Preparation method of benzofuran derivative containing thioester structure

Abstract

The invention discloses a preparation method of a benzofuran derivative containing a thioester structure, which comprises the following steps: reacting tris (dibenzylideneacetone) dipalladium, 4, 5-bis (diphenylphosphine-9, 9-dimethyl xanthene, sodium phosphate, aryl iodide propargyl ether and aryl phenol formate at 60 DEG C for 24 hours, and after the reaction is completed, removing the solvent, thereby obtaining the benzofuran derivative containing the thioester structure. And performing post-treatment to obtain the benzofuran derivative containing the thioester structure. The preparation method has the advantages of simple operation, cheap and easily available reaction starting raw materials, wide tolerance range of substrate functional groups, and high reaction efficiency. The aryl phenol formate is used as both a carbonyl source and a sulfur source, various benzofuran derivatives containing thioester structures can be synthesized according to actual needs, and the practicability of the method is widened while the operation is convenient.

Description

Technical Field

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

[0002] Thioesters are basic molecular structures that are often found in drugs and bioactive molecules and play an important role (J. Med. Chem., 2014, 57, 2832-2842). Compared with the corresponding acyl halides, they are highly active, air-stable, and easy to handle, which has aroused great interest and is widely used in the synthesis of esters, amides, aldehydes, and ketones. Therefore, a variety of reactions for preparing thioesters have been reported. Common synthetic methods mainly rely on the acylation of thiols with carboxylic acids and their derivatives, in addition to the condensation reaction of carboxylic acids with thiols and the oxidative coupling reaction of aldehydes with thiols under organic catalysis. However, the above strategies still have some disadvantages, such as low atom economy, high reaction temperature, and narrow substrate range. Considering the importance of thioesters, exploring more direct and more efficient methods to construct thioesters still attracts widespread attention.

[0003] In recent decades, palladium-catalyzed carbonylation has played an important role as a direct and efficient strategy for the synthesis of carbonyl compounds and heterocycles (Chem, 2019, 5, 526-552). As a necessary supplement, the preparation of thioesters through carbonylation has also become more attractive, and a series of thiocarbonylation reactions have also been reported. However, there are still some problems with the CO and thiols used in thiocarbonylation reactions: (1) CO gas is highly toxic, flammable and difficult to handle; (2) thiols have an unpleasant odor and usually poison transition metals due to their strong coordination and adsorption properties. Therefore, it is very important to find new carbonyl and sulfur sources. Among them, the thiocarbonylation reaction based on thioester transfer provides an efficient and convenient reaction route for the synthesis of thioesters, and a variety of thioester synthons have been developed.

[0004] On the other hand, as an important component of many natural products and bioactive molecules, benzoheterocycles play an important role in medicine, drug development and material science. At the same time, palladium-catalyzed intramolecular Heck cyclization / cross-coupling reactions have also attracted more attention in the construction of benzoheterocycles. Based on this, we developed palladium-catalyzed cyclization / thiocarbonylation reactions to synthesize a variety of benzofuran derivatives containing thioester structures. Starting from iodoaryl propargyl ethers and arylthiophenol formate, and using arylthiophenol formate as thioester precursor, a variety of benzofuran derivatives containing thioester structures were synthesized, which expanded the application of carbonylation reactions and provided a new synthetic route for the carbonylation of benzofuran derivatives containing thioester structures. Summary of the invention

[0005] The invention provides a method for preparing a benzofuran derivative containing a thioester structure. The method has simple steps, cheap and readily available reaction raw materials, strong reaction applicability, and compatibility with a variety of functional groups. Arylthiophenol formate is used as both a carbonyl source and a sulfur source, providing a new direction for the carbonylation synthesis of benzofuran derivatives containing a thioester structure.

[0006] A method for preparing a benzofuran derivative containing a thioester structure comprises the following steps: reacting a palladium catalyst, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, sodium phosphate, iodoaryl propargyl ether and arylphenol formate at 50-70° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the benzofuran derivative containing a thioester structure;

[0007] The structure of the iodinated aromatic propargyl ether is shown in formula (II):

[0008]

[0009] The structure of the arylphenol formate is shown in formula (III):

[0010]

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

[0012]

[0013] In formula (I) to (III), R is hydrogen or halogen, Ar is 1 is phenyl, substituted phenyl, naphthyl or thienyl, Ar 2 is a substituted phenyl group;

[0014] In Ar 1 and Ar 2 In the above, the substituent on the phenyl group is C1-C4 alkyl, methoxy, trifluoromethyl, Cl, F or Br.

