-[1,1'-biphenyl]-2-amine was replaced with an equal molar amount of 4'-chloro-[1,1'-biphenyl]-2-amine. The product was a colorless oily liquid, 0.784 g, with a yield of 80%.

[0081] (3) Preparation of phenanthridinethione

[0082] A. Preparation of 8-methylphenanthridine-6(5H)-thione (1b): 4'-Methyl-1,1'-biphenyl-2-isothiocyanate (0.855 g, 3.8 mmol), trifluoromethanesulfonic acid (TfOH) (1.58 g, 11.4 mmol), and CH2Cl2 (12 mL) were added to a 50 mL round-bottom flask under air. The mixture was refluxed at 40°C for 6 h. TLC confirmed complete conversion of the starting material. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous Na2CO3. A yellow solid precipitated, which was collected, washed with glacial H2O (3 × 10 mL), and dried to afford 8-methylphenanthridine-6(5H)-thione (1b) as a yellow solid, 0.795 g, in a 93% yield.

[0083] The structural characterization data are as follows:

[0084] 1 H NMR(400MHz, DMSO-d6)δ8.84(s,1H),8.33(t,J=6.4Hz,2H),7.64(d,J=8.0Hz,1H), 7.57(d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),7.27(t,J=7.6Hz,1H),2.46(s,3H).; 13 CNMR(150MHz,DMSO-d6)182.9,140.1,137.1,133.1,131.8,131.1,128.8,128.3,123.5,122.8,122.5,121.3,121.1,21.6.; HRMS(ESI):m / z calcd for chemical formula:C 14 H 12 NS[M+H] + 226.0685; found 226.0688.

[0085] B. 8-Methoxyphenanthridine-6(5H)-thione (1c) was prepared in the same manner as 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate was replaced with an equimolar amount of 4'-methoxy-1,1'-biphenyl-2-isothiocyanate. The product was a yellow solid, 0.809 g, with a yield of 92%.

[0086] The structural characterization data are as follows:

[0087] 1 H NMR (400MHz, DMSO-d6) δ8.57-8.29(m,3H),7.82-7.23(m,4H),3.91(s,3H).; 13CNMR(150MHz,DMSO-d6)182.8,159.4,135.7,132.1,129.0,125.0,124.8,124.1,123.0,122.7,120.7,117.7,112.9,55.9.; HRMS(ESI):m / z calcd for chemical formula:C 14 H 12 NOS[M+H] + 242.0634; found 242.0642.

[0088] C. 8-Fluorophenanthridine-6(5H)-thione (1d) was prepared using the same method as 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate was replaced with an equimolar amount of 4'-fluoro-1,1'-biphenyl-2-isothiocyanate. The product was a yellow solid, 0.586 g, with a yield of 79%.

[0089] The structural characterization data are as follows:

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=11.2Hz,1H),8.58(dd,J=9.2,5.6Hz,1H),8.38(d ,J=8.4Hz,1H),7.61(t,J=8.4Hz,2H),7.49(t,J=7.2Hz,1H),7.30(t,J=7.2Hz,1H).; 13 C NMR(150MHz,DMSO-d6)δ181.1,160.7(d,J C-F =240Hz),133.1(d,J C-F =5.9Hz),128.1,127.4,124.8,122.4,122.2,120.5,119.8,118.2,118.0,115.9(d,J C-F =22.8Hz). 19 F NMR(376MHz, DMSO-d6)δ-110.97(m).; HRMS(ESI):m / z calcd for chemical formula:C 13 H9NFS[M+H] + 230.04342; found 230.04355.

[0091] D. 8-Chlorophenanthridine-6(5H)-thione (1e) was prepared using the same method as 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate was replaced with an equal molar amount of 4'-chloro-1,1'-biphenyl-2-isothiocyanate. The product was a yellow solid, 0.659 g, with a yield of 84%.

[0092] The structural characterization data are as follows:

[0093] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.47(d,J=8.8Hz,1H),8.32(d,J=8.0Hz,1H),7.69(d d,J=8.8,2.4Hz,1H),7.61(d,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.25(t,J=8.0Hz,1H).; 13 C NMR (150MHz, DMSO-d6) δ181.5,142.6,132.6,131.9,131.0,130.7,129.5,129.3,124.9,123.3,122.9,120.4,110.0; HRMS (ESI): m / z calcd for chemical formula:C 13 H9NClS[M+H] + 246.01387; found 246.01389.

[0094] Example 1

[0095] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0096] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1.0 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1, volume ratio) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, mp 88-89°C, 48.0 mg, and 86% yield.

