Synthesis method of thioester compound

Abstract

The invention discloses a synthesis method of a thioester compound, which comprises the following steps: orderly mixing a sulfydryl-containing compound, an N-halogenated compound, a trivalent phosphine compound and carboxylic acid, and stirring at room temperature to construct a C-S bond, thereby obtaining a series of thioester compounds. According to the method, the synthesis of the thioester compound can be efficiently realized, and the used starting raw materials are rich in source, diversified in structure and low in price, so that the reaction cost is reduced, and the post-treatment steps of the reaction are simplified. The synthesis reaction operation is simple, the conditions are mild, the reaction is fast, the yield is high, the post-treatment is convenient, the amplification of the reaction can be realized, and the method has wide application prospect and practical value.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for efficiently converting thiol and carboxylic acid substances into thioester compounds under the action of N-halogenated compounds and trivalent phosphine. Background Art

[0002] Thioesters are important building blocks that are widely found in natural products, bioactive molecules, drugs, and materials. They are also widely used as efficient synthons in organic synthesis and can be transformed into various configurations, such as aldehydes, ketones, esters, amides, thioethers, and heterocycles. Traditional methods for synthesizing thioester compounds include thioester exchange (Org. Lett., 2023, 25, 7035), decarboxylation coupling (Org. Biomol. Chem., 2015, 13, 7323), oxidative coupling of aldehydes (J. Am. Chem. Soc., 2023, 145, 5846), carbonylation of halogenated aromatics with thiols and CO (J. Am. Chem. Soc., 2016, 138, 16794), coupling of halogenated aromatics with thiourea derivatives (Angew. Chem. Int. Ed., 2024, 63, e202407520), and thioesterification of amides (New J. Chem., 2019, 43, 9384), which are all effective methods for synthesizing thioesters. However, considering the abundance, stability and non-toxicity of carboxylic acids, direct deoxygenation of carboxylic acids is still an efficient and very ideal method. Conventional condensation reagents such as DCC (Angew. Chem. Int. Ed., 1978, 17, 522), EDC (J. Am. Chem. Soc., 1955, 4, 1067), PMHS (J. Org. Chem., 2019, 84, 7694), SO2F2 (Eur. J. Org. Chem., 2024, 27, e202400149) and pentafluoropyridine (Org. Biomol. Chem., 2022, 20, 8059) can be used to activate carboxylic acids, and then promote the coupling of activated carboxylic acid derivatives with thiols to achieve the synthesis of thioesters.

[0003] However, these reaction conditions are relatively harsh and the reagents are expensive. Therefore, there is still a need to develop a reaction that is mild, simple, high in yield, convenient for post-processing, and can be scaled up. On the basis of fully considering the economic and environmental costs, designing and developing a method for efficiently converting thiols into thioester compounds still has broad application prospects and practical value. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a method for synthesizing thioester compounds.

[0005] Technical solution: The present invention provides a method for synthesizing a thioester compound, wherein a compound containing a thiol group, an N-halogenated compound, a trivalent phosphine compound, and a carboxylic acid are stirred at room temperature to achieve the construction of a CS bond to obtain a thioester compound;

[0006] The specific operation steps are as follows: add a thiol compound, an N-halogenated compound, a trivalent phosphine compound and a solvent into a reaction container, stir to react at room temperature, then add a carboxylic acid and continue to stir, after the reaction is completed, remove the solvent, and simply separate by column chromatography to obtain the target product lipid compound;

[0007] The reaction scheme of the synthesis method is as follows:

[0008]

[0009] Wherein, R1 is an alkyl group or an aryl group, and R2 is a monosubstituted or polysubstituted group selected from hydrogen, alkyl, alkoxy, halogen, nitro, aryl, etc.;

[0010] The activation reagent is a kind of N-halosuccinimide, and its structure is:

[0011]

[0012] The additive is any one of trialkylphosphine, triarylphosphine and triaminophosphine;

[0013] The solvent is one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide and methanol.

