A method for the synthesis of aryl alkyl sulfides

Abstract

The application discloses a high-efficiency synthesis method of aryl alkyl sulfide. The method comprises the following steps: mixing sodium aryl sulfide (I), N-alkoxy phthalimide (II) and a solvent according to a specific proportion, and reacting at 60 DEG C under light for 10-24 hours to obtain the target product aryl alkyl sulfide (III). The method has the advantages of stable and easy-to-prepared raw materials, mild reaction conditions, simple experimental operation, good chemical selectivity and good functional group tolerance, and is a green chemical synthesis method with good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology and relates to a method for synthesizing aryl alkyl sulfides. Background Technology

[0002] Sulfur is a common and important element in many drugs, existing both as an active pharmaceutical ingredient and as a component of excipients (inactive ingredients). Among all sulfur-containing drugs approved by the U.S. Food and Drug Administration (FDA), the thioether functional group ranks third in frequency (8.8%), after sulfonamides (29%) and β-lactams (10.5%). Aryl alkyl sulfides are prominent structural units in both natural and synthetic molecules, possessing diverse biological activities and playing a significant role in drug development. Current synthetic methods for aryl alkyl sulfides generally suffer from harsh reaction conditions and low efficiency. Therefore, developing a synthetic method under visible light-induced redox neutral conditions is of high research value. The synthesis of aryl alkyl sulfides via a free radical-free radical coupling reaction of fatty alcohol derivatives with sodium arylthiophenol overcomes the limitations of traditional methods, while also expanding the diverse derivatization of fatty alcohols and achieving efficient utilization of alcohols. Summary of the Invention

[0003] In view of the above-mentioned technical problems existing in the prior art, the present invention aims to provide a photocatalytic method for synthesizing aryl alkyl sulfides, which constructs aryl alkyl sulfides through free radical-free radical coupling reaction, thereby providing a mild, environmentally friendly and efficient synthetic route.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] In an organic solvent, sodium arylthiophenol (I) and N-alkoxyphthalimide (II) were reacted at 60°C under light for 10–24 hours. After the reaction was completed, the reaction system was separated and purified to obtain the aryl alkyl sulfide (III). The structural formulas of Formula I, Formula II, and Formula III are as follows:

[0006]

[0007] R1 is selected from at least one of hydrogen, halogen, alkyl, phenyl, and alkoxy; R2 is selected from one of different substituted alkyl groups.

[0008] Preferably, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide, and more preferably dimethyl sulfoxide.

[0009] Preferably, the molar ratio of the N-alkoxyphthalimide to the sodium arylthiophenol is 1:1.5 to 2.

[0010] Preferably, the illumination conditions are violet light (390-440nm) and blue light (440-485nm).

[0011] Preferably, the reaction system is separated and purified. After concentration, the reaction system is separated and purified by column chromatography with silica gel. The eluent is a mixture of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 50-20:1. The eluent is collected and the solvent is evaporated to obtain the arylalkyl sulfide III.

[0012] Compared with the prior art, the beneficial effects of this invention are as follows:

[0013] The method for synthesizing aryl alkyl sulfides provided by this invention is scientific and reasonable. It provides a new route for synthesizing aryl alkyl sulfides by visible light-induced free radical-free radical coupling reaction of sodium arylthiophenol with N-alkoxyphthalimide. A variety of aryl alkyl sulfides with different structures have been obtained by this method. Its characteristics are simple synthesis method, good functional group compatibility, mild conditions and high chemical selectivity. Attached Figure Description

[0014] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0015] Figure 1 Chemical reaction formula for the preparation of aryl alkyl sulfide compounds;

[0016] Figure 2 The 1H NMR spectrum of compound IIIa prepared in Example 1;

[0017] Figure 3 The 1H NMR spectrum of compound IIIb prepared in Example 2;

[0018] Figure 4 The 1H NMR spectrum of compound IIIc prepared in Example 3;

[0019] Figure 5 The 1H NMR spectrum of compound IIId prepared in Example 4;

[0020] Figure 6 The image shows the carbon NMR spectrum of compound IIId prepared in Example 4. Detailed Implementation

[0021] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0022] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0023] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0024] General experimental procedure: Add sodium arylthiophenol I (0.15–0.2 mmol, 1.5–2.0 equiv.), N-alkoxyphthalimide II (0.1 mmol, 1.0 equiv.), and the reaction solvent to a 4 mL clear glass vial equipped with a magnetic stir bar. Irradiate the vial under visible light and react at 60 °C. Monitor the reaction mixture by TLC until reactant II is completely consumed. After the reaction is complete, purify the reaction mixture by column chromatography to obtain the target product III.

[0025] Example 1

[0026] Sodium arylthiophenol Ia (0.15 mmol, 1.5 equiv.), N-alkoxyphthalimide IIa (0.1 mmol, 1.0 equiv.), and dimethyl sulfoxide were added to a 4 mL clear glass vial equipped with a magnetic stir bar. The vial was irradiated under visible light at 390 nm and the reaction was carried out at 60 °C. The reaction mixture was monitored by TLC until the starting material IIa was completely consumed. After the reaction was complete, the reaction mixture was purified by column chromatography to obtain the target product IIIa.