[0097] The chemical reaction formula is as follows:

[0098]

[0099] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 1 to 4 ), confirm that the product is a pure target compound. The characterization data of the corresponding product are:

[0100] NMR (400MHz, CDCl3) δ8.62(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.32(d,J=8.4

[0101] Hz,1H),8.19(d,J=6.4Hz,1H),7.89(t,J=8.4Hz,1H),7.78-7.68(m,3H);

[0102] 13 C NMR(150MHz,CDCl3)δ151.0(q,J C-F =2.4Hz),143.9,133.3,131.5,130.3,129.2,129.1(q,J C-F =307.5Hz),128.0,127.9,126.4,126.3(q,J C-F =1.5Hz),123.8,122.5,122.1;

[0103] 19 F NMR(376MHz, CDCl3)δ-38.62(s);

[0104] HRMS(ESI):m / z calcd for chemical formula:C 14 H9F3NS[M+H] + 280.04023; found 280.04071.

[0105] Example 2

[0106] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3b):

[0107] 8-Methylphenanthridine-6(5H)-thione (45.0 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, and the pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 8-methyl-6-trifluoromethylthiophenanthridine (3b) as a white solid, mp 85-86°C, 49.9 mg, in 85% yield.

[0108] The chemical reaction formula is as follows:

[0109]

[0110] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 5 to 8 ), confirm that the product is the pure target compound.

[0111] 1 H NMR (400MHz, CDCl3) δ8.49 (d, J = 8.4Hz, 2H), 8.16 (d, J = 8.0Hz, 1H), 8.07 (s, 1H), 7.75-7.66 (m, 3H), 2.61 (s, 3H);

[0112] 13 C NMR(150MHz,CDCl3)δ150.6(q,J C-F=2.0Hz),143.6,138.2,133.2,131.1,130.2,129.1(q,J C-F =307.2Hz),128.8,127.9,126.4,125.7,123.9,122.4,121.9,21.7;

[0113] 19 F NMR(376MHz, CDCl3)δ-38.65(s);

[0114] HRMS(ESI):m / z calcd for chemical formula:C 15 H 10 F3NNaS[M+Na] + 316.0378; found 316.0381.

[0115] Example 3

[0116] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3c):

[0117] 8-Methoxyphenanthridine-6(5H)-thione (48.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by a barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 80:1) as eluents to obtain 8-methoxy-6-trifluoromethylthiophenanthridine (3c) as a white solid, mp 109-110°C, 53 mg, in 86% yield.

[0118] The chemical reaction formula is as follows:

[0119]

[0120] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 9 to 12 ), confirm that the product is the pure target compound.

[0121] 1H NMR (400MHz, CDCl3) δ8.52(d,J=9.2Hz,1H),8.45(d,J=8.0Hz,1H),8.16(d,J=7.6Hz,1H),7.72-7.66(m,3H),7.50(d,J=8.8Hz,1H),4.00(s,3H);

[0122] 13 C NMR(150MHz,CDCl3)δ159.1,149.6(q,J C-F =2.1Hz),143.1,130.3,129.2(q,J C-F =307.4Hz),128.2,128.1,128.0(q,J C-F =1.4Hz),127.7,124.2,124.0,122.4,121.6,106.3,55.6;

[0123] 19 F NMR(376MHz, CDCl3)δ-38.57(s);

[0124] HRMS(ESI):m / z calcd for chemical formula:C 15 H 10 F3NNaOS[M+Na] + 332.0327; found332.0340.

[0125] Example 4

[0126] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3d):

[0127] 8-Fluorophenanthridine-6(5H)-thione (45.8 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (as observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 50:1) as eluents to obtain 8-fluoro-6-trifluoromethylthiophenanthridine (3d) as a white solid, mp 90-91°C, 38 mg, in a 64% yield.

[0128] The chemical reaction formula is as follows:

[0129]

[0130] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 13 to 16 ), confirm that the product is the pure target compound.

[0131] 1 H NMR(400MHz, CDCl3)δ8.62(dd,J=9.2,5.2Hz,1H),8.48(d,J=8.0Hz,1H),,8.19( d,J=8.0Hz,1H),8.00(d,J=9.2Hz,1H),7.78-7.72(m,2H),7.64(t,J=9.2Hz,1H);

[0132] 13 C NMR(150MHz,CDCl3)δ161.5,(d,J C-F =248.9Hz),149.7(q,J C-F =2.1Hz),143.6,130.5,130.0,129.2,129.0(q,J C-F =307.2Hz),128.6,125.2(d,J C-F =8.3Hz),127.8(d,J C-F =9.6Hz),123.4,121.8,120.8(d,J C-F =23.7Hz),111.4(d,J C-F =23.0Hz);

[0133] 19 F NMR (376MHz, CDCl3) δ-38.64 (s), δ-110.05 (m);

[0134] HRMS(ESI):m / z calcd for chemical formula:C 14 H8NF4S[M+H] + 298.0308; found 298.0316.

