Synthesis method of amide ligand and copper-catalyzed thioether compound

Abstract

The invention relates to application of an amide ligand and a copper catalyst in preparation of thioether compounds. The compound is prepared from a substituted aromatic polyhalide compound and a thiophenol compound through a reaction under the action of an amide ligand and a cuprous catalyst, R1-X + R2SH-> R1-SR2, the structural formula of the amide ligand is shown in the specification, and the cuprous catalyst is cuprous halide or cuprous oxide.

Description

Technical Field

[0001] This invention relates to an amide ligand and its application in the synthesis of thioether compounds using copper catalysis, belonging to the field of organic chemical synthesis. Background Technology

[0002] Organosulfur compounds are an important class of organic compounds widely distributed in nature, with significant applications in life sciences, medicine, food, and functional materials. Therefore, developing simple and efficient methods to construct CS bonds for the synthesis of structurally diverse organosulfur compounds is of great importance.

[0003] Sulfur atoms are widely present in drug molecules, ranking fifth in abundance after carbon, hydrogen, oxygen, and nitrogen. According to literature, the U.S. Food and Drug Administration (FDA) has approved 362 sulfur-containing small molecule drugs over the past 100 years. In 2011, 24.8% and 22.5% of the top 200 best-selling retail and prescription drugs in the U.S., respectively, contained sulfur atoms in their molecular structures. Among the top 20 best-selling retail and prescription drugs, the proportion of sulfur-containing drugs increased to 40% and 25%, respectively. By 2012, all of the top ten best-selling drugs were sulfur-containing drugs.

[0004]

[0005] Sulfur-containing compounds play important roles in organic chemical reactions, organic synthesis, and drug therapy. Aryl sulfides have attracted widespread attention due to their pharmaceutical activity; therefore, many researchers have devoted considerable time to developing efficient, regioselective, and environmentally friendly methods for constructing CS bonds. Aryl sulfides are key structural fragments in many bioactive substances and drugs, such as: the bioactive natural compound Lissoclibadin6; the antibacterial agent AZD4407; the immunomodulator KRP-203; the human immunodeficiency virus protease inhibitor Nelfinavir used for HIV treatment; the anti-infective drug cefazolin; the microtubule inhibitor arylthioindole; the highly effective drug for acute respiratory viral infections, Arbidl Hydrochloride; and Ufiprazole, an important intermediate in the gastroesophageal reflux disease drug esomeprazole.

[0006] The preparation methods for thioether compounds currently include the following: (1) preparing symmetrical or asymmetrical thioethers by reacting thiophenols or thiols with haloalkanes under alkaline conditions; (2) preparing symmetrical thioethers by reacting sodium sulfide with haloalkanes; (3) preparing corresponding thioethers by reducing sulfones or sulfoxides; (4) obtaining corresponding thioethers by heating disulfides and reacting them with haloalkanes; and (5) preparing thioethers by CS coupling of aromatic heterohalides with thiols or thiophenols catalyzed by transition metals. Compared with the above preparation methods, transition metal catalysis has gradually become a research hotspot due to its high efficiency and environmental friendliness, such as palladium, nickel, and iridium-catalyzed CS coupling. However, transition metal-catalyzed CS coupling reactions generally require reaction temperatures above 100°C, resulting in high energy consumption in industrial production and the need for expensive metal catalysts, leading to high production costs. Therefore, finding a low-cost and low-energy-consumption method for preparing thioethers is particularly important. In recent years, amide ligand / copper catalysis systems have shown excellent performance in the construction of CN, CO, CP, and CC bonds in aryl halides. It is necessary to develop copper-catalyzed methods for the CS coupling reactions of halogenated aromatics and thiols with amide ligands, particularly for the CS coupling of heterohalides with thiols to prepare thioether compounds. Summary of the Invention

[0007] The first objective of this invention is to provide a method for synthesizing thioether compounds from aromatic heterohalides and thiols using amide ligand catalysis.

[0008] A second objective of this invention is to provide a method for synthesizing amide ligands.

[0009] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0010] Firstly, this invention provides the application of amide ligands and copper catalysts in the preparation of thioether compounds. The invention provides a method for preparing thioether compounds using amide ligands, involving the reaction of aromatic heterohalides and thiophenols, as shown in the following reaction formula:

[0011] R1-X+RSHR1-SR2

[0012] Where X represents fluorine, chlorine, bromine, and iodine atoms.

[0013] R 1 It is a furanyl, thiophene, naphthyl, pyrrolopyridyl, pyridyl, phenyl, ester, carboxyl, aldehyde, cyano, or a phenyl group substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, or halogen.