[0015] The molar ratio of the palladium catalyst, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and sodium phosphate is 0.05:0.05:2;

[0016] The substitution position of R is meta; Ar 1 The substitution position on the phenyl group is para, Ar 2 The substitution position on the phenyl group is the para position or the ortho position.

[0017] The reaction formula is as follows:

[0018]

[0019] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding benzofuran derivative containing a thioester structure. Column chromatography purification is a commonly used technical means in the art.

[0020] Preferably, R is hydrogen or F, Ar 1 is phenyl or substituted phenyl, naphthalene or thiophene, and the substituent on the phenyl is methyl, tert-butyl, methoxy, trifluoromethyl or Cl. In this case, the iodoaryl propargyl ether is easy to obtain and the reaction yield is high.

[0021] Preferably, Ar 2 The phenyl group is a substituted phenyl group, wherein the substituent on the phenyl group is a methyl group, a tert-butyl group, a methoxy group, a F group or a Br group, and the substituent on the phenyl group may be multiple. In this case, the arylphenol formate is easy to obtain, and the reaction yield is high.

[0022] The iodinated aromatic propargyl ether and arylphenol formate used to prepare the benzofuran derivative containing the thioester structure are relatively cheap and widely exist in nature. Preferably, the iodinated aromatic propargyl ether: arylphenol formate: palladium catalyst is 1:1.5-2:0.05-0.1 in terms of molar amount; and further preferably, the iodinated aromatic propargyl ether: arylphenol formate: palladium catalyst is 1:2:0.05 in terms of molar amount.

[0023] Preferably, the reaction time is 24 hours. Too long a reaction time will increase the reaction cost, and conversely it will be difficult to ensure the completeness of the reaction.

[0024] Preferably, the reaction is carried out in toluene. The amount of toluene used is sufficient to dissolve the raw materials well. The amount of toluene used for 0.2 mmol of iodinated aromatic propargyl ether is about 1-2 mL.

[0025] Preferably, the palladium catalyst is tris(dibenzylideneacetone)dipalladium. Among many palladium catalysts, tris(dibenzylideneacetone)dipalladium is relatively cheap, and the reaction efficiency is higher when tris(dibenzylideneacetone)dipalladium is used as a catalyst.

[0026] As a further preference, the benzofuran derivative containing a thioester structure is one of the compounds represented by formula (I-1) to formula (I-5):

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] In the above preparation method, the tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and sodium phosphate are generally commercially available products and can be easily obtained from the market.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows: using arylphenol formate as a thioester precursor, the preparation method is simple, easy to operate, and the post-treatment is simple. The starting raw materials for the reaction are cheap and readily available, the substrate functional group tolerance range is wide, and the reaction efficiency is high. A variety of benzofuran derivatives containing thioester structures can be synthesized according to actual needs, and the practicability is strong. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with specific embodiments.

[0035] Examples 1 to 15

[0036] According to the raw material ratio in Table 1, tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, sodium phosphate, iodoaryl propargyl ether (II) and arylphenol formate (III) were added to a 15 mL sealed tube, and then toluene (1 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 benzofuran derivative (I) containing a thioester structure. The reaction process is shown in the following formula:

[0037]

[0038] Table 1 Amount of raw materials added in Examples 1 to 15

[0039]

[0040]

[0041] Table 2

[0042]

[0043] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, tBu is tert-butyl, CF3 is trifluoromethyl, 2-thiophenyl is 2-thienyl, and naphthalenyl is naphthyl.

[0044] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0045] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ7.81 (dd, J=7.8, 1.5Hz, 1H), 7.46 (t, J=7.9Hz, 1H), 7.39–7.34 (m, 4H), 7.28–7.23(m,3H),7.22–7.19(m,3H),7.02(t,J=7.5Hz,1H),1H),5.02(s,2H),2.34(s,3H).

[0048] 13 C NMR (101MHz, CDCl3) δ189.7,156.4,139.6,135.0,133.7,131.9,130.1,130. 0,128.9,128.4,127.5,125.3,122.2,121.6,114.5,88.1,83.5,57.8,21.5.

