Preparation method of pyrone derivative containing thioester structure

Abstract

The invention discloses a preparation method of a pyrone derivative containing a thioester structure, which comprises the following steps: reacting a nickel catalyst, a ligand, manganese, carbonyl molybdenum, alkali, a 5-iodo-2H-pyrone derivative and a sulfonyl chloride compound at 90-110 DEG C for 12-20 hours, and after the reaction is completed, performing post-treatment to obtain the pyrone derivative containing the thioester structure. According to the preparation method, the sulfonyl chloride compound is used as a sulfur source, meanwhile, carbonyl molybdenum is used as a carbonyl source and a reducing agent, operation is easy, reaction starting raw materials are low in price and easy to obtain, the tolerance range of substrate functional groups is wide, and reaction efficiency is high. Various pyrone derivatives containing thioester structures can be synthesized according to actual needs, so that the method is convenient to operate, and the practicability of the method is widened.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a pyrone derivative containing a thioester structure. Background Art

[0002] Thioester compounds are widely present in many natural products, biomolecules and drugs. They act as important intermediates in various biological processes, such as acetyl-CoA, which is an acetyl donor in the citric acid cycle (ACSMed.Chem.Lett.2015,6,660-664). In addition, other thioesters are also commonly involved in the synthesis of many substances in cells, such as peptides, fatty acids, sterols, terpenes and porphyrins. Due to the high reactivity and strong electrophilicity of thioesters, they often play an important role as active acyl donors in various acylation reactions. In particular, in natural chemical connections, the reaction of C-terminal peptide thioesters with N-terminal cysteine ​​can achieve the connection between two polypeptides. Therefore, in addition to the traditional acylation reaction of thiols with acids and their derivatives, other reactions for synthesizing thioesters include acid-catalyzed condensation reactions, metal and organic catalyzed oxidative coupling reactions, etc.

[0003] In recent decades, transition metal-catalyzed carbonylation reactions have attracted increasing attention from academia and industry as an economical and efficient method for synthesizing carbonyl-containing compounds, and a series of thiocarbonylation reactions have also been developed for the preparation of thioesters (Chem 2019, 5, 526-552). However, the use of thiols as nucleophiles still has some disadvantages due to the odor and catalyst toxicity of thiols. Therefore, alternative sulfur sources such as thiosulfates, thioacetates, sulfonyl hydrazides and sulfonyl chlorides have been developed to address these problems. On the other hand, noble metals, including palladium, rhodium and ruthenium, are commonly used as catalysts in carbonylation reactions due to their excellent reactivity and efficiency. However, their high prices coupled with some expensive phosphine ligands limit their use, especially in large-scale reactions. Therefore, the use of cheap metals such as nickel is often more promising. In addition, 2H-pyrone is a valuable heterocycle that serves as a core skeleton in various natural compounds and exhibits a wide range of biological activities. Considering the superior biological activities and synthetic values ​​of thioesters and 2H-pyrones, constructing 2H-pyrones containing thioester structures is of great significance in pharmaceutical and organic synthesis.

[0004] Based on this, we developed a nickel-catalyzed carbonylation cyclization reaction to synthesize pyrone derivatives containing thioester structures. Starting from the simple and readily available 5-iodo-2H-pyrone and sulfonyl chloride compounds, carbonyl molybdenum was used as both a carbonyl source and a reducing agent to synthesize a variety of pyrone derivatives containing thioester structures, opening up a new route for the thiocarbonylation reaction involving sulfonyl chloride compounds. Summary of the invention

[0005] The invention provides a method for preparing a pyrone derivative containing a thioester structure. The preparation method has simple steps, and reaction raw materials are cheap and readily available, and are compatible with a variety of functional groups. The method has good reaction applicability, and a sulfonyl chloride compound is used as a sulfur source, and carbonyl molybdenum is used as both a carbonyl source and a reducing agent, thereby providing a new direction for the synthesis of pyrone derivatives containing a thioester structure.

[0006] A method for preparing a pyrone derivative containing a thioester structure comprises the following steps: reacting a nickel catalyst, a ligand, manganese, carbonyl molybdenum, a base, 5-iodo-2H-pyrone and a sulfonyl chloride compound at 90 to 110° C. for 12 to 20 hours, and after the reaction is complete, post-treating to obtain the pyrone derivative containing a thioester structure;

[0007] The structure of the 5-iodo-2H-pyrone 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 pyrone derivative containing a thioester structure is shown in formula (I):

[0012]

[0013] In formulas (I) to (III), R is a substituted or unsubstituted phenyl group or a cyclopropyl group, and the substituent on the phenyl group is a C1 to C4 alkyl group, a trifluoromethyl group or a halogen group;

[0014] Ar is a substituted or unsubstituted aryl group;

[0015] The substituent on the aryl group is a C1-C4 alkyl group, a C1-C4 alkoxy group or a phenyl group.

