Process for the preparation of benzopyran derivatives containing a thioester structure

Abstract

The application discloses a preparation method of a benzopyran derivative containing a thioester structure, and comprises the following steps: adding a propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide into a solvent to react at 50-70 DEG C for 0.5-5 h, then adding a sulfonyl chloride compound, a palladium catalyst, a ligand, a carbonyl molybdenum and a base to react at 80-100 DEG C for 20-28 hours, and after the reaction is completed, post-treatment is carried out to obtain the benzopyran derivative containing the thioester structure; the preparation method uses the sulfonyl chloride compound as a reactant and a sulfur source, uses the carbonyl molybdenum as a carbonyl source, has mild reaction conditions, simple operation, a wide functional group tolerance range of a substrate and high reaction efficiency. According to actual needs, various benzopyran derivatives containing the thioester structure can be synthesized, and the method is convenient to operate and wide in practicability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a benzopyran derivative containing a thioester structure. Background Technology

[0002] Thioesters are frequently used as important intermediates in organic and pharmaceutical synthesis, serving as crucial backbones for various drugs and biomolecules (J.Med.Chem., 2014, 57, 2832-2842). Compared to their corresponding acyl halides, thioesters are air-stable and easy to handle, allowing them to be used as active acyl donors in various organic transformations. For example, in natural chemical linkages, modified C-terminal polypeptide thioester fragments can undergo thioester transfer reactions with another polypeptide fragment containing an N-terminal cysteine ​​residue under neutral conditions, synthesizing a product with cysteine ​​as the linking site and achieving the linkage between two polypeptides. Based on this, the synthesis of thioesters has attracted widespread attention. The most common method is the acylation reaction of thiols with carboxylic acids and their derivatives. In addition, acid-catalyzed condensation reactions and metal-catalyzed and organocatalyzed oxidative coupling reactions have also been used as useful methods for the preparation of thioesters. Despite significant efforts in the synthesis of thioesters, the development of new and efficient routes remains a highly interesting area.

[0003] In recent decades, transition metal-catalyzed carbonylation reactions have attracted increasing attention due to their wide application in the synthesis of carbonyl-containing compounds (Chem. Rev., 2019, 119, 2090-2127). Consequently, various thiocarbonylation reactions have been developed and used to synthesize thioesters. However, the use of thiols in these thiocarbonylation reactions still has some drawbacks, as thiols have an unpleasant odor and often exhibit high toxicity to catalysts. To address these issues, various sulfur sources, including thiosulfates, thioacetates, and sulfonyl hydrazides, have been developed to replace thiols. Our research group has also recently reported a series of thiocarbonylation reactions using sulfonyl chlorides as sulfur sources. On the other hand, benzopyrans are a class of valuable heterocyclic compounds widely found in natural products, pharmaceuticals, and biomolecules. Considering the superior properties of thioesters and 2H-benzopyrans, the preparation of benzopyran derivatives containing thioester structures holds great promise.

[0004] Therefore, using propargyl ether compounds as raw materials, sulfonyl chloride as the sulfur source, and molybdenum carbonyl as the carbonyl group source, we synthesized a variety of benzopyran derivatives containing thioester structures via palladium-catalyzed thiocarbonylation. This reaction opens up a new synthetic route for the preparation of benzopyran derivatives containing thioester structures. Summary of the Invention

[0005] This invention provides a method for preparing benzopyran derivatives containing a thioester structure. The method is simple, uses inexpensive and readily available raw materials, is compatible with a variety of functional groups, and has good applicability. It uses sulfonyl chloride compounds as sulfur and molybdenum carbonyl as the carbonyl source, providing a new direction for the synthesis of benzopyran derivatives containing a thioester structure.

[0006] A method for preparing a benzopyran derivative containing a thioester structure includes the following steps: adding propargyl ether compound, hexafluoroisopropanol and N-iodosuccinimide to a solvent and reacting at 50-70°C for 0.5-5 h; then adding sulfonyl chloride compound, palladium catalyst, ligand, carbonyl molybdenum and base and reacting at 80-100°C for 20-28 h; after the reaction is complete, post-treatment is performed to obtain the benzopyran derivative containing a thioester structure.