[0135] Example 5

[0136] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3e):

[0137] 8-Chlorophenanthridine-6(5H)-thione (49 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by a barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 50:1) as eluents to obtain 8-chloro-6-trifluoromethylthiophenanthridine (3e) as a white solid, mp 97-98°C, 45 mg, in a 72% yield.

[0138] The chemical reaction formula is as follows:

[0139]

[0140] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 17-20 ), confirm that the product is the pure target compound.

[0141] 1 H NMR (400MHz, CDCl3) δ8.53(d,J=8.8Hz,1H),8.46(d,J=7.6Hz,1H),8.29(d,J=2.0Hz,1H),8.17(d,J=8.0Hz,1H),7.83-7.69(m,3H);

[0142] 13 C NMR(150MHz,CDCl3)δ149.6(q,J C-F =2.6Hz),143.8,134.0,132.1,131.6,130.4,129.6,128.9(q,J C-F =307.5Hz),128.5,127.2(q,J C-F =1.7Hz),125.7,124.2,123.2,121.9;

[0143] 19 F NMR(376MHz, CDCl3)δ-38.60(s);

[0144] HRMS(ESI):m / z calcd for chemical formula:C 14 H8ClF3NS[M+H] + 314.0013; found314.0021.

[0145] Example 6

[0146] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0147] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1.0 mol%), K2CO3 (55.4 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 23.4 mg, in a 42% yield.

[0148] Example 7

[0149] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0150] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), KHCO3 (40 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 37.4 mg, in a 67% yield.

[0151] Example 8

[0152] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0153] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), Na2CO3 (42.4 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid (20.1 mg, 36% yield).

[0154] Example 9

[0155] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0156] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), K3PO4 (84.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid (26.2 mg, 47% yield).

[0157] Example 10

[0158] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0159] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), K2HPO4 (69.6 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 34.6 mg, in a 62% yield.

[0160] Example 11

[0161] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0162] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), Li2CO3 (30 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 38.5 mg, in a 69% yield.

[0163] Example 12

[0164] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0165] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, and the pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The reaction mixture was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 41.9 mg, in a 75% yield.

[0166] Example 13

[0167] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0168] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of DMF were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times. The pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 36.8 mg, in a 66% yield.

[0169] Example 14

[0170] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0171] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, and the pressure in the Schlenk flask was maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 8.4 mg, in a 15% yield.

[0172] Example 15

[0173] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0174] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of acetone were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas three times, with the pressure in the Schlenk flask maintained at 1.0 atm (observed by the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA = 100:1) as eluents to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 35.7 mg, in a 64% yield.

[0175] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for synthesizing 6-trifluoromethylthiophenanthridine compounds, The structural formula of the 6-trifluoromethylthiophenanthridine compound is shown in formula (1): Formula (1) in, R is -H, -CH3, -OCH3, -F or -Cl; It is characterized in that the synthesis method comprises the following steps: Phenanthridinethione, a photocatalyst and a base are added to an organic solvent, and then CF3Br is introduced to carry out a visible light-induced reaction to obtain the 6-trifluoromethylthiophenanthridine compound; The structural formula of the phenanthridinethione is as follows: wherein R is -H, -CH3, -OCH3, -F or -Cl; The photocatalyst is fac-Ir III (ppy)3; The base is selected from K2CO3, KHCO 3、 Na2CO3, K3PO4, K2HPO4, Li2CO3, NaOAc, Et3N or 2,6-lutidine; The organic solvent is selected from CH3CN, DMF, DMSO, THF, acetone or 1,4-dioxane; The pressure of the CF3Br in the reaction system is 1.0-1.5 atm; The wavelength of the visible light is 390-460 nm.

2. The synthesis method according to claim 1, wherein The molar ratio of the phenanthridinethione to the base is (1-3): (2-6).

3. The synthesis method according to claim 1, wherein The amount of the photocatalyst used is 0.5-1.5 mol% of the molar amount of phenanthridinethione.

4. The synthesis method according to claim 1, characterized in that The induction reaction time is 12 to 48 hours.

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