[0014] Among them, the more preferred one is the above-mentioned R1 Compound X is selected from the following compounds:

[0015]

[0016] R 2 It is a furanyl, thiophene, pyrrolopyridyl, pyridyl, naphthyl, phenyl, ester, carboxyl, aldehyde, cyano, or a phenyl group substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, or halogen.

[0017] Among them, the more preferred one is the above-mentioned R 2 SH compounds are selected from the following compounds:

[0018]

[0019] The above-mentioned thioether reaction of the present invention is carried out with the participation of amide ligands, and a cuprous catalyst is also required in the reaction.

[0020] The cuprous catalyst can be cuprous halide or cuprous oxide, etc.; the cuprous halide can be cuprous chloride, cuprous bromide, cuprous iodide, etc.

[0021] The detailed process for further thioetherification is as follows: Cuprous catalyst, ligand, acid-binding agent and organic solvent are added to a reaction flask, purged with nitrogen three times, stirred at room temperature for 1 hour, aromatic heterohalides and thiophenols are added to the reaction system, the reaction is carried out at 25-120℃ for 1-48 hours, the reaction is monitored by TLC until the reaction is complete, the reaction solution is poured into water, extracted with ethyl acetate 2-3 times to obtain the organic phase, the organic phase is concentrated under reduced pressure, separated by column chromatography with ethyl acetate:n-heptane = 1:2-10, concentrated and dried to obtain thioethers.

[0022] The molar ratio of the aromatic heterohalogenated compound, thiophenol, cuprous catalyst, ligand, and acid-binding agent is in the range of 1:1 to 10:0.01 to 0.5:0.01 to 0.5:1 to 10.

[0023] More preferably, the molar ratio of aromatic heterohalogenated compound: thiophenol: cuprous catalyst: ligand: acid-binding agent is in the range of 1:1~5:0.01~0.2:0.01~0.3:1~5.

[0024] Furthermore, the thiol used in the reaction is selected from 4-methylthiophenol, 4-tert-butylthiophenol, 4-nitrothiophenol, and 4-aminothiophenol.

[0025] Furthermore, the organic solvent used in the reaction is selected from DMF, DMSO, 1,4-dioxane, DMAC, or toluene.

[0026] Furthermore, the volume fraction of the organic solvent in the reaction is 5V to 15V.

[0027] Furthermore, the preferred cuprous catalyst is cuprous chloride, cuprous bromide, cuprous iodide, or cuprous oxide;

[0028] Furthermore, the reaction temperature is 0–120°C, with 0–25°C being more preferred.

[0029] Furthermore, the acid-binding agent in the reaction is an inorganic base.

[0030] Furthermore, the acid-binding agent used in the reaction is preferably potassium tert-butoxide, potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.

[0031] Furthermore, the post-treatment method of the reaction solution is as follows: after pouring the reaction solution into water, extract it with ethyl acetate 2 to 3 times to obtain an organic phase. After concentrating the organic phase under reduced pressure, separate it by column chromatography with ethyl acetate: n-heptane = 1:2 to 10, concentrate and dry it to prepare thioether compounds.

[0032] This invention also provides a method for synthesizing amide ligands: amide compounds are prepared by reacting aromatic heteroamines with oxalyl chloride. The reaction formula is as follows:

[0033]

[0034] Among them, R 3 The substituents are furanyl, thiophene, naphthyl, phenyl, benzyl, phenyl substituted with one or more substituents, or benzyl substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, or halogen, etc.

[0035] The specific reaction process is as follows:

[0036] The aromatic amine compound is dissolved in an organic solvent, and a base is added dropwise at 0°C. The mixture is stirred at 0°C for 5–15 minutes while maintaining an internal temperature of 0°C. Oxaloyl chloride is slowly added dropwise to the reaction system. After the addition is complete, the reaction is allowed to proceed at room temperature for 2–5 hours. Once the reaction is complete as monitored by TLC, the solvent is removed by vacuum distillation, water is added, and the mixture is stirred for 1–2 hours. The mixture is then filtered, and the filter cake is washed 3–4 times with water and ethyl acetate. After vacuum drying, the amide ligand is obtained. The molar ratio of the aromatic amine compound, the base, and the oxaloyl chloride is in the range of 2.0–3.0:2.5–4.0:1.0.

[0037] Furthermore, the organic solvent is selected from dichloromethane, chloroform, toluene, tetrahydrofuran, and ethyl acetate.

[0038] Furthermore, the volume of the organic solvent is 10–30 V.