[0007] The structure of the propyl ether compound is shown in formula (II):

[0008]

[0009] The structure of the sulfonyl chloride compound is shown in formula (III):

[0010]

[0011] The structure of the benzopyran derivative containing the thioester structure is shown in formula (I):

[0012]

[0013] In equations (I) to (III), R 1 H, C1-C4 alkyl, phenyl, or C1-C4 alkoxy, R 2 The phenyl group is substituted or unsubstituted, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, or halogen, R 3 It is a C3-C6 alkyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy or halogen.

[0014] The molar ratio of the palladium catalyst, ligand, and base is 0.05:0.1:1.8;

[0015] R 1 The replacement position is the opposite position; R 2 R 3 The substitution position on the phenyl group is para.

[0016] The reaction formula is as follows:

[0017]

[0018] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding benzopyran derivative containing a thioester structure. Column chromatography purification is a commonly used technique in this field.

[0019] As a preferred option, R 1 It can be H, methyl, tert-butyl, or methoxy. R 2 The phenyl group may be substituted or unsubstituted, and the substituent on the phenyl group is a C1-C3 alkyl, methoxy, or Br. In this case, the propargyl ether compound is readily available, and the reaction yield is high.

[0020] As a preferred option, R 3 The phenyl group is isopropyl, cyclopropyl, or cyclohexyl, substituted or unsubstituted, wherein the substituent on the phenyl group is methyl, isopropyl, methoxy, Cl, or Br. In this case, the sulfonyl chloride compound is readily available, and the reaction yield is high.

[0021] The propargyl ether compound and sulfonyl chloride compound used to prepare benzopyran derivatives containing thioester structures are inexpensive and widely available in nature. Preferably, the molar ratio of propargyl ether compound: sulfonyl chloride compound: palladium catalyst is 1:1~1.5:0.05~0.1; more preferably, the molar ratio of propargyl ether compound: sulfonyl chloride compound: palladium catalyst is 1:1.3:0.05.

[0022] Preferably, the reaction time is 24 hours. A reaction time that is too long increases the reaction cost, while a reaction that is too long makes it difficult to guarantee the completeness of the reaction.

[0023] Preferably, the reaction is carried out in acetonitrile, and the amount of acetonitrile used is sufficient to dissolve the raw material well. The amount of acetonitrile used for 0.2 mmol propargyl ether compound is about 1 to 2 mL.

[0024] Preferably, the palladium catalyst is palladium acetate, which is relatively inexpensive among many palladium catalysts and has high reaction efficiency when used as a catalyst.

[0025] As a preferred option, the reaction method is as follows:

[0026] First, mix the propargyl ether compound, sulfonyl chloride compound and N-iodosuccinimide and react at 50-60°C for 1-2 hours. Then, add other substances and react at 80-100°C for 20-28 hours.

[0027] As a further preferred embodiment, the benzopyran derivative containing a thioester structure is one of the compounds shown in formulas (I-1) to (I-5):

[0028]

[0029] In the above preparation method, the sulfonyl chloride compound, molybdenum carbonyl, palladium acetate, tris(m-tolyl)phosphine, hexafluoroisopropanol, N-iodosuccinimide, and potassium phosphate are generally commercially available products that can be easily obtained from the market.

[0030] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0031] Using sulfonyl chloride compounds as raw materials and sulfur sources, the preparation method is simple, easy to operate, and the post-processing is convenient. The starting materials are inexpensive and readily available, the substrate functional group tolerance is wide, and the reaction efficiency is high. Various benzopyran derivatives containing thioester structures can be synthesized according to actual needs, making it highly practical. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments.