[0049] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0050]

[0051] 1 H NMR(400MHz, CDCl3)δ7.88(dd,J=7.8,1.7Hz,1H),7.53(t,J=7.1Hz,1H),7.41–7.36(m,4H),7.31– 7.26(m,3H),7.09(t,J=7.5Hz,1H),6.85(d,J=8.8Hz,2H),5.08(s,2H),3.82(s,3H),2.41(s,3H).

[0052] 13C NMR (101MHz, CDCl3) δ189.8,160.1,156.6,139.6,135.0,133.8,133.5,130.1, 130.1,127.4,125.3,121.5,114.5,114.3,114.1,88.1,82.2,58.0,55.4,21.5.

[0053] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=7.8, 1.6Hz, 1H), 7.52 (t, J=8.7Hz, 1H), 7.42 (d, J=8.0Hz, 2H), 7.28 –7.26(m,2H),7.25–7.21(m,3H),7.09(t,J=7.5Hz,1H),6.98–6.96(m,1H),5.08(s,2H),2.40(s,3H).

[0056] 13 C NMR (101MHz, CDCl3) δ189.7,156.3,139.6,135.0,133.8,133.0,130.1,130. 1,128.0,127.6,127.1,125.2,122.1,121.7,114.5,87.5,81.4,57.9,21.5.

[0057] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0058]

[0059] 1 H NMR (400MHz, CDCl3) δ7.85 (dd, J=7.8, 1.5Hz, 1H), 7.50 (t, J=8.7Hz, 1H), 7.46–7 .41(m,6H),7.32–7.24(m,4H),7.06(t,J=7.5Hz,1H),5.06(s,2H),1.33(s,9H).

[0060] 13 C NMR (101MHz, CDCl3) δ189.7,156.5,152.6,134.7,133.7,131.9,130.1,128. 9,128.4,127.6,126.4,125.4,122.3,121.6,114.6,88.1,83.5,57.9,31.4.

[0061] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0062]

[0063] 1 H NMR(400MHz, CDCl3)δ7.87(dd,J=7.8,1.6Hz,1H),7.60–7.50(m,3H),7.43(dd,J=7.6,1.7Hz,2H) ,7.39(d,J=8.4Hz,2H),7.34–7.30(m,3H),7.29–7.27(m,1H),7.09(t,J=7.3Hz,1H),5.09(s,2H).

[0064] 13 C NMR (101MHz, CDCl3) δ188.6,156.6,136.6,134.2,132.4,131.9,130.2,129.0,128.7,128.5,127.8,124.1,122.2,121.6,114.4,88.2,83.3,57.8.

Claims

1. A method for preparing a benzofuran derivative containing a thioester structure, characterized in that: The method comprises the following steps: reacting a palladium catalyst, a ligand, a base, an iodinated aromatic hydrocarbon propargyl ether and an aromatic phenol formate at 50 to 70° C. for 20 to 28 hours, and after the reaction is complete, post-treating to obtain the benzofuran derivative containing a thioester structure; The structure of the iodinated aromatic propargyl ether is shown in formula (II): The structure of the arylphenol formate is shown in formula (III): The structure of the benzofuran derivative containing a thioester structure is shown in formula (I): In formula (I) to (III), R is hydrogen or halogen, Ar is 1 is phenyl, substituted phenyl, naphthyl or thienyl, Ar 2 is a substituted phenyl group; In Ar 1 and Ar 2 In the above, the substituent on the phenyl group is one or more of C1-C4 alkyl, methoxy, trifluoromethyl, Cl, F or Br.

2. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: R is hydrogen or F, Ar 1 is phenyl or substituted phenyl, naphthyl or thienyl, and the substituent on the phenyl is methyl, tert-butyl, methoxy, trifluoromethyl or Cl.

3. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: Ar 2 is a substituted phenyl group, wherein the substituent on the phenyl group is one or more of methyl, tert-butyl, methoxy, F or Br.

4. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: In terms of molar amount, iodoaryl propargyl ether: aryl phenol formate: palladium catalyst: ligand: base = 1: 1.5-2: 0.05-0.1: 0.05-0.1: 1-2.

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

6. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: The palladium catalyst is tris(dibenzylideneacetone)dipalladium.

7. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: The ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

8. The method for preparing a benzofuran derivative containing a thioester structure according to claim 1, characterized in that: The alkali is sodium phosphate.

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

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