[0039] Furthermore, the alkali is selected from TEA, DIPEA, and DBU.

[0040] Specifically, and more preferably, the amide ligand is selected from one of the following:

[0041]

[0042] The beneficial effects of this invention are as follows:

[0043] This invention optimizes and improves the Ullmann reaction by using suitable ligands, bases, solvents, etc., and uses a catalytic amount of copper catalyst combined with amide ligands to efficiently catalyze the preparation of thioether compounds from aromatic heterohalides and thiophenols under relatively mild conditions, providing an efficient means for industrial production.

[0044] The CS bond formation reaction involving amide ligands catalyzes the reaction of aromatic heterohalides and thiophenols at room temperature to prepare thioethers. The reaction conditions are mild, energy consumption is low, and yield is high, making it suitable for industrial production. In the synthetic method described in this invention, on the one hand, aromatic heteroamines are used to prepare novel amide ligands for catalyzing the thioetherification reaction; on the other hand, a cuprous catalyst / amide ligand is used as a catalyst to catalyze the reaction of aromatic heterohalides and thiophenols, followed by post-processing to obtain the thioethers. The thioethers described represent an important structural unit widely found in the pesticide and pharmaceutical fields, and have broad application prospects in new drug development. Detailed Implementation

[0045] To further understand the present invention, a method for synthesizing amide ligands and copper-catalyzed thioether compounds provided by the present invention is described in detail below with reference to embodiments. It should be understood that the following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0046] Example 1:

[0047]

[0048] In a 250 mL round-bottom flask, benzylamine (4.29 g, 40 mmol, 2.0 eq.) and tetrahydrofuran were added sequentially and mixed thoroughly. The mixture was then placed in an ice bath at 0 °C. Triethylamine (5.06 g, 50 mmol, 2.5 eq.) was added dropwise and stirred for 10 minutes. Oxaloyl chloride (2.54 g, 20 mmol, 1.0 eq.) was slowly added dropwise to the reaction system, producing a large amount of white fumes. The reaction was carried out at 0 °C for 10 minutes until the white fumes disappeared. The reaction system was then moved to room temperature and reacted for 2 hours. After the reaction was completed, the solvent was removed, and 100 mL of water was added and stirred for 1 hour. After the reaction was completed, the mixture was filtered and washed 3-4 times with water and ethyl acetate to obtain a wet product. This wet product was then dried in a vacuum drying oven at 55 °C for 12 hours to obtain 3.5 g of dry product, with a yield of 65.3%. 1 H-NMR, the structure is correct. 1 H-NMR (400MHz, DMSO-d6): δ9.33–9.30(m,2H),7.32–7.26(m,10H),4.34(d,4H,J=6.4Hz).

[0049] Using the same reactants and following the same operating procedures, amide ligands were prepared with different equivalents of benzylamine, different types of bases, and different equivalents of bases, following the same reaction as described above. The results are shown in Table 1 below.

[0050] Table 1

[0051] serial number benzylamine equivalent Types of alkalis Alkali equivalent <![CDATA[Yield (%) a > 1 3.0eq. TEA 3.0eq. 65％ 2 2.5eq. DIPEA 2.5eq. 55％ 3 2.0eq. DBU 2.5eq. 52％ 4 2.0eq. TEA 4.0eq. 56％ 5 3.0eq. TEA 3.5eq. 60％

[0052] In Table 1, the superscript a This indicates the separation yield.

[0053] Using the same reactants and following the same operating procedures, intermediates were prepared with different types and volumes of organic solvents, following the same reaction as described above. The results are shown in Table 2 below:

[0054] Table 2

[0055] serial number organic solvents organic solvent volume <![CDATA[Yield (%) a > 1 dichloromethane 10V 35％ 2 chloroform 15V 33％ 3 Toluene 30V 25％ 4 Toluene 11V 32％ 5 Tetrahydrofuran 30V 56％ 6 Ethyl acetate 12V 32％

[0056] In Table 2, the superscript a The separation yield is indicated.

[0057] Example 2:

[0058]

[0059] The difference from Reaction Example 1 is that the substrate used is 1-naphthylamine, and the other reaction conditions and operating procedures are the same as in Reaction Example 1 (yield: 58.4%). 1H-NMR (400MHz, DMSO-d6): δ9.40(s,2H),8.20–8.18(m,2H),7.86–7.57(m,2H), 7.57–7.56(m,2H),7.55–7.54(m,4H),7.53–7.43(m,4H),4.81(d,4H,J=1.6Hz).

