Method for photocatalytic synthesis of thioamide

Abstract

The invention discloses a method for synthesizing thioamide through photocatalysis. According to the method, sulfur powder, ketonic acid and amine are taken as starting raw materials, and the thioamide compound is synthesized in a green and efficient manner through dehydration condensation, photooxidation reduction decarboxylation and coupling sulfur insertion at room temperature under blue light irradiation. The method designed by the invention is novel and efficient, the raw materials are green and odorless, the synthesis method is simple, the conditions are mild, the yield is higher, the substrate application range is wide, and the method has very strong popularization potential.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and specifically to a method for photocatalytic synthesis of thioamides. Background Art

[0002] As an amide isomer with unique physical properties and biological activities, thioamides exhibit excellent pharmacokinetic parameters and remarkable stability among peptide drug candidates, and are applied in many synthetic intermediates and clinical drugs. The synthesis of thioamides has always received extensive attention. The traditional synthesis method is to convert the carbonyl group of amides into a thiocarbonyl group using Lawesson's reagent or phosphorus pentasulfide. However, this method is limited by harsh reaction conditions, difficult operation, a narrow substrate scope, and the fact that most raw materials and by-products have a foul odor.

[0003] Elemental sulfur is an eight-membered ring of sulfur atoms, which is a cheap, non-toxic, and odorless source for introducing sulfur atoms. However, the application of elemental sulfur in organic synthesis is restricted by its harsh activation conditions. In recent years, there have been some reports on the synthesis of thioamides and thiopeptides under mild conditions through reactions involving elemental sulfur. However, these reactions have a limited substrate scope due to poor chemoselectivity.

[0004] Photocatalysis is a green, safe, and controllable method for organic synthesis. The reaction conditions for photocatalytic organic synthesis are milder, the reaction yield is higher, and it can effectively reduce production costs. The reaction of elemental sulfur involved in visible-light photocatalysis can be carried out under metal-free, oxidant-free, and even photocatalyst-free conditions. Elemental sulfur generates polysulfide radical anions through photoredox catalysis to construct carbon-sulfur bonds. Such reactions can be applied to the synthesis of various sulfur-containing compounds. Currently, there is no report on the method for synthesizing thioamides by photocatalytic elemental sulfur.

[0005] Therefore, it is very important to invent a method for highly efficient photocatalytic synthesis of thioamides with mild conditions, green and odorless raw materials, and wide applicability. Summary of the Invention

[0006] The object of the present invention is to provide a method for photocatalytic synthesis of thioamides. This method realizes the green and efficient synthesis of thioamide compounds from sulfur powder, keto acids, and amines as starting materials under room temperature conditions.

[0007] The technical solution of the present invention is specifically as follows:

[0008] A method for photocatalytic synthesis of thioamides, the general structural formula of thioamides is Structure I in the following figure:

[0009]

[0010] Wherein: R is phenyl, substituted phenyl or alkyl; among them, R being substituted phenyl includes 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 3-methylphenyl or 2-methylphenyl; R being substituted alkyl includes cyclohexyl, benzyl or phenethyl;

[0011] The preparation method is as follows:

[0012]

[0013] Preparation method of the target compound I: Dissolve compound II, compound III and sulfur powder in acetonitrile, protect with nitrogen, and react under blue light irradiation. After stopping the reaction, wash the reaction mixture with water, extract with ethyl acetate, remove the solvent under reduced pressure, and elute by column chromatography to obtain the target compound I.

[0014] As a further option of the preparation method, a photocatalyst is added when compound II and compound III are dissolved in acetonitrile, and the photocatalyst is tetrakarzole isophthalonitrile, eosin B, eosin Y or tris(2-phenylpyridine)iridium.

[0015] As a further option of the preparation method, the acetonitrile substitute is N,N-dimethylformamide or dimethyl sulfoxide.

[0016] As a further option of the preparation method, the concentration of the acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide is 0.1 M

[0017] As a further option of the preparation method, the molar ratio of compound II, compound III and sulfur powder is II:III:S8 = 1:1.5:3.

[0018] As a further option of the preparation method, the eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio V 石油醚 :V 乙酸乙酯 = 20:1 to 5:1.

[0019] As a further option of the preparation method, the reaction temperature of compound II, compound III and sulfur powder is room temperature.

[0020] The beneficial effects brought by the technical solution provided in the embodiments of the present application at least include the following

[0021] Beneficial effects:

[0022] The method involved in the present invention uses visible light of 10W 455nm to catalyze the reaction at room temperature, and uses sulfur powder as a reactant. The method involved in the present invention can easily prepare thioamide compounds. The raw materials are green and odorless. The synthesis method is simple and the conditions are mild. There are no metal additives and no oxidants, and the yield is relatively high. Description of the drawings

[0023] Figure 1 1H NMR spectrum of Product I-1 obtained in the embodiment of the present invention;

[0024] Figure 2 13C NMR spectrum of Product I-1 obtained in the embodiment of the present invention. Detailed implementation manners

[0025] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present application.

[0026] Example 1

[0027] Reaction formula of Example 1. The specific compounds II and III used and the structure of Product I-1 are shown in Formula 1. Experiments show that the organic solvent used in the present invention is acetonitrile, the highest yield of its reaction product is 88%, the optimal molar ratio of raw materials is Compound II-1:Compound III-1:sulfur powder = 1:1.5:3, and the optimal reaction concentration is 0.1 M.