[0014] Furthermore, the thiol compound is (hetero)arylthiophenol.

[0015] Furthermore, the carboxylic acid is a primary, secondary or tertiary carboxylic acid substituted with an alkyl or aryl group.

[0016] Furthermore, the molar ratio of the mercapto compound, the N-halogenated compound, the trivalent phosphine compound and the carboxylic acid is 1.0-1.1:1.0-1.1:1.0-1.1:1.0, preferably 1.0:1.1:1.1:1.0.

[0017] Beneficial effects: The specific advantages of the present invention are as follows:

[0018] 1. The present invention provides a convenient method for preparing thioester compounds, with mild reaction conditions, simple operation and convenient post-treatment.

[0019] 2. The starting materials used in the present invention are rich in sources, diverse in structure, and low in price, which not only reduces the cost of the reaction, but also simplifies the post-processing steps of the reaction.

[0020] 3. The synthetic method of the present invention has simple reaction operation, mild conditions, fast reaction, high yield, can realize reaction amplification, and has broad application prospects and practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The structure of Example 1 prepared by the present invention 1 HNMR spectrum.

[0022] Figure 2 The structure of Example 2 prepared by the present invention 1 HNMR spectrum.

[0023] Figure 3 The structure of Example 3 prepared by the present invention 1 HNMR spectrum.

[0024] Figure 4 The structure of Example 4 prepared by the present invention 1 HNMR spectrum.

[0025] Figure 5 The structure of Example 5 prepared by the present invention 1 HNMR spectrum.

[0026] Figure 6 The structure of Example 6 prepared by the present invention 1 HNMR spectrum.

[0027] Figure 7 The structure of Example 7 prepared by the present invention 1 HNMR spectrum.

[0028] Figure 8 The structure of Example 8 prepared by the present invention 1 HNMR spectrum.

[0029] Fig. 9 The structure of Example 9 prepared by the present invention 1 H NMR spectrum.

[0030] Fig.10 The structure of Example 10 prepared by the present invention 1 H NMR spectrum. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention will be described clearly and completely below so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the protection scope of the present invention. The embodiments described in the present invention are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention.

[0032] Example 1

[0033]

[0034] In a 10mL reaction tube, add 2-bromobenzenethiol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add benzoic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (90%). 1 HNMR(400MHz,Chloroform-d)δ7.94(dt,J=8.2,1.1Hz,2H),7.63(dd,J=8.0,1.3Hz,1H),7.54 –7.47(m,2H),7.38(t,J=7.7Hz,2H),7.28(tt,J=7.6,1.1Hz,1H),7.20(td,J=7.7,1.7Hz,1H).

[0035] Example 2

[0036]

[0037] In a 10mL reaction tube, add 3-methylthiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add benzoic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (97%). 1 HNMR(400MHz,Chloroform-d)δ8.06–7.98(m,2H),7.62–7.55(m,1H),7.47(dd,J=8.4,7.0Hz,2H),7.37–7.29(m,3H),7.27–7.22(m,1H),2.38(s,3H).

[0038] Example 3

[0039]

[0040] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add benzoic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (97%). 1 HNMR (400MHz, Chloroform-d) δ7.97–7.91(m,2H),7.58–7.52(m,1H),7.45–7.35(m,6H).

[0041] Example 4

[0042]

[0043] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add ibuprofen (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (89%). 1 HNMR(400MHz,Chloroform-d)δ7.34–7.28(m,2H),7.29–7.21(m,4H),7.12(d,J=7.9Hz,2H),3.94(q,J=7 .1Hz, 1H), 2.46 (d, J = 7.2Hz, 2H), 1.85 (hept, J = 6.8Hz, 1H), 1.55 (d, J = 7.1Hz, 3H), 0.90 (d, J = 6.6Hz, 6H).