[0060] Example 3:

[0061]

[0062] The difference from Reaction Example 1 is that the substrate used is 2-thiophene methylamine, and the other reaction conditions and operating procedures are the same as in Reaction Example 1 (yield: 66.4%). 1 H-NMR (400MHz, DMSO-d6): δ9.39–9.42(m,2H),7.37–7.39(m,2H),6.94–6.97(m,4H),4.47(d,4H,J=6.4Hz).

[0063] Example 4:

[0064]

[0065] The difference from Reaction Example 1 is that the substrate used is 2-furanylamine, and the other reaction conditions and operating procedures are the same as in Reaction Example 1 (yield: 62%). 1 H-NMR (400MHz, DMSO-d6): δ9.17–9.20 (m, 2H), 7.55 (d, 2H, J = 0.8Hz), 6.37–6.39 (m, 2H), 6.23 (d, 2H, J = 2.8Hz), 4.33 (d, 4H, J = 6.4Hz).

[0066] Example 5:

[0067]

[0068] The difference from Reaction Example 1 is that the substrate used is 2-phenylethylamine, while the other reaction conditions and operating procedures are the same as in Reaction Example 1 (yield: 73%). 1 H-NMR (400MHz, DMSO-d6): δ8.74–8.77(m,2H),7.27–7.31(m,4H),7.19–7.22(m,6H),3.34–3.78(m,5H),2.76–2.80(m,3H).

[0069] Example 6:

[0070]

[0071] CuI (0.015 g, 0.05 eq.), ligand (3)-c (0.015 g, 0.05 eq.), potassium tert-butoxide (0.224 g, 2.0 eq.), and 2 mL DMSO were added to the reaction flask. After purging with nitrogen three times, the mixture was stirred at room temperature for 1 hour. Then, iodobenzene (0.204 g, 1.0 eq.) and p-methylthiophenol (0.186 g, 1.5 eq.) were added to the reaction system. The reaction was carried out at 25 °C for 24 h. The reaction was monitored by TLC until it ended. The reaction solution was poured into water and extracted with ethyl acetate 2-3 times to obtain the organic phase. After the organic phase was concentrated under reduced pressure, it was separated by column chromatography with ethyl acetate: n-heptane = 1:10, concentrated, and dried to obtain phenyl p-toluene sulfide (yield: 90%). 1 H NMR(400MHz,Chloroform-d)δ7.46–7.30(m,5H),7.29–7.18(m,3H),2.41(s,1H).

[0072] Using the same reactants and the same operating procedures, reactions were carried out with different equivalents of p-methylthiophenol, different types of cuprous catalysts, different equivalents of cuprous catalysts, different types of ligands, and different equivalents of ligands. The results are shown in Table 3 below:

[0073] Table 3

[0074]

[0075] In Table 3, the superscript a This indicates the separation yield.

[0076] Using the same reactants and the same operating procedures, reactions were carried out with different types of acid-binding agents, different equivalent amounts of acid-binding agents, different types of organic solvents, different volumes of organic solvents, and different reaction temperatures. The results are shown in Table 2 below.

[0077] Table 4

[0078]

[0079] In Table 4, the superscript a This indicates the separation yield.

[0080] Example 7:

[0081]

[0082] The difference from Reaction Example 6 is that the substrate used is chlorobenzene, while the other reaction conditions and operating procedures are the same as in Reaction Example 6 (yield: 60%).

[0083] Example 8:

[0084]

[0085] The difference from Reaction Example 6 is that the substrate used is bromobenzene, while the other reaction conditions and operating procedures are the same as in Reaction Example 6 (yield: 71%).

[0086] Example 9:

[0087]

[0088] The difference from Reaction Example 6 is that the substrate used is p-tert-butylthiophenol, while the other reaction conditions and operating procedures are the same as in Reaction Example 6 (yield: 81%). 1 H NMR (400MHz, Chloroform-d) δ7.46–7.37(m,6H),7.37–7.32(m,2H),7.31–7.25(m,1H),1.41(s,9H).

[0089] Example 10:

[0090]

[0091] The difference from Reaction Example 6 is that the substrate used is p-nitrothiophenol, while the other reaction conditions and operating procedures are the same as in Reaction Example 6 (yield: 85%). 1 H NMR (400MHz, Chloroform-d) δ8.14–8.05(m,2H),7.63–7.53(m,2H),7.53–7.44(m,3H),7.26–7.17(m,2H).