[0016] The molar ratio of the nickel catalyst, the ligand and the base is 0.1:0.15:2;

[0017] The substitution position of R is the para position and the meta position; the substitution position on the aromatic group of Ar is the para position or the ortho position.

[0018] In the present invention, the reaction formula is exemplified as follows:

[0019]

[0020] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding pyrone derivative containing a thioester structure. Column chromatography purification is a commonly used technical means in the art.

[0021] Preferably, R is a substituted or unsubstituted phenyl group or a cyclopropyl group, and the substituent on the phenyl group is a methyl group, a propyl group, a tert-butyl group, a trifluoromethyl group, a F group or a Cl group. In this case, the 5-iodo-2H-pyrone is easily obtained and the reaction yield is high.

[0022] Preferably, Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group, a methoxy group, an isopropyl group, a tert-butyl group or a phenyl group. In this case, the sulfonyl chloride compound is easy to obtain, and the reaction yield is high.

[0023] The sulfonyl chloride compound used to prepare the pyrone derivative containing a thioester structure is relatively cheap and widely exists in nature. Preferably, the molar ratio of the sulfonyl chloride compound: the nickel catalyst is 1.5-2:0.1-0.2; and more preferably, the molar ratio of 5-iodo-2H-pyrone: the sulfonyl chloride compound: the nickel catalyst is 1:1.8:0.1.

[0024] Preferably, the reaction time is 16 hours. Too long a reaction time will increase the reaction cost, and conversely it will be difficult to ensure the completeness of the reaction.

[0025] Preferably, the reaction is carried out in acetonitrile, and the amount of acetonitrile used is sufficient to dissolve the raw materials well, and the amount of acetonitrile used for 0.2 mmol of 5-iodo-2H-pyrone is about 1-2 mL.

[0026] Preferably, the nickel catalyst is nickel iodide. Among various nickel catalysts, nickel iodide is relatively cheap and has a higher reaction efficiency when nickel iodide is used as a catalyst.

[0027] Preferably, the ligand is 4,4'-di-tert-butyl-2,2'-bipyridine. Using 4,4'-di-tert-butyl-2,2'-bipyridine as the ligand has the highest reaction efficiency.

[0028] Preferably, the base is potassium carbonate.

[0029] As a further preference, the pyrone derivative containing a thioester structure is one of the compounds represented by formula (I-1) to formula (I-5):

[0030]

[0031] In the above preparation method, the 5-iodo-2H-pyrone, sulfonyl chloride compound, carbonyl molybdenum, nickel iodide, 4,4'-di-tert-butyl-2,2'-bipyridine, manganese and potassium carbonate are generally commercially available products and can be easily obtained from the market.

[0032] Compared with the prior art, the invention has the following beneficial effects: using a sulfonyl chloride compound as a sulfur source, the preparation method is simple, easy to operate, and the post-treatment is simple; the reaction starting materials are cheap and readily available; the substrate functional group tolerance range is wide; and the reaction efficiency is high. A variety of pyrone derivatives containing thioester structures can be synthesized according to actual needs, and the invention has strong practicality. DETAILED DESCRIPTION

[0033] The present invention is further described below in conjunction with specific embodiments.

[0034] Examples 1 to 15

[0035] According to the raw material ratio in Table 1, nickel iodide, 4,4'-di-tert-butyl-2,2'-bipyridine, manganese, carbonyl molybdenum, potassium carbonate, 5-iodo-2H-pyrone (II) and sulfonyl chloride compound (III) were added to a 15 mL sealed tube, and then acetonitrile (1.5 mL) was added, mixed and stirred evenly, and reacted according to 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 pyrone derivative (I) containing a thioester structure. The reaction process is shown in the following formula:

[0036]

[0037] Table 1 Amount of raw materials added in Examples 1 to 15

[0038]

[0039]

[0040] Table 2

[0041]

[0042] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is a phenyl group, Me is a methyl group, OMe is a methoxy group, tBu is a tert-butyl group, iPr is an isopropyl group, Pr is an n-propyl group, and CF3 is a trifluoromethyl group.

[0043] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0044] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0045]

[0046] 1H NMR (400MHz, CDCl3) δ7.68–7.65(m,3H),7.54(t,J=7.4Hz,1H),7.47(t,J=7.4Hz,2H),7.23–7.18(m,4H),6.36(d,J=9.6Hz,1H),2.37(s,3H).