[0027]

[0028] Characterization data: Yellow oily substance (16.7 mg, 92% yield); 1 H NMR (400MHz, CDCl3) δ7.53 (m, J=1.9Hz, 2H), 7.29 (m, J=3.7Hz, 3H), 5.67 (m, J=2 .8Hz, 1H), 4.02 (m, J=4.7Hz, 2H), 2.39 (m, J=3.2Hz, 1H), 1.97 (m, J=2.2Hz, 3H).

[0029] Example 2

[0030] Sodium arylthiophenol Ib (0.2 mmol, 2.0 equiv.), N-alkoxyphthalimide IIb (0.1 mmol, 1.0 equiv.), and N,N-dimethylformamide were added to a 4 mL clear glass vial equipped with a magnetic stir bar. The vial was irradiated under 425 nm visible light and reacted at 60 °C. The reaction mixture was monitored by TLC until the starting material IIb was completely consumed. After the reaction was complete, the reaction mixture was purified by column chromatography to obtain the target product IIIb.

[0031]

[0032] Characterization data: Yellow oily substance (15.7 mg, 75% yield); 1 H NMR (400MHz, CDCl3) δ7.54 (q, J=2.8Hz, 2H), 7.33 (m, J=3.7Hz, 3H), 5.58 (t, J=6. 0Hz, 1H), 4.38 (q, J=5.2Hz, 1H), 3.98 (q, J=4.9Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H).

[0033] Example 3

[0034] Sodium arylthiophenol Ic (0.15 mmol, 1.5 equiv.), N-alkoxyphthalimide IIc (0.1 mmol, 1.0 equiv.), and N,N-dimethylformamide were added to a 4 mL clear glass vial equipped with a magnetic stir bar. The vial was irradiated under visible light at 456 nm and reacted at 60 °C. The reaction mixture was monitored by TLC until the starting material Hc was completely consumed. After the reaction was complete, the reaction mixture was purified by column chromatography to obtain the target product IIIc.

[0035]

[0036] Characterization data: Yellow oily substance (13.2 mg, 68% yield); 1 H NMR (400MHz, CDCl3) δ7.44 (d, J=8.1Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 5.61 (q, J=3.7Hz, 1H), 4.02 (m, J=4.2Hz, 2H), 2.38 (m, J=2.6Hz, 1H), 2.35 (s, 3H), 1.94 (m, J=2.7Hz, 3H).

[0037] Example 4

[0038] Sodium arylthiophenol Id (0.2 mmol, 2.0 equiv.), N-alkoxyphthalimide IId (0.1 mmol, 1.0 equiv.), and N,N-dimethylacetamide were added to a 4 mL clear glass vial equipped with a magnetic stir bar. The vial was irradiated under 405 nm visible light and reacted at 60 °C. The reaction mixture was monitored by TLC until the starting material IId was completely consumed. After the reaction was complete, the reaction mixture was purified by column chromatography to obtain the target product IIId.

[0039]

[0040] Characterization data: Yellow oily substance (16.6 mg, 80% yield); 1 H NMR (400MHz, CDCl3) δ7.46 (q, J=2.7Hz, 2H), 7.17 (d, J=8.2Hz, 2H), 5.62 (q, J=3.7Hz, 1H), 4.01 (m, J=5 .2Hz, 2H), 2.65 (q, J=7.6Hz, 2H), 2.37 (m, J=3.2Hz, 1H), 1.97 (m, J=2.8Hz, 3H), 1.25 (t, J=7.6Hz, 3H); 13 CNMR (101MHz, CDCl3) δ143.4, 132.0, 131.9, 128.4, 87.6, 67.3, 67.2, 32.6, 28.5, 24.9, 24.9, 15.5.

[0041] Examples 5-14

[0042] The reaction products and results with different substrate choices are shown in Table 1. The experimental procedures are as described in the general experimental procedures, and the general reaction formula is as follows. Figure 1 As shown.

[0043] Table 1. Reaction products and results with different substrate choices.

[0044]

[0045] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for the synthesis of arylalkyl sulfides, characterized in that, The process includes the following steps: Adding sodium arylthiophenol (I) and N-alkoxyphthalimide (II) as starting materials to an organic solvent, and reacting at 60°C under visible light for 10–24 hours to obtain arylalkyl sulfide (III); wherein the structural formulas of Formula I, Formula II, and Formula III are as follows: R1 is selected from at least one of hydrogen, halogen, alkyl, phenyl, and alkoxy; R2 is selected from one of a variety of substituted alkyl groups.

2. The method for synthesizing an aryl alkyl sulfide according to claim 1, characterized in that, The organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide.

3. The method for synthesizing an aryl alkyl sulfide according to claim 1, characterized in that, The molar ratio of the N-alkoxyphthalimide to the sodium arylthiophenol is 1:1.5 to 2.

4. The method for synthesizing an aryl alkyl sulfide according to claim 1, characterized in that, The illumination conditions are 390–485 nm.

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