[0092] Example 11:

[0093]

[0094] The difference from Reaction Example 6 is that the substrate used is p-aminothiophenol, while the other reaction conditions and operating procedures are the same as in Reaction Example 6 (yield: 83%). 1 H NMR (400MHz, Chloroform-d) δ7.49 (dd, J=7.7, 1.6Hz, 1H), 7.35–7.19 (m, 3H), 7.19–7.04 (m, 3H), 6.92–6.72 (m, 2H), 1.60 (s, 1H).

[0095] Example 12:

[0096]

[0097] The difference from Reaction Example 6 is that the substrate used is 2-iodopyridine, and the other reaction conditions and operating procedures are the same as those in Reaction Example 6 (yield: 81%). 1 H NMR(400MHz,Chloroform-d)δ8.41(ddd,J=4.9,2.0,0.9Hz,1H),7.50(d,J=8.1Hz,2H),7.42(td,J=7.8,1.9 Hz,1H),7.24(d,J=7.9Hz,2H),6.96(ddd,J=7.4,4.8,1.1Hz,1H),6.85(dt,J=8.1,1.1Hz,1H),2.40(s,3H).

[0098] Example 13:

[0099]

[0100] The difference from Reaction Example 6 is that the substrate used was 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine, while the other reaction conditions and operating procedures were the same as in Reaction Example 6 (yield: 69%). 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=2.1Hz,1H),8.06(d,J=2.0Hz,1H),7.23(d,J=3.5Hz,1 H),7.17–7.09(m,2H),7.06(d,J=8.0Hz,2H),6.45(d,J=3.5Hz,1H),3.92(s,3H),2.31(s,3H).

[0101] Comparative Example 1:

[0102] Similar to Example 6, the difference is that CuI and (3)-c were not added as catalysts in the reaction. After the reaction was complete, TLC monitoring showed that the raw materials were completely converted but there were many by-products. The product yield after purification was only 59%.

[0103] As can be seen from the above comparative examples, CuI and (3)-c catalysis are beneficial to improving reaction selectivity and product yield.

Claims

1. A method for preparing a thioether compound, characterized in that, It is prepared by reacting substituted aromatic heterohalides and thiophenolic compounds, in the presence of amide ligands and the action of cuprous catalyst. R 1 -X+R 2 SH→R 1 -SR 2 , The structural formula of the amide ligand is as follows: The cuprous catalyst is a cuprous halide or cuprous oxide; R 1 The substituent is furanyl, thiophene, pyrrolopyridyl, pyridyl, naphthyl, phenyl, ester, carboxyl, aldehyde, cyano, or a phenyl group substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, or halogen. X can be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. R 2 It is furanyl, thiophene, naphthyl, phenyl, or a phenyl group substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, or halogen, etc. R 3 The substituents are furanyl, thiophene, naphthyl, phenyl, benzyl, phenyl substituted with one or more substituents, or benzyl substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, or halogen, etc.

2. The preparation method according to claim 1, characterized in that, The reaction is as follows: R 1 -X+R 2 SH→R 1 -SR 2 , The amide ligand is: The cuprous catalyst is cuprous bromide, cuprous iodide, cuprous chloride, or cuprous oxide.

3. The preparation method according to claim 1 or 2, characterized in that, An acid-binding agent is added during the reaction.

4. The preparation method according to claim 3, characterized in that, The acid-binding agent is potassium tert-butoxide, potassium phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.

5. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic heterohalogenated compound: thiophenol compound: cuprous catalyst: ligand is in the range of 1:1 to 10: 0.01 to 0.5: 0.01 to 0.

5.

6. The preparation method according to claim 5, characterized in that, The molar ratio of the aromatic heterohalogenated compound: thiophenol: cuprous catalyst: ligand is in the range of 1:1 to 5: 0.01 to 0.2: 0.01 to 0.

3.

7. The preparation method according to claim 1, 2 or 3, characterized in that, The organic solvent used in the reaction is selected from DMF, DMSO, 1,4-dioxane, DMAC, or toluene.

8. The preparation method according to claim 1, 2 or 3, characterized in that, The reaction temperature is 0–120℃.

9. The preparation method according to claim 1 or 2, characterized in that, The amide ligand was prepared by reacting aromatic heteroamine compounds with oxalyl chloride. Where: R 3 The substituents are furanyl, thiophene, naphthyl, phenyl, benzyl, phenyl substituted with one or more substituents, or benzyl substituted with one or more substituents, wherein each substituent is independently methyl, phenyl, methoxy, trifluoromethyl, or halogen, etc.

10. A method for preparing a thioether compound, characterized in that, It is prepared by reacting substituted aromatic heterohalides and thiophenols in the presence of amide ligands and cuprous iodide.

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