[0047] 13 C NMR (101MHz, CDCl3) δ190.0,163.7,160.1,142.8,140.4,134.3,131.8,131.1,130.2,129.3,128.5,123.1,117.2,113.7,21.3.

[0048] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0049]

[0050] 1 H NMR (400MHz, CDCl3) δ7.67–7.64(m,3H),7.54(t,J=7.3Hz,1H),7.47(t,J=7.4Hz,2H ),7.22(d,J=8.7Hz,2H),6.93(d,J=8.8Hz,2H),6.34(d,J=9.6Hz,1H),3.81(s,3H).

[0051] 13 C NMR (101MHz, CDCl3) δ190.4,163.6,161.0,160.0,142.7,135.9,131.7,131.1,129.2,128.4,117.10,117.06,115.0,113.6,55.3.

[0052] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0053]

[0054] 1H NMR (400MHz, CDCl3) δ7.64(d,J=9.6Hz,1H),7.57(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),7.22(s,4H),6.31(d,J=9.6Hz,1H),2.42(s,3H),2.37(s,3H).

[0055] 13 C NMR (101MHz, CDCl3) δ190.1,163.9,160.2,142.8,142.5,140.3,134.3,130.2,129.25,129.22,128.2,123.2,116.8,113.2,21.6,21.3.

[0056] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0057]

[0058] 1 H NMR (400MHz, CDCl3) δ7.69–7.65(m,3H),7.25–7.20(m,4H),7.16(t,J=8.6Hz,2H),6.36(d,J=9.6Hz,1H),2.38(s,3H).

[0059] 13 C NMR(101MHz, CDCl3)δ189.7,164.73(d,J=254.0Hz),162.6,159.8,142.7,140.5,134.3,13 1.7,131.6,130.3,127.27(d,J=3.3Hz),122.9,117.0,115.84(d,J=22.2Hz),113.7,21.3.

[0060] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0061]

[0062] 1H NMR(400MHz,CDCl3)δ7.91(d,J=9.8Hz,1H),7.35(d,J=8.1Hz,2H),7.28(d,J=8.1Hz,2H),6.14(d,J=9.8Hz,1H),3.10–3.03(m,1H),2.40(s,3H),1.38–1.34(m,2H),1.15–1.10(m,2H).

[0063] 13 C NMR(101MHz,CDCl3)δ187.8,173.2,159.4,142.9,140.3,135.1,130.2,123.1,115.0,110.4,21.4,13.3,11.9。

Claims

1. A method for preparing a pyrone derivative containing a thioester structure, characterized in that: The method comprises the following steps: reacting a nickel catalyst, a ligand, manganese, carbonyl molybdenum, a base, a 5-iodo-2H-pyrone derivative and a sulfonyl chloride compound at 90 to 110° C. for 12 to 20 hours, and after the reaction is complete, post-treating to obtain the pyrone derivative containing a thioester structure; The structure of the 5-iodo-2H-pyrone derivative is shown in formula (II): The structure of the sulfonyl chloride compound is shown in formula (III): The structure of the pyrone derivative containing a thioester structure is shown in formula (I): In formulas (I) to (III), R is a cyclopropyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a C1 to C4 alkyl group, a trifluoromethyl group or a halogen group; Ar is a substituted or unsubstituted aryl group; The substituent on the aryl group is a C1-C4 alkyl group, a C1-C4 alkoxy group or a phenyl group.

2. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: R is a substituted or unsubstituted phenyl group or a cyclopropyl group, and the substituent on the phenyl group is a methyl group, a propyl group, a tert-butyl group, a trifluoromethyl group, a F group or a Cl group.

3. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group, a methoxy group, an isopropyl group, a tert-butyl group or a phenyl group.

4. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: In terms of molar amount, 5-iodo-2H-pyrone: sulfonyl chloride compound: carbonyl molybdenum: nickel catalyst: ligand: manganese: base = 1: 1.5-2: 1.5-2: 0.05-0.1: 0.1-0.2: 1-1.5: 1.5-2.

5. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: The reaction used acetonitrile as solvent.

6. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: The nickel catalyst is nickel iodide.

7. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: The ligand is 4,4'-di-tert-butyl-2,2'-bipyridine.

8. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: The alkali is potassium carbonate.

9. The method for preparing a pyrone derivative containing a thioester structure according to claim 1, characterized in that: The pyrone derivative containing a thioester structure is one of the compounds represented by formula (I-1) to formula (I-5):

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