[0033] Examples 1-15

[0034] According to the raw material ratio in Table 1, propargyl ether compound (II), hexafluoroisopropanol, N-iodosuccinimide, and acetonitrile (0.3 mL) were added to a 15 mL sealed tube and reacted at 60 °C for 1 h. Subsequently, sulfonyl chloride compound (III), palladium acetate, tris(m-tolyl)phosphine, molybdenum carbonyl, potassium phosphate, and acetonitrile (1 mL) were added, and the reaction was carried out under the reaction conditions in Table 2. After the reaction was completed, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding benzopyran derivative (I) containing a thioester structure. The reaction process is shown in the following formula:

[0035]

[0036] Table 1. Raw material addition amounts for Examples 1-15

[0037]

[0038] Table 2

[0039]

[0040] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, Me represents methyl, iPr represents isopropyl, OMe represents methoxy, and tBu represents tert-butyl.

[0041] Structural confirmation data of the compounds prepared in Examples 1-5:

[0042] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-1) containing a thioester structure prepared in Example 1 1 H NMR and 13 The C NMR detection data are as follows:

[0043]

[0044] 1 H NMR (400MHz, CDCl3) δ7.52–7.51(m,3H),7.38(d,J=3.6Hz,1H),7.36(d,J=2.3Hz,1H),7.32–7.28(m,1H),7.19(d,J=8.1Hz, 2H),7.14(d,J=8.2Hz,2H),6.99(d,J=8.1Hz,1H),6.93–6.89(m,1H),6.85(dd,J=7.8,1.7Hz,1H),5.11(s,2H),2.38(s,3H).

[0045] 13 C NMR (101MHz, CDCl3) δ190.1,155.3,142.3,139.6,135.4,134.6,131.6,129 .90,129.87,128.8,128.6,128.5,126.7,124.1,121.7,116.3,65.9,21.3.

[0046] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-2) containing a thioester structure prepared in Example 2 1 H NMR and 13 The C NMR detection data are as follows:

[0047]

[0048] 1 H NMR (400MHz, CDCl3) δ7.47–7.45(m,3H),7.33(d,J=3.8Hz,1H),7.31(d,J=2.2Hz,1H),7.28–7.23(m,1H),7.20(d,J=8.2Hz,2H),7.13(d,J=8.3H z,2H),6.94(d,J=8.1Hz,1H),6.88–6.84(m,1H),6.81(dd,J=7.8,1.7Hz,1H),5.07(s,2H),2.88(dt,J=13.8,6.9Hz,1H),1.21(d,J=6.9Hz,6H).

[0049] 13C NMR (101MHz, CDCl3) δ190.2,155.3,150.3,142.3,135.4,134.6,131.6,129.9,1 28.8,128.6,128.5,127.3,126.7,124.4,124.1,121.7,116.3,65.9,33.9,23.8.

[0050] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-3) containing a thioester structure prepared in Example 3 1 H NMR and 13 The C NMR detection data are as follows:

[0051]

[0052] 1 H NMR (400MHz, CDCl3) δ7.42–7.41(m,3H),7.24–7.20(m,3H),6.92(dd,J=8.1,0.8Hz,1H),6.85–6.81(m,1H),6.77(dd,J=7.8,1.6Hz, 1H),5.03(s,2H),3.48–3.41(m,1H),1.78–1.74(m,2H),1.53–1.50(m,1H),1.39–1.28(m,4H),1.23–1.17(m,2H),0.90–0.84(m,1H).

[0053] 13 C NMR (101MHz, CDCl3) δ190.9,155.1,140.8,135.8,131.2,129.6,128.5,128.3,128.3,127.1,124.2,121.6,116.1,65.8,42.3,32.7,25.8,25.5.

[0054] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-4) containing a thioester structure prepared in Example 4 1 H NMR and 13 The C NMR detection data are as follows:

[0055]

[0056] 1H NMR (400MHz, CDCl3) δ7.46–7.45(m,3H),7.32(d,J=3.6Hz,1H),7.31(d,J=2.3Hz,1H),7.14(d,J=8.0Hz,2H),7.08(d,J=8. 2Hz,2H),6.89(d,J=8.8Hz,1H),6.82(dd,J=8.8,2.9Hz,1H),6.35(d,J=2.9Hz,1H),5.00(s,2H),3.63(s,3H),2.33(s,3H).

