Process for the preparation of a pyrone derivative containing a thioester structure

Abstract

This invention discloses a method for preparing pyranone derivatives containing a thioester structure, comprising the following steps: reacting a nickel catalyst, a ligand, manganese, molybdenum carbonyl, a base, a 5-iodo-2H-pyranone derivative, and a sulfonyl chloride compound at 90–110 °C for 12–20 hours. After the reaction is complete, post-treatment yields the pyranone derivative containing the thioester structure. This preparation method uses a sulfonyl chloride compound as a sulfur source, and molybdenum carbonyl as both a carbonyl source and a reducing agent. It is simple to operate, uses readily available and inexpensive starting materials, has a wide tolerance range for substrate functional groups, and exhibits high reaction efficiency. Various pyranone derivatives containing thioester structures can be synthesized according to actual needs, simplifying the operation and broadening the applicability of this method.

Description

Technical Field

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

[0002] Thioesters are widely found in many natural products, biomolecules, and pharmaceuticals, serving as important intermediates in various biological processes. For example, acetyl-CoA is an acetyl donor in the citric acid cycle (ACSMed. Chem. Lett. 2015, 6, 660-664). Furthermore, other thioesters are commonly involved in the synthesis of many intracellular substances, such as peptides, fatty acids, sterols, terpenes, and porphyrins. Due to their high reactivity and strong electrophilicity, thioesters often play a crucial role as active acyl donors in various acylation reactions. In particular, in natural chemical linkages, the reaction of C-terminal peptide thioesters with N-terminal cysteine ​​can achieve the linkage between two polypeptides. Therefore, in addition to the traditional acylation reactions of thiols with acids and their derivatives, other reactions for the synthesis of thioesters include acid-catalyzed condensation reactions, metal-catalyzed and organocatalyzed 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 sulfur carbonylation reactions have been developed for the preparation of thioesters (Chem 2019, 5, 526-552). However, the use of thiols as nucleophiles still has some drawbacks due to their odor and catalyst toxicity. Therefore, alternative sulfur sources, such as thiosulfates, thioacetates, sulfonyl hydrazides, and sulfonyl chlorides, have been developed to address these issues. 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 price, coupled with the presence of some expensive phosphine ligands, limits their use, especially in large-scale reactions. Therefore, the use of inexpensive metals such as nickel is often more promising. In addition, 2H-pyranones are valuable heterocycles that serve as core skeletons in a variety of natural compounds and exhibit broad biological activities. Given the superior bioactivity and synthetic value of thioesters and 2H-pyranones, constructing 2H-pyranones 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 pyranone derivatives containing thioester structures. Starting with readily available 5-iodo-2H-pyranone and sulfonyl chloride compounds, and using molybdenum carbonyl as both the carbonyl source and reducing agent, we synthesized a variety of pyranone derivatives containing thioester structures, opening a new pathway for thiocarbonylation reactions involving sulfonyl chloride compounds. Summary of the Invention

[0005] This invention provides a method for preparing pyranone 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 sources, and molybdenum carbonyl serves as both a carbonyl source and a reducing agent, providing a new direction for the synthesis of pyranone derivatives containing a thioester structure.

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

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

[0012]

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

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

[0015] The substituents on the aryl group are C1-C4 alkyl, C1-C4 alkoxy, or phenyl.

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

[0017] The substitution positions of R are para and meta; the substitution positions of the aryl group of Ar are para or ortho.

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

[0019]

[0020] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding pyranone derivative containing a thioester structure. Column chromatography purification is a commonly used technique in this field.

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

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

[0023] The sulfonyl chloride compound used to prepare pyranone derivatives containing thioester structures is inexpensive and widely available in nature. Preferably, the ratio of sulfonyl chloride compound to nickel catalyst is 1.5-2:0.1-0.2 in molar amounts; more preferably, the ratio of 5-iodo-2H-pyranone to sulfonyl chloride compound to nickel catalyst is 1:1.8:0.1 in molar amounts.

[0024] Preferably, the reaction time is 16 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.

[0025] 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 of 5-iodo-2H-pyranone is about 1 to 2 mL.

[0026] Preferably, the nickel catalyst is nickel iodide, which is relatively inexpensive among many nickel catalysts and has high reaction efficiency when used as a catalyst.

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

[0028] Preferably, the alkali is potassium carbonate.

[0029] As a further preferred embodiment, the pyranone derivative containing a thioester structure is one of the compounds shown in formulas (I-1) to (I-5):

[0030]

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

[0032] Compared with existing technologies, the advantages of this invention are as follows: using sulfonyl chloride compounds as the sulfur source, the preparation method is simple, easy to operate, and the post-processing is convenient; the starting materials are inexpensive and readily available; the substrate has a wide range of functional group tolerances; and the reaction efficiency is high. Various pyranone derivatives containing thioester structures can be synthesized according to actual needs, making it highly practical. Detailed Implementation

[0033] The present invention will be further described below with reference to specific embodiments.

[0034] Examples 1-15

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

[0036]

[0037] Table 1. Raw material addition amounts for Examples 1-15

[0038]

[0039]

[0040] Table 2

[0041]

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

[0043] Structural confirmation data of the compounds prepared in Examples 1-5:

[0044] Nuclear magnetic resonance (NMR) of the pyranone derivative (I-1) containing a thioester structure prepared in Example 1 1 H NMR and 13 The C NMR detection data are as follows:

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

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

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

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

[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 pyranone derivative containing a thioester structure, characterized in that, comprising the steps of: placing a nickel catalyst, a ligand, manganese, a carbonyl molybdenum, a base, a 5-iodo-2H-pyrone derivative, and a sulfonyl chloride compound in a reaction vessel at a temperature of 90 to 110 o C-reacting for 12 to 20 hours, and after the reaction is complete, post-treating to obtain the pyrone derivative containing a sulfide structure; The structure of the 5-iodo-2H-pyranone derivative is shown in formula (II): ； The structure of the sulfonyl chloride compound is shown in formula (III): ； The structure of the pyranone derivative containing the thioester structure is shown in formula (I): ； In formulas (I) to (III), R is cyclopropyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is C1 to C4 alkyl, trifluoromethyl or halogen; Ar represents a substituted or unsubstituted phenyl group; The substituent on the phenyl group is a C1-C4 alkyl, C1-C4 alkoxy, or phenyl. The reaction uses acetonitrile as a solvent; The nickel catalyst is nickel iodide; The ligand is 4,4'-di-tert-butyl-2,2'-bipyridine; The alkali mentioned is potassium carbonate.

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

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

4. The method for preparing the pyranone derivative containing a thioester structure according to claim 1, characterized in that, In molar amounts, 5-iodo-2H-pyranone derivative: 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 the pyranone derivative containing a thioester structure according to claim 1, characterized in that, The pyranone derivative containing a thioester structure is one of the compounds shown in formulas (I-1) to (I-5): ； ； ； ； 。

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