A method for synthesizing a thioester compound

Abstract

The application discloses a synthesis method of thioester compounds. The method comprises the following steps: mixing a compound containing a mercapto group, an N-halogen compound, a trivalent phosphine compound and a carboxylic acid in order, stirring under room temperature conditions, and realizing the construction of a C-S bond to obtain a series of thioester compounds. The application can efficiently realize the synthesis of thioester compounds, the used starting materials are rich in sources, various in structure and low in price, the application not only reduces the cost of the reaction, but also simplifies the post-processing steps of the reaction. The synthesis reaction in the application is simple in operation and mild in conditions, fast in reaction, high in yield, convenient in post-processing, can realize the amplification of the reaction, and has wide application prospect and practical value.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and specifically relates to a method for the efficient conversion of thiols and carboxylic acids into thioesters under the action of N-halogenated compounds and trivalent phosphine. Background Technology

[0002] Thioesters are important structural units widely found in natural products, bioactive molecules, pharmaceuticals, and materials. They are also widely used as highly efficient synthons in organic synthesis, capable of being converted into various configurations such as aldehydes, ketones, esters, amides, thioethers, and heterocycles. Traditional methods for synthesizing thioesters 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), all of which are effective methods for synthesizing thioesters. However, considering the abundance, stability, and non-toxicity of carboxylic acids, direct deoxygenation of carboxylic acids remains a highly efficient and ideal method. Common condensing 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 the activated carboxylic acid derivative 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, has high yield, convenient post-processing, and can be scaled up. Considering both economic and environmental costs, designing and developing a method for the efficient conversion of thiols to thioesters still has broad application prospects and practical value. Summary of the Invention

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

[0005] Technical solution: The present invention provides a method for synthesizing thioester compounds, which involves stirring at room temperature in an ordered mixture of a compound containing a thiol group, an N-halogenated compound, a trivalent phosphine compound, and a carboxylic acid to construct CS bonds and obtain thioester compounds.

[0006] The specific operating steps are as follows: Add a mercapto compound, an N-halogenated compound, a trivalent phosphine compound and a solvent to a reaction vessel, stir the reaction at room temperature, then add a carboxylic acid and continue stirring. After the reaction is complete, remove the solvent and obtain the target product lipid compound by simple separation by column chromatography.

[0007] The reaction route for this synthesis method is as follows:

[0008]

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

[0010] The activating agent is an N-halosuccinimide, and its structure is as follows:

[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 a heteroarylthiophenol.

[0015] Furthermore, the carboxylic acid is a primary, secondary, or tertiary carboxylic acid, including those substituted with alkyl and aryl groups.

[0016] Furthermore, the molar ratio of the thiol 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 this invention are as follows:

[0018] 1. This invention provides a convenient method for the preparation of thioester compounds, with mild reaction conditions, simple operation, and convenient post-processing.

[0019] 2. The starting materials used in this invention are abundant, structurally diverse, and inexpensive, which not only reduces the cost of the reaction but also simplifies the post-processing steps.

[0020] 3. The synthesis method of the present invention has simple operation, mild conditions, fast reaction and high yield, and can realize the scale-up of the reaction, and has broad application prospects and practical value. Attached Figure Description

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

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

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

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

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

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

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

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

[0029] Figure 9 The structure of Example 9 prepared according to the present invention 1 H NMR spectrum.

[0030] Figure 10 The structure of Example 10 prepared according to the present invention 1 H NMR spectrum. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described 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 scope of protection of the present invention. The embodiments described in this invention are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0032] Example 1

[0033]

[0034] In a 10 mL reaction tube, 0.5 mmol of 2-bromothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of benzoic acid was added to the reaction system, and stirring was continued for another 5 hours. After the reaction was completed, the reaction system was concentrated, and the target product (90%) was obtained by column chromatography. 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 10 mL reaction tube, 0.5 mmol of 3-methylthiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of benzoic acid was added to the reaction system, and stirring was continued for another 5 hours. After the reaction was completed, the reaction system was concentrated, and the target product (97%) was obtained by column chromatography. 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of benzoic acid was added to the reaction system, and stirring was continued for another 5 hours. After the reaction was completed, the reaction system was concentrated, and the target product (97%) was obtained by column chromatography. 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of ibuprofen was added, and the mixture was stirred for another 5 hours. After the reaction was complete, the reaction mixture was 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of isocolic acid was added to the reaction system, and stirring was continued for another 5 hours. After the reaction was completed, the reaction system was concentrated, and the target product (56%) was obtained by column chromatography. 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of oxaprazine was added, and the mixture was stirred for another 5 hours. After the reaction was complete, the reaction mixture was 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of adamantane carboxylic acid was added, and the mixture was stirred for another 5 hours. After the reaction was complete, the reaction mixture was 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of Fmoc-O-tert-butyl-L-tyrosine was added, and the mixture was stirred for another 5 hours. After the reaction was complete, the reaction mixture was 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of N-CBZ-4-piperidinic acid was added, and the mixture was stirred for another 5 hours. After the reaction was complete, the reaction mixture was 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 10 mL reaction tube, 0.5 mmol of 4-chlorothiophenol, 0.6 mmol of N-chlorosuccinimide, and 2 mL of anhydrous tetrahydrofuran were added. After stirring at 25 °C for 1 hour, 0.6 mmol of trioctylphosphine was added, and the reaction was allowed to proceed for 5 minutes. Then, 0.5 mmol of benzoylformic acid was added to the reaction system, and stirring was continued for another 5 hours. After the reaction was completed, the reaction system was concentrated, and the target product (59%) was obtained by column chromatography. 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: Add a mercapto compound, an N-halogenated compound, a trivalent phosphine compound and a solvent to a reaction vessel, stir the reaction at room temperature, then add a carboxylic acid and continue stirring. After the reaction is complete, remove the solvent and obtain the target product lipid compound by simple separation by column chromatography. The reaction route for this synthesis method is as follows: ； Among them, R 1 It is alkyl or aryl, R 2 It can be hydrogen, alkyl, alkoxy, halogen, nitro, or aryl; The N-halogenated compound is an N-halogenated succinimide, and its structure is as follows: ； The trivalent phosphine compound is a trialkylphosphine or a triarylphosphine; The solvent is one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and methanol.

2. The method for synthesizing thioester compounds as described in claim 1, characterized in that: The thiol compound is an arylthiophenol.

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

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

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