[0057] 13 C NMR (101MHz, CDCl3) δ190.3,154.2,149.3,142.1,139.6,135.3,134.6,129. 9,128.9,128.5,127.6,124.8,124.1,116.9,116.8,113.6,66.0,55.7,21.3.

[0058] Nuclear magnetic resonance (NMR) of the benzopyran derivative (I-5) containing a thioester structure prepared in Example 5 1 H NMR and 13 The C NMR detection data are as follows:

[0059]

[0060] 1 H NMR(400MHz, CDCl3)δ7.60(d,J=8.4Hz,2H),7.29–7.24(m,1H),7.20–7.18(m,2H),7.17(d,J=5.1Hz,2H),7.12(d, J=8.2Hz,2H),6.95(d,J=8.1Hz,1H),6.87(t,J=7.5Hz,1H),6.76(dd,J=7.8,1.5Hz,1H),5.06(s,2H),2.34(s,3H).

[0061] 13 C NMR (101MHz, CDCl3) δ189.6,155.3,141.1,139.8,134.6,134.4,131.8,131.7 ,131.5,130.0,128.4,126.8,123.7,123.7,123.1,121.8,116.4,65.8,21.3..

Claims

1. A method for preparing a benzopyran derivative containing a thioester structure, characterized in that, The steps include: adding the propargyl ether compound, hexafluoroisopropanol, and N-iodosuccinimide to a solvent at 50-70°C. o The reaction proceeds at C for 0.5–5 h, followed by the addition of sulfonyl chloride compound, palladium catalyst, ligand, carbonyl molybdenum, and base at 80–100 °C. o C is reacted for 20-28 hours. After the reaction is complete, post-treatment is performed to obtain the benzopyran derivative containing the thioester structure. The structure of the propyl ether compound is shown in formula (II): ； The structure of the sulfonyl chloride compound is shown in formula (III): ； The structure of the benzopyran derivative containing the thioester structure is shown in formula (I): ； In equations (I) to (III), R 1 H, C1-C4 alkyl, phenyl, or C1-C4 alkoxy, R 2 The phenyl group is substituted or unsubstituted, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, or halogen, R 3 It is a C3-C6 alkyl, cyclopropyl or cyclohexyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy or halogen; The reaction uses acetonitrile as a solvent; The alkali mentioned is potassium phosphate; The palladium catalyst is palladium acetate; The ligand is tris(m-tolyl)phosphine.

2. The method for preparing the benzopyran derivative containing a thioester structure according to claim 1, characterized in that, R 1 It can be H, methyl, tert-butyl or methoxy.

3. The method for preparing the benzopyran derivative containing a thioester structure according to claim 1, characterized in that, R 2 The phenyl group may be substituted or unsubstituted, and the substituent on the phenyl group is a C1-C3 alkyl, methoxy, or Br.

4. The method for preparing the benzopyran derivative containing a thioester structure according to claim 1, characterized in that, R 3 It is an isopropyl, cyclopropyl, or cyclohexyl phenyl group, substituted or unsubstituted, wherein the substituent on the phenyl group is methyl, isopropyl, methoxy, Cl, or Br.

5. The method for preparing the benzopyran derivative containing a thioester structure according to claim 1, characterized in that, In molar amounts, the ratio of propargyl ether compound: sulfonyl chloride compound: carbonyl molybdenum: palladium catalyst: ligand: N-iodosuccinimide: base = 1:1.2~1.5:1~2: 0.05~0.1:0.1~0.2:1~1.5:1.5~2.

6. The method for preparing the benzopyran derivative containing a thioester structure according to claim 1, characterized in that, The benzopyran derivative containing a thioester structure is one of the compounds shown in formulas (I-1) to (I-5): ； ； ； ； 。

Images