[0028]

[0029] Specific experimental steps are as follows: Dissolve 32 mg (0.30 mmol, 0.1 equivalent) of Compound II-1, 68 mg (0.45 mmol, 0.15 equivalent) of Compound III-1 and 29 mg (0.90 mmol, 0.3 equivalent) of sulfur powder in 3 mL of acetonitrile, under nitrogen protection, place it under a 10 W 455 nm blue light irradiation at room temperature for reaction for 24 hours. Monitor the reaction by thin layer chromatography. After stopping the reaction, wash the reaction mixture with water, extract it with ethyl acetate, and rotary evaporate to remove the solvent under reduced pressure with a water pump. The residue is subjected to column chromatography on silica gel of 200 - 300 mesh, and the eluent (volume ratio V 石油醚 :V 乙酸乙酯 = 20:1 - 10:1) to obtain 60 mg of the compound shown in I-1. The product is identified by nuclear magnetic resonance (1H NMR, 13C NMR).

[0030] Product I-1 is a yellow powder, yield: 88%; 1 H NMR(400MHz,CDCl3)δ9.00(s,1H),7.85(d,J = 7.4Hz,2H),7.62(d,J = 8.2Hz,2H),7.47(dt,J = 27.9,7.4Hz,3H),7.25(d,J = 9.3Hz,2H),2.38(s,3H); 1313C NMR (100 MHz, CDCl3) δ 198.5, 143.1, 137.1, 136.6, 131.3, 129.7, 128.7, 126.8, 124.0, 21.3.

[0031] The method used in the examples for preparing other compounds (Compound I-2 to Compound I-6) of the present invention is the same as that in Example 1, and the reaction conditions are as follows: Compound II (0.3 mmol), Compound III (0.45 equiv), sulfur powder (0.9 equiv) were dissolved in 3 mL of acetonitrile, protected by nitrogen, and reacted under irradiation with 10 W 455 nm blue light at room temperature.

[0032] The structures and data characterizations of the obtained products are as follows:

[0033]

[0034] Product I-2 is a yellow powder, yield: 97%; 1 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.56 - 7.31 (m, 5H); 13 13C NMR (100 MHz, CDCl3) δ 198.8, 142.9, 137.6, 132.2, 131.6, 129.3, 128.8, 126.8, 125.2.

[0035] Product I-3 is a yellow powder, yield: 54%; 1 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.83 (d, J = 7.4 Hz, 2H), 7.63 - 7.37 (m, 5H), 7.32 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 2.39 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 198.5, 143.3, 139.2, 139.0, 131.3, 129.0, 128.7, 128.0, 126.8, 124.4, 121.0, 21.5.

[0036] Product I-4 is a yellow powder, yield: 41%; 1 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.57 - 7.47 (m, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.35 - 7.27 (m, 3H), 2.32 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 199.7, 142.1, 137.6, 134.4, 131.5, 131.1, 128.7, 128.3, 126.9, 18.0, (2C peaks are merged with other peaks).

[0037] Product I-5 is a yellow powder, yield: 77%; 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.42 (s, 4H), 7.29 (t, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 198.5, 143.0, 139.0, 131.4, 129.1, 128.7, 127.1, 126.8, 123.9.

[0038] Product I-6 is a yellow powder, yield: 56%; 1 H NMR (400 MHz, CDCl3) δ 7.73 - 7.66 (m, 2H), 7.48 - 7.41 (m, 2H), 7.40 - 7.33 (m, 2H), 4.53 (m, 1H), 2.24 - 2.12 (m, 2H), 1.78 (m, 2H), 1.69 (m, 1H), 1.53 - 1.39 (m, 2H), 1.38 - 1.17 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 197.8, 142.5, 131.0, 128.6, 126.7, 55.0, 31.7, 25.6, 24.8.

[0039] Product I-7 is a yellow powder, yield: 96%; 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.77 - 7.70 (m, 2H), 7.50 - 7.43 (m, 1H), 7.42 - 7.31 (m, 7H), 5.03 - 4.93 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 199.2, 141.6, 136.2, 131.2, 129.1, 128.6, 128.4, 128.3, 126.8, 51.0.

[0040] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, in any aspect, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention.

[0041] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for photocatalytic synthesis of thioamides, the general structural formula of thioamides being Structure I in the following figure: Wherein: R is phenyl, substituted phenyl or alkyl; wherein, R is a substituted phenyl group including 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 3-methylphenyl or 2-methylphenyl; R is a substituted alkyl group including cyclohexyl, benzyl or phenethyl; It is characterized in that the preparation method is as follows: Preparation method of target compound I: Dissolve compound II, compound III and sulfur powder in acetonitrile, protect with nitrogen, and react under blue light irradiation. After the reaction stops, wash the reaction mixture with water, extract with ethyl acetate, remove the solvent under reduced pressure, and elute by column chromatography to obtain the target compound I.

2. The method for photocatalytic synthesis of thioamides according to claim 1, characterized in that, When compound II and compound III are dissolved in acetonitrile, a photocatalyst is added. The photocatalyst is tetrakazolyl isophthalonitrile, eosin B, eosin Y or tris(2-phenylpyridine)iridium.

3. A method for photocatalytic synthesis of thioamides according to claim 1, characterized in that, The acetonitrile substitute is N,N-dimethylformamide or dimethyl sulfoxide.

4. A method for photocatalytic synthesis of thioamides according to claim 1, characterized in that, The concentration of the acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide is 0.1 M.

5. A method for photocatalytic synthesis of thioamides according to claim 1, characterized in that, The molar ratio of compound II, compound III and sulfur powder is II:III:S8 = 1:1.5:

3.

6. A method for photocatalytic synthesis of thioamides according to claim 1, characterized in that, The eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio V 石油醚 :V 乙酸乙酯 = 20:1 to 5:

1.

7. A method for photocatalytic synthesis of thioamides according to any one of claims 1-6, characterized in that, The reaction temperature of compound II, compound III and sulfur powder is room temperature.

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