[0044] Example 5

[0045]

[0046] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add isoxic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (56%). 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J=2.4Hz,1H),7.79(dd,J=7.6,1.4Hz,1H),7.44(td,J=7.4,1.4Hz,1 H),7.35(ddd,J=13.8,7.9,1.8Hz,2H),7.28–7.14(m,5H),6.94(d,J=8.4Hz,1H),5.07(s,2H),3.82(s,2H).

[0047] Example 6

[0048]

[0049] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add oxaprozin (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (67%). 1 HNMR (400MHz, Chloroform-d) δ7.67–7.61(m,2H),7.61–7.54(m,2H),7.36(dtd,J=11.2,5.4,2.2Hz,10H),3.32–3.20(m,4H).

[0050] Example 7

[0051]

[0052] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add adamantanecarboxylic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (46%). 1H NMR (400MHz, Chloroform-d) δ7.36 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 2.03 (dd, J = 40.4, 3.0 Hz, 9H), 1.80–1.69 (m, 6H).

[0053] Example 8

[0054]

[0055] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add Fmoc-O-tert-butyl-L-tyrosine (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (32%). 1 HNMR(400MHz,Chloroform-d)δ7.76(d,J=7.5Hz,2H),7.57(t,J=7.4Hz,2H),7.43–7.36(m,4H),7.33–7.24(m,4H),7.06(d,J=8. 1Hz, 2H), 6.95 (d, J = 8.0Hz, 2H), 4.44 (ddd, J = 32.2, 10.7, 6.9Hz, 2H), 4.22 (t, J = 6.9Hz, 1H), 3.11 (d, J = 6.4Hz, 2H), 1.33 (s, 11H).

[0056] Example 9

[0057]

[0058] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add N-CBZ-4-piperidinic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (67%). 1HNMR (400MHz, Chloroform-d) δ7.32–7.19(m,9H),5.04(s,2H),4.10(s,2H),2.82(t,J=12.6Hz,2H),2.66(ddd,J=11.1,7.3,3.8Hz,1H),1.90–1.58(m,4H).

[0059] Example 10

[0060]

[0061] In a 10mL reaction tube, add 4-chlorothiophenol (0.5mmol), N-chlorosuccinimide (0.6mmol) and anhydrous tetrahydrofuran (2mL). After stirring at 25°C for 1 hour, add trioctylphosphine (0.6mmol), react for 5 minutes, add benzoylformic acid (0.5mmol) to the reaction system, and continue stirring for 5 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product (59%). 1 HNMR (400MHz, Chloroform-d) δ8.19–8.14(m,2H),7.68(td,J=7.4,1.3Hz,1H),7.51(t,J=7.9Hz,2H),7.48–7.41(m,4H).

Claims

1. A method for synthesizing a thioester compound, characterized in that: The specific steps are as follows: adding a thiol compound, an N-halogenated compound, a trivalent phosphine compound and a solvent into a reaction container, stirring the reaction at room temperature, then adding a carboxylic acid and continuing to stir, after the reaction is completed, removing the solvent, and simply separating the target product lipid compound by column chromatography; The reaction scheme of the synthesis method is as follows: Among them, R 1 is an alkyl or aryl group, R 2 is hydrogen, alkyl, alkoxy, halogen, nitro or aryl; The activation reagent is a kind of N-halosuccinimide, and its structure is: The additive is any one of trialkylphosphine, triarylphosphine and triaminophosphine; The solvent is one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide and methanol.

2. The method for synthesizing thioester compounds according to claim 1, wherein: The thiol compound is (hetero)arylthiophenol.

3. The method for synthesizing thioester compounds as claimed in claim 1, characterized in that: The carboxylic acid is a primary, secondary or tertiary carboxylic acid including alkyl and aryl substitutions.

4. The method for synthesizing thioester compounds according to claim 1, characterized in that: The molar ratio of the mercapto compound, the N-halogenated compound, the trivalent phosphine compound and the carboxylic acid is 1.0-1.1:1.0-1.1:1.0-1.1:1.0.

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